@article {pmid39055649, year = {2024}, author = {Zheng, H and Liu, J and Sun, L and Meng, Z}, title = {The role of N-acetylcysteine in osteogenic microenvironment for bone tissue engineering.}, journal = {Frontiers in cell and developmental biology}, volume = {12}, number = {}, pages = {1435125}, doi = {10.3389/fcell.2024.1435125}, pmid = {39055649}, issn = {2296-634X}, abstract = {Bone defect is a common clinical symptom which can arise from various causes. Currently, bone tissue engineering has demonstrated positive therapeutic effects for bone defect repair by using seeding cells such as mesenchymal stem cells and precursor cells. N-acetylcysteine (NAC) is a stable, safe and highly bioavailable antioxidant that shows promising prospects in bone tissue engineering due to the ability to attenuate oxidative stress and enhance the osteogenic potential and immune regulatory function of cells. This review systematically introduces the antioxidant mechanism of NAC, analyzes the advancements in NAC-related research involving mesenchymal stem cells, precursor cells, innate immune cells and animal models, discusses its function using the classic oral microenvironment as an example, and places particular emphasis on the innovative applications of NAC-modified tissue engineering biomaterials. Finally, current limitations and future prospects are proposed, with the aim of providing inspiration for targeted readers in the field.}, }
@article {pmid39053861, year = {2024}, author = {Yu, H and Xie, Y and Lan, L and Ma, S and Mok, SWF and Wong, IN and Wang, Y and Zhong, G and Yuan, L and Zhao, H and Hu, X and Macrae, VE and He, S and Chen, G and Zhu, D}, title = {Sirt7 protects against vascular calcification via modulation of reactive oxygen species and senescence of vascular smooth muscle cells.}, journal = {Free radical biology & medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2024.07.021}, pmid = {39053861}, issn = {1873-4596}, abstract = {Vascular calcification is frequently seen in patients with chronic kidney disease (CKD), and significantly increases cardiovascular mortality and morbidity. Sirt7, a NAD[+]-dependent histone deacetylases, plays a crucial role in cardiovascular disease. However, the role of Sirt7 in vascular calcification remains largely unknown. Using in vitro and in vivo models of vascular calcification, this study showed that Sirt7 expression was significantly reduced in calcified arteries from mice administered with high dose of vitamin D3 (vD3). We found that knockdown or inhibition of Sirt7 promoted vascular smooth muscle cell (VSMC), aortic ring and vascular calcification in mice, whereas overexpression of Sirt7 had opposite effects. Intriguingly, this protective effect of Sirt7 on vascular calcification is dependent on its deacetylase activity. Unexpectedly, Sirt7 did not alter the osteogenic transition of VSMCs. However, our RNA-seq and subsequent studies demonstrated that knockdown of Sirt7 in VSMCs resulted in increased intracellular reactive oxygen species (ROS) accumulation, and induced an Nrf-2 mediated oxidative stress response. Treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly attenuated the inhibitory effect of Sirt7 on VSMC calcification. Furthermore, we found that knockdown of Sirt7 delayed cell cycle progression and accelerated cellular senescence of VSMCs. Taken together, our results indicate that Sirt7 regulates vascular calcification at least in part through modulation of ROS and cellular senescence of VSMCs. Sirt7 may be a potential therapeutic target for vascular calcification.}, }
@article {pmid38896955, year = {2024}, author = {Zhao, Q and Liu, G and Ding, Q and Zheng, F and Shi, X and Lin, Z and Liang, Y}, title = {The ROS/TXNIP/NLRP3 pathway mediates LPS-induced microglial inflammatory response.}, journal = {Cytokine}, volume = {181}, number = {}, pages = {156677}, doi = {10.1016/j.cyto.2024.156677}, pmid = {38896955}, issn = {1096-0023}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Microglia/metabolism/drug effects ; *Lipopolysaccharides/pharmacology ; *Carrier Proteins/metabolism ; Animals ; Mice ; *Reactive Oxygen Species/metabolism ; *Caspase 1/metabolism ; *Signal Transduction/drug effects ; *Inflammasomes/metabolism ; *Inflammation/metabolism/pathology ; Cell Line ; Acetylcysteine/pharmacology ; Calcium-Binding Proteins/metabolism ; Interleukin-1beta/metabolism ; Interleukin-18/metabolism ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Microfilament Proteins/metabolism ; Thioredoxins/metabolism ; CARD Signaling Adaptor Proteins/metabolism ; Sepsis-Associated Encephalopathy/metabolism/pathology ; CD68 Molecule ; }, abstract = {BACKGROUND: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction activated by microglia. The potential pathological changes of SAE are complex, and the cellular pathophysiological characteristics remains unclear. This study aims to explore the ROS/TXNIP/NLRP3 pathway mediated lipopolysaccharide (LPS)-induced inflammatory response in microglia.<br><br>METHODS: BV-2 cells were pre-incubated with 10&#xa0;&#x3bc;M N-acetyl-L-cysteine (NAC) for 2&#xa0;h, which were then reacted with 1&#xa0;&#x3bc;g/mL LPS for 24&#xa0;h. Western blot assay examined the protein levels of IBA1, CD68, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. The contents of inflammatory factor were detected by ELISA assay. The co-immunoprecipitation assay examined the interaction between TXNIP and NLRP3.<br><br>RESULTS: LPS was confirmed to promote the positive expressions of IBA1 and CD68 in BV-2 cells. The further experiments indicated that LPS enhanced ROS production and NLRP3 inflammasome activation in BV-2 cells. Moreover, we also found that NAC partially reversed the facilitation of LPS on the levels of ROS, IL-1&#x3b2;, IL-18, TXNIP, NLRP3, ASC, and Cleaved Caspase-1 in BV-2 cells. NAC treatment also notably alleviated the interaction between TXNIP and NLRP3 in BV-2 cells.<br><br>CONCLUSION: ROS inhibition mediated NLRP3 signaling inactivation by decreasing TXNIP expression.}, }
@article {pmid35051378, year = {2022}, author = {Ning, Z and Lan, J and Jiang, X and Zhong, G and Zhang, H and Wan, F and Wu, S and Tang, Z and Bilal, RM and Hu, L and Huang, R}, title = {Arsenic trioxide-induced autophagy affected the antioxidant capacity and apoptosis rate of chicken hepatocytes.}, journal = {Chemico-biological interactions}, volume = {354}, number = {}, pages = {109821}, doi = {10.1016/j.cbi.2022.109821}, pmid = {35051378}, issn = {1872-7786}, mesh = {Animals ; *Arsenic Trioxide/toxicity/pharmacology ; *Autophagy/drug effects ; *Hepatocytes/drug effects/metabolism ; *Chickens ; *Apoptosis/drug effects ; *Oxides/toxicity ; *Antioxidants/pharmacology ; Arsenicals ; Oxidative Stress/drug effects ; Sirolimus/pharmacology ; Cells, Cultured ; Acetylcysteine/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Adenine/analogs &amp; derivatives ; }, abstract = {Arsenic has recently received widespread attention due to its high toxicological effects on multiple animals; however, the mechanism underlying this toxicity is unclear. We investigated the damaging effects of arsenic trioxide (ATO) on hepatocytes and the effects of regulating autophagy on the hepatocyte damage induced by ATO exposure. First, we investigated the effects of ATO exposure (0, 0.6, 1.2, 2.4, and 4.8 μM) on the biochemical function and autophagy of chicken hepatocytes. The findings showed that as the concentration of ATO increased, the lactate dehydrogenase (LDH) concentration increased, more autophagosomes were observed via transmission electron microscopy (TEM), and the gene and protein expression levels of P62, LC3Ⅱ, and Beclin1 increased. Adding N-acetyl-l-cystine (NAC, 1 mM) attenuated autophagy and the hepatocyte damage induced by ATO. Then, we used rapamycin (Rapa) and 3-methylpurine (3-MA) to regulate the autophagy induced by exposure to 4.8 μM ATO and observed changes in the antioxidant capacity and apoptosis rate of chicken hepatocytes. Induction of autophagy reduced ATO-induced hepatocyte apoptosis but caused no significant effect on oxidative stress in chicken hepatocytes. Inhibition of autophagy exacerbated ATO-induced hepatocyte oxidative stress and apoptosis. These findings demonstrate that autophagy plays an important role in ATO-induced cell damage.}, }
@article {pmid39046019, year = {2024}, author = {Varela, ELP and Gomes, ARQ and Santos, ASBD and Cruz, JND and Carvalho, EP and Prazeres, BAPD and Dolabela, MF and Percario, S}, title = {Lycopene supplementation promoted increased survival and decreased parasitemia in mice with severe malaria: comparison with N-acetylcysteine.}, journal = {Anais da Academia Brasileira de Ciencias}, volume = {96}, number = {3}, pages = {e20230347}, doi = {10.1590/0001-3765202420230347}, pmid = {39046019}, issn = {1678-2690}, mesh = {Animals ; *Lycopene/therapeutic use/administration &amp; dosage/pharmacology ; *Parasitemia/drug therapy ; Mice ; *Malaria/drug therapy ; *Acetylcysteine/administration &amp; dosage/therapeutic use/pharmacology ; *Plasmodium berghei/drug effects ; *Antioxidants/therapeutic use/administration &amp; dosage ; *Dietary Supplements ; Oxidative Stress/drug effects ; Carotenoids/therapeutic use/administration &amp; dosage ; Male ; Disease Models, Animal ; Random Allocation ; }, abstract = {Oxidative stress is involved in the pathogenesis of malaria, causing anemia, respiratory complications, and cerebral malaria. To mitigate oxidative stress, we investigated the effect of nutritional supplementation whit lycopene (LYC) on the evolution of parasitemia and survival rate in mice infected with Plasmodium berghei ANKA (Pb), comparing to the effects promoted by N-acetylcysteine (NAC). Therefore, 175 mice were randomly distributed into 4 groups; Sham: untreated and uninfected animals; Pb: animals infected with Pb; LYC+Pb: animals treated with LYC and infected with Pb; NAC+Pb: animals treated with NAC and infected with Pb. The animals were followed for 12 days after infection, and survival and parasitemia rates were evaluated. There was a 40.1% increase in parasitemia in the animals of the Pb group on the 12th day, and a survival rate of 45%. LYC supplementation slowed the development of parasitemia to 19% and promoted a significative increase in the survival rate of 80% on the 12th day after infection, compared to the Pb group, effects superior to those promoted by NAC, providing strong evidence of the beneficial effect of LYC on in vivo malaria and stressing the importance of antioxidant supplementation in the treatment of this disease.}, }
@article {pmid39045541, year = {2024}, author = {Wu, X and Zhang, G and Du, X}, title = {Cigarette Smoke Extract Induces MUC5AC Expression Through the ROS/ IP3R/Ca[2+] Pathway in Calu-3 Cells.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {19}, number = {}, pages = {1635-1647}, pmid = {39045541}, issn = {1178-2005}, mesh = {*Mucin 5AC/metabolism/genetics ; Humans ; *Reactive Oxygen Species/metabolism ; *Smoke/adverse effects ; *Inositol 1,4,5-Trisphosphate Receptors/metabolism/genetics ; *Mucin-5B/metabolism/genetics ; *Calcium Signaling/drug effects ; Up-Regulation ; Oxidative Stress/drug effects ; Protein Serine-Threonine Kinases/metabolism/genetics ; Cell Line, Tumor ; Nicotiana/adverse effects ; RNA Interference ; Endoplasmic Reticulum Stress/drug effects ; Epithelial Cells/metabolism/drug effects ; Acetylcysteine/pharmacology ; Cigarette Smoking/adverse effects ; Calcium/metabolism ; X-Box Binding Protein 1 ; Endoribonucleases ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is caused by exposure to noxious external particles, air pollution, and the inhalation of cigarette smoke. Airway mucus hypersecretion particularly mucin5AC (MUC5AC), is a crucial pathological feature of COPD and is associated with its initiation and progression. In this study, we aimed to investigate the effects of cigarette smoke extract (CSE) on MUC5AC expression, particularly the mechanisms by which reactive oxygen species (ROS) induce MUC5AC expression.<br><br>METHODS: The effects of CSE on the expression of MUC5AC and mucin5B (MUC5B) were investigated in vitro in Calu-3 cells. MUC5AC and MUC5B expression levels were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA). Total cellular levels of ROS and Ca[2+] were determined using DCFH-DA and Fluo-4 AM. Subsequently, the expression levels of IP3R, IRE1&#x3b1;, p-IRE1&#x3b1; and XBP1s were measured by Western blotting. Gene silencing was achieved by using small-interfering RNAs.<br><br>RESULTS: Our findings revealed that exposure to CSE increased MUC5AC levels and upregulated ROS, IP3R/Ca[2+] and unfolded protein response (UPR)-associated factors. In addition, knockdown of IP3R using siRNA decreased CSE-induced Ca[2+] production, UPR-associated factors, and MUC5AC expression. Furthermore, 10 mM N-acetyl-l-cysteine (NAC) treatment suppressed the effects of CSE, including ROS generation, IP3R/ Ca[2+], UPR activation, and MUC5AC overexpression.<br><br>CONCLUSION: Our results suggest that ROS regulates CSE-induced UPR and MUC5AC overexpression through IP3R/ Ca[2+] signaling. Additionally, we identified NAC as a promising therapeutic agent for mitigating CSE-induced MUC5AC overexpression.}, }
@article {pmid39044301, year = {2024}, author = {Hao, WY and Wang, JX and Xu, XY and Chen, JL and Chen, Q and Li, YH and Zhu, GQ and Chen, AD}, title = {Chemerin in caudal division of nucleus tractus solitarius increases sympathetic activity and blood pressure.}, journal = {The European journal of neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1111/ejn.16475}, pmid = {39044301}, issn = {1460-9568}, support = {32071106//National Natural Science Foundation of China/ ; 31871148//National Natural Science Foundation of China/ ; 31571168//National Natural Science Foundation of China/ ; }, abstract = {Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague-Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin-9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α-NETA, superoxide scavenger tempol or N-acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin-9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin-9 was inhibited by α-NETA. The effects of cNTS microinjection of chemerin-9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK-801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin-9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1-mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin-9-induced responses.}, }
@article {pmid39042563, year = {2024}, author = {Jeon, M and Bae, S}, title = {In vitro effects of N-acetylcysteine in combination with antifungal agents against Malassezia pachydermatis isolated from canine otitis externa.}, journal = {Veterinary medicine and science}, volume = {10}, number = {5}, pages = {e1479}, doi = {10.1002/vms3.1479}, pmid = {39042563}, issn = {2053-1095}, mesh = {Animals ; Dogs ; *Malassezia/drug effects ; *Otitis Externa/veterinary/drug therapy/microbiology ; *Dog Diseases/drug therapy/microbiology ; *Antifungal Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Drug Therapy, Combination/veterinary ; *Microbial Sensitivity Tests/veterinary ; Male ; Female ; }, abstract = {BACKGROUND: Many clinicians prescribe antifungal agents to treat canine otitis externa (OE). However, studies evaluating the antifungal effects of N-acetylcysteine (NAC) and its combinations are limited.<br><br>HYPOTHESIS/OBJECTIVES: The aim of this study was to evaluate the antifungal effects of NAC alone and in combination with other antifungal agents against Malassezia pachydermatis isolated from canine OE.<br><br>MATERIALS AND METHODS: M. pachydermatis samples were collected from 13 dogs with OE. The final concentration of the inoculum suspensions of M. pachydermatis was 1-5&#xa0;&#xd7;&#xa0;10[6] colony forming units/mL. The concentrations of the test compounds ketoconazole (KTZ), terbinafine (TER), nystatin (NYS) and NAC were 0.02-300&#xa0;&#xb5;g/mL, 0.04-80&#xa0;&#xb5;g/mL, 0.16-40&#xa0;&#xb5;g/mL and 1.25-20&#xa0;mg/mL, respectively. The minimum inhibitory concentration (MIC) was measured to evaluate the susceptibility of the M. pachydermatis to KTZ, TER, NYS and NAC. The checkerboard testing method and fractional inhibitory concentration index were used to evaluate the effect of NAC in combination with KTZ, TER and NYS against M. pachydermatis.<br><br>RESULTS: The MIC90 values of M. pachydermatis were 4.6875-9.375&#xa0;&#xb5;g/mL, 1.25&#xa0;&#xb5;g/mL, 5-10&#xa0;&#xb5;g/mL and 10&#xa0;mg/mL for KTZ, TER, NYS and NAC, respectively. The synergistic effects of KTZ, TER and NYS with NAC were identified in 0/13, 2/13 and 0/13 isolates, respectively.<br><br>NAC had an antifungal effect against M. pachydermatis but did not exert synergistic effects when used with KTZ, TER and NYS. Thus, the use of NAC alone as a topical solution could be considered an effective treatment option for canine OE involving M. pachydermatis.}, }
@article {pmid39040524, year = {2024}, author = {Tomimoto, N and Takasaki, T and Sugiura, R}, title = {Arsenite treatment induces Hsp90 aggregatesdistinct from conventional stress granules in fission yeast.}, journal = {Microbial cell (Graz, Austria)}, volume = {11}, number = {}, pages = {242-253}, pmid = {39040524}, issn = {2311-2638}, abstract = {Various stress conditions, such as heat stress (HS) and oxidative stress, can cause biomolecular condensates represented by stress granules (SGs) via liquid-liquid phase separation. We have previously shown that Hsp90 forms aggregates in response to HS and that Hsp90 aggregates transiently co-localize with SGs as visualized by Pabp. Here, we showed that arsenite, one of the well-described SG-inducing stimuli, induces Hsp90 aggregates distinct from conventional SGs in fission yeast. Arsenite induced Hsp90 granules in a dose-dependent manner, and these granules were significantly diminished by the co-treatment with a ROS scavenger N-acetyl cysteine (NAC), indicating that ROS are required for the formation of Hsp90 granules upon arsenite stress. Notably, Hsp90 granules induced by arsenite do not overlap with conventional SGs as represented by eIF4G or Pabp, while HS-induced Hsp90 granules co-localize with SGs. Nrd1, an RNA-binding protein known as a HS-induced SG component, was recruited into Hsp90 aggregates but not to the conventional SGs upon arsenite stress. The non-phosphorylatable eIF2α mutants significantly delayed the Hsp90 granule formation upon arsenite treatment. Importantly, inhibition of Hsp90 by geldanamycin impaired the Hsp90 granule formation and reduced the arsenite tolerance. Collectively, arsenite stimulates two types of distinct aggregates, namely conventional SGs and a novel type of aggregates containing Hsp90 and Nrd1, wherein Hsp90 plays a role as a center for aggregation, and stress-specific compartmentalization of biomolecular condensates.}, }
@article {pmid39039898, year = {2024}, author = {Yifu, P}, title = {A review of antioxidant N-acetylcysteine in addressing polycystic ovary syndrome.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {40}, number = {1}, pages = {2381498}, doi = {10.1080/09513590.2024.2381498}, pmid = {39039898}, issn = {1473-0766}, mesh = {*Polycystic Ovary Syndrome/drug therapy/metabolism ; *Acetylcysteine/therapeutic use/pharmacology ; Humans ; Female ; *Antioxidants/therapeutic use/pharmacology ; *Oxidative Stress/drug effects ; }, abstract = {N-acetylcysteine (NAC), a compound known for its cysteine and glutathione precursor properties, has been used in therapeutic applications for many years. Recently, there has been increasing interest in exploring the potential benefits of NAC in addressing polycystic ovary syndrome (PCOS). However, the exact mechanisms underlying NAC's therapeutic and clinical uses remain not fully understood. This review aims to specifically investigate how NAC offers protection against PCOS. This involved an extensive systematic review of the literature, and it made use of PubMed, Embase, and Web of Science databases. By analyzing key findings from over 100 research papers, the potential mechanisms through which NAC produces its effects were explored and summarized. Most studies suggest that NAC, whether used on its own or in combination with other medications, has the potential to counteract oxidative stress, utilize its anti-inflammatory and anti-apoptotic properties, and offer benefits in managing PCOS. Moreover, NAC might have the potential to influence specific signaling pathways in insulin target cells and β cells. Diverse biological effects of NAC indicate its potential usefulness as a supplementary or therapeutic approach for managing PCOS. As a result, additional research is required to explore its potential in addressing PCOS.}, }
@article {pmid39039306, year = {2024}, author = {Chen, Y and Luo, X and Deng, C and Zhao, L and Gao, H and Zhou, J and Peng, L and Yang, H and Li, M and Zhang, W and Zhao, Y and Fei, Y}, title = {Immunometabolic alteration of CD4[+] T cells in the pathogenesis of primary Sjögren's syndrome.}, journal = {Clinical and experimental medicine}, volume = {24}, number = {1}, pages = {163}, pmid = {39039306}, issn = {1591-9528}, support = {3332022105//Fundamental Research Funds for the Central Universities/ ; 82172343//National Natural Science Foundation of China/ ; 81971545//National Natural Science Foundation of China/ ; 7242103//Beijing Natural Science Foundation Program/ ; 2022-PUMCH-C-039//National High Level Hospital Clinical Research Funding/ ; CIFMS 2023-I2M-C &amp; T-B-006//Chinese Academy of Medical Science Innovation Fund/ ; }, mesh = {Humans ; *Sjogren's Syndrome/immunology/metabolism/pathology ; *CD4-Positive T-Lymphocytes/immunology/metabolism ; *Glycolysis ; *Reactive Oxygen Species/metabolism ; Female ; Middle Aged ; Male ; Adult ; Th17 Cells/immunology ; Cell Differentiation ; Interferon-gamma/metabolism ; Interleukin-17/metabolism ; Th1 Cells/immunology ; }, abstract = {Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder wherein CD4[+] T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4[+] T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4[+] T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4[+] T cells, conducted flow cytometry to assess the effector function and differentiation of CD4[+] T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4[+] T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4[+] T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4[+] T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4[+] T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4[+] T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4[+] T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.}, }
@article {pmid39038059, year = {2024}, author = {Bandekar, M and Panda, D}, title = {Microtubule depolymerization induces ferroptosis in neuroblastoma cells.}, journal = {IUBMB life}, volume = {}, number = {}, pages = {}, doi = {10.1002/iub.2899}, pmid = {39038059}, issn = {1521-6551}, support = {JCB/2019/000016//Department of Science and Technology, Ministry of Science and Technology, India (The J.C. Bose fellowship)/ ; }, abstract = {Estramustine (EM), a clinically successful hormone-refractory anti-prostate cancer drug, exhibited potent anti-proliferative activity, depolymerized microtubules, blocked cells at mitosis, and induced cell death in different cancer cells. Altered iron metabolism is a feature of cancer cells. Using EM, we examined the plausible relationship between microtubule depolymerization and induction of ferroptosis in human neuroblastoma (SH-SY5Y and IMR-32) cells. EM reduced glutathione (GSH) levels and induced reactive oxygen species (ROS) generation. The pre-treatment of neuroblastoma cells with ROS scavengers (N-acetyl cysteine and dithiothreitol) reduced the anti-proliferative effects of EM. EM treatment increased labile iron pool (LIP), depleted glutathione peroxidase 4 (GPX4) levels, and lipid peroxidation, hallmark features of ferroptosis, highlighting ferroptosis induction. Ferroptosis inhibitors (deferoxamine mesylate and liproxstatin-1) abrogated the cytotoxic effects of EM, further confirming ferroptosis induction. Vinblastine and nocodazole also increased LIP and induced lipid peroxidation in neuroblastoma cells. This study provides evidence for the coupling of microtubule integrity to ferroptosis. The results also suggest that microtubule-depolymerizing agents may be considered for developing pro-ferroptosis chemotherapeutics.}, }
@article {pmid39037665, year = {2024}, author = {Gao, C and Wang, L and Fu, K and Cheng, S and Wang, S and Feng, Z and Yu, S and Yang, Z}, title = {N-Acetylcysteine Alleviates Necrotizing Enterocolitis by Depressing SESN2 Expression to Inhibit Ferroptosis in Intestinal Epithelial Cells.}, journal = {Inflammation}, volume = {}, number = {}, pages = {}, pmid = {39037665}, issn = {1573-2576}, support = {GSWS2021036//Gusu Talent Program/ ; SKY2022181//Science and Technology Project of Suzhou/ ; LGY2020045//Jiangsu Commission of Health/ ; SYH-32034-0103(2024007)//Jiangsu Medical Association Pediatric Medical Research Special Fund Project/ ; }, abstract = {Abstract-Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in neonates, and effective strategies to prevent and treat NEC are still lacking. Studies have shown that N-acetylcysteine (NAC) has protective effects against NEC, however, the specific mechanism underlying its effects on intestinal functions remains unclear. Recently, NAC has been shown to suppress ferroptosis in many diseases, while it is unclear whether the beneficial effects of NAC on NEC are related to ferroptosis. In this study, we revealed that ferroptosis was significantly induced in intestinal samples from infants with NEC. NAC alleviated intestinal inflammation, barrier damage and ferroptosis in multifactorial NEC models in vivo and in vitro. Sestrin2 (SESN2) was identified as an important mediator of NAC-induced ferroptosis resistance in intestinal epithelial cells. Furthermore, SESN2 knockdown inhibited the inflammatory response, alleviated barrier damage and ferroptosis in intestinal epithelial cells and enhanced the protective effects of NAC to a certain extent. Conversely, cells overexpressing SESN2 showed the opposite changes. In summary, our study demonstrated that NAC attenuates NEC progression by decreasing SESN2 expression to inhibit ferroptosis in intestinal epithelial cells, suggesting that NAC might be an effective clinical treatment for NEC.}, }
@article {pmid38639871, year = {2024}, author = {Nakai, A and Fukushima, Y and Yamamoto, A and Amatsu, Y and Chen, X and Nishigori, M and Yoshioka, Y and Kaneko, M and Koshiba, T and Watanabe, T}, title = {Increased ROS levels in mitochondrial outer membrane protein Mul1-deficient oocytes result in abnormal preimplantation embryogenesis.}, journal = {FEBS letters}, volume = {598}, number = {14}, pages = {1740-1752}, doi = {10.1002/1873-3468.14876}, pmid = {38639871}, issn = {1873-3468}, support = {26291032//Japan Society for the Promotion of Science/ ; 17H03667//Japan Society for the Promotion of Science/ ; 23H02096//Japan Society for the Promotion of Science/ ; //Nara Women's University Intramural Grant for Project Research/ ; }, mesh = {Animals ; *Oocytes/metabolism ; *Reactive Oxygen Species/metabolism ; Female ; *Embryonic Development/genetics ; Mice ; *Ubiquitin-Protein Ligases/metabolism/genetics/deficiency ; DNA Damage ; Acetylcysteine/pharmacology ; Blastocyst/metabolism ; Mitochondrial Membranes/metabolism ; Mice, Knockout ; Mitochondrial Proteins/metabolism/genetics/deficiency ; Mitochondria/metabolism ; }, abstract = {Reactive oxygen species (ROS) are associated with oocyte maturation inhibition, and N-acetyl-l-cysteine (NAC) partially reduces their harmful effects. Mitochondrial E3 ubiquitin ligase 1 (Mul1) localizes to the mitochondrial outer membrane. We found that female Mul1-deficient mice are infertile, and their oocytes contain high ROS concentrations. After fertilization, Mul1-deficient embryos showed a DNA damage response (DDR) and abnormal preimplantation embryogenesis, which was rescued by NAC addition and ROS depletion. These observations clearly demonstrate that loss of Mul1 in oocytes increases ROS concentrations and triggers DDR, resulting in abnormal preimplantation embryogenesis. We conclude that manipulating the mitochondrial ROS levels in oocytes may be a potential therapeutic approach to target infertility.}, }
@article {pmid39034050, year = {2024}, author = {Liyanage, W and Kale, N and Kannan, S and Kannan, RM}, title = {Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {100}, number = {}, pages = {119-155}, doi = {10.1016/bs.apha.2024.05.003}, pmid = {39034050}, issn = {1557-8925}, mesh = {*Dendrimers/chemistry ; *Acetylcysteine/pharmacology/therapeutic use/chemistry ; Humans ; Animals ; *Nanomedicine/methods ; COVID-19 Drug Treatment ; Drug Delivery Systems/methods ; Drug Development/methods ; }, abstract = {Drug discovery is challenging task with numerous obstacles in translating drug candidates into clinical products. Dendrimers are highly adaptable nanostructured polymers with significant potential to improve the chances of clinical success for drugs. Yet, dendrimer-based drug products are still in their infancy. However, Hydroxyl polyamidoamine (PAMAM) dendrimers showed significant promise in drug discovery efforts, owning their remarkable potential to selectively target and deliver drugs specifically to activated microglia and astrocytes at the site of brain injury in several preclinical models. After a decade's worth of academic research and pre-clinical efforts, the hydroxyl PAMAM dendrimer-N-acetyl cysteine conjugate (OP-101) nanomedicine has made a significant advancement in the field of nanomedicine and targeted delivery. The OP-101 conjugate, primarily developed and validated in academic labs, has now entered clinical trials as a potential treatment for hyperinflammation in hospitalized adults with severe COVID-19 through Ashvattha Therapeutics. This chapter, we delve into the journey of the hydroxyl PAMAM dendrimer-N-acetylcysteine (NAC) OP-101 formulation from the laboratory to the clinic. It will specifically focus on the design, synthesis, preclinical, and clinical development of OP-101, highlighting the potential it holds for the future of medicine and the positive Phase 2a results for treating severe COVID-19.}, }
@article {pmid39031462, year = {2024}, author = {Hsu, CS and Chang, SH and Yang, RC and Lee, CH and Lee, MS and Kao, JK and Shieh, JJ}, title = {Lipopolysaccharide-Induced Lysosomal Cell Death Through Reactive Oxygen Species in Rat Liver Cell Clone 9.}, journal = {Environmental toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1002/tox.24377}, pmid = {39031462}, issn = {1522-7278}, support = {NCHU-CCH-11007//National Chung Hsing University/Changhua Christian Hospital Joint Research Program/ ; TCVGH-1107304D//Taichung Veterans General Hospital Research Program/ ; MOST-109-2320-B-371-003//Ministry of Science and Technology, Taiwan/ ; }, abstract = {In sepsis, bacterial components, particularly lipopolysaccharide (LPS), trigger organ injuries such as liver dysfunction. Although sepsis induces hepatocyte damage, the mechanisms underlying sepsis-related hepatic failure remain unclear. In this study, we demonstrated that the LPS-treated rat hepatocyte cell line Clone 9 not only induced reactive oxygen species (ROS) generation and apoptosis but also increased the expression of the autophagy marker proteins LC3-II and p62, and decreased the expression of intact Lamp2A, a lysosomal membrane protein. Additionally, LPS increased lysosomal membrane permeability and galectin-3 puncta formation, and promoted lysosomal alkalization in Clone 9 cells. Pharmacological inhibition of caspase-8 and cathepsin D (CTSD) suppressed the activation of caspase-3 and rescued the viability of LPS-treated Clone 9 cells. Furthermore, LPS induced CTSD release associated with lysosomal leakage and contributed to caspase-8 activation. Pretreatment with the antioxidant N-acetylcysteine (NAC) not only diminished ROS generation and increased the cell survival rate, but also decreased the expression of activated caspase-8 and caspase-3 and increased the protein level of Lamp2A in LPS-treated Clone 9 cells. These results demonstrate that LPS-induced ROS causes lysosomal membrane permeabilization and lysosomal cell death, which may play a crucial role in hepatic failure in sepsis. Our results may facilitate the development of new strategies for sepsis management.}, }
@article {pmid39028629, year = {2024}, author = {Ye, JJ and Chen, ZY and Wang, QH and Liao, XY and Wang, XY and Zhang, CC and Liu, LR and Wei, Q and Bao, YG}, title = {Current treatment for male infertility: an umbrella review of systematic reviews and meta-analyses.}, journal = {Asian journal of andrology}, volume = {}, number = {}, pages = {}, doi = {10.4103/aja202428}, pmid = {39028629}, issn = {1745-7262}, abstract = {This umbrella review aimed to summarize and provide a general evaluation of the effectiveness of current treatments for male infertility and assess the quality of evidence and possible biases. An umbrella review of systematic reviews and meta-analyses available in PubMed, Web of Science, and Scopus, covering studies published up to October 2023, was conducted. Sperm concentration, morphology, and motility were used as endpoints to evaluate the effectiveness of the treatments. Of 2998 studies, 18 published meta-analyses were extracted, yielding 90 summary effects on sperm concentration (n = 36), sperm morphology (n = 26), and sperm motility (n = 28) on 28 interventions. None of the meta-analyses were classified as having low methodological quality, whereas 12 (66.7%) and 6 (33.3%) had high and moderate quality, respectively. Of the 90 summary effects, none were rated high-evidence quality, whereas 53.3% (n = 48), 25.6% (n = 23), and 21.1% (n = 19) were rated moderate, low, and very low, respectively. Significant improvements in sperm concentration, morphology, and motility were observed with pharmacological interventions (N-acetyl-cysteine, antioxidant therapy, aromatase inhibitors, selective estrogen receptor modulators, hormones, supplements, and alpha-lipoic acid) and nonpharmacological interventions (varicocele repair and redo varicocelectomy). In addition, vitamin supplementation had no significant positive effects on sperm concentration, motility, or morphology. Treatments for male infertility are increasingly diverse; however, the current evidence is poor because of the limited number of patients. Further well-designed studies on single treatment and high-quality meta-analysis of intertreatment comparisons are recommended.}, }
@article {pmid39028412, year = {2024}, author = {Zolnourian, A and Garland, P and Holton, P and Arora, M and Rhodes, J and Uff, C and Birch, T and Howat, D and Franklin, S and Galea, I and Bulters, D}, title = {A Randomised Controlled Trial of SFX-01 After Subarachnoid Haemorrhage - The SAS Study.}, journal = {Translational stroke research}, volume = {}, number = {}, pages = {}, pmid = {39028412}, issn = {1868-601X}, abstract = {SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28 days of SFX-01 300 mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUClast were 16.2, 277 and 415 h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R[2] = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.}, }
@article {pmid39028033, year = {2024}, author = {Arenhoevel, J and Kuppe, A and Addante, A and Wei, LF and Boback, N and Butnarasu, C and Zhong, Y and Wong, C and Graeber, SY and Duerr, J and Gradzielski, M and Lauster, D and Mall, MA and Haag, R}, title = {Thiolated polyglycerol sulfate as potential mucolytic for muco-obstructive lung diseases.}, journal = {Biomaterials science}, volume = {}, number = {}, pages = {}, doi = {10.1039/d4bm00381k}, pmid = {39028033}, issn = {2047-4849}, abstract = {Increased disulfide crosslinking of secreted mucins causes elevated viscoelasticity of mucus and is a key determinant of mucus dysfunction in patients with cystic fibrosis (CF) and other muco-obstructive lung diseases. In this study, we describe the synthesis of a novel thiol-containing, sulfated dendritic polyglycerol (dPGS-SH), designed to chemically reduce these abnormal crosslinks, which we demonstrate with mucolytic activity assays in sputum from patients with CF. This mucolytic polymer, which is based on a reportedly anti-inflammatory polysulfate scaffold, additionally carries multiple thiol groups for mucolytic activity and can be produced on a gram-scale. After a physicochemical compound characterization, we compare the mucolytic activity of dPGS-SH to the clinically approved N-acetylcysteine (NAC) using western blot studies and investigate the effect of dPGS-SH on the viscoelastic properties of sputum samples from CF patients by oscillatory rheology. We show that dPGS-SH is more effective than NAC in reducing multimer intensity of the secreted mucins MUC5B and MUC5AC and demonstrate significant mucolytic activity by rheology. In addition, we provide data for dPGS-SH demonstrating a high compound stability, low cytotoxicity, and superior reaction kinetics over NAC at different pH levels. Our data support further development of the novel reducing polymer system dPGS-SH as a potential mucolytic to improve mucus function and clearance in patients with CF as well as other muco-obstructive lung diseases.}, }
@article {pmid38376368, year = {2024}, author = {Ghani, H and Podwojniak, A and Tan, IJ and Fliorent, R and Jafferany, M}, title = {From tugs to treatments: a systematic review on pharmacological interventions for trichotillomania.}, journal = {Clinical and experimental dermatology}, volume = {49}, number = {8}, pages = {774-782}, doi = {10.1093/ced/llae052}, pmid = {38376368}, issn = {1365-2230}, mesh = {*Trichotillomania/drug therapy ; Humans ; *Acetylcysteine/therapeutic use ; *Selective Serotonin Reuptake Inhibitors/therapeutic use ; Aripiprazole/therapeutic use ; Behavior Therapy/methods ; }, abstract = {BACKGROUND: Trichotillomania (TTM) is a psychiatric disorder with dermatological consequences, characterized by recurrent hair pulling. It affects 1-3% of the population, and often coexists with other psychiatric disorders, leading to emotional distress. Effective management of TTM can be challenging because of underdiagnosis, symptom heterogeneity and stigma. Pharmacological interventions, including selective serotonin reuptake inhibitors and N-acetyl cysteine (NAC) are commonly used.<br><br>OBJECTIVES: To assess the existing literature on pharmacotherapy for TTM and identify potential avenues for future research and treatment advancements.<br><br>METHODS: A systematic review of the literature was performed using PubMed and Scopus databases within the past 10 years (PROSPERO: CRD42023454009). Included studies assessed pharmacotherapy for TTM and provided insights into current evidence and potential directions for future research and treatment advancements.<br><br>RESULTS: In total, 23 articles were identified that met inclusion criteria. The most successful interventions were NAC, aripiprazole and monoamine oxidase inhibitors. NAC was identified as the most impressive adjunctive therapy to selective serotonin reuptake inhibitors and behavioural therapies in treatment through its mechanism of decreased glutamate-induced excitatory neuronal damage, with adjunctive antioxidant properties. Most of the other therapeutics that were identified require further research and controlled trials to validate their findings.<br><br>CONCLUSIONS: Even if successful therapeutic outcomes are achieved, it is important to consider the patient's comorbidities and to combine pharmacological interventions with behavioural therapy interventions to comprehensively manage TTM.}, }
@article {pmid39019252, year = {2024}, author = {Rivera-Ingraham, GA and Martínez-Alarcón, D and Theuerkauff, D and Nommick, A and Lignot, JH}, title = {Two faces of one coin: Beneficial and deleterious effects of reactive oxygen species during short-term acclimation to hypo-osmotic stress in a decapod crab.}, journal = {Comparative biochemistry and physiology. Part A, Molecular &amp; integrative physiology}, volume = {}, number = {}, pages = {111700}, doi = {10.1016/j.cbpa.2024.111700}, pmid = {39019252}, issn = {1531-4332}, abstract = {Exposure to environmental changes often results in the production of reactive oxygen species (ROS), which, if uncontrolled, leads to loss of cellular homeostasis and oxidative distress. However, at physiological levels these same ROS are known to be key players in cellular signaling and the regulation of key biological activities (oxidative eustress). While ROS are known to mediate salinity tolerance in plants, little is known for the animal kingdom. In this study, we use the Mediterranean crab Carcinus aestuarii, highly tolerant to salinity changes in its environment, as a model to test the healthy or pathological role of ROS due to exposure to diluted seawater (dSW). Crabs were injected either with an antioxidant [N-acetylcysteine (NAC), 150 mg·kg[-1]] or phosphate buffered saline (PBS). One hour after the first injection, animals were either maintained in seawater (SW) or transferred to dSW and injections were carried out at 12-h intervals. After ≈48 h of salinity change, all animals were sacrificed and gills dissected for analysis. NAC injections successfully inhibited ROS formation occurring due to dSW transfer. However, this induced 55% crab mortality, as well as an inhibition of the enhanced catalase defenses and mitochondrial biogenesis that occur with decreased salinity. Crab osmoregulatory capacity under dSW condition was not affected by NAC, although it induced in anterior (non-osmoregulatory) gills a 146-fold increase in Na[+]/K[+]/2Cl[-] expression levels, reaching values typically observed in osmoregulatory tissues. We discuss how ROS influences the physiology of anterior and posterior gills, which have two different physiological functions and strategies during hyper-osmoregulation in dSW.}, }
@article {pmid39006976, year = {2024}, author = {Sadeghinejad, S and Mousavi, M and Zeidooni, L and Mansouri, E and Mohtadi, S and Khodayar, MJ}, title = {Ameliorative effects of umbelliferone against acetaminophen-induced hepatic oxidative stress and inflammation in mice.}, journal = {Research in pharmaceutical sciences}, volume = {19}, number = {1}, pages = {83-92}, pmid = {39006976}, issn = {1735-5362}, abstract = {BACKGROUND AND PURPOSE: Acetaminophen (APAP) is a commonly used antipyretic and pain reliever that its overdose causes acute liver toxicity. Umbelliferone (UMB) has many pharmacological effects. In this study, the hepatoprotective effect of UMB on acute hepatotoxicity induced by APAP was investigated.<br><br>EXPERIMENTAL APPROACH: Forty-nine male mice were separated into seven groups. The control received vehicle (i.p.), UMB group received UMB (120 mg/kg, i.p.), APAP group was treated with a single dose of APAP (350 mg/kg, i.p.), and pretreated groups received N-acetylcysteine (NAC, 200 mg/kg, i.p.) or different doses of UMB (30, 60, and 120 mg/kg, i.p.), respectively before APAP. Twenty-four hours after APAP injection, mice were sacrificed and blood and liver samples were collected. Then, serum and tissue samples were investigated for biochemical and histological studies.<br><br>FINDINGS/RESULTS: A single dose of APAP caused elevation in the serum liver enzymes, including alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. The amounts of thiobarbituric acid reactive substances, tumor necrosis factor-alpha, and nitric oxide increased in the mice's liver tissue. Moreover, the amount of total thiol and the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) significantly diminished in the APAP group. Histological results confirmed the hepatotoxicity induced by APAP. However, UMB (more effective at 60 and 120 mg/kg) lessened APAP-induced hepatic injuries, which is comparable with NAC effects.<br><br>CONCLUSION AND IMPLICATIONS: The findings of this study provided evidence that UMB ameliorates liver injury induced by APAP through its antioxidant and anti-inflammatory effects.}, }
@article {pmid39005460, year = {2024}, author = {Wellslager, B and Roberts, J and Chowdhury, N and Madan, L and Orellana, E and Yilmaz, &#xd6;}, title = {Porphyromonas gingivalis activates Heat-Shock-Protein 27 to drive a LC3C-specific probacterial form of select autophagy that is redox sensitive for intracellular bacterial survival in human gingival mucosa.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.07.01.601539}, pmid = {39005460}, issn = {2692-8205}, abstract = {Porphyromonas gingivalis , a major oral pathobiont, evades canonical host pathogen clearance in human primary gingival epithelial cells (GECs) by initiating a non-canonical variant of autophagy consisting of Microtubule-associated protein 1A/1B-light chain 3 (LC3)-rich autophagosomes, which then act as replicative niches. Simultaneously, P. gingivalis inhibits apoptosis and oxidative-stress, including extracellular-ATP (eATP)-mediated reactive-oxygen-species (ROS) production via phosphorylating Heat Shock Protein 27 (HSp27) with the bacterial nucleoside-diphosphate-kinase (Ndk). Here, we have mechanistically identified that P. gingivalis -mediated induction of HSp27 is crucial for the recruitment of the LC3 isoform, LC3C, to drive the formation of live P. gingivalis -containing Beclin1-ATG14-rich autophagosomes that are redox sensitive and non-degrading. HSp27 depletions of both infected GECs and gingiva-mimicking organotypic-culture systems resulted in the collapse of P. gingivalis -mediated autophagosomes, and abolished P. gingivalis -induced LC3C-specific autophagic-flux in a HSp27-dependent manner. Concurrently, HSp27 depletion accompanied by eATP treatment abrogated protracted Beclin 1-ATG14 partnering and decreased live intracellular P. gingivalis levels. These events were only partially restored via treatments with the antioxidant N-acetyl cysteine (NAC), which rescued the cellular redox environment independent of HSp27. Moreover, the temporal phosphorylation of HSp27 by the bacterial Ndk results in HSp27 tightly partnering with LC3C, hindering LC3C canonical cleavage, extending Beclin 1-ATG14 association, and halting canonical maturation. These findings pinpoint how HSp27 pleiotropically serves as a major platform-molecule, redox regulator, and stepwise modulator of LC3C during P. gingivalis -mediated non-canonical autophagy. Thus, our findings can determine specific molecular strategies for interfering with the host-adapted P. gingivalis ' successful mucosal colonization and oral dysbiosis.}, }
@article {pmid38804152, year = {2024}, author = {Wang, Y and Long, L and Luo, Q and Huang, X and Zhang, Y and Meng, X and Chen, D}, title = {Aflatoxin B1 induces ROS-dependent mitophagy by modulating the PINK1/Parkin pathway in HepG2 cells.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {135}, number = {2}, pages = {195-209}, doi = {10.1111/bcpt.14034}, pmid = {38804152}, issn = {1742-7843}, mesh = {Humans ; *Mitophagy/drug effects ; Hep G2 Cells ; *Reactive Oxygen Species/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Membrane Potential, Mitochondrial/drug effects ; *Protein Kinases/metabolism ; *Aflatoxin B1/toxicity ; *Adenosine Triphosphate/metabolism ; *NF-E2-Related Factor 2/metabolism/genetics ; Signal Transduction/drug effects ; Phosphoprotein Phosphatases/metabolism/genetics ; Mitochondria/drug effects/metabolism ; Acetylcysteine/pharmacology ; Mitochondrial Proteins/metabolism/genetics ; }, abstract = {Aflatoxin B1 (AFB1) is extremely harmful to both humans and animals. Mitophagy is a selective process of self-elimination and has an important role in controlling mitochondrial quality. The present study aimed to investigate the effect of reactive oxygen species (ROS) accumulation on AFB1-induced mitophagy in HepG2 cells to provide a new perspective from which to design novel therapeutic strategies to treat AFB1 poisoning. ROS release was induced in HepG2 cells with AFB1 (10 μmol/L). Cell autophagy activity, mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) levels, Parkin translocation and both the transcription and expression of mitophagy-related proteins were measured when N-acetyl-L-cysteine (NAC) partially decreased the ROS level, while the knockdown of nuclear factor erythroid 2-related factor 2 (Nrf2) resulted in a large accumulation of ROS. The results reveal that NAC pretreatment ameliorated the decline in both the MMP and the ATP levels while also activating phosphoglycerate mutase 5 (PGAM5)-PTEN-induced kinase 1 (PINK1)/Parkin, while the Nrf2 knockdown group exhibited the opposite trend. These results suggest that AFB1-induced mitophagy in HepG2 cells depends on ROS, and proper ROS activates mitophagy to play a protective role.}, }
@article {pmid39004668, year = {2024}, author = {Erichsen, PA and Dalhoff, K and Andersen, MA}, title = {Should high-dose N-acetylcysteine be given in cases of massive paracetamol overdoses: A narrative review.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {}, number = {}, pages = {}, pmid = {39004668}, issn = {1742-7843}, abstract = {N-acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20-21 h). The subject is further complicated because "massive overdoses" and "high-risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high-dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49-3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08-0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high-dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high-dose NAC regimen should be included in clinical practice.}, }
@article {pmid39004152, year = {2024}, author = {Chen, Q and Hu, R and Qiu, H and Li, S and Xiang, P and Lu, Y and Wang, X and Wang, T and Zhou, L and Zhang, W and Wen, E and Ma, L and Yu, C}, title = {REDD1 knockdown ameliorates endothelial cell senescence through repressing TXNIP-mediated oxidative stress.}, journal = {Mechanisms of ageing and development}, volume = {}, number = {}, pages = {111962}, doi = {10.1016/j.mad.2024.111962}, pmid = {39004152}, issn = {1872-6216}, abstract = {Endothelial cell senescence characterized by reactive oxygen species (ROS) accumulation and chronic inflammation is widely recognized as a key contributor to atherosclerosis (AS). Regulated in development and DNA damage response 1 (REDD1), a conserved stress-response protein that regulates ROS production, is involved in the pathogenesis of various age-related diseases. However, the role of REDD1 in endothelial cell senescence is still unclear. Here, we screened REDD1 as a differentially expressed senescence-related gene in the AS progression using bioinformatics methods, and validated the upregulation of REDD1 expression in AS plaques, senescent endothelial cells, and aging aorta by constructing AS mice, D-galactose (DG)-induced senescent endothelial cells and DG-induced accelerated aging mice, respectively. siRNA against REDD1 could improve DG-induced premature senescence of endothelial cells and inhibit ROS accumulation, similar to antioxidant N-Acetylcysteine (NAC) treatment. Meanwhile, NAC reduced the upregulation of REDD1 induced by DG, supporting the positive feedback loop between REDD1 and ROS contributes to endothelial cell senescence. Mechanistically, the regulatory effect of REDD1 on ROS might be related to the TXNIP-REDD1 interaction in DG-induced endothelial cell senescence. Collectively, experiments above provide evidence that REDD1 participates in endothelial cell senescence through repressing TXNIP-mediated oxidative stress, which may be involved in the progression of atherosclerosis.}, }
@article {pmid39003685, year = {2024}, author = {Dharshini, KS and Ameen, F and Anbazhagan, V}, title = {Mechanistic Investigation on the Antibacterial Activity of Biogenic Silver Nanoparticles Prepared Using Root Extract of Sarsaparilla and Demonstrated their In Vivo Efficacy in Zebrafish Model.}, journal = {Current microbiology}, volume = {81}, number = {9}, pages = {268}, pmid = {39003685}, issn = {1432-0991}, mesh = {Animals ; *Zebrafish ; *Silver/pharmacology/chemistry ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Metal Nanoparticles/chemistry ; *Plant Extracts/pharmacology/chemistry ; *Microbial Sensitivity Tests ; *Plant Roots/chemistry/microbiology ; Reactive Oxygen Species/metabolism ; Bacteria/drug effects ; }, abstract = {Antibiotic success rates are decreasing as drug-resistant bacteria become more prevalent, prompting the development of new therapeutic drugs. Herein, we demonstrated the antimicrobial activity of sarsaparilla root extract fabricated silver nanoparticles (sAgNPs). The UV-Visible spectra revealed that the surface Plasmon resonance maxima of sAgNPs were at 415 nm. Transmission electron microscopy confirms that the particles are spherical with size of 12-35 nm. The minimum inhibitory concentration (MIC) of sAgNPs against Escherichia coli, uropathogenic Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus was 62.5, 62.5, 62.5, 62.5, 125 and 125 µM, respectively. At 1X MIC, sAgNPs induces excess reactive oxygen species (ROS) production and disturbs the bacteria membrane intergity, causing cytoplamic membrane depolarization. Interestingly, antibacterial activity of sAgNPs was considerably reduced in the presence of an antioxidant, N-acetyl cysteine, suggesting that ROS-induced membrane damage is a plausible cause of cell death. In contrast to many studies that only report the in vitro activity of NPs, we determined the in vivo antibacterial efficacy using the zebrafish model. It was found that sAgNPs protect fish from infection by inhibiting bacterial growth and eliminating them from the fish. In addition, the catalytic potential of sAgNPs for wastewater decontamination was demonstrated by degrading organic pollutants such as methyl orange, congo red, reactive black, and acid blue. The pollutants degraded in less than 10 min, and the reaction follows pseudo-first-order kinetics. As a proof of concept, the catalytic potential of sAgNPs in degrading mixed dyes to satisfy industrial wastewater treatment needs was established. In summary, sAgNPs have the potential to act as nanocatalysts and nano-drugs, addressing key challenges in medical and environmental research.}, }
@article {pmid38997833, year = {2024}, author = {Shiozawa, A and Kajiwara, C and Ishii, Y and Tateda, K}, title = {Corrigendum to "N-acetyl-cysteine mediates protection against Mycobacterium avium through induction of human β-defensin-2" [Microb Infect 22 (10) (2020) 567-575].}, journal = {Microbes and infection}, volume = {}, number = {}, pages = {105388}, doi = {10.1016/j.micinf.2024.105388}, pmid = {38997833}, issn = {1769-714X}, }
@article {pmid38992233, year = {2024}, author = {Glass, KA and Stoecker, ZR and LeRoy, J and Palmer, CL and Stipek, J and Boley, S}, title = {Investigating a Novel Two-Bag N-Acetylcysteine Regimen for Acetaminophen Toxicity.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {}, number = {}, pages = {}, pmid = {38992233}, issn = {1937-6995}, abstract = {BACKGROUND: Acetaminophen toxicity remains one of the most common causes of liver failure and is treated with a course of n-acetylcysteine (NAC). This exceptionally effective medication is traditionally administered using a complicated three-bag protocol that is prone to administration errors.<br><br>OBJECTIVE: We aimed to assess whether switching to a novel two-bag protocol (150&#xa0;mg/kg over 1&#xa0;h followed by 150&#xa0;mg/kg over 20&#xa0;h) reduced administration errors while not increasing liver injury or anaphylactoid reactions.<br><br>METHODS: This was a retrospective chart review of hospital encounters for patients with acetaminophen toxicity, comparing outcomes before and after the change from a three-bag protocol to a two-bag protocol at two affiliated institutions. The primary outcome was incidence of medication errors with secondary outcomes including acute liver injury (ALI) and incidence of non-anaphylactoid allergic reactions (NAAR). The study was approved by the health system's Institutional Review Board.<br><br>RESULTS: 483 encounters were included for analysis (239 in the three-bag and 244 in the two-bag groups). NAAR were identified in 11 patients with no difference seen between groups. Similarly, no differences were seen in ALI. Medication administration errors were observed significantly less often in the two-bag group (OR 0.24) after adjusting for confounders.<br><br>CONCLUSION: Transitioning to a novel two-bag NAC regimen decreased administration errors. This adds to the literature that two-bag NAC regimens are not only safe but also may have significant benefits over the traditional NAC protocol.}, }
@article {pmid38990380, year = {2024}, author = {Lu, SH and Yun, TF and Kou, YR and Chang, YP}, title = {Preliminary evidence for therapeutic impact of intravesical glucosamine on protamine sulfate and potassium chloride-induced bladder overactivity in rat model.}, journal = {World journal of urology}, volume = {42}, number = {1}, pages = {405}, pmid = {38990380}, issn = {1433-8726}, support = {V105C-148//Taipei Veterans General Hospital/ ; }, mesh = {Animals ; *Urinary Bladder, Overactive/drug therapy ; Female ; *Rats, Sprague-Dawley ; Rats ; Administration, Intravesical ; *Protamines ; *Disease Models, Animal ; *Potassium Chloride ; *Glucosamine/pharmacology/therapeutic use/administration &amp; dosage ; }, abstract = {PURPOSE: To investigate the protective effect of intravesical glucosamine in treating overactive bladder (OAB).<br><br>METHODS: Ninety-two female Sprague-Dawley (SD) rats were divided into 4 groups i.e. protamine sulfate (PS), N-acetylcysteine (NAC), and glucosamine-treated PS (GPS), and normal saline control (NC) were used. We induced hyperactivity in rats via intravesical infusion of PS and potassium chloride (KCl), whereas the NC group underwent a sustained intravesical saline infusion for 1&#xa0;h. N-acetylcysteine (NAC), a potential antioxidant as well as anti-inflammatory agent was employed as positive control. Cystometrography (CMG) was then conducted to determine urodynamic parameters, i.e., leak point pressure (LPP, n&#x2009;=&#x2009;48) and inter-contractile interval, the duration between two voids (ICI, n&#x2009;=&#x2009;32).<br><br>RESULTS: LPP was significantly elevated in the GPS group (mean&#x2009;&#xb1;&#x2009;SD: 110.9&#x2009;&#xb1;&#x2009;6.2 mmHg) compared to the NC (81.0&#x2009;&#xb1;&#x2009;32.5 mmHg), PS (40.3&#x2009;&#xb1;&#x2009;10.9 mmHg), and NAC group (70.3&#x2009;&#xb1;&#x2009;19.4 mmHg). The cystometrogram data also reveals a prolonged ICI in the GPS group (241.3&#x2009;&#xb1;&#x2009;40.2&#xa0;s) compared to the NC group (216.0&#x2009;&#xb1;&#x2009;41.7&#xa0;s), PS group (128.8&#x2009;&#xb1;&#x2009;23.6&#xa0;s), and NAC group (193.8&#x2009;&#xb1;&#x2009;28.3&#xa0;s).<br><br>CONCLUSION: This preliminary study implies the ameliorative impact of GPS treatment on OAB in terms of improved urodynamic parameters, including LPP and ICI.}, }
@article {pmid38986690, year = {2024}, author = {Li, Z and Li, H and Wang, D and Peng, X and Syed, BM and Liu, Q}, title = {S-glutathionylation in hepatocytes is involved in arsenic-induced liver fibrosis through activation of the NLRP3 inflammasome, an effect alleviated by NAC.}, journal = {The Science of the total environment}, volume = {}, number = {}, pages = {174534}, doi = {10.1016/j.scitotenv.2024.174534}, pmid = {38986690}, issn = {1879-1026}, abstract = {Arsenic, a toxicant widely distributed in the environment, is considered as a risk factor for liver fibrosis. At present, the underlying mechanism still needs to be explored. In the present study, we found that, for mice, chronic exposure to arsenic induced liver fibrosis, activated the NLRP3 inflammasome, and increased the levels of reactive oxygen species (ROS). After hepatocytes were co-cultured with hepatic stellate cells (HSCs), we observed the arsenic-activated NLRP3 inflammasome in hepatocytes, and the co-cultured HSCs were activated. Further, we found that, in livers of mice, arsenic disturbed GSH metabolism and promoted protein S-glutathionylation. A 3D molecular docking simulation suggested that NLRP3 binds with GSH, which was confirmed by immunoprecipitation experiments. N-acetylcysteine (NAC) increased the levels of GSH in hepatocytes, which suppressed the S-glutathionylation of NLRP3 and blocked arsenic-induced activation of the NLRP3 inflammasome. Mechanistically, an imbalance of the redox state induced by arsenic promotes the S-glutathionylation of NLRP3, which regulates activation of the NLRP3 inflammasome, leading into the activation of HSCs. Moreover, NAC increases the levels of GSH to block arsenic-induced S-glutathionylation of NLRP3, thereby blocking arsenic-induced liver fibrosis. Thus, via activating HSCs, the S-glutathionylation of NLRP3 in hepatocytes is involved in arsenic-induced liver fibrosis, and, for hepatocytes, NAC alleviates these effects by increasing the levels of GSH. These results reveal a new mechanism and provide a possible therapeutic target for the liver fibrosis induced by environmental factors.}, }
@article {pmid38985827, year = {2024}, author = {Krause, BJ and Paz, AA and Garrud, TAC and Peñaloza, E and Vega-Tapia, F and Ford, SG and Niu, Y and Giussani, DA}, title = {Epigenetic regulation by hypoxia, N-acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos.}, journal = {The Journal of physiology}, volume = {}, number = {}, pages = {}, doi = {10.1113/JP286266}, pmid = {38985827}, issn = {1469-7793}, support = {PG/10/99/28656/BHF_/British Heart Foundation/United Kingdom ; 1220421//Fondo Nacional de Desarrollo Cient&#xed;fico y Tecnol&#xf3;gico/ ; }, abstract = {Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.}, }
@article {pmid38953310, year = {2024}, author = {Choi, EJ and Oh, HT and Lee, SH and Zhang, CS and Li, M and Kim, SY and Park, S and Chang, TS and Lee, BH and Lin, SC and Jeon, SM}, title = {Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-21}, doi = {10.1080/15548627.2024.2374692}, pmid = {38953310}, issn = {1554-8635}, abstract = {Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca[2+]. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H[+]-translocating ATPase.}, }
@article {pmid38814824, year = {2024}, author = {Zheng, F and Ye, C and Lei, JZ and Ge, R and Li, N and Bo, JH and Chen, AD and Zhang, F and Zhou, H and Wang, JJ and Chen, Q and Li, YH and Zhu, GQ and Han, Y}, title = {Intervention of Asprosin Attenuates Oxidative Stress and Neointima Formation in Vascular Injury.}, journal = {Antioxidants &amp; redox signaling}, volume = {}, number = {}, pages = {}, doi = {10.1089/ars.2023.0383}, pmid = {38814824}, issn = {1557-7716}, abstract = {Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury.}, }
@article {pmid38973318, year = {2024}, author = {Babu Balagopal, P and Kohli, R and Uppal, V and Averill, L and Shah, C and McGoogan, K and Di Guglielmo, M and Goran, M and Hossain, MJ}, title = {Effect of N-acetyl cysteine in children with metabolic dysfunction-associated steatotic liver disease-A pilot study.}, journal = {Journal of pediatric gastroenterology and nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1002/jpn3.12312}, pmid = {38973318}, issn = {1536-4801}, support = {1-14-CE-04//American Diabetes Association/ ; //Nemours Biomedical Research/ ; }, abstract = {BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its sequelae of more severe forms such as metabolic dysfunction-associated steatohepatitis (MASH) is rapidly increasing in children with the rise in obesity. Successful and sustainable treatments for MASLD are lacking in children. We determined the therapeutic effect of N-acetyl cysteine (NAC) on biomarkers of oxidative stress, inflammation and insulin resistance (IR), liver enzymes, liver fat fraction (LFF) and (LS) in children with obesity and biopsy-confirmed MASLD.<br><br>METHODS: Thirteen children (n&#x2009;=&#x2009;13; age: 13.6&#x2009;&#xb1;&#x2009;2.8 years; NAS score >2) underwent a double-blind, placebo-controlled trial of NAC (either 600 or 1200&#x2009;mg NAC/day) or placebo for 16 weeks. Measurements included LFF (magnetic resonance imaging), LS (ultrasound elastography), and body composition. Erythrocyte glutathione (GSH), liver enzymes, insulin, glucose, adiponectin, high-sensitivity c-reactive protein (hs-CRP), and interleukin-6 (IL-6) were also measured. HOMA-IR was calculated.<br><br>RESULTS: Sixteen-week NAC treatment improved (baseline adjusted between-group p&#x2009;<&#x2009;.05 for all) markers of inflammation (IL-6 and hs-CRP), oxidative stress (GSH), and insulin resistance (HOMA-IR) and reduced liver enzymes, LFF and LS. Body weight and body composition did not show beneficial changes.<br><br>CONCLUSIONS: Sixteen-week NAC treatment was well tolerated in children with obesity and MASLD and led to improvements in oxidative stress, inflammation and IR and liver outcomes. The results from this pilot study support further investigation of NAC as a therapeutic agent in children with MASLD.}, }
@article {pmid38972409, year = {2024}, author = {Huang, Y and Sun, Y and Huang, Q and Wu, S and Huang, Z and Hong, Y}, title = {Abamectin-induced behavioral alterations link to energy metabolism disorder and ferroptosis via oxidative stress in Chinese mitten crab, Eriocheir sinensis.}, journal = {The Science of the total environment}, volume = {}, number = {}, pages = {174558}, doi = {10.1016/j.scitotenv.2024.174558}, pmid = {38972409}, issn = {1879-1026}, abstract = {The increasing application of abamectin (ABM) in agriculture has raised concerns regarding its environmental safety and potential adverse effects on aquatic environment safety. In the present study, the toxic effects of ABM exposure on the adult Chinese mitten crab, Eriocheir sinensis were investigated, with a focus on locomotion impairment, behavioral changes, oxidative stress, energy metabolism disruption, and ferroptosis. Crabs were exposed to sublethal concentrations of ABM at 2, 20 and 200 μg/L. After 21 d chronic exposure to 200 μg/L, residual ABM in hepatopancreas and muscles were detected as 12.24 ± 6.67 and 8.75 ± 5.42 μg/Kg, respectively. By using acute exposure experiments (96 h), we observed significant locomotion and behavioral alterations, alongside biochemical evidences of oxidative stress and energy metabolism impairment. The presence of ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, was notably identified in the hepatopancreas. Functional tests with N-acetylcysteine (NAC) supplementation showed restored behavioral responses and decrease of ferroptosis levels. It suggests that mitigating oxidative stress could counteract ABM-induced toxicity. Our findings highlight the critical roles of oxidative stress and ferroptosis in mediating the toxic effects of ABM on E. sinensis, underscoring the need for strategies to mitigate environmental exposure to pesticides.}, }
@article {pmid38969277, year = {2024}, author = {Shi, W and Gao, Y and Yang, H and Li, H and Liu, T and Zhao, J and Wei, Z and Li Lin,  and Huang, Y and Guo, Y and Xu, A and Bai, Z and Xiao, X}, title = {Bavachinin, a main compound of Psoraleae Fructus, facilitates GSDMD-mediated pyroptosis and causes hepatotoxicity in mice.}, journal = {Chemico-biological interactions}, volume = {}, number = {}, pages = {111133}, doi = {10.1016/j.cbi.2024.111133}, pmid = {38969277}, issn = {1872-7786}, abstract = {Psoraleae Fructus (PF, Psoralea corylifolia L.), a traditional medicine with a long history of application, is widely used clinically for the treatment of various diseases. However, the reports of PF-related adverse reactions, such as hepatotoxicity, phototoxic dermatitis, and allergy, are increasing year by year, with liver injury being the mostly common. Our previous studies have demonstrated that PF and its preparations can cause liver injury in lipopolysaccharide (LPS)-mediated susceptibility mouse model, but the mechanism of PF-related liver injury is unclear. In this study, we showed that PF and bavachinin, a major component of PF, can directly induce the expression of caspase-1 and interleukin-1β (IL-1β), indicating that PF and bavachinin can directly triggered the activation of inflammasome. Furthermore, pretreatment with NLR family pyrin domain-containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome inhibitors, containing MCC950, ODN TTAGGG (ODN) and carnosol, all significantly reversed bavachinin-induced inflammasome activation. Mechanistically, bavachinin dose-dependently promote Gasdermin D (GSDMD) post-shear activation and then induce mitochondrial reactive oxygen species (mtROS) production and this effect is markedly inhibited by pretreatment with N-Acetylcysteine amide (NAC). In addition, combination treatment of LPS and bavachinin significantly induced liver injury in mice, but not LPS or bavachinin alone, and transcriptome analysis further validated these results. Thus, PF and bavachinin can induce the activation of inflammasome by promoting GSDMD cleavage and cause hepatotoxicity in mice. Therefore, PF, bavachinin, and PF-related preparations should be avoided in patients with inflammasome activation-associated diseases.}, }
@article {pmid38958792, year = {2024}, author = {Yan, Y and Huang, W and Lu, X and Chen, X and Shan, Y and Luo, X and Li, Y and Yang, X and Li, C}, title = {Zinc oxide nanoparticles induces cell death and consequently leading to incomplete neural tube closure through oxidative stress during embryogenesis.}, journal = {Cell biology and toxicology}, volume = {40}, number = {1}, pages = {51}, pmid = {38958792}, issn = {1573-6822}, support = {2021A1515110232//Guangdong Basic and Applied Basic Research Foundation/ ; 202201011394//the Science and Technology Program of Guangzhou/ ; 2022KTSCX025//Guangdong Scientific Research Platform and Projects for the Higher-educational Institution/ ; 20211112//Research Project of Traditional Chinese Medicine Bureau of Guangdong/ ; No.29//2021 Guangdong Province Undergraduate College Teaching Quality and Teaching Reform Engineering Construction Project/ ; }, mesh = {*Zinc Oxide/toxicity ; Animals ; *Oxidative Stress/drug effects ; Chick Embryo ; *Embryonic Development/drug effects ; Mice ; *Neural Tube/drug effects/embryology/metabolism ; Humans ; *Neural Tube Defects/chemically induced/metabolism/embryology/pathology ; *Reactive Oxygen Species/metabolism ; Apoptosis/drug effects ; Cell Death/drug effects ; Female ; Mitochondria/drug effects/metabolism ; Metal Nanoparticles/toxicity ; Autophagy/drug effects ; Cell Line, Tumor ; Nanoparticles/toxicity ; }, abstract = {The implementation of Zinc oxide nanoparticles (ZnO NPs) raises concerns regarding their potential toxic effects on human health. Although more and more researches have confirmed the toxic effects of ZnO NPs, limited attention has been given to their impact on the early embryonic nervous system. This study aimed to explore the impact of exposure to ZnO NPs on early neurogenesis and explore its underlying mechanisms. We conducted experiments here to confirm the hypothesis that exposure to ZnO NPs causes neural tube defects in early embryonic development. We first used mouse and chicken embryos to confirm that ZnO NPs and the Zn[2+] they release are able to penetrate the placental barrier, influence fetal growth and result in incomplete neural tube closure. Using SH-SY5Y cells, we determined that ZnO NPs-induced incomplete neural tube closure was caused by activation of various cell death modes, including ferroptosis, apoptosis and autophagy. Moreover, dissolved Zn[2+] played a role in triggering widespread cell death. ZnO NPs were accumulated within mitochondria after entering cells, damaging mitochondrial function and resulting in the over production of reactive oxygen species, ultimately inducing cellular oxidative stress. The N-acetylcysteine (NAC) exhibits significant efficacy in mitigating cellular oxidative stress, thereby alleviating the cytotoxicity and neurotoxicity brought about by ZnO NPs. These findings indicated that the exposure of ZnO NPs in early embryonic development can induce cell death through oxidative stress, resulting in a reduced number of cells involved in early neural tube closure and ultimately resulting in incomplete neural tube closure during embryo development. The findings of this study could raise public awareness regarding the potential risks associated with the exposure and use of ZnO NPs in early pregnancy.}, }
@article {pmid38958241, year = {2024}, author = {Zuo, XS and Wang, QY and Wang, SS and Li, G and Zhan, LY}, title = {The role of N-acetylcysteine on adhesion and biofilm formation of Candida parapsilosis isolated from catheter-related candidemia.}, journal = {Journal of medical microbiology}, volume = {73}, number = {7}, pages = {}, doi = {10.1099/jmm.0.001848}, pmid = {38958241}, issn = {1473-5644}, mesh = {*Biofilms/drug effects/growth &amp; development ; *Acetylcysteine/pharmacology ; Humans ; *Candida parapsilosis/drug effects/genetics/physiology ; *Catheter-Related Infections/microbiology ; *Candidemia/microbiology ; Fungal Proteins/genetics/metabolism ; Antifungal Agents/pharmacology ; }, abstract = {Objectives. Anti-fungal agents are increasingly becoming less effective due to the development of resistance. In addition, it is difficult to treat Candida organisms that form biofilms due to a lack of ability of drugs to penetrate the biofilms. We are attempting to assess the effect of a new therapeutic agent, N-acetylcysteine (NAC), on adhesion and biofilm formation in Candida parapsilosis clinical strains. Meanwhile, to detect the transcription level changes of adhesion and biofilm formation-associated genes (CpALS6, CpALS7, CpEFG1 and CpBCR1) when administrated with NAC in C. parapsilosis strains, furthermore, to explore the mechanism of drug interference on biofilms.Hypothesis/Gap statement. N-acetylcysteine (NAC) exhibits certain inhibitory effects on adhesion and biofilm formation in C. parapsilosis clinical strains from CRBSIs through: (1) down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections (CRBSIs), (2) regulating the metabolism and biofilm -forming factors of cell structure.Methods. To determine whether non-antifungal agents can exhibit inhibitory effects on adhesion, amounts of total biofilm formation and metabolic activities of C. parapsilosis isolates from candidemia patients, NAC was added to the yeast suspensions at different concentrations, respectively. Reverse transcription was used to detect the transcriptional levels of adhesion-related genes (CpALS6 and CpALS7) and biofilm formation-related factors (CpEFG1 and CpBCR1) in the BCR1 knockout strain, CP7 and CP5 clinical strains in the presence of NAC. To further explore the mechanism of NAC on the biofilms of C. parapsilosis, RNA sequencing was used to calculate gene expression, comparing the differences among samples. Gene Ontology (GO) enrichment analysis helps to illustrate the difference between two particular samples on functional levels.Results. A high concentration of NAC reduces the total amount of biofilm formation in C. parapsilosis. Following co-incubation with NAC, the expression of CpEFG1 in both CP7 and CP5 clinical strains decreased, while there were no significant changes in the transcriptional levels of CpBCR1 compared with the untreated strain. GO enrichment analysis showed that the metabolism and biofilm-forming factors of cell structure were all regulated after NAC intervention.Conclusions. The non-antifungal agent NAC exhibits certain inhibitory effects on clinical isolate biofilm formation by down-regulating the expression of the CpEFG1 gene, making it a highly potential candidate for the treatment of C. parapsilosis catheter-related bloodstream infections.}, }
@article {pmid38956487, year = {2024}, author = {Saad, M and Flament, J}, title = {Paracetamol overdose causing acute kidney injury without hepatotoxicity: a case report.}, journal = {International journal of emergency medicine}, volume = {17}, number = {1}, pages = {81}, pmid = {38956487}, issn = {1865-1372}, abstract = {BACKGROUND: Paracetamol is a widely used analgesic and antipyretic. Paracetamol-induced hepatotoxicity is well known, but nephrotoxicity without hepatotoxicity is rarely seen.<br><br>CASE PRESENTATION: We present a case of acute kidney injury without hepatotoxicity in paracetamol overdose. A 15-year-old girl was admitted 48&#xa0;h after she had taken 10&#xa0;g of paracetamol. She was complaining of abdominal pain and vomiting. Her blood level of creatinine was 1.20&#xa0;mg/dL on admission, with a peak at 3.67&#xa0;mg/dL 3 days later. The liver blood tests and blood paracetamol level were negative. She did not receive N-acetyl cysteine and was treated with intravenous fluid (crystalloid). The ultrasonography of the kidneys was normal. Her renal function returned almost to baseline 7 days after admission. It was concluded that the diagnosis was an acute kidney injury caused by acute tubular necrosis due to paracetamol overdose.<br><br>CONCLUSION: This case shows that nephrotoxicity can occur without hepatotoxicity in paracetamol overdose.}, }
@article {pmid38910554, year = {2024}, author = {Shao, Y and Zhang, Y and Zou, S and Wang, J and Li, X and Qin, M and Sun, L and Yin, W and Chang, X and Wang, S and Han, X and Wu, T and Chen, F}, title = {(-)-Epigallocatechin 3-gallate protects pancreatic β-cell against excessive autophagy-induced injury through promoting FTO degradation.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/15548627.2024.2370751}, pmid = {38910554}, issn = {1554-8635}, abstract = {Excessive macroautophagy/autophagy leads to pancreatic β-cell failure that contributes to the development of diabetes. Our previous study proved that the occurrence of deleterious hyperactive autophagy attributes to glucolipotoxicity-induced NR3C1 activation. Here, we explored the potential protective effects of (-)-epigallocatechin 3-gallate (EGCG) on β-cell-specific NR3C1 overexpression mice in vivo and NR3C1-enhanced β cells in vitro. We showed that EGCG protects pancreatic β cells against NR3C1 enhancement-induced failure through inhibiting excessive autophagy. RNA demethylase FTO (FTO alpha-ketoglutarate dependent dioxygenase) caused diminished m[6]A modifications on mRNAs of three pro-oxidant genes (Tlr4, Rela, Src) and, hence, oxidative stress occurs; by contrast, EGCG promotes FTO degradation by the ubiquitin-proteasome system in NR3C1-enhanced β cells, which alleviates oxidative stress, and thereby prevents excessive autophagy. Moreover, FTO overexpression abolishes the beneficial effects of EGCG on β cells against NR3C1 enhancement-induced damage. Collectively, our results demonstrate that EGCG protects pancreatic β cells against NR3C1 enhancement-induced excessive autophagy through suppressing FTO-stimulated oxidative stress, which provides novel insights into the mechanisms for the anti-diabetic effect of EGCG.Abbreviation 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ad: adenovirus; ALD: aldosterone; AUC: area under curve; βNR3C1 mice: pancreatic β-cell-specific NR3C1 overexpression mice; Ctrl: control; CHX: cycloheximide; DEX: dexamethasone; DHE: dihydroethidium; EGCG: (-)-epigallocatechin 3-gallate; FTO: FTO alpha-ketoglutarate dependent dioxygenase; GSIS: glucose-stimulated insulin secretion; HFD: high-fat diet; HG: high glucose; i.p.: intraperitoneal; IOD: immunofluorescence optical density; KSIS: potassium-stimulated insulin secretion; m[6]A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NO: nitric oxide; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NAC: N-acetylcysteine; NC: negative control; PBS: phosphate-buffered saline; PI: propidium iodide; OCR: oxygen consumption rate; Palm.: palmitate; RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); RNA-seq: RNA sequencing; O2[.-]: superoxide anion; SRC: Rous sarcoma oncogene; ROS: reactive oxygen species; T2D: type 2 diabetes; TEM: transmission electron microscopy; TLR4: toll-like receptor 4; TUNEL: terminal dUTP nick-end labeling; UTR: untranslated region; WT: wild-type.}, }
@article {pmid38947789, year = {2024}, author = {Gad, FA and Abdelghaffar Emam, M and Eldeeb, AA and Abdelhameed, AA and Soliman, MM and Alotaibi, KS and Albattal, SB and Abughrien, B}, title = {Mitigative Effects of l-Arginine and N-Acetyl Cysteine against Cisplatin-Induced Testicular Dysfunction and Toxicity through the Regulation of Antioxidant, Anti-inflammatory, and Antiapoptotic Markers: Role of miR-155 and miR-34c Expression.}, journal = {ACS omega}, volume = {9}, number = {25}, pages = {27680-27691}, pmid = {38947789}, issn = {2470-1343}, abstract = {Testicular dysfunction is a common adverse effect of cisplatin (CIS) administration as a chemotherapeutic drug. The current study has outlined the role of micro-RNAs (miR-155 and 34c) in CIS-induced testicular dysfunction and evaluated the protective effect of N-acetyl cysteine (NAC) and/or l-arginine (LA). Seven groups of Albino rats were used for this study. The control (C) group received physiological saline; the CIS group was injected CIS (7 mg/kg IP, once) on day 21 of the experiment; the NAC group was administered NAC (150 mg/kg intragastric, for 28 days); and the LA group was injected LA (50 mg/kg IP, for 28 days). NAC+CIS, LA+CIS, and NAC+LA+CIS groups received the above regime. CIS significantly reduced serum testosterone, LH, and FSH concentrations with decline of testicular enzyme activities. CIS caused significant elevation in testicular oxidative-stress biomarkers, inflammation-associated cytokines, and apoptosis markers, along with overexpression of miR-155 and low miR-34c expression. Additionally, marked testicular degenerative changes were observed in the examined histological section; a significant decrease in the expression of PCNA with significant increase in expressions of F4/80 and BAX was confirmed. The administration of NAC or LA upregulated testicular functions and improved histopathological and immunohistochemical changes as well as miRNA expression compared with the CIS-administered group. Rats receiving both NAC and LA showed a more significant ameliorative effect compared with groups receiving NAC or LA alone. In conclusion, NAC or LA showed an ameliorative effect against CIS-induced testicular toxicity and dysfunction through the regulation of antioxidant, anti-inflammatory, and antiapoptotic markers and via modulating miR-155 and miR-34c expression.}, }
@article {pmid38946815, year = {2024}, author = {Aldaghi, N and Kamalabadi-Farahani, M and Alizadeh, M and Alizadeh, A and Salehi, M}, title = {Enhancing pressure ulcer healing and tissue regeneration by using N-acetyl-cysteine loaded carboxymethyl cellulose/gelatin/sodium alginate hydrogel.}, journal = {Biomedical engineering letters}, volume = {14}, number = {4}, pages = {833-845}, pmid = {38946815}, issn = {2093-985X}, abstract = {Prolonged pressure on the skin can result in pressure ulcers, which may lead to serious complications, such as infection and tissue damage. In this study, we evaluated the effect of a carboxymethyl cellulose/gelatin/sodium alginate (CMC/Gel/Alg) hydrogel containing N-acetyl-cysteine (NAC) on the healing of pressure ulcers. Pressure ulcers were induced by applying a magnet to the dorsum of rat skin. The wounds were then treated with sterile gauze, ChitoHeal Gel[®], and CMC/Gel/Alg hydrogel dressings with or without NAC for the other groups. We evaluated the morphology, weight loss, swelling, rheology, blood compatibility, cytocompatibility, antioxidant capacity, and wound scratch of the prepared hydrogel. MTT assay revealed that the optimum concentration of NAC was 5 mg/ml, which induced higher cell proliferation and viability. Results of the histopathological evaluation showed increased wound closure, and complete re-epithelialization in the hydrogel-containing NAC group compared to the other groups. The CMC/Gel/Alg/5 mg/ml NAC hydrogel dressing showed 84% wound closure at 14 days after treatment. Immunohistochemical results showed a decrease in the level of TNF-α on day 14 compared day 7. Results of the qPCR assay revealed that NAC hydrogel increased the expression of Collagen type I and TGF-β1 and decreased MMP2 and MMP9 mRNA on the 14th day. The results suggest that the CMC/Gel/Alg/5 mg/ml NAC hydrogel with antioxidant properties is an appropriate dressing for wound healing.}, }
@article {pmid38946388, year = {2024}, author = {Sun, J and Zhang, X and Wang, L and Di Stefano, AFD and Zanin, V and Magrone, P and Yuan, Y}, title = {Author Correction: Phase I study of the pharmacokinetics and safety of single and multiple doses of intravenous N-acetylcysteine in healthy Chinese subjects.}, journal = {European review for medical and pharmacological sciences}, volume = {28}, number = {12}, pages = {3806}, doi = {10.26355/eurrev_202406_36449}, pmid = {38946388}, issn = {2284-0729}, abstract = {Eur Rev Med Pharmacol Sci 2023; 27 (24): 12103-12111-DOI: 10.26355/eurrev_202312_34808-PMID: 38164872, published online on December 22, 2023. After publication, the authors found that Table III's legend was the same as that of Table II. Therefore, Table III's legend has been corrected as follows: Table III. Plasma PK parameters following repeat doses of IV NAC 600 mg (n = 24). There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34808.}, }
@article {pmid38873925, year = {2024}, author = {Yin, Z and Zhang, J and Zhao, M and Liu, J and Xu, Y and Peng, S and Pan, W and Wei, C and Zheng, Z and Liu, S and Qin, JJ and Wan, J and Wang, M}, title = {EDIL3/Del-1 prevents aortic dissection through enhancing internalization and degradation of apoptotic vascular smooth muscle cells.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-21}, doi = {10.1080/15548627.2024.2367191}, pmid = {38873925}, issn = {1554-8635}, abstract = {Thoracic aortic dissection (TAD) is a severe disease, characterized by numerous apoptotic vascular smooth muscle cells (VSMCs). EDIL3/Del-1 is a secreted protein involved in macrophage efferocytosis in acute inflammation. Here, we aimed to investigate whether EDIL3 promoted the internalization and degradation of apoptotic VSMCs during TAD. The levels of EDIL3 were decreased in the serum and aortic tissue from TAD mice. Global edil3 knockout (edil3[-/-]) mice and edil3[-/-] bone marrow chimeric mice exhibited a considerable exacerbation in β-aminopropionitrile monofumarate (BAPN)-induced TAD, accompanied with increased apoptotic VSMCs accumulating in the damaged aortic tissue. Two types of phagocytes, RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were used for in vitro efferocytosis assay. edil3-deficient phagocytes exhibited inefficient internalization and degradation of apoptotic VSMCs. Instead, EDIL3 promoted the internalization phase through interacting with phosphatidylserine (PtdSer) on apoptotic VSMCs and binding to the macrophage ITGAV/αv-ITGB3/β3 integrin. In addition, EDIL3 accelerated the degradation phase through activating LC3-associated phagocytosis (LAP). Mechanically, following the engulfment, EDIL3 enhanced the activity of SMPD1/acid sphingomyelinase in the phagosome through blocking ITGAV-ITGB3 integrin, which facilitates phagosomal reactive oxygen species (ROS) production by NAPDH oxidase CYBB/NOX2. Furthermore, exogenous EDIL3 supplementation alleviated BAPN-induced TAD and promoted apoptotic cell clearance. EDIL3 may be a novel factor for the prevention and treatment of TAD.Abbreviations: BAPN: β-aminopropionitrile monofumarate; BMDM: bone marrow-derived macrophage; C12FDG: 5-dodecanoylaminofluorescein-di-β-D-galactopyranoside; CTRL: control; CYBB/NOX2: cytochrome b-245, beta polypeptide; DCFH-DA: 2',7'-dichlorofluorescin diacetate; EDIL3/Del-1: EGF-like repeats and discoidin I-like domains 3; EdU: 5-ethynyl-2'-deoxyuridine; EVG: elastic van Gieson; H&amp;E: hematoxylin and eosin; IL: interleukin; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NAC: N-acetylcysteine; PtdSer: phosphatidylserine; rEDIL3: recombinant EDIL3; ROS: reactive oxygen species; SMPD1: sphingomyelin phosphodiesterase 1; TAD: thoracic aortic dissection; TEM: transmission electron microscopy; VSMC: vascular smooth muscle cell; WT: wild-type.}, }
@article {pmid38718420, year = {2024}, author = {Gökalp, G and Nalbant, T and Bıcılıoğlu, Y}, title = {The Insidious Enemy of the Liver: The Situation in Childhood Acetaminophen Poisoning and Early N-AC Treatment.}, journal = {Pediatric emergency care}, volume = {40}, number = {7}, pages = {e89-e93}, doi = {10.1097/PEC.0000000000003176}, pmid = {38718420}, issn = {1535-1815}, mesh = {Humans ; *Acetaminophen/poisoning ; Retrospective Studies ; Female ; Male ; Cross-Sectional Studies ; Child ; Child, Preschool ; *Chemical and Drug Induced Liver Injury/etiology/epidemiology ; *Acetylcysteine/therapeutic use ; Infant ; Analgesics, Non-Narcotic/poisoning ; Drug Overdose ; Antidotes/therapeutic use ; Liver Transplantation ; Adolescent ; Liver ; }, abstract = {METHODS: This study was designed as a cross-sectional, observational, retrospective study. The variables of the study were paracetamol overdose, demographic information, poisoning mechanisms, clinical, laboratory findings, and clinical progression of the cases. The cases compared in whom treatment was initiated within the first 8 hours after poisoning and those in whom it was not. χ 2 , t test, and logistic regression analyses were conducted at appropriate facilities.<br><br>RESULTS: Three hundred forty-eight cases were included in the study. N-AC treatment was initiated within the first 8 hours after poisoning in 322 cases (92.5%), and 26 cases received N-AC treatment after 8 hours after poisoning. Liver toxicity developed in 6 cases (1.7%), and indications for liver transplantation were met in 36 cases (10.3%). Among the 26 cases for which treatment was not initiated within the first 8 hours, 18 cases (69.2%) had indications for liver transplantation (P < 0.01). It was found that N-AC within the first 8 hours reduced the risk by 43 times (P = 0.02) and being older than 6 years, being admitted to the intensive care unit, and having alanine aminotransferase values above 1000 U/L increased the risk significantly (P = 0.009, P = 0.005, P < 0.001). When a receiver operating characteristic curve was plotted for the 4th-hour blood acetaminophen level to predict liver transplantation, a value of 684.5 &#x3bc;g/mL emerged with 89% sensitivity and 93% specificity (area under the curve, 0.951).<br><br>CONCLUSIONS: As a result, this study demonstrates the protective effect of early-initiated N-AC therapy on liver toxicity in pediatric acetaminophen poisoning cases. It also highlights a significant impact of gastrointestinal decontamination methods.}, }
@article {pmid38944154, year = {2024}, author = {Higham, CS and Shimano, KA and Kharbanda, S and Chu, J and Cisneros, GS and Winestone, LE and Dara, J and Huang, JN and Hermiston, ML and Long-Boyle, JR and Dvorak, CC}, title = {Cyclophosphamide and thiotepa increases risk of transplant-associated thrombotic microangiopathy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2024.06.020}, pmid = {38944154}, issn = {2666-6367}, abstract = {BACKGROUND: Transplant associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic cell transplant (HCT) associated with endothelial injury resulting in severe end organ damage, acute and long-term morbidity, and mortality. Myeloablative conditioning is a known risk factor, though specific causative agents have not been identified. We hypothesized that the combination of cyclophosphamide and thiotepa (CY+TT) is particularly toxic to the endothelium, placing patients at elevated risk for TA-TMA.<br><br>METHODS: We conducted a retrospective review of pediatric and young adult patients who received conditioned autologous and allogeneic HCT between 2012 and August 2023 at UCSF Benioff Children's Hospital, San Francisco. We excluded patients undergoing gene therapy or triple tandem transplants for brain tumors. Neuroblastoma tandem transplants were classified a single transplant occurrence. High dose N-acetylcysteine (NAC) prophylaxis was incorporated into the institutional standard of care from December 2016-May 2019 and May 2022-August 2023. Defibrotide was given prophylactically to patients deemed high-risk for sinusoidal obstruction syndrome (SOS) per institutional guidelines or on clinical trial NCT#02851407 for SOS prophylaxis or NCT#03384693 for TA-TMA prophylaxis. Kaplan-Meier analysis was used to estimate the 1-year cumulative incidence of TA-TMA. Univariate analysis was performed for each of the potential risk factors of interest using log-rank tests and bivariate analysis with Cox regression models using backward selection and hazard ratios were built using all covariates with a univariate p-value <0.2 for allogeneic HCT. SPSS (v29) was used to estimate all summary statistics, cumulative incidences, and uni- and bi-variate analyses.<br><br>RESULTS: A total of 558 transplants were performed with 43 patients developing TA-TMA, for a 1-year cumulative incidence of 8.6% (95% CI, 5.9-11.3%) and 7.2% (95% CI, 2.9-11.5%) in allogeneic and autologous HCTs, respectively (p=0.62). In allogeneic recipients (n=417), the 1-year cumulative incidence of TA-TMA with CY+TT as part of conditioning was 35.7% (95% CI, 15.7-55.7%) compared to 11.7% (95% CI, 7.2-16.2%) with either CY or TT alone, and 1.2% (95% CI, 0-2.8%) if neither agent was included in the conditioning regimen (p<0.001). Use of either CY or TT (HR=10.14; p=0.002) or CY+TT (HR=35.93; p<0.001), viral infections (HR=4.3; p=0.017) and fungal infections (HR=2.98; p=0.027) were significant factors resulting in increased risk for developing TA-TMA. In subjects undergoing autologous HCT (n=141), the 1-year cumulative incidence of TA-TMA with CY+TT was 19.6% (95% CI, 8.8-30.6%) while TA-TMA did not occur in patients receiving either CY or TT alone or when neither were included (p<0.001). TA-TMA occurred only in patients with neuroblastoma receiving CY+TT as part of their conditioning. For autologous patients who received CY+TT, those who were CMV seronegative at the time of HCT had an incidence of TA-TMA of 6.7% (95% CI, 0.1-15.7%) compared to 38.1% (95% CI, 35-41.2%) for those CMV seropositive (p=0.007).<br><br>CONCLUSIONS: These data show that CY or TT alone or in combination as part of pre-transplant conditioning prior to HCT increase the incidence of TA-TMA. Alternative conditioning excluding the combination of CY+TT should be considered whenever possible to limit the development of TA-TMA.}, }
@article {pmid38943148, year = {2024}, author = {Üstüner, E and Yıldırım, E and Macun, HC and Ekici, H and Şahin, Y and Güncüm, E and Anteplioğlu, T and Elifoğlu, TB and Bozkaya, E}, title = {Ultrasonographic and histopathological investigation of the effect of N-acetylcysteine on doxorubicin-induced ovarian and uterine toxicity in rats.}, journal = {Journal of ovarian research}, volume = {17}, number = {1}, pages = {135}, pmid = {38943148}, issn = {1757-2215}, mesh = {Animals ; Female ; *Doxorubicin/toxicity ; *Acetylcysteine/pharmacology/therapeutic use ; Rats ; *Ovary/drug effects/pathology/diagnostic imaging ; *Ultrasonography ; *Uterus/drug effects/pathology/diagnostic imaging ; Antibiotics, Antineoplastic/toxicity/adverse effects ; }, abstract = {BACKGROUND: This study aimed to investigate the mitigating effect of N-acetylcysteine (NAC) on doxorubicin (DOX)-induced ovarian and uterine toxicity in rats using laboratory tests, ultrasonographic (US) imaging, and histopathology analysis.<br><br>METHODS: Forty-eight rats were divided into six groups (n&#x2009;=&#x2009;8) as follows: Group A (control) (0.5 mL saline administered intraperitoneally [IP]), Group B (a single 10&#xa0;mg/kg dose of DOX administered IP on day 1), Group C (a single 10&#xa0;mg/kg dose of DOX administered IP 24&#xa0;h before sacrifice), Group D (100&#xa0;mg/kg of NAC administered IP for 21 days), Group E (a single 10&#xa0;mg/kg dose of DOX administered IP on day 1 and 100&#xa0;mg/kg of NAC administered IP for 21 days), and Group F (100&#xa0;mg/kg of NAC administered IP for 21 days and a single 10&#xa0;mg/kg dose of DOX administered IP 24&#xa0;h before sacrifice). The ovaries were examined using B-mode US on days 1, 14, and 21, and the histopathological examinations of the ovaries and the uterus were undertaken after sacrifice on day 22.<br><br>RESULTS: Histomorphological analyses showed that ovarian weight decreased after DOX administration in Group B but not in Group E. US revealed a transient increase in ovarian size in Group B and E, reverting to baseline levels over time, as well as a progressive increase in peritoneal fluid in Groups B and E. Group B exhibited a significant decrease in the thickness of the endometrium and myometrium and uterine cornual length, which was not observed in Group E. Histopathological examination showed that DOX caused a decline in follicular count, especially in primordial, secondary, and Graafian follicles, and resulted in follicular atresia, predominantly in Group B. Destructive degeneration/necrosis and vascular changes were most prominently seen in the corpus luteum of Groups C and B. In NAC-treated rats (Groups E and F), although germ cell damage was present, atretic follicles and vascular changes, such as hyperemia and congestion, were reduced. The anti-m&#xfc;llerian hormone (AMH) level was the highest in Group F.<br><br>CONCLUSIONS: NAC, an antioxidant, attenuated DOX-induced gonadotoxicity in rats.}, }
@article {pmid38936520, year = {2024}, author = {Tang, M and Xia, W and Song, F and Liu, C and Wang, X and Zhou, H and Mai, K and He, G}, title = {Loss of Gcn2 exacerbates gossypol induced oxidative stress, apoptosis and inflammation in zebrafish.}, journal = {Fish &amp; shellfish immunology}, volume = {}, number = {}, pages = {109727}, doi = {10.1016/j.fsi.2024.109727}, pmid = {38936520}, issn = {1095-9947}, abstract = {Gossypol, a naturally occurring compound found in cottonseed meal, shows promising therapeutic potential for human diseases. However, within the aquaculture industry, it is considered an antinutritional factor. The incorporation of cottonseed meal into fish feed introduces gossypol, which induces intracellular stresses and hinders overall health of farmed fish. The aim of this study is to determine the role of General control nonderepressible 2 (gcn2), a sensor for intracellular stresses in gossypol-induced stress responses in fish. In the present study, we established two gcn2 knockout zebrafish lines. A feeding trial was conducted to assess the growth-inhibitory effect of gossypol in both wild type and gcn2 knockout zebrafish. The results showed that in the absence of gcn2, zebrafish exhibited increased oxidative stress and apoptosis when exposed to gossypol, resulting in higher mortality rates. In feeding trial, dietary gossypol intensified liver inflammation in gcn2[-/-] zebrafish, diminishing their growth and feed conversion. Remarkably, administering the antioxidant N-acetylcysteine (NAC) was effective in reversing the gossypol induced oxidative stress and apoptosis, thereby increasing the gossypol tolerance of gcn2[-/-] zebrafish. Exposure to gossypol induces more severe mitochondrial stress in gcn2[-/-] zebrafish, thereby inducing metabolic disorders. These results reveal that gcn2 plays a protective role in reducing gossypol-induced oxidative stress and apoptosis, attenuating inflammation responses, and enhancing the survivability of zebrafish in gossypol-challenged conditions. Therefore, maintaining appropriate activation of Gcn2 may be beneficial for fish fed diets containing gossypol.}, }
@article {pmid38929087, year = {2024}, author = {Dobariya, P and Xie, W and Rao, SP and Xie, J and Seelig, DM and Vince, R and Lee, MK and More, SS}, title = {Deletion of Glyoxalase 1 Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {6}, pages = {}, doi = {10.3390/antiox13060648}, pmid = {38929087}, issn = {2076-3921}, support = {R01-AG062469/NH/NIH HHS/United States ; NA//Center for Drug Design, Research Endowment Funds/ ; }, abstract = {Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose.}, }
@article {pmid38928002, year = {2024}, author = {Dymanowska-Dyjak, I and Frankowska, K and Abramiuk, M and Polak, G}, title = {Oxidative Imbalance in Endometriosis-Related Infertility-The Therapeutic Role of Antioxidants.}, journal = {International journal of molecular sciences}, volume = {25}, number = {12}, pages = {}, doi = {10.3390/ijms25126298}, pmid = {38928002}, issn = {1422-0067}, support = {DS121//Medical University of Lublin/ ; }, mesh = {*Endometriosis/metabolism/drug therapy/complications ; Humans ; Female ; *Antioxidants/therapeutic use ; *Oxidative Stress/drug effects ; *Infertility, Female/etiology/metabolism/drug therapy ; Acetylcysteine/therapeutic use/pharmacology ; }, abstract = {Endometriosis in half of affected women is closely related to problems with fertility. Endometriosis-associated infertility is caused by a wide range of abnormalities affecting the female reproductive tract, from oocyte quality impairment to disturbances in the eutopic endometrium or mechanical abnormalities resulting from disease progression. Since supportive antioxidant therapies, in addition to surgical treatment or assisted reproductive techniques (ARTs), have overall been proven to be effective tools in endometriosis management, the objective of our review was to analyze the role of antioxidant substances, including vitamins, micronutrients, N-acetylcysteine (NAC), curcumin, melatonin, and resveratrol, in endometriosis-related infertility. Most of these substances have been proven to alleviate the systemic oxidant predominance, which has been expressed through decreased oxidative stress (OS) markers and enhanced antioxidative defense. In addition, we demonstrated that the predominant effect of the aforementioned substances is the inhibition of the development of endometriotic lesions as well as the suppression of pro-inflammatory molecules. Although we can undoubtedly conclude that antioxidants are beneficial in fertility support, further studies explaining the detailed pathways of their action are needed.}, }
@article {pmid38923010, year = {2024}, author = {Gong, Z and Yang, S and Ling, S and Wang, H and Xu, X and Lin, Z}, title = {Dermatopathological features and successful treatment with topical antioxidant for ichthyosiform lesions in Mitchell syndrome caused by an ACOX1 variant.}, journal = {The Journal of dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1111/1346-8138.17346}, pmid = {38923010}, issn = {1346-8138}, support = {82373459//National Natural Science Foundation of China/ ; 82373500//National Natural Science Foundation of China/ ; }, abstract = {Peroxisomal acyl-CoA oxidase 1 (ACOX1), is a peroxisomal enzyme that catalyzes β-oxidation of very-long-chain fatty acids (VLCFA). The gain-of-function variant p.Asn237Ser in ACOX1 has been shown to cause Mitchell syndrome (MITCH), a neurodegenerative disorder characterized by episodic demyelination, hearing loss, and polyneuropathy, through the overproduction of hydrogen peroxide. Only eight cases of MITCH have been reported. While all these patients experienced cutaneous abnormalities, detailed skin features and potential treatment have not been documented. Herein, we report two MITCH patients who harbored a de novo heterozygous variant p.Asn237Ser in ACOX1 and experienced progressive ichthyosiform erythroderma. Skin histopathology revealed hyperkeratosis and parakeratosis with focal hypogranulosis as well as dyskeratotic keratinocytes. Lipid accumulation in the epidermis was observed using Oil Red O staining. Both patients exhibited a remarkable response to treatment with the topical antioxidant N-acetylcysteine (NAC), with Patient 1 achieving complete recovery after 3 months of consistent treatment. This study provides the first comprehensive description of the clinicopathological characteristics and effective treatment of skin lesions in MITCH patients. The successful treatment with topical NAC suggests excessive reactive oxygen species might play a significant role in the pathogenesis of skin lesions in MITCH.}, }
@article {pmid38918702, year = {2024}, author = {Kagemichi, N and Umemura, M and Ishikawa, S and Iida, Y and Takayasu, S and Nagasako, A and Nakakaji, R and Akimoto, T and Ohtake, M and Horinouchi, T and Yamamoto, T and Ishikawa, Y}, title = {Cytotoxic effects of the cigarette smoke extract of heated tobacco products on human oral squamous cell carcinoma: the role of reactive oxygen species and CaMKK2.}, journal = {The journal of physiological sciences : JPS}, volume = {74}, number = {1}, pages = {35}, pmid = {38918702}, issn = {1880-6562}, mesh = {Humans ; *Reactive Oxygen Species/metabolism ; *Mouth Neoplasms/metabolism/pathology ; Cell Line, Tumor ; *Smoke/adverse effects ; *Carcinoma, Squamous Cell/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism ; *Tobacco Products/adverse effects ; Apoptosis/drug effects ; Nicotiana/chemistry ; Calcium/metabolism ; Cell Survival/drug effects ; }, abstract = {BACKGROUND: The increasing prevalence of heated tobacco products (HTPs) has heightened concerns regarding their potential health risks. Previous studies have demonstrated the toxicity of cigarette smoke extract (CSE) from traditional tobacco's mainstream smoke, even after the removal of nicotine and tar. Our study aimed to investigate the cytotoxicity of CSE derived from HTPs and traditional tobacco, with a particular focus on the role of reactive oxygen species (ROS) and intracellular Ca[2+].<br><br>METHODS: A human oral squamous cell carcinoma (OSCC) cell line, HSC-3 was utilized. To prepare CSE, aerosols from HTPs (IQOS) and traditional tobacco products (1R6F reference cigarette) were collected into cell culture media. A cell viability assay, apoptosis assay, western blotting, and Fluo-4 assay were conducted. Changes in ROS levels were measured using electron spin resonance spectroscopy and the high-sensitivity 2',7'-dichlorofluorescein diacetate assay. We performed a knockdown of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) by shRNA lentivirus in OSCC cells.<br><br>RESULTS: CSE from both HTPs and traditional tobacco exhibited cytotoxic effects in OSCC cells. Exposure to CSE from both sources led to an increase in intracellular Ca[2+] concentration and induced p38 phosphorylation. Additionally, these extracts prompted cell apoptosis and heightened ROS levels. N-acetylcysteine (NAC) mitigated the cytotoxic effects and p38 phosphorylation. Furthermore, the knockdown of CaMKK2 in HSC-3 cells reduced cytotoxicity, ROS production, and p38 phosphorylation in response to CSE.<br><br>CONCLUSION: Our findings suggest that the CSE from both HTPs and traditional tobacco induce cytotoxicity. This toxicity is mediated by ROS, which are regulated through Ca[2+] signaling and CaMKK2 pathways.}, }
@article {pmid38915482, year = {2024}, author = {Mudambi, S and Fitzgerald, ME and Washington, DL and Pera, PJ and Huss, WJ and Paragh, G}, title = {Dual targeting of KDM1A and antioxidants is an effective anticancer strategy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.06.12.597953}, pmid = {38915482}, abstract = {Lysine Specific Demethylase 1 (KDM1A / LSD1) regulates mitochondrial respiration and stabilizes HIF-1A (hypoxia-inducible factor 1A). HIF-1A modulates reactive oxygen species (ROS) levels by increasing cellular glucose uptake, glycolysis, and endogenous antioxidants. The role of KDM1A in cellular ROS response has not previously been described. We determined the role of KDM1A in regulating the ROS response and the utility of KDM1A inhibitors in combination with ROS-inducing cancer therapies. Our results show that KDM1A inhibition sensitized cells to oxidative stress and increased total cellular ROS, which was mitigated by treatment with the antioxidant N-acetyl cysteine. KDM1A inhibition decreased basal mitochondrial respiration and impaired induction of HIF-1A after ROS exposure. Overexpression of HIF-1A salvaged cells from KDM1A inhibition enhanced sensitivity to ROS. Thus we found that increased sensitivity of ROS after KDM1A inhibition was mediated by HIF-1A and depletion of endogenous glutathione. We also show that KDM1A-specific inhibitor bizine synergized with antioxidant-depleting therapies, buthionine sulfoximine, and auranofin in rhabdomyosarcoma cell lines (Rh28 and Rh30). In this study, we describe a novel role for KDM1A in regulating HIF- 1A functions under oxidative stress and found that dual targeting of KDM1A and antioxidant systems may serve as an effective combination anticancer strategy.}, }
@article {pmid38904252, year = {2024}, author = {Panja, S and Nahomi, RB and Rankenberg, J and Michel, CR and Nagaraj, RH}, title = {Thiol-Mediated Enhancement of N[ε]-Acetyllysine Formation in Lens Proteins.}, journal = {ACS chemical biology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschembio.4c00174}, pmid = {38904252}, issn = {1554-8937}, abstract = {Lysine acetylation (AcK) is a prominent post-translational modification in eye lens crystallins. We have observed that AcK formation is preferred in some lysine residues over others in crystallins. In this study, we have investigated the role of thiols in such AcK formation. Upon incubation with acetyl-CoA (AcCoA), αA-Crystallin, which contains two cysteine residues, showed significantly higher levels of AcK than αB-Crystallin, which lacks cysteine residues. Incubation with thiol-rich γS-Crystallin resulted in higher AcK formation in αB-Crystallin from AcCoA. External free thiol (glutathione and N-acetyl cysteine) increased the AcK content in AcCoA-incubated αB-Crystallin. Reductive alkylation of cysteine residues significantly decreased (p < 0.001) the AcCoA-mediated AcK formation in αA-Crystallin. Introduction of cysteine residues within ∼5 Å of lysine residues (K92C, E99C, and V169C) in αB-Crystallin followed by incubation with AcCoA resulted in a 3.5-, 1.3- and 1.3-fold increase in the AcK levels when compared to wild-type αB-Crystallin, respectively. Together, these results suggested that AcK formation in α-Crystallin is promoted by the proximal cysteine residues and protein-free thiols through an S → N acetyl transfer mechanism.}, }
@article {pmid38899269, year = {2024}, author = {Qadir, NA and Stachler, L and Reddy, AD and Diaz-Garcia, G and Sottile, E}, title = {Polysubstance-Induced Hepatotoxicity and the Role of Supportive Management.}, journal = {Cureus}, volume = {16}, number = {5}, pages = {e60649}, pmid = {38899269}, issn = {2168-8184}, abstract = {With the continued rise of polysubstance use throughout the country, it has been shown to affect a multitude of organ systems. Drug-induced liver injury (DILI) has been widely documented in its association with salicylates or acetaminophen and the utility of using N-acetylcysteine (NAC) for its hepatoprotective effects. However, DILI caused by illicit drug use and guideline-directed management has had little research. We present the case of a 29-year-old female who presented with altered mental status. She was found to have a concomitant liver injury and was treated supportively without the use of NAC, with gradual improvement.}, }
@article {pmid38899149, year = {2024}, author = {Zou, H and Boboltz, A and Cheema, Y and Song, D and Cahn, D and Duncan, GA}, title = {Synthetic mucus barrier arrays as a nanoparticle formulation screening platform.}, journal = {RSC pharmaceutics}, volume = {1}, number = {2}, pages = {218-226}, pmid = {38899149}, issn = {2976-8713}, abstract = {A mucus gel layer lines the luminal surface of tissues throughout the body to protect them from infectious agents and particulates. As a result, nanoparticle drug delivery systems delivered to these sites may become trapped in mucus and subsequently cleared before they can reach target cells. As such, optimizing the properties of nanoparticle delivery vehicles, such as their surface chemistry and size, is essential to improving their penetration through the mucus barrier. In previous work, we developed a mucin-based hydrogel that has viscoelastic properties like that of native mucus which can be further tailored to mimic specific mucosal tissues and disease states. Using this biomimetic hydrogel system, a 3D-printed array containing synthetic mucus barriers was created that is compatible with a 96-well plate enabling its use as a high-throughput screening platform for nanoparticle drug delivery applications. To validate this system, we evaluated several established design parameters to determine their impact on nanoparticle penetration through synthetic mucus barriers. Consistent with the literature, we found nanoparticles of smaller size and coated with a protective PEG layer more efficiently penetrated through synthetic mucus barriers. In addition, we evaluated a mucolytic (tris(2-carboxyethyl) phosphine, TCEP) for use as a permeation enhancer for mucosal drug delivery. In comparison to N-acetyl cysteine (NAC), we found TCEP significantly improved nanoparticle penetration through a disease-like synthetic mucus barrier. Overall, our results establish a new high-throughput screening approach using synthetic mucus barrier arrays to identify promising nanoparticle formulation strategies for drug delivery to mucosal tissues.}, }
@article {pmid38897422, year = {2024}, author = {Russell-Guzmán, J and Américo-Da Silva, L and Cadagan, C and Maturana, M and Palomero, J and Estrada, M and Barrientos, G and Buvinic, S and Hidalgo, C and Llanos, P}, title = {Activation of the ROS/TXNIP/NLRP3 pathway disrupts insulin-dependent glucose uptake in skeletal muscle of insulin-resistant obese mice.}, journal = {Free radical biology &amp; medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.freeradbiomed.2024.06.011}, pmid = {38897422}, issn = {1873-4596}, abstract = {Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined. Here, we induced insulin resistance in C57BL/6J mice by feeding them for 8 weeks with a high-fat diet (HFD) and explored whether the ROS/TXNIP/NLRP3 pathway was involved in the induction of insulin resistance in skeletal muscle. Skeletal muscle fibers from insulin-resistant mice exhibited increased oxidative stress, as evidenced by elevated malondialdehyde levels, and altered peroxiredoxin 2 dimerization. Additionally, these fibers displayed augmented activation of the NLRP3 inflammasome, accompanied by heightened ROS-dependent proximity between TXNIP and NLRP3, which was abolished by the antioxidant N-acetylcysteine (NAC). Inhibition of the NLRP3 inflammasome with MCC950 or suppressing the ROS/TXNIP/NLRP3 pathway with NAC restored insulin-dependent glucose uptake in muscle fibers from insulin-resistant mice. These findings provide insights into the mechanistic link between oxidative stress, NLRP3 inflammasome activation, and obesity-induced insulin resistance in skeletal muscle.}, }
@article {pmid38892556, year = {2024}, author = {Liu, M and You, Y and Zhu, H and Chen, Y and Hu, Z and Duan, J}, title = {N-Acetylcysteine Alleviates Impaired Muscular Function Resulting from Sphingosine Phosphate Lyase Functional Deficiency-Induced Sphingoid Base and Ceramide Accumulation in Caenorhabditis elegans.}, journal = {Nutrients}, volume = {16}, number = {11}, pages = {}, pmid = {38892556}, issn = {2072-6643}, support = {82171551//National Natural Science Foundation of China/ ; 20232ACB205002//Jiangxi Provincial Natural Science Foundation/ ; }, mesh = {Animals ; *Caenorhabditis elegans/drug effects ; *Acetylcysteine/pharmacology ; *Ceramides/metabolism ; *Aldehyde-Lyases/metabolism ; *Sphingolipids/metabolism ; Reactive Oxygen Species/metabolism ; Antioxidants/pharmacology/metabolism ; Muscles/drug effects/metabolism ; RNA Interference ; Sphingosine/analogs &amp; derivatives/metabolism ; }, abstract = {Sphingosine-1-phosphate lyase (SPL) resides at the endpoint of the sphingolipid metabolic pathway, catalyzing the irreversible breakdown of sphingosine-1-phosphate. Depletion of SPL precipitates compromised muscle morphology and function; nevertheless, the precise mechanistic underpinnings remain elusive. Here, we elucidate a model of SPL functional deficiency in Caenorhabditis elegans using spl-1 RNA interference. Within these SPL-deficient nematodes, we observed diminished motility and perturbed muscle fiber organization, correlated with the accumulation of sphingoid bases, their phosphorylated forms, and ceramides (collectively referred to as the "sphingolipid rheostat"). The disturbance in mitochondrial morphology was also notable, as SPL functional loss resulted in heightened levels of reactive oxygen species. Remarkably, the administration of the antioxidant N-acetylcysteine (NAC) ameliorates locomotor impairment and rectifies muscle fiber disarray, underscoring its therapeutic promise for ceramide-accumulation-related muscle disorders. Our findings emphasize the pivotal role of SPL in preserving muscle integrity and advocate for exploring antioxidant interventions, such as NAC supplementation, as prospective therapeutic strategies for addressing muscle function decline associated with sphingolipid/ceramide metabolism disruption.}, }
@article {pmid38892427, year = {2024}, author = {Calderón Guzmán, D and Osnaya Brizuela, N and Ortíz Herrera, M and Valenzuela Peraza, A and Labra Ruíz, N and Juárez Olguín, H and Santamaria Del Angel, D and Barragán Mejía, G}, title = {N-Acetylcysteine Attenuates Cisplatin Toxicity in the Cerebrum and Lung of Young Rats with Artificially Induced Protein Deficiency.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38892427}, issn = {1422-0067}, mesh = {Animals ; *Cisplatin/adverse effects/toxicity ; *Acetylcysteine/pharmacology ; Rats ; *Rats, Wistar ; *Lung/drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; Male ; Cerebrum/drug effects/metabolism ; Glutathione/metabolism ; Neuroprotective Agents/pharmacology ; Antineoplastic Agents/adverse effects ; }, abstract = {Neurotoxicity is a major obstacle in the effectiveness of Cisplatin in cancer chemotherapy. In this process, oxidative stress and inflammation are considered to be the main mechanisms involved in brain and lung toxicity. The aim of the present work was to study the influence of the amount of protein on some oxidative parameters in the brain and lungs of rats treated with Cisplatin (CP) and N-Acetylcysteine (NAC) as neuroprotectors. Four groups of Wistar rats, each containing six animals, were fed with a protein diet at 7% for 15 days. Thereafter, the groups were given either a unique dose of CP[®] 5 mg/kg or NAC[®] 5 mg/kg as follows: group 1 (control), NaCl 0.9% vehicle; group 2, CP; group 3, NAC; and group 4, NAC + CP. The animals were sacrificed immediately after the treatments. Blood samples were collected upon sacrifice and used to measure blood triglycerides and glucose. The brain and lungs of each animal were obtained and used to assay lipid peroxidation (TBARS), glutathione (GSH), serotonin metabolite (5-HIAA), catalase, and the activity of Ca[+2], and Mg[+2] ATPase using validated methods. TBARS, H2O2, and GSH were found to be significantly decreased in the cortex and cerebellum/medulla oblongata of the groups treated with CP and NAC. The total ATPase showed a significant increase in the lung and cerebellum/medulla oblongata, while 5-HIAA showed the same tendency in the cortex of the same group of animals. The increase in 5-HIAA and ATPase during NAC and CP administration resulted in brain protection. This effect could be even more powerful when membrane fluidity is increased, thus proving the efficacy of combined NAC and CP drug therapy, which appears to be a promising strategy for future chemotherapy in malnourished patients.}, }
@article {pmid38892239, year = {2024}, author = {Wrotek, A and Badyda, A and Jackowska, T}, title = {Molecular Mechanisms of N-Acetylcysteine in RSV Infections and Air Pollution-Induced Alterations: A Scoping Review.}, journal = {International journal of molecular sciences}, volume = {25}, number = {11}, pages = {}, pmid = {38892239}, issn = {1422-0067}, support = {501-1-020-19-23.//Centre of Postgraduate Medical Education in Warsaw/ ; }, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Respiratory Syncytial Virus Infections/drug therapy/virology/metabolism ; Animals ; *Air Pollution/adverse effects ; ErbB Receptors/metabolism ; }, abstract = {N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important etiological factors of lower respiratory tract infections, and exposure to air pollution appears to be additionally associated with higher RSV incidence and disease severity. We aimed to systematically review the existing literature to determine which molecular mechanisms mediate the effects of NAC in an RSV infection and air pollution, and to identify the knowledge gaps in this field. A search for original studies was carried out in three databases and a calibrated extraction grid was used to extract data on the NAC treatment (dose, timing), the air pollutant type, and the most significant mechanisms. We identified only 28 studies conducted in human cellular models (n = 18), animal models (n = 7), and mixed models (n = 3). NAC treatment improves the barrier function of the epithelium damaged by RSV and air pollution, and reduces the epithelial permeability, protecting against viral entry. NAC may also block RSV-activated phosphorylation of the epidermal growth factor receptor (EGFR), which promotes endocytosis and facilitates cell entry. EGFR also enhances the release of a mucin gene, MUC5AC, which increases mucus viscosity and causes goblet cell metaplasia; the effects are abrogated by NAC. NAC blocks virus release from the infected cells, attenuates the cigarette smoke-induced shift from necrosis to apoptosis, and reverses the block in IFN-γ-induced antiviral gene expression caused by the inhibited Stat1 phosphorylation. Increased synthesis of pro-inflammatory cytokines and chemokines is induced by both RSV and air pollutants and is mediated by the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that are activated in response to oxidative stress. MCP-1 (monocyte chemoattractant protein-1) and RANTES (regulated upon activation, expressed and secreted by normal T cells) partially mediate airway hyperresponsiveness (AHR), and therapeutic (but not preventive) NAC administration reduces the inflammatory response and has been shown to reduce ozone-induced AHR. Oxidative stress-induced DNA damage and cellular senescence, observed during RSV infection and exposure to air pollution, can be partially reversed by NAC administration, while data on the emphysema formation are disputed. The review identified potential common molecular mechanisms of interest that are affected by NAC and may alleviate both the RSV infection and the effects of air pollution. Data are limited and gaps in knowledge include the optimal timing or dosage of NAC administration, therefore future studies should clarify these uncertainties and verify its practical use.}, }
@article {pmid38891420, year = {2024}, author = {Alatta, A and Nassar, M and Gorduysus, M and Alkhatib, W and Sayed, M}, title = {In Vitro Investigation of the Effects of Various Reducing Agents on Dentin Treated with Hydrogen Peroxide.}, journal = {Polymers}, volume = {16}, number = {11}, pages = {}, pmid = {38891420}, issn = {2073-4360}, support = {Research Project (G20) ID (89).//This research was supported by the Office of Vice Chancellor for Research and Graduate Studies, University of Sharjah, Sharjah, United Arab Emirates./ ; }, abstract = {We assessed the effect of non-protein thiols (NPSH), reduced glutathione (GSH) and n-acetylcysteine (NAC), on resin shear bond strength (SBS) to hydrogen peroxide (H2O2)-treated dentin, and their effects on the characteristics of dentin in comparison to ascorbic acid (AA) and sodium thiosulfate (STS). H2O2-treated dentin was conditioned with 5% AA, GSH, NAC, or STS applied for 1 or 5 min. The positive control group received H2O2 without antioxidant application, and the first negative control group received distilled water (DW). The specimens received resin bonding immediately after treatment except for the second negative control group (delayed bonding). Microhardness, roughness, and topography were studied. The SBS values of all antioxidants were statistically greater than the positive control group (p < 0.05); however, NAC and AA applied for 1 min demonstrated the highest values, which were comparable to delayed bonding. All treatments removed the smear layer except DW, H2O2, and STS. The negative effect of H2O2 on resin-dentin bonding was mitigated by the application of the antioxidants; however, their efficiencies were dependent on the antioxidant type and time of application. NAC was more effective in optimizing resin bonding to bleached dentin compared to GSH at 1 min application and STS at both application times but was comparable to AA. Negligible negative effects on the substrate's roughness and microhardness were detected. The antioxidant properties of the agent and its capacity to remove the smear layer are the processes underpinning the ability of a certain antioxidant to reverse the effect of H2O2 on bonding.}, }
@article {pmid38885324, year = {2024}, author = {Li, L and Xie, D and Yu, S and Ma, M and Fan, K and Chen, J and Xiu, M and Xie, K and Li, Y and Yong, G}, title = {WNK1 Interaction with KEAP1 Promotes NRF2 Stabilization to Enhance the Oxidative Stress Response in Hepatocellular Carcinoma.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-23-1167}, pmid = {38885324}, issn = {1538-7445}, abstract = {Cellular oxidative stress plays a key role in the development and progression of hepatocellular carcinoma (HCC). A better understanding of the processes that regulate reactive oxygen species (ROS) homeostasis could uncover improved strategies for treating HCC. Here, we identified WNK1 as an antioxidative factor and therapeutic target in HCC. In human HCC, WNK1 expression was increased and correlated with poor patient prognosis. WNK1 knockdown significantly inhibited cell proliferation and xenograft tumor growth. Mechanistically, WNK1 competed with NRF2 for binding to the partial Kelch domain of KEAP1, reducing NRF2 ubiquitination and promoting NRF2 accumulation and nuclear translocation to increase antioxidant response. WNK1 silencing increased H2O2-induced apoptosis and inhibited cell growth by elevating reactive oxygen species (ROS) levels, which could be rescued by treatment with the antioxidant N-acetylcysteine (NAC) and NRF2 activator tert-butylhydroquinone (tBHQ). Liver-specific WNK1 knockout mouse models of HCC substantiated that WNK1 promoted HCC development by regulating ROS levels. WNK463, an inhibitor of the WNK kinase family, suppressed HCC progression and altered the redox status. These findings suggest that WNK1 plays a critical role in HCC development and progression and that the WNK1-oxidative stress axis may be a promising therapeutic target for HCC.}, }
@article {pmid38885202, year = {2024}, author = {Guo, X and Zhang, M and Li, Y and Ding, Z and Liu, M and Li, W and Peng, Y and Zheng, J}, title = {CYP3A4-Mediated Metabolic Activation and Cytotoxicity of Chlortoluron.}, journal = {Chemical research in toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.chemrestox.3c00351}, pmid = {38885202}, issn = {1520-5010}, abstract = {Chlortoluron (CTU) is an herbicide extensively used in agricultural settings for crop cultivation. Its presence in water has been identified as a pollutant detrimental to aquatic species. The objective of the present study was to explore the metabolic activation and hepatotoxicity of CTU. Through human and rat liver microsomal incubations supplemented with CTU, nicotinamide adenine dinucleotide phosphate (NADPH), and either glutathione or N-acetyl cysteine, a benzylic alcohol metabolite (M1) was discerned, alongside a phenol metabolite (M2), a glutathione conjugate (M3), and an N-acetyl cysteine conjugate (M4). In rats exposed to CTU, biliary M3 and urinary M4 were detected in their bile and urine, respectively. The generation of M1 was detected in the presence of NADPH. The observation of M3 and M4 suggests the formation of an iminoquinone methide intermediate arising from the oxidation of M1. CYP3A4 was found to be the principal enzyme catalyzing the metabolic activation of CTU. Furthermore, CTU exhibited cytotoxic properties in cultured rat primary hepatocytes in a concentration-dependent pattern. Concomitant treatment of hepatocytes with ketoconazole mitigated their susceptibility to the cytotoxic effects of CTU.}, }
@article {pmid38884516, year = {2024}, author = {Tang, W and Zhu, D and Wu, F and Xu, JF and Yang, JP and Deng, ZP and Chen, XB and Papi, A and Qu, JM}, title = {Author Correction: Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion.}, journal = {European review for medical and pharmacological sciences}, volume = {28}, number = {11}, pages = {3697}, doi = {10.26355/eurrev_202406_36388}, pmid = {38884516}, issn = {2284-0729}, abstract = {Eur Rev Med Pharmacol Sci 2023; 27 (11): 5119-5127-DOI: 10.26355/eurrev_202306_32628-PMID: 37318485, published online on June 13, 2023. After publication, the authors have found some mistakes. This erratum corrects the following: In Figure 1, "4 withdrawal" has been corrected into "7 withdrawal" and "95 completed study" has been corrected into "97 corrected study" In the "Efficacy" paragraph at page 5123, "1.0 in the placebo group" has been corrected into "-1.0 in the placebo group". The legend of Table V has been corrected as follows: Table V. Published clinical studies of the mucolytic and expectorant efficacy of IV NAC in respiratory diseases. In Table V, the data regarding the Treatment groups (duration) by Grassi et al5 have been corrected as follows: NAC oral 200 mg TID NAC IM 300 mg BID NAC IV 500 mg OD (6 days) In Table V, the data regarding the Treatment groups (duration) by Henneghien et al8 have been corrected as follows: NAC oral 200 mg TID NAC IV 300 mg TID (3-10 days) NAC IV 500 mg BID (12 days) There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/32628.}, }
@article {pmid38880547, year = {2024}, author = {Yakovlev, AV and Detterer, AS and Yakovleva, OV and Hermann, A and Sitdikova, GF}, title = {H2S prevents the disruption of the blood-brain barrier in rats with prenatal hyperhomocysteinemia.}, journal = {Journal of pharmacological sciences}, volume = {155}, number = {4}, pages = {131-139}, doi = {10.1016/j.jphs.2024.05.001}, pmid = {38880547}, issn = {1347-8648}, mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; Pregnancy ; *Hyperhomocysteinemia/metabolism ; Female ; *Hydrogen Sulfide/metabolism ; *Neuroprotective Agents/pharmacology ; *Acetylcysteine/pharmacology ; *Cytokines/metabolism ; Homocysteine/blood/metabolism/analogs &amp; derivatives ; Rats, Wistar ; Sulfides/pharmacology/administration &amp; dosage ; Rats ; Male ; Pregnancy Complications ; Brain/metabolism ; L-Lactate Dehydrogenase/metabolism/blood ; Permeability ; Nitrites/metabolism/blood ; }, abstract = {Elevation of the homocysteine concentration in the plasma called hyperhomocysteinemia (hHCY) during pregnancy causes a number of pre- and postnatal developmental disorders. The aim of our study was to analyze the effects of H2S donors -NaHS and N-acetylcysteine (NAC) on blood-brain barrier (BBB) permeability in rats with prenatal hHCY. In rats with mild hHCY BBB permeability assessed by Evans Blue extravasation in brain increased markedly throughout life. Administration of NaHS or NAC during pregnancy attenuated hHCY-associated damage and increased endogenous concentrations of sulfides in brain tissues. Acute application of dl-homocysteine thiolactone induced BBB leakage, which was prevented by the NMDA receptor antagonist MK-801 or H2S donors. Rats with hHCY demonstrated high levels of NO metabolite - nitrites and proinflammatory cytokines (IL-1β, TNF-α, IL-6) in brain. Lactate dehydrogenase (LDH) activity in the serum was higher in rats with hHCY. Mitochondrial complex-I activity was lower in brain of hHCY rats. NaHS treatment during pregnancy restored levels of proinflammatory cytokines, nitrites and activity of the respiratory chain complex in brain as well as the LDH activity in serum. Our data suggest that H2S has neuroprotective effects against prenatal hHCY-associated BBB disturbance providing a potential strategy for the prevention of developmental impairments in newborns.}, }
@article {pmid38879122, year = {2024}, author = {Cai, J and Huang, J and Li, D and Zhang, X and Shi, B and Liu, Q and Fang, C and Xu, S and Zhang, Z}, title = {Hippo-YAP/TAZ-ROS signaling axis regulates metaflammation induced by SelenoM deficiency in high-fat diet-derived obesity.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2024.06.005}, pmid = {38879122}, issn = {2090-1224}, abstract = {INTRODUCTION: Metabolic inflammation (metaflammation) in obesity is primarily initiated by proinflammatory macrophage infiltration into adipose tissue. SelenoM contributes to the modulation of antioxidative stress and inflammation in multiple pathological processes; however, its roles in metaflammation and the proinflammatory macrophage (M1)-like state in adipose tissue have not been determined.<br><br>OBJECTIVES: We hypothesize that SelenoM could effectively regulate metaflammation via the Hippo-YAP/TAZ-ROS signaling axis in obesity derived from a high-fat diet.<br><br>METHODS: Morphological changes in adipose tissue were examined by hematoxylin-eosin (H&amp;E) staining and fluorescence microscopy. The glucose tolerance test (GTT) and insulin tolerance test (ITT) were used to evaluate the impact of SelenoM deficiency on blood glucose levels. RNA-Seq analysis, LC-MS analysis, Mass spectrometry analysis and western blotting were performed to detect the levels of genes and proteins related to glycolipid metabolism in adipose tissue.<br><br>RESULTS: Herein, we evaluated the inflammatory features and metabolic microenvironment of mice with SelenoM-deficient adipose tissues by multi-omics analyses. The deletion of SelenoM resulted in glycolipid metabolic disturbances and insulin resistance, thereby accelerating weight gain, adiposity, and hyperglycemia. Mice lacking SelenoM in white adipocytes developed severe adipocyte hypertrophy via impaired lipolysis. SelenoM deficiency aggravated the generation of ROS by reducing equivalents (NADPH and glutathione) in adipocytes, thereby promoting inflammatory cytokine production and the M1-proinflammatory reaction, which was related to a change in nuclear factor kappa-B (NF-&#x3ba;B) levels in macrophages. Mechanistically, SelenoM deficiency promoted metaflammation via Hippo-YAP/TAZ-ROS-mediated transcriptional regulation by targeting large tumor suppressor 2 (LATS2). Moreover, supplementation with N-acetyl cysteine (NAC) to reduce excessive oxidative stress partially rescued adipocyte inflammatory responses and macrophage M1 activation.<br><br>CONCLUSION: Our data indicate that SelenoM ameliorates metaflammation mainly via the Hippo-YAP/TAZ-ROS signaling axis in obesity. The identification of SelenoM as a key regulator of metaflammation presents opportunities for the development of novel therapeutic interventions targeting adipose tissue dysfunction in obesity.}, }
@article {pmid38876744, year = {2024}, author = {Goedert, M and Griesinger, C and Outeiro, TF and Riek, R and Schröder, GF and Spillantini, MG}, title = {Abandon the NAC in α-synuclein.}, journal = {The Lancet. Neurology}, volume = {23}, number = {7}, pages = {669}, doi = {10.1016/S1474-4422(24)00176-5}, pmid = {38876744}, issn = {1474-4465}, mesh = {Humans ; *alpha-Synuclein/metabolism ; Parkinson Disease/drug therapy ; Acetylcysteine/therapeutic use ; Animals ; }, }
@article {pmid38875923, year = {2024}, author = {Bagri, KM and de Andrade Abraham, C and Santos, AT and da Silva, WS and Costa, ML and Mermelstein, C}, title = {Rotenone inhibits embryonic chick myogenesis in a ROS-dependent mechanism.}, journal = {Tissue &amp; cell}, volume = {89}, number = {}, pages = {102423}, doi = {10.1016/j.tice.2024.102423}, pmid = {38875923}, issn = {1532-3072}, abstract = {Skeletal muscle function is highly dependent on the energy supply provided by mitochondria. Besides ATP production, mitochondria have several other roles, such as calcium storage, heat production, cell death signaling, autophagy regulation and redox state modulation. Mitochondrial function is crucial for skeletal muscle fiber formation. Disorders that affect mitochondria have a major impact in muscle development and function. Here we studied the role of mitochondria during chick skeletal myogenesis. We analyzed the intracellular distribution of mitochondria in myoblasts, fibroblasts and myotubes using Mitotracker labeling. Mitochondrial respiration was investigated in chick muscle cells. Our results show that (i) myoblasts and myotubes have more mitochondria than muscle fibroblasts; (ii) mitochondria are organized in long lines within the whole cytoplasm and around the nuclei of myotubes, while in myoblasts they are dispersed in the cytoplasm; (iii) the area of mitochondria in myotubes increases during myogenesis, while in myoblasts and fibroblasts there is a slight decrease; (iv) mitochondrial length increases in the three cell types (myoblasts, fibroblasts and myotubes) during myogenesis; (v) the distance of mitochondria to the nucleus increases in myoblasts and myotubes during myogenesis; (vi) Rotenone inhibits muscle fiber formation, while FCCP increases the size of myotubes; (vii) N-acetyl cysteine (NAC), an inhibitor of ROS formation, rescues the effects of Rotenone on muscle fiber size; and (viii) Rotenone induces the production of ROS in chick myogenic cells. The collection of our results suggests a role of ROS signaling in mitochondrial function during chick myogenesis.}, }
@article {pmid38870779, year = {2024}, author = {Liu, J and Bai, Y and Feng, Y and Liu, X and Pang, B and Zhang, S and Jiang, M and Chen, A and Huang, H and Chen, Y and Ling, J and Mei, L}, title = {ABCC1 deficiency potentiated noise-induced hearing loss in mice by impairing cochlear antioxidant capacity.}, journal = {Redox biology}, volume = {74}, number = {}, pages = {103218}, doi = {10.1016/j.redox.2024.103218}, pmid = {38870779}, issn = {2213-2317}, abstract = {The ABCC1 gene belongs to the ATP-binding cassette membrane transporter superfamily, which plays a crucial role in the efflux of various endogenous and exogenous substances. Mutations in ABCC1 can result in autosomal dominant hearing loss. However, the specific roles of ABCC1 in auditory function are not fully understood. Through immunofluorescence, we found that ABCC1 was expressed in microvascular endothelial cells (ECs) of the stria vascularis (StV) in the murine cochlea. Then, an Abcc1 knockout mouse model was established by using CRISPR/Cas9 technology to elucidate the role of ABCC1 in the inner ear. The ABR threshold did not significantly differ between WT and Abcc1[-/-] mice at any age studied. After noise exposure, the ABR thresholds of the WT and Abcc1[-/-] mice were significantly elevated. Interestingly, after 14 days of noise exposure, ABR thresholds largely returned to pre-exposure levels in WT mice but not in Abcc1[-/-] mice. Our subsequent experiments showed that microvascular integrity in the StV was compromised and that the number of outer hair cells and the number of ribbons were significantly decreased in the cochleae of Abcc1[-/-] mice post-exposure. Besides, the production of ROS and the accumulation of 4-HNE significantly increased. Furthermore, StV microvascular ECs were cultured to elucidate the role of ABCC1 in these cells under glucose oxidase challenge. Notably, 30 U/L glucose oxidase (GO) induced severe oxidative stress damage in Abcc1[-/-] cells. Compared with WT cells, the ROS and 4-HNE levels and the apoptotic rate were significantly elevated in Abcc1[-/-] cells. In addition, the reduced GSH/GSSG ratio was significantly decreased in Abcc1[-/-] cells after GO treatment. Taken together, Abcc1[-/-] mice are more susceptible to noise-induced hearing loss, possibly because ABCC1 knockdown compromises the GSH antioxidant system of StV ECs. The exogenous antioxidant N-acetylcysteine (NAC) may protect against oxidative damage in Abcc1[-/-] murine cochleae and ECs.}, }
@article {pmid38867461, year = {2024}, author = {Maxwell, MN and Marullo, AL and Valverde-Pérez, E and Slyne, AD and Murphy, BT and O'Halloran, KD}, title = {Chronic N-acetyl cysteine treatment does not improve respiratory system performance in the mdx mouse model of Duchenne muscular dystrophy.}, journal = {Experimental physiology}, volume = {}, number = {}, pages = {}, doi = {10.1113/EP091862}, pmid = {38867461}, issn = {1469-445X}, support = {FFP/19/6628 INSPIRE DMD/SFI_/Science Foundation Ireland/Ireland ; }, abstract = {Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin-deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N-acetylcysteine (NAC) has been shown to exert anti-inflammatory and anti-fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short-term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One-month-old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force-generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure-generating capacity. NAC treatment did not affect force-generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.}, }
@article {pmid38866114, year = {2024}, author = {Khan, AQ and Al-Tamimi, M and Anver, R and Agha, MV and Anamangadan, G and Raza, SS and Ahmad, F and Ahmad, A and Allam, M and Buddenkotte, J and Steinhoff, M and Uddin, S}, title = {Targeting of S-phase kinase associated protein 2 stabilized tumor suppressors leading to apoptotic cell death in squamous skin cancer cells.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {}, number = {}, pages = {167286}, doi = {10.1016/j.bbadis.2024.167286}, pmid = {38866114}, issn = {1879-260X}, abstract = {S-phase kinase-associated protein 2 (Skp2) is an F-box protein overexpressed in human cancers and linked with poor prognosis. It triggers cancer pathogenesis, including stemness and drug resistance. In this study, we have explored the potential role of Skp2 targeting in restoring the expression of tumor suppressors in human cutaneous squamous cell carcinoma (cSCC) cells. Our results showed that genetic and pharmacological Skp2 targeting markedly suppressed cSCC cell proliferation, colony growth, spheroid formation, and enhanced sensitization to chemotherapeutic drugs. Further, western blot results demonstrated restoration of tumor suppressor (KLF4) and CDKI (p21) and suppression of vimentin and survivin in Skp2-knocked-down cSCC cells. Importantly, we also explored that Skp2 targeting potentiates apoptosis of cSCC cells through MAPK signaling. Moreover, co-targeting of Skp2 and AKT resulted in increased cancer cell death. Interestingly, curcumin, a well-known naturally derived anticancer agent, also inhibits Skp2 expression with concomitant CDKI upregulation. In line, curcumin suppressed cSCC cell growth through ROS-mediated apoptosis, while the use of N-acetyl cysteine (NAC) reversed curcumin-induced cell death. Curcumin treatment also sensitized cSCC cells to conventional anticancer drugs, such as cisplatin and doxorubicin. Altogether, these data suggest that Skp2 targeting restores the functioning of tumor suppressors, inhibits the expression of genes associated with cell proliferation and stemness, and sensitizes cancer cells to anticancer drugs. Thus, genetic, and pharmacological ablation of Skp2 can be an important strategy for attenuating cancer pathogenesis and associated complications in skin squamous cell carcinoma.}, }
@article {pmid38862667, year = {2024}, author = {Kang, F and Wu, J and Hong, L and Zhang, P and Song, J}, title = {Iodine-125 seed inhibits proliferation and promotes apoptosis of cholangiocarcinoma cells by inducing the ROS/p53 axis.}, journal = {Functional &amp; integrative genomics}, volume = {24}, number = {3}, pages = {114}, pmid = {38862667}, issn = {1438-7948}, mesh = {*Cholangiocarcinoma/metabolism/radiotherapy/pathology/genetics/drug therapy ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Iodine Radioisotopes ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; Humans ; Cell Line, Tumor ; Bile Duct Neoplasms/metabolism/pathology/genetics/radiotherapy ; Acetylcysteine/pharmacology ; Benzothiazoles/pharmacology ; Signal Transduction/drug effects ; }, abstract = {With advances in radioactive particle implantation in clinical practice, Iodine-125 ([125]I) seed brachytherapy has emerged as a promising treatment for cholangiocarcinoma (CCA), showing good prognosis; however, the underlying molecular mechanism of the therapeutic effect of [125]I seed is unclear. To study the effects of [125]I seed on the proliferation and apoptosis of CCA cells. CCA cell lines, RBE and HCCC-9810, were treated with reactive oxygen species (ROS) scavenger acetylcysteine (NAC) or the p53 functional inhibitor, pifithrin-α hydrobromide (PFTα). Cell counting kit-8 (CCK-8) assay, 5-bromo-2-deoxy-uridine (BrdU) staining, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry assay were performed to test the radiation-sensitivity of [125]I seed toward CCA cells at different radiation doses (0.4 mCi and 0.8 mCi). 2,7-dichlorofluorescein diacetate (DCF-DA) assay, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot analysis were performed to assess the effect of [125]I seed on the ROS/p53 axis. A dose-dependent inhibitory effect of [125]I seeds on the proliferation of CCA cells was observed. The [125]I seed promoted apoptosis of CCA cells and induced the activation of the ROS/p53 pathway in a dose-dependent manner. NAC or PFTα treatment effectively reversed the stimulatory effect of [125]I seed on the proliferation of CCA cells. NAC or PFTα suppressed apoptosis and p53 protein expression induced by the [125]I seed. [125]I seed can inhibit cell growth mainly through the apoptotic pathway. The mechanism may involve the activation of p53 and its downstream apoptotic pathway by up-regulating the level of ROS in cells.}, }
@article {pmid38858642, year = {2024}, author = {Hao, J and Zhang, X and Hu, R and Lu, X and Wang, H and Li, Y and Cheng, K and Li, Q}, title = {Metabolomics combined with network pharmacology reveals a role for astragaloside IV in inhibiting enterovirus 71 replication via PI3K-AKT signaling.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {555}, pmid = {38858642}, issn = {1479-5876}, support = {81301426//the National Natural Science Foundation of China/ ; 201901D111329//the Provincial Natural Science Foundation of Shanxi/ ; 202102130501005//Key Research and Development Plan of Shanxi Province/ ; 2020SHFZ38//the Mega Research and Development Projects of L&#xfc;liang/ ; 2020ZDSYS17//the Key Laboratory Platform Construction Projects of L&#xfc;liang/ ; 2023SHFZ50//the Luliang City Social Development Key Research and Development Project/ ; 2022C25//the Shanxi Medical University Fenyang College Project/ ; }, mesh = {*Virus Replication/drug effects ; *Saponins/pharmacology ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; *Triterpenes/pharmacology ; Humans ; *Phosphatidylinositol 3-Kinases/metabolism ; *Network Pharmacology ; *Metabolomics ; *Enterovirus A, Human/drug effects ; }, abstract = {BACKGROUND: Astragaloside IV (AST-IV), as an effective active ingredient of Astragalus membranaceus (Fisch.) Bunge. It has been found that AST-IV inhibits the replication of dengue virus, hepatitis B virus, adenovirus, and coxsackievirus B3. Enterovirus 71 (EV71) serves as the main pathogen in severe hand-foot-mouth disease (HFMD), but there are no specific drugs available. In this study, we focus on investigating whether AST-IV can inhibit EV71 replication and explore the potential underlying mechanisms.<br><br>METHODS: The GES-1 or RD cells were infected with EV71, treated with AST-IV, or co-treated with both EV71 and AST-IV. The EV71 structural protein VP1 levels, the viral titers in the supernatant were measured using western blot and 50% tissue culture infective dose (TCID50), respectively. Network pharmacology was used to predict possible pathways and targets for AST-IV to inhibit EV71 replication. Additionally, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was used to investigate the potential targeted metabolites of AST-IV. Associations between metabolites and apparent indicators were performed via Spearman's algorithm.<br><br>RESULTS: This study illustrated that AST-IV effectively inhibited EV71 replication. Network pharmacology suggested that AST-IV inhibits EV71 replication by targeting PI3K-AKT. Metabolomics results showed that AST-IV achieved these effects by elevating the levels of hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-hydroxy-1&#xa0;H-indole-3- acetamide, oxypurinol, while reducing the levels of PC (14:0/15:0). Furthermore, AST-IV also mitigated EV71-induced oxidative stress by reducing the levels of MDA, ROS, while increasing the activity of T-AOC, CAT, GSH-Px. The inhibition of EV71 replication was also observed when using the ROS inhibitor N-Acetylcysteine (NAC). Additionally, AST-IV exhibited the ability to activate the PI3K-AKT signaling pathway and suppress EV71-induced apoptosis.<br><br>CONCLUSION: This study suggests that AST-IV may activate the cAMP and the antioxidant stress response by targeting eight key metabolites, including hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-Hydroxy-1&#xa0;H-indole-3-acetamide, oxypurinol and PC (14:0/15:0). This activation can further stimulate the PI3K-AKT signaling to inhibit EV71-induced apoptosis and EV71 replication.}, }
@article {pmid38857427, year = {2024}, author = {Zhang, R and Guan, S and Meng, Z and Deng, X and Lu, J}, title = {3-MCPD Induces Renal Cell Pyroptosis and Inflammation by Inhibiting ESCRT-III-Mediated Cell Repair and Mitophagy.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.4c01994}, pmid = {38857427}, issn = {1520-5118}, abstract = {3-Monochloropropane-1,2-diol (3-MCPD) is a chloropropyl alcohol contaminant mainly from the thermal processing of food and could affect kidneys. Pyroptosis is programmed cell death mediated by inflammasomes and gasdermins, and excessive cellular pyroptosis and inflammation can lead to tissue injury. In the present study, we found that 3-MCPD increased lactate dehydrogenase (LDH) levels in vitro and in vivo, increased the protein expression of NOD-like receptor family pyrin domain containing 3 (NLRP3), N-terminal domain of GSDMD (GSDMD-N), and cleaved caspase-1 and promoted the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), which induced renal cell pyroptosis and inflammation. Mechanistic studies indicated that the addition of N-acetylcysteine (NAC), a ROS scavenger, inhibited NLRP3 activation and attenuated pyroptosis. Furthermore, we revealed that 3-MCPD induced ROS accumulation by inhibiting ESCRT-III-mediated mitophagy. These results were further validated by the overexpression of charged multivesicular body protein 4B (CHMP4B), a key subunit of ESCRT-III, and the addition of the mitophagy activator carbonyl cyanide m-chlorophenylhydrazone (CCCP) and rapamycin (Rapa). Thus, our results showed that 3-MCPD could induce mitochondrial damage and produce ROS. 3-MCPD suppressed mitophagy, leading to the accumulation of damaged mitochondria and ROS, thereby activating NLRP3 and pyroptosis. Meanwhile, 3-MCPD-mediated suppression of ESCRT-III hindered the repair of GSDMD-induced cell membrane rupture, which further caused the occurrence of pyroptosis. Our findings provide new perspectives for studying the mechanisms underlying 3-MCPD-induced renal injury.}, }
@article {pmid38854233, year = {2024}, author = {Shah, N and Campbell, H and Patel, V and Moormeier, J}, title = {A Clinical Course of Repeated Supratherapeutic Ingestion of Acetaminophen.}, journal = {Cureus}, volume = {16}, number = {5}, pages = {e59883}, pmid = {38854233}, issn = {2168-8184}, abstract = {Acute liver failure (ALF) exemplifies a rapid decline in liver function among individuals with previously healthy livers, often manifesting through symptoms such as jaundice, confusion, and potentially life-threatening complications. Timely medical intervention, and, in severe instances, liver transplantation, are essential for enhancing outcomes and averting further deterioration. While the causes of ALF are multifaceted, in developed nations, it predominantly arises from drug-induced liver injury. Treatment primarily revolves around supportive measures, with severe cases necessitating liver transplantation. In instances where acute overdose with acetaminophen serves as the instigating factor, N-acetylcysteine (NAC) emerges as a pivotal component of management, as indicated by the Rumack-Matthew nomogram. The Rumack-Matthew nomogram guides treatment for acetaminophen overdose by correlating serum levels with the risk of liver damage. If levels exceed a set threshold, NAC is administered to prevent toxicity by replenishing glutathione. The decision to administer NAC is typically guided by this clinical tool, which aids healthcare providers in determining the appropriate course of action. NAC assumes a critical role in ameliorating the detrimental effects of acetaminophen overdose, particularly in averting liver damage, thus holding significant importance in patient care and recovery. While chronic acetaminophen overdose cases leading to ALF may also benefit from NAC, the supporting evidence remains weak. In this context, we present a case of ALF stemming from chronic acetaminophen ingestion, managed with NAC when liver transplantation was not a viable option.}, }
@article {pmid38847101, year = {2024}, author = {Li, G and Li, M and Deng, Q and Yan, C and Lv, H and Zhao, G and Li, Y and Feng, Y and Sun, F and Fu, Y and Li, Y and Zhao, Z}, title = {Design, Synthesis and Preliminary Bioactivity Evaluation of N-acetylcysteine Derivatives as Antioxidative and Anti-inflammatory Agents.}, journal = {ChemMedChem}, volume = {}, number = {}, pages = {e202400110}, doi = {10.1002/cmdc.202400110}, pmid = {38847101}, issn = {1860-7187}, abstract = {N-acetylcysteine (NAC) is a commonly used mucolytic agent and antidote for acetaminophen overdose. For pulmonary diseases, NAC exhibits antioxidative properties, regulates cytokine production, reduces apoptosis of lung epithelial cells, and facilitates the resolution of inflammation. However, the efficacy of NAC in clinical trials targeting different pathological conditions is constrained by its short half-life and low bioavailability. In the present study, a series of NAC derivatives were designed and synthesized to further enhance its pharmacological activity. Structure-activity relationship (SAR) studies were conducted to optimize the activating groups. In vitro evaluations revealed that compounds 4r, 4t, 4w, and 4x exhibited superior antioxidative and anti-inflammatory activities compared to the positive controls of NAC and fudosteine. The ADME prediction analysis indicated that these compounds exhibited a favorable pharmacological profile. In-vivo experiments with compound 4r demonstrated that the high-dose group (80 mg/kg) exhibited improved therapeutic effects in reversing the HPY level in mice with pulmonary fibrosis compared to the NAC group (500 mg/kg), further proving its superior oral bioavailability and therapeutic effect compared to NAC.}, }
@article {pmid38845374, year = {2024}, author = {Bhowmik, A and Chakraborty, S and Rohit, A and Chauhan, A}, title = {Transcriptomic responses of XDR Klebsiella pneumoniae to N-acetyl cysteine reveals suppression of major biogenesis pathways leading to bacterial killing and biofilm eradication.}, journal = {Journal of applied microbiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jambio/lxae136}, pmid = {38845374}, issn = {1365-2672}, abstract = {AIMS: Carbapenemase-producing K. pneumoniae is categorized as a "critical global priority-one" pathogen by WHO and new and efficient treatment options are warranted. This study aims to assess the antibacterial and antibiofilm potential of N-acetyl cysteine (NAC), against clinical isolates of extensively drug resistant (XDR) K. pneumoniae and elucidate the mechanism of killing.<br><br>METHODS AND RESULTS: XDR-K. pneumoniae were isolated from patients admitted to Madras Medical Mission Hospital, India. Antibiofilm activity of NAC was checked using in vitro continuous flow model and RNA sequencing was done using Illumina Novoseq. Data quality was checked using FastQC and MultiQC software. Our findings revealed that NAC at a concentration of 100&#xa0;mg/mL was safe, and could inhibit the growth and completely eradicate mature biofilms of all XDR- K. pneumoniae isolates. Transcriptomic responses in XDR- K. pneumoniae to NAC showed significant downregulation of the genes associated with crucial biogenesis pathways including electron transport chain and oxidoreductase activity besides a specific cluster of genes linked to ribosomal proteins.<br><br>CONCLUSIONS: Our results indicate that NAC kills the XDR- K. pneumoniae clinical isolates by shutting the overall metabolism and hence, successfully eradicate in vitro biofilms formed on catheters.}, }
@article {pmid38843996, year = {2024}, author = {Adiyeke, E and Bakan, N and Uvez, A and Arslan, DO and Kilic, S and Koc, B and Ozer, S and Saatci, O and Armutak, E&#x130;}, title = {THE EFFECT OF N- ACETYLCYSTEINE ON THE NEUROTOXICITY OF SEVOFLURANE IN DEVELOPING HIPPOCAMPUS CELLS.}, journal = {Neurotoxicology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuro.2024.05.006}, pmid = {38843996}, issn = {1872-9711}, abstract = {Sevoflurane, a common pediatric anesthetic, has been linked to neurodegeneration, raising safety concerns. This study explored N-acetylcysteine's protective potential against sevoflurane-induced neurotoxicity in rat hippocampi. Four groups were examined: Control: Received 6hours of 3l/min gas (air and 30% O2) and intraperitoneal saline. NAC: Received 6hours of 3l/min gas and 150mg/kg NAC intraperitoneally. Sev: Exposed to 6hours of 3l/min gas and 3% sevoflurane. Sev+NAC: Received 6hours of 3l/min gas, 3% sevoflurane, and 150mg/kg NAC. Protein levels of NRF-2, NLRP3, IL-1β, caspase-1, Beclin 1, p62, LC3A, and apoptosis markers were assessed. Sevoflurane and NAC alone reduced autophagy, while Sev+NAC group maintained autophagy levels. Sev group had elevated NRF-2, NLRP3, pNRF2, Caspase-1, and IL-1β, which were reduced in Sev+NAC. Apoptosis was higher in Sev, but Sev+NAC showed reduced apoptosis compared to the control. In summary, sevoflurane induced neurotoxicity in developing hippocampus, which was mitigated by N-acetylcysteine administration.}, }
@article {pmid38842239, year = {2024}, author = {Hassan, AA and Ismail, NR and Rezk, AE and Elfeky, HM and Mady, AM and Allam, AG and Abbas, KS}, title = {Efficacy of N-acetylcysteine in reducing the risk of postoperative atrial fibrillation in cardiothoracic surgery: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Minerva cardiology and angiology}, volume = {}, number = {}, pages = {}, doi = {10.23736/S2724-5683.24.06482-2}, pmid = {38842239}, issn = {2724-5772}, abstract = {INTRODUCTION: New-onset postoperative atrial fibrillation (POAF) is a common complication following cardiac surgeries. N-acetylcysteine (NAC) showed a significant reduction in the incidence of POAF. This review aimed to systematically summarize and Meta-analyze data from previously published Randomized Controlled Trials (RCTs).<br><br>EVIDENCE ACQUISITION: Electronic databases: PubMed, Cochrane, Embase, Scopus, and Web of Science were searched. Data was extracted and the quality of the included studies was assessed. A random-effects DerSimonian Laird model was employed for meta-analysis.<br><br>EVIDENCE SYNTHESIS: Fifteen RCTs were included in this study (NAC, N.=940; control, N.=935). In the NAC group, 16.38% developed POAF compared with 23.53% in the control group. NAC supplementation was associated with a decreased incidence of POAF in patients undergoing cardiothoracic surgery (RR 0.69; 95% CI 0.52, 0.91; P=0.008). Meta-regression of randomized trial data showed that the incidence of POAF was not related to the NAC dose (P=0.439). A subgroup analysis in terms of the time of NAC administration revealed that preoperative and postoperative NAC administration was the only subgroup that demonstrated a statistically significant difference (RR 0.48, 95% CI 0.32, 0.71; P=0.0003) compared with placebo and showed no heterogeneity.<br><br>CONCLUSIONS: Atrial fibrillation is a significant postoperative complication, particularly in cardiothoracic surgery. This study highlights the need for further research on optimal NAC dosing and timing, with evidence suggesting that preoperative and postoperative NAC administration may significantly decrease postoperative atrial fibrillation in cardiothoracic surgery patients, although limitations and variability in study designs need to be considered.}, }
@article {pmid38841121, year = {2024}, author = {Jenkins, DD and Garner, SS and Brennan, A and Morris, J and Bonham, K and Adams, L and Hunt, S and Moss, H and Badran, BW and George, MS and Wiest, DB}, title = {Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds.}, journal = {Frontiers in human neuroscience}, volume = {18}, number = {}, pages = {1373543}, pmid = {38841121}, issn = {1662-5161}, abstract = {OBJECTIVE: This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds.<br><br>METHODS: We treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100&#x2009;mg/kg/dose) was given by nasogastric (NG) administration every 6&#x2009;h for 4&#x2009;days, then combined with taVNS paired with 2 daily feeds for another 14&#x2009;days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone.<br><br>RESULTS: NAC 100&#x2009;mg/kg/dose every 6&#x2009;h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13&#x2009;&#xb1;&#x2009;0.08&#x2009;mM (p&#x2009;=&#x2009;0.01, compared to baseline). Mean daily feeding volumes increased over 14&#x2009;days of NAC&#x2009;+&#x2009;taVNS compared to the 14&#x2009;days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake.<br><br>CONCLUSION: In IDM failing oral feeds, NAC 100&#x2009;mg/kg/dose every 6&#x2009;h NG for 4&#x2009;days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.}, }
@article {pmid38836732, year = {2024}, author = {Chen, J and Zhu, Y and Zheng, C and Zhao, W and Liu, Q}, title = {Influence Factors of the Therapeutic Effect of Budesonide Combined with N-Acetylcysteine in Children with Mycoplasma Pneumoniae Infection Analyzed by Lasso-Logistic and Construction of a Nomogram Prediction Model.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {38836732}, issn = {1078-6791}, abstract = {OBJECTIVE: This study aims to analyze the factors influencing the efficacy of budesonide (BUD) combined with N-acetylcysteine (NAC) treatment in children with Mycoplasma pneumoniae (MP) infection through Lasso-Logistic analysis, construct a Nomogram predictive model, and provide personalized treatment plans for clinicians. Additionally, it aims to fill the knowledge gap regarding the treatment of MP-infected children with BUD combined with NAC.<br><br>METHODS: We retrospectively analyzed clinical data from 96 children treated with BUD and NAC for MP infection at our hospital from January 2022 to May 2023. Treatment outcomes were categorized as good or poor. Logistic regression and Lasso-Logistic analysis were used to identify independent factors influencing outcomes and construct a predictive Nomogram model, which was validated through ROC curve analysis.<br><br>RESULTS: Logistic regression identified prolonged fever (&#x2265;7 days), high fever, and elevated levels of TNF-&#x3b1;, IL-6, and CRP as independent risk factors for poor outcomes. The Nomogram model, based on these factors, demonstrated excellent predictive accuracy with a C-index of 0.992 and AUC values of 0.987 and 0.948 in the modeling and validation cohorts, respectively.<br><br>CONCLUSION: The developed Nomogram model provides clinicians with a reliable tool to predict poor treatment outcomes in children with MP infection treated with BUD and NAC, supporting more personalized and effective treatment plans.}, }
@article {pmid38759847, year = {2024}, author = {Shin, BJ and Kim, BJ and Paeng, EJ and Rifkin, JT and Moon, SH and Shin, SH and Ryu, BY}, title = {N-Acetyl-L-cysteine attenuates titanium dioxide nanoparticle (TiO2 NP)-induced autophagy in male germ cells.}, journal = {Environmental toxicology and pharmacology}, volume = {108}, number = {}, pages = {104466}, doi = {10.1016/j.etap.2024.104466}, pmid = {38759847}, issn = {1872-7077}, mesh = {*Titanium/toxicity ; Male ; *Autophagy/drug effects ; Animals ; *Acetylcysteine/pharmacology ; Mice ; *Reactive Oxygen Species/metabolism ; Cell Line ; *Cell Proliferation/drug effects ; *Metal Nanoparticles/toxicity ; Spermatogonia/drug effects ; Nanoparticles/toxicity ; }, abstract = {Titanium dioxide nanoparticles (TiO2 NPs) are widely used in consumer products, raising concerns about their impact on human health. This study investigates the effects of TiO2 NPs on male germ cells while focusing on cell proliferation inhibition and underlying mechanisms. This was done by utilizing mouse GC-1 spermatogonia cells, an immortalized spermatogonia cell line. TiO2 NPs induced a concentration-dependent proliferation inhibition with increased reactive oxygen species (ROS) generation. Notably, TiO2 NPs induced autophagy and decreased ERK phosphorylation. Treatment with the ROS inhibitor N-Acetyl-l-cysteine (NAC) alleviated TiO2 NPs-induced autophagy, restored ERK phosphorylation, and promoted cell proliferation. These findings call attention to the reproductive risks posed by TiO2 NPs while also highlighting NAC as a possible protective agent against reproductive toxins.}, }
@article {pmid38828636, year = {2024}, author = {Lu, J and Zhao, P and Ding, X and Liu, Y and Li, H}, title = {N-Acetylcysteine assists muscle development in offspring of mice subjected to maternal heat stress during pregnancy.}, journal = {Journal of the science of food and agriculture}, volume = {}, number = {}, pages = {}, doi = {10.1002/jsfa.13620}, pmid = {38828636}, issn = {1097-0010}, support = {No.32172725//National Natural Science Foundation of China/ ; 2023AAC02013//Ningxia Natural Science Foundation of China/ ; 2021YFC2101403//National Key Research and Development Program of China/ ; }, abstract = {BACKGROUND: Heat stress (HS) has been shown to affect reproductive performance and muscle development negatively in animals. N-Acetylcysteine (NAC) plays a pivotal role in enhancing the antioxidant performance in animals as a recognized antioxidant. The present study assesses the potential of NAC to modulate the reproductive performance and antioxidant function in pregnant mice exposed to HS. The role of NAC in muscle development of offspring mice was also explored.<br><br>RESULTS: The results showed that NAC supplementation from day 12 to day 18 of gestation increased the number of litters and enhanced the antioxidant function in pregnant mice under HS exposure. It improved the weight and body condition significantly in the offspring mice (P&#x2009;<&#x2009;0.05). The alleviation of HS-induced muscle impairment with NAC was consistent with the alleviation of apoptosis, the enrichment of the proliferation and differentiation in the offspring mice muscle. N-Acetylcysteine also reversed HS-induced reduction in the cross-sectional area of the leg muscle and increased the proportion of myosin heavy chain IIx (MYHCIIx) in the muscle fiber.<br><br>CONCLUSION: The results of the present study support the use of NAC at a dose of 100&#x2009;mg&#x2009;kg[-1] body weight as supplement for protecting the offspring derived from pregnant mice exposed to HS from muscle impairment by accelerating proliferation and differentiation. &#xa9; 2024 Society of Chemical Industry.}, }
@article {pmid38825302, year = {2024}, author = {Zhang, Y and Qu, Y and Cai, R and Gao, J and Xu, Q and Zhang, L and Kang, M and Jia, H and Chen, Q and Liu, Y and Ren, F and Zhou, MS}, title = {Atorvastatin ameliorates diabetic nephropathy through inhibiting oxidative stress and ferroptosis signaling.}, journal = {European journal of pharmacology}, volume = {}, number = {}, pages = {176699}, doi = {10.1016/j.ejphar.2024.176699}, pmid = {38825302}, issn = {1879-0712}, abstract = {Clinically, statins have long been used for the prevention and treatment of chronic renal diseases, however, the underlying mechanisms are not fully elucidated. The present study investigated the effects of atorvastatin on diabetes renal injury and ferroptosis signaling. A mouse model of diabetes was established by the intraperitoneal injection of streptozotocin (50 mg/kg/day) plus a high fat diet with or without atorvastatin treatment. Diabetes mice manifested increased plasma glucose and lipid profile, proteinuria, renal injury and fibrosis, atorvastatin significantly lowered plasma lipid profile, proteinuria, renal injury in diabetes mice. Atorvastatin reduced renal reactive oxygen species (ROS), iron accumulation and renal expression of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), transferrin receptor1 (TFR1), and increased renal expression of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor (NRF2) and ferritin heavy chain (FTH) in diabetes mice. Consistent with the findings in vivo, atorvastatin prevented high glucose-induced ROS formation and Fe[2+] accumulation, an increase in the expression of 4-HNE, MDA and TFR1, and a decrease in cell viability and the expression of NRF2, GPX4 and FTH in HK2 cells. Atorvastatin also reversed ferroptosis inducer erastin-induced ROS production, intracellular Fe[2+] accumulation and the changes in the expression of above-mentioned ferroptosis signaling molecules in HK2 cells. In addition, atorvastatin alleviated high glucose- or erastin-induced mitochondria injury. Ferroptosis inhibitor ferrostatin-1 and antioxidant N-acetylcysteine (NAC) equally reversed the expression of high glucose-induced ferroptosis signaling molecules. Our data support the notion that statins can inhibit diabetes-induced renal oxidative stress and ferroptosis, which may contribute to statins protection of diabetic nephropathy.}, }
@article {pmid38821668, year = {2024}, author = {Naser, H and Munn, K and Lawrence, R and Wright, R and Grewal, E and Williams, L and Doak, S and Jenkins, G}, title = {Human plasma can modulate micronucleus frequency in TK6 and OE33 cells in vitro.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {896}, number = {}, pages = {503766}, doi = {10.1016/j.mrgentox.2024.503766}, pmid = {38821668}, issn = {1879-3592}, mesh = {Humans ; *Micronucleus Tests ; *DNA Damage ; *Barrett Esophagus/pathology/genetics ; *Adenocarcinoma/pathology/genetics ; *Esophageal Neoplasms/genetics/pathology ; Plasma/metabolism ; Interleukin-8/metabolism/genetics ; Cell Line, Tumor ; Cell Cycle/drug effects ; Male ; Middle Aged ; Adult ; Cell Survival/drug effects ; Female ; Micronuclei, Chromosome-Defective ; Interferon-beta ; Aged ; }, abstract = {In this paper, we studied the potential genotoxic effects of human plasma from healthy volunteers, as well as patients with gastro-oesophageal reflux disease, Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) using the oesophageal adenocarcinoma cell line (OE33) and the lymphoblastoid cell line (TK6). Both TK6 and OE33 cells were treated with plasma (10 % volume, replacing foetal bovine serum (FBS) or horse serum (HS)) at different time points of 4 h (for the micronucleus (Mn) assay and the invasion assay) and 24 h (for the cell cycle studies). Plasma-induced effects on DNA damage levels, cell viability and the cell cycle were studied by the micronucleus assay, cytokinesis block proliferation index (CBPI) and flow cytometry respectively. The expression of IL-8 in supernatants of TK6 cells and IFN-β in OE33 cells was also analysed by enzyme-linked immunosorbent assay (ELISA). Finally, we carried out an assessment of cellular invasion of OE33 cells following plasma treatment. The results of the micronucleus assay confirmed the genotoxicity of direct plasma treatment from some participants through the increase in DNA damage in TK6 cells. Conversely, some individual patient plasma samples reduced background levels of TK6 cell Mn frequency, in an anti-genotoxic fashion. In TK6 cells, (on average) plasma samples from patients with Barrett's oesophagus induced higher micronucleus levels than healthy volunteers (p= 0.0019). There was little difference in Mn induction when using plasma versus serum to treat the cells in vitro. Cell cycle results showed that direct plasma treatment had a marked impact on OE33 cells at 24 h (p=0.0182 for BO and p=0.0320 for OAC) by decreasing the proportion of cells in the S phase, while plasma exposure was less impactful on the cell cycle of TK6 cells. Invasion of OE33 cells was also seen to be non-significantly affected by plasma treatment of OE33 cells. The addition of N-acetyl cysteine NAC in a dose-dependent matter did not alter the formation of Mn in TK6 cells, suggesting that reactive oxygen species (ROS) are not the root cause of plasma's genotoxicity. The concentration of IL-8 in TK6 cells and IFN-β in OE33 cells was significantly higher in cells treated with OAC-derived plasma than in the untreated negative control. Collectively, our results demonstrate that plasma-specific effects are detectable which helps us better understand some important aspects of the biology of blood-based biomarkers under development.}, }
@article {pmid38821596, year = {2024}, author = {Wang, YJ and Hao, YY and Lee, DH and Guo, XY and Sun, HN and Kwon, T}, title = {Hispidin Increases Cell Apoptosis and Ferroptosis in Prostate Cancer Cells Through Phosphatidylinositol-3-Kinase and Mitogen-activated Protein Kinase Signaling Pathway.}, journal = {Anticancer research}, volume = {44}, number = {6}, pages = {2533-2544}, doi = {10.21873/anticanres.17059}, pmid = {38821596}, issn = {1791-7530}, mesh = {Humans ; Male ; *Ferroptosis/drug effects ; *Prostatic Neoplasms/pathology/metabolism/drug therapy ; *Apoptosis/drug effects ; *Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; MAP Kinase Signaling System/drug effects ; Cell Movement/drug effects ; Signal Transduction/drug effects ; Mitochondria/drug effects/metabolism ; Pyridones/pharmacology ; Phosphatidylinositol 3-Kinase/metabolism ; Pyrones ; }, abstract = {BACKGROUND/AIM: Chemotherapy is mainly used in the clinical treatment of prostate cancer. Different anticancer mechanisms can induce cell death in various cancers. Reactive oxygen species (ROS) play crucial roles in cell proliferation, differentiation, apoptosis, and signal transduction. It is widely accepted that ROS accumulation is closely related to chemical drug-induced cancer cell death.<br><br>MATERIALS AND METHODS: We utilized the MTT assay to detect changes in cell proliferation. Additionally, colony formation and wound healing assay were conducted to investigate the effect of hispidin on cell colony formation and migration ability. Fluorescence microscopy was used to detect intracellular and mitochondrial ROS levels, while western blot was used for detection of cell apoptosis.<br><br>RESULTS: Hispidin treatment significantly decreased viability of PC3 and DU145 cancer cells but exhibited no cytotoxicity in WPMY-1 cells. Furthermore, hispidin treatment inhibited cell migration and colony formation and triggered cellular and mitochondrial ROS accumulation, leading to mitochondrial dysfunction and mitochondrion-dependent apoptosis. Moreover, hispidin treatment induced ferroptosis in PC3 cells. Scavenging of ROS with N-acetyl cysteine significantly inhibited hispidin-induced apoptosis by altering the expression of apoptosis-related proteins, such as cleaved caspase-3, 9, Bax, and Bcl2. Furthermore, hispidin treatment dramatically up-regulated MAPK (involving p38, ERK, and JNK proteins) and NF-kB signaling pathways while down-regulating AKT phosphorylation. Hispidin treatment also inhibited ferroptosis signaling pathways (involving P53, Nrf-2, and HO-1 proteins) in PC3 cells. In addition, inhibiting these signaling pathways via treatment with specific inhibitors significantly reversed hispidin-induced apoptosis, cellular ROS levels, mitochondrial dysfunction, and ferroptosis.<br><br>CONCLUSION: Hispidin may represent a potential candidate for treating prostate cancer.}, }
@article {pmid38818810, year = {2024}, author = {Li, X and Li, Y and Yu, H and Men, LL and Deng, G and Liu, Z and Du, JL}, title = {Oxidized LDL decreases the survival of bone marrow stem cells via inhibition of Bcl-2 expression.}, journal = {Tissue engineering. Part A}, volume = {}, number = {}, pages = {}, doi = {10.1089/ten.TEA.2024.0025}, pmid = {38818810}, issn = {1937-335X}, abstract = {Therapy with mesenchymal stem cells (MSCs) is considered an attractive strategy for the repair or regeneration of damaged tissues. However, low survival of MSCs limits their applications clinically. Oxidized low-density lipoprotein (ox-LDL) is significantly increased in patients with hyperlipidemia and decreases the survival of MSCs. Bcl-2 is critically involved in important cell functions including cell membrane integrity and cell survival. The present study was designed to test the hypothesis that ox-LDL attenuate the survival of MSCs via suppression of Bcl-2 expression. Bone marrow MSCs from C57BL/6 mice were cultured with ox-LDL at different concentrations (0-140 μg/ml) for 24 hours with native LDL as control. Ox-LDL treatment substantially decreased the survival of MSCs dose-dependently and enhanced the release of intracellular LDH in association with a significant decrease in Bcl-2 protein level without change in BAX protein expression in MSCs. Bcl-2 overexpression effectively protected MSCs against ox-LDL-induced damages with preserved cell numbers without significant increase in LDH release. Treatment with N-acetylcysteine (NAC) (1 mM) effectively preserved Bcl-2 protein expression in MSCs and significantly attenuated ox-LDL-induced decrease of cell number and increase in the release of intracellular LDH. These data indicated that ox-LDL treatment resulted in a significant damage of cell membrane and dramatically decreased the survival of MSCs dose-dependently through inhibition of Bcl-2 expression. NAC treatment significantly protected MSCs against the damage of cell membrane by ox-LDL and promoted the survival of MSCs in association with preserved Bcl-2 expression.}, }
@article {pmid38815788, year = {2024}, author = {Ge, L and Liu, P and Tian, L and Li, Y and Chen, L}, title = {Se-methylselenocysteine inhibits the progression of non-small cell lung cancer via ROS-mediated NF-κB signaling pathway.}, journal = {Experimental cell research}, volume = {}, number = {}, pages = {114101}, doi = {10.1016/j.yexcr.2024.114101}, pmid = {38815788}, issn = {1090-2422}, abstract = {Se-methylselenocysteine (MSC) is recognized for its potential in cancer prevention, yet the specific effects and underlying processes it initiates within non-small cell lung cancer (NSCLC) remain to be fully delineated. Employing a comprehensive array of assays, including CCK-8, colony formation, flow cytometry, MitoSOX Red staining, wound healing, transwell, and TUNEL staining, we evaluated MSC's effects on A549 and 95D cell lines. Our investigation extended to the ROS-mediated NF-κB signaling pathway, utilizing western blot analysis, P65 overexpression, and the application of IκB-α inhibitor (BAY11-7082) or N-acetyl-cysteine (NAC) to elucidate MSC's mechanism of action. In vivo studies involving subcutaneous xenografts in mice further confirmed MSC's inhibitory effect on tumor growth. Our findings indicated that MSC inhibited the proliferation of A549 and 95D cells, arresting cell cycle G0/G1 phase and reducing migration and invasion, while also inducing apoptosis and increasing intracellular ROS levels. This was accompanied by modulation of key proteins, including the upregulation of p21, p53, E-cadherin, Bax, cleaved caspase-3, cleaved-PARP, and downregulation of CDK4, SOD2, GPX-1. MSC was found to inhibit the NF-κB pathway, as evidenced by decreased levels of P-P65 and P-IκBα. Notably, overexpression of P65 and modulation of ROS levels with NAC could attenuate MSC's effects on cellular proliferation and metastasis. Moreover, MSC significantly curtailed tumor growth in vivo and disrupted the NF-κB signaling pathway. In conclusion, our research demonstrates that MSC exhibits anticancer effects against NSCLC by modulating the ROS/NF-κB signaling pathway, suggesting its potential as a therapeutic agent in NSCLC treatment.}, }
@article {pmid38812790, year = {2024}, author = {Chung, J and Jernigan, J and Menees, KB and Lee, JK}, title = {RGS10 mitigates high glucose-induced microglial inflammation via the reactive oxidative stress pathway and enhances synuclein clearance in microglia.}, journal = {Frontiers in cellular neuroscience}, volume = {18}, number = {}, pages = {1374298}, pmid = {38812790}, issn = {1662-5102}, abstract = {Microglia play a critical role in maintaining brain homeostasis but become dysregulated in neurodegenerative diseases. Regulator of G-protein Signaling 10 (RGS10), one of the most abundant homeostasis proteins in microglia, decreases with aging and functions as a negative regulator of microglia activation. RGS10-deficient mice exhibit impaired glucose tolerance, and high-fat diet induces insulin resistance in these mice. In this study, we investigated whether RGS10 modulates microglia activation in response to hyperglycemic conditions, complementing our previous findings of its role in inflammatory stimuli. In RGS10 knockdown (KD) BV2 cells, TNF production increased significantly in response to high glucose, particularly under proinflammatory conditions. Additionally, glucose uptake and GLUT1 mRNA levels were significantly elevated in RGS10 KD BV2 cells. These cells produced higher ROS and displayed reduced sensitivity to the antioxidant N-Acetyl Cysteine (NAC) when exposed to high glucose. Notably, both BV2 cells and primary microglia that lack RGS10 exhibited impaired uptake of alpha-synuclein aggregates. These findings suggest that RGS10 acts as a negative regulator of microglia activation not only in response to inflammation but also under hyperglycemic conditions.}, }
@article {pmid38812125, year = {2024}, author = {Chu, CS and Chen, YT and Liang, WZ}, title = {Investigation of the mechanisms behind ochratoxin A-induced cytotoxicity in human astrocytes and the protective effects of N-acetylcysteine.}, journal = {Journal of applied toxicology : JAT}, volume = {}, number = {}, pages = {}, doi = {10.1002/jat.4652}, pmid = {38812125}, issn = {1099-1263}, support = {//Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University/ ; }, abstract = {Ochratoxin A (OTA) is a type of mycotoxin commonly found in raw and processed foods. It is essential to be aware of this toxin, as it can harm your health if consumed in high quantities. OTA can induce toxic effects in various cell models. However, a more comprehensive understanding of the harmful effects of OTA on human astrocytes is required. This study evaluated OTA's neurotoxic effects on the Gibco® Human Astrocyte (GHA) cell line, its underlying mechanisms, and the antioxidant N-acetylcysteine (NAC) ability to prevent them. OTA exposure within 5-30 μM has induced concentration-dependent cytotoxicity. In the OTA-treated cells, the levels of reactive oxygen species (ROS) were found to be significantly increased, while the glutathione (GSH) contents were found to decrease considerably. The western blotting of OTA-treated cells has revealed increased Bax, cleaved caspase-9/caspase-3 protein levels, and increased Bax/Bcl-2 ratio. In addition, exposure to OTA has resulted in the induction of antioxidant responses associated with the protein expressions of Nrf2, HO-1, and NQO1. On the other hand, the pretreatment with NAC has partially alleviated the significant toxic effects of OTA. In conclusion, our findings suggest that oxidative stress and apoptosis are involved in the OTA-induced cytotoxicity in GHA cells. NAC could act as a protective agent against OTA-induced oxidative damage.}, }
@article {pmid38810310, year = {2024}, author = {Shen, P and Xue, M and Hu, Z and Han, L and Deng, X}, title = {Direct targeting of S100A9 with Icariin counteracted acetaminophen‑induced hepatotoxicity.}, journal = {International immunopharmacology}, volume = {136}, number = {}, pages = {112296}, doi = {10.1016/j.intimp.2024.112296}, pmid = {38810310}, issn = {1878-1705}, abstract = {Acetaminophen (APAP) is a widely used antipyretic and analgesic medication, but its overdose can induce acute liver failure with lack of effective therapies. Icariin is a bioactive compound derived from the herb Epimedium that displays hepatoprotective activities. Here, we explored the protective effects and mechanism of icariin on APAP-induced hepatotoxicity. Icariin (25/50 mg/kg) or N-Acetylcysteine (NAC, 300 mg/kg) were orally administered in wild-type C57BL/6 mice for 7 consecutive days before the APAP administration. Icariin attenuated APAP-induced acute liver injury in mice, as measured by alleviated serum enzymes activities and hepatic apoptosis. In vitro, icariin pretreatment significantly inhibited hepatocellular damage and apoptosis by reducing the BAX/Bcl-2 ratio as well as the expression of cleaved-caspase 3 and cleaved-PARP depended on the p53 pathway. Moreover, icariin attenuated APAP-mediated inflammatory response and oxidative stress via the Nrf2 and NF-κB pathways. Importantly, icariin reduced the expression of S100A9, icariin interacts with S100A9 as a direct cellular target, which was supported by molecular dynamics simulation and surface plasmon resonance assay (equilibrium dissociation constant, KD = 1.14 μM). In addition, the genetic deletion and inhibition of S100A9 not only alleviated APAP-induced injury but also reduced the icariin's protective activity in APAP-mediated liver injury. These data indicated that icariin targeted S100A9 to alleviate APAP-induced liver damage via the following signaling pathways NF-κB, p53, and Nrf2.}, }
@article {pmid38810283, year = {2024}, author = {Zhu, Y and Zhang, S and Shao, Y and Tang, L and Zhang, C and Tang, S and Lu, H}, title = {Regulatory role of oxidative stress in retrorsine - Induced apoptosis and autophagy in primary rat hepatocytes.}, journal = {Ecotoxicology and environmental safety}, volume = {279}, number = {}, pages = {116515}, doi = {10.1016/j.ecoenv.2024.116515}, pmid = {38810283}, issn = {1090-2414}, abstract = {Pyrrolizidine alkaloids (PAs) are a group of naturally occurring alkaloids widely present in plants. PAs are highly hepatotoxic and have been documented to cause many incidents of human and animal poisoning. Retrorsine (RTS) is a pyrrolizidine alkaloid (PA) derived from the Compositae Senecio, which has been shown to cause hepatotoxicity. Human liver poisoning occurs through the consumption of RTS-contaminated food, and animals can also be poisoned by ingesting RTS-containing toxic plants. The mechanism of RTS-induced liver toxicity is not fully understood. In this study, we demonstrated that RTS-induced oxidative stress plays a pivotal role in RTS-induced liver toxicity involving apoptosis and autophagy. The results showed that RTS treatment in the cultured Primary rat hepatocytes caused cytotoxicity and release of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in a time- and dose-dependent manner. Our study showed that treatment of RTS induced ROS and MDA (malondialdehyde, a lipid peroxidation marker) in the hepatocytes, and reduced antioxidant capacity (GSH content, SOD activity), suggesting RTS treatment caused oxidative stress response in the hepatocytes. Furthermore, we found that RTS induced apoptosis and autophagy in the hepatocytes, and RTS-induced apoptosis and autophagy could be alleviated by ROS scavenger N-acetylcysteine (NAC) and the MAPK pathway inhibitors suggesting ROS/MAPK signaling pathway plays a role in RTS induced apoptosis and autophagy. Collectively, this study reveals the regulatory mechanism of oxidative stress in RTS-induced apoptosis and autophagy in the hepatocytes, providing important insights of molecular mechanisms of hepatotoxicity induced by RTS and related pyrrolizidine alkaloids in liver. This mechanism provides a basis for the prevention and treatment of PA poisoning in humans and animals.}, }
@article {pmid38800031, year = {2024}, author = {Raeeszadeh, M and Arvand, S and Shojaee Moghadam, D and Akradi, L}, title = {Evaluation of the influence of N-acetylcysteine and broccoli extract on systemic paraquat poisoning: Implications for biochemical, physiological, and histopathological parameters in rats.}, journal = {Iranian journal of basic medical sciences}, volume = {27}, number = {7}, pages = {895-903}, pmid = {38800031}, issn = {2008-3866}, abstract = {OBJECTIVES: Paraquat (PQ), a potent environmental herbicide, is recognized for inducing irreparable toxic damage to biological systems. This study aimed to evaluate the effectiveness of N-acetylcysteine (NAC) and broccoli extract, individually and in combination, in alleviating PQ poisoning in rats, leveraging the exceptional anti-oxidant, anti-inflammatory, and anti-apoptotic properties of broccoli.<br><br>MATERIALS AND METHODS: Seventy Wistar rats were categorized into seven groups: C (control, vehicle), PQ (paraquat at 40 mg/kg), BC (broccoli extract at 300 mg/kg), NC (N-acetylcysteine at the same dose of 300 mg/kg), and combined groups PQ+BC, PQ+NC, and NC+PQ+BC, all administered equivalent doses. After 42 days, blood samples were collected to evaluate liver and kidney parameters, proinflammatory biomarkers, caspase-3, and caspase-9. Lung tissues were excised, with one part preserved for hydroxyproline and oxidative stress parameter measurement and another sectioned and stained for histopathological analysis.<br><br>RESULTS: The PQ group exhibited the highest lung-to-body weight (LW/BW) ratio, while the PQ+BC+NC group demonstrated the lowest ratio. Results indicated an elevated lung hydroxyproline concentration and a significant reduction in anti-oxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase, and total anti-oxidant capacity) (P<0.001). The PQ+BC group showed modified malondialdehyde levels, reaching a peak in the PQ group. Additionally, a significant decrease in tumor necrosis factor, interleukin-1, caspase-3, and caspase-9 was observed in the PQ+BC+NC group (P<0.01). Pulmonary edema, hyperemia, and severe hemorrhage observed in the PQ group were notably reduced in the PQ+BC+NC group.<br><br>CONCLUSION: The combination of active compounds from broccoli and NAC demonstrated significant systemic and pulmonary effects in mitigating PQ-induced toxicity.}, }
@article {pmid38800015, year = {2024}, author = {Fan, H and Le, JW and Sun, M and Zhu, JH}, title = {N-acetylcysteine protects septic acute kidney injury by inhibiting SIRT3-mediated mitochondrial dysfunction and apoptosis.}, journal = {Iranian journal of basic medical sciences}, volume = {27}, number = {7}, pages = {850-856}, pmid = {38800015}, issn = {2008-3866}, abstract = {OBJECTIVES: To investigate the protective effect of N-acetylcysteine (NAC) on septic acute kidney injury (SAKI) via regulating Sirtuin3 (SIRT3)-mediated mitochondrial dysfunction and apoptosis.<br><br>MATERIALS AND METHODS: By constructing SIRT3 knockout mice and culturing kidney tubular epithelial cells (KTECs), we assessed the changes of renal function and detected the protein expression of adenine nucleotide translocator (ANT), cyclophilin (CypD) and voltage-dependent anion channel (VDAC) using western-blotting, and simultaneously detected toll-like receptor 4 (TLR4), inhibitor of kappa B kinase (IKK&#x3b2;), inhibitor of Kappa B&#x3b1; (I&#x3ba;B&#x3b1;), and p65 protein expression. We observed mitochondrial damage of KTECs using a transmission electron microscope and assessed apoptosis by TdT-mediated dUTP Nick-End Labeling and flow cytometry.<br><br>RESULTS: SIRT3 deficiency led to the deterioration of renal function, and caused a significant increase in inducible nitric oxide synthase production, a decrease in mitochondrial volume, up-regulation of TLR4, I&#x3ba;B&#x3b1;, IKK&#x3b2;, and p65 proteins, and up-regulation of ANT, CypD and VDAC proteins. However, NAC significantly improved renal function and down-regulated the expression of TLR4, I&#x3ba;B&#x3b1;, IKK&#x3b2;, and p65 proteins. Furthermore, SIRT3 deficiency led to a significant increase in KTEC apoptosis, while NAC up-regulated the expression of SIRT3 and inhibited apoptosis.<br><br>CONCLUSION: NAC has a significant protective effect on SAKI by inhibiting SIRT3-mediated mitochondrial dysfunction and apoptosis of KTECs.}, }
@article {pmid38799536, year = {2024}, author = {Jamalvi, SA and Rauf, SA and Sherali, A and Ali, SK and Shah, HH and Jamalvi, F and Yogeeta, F and Dave, T}, title = {COVID-19 presenting as severe acute hepatitis in a pediatric patient with thalassemia minor: A case report.}, journal = {Clinical case reports}, volume = {12}, number = {6}, pages = {e8955}, pmid = {38799536}, issn = {2050-0904}, abstract = {KEY CLINICAL MESSAGE: This case emphasizes the significance of COVID-19 in pediatric patients presenting with unusual hepatic manifestations, urging clinicians to broaden their diagnostic lens. The unexpected elevation of SARS-CoV-2 antibodies and the effective use of N-acetyl cysteine highlight the importance of adaptability in treatment strategies.<br><br>ABSTRACT: This case report presents a unique manifestation of severe hepatic involvement in a 4-year-old girl with thalassemia minor and COVID-19. Despite the absence of prominent respiratory symptoms, the patient exhibited jaundice, elevated liver enzymes, and coagulopathy. Initial suspicion of viral hepatitis was replaced by the discovery of significantly elevated SARS-CoV-2 antibodies. A multidisciplinary approach, including gastroenterology consultation and an extensive workup, was pivotal in ruling out alternative etiologies. Unconventional use of N-acetyl cysteine contributed to clinical improvement, highlighting the need for adaptable treatment strategies. This case underscores the importance of heightened awareness in recognizing atypical presentations of COVID-19 in pediatric patients, especially those with underlying health conditions. Further exploration into nuanced manifestations and treatment approaches is warranted for comprehensive clinical management.}, }
@article {pmid38798604, year = {2024}, author = {Winterlind, EL and Malone, SG and Setzer, MR and Murphy, MA and Saunders, D and Gray, JC}, title = {N-acetylcysteine as a treatment for substance use cravings: A meta-analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2024.05.13.24306839}, pmid = {38798604}, abstract = {N-acetylcysteine (NAC) may serve as a novel pharmacotherapy for substance use and substance craving in individuals with substance use disorders (SUDs), possibly through its potential to regulate glutamate. Though prior meta-analyses generally support NAC's efficacy in reducing symptoms of craving, individual trials have found mixed results. The aims of the this updated meta-analysis were to (1) examine the efficacy of NAC in treating symptoms of craving in individuals with a SUD and (2) explore subgroup differences, risk of bias, and publication bias across trials. Database searches of PubMed, Cochrane Library, and ClinicalTrials.gov were conducted to identify relevant randomized control trials (RCTs). The meta-analysis consisted of 9 trials which analyzed data from a total of 623 participants. The most targeted substance in the clinical trials was alcohol (3/9; 33.3%), followed by tobacco (2/9; 22.2%) and multiple substances (2/9; 22.2%). Meta-analysis, subgroup analyses, and leave-one-out analyses were conducted to examine treatment effect on craving symptoms and adverse events (AEs). Risk of bias assessments, Egger's tests, and funnel plot tests were conducted to examine risk of bias and publication bias. NAC did not significantly outperform placebo in reducing symptoms of craving in the meta-analysis (SMD = 0.189, 95% CI = -0.015 - 0.393). Heterogeneity was very high in the meta-analysis (99.26%), indicating that findings may have been influenced by clinical or methodological differences in the study protocols. Additionally, results indicate that there may be publication bias present. There were no between-group differences in risk of AEs. Overall, our findings are contrary to those of prior meta-analyses, suggesting limited impact of NAC on substance craving. However, the high heterogeneity and presence of publication bias identified warrants cautious interpretation of the meta-analytic outcomes.}, }
@article {pmid38797057, year = {2024}, author = {Li, Y and Guo, M and Wang, Q and Zhou, H and Wu, W and Lin, H and Fan, H}, title = {Glaesserella parasuis serotype 5 induces pyroptosis via the RIG-I/MAVS/NLRP3 pathway in swine tracheal epithelial cells.}, journal = {Veterinary microbiology}, volume = {294}, number = {}, pages = {110127}, doi = {10.1016/j.vetmic.2024.110127}, pmid = {38797057}, issn = {1873-2542}, abstract = {Glaesserella parasuis (G. parasuis) is a common Gram-negative commensal bacterium in the upper respiratory tract of swine that can cause Glässer's disease under stress conditions. Pyroptosis is an important immune defence mechanism of the body that plays a crucial role in clearing pathogen infections and endogenous danger signals. This study aimed to investigate the mechanism of G. parasuis serotype 5 SQ (GPS5-SQ)-induced pyroptosis in swine tracheal epithelial cells (STECs). The results of the present study demonstrated that GPS5-SQ infection induces pyroptosis in STECs by enhancing the protein level of the N-terminal domain of gasdermin D (GSDMD-N) and activating the NOD-like receptor protein 3 (NLRP3) inflammasome. Furthermore, the levels of pyroptosis-related proteins, including GSDMD-N and cleaved caspase-1 were considerably decreased in STECs after the knockdown of retinoic acid inducible gene-I (RIG-I) and mitochondrial antiviral signaling protein (MAVS). These results indicated that GPS5-SQ might trigger pyroptosis through the activation of the RIG-I/MAVS/NLRP3 signaling pathway. More importantly, the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) repressed the activation of the RIG-I/MAVS/NLRP3 signaling and rescued the decrease in Occludin and zonula occludens-1 (ZO-1) after GPS5-SQ infection. Overall, our findings show that GPS5-SQ can activate RIG-I/MAVS/NLRP3 signaling and destroy the integrity of the epithelial barrier by inducing ROS generation in STECs, shedding new light on G. parasuis pathogenesis.}, }
@article {pmid38791242, year = {2024}, author = {Pascal, W and Smoliński, A and Gotowiec, M and Wojtkiewicz, M and Stachura, A and Pełka, K and Kopka, M and Quinn, KP and Woessner, AE and Grzelecki, D and Włodarski, P}, title = {Pre-Incisional and Multiple Intradermal Injection of N-Acetylcysteine Slightly Improves Incisional Wound Healing in an Animal Model.}, journal = {International journal of molecular sciences}, volume = {25}, number = {10}, pages = {}, pmid = {38791242}, issn = {1422-0067}, support = {1M15/NM1/17//Medical University of Warsaw/ ; MNiSW/2019/106/DIR/NN3//Polish Ministry of Science and Higher Education/ ; }, mesh = {Animals ; *Wound Healing/drug effects ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Rats ; *Rats, Sprague-Dawley ; Injections, Intradermal ; Disease Models, Animal ; Skin/drug effects/pathology/injuries ; Male ; Surgical Wound/drug therapy/pathology ; Collagen/metabolism ; Cicatrix/pathology/drug therapy ; }, abstract = {The objective of this study was to investigate if delivering multiple doses of N-acetylcysteine (NAC) post-surgery in addition to pre-incisional administration significantly impacts the wound healing process in a rat model. Full-thickness skin incisions were carried out on the dorsum of 24 Sprague-Dawley rats in six locations. Fifteen minutes prior to the incision, half of the sites were treated with a control solution, with the wounds on the contralateral side treated with solutions containing 0.015%, 0.03% and 0.045% of NAC. In the case of the NAC treated group, further injections were given every 8 h for three days. On days 3, 7, 14 and 60 post-op, rats were sacrificed to gather material for the histological analysis, which included histomorphometry, collagen fiber organization analysis, immunohistochemistry and Abramov scale scoring. It was determined that scars treated with 0.015% NAC had significantly lower reepithelization than the control at day 60 post-op (p = 0.0018). Scars treated with 0.045% NAC had a significantly lower collagen fiber variance compared to 0.015% NAC at day 14 post-op (p = 0.02 and p = 0.04) and a lower mean scar width than the control at day 60 post-op (p = 0.0354 and p = 0.0224). No significant differences in the recruitment of immune cells and histological parameters were found. The results point to a limited efficacy of multiple NAC injections post-surgery in wound healing.}, }
@article {pmid38788361, year = {2024}, author = {Cao, W and Zeng, Y and Su, Y and Gong, H and He, J and Liu, Y and Li, C}, title = {The involvement of oxidative stress and the TLR4/NF-κB/NLRP3 pathway in acute lung injury induced by high-altitude hypoxia.}, journal = {Immunobiology}, volume = {229}, number = {3}, pages = {152809}, doi = {10.1016/j.imbio.2024.152809}, pmid = {38788361}, issn = {1878-3279}, abstract = {OBJECTIVE: This study investigated the effect of oxidative stress and the TLR4/NF-κB/NLRP3 pathway on the pathogenesis of acute lung injury (ALI) induced by high-altitude hypoxia.<br><br>METHODS: Rats were placed in an animal hyperbaric oxygen chamber to establish a rat model of ALI induced by high-altitude hypoxia after treatment with N-acetylcysteine (NAC; a reactive oxygen species [ROS] inhibitor) or/and MCC950 (an NLPR3 inflammasome inhibitor). After modeling, the wet-to-dry weight ratio (W/D) of rat lung tissues was calculated. In lung tissues, ROS levels were detected with immunofluorescence, the enzyme activity was tested with the kit, and the expression of TLR4/NF-&#x3ba;B/NLRP3 pathway-related genes and proteins was measured with western blotting and qRT-PCR. The levels of inflammatory factors in the serum were quantified with ELISA.<br><br>RESULTS: After modeling, rats showed significantly increased W/D, ROS levels, and Malondialdehyde (MDA) concentrations and markedly diminished Superoxide dismutase (SOD) and Glutathione (GSH) concentrations in lung tissues (all P&#xa0;<&#xa0;0.01), accompanied by substantially enhanced serum levels of TNF-&#x3b1;, IL-6, and IL-1&#x3b2;, significantly reduced serum levels of IL-10, and remarkably augmented TLR4, NLRP3, p-NF-&#x3ba;B p65, NF-&#x3ba;B p65 mRNA, and Caspase-1 expression in lung tissues (all P&#xa0;<&#xa0;0.01). Furthermore, treatment with NAC or MCC950 alone or in combination prominently lowered the W/D of lung tissues (P&#xa0;<&#xa0;0.01), serum levels of TNF-&#x3b1; (P&#xa0;<&#xa0;0.05), IL-6 (P&#xa0;<&#xa0;0.05), and IL-1&#x3b2; (P&#xa0;<&#xa0;0.01), and NF-&#x3ba;B p65 expression and phosphorylation (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01) while significantly increasing SOD and GSH concentrations (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01) and serum levels of IL-10 (P&#xa0;<&#xa0;0.01) in modeled rats. Meanwhile, treatment of NAC alone or combined with MCC950 significantly reduced MDA concentration and ROS levels (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01) in modeled rats, and treatment of MCC950 alone or combined with NAC considerably declined TLR4, NLRP3, and Caspase-1 expression in modeled rats (P&#xa0;<&#xa0;0.05, P&#xa0;<&#xa0;0.01).<br><br>CONCLUSION: Inhibition of oxidative stress and the TLR4/NF-&#x3ba;B/NLRP3 pathway can ameliorate ALI in rats exposed to high-altitude hypoxia.}, }
@article {pmid38785564, year = {2024}, author = {Kobroob, A and Kumfu, S and Chattipakorn, N and Wongmekiat, O}, title = {Modulation of Sirtuin 3 by N-Acetylcysteine Preserves Mitochondrial Oxidative Phosphorylation and Restores Bisphenol A-Induced Kidney Damage in High-Fat-Diet-Fed Rats.}, journal = {Current issues in molecular biology}, volume = {46}, number = {5}, pages = {4935-4950}, pmid = {38785564}, issn = {1467-3045}, support = {075/2564//The Faculty of Medicine Endowment Fund for Medical Research, Chiang Mai University, Chiang Mai, Thailand/ ; }, abstract = {Bisphenol A (BPA) and high-fat diets (HFD) are known to adversely affect the kidneys. However, the combined effects of both cases on kidney health and the potential benefits of N-acetylcysteine (NAC) in mitigating these effects have not been investigated. To explore these aspects, male Wistar rats were fed with HFD and allocated to receive a vehicle or BPA. At week twelve, the BPA-exposed rats were subdivided to receive a vehicle or NAC along with BPA until week sixteen. Rats fed HFD and exposed to BPA showed renal dysfunction and structural abnormalities, oxidative stress, inflammation, and mitochondrial dysfunction, with alterations in key proteins related to mitochondrial oxidative phosphorylation (OXPHOS), bioenergetics, oxidative balance, dynamics, apoptosis, and inflammation. Treatment with NAC for 4 weeks significantly improved these conditions. The findings suggest that NAC is beneficial in protecting renal deterioration brought on by prolonged exposure to BPA in combination with HFD, and modulation of sirtuin 3 (SIRT3) signaling by NAC appears to play a key role in the preservation of homeostasis and integrity within the mitochondria by enhancing OXPHOS activity, maintaining redox balance, and reducing inflammation. This study provides valuable insights into potential therapeutic strategies for preserving kidney health in the face of environmental and dietary challenges.}, }
@article {pmid38781725, year = {2024}, author = {Nagano, S and Unuma, K and Aki, T and Uemura, K}, title = {N-acetylcysteine alleviates arsenic trioxide-induced reductions in hepatic catalase gene expression both in vitro and in vivo.}, journal = {Legal medicine (Tokyo, Japan)}, volume = {69}, number = {}, pages = {102458}, doi = {10.1016/j.legalmed.2024.102458}, pmid = {38781725}, issn = {1873-4162}, abstract = {Arsenic trioxide (ATO), one of the oldest and most frequently used poisons, is well-known in forensic science for inducing hepatotoxicity. The regulation of peroxisomal antioxidative enzyme catalase (CAT) involves intricate mechanisms at both transcriptional and post-transcriptional levels. However, the molecular mechanisms underlying the regulation of CAT gene expression in hepatic cells remain elusive. Furthermore, the regulation of CAT gene expression evident in animals administered with ATO in vivo is not well-explored, although several studies have revealed ATO-induced reductions in CAT enzymatic activity in rat livers. In this study, we revealed ATO-dependent reductions in CAT gene expression in both rat liver and Huh-7 human hepatoma cells. Our results indicate that the decline in CAT enzymatic activity can be attributed, at least in part, to the downregulation of its gene expression. The ATO-induced reduction in CAT expression was concurrent with the reduction in peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator (PGC)-1α and inactivation of PPARγ, both considered as positive regulators of CAT gene expression. Moreover, antioxidant N-acetylcysteine (NAC) demonstrated the capability to alleviate the downregulation of CAT gene expression both in vivo and in vitro. Additionally, NAC played a role in alleviating ATO-induced hepatotoxicity, potentially by mitigating the transcriptional downregulation of the CAT gene. Altogether, these results indicate that ATO exerts toxicity by inhibiting the antioxidant defense mechanism, which may be useful for forensic diagnosis of arsenic poisoning and clinical treatment of mitigating ATO-induced hepatotoxicity.}, }
@article {pmid38775255, year = {2024}, author = {Bolarinwa, AB and Oduwole, O and Okebe, J and Ogbenna, AA and Otokiti, OE and Olatinwo, AT}, title = {Antioxidant supplementation for sickle cell disease.}, journal = {The Cochrane database of systematic reviews}, volume = {5}, number = {5}, pages = {CD013590}, pmid = {38775255}, issn = {1469-493X}, mesh = {Humans ; *Anemia, Sickle Cell/drug therapy/blood ; *Antioxidants/therapeutic use ; Ascorbic Acid/therapeutic use ; Bias ; *Dietary Supplements ; Oxidative Stress/drug effects ; Placebos/therapeutic use ; Quality of Life ; *Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Sickle cell disease (SCD) refers to a group of genetic disorders characterized by the presence of an abnormal haemoglobin molecule called haemoglobin S (HbS). When subjected to oxidative stress from low oxygen concentrations, HbS molecules form rigid polymers, giving the red cell the typical sickle shape. Antioxidants have been shown to reduce oxidative stress and improve outcomes in other diseases associated with oxidative stress. Therefore, it is important to review and synthesize the available evidence on the effect of antioxidants on the clinical outcomes of people with SCD.<br><br>OBJECTIVES: To assess the effectiveness and safety of antioxidant supplementation for improving health outcomes in people with SCD.<br><br>SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 August 2023.<br><br>SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing antioxidant supplementation to placebo, other antioxidants, or different doses of antioxidants, in people with SCD.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed the risk of bias and certainty of the evidence, and reported according to Cochrane methodological procedures.<br><br>MAIN RESULTS: The review included 1609 participants in 26 studies, with 17 comparisons. We rated 13 studies as having a high risk of bias overall, and 13 studies as having an unclear risk of bias overall due to study limitations. We used GRADE to rate the certainty of evidence. Only eight studies reported on our important outcomes at six months. Vitamin C (1400 mg) plus vitamin E (800 mg) versus placebo Based on evidence from one study in 83 participants, vitamin C (1400 mg) plus vitamin E (800 mg) may not be better than placebo at reducing the frequency of crisis (risk ratio (RR) 1.18, 95% confidence interval (CI) 0.64 to 2.18), the severity of pain (RR 1.33, 95% CI 0.40 to 4.37), or adverse effects (AE), of which the most common were headache, nausea, fatigue, diarrhoea, and epigastric pain (RR 0.56, 95% CI 0.31 to 1.00). Vitamin C plus vitamin E may increase the risk of SCD-related complications (acute chest syndrome: RR 2.66, 95% CI 0.77 to 9.13; 1 study, 83 participants), and increase haemoglobin level (median (interquartile range) 90 (81 to 96) g/L versus 93.5 (84 to 105) g/L) (1 study, 83 participants) compared to placebo. However, the evidence for all the above effects is very uncertain. The study did not report on quality of life (QoL) of participants and their caregivers, nor on frequency of hospitalization. Zinc versus placebo Zinc may not be better than placebo at reducing the frequency of crisis at six months (rate ratio 0.62, 95% CI 0.17 to 2.29; 1 study, 36 participants; low-certainty evidence). We are uncertain whether zinc is better than placebo at improving sickle cell-related complications (complete healing of leg ulcers at six months: RR 2.00, 95% CI 0.60 to 6.72; 1 study, 34 participants; very low-certainty evidence). Zinc may be better than placebo at increasing haemoglobin level (g/dL) (MD 1.26, 95% CI 0.44 to 1.26; 1 study, 36 participants; low-certainty evidence). The study did not report on severity of pain, QoL, AE, and frequency of hospitalization. N-acetylcysteine versus placebo N-acetylcysteine (NAC) 1200 mg may not be better than placebo at reducing the frequency of crisis in SCD, reported as pain days (rate ratio 0.99 days, 95% CI 0.53 to 1.84; 1 study, 96 participants; low-certainty evidence). Low-certainty evidence from one study (96 participants) suggests NAC (1200 mg) may not be better than placebo at reducing the severity of pain (MD 0.17, 95% CI -0.53 to 0.87). Compared to placebo, NAC (1200 mg) may not be better at improving physical QoL (MD -1.80, 95% CI -5.01 to 1.41) and mental QoL (MD 2.00, 95% CI -1.45 to 5.45; very low-certainty evidence), reducing the risk of adverse effects (gastrointestinal complaints, pruritus, or rash) (RR 0.92, 95% CI 0.75 to 1.14; low-certainty evidence), reducing the frequency of hospitalizations (rate ratio 0.98, 95% CI 0.41 to 2.38; low-certainty evidence), and sickle cell-related complications (RR 5.00, 95% CI 0.25 to 101.48; very low-certainty evidence), or increasing haemoglobin level (MD -0.18 g/dL, 95% CI -0.40 to 0.04; low-certainty evidence). L-arginine versus placebo L-arginine may not be better than placebo at reducing the frequency of crisis (monthly pain) (RR 0.71, 95% CI 0.26 to 1.95; 1 study, 50 participants; low-certainty evidence). However, L-arginine may be better than placebo at reducing the severity of pain (MD -1.41, 95% CI -1.65 to -1.18; 2 studies, 125 participants; low-certainty evidence). One participant allocated to L-arginine developed hives during infusion of L-arginine, another experienced acute clinical deterioration, and a participant in the placebo group had clinically relevant increases in liver function enzymes. The evidence is very uncertain whether L-arginine is better at reducing the mean number of days in hospital compared to placebo (MD -0.85 days, 95% CI -1.87 to 0.17; 2 studies, 125 participants; very low-certainty evidence). Also, L-arginine may not be better than placebo at increasing haemoglobin level (MD 0.4 g/dL, 95% CI -0.50 to 1.3; 2 studies, 106 participants; low-certainty evidence). No study in this comparison reported on QoL and sickle cell-related complications. Omega-3 versus placebo Very low-certainty evidence shows no evidence of a difference in the risk of adverse effects of omega-3 compared to placebo (RR 1.05, 95% CI 0.74 to 1.48; 1 study, 67 participants). Very low-certainty evidence suggests that omega-3 may not be better than placebo at increasing haemoglobin level (MD 0.36 g/L, 95% CI -0.21 to 0.93; 1 study, 67 participants). The study did not report on frequency of crisis, severity of pain, QoL, frequency of hospitalization, and sickle cell-related complications.<br><br>AUTHORS' CONCLUSIONS: There was inconsistent evidence on all outcomes to draw conclusions on the beneficial and harmful effects of antioxidants. However, L-arginine may be better than placebo at reducing the severity of pain at six months, and zinc may be better than placebo at increasing haemoglobin level. We are uncertain whether other antioxidants are beneficial for SCD. Larger studies conducted on each comparison would reduce the current uncertainties.}, }
@article {pmid38774197, year = {2023}, author = {Sztolsztener, K and Dzięcioł, J and Chabowski, A}, title = {N-acetylcysteine acts as a potent anti-inflammatory agent altering the eicosanoid profile in the development of simple steatosis and its progression to hepatitis.}, journal = {Clinical and experimental hepatology}, volume = {9}, number = {4}, pages = {386-395}, pmid = {38774197}, issn = {2392-1099}, abstract = {AIM OF THE STUDY: We aimed to examine the influence of N-acetylcysteine (NAC) on the development of metabolic dysfunction-associated steatotic liver disease (MASLD) in rats with a specific focus on the eicosanoid pathway.<br><br>MATERIAL AND METHODS: The experiment was conducted on male Wistar rats fed a standard diet or a high-fat diet (HFD) for eight weeks. In the entire experiment, half of rats from both groups received intragastrically NAC solution prepared in normal saline. H + E staining was used for the histological assessment of liver tissue. The gas-liquid chromatography (GLC) technique was used for the assessment of the activity of n-3 and n-6 polyunsaturated fatty acid (PUFA) pathways and arachidonic acid concentration. ELISA and multiplex immunoassay kits were applied for the measurement of eicosanoid, cytokine, and chemokine levels. The Western blot technique was applied to determine the expression of proteins involved in the inflammation pathway.<br><br>RESULTS: NAC decreased hepatic n-6 PUFA activity in all examined lipid pools and decreased the hepatic content of arachidonic acid as a pro-inflammatory precursor in each lipid pool, especially in the phospholipid fraction in rats with fatty lipid disease. NAC administration abolished 5-LOX expression, leading to a decrease in the content of pro-inflammatory leukotriene B4 and leukotriene C4. In rats with steatosis, NAC weakened NF-&#x3ba;B expression and raised Nrf-2 expression, inhibiting the synthesis of pro-inflammatory cytokines and chemokines.<br><br>CONCLUSIONS: NAC treatment significantly rate-limited the progression of simple hepatic steatosis to hepatitis in a rat model of MASLD.}, }
@article {pmid38770316, year = {2024}, author = {Huang, HL and Cheng, N and Zhou, CX and Liang, J}, title = {Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury.}, journal = {Heliyon}, volume = {10}, number = {10}, pages = {e30947}, pmid = {38770316}, issn = {2405-8440}, abstract = {Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.}, }
@article {pmid38769217, year = {2024}, author = {Takahashi, K and Tanaka, T and Ishihara, A and Ohta, T}, title = {Strobilurin X acts as an anticancer drug by inhibiting protein synthesis and suppressing mitochondrial respiratory chain activity.}, journal = {Discover oncology}, volume = {15}, number = {1}, pages = {177}, pmid = {38769217}, issn = {2730-6011}, abstract = {PURPOSE: Strobilurins act as antifungal agents by inhibiting the mitochondrial respiratory chain. The cytotoxic activity of strobilurins, focusing on its anticancer activities, has been reported. However, the mechanisms involved in these activities remain unclear.<br><br>METHODS: The cytotoxic effects of strobilurin X isolated from the mycelium of Mucidula. venosolamellata were examined in human cancer cell lines (A549 and HeLa) and normal fibroblasts (WI-38).<br><br>RESULTS: Strobilurin X significantly decreased the viability of A549 and HeLa cells compared to that in the WI-38 cells after 48&#xa0;h of exposure. The EC50 values for cytotoxicity in the A549, HeLa, and WI-38 cells were 3.4, 5.4, and 16.8&#xa0;&#x3bc;g/mL, respectively. Strobilurin X inhibited the mitochondrial respiratory chain and enhanced the release of lactate in the A549 cells. The IC50 value of strobilurin X against the mitochondrial respiratory chain complex III activity was 139.8&#xa0;ng/mL. The cytotoxicity induced by strobilurin X was not completely rescued after adding uridine, methyl pyruvate, or N-acetyl cysteine. Furthermore, pharmacological approaches demonstrated that strobilurin X failed to modulate the mitogen-activated protein kinase family and phosphoinositide 3-kinase-Akt pathways; alternatively, it suppressed protein synthesis independent of uridine.<br><br>CONCLUSION: Strobilurin X induced cytotoxicity by blocking the mitochondrial respiratory chain and suppressing protein synthesis. These findings may aid in the development of novel anticancer drugs using strobilurins.}, }
@article {pmid38762757, year = {2024}, author = {Qi, Z and Yang, W and Xue, B and Chen, T and Lu, X and Zhang, R and Li, Z and Zhao, X and Zhang, Y and Han, F and Kong, X and Liu, R and Yao, X and Jia, R and Feng, S}, title = {ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.}, journal = {Autophagy}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/15548627.2024.2353548}, pmid = {38762757}, issn = {1554-8635}, abstract = {Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.}, }
@article {pmid38761382, year = {2024}, author = {Li, X and Xin, L and Yang, L and Yang, Y and Li, W and Zhang, M and Liao, Y and Sun, C and Li, W and Peng, Y and Zheng, J}, title = {Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo.}, journal = {Chemical research in toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.chemrestox.4c00008}, pmid = {38761382}, issn = {1520-5010}, abstract = {Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.}, }
@article {pmid38754743, year = {2024}, author = {Nguyen, UTT and Youn, E and Le, TAN and Ha, NM and Tran, SH and Lee, S and Cha, JW and Park, JS and Kwon, HC and Kang, K}, title = {Photodynamic treatment increases the lifespan and oxidative stress resistance of Caenorhabditis elegans.}, journal = {Free radical biology &amp; medicine}, volume = {221}, number = {}, pages = {98-110}, doi = {10.1016/j.freeradbiomed.2024.05.023}, pmid = {38754743}, issn = {1873-4596}, abstract = {Photodynamic therapy is a noninvasive treatment in which specific photosensitizers and light are used to produce high amounts of reactive oxygen species (ROS), which can be employed for targeted tissue destruction in cancer treatment or antimicrobial therapy. However, it remains unknown whether lower amounts of ROS produced by mild photodynamic therapy increase lifespan and stress resistance at the organism level. Here, we introduce a novel photodynamic treatment (PDTr) that uses 20 μM hypericin, a photosensitizer that originates from Hypericum perforatum, and orange light (590 nm, 5.4 W/m[2], 1 min) to induce intracellular ROS formation (ROS), thereby resulting in lifespan extension and improved stress resistance in C. elegans. The PDTr-induced increase in longevity was abrogated by N-acetyl cysteine, suggesting the hormetic response was driven by prooxidative mechanisms. PDTr activated the translocation of SKN-1/NRF-2 and DAF-16/FOXO, leading to elevated expression of downstream oxidative stress-responsive genes, including ctl-1, gst-4, and sod-3. In summary, our findings suggest a novel PDTr method that extends the lifespan of C. elegans under both normal and oxidative stress conditions through the activation of SKN-1 and DAF-16 via the involvement of many antioxidant genes.}, }
@article {pmid38750444, year = {2024}, author = {Li, YS and Xia, J and Chen, CY and Ren, SH and He, MR}, title = {Upregulated dual oxidase 1-induced oxidative stress and caspase-1-dependent pyroptosis reflect the etiologies of heart failure.}, journal = {BMC molecular and cell biology}, volume = {25}, number = {1}, pages = {16}, pmid = {38750444}, issn = {2661-8850}, support = {ZK2019A07//Songjiang District New round of Medical key discipline Construction Project (Cardiology Department)/ ; }, mesh = {*Pyroptosis ; *Heart Failure/metabolism/genetics ; *Oxidative Stress ; *Dual Oxidases/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; Humans ; *Doxorubicin/pharmacology ; *Caspase 1/metabolism ; *Up-Regulation ; Cell Line ; Interleukin-18/metabolism ; Interleukin-1beta/metabolism ; }, abstract = {BACKGROUND: Oxidative stress is implicated in the pathogenesis of heart failure. Dual oxidase 1 (DUOX1) might be important in heart failure development through its mediating role in oxidative stress. This study was designed to evaluate the potential role of DUOX1 in heart failure.<br><br>MATERIALS AND METHODS: AC16 cells were treated with 2 &#xb5;mol/L of doxorubicin (DOX) for 12, 24, and 48&#xa0;h to construct a heart failure model. DUOX1 overexpression and silencing in AC16 cell were established. DUOX1 expression was detected by Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Pyroptosis and reactive oxygen species (ROS) production were measured by flow cytometry.<br><br>RESULTS: Increased DUOX1 expression levels were observed after DOX treatment for 24&#xa0;h in AC16 cells. DUOX1 silencing inhibited DOX-induced pyroptosis and ROS production. The release of IL-1&#x3b2;, IL-18, and lactate dehydrogenase (LDH), and expression levels of pyroptosis-related proteins were also decreased. DUOX1 overexpression increased pyroptosis, ROS production, IL-1&#x3b2;, IL-18, and LDH release, and pyroptosis-related protein expression. N-acetyl-cysteine (NAC) significantly reversed DUOX1-induced pyroptosis, ROS, and related factors.<br><br>CONCLUSION: These results suggest that DUOX1-derived genotoxicity could promote heart failure development. In the process, oxidative stress and pyroptosis may be involved in the regulation of DUOX1 in heart failure.}, }
@article {pmid38749218, year = {2024}, author = {Han, YK and Lim, HJ and Jang, G and Jang, SY and Park, KM}, title = {Kidney ischemia/reperfusion injury causes cholangiocytes primary cilia disruption and abnormal bile secretion.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1870}, number = {6}, pages = {167225}, doi = {10.1016/j.bbadis.2024.167225}, pmid = {38749218}, issn = {1879-260X}, abstract = {BACKGROUND: Acute kidney injury (AKI) causes distant liver injury, to date, which causes poor outcomes of patients with AKI. Many studies have been performed to overcome AKI-associated liver injury. However, those studies have mainly focused on hepatocytes, and AKI-induced liver injury still remains a clinical problem. Here, we investigated the implication of cholangiocytes and their primary cilia which are critical in final bile secretion. Cholangiocyte, a lining cell of bile ducts, are the only liver epithelial cell containing primary cilium (a microtubule-based cell surface signal-sensing organelle).<br><br>METHODS: Cystathione &#x3b3;-lyase (CSE, a transsulfuration enzyme) deficient and wild-type mice were subjected to kidney ischemia followed by reperfusion (KIR). Some mice were administered with N-acetyl-cysteine (NAC).<br><br>RESULTS: KIR damaged hepatocytes and cholagiocytes, disrupted cholangiocytes primary cilia, released the disrupted ciliary fragments into the bile, and caused abnormal bile secretion. Glutathione (GSH) and H2S levels in the livers were significantly reduced by KIR, resulting in increased the ratio oxidized GSH to total GSH, and oxidation of tissue and bile. CSE and cystathione &#x3b2;-synthase (CBS) expression were lowered in the liver after KIR. NAC administration increased total GSH and H2S levels in the liver and attenuated KIR-induced liver injuries. In contrast, Cse deletion caused the reduction of total GSH levels and worsened KIR-induced liver injuries, including primary cilia damage and abnormal bile secretion.<br><br>CONCLUSIONS: These results indicate that KIR causes cholangiocyte damage, cholangiocytes primary cilia disruption, and abnormal bile secretion through reduced antioxidative ability of the liver.}, }
@article {pmid38740632, year = {2024}, author = {Boppana, TK and Mittal, S and Madan, K and Tiwari, P and Mohan, A and Hadda, V}, title = {Antioxidant therapies for obstructive sleep apnea: A systematic review and meta-analysis.}, journal = {Sleep &amp; breathing = Schlaf &amp; Atmung}, volume = {}, number = {}, pages = {}, pmid = {38740632}, issn = {1522-1709}, abstract = {PURPOSE: Obstructive sleep apnea (OSA) is a common clinical problem that is associated with adverse cardiovascular outcomes attributed to the oxidative stress due to sympathetic overstimulation. Treatment approaches targeting oxidative stress have been tried by multiple investigators. This systematic review and meta-analysis evaluated the efficacy and safety of such approaches.<br><br>METHODS: Pubmed and Embase databases were searched for human studies evaluating the utility of antioxidant therapies in patients with OSA.<br><br>RESULTS: A total of six studies (five randomized trials and one case-control study) were included, including 160 patients with OSA using N-acetyl cysteine, vitamin C, carbocysteine, superoxide dismutase, vitamin E, allopurinol, and their combinations. There was a significant improvement in flow-mediated dilatation (FMD) following antioxidants, with the pooled effect being 2.16 % (95% CI 1.65-2.67) using the random-effects model (I2 = 0% and p<0.001). It was also associated with a significant reduction in malondialdehyde levels and an increase in reduced glutathione (GSH) levels. There was also a significant improvement in the Epworth sleepiness scale, oxygen desaturation index, and minimum oxygen saturation during sleep without any significant adverse effects.<br><br>CONCLUSION: Antioxidant therapy in patients with OSA is associated with improved endothelial function, reduced oxidative stress, and improved sleep parameters. These results call for future multicentre studies with longer follow-ups to assess the utility of antioxidant therapy in patients with OSA.}, }
@article {pmid38735462, year = {2024}, author = {Li, M and Tang, S and Velkov, T and Shen, J and Dai, C}, title = {Copper exposure induces mitochondrial dysfunction and hepatotoxicity via the induction of oxidative stress and PERK/ATF4 -mediated endoplasmic reticulum stress.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {352}, number = {}, pages = {124145}, doi = {10.1016/j.envpol.2024.124145}, pmid = {38735462}, issn = {1873-6424}, abstract = {Copper is an essential trace element, and excessive exposure could result in hepatoxicity, however, the underlying molecular mechanisms remain incompletely understood. The present study is aimed to investigate the molecular mechanisms of copper sulfate (CuSO4) exposure-induced hepatoxicity both in vivo and in vitro. In vitro, HepG2 and L02 cells were exposed to various doses of CuSO4 for 24 h. Cell viability, ROS production, oxidative stress biomarkers, mitochondrial functions, ultrastructure, intracellular calcium (Ca[2+)] concentration, and the expression of proteins related to mitochondrial apoptosis and endoplasmic reticulum (ER) stress were assessed. In vivo, C57BL/6 mice were treated with CuSO4 at doses of 10 and 30 mg/kg BW/day and co-treated with 4-PBA at 100 mg/kg BW/day for 35 days. Subsequently, liver function, histopathological features, and protein expression were evaluated. Results found that exposure to CuSO4 at concentrations of 100-400 μM for 24 h significantly decreased the viabilities of HepG2 and L02 cells and it was in a dose-dependent manner. Additionally, CuSO4 exposure induced significant oxidative stress and mitochondrial dysfunction in HepG2 cells, which were partially ameliorated by the antioxidant N-acetylcysteine (NAC). Furthermore, CuSO4 exposure prominently triggered ER stress, as evidenced by the upregulation of GRP94, GRP78, phosphorylated forms of PERK and eIF2α, and CHOP proteins in livers of mice and HepG2 cells. NAC treatment significantly inhibited CuSO4 exposure -induced ER stress in HepG2 cells. Pharmacological inhibition of ER stress through co-treatment with 4-PBA and the PERK inhibitor GSK2606414, as well as genetic knockdown of ATF4, partially mitigated CuSO4-induced cytotoxicity in HepG2 cells by reducing mitochondrial dysfunction and inhibiting the mitochondrial apoptotic pathway. Moreover, 4-PBA treatment significantly attenuated CuSO4-induced caspase activation and hepatoxicity in mice. In conclusion, these results reveal that CuSO4-induced hepatotoxicity involves mitochondrial dysfunction and ER stress by activating oxidative stress induction and PERK/ATF4 pathway.}, }
@article {pmid38735082, year = {2024}, author = {Yu, N and Wu, X and Zhang, C and Qin, Q and Gu, Y and Ke, W and Liu, X and Zhang, Q and Liu, Z and Chen, M and Wang, K}, title = {NADPH and NAC synergistically inhibits chronic ocular hypertension-induced neurodegeneration and neuroinflammation through regulating p38/MAPK pathway and peroxidation.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {175}, number = {}, pages = {116711}, doi = {10.1016/j.biopha.2024.116711}, pmid = {38735082}, issn = {1950-6007}, abstract = {Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by neurodegeneration and neuroinflammation with retinal NAD/NADP and GSH decline. Nicotinamide adenine dinucleotide (NAD)/NAD phosphate (NADP) and glutathione (GSH) are two redox reducers in neuronal and glial metabolism. However, therapeutic strategies targeting NAD/NADP or GSH do not exert ideal effects, and the underlying mechanisms are still poorly understood. We assessed morphological changes in retinal ganglion cells (RGCs), the affected neurons in glaucoma, and Müller cells, the major glial cells in the retina, as well as the levels of phosphorylated p38 (p-p38) and Caspase-3 in glaucoma patients. We constructed a modified chronic ocular hypertensive rat model and an oxygen-glucose deprivation (OGD) cell model. After applying NADPH and N-acetylcysteine (NAC), a precursor to cysteine, the rate-limiting substrate in GSH biosynthesis, to cells, apoptosis, axonal damage and peroxidation were reduced in the RGCs of the NAC group and p-p38 levels were decreased in the RGCs of the NADPH group, while in stimulated Müller cells cultured individually or cocultured with RGCs, gliosis and p38/MAPK, rather than JNK/MAPK, activation were inhibited. The results were more synergistic in the rat model, where either NADPH or NAC showed crossover effects on inhibiting peroxidation and p38/MAPK pathway activation. Moreover, the combination of NADPH and NAC ameliorated RGC electrophysiological function and prevented Müller cell gliosis to the greatest extent. These data illustrated conjoined mechanisms in glaucomatous RGC injury and Müller cell gliosis and suggested that NADPH and NAC collaborate as a neuroprotective and anti-inflammatory combination treatment for glaucoma and other underlying human neurodegenerative diseases.}, }
@article {pmid38733769, year = {2024}, author = {Wang, R and Zhong, L and Wang, T and Sun, T and Yang, J and Liu, X and Wu, Y and Guo, Q and Gao, Y and Zhao, K}, title = {Inducing ubiquitination and degradation of TrxR1 protein by LW-216 promotes apoptosis in non-small cell lung cancer via triggering ROS production.}, journal = {Neoplasia (New York, N.Y.)}, volume = {53}, number = {}, pages = {101004}, pmid = {38733769}, issn = {1476-5586}, mesh = {*Carcinoma, Non-Small-Cell Lung/metabolism/pathology/drug therapy/genetics ; Humans ; *Thioredoxin Reductase 1/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Lung Neoplasms/metabolism/pathology/drug therapy ; *Apoptosis/drug effects ; Animals ; Mice ; *Ubiquitination ; *Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Proteolysis ; Cell Proliferation/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Disease Models, Animal ; Male ; Antineoplastic Agents/pharmacology ; }, abstract = {Thioredoxin reductases are frequently overexpressed in various solid tumors as a protective mechanism against heightened oxidative stress. Inhibitors of this system, such as Auranofin, are effective in eradicating cancer cells. However, the clinical significance of thioredoxin reductase 1 (TrxR1) in lung cancer, as well as the potential for its antagonist as a treatment option, necessitated further experimental validation. In this study, we observed significant upregulation of TrxR1 specifically in non-small cell lung cancer (NSCLC), rather than small cell lung cancer. Moreover, TrxR1 expression exhibited associations with survival rate, tumor volume, and histological classification. We developed a novel TrxR1 inhibitor named LW-216 and assessed its antitumor efficacy in NSCLC. Our results revealed that LW-216 is effectively bound with intracellular TrxR1 at sites R371 and G442, facilitating TrxR1 ubiquitination and suppressing TrxR1 expression, while not affecting TrxR2 expression. Treatment of LW-216-induced DNA damage and cell apoptosis in NSCLC cells through the generation of reactive oxygen species (ROS). Importantly, supplementation with N-acetylcysteine (NAC) or ectopic TrxR1 expression reversed LW-216-induced apoptosis. Furthermore, LW-216 displayed potent tumor growth inhibition in NSCLC cell-implanted mice, reducing TrxR1 expression in xenografts. Remarkably, LW-216 exhibited superior antitumor activity compared to Auranofin in vivo. Collectively, our research provides compelling evidence supporting the potential of targeting TrxR1 by LW-216 as a promising therapeutic strategy for NSCLC.}, }
@article {pmid38732054, year = {2024}, author = {Padalhin, A and Abueva, C and Ryu, HS and Yoo, SH and Seo, HH and Park, SY and Chung, PS and Woo, SH}, title = {Impact of Thermo-Responsive N-Acetylcysteine Hydrogel on Dermal Wound Healing and Oral Ulcer Regeneration.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38732054}, issn = {1422-0067}, support = {RS-2020-KD000027//Ministry of Science and ICT/ ; RS-2023-00247651//National Research Foundation of Korea/ ; NRF-2020R1A6A1A03043283//National Research Foundation of Korea/ ; }, mesh = {*Wound Healing/drug effects ; *Acetylcysteine/pharmacology ; Animals ; Rats ; Humans ; *Hydrogels/chemistry/pharmacology ; *Rats, Sprague-Dawley ; *Oral Ulcer/drug therapy/pathology ; Regeneration/drug effects ; Fibroblasts/drug effects ; Male ; Temperature ; Cell Survival/drug effects ; }, abstract = {This study investigates the efficacy of a thermo-responsive N-acetylcysteine (NAC) hydrogel on wound healing and oral ulcer recovery. Formulated by combining NAC with methylcellulose, the hydrogel's properties were assessed for temperature-induced gelation and cell viability using human fibroblast cells. In vivo experiments on Sprague Dawley rats compared the hydrogel's effects against saline, NAC solution, and a commercial NAC product. Results show that a 5% NAC and 1% methylcellulose solution exhibited optimal outcomes. While modest improvements in wound healing were observed, significant enhancements were noted in oral ulcer recovery, with histological analyses indicating fully regenerated mucosal tissue. The study concludes that modifying viscosity enhances NAC retention, facilitating tissue regeneration. These findings support previous research on the beneficial effects of antioxidant application on damaged tissues, suggesting the potential of NAC hydrogels in improving wound care and oral ulcer treatment.}, }
@article {pmid38731862, year = {2024}, author = {Yi, LX and Tan, EK and Zhou, ZD}, title = {Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson's Disease.}, journal = {International journal of molecular sciences}, volume = {25}, number = {9}, pages = {}, pmid = {38731862}, issn = {1422-0067}, support = {CS-IRG, OF-IRG, HLCA2022, STaR, OF-LCG 000207//National Medical Research Council/ ; Collaboration pilot grant//Duke-NUS Medical School/ ; }, mesh = {Animals ; Humans ; Dopamine/metabolism ; *Dopamine Agonists/therapeutic use/pharmacology ; Dopaminergic Neurons/drug effects/metabolism ; Drug Therapy, Combination ; Enzyme Inhibitors/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy/metabolism ; *Tyrosine 3-Monooxygenase/antagonists &amp; inhibitors/metabolism ; }, abstract = {There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.}, }
@article {pmid38730615, year = {2024}, author = {Forbes, M and Kempa, R and Mastrobuoni, G and Rayman, L and Pietzke, M and Bayram, S and Arlt, B and Spruessel, A and Deubzer, HE and Kempa, S}, title = {L-Glyceraldehyde Inhibits Neuroblastoma Cell Growth via a Multi-Modal Mechanism on Metabolism and Signaling.}, journal = {Cancers}, volume = {16}, number = {9}, pages = {}, pmid = {38730615}, issn = {2072-6694}, abstract = {Glyceraldehyde (GA) is a three-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits neuroblastoma cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and [13]C-labeling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in neuroblastoma cells. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. Analysis of nucleotide pools in L-GA-treated cells depicted a previously unreported observation, in which nucleotide biosynthesis is significantly inhibited. The inhibitory action of L-GA was partially relieved with the co-application of the antioxidant N-acetyl-cysteine. We present novel evidence for a simple sugar that inhibits cancer cell proliferation via dysregulating its fragile homeostatic environment.}, }
@article {pmid38729599, year = {2024}, author = {Wang, Z and Hu, Q and Tian, C and Wang, R and Jiao, Q and Chen, F and Wu, T and Wang, J and Zhu, Y and Liu, A and Zhang, W and Li, J and Shen, H}, title = {Prophylactic Effects of n-Acethylcysteine on Inflammation-induced Depression-like Behaviors in Mice.}, journal = {Neuroscience}, volume = {549}, number = {}, pages = {42-54}, doi = {10.1016/j.neuroscience.2024.05.005}, pmid = {38729599}, issn = {1873-7544}, abstract = {Depression, affecting individuals worldwide, is a prevalent mental disease, with an increasing incidence. Numerous studies have been conducted on depression, yet its pathogenesis remains elusive. Recent advancements in research indicate that disturbances in synaptic transmission, synaptic plasticity, and reduced neurotrophic factor expression significantly contribute to depression's pathogenesis. In our study, we utilized adult male C57BL/6J mice. Lipopolysaccharide (LPS) can induce both chronic and acute depression-like symptoms in mice, a widely used model for studying depression associated with inflammation. N-acetylcysteine (NAC) exhibits anti-inflammatory and ameliorative effects on depressive symptoms. This study sought to determine whether NAC use could mitigate inflammatory depressive behavior through the enhancement of synaptic transmission, synaptic plasticity, and increasing levels of brain-derived neurotrophic factor (BDNF). In this study, we discovered that in mice modeled with depression-like symptoms, the expression levels of dendrites, BDNF, and miniature excitatory postsynaptic potential (mEPSC) in glutamatergic neurons, as well as the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid glutamate receptors (AMPARs) GluA1 and GluA2 subunits, were significantly decreased. These findings suggest an impairment in the synaptic transmission of glutamatergic neurons. Following treatment with NAC, the previously mentioned levels improved, indicating an enhancement in both synaptic transmission and synaptic plasticity. Our results suggest that NAC exerts a protective effect on mouse models of inflammatory depression, potentially through the enhancement of synaptic transmission and plasticity, as well as the restoration of neurotrophic factor expression. These findings offer vital animal experimental evidence supporting NAC's role in mitigating inflammatory depressive behaviors.}, }
@article {pmid38726279, year = {2024}, author = {Zhao, MM and Wang, B and Huang, WX and Zhang, L and Peng, R and Wang, C}, title = {Verteporfin suppressed mitophagy via PINK1/parkin pathway in endometrial cancer.}, journal = {American journal of cancer research}, volume = {14}, number = {4}, pages = {1935-1946}, pmid = {38726279}, issn = {2156-6976}, abstract = {Endometrial cancer (EC) is a malignancy that poses a threat to woman's health worldwide. Building upon prior work, we explored the inhibitory effect of verteporfin on EC. We showed that verteporfin can damage the mitochondria of EC cells, leading to a decrease of mitochondrial membrane potential and an increase in ROS (reactive oxygen species). In addition, verteporfin treatment was shown to inhibit the proliferation and migration of EC cells, promote apoptosis, and reduce the expression of mitophagy-related proteins PINK1/parkin and TOM20. The ROS inhibitor N-Acetyl Cysteine was able to rescue the expression of PINK1/parkin proteins. This suggests that verteporfin may inhibit mitophagy by elevating ROS levels, thereby inhibiting EC cell viability. The effect of verteporfin on mitophagy supports further investigation as a potential therapeutic option for EC.}, }
@article {pmid38718763, year = {2024}, author = {Behtaj, D and Ghorbani, A and Eslamian, G and Malekpour Alamdari, N and Abbasi, M and Zand, H and Shakery, A and Shimi, G and Sohouli, MH and Fazeli Taherian, S}, title = {Ex vivo anti-senescence activity of N-acetylcysteine in visceral adipose tissue of obese volunteers.}, journal = {Obesity facts}, volume = {}, number = {}, pages = {}, doi = {10.1159/000539255}, pmid = {38718763}, issn = {1662-4033}, abstract = {INTRODUCTION: Excessive visceral adiposity is known to drive the onset of metabolic derangements, mostly involving oxidative stress, prolonged inflammation and cellular senescence. N-acetyl cysteine (NAC) is a synthetic form of L-cysteine with potential antioxidant, anti-inflammatory, and anti-senescence properties. This ex-vivo study aimed to determine the effect of NAC on some markers of senescence including β-galactosidase activity and p16, p53, p21, IL-6 and TNF-α gene expressions in visceral adipose tissue in obese adults.<br><br>METHODS: This ex-vivo experimental study involved 10 obese participants who were candidates for bariatric surgery. Duplicate biopsies from the abdominal visceral adipose tissue were obtained from the omentum. The biopsies were treated with or without NAC (5 and 10 mM). To evaluate adipose tissue senescence, beta-galactosidase (&#x3b2;-gal) activity and the expression of P16, P21, P53, IL-6, and TNF-&#x3b1; were determined. ANOVA test was employed to analyze the varying markers of cellular senescence and inflammation between treatment groups.<br><br>RESULTS: The NAC at concentrations of 5 mM and 10 mM resulted in a noteworthy reduction &#x3b2;-gal activity compared to the control group (P < 0.001). Additionally, the expression of P16, P21 and IL-6 was significantly reduced following treatment with NAC (5 mM) and NAC (10 mM) compared to the control group (All p<0.001).<br><br>DISCUSSION/CONCLUSION: Taken together, these data suggest the senotherapeutic effect of NAC, as it effectively reduces the activity of SA-&#x3b2;-gal and the expression of IL-6, P16, and P21 genes in the visceral adipose tissue of obese individuals.}, }
@article {pmid38715671, year = {2024}, author = {Zhao, W and Wang, K and Yu, L and Guo, Y and Li, Z}, title = {Dasatinib-induced pleural effusions, pericardial effusion and pulmonary arterial hypertension: a case report.}, journal = {Translational pediatrics}, volume = {13}, number = {4}, pages = {673-681}, pmid = {38715671}, issn = {2224-4344}, abstract = {BACKGROUND: Pleural effusion, pericardial effusion, and pulmonary arterial hypertension have been shown to have potential associations with the use of dasatinib in adults. However, due to the limited data regarding the efficacy and safety of tyrosine kinase inhibitors (TKIs) in pediatric patients necessities reliance on clinical experience gained from treating adults.<br><br>CASE DESCRIPTION: We present a case of a 12-year-old female patient with chronic myelogenous leukemia (CML) who developed significant right-sided pleural effusion, moderate pericardial effusion, and pulmonary arterial hypertension during dasatinib therapy. Dasatinib was promptly discontinued upon identification of these adverse events. This was followed by the use of bosentan for pulmonary hypertension, furosemide and spironolactone diuretics, prednisone anti-inflammatory, and especially a bold attempt to improve pulmonary endothelial permeability with acetyl cysteine aerosolization. At the same time, according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) data reported by the patient and combined with the actual situation, the appropriate TKI was selected for the patient to continue the CML treatment.<br><br>CONCLUSIONS: FAERS data gathered on OpenVigil indicates that the signal associated with pericardial effusion is stronger among individuals under the age of 18 when imatinib is used instead of dasatinib (exactly the reverse of the results in the adult group). However, this does not imply that dasatinib is safer for the smaller group. In our situation, dasatinib-induced adverse effects include pericardial effusion. As a result, while administering TKIs to pediatric patients, we still need to increase monitoring-particularly for pulmonary and cardiovascular toxicity-and take swift action in the event that a major adverse reaction occurs. In addition, it is important to report these adverse effects as much as possible in order to give pediatric patients utilizing TKIs more helpful information.}, }
@article {pmid38713059, year = {2024}, author = {Vargas-Barona, A and Bernáldez-Sarabia, J and Castro-Ceseña, AB}, title = {Lipid-polymer hybrid nanoparticles loaded with N-acetylcysteine for the modulation of neuroinflammatory biomarkers in human iPSC-derived PSEN2 (N141I) astrocytes as a model of Alzheimer's disease.}, journal = {Journal of materials chemistry. B}, volume = {12}, number = {21}, pages = {5085-5097}, doi = {10.1039/d4tb00521j}, pmid = {38713059}, issn = {2050-7518}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Nanoparticles/chemistry ; *Induced Pluripotent Stem Cells/metabolism/drug effects ; *Acetylcysteine/chemistry/pharmacology ; *Astrocytes/drug effects/metabolism ; Polymers/chemistry/pharmacology ; Lipids/chemistry ; Biomarkers/metabolism ; Particle Size ; Neuroinflammatory Diseases/drug therapy ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment associated with the accumulation of beta-amyloid protein (Aβ). Aβ activates glial cells in the brain, increasing the secretion of proinflammatory cytokines, which leads to neuroinflammation and neuronal death. Currently, there are no effective treatments that cure or stop its progression; therefore, AD is considered a global health priority. The main limitations are the low drug bioavailability and impermeability of the blood-brain barrier (BBB). Fortunately, nanomedicine has emerged as a promising field for the development of new nanosystems for the controlled and targeted delivery of drugs to the brain. Therefore, in this work, lipid-polymer hybrid nanoparticles (LPHNPs) conjugated with transferrin (Tf) to facilitate crossing the BBB and loaded with N-acetylcysteine (NAC) for its anti-inflammatory effect were synthesized, and their physicochemical characterization was carried out. Subsequently, an in vitro model involving human astrocytes derived from induced pluripotent stem cells (iPSC) from an AD-diagnosed patient was developed, which was brought to a reactive state by stimulation with lipopolysaccharides (LPSs). The cell culture was treated with either Tf-conjugated LPHNPs loaded with NAC (NAC-Tf-LPHNPs) at 0.25 mg mL[-1], or free NAC at 5 mM. The results showed that NAC-Tf-LPHNPs favorably modulated the expression of proinflammatory genes such as interleukin-1β (IL-1β), amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP). In addition, they reduced the secretion of the proinflammatory cytokines interleukin 6 (IL-6), IL-1β and interferon-gamma (INF-γ). Results for both cases were compared to the group of cells that did not receive any treatment. In contrast, free NAC only had this effect on the expression of IL-1β and the secretion of the cytokines IL-6 and INF-γ. These results indicate the potential of NAC-Tf-LPHNPs for AD treatment.}, }
@article {pmid38704503, year = {2024}, author = {Wajih, N and Erali, RA and Forsythe, SD and Schaaf, CR and Shen, P and Levine, EA and Soker, S and Morris, DL and Votanopoulos, KI}, title = {Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, pmid = {38704503}, issn = {1534-4681}, support = {CA249087//Foundation for the National Institutes of Health/ ; CA258692//Foundation for the National Institutes of Health/ ; }, abstract = {INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line.<br><br>PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37&#xa0;&#xb0;C and 42&#xa0;&#xb0;C with and without bromelain pretreatment.<br><br>RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p&#x2009;=&#x2009;0.0009) or NAC alone (47% versus 12.8%, p&#x2009;=&#x2009;0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p&#x2009;<&#x2009;0.001) and > 66% in 48 h (p&#x2009;<&#x2009;0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p&#x2009;=&#x2009;0.0001) and 35.5% (p&#x2009;=&#x2009;0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p&#x2009;=&#x2009;0.009) and Bcl-xL (p&#x2009;=&#x2009;0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p&#x2009;<&#x2009;0.03) and II (p&#x2009;<&#x2009;0.031) were increased; while ATG7 (p&#x2009;<&#x2009;0.01), ATG 12 (p&#x2009;<&#x2009;0.04), and Becline 1(p&#x2009;<&#x2009;0.03), expression decreased in bromelain-treated PTOs.<br><br>CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.}, }
@article {pmid38703034, year = {2024}, author = {Mato, S and Municio, S and Alonso, JL and Alonso, ER and Leon, I}, title = {Impact of the Acetyl Group on Cysteine: A Study of N-Acetyl-Cysteine through Rotational Spectroscopy.}, journal = {Chemphyschem : a European journal of chemical physics and physical chemistry}, volume = {}, number = {}, pages = {e202400191}, doi = {10.1002/cphc.202400191}, pmid = {38703034}, issn = {1439-7641}, abstract = {Herein, we report a spectroscopic study of N-acetyl-L-cysteine, an important antioxidant drug, using Fourier-transform microwave techniques and in isolated conditions. Two conformers are observed, where most stable structure adopts a cis disposition, and the second conformer has a lower abundance and adopts a trans disposition. The rotational constants and the barriers to methyl internal rotation are determined for each conformer, allowing a precise conformation identification. The results show that the cis form adopts an identical structure in the crystal, solution, and gas phases. Additionally, the structures are contrasted against those of cysteine.}, }
@article {pmid38702594, year = {2024}, author = {Sohouli, MH and Eslamian, G and Ardehali, SH and Raeissadat, SA and Shimi, G and Pourvali, K and Zand, H}, title = {Effects of N-acetylcysteine on the expressions of UCP1 and factors related to thyroid function in visceral adipose tissue of obese adults: a randomized, double-blind clinical trial.}, journal = {Genes &amp; nutrition}, volume = {19}, number = {1}, pages = {8}, pmid = {38702594}, issn = {1555-8932}, abstract = {BACKGROUND: Evidences have shown that obesity is influenced by various factors, including various hormones such as thyroid hormones and the body's metabolism rate. It seems that practical solutions such as weight loss diets and common drugs can affect these potential disorders. In this study, we investigate one of these common drugs, N-Acetylcysteine (NAC), on expressions of UCP1 and factors related to thyroid function in adults with obesity.<br><br>METHODS AND ANALYSIS: The current investigation was carried out as a randomized clinical trial (RCT) including 43 adults with obesity who were potential candidates for bariatric surgery. These individuals were randomly divided into two groups: 600&#xa0;mg of NAC (n&#x2009;=&#x2009;22) or placebo (n&#x2009;=&#x2009;21) for a duration of 8 weeks. Visceral adipose tissue was utilized in the context of bariatric surgery to investigate the gene expression of UCP1 and thyroid function. Polymerase chain reaction (PCR) was performed in duplicate for UCP1, DIO2, DIO3, THR&#x3b1; and &#x3b2;, and 18s RNA (as an internal control) using the provided instructions to investigate the expression of the respective genes.<br><br>RESULTS: Our findings revealed that after 8 weeks compared to placebo, NAC caused a significant decrease in the expression of the DIO3 gene as one of the genes related to thyroid function and metabolism. However, regarding other related genes, no statistically significant was found (despite the increase in UCP1, DIO2, and THR&#x3b1; expression and decrease in THR&#x3b2; expression). In addition, after adjustment of possible confounders, no significant effect was observed on anthropometric factors and serum levels of thyroid hormones.<br><br>CONCLUSION: The results of this study indicate that, following an 8-week period, NAC effectively decreases the expression of the DIO3 gene in the visceral fat tissue, in comparison to the placebo.}, }
@article {pmid38702220, year = {2024}, author = {Hodgson, S and Abouchedid, R and Cleary, K and Tile, N and Wong, A}, title = {Acute arsenic exposure secondary to deliberate self-poisoning with sheep dip.}, journal = {The American journal of emergency medicine}, volume = {80}, number = {}, pages = {226.e1-226.e3}, doi = {10.1016/j.ajem.2024.04.050}, pmid = {38702220}, issn = {1532-8171}, mesh = {Male ; Humans ; Middle Aged ; *Suicide, Attempted ; *Arsenic Poisoning ; *Acetylcysteine/therapeutic use ; *Arsenicals ; Arsenic Trioxide/poisoning ; Oxides/poisoning ; Antidotes/therapeutic use ; Unithiol/therapeutic use ; }, abstract = {A 53-year-old male patient presented to a regional hospital Emergency Department approximately 2 h post an intentional ingestion of Coopers Instant Wetting Powder Sheep Dip (66% arsenic trioxide, 23% sulphur and 0.42% rotenone), mixed in 600 mL water, as a suicide attempt. On arrival to the Emergency Department, the patient had nausea, vomiting and diarrhoea. Seven hours post ingestion, hypotension developed (BP 90/60 mmHg) and intravenous fluids were commenced. He later developed QTc prolongation. He was treated with 2,3-Dimercapto-1-propanesulfonic acid (DMPS) and N-acetylcysteine and improved without development of neurology. Further investigation of NAC efficacy in humans in the setting of acute arsenic poisoning is required and the optimal duration of treatment and dosing needs to be established. This case highlights an uncommon poisoning which presented to the Emergency Department, the acute symptoms of arsenic toxicity and considerations for management.}, }
@article {pmid38700012, year = {2024}, author = {Abouelgreed, TA and Amer, MA and Mamdouh, H and El-Sherbiny, AF and Aboelwafa, H and Fahmy, SF and Omar, OA and Abdelshakour, M and Elesawy, M and Sonbol, M and Maawad, AN and Elsayed, OK}, title = {The influence of oral antioxidants on men with infertility: a systemic review.}, journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica}, volume = {}, number = {}, pages = {12323}, doi = {10.4081/aiua.2024.12323}, pmid = {38700012}, issn = {2282-4197}, abstract = {OBJECTIVE: This study aims to investigate the current evidence regarding the impact of oral antioxidant supplementation on semen parameters of infertile men.<br><br>MATERIALS AND METHODS: We conducted a systematic search of PubMed, and Cochrane electronic databases, adhering to modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The focus was on studies exploring the effects of antioxidant therapy on infertile men, with an examination of antioxidants in terms of types, doses, rationale for use, and their impact on semen parameters measures.<br><br>RESULTS: A total of 18 studies that met the inclusion criteria were included in this study. Out of these, 14 studies reported a significantly positive influence of antioxidant therapy on basic semen parameters and advanced sperm function. These comprised 11 randomized clinical trials and 7 prospective studies. Commonly utilized antioxidants included Vitamin E, Vitamin C, carnitines, co-enzyme Q10, N-acetyl cysteine, zinc, selenium, folic acid, and lycopene.<br><br>CONCLUSIONS: Overall, antioxidants generally demonstrate a favorable effect on semen parameters of infertile men. However, further research is necessary to pinpoint the optimal antioxidant regimen that can be applied safely and effectively in clinical practice.}, }
@article {pmid38693878, year = {2024}, author = {Pandey, R and Pinon, V and Garren, M and Maffe, P and Mondal, A and Brisbois, EJ and Handa, H}, title = {N-Acetyl Cysteine-Decorated Nitric Oxide-Releasing Interface for Biomedical Applications.}, journal = {ACS applied materials &amp; interfaces}, volume = {16}, number = {19}, pages = {24248-24260}, pmid = {38693878}, issn = {1944-8252}, support = {R01 HL134899/HL/NHLBI NIH HHS/United States ; R01 HL157587/HL/NHLBI NIH HHS/United States ; }, mesh = {*Acetylcysteine/chemistry/pharmacology ; *Nitric Oxide/chemistry/metabolism/pharmacology ; *Staphylococcus aureus/drug effects ; *Escherichia coli/drug effects ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Biofilms/drug effects ; Polyethyleneimine/chemistry/pharmacology ; Biocompatible Materials/chemistry/pharmacology ; Microbial Sensitivity Tests ; Polyvinyl Chloride/chemistry ; Nitric Oxide Donors/chemistry/pharmacology ; }, abstract = {Biomedical devices are vulnerable to infections and biofilm formation, leading to extended hospital stays, high expenditure, and increased mortality. Infections are clinically treated via the administration of systemic antibiotics, leading to the development of antibiotic resistance. A multimechanistic strategy is needed to design an effective biomaterial with broad-spectrum antibacterial potential. Recent approaches have investigated the fabrication of innately antimicrobial biomedical device surfaces in the hope of making the antibiotic treatment obsolete. Herein, we report a novel fabrication strategy combining antibacterial nitric oxide (NO) with an antibiofilm agent N-acetyl cysteine (NAC) on a polyvinyl chloride surface using polycationic polyethylenimine (PEI) as a linker. The designed biomaterial could release NO for at least 7 days with minimal NO donor leaching under physiological conditions. The proposed surface technology significantly reduced the viability of Gram-negative Escherichia coli (>97%) and Gram-positive Staphylococcus aureus (>99%) bacteria in both adhered and planktonic forms in a 24 h antibacterial assay. The composites also exhibited a significant reduction in biomass and extra polymeric substance accumulation in a dynamic environment over 72 h. Overall, these results indicate that the proposed combination of the NO donor with mucolytic NAC on a polymer surface efficiently resists microbial adhesion and can be used to prevent device-associated biofilm formation.}, }
@article {pmid38693516, year = {2024}, author = {Ozawa, K and Packwood, W and Muller, MA and Qi, Y and Xie, A and Varlamov, O and McCarty, OJ and Chung, D and López, JA and Lindner, JR}, title = {Removal of endothelial surface-associated von villebrand factor suppresses accelerate datherosclerosis after myocardial infarction.}, journal = {Journal of translational medicine}, volume = {22}, number = {1}, pages = {412}, pmid = {38693516}, issn = {1479-5876}, support = {R35 HL145262/HL/NHLBI NIH HHS/United States ; NIH R01-HL078610/NH/NIH HHS/United States ; NIH R01-HL165422/NH/NIH HHS/United States ; R35-HL145262/NH/NIH HHS/United States ; R01 HL130046/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *von Willebrand Factor/metabolism ; *Myocardial Infarction/pathology/complications ; *ADAMTS13 Protein/metabolism ; Vascular Cell Adhesion Molecule-1/metabolism ; Mice ; Plaque, Atherosclerotic/pathology ; P-Selectin/metabolism ; Endothelial Cells/metabolism/drug effects ; Male ; Molecular Imaging ; Aorta/pathology/drug effects ; Acetylcysteine/pharmacology/therapeutic use ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI).<br><br>METHODS: Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIb&#x3b1;, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21.<br><br>RESULTS: Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIb&#x3b1; were all increased several-fold (p&#x2009;<&#x2009;0.01) in post-MI mice versus sham-treated animals at day 3 and 21. Treatment with NAC and ADAMTS13 significantly attenuated the post-MI increase for all four molecular targets by >&#x2009;50% (p&#x2009;<&#x2009;0.05 vs. non-treated at day 3 and 21). On aortic root histology, mice undergoing MI versus controls had 2-4 fold greater plaque size and macrophage content (p&#x2009;<&#x2009;0.05), approximately 20-fold greater platelet adhesion (p&#x2009;<&#x2009;0.05), and increased staining for markers of platelet transforming growth factor-&#x3b2;1 signaling. Accelerated plaque growth and inflammatory activation was almost entirely prevented by ADAMTS13 and NAC. Inhibition of FXI had no significant effect on molecular imaging signal or plaque morphology.<br><br>CONCLUSIONS: Plaque inflammatory activation in remote arteries after MI is strongly influenced by VWF-mediated platelet adhesion to the endothelium. These findings support investigation into new secondary preventive therapies for reducing non-culprit artery events after MI.}, }
@article {pmid38691522, year = {2024}, author = {Gao, X and Hu, Z and Wang, Y and Zhao, G and Shen, Y and Zhou, H and Liao, Y and Li, W and Peng, Y and Zheng, J}, title = {Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats.}, journal = {Journal of agricultural and food chemistry}, volume = {72}, number = {19}, pages = {10897-10908}, doi = {10.1021/acs.jafc.4c00400}, pmid = {38691522}, issn = {1520-5118}, mesh = {Animals ; Rats ; Male ; *Hepatocytes/metabolism/drug effects ; *Cytochrome P-450 CYP3A/metabolism/genetics ; *Rats, Sprague-Dawley ; *Activation, Metabolic ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; Insecticides/toxicity/metabolism ; Alkaloids/metabolism ; }, abstract = {Gramine (GRM), which occurs in Gramineae plants, has been developed to be a biological insecticide. Exposure to GRM was reported to induce elevations of serum ALT and AST in rats, but the mechanisms of the observed hepatotoxicity have not been elucidated. The present study aimed to identify reactive metabolites that potentially participate in the toxicity. In rat liver microsomal incubations fortified with glutathione or N-acetylcysteine, one oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetylcysteine conjugate (M3) were detected after exposure to GRM. The corresponding conjugates were detected in the bile and urine of rats after GRM administration. CYP3A was the main enzyme mediating the metabolic activation of GRM. The detected GSH and NAC conjugates suggest that GRM was metabolized to a quinone imine intermediate. Both GRM and M1 showed significant toxicity to rat primary hepatocytes.}, }
@article {pmid38688172, year = {2024}, author = {Chen, Y and Xu, M and Liu, XM and Wang, JX and Sun, MF and Song, JX and Guan, P and Ji, ES and Wang, N}, title = {Mechanistic study of Huangqi Guizhi Wuwu decoction amelioration of doxorubicin-induced cardiotoxicity by reducing oxidative stress and inhibiting cellular pyroptosis.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {175}, number = {}, pages = {116653}, doi = {10.1016/j.biopha.2024.116653}, pmid = {38688172}, issn = {1950-6007}, abstract = {Huangqi Guizhi Wuwu Decoction (HQGZWWD) has shown promising potential in treating various cardiovascular diseases. This study aimed to elucidate the molecular basis and therapeutic role of HQGZWWD in the treatment of doxorubicin (DOX)-induced myocardial injury. The HPLC fingerprint of HQGZWWD was used to analyze the active components. A DOX-induced myocardial damage rat model was developed, and the therapeutic effects of HQGZWWD were evaluated using echocardiography, myocardial enzyme levels, and hematoxylin and eosin staining. Network pharmacology was used to screen treatment targets, and western blotting and immunohistochemistry were performed to assess cellular pyroptosis levels. Oxidative stress levels were measured using assay kits, and mitochondrial damage was examined using transmission electron microscopy. An in vitro model of DOX-induced cell damage was established, and treatment was administered using serum containing HQGZWWD and N-acetylcysteine (NAC). Oxidative stress levels were detected using assay kits and DCFH-DA, whereas cellular pyroptosis levels were assessed through WB, immunofluorescence, and ELISA assays. HQGZWWD ameliorated DOX-induced myocardial injury. Network pharmacology identified IL-1β and IL-18 as crucial targets. HQGZWWD downregulated the protein levels of the inflammatory factors IL-1β and IL-18, inhibited the expression of GSDMD-NT, and simultaneously suppressed the synthesis of Caspase-1, ASC, NLRP3, and Caspase-11. Additionally, HQGZWWD inhibited oxidative stress, and the use of NAC as an oxidative stress inhibitor resulted in significant inhibition of the GSDMD-NT protein in H9C2 cells. These findings highlight the myocardial protective effects of HQGZWWD by inhibiting oxidative stress and suppressing both canonical and non-canonical pyroptotic pathways.}, }
@article {pmid38687644, year = {2024}, author = {Manhas, A and Arnold, CG and Bush, AM}, title = {Underreporting Supplements: A Case of Drug-induced Liver Injury Due to a Testosterone Booster.}, journal = {Military medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/milmed/usae136}, pmid = {38687644}, issn = {1930-613X}, abstract = {Acute liver injuries (ALIs) are caused by a wide range of etiologies, and determining the cause can often be challenging. Detailed history taking is essential in patients with liver injuries to promptly determine the underlying source of injury and for timely treatment and prognosis. A 27-year-old active duty man presented to the emergency department (ED) with jaundice. On medication reconciliation, he only reported taking acetaminophen for a recent upper respiratory infection. The patient had an ALI and was treated with N-acetyl cysteine for presumed acetaminophen toxicity. Initially, his liver-associated enzymes (LAEs) improved, but 2 weeks after discharge, he returned to the ED upon referral from ship medical for jaundice and worsening liver injury. Repeated query into the patient's history revealed that he was using a testosterone booster supplement for 6 months preceding initial hospitalization. After evaluation of other etiologies for liver injury returned negative, drug-induced liver injury from the testosterone booster was determined to be the underlying etiology. With discontinuation of the supplement, his liver injury improved. Hepatotoxicity is a major concern in supplement use; however, it is largely underreported. Supplements are often not recognized or reported as medications by patients, leading to failure to identify them as potential toxicants. This case highlights the importance of including supplement education and questioning in the evaluation of ALI and maintaining a high index of suspicion when other common etiologies of liver disease are negative.}, }
@article {pmid38687431, year = {2024}, author = {Giri, S and Anirvan, P and Vaidya, A and Praharaj, DL}, title = {Dengue-related acute liver failure-A scoping review.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {43}, number = {2}, pages = {407-424}, pmid = {38687431}, issn = {0975-0711}, mesh = {Humans ; *Liver Failure, Acute/etiology/epidemiology/therapy ; *Dengue/complications/epidemiology ; Risk Factors ; Liver Transplantation ; Female ; Male ; Child ; India/epidemiology ; Adult ; Incidence ; }, abstract = {Infection by dengue virus is common in tropical countries. Hepatic involvement in dengue can range from asymptomatic elevation of transaminases to life-threatening acute liver failure (ALF). Dengue-related ALF (DALF) is responsible for significant morbidity and mortality, especially in Southeast Asia. However, there is a scarcity of literature on DALF, necessitating a thorough examination of its clinical determinants and management strategies. All relevant studies related to DALF were reviewed until December 2023. Case reports, case series and studies reporting ALF in dengue infection were included. Demographics, clinical profiles, management and outcomes of DALF cases were analyzed, which revealed a predominance of DALF incidence in pediatric patients (1.1% to 15.8%) and an upward trend over the years, particularly in India. The proportion of ALF cases attributable to dengue was also higher among pediatric ALF patients (6.7% to 34.3%). Age ≤ 40 years, persistent nausea, vomiting and elevated serum bilirubin and alkaline phosphatase (ALP) with aspartate aminotransferase (AST) > 1000 IU/mL within the first five days of illness, more than 10% of atypical lymphocytes in peripheral blood, platelet count of < 50,000/cu·mm, severe hepatitis at presentation and baseline model for end-stage liver disease (MELD) > 15 were the risk factors for the development of DALF. Histopathological features of DALF included multi-lobular hepatic necrosis, steatosis and occasional cholestasis. Mortality in DALF ranged from 0% to 80%; admission pH and lactate strongly predicted mortality, while mortality was found to be significantly higher in patients with cirrhosis. N-Acetyl cysteine (NAC) has been used as a treatment modality with varying results. There is limited evidence regarding the use of extra-corporeal support systems, while candidate selection for liver transplantation (LT) in DALF remains poorly defined.}, }
@article {pmid38686842, year = {2024}, author = {Hamsho, M and Ranneh, Y and Fadel, A}, title = {Comments on "A Meta-Analysis of the Efficacy of L-Carnitine/L-Acetyl-Carnitine or N-Acetyl-Cysteine in Men with Idiopathic Asthenozoospermia".}, journal = {American journal of men's health}, volume = {18}, number = {2}, pages = {15579883241249109}, pmid = {38686842}, issn = {1557-9891}, mesh = {Humans ; Male ; *Acetylcysteine/therapeutic use/administration &amp; dosage ; *Asthenozoospermia/drug therapy ; *Carnitine/therapeutic use ; Meta-Analysis as Topic ; Acetylcarnitine/therapeutic use ; Treatment Outcome ; }, }
@article {pmid38686557, year = {2024}, author = {Yang, L and Wang, X and Ma, Z and Sui, Y and Liu, X}, title = {Fangchinoline inhibits growth and biofilm of Candida albicans by inducing ROS overproduction.}, journal = {Journal of cellular and molecular medicine}, volume = {28}, number = {9}, pages = {e18354}, pmid = {38686557}, issn = {1582-4934}, support = {20220505041ZP//the Science and Technology Development Plan Project of Jilin Province/ ; 20200201595JC//Natural Science Foundation of Jilin Province/ ; JJKH20231220KJ//the Education Department of Jilin Province/ ; }, mesh = {*Biofilms/drug effects/growth &amp; development ; *Candida albicans/drug effects/growth &amp; development ; *Antifungal Agents/pharmacology ; *Reactive Oxygen Species/metabolism ; *Benzylisoquinolines/pharmacology ; *Microbial Sensitivity Tests ; Hyphae/drug effects/growth &amp; development ; }, abstract = {Infections caused by Candida species, especially Candida albicans, threaten the public health and create economic burden. Shortage of antifungals and emergence of drug resistance call for new antifungal therapies while natural products were attractive sources for developing new drugs. In our study, fangchinoline, a bis-benzylisoquinoline alkaloid from Chinese herb Stephania tetrandra S. Moore, exerted antifungal effects on planktonic growth of several Candida species including C. albicans, with MIC no more than 50 μg/mL. In addition, results from microscopic, MTT and XTT reduction assays showed that fangchinoline had inhibitory activities against the multiple virulence factors of C. albicans, such as adhesion, hyphal growth and biofilm formation. Furthermore, this compound could also suppress the metabolic activity of preformed C. albicans biofilms. PI staining, followed by confocal laser scanning microscope (CLSM) analysis showed that fangchinoline can elevate permeability of cell membrane. DCFH-DA staining suggested its anti-Candida mechanism also involved overproduction of intracellular ROS, which was further confirmed by N-acetyl-cysteine rescue tests. Moreover, fangchinoline showed synergy with three antifungal drugs (amphotericin B, fluconazole and caspofungin), further indicating its potential use in treating C. albicans infections. Therefore, these results indicated that fangchinoline could be a potential candidate for developing anti-Candida therapies.}, }
@article {pmid38682430, year = {2024}, author = {Chen, HX and Wang, XY and Yu, B and Feng, CL and Cheng, GF and Zhang, L and Wang, JJ and Wang, Y and Guo, RW and Ji, XM and Xie, WJ and Chen, WL and Song, C and Zhang, X}, title = {Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field.}, journal = {Zoological research}, volume = {45}, number = {3}, pages = {478-491}, doi = {10.24272/j.issn.2095-8137.2023.410}, pmid = {38682430}, issn = {2095-8137}, mesh = {*Acetaminophen/toxicity ; Animals ; Mice ; *Chemical and Drug Induced Liver Injury ; *Drug Overdose ; *Analgesics, Non-Narcotic/toxicity ; Oxidative Stress/drug effects ; Male ; Magnetic Fields ; Acetylcysteine/therapeutic use/pharmacology ; }, abstract = {Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.}, }
@article {pmid38678953, year = {2024}, author = {Dou, M and Zhu, D and Cui, G and Li, H and Di, L and Wang, L}, title = {Euphorbia helioscopia L. exhibits promising therapeutic effects on hemangioendothelioma and melanoma through angiogenesis inhibition.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {129}, number = {}, pages = {155666}, doi = {10.1016/j.phymed.2024.155666}, pmid = {38678953}, issn = {1618-095X}, mesh = {Animals ; *Euphorbia/chemistry ; *Hemangioendothelioma/drug therapy ; *Reactive Oxygen Species/metabolism ; *Angiogenesis Inhibitors/pharmacology ; Humans ; *Apoptosis/drug effects ; *Cell Proliferation/drug effects ; Mice ; *Plant Extracts/pharmacology ; *Antineoplastic Agents, Phytogenic/pharmacology ; Cell Line, Tumor ; Melanoma/drug therapy ; Plant Leaves/chemistry ; Melanoma, Experimental/drug therapy ; Neovascularization, Pathologic/drug therapy ; Mice, Inbred C57BL ; Male ; Angiogenesis ; }, abstract = {BACKGROUND: Euphorbia helioscopia L (EHL), a widely used medicinal plant in traditional Chinese medicine, has shown promising effects on certain cancers. However, previous studies on EHL did not elucidate the underlying molecular mechanisms. Herein, for the first time, we present the strong therapeutic potential of EHL extracts on malignant hemangioendothelioma, a rare type of vascular tumor.<br><br>PURPOSE: To investigate the potential anti-tumor mechanism of extracts of EHL on hemangioendothelioma and melanoma.<br><br>METHODS: The dried stems and leaves of EHL were extracted with Ethyl Acetate and n-Butyl alcohol, yielding two crude extracts Ethyl Acetate fraction (EA) and n-Butyl alcohol fraction (Bu). EA and Bu were prepared to assess the potential mechanism by assays for cell proliferation, cell cycle, apoptosis, colony formation, tube formation, cellular metabolic activity, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, RNA expression and western blot. To further confirm the anti-tumor effect of EHL in vivo, we established hemangioendothelioma and melanoma tumor-bearing mouse model using node mice and administered with EA and Bu, tracked alterations in tumor volume and survival rate. Furthermore, tissue samples were obtained for histological, protein, and genetic investigations.<br><br>RESULTS: We demonstrate that the injection of EA and Bu, significantly inhibits tumor growth and prolongs the lifespan of tumor-bearing mice. Bu treatment exhibited a remarkable 33 % healing effect on the primary hemangioendothelioma tumor, bringing the survival rate to a level comparable to that of healthy mice. Mechanically, both EA and Bu impair respiratory chain complexes, leading to mitochondrial dysfunction and accumulation of reactive oxygen species (ROS), resulting in DNA damage, cell apoptosis, and finally blocked angiogenesis. While EA demonstrates robust inhibitory effects on cancer cell growth and a broader impact on metabolism in vitro, the in vivo effect of Bu surpasses that of EA in terms of strength. EA and Bu also exhibit potent anti-tumor effects on a primary melanoma model by inhibiting angiogenesis. Importantly, when compared to other compounds used in the treatment of hemangioendothelioma, EA and Bu demonstrate more profound anti-tumor effects.<br><br>CONCLUSION: For the first time, our findings reveal that EHL extracts, especially the high polarity compounds, exhibit potent anti-tumor effects by targeting cellular metabolism, specifically through the inhibition of mitochondria-related metabolic activities. This leads to the accumulation of ROS and effectively suppresses abnormal angiogenesis.}, }
@article {pmid38675591, year = {2024}, author = {Zigová, M and Miškufová, V and Budovská, M and Michalková, R and Mojžiš, J}, title = {Exploring the Antiproliferative and Modulatory Effects of 1-Methoxyisobrassinin on Ovarian Cancer Cells: Insights into Cell Cycle Regulation, Apoptosis, Autophagy, and Its Interactions with NAC.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {8}, pages = {}, pmid = {38675591}, issn = {1420-3049}, support = {APVV-16-0446//Slovak Research and Development Agency/ ; VEGA 1/0653/19//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Repub-lic/ ; VEGA 1/0498/23//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Republic/ ; VEGA 1/0446/22//Grant Agency of the Ministry of the Education, Science, Research and Sport of the Slovak Republic/ ; ITMS2014+: 313011V455//ERDF/ ; }, mesh = {Female ; Humans ; *Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology/chemistry ; *Apoptosis/drug effects ; *Autophagy/drug effects ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor/drug effects ; *Cell Proliferation/drug effects ; Cisplatin/pharmacology ; DNA Damage/drug effects ; Drug Resistance, Neoplasm/drug effects ; *Ovarian Neoplasms/drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; *Phytoalexins/pharmacology ; *Indoles/pharmacology ; Thiocarbamates/pharmacology ; }, abstract = {Ovarian cancer, a highly lethal malignancy among reproductive organ cancers, poses a significant challenge with its high mortality rate, particularly in advanced-stage cases resistant to platinum-based chemotherapy. This study explores the potential therapeutic efficacy of 1-methoxyisobrassinin (MB-591), a derivative of indole phytoalexins found in Cruciferae family plants, on both cisplatin-sensitive (A2780) and cisplatin-resistant ovarian cancer cells (A2780 cis). The findings reveal that MB-591 exhibits an antiproliferative effect on both cell lines, with significantly increased potency against cisplatin-sensitive cells. The substance induces alterations in the distribution of the cell cycle, particularly in the S and G2/M phases, accompanied by changes in key regulatory proteins. Moreover, MB-591 triggers apoptosis in both cell lines, involving caspase-9 cleavage, PARP cleavage induction, and DNA damage, accompanied by the generation of reactive oxygen species (ROS) and mitochondrial dysfunction. Notably, the substance selectively induces autophagy in cisplatin-resistant cells, suggesting potential targeted therapeutic applications. The study further explores the interplay between MB-591 and antioxidant N-acetylcysteine (NAC), in modulating cellular processes. NAC demonstrates a protective effect against MB-591-induced cytotoxicity, affecting cell cycle distribution and apoptosis-related proteins. Additionally, NAC exhibits inhibitory effects on autophagy initiation in cisplatin-resistant cells, suggesting its potential role in overcoming resistance mechanisms.}, }
@article {pmid38672493, year = {2024}, author = {Kamenshchyk, A and Belenichev, I and Oksenych, V and Kamyshnyi, O}, title = {Combined Pharmacological Modulation of Translational and Transcriptional Activity Signaling Pathways as a Promising Therapeutic Approach in Children with Myocardial Changes.}, journal = {Biomolecules}, volume = {14}, number = {4}, pages = {}, pmid = {38672493}, issn = {2218-273X}, mesh = {Humans ; *Signal Transduction/drug effects ; Child ; Animals ; Myocardium/metabolism/pathology ; Transcription, Genetic/drug effects ; Protein Biosynthesis/drug effects ; Cardiomegaly/drug therapy/metabolism/genetics ; }, abstract = {Myocardial hypertrophy is the most common condition that accompanies heart development in children. Transcriptional gene expression regulating pathways play a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy, and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed the downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pumps, and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs make combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.}, }
@article {pmid38672280, year = {2024}, author = {Altay, O and Yang, H and Yildirim, S and Bayram, C and Bolat, I and Oner, S and Tozlu, OO and Arslan, ME and Hacimuftuoglu, A and Shoaie, S and Zhang, C and Borén, J and Uhlén, M and Turkez, H and Mardinoglu, A}, title = {Combined Metabolic Activators with Different NAD+ Precursors Improve Metabolic Functions in the Animal Models of Neurodegenerative Diseases.}, journal = {Biomedicines}, volume = {12}, number = {4}, pages = {}, pmid = {38672280}, issn = {2227-9059}, support = {72110//Knut and Alice Wallenberg Foundation/ ; }, abstract = {BACKGROUND: Mitochondrial dysfunction and metabolic abnormalities are acknowledged as significant factors in the onset of neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). Our research has demonstrated that the use of combined metabolic activators (CMA) may alleviate metabolic dysfunctions and stimulate mitochondrial metabolism. Therefore, the use of CMA could potentially be an effective therapeutic strategy to slow down or halt the progression of PD and AD. CMAs include substances such as the glutathione precursors (L-serine and N-acetyl cysteine), the NAD+ precursor (nicotinamide riboside), and L-carnitine tartrate.<br><br>METHODS: Here, we tested the effect of two different formulations, including CMA1 (nicotinamide riboside, L-serine, N-acetyl cysteine, L-carnitine tartrate), and CMA2 (nicotinamide, L-serine, N-acetyl cysteine, L-carnitine tartrate), as well as their individual components, on the animal models of AD and PD. We assessed the brain and liver tissues for pathological changes and immunohistochemical markers. Additionally, in the case of PD, we performed behavioral tests and measured responses to apomorphine-induced rotations.<br><br>FINDINGS: Histological analysis showed that the administration of both CMA1 and CMA2 formulations led to improvements in hyperemia, degeneration, and necrosis in neurons for both AD and PD models. Moreover, the administration of CMA2 showed a superior effect compared to CMA1. This was further corroborated by immunohistochemical data, which indicated a reduction in immunoreactivity in the neurons. Additionally, notable metabolic enhancements in liver tissues were observed using both formulations. In PD rat models, the administration of both formulations positively influenced the behavioral functions of the animals.<br><br>INTERPRETATION: Our findings suggest that the administration of both CMA1 and CMA2 markedly enhanced metabolic and behavioral outcomes, aligning with neuro-histological observations. These findings underscore the promise of CMA2 administration as an effective therapeutic strategy for enhancing metabolic parameters and cognitive function in AD and PD patients.}, }
@article {pmid38672256, year = {2024}, author = {Chen, R and Zheng, Y and Zhou, C and Dai, H and Wang, Y and Chu, Y and Luo, J}, title = {N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress.}, journal = {Biomedicines}, volume = {12}, number = {4}, pages = {}, pmid = {38672256}, issn = {2227-9059}, abstract = {(1) Background: Sepsis-induced muscle atrophy is characterized by a loss of muscle mass and function which leads to decreased quality of life and worsens the long-term prognosis of patients. N-acetylcysteine (NAC) has powerful antioxidant and anti-inflammatory properties, and it relieves muscle wasting caused by several diseases, whereas its effect on sepsis-induced muscle atrophy has not been reported. The present study investigated the effect of NAC on sepsis-induced muscle atrophy and its possible mechanisms. (2) Methods: The effect of NAC on sepsis-induced muscle atrophy was assessed in vivo and in vitro using cecal ligation and puncture-operated (CLP) C57BL/6 mice and LPS-treated C2C12 myotubes. We used immunofluorescence staining to analyze changes in the cross-sectional area (CSA) of myofibers in mice and the myotube diameter of C2C12. Protein expressions were analyzed by Western blotting. (3) Results: In the septic mice, the atrophic response manifested as a reduction in skeletal muscle weight and myofiber cross-sectional area, which is mediated by muscle-specific ubiquitin ligases-muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle ring finger 1 (MuRF1). NAC alleviated sepsis-induced skeletal muscle wasting and LPS-induced C2C12 myotube atrophy. Meanwhile, NAC inhibited the sepsis-induced activation of the endoplasmic reticulum (ER) stress signaling pathway. Furthermore, using 4-Phenylbutyric acid (4-PBA) to inhibit ER stress in LPS-treated C2C12 myotubes could partly abrogate the anti-muscle-atrophy effect of NAC. Finally, NAC alleviated myotube atrophy induced by the ER stress agonist Thapsigargin (Thap). (4) Conclusions: NAC can attenuate sepsis-induced muscle atrophy, which may be related to downregulating ER stress.}, }
@article {pmid38671944, year = {2024}, author = {Kim, RJ and Park, HB}, title = {Protective and Regenerative Effects of Reconstituted HDL on Human Rotator Cuff Fibroblasts under Hypoxia: An In Vitro Study.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {4}, pages = {}, pmid = {38671944}, issn = {2076-3921}, support = {2021R1A2C1008931//National Research Foundation of Korea/ ; }, abstract = {Hypoxia and hypo-high-density lipoproteinemia (hypo-HDLemia) are proposed risk factors for rotator cuff tear. HDL is recognized for its potential benefits in ischemia-driven angiogenesis and wound healing. Nevertheless, research on the potential benefits of reconstituted HDL (rHDL) on human rotator cuff fibroblasts (RCFs) under hypoxia is limited. This study investigates the cytoprotective and regenerative effects of rHDL, as well as N-acetylcysteine (NAC), vitamin C (Vit C), and HDL on human RCFs under hypoxic conditions. Sixth-passage human RCFs were divided into normoxia, hypoxia, and hypoxia groups pretreated with antioxidants (NAC, Vit C, rHDL, HDL). Hypoxia was induced by 1000 µM CoCl2. In the hypoxia group compared to the normoxia group, there were significant increases in hypoxia-inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1), and Bcl-2/E1B-19kDa interacting protein 3 (BNIP3) expressions, along with reduced cell viability, elevated reactive oxygen species (ROS) production, apoptosis rate, expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase-1 (PARP-1), vascular endothelial growth factors (VEGF), and matrix metalloproteinase-2 (MMP-2), as well as decreased collagen I and III production, and markedly lower cell proliferative activity (p ≤ 0.039). These responses were significantly mitigated by pretreatment with rHDL (p ≤ 0.046). This study suggests that rHDL can enhance cell proliferation and collagen I and III production while reducing apoptosis in human RCFs under hypoxic conditions.}, }
@article {pmid38671832, year = {2024}, author = {Cai, J and Li, Y and Zhao, B and Bao, Z and Li, J and Sun, S and Chen, Y and Wu, X}, title = {N-Acetylcysteine Alleviates D-Galactose-Induced Injury of Ovarian Granulosa Cells in Female Rabbits by Regulating the PI3K/Akt/mTOR Signaling Pathway.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {4}, pages = {}, pmid = {38671832}, issn = {2076-3921}, abstract = {The ovary plays a crucial role in the reproductive system of female animals. Ovarian problems such as ovarian insufficiency, premature aging, polycystic ovary syndrome, and ovarian cysts may lead to ovulation disorders, abnormal hormone secretion, or luteal dysfunction, thereby increasing the risk of infertility and abortion. Only when the ovarian function and other organs in the reproductive system remain healthy and work normally can female animals be ensured to carry out reproductive activities regularly, improve the pregnancy rate and litter size, promote the healthy development of the fetus, and then improve their economic value. The follicle, as the functional unit of the ovary, is composed of theca cells, granulosa cells (GCs), and oocytes. GCs are the largest cell population and main functional unit in follicles and provide the necessary nutrients for the growth and development of follicles. N-acetylcysteine (NAC) is a prevalent and cell-permeable antioxidant molecule that effectively prevents apoptosis and promotes cellular survival. Over the past few years, its function in boosting reproductive performance in animals at the cellular level has been widely acknowledged. However, its specific role and mechanism in influencing GCs is yet to be fully understood. The objective of this study was to examine the effects of NAC on ovarian damage in female rabbits. For this purpose, D-galactose (D-gal) was first used to establish a model of damaged GCs, with exposure to 1.5 mg/mL of D-gal leading to substantial damage. Subsequently, varying concentrations of NAC were introduced to determine the precise mechanism through which it influences cell damage. Based on the results of the Cell Counting Kit-8 assay, flow cytometry, and Western blotting, it was found that 0.5 mg/mL of NAC could significantly suppress cell apoptosis and promote proliferation. In particular, it decreased the expression levels of Bax, p53, and Caspase-9 genes, while concurrently upregulating the expression of the BCL-2 gene. Moreover, NAC was found to alleviate intracellular oxidative stress, suppress the discharge of mitochondrial Cytochrome c, and boost the enzymatic activities of CAT (Catalase), GSH (Glutathione), and SOD (Superoxide dismutase). RNA sequencing analysis subsequently underscored the critical role of the PI3K/Akt/mTOR pathway in governing proliferation and apoptosis within GCs. These findings demonstrated that NAC could significantly influence gene expression within this pathway, thereby clarifying the exact relationship between the PI3K/Akt/mTOR signaling cascade and the underlying cellular processes controlling proliferation and apoptosis. In conclusion, NAC can reduce the expression of Bax, p53, and Caspase-9 genes, inhibit the apoptosis of GCs, improve cell viability, and resist D-gal-induced oxidative stress by increasing the activity of CAT, GSH, and SOD. The molecular mechanism of NAC in alleviating D-gal-induced ovarian GC injury in female rabbits by regulating the PI3K/Akt/mTOR signaling pathway provides experimental evidence for the effect of NAC on animal reproductive function at the cellular level.}, }
@article {pmid38670497, year = {2024}, author = {Liang, WZ and Chia, YY and Sun, HJ and Sun, GC}, title = {Exploration of beauvericin's toxic effects and mechanisms in human astrocytes and N-acetylcysteine's protective role.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {243}, number = {}, pages = {107734}, doi = {10.1016/j.toxicon.2024.107734}, pmid = {38670497}, issn = {1879-3150}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Astrocytes/drug effects ; *Oxidative Stress/drug effects ; *Depsipeptides/toxicity ; *Reactive Oxygen Species/metabolism ; *Apoptosis/drug effects ; Cell Line ; Antioxidants/pharmacology ; }, abstract = {Beauvericin (BEA) is a newly identified mycotoxin produced by various Fusarium species, and its contamination in food and animal feed is widespread globally. This mycotoxin demonstrates cytotoxic effects by inducing oxidative stress in multiple models. Furthermore, evidence indicates that BEA possesses diverse toxic activities, making it a promising candidate for toxicological research. Recent studies have highlighted the ability of BEA to traverse the blood-brain barrier, suggesting its potential neurotoxicity. However, limited information is available regarding the neurotoxic effects of BEA on human astrocytes. Therefore, this study aimed to assess the neurotoxic effects of BEA on the Gibco® Human Astrocyte (GHA) cell line and elucidate the underlying mechanisms. Additionally, the study aimed to investigate the protective effects of the antioxidant N-acetylcysteine (NAC) against BEA-induced toxicity. The data show that exposure to BEA within the 2.5-15 μM concentration range resulted in concentration-dependent cytotoxicity. BEA-treated cells exhibited significantly increased levels of reactive oxygen species (ROS), while intracellular glutathione (GSH) content was significantly reduced. Western blot analysis of cells treated with BEA revealed altered protein levels of Bax, cleaved caspase-9, and caspase-3, along with an increased Bax/Bcl-2 ratio, indicating the induction of apoptosis. Additionally, BEA exposure triggered antioxidant responses, as evidenced by increased protein expression of Nrf2, HO-1, and NQO1. Significantly, pretreatment with NAC partially attenuated the significant toxic effects of BEA. In conclusion, our findings suggest that BEA-induced cytotoxicity in GHA cells involves oxidative stress-associated apoptosis. Furthermore, NAC demonstrates potential as a protective agent against BEA-induced oxidative damage.}, }
@article {pmid38670245, year = {2024}, author = {Lu, W and Cheng, S and Xu, J and Xiao, Z and Yu, Y and Xie, Q and Fang, Y and Chen, R and Shen, B and Xie, Y and Ding, X}, title = {Roles of AhR/CYP1s signaling pathway mediated ROS production in uremic cardiomyopathy.}, journal = {Toxicology letters}, volume = {396}, number = {}, pages = {81-93}, doi = {10.1016/j.toxlet.2024.04.005}, pmid = {38670245}, issn = {1879-3169}, mesh = {Animals ; *Receptors, Aryl Hydrocarbon/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; *Uremia/metabolism ; *Myocytes, Cardiac/metabolism/drug effects/pathology ; *Signal Transduction ; *Indican/toxicity ; Humans ; *Cardiomyopathies/metabolism/pathology ; Rats ; Male ; *Rats, Sprague-Dawley ; Cell Line ; Basic Helix-Loop-Helix Transcription Factors/metabolism/genetics ; Oxidative Stress ; Disease Models, Animal ; Renal Insufficiency, Chronic/metabolism/pathology ; }, abstract = {PURPOSE: Uremic cardiomyopathy (UCM) is the leading cause of chronic kidney disease (CKD) related mortality. Uremic toxins including indoxyl sulfate (IS) play important role during the progression of UCM. This study was to explore the underlying mechanism of IS related myocardial injury.<br><br>METHODS: UCM rat model was established through five-sixths nephrectomy to evaluate its effects on blood pressure, cardiac impairment, and histological changes using echocardiography and histological analysis. Additionally, IS was administered to neonatal rat cardiomyocytes (NRCMs) and the human cardiomyocyte cell line AC16. DHE staining and peroxide-sensitive dye 2',7'-dichlorofluorescein diacetate (H2DCFDA) was conducted to assess the reactive oxygen species (ROS) production. Cardiomyocyte hypertrophy was estimated using wheat germ agglutinin (WGA) staining and immunofluorescence. Aryl hydrocarbon receptor (AhR) translocation was observed by immunofluorescence. The activation of AhR was evaluated by immunoblotting of cytochrome P450 1&#x202f;s (CYP1s) and quantitative real-time PCR (RT-PCR) analysis of AHRR and PTGS2. Additionally, the pro-oxidative and pro-hypertrophic effects were evaluated using the AhR inhibitor CH-223191, the CYP1s inhibitor Alizarin and the ROS scavenger N-Acetylcysteine (NAC).<br><br>RESULTS: UCM rat model was successfully established, and cardiac hypertrophy, accompanied by increased blood pressure, and myocardial fibrosis. Further research confirmed the activation of the AhR pathway in UCM rats including AhR translocation and downstream protein CYP1s expression, accompanied with increasing ROS production detected by DHE staining. In vitro experiment demonstrated a translocation of AhR triggered by IS, leading to significant increase of downstream gene expression. Subsequently study indicated a close relationship between the production of ROS and the activation of AhR/CYP1s, which was effectively blocked by applying AhR inhibitor, CYP1s inhibitor and siRNA against AhR. Moreover, the inhibition of AhR/CYP1s/ROS pathway collectively blocked the pro-hypertrophic effect of IS-mediated cardiomyopathy.<br><br>CONCLUSION: This study provides evidence that the AhR/CYP1s pathway is activated in UCM rats, and this activation is correlated with the uremic toxin IS. In vitro studies indicate that IS can stimulate the AhR translocation in cardiomyocyte, triggering to the production of intracellular ROS via CYP1s. This process leads to prolonged oxidative stress stimulation and thus contributes to the progression of uremic toxin-mediated cardiomyopathy.}, }
@article {pmid38669982, year = {2024}, author = {An, K and Fan, J and Lin, B and Han, Y}, title = {A lysosome-targeted fluorescent probe for fluorescence imaging of hypochlorous acid in living cells and in vivo.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {316}, number = {}, pages = {124316}, doi = {10.1016/j.saa.2024.124316}, pmid = {38669982}, issn = {1873-3557}, mesh = {*Hypochlorous Acid/analysis/metabolism ; *Lysosomes/metabolism/chemistry ; *Fluorescent Dyes/chemistry/chemical synthesis ; Animals ; *Zebrafish ; *Optical Imaging ; Humans ; RAW 264.7 Cells ; Mice ; Boron Compounds/chemistry ; Spectrometry, Fluorescence ; Pyridines/chemistry ; Limit of Detection ; }, abstract = {Lysosomes, as crucial acidic organelles in cells, play a significant role in cellular functions. The levels and distribution of hypochlorous acid (HOCl) within lysosomes can profoundly impact their biological functionality. Hence, real-time monitoring of the concentration of HOCl in lysosomes holds paramount importance for further understanding various physiological and pathological processes associated with lysosomes. In this study, we developed a bodipy-based fluorescent probe derived from pyridine and phenyl selenide for the specific detection of HOCl in aqueous solutions. Leveraging the probe's sensitive photoinduced electron transfer effect from phenyl selenide to the fluorophore, the probe exhibited satisfactory high sensitivity (with a limit of detection of 5.2 nM and a response time of 15 s) to hypochlorous acid. Further biological experiments confirmed that the introduction of the pyridine moiety enabled the probe molecule to selectively target lysosomes. Moreover, the probe successfully facilitated real-time monitoring of HOCl in cell models stimulated by N-acetylcysteine (NAC) and lipopolysaccharide (LPS), as well as in a normal zebrafish model. This provides a universal method for dynamically sensing HOCl in lysosomes.}, }
@article {pmid38665380, year = {2024}, author = {Gangadharan Nambiar, G and Gonzalez Szachowicz, S and Zirbes, CF and Hill, JJ and Powers, LS and Meyerholz, DK and Thornell, IM and Stoltz, DA and Fischer, AJ}, title = {Pancreatic enzymes digest obstructive meconium from cystic fibrosis pig intestines.}, journal = {Frontiers in pediatrics}, volume = {12}, number = {}, pages = {1387171}, pmid = {38665380}, issn = {2296-2360}, abstract = {INTRODUCTION: Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF. Meconium contains mucin glycoprotein, a potential substrate for pancreatic enzymes or mucolytics. Our study aim was to determine whether pancreatic enzymes in combination with mucolytic treatments dissolve obstructive meconium using the CF pig model.<br><br>METHODS: We collected meconium from CF pigs at birth and submerged it in solutions with and without pancreatic enzymes, including normal saline, 7% hypertonic saline, and the reducing agents N-acetylcysteine (NAC) and dithiothreitol (DTT). We digested meconium at 37 &#xb0;C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.<br><br>RESULTS AND DISCUSSION: In CF pigs, meconium appeared as a solid pigmented mass obstructing the ileum. Meconium microscopically contained mucus glycoprotein, cellular debris, and bile pigments. Meconium fragments released pigments with maximal absorption at 405&#x2005;nm after submersion in saline over approximately 8&#x2005;h. Pancreatic enzymes significantly increased pigment release and decreased residual meconium solids. DTT did not improve meconium digestion and the acidic reducing agent NAC worsened digestion. Pancreatic enzymes digested CF meconium best at neutral pH in isotonic saline. We conclude that pancreatic enzymes digest obstructive meconium from CF pigs, while hydrating or reducing agents alone were less effective. This work suggests a potential role for pancreatic enzymes in relieving obstruction due to MI in newborns with CF.}, }
@article {pmid38657455, year = {2024}, author = {Zhang, L and Xu, F and Yang, Y and Yang, L and Wu, Q and Sun, H and An, Z and Li, J and Wu, H and Song, J and Wu, W}, title = {PM2.5 exposure upregulates pro-inflammatory protein expression in human microglial cells via oxidant stress and TLR4/NF-κB pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {277}, number = {}, pages = {116386}, doi = {10.1016/j.ecoenv.2024.116386}, pmid = {38657455}, issn = {1090-2414}, mesh = {*Toll-Like Receptor 4/metabolism ; Humans ; *Particulate Matter/toxicity ; *Oxidative Stress/drug effects ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism ; *Reactive Oxygen Species/metabolism ; *Interleukin-6/metabolism ; *Cyclooxygenase 2/metabolism ; *Brain-Derived Neurotrophic Factor/metabolism ; Cell Line ; Up-Regulation/drug effects ; Signal Transduction/drug effects ; Air Pollutants/toxicity ; }, abstract = {Exposure to ambient PM2.5 is associated with neurodegenerative disorders, in which microglia activation plays a critical role. Thus far, the underlying mechanisms for PM2.5-induced microglia activation have not been well elucidated. In this study, a human microglial cell line (HMC3) was used as the in vitro model to examine the inflammatory effect (hall marker of microglia activation) of PM2.5 and regulatory pathways. The expression of inflammatory mediators including interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) as well as the brain derived neurotrophic factor (BDNF) were determined by ELISA and/or real-time PCR, respectively. Flow cytometry was used to measure the production of intracellular reactive oxygen species (ROS). Western blot was used to measure protein levels of Toll-like receptor 4 (TLR4), NF-κB inhibitor α (IκBα) and COX-2. It was shown that PM2.5 stimulation increased IL-6 and COX-2 expression but decreased BDNF expression in a dose-dependent manner. Further studies showed that PM2.5 triggered the formation of ROS and pre-treatment with the ROS scavenger acetylcysteine (NAC) significantly suppressed PM2.5-induced IL-6 and COX-2 expression. Moreover, the nuclear factor kappa B (NF-κB) inhibitor BAY11-7085 or the TLR4 neutralizing antibody markedly blocked PM2.5-induced IL-6 and COX-2 expression. However, NAC or BAY11-7085 exhibited minimal effect on PM2.5-induced BDNF down-regulation. In addition, pre-treatment with BAY11-7085 or TLR4 neutralizing antibody reduced ROS production induced by PM2.5, and NAC pre-treatment inhibited TLR4 expression and NF-κB activation induced by PM2.5. Collectively, PM2.5 treatment induced IL-6 and COX-2 but suppressed BDNF expression. PM2.5-induced IL-6 and COX-2 expression was mediated by interactive oxidative stress and TLR4/NF-κB pathway.}, }
@article {pmid38647950, year = {2024}, author = {Zhou, D and Yang, Y and Chen, J and Zhou, J and He, J and Liu, D and Zhang, A and Yuan, B and Jiang, Y and Xia, W and Han, R and Xia, Z}, title = {N-acetylcysteine Protects Against Myocardial Ischemia-Reperfusion Injury Through Anti-ferroptosis in Type 1 Diabetic Mice.}, journal = {Cardiovascular toxicology}, volume = {24}, number = {5}, pages = {481-498}, pmid = {38647950}, issn = {1559-0259}, support = {81970247//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Myocardial Reperfusion Injury/prevention &amp; control/pathology/metabolism/physiopathology ; *Acetylcysteine/pharmacology ; *Diabetes Mellitus, Experimental/drug therapy/complications ; Male ; *Diabetes Mellitus, Type 1/complications/drug therapy/metabolism ; *Antioxidants/pharmacology ; *Ferroptosis/drug effects ; *Mice, Inbred C57BL ; Myocardial Infarction/prevention &amp; control/pathology/metabolism/physiopathology/drug therapy ; Time Factors ; Myocardium/pathology/metabolism ; Mice ; Oxidative Stress/drug effects ; }, abstract = {The hearts of subjects with diabetes are vulnerable to ischemia-reperfusion injury (IRI). In contrast, experimentally rodent hearts have been shown to be more resistant to IRI at the very early stages of diabetes induction than the heart of the non-diabetic control mice, and the mechanism is largely unclear. Ferroptosis has recently been shown to play an important role in myocardial IRI including that in diabetes, while the specific mechanisms are still unclear. Non-diabetic control (NC) and streptozotocin-induced diabetic (DM) mice were treated with the antioxidant N-acetylcysteine (NAC) in drinking water for 4 week starting at 1 week after diabetes induction. Mice were subjected to myocardial IRI induced by occluding the coronary artery for 30 min followed by 2 h of reperfusion, subsequently at 1, 2, and 5 week of diabetes induction. The post-ischemic myocardial infarct size in the DM mice was smaller than that in NC mice at 1 week of diabetes but greater than that in the NC mice at 2 and 5 week of diabetes, which were associated with a significant increase of ferroptosis at 2 and 5 week but a significant reduction of ferroptosis at 1 week of diabetes. NAC significantly attenuated post-ischemic ferroptosis as well as oxidative stress and reduced infarct size at 2 and 5 week of diabetes. Application of erastin, a ferroptosis inducer, reversed the cardioprotective effects of NAC. It is concluded that increased oxidative stress and ferroptosis are the major factors attributable to the increased vulnerability to myocardial IRI in diabetes and that attenuation of ferroptosis represents a major mechanism whereby NAC confers cardioprotection against myocardial IRI in diabetes.}, }
@article {pmid38647195, year = {2024}, author = {Picchi, SC and Rebelatto, D and Martins, PMM and Blumer, S and Mesquita, GL and Hippler, FWR and Mattos, D and Boaretto, RM and Machado, MA and Takita, MA and Coletta-Filho, HD and de Souza, AA}, title = {N-acetylcysteine absorption and its potential dual effect improve fitness and fruit yield in Xylella fastidiosa infected plants.}, journal = {Pest management science}, volume = {}, number = {}, pages = {}, doi = {10.1002/ps.8137}, pmid = {38647195}, issn = {1526-4998}, support = {//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; }, abstract = {BACKGROUND: Xylella fastidiosa is a multi-host bacterium that can be detected in hundreds of plant species including several crops. Diseases caused by X. fastidiosa are considered a threat to global food production. The primary method for managing diseases caused by X. fastidiosa involves using insecticides to control the vector. Hence, it is necessary to adopt new and sustainable disease management technologies to control not only the insect but also the bacteria and plant health. We demonstrated that N-acetylcysteine (NAC), a low-cost cysteine analogue, is a sustainable molecule that can be used in agriculture to decrease the damage caused by X. fastidiosa and improve plant health.<br><br>RESULTS: Using [15]N-NAC we proved that this analogue was absorbed by the roots and transported to different parts of the plant. Inside the plant, NAC reduced the bacterial population by 60-fold and the number of xylem vessels blocked by bacterial biofilms. This reflected in a recovery of 0.28-fold of the daily sap flow compared to health plants. In addition, NAC-treated citrus variegated chlorosis (CVC) plants decreased the oxidative stress by improving the activity of detoxifying enzymes. Moreover, the use of NAC in field conditions positively contributed to the increase in fruit yield of CVC-diseased plants.<br><br>CONCLUSION: Our research not only advances the understanding of NAC absorption in plants, but also indicates its dual effect as an antimicrobial and antioxidant molecule. This, in turn, negatively affects bacterial survival while improving plant health by decreasing oxidative stress. Overall, the positive field-based evidence supports the viability of NAC as a sustainable agricultural application. &#xa9; 2024 Society of Chemical Industry.}, }
@article {pmid38643270, year = {2024}, author = {Bates, JN and Baby, SM and Getsy, PM and Coffee, GA and Hsieh, YH and Knauss, ZT and Dahan, A and Bubier, JA and MacFarlane, PM and Mueller, D and Lewis, SJ}, title = {L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {9091}, pmid = {38643270}, issn = {2045-2322}, support = {U01 DA051373/DA/NIDA NIH HHS/United States ; U01DA051373/DA/NIDA NIH HHS/United States ; }, mesh = {Rats ; Male ; Animals ; Fentanyl/pharmacology ; Acetylcysteine/*analogs &amp; derivatives ; Rats, Sprague-Dawley ; *Substance Withdrawal Syndrome ; Naloxone/pharmacology ; Narcotic Antagonists/pharmacology ; *Morphine Dependence ; Lysine/*analogs &amp; derivatives ; }, abstract = {N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 μmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 μmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 μg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.}, }
@article {pmid38641841, year = {2024}, author = {Sajedi, F and Abdi, A and Mehrpooya, M and Faramarzi, V and Mohammadi, Y and Sheida, F}, title = {Comparison of therapeutic effects of N-Acetylcysteine with pregabalin in improving the clinical symptoms of painful diabetic neuropathy: a randomized, double-blind clinical trial.}, journal = {Clinical diabetes and endocrinology}, volume = {10}, number = {1}, pages = {15}, pmid = {38641841}, issn = {2055-8260}, support = {IR.UMSHA.REC.1397.137//Hamadan University of Medical Sciences/ ; }, abstract = {OBJECTIVES: Painful diabetic neuropathy (PDN) is highly prevalent and annoyingly in patients with diabetes. The aim of this study was to investigate the effects of oral N-acetylcysteine (NAC) compared to pregabalin in PDN.<br><br>METHODS: One hundred two eligible patients with type 2 diabetes and PDN were randomly recievied pregabalin (150 mg/day) or N-Acetylcysteine (NAC) (600 mg/ twice a day) for 8 weeks. Mean pain score, Sleep interference score (SIS), Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and also, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.<br><br>RESULTS: NAC was well tolerated in all patients. The decrease in mean pain scores and increase in SIS was similar between two groups. More improvement in PGIC and CGIC from the baseline was reported in NAC group. NAC, significantly, decreased serum levels of MDA, and NO, but increased TAC, TTG, and CAT. Pregabalin, significantly, decreased serum levels of MDA, and NO and increased TAC.<br><br>DISCUSSION: NAC is efficacious in alleviate symptoms of PDN which is probably related to its antioxidant effects.<br><br>TRIAL REGISTRATION: The research protocol received approval from the Ethics Committee of Hamadan University of Medical Sciences (IR.UMSHA.REC.1397.137). The trial registry URL and number in Iranian Registry of Clinical Trials (IRCT): https://www.irct.ir/trial/33313 , IRCT20180814040795N2 (Registration date: 2019-01-21, Retrospectively registered).}, }
@article {pmid38641701, year = {2024}, author = {Hassan, YF and Shabaan, DA}, title = {Effect of N-acetylcysteine on hair follicle changes in mouse model of cyclophosphamide-induced alopecia: histological and biochemical study.}, journal = {Histochemistry and cell biology}, volume = {}, number = {}, pages = {}, pmid = {38641701}, issn = {1432-119X}, abstract = {Chemotherapy-induced alopecia (CIA) represents one of the most severe side effects of chemotherapy, which forces some patients to reject cancer treatment. The exact pathophysiological mechanisms of CIA are not clearly understood, which makes it difficult to discover efficient preventive or therapeutic procedures for this adverse effect. N-acetylcysteine (NAC) has a strong antioxidant activity as it stimulates glutathione synthesis and acts as an oxygen radical scavenger. The current study tried to investigate the efficacy of NAC in preserving biochemical parameters and hair follicle structure against cyclophosphamide (CYP) administration. In total, 40 adult female C57BL/6 mice were induced to enter anagen by depilation (day 0) and divided into four groups: group I (control), group II (CYP) received a single dose of CYP [150 mg/kg body weight (B.W.)/intraperitoneal injection (IP)] at day 9, group III (CYP &amp; NAC) received a single dose of CYP at day 9 as well as NAC (500 mg/kg B.W./day/IP) from day 6-16, and group IV (NAC) received NAC from day 6-16. CYP administration in group II induced an increase in malondialdehyde (MDA), decrease in superoxide dismutase (SOD), histological hair follicle dystrophy, disruption of follicular melanogenesis, overexpression of p53, and loss of ki67 immunoreactivity. NAC coadministration in group III reversed CYP-induced alterations in the biochemical parameters and preserved hair follicle structure, typical follicular melanin distribution as well as normal pattern of p53 and ki67 expression. These findings indicated that NAC could be used as an efficient and safe therapeutic option for hair loss induced by chemotherapy.}, }
@article {pmid38636660, year = {2024}, author = {Boeglin, WE and Stec, DF and Noguchi, S and Calcutt, MW and Brash, AR}, title = {The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {5}, pages = {107293}, pmid = {38636660}, issn = {1083-351X}, mesh = {*Glutathione/chemistry/metabolism ; *Sulfhydryl Compounds/chemistry ; Mass Spectrometry/methods ; Chromatography, High Pressure Liquid/methods ; Chromatography, Liquid/methods ; Mercaptoethanol/chemistry ; Liquid Chromatography-Mass Spectrometry ; }, abstract = {Unsaturated fatty acid ketones with αβ,γδ conjugation are susceptible to Michael addition of thiols, with unresolved issues on the site of adduction and precise structures of the conjugates. Herein we reacted 13-keto-octadecadienoic acid (13-oxo-ODE or 13-KODE) with glutathione (GSH), N-acetyl-cysteine, and β-mercaptoethanol and identified the adducts. HPLC-UV analyses indicated none of the products exhibit a conjugated enone UV chromophore, a result that conflicts with the literature and is relevant to the mass spectral interpretation of 1,4 versus 1,6 thiol adduction. Aided by the development of an HPLC solvent system that separates the GSH diastereomers and thus avoids overlap of signals in proton NMR experiments, we established the two major conjugates are formed by 1,6 addition of GSH at the 9-carbon of 13-oxo-ODE with the remaining double bond α to the thiol in the 10,11 position. N-acetyl cysteine reacts similarly, while β-mercaptoethanol gives equal amounts of 1,4 and 1,6 addition products. Equine glutathione transferase catalyzed 1,6 addition of GSH to the two major diastereomers in 44:56 proportions. LC-MS in positive ion mode gives a product ion interpreted before as evidence of 1,4-thiol adduction, whereas here we find this ion using the authentic 1,6 adduct. LC-MS with negative ion APCI gave a fragment selective for 1,4 adduction. These results clarify the structures of thiol conjugates of a prototypical unsaturated keto-fatty acid and have relevance to the application of LC-MS for the structural analysis of keto-fatty acid glutathione conjugation.}, }
@article {pmid38634668, year = {2024}, author = {Hakimi, F and Karimi Torshizi, MA and Hezavehei, M and Sharafi, M}, title = {Protective Effect of N-Acetylcysteine on Rooster Semen Cryopreservation.}, journal = {Biopreservation and biobanking}, volume = {}, number = {}, pages = {}, doi = {10.1089/bio.2023.0103}, pmid = {38634668}, issn = {1947-5543}, abstract = {Cryopreservation of avian semen is a useful reproductive technique in the poultry industry. However, during cooling, elevated reactive oxygen species (ROS) levels have destructive effects on both quality and function of thawed sperm. The aim of the current study is to investigate the antioxidant effects of N-acetylcysteine (NAC) during rooster semen cryopreservation. Semen samples were collected from ten Ross 308 broiler breeder roosters (32 weeks) and mixed. The mixed samples were divided into five equal parts and cryopreserved in Lake Buffer extender that contained different concentrations (0, 0.01, 0.1, 1, and 10 mM) of NAC. The optimum concentration of NAC was determined based on quality parameters of mobility, viability, membrane integrity, acrosome integrity, lipid peroxidation, and mitochondrial membrane potential after the freeze-thaw process. There was a higher percentage (p < 0.05) of total motility (TM) (60.9 ± 2.4%) and progressive motility (PM) (35.6 ± 1.9%) observed with the NAC-0.1 group compared to the other groups. Significantly higher percentages of viability (74.4 ± 2.3% and 71 ± 2.3%), membrane integrity (76.4 ± 1.5% and 74.7 ± 1.5%) and mitochondrial membrane potential (67.1 ± 1.6% and 66.3 ± 1.6%) were observed in the NAC-0.1 and NAC-1 groups compared to the other frozen groups (p < 0.05). The lowest percentage of lipid peroxidation and nonviable sperm was found in the NAC-0.1 and NAC-1 groups compared to the other groups (p < 0.05). The average path velocity (VAP), straight line velocity (VSL), curvilinear velocity (VCL), and acrosome integrity, were not affected by different concentrations of NAC in the thawed sperm (p > 0.05). Both NAC-0.1 and NAC-1 appear to be beneficial for maintaining the quality of rooster sperm after thawing.}, }
@article {pmid38633147, year = {2024}, author = {Shams, G and Allah, SA and Ezzat, R and Said, MA}, title = {Ameliorative effects of berberine and selenium against paracetamol-induced hepatic toxicity in rats.}, journal = {Open veterinary journal}, volume = {14}, number = {1}, pages = {292-303}, pmid = {38633147}, issn = {2218-6050}, mesh = {Humans ; Rats ; Male ; Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Acetaminophen/pharmacology ; *Selenium/pharmacology ; *Berberine/pharmacology/therapeutic use ; Oxidative Stress ; Rats, Wistar ; }, abstract = {BACKGROUND: Paracetamol (PCM) overdosing induces hepatotoxicity, which can result in death if the dose is high enough and the patients are not given N-acetyl cysteine. Berberine (BBR) has a variety of biological proprieties including anti-inflammatory and antioxidant activities.<br><br>AIM: Assessment of the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity in rats.<br><br>METHODS: This research involved 40 clinically healthy mature adult male albino rats, their weights ranged from 150 to 200 g and housed in standard conditions. Our study involved evaluating the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity via estimation of the liver function tests, determination of the antioxidant enzyme activities, lipid peroxidation markers, immune-modulatory effects, liver histopathological, and immunohistochemical studies.<br><br>RESULTS: Co-treatment of BBR (150 mg/kg BW) with selenium (5 mg/kg BW) showed significant improvement in the liver function parameters, the antioxidant enzyme activities, reduction in the nitric oxide (NO), lysozyme, malondialdehyde (MDA), TNF-&#x3b1;, and TGF-&#x3b2;1 levels, and marked elevation in the IgM levels.<br><br>CONCLUSION: Altogether, BBR, selenium, or both augment antioxidant activity and alleviate PCM-induced hepatic toxicity.}, }
@article {pmid38629620, year = {2024}, author = {Kim, SH and Kang, DW and Kwon, D and Jung, YS}, title = {Critical role of endoplasmic reticulum stress on bisphenol A-induced cytotoxicity in human keratinocyte HaCaT cells.}, journal = {Environmental toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1002/tox.24290}, pmid = {38629620}, issn = {1522-7278}, support = {2022R1I1A1A01070024//National Research Foundation of Korea/ ; //Korean Government (MSIT)/ ; 20014436//Technology Innovation Program/ ; //Ministry of Trade, Industry &amp; Energy (MOTIE, Korea)/ ; }, abstract = {Bisphenol A (BPA) is widely used in plastic and paper products, and its exposure can occur through skin contact or oral ingestion. The hazardous effects of BPA absorbed through the skin may be more severe; however, few studies have investigated the skin toxicity of BPA. This study investigated the effects of BPA on human epidermal keratinocyte cell lines, which is relevant for skin exposure. BPA treatment reduced cell viability in a time- and concentration-dependent manner and elevated oxidative and endoplasmic reticulum (ER) stress. N-acetylcysteine (NAC), an oxidative stress inhibitor, reduced BPA-induced reactive oxygen species (ROS) levels. However, only 10% of the decreased cell viability was restored at the highest NAC concentration. Treatment with tauroursodeoxycholic acid (TUDCA), which is an ER stress inhibitor, effectively countered the increase in ER stress-related proteins induced by BPA. Moreover, TUDCA treatment led to a reduction in oxidative stress, as demonstrated by the decrease in ROS levels, maintenance of mitochondrial membrane potential, and modulation of stress signaling proteins. Consequently, TUDCA significantly improved BPA-induced cytotoxicity in a concentration-dependent manner. Notably, combined treatment using TUDCA and NAC further reduced the BPA-induced ROS levels; however, no significant difference in cell viability was observed compared with that for TUDCA treatment alone. These findings indicated that the oxidative stress observed following BPA exposure was exacerbated by ER stress. Moreover, the principal factor driving BPA-induced cytotoxicity was indeed ER stress, which has potential implications for developing therapeutic strategies for diseases associated with similar stress responses.}, }
@article {pmid38622261, year = {2024}, author = {Liu, C and Zha, J and Sun, T and Kong, L and Zhang, X and Wang, D and Ni, G}, title = {Cold atmospheric plasma attenuates skin cancer via ROS induced apoptosis.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {518}, pmid = {38622261}, issn = {1573-4978}, mesh = {Animals ; *Skin Neoplasms/drug therapy/pathology ; *Carcinoma, Squamous Cell/drug therapy/pathology ; Reactive Oxygen Species/pharmacology ; Matrix Metalloproteinase 2/genetics ; Matrix Metalloproteinase 9/genetics ; *Plasma Gases/pharmacology ; Proliferating Cell Nuclear Antigen/genetics ; bcl-2-Associated X Protein ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; }, abstract = {BACKGROUND: Cold atmospheric plasma (CAP) has been widely used in biomedical research, especially in vitro cancer therapy. Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor originating from epidermal keratinocytes. However, the mechanism of CAP therapy on CSCC remains unclear.<br><br>METHODS AND RESULTS: The animal models of CSCC induced by 7,12-dimethylbenz(a) anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) were constructed. For the CAP treatment group, after each TPA application, CAP was administered for 3&#xa0;min twice weekly after drying. HE staining were used to detect the pathological status of tumor tissue in each group. The levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 were evaluated by western blot and qPCR. TUNEL staining were used to detect apoptosis in tumor tissues. In vivo, serum samples were used for ELISA of total ROS. MTT assay was used to detect the viability of A431 cells. Western blot and qPCR were used to detect the levels of PCNA, Bcl-2, Bax, MMP2 and MMP9 in A431 cells. A431 cell proliferation was examined by colony formation assay. The proportions of apoptosis of A431 cells were detected by flow cytometry. Transwell assessed the ability of A431 cells migration and proliferation. We found that CAP could induce skin cancer cells apoptosis and inhibit the progress of skin cancer. Through experiments in vitro, reactive oxygen species (ROS) generated by N-acetylcysteine (NAC) and CAP inhibited the proliferation and migration of A431 skin cancer cells while promoting apoptosis.<br><br>CONCLUSIONS: These evidences suggest the protective effect of CAP in CSCC, and CAP has the potential clinical application of CSCC.}, }
@article {pmid38618504, year = {2024}, author = {Ameri, A and Rahmati, A and Soroushfar, S and Lalehzari, M and Dehghani, T and Haghi-Aminjan, H and Shamseddin, J and Omidi, M}, title = {The Protective Effect of N-acetylcysteine against Deltamethrin-Induced Hepatotoxicity in Mice.}, journal = {Avicenna journal of medical biotechnology}, volume = {16}, number = {2}, pages = {88-94}, pmid = {38618504}, issn = {2008-2835}, abstract = {BACKGROUND: Exposure to pesticides is of concern to public health officials worldwide. Deltamethrin is a synthetic pyrethroid pesticide which is widely used in agriculture and veterinary medicine. Deltamethrin poisoning is always one of the concerns in medical centers due to the deltamethrin induced hepatotoxicity. This study evaluated the hepato-protective effects of N-acetylcysteine (NAC) against deltamethrin induced hepatotoxicity in mice.<br><br>METHODS: A total of 40 BALB/c male mice were randomly divided into four groups; the first group was used as a control (0.5 ml normal saline); Groups 2-4 were treated with NAC [160 mg/kg Body Weight (BW)], deltamethrin (50 mg/kg BW), and NAC plus deltamethrin. At 1 and 24 hr after treatment, the animals were sacrificed and blood and liver samples were obtained for analysis and the liver/body ration, hepatic enzymes as Aspartate aminotransferase (AST), Alanine Transaminase (ALT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH), Glutathione (GSH) content and Reactive Oxygen Species (ROS) level were measured. For comparison between more than two experimental groups, one-way ANOVA following Tukey test was used by SPSS software.<br><br>RESULTS: The deltamethrin significantly increased AST, ALT, ALP, and the level of ROS level at the end of 1 and 24 hr after treatment; while the LDH level and GSH content were decreased. Mice in the deltamethrin treated group had a higher liver/body weight ratio than in other treated groups after 24 hr. On the other hand, NAC in combination with deltamethrin significantly reduced the activities of AST, ALT, ALP, and increased GSH levels.<br><br>CONCLUSION: This study demonstrated that NAC has a hepatoprotective role against deltamethrin-induced toxicity.}, }
@article {pmid38611747, year = {2024}, author = {Abdelkader, I and Guisán, JM and Sayari, A and Fernández-Lorente, G}, title = {Various Strategies for the Immobilization of a Phospholipase C from Bacillus cereus for the Modulation of Its Biochemical Properties.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {7}, pages = {}, pmid = {38611747}, issn = {1420-3049}, mesh = {*Bacillus cereus ; Sepharose ; *Acetylcysteine ; Enzymes, Immobilized ; Type C Phospholipases ; *Glyoxylates ; }, abstract = {In this study, the effect of various immobilization methods on the biochemical properties of phospholipase C (PLC) from Bacillus cereus obtained from the oily soil located in Sfax, Tunisia, was described. Different supports were checked: octyl sepharose, glyoxyl agarose in the presence of N-acetyl cysteine, and Q-sepharose. In the immobilization by hydrophobic adsorption, a hyperactivation of the PLCBc was obtained with a fold of around 2 times. The recovery activity after immobilization on Q-sepharose and glyoxyl agarose in the presence of N-acetyl cysteine was 80% and 58%, respectively. Furthermore, the biochemical characterization showed an important improvement in the three immobilized enzymes. The performance of the various immobilized PLCBc was compared with the soluble enzyme. The derivatives acquired using Q-sepharose, octyl sepharose, and glyoxyl agarose were stable at 50 °C, 60 °C, and 70 °C. Nevertheless, the three derivatives were more stable in a large range of pH than the soluble enzyme. The three derivatives and the free enzyme were stable in 50% (v/v) ethanol, hexane, methanol, and acetone. The glyoxyl agarose derivative showed high long-term storage at 4 °C, with an activity of 60% after 19 days. These results suggest the sustainable biotechnological application of the developed immobilized enzyme.}, }
@article {pmid38608750, year = {2024}, author = {Salas, G and Litta, AA and Medeot, AC and Schuck, VS and Andermatten, RB and Miszczuk, GS and Ciriaci, N and Razori, MV and Barosso, IR and Sánchez Pozzi, EJ and Roma, MG and Basiglio, CL and Crocenzi, FA}, title = {NADPH oxidase-generated reactive oxygen species are involved in estradiol 17ß-d-glucuronide-induced cholestasis.}, journal = {Biochimie}, volume = {223}, number = {}, pages = {41-53}, doi = {10.1016/j.biochi.2024.04.002}, pmid = {38608750}, issn = {1638-6183}, abstract = {The endogenous metabolite of estradiol, estradiol 17β-D-glucuronide (E17G), is considered the main responsible of the intrahepatic cholestasis of pregnancy. E17G alters the activity of canalicular transporters through a signaling pathway-dependent cellular internalization, phenomenon that was attributed to oxidative stress in different cholestatic conditions. However, there are no reports involving oxidative stress in E17G-induced cholestasis, representing this the aim of our work. Using polarized hepatocyte cultures, we showed that antioxidant compounds prevented E17G-induced Mrp2 activity alteration, being this alteration equally prevented by the NADPH oxidase (NOX) inhibitor apocynin. The model antioxidant N-acetyl-cysteine prevented, in isolated and perfused rat livers, E17G-induced impairment of bile flow and Mrp2 activity, thus confirming the participation of reactive oxygen species (ROS) in this cholestasis. In primary cultured hepatocytes, pretreatment with specific inhibitors of ERK1/2 and p38MAPK impeded E17G-induced ROS production; contrarily, NOX inhibition did not affect ERK1/2 and p38MAPK phosphorylation. Both, knockdown of p47phox by siRNA and preincubation with apocynin in sandwich-cultured rat hepatocytes significantly prevented E17G-induced internalization of Mrp2, suggesting a crucial role for NOX in this phenomenon. Concluding, E17G-induced cholestasis is partially mediated by NOX-generated ROS through internalization of canalicular transporters like Mrp2, being ERK1/2 and p38MAPK necessary for NOX activation.}, }
@article {pmid38608558, year = {2024}, author = {Madhu, M and Santhoshkumar, S and Tseng, WB and Kumar, ASK and Tseng, WL}, title = {Synthesis of rhenium disulfide nanodots exhibiting pH-dependent fluorescence and phosphorescence for anticounterfeiting and hazardous gas detection.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {315}, number = {}, pages = {124240}, doi = {10.1016/j.saa.2024.124240}, pmid = {38608558}, issn = {1873-3557}, abstract = {The synthesis and characterization of ReS2 nanodots (NDs) are detailed, by highlighting their structure, morphological, and optical properties. ReS2 NDs were synthesized using NH4ReO4 as a rhenium source, thiourea as a sulfur source, and N-acetyl cysteine as a capping agent. The synthesis involved the hydrothermal reaction of these precursors, leading to the nucleation and growth of ReS2 NDs. Characterization techniques including transmission electron microscopy, energy dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy confirmed the formation of ReS2 NDs with a spherical morphology, crystalline structure, and rich sulfur sites. The fluorescence behavior of ReS2 NDs was found to be influenced by the solution pH, with fluorescence intensity increasing with rising pH values. This pH-dependent fluorescence response was attributed to the dissociation of functional groups and the subsequent impact on the excited-state proton transfer process. The fluorescence intensity of ReS2 NDs showed a correlation with solution pH, enabling pH detection from 3.0 to 12.5 with an interval of 0.5 pH unit. Additionally, the incorporation of ReS2 NDs into a polyvinyl alcohol (PVA) matrix resulted in pH-sensitive phosphorescence, offering a new avenue for pH sensing. The strong interaction between PVA and ReS2 NDs was proposed to enhance phosphorescence intensity and trigger a blue shift in the phosphorescent peak at high pH. The ReS2 NDs/PVA-deposited filter paper exhibited pH-sensitive fluorescence and phosphorescence, which could be utilized as unique identifiers or authentication markers. Moreover, the ReS2 NDs/PVA-deposited filter paper showed potential for discriminating between hydrogen chloride and ammonia, based on their distinct fluorescence and phosphorescence responses.}, }
@article {pmid38591866, year = {2024}, author = {Monou, PK and Andriotis, E and Tzetzis, D and Tzimtzimis, E and Panteris, E and Andreadis, D and Demiri, E and Vizirianakis, IS and Fatouros, DG}, title = {Evaluation of 3D-Printed Solid Microneedles Coated with Electrosprayed Polymeric Nanoparticles for Simultaneous Delivery of Rivastigmine and N-Acetyl Cysteine.}, journal = {ACS applied bio materials}, volume = {7}, number = {5}, pages = {2710-2724}, doi = {10.1021/acsabm.3c00750}, pmid = {38591866}, issn = {2576-6422}, mesh = {*Acetylcysteine/chemistry/pharmacology ; *Rivastigmine/chemistry/pharmacology/administration &amp; dosage ; Humans ; *Printing, Three-Dimensional ; *Needles ; *Nanoparticles/chemistry ; *Biocompatible Materials/chemistry/pharmacology ; *Materials Testing ; *Particle Size ; Drug Delivery Systems ; Skin/metabolism ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Cell Survival/drug effects ; }, abstract = {In the current study, coated microneedle arrays were fabricated by means of digital light processing (DLP) printing. Three different shapes were designed, printed, and coated with PLGA particles containing two different actives. Rivastigmine (RIV) and N-acetyl-cysteine (NAC) were coformulated via electrohydrodynamic atomization (EHDA), and they were incorporated into the PLGA particles. The two actives are administered as a combined therapy for Alzheimer's disease. The printed arrays were evaluated regarding their ability to penetrate skin and their mechanical properties. Optical microscopy and scanning electron microscopy (SEM) were employed to further characterize the microneedle structure. Confocal laser microscopy studies were conducted to construct 3D imaging of the coating and to simulate the diffusion of the particles through artificial skin samples. Permeation studies were performed to investigate the transport of the drugs across human skin ex vivo. Subsequently, a series of tape strippings were performed in an attempt to examine the deposition of the APIs on and within the skin. Light microscopy and histological studies revealed no drastic effects on the membrane integrity of the stratum corneum. Finally, the cytocompatibility of the microneedles and their precursors was evaluated by measuring cell viability (MTT assay and live/dead staining) and membrane damages followed by LDH release.}, }
@article {pmid38583854, year = {2024}, author = {Kim, NY and Shivanne Gowda, SG and Lee, SG and Sethi, G and Ahn, KS}, title = {Cannabidiol induces ERK activation and ROS production to promote autophagy and ferroptosis in glioblastoma cells.}, journal = {Chemico-biological interactions}, volume = {394}, number = {}, pages = {110995}, doi = {10.1016/j.cbi.2024.110995}, pmid = {38583854}, issn = {1872-7786}, mesh = {Humans ; *Autophagy/drug effects ; Beclin-1/metabolism ; *Cannabidiol/pharmacology ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/drug effects/metabolism ; *Ferroptosis/drug effects ; *Glioblastoma/metabolism/pathology/drug therapy ; MAP Kinase Signaling System/drug effects ; *Reactive Oxygen Species/metabolism ; }, abstract = {Small molecule-driven ERK activation is known to induce autophagy and ferroptosis in cancer cells. Herein the effect of cannabidiol (CBD), a phytochemical derived from Cannabis sativa, on ERK-driven autophagy and ferroptosis has been demonstrated in glioblastoma (GBM) cells (U87 and U373 cells). CBD imparted significant cytotoxicity in GBM cells, induced activation of ERK (not JNK and p38), and increased intracellular reactive oxygen species (ROS) levels. It increased the autophagy-related proteins such as LC3 II, Atg7, and Beclin-1 and modulated the expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4), SLC7A11, and TFRC. CBD significantly elevated the endoplasmic reticulum stress, ROS, and iron load, and decreased GSH levels. Inhibitors of autophagy (3-MA) and ferroptosis (Fer-1) had a marginal effect on CBD-induced autophagy/ferroptosis. Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS. Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.}, }
@article {pmid38583502, year = {2024}, author = {Kim, SG and Jeon, JH and Shin, SH and Varias, DC and Moon, SH and Ryu, BY}, title = {Inhibition of reactive oxygen species generation by N-Acetyl Cysteine can mitigate male germ cell toxicity induced by bisphenol analogs.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {188}, number = {}, pages = {114652}, doi = {10.1016/j.fct.2024.114652}, pmid = {38583502}, issn = {1873-6351}, mesh = {*Reactive Oxygen Species/metabolism ; Male ; *Phenols/toxicity ; Animals ; *Benzhydryl Compounds/toxicity ; *Acetylcysteine/pharmacology ; Mice ; *Cell Proliferation/drug effects ; *Apoptosis/drug effects ; Sesquiterpenes/pharmacology ; Cell Line ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Spermatogonia/drug effects/metabolism ; TOR Serine-Threonine Kinases/metabolism ; NF-kappa B/metabolism ; }, abstract = {The estrogen-like effect of bisphenol A (BPA) disrupting the maintenance of functional male germ cells is associated with male sub-fertility. This study investigated toxicity of male germ cells induced by four bisphenol analogs: BPA, BPAF, BPF, and BPS. The investigation of bisphenol analogs' impact on male germ cells included assessing proliferation, apoptosis induction, and the capacity to generate reactive oxygen species (ROS) in GC-1 spermatogonia (spg) cells, specifically type B spermatogonia. Additionally, the therapeutic potential and protective effects of N-Acetyl Cysteine (NAC) and NF-κB inhibitor parthenolide was evaluated. In comparison to BPA, BPF and BPS, BPAF exhibited the most pronounced adverse effect in GC-1 spg cell proliferation. This effect was characterized by pronounced inhibition of phosphorylation of PI3K, AKT, and mTOR, along with increased release of cytochrome c and subsequent cleavages of caspase 3, caspase 7, and poly (ADP-ribose) polymerase. Both NAC and parthenolide were effective reducing cellular ROS induced by BPAF. However, only NAC demonstrated a substantial recovery in proliferation, accompanied by a significant reduction in cytochrome c release and cleaved PARP. These results suggest that NAC supplementation may play an effective therapeutic role in countering germ cell toxicity induced by environmental pollutants with robust oxidative stress-generating capacity.}, }
@article {pmid38576186, year = {2024}, author = {Lopes, AR and Costa Silva, DG and Rodrigues, NR and Kemmerich Martins, I and Paganotto Leandro, L and Nunes, MEM and Posser, T and Franco, J}, title = {Investigating the impact of Psidium guajava leaf hydroalcoholic extract in improving glutamatergic toxicity-induced oxidative stress in Danio rerio larvae.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {87}, number = {11}, pages = {457-470}, doi = {10.1080/15287394.2024.2337366}, pmid = {38576186}, issn = {1528-7394}, mesh = {Animals ; Glutamates/toxicity ; Oxidative Stress ; Plant Extracts/pharmacology/therapeutic use ; Plant Leaves ; *Psidium ; *Zebrafish ; }, abstract = {Glutamate is one of the predominant excitatory neurotransmitters released from the central nervous system; however, at high concentrations, this substance may induce excitotoxicity. This phenomenon is involved in numerous neuropathologies. At present, clinically available pharmacotherapeutic agents to counteract glutamatergic excitotoxicity are not completely effective; therefore, research to develop novel compounds is necessary. In this study, the main objective was to determine the pharmacotherapeutic potential of the hydroalcoholic extract of Psidium guajava (PG) in a model of oxidative stress-induced by exposure to glutamate utilizing Danio rerio larvae (zebrafish) as a model. Data showed that treatment with glutamate produced a significant increase in oxidative stress, chromatin damage, apoptosis, and locomotor dysfunction. All these effects were attenuated by pre-treatment with the classical antioxidant N-acetylcysteine (NAC). Treatment with PG inhibited oxidative stress responsible for cellular damage induced by glutamate. However, exposure to PG failed to prevent glutamate-initiated locomotor damage. Our findings suggest that under conditions of oxidative stress, PG can be considered as a promising candidate for treatment of glutamatergic excitotoxicity and consequent neurodegenerative diseases.}, }
@article {pmid38565435, year = {2024}, author = {Liu, JJ and Zhang, X and Cai, BL and Qi, MM and Chi, YB and Peng, B and Zhang, DH}, title = {Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells.}, journal = {Journal of integrative medicine}, volume = {22}, number = {3}, pages = {286-294}, doi = {10.1016/j.joim.2024.03.007}, pmid = {38565435}, issn = {2095-4964}, mesh = {Humans ; Hep G2 Cells ; *Pentacyclic Triterpenes/pharmacology ; *Insulin Resistance ; *Ferroptosis/drug effects ; Triterpenes/pharmacology ; Cyclohexylamines/pharmacology ; Acetylcysteine/pharmacology ; Phenylenediamines/pharmacology ; Molecular Docking Simulation ; Phospholipid Hydroperoxide Glutathione Peroxidase/genetics/metabolism ; }, abstract = {OBJECTIVE: Research has shown that celastrol can effectively treat a variety of diseases, yet when passing a certain dosage threshold, celastrol becomes toxic, causing complications such as liver and kidney damage and erythrocytopenia, among others. With this dichotomy in mind, it is extremely important to find ways to preserve celastrol's efficacy while reducing or preventing its toxicity.<br><br>METHODS: In this study, insulin-resistant HepG2 (IR-HepG2) cells were prepared using palmitic acid and used for in vitro experiments. IR-HepG2 cells were treated with celastrol alone or in combination with N-acetylcysteine (NAC) or ferrostatin-1 (Fer-1) for 12, 24 or 48&#xa0;h, at a range of doses. Cell counting kit-8 assay, Western blotting, quantitative reverse transcription-polymerase chain reaction, glucose consumption assessment, and flow cytometry were performed to measure celastrol's cytotoxicity and whether the cell death was linked to ferroptosis.<br><br>RESULTS: Celastrol treatment increased lipid oxidation and decreased expression of anti-ferroptosis proteins in IR-HepG2 cells. Celastrol downregulated glutathione peroxidase 4 (GPX4) mRNA. Molecular docking models predicted that solute carrier family 7 member 11 (SLC7A11) and GPX4 were covalently bound by celastrol. Importantly, we found for the first time that the application of ferroptosis inhibitors (especially NAC) was able to reduce celastrol's toxicity while preserving its ability to improve insulin sensitivity in IR-HepG2 cells.<br><br>CONCLUSION: One potential mechanism of celastrol's cytotoxicity is the induction of ferroptosis, which can be alleviated by treatment with ferroptosis inhibitors. These findings provide a new strategy to block celastrol's toxicity while preserving its therapeutic effects. Please cite this article as: Liu JJ, Zhang X, Qi MM, Chi YB, Cai BL, Peng B, Zhang DH. Ferroptosis inhibitors reduce celastrol toxicity and preserve its insulin sensitizing effects in insulin resistant HepG2 cells. J Integr Med. 2024; 22(3): 286-294.}, }
@article {pmid38556154, year = {2024}, author = {Teixeira-Fonseca, JL and Souza, DS and Conceição, MRL and Marques, LP and Durço, AO and Silva, PLD and Joviano-Santos, JV and Santos-Miranda, A and Roman-Campos, D}, title = {In vivo tebuconazole administration impairs heart electrical function and facilitates the occurrence of dobutamine-induced arrhythmias: involvement of reactive oxygen species.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {187}, number = {}, pages = {114596}, doi = {10.1016/j.fct.2024.114596}, pmid = {38556154}, issn = {1873-6351}, mesh = {Humans ; Rats ; Animals ; Male ; Reactive Oxygen Species ; Rats, Wistar ; *Dobutamine ; *Arrhythmias, Cardiac/chemically induced ; Acetylcysteine ; Myocytes, Cardiac ; *Triazoles ; }, abstract = {Tebuconazole (TEB), a widely used pesticide in agriculture to combat fungal infections, is commonly detected in global food, potable water, groundwater, and human urine samples. Despite its known in vivo toxicity, its impact on heart function remains unclear. In a 28-day study on male Wistar rats (approximately 100 g), administering 10 mg/kg/day TEB or a vehicle (control) revealed no effect on body weight gain or heart weight, but an increase in the infarct area in TEB-treated animals. Notably, TEB induced time-dependent changes in in vivo electrocardiograms, particularly prolonging the QT interval after 28 days of administration. Isolated left ventricular cardiomyocytes exposed to TEB exhibited lengthened action potentials and reduced transient outward potassium current. TEB also increased reactive oxygen species (ROS) production in these cardiomyocytes, a phenomenon reversed by N-acetylcysteine (NAC). Furthermore, TEB-treated animals, when subjected to an in vivo dobutamine (Dob) and caffeine (Caf) challenge, displayed heightened susceptibility to severe arrhythmias, a phenotype prevented by NAC. In conclusion, TEB at the no observed adverse effect level (NOAEL) dose adversely affects heart electrical function, increases arrhythmic susceptibility, partially through ROS overproduction, and this phenotype is reversible by scavenging ROS with NAC.}, }
@article {pmid38555190, year = {2024}, author = {Papi, A and Alfano, F and Bigoni, T and Mancini, L and Mawass, A and Baraldi, F and Aljama, C and Contoli, M and Miravitlles, M}, title = {N-acetylcysteine Treatment in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis/Pre-COPD: Distinct Meta-analyses.}, journal = {Archivos de bronconeumologia}, volume = {60}, number = {5}, pages = {269-278}, doi = {10.1016/j.arbres.2024.03.010}, pmid = {38555190}, issn = {1579-2129}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Bronchitis, Chronic/drug therapy ; Disease Progression ; Expectorants/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; *Quality of Life ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {INTRODUCTION: N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. Oxidative stress is a key pathogenic mechanism in chronic respiratory conditions such as COPD and chronic bronchitis (CB). In these meta-analyses we investigated the efficacy of NAC in subjects with COPD or CB, the latter being a potential pre-COPD condition (CB/pre-COPD).<br><br>METHODS: The meta-analyses were conducted according to PRISMA guidelines. Exacerbations were assessed using total number of exacerbations. Improvement in patients' respiratory symptoms and/or patients quality of life (QoL) were measured by validated tools or assessed at the end of the study.<br><br>RESULTS: Twenty studies were included, of which seven evaluated NAC in patients with symptoms of CB/pre-COPD as entry criterion. NAC treated patients showed a significant reduction of the incidence of exacerbations as compared to placebo both in COPD (IRR=0.76; 95% confidence interval (CI) 0.59-0.99) and CB/pre-COPD (IRR=0.81; 95% CI 0.69-0.95). Sensitivity analyses in studies with duration higher than 5 months, confirmed the overall results. CB/pre-COPD patients treated with NAC were significantly more likely to experience an improvement in symptoms and/or QoL compared to placebo (odds ratio (OR)=3.47; 95% CI 1.92-6.26). A similar trend was observed in the few COPD studies evaluable. Sensitivity analyses showed a significant association of NAC with improvement in symptoms and/or QoL both in CB/pre-COPD and COPD patients.<br><br>CONCLUSIONS: These findings provide novel data of NAC on the improvement in symptoms and QoL in addition to prevention of exacerbations in COPD and CB/pre-COPD. PROSPERO registry no. CRD42023468154.}, }
@article {pmid38554666, year = {2024}, author = {Sriwastava, S and Elkhooly, M and Amatya, S and Shrestha, K and Kagzi, Y and Bhatia, D and Gupta, R and Jaiswal, S and Lisak, RP}, title = {Recent advances in the treatment of primary and secondary progressive Multiple Sclerosis.}, journal = {Journal of neuroimmunology}, volume = {390}, number = {}, pages = {578315}, doi = {10.1016/j.jneuroim.2024.578315}, pmid = {38554666}, issn = {1872-8421}, mesh = {Humans ; *Multiple Sclerosis, Chronic Progressive/drug therapy ; Animals ; }, abstract = {BACKGROUND: The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect neuroprotective and oligodendrocyte protective effects, providing a hopeful outlook for patients with primary and secondary progressive multiple sclerosis (PPMS and SPMS).<br><br>OBJECTIVES: The review aims to identify potential treatments and ongoing clinical trials for PPMS and SPMS, and compare their mechanisms of action, efficacy, and side effects with current treatments.<br><br>METHODS: We reviewed ongoing clinical trials for PPMS and SPMS on the NIH website, as well as articles from PubMed, Embase, and clinicaltrails.gov since 2010.<br><br>RESULTS: BTKIs like, tolebrutinib, and fenebrutinib are being explored as potential PMS treatments. Vidofludimus calcium, an orally available treatment, has shown a reduction of active and new MRI lesions. Other treatments like simvastatin, N-acetylcysteine (NAC), and alpha-lipoic acid are being explored for their antioxidant properties. AHSCT and mesenchymal stem cell therapy are experimental options for younger patients with high inflammatory activity.<br><br>CONCLUSIONS: SPMS and PPMS are being studied for new treatments and future trials should consider combination therapies targeting inflammation, demyelination, and neuronal death, as the pathogenesis of PMS involves complex factors.}, }
@article {pmid38551724, year = {2024}, author = {Adelusi, OB and Akakpo, JY and Eichenbaum, G and Sadaff, E and Ramachandran, A and Jaeschke, H}, title = {The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.}, journal = {Archives of toxicology}, volume = {98}, number = {6}, pages = {1843-1858}, pmid = {38551724}, issn = {1432-0738}, support = {DK102142/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; DK102142/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Acetaminophen/toxicity ; Male ; *Chemical and Drug Induced Liver Injury/prevention &amp; control/drug therapy ; *Mice, Inbred C57BL ; *Thrombopoietin/pharmacology ; *Liver/drug effects/metabolism/pathology ; *Liver Regeneration/drug effects ; Mice ; Acetylcysteine/pharmacology ; Pyrazoles/pharmacology ; Hepatocytes/drug effects ; Oxidative Stress/drug effects ; Receptors, Thrombopoietin/metabolism ; Cell Proliferation/drug effects ; }, abstract = {Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42-48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.}, }
@article {pmid38547615, year = {2024}, author = {Li, Z and Bao, Z and Tan, J and Chen, G and Ye, B and Zhao, J and Zhang, L and Xu, H}, title = {Neobractatin induces pyroptosis of esophageal cancer cells by TOM20/BAX signaling pathway.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {128}, number = {}, pages = {155547}, doi = {10.1016/j.phymed.2024.155547}, pmid = {38547615}, issn = {1618-095X}, mesh = {Animals ; Humans ; Male ; Mice ; *bcl-2-Associated X Protein/metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; *Esophageal Neoplasms/drug therapy/metabolism ; *Gasdermins ; Mice, Nude ; Mitochondria/drug effects/metabolism ; *Mitochondrial Precursor Protein Import Complex Proteins ; Phosphate-Binding Proteins/metabolism ; *Pyroptosis/drug effects ; *Reactive Oxygen Species/metabolism ; *Signal Transduction/drug effects ; Up-Regulation/drug effects ; }, abstract = {BACKGROUND: Emerging evidence suggests that pyroptosis, a form of programmed cell death, has been implicated in cancer progression. The involvement of specific proteins in pyroptosis is an area of growing interest. TOM20, an outer mitochondrial membrane protein, has recently garnered attention for its potential role in pyroptosis. Our previous study found that NBT could induce pyroptosis by ROS/JNK pathway in esophageal cancer cells.<br><br>PURPOSE: This study aims to investigate whether NBT induces pyroptosis and verify whether such effects are involved in up-regulation of TOM20 in esophageal cancer cells.<br><br>METHODS: The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN) was used to analyze the clinical significance of GSDME in esophageal cancer. MTT assay, morphological observation and Western blot were performed to verify the roles of TOM20 and BAX in NBT-induced pyroptosis after CRISPR-Cas9-mediated knockout. Immunofluorescence was used to determine the subcellular locations of BAX and cytochrome c. MitoSOX Red was employed to assess the mitochondrial reactive oxygen species (ROS) level. KYSE450 and TOM20 knockout KYSE450-/- xenograft models were established to elucidate the mechanisms involved in NBT-induced cell death.<br><br>RESULTS: In this study, NBT effectively upregulated the expression of TOM20 and facilitated the translocation of BAX to mitochondria, which promoted the release of cytochrome c from mitochondria to the cytoplasm, leading to the activation of caspase-9 and caspase-3, and finally induced pyroptosis. Knocking out TOM20 by CRISPR-Cas9 significantly inhibited the expression of BAX and the downstream BAX/caspase-3/GSDME pathway, which attenuated NBT-induced pyroptosis. The elevated mitochondrial ROS level was observed after NBT treatment. Remarkably, the inhibition of ROS by N-acetylcysteine (NAC) effectively suppressed the activation of TOM20/BAX pathway. Moreover, in vivo experiments demonstrated that NBT exhibited potent antitumor effects in both KYSE450 and TOM20 knockout KYSE450-/- xenograft models. Notably, the attenuated antitumor effects and reduced cleavage of GSDME were observed in the TOM20 knockout model.<br><br>CONCLUSION: These findings reveal that NBT induces pyroptosis through ROS/TOM20/BAX/GSDME pathway, which highlight the therapeutic potential of targeting TOM20 and GSDME, providing promising prospects for the development of innovative and effective treatment approaches for esophageal cancer.}, }
@article {pmid38547333, year = {2024}, author = {Smith, JE and Rockey, DC}, title = {Update on ischemic hepatitis.}, journal = {Current opinion in gastroenterology}, volume = {40}, number = {3}, pages = {143-147}, pmid = {38547333}, issn = {1531-7056}, mesh = {Humans ; *Hepatitis/complications ; Acetylcysteine/therapeutic use ; }, abstract = {PURPOSE OF REVIEW: Ischemic hepatitis (IH) refers to diffuse liver injury secondary to hypoperfusion. The condition is usually seen in the critical care setting and is associated with significant mortality. IH typically occurs in the setting of systemic hypotension superimposed on some form of underlying cardiac dysfunction. This review aims to report what is known and what is new about the etiology, pathophysiology, and clinical features associated with IH.<br><br>RECENT FINDINGS: In recent years, studies on IH have largely confirmed earlier reports regarding etiologies, comorbid conditions, and associated mortality. Recent study has also shed light on the potential treatment of IH with N -acetyl-cysteine (NAC).<br><br>SUMMARY: IH is typically associated with underlying cardiac disease, and patients with IH have a very high mortality rate. Treatment remains largely supportive, although the utility of agents such as NAC are being explored.}, }
@article {pmid38541080, year = {2024}, author = {Russo, C and Rusciano, D and Santangelo, R and Malaguarnera, L}, title = {Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {60}, number = {3}, pages = {}, pmid = {38541080}, issn = {1648-9144}, mesh = {Humans ; Edaravone/pharmacology ; Antioxidants/pharmacology ; Oxidative Stress ; *Eye Diseases ; *Retinal Diseases/drug therapy ; Ophthalmic Solutions ; }, abstract = {Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.}, }
@article {pmid38539819, year = {2024}, author = {Islam, A and Chang, YC and Tsao, NW and Wang, SY and Chueh, PJ}, title = {Calocedrus formosana Essential Oils Induce ROS-Mediated Autophagy and Apoptosis by Targeting SIRT1 in Colon Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {3}, pages = {}, pmid = {38539819}, issn = {2076-3921}, abstract = {Colorectal cancer is the most common cancer that affects both sexes and has a poor prognosis due to aggressiveness and chemoresistance. Essential oils isolated from Calocedrus formosana (CF-EOs) have been shown to demonstrate anti-termite, antifungal, anti-mosquito, and anti-microbial activities. However, the anticancer effects of CF-EOs are not yet fully understood. Therefore, the present study aimed to explore the molecular mechanism underlying CF-EOs-mediated anti-proliferative activity in colon cancer cells. Here, cell impedance measurements showed that CF-EOs inhibit proliferation in colon cancer cells with wild-type or mutant p53. Flow cytometry revealed that CF-EOs at 20, 50 µg/mL significantly induced ROS generation and autophagy in both HCT116 p53-wt and HCT116 p53-null cell lines, whereas pretreatment with the ROS scavenger N-acetyl cysteine (NAC) markedly attenuated these changes. CF-EOs also induced apoptosis at 50 µg/mL in both lines, as determined by flow cytometry. Protein analysis showed that CF-EOs markedly induced apoptosis markers, including Trail, cleaved caspase-3, cleaved caspase-9, and cleaved PARP, as well as autophagy markers, such as the levels of ULK1, Atg5, Atg6, Atg7, and the conversion of LC3-I to LC3-II. CF-EOs were further found to inhibit the activity and expression of the NAD[+]-dependent deacetylase SIRT1 to increase the levels of acetylated p53 (Ac-p53) in p53-wt cells and acetylated c-Myc (Ac-c-Myc) in p53-null cells, ultimately inducing apoptosis in both lines. Interestingly, suppression of SIRT1 by CF-EOs enhanced the acetylation of ULK1, which in turn prompted ROS-dependent autophagy in colon cancer cells. The induction of apoptosis and autophagy by CF-EOs suggests that they may have potential as a promising new approach for treating cancer. Collectively, our results suggest that essential oils isolated from Calocedrus formosana act as a promising anticancer agent against colon cancer cells by targeting SIRT1 to induce ROS-mediated autophagy and apoptosis.}, }
@article {pmid38537439, year = {2024}, author = {Chen, X and Zhu, N and Wu, Y and Zhang, Y and Zhang, Y and Jin, K and Zhou, Z and Chen, G and Wang, J}, title = {Withaferin A, a natural thioredoxin reductase 1 (TrxR1) inhibitor, synergistically enhances the antitumor efficacy of sorafenib through ROS-mediated ER stress and DNA damage in hepatocellular carcinoma cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {128}, number = {}, pages = {155317}, doi = {10.1016/j.phymed.2023.155317}, pmid = {38537439}, issn = {1618-095X}, mesh = {*Withanolides/pharmacology ; *Endoplasmic Reticulum Stress/drug effects ; Humans ; *Carcinoma, Hepatocellular/drug therapy ; *Reactive Oxygen Species/metabolism ; *Liver Neoplasms/drug therapy ; Animals ; *DNA Damage/drug effects ; *Drug Synergism ; *Sorafenib/pharmacology ; Cell Line, Tumor ; *Apoptosis/drug effects ; *Mice, Nude ; Thioredoxin Reductase 1/metabolism ; Mice, Inbred BALB C ; Cell Proliferation/drug effects ; Mice ; Xenograft Model Antitumor Assays ; Activating Transcription Factor 4/metabolism ; }, abstract = {BACKGROUND: Sorafenib (Sora), a multi-target tyrosine kinase inhibitor, is widely recognized as a standard chemotherapy treatment for advanced hepatocellular carcinoma (HCC). However, drug resistance mechanisms hinder its anticancer efficacy. Derived from Withania somnifera, Withaferin A (WA) exhibits remarkable anti-tumor properties as a natural bioactive compound. This study aimed to examine the mechanisms that underlie the impacts of Sora and WA co-treatment on HCC.<br><br>METHODS: Cell proliferation was evaluated through colony formation and MTT assays. Flow cytometry was employed to determine cellular apoptosis and reactive oxygen species (ROS) levels. The evaluation of apoptosis-related protein levels, DNA damage, and endoplasmic reticulum stress was conducte utilizing IHC staining and western blotting. Moreover, the caspase inhibitor Z-VAD-FMK, ATF4 siRNA, ROS scavenger N-acetyl cysteine (NAC), and TrxR1 shRNA were used to elucidate the underlying signaling pathways. To validate the antitumor effects of Sora/WA co-treatment, in vivo experiments were ultimately executed using Huh7 xenografts.<br><br>RESULTS: Sora/WA co-treatment demonstrated significant synergistic antitumor impacts both in vivo and in vitro. Mechanistically, the enhanced antitumor impact of Sora by WA was achieved through the inhibition of TrxR1 activity, resulting in ROS accumulation. Moreover, ROS generation induced the activation of DNA damage and endoplasmic reticulum (ER) stress pathways, eventually triggering cellular apoptosis. Pre-treatment with the antioxidant NAC significantly inhibited ROS generation, ER stress, DNA damage, and apoptosis induced by Sora/WA co-treatment. Additionally, the inhibition of ATF4 by small interfering RNA (siRNA) attenuated Sora/WA co-treatment-induced apoptosis. In vivo, Sora/WA co-treatment significantly suppressed tumor growth in HCC xenograft models and decreased TrxR1 activity in tumor tissues.<br><br>CONCLUSION: Our study suggests that WA synergistically enhances the antitumor effect of Sora, offering promising implications for evolving treatment approaches for HCC.}, }
@article {pmid38536095, year = {2024}, author = {Aragona, SE and Fabbri, C and Cammarota, G and Ciprandi, G and , }, title = {Probiotic mixture in patients after Helicobacter pylori eradication: a real-life experience.}, journal = {Minerva gastroenterology}, volume = {70}, number = {2}, pages = {197-207}, doi = {10.23736/S2724-5985.24.03634-9}, pmid = {38536095}, issn = {2724-5365}, mesh = {Humans ; *Probiotics/therapeutic use ; *Helicobacter Infections/drug therapy ; Male ; Female ; *Helicobacter pylori ; Middle Aged ; Adult ; Lacticaseibacillus rhamnosus ; Acetylcysteine/therapeutic use ; Treatment Outcome ; Aged ; Dysbiosis ; Dietary Supplements ; }, abstract = {BACKGROUND: Eradication for Helicobacter pylori usually induces digestive dysbiosis that, in turn, elicits symptoms. Consequently, probiotic supplementation may counterbalance the disturbed microbiota after this procedure. So, probiotics may restore microbiota homeostasis quickly relieve complaints.<br><br>METHODS: The current study evaluated the efficacy and safety of Abivisor[&#xae;], a food supplement containing Lacticaseibacillus rhamnosus LR06 (3 billion living cells), Lactiplantibacillus pentosus LPS01(100 million living cells), Lactiplantibacillus plantarum LP01 (1 billion living cells), and N-acetyl cysteine (60 mg). Patients were randomized into two groups (2:1). Group A took one stick/daily for 60 days after eradication. Group B was considered as control. Patients were evaluated at baseline (T0) and after 15 (T1), 30 (T2), and 60 (T3) days. The severity of digestive symptoms was measured by patients using a Visual Analog Scale. The percentage of patients with each symptom was also evaluated.<br><br>RESULTS: Abivisor[&#xae;] has significantly and progressively diminished intestinal symptoms' presence and severity at T1, T2, and even more at T3. Accordingly, the percentage of symptomatic patients diminished more rapidly and significantly in group A than in B. All patients well tolerated the food supplement.<br><br>CONCLUSIONS: The present study suggests that Abivisor[&#xae;] may be an effective and safe therapeutic option for managing patients undergoing H. pylori eradication.}, }
@article {pmid38535516, year = {2024}, author = {Tamur, S and Alyahya, B and Alsani, F and Bahauddin, AA and Aljaid, M and Al-Malki, S and Alzahrani, A and Khayat, A and Shams, A and Chalut, DS}, title = {Two versus Three Infusion Regimens of N-Acetylcysteine for Acetaminophen Overdose.}, journal = {Pediatric reports}, volume = {16}, number = {1}, pages = {232-242}, pmid = {38535516}, issn = {2036-749X}, abstract = {BACKGROUND: Acetaminophen overdose is a common clinical condition, often leading to liver toxicity. Current treatments involve the three-infusion N-Acetylcysteine (NAC) regimen (FDA-labeled), which may be complex, time-consuming, and need to be changed. An alternative uses two infusions instead, which offers possible advantages regarding simplicity and administration errors. This study sought to compare the respective efficacies and safety outcomes when treating acute acetaminophen overdose among children and adolescents.<br><br>METHODS: At Montreal Children's Hospital, a retrospective study was conducted comparing pre-2003 FDA-labelled three-infusion NAC therapy with a two-infusion regimen. Information was collected regarding patient demographics, NAC administration details, errors, rates of hepatotoxicity, and adverse reactions, and the statistical test Chi-square test was employed to obtain the results.<br><br>RESULTS: A total of 126 patients met the inclusion criteria. Of these patients, 65 received a two-infusion regimen, and 61 patients received the FDA-labeled regimen. The two-infusion group experienced significantly fewer administration errors (4 errors vs. 23 errors; p < 0.001), while the rates of hepatotoxicity between them were similar. There were no instances of liver transplantation or mortality due to either regimen. Adverse reactions occurred equally frequently between both regimens with no discernible difference-the meantime to administer NAC was 9 h for the two-infusion regimen and 8.5 h for FDA-labeled regimen groups, respectively. Three cases of hepatitis were successfully treated with timely NAC therapy, and no liver transplantation or mortality occurred. Adverse reactions, including anaphylactoid reactions, were observed in both groups but were resolved when temporarily stopped and restarted at a slower infusion rate.<br><br>CONCLUSIONS: The two-infusion NAC regimen proved similar efficacy at protecting liver damage and improving patient outcomes compared to its FDA-labeled three-stage counterpart, with significantly fewer administration errors for this version of NAC treatment, suggesting potential advantages in terms of safety and simplicity. Future research should investigate larger cohorts and more variables to validate these results further and optimize the management of acetaminophen overdose cases; further investigation should focus on dosing strategies, personalized approaches, and long-term patient care in this context.}, }
@article {pmid38534586, year = {2024}, author = {Domínguez-Martínez, J and López-Sánchez, J and García-Galván, F and Serrano, A and Barranco, V and Galván, JC and Rodríguez de la Fuente, &#xd3; and Carmona, N}, title = {Eco-Friendly Sol-Gel Coatings with Organic Corrosion Inhibitors for Lightweight AZ61 Alloy.}, journal = {Gels (Basel, Switzerland)}, volume = {10}, number = {3}, pages = {}, pmid = {38534586}, issn = {2310-2861}, support = {PID2019-104717RB-I00//Spanish Ministry of Economics Affairs and Digital Transformation/ ; PID2021-122980OB-C51//Spanish Ministry of Economic Affairs and Digital Transformation (MINECO)/ ; RYC2022-035912-I and RYC2021-031236-I//MCIN "Ram&#xf3;n y Cajal" Program/ ; }, abstract = {The latest advances in technology and materials science have catalyzed a transformative shift towards the adoption of environmentally conscious and lightweight materials across key sectors such as aeronautics, biomedical, and automotive industries. Noteworthy among these innovations are the magnesium-aluminum (Mg-Al) alloys employed in aeronautical applications, contributing to the overall reduction in aircraft weight and subsequently diminishing fuel consumption and mitigating atmospheric emissions. The present work delves into a study of the anti-corrosive properties inherent in various sol-gel coatings, leveraging a range of environmentally friendly corrosion inhibitors, specifically tailored for samples of the AZ61 alloy. Methodologically, the work involves the synthesis and application of sol-gel coatings on AZ61 alloy containing eco-friendly inhibitors: L-cysteine, N-acetyl-cysteine, curcumin and methylene blue. Subsequently, an accelerated corrosion test in a simulated saline environment is performed. Through microstructural and compositional analyses, the best inhibitors responses are achieved with inhibitors containing S, N heteroatoms and conjugated double bonds in their structure, probably due to the creation of a continuous MgCl2 layer. This research contributes to the ongoing discourse on protective eco-coatings, aligning with the broader paradigm shift towards sustainable and lightweight materials in key industries.}, }
@article {pmid38525131, year = {2024}, author = {Dong, G and Li, Q and Yu, C and Wang, Q and Zuo, D and Li, X}, title = {n-Acetylcysteine protects against diazinon-induced histopathological damage and apoptosis in renal tissue of rats.}, journal = {Toxicological research}, volume = {40}, number = {2}, pages = {285-295}, pmid = {38525131}, issn = {1976-8257}, abstract = {Diazinon (DZN) is a member of organophosphorus insecticides that has cytotoxic effects on different organs. n-Acetyl cysteine (NAC) is a widely used antioxidant in clinical, in vivo and in vitro studies. We evaluated the protective role of NAC against DZN-induced toxicity in kidney tissue of Wistar rats. 30 male Wistar rats were divided into 5 groups of control, single dose of DZN, continuous dose of DZN, single doses of DZN + NAC and continuous doses of DZN + NAC. Kidney function test (blood urea nitrogen, creatinine and uric acid) was provided. Levels of malondialdehyde (MDA), total antioxidant capacity (TAC) and total sulfhydryl (T-SH) were determined in renal tissues. Renal cells apoptosis was detected using TUNEL assay. The mRNA expressions of apoptosis, oxidative stress and inflammatory mediators, including B-cell lymphoma-2 (Bcl2), Bcl-2-associated X protein (Bax), superoxide dismutase (SOD), catalase (CAT), Interleukin 10 (IL-10), Tumor necrosis factor-α (TNF-α), Caspase-3 and Caspase-8 were analyzed in kidney tissues using Real Time PCR method. Chronic exposure to DZN was associated with severe morphological changes in the kidney, as well as impairment of its function and decreased kidney weights. Continues treatment with DZN significantly decreased the percentage of renal apoptotic cells as compared to rats treated with continuous dose of DZN alone (17.69 ± 3.67% vs. 39.46% ± 2.44%; p < 0.001). Continuous exposure to DZN significantly decreased TAC and T-SH contents, as well as SOD and CAT expression, but increased MDA contents in the kidney tissues (p < 0.001). A significant increase was observed in mRNA expression of Bax, Caspase-3, Caspase-8, as well as TNF-α following exposure to DZN, but the expression of IL-10 and Bcl2 was significantly decreased. NAC can protect kidney tissue against DZN-induced toxicity by elevating antioxidants capacity, mitigating oxidative stress, inflammation and apoptosis.}, }
@article {pmid38524728, year = {2024}, author = {Khasnavis, S and Belliveau, T and Arnsten, A and Fesharaki-Zadeh, A}, title = {Combined Use of Guanfacine and N-Acetylcysteine for the Treatment of Cognitive Deficits After Traumatic Brain Injury.}, journal = {Neurotrauma reports}, volume = {5}, number = {1}, pages = {226-231}, pmid = {38524728}, issn = {2689-288X}, abstract = {Traumatic Brain Injury (TBI) is a significant contributor to disability across the world. TBIs vary in severity, and most cases are designated mild TBI (mTBI), involving only brief loss of consciousness and no intracranial findings on imaging. Despite this categorization, many persons continue to report persistent cognitive changes in the months to years after injury, with particular impairment in the cognitive and executive functions of the pre-frontal cortex. For these persons, there are no currently approved medications, and treatment is limited to symptom management and cognitive or behavioral therapy. The current case studies explored the use of the alpha-2A adrenoreceptor agonist, guanfacine, combined with the antioxidant, N-acetylcysteine (NAC), in the treatment of post-TBI cognitive symptoms, based on guanfacine's ability to strengthen pre-frontal cortical function, and the open-label use of NAC in treating TBI. Two persons from our TBI clinic were treated with this combined regimen, with neuropsychological testing performed pre- and post-treatment. Guanfacine + NAC improved attention, processing speed, memory, and executive functioning with minimal side effects in both persons. These results encourage future placebo-controlled trials to more firmly establish the efficacy of guanfacine and NAC for the treatment of cognitive deficits caused by TBI.}, }
@article {pmid38522494, year = {2024}, author = {Mabrouk, NEL and Mastouri, M and Lizard, G and Aouni, M and Harizi, H}, title = {In vitro immunotoxicity effects of carbendazim were inhibited by n-acetylcysteine in microglial BV-2 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {97}, number = {}, pages = {105812}, doi = {10.1016/j.tiv.2024.105812}, pmid = {38522494}, issn = {1879-3177}, mesh = {*Acetylcysteine/pharmacology ; *Microglia ; Lipopolysaccharides/toxicity ; Benzimidazoles/toxicity ; Nitric Oxide ; *Carbamates ; }, abstract = {Carbendazim (CBZ) is a benzimidazole fungicide widely used worldwide in industrial, agricultural, and veterinary practices. Although, CBZ was found in all brain tissues causing serious neurotoxicity, its impact on brain immune cells remain scarcely understood. Our study investigated the in vitro effects of CBZ on activated microglial BV-2 cells. Lipopolysaccharide (LPS)-stimulated BV-2 cells were exposed to increasing concentrations of CBZ and cytokine release was measured by ELISA, and Cytometric Bead Array (CBA) assays. Mitochondrial superoxide anion (O2[·-]) generation was evaluated by Dihydroethidium (DHE) and nitric oxide (NO) was assessed by Griess reagent. Lipid peroxidation was evaluated by measuring the malonaldehyde (MDA) levels. The transmembrane mitochondrial potential (ΔΨm) was detected by cytometry analysis with dihexyloxacarbocyanine iodide (DiOC6(3)) assay. CBZ concentration-dependently increased IL-1β, IL-6, TNF-α and MCP-1 by LPS-activated BV-2 cells. CBZ significantly promoted oxidative stress by increasing NO, O2[·-] generation, and MDA levels. In contrast, CBZ significantly decreased ΔΨm. Pre-treatment of BV-2 cells with N-acetylcysteine (NAC) reversed all the above mentioned immunotoxic parameters, suggesting a potential protective role of NAC against CBZ-induced immunotoxicity via its antioxidant and anti-inflammatory effects on activated BV-2 cells. Therefore, microglial proinflammatory over-activation by CBZ may be a potential mechanism by which CBZ could induce neurotoxicity and neurodegenerative disorders.}, }
@article {pmid38520518, year = {2024}, author = {Cao, W and Zhang, J and Yu, S and Gan, X and An, R}, title = {N-acetylcysteine regulates oxalate induced injury of renal tubular epithelial cells through CDKN2B/TGF-β/SMAD axis.}, journal = {Urolithiasis}, volume = {52}, number = {1}, pages = {46}, pmid = {38520518}, issn = {2194-7236}, support = {No.81370803//National Natural Science Foundation of China/ ; No.81370803//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Male ; Rats ; Acetylcysteine/pharmacology ; Calcium Oxalate/metabolism ; Epithelial Cells/metabolism ; *Hyperoxaluria/chemically induced/metabolism ; *Oxalates/metabolism ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Transforming Growth Factor beta1/metabolism ; }, abstract = {This study was aimed to investigate the preventive effects of N-acetyl-L-cysteine (NAC) against renal tubular cell injury induced by oxalate and stone formation and further explore the related mechanism. Transcriptome sequencing combined with bioinformatics analysis were performed to identify differentially expressed gene (DEG) and related pathways. HK-2 cells were pretreated with or without antioxidant NAC/with or silencing DEG before exposed to sodium oxalate. Then, the cell viability, oxidative biomarkers of superoxidase dismutase (SOD) and malondialdehyde (MDA), apoptosis and cell cycle were measured through CCK8, ELISA and flow cytometry assay, respectively. Male SD rats were separated into control group, hyperoxaluria (HOx) group, NAC intervention group, and TGF-β/SMAD pathway inhibitor group. After treatment, the structure changes and oxidative stress and CaOx crystals deposition were evaluated in renal tissues by H&amp;E staining, immunohistochemical and Pizzolato method. The expression of TGF-β/SMAD pathway related proteins (TGF-β1, SMAD3 and SMAD7) were determined by Western blot in vivo and in vitro. CDKN2B is a DEG screened by transcriptome sequencing combined with bioinformatics analysis, and verified by qRT-PCR. Sodium oxalate induced declined HK-2 cell viability, in parallel with inhibited cellular oxidative stress and apoptosis. The changes induced by oxalate in HK-2 cells were significantly reversed by NAC treatment or the silencing of CDKN2B. The cell structure damage and CaOx crystals deposition were observed in kidney tissues of HOx group. Meanwhile, the expression levels of SOD and 8-OHdG were detected in kidney tissues of HOx group. The changes induced by oxalate in kidney tissues were significantly reversed by NAC treatment. Besides, expression of SMAD7 was significantly down-regulated, while TGF-β1 and SMAD3 were accumulated induced by oxalate in vitro and in vivo. The expression levels of TGF-β/SMAD pathway related proteins induced by oxalate were reversed by NAC. In conclusion, we found that NAC could play an anti-calculus role by mediating CDKN2B/TGF-β/SMAD axis.}, }
@article {pmid38518686, year = {2024}, author = {Kumar, S and Dhiman, M}, title = {Helicobacter pylori secretary Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation.}, journal = {Cellular immunology}, volume = {399-400}, number = {}, pages = {104811}, doi = {10.1016/j.cellimm.2024.104811}, pmid = {38518686}, issn = {1090-2163}, mesh = {Humans ; *Helicobacter pylori/immunology ; *Oxidative Stress ; *Reactive Oxygen Species/metabolism ; *Helicobacter Infections/immunology/metabolism ; *Inflammasomes/metabolism/immunology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Macrophages/metabolism/immunology ; Bacterial Proteins/metabolism ; Reactive Nitrogen Species/metabolism ; THP-1 Cells ; NADPH Oxidases/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Cell Differentiation/immunology ; }, abstract = {Helicobacter pylori-associated stomach infection is a leading cause of gastric ulcer and related cancer. H. pylori modulates the functions of infiltrated immune cells to survive the killing by reactive oxygen and nitrogen species (ROS and RNS) produced by these cells. Uncontrolled immune responses further produce excess ROS and RNS which lead to mucosal damage. The persistent oxidative stress is a major cause of gastric cancer. H. pylori regulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), nitric oxide synthase 2 (NOS2), and polyamines to control ROS and RNS release through lesser-known mechanisms. ROS and RNS produced by these pathways differentiate macrophages and T cells from protective to inflammatory phenotype. Pathogens-associated molecular patterns (PAMPs) induced ROS activates nuclear oligomerization domain (NOD), leucine rich repeats (LRR) and pyrin domain-containing protein 3 (NLRP3) inflammasome for the release of pro-inflammatory cytokines. This study evaluates the role of H. pylori secreted concentrated proteins (HPSCP) related oxidative stress role in NLRP3 inflammasome activation and macrophage differentiation. To perceive the role of ROS/RNS, THP-1 and AGS cells were treated with 10 μM diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 5 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively. Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively. The expression of gp91[phox] (NOX2), NOS2, NLRP3, CD86 and CD163 was analyzed through fluorescent microscopy. THP-1 macrophages growth was unaffected whereas the gastric epithelial AGS cells proliferated in response to higher concentration of HPSCP. ROS and myeloperoxidase (MPO) level increased in THP-1 cells and nitric oxide (NO) and lipid peroxidation significantly decreased in AGS cells. gp91[phox] expression was unchanged, whereas NOS2 and NLRP3 downregulated in response to HPSCP, but increased after inhibition of NO, ROS and MPO in THP-1 cells. HPSCP upregulated the expression of M1 and M2 macrophage markers, CD86 and CD163 respectively, which was decreased after the inhibition of ROS. This study concludes that there are multiple pathways which are generating ROS during H. pylori infection which further regulates other cellular processes. NO is closely associated with MPO and inhibition of NLRP3 inflammasome. The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.}, }
@article {pmid38518383, year = {2024}, author = {Sun, X and Qin, X and Liang, G and Chang, X and Zhu, H and Zhang, J and Zhang, D and Sun, Y and Feng, S}, title = {Manganese dioxide nanoparticles provoke inflammatory damage in BV2 microglial cells via increasing reactive oxygen species to activate the p38 MAPK pathway.}, journal = {Toxicology and industrial health}, volume = {40}, number = {5}, pages = {244-253}, doi = {10.1177/07482337241242508}, pmid = {38518383}, issn = {1477-0393}, mesh = {*Microglia ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Cell Line ; *Oxides ; *Manganese Compounds ; }, abstract = {With the widespread use of manganese dioxide nanoparticles (nano MnO2), health hazards have also emerged. The inflammatory damage of brain tissues could result from nano MnO2, in which the underlying mechanism is still unclear. During this study, we aimed to investigate the role of ROS-mediated p38 MAPK pathway in nano MnO2-induced inflammatory response in BV2 microglial cells. The inflammatory injury model was established by treating BV2 cells with 2.5, 5.0, and 10.0 μg/mL nano MnO2 suspensions for 12 h. Then, the reactive oxygen species (ROS) scavenger (20 nM N-acetylcysteine, NAC) and the p38 MAPK pathway inhibitor (10 μM SB203580) were used to clarify the role of ROS and the p38 MAPK pathway in nano MnO2-induced inflammatory lesions in BV2 cells. The results indicated that nano MnO2 enhanced the expression of pro-inflammatory cytokines IL-1β and TNF-α, elevated intracellular ROS levels and activated the p38 MAPK pathway in BV2 cells. Controlling intracellular ROS levels with NAC inhibited p38 MAPK pathway activation and attenuated the inflammatory response induced by nano MnO2. Furthermore, inhibition of the p38 MAPK pathway with SB203580 led to a decrease in the production of inflammatory factors (IL-1β and TNF-α) in BV2 cells. In summary, nano MnO2 can induce inflammatory damage by increasing intracellular ROS levels and further activating the p38 MAPK pathway in BV2 microglial cells.}, }
@article {pmid38513962, year = {2024}, author = {Liang, Z and Sun, G and Zhang, J and Zhang, Q and Li, X and Qin, S and Lv, S and Ding, J and Zhang, Q and Xia, Y and Lu, D}, title = {Protein phosphatase 4 mediates palmitic acid-induced endothelial dysfunction by decreasing eNOS phosphorylation at serine 633 in HUVECs.}, journal = {Experimental cell research}, volume = {437}, number = {1}, pages = {113998}, doi = {10.1016/j.yexcr.2024.113998}, pmid = {38513962}, issn = {1090-2422}, mesh = {Humans ; Phosphorylation ; *Nitric Oxide Synthase Type III/metabolism ; Palmitic Acid/pharmacology ; Serine/metabolism ; Reactive Oxygen Species ; Cells, Cultured ; Protein Phosphatase 2/metabolism ; *Vascular Diseases ; Nitric Oxide/metabolism ; *Phosphoprotein Phosphatases ; }, abstract = {Plasma saturated free fatty acid (FFA)-induced endothelial dysfunction (ED) contributes to the pathogenesis of atherosclerosis and cardiovascular diseases. However, the mechanism underlying saturated FFA-induced ED remains unclear. This study demonstrated that palmitic acid (PA) induced ED by activating the NADPH oxidase (NOX)/ROS signaling pathway to activate protein phosphatase 4 (PP4) and protein phosphatase 2A (PP2A), thereby reducing endothelial nitric oxide synthase (eNOS) phosphorylation at Ser633 and Ser1177, respectively. Okadaic acid (OA) and fostriecin (FST), which are inhibitors of PP2A, inhibited the PA-induced decreases in eNOS phosphorylation at Ser633 and Ser1177. The antioxidants N-acetylcysteine (NAC) and apocynin (APO) or knockdown of gp91phox or p67phox (NOX subunits) restored PA-mediated downregulation of PP4R2 protein expression and eNOS Ser633 phosphorylation. Knockdown of the PP4 catalytic subunit (PP4c) specifically increased eNOS Ser633 phosphorylation, while silencing the PP2A catalytic subunit (PP2Ac) restored only eNOS Ser1177 phosphorylation. Furthermore, PA dramatically decreased the protein expression of the PP4 regulatory subunit R2 (PP4R2) but not the other regulatory subunits. PP4R2 overexpression increased eNOS Ser633 phosphorylation, nitric oxide (NO) production, cell migration and tube formation but did not change eNOS Ser1177 phosphorylation levels. Coimmunoprecipitation (Co-IP) suggested that PP4R2 and PP4c interacted with the PP4R3α and eNOS proteins. In summary, PA decreases PP4R2 protein expression through the Nox/ROS pathway to activate PP4, which contributes to ED by dephosphorylating eNOS at Ser633. The results of this study suggest that PP4 is a novel therapeutic target for ED and ED-associated vascular diseases.}, }
@article {pmid38513858, year = {2024}, author = {Li, S and Gu, X and Zhang, M and Jiang, Q and Xu, T}, title = {Di (2-ethylhexyl) phthalate and polystyrene microplastics co-exposure caused oxidative stress to activate NF-κB/NLRP3 pathway aggravated pyroptosis and inflammation in mouse kidney.}, journal = {The Science of the total environment}, volume = {926}, number = {}, pages = {171817}, doi = {10.1016/j.scitotenv.2024.171817}, pmid = {38513858}, issn = {1879-1026}, mesh = {Animals ; Mice ; Antioxidants/metabolism ; *Diethylhexyl Phthalate/toxicity/metabolism ; Inflammation/chemically induced ; Kidney/metabolism ; *Microplastics/metabolism/toxicity ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Oxidative Stress ; *Phthalic Acids ; Plasticizers/toxicity/metabolism ; Plastics/metabolism/toxicity ; Polystyrenes/toxicity/metabolism ; *Pyroptosis ; }, abstract = {Polystyrene microplastic (PS-MPs) contamination has become a worldwide hotspot of concern, and its entry into organisms can cause oxidative stress resulting in multi-organ damage. The plasticizer di (2-ethylhexyl) phthalate (DEHP) is a common endocrine disruptor, these two environmental toxins often occur together, but their combined toxicity to the kidney and its mechanism of toxicity are unknown. Therefore, in this study, we established PS-MPS and/or DEHP-exposed mouse models. The results showed that alone exposure to both PS-MPs and DEHP caused inflammatory cell infiltration, cell membrane rupture, and content spillage in kidney tissues. There were also down-regulation of antioxidant enzyme levels, increased ROS content, activated of the NF-κB pathway, stimulated the levels of heat shock proteins (HSPs), pyroptosis, and inflammatory associated factors. Notably, the co-exposure group showed greater toxicity to kidney tissues, the cellular assay further validated these results. The introduction of the antioxidant n-acetylcysteine (NAC) and the NLRP3 inhibitor (MCC950) could mitigate the changes in the above measures. In summary, co-exposure of PS-MPs and DEHP induced oxidative stress that activated the NF-κB/NLRP3 pathway and aggravated kidney pyroptosis and inflammation, as well as that HSPs are also involved in this pathologic injury process. This study not only enriched the nephrotoxicity of plasticizers and microplastics, but also provided new insights into the toxicity mechanisms of multicomponent co-pollution in environmental.}, }
@article {pmid38513841, year = {2024}, author = {Malaviya, R and Meshanni, JA and Sunil, VR and Venosa, A and Guo, C and Abramova, EV and Vayas, KN and Jiang, C and Cervelli, JA and Gow, AJ and Laskin, JD and Laskin, DL}, title = {Role of macrophage bioenergetics in N-acetylcysteine-mediated mitigation of lung injury and oxidative stress induced by nitrogen mustard.}, journal = {Toxicology and applied pharmacology}, volume = {485}, number = {}, pages = {116908}, doi = {10.1016/j.taap.2024.116908}, pmid = {38513841}, issn = {1096-0333}, support = {P30 ES005022/ES/NIEHS NIH HHS/United States ; U54 AR055073/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; *Acetylcysteine/pharmacology ; *Mechlorethamine/toxicity ; Male ; *Energy Metabolism/drug effects ; Rats ; *Lung Injury/chemically induced/metabolism/pathology ; Rats, Sprague-Dawley ; Lung/drug effects/metabolism/pathology ; Macrophages/drug effects/metabolism ; Acute Lung Injury/chemically induced/metabolism/pathology ; Macrophages, Alveolar/drug effects/metabolism ; Chemical Warfare Agents/toxicity ; }, abstract = {Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.}, }
@article {pmid38508437, year = {2024}, author = {Liu, H and Wang, X and He, K and Chen, Z and Li, X and Ren, J and Zhao, X and Liu, S and Zhou, T and Chen, H}, title = {Oxidized DJ-1 activates the p-IKK/NF-κB/Beclin1 pathway by binding PTEN to induce autophagy and exacerbate myocardial ischemia-reperfusion injury.}, journal = {European journal of pharmacology}, volume = {971}, number = {}, pages = {176496}, doi = {10.1016/j.ejphar.2024.176496}, pmid = {38508437}, issn = {1879-0712}, mesh = {Animals ; Humans ; Rats ; Autophagy ; Beclin-1 ; Cysteine/pharmacology ; *Myocardial Reperfusion Injury/metabolism ; *NF-kappa B/metabolism ; PTEN Phosphohydrolase ; Rats, Sprague-Dawley ; }, abstract = {Patients with myocardial infarction have a much worse prognosis when they have myocardial ischemia-reperfusion (I/R) injury. Further research into the molecular basis of myocardial I/R injury is therefore urgently needed, as well as the identification of novel therapeutic targets and linkages to interventions. Three cysteine residues are present in DJ-1 at amino acids 46, 53, and 106 sites, with the cysteine at position 106 being the most oxidation-prone. This study sought to understand how oxidized DJ-1(C106) contributes to myocardial I/R damage. Rats' left anterior descending branches were tied off to establish a myocardial I/R model in vivo. A myocardial I/R model in vitro was established via anoxia/reoxygenation (A/R) of H9c2 cells. The results showed that autophagy increased after I/R, accompanied by the increased expression of oxidized DJ-1 (ox-DJ-1). In contrast, after pretreatment with NAC (N-acetylcysteine, a ROS scavenger) or Comp-23 (Compound-23, a specific antioxidant binding to the C106 site of DJ-1), the levels of ox-DJ-1, autophagy and LDH release decreased, and cell survival rate increased. Furthermore, the inhibition of interaction between ox-DJ-1 and PTEN could increase PTEN phosphatase activity, inhibit the p-IKK/NF-κB/Beclin1 pathway, reduce injurious autophagy, and alleviate A/R injury. However, BA (Betulinic acid, a NF-κB agonist) was able to reverse the protective effects produced by Comp-23 pretreatment. In conclusion, ox-DJ-1 could activate detrimental autophagy through the PTEN/p-IKK/NF-κB/Beclin1 pathway and exacerbate myocardial I/R injury.}, }
@article {pmid38507470, year = {2024}, author = {Yin, J and Ge, X and Ding, F and He, L and Song, K and Shi, Z and Ge, Z and Zhang, J and Ji, J and Wang, X and Zhao, N and Shu, C and Lin, F and Wang, Q and Zhou, Q and Cao, Y and Liu, W and Ye, D and Rich, JN and Wang, X and You, Y and Qian, X}, title = {Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly.}, journal = {Science translational medicine}, volume = {16}, number = {739}, pages = {eadg5553}, doi = {10.1126/scitranslmed.adg5553}, pmid = {38507470}, issn = {1946-6242}, mesh = {Humans ; *Glioblastoma/drug therapy ; Iron/metabolism ; *Glioma/drug therapy ; *Brain Neoplasms/drug therapy ; Neoplastic Stem Cells/pathology ; Sulfur/metabolism/therapeutic use ; Fumarates ; Cell Line, Tumor ; PTEN Phosphohydrolase/metabolism ; }, abstract = {Glioblastoma, the most lethal primary brain tumor, harbors glioma stem cells (GSCs) that not only initiate and maintain malignant phenotypes but also enhance therapeutic resistance. Although frequently mutated in glioblastomas, the function and regulation of PTEN in PTEN-intact GSCs are unknown. Here, we found that PTEN directly interacted with MMS19 and competitively disrupted MMS19-based cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) machinery in differentiated glioma cells. PTEN was specifically succinated at cysteine (C) 211 in GSCs compared with matched differentiated glioma cells. Isotope tracing coupled with mass spectrometry analysis confirmed that fumarate, generated by adenylosuccinate lyase (ADSL) in the de novo purine synthesis pathway that is highly activated in GSCs, promoted PTEN C211 succination. This modification abrogated the interaction between PTEN and MMS19, reactivating the CIA machinery pathway in GSCs. Functionally, inhibiting PTEN C211 succination by reexpressing a PTEN C211S mutant, depleting ADSL by shRNAs, or consuming fumarate by the US Food and Drug Administration-approved prescription drug N-acetylcysteine (NAC) impaired GSC maintenance. Reexpressing PTEN C211S or treating with NAC sensitized GSC-derived brain tumors to temozolomide and irradiation, the standard-of-care treatments for patients with glioblastoma, by slowing CIA machinery-mediated DNA damage repair. These findings reveal an immediately practicable strategy to target GSCs to treat glioblastoma by combination therapy with repurposed NAC.}, }
@article {pmid38505087, year = {2024}, author = {Liang, Z and Chen, Q and Pan, L and She, X and Chen, T}, title = {Mebendazole induces apoptosis and inhibits migration via the reactive oxygen species-mediated STAT3 signaling downregulation in non-small cell lung cancer.}, journal = {Journal of thoracic disease}, volume = {16}, number = {2}, pages = {1412-1423}, pmid = {38505087}, issn = {2072-1439}, abstract = {BACKGROUND: The incidence and mortality of non-small cell lung cancer (NSCLC) are extremely high. Previous research has confirmed that the signal transducer and activator of the transcription 3 (STAT3) protein critically participate in the tumorigenesis of NSCLC. Mebendazole (MBZ) has exerts a larger number of pharmacological activities and has anticancer effects in lung cancer, but its mechanism of action remains unclear. This study thus aimed to clarify the impacts of MBZ on NSCLC cell.<br><br>METHODS: Cell proliferation, migration, and apoptosis were investigated via cell counting kit 8 (CCK-8) assay, Transwell assay, colony formation assay, wound-healing assay, and flow cytometry. Reactive oxygen species (ROS) were detected with a multifunctional microplate reader. Markers of cell migration and apoptosis were detected with Western blotting. The transcriptional activity of STAT3 was detected via luciferase assay. ROS scavenger N-acetylcysteine (NAC) was used to determine the effect of MBZ on NSCLC via ROS-regulated STAT3 inactivation and apoptosis. A xenograft model was constructed in vivo to investigate the role of MBZ in NSCLC tumor growth.<br><br>RESULTS: The findings demonstrated that MBZ inhibited NSCLC cell proliferation and migration while promoting apoptosis through triggering ROS generation. In addition, the Janus kinase 2 (JAK2)-STAT3 signaling pathway was abrogated with the treatment of MBZ. NAC could distinctly weaken MBZ-induced apoptosis and STAT3 inactivation. Moreover, MBZ inhibited the tumor growth of NSCLC in vivo.<br><br>CONCLUSIONS: In summary, MBZ inhibited NSCLC cell viability and migration by inducing cell apoptosis via the ROS-JAK2-STAT3 signaling pathway. These data provide a theoretical basis for the use of MBZ in treating NSCLC.}, }
@article {pmid38503729, year = {2024}, author = {Rodrigues, ACBDC and Silva, SLR and Dias, IRSB and Costa, RGA and Oliveira, MS and Soares, MBP and Dias, RB and Valverde, LF and Rocha, CAG and Johnson, EM and Pina, C and Bezerra, DP}, title = {Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling.}, journal = {Cell death discovery}, volume = {10}, number = {1}, pages = {147}, pmid = {38503729}, issn = {2058-7716}, abstract = {Acute myeloid leukaemia (AML) is a haematological malignancy characterised by the accumulation of transformed myeloid progenitors in the bone marrow. Piplartine (PL), also known as piperlongumine, is a pro-oxidant small molecule extracted from peppers that has demonstrated antineoplastic potential in solid tumours and other haematological malignancies. In this work, we explored the potential of PL to treat AML through the use of a combination of cellular and molecular analyses of primary and cultured leukaemia cells in vitro and in vivo. We showed that PL exhibits in vitro cytotoxicity against AML cells, including CD34[+] leukaemia-propagating cells, but not healthy haematopoietic progenitors, suggesting anti-leukaemia selectivity. Mechanistically, PL treatment increased reactive oxygen species (ROS) levels and induced ROS-mediated apoptosis in AML cells, which could be prevented by treatment with the antioxidant scavenger N-acetyl-cysteine and the pancaspase inhibitor Z-VAD(OMe)-FMK. PL treatment reduced NFKB1 gene transcription and the level of NF-κB p65 (pS536), which was depleted from the nucleus of AML cells, indicating suppression of NF-κB p65 signalling. Significantly, PL suppressed AML development in a mouse xenograft model, and its combination with current AML treatments (cytarabine, daunorubicin and azacytidine) had synergistic effects, indicating translational therapeutic potential. Taken together, these data position PL as a novel anti-AML candidate drug that can target leukaemia stem/progenitors and is amenable to combinatorial therapeutic strategies.}, }
@article {pmid38503013, year = {2024}, author = {Li, Y and Long, W and Zhang, H and Zhao, M and Gao, M and Guo, W and Yu, L}, title = {Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.}, journal = {International immunopharmacology}, volume = {131}, number = {}, pages = {111844}, doi = {10.1016/j.intimp.2024.111844}, pmid = {38503013}, issn = {1878-1705}, mesh = {Mice ; Animals ; Male ; Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Diabetic Nephropathies/drug therapy/metabolism ; Irbesartan/therapeutic use ; NF-E2-Related Factor 2/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; Glucose ; *Diabetes Mellitus ; }, abstract = {OBJECTIVES: Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure.<br><br>METHODS: RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1&#x3b2; and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation.<br><br>CONCLUSIONS: Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.}, }
@article {pmid38500894, year = {2024}, author = {Harlivasari, AD and Susanto, AD and Taufik, FF and Ginting, TT}, title = {The Role of Twice-Daily N-acetylcysteine (NAC) 2400 mg in Smoking Cessation: A Randomized, Placebo-Controlled Trial in Indonesia.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54322}, pmid = {38500894}, issn = {2168-8184}, abstract = {INTRODUCTION: Tobacco smoking remains a health concern, especially in developing countries. Nicotine is significantly linked to many cancers and even second-hand exposure. Hence, smoking can increase the risk of lung and heart disease. This makes quitting smoking important and challenging. Success tends to rise by achieving abstinence with assisted pharmacology. These treatments aim to reduce symptoms of nicotine withdrawal. This is a preclinical trial on glutamate modulator in N-acetylcysteine (NAC) as a new potential treatment for smoking cessation. It is based on the administration of NAC related to elevated levels of dopamine in the central nervous system to accomplish successful smoking cessation.<br><br>AIM: This study evaluated the efficacy and tolerability of NAC for smoking cessation. The primary outcome was abstinence rate and the secondary outcomes of the study were to assess carbon monoxide exhalation value (COexh), the withdrawal symptoms, craving score, safety, and tolerability associated with the administration of NAC.<br><br>METHODS: This is a randomized clinical trial. Eligible smokers were treated with NAC 2400 mg twice daily (BID) or placebo to obtain a potential effective abstinence rate.&#xa0;Subjects recruited from the smoking cessation clinic were screened for eligibility and were&#xa0;randomized to either the NAC or placebo group. The trial consisted of a four-week treatment phase and participants were evaluated each week with a brief counseling. Intention to treat data analysis was performed from 2018 to 2019. Smoking cessation status was verified by measuring the amount of carbon monoxide exhaled and by documenting their smoking habits.&#xa0;Adverse events (AEs) have also been observed on each visit.<br><br>RESULTS: A total of 90&#xa0;male smokers with a mean (SD) age of 38.7 (11) years were randomized into two groups to receive NAC (n=45) and placebo (n=45). The primary outcome revealed that the abstinence rate was significantly higher for the NAC&#xa0;group than the placebo group (37.7% vs 6.6%; p=0.02). These findings were supported by data comparison between the NAC group and placebo group of COexh (ppm)&#xa0;(9.59&#xa0;&#xb1;7.4 vs 13,4&#xa0;&#xb1;6.1; p=0.04) and cigarette consumption/week (10 vs 46; p <0.001), which were statistically significant. Comparison of withdrawal with the Minnesota Nicotine Withdrawal Score between the&#xa0;NAC&#xa0;group and the placebo group showed lower values (8 (1-31) vs 11 (0-43); p=0.178), respectively, even though not statistically significant. Compared to the placebo group, the craving score (6 (2-29) vs 12 (6-31); p=0.04) in the NAC group was significantly lower. The most common adverse event was mild gastrointestinal effects (28.9%) and arthralgia (2.2%). No serious adverse events were detected.<br><br>CONCLUSIONS: &#xa0;Despite a small sample size, the data demonstrate the potential benefits of NAC that may help elevate abstinence rates and promote successful smoking cessation pharmacotherapy. Comprehensive treatment combining pharmacologic therapy and counseling increases smoking cessation success rates. It is essential to conduct a randomized multicenter study with a large population to support a sustained abstinence rate using NAC.}, }
@article {pmid38500550, year = {2024}, author = {Takasaki, T and Hamabe, Y and Touchi, K and Khandakar, GI and Ueda, T and Okada, H and Sakai, K and Nishio, K and Tanabe, G and Sugiura, R}, title = {ACA-28, an ERK MAPK Signaling Modulator, Exerts Anticancer Activity through ROS Induction in Melanoma and Pancreatic Cancer Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2024}, number = {}, pages = {7683793}, pmid = {38500550}, issn = {1942-0994}, mesh = {Humans ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Reactive Oxygen Species/metabolism ; *Melanoma/drug therapy ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; *Pancreatic Neoplasms/drug therapy ; }, abstract = {The extracellular signal-regulated kinase (ERK) MAPK pathway is dysregulated in various human cancers and is considered an attractive therapeutic target for cancer. Therefore, several inhibitors of this pathway are being developed, and some are already used in the clinic. We have previously identified an anticancer compound, ACA-28, with a unique property to preferentially induce ERK-dependent apoptosis in melanoma cells. To comprehensively understand the biological cellular impact induced by ACA-28, we performed a global gene expression analysis of human melanoma SK-MEL-28 cells exposed to ACA-28 using a DNA microarray. The transcriptome analysis identified nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcription factor that combats oxidative stress, as the most upregulated genetic pathway after ACA-28 treatment. Consistently, ACA-28 showed properties to increase the levels of reactive oxygen species (ROS) as well as Nrf2 protein, which is normally repressed by proteasomal degradation and activated in response to oxidative stresses. Furthermore, the ROS scavenger N-acetyl cysteine significantly attenuated the anticancer activity of ACA-28. Thus, ACA-28 activates Nrf2 signaling and exerts anticancer activity partly via its ROS-stimulating property. Interestingly, human A549 cancer cells with constitutively high levels of Nrf2 protein showed resistance to ACA-28, as compared with SK-MEL-28. Transient overexpression of Nrf2 also increased the resistance of cells to ACA-28, while knockdown of Nrf2 exerted the opposite effect. Thus, upregulation of Nrf2 signaling protects cancer cells from ACA-28-mediated cell death. Notably, the Nrf2 inhibitor ML385 substantially enhanced the cell death-inducing property of ACA-28 in pancreatic cancer cells, T3M4 and PANC-1. Our data suggest that Nrf2 plays a key role in determining cancer cell susceptibility to ACA-28 and provides a novel strategy for cancer therapy to combine the Nrf2 inhibitor and ACA-28.}, }
@article {pmid38498979, year = {2024}, author = {El-Habta, R and Af Bjerkén, S and Virel, A}, title = {N-acetylcysteine increases dopamine release and prevents the deleterious effects of 6-OHDA on the expression of VMAT2, α-synuclein, and tyrosine hydroxylase.}, journal = {Neurological research}, volume = {46}, number = {5}, pages = {406-415}, doi = {10.1080/01616412.2024.2325312}, pmid = {38498979}, issn = {1743-1328}, mesh = {*Vesicular Monoamine Transport Proteins/metabolism ; Humans ; *Oxidopamine/toxicity ; *alpha-Synuclein/metabolism ; *Dopamine/metabolism ; *Acetylcysteine/pharmacology ; *Tyrosine 3-Monooxygenase/metabolism ; Cell Line, Tumor ; Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; }, abstract = {OBJECTIVES: Current treatments for Parkinson's disease using pharmacological approaches alleviate motor symptoms but do not prevent neuronal loss or dysregulation of dopamine neurotransmission. In this article, we have explored the molecular mechanisms underlying the neuroprotective effect of the antioxidant N-acetylcysteine (NAC) on the damaged dopamine system.<br><br>METHODS: SH-SY5Y cells were differentiated towards a dopaminergic phenotype and exposed to 6-hydroxydopamine (6-OHDA) to establish an in vitro model of Parkinson's disease. We examined the potential of NAC to restore the pathological effects of 6-OHDA on cell survival, dopamine synthesis as well as on key proteins regulating dopamine metabolism. Specifically, we evaluated gene- and protein expression of tyrosine hydroxylase (TH), vesicle monoamine transporter 2 (VMAT2), and &#x3b1;-synuclein, by using qPCR and Western blot techniques. Moreover, we quantified the effect of NAC on total dopamine levels using a dopamine ELISA assay.<br><br>RESULTS: Our results indicate that NAC has a neuroprotective role in SH-SY5Y cells exposed to 6-OHDA by maintaining cell proliferation and decreasing apoptosis. Additionally, we demonstrated that NAC treatment increases dopamine release and protects SH-SY5Y cells against 6-OHDA dysregulations on the proteins TH, VMAT2, and &#x3b1;-synuclein.<br><br>CONCLUSIONS: Our findings contribute to the validation of compounds capable to restore dopamine homeostasis and shed light on the metabolic pathways that could be targeted to normalize dopamine turnover. Furthermore, our results highlight the effectiveness of the antioxidant NAC in the prevention of dopaminergic neurodegeneration in the present model.<br><br>ABBREVIATIONS: DAT, dopamine transporter; 6-OHDA, 6-hydroxydopamine; NAC, N-acetylcysteine; PARP, poly (ADP-ribose) polymerase; RA; retinoic acid; ROS, reactive oxygen species; TH, tyrosine hydroxylase; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; VMAT2, vesicle monoamine transporter 2.}, }
@article {pmid38497734, year = {2024}, author = {Li, X and Zou, J and Lin, A and Chi, J and Hao, H and Chen, H and Liu, Z}, title = {Oxidative Stress, Endothelial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus.}, journal = {Antioxidants &amp; redox signaling}, volume = {}, number = {}, pages = {}, doi = {10.1089/ars.2023.0524}, pmid = {38497734}, issn = {1557-7716}, abstract = {Significance: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality globally. Endothelial dysfunction is closely associated with the development and progression of CVDs. Patients with diabetes mellitus (DM) especially type 2 DM (T2DM) exhibit a significant endothelial cell (EC) dysfunction with substantially increased risk for CVDs. Recent Advances: Excessive reactive oxygen species (ROS) and oxidative stress are important contributing factors to EC dysfunction and subsequent CVDs. ROS production is significantly increased in DM and is critically involved in the development of endothelial dysfunction in diabetic patients. In this review, efforts are made to discuss the role of excessive ROS and oxidative stress in the pathogenesis of endothelial dysfunction and the mechanisms for excessive ROS production and oxidative stress in T2DM. Critical Issues: Although studies with diabetic animal models have shown that targeting ROS with traditional antioxidant vitamins C and E or other antioxidant supplements provides promising beneficial effects on endothelial function, the cardiovascular outcomes of clinical studies with these antioxidant supplements have been inconsistent in diabetic patients. Future Directions: Preclinical and limited clinical data suggest that N-acetylcysteine (NAC) treatment may improve endothelial function in diabetic patients. However, well-designed clinical studies are needed to determine if NAC supplementation would effectively preserve endothelial function and improve the clinical outcomes of diabetic patients with reduced cardiovascular morbidity and mortality. With better understanding on the mechanisms of ROS generation and ROS-mediated endothelial damages/dysfunction, it is anticipated that new selective ROS-modulating agents and effective personalized strategies will be developed for the management of endothelial dysfunction in DM.}, }
@article {pmid38496055, year = {2024}, author = {R, R and Routray, M}, title = {Management of Yellow Phosphorus-Induced Acute Liver Failure: A Case Report and Review of Literature.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e54223}, pmid = {38496055}, issn = {2168-8184}, abstract = {Three percent (3%) of yellow phosphorus is the active component of the rodenticide Ratol[®]. It is a potent hepatotoxin that leads to acute liver failure (ALF) with high mortality. There is no antidote available; the only definitive management is liver transplantation. Therapeutic plasma exchange, or plasmapheresis, appears to help these patients by removing the toxin, its metabolite, or the inflammatory mediators released in the body in response to the toxin. Here, we report a case of a 19-year-old male with an alleged history of Ratol[®] ingestion and ALF with acute kidney injury. He had a complete reversal of his condition with timely intervention in the form of plasmapheresis.}, }
@article {pmid38495889, year = {2024}, author = {Gupta, A and Song, MH and Youn, DH and Ku, D and Sasidharan Nair, V and Oh, K}, title = {Prolyl hydroxylase inhibition protects against murine MC903-induced skin inflammation by downregulating TSLP.}, journal = {Frontiers in immunology}, volume = {15}, number = {}, pages = {1330011}, pmid = {38495889}, issn = {1664-3224}, mesh = {Animals ; Mice ; *Prolyl Hydroxylases ; Interleukin-33 ; Reactive Oxygen Species ; *Dermatitis/drug therapy/etiology/prevention &amp; control ; Anti-Inflammatory Agents ; Inflammation ; Calcitriol/*analogs &amp; derivatives ; }, abstract = {Previously, we reported an anti-inflammatory effect of mTORC1 in a mouse model of type 2 skin inflammation. TSLP, one of the epithelial cell-derived cytokines, was upregulated by Raptor deficiency or rapamycin treatment, which was inhibited by dimethyloxalylglycine (DMOG). However, it remains unclear how DMOG regulates TSLP expression and type 2 skin inflammation. In this study, we investigated the protective effect of DMOG on MC903 (calcipotriol)-induced type 2 skin inflammation. Morphological and immunological changes were assessed by H-E staining, flow cytometry and RT-qPCR. DMOG treatment attenuated MC903-induced skin inflammation in a T cell-independent manner. The anti-inflammatory effect of DMOG was accompanied by downregulation of TSLP and IL-33, and supplementation with recombinant TSLP and IL-33 abolished the effect of DMOG. MC903 increased ROS levels in skin tissue, which was prevented by DMOG. Furthermore, the ROS scavenger N-acetylcysteine (NAC) downregulated TSLP and ameliorated MC903-induced skin inflammation, as did DMOG. Finally, the effect of DMOG on ROS and TSLP was reduced by HIF knockdown. These results suggest that DMOG downregulates TSLP and ROS through the HIF pathway, which reduces MC903-induced skin inflammation.}, }
@article {pmid38494703, year = {2024}, author = {Miyake, K and Mikami, Y and Asayama, T and Toriumi, T and Shinozuka, K and Tonogi, M and Yonehara, Y and Tsuda, H}, title = {Reactive oxygen species generation required for autophagy induction during butyrate- or propionate-induced release of damage-associated molecular patterns from dying gingival epithelial Ca9-22 cells.}, journal = {Journal of oral science}, volume = {66}, number = {2}, pages = {125-129}, doi = {10.2334/josnusd.23-0421}, pmid = {38494703}, issn = {1880-4926}, mesh = {Humans ; *Butyrates/pharmacology ; *Propionates/pharmacology ; Reactive Oxygen Species/metabolism ; Fatty Acids, Volatile/pharmacology ; Autophagy/physiology ; }, abstract = {PURPOSE: Bacterial cells in mature dental plaque produce a high concentration of short-chain fatty acids (SCFAs) such as butyrate and propionate. SCFA-treatment on human gingival epithelial Ca9-22 cells induced cell death. However, the exact mechanism underlying cell death remains unclear. In this study, the relationship between reactive oxygen species (ROS) and autophagy induction during SCFA-induced cell death was examined.<br><br>METHODS: Human gingival epithelial Ca9-22 cells were treated with butyrate or propionate to induce cell death and the number of dead cells were measured using SYTOX-green dye. A siRNA for ATG5 and N-acetylcysteine (NAC) were used for autophagy reduction and ROS-scavenging, respectively. Release of damage-associated molecular patterns (DAMPs) such as Sin3A-associated protein 130 (SAP130) and high-mobility group box 1 (HMGB1) were detected using western blot.<br><br>RESULTS: Reducing autophagy significantly suppressed SCFA-induced Ca9-22 cell death. ROS generation was observed upon SCFA treatment, and scavenging ROS with NAC decreased cell death. NAC also reduced the SCFA-induced increase in microtubule-associated protein 1 light chain 3B (LC3B)-I and LC3B-II, and mitigated the release of DAMPs.<br><br>CONCLUSION: The findings suggest that ROS generation is necessary for autophagy, which is required for SCFA-induced cell death and accompanying DAMP release.}, }
@article {pmid38488660, year = {2024}, author = {Cao, S and Yin, H and Li, X and Zeng, X and Liu, J}, title = {Nickel induces epithelial-mesenchymal transition in pulmonary fibrosis in mice via activation of the oxidative stress-mediated TGF-β1/Smad signaling pathway.}, journal = {Environmental toxicology}, volume = {39}, number = {6}, pages = {3597-3611}, doi = {10.1002/tox.24229}, pmid = {38488660}, issn = {1522-7278}, support = {22zx7153//Natural Science Foundation of Southwest University of Science and Technology/ ; }, mesh = {Animals ; *Epithelial-Mesenchymal Transition/drug effects ; *Nickel/toxicity ; *Oxidative Stress/drug effects ; *Transforming Growth Factor beta1/metabolism ; *Pulmonary Fibrosis/chemically induced/metabolism/pathology ; *Signal Transduction/drug effects ; Mice ; *Smad Proteins/metabolism ; Male ; Lung/drug effects/pathology/metabolism ; }, abstract = {Nickel (Ni) is recognized as a carcinogenic metal, and its widespread use has led to severe environmental and health problems. Although the lung is among the main organs affected by Ni, the precise mechanisms behind this effect remain poorly understood. This study aimed to elucidate the physiological mechanisms underlying Ni-induced pulmonary fibrosis (PF), using various techniques including histopathological detection, biochemical analysis, immunohistochemistry, western blotting, and quantitative real-time PCR. Mice were treated with nickel chloride (NiCl2), which induced PF (detected by Masson staining), up-regulation of α-smooth muscle actin (α-SMA), and collagen-1 mRNA and protein expression. NiCl2 was found to induce PF by: activation of the epithelial-mesenchymal transition (EMT) and the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway; up-regulation of protein and mRNA expression of TGF-β1, p-Smad2, p-Smad3, vimentin, and N-cadherin; and down-regulation of protein and mRNA expression of E-cadherin. In addition, NiCl2 treatment increased malondialdehyde content while inhibiting antioxidant activity, as indicated by decreased catalase, total antioxidant capacity, and superoxide dismutase activities, and glutathione content. Co-treatment with the effective antioxidant and free radical scavenger N-acetyl cysteine (NAC) plus NiCl2 was used to study the effects of oxidative stress in NiCl2-induced PF. The addition of NAC significantly mitigated NiCl2-induced PF, and reversed activation of the TGF-β1/Smad signaling pathway and EMT. NiCl2-induced PF was therefore shown to be due to EMT activation via the TGF-β1/Smad signaling pathway, mediated by oxidative stress.}, }
@article {pmid38480798, year = {2024}, author = {Zhu, C and Lu, Y and Wang, S and Song, J and Ding, Y and Wang, Y and Dong, C and Liu, J and Qiu, W and Qi, W}, title = {Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {6050}, pmid = {38480798}, issn = {2045-2322}, support = {No. 202003030451//Science and Technology Development Plan of Shandong Province/ ; No. KC2021-JX-0186-145//Beijing Science and Technology Innovation Medical Development Foundation/ ; No.202103030554//Health Science and Technology Development Plan Project/ ; }, mesh = {Mice ; Animals ; Humans ; Reactive Oxygen Species/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; Nortriptyline/pharmacology ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; *Stomach Neoplasms/drug therapy ; Drug Repositioning ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Oxidative Stress ; Apoptosis ; }, abstract = {Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)-NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.}, }
@article {pmid38474543, year = {2024}, author = {Beloglazkina, EK and Moiseeva, AA and Tsymbal, SA and Guk, DA and Kuzmin, MA and Krasnovskaya, OO and Borisov, RS and Barskaya, ES and Tafeenko, VA and Alpatova, VM and Zaitsev, AV and Finko, AV and Ol'shevskaya, VA and Shtil, AA}, title = {The Copper Reduction Potential Determines the Reductive Cytotoxicity: Relevance to the Design of Metal-Organic Antitumor Drugs.}, journal = {Molecules (Basel, Switzerland)}, volume = {29}, number = {5}, pages = {}, pmid = {38474543}, issn = {1420-3049}, support = {19-29-08007//Russian Foundation for Basic Research/ ; }, mesh = {Copper/chemistry ; Reducing Agents ; *Antineoplastic Agents/chemistry ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; *Coordination Complexes/chemistry ; Ligands ; }, abstract = {Copper-organic compounds have gained momentum as potent antitumor drug candidates largely due to their ability to generate an oxidative burst upon the transition of Cu[2+] to Cu[1+] triggered by the exogenous-reducing agents. We have reported the differential potencies of a series of Cu(II)-organic complexes that produce reactive oxygen species (ROS) and cell death after incubation with N-acetylcysteine (NAC). To get insight into the structural prerequisites for optimization of the organic ligands, we herein investigated the electrochemical properties and the cytotoxicity of Cu(II) complexes with pyridylmethylenethiohydantoins, pyridylbenzothiazole, pyridylbenzimidazole, thiosemicarbazones and porphyrins. We demonstrate that the ability of the complexes to kill cells in combination with NAC is determined by the potential of the Cu[+2] → Cu[+1] redox transition rather than by the spatial structure of the organic ligand. For cell sensitization to the copper-organic complex, the electrochemical potential of the metal reduction should be lower than the oxidation potential of the reducing agent. Generally, the structural optimization of copper-organic complexes for combinations with the reducing agents should include uncharged organic ligands that carry hard electronegative inorganic moieties.}, }
@article {pmid38472735, year = {2024}, author = {Farouk, F and Shebl, RI}, title = {LC-MS/MS determination of pyocyanin-N-acetyl cysteine adduct: application for understanding Pseudomonas aeruginosa virulence factor neutralization.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {40}, number = {5}, pages = {891-905}, pmid = {38472735}, issn = {1348-2246}, mesh = {*Acetylcysteine/chemistry/pharmacology ; Anti-Bacterial Agents/pharmacology/chemistry ; Liquid Chromatography-Mass Spectrometry ; *Pseudomonas aeruginosa/drug effects ; *Pyocyanine/metabolism/antagonists &amp; inhibitors/analysis/chemistry ; *Virulence Factors/antagonists &amp; inhibitors/metabolism ; }, abstract = {Combating Pseudomonas aeruginosa infection is challenging. It secretes pyocyanin (PCN) pigment that contributes to its virulence. Neutralizing PCN via reaction with thiol-containing compounds may represent a potential therapeutic option. This study investigates the neutralization reaction between PCN and N-acetyl cysteine (NAC) for bacterial inhibition and explores its mechanism of action. The neutralization adduct (PCN-NAC) was synthesized by reacting the purified PCN and NAC. The adduct was analyzed and its structure was elucidated. LC-MS/MS method was developed for the determination of PCN-NAC in P. aeruginosa cultures post-treatment with NAC (0-5 mg/mL). The corresponding anti-bacterial potential was estimated and compared to nanoparticles (NPs) alone and under stress conditions. In silico studies were performed to support explaining the mechanism of action. Results revealed that PCN-NAC was exclusively detected in NAC-treated cultures in a concentration-dependent manner. PCN-NAC concentration (230-915 µg/mL) was directly proportional to the reduction in the bacterial viable count (28.3% ± 7.1-87.5% ± 5.9) and outperformed all tested NPs, where chitosan NPs induced 56.9% ± 7.9 inhibition, followed by zinc NPs (49.4% ± 0.9) and gold NPs (17.8% ± 7.5) even post-exposure to different stress conditions. A concomitant reduction in PCN concentration was detected. In silico studies revealed possible interactions between key bacterial proteins and PCN-NAC rather than the NAC itself. These results pose NAC as a potential choice for the management of P. aeruginosa infection, where it neutralizes PCN via the formation of PCN-NAC adduct.}, }
@article {pmid38470079, year = {2024}, author = {Atefi, N and Ziaeifar, E and Seirafianpour, F and Sadeghzadeh-Bazargan, A and Amin, NG and Mozafarpoor, S and Abouie, A and Jafari, MA and Goodarzi, A}, title = {Evaluation of efficacy and safety of vitiligo treatment with micro-needling combined with N-Acetylcysteine and micro-needling alone: A double-blinded randomized controlled clinical trial.}, journal = {Journal of cosmetic dermatology}, volume = {23}, number = {6}, pages = {2220-2230}, doi = {10.1111/jocd.16274}, pmid = {38470079}, issn = {1473-2165}, mesh = {Humans ; *Vitiligo/therapy/drug therapy ; *Acetylcysteine/administration &amp; dosage/adverse effects/therapeutic use ; Double-Blind Method ; Female ; Adult ; Male ; Middle Aged ; Treatment Outcome ; Combined Modality Therapy/adverse effects/methods ; Young Adult ; Severity of Illness Index ; Dry Needling/adverse effects/methods ; Needles/adverse effects ; Adolescent ; Skin Pigmentation/drug effects ; }, abstract = {INTRODUCTION: Vitiligo is a skin pigmentation disorder caused by the selective degradation of melanocytes. This study investigates the therapeutic effects of microneedling with and without N-acetylcysteine (NAC) in patients with persistent and limited vitiligo.<br><br>METHOD: This research employed a clinical trial design with double-blind randomization. Individuals affected by vitiligo and seeking treatment at Rasool Akram Medical Complex were divided into two separate treatment groups. In the intervention group, 24 affected areas underwent meso-microneedling using 5% NAC ampoules over six sessions, in addition to the application of 4.7% NAC cream once daily on the specified area. Conversely, the control group, consisting of 22 lesions, underwent microneedling using distilled water during six sessions. The severity of lesions and the extent of repigmentation were gauged using the Modified VETI Score. Assessment of treatment efficacy was determined through both physician evaluations and patient feedback.<br><br>RESULTS: Twenty patients with a mean age of 36.4&#x2009;years were recruited. The mean percentage of lesions and their intensity were significantly improved 2&#x2009;weeks after the third session and 1&#x2009;month after the end of the treatment (p&#x2009;<&#x2009;0.01). There was no statistically significant difference between the intervention and control groups. Gender, age, family history, duration of disease, duration of disease stability, and history of hypothyroidism had no statistically significant relationship with patients' treatment outcomes (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSION: Microneedling with or without the application of NAC appears to be an effective treatment option for persistent vitiligo lesions. However, despite the higher improvement rate with the application of NAC, the difference was not significant.}, }
@article {pmid38469128, year = {2024}, author = {Gautam, N and Shrestha, N and Bhandari, S and Thapaliya, S}, title = {Severe dengue infection unmasking drug-induced liver injury: Successful management with N-acetylcysteine.}, journal = {Clinical case reports}, volume = {12}, number = {3}, pages = {e8578}, pmid = {38469128}, issn = {2050-0904}, abstract = {KEY CLINICAL MESSAGE: Clinicians in tuberculosis and dengue endemic regions should have heightened vigilance for drug-induced liver injury (DILI) overlapping with active infections, enabling prompt recognition and life-saving conservative management.<br><br>ABSTRACT: Severe dengue and drug-induced liver injury (DILI) are significant independent risk factors for acute liver failure. The co-occurrence of these conditions significantly complicates clinical management. Here, we describe the case of a 21-year-old Nepali female who developed acute liver failure during antitubercular therapy (ATT). The patient, presenting with fever and nausea after 3&#x2009;weeks of ATT, subsequently received a diagnosis of severe dengue. Laboratory evidence indicated markedly elevated transaminases (AST 4335&#x2009;U/L, ALT 1958&#x2009;U/L), total bilirubin (72&#x2009;&#x3bc;mol/L), and INR (>5). Prompt discontinuation of first-line ATT, initiation of a modified ATT regimen, and N-acetylcysteine (NAC) infusion facilitated the patient's recovery after a week of intensive care. This case underscores the potential for synergistic hepatotoxicity in regions where multiple endemic illnesses coincide. Early recognition of DILI, cessation of offending agents, and comprehensive intensive care are crucial interventions. While the definitive efficacy of NAC remains under investigation, its timely administration in these complex cases warrants exploration for its potential lifesaving benefits.}, }
@article {pmid38467612, year = {2024}, author = {Zhang, L and Shi, X and Zhang, L and Mi, Y and Zuo, L and Gao, S}, title = {A first-in-class TIMM44 blocker inhibits bladder cancer cell growth.}, journal = {Cell death &amp; disease}, volume = {15}, number = {3}, pages = {204}, pmid = {38467612}, issn = {2041-4889}, support = {81902565//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Mice ; Animals ; Humans ; *Signal Transduction ; Proto-Oncogene Proteins c-akt/metabolism ; Mice, Nude ; Urinary Bladder/metabolism ; Cell Proliferation ; *Urinary Bladder Neoplasms/drug therapy/genetics/metabolism ; Apoptosis ; Adenosine Triphosphate/pharmacology ; Cell Line, Tumor ; Mammals ; Mitochondrial Precursor Protein Import Complex Proteins ; }, abstract = {Mitochondria play a multifaceted role in supporting bladder cancer progression. Translocase of inner mitochondrial membrane 44 (TIMM44) is essential for maintaining function and integrity of mitochondria. We here tested the potential effect of MB-10 (MitoBloCK-10), a first-in-class TIMM44 blocker, against bladder cancer cells. TIMM44 mRNA and protein expression is significantly elevated in both human bladder cancer tissues and cells. In both patient-derived primary bladder cancer cells and immortalized (T24) cell line, MB-10 exerted potent anti-cancer activity and inhibited cell viability, proliferation and motility. The TIMM44 blocker induced apoptosis and cell cycle arrest in bladder cancer cells, but failed to provoke cytotoxicity in primary bladder epithelial cells. MB-10 disrupted mitochondrial functions in bladder cancer cells, causing mitochondrial depolarization, oxidative stress and ATP reduction. Whereas exogenously-added ATP and the antioxidant N-Acetyl Cysteine mitigated MB-10-induced cytotoxicity of bladder cancer cells. Genetic depletion of TIMM44 through CRISPR-Cas9 method also induced robust anti-bladder cancer cell activity and MB-10 had no effect in TIMM44-depleted cancer cells. Contrarily, ectopic overexpression of TIMM44 using a lentiviral construct augmented proliferation and motility of primary bladder cancer cells. TIMM44 is important for Akt-mammalian target of rapamycin (mTOR) activation. In primary bladder cancer cells, Akt-S6K1 phosphorylation was decreased by MB-10 treatment or TIMM44 depletion, but enhanced after ectopic TIMM44 overexpression. In vivo, intraperitoneal injection of MB-10 impeded bladder cancer xenograft growth in nude mice. Oxidative stress, ATP reduction, Akt-S6K1 inhibition and apoptosis were detected in MB-10-treated xenograft tissues. Moreover, genetic depletion of TIMM44 also arrested bladder cancer xenograft growth in nude mice, leading to oxidative stress, ATP reduction and Akt-S6K1 inhibition in xenograft tissues. Together, targeting overexpressed TIMM44 by MB-10 significantly inhibits bladder cancer cell growth in vitro and in vivo.}, }
@article {pmid38467037, year = {2024}, author = {Gakuba, C and Dumitrascu, AD and Marsan, PE and Legallois, D and Hanouz, JL and Vivien, D and Martinez De Lizarrondo, S and Gauberti, M and Cerasuolo, D}, title = {N-Acetylcysteine To Reduce Mortality For Patients Requiring Cardiac Catheterization or Cardiac Surgery: A Systematic Review And Meta-Analysis.}, journal = {Journal of cardiovascular pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1097/FJC.0000000000001551}, pmid = {38467037}, issn = {1533-4023}, abstract = {Multimers of von Willebrand factor (VWF) play a critical role in various processes inducing morbidity and mortality in cardiovascular risk patients. With the ability to reduce VWF multimers, N-acetylcysteine (NAC) could reduce mortality in patients undergoing coronary catheterization or cardiac surgery. However, its impact in perioperative period has never been studied so far in regard of its potential cardiovascular benefits. Then, four databases were searched for randomized controlled trials that compared in-hospital mortality between an experimental group, with NAC, and a control group without NAC, in patients undergoing coronary catheterization or cardiac surgery. The primary efficacy outcome was in-hospital mortality. Secondary outcomes were the occurrence of thrombotic events, major cardiovascular events, myocardial infarction, and contrast induced nephropathy. The safety outcome was occurrence of hemorrhagic events. Nineteen studies totaling 3718 patients were included. Pooled analysis demonstrated a reduction of in-hospital mortality associated with NAC: Odds Ratio (OR), 0.60; 95% CI, 0.39-0.92; P=0.02. The occurrence of secondary outcomes was not significantly reduced with NAC except for contrast-induced nephropathy. No difference was reported for hemorrhagic events. Subgroup analyses revealed a life-saving effect of NAC in a dose-dependent manner with reduction of in-hospital mortality for the NAC high-dose group, but not for the NAC standard-dose (<3500 mg) group. In conclusion, without being able to conclude on the nature of the mechanism involved, our review suggests a benefit of NAC in cardiovascular risk patients in perioperative period in terms of mortality and supports prospective confirmatory studies.}, }
@article {pmid38465147, year = {2024}, author = {Martinez-Ortega, JI and Perez Hernandez, FJ and Ortegon Blanco, AE}, title = {Acro-Ischemia Associated With SARS-CoV-2: A Case Report.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e53798}, pmid = {38465147}, issn = {2168-8184}, abstract = {COVID-19 is known to cause various cutaneous lesions, including acro-ischemic lesions (AIL), which are associated with poor prognosis. Anticoagulant therapy has shown positive responses in AIL patients. However, in this case study, we present a fatal AIL case despite anticoagulant therapy. We propose different treatment approaches based on the limited current data on acro-ischemia pathogenesis related to SARS-CoV-2. The clinical case involved a 59-year-old male with severe COVID-19 symptoms, including acrocyanosis and right hemiparesis. Despite receiving anticoagulant therapy, the patient's condition worsened, leading to necrosis in the left foot. The discussion focuses on the high-risk nature of AIL, the potential link between angiotensin-converting enzyme 2 (ACE2) receptors and vasculitis or thromboembolic manifestations, and the role of immune clots in AIL pathogenesis. Behçet syndrome is referenced as a model of inflammation-induced thrombosis, guiding the suggestion for immunosuppressant-based treatment in addition to anticoagulants. Additionally, three substances, N-acetyl cysteine, sulodexide, and hydroxychloroquine, are proposed.}, }
@article {pmid38460408, year = {2024}, author = {Liu, YL and Liu, JY and Zhu, XX and Wei, JH and Mi, SL and Liu, SY and Li, XL and Zhang, WW and Zhao, LL and Wang, H and Xu, DX and Gao, L}, title = {Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.}, journal = {Ecotoxicology and environmental safety}, volume = {274}, number = {}, pages = {116191}, doi = {10.1016/j.ecoenv.2024.116191}, pmid = {38460408}, issn = {1090-2414}, mesh = {Animals ; Male ; Mice ; Apoptosis ; Cell Proliferation ; DNA Breaks, Double-Stranded/drug effects ; DNA Repair ; *Marine Toxins/metabolism/toxicity ; Mice, Inbred ICR ; *Microcystins/metabolism/toxicity ; Semen ; *Sirtuins/drug effects/metabolism ; *Spermatogonia/drug effects/metabolism ; }, abstract = {The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 μg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.}, }
@article {pmid38460098, year = {2024}, author = {Nam, Y and Na, J and Ma, SX and Park, H and Park, H and Lee, E and Kim, H and Jang, SM and Ko, HS and Kim, S}, title = {DJ-1 protects cell death from a mitochondrial oxidative stress due to GBA1 deficiency.}, journal = {Genes &amp; genomics}, volume = {46}, number = {5}, pages = {519-529}, pmid = {38460098}, issn = {2092-9293}, support = {2022R1C1C1009937//National Research foundation of korea/ ; }, mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Antioxidants/metabolism ; Hydrogen Peroxide ; *Neuroblastoma ; Oxidative Stress ; Cell Death/physiology ; Mice, Knockout ; Protein Deglycase DJ-1/genetics/metabolism ; *Parkinson Disease ; }, abstract = {BACKGROUND: GBA1 mutations are the most common genetic risk factor for development of Parkinson's disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown.<br><br>OBJECTIVE: In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction.<br><br>METHODS: GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice.<br><br>RESULTS: We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H2O2-induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction.<br><br>CONCLUSION: Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations.}, }
@article {pmid38455771, year = {2024}, author = {Aulakh, G and Singh, A}, title = {A Case Report Demonstrating the Favorable Outcomes of Using N-acetylcysteine (NAC) in Managing Hepatic Injury Induced by Amphetamine-Related Drug Toxicity: Do We Underestimate Its Potential?.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e53697}, pmid = {38455771}, issn = {2168-8184}, abstract = {A 59-year-old male with a history of alcohol abuse presented with altered mental status. Upon examination, he was hypertensive and lethargic, and laboratory results revealed severe transaminitis, coagulopathy, and lactic acidosis, despite having normal serum alcohol levels. Additionally, his urine drug screen tested positive for methamphetamine. Following the exclusion of infectious, autoimmune, and other common causes of acute hepatitis, a diagnosis of methamphetamine-induced acute hepatitis was established. A non-acetaminophen toxicity N-acetylcysteine (NAC) protocol was initiated, resulting in a positive response with improvement in mentation and a decrease in liver enzyme levels. This case emphasizes the potential effectiveness of NAC in treating amphetamine-induced liver injury, supported by the limited available literature on the subject.}, }
@article {pmid38455596, year = {2024}, author = {Alkhattabi, NA and Khalifa, FK and Doghaither, HAA and Al-Ghafari, AB and Tarbiah, NI and Sabban, A}, title = {Protective effects of N-acetylcysteine and S-adenosyl-Lmethionine against nephrotoxicity and immunotoxicity induced by ochratoxin A in rats.}, journal = {International journal of health sciences}, volume = {18}, number = {2}, pages = {17-24}, pmid = {38455596}, issn = {1658-3639}, abstract = {OBJECTIVE: The present study was designed to investigate the nephroprotective and immunoprotective effects of S-adenosyl-L-methionine (SAMe) in comparison to N-acetylcysteine (NAC) against ochratoxin A (OTA) - intoxication.<br><br>METHODS: Forty-eight adult male Sprague-Dawley rats were categorized into four groups: Control; OTA intoxication (5 mg OTA/kg diet); OTA + NAC, rats received 200 mg NAC/day before feeding balanced diet contaminated with OTA; and (OTA + SAMe). Rats received 200 mg SAMe/day dissolved in distilled water orally just before feeding a balanced diet contaminated with OTA.<br><br>RESULTS: OTA administration altered serum kidney function biomarkers. These effects were pronouncedly alleviated by treatment with NAC. Results revealed a correlation between OTA-induced immunotoxicity and the reduced white blood cell (WBC) count. Treatments with SAMe significantly improved the WBCs count and hemoglobin concentration.<br><br>CONCLUSION: NAC and SAMe have a protective role against nephrotoxicity and immunotoxicity induced by continuous administration of OTA. NAC was more effective in reducing OTA nephrotoxicity, whereas SAMe was more potent than NAC in reducing OTA immunotoxicity.}, }
@article {pmid38451349, year = {2024}, author = {Revand, R and Dontham, A and Sarkar, S and Patil, A}, title = {Subacute Exposure to Gaseous Pollutants from Diesel Engine Exhaust Attenuates Capsaicin-Induced Cardio-Pulmonary Reflex Responses Involving Oxidant Stress Mechanisms in Adult Wistar Rats.}, journal = {Cardiovascular toxicology}, volume = {24}, number = {4}, pages = {396-407}, pmid = {38451349}, issn = {1559-0259}, mesh = {Rats ; Male ; Animals ; Rats, Wistar ; Vehicle Emissions/toxicity ; Capsaicin/pharmacology ; *Environmental Pollutants ; Gases ; Cysteine ; *Air Pollutants/toxicity ; Reflex ; }, abstract = {Intravenous injection of capsaicin produces vagal-mediated protective cardio-pulmonary (CP) reflexes manifesting as tachypnea, bradycardia, and triphasic blood pressure (BP) response in anesthetized rats. Particulate matter from diesel engine exhaust has been reported to attenuate these reflexes. However, the effects of gaseous constituents of diesel exhaust are not known. Therefore, the present study was designed to investigate the effects of gaseous pollutants in diesel exhaust, on capsaicin-induced CP reflexes in rat model. Adult male rats were randomly assigned to three groups: Non-exposed (NE) group, filtered diesel exhaust-exposed (FDE) group and N-acetyl cysteine (NAC)-treated FDE group. FDE group of rats (n = 6) were exposed to filtered diesel exhaust for 5 h a day for 5 days (D1-D5), and were taken for dissection on day 6 (D6), while NE group of rats (n = 6) remained unexposed. On D6, rats were anesthetized, following which jugular vein was cannulated for injection of chemicals, and femoral artery was cannulated to record the BP. Lead II electrocardiogram and respiratory movements were also recorded. Results show that intravenous injection of capsaicin (0.1 ml; 10 µg/kg) produced immediate tachypneic, hyperventilatory, hypotensive, and bradycardiac responses in both NE and FDE groups of rats. However, these capsaicin-induced CP responses were significantly attenuated in FDE group as compared to the NE group of rats. Further, FDE-induced attenuation of capsaicin-evoked CP responses were diminished in the N-acetyl cysteine-treated FDE rats. These findings demonstrate that oxidant stress mechanisms could possibly be involved in inhibition of CP reflexes by gaseous pollutants in diesel engine exhaust.}, }
@article {pmid38450909, year = {2024}, author = {Yan, H and Ding, J and Li, X and Li, S and Zhang, D}, title = {Arecoline induces neurotoxicity in HT22 cells via the promotion of endoplasmic reticulum stress and downregulation of the Nrf2/HO-1 pathway.}, journal = {Environmental toxicology}, volume = {39}, number = {6}, pages = {3410-3424}, doi = {10.1002/tox.24194}, pmid = {38450909}, issn = {1522-7278}, support = {202301AY070001-262//Science and Technology Foundation of Yunnan Provincial/ ; 2023Y0617//Scientific Research Foundation of the Education Department of Yunnan Province/ ; }, mesh = {*NF-E2-Related Factor 2/metabolism ; *Endoplasmic Reticulum Stress/drug effects ; Animals ; *Arecoline/toxicity ; Mice ; *Apoptosis/drug effects ; Cell Line ; *Reactive Oxygen Species/metabolism ; *Heme Oxygenase-1/metabolism ; Down-Regulation/drug effects ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Calcium/metabolism ; }, abstract = {Arecoline, the predominant bioactive substance extracted from areca nut (AN), is the world's fourth most frequently used psychoactive material. Research has revealed that chewing AN can affect the central nervous system (CNS) and may lead to neurocognitive deficits that are possibly linked to the action of arecoline. However, the mechanism behind the neurotoxicity caused by arecoline remains unclear. This study aimed to investigate the neurotoxic effects of arecoline and its underlying mechanism. The results showed that arecoline caused cytotoxicity against HT22 cells in a dose-dependent manner and induced apoptosis by upregulating the expression of pro-apoptotic caspase and Bcl-2 family proteins. Furthermore, arecoline escalated intracellular reactive oxygen species (ROS) levels and Ca[2+] concentration with increasing doses, thereby motivating endoplasmic reticulum stress (ERS) and ERS-associated apoptotic protein expression. Additionally, the study found that arecoline attenuates intracellular antioxidant defense by inhibiting the translocation of NF-E2-related factor-2 (Nrf2) into the nucleus and decreasing downstream Heme oxygenase-1 (HO-1) levels. The specific inhibitor Sodium 4-phenylbutyrate (4-PBA) can dramatically attenuate arecoline-mediated cell apoptosis and ERS-associated apoptotic pathway expression by blocking ERS. The antioxidant N-Acetylcysteine (NAC) also effectively reverses the arecoline-mediated increase of ERS-related apoptotic pathway protein levels by scavenging intracellular ROS accumulation. In conclusion, this study suggests that arecoline induces neurotoxicity in HT22 cells via ERS mediated by oxidative stress- and Ca[2+] disturbance, as well as by downregulation of the Nrf2/HO-1 pathway.}, }
@article {pmid38446318, year = {2024}, author = {Yang, R and Yan, F and Shen, J and Wang, T and Li, M and Ni, H}, title = {Geraniol attenuates oxygen-glucose deprivation/reoxygenation-induced ROS-dependent apoptosis and permeability of human brain microvascular endothelial cells by activating the Nrf-2/HO-1 pathway.}, journal = {Journal of bioenergetics and biomembranes}, volume = {56}, number = {3}, pages = {193-204}, pmid = {38446318}, issn = {1573-6881}, mesh = {Humans ; *Apoptosis/drug effects ; *Acyclic Monoterpenes/pharmacology ; *Reactive Oxygen Species/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Endothelial Cells/metabolism/drug effects ; *Glucose/metabolism ; *Heme Oxygenase-1/metabolism ; Oxygen/metabolism ; Brain/metabolism/blood supply ; Microvessels/metabolism/pathology/drug effects ; }, abstract = {Blood-brain barrier breakdown and ROS overproduction are important events during the progression of ischemic stroke aggravating brain damage. Geraniol, a natural monoterpenoid, possesses anti-apoptotic, cytoprotective, anti-oxidant, and anti-inflammatory activities. Our study aimed to investigate the effect and underlying mechanisms of geraniol in oxygen-glucose deprivation/reoxygenation (OGD/R)-induced human brain microvascular endothelial cells (HBMECs). Apoptosis, caspase-3 activity, and cytotoxicity of HBMECs were evaluated using TUNEL, caspase-3 activity, and CCK-8 assays, respectively. The permeability of HBMECs was examined using FITC-dextran assay. Reactive oxygen species (ROS) production was measured using the fluorescent probe DCFH-DA. The protein levels of zonula occludens-1 (ZO-1), occludin, claudin-5, β-catenin, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) were determined by western blotting. Geraniol showed no cytotoxicity in HBMECs. Geraniol and ROS scavenger N-acetylcysteine (NAC) both attenuated OGD/R-induced apoptosis and increase of caspase-3 activity and the permeability to FITC-dextran in HBMECs. Geraniol relieved OGD/R-induced ROS accumulation and decrease of expression of ZO-1, occludin, claudin-5, and β-catenin in HBMECs. Furthermore, we found that geraniol activated Nrf2/HO-1 pathway to inhibit ROS in HBMECs. In conclusion, geraniol attenuated OGD/R-induced ROS-dependent apoptosis and permeability in HBMECs through activating the Nrf2/HO-1 pathway.}, }
@article {pmid38445814, year = {2024}, author = {Iepsen, UW and Hjortdal, AR and Thuesen, AD and Finsen, SH and Hansen, PBL and Mortensen, SP}, title = {The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.}, journal = {Experimental physiology}, volume = {109}, number = {5}, pages = {779-790}, pmid = {38445814}, issn = {1469-445X}, support = {ID 101390//TrygFonden (Tryg Foundation)/ ; ID 20045//TrygFonden (Tryg Foundation)/ ; //The Capital Region of Denmark/ ; //The Beckett Foundation/ ; //The Ehrenreich Foundation/ ; //Dansk Selskab for Anaestesiologi og Intensiv Medicin (DASAIM)/ ; //The Region of Southern Denmark/ ; //The Danish Medical Research Council/ ; //Dansk Selskab for An&#xe6;stesiologi og Intensiv Medicin (DASAIM)/ ; }, mesh = {Humans ; Male ; *Calcium Channels, T-Type/metabolism/drug effects ; Aged ; *Calcium Channel Blockers/pharmacology ; *Nifedipine/pharmacology ; Pilot Projects ; Double-Blind Method ; *Endothelium, Vascular/drug effects/metabolism/physiology ; Dihydropyridines/pharmacology ; Vasodilation/drug effects/physiology ; Vasodilator Agents/pharmacology ; Blood Pressure/drug effects/physiology ; Regional Blood Flow/drug effects/physiology ; Organophosphorus Compounds/pharmacology ; Acetylcholine/pharmacology ; Leg/blood supply ; Nitroprusside/pharmacology ; Middle Aged ; *Nitrophenols ; }, abstract = {Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.}, }
@article {pmid38444903, year = {2024}, author = {Williams, EE and Quach, D and Daigh, A}, title = {Massive acetaminophen ingestion managed successfully with N-acetylcysteine, fomepizole, and renal replacement therapy.}, journal = {Clinical nephrology. Case studies}, volume = {12}, number = {}, pages = {22-25}, pmid = {38444903}, issn = {2196-5293}, abstract = {Acetaminophen ingestion is routinely managed with the antidote, N-acetylcysteine (NAC). Massive acetaminophen poisoning has been treated successfully with adjunctive therapies such as fomepizole and hemodialysis. Fomepizole functions by inhibiting cytochrome p560, which prevents tylenol from forming its toxic metabolite, NAPQI. Prior cases have demonstrated favorable outcomes and a significant drop in acetaminophen levels after a single session of intermittent hemodialysis and continuous veno-venous hemofiltration (CVVH). However, the recommended dosage adjustments of NAC and fomepizole while a patient is undergoing CVVH has not been well reported. We present a case of an 18-year-old male who presented after ingesting 125 g of tylenol. His 4-hour acetaminophen level was 738.6 µg/mL. He was treated with NAC, fomepizole, and a single 4-hour session of hemodialysis. His acetaminophen level remained elevated at 730 µg/mL despite the hemodialysis session. CVVH was initiated, and he was given intravenous NAC at 12.5 mg/kg/h, oral NAC at 70 mg/kg every 4 hours, and intravenous fomepizole at 10 mg/kg every 6 hours. His tylenol levels became undetectable 57 hours after ingestion, and he did not develop permanent liver toxicity. This case encourages the use of CVVH for massive tylenol ingestion when a single run of intermittent hemodialysis is not effective in lowering the tylenol level. NAC, fomepizole, and CVVH can prevent unfavorable outcomes in massive acetaminophen ingestion when provided at an appropriate dose and frequency.}, }
@article {pmid38444704, year = {2023}, author = {Rostamabadi, H and Samandari Bahraseman, MR and Esmaeilzadeh-Salestani, K}, title = {Froriepia subpinnata Leaf Extract-Induced Apoptosis in the MCF-7 Breast Cancer Cell Line by Increasing Intracellular Oxidative Stress.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {22}, number = {1}, pages = {e136643}, pmid = {38444704}, issn = {1726-6890}, abstract = {BACKGROUND: Froriepia subpinnata is one of the plants used in the diet of Iranian people. Previous studies have investigated the antioxidant and antibacterial effects of this plant extract, but no study has been conducted on its anticancer properties.<br><br>OBJECTIVES: In this study, we investigated the effect of F. subpinnata extract on MCF-7 breast cancer cells.<br><br>METHODS: The inhibitory effect of F. subpinnata leaf extract was determined on the growth of cancer cells by the MTT test. The ROS (reactive oxygen species) test was used to investigate the impact of the extract on intracellular oxidative stress. Flow cytometry and real-time PCR tests were used to investigate the apoptosis-related molecular processes. The GC-MS analysis was performed to determine the most abundant components.<br><br>RESULTS: The GC-MS analysis showed that phytol, mono-ethylhexyl phthalate (MEHP), cinnamaldehyde, and neophytadiene constituted 60% of the extracted content. The MTT assay demonstrated that F. subpinnata leaf extract caused 50% lethality at a 400 &#x3bc;g/mL dose in MCF7 cells. The F. subpinnata extract at low doses decreased the ROS level for 24 hours in MCF-7, but by increasing the concentration, the ROS levels increased. At the IC50 dose (inhibitory concentration (IC) associated with 50% impact), the ROS level increased 3.5 times compared to the control group. Examining the effect of N-acetyl cysteine (NAC) showed that this antioxidant agent could prevent the lethal impact of the extract and eliminate the ROS increase in MCF7 cells. Flow cytometry and real-time PCR results showed that the extract specifically induced apoptosis through the internal apoptosis pathway in this cancer cell line.<br><br>CONCLUSIONS: The F. subpinnata extract induced apoptosis by increasing ROS in MCF-7 cancer cells and can be considered for further studies.}, }
@article {pmid38438412, year = {2024}, author = {Park, WH}, title = {Propyl gallate induces cell death in human pulmonary fibroblast through increasing reactive oxygen species levels and depleting glutathione.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {5375}, pmid = {38438412}, issn = {2045-2322}, mesh = {Humans ; *Propyl Gallate/pharmacology ; Antioxidants/pharmacology ; Reactive Oxygen Species ; Catalase ; Cell Death ; Fibroblasts ; Glutathione ; Buthionine Sulfoximine/pharmacology ; *Chrysanthemum ; RNA, Small Interfering/genetics ; }, abstract = {Propyl gallate (PG) exhibits an anti-growth effect on various cell types. The present study investigated the impact of PG on the levels of reactive oxygen species (ROS) and glutathione (GSH) in primary human pulmonary fibroblast (HPF) cells. Moreover, the effects of N-acetyl cysteine (NAC, an antioxidant), L-buthionine sulfoximine (BSO, a GSH synthesis inhibitor), and small interfering RNA (siRNAs) against various antioxidant genes on ROS and GSH levels and cell death were examined in PG-treated HPF cells. PG (100-800 μM) increased the levels of total ROS and O2[·-] at early time points of 30-180 min and 24 h, whereas PG (800-1600 μM) increased GSH-depleted cell number at 24 h and reduced GSH levels at 30-180 min. PG downregulated the activity of superoxide dismutase (SOD) and upregulated the activity of catalase in HPF cells. Treatment with 800 μM PG increased the number of apoptotic cells and cells that lost mitochondrial membrane potential (MMP; ΔΨm). NAC treatment attenuated HPF cell death and MMP (ΔΨm) loss induced by PG, accompanied by a decrease in GSH depletion, whereas BSO exacerbated the cell death and MMP (ΔΨm) loss without altering ROS and GSH depletion levels. Furthermore, siRNA against SOD1, SOD2, or catalase attenuated cell death in PG-treated HPF cells, whereas siRNA against GSH peroxidase enhanced cell death. In conclusion, PG induced cell death in HPF cells by increasing ROS levels and depleting GSH. NAC was found to decrease HPF cell death induced by PG, while BSO enhanced cell death. The findings shed light on how manipulating the antioxidant system influence the cytotoxic effects of PG in HPF cells.}, }
@article {pmid38435146, year = {2024}, author = {Khan, S and Hughes, S and Hill, O}, title = {N-acetyl Cysteine Supplementation to Alleviate Skin Picking Disorder: A Case Report.}, journal = {Cureus}, volume = {16}, number = {2}, pages = {e53440}, pmid = {38435146}, issn = {2168-8184}, abstract = {There are body-focused repetitive behaviors, such as skin picking, trichotillomania, or nail biting, for which therapeutic interventions are available and can be tried, but unfortunately, there are no FDA-approved medications specifically for them. These disorders can cause functional impairment, disrupt activities of daily living, and be burdensome for both the patients and their loved ones. This case report will discuss an over-the-counter vitamin supplement, N-acetyl cysteine (NAC), that can be used safely but is often overlooked.}, }
@article {pmid38434559, year = {2024}, author = {Zeng, H and Zou, P and Chen, Y and Zhang, P and Shao, L}, title = {NOX4 aggravates doxorubicin-induced cardiomyocyte pyroptosis by increasing reactive oxygen species content and activating the NLRP3 inflammasome.}, journal = {Cardiovascular diagnosis and therapy}, volume = {14}, number = {1}, pages = {84-100}, pmid = {38434559}, issn = {2223-3652}, abstract = {BACKGROUND: Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4)-mediated reactive oxygen species (ROS) has been reported to induce cardiomyocyte apoptosis, but its effect on pyroptosis of cardiomyocytes has been rarely reported. This paper aimed to explore the effects of NOX4-mediated ROS production on doxorubicin (DOX)-induced myocardial injury and pyroptosis through nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3) inflammasome.<br><br>METHODS: HL-1 cells were treated with DOX or mice (30 mice were divided into five groups with six mice/group) underwent intraperitoneal injection with DOX (5 mg/kg, once a week, five times) to induce myocardial injury, followed by assessment of NOX4 and NLRP3 expression in cell supernatant and myocardial tissues. In cardiomyocyte HL-1 cells, cell proliferation was tested by MTT assay and the activity of ROS by probes. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and glutathione (GSH) activity were evaluated by kits. The expression of pyroptosis proteins was assessed by western blotting. Subsequently, the expression of NOX4 or NLRP3 was altered to determine the effect of NOX4 or NLRP3 expression on cardiomyocyte injury and pyroptosis. The animal models were utilized to evaluate the changes in the cardiac function of mice using an echocardiographic system, with these parameters measured including left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular end-diastolic diameter (LVEDD). Furthermore, the content of myocardial injury markers and the protein expression of pyroptosis proteins were determined to evaluate myocardial injury in the mice.<br><br>RESULTS: DOX treatment led to cardiomyocyte injury and pyroptosis, as evidenced by weakened LVEF, LVFS, and cell proliferation (P<0.05), elevated LVEDD, ROS, and MDA (P<0.05), increased expression of pyroptosis proteins (P<0.05), and decreased SOD and GSH (P<0.05). Additionally, NOX4 and NLRP3 were highly-expressed (P<0.05) in cell supernatant and myocardial tissues. In DOX-induced HL-1 cells, the overexpression of NOX4 intensified ROS levels to aggravate cardiomyocyte injury and pyroptosis, which was reversed by treatment of the ROS scavenger N-acetyl-cysteine. Furthermore, it was revealed that the combination of short hairpin RNA (sh)-NOX4 and overexpressed (oe)-NLRP3 reversed the cardioprotective effects of sh-NOX4 and increased myocardial tissue or cell injury and pyroptosis in vitro and in vivo. No mice died during the animal experiments, and only two were ruled out due to a weight loss greater than 20%.<br><br>CONCLUSIONS: NOX4-mediated ROS production activated NLRP3 inflammasome, thereby aggravating DOX-induced myocardial injury in vitro and in vivo.}, }
@article {pmid38432679, year = {2024}, author = {Roydeva, A and Milanova, A}, title = {LC-MS/MS determination of N-acetyl-l-cysteine in chicken plasma.}, journal = {Biomedical chromatography : BMC}, volume = {38}, number = {6}, pages = {e5854}, doi = {10.1002/bmc.5854}, pmid = {38432679}, issn = {1099-0801}, support = {BG-RRP-2.004-0006-C02//Bulgarian Ministry of Education and Science (MES) in the frames of Bulgarian National Recovery and Resilience Plan, Component "Innovative Bulgaria"/ ; //Trakia University, Bulgaria/ ; }, mesh = {Animals ; *Acetylcysteine/blood ; *Chickens ; Limit of Detection ; Linear Models ; Liquid Chromatography-Mass Spectrometry ; Reproducibility of Results ; Tandem Mass Spectrometry ; }, abstract = {N-acetyl-l-cysteine (NAC) shows beneficial effects in cases of aflatoxicosis and heat stress in poultry but little is known about its pharmacokinetics in chickens. Therefore, the study aimed to develop and validate a sensitive LC-MS/MS analytical method for quantitative analysis of NAC in chicken plasma. A split calibration curve approach was used for determination of NAC in chicken plasma. Standard curves for low (0.05-2.5 μg/ml) and high (2.5-100 μg/ml) ranges of concentrations were prepared. The standard curves for low (r[2] = 0.9987) and high (r[2] = 0.9899) concentrations were linear within the tested range. The limits of detection (LOD) and of quantification (LOQ) for the standard at low concentrations were 0.093 and 0.28 μg/ml, respectively. The accuracy was from 97.35 to 101.33%. The values of LOD and LOQ for the standard at high concentrations were 0.76 and 2.30 μg/ml, respectively. The accuracy was between 99.77 and 112.14%. The intra- and inter-day precisions for all concentrations from both standards did not exceed 8.57% and 10.69%, respectively. The recovery for all concentrations was between 92.45 and 105.52%. The validated method for determination of NAC in chicken plasma can be applied in future pharmacokinetic studies in chickens without dilution of samples and their repeated analysis.}, }
@article {pmid38431210, year = {2024}, author = {Stewart, GW}, title = {Pyroglutamate acidosis 2023. A review of 100 cases.}, journal = {Clinical medicine (London, England)}, volume = {24}, number = {2}, pages = {100030}, pmid = {38431210}, issn = {1473-4893}, mesh = {Humans ; *Pyrrolidonecarboxylic Acid ; *Acetaminophen/adverse effects ; *Acidosis/diagnosis/chemically induced ; Floxacillin/adverse effects/therapeutic use ; Anti-Bacterial Agents/adverse effects/therapeutic use ; }, abstract = {This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with under-nourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal.}, }
@article {pmid38422239, year = {2024}, author = {Tuncer, G and Aktas, Z and Basaran, S and Cagatay, A and Eraksoy, H}, title = {Effect of N-acetyl cysteine, rifampicin, and ozone on biofilm formation in pan-resistant Klebsiella pneumoniae: an experimental study.}, journal = {Sao Paulo medical journal = Revista paulista de medicina}, volume = {142}, number = {4}, pages = {e2023113}, pmid = {38422239}, issn = {1806-9460}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Ozone/pharmacology ; Rifampin/pharmacology ; Klebsiella pneumoniae ; Biofilms ; }, abstract = {BACKGROUND: To the best of our knowledge, this is the first study to evaluate the effectiveness of specific concentrations of antibiofilm agents, such as N-acetyl cysteine (NAC), rifampicin, and ozone, for the treatment of pan-resistant Klebsiella pneumoniae (PRKp).<br><br>OBJECTIVES: We evaluated the effectiveness of antibiofilm agents, such as NAC, rifampicin, and ozone, on biofilm formation in PRKp at 2, 6, 24, and 72 h.<br><br>DESIGN AND SETTING: This single-center experimental study was conducted on June 15, 2017, and July 15, 2018, at Istanbul Faculty of Medicine, Istanbul University, Turkey.<br><br>METHODS: Biofilm formation and the efficacy of these agents on the biofilm layer were demonstrated using colony counting and laser-screened confocal microscopy.<br><br>RESULTS: NAC at a final concentration of 2 &#x3bc;g/mL was administered to bacteria that formed biofilms (24 h), and no significant decrease was detected in the bacterial counts of all isolates (all P > 0.05). Rifampicin with a final concentration of 0.1 &#x3bc;g/mL was administered to bacteria that formed biofilm (24 h), and no significant decrease was detected in bacterial count (all P > 0.05). Notably, ozonated water of even 4.78 mg/L concentration for 72 h decreased the bacterial count by &#x2265; 2 log10.<br><br>CONCLUSION: Different approaches are needed for treating PRKp isolates. We demonstrate that PRKp isolates can be successfully treated with higher concentrations of ozone.}, }
@article {pmid38420829, year = {2024}, author = {Liao, L and Tao, P and Xu, Q and Chen, W and Chen, J and Liu, W and Liu, W and Hu, J and Lu, J}, title = {TRIM6 Promotes ROS-Mediated Inflammasome Activation and Pyroptosis in Renal Tubular Epithelial Cells via Ubiquitination and Degradation of GPX3 Protein.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {2}, pages = {58}, doi = {10.31083/j.fbl2902058}, pmid = {38420829}, issn = {2768-6698}, support = {NSFC-82074261//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Inflammasomes/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Interleukin-18/metabolism/pharmacology ; Pyroptosis ; Interleukin-6/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Signal Transduction ; Inflammation ; Acetylcysteine/metabolism/pharmacology ; Superoxide Dismutase/metabolism ; Epithelial Cells/metabolism ; Glutathione Peroxidase/metabolism/pharmacology ; Ubiquitination ; Malondialdehyde/metabolism ; RNA, Messenger/metabolism ; *Tripartite Motif Proteins ; *Ubiquitin-Protein Ligases ; }, abstract = {BACKGROUND: Pyroptosis is a critical form of cell death during the development of chronic kidney disease (CKD). Tripartite motif 6 (TRIM6) is an E3-ubiquitin ligase that participates in the progression renal fibrosis (RF). The aim of this study was to investigate the roles of TRIM6 and Glutathione peroxidase 3 (GPX3) in oxidative stress-induced inflammasome activation and pyroptosis in Ang-II treated renal tubular epithelial cells.<br><br>METHODS: To study its role in RF, TRIM6 expression was either reduced or increased in human kidney-2 (HK2) cells using lentivirus, and Ang-II, NAC and BMS-986299 were served as reactive oxygen species (ROS) inducer, ROS scavenger and NLRP3 agonist respectively. Pyroptosis and mitochondrial ROS were measured by flow cytometry. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were determined using commercial kits, while the levels of IL-1&#x3b2;, IL-18, IL-6, and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). Co-immunoprecipitation (Co-IP) assay was used to evaluate the interaction between TRIM6 and GPX3. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to measure mRNA and protein expression, respectively.<br><br>RESULTS: Treatment with Angiotensin II (Ang II) increased the protein and mRNA levels of TRIM6 in HK2 cells. Ang II also increased mitochondrial ROS production and the malondialdehyde (MDA) level, but decreased the levels of GSH and SOD. In addition, Ang II enhanced HK2 cell pyroptosis, increased the levels of IL-1&#x3b2;, IL-18, IL-6, and TNF-&#x3b1;, and promoted the expression of active IL-1&#x3b2;, NLRP3, caspase-1, and GSDMD-N proteins. These effects were reversed by knockdown of TRIM6 and by treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger. BMS-986299, an NLRP3 agonist treatment, did not affect ROS production in HK2 cells exposed to Ang II combined with NAC, but cell pyroptosis and inflammation were aggravated. Moreover, the overexpression of TRIM6 in HK2 cells resulted in similar effects to Ang II. NAC and GPX3 overexpression in HK2 cells could reverse ROS production, inflammation, and pyroptosis induced by TRIM6 overexpression. TRIM6 overexpression decreased the GPX3 protein level by promoting its ubiquitination, without affecting the GPX3 mRNA level. Thus, TRIM6 facilitates GPX3 ubiquitination, contributing to increased ROS levels and pyroptosis in HK2 cells.<br><br>CONCLUSIONS: TRIM6 increases oxidative stress and promotes the pyroptosis of HK2 cells by regulating GPX3 ubiquitination. These findings could contribute to the development of novel drugs for the treatment of RF.}, }
@article {pmid38420067, year = {2024}, author = {Ahmed Attari, MB and Zaman, T and Amjad, A and Khan, MH and Waqar, Z and Jabeen, S}, title = {Comparative Analysis of Outcomes in Acute Organophosphate Poisoning With and Without N-acetyl Cysteine Intervention.}, journal = {Cureus}, volume = {16}, number = {1}, pages = {e53155}, pmid = {38420067}, issn = {2168-8184}, abstract = {INTRODUCTION: Organophosphorus poisoning (OPP) stands as a significant health concern in numerous regions, especially in developing nations. Despite the rising complexities and case fatalities associated with exposure, the treatment approach has remained unchanged for many years. Based on clinical insights, certain pharmacologic agents have demonstrated utility in enhancing outcomes and reducing complications arising from this type of exposure.<br><br>OBJECTIVES: The objective of this study is to compare the outcome of N-acetyl cysteine in the treatment of acute organophosphate poisoning cases. In terms of a) its impact on the requirement of atropine, b) Length of hospital stay, and mortality.<br><br>METHODS: The study was conducted in the intensive care unit (ICU) of the General Hospital Lahore. Thirty patients with a history and clinical presentation indicative of acute organophosphorus poisoning were randomly divided into two groups in a 1:1 ratio. The treatment group received parenteral administration of atropine, pralidoxime, and N-acetylcysteine (NAC) as an adjuvant, and the control group received standard treatment for acute organophosphate (OP) toxicity.<br><br>RESULT: Throughout the study duration, 30 patients suffering acute organophosphate (OP) toxicity (14 men, 16 women) were examined, with an age mean of (25.83&#xb1;11.59) years. In the interventional group, only four patients required ICU admission, but in the control group, eight patients were admitted to ICU. The correlation result between the dose of atropine and length of hospital stays was not statistically significant between both study groups (<0.005). Plasma Cholinesterase (PChE) level (KU L-1) and total dose of Pralidoxime (g) were statistically significant in the length of hospital stay. The data was not normally distributed, so the non-parametric tests were applied. The Wilcoxon ranked test showed significant improvement in both the controlled and interventional groups because the p-value was (<0.005). Intergroup comparison analyzed by using the Mann-Whitney U test showed a significant reduction in the severity and other associated symptoms in the interventional group because the p-value was (0.001).<br><br>CONCLUSION: The outcome demonstrated that the NAC group had a decreased demand for atropine rather than Pralidoxime. In the NAC group, the length of hospital stay and mortality was decreased. The administration of NAC to the present study procedure for acute organophosphate (OP) poisoning is suggested.}, }
@article {pmid38417537, year = {2024}, author = {Yang, Y and Zhou, M and Huang, Y and Ye, X and Mo, Y and Huang, Y and Wang, S}, title = {LCP1-mediated cytoskeleton alterations involve in arsenite-triggered malignant phenotype of human immortalized prostate stromal cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {186}, number = {}, pages = {114548}, doi = {10.1016/j.fct.2024.114548}, pmid = {38417537}, issn = {1873-6351}, mesh = {Male ; Humans ; Cell Line ; Prostate ; Reactive Oxygen Species ; *Arsenic ; *Arsenites/toxicity ; Stromal Cells ; *Prostatic Neoplasms ; Phenotype ; Cytoskeleton ; Tumor Microenvironment ; Microfilament Proteins ; HMGB Proteins ; }, abstract = {The connection between continuous arsenic exposure and prostate cancer is already established. However, the exact mechanisms of arsenic tumorigenesis are far from clear. Here, we employed human prostate stromal immortalized cells (WPMY-1) continuous exposure to 1 and 2 μM arsenite for 29 weeks to identify the malignant phenotype and explore the underlying molecular mechanism. As expected, continuous low-dose arsenite exposure led to the malignant phenotype of WPMY-1 cells. Quantitative proteomics identified 517 differentially expressed proteins (DEPs), of which the most remarkably changed proteins (such as LCP1 and DDX58, etc.) and the bioinformatic analysis were focused on the regulation of cytoskeleton, cell adhesion, and migration. Further, cell experiments showed that continuous arsenite exposure altered cytoskeleton structure, enhanced cell adhesive capability, and raised the levels of reactive oxygen species (ROS), ATM, p-ATM, p-ERK1/2, and LCP1 proteins. N-acetylcysteine (NAC) treatment antagonized the increase of LCP1 proteins, and LCP1 knockdown partially restored F-actin organization caused by arsenic. Overall, the results demonstrated that ROS-ATM-ERK1/2 signaling pathway was involved in the activation of LCP1, leading to cytoskeleton alterations. These alterations are believed to play a significant role in arsenite-triggered tumor microenvironment cell-acquired malignant phenotype, which could provide potential biomarkers with therapeutic implications for prostate cancer.}, }
@article {pmid38414064, year = {2024}, author = {Smabers, LP and Wensink, E and Verissimo, CS and Koedoot, E and Pitsa, KC and Huismans, MA and Higuera Barón, C and Doorn, M and Valkenburg-van Iersel, LB and Cirkel, GA and Brousali, A and Overmeer, R and Koopman, M and Braat, MN and Penning de Vries, B and Elias, SG and Vries, RG and Kranenburg, O and Boj, SF and Roodhart, JM}, title = {Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {43}, number = {1}, pages = {61}, pmid = {38414064}, issn = {1756-9966}, mesh = {Humans ; Irinotecan/pharmacology/therapeutic use ; Oxaliplatin/pharmacology/therapeutic use ; *Colorectal Neoplasms/drug therapy/genetics ; Acetylcysteine/therapeutic use ; Precision Medicine ; Fluorouracil/pharmacology/therapeutic use ; *Colonic Neoplasms/drug therapy ; Organoids ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; }, abstract = {BACKGROUND: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies.<br><br>METHODS: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness.<br><br>RESULTS: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU &amp; oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU &amp; oxaliplatin was screened in a ratio, and 5-FU &amp; SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n&#x2009;=&#x2009;6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n&#x2009;=&#x2009;10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n&#x2009;=&#x2009;11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9&#x2009;months, p&#x2009;=&#x2009;0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p&#x2009;=&#x2009;0.003).<br><br>CONCLUSIONS: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.}, }
@article {pmid38408632, year = {2024}, author = {Guan, S and Qu, X and Wang, J and Zhang, D and Lu, J}, title = {3-Monochloropropane-1,2-diol esters induce HepG2 cells necroptosis via CTSB/TFAM/ROS pathway.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {186}, number = {}, pages = {114525}, doi = {10.1016/j.fct.2024.114525}, pmid = {38408632}, issn = {1873-6351}, mesh = {Humans ; *alpha-Chlorohydrin/toxicity/*analogs &amp; derivatives ; Reactive Oxygen Species/metabolism ; Necroptosis ; Esters/toxicity ; Hep G2 Cells ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; }, abstract = {3-monochloropropane-1,2-diol esters (3-MCPDE) are toxic substances that form in food thermal processing and have a diverse range of toxicities. In this study, we found that 3-MCPDE triggered necroptosis by RIPK1/RIPK3/MLKL pathway in HepG2 cells. Previous studies have shown that ROS is an important activator of RIPK1 and RIPK3. The data showed that 3-MCPDE induced excessive ROS production through mitochondrial damage. After treatment with ROS inhibitor N-acetylcysteine (NAC), 3-MCPDE-induced necroptosis was relieved. Further, we explored how 3-MCPDE destroys mitochondria. The data suggested that 3-MCPDE induced mitochondrial dysfunction through the CTSB/TFAM pathway. Overall, the results indicated that 3-MCPDE induced necroptosis through CTSB/TFAM/ROS pathway in HepG2 cells. Our study provided a new mechanism for 3-MCPDE hepatotoxicity.}, }
@article {pmid38408264, year = {2024}, author = {Doumi, I and Lang, L and Vileno, B and Deponte, M and Faller, P}, title = {Glutathione Protects other Cellular Thiols against Oxidation by Cu[II]-Dp44mT.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {30}, number = {21}, pages = {e202304212}, doi = {10.1002/chem.202304212}, pmid = {38408264}, issn = {1521-3765}, support = {ANR-10-IDEX-0002//Agence Nationale de la Recherche/ ; ITI-CSC-PFA-22//ITI LabEx Chimie des Syst&#xe8;mes Complexes/ ; DE 1431/20-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Copper/metabolism ; Sulfhydryl Compounds ; Oxidation-Reduction ; *Thiosemicarbazones ; Glutathione/metabolism ; Penicillamine/metabolism ; Acetylcysteine/metabolism ; }, abstract = {Cu-thiosemicarbazones have been intensively investigated for their application in cancer therapy or as antimicrobials. Copper(II)-di-2-pyridylketone-4,4-dimethyl-thiosemicarbazone (Cu[II]-Dp44mT) showed anticancer activity in the submicromolar concentration range in cell culture. The interaction of Cu[II]-Dp44mT with thiols leading to their depletion or inhibition was proposed to be involved in this activity. Indeed, Cu[II]-Dp44mT can catalyze the oxidation of thiols although with slow kinetics. The present work aims to obtain insights into the catalytic activity and selectivity of Cu[II]-Dp44mT toward the oxidation of different biologically relevant thiols. Reduced glutathione (GSH), L-cysteine (Cys), N-acetylcysteine (NAC), D-penicillamine (D-Pen), and the two model proteins glutaredoxin (Grx) and thioredoxin (Trx) were investigated. Cu[II]-Dp44mT catalyzed the oxidation of these thiols with different kinetics, with rates in the following order D-Pen>Cys≫NAC>GSH and Trx>Grx. Cu[II]-Dp44mT was more efficient than Cu[II] chloride for the oxidation of NAC and GSH, but not D-Pen and Cys. In mixtures of biologically relevant concentrations of GSH and either Cys, Trx, or Grx, the oxidation kinetics and spectral properties were similar to that of GSH alone, indicating that the interaction of these thiols with Cu[II]-Dp44mT is dominated by GSH. Hence GSH could protect other thiols against potential deleterious oxidation by Cu[II]-Dp44mT.}, }
@article {pmid38407768, year = {2024}, author = {Jimenez-Chavez, A and Pedroza-Herrera, G and Betancourt-Reyes, I and De Vizcaya Ruiz, A and Masuoka-Ito, D and Zapien, JA and Medina-Ramirez, IE}, title = {Aluminum enhances the oxidative damage of ZnO NMs in the human neuroblastoma SH-SY5Y cell line.}, journal = {Discover nano}, volume = {19}, number = {1}, pages = {36}, pmid = {38407768}, issn = {2731-9229}, support = {Fordecyt-Pronaces/568494/2020 and C-104/2021//CONAHCYT/ ; }, abstract = {Bare and doped zinc oxide nanomaterials (ZnO NMs) are of great interest as multifunctional platforms for biomedical applications. In this study, we systematically investigate the physicochemical properties of Aluminum doped ZnO (AZO) and its bio-interactions with neuroblastoma (SH-SY5Y) and red blood (RBCs) cells. We provide a comprehensive chemical and structural characterization of the NMs. We also evaluated the biocompatibility of AZO NMs using traditional toxicity assays and advanced microscopy techniques. The toxicity of AZO NMs towards SH-SY5Y cells, decreases as a function of Al doping but is higher than the toxicity of ZnO NMs. Our results show that N-acetyl cysteine protects SH-SY5Y cells against reactive oxygen species toxicity induced by AZO NMs. ZnO and AZO NMs do not exert hemolysis in human RBCs at the doses that cause toxicity (IC50) in neuroblastoma cells. The Atomic force microscopy qualitative analysis of the interaction of SH-SY5Y cells with AZO NMs shows evidence that the affinity of the materials with the cells results in morphology changes and diminished interactions between neighboring cells. The holotomographic microscopy analysis demonstrates NMs' internalization in SH-SY5Y cells, changes in their chemical composition, and the role of lipid droplets in the clearance of toxicants.}, }
@article {pmid38405665, year = {2024}, author = {Abdallah, R and Shaito, AA and Badran, A and Baydoun, S and Sobeh, M and Ouchari, W and Sahri, N and Eid, AH and Mesmar, JE and Baydoun, E}, title = {Fractionation and phytochemical composition of an ethanolic extract of Ziziphus nummularia leaves: antioxidant and anticancerous properties in human triple negative breast cancer cells.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1331843}, pmid = {38405665}, issn = {1663-9812}, abstract = {Natural products have long been utilized in traditional medicine as remedies to improve health and treat illnesses, and have had a key role in modern drug discovery. Recently, there has been a revived interest in the search for bioactives from natural sources as alternative or complementary modalities to synthetic medicines; especially for cancer treatment, which incidence and mortality rates are on the rise worldwide. Ziziphus nummularia has been widely used in traditional medicine for the treatment of various diseases. Its traditional uses and numerous ethnopharmacological properties may be attributed to its richness in bioactive metabolites. However, its phytochemical composition or chemopreventive effects against the aggressive triple-negative breast cancer (TNBC) are still poorly explored. Here, phytochemical composition of an ethanolic extract of Z. nummularia leaves (ZNE) and its chromatographically isolated fractions was identified both qualitatively by spectrophotometric assays and analytically by HPLC-PDA-MS/MS. The anti-proliferative effects of ZNE were tested in several cancer cell lines, but we focused on its anti-TNBC effects since they were not explored yet. The anti-cancerous potential of ZNE and its fractions was tested in vitro in MDA-MB-231, a TNBC cell line. Results showed that ZNE and its Fraction 6 (F6) reduced the viability of MDA-MB-231 cells. F6 decreased MDA-MB-231 viability more than crude ZNE or its other fractions. ZNE and F6 are rich in phytochemicals and HPLC-PDA-MS/MS analysis identified several metabolites that were previously reported to have anti-cancerous effects. Both ZNE and F6 showed potent antioxidant capacity in the DPPH assay, but promoted reactive oxygen species (ROS) production in MDA-MB-231 cells; an effect which was blunted by the antioxidant N-acetyl cysteine (NAC). NAC also blunted ZNE- and F6-induced reduction in TNBC cell viability. We also demonstrated that ZNE and F6 induced an arrest of the cell cycle, and triggered apoptosis- and autophagy-mediated cell death. ZNE and F6 inhibited metastasis-related cellular processes by modifying cell migration, invasion, and adhesion. Taken together, our findings reveal that Z. nummularia is rich in phytochemicals that can attenuate the malignant phenotype of TNBC and may offer innovative avenues for the discovery of new drug leads for treatment of TNBC and other cancers.}, }
@article {pmid38399445, year = {2024}, author = {Lu, HI and Chen, KL and Yen, CY and Chen, CY and Chien, TM and Shu, CW and Chen, YH and Jeng, JH and Chen, BH and Chang, HW}, title = {Michelia compressa-Derived Santamarine Inhibits Oral Cancer Cell Proliferation via Oxidative Stress-Mediated Apoptosis and DNA Damage.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {17}, number = {2}, pages = {}, pmid = {38399445}, issn = {1424-8247}, support = {MOST 111-2320-B-037-015-MY3//Ministry of Science and Technology/ ; #NSYSUKMU 112-P06//National Sun Yat-sen University-KMU Joint Research Project/ ; 111CM-KMU-05, 112CM-KMU-05//Chimei-KMU jointed project/ ; KMU-DK(A)112008//Kaohsiung Medical University/ ; KMU-TC112A04//Kaohsiung Medical University Research Center/ ; }, abstract = {The anti-oral cancer effects of santamarine (SAMA), a Michelia compressa var. compressa-derived natural product, remain unclear. This study investigates the anticancer effects and acting mechanism of SAMA against oral cancer (OC-2 and HSC-3) in parallel with normal (Smulow-Glickman; S-G) cells. SAMA selectively inhibits oral cancer cell viability more than normal cells, reverted by the oxidative stress remover N-acetylcysteine (NAC). The evidence of oxidative stress generation, such as the induction of reactive oxygen species (ROS) and mitochondrial superoxide and the depletion of mitochondrial membrane potential and glutathione, further supports this ROS-dependent selective antiproliferation. SAMA arrests oral cancer cells at the G2/M phase. SAMA triggers apoptosis (annexin V) in oral cancer cells and activates caspases 3, 8, and 9. SAMA enhances two types of DNA damage in oral cancer cells, such as γH2AX and 8-hydroxy-2-deoxyguanosine. Moreover, all of these anticancer mechanisms of SAMA are more highly expressed in oral cancer cells than in normal cells in concentration and time course experiments. These above changes are attenuated by NAC, suggesting that SAMA exerts mechanisms of selective antiproliferation that depend on oxidative stress while maintaining minimal cytotoxicity to normal cells.}, }
@article {pmid38397782, year = {2024}, author = {Tuell, D and Ford, G and Los, E and Stone, W}, title = {The Role of Glutathione and Its Precursors in Type 2 Diabetes.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {38397782}, issn = {2076-3921}, support = {C06RR0306551/NH/NIH HHS/United States ; }, abstract = {Type 2 diabetes (T2D) is a major worldwide health crisis affecting about 6.2% of the world's population. Alarmingly, about one in five children in the USA have prediabetes. Glutathione (GSH) and its precursors play a promising role in the prevention and management of type T2D. Oxidative stress (OxS) is a probable factor in both T2D initiation and progression. GSH is the major cytosolic water-soluble chemical antioxidant and emerging evidence supports its role in improving T2D outcomes. Dietary supplementation with N-acetyl-cysteine (NAC) and/or glycine (GLY), which are GSH precursors, has also been studied for possible beneficial effects on T2D. This review will focus on the underlying pathophysiological and molecular mechanisms linking GSH and its precursors with T2D and OxS. In addition to their traditional antioxidant roles, the in vivo effects of GSH/NAC/GLY supplements will be evaluated for their potential abilities to modulate the complex pro-oxidant pathophysiological factors (e.g., hyperglycemia) driving T2D progression. Positive feedback loops that amplify OxS over long time intervals are likely to result in irreversible T2D micro- and macro-vascular damage. Most clinical studies with GSH/NAC/GLY have focused on adults or the elderly. Future research with pediatric populations should be a high priority since early intervention is critical.}, }
@article {pmid38397769, year = {2024}, author = {Khan, S and Wang, T and Cobo, ER and Liang, B and Khan, MA and Xu, M and Qu, W and Gao, J and Barkema, HW and Kastelic, JP and Liu, G and Han, B}, title = {Antioxidative Sirt1 and the Keap1-Nrf2 Signaling Pathway Impair Inflammation and Positively Regulate Autophagy in Murine Mammary Epithelial Cells or Mammary Glands Infected with Streptococcus uberis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {2}, pages = {}, pmid = {38397769}, issn = {2076-3921}, support = {32172928//National Natural Science Foundation of China/ ; 31772813//National Natural Science Foundation of China/ ; G2022108009L//High-end Foreign Experts Recruitment Program/ ; 2019BBF02027//Ningxia Key Development Programs/ ; 6222031//Beijing Natural Science Foundation/ ; }, abstract = {Streptococcus uberis mastitis in cattle infects mammary epithelial cells. Although oxidative responses often remove intracellular microbes, S. uberis survives, but the mechanisms are not well understood. Herein, we aimed to elucidate antioxidative mechanisms during pathogenesis of S. uberis after isolation from clinical bovine mastitis milk samples. S. uberis's in vitro pathomorphology, oxidative stress biological activities, transcription of antioxidative factors, inflammatory response cytokines, autophagosome and autophagy functions were evaluated, and in vivo S. uberis was injected into the fourth mammary gland nipple of each mouse to assess the infectiousness of S. uberis potential molecular mechanisms. The results showed that infection with S. uberis induced early oxidative stress and increased reactive oxygen species (ROS). However, over time, ROS concentrations decreased due to increased antioxidative activity, including total superoxide dismutase (T-SOD) and malondialdehyde (MDA) enzymes, plus transcription of antioxidative factors (Sirt1, Keap1, Nrf2, HO-1). Treatment with a ROS scavenger (N-acetyl cysteine, NAC) before infection with S. uberis reduced antioxidative responses and the inflammatory response, including the cytokines IL-6 and TNF-α, and the formation of the Atg5-LC3II/LC3I autophagosome. Synthesis of antioxidants determined autophagy functions, with Sirt1/Nrf2 activating autophagy in the presence of S. uberis. This study demonstrated the evasive mechanisms of S. uberis in mastitis, including suppressing inflammatory and ROS defenses by stimulating antioxidative pathways.}, }
@article {pmid38396357, year = {2024}, author = {Kamel, AA and Nassar, AY and Meligy, FY and Omar, YA and Nassar, GAY and Ezzat, GM}, title = {Acetylated oligopeptide and N-acetylcysteine protect against iron overload-induced dentate gyrus hippocampal degeneration through upregulation of Nestin and Nrf2/HO-1 and downregulation of MMP-9/TIMP-1 and GFAP.}, journal = {Cell biochemistry and function}, volume = {42}, number = {2}, pages = {e3958}, doi = {10.1002/cbf.3958}, pmid = {38396357}, issn = {1099-0844}, mesh = {Animals ; Male ; Rats ; *Acetylcysteine/pharmacology/metabolism ; Caspases/metabolism ; Claudins/genetics ; Dentate Gyrus/metabolism/pathology ; Dextrans/metabolism/pharmacology ; Down-Regulation ; Glutathione/metabolism ; Hippocampus/metabolism/pathology ; Iron/metabolism/pharmacology ; *Iron Overload/complications/drug therapy ; Matrix Metalloproteinase 9/genetics/metabolism/pharmacology ; Nestin/genetics/metabolism/pharmacology ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism/pharmacology ; Up-Regulation ; *Oligopeptides/pharmacology ; Heme Oxygenase-1/drug effects ; Glial Fibrillary Acidic Protein/drug effects/metabolism ; }, abstract = {Iron accumulation in the brain causes oxidative stress, blood-brain barrier (BBB) breakdown, and neurodegeneration. We examined the preventive effects of acetylated oligopeptides (AOP) from whey protein on iron-induced hippocampal damage compared to N-acetyl cysteine (NAC). This 5-week study used 40 male albino rats. At the start, all rats received 150 mg/kg/day of oral NAC for a week. The 40 animals were then randomly divided into four groups: Group I (control) received a normal diet; Group II (iron overload) received 60 mg/kg/day intraperitoneal iron dextran 5 days a week for 4 weeks; Group III (NAC group) received 150 mg/kg/day NAC and iron dextran; and Group IV (AOP group) received 150 mg/kg/day AOP and iron dextran. Enzyme-linked immunosorbent assay, spectrophotometry, and qRT-PCR were used to measure MMP-9, tissue inhibitor metalloproteinase-1 (TIMP-1), MDA, reduced glutathione (GSH) levels, and nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Histopathological and immunohistochemical detection of nestin, claudin, caspase, and GFAP was also done. MMP-9, TIMP-1, MDA, caspase, and GFAP rose in the iron overload group, while GSH, Nrf2, HO-1, nestin, and claudin decreased. The NAC and AOP administrations improved iron overload-induced biochemical and histological alterations. We found that AOP and NAC can protect the brain hippocampus from iron overload, improve BBB disruption, and provide neuroprotection with mostly no significant difference from healthy controls.}, }
@article {pmid38392216, year = {2024}, author = {Shih, LJ and Hsu, PC and Chuu, CP and Shui, HA and Yeh, CC and Chen, YC and Kao, YH}, title = {Epigallocatechin-3-gallate Synergistically Enhanced Arecoline-Induced Cytotoxicity by Redirecting Cycle Arrest to Apoptosis.}, journal = {Current issues in molecular biology}, volume = {46}, number = {2}, pages = {1516-1529}, pmid = {38392216}, issn = {1467-3045}, support = {MOST106-2320-B-008-008-MY3, MOST109-2320-B-008-001-MY3//National Science and Technology Council/ ; 11001-62-021, TPCH-110-05//Taipei City Hospital; Department of Health, Taipei City Government/ ; TYAFGH-E-111053, TYAFGH-E-112050//Taoyuan Armed Forces General Hospital/ ; MND-MAB-110-025, MND-MAB-C-11107-111026//National Defense Medical Center/ ; }, abstract = {Carcinogens, such as arecoline, play a crucial role in cancer progression and continuous gene mutations by generating reactive oxygen species (ROS). Antioxidants can reduce ROS levels and potentially prevent cancer progression but may paradoxically enhance the survival of cancer cells. This study investigated whether epigallocatechin-3-gallate (EGCG), an antioxidant from green tea, could resolve this paradox. Prostate cancer cells (PC-3 cell line) were cultured and treated with arecoline combined with NAC (N-acetylcysteine) or EGCG; the combined effects on intracellular ROS levels and cell viability were examined using the MTT and DCFDA assays, respectively. In addition, apoptosis, cell cycle, and protein expression were investigated using flow cytometry and western blot analysis. Our results showed that EGCG, similar to NAC (N-acetylcysteine), reduced the intracellular ROS levels, which were elevated by arecoline. Moreover, EGCG not only caused cell cycle arrest but also facilitated cell apoptosis in arecoline-treated cells in a synergistic manner. These were evidenced by elevated levels of cyclin B1 and p27, and increased fragmentation of procaspase-3, PARP, and DNA. Our findings highlight the potential use of EGCG for cancer prevention and therapy.}, }
@article {pmid38390944, year = {2024}, author = {Alvarez, IA and Lee, M and Eshaq, RS and Leskova, W and Harris, NR}, title = {High Glucose Induces Oxidative Stress That Alters Glycocalyx Proteoglycan Levels in Primary Rat Retinal Microvascular Endothelial Cells and in Isolated Ophthalmic Arteries.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {31}, number = {1}, pages = {89-99}, pmid = {38390944}, issn = {1873-149X}, support = {R01 EY025632/EY/NEI NIH HHS/United States ; NEI EY025632/NH/NIH HHS/United States ; }, abstract = {Our purpose in this study was to identify the role played by oxidative stress in the changes to proteoglycans that occur under hyperglycemic conditions, using primary rat retinal microvascular endothelial cells (RRMEC) and cultured ophthalmic arteries. The cells and blood vessels obtained from rats were cultured in normal glucose (5.6 mM) and high glucose (25 mM) with or without N-acetylcysteine (NAC), an antioxidant. Intracellular oxidative stress was determined by measuring dihydroethidium (DHE) fluorescence and malondialdehyde (MDA)-modified protein levels. mRNA and protein levels were evaluated using quantitative real-time polymerase chain reaction and immunoblot, respectively. High glucose increased levels of glypican-1 mRNA and protein. The level of syndecan-1 mRNA also was increased, but its protein level was decreased, by high glucose. Evaluation of DHE and MDA showed that high glucose increased oxidative stress. These changes caused by high glucose were significantly reversed by NAC treatment. Matrix metalloproteinase-9 (MMP-9) levels, which increased under high glucose conditions, were suppressed by NAC treatment. Oxidative stress caused by hyperglycemia may be responsible for significant changes to the ocular endothelial glycocalyx.}, }
@article {pmid38385491, year = {2024}, author = {Zhao, X and Shan, G and Xing, D and Gao, H and Xiong, Z and Hui, W and Gong, M}, title = {UBE2L3 Promotes Oxidative Stress-regulated Necroptosis to Accelerate Osteosarcoma Progression.}, journal = {Recent patents on anti-cancer drug discovery}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115748928297557240212112531}, pmid = {38385491}, issn = {2212-3970}, abstract = {BACKGROUND: Osteosarcoma is a highly invasive bone marrow stromal tumor with limited treatment options. Oxidative stress plays a crucial role in the development and progression of tumors, but the underlying regulatory mechanisms are not fully understood. Recent studies have revealed the significant involvement of UBE2L3 in oxidative stress, but its specific role in osteosarcoma remains poorly investigated.<br><br>OBJECTIVE: This study aimed to explore the molecular mechanisms by which UBE2L3 promotes oxidative stress-regulated necroptosis to accelerate the progression of osteosarcoma using in vitro cell experiments.<br><br>METHODS: Human osteoblast hFOB1.19 cells and various human osteosarcoma cell lines (MG-63, U2OS, SJSA-1, HOS, and 143B) were cultured in vitro. Plasmids silencing UBE2L3 and negative control plasmids were transfected into U2OS and HOS cells. The cells were divided into the following groups: U2OS cell group, HOS cell group, si-NC-U2OS cell group, si-UBE2L3-U2OS cell group, si-NC-HOS cell group, and si-UBE2L3-HOS cell group. Cell viability and proliferation capacity were measured using the Tunnel method and clonogenic assay. Cell migration and invasion abilities were assessed by Transwell and scratch assays. Cell apoptosis was analyzed by flow cytometry, and ROS levels were detected using immunofluorescence. The oxidative stress levels in various cell groups and the expression changes of necroptosis-related proteins were assessed by PCR and WB. Through these experiments, we aim to evaluate the impact of oxidative stress on necroptosis and uncover the specific mechanisms by which targeted regulation of oxidative stress promotes tumor cell necroptosis as a potential therapeutic strategy for osteosarcoma.<br><br>RESULTS: The mRNA expression levels of UBE2L3 in human osteosarcoma cell lines were significantly higher than those in human osteoblast hFOB1.19 cells (p <0.01). UBE2L3 expression was significantly decreased in U2OS and HOS cells transfected with si-UBE2L3, indicating the successful construction of stable cell lines with depleted UBE2L3. Tunnel assay results showed a significant increase in the number of red fluorescent-labeled cells in si-UBE2L3 groups compared to si-NC groups in both cell lines, suggesting a pronounced inhibition of cell viability. Transwell assay demonstrated a significant reduction in invasion and migration capabilities of si-UBE2L3 groups in osteosarcoma cells. The clonogenic assay revealed significant suppression of proliferation and clonogenic ability in both U2OS and HOS cells upon UBE2L3 knockdown. Flow cytometry confirmed that UBE2L3 knockdown significantly enhanced apoptosis in U2OS and HOS cells. Immunofluorescence results showed that UBE2L3 silencing promoted oxidative stress levels in osteosarcoma cells and facilitated tumor cell death. WB analysis indicated a significant increase in phosphorylation levels of necroptosis-related proteins, RIP1, RIP3, and MLKL, in both osteosarcoma cell lines after UBE2L3 knockdown. In addition, the expression of necrosis-associated proteins was inhibited by the addition of the antioxidant N-acetylcysteine (NAC).<br><br>CONCLUSION: UBE2L3 is upregulated in osteosarcoma cells, and silencing of UBE2L3 promotes oxidative stress in these cells, leading to enhanced necroptosis and delayed progression of osteosarcoma.}, }
@article {pmid38381146, year = {2024}, author = {Rasouli, H and Razavi, BM and Ghasemzadeh Rahbardar, M and Sadeghian, H and Tabatabaee Yazdi, SA and Hosseinzadeh, H}, title = {Hepatoprotective effect of amifostine and WR-1065 on acetaminophen-induced liver toxicity on Wistar rats.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {38381146}, issn = {1432-1912}, support = {910351//Pharmaceutical Research Center and the Vice-Chancellor of Research, Mashhad University of Medical Sciences/ ; }, abstract = {PURPOSE: The most important problem with acetaminophen is its hepatotoxicity. N-acetylcysteine (NAC) is used to treat the hepatotoxicity of acetaminophen. Due to the structural similarities of this compound with amifostine, we decided to test the effect of this substance and its metabolite, WR-1065, on the hepatotoxicity of acetaminophen.<br><br>METHODS: The single-dose method contained 1. Control; 2. Acetaminophen (1 g/kg, gavage); 3-5. Acetaminophen&#x2009;+&#x2009;amifostine (100, 200, 400 mg/kg, i.p.); 6-8. Acetaminophen&#x2009;+&#x2009;WR-1065 (50, 100, 200 mg/kg, i.p.); and 9. Acetaminophen&#x2009;+&#x2009;NAC (100, 200 mg/kg, i.p.). The multiple-dose method included the same groups: amifostine (50, 100, 200 mg/kg), WR-1065 (25, 50, 100 mg/kg), and NAC (100 mg/kg). Then, animals were sacrificed, and blood samples were collected for measuring ALT, AST, ALP, and T-Bil, liver tissue for histopathological examination, MDA, and GSH amounts.<br><br>RESULTS: Acetaminophen increased the levels of MDA, T-Bil, ALT, AST, and ALP, decreased GSH levels, and augmented necrosis, neutrophils, lymphocytes, and macrophages in the port space in single-dose and multiple-dose studies. Amifostine and WR-1065 significantly reduced the levels of MDA, T-Bil, ALT, AST, ALP, increased GSH content, and ameliorated histopathological alterations in a single-dose and multiple-dose method compared to the acetaminophen group. Moreover, NAC caused a significant decrease in the levels of MDA, T-Bil, ALT, AST, and ALP, and reduced GSH amounts in single-dose and multiple-dose studies.<br><br>CONCLUSION: Amifostine and WR-1065 as antioxidant and hepatoprotective compounds are effective in reducing acetaminophen-induced hepatotoxicity with a similar effect to NAC and can be administered as an adjunct in the treatment of acetaminophen overdose.}, }
@article {pmid38379848, year = {2024}, author = {Lee, KI and Fang, KM and Kuo, CY and Huang, CF and Liu, SH and Liu, JM and Lai, WC and Chang, KC and Su, CC and Chen, YW}, title = {Roles of oxidative stress/JNK/ERK signals in paraquat-triggered hepatic apoptosis.}, journal = {Current research in toxicology}, volume = {6}, number = {}, pages = {100155}, pmid = {38379848}, issn = {2666-027X}, abstract = {Paraquat (PQ), a toxic and nonselective bipyridyl herbicide, is one of the most extensively used pesticides in agricultural countries. In addition to pneumotoxicity, the liver is an important target organ for PQ poisoning in humans. However, the mechanism of PQ in hepatotoxicity remains unclear. In this study, we found that exposure of rat hepatic H4IIE cells to PQ (0.1-2 mM) induced significant cytotoxicity and apoptosis, which was accompanied by mitochondria-dependent apoptotic signals, including loss of mitochondrial membrane potential (MMP), cytosolic cytochrome c release, and changes in the Bcl-2/Bax mRNA ratio. Moreover, PQ (0.5 mM) exposure markedly induced JNK and ERK1/2 activation, but not p38-MAPK. Blockade of JNK and ERK1/2 signaling by pretreatment with the specific pharmacological inhibitors SP600125 and PD98059, respectively, effectively prevented PQ-induced cytotoxicity, mitochondrial dysfunction, and apoptotic events. Additionally, PQ exposure stimulated significant oxidative stress-related signals, including reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion, which could be reversed by the antioxidant N-Acetylcysteine (NAC). Buffering the oxidative stress response with NAC also effectively abrogated PQ-induced hepatotoxicity, MMP loss, apoptosis, and phosphorylation of JNK and ERK1/2 protein, however, the JNK or ERK inhibitors did not suppress ROS generation in PQ-treated cells. Collectively, these results demonstrate that PQ exposure induces hepatic cell toxicity and death via an oxidative stress-dependent JNK/ERK activation-mediated downstream mitochondria-regulated apoptotic pathway.}, }
@article {pmid38376812, year = {2024}, author = {Radan, M and Abol Nejadian, F and Bayati, V and Hemmati, AA and Hoseinynejad, K and Mard, SA}, title = {N-acetyl cysteine augments adipose tissue-derived stem cell efficacy on inflammatory markers and regulatory T cell system balance in an allergic asthma model.}, journal = {The Journal of asthma : official journal of the Association for the Care of Asthma}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/02770903.2024.2321296}, pmid = {38376812}, issn = {1532-4303}, abstract = {BACKGROUND: Allergic asthma is a destructive inflammatory process in the respiratory system. The anti-inflammatory and antioxidant effects of N-acetylcysteine (NAC) have been reported in patients with obstructive pulmonary disease. On the other hand, several studies have shown the modulatory effects of mesenchymal stem cells on the immune system and inflammatory responses. Accordingly, the purpose of the current study was to evaluate the effect of administration of adipose tissue-derived stem cells (ADSCs) plus NAC on regulatory T cell system balance in an allergic asthma model.<br><br>METHODS: Eighty Sprague- Dawley rats were randomly divided into the following groups: Control, Plasmalite, Allergic asthma, Allergic asthma&#x2009;+&#x2009;ADSCs, NAC, Allergic asthma&#x2009;+&#x2009;NAC, Allergic asthma&#x2009;+&#x2009;ADSCs&#x2009;+&#x2009;NAC and Allergic asthma&#x2009;+&#x2009;Prednisolone. at the end of the experiment, arterial blood gas analysis, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), inflammatory cytokine concentration, total IgE and specific OVA-IgE levels, gene expression levels of CD4+-T cell subsets, pulmonary indicators, edema, and lung histopathology were evaluated in all groups.<br><br>RESULTS: Administration of NAC plus ADSCs demonstrated a significant decrease in total WBC and eosinophil counts, which was in line with remarkable decrease in IL-17 and TNF-&#x3b1; concentrations and increases in IL-10 level compared with other treated groups. NAC plus ADSC treatment showed significant increases in Treg gene expression, although Th17 and Th2 expression significantly decreased compared with that in prednisolone- treated rats.<br><br>CONCLUSION: The results of the present study documented that the administration of ADSCs plus NAC has an inhibitory effect on the inflammation caused by allergic asthma in a rat model. The improvement of inflammatory indexes was significantly higher than that with prednisolone treatment.}, }
@article {pmid38373369, year = {2024}, author = {Yuce, M and Yildirim, E and Ekinci, M and Turan, M and Ilhan, E and Aydin, M and Agar, G and Ucar, S}, title = {N-acetyl-cysteine mitigates arsenic stress in lettuce: Molecular, biochemical, and physiological perspective.}, journal = {Plant physiology and biochemistry : PPB}, volume = {207}, number = {}, pages = {108390}, doi = {10.1016/j.plaphy.2024.108390}, pmid = {38373369}, issn = {1873-2690}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Arsenic/toxicity ; Lactuca ; Hydrogen Peroxide/metabolism ; Antioxidants/metabolism ; Soil ; }, abstract = {Agricultural land contaminated with heavy metals such as non-biodegradable arsenic (As) has become a serious global problem as it adversely affects agricultural productivity, food security and human health. Therefore, in this study, we investigated how the administration of N-acetyl-cysteine (NAC), regulates the physio-biochemical and gene expression level to reduce As toxicity in lettuce. According to our results, different NAC levels (125, 250 and 500 μM) significantly alleviated the growth inhibition and toxicity induced by As stress (20 mg/L). Shoot fresh weight, root fresh weight, shoot dry weight and root dry weight (33.05%, 55.34%, 17.97% and 46.20%, respectively) were decreased in plants grown in As-contaminated soils compared to lettuce plants grown in soils without the addition of As. However, NAC applications together with As stress increased these growth parameters. While the highest increase in shoot fresh and dry weight (58.31% and 37.85%, respectively) was observed in 250 μM NAC application, the highest increase in root fresh and dry weight (75.97% and 63.07%, respectively) was observed in 125 μM NAC application in plants grown in As-polluted soils. NAC application decreased the amount of ROS, MDA and H2O2 that increased with As stress, and decreased oxidative damage by regulating hormone levels, antioxidant and enzymes involved in nitrogen metabolism. According to gene expression profiles, LsHIPP28 and LsABC3 genes have shown important roles in reducing As toxicity in leaves. This study will provide insight for future studies on how NAC applications develop resistance to As stress in lettuce.}, }
@article {pmid38369618, year = {2024}, author = {Sun, C and Zhang, M and Guan, C and Li, W and Peng, Y and Zheng, J}, title = {In vitro and in vivo metabolic activation and hepatotoxicity of chlorzoxazone mediated by CYP3A.}, journal = {Archives of toxicology}, volume = {98}, number = {4}, pages = {1095-1110}, pmid = {38369618}, issn = {1432-0738}, mesh = {Humans ; Rats ; Animals ; *Chlorzoxazone ; Cytochrome P-450 CYP3A/metabolism ; Activation, Metabolic ; Rats, Sprague-Dawley ; Microsomes, Liver/metabolism ; *Chemical and Drug Induced Liver Injury/etiology/metabolism ; Epoxy Compounds/metabolism ; Glutathione/metabolism ; }, abstract = {Chlorzoxazone (CZX), a benzoxazolone derivative, has been approved for the treatment of musculoskeletal disorders to relieve localized muscle spasm. However, its idiosyncratic toxicity reported in patients brought attention, particularly for hepatotoxicity. The present study for the first time aimed at the relationship between CZX-induced hepatotoxicity and identification of oxirane intermediate resulting from metabolic activation of CZX. Two N-acetylcysteine (NAC) conjugates (namely M1 and M2) and two glutathione (GSH) conjugates (namely M3 and M4) were detected in rat &amp; human microsomal incubations with CZX (200 μM) fortified with NAC or GSH, respectively. The formation of M1-M4 was NADPH-dependent and these metabolites were also observed in urine or bile of SD rats given CZX intragastrically at 10 mg/kg or 25 mg/kg. NAC was found to attach at C-6' of the benzo group of M1 by sufficient NMR data. CYPs3A4 and 3A5 dominated the metabolic activation of CZX. The two GSH conjugates were also observed in cultured rat primary hepatocytes after exposure to CZX. Inhibition of CYP3A attenuated the susceptibility of hepatocytes to the cytotoxicity of CZX (10-400 μM). The in vitro and in vivo studies provided solid evidence for the formation of oxirane intermediate of CZX. This would facilitate the understanding of the underlying mechanisms of toxic action of CZX.}, }
@article {pmid38369538, year = {2024}, author = {Wu, T and Liu, W and Chen, H and Hou, L and Ren, W and Zhang, L and Hu, J and Chen, H and Chen, C}, title = {Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {4008}, pmid = {38369538}, issn = {2045-2322}, support = {2023M731448//China Postdoctoral Science Foundation/ ; 2023M731011//China Postdoctoral Science Foundation/ ; 82203878//National Science Foundation of China/ ; U2102203//National Science Foundation of China/ ; 2023J01385//the Natural Science Foundation of Fujian Province/ ; 2020YFA0112300//National Key R&amp;D Program of China/ ; 202302AA310046//Biomedical Projects of Yunnan Key Science and Technology Program/ ; 202101AS070050//Yunnan Fundamental Research Projects/ ; YSZJGZZ-2020025//Yunnan (Kunming) Academician Expert Workstation/ ; }, mesh = {Humans ; *Triple Negative Breast Neoplasms/genetics ; Reactive Oxygen Species/metabolism ; Cell Proliferation ; Cell Line, Tumor ; Apoptosis ; DNA Damage ; *Pyrimidinones ; *Triazines ; }, abstract = {Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.}, }
@article {pmid38363806, year = {2024}, author = {Wu, T and Zhang, H and Zhang, P and James, TD and Sun, X}, title = {A Rationally Designed Prodrug for the Fluorogenic Labeling of Albumin and Theranostic Effects on Drug-Induced Liver Injury.}, journal = {Analytical chemistry}, volume = {96}, number = {8}, pages = {3498-3507}, doi = {10.1021/acs.analchem.3c05272}, pmid = {38363806}, issn = {1520-6882}, mesh = {Humans ; Antioxidants/pharmacology ; *Prodrugs/pharmacology/chemistry ; Precision Medicine ; Serum Albumin/chemistry ; Acetylcysteine ; Serum Albumin, Human ; *Chemical and Drug Induced Liver Injury ; }, abstract = {The development of small-molecular fluorogenic tools for the chemo-selective labeling of proteins in live cells is important for the evaluation of intracellular redox homeostasis. Dynamic imaging of human serum albumin (HSA), an antioxidant protein under oxidative stress with concomitant release of antioxidant drugs to maintain redox homeostasis, affords potential opportunities for disease diagnosis and treatment. In this work, we developed a nonfluorogenic prodrug named TPA-NAC, by introducing N-acetyl-l-cysteine (NAC) into a conjugated acceptor skeleton. Through combined thiol and amino addition, coupling with HSA results in fluorescence turn-on and drug release. It was reasoned that the restricted intramolecular motion of the probe under an HSA microenvironment after covalent bonding inhibited the nonradiative transitions. Furthermore, the biocompatibility and photochemical properties of TPA-NAC enabled it to image exogenous and endogenous HSA in living cells in a wash-free manner. Additionally, the released drug evoked upregulation of superoxide dismutase (SOD), which synergistically eliminated reactive oxygen species in a drug-induced liver injury model. This study provides insights into the design of new theranostic fluorescent prodrugs for chemo-selective protein labeling and disease treatments.}, }
@article {pmid38363133, year = {2024}, author = {Guzman, RM and Savolainen, NG and Hayden, OM and Lee, M and Osbron, CA and Liu, Z and Yang, H and Shaw, DK and Omsland, A and Goodman, AG}, title = {Drosophila melanogaster Sting mediates Coxiella burnetii infection by reducing accumulation of reactive oxygen species.}, journal = {Infection and immunity}, volume = {92}, number = {3}, pages = {e0056022}, pmid = {38363133}, issn = {1098-5522}, support = {R01 AI139051/AI/NIAID NIH HHS/United States ; R01 AI162819/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Coxiella burnetii ; Drosophila melanogaster/genetics/metabolism ; NF-kappa B/metabolism ; *Q Fever/microbiology ; Reactive Oxygen Species/metabolism ; }, abstract = {The Gram-negative bacterium Coxiella burnetii is the causative agent of query fever in humans and coxiellosis in livestock. C. burnetii infects a variety of cell types, tissues, and animal species including mammals and arthropods, but there is much left to be understood about the molecular mechanisms at play during infection in distinct species. Human stimulator of interferon genes (STING) induces an innate immune response through the induction of type I interferons (IFNs), and IFN promotes or suppresses C. burnetii replication, depending on tissue type. Drosophila melanogaster contains a functional STING ortholog (Sting) which activates NF-κB signaling and autophagy. Here, we sought to address the role of D. melanogaster Sting during C. burnetii infection to uncover how Sting regulates C. burnetii infection in flies. We show that Sting-null flies exhibit higher mortality and reduced induction of antimicrobial peptides following C. burnetii infection compared to control flies. Additionally, Sting-null flies induce lower levels of oxidative stress genes during infection, but the provision of N-acetyl-cysteine (NAC) in food rescues Sting-null host survival. Lastly, we find that reactive oxygen species levels during C. burnetii infection are higher in Drosophila S2 cells knocked down for Sting compared to control cells. Our results show that at the host level, NAC provides protection against C. burnetii infection in the absence of Sting, thus establishing a role for Sting in protection against oxidative stress during C. burnetii infection.}, }
@article {pmid38361325, year = {2024}, author = {Angeli, SI and Brown, CS and Holcomb, MA and Velandia, SL and Eshraghi, AA and Chiossone-Kerdel, JA and Hoffer, ME and Sanchez, C and Telischi, FF}, title = {Functional Hearing Preservation in Cochlear Implantation: The Miami Cocktail Effect.}, journal = {Otology &amp; neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology}, volume = {45}, number = {4}, pages = {376-385}, doi = {10.1097/MAO.0000000000004134}, pmid = {38361325}, issn = {1537-4505}, mesh = {Adult ; Humans ; Child ; *Cochlear Implantation/methods ; Case-Control Studies ; Prednisone ; Acetylcysteine ; Retrospective Studies ; Auditory Threshold ; Audiometry, Pure-Tone ; Hearing ; *Cochlear Implants ; Treatment Outcome ; }, abstract = {OBJECTIVE: To investigate if pharmacological treatment with prednisone and L-N-acetylcysteine (STE + NAC) influence functional hearing preservation in cochlear implant (CI) surgery.<br><br>STUDY DESIGNS: Preimplantation and postimplantation longitudinal case-control study.<br><br>SETTING: Tertiary referral center.<br><br>PATIENTS: Pediatric and adult recipients of CI with preimplantation functional hearing defined as an average of air-conducted thresholds at 125, 250, and 500 Hz (low-frequency pure-tone average [LFPTA]) <80 dB.<br><br>INTERVENTIONS: Preimplantation and postimplantation audiometry. Weight-adjusted oral prednisone and L-N-acetylcysteine starting 2 days before surgery (Miami cocktail). Prednisone was continued for 3 days and L-N-acetylcysteine for 12 days after surgery, respectively. Cochlear implantation with conventional length electrodes.<br><br>MAIN OUTCOME MEASURES: Proportion of patients with LFPTA <80 dB, and LFPTA change at 1-year postimplantation.<br><br>RESULTS: All 61 patients received intratympanic and intravenous dexamethasone intraoperatively, with 41 patients receiving STE + NAC and 20 patients not receiving STE + NAC. At 1-year postimplantation, the proportion of functional hearing preservation was 83% in the STE + NAC group compared with 55% of subjects who did not receive STE + NAC (p = 0.0302). The median LFPTA change for STE + NAC-treated and not treated subjects was 8.33 dB (mean, 13.82 &#xb1; 17.4 dB) and 18.34 dB (mean, 26.5 &#xb1; 23.4 dB), respectively (p = 0.0401, Wilcoxon rank test). Perioperative STE + NAC treatment resulted in 10 dB of LFPTA better hearing than when not receiving this treatment. Better low-frequency preimplantation hearing thresholds were predictive of postimplantation functional hearing. No serious side effects were reported.<br><br>CONCLUSION: Perioperative STE + NAC, "The Miami Cocktail," was safe and superior to intraoperative steroids alone in functional hearing preservation 1-year after cochlear implantation.}, }
@article {pmid38359293, year = {2024}, author = {Noch, EK and Palma, L and Yim, I and Bullen, N and Barnett, D and Walsh, A and Bhinder, B and Benedetti, E and Krumsiek, J and Gurvitch, J and Khwaja, S and Atlas, D and Elemento, O and Cantley, LC}, title = {Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {121}, number = {8}, pages = {e2317343121}, pmid = {38359293}, issn = {1091-6490}, support = {R35 CA197588/CA/NCI NIH HHS/United States ; S10 RR027699/RR/NCRR NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; Hydrogen Peroxide ; Peroxides ; *Glioblastoma/drug therapy/genetics/metabolism ; Proteomics ; Acetylcysteine/pharmacology ; Glucose ; Cell Line, Tumor ; *Brain Neoplasms/drug therapy/genetics ; }, abstract = {Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.}, }
@article {pmid38357896, year = {2024}, author = {Mestre-Bach, G and Potenza, MN}, title = {Pharmacological management of gambling disorder: an update of the literature.}, journal = {Expert review of neurotherapeutics}, volume = {24}, number = {4}, pages = {391-407}, doi = {10.1080/14737175.2024.2316833}, pmid = {38357896}, issn = {1744-8360}, mesh = {Humans ; *Gambling/drug therapy ; Naltrexone/therapeutic use ; *Behavior, Addictive/drug therapy/psychology ; Narcotic Antagonists/therapeutic use ; Selective Serotonin Reuptake Inhibitors ; }, abstract = {INTRODUCTION: Gambling disorder (GD) is a mental health condition characterized by persistent and problematic betting behavior. GD generates distress and impairment, and treatment options include psychological and pharmacological interventions.<br><br>AREAS COVERED: This narrative review explores existing pharmacological treatments for GD. The following classes of medications were considered: opioid-receptor antagonists (e.g. naltrexone and nalmefene), serotonin reuptake inhibitors (e.g. fluvoxamine, paroxetine, sertraline, escitalopram, and citalopram), glutamatergic agents (e.g. N-acetylcysteine (NAC), acamprosate, and memantine), mood stabilizers (e.g. topiramate, carbamazepine, lithium), and other medications (e.g. modafinil, nefazodone, olanzapine, haloperidol, tolcapone, and bupropion).<br><br>EXPERT OPINION: Due to the limitations of the studies reviewed, solid conclusions regarding the optimal choice of pharmacotherapy for individuals with GD are challenging to draw at this time. Despite some medications, such as naltrexone and nalmefene, showing promising results, efficacy has varied across studies. The review highlights current gaps/limitations, including small sample sizes, limited diversity in participant demographics, the need for exploring different gambling subtypes and treatment responses, high placebo response rates, lack of longer-term longitudinal information, limited investigation of neurobiological correlates and co-occurring disorders, and the importance of implementation research. Further research is needed to address these gaps and explore additional medications, as well as interventions like neuromodulation.}, }
@article {pmid38357503, year = {2024}, author = {Raas, Q and Wood, A and Stevenson, TJ and Swartwood, S and Liu, S and Kannan, RM and Kannan, S and Bonkowsky, JL}, title = {Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model.}, journal = {Frontiers in pediatrics}, volume = {12}, number = {}, pages = {1326886}, pmid = {38357503}, issn = {2296-2360}, abstract = {BACKGROUND: Mitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults.<br><br>METHODS: We report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts.<br><br>RESULTS: The patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes.<br><br>CONCLUSIONS: We developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.}, }
@article {pmid38354685, year = {2024}, author = {Cheng, C and Li, W and Ye, Y and Zhu, Y and Tang, M and Hu, Z and Su, H and Dang, C and Wan, J and Liu, Z and Gong, Y and Yao, LH}, title = {Lactate induces C2C12 myoblasts differentiation by mediating ROS/p38 MAPK signalling pathway.}, journal = {Tissue &amp; cell}, volume = {87}, number = {}, pages = {102324}, doi = {10.1016/j.tice.2024.102324}, pmid = {38354685}, issn = {1532-3072}, mesh = {Reactive Oxygen Species/metabolism ; *Lactic Acid/metabolism/pharmacology ; Cell Differentiation ; *p38 Mitogen-Activated Protein Kinases/metabolism ; Myoblasts/metabolism ; }, abstract = {Lactate serves not merely as an energy substrate for skeletal muscle but also regulates myogenic differentiation, leading to an elevation of reactive oxygen species (ROS) levels. The present study was focused on exploring the effects of lactate and ROS/p38 MAPK in promoting C2C12 myoblasts differentiation. Our results demonstrated that lactate increased C2C12 myoblasts differentiation at a range of physiological concentrations, accompanied by enhanced ROS contents. We used n-acetylcysteine (NAC, a ROS scavenger) pretreatment and found that it delayed lactate-induced C2C12 myoblast differentiation by upregulating Myf5 expression on days 5 and 7 and lowering MyoD and MyoG expression. The finding implies that lactate accompanies ROS-dependent manner to promote C2C12 myoblast differentiation. Additionally, lactate significantly increased p38 MAPK phosphorylation to promote C2C12 cell differentiation, but pretreatment with SB203580 (p38 MAPK inhibitor) reduced lactate-induced C2C12 myoblasts differentiation. whereas lactate pretreatment with NAC inhibited p38 MAPK phosphorylation in C2C12 cells, demonstrating that lactate mediated ROS and regulated the p38 MAPK signalling pathway to promote C2C12 cell differentiation. In conclusion, our results suggest that the promotion of C2C12 myoblasts differentiation by lactate is dependent on ROS and the p38 MAPK signalling pathway. These observations reveal a beneficial role for lactate in increasing myogenesis through ROS-sensitive mechanisms as well as providing new ideas regarding the positive impact of ROS in improving the function of skeletal muscle.}, }
@article {pmid38347533, year = {2024}, author = {Yang, Y and Wang, L and Huang, Z and Ge, L and Shi, J}, title = {N-acetylcysteine as a novel methacrylate-based resin cement component: effect on cell apoptosis and genotoxicity in human gingival fibroblasts.}, journal = {BMC oral health}, volume = {24}, number = {1}, pages = {222}, pmid = {38347533}, issn = {1472-6831}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Methacrylates/toxicity ; Resin Cements ; Reactive Oxygen Species ; Apoptosis ; DNA/pharmacology ; Fibroblasts ; Cell Survival ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) reduces the cytotoxicity and genotoxicity induced by monomers leached from dental composite resins. Herein, we investigated the effects of methacrylate-based resin cement used in dental implant restoration on apoptosis and genotoxicity, as well as the antiapoptotic and antigenotoxic capabilities of its component, NAC.<br><br>METHODS: The antioxidant NAC (0.1 or 1&#x2009;wt.%) was experimentally incorporated into the methacrylate-based dental resin cement Premier&#xae;. The Premier&#xae;&#x2009;+&#x2009;NAC (0.1 or 1&#x2009;wt.%) mixture was subsequently immersed into Dulbecco's modified Eagle's medium for 72&#x2009;h, and used to treat human gingival fibroblasts (HGFs). The viability of HGFs was determined using the XTT assay. The formation of deoxyribonucleic acid (DNA) double-strand breaks (DNA-DSBs) was determined using a &#x3b3;-H2AX assay. Reactive oxygen species (ROS), apoptosis, necrosis, and cell cycles were detected and analyzed using flow cytometry.<br><br>RESULTS: The eluate of Premier&#xae; significantly inhibited HGF proliferation in vitro by promoting a G1-phase cell cycle arrest, resulting in cell apoptosis. Significant ROS production and DNA-DSB induction were also found in HGFs exposed to the eluate. Incorporating NAC (1&#x2009;wt.%) into Premier&#xae; was found to reduce cell cytotoxicity, the percentage of G1-phase cells, cell apoptosis, ROS production, and DNA-DSB induction.<br><br>CONCLUSION: Incorporating NAC (1&#x2009;wt.%) into methacrylate-based resin cement Premier&#xae; decreases the cell cytotoxicity, ROS production, and DNA-DSBs associated with resin use, and further offers protective effects against the early stages of cell apoptosis and G1-phase cell cycle arrest in HGFs. Overall, our in vitro results indicate that the addition of NAC into methacrylate-based resin cements may have clinically beneficial effects on the cytotoxicity and genotoxicity of these materials.}, }
@article {pmid38340270, year = {2024}, author = {Ali, J and Thompson, M and Mackenzie, C}, title = {Assessing the frequency and types of errors involved in the use of a modified intravenous N-acetylcysteine protocol for acetaminophen overdose.}, journal = {CJEM}, volume = {26}, number = {3}, pages = {174-178}, pmid = {38340270}, issn = {1481-8043}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Acetaminophen/therapeutic use ; Antidotes ; *Drug Overdose/drug therapy/epidemiology ; *Poisons/therapeutic use ; Retrospective Studies ; }, abstract = {BACKGROUND: Acetaminophen overdose is a leading cause of acute liver failure in developing countries. N-acetylcysteine (NAC) is a highly effective antidote for acetaminophen hepatotoxicity, typically initiated in the emergency department. Due to a known high rate of errors with the standard three-bag IV NAC protocol, in 2019, the Ontario Poison Center changed to a modified 3% IV NAC one-bag protocol. This study was undertaken to determine the frequency and types of errors associated with the use of this protocol.<br><br>METHODS: Data were gathered via chart review of Ontario Poison Centre electronic medical record cases identified as receiving IV NAC for acetaminophen overdose between August 1 and September 30, 2022. 218 total charts were identified, and 188 were deemed eligible based on inclusion and exclusion criteria.<br><br>RESULTS: Errors were identified in 25% of charts, consisting of dosing errors in 11.7%, stopping errors in 9.0%, initiation errors in 3.7%, and interruptions in therapy in 3.2%. Dosing errors were the most common type of error (44.4%), with overdoses occurring three times more than underdoses. Errors were identified at 39% of geographic locations in the charts reviewed, with similar frequency in Ontario, Manitoba, and Nunavut. Clinical outcomes were similar in charts with and without errors.<br><br>INTERPRETATION: The rate of errors identified with this 3% IV NAC one-bag protocol is lower than reported for the standard three-bag protocol, but remains high due to dosing errors. Previously reported issues with prolonged interruptions in therapy with the standard three-bag protocol were low with the current 3% one-bag protocol. Although severe outcomes are rare, IV NAC overdose can be fatal. Identifying local factors in emergency departments that can contribute to administration errors (i.e., dose calculation, pump programming issues) can enhance the safety of this important antidote.}, }
@article {pmid38336380, year = {2024}, author = {Sams, MP and Iansavitchous, J and Astridge, M and Rysan, H and Xu, LS and Rodrigues de Oliveira, B and DeKoter, RP}, title = {N-Acetylcysteine Alters Disease Progression and Increases Janus Kinase Mutation Frequency in a Mouse Model of Precursor B-Cell Acute Lymphoblastic Leukemia.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {389}, number = {1}, pages = {40-50}, doi = {10.1124/jpet.123.002000}, pmid = {38336380}, issn = {1521-0103}, mesh = {Child ; Humans ; Mice ; Animals ; Child, Preschool ; Acetylcysteine/pharmacology/therapeutic use ; Janus Kinases ; Mutation Rate ; Reactive Oxygen Species/metabolism ; Precursor Cells, B-Lymphoid/metabolism ; *Drinking Water ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Janus Kinase 1/genetics/metabolism ; Mutation ; Janus Kinase 3/genetics/metabolism ; Disease Progression ; }, abstract = {B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-CreΔPB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence. Treatment of Mb1-CreΔPB mice with NAC in drinking water significantly reduced the frequency of CD19[+] pre-B-ALL cells infiltrating the thymus at 11 weeks of age. However, treatment with NAC did not reduce leukemia progression or increase survival by a median 16 weeks of age. NAC significantly altered gene expression in leukemias in treated mice. Mice treated with NAC had increased frequencies of activating mutations in genes encoding Janus kinases 1 and 3. In particular, frequencies of Jak3 R653H mutations were increased in mice treated with NAC compared with control drinking water. NAC opposed oxidization of PTEN protein ROS in cultured leukemia cells. These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies. SIGNIFICANCE STATEMENT: In a mouse model of precursor B-cell acute lymphoblastic leukemia associated with high levels of reactive oxygen species, treatment with N-acetylcysteine did not delay disease progression but instead selected for leukemic clones with activating R653H mutations in Janus kinase 3.}, }
@article {pmid38335769, year = {2024}, author = {Świętek, M and Marková, I and Malínská, H and Hüttl, M and Miklánková, D and Černá, K and Konefał, R and Horák, D}, title = {Tannic acid- and N-acetylcysteine-chitosan-modified magnetic nanoparticles reduce hepatic oxidative stress in prediabetic rats.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {235}, number = {}, pages = {113791}, doi = {10.1016/j.colsurfb.2024.113791}, pmid = {38335769}, issn = {1873-4367}, mesh = {Rats ; Animals ; Antioxidants/pharmacology/metabolism ; Acetylcysteine/pharmacology ; *Chitosan/pharmacology ; *Magnetite Nanoparticles ; *Prediabetic State/metabolism ; Silicon Dioxide/pharmacology ; Glutathione/metabolism ; Rats, Wistar ; Oxidative Stress ; Liver ; Superoxide Dismutase/metabolism ; *Polyphenols ; }, abstract = {Magnetic nanoparticles (MNPs) modified with tannic acid (TA) have shown remarkable success as an antioxidant and antimicrobial therapeutic agent. Herein, we report a synthetic procedure for the preparation of silica-coated MNPs modified with N-acetylcysteine-modified chitosan and TA. This was achieved by free-radical grafting of NAC onto chitosan (CS), a layer-by-layer technique for modifying negatively charged MNP@SiO2 nanoparticles with positively charged CS-NAC, and crosslinking CS with TA. The antioxidant and metabolic effects of MNP@SiO2-CS-NAC and MNP@SiO2-CS-NAC-TA nanoparticles were tested in a model of prediabetic rats with hepatic steatosis, the hereditary hypertriglyceridemic rats (HHTg). The particles exhibited significant antioxidant properties in the liver, increasing the activity of the antioxidant enzymes superoxide dismutase (SOD), glutathione reductase (GR) and glutathione peroxidase (GPx), decreasing the concentration of the lipoperoxidation product malondialdehyde (MDA), and improving the antioxidant status determined as the ratio of reduced to oxidized glutathione; in particular, TA increased some antioxidant parameters. MNPs carrying antioxidants such as NAC and TA could thus represent a promising therapeutic agent for the treatment of various diseases accompanied by increased oxidative stress.}, }
@article {pmid38330258, year = {2024}, author = {Mao, X and Zhao, G and Wang, Q and He, J and Liu, Y and Liu, T and Li, W and Peng, Y and Zheng, J}, title = {Chelerythrine Chloride is an Affinity-Labeling Inactivator of CYP3A4 by Modification of Cysteine239.}, journal = {Journal of medicinal chemistry}, volume = {67}, number = {4}, pages = {2802-2811}, doi = {10.1021/acs.jmedchem.3c01943}, pmid = {38330258}, issn = {1520-4804}, mesh = {Cytochrome P-450 CYP3A ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; *Alkaloids ; *Antineoplastic Agents ; *Benzophenanthridines ; }, abstract = {Chelerythrine chloride (CHE) is a quaternary benzo[c]phenanthridine alkaloid with an iminium group that was found to cause time- and concentration-dependent inhibition of CYP3A4. The loss of CYP3A4 activity was independent of NADPH. CYP3A4 competitive inhibitor ketoconazole and nucleophile N-acetylcysteine (NAC) slowed the inactivation. No recovery of CYP3A4 activity was observed after dialysis. Dihydrochelerythrine hardly inhibited CYP3A4, suggesting that the iminium group was primarily responsible for the inactivation. UV spectral analysis revealed that the maximal absorbance of CHE produced a significant red-shift after being mixed with NAC, suggesting that 1,2-addition possibly took place between the sulfhydryl group of NAC and iminium group of CHE. Molecular dynamics simulation and site-direct mutagenesis studies demonstrated that modification of Cys239 by the iminium group of CHE attributed to the inactivation. In conclusion, CHE is an affinity-labeling inactivator of CYP3A4. The observed enzyme inactivation resulted from the modification of Cys239 of CYP3A4 by the iminium group of CHE.}, }
@article {pmid38325272, year = {2024}, author = {Tian, T and Pang, H and Li, X and Ma, K and Liu, T and Li, J and Luo, Z and Li, M and Hou, Q and Hao, H and Dong, J and Du, H and Liu, X and Sun, Z and Zhao, C and Song, X and Jin, M}, title = {The role of DRP1 mediated mitophagy in HT22 cells apoptosis induced by silica nanoparticles.}, journal = {Ecotoxicology and environmental safety}, volume = {272}, number = {}, pages = {116050}, doi = {10.1016/j.ecoenv.2024.116050}, pmid = {38325272}, issn = {1090-2414}, mesh = {Adenosine Triphosphate ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; *Dynamins/metabolism ; *Mitophagy ; *Nanoparticles/toxicity ; Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; *Silicon Dioxide/pharmacology ; Superoxide Dismutase/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Animals ; Mice ; Cell Line, Tumor ; }, abstract = {Silica nanoparticles (SiNPs) are widely used in the biomedical field and can enter the central nervous system through the blood-brain barrier, causing damage to hippocampal neurons. However, the specific mechanism remains unclear. In this experiment, HT22 cells were selected as the experimental model in vitro, and the survival rate of cells under the action of SiNPs was detected by MTT method, reactive oxygen species (ROS), lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and adenosine triphosphate (ATP) were tested by the kit, the ultrastructure of the cells was observed by transmission electron microscope, membrane potential (MMP), calcium ion (Ca[2+]) and apoptosis rate were measured by flow cytometry, and the expressions of mitochondrial functional protein, mitochondrial dynein, mitochondrial autophagy protein as well as apoptosis related protein were detected by Western blot. The results showed that cell survival rate, SOD, CAT, GSH-Px, ATP and MMP gradually decreased with the increase of SiNPs concentration, while intracellular ROS, Ca[2+], LDH and apoptosis rate increased with the increase of SiNPs concentration. In total cellular proteins,the expressions of mitochondrial functional proteins VDAC and UCP2 gradually increased, the expression of mitochondrial dynamic related protein DRP1 increased while the expressions of OPA1 and Mfn2 decreased. The expressions of mitophagy related proteins PINK1, Parkin and LC3Ⅱ/LC3Ⅰ increased and P62 gradually decreased, as well as the expressions of apoptosis related proteins Apaf-1, Cleaved-Caspase-3, Caspase-3, Caspase-9, Bax and Cyt-C. In mitochondrial proteins, the expressions of mitochondrial dynamic related proteins DRP1 and p-DRP1 were increased, while the expressions of OPA1 and Mfn2 were decreased. Expressions of mitochondrial autophagy associated proteins PINK1, Parkin, LC3II/LC3I increased, P62 decreased gradually, as well as the expressions of apoptosis related proteins Cleaved-Caspase-3, Caspase-3, and Caspase-9 increased, and Cyt-C expressions decreased. To further demonstrate the role of ROS and DRP1 in HT22 cell apoptosis induced by SiNPs, we selected the ROS inhibitor N-Acetylcysteine (NAC) and Dynamin-related protein 1 (DRP1) inhibitor Mdivi-1. The experimental results indicated that the above effects were remarkably improved after the use of inhibitors, further confirming that SiNPs induce the production of ROS in cells, activate DRP1, cause excessive mitochondrial division, induce mitophagy, destroy mitochondrial function and eventually lead to apoptosis.}, }
@article {pmid38325270, year = {2024}, author = {Xiong, A and He, X and Liu, S and Ran, Q and Zhang, L and Wang, J and Jiang, M and Niu, B and Xiong, Y and Li, G}, title = {Oxidative stress-mediated activation of FTO exacerbates impairment of the epithelial barrier by up-regulating IKBKB via N6-methyladenosine-dependent mRNA stability in asthmatic mice exposed to PM2.5.}, journal = {Ecotoxicology and environmental safety}, volume = {272}, number = {}, pages = {116067}, doi = {10.1016/j.ecoenv.2024.116067}, pmid = {38325270}, issn = {1090-2414}, mesh = {Animals ; Mice ; *Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics/metabolism ; *Asthma/chemically induced/genetics ; *I-kappa B Kinase/metabolism ; Obesity ; Oxidative Stress/genetics ; Particulate Matter/toxicity ; RNA Stability ; RNA, Messenger/metabolism ; }, abstract = {In order to comprehend the underlying mechanisms contributing to the development and exacerbation of asthma resulting from exposure to fine particulate matter (PM2.5), we established an asthmatic model in fat mass and obesity-associated gene knockdown mice subjected to PM2.5 exposure. Histological analyses using hematoxylin-eosin (HE) and Periodic Acid-Schiff (PAS) staining revealed that the down-regulation of the fat mass and obesity-associated gene (Fto) expression significantly ameliorated the pathophysiological alterations observed in asthmatic mice exposed to PM2.5. Furthermore, the down-regulation of Fto gene expression effectively attenuated damage to the airway epithelial barrier. Additionally, employing in vivo and in vitro models, we elucidated that PM2.5 modulated FTO expression by inducing oxidative stress. Asthmatic mice exposed to PM2.5 exhibited elevated Fto expression, which correlated with increased levels of reactive oxygen species. Similarly, when cells were exposed to PM2.5, FTO expression was up-regulated in a ROS-dependent manner. Notably, the administration of N-acetyl cysteine successfully reversed the PM2.5-induced elevation in FTO expression. Concurrently, we performed transcriptome-wide Methylated RNA immunoprecipitation Sequencing (MeRIP-seq) analysis subsequent to PM2.5 exposure. Through the implementation of Gene Set Enrichment Analysis and m6A-IP-qPCR, we successfully identified inhibitor of nuclear factor kappa B kinase subunit beta (IKBKB) as a target gene regulated by FTO. Interestingly, exposure to PM2.5 led to increased expression of IKBKB, while m6A modification on IKBKB mRNA was reduced. Furthermore, our investigation revealed that PM2.5 also regulated IKBKB through oxidative stress. Significantly, the down-regulation of IKBKB effectively mitigated epithelial barrier damage in cells exposed to PM2.5 by modulating nuclear factor-kappa B (NF-κB) signaling. Importantly, we discovered that decreased m6A modification on IKBKB mRNA facilitated by FTO enhanced its stability, consequently resulting in up-regulation of IKBKB expression. Collectively, our findings propose a novel role for FTO in the regulation of IKBKB through m6A-dependent mRNA stability in the context of PM2.5-induced oxidative stress. Therefore, it is conceivable that the utilization of antioxidants or inhibition of FTO could represent potential therapeutic strategies for the management of asthma exacerbated by PM2.5 exposure.}, }
@article {pmid38323079, year = {2024}, author = {Hashmi, HZ and Khowaja, A and Moheet, A}, title = {Experimental pharmacological approaches to reverse impaired awareness of hypoglycemia-a review.}, journal = {Frontiers in pharmacology}, volume = {15}, number = {}, pages = {1349004}, pmid = {38323079}, issn = {1663-9812}, abstract = {The colossal global burden of diabetes management is compounded by the serious complication of hypoglycemia. Protective physiologic hormonal and neurogenic counterregulatory responses to hypoglycemia are essential to preserve glucose homeostasis and avert serious morbidity. With recurrent exposure to hypoglycemic episodes over time, these counterregulatory responses to hypoglycemia can diminish, resulting in an impaired awareness of hypoglycemia (IAH). IAH is characterized by sudden neuroglycopenia rather than preceding cautionary autonomic symptoms. IAH increases the risk of subsequent sudden and severe hypoglycemic episodes in patients with diabetes. The postulated causative mechanisms behind IAH are complex and varied. It is therefore challenging to identify a single effective therapeutic strategy. In this review, we closely examine the efficacy and feasibility of a myriad of pharmaceutical interventions in preventing and treating IAH as described in clinical and preclinical studies. Pharmaceutical agents outlined include N-acetyl cysteine, GABA A receptor blockers, opioid receptor antagonists, AMP activated protein kinase agonists, potassium channel openers, dehydroepiandrosterone, metoclopramide, antiadrenergic agents, antidiabetic agents and glucagon.}, }
@article {pmid38318818, year = {2024}, author = {Liu, J and Li, SM and Tang, YJ and Cao, JL and Hou, WS and Wang, AQ and Wang, C and Jin, CH}, title = {Jaceosidin induces apoptosis and inhibits migration in AGS gastric cancer cells by regulating ROS-mediated signaling pathways.}, journal = {Redox report : communications in free radical research}, volume = {29}, number = {1}, pages = {2313366}, pmid = {38318818}, issn = {1743-2928}, mesh = {Humans ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Flavonoids/pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Stomach Neoplasms/drug therapy/metabolism/pathology ; }, abstract = {Jaceosidin (JAC) is a natural flavonoid with anti-oxidant and other pharmacological activities; however, its anti-cancer mechanism remains unclear. We investigated the mechanism of action of JAC in gastric cancer cells. Cytotoxicity and apoptosis assays showed that JAC effectively killed multiple gastric cancer cells and induced apoptosis in human gastric adenocarcinoma AGS cells via the mitochondrial pathway. Network pharmacological analysis suggested that its activity was linked to reactive oxygen species (ROS), AKT, and MAPK signaling pathways. Furthermore, JAC accumulated ROS to up-regulate p-JNK, p-p38, and IκB-α protein expressions and down-regulate the p-ERK, p-STAT3, and NF-κB protein expressions. Cell cycle assay results showed that JAC accumulated ROS to up-regulate p21 and p27 protein expressions and down-regulate p-AKT, CDK2, CDK4, CDK6, Cyclin D1, and Cyclin E protein expressions to induce G0/G1 phase arrest. Cell migration assay results showed JAC accumulated ROS to down-regulate Wnt-3a, p-GSK-3β, N-cadherin, and β-catenin protein expressions and up-regulate E-cadherin protein expression to inhibit migration. Furthermore, N-acetyl cysteine pre-treatment prevented the change of these protein expressions. In summary, JAC induced apoptosis and G0/G1 phase arrest and inhibited migration through ROS-mediated signaling pathways in AGS cells.}, }
@article {pmid38318025, year = {2024}, author = {Liu, TH and Wu, JY and Huang, PY and Tsai, YW and Hsu, WH and Chuang, MH and Tang, HJ and Lai, CC}, title = {Clinical efficacy of N-acetylcysteine for COVID-19: A systematic review and meta-analysis of randomized controlled trials.}, journal = {Heliyon}, volume = {10}, number = {3}, pages = {e25179}, pmid = {38318025}, issn = {2405-8440}, abstract = {BACKGROUND: The association between N-acetylcysteine (NAC) and COVID-19 remains undetermined; therefore, this meta-analysis assessed the clinical efficacy of NAC in the treatment of patients with COVID-19.<br><br>METHODS: This study searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for studies published from their inception to December 17, 2022. Only randomized controlled trials (RCTs) that assessed the clinical efficacy of NAC for patients with COVID-19 were included.<br><br>RESULTS: Five RCTs involving 651 patients were included. There was no significant difference in mortality between the study group receiving NAC and the control group (15.6&#xa0;% [50/320] vs. 32.3&#xa0;%, [107/331]; risk ratio [RR]: 0.58; 95&#xa0;% confidence interval [CI]: 0.24-1.40). In addition, the two groups did not differ with respect to the incidence of invasive mechanical ventilation (RR: 0.93; 95&#xa0;% CI: 0.65-1.33), the risk of intensive care unit (ICU) admission (RR: 0.86; 95&#xa0;% CI: 0.62-1.21), the length of hospital stay (mean difference [MD]: 0.17 days; 95&#xa0;% CI: -0.67-1.01), and the length of ICU stay (MD: -0.77 days; 95&#xa0;% CI: -2.97-1.42).<br><br>CONCLUSIONS: The administration of NAC did not improve the clinical outcomes of patients with COVID-19; its routine use is not recommended for patients with SARS-CoV-2 infections.}, }
@article {pmid38317753, year = {2024}, author = {Jerome, RN and Zahn, LA and Abner, JJ and Joly, MM and Shirey-Rice, JK and Wallis, RS and Bernard, GR and Pulley, JM}, title = {Repurposing N-acetylcysteine for management of non-acetaminophen induced acute liver failure: an evidence scan from a global health perspective.}, journal = {Translational gastroenterology and hepatology}, volume = {9}, number = {}, pages = {2}, pmid = {38317753}, issn = {2415-1289}, support = {UL1 TR002243/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: The World Health Organization (WHO)'s Essential Medicines List (EML) plays an important role in advocating for access to key treatments for conditions affecting people in all geographic settings. We applied our established drug repurposing methods to one EML agent, N-acetylcysteine (NAC), to identify additional uses of relevance to the global health community beyond its existing EML indication (acetaminophen toxicity).<br><br>METHODS: We undertook a phenome-wide association study (PheWAS) of a variant in the glutathione synthetase (GSS) gene in approximately 35,000 patients to explore novel indications for use of NAC, which targets glutathione. We then evaluated the evidence regarding biologic plausibility, efficacy, and safety of NAC use in the new phenotype candidates.<br><br>RESULTS: PheWAS of GSS variant R418Q revealed increased risk of several phenotypes related to non-acetaminophen induced acute liver failure (ALF), indicating that NAC may represent a therapeutic option for treating this condition. Evidence review identified practice guidelines, systematic reviews, clinical trials, retrospective cohorts and case series, and case reports. This evidence suggesting benefit of NAC use in this subset of ALF patients. The safety profile of NAC in this literature was also concordant with existing evidence on safety of this agent in acetaminophen-induced ALF.<br><br>CONCLUSIONS: This body of literature indicates efficacy and safety of NAC in non-acetaminophen induced ALF. Given the presence of NAC on the EML, this medication is likely to be available across a range of resource settings; promulgating its use in this novel subset of ALF can provide healthcare professionals and patients with a valuable and safe complement to supportive care for this disease.}, }
@article {pmid38315254, year = {2024}, author = {Rodrigues, JP and da Costa Silva, JR and Ferreira, BA and Veloso, LI and Quirino, LS and Rosa, RR and Barbosa, MC and Rodrigues, CM and Gaspari, PBF and Beletti, ME and Goulart, LR and Corrêa, NCR}, title = {Development of collagenous scaffolds for wound healing: characterization and in vivo analysis.}, journal = {Journal of materials science. Materials in medicine}, volume = {35}, number = {1}, pages = {12}, pmid = {38315254}, issn = {1573-4838}, mesh = {Animals ; Mice ; *Acetylcysteine ; *Anti-Infective Agents/pharmacology ; Biocompatible Materials/chemistry ; *Chitosan/chemistry ; Collagen/chemistry ; Tissue Scaffolds/chemistry ; Wound Healing ; Polylysine/chemistry ; }, abstract = {The development of wound dressings from biomaterials has been the subject of research due to their unique structural and functional characteristics. Proteins from animal origin, such as collagen and chitosan, act as promising materials for applications in injuries and chronic wounds, functioning as a repairing agent. This study aims to evaluate in vitro effects of scaffolds with different formulations containing bioactive compounds such as collagen, chitosan, N-acetylcysteine (NAC) and ε-poly-lysine (ε-PL). We manufactured a scaffold made of a collagen hydrogel bioconjugated with chitosan by crosslinking and addition of NAC and ε-PL. Cell viability was verified by resazurin and live/dead assays and the ultrastructure of biomaterials was evaluated by SEM. Antimicrobial sensitivity was assessed by antibiogram. The healing potential of the biomaterial was evaluated in vivo, in a model of healing of excisional wounds in mice. On the 7th day after the injury, the wounds and surrounding skin were processed for evaluation of biochemical and histological parameters associated with the inflammatory process. The results showed great cell viability and increase in porosity after crosslinking while antimicrobial action was observed in scaffolds containing NAC and ε-PL. Chitosan scaffolds bioconjugated with NAC/ε-PL showed improvement in tissue healing, with reduced lesion size and reduced inflammation. It is concluded that scaffolds crosslinked with chitosan-NAC-ε-PL have the desirable characteristics for tissue repair at low cost and could be considered promising biomaterials in the practice of regenerative medicine.}, }
@article {pmid38314899, year = {2024}, author = {Li, L and Chen, D and Lin, X and Luo, J and Tan, J and Ding, D and Li, P}, title = {Antioxidative Stress-Induced Destruction to Cochlear Cells Caused by Blind Antioxidant Therapy.}, journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery}, volume = {170}, number = {5}, pages = {1421-1429}, doi = {10.1002/ohn.659}, pmid = {38314899}, issn = {1097-6817}, mesh = {*Antioxidants/pharmacology ; *Acetylcysteine/pharmacology ; *Ubiquinone/*analogs &amp; derivatives/pharmacology/therapeutic use ; *Cell Survival/drug effects ; Animals ; *Apoptosis/drug effects ; *Oxidative Stress/drug effects ; Mice ; Cochlea/drug effects/pathology ; Hair Cells, Auditory/drug effects/pathology ; Cell Count ; *Oligopeptides ; }, abstract = {OBJECTIVE: Verification that blind and excessive use of antioxidants leads to antioxidant stress which exacerbates cochlear cell damage.<br><br>STUDY DESIGN: Basic research.<br><br>SETTING: The Third Affiliated Hospital of Sun Yat-Sen University.<br><br>METHODS: We compared and quantified hair cell-like house ear institute-organ of corti 1 (HEI-OC1) cell density, cell viability, and apoptosis caused by different concentrations of N-acetylcysteine&#xa0;(NAC) via Hoechst staining, Cell Counting Kit 8, Hoechst with propidium iodide staining, and Annexin V with propidium iodide (PI) staining. Apoptosis induced by high concentrations of M40403 and coenzyme Q10 in cochlear explants was analyzed and compared by cochlear dissection and activated caspase 3 labeling.<br><br>RESULTS: With the increase of NAC concentration (0-1000&#x2009;&#x3bc;mol/L), cell density decreased consequently and reached the lowest at 1000&#x2009;&#x3bc;mol/L (****P&#x2009;&#x2264;&#x2009;.0001). Cell viability is also declining (**P&#x2009;<&#x2009;.01). The number of Annexin V-fluorescein isothiocyanate-labeled cells and PI-labeled cells increased with increasing NAC concentration after treatment of HEI-OC1 cells for 48&#x2009;hours. The proportion of apoptotic cells also rose (*P&#x2009;<&#x2009;.05, **P&#x2009;<&#x2009;.01). Cochlear hair cells (HCs) treated with low concentrations of M40403 and coenzyme Q10 for 48&#x2009;hours showed no damage. When the concentrations of M40403 and coenzyme Q10 were increased (concentrations&#xff1e;30&#x2009;&#x3bc;mol/L), HC damage began, followed by a dose-dependent increase in HC loss (*P&#x2009;<&#x2009;.001, **P&#x2009;<&#x2009;.0001). Activated caspase-3 was clearly apparent in cochlear explants treated with 50&#x2009;&#x3bc;mol/L M40403 and coenzyme Q10 compared with cochlear explants without added M40403 and coenzyme Q10.<br><br>CONCLUSION: These experimental results suggest that inappropriate application of antioxidants can cause severe damage to normal cochlear HCs.}, }
@article {pmid38309383, year = {2024}, author = {La Sala, L and Carlini, V and Conte, C and Macas-Granizo, MB and Afzalpour, E and Martin-Delgado, J and D'Anzeo, M and Pedretti, RFE and Naselli, A and Pontiroli, AE and Cappato, R}, title = {Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?.}, journal = {Pharmacological research}, volume = {201}, number = {}, pages = {107083}, doi = {10.1016/j.phrs.2024.107083}, pmid = {38309383}, issn = {1096-1186}, mesh = {Humans ; *MicroRNAs/genetics/therapeutic use ; *Non-alcoholic Fatty Liver Disease/drug therapy/genetics ; *Diabetes Mellitus, Type 2/drug therapy/genetics ; *Metabolic Diseases/drug therapy/genetics ; *Heart Diseases ; Oligonucleotides, Antisense/therapeutic use ; }, abstract = {Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.}, }
@article {pmid38305139, year = {2024}, author = {Frasson, I and Diamante, L and Zangrossi, M and Carbognin, E and Dalla Pietà, A and Penna, A and Rosato, A and Verin, R and Torrigiani, F and Salata, C and Dizanzo, MP and Vaccaro, L and Cacchiarelli, D and Richter, SN and Montagner, M and Martello, G}, title = {Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern.}, journal = {Journal of molecular cell biology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jmcb/mjae004}, pmid = {38305139}, issn = {1759-4685}, abstract = {The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants, some of which are resistant to vaccines and drugs targeting viral elements. Targeting host dependency factors, e.g. cellular proteins required for viral replication, would help prevent resistance. However, it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host factors. To this end, we compared three variants of concern and found that the host transcriptional response was conserved, differing only in kinetics and magnitude. Through CRISPR screening, we identified host genes required for infection by each variant. Most of the genes were shared by multiple variants. We validated our hits with small molecules and repurposed Food and Drug Administration-approved drugs. All the drugs were highly active against all the variants tested, including new variants that emerged during the study (Delta and Omicron). Mechanistically, we identified reactive oxygen species production as a key step in early virus replication. Antioxidants such as N-acetyl cysteine (NAC) were effective against all the variants in both human lung cells and a humanised mouse model. Our study supports the use of available antioxidant drugs, such as NAC, as a general and effective anti-COVID-19 approach.}, }
@article {pmid38304461, year = {2023}, author = {Balmuri, SR and Noaman, S and Usman, H and Niepa, THR}, title = {Altering the interfacial rheology of Pseudomonas aeruginosa and Staphylococcus aureus with N-acetyl cysteine and cysteamine.}, journal = {Frontiers in cellular and infection microbiology}, volume = {13}, number = {}, pages = {1338477}, pmid = {38304461}, issn = {2235-2988}, mesh = {Humans ; Acetylcysteine/pharmacology/metabolism ; *Cystic Fibrosis/complications/microbiology ; Staphylococcus aureus ; Pseudomonas aeruginosa ; Cysteamine/pharmacology/metabolism ; *Staphylococcal Infections/microbiology ; Anti-Bacterial Agents/pharmacology ; Biofilms ; Lung ; *Pseudomonas Infections/microbiology ; *Cysts ; }, abstract = {INTRODUCTION: Chronic lung infection due to bacterial biofilms is one of the leading causes of mortality in cystic fibrosis (CF) patients. Among many species colonizing the lung airways, Pseudomonas aeruginosa and Staphylococcus aureus are two virulent pathogens involved in mechanically robust biofilms that are difficult to eradicate using airway clearance techniques like lung lavage. To remove such biological materials, glycoside hydrolase-based compounds are commonly employed for targeting and breaking down the biofilm matrix, and subsequently increasing cell susceptibility to antibiotics.<br><br>MATERIALS AND METHODS: In this study, we evaluate the effects of N-acetyl cysteine (NAC) and Cysteamine (CYST) in disrupting interfacial bacterial films, targeting different components of the extracellular polymeric substances (EPS). We characterize the mechanics and structural integrity of the interfacial bacterial films using pendant drop elastometry and scanning electron microscopy.<br><br>RESULTS AND DISCUSSION: Our results show that the film architectures are compromised by treatment with disrupting agents for 6 h, which reduces film elasticity significantly. These effects are profound in the wild type and mucoid P. aeruginosa, compared to S. aureus. We further assess the effects of competition and cooperation between S. aureus and P. aeruginosa on the mechanics of composite interfacial films. Films of S. aureus and wild-type P. aeruginosa cocultures lose mechanical strength while those of S. aureus and mucoid P. aeruginosa exhibit improved storage modulus. Treatment with NAC and CYST reduces the elastic property of both composite films, owing to the drugs' ability to disintegrate their EPS matrix. Overall, our results provide new insights into methods for assessing the efficacy of mucolytic agents against interfacial biofilms relevant to cystic fibrosis infection.}, }
@article {pmid38299014, year = {2024}, author = {Vedaei, F and Newberg, AB and Alizadeh, M and Zabrecky, G and Navarreto, E and Hriso, C and Wintering, N and Mohamed, FB and Monti, D}, title = {Treatment effects of N-acetyl cysteine on resting-state functional MRI and cognitive performance in patients with chronic mild traumatic brain injury: a longitudinal study.}, journal = {Frontiers in neurology}, volume = {15}, number = {}, pages = {1282198}, pmid = {38299014}, issn = {1664-2295}, abstract = {Mild traumatic brain injury (mTBI) is a significant public health concern, specially characterized by a complex pattern of abnormal neural activity and functional connectivity. It is often associated with a broad spectrum of short-term and long-term cognitive and behavioral symptoms including memory dysfunction, headache, and balance difficulties. Furthermore, there is evidence that oxidative stress significantly contributes to these symptoms and neurophysiological changes. The purpose of this study was to assess the effect of N-acetylcysteine (NAC) on brain function and chronic symptoms in mTBI patients. Fifty patients diagnosed with chronic mTBI participated in this study. They were categorized into two groups including controls (CN, n = 25), and patients receiving treatment with N-acetyl cysteine (NAC, n = 25). NAC group received 50 mg/kg intravenous (IV) medication once a day per week. In the rest of the week, they took one 500 mg NAC tablet twice per day. Each patient underwent rs-fMRI scanning at two timepoints including the baseline and 3 months later at follow-up, while the NAC group received a combination of oral and IV NAC over that time. Three rs-fMRI metrics were measured including fractional amplitude of low frequency fluctuations (fALFF), degree centrality (DC), and functional connectivity strength (FCS). Neuropsychological tests were also assessed at the same day of scanning for each patient. The alteration of rs-fMRI metrics and cognitive scores were measured over 3 months treatment with NAC. Then, the correlation analysis was executed to estimate the association of rs-fMRI measurements and cognitive performance over 3 months (p < 0.05). Two significant group-by-time effects demonstrated the changes of rs-fMRI metrics particularly in the regions located in the default mode network (DMN), sensorimotor network, and emotional circuits that were significantly correlated with cognitive function recovery over 3 months treatment with NAC (p < 0.05). NAC appears to modulate neural activity and functional connectivity in specific brain networks, and these changes could account for clinical improvement. This study confirmed the short-term therapeutic efficacy of NAC in chronic mTBI patients that may contribute to understanding of neurophysiological effects of NAC in mTBI. These findings encourage further research on long-term neurobehavioral assessment of NAC assisting development of therapeutic plans in mTBI.}, }
@article {pmid38294834, year = {2024}, author = {Feng, R and Fan, Y and Zhang, X and Chen, L and Zhong, ZF and Wang, Y and Yu, H and Zhang, QW and Li, G}, title = {A Biomimetic Multifunctional Nanoframework for Symptom Relief and Restorative Treatment of Acute Liver Failure.}, journal = {ACS nano}, volume = {18}, number = {7}, pages = {5951-5964}, pmid = {38294834}, issn = {1936-086X}, abstract = {Acute liver failure (ALF) is a rare and serious condition characterized by major hepatocyte death and liver dysfunction. Owing to the limited therapeutic options, this disease generally has a poor prognosis and a high mortality rate. When ALF cannot be reversed by medications, liver transplantation is often needed. However, transplant rejection and the shortage of donor organs still remain major challenges. Most recently, stem cell therapy has emerged as a promising alternative for the treatment of liver diseases. However, the limited cell delivery routes and poor stability of live cell products have greatly hindered the feasibility and therapeutic efficacy of stem cell therapy. Inspired by the functions of mesenchymal stem cells (MSCs) primarily through the secretion of several factors, we developed an MSC-inspired biomimetic multifunctional nanoframework (MBN) that encapsulates the growth-promoting factors secreted by MSCs via combination with hydrophilic or hydrophobic drugs. The red blood cell (RBC) membrane was coated with the MBN to enhance its immunological tolerance and prolong its circulation time in blood. Importantly, the MBN can respond to the oxidative microenvironment, where it accumulates and degrades to release the payload. In this work, two biomimetic nanoparticles, namely, rhein-encapsulated MBN (RMBN) and N-acetylcysteine (NAC)-encapsulated MBN (NMBN), were designed and synthesized. In lipopolysaccharide (LPS)/d-galactosamine (D-GalN)-induced and acetaminophen (APAP)-induced ALF mouse models, RMBN and NMBN could effectively target liver lesions, relieve the acute symptoms of ALF, and promote liver cell regeneration by virtue of their strong antioxidative, anti-inflammatory, and regenerative activities. This study demonstrated the feasibility of the use of an MSC-inspired biomimetic nanoframework for treating ALF.}, }
@article {pmid38291912, year = {2024}, author = {Akakpo, JY and Olivos, H and Shrestha, B and Midey, A and Jaeschke, H and Ramachandran, A}, title = {Spatial analysis of renal acetaminophen metabolism and its modulation by 4-methylpyrazole with DESI mass spectrometry imaging.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {198}, number = {2}, pages = {328-346}, pmid = {38291912}, issn = {1096-0929}, support = {R01 DK102142/DK/NIDDK NIH HHS/United States ; TL1 TR002368/TR/NCATS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; Acetaminophen/toxicity/metabolism ; Fomepizole/therapeutic use ; Glutathione/metabolism ; Mice, Inbred C57BL ; Kidney/metabolism ; Mass Spectrometry ; Spatial Analysis ; *Acute Kidney Injury/chemically induced ; *Chemical and Drug Induced Liver Injury/drug therapy ; }, abstract = {Acute kidney injury (AKI) is a common complication in acetaminophen (APAP) overdose patients and can negatively impact prognosis. Unfortunately, N-acetylcysteine, which is the standard of care for the treatment of APAP hepatotoxicity does not prevent APAP-induced AKI. We have previously demonstrated the renal metabolism of APAP and identified fomepizole (4-methylpyrazole, 4MP) as a therapeutic option to prevent APAP-induced nephrotoxicity. However, the kidney has several functionally distinct regions, and the dose-dependent effects of APAP on renal response and regional specificity of APAP metabolism are unknown. These aspects were examined in this study using C57BL/6J mice treated with 300-1200 mg/kg APAP and mass spectrometry imaging (MSI) to provide spatial cues relevant to APAP metabolism and the effects of 4MP. We find that renal APAP metabolism and generation of the nonoxidative (APAP-GLUC and APAP-SULF) and oxidative metabolites (APAP-GSH, APAP-CYS, and APAP-NAC) were dose-dependently increased in the kidney. This was recapitulated on MSI which revealed that APAP overdose causes an accumulation of APAP and APAP GLUC in the inner medulla and APAP-CYS in the outer medulla of the kidney. APAP-GSH, APAP-NAC, and APAP-SULF were localized mainly to the outer medulla and the cortex where CYP2E1 expression was evident. Interestingly, APAP also induced a redistribution of reduced GSH, with an increase in oxidized GSH within the kidney cortex. 4MP ameliorated these region-specific variations in the formation of APAP metabolites in renal tissue sections. In conclusion, APAP metabolism has a distinct regional distribution within the kidney, the understanding of which provides insight into downstream mechanisms of APAP-induced nephrotoxicity.}, }
@article {pmid38290605, year = {2024}, author = {He, J and Ma, Y and Niu, X and Pei, J and Yan, R and Xu, F and Ma, J and Ma, X and Jia, S and Ma, W}, title = {Silver nanoparticles induce endothelial cytotoxicity through ROS-mediated mitochondria-lysosome damage and autophagy perturbation: The protective role of N-acetylcysteine.}, journal = {Toxicology}, volume = {502}, number = {}, pages = {153734}, doi = {10.1016/j.tox.2024.153734}, pmid = {38290605}, issn = {1879-3185}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Silver/toxicity ; *Metal Nanoparticles/toxicity ; Autophagy ; Human Umbilical Vein Endothelial Cells ; Lysosomes/metabolism ; Mitochondria/metabolism ; Cell Survival ; }, abstract = {Silver nanoparticles (AgNPs) are used increasingly often in the biomedical field, but their potential deleterious effects on the cardiovascular system remain to be elucidated. The primary aim of this study was to evaluate the toxic effects, and the underlying mechanisms of these effects, of AgNPs on human umbilical vein endothelial cells (HUVECs), as well as the protective role of N-acetylcysteine (NAC) against cytotoxicity induced by AgNPs. In this study, we found that exposure to AgNPs affects the morphology and function of endothelial cells which manifests as decreased cell proliferation, migration, and angiogenesis ability. Mechanistically, AgNPs can induce excessive cellular production of reactive oxygen species (ROS), leading to damage to cellular sub-organs such as mitochondria and lysosomes. More importantly, our data suggest that AgNPs causes autophagy defect, inhibits mitophagy, and finally activates the mitochondria-mediated apoptosis signaling pathway and evokes cell death. Interestingly, treatment with ROS scavenger-NAC can effectively suppress AgNP-induced endothelial damage.Our results indicate that ROS-mediated mitochondria-lysosome injury and autophagy dysfunction are potential factors of endothelial toxicity induced by AgNPs. This study may provide new evidence for the cardiovascular toxicity of AgNPs and serve as a reference for the safe use of nanoparticles(NPs) in the future.}, }
@article {pmid38290315, year = {2024}, author = {Li, L and Xu, H and Wang, Y and Zhang, Y and Ye, R and Li, W and Yang, J and Wu, J and Li, J and Jin, E and Cao, M and Li, X and Li, S and Liu, C}, title = {From inflammation to pyroptosis: Understanding the consequences of cadmium exposure in chicken liver cells.}, journal = {Ecotoxicology and environmental safety}, volume = {272}, number = {}, pages = {116004}, doi = {10.1016/j.ecoenv.2024.116004}, pmid = {38290315}, issn = {1090-2414}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Inflammasomes/metabolism ; Pyroptosis ; Cadmium/toxicity ; Chickens/metabolism ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2 ; *Chemical and Drug Induced Liver Injury, Chronic ; Inflammation/chemically induced ; }, abstract = {Hepatotoxicity is frequently observed following acute cadmium (Cd) exposure in chicken. Oxidative stress and subsequent inflammation are regarded as the main reasons for cadmium-induced liver injury. NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome-induced pyroptosis is involved in various inflammatory diseases, including liver injury. Poultry are more susceptible to harmful effects of heavy metals. However, the mechanism of cadmium-induced liver injury in chicken is still elusive. In this study, the effect of cadmium on chicken liver cells and the underlying mechanisms were investigated. The results showed mitochondria was damaged and excessive reactive oxygen species (ROS) were generated in chicken liver cell line LMH after cadmium exposure. Furthermore, cadmium-induced NLRP3 inflammasome activation and the cell membrane rupture indicated LMH cells pyroptosis. The ROS scavengers, acetylcysteine (NAC) and Mito-TEMPO prevented pyroptosis in LMH cells, suggesting that ROS were responsible for the activation of the NLRP3 inflammasome induced by cadmium. Additionally, anti-oxidative transcription factor Nrf2 was inhibited after cadmium exposure, explaining the excessive ROS generation. In summary, our study showed that cadmium leads to ROS generation by inducing mitochondrial damage and inhibiting Nrf2 activity, which promotes NLRP3 inflammasome activation and eventually induces pyroptosis in LMH cells.}, }
@article {pmid38288173, year = {2023}, author = {Shuka, N and Hasimi, E and Kristo, A and Simoni, L and Gishto, T and Shirka, E and Zaimi Petrela, E and Goda, A}, title = {Contrast-Induced Nephropathy in Interventional Cardiology: Incidence, Risk Factors, and Identification of High-Risk Patients.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51283}, pmid = {38288173}, issn = {2168-8184}, abstract = {AIM: This study aimed to study contrast-induced nephropathy (CIN) or more recent nomenclature contrast-associated acute kidney injury (CI-AKI) in patients undergoing percutaneous coronary procedures, evaluating CIN incidence, risk factors (RFs), and high-risk patients with CIN. Methods: This is a prospective, observational, unicentric trial of patients who underwent coronary angiography and/or percutaneous coronary intervention (PCI) in the University Hospital Center (UHC) "Mother Teresa" in Tirana, Albania, during 2016-2018. CIN was defined as an increase of 25% and/or by 0.5 mg/dL of serum creatinine (SCr) and high-risk patients with CIN as an increase by 50% and/or by 2 mg/dL and/or need for dialysis compared to the basal pre-procedural values. We evaluated RFs for CIN: preexisting renal lesion (PRL), heart failure (HF), age, diabetes mellitus (DM), anemia, and contrast quantity. Results: The incidence of CIN resulted in 14.4%. HF, PRL, and age ≥65 years resulted in independent RFs for CIN, whereas anemia, DM, and contrast quantity >100 mL did not. PRL proved to be the most important RF for CIN, whereas HF was the only independent RF for high-risk CIN patients.<br><br>CONCLUSIONS: The incidence of CIN coincides with the results in the literature. PRL, HF, and age &#x2265;65 years resulted in independent RFs for CIN; more and larger trials are needed to evaluate DM, anemia, and contrast quantity related to their impact on CIN. High-risk patients with CIN represent the most problematic patients of this pathology.}, }
@article {pmid38287817, year = {2024}, author = {Patil, K and Khan, AQ and Ahmad, F and Kuttikrishnan, S and Anver, R and Mateo, JM and Ahmad, A and Bhat, AA and Buddenkotte, J and Steinhoff, M and Uddin, S}, title = {Sanguinarine Triggers Apoptosis in Cutaneous Squamous Cell Carcinoma Cells through Reactive Oxygen Species-Dependent c-Jun N-Terminal Kinase Signaling Pathway.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {29}, number = {1}, pages = {40}, doi = {10.31083/j.fbl2901040}, pmid = {38287817}, issn = {2768-6698}, support = {MRC-01-23-065//Medical Research Center, Hamad Medical Corporation/ ; }, mesh = {Humans ; Reactive Oxygen Species/metabolism ; Benzophenanthridines/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Carcinoma, Squamous Cell/drug therapy ; *Skin Neoplasms/drug therapy ; Signal Transduction ; Apoptosis ; MAP Kinase Signaling System ; Cell Line, Tumor ; *Anthracenes ; *Isoquinolines ; }, abstract = {BACKGROUND: The benzophenanthridine Sanguinarine (Sng) is one of the most abundant root alkaloids with a long history of investigation and pharmaceutical applications. The cytotoxicity of Sng against various tumor cells is well-established; however, its antiproliferative and apoptotic potential against the cutaneous squamous cell carcinoma (cSCC) cells remains unknown. In the present study, we investigated the anti-cancer potential of Sng against cSCC cells and elucidated the underlying mechanisms relevant to the drug action.<br><br>METHODS: The inhibitory effect of Sng on cSCC cells was evaluated by analyzing cell viability, colony-forming ability and multi-caspase activity. Apoptosis was quantified through Annexin-V/Propidium iodide flow cytometric assay and antagonized by pan-caspase inhibitor z-VAD-FMK. Mitochondrial membrane potential (&#x394;&#x3a8;m) dysfunction was analyzed by JC-1 staining, whereas reactive oxygen species (ROS) generation was confirmed by pretreatment with N-acetylcysteine (NAC) and fluorogenic probe-based flow cytometric detection. The expression of cell cycle regulatory proteins, apoptotic proteins and MAPK signaling molecules was determined by Western blotting. Involvement of JNK, p38-MAPK and MEK/ERK in ROS-mediated apoptosis was investigated by pretreatment with SP600125 (JNK inhibitor), SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor), respectively. The stemness-targeting potential of Sng was assessed in tumor cell-derived spheroids.<br><br>RESULTS: Treatment with Sng decreased cell viability and colony formation in primary (A431) and metastatic (A388) cSCC cells in a time- and dose-dependent manner. Sng significantly inhibited cell proliferation by inducing sub-G0/G1 cell-cycle arrest and apoptosis in cSCC cells. Sng evoked ROS generation, intracellular glutathione (GSH) depletion, &#x394;&#x3a8;m depolarization and the activation of JNK pathway as well as that of caspase-3, -8, -9, and PARP. Antioxidant NAC inhibited ROS production, replenished GSH levels, and abolished apoptosis induced by Sng by downregulating JNK. Pretreatment with z-VAD-FMK inhibited Sng-mediated apoptosis. The pharmacological inhibition of JNK by SP600125 mitigated Sng-induced apoptosis in metastatic cSCC cells. Finally, Sng ablated the stemness of metastatic cSCC cell-derived spheroids.<br><br>CONCLUSION: Our results indicate that Sng exerts a potent cytotoxic effect against cSCC cells that is underscored by a mechanism involving multiple levels of cooperation, including cell-cycle sub-G0/G1 arrest and apoptosis induction through ROS-dependent activation of the JNK signaling pathway. This study provides insight into the potential therapeutic application of Sng targeting cSCC.}, }
@article {pmid38283455, year = {2023}, author = {Mohammed, HMI and Ahmad, F}, title = {Mushroom Poisoning: A Rare Etiology of Acute Liver Failure.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51144}, pmid = {38283455}, issn = {2168-8184}, abstract = {Acute liver failure is defined as a rapid deterioration in liver function, manifested by symptoms and signs of hepatic encephalopathy and disturbed synthetic function in a patient without Pre-existing cirrhosis and with an illness of less than 26 weeks duration. Mushroom poisoning as a cause of acute liver injury is rare but associated with deadly outcomes if not early recognized and treated. The mortality is very high in the case of amatoxin-containing mushrooms ingestion and liver transplantation is the only lifesaving option. Therefore, early recognition of a suspected patient who came with features of mushroom-related food poisoning, timely referral to a liver transplantation center, and adequate supportive management remain the main approaches of management in a patient with acute liver injury. We present a patient with gastroenteritis who ingested wild mushroom 14 hours prior to hospital admission with subsequent severe acute liver failure due to mushroom poisoning, successfully treated with urgent liver transplantation. This case study highlighted that careful evaluation of the symptoms and signs of acute liver failure in a patient with a history of mushroom ingestion can result in early referral to a liver transplant center, especially if the patient is systemically unwell.}, }
@article {pmid38282602, year = {2024}, author = {Park, HR and Harris, SM and Boldenow, E and Aronoff, DM and Rea, M and Xi, C and Loch-Caruso, R}, title = {The antioxidant N-acetyl cysteine inhibits cytokine and prostaglandin release in human fetal membranes stimulated ex vivo with lipoteichoic acid or live group B streptococcus.}, journal = {American journal of reproductive immunology (New York, N.Y. : 1989)}, volume = {91}, number = {1}, pages = {e13807}, pmid = {38282602}, issn = {1600-0897}, support = {P42 ES017198/ES/NIEHS NIH HHS/United States ; P30 ES001247/ES/NIEHS NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; R00 ES029548/ES/NIEHS NIH HHS/United States ; UL1 TR000433/TR/NCATS NIH HHS/United States ; UM1 TR004404/TR/NCATS NIH HHS/United States ; }, mesh = {Pregnancy ; Female ; Infant, Newborn ; Humans ; Cytokines/metabolism ; Lipopolysaccharides/pharmacology ; Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Acetylcysteine/pharmacology/metabolism ; Dinoprostone/metabolism ; Prostaglandins/metabolism ; Streptococcus agalactiae ; Extraembryonic Membranes/metabolism ; *Chorioamnionitis ; *Streptococcal Infections ; *Teichoic Acids ; }, abstract = {BACKGROUNDS: Infection during pregnancy is a significant public health concern due to the increased risk of adverse birth outcomes. Group B Streptococcus or Streptococcus agalactiae (GBS) stands out as a major bacterial cause of neonatal morbidity and mortality. We aimed to explore the involvement of reactive oxygen species (ROS) and oxidative stress pathways in pro-inflammatory responses within human fetal membrane tissue, the target tissue of acute bacterial chorioamnionitis.<br><br>METHODS: We reanalyzed transcriptomic data from fetal membrane explants inoculated with GBS to assess the impact of GBS on oxidative stress and ROS genes/pathways. We conducted pathway enrichment analysis of transcriptomic data using the Database for Annotation, Visualization and Integrated Discovery (DAVID), a web-based functional annotation/pathway enrichment tool. Subsequently, we conducted ex vivo experiments to test the hypothesis that antioxidant treatment could inhibit pathogen-stimulated inflammatory responses in fetal membranes.<br><br>RESULTS: Using DAVID analysis, we found significant enrichment of pathways related to oxidative stress or ROS in GBS-inoculated human fetal membranes, for example, "Response to Oxidative Stress" (FDR&#xa0;=&#xa0;0.02) and "Positive Regulation of Reactive Oxygen Species Metabolic Process" (FDR&#xa0;=&#xa0;2.6*10[-4]). There were 31 significantly changed genes associated with these pathways, most of which were upregulated after GBS inoculation. In ex vivo experiments with choriodecidual membrane explants, our study showed that co-treatment with N-acetylcysteine (NAC) effectively suppressed the release of pro-inflammatory cytokines (IL-6, IL-8, TNF-&#x3b1;) and prostaglandin PGE2, compared to GBS-treated explants (p&#xa0;<&#xa0;.05 compared to GBS-treated samples without NAC co-treatment). Furthermore, NAC treatment inhibited the release of cytokines and PGE2 stimulated by lipoteichoic acid (LTA) and lipopolysaccharide (LPS) in whole membrane explants (p&#xa0;<&#xa0;.05 compared to LTA or LPS-treated samples without NAC co-treatment).<br><br>CONCLUSIONS: Our study sheds light on the potential roles of ROS in governing the innate immune response to GBS infection, offering insights for developing strategies to mitigate GBS-related adverse outcomes.}, }
@article {pmid38279215, year = {2024}, author = {Castro, MC and Villagarcía, HG and Di Sarli Gutiérrez, L and Arbeláez, LG and Schinella, G and Massa, ML and Francini, F}, title = {Akt Signaling and Nitric Oxide Synthase as Possible Mediators of the Protective Effect of N-acetyl-L-cysteine in Prediabetes Induced by Sucrose.}, journal = {International journal of molecular sciences}, volume = {25}, number = {2}, pages = {}, pmid = {38279215}, issn = {1422-0067}, support = {CONICET (PIP-2021/2023)//Consejo Nacional de Investigaciones Cient&#xed;ficas y T&#xe9;cnicas/ ; M-231//National University of La Plata - Argentina/ ; PICT 2017-2993//FONCYT/ ; }, mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/metabolism ; *Prediabetic State/drug therapy ; Rats, Wistar ; *Diabetes Mellitus, Type 2/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Sucrose/pharmacology ; *Insulin Resistance ; Oxidative Stress ; Insulin/metabolism ; Signal Transduction ; Glucose/pharmacology ; Nitric Oxide/metabolism ; }, abstract = {The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes).}, }
@article {pmid38274165, year = {2024}, author = {Sun, YL and Chang, HF and Chiang, PH and Lin, MW and Lin, CH and Kuo, CM and Lin, TC and Lin, CS}, title = {Fabrication and application of glutathione biosensing SPCE strips with gold nanoparticle modification.}, journal = {RSC advances}, volume = {14}, number = {6}, pages = {3808-3819}, pmid = {38274165}, issn = {2046-2069}, abstract = {Glutathione (GSH) is a major antioxidant in organisms. An alteration in GSH concentration has been implicated in a number of pathological conditions. Therefore, GSH sensing has become a critical issue. In this study, a disposable strip used for tyrosinase-modified electrochemical testing was fabricated for the detection of GSH levels in vivo. The system is based on tyrosinase as a biorecognition element and a screen-printed carbon electrode (SPCE) as an amperometric transducer. On the tyrosinase-SPCE strips, the oxidation reaction from catechol to o-quinone was catalyzed by tyrosinase. The tyrosinase-SPCE strips were modified with gold nanoparticles (AuNPs). In the presence of AuNPs of 25 nm diameter, the cathodic peak current of cyclic voltammetry (CV) was significantly enhanced by 5.2 fold. Under optimized conditions (250 μM catechol, 50 mM phosphate buffer, and pH 6.5), the linear response of the tyrosinase-SPCE strips ranged from 31.25 to 500 μM GSH, with a detection limit of approximately 35 μM (S/N > 3). The tyrosinase-SPCE strips have been used to detect real samples of plasma and tissue homogenates in a mouse experiment. The mice were orally administrated with N-acetylcysteine (NAC) 100 mg kg[-1] once a day for 7 days; the plasma GSH significantly enhanced 2.8 fold as compared with saline-treated mice (1123 vs. 480 μM μg[-1] protein). NAC administration also could alleviate the adverse effect of GSH reduction in the mice treated with doxorubicin.}, }
@article {pmid38270755, year = {2024}, author = {Zhang, H and Huang, Y}, title = {Genome-wide identification and characterization of greenbug-inducible NAC transcription factors in sorghum.}, journal = {Molecular biology reports}, volume = {51}, number = {1}, pages = {207}, pmid = {38270755}, issn = {1573-4978}, mesh = {*Sorghum/genetics ; Edible Grain ; Genotype ; Acetylcysteine ; }, abstract = {BACKGROUND: Sorghum (Sorghum bicolor) is an important cereal crop grown worldwide because of its multipurpose uses such as food, forage, and bioenergy feedstock and its wide range of adaption even in marginal environments. Greenbug can cause severe damage to sorghum plants and yield loss. Plant NAC transcription factors (TFs) have been reported to have diverse functions in plant development and plant defense but has not been studied in sorghum yet.<br><br>METHODS AND RESULTS: In this study, a comprehensive analysis of the sorghum NAC (SbNAC) gene family was conducted through genome-wide analysis. A total of 112 NAC genes has been identified in the sorghum genome. These SbNAC genes are phylogenetically clustered into 15 distinct subfamilies and unevenly distribute in clusters at the telomeric ends of each chromosome. Twelve pairs of SbNAC genes are possibly involved in the segmental duplication among nine chromosomes except chromosome 10. Structure analysis showed the diverse structures with a highly variable number of exons in the SbNAC genes. Furthermore, most of the SbNAC genes showed specific temporal and spatial expression patterns according to the results of RNA-seq analysis, suggesting their diverse functions during sorghum growth and development. We have also identified nine greenbug-inducible SbNAC genes by comparing the expression profiles between two sorghum genotypes (susceptible BTx623 and resistant PI607900) in response to greenbug infestation.<br><br>CONCLUSIONS: Our systematic analysis of the NAC gene expression profiles provides both a preliminary survey into their roles in plant defense against insect pests and a useful reference for in-depth characterization of the SbNAC genes and the regulatory network that contributes genetic resistance to aphids.}, }
@article {pmid38269219, year = {2023}, author = {Schaefer, J and Khanna, D}, title = {Nutritional and Wellness Strategies for Neurological and Psychiatric Recovery From Post-COVID Syndrome and Post-acute Sequelae of COVID-19.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e51076}, pmid = {38269219}, issn = {2168-8184}, abstract = {The post-COVID syndrome was officially recognized as a disability under the Americans with Disabilities Act, indicating that this syndrome has made a significant impact on our populace. Also, post-acute sequelae of COVID-19 (PASC) is a term that describes the long-term health problems that some people experience after being infected with the virus that causes COVID-19. These problems can last for weeks, months, or even years, and can affect various parts of the body, such as the heart, lungs, brain, and blood vessels. This narrative review paper utilized the PubMed database to explore the pathophysiology of post-COVID syndrome's neurological and psychiatric symptoms and PASC and make therapeutic connections to the known mechanisms of various nutritional, supplemental, and wellness approaches. Searches were queried on the PubMed database between March 29 and April 16, 2022, using the phrases "long-covid," "post-COVID syndrome," "Vitamin D covid," "vitamin C covid," "omega-3 covid," "kynurenine covid," "whole-body hyperthermia," "mushrooms immunity," "n-acetyl cysteine covid," "mushrooms cognition," "sugar consumption inflammation," and "covid microbiome." Articles were screened for their relevance to the discussion of post-COVID syndrome's neurological and psychiatric pathophysiology at the discretion of the principal researcher. There were no limitations regarding publication years, but articles from 2005 to April 2022 were cited. Micro-ischemic disease, neuropathy, autoimmune processes, mast-cell activation, and impaired blood-brain barriers have all been implicated in the pathological processes of this syndrome with varying degrees of supportive evidence. The common denominators, however, are inflammation and oxidative stress. Therefore, a beneficial approach to dealing with the complications of post-COVID syndrome would be to reduce the exacerbations of these common denominators with lifestyle and nutritional changes. Replenishing nutritional deficiencies, supplementing with N-acetylcysteine, decreasing consumption of refined sugars, preventing dysbiosis of the microbiome, performing exercises, increasing dietary intake of mushrooms, utilizing beneficial herbs such as rosemary, and increasing the core body temperature through whole-body hyperthermia seem to show potential for efficacy in this pursuit. Considering the safety and evidence-based connections of the therapies explored for dealing with the post-Covid syndrome, it could be of great benefit and of little harm to our patients to include these considerations in formulating post-Covid treatment plans.}, }
@article {pmid38250216, year = {2024}, author = {Zavala-Valencia, AC and Velasco-Hidalgo, L and Martínez-Avalos, A and Castillejos-López, M and Torres-Espíndola, LM}, title = {Effect of N-Acetylcysteine on Cisplatin Toxicity: A Review of the Literature.}, journal = {Biologics : targets &amp; therapy}, volume = {18}, number = {}, pages = {7-19}, pmid = {38250216}, issn = {1177-5475}, abstract = {N-acetylcysteine (NAC) is a membrane-permeable cysteine precursor capable of enhancing the intracellular cysteine pool, enhancing cellular glutathione (GSH) synthesis, and thus potentiating the endogenous antioxidant mechanism. Late administration of NAC after cisplatin has been shown in different in vivo studies to reduce the side effects caused by various toxicities at different levels without affecting the antitumor efficacy of platinum, improving total and enzymatic antioxidant capacity and decreasing oxidative stress markers. These characteristics provide NAC with a rationale as a potentially effective chemo protectant in cisplatin-based therapeutic cycles. NAC represents a potential candidate as a chemoprotective agent to decrease toxicities secondary to cisplatin treatment. It suggests that it could be used in clinical trials, whereby the effective dose, timing, and route should be adjusted to optimize chemoprotection. This review provides an overview of the effect of NAC on cisplatin toxicity, a drug widely used in the clinic in adults and children.}, }
@article {pmid38247538, year = {2024}, author = {Sun, J and Chen, Y and Wang, T and Ali, W and Ma, Y and Liu, Z and Zou, H}, title = {Role of Mitochondrial Reactive Oxygen Species-Mediated Chaperone-Mediated Autophagy and Lipophagy in Baicalin and N-Acetylcysteine Mitigation of Cadmium-Induced Lipid Accumulation in Liver.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {38247538}, issn = {2076-3921}, support = {31872533//National Natural Science Foundation of China/ ; 32072933//National Natural Science Foundation of China/ ; 32273086//National Natural Science Foundation of China/ ; }, abstract = {Cadmium (Cd) is a major health concern globally and can accumulate and cause damage in the liver for which there is no approved treatment. Baicalin and N-acetylcysteine (NAC) have been found to have protective effects against a variety of liver injuries, but it is not clear whether their combined use is effective in preventing and treating Cd-induced lipid accumulation. The study found that Cd increased the production of mitochondrial reactive oxygen species (mROS) and elevated the level of chaperone-mediated autophagy (CMA). Interestingly, mROS-mediated CMA exacerbates the Cd-induced inhibition of lipophagy. Baicalin and NAC counteracted inhibition of lipophagy by attenuating Cd-induced CMA, suggesting an interplay between CMA elevation, mitochondrial destruction, and mROS formation. Maintaining the stability of mitochondrial structure and function is essential for alleviating Cd-induced lipid accumulation in the liver. Choline is an essential component of the mitochondrial membrane and is responsible for maintaining its structure and function. Mitochondrial transcriptional factor A (TFAM) is involved in mitochondrial DNA transcriptional activation and replication. Our study revealed that the combination of baicalin and NAC can regulate choline metabolism through TFAM and thereby maintain mitochondrial structure and functionality. In summary, the combination of baicalin and NAC plays a more beneficial role in alleviating Cd-induced lipid accumulation than the drug alone, and the combination of baicalin and NAC can stabilize mitochondrial structure and function and inhibit mROS-mediated CMA through TFAM-choline, thereby promoting lipophagy to alleviate Cd-induced lipid accumulation.}, }
@article {pmid38247506, year = {2024}, author = {Kyriakou, S and Demosthenous, N and Amery, T and Stewart, KJ and Winyard, PG and Franco, R and Pappa, A and Panayiotidis, MI}, title = {Naturally Derived Phenethyl Isothiocyanate Modulates Induction of Oxidative Stress via Its N-Acetylated Cysteine Conjugated form in Malignant Melanoma.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {13}, number = {1}, pages = {}, pmid = {38247506}, issn = {2076-3921}, abstract = {Phenethyl isothiocyanate (PEITC) is a secondary metabolic product yielded upon the hydrolysis of gluconasturtiin and it is highly accumulated in the flowers of watercress. The aim of the current study was to assess the role of a naturally derived PEITC-enriched extract in the induction of oxidative stress and to evaluate its anti-melanoma potency through the regulation of its metabolism with the concurrent production of the N-acetyl cysteine conjugated by-product. For this purpose, an in vitro melanoma model was utilized consisting of human primary (A375) cells as well as metastatic (COLO-679) malignant melanoma cells together with non-tumorigenic immortalized keratinocytes (HaCaT). Cytotoxicity was assessed via the Alamar Blue assay whereas the antioxidant/prooxidant activity of PEITC was determined via spectrophotometric assays. Finally, kinetic characterization of the end-product of PEITC metabolism was monitored via UPLC coupled to a tandem mass spectrometry (MS/MS). Our results indicate that although PhEF showed very minor antioxidant activity in a cell-free system, in a cell-based system, it can modulate the activity of key enzyme(s) involved in cellular antioxidant defense mechanism(s). In addition, we have shown that PhEF induces lipid and protein oxidation in a concentration-dependent manner, while its cytotoxicity is not only dependent on PEITC itself but also on its N-acetylated cysteine conjugated form.}, }
@article {pmid38246558, year = {2024}, author = {Hao, X and Liu, M and Zhang, X and Yu, H and Fang, Z and Gao, X and Chen, M and Shao, Q and Gao, W and Lei, L and Song, Y and Li, X and Liu, G and Du, X}, title = {Thioredoxin-2 suppresses hydrogen peroxide-activated nuclear factor kappa B signaling via alleviating oxidative stress in bovine adipocytes.}, journal = {Journal of dairy science}, volume = {107}, number = {6}, pages = {4045-4055}, doi = {10.3168/jds.2023-23465}, pmid = {38246558}, issn = {1525-3198}, mesh = {Animals ; Cattle ; *Hydrogen Peroxide/pharmacology/metabolism ; *Oxidative Stress/drug effects ; *NF-kappa B/metabolism ; *Signal Transduction/drug effects ; *Adipocytes/drug effects/metabolism ; *Thioredoxins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Female ; }, abstract = {During the periparturient period, both oxidative stress, and inflammation of adipose tissue are considered high risk factors for metabolic disorder of dairy cows. Oxidative stress can activate transcription factor nuclear factor kappa B (NF-κB), which lead to the upregulation of genes involved in inflammatory pathways. Thioredoxin-2 (TXN2) is a mitochondrial protein that regulates cellular redox by suppressing mitochondrial reactive oxygen species (ROS) generation in nonruminant, whereas the function of TXN2 in bovine adipocytes was unclear. Thus, the objective of this study was to evaluate how or by which mechanisms TXN2 regulates oxidative stress and NF-κB signaling pathway in bovine adipocytes. Bovine pre-adipocytes isolated from 5 healthy Holstein cows were differentiated and used for (1) treatment with different concentrations of hydrogen peroxide (H2O2; 0, 25, 50, 100, 200, or 400 μM) for 2 h; (2) transfection with or without TXN2 small interfering RNA (si-TXN2) for 48 h and then treated with or without 200 μM H2O2 for 2 h; (3) transfection with scrambled negative control siRNA (si-control) or si-TXN2 for 48 h, and then treatment with or without 10 mM N-acetylcysteine (NAC) for 2 h; (4) transfection with or without TXN2-overexpressing plasmid for 48 h and then treatment with or without 200 μM H2O2 for 2 h. High concentrations of H2O2 (200 and 400 μM) decreased protein and mRNA abundance of TXN2, reduced total antioxidant capacity (T-AOC) and ATP content in adipocytes. Moreover, 200 and 400 μM H2O2 reduced protein abundance of inhibitor of kappa B α (IκBα), increased phosphorylation of NF-κB and upregulated mRNA abundance of tumor necrosis factor-α (TNFA) and interleukin-1B (IL-1B), suggesting that H2O2-induced oxidative stress and activated NF-κB signaling pathway. Silencing of TXN2 increased intracellular ROS content, phosphorylation of NF-κB and mRNA abundance of TNFA and IL-1B, decreased ATP content and protein abundance of IκBα in bovine adipocytes. Knockdown of TXN2 aggravated H2O2-induced oxidative stress and inflammation. In addition, treatment with antioxidant NAC ameliorated oxidative stress and inhibited NF-κB signaling pathway in adipocytes transfected with si-TXN2. In bovine adipocytes treated with H2O2, overexpression of TXN2 reduced the content of ROS and elevated the content of ATP and T-AOC. Overexpression of TXN2 alleviated H2O2-induced inflammatory response in adipocytes, as demonstrated by decreased expression of phosphorylated NF-κB, TNFA, IL-1B, as well as increased expression of IκBα. Furthermore, the protein and mRNA abundance of TXN2 was lower in adipose tissue of dairy cows with clinical ketosis. Overall, our studies contribute to the understanding of the role of TXN2 in adipocyte oxidative stress and inflammatory response.}, }
@article {pmid38245726, year = {2024}, author = {Lee, JH and Jaiswal, MS and Jang, YS and Choi, JH and Kim, GC and Hong, JW and Hwang, DS}, title = {No-ozone cold plasma induces apoptosis in human neuroblastoma cell line via increased intracellular reactive oxygen species (ROS).}, journal = {BMC complementary medicine and therapies}, volume = {24}, number = {1}, pages = {46}, pmid = {38245726}, issn = {2662-7671}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; Caspase 3/metabolism ; *Plasma Gases/pharmacology/therapeutic use ; *Ozone/pharmacology/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/therapeutic use ; Cell Line, Tumor ; Apoptosis ; *Neuroblastoma/drug therapy/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: This study aimed to evaluate the effect of argon-based No-ozone Cold Plasma (NCP) on neuroblastoma cancer cell apoptosis.<br><br>METHODS: Experiments were performed with SK-N-SH and HS 68. Cell cultures were treated with NCP for 1, 3, and 5&#xa0;min. NCP was applied using three different strategies: direct NCP application to cell cultures, to only media, and to only cells. Evaluation of cell viability and the level of the reactive oxygen species (ROS) was performed. N-acetyl-L-cysteine (NAC) was also used to antagonize intracellular ROS. Cleaved caspase 3, PARP, aquaporin (AQP) 3 and 8 were detected.<br><br>RESULTS: NCP induced a gradual decrease in the SK-N-SH cell viability. In contrast, the viability of HS 68 cells did not change. SK-N-SH cells viability was reduced the most when the only media-NCP application strategy was employed. Intracellular ROS levels were significantly increased with time. Cleaved caspase 3 and PARP were increased at 6&#xa0;h after NCP application. SK-N-SH cells remained viable with NAC after NCP application. AQP 3 and 8 were over-expressed in SK-N-SH cells.<br><br>CONCLUSION: These findings demonstrate the anti-cancer effect of NCP on neuroblastoma cells. NCP enhanced the selective apoptosis of neuroblastoma cells due to the increased intracellular ROS.}, }
@article {pmid38236790, year = {2024}, author = {Tavanaeimanesh, H and Alinia, Z and Sadeghian Chaleshtori, S and Moosavian, H and Mohebi, Z and Daneshi, M}, title = {The efficacy of N-acetylcysteine in decreasing airway inflammation and mucus accumulation in horses with 18 hours of head confinement.}, journal = {Journal of veterinary internal medicine}, volume = {38}, number = {2}, pages = {1224-1231}, pmid = {38236790}, issn = {1939-1676}, mesh = {Animals ; *Acetylcysteine/therapeutic use ; Bronchoalveolar Lavage Fluid ; *Horse Diseases/drug therapy/prevention &amp; control ; Horses ; Inflammation/drug therapy/veterinary ; Mucus ; Prospective Studies ; Trachea ; Cross-Over Studies ; }, abstract = {BACKGROUND: During transportation many horses develop post-transportation infection, which can be life-threatening and end their sport career. Preventing mucus accumulation and inflammation during transportation is vital, emphasizing the need for effective strategies to enhance overall horse health welfare.<br><br>OBJECTIVES: Assess the impact of N-acetylcysteine (NAC) on mucus accumulation and inflammation in horses subjected to 18&#x2009;hours of head confinement.<br><br>ANIMALS: Six healthy crossbred horses, 5.3&#x2009;&#xb1;&#x2009;2.1&#x2009;years of age and weighing 387&#x2009;&#xb1;&#x2009;30&#x2009;kg.<br><br>METHODS: Prospective placebo-controlled cross-over design study. The horses' heads were restrained in their stalls for a period of 18&#x2009;hours. They were studied under 4 conditions: Not confined (NC): before head confinement, placebo (P), and confined head (CH): 18&#x2009;hours of head confinement without treatment, and N-Acetylcysteine (NAC): 18&#x2009;hours of head confinement treated with NAC before confinement (15&#x2009;mg/kg/day NAC PO for 3&#x2009;days). Bronchoalveolar lavage (BAL) was performed in each condition. Mucus accumulation along the trachea was evaluated by endoscopy.<br><br>RESULTS: Endoscopic scores were significantly different between CH and other conditions, whereas no significant differences were found among NC, P, and NAC. The BAL cell count (34&#x2009;291&#x2009;&#xb1;&#x2009;2624 cells/&#x3bc;L), neutrophil and lymphocyte count (18&#x2009;601&#x2009;&#xb1;&#x2009;3193 cells/&#x3bc;L and 3337.4&#x2009;&#xb1;&#x2009;593 cells/&#x3bc;L, respectively) in CH were significantly higher compared to NAC. Neutrophil percentage was significantly higher in CH (53.8&#x2009;&#xb1;&#x2009;8%) compared to horses that received NAC (20.08&#x2009;&#xb1;&#x2009;8%). Conversely, in comparison to NAC (66.33&#x2009;&#xb1;&#x2009;9%), the percentage of macrophages was significantly lower in CH (35.7&#x2009;&#xb1;&#x2009;10%).<br><br>CONCLUSIONS: N-acetylcysteine was found to significantly decrease mucus accumulation and inflammatory cell counts in horses with head confinement.}, }
@article {pmid38236698, year = {2024}, author = {Li, C and Li, X and Fan, A and He, N and Wu, D and Yu, H and Wang, K and Jiao, W and Zhao, X}, title = {Evidence for cytochrome P450 3A4-mediated metabolic activation of SCO-267.}, journal = {Biopharmaceutics &amp; drug disposition}, volume = {45}, number = {1}, pages = {30-42}, doi = {10.1002/bdd.2381}, pmid = {38236698}, issn = {1099-081X}, mesh = {Humans ; Rats ; Animals ; *Cytochrome P-450 CYP3A/metabolism ; Activation, Metabolic ; *Diabetes Mellitus, Type 2/metabolism ; Quinones/metabolism ; Imines/metabolism ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; *Piperidines ; *Pyridines ; *Benzoquinones ; }, abstract = {SCO-267 is a potent G-protein-coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO-267 in vitro and in vivo. Three SCO-267-derived glutathione (GSH) conjugates (M1-M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1-M2) together with two N-acetyl-cysteine conjugates (M4-M5) were detected in the bile of rats receiving SCO-267 at 10 mg/kg. The identified conjugates suggested the generation of quinone-imine and ortho-quinone intermediates. CYP3A4 was demonstrated to primarily catalyze the bioactivation of SCO-267. In addition, SCO-267 concentration-, time-, and NADPH-dependently inactivated CYP3A in human liver microsomes using testosterone as a probe substrate, along with KI and kinact values of 4.91 μM and 0.036 min[-1] , respectively. Ketoconazole (a competitive inhibitor of CYP3A) displayed no significant protective effect on SCO-267-induced CYP3A inactivation. However, inclusion of GSH showed significant protection. These findings revealed that SCO-267 undergoes a facile CYP3A4-catalyzed bioactivation with the generation of quinone-imine and ortho-quinone intermediates, which were assumed to be involved in SCO-267 induced CYP3A inactivation. These findings provide further insight into the bioactivation pathways involved in the generation of reactive, potentially toxic metabolites of SCO-267. Further studies are needed to evaluate the influence of SCO-267 metabolism on the safety of this drug in vivo.}, }
@article {pmid38234666, year = {2024}, author = {Yalçin, T and Kuloğlu, T and Tektemur, NK and Tektemur, A and Ozan, &#x130;E}, title = {Effects of N-acetylcysteine on spexin immunoreactivity in kidney tissues of rats treated with adriamycin.}, journal = {Iranian journal of basic medical sciences}, volume = {27}, number = {2}, pages = {233-240}, pmid = {38234666}, issn = {2008-3866}, abstract = {OBJECTIVES: Due to its negative side effects, mainly nephrotoxicity, adriamycin (ADR) is used fairly infrequently. The purpose of this study is to investigate the effects of N-acetyl cysteine (NAC) on the immunoreactivity of spexin (SPX) in the kidney tissues of rats given ADR.<br><br>MATERIALS AND METHODS: A total of 28 male Sprague-Dawley rats were randomly assigned to four groups (n=7): control (no intervention), NAC (150 mg/kg/day, administered intraperitoneally), ADR (single dose of 15 mg/kg, administered intraperitoneally), and ADR+NAC (single dose of 15 mg/kg ADR + 150 mg/kg/day NAC, both administered intraperitoneally). The experiment was concluded on the 15[th] day.<br><br>RESULTS: The administration of ADR resulted in biochemical and histopathological alterations in the kidney. It was found that ADR treatment led to elevated levels of TOS (total oxidative stress), apoptosis, and SPX. Conversely, when NAC was administered as a treatment, it effectively reduced TOS, apoptosis, and SPX levels. These findings suggest that SPX may contribute to the development of ADR-induced kidney damage.<br><br>CONCLUSION: Further investigations are warranted to gain a comprehensive understanding of kidney damage, and specifically to elucidate the role of SPX in this context. Additionally, these studies can pave the way for exploring novel therapeutic strategies targeting SPX to prevent and/or treat the development of kidney damage.}, }
@article {pmid38233317, year = {2024}, author = {Jung, E and Romero, R and Suksai, M and Gotsch, F and Chaemsaithong, P and Erez, O and Conde-Agudelo, A and Gomez-Lopez, N and Berry, SM and Meyyazhagan, A and Yoon, BH}, title = {Clinical chorioamnionitis at term: definition, pathogenesis, microbiology, diagnosis, and treatment.}, journal = {American journal of obstetrics and gynecology}, volume = {230}, number = {3S}, pages = {S807-S840}, doi = {10.1016/j.ajog.2023.02.002}, pmid = {38233317}, issn = {1097-6868}, mesh = {Female ; Infant, Newborn ; Pregnancy ; Humans ; *Chorioamnionitis/diagnosis/drug therapy/etiology ; Clarithromycin/therapeutic use ; *Postpartum Hemorrhage/drug therapy ; *Neonatal Sepsis/diagnosis/drug therapy ; Anti-Bacterial Agents/therapeutic use ; Amniotic Fluid/microbiology ; Inflammation/metabolism ; Tachycardia ; }, abstract = {Clinical chorioamnionitis, the most common infection-related diagnosis in labor and delivery units, is an antecedent of puerperal infection and neonatal sepsis. The condition is suspected when intrapartum fever is associated with two other maternal and fetal signs of local or systemic inflammation (eg, maternal tachycardia, uterine tenderness, maternal leukocytosis, malodorous vaginal discharge or amniotic fluid, and fetal tachycardia). Clinical chorioamnionitis is a syndrome caused by intraamniotic infection, sterile intraamniotic inflammation (inflammation without bacteria), or systemic maternal inflammation induced by epidural analgesia. In cases of uncertainty, a definitive diagnosis can be made by analyzing amniotic fluid with methods to detect bacteria (Gram stain, culture, or microbial nucleic acid) and inflammation (white blood cell count, glucose concentration, interleukin-6, interleukin-8, matrix metalloproteinase-8). The most common microorganisms are Ureaplasma species, and polymicrobial infections occur in 70% of cases. The fetal attack rate is low, and the rate of positive neonatal blood cultures ranges between 0.2% and 4%. Intrapartum antibiotic administration is the standard treatment to reduce neonatal sepsis. Treatment with ampicillin and gentamicin have been recommended by professional societies, although other antibiotic regimens, eg, cephalosporins, have been used. Given the importance of Ureaplasma species as a cause of intraamniotic infection, consideration needs to be given to the administration of antimicrobial agents effective against these microorganisms such as azithromycin or clarithromycin. We have used the combination of ceftriaxone, clarithromycin, and metronidazole, which has been shown to eradicate intraamniotic infection with microbiologic studies. Routine testing of neonates born to affected mothers for genital mycoplasmas could improve the detection of neonatal sepsis. Clinical chorioamnionitis is associated with decreased uterine activity, failure to progress in labor, and postpartum hemorrhage; however, clinical chorioamnionitis by itself is not an indication for cesarean delivery. Oxytocin is often administered for labor augmentation, and it is prudent to have uterotonic agents at hand to manage postpartum hemorrhage. Infants born to mothers with clinical chorioamnionitis near term are at risk for early-onset neonatal sepsis and for long-term disability such as cerebral palsy. A frontier is the noninvasive assessment of amniotic fluid to diagnose intraamniotic inflammation with a transcervical amniotic fluid collector and a rapid bedside test for IL-8 for patients with ruptured membranes. This approach promises to improve diagnostic accuracy and to provide a basis for antimicrobial administration.}, }
@article {pmid38230777, year = {2024}, author = {Nili-Ahmadabadi, A and Abdpour, S and Omidifar, N and Hashemi, SA and Mousavi, SM and Ahmadabadi, MN}, title = {Therapeutic potentials of N-acetylcysteine immobilized polyrhodanine nanoparticles toward acetaminophen-induced acute hepatotoxicity in rat.}, journal = {Chemical biology &amp; drug design}, volume = {103}, number = {1}, pages = {e14430}, doi = {10.1111/cbdd.14430}, pmid = {38230777}, issn = {1747-0285}, support = {//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; }, mesh = {Rats ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; Acetaminophen/toxicity ; Antioxidants/pharmacology/therapeutic use ; Saline Solution/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Liver ; *Nanoparticles ; Sulfhydryl Compounds ; }, abstract = {N-acetylcysteine (NAC) is a recommended drug for treating acetaminophen (APAP) intoxication. Due to NAC's low bioavailability, this study aimed to use polyrhodanine (PR) nanoparticles (NPs) as a drug carrier to improve the effectiveness of NAC. After preparation and characterization of NAC loaded on PR, 30 rats were randomly divided into five groups of six. The first group (control) received normal saline. Groups 2-5 were treated with normal saline, PR, NAC, and NAC loaded on PR, respectively. The treatments were started 4 h after oral administration of APAP (2000 mg kg[-1]). After 48 h, the animals were anesthetized, and liver function indices and oxidative stress were measured in tissue and serum samples. The APAP administration can increase aminotransferases and alkaline phosphatase enzymes in serum, decreasing the total antioxidant capacity and thiol groups and increasing lipid peroxidation in liver tissue. Administration of PR-NAC could effectively improve the level of serum-hepatic enzymes, total antioxidant capacity and thiol groups, lipid peroxidation, and pathological changes in liver tissue in animals poisoned with APAP. PR-NAC has a significant therapeutic effect on preventing acute hepatotoxicity caused by APAP, and its effectiveness can be associated with an improvement in the oxidant/antioxidant balance of liver tissue.}, }
@article {pmid38230207, year = {2024}, author = {Wang, Q and Lin, B and Wei, H and Wang, X and Nie, X and Shi, Y}, title = {AQP3 Promotes the Invasion and Metastasis in Cervical Cancer by Regulating NOX4-derived H2O2 Activation of Syk/PI3K/Akt Signaling Axis.}, journal = {Journal of Cancer}, volume = {15}, number = {4}, pages = {1124-1137}, pmid = {38230207}, issn = {1837-9664}, abstract = {Unrestrained chronic inflammation leads to the abnormal activity of NOX4 and the subsequent production of excessive hydrogen peroxide (H2O2). Excessive H2O2 signaling triggered by prolonged inflammation is thought to be one of the important reasons for the progression of some types of cancer including cervical cancer. Aquaporin 3 (AQP3) is a member of the water channel protein family, and it remains unknown whether AQP3 can regulate the transmembrane transport of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4)-derived H2O2 induced by the stimulation of inflammatory factors to facilitate the malignant progression in cervical cancer. In this study, cervical cancer HeLa cell line was respectively treated with diphenyleneiodonium (DPI), N-Acetylcysteine (NAC) or lentivirus-shRNA- AQP3. Plate cloning, cell migration or transwell invasion assays, etc. were performed to detect the invasive and migration ability of the cells. Western blot and CO-IP were used to analyze the mechanism of AQP3 regulating H2O2 conduction. Finally, in vivo assays were performed for validation in nude mice. AQP3 Knockdown, DPI or NAC treatments all reduced intracellular H2O2 influx, and the activation of Syk/PI3K/Akt signal axis was inhibited, the migration and invasive ability of the cells was attenuated. In vivo assays confirmed that the excessive H2O2 transport through AQP3 enhanced the infiltration and metastasis of cervical cancer. These results suggest that AQP3 activates H2O2/Syk/PI3K/Akt signaling axis through regulating NOX4-derived H2O2 transport to contribute to the progression of cervical cancer, and AQP3 may be a potential target for the clinical treatment of advanced cervical cancer.}, }
@article {pmid38216781, year = {2024}, author = {Zhao, Q and Yu, M and Li, J and Guo, Y and Wang, Z and Hu, K and Xu, F and Liu, Y and Li, L and Wan, D and Zhao, Y and Shang, J and Zhang, J}, title = {GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis.}, journal = {Discover oncology}, volume = {15}, number = {1}, pages = {8}, pmid = {38216781}, issn = {2730-6011}, support = {No. 212102310124//the Key Scientific and Technological Project of Henan Province/ ; No. 222102310083//the Key Scientific and Technological Project of Henan Province/ ; No. 222300420306//the Natural Science Foundation of Henan/ ; No. 2023BP0206//the Project of Basic Research Fund of Henan Institute of Medical and Pharmacological Sciences/ ; }, abstract = {Glutamate dehydrogenase 1 (GLUD1) is an important enzyme in glutamine metabolism. Previously, we found GLUD1 was down-regulated in tumor tissues of hepatocellular carcinoma (HCC) patients by proteomics study. To explore its role in the progression of HCC, the expressional level of GLUD1 was firstly examined and presented as that both the protein and mRNA levels were down-regulated in tumor tissues compared to the normal liver tissues. GLUD1 overexpression significantly inhibited HCC cells proliferation, migration, invasion and tumor growth both in vitro and in vivo, while GLUD1 knocking-down promoted HCC progression. Metabolomics study of GLUD1 overexpressing and control HCC cells showed that 129 differentially expressed metabolites were identified, which mainly included amino acids, bases, and phospholipids. Moreover, metabolites in mitochondrial oxidative phosphorylation system (OXPHOS) were differentially expressed in GLUD1 overexpressing cells. Mechanistic studies showed that GLUD1 overexpression enhanced mitochondrial respiration activity and reactive oxygen species (ROS) production. Excessive ROS lead to mitochondrial apoptosis that was characterized by increased expression levels of p53, Cytochrome C, Bax, Caspase 3 and decreased expression level of Bcl-2. Furthermore, we found that the p38/JNK MAPK pathway was activated in GLUD1 overexpressing cells. N-acetylcysteine (NAC) treatment eliminated cellular ROS and blocked p38/JNK MAPK pathway activation, as well as cell apoptosis induced by GLUD1 overexpression. Taken together, our findings suggest that GLUD1 inhibits HCC progression through regulating cellular metabolism and oxidative stress state, and provide that ROS generation and p38/JNK MAPK pathway activation as promising methods for HCC treatment.}, }
@article {pmid38216081, year = {2024}, author = {Zhu, G and Zeng, Y and Peng, W and Lu, C and Cai, H and Abuduxukuer, Z and Chen, Y and Chen, K and Song, X and Song, Y and Ye, L and Wang, J and Jin, M}, title = {Edaravone alleviated allergic airway inflammation by inhibiting oxidative stress and endoplasmic reticulum stress.}, journal = {European journal of pharmacology}, volume = {966}, number = {}, pages = {176317}, doi = {10.1016/j.ejphar.2024.176317}, pmid = {38216081}, issn = {1879-0712}, mesh = {Mice ; Animals ; *Immunity, Innate ; Edaravone/pharmacology/therapeutic use ; Cytokines/metabolism ; Endoribonucleases/metabolism ; Hydrogen Peroxide/pharmacology ; Lymphocytes ; Protein Serine-Threonine Kinases/metabolism ; *Asthma/metabolism ; Lung ; Inflammation/drug therapy/metabolism ; Oxidative Stress ; Oxidants/pharmacology ; Pyroglyphidae/metabolism ; Disease Models, Animal ; }, abstract = {Oxidative stress and endoplasmic reticulum stress (ERS) was associated with the development of asthma. Edaravone (EDA) plays a classical role to prevent the occurrence and development of oxidative stress-related diseases. Herein, we investigated the involvement and signaling pathway of EDA in asthma, with particular emphasis on its impact on type 2 innate lymphoid cells (ILC2) and CD4[+]T cells, and then further elucidated whether EDA could inhibit house dust mite (HDM)-induced allergic asthma by affecting oxidative stress and ERS. Mice received intraperitoneally injection of EDA (10 mg/kg, 30 mg/kg), dexamethasone (DEX) and N-acetylcysteine (NAC), with the latter two used as positive control drugs. DEX and high dose of EDA showed better therapeutic effects in alleviating airway inflammation and mucus secretion in mice, along with decreasing eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF) than NAC. Further, the protein levels of IL-33 in lung tissues were inhibited by EDA, leading to reduced activation of ILC2s in the lung. EDA treatment alleviated the activation of CD4[+] T cells in lung tissues of HDM-induced asthmatic mice and reduced Th2 cytokine secretion in BALF. ERS-related markers (p-eIF2α, IRE1α, CHOP, GRP78) were decreased after treatment of EDA compared to HDM group. Malondialdehyde (MDA), glutathione (GSH), hydrogen peroxide (H2O2), and superoxide dismutase (SOD) were detected to evaluate the oxidant stress in lung tissues. EDA showed a protective effect against oxidant stress. In conclusion, our findings demonstrated that EDA could suppress allergic airway inflammation by inhibiting oxidative stress and ERS, suggesting to serve as an adjunct medication for asthma in the future.}, }
@article {pmid38215974, year = {2024}, author = {Eslami Ghayour, A and Nazari, S and Keramat, F and Shahbazi, F and Eslami-Ghayour, A}, title = {Evaluation of the efficacy of N-acetylcysteine and bromhexine compared with standard care in preventing hospitalization of outpatients with COVID-19: a double blind randomized clinical trial.}, journal = {Revista clinica espanola}, volume = {224}, number = {2}, pages = {86-95}, doi = {10.1016/j.rceng.2023.12.011}, pmid = {38215974}, issn = {2254-8874}, mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; Outpatients ; COVID-19 Vaccines ; *Bromhexine ; Iran ; Treatment Outcome ; Hospitalization ; }, abstract = {INTRODUCTION AND AIM: Since its emergence in December 2019, the coronavirus disease caused by the severe acute respiratory syndrome coronavirus 2 has become a global emergency, spreading rapidly worldwide. In response to the early referral of these patients to outpatient health centers, we decided to seek more effective treatments in the early stages of their referral. This study aims to prevent both the progression and deterioration of the physical conditions of COVID-19 patients, reduce the rate of referrals, and mitigate the risks of hospitalization and death.<br><br>MATERIAL AND METHODS: Conducted at Dibaj Therapeutic Center, Hamadan City, Iran, a double-blind randomized controlled trial encompassed 225 COVID-19 patients from April to September 2022. Ethical approval was obtained from Hamadan University of Medical Sciences (Approval No.: IR.UMSHA.REC.1400.957), with the protocol registered in the Iranian Registry of Clinical Trials (Registration No. : IRCT20220302054167N1). In this study, we included patients who tested positive for COVID-19- PCR and were symptomatic, excluding those who were pregnant or had received a COVID-19 vaccine. Patients with oxygen saturation above 92% were allocated to three groups: Group A received N-acetylcysteine, Group B received Bromhexine, and Group C received standard care. Follow-ups on oxygen levels, symptoms, and hospitalization needs were conducted on days 7 and 14, with hospitalized patients monitored for one month post-hospitalization.<br><br>RESULTS: The study found that both N-acetylcysteine and Bromhexine can effectively reduce hospitalization rates and mortality and shorten the duration of hospitalization. The third visit of patients who received N-acetylcysteine showed an increase of 1.33% in oxygen saturation compared to their first visit, and in patients who received Bromhexine, this increase was 1.19%. The mortality rate was 9.33% in the control group and zero in both groups of patients who received medication.<br><br>CONCLUSION: In conclusion, the results of this study indicate that NAC and bromhexine may be effective in the treatment of patients with positive COVID-19, with a lower hospitalization rate, shorter hospitalization, faster recovery time, and reduced mortality compared to the control group.}, }
@article {pmid38215930, year = {2024}, author = {Katebi, SN and Torkaman-Boutorabi, A and Riahi, E and Haghparast, A}, title = {N-acetylcysteine attenuates accumbal core neuronal activity in response to morphine in the reinstatement of morphine CPP in morphine extinguished rats.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {131}, number = {}, pages = {110942}, doi = {10.1016/j.pnpbp.2024.110942}, pmid = {38215930}, issn = {1878-4216}, mesh = {Humans ; Rats ; Animals ; *Morphine/pharmacology ; *Acetylcysteine/pharmacology ; Rats, Wistar ; Extinction, Psychological/physiology ; Nucleus Accumbens ; Neurons ; }, abstract = {Numerous studies have suggested that N-acetylcysteine (NAC), has the potential to suppress drug craving in people with substance use disorder and reduce drug-seeking behaviors in animals. The nucleus accumbens (NAc) plays a crucial role in the brain's reward system, with the nucleus accumbens core (NAcore) specifically implicated in compulsive drug seeking and relapse. In this study, we aimed to explore the impact of subchronic NAC administration during the extinction period and acute NAC administration on the electrical activity of NAcore neurons in response to a priming dose of morphine in rats subjected to extinction from morphine-induced place preference (CPP).We conducted single-unit recordings in anesthetized rats on the reinstatement day, following the establishment of morphine-induced conditioned place preference (7 mg/kg, s.c., 3 days), and subsequent drug-free extinction. In the subchronically NAC-treated groups, rats received daily injections of either NAC (50 mg/kg; i.p.) or saline during the extinction period. On the reinstatement day, we recorded the spontaneous activity of NAcore neurons for 15 min, administered a priming dose of morphine, and continued recording for an additional 45 min. While morphine excited most recorded neurons in saline-treated rats, it failed to alter firing rates in NAC-treated rats that had received NAC during the extinction period. For acutely NAC-treated animals, we recorded the baseline activity of NAcore neurons for 10 min before administering a single injection of either NAC (50 mg/kg; i.p.) or saline in rats with no treatment during the extinction. Following 30 min of recording and a priming dose of morphine (1 mg/kg, s.c.), the recording continued for an additional 30 min. The firing activity of NAcore neurons did not show significant changes after morphine or NAC injection. In conclusion, our findings emphasize that daily NAC administration during the extinction period significantly attenuates the morphine-induced increase in firing rates of NAcore neurons during the reinstatement of morphine CPP. However, acute NAC injection does not produce the same effect. These results suggest that modulating glutamate transmission through daily NAC during extinction may effectively inhibit the morphine place preference following the excitatory effects of morphine on NAcore neurons.}, }
@article {pmid38213396, year = {2023}, author = {Fort, TD and Cain, ME}, title = {Inefficacy of N-acetylcysteine in mitigating cue-induced amphetamine-seeking.}, journal = {Addiction neuroscience}, volume = {8}, number = {}, pages = {}, pmid = {38213396}, issn = {2772-3925}, support = {P20 GM113109/GM/NIGMS NIH HHS/United States ; R15 DA035435/DA/NIDA NIH HHS/United States ; }, abstract = {Glutamatergic imbalances are characteristic of SUDs. Astrocytic and neuronal transporters help regulate glutamate homeostasis and disruptions in this homeostasis engender SUD. The cysteine-glutamate exchanger (xCT) is primarily localized on astrocytes and maintains glutamate concentrations. This process is disrupted by cocaine use, and the therapeutic N-acetylcysteine (NAC) lowers cue-induced relapse to cocaine by restoring xCT function. However, little research has shown how these effects extend to other psychostimulants, such as amphetamine (AMP). Here, we assessed xCT expression following relapse to AMP cues, and if NAC can attenuate relapse via changes to astrocyte and xCT expression. We administered NAC (100 mg/kg ip) daily during a 14-day abstinence period following AMP (0.1 mg/kg/infusion; 2 h sessions) self-administration. Relapse was tested following one (WD 1) or 14 days (WD 14) of withdrawal. The overall number of astrocytes was also quantified within the medial prefrontal cortex (mPFC) and nucleus accumbens (ACb). NAC failed to lower cue-induced AMP craving via cue-induced relapse and reinstatement testing. Cue-induced craving did not increase from WD 1 to WD 14. AMP-exposed rats had greater astrocyte counts in the mPFC and ACb when compared AMP-naïve rats. Repeated injection with NAC decreased xCT expression within the mPFC and ACb. Overall, these results suggest that NAC may be an ineffective treatment option for lowering cue-induced relapse to AMP. Further, the results suggest that stimulating xCT via NAC may not be an effective therapeutic approach for decreasing cue-seeking for AMP.}, }
@article {pmid38212360, year = {2024}, author = {Komakula, S and Bhatia, R and Sahib, A and Upadhyay, A and S, LJ and Garg, A and Y, VV and Pandit, AK and Vibha, D and Singh, MB and Tripathi, M and Srivastava, MVP}, title = {Safety and efficacy of N-acetylcysteine (NAC) as an adjunct to standard treatment in patients with acute ischemic stroke: a randomized controlled pilot trial (NACTLYS).}, journal = {Scientific reports}, volume = {14}, number = {1}, pages = {1103}, pmid = {38212360}, issn = {2045-2322}, mesh = {Humans ; Tissue Plasminogen Activator/adverse effects ; Acetylcysteine/adverse effects ; Pilot Projects ; *Ischemic Stroke/etiology ; Treatment Outcome ; Fibrinolytic Agents/adverse effects ; *Stroke ; Cerebral Hemorrhage/complications ; *Brain Ischemia/complications ; Thrombolytic Therapy/adverse effects ; }, abstract = {There is a pressing clinical need for thrombolytic agents that can effectively disaggregate arterial thrombi in acute ischemic stroke without significantly increasing the risk of bleeding. This pilot study aimed to investigate the safety and efficacy of N-acetylcysteine (NAC) as an adjunctive therapy to intravenous recombinant tissue plasminogen activator (rtPA or alteplase). A randomized, open-label, blinded assessor pilot study was conducted. Patients presenting with an acute ischemic stroke within 4.5 h from onset were randomized into two groups: intravenous NAC and rtPA or rtPA alone. Primary outcomes included intracerebral hemorrhage, symptomatic intracerebral hemorrhage, extracranial bleeding, and adverse reactions. Secondary outcomes comprised major neurological improvement assessed by (National Institute of Health Stroke Scale) NIHSS at 24 h, recanalization on first run of angiography in patients who underwent thrombectomy or on repeat vascular imaging at 24 h, modified Rankin scale, and three-month mortality. Forty patients were enrolled, with 21 receiving only rtPA and 19 receiving NAC with rtPA. Baseline characteristics were comparable among groups. No significant differences were observed in adverse events (p = 0.99), intracranial hemorrhage (p = 0.21), symptomatic intracerebral hemorrhage (p = 0.47), or extracranial bleeding (p = 0.21). Median NIHSS at 24 h was significantly lower in the intervention group (p = 0.03). Functional outcomes and three-month mortality were similar between groups (p = 0.85 and p = 0.99 respectively). The co-administration of N-acetylcysteine with alteplase did not significantly alter safety profiles, morbidity, or mortality at 3 months. While no substantial differences were noted, a slightly improved early neurological outcome was observed in the intervention arm. The study's findings were constrained by a small sample size, emphasizing the necessity for future large-scale trials to comprehensively evaluate the safety and efficacy of N-acetylcysteine as a thrombolytic agent in acute ischemic stroke.Trial Registration Clinical Trials Registry India-CTRI/2019/05/019305.}, }
@article {pmid38212034, year = {2023}, author = {Ma, TX and Li, JT and Li, J and Zhang, Y and Liang, JQ}, title = {[Guiqi Yiyuan Ointment protects rat left lung from bystander effect of right lung injury induced by ~(12)C~(6+) beam].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {48}, number = {24}, pages = {6740-6748}, doi = {10.19540/j.cnki.cjcmm.20230914.702}, pmid = {38212034}, issn = {1001-5302}, mesh = {Rats ; Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; NF-kappa B/genetics/metabolism ; Inflammasomes/metabolism ; *Lung Injury/etiology/genetics ; Reactive Oxygen Species/metabolism ; Bystander Effect ; Ointments ; Rats, Wistar ; Lung/metabolism ; Caspase 1/metabolism ; RNA, Messenger ; Superoxide Dismutase ; }, abstract = {This study observed the effects of Guiqi Yiyuan Ointment(GQYY) on the left lung subjecting to bystander effect of right lung injury induced by ~(12)C~(6+) beam in rats and decipher the underlying mechanism from NOD-like receptor protein 3(NLRP3)/apoptosis-associated speck-like protein containing a CARD(ASC)/cysteinyl aspartate specific proteinase-1(caspase-1) pathway. Wistar rats were randomized into 7 groups: blank, model, inhibitor [200 mg·kg~(-1), N-acetylcysteine(NAC)], western drug [140 mg·kg~(-1) amifostine(AMI)], and high-, medium-, and low-dose(4.8, 2.4, and 1.2 g·kg~(-1), respectively) GQYY groups. The model of bystander effect damage was established by 4 Gy ~(12)C~(6+) beam irradiation of the right lung(with the other part shielded by a lead plate). The pathological changes in the lung tissue, the level of reactive oxygen species(ROS) in the lung tissue, and the levels of superoxide dismutase(SOD) and malondialdehyde(MDA) in the serum were observed and measured in each group. Furthermore, the mRNA and protein levels of NLRP3, ASC, caspase-1, and phosphorylated nuclear factor-κB p65(p-NF-κB p65)/nuclear factor-κB p65(NF-κB p65) were determined. Compared with the blank group, the model group showed thickened alveolar wall, narrowed alveolar cavity, and presence of massive red blood cells and inflammatory infiltration in the alveolar wall and alveolar cavity. In addition, the model group showed elevated ROS levels in both left and right lungs, elevated MDA level, lowered SOD level, and up-regulated mRNA and protein levels of NLRP3, ASC, caspase-1, and p-NF-κB p65/NF-κB p65. Compared with the model group, the drug administration in all the groups reduced inflammatory cell infiltration in the lung tissue. The inhibitor group and the western drug group showed enlarged alveolar cavity, thinned interstitium, and reduced inflammation. There was a small amount of alveolar wall rupture in the high-and medium-dose GQYY groups and reduced inflammatory cell infiltration in the low dose GQYY group. Compared with the model group, drug administration lowered level of ROS in the left and right lungs, lowered the MDA level, elevated the SOD level, and down-regulated the mRNA and protein levels of NLRP3, ASC, caspase-1, and p-NF-κB p65/NF-κB p65. GQYY can effectively reduce the damage caused by radiation and bystander effect, which may be associated with the ROS-mediated NLRP3 inflammasome activation.}, }
@article {pmid38211826, year = {2024}, author = {Li, X and Kong, L and Pan, J and Liu, H and Wang, C and Xu, S and Liu, W and Sun, J}, title = {N-acetylcysteine protects against neurodevelopmental injuries induced by methylmercury exposure during pregnancy and lactation.}, journal = {Brain research}, volume = {1827}, number = {}, pages = {148761}, doi = {10.1016/j.brainres.2024.148761}, pmid = {38211826}, issn = {1872-6240}, mesh = {Humans ; Pregnancy ; Female ; Animals ; Mice ; *Acetylcysteine/pharmacology ; *Methylmercury Compounds/toxicity ; Lactation ; Antioxidants/pharmacology ; Brain ; }, abstract = {As an extremely dangerous environmental contaminant, methylmercury (MeHg) results in detrimental health effects in human brain nervous system, one of its main targets. However, as a developmental toxicant, the brain of offspring is vulnerable to MeHg during pregnancy and lactation exposure. Unfortunately, mechanisms of neurodevelopmental injuries induced by MeHg have not been fully elucidated. N-acetylcysteine (NAC) has been used for several decades as an antioxidant to antagonize oxidative stress. However, the molecular mechanisms of NAC alleviating MeHg-induced neurodevelopmental toxicity are not clear. Here, for evaluation of the dose-dependent effects of MeHg exposure on neurodevelopmental injuries of offspring, and the possible protective effects of NAC, the pregnant female mice were exposed to MeHg (4, 8, 12 mg/L, respectively) and NAC (50, 100, 150 mg/kg, respectively) from gestational day 1 (GD1) to postnatal day 21 (PND21). Our results indicated that administering MeHg caused behavioral impairment and neuronal injuries in the cerebral cortex of newborn mice. MeHg dose-dependently caused reactive oxygen species (ROS) overproduction and oxidative stress aggravation, together with expression of Nrf2, HO-1, Notch1, and p21 up-regulation, and CDK2 inhibition. NAC treatment dose-dependently antagonized MeHg-induced oxidative stress that may contribute to alleviating neurobehavioral and neurodevelopmental impairments. These results give insight into that NAC can protect against MeHg-induced neurodevelopmental toxicity by its antioxidation capacity.}, }
@article {pmid38206362, year = {2024}, author = {Baumel-Alterzon, S and Katz, LS and Lambertini, L and Tse, I and Heidery, F and Garcia-Ocaña, A and Scott, DK}, title = {NRF2 is required for neonatal mouse beta cell growth by maintaining redox balance and promoting mitochondrial biogenesis and function.}, journal = {Diabetologia}, volume = {67}, number = {3}, pages = {547-560}, pmid = {38206362}, issn = {1432-0428}, support = {DK128387-01A1/DK/NIDDK NIH HHS/United States ; R01DK114338/DK/NIDDK NIH HHS/United States ; R01DK130300/DK/NIDDK NIH HHS/United States ; DK128387-01A1/DK/NIDDK NIH HHS/United States ; R01DK114338/DK/NIDDK NIH HHS/United States ; R01DK130300/DK/NIDDK NIH HHS/United States ; }, mesh = {Male ; Humans ; Mice ; Animals ; Child ; Infant, Newborn ; Infant ; Blood Glucose/metabolism ; Antioxidants/metabolism ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2/genetics ; Animals, Newborn ; Organelle Biogenesis ; *Insulin-Secreting Cells/metabolism ; Glucose/metabolism ; Oxidation-Reduction ; DNA, Mitochondrial/metabolism ; Adenosine Triphosphate/metabolism ; *Insulins ; }, abstract = {AIMS/HYPOTHESIS: All forms of diabetes result from insufficient functional beta cell mass. Due to the relatively limited expression of several antioxidant enzymes, beta cells are highly vulnerable to pathological levels of reactive oxygen species (ROS), which can lead to the reduction of functional beta cell mass. During early postnatal ages, both human and rodent beta cells go through a burst of proliferation that quickly declines with age. The exact mechanisms that account for neonatal beta cell proliferation are understudied but mitochondrial release of moderated ROS levels has been suggested as one of the main drivers. We previously showed that, apart from its conventional role in protecting beta cells from oxidative stress, the nuclear factor erythroid 2-related factor 2 (NRF2) is also essential for beta cell proliferation. We therefore hypothesised that NRF2, which is activated by ROS, plays an essential role in beta cell proliferation at early postnatal ages.<br><br>METHODS: Beta cell NRF2 levels and beta cell proliferation were measured in pancreatic sections from non-diabetic human cadaveric donors at different postnatal ages, childhood and adulthood. Pancreatic sections from 1-, 7-, 14- and 28-day-old beta cell-specific Nrf2 (also known as Nfe2l2)-knockout mice (&#x3b2;Nrf2KO) or control (Nrf2[lox/lox]) mice were assessed for beta cell NRF2 levels, beta cell proliferation, beta cell oxidative stress, beta cell death, nuclear beta cell pancreatic duodenal homeobox protein 1 (PDX1) levels and beta cell mass. Seven-day-old &#x3b2;Nrf2KO and Nrf2[lox/lox] mice were injected daily with N-acetylcysteine (NAC) or saline (154 mmol/l NaCl) to explore the potential contribution of oxidative stress to the phenotypes seen in &#x3b2;Nrf2KO mice at early postnatal ages. RNA-seq was performed on 7-day-old &#x3b2;Nrf2KO and Nrf2[lox/lox] mice to investigate the mechanisms by which NRF2 stimulates beta cell proliferation at early postnatal ages. Mitochondrial biogenesis and function were determined using dispersed islets from 7-day-old &#x3b2;Nrf2KO and Nrf2[lox/lox] mice by measuring MitoTracker intensity, mtDNA/gDNA ratio and ATP/ADP ratio. To study the effect of neonatal beta cell-specific Nrf2 deletion on glucose homeostasis in adulthood, blood glucose, plasma insulin and insulin secretion were determined and a GTT was performed on 3-month-old &#x3b2;Nrf2KO and Nrf2[lox/lox] mice fed on regular diet (RD) or high-fat diet (HFD).<br><br>RESULTS: The expression of the master antioxidant regulator NRF2 was increased at early postnatal ages in both human (1 day to 19 months old, 31%) and mouse (7 days old, 57%) beta cells, and gradually declined with age (8% in adult humans, 3.77% in adult mice). A significant correlation (R[2]=0.568; p=0.001) was found between beta cell proliferation and NRF2 levels in human beta cells. Seven-day-old &#x3b2;Nrf2KO mice showed reduced beta cell proliferation (by 65%), beta cell nuclear PDX1 levels (by 23%) and beta cell mass (by 67%), and increased beta cell oxidative stress (threefold) and beta cell death compared with Nrf2[lox/lox] control mice. NAC injections increased beta cell proliferation in 7-day-old &#x3b2;Nrf2KO mice (3.4-fold) compared with saline-injected &#x3b2;Nrf2KO mice. Interestingly, RNA-seq of islets isolated from 7-day-old &#x3b2;Nrf2KO mice revealed reduced expression of mitochondrial RNA genes and genes involved in the electron transport chain. Islets isolated from 7-day old &#x3b2;Nrf2KO mice presented reduced MitoTracker intensity (by 47%), mtDNA/gDNA ratio (by 75%) and ATP/ADP ratio (by 68%) compared with islets from Nrf2[lox/lox] littermates. Lastly, HFD-fed 3-month-old &#x3b2;Nrf2KO male mice displayed a significant reduction in beta cell mass (by 35%), a mild increase in non-fasting blood glucose (1.2-fold), decreased plasma insulin (by 14%), and reduced glucose tolerance (1.3-fold) compared with HFD-fed Nrf2[lox/lox] mice.<br><br>CONCLUSIONS/INTERPRETATION: Our study highlights NRF2 as an essential transcription factor for maintaining neonatal redox balance, mitochondrial biogenesis and function and beta cell growth, and for preserving functional beta cell mass in adulthood under metabolic stress.<br><br>DATA AVAILABILITY: Sequencing data are available in the NCBI Gene Expression Omnibus, accession number GSE242718 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE242718).}, }
@article {pmid38204261, year = {2024}, author = {ALRashdi, BM and Hussein, MM and Mohammed, RM and Abdelhamed, NW and Asaad, ME and Alruwaili, M and Alrashidi, SM and Habotta, OA and Abdel Moneim, AE and Ramadan, SS}, title = {Turmeric Extract-loaded Selenium Nanoparticles Counter Doxorubicin-induced Hepatotoxicity in Mice via Repressing Oxidative Stress, Inflammatory Cytokines, and Cell Apoptosis.}, journal = {Anti-cancer agents in medicinal chemistry}, volume = {24}, number = {6}, pages = {443-453}, pmid = {38204261}, issn = {1875-5992}, support = {DSR-2021-03-03112//Deanship of Scientific Research at Jouf University/ ; }, mesh = {Animals ; *Doxorubicin/pharmacology ; *Oxidative Stress/drug effects ; Mice ; *Selenium/chemistry/pharmacology ; *Apoptosis/drug effects ; *Plant Extracts/pharmacology/chemistry ; *Cytokines/metabolism ; *Nanoparticles/chemistry ; Male ; Curcuma/chemistry ; Chemical and Drug Induced Liver Injury/drug therapy/metabolism/pathology ; Dose-Response Relationship, Drug ; Structure-Activity Relationship ; Antibiotics, Antineoplastic/pharmacology ; Cell Proliferation/drug effects ; }, abstract = {BACKGROUND: Doxorubicin (DOX) is an antitumor anthracycline used to treat a variety of malignancies; however, its clinical use is associated with noticeable hepatotoxicity. Therefore, the current study was designed to delineate if biosynthesized SeNPs with turmeric extract (Tur-SeNPs) could alleviate DOX-induced hepatic adverse effects.<br><br>METHODS: Mice were orally post-treated with Tur extract, Tur-SeNPs, or N-acetyl cysteine after the intraperitoneal injection of DOX.<br><br>RESULTS: Our findings have unveiled a remarkable liver attenuating effect in DOX-injected mice post-treated with Tur-SeNPs. High serum levels of ALT, AST, ALP, and total bilirubin induced by DOX were significantly decreased by Tur-SeNPs therapy. Furthermore, Tur-SeNPs counteracted DOX-caused hepatic oxidative stress, indicated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and mRNA expression levels of Nrf-2. Noteworthily, decreased hepatic IL-1&#x3b2;, TNF-&#x3b1;, and NF-&#x3ba;B p65 levels in addition to downregulated iNOS gene expression in Tur-SeNPs-treated mice have indicated their potent antiinflammatory impact. Post-treatment with Tur-SeNPs also mitigated the hepatic apoptosis evoked by DOX injection. A liver histological examination confirmed the biochemical and molecular findings.<br><br>CONCLUSIONS: In brief, the outcomes have demonstrated Tur loaded with nanoselenium to successfully mitigate the liver damage induced by DOX via blocking oxidative stress, and inflammatory and apoptotic signaling.}, }
@article {pmid38203377, year = {2023}, author = {Govoni, S and Fantucci, P and Marchesi, N and Vertemara, J and Pascale, A and Allegri, M and Calvillo, L and Vanoli, E}, title = {N-Acetylcysteine Antagonizes NGF Activation of TrkA through Disulfide Bridge Interaction, an Effect Which May Contribute to Its Analgesic Activity.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203377}, issn = {1422-0067}, support = {GU Serie Generale n. 92 , April 19, 2014//MIUR (ministry of University and Research) GU Serie Generale n. 92 , April 19, 2014, funding Neuheart S.r.l. (516.456 &#x20ac;) for the project having the title "Sviluppo di farmaci agonisti ed antagonisti delle neurotrofine (Development of neurotrophin-receptor/ ; }, mesh = {Humans ; *Acetylcysteine/pharmacology ; Nerve Growth Factor/pharmacology ; *Neuroblastoma ; Analgesics/pharmacology ; Disulfides ; }, abstract = {N-acetylcysteine (NAC), a mucolytic agent and an antidote to acetaminophen intoxication, has been studied in experimental conditions and trials exploring its analgesic activity based on its antioxidant and anti-inflammatory properties. The purpose of this study is to investigate additional mechanisms, namely, the inhibition of nerve growth factor (NGF) and the activation of the Tropomyosin receptor kinase A (TrkA) receptor, which is responsible for nociception. In silico studies were conducted to evaluate dithiothreitol and NAC's interaction with TrkA. We also measured the autophosphorylation of TrkA in SH-SY5Y cells via ELISA to assess NAC's in vitro activity against NGF-induced TrkA activation. The in silico and in vitro tests show that NAC interferes with NGF-induced TrkA activation. In particular, NAC breaks the disulfide-bound Cys 300-345 of TrkA, perturbing the NGF-TrkA interaction and producing a rearrangement of the binding site, inducing a consequent loss of their molecular recognition and spatial reorganization, which are necessary for the induction of the autophosphorylation process. The latter was inhibited by 40% using 20 mM NAC. These findings suggest that NAC could have a role as a TrkA antagonist, an action that may contribute to the activity and use of NAC in various pain states (acute, chronic, nociplastic) sustained by NGF hyperactivity and/or accompanied by spinal cord sensitization.}, }
@article {pmid38203359, year = {2023}, author = {Boguszewicz, &#x141; and Bieleń, A and Ciszek, M and Skorupa, A and Mrochem-Kwarciak, J and Składowski, K and Sokół, M}, title = {Metabolomic Insight into Implications of Induction Chemotherapy Followed by Concomitant Chemoradiotherapy in Locally Advanced Head and Neck Cancer.}, journal = {International journal of molecular sciences}, volume = {25}, number = {1}, pages = {}, pmid = {38203359}, issn = {1422-0067}, mesh = {Humans ; Squamous Cell Carcinoma of Head and Neck/therapy ; *Induction Chemotherapy ; Phosphorylcholine ; *Head and Neck Neoplasms/therapy ; Chemoradiotherapy/adverse effects ; Betaine ; Serine ; Tyrosine ; Lipids ; }, abstract = {The present study compares two groups of locally advanced patients with head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (cCHRT), specifically those for whom it is a first-line treatment and those who have previously received induction chemotherapy (iCHT). The crucial question is whether iCHT is a serious burden during subsequent treatment for LA-HNSCC and how iCHT affects the tolerance to cCHRT. Of the 107 LA-HNSCC patients, 54 received cisplatin-based iCHT prior to cCHRT. The patients were clinically monitored at weekly intervals from the day before until the completion of the cCHRT. The 843 blood samples were collected and divided into two aliquots: for laboratory blood tests and for nuclear magnetic resonance (NMR) spectroscopy (a Bruker 400 MHz spectrometer). The NMR metabolites and the clinical parameters from the laboratory blood tests were analyzed using orthogonal partial least squares analysis (OPLS) and the Mann-Whitney U test (MWU). After iCHT, the patients begin cCHRT with significantly (MWU p-value < 0.05) elevated blood serum lipids, betaine, glycine, phosphocholine, and reticulocyte count, as well as significantly lowered NMR inflammatory markers, serine, hematocrit, neutrophile, monocyte, red blood cells, hemoglobin, and CRP. During cCHRT, a significant increase in albumin and psychological distress was observed, as well as a significant decrease in platelet, N-acetyl-cysteine, tyrosine, and phenylalanine, in patients who received iCHT. Importantly, all clinical symptoms (except the decreased platelets) and most metabolic alterations (except for betaine, serine, tyrosine, glucose, and phosphocholine) resolve until the completion of cCHRT. In conclusion, iCHT results in hematological toxicity, altered lipids, and one-carbon metabolism, as well as downregulated inflammation, as observed at the beginning and during cCHRT. However, these complications are temporary, and most of them resolve at the end of the treatment. This suggests that iCHT prior to cCHRT does not pose a significant burden and should be considered as a safe treatment option for LA-HNSCC.}, }
@article {pmid38199597, year = {2024}, author = {Yuan, Z and Yi, G and Ma, R and Wang, Z and Hu, J and Zhao, W and Hu, Y}, title = {Aldehyde oxidase 1 promotes gallbladder carcinogenesis through ROS-mediated activation of the Wnt/β-catenin pathway.}, journal = {Cellular signalling}, volume = {116}, number = {}, pages = {111042}, doi = {10.1016/j.cellsig.2024.111042}, pmid = {38199597}, issn = {1873-3913}, mesh = {Animals ; Humans ; Mice ; Aldehyde Oxidase ; beta Catenin ; Carcinogenesis ; *Gallbladder Neoplasms ; Reactive Oxygen Species ; Wnt Signaling Pathway ; }, abstract = {BACKGROUND: Aldehyde oxidase 1 (AOX1) is associated with various pathophysiological processes, including cancer. Specifically, AOX1 has been demonstrated to have a close relationship with the progression of certain cancers. However, the expression, function, and mechanisms of action of AOX1 in gallbladder cancer (GBC) remain unclear.<br><br>METHODS: Utilizing immunohistochemistry, the study quantified the prevalence of AOX1 within tissues of gallbladder carcinoma and those of the surrounding non-cancerous regions. In vitro assays using gallbladder carcinoma cell lines with modulated AOX1 expression levels were performed to assess the protein's role in cell proliferation, migration, and invasion. Furthermore, flow cytometry techniques were harnessed to determine the influence of AOX1 on the content of reactive oxygen species (ROS) in these cells. Additionally, the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt/&#x3b2;-catenin signaling pathway markersin cells with varied AOX1 expression, detected through Western blot analyses. An in vivo xenograft model involving athymic mice was implemented to explore the influence of AOX1 on gallbladder tumor growth, with Western blot analysis applied to measure EMT marker expression in the resulting tumours.<br><br>RESULTS: Elevated AOX1 protein levels have been observed in gallbladder carcinoma tissues, with such upregulation linked to a negative prognostic outlook for patients. In vitro analyses demonstrate that enhanced AOX1 expression facilitates gallbladder carcinoma cell proliferation, migration, and invasion, while AOX1 suppression yields an inhibitory effect on these cellular behaviors. Western blot results reveal an inverse relationship between AOX1 and E-cadherin levels, yet was positively correlation with N-cadherin, Vimentin, and Snail within both gallbladder cancer cells and in vivo xenograft tumours. Further mechanistic investigation indicates that AOX1 elevation augments reactive oxygen species (ROS) production and initiates the Wnt/&#x3b2;-catenin signaling pathway in these cells. The application of N-acetylcysteine (NAC) and/or KY1797K attenuates the proliferative, migratory, and invasive enhancements imparted by AOX1 overexpression and reinforces these effects when AOX1 is silenced-achieved through ROS mitigation and the obstruction of the Wnt/&#x3b2;-catenin pathway. In vivo studies corroborate these findings, showing AOX1 overexpression to amplify xenograft tumor growth and mesenchymal marker expression, whereas AOX1 interference did the opposite.<br><br>CONCLUSIONS: The study indicates that AOX1 functions as a carcinogenic factor in gallbladder carcinoma, enhancing cell proliferation, migration, invasion, and the EMT. These effects are driven by the activation of the Wnt/&#x3b2;-catenin pathway mediated by reactive oxygen species (ROS). Therefore,AOX1 presents potential as a valuable prognostic and diagnostic marker as well as a target for therapeutic intervention in the gallbladder cancer.}, }
@article {pmid38194754, year = {2024}, author = {Yang, D and Yu, X and Li, X and Yu, B and Peng, H}, title = {Protective effects of l-cysteine and N-acetyl-l-cysteine on boar sperm quality during hypothermic liquid storage with bovine serum albumin as a protectant.}, journal = {Theriogenology}, volume = {216}, number = {}, pages = {185-195}, doi = {10.1016/j.theriogenology.2023.12.030}, pmid = {38194754}, issn = {1879-3231}, mesh = {Male ; Swine ; Animals ; *Semen ; Acetylcysteine/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Serum Albumin, Bovine/pharmacology/metabolism ; Antioxidants/pharmacology/metabolism ; AMP-Activated Protein Kinases/metabolism ; Sperm Motility ; Spermatozoa/physiology ; Semen Analysis/veterinary ; Glutathione/metabolism ; Adenosine Triphosphate/metabolism ; *Semen Preservation/veterinary/methods ; }, abstract = {Hypothermic liquid storage at 4-5 °C has emerged as a novel approach for preserving boar semen, offering innovative possibilities for semen preservation. However, this method also presents challenges, including cold shock and excessive reactive oxygen species (ROS) production. Therefore, reducing oxidative damage induced by low temperatures becomes essential while supplementing appropriate protectants. In this study, we investigated the efficacy of Bovine Serum Albumin (BSA) compared to Polyvinylpyrrolidone (PVP) and Skim Milk Powder (SMP) in maintaining boar sperm motility and progressive motility using computer-assisted sperm analysis (CASA). Among the tested concentrations, 4 g/L of BSA exhibited the best protective effect. Subsequently, we supplemented different concentrations of l-cysteine (LC) and N-acetyl-l-cysteine (NAC) as additives in the presence of BSA as a protectant. Our results demonstrated that 1 mmol/L of LC and 0.5 mmol/L of NAC exhibited superior protection of sperm quality compared to other concentrations. Furthermore, the 1 mmol/L LC and 0.5 mmol/L NAC groups showed significantly improved plasma membrane integrity and acrosome integrity compared to the control group. These groups also exhibited enhanced antioxidant capacity, evidenced by increased mitochondrial membrane potential (MMP), ATP production, total superoxide dismutase (T-SOD) activity, total antioxidant capacity (T-AOC), glutathione (GSH), glutathione peroxidase (GSH-PX), and GPX-4 levels. Additionally, they demonstrated decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, as well as reduced oxidized glutathione (GSSG) and glutathione reductase (GR) levels. Furthermore, LC and NAC treatment enhanced AMP-activated protein kinase (AMPK) phosphorylation. However, inhibiting AMPK using compound C did not inhibit the protective effects of LC and NAC on low-temperature preserved boar sperm. These findings suggest that 4 g/L BSA can serve as an effective protectant for hypothermic liquid storage of boar semen. Additionally, LC and NAC supplementation reduces oxidative damage by enhancing antioxidant capacity rather than through AMPK-mediated ATP supplementation. These results contribute to advancing the application of LC and NAC in hypothermic liquid storage of boar semen.}, }
@article {pmid38191622, year = {2024}, author = {Romero-Miguel, D and Casquero-Veiga, M and Lamanna-Rama, N and Torres-Sánchez, S and MacDowell, KS and García-Partida, JA and Santa-Marta, C and Berrocoso, E and Leza, JC and Desco, M and Soto-Montenegro, ML}, title = {N-acetylcysteine during critical neurodevelopmental periods prevents behavioral and neurochemical deficits in the Poly I:C rat model of schizophrenia.}, journal = {Translational psychiatry}, volume = {14}, number = {1}, pages = {14}, pmid = {38191622}, issn = {2158-3188}, mesh = {Female ; Pregnancy ; Rats ; Animals ; Rats, Wistar ; *Acetylcysteine/pharmacology ; *Schizophrenia/drug therapy/prevention &amp; control ; Poly I-C ; Inflammation ; }, abstract = {Schizophrenia is a chronic neurodevelopmental disorder with an inflammatory/prooxidant component. N-acetylcysteine (NAC) has been evaluated in schizophrenia as an adjuvant to antipsychotics, but its role as a preventive strategy has not been sufficiently explored. We aimed to evaluate the potential of NAC administration in two-time windows before the onset of symptoms in a schizophrenia-like maternal immune stimulation (MIS) rat model. Pregnant Wistar rats were injected with Poly I:C or Saline on gestational day (GD) 15. Three different preventive approaches were evaluated: 1) NAC treatment during periadolescence in the offspring (from postnatal day [PND] 35 to 49); 2) NAC treatment during pregnancy after MIS challenge until delivery (GD15-21); and 3) NAC treatment throughout all pregnancy (GD1-21). At postnatal day (PND) 70, prepulse inhibition (PPI) and anxiety levels were evaluated. In vivo magnetic resonance (MR) imaging was acquired on PND100 to assess structural changes in gray and white matter, and brain metabolite concentrations. Additionally, inflammation and oxidative stress (IOS) markers were measured ex vivo in selected brain regions. MIS offspring showed behavioral, neuroanatomical, and biochemical alterations. Interestingly, NAC treatment during periadolescence prevented PPI deficits and partially counteracted some biochemical imbalances. Moreover, NAC treatments during pregnancy not only replicated the beneficial outcomes reported by the treatment in periadolescence, but also prevented some neuroanatomical deficits, including reductions in hippocampal and corpus callosum volumes. This study suggests that early reduction of inflammation and prooxidation could help prevent the onset of schizophrenia-like symptoms, supporting the importance of anti-IOS compounds in ameliorating this disorder.}, }
@article {pmid38190586, year = {2024}, author = {Lebrun, F and Levard, D and Lemarchand, E and Yetim, M and Furon, J and Potzeha, F and Marie, P and Lesept, F and Blanc, M and Haelewyn, B and Rubio, M and Letourneur, A and Violle, N and Orset, C and Vivien, D}, title = {Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages.}, journal = {Blood advances}, volume = {8}, number = {5}, pages = {1330-1344}, pmid = {38190586}, issn = {2473-9537}, support = {EP-D-14-002/EPA/EPA/United States ; }, mesh = {Mice ; Animals ; Humans ; Tissue Plasminogen Activator/pharmacology/therapeutic use ; Mice, Obese ; *Stroke/drug therapy/etiology ; Hemorrhage ; Inflammation/drug therapy ; *Ischemic Stroke/complications/drug therapy ; *Hyperglycemia/complications/drug therapy ; }, abstract = {The pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.}, }
@article {pmid38188454, year = {2024}, author = {El-Sobky, H and El-Shanawany, SM and Ghanem, M and Atef, M}, title = {Role of N-acetylcysteine and vitamin B complex in improving outcomes of corrosive ingestion.}, journal = {Toxicology research}, volume = {13}, number = {1}, pages = {tfad125}, pmid = {38188454}, issn = {2045-452X}, abstract = {BACKGROUND: Corrosive ingestion remains a worldwide public health problem. To date, there are no specific medications with approved efficacy in reducing gastrointestinal injury progression following corrosive ingestion.<br><br>AIM: The current study assessed the efficacy of N-acetylcysteine (NAC) and vitamin B complex as adjuvant therapy in improving the outcome of patients with corrosive ingestion.<br><br>SUBJECTS AND METHODS: The study included 92 patients with acute corrosive ingestion admitted to Alexandria Poison Center. Patients were distributed into four equal-sized groups and managed as such; Group I received the standard treatment protocol. The other three groups received IV antioxidants in addition to the standard treatment; Group II received NAC, Group III received vitamin B complex, and Group IV received both NAC and vitamin B complex. To assess occurrence of delayed complications, barium swallow and meal were done 21&#xa0;days after acute corrosive ingestion, and every patient was followed up for one year.<br><br>RESULTS: Start of oral intake was earliest among patients in Group II, and as a result, the need for parenteral nutrition decreased significantly with a subsequent decrease in duration of hospitalization. The highest percentage of patients showing normal findings of barium swallow and meal was among the two groups that received NAC (72.7% in Group II and 77.8% in Group IV). Group IV patients who received NAC and vitamin B complex had no esophageal strictures with improved outcomes.<br><br>CONCLUSION: NAC and vitamin B complex enhanced recovery in the acute stage, in addition to prevention of delayed complications, especially esophageal strictures.<br><br>HIGHLIGHTS: Acute corrosive ingestion is associated with high morbidity because of its catastrophic presentation and lifelong complications.This study was conducted on 92 patients admitted to Alexandria Poison Center (APC).IV NAC significantly decreased the time needed for starting oral intake after acute corrosive ingestion and consequently, the need for parenteral nutrition and duration of hospitalization.No patients suffered from esophageal strictures in the group which received both IV NAC and vitamin B complex.Both NAC and vitamin B complex improved the outcome of patients after ingestion of corrosives whether acids or alkalis.}, }
@article {pmid38187538, year = {2023}, author = {Dobariya, P and Xie, W and Rao, SP and Xie, J and Seelig, DM and Vince, R and Lee, MK and More, SS}, title = {Deletion of Glyoxalase 1 exacerbates acetaminophen-induced hepatotoxicity in mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38187538}, support = {R01 AG062469/AG/NIA NIH HHS/United States ; }, abstract = {Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC) has a narrow therapeutic window and early treatment is essential for satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late-presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end-products (AGEs) and consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase-1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in APAP mediated activation of RAGE and downstream cell-death cascades. Constitutive Glo-1 knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were employed as tools. Our findings show elevated oxidative stress, activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild type controls. A unique feature of the hepatic necrosis in GKO mice is the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than inflammation seen in wild type. The GSH surrogate and general antioxidant, ψ-GSH alleviated APAP toxicity irrespective of Glo-1 status, suggesting that oxidative stress being the primary driver of APAP toxicity. Overall, exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against initial stages of APAP overdose.}, }
@article {pmid38184979, year = {2024}, author = {Zhou, J and Zhang, Y and Zeng, L and Wang, X and Xiang, W and Su, P}, title = {Cadmium exposure induces pyroptosis of TM4 cells through oxidative stress damage and inflammasome activation.}, journal = {Ecotoxicology and environmental safety}, volume = {270}, number = {}, pages = {115930}, doi = {10.1016/j.ecoenv.2024.115930}, pmid = {38184979}, issn = {1090-2414}, mesh = {Male ; Humans ; *Inflammasomes/metabolism ; *Cadmium/toxicity ; Reactive Oxygen Species ; Pyroptosis ; Signal Transduction ; Oxidative Stress ; Acetylcysteine/pharmacology ; }, abstract = {Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1β (IL-1β) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11-7082 (BAY) alleviate the release of IL-1β and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.}, }
@article {pmid38169912, year = {2023}, author = {Abdo, M and Kohaf, N and Hammad, MA and Ping, CC}, title = {The Role of Oral Ascorbic Acid Administration in Combination With IV N-acetylcysteine in Delaying Inflammatory Cascade in Sepsis: A Case Report.}, journal = {Cureus}, volume = {15}, number = {12}, pages = {e49868}, pmid = {38169912}, issn = {2168-8184}, abstract = {Sepsis is a life-threatening emergency that arises owing to a dysregulated host response to infection, leading to existence organ dysfunction. Vitamin C administration has led to a lower mortality rate in sepsis. N-acetylcysteine (NAC) treatment during sepsis improves hepatic function and enhances tissue oxygenation. The objective of this case report is to investigate the synergistic effect of the combination of vitamin C, thiamine, and NAC in delaying sepsis cascade and prolongation of survival time. In this case report, an oral dose of vitamin C 500 mg three times daily in combination with IV thiamine 100 mg three times daily, IV NAC, and hydrocortisone stress dose resulted in 12 days of survival of an immunocompromised patient with ventilator-associated pneumonia on single anti-pseudomonas beta-lactam antibiotic. The patient was a 60-year-old Malay female with previous bone marrow transplantation surgery and a medical history of ischemic stroke on phenytoin and valproate therapy. The patient was transferred to a medical ward in Penang General Hospital, Malaysia, due to community-acquired pneumonia. She was on ceftriaxone for five days, then sedated and ventilated in the ICU, with a shift to cefepime for three days, which was then changed to meropenem for nine days until the last day of life. Total anti-pseudomonas coverage was 12 days. The patient had multiple comorbidities from phenytoin-induced hepatic encephalopathy, acute kidney injury, and three sessions of hemodialysis. IV vitamin C was not available, so an oral dose was administered with potential efficacy in delaying the sepsis inflammatory cascade, leading to the use of a single (not double) anti-pseudomonas antibiotic for 12 days. Prolonged survival duration may be expected in the case of normal bone marrow patients with ventilator-associated pneumonia sepsis. In conclusion, Vitamin C, thiamine, and NAC combination resulted in delayed sepsis progression for 12 days and the survival of the immunocompromised patient on a single anti-pseudomonas beta-lactam antibiotic.}, }
@article {pmid38169324, year = {2024}, author = {Bildik, G and Gray, JP and Mao, W and Yang, H and Ozyurt, R and Orellana, VR and De Wever, O and Carey, MS and Bast, RC and Lu, Z}, title = {DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas.}, journal = {Autophagy}, volume = {20}, number = {3}, pages = {675-691}, pmid = {38169324}, issn = {1554-8635}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA083639/CA/NCI NIH HHS/United States ; P50 CA217685/CA/NCI NIH HHS/United States ; R01 CA266187/CA/NCI NIH HHS/United States ; }, mesh = {Female ; Humans ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Autophagy/physiology ; *Ovarian Neoplasms/drug therapy/genetics/metabolism ; *Pancreatic Neoplasms/drug therapy/genetics/pathology ; *Carcinoma, Pancreatic Ductal/pathology ; Chloroquine/pharmacology ; }, abstract = {Pancreatic ductal adenocarcinoma (PDAC) and low-grade ovarian cancer (LGSOC) are characterized by the prevalence of KRAS oncogene mutations. DIRAS3 is the first endogenous non-RAS protein that heterodimerizes with RAS, disrupts RAS clustering, blocks RAS signaling, and inhibits cancer cell growth. Here, we found that DIRAS3-mediated KRAS inhibition induces ROS-mediated apoptosis in PDAC and LGSOC cells with KRAS mutations, but not in cells with wild-type KRAS, by downregulating NFE2L2/Nrf2 transcription, reducing antioxidants, and inducing oxidative stress. DIRAS3 also induces cytoprotective macroautophagy/autophagy that may protect mutant KRAS cancer cells from oxidative stress, by inhibiting mutant KRAS, activating the STK11/LKB1-PRKAA/AMPK pathway, increasing lysosomal CDKN1B/p27 localization, and inducing autophagic gene expression. Treatment with chloroquine or the novel dimeric chloroquine analog DC661 significantly enhances DIRAS3-mediated inhibition of mutant KRAS tumor cell growth in vitro and in vivo. Taken together, our study demonstrates that DIRAS3 plays a critical role in regulating mutant KRAS-driven oncogenesis in PDAC and LGSOC.Abbreviations: AFR: autophagic flux reporter; ATG: autophagy related; CQ: chloroquine; DCFDA: 2'-7'-dichlorodihydrofluorescein diacetate; DIRAS3: DIRAS family GTPase 3; DOX: doxycycline; KRAS: KRAS proto-oncogene, LGSOC: low-grade serous ovarian cancer; MiT/TFE: microphthalmia family of transcription factors; NAC: N-acetylcysteine; PDAC: pancreatic ductal adenocarcinoma; ROS: reactive oxygen species; TFEB: transcription factor EB.}, }
@article {pmid38165196, year = {2023}, author = {Cole, JB and Oakland, CL and Lee, SC and Considine, KA and Rudis, MI and Swanson, AL and Olives, TD}, title = {Is Two Better Than Three? A Systematic Review of Two-bag Intravenous N-acetylcysteine Regimens for Acetaminophen Poisoning.}, journal = {The western journal of emergency medicine}, volume = {24}, number = {6}, pages = {1131-1145}, pmid = {38165196}, issn = {1936-9018}, mesh = {Child ; Humans ; *Acetaminophen/poisoning ; *Acetylcysteine/therapeutic use/adverse effects ; Analgesics, Non-Narcotic/therapeutic use ; Antidotes/therapeutic use ; *Drug Overdose/drug therapy ; *Drug-Related Side Effects and Adverse Reactions ; Infusions, Intravenous ; }, abstract = {INTRODUCTION: Acetaminophen poisoning is commonly treated by emergency physicians. First-line therapy is N-acetylcysteine (NAC), traditionally administered intravenously via a US Food and Drug Administration (FDA)-approved three-bag protocol in which each bag has a unique concentration and infusion duration. Recently, simplified, off-label two-bag NAC infusion protocols have become more common. The purpose of this review is to summarize the effectiveness and safety of two-bag NAC.<br><br>METHODS: We undertook a comprehensive search of PubMed, EMBASE, and MEDLINE from inception to December 13, 2022, for articles describing human acetaminophen poisonings treated with two-bag NAC, defined as any regimen involving two discrete infusions in two separate bags. Outcomes included effectiveness (measured by incidence of liver injury); incidence of non-allergic anaphylactoid reactions (NAAR); gastrointestinal, cutaneous, and systemic reactions; treatments for NAARs; incidence of NAC-related medication errors; and delays or interruptions in NAC administration.<br><br>RESULTS: Twelve articles met final inclusion, 10 of which compared two-bag NAC to the three-bag regimen. Nine articles evaluated the two-bag/20-hour regimen, a simplified version of the FDA-approved three-bag regimen in which the traditional first and second bags are combined into a single four-hour infusion. Nine articles assessed comparative effectiveness of two-bag NAC in terms of liver injury, most commonly assessed for by incidence of hepatotoxicity (aspartate aminotransferase or alanine aminotransferase&#x2009;>1,000 international units per liter). No difference in liver injury was observed between two-bag and three-bag regimens. Of nine articles comparing incidence of NAARs, eight demonstrated statistically fewer NAARs with two-bag regimens, and one showed no difference. In seven articles evaluating treatment for NAARs (antihistamines, corticosteroids, epinephrine), all showed that patients received fewer medications for NAARs with two-bag NAC. Three articles evaluated NAC-related medication errors; two demonstrated no difference, while one study evaluating only children showed fewer errors with two-bag NAC. Two studies evaluated delays and/or interruptions in NAC infusions; both favored two-bag NAC.<br><br>CONCLUSION: For patients with acetaminophen poisoning, two-bag NAC regimens appear to have similar outcomes to the traditional three-bag regimen in terms of liver injury. Two-bag NAC regimens are associated with fewer adverse events and fewer treatments for those events than the three-bag regimen and fewer interruptions in antidotal therapy.}, }
@article {pmid38164872, year = {2023}, author = {Sun, J and Zhang, X and Wang, L and Di Stefano, AFD and Zanin, V and Magrone, P and Yuan, Y}, title = {Phase I study of the pharmacokinetics and safety of single and multiple doses of intravenous N-acetylcysteine in healthy Chinese subjects.}, journal = {European review for medical and pharmacological sciences}, volume = {27}, number = {24}, pages = {12103-12111}, doi = {10.26355/eurrev_202312_34808}, pmid = {38164872}, issn = {2284-0729}, mesh = {Female ; Humans ; Male ; *Acetylcysteine/administration &amp; dosage/pharmacokinetics ; Administration, Intravenous ; Administration, Oral ; Area Under Curve ; China ; Dose-Response Relationship, Drug ; Healthy Volunteers ; East Asian People ; }, abstract = {OBJECTIVE: The aim of the study was to determine the pharmacokinetics (PK) and safety of single and repeat doses of intravenous (IV) N-acetylcysteine (NAC) in Chinese subjects.<br><br>PATIENTS AND METHODS: A total of 24 healthy male and female Chinese subjects aged 19-40 years were enrolled in this open-label phase I study. All subjects received a single dose of NAC 600&#xa0;mg IV on day 1 and, after a 3-day washout, received repeat doses of NAC 600&#xa0;mg IV (twice daily on days 4 and 5 and once on day 6).<br><br>RESULTS: Following a single dose, plasma NAC concentrations peaked rapidly, starting to fall at the end of the 5-minute infusion in a multiphasic manner. Mean Cmax was 83.30 &#x3bc;g/mL (CV% 30.7%), median Tmax was 0.083&#xa0;h (range 0.08-0.25 h), and mean AUC(0-12 h) was 81.87 h*&#x3bc;g/mL (CV 14.0%). Following repeat dosing, Cmax was approximately 20% higher than after a single dose, with similar Tmax. Total exposure AUC(0-12) was 13% higher at steady state than after single dosing. The accumulation ratio was approximately 1.13, indicating only a slight accumulation with multiple dosing. NAC was eliminated with T1/2 of approximately 8 hours. Around 15% of the total NAC dose was excreted in the urine in the 32 hours post-dose, keeping with extensive NAC metabolism and transformation. Renal clearance of NAC was 995.2 mL/h (CV 50.2%). IV NAC was well tolerated after both single and multiple dosing.<br><br>CONCLUSIONS: This is the first robust study evaluating the PK and safety of IV NAC 600 mg in Chinese subjects and provides important data if this agent is to be used IV as a mucolytic in this population.}, }
@article {pmid38159349, year = {2024}, author = {Erkovich, AV and Korotkova, EI and Dorozhko, EV and Plotnikov, EV and Semin, VO and Chernova, AP and Barek, J and Solomonenko, AN and Aseeva, NV}, title = {A novel impedimetric sensor based on N-acetyl-L-cysteine for the determination of hydroxyl radicals in cell cultures in vitro.}, journal = {Talanta}, volume = {270}, number = {}, pages = {125600}, doi = {10.1016/j.talanta.2023.125600}, pmid = {38159349}, issn = {1873-3573}, mesh = {*Hydroxyl Radical ; Acetylcysteine ; Electrochemical Techniques/methods ; Gold/chemistry ; Electrodes ; Cell Culture Techniques ; Immunoglobulin E ; *Biosensing Techniques/methods ; Limit of Detection ; }, abstract = {We report a novel impedimetric sensor based on a graphite electrode impregnated with polyethylene and paraffin under vacuum (IGE) modified with electrochemically deposited gold and a self-assembled monolayer of N-acetyl-L-cysteine (NAC/Au/IGE) for selective and sensitive determination of extracellular hydroxyl radicals (OH[•]) generated by living cells. The application of a sulphur-containing molecule oxidized by OH[•] predicts the high selectivity of the sensor, and the utilization of the non-faradaic impedance spectroscopy for recording an analytical response makes it possible to achieve superior sensitivity with a detection limit of 0.01 nM and a linear dynamic range of 0.08-8 nM. Meanwhile, NAC/Au/IGE demonstrated a strong potential of detecting OH[•] generated by biological objects via successful determination of extracellular hydroxyl radicals generated by normal fibroblast cells and prostate carcinoma cells.}, }
@article {pmid38157955, year = {2024}, author = {Asuku, AO and Ayinla, MT and Ajibare, AJ and Olajide, TS}, title = {Mercury chloride causes cognitive impairment, oxidative stress and neuroinflammation in male Wistar rats: The potential protective effect of 6-gingerol-rich fraction of Zingiber officinale via regulation of antioxidant defence system and reversal of pro-inflammatory markers increase.}, journal = {Brain research}, volume = {1826}, number = {}, pages = {148741}, doi = {10.1016/j.brainres.2023.148741}, pmid = {38157955}, issn = {1872-6240}, mesh = {Rats ; Male ; Animals ; Antioxidants/pharmacology/metabolism ; Rats, Wistar ; *Zingiber officinale ; Chlorides ; Neuroinflammatory Diseases ; Mercuric Chloride/toxicity ; Tumor Necrosis Factor-alpha/metabolism ; NF-kappa B/metabolism ; Interleukin-6 ; Acetylcholinesterase ; Oxidative Stress ; Glutathione/metabolism ; Acetylcysteine/pharmacology ; Superoxide Dismutase/metabolism ; *Mercury/pharmacology ; *Cognitive Dysfunction ; *Catechols ; *Fatty Alcohols ; }, abstract = {This study investigated the effects of 6-gingerol-rich fraction of Zingiber officinale (6-GIRIFZO) on mercury chloride (HgCl2)-induced neurotoxicity in Wistar rats. Thirty -five male Wistar rats weighing between (150-200 g) were divided randomly into five groups (n = 7): group 1: control, received 0.5 mL of normal saline, group 2: received HgCl2 (5 mg/kg), group 3: received N-acetylcysteine (NAC) (50 mg/kg) as well as HgCl2 (5 mg/kg), group 4: received 6-GIRIFZO (100 mg/kg) and HgCl2 (5 mg/kg), group 5: had 6-GIRIFZO (200 mg/kg) and HgCl2 (5 mg/kg), consecutively for 14 days. On the day14, the rats were subjected to behavioural tests using a Morris water maze and novel object recognition tests. The rats were then euthanized to obtain brain samples for the determination of biochemical parameters (acetylcholinesterase (AchE), nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione (GSH), tumor necrosis factor- alpha (TNF-α), nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β) and interleukin-6 (IL-6)) using standard methods. The result revealed a significant increase in escape latency and a significant decrease in recognition ratio in the rats that were exposed to HgCl2 only. However, 6-GIRIFZO produced a significant reduction in the escape latency and (p < 0.05) increase in the recognition ratio. Similarly, HgCl2 exposure caused a significant (p < 0.05) decrease in the brain SOD, GPx, CAT, GSH with increased brain levels of MDA, NO, AchE, TNF-α, NF-κB, IL-1β and IL-6. Similarly to the standard drug, NAC, 6-GIRIFZO (100 and 200 mg/kg) significantly (p < 0.05) increased brain SOD, GPx, CAT, and GSH levels with decreased concentrations of MDA, NO, AchE, TNF-α, NF-κB, IL-1β and IL-6. Also, pre-treatment with 6-GIRIFZO prevented the HgCl2-induced morphological aberrations in the rats. This study concludes that 6-GIRIFZO prevents HgCl2-induced cognitive deficit via reduction of brain inflammation as well as oxidative stress in rats.}, }
@article {pmid38157913, year = {2024}, author = {Wang, Y and Xing, C and Cai, B and Qiu, W and Zhai, J and Zeng, Y and Zhang, A and Shi, S and Zhang, Y and Yang, X and Fu, TM and Shen, H and Wang, C and Zhu, L and Ye, J}, title = {Impact of antioxidants on PM2.5 oxidative potential, radical level, and cytotoxicity.}, journal = {The Science of the total environment}, volume = {912}, number = {}, pages = {169555}, doi = {10.1016/j.scitotenv.2023.169555}, pmid = {38157913}, issn = {1879-1026}, mesh = {Cricetinae ; Animals ; *Antioxidants/metabolism ; beta Carotene ; *Air Pollutants/toxicity/analysis ; CHO Cells ; Vitamin A ; Cricetulus ; Particulate Matter/toxicity/analysis ; Vitamin E ; Glutathione ; Oxidative Stress ; *Hydroquinones ; }, abstract = {Antioxidants are typically seen as agents that mitigate environmental health risks due to their ability to scavenge free radicals. However, our research presents a paradox where these molecules, particularly those within lung fluid, act as prooxidants in the presence of airborne particulate matter (PM2.5), thus enhancing PM2.5 oxidative potential (OP). In our study, we examined a range of antioxidants found in the respiratory system (e.g., vitamin C, glutathione (GSH), and N-acetylcysteine (NAC)), in plasma (vitamin A, vitamin E, and β-carotene), and in food (tert-butylhydroquinone (TBHQ)). We aimed to explore antioxidants' prooxidant and antioxidant interactions with PM2.5 and the resulting OP and cytotoxicity. We employed OH generation assays and electron paramagnetic resonance assays to assess the pro-oxidative and anti-oxidative effects of antioxidants. Additionally, we assessed cytotoxicity interaction using a Chinese hamster ovary cell cytotoxicity assay. Our findings revealed that, in the presence of PM2.5, all antioxidants except vitamin E significantly increased the PM2.5 OP by generating more OH radicals (OH generation rate: 0.16-24.67 pmol·min[-1]·m[-3]). However, it's noteworthy that these generated OH radicals were at least partially neutralized by the antioxidants themselves. Among the pro-oxidative antioxidants, vitamin A, β-carotene, and TBHQ showed the least ability to quench these radicals, consistent with their observed impact in enhancing PM2.5 cytotoxicity (PM2.5 LC50 reduced to 91.2 %, 88.8 %, and 75.1 % of PM2.5's original level, respectively). Notably, vitamin A and TBHQ-enhanced PM2.5 OP were strongly associated with the presence of metals and organic compounds, particularly with copper (Cu) contributing significantly (35 %) to TBHQ's pro-oxidative effect. Our study underscores the potential health risks associated with the interaction between antioxidants and ambient pollutants.}, }
@article {pmid38154185, year = {2024}, author = {Dong, B and Jiang, Y and Shi, B and Zhang, Z and Zhang, Z}, title = {Selenomethionine alleviates decabromodiphenyl ether-induced oxidative stress and ferroptosis via the NRF2/GPX4 pathway in the chicken brain.}, journal = {Journal of hazardous materials}, volume = {465}, number = {}, pages = {133307}, doi = {10.1016/j.jhazmat.2023.133307}, pmid = {38154185}, issn = {1873-3336}, mesh = {Chick Embryo ; Animals ; *Selenomethionine ; Chickens ; NF-E2-Related Factor 2 ; Antioxidants ; *Ferroptosis ; Oxidative Stress ; Brain ; *Halogenated Diphenyl Ethers ; }, abstract = {Decabromodiphenyl ether (BDE209) is a toxic environmental pollutant that can cause neurotoxicity, behavioral abnormalities, and cognitive impairment in animals. However, the specific mechanisms of BDE209-induced neurological injury and effective preventative and therapeutic interventions are lacking. Even though selenomethionine (Se-Met) has a significant detoxification effect and protects the nervous system, it remains unclear whether Se-Met can counteract the toxic effects of BDE209. For the in vivo test, we randomly divided 60 1-week-old hy-line white variety chicks into the Con, BDE209, Se-Met, and BDE209 +Se-Met groups. In vitro experiments were performed, exposing chick embryo brain neurons to BDE209, Se-Met, N-Acetylcysteine (NAC, a ROS inhibitor), and RSL3 (a GPX4 inhibitor). We demonstrated that BDE209 induced oxidative stress and ferroptosis in the chicken brain, which mainly manifested as mitochondrial atrophy, cristae breakage, increased Fe[2+] and MDA content, decreased antioxidant enzyme activity, and the inhibition of the NRF2/GPX4 signaling pathway in the brain neurons. However, Se-Met supplementation reversed these changes by activating the NRF2/GPX4 pathway, reducing mitochondrial damage, enhancing antioxidant enzyme activity, and alleviating ferroptosis. This study provides insight into the mechanism of BDE209-related neurotoxicity and suggests Se-Met as an effective preventative and control measure against BDE209 poisoning.}, }
@article {pmid38150719, year = {2024}, author = {Liu, J and Yan, P and Liu, X and Long, Z and Bing, T and Zhang, N and Shangguan, D}, title = {Heptamethine Cyanine-Based Molecule Release Triggered by Mitochondrial ROS.}, journal = {ACS applied bio materials}, volume = {7}, number = {1}, pages = {362-368}, doi = {10.1021/acsabm.3c00955}, pmid = {38150719}, issn = {2576-6422}, mesh = {Reactive Oxygen Species ; *Hydrogen Peroxide ; *Mitochondria ; Fluorescent Dyes ; Acetylcysteine/pharmacology ; }, abstract = {Conditionally activated molecule release in live cells would provide spatiotemporal control for the study and intervention of biological processes, e.g., bioactive molecule monitoring and controlled drug release. Mitochondria are the main sites of reactive oxygen species (ROS) production in cells. Here, we report an ROS-triggered molecule release strategy in mitochondria. A molecule IRTO with dual targeting groups was designed by covalently linking IR-780 (a mitochondrial targeted heptamethine cyanine) and 4-aminobutyl-thiazole orange (NH2-TO, a nuclear dye). IRTO diffused into live cells and first accumulated in mitochondria. As the cyanine moiety reacted with mitochondrial ROS directly or with the help of mitochondrial cytochromes, NH2-TO was released, escaped from mitochondria, and finally located in the nucleus. This process could be visualized by fluorescent imaging, i.e., red fluorescence (from the cyanine moiety of IRTO) first located in mitochondria, and green fluorescence (from NH2-TO) appeared and gradually enhanced in the nucleus with the increase of incubation time. The addition of H2O2 or lipopolysaccharide (LPS, an ROS accelerator) could accelerate the release of NH2-TO, whereas N-acetyl-l-cysteine (NAC, an ROS inhibitor) and mitoquinone mesylate (MitoQ, a mitochondrial ROS scavenger) could obviously decrease the release of NH2-TO. These results suggest that IRTO could serve as a fluorescent probe for monitoring ROS in mitochondria and that IR-780 might be a promising endogenous ROS-triggered molecule release platform.}, }
@article {pmid38145809, year = {2024}, author = {Shore, R and Behlen, J and McBee, D and Prayaga, K and Haugen, F and Craig, L and Shields, M and Mustapha, T and Harvey, N and Johnson, N}, title = {Lactational transfer of sulforaphane-N-acetylcysteine in vivo and in human breast milk.}, journal = {Toxicology and applied pharmacology}, volume = {482}, number = {}, pages = {116796}, pmid = {38145809}, issn = {1096-0333}, support = {P30 ES029067/ES/NIEHS NIH HHS/United States ; R01 ES028866/ES/NIEHS NIH HHS/United States ; T32 ES026568/ES/NIEHS NIH HHS/United States ; }, mesh = {Mice ; Animals ; Child ; Infant, Newborn ; Humans ; Female ; *Acetylcysteine/pharmacology ; *Lactation ; Breast Feeding ; NF-E2-Related Factor 2/genetics/metabolism ; Milk, Human/metabolism ; Isothiocyanates/pharmacology ; *Sulfoxides ; }, abstract = {Sulforaphane (SFN) is a bioactive phytonutrient found in cruciferous vegetables. There is a lack of detailed information on the lactational transfer of SFN and SFN metabolites, and potential pharmacological effects on breastfeeding infants. We carried out two maternal supplementation studies in a mouse model, wherein lactating dams received either vehicle, 300 or 600 ppm SFN from postnatal day (PND) 1 to 5, or in a second experiment, vehicle or 600 ppm SFN from PND 1 to 14. The parent compound was only detectable in milk and plasma from dams receiving 600 ppm SFN for five days. The predominant metabolite SFN-N-acetylcysteine (SFN-NAC) was readily detected in milk from dams receiving 300 and 600 ppm SFN for five days or 600 ppm for 14 days. Maternal SFN-NAC plasma levels were elevated in both 600 ppm groups. Maternal hepatic and pulmonary expression of NRF2-related genes, Nqo1, Gsta2, Gstm1, and Gstp1, were significantly increased, generally following a dose-response; however, offspring induction varied. PND5 neonates in the 600-ppm group exhibited significantly elevated expression of Nqo1, Gsta2, and Gstp1 in liver, and Gstm1 and Gstp1 in lung. Findings support maternal dietary supplementation with SFN induces NRF2-related gene expression in neonates via lactational transfer of SFN-NAC. However, NQO1 enzyme activity was not significantly elevated, highlighting the need to optimize dosing strategy. Additionally, in a pilot investigation of lactating women consuming a typical diet, without any purified SFN supplementation, 7 out of 8 breast milk samples showed SFN-NAC above the limit of quantification (LOQ). Notably, the one sample below the LOQ was collected from the only participant who reported no consumption of cruciferous vegetables in the past 24 h. The parent compound was not detected in any of the human breast milk samples. Overall, these data indicate lactational transfer of SFN-NAC at dietary relevant levels. Future studies are needed to evaluate pharmacokinetics and pharmacodynamics of lactational transfer for potential preventive or therapeutic effects in breastfeeding children.}, }
@article {pmid38142783, year = {2024}, author = {Singh, B and Patwardhan, RS and Pal, D and Maurya, DK and Singh, BG and Checker, R and Sharma, D and Sandur, SK}, title = {Repurposing of FDA approved kinase inhibitor bosutinib for mitigation of radiation induced damage via inhibition of JNK pathway.}, journal = {Toxicology and applied pharmacology}, volume = {482}, number = {}, pages = {116792}, doi = {10.1016/j.taap.2023.116792}, pmid = {38142783}, issn = {1096-0333}, mesh = {Animals ; Humans ; Mice ; *Aniline Compounds/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; DNA Damage ; *Drug Repositioning ; MAP Kinase Signaling System ; *Nitriles/pharmacology/therapeutic use ; *Quinolines/pharmacology/therapeutic use ; *Radiation Injuries/prevention &amp; control ; *Radiation-Protective Agents/pharmacology/therapeutic use ; }, abstract = {Radiotherapy is a common modality for cancer treatment. However, it is often associated with normal tissue toxicity in 20-80% of the patients. Radioprotectors can improve the outcome of radiotherapy by selectively protecting normal cells against radiation toxicity. In the present study, compound libraries containing 54 kinase inhibitors and 80 FDA-approved drugs were screened for radioprotection of lymphocytes using high throughput cell analysis. A second-generation FDA-approved kinase inhibitor, bosutinib, was identified as a potential radioprotector for normal cells. The radioprotective efficacy of bosutinib was evinced from a reduction in radiation induced DNA damage, caspase-3 activation, DNA fragmentation and apoptosis. Oral administration of bosutinib protected mice against whole body irradiation (WBI) induced morbidity and mortality. Bosutinib also reduced radiation induced bone-marrow aplasia and hematopoietic damage in mice exposed to 4 Gy and 6 Gy dose of WBI. Mechanistic studies revealed that the radioprotective action of bosutinib involved interaction with cellular thiols and modulation of JNK pathway. The addition of glutathione and N-acetyl cysteine significantly reduced the radioprotective efficacy of bosutinib. Moreover, bosutinib did not protect cancer cells against radiation induced toxicity. On the contrary, bosutinib per se exhibited anticancer activity against human cancer cell lines. The results highlight possible use of bosutinib as a repurposable radioprotective agent for mitigation of radiation toxicity in cancer patients undergoing radiotherapy.}, }
@article {pmid38141851, year = {2024}, author = {Jayaram, L and King, PT and Hunt, J and Lim, M and Park, C and Hu, E and Dousha, L and Ha, P and Bartlett, JB and Southcott, AM and Muruganandan, S and Vogrin, S and Rees, MA and Dean, OM and Wong, CA}, title = {Evaluation of high dose N- Acetylcysteine on airway inflammation and quality of life outcomes in adults with bronchiectasis: A randomised placebo-controlled pilot study.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {84}, number = {}, pages = {102283}, doi = {10.1016/j.pupt.2023.102283}, pmid = {38141851}, issn = {1522-9629}, mesh = {Adult ; Humans ; Male ; Aged ; *Acetylcysteine/adverse effects ; Quality of Life ; Pilot Projects ; *Bronchiectasis/drug therapy ; Inflammation/drug therapy ; Anti-Inflammatory Agents/adverse effects ; Double-Blind Method ; }, abstract = {BACKGROUND: High dose N acetylcysteine (NAC), a mucolytic, anti-inflammatory and antioxidant agent has been shown to significantly reduce exacerbations, and improve quality of life in placebo controlled, double blind randomised (RCT) studies in patients with COPD, and in an open, randomised study in bronchiectasis. In this pilot, randomised, double-blind, placebo-controlled study, we wished to investigate the feasibility of a larger clinical trial, and the anti-inflammatory and clinical benefits of high dose NAC in bronchiectasis.<br><br>AIMS: Primary outcome: to assess the efficacy of NAC 2400&#xa0;mg/day at 6 weeks on sputum neutrophil elastase (NE), a surrogate marker for exacerbations. Secondary aims included assessing the efficacy of NAC on sputum MUC5B, IL-8, lung function, quality of life, and adverse effects.<br><br>METHODS: Participants were randomised to receive 2400&#xa0;mg or placebo for 6 weeks. They underwent 3 visits: at baseline, week 3 and week 6 where clinical and sputum measurements were assessed.<br><br>RESULTS: The study was stopped early due to the COVID pandemic. In total 24/30 patients were recruited, of which 17 completed all aspects of the study. Given this, a per protocol analysis was undertaken: NAC (n&#xa0;=&#xa0;9) vs placebo (n&#xa0;=&#xa0;8): mean age 72 vs 62 years; male gender: 44% vs 50%; baseline median FEV11.56&#xa0;L (mean 71.5 % predicted) vs 2.29L (mean 82.2% predicted). At 6 weeks, sputum NE fell by 47% in the NAC group relative to placebo (mean fold difference (95%CI: 0.53 (0.12,2.42); MUC5B increased by 48% with NAC compared with placebo. Lung function, FVC improved significantly with NAC compared with placebo at 6 weeks (mean fold difference (95%CI): 1.10 (1.00, 1.20), p&#xa0;=&#xa0;0.045. Bronchiectasis Quality of life measures within the respiratory and social functioning domains demonstrated clinically meaningful improvements, with social functioning reaching statistical significance. Adverse effects were similar in both groups.<br><br>CONCLUSION: High dose NAC exhibits anti-inflammatory benefits, and improvements in aspects of quality of life and lung function measures. It is safe and well tolerated. Further larger placebo controlled RCT's are now warranted examining its role in reducing exacerbations.}, }
@article {pmid38136214, year = {2023}, author = {Yang, Y and Liu, Z and Wu, J and Bao, S and Wang, Y and Li, J and Song, T and Sun, Y and Pi, J}, title = {Nrf2 Mitigates RANKL and M-CSF Induced Osteoclast Differentiation via ROS-Dependent Mechanisms.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38136214}, issn = {2076-3921}, support = {81830099 (J.P.), 82020108027 (J.P.), 82204090 (Z.L.)//National Natural Science Foundation of China/ ; 2018YFC1311600 (J.P.)//National Key R&amp;D Program of China of the Ministry of Science and Technology of the People's Republic of China/ ; 2022JH2/101300028 (Y.R.)//The Liaoning Applied Basic Research Program/ ; 2022-BS-131, (Z.L.)//Liaoning Provincial Department of Science and Technology Doctoral Launch/ ; 2023JH2/101300024 (Y.S.)//The Liaoning Applied Basic Research Program/ ; }, abstract = {Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been shown to be a negative regulator of osteoclast differentiation, but the precise mechanisms have not yet been established. We examined the precise roles of Nrf2 in regulating antioxidants and reactive oxygen species (ROS) levels, especially the cytoplasmic and mitochondrial ROS during osteoclastogenesis in vitro. In the current study, we found that the absence of Nrf2 promotes osteoclast differentiation in bone-marrow-derived macrophages (BMMs) and RAW 264.7 cells. The receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) significantly lowered the levels of Nrf2 and its downstream antioxidant enzymes at mRNA and/or protein levels during osteoclast differentiation in the BMMs of mice and RAW 264.7 mouse leukemic monocytes. Compared to the wild-type cells, Nrf2-deficient cells exhibited heightened sensitivity to both transient RANKL-induced cytoplasmic ROS and prolonged RANKL and M-CSF-induced cytoplasmic and mitochondrial ROS accumulation. Furthermore, exogenous antioxidant agents, including N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and mitoquinone mesylate (MitoQ), exhibited substantial capability to suppress the elevation of ROS levels during osteoclast differentiation induced by Nrf2 deficiency, and they consequently inhibited osteoclast differentiation augmented by the lack of Nrf2. The activation of phosphorylated c-FOS resulting from elevated ROS promoted osteoclast differentiation. The inhibition of c-FOS blocked osteoclast differentiation, which was elevated by Nrf2-deficiency. Taken together, these data reveal that Nrf2 effectively decreased the accumulation of intracellular ROS and the phosphorylation of c-FOS during osteoclastic differentiation by regulating antioxidant enzymes and subsequently inhibited RANKL-induced osteoclast differentiation.}, }
@article {pmid38136193, year = {2023}, author = {Cui, Y and Zhu, Q and Hao, H and Flaker, GC and Liu, Z}, title = {N-Acetylcysteine and Atherosclerosis: Promises and Challenges.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38136193}, issn = {2076-3921}, support = {R01 HL148196/HL/NHLBI NIH HHS/United States ; RF1 NS132279/NS/NINDS NIH HHS/United States ; }, abstract = {Atherosclerosis remains a leading cause of cardiovascular diseases. Although the mechanism for atherosclerosis is complex and has not been fully understood, inflammation and oxidative stress play a critical role in the development and progression of atherosclerosis. N-acetylcysteine (NAC) has been used as a mucolytic agent and an antidote for acetaminophen overdose with a well-established safety profile. NAC has antioxidant and anti-inflammatory effects through multiple mechanisms, including an increase in the intracellular glutathione level and an attenuation of the nuclear factor kappa-B mediated production of inflammatory cytokines like tumor necrosis factor-alpha and interleukins. Numerous animal studies have demonstrated that NAC significantly decreases the development and progression of atherosclerosis. However, the data on the outcomes of clinical studies in patients with atherosclerosis have been limited and inconsistent. The purpose of this review is to summarize the data on the effect of NAC on atherosclerosis from both pre-clinical and clinical studies and discuss the potential mechanisms of action of NAC on atherosclerosis, as well as challenges in the field.}, }
@article {pmid38136155, year = {2023}, author = {Ovalle Rodríguez, P and Ramírez Ortega, D and Blanco Ayala, T and Roldán Roldán, G and Pérez de la Cruz, G and González Esquivel, DF and Gómez-Manzo, S and Sánchez Chapul, L and Salazar, A and Pineda, B and Pérez de la Cruz, V}, title = {Modulation of Kynurenic Acid Production by N-acetylcysteine Prevents Cognitive Impairment in Adulthood Induced by Lead Exposure during Lactation in Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {12}, pages = {}, pmid = {38136155}, issn = {2076-3921}, support = {286885//Consejo Nacional de Humanidades, Ciencias y Tecnolog&#xed;as/ ; }, abstract = {Lead (Pb[2+]) exposure during early life induces cognitive impairment, which was recently associated with an increase in brain kynurenic acid (KYNA), an antagonist of NMDA and alpha-7 nicotinic receptors. It has been described that N-acetylcysteine (NAC) favors an antioxidant environment and inhibits kynurenine aminotransferase II activity (KAT II, the main enzyme of KYNA production), leading to brain KYNA levels decrease and cognitive improvement. This study aimed to investigate whether the NAC modulation of the brain KYNA levels in mice ameliorated Pb[2+]-induced cognitive impairment. The dams were divided into four groups: Control, Pb[2+], NAC, and Pb[2+]+NAC, which were given drinking water or 500 ppm lead acetate in the drinking water ad libitum, from 0 to 23 postnatal days (PNDs). The NAC and Pb[2+]+NAC groups were simultaneously fed NAC (350 mg/day) in their chow from 0 to 23 PNDs. At PND 60, the effect of the treatment with Pb[2+] and in combination with NAC on learning and memory performance was evaluated. Immediately after behavioral evaluation, brain tissues were collected to assess the redox environment; KYNA and glutamate levels; and KAT II activity. The NAC treatment prevented the long-term memory deficit exhibited in the Pb[2+] group. As expected, Pb[2+] group showed redox environment alterations, fluctuations in glutamate levels, and an increase in KYNA levels, which were partially avoided by NAC co-administration. These results confirmed that the excessive KYNA levels induced by Pb[2+] were involved in the onset of cognitive impairment and could be successfully prevented by NAC treatment. NAC could be a tool for testing in scenarios in which KYNA levels are associated with the induction of cognitive impairment.}, }
@article {pmid38126172, year = {2024}, author = {Bresette, CA and Ashworth, KJ and Di Paola, J and Ku, DN}, title = {N-Acetyl Cysteine Prevents Arterial Thrombosis in a Dose-Dependent Manner In Vitro and in Mice.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {44}, number = {2}, pages = {e39-e53}, doi = {10.1161/ATVBAHA.123.319044}, pmid = {38126172}, issn = {1524-4636}, mesh = {Mice ; Humans ; Animals ; Platelet Aggregation Inhibitors/pharmacology ; Acetylcysteine/pharmacology ; *Thrombosis/chemically induced/prevention &amp; control/drug therapy ; Platelet Aggregation ; Blood Platelets/metabolism ; *Thromboembolism ; Hemorrhage/metabolism ; von Willebrand Factor/metabolism ; }, abstract = {BACKGROUND: Platelet-rich thrombi occlude arteries causing fatal infarcts like heart attacks and strokes. Prevention of thrombi by current antiplatelet agents can cause major bleeding. Instead, we propose using N-acetyl cysteine (NAC) to act against the protein VWF (von Willebrand factor), and not platelets, to prevent arterial thrombi from forming.<br><br>METHODS: NAC was assessed for its ability to prevent arterial thrombosis by measuring platelet accumulation rate and occlusion time using a microfluidic model of arterial thrombosis with human blood. Acute clot formation, clot stability, and tail bleeding were measured in vivo with the murine modified Folts model. The effect of NAC in the murine model after 6 hours was also measured to determine any persistent effects of NAC after it has been cleared from the blood.<br><br>RESULTS: We demonstrate reduction of thrombi formation following treatment with NAC in vitro and in vivo. Human whole blood treated with 3 or 5 mmol/L NAC showed delayed thrombus formation 2.0&#xd7; and 3.7&#xd7; longer than control, respectively (P<0.001). Blood treated with 10 mmol/L NAC did not form an occlusive clot, and no macroscopic platelet aggregation was visible (P<0.001). In vivo, a 400-mg/kg dose of NAC prevented occlusive clots from forming in mice without significantly affecting tail bleeding times. A lower dose of NAC significantly reduced clot stability. Mice given multiple injections showed that NAC has a lasting and cumulative effect on clot stability, even after being cleared from the blood (P<0.001).<br><br>CONCLUSIONS: Both preclinical models demonstrate that NAC prevents thrombus formation in a dose-dependent manner without significantly affecting bleeding time. This work highlights a new pathway for preventing arterial thrombosis, different from antiplatelet agents, using an amino acid derivative as an antithrombotic therapeutic.}, }
@article {pmid38118330, year = {2024}, author = {Fu, X and Song, L and Chen, L and Jin, S and Duan, Z and Zhang, B and Xing, Y and Wang, Y}, title = {Mechanistic insights into aniline-induced liver injury: Role of the mmu_circ_26984/Myh9/NLRP3 axis and modulation by N-acetylcysteine.}, journal = {Ecotoxicology and environmental safety}, volume = {270}, number = {}, pages = {115826}, doi = {10.1016/j.ecoenv.2023.115826}, pmid = {38118330}, issn = {1090-2414}, mesh = {Animals ; Mice ; *Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury, Chronic ; In Situ Hybridization, Fluorescence ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; RNA, Circular ; Aniline Compounds/toxicity ; Cytoskeletal Proteins ; Myosin Heavy Chains ; }, abstract = {Aniline is a widely used chemical. Chronic or high-dose exposure to aniline can lead to hepatocellular damage. Although the hepatic pathogenicity of aniline has been established in previous studies, studies involving pathogenic genes during aniline-induced liver injury are limited. Our study first discovered and identified the role and mechanism underlying a new circRNA mmu_circ_26984 in aniline-induced chemical liver injury. Further, we discuss the protective effect of N-acetylcysteine (NAC) in this pathway. After constructing in vitro and in vivo models of aniline treatment, we screened the circRNA with significant differences in expression in AML12 cells from control and aniline-treated groups by circRNA microarray analysis. Next, using RNA pulldown, liquid chromatography-mass spectrometry (LC-MS), and RNA immunoprecipitation, we analyzed the relationship between mmu_circ_26984 and myosin heavy chain 9 (Myh9). Subsequently, we determined the specific mechanism of action of mmu_circ_26984 and Myh9 in aniline-induced liver injury and the protective effect of NAC against aniline-induced liver injury process using Cell Counting Kit-8, Western blot, RNA extraction, a reverse transcription quantitative polymerase chain reaction (RT-qPCR), fluorescence in situ hybridization, immunohistochemistry, and immunofluorescence. The expression of mmu_circ_26984 was significantly increased in liver tissues and AML12 cells of aniline-treated mice compared with the control group. This high expression of mmu_circ_26984 increased the expression of injury-related inflammatory factors, such as NLRP3, Caspase-1, IL-18, and IL-1β in vivo and ex vivo, which exacerbated the level of liver injury. The interaction of mmu_circ_26984 with Myh9 also affected the course of liver injury. Mmu_circ_26984 overexpression and reduced treatment affected the levels of Myh9 expression in AML12 cells, as well as downstream inflammatory factors associated with injury, such as NLRP3. In addition, NAC reduced the process of liver injury mediated by the mmu_circ_26984/Myh9/NLRP3 axis. In conclusion, mmu_circ_26984 is a potential molecular marker and therapeutic target in the process of aniline-induced liver injury that can mediate aniline-exposure-induced liver injury via modulation of the mmu_circ_26984/Myh9/NLRP3 axis, and NAC can effectively attenuate the effect of this liver injury.}, }
@article {pmid38115863, year = {2023}, author = {Gugsa, E and Molla, TS and Bekele, T and Dejenie, TA}, title = {Hepatoprotective effect of hydromethanol extract of Otostegia integrifolia benth leaves in isoniazid and rifampicin induced Swiss albino mice.}, journal = {Metabolism open}, volume = {20}, number = {}, pages = {100255}, pmid = {38115863}, issn = {2589-9368}, abstract = {INTRODUCTION: Drug-induced liver injury is the most common cause of acute liver failure. Off-Target effect "hepatotoxicity "frequently detected during clinical examination of patients on anti-Tb medication particularly isoniazid (INH), and rifampin (RMP). However, there is no any treatment option against isoniazid and rifampicin induced hepatotoxicity. It is, therefore, necessary to search for effective affordable and safe drugs from medicinal plants for the prevention of liver toxicity caused by isoniazid and rifampicin. The aim the current study is to evaluate hepatoprotective effect of hydro methanol extract from Otostegia integrifolia leaves in isoniazid and rifampicin-induced hepatotoxicity in Swiss albino mice.<br><br>METHODS: O. integrifolia leaves powder was macerated in hydromethanol and thirty Swiss albino mice 29.0-40.6&#xa0;g were grouped in to five groups. Group I were given 20&#xa0;ml/kg distilled water, group II were given 100&#xa0;mg INH and 150&#xa0;mg RIF per kg body weight. Group III, group IV, and group V were given 200&#xa0;mg extract, 400&#xa0;mg extract, and 100&#xa0;mg of N-acetyl cysteine respectively per kg 1hr before induction with 100&#xa0;mg INH plus 150&#xa0;mg RIF per kg. The treatments were followed for 14 days. On the 15th day, all mice were anaesthetized with diethyl ether; blood samples were collected for the assessment liver enzyme and function test.<br><br>RESULTS: Group II mice's serum ALT, AST and total bilirubin levels were significantly increased and serum total protein and albumin levels were significantly decreased as compared with group I mice. The groups of mice treated with O. integrifolia at a dose of 400&#xa0;mg/kg and N-acetyl cysteine AST, ALT and total bilirubin level were significantly decreased; and total protein and albumin levels were significantly (P&#xa0;<&#xa0;0.05) increased as compared with group II. The liver index of the group IV showed decreased (P&#xa0;<&#xa0;0.05) as compared to the group II.<br><br>CONCLUSION: Evidence from our study revealed that the hydromethanol extract of O. integrifolia has a hepatoprotective effect against isoniazid and rifampicin-induced hepatotoxicity in Swiss Albino mice. This protective effect of O. integrifolia extract may be based on its metal ion reducing power, free radical scavenging activity, and anti-inflammatory activity and could be used as a potential therapeutic option.}, }
@article {pmid38115663, year = {2023}, author = {Wang, L and Quan, C and Liu, S and Sun, Y and Liu, Y and Zhang, L}, title = {[KEAP1/PGAM5/AIFM1 mediated oxeiptosis pathway in TDCIPP-induced reduction of TM4 cell viability].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {52}, number = {6}, pages = {979-992}, doi = {10.19813/j.cnki.weishengyanjiu.2023.06.019}, pmid = {38115663}, issn = {1000-8020}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Cell Survival ; *NF-E2-Related Factor 2/metabolism ; *Phosphoprotein Phosphatases/metabolism/pharmacology ; }, abstract = {OBJECTIVE: To investigate the toxic effects and potential mechanisms of tri(1, 3-dichloro-2-propyl) phosphate(TDCIPP) exposure on the mouse testicular supporting cell line(TM4 cells).<br><br>METHODS: TM4 cells were treated with different concentrations of TDCIPP(0, 12.5, 25 and 50 &#x3bc;mol/L), or 50 &#x3bc;mol/L TDCIPP combined with antioxidant N-acetylcysteine(NAC) for 24 h. Cell viability was assessed using the CCK8 assay, intracellular ROS levels were detected using the DCFH-DA probe, and the protein levels of oxeiptosis-related proteins, such as KEAP1, PGAM5, AIFM1 and phosphorylated AIFM1(p-AIFM1), were detected using Western blot.<br><br>RESULTS: TDCIPP dose-dependently reduced TM4 cell viability(P<0.05). ROS levels in TM4 cells treated with 12.5, 25 and 50 &#x3bc;mol/L TDCIPP were 9.44&#xb1;1.42, 17.25&#xb1;1.81 and 18.38&#xb1;2.66, respectively, significantly higher than the control group&apos;s 5.08&#xb1;0.90(P<0.05). ROS levels in the 5 mmol/L NAC+50 &#x3bc;mol/L TDCIPP group were 14.70&#xb1;0.50, significantly lower than the corresponding TDCIPP group&apos;s 26.44&#xb1;0.73(P<0.05). The activity of TM4 cells in KEAP1siRNA+TDCIPP group and PGAM5siRNA+TDCIPP group were 77.00&#xb1;1.73 and 76.67&#xb1;1.53, respectively, significantly higher than TDCIPP group 68.67&#xb1;1.53(P<0.05). The relative expression of KEAP1 protein in TM4 cells treated with 25 and 50 &#x3bc;mol/L TDCIPP were 0.77&#xb1;0.04 and 0.82&#xb1;0.02, respectively, significantly higher than the control group&apos;s 0.57&#xb1;0.01(P<0.05). The relative expression of PGAM5 protein in TDCIPP-treated TM4 cells were 1.17&#xb1;0.04, 1.38&#xb1;0.03 and 1.41&#xb1;0.03, respectively, significantly higher than the control group&apos;s 0.81&#xb1;0.02(P<0.05). The relative expression of AIFM1 protein were 0.42&#xb1;0.01, 0.63&#xb1;0.01 and 0.68&#xb1;0.02, respectively, significantly higher than the control group&apos;s 0.34&#xb1;0.02(P<0.05). The relative expression of p-AIFM1 protein were 1.73&#xb1;0.02, 1.52&#xb1;0.02 and 0.73&#xb1;0.01, respectively, significantly lower than the control group&apos;s 2.25&#xb1;0.02(P<0.05). In the 5 mmol/L NAC+50 &#x3bc;mol/L TDCIPP group, the relative expression of KEAP1, PGAM5 and AIFM1 proteins in TM4 cells were 0.61&#xb1;0.01, 0.58&#xb1;0.01 and 0.48&#xb1;0.03, respectively, significantly lower than the TDCIPP group&apos;s 0.86&#xb1;0.12(P<0.05), 0.74&#xb1;0.02(P<0.05) and 0.92&#xb1;0.01(P<0.05). The relative expression of p-AIFM1 protein in the 5 mmol/L NAC+50 &#x3bc;mol/L TDCIPP group was 0.45&#xb1;0.11, significantly higher than the TDCIPP group&apos;s 0.23&#xb1;0.01(P<0.05).<br><br>CONCLUSION: The reduction of TM4 cell viability induced by TDCIPP may be related to ROS-mediated regulation of the KEAP1/PGAM5/AIFM1 pathway, leading to oxeiptosis.}, }
@article {pmid38111943, year = {2023}, author = {Jing, RH and Hu, CH and Qi, TT and Ma, B}, title = {Role of reactive oxygen species in epithelial-mesenchymal transition and apoptosis of human lens epithelial cells.}, journal = {International journal of ophthalmology}, volume = {16}, number = {12}, pages = {1935-1941}, pmid = {38111943}, issn = {2222-3959}, abstract = {AIM: To investigate the role of reactive oxygen species (ROS) in epithelial-mesenchymal transition (EMT) and apoptosis of human lens epithelial cells (HLECs).<br><br>METHODS: Flow cytometry was used to assess ROS production after transforming growth factor &#x3b2;2 (TGF-&#x3b2;2) induction. Apoptosis of HLECs after H2O2 and TGF-&#x3b2;2 interference with or without ROS scavenger N-acetylcysteine (NAC) were assessed by flow cytometry. The corresponding protein expression levels of the EMT marker &#x3b1;-smooth muscle actin (&#x3b1;-SMA), the extracellular matrix (ECM), marker fibronectin (Fn), and apoptosis-associated proteins were detected by using Western blotting in the presence of an ROS scavenger (NAC). Wound-healing and Transwell assays were used to assess the migration capability of HLECs.<br><br>RESULTS: TGF-&#x3b2;2 stimulates ROS production within 8h in HLECs. Additionally, TGF-&#x3b2;2 induced HLECs cell apoptosis, EMT/ECM synthesis protein markers expression, and pro-apoptotic proteins production; nonetheless, NAC treatment prevented these responses. Similarly, TGF-&#x3b2;2 promoted HLECs cell migration, whereas NAC inhibited cell migration. We further determined that although ROS initiated apoptosis, it only induced the accumulation of the EMT marker &#x3b1;-SMA protein, but not COL-1 or Fn.<br><br>CONCLUSION: ROS contribute to TGF-&#x3b2;2-induced EMT/ECM synthesis and cell apoptosis of HLECs; however, ROS alone are not sufficient for EMT/ECM synthesis.}, }
@article {pmid38111454, year = {2023}, author = {Hakobyan, N and Yadav, R and Pokhrel, A and Wasifuddin, M and John, MJ and Yadav, S and Boris, A}, title = {Miller-Fisher Syndrome Unveiled in the Presence of Cholangiocarcinoma.}, journal = {Cureus}, volume = {15}, number = {11}, pages = {e49016}, pmid = {38111454}, issn = {2168-8184}, abstract = {Miller-Fisher syndrome (MFS) is a rare variant of Guillain-Barré syndrome, characterized by ataxia, areflexia, ophthalmoplegia, and possible facial, swallowing and limb weakness alongside respiratory failure. Variations within MFS may include respiratory and limb weakness and Bickerstaff brainstem encephalitis (BBE), marked by altered consciousness, ataxia, ophthalmoparesis, and paradoxical hyperreflexia. MFS can emerge in both children and adults, often following bacterial or viral illness. While autoimmune-driven nerve damage occurs, most MFS patients recover within six months without specific treatment, with a low risk of lasting neurological deficits or relapses. Rarely fatal, MFS's co-occurrence with cholangiocarcinoma (CCA) presents unique management challenges. CCA, primarily affecting bile ducts, has a bleak prognosis; surgical resection offers limited cure potential due to late-stage detection and high recurrence rates. Advances in CCA's molecular understanding have led to novel diagnostic and therapeutic approaches, requiring a comprehensive interdisciplinary care approach for optimal MFS and CCA management outcomes. Herein, we present a 50-year-old male with a complex medical history who was admitted to the hospital due to abdominal discomfort, nausea, vomiting, and ascites. Imaging revealed pneumonia and secondary bacterial peritonitis. Later, he developed neurological symptoms, including weakness, gait abnormalities, and brainstem symptoms, leading to the diagnosis of MFS. Despite treatment efforts, his condition deteriorated, leading to acute liver failure and unexplained anasarca. N-acetyl cysteine was initiated for liver issues. Neurologically, he showed quadriparesis and areflexia. Intravenous immunoglobulin (IVIG) treatment improved his neurological symptoms but worsened gastrointestinal issues, including ileus and elevated CA19-9 levels, suggesting a potential carcinoma. A liver biopsy was performed. After IVIG treatment, he experienced widespread discomfort, emotional unresponsiveness, swallowing difficulties, and aspiration risk, ultimately leading to his demise.}, }
@article {pmid38109166, year = {2023}, author = {Sangeet, S and Khan, A}, title = {An in-silico approach to identify bioactive phytochemicals from Houttuynia cordata Thunb. As potential inhibitors of human glutathione reductase.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {}, number = {}, pages = {1-20}, doi = {10.1080/07391102.2023.2294181}, pmid = {38109166}, issn = {1538-0254}, abstract = {Cellular infections are central to the etiology of various diseases, notably cancer and malaria. Counteracting cellular oxidative stress via the inhibition of glutathione reductase (GR) has emerged as a promising therapeutic strategy. Houttuynia cordata, a medicinal plant known for its potent antioxidant properties, has been the focus of our investigation. In this study, we conducted comprehensive in silico analyses involving the phytochemical constituents of H. cordata to identify potential natural GR inhibitors. Our methodological approach encompassed multiple in silico techniques, including molecular docking, molecular dynamics simulations, MMPBSA analysis, and dynamic cross-correlation analysis. Out of 13 docked phytochemicals, Quercetin, Quercitrin, and Sesamin emerged as particularly noteworthy due to their exceptional binding affinities for GR. Notably, our investigation demonstrated that Quercetin and Sesamin exhibited promising outcomes compared to the well-established pharmaceutical agent N-acetylcysteine (NAC). Molecular dynamics analyses provided insights into the ability of these phytochemicals to induce structural compaction and stabilization of the GR protein, as evidenced by changes in radius of gyration and solvent-accessible surface area. Moreover, MMPBSA analysis highlighted the crucial roles of specific residues, namely Gly27, Gly28, Ser51, His52, and Val61, in mediating essential interactions with these phytochemicals. Furthermore, an assessment of Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME-Tox) profiles underscored the favourable drug-like attributes of these phytochemicals. Thus, the current findings underscore the immense potential of Houttuynia cordata phytochemicals as potent antioxidants with the capacity to combat a spectrum of maladies, including malaria and cancer. This study not only unveils novel therapeutic avenues but also underscores the distinctive outcomes and paramount significance of harnessing H. cordata phytochemicals for their efficacious antioxidant properties.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid38107500, year = {2023}, author = {Tang, C and Wang, L and Chen, Z and Yang, J and Gao, H and Guan, C and Gu, Q and He, S and Yang, F and Chen, S and Ma, L and Zhang, Z and Zhao, Y and Tang, L and Xu, Y and Hu, Y and Luo, X}, title = {Efficacy and Safety of Hydrogen Therapy in Patients with Early-Stage Interstitial Lung Disease: A Single-Center, Randomized, Parallel-Group Controlled Trial.}, journal = {Therapeutics and clinical risk management}, volume = {19}, number = {}, pages = {1051-1061}, pmid = {38107500}, issn = {1176-6336}, abstract = {PURPOSE: Several in vivo experiments have shown that molecular hydrogen is a promising therapeutic agent for interstitial lung diseases (ILD). In this study, hydrogen therapy was investigated to determine whether it is superior to N-Acetylcysteine (NAC) for the treatment of patients with early-stage ILD.<br><br>PATIENTS AND METHODS: A prospective, single-center, randomized, controlled clinical trial was conducted in 87 patients with early-stage ILD. Hydrogen or NAC therapy was randomly assigned (1:1 ratio) to the eligible patients. The primary endpoint was the change in the high-resolution computed tomography (HRCT) and composite physiologic index (CPI) scores from baseline to week 48. Pulmonary function was evaluated as a secondary endpoint, and adverse events were recorded for safety analysis.<br><br>RESULTS: The rate of HRCT image improvement from the baseline in the HW group (63.6%) was higher than that in the NAC group (39.5%). A significant decrease in CPI and improvement in DLCO-sb were observed in the hydrogen group compared with those in the control group. Changes in other pulmonary function parameters, including FVC, FEV1, FEV1/FVC%, and TLC, were not significantly different between the two groups. Adverse events were reported in 7 (15.9%) patients in the HW group and 10 (23.3%) patients in the NAC group, but the difference was not significant (P=0.706).<br><br>CONCLUSION: Hydrogen therapy exhibits superior efficacy and acceptable safety compared with NAC therapy in patients with early-stage ILD.}, }
@article {pmid38105264, year = {2023}, author = {Musillo, C and Creutzberg, KC and Collacchi, B and Ajmone-Cat, MA and De Simone, R and Lepre, M and Amrein, I and Riva, MA and Berry, A and Cirulli, F}, title = {Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity.}, journal = {Translational psychiatry}, volume = {13}, number = {1}, pages = {399}, pmid = {38105264}, issn = {2158-3188}, mesh = {Animals ; Female ; Male ; Mice ; Pregnancy ; Hippocampus/metabolism ; Hypothalamo-Hypophyseal System/metabolism ; *Obesity, Maternal/metabolism ; Pituitary-Adrenal System/metabolism ; *Prenatal Exposure Delayed Effects ; Stress, Psychological/metabolism ; }, abstract = {Maternal obesity has been recognized as a stressor affecting the developing fetal brain, leading to long-term negative outcomes comparable to those resulting from maternal psychological stress, although the mechanisms have not been completely elucidated. In this study, we tested the hypothesis that adverse prenatal conditions as diverse as maternal stress and maternal obesity might affect emotional regulation and stress response in the offspring through common pathways, with a main focus on oxidative stress and neuroplasticity. We contrasted and compared adolescent male and female offspring in two mouse models of maternal psychophysical stress (restraint during pregnancy - PNS) and maternal obesity (high-fat diet before and during gestation - mHFD) by combining behavioral assays, evaluation of the hypothalamic-pituitary-adrenal (HPA) axis reactivity, immunohistochemistry and gene expression analysis of selected markers of neuronal function and neuroinflammation in the hippocampus, a key region involved in stress appraisal. Prenatal administration of the antioxidant N-acetyl-cysteine (NAC) was used as a strategy to protect fetal neurodevelopment from the negative effects of PNS and mHFD. Our findings show that these two stressors produce overlapping effects, reducing brain anti-oxidant defenses (Nrf-2) and leading to sex-dependent impairments of hippocampal Bdnf expression and alterations of the emotional behavior and HPA axis functionality. Prenatal NAC administration, by restoring the redox balance, was able to exert long-term protective effects on brain development, suggesting that the modulation of redox pathways might be an effective strategy to target common shared mechanisms between different adverse prenatal conditions.}, }
@article {pmid38104651, year = {2024}, author = {Wen, T and Xie, J and Ma, L and Hao, Z and Zhang, W and Wu, T and Li, L}, title = {Vitamin D Receptor Activation Reduces Hepatic Inflammation via Enhancing Macrophage Autophagy in Cholestatic Mice.}, journal = {The American journal of pathology}, volume = {194}, number = {3}, pages = {369-383}, doi = {10.1016/j.ajpath.2023.11.016}, pmid = {38104651}, issn = {1525-2191}, mesh = {Animals ; Mice ; Acetylcysteine ; Autophagy/physiology ; *Cholestasis/metabolism ; *Inflammasomes/metabolism ; Inflammation/metabolism ; Interleukin-1beta/metabolism ; Macrophages/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Calcitriol/metabolism ; }, abstract = {Macrophage autophagy dysfunction aggravates liver injury by activating inflammasomes, which can cleave pro-IL-1β to its active, secreted form. We investigated whether the vitamin D/vitamin D receptor (VDR) axis could up-regulate macrophage autophagy function to inhibit the activation of inflammasome-dependent IL-1β during cholestasis. Paricalcitol (PAL; VDR agonist) was intraperitoneally injected into bile duct-ligated mice for 5 days. Up-regulation of VDR expression by PAL reduced liver injury by reducing the oxidative stress-induced inflammatory reaction in macrophages. Moreover, PAL inhibited inflammasome-dependent IL-1β generation. Mechanistically, the knockdown of VDR increased IL-1β generation, whereas VDR overexpression exerted the opposite effect following tert-butyl hydroperoxide treatment. The inflammasome antagonist glyburide, the caspase-1-specific inhibitor YVAD, and the reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) blocked the increase in Vdr shRNA-induced IL-1β production. Interestingly, up-regulation of VDR also enhanced macrophage autophagy. Autophagy reduction impaired the up-regulation of VDR-inhibited macrophage inflammasome-generated IL-1β, whereas autophagy induction showed a synergistic effect with VDR overexpression through ROS-p38 mitogen-activated protein kinase (MAPK) pathway. This result was confirmed by p38 MAPK inhibitor, MAPK activator, and ROS inhibitor NAC. Collectively, PAL triggered macrophage autophagy by suppressing activation of the ROS-p38 MAPK pathway, which, in turn, suppressed inflammasome-generated cleaved, active forms of IL-1β, eventually leading to reduced inflammation. Thus, triggering the VDR may be a potential target for the anti-inflammatory treatment of cholestatic liver disease.}, }
@article {pmid38101763, year = {2024}, author = {Fu, C and Yang, C and Ni, C and Wang, L and Hou, J}, title = {Echinococcus granulosus cyst fluid inhibits the type I interferon response by promoting ROS in macrophages.}, journal = {Acta tropica}, volume = {250}, number = {}, pages = {107101}, doi = {10.1016/j.actatropica.2023.107101}, pmid = {38101763}, issn = {1873-6254}, mesh = {Animals ; *Interferon Type I ; *Echinococcus granulosus/metabolism ; Reactive Oxygen Species ; Cyst Fluid ; Macrophages/metabolism ; Nucleotidyltransferases/metabolism ; }, abstract = {In cystic echinococcosis (CE), Echinococcus granulosus cystic fluid (EgCF) could impede macrophage-mediated immunity. However, whether EgCF is implicated in the type I interferon response remains to be established. Here, we revealed that EgCF reduced 2'3'-cGAMP-induced IFN-β production in macrophages by inhibiting the cGAS-STING-IRF3 signaling. EgCF also increased the intracellular reactive oxygen species (ROS) levels. Administration of the ROS inhibitor N-acetylcysteine (NAC) restored the cGAS-STING-IRF3 signaling, which, in turn, upregulated IFN-β expression. The findings disclose that EgCF could increase macrophage ROS levels, thereby blocking cGAS-STING-IRF3 signaling and repressing the IFN-I response.}, }
@article {pmid38092096, year = {2024}, author = {Zhu, R and Shang, GJ and Zhang, BY and Wang, HT and Li, L and Wei, XF and Li, DL and Yang, ZY and Qu, ZH and Quan, YN and Liu, SY and Wang, YT and Meng, ST and Wu, LF and Qin, GX}, title = {Unlocking the potential of N-acetylcysteine: Improving hepatopancreas inflammation, antioxidant capacity and health in common carp (Cyprinus carpio) via the MAPK/NF-κB/Nrf2 signalling pathway.}, journal = {Fish &amp; shellfish immunology}, volume = {144}, number = {}, pages = {109294}, doi = {10.1016/j.fsi.2023.109294}, pmid = {38092096}, issn = {1095-9947}, mesh = {Animals ; *Antioxidants/metabolism ; NF-kappa B/metabolism ; Acetylcysteine/pharmacology ; *Carps/metabolism ; NF-E2-Related Factor 2/metabolism ; Hepatopancreas/metabolism ; Signal Transduction ; Diet/veterinary ; Inflammation/veterinary ; Glutathione ; Dietary Supplements ; }, abstract = {N-acetylcysteine (NAC) positively contributes to enhancing animal health, regulating inflammation and reducing stress by participating in the synthesis of cysteine, glutathione, and taurine in the body. The present study aims to investigate the effects of dietary different levels of NAC on the morphology, function and physiological state of hepatopancreas in juvenile common carp (Cyprinus carpio). 450 common carps were randomly divided into 5 groups: N1 (basal diet), N2 (1.5 g/kg NAC diet), N3 (3.0 g/kg NAC diet), N4 (4.5 g/kg NAC diet) and N5 (6.0 g/kg NAC diet), and fed for 8 weeks. The results indicated that dietary 3.0-6.0 g/kg NAC reduced hepatopancreas lipid vacuoles and nuclear translocation, and inhibited apoptosis in common carp. Simultaneously, the activities of hepatopancreas alanine aminotransferase and aspartate aminotransferase progressively increased with rising dietary NAC levels. Dietary NAC enhanced the non-specific immune function of common carp, and exerted anti-inflammatory effects by inhibiting the MAPK/NF-κB signaling pathway. Additionally, dietary 3.0-6.0 g/kg NAC significantly improved the antioxidant capacity of common carp, which was associated with enhanced glutathione metabolism, clearance of ROS and the activation of Nrf2 signaling pathway. In summary, NAC has the potential to alleviate inflammation, mitigate oxidative stress and inhibit apoptosis via the MAPK/NF-κB/Nrf2 signaling pathway, thereby improving hepatopancreas function and health of common carp. The current findings provide a theoretical basis for promoting the application of NAC in aquaculture and ecological cultivation of aquatic animals.}, }
@article {pmid38091079, year = {2024}, author = {Mohamad, EA and Ali, AA and Sharaky, M and El-Gebaly, RH}, title = {Niosomes loading N-acetyl-L-cysteine for cancer treatment in vivo study.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {397}, number = {6}, pages = {4339-4353}, pmid = {38091079}, issn = {1432-1912}, mesh = {Animals ; *Acetylcysteine/pharmacology/administration &amp; dosage ; Male ; *Mice, Inbred BALB C ; *Liposomes ; Mice ; Oxidative Stress/drug effects ; Antineoplastic Agents/administration &amp; dosage/pharmacology ; Cell Line, Tumor ; Apoptosis/drug effects ; DNA Damage/drug effects ; Tumor Burden/drug effects ; Drug Carriers ; }, abstract = {Scientists are seeking to find an effective treatment for tumors that has no side effects. N-Acetyl-l-cysteine (NAC) is a thiol compound extracted from garlic. Current study explores the potential of NAC-loaded niosomes (NAC-NIO) for tumor treatment in mice. NAC-loaded niosomes' efficiency, morphology, UV absorption, size distribution, zeta potential, release, and FTIR analysis were evaluated. For vivo study, 25 male BALB/c mice were divided to five groups: gp1 negative control (receive saline), gp2 positive control (tumor group), gp3 treated with NAC, gp4 treated with NAC-NIO at the same time of tumor injection, and gp5 treated with NAC-NIO after tumor growth (day 14). The impact of NAC-NIO on the tumor treatment was evaluated by measuring tumor size progress, comet assay, oxidative stress parameters (GSH, nitric oxide, MDA), western blot analysis, and histopathological investigation of tissues. NAC-NIO showed 72 ± 3% encapsulation efficiency and zeta potential - 5.95 mV with spherical shape. It was found that oral administration of NAC-NIO in a dose of 50 mg/kg provided significant protection against tumor cells. Our formulation decreases DNA injury significantly (P < 0.05). It was noticed that NAC-NIO can increase oxidative stress levels in tumor tissue. On the other hand, the caspase 3 and caspase 9 gene expression were upregulated significantly (P < 0.001) in mice administrated NAC-NIO compared with all other groups. Histological studies confirmed the protective effect of NAC-NIO against tumor especially for treatment during tumor growth protocol. The results suggested that oral delivery of NAC-NIO formulation improved antioxidant effect.}, }
@article {pmid38088332, year = {2024}, author = {Bahoush, G and Rahab, M and Ahmadvand, P}, title = {Can N-acetylcysteine reduce red blood cell transfusion burden in patients with transfusion-dependent β-thalassemia?.}, journal = {Pediatric hematology and oncology}, volume = {41}, number = {4}, pages = {251-259}, doi = {10.1080/08880018.2023.2292556}, pmid = {38088332}, issn = {1521-0669}, mesh = {Humans ; *beta-Thalassemia ; Erythrocyte Transfusion ; Acetylcysteine/therapeutic use ; Quality of Life ; *Iron Overload/drug therapy/etiology ; Hemoglobins/analysis ; }, abstract = {Patients with beta-thalassemia major require lifelong and frequent red blood cell transfusions for survival, impacting their quality of life and life expectancy. This treatment approach poses risks of organ damage, iron overload, and increased transfusion-transmitted diseases. N-acetylcysteine (NAC) has been studied for its potential antioxidant effects on hemoglobin stability, aiming to reduce the burden of red blood cell transfusions. To explore this possibility further, we conducted a quasi-experimental study involving 35 individuals with thalassemia major over six months All subjects were already receiving iron chelators and blood transfusions. They were given a daily oral dose of 10 mg/kg NAC for three months. After three months of treatment with NAC, the serum levels of ferritin and liver enzymes (SGOT and SGPT) did not show significant changes (p = 0.35, p = 0.352, and p = 0.686, respectively). However, the red blood cell transfusion burden was significantly reduced in all patients after NAC therapy (p = 0.029), with no corresponding decrease in serum hemoglobin levels (p = 0.931), indicating maintained hemoglobin concentration despite reduced transfusion volume. The study indicates that NAC can effectively decrease the burden of red blood cell transfusions without significant toxicity in these patients. This finding suggests the potential for NAC as a cost-effective and manageable treatment option for these patients. A larger clinical trial with more robust statistical methods could further confirm these results and pave the way for using NAC as a valuable therapeutic agent for managing beta-thalassemia major patients.}, }
@article {pmid38088264, year = {2023}, author = {Kandhari, K and Kant, R and Mishra, N and Agarwal, C and Agarwal, R}, title = {Phenylarsine oxide induced corneal injury involves oxidative stress mediated unfolded protein response and ferroptotic cell death: Amelioration by NAC.}, journal = {Free radical biology &amp; medicine}, volume = {209}, number = {Pt 2}, pages = {265-281}, pmid = {38088264}, issn = {1873-4596}, support = {U01 EY030405/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Rabbits ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Irritants ; *Arsenicals ; *Corneal Injuries/chemically induced ; Oxidative Stress ; Unfolded Protein Response ; Cell Death ; }, abstract = {Phenylarsine oxide (PAO), an analog of lewisite, is a highly toxic trivalent arsenical and a potential chemical warfare agent. PAO-induced toxicity has been studied in lung, liver, and skin tissues. Nevertheless, very few studies have been published to comprehend the impact of PAO-induced toxicity on ocular tissues, even though eyes are uniquely vulnerable to injury by vesicants. Notably, arsenical vesicants such as lewisite have been shown to cause edema of eyelids, inflammation, massive corneal necrosis, and blindness. Accordingly, human corneal epithelial cells were used to study the effects of PAO exposure. PAO (100 and 200 nM) induced significant oxidative stress in corneal epithelial cells. Simultaneous treatment with N-acetyl-l-cysteine (NAC), an FDA-approved antioxidant, reversed the PAO-induced toxicity in human corneal epithelial cells. Furthermore, oxidative stress induction by PAO was accompanied by unfolded protein response (UPR) signaling activation and ferroptotic cell death. Further, to validate the findings of our in vitro studies, we optimized injury biomarkers and developed an ex vivo rabbit corneal culture model of PAO exposure. Investigations using PAO in ex vivo rabbit corneas revealed similar results. PAO (5 or 10 μg) for 3, 5, and 10 min caused moderate to extensive corneal epithelial layer degradation and reduced the epithelial layer thickness in a concentration- and time-dependent manner. Similar to human corneal cells, injuries by PAO in ex vivo cultured rabbit corneas were also associated with elevated oxidative stress, UPR signaling, and ferroptosis induction. NAC mitigated PAO-induced corneal injuries in rabbit ex vivo cornea culture as well. The reversal of PAO toxicity upon NAC treatment observed in our studies could be attributed to its antioxidant properties. These findings suggest that PAO exposure can cause significant corneal injury and highlight the need for further mechanistic studies to better understand the pathobiology of different arsenical vesicants, including PAO and lewisite.}, }
@article {pmid38086481, year = {2024}, author = {Wu, Q and Liu, C and Liu, D and Wang, Y and Qi, H and Liu, X and Zhang, Y and Chen, H and Zeng, Y and Li, J}, title = {Polystyrene nanoplastics-induced lung apoptosis and ferroptosis via ROS-dependent endoplasmic reticulum stress.}, journal = {The Science of the total environment}, volume = {912}, number = {}, pages = {169260}, doi = {10.1016/j.scitotenv.2023.169260}, pmid = {38086481}, issn = {1879-1026}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Microplastics ; Polystyrenes/toxicity ; Endoplasmic Reticulum Chaperone BiP ; Endoribonucleases/pharmacology ; *Ferroptosis ; Protein Serine-Threonine Kinases ; Lung/metabolism ; Acetylcysteine/pharmacology ; Apoptosis ; Endoplasmic Reticulum Stress ; }, abstract = {It has been shown that exposure to nanoplastics (MNPs) through inhalation can induce pulmonary toxicity, but the toxicological mechanism of MNPs on the respiratory system remains unclear. Therefore, we explored the toxicological mechanism of exposure to polystyrene nanoplastics (PS-NPs) (0.05, 0.15, 0.2 mg/mL) on BEAS-2B cells. Results revealed that PS-NPs induce oxidative stress, increased apoptosis rate measured by flow cytometry, the key ferroptosis protein (GPX4 and FTH1) reduction, increased iron content, mitochondrial alterations, and increased malondialdehyde (MDA) level. Besides, consistent results were observed in mice exposed to PS-NPs (5 mg/kg/2d, 10 mg/kg/2d). Thus, we proved that PS-NPs induced cell death and lung damage through apoptosis and ferroptosis. In terms of mechanism, the elevation of the endoplasmic reticulum (ER) stress protein expression (IRE1α, PERK, XBP1S, and CHOP) revealed that PS-NPs induce lung damage by activating the two main ER stress pathways. Furthermore, the toxicological effects of PS-NPs observed in this study are attenuated by the ROS inhibitor N-acetylcysteine (NAC). Collectively, NPs-induced apoptosis and ferroptosis are attenuated by NAC via inhibiting the ROS-dependent ER stress in vitro and in vivo. This improves our understanding of the mechanism by which PS-NPs exposure leads to pulmonary injury and the potential protective effects of NAC.}, }
@article {pmid38079440, year = {2023}, author = {Graham, RE and Elliott, RJR and Munro, AF and Carragher, NO}, title = {A cautionary note on the use of N-acetylcysteine as a reactive oxygen species antagonist to assess copper mediated cell death.}, journal = {PloS one}, volume = {18}, number = {12}, pages = {e0294297}, pmid = {38079440}, issn = {1932-6203}, mesh = {Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology/chemistry ; *Copper/chemistry ; Disulfiram/pharmacology ; Cell Death ; Apoptosis ; Antioxidants/pharmacology ; Ionophores/pharmacology ; }, abstract = {A new form of cell death has recently been proposed involving copper-induced cell death, termed cuproptosis. This new form of cell death has been widely studied in relation to a novel class of copper ionophores, including elesclomol and disulfiram. However, the exact mechanism leading to cell death remains contentious. The oldest and most widely accepted biological mechanism is that the accumulated intracellular copper leads to excessive build-up of reactive oxygen species and that this is what ultimately leads to cell death. Most of this evidence is largely based on studies using N-acetylcysteine (NAC), an antioxidant, to relieve the oxidative stress and prevent cell death. However, here we have demonstrated using inductively coupled mass-spectrometry, that NAC pretreatment significantly reduces intracellular copper uptake triggered by the ionophores, elesclomol and disulfiram, suggesting that reduction in copper uptake, rather than the antioxidant activity of NAC, is responsible for the diminished cell death. We present further data showing that key mediators of reactive oxygen species are not upregulated in response to elesclomol treatment, and further that sensitivity of cancer cell lines to reactive oxygen species does not correlate with sensitivity to these copper ionophores. Our findings are in line with several recent studies proposing the mechanism of cuproptosis is instead via copper mediated aggregation of proteins, resulting in proteotoxic stress leading to cell death. Overall, it is vital to disseminate this key piece of information regarding NAC's activity on copper uptake since new research attributing the effect of NAC on copper ionophore activity to quenching of reactive oxygen species is being published regularly and our studies suggest their conclusions may be misleading.}, }
@article {pmid38079000, year = {2023}, author = {AbdelRazek, M and Mohamed, O and Ashour, R and Alemam, M and El-Gelany, M and Abdel-Kader, MS}, title = {Effect of co-trimoxazole and N-acetylcysteine alone and in combination on bacterial adherence on ureteral stent surface.}, journal = {Urolithiasis}, volume = {52}, number = {1}, pages = {11}, pmid = {38079000}, issn = {2194-7236}, mesh = {Adult ; Child ; Humans ; *Acetylcysteine/therapeutic use/pharmacology ; Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use ; Prospective Studies ; Escherichia coli ; *Ureter/surgery/microbiology ; Stents/adverse effects/microbiology ; Bacteria ; }, abstract = {To assess the effect of co-trimoxazole and N-acetylcysteine (NAC), alone and in combination, on bacterial adherence to biofilm formed on ureteral stent surfaces. This prospective randomized study was conducted on 636 patients who underwent double J ureteral stent insertion after variable urological procedures. Patients were randomized into four groups: A (n = 165), no antibiotics or mucolytics during stent indwelling; B (n = 153), oral NAC (200 mg/day for children aged < 12 years old and 600 mg/day for adults) during stent indwelling; C (n = 162), oral co-trimoxazole (2 mg TMP/kg/day) during stent indwelling; and D (n = 156), both oral NAC and co-trimoxazole during stent indwelling. Two weeks following double J stent (JJ stent) insertion, urinalysis was performed on all patients and urine culture was done for all the patients at the day of double J stent removal. The stent was removed 2 weeks postoperatively, and a stent segment sized 3-5 cm from the bladder segment of the stent was sent for culture. Positive stent cultures were found in 63.6% (105/165), 43.1% (66/153), 37% (60/162), and 19.2% (30/156) patients of groups A, B, C, and D, respectively. E. coli was the organism most commonly isolated from the stent culture in all groups. The combination of co-trimoxazole and NAC was more effective in reducing bacterial adherence on ureteral stent surfaces than either alone.}, }
@article {pmid38076819, year = {2023}, author = {Zou, H and Boboltz, A and Cheema, Y and Song, D and Duncan, GA}, title = {Synthetic mucus barrier arrays as a nanoparticle formulation screening platform.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {38076819}, support = {R21 AI142050/AI/NIAID NIH HHS/United States ; }, abstract = {A mucus gel layer lines the luminal surface of tissues throughout the body to protect them from infectious agents and particulates. As a result, nanoparticle drug delivery systems delivered to these sites may become trapped in mucus and subsequently cleared before they can reach target cells. As such, optimizing the properties of nanoparticle delivery vehicles, such as their surface chemistry and size, is essential to improving their penetration through the mucus barrier. In previous work, we developed a mucin-based hydrogel that has viscoelastic properties like that of native mucus which can be further tailored to mimic specific mucosal tissues and disease states. Using this biomimetic hydrogel system, a 3D-printed array containing synthetic mucus barriers was created that is compatible with a 96-well plate enabling its use as a high-throughput screening platform for nanoparticle drug delivery applications. To validate this system, we evaluated several established design parameters to determine their impact on nanoparticle penetration through synthetic mucus barriers. Consistent with the literature, we found nanoparticles of smaller size and coated with a protective PEG layer more efficiently penetrated through synthetic mucus barriers. In addition, we evaluated a mucolytic (tris (2-carboxyethyl) phosphine, TCEP) for use as a permeation enhancer for mucosal drug delivery. In comparison to N-acetyl cysteine (NAC), we found TCEP significantly improved nanoparticle penetration through a disease-like synthetic mucus barrier. Overall, our results establish a new high-throughput screening approach using synthetic mucus barrier arrays to identify promising nanoparticle formulation strategies for drug delivery to mucosal tissues.}, }
@article {pmid38072040, year = {2024}, author = {Xiao, Y and Huang, Z and Wang, Y and Wang, Y and Yu, L and Yang, J and Zou, H and Wan, W and Yang, X}, title = {Xanthohumol attenuates collagen synthesis in scleroderma skin fibroblasts by ROS/Nrf2/TGFβ1/Smad3 pathway.}, journal = {European journal of pharmacology}, volume = {963}, number = {}, pages = {176227}, doi = {10.1016/j.ejphar.2023.176227}, pmid = {38072040}, issn = {1879-0712}, mesh = {Humans ; Collagen/metabolism ; Fibroblasts ; Fibrosis ; *NF-E2-Related Factor 2/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; *Scleroderma, Systemic/drug therapy/metabolism/pathology ; Skin ; Transforming Growth Factor beta/drug effects/metabolism ; Smad3 Protein/drug effects/metabolism ; }, abstract = {Skin fibrosis, the most obvious clinical manifestation of systemic sclerosis (SSc), has a high unmet need for treatment. Xanthohumol (Xn) has been shown to have beneficial effects on fibrotic diseases, but its efficacy in SSc remains unreported. This study aims to elucidate the effects and mechanisms of Xn on collagen synthesis in SSc skin fibroblasts (SScF). We found increased collagen production in SScF cultured in vitro, accompanied by dysregulated levels of oxidative stress. Cell experiments showed that Xn inhibited cell proliferation and promoted apoptosis. In addition, Xn was shown for the first time to upregulate reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2)levels in SScF, and when combined with the ROS scavenger N-acetylcysteine (NAC), Nrf2 expression was decreased. Importantly, we demonstrated that Xn significantly attenuated collagen synthesis by blocking the fibrotic classical transforming growth factor beta 1 (TGFβ1)/Smad3 pathway, which interestingly was upregulated when combined with the Nrf2 inhibitor 385. Taken together, Xn suppressed the TGFβ1/Smad3 pathway to ameliorate collagen overproduction by promoting ROS-induced oxidative stress damage and activating Nrf2, suggesting that Xn administration may be an emerging therapeutic strategy for skin fibrosis in SSc.}, }
@article {pmid38071432, year = {2024}, author = {Şehirli, A&#xd6; and Aksoy, U and Sibai, A and Orhan, K and Sayıner, S}, title = {Effects of N-acetyl-L-cysteine against apical periodontitis in rats with adriamycin-induced cardiomyopathy and nephropathy.}, journal = {International endodontic journal}, volume = {57}, number = {2}, pages = {195-207}, doi = {10.1111/iej.14010}, pmid = {38071432}, issn = {1365-2591}, mesh = {Rats ; Animals ; Rats, Wistar ; Acetylcysteine/pharmacology/therapeutic use ; Doxorubicin ; *Periapical Periodontitis/chemically induced/drug therapy ; *Cardiomyopathies/chemically induced/drug therapy ; Body Weight ; }, abstract = {AIM: This study aimed to investigate the potential protective effects of N-acetyl-L-cysteine (NAC) against apical periodontitis (AP) in rats with adriamycin (ADR)-induced kidney and heart diseases.<br><br>METHODOLOGY: Fourty-eight Wistar albino rats were divided into six groups: (1) Control group, (2) ADR group (1&#x2009;mg/kg/day ip for 10&#x2009;days), (3) AP Group (1st mandibular molar tooth), (4) AP&#x2009;+&#x2009;ADR Group, (5) AP&#x2009;+&#x2009;NAC group (150&#x2009;mg/kg/day ip), and (6) AP&#x2009;+&#x2009;ADR&#x2009;+&#x2009;NAC group. After 3&#x2009;weeks, the rats were decapitated and blood and tissue samples (heart, kidney, and jaw) were collected. Tissue samples were evaluated by biochemical (inflammatory cytokines and hemodynamic parameters) and radiological analyses. One-way anova with Tukey post hoc tests was used to compare data, considering p&#x2009;<&#x2009;.05 as statistically significant.<br><br>RESULTS: The serum levels of TNF-&#x3b1;, IL-1&#x3b2;, BUN, Creatinine, CK, and LDH were elevated in the test groups compared with the control group, and treatment with NAC reduced these levels (p&#x2009;<&#x2009;.05). Heart and kidney tissue analysis showed a higher heart-to-body weight ratio (HW/BW) and kidney-to-body weight ratio (KW/BW) in the test groups compared with the control group (p&#x2009;<&#x2009;.05). No significant differences in HW/BW and KW/BW were found between the control and AP&#x2009;+&#x2009;NAC groups. Volumetric apical bone resorption analysis showed an increase in periapical radiolucencies in AP-induced groups indicating apical periodontitis. NAC treatment reduced the total area and volume of resorption cavities (p&#x2009;<&#x2009;.05).<br><br>CONCLUSIONS: The results suggest that NAC's antioxidant and anti-inflammatory effects can reduce adriamycin-mediated heart and kidney damage and may have a positive effect on apical periodontitis in individuals with nephropathy and cardiomyopathy.}, }
@article {pmid38071049, year = {2023}, author = {Lu, M and He, CL and Wu, ZT and Lyu, Y and Duan, XH and Wang, BX and Wang, SX and Wang, JH and Liang, R}, title = {[Effect of Baicalin on Pyroptosis of Diffuse Large B-Cell Lymphoma Cell Lines DB and Its Mechanism].}, journal = {Zhongguo shi yan xue ye xue za zhi}, volume = {31}, number = {6}, pages = {1706-1713}, doi = {10.19746/j.cnki.issn.1009-2137.2023.06.016}, pmid = {38071049}, issn = {1009-2137}, mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Reactive Oxygen Species/metabolism/pharmacology ; Pyroptosis ; Cell Line ; RNA, Messenger ; *Lymphoma, Large B-Cell, Diffuse ; }, abstract = {OBJECTIVE: To investigate the effect of Baicalin on the proliferation and pyroptosis of diffuse large B-cell lymphoma cell line DB and its mechanism.<br><br>METHODS: DB cells were treated with baicalin at different concentrations (0, 5, 10, 20, 40 &#x3bc;mol/L). Cell proliferation was detected by CCK-8 assay and half maximal inhibitory concentration (IC50) was calculated. The morphology of pyroptosis was observed under an inverted microscope, the integrity of the cell membrane was verified by LDH content release assay, and the expressions of pyroptosis-related mRNA and protein (NLRP3, GSDMD, GSDME, N-GSDMD, N-GSDME) were detected by real-time fluorescence quantitative PCR and Western blot. In order to further clarify the relationship between baicalin-induced pyroptosis and ROS production in DB cells, DB cells were divided into control group, baicalin group, NAC group and NAC combined with baicalin group. DB cells in the NAC group were pretreated with ROS inhibitor N-acetylcysteine (NAC) 2 mmol/L for 2 h. Baicalin was added to the combined treatment group after pretreatment, and the content of reactive oxygen species (ROS) in the cells was detected by DCFH-DA method after 48 hours of culture.<br><br>RESULTS: Baicalin inhibited the proliferation of DB cells in a dose-dependent manner (r=-0.99), and the IC50 was 20.56 &#x3bc;mol/L at 48 h. The morphological changes of pyroptosis in DB cells were observed under inverted microscope. Compared with the control group, the release of LDH in the baicalin group was significantly increased (P<0.01), indicating the loss of cell membrane integrity. Baicalin dose-dependently increased the expression levels of NLRP3, N-GSDMD, and N-GSDME mRNA and protein in the pyroptosis pathway (P<0.05). Compared with the control group, the level of ROS in the baicalin group was significantly increased (P<0.05), and the content of ROS in the NAC group was significantly decreased (P<0.05). Compared with the NAC group, the content of ROS in the NAC + baicalin group was increased. Baicalin significantly attenuated the inhibitory effect of NAC on ROS production (P<0.05). Similarly, Western blot results showed that compared with the control group, the expression levels of pyroptosis-related proteins was increased in the baicalin group (P<0.05). NAC inhibited the expression of NLRP3 and reduced the cleavage of N-GSDMD and N-GSDME (P<0.05). Compared with the NAC group, the NAC + baicalin group had significantly increased expression of pyroptosis-related proteins. These results indicate that baicalin can effectively induce pyroptosis in DB cells and reverse the inhibitory effect of NAC on ROS production.<br><br>CONCLUSION: Baicalin can inhibit the proliferation of DLBCL cell line DB, and its mechanism may be through regulating ROS production to affect the pyroptosis pathway.}, }
@article {pmid38069498, year = {2024}, author = {Tiouririne, NA and Kalelioglu, T and Seneviratne, C and Wang, XQ}, title = {Safety and tolerability of topiramate and N-acetyl cysteine combination in individuals with alcohol use disorder: a 12 week, randomized, double-blind, pilot study.}, journal = {Alcohol and alcoholism (Oxford, Oxfordshire)}, volume = {59}, number = {2}, pages = {}, doi = {10.1093/alcalc/agad082}, pmid = {38069498}, issn = {1464-3502}, support = {//University of Virginia/ ; }, mesh = {Humans ; Alcohol Drinking ; *Alcoholism/drug therapy/psychology ; Cysteine ; Double-Blind Method ; Glutathione/metabolism ; Pilot Projects ; *Topiramate/adverse effects ; Treatment Outcome ; Drug Combinations ; }, abstract = {Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.}, }
@article {pmid38068931, year = {2023}, author = {Pérez-Torres, I and Aisa-Álvarez, A and Casarez-Alvarado, S and Borrayo, G and Márquez-Velasco, R and Guarner-Lans, V and Manzano-Pech, L and Cruz-Soto, R and Gonzalez-Marcos, O and Fuentevilla-Álvarez, G and Gamboa, R and Saucedo-Orozco, H and Franco-Granillo, J and Soto, ME}, title = {Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects.}, journal = {International journal of molecular sciences}, volume = {24}, number = {23}, pages = {}, pmid = {38068931}, issn = {1422-0067}, mesh = {Humans ; Antioxidants/therapeutic use ; Interleukin-6 ; Cytokine Release Syndrome/drug therapy ; Interleukin-10 ; *Shock, Septic/drug therapy ; Reproducibility of Results ; Oxidative Stress ; Ascorbic Acid/therapeutic use ; Vitamin E/therapeutic use ; Acetylcysteine/therapeutic use ; *Melatonin/therapeutic use ; Adjuvants, Immunologic/therapeutic use ; }, abstract = {Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3[-] and NO2[-]), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.}, }
@article {pmid38067442, year = {2023}, author = {Lee, BH and Song, E and Hong, J}, title = {Interaction of Thiol Antioxidants with α,β-Unsaturated Ketone Moiety: Its Implication for Stability and Bioactivity of Curcuminoids.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {23}, pages = {}, pmid = {38067442}, issn = {1420-3049}, support = {2021R1F1A1051466//National Research Foundation of Korea/ ; IHS GNU-2022-04//Institute of Health Sciences of Gyeongsang National University/ ; 2022//The research grant of the Gyeongsang National University/ ; }, mesh = {*Antioxidants/pharmacology ; Diarylheptanoids ; *Curcumin/pharmacology ; Sulfhydryl Compounds/pharmacology ; Glutathione/pharmacology ; Acetylcysteine/pharmacology ; }, abstract = {Many biological functions of curcumin have been reported. As certain bioactivities of curcumin are eliminated by antioxidants, reactive oxygen species generated by curcumin have been suggested as a relevant mechanism. In the present study, the effects of different types of antioxidants on the stability and bioactivities of curcumin were analyzed. High concentrations (>4 mM) of thiol antioxidants, including N-acetylcysteine (NAC), glutathione (GSH), and β-mercaptoethanol, accelerated the decomposition of curcumin and other curcuminoids; the submillimolar levels (<0.5 mM) of GSH and NAC rather improved their stability. Ascorbic acid or superoxide dismutase also stabilized curcumin, regardless of their concentration. The cellular levels and bioactivities of curcumin, including its cytotoxicity and the induction of heme oxygenase-1, were significantly reduced in the presence of 8 mM of GSH and NAC. The effects were enhanced in the presence of submillilmolar GSH and NAC, or non-thiol antioxidants. The present results indicate that antioxidants with a reduced thiol group could directly interact with the α,β-unsaturated carbonyl moiety of curcuminoids and modulate their stability and bioactivity.}, }
@article {pmid38065397, year = {2024}, author = {Li, F and Zhu, X and Xu, X and Zhou, J and Lu, R and Wang, S and Xing, G and Ye, Y}, title = {Dibromoacetonitrile induced autophagy by mediating the PERK signalling pathway and ROS interaction in HT22 cell.}, journal = {Toxicology}, volume = {501}, number = {}, pages = {153698}, doi = {10.1016/j.tox.2023.153698}, pmid = {38065397}, issn = {1879-3185}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Protein Kinases/metabolism ; *Signal Transduction ; Endoplasmic Reticulum/metabolism ; Autophagy ; Endoplasmic Reticulum Stress ; Apoptosis ; Mammals/metabolism ; }, abstract = {Dibromoacetonitrile (DBAN) is a high-risk haloacetonitrile (HAN) generated as a byproduct of chloramine disinfection in drinking water. DBAN-induced neurotoxicity in mouse hippocampal neuronal cells (HT22) and mammals was observed to be related to reactive oxygen species (ROS). ROS, endoplasmic reticulum stress (ERS) and autophagy play crucial roles in regulating a variety of cellular processes. However, whether ERS and autophagy are associated with HAN-responsive apoptosis remains unclear. This study indicated that DBAN (10 μM, 24 h) activated the ERS protein kinase like endoplasmic reticulum kinase (PERK) signaling pathway. The ERS inhibitor 4-phenylbutyric acid (4-PBA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, indicating that activation of the ERS PERK pathway mediates DBAN induced cytotoxicity. Moreover, DBAN activated autophagy. The autophagy inhibitor 3-methyladenine(3-MA) reversed DBAN-inhibited cell viability and alleviated DBAN-induced apoptosis in HT22 cell, suggesting that autophagy activation mediates DBAN-induced cell toxicity. Notably, the results showed that 4-PBA inhibited DBAN-activated autophagy, demonstrating that ERS-PERK promotes DBAN-induced cellular autophagy. Pretreatment with antioxidant N-acetylcysteine (NAC) inhibited the increase in ROS production and the activation of ERS, and protected cells from toxicity. Furthermore, 4-PBA pretreatment reduced the increase in ROS production, indicating that the ROS and PERK promote each other and form a positive feedback loop. ROS also promoted DBAN-induced autophagy. In summary, our findings indicate that DBAN induced autophagy by mediating the PERK signalling pathway and ROS interaction, leading to HT22 cell damage. Accordingly, targeting these pathogenic mechanisms may provide a potential target and theoretical basis for preventing and improving HAN-induced neurotoxicity.}, }
@article {pmid38062506, year = {2023}, author = {Kuo, SH and Hsu, WL and Wu, CY and Lai, YC and Chen, TC}, title = {Dolutegravir-induced growth and lifespan effects in Caenorhabditis elegans.}, journal = {BMC pharmacology &amp; toxicology}, volume = {24}, number = {1}, pages = {74}, pmid = {38062506}, issn = {2050-6511}, support = {kmtth-104-019, kmtth-107-045, kmtth-109-001, kmtth-109-030, Kmtth-110-014//Kaohsiung Municipal Ta- Tung Hospital, Kaohsiung Medical University, Taiwan/ ; }, mesh = {Humans ; Animals ; *HIV Integrase Inhibitors/pharmacology/therapeutic use ; Caenorhabditis elegans ; Longevity ; *HIV Infections/drug therapy ; Reactive Oxygen Species ; *Drug-Related Side Effects and Adverse Reactions ; }, abstract = {BACKGROUND: Integrase strand transfer inhibitor (INSTIs)-based combination antiretroviral treatment in people living with HIV (PLWH) has been reportedly correlated with several adverse effects, such as weight gain, fetal defects or psychiatric disorders.<br><br>METHODS: To comprehensively understand the adverse effect of INSTIs, our study utilized Caenorhabditis Elegans (C. elegans) as a model to investigate how dolutegravir (DTG) affected its life cycle, growth, reproduction and lifespan.<br><br>RESULTS: Our results indicated that DTG enhanced body growth at the early stage of treatment, but no change was detected for long-term treatment. The treatment also influenced the reproductive system, decreased egg-hatching but had no effect on egg-laying. Besides, DTG resulted in lifespan reduction, which is dependent on increased levels of reactive oxidative species (ROS) accumulation. Treatment with N-acetyl-cysteine (NAC) in worms restrained intracellular ROS accumulation and improved DTG-induced lifespan reduction.<br><br>CONCLUSIONS: Our study demonstrates for the first time the effect of DTG treatment on life cycle. DTG-induced adverse effects are potentially associated with intracellular ROS accumulation. Quenching ROS accumulation might provide a novel strategy for dealing with the adverse effects of INSTIs.}, }
@article {pmid38061079, year = {2024}, author = {Zhang, B and Huang, C and Xu, D and Huang, K and Li, Y and Jiao, L and Fu, B and Li, S and Li, Y}, title = {Patulin induces ROS-dependent cardiac cell toxicity by inducing DNA damage and activating endoplasmic reticulum stress apoptotic pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {269}, number = {}, pages = {115784}, doi = {10.1016/j.ecoenv.2023.115784}, pmid = {38061079}, issn = {1090-2414}, mesh = {Animals ; Humans ; *Patulin/toxicity/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; DNA Damage ; Apoptosis ; Endoplasmic Reticulum Stress ; }, abstract = {Patulin (PAT) is one of the mycotoxins commonly found in agricultural products and fruits, and has obvious toxic effects on animals and humans. PAT has been found to cause myocardial toxicity and oxidative damage, but the mechanism of myocardial toxicity remained to be elucidated. We investigated the toxic effects and potential mechanisms of PAT on human cardiomyocytes and explored the effects of reactive oxygen species (ROS) on them. The study showed that treatment with PAT for 24 h decreased cell viability and superoxide dismutase (SOD) activity, and increased ROS and lactate dehydrogenase (LDH) levels. Moreover, in addition to detecting increased γ-H2AX expression and observing nuclear damage, the comet assay also showed increased DNA tail distance in the PAT-treated group, followed by an increase in phosphorylation of the p53 protein and p21 protein expression, and a decrease in CDK1 and Cyclin B1 protein expression, and G2/M phase arrest. In addition, PAT induced endoplasmic reticulum stress (ERS) and induced apoptosis, as evidenced by Ca[2+] increase, ER enlargement and swelling, and upregulation of ERS-related genes and proteins expression, and increased expression of three apoptotic pathway proteins under ERS, including CHOP, JNK, and caspase-12. Meanwhile, N-acetylcysteine (NAC, a ROS scavenger) reversed the negative effects of PAT treatment on cells. These results clarify that excessive ROS production by PAT-treated AC16 cells not only causes DNA damage, leading to cell cycle arrest, but also causes ERS, which triggers apoptotic pathways to cause apoptosis.}, }
@article {pmid38060590, year = {2023}, author = {Yoldaş, MA and Bekdaş, M and Danış, A and Çetinkaya, A and Düzcü, SE and Alışık, M and Kocabey, H and Türel, &#x130; and Dinçel, GK}, title = {Protective and therapeutic effects of okra seed in acute nontraumatic brain injury.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/00207454.2023.2292948}, pmid = {38060590}, issn = {1563-5279}, abstract = {AIM: The purpose of this study was to examine the protective and therapeutic effects of okra (Abelmoschus esculentus [AE]) seed extract, with its known antioxidant, immunomodulatory, and anti-inflammatory properties, in an acetaminophen (paracetamol, N-acetyl- para-aminophenol)-induced model of hepatotoxicity and subsequent acute non-traumatic brain damage.<br><br>MATERIAL AND METHOD: Forty male Wistar rats were randomly divided into five equal groups, control, paracetamol (P), okra seed extract (AE), okra seed extract&#x2009;+&#x2009;paracetamol (P&#x2009;+&#x2009;AE), and okra seed extract&#x2009;+&#x2009;paracetamol&#x2009;+&#x2009;N-acetyl cysteine (NAC) (P&#x2009;+&#x2009;AE&#x2009;+&#x2009;N). AE was administered by oral gavage through a gastric tube at 600&#x2009;mg/kg/day for seven days. On the eighth day of the procedure, a single 1&#x2009;g/kg dose of paracetamol and 300&#x2009;mg/kg NAC were injected via the intraperitoneal route 1.5&#x2009;h after AE administration. Rat tissue specimens were subsequently subjected to biochemical and histopathological analyses. Levels of markers such as S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE), and matrix membrane metalloproteinase-9 (MMP-9) were investigated from rat serum specimens. Malondialdehyde (MDA) and superoxide dismutase (SOD) were also measured to determine oxidant-antioxidant status.<br><br>RESULTS: S100B, NSE, MMP-9, MDA levels, and SOD enzyme activities were examined using biochemical methods. MDA levels were significantly lower in the P&#x2009;+&#x2009;AE group and MMP-9 levels in the AE, P&#x2009;+&#x2009;AE, and P&#x2009;+&#x2009;AE&#x2009;+&#x2009;N groups compared to the P group. Histopathological examination results supported the biochemical findings.<br><br>CONCLUSION: Okra seed extract exhibits a protective and therapeutic effect against non-traumatic brain damage resulting from acute paracetamol intoxication. We think that this benefit of AE derives from its antioxidant property.}, }
@article {pmid38043497, year = {2024}, author = {Bai, W and Liu, D and Cheng, Q and Yang, X and Zhu, L and Qin, L and Fang, J}, title = {Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2.}, journal = {Translational oncology}, volume = {40}, number = {}, pages = {101850}, pmid = {38043497}, issn = {1936-5233}, abstract = {PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. Despite cure rates of higher than 85 %, refractory or relapsed ALL still exhibits a bleak prognosis indicative of the dearth of treatment modalities specific for relapsed or refractory ALL. Prior research has implicated metabolic alterations in leukemia pathogenesis, and literature on the therapeutic efficacy of arsenic compounds targeting metabolic pathways in B-cell acute lymphoblastic leukemia (B-ALL) cells is scarce.<br><br>METHODS: A compound extracted from realgar, tetraarsenic tetrasulfide (As4S4), and its antitumor effects on B-ALL were experimentally examined in vitro and in vivo.<br><br>RESULTS: As4S4 apparently targets B-ALL cells by inducing specific cellular responses, including apoptosis, G2/M arrest, and ferroptosis. Interestingly, these effects are attributed to reactive oxygen species (ROS) accumulation, and increased ROS levels have been linked to both the mitochondria-dependent caspase cascade and the activation of p53 signaling. The ROS scavenger N-acetylcysteine (NAC) can counteract the effects of As4S4 treatment on Nalm-6 and RS4;11 cells. Specifically, by targeting Hexokinase-2 (HK2), As4S4 induces alterations in mitochondrial membrane potential and disrupts glucose metabolism, leading to ROS accumulation, and was shown to inhibit B-ALL cell proliferation in vitro and in vivo. Intriguingly, overexpression of HK2 can partially desensitize B-ALL cells to As4S4 treatment.<br><br>CONCLUSION: Tetraarsenic tetrasulfide can regulate the Warburg effect by controlling HK2 expression, a finding that provides both new mechanistic insight into metabolic alterations and pharmacological evidence for the clinical treatment of B-ALL.}, }
@article {pmid38043329, year = {2024}, author = {Andrade, BF and Guimarães, AS and do Carmo, LR and Tanaka, MS and Fontes, PR and Ramos, ALS and Ramos, EM}, title = {S-nitrosothiols as nitrite alternatives: Effects on residual nitrite, lipid oxidation, volatile profile, and cured color of restructured cooked ham.}, journal = {Meat science}, volume = {209}, number = {}, pages = {109397}, doi = {10.1016/j.meatsci.2023.109397}, pmid = {38043329}, issn = {1873-4138}, mesh = {*Meat Products/analysis ; Sodium Nitrite ; *S-Nitrosothiols/chemistry ; Lipids ; Acetylcysteine/*analogs &amp; derivatives ; }, abstract = {This study evaluated the use of the S-nitrosothiols, S-nitroso-N-acetylcysteine (NAC-SNO) and S-nitroso-N-acetylcysteine ethyl ester (NACET-SNO), at different concentrations (25-300 mg nitrite equivalent - NEq/kg) as sodium nitrite substitutes in restructured cooked hams. The pH value and instrumental cured color were not affected by the type or amount of curing agent used. Products with 25 and 50 mg/kg ingoing nitrite had lower thiobarbituric acid-reactive substance values than those with equimolar amounts of S-nitrosothiols. Products with >150 mg NEq/kg of S-nitrosothiols had residual nitrite similar to 50 mg/kg nitrite, and this resulted in the same volatile compound profile as nitrite added in equimolar amounts. A 300 mg NEq/kg of S-nitrosothiols was required to obtain a similar and minimally stable cured pink color perception as sliced samples with 50-150 mg/kg added nitrite. The results obtained reinforce the great potential of both alternative curing agents in the complete replacement of nitrite by equimolar amounts in restructured cooked products; however, differences in cured color stability should be considered.}, }
@article {pmid38042493, year = {2024}, author = {Richartz, N and Pietka, W and Yadav, A and Bostad, M and Bhagwat, S and Naderi, S and Naderi, EH and Stokke, T and Ruud, E and Blomhoff, HK}, title = {N-acetyl cysteine turns EPAC activators into potent killers of acute lymphoblastic leukemia cells.}, journal = {The Journal of biological chemistry}, volume = {300}, number = {1}, pages = {105509}, pmid = {38042493}, issn = {1083-351X}, mesh = {Animals ; Child ; Humans ; Mice ; *Acetylcysteine/pharmacology/therapeutic use ; *Cyclic AMP/analogs &amp; derivatives/pharmacology/therapeutic use ; DNA/drug effects ; *Guanine Nucleotide Exchange Factors/agonists ; Mice, Inbred NOD ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Male ; Female ; Child, Preschool ; *Thionucleotides/pharmacology/therapeutic use ; DNA Damage ; Drug Therapy, Combination ; }, abstract = {Today, the majority of patients with pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL, hereafter ALL) survive their disease, but many of the survivors suffer from life-limiting late effects of the treatment. ALL develops in the bone marrow, where the cells are exposed to cAMP-generating prostaglandin E2. We have previously identified the cAMP signaling pathway as a putative target for improved efficacy of ALL treatment, based on the ability of cAMP signaling to reduce apoptosis induced by DNA damaging agents. In the present study, we have identified the antioxidant N-acetyl cysteine (NAC) as a powerful modifier of critical events downstream of the cell-permeable cAMP analog 8-(4-chlorophenylthio) adenosine-3', 5'- cyclic monophosphate (8-CPT). Accordingly, we found NAC to turn 8-CPT into a potent killer of ALL cells in vitro both in the presence and absence of DNA damaging treatment. Furthermore, we revealed that NAC in combination with 8-CPT is able to delay the progression of ALL in a xenograft model in NOD-scid IL2Rγ[null] mice. NAC was shown to rely on the ability of 8-CPT to activate the guanine-nucleotide exchange factor EPAC, and we demonstrated that the ALL cells are killed by apoptosis involving sustained elevated levels of calcium imposed by the combination of the two drugs. Taken together, we propose that 8-CPT in the presence of NAC might be utilized as a novel strategy for treating pediatric ALL patients, and that this powerful combination might be exploited to enhance the therapeutic index of current ALL targeting therapies.}, }
@article {pmid38042273, year = {2023}, author = {Akakpo, JY and Ramachandran, A and Rumack, BH and Wallace, DP and Jaeschke, H}, title = {Lack of mitochondrial Cyp2E1 drives acetaminophen-induced ER stress-mediated apoptosis in mouse and human kidneys: Inhibition by 4-methylpyrazole but not N-acetylcysteine.}, journal = {Toxicology}, volume = {500}, number = {}, pages = {153692}, pmid = {38042273}, issn = {1879-3185}, support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; U54 DK126126/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; *Acetaminophen/toxicity ; Acetylcysteine/pharmacology/metabolism ; Fomepizole/pharmacology/therapeutic use ; Antidotes/pharmacology ; Cytochrome P-450 CYP2E1/metabolism ; Mice, Inbred C57BL ; Liver ; Apoptosis ; Mitochondria/metabolism ; Kidney/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; }, abstract = {Acetaminophen (APAP) overdose causes liver injury and acute liver failure, as well as acute kidney injury, which is not prevented by the clinical antidote N-acetyl-L-cysteine (NAC). The absence of therapeutics targeting APAP-induced nephrotoxicity is due to gaps in understanding the mechanisms of renal injury. APAP metabolism through Cyp2E1 drives cell death in both the liver and kidney. We demonstrate that Cyp2E1 is localized to the proximal tubular cells in mouse and human kidneys. Virtually all the Cyp2E1 in kidney cells is in the endoplasmic reticulum (ER), not in mitochondria. By contrast, hepatic Cyp2E1 is in both the ER and mitochondria of hepatocytes. Consistent with this subcellular localization, a dose of 600 mg/kg APAP in fasted C57BL/6J mice induced the formation of APAP protein adducts predominantly in mitochondria of hepatocytes, but the ER of the proximal tubular cells of the kidney. We found that reactive metabolite formation triggered ER stress-mediated activation of caspase-12 and apoptotic cell death in the kidney. While co-treatment with 4-methylpyrazole (4MP; fomepizole) or the caspase inhibitor Ac-DEVD-CHO prevented APAP-induced cleavage of procaspase-12 and apoptosis in the kidney, treatment with NAC had no effect. These mechanisms are clinically relevant because 4MP but not NAC also significantly attenuated APAP-induced apoptotic cell death in primary human kidney cells. We conclude that reactive metabolite formation by Cyp2E1 in the ER results in sustained ER stress that causes activation of procaspase-12, triggering apoptosis of proximal tubular cells, and that 4MP but not NAC may be an effective antidote against APAP-induced kidney injury.}, }
@article {pmid38034812, year = {2023}, author = {Wang, L and Xu, Y and Zhao, X and Zhu, X and He, X and Sun, A and Zhuang, G}, title = {Antagonistic effects of N-acetylcysteine on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast cells.}, journal = {Heliyon}, volume = {9}, number = {11}, pages = {e21847}, pmid = {38034812}, issn = {2405-8440}, abstract = {Lead (Pb) is a heavy metal that can have harmful effects on the environment, which has severe cytotoxicity in many animal tissues. N-acetylcysteine (NAC) has antioxidant activity, reducing lead-induced oxidative stress and apoptosis, but its role in chicken cells is unknown. The current study explored the antagonistic effect of NAC on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast (CEF). In this study, CEF was used as a model to measure the cytotoxic effects of lead nitrate at different concentrations, demonstrating a dose-dependent effect on CEF activity. Employing inverted microscopy, the investigation of morphological alterations in CEF cells was conducted. Fluorescence staining methodology enabled the assessment of reactive oxygen species (ROS) levels within CEF cells. Moreover, an enzyme-linked immunosorbent assay was utilized to detect the presence of oxidative damage indicators encompassing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) activity, malondialdehyde (MDA) content, and total antioxidant capacity (T-AOC) within CEF cells. Furthermore, the determination of the apoptosis rate of CEF cells was accomplished through the utilization of the Hoechst 33258 staining method in combination with the Annexin V-FITC dual staining method. By using RT-qPCR for detection, lead treatment increased expression of pro-apoptotic genes, caspase-3, and caspase-9, and reduced expression of anti-apoptotic genes, Bcl-2, and BI-1. Reduced antioxidant capacity was shown by increased ROS and MDA levels in CEF cells after lead treatment. The results showed that NAC inhibited the expression of caspase-3 and caspase-9 in lead-treated CEF cells, while NAC had a certain inhibitory effect on the relative expression of Bcl-2 and BI-1 mRNA in lead-induced CEF cells. NAC significantly reduced lead-induced oxidative damage and apoptosis. Overall, our results demonstrate a novel protective effect of NAC against lead-induced injury in chicken cells, providing a theoretical basis for future investigations of drugs that are effective in preventing lead poisoning in animals.}, }
@article {pmid38031002, year = {2023}, author = {Zhang, XL and Cao, Y and Zheng, B}, title = {Efficacy of N-acetylcysteine plus pirfenidone in the treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis.}, journal = {BMC pulmonary medicine}, volume = {23}, number = {1}, pages = {479}, pmid = {38031002}, issn = {1471-2466}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Pyridones/adverse effects ; Treatment Outcome ; *Idiopathic Pulmonary Fibrosis ; }, abstract = {BACKGROUND: Numerous studies have demonstrated the potential of pirfenidone to enhance the prognosis of patients afflicted with idiopathic pulmonary fibrosis (IPF). Although N-acetylcysteine (NAC) is utilized as an antioxidant in IPF treatment, the combination of NAC and pirfenidone has produced inconsistent outcomes in certain studies. To assess the clinical effectiveness and safety of NAC plus pirfenidone (designated as the treatment group) versus pirfenidone monotherapy (designated as the control group), we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs).<br><br>METHODS: RCTs of NAC plus pirfenidone were reviewed searching from databases and networks of unpublished and published studies in any language. Using pair-wise meta-analysis, changes in pulmonary function test (PFT) parameters and safety were evaluated.<br><br>RESULTS: Two independent reviewers selected and obtained data from 5 RCTs (n&#x2009;=&#x2009;398), comprising 1 study from Japan, 1 from Europe, and 3 from China. NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of skin effects(RR 1.26 [95%CI 0.64 to 2.45]) and mortality(RR 0.35 [95%CI 0.07 to 1.68])(both moderate certainty). NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of at least one side effects(RR 1.00 [95%CI 0.84 to 1.19]; low certainty),severe side effects(RR 0.67 [95%CI 0.30 to 1.47]; low certainty) and gastrointestinal effects(RR 0.67 [95%CI 0.41 to 1.09]; low certainty) with possibly no effect in &#x394;%DLco(SMD -0.17 [95%CI -0.15 to 0.48]; low certainty). Meanwhile, the effect of NAS plus pirfenidone as compared to pirfenidone monotherapy on &#x394;FVC(SMD 0.18 [95%CI -0.68 to 1.05]), &#x394;%FVC(SMD -2.62 [95%CI -5.82 to 0.59]) and &#x394;6MWT(SMD -0.35 [95%CI -0.98 to 0.28]) is uncertain(extremely low certainty).<br><br>CONCLUSION: Moderate certainty evidence suggests that NAS plus pirfenidone, compared to pirfenidone monotherapy for IPF, does not reduce the incidence of skin effects and mortality.}, }
@article {pmid38019375, year = {2023}, author = {Roy, A and Goenka, MK}, title = {Simethicone and N-acetyl cysteine in improving mucosal visibility: Towards a "clearer view" during endoscopy.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {}, number = {}, pages = {}, pmid = {38019375}, issn = {0975-0711}, }
@article {pmid38018602, year = {2023}, author = {Atefi, N and Goodarzi, A and Riahi, T and Khodabandehloo, N and Talebi Taher, M and Najar Nobari, N and Seirafianpour, F and Mahdi, Z and Baghestani, A and Valizadeh, R}, title = {Evaluation of the efficacy and safety of oral N-acetylcysteine in patients with COVID-19 receiving the routine antiviral and hydroxychloroquine protocol: A randomized controlled clinical trial.}, journal = {Immunity, inflammation and disease}, volume = {11}, number = {11}, pages = {e1083}, pmid = {38018602}, issn = {2050-4527}, mesh = {Humans ; *Ritonavir/therapeutic use ; *COVID-19 ; Antiviral Agents/adverse effects ; Hydroxychloroquine/adverse effects ; Atazanavir Sulfate/adverse effects ; Acetylcysteine/therapeutic use ; C-Reactive Protein ; SARS-CoV-2 ; COVID-19 Drug Treatment ; Inflammation/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: The current absence of gold-standard or all-aspect favorable therapies for COVID-19 renders a focus on multipotential drugs proposed to prevent or treat this infection or ameliorate its signs and symptoms vitally important. The present well-designed randomized controlled trial (RCT) sought to evaluate the efficacy and safety of N-acetylcysteine (NAC) as adjuvant therapy for 60 hospitalized Iranian patients with COVID-19.<br><br>METHODS: Two 30-person diets, comprising 15 single diets of Kaletra (lopinavir/ritonavir) + hydroxychloroquine (HCQ) with/without NAC (600 mg TDS) and atazanavir/ritonavir + HCQ with/without NAC (600 mg TDS), were administered in the study.<br><br>RESULTS: At the end of the study, a further decrease in C-reactive protein was observed in the NAC group (P&#x2009;=&#x2009;0.008), and no death occurred in the atazanavir/ritonavir + HCQ + NAC group, showing that the combination of these drugs may reduce mortality. The atazanavir/ritonavir + HCQ and atazanavir/ritonavir + NAC groups exhibited the highest O2 saturation at the end of the study and a significant rise in O2 saturation following intervention commencement, including NAC (P&#x2009;>&#x2009;0.05). Accordingly, oral or intravenous NAC, if indicated, may enhance O2 saturation, blunt the inflammation trend (by reducing C-reactive protein), and lower mortality in hospitalized patients with COVID-19.<br><br>CONCLUSION: The NAC could be more effective as prophylactic or adjuvant therapy in stable non-severe cases of COVID-19 with a particularly positive role in the augmentation of O2 saturation and faster reduction of the CRP level and inflammation or could be effective for better controlling of COVID-19 or its therapy-related side effects.}, }
@article {pmid38016189, year = {2023}, author = {Rosas-Gutiérrez, GDC and Fernández-Hernández, JP and Olea-González, AI}, title = {[Efficacy of intratympanic infiltration of N-acetyl cysteine in cisplatin ototoxicity].}, journal = {Revista medica del Instituto Mexicano del Seguro Social}, volume = {61}, number = {Suppl 2}, pages = {S318-S322}, pmid = {38016189}, issn = {2448-5667}, mesh = {Humans ; Middle Aged ; Cisplatin/adverse effects ; *Antineoplastic Agents/adverse effects ; Acetylcysteine/therapeutic use/pharmacology ; *Ototoxicity ; Prospective Studies ; }, abstract = {INTRODUCTION: Currently there is no approved preventive or therapeutic pharmacological treatment to treat ototoxicity caused by cisplatin. N-acetyl cysteine (NAC) is a safe and inexpensive antioxidant that has been studied as an otoprotective alternative.<br><br>OBJECTIVE: To describe the efficacy of intratympanic infiltration of NAC as prevention and treatment of ototoxicity induced in patients treated with cisplatin.<br><br>MATERIAL AND METHODS: Open, longitudinal, prospective, randomized clinical trial in cancer patients treated with cisplatin who met the inclusion criteria. Out of the sample of 22 patients, 11 underwent intratympanic NAC infiltration and 11 were taken as a control group. It was performed an audiometry at the beginning and one month after on all patients.<br><br>RESULTS: A sample of 22 patients with a mean age of 53 (&#xb1;13) was collected. In our sample of 11 patients with infiltration in both ears, 1 ear showed improvement; on the other hand, in the control group that was not infiltrated, 4 showed an increase in hearing loss from mild to moderate in all 4 cases, 2 in the left ear and 2 in the right ear (Spearman's Rho = 0.93, p &#x2264; 0.001). Relative risk was of 1.22.<br><br>CONCLUSIONS: An association can be observed that intratympanic NAC could become an alternative for the prevention and treatment of cisplatin-induced ototoxicity.}, }
@article {pmid38015959, year = {2023}, author = {Bosman, M and Krüger, DN and Favere, K and De Meyer, GRY and Franssen, C and Van Craenenbroeck, EM and Guns, PJ}, title = {Dexrazoxane does not mitigate early vascular toxicity induced by doxorubicin in mice.}, journal = {PloS one}, volume = {18}, number = {11}, pages = {e0294848}, pmid = {38015959}, issn = {1932-6203}, mesh = {Mice ; Animals ; Male ; *Dexrazoxane/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Cardiotoxicity/drug therapy/prevention &amp; control/metabolism ; Acetylcholine/metabolism ; Doxorubicin/toxicity/metabolism ; Mice, Inbred C57BL ; Myocytes, Cardiac/metabolism ; Antibiotics, Antineoplastic/pharmacology ; }, abstract = {Apart from cardiotoxicity, the chemotherapeutic agent doxorubicin (DOX) provokes acute and long-term vascular toxicity. Dexrazoxane (DEXRA) is an effective drug for treatment of DOX-induced cardiotoxicity, yet it remains currently unknown whether DEXRA prevents vascular toxicity associated with DOX. Accordingly, the present study aimed to evaluate the protective potential of DEXRA against DOX-related vascular toxicity in a previously-established in vivo and ex vivo model of vascular dysfunction induced by 16 hour (h) DOX exposure. Vascular function was evaluated in the thoracic aorta in organ baths, 16h after administration of DOX (4 mg/kg) or DOX with DEXRA (40 mg/kg) to male C57BL6/J mice. In parallel, vascular reactivity was evaluated after ex vivo incubation (16h) of murine aortic segments with DOX (1 μM) or DOX with DEXRA (10 μM). In both in vivo and ex vivo experiments, DOX impaired acetylcholine-stimulated endothelium-dependent vasodilation. In the ex vivo setting, DOX additionally attenuated phenylephrine-elicited vascular smooth muscle cell (VSMC) contraction. Importantly, DEXRA failed to prevent DOX-induced endothelial dysfunction and hypocontraction. Furthermore, RT-qPCR and Western blotting showed that DOX decreased the protein levels of topoisomerase-IIβ (TOP-IIβ), a key target of DEXRA, in the heart, but not in the aorta. Additionally, the effect of N-acetylcysteine (NAC, 10 μM), a reactive oxygen species (ROS) scavenger, was evaluated ex vivo. NAC did not prevent DOX-induced impairment of acetylcholine-stimulated vasodilation. In conclusion, our results show that DEXRA fails to prevent vascular toxicity resulting from 16h DOX treatment. This may relate to DOX provoking vascular toxicity in a ROS- and TOP-IIβ-independent way, at least in the evaluated acute setting. However, it is important to mention that these findings only apply to the acute (16h) treatment period, and further research is warranted to delineate the therapeutic potential of DEXRA against vascular toxicity associated with longer-term repetitive DOX dosing.}, }
@article {pmid38013123, year = {2024}, author = {Alhajj, N and Yahya, MFZR and O'Reilly, NJ and Cathcart, H}, title = {Development and characterization of a spray-dried inhalable ternary combination for the treatment of Pseudomonas aeruginosa biofilm infection in cystic fibrosis.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {192}, number = {}, pages = {106654}, doi = {10.1016/j.ejps.2023.106654}, pmid = {38013123}, issn = {1879-0720}, mesh = {Humans ; Pseudomonas aeruginosa ; *Cystic Fibrosis/drug therapy ; Powders ; Particle Size ; Respiratory Aerosols and Droplets ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Administration, Inhalation ; Acetylcysteine ; Drug Combinations ; Biofilms ; Dry Powder Inhalers/methods ; *Pseudomonas Infections/drug therapy ; }, abstract = {Cystic fibrosis (CF) is an inherited lung disease characterised by the accumulation of thick layers of dried mucus in the lungs which serve as a nidus for chronic infection. Pseudomonas aeruginosa is the predominant cause of chronic lung infection in cystic fibrosis. The dense mucus coupled with biofilm formation hinder antibiotic penetration and prevent them from reaching their target. Mucoactive agents are recommended in the treatment of CF in combination with antibiotics. In spite of the extensive research in developing novel drug combinations for the treatment of lung infection in CF, to our knowledge, there is no study that combines antibiotic, antibiofilm and mucoactive agent in a single inhaled dry powder formulation. In the present study, we investigate the possibility of adding a mucoactive agent to our previously developed ciprofloxacinquercetin (antibiotic-antibiofilm) dry powder for inhalation. Three mucoactive agents, namely mannitol (MAN), N-acetyl-L-cysteine (NAC) and ambroxol hydrochloride (AMB), were investigated for this purpose. The ternary combinations were prepared via spray drying without the addition of excipients. All ternary combinations conserved or improved the antibacterial and biofilm inhibition activities of ciprofloxacin against P. aeruginosa (ATCC 10145). The addition of AMB resulted in an amorphous ternary combination (SD-CQA) with superior physical stability as indicated by DSC and nonambient XRPD. Furthermore, SD-CQA displayed better in vitro aerosolization performance (ED ∼ 71 %; FPF ∼ 49 %) compared to formulations containing MAN and NAC (ED ∼ 64 % and 44 %; FPF ∼ 44 % and 29 %, respectively). In conclusion, a ternary drug combination powder with suitable aerosolization, physical stability and antibacterial/antibiofilm properties was prepared by a single spray drying step.}, }
@article {pmid38011683, year = {2024}, author = {Duan, F and Liu, C and Chang, C and Song, S and Zhai, H and Cheng, J and Yang, S}, title = {Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis.}, journal = {The American journal of drug and alcohol abuse}, volume = {50}, number = {2}, pages = {191-206}, doi = {10.1080/00952990.2023.2266117}, pmid = {38011683}, issn = {1097-9891}, mesh = {*Pentoxifylline/therapeutic use ; Humans ; *Hepatitis, Alcoholic/drug therapy/mortality ; *Granulocyte Colony-Stimulating Factor/therapeutic use ; *Network Meta-Analysis ; *Drug Therapy, Combination ; Randomized Controlled Trials as Topic ; }, abstract = {Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results.Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH.Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls).Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome.Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.}, }
@article {pmid38004075, year = {2023}, author = {Aydin, H and Bulmus, O and Korkut, O and Altun, E and Ulusal, AE}, title = {An Evaluation of the Effectiveness of Melatonin and n-Acetylcysteine in Cerebral Ischemia-Reperfusion Injury in Adult Rats.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {11}, pages = {}, pmid = {38004075}, issn = {1648-9144}, support = {2020/111//Bal&#x131;kesir University/ ; }, mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Melatonin/pharmacology/therapeutic use ; Rats, Wistar ; Antioxidants/pharmacology/therapeutic use ; *Reperfusion Injury/drug therapy ; }, abstract = {Background and Objectives: The purpose of this study was to apply histopathological and immunohistochemical methods to compare the protective efficacy of melatonin and N-acetylcysteine (NAC) application in rats with experimental brain ischemia/reperfusion (I/R) injury induced through occlusion of the middle cerebral artery (MCA), and to evaluate the protective effect of their combined use. Materials and Methods: Forty-one young adult male Wistar albino rats were divided into five groups-control (n = 8), I/R group (n = 8), melatonin (n = 8), NAC (n = 8), and melatonin + NAC (n = 9). Results: All scores differed between the groups, apart from vascular congestion (p < 0.05). At two-way comparisons, all histological scores were significantly higher in the I/R group than in the control group (p < 0.05). No change occurred in the vascular congestion scores with the administration of melatonin, although decreases were determined in all other scores. These decreases were statistically significant for cellular eosinophilic pyknotic degeneration, vacuolization, and edema (p < 0.05). All histopathological scores in the group administered NAC together with melatonin were significantly lower than in the I/R group (p < 0.05). Conclusions: The combined use of NAC and melatonin, the neuroprotective efficacy of which on histopathological parameters is shown in this study, now needs to be supported by further research.}, }
@article {pmid38004033, year = {2023}, author = {Chiu, AH and Wang, CJ and Lin, YL and Wang, CL and Chiang, TI}, title = {N-Acetylcysteine Alleviates the Progression of Chronic Kidney Disease: A Three-Year Cohort Study.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {11}, pages = {}, pmid = {38004033}, issn = {1648-9144}, mesh = {Humans ; Cohort Studies ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Glomerular Filtration Rate ; Disease Progression ; Risk Factors ; *Renal Insufficiency, Chronic/complications/drug therapy/epidemiology ; *Kidney Failure, Chronic/epidemiology ; }, abstract = {Background and Objectives: The prevalence of chronic kidney disease (CKD) is approximately 10% of the population in many countries. CKD progresses to end-stage renal disease (ESRD), resulting in adverse outcomes, prolonged hospitalization, and increased healthcare costs. Therefore, reducing CKD progression to ESRD is recognized as an important health issue. Materials and Methods: Data from the study participants with stage 3 to stage 5 CKD (n = 7668) were collected from the National Health Insurance (NHI) program in Taiwan (1 November 2014 to 31 December 2020). CKD patients who had ingested or not ingested N-acetylcysteine (NAC) for three years were divided into the study group (NAC users; n = 165) and the control group (NAC non-users; n = 165) to explore whether NAC use could alleviate CKD progression and reduce the risks associated with hemodialysis in CKD patients. Results: The levels of serum creatinine (SCr) and estimated globular filtration rate (eGFR) were nearly unchanged and/or slightly changed in NAC users, but the SCr levels were slightly increased, and the eGFR levels were significantly decreased in NAC non-users at the six-month interval during the three years. A statistical difference was observed between the two groups for both levels from 12 months to 36 months. The incidence rate of hemodialysis was significantly lower in NAC users than in non-NAC users (4.8% vs. 12.7%, Wald test = 5.947, p = 0.015, OR = 34.9). These results indicated that NAC use may improve renal function of CKD patients by modulating SCr and eGFR and, in turn, reducing the risk of hemodialysis. Conclusions: We investigated whether NAC could be used to reduce CKD progression to ESRD. For the three-year retrospective study, the incidence rate of hemodialysis was significantly lower in NAC users than in non-NAC users via modulating SCr and eGRF levels. NAC use might be a useful clinical approach for reducing CKD progression to ESRD.}, }
@article {pmid38001773, year = {2023}, author = {Banik, A and Eum, J and Hwang, BJ and Kee, Y}, title = {Differential Neuroprotective Effects of N-Acetylcysteine against Dithianon Toxicity in Glutamatergic, Dopaminergic, and GABAergic Neurons: Assessment Using Zebrafish.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {11}, pages = {}, pmid = {38001773}, issn = {2076-3921}, support = {NRF-2019M3C7A1031836//Ministry of Science and ICT/ ; NRF-2020R1I1A3063583//Ministry of Education/ ; }, abstract = {Despite the widespread agricultural use of dithianon as an antifungal agent, its neurotoxic implications for humans and wildlife have not been comprehensively explored. Using zebrafish embryonic development as our model, we found that dithianon treatment induced behavioral alterations in zebrafish larvae that appeared normal. Detailed quantitative analyses showed that dithianon at ≥0.0001 µgmL[-1] induced cytoplasmic and mitochondrial antioxidant responses sequentially, followed by the disruption of mitochondrial and cellular homeostasis. Additionally, dithianon at 0.01 and 0.1 µgmL[-1] downregulated the expressions of glutamatergic (slc17a6b), GABAergic (gad1b), and dopaminergic (th) neuronal markers. Contrarily, dithianon upregulated the expression of the oligodendrocyte marker (olig2) at concentrations of 0.001 and 0.01 µgmL[-1], concurrently suppressing the gene expression of the glucose transporter slc2a1a/glut1. Particularly, dithianon-induced increase in reactive oxygen species (ROS) production was reduced by both N-acetylcysteine (NAC) and betaine; however, only NAC prevented dithianon-induced mortality of zebrafish embryos. Moreover, NAC specifically prevented dithianon-induced alterations in glutamatergic and dopaminergic neurons while leaving GABAergic neurons unaffected, demonstrating that the major neurotransmission systems in the central nervous system differentially respond to the protective effects. Our findings contribute to a better understanding of the neurotoxic potential of dithianon and to developing preventive strategies.}, }
@article {pmid38000947, year = {2024}, author = {Alvarez, R and Kurfis, J and Hendrickson, M and Sem, DS}, title = {Real-time thiol detection in iPSC-derived neuron cultures using SemKur-IM, a novel fluorescent dithio probe.}, journal = {SLAS discovery : advancing life sciences R &amp; D}, volume = {29}, number = {3}, pages = {100127}, doi = {10.1016/j.slasd.2023.11.003}, pmid = {38000947}, issn = {2472-5560}, mesh = {*Induced Pluripotent Stem Cells/drug effects/metabolism/cytology ; *Neurons/drug effects/metabolism ; *Sulfhydryl Compounds/pharmacology/chemistry ; Humans ; *Fluorescent Dyes/chemistry ; Oxidative Stress/drug effects ; Glutathione/metabolism ; Acetylcysteine/pharmacology ; Cells, Cultured ; Oxidation-Reduction/drug effects ; }, abstract = {Neurological disorders associated with inflammation and oxidative stress show reduced glutathione (GSH) levels in the human brain. Drug discovery efforts and pharmacological studies would benefit from tools (e.g. chemical probes) that detect changes to oxidative stress, from the perspective of physiologically-relevant reporters like cellular thiols, including GSH. To this end, we have developed a fluorescence visualization assay using iPSC-derived cortical glutamatergic neurons that were loaded with 25 μM of a novel thiol-detection fluorescent probe, SemKur-IM. This probe enables visualization of cellular thiol level changes in the neuronal somas and neurites, in response exposure to N-acetyl-cysteine (NAC). Cellular thiol redox state was observed to change, based on an increase in green fluorescence (485 nm excitation maximum; 525 nm emission maximum) due to changes in thiol levels, from 0 to 40 mM. Interestingly, prior to treatment with NAC, cells did not appear to have significant levels of reduced thiols. Our studies demonstrate the utility of SemKur-IM in the detection of thiol levels in live cells in response to chemical exposures, such as from drugs that return the cell to a healthier reduced state. An initial application to screening the effects of an Alzheimer's disease drug candidate, Posiphen, using fluorescence cell sorting is presented. Other potential applications include high throughput screening of central nervous system (CNS) drugs thought to work by affecting cellular redox state in neurons.}, }
@article {pmid38000302, year = {2023}, author = {Liang, M and Deng, J and Gu, J and Yang, J and Ge, F and Huang, C and Wu, W}, title = {TMBPF-induced neurotoxicity and oxidative stress in zebrafish larvae: impacts on central nervous system development and dopamine neurons.}, journal = {Ecotoxicology and environmental safety}, volume = {268}, number = {}, pages = {115710}, doi = {10.1016/j.ecoenv.2023.115710}, pmid = {38000302}, issn = {1090-2414}, mesh = {Humans ; Animals ; *Zebrafish/metabolism ; *Dopaminergic Neurons/metabolism ; Larva ; Dopamine/metabolism ; Benzhydryl Compounds/metabolism ; Oxidative Stress ; Central Nervous System ; Acetylcysteine/pharmacology ; }, abstract = {Bisphenol A (BPA), a common bisphenol molecule, is well known in the environment as an endocrine disruptor. Furthermore, BPs (BPA, BPS, BPF, and BPAF) have been shown in recent years to be neurotoxic to zebrafish. Tetramethyl bisphenol F (TMBPF) has recently been introduced as a substitute for bisphenol A (BPA) in various industries, including plastics and food contact coatings. However, a growing number of studies have demonstrated that the toxicity of some BPA substitutes is similar to or even stronger than BPA, posing potential harm to human health and the environment. In this study, we used zebrafish larvae as a model to investigate the neurodevelopmental effects of TMBPF at different concentrations (0, 0.25, 0.5, 1, 2, 4 and 8 mg/L). Our results showed that exposure to TMBPF at concentrations higher than 4 mg/L for 72 h post-fertilization (hpf) resulted in zebrafish mortality, whereas exposure to 2 mg/L for 144 hpf caused deformities. Furthermore, TMBPF exposure inhibited the development of the central nervous system, motor nerves, and dopamine neurons in zebrafish. Real-time polymerase chain reaction (PCR) analysis revealed that TMBPF exposure significantly down-regulated the expression of oxidative stress-related genes (Cu/Zn-SOD, Mn-SOD, and CAT) and neurodevelopmental genes (mbp, gafp, and syn2a), while up-regulated the expression of dopamine-related genes (th1, th2, and dat). Notably, treatment with the antioxidant N-acetylcysteine (NAC) alleviated TMBPF-induced toxicity. NAC can regulate the expression of genes related to oxidative stress, neurodevelopment and dopamine development, and make the nerve development of zebrafish normal. Overall, our research suggested that TMBPF may disrupt the development of the early central nervous system and dopamine neurons, leading to abnormal motor behavior in zebrafish larvae. These results highlight the potential risks associated with the use of TMBPF in various industries and the importance to evaluate its potential risks to human health and the environment.}, }
@article {pmid37996048, year = {2024}, author = {Cao, L and Shao, N and Du, J and Zhu, H and Gao, J and Li, Q and Sun, Y and Hu, J and Yin, G and Xu, G}, title = {Involvement of reactive oxygen species (ROS) in the hepatopancreatic cytotoxicity, oxidative stress, and apoptosis induced by microcystin-LR in Eriocheir sinensis.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {276}, number = {}, pages = {109801}, doi = {10.1016/j.cbpc.2023.109801}, pmid = {37996048}, issn = {1532-0456}, mesh = {Animals ; Reactive Oxygen Species/metabolism ; *Brachyura/metabolism ; Oxidative Stress ; Microcystins/toxicity ; Apoptosis ; }, abstract = {There is limited knowledge about the toxicity of Microcystin-LR (MC-LR) in crustaceans, despite its high toxicity to aquatic organisms. This research aimed to explore the effects of MC-LR on cytotoxicity, oxidative stress, and apoptosis in the hepatopancreas of Eriocheir sinensis, as well as elucidate the involvement of reactive oxygen species (ROS) and potential mechanisms of toxicity. In vivo and in vitro exposures of crabs to MC-LR and N-acetylcysteine (NAC) were performed, followed by assessments of cell morphology, viability, tissue pathology, biochemical indicators, gene expression, and hepatopancreatic transcriptome. Results revealed that MC-LR facilitated the entry of the MC-LR transporter oatp3a into hepatopancreatic cells, leading to upregulated expression of phase I detoxification enzyme genes (cyp4c, cyp2e1, and cyp3) and downregulated the phase II enzyme genes (gst1, gpx, gsr2, gclc, and nqo1), resulting in increased ROS levels and cytotoxic effects. MC-LR exhibited cytotoxicity, reducing cell viability and inducing abnormal nuclear morphology with a 48 h-IC50 value of approximately 120 μm. MC-LR exposure caused biochemical changes indicative of oxidative stress damage and evident hepatopancreatic lesions. Additionally, MC-LR exposure regulated the levels of bax and bcl-2 expression, activating caspase 3 and 6 to induce cell apoptosis. Intervention with NAC attenuated MC-LR-induced ROS production and associated toxic effects. Transcriptome analysis revealed enrichment of differentially expressed genes in pathways related to cytochrome P450-mediated xenobiotic metabolism and the FoxO signaling pathway. These findings shed light on the potential mechanisms underlying MC-LR toxicity and provide valuable references for further research and conservation efforts regarding the health of aquatic animals.}, }
@article {pmid37992493, year = {2024}, author = {Deng, YQ and Gao, M and Lu, D and Liu, QP and Zhang, RJ and Ye, J and Zhao, J and Feng, ZH and Li, QZ and Zhang, H}, title = {Compound-composed Chinese medicine of Huachansu triggers apoptosis of gastric cancer cells through increase of reactive oxygen species levels and suppression of proteasome activities.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {123}, number = {}, pages = {155169}, doi = {10.1016/j.phymed.2023.155169}, pmid = {37992493}, issn = {1618-095X}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Stomach Neoplasms/drug therapy/metabolism ; Proteasome Endopeptidase Complex ; Proto-Oncogene Proteins c-akt/metabolism ; Medicine, Chinese Traditional ; Phosphatidylinositol 3-Kinases/metabolism ; Proteomics ; Cell Line, Tumor ; Apoptosis ; *Amphibian Venoms ; }, abstract = {BACKGROUND: Huachansu (HCS), a known Chinese patent drug extracted from the Chinese toad skin, is frequently used for the treatment of various advanced cancers, especially gastric cancer, due to the good therapeutic effect. However, it is rather difficult to clarify the active substances and molecular mechanisms involved owing to the lack of appropriate research strategies. We recently proposed the concept and research ideas of compound-composed Chinese medicine formula.<br><br>PURPOSE: To discover compound-composed Chinese medicine from Huachansu and to explore its mechanism of action in inducing apoptosis of gastric cancer cells.<br><br>METHOD: Network pharmacology combined with serum pharmacochemistry was utilized to screen the predominant active constituents from HCS against gastric cancer. Then, the compound-composed Chinese medicine of HCS (CCMH) was prepared according to their relative contents in serum. The pharmacological effects and potential mechanisms for CCMH were investigated by assays for cell viability, cell cycle, apoptosis, mitochondrial membrane potential (MMP), proteomics, reactive oxygen species (ROS), N-Acetylcysteine (NAC) antagonism, proteasome activity, and western blot.<br><br>RESULTS: CCMH was comprised of arenobufagin (11.14%), bufalin (18.67%), bufotalin (7.33%), cinobufagin (16.67%), cinobufotalin (16.74%), gamabufotalin (8.45%), resibufogenin (12.03%), and telocinobufagin (8.97%). CCMH evidently induced proliferation inhibition, cell cycle arrest, apoptosis, and MMP collapse in gastric cancer cells, possessing the better activities than HCS. Proteomic analysis showed that CCMH influenced ROS pathway, ubiquitin proteasome system, and PI3K/Akt and MAPK signaling pathways. CCMH markedly enhanced intracellular ROS levels in gastric cancer cells, which was reversed by NAC. Accordingly, NAC antagonized the apoptosis-inducing effect of CCMH. Significantly decreased proteasome 20S activity by CCMH was observed in gastric cancer cells. CCMH also regulated the expression of key proteins in PI3K/Akt and MAPK signaling pathways.<br><br>CONCLUSION: CCMH possesses more significant apoptotic induction effects on gastric cancer cells than HCS, which is achieved primarily through suppression of proteasome activities and increase of ROS levels, followed by regulating PI3K/Akt and MAPK signaling pathways. Network pharmacology combined with serum pharmacochemistry is an effective strategy for discovering compound-composed Chinese medicine from traditional Chinese medicine, which can help clarify the pharmacological substances and mechanisms of action for traditional Chinese medicine.}, }
@article {pmid37987619, year = {2023}, author = {Marcano-Gómez, EC and de Souza, ABF and Machado-Junior, PA and Rodríguez-Herrera, AJ and Castro, TF and da Silva, SPG and Vieira, RG and Talvani, A and Nogueira, KOPC and de Oliveira, LAM and Bezerra, FS}, title = {N-acetylcysteine modulates redox imbalance and inflammation in macrophages and mice exposed to formaldehyde.}, journal = {Free radical research}, volume = {57}, number = {6-12}, pages = {444-459}, doi = {10.1080/10715762.2023.2284636}, pmid = {37987619}, issn = {1029-2470}, mesh = {Mice ; Animals ; *Acetylcysteine/pharmacology ; *Lung ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Oxidation-Reduction ; Formaldehyde/toxicity/metabolism ; Oxidative Stress ; Inflammation/chemically induced/drug therapy/metabolism ; Macrophages/metabolism ; Antioxidants/metabolism ; }, abstract = {This study aimed to evaluate the protective role of N-acetylcysteine (NAC) in cells and mice exposed to formaldehyde. For the in vitro study, J774A.1 macrophages cells were incubated for 8, 16 and 24 h with formaldehyde or NAC to assess cell viability and reactive oxygen species (ROS). In the in vivo study, C57BL/6 mice (n = 48) were divided into 6 groups: control (CG), vehicle (VG) that received saline by orogastric gavage, a group exposed to formaldehyde 1% (FG) and formaldehyde exposed groups that received NAC at doses of 100, 150 and 200 mg/Kg (FN100, FN150 and FN200) for a period of 5 days. In vitro, formaldehyde promoted a decrease in cell viability and increased ROS, while NAC reduced formaldehyde-induced ROS production. Animals exposed to formaldehyde presented higher leukocyte counts in the blood and in the bronchoalveolar lavage fluid, and promoted secretion of inflammatory markers IL-6, IL-15, and IL-10. The exposure to formaldehyde also promoted redox imbalance and oxidative damage characterized by increased activities of superoxide dismutase, catalase, decreased GSH/GSSG ratio, as well as it increased levels of protein carbonyls and lipid peroxidation. NAC administration after formaldehyde exposure attenuated oxidative stress markers, secretion of inflammatory mediators and lung inflammation. In conclusion, both in in vitro and in vivo models, NAC administration exerted protective effects, which modulated the inflammatory response and redox imbalance, thus preventing the development airway injury induced by formaldehyde exposure.}, }
@article {pmid37984752, year = {2024}, author = {Zhang, WY and Zhao, CM and Wang, CS and Xie, X and Li, YQ and Chen, BB and Feng, L and Jiang, P}, title = {Methylglyoxal accumulation contributes to accelerated brain aging in spontaneously hypertensive rats.}, journal = {Free radical biology &amp; medicine}, volume = {210}, number = {}, pages = {108-119}, doi = {10.1016/j.freeradbiomed.2023.11.012}, pmid = {37984752}, issn = {1873-4596}, mesh = {Rats ; Animals ; Rats, Inbred SHR ; *Pyruvaldehyde ; *Hypertension/metabolism ; Aging ; Acetylcysteine ; Brain/metabolism ; }, abstract = {While it is well-acknowledged that neurovascular dysfunction in hypertension is tightly associated with accelerated brain aging, we contend that the deleterious effects of hypertension may extend beyond affecting only the arteries. Methylglyoxal (MG) derived from glycolysis, is involved in the accumulation of advanced glycated end products (AGEs), which are the hallmarks of neurodegenerative disorders. Therefore, the present study aims to firstly investigate the role of MG metabolism in the hypertension-accelerated brain aging process. The results of our study indicate that the levels of MG increase with age in both the plasma and hippocampus of SHRs at 12, 16, and 30 weeks old. AGE methylglyoxal-hydro imidazoline-1 (MG-H1) is primarily localized in astrocytes, while its presence was not observed in neurons and microglia within the hypertensive hippocampus. Our observations also suggest that angiotensin II (Ang II) enhances glucose uptake and glycolysis while reducing the expression of Glo1 in cultured astrocytes. N-acetylcysteine (NAC) was found to counteract the increase in escape latency and inhibit the activation of the AGEs-RAGE axis in 30-week-old SHRs. NAC decreased Iba-1 immunofluorescence intensity, inhibited the levels of pro-inflammatory markers, and enhanced the abundance of anti-inflammatory markers in the hippocampus of SHRs. Moreover, NAC reduced the immunofluorescence signal of 4HNE and increased the content of GSH and SOD in SHRs. Finally, NAC was observed to inhibit apoptosis in the hippocampus of SHRs. Collectively, we firstly showed the enhanced accumulation of MG in the hypertensive brain, whereas the clearance of MG by NAC treatment mitigated the aging process and attenuated AGEs generation, neuroinflammation, and oxidative damage.}, }
@article {pmid37982208, year = {2023}, author = {Allam, A and Ali, AA and Abdel Baky, NA and Balah, A}, title = {Omeprazole induces profibrotic gene expression in rat kidney: implication of TGF-β/Smad signaling pathway.}, journal = {Drug and chemical toxicology}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/01480545.2023.2282377}, pmid = {37982208}, issn = {1525-6014}, abstract = {Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications. However, PPI usage is linked to a higher risk of both acute and chronic renal damage by mechanisms not entirely known. The present study demonstrates that omeprazole (10 mg/kg body weight, i.p.) causes TGF-β/Smad signaling activation and subsequent expression of the profibrotic genes CTGF and TIMP-1 in rat kidney. Increased production of CTGF and TIMP-1 accompany activation of the TGF-β/Smad signaling cascade. However, simultaneous treatment of omeprazole and the TGF-β inhibitor, disitertide (P144) (1 mg/kg body weight i.p.) suppresses the TGF-β/Smad signaling pathway and subsequent production of CTGF and TIMP-1. Additionally, TGF-β level in rat kidney was highly reduced in animals treated with the ROS (reactive oxygen species) scavenger, N-acetyl cysteine (NAC) (100 mg/kg body weight i.p.) before omeprazole administration. Furthermore, the reduction in SOD activity brought by omeprazole was returned to the normal level in those animals. However, MDA level increased by omeprazole was highly reduced in the presence of NAC. Collectively, the current findings demonstrate that omeprazole has the ability to promote the expression of the profibrotic genes CTGF and TIMP-1 in a ROS and TGF-β dependent manner. The present study suggests the co-use of ROS scavenger to improve the therapeutic use of the PPI omeprazole.}, }
@article {pmid37971568, year = {2023}, author = {Sırrı Akosman, M and Türkmen, R and Demirel, HH}, title = {The protective effect of N-acetylcysteine against MK-801-induced neurodegeneration in mice.}, journal = {Molecular biology reports}, volume = {50}, number = {12}, pages = {10287-10299}, pmid = {37971568}, issn = {1573-4978}, support = {17.Kariyer.45//Afyon Kocatepe &#xdc;niversitesi/ ; }, mesh = {Humans ; Mice ; Animals ; Male ; *Acetylcysteine/pharmacology ; *Dizocilpine Maleate/pharmacology ; Quality of Life ; Antioxidants/pharmacology ; Excitatory Amino Acid Antagonists ; Protective Agents ; }, abstract = {BACKGROUND: Neurological disorders result in not only a decline in the quality of life of patients but also a global economic burden. Therefore, protective medicine becomes more important for society. MK-801 is a chemical agent used to understand the etiology of behavioral disorders and brain degeneration in animal models. This study aims to determine whether N-acetylcysteine (NAC) is useful to treat brain degeneration caused by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist.<br><br>METHODS AND RESULTS: Four groups were formed by dividing 24 male BALB/c mice into groups of six. The control group was given a saline solution (10 ml/kg-i.p.). MK-801 (1&#xa0;mg/kg-i.p.) was given alone to one group, and it was given with NAC (100&#xa0;mg/kg-i.p.) to another group, while the last group was given only NAC (100&#xa0;mg/kg-i.p.). The administration of drugs lasted for fourteen days. After the behavioral tests (open field and elevated plus-maze), all animals were euthanised, and brain tissues were collected for real-time PCR, TAS-TOS analysis, hematoxylin-eosin, Kluver-Barrera, and TUNEL staining. In the MK-801 group, besides nuclear shrinkage in neurons, glial cell infiltration, vacuolization in cortical neurons, white matter damage, and apoptosis were observed.<br><br>CONCLUSION: In the mice given NAC as a protective agent, it was observed that behavioral problems improved, antioxidant levels increased, and nuclear shrinkage, glial cell infiltration, vacuolization in neurons, and white matter degeneration were prevented. Moreover, MBP expression increased, and the number of TUNEL-positive cells significantly decreased. As a result, it was observed that NAC may have a protective effect against brain degeneration.}, }
@article {pmid37969394, year = {2023}, author = {Wang, ZQ and Li, YQ and Wang, DY and Shen, YQ}, title = {Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity.}, journal = {Translational cancer research}, volume = {12}, number = {10}, pages = {2911-2922}, pmid = {37969394}, issn = {2219-6803}, abstract = {BACKGROUND: As a new form of cell death, ferroptosis has been shown to have inhibitory effects on a variety of tumor cells except oral squamous cell carcinoma (OSCC). There were few investigations on the effects and molecular mechanisms of piperlongumine (PL, a ferroptosis inducer) and CB-839 (a GLS1 inhibitor which promotes ferroptosis) on OSCC cells. This article assesses the anticancer effect and mechanism of PL as well as combined with CB-839.<br><br>METHODS: OSCC cells were treated with specified concentration of PL alone or with ferroptosis inhibitor Ferrostatin-1 (Fer-1) and antioxidant N-Acetylcysteine (NAC) to assess their effects on biological characteristics such as cell proliferation, cell death and intracellular ferroptosis related pathways. Also, cells were treated with PL combined with CB-839 to evaluate the synergistic effect of CB-839 on PL's anticancer effects.<br><br>RESULTS: The results showed that the proliferation rate of PL-treated OSCC cells were decreased in a dose- and time-dependent manner. PL can induce OSCC cells apoptosis. Lipid peroxidation (LPO) and intracellular reactive oxygen species (ROS) were accumulated after PL treatment. We found some protein changes significantly such as the expression of DMT1 increased, and the expression of FTH1, SLC7A11 and GPX4 decreased. In addition, the anti-proliferation effect of PL can be reversed by Fer-1 and NAC and the level of LPO and ROS was decreased accordingly. Importantly, we found that PL and CB-839 in combination could decrease the cell viability and the LPO level synergistically, accompanied by a large consumption of glutathione (GSH). These evidences prove that PL can induce ferroptosis of OSCC cells, which can be enhanced by CB-839.<br><br>CONCLUSIONS: Our study suggested that the nature product PL can induce the ferroptotic death of OSCC cells, which is further enhanced when combined with CB-839. The synergistic anticancer effect of these two may prove new strategy for OSCC treatment.}, }
@article {pmid37965267, year = {2023}, author = {Manoharan, A and Farrell, J and Aldilla, VR and Whiteley, G and Kriel, E and Glasbey, T and Kumar, N and Moore, KH and Manos, J and Das, T}, title = {N-acetylcysteine prevents catheter occlusion and inflammation in catheter associated-urinary tract infections by suppressing urease activity.}, journal = {Frontiers in cellular and infection microbiology}, volume = {13}, number = {}, pages = {1216798}, pmid = {37965267}, issn = {2235-2988}, mesh = {Humans ; Urinary Catheterization ; Acetylcysteine/pharmacology ; Urease ; *Proteus Infections/drug therapy/prevention &amp; control/microbiology ; Proteus mirabilis ; *Urinary Tract Infections/prevention &amp; control/microbiology ; Catheters ; Inflammation/prevention &amp; control ; Anti-Inflammatory Agents/pharmacology ; Biofilms ; }, abstract = {INTRODUCTION: Proteus mirabilis is a key pathobiont in catheter-associated urinary tract infections (CA-UTIs), which is well known to form crystalline biofilms that occlude catheters. Urease activity alkylates urine through the release of ammonia, consequentially resulting in higher levels of Mg[2+] and Ca[2+] and formation of crystals. In this study, we showed that N-acetyl cysteine (NAC), a thiol antioxidant, is a potent urease inhibitor that prevents crystalline biofilm formation.<br><br>METHODS: To quantify urease activity, Berthelot's method was done on bacterial extracts treated with NAC. We also used an in vitro catheterised glass bladder model to study the effect of NAC treatment on catheter occlusion and biofilm encrustation in P. mirabilis infections. Inductively-coupled plasma mass spectrometry (ICP-MS) was performed on catheter samples to decipher elemental profiles.<br><br>RESULTS: NAC inhibits urease activity of clinical P. mirabilis isolates at concentrations as low as 1 mM, independent of bacterial killing. The study also showed that NAC is bacteriostatic on P. mirabilis, and inhibited biofilm formation and catheter occlusion in an in vitro. A significant 4-8log10 reduction in viable bacteria was observed in catheters infected in this model. Additionally, biofilms in NAC treated catheters displayed a depletion of calcium, magnesium, or phosphates (>10 fold reduction), thus confirming the absence of any urease activity in the presence of NAC. Interestingly, we also showed that not only is NAC anti-inflammatory in bladder epithelial cells (BECs), but that it mutes its inflammatory response to urease and P. mirabilis infection by reducing the production of IL-6, IL-8 and IL-1b.<br><br>DISCUSSION: Using biochemical, microbiological and immunological techniques, this study displays the functionality of NAC in preventing catheter occlusion by inhibiting urease activity. The study also highlights NAC as a strong anti-inflammatory antibiofilm agent that can target both bacterial and host factors in the treatment of CA-UTIs.}, }
@article {pmid37965065, year = {2023}, author = {Wei, H and Liu, R and Zhao, M and Ma, Y and He, Y and Sun, X}, title = {Ischemia‒Reperfusion accelerates neointimal hyperplasia via IL-1β-mediated pyroptosis after balloon injury in the rat carotid artery.}, journal = {Biochemistry and biophysics reports}, volume = {36}, number = {}, pages = {101567}, pmid = {37965065}, issn = {2405-5808}, abstract = {BACKGROUND: Ischemia‒reperfusion (IR) is a pathological process that causes secondary damage to blood vessels. However, whether IR can further worsen neointima formation after balloon injury and the detailed mechanism are unclear.<br><br>METHODS: An in vivo model of balloon injury to the rat carotid artery was established to study the effect of IR following balloon injury on neointima formation. Smooth muscle cells (SMCs) were isolated from rat aortas and exposed to hypoxia-reoxygenation to mimic the IR process in vitro. The in vitro cell model was used to investigate the mechanism of IR-mediated neointima formation after balloon injury, which was further confirmed in an in vivo rat model.<br><br>RESULTS: IR aggravated neointima formation in the rat carotid artery 2 weeks after balloon injury compared with that observed in the absence of balloon injury (P&#xa0;<&#xa0;0.001). Compared with that of normal SMCs in the rat carotid artery, the expression of IL-1&#x3b2;, a key proinflammatory cytokine associated with pyroptosis, was increased more than 3-fold in the IR-induced neointima (P&#xa0;<&#xa0;0.0001) and contributed to the proliferation and migration of rat primary aortic SMCs (P&#xa0;<&#xa0;0.0001). This process was alleviated by the antioxidant acetylcysteine (NAC), suggesting its partial dependence on intracellular ROS. In the rat model of IR following balloon injury in the carotid artery, the carotid artery that was locally transfected with AAV carrying sh-IL-1&#x3b2; or sh-caspase-1, which alleviated neointima formation, as indicated by a reduction in intima-media thickness in the rat carotid artery (P&#xa0;<&#xa0;0.0001).<br><br>CONCLUSION: Our results suggested that IR could promote IL-1&#x3b2; production in SMCs in the carotid artery after balloon injury and aggravate neointimal hyperplasia, which was alleviated by silencing caspase-1/IL-1&#x3b2; signaling in SMCs in the carotid artery. These results suggest that IL-1&#x3b2; may be an effective target to combat IR-related neointima formation.}, }
@article {pmid37963954, year = {2023}, author = {Akkahadsee, P and Sawangjit, R and Phumart, P and Chaiyakunapruk, N and Sakloetsakun, D}, title = {Systematic review and network meta-analysis of efficacy and safety of interventions for preventing anti-tuberculosis drug induced liver injury.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19880}, pmid = {37963954}, issn = {2045-2322}, mesh = {Humans ; *Antitubercular Agents/adverse effects ; Network Meta-Analysis ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention &amp; control ; }, abstract = {Anti-tuberculosis drug induced liver injury (Anti-TB DILI) is the most common adverse events (AEs) necessitating therapy interruption but there is no preventing regimen. This study aimed to examine the efficacy and safety of herbs/alternative medicines for preventing anti-TB DILI. Relevant articles were identified through a systematic search in 5 international databases from inception till March 2022. All randomized controlled trials (RCT) assessing the effects of herbal or alternative medicines against anti-TB DILI were included. The network meta-analysis (NMA) was used to synthesize the evidence for preventing hepatotoxicity using a random-effects model. A total of 3423 patients from 14 RCTs were included. The NMA indicated that supplementation of Turmeric plus Tinospora cordifolia (RR 0.07; 95% CI 0.02 to 0.28), and N-acetyl cysteine (NAC) (RR 0.09; 95% CI 0.01 to 0.75) significantly reduced the incidence of anti-TB DILI compared with placebo. In addition, poly herbal product significantly reduced alkaline phosphatase (ALP) (MD - 21.80; 95% CI - 33.80 to - 9.80) and total bilirubin (Tbil) compared with placebo (MD - 0.51; 95% CI - 0.76 to - 0.26). There was no statistically significant difference in the occurrence of AEs in any intervention. In conclusion, Turmeric plus Tinospora cordifolia, NAC and poly-herbal product may provide benefit for preventing anti-TB DILI in TB patients. However, these findings are based on a small number of studies. Additional studies are warranted to confirm the findings.}, }
@article {pmid37960276, year = {2023}, author = {Diniz, MS and Magalhães, CC and Tocantins, C and Grilo, LF and Teixeira, J and Pereira, SP}, title = {Nurturing through Nutrition: Exploring the Role of Antioxidants in Maternal Diet during Pregnancy to Mitigate Developmental Programming of Chronic Diseases.}, journal = {Nutrients}, volume = {15}, number = {21}, pages = {}, pmid = {37960276}, issn = {2072-6643}, support = {SFRH/BPD/116061/2016; SFRH/BD/11934/2022; SFRH/BD/11924/2022; SFRH/BD/5539/2020//ERDF funds through the Operational Programme for Competitiveness/ ; HORIZON-HLTH-2022-STAYHLTH-101080329-2; PTDC/DTP-DES/1082/2014 (POCI-01-0145-FEDER-016657), CENTRO-01-0246-FEDER- 000010 (Multidisciplinary Institute of Ageing in Coimbra), strategic projects UIDB/04539/2020, UIDP/04539/2020, LA/P/0058/2020//ERDF funds through the Operational Programme for Competitiveness-COMPETE 2020/ ; }, mesh = {Pregnancy ; Female ; Humans ; Antioxidants/pharmacology ; *Prenatal Exposure Delayed Effects/prevention &amp; control/etiology ; Resveratrol/pharmacology ; *Diabetes, Gestational/prevention &amp; control ; *Pregnancy Complications/prevention &amp; control ; Diet ; *Obesity, Maternal/complications ; Fetal Growth Retardation/prevention &amp; control ; Chronic Disease ; }, abstract = {Chronic diseases represent one of the major causes of death worldwide. It has been suggested that pregnancy-related conditions, such as gestational diabetes mellitus (GDM), maternal obesity (MO), and intra-uterine growth restriction (IUGR) induce an adverse intrauterine environment, increasing the offspring's predisposition to chronic diseases later in life. Research has suggested that mitochondrial function and oxidative stress may play a role in the developmental programming of chronic diseases. Having this in mind, in this review, we include evidence that mitochondrial dysfunction and oxidative stress are mechanisms by which GDM, MO, and IUGR program the offspring to chronic diseases. In this specific context, we explore the promising advantages of maternal antioxidant supplementation using compounds such as resveratrol, curcumin, N-acetylcysteine (NAC), and Mitoquinone (MitoQ) in addressing the metabolic dysfunction and oxidative stress associated with GDM, MO, and IUGR in fetoplacental and offspring metabolic health. This approach holds potential to mitigate developmental programming-related risk of chronic diseases, serving as a probable intervention for disease prevention.}, }
@article {pmid37958311, year = {2023}, author = {Abdalbari, FH and Martinez-Jaramillo, E and Forgie, BN and Tran, E and Zorychta, E and Goyeneche, AA and Sabri, S and Telleria, CM}, title = {Auranofin Induces Lethality Driven by Reactive Oxygen Species in High-Grade Serous Ovarian Cancer Cells.}, journal = {Cancers}, volume = {15}, number = {21}, pages = {}, pmid = {37958311}, issn = {2072-6694}, support = {2020//Ovarian Cancer Canada/ ; }, abstract = {High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease.}, }
@article {pmid37950627, year = {2023}, author = {Sultanli, S and Schneider, J and Burkart, SS and Binder, M and Kubatzky, KF}, title = {Cellular ROS tolerance determines the effect of plumbagin on osteoclast differentiation.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {37}, number = {12}, pages = {e23293}, doi = {10.1096/fj.202301415R}, pmid = {37950627}, issn = {1530-6860}, mesh = {*Osteoclasts/metabolism ; Reactive Oxygen Species/metabolism ; *Naphthoquinones/pharmacology ; Cell Differentiation ; RANK Ligand/pharmacology/metabolism ; }, abstract = {Plumbagin is used in traditional medicine because of its anti-inflammatory and anti-microbial properties. As a naphthoquinone, plumbagin triggers the production of reactive oxygen species (ROS). In vitro cancer studies showed that plumbagin triggers apoptosis in cancer cells through ROS production. As cancer-mediated chronic inflammation can affect bone density, it was hypothesized that plumbagin might directly inhibit the formation of bone-resorbing osteoclasts. We previously showed that the effect of plumbagin on osteoclastogenesis differed between bone marrow-derived macrophages and the macrophage cell line RAW 264.7. Although RAW 264.7 macrophages are able to initiate the gene program required for osteoclastogenesis, only primary macrophages successfully differentiate into osteoclasts. Here, we show that RAW 264.7 cells are more sensitive toward plumbagin-induced apoptosis. In the presence of plumbagin and the cytokine RANKL, which triggers ROS production to drive osteoclastogenesis, RAW 264.7 macrophages produce increased amounts of ROS and die. Addition of the ROS scavenger N-acetyl cysteine prevented cell death, linking the failure to differentiate to increased ROS levels. RAW 264.7 cells show reduced expression of genes protective against oxidative stress, while primary macrophages have a higher tolerance toward ROS. Our data suggest that it is indispensable to consider cell (line)-intrinsic properties when studying phytochemicals.}, }
@article {pmid37949132, year = {2024}, author = {Ye, Y and Liu, B and Wang, Z and Liu, L and Zhang, Q and Zhang, Q and Jiang, W}, title = {Sodium p-perfluorous nonenoxybenzene sulfonate induces ROS-mediated necroptosis by directly targeting catalase in HepG2 cells.}, journal = {The Science of the total environment}, volume = {910}, number = {}, pages = {168446}, doi = {10.1016/j.scitotenv.2023.168446}, pmid = {37949132}, issn = {1879-1026}, mesh = {Humans ; Reactive Oxygen Species ; Catalase ; Hep G2 Cells ; Necroptosis ; Molecular Docking Simulation ; Necrosis/chemically induced ; *Alkanesulfonic Acids/toxicity ; Alkanesulfonates ; *Fluorocarbons/toxicity ; }, abstract = {Sodium p-perfluorous nonenoxybenzene sulfonate (OBS) has been widely used as a substitute for perfluorooctane sulfonic acid (PFOS) because of its high surface activity and low cost, but the knowledge of its biological effects is still limited. In this study, we compared the toxic effects of OBS and PFOS on human hepatoma cells (HepG2). OBS resulted in lower cell viability, higher ROS levels, and more severe necrosis than PFOS, indicating that OBS caused higher cytotoxicity than PFOS. In this process, OBS induced a burst of ROS and downregulation of catalase (CAT). OBS-induced oxidative stress was recovered after the CAT overexpression, but the CAT levels were not reversed after N-acetylcysteine (NAC) pretreatment. This indicates that the downregulated CAT is an upstream signal of the ROS burst. Moreover, drug affinity targeting assay, spectroscopic analysis and molecular docking were conducted, showing that OBS directly targeted CAT and therefore downregulated CAT. In addition, we found that OBS-induced necrosis is RIP1/RIP3-dependent programmed necroptosis. In summary, OBS directly targets CAT to reduce CAT levels and induces oxidative stress and necroptosis. Our findings are helpful to understand the toxicity of OBS and to evaluate the safety of OBS as a substitute for PFOS.}, }
@article {pmid37945228, year = {2023}, author = {Wang, Y and Wang, A and Zhao, G and Liu, S and Li, K and Li, W and Peng, Y and Zheng, J}, title = {Glutathione conjugation and protein modification resulting from metabolic activation of pesticide metalaxyl in vitro and in vivo.}, journal = {Pesticide biochemistry and physiology}, volume = {196}, number = {}, pages = {105606}, doi = {10.1016/j.pestbp.2023.105606}, pmid = {37945228}, issn = {1095-9939}, mesh = {Rats ; Humans ; Mice ; Animals ; Activation, Metabolic ; *Pesticides/toxicity/metabolism ; Cysteine/metabolism/pharmacology ; Microsomes, Liver/metabolism ; Glutathione/metabolism ; }, abstract = {Metalaxyl (MTL), a germicidal agent, is widely used in agriculture. Due to the biological amplification effect, MTL entering the ecological environment would result in a threat to human health through the food chain. MTL is reportedly accumulated in liver. The objectives of the study included investigating the metabolic activation of MTL in liver and defining the mechanisms participating in the hepatotoxicity of MTL. The corresponding glutathione (GSH), N-acetylcysteine (NAC) conjugate, and cysteine conjugates were observed in liver microsomes, prepared from liver tissues of mice, containing MTL and GSH, NAC or cysteine. These conjugates were also detected in urine and bile of rats receiving MTL. Apparently, MTL was biotransformed to a quinone imine intermediate dose-dependently attacking the thiols and cysteine residues of protein. The bioactivation of MTL required cytochrome P450 enzymes, and CYP3A dominated the bio-activation of MTL.}, }
@article {pmid37944606, year = {2024}, author = {Sun, W and Xu, T and Lin, H and Yin, Y and Xu, S}, title = {BPA and low-Se exacerbate apoptosis and autophagy in the chicken bursa of Fabricius by regulating the ROS/AKT/FOXO1 pathway.}, journal = {The Science of the total environment}, volume = {908}, number = {}, pages = {168424}, doi = {10.1016/j.scitotenv.2023.168424}, pmid = {37944606}, issn = {1879-1026}, mesh = {Animals ; Humans ; *Chickens/metabolism ; Reactive Oxygen Species/metabolism ; *Bursa of Fabricius/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Apoptosis ; Oxidative Stress ; Autophagy ; Forkhead Box Protein O1/metabolism/pharmacology ; }, abstract = {Bisphenol A (BPA) is a ubiquitous environmental pollutant that can have harmful effects on human and animal immune systems by inducing oxidative stress. Selenium (Se) deficiency damages immune organ tissues and exhibits synergistic effects on the toxicity of environmental pollutants. However, oxidative stress, cell apoptosis, and autophagy caused by the combination of BPA and low-Se, have not been studied in the bursa of Fabricius of the immune organ of poultry. Therefore, in this study, BPA and/or low-Se broiler models and chicken lymphoma cells (MDCC-MSB-1 cells) models were established to investigate the effects of BPA and/or low-Se on the bursa of Fabricius of poultry. The data showed that BPA and/or low-Se disrupted the normal structure of the bursa of Fabricius, BPA (60 μM) significantly reduced the activity of MDCC-MSB-1 cells and disrupted normal morphology (IC50 = 192.5 ± 1.026 μM). Compared with the Control group, apoptosis and autophagy were increased in the BPA or low-Se groups, and the generation of reactive oxygen species (ROS) was increased. This inhibited the AKT/FOXO1 pathway, leading to mitochondrial fusion/division imbalance (Mfn1, Mfn2, OPA1 were increased, DRP1 was decreased) and dysfunction (CI-NDUFB8, CII-SDHB, CIII-UQCRC2, CIV-MTCO1, CV-ATP5A1, ATP). Furthermore, combined exposure of BPA and low-Se aggravated the above-mentioned changes. Treatment with N-acetylcysteine (NAC) reduced ROS levels and activated the AKT/FOXO1 pathway to further alleviate BPA and low-Se-induced apoptosis and autophagy. Apoptosis induced by low-Se + BPA was exacerbated after 3-Methyladenine (3-MA, autophagy inhibitor) treatment. Together, these results indicated that BPA and low-Se aggravated apoptosis and autophagy of the bursa of Fabricius in chickens by regulating the ROS/AKT/FOXO1 pathway.}, }
@article {pmid37942159, year = {2023}, author = {Zhang, H and Gong, J and Zhang, S and Luo, L and Luo, C and Bi, K and Wang, L and Kan, X and Tian, Z and Wang, X}, title = {N-acetylcysteine attenuates the incidence of phlebitis induced by carbomer/vinorelbine gel.}, journal = {Heliyon}, volume = {9}, number = {11}, pages = {e21235}, pmid = {37942159}, issn = {2405-8440}, abstract = {BACKGROUND: The high incidence and severe clinical manifestations of phlebitis pose a complex and urgent clinical challenge. The rapid and simple establishment of animal phlebitis models and the development of preventive strategies are crucial to resolving this problem.<br><br>METHODS: In this study, we established such models by mixing vinorelbine ditartrate (VNR) and carbomer to form a sustained-release gel carrier, and then injected it around the veins rather than inside the vessels. Furthermore, we analyzed the efficacy of the carbomer/VNR gel in inducing phlebitis by monitoring the morphology of the veins using HE staining, immunohistochemical and immunofluorescence staining, and western blotting. Reactive oxygen species (ROS) and lipid peroxidation levels were determined using flow cytometry. Finally, we evaluated the inhibitory effect of N-acetylcysteine (NAC) on VNR-induced phlebitis in rabbits and rats.<br><br>RESULTS: Our findings suggested that the carbomer/VNR gel rapidly and easily induced phlebitis due to by retention of the gel in situ, wrapping the veins, and the prolonged release of VNR. NAC alleviated the VNR-induced oxidative stress response and expression of inflammatory cytokines by attenuating mitochondrial damage in venous endothelial cells, thereby preventing the occurrence of phlebitis in rabbits and rats.<br><br>CONCLUSION: The in situ carbomer/VNR gel provides a rapid and simple method for establishing an animal model to study the pathogenesis of phlebitis. Furthermore, the observed therapeutic effect of NAC highlights its novel and efficacious role in preventing and treating phlebitis.}, }
@article {pmid37937383, year = {2023}, author = {Fayed, MS and Brooks, J and Seaquist, ER and Kumar, A and Moheet, A and Eberly, L and Mishra, U and Coles, LD}, title = {Population Pharmacokinetic Model of N-Acetylcysteine During Periods of Recurrent Hypoglycemia in Healthy Volunteers.}, journal = {Clinical pharmacology in drug development}, volume = {12}, number = {12}, pages = {1234-1240}, doi = {10.1002/cpdd.1338}, pmid = {37937383}, issn = {2160-7648}, support = {2-SRA-2014-272-M-R/JDRF/Juvenile Diabetes Research Foundation/United States ; P30 DK020593/DK/NIDDK NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Acetylcysteine/pharmacokinetics ; Cross-Over Studies ; Glutathione/metabolism ; Healthy Volunteers ; *Hypoglycemia ; }, abstract = {Recurrent hypoglycemia leads to impaired awareness of hypoglycemia where the blood glucose threshold that elicits the counterregulatory response is lowered. Hypoglycemia-induced oxidative stress is hypothesized to contribute to impaired awareness of hypoglycemia development and hypoglycemia-associated autonomic failure. Our group conducted a randomized, double-blinded, placebo-controlled, crossover study in healthy individuals undergoing experimentally induced recurrent hypoglycemia to evaluate the impact of intravenous N-acetylcysteine (NAC) during experimental hypoglycemia to preserve the counterregulatory response to subsequent hypoglycemia. The work presented herein aimed to characterize the NAC pharmacokinetics and its effects on oxidative stress. Whole blood and plasma samples were collected at specified time points during separate NAC and placebo infusions from 10 healthy volunteers. Samples were analyzed for NAC, cysteine, and glutathione (GSH) concentrations. A 2-compartment population NAC pharmacokinetic model was developed. Estimates for central compartment clearance and volume of distribution were 19.8 L/h, and 12.2 L, respectively, for a 70-kg person. Peripheral compartment clearance and volume of distribution estimates were 34.9 L/h and 13.1 L, respectively, for a 70-kg person. The PK parameters estimated here were different from those reported in the literature, suggesting a higher NAC clearance during hypoglycemic episodes. NAC leads to a significant increase in circulating cysteine concentration in a NAC concentration-dependent manner, suggesting rapid biotransformation. A transient decrease in plasma GSH was observed, supporting the hypothesis that NAC can act as a reducing agent displacing glutathione from the disulfide bond allowing for increased clearance and/or distribution of GSH.}, }
@article {pmid37931470, year = {2023}, author = {Bauzá-Thorbrügge, M and Peris, E and Zamani, S and Micallef, P and Paul, A and Bartesaghi, S and Benrick, A and Wernstedt Asterholm, I}, title = {NRF2 is essential for adaptative browning of white adipocytes.}, journal = {Redox biology}, volume = {68}, number = {}, pages = {102951}, pmid = {37931470}, issn = {2213-2317}, mesh = {Animals ; Mice ; Acetylcysteine/pharmacology ; Adaptation, Physiological ; Adipocytes, Brown/metabolism ; *Adipocytes, White/metabolism ; Adipose Tissue, Brown/metabolism ; Adipose Tissue, White/metabolism ; Antioxidants/pharmacology/metabolism ; Lactates/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes.}, }
@article {pmid37926333, year = {2024}, author = {Aslanlar, DA and Vişneci, EF and Oz, M and Nurullahoglu Atalik, KE}, title = {N-acetylcysteine ameliorates chemotherapy-induced impaired anxiety and depression-like behaviors by regulating inflammation, oxidative and cholinergic status, and BDNF release.}, journal = {Behavioural brain research}, volume = {458}, number = {}, pages = {114740}, doi = {10.1016/j.bbr.2023.114740}, pmid = {37926333}, issn = {1872-7549}, mesh = {Rats ; Humans ; Male ; Animals ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology/therapeutic use ; Brain-Derived Neurotrophic Factor ; Rats, Wistar ; Depression/chemically induced/drug therapy ; Acetylcholinesterase ; Methotrexate ; Oxidative Stress ; Inflammation/chemically induced/drug therapy ; Anxiety/chemically induced/drug therapy ; *Antineoplastic Agents/pharmacology ; Cholinergic Agents/pharmacology ; }, abstract = {Mood disorders caused by chemotherapy have become more important as the survival of cancer patients increases, and new studies in this field will contribute to the prevention of this disorder. For this purpose, we used methotrexate, a chemotherapeutic agent frequently preferred in oncological cases. Mtx was administered as a single dose of 100 mg/kg intraperitoneally to male Wistar albino rats. Since oxidative stress plays an important role in chemotherapy-induced emotional impairment, n-acetylcysteine (NAC), a potent antioxidant, was administered at 500 mg/kg in two doses before Mtx administration. We evaluated anxiety and depression-like behaviors 24 h after Mtx administration, as well as some oxidative and inflammatory markers in blood serum and hippocampal tissue, acetylcholinesterase activity (AChE), and brain-derived neurotrophic factor (BDNF) release in hippocampal tissue. In rats, Mtx induced anxiety and depression-like behaviors as well as abnormalities in oxidative and inflammatory markers in blood serum and hippocampal tissue, increased AChE activity in hippocampal tissue, and decreased BDNF release. NAC treatment was found to ameliorate Mtx-induced anxiety and depression-like behaviors, increase antioxidant capacity, reduce oxidative stress and inflammatory response, and regulate AChE activity and BDNF release. In conclusion, the fact that NAC treatment of Mtx was effective is important for revising the treatment strategies for individuals suffering from this disorder, and this effect is thought to be related to the antioxidant and anti-inflammatory power of NAC.}, }
@article {pmid37923393, year = {2024}, author = {Wang, H and Chang, Y and Liu, X and Liu, L and Hua, M and Li, A}, title = {Protective effects of baicalin on diethyl nitrosamine-induced liver cirrhosis by suppressing oxidative stress and inflammation.}, journal = {Chemical biology &amp; drug design}, volume = {103}, number = {1}, pages = {e14386}, doi = {10.1111/cbdd.14386}, pmid = {37923393}, issn = {1747-0285}, support = {//National Natural Science Foundation of China/ ; }, mesh = {Rats ; Animals ; Reactive Oxygen Species/metabolism ; *Liver Cirrhosis/chemically induced/drug therapy ; Liver ; Oxidative Stress ; Inflammation/chemically induced/drug therapy/metabolism ; *Nitrosamines/adverse effects/metabolism ; *Flavonoids ; }, abstract = {Baicalin (BA) is a natural product extract with anti-inflammatory, antioxidant, and hepatoprotective properties. Given that the exact underlying mechanisms responsible for the impact of BA on liver cirrhosis remain ambiguous, a detailed investigation is sorely needed. Accordingly, a rat liver cirrhosis model was established via the intraperitoneal injection of diethyl nitrosamine (DEN, 100 mg/kg). Following the modeling, these rats were given BA (100 mg/kg) or N-acetylcysteine (NAC, 150 mg/kg) alone or in combination. The pathological morphology of rat liver tissues in each group was observed by hematoxylin and eosin staining and Masson's trichrome staining. The expression of fibrosis-related proteins was evaluated by Western blot, and the levels of liver function-related biochemical indexes, oxidative stress-related indexes, and inflammatory factors in the serum by enzyme-linked immunosorbent assays (ELISA). The level of mitochondrial reactive oxygen species was measured by flow cytometry. The results depicted that in the rat model of DEN-induced liver cirrhosis, BA reduced the expression of fibrosis-related proteins (collagen type I alpha 1, α-smooth muscle actin, and transforming growth factor-β1), thereby alleviating the structural fibrosis of liver tissue. Furthermore, BA could diminish the level of mitochondrial reactive oxygen species, and the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1), while promoting albumin, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels. Notably, all these effects of BA above were strengthened following the combined treatment of BA and NAC. On the whole, BA suppresses liver fibrosis by inhibiting oxidative stress and inflammation, thereby exerting a hepatoprotective effect.}, }
@article {pmid37923985, year = {2023}, author = {Huang, Z and Han, Y and Zhang, X and Sun, Y and Lin, Y and Feng, L and Zhou, T and Wang, Z}, title = {Acetylcysteine increases sensitivity of ceftazidime-avibactam-resistant enterobacterales with different enzymatic resistance to ceftazidime-avibactam in vitro and in vivo.}, journal = {BMC microbiology}, volume = {23}, number = {1}, pages = {321}, pmid = {37923985}, issn = {1471-2180}, mesh = {Animals ; Mice ; *Anti-Bacterial Agents/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Ceftazidime/pharmacology ; Azabicyclo Compounds/pharmacology ; Drug Combinations ; *Gammaproteobacteria/metabolism ; Microbial Sensitivity Tests ; beta-Lactamases/metabolism ; }, abstract = {BACKGROUND: Ceftazidime-avibactam (CZA) improves treatment outcomes for infections caused by carbapenem-resistant organisms, but has led to serious bacterial resistance. Acetylcysteine (NAC) is an approved medication that protects the respiratory tract through antioxidant and anti-inflammatory effects.<br><br>RESULTS: This study found that NAC combined with CZA effectively inhibits the growth of CZA-resistant clinical Enterobacterales strains. The CZA/NAC combination inhibits biofilm formation in vitro and decreases bacterial burden in a mouse thigh infection model. The combination is biocompatible and primarily increases cell membrane permeability to cause bacterial death.<br><br>CONCLUSIONS: These findings prove that the CZA/NAC combination has potential as a treatment for CZA-resistant Enterobacterales infections.}, }
@article {pmid37923778, year = {2023}, author = {Clarke, G and Mao, J and Fan, Y and Hann, A and Gupta, A and Nutu, A and Buckel, E and Kayani, K and Murphy, N and Bangash, MN and Casey, AL and Wootton, I and Lawson, AJ and Dasari, BVM and Perera, MTPR and Mergental, H and Afford, SC}, title = {N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {19022}, pmid = {37923778}, issn = {2045-2322}, support = {/WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; }, mesh = {Humans ; *Liver Transplantation/methods ; *Methemoglobinemia ; Acetylcysteine/pharmacology ; Organ Preservation/methods ; Methemoglobin ; Liver ; Perfusion/methods ; }, abstract = {Extended duration of normothermic machine perfusion (NMP) provides opportunities to resuscitate suboptimal donor livers. This intervention requires adequate oxygen delivery typically provided by a blood-based perfusion solution. Methaemoglobin (MetHb) results from the oxidation of iron within haemoglobin and represents a serious problem in perfusions lasting > 24 h. We explored the effects of anti-oxidant, N-acetylcysteine (NAC) on the accumulation of methaemoglobin. NMP was performed on nine human donor livers declined for transplantation: three were perfused without NAC (no-NAC group), and six organs perfused with an initial NAC bolus, followed by continuous infusion (NAC group), with hourly methaemoglobin perfusate measurements. In-vitro experiments examined the impact of NAC (3 mg) on red cells (30 ml) in the absence of liver tissue. The no-NAC group sustained perfusions for an average of 96 (range 87-102) h, universally developing methaemoglobinaemia (≥ 2%) observed after an average of 45 h, with subsequent steep rise. The NAC group was perfused for an average of 148 (range 90-184) h. Only 2 livers developed methaemoglobinaemia (peak MetHb of 6%), with an average onset of 116.5 h. Addition of NAC efficiently limits formation and accumulation of methaemoglobin during NMP, and allows the significant extension of perfusion duration.}, }
@article {pmid37921125, year = {2023}, author = {Zhao, J and Han, M and Tian, Y and Zhao, P and Liu, X and Dong, H and Feng, S and Li, J}, title = {N-acetylcysteine Attenuates Cigarette Smoke-induced Alveolar Epithelial Cell Apoptosis through Reactive Oxygen Species Depletion and Glutathione Replenish In vivo and In vitro.}, journal = {Current pharmaceutical biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892010257526231019143524}, pmid = {37921125}, issn = {1873-4316}, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. N-acetylcysteine (NAC) is well known for its antioxidant properties, along with potential protective effects on COPD. However, the molecular mechanism of NAC against the apoptosis of alveolar epithelial cells (AECs) in COPD remains unclear.<br><br>OBJECTIVE: This study aimed to explore the anti-apoptosis effect of NAC in COPD mice and alveolar epithelial cells.<br><br>METHODS: In the present study, the mouse model of COPD was established by cigarette smoke (CS), and mouse alveolar epithelial (MLE-12) cells were treated with cigarette smoke extract (CSE). TdT-mediated dUTP nick-end labeling (TUNEL) assay, reverse transcription polymerase chain reaction (RT-PCR), and western blot were performed to evaluate the effects of NAC on apoptosis, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Meanwhile, LButhionine- sulfoximine (BSO), a glutathione (GSH) inhibitor, was used to uncover the mechanism of COPD treatment by NAC.<br><br>RESULTS: We found that NAC pretreatment could attenuate the protein levels of apoptosis, ER stress, and mitochondrial dysfunction-related genes caused by CS in vivo. Meanwhile, CSE could decrease MLE-12 cell viability, which was prevented by apoptosis inhibitor ZVAD-FMK but not necroptosis inhibitor necrostatin-1. Pretreatment of MLE-12 cells with NAC increased cellular GSH levels, inhibited cellular and mitochondrial reactive oxygen species (ROS) accumulation, and decreased protein level of apoptosis, ER stress, and mitochondrial dysfunctionrelated genes. Moreover, experiment results showed that BSO could completely reverse the beneficial effects of NAC.<br><br>CONCLUSION: Our study confirmed that NAC can attenuate CS-induced AEC apoptosis via alleviating ROS-mediated ER stress and mitochondrial dysfunction pathway, and the mechanism was found to be related to replenishing the cellular GSH content.}, }
@article {pmid37918853, year = {2024}, author = {Bryan, A and Pingali, P and Faber, A and Landry, J and Akakpo, JY and Jaeschke, H and Li, H and Lee, WS and May, L and Patel, B and Neuwelt, A}, title = {High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {388}, number = {1}, pages = {209-217}, pmid = {37918853}, issn = {1521-0103}, support = {IK2 BX004914/BX/BLRD VA/United States ; P30 CA016059/CA/NCI NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; *Cytochrome P-450 CYP2E1/metabolism ; Fomepizole ; Mice, Inbred NOD ; Liver/metabolism ; Acetylcysteine/pharmacology ; }, abstract = {Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgamma[null] mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.}, }
@article {pmid37918281, year = {2024}, author = {Li, Y and Yang, X and Bao, T and Sun, X and Li, X and Zhu, H and Zhang, B and Ma, T}, title = {Radix Astragali decoction improves liver regeneration by upregulating hepatic expression of aquaporin-9.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {122}, number = {}, pages = {155166}, doi = {10.1016/j.phymed.2023.155166}, pmid = {37918281}, issn = {1618-095X}, mesh = {Mice ; Animals ; Liver Regeneration ; Hydrogen Peroxide/metabolism ; Liver ; *Drugs, Chinese Herbal/chemistry ; *Astragalus Plant/chemistry ; *Aquaporins/genetics/metabolism/pharmacology ; }, abstract = {BACKGROUND: The therapeutic efficacy of liver injuries heavily relies on the liver's remarkable regenerative capacity, necessitating the maintenance of glycose/lipids homeostasis and oxidative eustasis during the recovery process. Astragali Radix, an herbal tonic widely used in China and many other countries, is believed to have many positive effects, including immune stimulation, nourishing, antioxidant, liver protection, diuresis, anti-diabetes, anti-cancer and expectorant. Astragali Radix is widely integrated into hepatoprotective formulas as it is believed to facilitate liver regeneration. Nevertheless, the precise molecular pharmacological mechanisms underlying this hepatoprotective effect remain elusive.<br><br>PURPOSE: To investigate the improving effects of Astragali Radix on liver regeneration and the underlying mechanisms.<br><br>METHODS: A mouse model of 70% partial hepatectomy (PHx) was employed to investigate the impact of Radix Astragali decoction (HQD) on liver regeneration. HQD was orally administered for 7 days before the PHx procedure and throughout the experiment. N-acetylcysteine (NAC) was used as a positive control for liver regeneration. Liver regeneration was assessed by evaluating the liver-to-body weight ratio (LW/BW) and the expression of representative cell proliferation marker proteins. Oxidative stress and glucose metabolism were analyzed using biochemical assays, Western blotting, dihydroethidium (DHE) fluorescence, and periodic acid-Schiff (PAS) staining methods. To understand the role of AQP9 as a potential molecular target of HQD in promoting liver regeneration, td-Tomato-tagged AQP9 transgenic mice (AQP9-RFP) were employed to determine the expression pattern of AQP9 protein. AQP9 knockout mice (AQP9[-/-]) were used to assess the specific targeting of AQP9 in the promotion of liver regeneration by HQD.<br><br>RESULTS: HQD significantly upregulated hepatic AQP9 expression, alleviated liver injury and promoted liver regeneration in wild-type (AQP9[+/+]) mice after 70% PHx. However, the beneficial impact of HQD on liver regeneration was absent in AQP9 gene knockout (AQP9[-/-]) mice. Moreover, HQD facilitated the uptake of glycerol by hepatocytes, enhanced gluconeogenesis, and concurrently reduced H2O2 content and oxidative stress levels in AQP9[+/+] but not AQP9[-/-] mouse livers. Additionally, main active substance of Radix Astragali, astragaloside IV (AS-IV) and cycloastragenol (CAG), demonstrated substantial upregulation of AQP9 expression and promoted liver regeneration in AQP9[+/+] but not AQP9[-/-] mice.<br><br>CONCLUSION: This study is the first to demonstrate that Radix Astragali and its main active constituents (AS-IV and CAG) improve liver regeneration by upregulating the expression of AQP9 in hepatocytes to increase gluconeogenesis and reduce oxidative stress. The study revealed novel molecular pharmacological mechanisms of Radix Astragali and provided a promising therapeutic target of liver diseases.}, }
@article {pmid37913693, year = {2023}, author = {Yilmaz, H and Mercantepe, F and Tumkaya, L and Mercantepe, T and Yilmaz, A and Yilmaz Rakici, S}, title = {The potential antioxidant effect of N-acetylcysteine on X-ray ionizing radiation-induced pancreas islet cell toxicity.}, journal = {Biochemical and biophysical research communications}, volume = {685}, number = {}, pages = {149154}, doi = {10.1016/j.bbrc.2023.149154}, pmid = {37913693}, issn = {1090-2104}, mesh = {Humans ; Male ; Rats ; Animals ; Antioxidants/pharmacology ; Acetylcysteine/pharmacology ; X-Rays ; Caspase 3/metabolism ; Glucagon ; Saline Solution/pharmacology ; Sodium Chloride/pharmacology ; Oxidative Stress ; Glutathione/metabolism ; Radiation, Ionizing ; *Radiation Injuries/drug therapy/prevention &amp; control ; *Islets of Langerhans/metabolism ; *Insulins ; }, abstract = {PURPOSE: Previous research has highlighted the impact of X-ray irradiation-induced organ damage, on cancer patients after radiation therapy. The ionizing radiation-induced oxidative stress causes injury to the pancreatic islet cells of Langerhans. We used histopathological, immunohistochemical, and biochemical analyses to examine α- and β-cells in the islets of Langerhans in rats undergoing whole-body x-ray ionizing radiation, a group of which was treated with NAC.<br><br>MATERIAL AND METHODS: Twenty-four male rats were randomly divided into 3 groups, one control, and two experimental groups. Group I (Control) was administered only saline solution (0.09% NaCl) by oral gavage for 7 days. Group II (IR) was administrated whole body single dose 6 Gray ionizing radiation (IR) and saline solution (0.09% NaCl) by oral gavage for 7 days. Group III (IR&#xa0;+&#xa0;NAC) was administered 300&#xa0;mg/kg NAC (N-acetylcysteine) by oral gavage for 7 days, 5 days before, and 2 days after 6 Gray IR application.<br><br>RESULTS: In the X-ray irradiation group, we observed diffuse necrotic endocrine cells in the islets of Langerhans. In addition, we found that Caspase-3, malondialdehyde (MDA) levels increased, and insulin, glucagon, and glutathione (GSH) levels decreased in the IR group compared to the control group. In contrast, we observed a decrease in Caspase-3, and MDA levels in necrotic endocrine cells, and an increase in insulin, glucagon, and GSH levels in the IR&#xa0;+&#xa0;NAC group compared to the IR group.<br><br>CONCLUSION: This study provides evidence for the beneficial effects of N-acetyl cysteine on islets of Langerhans cells with X-ray ionizing-radiation-induced damage in a rat model.}, }
@article {pmid37913572, year = {2023}, author = {Feng, Q and Hu, K and Hu, H and Lu, Y and Zhang, H and Wang, G and Zhang, Q and Xu, Z and Gao, X and Jia, X and Zhu, H and Song, D and Yi, H and Peng, Y and Wu, X and Li, B and Zhu, W and Shi, J}, title = {Berberine derivative DCZ0358 induce oxidative damage by ROS-mediated JNK signaling in DLBCL cells.}, journal = {International immunopharmacology}, volume = {125}, number = {Pt A}, pages = {111139}, doi = {10.1016/j.intimp.2023.111139}, pmid = {37913572}, issn = {1878-1705}, mesh = {Humans ; Apoptosis ; *Berberine/pharmacology ; Cell Line, Tumor ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/pathology ; MAP Kinase Signaling System ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {The most common neoplasm among adult lymphomas is diffuse large B-cell lymphoma (DLBCL), typically characterized by pain-free and progressive lymph node enlargement. Due to high heterogeneity of DLBCL, 30-40 % of patients are resistant to R-CHOP standard chemoimmunotherapy. DCZ0358 is a new compound designed and synthesized from berberine by our group and the molecular mechanism by which it inhibited DLBCL growth has attracted our widespread attention. In this study, we employed the CCK8 assay to reveal that DCZ0358 inhibited proliferation in a dependent manner of time and dosage of DLBCL cells. Moreover, flowcytometry and western blot results showed that DCZ0358 downregulated the expression of CDK4, CDK6 and CyclinD1 to block cell cycle progression in G0/G1 phase. Furthermore, DCZ0358 enhanced mitochondrial membrane potential depolarization, promoted mitochondrial permeability transport pore openness, increased cytoplastic Ca2+ levels and decreased intracellular adenosine triphosphate production, which led to mitochondrial dysfunction. In particular, DCZ0358 treatment triggered cell apoptosis and elevated intracellular reactive oxygen species (ROS) levels, which subsequently mediated JNK pathway activation. Further research indicated the pre-treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358. Most importantly, DCZ0358 exhibited synergistic anti-tumor effects when combined with etoposide, a common clinical anti-DLBCL drug, both in vitro and certainly in vivo. Above results demonstrated anti-tumor molecular mechanism of DCZ0358 in DLBCL cells and highlighted the ROS/JNK/DNA damage pathway as a potential target in therapies, which have implications for the development of more effective clinical treatments for DLBCL.}, }
@article {pmid37908648, year = {2023}, author = {Li, H and Deng, X and Zhang, Z and Yang, Z and Huang, H and Ye, X and Zhong, L and Xu, G and Liu, R and Fang, Y}, title = {Nitric oxide/paclitaxel micelles enhance anti-liver cancer effects and paclitaxel sensitivity by inducing ferroptosis, endoplasmic reticulum stress and pyroptosis.}, journal = {RSC advances}, volume = {13}, number = {45}, pages = {31772-31784}, pmid = {37908648}, issn = {2046-2069}, abstract = {The objective of this study was to investigate the anticancer activities of biodegradable polymeric micelles composed of monomethoxy poly(ethylene glycol), polylactic acid, and nitric oxide (mPEG-PLA-NO) loaded with paclitaxel (PTX) as a nanomedicine delivery system. We aimed to compare the anticancer effects of these NO/PTX micelles with PTX alone and elucidate their mechanism of action. We evaluated the impact of NO/PTX and PTX on cell viability using Cell Counting Kit-8 (CCK8) assays conducted on the Bel-7402 liver cancer cell line. Additionally, we employed H22 xenografted mice to assess the in vivo tumor growth inhibitory activity of NO/PTX. To examine the cytotoxicity of NO/PTX, the intracellular levels of reactive oxygen species (ROS), and the expression of ferroptosis-related proteins, we conducted experiments in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) or the ROS inhibitor N-acetyl cysteine (NAC). Furthermore, we investigated the expression of endoplasmic reticulum stress (ERS) and apoptosis-associated proteins. Our results demonstrated that NO/PTX exhibited enhanced anticancer effects compared to PTX alone in both Bel-7402 cells and H22 xenografted mice. The addition of Fer-1 or NAC reduced the anticancer activity of NO/PTX, indicating the involvement of ferroptosis and ROS in its mechanism of action. Furthermore, NO/PTX modulated the expression of proteins related to ERS and apoptosis, indicating the activation of these cellular pathways. The anticancer effects of NO/PTX in liver cancer cells were mediated through the induction of ferroptosis, pyroptosis, ERS, and apoptosis-associated networks. Ferroptosis and pyroptosis were activated by treatment of NO/PTX at low concentration, whereas ERS was induced to trigger apoptosis at high concentration. The superior anti-tumor effect of NO/PTX may be attributed to the downregulation of a multidrug resistance transporter and the sensitization of cells to PTX chemotherapy. In summary, our study highlights the potential of mPEG-PLA-NO micelles loaded with PTX as a nanomedicine delivery system for liver cancer treatment. The observed enhancement in anticancer activity, combined with the modulation of key cellular pathways, provides valuable insights into the therapeutic potential of NO/PTX in overcoming resistance and improving treatment outcomes in liver cancer patients.}, }
@article {pmid37902021, year = {2023}, author = {ALRashdi, BM and Mohamed, RA and Mohamed, AH and Samoul, FA and Mohamed, MI and Moussa, MM and Alrashidi, SM and Dawod, B and Habotta, OA and Abdel Moneim, AE and Ramadan, SS}, title = {Therapeutic activity of green synthesized selenium nanoparticles from turmeric against cisplatin-induced oxido-inflammatory stress and cell death in mice kidney.}, journal = {Bioscience reports}, volume = {43}, number = {11}, pages = {}, pmid = {37902021}, issn = {1573-4935}, mesh = {Mice ; Animals ; *Cisplatin/adverse effects ; *Selenium/pharmacology/metabolism ; Curcuma ; Kidney/pathology ; Apoptosis ; Oxidative Stress ; }, abstract = {Cisplatin (CDDP) is a commonly prescribed chemotherapeutic agent; however, its associated nephrotoxicity limits its clinical efficacy and sometimes requires discontinuation of its use. The existing study was designed to explore the reno-therapeutic efficacy of turmeric (Tur) alone or conjugated with selenium nanoparticles (Tur-SeNPs) against CDDP-mediated renal impairment in mice and the mechanisms underlying this effect. Mice were orally treated with Tur extract (200 mg/kg) or Tur-SeNPs (0.5 mg/kg) for 7 days after administration of a single dose of CDDP (5 mg/kg, i.p.). N-acetyl cysteine NAC (100 mg/kg) was used as a standard antioxidant compound. The results revealed that Tur-SeNPs counteracted CDDP-mediated serious renal effects in treated mice. Compared with the controls, Tur or Tur-SeNPs therapy remarkably decreased the kidney index along with the serum levels of urea, creatinine, Kim-1, and NGAL of the CDDP-injected mice. Furthermore, Tur-SeNPs ameliorated the renal oxidant status of CDDP group demonstrated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and gene expression levels of HO-1. Noteworthy, lessening of renal inflammation was exerted by Tur-SeNPs via lessening of IL-6 and TNF-α besides down-regulation of NF-κB gene expression in mouse kidneys. Tur-SeNPs treatment also restored the renal histological features attained by CDDP challenge and hindered renal apoptosis through decreasing the Bax levels and increasing Bcl-2 levels. Altogether, these outcomes suggest that the administration of Tur conjugated with SeNPs is effective neoadjuvant chemotherapy to guard against the renal adverse effects that are associated with CDDP therapy.}, }
@article {pmid37899576, year = {2024}, author = {Sozer Karadagli, S and Gursoy, P}, title = {Liver toxicity with ribociclib in a patient with metastatic hormone receptor positive postmenopausal breast cancer.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {30}, number = {2}, pages = {404-407}, doi = {10.1177/10781552231208390}, pmid = {37899576}, issn = {1477-092X}, mesh = {Female ; Humans ; *Aminopyridines/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Breast Neoplasms/drug therapy/pathology ; Cysteine/therapeutic use ; *Drug-Related Side Effects and Adverse Reactions/drug therapy ; Liver ; Postmenopause ; *Purines/adverse effects ; Receptor, ErbB-2 ; }, abstract = {INTRODUCTION: In recent years, highly selective reversible CDK4/6 inhibitors have been combined with aromatase inhibitors for their efficacy and ease of application in the treatment of advanced stage of hormone-responsive breast cancers. Oral use of these drugs facilitates patient compliance. However, adverse drug reactions are reported due to these drugs, in the literature. Diverse adverse reactions such as skin reactions, liver toxicity, and vitiligo with ribociclib have been reported.<br><br>CASE REPORT: In this study, we present of liver toxicity due to the use of ribociclib in a case of advanced breast cancer with metastases. It is noteworthy that the patient did not have any other concomitant disease and did not take any other medication.<br><br>MANAGEMENT AND OUTCOME: After the 600&#x2005;mg initial dose of ribociclib, neutropenia occurred at the beginning of the therapy, the dose was reduced to 400&#x2005;mg, and liver enzymes started to rise in the second month of the therapy. In the fifth month of the intermittent treatment period, liver toxicity was grade 3.<br><br>DISCUSSION: Liver adverse reaction occurred due to ribociclib use in the patient who had no history of any other disease. The Naranjo algorithm score was evaluated as 9. Considering the excretion of ribociclib by sulfation, cysteine conjugation, and glucuronidation, which are phase II reactions, n-acetyl cysteine (NAC) treatment (600&#x2005;mg/day) was started for the patient. NAC therapy is recommended to reduce elevated liver enzymes in the case. The patient's treatment has been continuing with palbociclib for 5 months. No increase in liver enzymes was observed.}, }
@article {pmid37895148, year = {2023}, author = {Yang, YF and Singh, S}, title = {Pharmacogenomic Landscape of Ivermectin and Selective Antioxidants: Exploring Gene Interplay in the Context of Long COVID.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37895148}, issn = {1422-0067}, mesh = {Humans ; *COVID-19/genetics ; Antioxidants/therapeutic use ; Post-Acute COVID-19 Syndrome ; Ivermectin/therapeutic use ; Pandemics ; Anthocyanins ; Pharmacogenetics ; *MicroRNAs/genetics ; }, abstract = {COVID-19 pandemic has caused widespread panic and fear among the global population. As such, repurposing drugs are being used as viable therapeutic options due to the limited effective treatments for Long COVID symptoms. Ivermectin is one of the emerging repurposed drugs that has been shown effective to have antiviral effects in clinical trials. In addition, antioxidant compounds are also gaining attention due to their capabilities of reducing inflammation and severity of symptoms. Due to the absence of knowledge in pharmacogenomics and modes of actions in the human body for these compounds, this study aims to provide a pharmacogenomic profile for the combination of ivermectin and six selected antioxidants (epigallocatechin gallate (EGCG), curcumin, sesamin, anthocyanins, quercetin, and N-acetylcysteine (NAC)) as potentially effective regimens for long COVID symptoms. Results showed that there were 12 interacting genes found among the ivermectin, 6 antioxidants, and COVID-19. For network pharmacology, the 12 common interacting genes/proteins had the highest associations with Pertussis pathway, AGE-RAGE signaling pathway in diabetic complications, and colorectal cancer in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Disease analyses also revealed that the top three relevant diseases with COVID-19 infections were diabetes mellitus, ischemia, reperfusion injury. We also identified 6 potential target microRNAs (miRNAs) of the 12 commonly curated genes used as molecular biomarkers for COVID-19 treatments. The established pharmacogenomic network, disease analyses, and identified miRNAs could facilitate developments of effective regimens for chronic sequelae of COVID-19 especially in this post-pandemic era. However, further studies and clinical trials are needed to substantiate the effectiveness and dosages for COVID-19 treatments.}, }
@article {pmid37894999, year = {2023}, author = {Li, R and Kato, H and Fumimoto, C and Nakamura, Y and Yoshimura, K and Minagawa, E and Omatsu, K and Ogata, C and Taguchi, Y and Umeda, M}, title = {Essential Amino Acid Starvation-Induced Oxidative Stress Causes DNA Damage and Apoptosis in Murine Osteoblast-like Cells.}, journal = {International journal of molecular sciences}, volume = {24}, number = {20}, pages = {}, pmid = {37894999}, issn = {1422-0067}, support = {No. 23K19761//Japan Society for the Promotion of Science/ ; No. 21K09946//Japan Society for the Promotion of Science/ ; No. 22K09993//Japan Society for the Promotion of Science/ ; }, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Oxidative Stress ; *Apoptosis ; Acetylcysteine/pharmacology/metabolism ; DNA Damage ; Osteoblasts/metabolism ; Amino Acids, Essential/metabolism ; }, abstract = {Intracellular nutrient metabolism, particularly the metabolism of essential amino acids (EAAs), is crucial for cellular functions, including energy production and redox homeostasis. An EAA deficiency can lead to cellular dysfunction and oxidative stress. This study explores the mechanisms underlying cellular responses to EAA starvation, focusing on ROS-induced DNA damage and apoptosis. MC3T3-E1 cells were subjected to EAA starvation, and various assays were conducted to assess cell proliferation, survival, DNA damage, and apoptosis. The antioxidant N-acetylcysteine (NAC) was employed to block ROS formation and mitigate cellular damage. Gene expression and Western blot analyses were performed to elucidate molecular pathways. EAA starvation-induced ROS generation, DNA damage, and apoptosis in MC3T3-E1 cells. NAC administration effectively reduced DNA damage and apoptosis, highlighting the pivotal role of ROS in mediating these cellular responses during EAA deficiency. This study demonstrates that EAA starvation triggers ROS-mediated DNA damage and apoptosis, offering insights into the intricate interplay between nutrient deficiency, oxidative stress, and programmed cell death. NAC emerges as a potential therapeutic intervention to counteract these adverse effects.}, }
@article {pmid37894565, year = {2023}, author = {Ntorkou, M and Tsanaktsidou, E and Chachlioutaki, K and Fatouros, DG and Markopoulou, CK}, title = {In Vitro Permeability Study of Homotaurine Using a High-Performance Liquid Chromatography with Fluorescence Detection Pre-Column Derivatization Method.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {20}, pages = {}, pmid = {37894565}, issn = {1420-3049}, mesh = {*Acetylcysteine/chemistry ; Chromatography, High Pressure Liquid/methods ; *Memantine ; o-Phthalaldehyde/chemistry ; Indicators and Reagents ; Tiopronin ; Reproducibility of Results ; }, abstract = {Homotaurine (HOM) is considered a promising drug for the treatment of Alzheimer's and other neurodegenerative diseases. In the present work, a new high-performance liquid chromatography with fluorescence detection (HPLC-FLD) (λex. = 340 nm and λem. = 455 nm) method was developed and validated for the study of substance permeability in the central nervous system (CNS). Analysis was performed on a RP-C18 column with a binary gradient elution system consisting of methanol-potassium phosphate buffer solution (pH = 7.0, 0.02 M) as mobile phase. Samples of homotaurine and histidine (internal standard) were initially derivatized with ortho-phthalaldehyde (OPA) (0.01 M), N-acetylcysteine (0.01 M) and borate buffer (pH = 10.5; 0.05 M). To ensure the stability and efficiency of the reaction, the presence of different nucleophilic reagents, namely (a) 2-mercaptoethanol (2-ME), (b) N-acetylcysteine (NAC), (c) tiopronin (Thiola), (d) 3-mercaptopropionic acid (3-MPA) and (e) captopril, was investigated. The method was validated (R[2] = 0.9999, intra-day repeatability %RSD < 3.22%, inter-day precision %RSD = 1.83%, limits of detection 5.75 ng/mL and limits of quantification 17.43 ng/mL, recovery of five different concentrations 99.75-101.58%) and successfully applied to investigate the in vitro permeability of homotaurine using Franz diffusion cells. The apparent permeability (Papp) of HOM was compared with that of memantine, which is considered a potential therapeutic drug for various CNSs. Our study demonstrates that homotaurine exhibits superior permeability through the simulated blood-brain barrier compared to memantine, offering promising insights for enhanced drug delivery strategies targeting neurological conditions.}, }
@article {pmid37891946, year = {2023}, author = {Tieu, S and Charchoglyan, A and Paulsen, L and Wagter-Lesperance, LC and Shandilya, UK and Bridle, BW and Mallard, BA and Karrow, NA}, title = {N-Acetylcysteine and Its Immunomodulatory Properties in Humans and Domesticated Animals.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {37891946}, issn = {2076-3921}, abstract = {N-acetylcysteine (NAC), an acetylated derivative of the amino acid L-cysteine, has been widely used as a mucolytic agent and antidote for acetaminophen overdose since the 1960s and the 1980s, respectively. NAC possesses antioxidant, cytoprotective, anti-inflammatory, antimicrobial, and mucolytic properties, making it a promising therapeutic agent for a wide range of diseases in both humans and domesticated animals. Oxidative stress and inflammation play a major role in the onset and progression of all these diseases. NAC's primary role is to replenish glutathione (GSH) stores, the master antioxidant in all tissues; however, it can also reduce levels of pro-inflammatory tumor necrosis factor-alpha (TNF-∝) and interleukins (IL-6 and IL-1β), inhibit the formation of microbial biofilms and destroy biofilms, and break down disulfide bonds between mucin molecules. Many experimental studies have been conducted on the use of NAC to address a wide range of pathological conditions; however, its effectiveness in clinical trials remains limited and studies often have conflicting results. The purpose of this review is to provide a concise overview of promising NAC usages for the treatment of different human and domestic animal disorders.}, }
@article {pmid37886069, year = {2023}, author = {Pacios, O and Blasco, L and Ortiz Cartagena, C and Bleriot, I and Fernández-García, L and López, M and Barrio-Pujante, A and Cuenca, FF and Aracil, B and Oteo-Iglesias, J and Tomás, M}, title = {Molecular studies of phages-Klebsiella pneumoniae in mucoid environment: innovative use of mucolytic agents prior to the administration of lytic phages.}, journal = {Frontiers in microbiology}, volume = {14}, number = {}, pages = {1286046}, pmid = {37886069}, issn = {1664-302X}, abstract = {Mucins are important glycoproteins that form a protective layer throughout the gastrointestinal and respiratory tracts. There is scientific evidence of increase in phage-resistance in the presence of mucin for some bacterial pathogens. Manipulation in mucin composition may ultimately influence the effectiveness of phage therapy. In this work, two clinical strains of K. pneumoniae (K3574 and K3325), were exposed to the lytic bacteriophage vB_KpnS-VAC35 in the presence and absence of mucin on a long-term co-evolution assay, in an attempt to mimic in vitro the exposure to mucins that bacteria and their phages face in vivo. Enumerations of the bacterial and phage counts at regular time intervals were conducted, and extraction of the genomic DNA of co-evolved bacteria to the phage, the mucin and both was performed. We determined the frequency of phage-resistant mutants in the presence and absence of mucin and including a mucolytic agent (N-acetyl L-cysteine, NAC), and sequenced them using Nanopore. We phenotypically demonstrated that the presence of mucin induces the emergence of bacterial resistance against lytic phages, effectively decreased in the presence of NAC. In addition, the genomic analysis revealed some of the genes relevant to the development of phage resistance in long-term co-evolution, with a special focus on the mucoid environment. Genes involved in the metabolism of carbohydrates were mutated in the presence of mucin. In conclusion, the use of mucolytic agents prior to the administration of lytic phages could be an interesting therapeutic option when addressing K. pneumoniae infections in environments where mucin is overproduced.}, }
@article {pmid37885115, year = {2024}, author = {Salehi, AM and Hasanzarrini, M and Salehi, H and Jenabi, E}, title = {Liraglutide and Liver Injury: Rare Case Report with Literature Review.}, journal = {Endocrine, metabolic &amp; immune disorders drug targets}, volume = {24}, number = {6}, pages = {725-729}, doi = {10.2174/0118715303180615231011053011}, pmid = {37885115}, issn = {2212-3873}, mesh = {Humans ; Female ; Adult ; *Liraglutide/adverse effects ; *Diabetes Mellitus, Type 2/diagnosis/drug therapy/chemically induced ; Hypoglycemic Agents/adverse effects ; Glucagon-Like Peptide 1 ; Liver ; }, abstract = {BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus (T2DM). So far, few severe side effects have been reported for it.<br><br>CASE PRESENTATION: A 41-year-old woman was admitted to the Emergency Room with diffuse abdominal pain. The patient had a known case of T2DM, fatty liver disease, and hypertension and was treated with Metformin, Liraglutide, and Losartan. Her liver functional test (LFT) was consistent with hepatocellular injury; however, laboratory tests and abdominal ultrasound were used to rule out autoimmune hepatitis. Due to concerns for drug-induced liver injury (DILL), liraglutide was discontinued and N-acetyl cysteine was prescribed. On the fifth day of hospitalization, the patient's symptoms resolved and his LFT started to decrease on the sixth day after 2 months, the patient's liver enzyme levels returned to normal.<br><br>CONCLUSION: Liraglutide is one of the most important drugs in the treatment of T2DM.The most common side effects of this drug are constipation, nausea, vomiting, diarrhea, indigestion, and loss of appetite. In rare cases, symptoms of thyroid cancer, pancreatitis, and hypoglycemia have been reported, however, DILL is one of the extremely rare side effect of Liraglutide. It is important to increase the awareness of physicians about the liver injury of Liraglutide.}, }
@article {pmid37884214, year = {2023}, author = {Kshirsagar, S and Dandekar, A and Srivastava, RK and Khan, J and Muzaffar, S and Athar, M and Banga, AK}, title = {Microneedle-mediated transdermal delivery of N-acetyl cysteine as a potential antidote for lewisite injury.}, journal = {International journal of pharmaceutics}, volume = {647}, number = {}, pages = {123547}, pmid = {37884214}, issn = {1873-3476}, support = {U01 AR078544/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; *Antidotes ; *Acetylcysteine ; Administration, Cutaneous ; Skin ; Drug Delivery Systems ; Needles ; }, abstract = {Lewisite is a chemical warfare agent intended for use in World War and a potential threat to the civilian population due to presence in stockpiles or accidental exposure. Lewisite-mediated skin injury is characterized by acute erythema, pain, and blister formation. N-acetyl cysteine (NAC) is an FDA-approved drug for acetaminophen toxicity, identified as a potential antidote against lewisite. In the present study, we have explored the feasibility of rapid NAC delivery through transdermal route for potentially treating chemical warfare toxicity. NAC is a small, hydrophilic molecule with limited passive delivery through the skin. Using skin microporation with dissolving microneedles significantly enhanced the delivery of NAC into and across dermatomed human skin in our studies. Microporation followed by application of solution (poke-and-solution) resulted in the highest in vitro delivery (509.84 ± 155.04 µg/sq·cm) as compared to poke-and-gel approach (474.91 ± 70.09 µg/sq·cm) and drug-loaded microneedles (226.89 ± 33.41 µg/sq·cm). The lag time for NAC delivery through poke-and-solution approach (0.23 ± 0.04 h) was close to gel application (0.25 ± 0.02 h), with the highest for drug-loaded microneedles (1.27 ± 1.16 h). Thus, we successfully demonstrated the feasibility of rapid NAC delivery using various skin microporation approaches for potential treatment against lewisite-mediated skin toxicity.}, }
@article {pmid37877516, year = {2023}, author = {Li, S and Yang, N and Ma, Q and Li, S and Tong, S and Luo, J and Song, X and Yang, H}, title = {Tailoring Oxidation Responsiveness of Gold Nanoclusters via Ligand Engineering for Imaging Acute Kidney Injury.}, journal = {Analytical chemistry}, volume = {95}, number = {44}, pages = {16153-16159}, doi = {10.1021/acs.analchem.3c02698}, pmid = {37877516}, issn = {1520-6882}, mesh = {Animals ; Mice ; Gold/chemistry ; Ligands ; Diagnostic Imaging ; *Acute Kidney Injury ; *Metal Nanoparticles/chemistry ; }, abstract = {Gold nanoclusters (AuNCs) have shown great promise for in vivo imaging because of their definable structure, tunable photoluminescence (PL), and desired renal clearance. However, current understanding of the responsiveness of AuNCs to biological substances is still limited, which may hamper their biomedical applications. Herein, we explore the oxidation responsiveness of near-infrared II (NIR-II) luminescent AuNCs capped with two different ligands, which can be optimized for high-efficiency NIR-II PL imaging of mice acute kidney injury (AKI) featuring high-level peroxynitrite anions (ONOO[-]). We found that in the presence of ONOO[-], N-acetylcysteine-capped AuNCs (NAC-AuNCs) tended to be oxidized more easily than that capped with the macromolecular mercapto-β-cyclodextrin (CDS-AuNCs), resulting in the aggregation of NAC-AuNCs into large-sized assemblies, which was not observed in CDS-AuNCs. The oxidation-triggered morphology, composition, and NIR-II PL changes in NAC-AuNCs were then systematically studied. We finally demonstrated that NAC-AuNCs can be implemented for sensitive NIR-II PL imaging of mice AKI, facilitated by the synergetic in situ AuNC aggregation and decreased glomerular filtration rate (GFR) in the injured kidney, which outperforms the methods solely based on the decreased GFR effect. Therefore, this work highlights the critical significance of ligand engineering in AuNCs and may motivate future design of AuNCs for diverse bioimaging applications.}, }
@article {pmid37877260, year = {2023}, author = {Wilson, SH and Sirianni, JM and Bridges, KH and Wolf, BJ and Valente, IE and Scofield, MD}, title = {The impact of intraoperative N-acetylcysteine on opioid consumption following spine surgery: a randomized pilot trial.}, journal = {Pain management}, volume = {13}, number = {10}, pages = {593-602}, pmid = {37877260}, issn = {1758-1877}, support = {R01 DA054154/DA/NIDA NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; UL1TR001450/TR/NCATS NIH HHS/United States ; UL1TR001450/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Acetylcysteine/therapeutic use ; *Analgesics, Opioid/therapeutic use ; Double-Blind Method ; Pain, Postoperative/drug therapy ; Pilot Projects ; Prospective Studies ; }, abstract = {Aim: N-acetylcysteine (NAC) decreases inflammation and could augment perioperative analgesia. Materials &amp; methods: This prospective pilot trial examined postoperative opioid consumption at 12 h following intraoperative NAC. In phase I, 20 adults scheduled for posterior spine surgery were randomized to NAC (0, 50, 100 and 150 mg/kg) to determine the optimal dose. In phase II, 30 patients were randomized to placebo or NAC (150 mg/kg). Opioid consumption, pain ratings and time to opioid rescue were recorded. Results: Postoperative opioid consumption was reduced in the NAC group 19.3% at 12 h and 20% at 18 and 36 h. Opioid consumption was reduced 22-24% in the NAC group at all times after adjusting for intraoperative opioid administration. NAC subjects reported lower pain scores relative to placebo. Conclusion: Subjects randomized to NAC consumed less postoperative opioids and reported less pain versus placebo. Larger randomized controlled trials are needed to further evaluate NAC for analgesia. Clinical Trial Registration: NCT04562597 (ClinicalTrials.gov).}, }
@article {pmid37870740, year = {2024}, author = {Agarwal, A and Jayashree, M and Angurana, SK and Sharma, R and Ghosh, A and Singh, MP and Nallasamy, K and Bansal, A}, title = {Clinical Profile, Intensive Care Needs and Predictors of Outcome Among Children Admitted with Non-COVID Severe Acute Respiratory Illness (SARI) During the Pandemic.}, journal = {Indian journal of pediatrics}, volume = {91}, number = {4}, pages = {329-336}, pmid = {37870740}, issn = {0973-7693}, mesh = {Child ; Humans ; SARS-CoV-2 ; Pandemics ; Retrospective Studies ; *COVID-19 ; Critical Care ; *Respiratory Insufficiency ; }, abstract = {OBJECTIVES: To study the epidemiology of non-coronavirus disease-2019 (non-COVID-19) respiratory viral infections with respect to their clinical profile, intensive care needs and predictors of outcome once the non-pharmacological interventions (NPI) during the coronavirus disease-2019 (COVID-19) pandemic were relaxed.<br><br>METHODS: Retrospective analysis of children with Severe Acute Respiratory Illness (SARI) who were SARS-CoV-2 negative, admitted to the Pediatric Emergency/Intensive Care Unit (PICU) from July 2021 through October 2021 was conducted.<br><br>RESULTS: One hundred and thirty nine children with median age of 11 (4-28.5) mo were included. Besides respiratory symptoms in all, diarrhea was reported in 90 (64.7%) children. Nearly half (n&#xa0;=&#xa0;66; 47%) presented in hypoxemic respiratory failure (SpO2 <88%). Fifty-two (37.4%) children had co-morbidities, commonest being congenital heart disease in 12 (23.1%). Baseline parameters revealed leukopenia (specifically lymphopenia) 39 (28%), elevated aspartate transaminase [Serum glutamic-oxaloacetic transaminase (SGOT)] in 108 (77.6%), elevated N-acetyl-cysteine-activated creatinine kinase (CK-NAC) 23 (79%) and lactate dehydrogenase (LDH) 15 (88%). Intensive care needs included mechanical ventilation 51 (36.6%), vasoactive support 34 (24.5%), and renal replacement therapy 10 (7.1%). Forty-two (30.2%) children developed multi-organ dysfunction syndrome (MODS). One hundred and three (74.1%) children were discharged, 31 (22.3%) died, and 5 (3.6%) left against medical advice. On multivariate regression analysis, elevated liver enzymes (>5 times normal), hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted mortality.<br><br>CONCLUSIONS: A surge in non-COVID SARI was observed once lockdown measures were relaxed. Nearly 1/3[rd] progressed to multi-organ failure and died. Elevated liver enzymes, hypoxemic respiratory failure at admission, hypotensive shock and MODS predicted death.}, }
@article {pmid37869073, year = {2023}, author = {Ye, R and Ma, S and Chen, Y and Shan, J and Tan, L and Su, L and Tong, Y and Zhao, Z and Chen, H and Fu, M and Guo, Z and Zuo, X and Yu, J and Zhong, W and Zeng, J and Liu, F and Chai, C and Guan, X and Wang, Z and Liu, T and Liang, J and Zhang, Y and Shi, H and Wen, Z and Xia, H and Zhang, R}, title = {Single cell RNA-sequencing analysis reveals that N-acetylcysteine partially reverses hepatic immune dysfunction in biliary atresia.}, journal = {JHEP reports : innovation in hepatology}, volume = {5}, number = {11}, pages = {100908}, pmid = {37869073}, issn = {2589-5559}, abstract = {BACKGROUND &amp; AIMS: Our previous study indicated that CD177[+] neutrophil activation has a vital role in the pathogenesis of biliary atresia (BA), which is partially ameliorated by N-acetylcysteine (NAC) treatment. Here, we evaluated the clinical efficacy of NAC treatment and profiled liver-resident immune cells via single cell RNA-sequencing (scRNA-seq) analysis to provide a comprehensive immune landscape of NAC-derived immune regulation.<br><br>METHODS: A pilot clinical study was conducted to evaluate the potential effects of intravenous NAC treatment on infants with BA, and a 3-month follow-up was carried out to assess treatment efficacy. scRNA-seq analysis of liver CD45[+] immune cells in the control (n&#xa0;= 4), BA (n&#xa0;= 6), and BA&#xa0;+ NAC (n&#xa0;= 6) groups was performed and the effects on innate cells, including neutrophil and monocyte-macrophage subsets, and lymphoid cells were evaluated.<br><br>RESULTS: Intravenous NAC treatment demonstrated beneficial efficacy for infants with BA by improving bilirubin metabolism and bile acid flow. Two hepatic neutrophil subsets of innate cells were identified by scRNA-seq analysis. NAC treatment suppressed oxidative phosphorylation and reactive oxygen species production in immature neutrophils, which were transcriptionally and functionally similar to CD177[+] neutrophils. We also observed the suppression of hepatic monocyte-mediated inflammation, decreased levels of oxidative phosphorylation, and M1 polarisation in Kupffer-like macrophages by NAC. In lymphoid cells, enhancement of humoral immune responses and attenuation of cellular immune responses were observed after NAC treatment. Moreover, cell-cell interaction analysis showed that innate/adaptive proinflammatory responses were downregulated by NAC.<br><br>CONCLUSIONS: Our clinical and scRNA-seq data demonstrated that intravenous NAC treatment partially reversed liver immune dysfunction, alleviated the proinflammatory responses in BA by targeting innate cells, and exhibited beneficial clinical efficacy.<br><br>IMPACT AND IMPLICATIONS: BA is a serious liver disease that affects newborns and has no effective drug treatment. In this study, scRNA-seq showed that NAC treatment can partially reverse the immune dysfunction of neutrophil extracellular trap-releasing CD177+ neutrophils and Kupffer cells, and lower the inflammatory responses of other innate immune cells in BA. In consequence, intravenous NAC treatment improved the clinical outcomes of patients with BA in term of bilirubin metabolism.}, }
@article {pmid37865270, year = {2023}, author = {Lefèvre, CR and Le Divenah, F and Collet, N and Pelletier, R and Robert, E and Ropert, M and Pawlowski, M and Gicquel, T and Bendavid, C}, title = {Avoiding falsely low creatinine concentrations measured in patients treated with N-acetylcysteine for acetaminophen intoxication using enzymo-amperometric method - An in vitro and in vivo study.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {551}, number = {}, pages = {117611}, doi = {10.1016/j.cca.2023.117611}, pmid = {37865270}, issn = {1873-3492}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Acetaminophen ; Creatinine ; Retrospective Studies ; Peroxidase ; Peroxidases ; }, abstract = {BACKGROUND: Circulating creatinine is a biomarker of paramount importance in clinical practice. In cases of acetaminophen (APAP) intoxication, the antidote, N-acetylcysteine (NAC), interferes with commonly used creatininase-peroxidase methods. This study aimed to assess whether creatininase-amperometric methods were affected in this context.<br><br>METHODS: This study includes in vitro interference tests, involving four creatinine assays using NAC-spiked plasma pools and an in vivo retrospective study comparing creatininase-peroxidase and creatininase-amperometric measurements in patients presenting with NAC-treated APAP poisoning.<br><br>RESULTS: Creatininase-peroxidase method was impacted by NAC interference in a clinically-significant manner at therapeutic NAC levels (basal value recovery of 80&#xa0;% and 70&#xa0;% for 500 and 1000&#xa0;mg.L[-1] of NAC, respectively), surpassing the desirable Reference Change Value (RCV%). Enzymo-amperometric methods were not impacted. Among patients, a mean bias of -45.2&#xa0;&#xb1;&#xa0;28.0&#xa0;% was observed for the peroxidase detection method compared to the amperometric in those who received NAC prior plasma sampling and -2.7&#xa0;&#xb1;&#xa0;5.4&#xa0;% in those who did not.<br><br>CONCLUSIONS: Our findings indicate that enzymo-amperometric creatinine assays remain unaffected by NAC interference due to the absence of the peroxidase step in the analytical process. Therefore, these methods are suitable to prevent spurious hypocreatininemia in APAP intoxicated patients undergoing NAC therapy.}, }
@article {pmid37864839, year = {2024}, author = {Chao, SP and Cheng, WL and Yi, W and Cai, HH and Deng, K and Cao, JL and Zeng, Z and Wang, H and Wu, X}, title = {N-Acetylcysteine Alleviates Phenylephrine-Induced Cardiomyocyte Dysfunction via Engaging PI3K/AKT Signaling Pathway.}, journal = {American journal of hypertension}, volume = {37}, number = {3}, pages = {230-238}, doi = {10.1093/ajh/hpad100}, pmid = {37864839}, issn = {1941-7225}, support = {HHYC2019003//yellow crane of excellence program/ ; ZNXKPY2021011//Zhongnan disciplinary platform/ ; }, mesh = {Rats ; Animals ; *Phosphatidylinositol 3-Kinase/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Myocytes, Cardiac/metabolism ; Reactive Oxygen Species/metabolism ; Antioxidants/pharmacology ; Phenylephrine/pharmacology ; Signal Transduction ; Oxidative Stress ; Apoptosis ; }, abstract = {BACKGROUND: Increased reactive oxygen species (ROS) and oxidative stress response lead to cardiomyocyte hypertrophy and apoptosis, which play crucial roles in the pathogenesis of heart failure. The purpose of current research was to explore the role of antioxidant N-acetylcysteine (NAC) on cardiomyocyte dysfunction and the underlying molecular mechanisms.<br><br>METHODS AND RESULTS: Compared with control group without NAC treatment, NAC dramatically inhibited the cell size of primary cultured neonatal rat cardiomyocytes (NRCMs) tested by immunofluorescence staining and reduced the expression of representative markers associated with hypertrophic, fibrosis and apoptosis subjected to phenylephrine administration examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Moreover, enhanced ROS expression was attenuated, whereas activities of makers related to oxidative stress response examined by individual assay Kits, including total antioxidation capacity (T-AOC), glutathione peroxidase (GSH-Px), and primary antioxidant enzyme Superoxide dismutase (SOD) were induced by NAC treatment in NRCMs previously treated with phenylephrine. Mechanistically, we noticed that the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and AKT were increased by NAC stimulation. More importantly, we identified that the negative regulation of NAC in cardiomyocyte dysfunction was contributed by PI3K/AKT signaling pathway through further utilization of PI3K/AKT inhibitor (LY294002) or agonist (SC79).<br><br>CONCLUSIONS: Collected, NAC could attenuate cardiomyocyte dysfunction subjected to phenylephrine, partially by regulating the ROS-induced PI3K/AKT-dependent signaling pathway.}, }
@article {pmid37860953, year = {2024}, author = {Dos Santos, AC and França, TCS and Venzon, L and Polli, V and Polleti, G and Trembulak, E and Pilati, SFM and da Silva, LM}, title = {Are silymarin and N-acetylcysteine able to prevent liver damage mediated by multiple factors? Findings against ethanol plus LPS-induced liver injury in mice.}, journal = {Journal of biochemical and molecular toxicology}, volume = {38}, number = {1}, pages = {e23560}, doi = {10.1002/jbt.23560}, pmid = {37860953}, issn = {1099-0461}, mesh = {Mice ; Animals ; Acetylcysteine/pharmacology ; *Silymarin/pharmacology ; Lipopolysaccharides/toxicity ; Interleukin-10 ; Ethanol/toxicity ; *Chemical and Drug Induced Liver Injury, Chronic/pathology ; Interleukin-6/pharmacology ; Liver/pathology ; Antioxidants/pharmacology ; Glutathione ; Transaminases/pharmacology ; }, abstract = {This study investigated the effect of N-acetylcysteine (NAC) and silymarin (SIL) in the liver of mice exposed to ethanol and lipopolysaccharides (LPS). Mice were divided into four groups (n = 6): naive, vehicle, NAC (200 mg/kg), and SIL (200 mg/kg). Treatments were given orally (po) once daily for 10 days. Liver injury was induced by administration of ethanol (30%, po) for 10 days, once daily, followed by a single administration of LPS (2 mg/kg, ip) 24 h before euthanasia. After the treatment period, animals were euthanized, and liver and blood samples were collected. NAC, but not SIL, prevented the increase in oxalacetic glutamic transaminase (OGT) and pyruvic glutamic transaminase (PGT) serum levels. NAC and SIL did not restore levels of reduced glutathione or hepatic malonaldehyde. The treatments with NAC or SIL showed no difference in the activity of glutathione S-transferase, superoxide dismutase, and catalase compared to vehicle group. Myeloperoxidase and N-acetylglucosaminidase activities are increased, as well as the IL-6 and IL-10 levels in the liver. The treatment with NAC, but not SIL, reduced the N-acetylglucosamines activity and the IL-6 and IL-10 amount in the liver. Histological findings revealed microsteatosis in the vehicle group, which was not prevented by SIL but was partially reduced in animals receiving NAC. Unlike other liver injury models, NAC (200 mg/kg) or SIL (200 mg/kg) did not positively affect antioxidant patterns in liver tissue of animals exposed to ethanol plus LPS, but NAC treatment displays anti-inflammatory properties in this model.}, }
@article {pmid37859626, year = {2023}, author = {Wang, J and Zhang, C and Zhao, R and Wang, P and Jin, M and Xu, J}, title = {Antioxidant N-acetylcysteine removing ROS: an antifouling strategy inspired by mussels.}, journal = {Environmental science. Processes &amp; impacts}, volume = {25}, number = {12}, pages = {1962-1973}, doi = {10.1039/d3em00191a}, pmid = {37859626}, issn = {2050-7895}, mesh = {Animals ; *Biofouling/prevention &amp; control ; Antioxidants ; Acetylcysteine/pharmacology ; Reactive Oxygen Species ; Ecosystem ; *Bivalvia ; Dihydroxyphenylalanine ; }, abstract = {Marine biofouling is a thorny issue that causes serious economic losses and adverse ecological impacts on marine ecosystems. Effective and promising antifouling strategies such as surface hydration, flow shear force, and lubricant injection have been developed to address this challenge. However, for the complex marine environment, they still appear inadequate. Mussels are a common fouling organism with strong surface adhesion ability. However, when hypoxia and the oxidative cross-linking reaction of 3,4-dihydroxy phenyl-L-alanine (DOPA) in the structure of adhesion proteins are disrupted, their adhesion ability will be greatly reduced. Inspired by this, we developed an effective antifouling strategy based on reactive oxygen species (ROS) scavenging using N-acetylcysteine (NAC) and evaluated its performance. As a ROS scavenger interfered with the oxidative cross-linking reaction of DOPA in an aqueous solution, the adhesion of DOPA was also affected on the surface of NAC functionalized polyvinyl chloride (PVC) (PVC-NAC). In addition, the colonization level of mussels and the adhesion rate of marine bacteria and benthic diatoms on PVC-NAC were low. The antifouling strategy proposed in this paper was eco-friendly and broad-spectrum, and may provide a new idea for solving marine biofouling and reducing the environmental and economic impacts of fouling organisms.}, }
@article {pmid37858742, year = {2023}, author = {Tüfekci, KK and Tatar, M and Terzi, F and Bakirhan, EG}, title = {An investigation of the endoplasmic reticulum stress in obesity exposure in the prenatal period.}, journal = {Journal of chemical neuroanatomy}, volume = {134}, number = {}, pages = {102348}, doi = {10.1016/j.jchemneu.2023.102348}, pmid = {37858742}, issn = {1873-6300}, mesh = {Humans ; Rats ; Female ; Animals ; Pregnancy ; Infant ; *Acetylcysteine ; *Endoplasmic Reticulum Stress ; Obesity ; Endoplasmic Reticulum Chaperone BiP ; Hippocampus/metabolism ; }, abstract = {OBJECTIVES: Exposure to maternal obesity has been shown to make offspring more prone to cognitive and metabolic disorders later in life. Although the underlying mechanisms are unclear, the role of endoplasmic reticulum (ER) stress in the fetal programming process is remarkable. ER stress can be activated by many chronic diseases, including obesity and diabetes. Therefore, our study aimed to investigate the role of ER stress caused by maternal diet-induced obesity in the offspring hippocampus. We also evaluated the protective effect of N-acetylcysteine (NAC) against ER stress.<br><br>METHODS: A rat obesity model was created by providing a high-fat (60 % kcal) diet. N-acetylcysteine (NAC) was administered at a dosage of 150&#xa0;mg/kg via the intragastric route. The animals were mated at the age of 12 weeks. The same diet was maintained during pregnancy and lactation. The experiment was terminated on the postnatal 28th day, and the offspring's brain tissues were examined. Immunohistochemical staining for ER stress markers was performed on sections taken from tissues after routine histological procedures.<br><br>RESULTS: The results revealed increased GRP78, PERK, and eIF2&#x3b1; immunoreactivities in the hippocampal dentate gyrus (DG) and cornu ammonis 1 (CA1) regions in the obese group offspring, while the expression of those markers in those regions normalized with NAC supplementation (p&#xa0;<&#xa0;0.01). Statistical analysis of XBP1 immunoreactivity H-scores revealed no difference between the study groups (p&#xa0;>&#xa0;0.05).<br><br>DISCUSSION: These results suggest that exposure to obesity during the prenatal period may cause increased ER stress in hippocampal neurons, which have an important role in the regulation of learning, memory and behavior, and this may contribute to decreased cognitive performance. On the other hand, NAC stands out as an effective agent that can counteract hippocampal ER stress.}, }
@article {pmid37858609, year = {2024}, author = {Roy, P and Kandel, R and Sawant, N and Singh, KP}, title = {Estrogen-induced reactive oxygen species, through epigenetic reprogramming, causes increased growth in breast cancer cells.}, journal = {Molecular and cellular endocrinology}, volume = {579}, number = {}, pages = {112092}, doi = {10.1016/j.mce.2023.112092}, pmid = {37858609}, issn = {1872-8057}, mesh = {Humans ; Female ; Reactive Oxygen Species/metabolism ; *Breast Neoplasms/genetics/metabolism ; Estrogens/pharmacology ; Estradiol/pharmacology ; Epigenesis, Genetic ; }, abstract = {Despite the progress made in cancer diagnosis and treatment, breast cancer remains the second leading cause of cancer-related death among the women. Exposure to elevated levels of endogenous estrogen or environmental estrogenic chemicals is an important risk factor for breast cancer. Estrogen metabolites and ROS generated during estrogen metabolism are known to play a critical role in estrogen carcinogenesis. However, the molecular mechanisms through which estrogen-induced ROS regulate gene expression is not clear. Epigenetic changes of DNA methylation and histone modifications are known to regulate genes expression. Therefore, the objective of this study was to evaluate whether estrogen-induced ROS, through aberrant expression of epigenetic regulatory genes and epigenetic reprogramming, causes growth of breast cancer cells. Estrogen responsive MCF-7 and T47D human breast cancer cells were exposed to natural estrogen 17 beta-estradiol (E2) and synthetic estrogen Diethylstilbestrol (DES) both alone and in combination with antioxidant N-acetyl cysteine. Effects of NAC-mediated scavenging of estrogen-induced ROS on cell growth, gene expression, and histone modifications were measured. The result of MTT and cell cycle analysis revealed significant abrogation of E2 and DES-induced growth by scavenging ROS through NAC. E2 and DES caused significant changes in expression of epigenetic regulatory genes for DNA methylation and histone modifications as well as changes in both gene activating and repressive marks in the Histone H3. NAC restored the expression of epigenetic regulatory genes and changes in histone marks. Novel findings of this study suggest that estrogen can induce growth of breast cancer cells through ROS-dependent regulation of epigenetic regulatory genes and epigenetic reprogramming of histone marks.}, }
@article {pmid37853974, year = {2023}, author = {Nalbant, K and Erden, S}, title = {Possible effects of N-acetylcysteine in autism spectrum disorders: major clinical aspects, eating behaviors, and sleeping habits.}, journal = {The Turkish journal of pediatrics}, volume = {65}, number = {5}, pages = {832-844}, doi = {10.24953/turkjped.2022.573}, pmid = {37853974}, issn = {2791-6421}, mesh = {Child, Preschool ; Humans ; Child ; *Autism Spectrum Disorder/drug therapy ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Sleep ; Feeding Behavior ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is a promising agent for reducing irritability and hyperactivity and enhancing social responsiveness in children with autism spectrum disorders (ASD). This study aims to examine the effects of NAC on cardinal symptoms, eating, and sleeping habits in preschool children with autism.<br><br>METHODS: The medical records of ASD patients were investigated retrospectively. 37 children with ASD who regularly received oral NAC in two divided doses per day (400-600 mg/day) for 8 weeks were included as the study group. The control group consisted of 21 children with ASD who were recommended NAC but never used it. The initial and second assessment scores after 8 weeks of regular use of the NAC group and control group on the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Children Eating Behavior Questionnaire (CEBQ), and the Sleep Habits Questionnaire (CSHQ) were compared.<br><br>RESULTS: Our findings suggested that oral NAC alleviated the intensity of cardinal autistic symptoms in areas of social withdrawal, interpersonal relationships, body use, listening response, and verbal communication. Corresponding problem behaviors such as irritability, stereotypic behavior, and hyperactivity were reduced. It was determined that there was no difference between the two groups in terms of eating behaviors and sleeping habits.<br><br>CONCLUSIONS: According to the results, NAC alleviated the severity of cardinal symptoms and reduced problem behaviors in autism. Additional trials with more systematic planning, controlling for confounding effects, and long-term follow-up should be provided in future studies.}, }
@article {pmid37852631, year = {2023}, author = {Fond, G and Mallet, J and Urbach, M and Benros, ME and Berk, M and Billeci, M and Boyer, L and Correll, CU and Fornaro, M and Kulkarni, J and Leboyer, M and Llorca, PM and Misdrahi, D and Rey, R and Schürhoff, F and Solmi, M and Sommer, IEC and Stahl, SM and Pignon, B and Berna, F}, title = {Adjunctive agents to antipsychotics in schizophrenia: a systematic umbrella review and recommendations for amino acids, hormonal therapies and anti-inflammatory drugs.}, journal = {BMJ mental health}, volume = {26}, number = {1}, pages = {}, pmid = {37852631}, issn = {2755-9734}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Amino Acids/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; *Antipsychotic Agents/therapeutic use ; *Schizophrenia/drug therapy ; Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; }, abstract = {QUESTION: This umbrella review and guidelines aimed to provide evidence to support the rational choice of selected adjunctive therapies for schizophrenia.<br><br>STUDY SELECTION AND ANALYSIS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and World Federation of Societies of Biological Psychiatry (WFSBP)-grading recommendations, 63 randomised control trials (RCTs) (of which 4219 unique participants have completed the RCTs) and 29 meta-analyses were analysed.<br><br>FINDINGS: Provisional recommendations (WFSBP-grade 1) could be made for two molecules in augmentation to antipsychotics: (1) N-acetyl-cysteine (NAC, 1200-3600&#x2009;mg/day, for >12 consecutive weeks) in improving negative symptoms, general psychopathology (positive and negative syndrome scale for schizophrenia (PANSS) general psychopathology factor (G)-G subscale), with the RCTs with the longer duration showing the most robust findings; (2) polyunsaturated fatty acids (3000&#x2009;mg/day of eicosapentaenoic acid, for >12 weeks) in improving general psychopathology. Weaker recommendations (ie, WFSBP-grade 2) could be drawn for sarcosine (2&#x2009;g/day) and minocycline (200-300&#x2009;mg/day) for improving negative symptoms in chronic schizophrenia (not early schizophrenia), and NAC for improving positive symptoms and cognition. Weak recommendations are not ready for clinical practice. There is provisional evidence that oestrogens and raloxifene are effective in some patients, but further research is needed to determine their benefit/risk ratio.<br><br>CONCLUSIONS: The results of this umbrella review should be interpreted with caution as the number of RCTs included in the meta-analyses was generally small and the effect sizes were weak or medium. For NAC, two RCTs with low risk of bias have provided conflicting results and the WFSBP-grade recommendation included also the results of meta-analyses. These drugs could be provisionally prescribed for patients for whom no other treatments have been effective, but they should be discontinued if they prove ineffective.}, }
@article {pmid37851785, year = {2023}, author = {Brasil, VP and Siqueira, RM and Campos, FG and Yoshitani, MM and Pereira, GP and Mendonça, RLDS and Kanno, DT and Pereira, JA and Martinez, CAR}, title = {Mucin levels in glands of the colonic mucosa of rats with diversion colitis subjected to enemas containing sucralfate and n-acetylcysteine alone or in combination.}, journal = {Acta cirurgica brasileira}, volume = {38}, number = {}, pages = {e384023}, pmid = {37851785}, issn = {1678-2674}, mesh = {Rats ; Animals ; *Sucralfate/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Rats, Wistar ; Colon ; *Colitis/drug therapy/prevention &amp; control ; Mucins ; Sialomucins ; Intestinal Mucosa ; Enema/methods ; }, abstract = {PURPOSE: To evaluate the tissue content of neutral and acidic mucins, sulfomucins and sialomucins in colonic glands devoid of intestinal transit after enemas containing sucralfate and n-acetylcysteine alone or in combination.<br><br>METHODS: Sixty-four rats underwent intestinal transit bypass. A colonic segment was collected to compose the white group (without intervention). After derivation, the animals were divided into two groups according to whether enemas were performed daily for two or four weeks. Each group was subdivided into four subgroups according to the substance used: control group: saline 0.9%; sucralfate group (SCF): SCF 2 g/kg/day; n-acetylcysteine group (NAC): NAC 100 mg/kg/day; and SCF+NAC group: SCF 2 g/kg/day + NAC 100 mg/kg/day.Neutral and acidic mucins were stained by periodic acid-Schiff and alcian-blue techniques, respectively. The distinction between sulfomucins and sialomucin was made by the high alcian-blue iron diamine technique. The content of mucins in the colonic glands was measured by computerized morphometry. The inflammatory score was assessed using a validated scale. The results between the groups were compared by the Mann-Whitney's test, while the variation according to time by the Kruskal-Wallis' test (Dunn's post-test). A significance level of 5% was adopted.<br><br>RESULTS: There was reduction in the inflammatory score regardless of the application of isolated or associated substances. Intervention with SCF+NAC increased the content of all mucin subtypes regardless of intervention time.<br><br>CONCLUSIONS: The application of SCF+NAC reduced the inflammatory process of the colonic mucosa and increased the content of different types of mucins in the colonic glands of segments excluded from fecal transit.}, }
@article {pmid37848768, year = {2023}, author = {Nabi, Z and Vamsi, M and Goud, R and Sayyed, M and Basha, J and Reddy, PM and Reddy, R and Reddy, P and Manchu, C and Darisetty, S and Gupta, R and Tandan, M and Rao, GV and Reddy, DN}, title = {Pre-medication with simethicone and N-acetyl cysteine for improving mucosal visibility during upper gastrointestinal endoscopy: A randomized controlled trial.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {}, number = {}, pages = {}, pmid = {37848768}, issn = {0975-0711}, abstract = {BACKGROUND AND AIM: Diagnostic performance of esophagogastroduodenoscopy (EGD) may be compromized due to adherent mucus and foam. In this study, we aimed at assessing the impact of premedication on mucosal visibility during endoscopy.<br><br>METHODS: This is a double-blinded (patient and investigator), randomized trial conducted at a tertiary care centre. Patients were randomized into four groups: A (water), B (simethicone [S]), C (N-acetyl cysteine [NAC]), D (S&#x2009;+&#x2009;NAC). Premedication solutions were administered 10-30&#xa0;minutes before endoscopy and mucosal visibility graded from 1&#xa0;(best) to 4&#xa0;(worst) (1 best, 4 worst). Total mucosal visibility scores (TMVS) from six sites ranged from 6 (best) to 24 (worst) points. The primary outcome of study was comparison of TMVS between simethicone and combination (S&#x2009;+&#x2009;NAC) premedication groups. Secondary outcomes were adverse events and impact of endoscopy timing on TMVS.<br><br>RESULTS: Total 800 patients (39&#xa0;years, 68.8% males) were randomized into four groups. Median TMVS were significantly lower in groups B (7 [6-8]) and D (8 [6-9]) as compared to A (11 [9-13]) and C (10 [8-12]). Proportion of cases with adequate gastric mucosal visibility (score&#x2009;<&#x2009;7) was 26% in group A, 71% in group B, 36% in group C and 79% in group D. There was no difference in TMVS in groups A and C (p&#x2009;=&#x2009;0.137). TMVS were significantly lower in late (>&#x2009;20-30&#xa0;minutes) vs. early (10-20&#xa0;minutes) endoscopy sub-group (8 [7-11] vs, 9 ([7-11], p&#x2009;=&#x2009;0.001). However, TMVS were similar between group B and group D in early endoscopy group (p&#x2009;=&#x2009;0.451). There was no significant difference in the lesion detection rate among the different premedication drugs (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSIONS: Premedication with simethicone or combination (simethicone and NAC) significantly improves mucosal visibility during EGD. If early endoscopy is indicated, simethicone provides similar mucosal visibility and may be an effective alternative to combined premedication.<br><br>TRIAL REGISTRATION: NCT05951712.}, }
@article {pmid37845590, year = {2024}, author = {Dai, Y and Sang, XB and Bai, WP}, title = {N-acetylcysteine and Hydroxychloroquine Ameliorate ADMA-Induced Fetal Growth Restriction in Mice via Regulating Oxidative Stress and Autophagy.}, journal = {Reproductive sciences (Thousand Oaks, Calif.)}, volume = {31}, number = {3}, pages = {779-790}, pmid = {37845590}, issn = {1933-7205}, support = {2021-q03//Youth Fund of Beijing Shijitan Hospital/ ; }, mesh = {Humans ; Pregnancy ; Mice ; Female ; Animals ; *Placenta/metabolism ; *Acetylcysteine/pharmacology/therapeutic use/metabolism ; Fetal Growth Retardation/chemically induced/drug therapy/metabolism ; Hydroxychloroquine/pharmacology/therapeutic use/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Oxidative Stress ; TOR Serine-Threonine Kinases/metabolism ; Autophagy ; Arginine/*analogs &amp; derivatives ; }, abstract = {Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR.}, }
@article {pmid37841396, year = {2023}, author = {Liu, J and Su, H and Jin, X and Wang, L and Huang, J}, title = {The effects of N-acetylcysteine supplement on metabolic parameters in women with polycystic ovary syndrome: a systematic review and meta-analysis.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1209614}, pmid = {37841396}, issn = {2296-861X}, abstract = {OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common endocrine disease, often accompanied by metabolic disorders. Metformin, as an insulin sensitizer, is widely used to improve the metabolic function of PCOS, but may have gastrointestinal side effects. Emerging evidence suggests that N-acetylcysteine (NAC) improves metabolic parameters in PCOS and may be a potential alternative to metformin.<br><br>METHODS: We searched four online databases, PubMed, Embase, Web of Science, and Cochrane Library, from inception to April 1, 2023. The I[2] statistic and Cochrane's Q test were employed to determine heterogeneity between studies, with an I[2] value >50% or p&#x2009;<&#x2009;0.1 considered significant. The data were expressed as standardized mean differences and corresponding 95% confidence intervals.<br><br>RESULTS: A total of 11 randomized controlled trials were included in the final analysis, including 869 women with PCOS. The results showed that NAC caused more changes in body mass index (SMD: -0.16, 95% CI: -0.40 to 0.08), body weight (SMD: -0.25, 95% CI: -0.50 to 0.00), fasting insulin (SMD: -0.24, 95% CI: -0.53 to 0.06), ratio of fasting blood glucose to fasting insulin (SMD: 0.38, 95% CI: -0.33 to 1.08), total cholesterol (SMD: -0.11, 95% CI: -0.39 to 0.17), triglycerides (SMD: -0.18, 95% CI: -0.63 to 0.28), and low-density lipoprotein (SMD: -0.09, 95% CI: -0.51 to 0.33) compared with metformin. Compared with metformin or placebo, NAC significantly reduced fasting blood-glucose levels (SMD: -0.23, 95% CI: -0.43 to -0.04; SMD: -0.54, 95% CI: -1.03 to -0.05, respectively). In addition, NAC significantly reduced total cholesterol (SMD: -0.74, 95% CI: -1.37 to -0.12), and this effect was observed when NAC was compared with placebo. However, NAC reduced HDL levels in women with PCOS compared with metformin (SMD: -0.14, 95% CI: -0.42 to 0.14).<br><br>CONCLUSION: This study suggests that NAC is effective in improving metabolic parameters in PCOS and may be a promising nutritional supplement for the treatment of PCOS.Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=415172, identifier CRD42022339171.}, }
@article {pmid37839787, year = {2023}, author = {Zhu, S and Wu, H and Cui, H and Guo, H and Ouyang, Y and Ren, Z and Deng, Y and Geng, Y and Ouyang, P and Wu, A and Deng, J and Deng, H}, title = {Induction of mitophagy via ROS-dependent pathway protects copper-induced hypothalamic nerve cell injury.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {181}, number = {}, pages = {114097}, doi = {10.1016/j.fct.2023.114097}, pmid = {37839787}, issn = {1873-6351}, mesh = {Male ; Mice ; Animals ; *Mitophagy ; Copper/toxicity ; Reactive Oxygen Species/metabolism ; *Mitochondrial Diseases ; Neurons/metabolism ; }, abstract = {Copper (Cu) is one of the essential trace elements in the body, but excessive amounts of Cu harm multiple organs and tissues such as liver, kidneys, testis, ovaries, and brain. However, the mechanism of hypothalamic neurotoxicity induced by Cu is still unknown. This study examined the relationship between reactive oxygen species (ROS) and mitophagy in mouse hypothalamus treated with high Cu. The results demonstrated that high levels of copper sulfate (CuSO4) could cause histopathological and neuronal changes in the mouse hypothalamus, produce a large amount of ROS, induce mitophagy, and lead to an imbalance of mitochondrial fusion/fission. The main manifestations are an increase in the expression levels of LC3-II/LC3-I, p62, DRP1, and FIS1, and a decrease in the expression levels of MFN1 and MFN2. Cu can induce mitophagy also was confirmed by LC3 co-localization with TOMM20 (mitochondrial marker). Next, the effect of oxidative stress on CuSO4-induced mitophagy was demonstrated. The results showed that ROS inhibitor N-acetylcysteine (NAC) diminished CuSO4-induced mitophagy and reversed the disturbance of mitochondrial dynamics. Additionally, a study was carried out to evaluate the role of mitophagy in CuSO4-induced hypothalamic injury. The inhibition of mitophagy using mitophagy inhibitor (Mdivi-1) decreased cell viability and promoted CuSO4-inhibited mitochondrial fusion. The aforementioned results suggested that CuSO4 induced mitophagy via oxidative stress in N38 cells and mouse hypothalamus, and that the activation of mitophagy might generate protective mechanisms by alleviating Cu-induced mitochondrial dynamics disorder. This study provided a novel approach and theoretical basis for studying and preventing Cu neurotoxicity.}, }
@article {pmid37836642, year = {2023}, author = {Samide, A and Dobriţescu, A and Tigae, C and Spînu, CI and Oprea, B}, title = {Experimental and Computational Study on Inhibitory Effect and Adsorption Properties of N-Acetylcysteine Amino Acid in Acid Environment.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {19}, pages = {}, pmid = {37836642}, issn = {1420-3049}, abstract = {Potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) were applied to study the inhibitory effect of N-acetylcysteine (NAC) on corrosion inhibition of carbon steel in hydrochloric acid solution. N-acetylcysteine influenced the iron dissolution to a greater extent than the hydrogen evolution reaction acting as a mixed inhibitor, predominantly anodic. The charge transfer resistance (Rct) gradually increased with the inhibitor concentration. From both methods, the inhibition efficiency (IE) reached a value of 89 ± 1% and NAC adsorption followed the Temkin isotherm. The value of adsorption Gibbs energy (ΔGadso), around -35 kJ mol[-1], indicated a spontaneous adsorption and mixed action mechanism, with NAC chemical adsorption prevailing over physical one. New data will be reported by the computational study, that was performed using the density functional theory (DFT) method in aqueous phase. Quantum chemical descriptors were determined by B3LYP theory level with 6-31G+(d) basis set. Metropolis Monte Carlo atomistic simulation was used to reveal the adsorption configuration and interactions between acetylcysteine molecules and the carbon steel surface. Theoretical results were consistent with the experimental data, showing that the inhibitor action mechanism consisted of mainly chemisorption of its molecules on the carbon steel surface accompanied by van der Waals forces and electrostatic interactions.}, }
@article {pmid37836605, year = {2023}, author = {Doroudian, M and Thibault, ME and Gailer, J}, title = {N-Acetylcysteine Displaces Glutathionyl-Moieties from Hg[2+] and MeHg[+] to Form More Hydrophobic Complexes at Near-Physiological Conditions.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {19}, pages = {}, pmid = {37836605}, issn = {1420-3049}, mesh = {Animals ; Humans ; Acetylcysteine ; *Methylmercury Compounds/chemistry ; *Mercury/analysis ; Glutathione/analysis ; Sulfhydryl Compounds ; Mammals ; }, abstract = {The anthropogenic release of Hg is associated with an increased human exposure risk. Since Hg[2+] and MeHg[+] have a high affinity for thiols, their interaction with L-glutathione (GSH) within mammalian cells is fundamentally involved in their toxicological chemistry and excretion. To gain insight into the interaction of these mercurials with multiple small molecular weight thiols, we have investigated their competitive interactions with GSH and N-acetylcysteine (NAC) at near-physiological conditions, using a liquid chromatographic approach. This approach involved the injection of each mercurial onto a reversed-phase (RP)-HPLC column (37 °C) using a PBS buffer mobile phase containing 5.0 mM GSH to simulate cytosolic conditions with Hg being detected in the column effluent by an inductively coupled plasma atomic emission spectrometer (ICP-AES). When the 5.0 mM GSH mobile phase was amended with up to 10 mM NAC, gradually increasing retention times of both mercurials were observed. To explain this behavior, the experiment with 5.0 mM NAC and 5.0 mM GSH was replicated using 50 mM Tris buffer (pH 7.4), and the Hg-containing fractions were analyzed by electrospray ionization mass spectrometry. The results revealed the presence of Hg(GS)(NAC) and Hg(NAC)2 for Hg[2+] and MeHg(GS) and MeHg(NAC) for MeHg[+], which suggests that the coordination/displacement of GS-moieties from each mercurial by the more hydrophobic NAC can explain their retention behavior. Since the biotransformations of both mercurials were observed at near-physiological conditions, they are of toxicological relevance as they provide a biomolecular explanation for some results that were obtained when animals were administered with each mercurial and NAC.}, }
@article {pmid37835464, year = {2023}, author = {Bryan, A and Pingali, P and Joslyn, M and Li, H and Bernas, T and Koblinski, J and Landry, J and Lee, WS and Patel, B and Neuwelt, A}, title = {High-Dose Acetaminophen with N-acetylcysteine Rescue Inhibits M2 Polarization of Tumor-Associated Macrophages.}, journal = {Cancers}, volume = {15}, number = {19}, pages = {}, pmid = {37835464}, issn = {2072-6694}, support = {IK2 BX004914/BX/BLRD VA/United States ; P30 CA016059/CA/NCI NIH HHS/United States ; }, abstract = {High-dose acetaminophen (AAP) with N-acetylcysteine (NAC) rescue is among the few treatments that has shown activity in phase I trials without achieving dose-limiting toxicity that has not progressed to evaluation in later line studies. While the anti-tumor effects of AAP/NAC appear not to be mediated by glutathione depletion and free radical injury, the mechanism of anti-tumor effects of AAP/NAC has not been definitively characterized. In vitro, the effects of AAP/NAC were evaluated on bone marrow derived macrophages. Effects of AAP on IL-4/STAT6 (M2) or IFN/LPS/STAT1 (M1) signaling and downstream gene and protein expression were studied. NAC reversed the AAP toxicity in the normal liver but did not reverse AAP cytotoxicity against tumor cells in vitro. AAP/NAC selectively inhibited IL-4-induced STAT6 phosphorylation but not IFN/LPS-induced STAT1 phosphorylation. Downstream, AAP/NAC inhibited IL-4 induction of M2-associated genes and proteins but did not inhibit the IFN/LPS induction of M1-associated genes and proteins. In vivo, AAP/NAC inhibited tumor growth in EF43.fgf4 and 4T1 triple-negative breast tumors. Flow cytometry of tumor-associated macrophages revealed that AAP/NAC selectively inhibited M2 polarization. The anti-tumor activity of high-dose AAP/NAC is lost in macrophage-depleted mouse syngeneic tumor models, suggesting a macrophage-dependent mechanism of action. In conclusion, our study is the first to show that high-dose AAP/NAC has profound effects on the tumor immune microenvironment that facilitates immune-mediated inhibition of tumor growth.}, }
@article {pmid37834105, year = {2023}, author = {Gan, P and Li, P and Zhang, X and Li, H and Ma, S and Zong, D and He, C}, title = {Comparative Transcriptomic and Metabolomic Analyses of Differences in Trunk Spiral Grain in Pinus yunnanensis.}, journal = {International journal of molecular sciences}, volume = {24}, number = {19}, pages = {}, pmid = {37834105}, issn = {1422-0067}, support = {YUWR-CYJS-2020-018//Yunnan Provincial "Ten-Thousand Program" for Leading Industry Innovation/ ; 202005AF150020//Applied Basic Research Programs of Yunnan Provincial Expert Workstation/ ; }, mesh = {*Transcriptome ; *Pinus/genetics ; Gene Expression Profiling ; Metabolomics ; Metabolome ; Edible Grain/genetics ; Deoxyuridine ; Gene Expression Regulation, Plant ; }, abstract = {Having a spiral grain is considered to be one of the most important wood properties influencing wood quality. Here, transcriptome profiles and metabolome data were analyzed in the straight grain and twist grain of Pinus yunnanensis. A total of 6644 differential expression genes were found between the straight type and the twist type. A total of 126 differentially accumulated metabolites were detected. There were 24 common differential pathways identified from the transcriptome and metabolome, and these pathways were mainly annotated in ABC transporters, arginine and proline metabolism, flavonoid biosynthesis, isoquinoline alkaloid biosynthesis, linoleic acid metabolism, phenylpropanoid, tryptophan metabolism, etc. A weighted gene coexpression network analysis showed that the lightblue4 module was significantly correlated with 2'-deoxyuridine and that transcription factors (basic leucine zipper (bZIP), homeodomain leucine zipper (HD-ZIP), basic helix-loop-helix (bHLH), p-coumarate 3-hydroxylase (C3H), and N-acetylcysteine (NAC)) play important roles in regulating 2'-deoxyuridine, which may be involved in the formation of spiral grains. Meanwhile, the signal transduction of hormones may be related to spiral grain, as previously reported. ARF7 and MKK4_5, as indoleacetic acid (IAA)- and ethylene (ET)-related receptors, may explain the contribution of plant hormones in spiral grain. This study provided useful information on spiral grain in P. yunnanensis by transcriptome and metabolome analyses and could lay the foundation for future molecular breeding.}, }
@article {pmid37827291, year = {2023}, author = {Hu, TH and Wu, JC and Huang, ST and Chu, TH and Han, AJ and Shih, TW and Chang, YC and Yang, SM and Ko, CY and Lin, YW and Kung, ML and Tai, MH}, title = {HDGF stimulates liver tumorigenesis by enhancing reactive oxygen species generation in mitochondria.}, journal = {The Journal of biological chemistry}, volume = {299}, number = {11}, pages = {105335}, pmid = {37827291}, issn = {1083-351X}, mesh = {Animals ; Mice ; *Carcinoma, Hepatocellular/genetics/pathology ; Reactive Oxygen Species ; Carcinogenesis/genetics ; }, abstract = {Hepatoma-derived growth factor (HDGF) overexpression and uncontrolled reactive oxygen species (ROS) accumulation are involved in malignant transformation and poor prognosis in various types of cancer. However, the interplay between HDGF and ROS generation has not been elucidated in hepatocellular carcinoma. Here, we first analyzed the profile of HDGF expression and ROS production in newly generated orthotopic hepatomas by ultrasound-guided implantation. In situ superoxide detection showed that HDGF-overexpressing hepatomas had significantly elevated ROS levels compared with adjacent nontumor tissues. Consistently, liver tissues from HDGF-deficient mice exhibited lower ROS fluorescence than those from age- and sex-matched WT mice. ROS-detecting fluorescent dyes and flow cytometry revealed that recombinant HDGF (rHDGF) stimulated the production of superoxide anion, hydrogen peroxide, and mitochondrial ROS generation in cultured hepatoma cells in a dose-dependent manner. In contrast, the inactive Ser103Ala rHDGF mutant failed to promote ROS generation or oncogenic behaviors. Seahorse metabolic flux assays revealed that rHDGF dose dependently upregulated bioenergetics through enhanced basal and total oxygen consumption rate, extracellular acidification rate, and oxidative phosphorylation in hepatoma cells. Moreover, antioxidants of N-acetyl cysteine and MitoQ treatment significantly inhibited HDGF-mediated cell proliferation and invasive capacity. Genetic silencing of superoxide dismutase 2 augmented the HDGF-induced ROS generation and oncogenic behaviors of hepatoma cells. Finally, genetic knockdown nucleolin (NCL) and antibody neutralization of surface NCL, the HDGF receptor, abolished the HDGF-induced increase in ROS and mitochondrial energetics. In conclusion, this study has demonstrated for the first time that the HDGF/NCL signaling axis induces ROS generation by elevating ROS generation in mitochondria, thereby stimulating liver carcinogenesis.}, }
@article {pmid37823177, year = {2023}, author = {Haugsten Hansen, M and Sadredini, M and Hasic, A and Eriksen, M and Stokke, MK}, title = {Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1223496}, pmid = {37823177}, issn = {2297-055X}, abstract = {BACKGROUND: Arrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious.<br><br>METHODS: MI was induced in 7 male and 7 female pigs (Norwegian landrace, 35-40&#x2005;kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90&#x2005;min, before observation for 1&#x2005;h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70&#x2005;min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60&#x2005;min of ischemia, and 5 and 60&#x2005;min of reperfusion. ECG and invasive blood pressure were monitored throughout.<br><br>RESULTS: The protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5&#x2005;min of reperfusion compared to baseline, but not at 60&#x2005;min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion.<br><br>CONCLUSION: Myocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias.}, }
@article {pmid37820773, year = {2023}, author = {Gustafson, &#xc5; and Elfsmark, L and Karlsson, T and Jonasson, S}, title = {N-acetyl cysteine mitigates lung damage and inflammation after chlorine exposure in vivo and ex vivo.}, journal = {Toxicology and applied pharmacology}, volume = {479}, number = {}, pages = {116714}, doi = {10.1016/j.taap.2023.116714}, pmid = {37820773}, issn = {1096-0333}, mesh = {Mice ; Animals ; Swine ; *Acetylcysteine/pharmacology/therapeutic use ; Chlorine/toxicity ; *Lung Injury/chemically induced/drug therapy/prevention &amp; control ; Antioxidants/pharmacology ; Lung ; Inflammation/chemically induced/drug therapy ; Inflammation Mediators ; }, abstract = {The objective of this study was to explore the effects of antioxidant treatments, specifically N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), in a mouse model of chlorine (Cl2)-induced lung injury. Additionally, the study aimed to investigate the utility of pig precision-cut lung slices (PCLS) as an ex vivo alternative for studying the short-term effects of Cl2 exposure and evaluating antioxidant treatments. The toxicological responses were analyzed in Cl2-exposed mice (inflammation, airway hyperresponsiveness (AHR)) and PCLS (viability, cytotoxicity, inflammatory mediators). Airways contractions were assessed using a small ventilator for mice and electric-field stimulation (EFS) for PCLS. Antioxidant treatments were administered to evaluate their effects. In Cl2-exposed mice, NAC treatment did not alleviate AHR, but it did reduce the number of neutrophils in bronchoalveolar lavage fluid and inflammatory mediators in lung tissue. In PCLS, exposure to Cl2 resulted in concentration-dependent toxicity, impairing the lung tissue's ability to respond to EFS-stimulation. NAC treatment increased viability, mitigated the toxic responses caused by Cl2 exposure, and maintained contractility comparable to unexposed controls. Interestingly, NACA did not provide any additional treatment effect beyond NAC in both models. In conclusion, the establishment of a pig model for Cl2-induced lung damage supports further investigation of NAC as a potential treatment. However, the lack of protective effects on AHR after NAC treatment in mice suggests that NAC alone may not be sufficient as a complete treatment for Cl2 injuries. Optimization of existing medications with a polypharmacy approach may be more successful in addressing the complex sequelae of Cl2-induced lung injury.}, }
@article {pmid37817304, year = {2024}, author = {Ezhilarasan, D and Shree Harini, K and Karthick, M and Selvaraj, C}, title = {Ethyl gallate concurrent administration protects against acetaminophen-induced acute liver injury in mice: An in vivo and in silico approach.}, journal = {Chemical biology &amp; drug design}, volume = {103}, number = {1}, pages = {e14369}, doi = {10.1111/cbdd.14369}, pmid = {37817304}, issn = {1747-0285}, mesh = {Mice ; Animals ; *Antioxidants/pharmacology/therapeutic use/metabolism ; Acetaminophen/toxicity ; Liver ; Gallic Acid/metabolism/pharmacology ; Anti-Inflammatory Agents/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Oxidative Stress ; }, abstract = {Acetaminophen (APAP) in high doses causes acute liver injury and acute liver failure. Ethyl gallate (EG) is a natural polyphenol, possessing antioxidant, anti-inflammatory, and anti-microbial properties. Therefore, in this study, we evaluated the protective role of EG against APAP-induced acute liver injury in mice. Acute liver injury was induced by a single dose of APAP (400 mg/kg., i.p.). In separate groups, EG (10 mg/kg), EG (20 mg/kg), and N-acetylcysteine (NAC; 1200 mg/kg., i.p.) were administered concurrently with APAP. The mice were sacrificed after 24 h of treatment. Liver marker enzymes of hepatotoxicity, antioxidant markers, inflammatory markers, and histopathological studies were done. APAP administration caused a significant elevation of marker enzymes of hepatotoxicity and lipid peroxidation. APAP administration also decreased enzymic and nonenzymic antioxidants. Acute APAP intoxication induced nuclear factor κ B, tumor necrosis factor-α, interleukin-1, p65, and p52 and downregulated IκB gene expressions. Our histopathological studies have confirmed the presence of centrilobular necrosis, 24 h after APAP intoxication. All the above abnormalities were significantly inhibited in groups of mice that were concurrently administered with APAP + EG and APAP + NAC. Our in silico analysis further confirms that hydroxyl groups of EG interact with the above inflammatory proteins at the 3,4,5-trihydroxybenzoic acid region. These effects of EG against APAP-induced acute liver injury could be attributed to its antioxidative, free radical scavenging, and anti-inflammatory potentials. Therefore, this study suggests that EG can be an efficient therapeutic approach to protect the liver from APAP intoxication.}, }
@article {pmid37814098, year = {2023}, author = {Chitolina, R and Reis, CG and Stahlhofer-Buss, T and Linazzi, A and Benvenutti, R and Marcon, M and Herrmann, AP and Piato, A}, title = {Effects of N-acetylcysteine and acetyl-L-carnitine on acute PTZ-induced seizures in larval and adult zebrafish.}, journal = {Pharmacological reports : PR}, volume = {75}, number = {6}, pages = {1544-1555}, pmid = {37814098}, issn = {2299-5684}, mesh = {Animals ; Humans ; Adult ; *Zebrafish ; Acetylcysteine/therapeutic use ; Acetylcarnitine/adverse effects ; Larva ; Pentylenetetrazole/toxicity ; Seizures/chemically induced/drug therapy ; *Epilepsy/drug therapy ; Anticonvulsants/therapeutic use ; Disease Models, Animal ; }, abstract = {BACKGROUND: Epilepsy is a prevalent neurological disease, affecting approximately 1-2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to current pharmacological treatments. Consequently, exploring alternative therapeutic options for managing this condition is crucial. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of glutamatergic neurotransmission.<br><br>METHODS: This study aimed to assess the effects of varying concentrations (0.1, 1.0, and 10&#xa0;mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances.<br><br>RESULTS: Our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and increased latencies to higher scores of epileptic seizures.<br><br>CONCLUSION: Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.}, }
@article {pmid37812881, year = {2023}, author = {Zeng, Z and Li, T and Liu, X and Ma, Y and Luo, L and Wang, Z and Zhao, Z and Li, H and He, X and Zeng, H and Tao, Y and Chen, Y}, title = {DNA dioxygenases TET2 deficiency promotes cigarette smoke induced chronic obstructive pulmonary disease by inducing ferroptosis of lung epithelial cell.}, journal = {Redox biology}, volume = {67}, number = {}, pages = {102916}, pmid = {37812881}, issn = {2213-2317}, mesh = {Animals ; Humans ; Mice ; *Cigarette Smoking/adverse effects ; *Dioxygenases/metabolism/pharmacology ; DNA/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Epithelial Cells/metabolism ; *Ferroptosis/genetics ; Inflammation/metabolism ; Lung/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; *Pulmonary Disease, Chronic Obstructive/chemically induced/genetics ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality currently. Long-term exposure of cigarette smoke (CS) inducing persistent inflammation, small airway remodeling and emphysematous lung are the distinguishing features of COPD. Ferroptosis, occurred in lung epithelial cells has recently been reported to be associated with COPD pathogenesis. DNA dioxygenase ten-eleven translocation 2 (TET2) is an important demethylase and its genetic mutation is associated with low forced expiratory volume in 1 s (FEV1) of lung function. However, its role in COPD remains elusive. Here, we found that TET2 regulates CS induced lipid peroxidation through demethylating glutathione peroxidase 4 (GPx4), thus alleviating airway epithelial cell ferroptosis in COPD. TET2 protein levels were mainly reduced in the airway epithelia of COPD patients, mouse models, and CS extract-treated bronchial epithelial cells. The deletion of TET2 triggered ferroptosis and further exaggerated CS-induced airway remodeling, inflammation, and emphysema in vivo. Moreover, we demonstrated that TET2 silencing intensified ferroptosis, while TET2 overexpression inhibited ferroptosis in airway epithelial cell treated with CSE. Mechanically, TET2 protected airway epithelial cells from CS-induced lipid peroxidation and ferroptosis through demethylating the promoter of glutathione peroxidase 4 (GPx4). Finally, co-administration of methylation inhibitor 5'-aza-2'-deoxycytidine (5-AZA) and the antioxidant N-acetyl-cysteine (NAC) have more protective effects on CS-induced COPD than either administration alone. Overall, our study reveals that TET2 is an essential modulator in the lipid peroxidation and ferroptosis of airway epithelial cell, and could act as a potential therapeutic target for CS-induced COPD.}, }
@article {pmid37810545, year = {2023}, author = {Brown, C and Wang, J and Jiang, H and Elias, MF}, title = {Homocysteine Reduction for Stroke Prevention: Regarding the Recent AHA/ASA 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack.}, journal = {Pharmacogenomics and personalized medicine}, volume = {16}, number = {}, pages = {895-900}, pmid = {37810545}, issn = {1178-7066}, abstract = {Reduction of secondary ischemic stroke risk following an initial stroke is an important goal. The 2021 Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack assembles opportunities for up to 80% secondary stroke reduction. Homocysteine reduction was not included in the recommendations. The reduction of homocysteine with low doses of folic acid has been shown to reduce ischemic stroke and all stroke. This has been obscured by studies using high doses of folic acid and cyanocobalamin in patients with renal failure and Methylenetetrahydrofolate reductase (MTHFR) polymorphisms. The confounding impacts of high dose folic acid and cyanocobalamin toxicity in renal failure and MTHFR C677T subgroups are discussed. New studies show that their toxicity is due to non-bioequivalence to the natural dietary forms, L-methylfolate and methylcobalamin. Low doses of folic acid and cyanocobalamin are safer than high doses for these subpopulations. Even lower toxicity with greater effectiveness for reducing homocysteine is seen with L-methylfolate and methylcobalamin, which are safe at high doses. Retinal vascular imaging is a noninvasive method for evaluating central nervous system (CNS) microangiopathy. A formulation containing l-methylfolate and methylcobalamin has been shown to reduce homocysteine and increase perfusion in diabetic retinopathy. This supports homocysteine intervention for CNS ischemia. Future ischemic stroke intervention studies could benefit from monitoring retinal perfusion to estimate the impact of risk reduction strategies. The omission of a recommendation for homocysteine and secondary stroke reduction through the use of B vitamins should be reconsidered in light of re-analysis of major B vitamin intervention studies and new technologies for monitoring CNS perfusion. We recommend revision of the 2021 Guideline to include homocysteine reduction with low doses of folic acid and cyanocobalamin, or better yet, L-methylfolate and methylcobalamin, making a good clinical guideline better.}, }
@article {pmid37804692, year = {2023}, author = {Guo, Y and Huang, C and Xu, C and Qiu, L and Yang, F}, title = {Dysfunction of ZNF554 promotes ROS-induced apoptosis and autophagy in Fetal Growth Restriction via the p62-Keap1-Nrf2 pathway.}, journal = {Placenta}, volume = {143}, number = {}, pages = {34-44}, doi = {10.1016/j.placenta.2023.09.009}, pmid = {37804692}, issn = {1532-3102}, mesh = {Female ; Humans ; Pregnancy ; Antioxidants/metabolism ; *Apoptosis/genetics ; Autophagy ; Cell Line, Tumor ; *Fetal Growth Retardation/genetics/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; *Placenta/metabolism ; Reactive Oxygen Species/metabolism ; Trophoblasts/metabolism ; *Kruppel-Like Transcription Factors/genetics/metabolism ; }, abstract = {Fetal growth restriction (FGR) is one of the most common complications of an abnormal pregnancy. Placental dysplasia has been established as a significant contributing factor to FGR. Zinc finger protein 554 (ZNF554) is a member of the Krüppel-associated box domain zinc finger protein subfamily, primarily expressed in the placenta and essential for maintaining normal pregnancy outcomes. However, its precise role in FGR remains uncertain. In this study, we confirmed that ZNF554 was low expressed in the placenta of the FGR pregnancy. To further elucidate the impact of ZNF554 on trophoblasts, we conducted experiments using siRNA and overexpression plasmids on HTR8/SVneo and JEG3 cells. Our findings revealed that silencing ZNF554 increased apoptosis and inhibited migration and invasion, while overexpression reduced apoptosis and promoted migration and invasion. Notably, ZNF554 knockdown decreased cellular antioxidant capacity and elevated the production of reactive oxygen species (ROS). Conversely, ZNF554 activated the nuclear factor E2-related factor 2 (NRF2) signaling pathway, exerting its antioxidant effects. Additionally, ZNF554 knockdown promoted cellular autophagy by suppressing P62 and enhancing LC3-II/LC3-I expression. Importantly, the antioxidant N-acetylcysteine (NAC) partially mitigated the impact of ZNF554 knockdown on mitochondrial ROS in trophoblast cells and subsequent effects on cellular autophagy and apoptosis. In conclusion, our results suggest that ZNF554 plays a pivotal role in modulating trophoblast cell invasion and may serve as a prognostic marker and potential therapeutic target for FGR.}, }
@article {pmid37801672, year = {2024}, author = {Orhan, &#xd6; and Talay, MN}, title = {Methemoglobinemia and acute ıntravascular hemolysis after naphthalene poisoning in a pediatric patient.}, journal = {Archivos argentinos de pediatria}, volume = {122}, number = {2}, pages = {e202310095}, doi = {10.5546/aap.2023-10095.eng}, pmid = {37801672}, issn = {1668-3501}, mesh = {Humans ; Male ; Child ; Infant ; Child, Preschool ; Hemolysis ; *Methemoglobinemia/chemically induced/diagnosis ; *Anemia, Hemolytic/diagnosis ; Ascorbic Acid ; Naphthalenes ; }, abstract = {Poisoning by naphthalene is uncommon in children. It is a type of poisoning brought on by ingesting, inhaling, or coming into touch with naphthalene-containing substances on the skin. Patients typically present with an initial onset of dark brown urine, watery diarrhea, and bile vomit. The signs include fever, tachycardia, hypotension, and low pulse oximetry readings even with oxygen support. Hemolytic anemia, methemoglobinemia, renal failure, and hyperbilirubinemia are all detected in blood tests. Erythrocyte transfusion, ascorbic acid, methylene blue, and N-acetylcysteine (NAC) therapies are provided to inpatients in addition to symptomatic treatment. We present a 23-month-old male patient who developed methemoglobinemia and acute ıntravascular hemolysis, who was followed up in the intensive care unit for five days due to naphthalene intoxication. Although naphthalene poisoning is very rare, it should be known that it has fatal consequences, and more care should be taken in its use and sale.}, }
@article {pmid37798944, year = {2024}, author = {Vélez, EJ and Schnebert, S and Goguet, M and Balbuena-Pecino, S and Dias, K and Beauclair, L and Fontagné-Dicharry, S and Véron, V and Depincé, A and Beaumatin, F and Herpin, A and Seiliez, I}, title = {Chaperone-mediated autophagy protects against hyperglycemic stress.}, journal = {Autophagy}, volume = {20}, number = {4}, pages = {752-768}, pmid = {37798944}, issn = {1554-8635}, mesh = {Animals ; *Chaperone-Mediated Autophagy/drug effects/physiology/genetics ; *Lysosomes/metabolism/drug effects ; *Oncorhynchus mykiss/metabolism ; *Glucose/metabolism ; Hyperglycemia/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Lysosomal-Associated Membrane Protein 2/metabolism/genetics ; Autophagy/physiology/genetics/drug effects ; Molecular Chaperones/metabolism ; Humans ; }, abstract = {Chaperone-mediated autophagy (CMA) is a major pathway of lysosomal proteolysis critical for cellular homeostasis and metabolism, and whose defects have been associated with several human pathologies. While CMA has been well described in mammals, functional evidence has only recently been documented in fish, opening up new perspectives to tackle this function under a novel angle. Now we propose to explore CMA functions in the rainbow trout (RT, Oncorhynchus mykiss), a fish species recognized as a model organism of glucose intolerance and characterized by the presence of two paralogs of the CMA-limiting factor Lamp2A (lysosomal associated membrane protein 2A). To this end, we validated a fluorescent reporter (KFERQ-PA-mCherry1) previously used to track functional CMA in mammalian cells, in an RT hepatoma-derived cell line (RTH-149). We found that incubation of cells with high-glucose levels (HG, 25 mM) induced translocation of the CMA reporter to lysosomes and/or late endosomes in a KFERQ- and Lamp2A-dependent manner, as well as reduced its half-life compared to the control (5 mM), thus demonstrating increased CMA flux. Furthermore, we observed that activation of CMA upon HG exposure was mediated by generation of mitochondrial reactive oxygen species, and involving the antioxidant transcription factor Nfe2l2/Nrf2 (nfe2 like bZIP transcription factor 2). Finally, we demonstrated that CMA plays an important protective role against HG-induced stress, primarily mediated by one of the two RT Lamp2As. Together, our results provide unequivocal evidence for CMA activity existence in RT and highlight both the role and regulation of CMA during glucose-related metabolic disorders.Abbreviations: AREs: antioxidant response elements; CHC: α-cyano -4-hydroxycinnamic acid; Chr: chromosome; CMA: chaperone-mediated autophagy; CT: control; DMF: dimethyl fumarate; Emi: endosomal microautophagy; HG: high-glucose; HMOX1: heme oxygenase 1; H2O2: hydrogen peroxide; KFERQ: lysine-phenylalanine-glutamate-arginine-glutamine; LAMP1: lysosomal associated membrane protein 1; LAMP2A: lysosomal associated membrane protein 2A; MCC: Manders' correlation coefficient; Manders' correlation coefficient Mo: morpholino oligonucleotide; NAC: N-acetyl cysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; PA-mCherry: photoactivable mCherry; PCC: Pearson's correlation coefficient; ROS: reactive oxygen species; RT: rainbow trout; siRNAs: small interfering RNAs; SOD: superoxide dismutase; Tsg101: tumor susceptibility 101; TTFA: 2-thenoyltrifluoroacetone; WGD: whole-genome duplication.}, }
@article {pmid37797590, year = {2023}, author = {Palkovits, S and Schlatter, A and Ruiss, M and Georgiev, S and Zeilinger, J and Pilwachs, C and Findl, O}, title = {Occurrence of Corneal Staining after Cataract Surgery with and without Chitosan-N-Acetylcysteine Eye Drops.}, journal = {Ophthalmic research}, volume = {66}, number = {1}, pages = {1293-1299}, pmid = {37797590}, issn = {1423-0259}, mesh = {Humans ; Ophthalmic Solutions ; Acetylcysteine/therapeutic use/pharmacology ; *Chitosan ; *Cataract Extraction/adverse effects ; *Cataract ; *Dry Eye Syndromes ; }, abstract = {INTRODUCTION: The objective of this study was to evaluate the prevalence of ocular surface damage assessed by corneal staining scores right after cataract surgery and whether it can be prevented using chitosan-N-acetylcysteine (C-NAC) eye drops.<br><br>METHODS: We included patients scheduled for routine cataract surgery. Each patient was randomly assigned to one of three groups. Patients in group 1 underwent routine cataract surgery with no additional eye drops. In group 2, patients received C-NAC eye drops after cataract surgery, and in group 3, C-NAC was applied both before and after surgery. Both groups continued the treatment once daily for 4 days. Ocular surface alteration was assessed using the National Eye Institute (NEI) score, and the visual analog scale (VAS) was used to evaluate subjective complaints.<br><br>RESULTS: Thirty-six patients were included in the final analyses. One hour after cataract surgery, a statistically significant increase in corneal fluorescein staining was observed in all groups, which decreased again after 1 week. There was no significant difference between the groups 1 h after cataract surgery, though a tendency toward lower NEI scores was observed during this time point in group 3.<br><br>DISCUSSION: Cataract surgery induced ocular surface staining and subjective complaints after 1 h. However, the increase in VAS score was small and probably not clinically relevant. The application of perioperative C-NAC eye drops did reduce the rate of corneal staining after cataract surgery in a clinically relevant manner.}, }
@article {pmid37797457, year = {2023}, author = {Liu, F and Li, Y and Zhu, J and Li, Y and Zhu, D and Luo, J and Kong, L}, title = {γ-Glutamyltranspeptidase-Activated Near-Infrared fluorescent probe for visualization of Drug-Induced liver injury.}, journal = {Bioorganic chemistry}, volume = {141}, number = {}, pages = {106899}, doi = {10.1016/j.bioorg.2023.106899}, pmid = {37797457}, issn = {1090-2120}, mesh = {Humans ; *Fluorescent Dyes ; Cell Line ; Hep G2 Cells ; *Chemical and Drug Induced Liver Injury/diagnosis ; gamma-Glutamyltransferase ; Glutathione ; }, abstract = {Drug-induced liver injury (DILI), induced by overdose or chronic administration of drugs, has become the leading cause of acute liver failure. Therefore, an accurate diagnostic method for DILI is critical to improve treatment efficiency. The production of γ-glutamyltranspeptidase (GGT) is closely related to the progression of drug-induced hepatotoxicity. KL-Glu exhibits a prominent GGT-activated NIR fluorescence (734 nm) with a large Stokes shift (137 nm) and good sensitivity/selectivity, making it favorable for real-time detection of endogenous GGT activity. Using this probe, we evaluated the GGT up-regulation under the acetaminophen-induced liver injury model. Moreover, KL-Glu was successfully used to assess liver injury induced by the natural active ingredient triptolide and the effective amelioration upon treatment with N-acetyl cysteine (NAC) or Glutathione (GSH) in cells and in vivo by fluorescent trapping the fluctuation of GGT for the first time. Therefore, the fluorescent probe KL-Glu can be used as a potential tool to explore the function of GGT in the progression of DILI and for the early diagnosis and prognostic evaluation of DILI.}, }
@article {pmid37795573, year = {2023}, author = {Jung, IR and Ahima, RS and Kim, SF}, title = {Inositol polyphosphate multikinase modulates free fatty acids-induced insulin resistance in primary mouse hepatocytes.}, journal = {Journal of cellular biochemistry}, volume = {124}, number = {11}, pages = {1695-1704}, doi = {10.1002/jcb.30478}, pmid = {37795573}, issn = {1097-4644}, support = {R01 DK135751/DK/NIDDK NIH HHS/United States ; }, mesh = {Mice ; Animals ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Fatty Acids, Nonesterified/pharmacology ; *Insulin Resistance ; *Non-alcoholic Fatty Liver Disease ; Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism ; Insulin/pharmacology ; Hepatocytes/metabolism ; }, abstract = {Insulin resistance is a critical mediator of the development of nonalcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of NAFLD. Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of protein kinase B (Akt) phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-acetyl cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.}, }
@article {pmid37794966, year = {2023}, author = {Sohouli, MH and Eslamian, G and Malekpour Alamdari, N and Abbasi, M and Fazeli Taherian, S and Behtaj, D and Zand, H}, title = {Effects of N-acetylcysteine on aging cell and obesity complications in obese adults: a randomized, double-blind clinical trial.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1237869}, pmid = {37794966}, issn = {2296-861X}, abstract = {BACKGROUND: We decided to conduct this study with the aim of investigating the effects of N-Acetylcysteine (NAC) on obesity complications and senescence of visceral adipose tissue in obese adults.<br><br>METHODS AND ANALYSIS: The present study was conducted as a randomized clinical trial (RCT) (Clinical trial registry number: IRCT20220727055563N1) on 40 obese adults candidates for bariatric surgery, who were randomly assigned to receive 600&#x2009;mg of NAC (n&#x2009;=&#x2009;20) or placebo as a control (n&#x2009;=&#x2009;20) for 4&#x2009;weeks. During bariatric surgery, visceral adipose tissue was used to examine gene expression and senescence cells using SA-&#x3b2;-gal.<br><br>RESULTS: Our findings showed that intervention with NAC significantly reduces SA-&#x3b2;-gal activity (as a marker of senescence) and expression of p16 and interleukin 6 (IL-6) genes in the visceral adipose tissue compared to placebo in obese adults for 4&#x2009;weeks. In addition, our findings showed the potential and beneficial effect of NAC administration on reducing the levels of inflammatory factors including IL-6 and high-sensitivity C-reactive protein (hs-CRP), as well as the level of fasting blood sugar (FBS), homeostatic model assessment of insulin resistance (HOMA-IR), and insulin compared to placebo after adjusting for confounders. No significant effect was indicated on anthropometric factors and lipid profile.<br><br>CONCLUSION: Findings showed that NAC, in addition to having a potential beneficial effect on reducing some of the complications caused by obesity, seems to have synolytic/senomorphic potential as well.<br><br>CLINICAL TRIAL REGISTRATION: [https://clinicaltrials.gov/], identifier [IRCT20220727055563N1].}, }
@article {pmid37790388, year = {2023}, author = {DeLouise, L and Piraino, L and Chen, CY and Mereness, J and Dunman, P and Benoit, D and Ovitt, C}, title = {Identifying novel radioprotective drugs via salivary gland tissue chip screening.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37790388}, support = {F31 DE029658/DE/NIDCR NIH HHS/United States ; T32 ES007026/ES/NIEHS NIH HHS/United States ; UG3 DE027695/DE/NIDCR NIH HHS/United States ; }, abstract = {During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is FDA approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin were also tested to validate the ability of the assays to detect cell damage and radioprotection. All of the drugs except NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified exhibiting mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetic and pharmacodynamic data from the PubChem database. This led us to test Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited radioprotection equivalent to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with non-antioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.}, }
@article {pmid37790125, year = {2023}, author = {Zhu, R and Zheng, R and Deng, B and Liu, P and Wang, Y}, title = {Association of N-acetylcysteine use with contrast-induced nephropathy: an umbrella review of meta-analyses of randomized clinical trials.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1235023}, pmid = {37790125}, issn = {2296-858X}, abstract = {BACKGROUND: The effectiveness of N-acetylcysteine (NAC) in treating contrast-induced nephropathy (CIN) has been the subject of conflicting meta-analyses, but the strength of the evidence for these correlations between NAC use and CIN has not been measured overall.<br><br>OBJECTIVE: To evaluate the data from randomized clinical studies (RCTs) that examined the relationships between NAC use and CIN in meta-analyses.<br><br>METHODS: Between the creation of the database and April 2023, searches were made in PubMed, Cochrane Library, EMBASE, and Web of Science. N-acetylcysteine, contrast-induced nephropathy, or contrast-induced renal disease were among the search keywords used, along with terms including systematic review and meta-analysis. The Assessment of Multiple Systematic Reviews, version 2, which assigned grades of extremely low, low, moderate, or high quality to each meta-analysis's scientific quality, was used to evaluate each meta-analysis. The confidence of the evidence in meta-analyses of RCTs was evaluated using the Grading of Recommendation, Assessment, Development and Evaluations method, with evidence being rated as very low, low, moderate, or high.<br><br>RESULTS: In total, 493 records were screened; of those, 46 full-text articles were assessed for eligibility, and 12 articles were selected for evidence synthesis as a result of the screening process. Based on the pooled data, which was graded as moderate-quality evidence, it can be concluded that NAC can decrease CIN (OR 0.72, 95% CI 0.65-0.79, p&#x2009;<&#x2009;0.00001) and blood levels of serum creatinine (MD -0.09, 95% CI -0.17 to -0.01, p&#x2009;=&#x2009;0.03). In spite of this, there were no associations between NAC and dialysis requirement or mortality in these studies.<br><br>CONCLUSION: The results of this umbrella review supported that the renal results were enhanced by NAC. The association was supported by moderate-quality evidence.<br><br>[https://clinicaltrials.gov/], identifier [CRD42022367811].}, }
@article {pmid37782109, year = {2023}, author = {Pertiwi, H and Majdeddin, M and Degroote, J and Zhang, H and Michiels, J}, title = {N-acetyl-L-cysteine improves the performance of chronic cyclic heat-stressed finisher broilers but has no effect on tissue glutathione levels.}, journal = {British poultry science}, volume = {64}, number = {6}, pages = {751-762}, doi = {10.1080/00071668.2023.2264234}, pmid = {37782109}, issn = {1466-1799}, mesh = {Animals ; *Acetylcysteine ; Antioxidants/metabolism ; Chickens ; Cystine ; Glutathione ; Diet/veterinary ; *Amino Acids, Sulfur ; Heat-Shock Response ; Butyrates ; Dietary Supplements ; Animal Feed/analysis ; }, abstract = {1. It was hypothesised that dietary N-acetyl-L-cysteine (NAC) in feed, as a source of cysteine, could improve the performance of heat-stressed finisher broilers by fostering glutathione (GSH) synthesis. GSH is the most abundant intracellular antioxidant for which the sulphur amino acid cysteine is rate limiting for its synthesis.2. In the first experiment, four levels of NAC: 0, 500, 1000 and 2000 mg/kg were added to a diet with a suboptimal level of sulphur amino acids in the finisher phase. In the second experiment, NAC was compared to other sulphur amino acid sources at equal molar amounts of digestible sulphur amino acids. Birds were allocated to four groups: control, 2000 mg/kg NAC, 1479 mg/kg L-cystine, and 2168 mg/kg Ca-salt of 2-hydroxy-4-(methylthio)butanoic acid. A chronic cyclic heat stress model (temperature was increased to 34°C for 7 h daily) was initiated at 28 d of age.3. In the first experiment, growth performance and feed efficiency in the finisher phase were significantly improved by graded NAC. ADG was 88.9, 92.2, 93.7 and 97.7 g/d, and the feed-to-gain ratio was 2.18, 1.91, 1.85 and 1.81 for the 0, 500, 1000 and 2000 mg/kg NAC treatments, respectively. However, liver and heart GSH levels were not affected by NAC. On d 29, liver gene transcript of cystathionine-beta-synthase like was reduced by NAC, which suggested reduced trans-sulphuration activity. The second experiment showed that L-cystine and Ca-salt of 2-hydroxy-4-(methylthio) butanoic acid were more effective in improving performance than NAC.4. In conclusion, N-acetyl-L-cysteine improved dose-dependently growth and feed efficiency in heat-stressed finishing broilers. However, this was not associated with changes in tissue GSH levels, but more likely worked by sparing methionine and/or NAC's and cysteine's direct antioxidant properties.}, }
@article {pmid37781647, year = {2023}, author = {Miyashita, L and Foley, G and Semple, S and Gibbons, JM and Pade, C and McKnight, &#xc1; and Grigg, J}, title = {Curbside particulate matter and susceptibility to SARS-CoV-2 infection.}, journal = {The journal of allergy and clinical immunology. Global}, volume = {2}, number = {4}, pages = {100141}, pmid = {37781647}, issn = {2772-8293}, abstract = {BACKGROUND: Biologic plausibility for the association between exposure to particulate matter (PM) less than 10 μm in aerodynamic diameter (PM10) and coronavirus disease 2019 (COVID-19) morbidity in epidemiologic studies has not been determined. The upregulation of angiotensin-converting enzyme 2 (ACE2), the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) entry receptor on host cells, by PM10 is a putative mechanism.<br><br>OBJECTIVE: We sought to assess the effect of PM10 on SARS-CoV-2 infection of cells in&#xa0;vitro.<br><br>METHODS: PM10 from the curbside of London's Marylebone Road and from exhaust emissions was collected by cyclone. A549 cells, human primary nasal epithelial cells (HPNEpCs), SARS-CoV-2-susceptible Vero-E6 and Calu3 cells were cultured with PM10. ACE2 expression (as determined by median fluorescent intensity) was assessed by flow cytometry, and ACE2 mRNA transcript level was assessed by PCR. The role of oxidative stress was determined by N-acetyl cysteine. The cytopathic effect of SARS-CoV-2 (percentage of infection enhancement) and expression of SARS-CoV-2 genes' open reading frame (ORF) 1ab, S protein, and N protein (focus-forming units/mL) were assessed in Vero-E6 cells. Data were analyzed by either the Mann-Whitney U test or Kruskal-Wallis test with the Dunn multiple comparisons test.<br><br>RESULTS: Curbside PM10 at concentrations of 10 &#x3bc;g/mL or more increased ACE2 expression in A549 cells (P&#xa0;= .0021). Both diesel PM10 and curbside PM10 in a concentration of 10 &#x3bc;g/mL increased ACE2 expression in HPNEpCs (P&#xa0;= .0022 and P&#xa0;= .0072, respectively). ACE2 expression simulated by curbside PM10 was attenuated by N-acetyl cysteine in HPNEpCs (P&#xa0;= .0464). Curbside PM10 increased ACE2 expression in Calu3 cells (P&#xa0;= .0256). In Vero-E6 cells, curbside PM10 increased ACE2 expression (P&#xa0;= .0079), ACE2 transcript level (P&#xa0;= .0079), SARS-CoV-2 cytopathic effect (P&#xa0;= .0002), and expression of the SARS-CoV-2 genes' ORF1ab, S protein, and N protein (P&#xa0;= .0079).<br><br>CONCLUSIONS: Curbside PM10 increases susceptibility to SARS-COV-2 infection in&#xa0;vitro.}, }
@article {pmid37779397, year = {2023}, author = {Heidari, B and Seyedian, ZA and Mehrpooya, M and Ahmadimoghaddam, D and Mirjalili, M and Ghiasian, M}, title = {N-Acetyl Cysteine as an Add-on Therapy is Useful in Treating Acute Lumbar Radiculopathy Caused by Disc Herniation: Results of a Randomized, Controlled Clinical Trial.}, journal = {Reviews on recent clinical trials}, volume = {18}, number = {4}, pages = {288-299}, doi = {10.2174/0115748871250545230919055109}, pmid = {37779397}, issn = {1876-1038}, support = {No: 140004293667//Hamadan University of Medical Sciences/ ; }, mesh = {Humans ; *Intervertebral Disc Displacement/complications/diagnosis/drug therapy ; *Radiculopathy/drug therapy/etiology/diagnosis ; Cysteine/therapeutic use ; Lumbar Vertebrae ; Treatment Outcome ; Pain/complications/drug therapy ; Anti-Inflammatory Agents, Non-Steroidal ; }, abstract = {BACKGROUND: Available experimental and clinical evidence indicates that N-Acetyl cysteine (NAC) may have an analgesic role in specific pain conditions, particularly neuropathic pain. Thus, we hypothesized that NAC supplementation might be also helpful in decreasing pain and improving pain-related disability in patients with acute radiculopathy. We designed this study to investigate the potential use of NAC-adjunctive treatment to Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) in patients with acute radiculopathy secondary to lumbar intervertebral disc herniation.<br><br>METHODS: Sixty-two patients diagnosed with acute lumbar radiculopathy associated with disc herniation were randomly allocated to the NAC or the placebo groups. Besides naproxen at a dose of 500 mg twice a day, participants based on their allocation group started with NAC or matched placebo at a dose of 600 mg twice a day for eight weeks. The pain severity, measured by the Visual Analog Scale (VAS), and pain-related disability measured by the Oswestry Disability Index (ODI) were measured at baseline and weeks 2, 4, and 8 of treatment. Global improvement of symptoms rated by Patient and Clinical Global Impressions of Change (PGIC and CGIC) was also recorded at the end of week 8. All analyses were conducted on an Intentionto- Treat (ITT) analysis data set.<br><br>RESULTS: A comparison of the VAS and ODI scores at weeks 2 and 4 of the treatment between the two groups did not show a significant difference. In contrast, from week 4 to week 8, we noticed a significantly greater reduction in the mean VAS and ODI scores in the NAC group compared to the placebo group (p-value <0.001 for both variables). In parallel with these results, also, more NAC-treated than placebo-treated patients achieved treatment success defined as ''very much'' or ''much improved'' on CGIC and PGIC scales, and these differences reached a significant level (p-value = .011 and p-value = .043).<br><br>CONCLUSIONS: This study suggested that NAC might be a relevant candidate for adjunct therapy in managing acute lumbar radiculopathy. Additional clinical trials are needed to validate these findings.}, }
@article {pmid37778984, year = {2023}, author = {Kaji, T and Kuroishi, T and Bando, K and Takahashi, M and Sugawara, S}, title = {N-acetyl cysteine inhibits IL-1α release from murine keratinocytes induced by 2-hydroxyethyl methacrylate.}, journal = {The Journal of toxicological sciences}, volume = {48}, number = {10}, pages = {557-569}, doi = {10.2131/jts.48.557}, pmid = {37778984}, issn = {1880-3989}, mesh = {Mice ; Animals ; *Acetylcysteine/pharmacology ; Reactive Oxygen Species/metabolism ; *Calpain ; Methacrylates/toxicity/chemistry ; Keratinocytes/metabolism ; Inflammation ; }, abstract = {The hydrophilic compound 2-hydroxyethyl methacrylate (HEMA) is a major component of dental bonding materials, and it enhances the binding of resin-composites to biomolecules. However, HEMA is a well-known contact sensitizer. We reported previously that intradermal injection of HEMA induces the production of IL-1 locally in the skin. Keratinocytes are the first barrier against chemical insults and constitutively express IL-1α. In this study, we analyzed whether HEMA induces the production of inflammatory cytokines from murine keratinocyte cell line Pam212 cells. We demonstrated that HEMA induced the release of 17-kDa mature IL-1α and caused cytotoxicity. The activity of calpain, an IL-1α processing enzyme, was significantly higher in HEMA-treated cells. The thiol-containing antioxidant N-acetyl cysteine (NAC) inhibited HEMA-induced IL-1α release but not cytotoxicity. NAC inhibited intracellular calpain activity and reactive oxygen species (ROS) production induced by HEMA. NAC post-treatment also inhibited IL-1α release and intracellular ROS production induced by HEMA. Furthermore, HEMA-induced in vivo inflammation also inhibited by NAC. NAC inhibited polymerization of HEMA through adduct formation via sulfide bonds between the thiol group of NAC and the reactive double bond of HEMA. HEMA-induced IL-1α release and cytotoxicity were also inhibited if HEMA and NAC were pre-incubated before adding to the cells. These results suggested that NAC inhibited IL-1α release through decreases in intracellular ROS and the adduct formation with HEMA. We concluded that HEMA induces IL-1α release from skin keratinocytes, and NAC may be a promising candidate as a therapeutic agent against inflammation induced by HEMA.}, }
@article {pmid37777475, year = {2024}, author = {Khoury, ES and Patel, RV and O'Ferrall, C and Fowler, A and Sah, N and Sharma, A and Gupta, S and Scafidi, S and Kurtz, JS and Olmstead, SJ and Kudchadkar, SR and Kannan, RM and Blue, ME and Kannan, S}, title = {Dendrimer nanotherapy targeting of glial dysfunction improves inflammation and neurobehavioral phenotype in adult female Mecp2-heterozygous mouse model of Rett syndrome.}, journal = {Journal of neurochemistry}, volume = {168}, number = {5}, pages = {841-854}, pmid = {37777475}, issn = {1471-4159}, support = {F32 NS010085/NS/NINDS NIH HHS/United States ; P50 HD103538/HD/NICHD NIH HHS/United States ; R01 NS113140/NS/NINDS NIH HHS/United States ; R21NS10085/NS/NINDS NIH HHS/United States ; P50 HD103538/HD/NICHD NIH HHS/United States ; //Hartwell Foundation/ ; R01 NS113140/NS/NINDS NIH HHS/United States ; R21NS10085/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Rett Syndrome/genetics/drug therapy ; Female ; *Methyl-CpG-Binding Protein 2/genetics ; Mice ; *Neuroglia/drug effects/metabolism ; *Disease Models, Animal ; *Dendrimers ; Phenotype ; Mice, Inbred C57BL ; Neuroinflammatory Diseases/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; Inflammation/drug therapy/metabolism ; Heterozygote ; Behavior, Animal/drug effects ; }, abstract = {Rett syndrome is an X-linked neurodevelopmental disorder caused by mutation of Mecp2 gene and primarily affects females. Glial cell dysfunction has been implicated in in Rett syndrome (RTT) both in patients and in mouse models of this disorder and can affect synaptogenesis, glial metabolism and inflammation. Here we assessed whether treatment of adult (5-6 months old) symptomatic Mecp2-heterozygous female mice with N-acetyl cysteine conjugated to dendrimer (D-NAC), which is known to target glia and modulate inflammation and oxidative injury, results in improved behavioral phenotype, sleep and glial inflammatory profile. We show that unbiased global metabolomic analysis of the hippocampus and striatum in adult Mecp2-heterozygous mice demonstrates significant differences in lipid metabolism associated with neuroinflammation, providing the rationale for targeting glial inflammation in this model. Our results demonstrate that treatment with D-NAC (10 mg/kg NAC) once weekly is more efficacious than equivalently dosed free NAC in improving the gross neurobehavioral phenotype in symptomatic Mecp2-heterozygous female mice. We also show that D-NAC therapy is significantly better than saline in ameliorating several aspects of the abnormal phenotype including paw clench, mobility, fear memory, REM sleep and epileptiform activity burden. Systemic D-NAC significantly improves microglial proinflammatory cytokine production and is associated with improvements in several aspects of the phenotype including paw clench, mobility, fear memory, and REM sleep, and epileptiform activity burden in comparison to saline-treated Mecp2-hetereozygous mice. Systemic glial-targeted delivery of D-NAC after symptom onset in an older clinically relevant Rett syndrome model shows promise in improving neurobehavioral impairments along with sleep pattern and epileptiform activity burden. These findings argue for the translational value of this approach for treatment of patients with Rett Syndrome.}, }
@article {pmid37774561, year = {2023}, author = {Blum, K and Ashford, JW and Kateb, B and Sipple, D and Braverman, E and Dennen, CA and Baron, D and Badgaiyan, R and Elman, I and Cadet, JL and Thanos, PK and Hanna, C and Bowirrat, A and Modestino, EJ and Yamamoto, V and Gupta, A and McLaughlin, T and Makale, M and Gold, MS}, title = {Dopaminergic dysfunction: Role for genetic &amp; epigenetic testing in the new psychiatry.}, journal = {Journal of the neurological sciences}, volume = {453}, number = {}, pages = {120809}, doi = {10.1016/j.jns.2023.120809}, pmid = {37774561}, issn = {1878-5883}, abstract = {Reward Deficiency Syndrome (RDS), particularly linked to addictive disorders, costs billions of dollars globally and has resulted in over one million deaths in the United States (US). Illicit substance use has been steadily rising and in 2021 approximately 21.9% (61.2 million) of individuals living in the US aged 12 or older had used illicit drugs in the past year. However, only 1.5% (4.1 million) of these individuals had received any substance use treatment. This increase in use and failure to adequately treat or provide treatment to these individuals resulted in 106,699 overdose deaths in 2021 and increased in 2022. This article presents an alternative non-pharmaceutical treatment approach tied to gene-guided therapy, the subject of many decades of research. The cornerstone of this paradigm shift is the brain reward circuitry, brain stem physiology, and neurotransmitter deficits due to the effects of genetic and epigenetic insults on the interrelated cascade of neurotransmission and the net release of dopamine at the Ventral Tegmental Area -Nucleus Accumbens (VTA-NAc) reward site. The Genetic Addiction Risk Severity (GARS) test and pro-dopamine regulator nutraceutical KB220 were combined to induce "dopamine homeostasis" across the brain reward circuitry. This article aims to encourage four future actionable items: 1) the neurophysiologically accurate designation of, for example, "Hyperdopameism /Hyperdopameism" to replace the blaming nomenclature like alcoholism; 2) encouraging continued research into the nature of dysfunctional brainstem neurotransmitters across the brain reward circuitry; 3) early identification of people at risk for all RDS behaviors as a brain check (cognitive testing); 4) induction of dopamine homeostasis using "precision behavioral management" along with the coupling of GARS and precision Kb220 variants; 5) utilization of promising potential treatments include neuromodulating modalities such as Transmagnetic stimulation (TMS) and Deep Brain Stimulation(DBS), which target different areas of the neural circuitry involved in addiction and even neuroimmune agents like N-acetyl-cysteine.}, }
@article {pmid37773178, year = {2023}, author = {Koning, T and Cordova, F and Aguilar, G and Sarmiento, J and Mardones, GA and Boric, M and Varas-Godoy, M and Lladser, A and Duran, WN and Ehrenfeld, P and Sanchez, FA}, title = {S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis.}, journal = {Biological research}, volume = {56}, number = {1}, pages = {51}, pmid = {37773178}, issn = {0717-6287}, support = {R01 GM122940/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/pathology ; Cell Adhesion ; Endothelial Cells ; Vascular Cell Adhesion Molecule-1/metabolism ; Nitric Oxide/metabolism ; Melanoma, Cutaneous Malignant ; }, abstract = {BACKGROUND: Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown.<br><br>RESULTS: We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases.<br><br>CONCLUSIONS: S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.}, }
@article {pmid37771516, year = {2023}, author = {Meziu, E and Shehu, K and Koch, M and Schneider, M and Kraegeloh, A}, title = {Impact of mucus modulation by N-acetylcysteine on nanoparticle toxicity.}, journal = {International journal of pharmaceutics: X}, volume = {6}, number = {}, pages = {100212}, pmid = {37771516}, issn = {2590-1567}, abstract = {Human respiratory mucus is a biological hydrogel that forms a protective barrier for the underlying epithelium. Modulation of the mucus layer has been employed as a strategy to enhance transmucosal drug carrier transport. However, a drawback of this strategy is a potential reduction of the mucus barrier properties, in particular in situations with an increased exposure to particles. In this study, we investigated the impact of mucus modulation on its protective role. In vitro mucus was produced by Calu-3 cells, cultivated at the air-liquid interface for 21 days and used for further testing as formed on top of the cells. Analysis of confocal 3D imaging data revealed that after 21 days Calu-3 cells secrete a mucus layer with a thickness of 24 ± 6 μm. Mucus appeared to restrict penetration of 500 nm carboxyl-modified polystyrene particles to the upper 5-10 μm of the layer. Furthermore, a mucus modulation protocol using aerosolized N-acetylcysteine (NAC) was developed. This treatment enhanced the penetration of particles through the mucus down to deeper layers by means of the mucolytic action of NAC. These findings were supported by cytotoxicity data, indicating that intact mucus protects the underlying epithelium from particle-induced effects on membrane integrity. The impact of NAC treatment on the protective properties of mucus was probed by using 50 and 100 nm amine-modified and 50 nm carboxyl-modified polystyrene nanoparticles, respectively. Cytotoxicity was only induced by the amine-modified particles in combination with NAC treatment, implying a reduced protective function of modulated mucus. Overall, our data emphasize the importance of integrating an assessment of the protective function of mucus into the development of therapy approaches involving mucus modulation.}, }
@article {pmid37769128, year = {2023}, author = {Chakraborty, S and Bhattacharya, I and Mitra, RK}, title = {Solvation Plays a Key Role in Antioxidant-Mediated Attenuation of Elevated Creatinine Level: An In Vitro Spectroscopic Investigation.}, journal = {The journal of physical chemistry. B}, volume = {127}, number = {40}, pages = {8576-8585}, doi = {10.1021/acs.jpcb.3c05334}, pmid = {37769128}, issn = {1520-5207}, mesh = {Humans ; *Antioxidants ; Creatinine/urine ; Ascorbic Acid ; *Kidney Diseases ; Spectroscopy, Fourier Transform Infrared ; Acetylcysteine ; }, abstract = {An elevated level of creatinine (CRN) is a mark of kidney ailment, and prolonged retention of such condition could lead to renal failure, associated with severe ischemia. Antioxidants are clinically known to excrete CRN from the body through urine, thereby reducing its level in blood. The molecular mechanism of such an exclusion process is still illusive. As the excretion channel is urine, solvation of the solute is expected to play a pivotal role. Here, we report a detailed time-domain and frequency-domain terahertz (THz) spectroscopic investigation to understand the solvation of CRN in the presence of two model antioxidants, mostly used to treat elevated CRN level: N-Acetyl-l-cysteine (NAC) and ascorbic acid (ASC). FTIR spectroscopy in the mid-infrared region and UV absorption spectroscopy measurements coupled with quantum chemical calculations [at the B3LYP/6-311G++(d,p) level] reveal that both NAC and ASC form HBonded complexes with CRN and rapidly undergo a barrier-less proton transfer process to form creatinium ions. THz measurements provide explicit evidence of the formation of highly solvated complexes compared with bare CRN, which eventually enables its excretion through urine. These observations could provide a foundation for designing more beneficial drugs to resolve kidney diseases..}, }
@article {pmid37767143, year = {2023}, author = {Alizadeh, N and Yaryari, AM and Behnoush, AH and Raoufinejad, K and Behnoush, B}, title = {Late N-acetylcysteine for successful recovery of acetaminophen-related acute liver failure: A case report.}, journal = {Clinical case reports}, volume = {11}, number = {9}, pages = {e7946}, pmid = {37767143}, issn = {2050-0904}, abstract = {Acetaminophen toxicity is one of the leading causes of liver failure. Although N-acetylcysteine (NAC) is generally successful in preventing acetaminophen hepatotoxicity when given in a timely manner, if not prescribed in the early golden time, the only practical way to save the patient might be liver transplantation. The case presented was a 20-year-old female with an acetaminophen overdose (30 g), for which more than 24 h had passed since the ingestion. Despite the critical clinical condition, loss of consciousness (Glasgow Coma Score of 4) of the patient, and passing the golden time of antidote administration, the decision was made by the healthcare team to administer NAC. After transferring the patient to the intensive care unit, the three-bag NAC regimen was initiated and appropriate monitoring was performed. After this, the regimen of 3 g q8h was continued for the patient. The patient's condition began to improve slowly on the second day and then she was extubated on the fourth day. Finally, she was discharged on the tenth day. Although the golden period of antidote administration had passed outwardly, there was no need for a liver transplant and the patient recovered successfully with late NAC administration. Hence, clinicians can benefit from the use of NAC even in the late phases of acetaminophen liver toxicity.}, }
@article {pmid37766400, year = {2023}, author = {Benizio, E and Moreira-Espinoza, MJ and Triquell, MF and Mezzano, L and Díaz-Luján, CM and Fretes, RE}, title = {Pro-inflammatory cytokines are modified during the multiplication of Trypanosoma cruzi within the placental chorionic villi and are associated with the level of infection via the signaling pathway NF-κB.}, journal = {American journal of reproductive immunology (New York, N.Y. : 1989)}, volume = {90}, number = {4}, pages = {e13777}, doi = {10.1111/aji.13777}, pmid = {37766400}, issn = {1600-0897}, mesh = {Pregnancy ; Female ; Humans ; NF-kappa B ; Chorionic Villi ; Placenta ; Interleukin-10 ; *Trypanosoma cruzi ; Cytokines ; Tumor Necrosis Factor-alpha ; Signal Transduction ; *Chagas Disease ; }, abstract = {PROBLEM: Congenital Trypanosoma cruzi (T. cruzi) infection has been associated with changes in the levels of TNF-α and IFN-γ during the pregnancy. Therefore, we propose to study the participation and dynamics of proinflammatory cytokines in the infection process of placental explants infected by T. cruzi in vitro.<br><br>METHOD OF STUDY: Chorionic villous explants (CVE) obtained of human term placentas (n&#xa0;=&#xa0;8) from normal pregnancies were cultured with 10[5] trypomastigotes/mL of Tulahuen strain DTU VI for 0, 2, 4, 16, 24, 48 and 72&#xa0;h. Explants were treated with sulfasalazine (SULF) (5&#xa0;mM) and N-acetyl-cysteine (NAC) (15&#xa0;mM), as inhibitors molecules of NF-&#x3ba;B pathway, or LPS (1&#xa0;&#x3bc;g/mL) for 24 and 72&#xa0;h p.i. Motile trypomastigotes were counted in culture supernatants. Immunohistochemistry and ELISA for TNF-&#x3b1;, IFN-&#x3b3;, IL-1&#x3b2;, IL-4, and IL-10 were performed in CVE and culture supernatants respectively. The parasite load was measured by RT-qPCR.<br><br>RESULTS: T. cruzi invades the chorionic villi from 4&#xa0;h p.i. increasing significantly its DNA at 48 and 72&#xa0;h p.i. of culture (parasite multiplication phase). They were detected in stromal cells, which was related to elevation of TNF-&#x3b1;, IL-1&#x3b2;, IFN-&#x3b3;, and IL-10. The inhibition of NF-&#x3ba;B activity in the explants decreased the production of the analyzed cytokines, showing elevated levels of T. cruzi DNA during the multiplication phase of the parasite.<br><br>CONCLUSIONS: Placental tissue modifies the secretion of pro-inflammatory cytokines during the phase of parasite multiplication, but not during the invasion phase, which in turns modifies the level of infection via the signaling pathway NF-&#x3ba;B.}, }
@article {pmid37762548, year = {2023}, author = {Chen, JS and Chiu, SC and Huang, SY and Chang, SF and Liao, KF}, title = {Isolinderalactone Induces Apoptosis, Autophagy, Cell Cycle Arrest and MAPK Activation through ROS-Mediated Signaling in Colorectal Cancer Cell Lines.}, journal = {International journal of molecular sciences}, volume = {24}, number = {18}, pages = {}, pmid = {37762548}, issn = {1422-0067}, support = {TCMF-A 108-014//Buddhist Tzu Chi Medical Foundation/ ; TTCRD110-21//Buddhist Tzu Chi Medical Foundation/ ; TTCRD110-31//Buddhist Tzu Chi Medical Foundation/ ; TTCRD111-33//Buddhist Tzu Chi Medical Foundation/ ; }, mesh = {Humans ; Apoptosis ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; G2 Phase Cell Cycle Checkpoints ; Cell Cycle Checkpoints ; *Sesquiterpenes/pharmacology ; Autophagy ; *Colorectal Neoplasms/drug therapy ; Cell Proliferation ; }, abstract = {Colorectal cancer (CRC) is one of the most common malignancies worldwide. Isolinderalactone (ILL), a sesquiterpene isolated from the root extract of Lindera aggregata, has been reported to exhibit anti-proliferative and anti-metastatic activities in various cancer cell lines. However, the mechanisms associated with its antitumor effects on CRC cells remain unclear. ILL treatment significantly suppressed proliferation and induced cell cycle G2/M arrest in CRC cells by inhibiting the expression of cyclin B, p-cdc2, and p-cdc25c and up-regulating the expression of p21. In addition, ILL induced mitochondria-associated apoptosis through the up-regulation of cleaved -caspase-9 and -3 expression. ILL induced autophagy by increasing the levels of LC3B in CRC cells, which was partially rescued by treatment with an autophagy inhibitor (chloroquine). Furthermore, ILL increases the accumulation of reactive oxygen species (ROS) and activates the MAPK pathway. Application of the ROS scavenger, N-acetyl cysteine (NAC), effectively inhibited ILL toxicity and reversed ILL-induced apoptosis, cell cycle arrest, autophagy, and ERK activation. Taken together, these results suggest that ILL induces G2/M phase arrest, apoptosis, and autophagy and activates the MAPK pathway via ROS-mediated signaling in human CRC cells.}, }
@article {pmid37761021, year = {2023}, author = {Ahmad, IM and Dafferner, AJ and Salloom, RJ and Abdalla, MY}, title = {Heme Oxygenase-1 Inhibition Modulates Autophagy and Augments Arsenic Trioxide Cytotoxicity in Pancreatic Cancer Cells.}, journal = {Biomedicines}, volume = {11}, number = {9}, pages = {}, pmid = {37761021}, issn = {2227-9059}, abstract = {Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form, accounting for more than 90% of all pancreatic malignancies. In a previous study, we found that hypoxia and chemotherapy induced expression of Heme Oxygenase-1 (HO-1) in PDAC cells and tissues. Arsenic trioxide (ATO) is the first-line chemotherapeutic drug for acute promyelocytic leukemia (APL). ATO increases the generation of reactive oxidative species (ROS) and induces apoptosis in treated cells. The clinical use of ATO for solid tumors is limited due to severe systemic toxicity. In order to reduce cytotoxic side effects and resistance and improve efficacy, it has become increasingly common to use combination therapies to treat cancers. In this study, we used ATO-sensitive and less sensitive PDAC cell lines to test the effect of combining HO-1 inhibitors (SnPP and ZnPP) with ATO on HO-1 expression, cell survival, and other parameters. Our results show that ATO significantly induced the expression of HO-1 in different PDAC cells through the p38 MAPK signaling pathway. ROS production was confirmed using the oxygen-sensitive probes DCFH and DHE, N-acetyl cysteine (NAC), an ROS scavenger, and oxidized glutathione levels (GSSG). Both ATO and HO-1 inhibitors reduced PDAC cell survival. In combined treatment, inhibiting HO-1 significantly increased ATO cytotoxicity, disrupted the GSH cycle, and induced apoptosis as measured using flow cytometry. ATO and HO-1 inhibition modulated autophagy as shown by increased expression of autophagy markers ATG5, p62, and LC3B in PDAC cells. This increase was attenuated by NAC treatment, indicating that autophagy modulation was through an ROS-dependent mechanism. In conclusion, our work explored new strategies that could lead to the development of less toxic and more effective therapies against PDAC by combining increased cellular stress and targeting autophagy.}, }
@article {pmid37760016, year = {2023}, author = {Mokra, D and Mokry, J and Barosova, R and Hanusrichterova, J}, title = {Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {9}, pages = {}, pmid = {37760016}, issn = {2076-3921}, support = {APVV-15_0075//Slovak Research and Development Agency/ ; APVV-18-0084//Slovak Research and Development Agency/ ; APVV-22-0342//Slovak Research and Development Agency/ ; VEGA 1/0131/22//VEGA/ ; VEGA 1/0093/22//VEGA/ ; }, abstract = {N-acetylcysteine (NAC) is widely used because of its mucolytic effects, taking part in the therapeutic protocols of cystic fibrosis. NAC is also administered as an antidote in acetaminophen (paracetamol) overdosing. Thanks to its wide antioxidative and anti-inflammatory effects, NAC may also be of benefit in other chronic inflammatory and fibrotizing respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, idiopathic lung fibrosis, or lung silicosis. In addition, NAC exerts low toxicity and rare adverse effects even in combination with other treatments, and it is cheap and easily accessible. This article brings a review of information on the mechanisms of inflammation and oxidative stress in selected chronic respiratory diseases and discusses the use of NAC in these disorders.}, }
@article {pmid37746996, year = {2023}, author = {Abushanab, D and Gasim, M and Devi, D and Elbdairy, M and Elqasass, H and Ahmed, N and Vincent, M and Abdul Rouf, PV and Mohammed, HR and Hail, MA and Thomas, B and Elkassem, W and Hanssens, Y and Elgassim, M and Elmoheen, A and Azad, A and Mohammed, S and Salem, W}, title = {Patterns and outcomes of paracetamol poisoning management in Hamad Medical Corporation, Qatar: A retrospective cohort study.}, journal = {Medicine}, volume = {102}, number = {38}, pages = {e34872}, pmid = {37746996}, issn = {1536-5964}, mesh = {Young Adult ; Humans ; Adolescent ; Adult ; Qatar/epidemiology ; Acetaminophen ; Retrospective Studies ; *Drug-Related Side Effects and Adverse Reactions ; *Drug Overdose/therapy ; Acetylcysteine/therapeutic use ; }, abstract = {We aimed to investigate the characteristics and clinical outcomes of paracetamol poisoning and paracetamol overdose in Qatar. This retrospective cohort study included patients admitted to the emergency department (ED). We included patients who presented with excessive paracetamol ingestion, between December 2018 and September 2019. The primary outcomes were describing the characteristics and outcomes of paracetamol overdose (from a suicidal overdose or accidental overdose, dose ≤ 150 mg/kg, when serum levels of <60 mmol/L) or dose ingested (≤75 mg/kg) with staggered ingestion poisoning due to suicidal attempt or accidental attempt, defined as the dose ingested (>150 mg/kg), acute ingestion, nomogram level more than the treatment line, or dose ingested (>75 mg/kg) with staggered ingestion, and assessing the management of excessive paracetamol ingestion. Secondary outcomes included evaluation of the time difference between ingestion and time of administration, hospitalization, and adverse drug events. Significant differences were detected between patients who presented with paracetamol overdose and those who presented with paracetamol toxicity. A total of 69 patients were analyzed, of whom 43 received paracetamol overdose (mean age 27.5 ± 11.1 years) and 26 had paracetamol poisoning (mean age 25 ± 6.22 years). Paracetamol poisoning was identified in 26% of the patients with a 24.3% history of psychiatric illness, compared to 18.6% with paracetamol overdose. More patients presented with paracetamol toxicity in the time between ingestion and obtaining serum levels compared to the overdose group. A significantly longer length of hospitalization was observed in the toxicity group. A significantly higher number of patients in the toxicity group received N-acetylcysteine (NAC). More hypotension and rashes were observed among those who received NAC in the toxicity group. Patients presenting to the ED due to paracetamol toxicity are not uncommon, and most cases occur in young adults, and few in patients with a history of psychiatric illness, suggesting that preventive approaches are highly required.}, }
@article {pmid37742933, year = {2023}, author = {Zhuang, J and Yuan, Q and Chen, C and Liu, G and Zhong, Z and Zhu, K and Guo, J}, title = {Nanosecond pulsed cold atmospheric plasma jet suppresses proliferation and migration of human glioblastoma cells via apoptosis promotion and EMT inhibition.}, journal = {Archives of biochemistry and biophysics}, volume = {747}, number = {}, pages = {109757}, doi = {10.1016/j.abb.2023.109757}, pmid = {37742933}, issn = {1096-0384}, mesh = {Humans ; *Glioblastoma/metabolism ; Epithelial-Mesenchymal Transition ; Reactive Oxygen Species ; Apoptosis ; Cell Proliferation ; Cell Line, Tumor ; Cell Movement ; *Brain Neoplasms/metabolism ; }, abstract = {Glioblastoma (GBM) is one of the most aggressive and challenging cancers to treat. Despite extensive research on dozens of cancer cells, including GBM, the effect of cold atmospheric plasma (CAP) on the invasive migration of GBM cells has received limited attention, and the underlying mechanisms remain poorly understood. This study aims to investigate the potential molecular mechanism of ns-CAPJ in inhibiting the invasive migration of human GBM cells. The findings indicate that ns-CAPJ significantly reduces GBM cell invasion and migration, and induces apoptosis in GBM cells. Further mechanistic studies demonstrate a direct correlation between the suppression of the epithelial-mesenchymal transition (EMT) signaling pathway and ns-CAPJ's inhibitory effect on GBM cell invasion and migration. Additionally, combined with the N-acetyl cysteine (NAC, a ROS inhibitor) assay, we found that the ROS stimulated by the ns-CAPJ plays an important role in suppressing the EMT process. This work is expected to provide new insight into understanding the molecular mechanisms of how ns-CAPJ inhibits the proliferation and migration of human GBM cells.}, }
@article {pmid37742495, year = {2023}, author = {Zeng, Y and Yang, Q and Ouyang, Y and Lou, Y and Cui, H and Deng, H and Zhu, Y and Geng, Y and Ouyang, P and Chen, L and Zuo, Z and Fang, J and Guo, H}, title = {Nickel induces blood-testis barrier damage through ROS-mediated p38 MAPK pathways in mice.}, journal = {Redox biology}, volume = {67}, number = {}, pages = {102886}, pmid = {37742495}, issn = {2213-2317}, mesh = {Mice ; Male ; Animals ; *p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; *Blood-Testis Barrier/metabolism ; Reactive Oxygen Species/metabolism ; Nickel/toxicity/metabolism ; Testis/metabolism ; }, abstract = {Nickel (Ni) is an essential common environmental contaminant, it is hazardous to male reproduction, but the precise mechanisms are still unknown. Blood-testis barrier (BTB), an important testicular structure consisting of connections between sertoli cells, is the target of reproductive toxicity caused by many environmental toxins. In this study, ultrastructure observation and BTB integrity assay results indicated that NiCl2 induced BTB damage. Meanwhile, BTB-related proteins including the tight junction (TJ), adhesion junction (AJ) and the gap junction (GJ) protein expression in mouse testes as well as in sertoli cells (TM4) were significantly decreased after NiCl2 treatment. Next, the antioxidant N-acetylcysteine (NAC) was co-treated with NiCl2 to study the function of oxidative stress in NiCl2-mediated BTB deterioration. The results showed that NAC attenuated testicular histopathological damage, and the expression of BTB-related proteins were markedly reversed by NAC co-treatment in vitro and vivo. Otherwise, NiCl2 activated the p38 MAPK signaling pathway. And, NAC co-treatment could significantly inhibit p38 activation induced by NiCl2 in TM4 cells. Furthermore, in order to confirm the role of the p38 MAPK signaling pathway in NiCl2-induced BTB impairment, a p38 inhibitor (SB203580) was co-treated with NiCl2 in TM4 cells, and p38 MAPK signaling inhibition significantly restored BTB damage induced by NiCl2 in TM4 cells. These results suggest that NiCl2 treatment destroys the BTB, in which the oxidative stress-mediated p38 MAPK signaling pathway plays a vital role.}, }
@article {pmid37741428, year = {2023}, author = {Araujo, AM and Cerqueira, SVS and Menezes-Filho, JER and Heimfarth, L and Matos, KKOG and Mota, KO and Conceição, MRL and Marques, LP and Roman-Campos, D and Santos-Neto, AGD and Albuquerque-Júnior, RLC and Santos, VCO and Vasconcelos, CML}, title = {Naringin improves post-ischemic myocardial injury by activation of KATP channels.}, journal = {European journal of pharmacology}, volume = {958}, number = {}, pages = {176069}, doi = {10.1016/j.ejphar.2023.176069}, pmid = {37741428}, issn = {1879-0712}, abstract = {Naringin (NRG) is a flavonoid with recognized cardioprotective effects. Then, it was investigated the cardioprotective mechanisms of NRG against ischemia-reperfusion (I/R) injury. The rats were pretreated for 7 days (v.o.) with NRG (25 mg/kg) or n-acetylcysteine (NAC, 100 mg/kg) and their isolated hearts were subjected to global ischemia (30 min) and reperfusion (60 min). Furthermore, isolated hearts were perfused with 5 μM NRG in the presence of 10 μM glibenclamide (GLI) and subjected to I/R protocol. In healthy ventricular cardiomyocyte, it was evaluated the acute effect of 5 μM NRG on the GLI sensitive current. The results showed that NRG pretreatment restored the cardiac function and electrocardiogram (ECG) alterations induced by I/R injury, decreasing arrhythmia scores and the occurrence of severe arrhythmias. Lactate dehydrogenase and infarct area were decreased while superoxide dismutase (SOD), catalase and citrate synthase activities increased. Expression of SOD CuZn and SOD Mn not was altered. NRG treatment decreased reactive oxygen species (ROS) generation and lipid peroxidation without alter sulfhydryl groups and protein carbonylation. Also, NRG (5 μM) increased the glibenclamide sensitive current in isolated cardiomyocytes. In isolated heart, the cardioprotection of NRG was significantly reduced by GLI. Furthermore, NRG promoted downregulation of Bax expression and Bax/Bcl-2. Histopathological analysis showed that NRG decreased cell edema, cardiomyocytes and nucleus diameter. Thus, NRG has a cardioprotective effect against cardiac I/R injury which is mediated by its antioxidant and antiapoptotic actions and KATP channels activation.}, }
@article {pmid37741051, year = {2023}, author = {Fayyazi, F and Ebrahimi, V and Mamaghani, MM and Abgharmi, BA and Zarrini, G and Mosarrezaii, A and Charkhian, H and Gholinejad, Z}, title = {N-Acetyl cysteine amide and cerium oxide nanoparticles as a drug delivery for ischemic stroke treatment: Inflammation and oxidative stress crosstalk.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {80}, number = {}, pages = {127300}, doi = {10.1016/j.jtemb.2023.127300}, pmid = {37741051}, issn = {1878-3252}, mesh = {Humans ; Rats ; Animals ; Antioxidants/pharmacology/metabolism ; Chitinase-3-Like Protein 1/pharmacology ; *Ischemic Stroke ; Olive Oil/pharmacology ; Oxidative Stress ; *Cerium/pharmacology ; Inflammation/drug therapy/pathology ; *Nanoparticles ; Acetylcysteine/pharmacology ; Drug Delivery Systems ; Anti-Bacterial Agents/pharmacology ; Urea ; Amides/pharmacology ; }, abstract = {BACKGROUND: Inflammation and oxidative stress crosstalk is involved in the ischemic stroke(IS) pathogenesis and the new therapeutic options should be offered based on the targets that are critical in the golden hour of IS. YKL-40 and total antioxidant capacity(TAC), the inflammation and oxidative stress biomarkers, provide us with clues for proper intervention targets. N-acetyl cysteine amide (NACA), a lipophilic antioxidant, with a nanoparticle-based drug delivery system is permeable enough to penetrate blood-brain barrier (BBB) and was proposed as a new treatment option for IS. In this study, we evaluated the YKL-40 and TAC levels in the sera of IS patients to elucidate the best intervention target. A rat tissue model is used to assess the NACA efficiency. The microbiology tests performed to figure out the potential NACA and antibiotics interactions.<br><br>MATERIAL AND METHODS: The YKL-40 and TAC were measured in the serum of IS patients by ELISA and FRAP methods, respectively. The serum samples were obtained 12&#xa0;h after the patient's admission and meantime other laboratory findings and NIHSS-based prognosis were recorded. In the animal study, the brain cortex, liver, kidney, adipose, and the heart of healthy rats were dissected and then incubated in DMEM cell culture media containing 50 micrograms/milliliter of nanoparticles; the nanoparticles were titanium dioxide nanoparticles (TiO2 NPs), copper oxide nanoparticles (CuO NPs) and cerium dioxide nanoparticles (CeO2 NPs). Olive oil and human serum albumin solution were exposed to the nanoparticles with and without NACA. TAC was measured in the supernatant culture media. With similar concentrations and settings, we evaluated the NACA, nanoparticle, and antibiotics interactions on pseudomonas aeruginosa.<br><br>RESULTS: There was a nonparametric correlation between YKL-40 levels and post stroke serum TAC levels. Nonsmokers had higher YKL-40 and TAC levels than smokers. A new calculated variable, urea*lymphocyte/age, predicts a poor prognosis with an acceptable AUC (0.708). Exposing to the nanoparticles, the liver, kidney, and brain had a significantly higher TAC than adipose and cardiac tissue. The NACA had an ameliorative effect against TiO2 NPs in the brain. This effectiveness of NACA was also observed against CuO NPs treatment. However, the CeO2 NPs exert a strong antioxidant property by reducing the TAC in the brain tissue but not the others. Albumin showed antioxidant properties by itself, but olive oil had an inert behavior. NACA had no interaction with the action of routine antibiotics.<br><br>CONCLUSION: Oxidative stress but not inflammation is the best point for intervention in IS patients because YKL-40 has not a relationship with NIHSS score. The CeO2 NPs and NACA combination are eligible option to develop antioxidant-based drug for the treatment of IS. As a complementary finding, the urea*lymphocyte/age is proposed as a NIHSS-based prognosis biomarker.}, }
@article {pmid37739116, year = {2023}, author = {Mushtaq, I and Mushtaq, I and Akhlaq, A and Usman, S and Ishtiaq, A and Khan, M and Mustafa, G and Khan, MS and Urooj, I and Bibi, S and Liaqat, F and Akhtar, Z and Murtaza, I}, title = {Cardioprotective effect of tetra(aniline) containing terpolymers through miR-15a-5p and MFN-2 regulation against hypertrophic responses.}, journal = {Archives of biochemistry and biophysics}, volume = {747}, number = {}, pages = {109763}, doi = {10.1016/j.abb.2023.109763}, pmid = {37739116}, issn = {1096-0384}, abstract = {OBJECTIVE: Cardiac hypertrophy is a condition of abnormal cardiomyocyte enlargement accompanied by ventricular wall thickening. The study aims to investigate the role of miR-15a-5p in the regulation of mitofusin-2 (MFN-2) and to explore the cardioprotective effect of terpolymers ES-37 and L-37.<br><br>METHODS: In this study, the Sprague Dawley rats' cardiac hypertrophic model was established by administering 5&#xa0;mg/kg Isoproterenol subcutaneously every other day for 14 days. As treatment rats received NAC (50&#xa0;mg/kg), NAC treatment (50&#xa0;mg/kg NAC&#xa0;+&#xa0;5&#xa0;mg/kg ISO), ES-37 (1&#xa0;mg/kg) and ES-37 treatment (1&#xa0;mg/kg ES-37+5&#xa0;mg/kg ISO), L-37 (1&#xa0;mg/kg) and L-37 treatment (1&#xa0;mg/kg L-37+5&#xa0;mg/kg ISO). subcutaneously every other day for 14 days. NAC, ES 37 and L-37 were given after 1&#xa0;h of Isoproterenol administration in treatment groups. Cardiac hypertrophy was confirmed through morphological and histological analysis. For estimation of oxidative stress profiling, ROS and TBARS and antioxidative profiling superoxide dismutase (SOD), Catalase, and Glutathione (GSH) levels were checked. Triglyceride, cholesterol, alanine transaminase (ALT), and aspartate transaminase (AST) were performed to evaluate levels of lipid profiling and liver profiling. Molecular expression analysis was checked through real-time PCR, and western blotting both at the transcriptional and translational levels. Molecular docking studies were performed to study the interactions and modes of binding between the synthetic polymers with three proteins (Mitofusin-2, DRP-1 and PUMA). All the studies were carried out using the AutoDock Vina software and the protein-ligand complexes were visualized in Biovia Discovery Studio. Cardiac hypertrophy was confirmed by the relative changes in the cellular structure of the heart by histopathological examination and physiological changes by estimating organ weights. Biochemical profiling results depict elevated oxidative and lipid profiles signify myocardial damage. N-acetyl cysteine (NAC), ES-37, and L-37 overcome the cardiac hypertrophic responses through attenuating oxidative stress and enhancing the antioxidative signaling mechanism. miR-15a-5p was identified as hypertrophic microRNA directly regulating the expression of Mitofusin-2 (MFN-2). Significantly increased expression of miR-15a-5p, Dynamin related protein 1 (Drp1), and P53 upregulated modulator of apoptosis (PUMA), was observed in the disease group, whereas MFN-2 expression was observed downregulated. N-acetyl cysteine (NAC), ES-37, and L-37 showed increased expression of antiapoptotic maker MFN-2 and decreased expression of miR-15a-5p, Drp1, and PUMA in treatment groups suggesting their cardioprotective role in attenuation of cardiac hypertrophy. An analysis of the docking results shows that ES-37 has greater binding affinity with the target proteins compared to L-37, with the highest binding values reported for MFN-2.<br><br>CONCLUSION: The physiochemical properties of ES-37 and L-37 predicted it as a good drug-like molecule and its mechanism of action is predictably through inhibition of ROS. Molecular docking results shows that the polymer ES-37 has greater binding affinity with the target proteins compared to L-37, with the highest binding values reported for MFN-2. Thus, the study validates the role and targeting of miR-15a-5p and MFN-2 in cardiac hypertrophy as well as the therapeutic potential of NAC, ES-37, and L-37 in overcoming oxidative stress and myocardial damage.}, }
@article {pmid37732506, year = {2023}, author = {Sharma, S and Sharma, V and Taneja, S and Alka Bhatia,  and Anand, A and Patil, AN and Banerjee, D}, title = {Scopoletin a potential phytochemical therapy for antitubercular treatment drug induced liver injury (ATT-DILI) model in Wistar rats.}, journal = {Journal of complementary &amp; integrative medicine}, volume = {20}, number = {4}, pages = {797-803}, pmid = {37732506}, issn = {1553-3840}, mesh = {Rats ; Animals ; Rats, Wistar ; *Scopoletin/pharmacology/therapeutic use/metabolism ; Plant Extracts/pharmacology/therapeutic use ; Antitubercular Agents/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy ; Liver ; Bilirubin/metabolism ; Alkaline Phosphatase/metabolism ; Carbon Tetrachloride/metabolism/pharmacology ; Alanine Transaminase/metabolism ; }, abstract = {OBJECTIVES: The hepatoprotective properties of scopoletin have been explored in carbon tetrachloride (CCl4) induced liver injury but not in drug-induced liver injury (DILI) scenarios. Only N-acetyl-cysteine (NAC) has proven efficacy in DILI treatment. Accordingly, we conducted a study to assess the hepatoprotective action of scopoletin in the anti-tubercular treatment (ATT)-DILI model in Wistar rats, if any.<br><br>METHODS: A total of 36 rats were evaluated, with six in each group. A 36-day ATT at 100&#x202f;mg/kg dose for isoniazid, 300&#x202f;mg/kg for rifampicin and 700&#x202f;mg/kg for pyrazinamide were fed to induce hepatotoxicity in rats. Group I and II-VI received normal saline and ATT, respectively. Oral scopoletin (1,5 and 10&#x202f;mg/kg) and NAC 150&#x202f;mg/kg were administered in groups III, IV, V and VI, respectively, once daily for the last&#xa0;15&#xa0;days of the experiment. LFT monitoring was performed at baseline, days 21, 28, and 36. Rats were sacrificed for the histopathology examination.<br><br>RESULTS: Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin levels were significantly increased in group II (receiving ATT) compared to normal control on day 28 and day 36 (p<0.05). All three doses of scopoletin and NAC groups led to the resolution of AST, ALT, ALP, and bilirubin changes induced by ATT medications effect beginning by day 28 and persisting on day 36 (p<0.01). An insignificant effect was observed on albumin and total protein levels. The effect was confirmed with antioxidants and histopathology analysis.<br><br>CONCLUSIONS: The study confirms the hepatoprotective efficacy of scopoletin in a more robust commonly encountered liver injury etiology.}, }
@article {pmid37730076, year = {2023}, author = {Zhou, X and Chen, Q and Chen, L and Liao, X and Wang, Z and Zhu, F}, title = {The effect of reactive oxygen species (ROS) in immunity and WSSV infection of Scylla paramamosain.}, journal = {Fish &amp; shellfish immunology}, volume = {141}, number = {}, pages = {109075}, doi = {10.1016/j.fsi.2023.109075}, pmid = {37730076}, issn = {1095-9947}, mesh = {Animals ; Reactive Oxygen Species ; *Brachyura ; *White spot syndrome virus 1/physiology ; Arthropod Proteins ; Immunity, Innate/genetics ; *Virus Diseases ; Superoxide Dismutase ; Hemocytes ; }, abstract = {Reactive oxygen species (ROS) are typically regarded as being generated by the cellular respiratory chain or by cells under pathological damage, which play a crucial role as signaling molecules in promoting hemocytes circulation and normal cellular physiological functions. In this study, the antioxidant N-acetylcysteine (NAC) was used to reduce ROS in vivo and in vitro, which to analyze the effect of ROS on innate immunity and viral infection of mud crab. The total hemocyte count (THC), phenoloxidase (PO), superoxide dismutase (SOD) activity, immune-relative genes were analyzed, respectively. Moreover, the effect of ROS on WSSV infection was analyzed by THC and hemocytes apoptosis. The data showed that NAC could effectively remove and inhibit intracellular ROS. The THC of NAC group was reduced at 12 h and 24 h compared with that of control. And the inhibition of ROS by NAC could increase the SOD activity with control group, while increased the PO activity caused by early WSSV infection. And NAC could up-regulate the expression of MCM7, JAK, TLR and proPO significantly, while down-regulate the expression of Astakine, proPO, caspase and p53. Similarly, NAC could inhibit WSSV-induced apoptosis of S. paramamosain hemocytes. The data illustrated that ROS participates in the interaction between hemocytes and virus infection by regulating innate immunity. Especially, after NAC inhibited ROS, the expression of hemocytes proliferation gene Astakine was also inhibited, which may indicate that ROS is related to the process of hemocytes proliferation. The data will show a preliminary exploration on the regulatory role of ROS in crustacean immune system.}, }
@article {pmid37726091, year = {2023}, author = {Sun, Z and Wu, K and Feng, C and Lei, XG}, title = {Selenium-dependent glutathione peroxidase 1 regulates transcription of elongase 3 in murine tissues.}, journal = {Free radical biology &amp; medicine}, volume = {208}, number = {}, pages = {708-717}, doi = {10.1016/j.freeradbiomed.2023.09.010}, pmid = {37726091}, issn = {1873-4596}, mesh = {Humans ; Male ; Mice ; Animals ; Infant ; *Glutathione Peroxidase GPX1 ; *Selenium/metabolism ; Glutathione Peroxidase/genetics/metabolism ; Fatty Acid Elongases/genetics/metabolism ; Diquat/metabolism ; HEK293 Cells ; Mice, Knockout ; RNA, Messenger/metabolism ; Liver/metabolism ; }, abstract = {We have previously shown dysregulated lipid metabolism in tissues of glutathione peroxidase 1 (GPX1) overexpressing (OE) or deficient (KO) mice. This study explored underlying mechanisms of GPX1 in regulating tissue fatty acid (FA) biosynthesis. GPX1 OE, KO, and wild-type (WT) mice (n = 5, male, 3-6 months old) were fed a Se-adequate diet (0.3 mg/kg) and assayed for liver and adipose tissue FA profiles and mRNA levels of key enzymes of FA biosynthesis and redox-responsive transcriptional factors (TFs). These three genotypes of mice (n = 5) were injected intraperitoneally with diquat, ebselen, and N-acetylcysteine (NAC) at 10, 50, and 50 mg/kg of body weight, respectively, and killed at 0 and 12 h after the injections to detect mRNA levels of FA elongases and desaturases and the TFs in the liver and adipose tissue. A luciferase reporter assay with targeted deletions of mouse Elovl3 promoter was performed to determine transcriptional regulations of the gene by GPX1 mimic ebselen in HEK293T cells. Compared with WT, GPX1 OE and KO mice had 9-42% lower (p < 0.05) and 36-161% higher (p < 0.05) concentrations of C20:0, C22:0, and C24:0 in these two tissues, respectively, along with reciprocal increases and decreases (p < 0.05) of Elovl3 transcripts. Ebselen and NAC decreased (p < 0.05), whereas diquat decreased (p < 0.05), Elovl3 transcripts in the two tissues. Overexpression and knockout of GPX1 decreased (p < 0.05) and increased (p < 0.05) ELOVL3 levels in the two tissues, respectively. Three TFs (GABP, SP1, and DBP) were identified to bind the Elovl3 promoter (-1164/+33 base pairs). Deletion of DBP (-98/-86 base pairs) binding domain in the promoter attenuated (13%, p < 0.05) inhibition of ebselen on Elovl3 promoter activation. In summary, GPX1 overexpression down-regulated very long-chain FA biosynthesis via transcriptional inhibition of the Elovl3 promoter activation.}, }
@article {pmid37716334, year = {2023}, author = {Chung, TW and Cheng, CL and Liu, YH and Huang, YC and Chen, WP and Panda, AK and Chen, WL}, title = {Dopamine-dependent functions of hyaluronic acid/dopamine/silk fibroin hydrogels that highly enhance N-acetyl-L-cysteine (NAC) delivered from nasal cavity to brain tissue through a near-infrared photothermal effect on the NAC-loaded hydrogels.}, journal = {Biomaterials advances}, volume = {154}, number = {}, pages = {213615}, doi = {10.1016/j.bioadv.2023.213615}, pmid = {37716334}, issn = {2772-9508}, mesh = {Rats ; Animals ; *Fibroins ; Acetylcysteine/pharmacology ; Hyaluronic Acid/pharmacology ; Dopamine/pharmacology ; Hydrogels/pharmacology ; Nasal Cavity ; Brain ; }, abstract = {Hyaluronic acid/silk fibroin (HA/SF or HS) hydrogels with remarkable mechanical characteristics have been reported as tissue engineering biomaterials. Herein, the addition of dopamine/polydopamine (DA/PDA) to HS hydrogels to develop multifunctional HA/PDA/SF (or HDS) hydrogels for the delivery of drugs such as N-acetyl-L-cysteine (NAC) from nasal to brain tissue is examined. Herein, DA-dependent functions of HDS hydrogels with highly adhesive forces, photothermal response (PTR) effects generated by near infrared (NIR) irradiation, and anti-oxidative effects were demonstrated. An in-vitro study shows that the HDS/NAC hydrogels could open tight junctions in the RPMI 2650 cell line, a model cell of the nasal mucosa, as demonstrated by the decreased values of transepithelial electrical resistance (TEER) and more discrete ZO-1 staining than those for the control group. This effect was markedly enhanced by NIR irradiation of the HDS/NAC-NIR hydrogels. Compared to the results obtained using NAC solution, an in-vivo imaging study (IVIS) in rats showed an approximately nine-fold increase in the quantity of NAC delivered from the nasal cavity to the brain tissue in the span of 2 h through the PTR effect generated by the NIR irradiation of the nasal tissue and administration of the HDS/NAC hydrogels. Herein, dopamine-dependent multifunctional HDS hydrogels were studied, and the nasal administration of HDS/NAC-NIR hydrogels with PTR effects generated by NIR irradiation was found to have significantly enhanced NAC delivery to brain tissues.}, }
@article {pmid37715092, year = {2024}, author = {Peng, HX and Chai, F and Chen, KH and Huang, YX and Wei, GJ and Yuan, H and Pang, YF and Luo, SH and Wang, CF and Chen, WC}, title = {Reactive Oxygen Species-Mediated Mitophagy and Cell Apoptosis are Involved in the Toxicity of Aluminum Chloride Exposure in GC-2spd.}, journal = {Biological trace element research}, volume = {202}, number = {6}, pages = {2616-2629}, pmid = {37715092}, issn = {1559-0720}, support = {2020KY13017//Guangxi University Young and Middle-aged Teachers' Basic Ability Improvement Project/ ; GZZC2020248//Guangxi Zhuang Autonomous Region Administration of Traditional Chinese Medicine Self-financing Scientific Research Project/ ; Z20201416//Guangxi Zhuang Autonomous Region Health and Health Commission Self-financing Scientific Research Course/ ; 81960303//National Natural Science Foundation of China/ ; 2020GXNSFAA297257)//Guangxi Natural Science Foundation Project/ ; }, mesh = {*Aluminum Chloride/toxicity ; Animals ; *Apoptosis/drug effects ; Male ; *Reactive Oxygen Species/metabolism ; *Mitophagy/drug effects ; Mice ; Membrane Potential, Mitochondrial/drug effects ; Testis/drug effects/metabolism/pathology ; Cell Survival/drug effects ; Spermatocytes/drug effects/metabolism ; Cell Line ; Chlorides/toxicity ; Aluminum Compounds/toxicity ; }, abstract = {Aluminum chloride is an inorganic polymeric coagulant commonly found in daily life and various materials. Although male reproductive toxicity has been associated with AlCl3 exposure, the underlying mechanism remains unclear. This study aimed to examine the impact of AlCl3 exposure on mitophagy and mitochondrial apoptosis in testicular tissue and mouse spermatocytes. Reactive oxygen species (ROS) and ATP levels were measured in GC-2spd after AlCl3 exposure using a multifunctional enzyme labeler. The changes in mitochondrial membrane potential (MMP) and TUNEL were observed through confocal laser microscopy, and the expression of proteins associated with mitophagy and apoptosis was analyzed using Western blot. Our results demonstrated that AlCl3 exposure disrupted mitophagy and increased apoptosis-related protein expression in testicular tissues. In the in vitro experiments, AlCl3 exposure induced ROS production, suppressed cell viability and ATP production, and caused a decrease in MMP, leading to mitophagy and cell apoptosis in GC-2spd cells. Intervention with N-acetylcysteine (NAC) reduced ROS production and partially restored mitochondrial function, thereby reversing the resulting mitophagy and cell apoptosis. Our findings provide evidence that ROS-mediated mitophagy and cell apoptosis play a crucial role in the toxicity of AlCl3 exposure in GC-2spd. These results contribute to the understanding of male reproductive toxicity caused by AlCl3 exposure and offer a foundation for future research in this area.}, }
@article {pmid37714033, year = {2023}, author = {Ma, R and Sun, T and Wang, X and Ren, K and Min, T and Xie, X and Wang, D and Li, K and Zhang, Y and Zhu, K and Mo, C and Dang, C and Yang, Y and Zhang, H}, title = {Chronic exposure to low-dose deltamethrin can lead to colon tissue injury through PRDX1 inactivation-induced mitochondrial oxidative stress injury and gut microbial dysbiosis.}, journal = {Ecotoxicology and environmental safety}, volume = {264}, number = {}, pages = {115475}, doi = {10.1016/j.ecoenv.2023.115475}, pmid = {37714033}, issn = {1090-2414}, mesh = {Humans ; Animals ; Mice ; Dysbiosis/chemically induced ; *Gastrointestinal Microbiome ; Colon ; Oxidative Stress ; Acetylcysteine ; Peroxiredoxins/genetics ; }, abstract = {OBJECTIVE: To date, it is unclear whether deltamethrin (DLM) intake causes damage to colon tissue. Hence, in this study, we aimed to clarify the effect of long-term exposure to low-dose DLM on colon tissues, and its potential mechanisms.<br><br>METHODS: Mice were treated with DLM (0.2&#xa0;mg/kg/day) or DLM combined with N-acetyl-l-cysteine (NAC) (50&#xa0;mg/kg/day) for 8 weeks. Human colon cancer cells (HCT-116) were treated with DLM (0, 25, 50, or 100&#xa0;&#xb5;M), NAC (2&#xa0;mM), or overexpression plasmids targeting peroxiredoxin 1 (PRDX1) for 48&#xa0;h. DLM was detected using a DLM rapid detection card. Colon injury was evaluated using haematoxylin and eosin staining and transmission electron microscopy. Apoptosis was determined using immunofluorescence staining (IF), western blotting (WB) and flow cytometry (FC) assays. MitoTracker, JC-1, and glutathione (GSH) detection were used to detect mitochondrial oxidative stress. Intestinal flora were identified by 16&#xa0;S rDNA sequencing.<br><br>RESULTS: DLM accumulation was detected in the colon tissue and faeces of mice following long-term intragastric administration. Interestingly, our results showed that, even at a low dose, long-term intake of DLM resulted in severe weight loss and decreased the disease activity index scores and colon length. The results of IF, WB, and FC showed that DLM induced apoptosis in the colon tissue and cells. MitoTracker, JC-1, and GSH assays showed that DLM increased mitochondrial stress in colonic epithelial cells. Mechanistic studies have shown that increased mitochondrial stress and apoptosis are mediated by PRDX1 inhibition. Further experiments showed that PRDX1 overexpression significantly reduced DLM-induced oxidative stress injury and apoptosis. In addition, we observed that chronic exposure to DLM altered the composition of the intestinal flora in mice, including an increase in Odoribacter and Bacteroides and a decrease in Lactobacillus. The gut microbial richness decreased after DLM exposure in mice. Supplementation with NAC both in vivo and in vitro alleviated DLM-induced oxidative stress injury, colonic epithelial cell apoptosis, and gut microbial dysbiosis.<br><br>CONCLUSION: Chronic exposure to DLM, even at small doses, can cause damage to the colon tissue, which cannot be ignored. The production and use of pesticides such as DLM should be strictly regulated during agricultural production.}, }
@article {pmid37712506, year = {2024}, author = {Zhang, Q and Liu, Z and Wang, T and Yu, M and Li, X}, title = {Efficacy and acceptability of adjunctive n-acetylcysteine for psychotic disorders: Systematic review and meta-analysis.}, journal = {Human psychopharmacology}, volume = {39}, number = {2}, pages = {e2880}, doi = {10.1002/hup.2880}, pmid = {37712506}, issn = {1099-1077}, mesh = {Humans ; Acetylcysteine/therapeutic use ; *Antipsychotic Agents/therapeutic use ; *Schizophrenia/drug therapy ; *Psychotic Disorders/drug therapy ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: N-acetylcysteine (NAC) augmentation of antipsychotic medication has been studied in psychotic disorders but the results are inconsistent. This meta-analysis aimed to evaluate the efficacy and acceptability of NAC as an augmentation strategy for psychotic disorders.<br><br>METHODS: PubMed, Web of Science, EMBASE, PsycINFO, Cochrane Library, and ClinicalTrials.gov were searched until the date of November 28, 2022. The inclusion criteria were randomized controlled trials (RCTs) comparing NAC and placebo in patients with psychotic disorders. The outcomes were the psychotic symptoms measured by the Positive and Negative Syndrome Scale (PANSS) and drop-out rates.<br><br>RESULTS: A total of 594 patients from eight trials were included. The results showed that no difference was found in score changes of PANSS total, positive, negative, or general psychopathology scale scores between the NAC group and placebo group in both time points (&#x2264;24&#xa0;weeks and >24&#xa0;weeks). There was also no statistical difference in drop-out rates between the two groups.<br><br>CONCLUSION: For the moment, it is not appropriate to recommend NAC as an augmentation of antipsychotic medication to treat psychotic disorders in routine clinical practice.}, }
@article {pmid37711440, year = {2023}, author = {Yamamoto, T and Tanji, M and Mitsunaga, F and Nakamura, S}, title = {SARS-CoV-2 sublingual vaccine with RBD antigen and poly(I:C) adjuvant: Preclinical study in cynomolgus macaques.}, journal = {Biology methods &amp; protocols}, volume = {8}, number = {1}, pages = {bpad017}, pmid = {37711440}, issn = {2396-8923}, abstract = {Mucosal vaccine for sublingual route was prepared with recombinant SARS-CoV-2 spike protein receptor binding domain (RBD) antigen and poly(I:C) adjuvant components. The efficacy of this sublingual vaccine was examined using Cynomolgus macaques. Nine of the macaque monkeys were divided into three groups of three animals: control [just 400 µg poly(I:C) per head], low dose [30 µg RBD and 400 µg poly(I:C) per head], and high dose [150 µg RBD and 400 µg poly(I:C) per head], respectively. N-acetylcysteine (NAC), a mild reducing agent losing mucin barrier, was used to enhance vaccine delivery to mucosal immune cells. RBD-specific IgA antibody secreted in pituita was detected in two of three monkeys of the high dose group and one of three animals of the low dose group. RBD-specific IgG and/or IgA antibodies in plasma were also detected in these monkeys. These indicated that the sublingual vaccine stimulated mucosal immune response to produce antigen-specific secretory IgA antibodies in pituita and/or saliva. This sublingual vaccine also affected systemic immune response to produce IgG (IgA) in plasma. Little RBD-specific IgE was detected in plasma, suggesting no allergic antigenicity of this sublingual vaccine. Thus, SARS-CoV-2 sublingual vaccine consisting of poly(I:C) adjuvant showed reasonable efficacy in a non-human primate model.}, }
@article {pmid37710183, year = {2023}, author = {Du, YX and Zhao, YT and Sun, YX and Xu, AH}, title = {Acid sphingomyelinase mediates ferroptosis induced by high glucose via autophagic degradation of GPX4 in type 2 diabetic osteoporosis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {29}, number = {1}, pages = {125}, pmid = {37710183}, issn = {1528-3658}, mesh = {Animals ; Rats ; Autophagy ; Ceramides ; *Diabetes Mellitus, Type 2 ; *Ferroptosis ; Glucose ; *Osteoporosis/drug therapy/etiology ; Reactive Oxygen Species ; Sphingomyelin Phosphodiesterase/genetics ; X-Ray Microtomography ; }, abstract = {BACKGROUND: Ferroptosis has been implicated in the pathological process of type 2 diabetic osteoporosis (T2DOP), although the specific underlying mechanisms remain largely unknown. This study aimed to clarify the role and possible mechanism of acid sphingomyelinase (ASM)-mediated osteoblast ferroptosis in T2DOP.<br><br>METHODS: We treated hFob1.19 cells with normal glucose (NG) and different concentrations of high glucose (HG, 26.25 mM, 35 mM, or 43.75 mM) for 48&#xa0;h. We then measured cell viability and osteogenic function, quantified ferroptosis and autophagy levels, and measured the levels of ASM and ceramide in the cells. To further investigate the specific mechanism, we examined these indicators by knocking down ASM expression, hydroxychloroquine (HCQ) treatment, or N-acetylcysteine (NAC) treatment. Moreover, a T2DOP rat model was induced and microcomputed tomography was used to observe the bone microstructure. We also evaluated the serum levels of iron metabolism-associated factors, ceramide and lipid peroxidation (LPO) and measured the expression of ASM, LC3 and GPX4 in bone tissues.<br><br>RESULTS: HG inhibited the viability and osteogenic function of osteoblasts by inducing ferroptosis in a concentration-dependent manner. Furthermore, the expression of ASM and ceramide and autophagy levels were increased by HG treatment, and these factors were required for the HG-induced reactive oxygen species (ROS) generation and LPO. Similarly, inhibiting intracellular ROS also reduced HG-induced ASM activation and autophagy. ASM-mediated activation of autophagy was crucial for HG-induced degradation of GPX4, and inhibiting ASM improved osteogenic function by decreasing HG-induced autophagy, GPX4 degradation, LPO and subsequent ferroptosis. We also found that inhibiting ASM could alleviated ferroptosis and autophagy and improved osteogenic function in a T2DOP rat model.<br><br>CONCLUSION: ASM-mediated autophagy activation induces osteoblast ferroptosis under HG conditions through the degradation of GPX4, providing a novel mechanistic insight into the treatment and prevention of T2DOP.}, }
@article {pmid37705917, year = {2023}, author = {Granata, S and Bruschi, M and Verlato, A and Pontrelli, P and Gesualdo, L and Stallone, G and Zaza, G}, title = {Autophagy Activation in Peripheral Blood Mononuclear Cells of Peritoneal Dialysis Patients.}, journal = {Kidney international reports}, volume = {8}, number = {9}, pages = {1852-1863}, pmid = {37705917}, issn = {2468-0249}, abstract = {INTRODUCTION: The complete systemic deregulated biological network in patients on peritoneal dialysis (PD) is still only partially defined. High-throughput/omics techniques may offer the possibility to analyze the main biological fingerprints associated with this clinical condition.<br><br>METHODS: We applied an innovative bioinformatic analysis of gene expression microarray data (mainly based on support vector machine (SVM) learning) to compare the transcriptomic profile of peripheral blood mononuclear cells (PBMCs) of healthy subjects (HS), chronic kidney disease (CKD) patients, and patients on PD divided into a microarray group (5 HS, 9 CKD, and 10 PD) and a validation group (10 HS, 15 CKD, and 15 PD). Classical well-standardized biomolecular approaches (western blotting and flow cytometry) were used to validate the transcriptomic results.<br><br>RESULTS: Bioinformatics revealed a distinctive PBMC transcriptomic profiling for PD versus CKD and HS (n&#xa0;= 419 genes). Transcripts encoding for key elements of the autophagic pathway were significantly upregulated in PD, and the autophagy related 5 (ATG5) reached the top level of discrimination [-Log10 P-value&#xa0;= 11.3, variable importance in projection (VIP) score&#xa0;= 4.8, SVM rank:1]. Protein levels of ATG5 and microtubule associated protein 1 light chain 3 beta (LC3B), an important constituent of the autophagosome, validated microarray results. In addition, the incubation of PBMCs of HS with serum of patients on PD upregulated both proteins. Autophagy in PBMCs from patients on PD was attenuated by N-acetyl-cysteine or Resatorvid treatment.<br><br>CONCLUSIONS: Our data demonstrated, for the first time, that the autophagy pathway is activated in immune-cells of patients on PD, and this may represent a novel therapeutic target.}, }
@article {pmid37705749, year = {2023}, author = {Wang, L and Huang, B and Zeng, Y and Yang, J and Li, Z and Ng, JPL and Xu, X and Su, L and Yun, X and Qu, L and Chen, R and Luo, W and Wang, Y and Chen, C and Yang, L and Qu, Y and Zhang, W and Chan, JTW and Wang, X and Law, BYK and Mok, SWF and Chung, SK and Wong, VKW}, title = {N-Acetylcysteine overcomes epalrestat-mediated increase of toxic 4-hydroxy-2-nonenal and potentiates the anti-arthritic effect of epalrestat in AIA model.}, journal = {International journal of biological sciences}, volume = {19}, number = {13}, pages = {4082-4102}, pmid = {37705749}, issn = {1449-2288}, mesh = {Humans ; Animals ; Rats ; *Acetylcysteine/therapeutic use ; Leukocytes, Mononuclear ; Aldehydes ; *Arthritis, Rheumatoid/drug therapy ; }, abstract = {Epalrestat, an aldose reductase inhibitor (ARI), has been clinically adopted in treating diabetic neuropathy in China and Japan. Apart from the involvement in diabetic complications, AR has been implicated in inflammation. Here, we seek to investigate the feasibility of clinically approved ARI, epalrestat, for the treatment of rheumatoid arthritis (RA). The mRNA level of AR was markedly upregulated in the peripheral blood mononuclear cells (PBMCs) of RA patients when compared to those of healthy donors. Besides, the disease activity of RA patients is positively correlated with AR expression. Epalrestat significantly suppressed lipopolysaccharide (LPS) induced TNF-α, IL-1β, and IL-6 in the human RA fibroblast-like synoviocytes (RAFLSs). Unexpectedly, epalrestat treatment alone markedly exaggerated the disease severity in adjuvant induced arthritic (AIA) rats with elevated Th17 cell proportion and increased inflammatory markers, probably resulting from the increased levels of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA). Interestingly, the combined treatment of epalrestat with N-Acetylcysteine (NAC), an anti-oxidant, to AIA rats dramatically suppressed the production of 4-HNE, MDA and inflammatory cytokines, and significantly improved the arthritic condition. Taken together, the anti-arthritic effect of epalrestat was diminished or even overridden by the excessive accumulation of toxic 4-HNE or other reactive aldehydes in AIA rats due to AR inhibition. Co-treatment with NAC significantly reversed epalrestat-induced upregulation of 4-HNE level and potentiated the anti-arthritic effect of epalrestat, suggesting that the combined therapy of epalrestat with NAC may sever as a potential approach in treating RA. Importantly, it could be regarded as a safe intervention for RA patients who need epalrestat for the treatment of diabetic complications.}, }
@article {pmid37705237, year = {2024}, author = {Sheng, Y and Zhang, C and Cai, D and Xu, G and Chen, S and Li, W and Dong, J and Shen, B and Tang, J and Xu, L}, title = {2,2',4,4'-Tetrabromodiphenyl ether and cadmium co-exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME-dependent pyroptosis in renal tubular epithelial cells.}, journal = {Environmental toxicology}, volume = {39}, number = {1}, pages = {289-298}, doi = {10.1002/tox.23957}, pmid = {37705237}, issn = {1522-7278}, support = {2023RC101//Medical Health Science and Technology Project of Zhejiang Provincial Health Commission/ ; 22206059//National Natural Science Foundation of China/ ; 2023R417A016//Zhejiang Provincial University Students Science and Technology Innovation Activity/ ; }, mesh = {*Receptors, Aryl Hydrocarbon/metabolism ; *Cadmium/toxicity ; Caspase 3/metabolism ; Reactive Oxygen Species/metabolism ; Pyroptosis ; Ether ; Epithelial Cells/metabolism ; }, abstract = {We have previously found that a mixture exposure of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand-receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE-47 (50 μM) or Cd (5 μM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co-treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N-acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved-caspase-3 and gasdermin E N-terminal (GSDME-NT), while caspase-8, caspase-3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE-47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME-dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.}, }
@article {pmid37701655, year = {2023}, author = {Eslami, G and Ghorbani, A and Akbari, J and Farmoudeh, A and Faghih, F and Moghimi, M}, title = {Efficacy of Oral Mucoadhesive N-Acetylcysteine Tablets in Treatment of Recurrent Aphthous Stomatitis: A Randomized Double-Blind, Placebo-Controlled Clinical Trial.}, journal = {Frontiers in dentistry}, volume = {20}, number = {}, pages = {18}, pmid = {37701655}, issn = {2676-296X}, abstract = {Objectives: This study aimed to assess the efficacy of oral mucoadhesive N-acetylcysteine (NAC) tablets for treatment of recurrent aphthous stomatitis (RAS). Materials and Methods: Forty-nine patients with RAS were randomized to receive mucoadhesive NAC tablets (n=25) or placebo (n=24). Tablets were prescribed three times a day for 7 days in each group. Pain intensity was evaluated with visual analog scale (VAS) three times a day from day 1 to day 7. Also, patients were clinically examined on days 0 (before entering the study), 3, 5, and 7 using a metal caliper to measure the diameter of the lesions. The data were statistically analyzed and P<0.05 was considered statistically significant. Results: Regarding the VAS score, all participants in the treatment group showed complete recovery on day 7 (P<0.01). Also, the diameter of the lesions was significantly smaller in the treatment group than the placebo group at the end of the study (P<0.001). Conclusion: The results of this clinical trial showed for the first time that mucoadhesive NAC tablets can significantly decrease pain and the diameter of RAS lesions without any systemic complications.}, }
@article {pmid37696227, year = {2023}, author = {Chan, CY and Conley, SF and Salameh, S and Sayegh, J and Wurzba, SDS and Grenier, K and Linn, DT and Partain, MP and Daniel, SJ}, title = {Otologic safety of intratympanic N-acetylcysteine in an animal model.}, journal = {International journal of pediatric otorhinolaryngology}, volume = {173}, number = {}, pages = {111702}, doi = {10.1016/j.ijporl.2023.111702}, pmid = {37696227}, issn = {1872-8464}, mesh = {Humans ; Animals ; Guinea Pigs ; *Acetylcysteine/pharmacology ; *Ototoxicity ; Models, Animal ; Ciprofloxacin ; Dexamethasone ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC) is an anti-oxidant and mucolytic effective against bacterial biofilms, making it useful in the treatment of chronically discharging ears that are unresponsive to traditional treatment methods. The objective of this study was to evaluate the otologic safety of intratympanic NAC combined with Ciprodex® in an animal model.<br><br>METHODS: Baseline distortion product otoacoustic emissions (DPOAE) and auditory brainstem response (ABR) measurements were performed for both ears on thirteen guinea pigs from the animal care research facilities of the McGill University Health Center. This was followed by intratympanic administration of control solution (Ciprofloxacin 0.3%/Dexamethasone 0.1%) to the left ear and experimental solution (1.25% NAC/Ciprofloxacin 0.3%/Dexamethasone 0.1%) to the right ear. Three additional intratympanic injections were performed over the next fourteen days. DPOAE and ABR measurements were repeated 3-4 weeks after the initial procedure. Outcome measures included differences in DPOAE and ABR thresholds after intervention, clinical evidence of vestibular dysfunction and histological evidence of ototoxicity.<br><br>RESULTS: There were no significant differences in the ABR thresholds and DPOAE results of the control and experimental ears at baseline and after intervention. There was neither clinical manifestation of vestibular dysfunction nor histological evidence of ototoxicity.<br><br>CONCLUSION: Our study suggests that intratympanic 1.25% NAC with ciprofloxacin and dexamethasone is safe in guinea pigs and support its potential use in the treatment of chronically discharging ears. Further studies in humans are required to analyze its efficacy relative to conventional treatments.<br><br>LEVEL OF EVIDENCE: Animal Research.}, }
@article {pmid37692935, year = {2023}, author = {Zhang, J and Xu, X and Liang, Y and Wu, X and Qian, Z and Zhang, L and Wang, T}, title = {Particulate matter promotes the epithelial to mesenchymal transition in human lung epithelial cells via the ROS pathway.}, journal = {American journal of translational research}, volume = {15}, number = {8}, pages = {5159-5167}, pmid = {37692935}, issn = {1943-8141}, abstract = {OBJECTS: Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased rates of chronic cardiopulmonary diseases, including asthma and idiopathic pulmonary fibrosis (IPF). Several investigations have suggested that the epithelial-to-mesenchymal transition (EMT) may contribute to the complex pathobiology of environmental exposure-mediated pulmonary fibrosis. The present study was designed to characterize the mechanisms of PM-mediated EMT in human lung epithelial cells (HBECs).<br><br>METHODS AND RESULTS: PM induced significant dose (0-100 &#x3bc;g/ml) and time (0-72 h)-dependent increases in transforming growth factor &#x3b2; (TGF&#x3b2;) and fibronectin (FN) protein levels in HBECs lysates. PM-activated TGF&#x3b2; and FN protein production in HBECs was prevented by the antioxidant N-acetyl-cysteine (NAC, 5 mM). Furthermore, the NF-&#x3ba;B inhibitor BAY11-7082 (5 &#x3bc;M) abolished PM-induced FN production in HBECs. Biomarkers of EMT (ACTA2, SNAIL1 and SNAIL2) in PM-treated HBECs were significantly increased at the mRNA level compared to control cells.<br><br>CONCLUSIONS: These results demonstrate that PM increases protein levels of TGF&#x3b2; and FN via reactive oxygen species (ROS)-dependent pathways. In addition, PM exposure induces EMT in human lung epithelial cells, supporting a novel mechanism for PM-induced pulmonary fibrosis.}, }
@article {pmid37692924, year = {2023}, author = {Zhang, J and Wu, X and Liang, Y and Kelly, G and Burt, JM and Zhang, L and Wang, T}, title = {Particulate matter increases connexin 43 expression and exacerbates endothelial barrier disruption.}, journal = {American journal of translational research}, volume = {15}, number = {8}, pages = {5099-5109}, pmid = {37692924}, issn = {1943-8141}, abstract = {OBJECTIVES: Particulate Matter (PM) air pollution is known to exacerbate cardiopulmonary diseases. We previously demonstrated that PM mediates endothelial injury and barrier disruption by modulating the endothelial cytoskeleton and cell-cell junctions, but the effects of PM exposure on cell-cell communication and gap junction activity are still unknown.<br><br>METHODS: This study focused on the characterization of PM-regulated endothelial dysfunction through connexin 43 (Cx43), the most abundant gap junction protein expressed in lung endothelial cells (ECs), using cultured human lung endothelial cells and a well-characterized PM sample.<br><br>RESULTS: PM exposure induced a time-dependent increase of Cx43 in human lung ECs at both the mRNA and protein levels. N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, significantly suppressed PM-induced Cx43 expression. Cx43 proteins on the plasma membrane and ER/Golgi apparatus were elevated in response to a PM challenge. In addition, PM induced gap junction activity, which was indicated by green fluorescence dye transfer between two adjacent ECs. Moreover, GAP27, a selective Cx43 channel inhibitor, attenuated PM-induced human lung EC barrier disruption, which was reflected by rescued trans-endothelial electrical resistance (TER) with an electric cell-substrate impedance sensing system. Moreover, knocking down Cx43 alleviated PM-induced myosin light chain (MLC) phosphorylation.<br><br>CONCLUSIONS: These results strongly suggest that Cx43 plays a key role in PM-mediated endothelial barrier disruption and signal transduction. Cx43 may be a therapeutic target in PM-mediated cardiopulmonary disorders.}, }
@article {pmid37685966, year = {2023}, author = {Muñoz-Sánchez, G and Godínez-Méndez, LA and Fafutis-Morris, M and Delgado-Rizo, V}, title = {Effect of Antioxidant Supplementation on NET Formation Induced by LPS In Vitro; the Roles of Vitamins E and C, Glutathione, and N-acetyl Cysteine.}, journal = {International journal of molecular sciences}, volume = {24}, number = {17}, pages = {}, pmid = {37685966}, issn = {1422-0067}, mesh = {Horses ; Animals ; *Antioxidants/pharmacology ; *Vitamin E/pharmacology ; Acetylcysteine/pharmacology ; Lipopolysaccharides/pharmacology ; Glutathione Disulfide ; Reactive Oxygen Species ; Glutathione ; Ascorbic Acid/pharmacology ; Vitamins ; Dietary Supplements ; }, abstract = {Neutrophil extracellular traps (NETs) require reactive oxygen species (ROS) to eliminate pathogens by inducing oxidative stress. However, this process can also cause tissue damage to the host. Neutrophils contain high concentrations of vitamin C (1.5 mM) compared to the bloodstream (0.1 mM), and this antioxidant can interact with vitamin E and glutathione (GSH) inside the cell to maintain the redox balance. Previous studies have investigated the effect of vitamins E or C and N-acetyl cysteine (NAC) on NET formation, but the interactions of these molecules in neutrophils remain unknown. In this study, we investigated the effect of antioxidants alone and two combinations on NET formation and oxidative stress. Neutrophils were pre-loaded with GSH + NAC or vitamin E + vitamin C + GSH + NAC (termed ALL), and LPS-induced NET formation was assessed using fluorometry and immunofluorescence. Antioxidant effects were evaluated by measuring the total antioxidant capacity (TAC), GSH/GSSG ratio, ROS production, nitrite + nitrate levels, and lipid peroxidation. Our results showed that even low doses of antioxidants are capable of decreasing NETs. Furthermore, the combinations augmented TAC and GSH/GSSG ratio and decreased ROS, nitrites + nitrates, and malondialdehyde (MDA) levels in supplemented neutrophils in vitro.}, }
@article {pmid37684590, year = {2023}, author = {Liu, S and Guan, Y and Weng, Y and Liao, B and Tong, L and Hao, Z and Chen, J and Shi, J and Cheng, T}, title = {Genome-wide identification of the NAC gene family and its functional analysis in Liriodendron.}, journal = {BMC plant biology}, volume = {23}, number = {1}, pages = {415}, pmid = {37684590}, issn = {1471-2229}, support = {32101546//National Natural Science Foundation of China/ ; 32071784//National Natural Science Foundation of China/ ; 2021YFD2200103//National Key Research and Development Program of China during the 14th Five-year Plan Period/ ; PAPD//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; PAPD//Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; }, mesh = {*Liriodendron ; Acetylcysteine ; Cell Nucleus ; Cytoplasm ; }, abstract = {As one of the largest plant specific transcription factor families, NAC family members play an important role in plant growth, development and stress resistance. To investigate the function of NAC transcription factors during abiotic stress, as well as during somatic embryogenesis, we identified and characterized the NAC gene family in Liriodendron chinense. We found that most LcNAC members contain more than three exons, with a relatively conserved gene and motif structure, especially at the N-terminus. Interspecies collinearity analysis revealed a closer relationship between the L. chinense NACs and the P. trichocarpa NACs. We analyzed the expression of LcNAC in different tissues and under three abiotic stresses. We found that 12 genes were highly expressed during the ES3 and ES4 stages of somatic embryos, suggesting that they are involved in the development of somatic embryos. 6 LcNAC genes are highly expressed in flower organs. The expression pattern analysis of LcNACs based on transcriptome data and RT-qPCR obtained from L. chinense leaves indicated differential expression responses to drought, cold, and heat stress. Genes in the NAM subfamily expressed differently during abiotic stress, and LcNAC6/18/41/65 might be the key genes in response to abiotic stress. LcNAC6/18/41/65 were cloned and transiently transformed into Liriodendron protoplasts, where LcNAC18/65 was localized in cytoplasm and nucleus, and LcNAC6/41 was localized only in nucleus. Overall, our findings suggest a role of the NAC gene family during environmental stresses in L. chinense. This research provides a basis for further study of NAC genes in Liriodendron chinense.}, }
@article {pmid37683986, year = {2023}, author = {Lapenna, D}, title = {Glutathione and glutathione-dependent enzymes: From biochemistry to gerontology and successful aging.}, journal = {Ageing research reviews}, volume = {92}, number = {}, pages = {102066}, doi = {10.1016/j.arr.2023.102066}, pmid = {37683986}, issn = {1872-9649}, mesh = {Humans ; Aged ; *Antioxidants/metabolism ; Hydrogen Peroxide ; Glutathione/metabolism ; Glutamate-Cysteine Ligase/genetics/metabolism ; Acetylcysteine ; Glycine ; *Geriatrics ; }, abstract = {The tripeptide glutathione (GSH), namely γ-L-glutamyl-L-cysteinyl-glycine, is an ubiquitous low-molecular weight thiol nucleophile and reductant of utmost importance, representing the central redox agent of most aerobic organisms. GSH has vital functions involving also antioxidant protection, detoxification, redox homeostasis, cell signaling, iron metabolism/homeostasis, DNA synthesis, gene expression, cysteine/protein metabolism, and cell proliferation/differentiation or death including apoptosis and ferroptosis. Various functions of GSH are exerted in concert with GSH-dependent enzymes. Indeed, although GSH has direct scavenging antioxidant effects, its antioxidant function is substantially accomplished by glutathione peroxidase-catalyzed reactions with reductive removal of H2O2, organic peroxides such as lipid hydroperoxides, and peroxynitrite; to this antioxidant activity also contribute peroxiredoxins, enzymes further involved in redox signaling and chaperone activity. Moreover, the detoxifying function of GSH is basically exerted in conjunction with glutathione transferases, which have also antioxidant properties. GSH is synthesized in the cytosol by the ATP-dependent enzymes glutamate cysteine ligase (GCL), which catalyzes ligation of cysteine and glutamate forming γ-glutamylcysteine (γ-GC), and glutathione synthase, which adds glycine to γ-GC resulting in GSH formation; GCL is rate-limiting for GSH synthesis, as is the precursor amino acid cysteine, which may be supplemented as N-acetylcysteine (NAC), a therapeutically available compound. After its cell export, GSH is degraded extracellularly by the membrane-anchored ectoenzyme γ-glutamyl transferase, a process occurring, as GSH synthesis and export, in the γ-glutamyl cycle. GSH degradation occurs also intracellularly by the cytoplasmic enzymatic ChaC family of γ-glutamyl cyclotransferase. Synthesis and degradation of GSH, together with its export, translocation to cell organelles, utilization for multiple essential functions, and regeneration from glutathione disulfide by glutathione reductase, are relevant to GSH homeostasis and metabolism. Notably, GSH levels decline during aging, an alteration generally related to impaired GSH biosynthesis and leading to cell dysfunction. However, there is evidence of enhanced GSH levels in elderly subjects with excellent physical and mental health status, suggesting that heightened GSH may be a marker and even a causative factor of increased healthspan and lifespan. Such aspects, and much more including GSH-boosting substances administrable to humans, are considered in this state-of-the-art review, which deals with GSH and GSH-dependent enzymes from biochemistry to gerontology, focusing attention also on lifespan/healthspan extension and successful aging; the significance of GSH levels in aging is considered also in relation to therapeutic possibilities and supplementation strategies, based on the use of various compounds including NAC-glycine, aimed at increasing GSH and related defenses to improve health status and counteract aging processes in humans.}, }
@article {pmid37681263, year = {2023}, author = {Pepin, L and Matsler, N and Fontes, A and Heard, K and Flaherty, BF and Monte, AA}, title = {Fomepizole Therapy for Acetaminophen-Induced Liver Failure in an Infant.}, journal = {Pediatrics}, volume = {152}, number = {4}, pages = {}, doi = {10.1542/peds.2022-061033}, pmid = {37681263}, issn = {1098-4275}, abstract = {Acetaminophen overdose is common in the pediatric population. N-acetylcysteine (NAC) is effective at preventing liver injury in most patients when started shortly after the overdose. Delays to therapy increase risk of hepatotoxicity and liver failure that may necessitate organ transplant. Animal studies have demonstrated fomepizole may provide added benefit in acetaminophen overdose because of its ability to block the metabolic pathway that produces the toxic acetaminophen metabolite and downstream inhibition of oxidative stress pathways that lead to cell death. Several adult case reports describe use of fomepizole in patients at higher risk for poor outcomes despite NAC. We describe a case of a 7-month-old female who presented in acute liver failure with persistently elevated acetaminophen concentration secondary to repeated supratherapeutic doses of acetaminophen to manage fever. Fomepizole and NAC antidotes were used in the management of the patient. She fully recovered despite demonstrating multiple markers of poor outcome on initial presentation. Although randomized trials are lacking, this case suggests that fomepizole may safely provide additional benefit in pediatric patients at risk for severe acetaminophen toxicity.}, }
@article {pmid37680754, year = {2023}, author = {Alqahtani, QH and Fadda, LM and Alhusaini, AM and Hasan, IH and Ali, HM}, title = {Involvement of Nrf2, JAK and COX pathways in acetaminophen-induced nephropathy: Role of some antioxidants.}, journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society}, volume = {31}, number = {10}, pages = {101752}, pmid = {37680754}, issn = {1319-0164}, abstract = {OBJECTIVES: Acetaminophen (APAP)-induced nephrotoxicity is detrimental consequence for which there has not been a standardized therapeutic regimen. Although, N-acetylcysteine (NAC) is a well-known antidote used in APAP-induced hepatotoxicity, its benefit in nephrotoxicity caused by APAP is almost lacking. This study aimed to compare the possible protective effect of thymoquinone (TQ), curcumin (CR), and α-lipoic acid (α-LA), either in solo or in combination regimens with that of NAC against APAP-induced renal injury.<br><br>DESIGN AND METHOD: Rats were divided into nine groups; control group, APAP intoxicated group (1000&#x202f;mg/kg; orally), and the remaining seven groups received, in addition to APAP, oral doses of NAC, TQ, CR, &#x3b1;-LA, CR plus TQ, TQ plus &#x3b1;-LA, or CR plus &#x3b1;-LA. The first dose of the aforementioned antioxidants was given 24&#x202f;h before APAP, and then the second dose was given 2&#x202f;h after APAP, whereas the last dose was given 10&#x202f;h after administration of APAP.<br><br>RESULTS: Treatment with APAP elevated kidney markers like serum uric acid, urea, and creatinine. In addition, it increased the serum level of tumor necrosis factor alpha (TNF-&#x3b1;), interleukin-1beta (IL-1&#x3b2;) and thiobarbituric acid reactive species (TBARS). Also, the protein expression of renal janus kinase (JAK) and cyclooxygenase (COX)-2 were all upregulated by APAP. In contrast, the expression of Nrf2 and the renal levels of superoxide dismutase and glutathione were downregulated. Treatment with the indicated natural antioxidants resulted in amelioration of the aberrated parameters through exhibiting anti-inflammatory, antioxidant and free radical-scavenging effects with a variable degree.<br><br>CONCLUSION: The combined administration of CR and TQ exerted the most potent protection against APAP-induced nephrotoxicity through its anti-inflammatory and free radical-scavenging effects (antioxidant) which were comparable to that of NAC-treatment.}, }
@article {pmid37670970, year = {2023}, author = {Zhang, Z and Luan, Q and Hao, W and Cui, Y and Li, Y and Li, X}, title = {NOX4-derived ROS Regulates Aerobic Glycolysis of Breast Cancer through YAP Pathway.}, journal = {Journal of Cancer}, volume = {14}, number = {13}, pages = {2562-2573}, pmid = {37670970}, issn = {1837-9664}, abstract = {Background: NOX4 is highly expressed in breast cancer and is closely associated with cell invasion and metastasis. The involvement of NOX4 in glycolysis in breast cancer remains unclear. The aim of this study was to investigate the role and mechanism of NOX4 in glycolysis in breast cancer. Methods: NOX4 expression in breast cancer cells was detected by qRT-PCR and western blotting. siRNAs and plasmids were used to silence or enhance the expression of NOX4. The mRNA and protein expression of HK2, GLUT1, PKM2, LDHA, and YAP was detected by qRT-PCR and western blotting, and the [18]F-FDG uptake rate was detected by γ-radiometer. Detection of reactive oxygen species (ROS) in cells was performed using a commercial ROS kit. After transfection, CCK8, EDU and Transwell experiments were conducted to detect cell proliferation and migration ability. MicroPET imaging was used to detect the effects of NOX4 on tumor metabolism. Immunohistochemistry was used to detect the expression of NOX4, glycolytic enzymes HK2, GLUT1, PKM2, LDHA, the proliferation index KI67, and the activation of YAP pathway molecule. Results: In this study, the expression of NOX4 in MDA-MB-231 and MDA-MB-453 was higher than in MCF10A. qRT-PCR and western blotting experiments showed that NOX4 downregulation decreased the expression of glycolytic enzymes HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Conversely, the overexpression of NOX4 enhanced the expression of HK2, GLUT1, PKM2, LDHA, and 18F-FDG uptake. Proliferation and migration experiments showed that after down-regulation of NOX4, cell proliferation and migration ability decreased, while NOX4 overexpression promoted cell proliferation and migration ability. Additionally, ROS content and YAP expression decreased after NOX4 down-regulation, while ROS content and YAP expression increased following NOX4 overexpression, which was reversed by N-acetyl cysteine (NAC), a ROS inhibitor. Furthermore, exposure to NAC and Peptide17, a YAP inhibitor, blocked the increase in glycolytic enzyme expression, and the enhancement of proliferation and migration caused by NOX4 overexpression. In addition, in animal experiments, the results of the MicroPET imaging showed that the glucose metabolism rate of the NOX4 inhibitor group was significantly lower than that of the control group. ROS levels in the NOX4 inhibitor group was lower than that in the control group. Immunohistochemistry showed that the expression of HK2, GLUT1, PKM2, LDHA, KI67, and YAP in the NOX4 knock-down group were decreased. Conclusions: NOX4 affects breast cancer glycolysis through ROS-induced activation of the YAP pathway, further promoting the proliferation and migration of breast cancer cells.}, }
@article {pmid37670199, year = {2023}, author = {Kaya, S and Yalcın, T and Tektemur, A and Kuloğlu, T}, title = {N-Acetylcysteine may exert hepatoprotective effect by regulating Meteorin-Like levels in Adriamycin-induced liver injury.}, journal = {Cell stress &amp; chaperones}, volume = {28}, number = {6}, pages = {849-859}, pmid = {37670199}, issn = {1466-1268}, support = {TF.21.11//Firat University Scientific Research Projects Management Unit/ ; }, mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/metabolism/therapeutic use ; Doxorubicin/toxicity ; Caspase 3/metabolism ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy/metabolism/pathology ; Liver/metabolism ; Antioxidants/metabolism ; Oxidative Stress ; }, abstract = {Adriamycin (ADR) is an important chemotherapeutic drug, but it has serious side effects such as hepatotoxicity. This study aimed to evaluate whether N-acetylcysteine (NAC) has hepatoprotective effects against ADR-induced hepatotoxicity in rats. In addition, it was aimed to determine how Meteorin-Like (MtrnL), which has pleiotropic effects on immunology, inflammation, and metabolism, is affected by ADR and/or NAC applications in liver tissue. 28 rats were randomly assigned to one of four equal groups in the study: control (no treatment), NAC (150 mg/kg/day of NAC intraperitoneally (i.p), ADR (15 mg/kg only on the first day of the experiment), and ADR + NAC (ADR 15 mg/kg on the first day of the experiment + 150 mg/kg/day NAC i.p). After 15 days, liver enzyme levels in serum, oxidant/antioxidant parameters in liver tissue, histopathological changes, caspase 3 (Casp3) and heat shock protein 70 (HSP-70) immunoreactivities, and MtrnL levels were examined. Histopathological changes, liver enzyme levels, as well as HSP-70, and Casp3 immunoreactivities increased due to ADR application. Additionally, MtrnL levels in liver tissue were significantly increased as a result of ADR application. However, it was detected that the NAC application significantly regulated the ADR-induced changes. Furthermore, it was determined that NAC administration regulated the changes in ADR-induced oxidative stress parameters. We propose that NAC may exert a hepatoprotective effect by regulating ADR-induced altered oxidative stress parameters, MtrnL levels, Casp3, and HSP-70 immunoreactivities in the liver.}, }
@article {pmid37666440, year = {2023}, author = {Wang, X and Zhou, P and Zhang, Z and Huang, Q and Chen, X and Ji, L and Cheng, X and Shi, Y and Yu, S and Tang, J and Sun, C and Zhao, X and Yu, J}, title = {A Drosophila model of gestational antimony exposure uncovers growth and developmental disorders caused by disrupting oxidative stress homeostasis.}, journal = {Free radical biology &amp; medicine}, volume = {208}, number = {}, pages = {418-429}, doi = {10.1016/j.freeradbiomed.2023.09.002}, pmid = {37666440}, issn = {1873-4596}, mesh = {Animals ; *Antimony/toxicity ; *Drosophila/metabolism ; Developmental Disabilities ; Oxidative Stress ; Antioxidants/pharmacology/metabolism ; Glutathione/metabolism ; Acetylcysteine/pharmacology/metabolism ; }, abstract = {The toxic heavy metal antimony (Sb) is ubiquitous in our daily lives. Various models have shown that Sb induces neuronal and reproductive toxicity. However, little is known about the developmental toxicity of Sb exposure during gestation and the underlying mechanisms. To study its effects on growth and development, Drosophila stages from eggs to pupae were exposed to different Sb concentrations (0, 0.3, 0.6 and 1.2 mg/mL Sb); RNA sequencing was used to identify the underlying mechanism. The model revealed that prenatal Sb exposure significantly reduced larval body size and weight, the pupation and eclosion rates, and the number of flies at all stages. With 1.2 mg/mL Sb exposure in 3rd instar larvae, 484 genes were upregulated and 694 downregulated compared to controls. Biological analysis showed that the disrupted transcripts were related to the oxidative stress pathway, as verified by reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and glutathione (GSH) intervention experiments. Sb exposure induced oxidative stress imbalance could be rectified by chelation and antioxidant effects of NAC/GSH. The Drosophila Schneider 2 (S2) model further demonstrated that NAC and GSH greatly ameliorated cell death induced by Sb exposure. In conclusion, gestational Sb exposure disrupted oxidative stress homeostasis, thereby impairing growth and development.}, }
@article {pmid37662796, year = {2023}, author = {Çavuş, UY and Yılmaz, A and Tascanov, MB and Ocak, M}, title = {Efficacy of combination of N-acetylcysteine and primrose in spinal cord injury; an experimental study.}, journal = {Heliyon}, volume = {9}, number = {9}, pages = {e19350}, pmid = {37662796}, issn = {2405-8440}, abstract = {INTRODUCTION: Spinal cord trauma represents a major cause of emergency department admissions, with high morbidity and mortality rates. It requires early and urgent treatment. This experimental study assessed the effectiveness of a combination of primrose and N-acetylcysteine (NAC) in managing spinal cord injury (SCI).<br><br>METHODS: We divided 46 adult male Wistar albino rats (6-8 months old, weighing 300-350&#xa0;g) into five groups. Group 1 (n&#xa0;=&#xa0;10) received only primrose; group 2 (n&#xa0;=&#xa0;10) received only NAC; group 3 (n&#xa0;=&#xa0;10) received a combination of NAC and primrose; group 4 (n&#xa0;=&#xa0;10) received no intervention (first control group); group 5 (n&#xa0;=&#xa0;10) underwent laminectomy only (second control group). Intergroup neurological and motor function were evaluated on days 1, 7, and 14. Oxidative biochemical markers, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), and malondialdehyde (MDA), were measured.<br><br>RESULTS: Significant differences were recorded in the GPX, SOD, and MDA values of groups 1, 2, 3, and 4 (p&#xa0;<&#xa0;0.001, p&#xa0;=&#xa0;0.005, and p&#xa0;=&#xa0;0.097, respectively). Groupwise comparisons were conducted to identify the clinical significance of these markers. GPX and SOD levels were significantly higher in group 1 than in group 2; MDA levels were lower in group 1. GPX and SOD levels were significantly higher than in group 3 than in group 1; MDA levels were lower in group 3. Compared with group 5, group 1 demonstrated significantly higher GPX and SOD levels and lower MDA levels. Results in group 2 were similar to results in group 5. In group 3, GPX and SOD levels were significantly higher than in groups 2 and 5; MDA levels were significantly lower. Comparisons according to inclined plane angle level and motor function values revealed significant results on day 14, in favor of group 3 rats that had received the combined treatment.<br><br>CONCLUSION: The combined administration of NAC and primrose for traumatic SCI was more effective than either treatment alone in terms of improving biochemical and neurological functions. These findings suggest that the combination of NAC and primrose can serve as an effective treatment option for traumatic SCI.}, }
@article {pmid37661403, year = {2023}, author = {Kadota, Y and Yamanokuchi, R and Ohnishi, N and Matsuoka, M and Kawakami, T and Sato, M and Suzuki, S}, title = {Metallothionein Gene Deficiency Facilitates the Differentiation of C2C12 Myoblasts into Slow-Twitch Myotubes.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {46}, number = {9}, pages = {1240-1248}, doi = {10.1248/bpb.b23-00165}, pmid = {37661403}, issn = {1347-5215}, mesh = {Animals ; Mice ; *Muscle Fibers, Skeletal ; Cell Differentiation ; *Muscle, Skeletal ; Myoblasts ; Muscular Atrophy ; Acetylcysteine ; Antioxidants ; }, abstract = {Metallothionein (MT) 1 and 2 are ubiquitously expressed cysteine-rich, low molecular weight proteins. MT expression is upregulated in skeletal muscle during aging. MTs also play role in multiple types of skeletal muscle atrophy. Meanwhile, it has been reported that MT1 and MT2 gene deficiency increases myogenesis in MT knockout (MTKO) mice. However, little is known about the effect of MTs on muscle formation and atrophy. In this study, we investigated the effect of MT1 and MT2 gene knock-out using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (CRISPR-Cas9) system in an in vitro skeletal muscle differentiation model (C2C12 cell line). MT deficiency promoted myogenic differentiation and myotube formation in C2C12 cells. Muscle-specific transcription factors MyoD and myogenin were found to be upregulated at the late stage of myotube differentiation in MTKO cells. Furthermore, the fast-twitch myosin heavy chain (MyHC) protein expression was similar in MTKO and mock-transfected myotubes, but slow-MyHC expression was higher in MTKO cells than in mock cells. The MT gene deletion did not affect the number of fast MyHC-positive myotubes but increased the number of slow MyHC-positive myotubes. Treatment with the antioxidant N-acetylcysteine (NAC) inhibited the increase in the number of slow MyHC-positive myotubes as well as slow-MyHC expression in MTKO cells. In contrast, NAC treatment did not alter the number of fast MyHC-positive myotubes or the expression of fast-MyHC in MTKO cells. These results suggest that the antioxidant effects of MTs may be involved in slow-twitch myofiber formation in skeletal muscle.}, }
@article {pmid37659111, year = {2023}, author = {Fraternale, A and Green, KA and Schiavano, GF and Bruschi, M and Retini, M and Magnani, M and Green, WR}, title = {Inhibition of myeloid-derived suppressor cell (MDSC) activity by redox-modulating agents restores T and B cell proliferative responses in murine AIDS.}, journal = {International immunopharmacology}, volume = {124}, number = {Pt A}, pages = {110882}, doi = {10.1016/j.intimp.2023.110882}, pmid = {37659111}, issn = {1878-1705}, abstract = {The mechanisms by which myeloid-derived suppressor cells (MDSCs) mediate inhibition prominently include the production of reactive nitrogen species, in particular those generated by inducible nitric oxide synthase (iNOS), and reactive oxygen species. LP-BM5 murine retroviral infection results in a profound immunodeficiency, known as murine AIDS, as well as in increased numbers and activity of monocytic-type MDSCs (M-MDSCs) that suppress both T and B cell responses. While M-MDSCs suppress T cells ex vivo in a fully iNOS/NO-dependent manner, M-MDSC suppression of B cell responses is only partially due to iNOS/NO. This study preliminarily explored the role of two redox-modulating compounds in inhibiting the M-MDSC suppressive activity in LP-BM5 infection. The tested molecules were: I-152 consisting in a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-cysteamine (SMEA) and C4-GSH that is the n-butanoyl glutathione (GSH) derivative. The results show that both molecules, tested in a concentration range between 3 and 20 mM, blocked the M-MDSC suppression of activated B and T cells ex vivo and restored their proliferative capacity in vivo. Ex vivo I-152 blockade of M-MDSC suppressiveness was more significant for T cell (about 70%) while M-MDSC blockade by C4-GSH was preferential for B cell responsiveness (about 60%), which was also confirmed by in vivo investigation. Beyond insights into redox-dependent suppressive effector mechanism(s) of M-MDSCs in LP-BM5 infection, these findings may ultimately be important to identify new immunotherapeutics against infectious diseases.}, }
@article {pmid37654348, year = {2023}, author = {Veeraiyan, M and Kumar, YP and Chandhar, CY and Priyanka, Y and Jaiswal, M and Kemasaram, D}, title = {Evaluation of Smear Layer Removal and Micro Hardness Alteration of Radicular Dentin after Using Various Chelating Agents - An Atomic Force Microscopic Study.}, journal = {Journal of pharmacy &amp; bioallied sciences}, volume = {15}, number = {Suppl 1}, pages = {S582-S587}, pmid = {37654348}, issn = {0976-4879}, abstract = {BACKGROUND AND AIMS: For endodontic therapy to be successful, the smear layer produced by the root canal instruments must be removed. The study's objective is to evaluate the effectiveness of radicular dentin microhardness modification and smear layer removal utilizing various chelating agents.<br><br>MATERIALS AND METHODS: Extracted human mandibular single-rooted premolar teeth were selected for the study. The specimens were sectioned to obtain a standard root length and, working length determination was done. Cleaning and shaping were done in all the samples till the size F3 (Protaper universal). Based on the chelating agents using samples were randomly divided into four groups, Group-I: Saline (negative control), Group-II: 17% EDTA (DeSmear, Ahmedabad, Gujarat) (positive control), Group-III: 0.2% Chitosan (Everest-Biotech, Bengaluru), Group-IV: 20% N-Acetyl cysteine (NAC) (Sisco Research Laboratories, Mumbai), Group-V: 5% Pentetic acid (New Alliance Fine chem Pvt Ltd, Mumbai). All the samples were prepared for smear layer removal and surface roughness evaluation using an atomic force microscope.<br><br>RESULTS: It was observed that significantly (P = 0.000) the mean roughness average was higher among group II EDTA (148 &#xb1; 8.5) followed by group III 0.2% Chitosan (92.5 &#xb1; 3.42), group IV 20% NAC (85.2 &#xb1; 2.17), and group V 5% Pentetic acid (73.3 &#xb1; 3.39) and least by group I Saline (59.3 &#xb1; 3.31). The highest smear layer removal was seen with group II (EDTA) followed by group III (0.2% Chitosan), group IV (20% NAC), and group V (Pentetic acid).<br><br>CONCLUSION: All the chelating agents removed smear layer in coronal third, middle third whereas none of them were able to entirely eliminate from the apical third. Chitosan with smear layer removal capacity equal to EDTA with limited roughness can be considered as a valid alternative as final irrigant.}, }
@article {pmid37654090, year = {2024}, author = {Frediani, JK and Lal, AA and Kim, E and Leslie, SL and Boorman, DW and Singh, V}, title = {The role of diet and non-pharmacologic supplements in the treatment of chronic neuropathic pain: A systematic review.}, journal = {Pain practice : the official journal of World Institute of Pain}, volume = {24}, number = {1}, pages = {186-210}, doi = {10.1111/papr.13291}, pmid = {37654090}, issn = {1533-2500}, mesh = {Humans ; Adult ; Acetylcarnitine/therapeutic use ; Magnesium/therapeutic use ; *Thioctic Acid/therapeutic use ; *Carnosine/therapeutic use ; Glutamine/therapeutic use ; Cysteine/therapeutic use ; Prospective Studies ; Dietary Supplements ; Vitamins/therapeutic use ; *Neuralgia/drug therapy ; Vitamin E/therapeutic use ; Ascorbic Acid/therapeutic use ; Diet ; Antioxidants/therapeutic use ; Vitamin B 12 ; *Complex Regional Pain Syndromes ; Vitamin D/therapeutic use ; }, abstract = {BACKGROUND/IMPORTANCE: Dietary interventions, vitamins, and nutritional supplementation are playing an increasingly important role in the management of neuropathic pain. Current pharmacological treatments are poorly tolerated and ineffective in many cases.<br><br>OBJECTIVE: This systematic review aims to study the efficacy of dietary interventions, vitamins, and nutritional supplementation in the management of chronic neuropathic pain in adults.<br><br>EVIDENCE REVIEW: The review followed PRISMA guidelines and was registered with PROSPERO (#CRD42022300312). Ten databases and gray literature, including Embase.com, MEDLINE and Web of Science, were systematically searched using a combination of keywords and controlled vocabulary related to chronic neuropathic pain and oral non-pharmacological supplements. Studies on adult humans published between 2000 and 2021 were considered for inclusion. The Cochrane Handbook was used to assess risk of bias, and Grading of Recommendations Assessment, Development, and Evaluation was used to determine overall quality of evidence.<br><br>FINDINGS: Forty studies were included in the final review, and results were categorized according to pain type including pain related to chemotherapy-induced peripheral neuropathy (CIPN, 22 studies, including 3 prospective cohorts), diabetic peripheral neuropathy (DPN, 13 studies, including 2 prospective), complex regional pain syndrome (CRPS-I, 3 studies, including 1 prospective), and other (2 studies, both RCT). The CIPN studies used various interventions including goshajinkigan (4 studies), vitamin E (5), vitamin B12 (3), glutamine (3), N-acetyl-cysteine (2), acetyl-l-carnitine (2), guilongtonluofang (1), ninjin'yoeito (1), alpha-lipoic acid (1), l-carnosine (1), magnesium and calcium (1), crocin (1), and antioxidants (1), with some studies involving multiple interventions. All CIPN studies involved varying cancers and/or chemotherapies, advising caution for generalizability of results. Interventions for DPN included alpha-lipoic acid (5 studies), vitamin B12 (3), acetyl-l-carnitine (3), vitamin E (1), vitamin D (2), and a low-fat plant-based diet (1). Vitamin C was studied to treat CRPS-I (3 studies, including 1 prospective). Magnesium (1) and St. John's wort (1) were studied for other or mixed neuropathologies.<br><br>CONCLUSIONS: Based on the review, we cannot recommend any supplement use for the management of CIPN, although further research into N-acetyl-cysteine, l-carnosine, crocin, and magnesium is warranted. Acetyl-l-carnitine was found to be likely ineffective or harmful. Alpha-lipoic acid was not found effective. Studies with goshajinkigan, vitamin B12, vitamin E, and glutamine had conflicting results regarding efficacy, with one goshajinkigan study finding it harmful. Guilongtonluofang, ninjin'yoeito, and antioxidants showed various degrees of potential effectiveness. Regarding DPN, our review supports the use of alpha-lipoic acid, acetyl-l-carnitine, and vitamin D. The early use of vitamin C prophylaxis for the development of CRPS-I also seems promising. Further research is warranted to confirm these findings.}, }
@article {pmid37652392, year = {2023}, author = {Xu, Y and Zhao, Z and Geng, Z and Zhou, H and Yang, C and Wang, Y and Kuerban, B and Xiao, Y and Luo, G}, title = {Enhancement of recombinant human interleukin-22 production by fusing with human serum albumin and supplementing N-acetylcysteine in Pichia Pastoris.}, journal = {Protein expression and purification}, volume = {212}, number = {}, pages = {106360}, doi = {10.1016/j.pep.2023.106360}, pmid = {37652392}, issn = {1096-0279}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *Serum Albumin, Human/genetics ; Ascorbic Acid/pharmacology ; Interleukin-22 ; }, abstract = {Interleukin-22 (IL-22) plays an important role in the treatment of organ failure, which can induce anti-apoptotic and proliferative signaling pathways; Nevertheless, the practical utilization of IL-22 is hindered by the restricted efficacy of its production. Pichia pastoris presents a viable platform for both industrial and pharmaceutical applications. In this study, we successfully generated a fusion protein consisting of truncated human serum albumin and human IL-22 (HSA-hIL-22) using P. pastoris, and examined the impact of antioxidants on HSA-hIL-22 production. We have achieved the production of HSA-hIL-22 in the culture medium at a yield of approximately 2.25 mg/ml. Moreover, 0-40 mM ascorbic acid supplementation did not significantly affect HSA-hIL-22 production or the growth rate of the recombinant strain. However, 80 mM ascorbic acid treatment had a detrimental effect on the expression of HSA-hIL-22. In addition, 5-10 mM N-acetyl-l-cysteine (NAC) resulted in an increase of HSA-hIL-22 production, accompanied by a reduction in the growth rate of the recombinant strain. Conversely, 20-80 mM NAC supplementation inhibited the growth of the recombinant strains and reduced intact HSA-hIL-22 production. However, neither NAC nor ascorbic acid exhibited any effect on superoxide dismutase (SOD) and malondialdehyde (MDA) levels, except that NAC increased GSH content. Furthermore, our findings indicate that recombinant HSA-hIL-22, which demonstrated the ability to stimulate the proliferation of HepG2 cells, possesses bioactivity. In addition, NAC did not affect HSA-hIL-22 bioactivity. In conclusion, our study demonstrates that NAC supplementation can enhance the secretion of functional HSA-hIL-22 proteins produced in P. pastoris without compromising their activity.}, }
@article {pmid37647428, year = {2023}, author = {Sun, X and Sun, Y and Cao, S and Liu, X}, title = {Effects of N-acetyl-L-cysteine polysulfides on periodontitis in a mouse model.}, journal = {Immunity, inflammation and disease}, volume = {11}, number = {8}, pages = {e959}, pmid = {37647428}, issn = {2050-4527}, mesh = {Animals ; Mice ; *Acetylcysteine/pharmacology ; Lipopolysaccharides/toxicity ; Toll-Like Receptor 4/genetics ; *Periodontitis/drug therapy ; Tumor Necrosis Factor-alpha ; Disease Models, Animal ; }, abstract = {BACKGROUND: Polysulfides are reported to be involved in various important biological processes. N-acetyl-l-cysteine polysulfide with 2 sulfane sulfur atoms (NAC-S2) regulates diverse toll-like receptor (TLR) signaling pathways. Here, we aimed to determine the role of NAC-S2 in periodontitis and explore the potential mechanism.<br><br>METHODS: A periodontitis mouse model was established by ligating the subgingival between the first and second molars in wild-type, TLR4[-/-] , and Myd88[-/-] mice.<br><br>RESULTS: NAC-S2 did not affect the proportion of macrophages (CD11b[+] F4/80[+]) or neutrophils (CD11b[+] GR-1[+]) in the bone marrow. Mechanically, lipopolysaccharides (LPS), Zymosan A, or poly I: C induced tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1&#x3b2; expression in bone marrow-derived macrophages (BMDMs) could be inhibited by NAC-S2. On the other hand, NAC-S2 suppressed the phosphorylation levels of I&#x3ba;B-&#x3b1;, p65, and I&#x3ba;B kinase (IKK)-&#x3b2; induced by LPS in BMDMs, while LPS induced phosphorylation of ERK1/2, p38, and transforming growth factor &#x3b2;-activated kinase 1 (TAK1) could not be affected by NAC-S2. In wild-type periodontitis mice, NAC-S2 administration decreased the cemento-enamel-junction-alveolar bone crest (CEJ-ABC) distance and the relative mRNA expression of TNF, IL-6, and IL-1&#x3b2;, while such phenomena could not be observed in TLR4 deficiency or Myd88 deficiency mice.<br><br>CONCLUSIONS: All of these results indicate that NAC-S2 ameliorates TLR4/NF-&#x3ba;B pathway mediated inflammation in mouse periodontitis model.}, }
@article {pmid37645523, year = {2023}, author = {Mi, K and Wu, S and Lv, C and Meng, Y and Yin, W and Li, H and Li, J and Yuan, H}, title = {Comparing the efficacy and safety of medications in adults with hypertrophic cardiomyopathy: a systematic review and network meta-analysis.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1190181}, pmid = {37645523}, issn = {2297-055X}, abstract = {BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. The purpose of this study was to evaluate the efficacy and safety of several medications and recommend better drug treatments for adults with HCM.<br><br>METHODS: A review of PubMed, Embase, the Cochrane Controlled Register of Trials (CENTRAL), ClinicalTrials.gov and CNKI databases was conducted for studies on the efficacy and safety of drugs for adults with HCM. A frequentist random effects model was used in this network analysis.<br><br>RESULTS: This network meta-analysis included 7 studies assessing seven medications, 6 studies evaluating monotherapy and 1 study evaluating combination therapy. Based on the network meta-analysis results, xiaoxinbi formula plus metoprolol (MD -56.50% [-72.43%, -40.57%]), metoprolol (MD -47.00% [-59.07%, -34.93%]) and mavacamten (MD -34.50% [-44.75%, -24.25%]) significantly reduced the resting left ventricular outflow tract gradient (LVOTG) in comparison with placebo. Resting LVOTG could also be reduced with N-acetylcysteine (NAC). The incidence of adverse drug reactions was not significantly different between the placebo group and the treatment group.<br><br>CONCLUSION: For adults with HCM, the top 4 treatments included xiaoxinbi formula plus metoprolol, metoprolol, mavacamten and NAC.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=374222], identifier [CRD42022374222].}, }
@article {pmid37635852, year = {2023}, author = {Ng, WW and Tong, HF and Ng, WY and Yeung, JK and Young, JK and Woo, RK and Wong, MM}, title = {Pyroglutamic Acidosis - An Underrecognised Entity Associated with Acetaminophen Use.}, journal = {Romanian journal of anaesthesia and intensive care}, volume = {30}, number = {1}, pages = {26-30}, pmid = {37635852}, issn = {2392-7518}, abstract = {Pyroglutamic acidosis (PGA) is an underrecognized entity characterised by raised anion gap metabolic acidosis (RAGMA) and urinary hyper-excretion of pyroglutamic acid. It is frequently associated with chronic acetaminophen (APAP) ingestion. We report the case of a 73-year-old man with invasive pulmonary aspergillosis treated with voriconazole and APAP for analgesia with a cumulative dose of 160 g over 40 days. PGA was suspected as he developed severe RAGMA and common causes were excluded. Diagnosis was confirmed via urinary organic acid analysis which showed significant hyper-excretion of pyroglutamic acid. APAP was discontinued, and N-acetylcysteine (NAC) was administered. His RAGMA rapidly resolved following treatment.}, }
@article {pmid37634582, year = {2023}, author = {Feng, C and Bai, H and Chang, X and Wu, Z and Dong, W and Ma, Q and Yang, J}, title = {Aflatoxin B1-induced early developmental hepatotoxicity in larvae zebrafish.}, journal = {Chemosphere}, volume = {340}, number = {}, pages = {139940}, doi = {10.1016/j.chemosphere.2023.139940}, pmid = {37634582}, issn = {1879-1298}, mesh = {Animals ; Aflatoxin B1/toxicity ; Zebrafish/genetics ; *Fatty Liver ; Acetylcysteine ; Larva/genetics ; *Chemical and Drug Induced Liver Injury ; }, abstract = {Aflatoxin B1 (AFB1) is a ubiquitous mycotoxin that causes oxidative damage in various organs. At present, the research studies on AFB1 are primarily focused on its effects on the terrestrial environment and animals. However, its toxicity mechanism in aquatic environments and aquatic animals has not been largely explored. Thus, in this study, zebrafish was used as a model to study the toxicity mechanism of AFB1 on the liver of developing larvae. The results showed that AFB1 exposure inhibited liver development and promoted fat accumulation in the liver. Transcriptome sequencing analysis showed that AFB1 affected liver redox metabolism and oxidoreductase activity. KEGG analysis showed that AFB1 inhibited the expression of gsto1, gpx4a, mgst3a, and idh1 in the glutathione metabolizing enzyme gene pathway, resulting in hepatic oxidative stress. At the same time, AFB1 also inhibited the expression of acox1, acsl1b, pparα, fabp2, and cpt1 genes in peroxidase and PPAR metabolic pathways, inducing hepatic steatosis and lipid droplet accumulation. Antioxidant N-Acetyl-l-cysteine (NAC) preconditioning up-regulated gsto1, gpx4a and idh1 genes, and improved the AFB1-induced lipid droplet accumulation in the liver. In summary, AFB1 induced hepatic oxidative stress and steatosis, resulting in abnormal liver fat metabolism and accumulation of cellular lipid droplets. NAC could be used as a potential preventative drug to improve AFB1-induced fat accumulation.}, }
@article {pmid37632646, year = {2023}, author = {Chen, HY and Chen, RLC and Hsieh, BC and Cheng, TJ}, title = {Determination of o-phthalaldehyde for dose verification of the clinical disinfectant by fluorescent sequential injection analysis.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {39}, number = {12}, pages = {2007-2017}, pmid = {37632646}, issn = {1348-2246}, support = {MOST-105-2313-B-002-022//Ministry of Science and Technology of Taiwan/ ; MOST-107-2313-B-002-015//Ministry of Science and Technology of Taiwan/ ; }, mesh = {*o-Phthalaldehyde/analysis ; *Disinfectants ; Reproducibility of Results ; Glutaral ; Coloring Agents ; }, abstract = {A new automated, generic analytical approach for determining the clinical disinfectant o-phthalaldehyde (OPA) is reported in this study. The proposed sequential injection analysis (SIA) is based on the online reaction of the OPA with glycine/N-acetylcysteine (NAC) in a neutral medium (pH = 7.0) to form a highly fluorescent isoindole derivative. All critical flow and reaction variables were investigated, while validation was carried out in the linearity detection range (0.0075-0.02%). As a result, excellent linearity (R[2] > 0.99) and precision (1.5-2.4% for repeatability and 0.7-2.2% for reproducibility) were achieved for the reference OPA solutions. Furthermore, reasonable concentration verification of OPA disinfection (0.2-0.6%) in healthcare institutes can be achieved using the developed fluorescent SIA due to its good sensitivity (0.111 V/%) and precision (1.0-2.3% for intermediate precision) around the minimum effective concentration (MEC) of 0.3% for Cidex-OPA disinfectant.}, }
@article {pmid37631065, year = {2023}, author = {Blagov, AV and Orekhova, VA and Sukhorukov, VN and Melnichenko, AA and Orekhov, AN}, title = {Potential Use of Antioxidant Compounds for the Treatment of Inflammatory Bowel Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {8}, pages = {}, pmid = {37631065}, issn = {1424-8247}, support = {23-65-10014//Russian Science Foundation/ ; }, abstract = {Since inflammatory bowel diseases (IBDs) are chronic, the development of new effective therapeutics to combat them does not lose relevance. Oxidative stress is one of the main pathological processes that determines the progression of IBD. In this regard, antioxidant therapy seems to be a promising approach. The role of oxidative stress in the development and progression of IBD is considered in detail in this review. The main cause of oxidative stress in IBD is an inadequate response of leukocytes to dysbiosis and food components in the intestine. Passage of immune cells through the intestinal barrier leads to increased ROS concentration and the pathological consequences of exposure to oxidative stress based on the development of inflammation and impaired intestinal permeability. To combat oxidative stress in IBD, several promising natural (curcumin, resveratrol, quercetin, and melatonin) and artificial antioxidants (N-acetylcysteine (NAC) and artificial superoxide dismutase (aSOD)) that had been shown to be effective in a number of clinical trials have been proposed. Their mechanisms of action on pathological events in IBD and clinical manifestations from their impact have been determined. The prospects for the use of other antioxidants that have not yet been tested in the treatment of IBD, but have the properties of potential therapeutic candidates, have been also considered.}, }
@article {pmid37628913, year = {2023}, author = {Alkandari, AF and Madhyastha, S and Rao, MS}, title = {N-Acetylcysteine Amide against Aβ-Induced Alzheimer's-like Pathology in Rats.}, journal = {International journal of molecular sciences}, volume = {24}, number = {16}, pages = {}, pmid = {37628913}, issn = {1422-0067}, support = {YM07/19//Kuwait University/ ; }, mesh = {Male ; Rats ; Animals ; Acetylcysteine/pharmacology ; Rats, Wistar ; *Alzheimer Disease/chemically induced/drug therapy ; Synaptophysin ; *Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides ; Gliosis/chemically induced/drug therapy ; Glutathione ; }, abstract = {Oxidative stress with a depletion of glutathione is a key factor in the initiation and progression of Alzheimer's disease (AD). N-Acetylcysteine (NAC), a glutathione precursor, provides neuroprotective effects in AD animal models. Its amide form, N-Acetylcysteine amide (NACA), has an extended bioavailability compared to NAC. This study evaluates the neuroprotective effects of NACA against Aβ1-42 peptide-induced AD-like pathology in rats. Male Wistar rats (2.5 months old) were divided into five groups: Normal Control (NC), Sham (SH), Aβ, Aβ + NACA and NACA + Aβ + NACA (n = 8 in all groups). AD-like pathology was induced by the intracerebroventricular infusion of Aβ1-42 peptide into the lateral ventricle. NACA (75 mg/kg) was administered either as a restorative (i.e., injection of NACA for 7 consecutive days after inducing AD-like pathology (Aβ + N group)), or as prophylactic (for 7 days before and 7 days after inducing the pathology (N + Aβ + N group)). Learning and memory, neurogenesis, expression of AD pathology markers, antioxidant parameters, neuroprotection, astrogliosis and microgliosis were studied in the hippocampus and the prefrontal cortex. All data were analyzed with a one-way ANOVA test followed by Bonferroni's multiple comparison test. NACA treatment reversed the cognitive deficits and reduced oxidative stress in the hippocampus and prefrontal cortex. Western blot analysis for Tau, Synaptophysin and Aβ, as well as a histopathological evaluation through immunostaining for neurogenesis, the expression of neurofibrillary tangles, β-amyloid peptide, synaptophysin, neuronal morphology and gliosis, showed a neuroprotective effect of NACA. In conclusion, this study demonstrates the neuroprotective effects of NACA against β-amyloid induced AD-like pathology.}, }
@article {pmid37628819, year = {2023}, author = {Heiserman, JP and Minhas, Z and Nikpayam, E and Cheon, DJ}, title = {Targeting Heat Shock Protein 27 and Fatty Acid Oxidation Augments Cisplatin Treatment in Cisplatin-Resistant Ovarian Cancer Cell Lines.}, journal = {International journal of molecular sciences}, volume = {24}, number = {16}, pages = {}, pmid = {37628819}, issn = {1422-0067}, support = {1/CX/CSRD VA/United States ; }, mesh = {Humans ; Female ; *Cisplatin/pharmacology ; HSP27 Heat-Shock Proteins/genetics ; Reactive Oxygen Species ; Neoplasm Recurrence, Local ; *Ovarian Neoplasms/drug therapy ; Cell Line ; Fatty Acids ; }, abstract = {Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors in vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin's cytotoxic effect.}, }
@article {pmid37628771, year = {2023}, author = {Staskiewicz, A and Wong, E and Tucker, M and Farhin, R and Park, J and Saade, R and Alkhazali, T and Dang, T and Wang, X}, title = {Cytotoxic and Apoptotic Effects of Pinostilbene and Bortezomib Combination Treatment on Human Multiple Myeloma Cells.}, journal = {International journal of molecular sciences}, volume = {24}, number = {16}, pages = {}, pmid = {37628771}, issn = {1422-0067}, mesh = {Humans ; Bortezomib/pharmacology ; Caspase 3 ; *Multiple Myeloma/drug therapy ; Antioxidants ; *Antineoplastic Agents ; Resveratrol/pharmacology ; Tumor Microenvironment ; }, abstract = {Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow characterized by bone lesions, hypercalcemia, anemia, and renal failure. Bortezomib (BTZ), a common treatment for MM, is a proteasome inhibitor that induces apoptosis in MM cells. However, high doses of BTZ can be very toxic, signifying a need for a synergistic drug combination to improve treatment efficacy. Resveratrol (RES), a phenolic compound found in grapes, has been shown to inhibit MM cell growth. We sought to identify a synergistic combination of BTZ with a RES derivative and analyze the effects on reducing viability and inducing apoptosis in human MM cells. BTZ as well as RES and its derivatives pinostilbene (PIN) and piceatannol (PIC) decreased MM cell viability in a dose- and time-dependent manner and increased expression of cleaved proapoptotic proteins poly(ADP-ribose) polymerase 1 (PARP1) and caspase-3 in a dose-dependent manner. The combination of 5 nM BTZ and 5 μM PIN was identified to have synergistic cytotoxic effects in MM RPMI 8226 cells. MM RPMI 8226 cells treated with this combination for 24 h showed increased cleaved PARP1 and caspase-3 expression and higher percentages of apoptotic cells versus cells treated with the individual compounds alone. The treatment also showed increased apoptosis induction in MM RPMI 8226 cells co-cultured with human bone marrow stromal HS-5 cells in a Transwell model used to mimic the bone marrow microenvironment. Expression of oxidative stress defense proteins (catalase, thioredoxin, and superoxide dismutase) in RPMI 8226 cells were reduced after 24 h treatment, and cytotoxic effects of the treatment were ameliorated by antioxidant N-acetylcysteine (NAC), suggesting the treatment impacts antioxidant levels in RPMI 8226 cells. Our results suggest that this combination of BTZ and PIN decreases MM cell viability synergistically by inducing apoptosis and oxidative stress in MM cells.}, }
@article {pmid37627587, year = {2023}, author = {Cuevas-López, B and Romero-Ramirez, EI and García-Arroyo, FE and Tapia, E and León-Contreras, JC and Silva-Palacios, A and Roldán, FJ and Campos, ONM and Hernandez-Esquivel, L and Marín-Hernández, A and Gonzaga-Sánchez, JG and Hernández-Pando, R and Pedraza-Chaverri, J and Sánchez-Lozada, LG and Aparicio-Trejo, OE}, title = {NAC Pre-Administration Prevents Cardiac Mitochondrial Bioenergetics, Dynamics, Biogenesis, and Redox Alteration in Folic Acid-AKI-Induced Cardio-Renal Syndrome Type 3.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {8}, pages = {}, pmid = {37627587}, issn = {2076-3921}, support = {21-1252//Instituto Nacional de Cardiolog&#xed;a/ ; }, abstract = {The incidence of kidney disease is increasing worldwide. Acute kidney injury (AKI) can strongly favor cardio-renal syndrome (CRS) type 3 development. However, the mechanism involved in CRS development is not entirely understood. In this sense, mitochondrial impairment in both organs has become a central axis in CRS physiopathology. This study aimed to elucidate the molecular mechanisms associated with cardiac mitochondrial impairment and its role in CRS development in the folic acid-induced AKI (FA-AKI) model. Our results showed that 48 h after FA-AKI, the administration of N-acetyl-cysteine (NAC), a mitochondrial glutathione regulator, prevented the early increase in inflammatory and cell death markers and oxidative stress in the heart. This was associated with the ability of NAC to protect heart mitochondrial bioenergetics, principally oxidative phosphorylation (OXPHOS) and membrane potential, through complex I activity and the preservation of glutathione balance, thus preventing mitochondrial dynamics shifting to fission and the decreases in mitochondrial biogenesis and mass. Our data show, for the first time, that mitochondrial bioenergetics impairment plays a critical role in the mechanism that leads to heart damage. Furthermore, NAC heart mitochondrial preservation during an AKI event can be a valuable strategy to prevent CRS type 3 development.}, }
@article {pmid37625774, year = {2023}, author = {Jhuo, JY and Tong, ZJ and Ku, PH and Cheng, HW and Wang, HT}, title = {Acrolein induces mitochondrial dysfunction and insulin resistance in muscle and adipose tissues in vitro and in vivo.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {336}, number = {}, pages = {122380}, doi = {10.1016/j.envpol.2023.122380}, pmid = {37625774}, issn = {1873-6424}, abstract = {Type 2 diabetes mellitus (DM) is a common chronic condition characterized by persistent hyperglycemia and is associated with insulin resistance (IR) in critical glucose-consuming tissues, including skeletal muscle and adipose tissue. Oxidative stress and mitochondrial dysfunction are known to play key roles in IR. Acrolein is a reactive aldehyde found in the diet and environment that is generated as a fatty acid product through the glucose autooxidation process under hyperglycemic conditions. Our previous studies have shown that acrolein impairs insulin sensitivity in normal and diabetic mice, and this effect can be reversed by scavenging acrolein. This study demonstrated that acrolein increased oxidative stress and inhibited mitochondrial respiration in differentiated C2C12 myotubes and differentiated 3T3-L1 adipocytes. As a result, insulin signaling pathways were inhibited, leading to reduced glucose uptake. Treatment with acrolein scavengers, N-acetylcysteine, or carnosine ameliorated mitochondrial dysfunction and inhibited insulin signaling. Additionally, an increase in acrolein expression correlated with mitochondrial dysfunction in the muscle and adipose tissues of diabetic mice. These findings suggest that acrolein-induced mitochondrial dysfunction contributes to IR, and scavenging acrolein is a potential therapeutic approach for treating IR.}, }
@article {pmid37625683, year = {2023}, author = {Zhao, S and Li, Y and Li, G and Ye, J and Wang, R and Zhang, X and Li, F and Gao, C and Li, J and Jiang, J and Mi, Y}, title = {PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer.}, journal = {European journal of pharmacology}, volume = {957}, number = {}, pages = {176004}, doi = {10.1016/j.ejphar.2023.176004}, pmid = {37625683}, issn = {1879-0712}, mesh = {Humans ; Animals ; Mice ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Phosphatidylinositol 3-Kinases ; Reactive Oxygen Species ; *Lung Neoplasms/drug therapy ; TOR Serine-Threonine Kinases ; Polo-Like Kinase 1 ; }, abstract = {Small molecule drugs are of significant importance in the treatment of non-small cell lung cancer (NSCLC). Here, we explored biological effects of the PI3K/mTOR inhibitor VS-5584 on NSCLC. Our findings indicated that VS-5584 administration resulted in a dose-dependent inhibition of NSCLC cell proliferation, as well as the induction of apoptosis and cycle arrest. Additionally, we observed a significant increase in intracellular reactive oxygen species (ROS) levels following VS-5584 treatment. The use of the ROS inhibitor N-acetylcysteine (NAC) effectively reduced ROS levels and decreased the proportion of apoptotic cells. Treatment with VS-5584 led to an upregulation of genes associated with apoptosis and cell cycle, such as c-caspase 3 and P21. Conversely, a downregulation of cyclin-dependent kinase 1 (CDK1) expression was observed. Next, transcriptome analyses revealed that VS-5584 treatment altered the abundance of 1520 genes/transcripts in PC-9 cells, one of which was polo-like kinase 1 (PLK1). These differentially expressed genes were primarily enriched in biological processes such as cell cycle regulation and cell apoptosis, which are closely linked to the P53 and apoptosis pathways. Co-treatment with VS-5584 and PLK1 inhibitor NMS-P937 resulted in enhanced cancer cell death, exhibiting synergistic inhibitory activity. Notably, VS-5584 inhibited the growth of NSCLC in a patient-derived xenograft (PDX) mouse model without observable abnormalities in major organs. Overall, VS-5584 effectively suppressed the growth of NSCLC cells both in vitro and in vivo. VS-5584 combined with NMS-P937 exhibited a synergistic effect in inhibiting NSCLC cell growth. These findings suggest that VS-5584 has potential as a therapeutic strategy for treating NSCLC.}, }
@article {pmid37621062, year = {2023}, author = {Chen, H and Zhou, H and Luo, C and Zong, K and Fu, Y and Li, W and Luo, C and Xue, G and Jiang, E and Duan, Y and Luo, T and Jiang, Y}, title = {Efficacy of treatment with N-acetylcysteine inhalation for AECOPD: A propensity-score-matched cohort study.}, journal = {The clinical respiratory journal}, volume = {17}, number = {10}, pages = {1038-1047}, pmid = {37621062}, issn = {1752-699X}, support = {2021-55//Social Undertakings and Livelihood Security Special Projects, the Science and Technology Bureau of Banan District, Chongqing/ ; }, mesh = {Humans ; *Acetylcysteine/adverse effects ; Cohort Studies ; Retrospective Studies ; Propensity Score ; *Pulmonary Disease, Chronic Obstructive ; Disease Progression ; }, abstract = {INTRODUCTION: N-acetylcysteine (NAC) prevents acute exacerbations of chronic obstructive pulmonary disease (AECOPD). However, the value of NAC inhalation in the treatment of patients with AECOPD is still poorly understood. The study was conducted to evaluate the efficacy of NAC inhalation in AECOPD patients requiring hospitalization.<br><br>METHODS: In this single institutional, retrospective cohort study, all patients with AECOPD requiring hospitalization between January 2021 and January 2022 were included. Patients were divided into NAC group and Non-NAC group according to whether being treated with NAC inhalation and were matched using the propensity score. The primary outcome was a composite of progression to ventilation requirement, in-hospital mortality and readmission for AECOPD within 30&#x2009;days. The effect on the mean hospitalized days, blood gas indexes and the incidence rate of adverse drug events were compared between the two groups.<br><br>RESULTS: Ninety-six patients in the NAC group were matched with 96 patients in the Non-NAC group. The differences in the primary composite end point (NAC group vs Non-NAC group, 5.2% vs 16.7%; P&#x2009;=&#x2009;0.011) were significant. The median time to discharge was shorter in the NAC group (8.3 vs. 9.1&#x2009;days, P&#x2009;=&#x2009;0.030). The NAC group presented a larger increase in partial pressure of arterial oxygen (Pa O2) and a higher ratio of self-reported symptomatic improvement from admission to day 5. There was no definite difference between the two groups in the frequency of adverse event.<br><br>CONCLUSION: NAC inhalation is associated with an improved clinical outcome. A further study should be conducted to confirm the clinical usefulness of NAC inhalation in AECOPD patients.}, }
@article {pmid37611476, year = {2023}, author = {Sun, S and Zhang, C and Zhang, Q and Li, C and Huang, D and Ding, R and Cao, J and Hao, J}, title = {Role of ROS-mediated PERK/ATF4 signaling activation in extracorporeal tube formation injury of human umbilical vein endothelial cells induced by cooking oil fume PM2.5 exposure.}, journal = {Ecotoxicology and environmental safety}, volume = {263}, number = {}, pages = {115332}, doi = {10.1016/j.ecoenv.2023.115332}, pmid = {37611476}, issn = {1090-2414}, mesh = {Humans ; Human Umbilical Vein Endothelial Cells ; Reactive Oxygen Species ; *Acetylcysteine/pharmacology ; *Cooking ; Gases ; Particulate Matter/toxicity ; Activating Transcription Factor 4/genetics ; }, abstract = {Cooking oil fume-derived PM2.5 (COF-PM2.5) is a major source of indoor air contamination in China, which has been demonstrated to be a hazard factor of cardiovascular and cerebrovascular diseases. This study aimed to investigate the role of ROS-mediated PERK/ATF4 signaling activation in COF-PM2.5-inhibited extracorporeal tube formation in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with 100 μg/mL COF-PM2.5 at different times, with or without 100 nM PERK activity inhibitor GSK2606414 (GSK) or 200 μM antioxidant N-acetylcysteine (NAC) pretreatment. Our results showed that COF-PM2.5 exposure can inhibit extracorporeal tube formation and down-regulate VEGFR2 expression in HUVECs. Furthermore, our data indicated that COF-PM2.5 exposure can activate the PERK/ATF4 signaling in HUVECs. Mechanistically, pretreatment with GSK interdicted PERK/ATF4 signaling, thereby reversing COF-PM2.5-downregulated VEGFR2 protein expression in HUVECs. Furthermore, NAC reversed VEGFR2 expression downregulated induced by COF-PM2.5 by inhibiting the upregulation of intracellular ROS levels and PERK/ATF4 signaling in HUVECs. As above, COF-PM2.5 exposure could induce ROS release from HUVECs, which in turn activate the endoplasmic reticulum PERK/ATF4 signaling and inhibit tube formation of HUVECs.}, }
@article {pmid37609158, year = {2023}, author = {Gupta, K and Chen, D and Wells, RG}, title = {Microcystin-RR is a biliary toxin selective for neonatal cholangiocytes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37609158}, support = {P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 DK119290/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Biliary atresia is a fibrosing cholangiopathy affecting neonates that is thought to be caused by a prenatal environmental insult to the bile duct. Biliatresone, a plant toxin with an α-methylene ketone group, was previously implicated in toxin-induced biliary atresia in Australian livestock, but is found in a limited location and is highly unlikely to be a significant human toxin. We hypothesized that other molecules with α-methylene ketone groups, some with the potential for significant human exposure, might also be biliary toxins.<br><br>APPROACH AND RESULTS: We focused on the family of microcystins, cyclic peptide toxins from blue-green algae that have an &#x3b1;-methylene ketone group and are found worldwide, particularly during harmful algal blooms. We found that microcystin-RR, but not 6 other microcystins, caused damage to cell spheroids made using cholangiocytes isolated from 2-3-day-old mice, but not from adult mice. We also found that microcystin-RR caused occlusion of extrahepatic bile duct explants from 2-day-old mice, but not 18-day-old mice. Microcystin-RR caused elevated reactive oxygen species in neonatal cholangiocytes, and treatment with N-acetyl cysteine partially prevented microcystin-RRinduced lumen closure, suggesting a role for redox homeostasis in its mechanism of action.<br><br>CONCLUSIONS: This study highlights the potential for environmental toxins to cause neonatal biliary disease and identifies microcystin-RR acting via increased redox stress as a possible neonatal bile duct toxin.}, }
@article {pmid37607187, year = {2023}, author = {da Silva, RHS and de Moura, M and de Paula, L and Arantes, KC and da Silva, M and de Amorim, J and Miguel, MP and Martins, DB and de Melo E Silva, D and Melo, MM and Botelho, AFM}, title = {Effects of coenzyme Q10 and N-acetylcysteine on experimental poisoning by paracetamol in Wistar rats.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0290268}, pmid = {37607187}, issn = {1932-6203}, mesh = {Adult ; Humans ; Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; *Acetaminophen ; Rats, Wistar ; Saline Solution ; }, abstract = {Paracetamol (PAR) is a drug widely used in human and veterinary medicine as an analgesic and antipyretic, often involved in cases of intoxication. The most common clinical signs result from damage to red blood cells and hepatocytes, and this intoxication is considered a model for the induction of acute liver failure. In the present study, the hepatoprotective effects of coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC) against experimental paracetamol (PAR) poisoning were analysed. Thirty-five adult Wistar rats (Rattus novergicus albinus) were randomly assigned to five groups, and thirty-one of these survived the treatments. Negative control group (CON-) received 1mL of 0.9% NaCl orally (PO). Other groups received 1.2g/kg of PAR (PO). Positive control group (CON+) received only PAR. NAC group received 800 mg/kg intraperitoneally (IP) of NAC 1h after the administration of PAR and at 12 h received 1mL of 0.9% NaCl, IP. The fourth group (CoQ10) received 1h and 12 h after intoxication, CoQ10 (10mg/kg IP). And the fifth group (NAC+CoQ10) received NAC (800mg/kg, IP) and CoQ10 (10mg/kg, IP). After 12 hours, the rats were euthanized and necropsied to collect liver and kidney tissues for histopathological evaluation and electronic microscopy. A single dose of PAR caused severe acute hepatitis. NAC couldn't reverse the liver and kidney damages. The group that received CoQ10 and NAC had moderate liver damage, while the group that received only CoQ10 had lower values of liver enzymes and mild liver and kidney damage. Animals that received treatment with CoQ10 or NAC+CoQ10 presented normal hepatocyte mitochondria and nuclei. Although CoQ10 couldn't reverse PAR organ damage, results indicate promising hepatoprotection in Wistar rats.}, }
@article {pmid37604367, year = {2023}, author = {Wang, X and Tian, X and Yan, H and Zhu, T and Ren, H and Zhou, Y and Zhao, D and Xu, D and Lian, X and Fang, L and Yu, Y and Liao, X and Liu, Y and Sun, J}, title = {Exposure to salinomycin dysregulates interplay between mitophagy and oxidative response to damage the porcine jejunal cells.}, journal = {The Science of the total environment}, volume = {900}, number = {}, pages = {166441}, doi = {10.1016/j.scitotenv.2023.166441}, pmid = {37604367}, issn = {1879-1026}, mesh = {Animals ; Swine ; *Mitophagy ; Kelch-Like ECH-Associated Protein 1 ; *Ecosystem ; Reactive Oxygen Species ; Chickens ; NF-E2-Related Factor 2 ; Antioxidants ; Oxidative Stress ; Protein Kinases ; }, abstract = {Salinomycin (SAL) has caused widespread pollution as a feed additive and growth promoter in livestock such as pigs, exerting a negative impact on public health. The toxicity mechanism of SAL has been widely studied in chickens, but the underlying mechanisms of SAL-induced toxicity to pigs and the ecosystem remain undefined. In this study, we explored the potential damage of SAL in IPEC-J2 cells to identify the effects of excessive SAL on the interplay between mitophagy and oxidative stress. The results showed that a concentration-dependent response was observed for SAL in altering cellular morphology and inducing cell death in IPEC-J2 cells, including the induction of cell cycle arrest and lactic dehydrogenase (LDH) release. Meanwhile, we found that excessive SAL led to oxidative damage by activating the Nrf2/Keap1/HO-1 pathway, accompanied by reactive oxygen species (ROS) elevation and the reduction of antioxidant enzyme activity. We also found that PINK1/Parkin-dependent mitophagy was activated by SAL exposure, particularly with mitochondrial membrane potential reduction. Interestingly, SAL-induced oxidative damages were prevented after the autophagy inhibitor 3-methyladenine (3-MA) treatment, and mitophagy was alleviated following ROS scavenger (N-acetylcysteine, NAC) treatment. Overall, our findings showed that SAL stimulated oxidative stress and mitophagy in IPEC-J2 cells resulting in cellular injury, and there was a strong connection between SAL-induced oxidative stress and mitophagy. Targeting ROS/PINK1/Parkin-dependent mitophagy and oxidative stress could be a novel protective mechanism in SAL-induced cell damage.}, }
@article {pmid37598316, year = {2023}, author = {Etemadi, Y and Akakpo, JY and Ramachandran, A and Jaeschke, H}, title = {Nrf2 as a therapeutic target in acetaminophen hepatotoxicity: A case study with sulforaphane.}, journal = {Journal of biochemical and molecular toxicology}, volume = {37}, number = {12}, pages = {e23505}, pmid = {37598316}, issn = {1099-0461}, support = {TL1 TR002368/TR/NCATS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; NF-E2-Related Factor 2/metabolism ; Antidotes/pharmacology/therapeutic use/metabolism ; Mice, Inbred C57BL ; Liver/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention &amp; control ; }, abstract = {Acetaminophen (APAP) overdose can cause severe liver injury and acute liver failure. The only clinically approved antidote, N-acetylcysteine (NAC), is highly effective but has a narrow therapeutic window. In the last 2 decades, activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates acute phase proteins and antioxidant defense genes, has emerged as a putative new therapeutic target against APAP hepatotoxicity. However, virtually all studies that propose Nrf2 activation as mechanism of protection used prolonged pretreatment, which is not a clinically feasible approach to treat a drug overdose. Therefore, the objective of this study was to assess if therapeutic activation of Nrf2 is a viable approach to treat liver injury after APAP overdose. We used the water-soluble Nrf2 activator sulforaphane (SFN; 5 mg/kg) in a murine model of APAP hepatotoxicity (300 mg/kg). Our results indicate that short-term treatment (≤3 h) with SFN alone did not activate Nrf2 or its target genes. However, posttreatment with SFN after APAP partially protected at 6 h likely due to more rapid activation of the Nrf2-target gene heme oxygenase-1. A direct comparison of SFN with NAC given at 1 h after APAP showed a superior protection with NAC, which was maintained at 24 h unlike with SFN. Thus, Nrf2 activators have inherent problems like the need to create a cellular stress to activate Nrf2 and delayed adaptive responses which may hamper sustained protection against APAP hepatotoxicity. Thus, compared to the more direct acting antidote NAC, Nrf2 activators are less suitable for this indication.}, }
@article {pmid37596428, year = {2023}, author = {Clark, RSB and Empey, PE and Kochanek, PM and Bell, MJ}, title = {N-Acetylcysteine and Probenecid Adjuvant Therapy for Traumatic Brain Injury.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {20}, number = {6}, pages = {1529-1537}, pmid = {37596428}, issn = {1878-7479}, support = {R01 NS069247/NS/NINDS NIH HHS/United States ; }, mesh = {Child ; Humans ; *Probenecid/therapeutic use/pharmacology ; Acetylcysteine/therapeutic use/pharmacology ; Pilot Projects ; *Brain Injuries, Traumatic/drug therapy ; Brain ; Blood-Brain Barrier ; }, abstract = {N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to cross the blood-brain barrier (BBB), achieve therapeutic concentrations in brain, demonstrate target engagement, among other things, that have hampered successful translation. A pharmacologic strategy for overcoming poor BBB permeability and/or efflux out of the brain of organic acid-based, small molecule therapeutics such as NAC is co-administration with a targeted or nonselective membrane transporter inhibitor. Probenecid is a classic ATP-binding cassette and solute carrier inhibitor that blocks transport of organic acids, including NAC. Accordingly, combination therapy using probenecid as an adjuvant with NAC represents a logical neurotherapeutic strategy for treatment of TBI (and other CNS diseases). We have completed a proof-of-concept pilot study using this drug combination in children with severe TBI-the Pro-NAC Trial (ClinicalTrials.gov NCT01322009). In this review, we will discuss the background and rationale for combination therapy with probenecid and NAC in TBI, providing justification for further clinical investigation.}, }
@article {pmid37595880, year = {2023}, author = {Yang, L and Mei, G and Yang, Y and Cui, J and Peng, S and Peng, Z and Cheng, Y}, title = {Hexachlorocyclohexane impairs human sperm motility by affecting lysine glutarylation and mitochondrial functions.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {179}, number = {}, pages = {113991}, doi = {10.1016/j.fct.2023.113991}, pmid = {37595880}, issn = {1873-6351}, mesh = {Humans ; Male ; *Hexachlorocyclohexane ; *Lysine ; Reactive Oxygen Species ; Sperm Motility ; Semen ; Acetylcysteine ; Mitochondria ; }, abstract = {Decreased sperm motility is a leading cause of male infertility and persistent organic pollutants are known to contribute significantly to the development of this disease. The effects of organochlorine pesticides such as hexachlorocyclohexane (HCH) on human sperm function and their mechanisms of action have received much attention, but are still not fully understood. Herein, we discovered that HCH has a concentration- and time-dependent inhibitory effect on human sperm motility in vitro. Moreover, HCH could reduce the levels of lysine glutarylation (Kglu) and glucose-6-phosphate dehydrogenase activity in sperm. Meanwhile, HCH could increase reactive oxygen species and thereby lead to mitochondrial depolarization and the down-regulation of adenosine triphosphate levels. In particular, we observed that sodium glutarate (Na-glu), the precursor of glutaryl-CoA, could alleviate the inhibitory effect of HCH on sperm Kglu levels, whereas the ROS scavenger N-acetyl-L-cysteine (NAC) had no effect. Intriguingly, both Na-glu and NAC were able to partially inhibit the HCH-induced increase in sperm ROS levels and impaired sperm motility. In conclusion, we propose that HCH inhibits sperm Kglu, leading to the disruption of mitochondrial energy metabolism, which in turn adversely affects sperm motility.}, }
@article {pmid37595477, year = {2023}, author = {Zhu, X and Song, Y and Wang, X and Zhou, Y and Chai, Y and Yuan, R}, title = {Copper nanoclusters electrochemiluminescence with tunable near-infrared emission wavelength for ultrasensitive detection of matrix metalloproteinase-2.}, journal = {Biosensors &amp; bioelectronics}, volume = {238}, number = {}, pages = {115580}, doi = {10.1016/j.bios.2023.115580}, pmid = {37595477}, issn = {1873-4235}, mesh = {Humans ; *Copper ; Matrix Metalloproteinase 2 ; *Biosensing Techniques ; Methionine ; Racemethionine ; Acetylcysteine ; }, abstract = {Herein, the methionine (Met)/N-acetyl-L-cysteine (NAC) templated copper nanoclusters (Met/NAC-Cu NCs) with tunable near-infrared region (NIR) electrochemiluminescence (ECL) emission wavelength was firstly synthesized as emitter for the ultrasensitive detection of matrix metalloproteinase-2 (MMP-2). Significantly, the NAC played the role of template and reductant of cupric to acquire Cu NCs, and the surface defect regulator Met was used to connect NAC through -S-S- bond, which could heighten the surface defect of Cu NCs to continuously regulate the maximum ECL emission by successively controlling the molar ratio of Met and NAC, leading to the ECL emission wavelength of Cu NCs ranged from 680 nm to 750 nm. In addition, a rapid target triggered catalyst hairpin assembly (CHA) recycling amplification strategy was constructed through orderly and equidistantly arranging hairpin to increase its local concentration, resulting in greatly accelerated signal amplification efficiency and reaction rate. As a proof of concept, based on Met/NAC-Cu NCs as NIR ECL emitter and effective signal amplification tactic, a super-sensitive ECL biosensor was fabricated to detect target MMP-2 with the detection limit (LOD) as low as 1.65 fg/mL and successfully utilized for detecting of MMP-2 that from Hela and MCF-7 cancer cells. This research provided a wonderful avenue for regulating the optical performance of metal nanoclusters-based ECL emitters, and the developed neoteric NIR ECL emitter with the merits of less photochemical damage and deeper tissue penetration exhibited great potential in ultrasensitive biosensing and high-definition ECL imaging.}, }
@article {pmid37594415, year = {2023}, author = {Le-Vinh, B and Steinbring, C and Nguyen Le, NM and Matuszczak, B and Bernkop-Schnürch, A}, title = {S-Protected Thiolated Chitosan versus Thiolated Chitosan as Cell Adhesive Biomaterials for Tissue Engineering.}, journal = {ACS applied materials &amp; interfaces}, volume = {15}, number = {34}, pages = {40304-40316}, pmid = {37594415}, issn = {1944-8252}, mesh = {*Chitosan ; Biocompatible Materials/pharmacology ; Tissue Engineering ; Acetylcysteine ; Carbodiimides ; Cryogels ; }, abstract = {Chitosan (Ch) and different Ch derivatives have been applied in tissue engineering (TE) because of their biocompatibility, favored mechanical properties, and cost-effectiveness. Most of them, however, lack cell adhesive properties that are crucial for TE. In this study, we aimed to design an S-protected thiolated Ch derivative exhibiting high cell adhesive properties serving as a scaffold for TE. 3-((2-Acetamido-3-methoxy-3-oxopropyl)dithio) propanoic acid was covalently attached to Ch via a carbodiimide-mediated reaction. Low-, medium-, and high-modified Chs (Ch-SS-1, Ch-SS-2, and Ch-SS-3) with 54, 107 and 140 μmol of ligand per gram of polymer, respectively, were tested. In parallel, three thiolated Chs, namely Ch-SH-1, Ch-SH-2, and Ch-SH-3, were prepared by conjugating N-acetyl cysteine to Ch at the same degree of modification to compare the effectiveness of disulfide versus thiol modification on cell adhesion. Ch-SS-1 showed better cell adhesion capability than Ch-SS-2 and Ch-SS-3. This can be explained by the more lipophilic surfaces of Ch-SS as a higher modification was made. Although Ch-SH-1, Ch-SH-2, and Ch-SH-3 were shown to be good substrates for cell adhesion, growth, and proliferation, Ch-SS polymers were superior to Ch-SH polymers in the formation of 3D cell cultures. Cryogels structured by Ch-SS-1 (SSg) resulted in homogeneous scaffolds with tunable pore size and mechanical properties by changing the mass ratio between Ch-SS-1 and heparin used as a cross-linker. SSg scaffolds possessing interconnected microporous structures showed good cell migration, adhesion, and proliferation. Therefore, Ch-SS can be used to construct tunable cryogel scaffolds that are suitable for 3D cell culture and TE.}, }
@article {pmid37591474, year = {2023}, author = {Singh, S and Wairkar, S}, title = {Long-circulating thiolated chitosan nanoparticles of nintedanib with N-acetyl cysteine for treating idiopathic pulmonary fibrosis: In vitro assessment of cytotoxicity, antioxidant, and antifibrotic potential.}, journal = {International journal of pharmaceutics}, volume = {644}, number = {}, pages = {123322}, doi = {10.1016/j.ijpharm.2023.123322}, pmid = {37591474}, issn = {1873-3476}, mesh = {Chitosan/chemistry ; Acetylcysteine/chemistry ; Sulfhydryl Compounds/chemistry ; *Idiopathic Pulmonary Fibrosis/drug therapy ; Antioxidants/chemistry/pharmacology ; Cell Line ; Particle Size ; Humans ; Cell Survival/drug effects ; *Nanoparticles/chemistry ; }, abstract = {Nintedanib (NIN) is one of the FDA-approved tyrosine kinase inhibitor drugs used to treat idiopathic pulmonary fibrosis (IPF). This study aimed to formulate a long-circulating injection of Nintedanib to treat bedridden patients with IPF. Nintedanib was incorporated into chitosan nanoparticles (NIN-NP) via the ionic gelation method, and N-acetyl cysteine (NAC), a known antioxidant and mucolytic agent, was added to the NIN-NP (NAC-NIN-NP). The lyophilized formulation had a particle size of 174 nm, a polydispersity index of 0.511, and a zeta potential of 18.6 mV. The spherical nanoparticles were observed in transmission electron microscopy, whereas field emission scanning electron microscopy showed irregular clusters of NP. The thiolation of the chitosan in NAC-NIN-NP was confirmed by ATR-FTIR and NMR, which improved drug release profiles showing >90 % drug release that was 2.42-folds greater than NIN-NP lasting for five days. The DPPH assay showed that adding NAC increased the % inhibition of oxidation in blank-NP (from 54.59 % to 87.17 %) and NIN-NP (58.65 %-89.19 %). The MTT assay on A549 cells showed 67.57 % cell viability by NAC-NIN-NP with an IC50 value of 28 μg/mL. The NAC formulation reduced hydroxyproline content (56.77 μg/mL) compared to NIN-NP (69.48 μg/mL) in WI-38 cell lines. Meanwhile, the healthy cells count with NAC-NIN-NP was higher (5.104 × 10[3]) than with NIN-NP (4.878 × 10[3]). In Hoechst staining, no significant damage to DNA was observed by the drug or formulation. Therefore, NAC-NIN-NP could be a promising treatment option for IPF patients and can be studied further clinically.}, }
@article {pmid37580920, year = {2023}, author = {Niloufar Darbandi, - and Samira Moghadasi, - and Hamid Reza Momeni, - and Matin Ramezani, -}, title = {Comparing the acute and chronic effects of metformin and antioxidant protective effects of N-acetyl cysteine on memory retrieval and oxidative stress in rats with Alzheimer's disease.}, journal = {Pakistan journal of pharmaceutical sciences}, volume = {36}, number = {3}, pages = {731-739}, pmid = {37580920}, issn = {1011-601X}, mesh = {Rats ; Animals ; Antioxidants/pharmacology ; Acetylcysteine/pharmacology ; *Alzheimer Disease/chemically induced/drug therapy ; *Metformin/pharmacology ; Oxidative Stress ; Streptozocin/pharmacology ; Disease Models, Animal ; Maze Learning ; }, abstract = {It has been suggested that oxidative stress plays an important role in neural degeneration and Alzheimer's disease. Some studies have shown that metformin has some beneficial effects on the brain and reduces oxidative stress, while others reveal that metformin increases oxidative stress in diabetic patients. In this study acute and chronic effects of metformin and antioxidant protective effects of N-acetyl cysteine in Alzheimeric rats were investigated. Animals were divided into seven groups (n=8): Control, STZ, STZ + metformin (one, three and eleven weeks), STZ+ metformin (eleven weeks) +N-acetyl cysteine (eleven weeks) and N-acetyl cysteine (eleven weeks). ICV injections of saline (1μl/rat) or STZ (3mg/kg) and IP injections of Saline (1ml/kg), metformin (200mg/kg) and/or N-acetyl cysteine (100mg/kg) were done. Memory retrieval, CA1 neurons density and serums oxidative stress were investigated. STZ injections reduced memory retention, intact neurons and increased serum oxidative stress compared to the control (p<0/001). Metformin injection for one and three weeks (but not eleven weeks) improved the effects of STZ (p<0/001). Administration of N-acetylcysteine with metformin (eleven weeks) improved STZ bad effects (p<0/001). It seems that acute and chronic consumption of metformin have different effects on memory retrieval, CA1 neurons and serum oxidative stress factors in AD rats.}, }
@article {pmid37579929, year = {2023}, author = {Kolomaznik, M and Hanusrichterova, J and Mikolka, P and Kosutova, P and Vatecha, M and Zila, I and Mokra, D and Calkovska, A}, title = {Efficiency of exogenous surfactant combined with intravenous N-acetylcysteine in two-hit rodent model of ARDS.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {316}, number = {}, pages = {104138}, doi = {10.1016/j.resp.2023.104138}, pmid = {37579929}, issn = {1878-1519}, mesh = {Rats ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Lung Injury ; Antioxidants/pharmacology/therapeutic use ; Surface-Active Agents ; Rodentia ; *Hyperoxia ; Rats, Wistar ; Lung ; *Pulmonary Surfactants/pharmacology ; *Respiratory Distress Syndrome ; }, abstract = {Accumulation of reactive oxygen species during hyperoxia together with secondary bacteria-induced inflammation leads to lung damage in ventilated critically ill patients. Antioxidant N-acetylcysteine (NAC) in combination with surfactant may improve lung function. We compared the efficacy of NAC combined with surfactant in the double-hit model of lung injury. Bacterial lipopolysaccharide (LPS) instilled intratracheally and hyperoxia were used to induce lung injury in Wistar rats. Animals were mechanically ventilated and treated intravenously with NAC alone or in combination with intratracheal surfactant (poractant alfa; PSUR+NAC). Control received saline. Lung functions, inflammatory markers, oxidative damage, total white blood cell (WBC) count and lung oedema were evaluated during 4 hrs. Administration of NAC increased total antioxidant capacity (TAC) and decreased IL-6. This effect was potentiated by the combined administration of surfactant and NAC. In addition, PSUR+NAC reduced the levels of TNFα, IL-1ß, and TAC compared to NAC only and improved lung injury score. The combination of exogenous surfactant with NAC suppresses lung inflammation and oxidative stress in the experimental double-hit model of lung injury.}, }
@article {pmid37577725, year = {2023}, author = {da Paz Martins, AS and de Andrade, KQ and de Araújo, ORP and da Conceição, GCM and da Silva Gomes, A and Goulart, MOF and Moura, FA}, title = {Extraintestinal Manifestations in Induced Colitis: Controversial Effects of N-Acetylcysteine on Colon, Liver, and Kidney.}, journal = {Oxidative medicine and cellular longevity}, volume = {2023}, number = {}, pages = {8811463}, pmid = {37577725}, issn = {1942-0994}, mesh = {Humans ; Male ; Mice ; Animals ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; Interleukin-10/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Hydrogen Peroxide/pharmacology ; Glutathione Disulfide/metabolism ; *Colitis/chemically induced/complications/drug therapy ; Colon ; *Colitis, Ulcerative/chemically induced/drug therapy/pathology ; Antioxidants/pharmacology ; Inflammation/pathology ; Oxidative Stress ; Liver/metabolism ; Glutathione/metabolism ; Superoxide Dismutase/metabolism ; Dextran Sulfate/toxicity ; }, abstract = {Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD) characterized by continuous inflammation in the colonic mucosa. Extraintestinal manifestations (EIM) occur due to the disruption of the intestinal barrier and increased permeability caused by redox imbalance, dysbiosis, and inflammation originating from the intestine and contribute to morbidity and mortality. The aim of this study is to investigate the effects of oral N-acetylcysteine (NAC) on colonic, hepatic, and renal tissues in mice with colitis induced by dextran sulfate sodium (DSS). Male Swiss mice received NAC (150 mg/kg/day) in the drinking water for 30 days before and during (DSS 5% v/v; for 7 days) colitis induction. On the 38[th] day, colon, liver, and kidney were collected and adequately prepared for the analysis of oxidative stress (superoxide dismutase (SOD), catalase (CAT), glutathione reduced (GSH), glutathione oxidized (GSSG), malondialdehyde (MDA), and hydrogen peroxide (H2O2)) and inflammatory biomarkers (myeloperoxidase (MPO) -, tumor necrosis factor alpha - (TNF-α, and interleukin-10 (IL-10)). In colon, NAC protected the histological architecture. However, NAC did not level up SOD, in contrast, it increased MDA and pro-inflammatory effect (increased of TNF-α and decreased of IL-10). In liver, colitis caused both oxidative (MDA, SOD, and GSH) and inflammatory damage (IL-10). NAC was able only to increase GSH and GSH/GSSG ratio. Kidney was not affected by colitis; however, NAC despite increasing CAT, GSH, and GSH/GSSG ratio promoted lipid peroxidation (increased MDA) and pro-inflammatory action (decreased IL-10). Despite some beneficial antioxidant effects of NAC, the negative outcomes concerning irreversible oxidative and inflammatory damage in the colon, liver, and kidney confirm the nonsafety of the prophylactic use of this antioxidant in models of induced colitis, suggesting that additional studies are needed, and its use in humans not yet recommended for the therapeutic routine of this disease.}, }
@article {pmid37575813, year = {2023}, author = {Le, D and Hydro, BA and Jones, CL and Beauchamp, GA}, title = {Weight Loss or Liver Loss: A Case Report on Fulminant Hepatic Failure Secondary to Garcinia cambogia Supplementation.}, journal = {Cureus}, volume = {15}, number = {7}, pages = {e41778}, pmid = {37575813}, issn = {2168-8184}, abstract = {This case describes a 56-year-old man with a past medical history including sickle cell trait requiring blood transfusions, who presented to the emergency department (ED) with generalized weakness and fatigue following Garcinia cambogia supplementation. Initial laboratory abnormalities included: aspartate aminotransferase (AST) and alanine transaminase (ALT) 4,222 U/L and 4,664 U/L respectively, alkaline phosphatase 215 U/L, international normalized ratio (INR) 3.2, and his model for end-stage liver disease was 37. Creatinine, hemoglobin and hematocrit, and ferritin levels were all elevated. The differential diagnosis for his acute illness was broad ranging from hemochromatosis, anabolic steroid use, and portal venous thrombosis. The patient was started on N-acetylcysteine (NAC) and his liver function improved. He was discharged on hospital day 10 and instructed to discontinue his supplements and follow up for repeat blood work. This case explores the critical management of G. cambogia toxicity. The patient explored G. cambogia as an herbal supplementation resulting in weight loss, worsening generalized fatigue, and fulminant hepatic failure.}, }
@article {pmid37575276, year = {2023}, author = {Tanomrat, R and Naktubtim, C and Aimvijarn, P and Suwannalert, P}, title = {N-acetylcysteine improves the inhibitory effect of Quercetin-rich onion extract on HT-29 and HCT-116 colorectal cancer migration and invasion through iNOS suppression.}, journal = {International journal of medical sciences}, volume = {20}, number = {9}, pages = {1123-1134}, pmid = {37575276}, issn = {1449-1907}, mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; *Colorectal Neoplasms/drug therapy/genetics/metabolism ; Glutathione/pharmacology ; Intercellular Adhesion Molecule-1 ; Matrix Metalloproteinase 2/genetics ; Onions ; Quercetin/pharmacology/therapeutic use ; }, abstract = {As colorectal cancer (CRC) usually presents at an advanced stage, it responds poorly to traditional surgery and chemoradiotherapy. Reactive oxygen species (ROSs) are a critical factor in cancer progression. Quercetin, a bioflavonoid derived from onion peel extract, provides great anti-oxidant and anti-cancer potential. Therefore, quercetin in combination with N-Acetylcysteine (NAC), a well-known anti-oxidant and adjuvant agent in cancer-chemotherapeutic drugs, was considered as a way of increasing treatment efficacy. Thus, this study aimed to evaluate the improvement effect of quercetin in combination with NAC in human CRC (HT-29 and HCT-116) cell progression, migration and invasion. Firstly, the effects of quercetin, NAC, and the combination of quercetin and NAC on cellular oxidants and glutathione levels were evaluated. Cell viability, anti-migrative activity and invasive activity were determined by MTT, wound healing, and Matrigel invasion tests, respectively. Then, the proteins involved in cell migration, invasion, and cellular oxidants were investigated. Moreover, the gene expression and overall survival were further validated by the GEPIA2 database. The results reveal that the combination was most effective in decreasing cellular oxidants and increasing glutathione levels, while there was a significant decrease in cancer cell migration and invasion involved in the suppression of iNOS, ICAM-1, and MMP-2 proteins. Furthermore, bioinformatic analysis verified that iNOS, ICAM-1, and MMP-2 were highly expressed in CRC tissue and also associated with a poor prognosis. This study demonstrated that Quercetin has higher efficacy when used in combination with NAC, representing a potential combination agent for anti-cancer drug development.}, }
@article {pmid37573526, year = {2023}, author = {Rasaeifar, K and Zavareh, S and Hajighasem-Kashani, M and Nasiri, M}, title = {Effects of pulsed electromagnetic fields and N-acetylcysteine on transplantation of vitrified mouse ovarian tissue.}, journal = {Electromagnetic biology and medicine}, volume = {42}, number = {2}, pages = {67-80}, doi = {10.1080/15368378.2023.2246503}, pmid = {37573526}, issn = {1536-8386}, mesh = {Mice ; Female ; Animals ; *Acetylcysteine/pharmacology ; *Tumor Necrosis Factor-alpha/genetics ; Electromagnetic Fields ; Fibroblast Growth Factor 2 ; Interleukin-6 ; Vascular Endothelial Growth Factor A/genetics ; Antioxidants/pharmacology/metabolism ; }, abstract = {In this experimental study, adult female NMRI mice were randomly assigned to five groups: control ;(fresh ovarian transplantation, OT); sham ;(vitrified OT); NAC ;(vitrified OT treated with N-acetyl cysteine, NAC); EMF ;(vitrified OT treated with pulsed electromagnetic fields, PEMF); and NAC+EMF ;(vitrified OT combined with NAC and PEMF). We conducted histological assessments to evaluate follicle reservation and vascularization. Furthermore, we examined the relative expression of Fgf-2, Vegf, Tnf-α, Il-6, Il-1, and Cd31 genes on days 2 and 7 after OT. Additionally, we measured total antioxidant capacity (TAC), malondialdehyde (MDA) levels, as well as the activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Our results demonstrated that NAC, PEMF, and NAC+PEMF treatments significantly increased the number of follicles. Moreover, we observed a more pronounced development of vascularization in the NAC, PEMF, and PEMF+NAC groups. The relative expression levels of Fgf-2, Vegf, Tnf-α, Il-1β, and Il-6 were significantly elevated in the NAC, PEMF, and NAC+PEMF groups. Notably, TAC levels decreased significantly in the NAC group compared to the control group. Additionally, the MDA level showed a significant decrease in the PEMF+NAC group when compared to the other groups. Overall, the combination of NAC and PEMF exhibited a synergistic effect in promoting angiogenesis and protecting against oxidative stress and inflammation during OT.}, }
@article {pmid37572985, year = {2023}, author = {Kim, D and Oh, E and Kim, H and Baek, SM and Cho, J and Kim, EH and Choi, S and Bian, Y and Kim, W and Bae, ON}, title = {Mono-(2-ethylhexyl)-phthalate potentiates methylglyoxal-induced blood-brain barrier damage via mitochondria-derived oxidative stress and bioenergetic perturbation.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {179}, number = {}, pages = {113985}, doi = {10.1016/j.fct.2023.113985}, pmid = {37572985}, issn = {1873-6351}, mesh = {Rats ; Animals ; *Diethylhexyl Phthalate/toxicity ; Pyruvaldehyde ; Blood-Brain Barrier/metabolism ; Endothelial Cells/metabolism ; Oxidative Stress ; Energy Metabolism ; Mitochondria/metabolism ; }, abstract = {Phthalates in contaminated foods and personal care products are one of the most frequently exposed chemicals with a public health concern. Phthalate exposure is related to cardiovascular diseases, including diabetic vascular complications and cerebrovascular diseases, yet the mechanism is still unclear. The blood-brain barrier (BBB) integrity disruption is strongly associated with cardiovascular and neurological disease exacerbation. We investigated BBB damage by di-(2-ethylhexyl) phthalate (DEHP) or its metabolite mono-(2-ethylhexyl) phthalate (MEHP) using brain endothelial cells and rat models. BBB damage by the subthreshold level of MEHP, but not a DEHP, significantly increased by the presence of methylglyoxal (MG), a reactive dicarbonyl compound whose levels increase in the blood in hyperglycemic conditions in diabetic patients. Significant potentiation in apoptosis and autophagy activation, mitochondria-derived reactive oxygen species (ROS) production, and mitochondrial metabolic disturbance were observed in brain ECs by co-exposure to MG and MEHP. N-acetyl cysteine (NAC) restored autophagy activation as well as tight junction protein impairment induced by co-exposure to MG and MEHP. Intraperitoneal administration of MG and MEHP significantly altered mitochondrial membrane potential and tight junction integrity in rat brain endothelium. This study may provide novel insights into enhancing phthalate toxicity in susceptible populations, such as diabetic patients.}, }
@article {pmid37569897, year = {2023}, author = {Khashab, R and Gutman-Sharabi, N and Shabtai, Z and Landau, R and Halperin, R and Fay-Karmon, T and Leibowitz, A and Sharabi, Y}, title = {Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {15}, pages = {}, pmid = {37569897}, issn = {1422-0067}, mesh = {Rats ; Animals ; *Parkinson Disease/drug therapy/etiology/metabolism ; Rotenone/pharmacology ; Dopamine/metabolism ; Selegiline ; Aldehyde Dehydrogenase/metabolism ; Monoamine Oxidase Inhibitors/pharmacology ; Acetylcysteine/pharmacology ; }, abstract = {The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment.}, }
@article {pmid37569463, year = {2023}, author = {Pieri, BLDS and Rodrigues, MS and Farias, HR and Silveira, GB and Ribeiro, VSGDC and Silveira, PCL and De Souza, CT}, title = {Role of Oxidative Stress on Insulin Resistance in Diet-Induced Obesity Mice.}, journal = {International journal of molecular sciences}, volume = {24}, number = {15}, pages = {}, pmid = {37569463}, issn = {1422-0067}, abstract = {Insulin resistance is the link between obesity and type 2 diabetes mellitus. The molecular mechanism by which obese individuals develop insulin resistance has not yet been fully elucidated; however, inconclusive and contradictory studies have shown that oxidative stress may be involved in the process. Thus, this study aimed to evaluate the effect of reactive species on the mechanism of insulin resistance in diet-induced obese mice. Obese insulin-resistant mice were treated with N-acetylcysteine (NAC; 50 mg/kg per day, for 15 days) by means of oral gavage. Twenty-four hours after the last NAC administration, the animals were euthanized and their tissues were extracted for biochemical and molecular analyses. NAC supplementation induced improved insulin resistance and fasting glycemia, without modifications in food intake, body weight, and adiposity. Obese mice showed increased dichlorofluorescein (DCF) oxidation, reduced catalase (CAT) activity, and reduced glutathione levels (GSH). However, treatment with NAC increased GSH and CAT activity and reduced DCF oxidation. The gastrocnemius muscle of obese mice showed an increase in nuclear factor kappa B (NFκB) and protein tyrosine phosphatase (PTP1B) levels, as well as c-Jun N-terminal kinase (JNK) phosphorylation compared to the control group; however, NAC treatment reversed these changes. Considering the molecules involved in insulin signaling, there was a reduction in insulin receptor substrate (IRS) and protein kinase B (Akt) phosphorylation. However, NAC administration increased IRS and Akt phosphorylation and IRS/PI3k (phosphoinositide 3-kinase) association. The results demonstrated that oxidative stress-associated obesity could be a mechanism involved in insulin resistance, at least in this animal model.}, }
@article {pmid37569345, year = {2023}, author = {Kang, M and Kang, JH and Sim, IA and Seong, DY and Han, S and Jang, H and Lee, H and Kang, SW and Kim, SY}, title = {Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.}, journal = {International journal of molecular sciences}, volume = {24}, number = {15}, pages = {}, pmid = {37569345}, issn = {1422-0067}, support = {NRF- 2019M3A9G1104345//National Research Foundation of Korea/ ; }, mesh = {*Glucose/deficiency ; *Adenosine Triphosphate/metabolism ; Pentose Phosphate Pathway ; *Reactive Oxygen Species/metabolism ; NADP/metabolism ; Glutathione/metabolism ; Acetylcysteine/metabolism/pharmacology ; PC-3 Cells ; Humans ; *Neoplasms/metabolism/pathology ; Cell Death ; }, abstract = {In previous work, we showed that cancer cells do not depend on glycolysis for ATP production, but they do on fatty acid oxidation. However, we found some cancer cells induced cell death after glucose deprivation along with a decrease of ATP production. We investigated the different response of glucose deprivation with two types of cancer cells including glucose insensitive cancer cells (GIC) which do not change ATP levels, and glucose sensitive cancer cells (GSC) which decrease ATP production in 24 h. Glucose deprivation-induced cell death in GSC by more than twofold after 12 h and by up to tenfold after 24 h accompanied by decreased ATP production to compare to the control (cultured in glucose). Glucose deprivation decreased the levels of metabolic intermediates of the pentose phosphate pathway (PPP) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in both GSC and GIC. However, glucose deprivation increased reactive oxygen species (ROS) only in GSC, suggesting that GIC have a higher tolerance for decreased NADPH than GSC. The twofold higher ratio of reduced/oxidized glutathione (GSH/GSSG) in GIS than in GSC correlates closely with the twofold lower ROS levels under glucose starvation conditions. Treatment with N-acetylcysteine (NAC) as a precursor to the biologic antioxidant glutathione restored ATP production by 70% and reversed cell death caused by glucose deprivation in GSC. The present findings suggest that glucose deprivation-induced cancer cell death is not caused by decreased ATP levels, but rather triggered by a failure of ROS regulation by the antioxidant system. Conclusion is clear that glucose deprivation-induced cell death is independent from ATP depletion-induced cell death.}, }
@article {pmid37567958, year = {2023}, author = {Bhattacharya, R and Saini, S and Ghosh, S and Roy, P and Ali, N and Parvez, MK and Al-Dosari, MS and Mishra, AK and Singh, LR}, title = {Organosulfurs, S-allyl cysteine and N-acetyl cysteine sequester di-carbonyls and reduces carbonyl stress in HT22 cells.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {13071}, pmid = {37567958}, issn = {2045-2322}, mesh = {*Acetylcysteine/pharmacology ; *Cysteine/metabolism ; Glycation End Products, Advanced/metabolism ; Antioxidants/pharmacology ; Maillard Reaction ; }, abstract = {Diabetes, characterized by high blood glucose level, is a progressive metabolic disease that leads to serious health complications. One of the major pathological consequences associated with diabetes is the accumulation of highly reactive carbonyl compounds called advanced glycation end products (AGEs). Most of the AGEs are dicarbonyls and have the potential to covalently modify proteins especially at the lysine residues in a non-enzymatic fashion (a process termed as glycation) resulting in the functional impairment and/or toxic gain in function. Therefore, non-toxic small molecules that can inhibit glycation are of interest for the therapeutic intervention of diabetes. In the present communication, we have investigated the effect of organosulfurs (S-allyl cysteine, SAC and N-acetyl cysteine, NAC) that are major principal components of Allium sativa against the glycation of different proteins. We discovered that both SAC and NAC are potent anti-glycating agents. We also found that both SAC and NAC reduce ROS level and inhibit apoptosis caused by protein glycation.}, }
@article {pmid37567916, year = {2023}, author = {Naushad, SM and Mandadapu, G and Ramaiah, MJ and Almajhdi, FN and Hussain, T}, title = {The role of TLR7 agonists in modulating COVID-19 severity in subjects with loss-of-function TLR7 variants.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {13078}, pmid = {37567916}, issn = {2045-2322}, mesh = {Humans ; Male ; Adaptor Proteins, Signal Transducing/metabolism ; Adjuvants, Immunologic ; *COVID-19/genetics ; Myeloid Differentiation Factor 88/genetics/metabolism ; RNA, Viral ; SARS-CoV-2/genetics ; *Toll-Like Receptor 7/agonists/genetics ; COVID-19 Drug Treatment ; }, abstract = {We investigate the mechanism associated with the severity of COVID-19 in men with TLR7 mutation. Men with loss-of-function (LOF) mutations in TLR7 had severe COVID-19. LOF mutations in TLR7 increased the risk of critical COVID by 16.00-fold (95% confidence interval 2.40-106.73). The deleterious mutations affect the binding of SARS-CoV2 RNA (- 328.66 ± 26.03 vs. - 354.08 ± 27.70, p = 0.03) and MYD88 (β: 40.279, p = 0.003) to TLR7 resulting in the disruption of TLR7-MyD88-TIRAP complex. In certain hypofunctional variants and all neutral/benign variants, there is no disruption of TLR7-MyD88-TIRAP complex and four TLR7 agonists showed binding affinity comparable to that of wild protein. N-acetylcysteine (NAC) also showed a higher binding affinity for the LOF variants (p = 0.03). To conclude, TLR7 LOF mutations increase the risk of critical COVID-19 due to loss of viral RNA sensing ability and disrupted MyD88 signaling. Majority of hypofunctional and neutral variants of TLR7 are capable of carrying MyD88 signaling by binding to different TLR7 agonists and NAC.}, }
@article {pmid37567457, year = {2023}, author = {Zheng, X and Su, F and Lei, M and Li, J and Zhang, C and Zhang, Y and Wei, M and Li, W and Chen, S and Liu, Y and Gao, Q and Hao, L}, title = {The novel peptide athycaltide-1 attenuates Ang II-induced pathological myocardial hypertrophy by reducing ROS and inhibiting the activation of CaMKII and ERK1/2.}, journal = {European journal of pharmacology}, volume = {957}, number = {}, pages = {175969}, doi = {10.1016/j.ejphar.2023.175969}, pmid = {37567457}, issn = {1879-0712}, mesh = {Animals ; Mice ; Angiotensin II/adverse effects/metabolism/toxicity ; Calcium Signaling ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Cardiomegaly/chemically induced/drug therapy/metabolism ; Cells, Cultured ; *MAP Kinase Signaling System ; Myocytes, Cardiac ; Peptides/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Pathological myocardial hypertrophy initially develops as an adaptive response to cardiac stress, which can be induced by many diseases. It is accompanied by adverse cardiovascular events, including heart failure, arrhythmias, and death. The purpose of this research was to explore the molecular mechanism of a novel peptide Athycaltide-1 (ATH-1) in the treatment of Ang II-induced pathological myocardial hypertrophy. In this study, the mRNA of Control group, Ang II group, ATH-1 group and Losartan group mice were sequenced by high-throughput sequencing technology. The results showed that the differentially expressed genes (DEGs) were significantly enriched in cell response to oxidative stress, regulation of reactive oxygen species metabolism and calmodulin binding. Then, the oxidation level of mouse hearts and H9c2 cardiomyocytes in each group and the expression of key proteins of CaMKII/HDAC/MEF2C and ERK1/2 signaling pathways were detected to preliminarily verify the positive effect of ATH-1. At the same time, the effect of ATH-1 was further determined by adding reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC) and CaMKII inhibitor AIP in vitro. The results showed that ATH-1 could significantly reduce the level of oxidative stress in hypertrophic cardiomyocytes and inhibiting the activation of CaMKII and ERK1/2.}, }
@article {pmid37562904, year = {2023}, author = {Sukumaran, D and Usharani, P and Paramjyothi, GK and Subbalaxmi, MVS and Sireesha, K and Abid Ali, M}, title = {A study to evaluate the hepatoprotective effect of N- acetylcysteine on anti tuberculosis drug induced hepatotoxicity and quality of life.}, journal = {The Indian journal of tuberculosis}, volume = {70}, number = {3}, pages = {303-310}, doi = {10.1016/j.ijtb.2022.05.012}, pmid = {37562904}, issn = {0019-5707}, mesh = {Humans ; Acetylcysteine/therapeutic use/pharmacology ; Quality of Life ; Prospective Studies ; *Tuberculosis/drug therapy ; *Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control ; Bilirubin ; Biomarkers ; }, abstract = {BACKGROUND: Drug induced liver injury (DILI) is a serious adverse effect caused by first-line anti-TB (ATT) drugs, limiting the TB-treatment. The tissue inflammation induced by free radical burst and poor dietary intake in TB induces oxidative stress, which was proposed as one of the mechanisms responsible for ATT induced DILI. N-acetylcysteine (NAC) exerts a hepato-protective effect by enhancing the cellular antioxidant defense mechanism. There are few studies evaluating the effect of NAC on ATT induced DILI in Indian-population.<br><br>METHODS: This is a prospective, randomized, double-blind, placebo-controlled, parallel-group study. Thirty-eight newly diagnosed TB patients on first-line ATT with normal liver function test (LFT) were recruited and randomized to receive either NAC 600 mg tablet or placebo twice daily for 4 weeks and followed-up for next 4 weeks. LFT [AST, ALT, ALP and Total bilirubin] was assessed at baseline, 2, 4 and 8 weeks. Oxidative-stress biomarkers [Malondialdehyde (MDA), Nitric Oxide (NO), Glutathione (GSH)] and quality of life (QOL) by SF-36 questionnaire were assessed at baseline, 4 and 8 weeks. Adverse Drug Reactions (ADRs) were monitored at every visit. Compliance was assessed by pill-count method.<br><br>RESULTS: Baseline characteristics were homogenous among both the groups. In the NAC group, there was significant reduction in ALT (p&#xa0;<&#xa0;0.01), ALP (p&#xa0;<&#xa0;0.01), total bilirubin (p&#xa0;<&#xa0;0.001) at 4 weeks compared to baseline. AST, MDA and NO showed a reduction of 19%, 21.6% and 5.5% respectively from baseline and GSH at showed an increase of 2.6% from baseline at 4 weeks in the NAC group, however these were not statistically significant. These effects in LFT and oxidative biomarkers persisted even at the end of 8 weeks. Significant improvement from baseline in QOL was observed in both the groups (p&#xa0;<&#xa0;0.05). Between group analysis showed, significant reduction in ALT (p&#xa0;<&#xa0;0.05) and AST (p&#xa0;<&#xa0;0.05) in NAC group at 4 weeks, whereas bilirubin, MDA, NO and GSH showed improvement at 4 weeks compared to placebo in NAC group, however it was not statistically significant. This improvement in the LFT and oxidative biomarkers continued even at the end of 8 weeks. Itching and rashes were the most common ADRs, with similar incidence in both the groups. Compliance to treatment was good in both the groups.<br><br>CONCLUSION: Significant improvement in liver function parameters is suggestive of hepatoprotective effect of NAC. This observed effect at 4 weeks was found to be persistent at 8 weeks, which signifies prolonged hepato-protective effect of NAC. Long duration studies with large sample size are required for further confirmation of hepato-protective action of NAC.}, }
@article {pmid37562091, year = {2023}, author = {Geng, Y and Liu, P and Xie, Y and Liu, Y and Zhang, X and Hou, X and Zhang, L}, title = {Xanthatin suppresses pancreatic cancer cell growth via the ROS/RBL1 signaling pathway: In vitro and in vivo insights.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {119}, number = {}, pages = {155004}, doi = {10.1016/j.phymed.2023.155004}, pmid = {37562091}, issn = {1618-095X}, mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; Mice, Nude ; Cell Line, Tumor ; *Signal Transduction ; Cell Proliferation ; Apoptosis ; Cell Transformation, Neoplastic ; *Pancreatic Neoplasms/drug therapy ; }, abstract = {BACKGROUND: As a malignant digestive system tumor, pancreatic cancer has a high mortality rate. Xanthatin is a sesquiterpene lactone monomer compound purified from the traditional Chinese herb Xanthium strumarium L. It has been reported that Xanthatin exhibits inhibitory effects on various cancer cells in retinoblastoma, glioma, hepatoma, colon cancer, lung cancer, as well as breast cancer. However, in pancreatic cancer cells, only one report exists on the suppression of Prostaglandin E2 synthesis and the induction of caspase 3/7 activation in Xanthatin-treated MIA PaCa-2 cells, while systematic in vitro and in vivo investigations and related mechanisms have yet to be explored.<br><br>PURPOSE: This research aims to explore the in vitro and in vivo effects of Xanthatin on pancreatic cancer and its molecular mechanisms.<br><br>METHODS: The anticancer effects and mechanisms of Xanthatin on pancreatic cancer cells were assessed through employing cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, carboxyfluorescein diacetate succinimidyl ester (CFDA SE) cell proliferation assay, colony formation assay, wound healing assay, transwell assay, Annexin V-FITC/propidium iodide (PI) dual staining, Hoechst nuclear staining, Western blot analysis, phosphoproteomics, and reactive oxygen species (ROS) measurement. The in vivo anticancer effects of Xanthatin on pancreatic cancer cells were studied using a nude mouse model.<br><br>RESULTS: The present study showed that Xanthatin can prevent the proliferation and metastasis of pancreatic cancer cells and trigger the exposure of phosphatidylserine (PS), chromatin condensation, and caspase activation, thereby inducing apoptosis. Phosphoproteomic analysis indicated that Xanthatin inhibits the phosphorylation of the proliferation-associated protein RBL1, and oxidative stress can lead to RBL1 dephosphorylation. Further investigation revealed that Xanthatin significantly upregulates ROS levels in pancreatic cancer cells, and the antioxidant N-acetylcysteine (NAC) can reverse Xanthatin-induced cell proliferation inhibition and apoptosis. In addition, Xanthatin can suppress pancreatic cancer cell growth in a xenograft nude mouse model with low toxicity to the mice.<br><br>CONCLUSION: Xanthatin may inhibit the proliferation of pancreatic cancer cells and trigger apoptosis through the ROS/RBL1 signaling pathway.}, }
@article {pmid37561633, year = {2023}, author = {Yao, H and Chen, X and Wang, T and Kashif, M and Qiao, X and Tüksammel, E and Larsson, LG and Okret, S and Sayin, VI and Qian, H and Bergo, MO}, title = {A MYC-controlled redox switch protects B lymphoma cells from EGR1-dependent apoptosis.}, journal = {Cell reports}, volume = {42}, number = {8}, pages = {112961}, doi = {10.1016/j.celrep.2023.112961}, pmid = {37561633}, issn = {2211-1247}, abstract = {Refractory and relapsed B cell lymphomas are often driven by the difficult-to-target oncogene MYC. Here, we report that high MYC expression stimulates proliferation and protects B lymphoma cells from apoptosis under normal oxidative stress levels and that compounds including N-acetylcysteine (NAC) and vitamin C (VitC) induce apoptosis by reducing oxidative stress. NAC and VitC injections effectively reduce tumor growth in lymphoma cells with high MYC expression but not in those with low MYC expression. MYC knockdown confers tumor resistance to NAC and VitC, while MYC activation renders B cells sensitive to these compounds. Mechanistically, NAC and VitC stimulate MYC binding to EGR1 through Cys117 of MYC, shifting its transcriptional output from cell cycle to apoptosis gene expression. These results identify a redox-controlled mechanism for MYC's role in maintaining proliferation and preventing apoptosis, offering a potential therapeutic rationale for evaluating NAC or VitC in patients with MYC-driven B cell lymphoma.}, }
@article {pmid37559860, year = {2023}, author = {Mitchell, MC and Rogers, C}, title = {A Case of Cocaine-Induced Acute Liver Failure Reversed With N-Acetylcysteine.}, journal = {Cureus}, volume = {15}, number = {7}, pages = {e41579}, pmid = {37559860}, issn = {2168-8184}, abstract = {Acute liver failure (ALF) is a life-threatening injury that is most often caused by drug-induced injury, including acetaminophen overdose, in the United States. The hallmarks of ALF are hepatic encephalopathy and coagulopathy in a patient without an established history of liver disease. While acetaminophen overdose has an antidote, that is N-acetylcysteine (NAC), when given acutely, most other causes of hepatic failure require an urgent liver transplant. In this paper, we report a case of cocaine-induced acute liver failure that was reversed with the administration of NAC. Our case began when a middle-aged male presented to the emergency department complaining of nausea, vomiting, fatigue, and confusion for the past three days. His past medical history was pertinent for a history of opioid use disorder and his physical exam was remarkable for somnolence, asterixis, and periumbilical ecchymoses. His initial lab results showed markedly elevated liver function tests, prolonged coagulation studies, and a urine drug screen that was positive for cocaine. During the patient's interview, his vital signs became unstable. He was intubated for airway protection and transferred to a tertiary care facility for liver transplant evaluation with the diagnosis of cocaine-induced acute liver failure. There he received NAC, lactulose, rifaximin, and vasopressors. On day two of treatment, his clinical condition greatly improved, and he was extubated. He continued to receive NAC until day five when his liver function tests and coagulopathy improved enough to stop treatment. This case report highlights the clinical benefit of NAC in a case of cocaine-induced acute liver failure, improving the patient's survival and eliminating his need for a liver transplant.}, }
@article {pmid37558010, year = {2023}, author = {Zhong, G and Guo, Y and Gong, X and Xu, M and Wang, Q and Wu, M and Zhang, X and Liang, Y and Zhao, W and Wang, H and Ye, J}, title = {Enhanced glycolysis by ATPIF1 gene inactivation increased the anti-bacterial activities of neutrophils through induction of ROS and lactic acid.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1869}, number = {8}, pages = {166820}, doi = {10.1016/j.bbadis.2023.166820}, pmid = {37558010}, issn = {1879-260X}, mesh = {Adenosine Triphosphate/metabolism ; Escherichia coli/metabolism ; Gene Silencing ; Glycolysis ; *Neutrophils/metabolism ; Nitric Oxide Synthase/metabolism ; *Peritonitis ; Reactive Oxygen Species/metabolism ; Animals ; Mice ; ATPase Inhibitory Protein ; }, abstract = {ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein that regulates the activity of FoF1-ATP synthase. Mice lacking ATPIF1 throughout their bodies (Atpif1[-/-]) exhibit a reduction in the number of neutrophils. However, it remains unclear whether the inactivation of ATPIF1 impairs the antibacterial function of mice, this study aimed to evaluate it using a mouse peritonitis model. Mice were intraperitoneally injected with E. coli to induce peritonitis, and after 24 h, the colonies of E. coli were counted in agarose plates containing mice peritoneal lavage fluids (PLF) or extract from the liver. Neutrophils were analyzed for glucose metabolism in glycolysis following LPS stimulation. Reactive oxygen species (ROS) and lactic acid (LA) levels in neutrophils were measured using flow cytometry and Seahorse analysis, respectively. N-Acetylcysteine (NAC) and 2-Deoxy-d-glucose (2-DG) were employed to assess the role of ROS and LA in neutrophil bactericidal activity. RNA-seq analysis was conducted in neutrophils to investigate potential mechanisms. In ATPIF1[-/-] neutrophils, bactericidal activity was enhanced, accompanied by increased levels of ROS and LA compared to wildtype neutrophils. The augmented bactericidal activity of ATPIF1[-/-] neutrophils was reversed by pretreatment with NAC or 2-DG. RNA-seq analysis revealed downregulation of multiple genes involved in glutathione metabolism, pyruvate oxidation, and heme synthesis, along with increased expression of inflammatory and apoptotic genes. This study suggests that the inactivation of the Atpif1 gene enhances glucose metabolism in neutrophils, resulting in increased bactericidal activity mediated by elevated levels of ROS and LA. Inhibiting ATPIF1 may be a potential approach to enhance antibacterial immunity.}, }
@article {pmid37556466, year = {2023}, author = {Yu, H and Lv, M and Zhang, S and Zou, K and Qian, Y and Lv, S}, title = {Combination therapy with budesonide and acetylcysteine alleviates LPS-induced acute lung injury via the miR-381/NLRP3 molecular axis.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0289818}, pmid = {37556466}, issn = {1932-6203}, mesh = {Animals ; Rats ; *Acetylcysteine/therapeutic use ; *Acute Lung Injury/chemically induced/drug therapy/metabolism ; *Budesonide/therapeutic use ; Lipopolysaccharides/adverse effects ; Lung/pathology ; *MicroRNAs/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; *Pulmonary Edema/pathology ; Signal Transduction ; }, abstract = {BACKGROUND: Acute lung injury (ALI) usually has a high morbidity and mortality rate, but the current treatment is relatively scarce. Both budesonide (Bud) and N-acetylcysteine (NAC) exhibit protective effects in ALI, so we further investigated whether they have a synergistic effect on ALI when used together.<br><br>METHODS: Establishment of a rat model of ALI with Lipopolysaccharide (LPS). Bud and NAC were administered by nebulized inhalation alone or in combination. Subsequently, HE staining was performed to observe the pathological changes in lungs of rat. Evans blue staining was implemented to assess alveolar permeability, and the pulmonary edema was assessed by measuring the ratio of wet to dry weight of the lung. Moreover, a TUNEL kit was served to test apoptosis in lung tissues. Western blot and immunohistochemistry were analyzed for expression of scorch-related proteins and NLRP3 in lung tissue, respectively. ELISA was implemented to detect inflammatory factor levels in BALF. and RT-qPCR was utilized to assess the expression level of miR-381. After stable transfection of miR-381 inhibitor or OE-NLRP3 in BEAS-2B treated with LPS, Bud and NAC, miR-381 expression was assessed by RT-qPCR, scorch death-related protein expression was measured by western blot, cell proliferation/viability was assayed by CCK-8, apoptosis was measured by flow cytometry, and ELISA was implemented to assess inflammatory factor levels. Furthermore, the Dual-luciferase assay was used to verify the targeting relationship.<br><br>RESULTS: Bud and NAC treatment alone or in combination with nebulized inhalation attenuated the increased alveolar permeability, pulmonary edema, inflammatory response and scorching in LPS-induced ALI rats, and combined treatment with Bud and NAC was the most effective. In addition, combined treatment with Bud and NAC upregulated miR-381 expression and inhibited NLRP3 expression in cellular models and LPS-induced ALI rats. Transfection of the miR-381 inhibitor and OE-NLRP3 partially reversed the protective effects of Bud and NAC combination treatment on BEAS-2B cell proliferation inhibition, apoptosis, focal death and the inflammatory response.<br><br>CONCLUSION: Combined Bud and NAC nebulization therapy alleviates LPS-induced ALI by modulating the miR-381/NLRP3 molecular axis.}, }
@article {pmid37555614, year = {2024}, author = {Stannard, LM and Doherty, A and Chapman, KE and Doak, SH and Jenkins, GJ}, title = {Multi-endpoint analysis of cadmium chloride-induced genotoxicity shows role for reactive oxygen species and p53 activation in DNA damage induction, cell cycle irregularities, and cell size aberrations.}, journal = {Mutagenesis}, volume = {39}, number = {1}, pages = {13-23}, pmid = {37555614}, issn = {1464-3804}, support = {NC/R001375/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, mesh = {*Tumor Suppressor Protein p53/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Cadmium Chloride/toxicity/metabolism ; DNA Damage ; Cell Cycle ; Carcinogens/toxicity ; }, abstract = {Cadmium chloride (CdCl2) is a known genotoxic carcinogen, with a mechanism of action thought to partly involve the generation of reactive oxygen species (ROS). We applied here a multi-endpoint approach in vitro to explore the impact of CdCl2 on both the genome and on wider cell biology pathways relevant to cancer. Multi-endpoint approaches are believed to offer greater promise in terms of understanding the holistic effects of carcinogens in vitro. This richer understanding may help better classification of carcinogens as well as allowing detailed mechanisms of action to be identified. We found that CdCl2 caused DNA damage [micronuclei (MN)] in both TK6 and NH32 cells in a dose-dependent manner after 4 h exposure (plus 23 h recovery), with lowest observable effect levels (LOELs) for MN induction of 1 μM (TK6) and 1.6 μM (NH32). This DNA damage induction in TK6 cells was ROS dependent as pretreatment with the antioxidant N-Acetyl Cysteine (1 mM), abrogated this effect. However, 2',7'-dichlorofluorescin diacetate was not capable of detecting the ROS induced by CdCl2. The use of NH32 cells allowed an investigation of the role of p53 as they are a p53 null cell line derived from TK6. NH32 showed a 10-fold increase in MN in untreated cells and a similar dose-dependent effect after CdCl2 treatment. In TK6 cells, CdCl2 also caused activation of p53 (accumulation of total and phosphorylated p53), imposition of cell cycle checkpoints (G2/M) and intriguingly the production of smaller and more eccentric (elongated) cells. Overall, this multi-endpoint study suggests a carcinogenic mechanism of CdCl2 involving ROS generation, oxidative DNA damage and p53 activation, leading to cell cycle abnormalities and impacts of cell size and shape. This study shows how the integration of multiple cell biology endpoints studied in parallel in vitro can help mechanistic understanding of how carcinogens disrupt normal cell biology.}, }
@article {pmid37554797, year = {2023}, author = {Zhou, Q and Zhou, Q and Xia, R and Zhang, P and Xie, Y and Yang, Z and Khan, A and Zhou, Z and Tan, W and Liu, L}, title = {Swertiamarin or heat-transformed products alleviated APAP-induced hepatotoxicity via modulation of apoptotic and Nrf-2/NF-κB pathways.}, journal = {Heliyon}, volume = {9}, number = {8}, pages = {e18746}, pmid = {37554797}, issn = {2405-8440}, abstract = {OBJECTIVE: Swertiamarin (STM) belongs to iridoid class of compounds, and the heat-transformed products (HTPS) are produced by STM in the process of drug processing. The purpose of this study was to explore the protective effect and mechanism of STM or HTPS on acetaminophen (APAP)-induced hepatotoxicity.<br><br>METHODS: Mice and L-O2 cells were given APAP to establish the hepatotoxicity model in vivo and in vitro. The effects of STM or HTPS on oxidative stress, inflammation, and apoptosis induced by APAP were evaluated, with N-acetylcysteine (NAC) as a positive control.<br><br>RESULTS: STM or HTPS reduced the APAP-induced apoptosis of L-O2 cells and significantly alleviated the liver injury index induced by APAP (p&#xa0;<&#xa0;0.01, 0.005) Interestingly, HTPS had better protective effect against APAP-induced hepatotoxicity than STM (p&#xa0;<&#xa0;0.05). In addition STM or HTPS improved the histological abnormalities; inhibited lipid peroxidation and reduced the level of inflammatory mediators. They also activated the defense system of nuclear factor erythroid 2 related factor 2 (Nrf-2) and inhibited nuclear factor-&#x3ba; B (NF-&#x3ba;B).}, }
@article {pmid37547958, year = {2023}, author = {Wang, X and Liu, B and Liu, Y and Wang, Y and Wang, Z and Song, Y and Xu, J and Xue, C}, title = {Antioxidants ameliorate oxidative stress in alcoholic liver injury by modulating lipid metabolism and phospholipid homeostasis.}, journal = {Lipids}, volume = {58}, number = {5}, pages = {229-240}, doi = {10.1002/lipd.12377}, pmid = {37547958}, issn = {1558-9307}, mesh = {Mice ; Animals ; *Antioxidants/pharmacology/metabolism ; Lipid Metabolism ; Mice, Inbred C57BL ; Liver/metabolism ; Oxidative Stress ; *Liver Diseases, Alcoholic/drug therapy/metabolism ; Ethanol/metabolism/pharmacology ; Ascorbic Acid/metabolism/pharmacology ; Triglycerides/metabolism ; Homeostasis ; Phospholipids/metabolism ; }, abstract = {Alcoholic liver disease (ALD) is a significant risk factor in the global disease burden. The antioxidants vitamin C (Vc) and N-acetyl cysteine (NAC) have shown hepatoprotective effects in preventing and treating ALD. However, the correlation between the improved effect of antioxidants and lipid metabolism is still unclear. In this study, AML12 cells and C57BL/6 mice stimulated with alcohol were used to investigate the protective effects and potential mechanisms of two antioxidants (Vc and NAC) on alcoholic liver injury. Results showed that Vc and NAC attenuated intracellular lipid accumulation and oxidative damage induced by excessive alcohol exposure in hepatic AML12 cells. The in vivo results indicated that antioxidants ameliorated alcohol-induced changes in histopathology, reducing the levels of alcohol metabolizing factors and aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), and total cholesterol (TC) contents, which demonstrated that antioxidants effectively mitigated liver injury in ALD mice. Further studies showed that antioxidants reversed the disruption of fatty acid (FA) synthesis and lipid transport induced by alcohol exposure, and restored phospholipid levels. Especially, Vc and NAC increased the endogenous antioxidant plasmenyl phosphatidylethanolamine (PlsEtn). Additionally, antioxidants ameliorated the alcohol-impaired mitochondrial function and inhibited excessive oxidative stress. In conclusion, antioxidants can regulate lipid metabolism and phospholipid homeostasis, which in turn inhibit oxidative stress and thereby exert protective effects against ALD.}, }
@article {pmid37547194, year = {2023}, author = {Summerlin, JA and Wang, KM and McMahon, AJ and Lund, JA}, title = {Effect of a pharmacist-based toxicology consult service on appropriate use of intravenous N-acetylcysteine for acetaminophen toxicity: A retrospective cohort study.}, journal = {International journal of critical illness and injury science}, volume = {13}, number = {2}, pages = {54-59}, pmid = {37547194}, issn = {2229-5151}, abstract = {BACKGROUND: Incorporating clinical pharmacists on the medical team has been associated with fewer medication errors and increased error interception. Due to the logistical complexities of the intravenous (IV) N-acetylcysteine (NAC) regimen for acetaminophen toxicity, many opportunities for medication errors exist. A pharmacist-based toxicology consultation service was implemented at our institution, allowing pharmacists to formally aid in the management of toxicology patients throughout their hospital admission, including those with acetaminophen toxicity. The purpose of this study was to evaluate the effect of a house-wide pharmacist-based toxicology consult service on errors associated with IV NAC treatment for patients admitted with acetaminophen toxicity.<br><br>METHODS: A retrospective, pre-post cohort study was conducted on patients who received IV NAC for acetaminophen toxicity. The intervention evaluated was the implementation of a pharmacist-based toxicology consult service, known as the pharmacy toxicology team. The primary end point was the incidence of an error associated with IV NAC. An error was defined as the composite of inappropriate dose, administration rate, initiation, continuation, or discontinuation.<br><br>RESULTS: Eighty-four patients were included; 30 patients in the pregroup, and 54 patients in the postgroup. Fewer patients experienced an error in the postgroup compared to the pregroup (30% vs 63%, P = 0.003).<br><br>CONCLUSION: The implementation of this unique pharmacist-based toxicology consult service was associated with fewer patients experiencing an error related to IV NAC therapy for acetaminophen toxicity. Application of this data may aid in the justification for development of clinical pharmacist-based toxicology consult services at other institutions.}, }
@article {pmid37545886, year = {2023}, author = {Pimentel, BNADS and De Annunzio, SR and Assis, M and Barbugli, PA and Longo, E and Vergani, CE}, title = {Biocompatibility and inflammatory response of silver tungstate, silver molybdate, and silver vanadate microcrystals.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {11}, number = {}, pages = {1215438}, pmid = {37545886}, issn = {2296-4185}, abstract = {Silver tungstate (α-Ag2WO4), silver molybdate (β-Ag2MoO4), and silver vanadate (α-AgVO3) microcrystals have shown interesting antimicrobial properties. However, their biocompatibility is not yet fully understood. Cytotoxicity and the inflammatory response of silver-containing microcrystals were analyzed in THP-1 and THP-1 differentiated as macrophage-like cells, with the alamarBlue™ assay, flow cytometry, confocal microscopy, and ELISA. The present investigation also evaluated redox signaling and the production of cytokines (TNFα, IL-1β, IL-6, and IL-8) and matrix metalloproteinases (MMP-8 and -9). The results showed that α-AgVO3 (3.9 μg/mL) did not affect cell viability (p > 0.05). α-Ag2WO4 (7.81 μg/mL), β-Ag2MoO4 (15.62 μg/mL), and α-AgVO3 (15.62 μg/mL) slightly decreased cell viability (p ≤ 0.003). All silver-containing microcrystals induced the production of O2 [-] and this effect was mitigated by Reactive Oxygen Species (ROS) scavenger and N-acetylcysteine (NAC). TNFα, IL-6 and IL-1β were not detected in THP-1 cells, while their production was either lower (p ≤ 0.0321) or similar to the control group (p ≥ 0.1048) for macrophage-like cells. The production of IL-8 by both cellular phenotypes was similar to the control group (p ≥ 0.3570). The release of MMP-8 was not detected in any condition in THP-1 cells. Although MMP-9 was released by THP-1 cells exposed to α-AgVO3 (3.9 μg/mL), no significant difference was found with control (p = 0.7). Regarding macrophage-like cells, the release of MMP-8 and -9 decreased in the presence of all microcrystals (p ≤ 0.010). Overall, the present work shows a promising biocompatibility profile of, α-Ag2WO4, β-Ag2MoO4, and α-AgVO3 microcrystals.}, }
@article {pmid37545163, year = {2023}, author = {Nayak, J and P, SV and Sahoo, SK and Kumar, M and Vashistha, VK and Kumar, R}, title = {Computational insight of antioxidant and doxorubicin combination for effective cancer therapy.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/07391102.2023.2242507}, pmid = {37545163}, issn = {1538-0254}, abstract = {Doxorubicin (DOX) is the most effective antineoplastic agent, destroys cancer cells by interrupting cellular function. However, the serious side effects on the heart limits its utility. To curb these unwanted side effects, nutritionist recommend antioxidants use along with DOX while chemotherapy. But it was not supported by various oncologists as it can alter the toxicity of DOX towards cancer cells. Therefore, here we explored the in silico pharmacokinetics and combination effect of DOX and antioxidants on topoisomerases-II (Top-II) and cyclophilin D (Cyp-D) therapeutic targets involved in cancer proliferation and post-myocardial infarction, respectively. The molecular docking study was conducted on target proteins and DOX including most prescribed antioxidants (melatonin, N-acetylcysteine (NAC), glutathione (GSH), β-carotene and vitamin C). GSH showed effective binding potential for Top-II and Cyp-D active sites, but other considered antioxidants possess low binding affinity. The highest docked conformations were subjected to molecular dynamics (MD) simulations to understand conformer stability of DOX and GSH with Cyp-D and Top-II for 100 ns. The results revealed that ligands pose at Top-II active sites where DOX showed strong binding affinity to DNA binding pocket and GSH to a buried site. The computational data summarised and proposed the GSH and DOX combination as antagonist effects on Top-II. Conversely, the binding compactness of GSH improved due to surface fit at the active pocket of Cyp-D and completely blocking DOX binding affinity, suppress adverse reactions of post-myocardial infarction.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid37544576, year = {2023}, author = {Su, AL and Lash, LH and Loch-Caruso, R}, title = {N-Acetyl-L-cysteine and aminooxyacetic acid differentially modulate toxicity of the trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine in human placental villous trophoblast BeWo cells.}, journal = {Toxicology}, volume = {495}, number = {}, pages = {153611}, pmid = {37544576}, issn = {1879-3185}, support = {P30 ES017885/ES/NIEHS NIH HHS/United States ; P42 ES017198/ES/NIEHS NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; T32 HD079342/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; Pregnancy ; *Acetylcysteine/pharmacology/metabolism ; Cysteine ; *Trichloroethylene/toxicity/metabolism ; Placenta/metabolism ; Aminooxyacetic Acid/metabolism/pharmacology ; Trophoblasts/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Hydrogen Peroxide/metabolism ; RNA, Messenger/metabolism ; }, abstract = {Trichloroethylene (TCE) is a known human carcinogen with toxicity attributed to its metabolism. S-(1,2-Dichlorovinyl)-L-cysteine (DCVC) is a metabolite of TCE formed downstream in TCE glutathione (GSH) conjugation and is upstream of several toxic metabolites. Despite knowledge that DCVC stimulates reactive oxygen species (ROS) generation and apoptosis in placental cells, the extent to which these outcomes are attributable to DCVC metabolism is unknown. The current study used N-acetyl-L-cysteine (NAC) at 5 mM and aminooxyacetic acid (AOAA) at 1 mM as pharmacological modifiers of DCVC metabolism to investigate DCVC toxicity at concentrations of 5-50 µM in the human placental trophoblast BeWo cell model capable of forskolin-stimulated syncytialization. Exposures of unsyncytialized BeWo cells, BeWo cells undergoing syncytialization, and syncytialized BeWo cells were studied. NAC pre/co-treatment with DCVC either failed to inhibit or exacerbated DCVC-induced H2O2 abundance, PRDX2 mRNA expression, and BCL2 mRNA expression. Although NAC increased mRNA expression of CYP3A4, which would be consistent with increased generation of the toxic metabolite N-acetyl-DCVC sulfoxide (NAcDCVCS), a CYP3A4 inhibitor ketoconazole did not significantly alter BeWo cell responses. Moreover, AOAA failed to inhibit cysteine conjugate β-lyase (CCBL), which bioactivates DCVC, and did not affect the percentage of nuclei condensed or fragmented, a measure of apoptosis, in all BeWo cell models. However, syncytialized cells had higher CCBL activity compared to unsyncytialized cells, suggesting that the former may be more sensitive to DCVC toxicity. Together, although neither NAC nor AOAA mitigated DCVC toxicity, differences in CCBL activity and potentially CYP3A4 expression dictated the differential toxicity derived from DCVC.}, }
@article {pmid37540942, year = {2023}, author = {Kanaan, RA and Oliver, G and Dharan, A and Sendi, S and Maier, A and Mohebbi, M and Ng, C and Back, SE and Kalivas, P and Berk, M}, title = {A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-Acetylcysteine for treatment-resistant PTSD.}, journal = {Psychiatry research}, volume = {327}, number = {}, pages = {115398}, doi = {10.1016/j.psychres.2023.115398}, pmid = {37540942}, issn = {1872-7123}, mesh = {Adult ; Humans ; *Acetylcysteine/pharmacology/therapeutic use ; *Stress Disorders, Post-Traumatic/drug therapy ; Double-Blind Method ; Treatment Outcome ; }, abstract = {BACKGROUND: PTSD may involve oxidative stress, and N-acetylcysteine (NAC) may reduce the impact of oxidative stress in the brain. This study aims to investigate the efficacy of adjuvant NAC in people with treatment-resistant PTSD.<br><br>METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adults with PTSD unresponsive to first-line treatment. The intervention was either oral NAC 2.7&#xa0;g/day or placebo for 12 weeks. The primary outcome was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 12 weeks compared with baseline. Secondary outcomes included depression and substance craving. Follow-up measures were obtained at 16 and 64-weeks.<br><br>RESULTS: 133 patients were assessed, with 105 randomised; 81 participants completed the 12-week trial, 79 completed week-16 follow-up, and 21 completed week-64 follow-up. There were no significant differences between those taking NAC and those taking placebo in CAPS-5 scores at week 12, nor in secondary outcomes. Significant between-group differences were observed at week 64 in craving duration (Cohen's d&#xa0;=&#xa0;1.61) and craving resistance (Cohen's d&#xa0;=&#xa0;1.03), both in favour of NAC.<br><br>CONCLUSION: This was the first multicentre, double-blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. No benefit of NAC was observed in this group beyond that provided by placebo at end of the trial.<br><br>TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004.}, }
@article {pmid37540386, year = {2023}, author = {Zhang, J and Sun, J and Zhang, Y and Zhang, M and Liu, X and Yang, L and Yin, Y}, title = {Dehydrocostus lactone inhibits Candida albicans growth and biofilm formation.}, journal = {AMB Express}, volume = {13}, number = {1}, pages = {82}, pmid = {37540386}, issn = {2191-0855}, support = {2019SCZT053//the Special Fund for Medical Professionals of Jilin Province/ ; }, abstract = {Candida albicans infections are threatening public health but there are only several antifungal drugs available. This study was to assess the effects of dehydrocostus lactone (DL) on the Candida albicans growth and biofilms Microdilution assays revealed that DL inhibits a panel of standard Candida species, including C. albicans, as well as 9 C. albicans clinical isolates. The morphological transition of C. albicans in RPMI-1640 medium and the adhesion to polystyrene surfaces can also be decreased by DL treatment, as evidenced by microscopic, metabolic activity and colony forming unit (CFU) counting assays. The XTT assay and microscopy inspection demonstrated that DL can inhibit the biofilms of C. albicans. Confocal microscopy following propidium iodide (PI) staining and DCFH-DA staining after DL treatment revealed that DL can increase the membrane permeability and intracellular reactive oxygen species (ROS) production. N-acetyl-cysteine could mitigate the inhibitory effects of DL on growth, morphological transition and biofilm formation, further confirming that ROS production induced by DL contributes to its antifungal and antibiofilm effects. This study showed that DL demonstrated antifungal and antibiofilm activity against C. albicans. The antifungal mechanisms may involve membrane damage and ROS overproduction. This study shows the potential of DL to fight Candida infections.}, }
@article {pmid37537647, year = {2023}, author = {Refsnes, M and Skuland, T and Jørgensen, R and Sæter-Grytting, V and Snilsberg, B and Øvrevik, J and Holme, JA and Låg, M}, title = {Role of different mechanisms in pro-inflammatory responses triggered by traffic-derived particulate matter in human bronchiolar epithelial cells.}, journal = {Particle and fibre toxicology}, volume = {20}, number = {1}, pages = {31}, pmid = {37537647}, issn = {1743-8977}, mesh = {Humans ; *Particulate Matter/toxicity ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Cyclooxygenase 2 ; Cytochrome P-450 CYP1A1/genetics ; Plasminogen Activator Inhibitor 2/metabolism/pharmacology ; Cytokines/metabolism ; Epithelial Cells ; Vehicle Emissions/toxicity ; *Air Pollutants/toxicity/metabolism ; }, abstract = {BACKGROUND: Traffic-derived particles are important contributors to the adverse health effects of ambient particulate matter (PM). In Nordic countries, mineral particles from road pavement and diesel exhaust particles (DEP) are important constituents of traffic-derived PM. In the present study we compared the pro-inflammatory responses of mineral particles and DEP to PM from two road tunnels, and examined the mechanisms involved.<br><br>METHODS: The pro-inflammatory potential of 100&#xa0;&#xb5;g/mL coarse (PM10-2.5), fine (PM2.5-0.18) and ultrafine PM (PM0.18) sampled in two road tunnels paved with different stone materials was assessed in human bronchial epithelial cells (HBEC3-KT), and compared to DEP and particles derived from the respective stone materials. Release of pro-inflammatory cytokines (CXCL8, IL-1&#x3b1;, IL-1&#x3b2;) was measured by ELISA, while the expression of genes related to inflammation (COX2, CXCL8, IL-1&#x3b1;, IL-1&#x3b2;, TNF-&#x3b1;), redox responses (HO-1) and metabolism (CYP1A1, CYP1B1, PAI-2) was determined by qPCR. The roles of the aryl hydrocarbon receptor (AhR) and reactive oxygen species (ROS) were examined by treatment with the AhR-inhibitor CH223191 and the anti-oxidant N-acetyl cysteine (NAC).<br><br>RESULTS: Road tunnel PM caused time-dependent increases in expression of CXCL8, COX2, IL-1&#x3b1;, IL-1&#x3b2;, TNF-&#x3b1;, COX2, PAI-2, CYP1A1, CYP1B1 and HO-1, with fine PM as more potent than coarse PM at early time-points. The stone particle samples and DEP induced lower cytokine release than all size-fractionated PM samples for one tunnel, and versus fine PM for the other tunnel. CH223191 partially reduced release and expression of IL-1&#x3b1; and CXCL8, and expression of COX2, for fine and coarse PM, depending on tunnel, response and time-point. Whereas expression of CYP1A1 was markedly reduced by CH223191, HO-1 expression was not affected. NAC reduced the release and expression of IL-1&#x3b1; and CXCL8, and COX2 expression, but augmented expression of CYP1A1 and HO-1.<br><br>CONCLUSIONS: The results indicate that the pro-inflammatory responses of road tunnel PM in HBEC3-KT cells are not attributed to the mineral particles or DEP alone. The pro-inflammatory responses seem to involve AhR-dependent mechanisms, suggesting a role for organic constituents. ROS-mediated mechanisms were also involved, probably through AhR-independent pathways. DEP may be a contributor to the AhR-dependent responses, although other sources may be of importance.}, }
@article {pmid37537538, year = {2023}, author = {Duan, Y and Wu, W and Cui, J and Matsubara, JA and Kazlauskas, A and Ma, G and Li, X and Lei, H}, title = {Ligand-independent activation of platelet-derived growth factor receptor β promotes vitreous-induced contraction of retinal pigment epithelial cells.}, journal = {BMC ophthalmology}, volume = {23}, number = {1}, pages = {344}, pmid = {37537538}, issn = {1471-2415}, support = {2020004//Health Commission of Shanxi Province/ ; 2022-203//Research Project Supported by Shanxi Scholarship Council of China/ ; 2021RC005//Shanxi Bethune Hospital Foundation/ ; 2022Jx22//Shanxi Bethune Hospital Education and Teaching Reform Foundation/ ; 202103021224345//Natural Science Foundation of Shanxi province/ ; 2021JJ41030//Natural Science Foundation of&#xa0;Hunan Province/ ; 82171085//National Natural Science Foundation of China/ ; 82070989//National Natural Science Foundation of China/ ; 19JCZDJC64000//Natural Science Foundation of Tianjin City/ ; G2022026027L//Introduction plan of high-level foreign experts/ ; }, mesh = {Humans ; *Receptor, Platelet-Derived Growth Factor beta/genetics/metabolism ; Retinal Pigment Epithelium/pathology ; Proto-Oncogene Proteins c-akt ; Ligands ; Reactive Oxygen Species/metabolism ; *Vitreoretinopathy, Proliferative/genetics/metabolism ; Platelet-Derived Growth Factor/metabolism ; Epithelial Cells/metabolism ; Retinal Pigments/metabolism ; Cell Movement ; }, abstract = {BACKGROUND: Epiretinal membranes in patients with proliferative vitreoretinopathy (PVR) consist of extracellular matrix and a number of cell types including retinal pigment epithelial (RPE) cells and fibroblasts, whose contraction causes retinal detachment. In RPE cells depletion of platelet-derived growth factor (PDGF) receptor (PDGFR)β suppresses vitreous-induced Akt activation, whereas in fibroblasts Akt activation through indirect activation of PDGFRα by growth factors outside the PDGF family (non-PDGFs) plays an essential role in experimental PVR. Whether non-PDGFs in the vitreous, however, were also able to activate PDGFRβ in RPE cells remained elusive.<br><br>METHODS: The CRISPR/Cas9 technology was utilized to edit a genomic PDGFRB locus in RPE cells derived from an epiretinal membrane (RPEM) from a patient with PVR, and a retroviral vector was used to express a truncated PDGFR&#x3b2; short of a PDGF-binding domain in the RPEM cells lacking PDGFR&#x3b2;. Western blot was employed to analyze expression of PDGFR&#x3b2; and &#x3b1;-smooth muscle actin, and signaling events (p-PDGFR&#x3b2; and p-Akt). Cellular assays (proliferation, migration and contraction) were also applied in this study.<br><br>RESULTS: Expression of a truncated PDGFR&#x3b2; lacking a PDGF-binding domain in the RPEM cells whose PDGFRB gene has been silent using the CRISPR/Cas9 technology restores vitreous-induced Akt activation as well as cell proliferation, epithelial-mesenchymal transition, migration and contraction. In addition, we show that scavenging reactive oxygen species (ROS) with N-acetyl-cysteine and inhibiting Src family kinases (SFKs) with their specific inhibitor SU6656 blunt the vitreous-induced activation of the truncated PDGFR&#x3b2; and Akt as well as the cellular events related to the PVR pathogenesis. These discoveries suggest that in RPE cells PDGFR&#x3b2; can be activated indirectly by non-PDGFs in the vitreous via an intracellular pathway of ROS/SFKs to facilitate the development of PVR, thereby providing novel opportunities for PVR therapeutics.<br><br>CONCLUSION: The data shown here will improve our understanding of the mechanism by which PDGFR&#x3b2; can be activated by non-PDGFs in the vitreous via an intracellular route of ROS/SFKs and provide a conceptual foundation for preventing PVR by inhibiting PDGFR&#x3b2; transactivation (ligand-independent activation).}, }
@article {pmid37536438, year = {2023}, author = {Martis, RM and Grey, AC and Wu, H and Wall, GM and Donaldson, PJ and Lim, JC}, title = {N-Acetylcysteine amide (NACA) and diNACA inhibit H2O2-induced cataract formation ex vivo in pig and rat lenses.}, journal = {Experimental eye research}, volume = {234}, number = {}, pages = {109610}, doi = {10.1016/j.exer.2023.109610}, pmid = {37536438}, issn = {1096-0007}, mesh = {Rats ; Animals ; Swine ; Acetylcysteine/adverse effects ; Hydrogen Peroxide/pharmacology ; Cystine/adverse effects ; Chromatography, Liquid ; Rats, Wistar ; Tandem Mass Spectrometry ; *Lens, Crystalline/metabolism ; *Cataract/chemically induced ; Antioxidants ; Oxidative Stress ; Glutathione/metabolism ; Proteins ; Glutathione Disulfide ; }, abstract = {Oxidative stress plays a central role in cataract formation suggesting that antioxidants might slow cataract progression. The anticataract activity of N-acetylcysteine amide (NACA) and (2 R, 2 R')-3,3'-disulfanediyl bis(2-acetamidopropanamide) (diNACA) and/or N-acetylcysteine (NAC), were evaluated in porcine and rat lens models. Cataractogenesis via oxidation was induced with H2O2 and/or glucose oxidase (GO). Porcine lenses were incubated in 0.1 mM, 1 mM, or 10 mM NAC, NACA or diNACA for 24 h. Lenses were then transferred to media containing 0.75 mM H2O2 and 4.63U of GO in order to maintain a constant H2O2 level for an additional 8 h. At the end of incubation, lenses were imaged under darkfield microscopy. Separately, rat lenses were extracted from 3-week-old Wistar rats and incubated with either 10 mM NACA or 10 mM diNACA for 24 h prior to treatment with 0.2U GO to generate a steady source of ∼0.6 mM H2O2. Rat lenses were analyzed by LC-MS/MS to quantify changes in cysteine, cystine, glutathione (GSH) or oxidised glutathione (GSSG) levels in the lens epithelium, cortex or core. Pre-treatment with NACA or diNACA followed by oxidation with H2O2 and/or GO to stimulate cataract formation afforded rapid assessment in ex vivo porcine (32 h) and rat (48 h) lens models. Pre-treatment of isolated porcine lenses with 0.1 mM, 1 mM or 10 mM of either NAC, NACA or diNACA followed by H2O2/GO treatment resulted in reduced lens opacity relative to the lenses exposed to H2O2/GO, with NACA and diNACA reducing opacities to a greater extent than NAC. Rat lenses incubated with 10 mM NACA or 10 mM diNACA without exposure to H2O2 showed no signs of opacities. Pre-treatment of rat lenses with 10 mM NACA or 10 mM diNACA, followed by GO cataract induction resulted in reduced opacities compared to control (GO alone). LC-MS/MS analyses revealed that NACA, but not diNACA, increased cysteine, cystine and GSH levels in rat lens epithelium and cortex regions. Taken together, both NACA and diNACA inhibited cataract formation to a greater extent than NAC (all at 1-10 mM) in an ex vivo porcine lens model. Both NACA and diNACA (both at 10 mM) reduced cataract formation in rat lenses. Based on LC-MS/MS analyses, NACA-induced reduction in opacity observed in rat lenses was attributed to enhanced cysteine and GSH levels while the diNACA-induced reduction in opacity induced did not consistently increase cysteine, cystine and GSH levels and, therefore, appears to involve a different antioxidant mechanism. These screening studies warrant further testing of NACA and diNACA as anticataract agents.}, }
@article {pmid37536084, year = {2023}, author = {Takeda, H and Murakami, S and Liu, Z and Sawa, T and Takahashi, M and Izumi, Y and Bamba, T and Sato, H and Akaike, T and Sekine, H and Motohashi, H}, title = {Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.}, journal = {Redox biology}, volume = {65}, number = {}, pages = {102834}, pmid = {37536084}, issn = {2213-2317}, mesh = {Mice ; Animals ; *Cystine ; Feedback ; *Lipopolysaccharides ; Macrophages/metabolism ; Acetylcysteine ; Sulfur/metabolism ; Amino Acid Transport System y+/genetics/metabolism ; }, abstract = {The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.}, }
@article {pmid37534881, year = {2023}, author = {Ding, W and Fan, JH and Zhong, LR and Wang, NX and Liu, LH and Zhang, HB and Wang, L and Wang, MQ and He, BL and Wei, AY}, title = {N-acetylcysteine ameliorates erectile dysfunction in rats with hyperlipidemia by inhibiting oxidative stress and corpus cavernosum smooth muscle cells phenotypic modulation.}, journal = {Asian journal of andrology}, volume = {26}, number = {1}, pages = {99-106}, pmid = {37534881}, issn = {1745-7262}, abstract = {Hyperlipidemia is a major risk factor for erectile dysfunction (ED). Oxidative stress and phenotypic modulation of corpus cavernosum smooth muscle cells (CCSMCs) are the key pathological factors of ED. N-acetylcysteine (NAC) can inhibit oxidative stress; however, whether NAC can alleviate pathological variations in the corpus cavernosum and promote erectile function recovery in hyperlipidemic rats remains unclear. A hyperlipidemia model was established using 27 eight-week-old male Sprague-Dawley (SD) rats fed a high-fat and high-cholesterol diet (hyperlipidemic rats, HR). In addition, 9 male SD rats were fed a normal diet to serve as controls (NC). HR rats were divided into three groups: HR, HR+normal saline (NS), and HR+NAC (n = 9 for each group; NS or NAC intraperitoneal injections were administered daily for 16 weeks). Subsequently, the lipid profiles, erectile function, oxidative stress, phenotypic modulation markers of CCSMCs, and tissue histology were analyzed. The experimental results revealed that erectile function was significantly impaired in the HR and HR + NS groups, but enhanced in the HR + NAC group. Abnormal lipid levels, over-activated oxidative stress, and multi-organ lesions observed in the HR and HR + NS groups were improved in the HR + NAC group. Moreover, the HR group showed significant phenotypic modulation of CCSMCs, which was also inhibited by NAC treatment. This report focuses on the therapeutic effect of NAC in restoring erectile function using a hyperlipidemic rat model by preventing CCSMC phenotypic modulation and attenuating oxidative stress.}, }
@article {pmid37534078, year = {2023}, author = {Alam, MS and Hasan, MN and Maowa, Z and Khatun, F and Nazir, KHMNH and Alam, MZ}, title = {N-acetylcysteine reduces severity and mortality in COVID-19 patients: A systematic review and meta-analysis.}, journal = {Journal of advanced veterinary and animal research}, volume = {10}, number = {2}, pages = {157-168}, pmid = {37534078}, issn = {2311-7710}, abstract = {OBJECTIVES: Recent clinical studies suggest that oxidative stress is one of the key players in the pathogenesis of coronavirus disease 2019 (COVID-19), and N-acetylcysteine (NAC), a potent antioxidant, has been shown to improve clinical outcomes in COVID-19 patients. We conducted a systematic review and meta-analysis of the literature published on the therapeutic intervention of NAC on COVID-19 infection.<br><br>METHODS: We searched PubMed, Google Scholar, and Science Direct. We identified and screened eight studies with 20,503 participants, including 2,852 in the NAC-treated group and 17,651 in the placebo group, which reported the effect of NAC on COVID-19 infection. A meta-analysis was performed using forest plots under fixed effect estimates based on the standardized mean difference (SMD) and risk ratio (RR).<br><br>RESULTS: Pooled analysis showed that NAC was associated with lower mortality in patients with COVID-19 compared with the placebo group [RR, 0.65; (95% CI: 0.56 to 0.75); p < 0.0001]. Similarly, C-reactive protein (CRP) [SMD, -0.32; (95% CI: -56 to -0.09); p = 0.0070] and D-dimer [SMD, -0.35, (95% CI: -0.59 to -0.10; p = 0.0062] levels were significantly decreased, and the oxygenation marker, PaO2/FiO2 ratio, was increased in the NAC-treated group compared with the placebo group [SMD, 0.76; (95% CI: 0.48 to 1.03); p < 0.0001].<br><br>CONCLUSION: Although the number of included studies was minimal, this meta-analysis suggests that NAC may have a positive effect on COVID-19 outcomes, specifically, a significant decrease in CRP and D-dimer levels and a significant increase in oxygen saturation, which decreased mortality. We have also presented a comprehensive review of the role and mechanisms of NAC in patients with COVID-19.}, }
@article {pmid37532734, year = {2023}, author = {Chen, W and Yin, Y and Zhang, Z}, title = {Effects of N-acetylcysteine on CG8005 gene-mediated proliferation and apoptosis of Drosophila S2 embryonic cells.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {12502}, pmid = {37532734}, issn = {2045-2322}, mesh = {Animals ; Male ; *Acetylcysteine/pharmacology ; *Antioxidants/pharmacology ; Apoptosis ; Cell Proliferation ; *Drosophila/embryology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Drosophila Proteins/genetics/physiology ; }, abstract = {To investigate the effect of the antioxidant N-acetylcysteine (NAC) on the proliferation and apoptosis in CG8005 gene-interfering Drosophila S2 embryonic cells by scavenging intracellular reactive oxygen species (ROS). The interfering efficiency of CG8005 gene in Drosophila S2 embryonic cells was verified by real-time quantitative PCR (qRT-PCR). Different concentrations of NAC and phosphate buffered saline (PBS) were used to affect the Drosophila S2 embryonic cells. The growth state of Drosophila S2 embryonic cells was observed by light microscope. Two probes dihydroethidium (DHE) and 2,7-dichlorodihydrofluorescein-acetoacetate (DCFH-DA) were used to observe the ROS production in each group after immunofluorescence staining. TUNEL staining and flow cytometry were used to investigate the apoptosis level of Drosophila S2 embryos, and CCK-8 (Cell Counting Kit-8) was used to detect the cell viability of Drosophila S2 embryos. The knockdown efficiency of siCG8005-2 fragment was high and stable, which was verified by interference efficiency (P < 0.05). There was no significant change in the growth of Drosophila S2 embryonic cells after the treatment of NAC as compared to PBS group. Moreover, knockdowning CG8005 gene resulted in an increase in ROS and apoptosis in Drosophila S2 embryonic cells (P < 0.05) and a decrease in proliferation activity (P < 0.05). In addition, the pretreatment of antioxidant NAC could inhibit ROS production in Drosophila S2 embryonic cells (P < 0.05), reduce cell apoptosis (P < 0.05), and improve cell survival (P < 0.05). The CG8005 gene in Drosophila S2 embryonic cells could regulate the proliferation and apoptosis of S2 embryonic cells by disrupting the redox homeostasis, and antioxidant NAC could inhibit cell apoptosis and promotes cell proliferation by scavenging ROS in Drosophila S2 embryonic cells, which is expected to provide novel insights for the pathogenesis of male infertility and spermatogenesis.}, }
@article {pmid37531905, year = {2023}, author = {Zhai, BW and Zhao, H and Zhu, HL and Huang, H and Zhang, MY and Fu, YJ}, title = {Triterpene acids from Rosa roxburghii Tratt fruits exert anti-hepatocellular carcinoma activity via ROS/JNK signaling pathway-mediated cell cycle arrest and mitochondrial apoptosis.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {119}, number = {}, pages = {154960}, doi = {10.1016/j.phymed.2023.154960}, pmid = {37531905}, issn = {1618-095X}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; MAP Kinase Signaling System ; *Rosa ; Fruit ; *Carcinoma, Hepatocellular/pathology ; Cell Cycle Checkpoints ; Apoptosis ; Hep G2 Cells ; *Triterpenes/pharmacology ; *Liver Neoplasms/pathology ; Cell Line, Tumor ; }, abstract = {BACKGROUND: Rosa roxburghii Tratt (RRT) is a famous healthy and medicinal edible fruit in southwest China and has been shown to have some hepatoprotective properties. However, whether the active components, such as the triterpene acids from Rosa roxburghii Tratt fruits (TAR), have anti-hepatocellular carcinoma (HCC) effects and the potential molecular mechanisms are still unclear.<br><br>PURPOSE: This study aimed to investigate the anti-HCC effects and potential action mechanisms of triterpene components in RRT fruits.<br><br>METHODS: The triterpene acids in TAR were analyzed by using UPLC-Q-Exactive Orbitrap/MS, and the main components were virtual screening for targets based on pharmacophore and then performed enrichment analysis. HepG2 cells were used for in vitro experiments, including MTT assay, wound healing assay, and flow cytometry to detect cell cycle, reactive oxygen species (ROS) level, caspase-3 activity, and mitochondrial membrane potential (MMP) changes. Moreover, the western blot was used to detect mitochondrial apoptosis and ROS/ c-Jun N-terminal kinase (JNK) signaling pathway-related proteins.<br><br>RESULTS: The main components in TAR are pentacyclic triterpene acids (mainly euscaphic acid and roxburic acid). TAR could inhibit cell viability, cell migration ability and suppress the proliferation of HepG2 cells through G2/M cell cycle arrest. On the other hand, TAR could induce HepG2 cells apoptosis, which was achieved by causing the accumulation of ROS and activation of the JNK signaling pathway, and our research showed that this apoptosis was mediated through the mitochondrial pathway. In addition, the free radical scavenger N-acetyl cysteine (NAC) could attenuate TAR-induced ROS accumulation and JNK signaling pathway activation, which ultimately reversed mitochondrial apoptosis.<br><br>CONCLUSION: TAR could activate the ROS/JNK signaling pathway, which could inhibit the proliferation through G2/M cell cycle arrest and promote apoptosis through the mitochondrial pathway in HCC cells. This supports the anti-tumor potential in RRT fruits.}, }
@article {pmid37522842, year = {2023}, author = {Pan, X and Giustarini, D and Lang, F and Rossi, R and Wieder, T and Köberle, M and Ghashghaeinia, M}, title = {Desipramine induces eryptosis in human erythrocytes, an effect blunted by nitric oxide donor sodium nitroprusside and N-acetyl-L-cysteine but enhanced by Calcium depletion.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {22}, number = {17}, pages = {1827-1853}, pmid = {37522842}, issn = {1551-4005}, mesh = {Humans ; *Nitric Oxide Donors/pharmacology/metabolism ; Nitroprusside/pharmacology/metabolism ; *Eryptosis ; Calcium/metabolism ; Acetylcysteine/pharmacology ; Desipramine/pharmacology/metabolism ; Erythrocytes/metabolism ; Glutathione/metabolism/pharmacology ; Annexins/metabolism/pharmacology ; Phosphatidylserines/metabolism ; Cell Size ; Ceramides/metabolism ; Reactive Oxygen Species/metabolism ; Oxidative Stress ; }, abstract = {Background: Desipramine a representative of tricyclic antidepressants (TCAs) promotes recovery of depressed patients by inhibition of reuptake of neurotransmitters serotonin (SER) and norepinephrine (NE) in the presynaptic membrane by directly blocking their respective transporters SERT and NET.Aims: To study the effect of desipramine on programmed erythrocyte death (eryptosis) and explore the underlying mechanisms.Methods: Phosphatidylserine (PS) exposure on the cell surface as marker of cell death was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry. Hemolysis was determined photometrically, and intracellular glutathione [GSH]i from high performance liquid chromatography.Results: Desipramine dose-dependently significantly enhanced the percentage of annexin-V-binding cells and didn´t impact glutathione (GSH) synthesis. Desipramine-induced eryptosis was significantly reversed by pre-treatment of erythrocytes with either nitric oxide (NO) donor sodium nitroprusside (SNP) or N-acetyl-L-cysteine (NAC). The highest inhibitory effect was obtained by using both inhibitors together. Calcium (Ca[2+]) depletion aggravated desipramine-induced eryptosis. Changing the order of treatment, i.e. desipramine first followed by inhibitors, could not influence the inhibitory effect of SNP or NAC.Conclusion: Antidepressants-caused intoxication can be treated by SNP and NAC, respectively. B) Patients with chronic hypocalcemia should not be treated with tricyclic anti-depressants or their dose should be noticeably reduced.}, }
@article {pmid37522559, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Huerta-Yepez, S and Maharaj, D and Jewett, A}, title = {The Potential Role of Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis (ALS); A Longitudinal Case Study Comparing Patients with Genetically Identical Healthy Twin.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {27-39}, doi = {10.1615/CritRevImmunol.2023047233}, pmid = {37522559}, issn = {1040-8401}, abstract = {Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neurons. The causes of ALS are heterogeneous, and are only partially understood to date. We studied percentage and function of immune cell subsets in particular natural killer (NK) and CD8+ T cells in an ALS patient and compared the results to those obtained from his genetically identical healthy twin in a longitudinal study. We found several basic mechanisms which were potentially involved in the disease induction and progression. Our findings demonstrate that ALS patient's peripheral blood contained higher NK and B cells and, lower T cell percentages compared with the healthy twin brother's peripheral blood. Significantly increased interferon-gamma secretion by anti-CD3/28 monoclonal antibody-treated peripheral blood mononuclear cells, and sorted CD8+ T cells were observed in the ALS patient, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism of ALS progression. Significant increase in NK cell function due to genetic mutations in ALS associated genes may partly be responsible for the increase expansion and function of CD8+ T cells with effector/memory phenotype, in addition to direct activation and expansion of antigen specific T cells by such mutations. Weekly N-acetyl cysteine infusion to block cell death in patient in addition to a number of other therapies listed in this paper were not effective, and even though the treatments might have extended the patient's life, it was not curative. Therefore, activated CD8+ T and NK cells are likely cells targeting motor neurons in the patient, and strategies should be designed to decrease the aggressive nature of these cells to achieve longer lasting therapeutic benefits.}, }
@article {pmid37522557, year = {2023}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Huerta-Yepez, S and Maharaj, D and Malarkannan, S and Jewett, A}, title = {Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis.}, journal = {Critical reviews in immunology}, volume = {43}, number = {1}, pages = {1-11}, doi = {10.1615/CritRevImmunol.2023047235}, pmid = {37522557}, issn = {1040-8401}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/therapy/metabolism ; Motor Neurons/metabolism/pathology ; Superoxide Dismutase-1/genetics/metabolism/pharmacology ; Cytokines/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.}, }
@article {pmid37522109, year = {2023}, author = {Girone, N and Benatti, B and Molteni, L and Cassina, N and Giacovelli, L and Arici, C and Dell'Osso, B}, title = {Partial Response to Antidepressant Treatment: The Role of Nutraceutical Compounds.}, journal = {Clinical neuropsychiatry}, volume = {20}, number = {3}, pages = {183-192}, pmid = {37522109}, issn = {2385-0787}, abstract = {OBJECTIVE: Depression represents one of the most severe psychiatric disorders, characterized by low mood episodes, as well as loss of interest. Major Depressive Episodes (MDE) treatment relies primarily on monoaminergic prescriptions. However, although the presence of many antidepressant medications, their efficacy is still partial. A promising intervention to improve antidepressant treatment may be the use of adjunctive nutraceuticals. Aim of the present study was to assess the efficacy of a N-Acetyl-cysteine, S-Adenosyl-L-Methionine and Folic acid's combination for the treatment of depressive symptoms in a sample of MDE patients.<br><br>METHOD: Fifty outpatients with a MDE diagnosis in the context of different psychiatric disorders such as Major Depression, Bipolar Disorder, Anxiety disorders, and Personality disorders were recruited. The sample was divided into different groups based on the nutraceutical administration: a) concurrently with an AD (starter group); b) add-on to an already prescribed treatment; c) single treatment.<br><br>RESULTS: A significant reduction of CGI-Severity and Improvement scores from baseline to the end of treatment was found. Moreover, the starter group showed a significantly greater CGI-Improvement score compared to the other groups. Ninety-four percent of patients did not show any side effects.<br><br>CONCLUSIONS: The present study showed promising results for the use of nutraceuticals in the add-on treatment of MDE. Those compounds may be considered a versatile, tolerable, and effective add-on treatment for the reduction of depressive symptoms impact and for improving the functioning of patients affected by MDE.}, }
@article {pmid37521669, year = {2023}, author = {Shalaby, AS and Eid, HH and El-Shiekh, RA and Mohamed, OG and Tripathi, A and Al-Karmalawy, AA and Sleem, AA and Morsy, FA and Ibrahim, KM and Tadros, SH and Youssef, FS}, title = {Taming Food-Drug Interaction Risk: Potential Inhibitory Effects of Citrus Juices on Cytochrome Liver Enzymes Can Safeguard the Liver from Overdose Paracetamol-Induced Hepatotoxicity.}, journal = {ACS omega}, volume = {8}, number = {29}, pages = {26444-26457}, pmid = {37521669}, issn = {2470-1343}, abstract = {Paracetamol overdose is the leading cause of drug-induced hepatotoxicity worldwide. Because of N-acetyl cysteine's limited therapeutic efficacy and safety, searching for alternative therapeutic substitutes is necessary. This study investigated four citrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco × Citrus sinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. Ruby Red (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-induced liver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samples resulted in the identification of about 40 metabolites belonging to different phytochemical classes. Phenolic compounds were the most abundant, with the total content ranked from 609.18 to 1093.26 μg gallic acid equivalent (GAE)/mL juice. The multivariate data analysis revealed that phloretin 3',5'-di-C-glucoside, narirutin, naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin (acacetin-7-O-neohesperidoside), sinensetin, nobiletin, and tangeretin represented the crucial discriminatory metabolites that segregated the analyzed samples. Nevertheless, the antioxidant activity of the samples was 1135.91-2913.92 μM Trolox eq/mL juice, 718.95-3749.47 μM Trolox eq/mL juice, and 2304.74-4390.32 μM Trolox eq/mL juice, as revealed from 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducing antioxidant power, and oxygen radical absorbance capacity, respectively. The in vivo paracetamol-induced hepatotoxicity model in rats was established and assessed by measuring the levels of hepatic enzymes and antioxidant biomarkers. Interestingly, the concomitant administration of citrus juices with a toxic dose of paracetamol effectively recovered the liver injury, as confirmed by normal sections of hepatocytes. This action could be due to the interactions between the major identified metabolites (hesperidin, hesperetin, phloretin 3',5'-di-C-glucoside, fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6',7'-dihydroxybergamottin, naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1, and CYP1A2), as revealed from the molecular docking study. The most promising compounds in the three docking processes were hesperidin, fortunellin, poncirin, and naringin. Finally, a desirable food-drug interaction was achieved in our research to overcome paracetamol overdose-induced hepatotoxicity.}, }
@article {pmid37520878, year = {2023}, author = {Afaghi, S and Moghimi, N and Malekpour Alamdari, N and Rahimi, FS and Irilouzadian, R and Esmaeili Tarki, F and Moghimi, M and Besharat, S and Salehi Omran, H and Karimi, A}, title = {N-acetylcysteine as adjuvant therapy for hospitalized Covid-19 patients: A single-center prospective cohort study.}, journal = {Caspian journal of internal medicine}, volume = {14}, number = {3}, pages = {543-552}, pmid = {37520878}, issn = {2008-6164}, abstract = {BACKGROUND: Whilst over two years have passed since the COVID-19 pandemic's emergence, the proper management of the disease remains challenging. N-acetylcysteine (NAC) as a potentially effective therapeutic option has been suggested by studies, while the exact clinical role of this agent is yet to be evaluated.<br><br>METHODS: This prospective case-control study was conducted in a major referral respiratory center in Tehran, Iran. We enrolled 217 patients treated with an intravenous daily dose of 1500 mg NAC as a case group; and 245 control patients who did not receive NAC. Two groups were matched based on other treatments, socio-demographics, medical history, and comorbidities.<br><br>RESULTS: After ten days of adjuvant therapy with NAC, patients in the NAC group and control group had median room-air SpO2 of 91% and 88%, respectively (P=0.02). Also, the SpO2 to FiO2 ratio had a median of 463 and 421 in the case and control groups, respectively (P=0.01). Furthermore, the case group's hospitalization period was three days shorter (P=0.002). Further, cough, dyspnea, and decreased appetite were reported to have a significantly lower incidence in the case group (P=0.03, 0.001, 0.008).<br><br>CONCLUSION: We showed that a daily intravenous dose of NAC in hospitalized COVID-19 patients could shorten the hospital stay and improve some clinical symptoms; however, it does not remarkably improve the risk of ICU admission and the 28 days in-hospital mortality rate.}, }
@article {pmid37519003, year = {2023}, author = {Zhuo, Y and Chen, H and Liu, C and Zhang, Y and Fang, J and Li, M and Wang, Z and Jiang, Q and Yu, L and Pan, H and Wang, Q}, title = {Covalent Modification of Proteins by Osthole Reactive Metabolites using Proteomic Approaches.}, journal = {Current drug metabolism}, volume = {24}, number = {8}, pages = {611-620}, doi = {10.2174/1389200224666230727123006}, pmid = {37519003}, issn = {1875-5453}, abstract = {BACKGROUND: Osthole (OST) is a bioactive natural coumarin derived from the plant Cnidium monnieri (L.) Cusson fruit (She Chuang Zi), which has various pharmacological and biological activities. OST contains an α,β- unsaturated lactone, which is an electrophilic group that tends to be metabolized into reactive metabolites (RMs). Then, RMs are able to covalently modify nucleophilic amino acid (AA) residues of target proteins. However, few researchers considered the contribution of the covalent modification induced by OST or its metabolites.<br><br>OBJECTIVE: This study aims to investigate the metabolic profile and the metabolites-protein modification of OST.<br><br>METHODS: The metabolites of OST were qualitatively identified using UHPLC-Q-TOF-MS. The RMs modification patterns and potentially modified AA residues were confirmed by UHPLC-Q-TOF-MS using rat liver microsomes (RLMs) and model AAs. Finally, the modified peptides derived from high-abundance microsomal peptides were separated via nano-LC-Orbitrap-MS, and then RM-modified proteins were identified using a proteome discoverer.<br><br>RESULTS: In the presence of RLMs, OST could rapidly be metabolized within 1 h and hardly identified at 4 h. We detected 10 OST metabolites, 13 OST metabolites-NAC (N-acetyl cysteine) adducts, 3 NAL (N-acetyl lysine) adducts, and 11 GSH (glutathione) adducts. Furthermore, 16 RM-modified protein targets were identified, many of which are included in the essential biological processes of OST's anti-Alzheimer's disease (AD) and anti-tumor.<br><br>CONCLUSION: This study provides a novel perspective on the molecular mechanism of OST's pharmacological activities, as well as identifies potential targets for further development and application of OST and other Natural products (NPs).}, }
@article {pmid37517999, year = {2023}, author = {Cazzola, M and Page, CP and Wedzicha, JA and Celli, BR and Anzueto, A and Matera, MG}, title = {Use of thiols and implications for the use of inhaled corticosteroids in the presence of oxidative stress in COPD.}, journal = {Respiratory research}, volume = {24}, number = {1}, pages = {194}, pmid = {37517999}, issn = {1465-993X}, mesh = {Humans ; *Antioxidants/therapeutic use/pharmacology ; Sulfhydryl Compounds/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/diagnosis/drug therapy/chemically induced ; Adrenal Cortex Hormones ; Oxidative Stress ; Acetylcysteine/therapeutic use ; Inflammation/drug therapy ; Expectorants/therapeutic use ; }, abstract = {BACKGROUND: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination.<br><br>MAIN BODY: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS.<br><br>CONCLUSIONS: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD.}, }
@article {pmid37517847, year = {2023}, author = {}, title = {Retraction notice to "Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial".}, journal = {Fertility and sterility}, volume = {120}, number = {2}, pages = {395}, doi = {10.1016/j.fertnstert.2023.06.016}, pmid = {37517847}, issn = {1556-5653}, }
@article {pmid37511170, year = {2023}, author = {Kubovcikova, M and Sobotova, R and Zavisova, V and Antal, I and Khmara, I and Lisnichuk, M and Bednarikova, Z and Jurikova, A and Strbak, O and Vojtova, J and Mikolka, P and Gombos, J and Lokajova, A and Gazova, Z and Koneracka, M}, title = {N-Acetylcysteine-Loaded Magnetic Nanoparticles for Magnetic Resonance Imaging.}, journal = {International journal of molecular sciences}, volume = {24}, number = {14}, pages = {}, pmid = {37511170}, issn = {1422-0067}, support = {ITMS 313011AVG3//Operational Programme Integrated Infrastructure co-funded by ERDF/ ; APVV-18-0284, APVV SK-TW-21-0004//the Slovak Research and Development Agency/ ; EGA 02/0176/21, VEGA 02/0164/22, VEGA 02/0049/23//Slovak Grant Agency/ ; IMTS: 313011BWX6//The application of spectroscopic methods for early, non-invasive real-time identification of selected diseases using gasses released from lungs and skin/ ; ITMS: 313011AVG3 "BIOVID"//he Operational Program Integrated Infrastructure funded by the ERDF ITMS2014+ 313011T553 "DIAGNAD"/ ; }, mesh = {*Magnetite Nanoparticles/chemistry ; Contrast Media/chemistry ; Acetylcysteine/pharmacology ; Magnetic Resonance Imaging/methods ; *Nanoparticles/chemistry ; Adsorption ; }, abstract = {Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by the rapid onset of lung inflammation Therefore, monitoring the spatial distribution of the drug directly administered to heterogeneously damaged lungs is desirable. In this work, we focus on optimizing the drug N-acetylcysteine (NAC) adsorption on poly-l-lysine-modified magnetic nanoparticles (PLLMNPs) to monitor the drug spatial distribution in the lungs using magnetic resonance imaging (MRI) techniques. The physicochemical characterizations of the samples were conducted in terms of morphology, particle size distributions, surface charge, and magnetic properties followed by the thermogravimetric quantification of NAC coating and cytotoxicity experiments. The sample with the theoretical NAC loading concentration of 0.25 mg/mL was selected as an optimum due to the hydrodynamic nanoparticle size of 154 nm, the surface charge of +32 mV, good stability, and no cytotoxicity. Finally, MRI relaxometry confirmed the suitability of the sample to study the spatial distribution of the drug in vivo using MRI protocols. We showed the prevailing transverse relaxation with high transverse relaxivity values and a high r2[(]*[)]/r1 ratio, causing visible hypointensity in the final MRI signal. Furthermore, NAC adsorption significantly affects the relaxation properties of PLLMNPs, which can help monitor drug release in vitro/in vivo.}, }
@article {pmid37509878, year = {2023}, author = {Mao, B and Ren, B and Wu, J and Tang, X and Zhang, Q and Zhao, J and Zhang, L and Chen, W and Cui, S}, title = {The Protective Effect of Broccoli Seed Extract against Lipopolysaccharide-Induced Acute Liver Injury via Gut Microbiota Modulation and Sulforaphane Production in Mice.}, journal = {Foods (Basel, Switzerland)}, volume = {12}, number = {14}, pages = {}, pmid = {37509878}, issn = {2304-8158}, support = {2020B020226008//Key-Area Research and Development Program of Guangdong Province/ ; 31972086//National Natural Science Foundation of China/ ; }, abstract = {Broccoli seed extract (BSE) is rich in glucoraphanin (GRP), which may be transformed by intestinal microbes into sulforaphane (SFN), a compound with strong anti-inflammatory and antioxidant activities. Liver injury usually presents with inflammation and oxidative damage. Thus, dietary BSE supplementation may be an effective approach for alleviating liver injury. In this study, a mouse lipopolysaccharide (LPS)-induced acute liver injury model was used to evaluate the preventive effect of BSE and explore the relevant mechanisms. Compared with the LPS model group, the mice in the BSE group showed significantly lower activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) and higher levels of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. Meanwhile, BSE significantly reduced the levels of pro-inflammatory cytokines (including IL-6 and TNF-α) in the liver and increased the level of anti-inflammatory factor (IL-10), indicating that BSE had a good preventive effect on acute liver injury. Additionally, after BSE intervention, the diversity of intestinal microbiota in the mice was higher than that in the LPS model group. The relative abundance of Akkermansia and Lactobacillus increased, while the relative abundance of Xylanophilum decreased. A correlation analysis revealed that the activities of SOD, GSH-Px, CAT and levels of IL-10 were positively correlated with the relative abundance of Lactobacillus. Furthermore, sulforaphane (SFN) and (Sulforaphane-N-Acetyl-Cysteine) SFN-NAC were detected in the urine of the mice after BSE intervention. Both q-PCR and an immunohistochemical analysis showed that BSE significantly regulated the expression level of the NF-κB (IκB-α, NF-κB) and Nrf2 (Nrf2, p-Nrf2 and HO-1) signaling pathways in the liver. In conclusion, BSE was shown to reduce LPS-induced acute liver injury through the conversion of glucoraphanin into sulforaphane and the regulation of the gut microbiota composition. These results suggest that BSE could be a promising ingredient in functional foods.}, }
@article {pmid37508477, year = {2023}, author = {Siemsen, BM and Denton, AR and Parrila-Carrero, J and Hooker, KN and Carpenter, EA and Prescot, ME and Brock, AG and Westphal, AM and Leath, MN and McFaddin, JA and Jhou, TC and McGinty, JF and Scofield, MD}, title = {Heroin Self-Administration and Extinction Increase Prelimbic Cortical Astrocyte-Synapse Proximity and Alter Dendritic Spine Morphometrics That Are Reversed by N-Acetylcysteine.}, journal = {Cells}, volume = {12}, number = {14}, pages = {}, pmid = {37508477}, issn = {2073-4409}, support = {F32 DA50427/NH/NIH HHS/United States ; T32 DA007288/NH/NIH HHS/United States ; DA046373/NH/NIH HHS/United States ; R01 DA054154/DA/NIDA NIH HHS/United States ; DA05154/NH/NIH HHS/United States ; DA037327/NH/NIH HHS/United States ; K01 DA053434/NH/NIH HHS/United States ; DA033680-11/NH/NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; P50 DA046373/DA/NIDA NIH HHS/United States ; DA044468/NH/NIH HHS/United States ; }, mesh = {Rats ; Animals ; Male ; Rats, Sprague-Dawley ; *Heroin/pharmacology ; *Acetylcysteine/pharmacology ; Astrocytes ; Synapses ; Glutamates ; Recurrence ; }, abstract = {Clinical and preclinical studies indicate that adaptations in corticostriatal neurotransmission significantly contribute to heroin relapse vulnerability. In animal models, heroin self-administration and extinction produce cellular adaptations in both neurons and astrocytes within the nucleus accumbens (NA) core that are required for cue-induced heroin seeking. Specifically, decreased glutamate clearance and reduced association of perisynaptic astrocytic processes with NAcore synapses allow glutamate release from prelimbic (PrL) cortical terminals to engage synaptic and structural plasticity in NAcore medium spiny neurons. Normalizing astrocyte glutamate homeostasis with drugs like the antioxidant N-acetylcysteine (NAC) prevents cue-induced heroin seeking. Surprisingly, little is known about heroin-induced alterations in astrocytes or pyramidal neurons projecting to the NAcore in the PrL cortex (PrL-NAcore). Here, we observe functional adaptations in the PrL cortical astrocyte following heroin self-administration (SA) and extinction as measured by the electrophysiologically evoked plasmalemmal glutamate transporter 1 (GLT-1)-dependent current. We likewise observed the increased complexity of the glial fibrillary acidic protein (GFAP) cytoskeletal arbor and increased association of the astrocytic plasma membrane with synaptic markers following heroin SA and extinction training in the PrL cortex. Repeated treatment with NAC during extinction reversed both the enhanced astrocytic complexity and synaptic association. In PrL-NAcore neurons, heroin SA and extinction decreased the apical tuft dendritic spine density and enlarged dendritic spine head diameter in male Sprague-Dawley rats. Repeated NAC treatment during extinction prevented decreases in spine density but not dendritic spine head expansion. Moreover, heroin SA and extinction increased the co-registry of the GluA1 subunit of AMPA receptors in both the dendrite shaft and spine heads of PrL-NAcore neurons. Interestingly, the accumulation of GluA1 immunoreactivity in spine heads was further potentiated by NAC treatment during extinction. Finally, we show that the NAC treatment and elimination of thrombospondin 2 (TSP-2) block cue-induced heroin relapse. Taken together, our data reveal circuit-level adaptations in cortical dendritic spine morphology potentially linked to heroin-induced alterations in astrocyte complexity and association at the synapses. Additionally, these data demonstrate that NAC reverses PrL cortical heroin SA-and-extinction-induced adaptations in both astrocytes and corticostriatal neurons.}, }
@article {pmid37507934, year = {2023}, author = {Eligini, S and Munno, M and Atlas, D and Banfi, C}, title = {N-acetylcysteine Amide AD4/NACA and Thioredoxin Mimetic Peptides Inhibit Platelet Aggregation and Protect against Oxidative Stress.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {37507934}, issn = {2076-3921}, support = {Ricerca Corrente//Italian Ministry of Health, Rome, Italy/ ; }, abstract = {In the present study, we tested the effect of small-molecular-weight redox molecules on collagen-induced platelet aggregation. We used N-acetylcysteine amide (AD4/NACA), the amide form of N-acetylcysteine (NAC), a thiol antioxidant with improved lipophilicity and bioavailability compared to NAC, and the thioredoxin-mimetic (TXM) peptides, TXM-CB3, TXM-CB13, and TXM-CB30. All compounds significantly inhibited platelet aggregation induced by collagen, with TXM-peptides and AD4 being more effective than NAC. The levels of TxB2 and 12-HETE, the main metabolites derived from the cyclooxygenase and lipoxygenase pathways following platelet activation, were significantly reduced in the presence of AD4, TXM peptides, or NAC, when tested at the highest concentration (0.6 mM). The effects of AD4, TXM-peptides, and NAC were also tested on the clotting time (CT) of whole blood. TXM-CB3 and TXM-CB30 showed the greatest increase in CT. Furthermore, two representative compounds, TXM-CB3 and NAC, showed an increase in the anti-oxidant free sulfhydryl groups of plasma detected via Ellman's method, suggesting a contribution of plasma factors to the antiaggregating effects. Our results suggest that these small-molecular-weight redox peptides might become useful for the prevention and/or treatment of oxidative stress conditions associated with platelet activation.}, }
@article {pmid37507913, year = {2023}, author = {Martinez-Banaclocha, MA}, title = {Targeting the Cysteine Redox Proteome in Parkinson's Disease: The Role of Glutathione Precursors and Beyond.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {37507913}, issn = {2076-3921}, abstract = {Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and intercellular communication. In addition, cell rejuvenation requires silencing some transcription factors and the activation of pluripotency, indicating that hidden molecular networks must integrate and synchronize all these cellular mechanisms. Therefore, in addition to gene sequence expansions and variations associated with senescence, the optimization of transcriptional regulation and protein crosstalk is essential. The protein cysteinome is crucial in cellular regulation and plays unexpected roles in the aging of complex organisms, which show cumulative somatic mutations, telomere attrition, epigenetic modifications, and oxidative dysregulation, culminating in cellular senescence. The cysteine thiol groups are highly redox-active, allowing high functional versatility as structural disulfides, redox-active disulfides, active-site nucleophiles, proton donors, and metal ligands to participate in multiple regulatory sites in proteins. Also, antioxidant systems control diverse cellular functions, including the transcription machinery, which partially depends on the catalytically active cysteines that can reduce disulfide bonds in numerous target proteins, driving their biological integration. Since we have previously proposed a fundamental role of cysteine-mediated redox deregulation in neurodegeneration, we suggest that cellular rejuvenation of the cysteine redox proteome using GSH precursors, like N-acetyl-cysteine, is an underestimated multitarget therapeutic approach that would be particularly beneficial in Parkinson's disease.}, }
@article {pmid37507904, year = {2023}, author = {Chamorro, B and Izquierdo-Bermejo, S and Martín-de-Saavedra, MD and López-Muñoz, F and Chioua, M and Marco-Contelles, J and Oset-Gasque, MJ}, title = {Neuroprotective and Antioxidant Properties of CholesteroNitrone ChN2 and QuinolylNitrone QN23 in an Experimental Model of Cerebral Ischemia: Involvement of Necrotic and Apoptotic Cell Death.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {37507904}, issn = {2076-3921}, support = {"MITOPI" and "NENTS"//Camilo Jos&#xe9; Cela University/ ; SAF2015-65586-R//Spanish Ministry of Economy and Competitiveness/ ; PID2021-122723OA100//Spanish Research Agency/ ; }, abstract = {Ischemic stroke is the leading cause of disability and the second leading cause of death worldwide. However, current therapeutic strategies are scarce and of limited efficacy. The abundance of information available on the molecular pathophysiology of ischemic stroke has sparked considerable interest in developing new neuroprotective agents that can target different events of the ischemic cascade and may be used in combination with existing treatments. In this regard, nitrones represent a very promising alternative due to their renowned antioxidant and anti-inflammatory effects. In this study, we aimed to further investigate the neuroprotective effects of two nitrones, cholesteronitrone 2 (ChN2) and quinolylnitrone 23 (QN23), which have previously shown great potential for the treatment of stroke. Using an experimental in vitro model of cerebral ischemia, we compared their anti-necrotic, anti-apoptotic, and antioxidant properties with those of three reference compounds. Both ChN2 and QN23 demonstrated significant neuroprotective effects (EC50 = 0.66 ± 0.23 μM and EC50 = 2.13 ± 0.47 μM, respectively) comparable to those of homo-bis-nitrone 6 (HBN6) and N-acetylcysteine (NAC) and superior to those of α-phenyl-N-tert-butylnitrone (PBN). While primarily derived from the nitrones' anti-necrotic capacities, their anti-apoptotic effects at high concentrations and antioxidant powers-especially in the case of QN23-also contribute to their neuroprotective effects.}, }
@article {pmid37507857, year = {2023}, author = {Sahasrabudhe, SA and Terluk, MR and Kartha, RV}, title = {N-acetylcysteine Pharmacology and Applications in Rare Diseases-Repurposing an Old Antioxidant.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {7}, pages = {}, pmid = {37507857}, issn = {2076-3921}, abstract = {N-acetylcysteine (NAC), a precursor of cysteine and, thereby, glutathione (GSH), acts as an antioxidant through a variety of mechanisms, including oxidant scavenging, GSH replenishment, antioxidant signaling, etc. Owing to the variety of proposed targets, NAC has a long history of use as a prescription product and in wide-ranging applications that are off-label as an over-the-counter (OTC) product. Despite its discovery in the early 1960s and its development for various indications, systematic clinical pharmacology explorations of NAC pharmacokinetics (PK), pharmacodynamic targets, drug interactions, and dose-ranging are sorely limited. Although there are anecdotal instances of NAC benefits in a variety of diseases, a comprehensive review of the use of NAC in rare diseases does not exist. In this review, we attempt to summarize the existing literature focused on NAC explorations in rare diseases targeting mitochondrial dysfunction along with the history of NAC usage, approved indications, mechanisms of action, safety, and PK characterization. Further, we introduce the research currently underway on other structural derivatives of NAC and acknowledge the continuum of efforts through pre-clinical and clinical research to facilitate further therapeutic development of NAC or its derivatives for rare diseases.}, }
@article {pmid37503600, year = {2023}, author = {Onay, ZR and Ayhan, Y and Can Oksay, S and Mavi, D and Bilgin, G and Toksoz Yıldırım, A and Canbolat Ayhan, A and Girit, S}, title = {The First Definition of Pulmonary Component of Hypereosinophilic Syndrome: Bronchial Casts.}, journal = {Thoracic research and practice}, volume = {24}, number = {1}, pages = {49-52}, pmid = {37503600}, issn = {2979-9139}, abstract = {Hypereosinophilic syndrome is a heterogeneous disease characterized by eosinophilic tissue inflammation and eosinophilia. Pulmonary involvement could be seen in up to 55% among children with hypereosinophilic syndrome. A 3-year-old boy with chronic hypereosinophilia and respiratory complaints was diagnosed with idiopathic hypereosinophilic syndrome. Atelectasis was detected in the radiological evaluation, and bronchial casts with eosinophilic structures were removed by bronchoscopy. Steroid, inhaled hypertonic saline, inhaled bronchodilator, inhaled corticosteroid, and leukotriene receptor antagonist were used for 1 year in the management of hypereosinophilic syndrome, and related eosinophilic casts and repetitive bronchoscopies were administered for removal of the casts. The patient was successfully managed with an inhaled N-acetyl cysteine treatment. In children, the long-term prognosis of hypereosinophilic syndrome is uncertain. Comprehensive diagnostic tests are required for the early diagnosis and management of pediatric hypereosinophilic syndrome. In the presented case, the rare occurrence of pulmonary involvement of hypereosinophilic syndrome in a 3 year-old-boy with recurrent hypereosinophilic casts and its management were discussed.}, }
@article {pmid37503369, year = {2023}, author = {Methods In Medicine, CAM}, title = {Retracted: N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells.}, journal = {Computational and mathematical methods in medicine}, volume = {2023}, number = {}, pages = {9819038}, pmid = {37503369}, issn = {1748-6718}, abstract = {[This retracts the article DOI: 10.1155/2021/7596343.].}, }
@article {pmid37503292, year = {2023}, author = {Piraino, L and Chen, CY and Mereness, J and Dunman, PM and Ovitt, C and Benoit, D and DeLouise, L}, title = {Identifying novel radioprotective drugs via salivary gland tissue chip screening.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.07.12.548707}, pmid = {37503292}, abstract = {During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Following validation, we tested other reported radioprotective drugs, including, Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin, confirming that all drugs but NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified with mechanisms of action other than antioxidant activity. Hits were down-selected using EC 50 values and pharmacokinetics and pharmacodynamics data from the PubChem database leading to testing of Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited equivalent radioprotection to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with nonantioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.}, }
@article {pmid37499713, year = {2023}, author = {He, D and Qian, L and Chen, X and He, B and Li, J}, title = {Durable cellulose paper by grafting thiol groups and controlling silver deposition for ultrahigh electromagnetic interference shielding.}, journal = {International journal of biological macromolecules}, volume = {248}, number = {}, pages = {125972}, doi = {10.1016/j.ijbiomac.2023.125972}, pmid = {37499713}, issn = {1879-0003}, mesh = {*Ammonia ; *Silver ; Acetylcysteine ; Cellulose ; Electric Conductivity ; Sulfhydryl Compounds ; }, abstract = {Electromagnetic interference (EMI) shielding paper with durability and high effectiveness is of significant importance to long-term service for preventing EMI pollution. Herein, we report a practical method for preparing cellulose paper/Ag composite with outstanding durable and ultrahigh EMI shielding performance by electroless silver plating. The silver deposition process, the surface morphology, the silver content and conductivity of the composite can be controlled by varying the amount of N-acetyl-L-cysteine (NAC) grafted onto the cellulose fibers and ammonia amount for silver-ammonia complex formation. Moreover, the grafted NAC with thiol groups on cellulose can enhance the adhesion between silver and cellulose paper, meanwhile, NAC as the reducing agent can result in a more complete flower-shaped silver structure and reducing the reflection of electromagnetic waves in silver layer. The composite exhibited excellent conductivity, EMI shielding effectiveness (SE) up to 106 dB and outstanding durability. After 10,000 bending times and 60 abrasion cycles respectively, the electrical resistance of the composite only increased from 0.030 Ω/sq. to 0.041 Ω/sq. and 0.050 Ω/sq., and the EMI SE decreased to 102 dB and 105 dB.}, }
@article {pmid37495528, year = {2023}, author = {Korkmaz, Y and Gungor, H and Demirbas, A and Dik, B}, title = {Pomegranate peel extract, N-Acetylcysteine and their combination with Ornipural alleviate Cadmium-induced toxicity in rats.}, journal = {The Journal of veterinary medical science}, volume = {85}, number = {9}, pages = {990-997}, pmid = {37495528}, issn = {1347-7439}, mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology ; Rats, Wistar ; Cadmium/toxicity ; *Pomegranate ; Plant Extracts/pharmacology/therapeutic use ; }, abstract = {Cadmium is a major environmental pollutant and a highly toxic metal. It was aimed to determine the effects of pomegranate peel extract (PPE), N-acetylcysteine (NAC) alone and along with Ornipural on cadmium-induced toxicity. Forty-six Wistar Albino male rats were divided into 6 groups and the groups were formed into healthy control, Cadmium group (5 mg/kg/day, oral), Cadmium + Pomegranate peel extract (500 mg/kg, oral), Cadmium + N-acetylcysteine (100 mg/kg, oral), Cadmium + Pomegranate peel extract (500 mg/kg, oral) + Ornipural (1 mL/kg, subcutaneous) and Cadmium + N-acetylcysteine (100 mg/kg, oral) + Ornipural (1 mL/kg, subcutaneous). Cadmium accumulated heavily in both liver and kidney tissue. The administration of N-acetylcysteine and pomegranate peel extract alone reduced cadmium levels in both tissues. N-acetylcysteine treatment prevented the increase in ALT and MDA levels by cadmium damage. N-acetylcysteine + Ornipural treatment inhibited the increase in liver 8-OHdG level in the liver. N-acetylcysteine and N-acetylcysteine + Ornipural treatments prevented the reduced serum MMP2 level. N-acetylcysteine and Pomegranate peel extract + Ornipural treatments significantly reduced the increased liver iNOS level in the liver. In conclusion, NAC therapy may be a successful treatment option for cadmium toxicity. However, further research is needed on the effects of PPE and Ornipural combinations for the treatment of cadmium toxicity. In future studies, various doses of these treatment options (with chelators) should be investigated for cadmium toxicity.}, }
@article {pmid37495077, year = {2023}, author = {Ding, Q and Sun, B and Wang, M and Li, T and Li, H and Han, Q and Liao, J and Tang, Z}, title = {N-acetylcysteine alleviates oxidative stress and apoptosis and prevents skeletal muscle atrophy in type 1 diabetes mellitus through the NRF2/HO-1 pathway.}, journal = {Life sciences}, volume = {329}, number = {}, pages = {121975}, doi = {10.1016/j.lfs.2023.121975}, pmid = {37495077}, issn = {1879-0631}, mesh = {Dogs ; Animals ; Antioxidants/metabolism ; Acetylcysteine/pharmacology/metabolism ; NF-E2-Related Factor 2/metabolism ; *Diabetes Mellitus, Type 1/complications/drug therapy/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; bcl-2-Associated X Protein/metabolism ; Signal Transduction ; Oxidative Stress ; Muscular Atrophy/drug therapy/prevention &amp; control/metabolism ; Muscle, Skeletal/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis ; *Insulins/metabolism/pharmacology ; }, abstract = {AIMS: Type 1 diabetes mellitus (T1DM) has been linked to the occurrence of skeletal muscle atrophy. Insulin monotherapy may lead to excessive blood glucose fluctuations. N-acetylcysteine (NAC), a clinically employed antioxidant, possesses cytoprotective, anti-inflammatory, and antioxidant properties. The objective of our study was to evaluate the viability of NAC as a supplementary treatment for T1DM, specifically regarding its therapeutic and preventative impacts on skeletal muscle.<br><br>MAIN METHODS: Here, we used beagles as T1DM model for 120d to explore the mechanism of NRF2/HO-1-mediated skeletal muscle oxidative stress and apoptosis and the therapeutic effects of NAC. Oxidative stress and apoptosis related factors were analyzed by immunohistochemistry, immunofluorescence, western blotting, and RT-qPCR assay.<br><br>KEY FINDINGS: The findings indicated that the co-administration of NAC and insulin led to a reduction in creatine kinase levels, preventing weight loss and skeletal muscle atrophy. Improvement in the reduction of muscle fiber cross-sectional area. The expression of Atrogin-1, MuRF-1 and MyoD1 was downregulated, while Myh2 and MyoG were upregulated. In addition, CAT and GSH-Px levels were increased, MDA levels were decreased, and redox was maintained at a steady state. The decreased of key factors in the NRF2/HO-1 pathway, including NRF2, HO-1, NQO1, and SOD1, while KEAP1 increased. In addition, the apoptosis key factors Caspase-3, Bax, and Bak1 were found to be downregulated, while Bcl-2, Bcl-2/Bax, and CytC were upregulated.<br><br>SIGNIFICANCE: Our findings demonstrated that NAC and insulin mitigate oxidative stress and apoptosis in T1DM skeletal muscle and prevent skeletal muscle atrophy by activating the NRF2/HO-1 pathway.}, }
@article {pmid37491222, year = {2023}, author = {Mahfouz Omer, SM and El-Sherbiny, RH and El-Desouky, SS}, title = {Effect of N-Acetylcysteine on initial Carious Enamel Lesions in primary teeth: an In-vitro study.}, journal = {BMC oral health}, volume = {23}, number = {1}, pages = {520}, pmid = {37491222}, issn = {1472-6831}, mesh = {Humans ; *Dental Caries/therapy ; Acetylcysteine/pharmacology/therapeutic use ; Dental Enamel ; Fluorides/pharmacology ; Tooth, Deciduous ; Tooth Remineralization/methods ; }, abstract = {BACKGROUND: Dental caries initiates with non-cavitated enamel lesions as the first stage. The cariogenic potential of N-Acetylcysteine (NAC) may be due to its usage frequency and form. This study aimed to evaluate the impact of exposure time of NAC on initial enamel caries-like lesions in primary teeth by assessing the morphological alteration using a scanning electron microscope (SEM) and mineral content using energy dispersive x-ray spectroscopy (EDX).<br><br>METHODS: Forty primary incisor teeth were randomly divided into 4 groups S, S1, S2, and S3 (10 specimens/group). Teeth crowns were cut from their roots and inserted into an acrylic mold with its buccal surface directed upward. Centrally isolated enamel window (2&#x2009;&#xd7;&#x2009;2&#xa0;mm) on the tooth was done. Ten specimens were selected to evaluate normal enamel while the remaining thirty specimens were immersed in demineralizing solution for 96&#xa0;h to produce enamel caries-like lesions. PH cycling was performed by immersing each tooth sample in 20 mL of demineralizing solution for 3&#xa0;h then, preserved for the remaining day hours in 10 ml of artificial saliva interspersed with treatments applications with 10 ml NAC for 10&#xa0;min twice a day for one- or three-months different treatment modalities. Thermocycling was done for all specimens then they were subjected to SEM and EDX analysis. ANOVA and Bonferroni post hoc tests were utilized in data analysis.<br><br>RESULTS: In teeth treated by NAC for 3 months (group-S3), SEM images showed severe loss of enamel architecture with large NAC deposits detected. A meaningful difference was observed among different groups concerning calcium, phosphorus, fluoride, ca/P ratio, carbon, nitrogen, and oxygen contents (P&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: NAC had a detrimental impact on enamel caries-like lesions in human primary teeth.}, }
@article {pmid37487871, year = {2023}, author = {Wang, L and Zhang, X and Xu, M and Zheng, G and Chen, J and Li, S and Cui, J and Zhang, S}, title = {Implication of ferroptosis in hepatic toxicity upon single or combined exposure to polystyrene microplastics and cadmium.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {334}, number = {}, pages = {122250}, doi = {10.1016/j.envpol.2023.122250}, pmid = {37487871}, issn = {1873-6424}, mesh = {Humans ; Microplastics/toxicity ; Polystyrenes/toxicity ; Cadmium/toxicity ; Plastics/toxicity ; Reactive Oxygen Species ; *Ferroptosis ; Antioxidants ; *Water Pollutants, Chemical/toxicity ; }, abstract = {Microplastics (MPs) are a newly emerging type of pollutants. To date, MPs have been found in the atmosphere, soil, water, and even in human samples, posing a non-negligible threat to humans. Furthermore, multiple heavy metals have been found to co-exist with MPs or be absorbed by MPs. This leads to a widespread concern about their combined toxicity, which is currently elusive. Herein, we investigated the single or combined toxic effects of polystyrene MPs (PS-MPs) and cadmium chloride (CdCl2) on the liver and hepatocytes. After co-incubation, cadmium (Cd) can be absorbed by PS-MPs, resulting in physiochemical alterations of PS-MPs. In vivo and in vitro experiments revealed that PS-MPs solely or together with CdCl2 induced ferroptosis in hepatocytes, a newly defined programmed cell death characterized by lipid oxidation and iron accumulation. PS-MPs exerted more ferroptotic effect on hepatocytes than CdCl2, and combined exposure to PS-MPs and CdCl2 enhanced their ferroptotic effect, mainly by stimulating reactive oxygen species (ROS) production and inhibiting antioxidant activity. Upon single or combined exposure to PS-MPs and CdCl2, the induction of ferroptosis in hepatocytes can be inhibited by N-acetyl-cysteine (NAC, an ROS scavenger), deferoxamine (DFO, an iron chelator), and particularly ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor). Fer-1 efficiently rescued the cell viability of hepatocytes upon exposure to PS-MPs and CdCl2 through enhancing the antioxidant system via upregulating GPX4 and SLC7A11. These findings would contribute to an in-depth understanding of the single and combined toxicity of microplastics and cadmium.}, }
@article {pmid37487865, year = {2023}, author = {Samandari-Bahraseman, MR and Khorsand, B and Zareei, S and Amanlou, M and Rostamabadi, H}, title = {Various concentrations of hesperetin induce different types of programmed cell death in human breast cancerous and normal cell lines in a ROS-dependent manner.}, journal = {Chemico-biological interactions}, volume = {382}, number = {}, pages = {110642}, doi = {10.1016/j.cbi.2023.110642}, pmid = {37487865}, issn = {1872-7786}, mesh = {Humans ; Female ; *Hesperidin/pharmacology ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Apoptosis ; Cell Line, Tumor ; Superoxide Dismutase/metabolism ; *Breast Neoplasms ; }, abstract = {The polyphenolic component of citrus fruits, hesperetin (Hst), is a metabolite of hesperidin. In this study, we examined the effect of varying doses and exposure times of hesperetin on MCF-7 and MDA-MB-231 cancer cells, as well as MCF-10A normal cells. By using MTT assay, real-time PCR, western blot, and flow cytometry, we determined the effects of Hst on cell viability, ROS levels, and markers of cell death. Furthermore, molecular docking was used to identify Hst targets that might be involved in ROS-dependent cell death. According to the results, different concentrations of Hst induced different modes of cell death at specific ROS levels. Paraptosis occurred in all cell lines at concentration ranges of IC35 to IC60, and apoptosis occurred at concentrations greater than IC65. In addition, MDA-MB-231 cells were subjected to senescence at sub-toxic doses when treated for a long period of time. When Hst levels were higher, N-acetylcysteine (NAC)'s effect on neutralizing ROS was more pronounced. According to the docking results, Hst may interact with several proteins involved in the regulation of ROS. As an example, the interaction of CCS (Copper chaperone for superoxide dismutase) with Hst might interfere with its chaperone function in folding SOD-1 (superoxide dismutase enzyme), contributing to an increase in cytoplasmic ROS levels. Finally, depending on the ROS level, Hst induces various modes of cell death.}, }
@article {pmid37487439, year = {2023}, author = {Aki, T and Tanaka, H and Funakoshi, T and Unuma, K and Uemura, K}, title = {Excessive N-acetylcysteine exaggerates glutathione redox homeostasis and apoptosis during acetaminophen exposure in Huh-7 human hepatoma cells.}, journal = {Biochemical and biophysical research communications}, volume = {676}, number = {}, pages = {66-72}, doi = {10.1016/j.bbrc.2023.07.023}, pmid = {37487439}, issn = {1090-2104}, mesh = {Humans ; Acetylcysteine/metabolism ; Acetaminophen/toxicity ; *Carcinoma, Hepatocellular/pathology ; *Chemical and Drug Induced Liver Injury/pathology ; Glutathione/metabolism ; *Liver Neoplasms/pathology ; Apoptosis ; Oxidation-Reduction ; Homeostasis ; Liver/metabolism ; }, abstract = {Acetaminophen (APAP) hepatotoxicity is one of the biggest drawbacks of this relatively safe and widely used drug. In addition to its hepatotoxicity, APAP also cause comparable levels of toxicity on human hepatoma cells. Here we show activation of the intrinsic caspase-9/3 pathway of apoptosis followed by gasdermin E (GSDME) cleavage and subsequent ballooning in APAP (10 mM, 72 h)-treated Huh-7 human hepatocarcinoma cells. N-acetylcysteine (NAC), an antioxidant currently used as an antidote for APAP overdose, does not alleviate APAP toxicity in Huh-7 cells; NAC overdose (10 mM) rather aggravates APAP toxicity. NAC overdose not only aggravates cell death, but also decreases the cellular GSH/GSSG ratio, an indicator of redox homeostasis of glutathione. These results show for the first time that APAP-induced apoptosis in hepatoma cells is followed by secondary necrosis via the caspase-3/GSDME pathway. NAC overdose (10 mM) not only worsens the glutathione redox status, but also accelerates this pathway.}, }
@article {pmid37480966, year = {2024}, author = {Ni, X and Yu, S and Jiang, X and Wu, F and Zhou, J and Mao, D and Wang, H and Tao, Y and Liu, Y and Jin, F}, title = {Celastrus orbiculatus Thunb. extract targeting DJ-1 inhibits non-small cell lung cancer invasion and metastasis through mitochondrial-induced ROS accumulation.}, journal = {Journal of ethnopharmacology}, volume = {318}, number = {Pt A}, pages = {116944}, doi = {10.1016/j.jep.2023.116944}, pmid = {37480966}, issn = {1872-7573}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; *Celastrus/chemistry ; Reactive Oxygen Species ; Plant Extracts/pharmacology/therapeutic use/chemistry ; Cell Line, Tumor ; *Lung Neoplasms/drug therapy ; Mitochondria ; }, abstract = {Celastrus orbiculatus Thunb. is an ancient traditional Chinese herb with a long history of medicinal use. The ethyl acetate extract of Celastrus orbiculatus Thunb. (COE) has been shown to have anti-tumor effects in various preclinical studies. However, the anti-invasive and metastatic efficacy of COE in non-small cell lung cancer (NSCLC) and the mechanism by which COE regulates cellular oxidation levels are yet to be elucidated.<br><br>AIM: To study the anti-dissemination effect of COE on NSCLC and to elucidate the molecular mechanism of COE in regulating cellular oxidation levels and its effect on lung cancer invasion and metastasis.<br><br>METHODS: CCK-8 assay was used to detect the toxic effects of COE on NSCLC. Transwell assay and high-content imaging was used to detect the Motility of NSCLC. Transmission electron microscopy and three-dimensional (3D) imaging of mitochondrial fluorescence were employed to detect the number and structure of mitochondria. JC-1 probe was used to detect the level of mitochondrial membrane potential. Firefly luciferase assay was used to detect the level of total intracellular ATP. MitoSox probe and DCFH-DA probe were applied to detect the level of reactive oxygen species (ROS) inside the mitochondria and the total intracellular ROS, respectively. Immunohistochemistry was used to detect protein expression in xenograft tumors.<br><br>RESULTS: COE inhibited motility and induced DJ-1 downregulation in NSCLC at low toxic concentrations, and the antiseptic effect of COE was reduced significantly after the overexpression of DJ-1. COE induced structural disruption of mitochondria in NSCLC and accumulation of superoxide compounds, decreased the volume of membrane potential depolarization, and impaired energy production, ultimately leading to a large accumulation of ROS at the cellular level. The antioxidant acetylcysteine (NAC) significantly reversed the antiseptic capacity of COE. In a xenograft tumor model, protein expression of DJ-1, E-cadherin, N-cadherin, and MMP-2 in COE group was significantly changed compared to the model group.<br><br>CONCLUSION: In the present study, COE inhibited NSCLC invasion and metastasis and was associated with the downregulation of DJ-1 and elevated ROS. COE-mediated downregulation of DJ-1 may be the primary cause of mitochondrial structural and functional dysfunction in NSCLC, eventually leading to ROS accumulation.}, }
@article {pmid37477247, year = {2024}, author = {Debnath, U and Mitra, A and Dewaker, V and Prabhakar, YS and Tadala, R and Krishnan, K and Wagh, P and Velusamy, U and Baliyan, A and Kurpad, AV and Bhattacharyya, P and Mandal, AK}, title = {Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine: an exploration of probable mechanism of action to combat COVID-19.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {42}, number = {10}, pages = {5042-5052}, doi = {10.1080/07391102.2023.2234031}, pmid = {37477247}, issn = {1538-0254}, mesh = {*Spike Glycoprotein, Coronavirus/chemistry/metabolism ; *Acetylcysteine/pharmacology/chemistry ; Humans ; *SARS-CoV-2/drug effects/metabolism ; *Angiotensin-Converting Enzyme 2/metabolism/chemistry ; *Protein Binding ; *COVID-19/virology ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; COVID-19 Drug Treatment ; Protein Conformation ; Binding Sites ; Antiviral Agents/pharmacology/chemistry ; }, abstract = {The infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) resulted in a pandemic with huge death toll and economic consequences. The virus attaches itself to the human epithelial cells through noncovalent bonding of its spike protein with the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. Based on in silico studies we hypothesized that perturbing the functionally active conformation of spike protein through the reduction of its solvent accessible disulfide bonds, thereby disintegrating its structural architecture, may be a feasible strategy to prevent infection by reducing the binding affinity towards ACE2 enzyme. Proteomics data showed that N-acetyl cysteine (NAC), an antioxidant and mucolytic agent been widely in use in clinical medicine, forms covalent conjugates with solvent accessible cysteine residues of spike protein that were disulfide bonded in the native state. Further, in silico analysis indicated that the presence of the selective covalent conjugation of NAC with Cys525 perturbed the stereo specific orientations of the interacting key residues of spike protein that resulted in threefold weakening in the binding affinity of spike protein with ACE2 receptor. Interestingly, almost all SARS-CoV-2 variants conserved cystine residues in the spike protein. Our finding results possibly provides a molecular basis for identifying NAC and/or its analogues for targeting Cys-525 of the viral spike protein as fusion inhibitor and exploring in vivo pharmaco-preventive and its therapeutic potential activity for COVID-19 disease. However, in-vitro assay and animal model-based experiment are required to validate the probable mechanism of action.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid37476961, year = {2024}, author = {Gao, Y and Wu, F and He, W and Cai, Z and Pang, J and Zheng, Y}, title = {Reactive Oxygen Species-Related Disruptions to Cochlear Hair Cell and Stria Vascularis Consequently Leading to Radiation-Induced Sensorineural Hearing Loss.}, journal = {Antioxidants &amp; redox signaling}, volume = {40}, number = {7-9}, pages = {470-491}, doi = {10.1089/ars.2022.0161}, pmid = {37476961}, issn = {1557-7716}, mesh = {Mice ; Animals ; *Stria Vascularis/pathology/physiology ; Reactive Oxygen Species ; Mice, Inbred C57BL ; *Hearing Loss, Sensorineural/chemically induced/pathology ; Hair Cells, Auditory, Outer/pathology/physiology ; Acetylcysteine/pharmacology ; }, abstract = {Aims: Radiation-induced sensorineural hearing loss (RISNHL) is one of the major side effects of radiotherapy for head and neck cancers. At present, no effective clinical treatment or prevention is available for RISNHL. This study thus aimed to investigate the cochlear pathology so that the underlying mechanisms of RISNHL may be elucidated, consequently paving the way for potential protective strategies to be developed. Results: Functional and morphological impairment in the stria vascularis (SV) was observed after irradiation (IR), as indicated by endocochlear potential (EP) reduction, hyperpermeability, and SV atrophy. The expression of zonulae occludins-1 was found to have decreased after IR. The loss of outer hair cells (OHCs) occurred later than SV damage. The disruption to the SV and OHCs could be attributed to reactive oxygen species (ROS)-related damage. In addition, EP shifts and the loss of OHCs were reduced when ROS was reduced by N-acetylcysteine (NAC) in C57BL/6 mice, attenuating auditory threshold shifts. Innovation: The damage to the SV was found to occur before OHC loss. ROS-related damage accounted for SV damage and OHC loss. The incidences of SV damage and OHC loss were decreased through ROS modulation by NAC, subsequently preventing RISNHL, suggesting the possible role of NAC as a possible protective agent against RISNHL. Conclusion: The findings from this study suggest oxidative stress-induced early SV injury and late OHC loss to be the key factors leading to RISNHL. NAC prevents IR-induced OHC loss, and attenuates auditory brainstem response and EP shifts by regulating the level of oxidative stress. Antioxid. Redox Signal. 40, 470-491.}, }
@article {pmid37465907, year = {2023}, author = {Morley, KC and Peruch, S and Adams, C and Towers, E and Tremonti, C and Watt, J and Jamshidi, N and Haber, PS}, title = {N acetylcysteine in the treatment of alcohol use disorder: a randomized, double-blind, placebo-controlled trial.}, journal = {Alcohol and alcoholism (Oxford, Oxfordshire)}, volume = {58}, number = {5}, pages = {553-560}, doi = {10.1093/alcalc/agad044}, pmid = {37465907}, issn = {1464-3502}, support = {//MRFF Practitioner Fellowship/ ; }, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *Alcoholism/drug therapy ; Double-Blind Method ; Treatment Outcome ; Male ; Female ; Adult ; Middle Aged ; Aged ; }, abstract = {N-acetyl cysteine (NAC) is a potent antioxidant that modulates glutamatergic signalling which is thought to play a role in alcohol use disorder (AUD). There have been no clinical trials investigating NAC for AUD. We aimed to conduct a 28 day double-blind, placebo-controlled (PL) randomized trial of NAC in the treatment of AUD (NCT03879759). A total of 42 participants with AUD (56% alcohol-related liver disease) were randomized to receive placebo or NAC 2400 mg/day. Feasibility outcomes included treatment retention and adverse events. Primary clinical outcomes included alcohol consumption (heavy drinking days, standard drinks per drinking day). Secondary clinical outcome measures included craving, liver tests, and psychological outcomes. There were no significant differences in overall retention between treatment groups (χ2(1) = 0.14, P = 0.71: 86% vs 76% for placebo and NAC, respectively). The most commonly reported adverse event in NAC-treated individuals included headache (14%). For standard drinks per drinking day, there was a significant overall effect of time (F = 9.18, P < 0.001), no significant effect of treatment (F = 0.75, P = 0.79), and a significant time x treatment (NAC vs PL) effect (F = 2.73, P < 0.05). For number of heavy drinks per day, there was a significant overall effect of time (F = 3.16, P < 0.05) but no significant effect of treatment or time x treatment (P = 0.17). There were no significant NAC vs PL effects on secondary clinical outcome measures. In the first trial of NAC for the management of AUD, NAC appears to be feasible and safe. Although there was a significant effect of NAC vs placebo on some alcohol measures such as drinks per drinking day, there does appear to be a variable pattern of effect across time suggesting that a larger trial incorporating a longer treatment duration is now required to determine efficacy.}, }
@article {pmid37463651, year = {2023}, author = {Huang, M and Zou, M and Mao, S and Xu, W and Hong, Y and Wang, H and Gui, F and Yang, L and Lian, F and Chen, R}, title = {3,5,6-Trichloro-2-pyridinol confirms ototoxicity in mouse cochlear organotypic cultures and induces cytotoxicity in HEI-OC1 cells.}, journal = {Toxicology and applied pharmacology}, volume = {475}, number = {}, pages = {116612}, doi = {10.1016/j.taap.2023.116612}, pmid = {37463651}, issn = {1096-0333}, mesh = {Animals ; Mice ; Reactive Oxygen Species/metabolism ; *Ototoxicity ; Microphysiological Systems ; *Antineoplastic Agents/pharmacology ; Pyridines/pharmacology ; Apoptosis ; Cisplatin/pharmacology ; }, abstract = {The metabolite of organophosphate pesticide chlorpyrifos (CPF), 3,5,6-Trichloro-2-pyridinol (TCP), is persistent and mobile toxic substance in soil and water environments, exhibiting cytotoxic, genotoxic, and neurotoxic properties. However, little is known about its effects on the peripheral auditory system. Herein, we investigated the effects of TCP exposure on mouse postnatal day 3 (P3) cochlear culture and an auditory cell line HEI-OC1 to elucidate the underlying molecular mechanisms of ototoxicity. The damage of TCP to outer hair cells (OHC) and support cells (SC) was observed in a dose and time-dependent manner. OHC and SC were a significant loss from basal to apical turn of the cochlea under exposure over 800 μM TCP for 96 h. As TCP concentrations increased, cell viability was reduced whereas reactive oxygen species (ROS) generation, apoptotic cells, and the extent of DNA damage were increased, accordingly. TCP-induced phosphorylation of the p38 and JNK MAPK are the downstream effectors of ROS. The antioxidant agent, N-acetylcysteine (NAC), could reverse TCP-mediated intracellular ROS generation, inhibit the expressive level of cleaved-caspase 3 and block phosphorylation of p38/JNK. Overall, this is the first demonstration of TCP damaging to peripheral sensory HCs and SC in organotypic cultures from the postnatal cochlea. Data also showed that TCP exposure induced oxidase stress, cell apoptosis and DNA damage in the HEI-OC1 cells. These findings serve as an important reference for assessing the risk of TCP exposure.}, }
@article {pmid37458841, year = {2023}, author = {Platt, I and Bisgin, A and Kilavuz, S}, title = {Ethylmalonic Encephalopathy: a literature review and two new cases of mild phenotype.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {44}, number = {11}, pages = {3827-3852}, pmid = {37458841}, issn = {1590-3478}, abstract = {BACKGROUND: Ethylmalonic encephalopathy (EE) is a rare intoxication-type metabolic disorder with multisystem involvement. It is caused by mutations in ETHE1, which encodes the ETHE1 enzyme in the mitochondrial matrix that plays a key role in hydrogen sulfide (H2S) detoxification acting as a sulphur dioxygenase.<br><br>RESULTS: This review focuses on the clinical, metabolic, genetic and neuroradiological features of 70 reported cases, including two new cases. The common manifestations of EE are psychomotor regression, hypotonia, developmental delay, petechia, pyramidal signs, chronic diarrhoea, orthostatic acrocyanosis and failure to thrive, respectively. A significant difference was found in EMA and C4 levels (p=0.003, p=0.0236)&#xa0;between classical and mild phenotypes. Urinary EMA, C4 and C5 levels were found to exhibit normal values in milder cases during attack-free periods. The most common ETHE1 gene homozygous state mutations were (p.R163Q) (c.488G>A), exon 4 deletion, (p.R163W)(c.487C>T), (p.Glu44ValfsTer62)(c.131_132delAG) and (p.M1I)(c.3G>T) mutations, respectively. Fifty-two patients underwent cranial MRI. Basal ganglia signal alterations were detected in 42 cases. Of the 70 cases, eight had a mild phenotype and slow neurological progression with low levels of ethylmalonic acid (EMA) and C4 acylcarnitine. The current age of alive patients in the published articles with mild phenotype was significantly higher than the classical phenotype. (p=0.002). Reducing the accumulation and inducing detoxification of sulfide is the main long-term treatment strategy for EE, including metronidazole, N-acetylcysteine (NAC), dietary modification, liver transplantation and continuous renal replacement therapy (CRRT).<br><br>CONCLUSION: Measuring EMA and C4 acylcarnitine during metabolic attacks is critical to diagnosing EE, allowing for early treatment initiation to prevent further encephalopathic crises. Experience with liver transplantation, diet and CRRT, is currently limited. An early multidisciplinary approach with combination therapies is vital to prevent irreversible neurological damage.}, }
@article {pmid37458150, year = {2023}, author = {Gayatri Devi, R and Ezhilarasan, D}, title = {Concurrent administration of farnesol protects acetaminophen-induced acute hepatic necrosis in mice.}, journal = {Journal of biochemical and molecular toxicology}, volume = {37}, number = {11}, pages = {e23478}, doi = {10.1002/jbt.23478}, pmid = {37458150}, issn = {1099-0461}, mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; Antioxidants/metabolism ; Farnesol/pharmacology/metabolism ; NF-kappa B/metabolism ; Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control/metabolism ; Liver/metabolism ; Glutathione/metabolism ; Necrosis ; Transaminases/metabolism/pharmacology ; Alanine Transaminase ; }, abstract = {Acetaminophen (APAP) is known to cause acute liver injury and acute liver failure in Western countries. This study investigates the protective role of farnesol (FAR) (C15 H26 O), a natural sesquiterpene alcohol in essential oils, against APAP-induced acute liver necrosis in mice. Mice were injected with a single dose of APAP (300 mg/kg) via an intraperitoneal route. Different groups of mice were concurrently treated with a single dose of FAR 25 mg/kg, FAR 50 mg/kg, and N-acetylcysteine. APAP administration caused a significant increase in transaminase activities and malondialdehyde (MDA) levels in the serum and liver tissue, respectively, with a concomitant decrease in intracellular antioxidants, including reduced glutathione (GSH) in the liver tissue. APAP intoxication upregulated proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, nuclear factor-κB (NF-κB), and IκB kinase β in the liver tissue. FAR and N-acetylcysteine (NAC) administrations concurrently with APAP prevented serum transaminase increase in serum and MDA levels in the liver tissue. A high dose of FAR and NAC treatments significantly inhibited GSH and other antioxidant depletion. FAR and NAC treatments also downregulated the expression of proinflammatory markers. FAR treatments protects against APAP-induced acute liver injury and offers antioxidant and anti-inflammatory effects by inhibiting the NF-κB pathway involved in the transcription of genes responsible for inflammatory cytokine synthesis.}, }
@article {pmid37454274, year = {2023}, author = {Celebi, NK and Ozturk, SK and Palaoglu, I and Somay, A and Yaprak, G and Algul, E and Deveci, HS}, title = {Investigation of the efficacy of systemic N-Acetyl Cysteine therapy preventing nasal mucositis following radiotherapy.}, journal = {Rhinology}, volume = {61}, number = {5}, pages = {470-480}, doi = {10.4193/Rhin22.487}, pmid = {37454274}, issn = {0300-0729}, mesh = {Rats ; Animals ; Humans ; Female ; *Mucositis/etiology/prevention &amp; control/pathology ; Quality of Life ; Rats, Sprague-Dawley ; Nasal Mucosa ; Acetylcysteine/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Radiotherapy (RT) is one of the main methods used in the treatment of head and neck cancers but may cause mucosal side effects in the tumor area and surrounding structures. These include nasal mucosal disorders and chronic rhinosinusitis due to disruption of the mucociliary system. This situation seriously affects the quality of life of the patients and there is no accepted effective method for its treatment yet. In our study, we aimed to examine the side effects of RT on the nasal mucosa and mucociliary system and to investigate histopathologically and immunohistochemically the effectiveness of N-acetyl cysteine (NAC) in preventing these side effects of RT.<br><br>METHODOLOGY: The study was carried out with 30 female Sprague Dawley rats devided in three groups. No intervention was made in the control group. On the second day of the experiment, 30 Gy radiotherapy was applied to the head area in the RT group. NAC was administered intraperitoneally at a dose of 1 g/kg/day for 14 days from the first day of the study to the RT+ NAC group. On the second day, 30 Gy of radiotherapy was applied to the head area 1 hour after the NAC application. On the 14th day, 1 hour after NAC was applied to the RT+NAC group, all animals were sacrificed. The nasal mucosa samples were stained with hematoxylin-eosin, and the intensity and extent of staining sentan in the nasopharyngeal tissue samples were evaluated by immunohistochemical staining using anti-SNTN antibody.<br><br>RESULTS: The loss of cilia in the nasal tissue was lower in the RT+NAC group than in the RT group. The intensity and extent of staining in the nasopharyngeal tissue of Sentan was higher in the RT+NAC group than in the RT group. Mucosal neutrophil and mononuclear inflammatory cell infiltration in the nasal tissue, vascular dilatation, hyperemia and hemorrhage, erosion and shedding of the mucosal epithelium, mucosal ulceration were found to be similar in the RT+NAC group and the control group. It was milder in the RT+NAC group than in the RT group, but not statistically significant.<br><br>CONCLUSIONS: Radiotherapy caused pathological changes in the nasal mucosa, caused loss of cilia and a decrease in the level of Sentan, the cilia apical protein. The results of our study showed that NAC treatment can reduce the side effects of RT on the nasal mucosa. It also showed that NAC was effective in preventing the loss of cilia, which is the building block of the mucociliary system, and improving the expression of Sentan.}, }
@article {pmid37439802, year = {2023}, author = {Park, SY and Lee, KH}, title = {Comparison of Cytotoxicity and Genotoxicity in Three Types of Indirect Restorative Materials on Human Periodontal Stem Cells.}, journal = {Oral health &amp; preventive dentistry}, volume = {21}, number = {}, pages = {243-250}, doi = {10.3290/j.ohpd.b4211055}, pmid = {37439802}, issn = {1757-9996}, mesh = {Humans ; Reactive Oxygen Species ; *Dental Materials ; *Glass Ionomer Cements/toxicity ; Stem Cells ; Materials Testing ; Composite Resins/toxicity ; }, abstract = {PURPOSE: This study aimed to compare the cell toxicity and biological characteristics of Ketac GIC (glass-ionomer cement), Nexus RMGIC (resin-modified glass-ionomer cement), and RelyX RC (resin cement) in human periodontal stem cells (PDSCs).<br><br>MATERIALS AND METHODS: To compare the effects of Ketac GIC, Nexus RMGIC, and RelyX RC on PDSCs, the cements were diluted from 1:2 to 1:8. PDSCs were then treated with the serially diluted cements with or without N-acetyl-cysteine (NAC), and cell survival was measured using water-soluble tetrazolium salt (WST-1) assay. Intracellular reactive oxygen species (ROS) was measured using 2',7'-dichlorofluorescin diacetate (DCFDA), and western blot analysis was performed to observe phosphorylation and activation of extracellular signal-regulated kinase (ERK) by Nexus RMGIC or RelyX RC.<br><br>RESULTS: Cell death and proliferation were dose-dependently reduced following Nexus RMGIC or RelyX RC treatment. In addition, Nexus RMGIC or RelyX RC showed an increase intracellular ROS generation compared to Ketac GIC. Pretreatment with NAC confirmed the suppression of cell toxicity and ROS generation induced by Nexus RMGIC or RelyX RC. Nexus RMGIC or RelyX RC activates ERK phosphorylation, not p38 phosphorylation, in PDSCs.<br><br>CONCLUSION: This study showed that the treatment with Nexus RMGIC or RelyX generates intracellular ROS and cell death through the ERK signaling pathway in PDSCs. In contrast, these effects were not observed with Ketac GIC, indicating that resin-based materials may have cytotoxic and genotoxic effects on PDSCs.}, }
@article {pmid37439200, year = {2023}, author = {Kim, K and Cort, TA and Kunz, EM and Moerschel, J and Palzkill, VR and Dong, G and Moparthy, CN and Anderson, EM and Fazzone, B and O'Malley, KA and Robinson, ST and Berceli, SA and Ryan, TE and Scali, ST}, title = {N-acetylcysteine treatment attenuates hemodialysis access-related limb pathophysiology in mice with chronic kidney disease.}, journal = {American journal of physiology. Renal physiology}, volume = {325}, number = {3}, pages = {F271-F282}, pmid = {37439200}, issn = {1522-1466}, support = {P30 AG050911/AG/NIA NIH HHS/United States ; R01 HL148597/HL/NHLBI NIH HHS/United States ; }, mesh = {Male ; Female ; Animals ; Mice ; Acetylcysteine/pharmacology ; Renal Dialysis ; *Renal Insufficiency, Chronic/therapy/etiology ; *Kidney Failure, Chronic/therapy ; *Arteriovenous Shunt, Surgical/adverse effects ; *Arteriovenous Fistula ; Retrospective Studies ; }, abstract = {The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW &amp; NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.}, }
@article {pmid37435843, year = {2023}, author = {Su, M and Zhao, Y and Li, M and Jia, C and Liu, H and Zhang, Y and Li, W and Peng, Y and Zheng, J}, title = {Evidence for the Metabolic Activation of Deferasirox In Vitro and In Vivo.}, journal = {Chemical research in toxicology}, volume = {36}, number = {8}, pages = {1255-1266}, doi = {10.1021/acs.chemrestox.2c00416}, pmid = {37435843}, issn = {1520-5010}, mesh = {Rats ; Animals ; Activation, Metabolic ; Deferasirox/pharmacology/metabolism ; *Liver/metabolism ; *Hepatocytes/metabolism ; Microsomes, Liver/metabolism ; Acetylcysteine/metabolism ; Glutathione/metabolism ; }, abstract = {Deferasirox (DFS) is used for the treatment of iron accumulation caused by the need for long-term blood transfusions, such as thalassemia or other rare anemia. Liver injury due to exposure to DFS has been documented, and the toxic mechanisms of DFS are unknown. The present study aimed to investigate the reactive metabolites of DFS in vitro and in vivo to help us understand the mechanisms of DFS hepatotoxicity. Two hydroxylated metabolites (5-OH and 5'-OH) were identified during incubation of DFS-supplemented rat liver microsomes. Such microsomal incubations fortified with glutathione (GSH) or N-acetylcysteine (NAC) as capture agents offered two GSH conjugates and two NAC conjugates. These GSH conjugates and NAC conjugates were also detected in bile and urine of rats given DFS. CYP1A2 and CYP3A4 were found to dominate the metabolic activation of DFS. Administration of DFS induced decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole and 1-aminobenzotrizole made hepatocytes less susceptible to the cytotoxicity of DFS.}, }
@article {pmid37434745, year = {2023}, author = {Zhao, C and Yin, Y and Zhu, C and Zhu, M and Ji, T and Li, Z and Cai, J}, title = {Drug therapies for treatment of idiopathic pulmonary fibrosis: a systematic review, Bayesian network meta-analysis, and cost-effectiveness analysis.}, journal = {EClinicalMedicine}, volume = {61}, number = {}, pages = {102071}, pmid = {37434745}, issn = {2589-5370}, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis and a high economic burden for individuals and healthcare resources. Studies of the costs associated with the efficiency of IPF medications are scarce. We aimed to conduct a network meta-analysis (NMA) and cost-effectiveness analysis to identify the optimum pharmacological strategy among all currently available IPF regimens.<br><br>METHODS: We first performed a systematic review and network meta-analysis. We searched eight databases for eligible randomised controlled trials (RCTs) published, in any language, between January 1, 1992 and July 31, 2022, that investigated the efficacy or tolerability (or both) of drug therapies for the treatment of IPF. The search was updated on February 1, 2023. Eligible RCTs were enrolled, with no restriction on dose, duration, or length of follow-up, if they included at least one of: all-cause mortality, acute exacerbation rate, disease progression rate, serious adverse events, and any adverse events under investigation. A subsequent Bayesian NMA within random-effects models was performed, followed by a cost-effectiveness analysis using the data obtained from our NMA, by developing a Markov model from the US payer's perspective. Assumptions were checked by deterministic and probabilistic sensitivity approaches to identify sensitive factors. We prospectively registered the protocol (CRD42022340590) in PROSPERO.<br><br>FINDINGS: 51 publications comprising 12,551 participants with IPF were analysed for the NMA, and the findings indicated that pirfenidone and N-acetylcysteine (NAC)&#xa0;+ pirfenidone were the most efficacious and tolerable. The pharmacoeconomic analysis showed that NAC&#xa0;+&#xa0;pirfenidone was associated with the highest potentiality of being cost-effective at willingness-to-pay (WTP) thresholds of US$150,000 and $200,000, on the basis of quality-adjusted life years (QALYs), disability-adjusted life years (DALYs) and mortality, with the probability ranging from 53% to 92%. NAC was the minimum cost agent. Compared with placebo, NAC&#xa0;+&#xa0;pirfenidone improved effectiveness by increasing QALYs by 7.02, and reducing DALYs by 7.10 and deaths by 8.40, whilst raising overall costs by $516,894.<br><br>INTERPRETATION: This NMA and cost-effectiveness analysis suggests that NAC&#xa0;+&#xa0;pirfenidone is the most cost-effective option for treatment of IPF at WTP thresholds of $150,000 and $200,000. However, given that clinical practice guidelines have not addressed the application of this therapy, large well-designed and multicentre trials are warranted to provide a better picture of IPF management.<br><br>FUNDING: None.}, }
@article {pmid37429745, year = {2023}, author = {Emelogu, IK and Tran, CN and Greene, WR and Novak, JD}, title = {Successful treatment of distal intestinal obstruction syndrome with N-acetylcysteine and polyethylene glycol via colonoscopy.}, journal = {Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society}, volume = {22}, number = {6}, pages = {1123-1124}, doi = {10.1016/j.jcf.2023.06.014}, pmid = {37429745}, issn = {1873-5010}, mesh = {Humans ; Female ; Middle Aged ; Polyethylene Glycols ; Acetylcysteine ; *Cystic Fibrosis/diagnosis ; *Intestinal Obstruction/diagnosis/etiology/therapy ; Colonoscopy ; }, abstract = {We describe a case of a 46-year-old woman with cystic fibrosis who presented with several days of abdominal pain and distension. She was found to have a small bowel obstruction with inspissated stool in the distal ileum on CT imaging. Despite initial management with conservative measures, her symptoms worsened. She was taken for urgent colonoscopy with administration of 4% N-acetylcysteine (NAC) and polyethylene glycol (PEG) at the distal ileum with resultant dissolution of the fecalith. Over the following days, her symptoms improved, and she was discharged with outpatient follow-up.}, }
@article {pmid37428372, year = {2023}, author = {Fraguas, S and Molina, MD and Cebrià, F}, title = {Colorimetric Whole-Mount In Situ Hybridization in Planarians.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2680}, number = {}, pages = {81-91}, pmid = {37428372}, issn = {1940-6029}, mesh = {Animals ; *Planarians/genetics ; In Situ Hybridization ; Colorimetry ; RNA, Messenger/genetics ; Digoxigenin ; }, abstract = {Whole-mount in situ hybridization (WISH) is an extremely useful technique for visualizing specific mRNA targets and solving many biological questions. In planarians, this method is really valuable, for example, for determining gene expression profiles during whole-body regeneration and analyzing the effects of silencing any gene to determine their functions. In this chapter, we present in detail the WISH protocol routinely used in our lab, using a digoxigenin-labelled RNA probe and developing with NBT-BCIP. This protocol is basically that already described in Currie et al. (EvoDevo 7:7, 2016), which put together several modifications developed from several laboratories in recent years that improved the original protocol developed in the laboratory of Kiyokazu Agata in 1997. Although this protocol, or slight modifications of it, is the most common protocol in the planarian field for NBT-BCIP WISH, our results show that key steps such as the use and time of NAC treatment to remove the mucus need to be taken into account depending on the nature of the gene analyzed, especially for the epidermal markers.}, }
@article {pmid37427326, year = {2023}, author = {Mousavinezhad-Moghaddam, M and Behnam-Rassouli, M and Valizadeh, N and Mahdavi-Shahri, N and Rezaee, SA}, title = {Thiamine as a peripheral neuro-protective agent in comparison with N-acetyl cysteine in axotomized rats.}, journal = {Iranian journal of basic medical sciences}, volume = {26}, number = {8}, pages = {919-926}, pmid = {37427326}, issn = {2008-3866}, abstract = {OBJECTIVES: In this study, the impact of thiamine (Thi), N-acetyl cysteine (NAC), and dexamethasone (DEX) were investigated in axotomized rats, as a model for neural injury.<br><br>MATERIALS AND METHODS: Sixty-five axotomized rats were divided into two different experimental approaches, the first experiments included five study groups (n=5): intrathecal Thi (Thi.it), intraperitoneal (Thi), NAC, DEX, and control. Cell survival was assessed in L5DRG in the 4[th] week by histological assessment. In the second study, 40 animals were engaged to assess Bcl-2, Bax, IL-6, and TNF-&#x3b1; expression in L4-L5DRG in the 1[st] and 2[nd] weeks after sural nerve axotomy under treatment of these agents (n=10).<br><br>RESULTS: Ghost cells were observed in morphological assessment of L5DRG sections, and following stereological analysis, the volume and neuronal cell counts significantly were improved in the NAC and Thi.it groups in the 4[th] week (P<0.05). Although Bcl-2 expression did not show significant differences, Bax was reduced in the Thi group (P=0.01); and the Bcl-2/Bax ratio increased in the NAC group (1[st] week, P<0.01). Furthermore, the IL-6 and TNF-&#x3b1; expression decreased in the Thi and NAC groups, on the 1[st] week of treatment (P&#x2264;0.05 and P<0.01). However, in the 2[nd] week, the IL-6 expression in both Thi and NAC groups (P<0.01), and the TNF-&#x3b1; expression in the DEX group (P=0.05) were significantly decreased.<br><br>CONCLUSION: The findings may classify Thi in the category of peripheral neuroprotective agents, in combination with routine medications. Furthermore, it had strong cell survival effects as it could interfere with the destructive effects of TNF-&#x3b1; by increasing Bax.}, }
@article {pmid37422055, year = {2023}, author = {Huang, J and Pang, X and Zhang, X and Qiu, W and Zhang, X and Wang, R and Xie, W and Bai, Y and Zhou, S and Liao, J and Xiong, Z and Tang, Z and Su, R}, title = {N-acetylcysteine combined with insulin attenuates myocardial injury in canines with type 1 diabetes mellitus by modulating TNF-α-mediated apoptotic pathways and affecting linear ubiquitination.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {262}, number = {}, pages = {1-11}, doi = {10.1016/j.trsl.2023.07.003}, pmid = {37422055}, issn = {1878-1810}, mesh = {Humans ; Animals ; Dogs ; *NF-kappa B/metabolism ; Tumor Necrosis Factor-alpha ; Insulin/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; *Diabetes Mellitus, Type 1/complications/drug therapy ; Apoptosis ; Ubiquitination ; }, abstract = {The exact pathogenesis of type 1 diabetes mellitus (DM) is still unclear. Numerous organs, including the heart, will suffer damage and malfunction as a result of long-term hyperglycemia. Currently, insulin therapy alone is still not the best treatment for type 1 DM. In order to properly treat and manage patients with type 1 DM, it is vital to seek a combination that includes both insulin and additional medications. This study aims to explore the therapeutic effect and mechanism of N-acetylcysteine (NAC) combined with insulin on type 1 DM. By giving beagle canines injections of streptozotocin (STZ) and alloxan (ALX) (20 mg/kg each), a model of type 1 DM was created. The results showed that this combination could effectively control blood sugar level, improve heart function, avoid the damage of mitochondria and myocardial cells, and prevent the excessive apoptosis of myocardial cells. Importantly, the combination can activate nuclear factor kappa-B (NF-κB) by promoting linear ubiquitination of receptor-interacting protein kinase 1 (RIPK1) and NF-κB-essential modulator (NEMO) and inhibitor of NF-κB (IκB) phosphorylation. The combination can increase the transcription and linear ubiquitination of Cellular FLICE (FADD-like IL-1β-converting enzyme) -inhibitory protein (c-FLIP), diminish the production of cleaved-caspase-8 p18 and cleaved-caspase-3 to reduce apoptosis. This study confirmed that NAC combined with insulin can promote the linear ubiquitination of RIPK1, NEMO and c-FLIP and regulate the apoptosis pathway mediated by TNF-α to attenuate the myocardial injury caused by type 1 DM. Meanwhile, the research served as a resource when choosing a clinical strategy for DM cardiac complications.}, }
@article {pmid37419616, year = {2023}, author = {Medipally, A and Xiao, M and Satoskar, AA and Biederman, L and Dasgupta, A and Ivanov, I and Mikhalina, G and Rovin, B and Brodsky, SV}, title = {N-acetylcysteine ameliorates hematuria-associated tubulointerstitial injury in 5/6 nephrectomy mice.}, journal = {Physiological reports}, volume = {11}, number = {13}, pages = {e15767}, pmid = {37419616}, issn = {2051-817X}, support = {R01 DK117102/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Mice ; Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Warfarin/adverse effects ; Reactive Oxygen Species ; Tumor Necrosis Factor-alpha ; Mice, Inbred C57BL ; Kidney ; Nephrectomy ; Hematuria/etiology/chemically induced ; *Renal Insufficiency, Chronic/complications/drug therapy/chemically induced ; Fibrosis ; }, abstract = {Chronic kidney disease (CKD) is characterized by increased interstitial fibrosis and tubular atrophy (IFTA) in the kidney. Chronic hematuria is a hallmark of several human kidney diseases and often is seen in patients on anticoagulation therapy. We had previously demonstrated that chronic hematuria associated with warfarin increases IFTA in 5/6 nephrectomy (5/6NE) rats, and such treatment increases reactive oxygen species (ROS) in the kidney. The goal of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the progression of IFTA in 5/6NE mice. 5/6NE C57BL/6 and 5/6NE 129S1/SvImJ mice were treated with warfarin alone or with warfarin and NAC for 23 weeks. Serum creatinine (SCr), hematuria, blood pressure (BP), and ROSs in the kidney were measured; kidney morphology was evaluated. Warfarin doses were titrated to achieve prothrombin time (PT) increase to the levels seen with therapeutic human doses. Warfarin treatment resulted in an increased SCr, systolic BP, hematuria, expression of TGF-ß and ROS in the kidney in both mouse strains. Tumor necrosis factor alpha (TNF-ɑ) levels in the serum were increased in 5/6NE mice treated with warfarin. IFTA was increased as compared with control 5/6NE mice, and this increase in IFTA was more prominent in 129S1/SvImJ than in C57BL/6 mice. NAC ameliorated the warfarin-associated increase in SCr and BP but not hematuria. IFTA, TGF-ß, and ROS in the kidney as well as TNF-ɑ levels in the serum were reduced in mice treated with NAC and warfarin as compared to mice treated with warfarin alone. NAC mitigates the increase in SCr and IFTA in mice with chronic hematuria by reducing oxidative stress in the kidney. This data open novel possibilities for treatments in CKD patients.}, }
@article {pmid37419232, year = {2023}, author = {Kwok, WT and Kwak, HA and Andreazza, AC}, title = {N-acetylcysteine modulates rotenone-induced mitochondrial Complex I dysfunction in THP-1 cells.}, journal = {Mitochondrion}, volume = {72}, number = {}, pages = {1-10}, doi = {10.1016/j.mito.2023.07.001}, pmid = {37419232}, issn = {1872-8278}, mesh = {Humans ; *Acetylcysteine/pharmacology/metabolism ; *Rotenone/toxicity ; THP-1 Cells ; Superoxides/metabolism ; Oxidative Stress ; Electron Transport Complex I/metabolism ; DNA, Mitochondrial/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Mitochondrial Complex I dysfunction and oxidative stress have been part of the pathophysiology of several diseases ranging from mitochondrial disease to chronic diseases such as diabetes, mood disorders and Parkinson's Disease. Nonetheless, to investigate the potential of mitochondria-targeted therapeutic strategies for these conditions, there is a need further our understanding on how cells respond and adapt in the presence of Complex I dysfunction. In this study, we used low doses of rotenone, a classical inhibitor of mitochondrial complex I, to mimic peripheral mitochondrial dysfunction in THP-1 cells, a human monocytic cell line, and explored the effects of N-acetylcysteine on preventing this rotenone-induced mitochondrial dysfunction. Our results show that in THP-1 cells, rotenone exposure led to increases in mitochondrial superoxide, levels of cell-free mitochondrial DNA, and protein levels of the NDUFS7 subunit. N-acetylcysteine (NAC) pre-treatment ameliorated the rotenone-induced increase of cell-free mitochondrial DNA and NDUFS7 protein levels, but not mitochondrial superoxide. Furthermore, rotenone exposure did not affect protein levels of the NDUFV1 subunit but induced NDUFV1 glutathionylation. In summary, NAC may help to mitigate the effects of rotenone on Complex I and preserve the normal function of mitochondria in THP-1 cells.}, }
@article {pmid37415931, year = {2023}, author = {Kaya, ZB and Karakoc, E and McLean, PJ and Saka, E and Atilla, P}, title = {Post-inflammatory administration of N-acetylcysteine reduces inflammation and alters receptor levels in a cellular model of Parkinson's disease.}, journal = {FASEB bioAdvances}, volume = {5}, number = {7}, pages = {263-276}, pmid = {37415931}, issn = {2573-9832}, abstract = {Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha-synuclein (α-syn). Although the formation of α-syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll-like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α-syn and modulate its uptake by other cells. Lymphocyte-activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α-syn internalization; however, a recent study has disputed this role. Internalized α-syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-2, and IL-6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if N-acetylcysteine (NAC), an anti-inflammatory and anti-carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti-inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild-type α-syn were treated with TNF-α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF-α-induced inflammation and apoptosis. SNCA gene transcription and α-syn protein expression were validated by q-PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q-PCR. TNF-α not only increased inflammation but also increased endogenous and overexpressed α-syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation-mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha-synuclein overexpression, via a TLR2-associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD.}, }
@article {pmid37415366, year = {2023}, author = {Su, Y and Chen, L and Yang, J}, title = {Network pharmacology and in vitro experiments reveal that Noscapine induces ROS-mediated apoptosis and cell cycle arrest via PI3K/Akt/FoxO3a signaling pathway in human bladder cancer cells.}, journal = {Current cancer drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/1568009623666230706153936}, pmid = {37415366}, issn = {1873-5576}, abstract = {BACKGROUND: Noscapine (NA) has been demonstrated to have antitussive and antitumoral activities. Nonetheless, the potential mechanism of action on Bladder Cancer (BLCA) is yet to be completely grasped.<br><br>METHODS: The targets of NA action and bladder cancer disease targets were found by the database. Construct the PPI network. Subsequently, conduct pathway enrichment of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) on core targets. A "drug-disease-target-pathway" network map was made. Cytotoxicity was examined via CCK-8 and colony formation assays. Both a scratch test and a transwell assay confirmed that NA was capable of suppressing the invasiveness and migratory potential of bladder cancer cells. Hoechst 33342 staining was used to visualize NA-induced apoptosis in bladder cancer cells. Flow cytometry was employed to investigate the induction of apoptosis, the distribution of the cell cycle, the production of Reactive Oxygen Species (ROS), and the Mitochondrial Membrane Potential (MMP). The Western blot was applied to show the expression of proteins that are implicated in the pathway, cell cycle, apoptotic process, and proliferation.<br><br>RESULTS: 198 Noscapine-BLCA-related targets were obtained. GO functional enrichment analysis yielded 428 entries (P < 0.05 and FDR < 0.05). KEGG pathway enrichment analysis identified 138 representative signaling pathways (P < 0.01 and FDR < 0.01). NA concentration-dependently suppressed cell growth and colony formation, along with the invasiveness and migratory potential of bladder cancer cells, by promoting apoptosis, a cell cycle arrest in the G2/M phase, generation of ROS, and depolarization of MMPs. In addition, Western blotting illustrated that NA down-regulated the protein levels associated with pathway, anti-apoptotic proteins, proliferation-related proteins, and cell cycle promoters but up-regulated pro-apoptotic proteins, cell cycle modulators, and Endoplasmic Reticulum (ER) stress expression. Pretreatment with Acetylcysteine N-acetyl-L-cysteine (NAC) and YS-49 counteracted the influence of NA on ROS induction and apoptosis.<br><br>CONCLUSIONS: Noscapine induces ROS-mediated apoptosis and cell cycle arrest via PI3K/Akt/FoxO3a signaling pathway in human BLCA cells.}, }
@article {pmid37405379, year = {2023}, author = {Gamarra-Morales, Y and Herrera-Quintana, L and Molina-López, J and Vázquez-Lorente, H and Machado-Casas, JF and Castaño-Pérez, J and Pérez-Villares, JM and Planells, E}, title = {Response to Intravenous N-Acetylcysteine Supplementation in Critically Ill Patients with COVID-19.}, journal = {Nutrients}, volume = {15}, number = {9}, pages = {}, pmid = {37405379}, issn = {2072-6643}, support = {Project FIS PI10/1993//Instituto de Salud Carlos III/ ; REF. A-CTS-708-UGR20//Consejer&#xed;a de Educaci&#xf3;n/ ; }, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *COVID-19 ; Critical Illness/therapy ; Glutathione ; Dietary Supplements ; }, abstract = {Administering N-acetylcysteine (NAC) could counteract the effect of free radicals, improving the clinical evolution of patients admitted to the Intensive Care Unit (ICU). This study aimed to investigate the clinical and biochemical effects of administering NAC to critically ill patients with COVID-19. A randomized controlled clinical trial was conducted on ICU patients (n = 140) with COVID-19 and divided into two groups: patients treated with NAC (NAC-treated group) and patients without NAC treatment (control group). NAC was administered as a continuous infusion with a loading dose and a maintenance dose during the study period (from admission until the third day of ICU stay). NAC-treated patients showed higher PaO2/FiO2 (p ≤ 0.014) after 3 days in ICU than their control group counterparts. Moreover, C-reactive protein (p ≤ 0.001), D-dimer (p ≤ 0.042), and lactate dehydrogenase (p ≤ 0.001) levels decreased on the third day in NAC-treated patients. Glutathione concentrations decreased in both NAC-treated (p ≤ 0.004) and control (p ≤ 0.047) groups after 3 days in ICU; whereas glutathione peroxidase did not change during the ICU stay. The administration of NAC manages to improve the clinical and analytical response of seriously ill patients with COVID-19 compared to the control group. NAC is able to stop the decrease in glutathione concentrations.}, }
@article {pmid37401850, year = {2023}, author = {Xiao, P and Chen, X and Dong, Z and Fan, W and Chen, Y and Su, J and Wang, Q and Ma, L}, title = {BNIP3 overexpression may promote myeloma cell apoptosis by enhancing sensitivity to bortezomib via the p38 MAPK pathway.}, journal = {Hematology (Amsterdam, Netherlands)}, volume = {28}, number = {1}, pages = {2231739}, doi = {10.1080/16078454.2023.2231739}, pmid = {37401850}, issn = {1607-8454}, mesh = {Humans ; *p38 Mitogen-Activated Protein Kinases/metabolism/pharmacology ; Bortezomib/pharmacology ; Caspase 3/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism/pharmacology ; *Multiple Myeloma/drug therapy/genetics ; Apoptosis ; Proto-Oncogene Proteins c-bcl-2/metabolism/pharmacology ; Membrane Proteins/genetics/metabolism ; Proto-Oncogene Proteins/metabolism ; }, abstract = {BACKGROUND: BCL2-interacting protein 3 (BNIP3) expression varies among cancers, and its role in myeloma cells remains unknown. We investigated the role of BNIP3 overexpression in myeloma cells, and particularly its effects on apoptosis and mitochondria.<br><br>METHODS: A BNIP3-overexpressing plasmid was transfected into the MM.1S and RPMI8226 myeloma cell lines. Transfected cell apoptosis rate and mitochondrial function were determined via flow cytometry and western blotting. We verified the signaling pathway underlying myeloma cell sensitivity to bortezomib (BTZ).<br><br>RESULTS: Cell lines carrying the BNIP3-overexpressing plasmid exhibited higher rates of apoptosis and expression of Bax and Cleaved caspase 3 protein than the vector group, and less Bcl-2 protein expression than the control cells. Relative to the vector group, BNIP3-overexpressing strains contained more reactive oxygen species (ROS) and exhibited mitochondrial membrane potential (MMP) and dynamin-related protein 1 (Drp1) upregulation and mitofusin-1 (Mfn1) downregulation. BTZ supplementation increased BNIP3 expression. Relative to the BNIP3-OE group, the BNIP3-OE BTZ-treated group exhibited upregulated Bax and Cleaved caspase 3 protein expression, downregulated Bcl-2 protein expression, higher apoptosis rates, ROS levels, MMP, and Drp1 expression, and lower Mfn1 expression. BTZ treatment induced p38 MAPK (mitogen-activated protein kinase) signaling pathway activation in BNIP3-OE cells. Upon adding N-acetylcysteine (NAC) and the p38 MAPK inhibitor SB203580, the affected index levels returned to the baseline.<br><br>CONCLUSIONS: BNIP3 overexpression induced apoptosis in myeloma cells and increased myeloma cell sensitivity to BTZ. These effects may be mediated by the ROS/p38 MAPK signaling pathway.}, }
@article {pmid37399733, year = {2023}, author = {Yi, SJ and Jang, YJ and Lee, S and Cho, SJ and Kang, K and Park, JI and Chae, HJ and Kim, HR and Kim, K}, title = {TMBIM6 deficiency leads to bone loss by accelerating osteoclastogenesis.}, journal = {Redox biology}, volume = {64}, number = {}, pages = {102804}, pmid = {37399733}, issn = {2213-2317}, mesh = {Animals ; Male ; Mice ; *Bone Resorption/genetics ; Cell Differentiation ; *Membrane Proteins/genetics ; Mice, Inbred C57BL ; Mice, Knockout ; *Osteoclasts/cytology ; *Osteogenesis ; RANK Ligand/metabolism ; Signal Transduction ; Transcription Factor RelA/metabolism ; Oxidation-Reduction ; }, abstract = {TMBIM6 is an endoplasmic reticulum (ER) protein that modulates various physiological and pathological processes, including metabolism and cancer. However, its involvement in bone remodeling has not been investigated. In this study, we demonstrate that TMBIM6 serves as a crucial negative regulator of osteoclast differentiation, a process essential for bone remodeling. Our investigation of Tmbim6-knockout mice revealed an osteoporotic phenotype, and knockdown of Tmbim6 inhibited the formation of multinucleated tartrate-resistant acid phosphatase-positive cells, which are characteristic of osteoclasts. Transcriptome and immunoblot analyses uncovered that TMBIM6 exerts its inhibitory effect on osteoclastogenesis by scavenging reactive oxygen species and preventing p65 nuclear localization. Additionally, TMBIM6 depletion was found to promote p65 localization to osteoclast-related gene promoters. Notably, treatment with N-acetyl cysteine, an antioxidant, impeded the osteoclastogenesis induced by TMBIM6-depleted cells, supporting the role of TMBIM6 in redox regulation. Furthermore, we discovered that TMBIM6 controls redox regulation via NRF2 signaling pathways. Our findings establish TMBIM6 as a critical regulator of osteoclastogenesis and suggest its potential as a therapeutic target for the treatment of osteoporosis.}, }
@article {pmid37397917, year = {2023}, author = {Sobh, ZK and Abd-Elhameed, A}, title = {The therapeutic benefit of antioxidants on the outcome of acute aluminum phosphide poisoning: a systemic review and meta-analysis.}, journal = {Toxicology research}, volume = {12}, number = {3}, pages = {345-354}, pmid = {37397917}, issn = {2045-452X}, abstract = {This systematic review and meta-analysis pool evidence available from clinical trials to verify the effect of antioxidants on the outcome of acute aluminum phosphide (AlP) poisoning. A systematic review complied with "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) Protocols. Meta-analysis was conducted on 10 studies that fulfill eligibility criteria. Four antioxidants were implemented: N-Acetyl cysteine (NAC), L-Carnitine, Vitamin E, and Co-enzyme Q10 (Co Q10). Risk of bias, publication bias, and heterogeneity were assessed to ensure the results' reliability. Antioxidants significantly decrease mortality of acute AlP poisoning around three folds (OR = 2.684, 95% CI: 1.764-4.083; P < .001) and decrease the need for intubation and mechanical ventilation by two folds (OR = 2.391, 95% CI 1.480-3.863; P < .001) compared with control. Subgroup analysis revealed that NAC significantly decreases mortality by nearly three folds (OR = 2.752, 95% CI: 1.580-4.792; P < .001), and vitamin E significantly decreases mortality by nearly six folds (OR = 5.667, 95% CI: 1.178-27.254; P = .03) compared with control. L-Carnitine showed a borderline significance (P = .050). Co Q10 decreased the mortality compared with the control; however, the difference was not statistically significant (P = .263). This meta-analysis provides solid evidence regarding the efficacy of antioxidants in improving the outcome of acute AlP poisoning with reference to NAC. Wide confidence interval and small relative weight affect reliability regarding vitamin E efficacy. Future clinical trials and meta-analyses are recommended. To our knowledge, no previous meta-analysis was conducted to investigate the efficacy of treatment modalities for acute AlP poisoning.}, }
@article {pmid37393553, year = {2023}, author = {Ahmad, H and Crotts, MS and Jacobs, JC and Baer, RW and Cox, JL}, title = {Shikonin Causes Non-apoptotic Cell Death in B16F10 Melanoma.}, journal = {Anti-cancer agents in medicinal chemistry}, volume = {23}, number = {16}, pages = {1880-1887}, doi = {10.2174/1871520623666230701000338}, pmid = {37393553}, issn = {1875-5992}, mesh = {Humans ; Apoptosis ; Necrosis ; Reactive Oxygen Species/metabolism ; Cysteine/pharmacology ; Cell Line, Tumor ; *Naphthoquinones/pharmacology ; *Melanoma ; }, abstract = {BACKGROUND: Melanoma treatment is highly resistant to current chemotherapeutic agents. Due to its resistance towards apoptotic cell death, non-apoptotic cell death pathways are sought after.<br><br>OBJECTIVE: We investigated a Chinese herbal medicine, shikonin, and its effect on B16F10 melanoma cells in vitro.<br><br>METHODS: Cell growth of B16F10 melanoma cells treated with shikonin was analyzed using an MTT assay. Shikonin was combined with necrostatin, an inhibitor of necroptosis; caspase inhibitor; 3-methyladenine, an inhibitor of autophagy; or N-acetyl cysteine, an inhibitor of reactive oxygen species. Flow cytometry was used to assess types of cell death resulting from treatment with shikonin. Cell proliferation was also analyzed utilizing a BrdU labeling assay. Monodansylcadaverine staining was performed on live cells to gauge levels of autophagy. Western blot analysis was conducted to identify specific protein markers of necroptosis including CHOP, RIP1, and pRIP1. MitoTracker staining was utilized to identify differences in mitochondrial density in cells treated with shikonin.<br><br>RESULTS: Analysis of MTT assays revealed a large decrease in cellular growth with increasing shikonin concentrations. The MTT assays with necrostatin, 3-methyladenine, and N-acetyl cysteine involvement, suggested that necroptosis, autophagy, and reactive oxygen species are a part of shikonin's mechanism of action. Cellular proliferation with shikonin treatment was also decreased. Western blotting confirmed that shikonin-treated melanoma cells increase levels of stress-related proteins, e.g., CHOP, RIP, pRIP.<br><br>CONCLUSION: Our findings suggest that mainly necroptosis is induced by the shikonin treatment of B16F10 melanoma cells. Induction of ROS production and autophagy are also involved.}, }
@article {pmid37393521, year = {2023}, author = {Chen, M and Hu, C and Yang, L and Guo, Q and Liang, Y and Wang, W}, title = {Saikosaponin-D induces the pyroptosis of lung cancer by increasing ROS and activating the NF-κB/NLRP3/caspase-1/GSDMD pathway.}, journal = {Journal of biochemical and molecular toxicology}, volume = {37}, number = {8}, pages = {e23444}, doi = {10.1002/jbt.23444}, pmid = {37393521}, issn = {1099-0461}, mesh = {Humans ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Pyroptosis ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Caspase 1/metabolism ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Acetylcysteine/pharmacology ; *Lung Neoplasms/drug therapy ; Inflammasomes/metabolism ; Tumor Microenvironment ; Phosphate-Binding Proteins/pharmacology ; Pore Forming Cytotoxic Proteins/metabolism/pharmacology ; }, abstract = {Saikosaponin-D (SSD), an active ingredient in Bupleurum chinense, exerts anticancer effects in various cancers by inhibiting cancer proliferation and inducing apoptosis. However, whether SSD can induce other forms of cell death is unknown. The current study aims to demonstrate that SSD can induce pyroptosis in non-small-cell lung cancer. In this study, HCC827 and A549 non-small-cell lung cancer cells were treated with different concentrations of SSD for 1.5 h. HE and TUNEL staining were used to verify cell damage caused by SSD. Immunofluorescence and western blotting were performed to verify the effect of SSD on the NF-κB/NLRP3/caspase-1/gasdermin D (GSDMD) pathway. Changes in inflammatory factors were detected by ELISAs. Finally, the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) was introduced to verify that SSD induces pyroptosis through the ROS/NF-κB pathway. The results of the HE and TUNEL staining showed that SSD resulted in balloon-like swelling of NSCLC cells accompanied by increased DNA damage. Immunofluorescence and western blot assays confirmed that SSD treatment activated the NLRP3/caspase-1/GSDMD pathway, stimulated an increase in ROS levels and activated NF-κB in lung cancer cells. The ROS scavenger N-acetylcysteine significantly attenuated SSD-induced NF-κB/NLRP3/caspase-1/GSDMD pathway activation and inhibited the release of the inflammatory cytokines IL-1β and IL-18. In conclusion, SSD induced lung cancer cell pyroptosis by inducing ROS accumulation and activating the NF-κB/NLRP3/caspase-1/GSDMD pathway. These experiments lay the foundation for the application of SSD in the treatment of non-small-cell lung cancer and regulation of the lung cancer immune microenvironment.}, }
@article {pmid37392235, year = {2024}, author = {Kouka, M and Bevern, N and Bitter, J and Guntinas-Lichius, O}, title = {N-Acetylcysteine combined with prednisolone treatment shows better hearing outcome than treatment with prednisolone alone for patients with idiopathic sudden sensorineural hearing loss: a retrospective observational study.}, journal = {European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery}, volume = {281}, number = {1}, pages = {107-116}, pmid = {37392235}, issn = {1434-4726}, mesh = {Humans ; Female ; Middle Aged ; Male ; Prednisolone/therapeutic use ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Glucocorticoids ; *Hearing Loss, Sudden/diagnosis/drug therapy ; *Hearing Loss, Sensorineural/diagnosis/drug therapy ; Audiometry, Pure-Tone ; Hearing ; Treatment Outcome ; }, abstract = {OBJECTIVES: Internationally, corticosteroids are still the mainstay treatment for patients with idiopathic sudden sensorineural hearing loss (ISSHL). This is a retrospective monocentric study investing the impact of adding N-acetylcysteine (NAC) to prednisolone treatment on patients with ISSHL at a tertiary university otorhinolaryngology department.<br><br>METHODS: 793 patients (median age 60&#xa0;years; 50.9% women) with a new diagnosis of ISSHL from 2009 to 2015 were included in the study. 663 patients received NAC administration in addition to standard tapered prednisolone treatment. Univariate and multivariable analysis were performed to identify independent factors regarding negative prognosis of hearing recovery.<br><br>RESULTS: Mean initial ISSHL and hearing gain after treatment in 10-tone pure tone audiometry (PTA) were 54.8&#x2009;&#xb1;&#x2009;34.5&#xa0;dB and 15.2&#x2009;&#xb1;&#x2009;21.2&#xa0;dB, respectively. In univariate analysis, treatment with prednisolone and NAC was associated with a positive prognosis of hearing recovery in the Japan classification in 10-tone PTA. In multivariable analysis on Japan classification in 10-tone PTA including all significant factors from univariate analysis, negative prognosis of hearing recovery were age&#x2009;>&#x2009;median (odds ratio [OR] 1.648; 95% confidence interval [CI] 1.139-2.385; p&#x2009;=&#x2009;0.008), diseased opposite ear (OR 3.049; CI 2.157-4.310; p&#x2009;<&#x2009;0.001), pantonal ISSHL (OR 1.891; CI 1.309-2.732; p&#x2009;=&#x2009;0.001) and prednisolone alone without NAC treatment (OR 1.862; CI 1.200-2.887; p&#x2009;=&#x2009;0.005).<br><br>CONCLUSIONS: Prednisolone treatment combined with NAC resulted in better hearing outcomes in patients with ISSHL than treatment without NAC.}, }
@article {pmid37387512, year = {2023}, author = {Sobh, ZK and Kholief, M and Sobh, EK and Balah, MIF}, title = {Exploring research gaps and trends in the management of acute phosphide poisoning: a systematic review.}, journal = {Critical reviews in toxicology}, volume = {53}, number = {3}, pages = {181-206}, doi = {10.1080/10408444.2023.2225539}, pmid = {37387512}, issn = {1547-6898}, mesh = {Animals ; *Pesticides/toxicity ; Evidence Gaps ; Antidotes ; Acetylcysteine/therapeutic use ; Aluminum Compounds/toxicity ; }, abstract = {Metal phosphides are highly toxic pesticides that result in high morbidities and mortalities worldwide. This systematic review included 350 studies that fulfilled the eligibility criteria. There were significant rising trends of studies on acute aluminum phosphide (AlP) and zinc phosphide (Zn3P2) poisoning (p-values = <.001), pointing to an increased number of phosphide-intoxicated patients. Acute AlP poisoning studies represented 81%, 89.3%, and 97.7% of all descriptive, analytical, and experimental interventional studies included in this review, respectively. High AlP poisoning mortality explains great research interest in AlP poisoning. Thus, after 2016, nearly half (49.7%) of studies on acute AlP poisoning were issued. Also, 78.82% of experimental interventional studies on AlP poisoning were published after 2016. The trends of in-vitro, animal, and clinical studies on AlP poisoning significantly increased with p-values equal to .021, <.001, and <.001, respectively. Seventy-nine treatment modalities for acute AlP poisoning were pooled from 124 studies; 39 management-related case reports, 12 in-vitro studies, 39 animal studies, and 34 clinical studies. All therapeutic modalities were summarized to formulate an integrated and comprehensive overview. For clinicians, therapeutic modalities significantly decreased mortality of acute AlP poisoning in clinical trials included extracorporeal membrane oxygenation (ECMO), N-acetyl cysteine (NAC), vitamin E, glucose-insulin-potassium (GIK) infusion, fresh packed RBCs infusion, and GIT decontamination using oils. However, meta-analyses are needed to provide solid evidence regarding their efficacies. To date, there is no effective antidote nor evidence-based standardized protocol for managing acute AlP poisoning. This article outlined the potential research gaps in phosphide poisoning that might promote and direct future medical research in this context.}, }
@article {pmid37386885, year = {2023}, author = {Khalatbari Mohseni, G and Hosseini, SA and Majdinasab, N and Cheraghian, B}, title = {Effects of N-acetylcysteine on oxidative stress biomarkers, depression, and anxiety symptoms in patients with multiple sclerosis.}, journal = {Neuropsychopharmacology reports}, volume = {43}, number = {3}, pages = {382-390}, pmid = {37386885}, issn = {2574-173X}, mesh = {Humans ; *Acetylcysteine/therapeutic use/pharmacology ; Anxiety/drug therapy/etiology ; Biomarkers ; Depression/drug therapy/etiology ; Glutathione/metabolism/pharmacology ; *Multiple Sclerosis/complications/drug therapy ; Oxidative Stress ; }, abstract = {AIM: N-acetylcysteine (NAC), a thiol-containing antioxidant and glutathione (GSH) precursor, attenuates oxidative stress, and possibly improves psychiatric disorders. This study aimed to evaluate the effects of oral NAC on oxidative stress, depression, and anxiety symptoms in patients with multiple sclerosis (MS).<br><br>METHODS: This clinical trial was conducted on 42 MS patients randomly assigned to intervention (n&#x2009;=&#x2009;21) and control (n&#x2009;=&#x2009;21) groups. The intervention group received 600&#x2009;mg of NAC twice daily for 8&#x2009;weeks, and the control group received a placebo with the same prescription form. An analysis of serum malondialdehyde (MDA), serum nitric oxide (NO), and erythrocyte GSH was carried out on both groups, along with a complete blood count. The Hospital Anxiety and Depression Scale (HADS) was used to assess symptoms of depression (HADS-D) and anxiety (HADS-A).<br><br>RESULTS: Compared to the control group, NAC consumption significantly decreased serum MDA concentrations (-0.33 [-5.85-2.50] vs. 2.75 [-0.25-5.22] &#x3bc;mol/L; p&#x2009;=&#x2009;0.03) and HADS-A scores (-1.6&#x2009;&#xb1;&#x2009;2.67 vs. 0.33&#x2009;&#xb1;&#x2009;2.83; p&#x2009;=&#x2009;0.02). No significant changes were observed in serum NO concentrations, erythrocyte GSH levels, and HADS-D scores (p&#x2009;>&#x2009;0.05).<br><br>CONCLUSIONS: Based on the findings of the present study, NAC supplementation for 8&#x2009;weeks decreased lipid peroxidation and improved anxiety symptoms in MS patients. The aforementioned results suggest that adjunctive therapy with NAC can be considered an effective strategy for MS management. Further randomized controlled studies are warranted.}, }
@article {pmid37386836, year = {2023}, author = {Tan, KT and Shih, YH and Gong, JY and Zhang, X and Huang, CY and Su, JH and Sheu, JH and Lin, CC}, title = {Dihydroaustrasulfone alcohol induces apoptosis in nasopharyngeal cancer cells by inducing reactive oxygen species-dependent inactivation of the PI3K/AKT pathway.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {27}, number = {4}, pages = {383-398}, pmid = {37386836}, issn = {1226-4512}, abstract = {Dihydroaustrasulfone alcohol (DA), the synthetic precursor of a natural compound (austrasulfone) isolated from the coral species Cladiella australis, has shown cytotoxic effects against cancer cells. However, it is unknown whether DA has antitumor effects on nasopharyngeal carcinoma (NPC). In this study, we determined the antitumor effects of DA and investigated its mechanism of action on human NPC cells. The MTT assay was used to determine the cytotoxic effect of DA. Subsequently, apoptosis and reactive oxygen species (ROS) analyses were performed by using flow cytometry. Apoptotic and PI3K/AKT pathway-related protein expression was determined using Western blotting. We found that DA significantly reduced the viability of NPC-39 cells and determined that apoptosis was involved in DA-induced cell death. The activity of caspase-9, caspase-8, caspase-3, and PARP induced by DA suggested caspase-mediated apoptosis in DA-treated NPC-39 cells. Apoptosis-associated proteins (DR4, DR5, FAS) in extrinsic pathways were also elevated by DA. The enhanced expression of proapoptotic Bax and decreased expression of antiapoptotic BCL-2 suggested that DA mediated mitochondrial apoptosis. DA reduced the expression of pPI3K and p-AKT in NPC-39 cells. DA also reduced apoptosis after introducing an active AKT cDNA, indicating that DA could block the PI3K/AKT pathway from being activated. DA increased intracellular ROS, but N-acetylcysteine (NAC), a ROS scavenger, reduced DA-induced cytotoxicity. NAC also reversed the chances in pPI3K/AKT expression and reduced DA-induced apoptosis. These findings suggest that ROS-mediates DA-induced apoptosis and PI3K/AKT signaling inactivation in human NPC cells.}, }
@article {pmid37386230, year = {2023}, author = {Li, A and Cao, W}, title = {Downregulation of SODD mediates carnosol-induced reduction in cell proliferation in esophageal adenocarcinoma cells.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {10580}, pmid = {37386230}, issn = {2045-2322}, mesh = {Humans ; Down-Regulation ; Caspase 3 ; *Hydrogen Peroxide ; Reactive Oxygen Species ; *Adenocarcinoma/drug therapy ; Cell Proliferation ; NADPH Oxidases ; }, abstract = {Esophageal adenocarcinoma carries a poor prognosis associated with a 5-year survival rate of 12.5-20%. Therefore, a new therapeutic modality is needed for this lethal tumor. Carnosol is a phenolic diterpene purified from the herbs such as rosemary and Mountain desert sage and has been shown to have anticancer activities in multiple cancers. In this study we examined the effect of carnosol on cell proliferation in esophageal adenocarcinoma cells. We found that carnosol dose-dependently decreased cell proliferation in FLO-1 esophageal adenocarcinoma cells and significantly increased caspase-3 protein, indicating that carnosol decreases cell proliferation and increases cell apoptosis in FLO-1 cells. Carnosol significantly increased H2O2 production and N-acetyl cysteine, a reactive oxygen species (ROS) scavenger, significantly inhibited carnosol-induced decrease in cell proliferation, indicating that ROS may mediate carnosol-induced decrease in cell proliferation. Carnosol-induced decrease in cell proliferation was partially reversed by NADPH oxidase inhibitor apocynin, suggesting that NADPH oxidases may be partially involved in carnosol's effect. In addition, carnosol significantly downregulated SODD protein and mRNA expression and knockdown of SODD significantly inhibited the carnosol-induced reduction in cell proliferation, suggesting that downregulation of SODD may contribute to carnosol-induced reduction in cell proliferation. We conclude that carnosol dose-dependently decreased cell proliferation and significantly increased caspase-3 protein. Carnosol's effect may be through the overproduction of ROS and the downregulation of SODD. Carnosol might be useful for the treatment of esophageal adenocarcinoma.}, }
@article {pmid37385335, year = {2023}, author = {Wang, H and Zhang, Z and Sittirattanayeunyong, S and Hongpaisan, J}, title = {Association of Apolipoprotein E4-related Microvascular Disease in the Alzheimer's Disease Hippocampal CA1 Stratum Radiatum.}, journal = {Neuroscience}, volume = {526}, number = {}, pages = {204-222}, pmid = {37385335}, issn = {1873-7544}, support = {R01 AG058884/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Apolipoprotein E4/genetics/metabolism ; Apolipoproteins E ; CA1 Region, Hippocampal/pathology ; *Echinomycin/metabolism ; Hippocampus/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Current data suggest a hypothesis of vascular pathogenesis for the development and progression of Alzheimer's disease (AD). To investigate this, we studied the association of apolipoprotein E4 (APOE4) gene on microvessels in human autopsy-confirmed AD with and without APOE4, compared with age/sex-matched control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) and endothelial cell density, reflecting aging progression. In AD + APOE4, an increase in strong oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), VEGF, and endothelial cell density were associated with increased diameter of arterioles and perivascular space dilation. In cultured human brain microvascular cells (HBMECs), treatment of ApoE4 protein plus amyloid-β (Aβ) oligomers increased superoxide production and the apoptotic marker cleaved caspase 3, sustained hypoxia inducible factor-1α (HIF-1α) stability that was associated with an increase in MnSOD, VEGF, and cell density. This cell over-proliferation was inhibited with the antioxidants N-acetyl cysteine and MnTMPyP, the HIF-1α inhibitor echinomycin, the VEGFR-2 receptor blocker SU1498, the protein kinase C (PKC) ε knock-down (KD) and the extracellular signal-regulated kinase 1/2 (ERK) inhibitor FR180204. The PKCε KD and echinomycin decreased VEGF and/or ERK. In conclusion, AD capillaries and arterioles in hippocampal CA1 stratum radiatum of non-APOE4 carriers are related with aging, while those in APOE4 carriers with AD are related with pathogenesis of cerebrovascular disease.}, }
@article {pmid37377100, year = {2023}, author = {Zhang, YH and Wang, T and Li, YF and Deng, YN and He, XL and Wang, LJ}, title = {N-acetylcysteine improves autism-like behavior by recovering autophagic deficiency and decreasing Notch-1/Hes-1 pathway activity.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {248}, number = {11}, pages = {966-978}, pmid = {37377100}, issn = {1535-3699}, mesh = {Rats ; Humans ; Animals ; Female ; *Autistic Disorder/drug therapy ; Acetylcysteine/pharmacology ; Behavior, Animal ; *Neuroblastoma ; Valproic Acid/adverse effects ; Disease Models, Animal ; *Prenatal Exposure Delayed Effects/chemically induced ; }, abstract = {N-acetylcysteine (NAC) has been reported to improve social interaction behavior, irritability, self-injury, and anxiety-like behavior in autism. However, the molecular mechanism underlying the therapeutic roles of NAC in autism remains unknown. This study mainly aimed to investigate the therapeutic effect of NAC on valproic acid (VPA)-induced autism model and the underlying mechanisms. Our results showed that NAC ameliorated the deficits in sociability and the anxiety- and repetitive-like behaviors displayed by VPA-exposed rats. In addition, VPA exposure induced autophagic deficiency and enhanced Notch-1/Hes-1 pathway activity based on lowered Beclin-1 and LC3B levels, while increased expression of p62, Notch-1, and Hes-1 expression at the protein level. However, NAC recovered VPA-induced autophagic deficiency and reduced Notch-1/Hes-1 pathway activity in a VPA-exposed autism rat model and SH-SY5Y neural cells. The present results demonstrated that NAC improves autism-like behavioral abnormalities by inactivating Notch-1/Hes-1 signaling pathway and recovering autophagic deficiency. Taken together, this study helps to elucidate a novel molecular mechanism that underlies the therapeutic actions of NAC in autism and suggests its potential to ameliorate behavioral abnormalities in neurodevelopmental disorders.}, }
@article {pmid37374326, year = {2023}, author = {Cervantes-Pérez, LA and Cervantes-Guevara, G and Cervantes-Pérez, E and Cervantes-Cardona, GA and Nápoles-Echauri, A and González-Ojeda, A and Fuentes-Orozco, C and Cervantes-Pérez, G and Reyes-Torres, CA and Hernández-Mora, FJ and Ron-Magaña, AL and Vázquez-Beltrán, JC and Hernández-Rivas, MI and Ramírez-Ochoa, S}, title = {Evaluation of the Effects of Atorvastatin and N-Acetyl Cysteine on Platelet Counts in Patients with Primary Immune Thrombocytopenia: An Exploratory Clinical Trial.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {59}, number = {6}, pages = {}, pmid = {37374326}, issn = {1648-9144}, mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Atorvastatin/pharmacology/therapeutic use ; Platelet Count ; *Purpura, Thrombocytopenic, Idiopathic/drug therapy ; *Thrombocytopenia/drug therapy ; Treatment Outcome ; }, abstract = {Objective: We aimed to evaluate the efficacy of the combination of atorvastatin and N-acetyl cysteine in increasing platelet counts in patients with immune thrombocytopenia who were resistant to steroid therapy or had a relapse after treatment. Material and Methods: The patients included in this study received oral treatment of atorvastatin at a dose of 40 mg daily and N-acetyl cysteine at a dose of 400 mg every 8 h. The desired treatment duration was 12 months, but we included patients who completed at least 1 month of treatment in the analysis. The platelet counts were measured prior to the administration of the study treatment and in the first, third, sixth, and twelfth months of treatment (if available). A p value < 0.05 was considered statistically significant. Results: We included 15 patients who met our inclusion criteria. For the total treatment duration, the global response was 60% (nine patients); eight patients (53.3%) had a complete response and one patient (6.7%) had a partial response. Six patients (40%) were considered as having undergone treatment failure. Of the responder group, five patients maintained a complete response after treatment (55.5%), three patients maintained a partial response (33.3%), and one patient (11.1%) lost their response to the treatment. All of the patients in the responder group had significant increases in their platelet counts after treatment (p < 0.05). Conclusion: This study provides evidence of a possible treatment option for patients with primary immune thrombocytopenia. However, further studies are needed.}, }
@article {pmid37372022, year = {2023}, author = {Notaro, A and Lauricella, M and Di Liberto, D and Emanuele, S and Giuliano, M and Attanzio, A and Tesoriere, L and Carlisi, D and Allegra, M and De Blasio, A and Calvaruso, G and D'Anneo, A}, title = {A Deadly Liaison between Oxidative Injury and p53 Drives Methyl-Gallate-Induced Autophagy and Apoptosis in HCT116 Colon Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {37372022}, issn = {2076-3921}, support = {FFR-D15 D'Anneo; FFR-D03-Lauricella//This work was partially sustained by Finalized Research Funding (FFR 2022), FFR-D15 D'Anneo and FFR-D03-Lauricella, Universit&#xe0; degli Studi di Palermo, Palermo, Italy./ ; }, abstract = {Methyl gallate (MG), which is a gallotannin widely found in plants, is a polyphenol used in traditional Chinese phytotherapy to alleviate several cancer symptoms. Our studies provided evidence that MG is capable of reducing the viability of HCT116 colon cancer cells, while it was found to be ineffective on differentiated Caco-2 cells, which is a model of polarized colon cells. In the first phase of treatment, MG promoted both early ROS generation and endoplasmic reticulum (ER) stress, sustained by elevated PERK, Grp78 and CHOP expression levels, as well as an upregulation in intracellular calcium content. Such events were accompanied by an autophagic process (16-24 h), where prolonging the time (48 h) of MG exposure led to cellular homeostasis collapse and apoptotic cell death with DNA fragmentation and p53 and γH2Ax activation. Our data demonstrated that a crucial role in the MG-induced mechanism is played by p53. Its level, which increased precociously (4 h) in MG-treated cells, was tightly intertwined with oxidative injury. Indeed, the addition of N-acetylcysteine (NAC), which is a ROS scavenger, counteracted the p53 increase, as well as the MG effect on cell viability. Moreover, MG promoted p53 accumulation into the nucleus and its inhibition by pifithrin-α (PFT-α), which is a negative modulator of p53 transcriptional activity, enhanced autophagy, increased the LC3-II level and inhibited apoptotic cell death. These findings provide new clues to the potential action of MG as a possible anti-tumor phytomolecule for colon cancer treatment.}, }
@article {pmid37371987, year = {2023}, author = {Caridade-Silva, R and Araújo, B and Martins-Macedo, J and Teixeira, FG}, title = {N-Acetylcysteine Treatment May Compensate Motor Impairments through Dopaminergic Transmission Modulation in a Striatal 6-Hydroxydopamine Parkinson's Disease Rat Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {37371987}, issn = {2076-3921}, support = {POCI-01-0145-FEDER-029751//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; MB-28-2019//Santa Casa da Miseric&#xf3;rdia de Lisboa/ ; }, abstract = {Preventing degeneration and the loss of dopaminergic neurons (DAn) in the brain while mitigating motor symptoms remains a challenge in Parkinson's Disease (PD) treatment development. In light of this, developing or repositioning potential disease-modifying approaches is imperative to achieve meaningful translational gains in PD research. Under this concept, N-acetylcysteine (NAC) has revealed promising perspectives in preserving the dopaminergic system capability and modulating PD mechanisms. Although NAC has been shown to act as an antioxidant and (neuro)protector of the brain, it has yet to be acknowledged how this repurposed drug can improve motor symptomatology and provide disease-modifying properties in PD. Therefore, in the present work, we assessed the impact of NAC on motor and histological deficits in a striatal 6-hydroxydopamine (6-OHDA) rat model of PD. The results revealed that NAC enhanced DAn viability, as we found that it could restore dopamine transporter (DAT) levels compared to the untreated 6-OHDA group. Such findings were positively correlated with a significant amelioration in the motor outcomes of the 6-OHDA-treated animals, demonstrating that NAC may, somehow, be a modulator of PD degenerative mechanisms. Overall, we postulated a proof-of-concept milestone concerning the therapeutic application of NAC. Nevertheless, it is extremely important to understand the complexity of this drug and how its therapeutical properties interact with the cellular and molecular PD mechanisms.}, }
@article {pmid37371878, year = {2023}, author = {Balázs, G and Balajthy, A and Seri, I and Hegyi, T and Ertl, T and Szabó, T and Röszer, T and Papp, &#xc1; and Balla, J and Gáll, T and Balla, G}, title = {Prevention of Chronic Morbidities in Extremely Premature Newborns with LISA-nCPAP Respiratory Therapy and Adjuvant Perinatal Strategies.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {37371878}, issn = {2076-3921}, support = {11003//E&#xf6;tv&#xf6;s Lor&#xe1;nd Research Network/ ; OTKA-K 132828//Hungarian Government grants/ ; OTKA NKFI 142939//Hungarian Government grants/ ; TKP2021-EGA-18//Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund/ ; }, abstract = {Less invasive surfactant administration techniques, together with nasal continuous airway pressure (LISA-nCPAP) ventilation, an emerging noninvasive ventilation (NIV) technique in neonatology, are gaining more significance, even in extremely premature newborns (ELBW), under 27 weeks of gestational age. In this review, studies on LISA-nCPAP are compiled with an emphasis on short- and long-term morbidities associated with prematurity. Several perinatal preventative and therapeutic investigations are also discussed in order to start integrated therapies as numerous organ-saving techniques in addition to lung-protective ventilations. Two thirds of immature newborns can start their lives on NIV, and one third of them never need mechanical ventilation. With adjuvant intervention, these ratios are expected to be increased, resulting in better outcomes. Optimized cardiopulmonary transition, especially physiologic cord clamping, could have an additively beneficial effect on patient outcomes gained from NIV. Organ development and angiogenesis are strictly linked not only in the immature lung and retina, but also possibly in the kidney, and optimized interventions using angiogenic growth factors could lead to better morbidity-free survival. Corticosteroids, caffeine, insulin, thyroid hormones, antioxidants, N-acetylcysteine, and, moreover, the immunomodulatory components of mother's milk are also discussed as adjuvant treatments, since immature newborns deserve more complex neonatal interventions.}, }
@article {pmid37371872, year = {2023}, author = {Petricca, S and Carnicelli, V and Luzi, C and Cinque, B and Celenza, G and Iorio, R}, title = {Oxidative Stress, Cytotoxic and Inflammatory Effects of Azoles Combinatorial Mixtures in Sertoli TM4 Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {6}, pages = {}, pmid = {37371872}, issn = {2076-3921}, support = {07-RIA 2021 IORIO ROBERTO//intramural "DISCAB GRANT 2021 (code 07-RIA 2021 IORIO ROBERTO)"/ ; grant number CUP E11I18000300005//grant from MIUR (Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca, Italy) to Roberto Iorio./ ; }, abstract = {Triazole and imidazole fungicides are an emerging class of contaminants with an increasing and ubiquitous presence in the environment. In mammals, their reproductive toxicity has been reported. Concerning male reproduction, a combinatorial activity of tebuconazole (TEB; triazole fungicide) and econazole (ECO; imidazole compound) in inducing mitochondrial impairment, energy depletion, cell cycle arrest, and the sequential activation of autophagy and apoptosis in Sertoli TM4 cells (SCs) has recently been demonstrated. Given the strict relationship between mitochondrial activity and reactive oxygen species (ROS), and the causative role of oxidative stress (OS) in male reproductive dysfunction, the individual and combined potential of TEB and ECO in inducing redox status alterations and OS was investigated. Furthermore, considering the impact of cyclooxygenase (COX)-2 and tumor necrosis factor-alpha (TNF-α) in modulating male fertility, protein expression levels were assessed. In the present study, we demonstrate that azoles-induced cytotoxicity is associated with a significant increase in ROS production, a drastic reduction in superoxide dismutase (SOD) and GSH-S-transferase activity levels, and a marked increase in the levels of oxidized (GSSG) glutathione. Exposure to azoles also induced COX-2 expression and increased TNF-α production. Furthermore, pre-treatment with N-acetylcysteine (NAC) mitigates ROS accumulation, attenuates COX-2 expression and TNF-α production, and rescues SCs from azole-induced apoptosis, suggesting a ROS-dependent molecular mechanism underlying the azole-induced cytotoxicity.}, }
@article {pmid37371417, year = {2023}, author = {Du, Y and Chen, L and Qiao, H and Zhang, L and Yang, L and Zhang, P and Wang, J and Zhang, C and Jiang, W and Xu, R and Zhang, X}, title = {Hydrogen-Rich Saline-A Novel Neuroprotective Agent in a Mouse Model of Experimental Cerebral Ischemia via the ROS-NLRP3 Inflammasome Signaling Pathway In Vivo and In Vitro.}, journal = {Brain sciences}, volume = {13}, number = {6}, pages = {}, pmid = {37371417}, issn = {2076-3425}, support = {Grant number: 81974184//the National Natural Science Foundation of China/ ; grant number : 20211706//the Key Project of Medical Science Research of Hebei Province in 2021/ ; }, abstract = {BACKGROUND: Our previous research revealed that inflammation plays an important role in the pathophysiology of cerebral ischemia. The function of the NOD-like receptor protein 3 (NLRP3) inflammasome is to activate the inflammatory process. Recent findings suggest that reactive oxygen species (ROS) are essential secondary messengers that activate the NLRP3 inflammasome. Hydrogen-rich saline (HS) has attracted attention for its anti-inflammatory properties. However, the protective effect and possible mechanism of HSin brain ischemia have not been well elucidated.<br><br>METHODS: To test the therapeutic effect of HS, we established a mouse model of distal middle cerebral artery occlusion (dMCAO) and an in vitro model of BV2 cells induced by lipopolysaccharide (LPS). The ROS scavenger N-acetylcysteine (NAC) was used to investigate the underlying mechanisms of HS.<br><br>RESULTS: HS significantly improved neurological function, reduced infarct volume, and increased cerebral blood flow in a dMCAO mouse model. ROS, NLRP3, Caspase-1, and IL-1&#x3b2; expression increased after cerebral ischemia, and this was reversed by HS treatment. In BV2 cells, the application of NAC further demonstrated that HS could effectively inhibit the expression of the ROS-activated NLRP3 inflammasome.<br><br>CONCLUSIONS: HS, as a novel therapeutic option, could exert protect the brain by inhibiting the activation of the ROS-NLRP3 signaling pathway after cerebral ischemia.}, }
@article {pmid37370701, year = {2023}, author = {Khalil, R and Green, RJ and Sivakumar, K and Varandani, P and Bharadwaj, S and Mohapatra, SS and Mohapatra, S}, title = {Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer.}, journal = {Cancers}, volume = {15}, number = {12}, pages = {}, pmid = {37370701}, issn = {2072-6694}, support = {I01 BX003413/BX/BLRD VA/United States ; IK6 BX004212/BX/BLRD VA/United States ; }, abstract = {Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)-a herbal compound-and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.}, }
@article {pmid37368450, year = {2023}, author = {Choudhary, M and Pereira, J and Davidson, EB and Colee, J and Santra, S and Jones, JB and Paret, ML}, title = {Improved Persistence of Bacteriophage Formulation with Nano N-Acetylcysteine-Zinc Sulfide and Tomato Bacterial Spot Disease Control.}, journal = {Plant disease}, volume = {107}, number = {12}, pages = {3933-3942}, doi = {10.1094/PDIS-02-23-0255-RE}, pmid = {37368450}, issn = {0191-2917}, mesh = {*Bacteriophages ; Acetylcysteine/pharmacology ; *Solanum lycopersicum ; *Zinc Oxide ; Bacteria ; *Bacterial Infections ; }, abstract = {Bacteriophages are biocontrol agents used to manage bacterial diseases. They have long been used against plant pathogenic bacteria; however, several factors impede their use as a reliable disease management strategy. Short-lived persistence on plant surfaces under field conditions results mainly from rapid degradation by exposure to ultraviolet (UV) light. Currently, there are no effective commercial formulations that protect phages from UV. The phage ΦXp06-02-1, which lyses strains of the tomato bacterial spot pathogen Xanthomonas perforans, was mixed with different concentrations of the nanomaterial N-acetylcysteine surface-coated manganese-doped zinc sulfide (NAC-ZnS; 3.5 nm). In vitro, NAC-ZnS at 10,000 μg/ml formulated phage, when exposed to UV for 1 min, provided statistically equivalent plaque-forming unit (PFU) recovery as phages that were not exposed to UV. NAC-ZnS had no negative effect on the phage's ability to lyse bacterial cells under in vitro conditions. NAC-ZnS reduced phage degradation over time in comparison with the nontreated control, whereas N-acetylcysteine-zinc oxide (NAC-ZnO) had no effect. In fluorescent light, without UV exposure, NAC-ZnO-formulated phages were more infective than NAC-ZnS-formulated phages. The nanomaterial-phage mixture did not cause any phytotoxicity when applied to tomato plants. Following exposure to sunlight, the NAC-ZnS formulation improved phage persistence in the phyllosphere by 15 times compared with nonformulated phages. NAC-ZnO-formulated phage populations were undetectable within 32 h, whereas NAC-ZnS-formulated phage populations were detected at 10[3] PFU/g. At 4 h of sunlight exposure, NAC-ZnS-formulated phages at 1,000 μg/ml significantly reduced tomato bacterial spot disease severity by 16.4% compared with nonformulated phages. These results suggest that NAC-ZnS can be used to improve the efficacy of phages for bacterial diseases.}, }
@article {pmid37368329, year = {2023}, author = {Fesharaki Zadeh, A and Arnsten, AFT and Wang, M}, title = {Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID.}, journal = {Neurology international}, volume = {15}, number = {2}, pages = {725-742}, pmid = {37368329}, issn = {2035-8385}, support = {P30 AG066508/AG/NIA NIH HHS/United States ; R01 AG061190/AG/NIA NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, abstract = {Sustained cognitive deficits are a common and debilitating feature of "long COVID", but currently there are no FDA-approved treatments. The cognitive functions of the dorsolateral prefrontal cortex (dlPFC) are the most consistently afflicted by long COVID, including deficits in working memory, motivation, and executive functioning. COVID-19 infection greatly increases kynurenic acid (KYNA) and glutamate carboxypeptidase II (GCPII) in brain, both of which can be particularly deleterious to PFC function. KYNA blocks both NMDA and nicotinic-alpha-7 receptors, the two receptors required for dlPFC neurotransmission, and GCPII reduces mGluR3 regulation of cAMP-calcium-potassium channel signaling, which weakens dlPFC network connectivity and reduces dlPFC neuronal firing. Two agents approved for other indications may be helpful in restoring dlPFC physiology: the antioxidant N-acetyl cysteine inhibits the production of KYNA, and the α2A-adrenoceptor agonist guanfacine regulates cAMP-calcium-potassium channel signaling in dlPFC and is also anti-inflammatory. Thus, these agents may be helpful in treating the cognitive symptoms of long COVID.}, }
@article {pmid37368165, year = {2023}, author = {Barrera-Chimal, J and Henley, N and Grant, MP and Cenatus, S and Geraldes, P and Pichette, V and Gerarduzzi, C}, title = {Tungsten toxicity on kidney tubular epithelial cells induces renal inflammation and M1-macrophage polarization.}, journal = {Cell biology and toxicology}, volume = {39}, number = {6}, pages = {3061-3075}, pmid = {37368165}, issn = {1573-6822}, mesh = {Male ; Mice ; Animals ; *Tungsten/toxicity ; Culture Media, Conditioned ; *Kidney ; Macrophages ; Epithelial Cells ; NF-kappa B ; Inflammation/chemically induced ; }, abstract = {Tungsten is widely used in medical, industrial, and military applications. The environmental exposure to tungsten has increased over the past several years, and few studies have addressed its potential toxicity. In this study, we evaluated the effects of chronic oral tungsten exposure (100 ppm) on renal inflammation in male mice. We found that 30- or 90-day tungsten exposure led to the accumulation of LAMP1-positive lysosomes in renal tubular epithelial cells. In addition, the kidneys of mice exposed to tungsten showed interstitial infiltration of leukocytes, myeloid cells, and macrophages together with increased levels of proinflammatory cytokines and p50/p65-NFkB subunits. In proximal tubule epithelial cells (HK-2) in vitro, tungsten induced a similar inflammatory status characterized by increased mRNA levels of CSF1, IL34, CXCL2, and CXCL10 and NFkB activation. Moreover, tungsten exposure reduced HK-2 cell viability and enhanced reactive oxygen species generation. Conditioned media from HK-2 cells treated with tungsten induced an M1-proinflammatory polarization of RAW macrophages as evidenced by increased levels of iNOS and interleukin-6 and decreased levels of the M2-antiinflammatory marker CD206. These effects were not observed when RAW cells were exposed to conditioned media from HK-2 cells treated with tungsten and supplemented with the antioxidant N-acetylcysteine (NAC). Similarly, direct tungsten exposure induced M1-proinflammatory polarization of RAW cells that was prevented by NAC co-treatment. Altogether, our data suggest that prolonged tungsten exposure leads to oxidative injury in the kidney ultimately leading to chronic renal inflammation characterized by a proinflammatory status in kidney tubular epithelial cells and immune cell infiltration.}, }
@article {pmid37360438, year = {2023}, author = {Maria Francis, Y and Karunakaran, B and Ashfaq, F and Yahia Qattan, M and Ahmad, I and Alkhathami, AG and Idreesh Khan, M and Varadhan, M and Govindan, L and Ponnusamy Kasirajan, S}, title = {Mercuric Chloride Induced Nephrotoxicity: Ameliorative Effect of Carica papaya Leaves Confirmed by Histopathology, Immunohistochemistry, and Gene Expression Studies.}, journal = {ACS omega}, volume = {8}, number = {24}, pages = {21696-21708}, pmid = {37360438}, issn = {2470-1343}, abstract = {The present study analyzes the efficacy of the ethanolic extract of C. papaya leaves (ECP) against HgCl2-induced nephrotoxicity. The effects on the biochemical and percentage of body and organ weight against HgCl2-induced nephrotoxicity in female Wistar rats were studied. Wistar rats were divided into five groups with six animals in each group: control, HgCl2 (2.5 mg/kg b.w.), N-acetylcysteine (NAC 180 mg/kg) + HgCl2, ECP (300 mg/kg b.w.) + HgCl2, and ECP (600 mg/kg) + HgCl2 groups. After 28 days of study, animals were sacrificed on the 29th day to harvest the blood and kidneys for further analysis. The effect ECP was analyzed by immunohistochemistry (NGAL) and real-time PCR (KIM-1 and NGAL mRNA) in HgCl2-induced nephrotoxicity. The results revealed that the HgCl2 group showed prominent damage in the proximal tubules and glomerulus of nephrons and enormous expression of NGAL in immunohistochemistry and KIM-1 and NGAL in real-time PCR compared to the control group. The simultaneous pretreatment with NAC (180 mg/kg) and ECP (600 and 300 mg/kg) reduced renal damage and expression of NGAL in immunohistochemistry and KIM-1 and NGAL gene in real-time PCR. This study attests to the nephroprotective effect of ECP against HgCl2-induced toxicity.}, }
@article {pmid37360166, year = {2023}, author = {Mazumdar, R and Eberhart, JK}, title = {Loss of Nicotinamide nucleotide transhydrogenase sensitizes embryos to ethanol-induced neural crest and neural apoptosis via generation of reactive oxygen species.}, journal = {Frontiers in neuroscience}, volume = {17}, number = {}, pages = {1154621}, pmid = {37360166}, issn = {1662-4548}, support = {T32 AA007471/AA/NIAAA NIH HHS/United States ; }, abstract = {Fetal alcohol spectrum disorders (FASD) are a continuum of birth defects caused by prenatal alcohol exposure. FASD are the most common environmentally induced birth defect and are highly variable. The genetics of an individual influence the severity of their FASD phenotype. However, the genes that sensitize an individual to ethanol-induced birth defects are largely unknown. The ethanol-sensitive mouse substrain, C57/B6J, carries several known mutations including one in Nicotinamide nucleotide transhydrogenase (Nnt). Nnt is a mitochondrial transhydrogenase thought to have an important role in detoxifying reactive oxygen species (ROS) and ROS has been implicated in ethanol teratogenesis. To directly test the role of Nnt in ethanol teratogenesis, we generated zebrafish nnt mutants via CRISPR/Cas9. Zebrafish embryos were dosed with varying concentrations of ethanol across different timepoints and assessed for craniofacial malformations. We utilized a ROS assay to determine if this could be a contributing factor of these malformations. We found that exposed and unexposed mutants had higher levels of ROS compared to their wildtype counterparts. When treated with ethanol, nnt mutants experienced elevated apoptosis in the brain and neural crest, a defect that was rescued by administration of the antioxidant, N-acetyl cysteine (NAC). NAC treatment also rescued most craniofacial malformations. Altogether this research demonstrates that ethanol-induced oxidative stress leads to craniofacial and neural defects due to apoptosis in nnt mutants. This research further supports the growing body of evidence implicating oxidative stress in ethanol teratogenesis. These findings suggest that antioxidants can be used as a potential therapeutic in the treatment of FASD.}, }
@article {pmid37356397, year = {2023}, author = {Zhang, Q and Liu, W and Li, Q and Zeng, Y and Wu, M and Wu, T and Guo, S and Wang, L and Zhao, D and Yi, D and Hou, Y}, title = {Protective effects and mechanisms of N-acetylcysteine on indomethacin-induced intestinal injury in a porcine model.}, journal = {Ecotoxicology and environmental safety}, volume = {262}, number = {}, pages = {115173}, doi = {10.1016/j.ecoenv.2023.115173}, pmid = {37356397}, issn = {1090-2414}, abstract = {This study aimed to investigate the effect of N-acetylcysteine (NAC) on indomethacin (IDMT)-induced intestinal injury in a piglet model and explore the underlying molecular mechanisms. Piglets were randomly divided into 3 treatment groups: (1) control group; (2) IDMT group; (3) NAC+IDMT group. The results showed that NAC administration significantly increased the average daily gain of piglets, attenuated the intestine hyperemia, and restored normal jejunal morphology. Further studies indicated that NAC administration significantly increased plasma citrulline concentration and jejunal villin expression, but decreased the content of proinflammatory cytokines in plasma and jejunum of IDMT-stimulated piglets. NAC administration selectively decreased the proportion of eosinophils but not neutrophils in plasma. Furthermore, NAC administration significantly increased the activities of superoxide dismutase and catalase in plasma but decreased the concentrations of hydrogen peroxide (plasma) and malondialdehyde (plasma and jejunum), as well as the activity of myeloperoxidase (jejunum) when comparing NAC+IDMT group with IDMT group. Gene Ontology analysis showed that the significantly enriched molecular function term was "ubiquitin-like protein ligase binding" for NAC+IDMT versus IDMT differentially regulated genes. In the biological process category, differentially regulated genes of NAC+IDMT versus IDMT were mainly enriched in immune-related terms. The major enrichments for differentially regulated proteins (DRPs) of NAC+IDMT versus IDMT were terms involved in lipid metabolism and immune response. KEGG pathway enrichment analysis showed that "arginine biosynthesis" was a significant enrichment term for the DRPs of NAC+IDMT versus IDMT. Further studies demonstrated that NAC administration up-regulated argininosuccinate synthase 1 mRNA expression and down-regulated arginase mRNA expression in the jejunum of IDMT-stimulated piglets. Moreover, the content of nitric oxide was restored to a normal level with the reduction of nitric oxide synthase activity. NAC administration ameliorated intestinal injury in IDMT-challenged piglets by enhancing antioxidant and anti-inflammatory functions and modulating arginine metabolism in the small intestine.}, }
@article {pmid37351787, year = {2023}, author = {Kim, B and Lee, SM and Park, SJ and Lee, S and Kim, T}, title = {Role of Klotho and N-acetylcysteine in Oxidative Stress Associated with the Vitrification of Ovarian Tissue Cytoprotective Function of Klotho in Cryopreservation.}, journal = {Tissue engineering and regenerative medicine}, volume = {20}, number = {4}, pages = {637-646}, pmid = {37351787}, issn = {2212-5469}, support = {NRF-2016R1C1B3015250//National Research Foundation of Korea Grant/ ; }, mesh = {*Vitrification ; *Acetylcysteine/pharmacology/metabolism ; Reactive Oxygen Species/metabolism/pharmacology ; Cryopreservation/methods ; Oxidative Stress ; }, abstract = {BACKGROUND: Cryopreservation can cause mechanical and chemical stress, ultimately leading to the formation of reactive oxygen species (ROS) and oxidative stress. ROS inhibits the expression of antioxidant enzymes in cells, resulting in increased DNA fragmentation and apoptosis. In this paper, we used a vitrification method that has the advantage of producing less ice crystal formation, cost-effectiveness, and time efficiency during cryopreservation. The objective of this paper is to evaluate the degree of protection of ovarian tissue against oxidative stress when N-acetylcysteine (NAC) and Klotho proteins are treated in the vitrification process of ovarian tissue. METHODS: The control group and the cryopreservation groups were randomly assigned, and treated NAC, Klotho, or the combination (NAC + Klotho). The cell morphological change, DNA damage, senescence, and apoptosis of each group after the freeze-thaw process were compared using transmission electron microscopy, immunohistochemistry, and western blot analysis.<br><br>RESULTS: Both NAC and Klotho were found to be more effective at protecting against DNA damage than the control; however, DNA damage was greater in the NAC&#x2009;+&#x2009;Klotho group than in the group treated with NAC and Klotho, respectively. DNA damage and cellular senescence were also reduced during the vitrification process when cells were treated with NAC, Klotho, or the combination (NAC&#x2009;+&#x2009;Klotho). NAC increased apoptosis during cryopreservation, whereas Klotho inhibited apoptosis and NAC-induced apoptosis.<br><br>CONCLUSION: This study highlights Klotho's benefits in inhibiting DNA damage, cell senescence, and apoptosis, including NAC-induced apoptosis, despite its unclear role in vitrification.}, }
@article {pmid37350963, year = {2023}, author = {Peng, N and Geng, Y and Ouyang, J and Liu, S and Yuan, F and Wan, Y and Chen, W and Yu, B and Tang, Y and Su, L and Liang, H and Wang, JH and Liu, J}, title = {Endothelial glycocalyx injury is involved in heatstroke-associated coagulopathy and protected by N-acetylcysteine.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1159195}, pmid = {37350963}, issn = {1664-3224}, mesh = {Rats ; Animals ; Acetylcysteine/pharmacology ; Endothelial Cells ; Glycocalyx ; Reactive Oxygen Species ; Hydrogen Peroxide ; Retrospective Studies ; *Blood Coagulation Disorders/drug therapy/etiology ; *Heat Stroke/drug therapy ; *Sepsis/complications ; }, abstract = {INTRODUCTION: Damage to endothelial glycocalyx (EGCX) can lead to coagulation disorders in sepsis. Heat stroke (HS) resembles sepsis in many aspects; however, it is unclear whether EGCX injury is involved in its pathophysiology. The purpose of this study was to examine the relationship between the damage of EGCX and the development of coagulation disorders during HS.<br><br>METHODS: We retrospectively collected 159 HS patients and analyzed coagulation characteristics and prognosis of HS patients with or without disseminated intravascular coagulation (DIC). We also replicated a rat HS model and measured coagulation indexes, pulmonary capillary EGCX injury in HS rats. Finally, we evaluated the effect of the antioxidant N-acetylcysteine (NAC) on HS-initiated EGCX injury and coagulation disorders.<br><br>RESULTS: Clinical data showed that HS patients complicated with DIC had a higher risk of death than HS patients without DIC. In a rat HS model, we found that rats subjected to heat stress developed hypercoagulability and platelet activation at the core body temperature of 43&#xb0;C, just before the onset of HS. At 24&#xa0;h of HS, the rats showed a consumptive hypo-coagulation state. The pulmonary capillary EGCX started to shed at 0&#xa0;h of HS and became more severe at 24&#xa0;h of HS. Importantly, pretreatment with NAC substantially alleviated EGCX damage and reversed the hypo-coagulation state in HS rats. Mechanically, HS initiated reactive oxidative species (ROS) generation, while ROS could directly cause EGCX damage. Critically, NAC protected against EGCX injury by attenuating ROS production in heat-stressed or hydrogen peroxide (H2O2)-stimulated endothelial cells.<br><br>DISCUSSION: Our results indicate that the poor prognosis of HS patients correlates with severe coagulation disorders, coagulation abnormalities in HS rats are associated with the damage of EGCX, and NAC improves HS-induced coagulopathy, probably through its protection against EGCX injury by preventing ROS generation.}, }
@article {pmid37349241, year = {2023}, author = {Iqbal, P and Karki, P and Abdelmottaleb, W and Al-Khazraji, Y and Mirza Fawad, A and Madani, K and Ahmed, F and Nawaz, S and Jamshaid, MB and Fernando, QM}, title = {Asymptomatic COVID-19 presenting with features of mixed pattern acute liver injury in a young healthy female, a case report.}, journal = {Journal of infection and public health}, volume = {16}, number = {9}, pages = {1481-1484}, pmid = {37349241}, issn = {1876-035X}, mesh = {Humans ; Female ; *COVID-19 ; Liver/diagnostic imaging ; Acetylcysteine ; }, abstract = {COVID-19 associated severe acute liver injury in a young healthy patient has not been reported much in the literature. And currently, there are no standard management guidelines. We want to report a case of acute liver injury of mixed pattern in a young healthy female with asymptomatic COVID-19 infection. She presented with abdominal pain, nausea, vomiting and yellowish discoloration of her skin. Further laboratory investigations revealed mixed pattern liver injury with highly raised liver enzymes. She was managed with N-acetyl cysteine protocol and monitoring of her liver enzymes. Other causes of acute liver injury were ruled out. She remained stable during her hospital stay and follow up. Our aim is to highlight the significance of acute liver injury in COVID 19 patients that may lead to fatal outcomes if not managed and monitored accordingly.}, }
@article {pmid37348685, year = {2023}, author = {Cui, J and Xu, T and Lv, H and Guo, MY}, title = {Zinc deficiency causes oxidative stress, endoplasmic reticulum stress, apoptosis and inflammation in hepatocytes in grass carp.}, journal = {Fish &amp; shellfish immunology}, volume = {139}, number = {}, pages = {108905}, doi = {10.1016/j.fsi.2023.108905}, pmid = {37348685}, issn = {1095-9947}, mesh = {Animals ; Diet ; *Carps ; Inflammation/chemically induced/veterinary ; Oxidative Stress ; Apoptosis ; Hepatocytes ; *Malnutrition ; Zinc/pharmacology ; Endoplasmic Reticulum Stress ; RNA, Messenger ; }, abstract = {A lack of the trace element zinc (Zn) in freshwater environments causes slow growth and malnutrition and affects the normal biological functions of organisms. In this study, a Zn deficiency model of grass carp hepatocytes was established with TPEN. Acetylcysteine (NAC) was used as an inhibitor. TPEN was added to L8824 cell culture medium, and LDH, AST, ALT, and AKP activities were enhanced in a Zn-deficient environment, leading to abnormal hepatopancreas function. Fluorescence microscopy showed an increase in ROS levels, and antioxidant enzyme activity assays revealed that SOD, CAT, GSH-PX, and T-AOC activities were decreased, indicating oxidative stress caused by Zn deficiency. The RT‒PCR results showed that the mRNA expression of GRP78, PERK, EIF2α, ATF4, and Chop was increased due to the addition of TPEN. Calcium kits showed increased Ca[2+] levels. The RT‒PCR results showed that the mRNA expression levels of Caspase-12, Caspase-9, Caspase-3, and PARP apoptotic were increased due to the addition of TPEN. RT‒PCR and ELISA showed that the expression levels of interleukin-1β (IL-1β), interleukin-8 (IL-8), tumour necrosis factor (TNF-α), and inducible nitric oxide synthase (iNOS) were increased. This led to the conclusion that Zn deficiency in the freshwater environment caused inflammation and apoptosis in hepatocytes in grass carp. For the first time, apoptosis caused by endoplasmic reticulum stress in grass carp hepatocytes due to Zn deficiency was studied in the context of Ca[2+]. The present study provided some insight into the adverse effects of Zn deficiency in freshwater environments on fish.}, }
@article {pmid37333506, year = {2023}, author = {Chethan, GE and De, UK and Singh, MK and Chander, V and Raja, R and Paul, BR and Choudhary, OP and Thakur, N and Sarma, K and Prasad, H}, title = {Antioxidant supplementation during treatment of outpatient dogs with parvovirus enteritis ameliorates oxidative stress and attenuates intestinal injury: A randomized controlled trial.}, journal = {Veterinary and animal science}, volume = {21}, number = {}, pages = {100300}, pmid = {37333506}, issn = {2451-943X}, abstract = {A prospective randomized controlled clinical study was conducted to determine whether antioxidant supplementation as an adjunct therapy alters hemogram, oxidative stress, serum intestinal fatty acid binding protein-2 (IFABP-2) level, fecal viral load, clinical score (CS) and survivability in outpatient canine parvovirus enteritis (CPVE) dogs. The dogs with CPVE were randomized to one of the five treatment groups: supportive treatment (ST) alone, ST with N-acetylcysteine (ST+NAC), resveratrol (ST+RES), coenzyme Q10 (ST+CoQ10) or ascorbic acid (ST+AA). The primary outcome measures were reduction of CS and fecal HA titre, and enhancement of survivability. Secondary outcome measures were reduction of oxidative stress indices and IFABP-2 level from day 0 to day 7. The mean CS and HA titre were significantly (P < 0.05) decreased from day 0 to 7 in ST and all antioxidant groups. The supplementations of NAC, RES and AA along with ST markedly (P < 0.05) reduced the concentrations of malondialdehyde, nitric oxide and IFABP-2 on day 7 as compared to ST alone. Additionally, NAC and RES supplementations markedly (P < 0.05) improved the total leukocyte count and neutrophil count in CPVE-affected dogs. NAC and RES could serve as better antioxidants for the amelioration of oxidative stress in CPVE but, the antioxidants did not confer any additional benefits in reduction of CS, fecal HA tire, or survivability when compared with ST alone.}, }
@article {pmid37332579, year = {2023}, author = {Csiki, DM and Ababneh, H and Tóth, A and Lente, G and Szöőr, &#xc1; and Tóth, A and Fillér, C and Juhász, T and Nagy, B and Balogh, E and Jeney, V}, title = {Hypoxia-inducible factor activation promotes osteogenic transition of valve interstitial cells and accelerates aortic valve calcification in a mice model of chronic kidney disease.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1168339}, pmid = {37332579}, issn = {2297-055X}, abstract = {INTRODUCTION: Valve calcification (VC) is a widespread complication in chronic kidney disease (CKD) patients. VC is an active process with the involvement of in situ osteogenic transition of valve interstitial cells (VICs). VC is accompanied by the activation of hypoxia inducible factor (HIF) pathway, but the role of HIF activation in the calcification process remains undiscovered.<br><br>METHODS AND RESULT: Using in vitro and in vivo approaches we addressed the role of HIF activation in osteogenic transition of VICs and CKD-associated VC. Elevation of osteogenic (Runx2, Sox9) and HIF activation markers (HIF-1&#x3b1; and HIF-2&#x3b1;) and VC occurred in adenine-induced CKD mice. High phosphate (Pi) induced upregulation of osteogenic (Runx2, alkaline-phosphatase, Sox9, osteocalcin) and hypoxia markers (HIF-1&#x3b1;, HIF-2&#x3b1;, Glut-1), and calcification in VICs. Down-regulation of HIF-1&#x3b1; and HIF-2&#x3b1; inhibited, whereas further activation of HIF pathway by hypoxic exposure (1% O2) or hypoxia mimetics [desferrioxamine, CoCl2, Daprodustat (DPD)] promoted Pi-induced calcification of VICs. Pi augmented the formation of reactive oxygen species (ROS) and decreased viability of VICs, whose effects were further exacerbated by hypoxia. N-acetyl cysteine inhibited Pi-induced ROS production, cell death and calcification under both normoxic and hypoxic conditions. DPD treatment corrected anemia but promoted aortic VC in the CKD mice model.<br><br>DISCUSSION: HIF activation plays a fundamental role in Pi-induced osteogenic transition of VICs and CKD-induced VC. The cellular mechanism involves stabilization of HIF-1&#x3b1; and HIF-2&#x3b1;, increased ROS production and cell death. Targeting the HIF pathways may thus be investigated as a therapeutic approach to attenuate aortic VC.}, }
@article {pmid37325649, year = {2023}, author = {Chaumond, E and Peron, S and Daniel, N and Le Gouar, Y and Guédon, &#xc9; and Williams, DL and Le Loir, Y and Jan, G and Berkova, N}, title = {Development of innate immune memory by non-immune cells during Staphylococcus aureus infection depends on reactive oxygen species.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1138539}, pmid = {37325649}, issn = {1664-3224}, mesh = {Female ; Humans ; Animals ; Cattle ; Reactive Oxygen Species ; *Immunity, Innate ; Staphylococcus aureus ; Trained Immunity ; Interleukin-8 ; Interleukin-6 ; *Staphylococcal Infections ; }, abstract = {INTRODUCTION: The mechanisms underlying innate immune memory (trained immunity) comprise epigenetic reprogramming of transcriptional pathways associated with alterations of intracellular metabolism. While the mechanisms of innate immune memory carried out by immune cells are well characterized, such processes in non-immune cells, are poorly understood. The opportunistic pathogen, Staphylococcus aureus, is responsible for a multitude of human diseases, including pneumonia, endocarditis and osteomyelitis, as well as animal infections, including chronic cattle mastitis that are extremely difficult to treat. An induction of innate immune memory may be considered as a therapeutic alternative to fight S. aureus infection.<br><br>METHODS: In the current work, we demonstrated the development of innate immune memory in non-immune cells during S. aureus infection employing a combination of techniques including Enzyme-linked immunosorbent assay (ELISA), microscopic analysis, and cytometry.<br><br>RESULTS: We observed that training of human osteoblast-like MG-63 cells and lung epithelial A549 cells with &#x3b2;-glucan increased IL-6 and IL-8 production upon a stimulation with S. aureus, concomitant with histones modifications. IL-6 and IL-8 production was positively correlated with an acetylation of histone 3 at lysine 27 (H3K27), thus suggesting epigenetic reprogramming in these cells. An addition of the ROS scavenger N-Acetylcysteine, NAC, prior to &#x3b2;-glucan pretreatment followed by an exposure to S. aureus, resulted in decreased IL-6 and IL-8 production, thereby supporting the involvement of ROS in the induction of innate immune memory. Exposure of cells to Lactococcus lactis resulted in increased IL-6 and IL-8 production by MG-63 and A549 cells upon a stimulation with S. aureus that was correlated with H3K27 acetylation, suggesting the ability of this beneficial bacterium to induce innate immune memory.<br><br>DISCUSSION: This work improves our understanding of innate immune memory in non-immune cells in the context of S. aureus infection. In addition to known inducers, probiotics may represent good candidates for the induction of innate immune memory. Our findings may help the development of alternative therapeutic approaches for the prevention of S. aureus infection.}, }
@article {pmid37323955, year = {2022}, author = {Memudu, AE}, title = {The Efficacy of N-Acetyl-Cysteine (NAC) Supplementation in FST Model for Screening Antidepressants.}, journal = {Basic and clinical neuroscience}, volume = {13}, number = {6}, pages = {839-854}, pmid = {37323955}, issn = {2008-126X}, abstract = {INTRODUCTION: The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug.<br><br>METHODS: Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 &#x3bc;m thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC).<br><br>RESULTS: Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug.<br><br>CONCLUSION: NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.}, }
@article {pmid37318485, year = {2023}, author = {Tang, W and Zhu, D and Wu, F and Xu, JF and Yang, JP and Deng, ZP and Chen, XB and Papi, A and Qu, JM}, title = {Intravenous N-acetylcysteine in respiratory disease with abnormal mucus secretion.}, journal = {European review for medical and pharmacological sciences}, volume = {27}, number = {11}, pages = {5119-5127}, doi = {10.26355/eurrev_202306_32628}, pmid = {37318485}, issn = {2284-0729}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Expectorants/therapeutic use ; *Ambroxol/therapeutic use ; *Respiration Disorders ; Mucus ; Double-Blind Method ; }, abstract = {OBJECTIVE: Evidence for the mucolytic and expectorant efficacy of intravenous (IV) N-acetylcysteine (NAC) is limited. This study aimed to evaluate in a large, multicenter, randomized, controlled, subject, and rater-blinded study whether IV NAC is superior to placebo and non-inferior to ambroxol in improving sputum viscosity and expectoration difficulty.<br><br>PATIENTS AND METHODS: A total of 333 hospitalized subjects from 28 centers in China with respiratory disease (such as acute bronchitis, chronic bronchitis and exacerbations, emphysema, mucoviscidosis, and bronchiectasis) and abnormal mucus secretion were randomly allocated in a 1:1:1 ratio to receive NAC 600 mg, ambroxol hydrochloride 30 mg, or placebo as an IV infusion twice daily for 7 days. Mucolytic and expectorant efficacy was assessed by ordinal categorical 4-point scales and analyzed by stratified and modified Mann-Whitney U statistics.<br><br>RESULTS: NAC showed consistent and statistically significant superiority to placebo and non-inferiority to ambroxol in change from baseline to day 7 in both sputum viscosity scores [mean (SD) difference 0.24 (0.763), p<0.001 vs. placebo] and expectoration difficulty score [mean (SD) difference 0.29 (0.783), p=0.002 vs. placebo]. Safety findings confirm the good tolerability profile of IV NAC reported from previous small studies, and no new safety concerns were identified.<br><br>CONCLUSIONS: This is the first large, robust study of the efficacy of IV NAC in respiratory diseases with abnormal mucus secretion. It provides new evidence for IV NAC administration in this indication in clinical situations where the IV route is preferred.}, }
@article {pmid37312532, year = {2023}, author = {Gupta, M and Gupta, S and Sood, D and Gupta, A and Jesrani, G}, title = {Role of N-acetylcysteine in liver injury due to dengue fever.}, journal = {Tropical doctor}, volume = {53}, number = {4}, pages = {475-480}, doi = {10.1177/00494755231176317}, pmid = {37312532}, issn = {1758-1133}, mesh = {Humans ; Acetaminophen/toxicity ; *Acetylcysteine/therapeutic use ; *Dengue/complications/drug therapy ; *Liver Failure, Acute/drug therapy/etiology ; }, abstract = {Dengue fever (DF) is a common mosquito-borne viral infection which is endemic in Southeast Asia. Liver involvement may vary from asymptomatic elevation of liver enzymes to fulminant hepatitis. Although the valuable effects of N-acetylcysteine (NAC) in paracetamol toxicity and non-paracetamol liver failure have been extensively studied, its use in DF-associated hepatitis remains unclear. We made a literature search in an online format from libraries such as PubMed, Google Scholar, and EMBASE, and selected 33 articles including original research articles, case reports, and systemic analyses. The majority of the articles reviewed had a positive outcome but treatment strategies involved NAC together with supportive care. Hence, data on sole use of NAC from large randomised control trials remain unclear.}, }
@article {pmid37311880, year = {2023}, author = {Li, J and Zhang, Y and Kong, D and Su, J and Wei, Y and Liu, X and Lu, S and Wang, J and Huang, F}, title = {Association between N-acetylcysteine treatment and in-hospital mortality in adult patients with acquired thrombotic thrombocytopenic purpura: a cohort study.}, journal = {Annals of hematology}, volume = {102}, number = {8}, pages = {2257-2265}, doi = {10.1007/s00277-023-05295-2}, pmid = {37311880}, issn = {1432-0584}, support = {GSWS2020006//Gusu Health Talents Programme/ ; SDFEYJC2105//Pre-Research Fund Project of the Second Affiliated Hospital of Soochow University/ ; }, mesh = {Humans ; Adult ; *Purpura, Thrombotic Thrombocytopenic/diagnosis ; Acetylcysteine/therapeutic use ; Retrospective Studies ; Cohort Studies ; Hospital Mortality ; Plasma Exchange ; }, abstract = {Acquired thrombotic thrombocytopenic purpura (aTTP) is a fatal hematologic disease. Despite the currently high standards of care, some patients who develop refractory or recurrent disease still have a poor prognosis. Although N-acetylcysteine (NAC) is recommended for the treatment of aTTP, its use in aTTP treatment is still controversial. We aimed to evaluate the association of NAC with mortality in patients with aTTP. This was a retrospective cohort study of patients with aTTP with in-hospital mortality as the primary outcome and time to platelet recovery and neurological recovery as secondary outcomes. We used multifactorial COX regression analysis to check for an association of NAC with mortality. Moreover, we performed a sensitivity analysis check the stability of our results. Finally, 89 patients with aTTP were enrolled. After adjusting for potential confounders, we found NAC to be associated with 75% lower in-hospital mortality (HR = 0.25, 95% CI = 0.1-0.64). The results of sensitivity analyses performed remained stable as the risk of in-hospital mortality in patients reduced in patients with comorbid neurological symptoms (HR = 0.23, 95% CI = 0.06-0.89). However, NAC use did not affect the time to platelet recovery (HR = 1.19, 95% CI = 0.57-2.5) or neurological recovery (HR = 0.32, 95% CI = 0.08-1.25) in patients with aTTP. NAC treatment reduces in-hospital mortality in patients with aTTP but does not shorten the time to platelet recovery or neurological recovery.}, }
@article {pmid37309335, year = {2023}, author = {Martini, N and Singla, P and Arbuckle, E and Goyal, G and Liu, Q and Santos-Zabala, ML and Zainah, H}, title = {SARS-CoV-2-Induced Autoimmune Hepatitis.}, journal = {Cureus}, volume = {15}, number = {5}, pages = {e38932}, pmid = {37309335}, issn = {2168-8184}, abstract = {Few case reports discuss the incidences of autoimmune hepatitis (AIH) in patients after SARS-CoV-2 infection. Here, we present a case of SARS-CoV-2-induced AIH in a male patient who came into the emergency department with complaints of weight loss, poor oral intake, nausea, dark-colored urine, clay-colored stools, and scleral icterus, which began two weeks after he tested positive for SARS-CoV-2 PCR. Liver biopsy and subsequent histology confirmed the diagnosis of AIH with the most probable etiology being SARS-CoV-2 infection. The patient was treated with N-acetylcysteine (NAC) and steroids with clinical improvement and eventual discharge home. Our goal is to provide a clinical presentation, treatment, and outcome in a patient with SARS-CoV-2-induced AIH.}, }
@article {pmid37302535, year = {2023}, author = {Scaramboni, C and Arruda Moura Campos, ML and Junqueira Dorta, D and Palma de Oliveira, D and Batistuzzo de Medeiros, SR and de Oliveira Galvão, MF and Dreij, K}, title = {Reactive oxygen species-dependent transient induction of genotoxicity by retene in human liver HepG2 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {91}, number = {}, pages = {105628}, doi = {10.1016/j.tiv.2023.105628}, pmid = {37302535}, issn = {1879-3177}, mesh = {Humans ; Reactive Oxygen Species ; Hep G2 Cells ; *Particulate Matter ; *DNA Damage ; Oxidative Stress ; Liver ; }, abstract = {Retene is a polycyclic aromatic hydrocarbon (PAH) emitted mainly by biomass combustion, and despite its ubiquity in atmospheric particulate matter (PM), studies concerning its potential hazard to human health are still incipient. In this study, the cytotoxicity and genotoxicity of retene were investigated in human HepG2 liver cells. Our data showed that retene had minimal effect on cell viability, but induced DNA strand breaks, micronuclei formation, and reactive oxygen species (ROS) formation in a dose- and time-dependent manner. Stronger effects were observed at earlier time points than at longer, indicating transient genotoxicity. Retene activated phosphorylation of Checkpoint kinase 1 (Chk1), an indicator of replication stress and chromosomal instability, which was in accordance with increased formation of micronuclei. A protective effect of the antioxidant N-acetylcysteine (NAC) towards ROS generation and DNA damage signaling was observed, suggesting oxidative stress as a key mechanism of the observed genotoxic effects of retene in HepG2 cells. Altogether our results suggest that retene may contribute to the harmful effects caused by biomass burning PM and represent a potential hazard to human health.}, }
@article {pmid37299425, year = {2023}, author = {Fernández-Lázaro, D and Domínguez-Ortega, C and Busto, N and Santamaría-Peláez, M and Roche, E and Gutiérez-Abejón, E and Mielgo-Ayuso, J}, title = {Influence of N-Acetylcysteine Supplementation on Physical Performance and Laboratory Biomarkers in Adult Males: A Systematic Review of Controlled Trials.}, journal = {Nutrients}, volume = {15}, number = {11}, pages = {}, pmid = {37299425}, issn = {2072-6643}, mesh = {Male ; Adult ; Humans ; *Acetylcysteine/pharmacology ; *Antioxidants ; Dietary Supplements ; Glutathione ; Physical Functional Performance ; Biomarkers ; Randomized Controlled Trials as Topic ; }, abstract = {N-acetylcysteine (NAC) is used as a sports supplement for its ability to modulate exercise-induced oxidative damage through its antioxidant actions and maintenance of glutathione homeostasis, positioning NAC as a strategy to improve physical performance. We aimed to evaluate the current evidence on the benefits of NAC supplementation on physical performance and laboratory biomarkers in adult men. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically reviewed studies indexed in the Web of Science, Scopus, and PubMed to assess the effects of NAC on physical performance, laboratory biomarkers, and adverse effects in adult men. Original articles published up to 30 April 2023 with a controlled trial design comparing NAC supplementation with a control group were included. The modified McMaster Critical Review Form for Quantitative Studies was used as an assessment tool and the Cochrane Risk of Bias was applied. Of the 777 records identified in the search, 16 studies met the inclusion and exclusion criteria. Overall, most of the trials reported beneficial effects of NAC supplementation and no serious adverse events were reported. Participants supplemented with NAC showed significant improvements in exercise performance, antioxidant capacity, and glutathione homeostasis. However, there was no clear evidence of beneficial effects of NAC supplementation on haematological markers, inflammatory response, and muscle behaviour. NAC supplementation appears to be safe and may regulate glutathione homeostasis, have antioxidant effects, and improve exercise performance. However, further studies are needed to clarify the relevance of its use.}, }
@article {pmid37298254, year = {2023}, author = {Tyuryaeva, I and Lyublinskaya, O}, title = {Expected and Unexpected Effects of Pharmacological Antioxidants.}, journal = {International journal of molecular sciences}, volume = {24}, number = {11}, pages = {}, pmid = {37298254}, issn = {1422-0067}, support = {21-74-20178//Russian Science Foundation/ ; }, mesh = {*Antioxidants/pharmacology ; *Acetylcysteine/pharmacology ; Hydrogen Peroxide ; Ascorbic Acid/pharmacology ; Polyphenols/pharmacology ; }, abstract = {In this review, we have collected the existing data on the bioactivity of antioxidants (N-acetylcysteine, polyphenols, vitamin C) which are traditionally used in experimental biology and, in some cases, in the clinic. Presented data show that, despite the capacity of these substances to scavenge peroxides and free radicals in cell-free systems, their ability to exhibit these properties in vivo, upon pharmacological supplementation, has not been confirmed so far. Their cytoprotective activity is explained mainly by the ability not to suppress, but to activate multiple redox pathways, which causes biphasic hormetic responses and highly pleiotropic effects in cells. N-acetylcysteine, polyphenols, and vitamin C affect redox homeostasis by generating low-molecular-weight redox-active compounds (H2O2 or H2S), known for their ability to stimulate cellular endogenous antioxidant defense and promote cytoprotection at low concentrations but exert deleterious effects at high concentrations. Moreover, the activity of antioxidants strongly depends on the biological context and mode of their application. We show here that considering the biphasic and context-dependent response of cells on the pleiotropic action of antioxidants can help explain many of the conflicting results obtained in basic and applied research and build a more logical strategy for their use.}, }
@article {pmid37297001, year = {2023}, author = {Becker, AL and Indra, AK}, title = {Oxidative Stress in Melanoma: Beneficial Antioxidant and Pro-Oxidant Therapeutic Strategies.}, journal = {Cancers}, volume = {15}, number = {11}, pages = {}, pmid = {37297001}, issn = {2072-6694}, support = {ME210206P1//United States Department of Defense/ ; }, abstract = {Cutaneous melanoma ranks as the fifth most common cancer in the United States and represents one of the deadliest forms of skin cancer. While recent advances in systemic targeted therapies and immunotherapies have positively impacted melanoma survival, the survival rate of stage IV melanoma remains at a meager 32%. Unfortunately, tumor resistance can impede the effectiveness of these treatments. Oxidative stress is a pivotal player in all stages of melanoma progression, with a somewhat paradoxical function that promotes tumor initiation but hinders vertical growth and metastasis in later disease. As melanoma progresses, it employs adaptive mechanisms to lessen oxidative stress in the tumor environment. Redox metabolic rewiring has been implicated in acquired resistance to BRAF/MEK inhibitors. A promising approach to enhance the response to therapy involves boosting intracellular ROS production using active biomolecules or targeting enzymes that regulate oxidative stress. The complex interplay between oxidative stress, redox homeostasis, and melanomagenesis can also be leveraged in a preventive context. The purpose of this review is to provide an overview of oxidative stress in melanoma, and how the antioxidant system may be manipulated in a therapeutic context for improved efficacy and survival.}, }
@article {pmid37288204, year = {2023}, author = {Turk, A and Ulas, M and Karadag, A and Kocaman, N and Onalan, E and Kuloglu, T}, title = {The Effects of N-acetylcysteine on Transient Receptor Potential Melastatin 2 Channels Activation and Expression in Testicular Tissue of Diabetic Rats.}, journal = {Cureus}, volume = {15}, number = {5}, pages = {e38661}, pmid = {37288204}, issn = {2168-8184}, abstract = {INTRODUCTION: Diabetes mellitus (DM) is a common, chronic metabolic disease that has harmful effects on many diverse tissues, including the testis. One of the ways of tissue damage is the modification of transient receptor potential melastatin 2 (TRPM2) channels by increased reactive oxygen species (ROS). In our study for the first time, it was aimed to investigate TRPM2 channel activation in testicular tissues of diabetic rats induced by streptozotosin (STZ) and to examine the efficacy of N-acetylcysteine (NAC) treatment, which is an antioxidant.<br><br>METHODS: In our study, 28 Wistar albino male rats aged 8-10 weeks were used, and animals were divided into four groups: control group, NAC group, DM group, and DM + NAC group. The experimental phase was designed as eight weeks. The malondialdehyde&#xa0;(MDA)&#xa0;level, which is an indicator for lipid peroxidation due to oxidative stress, was measured by the spectrophotometric method. The Tunel assay was used to determine apoptosis on testicular tissue. TRPM2 immunoreactivity was determined by the avidin-biotin-peroxidase complex method, and quantitative polymerase chain reaction (QPCR) was used to determine TRPM2 expression levels.<br><br>RESULTS: It was seen that MDA levels were significantly increased in the DM group and decreased after NAC treatment. Similarly, it was observed that apoptosis levels, which increased significantly in diabetic rats, decreased to the levels of the control group after treatment. It was seen that TRPM2 activation and expression levels were significantly decreased in the DM group.<br><br>CONCLUSION: &#xa0;The results of this study show that NAC regulates TRPM2 activation in the testicular tissue of patients with diabetes and has tissue-protective properties.}, }
@article {pmid37285741, year = {2023}, author = {Luo, L and Pervaiz, S and Clement, MV}, title = {A superoxide-driven redox state promotes geroconversion and resistance to senolysis in replication-stress associated senescence.}, journal = {Redox biology}, volume = {64}, number = {}, pages = {102757}, pmid = {37285741}, issn = {2213-2317}, mesh = {*Superoxides/metabolism ; *Hydrogen Peroxide/metabolism ; Cellular Senescence ; Tumor Suppressor Protein p53/metabolism ; Oxidation-Reduction ; }, abstract = {Using S-phase synchronized RPE1-hTERT cells exposed to the DNA damaging agent, methyl methanesulfonate, we show the existence of a redox state associated with replication stress-induced senescence termed senescence-associated redox state (SA-redox state). SA-redox state is characterized by its reactivity with superoxide-sensing fluorescent probes such as dihydroethidine, lucigenin and mitosox and peroxynitrite or hydroxyl radical sensing probe hydroxyphenyl fluorescein (HPF) but not the hydrogen peroxide (H2O2) reactive fluorescent probe CM-H2DCFDA. Measurement of GSH and GSSH also reveals that SA-redox state mitigates the level of total GSH rather than oxidizes GSH to GSSG. Moreover, supporting the role of superoxide (O2[.-]) in the SA-redox state, we show that incubation of senescent RPE1-hTERT cells with the O2[.-] scavenger, Tiron, decreases the reactivity of SA-redox state with the oxidants' reactive probes lucigenin and HPF while the H2O2 antioxidant N-acetyl cysteine has no effect. SA-redox state does not participate in the loss of proliferative capacity, G2/M cell cycle arrest or the increase in SA-β-Gal activity. However, SA-redox state is associated with the activation of NF-κB, dictates the profile of the Senescence Associated Secretory Phenotype, increases TFEB protein level, promotes geroconversion evidenced by increased phosphorylation of S6K and S6 proteins, and influences senescent cells response to senolysis. Furthermore, we provide evidence for crosstalk between SA redox state, p53 and p21. While p53 mitigates the establishment of SA-redox state, p21 is critical for the sustained reinforcement of the SA-redox state involved in geroconversion and resistance to senolysis.}, }
@article {pmid37279380, year = {2023}, author = {Liu, X and Hou, Y and Yang, M and Xin, X and Deng, Y and Fu, R and Xiang, X and Cao, N and Liu, X and Yu, W and Yang, B and Zhou, Y}, title = {N-Acetyl-l-cysteine-Derived Carbonized Polymer Dots with ROS Scavenging via Keap1-Nrf2 Pathway Regulate Alveolar Bone Homeostasis in Periodontitis.}, journal = {Advanced healthcare materials}, volume = {12}, number = {26}, pages = {e2300890}, doi = {10.1002/adhm.202300890}, pmid = {37279380}, issn = {2192-2659}, mesh = {Mice ; Humans ; Animals ; Reactive Oxygen Species/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; Acetylcysteine/pharmacology/metabolism ; NF-E2-Related Factor 2/metabolism ; Osteogenesis ; Antioxidants/metabolism ; Oxidative Stress ; *Periodontitis/drug therapy/metabolism ; *Bone Resorption ; Homeostasis ; }, abstract = {Periodontitis is a type of chronic inflammatory oral disease characterized by the destruction of periodontal connective tissue and progressive alveolar bone resorption. As oxidative stress is the key cause of periodontitis in the early periodontal microenvironment, antioxidative therapy has been considered a viable treatment for periodontitis. However, more stable and effective reactive oxygen species (ROS)-scavenging nanomedicines are still highly needed due to the instability of traditional antioxidants. Herein, a new type of N-acetyl-l-cysteine (NAC)-derived red fluorescent carbonized polymer dots (CPDs) has been synthesized with excellent biocompatibility, which can serve as an extracellular antioxidant to scavenge ROS effectively. Moreover, NAC-CPDs can promote osteogenic differentiation in human periodontal ligament cells (hPDLCs) under H2 O2 stimulation. In addition, NAC-CPDs are capable of targeted accumulation in alveolar bone in vivo, reducing the level of alveolar bone resorption in periodontitis mice, as well as performing fluorescence imaging in vitro and in vivo. In terms of mechanism, NAC-CPDs may regulate redox homeostasis and promote bone formation in the periodontitis microenvironment by modulating the kelch-like ECH-associated protein l (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. This study provides a new strategy for the application of CPDs theranostic nanoplatform for periodontitis.}, }
@article {pmid37278488, year = {2023}, author = {Colli, A and Fraquelli, M and Prati, D and Casazza, G}, title = {Granulocyte colony-stimulating factor with or without stem or progenitor cell or growth factors infusion for people with compensated or decompensated advanced chronic liver disease.}, journal = {The Cochrane database of systematic reviews}, volume = {6}, number = {6}, pages = {CD013532}, pmid = {37278488}, issn = {1469-493X}, mesh = {Adult ; Humans ; *Esophageal and Gastric Varices/complications ; Quality of Life ; *Acute-On-Chronic Liver Failure/complications ; Gastrointestinal Hemorrhage ; Liver Cirrhosis/complications ; Stem Cells ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Intercellular Signaling Peptides and Proteins ; *Erythropoietin ; Growth Hormone ; }, abstract = {BACKGROUND: Advanced chronic liver disease is characterised by a long compensated phase followed by a rapidly progressive 'decompensated' phase, which is marked by the development of complications of portal hypertension and liver dysfunction. Advanced chronic liver disease is considered responsible for more than one million deaths annually worldwide. No treatment is available to specifically target fibrosis and cirrhosis; liver transplantation remains the only curative option. Researchers are investigating strategies to restore liver functionality to avoid or slow progression towards end-stage liver disease. Cytokine mobilisation of stem cells from the bone marrow to the liver could improve liver function. Granulocyte colony-stimulating factor (G-CSF) is a 175-amino-acid protein currently available for mobilisation of haematopoietic stem cells from the bone marrow. Multiple courses of G-CSF, with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, might be associated with accelerated hepatic regeneration, improved liver function, and survival.<br><br>OBJECTIVES: To evaluate the benefits and harms of G-CSF with or without stem or progenitor cell or growth factors (erythropoietin or growth hormone) infusion, compared with no intervention or placebo in people with compensated or decompensated advanced chronic liver disease.<br><br>SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and two trial registers (October 2022) together with reference-checking and web-searching to identify additional studies. We applied no restrictions on language and document type.<br><br>SELECTION CRITERIA: We only included randomised clinical trials comparing G-CSF, independent of the schedule of administration, as a single treatment or combined with stem or progenitor cell infusion, or with other medical co-interventions, with no intervention or placebo, in adults with chronic compensated or decompensated advanced chronic liver disease or acute-on-chronic liver failure. We included trials irrespective of publication type, publication status, outcomes reported, or language.<br><br>DATA COLLECTION AND ANALYSIS: We followed standard Cochrane procedures. All-cause mortality, serious adverse events, and health-related quality of life were our primary outcomes, and liver disease-related morbidity, non-serious adverse events, and no improvement of liver function scores were our secondary outcomes. We undertook meta-analyses, based on intention-to-treat, and presented results using risk ratios (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI) and I[2] statistic values as a marker of heterogeneity. We assessed all outcomes at maximum follow-up. We determined the certainty of evidence using GRADE, evaluated the risk of small-study effects in regression analyses, and conducted subgroup and sensitivity analyses.<br><br>MAIN RESULTS: We included 20 trials (1419 participants; sample size ranged from 28 to 259), which lasted between 11 and 57 months. Nineteen trials included only participants with decompensated cirrhosis; in one trial, 30% had compensated cirrhosis. The included trials were conducted in Asia (15), Europe (four), and the USA (one). Not all trials provided data for our outcomes. All trials reported data allowing intention-to-treat analyses. The experimental intervention consisted of G-CSF alone or G-CSF plus any of the following: growth hormone, erythropoietin, N-acetyl cysteine, infusion of CD133-positive haemopoietic stem cells, or infusion of autologous bone marrow mononuclear cells. The control group consisted of no intervention in 15 trials and placebo (normal saline) in five trials. Standard medical therapy (antivirals, alcohol abstinence, nutrition, diuretics, &#x3b2;-blockers, selective intestinal decontamination, pentoxifylline, prednisolone, and other supportive measures depending on the clinical status and requirement) was administered equally to the trial groups. Very low-certainty evidence suggested a decrease in mortality with G-CSF, administered alone or in combination with any of the above, versus placebo (RR 0.53, 95% CI 0.38 to 0.72; I[2] = 75%; 1419 participants; 20 trials). Very low-certainty evidence suggested no difference in serious adverse events (G-CSF alone or in combination versus placebo: RR 1.03, 95% CI 0.66 to 1.61; I[2] = 66%; 315 participants; three trials). Eight trials, with 518 participants, reported no serious adverse events. Two trials, with 165 participants, used two components of the quality of life score for assessment, with ranges from 0 to 100, where higher scores indicate better quality of life, with a mean increase from baseline of the physical component summary of 20.7 (95% CI 17.4 to 24.0; very low-certainty evidence) and a mean increase from baseline of the mental component summary of 27.8 (95% CI 12.3 to 43.3; very low-certainty evidence). G-CSF, alone or in combination, suggested a beneficial effect on the proportion of participants who developed one or more liver disease-related complications (RR 0.40, 95% CI 0.17 to 0.92; I[2] = 62%; 195 participants; four trials; very low-certainty evidence). When we analysed the occurrences of single complications, there was no suggestion of a difference between G-CSF, alone or in combination, versus control, in participants in need of liver transplantation (RR 0.85, 95% CI 0.39 to 1.85; 692 participants; five trials), in the development of hepatorenal syndrome (RR 0.65, 95% CI 0.33 to 1.30; 520 participants; six trials), in the occurrence of variceal bleeding (RR 0.68, 95% CI 0.37 to 1.23; 614 participants; eight trials), and in the development of encephalopathy (RR 0.56, 95% CI 0.31 to 1.01; 605 participants; seven trials) (very low-certainty evidence). The same comparison suggested that G-CSF reduces the development of infections (including sepsis) (RR 0.50, 95% CI 0.29 to 0.84; 583 participants; eight trials) and does not improve liver function scores (RR 0.67, 95% CI 0.53 to 0.86; 319 participants; two trials) (very low-certainty evidence).<br><br>AUTHORS' CONCLUSIONS: G-CSF, alone or in combination, seems to decrease mortality in people with decompensated advanced chronic liver disease of whatever aetiology and with or without acute-on-chronic liver failure, but the certainty of evidence is very low because of high risk of bias, inconsistency, and imprecision. The results of trials conducted in Asia and Europe were discrepant; this could not be explained by differences in participant selection, intervention, and outcome measurement. Data on serious adverse events and health-related quality of life were few and inconsistently reported. The evidence is also very uncertain regarding the occurrence of one or more liver disease-related complications. We lack high-quality, global randomised clinical trials assessing the effect of G-CSF on clinically relevant outcomes.}, }
@article {pmid37275759, year = {2023}, author = {Karimi, M and Ghasemzadeh Rahbardar, M and Razavi, BM and Hosseinzadeh, H}, title = {Amifostine inhibits acrylamide-induced hepatotoxicity by inhibiting oxidative stress and apoptosis.}, journal = {Iranian journal of basic medical sciences}, volume = {26}, number = {6}, pages = {662-668}, pmid = {37275759}, issn = {2008-3866}, abstract = {OBJECTIVES: Acrylamide (ACR) is a toxic chemical agent that can induce hepatotoxicity through different mechanisms including oxidative stress and apoptosis. Amifostine is an important hepatoprotective and anti-oxidant compound. In this research, the hepatoprotective effect of amifostine on ACR-induced hepatotoxicity in rats has been investigated.<br><br>MATERIALS AND METHODS: Male Wistar rats were randomly divided into 7 groups, including: 1. Control group, 2. ACR (50 mg/kg, 11 days, IP), 3-5. ACR+ amifostine (25, 50, 100 mg/kg, 11 days, IP), 6. ACR+ N-acetyl cysteine (NAC) (200 mg/kg, 11 days, IP), and 7. Amifostine (100 mg/kg, 11 days, IP). At the end of the injection period, animals' liver samples were collected to determine the content of glutathione (GSH), malondialdehyde (MDA), and apoptotic proteins (B-cell lymphoma 2 (Bcl2), Bcl-2-associated X protein (Bax), and cleaved caspase-3. Serum samples were also collected to measure alanine transaminase (ALT) and aspartate transaminase (AST) levels.<br><br>RESULTS: Administration of ACR increased MDA, Bax/Bcl2 ratio, cleaved caspase-3, ALT, and AST levels, and decreased GSH content compared with the control group. The administration of amifostine with ACR decreased MDA, Bax/Bcl2 ratio, cleaved caspase-3, ALT, and AST levels, and increased GSH content compared with the ACR group. Receiving NAC along with ACR reversed the alterations induced by ACR.<br><br>CONCLUSION: This study shows that pretreatment with amifostine can reduce ACR-induced toxicity in the liver tissue of rats. Since oxidative stress is one of the most important mechanisms in ACR toxicity, amifostine probably reduces the toxicity of ACR by increasing the anti-oxidant and anti-apoptotic capacity of the hepatic cells.}, }
@article {pmid37271412, year = {2023}, author = {Herbst, ED and Pennington, DL and Borsari, B and Manuel, J and Yalch, M and Alcid, E and Martinez Rivas, M and Delacruz, J and Rossi, N and Garcia, B and Wong, N and Batki, SL}, title = {N-acetylcysteine for smoking cessation among dual users of tobacco and cannabis: Protocol and rationale for a randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {131}, number = {}, pages = {107250}, pmid = {37271412}, issn = {1559-2030}, support = {I21 HX003410/HX/HSRD VA/United States ; IK2 CX001510/CX/CSRD VA/United States ; R25 MH060482/MH/NIMH NIH HHS/United States ; }, mesh = {Adult ; Humans ; *Smoking Cessation/methods ; *Cannabis ; Acetylcysteine/therapeutic use ; *Tobacco Use Disorder/therapy ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Tobacco and cannabis co-use is a growing public health problem. The synergistic effects of cannabis and nicotine on neurobiological systems that mediate reward and shared environmental cues reinforcing use may make tobacco smoking cessation more difficult. N-acetylcysteine (NAC), an FDA-approved medication and over-the-counter supplement, has shown promise in animal studies and randomized controlled trials (RCTs) in reducing tobacco and cannabis craving and use. NAC's potential efficacy in treating addiction may be attributable to its central nervous system effects in reducing excessive glutamatergic activity, oxidative stress, and inflammation. To date, no RCT has examined NAC for smoking cessation among dual users of tobacco and cannabis.<br><br>METHOD: In a double-blind, placebo-controlled RCT, we will examine NAC for smoking cessation among dual users of tobacco and cannabis. Sixty adult cigarette-cannabis co-users are randomized to receive NAC 3600&#xa0;mg per day or placebo over 8&#xa0;weeks. Participants in both groups receive 8 weekly cognitive behavioral therapy sessions addressing smoking cessation and cannabis reduction. Outcomes are assessed at Weeks 0, 4, 8, and 12. Primary aims are to determine NAC's efficacy in decreasing cigarette craving, nicotine dependence, and use; and cannabis craving and use. Exploratory aims include examination of changes in neurocognition with NAC and their potential mediational effects on cigarette and cannabis use outcomes.<br><br>CONCLUSION: Results will inform smoking cessation treatment among dual users of tobacco and cannabis.<br><br>CLINICALTRIALS: gov Identifier: NCT04627922.}, }
@article {pmid37271104, year = {2023}, author = {Fujiwara, N and Yamashita, S and Okamoto, M and Cooley, MA and Ozaki, K and Everett, ET and Suzuki, M}, title = {Perfluorooctanoic acid-induced cell death via the dual roles of ROS-MAPK/ERK signaling in ameloblast-lineage cells.}, journal = {Ecotoxicology and environmental safety}, volume = {260}, number = {}, pages = {115089}, pmid = {37271104}, issn = {1090-2414}, support = {K02 DE029531/DE/NIDCR NIH HHS/United States ; R01 DE027648/DE/NIDCR NIH HHS/United States ; }, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Ameloblasts/metabolism ; Cell Death ; Necrosis ; }, abstract = {Perfluorooctanoic acid (PFOA) is an artificial fluorinated organic compound that has generated increased public attention due to its potential health hazards. Unsafe levels of PFOA exposure can affect reproduction, growth and development. During tooth enamel development (amelogenesis), environmental factors including fluoride can cause enamel hypoplasia. However, the effects of PFOA on ameloblasts and tooth enamel formation remain largely unknown. In the present study we demonstrate several PFOA-mediated cell death pathways (necrosis/necroptosis, and apoptosis) and assess the roles of ROS-MAPK/ERK signaling in PFOA-mediated cell death in mouse ameloblast-lineage cells (ALC). ALC cells were treated with PFOA. Cell proliferation and viability were analyzed by MTT assays and colony formation assays, respectively. PFOA suppressed cell proliferation and viability in a dose dependent manner. PFOA induced both necrosis (PI-positive cells) and apoptosis (cleaved-caspase-3, γH2AX and TUNEL-positive cells). PFOA significantly increased ROS production and up-regulated phosphor-(p)-ERK. Addition of ROS inhibitor N-acetyl cysteine (NAC) suppressed p-ERK and decreased necrosis, and increased cell viability compared to PFOA alone, whereas NAC did not change apoptosis. This suggests that PFOA-mediated necrosis was induced by ROS-MAPK/ERK signaling, but apoptosis was not associated with ROS. Addition of MAPK/ERK inhibitor PD98059 suppressed necrosis and increased cell viability compared to PFOA alone. Intriguingly, PD98059 augmented PFOA-mediated apoptosis. This suggests that p-ERK promoted necrosis but suppressed apoptosis. Addition of the necroptosis inhibitor Necrostatin-1 restored cell viability compared to PFOA alone, while pan-caspase inhibitor Z-VAD did not mitigate PFOA-mediated cell death. These results suggest that 1) PFOA-mediated cell death was mainly caused by necrosis/necroptosis by ROS-MAPK/ERK signaling rather than apoptosis, 2) MAPK/ERK signaling plays the dual roles (promoting necrosis and suppressing apoptosis) under PFOA treatment. This is the initial report to indicate that PFOA could be considered as a possible causative factor for cryptogenic enamel malformation. Further studies are required to elucidate the mechanisms of PFOA-mediated adverse effects on amelogenesis.}, }
@article {pmid37270170, year = {2023}, author = {Guo, Y and Zhou, A and Zhang, Y and Chen, Y and Chen, Y and Gao, Y and Miao, X}, title = {Serum response factor activates peroxidasin transcription to block senescence of hepatic stellate cells.}, journal = {Life sciences}, volume = {328}, number = {}, pages = {121824}, doi = {10.1016/j.lfs.2023.121824}, pmid = {37270170}, issn = {1879-0631}, mesh = {Mice ; Animals ; *Hepatic Stellate Cells/metabolism ; *Serum Response Factor/genetics/metabolism ; Liver Cirrhosis/pathology ; Liver/metabolism ; Extracellular Matrix Proteins/metabolism ; Mice, Knockout ; Peroxidasin ; }, abstract = {AIMS: Aberrant liver fibrosis is a hallmark event in end-stage liver diseases. Hepatic stellate cells (HSCs) are considered the major source of myofibroblasts in the liver that produce extracellular matrix proteins to promote liver fibrosis. HSCs undergo senescence in response to various stimuli, a process that can be exploited to dampen liver fibrosis. We investigated the role of serum response factor (SRF) in this process.<br><br>METHODS AND MATERIALS: Senescence was induced HSCs by serum withdrawal or progressive passage. DNA-protein interaction was evaluated by chromatin immunoprecipitation (ChIP).<br><br>RESULTS: SRF expression was down-regulated in HSCs entering into senescence. Coincidently, SRF depletion by RNAi accelerated HSC senescence. Of note, treatment of an anti-oxidant (N-acetylcysteine or NAC) blocked HSC senescence by SRF deficiency suggesting that SRF may antagonize HSC senescence by eliminating excessive reactive oxygen species (ROS). PCR-array based screening identified peroxidasin (PXDN) as a potential target for SRF in HSCs. PXDN expression was inversely correlated with HSC senescence whereas PXDN knockdown accelerated HSC senescence. Further analysis reveals that SRF directly bound to the PXDN promoter and activated PXDN transcription. Consistently, PXDN over-expression protected whereas PXDN depletion amplified HSC senescence. Finally, PXDN knockout mice displayed diminished liver fibrosis compared to wild type mice when subjected to bile duct ligation (BDL).<br><br>SIGNIFICANCE: Our data suggest that SRF, via its downstream target PXDN, plays a key role in regulating HSC senescence.}, }
@article {pmid37266883, year = {2023}, author = {Guo, W and Jing, W}, title = {N-Acetyl-L-Cysteine Reduces Cervical Carcinogenesis by Promoting Apoptosis.}, journal = {Drugs in R&amp;D}, volume = {23}, number = {2}, pages = {165-174}, pmid = {37266883}, issn = {1179-6901}, mesh = {Humans ; Female ; Animals ; Mice ; *Uterine Cervical Neoplasms/drug therapy/genetics/pathology ; Acetylcysteine/pharmacology/therapeutic use ; Cell Line, Tumor ; *Papillomavirus Infections/metabolism ; Apoptosis ; Carcinogenesis ; }, abstract = {BACKGROUND AND OBJECTIVE: Cervical cancer is the fourth leading cause of cancer death in women, and is one of the most common malignant tumors of the reproductive system. However, more effective treatment for cervical cancer is needed. In this study, we aim to investigate whether N-acetyl-L-cysteine (NAC) could inhibit the proliferation of human papillomavirus (HPV)-positive cells, and reduce cervical carcinogenesis.<br><br>METHODS: The cervical cancer cell lines SiHa, HeLa, HPV-negative cell line C33A, and the immortalized human cervical keratinocyte cells S12 were used. The protein expression was determined using Western blot assay. mRNA expression was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation was determined by Cell Counting Kit-8 assay. Cell apoptosis was evaluated using Annexin V-FITC apoptosis kits. The numbers of colonies were measured using colony-forming assay. Xenograft tumor necrosis and HPV16 E7 expression were determined using hematoxylin and eosin (H&amp;E) staining and immunohistochemistry.<br><br>RESULTS: Our results showed that NAC treatment at the concentration of 1.5&#xa0;mM significantly promoted cell apoptosis and reduced cell growth by inhibiting HPV16 E7 expression. NAC inhibited HPV16-oncoprotein-induced hypoxia-inducible factor (HIF)-1&#x3b1; protein expression and Akt activation in&#xa0;vitro. Additionally, NAC suppressed tumor growth, as evidenced by the smaller tumor size in the xenograft mouse model and decreased HPV16 E7 expression in tumor tissues.<br><br>CONCLUSION: Our findings demonstrate that NAC exhibits the potential to promote HPV-positive cell apoptosis, and suppress the proliferation of HPV-positive cells by inhibiting cell inhibitor of apoptosis protein 2 and HIF-1&#x3b1;.}, }
@article {pmid37264973, year = {2023}, author = {Sun, J and Wang, Y and Du, Y and Zhang, W and Liu, Z and Bai, J and Cui, G and Du, Z}, title = {Involvement of the JNK/HO‑1/FTH1 signaling pathway in nanoplastic‑induced inflammation and ferroptosis of BV2 microglia cells.}, journal = {International journal of molecular medicine}, volume = {52}, number = {1}, pages = {}, pmid = {37264973}, issn = {1791-244X}, mesh = {Humans ; *Ferroptosis ; Microplastics/metabolism/pharmacology ; Microglia/metabolism ; MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Inflammation/metabolism ; Ferritins/metabolism/pharmacology ; Oxidoreductases/metabolism/pharmacology ; }, abstract = {Nanoplastics (NPs) are a newly discovered type of environmental pollutant. The potential for neurotoxicity caused by NPs and their mechanisms are unclear. The present study aimed to determine the molecular mechanism underlying neurotoxicity induced by NPs. Microglia (BV2) cells were used for in vitro studies, and it was found that NPs invaded cells, activated inflammasomes, induced the release of significant quantities of inflammatory factors by detection of inflammatory response‑associated proteins through Western blot and ELISA. By detection of FITC, SOD, GSH, cellular iron level, and ferroptosis‑related proteins, it was found that NPs compromised the anti‑oxidative mechanisms of cells, increased intracellular lipid peroxidation and Fe2+ concentration and triggered inflammatory reactions and ferroptosis. Pretreatment with reactive oxygen species (ROS) inhibitor N‑acetylcysteine (NAC) alleviated induction of inflammatory reactions and ferroptosis of cells. In addition, inhibiting expression of c‑Jun N‑terminal kinase (JNK) increased expression of heme oxygenase (HO‑1), resulting in decreased ferroptosis, indicating that the JNK/HO‑1 signaling pathway was involved in NP‑induced effects on ferroptosis in BV2 cells. In conclusion, NPs could induce inflammatory responses and ferroptosis in BV2 cells. JNK/HO‑1 mediated ferroptosis may serve an important role in the toxicity of microglia induced by NPs. This study provided novel evidence for the toxic effects of NPs and highlighted a theoretical mechanistic basis for safe prevention and treatment of plastic pollution‑induced neurotoxicity.}, }
@article {pmid37263335, year = {2023}, author = {Zong, Q and Peng, X and Ding, Y and Wu, H and Lu, C and Ye, J and Sun, W and Zhang, J and Zhai, Y}, title = {Multifunctional hydrogel wound dressing with rapid on-demand degradation property based on aliphatic polycarbonate and chitosan.}, journal = {International journal of biological macromolecules}, volume = {244}, number = {}, pages = {125138}, doi = {10.1016/j.ijbiomac.2023.125138}, pmid = {37263335}, issn = {1879-0003}, mesh = {Humans ; *Chitosan ; Hydrogels/pharmacology ; Antioxidants/pharmacology ; Anti-Bacterial Agents/pharmacology ; Bandages ; Carbonates ; }, abstract = {The multifunctional hydrogel dressings are effective strategy to treat chronic wounds of diabetes. In addition, the ability of selective degradation on demand to change dressings could provide better patient compliance. Here, an injectable, self-healing hydrogel with rapid degradability on-demand is designed to promote the healing of diabetes wounds. The block copolymer formed by aldehyde modified aliphatic cyclic carbonate monomer with polyethylene glycol (MBP) and chitosan (CS) were crosslinked through the Schiff base bond to obtain a hydrogel with excellent injectability and self-healing ability. Due to the presence of carbonate bonds in MBP, it showed the rapid on-demand degradation characteristics triggered by N-acetylcysteine (NAC). At the same time, gallic acid (GA) was loaded into the hydrogel, giving the hydrogel dressing antioxidant. In vivo and in vitro experiments showed that the hydrogel wound dressing possesses good natures, such as antibacterial, antioxidant, and friendly cell compatibility, which could promote wound healing. Overall, the multifunctional hydrogel wound dressings with rapid on-demand degradation characteristics are more practical for clinical applications.}, }
@article {pmid37260659, year = {2023}, author = {Alaska, YA and Alghadeer, SM and Alrabiah, AA and Harb, A and Almadi, B}, title = {Assessment of N-acetylcysteine use for acetaminophen overdose in the emergency department of a community teaching hospital: A pilot study.}, journal = {Saudi journal of anaesthesia}, volume = {17}, number = {2}, pages = {168-173}, pmid = {37260659}, issn = {1658-354X}, abstract = {INTRODUCTION: N-acetylcysteine (NAC) is the first-line treatment for acetaminophen (APAP) overdose. However, using NAC inappropriately is associated with an increased risk of adverse effects as well as a substantial increase in hospitalization and healthcare costs. This study aims to assess NAC utilization for acute APAP overdose in the emergency department of a community teaching hospital in Saudi Arabia.<br><br>METHODS: A retrospective chart review in which the patients initiated on an NAC secondary to acute APAP overdose at KSUMC during the period of June 2015 till November 2018 were included and assessed based on developed validated evident-based protocol for administering NAC for acute APAP ingestion.<br><br>RESULTS: A total of 29 patients received NAC treatment for acute APAP overdose; 15 of which were adults, and 14 were pediatrics. Appropriate prescribing of NAC was observed in 14 (48.28%) patients, whereas NAC was inappropriately indicated for 15 (51.72%) patients; 9 of them were adults and 6 patients were pediatric. APAP-Ingestion <150 mg/kg (<200 mg/kg in children) was the most common reason for inappropriate use (n = 7, 46.67%) followed by administering NAC <4 hours post-APAP ingestion (n = 4, 26.67%).<br><br>CONCLUSION: Improper NAC administration appears to be a significant issue among patients with APAP overdose. The utilization of a protocol for the management of APAP overdose will reduce the unnecessary usage of NAC.}, }
@article {pmid37259793, year = {2023}, author = {Li, G and Chen, Y and Wu, M and Chen, K and Zhang, D and Zhang, R and Yang, G and Huang, X}, title = {Di (2-ethyl) hexyl phthalate induces liver injury in chickens by regulating PTEN/PI3K/AKT signaling pathway via reactive oxygen species.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {270}, number = {}, pages = {109639}, doi = {10.1016/j.cbpc.2023.109639}, pmid = {37259793}, issn = {1532-0456}, mesh = {Animals ; Female ; Male ; Apoptosis/physiology ; *Chickens/metabolism ; *Diethylhexyl Phthalate/toxicity ; Liver/metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; PTEN Phosphohydrolase/genetics/metabolism ; Reactive Oxygen Species/metabolism ; RNA, Messenger/metabolism ; Signal Transduction ; }, abstract = {Di (2-ethyl) hexyl phthalate (DEHP) is a common environmental endocrine disruptor that induces oxidative stress, posing a significant threat to human and animal health. Oxidative stress can activate the PTEN/PI3K/AKT pathway, which is closely related to cell apoptosis. However, it is unclear whether DEHP induces apoptosis of chicken liver cells by regulating the PTEN/PI3K/AKT pathway through oxidative stress. In this experiment, male laying hens were continuously exposed to 400 mg/kg, 800 mg/kg, and 1600 mg/kg DEHP for 14 d, 28 d, and 42 d. The results showed that liver injury was aggravated with the dose of DEHP gavage, and the ROS/MDA levels in L, M, and H DEHP exposure groups were significantly increased, while the T-AOC/T-SOD/GSH-PX levels were decreased. Meanwhile, DEHP exposure up-regulated the mRNA and protein expression levels of PTEN/Bax/Caspase-9/Caspase-3 and down-regulated the mRNA and protein expression levels of PI3K/AKT/BCL-2, indicating that DEHP may lead to hepatocyte apoptosis through ROS regulation of PTEN/PI3K/AKT axis. In order to further clarify the relationship between oxidative stress and liver injury, we treated chicken hepatocellular carcinoma cell line (LMH) with 2.5 mM N-acetylcysteine (NAC). NAC attenuated these phenomena. In summary, our study suggests that DEHP can induce apoptosis of chicken liver through ROS activation of the PTEN/PI3K/AKT axis.}, }
@article {pmid37257582, year = {2023}, author = {Peng, H and Zhang, J and Zhang, Z and Turdi, S and Han, X and Liu, Q and Hu, H and Ye, H and Dong, M and Duan, Y and Yang, Y and Ashrafizadeh, M and Rabiee, N and Ren, J}, title = {Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced cardiac anomalies through reconciliation of autophagy and ferroptosis.}, journal = {Life sciences}, volume = {328}, number = {}, pages = {121821}, doi = {10.1016/j.lfs.2023.121821}, pmid = {37257582}, issn = {1879-0631}, mesh = {Mice ; Animals ; *Ferroptosis ; Lipopolysaccharides/pharmacology ; Caspase 3/metabolism ; Catalase/metabolism ; Antioxidants/pharmacology/metabolism ; Myocytes, Cardiac/metabolism ; *Heart Defects, Congenital/metabolism ; Autophagy ; }, abstract = {Lipopolysaccharide (LPS) from Gram-negative bacteria is a major contributor to cardiovascular failure, but the signaling mechanisms underlying its stress response are not fully understood. This study aimed to investigate the effect of the antioxidant enzyme catalase on LPS-induced cardiac abnormalities and the mechanisms involved, with particular focus on the interplay between autophagy, ferroptosis, and apoptosis. Cardiac-specific catalase (CAT) overexpression and wild-type (WT) mice were stimulated with LPS (6 mg/kg, intravenous injection), and cardiac morphology and function were evaluated. Oxidative stress, ferroptosis, apoptosis, and mitochondrial status were monitored, and survival curves were plotted based on the results of LPS stimulation. The results showed that, compared with WT mice, mice overexpressing catalase had a higher survival rate under LPS stimulation. Ultrasound echocardiography, cardiomyocyte characteristics, and Masson's trichrome staining showed that LPS inhibited cardiac function and caused cardiac fibrosis, while catalase alleviated these adverse effects. LPS increased apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), increased O2[·-] production, induced inflammation (TNF-α), autophagy, iron toxicity, and carbonyl damage, and significantly damaged mitochondria (mitochondrial membrane potential, mitochondrial proteins, and ultrastructure). These effects were significantly alleviated by catalase. Interestingly, the antioxidant N-acetylcysteine, autophagy inhibitor 3-methyladenine, and ferroptosis inhibitor lipostatin-1 all eliminated the LPS-induced contraction dysfunction and ferroptosis (using lipid peroxidation). Induction of ferroptosis could eliminate the cardioprotective effect of NAC. In conclusion, catalase rescues LPS-induced cardiac dysfunction by regulating oxidative stress, autophagy, ferroptosis, apoptosis, and mitochondrial damage in cardiomyocytes.}, }
@article {pmid37256605, year = {2023}, author = {Wu, S and Shi, Y and Jiang, L and Bu, W and Zhang, K and Lin, W and Pan, C and Xu, Z and Du, J and Chen, H and Wang, H}, title = {N-Acetylcysteine-Derived Carbon Dots for Free Radical Scavenging in Intervertebral Disc Degeneration.}, journal = {Advanced healthcare materials}, volume = {12}, number = {24}, pages = {e2300533}, doi = {10.1002/adhm.202300533}, pmid = {37256605}, issn = {2192-2659}, mesh = {Humans ; *Intervertebral Disc Degeneration/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism ; Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Nucleus Pulposus/metabolism/pathology ; }, abstract = {Intervertebral disc degeneration (IVDD) is associated with oxidative stress induced reactive oxygen species (ROS) dynamic equilibrium disturbance. Nanozymes, as nanomaterials with enzyme-like activity, can regulate intro-cellular ROS levels. In this study, a new carbon dots nanozyme, N-acetylcysteine-derived carbon dots (NAC-CDs), is developed and proved to be an ideal antioxidant and anti-senescent agent in IVDD management. The results confirmed the NAC-CDs have satisfactory biocompatibility and strong superoxide dismutase (250 U mg[-1]), catalase, glutathioneperoxidase-like activity, and total antioxidant capacity. Then, the powerful free radical scavenging and antioxidant ability of NAC-CDs are demonstrated in vitro as observing the reduced ROS in H2 O2 induced senescent nucleus pulposus cells (NPCs), in which the elimination efficiency of toxic ROS is more than 90%. NAC-CDs also maintained mitochondrial homeostasis and suppressed cellular senescence, subsequently inhibited the expression of inflammatory factors in NPCs. In vivo, evaluations of imaging and tissue morphology assessments suggested that disc height index, magnetic resonance imaging grade and histological score are significantly improved from the degenerative models when NAC-CDs is applied. In conclusion, the study developed a novel carbon dots nanozyme, which efficiently rescues IVDD from ROS induced NPCs senescence and provides a potential strategy in management of IVDD in clinic.}, }
@article {pmid37256235, year = {2023}, author = {Yang, K and Kim, HH and Shim, YR and Ryu, T and Kim, CW}, title = {Comprehensive transcriptomic analysis and meta-analysis identify therapeutic effects of N-acetylcysteine in nonalcoholic fatty liver disease.}, journal = {Frontiers in pharmacology}, volume = {14}, number = {}, pages = {1186582}, pmid = {37256235}, issn = {1663-9812}, abstract = {Introduction: The continuous rise in the prevalence of nonalcoholic fatty liver disease (NAFLD) is emerging as a global health issue. Although the protective effects of N-acetylcysteine (NAC), an antioxidant, against various diseases have been reported, it is still unclear whether NAC has therapeutic potential in NAFLD. Thus, the present meta-analysis aimed to investigate the efficacy of NAC on NAFLD in preclinical studies. Methods: By searching PubMed, Web of Science, and Cochrane Library, 13 studies were included. The methodological quality was assessed based on the SYstematic Review Centre for Laboratory animal Experimentation guideline, and heterogeneity was evaluated with I [2] and p values. Publication bias was assessed by Egger's test and sensitivity analysis was performed. Results: The results showed that NAC treatment significantly improved systemic and hepatic lipid metabolism (p < 0.01), inflammation-related liver injury (p < 0.01), glucose intolerance (p < 0.05), and hepatic steatosis (p < 0.01) by restoring hepatic glutathione (GSH) (p < 0.05) and GSH reductase (p < 0.05) levels compared to controls in NAFLD-induced animals. Consistently, in bulk, single-cell, and spatial transcriptomics data, the abovementioned target pathways of NAC were strongly associated with NAFLD development in mice and patients. Conclusion: Our study suggests that NAC has therapeutic potential for NAFLD and should be considered for future clinical trials.}, }
@article {pmid37254915, year = {2023}, author = {Vishnevetskii, DV and Averkin, DV and Efimov, AA and Lizunova, AA and Shamova, OV and Vladimirova, EV and Sukhareva, MS and Mekhtiev, AR}, title = {L-Cysteine and N-acetyl-L-cysteine-mediated synthesis of nanosilver-based sols and hydrogels with antibacterial and antibiofilm properties.}, journal = {Journal of materials chemistry. B}, volume = {11}, number = {25}, pages = {5794-5804}, doi = {10.1039/d3tb00261f}, pmid = {37254915}, issn = {2050-7518}, mesh = {Humans ; *Acetylcysteine/pharmacology ; Hydrogels/pharmacology ; *Metal Nanoparticles/chemistry ; Silver/pharmacology/chemistry ; Microbial Sensitivity Tests ; Anti-Bacterial Agents/chemistry ; Bacteria ; Biofilms ; }, abstract = {The need of the synthesis of a new generation of medicines aimed at combating bacteria and biofilms that cause various infections is a great urgency. There has been a gradual decrease in the conventional techniques of treatment with the use of antibiotics. Consequently, much effort has focused on the search for new methods and approaches to obtain antibacterial drugs and determine their rational use such that microorganisms do not acquire resistance. Although silver nanoparticles (AgNPs) and silver nanoclusters (AgNCs) have exhibited certain levels of effectiveness against multidrug-resistant bacteria and biofilms, there are very few simple, cheap and easy-to-scale methods to obtain AgNPs and AgNCs with well-desired characteristics. In this study, we carried out the one-pot synthesis of sols and gels containing AgNPs and AgNCs using only L-cysteine (CYS) or N-acetyl-L-cysteine (NAC), as bioreducing/capping/gel-forming agents, and different silver salts - nitrate, nitrite and acetate. HRTEM, SAED, EDX mapping, AFM, SEM, EDX, ICP-MS and FTIR spectroscopy analysis confirmed the formation of spherical/elliptical CYS-AgNP and NAC-AgNC particles consisting of AgNPs or AgNCs "core" and CYS/Ag[+] or NAC/Ag[+] complexes "shell" with mean average diameters of 10 and 5 nm, respectively. UV-Vis spectroscopy fixed the localized surface plasmon resonance (LSPR) at 390-420 nm for the CYS-AgNPs systems and LSPR absence for the NAC-AgNCs ones. DLS and nanoparticle tracking analysis (NTA) data indicated that the mean average diameter of the particles is about 80 nm for the CYS-AgNPs systems and 20 nm for the NAC-AgNCs ones. The Zeta potential measurements showed that the particles possess positive and negative charge values for CYS-AgNPs and NAC-AgNCs systems, respectively. The prepared materials demonstrated the high antibacterial activity against the most common types of bacteria at the MIC range of 10-100 μM, wherein the effect of the NAC-AgNCs systems is 2 times stronger than that of the CYS-AgNPs ones. Both systems are non-toxic or have low-toxicity at 300 μM for normal human cells: erytrocytes, fibroblasts and macrophages. Sols and hydrogels in the concentration range of 20-40 μM showed the complete inhibition of the formation of biofilms from Acinetobacter baumannii and Pseudomonas aeruginosa, which belong to the ESKAPE pathogenes group and represent the most serious problem in practical medicine. NAC-AgNCs systems were the most active. The simple strategy of the preparation of AgNP/AgNC-based sols and gels, along with their pronounced antibacterial and antibiofilm activity, could open new perspectives for its applications in medicine.}, }
@article {pmid37248505, year = {2023}, author = {Sun, D and Zhang, G and Xie, M and Wang, Y and Liang, X and Tu, M and Su, Z and Zeng, R}, title = {Softness enhanced macrophage-mediated therapy of inhaled apoptotic-cell-inspired nanosystems for acute lung injury.}, journal = {Journal of nanobiotechnology}, volume = {21}, number = {1}, pages = {172}, pmid = {37248505}, issn = {1477-3155}, support = {210715094530570//Science and Technology Planning Project of Shaoguan/ ; 2021KQNCX085//Foundation for Young Talents in Higher Education of Guangdong/ ; 31971270//National Natural Science Foundation of China/ ; 31370974//National Natural Science Foundation of China/ ; 2020B1515120078//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 202002020001//Science and Technology Program of Guangzhou/ ; }, mesh = {Mice ; Animals ; *Lung/metabolism ; *Acute Lung Injury/chemically induced/drug therapy ; Macrophages/metabolism ; Acetylcysteine/metabolism/pharmacology/therapeutic use ; }, abstract = {Engineered nanosystems offer a promising strategy for macrophage-targeted therapies for various diseases, and their physicochemical parameters including surface-active ligands, size and shape are widely investigated for improving their therapeutic efficacy. However, little is known about the synergistic effect of elasticity and surface-active ligands. Here, two kinds of anti-inflammatory N-acetylcysteine (NAC)-loaded macrophage-targeting apoptotic-cell-inspired phosphatidylserine (PS)-containing nano-liposomes (PSLipos) were constructed, which had similar size and morphology but different Young's modulus (E) (H, ~ 100 kPa > Emacrophage vs. L, ~ 2 kPa < Emacrophage). Interestingly, these PSLipos-NAC showed similar drug loading and encapsulation efficiency, and in vitro slow-release behavior of NAC, but modulus-dependent interactions with macrophages. Softer PSLipos-L-NAC could resist macrophage capture, but remarkably prolong their targeting effect period on macrophages via durable binding to macrophage surface, and subsequently more effectively suppress inflammatory response in macrophages and then hasten inflammatory lung epithelial cell wound healing. Especially, pulmonary administration of PSLipos-L-NAC could significantly reduce the inflammatory response of M1-like macrophages in lung tissue and promote lung injury repair in a bleomycin-induced acute lung injury (ALI) mouse model, providing a potential therapeutic approach for ALI. The results strongly suggest that softness may enhance ligand-directed macrophage-mediated therapeutic efficacy of nanosystems, which will shed new light on the design of engineered nanotherapeutics.}, }
@article {pmid37247196, year = {2023}, author = {Ferretti, S and Curatola, A and Chiaretti, A and Graglia, B and Gatto, A and Capossela, L and Pansini, V}, title = {Early treatment with N-acetylcysteine reduces hepatotoxicity in acute acetaminophen poisoning.}, journal = {Acta bio-medica : Atenei Parmensis}, volume = {94}, number = {S1}, pages = {e2023033}, doi = {10.23750/abm.v94iS1.13714}, pmid = {37247196}, issn = {2531-6745}, mesh = {Adult ; Child ; Female ; Adolescent ; Humans ; Acetylcysteine/therapeutic use ; Acetaminophen/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology/prevention &amp; control ; *Drug Overdose/drug therapy ; *COVID-19 ; *Digestive System Diseases ; }, abstract = {During the outbreak of COVID19 measures taken to contain the spread of the virus have influenced the mental well-being of adults and adolescents. Acetaminophen overdose is the major cause of drug intoxication among children and adolescents. We reported a case of a 15-year- old girl referred to our Emergency Department 3 hours after ingestion of 10 g of paracetamol for suicidal purposes. She promptly started the administration of intravenous N-acetylcysteine (NAC) and the patient was discharged after 5 days of hospitalization in good clinical condition and with neuropsychiatric follow-up. Our case shows that the timing of the intravenous NAC administration is considered the most important factor in the prevention of acetaminophen-induced hepatic failure, despite high serum levels after acetaminophen ingestion.}, }
@article {pmid37245532, year = {2023}, author = {Yang, H and Li, X and Jin, H and Turkez, H and Ozturk, G and Doganay, HL and Zhang, C and Nielsen, J and Uhlén, M and Borén, J and Mardinoglu, A}, title = {Longitudinal metabolomics analysis reveals the acute effect of cysteine and NAC included in the combined metabolic activators.}, journal = {Free radical biology &amp; medicine}, volume = {204}, number = {}, pages = {347-358}, doi = {10.1016/j.freeradbiomed.2023.05.013}, pmid = {37245532}, issn = {1873-4596}, mesh = {Humans ; *Acetylcysteine/metabolism ; *Cysteine ; NAD ; Glutathione/metabolism ; Metabolomics ; Niacinamide ; }, abstract = {Growing evidence suggests that the depletion of plasma NAD[+] and glutathione (GSH) may play an important role in the development of metabolic disorders. The administration of Combined Metabolic Activators (CMA), consisting of GSH and NAD[+] precursors, has been explored as a promising therapeutic strategy to target multiple altered pathways associated with the pathogenesis of the diseases. Although studies have examined the therapeutic effect of CMA that contains N-acetyl-l-cysteine (NAC) as a metabolic activator, a system-wide comparison of the metabolic response to the administration of CMA with NAC and cysteine remains lacking. In this placebo-controlled study, we studied the acute effect of the CMA administration with different metabolic activators, including NAC or cysteine with/without nicotinamide or flush free niacin, and performed longitudinal untargeted-metabolomics profiling of plasma obtained from 70 well-characterized healthy volunteers. The time-series metabolomics data revealed the metabolic pathways affected after the administration of CMAs showed high similarity between CMA containing nicotinamide and NAC or cysteine as metabolic activators. Our analysis also showed that CMA with cysteine is well-tolerated and safe in healthy individuals throughout the study. Last, our study systematically provided insights into a complex and dynamics landscape involved in amino acid, lipid and nicotinamide metabolism, reflecting the metabolic responses to CMA administration containing different metabolic activators.}, }
@article {pmid37242324, year = {2023}, author = {Gao, Y and Li, J and Guo, X and Guan, L and Wang, J and Huang, X and Wang, W and Yang, H}, title = {L-Tyrosine Limits Mycobacterial Survival in Tuberculous Granuloma.}, journal = {Pathogens (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37242324}, issn = {2076-0817}, support = {82270006//National Natural Science Foundation of China/ ; 82070007//National Natural Science Foundation of China/ ; 2021YFA1300902//National Key R&amp;D Program of China/ ; }, abstract = {Caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), tuberculosis (TB) remains a massive global public health issue. A well-known and key TB trait is caseous necrotic granuloma, which allows mycobacteria to reactivate and disseminate, thus confounding TB eradication programs. Amino acid (AA) metabolism is key to regulating immune responses in Mtb infections; however, it is currently unclear if AAs can be used to treat tuberculous granulomas. Here, we screened 20 proteinogenic AAs using a Mycobacterium marinum-infected zebrafish granuloma model. Only L-tyrosine simultaneously reduced Mycobacterium marinum (M. marinum) levels in zebrafish larvae and adults and inhibited intracellular pathogen survival levels. Mechanistically, L-tyrosine significantly upregulated interferon-γ (IFN-γ) expression in M. marinum -infected zebrafish adults but not in larvae. Using N-acetylcysteine (NAC) to inhibit reactive oxygen species (ROS), L-tyrosine appeared to inhibit Mtb intracellular survival by promoting ROS production. Thus, L-tyrosine as a non-essential AA may reduce mycobacterial survival in both macrophages and tuberculous granulomas. Our research provides a platform for the clinical development of AAs for active or latent TB patients infected with drug-sensitive or drug-resistant Mtb.}, }
@article {pmid37239911, year = {2023}, author = {Kenari, F and Molnár, S and Borges, ID and Napolitano, HB and Perjési, P}, title = {(E)-2-Benzylidenecyclanones: Part XVIII Study the Possible Link between Glutathione Reactivity and Cancer Cell Cytotoxic Effects of Some Cyclic Chalcone Analogs A Comparison of the Reactivity of the Open-Chain and the Seven-Membered Homologs.}, journal = {International journal of molecular sciences}, volume = {24}, number = {10}, pages = {}, pmid = {37239911}, issn = {1422-0067}, support = {EFOP-3.6.1.-16-2016-00004//European Council/ ; }, mesh = {*Chalcone/pharmacology ; *Chalcones/pharmacology ; Glutathione/metabolism ; Acetylcysteine/chemistry ; Chromatography, High Pressure Liquid ; *Antineoplastic Agents/pharmacology ; Sulfhydryl Compounds/chemistry ; *Neoplasms ; }, abstract = {Non-enzymatic thiol addition into the α,β-unsaturated carbonyl system is associated with several biological effects. In vivo, the reactions can form small-molecule thiol (e.g., glutathione) or protein thiol adducts. The reaction of two synthetic (4'-methyl- and 4'-methoxy substituted) cyclic chalcone analogs with reduced glutathione (GSH) and N-acetylcysteine (NAC) was studied by (high-pressure liquid chromatography-ultraviolet spectroscopy) HPLC-UV method. The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The structure of the formed adducts was confirmed by (high-pressure liquid chromatography-mass spectrometry) HPLC-MS. The incubations were performed under three different pH conditions (pH 3.2/3.7, 6.3/6.8, and 8.0/7.4). The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended on the substitution and the pH. The frontier molecular orbitals and the Fukui function were carried out to investigate the effects on open-chain and seven-membered cyclic analogs. Furthermore, machine learning protocols were used to provide more insights into physicochemical properties and to support the different thiol-reactivity. HPLC analysis indicated diastereoselectivity of the reactions. The observed reactivities do not directly relate to the different in vitro cancer cell cytotoxicity of the compounds.}, }
@article {pmid37237960, year = {2023}, author = {Giustarini, D and Milzani, A and Dalle-Donne, I and Rossi, R}, title = {How to Increase Cellular Glutathione.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37237960}, issn = {2076-3921}, abstract = {Glutathione (GSH) has special antioxidant properties due to its high intracellular concentration, ubiquity, and high reactivity towards electrophiles of the sulfhydryl group of its cysteine moiety. In most diseases where oxidative stress is thought to play a pathogenic role, GSH concentration is significantly reduced, making cells more susceptible to oxidative damage. Therefore, there is a growing interest in determining the best method(s) to increase cellular glutathione for both disease prevention and treatment. This review summarizes the major strategies for successfully increasing cellular GSH stores. These include GSH itself, its derivatives, NRf-2 activators, cysteine prodrugs, foods, and special diets. The possible mechanisms by which these molecules can act as GSH boosters, their related pharmacokinetic issues, and their advantages and disadvantages are discussed.}, }
@article {pmid37237933, year = {2023}, author = {Edemann-Callesen, H and Bernhardt, N and Hlusicka, EB and Hintz, F and Habelt, B and Winter, R and Neubert, I and Pelz, M and Filla, A and Soto-Montenegro, ML and Winter, C and Hadar, R}, title = {Supplement Treatment with NAC and Omega-3 Polyunsaturated Fatty Acids during Pregnancy Partially Prevents Schizophrenia-Related Outcomes in the Poly I:C Rat Model.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37237933}, issn = {2076-3921}, support = {DFG WI2140/4-1//Deutsche Forschungsgemeinschaft/ ; }, abstract = {BACKGROUND: Heightened levels of inflammation and oxidative stress are thought to be involved in the pathophysiology of schizophrenia. We aimed to assess whether intake of anti-inflammatory and anti-oxidant drugs during pregnancy prevents later schizophrenia-related outcomes in a neurodevelopmental rat model of this disorder.<br><br>METHODS: Pregnant Wistar rats were injected with polyriboinosinic-polyribocytidilic acid (Poly I:C) or saline and subsequently treated with either N-acetyl cysteine (NAC) or omega-3 polyunsaturated fatty acids (PUFAs) until delivery. Controls rats received no treatment. In the offspring, neuroinflammation and anti-oxidant enzyme activity were assessed on postnatal day (PND) 21, 33, 48, and 90. Behavioral testing was performed at PND 90, followed by post-mortem neurochemical assessment and ex vivo MRI.<br><br>RESULTS: The supplement treatment led to a quicker restoration of the wellbeing of dams. In the adolescent Poly I:C offspring, the supplement treatment prevented an increase in microglial activity and partially prevented a deregulation in the anti-oxidant defense system. In the adult Poly I:C offspring, supplement treatment partially prevented dopamine deficits, which was paralleled by some changes in behavior. Exposure to omega-3 PUFAs prevented the enlargement of lateral ventricles.<br><br>CONCLUSION: Intake of over-the-counter supplements may assist in especially targeting the inflammatory response related to schizophrenia pathophysiology, aiding in diminishing later disease severity in the offspring.}, }
@article {pmid37237886, year = {2023}, author = {Kim, JE and Lee, DS and Kim, TH and Park, H and Kang, TC}, title = {Distinct Roles of CK2- and AKT-Mediated NF-κB Phosphorylations in Clasmatodendrosis (Autophagic Astroglial Death) within the Hippocampus of Chronic Epilepsy Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {37237886}, issn = {2076-3921}, support = {No. 2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; }, abstract = {The downregulation of glutathione peroxidase-1 (GPx1) plays a role in clasmatodendrosis (an autophagic astroglial death) in the hippocampus of chronic epilepsy rats. Furthermore, N-acetylcysteine (NAC, a GSH precursor) restores GPx1 expression in clasmatodendritic astrocytes and alleviates this autophagic astroglial death, independent of nuclear factor erythroid-2-related factor 2 (Nrf2) activity. However, the regulatory signal pathways of these phenomena have not been fully explored. In the present study, NAC attenuated clasmatodendrosis by alleviating GPx1 downregulation, casein kinase 2 (CK2)-mediated nuclear factor-κB (NF-κB) serine (S) 529 and AKT-mediated NF-κB S536 phosphorylations. 2-[4,5,6,7-Tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazole-1-yl]acetic acid (TMCB; a selective CK2 inhibitor) relieved clasmatodendritic degeneration and GPx1 downregulation concomitant with the decreased NF-κB S529 and AKT S473 phosphorylations. In contrast, AKT inhibition by 3-chloroacetyl-indole (3CAI) ameliorated clasmatodendrosis and NF-κB S536 phosphorylation, while it did not affect GPx1 downregulation and CK2 tyrosine (Y) 255 and NF-κB S529 phosphorylations. Therefore, these findings suggest that seizure-induced oxidative stress may diminish GPx1 expression by increasing CK2-mediated NF-κB S529 phosphorylation, which would subsequently enhance AKT-mediated NF-κB S536 phosphorylation leading to autophagic astroglial degeneration.}, }
@article {pmid37235225, year = {2023}, author = {Li, X and Zhao, Z and Qu, Z and Li, X and Zhang, Z and Liang, X and Chen, J and Li, J}, title = {A Review of Traditional and Emerging Residual Chlorine Quenchers on Disinfection By-Products: Impact and Mechanisms.}, journal = {Toxics}, volume = {11}, number = {5}, pages = {}, pmid = {37235225}, issn = {2305-6304}, support = {BK20210737//the Natural Science Foundation of Jiangsu Province/ ; 2022M713301//China Postdoctoral Science Foundation/ ; 2021YXBKWKY026//the initial Scientific Research Fund of Soochow University, the Student's Extracurricular Scientific Research Fund of Medical College of Soochow University/ ; GWZX202204//the Suzhou Found for Prevention and Control Technology of critical illness and infectious diseases/ ; }, abstract = {Disinfection by-products (DBPs) are the most common organic contaminants in tap water and are of wide concern because of their highly developmental toxic, cytotoxic, and carcinogenic properties. Typically, to control the proliferation of pathogenic microorganisms, a certain concentration of residual chlorine is retained in the factory water, which reacts with the natural organic matter and the disinfection by-products that have been formed, thus affecting the determination of DBPs. Therefore, to obtain an accurate concentration, residual chlorine in tap water needs to be quenched prior to treatment. Currently, the most commonly used quenching agents are ascorbic acid, sodium thiosulfate, ammonium chloride, sodium sulfite, and sodium arsenite, but these quenching agents can cause varying degrees of DBPs degradation. Therefore, in recent years, researchers have attempted to find emerging chlorine quenchers. However, no studies have been conducted to systematically review the effects of traditional quenchers and new ones on DBPs, as well as their advantages, disadvantages, and scope of application. For inorganic DBPs (bromate, chlorate, and chlorite), sodium sulfite has been proven to be the ideal chlorine quencher. For organic DBPs, although ascorbic acid caused the degradation of some DBPs, it remains the ideal quenching agent for most known DBPs. Among the studied emerging chlorine quenchers, n-acetylcysteine (NAC), glutathione (GSH), and 1,3,5-trimethoxybenzene are promising for their application as the ideal chlorine quencher of organic DBPs. The dehalogenation of trichloronitromethane, trichloroacetonitrile, trichloroacetamide, and bromochlorophenol by sodium sulfite is caused by nucleophilic substitution reaction. This paper takes the understanding of DBPs and traditional and emerging chlorine quenchers as a starting point to comprehensively summarize their effects on different types of DBPs, and to provide assistance in understanding and selecting the most suitable residual chlorine quenchers during DBPs research.}, }
@article {pmid37234375, year = {2023}, author = {Chennupati, R and Solga, I and Wischmann, P and Dahlmann, P and Celik, FG and Pacht, D and Şahin, A and Yogathasan, V and Hosen, MR and Gerdes, N and Kelm, M and Jung, C}, title = {Chronic anemia is associated with systemic endothelial dysfunction.}, journal = {Frontiers in cardiovascular medicine}, volume = {10}, number = {}, pages = {1099069}, pmid = {37234375}, issn = {2297-055X}, abstract = {BACKGROUND: In acute myocardial infarction and heart failure, anemia is associated with adverse clinical outcomes. Endothelial dysfunction (ED) is characterized by attenuated nitric oxide (NO)-mediated relaxation responses which is poorly studied in chronic anemia (CA). We hypothesized that CA is associated with ED due to increased oxidative stress in the endothelium.<br><br>METHODS: CA was induced by repeated blood withdrawal in male C57BL/6J mice. Flow-Mediated Dilation (FMD) responses were assessed in CA mice using ultrasound-guided femoral transient ischemia model. Tissue organ bath was used to assess vascular responsiveness of aortic rings from CA mice, and in aortic rings incubated with red blood cells (RBCs) from anemic patients. In the aortic rings from anemic mice, the role of arginases was assessed using either an arginase inhibitor (Nor-NOHA) or genetic ablation of arginase 1 in the endothelium. Inflammatory changes in plasma of CA mice were examined by ELISA. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), myeloperoxidase (MPO), 3-Nitrotyrosine levels, and 4-Hydroxynonenal (4-HNE) were assessed either by Western blotting or immunohistochemistry. The role of reactive oxygen species (ROS) in ED was assessed in the anemic mice either supplemented with N-Acetyl cysteine (NAC) or by in vitro pharmacological inhibition of MPO.<br><br>RESULTS: The FMD responses were diminished with a correlation to the duration of anemia. Aortic rings from CA mice showed reduced NO-dependent relaxation compared to non-anemic mice. RBCs from anemic patients attenuated NO-dependent relaxation responses in murine aortic rings compared to non-anemic controls. CA results in increased plasma VCAM-1, ICAM-1 levels, and an increased iNOS expression in aortic vascular smooth muscle cells. Arginases inhibition or arginase1 deletion did not improve ED in anemic mice. Increased expression of MPO and 4-HNE observed in endothelial cells of aortic sections from CA mice. NAC supplementation or inhibition of MPO improved relaxation responses in CA mice.<br><br>CONCLUSION: Chronic anemia is associated with progressive endothelial dysfunction evidenced by activation of the endothelium mediated by systemic inflammation, increased iNOS activity, and ROS production in the arterial wall. ROS scavenger (NAC) supplementation or MPO inhibition are potential therapeutic options to reverse the devastating endothelial dysfunction in chronic anemia.}, }
@article {pmid37226070, year = {2023}, author = {Torres-Maure, M and Tapia-Ib Áñez, EX and Gamarra-L Ázaro, A and Bellido-Caparó, &#xc1; and García-Encinas, C}, title = {[Use of the Scottish and Newcastle Anti-Emetic Pretreatment (SNAP) scheme in recovery from massive overdose of acetaminophen poisoning with acute liver failure - Case report].}, journal = {Revista de gastroenterologia del Peru : organo oficial de la Sociedad de Gastroenterologia del Peru}, volume = {43}, number = {1}, pages = {53-56}, pmid = {37226070}, issn = {1609-722X}, mesh = {Female ; Humans ; Adolescent ; *Antiemetics/therapeutic use ; Acetaminophen ; Gastrointestinal Agents ; *Liver Failure, Acute/chemically induced/drug therapy ; Scotland ; }, abstract = {Acetaminophen is a drug widely used in the world and easily accessible due to its antipyretic, analgesics characteristics, among others (1); however, exposure to toxic doses causes organic damage and even death. We present the case of an 18-year-old female patient who ingested 40 grams of acetaminophen and developed severe liver dysfunction, being treated with N-acetylcysteine (NAC) antidotal therapy according to the simplified scheme: Scottish and Newcastle Anti-emetic Pretreatment Paracetamol Poisoning Study Regimen (SNAP), presenting improvement in the clinical course and decrease in liver profiles, coagulation disorder, INR and resolution of the condition.}, }
@article {pmid37225709, year = {2023}, author = {Zhang, S and Liu, Q and Chang, M and Pan, Y and Yahaya, BH and Liu, Y and Lin, J}, title = {Chemotherapy impairs ovarian function through excessive ROS-induced ferroptosis.}, journal = {Cell death &amp; disease}, volume = {14}, number = {5}, pages = {340}, pmid = {37225709}, issn = {2041-4889}, mesh = {Female ; Animals ; Reactive Oxygen Species ; *Ferroptosis ; Apoptosis ; Ovary ; *Antineoplastic Agents/toxicity ; }, abstract = {Chemotherapy was conventionally applied to kill cancer cells, but regrettably, they also induce damage to normal cells with high-proliferative capacity resulting in cardiotoxicity, nephrotoxicity, peripheral nerve toxicity, and ovarian toxicity. Of these, chemotherapy-induced ovarian damages mainly include but are not limited to decreased ovarian reserve, infertility, and ovarian atrophy. Therefore, exploring the underlying mechanism of chemotherapeutic drug-induced ovarian damage will pave the way to develop fertility-protective adjuvants for female patients during conventional cancer treatment. Herein, we firstly confirmed the abnormal gonadal hormone levels in patients who received chemotherapy and further found that conventional chemotherapeutic drugs (cyclophosphamide, CTX; paclitaxel, Tax; doxorubicin, Dox and cisplatin, Cis) treatment significantly decreased both the ovarian volume of mice and the number of primordial and antral follicles and accompanied with the ovarian fibrosis and reduced ovarian reserve in animal models. Subsequently, Tax, Dox, and Cis treatment can induce the apoptosis of ovarian granulosa cells (GCs), likely resulting from excessive reactive oxygen species (ROS) production-induced oxidative damage and impaired cellular anti-oxidative capacity. Thirdly, the following experiments demonstrated that Cis treatment could induce mitochondrial dysfunction through overproducing superoxide in GCs and trigger lipid peroxidation leading to ferroptosis, first reported in chemotherapy-induced ovarian damage. In addition, N-acetylcysteine (NAC) treatment could alleviate the Cis-induced toxicity in GCs by downregulating cellular ROS levels and enhancing the anti-oxidative capacity (promoting the expression of glutathione peroxidase, GPX4; nuclear factor erythroid 2-related factor 2, Nrf2 and heme oxygenase-1, HO-1). Our study confirmed the chemotherapy-induced chaotic hormonal state and ovarian damage in preclinical and clinical examination and indicated that chemotherapeutic drugs initiated ferroptosis in ovarian cells through excessive ROS-induced lipid peroxidation and mitochondrial dysfunction, leading to ovarian cell death. Consequently, developing fertility protectants from the chemotherapy-induced oxidative stress and ferroptosis perspective will ameliorate ovarian damage and further improve the life quality of cancer patients.}, }
@article {pmid37224776, year = {2023}, author = {Li, J and Zhou, J and Zhao, N and Li, Z and Xu, X and Tang, J and Li, Z and Zhang, X and Wu, Y and Li, Q and Zhang, Q and Jiang, J}, title = {EM-2, a natural sesquiterpene lactone from Elephantopus mollis H.B.K., enhanced the sensitivity of breast cancer cells to epirubicin by blocking protective autophagy.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {116}, number = {}, pages = {154878}, doi = {10.1016/j.phymed.2023.154878}, pmid = {37224776}, issn = {1618-095X}, mesh = {Humans ; Female ; Epirubicin ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; *Breast Neoplasms/drug therapy/pathology ; Autophagy ; Apoptosis ; *Sesquiterpenes/pharmacology ; Cell Proliferation ; }, abstract = {BACKGROUND: EM-2, a natural sesquiterpene lactone isolated from Elephantopus mollis H.B.K., showed a good anti-breast cancer effect when combined with epirubicin (EPI). However, its synergistic sensitization mechanism remains unclear.<br><br>PURPOSE: This study aimed to determine the therapeutic effect and possible synergistic mechanism of EM-2 with EPI in vivo and in vitro and to provide an experimental basis for the treatment of human breast cancer.<br><br>METHODS: Cell proliferation was measured with MTT and colony formation assays. Apoptosis and reactive oxygen species (ROS) levels were examined through flow cytometry, and the expression levels of proteins related to apoptosis, autophagy, endoplasmic reticulum stress, and DNA damage were detected through Western blot analysis. Moreover, the caspase inhibitor Z-VAD-FMK, autophagy inhibitors bafilomycin A1 and chloroquine, ER stress inhibitor 4-phenylbutyric acid, and ROS scavenger N-acetyl cysteine were applied to verify signaling pathways. Breast cancer cell lines were used to evaluate the antitumor functions of EM-2 and EPI in vitro and in vivo.<br><br>RESULTS: We demonstrated that in MDA-MB-231 and SKBR3 cells, the IC50 of EPI combined with EM-2 (IC20) was 37.909 and 33.889 times lower than that of EPI alone, respectively. Further study verified that in EPI-resistant lines (MDA-MB-231/EPI), the IC50 of EPI combined with EM-2 (IC20) was 26.305 times lower than that of EPI alone. Mechanistically, EM-2 could reverse the protective effect of EPI against autophagy in SKBR3 and MDA-MB-231 cells. EM-2 and EPI could trigger ER stress. When EM-2 and EPI were used in combination, ER stress was continuously activated, and ER stress-mediated apoptosis was induced. Meanwhile, EM-2 combined with EPI promoted DNA damage then induced apoptosis. In vivo, the volume of breast cancer xenografts in the combination group was smaller than that in the control, EM-2, and EPI groups. Immunohistochemical experiments demonstrated that the combination of EM-2 and EPI could block autophagy and promote ER stress in vivo.<br><br>CONCLUSION: EM-2 enhances the sensitivity of MDA-MB-231, SKBR3, and EPI-resistant cells to EPI.}, }
@article {pmid37224750, year = {2023}, author = {Gu, L and He, X and Zhang, Y and Li, S and Tang, J and Ma, R and Yang, X and Huang, H and Peng, Y and Xie, Y and Peng, Z and Meng, J and Hu, G and Tao, L and Liu, X and Yang, H}, title = {Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {164}, number = {}, pages = {114844}, doi = {10.1016/j.biopha.2023.114844}, pmid = {37224750}, issn = {1950-6007}, mesh = {Mice ; Animals ; *MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Acetaminophen/metabolism ; Lipopolysaccharides/pharmacology ; Anisomycin/metabolism/pharmacology ; Liver ; *Liver Failure, Acute/chemically induced/drug therapy/prevention &amp; control ; Pyridones/pharmacology ; Necrosis/metabolism ; Mice, Inbred C57BL ; Hepatocytes ; }, abstract = {AIMS: Acute liver failure (ALF) is a life-threatening disease characterized by abrupt and extensive hepatic necrosis and apoptosis, resulting in high mortality. The approved drug, N-acetylcysteine (NAC), is only effective for acetaminophen (APAP)-associated ALF at the early stage. Thus, we investigate whether fluorofenidone (AKF-PD), a novel antifibrosis pyridone agent, protects against ALF in mice and explore its underlying mechanisms.<br><br>METHODS: ALF mouse models were established using APAP or lipopolysaccharide/D-galactosamine (LPS/D-Gal). Anisomycin and SP600125 were used as JNK activator and inhibitor, respectively, and NAC served as a positive control. Mouse hepatic cell line AML12 and primary mouse hepatocytes were used for in vitro studies.<br><br>RESULTS: AKF-PD pretreatment alleviated APAP-induced ALF with decreased necrosis, apoptosis, reactive oxygen species (ROS) markers, and mitochondrial permeability transition in liver. Additionally, AKF-PD alleviated mitochondrial ROS stimulated by APAP in AML12 cells. RNA-sequencing in the liver and subsequent gene set enrichment analysis showed that AKF-PD significantly impacted MAPK and IL-17 pathway. In vitro and in vivo studies demonstrated that AKF-PD inhibited APAP-induced phosphorylation of MKK4/JNK, while SP600125 only inhibited JNK phosphorylation. The protective effect of AKF-PD was abolished by anisomycin. Similarly, AKF-PD pretreatment abolished hepatotoxicity caused by LPS/D-Gal, decreased ROS levels, and diminished inflammation. Furthermore, unlike NAC, AKF-PD, inhibited the phosphorylation of MKK4 and JNK upon pretreatment, and improved survival in cases of LPS/D-Gal-induced mortality with delayed dosing.<br><br>CONCLUSIONS: In summary, AKF-PD can protect against ALF caused by APAP or LPS/D-Gal, in part, via regulating MKK4/JNK pathway. AKF-PD might be a novel candidate drug for ALF.}, }
@article {pmid37223155, year = {2023}, author = {Stashin, AR and Fikse, DJ and Orta, AM and Briggs, RP and Wheatley, SM and Koons, AL}, title = {You Dropped the Bomb on Me: A Case Series of Carbon Tetrachloride Toxicity.}, journal = {Cureus}, volume = {15}, number = {4}, pages = {e37879}, pmid = {37223155}, issn = {2168-8184}, abstract = {Carbon tetrachloride (CCl4) is a halogenated hydrocarbon that is a colorless, clear liquid with a sweetish, ether-like, nonirritant odor. It was previously used in dry cleaning agents, refrigerants, and fire extinguishers. CCl4 toxicity is rarely observed. Two patients with acute hepatitis following exposure to a CCl4-containing antique fire extinguisher are presented. A son (patient 1) and father (patient 2) were admitted to the hospital with acute, unexplained elevated transaminases. After extensive questioning, they reported recent exposure to a large amount of CCl4 when an antique firebomb shattered in their home. Both patients cleaned the debris without personal protective equipment and slept in the contaminated area. The patients presented to the emergency department (ED) at varying times between 24 and 72 hours after CCl4 exposure. Both patients received intravenous N-acetylcysteine (NAC); patient 1 also received oral cimetidine. Both recovered uneventfully without sequelae. Extensive workup for other causes of elevated transaminases was unremarkable. Serum analyses for CCl4 were also unremarkable due to the delay between exposure and hospital presentation. CCl4 is a potent hepatotoxin. CCl4 metabolism via cytochrome CYP2E1 produces its toxic metabolite, the trichloromethyl radical. This radical covalently binds to hepatocyte macromolecules and causes lipid peroxidation and oxidative damage with ensuing centrilobular necrosis. Treatment is not well established, but NAC is likely beneficial via glutathione repletion and antioxidant effects. Cimetidine blocks cytochrome P450 and, thus, metabolite formation. Cimetidine may also promote the stimulation of regenerative processes acting on DNA synthesis. CCl4 toxicity is rare and infrequently reported in current literature but should be maintained in the differential of acute hepatitis. Two patients presenting nearly identically - at two different ages but from the same household - offered a clue to this enigmatic diagnosis.}, }
@article {pmid37217712, year = {2023}, author = {Fakhouri, H and Bakulić, MP and Zhang, I and Yuan, H and Bain, D and Rondepierre, F and Brevet, PF and Maršić, &#x17d;S and Antoine, R and Bonačić-Koutecký, V and Maysinger, D}, title = {Ligand impact on reactive oxygen species generation of Au10 and Au25 nanoclusters upon one- and two-photon excitation.}, journal = {Communications chemistry}, volume = {6}, number = {1}, pages = {97}, pmid = {37217712}, issn = {2399-3669}, support = {RGPIN 2020-07011//Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)/ ; }, abstract = {In photodynamic therapy (PDT), light-sensitive photosensitizers produce reactive oxygen species (ROS) after irradiation in the presence of oxygen. Atomically-precise thiolate-protected gold nanoclusters are molecule-like nanostructures with discrete energy levels presenting long lifetimes, surface biofunctionality, and strong near-infrared excitation ideal for ROS generation in PDT. We directly compare thiolate-gold macromolecular complexes (Au10) and atomically-precise gold nanoclusters (Au25), and investigate the influence of ligands on their photoexcitation. With the ability of atomically-precise nanochemistry, we produce Au10SG10, Au10AcCys10, Au25SG18, and Au25AcCys18 (SG: glutathione; AcCys: N-acetyl-cysteine) fully characterized by high-resolution mass spectrometry. Our theoretical investigation reveals key factors (energetics of excited states and structural influence of surface ligands) and their relative importance in singlet oxygen formation upon one- and two-photon excitation. Finally, we explore ROS generation by gold nanoclusters in living cells with one- and two-photon excitation. Our study presents in-depth analyses of events within gold nanoclusters when photo-excited both in the linear and nonlinear optical regimes, and possible biological consequences in cells.}, }
@article {pmid37217588, year = {2023}, author = {Beloosesky, R and Gutzeit, O and Ginsberg, Y and Khatib, N and Ross, MG and Weiner, Z and Zmora, O}, title = {Intestine and brain TLR-4 modulation following N-acetyl-cysteine treatment in NEC rodent model.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {8241}, pmid = {37217588}, issn = {2045-2322}, mesh = {Animals ; Rats ; Acetylcysteine/pharmacology ; Animals, Newborn ; Brain/metabolism ; *Brain Injuries/metabolism ; Disease Models, Animal ; *Enterocolitis, Necrotizing/drug therapy/metabolism ; Glutathione/metabolism ; Ileum/metabolism ; Intestines ; Rats, Sprague-Dawley ; Rodentia/metabolism ; Toll-Like Receptor 4/metabolism ; }, abstract = {Necrotizing enterocolitis (NEC) brain injury is mediated through Toll-like receptor 4 (TLR4) on the intestinal epithelium and brain microglia. Our aim was to determine whether postnatal and/or prenatal NAC can modify NEC associated intestinal and brain TLR4 expression and brain glutathione levels in a rat model of NEC. Newborn Sprague-Dawley rats were randomized into three groups: Control (n = 33); NEC (n = 32)-hypoxia and formula feeding; and NEC-NAC (n = 34)-received NAC (300 mg/kg IP) in addition to NEC conditions. Two additional groups included pups of dams treated once daily with NAC (300 mg/kg IV) for the last 3 days of pregnancy: NAC-NEC (n = 33) or NAC-NEC-NAC (n = 36) with additional postnatal NAC. Pups were sacrificed on the fifth day, and ileum and brains harvested for TLR-4 and glutathione protein levels. Brain and ileum TLR-4 protein levels were significantly increased in NEC offspring as compared to control (brain 2.5 ± 0.6 vs. 0.88 ± 0.12 U and ileum 0.24 ± 0.04 vs. 0.09 ± 0.01, p < 0.05). When NAC was administered only to dams (NAC-NEC) a significant decrease in TLR-4 levels was demonstrated in both offspring brain (1.53 ± 0.41 vs. 2.5 ± 0.6 U, p < 0.05) and ileum (0.12 ± 0.03 vs. 0.24 ± 0.04 U, p < 0.05) as compared to NEC. The same pattern was demonstrated when NAC was administered only or postnatally. The decrease in brain and ileum glutathione levels observed in NEC offspring was reversed with all NAC treatment groups. NAC reverses the increase in ileum and brain TLR-4 levels and the decrease in brain and ileum glutathione levels associated with NEC in a rat model, and thus may protect from NEC associated brain injury.}, }
@article {pmid37216221, year = {2023}, author = {Aswani, SS and Mohan, MS and Aparna, NS and Boban, PT and Saja, K}, title = {Oxidized LDL-mediated upregulation of ADAMTS-4 in monocytes/macrophages involves ROS-NF-κB-SIRT-1 pathway.}, journal = {Physiology international}, volume = {110}, number = {2}, pages = {173-190}, doi = {10.1556/2060.2023.00170}, pmid = {37216221}, issn = {2498-602X}, mesh = {Humans ; *Atherosclerosis/metabolism ; Leukocytes, Mononuclear ; Macrophages/metabolism ; Monocytes/metabolism ; *NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Resveratrol/metabolism ; RNA, Messenger/metabolism ; Up-Regulation ; *ADAMTS4 Protein/metabolism ; }, abstract = {BACKGROUND AND AIMS: ADAMTS-4 is a protease enzyme involved in vascular remodeling and atherosclerosis. It was found to be upregulated in macrophages seen in atherosclerotic lesions. This study aimed to investigate the expression and regulation of ADAMTS-4 in oxidized LDL-induced human monocytes/macrophages system.<br><br>METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from human blood,&#xa0;and treated with oxidized LDL (50 &#x3bc;g mL-1) were used as the model system for the study. mRNA and protein expressions were studied by PCR, ELISA, and western blot analysis. ROS production and cell&#xa0;viability were determined by DCFDA staining and MTT assay, respectively.<br><br>RESULTS: In the presence of oxidized LDL, monocytes get differentiated into macrophages, which were confirmed by the increased expression of macrophage differentiation markers and pro-inflammatory cytokine TNF-&#x3b1;. Oxidized LDL&#xa0;increased the mRNA and protein expression of ADAMTS-4 in monocytes/macrophages. N- Acetyl cysteine, ROS scavenger, downregulate the protein expression of ADAMTS-4. The expression of ADAMTS-4 was&#xa0;decreased significantly in the presence of NF-&#x3ba;B inhibitors. SIRT-1 activity was&#xa0;significantly downregulated in the macrophages and was reversed in the presence of the SIRT-1 agonist, resveratrol. Acetylation of NF-&#x3ba;B and hence the expression of ADAMTS-4 were significantly downregulated in the presence of SIRT-1 activator, resveratrol.<br><br>CONCLUSIONS: Our study suggests that oxidized LDL significantly upregulated the expression of ADAMTS-4 in the monocytes/macrophages through ROS- NF-&#x3ba;B- SIRT-1 pathway.}, }
@article {pmid37207578, year = {2023}, author = {Li, XL and Liu, YL and Liu, JY and Zhu, YY and Zhu, XX and Zhang, WW and Li, J and Zhao, Y and Zhao, LL and Zhang, C and Wang, H and Xu, DX and Gao, L}, title = {1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {259}, number = {}, pages = {115027}, doi = {10.1016/j.ecoenv.2023.115027}, pmid = {37207578}, issn = {1090-2414}, mesh = {Male ; Mice ; Animals ; *Testis/metabolism ; *Antioxidants/metabolism ; Eukaryotic Initiation Factor-2/metabolism ; Endoplasmic Reticulum Stress/physiology ; Testosterone/metabolism ; Oxidative Stress ; Acetylcysteine/pharmacology/metabolism ; }, abstract = {Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.}, }
@article {pmid37206223, year = {2023}, author = {Porterfield, JE and Sharma, R and Jimenez, AS and Sah, N and McCracken, S and Zhang, L and An, HT and Lee, S and Kannan, S and Sharma, A and Kannan, RM}, title = {Galactosylated hydroxyl-polyamidoamine dendrimer targets hepatocytes and improves therapeutic outcomes in a severe model of acetaminophen poisoning-induced liver failure.}, journal = {Bioengineering &amp; translational medicine}, volume = {8}, number = {3}, pages = {e10486}, pmid = {37206223}, issn = {2380-6761}, abstract = {Toxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose-conjugated hydroxyl polyamidoamine dendrimer (D4-Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)-induced liver failure. D4-Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non-Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4-Gal conjugated to N-acetyl cysteine (NAC) was tested in a mouse model of APAP-induced liver failure. A single intravenous dose of a conjugate of D4-Gal and NAC (Gal-d-NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4-Gal is effective in targeting and delivering therapies to hepatocytes and Gal-D-NAC has the potential to salvage and treat liver injury with a broader therapeutic window.}, }
@article {pmid37205206, year = {2023}, author = {Ajitkumar, A and Mohan, G and Ghose, M and Yarrarapu, S and Afiniwala, S}, title = {Drug-Induced Liver Injury Secondary to Turmeric Use.}, journal = {European journal of case reports in internal medicine}, volume = {10}, number = {5}, pages = {003845}, pmid = {37205206}, issn = {2284-2594}, abstract = {UNLABELLED: Turmeric is a herbal medication and spice which has been used for thousands of years in traditional Eastern medicine for its flavour, colour, and purported anti-inflammatory, antioxidant, antineoplastic and antimicrobial properties. It has recently garnered interest and popularity worldwide for these reasons. While turmeric supplements are generally safe, some reports of toxicity are emerging. Compounds like piperine are added to turmeric to enhance its bioavailability, potentially contributing to its toxicity. Here, we describe a 55-year-old woman with progressive jaundice and elevated bilirubin and liver enzymes but no evidence of acute liver failure. She was treated with N-acetyl cysteine (NAC) for 24 hours and liver function tests (LFTs) were closely monitored. As a downtrend in LFTs was noted and the patient remained asymptomatic, she was discharged with close outpatient follow-up. LFTs eventually normalized 2 months after the initial presentation. Clinicians must keep this differential in mind when evaluating acute liver injury. With our case report, we question the utility of NAC in non-acetaminophen-related liver injury and encourage further studies.<br><br>LEARNING POINTS: Eliciting information on recent drug or supplement use should be part of comprehensive history-taking to evaluate acute liver injury.Turmeric supplements which may contain piperine to enhance bioavailability are a potential source of acute liver injury.The role of N-acetyl cysteine in managing non-acetaminophen-related liver injury is unclear and further studies are required.}, }
@article {pmid37203858, year = {2023}, author = {Oliva, A and Pallecchi, L and Rossolini, GM and Travaglino, F and Zanatta, P}, title = {Rationale and evidence for the adjunctive use of N-acetylcysteine in multidrug-resistant infections.}, journal = {European review for medical and pharmacological sciences}, volume = {27}, number = {9}, pages = {4316-4325}, doi = {10.26355/eurrev_202305_32342}, pmid = {37203858}, issn = {2284-0729}, mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Drug Resistance, Multiple, Bacterial ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Expectorants/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; *Klebsiella Infections/drug therapy/microbiology ; Klebsiella pneumoniae ; Microbial Sensitivity Tests ; }, abstract = {Bacterial multidrug resistance has been a serious issue for healthcare systems in recent decades, responsible for many infections and deaths. Due to the increasing incidence of antimicrobial resistance and scarce treatment options, research is focused on finding possible therapeutic adjuvants able to increase the efficacy of antibiotics. The aim of this article is a review of available evidence on the use of N-acetylcysteine (NAC). MEDLINE/PubMed was searched for appropriate keywords. In vitro and in vivo preclinical studies, clinical studies, reviews, and meta-analyses were retrieved and selected based on relevance. A narrative review article was written, reporting published evidence and the expert opinion of the authors. Among possible adjunctive treatments, NAC has attracted the interest of researchers as a candidate for re-purposing. It is a widely used drug with a good tolerability profile, mainly used as a mucolytic agent, with antioxidant, anti-inflammatory properties and antibacterial activity. NAC acts on different mechanisms and stages of infections, resulting in inhibition of biofilm formation, disruption of preformed biofilms, and reduction of bacterial viability. NAC may be administered as an aerosol in many types of infections, including cystic fibrosis, bronchiectasis and infective flare of chronic obstructive pulmonary disease (COPD), and by the intravenous route in severe systemic infections (including septic shock) such as those caused by carbapenemase (KPC)-producing Klebsiella pneumoniae (Kp) and Carbapenem-Resistant Acinetobacter baumannii (CR-Ab). A rationale exists for using NAC as an adjunctive treatment in multidrug-resistant (MDR) infections, based on in vitro, in vivo and clinical evidence, and future research is needed to identify candidate patients and optimal schedules for specific clinical conditions.}, }
@article {pmid37196773, year = {2023}, author = {Qiu, D and Song, S and Chen, N and Bian, Y and Yuan, C and Zhang, W and Duan, H and Shi, Y}, title = {NQO1 alleviates renal fibrosis by inhibiting the TLR4/NF-κB and TGF-β/Smad signaling pathways in diabetic nephropathy.}, journal = {Cellular signalling}, volume = {108}, number = {}, pages = {110712}, doi = {10.1016/j.cellsig.2023.110712}, pmid = {37196773}, issn = {1873-3913}, mesh = {Animals ; Humans ; Mice ; Cytokines ; *Diabetes Mellitus, Type 2 ; *Diabetic Nephropathies/metabolism ; Epithelial-Mesenchymal Transition ; Fibrosis ; Inflammation/metabolism ; *NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; Toll-Like Receptor 4/metabolism ; Transforming Growth Factor beta1/metabolism ; }, abstract = {OBJECTIVE: Diabetic nephropathy (DN) is one of the main complications of diabetes, and inflammation and fibrosis play an important role in its progression. NAD(P)H: quinone oxidoreductase 1 (NQO1) protects cells from oxidative stress and damage caused by toxic quinones. In the present study, we aimed to investigate the protective effects of NQO1 against diabetes-induced renal inflammation and fibrosis and the underlying mechanisms.<br><br>METHODS: In vivo, the kidneys of type 2 diabetes model db/db mice were infected with adeno-associated virus vectors to induce NQO1 overexpression. In vitro, human renal tubular epithelial (HK-2) cells transfected with NQO1 pcDNA3.1(+) were cultured under high-glucose (HG) conditions. Gene and protein expression was assessed by quantitative real-time PCR, Western blotting, immunofluorescence, and immunohistochemical staining. Mitochondrial reactive oxygen species (ROS) were detected with MitoSOX Red.<br><br>RESULT: Our study revealed that the expression of NQO1 was markedly downregulated and that Toll-like receptor (TLR)4 and TGF-&#x3b2;1 expression was upregulated in vivo and in vitro under diabetic conditions. Overexpression of NQO1 suppressed proinflammatory cytokine (IL-6, TNF-&#x3b1;, MCP-1) secretion, extracellular matrix (ECM) (collagen IV, fibronectin) accumulation and epithelial-mesenchymal transition (EMT) (&#x3b1;-SMA, E-cadherin) in the db/db mouse kidneys and HG-cultured HK-2 cells. Furthermore, NQO1 overexpression ameliorated HG-induced TLR4/NF-&#x3ba;B and TGF-&#x3b2;/Smad pathways activation. Mechanistic studies demonstrated that a TLR4 inhibitor (TAK-242) suppressed the TLR4/NF-&#x3ba;B signaling pathway, proinflammatory cytokine secretion, EMT and ECM-related protein expression in HG-exposed HK-2 cells. In addition, we found that the antioxidants N-acetylcysteine (NAC) and tempol increased the expression of NQO1 and decreased the expression of TLR4, TGF-&#x3b2;1, Nox1, and Nox4 and ROS production in HK-2 cells cultured under HG conditions.<br><br>CONCLUSIONS: These data suggest that NQO1 alleviates diabetes-induced renal inflammation and fibrosis by regulating the TLR4/NF-&#x3ba;B and TGF-&#x3b2;/Smad signaling pathways.}, }
@article {pmid37193781, year = {2023}, author = {Kuo, CW and Su, PL and Huang, TH and Lin, CC and Chen, CW and Tsai, JS and Liao, XM and Chan, TY and Shieh, CC}, title = {Cigarette smoke increases susceptibility of alveolar macrophages to SARS-CoV-2 infection through inducing reactive oxygen species-upregulated angiotensin-converting enzyme 2 expression.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {7894}, pmid = {37193781}, issn = {2045-2322}, mesh = {Humans ; Mice ; Animals ; *COVID-19 ; Reactive Oxygen Species ; Macrophages, Alveolar/metabolism ; SARS-CoV-2/metabolism ; Angiotensin-Converting Enzyme 2/genetics ; *Cigarette Smoking ; Peptidyl-Dipeptidase A/metabolism ; }, abstract = {Alveolar macrophages (AMs) are the drivers of pulmonary cytokine storm in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to investigate clinical-regulatory factors for the entrance protein of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) in AMs. Human AMs were collected from 56 patients using bronchoalveolar lavage. ACE2 expression in AMs was positively correlated with smoking pack-year (Spearman's r = 0.347, P = 0.038). In multivariate analysis, current smoking was associated with increased ACE2 in AMs (β-coefficient: 0.791, 95% CI 0.019-1.562, P = 0.045). In vitro study, ex-vivo human AMs with higher ACE2 were more susceptible to SARS-CoV-2 pseudovirus (CoV-2 PsV). Treating human AMs using cigarette smoking extract (CSE) increases the ACE2 and susceptibility to CoV-2 PsV. CSE did not significantly increase the ACE2 in AMs of reactive oxygen species (ROS) deficient Cybb[-/-] mice; however, exogenous ROS increased the ACE2 in Cybb[-/-] AMs. N-acetylcysteine (NAC) decreases ACE2 by suppressing intracellular ROS in human AMs. In conclusion, cigarette smoking increases the susceptibility to SARS-CoV-2 by increasing ROS-induced ACE2 expression of AMs. Further investigation into the preventive effect of NAC on the pulmonary complications of COVID-19 is required.}, }
@article {pmid37190230, year = {2023}, author = {Ajouaou, Y and Magnani, E and Madakashira, B and Jenkins, E and Sadler, KC}, title = {atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers.}, journal = {Cancers}, volume = {15}, number = {8}, pages = {}, pmid = {37190230}, issn = {2072-6694}, support = {AJF2018098//Al Jalila Foundation/ ; ADHPG-CGSB//Tamkeen under the NYU Abu Dhabi Research Institute Award/ ; RE188//REF/ ; To KCS//NYUAD Faculty Research Fund/ ; }, abstract = {The ataxia-telangiectasia mutated (atm) gene is activated in response to genotoxic stress and leads to activation of the tp53 tumor suppressor gene which induces either senescence or apoptosis as tumor suppressive mechanisms. Atm also serves non-canonical functions in the response to oxidative stress and chromatin reorganization. We previously reported that overexpression of the epigenetic regulator and oncogene Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) in zebrafish hepatocytes resulted in tp53-dependent hepatocyte senescence, a small liver and larval lethality. We investigated the role of atm on UHRF1-mediated phenotypes by generating zebrafish atm mutants. atm[-/-] adults were viable but had reduction in fertility. Embryos developed normally but were protected from lethality caused by etoposide or H2O2 exposure and failed to fully upregulate Tp53 targets or oxidative stress response genes in response to these treatments. In contrast to the finding that Tp53 prevents the small liver phenotype caused by UHRF1 overexpression, atm mutation and exposure to H2O2 further reduced the liver size in UHRF1 overexpressing larvae whereas treatment with the antioxidant N-acetyl cysteine suppressed this phenotype. We conclude that UHRF1 overexpression in hepatocytes causes oxidative stress, and that loss of atm further enhances this, triggering elimination of these precancerous cells, leading to a small liver.}, }
@article {pmid37183639, year = {2023}, author = {Zi, Y and Liao, K and Chen, H}, title = {[Cigarette Smoke Induces Gefitinib Resistance in NSCLC Cells via ROS/Sirt3/SOD2 Pathway].}, journal = {Zhongguo fei ai za zhi = Chinese journal of lung cancer}, volume = {26}, number = {4}, pages = {245-256}, pmid = {37183639}, issn = {1999-6187}, mesh = {Humans ; Gefitinib/pharmacology/therapeutic use ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism ; *Sirtuin 3/genetics/therapeutic use ; *Lung Neoplasms/drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism/therapeutic use ; *Antineoplastic Agents/therapeutic use ; *Cigarette Smoking ; Sincalide/therapeutic use ; ErbB Receptors/metabolism ; Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor ; }, abstract = {BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations are the most common driver mutations in non-small cell lung cancer (NSCLC). To prolong the survival of the patients, EGFR tyrosine kinase inhibitors (TKIs) resistance in NSCLC is a major challenge that needs to be addressed urgently, and this study focuses on investigating the mechanism of cigarette smoke (CS) induced Gefitinib resistance in NSCLC.<br><br>METHODS: PC-9 and A549 cells were cultured in vitro and treated with 1 &#xb5;mol/L Gefitinib for 4 h and 10% cigarette smoke extract (CSE) for 48 h. Western blot was used to detect Sirtuin 3 (Sirt3) and superoxide dismutase 2 (SOD2) protein expressions; DCFH-DA probe was used to detect intracellular reactive oxygen species (ROS); CCK-8 kit was used to detect cell activity, and EdU was used to detect cell proliferation ability. Sirt3 overexpression plasmid (OV-Sirt3) was transfected in PC-9 and A549 cells and treated with 1 &#xb5;mol/L Gefitinib for 4 h and 10% CSE for 48 h after N-acetylcysteine (NAC) action. The expressions of Sirt3 and SOD2 were detected by Western blot; the ROS level in the cells was detected by DCFH-DA probe, and the cell activity was detected by CCK-8.<br><br>RESULTS: CSE induced an increase in the 50% inhibitory concentration (IC50) of both PC-9 and A549 cells to Gefitinib (P<0.01) and enhanced the proliferation of PC-9 and A549 cells, suggesting that CS induced Gefitinib resistance in NSCLC. ROS was involved in CSE-induced Gefitinib resistance (P<0.05). CSE induced low expressions of Sirt3 and SOD2 (P<0.01), and Sirt3/SOD2 was associated with poor prognosis in lung cancer patients (P<0.05). OV-Sirt3 in PC-9 and A549 cells reversed CSE-induced Gefitinib resistance (P<0.05) and significantly reduced ROS production. NAC reversed CSE-induced Gefitinib resistance in PC-9 and A549 cells (P<0.05).<br><br>CONCLUSIONS: The ROS/Sirt3/SOD2 pathway is involved in CS-induced Gefitinib resistance in NSCLC.}, }
@article {pmid37176778, year = {2023}, author = {Mirea, L and Cobilinschi, C and Ungureanu, R and Cotae, AM and Darie, R and Tincu, R and Avram, O and Constantinescu, S and Minoiu, C and Baetu, A and Grintescu, IM}, title = {A Trend towards Diaphragmatic Muscle Waste after Invasive Mechanical Ventilation in Multiple Trauma Patients-What to Expect?.}, journal = {Journal of clinical medicine}, volume = {12}, number = {9}, pages = {}, pmid = {37176778}, issn = {2077-0383}, abstract = {Considering the prioritization of life-threatening injuries in trauma care, secondary dysfunctions such as ventilator-induced diaphragmatic dysfunction (VIDD) are often overlooked. VIDD is an entity induced by muscle inactivity during invasive mechanical ventilation, associated with a profound loss of diaphragm muscle mass. In order to assess the incidence of VIDD in polytrauma patients, we performed an observational, retrospective, longitudinal study that included 24 polytraumatized patients. All included patients were mechanically ventilated for at least 48 h and underwent two chest CT scans during their ICU stay. Diaphragmatic thickness was measured by two independent radiologists on coronal and axial images at the level of celiac plexus. The thickness of the diaphragm was significantly decreased on both the left and right sides (left side: -0.82 mm axial p = 0.034; -0.79 mm coronal p = 0.05; right side: -0.94 mm axial p = 0.016; -0.91 coronal p = 0.013). In addition, we obtained a positive correlation between the number of days of mechanical ventilation and the difference between the two measurements of the diaphragm thickness on both sides (r =0.5; p = 0.02). There was no statistically significant correlation between the body mass indexes on admission, the use of vitamin C or N-acetyl cysteine, and the differences in diaphragmatic thickness.}, }
@article {pmid37175458, year = {2023}, author = {Lee, MY and Shiau, JP and Tang, JY and Hou, MF and Primus, PS and Kao, CL and Choo, YM and Chang, HW}, title = {Boesenbergia stenophylla-Derived Stenophyllol B Exerts Antiproliferative and Oxidative Stress Responses in Triple-Negative Breast Cancer Cells with Few Side Effects in Normal Cells.}, journal = {International journal of molecular sciences}, volume = {24}, number = {9}, pages = {}, pmid = {37175458}, issn = {1422-0067}, support = {MOST 111-2320-B-037-015-MY3; MOST 110-2314-B-037-074-MY3; MOST 109-2923-M-037-001-MY3; MOST 111-2113-M-037-014//Ministry of Science and Technology/ ; KMU-DK(A)112008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; GPF055B-2018 and ST004-2018//University of Malaya/ ; }, mesh = {Humans ; *Triple Negative Breast Neoplasms/drug therapy ; DNA Damage ; Cell Proliferation ; Cell Line, Tumor ; Oxidative Stress ; Apoptosis ; Acetylcysteine/pharmacology ; }, abstract = {Triple-negative breast cancer (TNBC) is insensitive to target therapy for non-TNBC and needs novel drug discovery. Extracts of the traditional herb Boesenbergia plant in Southern Asia exhibit anticancer effects and contain novel bioactive compounds but merely show cytotoxicity. We recently isolated a new compound from B. stenophylla, stenophyllol B (StenB), but the impact and mechanism of its proliferation-modulating function on TNBC cells remain uninvestigated. This study aimed to assess the antiproliferative responses of StenB in TNBC cells and examine the drug safety in normal cells. StenB effectively suppressed the proliferation of TNBC cells rather than normal cells in terms of an ATP assay. This preferential antiproliferative function was alleviated by pretreating inhibitors for oxidative stress (N-acetylcysteine (NAC)) and apoptosis (Z-VAD-FMK). Accordingly, the oxidative-stress-related mechanisms were further assessed. StenB caused subG1 and G2/M accumulation but reduced the G1 phase in TNBC cells, while normal cells remained unchanged between the control and StenB treatments. The apoptosis behavior of TNBC cells was suppressed by StenB, whereas that of normal cells was not suppressed according to an annexin V assay. StenB-modulated apoptosis signaling, such as for caspases 3, 8, and 9, was more significantly activated in TNBC than in normal cells. StenB also caused oxidative stress in TNBC cells but not in normal cells according to a flow cytometry assay monitoring reactive oxygen species, mitochondrial superoxide, and their membrane potential. StenB induced greater DNA damage responses (γH2AX and 8-hydroxy-2-deoxyguanosine) in TNBC than in normal cells. All these StenB responses were alleviated by NAC pretreatment. Collectively, StenB modulated oxidative stress responses, leading to the antiproliferation of TNBC cells with little cytotoxicity in normal cells.}, }
@article {pmid37174730, year = {2023}, author = {Aisa-Álvarez, A and Pérez-Torres, I and Guarner-Lans, V and Manzano-Pech, L and Cruz-Soto, R and Márquez-Velasco, R and Casarez-Alvarado, S and Franco-Granillo, J and Núñez-Martínez, ME and Soto, ME}, title = {Randomized Clinical Trial of Antioxidant Therapy Patients with Septic Shock and Organ Dysfunction in the ICU: SOFA Score Reduction by Improvement of the Enzymatic and Non-Enzymatic Antioxidant System.}, journal = {Cells}, volume = {12}, number = {9}, pages = {}, pmid = {37174730}, issn = {2073-4409}, mesh = {Humans ; Antioxidants/therapeutic use ; *Shock, Septic/drug therapy ; Multiple Organ Failure/drug therapy ; Organ Dysfunction Scores ; *Selenium ; Vitamin E/therapeutic use ; Ascorbic Acid/therapeutic use ; *Melatonin ; Vitamins ; Intensive Care Units ; }, abstract = {BACKGROUND AND AIM: Here, we assess the effect of adjuvant antioxidant therapies in septic shock patients with organ dysfunction and their effect on the enzymatic and non-enzymatic antioxidant systems.<br><br>METHODS: Randomized clinical trial run between 2018 and 2022. One hundred and thirty-one patients with septic shock were included in five groups with 25, 27, 24, 26 and 29 patients each. Group 1 received vitamin C (Vit C), Group 2 vitamin E (Vit E), Group 3 n-acetylcysteine (NAC), Group 4 melatonin (MT) and group 5 no treatment. All antioxidants were administered orally or through a nasogastric tube for 5 days as an adjuvant to standard therapy.<br><br>RESULTS: All patients had multiple organ failure (MOF) and low Vit C levels. Vit C therapy decreased CRP, PCT and NO3[-]/NO2[-] but increased Vit C levels. The SOFA score decreased with MT in 75%, Vit C 63% and NAC 50% vs. controls 33% (p = 0.0001, p = 0.03 and p = 0.001 respectively). MT diminished lipid peroxidation (LPO) (p = 0.01) and improved total antioxidant capacity (TAC) (p = 0.04). Vit E increased thiol levels (p = 0.02) and tended to decrease LPO (p = 0.06). Selenium levels were decreased in the control group (p = 0.04).<br><br>CONCLUSIONS: Antioxidants used as an adjuvant therapy in the standard treatment of septic shock decrease MOF and oxidative stress markers. They increase the TAC and thiols, and maintain selenium levels.}, }
@article {pmid37171598, year = {2023}, author = {Español, I and Leal, JD and Blanquer, M and García-Candel, F and Heredia, A and Gómez-Espuch, J and González, C and Montserrat, J and Díaz-Carrasco, MS and Martínez, A and Moraleda, JM}, title = {N-Acetylcistein for thrombotic thrombocytopenic purpura: an observational case series study.}, journal = {Annals of hematology}, volume = {102}, number = {8}, pages = {2069-2075}, pmid = {37171598}, issn = {1432-0584}, mesh = {Humans ; *Purpura, Thrombotic Thrombocytopenic/diagnosis/drug therapy ; ADAMTS13 Protein ; Rituximab/therapeutic use ; Plasma Exchange ; Acetylcysteine/therapeutic use ; }, abstract = {Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. N-Acetylcysteine (NAC) rapidly degrades ultra-large von Willebrand factor multimers by disrupting the disulfide bonds. We report a series of twelve consecutive patients diagnosed with acquired TTP successfully treated with high-dose NAC (150 mg/kg/day) in combination with plasma exchange and steroids. Eight patients also received rituximab. Two patients presented refractory TTP. All patients achieved a quick clinical response in a median time of 5.5 days after starting NAC and are alive after a median follow-up of 29 months. The treatment was feasible and well tolerated. These data provide further evidence of the potential benefit and safety of adding NAC to the standard of care.}, }
@article {pmid37168338, year = {2023}, author = {Lee, YP and Lin, CR and Chen, SS and Chen, RJ and Wu, YH and Chen, YH and Huang, BM}, title = {Combination treatment of cordycepin and radiation induces MA-10 mouse Leydig tumor cell death via ROS accumulation and DNA damage.}, journal = {American journal of cancer research}, volume = {13}, number = {4}, pages = {1329-1346}, pmid = {37168338}, issn = {2156-6976}, abstract = {Leydig cell tumor is the most frequent non-germ cell tumors of testis. The biggest challenge of using radiotherapy to treat testicular cancer is in effectively killing cancer cells and maintaining reproductive function after treatment. Our recently published article showed that cordycepin could enhance radiosensitivity to induce mouse Leydig tumor cell apoptosis by inducing cell cycle arrest, caspase pathway and endoplasmic reticulum (ER) stress. In the present study, the potency and mechanism of a previous combination treatment protocol on reactive oxygen species (ROS) induction and DNA damage were further investigated. Our results reveal that 25 μM cordycepin plus 4 Gy radiation leads to ROS accumulation accompanied by a decrease in heme oxygenase (HO)-1 protein expression in MA-10 mouse Leydig tumor cells. Subsequently, pronounced DNA damage with phosphorylated H2A histone family member X (γ-H2AX) increase and activation of DNA damage-related signaling pathways including double and single stranded break-induced ataxia telangiectasia mutated (ATM)/checkpoint kinase (Chk)2 and ataxia telangiectasia mutated and Rad3 related (ATR)/Chk1 signaling axes were identified. p53-dependent pathway was then initiated ultimately leading to cell death. Preincubated with free radical scavenger, N-acetylcysteine (NAC), down-regulated γ-H2AX expression in treated cells and partially reduced cell death, indicating that ROS overproduction is involved in combination treatment-induced DNA damage. Furthermore, the combination treatment effectively inhibited tumor growth as reflected in the reduction of tumor volume, size and weight, and high expression level of γ-H2AX in tumor tissue in vivo, suggesting that the combination treatment inhibited tumor growth via causing DNA damage in MA-10 cells. In summary, these results expound that the combination treatment of cordycepin and radiation induces MA-10 mouse Leydig tumor cell death through ROS accumulation and DNA damage. This finding can serve as a reference guideline for future clinical therapy of testicular cancer and provide potential targets for anti-cancer drug design.}, }
@article {pmid37162825, year = {2023}, author = {Jung, IR and Ahima, RS and Kim, SF}, title = {IPMK modulates FFA-induced insulin resistance in primary mouse hepatocytes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37162825}, support = {R01 DK135751/DK/NIDDK NIH HHS/United States ; }, abstract = {Insulin resistance is a critical mediator of the development of non-alcoholic fatty liver disease (NAFLD). An excess influx of fatty acids to the liver is thought to be a pathogenic cause of insulin resistance and the development of non-alcoholic fatty liver disease (NAFLD). Although elevated levels of free fatty acids (FFA) in plasma contribute to inducing insulin resistance and NAFLD, the molecular mechanism is not completely understood. This study aimed to determine whether inositol polyphosphate multikinase (IPMK), a regulator of insulin signaling, plays any role in FFA-induced insulin resistance in primary hepatocytes. Here, we show that excess FFA decreased IPMK expression, and blockade of IPMK decrease attenuated the FFA-induced suppression of Akt phosphorylation in primary mouse hepatocytes (PMH). Moreover, overexpression of IPMK prevented the FFA-induced suppression of Akt phosphorylation by insulin, while knockout of IPMK exacerbated insulin resistance in PMH. In addition, treatment with MG132, a proteasomal inhibitor, inhibits FFA-induced decrease in IPMK expression and Akt phosphorylation in PMH. Furthermore, treatment with the antioxidant N-Acetyl Cysteine (NAC) significantly attenuated the FFA-induced reduction of IPMK and restored FFA-induced insulin resistance in PMH. In conclusion, our findings suggest that excess FFA reduces IPMK expression and contributes to the FFA-induced decrease in Akt phosphorylation in PMH, leading to insulin resistance. Our study highlights IPMK as a potential therapeutic target for preventing insulin resistance and NAFLD.}, }
@article {pmid37155080, year = {2023}, author = {Wang, W and Zeng, J and Luo, P and Fang, J and Pei, Q and Yan, J and Zhu, C and Chen, W and Liu, Y and Huang, Z and Huang, Y and Wu, C and Pan, X}, title = {Engineered lipid liquid crystalline nanoparticles as an inhaled nanoplatform for mucus penetration enhancement.}, journal = {Drug delivery and translational research}, volume = {13}, number = {11}, pages = {2834-2846}, pmid = {37155080}, issn = {2190-3948}, mesh = {*Drug Carriers/chemistry ; *Nanoparticles/chemistry ; Mucus/metabolism ; Mucins ; Acetylcysteine ; Lipids/chemistry ; }, abstract = {Nanocarrier-assisted pulmonary drug delivery system has been widely employed for lung local disease treatment due to its enhanced drug lesion accumulation and reduced systematical side effects. However, the mucus barriers covered on the epithelia of trachea and bronchial tree construct a dense barrier for inhaled nanocarrier transport, which compromises the therapeutical effects. In this study, a lipid liquid crystalline nanoparticle NLP@Z with surface zwitterion material hexadecyl betaine (HB) modification and N-acetylcysteine (NAC) encapsulation was presented to exert the combination strategy of mucus-inert surface and mucus degradation. The HB modification endowed NLP@Z mucus-inert surface to inhibit the interaction between NLP@Z and mucins, and the encapsulated NAC could effectively degrade the mucins and further decrease the mucus viscosity. This combination strategy was proved to significantly promote the mucus penetration performance and enhance epithelial cell uptake. In addition, the proposed NLP@Z was equipped with desired nebulization property, which could be served as a potential pulmonary delivery nanoplatform. In summary, the proposed NLP@Z highlights the employment of the combination strategy for mucus penetration enhancement in pulmonary delivery, which may become a versatile platform for lung disease therapy.}, }
@article {pmid37151623, year = {2023}, author = {Wu, X and Cao, Z and Ni, J and Zheng, X and Zhu, L and Xin Wang,  and Lv, J and Zhou, S and Ding, Y and Wu, R}, title = {Compatibility and aerosol characteristics of beclomethasone mixed with N-acetylcysteine.}, journal = {Heliyon}, volume = {9}, number = {4}, pages = {e15357}, pmid = {37151623}, issn = {2405-8440}, abstract = {Mixing different kind inhalation medications for simultaneous inhalation is widely used in the treatment of chronic respiratory diseases, and it can minimize the administration time and improve patient adherence. To our knowledge, it is unclear whether beclomethasone (BDP, Clenil®) can bemixed with acetylcysteine (NAC, Fluimucil®), because the in vitro physico-chemical compatibility and aerosol characteristics of the mixture are unknown. In this study, we investigated physical compatibility, including the appearance, pH, osmotic pressure and chemical stability, as well as aerosol characteristics, including particle size corresponding to 10%/50%/90% of the cumulative percentage of total particle volume (X10/X50/X90), volume median droplet diameter (VMD), mass median aerodynamic diameter (MMAD), fine particle fraction (FPF), fine particle dose (FPD) and geometric standard deviation (GSD), delivery rate, and total delivery of the above solutions. After mixing, there were no significant changes in visual appearance, pH, osmolality and drug content of the mixtures at room temperature for 12 h. The FDP of BDP in the mixture decreased by 16.49%, whereas the NAC increased by 10.85%. The delivery rates of BDP and NAC in the mixture decreased by 66.05% and 45.54%, and total delivery increased by 13.20% and 25.29%, respectively. However, the MMAD, FPF, particle size and GSD of the mixture were almost unchanged. We demonstrated that these admixtures are physico-chemically compatible but that coadministration of beclomethasone with acetylcysteine can markedly affect output and aerosol characteristics.}, }
@article {pmid37151359, year = {2023}, author = {Elkhateeb, N and Hyde, S and Hogg, SL and Allsop, D and Shankar, A and Deegan, P and Tan, CY}, title = {Paracetamol toxicity in classic homocystinuria: Effect of N-acetylcysteine on total homocysteine.}, journal = {JIMD reports}, volume = {64}, number = {3}, pages = {238-245}, pmid = {37151359}, issn = {2192-8304}, abstract = {Classical homocystinuria (HCU) is caused by cystathionine β-synthase deficiency leading to impaired homocysteine transsulfuration and accumulation of homocysteine and methionine. Patients present with a wide spectrum of manifestations including ocular, skeletal, neuropsychiatric, and vascular manifestations. We report a 48-year-old female with pyridoxine-unresponsive HCU treated with betaine, cyanocobalamin, and folate. Her diet was non-restricted due to intolerance of low-methionine diet. She was admitted to hospital following a fall, with multiple fractures and subsequently developed acute liver failure with encephalopathy. Shock, sepsis, and liver ischaemia/thrombosis were excluded. In the context of glutathione depletion expected in HCU, hepatic dysfunction was presumed to be due to iatrogenic paracetamol toxicity, despite paracetamol intake at conventional therapeutic dose, with role of hypermethioninemia as a contributing factor being uncertain. Betaine was discontinued on hospital admission. N-Acetylcysteine (NAC) infusion was initiated. Plasma total homocysteine (tHcy) was 3.4 μmol/L 9 days following initiation of NAC treatment with a markedly elevated plasma methionine of 1278 μmol/L. tHcy concentration returned to pre-admission baseline after NAC was discontinued. Recovery following this episode was slow with a prolonged cholestatic phase and gradual improvement in jaundice and coagulopathy. We recommend that paracetamol should be administered cautiously in HCU patients due to underlying glutathione depletion and risk of toxicity even at therapeutic doses. NAC is clearly effective in lowering tHcy in classical HCU in the short-term however further research is required to assess clinical efficacy and use as a potential therapy in classical HCU.}, }
@article {pmid37147916, year = {2023}, author = {Hamedinasab, H and Rezayan, AH and Jaafari, MR and Mashreghi, M and Alvandi, H}, title = {The protective effect of N-acetylcysteine against liposome and chitosan-induced cytotoxicity.}, journal = {Journal of microencapsulation}, volume = {40}, number = {5}, pages = {357-365}, doi = {10.1080/02652048.2023.2209646}, pmid = {37147916}, issn = {1464-5246}, mesh = {Acetylcysteine/pharmacology ; Antioxidants ; *Chitosan/toxicity ; Drug Liberation ; Liposomes ; *Nanoparticles ; Particle Size ; }, abstract = {AIM: N-acetylcysteine (NAC) is an antioxidant used to moderate liposome and chitosan-induced cell cytotoxicity at their high concentrations.<br><br>METHODS: Liposome and chitosan were prepared and characterised. The cytotoxicity effect of liposome with NAC-loaded liposome (liposome-NAC) and chitosan solution with chitosan solution containing NAC (chitosan-NAC) on the A549 cell line was compared.<br><br>RESULTS: Particle size, zeta potential, and NAC drug release for liposome were 125.9&#x2009;&#xb1;&#x2009;8&#x2009;nm, -34.7&#x2009;&#xb1;&#x2009;2.1&#x2009;mV, and 51.1%&#x2009;&#xb1;&#x2009;3%, respectively. Scanning electron microscope (SEM) and transmission electron microscope (TEM) indicated spherical shape of liposome. Encapsulation efficiency of liposome-NAC was 12%&#x2009;&#xb1;&#x2009;0.98%. Particle size and zeta potential for chitosan solution were 361&#x2009;&#xb1;&#x2009;11.3&#x2009;nm and 10.8&#x2009;&#xb1;&#x2009;1.52&#x2009;mV. Stability storage study indicated good stability of chitosan and liposome. Cell viability of liposome-NAC and chitosan-NAC significantly was higher than liposome and chitosan at all four concentrations.<br><br>CONCLUSIONS: NAC has a protective effect against liposome and chitosan-induced cell toxicity.}, }
@article {pmid37147040, year = {2023}, author = {Bhatara, VS and Daniel, J and Whitman, C and Vik, T and Bernstein, B and Simkin, DR}, title = {Complementary/Integrative Medicine Treatment and Prevention of Youth Psychosis.}, journal = {Child and adolescent psychiatric clinics of North America}, volume = {32}, number = {2}, pages = {273-296}, doi = {10.1016/j.chc.2022.08.009}, pmid = {37147040}, issn = {1558-0490}, mesh = {Adolescent ; Humans ; *Integrative Medicine ; *Psychotic Disorders/drug therapy/prevention &amp; control ; *Antipsychotic Agents/therapeutic use ; *Fatty Acids, Omega-3/therapeutic use ; }, abstract = {The rationale for CIM treatments in youth psychoses is to optimize treatment by targeting symptoms not resolved by antipsychotics, such as negative symptoms (major drivers of disability). Adjunctive omega-3 fatty acids (ω-3 FA) or N-acetyl cystine (NAC usage for > 24-week) can potentially reduce negative symptoms and improve function. ω-3 FA or exercise may prevent progression to psychosis in youth (in prodromal stage). Weekly 90-minute moderate to vigorous physical activity or aerobic exercise can reduce positive and negative symptoms. Awaiting better research, CIM agents are also recommended because they are devoid of any serious side-effects.}, }
@article {pmid37142668, year = {2023}, author = {Cheng, G and Hardy, M and Kalyanaraman, B}, title = {Antiproliferative effects of mitochondria-targeted N-acetylcysteine and analogs in cancer cells.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {7254}, pmid = {37142668}, issn = {2045-2322}, mesh = {Humans ; Mice ; Animals ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Reactive Oxygen Species/pharmacology ; Mitochondria ; *Pancreatic Neoplasms/drug therapy ; }, abstract = {N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma. NAC is not readily bioavailable and is used in high concentrations. The effects of NAC have been attributed to its antioxidant and redox signaling role in mitochondria. New thiol-containing molecules targeted to mitochondria are needed. Here, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito10-NAC) that is functionally similar to NAC was synthesized and studied. Mito10-NAC has a free sulfhydryl group and is more hydrophobic than NAC. Mito10-NAC is nearly 2000-fold more effective than NAC in inhibiting several cancer cells, including pancreatic cancer cells. Methylation of NAC and Mito10-NAC also inhibited cancer cell proliferation. Mito10-NAC inhibits mitochondrial complex I-induced respiration and, in combination with monocarboxylate transporter 1 inhibitor, synergistically decreased pancreatic cancer cell proliferation. Results suggest that the antiproliferative effects of NAC and Mito10-NAC are unlikely to be related to their antioxidant mechanism (i.e., scavenging of reactive oxygen species) or to the sulfhydryl group-dependent redox modulatory effects.}, }
@article {pmid37140849, year = {2023}, author = {Zhao, Y and Wang, L and Liu, M and Du, A and Qiu, M and Shu, H and Li, L and Kong, X and Sun, W}, title = {ROS inhibition increases KDM6A-mediated NOX2 transcription and promotes macrophages oxidative stress and M1 polarization.}, journal = {Cell stress &amp; chaperones}, volume = {28}, number = {4}, pages = {375-384}, pmid = {37140849}, issn = {1466-1268}, mesh = {Reactive Oxygen Species/metabolism ; *Histones ; *Macrophages ; Oxidative Stress ; Interleukin-6/metabolism ; Histone Demethylases/pharmacology ; }, abstract = {Reactive oxygen species (ROS) play an essential role in macrophage polarization. However, the adverse effects of ROS reduction by influencing epigenetics are often ignored. In this study, lipopolysaccharide (LPS) was used to stimulate macrophages to increase the ROS in cells, and N-acetylcysteine (NAC) was used to reduce ROS. Inflammatory factors such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were used to evaluate the M1 polarization level of macrophages. Chip was used to detect the tri-methylation at lysine 27 of histone H3 (H3K27me3) level at the promoter site. It was found that the decrease of ROS in macrophages would also cause the increase of the H3K27me3 demethylase KDM6A and lead to the reduction of H3K27me3 in the NOX2 promoter, which would increase the transcription level of NOX2 and the production of ROS and ultimately promote the production of inflammatory factors. Knockout of KDM6A can reduce the transcription of NOX2 and the production of ROS of macrophages, thus preventing the M1 polarization of macrophages. The elimination of ROS in macrophages will affect macrophages by increasing KDM6A and making them produce more ROS, thus inducing oxidative stress. In comparison, direct inhibition of KDM6A can reduce ROS production and inhibit macrophage M1 polarization more effectively.}, }
@article {pmid37139830, year = {2023}, author = {Maiti, S and Nazmeen, A and Banerjee, A}, title = {Significant impact of redox regulation of estrogen-metabolizing proteins on cellular stress responses.}, journal = {Cell biochemistry and function}, volume = {41}, number = {4}, pages = {461-477}, doi = {10.1002/cbf.3796}, pmid = {37139830}, issn = {1099-0844}, mesh = {Humans ; *Cysteine/metabolism ; *Estrogens ; Estradiol ; Oxidation-Reduction ; Mutagenesis, Site-Directed ; }, abstract = {The ultimate driving force, stress, promotes adaptability/evolution in proliferating organisms, transforming tumorigenic growth. Estradiol (E2) regulates both phenomena. In this study, bioinformatics-tools, site-directed-mutagenesis (human estrogen-sulfotransferase/hSULT1E1), HepG2 cells tested with N-acetyl-cysteine (NAC/thiol-inducer) or buthionine-sulfoxamine (BSO/thiol-depletory) were evaluated for hSULT1E1 (estradiol-sulphating/inactivating) functions. Reciprocal redox regulation of steroid sulfatase (STS, E2-desulfating/activating) results in the Cys-formylglycine transition by the formylglycine-forming enzyme (FGE). The enzyme sequences and structures were examined across the phylogeny. Motif/domain and the catalytic conserve sequences and protein-surface-topography (CASTp) were investigated. The E2 binding to SULT1E1 suggests that the conserved-catalytic-domain in this enzyme has critical Cysteine 83 at position. This is strongly supported by site-directed mutagenesis/HepG2-cell research. Molecular-docking and superimposition studies of E2 with the SULT1E1 of representative species and to STS reinforce this hypothesis. SULT1E1-STS are reciprocally activated in response to the cellular-redox-environment by the critical Cys of these two enzymes. The importance of E2 in organism/species proliferation and tissue tumorigenesis is highlighted.}, }
@article {pmid37137784, year = {2023}, author = {Beyler, O and Demir, C}, title = {Use of n-acetylcysteine therapy in patients with relapsed refractory thrombotic thrombocytopenic purpura.}, journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis}, volume = {62}, number = {4}, pages = {103713}, doi = {10.1016/j.transci.2023.103713}, pmid = {37137784}, issn = {1473-0502}, mesh = {Humans ; *Purpura, Thrombotic Thrombocytopenic/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; von Willebrand Factor/therapeutic use ; Plasma Exchange ; *Anemia, Hemolytic ; *Thrombosis/drug therapy ; ADAMTS13 Protein/therapeutic use ; }, abstract = {There is limited data on the use of NAC in the literature. We would like to present the satisfactory results we obtained in our resistant and relapsed patients as a case series.Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by ADAMTS13 (a disintegrin with thrombospondin type 1 motif and metalloprotease activity, member13) deficiency. Von Willebrand factor (vWF) initiates platelet aggregation and thus thrombus formation. The multimers of vWF are cleaved by ADAMTS13. Because of the decreased activity of ADAMTS13, ultra-large multimers accumulate and end-organ damage occurs. TTP is characterized by microangiopathic hemolytic anemia (MAHA), severe thrombocytopenia, and organ ischemia resulting from vascular occlusion caused by thrombi. Plasma exchange therapy (PEX) remains the mainstay of TTP therapy. Patients who do not respond to PEX and corticosteroids require additional treatments such as rituximab and caplacizumab. NAC reduces disulfide bonds in mucin polymers through its free sulfhydryl group. Thus, the size and viscosity of the mucins are reduced. VWF is structurally similar to mucin. Based on this similarity, Chen and colleagues showed that NAC can reduce the size and reactivity of ultralarge multimers of vWF, such as ADAMTS13. Currently, there is not much information to suggest that NAC has any clinical value in the treatment of TTP. In this case series of 4 refractory patients, we would like to present the responses we obtained with the addition of NAC therapy. NAC can be added to PEX and glucocorticoid therapy as supportive therapy, especially in unresponsive patients.}, }
@article {pmid37134194, year = {2023}, author = {Orgel, E and Knight, KR and Chi, YY and Malvar, J and Rushing, T and Mena, V and Eisenberg, LS and Rassekh, SR and Ross, CJD and Scott, EN and Neely, M and Neuwelt, EA and Muldoon, LL and Freyer, DR}, title = {Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {29}, number = {13}, pages = {2410-2418}, pmid = {37134194}, issn = {1557-3265}, support = {K23 DC014291/DC/NIDCD NIH HHS/United States ; UL1 TR000130/TR/NCATS NIH HHS/United States ; UL1 TR001855/TR/NCATS NIH HHS/United States ; }, mesh = {Adolescent ; Humans ; Child ; Cisplatin/adverse effects ; Acetylcysteine/therapeutic use/adverse effects ; *Hearing Loss/chemically induced/prevention &amp; control ; *Neoplasms/drug therapy/chemically induced ; Administration, Intravenous ; }, abstract = {PURPOSE: Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL.<br><br>PATIENTS AND METHODS: In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations.<br><br>RESULTS: Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021-0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011-0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection.<br><br>CONCLUSIONS: NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.}, }
@article {pmid37134105, year = {2023}, author = {Shim, JY and Chung, JO and Jung, D and Kang, PS and Park, SY and Kendi, AT and Lowe, VJ and Lee, S}, title = {Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells.}, journal = {PloS one}, volume = {18}, number = {5}, pages = {e0281496}, pmid = {37134105}, issn = {1932-6203}, mesh = {Humans ; Mitophagy ; Reactive Oxygen Species/metabolism ; Streptozocin/pharmacology ; *Insulin-Secreting Cells/metabolism ; Protein Kinases/metabolism ; *Diabetes Mellitus/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Tumor Suppressor Proteins/metabolism ; }, abstract = {Diabetes mellitus (DM) is one of the most researched metabolic diseases worldwide. It leads to extensive complications such as cardiovascular disease, nephropathy, retinopathy, and peripheral and central nervous system through an inability to produce or respond to insulin. Although oxidative stress-mediated mitophagy has been reported to play an important role in the pathogenesis of DM, specific studies are still lacking as well as remain highly controversial. Here, we found that Parkin-mediated mitophagy in pancreatic β cells under streptozotocin (STZ)-diabetic stress was induced by Polo-like kinase 3 (Plk3) and inhibited by the transcription factor Forkhead Box O3A (FOXO3A). STZ stress induces mitochondrial recruitment of Parkin through Plk3-mediated mitochondrial reactive oxygen species (ROS) generation, which causes pancreatic cell damage. Conversely, FOXO3A acts as negative feedback to prevent diabetic stress by inhibiting Plk3. Meanwhile, antioxidants including N-acetylcysteine (NAC) and natural COA water scientifically block these mitochondrial ROS and mitochondrial recruitment of Parkin by inhibiting Plk3. Through a 3D organoid ex vivo model, we confirmed that not only ROS inhibitors but also mitophagy inhibitory factors such as 3-MA or Parkin deletion can compensate for pancreatic cell growth and insulin secretion under STZ diabetic stress. These findings suggest that the Plk3-mtROS-PINK1-Parkin axis is a novel mitophagy process that inhibits pancreatic β-cell growth and insulin secretion and FOXO3A and antioxidants may provide new alternatives for effective diabetes treatment strategies in the future.}, }
@article {pmid37132544, year = {2023}, author = {Wilson, MM and Danielian, PS and Salus, G and Ferretti, R and Whittaker, CA and Lees, JA}, title = {BMI1 is required for melanocyte stem cell maintenance and hair pigmentation.}, journal = {Pigment cell &amp; melanoma research}, volume = {36}, number = {5}, pages = {399-406}, doi = {10.1111/pcmr.13088}, pmid = {37132544}, issn = {1755-148X}, support = {P01 CA042063/CA/NCI NIH HHS/United States ; P30 CA014051/CA/NCI NIH HHS/United States ; }, mesh = {Mice ; Animals ; Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism ; *Melanoma/metabolism ; Proto-Oncogene Proteins ; *Skin Neoplasms/metabolism ; Stem Cells/metabolism ; Polycomb Repressive Complex 1/genetics/metabolism ; Pigmentation ; Melanocytes/metabolism ; Hair/metabolism ; }, abstract = {The epigenetic repressor BMI1 plays an integral role in promoting the self-renewal and proliferation of many adult stem cell populations, and also tumor types, primarily through silencing the Cdkn2a locus, which encodes the tumor suppressors p16[Ink4a] and p19[Arf] . However, in cutaneous melanoma, BMI1 drives epithelial-mesenchymal transition programs, and thus metastasis, while having little impact on proliferation or primary tumor growth. This raised questions about the requirement and role for BMI1 in melanocyte stem cell (McSC) biology. Here, we demonstrate that murine melanocyte-specific Bmi1 deletion causes premature hair greying and gradual loss of melanocyte lineage cells. Depilation enhances this hair greying defect, accelerating depletion of McSCs in early hair cycles, suggesting that BMI1 acts to protect McSCs against stress. RNA-seq of McSCs, harvested before onset of detectable phenotypic defects, revealed that Bmi1 deletion derepresses p16[Ink4a] and p19[Arf] , as observed in many other stem cell contexts. Additionally, BMI1 loss downregulated the glutathione S-transferase enzymes, Gsta1 and Gsta2, which can suppress oxidative stress. Accordingly, treatment with the antioxidant N-acetyl cysteine (NAC) partially rescued melanocyte expansion. Together, our data establish a critical function for BMI1 in McSC maintenance that reflects a partial role for suppression of oxidative stress, and likely transcriptional repression of Cdkn2a.}, }
@article {pmid37131727, year = {2023}, author = {Everton, E and Del Rio-Moreno, M and Villacorta-Martin, C and Singh Bawa, P and Lindstrom-Vautrin, J and Muramatsu, H and Rizvi, F and Smith, AR and Tam, Y and Pardi, N and Kineman, R and Waxman, DJ and Gouon-Evans, V}, title = {Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2023.04.17.537197}, pmid = {37131727}, support = {I01 BX004448/BX/BLRD VA/United States ; TL1 TR001410/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity.<br><br>APPROACH AND RESULTS: Our results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe nonintegrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice.<br><br>CONCLUSIONS: Our study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.}, }
@article {pmid37123961, year = {2023}, author = {Mitra, JK and Hansda, U and Bandyopadhyay, D and Sarkar, S and Sahoo, J}, title = {The role of a combination of N-acetylcysteine and magnesium sulfate as adjuvants to standard therapy in acute organophosphate poisoning: A randomized controlled trial.}, journal = {Heliyon}, volume = {9}, number = {4}, pages = {e15376}, pmid = {37123961}, issn = {2405-8440}, abstract = {BACKGROUND: Mortality in acute organophosphate (OP) poisoning remains high despite current standard therapy with atropine and oximes. Due to dose-limiting side effects of atropine, novel therapies are targeting other putative mechanisms of injury, including oxidative damage, to reduce atropine dosage.<br><br>OBJECTIVES: N-acetylcysteine (NAC) and magnesium sulfate (MgSO4) have different mechanisms of actions and should act synergistically in OP poisoning. In this study, we wanted to evaluate whether this novel combination, used as an adjuvant to standard care, could improve clinical outcomes.<br><br>METHODS: The study was conducted in the Emergency Department and ICU of AIIMS Bhubaneswar (a tertiary care center and government teaching institute) between July 2019 and July 2021. Eighty-eight adult patients with history and clinical features of acute OP poisoning were randomly allocated (1:1) into two groups. The Study group received 600&#xa0;mg NAC via nasogastric tube thrice daily for 3 days plus a single dose of 4&#xa0;g Inj. MgSO4 IV on first day and the Control group received suitably matched placebo (double-blinding) - in addition to standard care in both the groups. The primary outcome measure was to compare the total dose of Inj. Atropine required (cumulative over the entire treatment duration) between the control group and the study group receiving NAC and MgSO4. The secondary outcome measures were lengths of ICU and hospital stays, need and duration of mechanical ventilation, the differences in BuChE activity, oxidative stress biomarkers - MDA and GSH levels, the incidences of adverse effects including delayed sequalae like intermediate syndrome and OPIDN, and comparison of mortality between the two groups.<br><br>RESULTS: Data from 43 patients in Control and 42 patients in Study group was finally analyzed. The baseline parameters were comparable. Total atropine requirements were lower in the Study group [175.33&#xa0;&#xb1;&#xa0;81.25&#xa0;mg (150.01-200.65)] compared to the Control [210.63&#xa0;&#xb1;&#xa0;102.29&#xa0;mg (179.15-242.11)] [Mean&#xa0;&#xb1;&#xa0;SD (95% CI)], but was not statistically significant. No significant differences in any of the other clinical or biochemical parameters were noted.<br><br>CONCLUSION: The N-acetylcysteine and MgSO4 combination as adjuvants failed to significantly reduce atropine requirements, ICU/hospital stay, mechanical ventilatory requirements, mortality and did not offer protection against oxidative damage.}, }
@article {pmid37122089, year = {2023}, author = {Huang, S and Zhang, L and Luo, J and Wu, D and Ma, K and Chen, Y and Ma, S and Feng, L and Li, F and Liu, D and Deng, J and Tan, C}, title = {Cysteamine and N-Acetyl-cysteine Alleviate Placental Oxidative Stress and Barrier Function Damage Induced by Deoxynivalenol.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {18}, pages = {6846-6858}, doi = {10.1021/acs.jafc.3c00399}, pmid = {37122089}, issn = {1520-5118}, mesh = {Pregnancy ; Animals ; Female ; Swine ; *Placenta/metabolism ; *Cysteamine/metabolism/pharmacology ; Antioxidants/pharmacology/metabolism ; Acetylcysteine/pharmacology/metabolism ; Oxidative Stress ; }, abstract = {Sows are highly sensitive to deoxynivalenol (DON) and susceptible to reproductive toxicity caused by oxidative stress, but the potential mechanisms and effective interventions remain unclear. Here, we investigated the role of two antioxidants (cysteamine and N-acetyl-cysteine) in regulating the reproductive performance, redox status, and placental barrier function of sows and their potential mechanisms under DON exposure. Maternal dietary supply of antioxidants from day 85 of gestation to parturition reduced the incidence of stillbirths and low-birth-weight piglets under DON exposure. Moreover, the alleviation of DON-induced reproductive toxicity by dietary antioxidants was associated with the alleviation of placental oxidative stress, the enhancement of the placental barrier, and the vascular function of sows. Furthermore, in vivo and in vitro vascularized placental barrier modeling further demonstrated that antioxidants could reverse both DON transport across the placenta and DON-induced increase of placental barrier permeability. The molecular mechanism of antioxidant resistance to DON toxicity may be related to the signal transducer and activator of the transcription-3-occludin/zonula occludens-1 signaling pathway. Collectively, these results demonstrate the potential of antioxidants to protect the mother from DON-induced reproductive toxicity by alleviating placental oxidative stress and enhancing the placental barrier.}, }
@article {pmid37119245, year = {2023}, author = {Wong, KK and Kua, KP and Ooi, KS and Cheah, FC}, title = {The effects of N-acetylcysteine on lung alveolar epithelial cells infected with respiratory syncytial virus.}, journal = {The Malaysian journal of pathology}, volume = {45}, number = {1}, pages = {43-50}, pmid = {37119245}, issn = {0126-8635}, mesh = {Child ; Infant ; Humans ; Child, Preschool ; Acetylcysteine/pharmacology/metabolism ; Alveolar Epithelial Cells/metabolism ; Epithelial Cells/metabolism ; *Respiratory Syncytial Virus, Human/metabolism ; Lung ; *Respiratory Syncytial Virus Infections/drug therapy/metabolism ; }, abstract = {INTRODUCTION: Respiratory syncytial virus (RSV) is one of the most common causes of acute lower respiratory infection in infants and young children. Mucolytic agents, such as acetylcysteine and carbocysteine have reported benefits in alleviating acute upper or lower respiratory infections. Among these, N-acetylcysteine (NAC) has cyto-protective effects when cells are infected with the RSV.<br><br>MATERIALS AND METHODS: Our study investigated primarily the dose-dependent effects of NAC on respiratory alveolar epithelial (A549) cells when co-cultured with RSV in vitro. Three different concentrations of NAC were used, 0.1 mM, 1 mM, and 10 mM. The cytotoxicity of RSV-infected cells was measured by lactate dehydrogenase and antiviral activity of NAC on cell cultures was evaluated by immunofluorescence.<br><br>RESULTS: Pre-treatment with the highest dose, 10 mM NAC, resulted in features of cell injury even without RSV infection. The proportion of cells infected by RSV and RSV-induced cell death decreased by more than 3-fold when cells were pre-treated with 1 mM NAC. Pre-treatment at the lowest dose, 0.1 mM, did not show any significant changes.<br><br>CONCLUSION: A moderate dose of NAC (1 mM) appeared protective of RSV infection to lung alveolar epithelial cells. However, a higher dose of NAC (10 mM) may be relatively toxic and injurious to these cells.}, }
@article {pmid37119225, year = {2023}, author = {Russell, SE and Skvarc, DR and Mohebbi, M and Camfield, D and Byrne, LK and Turner, A and Ashton, MM and Berk, M and Dodd, S and Malhi, GS and Cotton, SM and Bush, AI and Dean, OM}, title = {The Impact of N-acetylcysteine on Major Depression: Qualitative Observation and Mixed Methods Analysis of Participant Change during a 12-week Randomised Controlled Trial.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {21}, number = {2}, pages = {320-331}, pmid = {37119225}, issn = {1738-1088}, abstract = {OBJECTIVE: N-acetylcysteine (NAC) is a novel therapeutic agent with multiple mechanisms of action in the central nervous system and a favourable side effect profile. Clinical evidence indicates that adjunctive NAC may reduce the severity of depressive symptoms in individuals with major depressive disorder (MDD).<br><br>METHODS: A 12-week randomised controlled trial of 2,000 mg/day adjunctive NAC for MDD found no significant improvement at the primary endpoint (week 12) but did see improvements at the post-discontinuation interview (week 16). Within the context of patient-centered treatment, mixed-methods qualitative analysis was also included to explore factors that may determine individual responses to adjunctive NAC treatment. These data were drawn, under blinded conditions, from clinician notes recorded in the case report form. Using the DSM-5 symptom profile for MDD as the initial framework, themes were developed and explored. Frequencies were compared between placebo and NAC groups.<br><br>RESULTS: Per protocol analysis of individual themes across the six interviews revealed group differences in favour of NAC for overall depressive affect, optimism, relationships and reduced functional impairment.<br><br>CONCLUSION: This study provides further evidence for the utility of the mixed methods approach complimenting the primary findings using traditional quantitative analyses, as well as being able to capture additional, often more subtle, evidence of individual symptom-level change that reflects improvement in functional abilities in response to NAC supplementation. The use of mixed methods to explore outcomes from psychiatric studies should be considered in future to work towards improved patient-centred care and both confirm quantitative findings and generate novel hypotheses.}, }
@article {pmid37118950, year = {2023}, author = {Kim, KH and Park, MJ and Park, NC and Park, HJ}, title = {Effect of N-acetyl-L-cysteine on Testicular Tissue in Busulfan-Induced Dysfunction in the Male Reproductive System.}, journal = {The world journal of men's health}, volume = {41}, number = {4}, pages = {882-891}, pmid = {37118950}, issn = {2287-4208}, support = {20200007/PNUH/Pusan National University Hospital/Korea ; }, abstract = {PURPOSE: This study aimed to evaluate the protective effect of N-acetyl-L-cysteine (NAC) as an antioxidant on busulfan-induced testicular dysfunction in mice and elucidate its possible mechanism of action.<br><br>MATERIALS AND METHODS: Thirty-two C57BL/6 male mice were randomly divided into four groups (n=8/group) as follows: (1) control group (oral administration of saline [0.1 mL daily] for 35 days); (2) NAC group (oral administration of NAC [10 mg/kg daily] for 35 days); (3) busulfan group (double intraperitoneal injections of 20 mg/kg; total dose of 40 mg/kg); and (4) busulfan+NAC group (after double intraperitoneal injections of 20 mg/kg; total dose of 40 mg/kg, NAC administration [10 mg/kg daily] for 35 days). The testes were removed, weighed, and subjected to sperm parameter analysis and morphology assessment. Reproductive hormone, serum/testicular reactive oxygen species (ROS) level, oxidative stress and antioxidant markers were evaluated. The testicular expression of Nrf2 and HO-1 was examined using RT-qPCR.<br><br>RESULTS: Busulfan treatment significantly decreased testicular weight, sperm count, and serum testosterone levels. Atrophy and degeneration of germinal epithelium were observed in the busulfan group. NAC administration after busulfan treatment partially attenuated the deterioration of testis weight, sperm quality, serum hormones, histomorphometric changes, and oxidative and antioxidative status. NAC treatment resulted in a considerable improvement in Nrf2 and HO-1 mRNA expression levels.<br><br>CONCLUSIONS: This study provides compelling evidence that NAC as a potent antioxidant has significant protective effects against busulfan-induced male reproductive impairment possibly through modification of the Nrf2/HO-1 signaling pathway.}, }
@article {pmid37116249, year = {2023}, author = {Bilister Egilmez, C and Azak Pazarlar, B and Erdogan, MA and Erbas, O}, title = {N-acetyl cysteine: A new look at its effect on PTZ-induced convulsions.}, journal = {Epilepsy research}, volume = {193}, number = {}, pages = {107144}, doi = {10.1016/j.eplepsyres.2023.107144}, pmid = {37116249}, issn = {1872-6844}, mesh = {Rats ; Animals ; Pentylenetetrazole/toxicity ; Rats, Sprague-Dawley ; *Myoclonus/drug therapy ; Acetylcysteine/adverse effects ; Electroencephalography ; *Epilepsy/drug therapy ; Seizures/chemically induced/drug therapy ; Superoxide Dismutase ; Anticonvulsants/adverse effects ; Disease Models, Animal ; }, abstract = {INTRODUCTION/AIM: Epilepsy is widely investigated as a common neurological disease requiring pharmacologically effective agents. N-acetyl cysteine (NAC), has become a remarkable molecule with its role in both antioxidant and glutaminergic modulation. There are many points and processes waiting to be revealed regarding the role of NAC in epilepsy.<br><br>MATERIALS AND METHODS: Pentylenetetrazole (PTZ) was administered to induce seizures in a total number of 48 Sprague-Dawley rats. 35&#xa0;mg/kg PTZ dose as a sub-convulsive dose was administered to 24 animals to monitor EEG changes, while 70&#xa0;mg/kg PTZ dose which was a convulsive dose was administered to 24 animals to determine seizure-related behavioral changes with the Racine's scale. 30&#xa0;min before the seizure-induced procedure, NAC was administered at doses of 300 and 600&#xa0;mg/kg as pretreatment to investigate anti-seizure and anti-oxidative effects. The spike percentage, the stage of convulsion, and the onset time of the first myoclonic jerk were evaluated to determine the anti-seizure effect. Furthermore, its effect on oxidative stress was determined by measuring both malondialdehyde (MDA) level and superoxide dismutase (SOD) enzyme activity.<br><br>RESULTS: There was a dose-dependent reduction in the seizure stage and prolonged onset time of the first myoclonic jerk in rats with NAC pretreatment. EEG recordings resulted in a dose-dependent decrease in spike percentages. Moreover, the same dose-dependent changes were observed in oxidative stress biomarkers, both 300&#xa0;mg/kg NAC and 600&#xa0;mg/kg decreased MDA levels and ameliorated SOD activity.<br><br>CONCLUSION: We can report that 300&#xa0;mg/kg and 600&#xa0;mg/kg doses of NAC are promising with their reducing effect on convulsions and have a beneficial effect by preventing oxidative stress. In addition, NAC has been also determined that this effect is dose-dependent. Detailed and comparative studies are needed on the convulsion-reducing effect of NAC in epilepsy.}, }
@article {pmid37113636, year = {2023}, author = {Salajegheh, F and Shafieipour, S and Najminejad, Z and Pourzand, P and Nakhaie, M and Jahangiri, S and Sarmadian, R and Gilani, A and Rukerd, MRZ}, title = {HAV-induced acalculous cholecystitis: A case report and literature review.}, journal = {Clinical case reports}, volume = {11}, number = {4}, pages = {e7254}, pmid = {37113636}, issn = {2050-0904}, abstract = {Hepatitis A virus (HAV) has some life-threatening extrahepatic complications, such as acute acalculous cholecystitis (AAC). We present HAV-induced AAC in a young female, based on clinical, laboratory, and imaging findings, and conduct a literature review. The patient became irritable, which progressed to lethargy, as well as a significant decline in liver function, indicating acute liver failure (ALF). She was immediately managed in the intensive care unit with close airway and hemodynamic monitoring after being diagnosed with ALF (ICU). The patient's condition was improving, despite only close monitoring and supportive treatment with ursodeoxycholic acid (UDCA) and N-acetyl cysteine (NAC).}, }
@article {pmid37111348, year = {2023}, author = {Soto, ME and Manzano-Pech, L and Palacios-Chavarría, A and Valdez-Vázquez, RR and Guarner-Lans, V and Pérez-Torres, I}, title = {N-Acetyl Cysteine Restores the Diminished Activity of the Antioxidant Enzymatic System Caused by SARS-CoV-2 Infection: Preliminary Findings.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {4}, pages = {}, pmid = {37111348}, issn = {1424-8247}, support = {312167//Consejo Nacional de Ciencia y Tecnolog&#xed;a (CONACYT) M&#xe9;xico/ ; }, abstract = {SARS-CoV-2 infects type II pneumocytes and disrupts redox homeostasis by overproducing reactive oxygen species (ROS). N-acetyl cysteine (NAC) is a precursor of the synthesis of glutathione (GSH) and it restores the loss of redox homeostasis associated to viral infections. The aim of the study is to evaluate the effect of the treatment with NAC on the enzymatic antioxidant system in serum from patients infected by SARS-CoV-2. We evaluated the enzymatic activities of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), -S-transferase (GST), and reductase (GR) by spectrophotometry and the concentrations of the glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO2[-]), and lipid peroxidation (LPO) in serum. The activity of the extracellular super oxide dismutase (ecSOD) was determined by native polyacrylamide gels, and 3-nitrotyrosine (3-NT) was measured by ELISA. A decrease in the activities of the ecSOD, TrxR, GPx, GST GR, (p = 0 ≤ 0.1), and the GSH, TAC, thiols, and NO2[-] (p ≤ 0.001) concentrations and an increase in LPO and 3-NT (p = 0.001) concentrations were found in COVID-19 patients vs. healthy subjects. The treatment with NAC as an adjuvant therapy may contribute to a reduction in the OS associated to the infection by SARS-CoV-2 through the generation of GSH. GSH promotes the metabolic pathways that depend on it, thus contributing to an increase in TAC and to restore redox homeostasis.}, }
@article {pmid37109533, year = {2023}, author = {Amante, C and De Soricellis, C and Luccheo, G and Luccheo, L and Russo, P and Aquino, RP and Del Gaudio, P}, title = {Flogomicina: A Natural Antioxidant Mixture as an Alternative Strategy to Reduce Biofilm Formation.}, journal = {Life (Basel, Switzerland)}, volume = {13}, number = {4}, pages = {}, pmid = {37109533}, issn = {2075-1729}, abstract = {The National Institute of Health has reported that approximately 80% of chronic infections are associated with biofilms, which are indicated as one of the main reasons for bacteria's resistance to antimicrobial agents. Several studies have revealed the role of N-acetylcysteine (NAC), in reducing biofilm formation induced by different microorganisms. A novel mixture made up of NAC and different natural ingredients (bromelain, ascorbic acid, Ribes nigrum, resveratrol, and pelargonium) has been developed in order to obtain a pool of antioxidants as an alternative strategy for biofilm reduction. The study has demonstrated that the mixture is able to significantly enhance NAC activity against different Gram-positive and Gram-negative bacteria. It has shown an increase in NAC permeation in vitro through an artificial fluid, moving from 2.5 to 8 μg/cm[2] after 30 min and from 4.4 to 21.6 μg/cm[2] after 180 min, and exhibiting a strongly fibrinolytic activity compared to the single components of the mixture. Moreover, this novel mixture has exhibited an antibiofilm activity against S aureus and the ability to reduce S. aureus growth by more than 20% in a time-killing assay, while on E. coli, and P. mirabilis, the growth was reduced by more than 80% compared to NAC. The flogomicina mixture has also been proven capable of reducing bacterial adhesion to abiotic surfaces of E.coli, by more than 11% concerning only the NAC. In combination with amoxicillin, it has been shown to significantly increase the drug's effectiveness after 14 days, offering a safe and natural way to reduce the daily dosage of antibiotics in prolonged therapies and consequently, reduce antibiotic resistance.}, }
@article {pmid37108758, year = {2023}, author = {Zadrożniak, M and Szymański, M and Łuszczki, JJ}, title = {N-Acetyl-L-cysteine Affects Ototoxicity Evoked by Amikacin and Furosemide Either Alone or in Combination in a Mouse Model of Hearing Threshold Decrease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108758}, issn = {1422-0067}, support = {474/CU/CSP VA/United States ; }, mesh = {Mice ; Animals ; Amikacin/toxicity ; Furosemide/adverse effects ; Acetylcysteine/adverse effects ; *Ototoxicity ; *Hearing Loss/chemically induced/drug therapy/prevention &amp; control ; Anti-Bacterial Agents/adverse effects ; Hearing ; Aminoglycosides ; *Deafness ; Auditory Threshold ; }, abstract = {Drug-induced ototoxicity resulting from therapy with aminoglycoside antibiotics and loop diuretics is one of the main well-known causes of hearing loss in patients. Unfortunately, no specific protection and prevention from hearing loss are recommended for these patients. This study aimed at evaluating the ototoxic effects produced by mixtures of amikacin (AMI, an aminoglycoside antibiotic) and furosemide (FUR, a loop diuretic) in the mouse model as the hearing threshold decreased by 20% and 50% using auditory brainstem responses (ABRs). Ototoxicity was produced by the combinations of a constant dose of AMI (500 mg/kg; i.p.) on FUR-induced hearing threshold decreases, and a fixed dose of FUR (30 mg/kg; i.p.) on AMI-induced hearing threshold decreases, which were determined in two sets of experiments. Additionally, the effects of N-acetyl-L-cysteine (NAC; 500 mg/kg; i.p.) on the hearing threshold decrease of 20% and 50% were determined by means of an isobolographic transformation of interactions to detect the otoprotective action of NAC in mice. The results indicate that the influence of a constant dose of AMI on FUR-induced hearing threshold decreases was more ototoxic in experimental mice than a fixed dose of FUR on AMI-induced ototoxicity. Moreover, NAC reversed the AMI-induced, but not FUR-induced, hearing threshold decreases in this mouse model of hearing loss. NAC could be considered an otoprotectant in the prevention of hearing loss in patients receiving AMI alone and in combination with FUR.}, }
@article {pmid37108481, year = {2023}, author = {Brivio, P and Gallo, MT and Gruca, P and Lason, M and Litwa, E and Fumagalli, F and Papp, M and Calabrese, F}, title = {Chronic N-Acetyl-Cysteine Treatment Enhances the Expression of the Immediate Early Gene Nr4a1 in Response to an Acute Challenge in Male Rats: Comparison with the Antidepressant Venlafaxine.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108481}, issn = {1422-0067}, mesh = {Animals ; Male ; Rats ; *Acetylcysteine/pharmacology/therapeutic use ; Antidepressive Agents/therapeutic use ; *Genes, Immediate-Early ; Rats, Wistar ; Venlafaxine Hydrochloride/pharmacology/therapeutic use ; }, abstract = {Despite several antidepressant treatments being available in clinics, they are not effective in all patients. In recent years, N-acetylcysteine (NAC) has been explored as adjunctive therapy for many psychiatric disorders, including depression, for its antioxidant properties. Given the promising efficacy of this compound for the treatment of such pathologies, it is fundamental to investigate, at the preclinical level, the ability of the drug to act in the modulation of neuroplastic mechanisms in basal conditions and during challenging events in order to highlight the potential features of the drug useful for clinical efficacy. To this aim, adult male Wistar rats were treated with the antidepressant venlafaxine (VLX) (10 mg/kg) or NAC (300 mg/kg) for 21 days and then subjected to 1 h of acute restraint stress (ARS). We found that NAC enhanced the expression of several immediate early genes, markers of neuronal plasticity in the ventral and dorsal hippocampus, prefrontal cortex and amygdala, and in particular it mediated the acute-stress-induced upregulation of Nr4a1 expression more than VLX. These data suggested the ability of NAC to induce coping strategies to face external challenges, highlighting its potential for the improvement of neuroplastic mechanisms for the promotion of resilience, in particular via the modulation of Nr4a1.}, }
@article {pmid37108119, year = {2023}, author = {Chadwick, W and Maudsley, S and Hull, W and Havolli, E and Boshoff, E and Hill, MDW and Goetghebeur, PJD and Harrison, DC and Nizami, S and Bedford, DC and Coope, G and Real, K and Thiemermann, C and Maycox, P and Carlton, M and Cole, SL}, title = {The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {24}, number = {8}, pages = {}, pmid = {37108119}, issn = {1422-0067}, mesh = {Mice ; Humans ; Animals ; *Alzheimer Disease/genetics/pathology ; Amyloid beta-Peptides/genetics ; Memory ; *Cognition Disorders ; Animals, Genetically Modified ; Disease Models, Animal ; }, abstract = {Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.}, }
@article {pmid37107344, year = {2023}, author = {Romero-Miguel, D and Casquero-Veiga, M and Fernández, J and Lamanna-Rama, N and Gómez-Rangel, V and Gálvez-Robleño, C and Santa-Marta, C and Villar, CJ and Lombó, F and Abalo, R and Desco, M and Soto-Montenegro, ML}, title = {Maternal Supplementation with N-Acetylcysteine Modulates the Microbiota-Gut-Brain Axis in Offspring of the Poly I:C Rat Model of Schizophrenia.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107344}, issn = {2076-3921}, support = {project number PI17/01766, and grant number BA21/00030//Ministerio de Ciencia e Innovaci&#xf3;n, Instituto de Salud Carlos III, co-financed by the European Regional Development Fund (ERDF), "A way to make Europe"/ ; project PID2021-128862OB-I00//MCIN /AEI /10.13039/501100011033 / FEDER, UE/ ; project number CB07/09/0031//CIBER de Salud Mental - Instituto de Salud Carlos III/ ; project numbers 2017/085, 2022/008917//Delegaci&#xf3;n del Gobierno para el Plan Nacional sobre Drogas/ ; 2016/01//Fundaci&#xf3;n Alicia Koplowitz/ ; grant, PEJD-2018-PRE/BMD-7899//Consejer&#xed;a de Educaci&#xf3;n e investigaci&#xf3;n, Comunidad de Madrid, co-funded by the European Social Fund "Investing in your future"/ ; "Programa Intramural de Impulso a la I+D+I 2019"//Instituto de investigaci&#xf3;n Sanitaria Gregorio Mara&#xf1;&#xf3;n/ ; PT20/00044//Ministerio de Ciencia e Innovaci&#xf3;n, Instituto de Salud Carlos III/ ; x//The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovaci&#xf3;n (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505)/ ; Contrato Intramural Postdoctoral//FINBA/ ; SV-PA-21-AYUD/2021/51347//Ayudas para grupos de investigaci&#xf3;n de organismos del Principado de Asturias/ ; }, abstract = {The microbiota-gut-brain axis is a complex interconnected system altered in schizophrenia. The antioxidant N-acetylcysteine (NAC) has been proposed as an adjunctive therapy to antipsychotics in clinical trials, but its role in the microbiota-gut-brain axis has not been sufficiently explored. We aimed to describe the effect of NAC administration during pregnancy on the gut-brain axis in the offspring from the maternal immune stimulation (MIS) animal model of schizophrenia. Pregnant Wistar rats were treated with PolyI:C/Saline. Six groups of animals were studied according to the study factors: phenotype (Saline, MIS) and treatment (no NAC, NAC 7 days, NAC 21 days). Offspring were subjected to the novel object recognition test and were scanned using MRI. Caecum contents were used for metagenomics 16S rRNA sequencing. NAC treatment prevented hippocampal volume reduction and long-term memory deficits in MIS-offspring. In addition, MIS-animals showed lower bacterial richness, which was prevented by NAC. Moreover, NAC7/NAC21 treatments resulted in a reduction of proinflammatory taxons in MIS-animals and an increase in taxa known to produce anti-inflammatory metabolites. Early approaches, like this one, with anti-inflammatory/anti-oxidative compounds, especially in neurodevelopmental disorders with an inflammatory/oxidative basis, may be useful in modulating bacterial microbiota, hippocampal size, as well as hippocampal-based memory impairments.}, }
@article {pmid37107324, year = {2023}, author = {Zhou, Z and Qi, J and Wu, Y and Li, C and Bao, W and Lin, X and Zhu, A}, title = {Nuciferine Effectively Protects Mice against Acetaminophen-Induced Liver Injury.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107324}, issn = {2076-3921}, support = {82104520//National Natural Science Foundation of China/ ; 82200663//National Natural Science Foundation of China/ ; 2021J05045//Natural Science Foundation of Fujian Province/ ; 2022J01199//Natural Science Foundation of Fujian Province/ ; }, abstract = {Acetaminophen (APAP) overdose still poses a major clinical challenge and is a leading cause of acute liver injury (ALI). N-acetylcysteine (NAC) is the only approved antidote to treat APAP toxicity while NAC therapy can trigger side effects including severe vomiting and even shock. Thus, new insights in developing novel therapeutic drugs may pave the way for better treatment of APAP poisoning. Previous research has reported that nuciferine (Nuci) possesses anti-inflammatory and antioxidant properties. Therefore, the objective of this study was proposed to investigate the hepatoprotective effects of Nuci and explore its underlying mechanisms. Mice were intraperitoneally (i.p.) administered with APAP (300 mg/kg) and subsequently injected with Nuci (25, 50, and 100 mg/kg, i.p.) at 30 min after APAP overdose. Then, all mice were sacrificed at 12 h after APAP challenge for further analysis. Nuci-treated mice did not show any side effects and our results revealed that treating Nuci significantly attenuated APAP-induced ALI, as confirmed by histopathological examinations, biochemical analysis, and diminished hepatic oxidative stress and inflammation. The in silico prediction and mRNA-sequencing analysis were performed to explore the underlying mechanisms of Nuci. GO and KEGG enrichment of the predicted target proteins of Nuci includes reactive oxygen species, drug metabolism of cytochrome P450 (CYP450) enzymes, and autophagy. Furthermore, the mRNA-sequencing analyses indicated that Nuci can regulate glutathione metabolic processes and anti-inflammatory responses. Consistently, we found that Nuci increased the hepatic glutathione restoration but decreased APAP protein adducts in damaged livers. Western blot analysis further confirmed that Nuci effectively promoted hepatic autophagy in APAP-treated mice. However, Nuci could not affect the expression levels of the main CYP450 enzymes (CYP1A2, CYP2E1, and CYP3A11). These results demonstrated that Nuci may be a potential therapeutic drug for APAP-induced ALI via amelioration of the inflammatory response and oxidative stress, regulation of APAP metabolism, and activation of autophagy.}, }
@article {pmid37107239, year = {2023}, author = {Boonnate, P and Kariya, R and Okada, S}, title = {Shikonin Induces ROS-Dependent Apoptosis Via Mitochondria Depolarization and ER Stress in Adult T Cell Leukemia/Lymphoma.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107239}, issn = {2076-3921}, support = {22K08482//Grants-in-Aid for Science Research from the Ministry of Education, Science, Sports, and Culture of Japan/ ; }, abstract = {Adult T cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy that develops in some elderly human T-cell leukemia virus (HTVL-1) carriers. ATLL has a poor prognosis despite conventional and targeted therapies, and a new safe and efficient therapy is required. Here, we examined the anti-ATLL effect of Shikonin (SHK), a naphthoquinone derivative that has shown several anti-cancer activities. SHK induced apoptosis of ATLL cells accompanied by generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, and induction of endoplasmic reticulum (ER) stress. Treatment with a ROS scavenger, N-acetylcysteine (NAC), blocked both loss of mitochondrial membrane potential and ER stress, and prevented apoptosis of ATLL cells, indicating that ROS is an upstream trigger of SHK-induced apoptosis of ATLL cells through disruption of the mitochondrial membrane potential and ER stress. In an ATLL xenografted mouse model, SHK treatment suppressed tumor growth without significant adverse effects. These results suggest that SHK could be a potent anti-reagent against ATLL.}, }
@article {pmid37107211, year = {2023}, author = {Dimitriadis, F and Borgmann, H and Struck, JP and Salem, J and Kuru, TH}, title = {Antioxidant Supplementation on Male Fertility-A Systematic Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {4}, pages = {}, pmid = {37107211}, issn = {2076-3921}, abstract = {UNLABELLED: Our aim was to review the current literature regarding the effect of antioxidant supplementation (AS) on male fertility parameters, as AS is commonly used to treat male infertility due to the availability and affordability of antioxidants in many parts of the world.<br><br>MATERIALS AND METHODS: PubMed, Medline, and Cochrane electronic bibliographies were searched using the modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate studies on the benefit of antioxidant therapy on infertile men. Results were analyzed regarding the following aspects: (a) ingredient and dose; (b) potential mechanism of action and rationale for use; and (c) effect on various reported outcomes.<br><br>RESULTS: Thus, 29 studies found a substantial positive effect of AS on outcomes of assisted reproductive therapy (ART), WHO semen parameters, and live-birth rate. Carnitines, Vitamin E and C, N-acetyl cysteine, coenzyme Q10, selenium, zinc, folic acid, and lycopene were beneficial ingredients. Nevertheless, some studies did not show a substantial change in one or more factors.<br><br>CONCLUSION: AS seems to have a positive effect on male fertility. Environmental factors may play an increasing role in fertility. Further studies are needed to determine the optimal AS combination and the influence of environmental factors.}, }
@article {pmid37102780, year = {2023}, author = {Pillai, K and Mekkawy, AH and Akhter, J and Morris, DL}, title = {Effect of Nebulized BromAc on Rheology of Artificial Sputum: Relevance to Muco-Obstructive Respiratory Diseases.}, journal = {Advances in respiratory medicine}, volume = {91}, number = {2}, pages = {146-163}, pmid = {37102780}, issn = {2543-6031}, support = {N.A//Mucpahrm pty ltd/ ; }, mesh = {Humans ; Acetylcysteine/therapeutic use/pharmacology ; Sputum ; Bromelains/therapeutic use/pharmacology ; *COVID-19 ; Expectorants/therapeutic use/pharmacology ; *Respiration Disorders ; Rheology ; }, abstract = {Respiratory diseases such as cystic fibrosis, COPD, and COVID-19 are difficult to treat owing to viscous secretions in the airways that evade mucocilliary clearance. Earlier studies have shown success with BromAc as a mucolytic agent. Hence, we tested the formulation on two gelatinous airway representative sputa models, to determine whether similar efficacy exist. Sputum lodged in an endotracheal tube was treated to aerosol N-acetylcysteine, bromelain, or their combination (BromAc). After measuring the particle size of aerosolized BromAc, the apparent viscosity was measured using a capillary tube method, whilst the sputum flow was assessed using a 0.5 mL pipette. Further, the concentration of the agents in the sputa after treatment were quantified using chromogenic assays. The interaction index of the different formulations was also determined. Results indicated that the mean particle size of BromAc was suitable for aerosol delivery. Bromelain and N-acetylcysteine affected both the viscosities and pipette flow in the two sputa models. BromAc showed a greater rheological effect on both the sputa models compared to individual agents. Further, a correlation was found between the rheological effects and the concentration of agents in the sputa. The combination index using viscosity measurements showed synergy only with 250 µg/mL bromelain + 20 mg/mL NAC whilst flow speed showed synergy for both combinations of bromelain (125 and 250 µg/mL) with 20 mg/mL NAC. Hence, this study indicates that BromAc may be used as a successful mucolytic for clearing airway congestion caused by thick mucinous immobile secretions.}, }
@article {pmid37100568, year = {2023}, author = {Balani, KA and Sahasrabudhe, TR and Mehta, K and Mirza, S}, title = {TB patients: Is sputum disinfection important?.}, journal = {The Indian journal of tuberculosis}, volume = {70}, number = {2}, pages = {142-146}, doi = {10.1016/j.ijtb.2022.03.027}, pmid = {37100568}, issn = {0019-5707}, mesh = {Humans ; *Mycobacterium tuberculosis ; Case-Control Studies ; Disinfection ; Sputum/microbiology ; *Tuberculosis, Pulmonary/drug therapy/prevention &amp; control/microbiology ; *Disinfectants/pharmacology/therapeutic use ; Phenols/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Patients with pulmonary tuberculosis (TB) may produce large amount of infectious sputum which needs to be handled carefully both in health care and household settings. As mycobacteria may survive for long duration in sputum; proper collection, disinfection and disposal is necessary to avoid potential disease transmission. We aimed to assess the efficacy of bedside disinfectant treatment of sputum produced by TB patients using easily available disinfectants that can be used both in TB wards and household settings, to sterilize the infected sputum and compared it with sputum without disinfectant treatment.<br><br>METHODS: It was a prospective case control study. Sputum of total 95 patients with sputum smear positive pulmonary tuberculosis was collected in sputum containers with lids. Patients on anti-tubercular treatment for more than 2 weeks were excluded. Each patient was given 3 sterile sputum containers to expectorate, Container A containing 5% Phenol solution, Container B containing 4.8% Chloroxylenol and Container C without any disinfectant, acting as a control. Thick sputum was liquified with Mucolytic agent N-acetyl cysteine (NAC). Aliquots of the sputum were sent for culture in Lowenstein-Jensen medium on day 0 (to confirm alive mycobacteria) and on day 1 i.e., after 24 hours (to evaluate effective sterilization). Drug resistance testing was done on all grown mycobacteria.<br><br>RESULTS: If the samples on day 0 did not grow mycobacteria (indicating non-viable mycobacteria) or day 1 sample grew contaminants in any of the three containers, they were excluded from the analysis (15/95). In remaining 80 patients, bacilli were alive on day 0 and remained alive even after 24 hours (day 1) in control samples (without disinfectants). The sputum was effectively disinfected resulting in no growth after 24 hours (day 1) in 71/80 (88.75%) containing 5% Phenol and 72/80 (90%) with 4.8% Chloroxylenol. The efficacy of disinfection was 71/73 (97.2%) and 72/73 (98.6%) for drug sensitive mycobacteria respectively. The mycobacteria however remained alive with these disinfectants in all 7 samples of drug-resistant mycobacteria with an efficacy of 0%.<br><br>CONCLUSION: We recommend use of simple disinfectants like 5% Phenol or 4.8% Chloroxylenol for safe disposal of sputum of pulmonary tuberculosis patients. It is necessary as sputum collected without disinfection remained infectious after 24 hours. Resistance of all drug resistant mycobacteria to disinfectants was a novel chance finding. This needs further confirmatory studies.}, }
@article {pmid37090713, year = {2023}, author = {Zhang, X and Xu, L and Ma, W and Shi, B and Liu, Q and Song, Y and Fang, C and Liu, P and Qiao, S and Cai, J and Zhang, Z}, title = {N-acetyl-L-cysteine alleviated the oxidative stress-induced inflammation and necroptosis caused by excessive NiCl2 in primary spleen lymphocytes.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1146645}, pmid = {37090713}, issn = {1664-3224}, mesh = {Mice ; Animals ; *Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Spleen/metabolism ; Necroptosis ; Hydrogen Peroxide/metabolism ; Oxidative Stress ; Inflammation/metabolism ; Lymphocytes/metabolism ; RNA, Messenger/metabolism ; }, abstract = {INTRODUCTION: Nickel (Ni) is widely used in industrial manufacturing and daily life due to its excellent physical and chemical properties. However, Ni has the potential to harm animals' immune system, and spleen is a typical immune organ. Therefore, it is crucial to understand the mechanism of NiCl2 damage to the spleen. The purpose of this study is to investigate the effects of different concentrations of NiCl2 exposure and intervening with strong antioxidants on spleen lymphocytes to better understand the damage mechanism of Ni on spleen lymphocytes.<br><br>METHODS: In this experiment, mice spleen lymphocytes were used as the research object. We first measured the degree of oxidative stress, inflammation, and necroptosis caused by different NiCl2 concentrations. Subsequently, we added the powerful antioxidant N-acetyl-L-cysteine (NAC) and used hydrogen peroxide (H2O2) as the positive control in subsequent experiments.<br><br>RESULTS: Our findings demonstrated that NiCl2 could cause spleen lymphocytes to produce a large number of reactive oxygen species (ROS), which reduced the mRNA level of antioxidant enzyme-related genes, the changes in GSH-PX, SOD, T-AOC, and MDA, the same to the mitochondrial membrane potential. ROS caused the body to produce an inflammatory response, which was manifested by tumor necrosis factor (TNF-&#x3b1;) in an immunofluorescence experiment, and the mRNA level of related inflammatory genes significantly increased. In the case of caspase 8 inhibition, TNF-&#x3b1; could cause the occurrence of necroptosis mediated by RIP1, RIP3, and MLKL. AO/EB revealed that spleen lymphocytes exposed to NiCl2 had significant necroptosis, and the mRNA and protein levels of RIP1, RIP3, and MLKL increased significantly. Moreover, the findings demonstrated that NAC acted as an antioxidant to reduce oxidative stress, inflammation, and necroptosis caused by NiCl2 exposure.<br><br>DISCUSSION: Our findings showed that NiCl2 could cause oxidative stress, inflammation, and necroptosis in mice spleen lymphocytes, which could be mitigated in part by NAC. The study provides a point of reference for understanding the toxicological effect of NiCl2. The study suggests that NAC may be useful in reducing the toxicological effect of NiCl2 on the immune system. The research may contribute to the development of effective measures to prevent and mitigate the toxicological effects of NiCl2 on the immune system.}, }
@article {pmid37087805, year = {2023}, author = {Dong, H and Li, H and Fang, L and Zhang, A and Liu, X and Xue, F and Chen, Y and Liu, W and Chi, Y and Wang, W and Sun, T and Ju, M and Dai, X and Yang, R and Fu, R and Zhang, L}, title = {Increased reactive oxygen species lead to overactivation of platelets in essential thrombocythemia.}, journal = {Thrombosis research}, volume = {226}, number = {}, pages = {18-29}, doi = {10.1016/j.thromres.2023.04.001}, pmid = {37087805}, issn = {1879-2472}, mesh = {Mice ; Animals ; *Thrombocythemia, Essential/drug therapy/genetics ; Reactive Oxygen Species/metabolism ; Janus Kinases/metabolism/pharmacology ; Signal Transduction ; STAT Transcription Factors/metabolism/pharmacology ; Blood Platelets/metabolism ; *Thrombosis/metabolism ; Acetylcysteine/metabolism/pharmacology ; }, abstract = {INTRODUCTION: Platelet function, rather than platelet count, plays a crucial role in thrombosis in essential thrombocythemia (ET). However, little is known about the abnormal function of platelets in ET. Here, we investigated the functional characteristics of platelets in ET hemostasis to explore the causes of ET platelet dysfunction and new therapeutic strategies for ET.<br><br>MATERIALS AND METHODS: We analyzed platelet aggregation, activation, apoptosis, and reactive oxygen species (ROS) in ET patients and JAK2V617F-positive ET-like mice. The effects of ROS on platelet function and the underlying mechanism were investigated by inhibiting ROS using N-acetylcysteine (NAC).<br><br>RESULTS: Platelet aggregation, activation, apoptosis, ROS, and clot retraction were elevated in ET. No significant differences were observed between ET patients with JAK2V617F or CALR mutations. Increased ROS activated the JAK-STAT pathway, which may further influence platelet function. Inhibition of platelet ROS by NAC reduced platelet aggregation, activation, and apoptosis, and prolonged bleeding time. Furthermore, NAC treatment reduced platelet count in ET-like mice by inhibiting platelet production from megakaryocytes.<br><br>CONCLUSIONS: Elevated ROS in ET platelets resulted in enhanced platelet activation, function and increased risk of thrombosis. NAC offers a potential therapeutic strategy for reducing platelet count.}, }
@article {pmid37084995, year = {2023}, author = {Li, Y and Guo, M and Niu, S and Shang, M and Chang, X and Sun, Z and Zhang, R and Shen, X and Xue, Y}, title = {ROS and DRP1 interactions accelerate the mitochondrial injury induced by polystyrene nanoplastics in human liver HepG2 cells.}, journal = {Chemico-biological interactions}, volume = {379}, number = {}, pages = {110502}, doi = {10.1016/j.cbi.2023.110502}, pmid = {37084995}, issn = {1872-7786}, mesh = {Humans ; *Microplastics/toxicity ; Reactive Oxygen Species/metabolism ; *Polystyrenes/toxicity ; Hep G2 Cells ; Plastics/metabolism/pharmacology ; Dynamins/metabolism ; Mitochondria ; Liver/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis ; }, abstract = {Microplastics have become a serious environmental pollutant and subsequently have harmful effects on human health. Thus, the impacts of microplastics on human cells need to be explored. In the present study, the cytotoxic effects at the subcellular-organelle levels to polystyrene nanoplastics (PS-NPs, diameter 21.5 ± 2.7 nm) were investigated in the human hepatocellular carcinoma (HepG2) cell line. The cell viability exposed to PS-NPs at the concentrations of 6.25, 12.5, 25 and 50 μg/mL for 24 h diminished in a concentration-dependent manner. The PS-NPs treatment induced mitochondrial injuries, including morphological changes, decreased adenosine triphosphate (ATP) production and the loss of mitochondrial membrane potentials (MMP). The PS-NPs treatment could further spark cell apoptosis by upregulating caspase 3, caspase 9, cytochrome c, and Bcl-2 associated X protein (Bax)/B-cell lymphoma-2 (Bcl-2) in HepG2 cells, which is related to the mitochondrial dysfunction. PS-NPs exposure stimulated the excessive cellular reactive oxygen species (ROS) production and also induced mitochondrial fission by upregulating dynamin-related protein 1 (DRP1) and P-DRP1, but downregulating optic atrophy protein 1 (OPA1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) expression levels. The above effects on mitochondria damage induced by PS-NPs were reversed by the pretreatment of N-acetylcysteine (NAC), mitochondrial division inhibitor 1 (Mdivi-1) and DRP1 siRNA. The results suggested that the interaction between ROS and DRP1-dependent mitochondrial division could promote mitochondrial lesions and mitochondria-related apoptosis caused by PS-NPs. These findings on molecular mechanisms provide a theoretical basis for preventing the hazards caused by microplastics to human health.}, }
@article {pmid37080569, year = {2023}, author = {Addante, A and Raymond, W and Gitlin, I and Charbit, A and Orain, X and Scheffler, AW and Kuppe, A and Duerr, J and Daniltchenko, M and Drescher, M and Graeber, SY and Healy, AM and Oscarson, S and Fahy, JV and Mall, MA}, title = {A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases.}, journal = {The European respiratory journal}, volume = {61}, number = {5}, pages = {}, pmid = {37080569}, issn = {1399-3003}, support = {P01 HL128191/HL/NHLBI NIH HHS/United States ; R01 HL080414/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Humans ; Mice ; Animals ; Expectorants/therapeutic use ; Sulfhydryl Compounds/pharmacology/therapeutic use ; *Cystic Fibrosis ; Acetylcysteine/pharmacology/therapeutic use ; Sputum ; *Lung Diseases, Obstructive/drug therapy ; Inflammation/pathology ; Carbohydrates/pharmacology/therapeutic use ; Lung ; }, abstract = {BACKGROUND: Mucin disulfide cross-links mediate pathologic mucus formation in muco-obstructive lung diseases. MUC-031, a novel thiol-modified carbohydrate compound, cleaves disulfides to cause mucolysis. The aim of this study was to determine the mucolytic and therapeutic effects of MUC-031 in sputum from patients with cystic fibrosis (CF) and mice with muco-obstructive lung disease (βENaC-Tg mice).<br><br>METHODS: We compared the mucolytic efficacy of MUC-031 and existing mucolytics (N-acetylcysteine (NAC) and recombinant human deoxyribonuclease I (rhDNase)) using rheology to measure the elastic modulus (G') of CF sputum, and we tested effects of MUC-031 on airway mucus plugging, inflammation and survival in &#x3b2;ENaC-Tg mice to determine its mucolytic efficacy in vivo.<br><br>RESULTS: In CF sputum, compared to the effects of rhDNase and NAC, MUC-031 caused a larger decrease in sputum G', was faster in decreasing sputum G' by 50% and caused mucolysis of a larger proportion of sputum samples within 15&#x2005;min of drug addition. Compared to vehicle control, three treatments with MUC-031 in 1&#x2005;day in adult &#x3b2;ENaC-Tg mice decreased airway mucus content (16.8&#xb1;3.2 versus 7.5&#xb1;1.2&#x2005;nL&#xb7;mm[-2], p<0.01) and bronchoalveolar lavage cells (73&#x2009;833&#xb1;6930 versus 47&#x2009;679&#xb1;7736 cells&#xb7;mL[-1], p<0.05). Twice-daily treatment with MUC-031 for 2&#x2005;weeks also caused decreases in these outcomes in adult and neonatal &#x3b2;ENaC-Tg mice and reduced mortality from 37% in vehicle-treated &#x3b2;ENaC-Tg neonates to 21% in those treated with MUC-031 (p<0.05).<br><br>CONCLUSION: MUC-031 is a potent and fast-acting mucolytic that decreases airway mucus plugging, lessens airway inflammation and improves survival in &#x3b2;ENaC-Tg mice. These data provide rationale for human trials of MUC-031 in muco-obstructive lung diseases.}, }
@article {pmid37079050, year = {2023}, author = {Hannon Barroeta, P and O'Sullivan, MJ and Zisterer, DM}, title = {The role of the Nrf2/GSH antioxidant system in cisplatin resistance in malignant rhabdoid tumours.}, journal = {Journal of cancer research and clinical oncology}, volume = {149}, number = {11}, pages = {8379-8391}, pmid = {37079050}, issn = {1432-1335}, mesh = {Humans ; Child ; *Cisplatin/pharmacology ; Antioxidants/pharmacology ; *Rhabdoid Tumor/drug therapy ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/metabolism ; Glutathione/metabolism ; Buthionine Sulfoximine ; Apoptosis ; Cell Line, Tumor ; }, abstract = {PURPOSE: Malignant rhabdoid tumour (MRT) is a rare and aggressive childhood malignancy that occurs in the kidneys or central nervous system and is associated with very poor prognosis. Chemoresistance is a major issue in the treatment of this malignancy leading to an urgent need for a greater understanding of its underlying mechanisms in MRT and novel treatment strategies for MRT patients. The balance between oxidative stress mediated by reactive oxygen species (ROS) and the antioxidant system has become a subject of interest in cancer therapy research. Studies have implicated key players of the antioxidant system in chemotherapeutic including the well-known antioxidant glutathione (GSH) and the transcription factor nuclear erythroid-related factor-2 (Nrf2). METHODS: This study evaluated the role of these components in the response of MRT cells to treatment with the commonly used chemotherapeutic agent, cisplatin.<br><br>RESULTS: This study characterised the basal levels of GSH, ROS and Nrf2 in a panel of MRT cell lines and found a correlation between the expression profile of the antioxidant defence system and cisplatin sensitivity. Results showed that treatment with ROS scavenger N-acetylcysteine (NAC) protected cells from cisplatin-induced ROS and apoptosis. Interestingly, depleting GSH levels with the inhibitor buthionine sulphoximine (BSO) enhanced cisplatin-induced ROS and sensitised cells to cisplatin. Lastly, targeting Nrf2 with the small molecule inhibitor ML385 or by siRNA diminished GSH levels, enhanced ROS and sensitised resistant MRT cells to cisplatin.<br><br>CONCLUSIONS: These results suggest that targeting the Nrf2/GSH antioxidant system may present a novel therapeutic strategy to combat chemoresistance in rhabdoid tumours.}, }
@article {pmid37075699, year = {2023}, author = {Yap, YS and Hu, J}, title = {Exploiting metabolic vulnerabilities in breast cancers with NF1 loss.}, journal = {Cell reports. Medicine}, volume = {4}, number = {4}, pages = {101010}, pmid = {37075699}, issn = {2666-3791}, mesh = {Humans ; Female ; Neurofibromin 1/genetics/metabolism ; *Breast Neoplasms/drug therapy ; Phosphatidylinositol 3-Kinases/metabolism ; *Biochemical Phenomena ; }, abstract = {Auf der Maur et al.[1] identify neurofibromin 1 (NF1) loss as a mechanism of resistance to PI3K inhibitor in breast cancer cells. NF1 loss leads to enhanced glycolysis, which may be targeted with the antioxidant N-acetyl cysteine (NAC).}, }
@article {pmid37072676, year = {2023}, author = {Jensen, GS and Cruickshank, D and Hamilton, DE}, title = {Disruption of Established Bacterial and Fungal Biofilms by a Blend of Enzymes and Botanical Extracts.}, journal = {Journal of microbiology and biotechnology}, volume = {33}, number = {6}, pages = {715-723}, pmid = {37072676}, issn = {1738-8872}, mesh = {Humans ; Anti-Bacterial Agents/pharmacology/metabolism ; Staphylococcus aureus ; *Anti-Infective Agents/pharmacology ; *Staphylococcal Infections/microbiology ; Biofilms ; Pseudomonas aeruginosa ; Microbial Sensitivity Tests ; }, abstract = {Microbial biofilms are resilient, immune-evasive, often antibiotic-resistant health challenges, and increasingly the target for research into novel therapeutic strategies. We evaluated the effects of a nutraceutical enzyme and botanical blend (NEBB) on established biofilm. Five microbial strains with known implications in chronic human illnesses were tested: Candida albicans, Staphylococcus aureus, Staphylococcus simulans (coagulase-negative, penicillin-resistant), Borrelia burgdorferi, and Pseudomonas aeruginosa. The strains were allowed to form biofilm in vitro. Biofilm cultures were treated with NEBB containing enzymes targeted at lipids, proteins, and sugars, also containing the mucolytic compound N-acetyl cysteine, along with antimicrobial extracts from cranberry, berberine, rosemary, and peppermint. The post-treatment biofilm mass was evaluated by crystal-violet staining, and metabolic activity was measured using the MTT assay. Average biofilm mass and metabolic activity for NEBB-treated biofilms were compared to the average of untreated control cultures. Treatment of established biofilm with NEBB resulted in biofilm-disruption, involving significant reductions in biofilm mass and metabolic activity for Candida and both Staphylococcus species. For B. burgdorferi, we observed reduced biofilm mass, but the remaining residual biofilm showed a mild increase in metabolic activity, suggesting a shift from metabolically quiescent, treatment-resistant persister forms of B. burgdorferi to a more active form, potentially more recognizable by the host immune system. For P. aeruginosa, low doses of NEBB significantly reduced biofilm mass and metabolic activity while higher doses of NEBB increased biofilm mass and metabolic activity. The results suggest that targeted nutraceutical support may help disrupt biofilm communities, offering new facets for integrative combinational treatment strategies.}, }
@article {pmid37072331, year = {2023}, author = {Khazaie, S and Jafari, M and Golamloo, M and Asgari, A and Heydari, J and Salehi, M and Salem, F}, title = {Cumulative Effects of Paraoxon and Leptin on Oxidative Damages in Rat Tissues: Prophylactic and Therapeutic Roles of N-Acetylcysteine.}, journal = {Biochemistry. Biokhimiia}, volume = {88}, number = {2}, pages = {165-178}, doi = {10.1134/S0006297923020013}, pmid = {37072331}, issn = {1608-3040}, mesh = {Rats ; Male ; Animals ; *Antioxidants/pharmacology/metabolism ; *Acetylcysteine/pharmacology ; Paraoxon/toxicity ; Rats, Wistar ; Leptin/pharmacology ; Oxidative Stress ; }, abstract = {Exposure to paraoxon (POX) and leptin (LP) could cause an imbalance between oxidants and antioxidants in an organism, which can be prevented by introduction of exogenous antioxidants such as N-acetylcysteine (NAC). The aim of this study was to evaluate synergic or additive effects of administration of exogenous LP plus POX on the antioxidant status, as well as the prophylactic and therapeutic roles of NAC in various rat tissues. Fifty-four male Wistar rats were divided into nine groups treated with different compounds: Control (no treatment), POX (0.7 mg/kg), NAC (160 mg/kg), LP (1 mg/kg), POX+LP, NAC-POX, POX-NAC, NAC-POX+LP, and POX+LP-NAC. In the last five groups, only the order of administered compounds differed. After 24 h, plasma and tissues were sampled and examined. The results showed that administration of POX plus LP significantly increased biochemical indices in plasma and antioxidant enzymes activities and decreased glutathione content in the liver, erythrocytes, brain, kidney, and heart. In addition, cholinesterase and paraoxonase 1 activities in the POX+LP-treated group were decreased and malondialdehyde level was increased in the liver, erythrocytes, and brain. However, administration of NAC rectified induced changes although not to the same extent. Our study suggests that POX or LP administration engage the oxidative stress system per se; however, their combination did not produce significantly greater effects. Moreover, both prophylactic and therapeutic treatments of rats with NAC supported the antioxidant defense against oxidative damage in tissues, most probably through both its free radical scavenging ability and maintaining intracellular GSH levels. It can therefore be suggested that NAC has particularly protective effects against POX or/and LP toxicity.}, }
@article {pmid37072049, year = {2023}, author = {Hao, XS and Feng, PP and Zhang, YY and Wang, FZ and Wang, GL and Fei, HR}, title = {Scutebarbatine A induces ROS-mediated DNA damage and apoptosis in breast cancer cells by modulating MAPK and EGFR/Akt signaling pathway.}, journal = {Chemico-biological interactions}, volume = {378}, number = {}, pages = {110487}, doi = {10.1016/j.cbi.2023.110487}, pmid = {37072049}, issn = {1872-7786}, mesh = {Humans ; Female ; Reactive Oxygen Species/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Superoxides ; *Breast Neoplasms/drug therapy ; Signal Transduction ; *Antineoplastic Agents/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; Apoptosis ; DNA Damage ; ErbB Receptors/metabolism ; MAP Kinase Signaling System ; Cell Line, Tumor ; }, abstract = {Scutebarbatine A (SBT-A), a diterpenoid alkaloid, has exerted cytotoxicity on hepatocellular carcinoma cells in our previous works. Here, the antitumor activity of SBT-A in breast cancer cells and the underlying mechanism were explored. The anti-proliferative effect of SBT-A was measured by trypan blue staining, 5-ethynyl-2'-deoxyuridine (EdU) incorporation and colony formation assay. DNA double-strand breaks (DSBs) were evaluated by observing the nuclear focus formation of γ-H2AX. Cell cycle distribution was assessed by flow cytometry. Apoptosis was determined by a TUNEL assay. Intracellular reactive oxygen species (ROS) generation and superoxide production were measured with 2', 7'-dichlorofluorescein diacetate (DCFH-DA) and dihydroethidium (DHE) staining, respectively. The results indicated that SBT-A showed a dose-dependent cytotoxic effect against breast cancer cells while revealing less toxicity toward MCF-10A breast epithelial cells. Moreover, SBT-A remarkably induced DNA damage, cell cycle arrest and apoptosis in both MDA-MB-231 and MCF-7 cells. SBT-A treatment increased the levels of ROS and cytosolic superoxide production. Pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to block viability reduction, DNA damage, apoptosis and endoplasmic reticulum (ER) stress caused by SBT-A. By exposure to SBT-A, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) was upregulated, while the phosphorylation of extracellular signal-regulated kinase (ERK) was downregulated. In addition, SBT-A inhibited the EGFR signaling pathway by decreasing EGFR expression and phosphorylation of Akt and p70S6K. As mentioned above, SBT-A has a potent inhibitory effect on breast cancer cells through induction of DNA damage, apoptosis and ER stress via ROS generation and modulation of MAPK and EGFR/Akt signaling pathway.}, }
@article {pmid37071164, year = {2023}, author = {Maestro, C and Leache, L and Gutiérrez-Valencia, M and Saiz, LC and Gómez, H and Bacaicoa, MC and Erviti, J}, title = {Efficacy and safety of N-acetylcysteine for preventing post-intravenous contrast acute kidney injury in patients with kidney impairment: a systematic review and meta-analysis.}, journal = {European radiology}, volume = {33}, number = {9}, pages = {6569-6581}, pmid = {37071164}, issn = {1432-1084}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Contrast Media/adverse effects ; *Acute Kidney Injury/etiology ; Renal Replacement Therapy/adverse effects/methods ; Kidney ; }, abstract = {OBJECTIVES: N-Acetylcysteine (NAC) may confer protection against post-contrast acute kidney injury (PC-AKI), although evidence is sparse and conflicting. The objective was to analyse the evidence on the efficacy and safety of NAC vs no administration of NAC in preventing PC-AKI in patients with pre-existing kidney impairment undergoing a non-interventional radiological examination requiring intravenous (IV) contrast media (CM) administration.<br><br>METHODS: We carried out a systematic review including randomised controlled trials (RCTs) published in MEDLINE, EMBASE, and Clinicaltrials.gov up to May 2022. The primary outcome was PC-AKI. Secondary outcomes included the requirement of renal replacement therapy, all-cause mortality, serious adverse events, and length of hospital stay. We conducted the meta-analyses using the Mantel-Haenszel method and following a random-effects model.<br><br>RESULTS: NAC was not associated with a significant reduction in PC-AKI (RR 0.47, 95%CI 0.20 to 1.11; 8 studies; 545 participants; I[2]: 56%; low certainty), all-cause mortality (RR 0.67, 95%CI 0.29 to 1.54; 2 studies; 129 participants; very low certainty), or length of hospital stay (mean difference 9.2&#xa0;days, 95%CI&#x2009;-&#x2009;20.08 to 38.48; 1 study; 42 participants; very low certainty). The impact on other outcomes could not be determined.<br><br>CONCLUSIONS: NAC may not reduce the risk of PC-AKI or all-cause mortality in people with kidney impairment who receive an IV CM prior to radiological imaging, although the certainty of the evidence is very low or low.<br><br>CLINICAL RELEVANCE STATEMENT: Our review concludes that prophylactic administration of N-acetylcysteine may not significantly reduce the risk of acute kidney injury in patients with kidney impairment receiving an intravenous contrast media prior to non-interventional radiological imaging, which may support decision making in this common clinical scenario.<br><br>KEY POINTS: &#x2022; N-Acetylcysteine may not significantly reduce the risk of acute kidney injury in patients with kidney impairment receiving an intravenous contrast media prior to non-interventional radiological imaging. &#x2022; All-cause mortality and length of hospital stay would not be decreased with the administration of N-Acetylcysteine in this setting.}, }
@article {pmid37069635, year = {2023}, author = {Jia, D and Guo, S and Jia, Z and Gao, Z and You, K and Gong, J and Li, S}, title = {N-acetylcysteine in the Donor, Recipient, or Both Donor and Recipient in Liver Transplantation: A Systematic Review With Meta-analysis and Trial Sequential Analysis.}, journal = {Transplantation}, volume = {107}, number = {9}, pages = {1976-1990}, doi = {10.1097/TP.0000000000004597}, pmid = {37069635}, issn = {1534-6080}, mesh = {Humans ; Acetylcysteine/adverse effects ; *Liver Transplantation/adverse effects ; Graft Survival ; Transferases ; *Reperfusion Injury/etiology/prevention &amp; control ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is a potentially effective drug for treating ischemia-reperfusion injury in transplanted livers, but its effect remains controversial.<br><br>METHODS: A systematic review and meta-analysis of relevant clinical trials published and registered in the Cochrane Library, MEDLINE, EMBASE, ClinicalTrial.gov , WHO ICTRP, etc, before March 20, 2022 were conducted and registered with PROSPERO (CRD42022315996). Data were pooled using a random effects model or a fixed effects model based on the amount of heterogeneity.<br><br>RESULTS: Thirteen studies with 1121 participants, 550 of whom received NAC, were included. Compared with the control, NAC significantly reduced the incidence of primary graft nonfunction (relative risk [RR], 0.27; 95% confidence interval [CI], 0.08-0.96), the incidence of postoperative complications (RR, 0.52; 95% CI, 0.41-0.67), the peak postoperative aspartate transferase level (mean difference [MD], -267.52; 95% CI, -345.35 to -189.68), and the peak alanine transferase level (MD, -293.29; 95% CI, -370.39 to -216.20). NAC also improved 2-y (RR, 1.18; 95% CI, 1.01-1.38) graft survival rate. However, NAC increased the intraoperative cryoprecipitate (MD, 0.94; 95% CI, 0.42-1.46) and red blood cell (MD, 0.67; 95% CI, 0.15-1.19) requirements. Moreover, NAC was administered in various modes in these studies, including to the donor, recipient, or both. Subgroup analysis and network meta-analysis showed that NAC administration to recipients could play a more significant role than the other 2 administration modes.<br><br>CONCLUSIONS: Our study supports the protective effect of NAC against LT-induced ischemia-reperfusion injury and shows better clinical outcomes of NAC administration to recipients.}, }
@article {pmid37066621, year = {2023}, author = {Mazrad, ZAI and Leiske, MN and Tabor, RF and Nicolazzo, JA and Kempe, K}, title = {Comparison of the Anti-inflammatory Activity and Cellular Interaction of Brush Polymer-N-Acetyl Cysteine Conjugates in Human and Murine Microglial Cell Lines.}, journal = {Molecular pharmaceutics}, volume = {20}, number = {5}, pages = {2686-2701}, doi = {10.1021/acs.molpharmaceut.3c00140}, pmid = {37066621}, issn = {1543-8392}, mesh = {Mice ; Humans ; Animals ; *Microglia/metabolism ; *Polymers/metabolism ; Lipopolysaccharides/pharmacology ; Neuroinflammatory Diseases ; Anti-Inflammatory Agents/pharmacology/metabolism ; Acetylcysteine/chemistry ; }, abstract = {Microglia-mediated neuroinflammation is commonly associated with neurodegeneration and has been implicated in several neurological disorders, such as Alzheimer's disease and Parkinson's disease. Therefore, it is crucial to develop a detailed understanding of the interaction of potential nanocarriers with microglial cells to efficiently deliver anti-inflammatory molecules. In this study, we applied brush polymers as a modular platform to systematically investigate their association with murine (BV-2) and human (HMC3) microglial cell lines in the presence and absence of the pro-inflammatory inducer lipopolysaccharide (LPS) using flow cytometry. Brush polymers of different sizes and shapes, ranging from ellipsoid to worm-like cylinders, were prepared through a combination of the two building blocks carboxylated N-acylated poly(aminoester)s (NPAEs)-based polymers and poly(2-ethyl-2-oxazoline)-NH2 (PEtOx-NH2) and characterized by [1]H NMR spectroscopy, size exclusion chromatography, and small-angle neutron scattering. Generally, ellipsoidal particles showed the highest cellular association. Moreover, while no significant differences in murine cell association were observed, the brush polymers revealed a significant accumulation in LPS-activated human microglia compared to resting cells, emphasizing their higher affinity to activated HMC3 cells. Brush polymers with the highest cell association were further modified with the anti-inflammatory agent N-acetyl cysteine (NAC) in a reversible manner. The brush polymer-NAC conjugates were found to significantly attenuate the production of interleukin 6 (p < 0.001) in LPS-activated HMC3 cells compared to LPS-activated BV-2 cells. Thus, the presented brush polymer-NAC conjugates showed a high anti-inflammatory activity in human microglia, suggesting their potential for disease-targeted therapy of microglial-mediated neuroinflammation in the future.}, }
@article {pmid37065769, year = {2023}, author = {Gonzales-Moreno, C and Fernandez-Hubeid, LE and Holgado, A and Virgolini, MB}, title = {Low-dose N-acetyl cysteine prevents paraquat-induced mortality in Caenorhabditis elegans.}, journal = {microPublication biology}, volume = {2023}, number = {}, pages = {}, pmid = {37065769}, issn = {2578-9430}, abstract = {Exposure to the herbicide paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium dichloride) affects the redox balance of the cell, an effect that can be restored by antioxidants, including N-acetyl cysteine (NAC). One hour of exposure to PQ (0 mM, 10 mM, 50 mM, or 100 mM) dose-dependently increased mortality in Caenorhabditis elegans after exposure (immediate toxicity), while this effect was more evident 24 hours thereafter (delayed toxicity). Importantly, pretreatment with NAC 0.5 mM for one hour partially prevented mortality in the immediate assay, while it had no effect in the delayed test, revealing the importance of long-term studies when evaluating toxicity.}, }
@article {pmid37062330, year = {2023}, author = {Xue, J and Li, Z and Li, X and Hua, C and Shang, P and Zhao, J and Liu, K and Xie, F}, title = {Evaluation of cigarette smoke-induced oxidative stress and inflammation in BEAS-2B cells based on a lung microfluidic chip.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {176}, number = {}, pages = {113787}, doi = {10.1016/j.fct.2023.113787}, pmid = {37062330}, issn = {1873-6351}, mesh = {*Microfluidics ; *Cigarette Smoking ; Lung ; Oxidative Stress ; Inflammation/chemically induced/pathology ; Nicotiana ; }, abstract = {Oxidative stress and inflammation induced by cigarette smoking are associated with the pathology process of various chronic respiratory diseases, including asthma, emphysema, chronic obstructive pulmonary disease and cancer. Compared with conventional cell culture techniques, microfluidic chips can provide a continuous nutrient supply, mimic the in vivo physiological microenvironment of the cells, and conduct an integrated and flexible analysis of cell status and functions. Here, we designed and fabricated a bionic-lung chip, which was applied to perform cigarette smoke exposure of BEAS-2B cells cultured at the gas-liquid interface. The oxidative stress and inflammation in the cells exposed to cigarette smoke were investigated on chip. The results showed that cellular damage, oxidative stress and inflammatory response induced by cigarette smoke in the chip were dependent on smoke concentration and time after smoke exposure. N-Acetylcysteine (NAC) significantly inhibited these effects of cigarette smoke exposure on the cells at the gas-liquid interface within the chip.}, }
@article {pmid37059385, year = {2023}, author = {Mao, Z and Li, H and Zhao, XL and Zeng, XH}, title = {Hydrogen sulfide protects Sertoli cells against toxicant Acrolein-induced cell injury.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {176}, number = {}, pages = {113784}, doi = {10.1016/j.fct.2023.113784}, pmid = {37059385}, issn = {1873-6351}, mesh = {Male ; Humans ; *Hydrogen Sulfide/pharmacology/metabolism ; Sertoli Cells/metabolism ; Acrolein/toxicity ; Sulfides/pharmacology ; Antioxidants/pharmacology ; }, abstract = {Acrolein (ACR), a highly toxic α,β-unsaturated aldehyde, is considered to be a common mediator behind the reproductive injury induced by various factors. However, the understanding of its reproductive toxicity and prevention in reproductive system is limited. Given that Sertoli cells provide the first-line defense against various toxicants and that dysfunction of Sertoli cell causes impaired spermatogenesis, we, therefore, examined ACR cytotoxicity in Sertoli cells and tested whether hydrogen sulfide (H2S), a gaseous mediator with potent antioxidative actions, could have a protective effect. Exposure of Sertoli cells to ACR led to cell injury, as indicated by reactive oxygen species (ROS) generation, protein oxidation, P38 activation and ultimately cell death that was prevented by antioxidant N-acetylcysteine (NAC). Further studies revealed that ACR cytotoxicity on Sertoli cells was significantly exacerbated by the inhibition of H2S-synthesizing enzyme cystathionine γ-lyase (CSE), while significantly suppressed by H2S donor Sodium hydrosulfide (NaHS). It was also attenuated by Tanshinone IIA (Tan IIA), an active ingredient of Danshen that stimulated H2S production in Sertoli cells. Apart from Sertoli cells, H2S also protected the cultured germ cells from ACR-initiated cell death. Collectively, our study characterized H2S as endogenous defensive mechanism against ACR in Sertoli cells and germ cells. This property of H2S could be used to prevent and treat ACR-related reproductive injury.}, }
@article {pmid37058841, year = {2023}, author = {Wang, Y and Zhang, F and Liu, J and Yang, B and Yuan, Y and Zhou, Y and Bi, S}, title = {A fluorescence nanoprobe of N-Acetyl-L-Cysteine capped CdTe QDs for sensitive detection of nitrofurazone.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {297}, number = {}, pages = {122709}, doi = {10.1016/j.saa.2023.122709}, pmid = {37058841}, issn = {1873-3557}, mesh = {Animals ; Cattle ; *Quantum Dots/chemistry ; Acetylcysteine ; *Cadmium Compounds/chemistry ; Fluorescence ; Tellurium/chemistry ; Nitrofurazone ; Spectroscopy, Fourier Transform Infrared ; Spectrometry, Fluorescence/methods ; }, abstract = {A method was established for detecting the content of nitrofurazone (NFZ) by fluorescence quenching of N-Acetyl-L-Cysteine (NAC) coated cadmium telluride quantum dots (CdTe QDs). By means of transmission electron microscopy (TEM) and multispectral methods such as fluorescence and ultraviolet visible spectra (UV-vis), the synthesized CdTe QDs were characterized. The quantum yield (φ) of CdTe QDs was measured as 0.33 by reference method. The CdTe QDs had a better stability, the RSD of fluorescence intensity was 1.51% in three months. NFZ quenching the emission light of CdTe QDs was observed. The analyses of Stern-Volmer and time-resolved fluorescence suggested the quenching was static. The binding constants (Ka) between NFZ and CdTe QDs were 1.14 × 10[4] (293 K), 0.74 × 10[4] (303 K) and 0.51 × 10[4] (313 K) L mol[-1]. The hydrogen bond or van der Waals force was the dominated binding force between NFZ and CdTe QDs. The interaction was further characterized by UV-vis absorption as well as Fourier transform infrared spectra (FT-IR). Using fluorescence quenching effect, a quantitative determination of NFZ was carried out. The optimal experimental conditions were studied and determined as following: pH was 7 and contact time was 10 min. The effects of reagent addition sequence, temperature and the foreign substances including some metals (Mg[2+]; Zn[2+]; Ca[2+]; K[+]; Cu[2+]), glucose, bovine serum albumin (BSA) and furazolidone on the determination were studied. There was a high correlation between the concentration of NFZ (0.40 - 39.63 μg mL[-1]) and F0/F with the standard curve F0/F = 0.0262c + 0.9910 (r = 0.9994). The detection limit (LOD) reached 0.04 μg mL[-1] (3S0/S). The contents of NFZ in beef and bacteriostatic liquid were detected. The recovery of NFZ was 95.13% - 103.03% and RSD was 0.66% - 1.37% (n = 5).}, }
@article {pmid37056637, year = {2023}, author = {Mokhtari, Z and Raeeszadeh, M and Akradi, L}, title = {Comparative Effect of the Active Substance of Thyme with N-Acetyl Cysteine on Hematological Parameters and Histopathological Changes of Bone Marrow and Liver in Rat Models of Acetaminophen Toxicity.}, journal = {Analytical cellular pathology (Amsterdam)}, volume = {2023}, number = {}, pages = {1714884}, pmid = {37056637}, issn = {2210-7185}, mesh = {Animals ; Rats ; Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Bone Marrow ; *Chemical and Drug Induced Liver Injury/drug therapy/pathology ; Liver ; Rats, Wistar ; *Thymus Plant ; }, abstract = {Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac + 100Ex, Ac + 200Ex, and Ac + 400Ex groups (acetaminophen + thyme extract at doses of 100, 200, 400 mg/kg); and Ac + NA group (acetaminophen + NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac + NA and Ac + 200Ex groups (P = 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac + 400Ex groups showed significant differences from those of the other test groups (P < 0.001). Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) enzymes in Ac + 200Ex and Ac + NA groups showed a significant decrease compared to those of the other treatment groups (P = 0.043). Total antioxidant capacity (TAC) and glutathione peroxidase (GPx) had the lowest levels in Ac and Ac + 400Ex groups, while malondialdehyde (MDA) had the highest content. In this regard, the liver histopathological indices (necrosis, hyperemia, and hemorrhage) in the Ac + 200Ex and Ac + NA groups reached their lowest grades in the treatment groups. The mean number of erythroid and myeloid cells in the Ac group reached the lowest (17.40 ± 3.48). The microscopic appearance of the bone marrow cells was different from normocytosis in the control group to hypocytosis in the Ac and Ac + 400Ex groups. Thymol, as an effective ingredient in thyme extract at a dose of 200 mg/kg compared to NAC, had a unique effect on reducing bone marrow and liver cell-tissue changes due to the acetaminophen toxicity.}, }
@article {pmid37055935, year = {2023}, author = {Xue, Q and Kang, R and Klionsky, DJ and Tang, D and Liu, J and Chen, X}, title = {Copper metabolism in cell death and autophagy.}, journal = {Autophagy}, volume = {19}, number = {8}, pages = {2175-2195}, pmid = {37055935}, issn = {1554-8635}, support = {R35 GM131919/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Autophagy/physiology ; Tumor Suppressor Protein p53 ; Apoptosis Inducing Factor ; Copper ; Ubiquinone ; Electron Transport Complex IV ; Autophagy-Related Protein-1 Homolog ; Proto-Oncogene Proteins p21(ras) ; Apoptosis/physiology ; Caspases ; Hypoxia-Inducible Factor 1 ; Superoxide Dismutase ; *Neoplasms ; Ions ; Proto-Oncogene Proteins c-bcl-2 ; }, abstract = {Copper is an essential trace element in biological systems, maintaining the activity of enzymes and the function of transcription factors. However, at high concentrations, copper ions show increased toxicity by inducing regulated cell death, such as apoptosis, paraptosis, pyroptosis, ferroptosis, and cuproptosis. Furthermore, copper ions can trigger macroautophagy/autophagy, a lysosome-dependent degradation pathway that plays a dual role in regulating the survival or death fate of cells under various stress conditions. Pathologically, impaired copper metabolism due to environmental or genetic causes is implicated in a variety of human diseases, such as rare Wilson disease and common cancers. Therapeutically, copper-based compounds are potential chemotherapeutic agents that can be used alone or in combination with other drugs or approaches to treat cancer. Here, we review the progress made in understanding copper metabolic processes and their impact on the regulation of cell death and autophagy. This knowledge may help in the design of future clinical tools to improve cancer diagnosis and treatment.Abbreviations: ACSL4, acyl-CoA synthetase long chain family member 4; AIFM1/AIF, apoptosis inducing factor mitochondria associated 1; AIFM2, apoptosis inducing factor mitochondria associated 2; ALDH, aldehyde dehydrogenase; ALOX, arachidonate lipoxygenase; AMPK, AMP-activated protein kinase; APAF1, apoptotic peptidase activating factor 1; ATF4, activating transcription factor 4; ATG, autophagy related; ATG13, autophagy related 13; ATG5, autophagy related 5; ATOX1, antioxidant 1 copper chaperone; ATP, adenosine triphosphate; ATP7A, ATPase copper transporting alpha; ATP7B, ATPase copper transporting beta; BAK1, BCL2 antagonist/killer 1; BAX, BCL2 associated X apoptosis regulator; BBC3/PUMA, BCL2 binding component 3; BCS, bathocuproinedisulfonic acid; BECN1, beclin 1; BID, BH3 interacting domain death agonist; BRCA1, BRCA1 DNA repair associated; BSO, buthionine sulphoximine; CASP1, caspase 1; CASP3, caspase 3; CASP4/CASP11, caspase 4; CASP5, caspase 5; CASP8, caspase 8; CASP9, caspase 9; CCS, copper chaperone for superoxide dismutase; CD274/PD-L1, CD274 molecule; CDH2, cadherin 2; CDKN1A/p21, cyclin dependent kinase inhibitor 1A; CDKN1B/p27, cyclin-dependent kinase inhibitor 1B; COMMD10, COMM domain containing 10; CoQ10, coenzyme Q 10; CoQ10H2, reduced coenzyme Q 10; COX11, cytochrome c oxidase copper chaperone COX11; COX17, cytochrome c oxidase copper chaperone COX17; CP, ceruloplasmin; CYCS, cytochrome c, somatic; DBH, dopamine beta-hydroxylase; DDIT3/CHOP, DNA damage inducible transcript 3; DLAT, dihydrolipoamide S-acetyltransferase; DTC, diethyldithiocarbamate; EIF2A, eukaryotic translation initiation factor 2A; EIF2AK3/PERK, eukaryotic translation initiation factor 2 alpha kinase 3; ER, endoplasmic reticulum; ESCRT-III, endosomal sorting complex required for transport-III; ETC, electron transport chain; FABP3, fatty acid binding protein 3; FABP7, fatty acid binding protein 7; FADD, Fas associated via death domain; FAS, Fas cell surface death receptor; FASL, Fas ligand; FDX1, ferredoxin 1; GNAQ/11, G protein subunit alpha q/11; GPX4, glutathione peroxidase 4; GSDMD, gasdermin D; GSH, glutathione; HDAC, histone deacetylase; HIF1, hypoxia inducible factor 1; HIF1A, hypoxia inducible factor 1 subunit alpha; HMGB1, high mobility group box 1; IL1B, interleukin 1 beta; IL17, interleukin 17; KRAS, KRAS proto-oncogene, GTPase; LOX, lysyl oxidase; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAP1LC3, microtubule associated protein 1 light chain 3; MAP2K1, mitogen-activated protein kinase kinase 1; MAP2K2, mitogen-activated protein kinase kinase 2; MAPK, mitogen-activated protein kinases; MAPK14/p38, mitogen-activated protein kinase 14; MEMO1, mediator of cell motility 1; MT-CO1/COX1, mitochondrially encoded cytochrome c oxidase I; MT-CO2/COX2, mitochondrially encoded cytochrome c oxidase II; MTOR, mechanistic target of rapamycin kinase; MTs, metallothioneins; NAC, N-acetylcysteine; NFKB/NF-Κb, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NPLOC4/NPL4, NPL4 homolog ubiquitin recognition factor; PDE3B, phosphodiesterase 3B; PDK1, phosphoinositide dependent protein kinase 1; PHD, prolyl-4-hydroxylase domain; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PMAIP1/NOXA, phorbol-12-myristate-13-acetate-induced protein 1; POR, cytochrome P450 oxidoreductase; PUFA-PL, PUFA of phospholipids; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; SCO1, synthesis of cytochrome C oxidase 1; SCO2, synthesis of cytochrome C oxidase 2; SLC7A11, solute carrier family 7 member 11; SLC11A2/DMT1, solute carrier family 11 member 2; SLC31A1/CTR1, solute carrier family 31 member 1; SLC47A1, solute carrier family 47 member 1; SOD1, superoxide dismutase; SP1, Sp1 transcription factor; SQSTM1/p62, sequestosome 1; STEAP4, STEAP4 metalloreductase; TAX1BP1, Tax1 binding protein 1; TEPA, tetraethylenepentamine; TFEB, transcription factor EB; TM, tetrathiomolybdate; TP53/p53, tumor protein p53; TXNRD1, thioredoxin reductase 1; UCHL5, ubiquitin C-terminal hydrolase L5; ULK1, Unc-51 like autophagy activating kinase 1; ULK1, unc-51 like autophagy activating kinase 1; ULK2, unc-51 like autophagy activating kinase 2; USP14, ubiquitin specific peptidase 14; VEGF, vascular endothelial gro wth factor; XIAP, X-linked inhibitor of apoptosis.}, }
@article {pmid37054769, year = {2023}, author = {Vongsfak, J and Apaijai, N and Chunchai, T and Pintana, H and Arunsak, B and Maneechote, C and Singhanat, K and Wu, D and Liang, G and Chattipakorn, N and Chattipakorn, SC}, title = {Acute administration of myeloid differentiation factor 2 inhibitor and N-acetyl cysteine attenuate brain damage in rats with cardiac ischemia/reperfusion injury.}, journal = {Archives of biochemistry and biophysics}, volume = {740}, number = {}, pages = {109598}, doi = {10.1016/j.abb.2023.109598}, pmid = {37054769}, issn = {1096-0384}, mesh = {Rats ; Male ; Animals ; Acetylcysteine/pharmacology/therapeutic use ; *Myocardial Reperfusion Injury/drug therapy/metabolism ; *Reperfusion Injury/drug therapy/pathology ; Brain/metabolism ; Oxidative Stress ; *Encephalitis/pathology ; Ischemia/pathology ; }, abstract = {Inflammation and oxidative stress are mechanisms which potentially underlie the brain damage that can occur after cardiac ischemic and reperfusion (I/R) injury. 2i-10 is a new anti-inflammatory agent, acting via direct inhibition of myeloid differentiation factor 2 (MD2). However, the effects of 2i-10 and the antioxidant N-acetylcysteine (NAC) on pathologic brain in cardiac I/R injury are unknown. We hypothesized that 2i-10 and NAC offer similar neuroprotection levels against dendritic spine reduction through attenuation of brain inflammation, loss of tight junction integrity, mitochondrial dysfunction, reactive gliosis, and suppression of AD protein expression in rats with cardiac I/R injury. Male rats were allocated to either sham or acute cardiac I/R group (30 min of cardiac ischemia and 120 min of reperfusion). Rats in cardiac I/R group were given one of following treatments intravenously at the onset of reperfusion: vehicle, 2i-10 (20 or 40 mg/kg), and NAC (75 or 150 mg/kg). The brain was then used to determine biochemical parameters. Cardiac I/R led to cardiac dysfunction with dendritic spine loss, loss of tight junction integrity, brain inflammation, and mitochondrial dysfunction. Treatment with 2i-10 (both doses) effectively reduced cardiac dysfunction, tau hyperphosphorylation, brain inflammation, mitochondrial dysfunction, dendritic spine loss, and improved tight junction integrity. Although both doses of NAC effectively reduced brain mitochondrial dysfunction, treatment using a high dose of NAC reduced cardiac dysfunction, brain inflammation, and dendritic spine loss. In conclusion, treatment with 2i-10 and a high dose of NAC at the onset of reperfusion alleviated brain inflammation and mitochondrial dysfunction, consequently reducing dendritic spine loss in rats with cardiac I/R injury.}, }
@article {pmid37052190, year = {2023}, author = {Chin, HK and Lu, MC and Hsu, KC and El-Shazly, M and Tsai, TN and Lin, TY and Shih, SP and Lin, TE and Wen, ZH and Yang, YSH and Liu, YC}, title = {Exploration of anti-leukemic effect of soft coral-derived 13-acetoxysarcocrassolide: Induction of apoptosis via oxidative stress as a potent inhibitor of heat shock protein 90 and topoisomerase II.}, journal = {The Kaohsiung journal of medical sciences}, volume = {39}, number = {7}, pages = {718-731}, doi = {10.1002/kjm2.12678}, pmid = {37052190}, issn = {2410-8650}, support = {KAFGH_D_110031//Kaohsiung Armed Forces General Hospital/ ; KMUH DK(B)110001-3//Kaohsiung Medical University Hospital/ ; MOST 107-2320-B-259-004-MY3//Ministry of Science and Technology/ ; MOST 110-2314-B-037-083//Ministry of Science and Technology/ ; MOST 110-2320-B259-001-MY3//Ministry of Science and Technology/ ; 109T2560-5//National Dong Hwa University/ ; 110T2560-5//National Dong Hwa University/ ; NHRI-111A1-CACO-03222109//National Health Research Institutes/ ; }, mesh = {Humans ; Animals ; Mice ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Molecular Docking Simulation ; *Anthozoa/metabolism ; Oxidative Stress ; Apoptosis ; *Antineoplastic Agents/pharmacology/therapeutic use ; DNA Topoisomerases, Type II/metabolism ; Heat-Shock Proteins/metabolism/pharmacology ; }, abstract = {13-Acetoxysarcocrassolide (13-AC) is a marine cembranoid derived from the aquaculture soft coral of Lobophytum crassum. The cytotoxic effect of 13-AC against leukemia cells was previously reported but its mechanism of action is still unexplored. In the current study, we showed that 13-AC induced apoptosis of human acute lymphoblastic leukemia Molt4 cells, as evidenced by the cleavage of PARP and caspases, phosphatidylserine externalization, as well as the disruption of mitochondrial membrane potential. The use of N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, attenuated the cytotoxic effect induced by 13-AC. Molecular docking and thermal shift assay indicated that the cytotoxic mechanism of action of 13-AC involved the inhibition of heat shock protein 90 (Hsp 90) activity by eliciting the level of Hsp 70 and topoisomerase IIα in Molt4 cells. 13-AC also exhibited potent antitumor activity by reducing the tumor volume (48.3%) and weight (72.5%) in the in vivo Molt4 xenograft mice model. Our findings suggested that the marine cembranoid, 13-AC, acted as a dual inhibitor of Hsp 90 and topoisomerase IIα, exerting more potent apoptotic activity via the enhancement of ROS generation.}, }
@article {pmid37051421, year = {2022}, author = {Sharma, S and Anand, A and Bhatia, A and Sharma, V and Singh, AK and Banerjee, D and Patil, AN}, title = {Pharmacological Evaluation of Scopoletin in the Carbon Tetrachloride-Induced Hepatotoxicity Model in Wistar Rats.}, journal = {Journal of pharmacy &amp; bioallied sciences}, volume = {14}, number = {4}, pages = {201-206}, pmid = {37051421}, issn = {0976-4879}, abstract = {BACKGROUND: Several phyto-chemicals have been identified and suggested as potential therapeutic options for hepatotoxicity management.<br><br>OBJECTIVE: To assess the hepatoprotective effect of scopoletin, a pure phyto-chemical, in carbon tetrachloride (CCl4)-induced hepatotoxicity model in Wistar rats.<br><br>METHODS: Thirty-six rats in total, six in each group, were utilized in this study. Animals in group 1 received normal saline; those in group 2 received carbon tetrachloride in olive oil (0.5 ml/kg, i.p. in ratio 1:1); those in groups 3, 4, and 5 received oral scopoletin (1 mg/kg, 5 mg/kg, 10 mg/kg dose-wise groups); and those in group 6 received N-acetyl cysteine (NAC) 150 mg/kg. Blood sampling was performed on day -3, day 1, and day 7 of the CCl4 administration. Rats were sacrificed on day 7 of the experiment for histological examination and oxidative stress measurement of the liver.<br><br>RESULTS: The 5 mg/kg scopoletin group showed a maximum reduction in AST levels [727.33 &#xb1; 29.15 in medium dose (MD) group vs 1526.66 &#xb1; 60.72 in the experimental control (EC) group (P < 0.001) and ALT levels of 532.66 &#xb1; 24.23 in MD group vs 894.83 &#xb1; 52.47 in EC (P < 0.01)]. The dose-dependent action was not observed with scopoletin doses. The protective effect of scopoletin was confirmed by MDA and GSH levels (P < 0.05) coupled with histo-pathological findings. In the present study, a reversible model of CCl4-induced hepatotoxicity was observed to get normalized in a week's time.<br><br>CONCLUSION: The study confirms the hepatoprotective action of scopoletin in an acute model of hepatic injury with the putative anti-oxidant mechanism.}, }
@article {pmid37049804, year = {2023}, author = {Xu, Y and Geng, Z and Yang, C and Zhou, H and Wang, Y and Kuerban, B and Luo, G}, title = {Effect of N-acetyl-l-cysteine on Cell Phenotype and Autophagy in Pichia pastoris Expressing Human Serum Albumin and Porcine Follicle-Stimulating Hormone Fusion Protein.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {7}, pages = {}, pmid = {37049804}, issn = {1420-3049}, support = {32102542//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Swine ; Humans ; *Acetylcysteine/pharmacology/metabolism ; *Serum Albumin, Human/metabolism ; Pichia/genetics/metabolism ; Recombinant Proteins/metabolism ; Autophagy ; Follicle Stimulating Hormone/metabolism ; Phenotype ; Recombinant Fusion Proteins/genetics ; }, abstract = {Pichia pastoris is widely used for the production of recombinant proteins, but the low secretion efficiency hinders its wide application in biopharmaceuticals. Our previous study had shown that N-acetyl-l-cysteine (NAC) promotes human serum albumin and porcine follicle-stimulating hormone fusion protein (HSA-pFSHβ) secretion by increasing intracellular GSH levels, but the downstream impact mechanism is not clear. In this study, we investigated the roles of autophagy as well as cell phenotype in NAC promoting HSA-pFSHβ secretion. Our results showed that NAC slowed down the cell growth rate, and its effects were unaffected by Congo Red and Calcofluor White. Moreover, NAC affected cell wall composition by increasing chitin content and decreasing β-1,3-glucan content. In addition, the expressions of vesicular pathway and autophagy-related genes were significantly decreased after NAC treatment. Further studies revealed that autophagy, especially the cytoplasm-to-vacuole targeting (Cvt) pathway, mitophagy and pexophagy, was significantly increased with time, and NAC has a promoting effect on autophagy, especially at 48 h and 72 h of NAC treatment. However, the disruption of mitophagy receptor Atg32, but not pexophagy receptor Atg30, inhibited HSA-pFSHβ production, and neither of them inhibited the NAC-promoted effect of HSA-pFSHβ. In conclusion, vesicular transport, autophagy and cell wall are all involved in the NAC-promoted HSA-pFSHβ secretion and that disruption of the autophagy receptor alone does not inhibit the effect of NAC.}, }
@article {pmid37048082, year = {2023}, author = {Seo, YN and Baik, JS and Lee, SM and Lee, JE and Ahn, HR and Lim, MS and Park, MT and Kim, SD}, title = {Ionizing Radiation Selectively Increases CXC Ligand 10 Level via the DNA-Damage-Induced p38 MAPK-STAT1 Pathway in Murine J774A.1 Macrophages.}, journal = {Cells}, volume = {12}, number = {7}, pages = {}, pmid = {37048082}, issn = {2073-4409}, mesh = {Animals ; Mice ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Endothelial Cells/metabolism ; Ligands ; Macrophages/metabolism ; Radiation, Ionizing ; DNA ; STAT1 Transcription Factor/metabolism ; }, abstract = {Ionizing radiation (IR) is an important means of tumor treatment in addition to surgery and drugs. Attempts have been made to improve the efficiency of radiotherapy by identifying the various biological effects of IR on cells. Components of the tumor microenvironment, such as macrophages, fibroblasts, and vascular endothelial cells, influence cancer treatment outcomes through communication with tumor cells. In this study, we found that IR selectively increased the production of CXC motif chemokine ligand 10 (CXCL10), which is emerging as an important biomarker for determining the prognosis of anticancer treatments, without changing the levels of CXCL9 and CXCL11 in murine J774A.1 macrophages. Pretreatment with KU55933, an ataxia telangiectasia mutated (ATM) kinase inhibitor, significantly inhibited IR-induced CXCL10 production. In contrast, pretreatment with N-acetyl-cysteine or glutathione, a reactive oxygen species scavenger, did not inhibit IR-induced CXCL10 production. Further, we attempted to identify the intracellular molecular target associated with the IR-induced increase in CXCL10 secretion by J774A.1 macrophages. IR phosphorylated p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1) in J774A.1 macrophages, and p38 MAPK and STAT1 were involved in CXCL10 via IR using pharmacological inhibitors (SB203580 and fludarabine, respectively) and the siRNA technique.}, }
@article {pmid37044095, year = {2023}, author = {Auf der Maur, P and Trefny, MP and Baumann, Z and Vulin, M and Correia, AL and Diepenbruck, M and Kramer, N and Volkmann, K and Preca, BT and Ramos, P and Leroy, C and Eichlisberger, T and Buczak, K and Zilli, F and Okamoto, R and Rad, R and Jensen, MR and Fritsch, C and Zippelius, A and Stadler, MB and Bentires-Alj, M}, title = {N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer.}, journal = {Cell reports. Medicine}, volume = {4}, number = {4}, pages = {101002}, pmid = {37044095}, issn = {2666-3791}, mesh = {Humans ; Mice ; Animals ; Female ; *Breast Neoplasms/drug therapy/genetics/metabolism ; Phosphatidylinositol 3-Kinase ; Acetylcysteine/pharmacology ; Class I Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/genetics ; }, abstract = {A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CA[H1047R]-mutated murine tumor model reveal NF1 loss in mammary tumors resistant to the phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor alpelisib. Depletion of NF1 in PIK3CA[H1047R] breast cancer cell lines and a patient-derived organoid model shows that NF1 loss reduces sensitivity to PI3Kα inhibition and correlates with enhanced glycolysis and lower levels of reactive oxygen species (ROS). Unexpectedly, the antioxidant N-acetylcysteine (NAC) sensitizes NF1 knockout cells to PI3Kα inhibition and reverts their glycolytic phenotype. Global phospho-proteomics indicates that combination with NAC enhances the inhibitory effect of alpelisib on mTOR signaling. In public datasets of human breast cancer, we find that NF1 is frequently mutated and that such mutations are enriched in metastases, an indication for which use of PI3Kα inhibitors has been approved. Our results raise the attractive possibility of combining PI3Kα inhibition with NAC supplementation, especially in patients with drug-resistant metastases associated with NF1 loss.}, }
@article {pmid37040789, year = {2023}, author = {Xing, S and Guo, Z and Lang, J and Zhou, M and Cao, J and He, H and Yu, L and Zhou, Y}, title = {N-Acetyl-l-cysteine ameliorates gestational diabetes mellitus by inhibiting oxidative stress.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {39}, number = {1}, pages = {2189969}, doi = {10.1080/09513590.2023.2189969}, pmid = {37040789}, issn = {1473-0766}, mesh = {Pregnancy ; Female ; Humans ; Mice ; Animals ; *Diabetes, Gestational ; Acetylcysteine ; Blood Glucose ; NF-E2-Related Factor 2 ; Oxidative Stress ; }, abstract = {Objective: Gestational diabetes mellitus (GDM) affects 7% of pregnant women worldwide. How to effectively treat GDM has always been a concern of people.Research methods: In this study, a diabetes model was established by drug-induced mice. Subsequently, the blood glucose levels and serum insulin changes of the mice after N-acetyl-l-cysteine (NAC) treatment were observed. At the same time, the effect of NAC on reproduction of GDM mice was recorded.Results of the study: Mice fed NAC showed significantly improved glucose tolerance and insulin sensitivity compared to Diabetic/Control. Total serum cholesterol, serum triglycerides, and serum low-density lipoprotein were significantly reduced, and atherosclerosis index was much lower than in control mice. In addition, Diabetic/Control mice had lower litter sizes and higher birth weights. NAC treatment significantly restored litter size and reduced birth weight in Diabetic/Control mice. It was found in WB assay that the NAC-fed group significantly increased nuclear Nrf2 and HO-1 expression levels.Conclusion: NAC can improve blood glucose tolerance in GDM mice; NAC effectively relieves the symptoms of hyperlipidemia caused by GDM; NAC enhances the expression of Nrf2/HO-1 in the liver, thereby restoring redox homeostasis. NAC can reduce gestational diabetes-related disease indicators by oral administration, and has a beneficial effect on the offspring of pregnant mice (reduces its diabetes disease indicators).}, }
@article {pmid37033589, year = {2023}, author = {Sharieff, S and Idrees, A and Rafai, W and Bukhari, SUS}, title = {Use of Oral N-Acetylcysteine (NAC) in Non-Acetaminophen-Induced Acute Hepatic Failure.}, journal = {Cureus}, volume = {15}, number = {3}, pages = {e35852}, pmid = {37033589}, issn = {2168-8184}, abstract = {BACKGROUND: Acute liver failure (ALF) is a syndrome rather than a specific disease with several possible causes, and viral hepatitis is a major cause. The objective of the study was to assess the benefit of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF).<br><br>METHODS: A total of six patients with a diagnosis of acute liver failure (ALF) were included in the study. All six patients received oral NAC for 72 hrs. The parameters evaluated were demographic, clinical, biochemical, outcome, and length of ICU and hospital stay. The primary outcome was a reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate the safety of NAC and assess factors predicting mortality.<br><br>RESULTS: All patients improved and returned to normal or near-normal liver function with the use of NAC. No side effects were noted, and the use of NAC was associated with a shorter hospital stay.<br><br>CONCLUSION: In patients with non-acetaminophen-related acute liver failure, N-acetyl-L-cysteine (NAC)&#xa0;significantly improves overall survival and also decreases the length of hospital stay.}, }
@article {pmid37027944, year = {2023}, author = {Wang, M and Xu, J and Zhao, Z and Gong, L and Su, Y and Fang, Z and Chen, P and Liu, Y and Zhang, L and Xu, F}, title = {Triphenyl phosphate induced apoptosis of mice testicular Leydig cells and TM3 cells through ROS-mediated mitochondrial fusion inhibition.}, journal = {Ecotoxicology and environmental safety}, volume = {256}, number = {}, pages = {114876}, doi = {10.1016/j.ecoenv.2023.114876}, pmid = {37027944}, issn = {1090-2414}, mesh = {Mice ; Animals ; Male ; *Leydig Cells/metabolism ; Reactive Oxygen Species/metabolism ; *Mitochondrial Dynamics ; Mice, Inbred C57BL ; Apoptosis ; Mitochondrial Proteins/metabolism ; Organophosphates/metabolism ; Testosterone/metabolism ; }, abstract = {Triphenyl phosphate (TPHP) is a widely used organophosphate flame retardant and has biological toxicity. Previous studies showed TPHP can restrain testosterone biosynthesis in Leydig cells, while the underlying mechanisms remain unclear. In this study, C57BL/6J male mice were exposed to 0, 5, 50, and 200 mg/kg B.W. of TPHP for 30 d by oral, as well as TM3 cells were treated with 0, 50, 100, and 200 μM of TPHP for 24 h. Results showed that TPHP induced testes damage, including spermatogenesis disorders and testosterone synthesis inhibition. Meanwhile, TPHP can cause apoptosis in testicular Leydig cells and TM3 cells, as evidenced by the increased apoptosis rate and decreased Bcl-2/Bax ratio. Moreover, TPHP disrupted mitochondrial ultrastructure of testicular Leydig cells and TM3 cells, reduced healthy mitochondria content and depressed mitochondrial membrane potential of TM3 cells, as well as inhibited mitochondrial fusion proteins mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (Opa1) expression, without effect on mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission 1 (Fis1) in testicular tissue and/or TM3 cells. Then, the mitochondrial fusion promoter M1 was used to pre-treat TPHP-exposed TM3 cells to determine the roles of mitochondrial fusion inhibition in TPHP-induced Leydig cells apoptosis. The results showed M1 pretreatment alleviated the above changes and further mitigated TM3 cells apoptosis and testosterone levels decreased, indicating TPHP induced TM3 cells apoptosis by inhibited mitochondrial fusion. Intriguingly, the intervention experiment of N-acetylcysteine (NAC) showed that TPHP-induced mitochondrial fusion inhibition is ROS dependent, because inhibition of ROS overproduction alleviated mitochondrial fusion inhibition, and subsequently relieved TPHP-induced apoptosis in TM3 cells. In summary, above data revealed that apoptosis is a specific mechanism for TPHP-induced male reproductive toxicity, and that ROS-mediated mitochondrial fusion inhibition is responsible for Leydig cells apoptosis caused by TPHP.}, }
@article {pmid37017249, year = {2023}, author = {Uehara, H and Itoigawa, Y and Morikawa, D and Koga, A and Tsurukami, H and Maruyama, Y and Ishijima, M}, title = {The Effect of Vitamin C and N-Acetylcysteine on Tendon-to-Bone Healing in a Rodent Model of Rotator Cuff Repair.}, journal = {The American journal of sports medicine}, volume = {51}, number = {6}, pages = {1596-1607}, doi = {10.1177/03635465231160772}, pmid = {37017249}, issn = {1552-3365}, mesh = {Rats ; Animals ; *Rotator Cuff/physiology ; Acetylcysteine/pharmacology/therapeutic use ; Matrix Metalloproteinase 13 ; Wound Healing/physiology ; Collagen/metabolism ; Rodentia/metabolism ; Rats, Sprague-Dawley ; Ascorbic Acid/pharmacology/therapeutic use ; Superoxide Dismutase-1/pharmacology ; Tendons/surgery ; *Rotator Cuff Injuries/drug therapy/surgery/pathology ; Biomechanical Phenomena ; }, abstract = {BACKGROUND: Oxidative stress inhibits tendon-to-bone healing after rotator cuff repair. Regulation of oxidative stress has the potential to accelerate this healing, but its mechanism remains unclear.<br><br>PURPOSE: To investigate the effects of reducing oxidative stress by applying antioxidants, such as N-acetylcysteine (NAC) and vitamin C (VC), on rotator cuff repair in a rat rotator cuff repair model.<br><br>STUDY DESIGN: Controlled laboratory study.<br><br>METHODS: A total of 48 Sprague Dawley rats underwent bilateral surgery to repair the infraspinatus tendon to its insertion site 1 week after detachment. Rats were assigned to either the NAC group, the VC group, or a control group. Histological evaluation was performed via hematoxylin-eosin or toluidine blue staining, and oxidative stress was assessed via dihydroethidium intensity and protein carbonyl concentration at 3 and 6 weeks. Superoxide dismutase 1 (SOD1), SOD2, SOD3, peroxiredoxin 5, collagen type I (COL1), COL3, matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 expression and SOD activity were determined at 3 and 6 weeks. Biomechanical tests were performed at 6 and 12 weeks.<br><br>RESULTS: Histological evaluation showed that the number of chondrocytes in the NAC group at 6 weeks and in the VC group at 3 and 6 weeks, the area of fibrocartilage at 6 weeks in the VC group, and collagen fibers at 6 weeks in the NAC and VC groups were significantly increased compared with those in the control group. Dihydroethidium intensity at 3 and 6 weeks and protein carbonyls at 6 weeks in the NAC and VC groups were significantly decreased. SOD1 expression and SOD activity at 3 weeks in the VC group and peroxiredoxin 5 expression at 6 weeks in the NAC group were significantly upregulated compared with that in the control group. COL3 expression was significantly upregulated at 6 weeks in the VC group, and MMP-13 expression was significantly decreased at 6 weeks in the NAC and VC groups. The biomechanical strength showed no significant difference.<br><br>CONCLUSION: Antioxidant treatment, via NAC or VC administration, reduced oxidative stress in the rotator cuff repair site and accelerated healing.<br><br>CLINICAL RELEVANCE: These findings provide essential indications to develop clinical strategies for improved healing after rotator cuff surgical repair in patients.}, }
@article {pmid37016183, year = {2023}, author = {Yalçın, T and Kaya, S and Kuloğlu, T and Yiğin, A}, title = {N-Acetylcysteine May Regulate Altered Meteorin-Like Levels in Testicular Tissue due to Aluminum Exposure.}, journal = {Biological trace element research}, volume = {201}, number = {11}, pages = {5335-5345}, pmid = {37016183}, issn = {1559-0720}, mesh = {Rats ; Animals ; Male ; *Acetylcysteine/pharmacology ; *Aluminum/metabolism ; Testis ; Rats, Sprague-Dawley ; Antioxidants/pharmacology/metabolism ; Oxidative Stress ; Inflammation/metabolism ; }, abstract = {Aluminum (AL) is a heavy metal known to have toxic effects on the reproductive system. It is known that N-acetylcysteine (NAC), which has an antioxidant effect, is a useful chelator for heavy metals. This study aimed to determine whether NAC may reduce AL-induced oxidative stress, inflammation, and germ cell apoptosis in testicular tissues and its effects on meteorin-like (METRNL) levels, which are known to play a role in energy metabolism. In this experimental study, 28 Sprague-Dawley male rats were randomly divided into 4 groups (n = 7): control, AL (30 mg/kg/day AL), AL + NAC (30 mg/kg/day AL + 150 mg/kg/day NAC), and NAC (150 mg/kg/day NAC). All AL and NAC applications were performed intraperitoneally for 14 days. At the end of the experiment, the effects of AL and/or NAC applications on testicular tissue were examined histomorphometrically, histopathologically, immunohistochemically, and biochemically. It was determined that AL exposure caused histomorphometric and histopathological changes, oxidative stress, apoptosis of germ cells, and inflammation in testicular tissues. In addition, AL caused an increase in METRNL levels. It was determined that NAC treatment significantly reduced the negative effects of AL. NAC therapy may be a protective strategy in reproductive toxicity due to AL exposure.}, }
@article {pmid37015815, year = {2023}, author = {Fleming, K and George, JL and Bazelak, SJ and Roeske, JA and Biggs, AD and Landry, CM and Lipchik, RJ and Truwit, JD}, title = {Optimizing Respiratory Therapy Resources by De-Implementing Low-Value Care.}, journal = {Respiratory care}, volume = {68}, number = {5}, pages = {559-564}, pmid = {37015815}, issn = {1943-3654}, mesh = {Humans ; *Low-Value Care ; Pandemics ; *COVID-19/therapy ; Respiratory Therapy ; Acetylcysteine ; }, abstract = {BACKGROUND: Our institution was experiencing a respiratory therapy staffing crisis during the COVID-19 pandemic, in part due to excessive workload. We identified an opportunity to reduce burden by limiting use of 3% hypertonic saline and/or N-acetylcysteine nebulizer therapies (3%HTS/NAC).<br><br>METHODS: Leveraging the science of de-implementation, we established a policy empowering respiratory therapists to discontinue 3%HTS/NAC not meeting the American Association for Respiratory Care (AARC) Clinical Practice Guideline: Effectiveness of Pharmacologic Airway Clearance Therapies in Hospitalized Patients. After a 3-month period of educating physicians and advanced practice practitioners the policy went to into effect. Outcomes measured included monthly number of treatments, orders, and full-time employees associated with administering nebulized 3%HTS/NAC.<br><br>RESULTS: Post policy activation, the monthly mean 3%HTS/NAC treatments were significantly reduced to 547.5 &#xb1; 284.3 from 3,565.2 &#xb1; 596.4 (P < .001) as were the associated monthly mean of full-time employees, 0.8 &#xb1; 0.41 from 5.1 &#xb1; 0.86 (P < .001). The monthly mean 3%HTS/NAC orders also fell to 93.8 &#xb1; 31.5 from 370.0 &#xb1; 46.9 (P < .001). Monthly mean non-3%HTS/NAC treatments remained stable; post policy was 3,089.4 &#xb1; 611.4 and baseline 3,279.6 &#xb1; 695.0 (P = 1.0).<br><br>CONCLUSIONS: Implementing a policy that empowers respiratory therapists to promote adherence to AARC Clinical Guidelines reduced low-value therapies, costs, and staffing needs.}, }
@article {pmid37010946, year = {2023}, author = {Sumit,  and Maravajjala, KS and Khanna, S and Kachwal, V and Swetha, KL and Manabala, S and Chowdhury, R and Roy, A and Laskar, IR}, title = {Rational Molecular Designing of Aggregation-Enhanced Emission (AEE) Active Red-Emitting Iridium(III) Complexes: Effect of Lipophilicity and Nanoparticle Encapsulation on Photodynamic Therapy Efficacy.}, journal = {ACS applied bio materials}, volume = {6}, number = {4}, pages = {1445-1459}, doi = {10.1021/acsabm.2c00998}, pmid = {37010946}, issn = {2576-6422}, mesh = {Humans ; Iridium/pharmacology ; Reactive Oxygen Species ; *Coordination Complexes/pharmacology ; *Photochemotherapy ; }, abstract = {Two "aggregation-enhanced emission" (AEE) active cyclometalated phosphorescent iridium(III) complexes, SM2 and SM4, were synthesized to evaluate the influence of lipophilicity on photodynamic therapy efficacy. Compared to SM2, SM4 had a higher logP due to the presence of naphthyl groups. As observed by confocal microscopy, this increased lipophilicity of SM4 significantly enhanced its cellular uptake in breast cancer cells. Both the molecules were found to be noncytotoxic under nonirradiating conditions. However, with light irradiation, SM4 exhibited significant cytotoxicity at a 500 nM dose, whereas SM2 remained noncytotoxic, signifying the influence of lipophilicity on cellular internalization and cytotoxicity. Mechanistically, light-irradiated SM4-treated cancer cells exhibited a significant increase in the intracellular reactive oxygen species (ROS) level. Neutralizing ROS with N-acetylcysteine (NAC) pretreatment partly abolished the cytotoxic ability, indicating ROS as one of the major effectors of cell cytotoxicity. Two nanoparticle (NP) formulations of SM4 were developed to improve the intracellular delivery: a PLGA-based NP and a Soluplus-based micelle. Interestingly, PLGA and Soluplus NP formulations exhibited a 10- and 22-fold increased emission intensity, respectively, compared to SM4. There was also an increase in the excited-state lifetime. Additionally, the Soluplus-based micelles encapsulating SM4 exhibited enhanced cellular uptake and increased cytotoxicity compared to the PLGA NPs encapsulating SM4. Altogether, the current study indicates the importance of rational molecular designing and the significance of a proper delivery vector for improving photodynamic therapy efficacy.}, }
@article {pmid37005695, year = {2023}, author = {Mpagama, SG and Mvungi, HC and Mbelele, PM and Semvua, HH and Liyoyo, AA and de Guex, KP and Sloan, D and Kibiki, GS and Boeree, M and Phillips, PPJ and Heysell, SK}, title = {Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania.}, journal = {Pilot and feasibility studies}, volume = {9}, number = {1}, pages = {55}, pmid = {37005695}, issn = {2055-5784}, support = {D43 TW012247/TW/FIC NIH HHS/United States ; R34 AI112371/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Adverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications.<br><br>METHODS: This is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900&#xa0;mg daily, and an interventional arm of NAC 900&#xa0;mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong'oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24&#xa0;weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model.<br><br>DISCUSSION: Given that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials.<br><br>TRIAL REGISTRATION: PACTR202007736854169 Registered 03 July 2020.}, }
@article {pmid37003188, year = {2023}, author = {Dong, Y and Han, F and Su, Y and Sun, B and Zhao, W and Pan, C}, title = {High uric acid aggravates apoptosis of lung epithelial cells induced by cigarette smoke extract through downregulating PRDX2 in chronic obstructive pulmonary disease.}, journal = {International immunopharmacology}, volume = {118}, number = {}, pages = {110056}, doi = {10.1016/j.intimp.2023.110056}, pmid = {37003188}, issn = {1878-1705}, mesh = {Humans ; Animals ; Mice ; Uric Acid/adverse effects ; Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Cigarette Smoking/adverse effects ; Lung ; *Pulmonary Disease, Chronic Obstructive/metabolism ; Apoptosis ; Nicotiana ; Epithelial Cells ; RNA, Small Interfering/genetics ; Peroxiredoxins/genetics/adverse effects ; }, abstract = {Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens the elevation of reactive oxygen species (ROS) and thus leads to apoptosis. Hyperuricemia has been considered as a risk factor for COPD. However, the underlying mechanism for this aggravating effect remains unclear. The current study sought to examine the role of high uric acid (HUA) in COPD using cigarette smoke extract (CSE) exposed murine lung epithelial (MLE-12) cells. Our data showed that CSE induced the increase of ROS, mitochondrial dynamics disorder, and apoptosis, while HUA treatment aggravated the effects of CSE. Further studies suggested that HUA decreased the expression of antioxidant enzyme-peroxiredoxin-2 (PRDX2). Overexpression of PRDX2 inhibited excessive ROS generation, mitochondrial dynamics disorder, and apoptosis induced by HUA. Knockdown of PRDX2 by small interfering RNA (siRNA) promoted ROS generation, mitochondrial dynamics disorder, and apoptosis in MLE-12 cells treated with HUA. However, antioxidant N-acetylcysteine (NAC) reversed the effects of PRDX2-siRNA on MLE-12 cells. In conclusion, HUA aggravated CSE-induced cellular ROS levels and led to ROS-dependent mitochondrial dynamics disorder and apoptosis in MLE-12 cells through downregulating PRDX2.}, }
@article {pmid36991205, year = {2023}, author = {Jin, X and Wu, P and Li, P and Xiong, C and Gui, M and Huang, W}, title = {Transcriptome analysis reveals insight into the protective effect of N-acetylcysteine against cadmium toxicity in Ganoderma lucidum (Polyporales: Polyporaceae).}, journal = {Environmental science and pollution research international}, volume = {30}, number = {20}, pages = {58436-58449}, pmid = {36991205}, issn = {1614-7499}, support = {2019ZG00906//Yunnan Agricultural University/ ; 2022ZZCX028-001//Sichuan Academy of Agricultural Sciences/ ; }, mesh = {Humans ; Animals ; *Reishi/genetics/metabolism ; Acetylcysteine/pharmacology ; Cadmium/metabolism ; *Polyporaceae/genetics/metabolism ; *Polyporales/genetics/metabolism ; Hydrogen Peroxide/metabolism ; Gene Expression Profiling ; *Ganoderma/metabolism ; }, abstract = {Ganoderma lucidum is widely cultivated and used as traditional medicine in China and other Asian countries. As a member of macrofungi, Ganoderma lucidum is also prone to bioaccumulation of cadmium and other heavy metals in a polluted environment, which affects the growth and production of Ganoderma lucidum, as well as human health. N-Acetyl-L-cysteine (NAC) is considered a general antioxidant and free radical scavenger that is involved in the regulation of various stress responses in plants and animals. However, whether NAC could regulate cadmium stress responses in macrofungi, particularly edible fungi, is still unknown. In this work, we found that the exogenous NAC could alleviate Cd-induced growth inhibition and reduce the cadmium accumulation in Ganoderma lucidum. The application of the NAC cloud also inhibit cadmium-induced H2O2 production in the mycelia. By using transcriptome analysis, 2920 and 1046 differentially expressed unigenes were identified in "Cd100 vs CK" and "NAC_Cd100 vs Cd100," respectively. These differential unigenes were classified into a set of functional categories and pathways, which indicated that various biological pathways may play critical roles in the protective effect of NAC against Cd‑induced toxicity in Ganoderma lucidum. Furthermore, it suggested that the ATP-binding cassette transporter, ZIP transporter, heat shock protein, glutathione transferases, and Cytochrome P450 genes contributed to the increased tolerance to cadmium stress after NAC application in Ganoderma lucidum. These results provide new insight into the physiological and molecular response of Ganoderma lucidum to cadmium stress and the protective role of NAC against cadmium toxicity.}, }
@article {pmid36988041, year = {2023}, author = {Nesterowicz, M and Żendzian-Piotrowska, M and Ładny, JR and Zalewska, A and Maciejczyk, M}, title = {Biochemical and Biophysical in Vitro Studies and Systematic Literature Review on the Antioxidant and Antiglycation Activities of Trazodone.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {57}, number = {2}, pages = {82-104}, doi = {10.33594/000000617}, pmid = {36988041}, issn = {1421-9778}, support = {SUB/1/DN/22/002/3330//Medical University of Bialystok/Poland ; SUB/1/DN/20/001/3330//Medical University of Bialystok/Poland ; SUB/1/DN/21/001/3330//Medical University of Bialystok/Poland ; }, mesh = {*Antioxidants/metabolism ; *Trazodone/pharmacology ; Glycosylation ; Advanced Oxidation Protein Products/metabolism ; Molecular Docking Simulation ; Glycation End Products, Advanced/metabolism ; Serum Albumin, Bovine/chemistry/metabolism ; Glyoxal/chemistry ; Glucose ; }, abstract = {BACKGROUND/AIMS: Trazodone is a selective serotonin reuptake inhibitor; however, other mechanisms of the drug's anti-depressive properties have also been postulated. Hence, the aim of the study was to perform a systematic review and assess antiglycoxidative properties of trazodone in in vitro models.<br><br>METHODS: Trazodone's scavenging and chelating properties were measured with spectrophotometric method. The impact of the drug on carbonyl/oxidative stress was marked in the bovine serum albumin (BSA) model where sugars (glucose, fructose, galactose, ribose) and aldehydes (glyoxal and methylglyoxal) were used as glycation agents. Aminoguanidine and N-acetylcysteine (NAC) were applied as reference glycation/free radical inhibitors. Glycation biomarkers (kynurenine, N-formylkynurenine, dityrosine as well as advanced glycation end products contents) were assessed spectrofluorometrically. Concentrations of oxidation parameters (total thiols (TTs), protein carbonyls (PCs) and also advanced oxidation protein products (AOPPs) levels) were determined spectrophotometrically.<br><br>RESULTS: We demonstrated that trazodone poorly scavenged radicals (hydroxyl radical, nitric oxide, hydrogen peroxide and 2,2-diphenyl-1-picrylhydrazyl radical) and showed low ferrous ion chelating, unlike aminoguanidine and NAC. Sugars/aldehydes caused enhancement of glycation parameters, as well as a decrease of TTs and an increase of PCs and AOPPs levels compared to BSA incubated alone. Trazodone did not reduce oxidation parameters to the baseline (BSA) and significantly exacerbated glycation markers in comparison with both BSA and BSA+glycators. The content of glycation products was markedly lower in aminoguanidine and NAC than in trazodone. The molecular docking of trazodone to BSA revealed its very low affinity, which may indicate non-specific binding of trazodone, facilitating the attachment of glycation factors.<br><br>CONCLUSION: According to our findings, it may be concluded that trazodone poorly counteracts oxidation and intensifies glycation in vitro. A possible mechanism for antiglycoxidative effect of trazodone in vivo may be the enhancement of the body's adaptive response, as indicated by the results of our systematic review.}, }
@article {pmid36986816, year = {2023}, author = {Eulálio, D and Pires Figueiredo, M and Taviot-Gueho, C and Leroux, F and Dos Reis Serra, CH and Faria, DLA and Constantino, VRL}, title = {Development of Dipeptide N-acetyl-L-cysteine Loaded Nanostructured Carriers Based on Inorganic Layered Hydroxides.}, journal = {Pharmaceutics}, volume = {15}, number = {3}, pages = {}, pmid = {36986816}, issn = {1999-4923}, support = {88887.352040/2019-00//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; 149404/2018-2//National Council for Scientific and Technological Development/ ; 2016/13862-9//S&#xe3;o Paulo Research Foundation/ ; 2012/13119-3//S&#xe3;o Paulo Research Foundation/ ; 2016/21070-5//S&#xe3;o Paulo Research Foundation/ ; INCT-INEO 2014/50869-6//S&#xe3;o Paulo Research Foundation/ ; 314034/2021-8//National Council for Scientific and Technological Development/ ; PRC-Projets de recherch&#xe9; conjoints 1688 and SPRINT-S&#xe3;o Paulo Researchers in International Collaboration 2016/50317-9//Research Academic Cooperation Agreement PRC-CNRS-FAPESP/ ; }, abstract = {N-acetyl-L-cysteine (NAC), a derivative of the L-cysteine amino acid, presents antioxidant and mucolytic properties of pharmaceutical interest. This work reports the preparation of organic-inorganic nanophases aiming for the development of drug delivery systems based on NAC intercalation into layered double hydroxides (LDH) of zinc-aluminum (Zn2Al-NAC) and magnesium-aluminum (Mg2Al-NAC) compositions. A detailed characterization of the synthesized hybrid materials was performed, including X-ray diffraction (XRD) and pair distribution function (PDF) analysis, infrared and Raman spectroscopies, solid-state [13]carbon and [27]aluminum nuclear magnetic resonance (NMR), simultaneous thermogravimetric and differential scanning calorimetry coupled to mass spectrometry (TG/DSC-MS), scanning electron microscopy (SEM), and elemental chemical analysis to assess both chemical composition and structure of the samples. The experimental conditions allowed to isolate Zn2Al-NAC nanomaterial with good crystallinity and a loading capacity of 27.3 (m/m)%. On the other hand, NAC intercalation was not successful into Mg2Al-LDH, being oxidized instead. In vitro drug delivery kinetic studies were performed using cylindrical tablets of Zn2Al-NAC in a simulated physiological solution (extracellular matrix) to investigate the release profile. After 96 h, the tablet was analyzed by micro-Raman spectroscopy. NAC was replaced by anions such as hydrogen phosphate by a slow diffusion-controlled ion exchange process. Zn2Al-NAC fulfil basic requirements to be employed as a drug delivery system with a defined microscopic structure, appreciable loading capacity, and allowing a controlled release of NAC.}, }
@article {pmid36986437, year = {2023}, author = {Badr, AM and Al-Kharashi, LA and Attia, H and Alshehri, S and Alajami, HN and Ali, RA and Mahran, YF}, title = {TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {3}, pages = {}, pmid = {36986437}, issn = {1424-8247}, support = {NA//King Saud University/ ; }, abstract = {BACKGROUND: Cisplatin (Cp) is an antineoplastic agent with a dose-limiting nephrotoxicity. Cp-induced nephrotoxicity is characterized by the interplay of oxidative stress, inflammation, and apoptosis. Toll-4 receptors (TLR4) and NLPR3 inflammasome are pattern-recognition receptors responsible for activating inflammatory responses and are assigned to play a significant role with gasdermin (GSDMD) in acute kidney injuries. N-acetylcysteine (NAC) and chlorogenic acid (CGA) have documented nephroprotective effects by suppressing oxidative and inflammatory pathways. Therefore, the current study aimed to investigate the contribution of the upregulation of TLR4/inflammasomes/gasdermin signaling to Cp-induced nephrotoxicity and their modulation by NAC or CGA.<br><br>METHODS: A single injection of Cp (7 mg/kg, i.p.) was given to Wistar rats. Rats received either NAC (250 mg/kg, p.o.) and/or CGA (20 mg/kg, p.o.) one week before and after the Cp injection.<br><br>RESULTS: Cp-induced acute nephrotoxicity was evident by the increased blood urea nitrogen and serum creatinine and histopathological insults. Additionally, nephrotoxicity was associated with increased lipid peroxidation, reduced antioxidants, and elevated levels of inflammatory markers (NF-&#x3ba;B and TNF-&#x3b1;) in the kidney tissues. Moreover, Cp upregulated both TLR4/NLPR3/interleukin-1beta (IL-1&#x3b2;) and caspase-1/GSDMD-signaling pathways, accompanied by an increased Bax/BCL-2 ratio, indicating an inflammatory-mediated apoptosis. Both NAC and/or CGA significantly corrected these changes.<br><br>CONCLUSIONS: This study emphasizes that inhibition of TLR4/NLPR3/IL-1&#x3b2;/GSDMD might be a novel mechanism of the nephroprotective effects of NAC or CGA against Cp-induced nephrotoxicity in rats.}, }
@article {pmid36982552, year = {2023}, author = {Meliante, PG and Zoccali, F and Cascone, F and Di Stefano, V and Greco, A and de Vincentiis, M and Petrella, C and Fiore, M and Minni, A and Barbato, C}, title = {Molecular Pathology, Oxidative Stress, and Biomarkers in Obstructive Sleep Apnea.}, journal = {International journal of molecular sciences}, volume = {24}, number = {6}, pages = {}, pmid = {36982552}, issn = {1422-0067}, support = {Prot. N.0000625//BANCA D'ITALIA/ ; DSB.AD007.256//National Research Council/ ; }, mesh = {Humans ; *Pathology, Molecular ; Oxidative Stress ; *Sleep Apnea, Obstructive/pathology ; Antioxidants/therapeutic use/metabolism ; Biomarkers/metabolism ; Hypoxia/metabolism ; }, abstract = {Obstructive sleep apnea syndrome (OSAS) is characterized by intermittent hypoxia (IH) during sleep due to recurrent upper airway obstruction. The derived oxidative stress (OS) leads to complications that do not only concern the sleep-wake rhythm but also systemic dysfunctions. The aim of this narrative literature review is to investigate molecular alterations, diagnostic markers, and potential medical therapies for OSAS. We analyzed the literature and synthesized the evidence collected. IH increases oxygen free radicals (ROS) and reduces antioxidant capacities. OS and metabolic alterations lead OSAS patients to undergo endothelial dysfunction, osteoporosis, systemic inflammation, increased cardiovascular risk, pulmonary remodeling, and neurological alterations. We treated molecular alterations known to date as useful for understanding the pathogenetic mechanisms and for their potential application as diagnostic markers. The most promising pharmacological therapies are those based on N-acetylcysteine (NAC), Vitamin C, Leptin, Dronabinol, or Atomoxetine + Oxybutynin, but all require further experimentation. CPAP remains the approved therapy capable of reversing most of the known molecular alterations; future drugs may be useful in treating the remaining dysfunctions.}, }
@article {pmid36981595, year = {2023}, author = {Anastasi, E and Scaramuzzino, S and Viscardi, MF and Viggiani, V and Piccioni, MG and Cacciamani, L and Merlino, L and Angeloni, A and Muzii, L and Porpora, MG}, title = {Efficacy of N-Acetylcysteine on Endometriosis-Related Pain, Size Reduction of Ovarian Endometriomas, and Fertility Outcomes.}, journal = {International journal of environmental research and public health}, volume = {20}, number = {6}, pages = {}, pmid = {36981595}, issn = {1660-4601}, mesh = {Pregnancy ; Female ; Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; *Endometriosis/complications/drug therapy ; Dysmenorrhea/complications ; Acetylcysteine/therapeutic use ; *Dyspareunia/complications ; Prospective Studies ; Cohort Studies ; Neoplasm Recurrence, Local ; Fertility ; }, abstract = {BACKGROUND: Endometriosis is a chronic, estrogen-dependent, inflammatory disease, whose pivotal symptoms are dysmenorrhea, dyspareunia, and chronic pelvic pain (CPP). Besides the usual medical treatments, recent evidence suggests there are potential benefits of oral N-acetylcysteine (NAC) on endometriotic lesions and pain. The primary objective of this prospective single-cohort study was to confirm the effectiveness of NAC in reducing endometriosis-related pain and the size of ovarian endometriomas. The secondary objective was to assess if NAC may play a role in improving fertility and reducing the Ca125 serum levels.<br><br>METHODS: Patients aged between 18-45 years old with a clinical/histological diagnosis of endometriosis and no current hormonal treatment or pregnancy were included in the study. All patients received quarterly oral NAC 600 mg, 3 tablets/day for 3 consecutive days of the week for 3 months. At baseline and after 3 months, dysmenorrhea, dyspareunia and CPP were assessed using the Visual Analog Scale score (VAS), while the size of the endometriomas was estimated through a transvaginal ultrasound. Analgesics (NSAIDs) intake, the serum levels of Ca125 and the desire for pregnancy were also investigated. Finally, the pregnancy rate of patients with reproductive desire was evaluated.<br><br>RESULTS: One hundred and twenty patients were recruited. The intensity of dysmenorrhea, dyspareunia and CPP significantly improved (p < 0.0001). The use of NSAIDs (p = 0.001), the size of the endometriomas (p < 0.0001) and the serum levels of Ca125 (p < 0.0001) significantly decreased. Among the 52 patients with reproductive desire, 39 successfully achieved pregnancy within 6 months of starting therapy (p = 0.001).<br><br>CONCLUSIONS: Oral NAC improves endometriosis-related pain and the size of endometriomas. Furthermore, it decreases Ca125 serum levels and may improve fertility in patients with endometriosis.}, }
@article {pmid36978904, year = {2023}, author = {Kwak, AW and Kim, WK and Lee, SO and Yoon, G and Cho, SS and Kim, KT and Lee, MH and Choi, YH and Lee, JY and Park, JW and Shim, JH}, title = {Licochalcone B Induces ROS-Dependent Apoptosis in Oxaliplatin-Resistant Colorectal Cancer Cells via p38/JNK MAPK Signaling.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, pmid = {36978904}, issn = {2076-3921}, support = {2019R1A2C1005899//the Basic Science Research Program of the National Research Foundation Korea (NRF/ ; 2022R1A5A8033794//NRF grant funded by the Korean government (MSIT)/ ; }, abstract = {Licochalcone B (LCB) exhibits anticancer activity in oral cancer, lung cancer, and hepatocellular carcinoma cells. However, little is known about its antitumor mechanisms in human oxaliplatin-sensitive and -resistant colorectal cancer (CRC) cells. The purpose of the present study was to investigate the antitumor potential of LCB against human colorectal cancer in vitro and analyze its molecular mechanism of action. The viability of CRC cell lines was evaluated using the MTT assay. Flow cytometric analyses were performed to investigate the effects of LCB on apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) dysfunction, and multi-caspase activity in CRC cells. The results demonstrated that LCB induced a reduction in cell viability, apoptosis, G2/M cell cycle arrest, ROS generation, MMP depolarization, activation of multi-caspase, and JNK/p38 MAPK. However, p38 (SB203580) and JNK (SP600125) inhibitors prevented the LCB-induced reduction in cell viability. The ROS scavenger N-acetylcysteine (NAC) inhibited LCB-induced reduction in cell viability, apoptosis, cell cycle arrest, ROS generation, MMP depolarization, and multi-caspase and JNK/p38 MAPK activities. Taken together, LCB has a potential therapeutic effect against CRC cells through the ROS-mediated JNK/p38 MAPK signaling pathway. Therefore, we expect LCB to have promising potential as an anticancer therapeutic and prophylactic agent.}, }
@article {pmid36978427, year = {2023}, author = {Walter, H and Verspohl, J and Meißner, J and Oltmanns, H and Geks, AK and Busse, C}, title = {In Vitro Antimicrobial Activity of N-Acetylcysteine against Pathogens Most Commonly Associated with Infectious Keratitis in Dogs and Cats.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {12}, number = {3}, pages = {}, pmid = {36978427}, issn = {2079-6382}, support = {60013053//CP Pharma/ ; }, abstract = {To determine the in vitro antimicrobial activity of N-acetylcysteine (NAC) against common pathogens associated with infectious keratitis in dogs and cats, clinical isolates of Staphylococcus (S.) pseudintermedius (n = 20), Streptococcus (St.) canis (n = 10) and Pseudomonas (P.) aeruginosa (n = 7) of canine and feline infectious ulcerative keratitis and a quality control strain (P. aeruginosa DSM 19880) were tested. The minimal inhibitory concentration (MIC) of NAC concentrations was determined using microdilution methodology. For S. pseudintermedius and P. aeruginosa, NAC concentrations in the range of 1.56 mg/mL (0.156%) to 100 mg/mL (10%), and for St. canis, concentrations ranging from 0.195 mg/mL (0.0195%) to 6.25 mg/mL (0.625%) were tested. For S. pseudintermedius, the MIC was 3.12 mg/mL (0.312%) for all tested isolates. For P. aeruginosa isolates and the quality control strain, the MIC ranged from 3.12 mg/mL (0.312%) to 6.25 mg/mL (0.625%). For St. canis, the MIC ranged from 1.56 mg/mL (0.156%) to 3.12 mg/mL (0.312%). NAC has an in vitro antimicrobial activity against three bacterial species commonly found in infectious keratitis in dogs and cats and therefore may be a promising alternative or adjuvant to topical antibiotics. The results warrant a clinical pilot study to assess the potential of NAC to reduce or replace the use of topical antibiotics in line with the One Health approach.}, }
@article {pmid36976990, year = {2023}, author = {Wang, W and Guan, J and Feng, Y and Liu, S and Zhao, Y and Xu, Y and Xu, H and Fu, F}, title = {Polystyrene Microplastics Induced Ovarian Toxicity in Juvenile Rats Associated with Oxidative Stress and Activation of the PERK-eIF2α-ATF4-CHOP Signaling Pathway.}, journal = {Toxics}, volume = {11}, number = {3}, pages = {}, pmid = {36976990}, issn = {2305-6304}, support = {20194BCJ22004//Research Foundation from Academic and Technical Leaders of Major Disciplines in Jiangxi Province, China/ ; }, abstract = {Numerous reports confirm that microplastics exposure could induce reproductive toxicity in mammals. However, the effects of microplastics exposure during juveniles on ovarian apoptosis through oxidative and endoplasmic reticulum (ER) stresses remains unclear, which is the focus of our study. In the present study, female rats (4 weeks old) were exposed to polystyrene microplastics (PS-MPs, 1 μm) at different dosages (0, 0.5, and 2.0 mg/kg) for 28 days. Findings revealed that 2.0 mg/kg of PS-MPs distinctly increased the atretic follicle ratio in the ovary and dramatically reduced the serum levels of estrogen and progesterone. Additionally, the oxidative stress indicators declined, including the activity of superoxide dismutase and catalase, whereas the malondialdehyde content in the ovary was considerably enhanced in the 2.0 mg/kg PS-MPs group. Furthermore, the expressions of genes related to ER stress (PERK, eIF2α, ATF4, and CHOP) and apoptosis were remarkably elevated in the 2.0 mg/kg PS-MPs group compared with those in the control group. We found that PS-MPs induced oxidative stress and activated the PERK-eIF2α-ATF4-CHOP signaling pathway in juvenile rats. Moreover, with the oxidative stress inhibitor N-acetyl-cysteine and eIF2α dephosphorylation blocker Salubrinal treatment, ovarian damage induced by PS-MPs was repaired and associated enzyme activities were improved. Overall, our results indicated that PS-MPs exposure induced ovarian injury associated with oxidative stress and activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in juvenile rats, providing new prospects for assessing the health risks of children exposed to microplastics.}, }
@article {pmid36974638, year = {2023}, author = {Fayed, A and Hammad, AA and Abdulazim, DO and Hammad, H and Amin, M and Elhadidy, S and Salem, MM and ElAzim, IMA and Zsom, L and Csongradi, E and Soliman, KM and Sharaf El Din, UA}, title = {Is the combination of linagliptin and allopurinol better prophylaxis against post-contrast acute kidney injury? A multicenter prospective randomized controlled study.}, journal = {Renal failure}, volume = {45}, number = {1}, pages = {2194434}, pmid = {36974638}, issn = {1525-6049}, mesh = {Humans ; *Acute Kidney Injury/chemically induced/etiology/prevention &amp; control ; *Allopurinol/administration &amp; dosage/therapeutic use ; *Diabetic Nephropathies/classification/complications/diagnosis ; Kidney Failure, Chronic/complications/diagnosis ; *Linagliptin/administration &amp; dosage/therapeutic use ; Prospective Studies ; Renal Insufficiency, Chronic/classification/complications/diagnosis ; *Contrast Media/adverse effects ; Chemoprevention/methods ; Drug Therapy, Combination ; Acetylcysteine/administration &amp; dosage/therapeutic use ; *Protective Agents/administration &amp; dosage/adverse effects/therapeutic use ; Saline Solution/administration &amp; dosage/therapeutic use ; }, abstract = {BACKGROUND: Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD.<br><br>METHODS: Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2&#x2009;days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2[nd] received allopurinol, the 3[rd] group received linagliptin, and the 4[th] received both allopurinol and linagliptin. Post-procedure follow-up for kidney functions was conducted for 2&#x2009;weeks in all patients.<br><br>RESULTS: 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (p&#x2009;<&#x2009;0.02 and <0.03, respectively). None of the post-contrast AKI cases required dialysis.<br><br>CONCLUSION: Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view.<br><br>NCT03470454.}, }
@article {pmid36974603, year = {2023}, author = {Zhang, C and Zhou, T and Li, Y and Dai, W and Du, S}, title = {Activation of the CncC pathway is involved in the regulation of P450 genes responsible for clothianidin resistance in Bradysia odoriphaga.}, journal = {Pest management science}, volume = {79}, number = {9}, pages = {3071-3079}, doi = {10.1002/ps.7482}, pmid = {36974603}, issn = {1526-4998}, support = {//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Reactive Oxygen Species ; Neonicotinoids/pharmacology/metabolism ; *Insecticides/pharmacology ; Nematocera/genetics ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Insecticide Resistance/genetics ; Larva/genetics/metabolism ; }, abstract = {BACKGROUND: Insect cytochrome P450 monooxygenases (P450s) play a key role in the detoxification metabolism of insecticides and their overexpression is often associated with insecticide resistance. Our previous research showed that the overexpression of four P450 genes is responsible for clothianidin resistance in B. odoriphaga. In this study, we characterized another P450 gene, CYP6FV21, associated with clothianidin resistance. However, the molecular basis for the overexpression of P450 genes in clothianidin-resistant strain remains obscure in B. odoriphaga.<br><br>RESULTS: In this study, the CYP6FV21 gene was significantly overexpressed in the clothianidin-resistant (CL-R) strain. Clothianidin exposure significantly increased the expression level of CYP6FV21. Knockdown of CYP6FV21 significantly increased the susceptibility of B. odoriphaga larvae to clothianidin. The transcription factor Cap 'n' Collar isoform-C (CncC) was highly expressed in the midgut of larvae in B. odoriphaga. The expression level of CncC was higher in the CL-R strain compared with the susceptible (SS) strain. Clothianidin exposure caused reactive oxygen species (ROS) accumulation and significantly increased the expression level of CncC. Knockdown of CncC caused a significant decrease in the expression of CYP3828A1 and CYP6FV21, and P450 enzyme activity, and led to a significant increase in mortality after exposure to lethal concentration at 30% (LC30) of&#xa0;clothianidin. After treatment with CncC agonist curcumin, the P450 activity and the expression levels of CYP3828A1 and CYP6FV21 significantly increased, and larval sensitivity to clothianidin decreased. The ROS scavenger N-acetylcysteine (NAC) treatment significantly inhibited the expression levels of CncC, CYP3828A1 and CYP6FV21 in response to clothianidin exposure and increased larval sensitivity to clothianidin.<br><br>CONCLUSION: Taken together, these results indicate that activation of the CncC pathway by the ROS burst plays a critical role in clothianidin resistance by regulating the expression of CYP3828A1 and CYP6FV21 genes in B. odoriphaga. This study provides more insight into the mechanisms underlying B. odoriphaga larval resistance to clothianidin. &#xa9; 2023 Society of Chemical Industry.}, }
@article {pmid36971326, year = {2023}, author = {Patwardhan, RS and Kundu, K and Purohit, V and Kumar, BK and Singh, B and Thoh, M and Undavia, K and Bhilwade, HN and Nayak, SK and Sharma, D and Sandur, SK}, title = {Malabaricone C, a constituent of spice Myristica malabarica, exhibits anti-inflammatory effects via modulation of cellular redox.}, journal = {Journal of biosciences}, volume = {48}, number = {2}, pages = {}, pmid = {36971326}, issn = {0973-7138}, mesh = {Mice ; Animals ; *Myristica/metabolism ; Spices ; Oxidation-Reduction ; NF-kappa B/genetics/metabolism ; Cytokines/genetics/metabolism ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {The present study primarily focuses on the efficacy of Malabaricone C (Mal C) as an anti-inflammatory agent. Mal C inhibited mitogen-induced T-cell proliferation and cytokine secretion. Mal C significantly reduced cellular thiols in lymphocytes. N-acetyl cysteine (NAC) restored cellular thiol levels and abrogated Mal C-mediated inhibition of T-cell proliferation and cytokine secretion. Physical interaction between Mal C and NAC was evinced from HPLC and spectral analysis. Mal C treatment significantly inhibited concanavalin A-induced phosphorylation of ERK/JNK and DNA binding of NF-κB. Administration of Mal C to mice suppressed T-cell proliferation and effector functions ex vivo. Mal C treatment did not alter the homeostatic proliferation of T-cells in vivo but completely abrogated acute graft-versus-host disease (GvHD)-associated morbidity and mortality. Our studies indicate probable use of Mal C for prophylaxis and treatment of immunological disorders caused due to hyper-activation of T-cells.}, }
@article {pmid36968922, year = {2023}, author = {Altaf, F and Qureshi, ZA and Kandhi, S and Khaja, M}, title = {Clinical Conundrum of Acute Hepatitis B With Concurrent Hepatitis E Infection Leading to Severe Acute Liver Injury.}, journal = {Cureus}, volume = {15}, number = {2}, pages = {e35216}, pmid = {36968922}, issn = {2168-8184}, abstract = {Acute liver injury in the setting of acute fulminant hepatitis caused by the hepatitis B virus (HBV) can occur both during primary infection and after chronic HBV reactivation. Guidelines recommend considering antiviral therapy in both cases. Antiviral therapy with a nucleoside analog may be beneficial in patients with acute liver failure from acute HBV infection, though not all studies have shown a benefit. This is a case of a 53-year-old woman with a past medical history of untreated hepatitis C with undetectable viral load and right breast cancer status post lumpectomy, who presented to the emergency department with complaints of yellowish skin and sclera discoloration with right upper quadrant pain for one week. She was a known intravenous drug abuser and binge alcohol user. Her labs were positive for hepatitis B, hepatitis E, and hepatitis C viruses. She also had elevated liver enzymes with hyperbilirubinemia showing severe acute liver injury. Computed tomography of the abdomen and pelvis with contrast was normal, and the abdominal ultrasound showed homogenous echotexture of the liver without a focal lesion. The patient was diagnosed with acute fulminant hepatitis B. After initial hemodynamic stabilization, N-acetylcysteine (NAC) and tenofovir were started, and transaminases were followed. Liver function tests showed a downtrend, and, in a few weeks, they came to baseline. Hepatitis B viral load became undetectable as well. Acute hepatitis B infection is seldom treated. The presented case depicts the use of tenofovir in the setting of severe acute liver injury due to hepatitis B. Starting antiviral therapy (especially tenofovir disoproxil fumarate) early in the disease course was shown to have very assuring results with complete resolution of symptoms and normalization of liver function tests. The treatment protocol for acute HBV deserves further investigation.}, }
@article {pmid36965604, year = {2023}, author = {Camus, MF and Rodriguez, E and Kotiadis, V and Carter, H and Lane, N}, title = {Redox stress shortens lifespan through suppression of respiratory complex I in flies with mitonuclear incompatibilities.}, journal = {Experimental gerontology}, volume = {175}, number = {}, pages = {112158}, doi = {10.1016/j.exger.2023.112158}, pmid = {36965604}, issn = {1873-6815}, support = {BB/S003681/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Female ; *Longevity/genetics ; *Electron Transport Complex I ; Drosophila melanogaster/genetics ; Hydrogen Peroxide ; Oxidation-Reduction ; }, abstract = {Incompatibilities between mitochondrial and nuclear genes can perturb respiration, biosynthesis, signaling and gene expression. Here we investigate whether mild mitonuclear incompatibilities alter the physiological response to redox stress induced by N-acetyl cysteine (NAC). We studied three Drosophila melanogaster lines with mitochondrial genomes that were either coevolved (WT) or mildly mismatched (BAR, COX) to an isogenic nuclear background. Responses to NAC varied substantially with mitonuclear genotype, sex, tissue and dose. NAC caused infertility and high mortality in some groups, but not others. Using tissue-specific high-resolution fluorespirometry, we show that NAC did not alter H2O2 flux but suppressed complex I-linked respiration in female flies, while maintaining a reduced glutathione pool. The high mortality in BAR females was associated with severe (>50 %) suppression of complex I-linked respiration, rising H2O2 flux in the ovaries, and significant oxidation of the glutathione pool. Our results suggest that redox stress is attenuated by the suppression of complex-I linked respiration, to the point of death in some mitonuclear lines. We propose that suppression of complex I-linked respiration is a general mechanism to maintain redox homeostasis in tissues, which could offset oxidative stress in ageing, producing a metabolic phenotype linked with epigenetic changes and age-related decline.}, }
@article {pmid36964576, year = {2023}, author = {Peng, C and Li, X and Ao, F and Li, T and Guo, J and Liu, J and Zhang, X and Gu, J and Mao, J and Zhou, B}, title = {Mitochondrial ROS driven by NOX4 upregulation promotes hepatocellular carcinoma cell survival after incomplete radiofrequency ablation by inducing of mitophagy via Nrf2/PINK1.}, journal = {Journal of translational medicine}, volume = {21}, number = {1}, pages = {218}, pmid = {36964576}, issn = {1479-5876}, mesh = {Humans ; Mitophagy ; *Carcinoma, Hepatocellular/pathology ; Reactive Oxygen Species/metabolism ; NF-E2-Related Factor 2/metabolism ; Up-Regulation ; Cell Survival ; Protein Kinases/metabolism ; *Liver Neoplasms/pathology ; Neoplasm Recurrence, Local/pathology ; Mitochondria/metabolism ; *Radiofrequency Ablation ; NADPH Oxidase 4/metabolism ; }, abstract = {BACKGROUND: The recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) remains a major clinical problem. Cells that survive the sublethal heat stress that is induced by incomplete RFA are the main source of HCC relapse. Heat stress has long been reported to increase intracellular reactive oxygen species (ROS) generation. Although ROS can induce apoptosis, a pro-survival effect of ROS has also been demonstrated. However, the role of ROS in HCC cells exposed to sublethal heat stress remains unclear.<br><br>METHODS: HepG2 and HuH7 cells were used for this experiment. Insufficient RFA was performed in cells and in a xenograft model. ROS and antioxidant levels were measured. Apoptosis was analyed by Annexin-V/PI staining and flow cytometry. Protein expression was measured using western blotting. Colocalization of lysosomes and mitochondria was analyzed to assess mitophagy. Corresponding activators or inhibitors were applied to verify the function of specific objectives.<br><br>RESULTS: Here,we showed that sublethal heat stress induced a ROS burst, which caused acute oxidative stress. This ROS burst was generated by mitochondria, and it was initiated by upregulated NOX4 expression in the mitochondria. N-acetylcysteine (NAC) decreased HCC cell survival under sublethal heat stress conditions in vivo and in vitro. NOX4 triggers the production of mitochondrial ROS (mtROS), and NOX4 inhibitors or siNOX4 also decreased HCC cell survival under sublethal heat stress conditions in vitro. Increased mtROS trigger PINK1-dependent mitophagy to eliminate the mitochondria that are damaged by sublethal heat stress and to protect cells from apoptosis. Nrf2 expression was elevated in response to this ROS burst and mediated the ROS burst-induced increase in PINK1 expression after sublethal heat stress.<br><br>CONCLUSION: These data confirmed that the ROS burst that occurs after iRFA exerted a pro-survival effect. NOX4 increased the generation of ROS by mitochondria. This short-term ROS burst induced PINK1-dependent mitophagy to eliminate damaged mitochondria by increasing Nrf2 expression.}, }
@article {pmid36963348, year = {2023}, author = {Zhao, K and Han, D and He, SR and Wu, LY and Liu, WY and Zhong, ZM}, title = {N-acetyl-L-cysteine attenuates oxidative stress-induced bone marrow endothelial cells apoptosis by inhibiting BAX/caspase 3 pathway.}, journal = {Biochemical and biophysical research communications}, volume = {656}, number = {}, pages = {115-121}, doi = {10.1016/j.bbrc.2023.03.045}, pmid = {36963348}, issn = {1090-2104}, mesh = {*Acetylcysteine/pharmacology/metabolism ; bcl-2-Associated X Protein/metabolism ; *Endothelial Cells/metabolism ; Caspase 3/metabolism ; Bone Marrow/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Apoptosis ; }, abstract = {Bone marrow endothelial cells (BMECs) play a crucial role in the maintenance of bone homeostasis. The decline in BMECs is associated with abnormal bone development and loss. At present, the mechanism of age-related oxidative stress enhancement in BMEC dysfunction remains unclear. Our experiment explored injury caused by oxidative stress enhancement in BMECs both in vivo and in vitro. The BMECs, indicators of oxidative stress, bone mass, and apoptosis-related proteins were analyzed in different age groups. We also evaluated the ability of N-Acetyl-L-cysteine (NAC) attenuate oxidative stress injury in BMECs. NAC treatment attenuated reactive oxygen species (ROS) overgeneration and apoptosis in BMECs in vitro and alleviated the loss of BMECs and bone mass in vivo. In conclusion, this study could improve our understanding of the mechanism of oxidative stress-induced BMECs injury and whether NAC has therapeutic potential in senile osteoporosis.}, }
@article {pmid36961435, year = {2023}, author = {Li, Z and Wu, L and Huang, Z and Lv, B and Fu, Y and Zhou, L and Fu, X}, title = {CCCP Facilitates Aminoglycoside to Kill Late Stationary-Phase Escherichia coli by Elevating Hydroxyl Radical.}, journal = {ACS infectious diseases}, volume = {9}, number = {4}, pages = {801-814}, doi = {10.1021/acsinfecdis.2c00522}, pmid = {36961435}, issn = {2373-8227}, mesh = {Humans ; *Escherichia coli ; *Aminoglycosides/pharmacology/chemistry ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology ; Hydroxyl Radical/pharmacology ; Anti-Bacterial Agents/pharmacology ; Tobramycin/pharmacology ; }, abstract = {Improving the efficacy of existing antibiotics is significant for combatting antibiotic resistance that poses a major threat to human health. Carbonyl cyanide m-chlorophenylhydrazine (CCCP), a well-known protonophore for dissipating proton motive force (PMF), has been widely used to block the PMF-dependent uptake of aminoglycoside antibiotics and thus suppress aminoglycoside lethality. Here, we report that CCCP and its functional analog FCCP, but not other types of protonophores, unprecedently potentiate aminoglycosides (e.g., tobramycin and gentamicin) by 3-4 orders of magnitude killing of Escherichia coli, Staphylococcus aureus, Shigella flexneri, and Vibrio alginolyticus cells in stationary phase but not these cells in exponential phase nor other 12 bacterial species we examined. Overall, the effect of CCCP on aminoglycoside lethality undergoes a gradual transition from suppression against E. coli exponential-phase cells to potentiation against late stationary-phase cells, with the cell growth status and culture medium being crucial. Consistently, disturbance of the PMF by changing transmembrane proton gradient (ΔpH) or electric potential (ΔΨ) also potentiates tobramycin. Nevertheless, CCCP neither increases the intracellular concentration of tobramycin nor decreases the MIC of the antibiotic, thus excluding that CCCP acts as an efflux pump inhibitor to potentiate aminoglycosides. Rather, we show that the combined treatment dramatically enhances the cellular level of hydroxyl radical under both aerobic and anaerobic culturing conditions, under which the antioxidant N-acetyl cysteine fully suppresses both hydroxyl radical accumulation and cell death. Together, these findings open a new avenue to develop certain protonophores as aminoglycoside adjuvants against pathogens in stationary phase and also illustrate an essential role of hydroxyl radical in aminoglycoside lethality regardless of aerobic respiration.}, }
@article {pmid36950489, year = {2023}, author = {Thomas, L and Chandran, J and Goel, A and Jacob, E and Chacko, B and Subramani, K and Agarwal, I and Varughese, S and David, VG and Daniel, D and Mammen, J and Balakrishnan, V and Balasubramanian, KA and Lionel, AP and Adhikari, DD and Abhilash, KPP and Elias, E and Eapen, CE and Zachariah, U}, title = {Improving Transplant-free Survival With Low-volume Plasma Exchange to Treat Children With Rodenticide Induced Hepatotoxicity.}, journal = {Journal of clinical and experimental hepatology}, volume = {13}, number = {2}, pages = {252-258}, pmid = {36950489}, issn = {0973-6883}, abstract = {BACKGROUND: In a prior report, no patient with rodenticidal hepatotoxicity who met Kochi criteria (MELD score ≥36 or baseline INR ≥6 with hepatic encephalopathy) (PMID: 26310868) for urgent liver transplantation survived with medical management alone. Plasma exchange (PLEX) may improve survival in these patients.<br><br>OBJECTIVES: We describe our experience with low-volume PLEX (PLEX-LV) in treating rodenticide ingestion induced hepatotoxicity in children.<br><br>METHODS: From prospectively collected database of rodenticidal hepatotoxicity patients managed as in-patient with department of Hepatology from December 2017 to August 2021, we retrospectively studied outcomes in children (&#x2264;18 years). Hepatotoxicity was categorized as acute liver injury (ALI, coagulopathy alone) or acute liver failure (ALF, coagulopathy and encephalopathy). Kochi criteria was used to assess need for urgent liver transplantation. The primary study outcome was one-month survival.<br><br>RESULTS: Of the 110 rodenticidal hepatotoxicity patients, 32 children (females: 56%; age: 16 [4.7-18] years; median, range) constituted the study patients. The study patients presented 4 (1-8) days after poison consumption (impulsive suicidal intent:31, accidental:1). Twenty children (62%) had ALI [MELD: 18 (8-36)] and 12 (38%) had ALF [MELD: 37 (24-45)].All children received standard medical care, including N-acetyl cysteine; ALF patients also received anti-cerebral edema measures. None of the patient families opted for liver transplantation. Seventeen children (ALI: 6, ALF: 11) were treated with PLEX-LV (3 [1-5] sessions, volume of plasma exchanged per session: 26 [13-38] ml/kg body weight) and peri-procedure low dose prednisolone.At 1 month, 28 of the 32 children (87.5%) were alive (4 ALF patients died). Of 10 children who met Kochi listing criteria for urgent liver transplantation, two children were ineligible for PLEX-LV (due to hemodynamic instability) and of the remaining 8 children treated by PLEX-LV, 6 (75%) survived.<br><br>CONCLUSIONS: PLEX-LV shows promise as an effective non-liver transplant treatment in children with rodenticidal hepatotoxicity.}, }
@article {pmid36947366, year = {2023}, author = {Ezzat, GM and Nassar, AY and Bakr, MH and Mohamed, S and Nassar, GA and Kamel, AA}, title = {Acetylated Oligopeptide and N-acetyl cysteine Protected Against Oxidative Stress, Inflammation, Testicular-Blood Barrier Damage, and Testicular Cell Death in Iron-Overload Rat Model.}, journal = {Applied biochemistry and biotechnology}, volume = {195}, number = {8}, pages = {5053-5071}, pmid = {36947366}, issn = {1559-0291}, mesh = {Male ; Rats ; Animals ; *Acetylcysteine/pharmacology/metabolism ; Testis ; NF-kappa B/metabolism ; Beclin-1/metabolism ; Claudin-1/metabolism ; Dextrans/metabolism ; Oxidative Stress ; Antioxidants/pharmacology ; *Iron Overload/drug therapy/metabolism/pathology ; Inflammation/drug therapy/metabolism ; Glutathione/metabolism ; Cell Death ; Testosterone/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Iron/metabolism ; }, abstract = {Multiple organs, including the testes, are damaged by iron overload. It has been shown that N-acetyl cysteine (NAC) influences oxidative stress in iron overload. The present study aimed to evaluate the roles of acetylated peptide (AOP) and NAC in the inhibition of iron-overload induced-testicular damage. At the beginning of the experiment, NAC (150 mg /kg) was given for a week to all 40 rats. Then, four groups were formed by dividing the animals (10 rats/group). Group I included healthy control rats. Group II (iron overload) was given intraperitoneal iron dextran (60 mg/kg/day) 5 days a week for 4 weeks. Group III (NAC) was given NAC orally at a dose of 150 mg/kg/day for 4 weeks in addition to iron dextran. Group IV (AOP) was given AOP orally at a dose of 150 mg/kg/day for 4 weeks besides iron dextran. When the experiment time was over, testosterone serum level, testicular B cell lymphoma-2 (BCL-2) and protein kinase B (PKB) protein levels, nuclear factor kappa-B (NF-κB), and Beclin1 mRNA expression levels, and malondialdehyde (MDA), and reduced glutathione (GSH) were determined by ELISA, quantitative reverse transcription-PCR, and chemical methods. Finally, histopathological examinations and immunohistochemical detection of claudin-1 and CD68 were performed. The iron overload group exhibited decreased testosterone, BCL-2, PKB, claudin-1, and GSH and increased MDA, NF-κB, Beclin1, and CD68, while both NAC and AOP treatments protected against the biochemical and histopathological disturbances occurring in the iron overload model. We concluded that NAC and AOP can protect against testes damage by iron overload via their antioxidant, anti-inflammatory, antiapoptotic, and ant-autophagic properties. The NAC and AOP may be used as preventative measures against iron overload-induced testicular damage.}, }
@article {pmid36945164, year = {2023}, author = {Kemahli, E and Uyeturk, U and Cetinkaya, A and Erimsah, S and Uyeturk, U and Gucuk, A}, title = {Protective Effects of N-Acetyl Cysteine on Undescended Testis after Orchiopexy: A Rat-model Study.}, journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP}, volume = {33}, number = {3}, pages = {319-324}, doi = {10.29271/jcpsp.2023.03.319}, pmid = {36945164}, issn = {1681-7168}, mesh = {Humans ; Pregnancy ; Female ; Male ; Rats ; Animals ; *Testis ; *Cryptorchidism/surgery ; Orchiopexy ; Acetylcysteine/pharmacology ; Flutamide ; Semen ; Antioxidants/pharmacology ; }, abstract = {UNLABELLED: ABSTRACT Objective: To assess the effectiveness of utilising N-acetyl cysteine (NAC) to treat tissue damage brought on by undescended testis (UT) in rats after orchiopexy.<br><br>STUDY DESIGN: Experimental study. Place and Duration of the Study: Bolu Abant &#x130;zzet Baysal University, Bolu, Turkey, from January 2018 to June 2020.<br><br>METHODOLOGY: The UT model was created by administering flutamide to pregnant rats. Four groups of animals were created as the control group (offsprings of pregnant rats without flutamide), group II (UT), group III (UT + orchiopexy), and group IV (UT + orchiopexy + NAC); each containing eight animals.<br><br>RESULTS: Group IV had a higher level of glutathione peroxidase than groups III and II (p=0.001 and p=0.002, respectively). Malondialdehyde was reduced in group IV compared with groups III and II (both p<0.001). There were differences in mean apoptotic cell counts (ACC) among the groups (p<0.001). ACC in group IV was lower than in group III (p<0.001). Sperm counts were higher in group IV than &#x131;n groups III and II, and in group III they were higher than group II (p<0.001 all) and similar between groups IV and control group (p=0.102).<br><br>CONCLUSION: Orchiopexy reduced UT-related testicular damage, additionally using NAC following orchiopexy may further reduce testicular damage through its antioxidant effects.<br><br>KEY WORDS: Undescended testis, Testis damage, Orchiopexy, N-acetyl cysteine, Antioxidant.}, }
@article {pmid36941865, year = {2023}, author = {Sztolsztener, K and Bzdęga, W and Hodun, K and Chabowski, A}, title = {N-Acetylcysteine Decreases Myocardial Content of Inflammatory Mediators Preventing the Development of Inflammation State and Oxidative Stress in Rats Subjected to a High-Fat Diet.}, journal = {International journal of inflammation}, volume = {2023}, number = {}, pages = {5480199}, pmid = {36941865}, issn = {2090-8040}, abstract = {Arachidonic acid (AA) is a key precursor for proinflammatory and anti-inflammatory derivatives that regulate the inflammatory response. The modulation of AA metabolism is a target for searching a therapeutic agent with potent anti-inflammatory action in cardiovascular disorders. Therefore, our study aims to determine the potential preventive impact of N-acetylcysteine (NAC) supplementation on myocardial inflammation and the occurrence of oxidative stress in obesity induced by high-fat feeding. The experiment was conducted for eight weeks on male Wistar rats fed a standard chow or a high-fat diet (HFD) with intragastric NAC supplementation. The Gas-Liquid Chromatography (GLC) method was used to quantify the plasma and myocardial AA levels in the selected lipid fraction. The expression of proteins included in the inflammation pathway was measured by the Western blot technique. The concentrations of arachidonic acid derivatives, cytokines and chemokines, and oxidative stress parameters were determined by the ELISA, colorimetric, and multiplex immunoassay kits. We established that in the left ventricle tissue NAC reduced AA concentration, especially in the phospholipid fraction. NAC administration ameliorated the COX-2 and 5-LOX expression, leading to a decrease in the PGE2 and LTC4 contents, respectively, and augmented the 12/15-LOX expression, increasing the LXA4 content. In obese rats, NAC ameliorated NF-κB expression, inhibiting the secretion of proinflammatory cytokines. NAC also affected the antioxidant levels in HFD rats through an increase in GSH and CAT contents with a simultaneous decrease in the levels of 4-HNE and MDA. We concluded that NAC treatment weakens the NF-κB signaling pathway, limiting the development of myocardial low-grade inflammation, and increasing the antioxidant content that may protect against the development of oxidative stress in rats with obesity induced by an HFD.}, }
@article {pmid36941180, year = {2023}, author = {Danışan, G and Taydaş, O and Özdemir, M and Ateş, &#xd6;F and Küpeli, A and Öğüşlü, U and Erkin, A and Neşelioğlu, S and Eren, F}, title = {Dynamic thiol-disulphide homeostasis as a biomarker for predicting the development of contrast medium-associated acute kidney injury in the endovascular treatment of peripheral arterial disease: should intravenous N-acetylcysteine be given before the procedure?.}, journal = {Clinical radiology}, volume = {78}, number = {6}, pages = {466-472}, doi = {10.1016/j.crad.2023.02.016}, pmid = {36941180}, issn = {1365-229X}, mesh = {Adult ; Humans ; Acetylcysteine ; Biomarkers ; Disulfides ; Sulfhydryl Compounds ; Serum Albumin ; Contrast Media/adverse effects ; *Acute Kidney Injury/prevention &amp; control ; Homeostasis ; *Peripheral Arterial Disease ; }, abstract = {AIM: To determine the predictive ability of serum thiol-disulphide levels for contrast medium-associated acute kidney injury (CA-AKI) after endovascular treatment (EVT) of peripheral arterial disease (PAD) and evaluate the efficacy of intravenous N-acetylcysteine (NAC) in preventing CA-AKI.<br><br>MATERIAL AND METHODS: This double-blind, randomised controlled study included 85 consecutive adult patients who underwent EVT for PAD. Patients were divided into NAC negative (NAC-) and positive (NAC+) groups. While the NAC- group received only 500 ml saline, the NAC&#xa0;+&#xa0;group received 500 ml saline plus intravenous 600 mg NAC before the procedure. Intra- and intergroup patient characteristics, procedural details, preoperative thiol-disulphide levels, and ischaemia-modified albumin (IMA) levels were recorded.<br><br>RESULTS: There was a significant difference between NAC- and NAC&#xa0;+&#xa0;groups regarding native thiol, total thiol, disulphide/native thiol ratio (D/NT), and disulphide/total thiol ratio (D/TT). There was also a significant difference between the NAC- (33.3%) and NAC+ (13%) groups in CA-AKI development. Logistic regression analysis showed that the D/TT (OR 2.463) and D/NT (OR 2.121) were the most influential parameters for CA-AKI development. In the receiver operating characteristic (ROC) curve analysis, the sensitivity of native thiol to detect the development of CA-AKI was 89.1%. The negative predictive values of native thiol and total thiol were 95.6% and 94.1%, respectively.<br><br>CONCLUSION: The serum thiol-disulphide level can be used as a biomarker to detect CA-AKI development and reveal patients with a low risk for CA-AKI development before EVT of PAD. Furthermore, thiol-disulphide levels allow for the indirect quantitative monitoring of NAC. Preprocedural intravenous NAC administration significantly inhibits CA-AKI development.}, }
@article {pmid36933581, year = {2023}, author = {Ayed-Boussema, I and Rjiba-Touati, K and Hamdi, H and Chaabani, H and Abid-Essefi, S}, title = {Oxidative stress-mediated mitochondrial apoptosis induced by the acaricide, fenpyroximate, on cultured human colon cancer HCT 116 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {89}, number = {}, pages = {105587}, doi = {10.1016/j.tiv.2023.105587}, pmid = {36933581}, issn = {1879-3177}, mesh = {Humans ; HCT116 Cells ; *Acaricides/pharmacology ; Reactive Oxygen Species/metabolism ; Caspase 3/metabolism ; Oxidative Stress ; *Colonic Neoplasms ; Apoptosis ; RNA, Messenger/metabolism ; Membrane Potential, Mitochondrial ; }, abstract = {Fenpyroximate (FEN) is an acaricide that inhibits mitochondrial electron transport at the NADH-coenzyme Q oxidoreductase (complex I). The present study was designed to investigate the molecular mechanisms underling FEN toxicity on cultured human colon carcinoma cells (HCT116). Our data showed that FEN induced HCT116 cell mortality in a concentration dependent manner. FEN arrested cell cycle in G0/G1 phase and increased DNA damage as assessed by comet assay. Induction of apoptosis was confirmed in HCT116 cells exposed to FEN by AO-EB staining and Annexin V-FITC/PI double staining assay. Moreover, FEN induced a loss in mitochondrial membrane potential (MMP), increased p53 and Bax mRNA expression and decreased bcl2 mRNA level. An increase in caspase 9 and caspase 3 activities was also detected. All toghether, these data suggest that FEN induce apoptosis in HCT116 cells via mitochondrial pathway. To check the implication of oxidative stress in FEN-induced cell toxicity, we examined the oxidative stress statue in HCT116 cells exposed to FEN and we tested the effect of a powerful antioxidant, N-acetylcystein (NAC), on FEN-caused toxicity. It was observed that FEN enhanced ROS generation and MDA levels and disturbed SOD and CAT activities. Besides, cell treatment with NAC significantly protected cells from mortality, DNA damage, loss of MMP, and caspase 3 activity induced by FEN. To the best of our knowledge, this is the first study showing that FEN induced mitochondrial apoptosis via ROS generation and oxidative stress.}, }
@article {pmid36927162, year = {2023}, author = {Huang, C and Kuo, S and Lin, L and Yang, Y}, title = {The efficacy of N-acetylcysteine in chronic obstructive pulmonary disease patients: a meta-analysis.}, journal = {Therapeutic advances in respiratory disease}, volume = {17}, number = {}, pages = {17534666231158563}, pmid = {36927162}, issn = {1753-4666}, mesh = {Humans ; *Acetylcysteine/adverse effects ; Disease Progression ; Vital Capacity ; *Pulmonary Disease, Chronic Obstructive/diagnosis/drug therapy ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) may reduce acute exacerbations of chronic obstructive pulmonary disease through an antioxidant effect. Due to the heterogeneity in studies, the currently available data do not confirm the efficacy of oral NAC therapy in chronic obstructive pulmonary disease patients. We hypothesize that chronic obstructive pulmonary disease patients receiving regular oral NAC therapy do not achieve improved clinical outcomes.<br><br>OBJECTIVES: The purpose of this meta-analysis was to determine the efficacy of long-term oral NAC therapy in chronic obstructive pulmonary disease patients.<br><br>DATA SOURCES AND METHODS: The literature search was performed using the PubMed, Web of Science, and Cochrane Library databases to identify all included clinical studies. Studies were eligible for inclusion only if they directly compared the outcomes of NAC versus placebo in adults with chronic obstructive pulmonary disease between 1 January 2000 and 30 May 2022. All studies were included if they reported one or more of the following outcomes: number of patients with no acute exacerbations, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), St George's Respiratory Questionnaire score, glutathione level, and adverse events.<br><br>RESULTS: Nine randomized controlled trials were included in the meta-analysis. There were 1061 patients in the NAC group and 1076 patients in the placebo group. The current meta-analysis provides evidence that the number of patients with no acute exacerbations (965 patients receiving NAC therapy, 979 control group patients), change in FEV1 (433 patients receiving NAC therapy, 447 control group patients), change in FVC (177 patients receiving NAC therapy, 180 control group patients), change in St George's Respiratory Questionnaire score (128 patients receiving NAC therapy, 131 control group patients), change in glutathione levels (38 patients receiving NAC therapy, 40 control group patients), and adverse events (832 patients receiving NAC therapy, 846 control group patients) were not significantly different between the two groups.<br><br>CONCLUSION: NAC did not reduce the risk of acute exacerbation or ameliorate the decline in lung volume in chronic obstructive pulmonary disease patients.}, }
@article {pmid36923901, year = {2023}, author = {Lima, EMF and Almeida, FA and Sircili, MP and Bueris, V and Pinto, UM}, title = {N-acetylcysteine (NAC) attenuates quorum sensing regulated phenotypes in Pseudomonas aeruginosa PAO1.}, journal = {Heliyon}, volume = {9}, number = {3}, pages = {e14152}, pmid = {36923901}, issn = {2405-8440}, abstract = {The expression of many virulence genes in bacteria is regulated by quorum sensing (QS), and the inhibition of this mechanism has been intensely investigated. N-acetylcysteine (NAC) has good antibacterial activity and is able to interfere with biofilm-related respiratory infections, but little is known whether this compound has an effect on bacterial QS communication. This work aimed to evaluate the potential of NAC as a QS inhibitor (QSI) in Pseudomonas aeruginosa PAO1 through in silico and in vitro analyses, as well as in combination with the antibiotic tobramycin. Initially, a molecular docking analysis was performed between the QS regulatory proteins, LasR and RhlR, of P. aeruginosa with NAC, 3-oxo-C12-HSL, C4-HSL, and furanone C30. The NAC sub-inhibitory concentration was determined by growth curves. Then, we performed in vitro tests using the QS reporter strains P. aeruginosa lasB-gfp and rhlA-gfp, as well as the expression of QS-related phenotypes. Finally, the synergistic effect of NAC with the antibiotic tobramycin was calculated by fractional inhibitory concentrations index (FICi) and investigated against bacterial growth, pigment production, and biofilm formation. In the molecular docking study, NAC bound to LasR and RhlR proteins in a similar manner to the AHL cognate, suggesting that it may be able to bind to QS receptor proteins in vivo. In the biosensor assay, the GFP signal was turned down in the presence of NAC at 1000, 500, 250, and 125 μM for lasB-gfp and rhlA-gfp (p < 0.05), suggesting a QS inhibitory effect. Pyocyanin and rhamnolipids decreased (p < 0.05) up to 34 and 37%, respectively, in the presence of NAC at 125 μM. Swarming and swimming motilities were inhibited (p < 0.05) by NAC at 250 to 10000 μM. Additionally, 2500 and 10000 μM of NAC reduced biofilm formation. NAC-tobramycin combination showed synergistic effect with FICi of 0.8, and the best combination was 2500-1.07 μM, inhibiting biofilm formation up to 60%, besides reducing pyocyanin and pyoverdine production. Confocal microscopy images revealed a stronger, dense, and compact biofilm of P. aeruginosa PAO1 control, while the biofilm treated with NAC-tobramycin became thinner and more dispersed. Overall, NAC at low concentrations showed promising anti-QS properties against P. aeruginosa PAO1, adding to its already known effect as an antibacterial and antibiofilm agent.}, }
@article {pmid36923240, year = {2023}, author = {Zhai, T and Zhang, J and Zhang, J and Liu, B and Zhou, Z and Liu, F and Wu, Y}, title = {Cathelicidin promotes liver repair after acetaminophen-induced liver injury in mice.}, journal = {JHEP reports : innovation in hepatology}, volume = {5}, number = {4}, pages = {100687}, pmid = {36923240}, issn = {2589-5559}, abstract = {BACKGROUND &amp; AIMS: Acetaminophen (APAP)-induced acute liver injury (AILI) is a leading cause of acute liver failure (ALF). N-acetylcysteine (NAC) is only effective within 24 h after APAP intoxication, raising an urgent need for alternative approaches to treat this disease. This study aimed to test whether cathelicidin (Camp), which is a protective factor in chronic liver diseases, protects mice against APAP-induced liver injury and ALF.<br><br>METHODS: A clinically relevant AILI model and an APAP-induced ALF model were generated in mice. Genetic and pharmacological approaches were used to interfere with the levels of cathelicidin in&#xa0;vivo.<br><br>RESULTS: An increase in hepatic pro-CRAMP/CRAMP (the precursor and mature forms of mouse cathelicidin) was observed in APAP-intoxicated mice. Upregulated cathelicidin was derived from liver-infiltrating neutrophils. Compared with wild-type littermates, Camp knockout had no effect on hepatic injury but dampened hepatic repair in AILI and reduced survival in APAP-induced ALF. CRAMP administration reversed impaired liver recovery observed in APAP-challenged Camp knockout mice. Delayed CRAMP, CRAMP(1-39) (the extended form of CRAMP), or LL-37 (the mature form of human cathelicidin) treatment exhibited a therapeutic benefit for AILI. Co-treatment of cathelicidin and NAC in AILI displayed a stronger hepatoprotective effect than NAC alone. A similar additive effect of CRAMP(1-39)/LL-37 and NAC was observed in APAP-induced ALF. The pro-reparative role of cathelicidin in the APAP-damaged liver was attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced neutrophil phagocytosis of necrotic cell debris in an autocrine manner.<br><br>CONCLUSIONS: Cathelicidin reduces APAP-induced liver injury and ALF in mice by promoting liver recovery via facilitating inflammation resolution, suggesting a therapeutic potential for late-presenting patients with AILI with or without ALF.<br><br>IMPACT AND IMPLICATIONS: Acetaminophen-induced acute liver injury is a leading cause of acute liver failure. The efficacy of N-acetylcysteine, the only clinically approved drug against acetaminophen-induced acute liver injury, is significantly reduced for late-presenting patients. We found that cathelicidin exhibits a great therapeutic potential in mice with acetaminophen-induced liver injury or acute liver failure, which makes up for the limitation of N-acetylcysteine therapy by specifically promoting liver repair after acetaminophen intoxication. The pro-reparative role of cathelicidin, as a key effector molecule of neutrophils, in the APAP-injured liver is attributed to an accelerated resolution of inflammation at the onset of liver repair, possibly through enhanced phagocytic function of neutrophils in an autocrine manner.}, }
@article {pmid36922946, year = {2023}, author = {El Khoury, R and Ramirez, SP and Loyola, CD and Joddar, B}, title = {Demonstration of doxorubicin's cardiotoxicity and screening using a 3D bioprinted spheroidal droplet-based system.}, journal = {RSC advances}, volume = {13}, number = {12}, pages = {8338-8351}, pmid = {36922946}, issn = {2046-2069}, support = {G12 MD007592/MD/NIMHD NIH HHS/United States ; SC1 HL154511/HL/NHLBI NIH HHS/United States ; }, abstract = {Doxorubicin (DOX) is a highly effective anthracycline chemotherapy agent effective in treating a broad range of life-threatening malignancies but it causes cardiotoxicity in many subjects. While the mechanism of its cardiotoxic effects remains elusive, DOX-related cardiotoxicity can lead to heart failure in patients. In this study, we investigated the effects of DOX-induced cardiotoxicity on human cardiomyocytes (CMs) using a three-dimensional (3D) bioprinted cardiac spheroidal droplet based-system in comparison with the traditional two-dimensional cell (2D) culture model. The effects of DOX were alleviated with the addition of N-acetylcysteine (NAC) and Tiron. Caspase-3 activity was quantified, and reactive oxygen species (ROS) production was measured using dihydroethidium (DHE) staining. Application of varying concentrations of DOX (0.4 μM-1 μM) to CMs revealed a dose-specific response, with 1 μM concentration imposing maximum cytotoxicity and 0.22 ± 0.11% of viable cells in 3D samples versus 1.02 ± 0.28% viable cells in 2D cultures, after 5 days of culture. Moreover, a flow cytometric analysis study was conducted to study CMs proliferation in the presence of DOX and antioxidants. Our data support the use of a 3D bioprinted cardiac spheroidal droplet as a robust and high-throughput screening model for drug toxicity. In the future, this 3D spheroidal droplet model can be adopted as a human-derived tissue-engineered equivalent to address challenges in other various aspects of biomedical pre-clinical research.}, }
@article {pmid36917985, year = {2023}, author = {Duan, J and Matute, JD and Unger, LW and Hanley, T and Schnell, A and Lin, X and Krupka, N and Griebel, P and Lambden, C and Sit, B and Grootjans, J and Pyzik, M and Sommer, F and Kaiser, S and Falk-Paulsen, M and Grasberger, H and Kao, JY and Fuhrer, T and Li, H and Paik, D and Lee, Y and Refetoff, S and Glickman, JN and Paton, AW and Bry, L and Paton, JC and Sauer, U and Macpherson, AJ and Rosenstiel, P and Kuchroo, VK and Waldor, MK and Huh, JR and Kaser, A and Blumberg, RS}, title = {Endoplasmic reticulum stress in the intestinal epithelium initiates purine metabolite synthesis and promotes Th17 cell differentiation in the gut.}, journal = {Immunity}, volume = {56}, number = {5}, pages = {1115-1131.e9}, pmid = {36917985}, issn = {1097-4180}, support = {R37 DK044319/DK/NIDDK NIH HHS/United States ; R01 DK088199/DK/NIDDK NIH HHS/United States ; R01 DK051362/DK/NIDDK NIH HHS/United States ; R01 DK053056/DK/NIDDK NIH HHS/United States ; R01 AI169075/AI/NIAID NIH HHS/United States ; 106260/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; R01 DK117565/DK/NIDDK NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; 222497/Z/21/Z/WT_/Wellcome Trust/United Kingdom ; R01 DK044319/DK/NIDDK NIH HHS/United States ; R01 DK015070/DK/NIDDK NIH HHS/United States ; R01 AI042347/AI/NIAID NIH HHS/United States ; R37 DK015070/DK/NIDDK NIH HHS/United States ; R01 DK110559/DK/NIDDK NIH HHS/United States ; K12 HD000850/HD/NICHD NIH HHS/United States ; P30 DK034854/DK/NIDDK NIH HHS/United States ; R56 DK053056/DK/NIDDK NIH HHS/United States ; P30 DK020595/DK/NIDDK NIH HHS/United States ; }, mesh = {*Endoplasmic Reticulum Stress/drug effects ; *Intestinal Mucosa/drug effects/metabolism ; *Th17 Cells/cytology/metabolism ; Cell Differentiation ; Humans ; Animals ; Mice ; Mice, Transgenic ; Anti-Bacterial Agents/pharmacology ; }, abstract = {Intestinal IL-17-producing T helper (Th17) cells are dependent on adherent microbes in the gut for their development. However, how microbial adherence to intestinal epithelial cells (IECs) promotes Th17 cell differentiation remains enigmatic. Here, we found that Th17 cell-inducing gut bacteria generated an unfolded protein response (UPR) in IECs. Furthermore, subtilase cytotoxin expression or genetic removal of X-box binding protein 1 (Xbp1) in IECs caused a UPR and increased Th17 cells, even in antibiotic-treated or germ-free conditions. Mechanistically, UPR activation in IECs enhanced their production of both reactive oxygen species (ROS) and purine metabolites. Treating mice with N-acetyl-cysteine or allopurinol to reduce ROS production and xanthine, respectively, decreased Th17 cells that were associated with an elevated UPR. Th17-related genes also correlated with ER stress and the UPR in humans with inflammatory bowel disease. Overall, we identify a mechanism of intestinal Th17 cell differentiation that emerges from an IEC-associated UPR.}, }
@article {pmid36916401, year = {2023}, author = {Lin, YP and Hseu, YC and Thiyagarajan, V and Vadivalagan, C and Pandey, S and Lin, KY and Hsu, YT and Liao, JW and Lee, CC and Yang, HL}, title = {The in vitro and in vivo anticancer activities of Antrodia salmonea through inhibition of metastasis and induction of ROS-mediated apoptotic and autophagic cell death in human glioblastoma cells.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {158}, number = {}, pages = {114178}, doi = {10.1016/j.biopha.2022.114178}, pmid = {36916401}, issn = {1950-6007}, mesh = {Animals ; Mice ; Humans ; *Autophagic Cell Death ; Reactive Oxygen Species/metabolism ; Mice, Nude ; Phosphatidylinositol 3-Kinases/metabolism ; *Glioblastoma/drug therapy ; Annexin A5 ; Apoptosis ; Autophagy ; Cell Line, Tumor ; }, abstract = {BACKGROUND: Antrodia salmonea (AS) exhibits anticancer activities against various cancers.<br><br>OBJECTIVE: This study investigated the anticancer activities of AS on human glioblastoma (GBM8401 and U87MG) cells both in vitro and in vivo and explained the underlying molecular mechanism.<br><br>METHODS: MTT, colony formation, migration/invasion assay, immunoblotting, immunofluorescence, TUNEL, Annexin V/PI staining, AO staining, GFP-LC3 transfection, TEM, qPCR, siLC3, DCFH2-DA assay, and xenografted-nude mice were used to assess the potential of AS therapy.<br><br>RESULTS: AS treatment retarded growth and suppressed colony formation in glioblastoma cells. AS attenuates EMT by suppressing invasion and migration, increasing E-cadherin expression, decreasing Twist, Snail, and N-cadherin expression, and inhibiting Wnt/&#x3b2;-catenin pathways in GBM8401 and U87MG cells. Furthermore, AS induced apoptosis by activating caspase-3, cleaving PARP, and dysregulating Bax and Bcl-2 in both cell lines. TUNEL assay and Annexin V/PI staining indicated AS-mediated late apoptosis. Interestingly, AS induced autophagic cell death by LC3-II accumulation, AVO formation, autophagosome GFP-LC3 puncta, p62/SQSTM1 expression, and ATG4B inhibition in GBM8401 and U87MG cells. TEM data revealed that AS favored autophagosome and autolysosome formation. The autophagy inhibitors 3-MA/CQ and LC3 knockdown suppressed AS-induced apoptosis in glioblastoma cells, indicating that the inhibition of autophagy decreased AS-induced apoptosis. Notably, the antioxidant N-acetylcysteine (NAC) inhibited AS-mediated ROS production and AS-induced apoptotic and autophagic cell death. Furthermore, AS induced ROS-mediated inhibition of the PI3K/AKT/mTOR signaling pathway. AS reduced the tumor burden in GBM8401-xenografted nude mice and significantly modulated tumor xenografts by inducing anti-EMT, apoptosis, and autophagy. AS could be a potential antitumor agent in human glioblastoma treatment.}, }
@article {pmid36916093, year = {2023}, author = {Zhou, Z and Zhang, H}, title = {CHAC1 exacerbates LPS-induced ferroptosis and apoptosis in HK-2 cells by promoting oxidative stress.}, journal = {Allergologia et immunopathologia}, volume = {51}, number = {2}, pages = {99-110}, pmid = {36916093}, issn = {1578-1267}, mesh = {Animals ; Humans ; Mice ; *Acute Kidney Injury/chemically induced ; Apoptosis ; Caspase 3/metabolism/pharmacology ; *Ferroptosis ; Lipopolysaccharides/adverse effects ; Oxidative Stress ; Poly(ADP-ribose) Polymerase Inhibitors/adverse effects ; *Sepsis/metabolism ; }, abstract = {BACKGROUND: Sepsis-induced acute kidney injury (AKI) is a singularly grievous and life-threatening syndrome. Its pathogenesis is closely related to inflammatory response, apoptosis, oxidative stress, and ferroptosis. Cation transport regulator-like protein 1 (CHAC1), as a proapoptic factor, may be involved in apoptosis, oxidative stress, and ferroptosis. This study aimed to explore the role of CHAC1 in the lipopolysaccharide (LPS)-induced the human renal proximal tubular epithelial (HK-2) cells.<br><br>METHODS: HK-2 cells were challenged with LPS to construct a model of sepsis-induced AKI in vitro. The role of CHAC1 in the LPS-induced HK-2 cells was explored using Western blot assay, cell counting kit-8 (CCK-8), flow cytometry, and colorimetric assays. Additionally, N-acetyl cysteine (NAC) was incubated with HK-2 cells to define deeply the relation between oxidative stress and apoptosis or ferroptosis.<br><br>RESULTS: The expression of CHAC1 was enhanced in the kidney tissues of mice with sepsis--induced multiple organ dysfunction syndrome (MODS), through the Gene Expression Omnibus database (GSE60088 microarray dataset), and in the LPS-induced HK-2 cells. The cell viability was significantly reduced by LPS treatment, which was at least partly restored by the transfection of siCHAC1#1 and siCHAC1#2 but not siNC. In addition, down-regulation of CHAC1 counteracted the LPS-induced reactive oxygen species level and malonaldehyde concentrations while restored the LPS-induced glutathione concentrations. Meanwhile, interference of CHAC1 neutralized LPS-induced apoptosis rate, and the relative level of cleaved poly(ADP-ribose) polymerase (PARP)/PARP, and cleaved caspase-3/caspase-3. In addition, silencing of CHAC1 recovered the LPS-induced enhanced protein level of glutathione peroxidase 4 (GPx4) whereas antagonized the LPS-induced relative protein level of ACSL4 and that of iron. Moreover, application of NAC inverted the effect of CHAC1 on apoptosis and ferroptosis in HK-2 cells.<br><br>CONCLUSION: CHAC1 exacerbated ferroptosis and apoptosis by enhancing oxidative stress in LPS-induced HK-2 cells.}, }
@article {pmid36915477, year = {2023}, author = {Jin, S and Yoon, SJ and Jung, NY and Lee, WS and Jeong, J and Park, YJ and Kim, W and Oh, DB and Seo, J}, title = {Antioxidants prevent particulate matter-induced senescence of lung fibroblasts.}, journal = {Heliyon}, volume = {9}, number = {3}, pages = {e14179}, pmid = {36915477}, issn = {2405-8440}, abstract = {Particulate matter (PM) contributes to human diseases, particularly lung disease; however, the molecular mechanism of its action is yet to be determined. Herein, we found that prolonged PM exposure induced the cellular senescence of normal lung fibroblasts via a DNA damage-mediated response. This PM-induced senescence (PM-IS) was only observed in lung fibroblasts but not in A549 lung adenocarcinoma cells. Mechanistic analysis revealed that reactive oxygen species (ROS) activate the DNA damage response signaling axis, increasing p53 phosphorylation, ultimately leading to cellular senescence via an increase in p21 expression without affecting the p16-pRB pathway. A549 cells, instead, were resistant to PM-IS due to the PM-induced ROS production suppression. Water-soluble antioxidants, such as vitamin C and N-Acetyl Cysteine, were found to alleviate PM-IS by suppressing ROS production, implying that antioxidants are a promising therapeutic intervention for PM-mediated lung pathogenesis.}, }
@article {pmid36914351, year = {2023}, author = {Song, WJ and Liu, PP and Meng, ZQ and Jie Ding, S and Xia Li, H}, title = {N-acetylcysteine promotes the proliferation of porcine adipose-derived stem cells during in vitro long-term expansion for cultured meat production.}, journal = {Food research international (Ottawa, Ont.)}, volume = {166}, number = {}, pages = {112606}, doi = {10.1016/j.foodres.2023.112606}, pmid = {36914351}, issn = {1873-7145}, mesh = {Animals ; Swine ; *Adipose Tissue/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Stem Cells/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Cell Proliferation ; }, abstract = {Cultured meat is an efficient, safe and sustainable meat production technology. Adipose-derived stem cell (ADSC) is a promising cell type for cultured meat. In vitro, obtaining numerous of ADSCs is a pivotal step for cultured meat. In this research, we demonstrated that the proliferation and adipogenic differentiation of ADSCs significantly decreased during serial passage. Then, senescence β-galactosidase (SA-β-gal) staining showed that the positive rate of P9 ADSCs was 7.74-fold than P3 ADSCs. Subsequently, RNA sequencing (RNA-seq) was performed for P3 and P9 ADSCs and found that PI3K-AKT pathway was up-regulated, but cell cycle and DNA repair pathway were down-regulated in P9 ADSCs. Then, N-Acetylcysteine (NAC) was added during long-term expansion and showed that NAC enhanced the ADSCs proliferation and maintained adipogenic differentiation. Finally, RNA-seq was performed for P9 ADSCs cultured with or without NAC and showed that NAC restored the cell cycle and DNA repair pathway in P9 ADSCs. These results highlighted that NAC was an excellent supplement for large-scale expansion of porcine ADSCs for cultured meat.}, }
@article {pmid36913130, year = {2023}, author = {Arteaga-Henríquez, G and Gisbert, L and Ramos-Quiroga, JA}, title = {Immunoregulatory and/or Anti-inflammatory Agents for the Management of Core and Associated Symptoms in Individuals with Autism Spectrum Disorder: A Narrative Review of Randomized, Placebo-Controlled Trials.}, journal = {CNS drugs}, volume = {37}, number = {3}, pages = {215-229}, pmid = {36913130}, issn = {1179-1934}, mesh = {Humans ; Acetylcysteine/therapeutic use ; *Anti-Inflammatory Agents/therapeutic use ; *Autism Spectrum Disorder/drug therapy ; Celecoxib/therapeutic use ; *Fatty Acids, Omega-3/therapeutic use ; Minocycline/therapeutic use ; Prednisolone/therapeutic use ; Randomized Controlled Trials as Topic ; *Immunologic Factors/therapeutic use ; }, abstract = {Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a so far poorly understood underlying pathogenesis, and few effective therapies for core symptoms. Accumulating evidence supports an association between ASD and immune/inflammatory processes, arising as a possible pathway for new drug intervention. However, current literature on the efficacy of immunoregulatory/anti-inflammatory interventions on ASD symptoms is still limited. The aim of this narrative review was to summarize and discuss the latest evidence on the use of immunoregulatory and/or anti-inflammatory agents for the management of this condition. During the last 10 years, several randomized, placebo-controlled trials on the effectiveness of (add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, N-acetylcysteine (NAC), sulforaphane (SFN), and/or omega-3 fatty acids have been performed. Overall, a beneficial effect of prednisolone, pregnenolone, celecoxib, and/or omega-3 fatty acids on several core symptoms, such as stereotyped behavior, was found. (Add-on) treatment with prednisolone, pregnenolone, celecoxib, minocycline, NAC, SFN, and/or omega-3 fatty acids was also associated with a significantly higher improvement in other symptoms, such as irritability, hyperactivity, and/or lethargy when compared with placebo. The mechanisms by which these agents exert their action and improve symptoms of ASD are not fully understood. Interestingly, studies have suggested that all these agents may suppress microglial/monocyte proinflammatory activation and also restore several immune cell imbalances (e.g., T regulatory/T helper-17 cell imbalances), decreasing the levels of proinflammatory cytokines, such as interleukin (IL)-6 and/or IL-17A, both in the blood and in the brain of individuals with ASD. Although encouraging, the performance of larger randomized placebo-controlled trials, including more homogeneous populations, dosages, and longer periods of follow-up, are urgently needed in order to confirm the findings and to provide stronger evidence.}, }
@article {pmid36912486, year = {2023}, author = {Tashiro, M and Konishi, M and Watanabe, M and Yokoyama, U}, title = {Reduction of intracellular Mg[2+] caused by reactive oxygen species in rat ventricular myocytes.}, journal = {American journal of physiology. Cell physiology}, volume = {324}, number = {4}, pages = {C963-C969}, doi = {10.1152/ajpcell.00490.2022}, pmid = {36912486}, issn = {1522-1563}, mesh = {Rats ; Animals ; *Myocytes, Cardiac/metabolism ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; *Hydrogen Peroxide/metabolism ; Biological Transport ; Ions/metabolism ; Calcium/metabolism ; }, abstract = {The concentration of intracellular free Mg[2+] ([Mg[2+]]i) should be maintained strictly for the regulation of cellular functions. Since reactive oxygen species (ROS) are liable to increase in various pathological conditions and induce cellular damage, we investigated whether ROS affect intracellular Mg[2+] homeostasis. We measured [Mg[2+]]i in ventricular myocytes from Wistar rats using the fluorescent indicator, mag-fura-2. The administration of hydrogen peroxide (H2O2) decreased [Mg[2+]]i in Ca[2+]-free Tyrode's solution. Intracellular free Mg[2+] was also reduced by endogenous ROS as generated by pyocyanin, which was inhibited by pretreatment with n-acetyl cysteine (NAC). The rate of change in [Mg[2+]]i by 500 μM H2O2 in 5 min (on average, -0.61 μM/s) was independent of extracellular Na[+], and intra- and extracellular Mg[2+] concentrations. When extracellular Ca[2+] was present, the rate of Mg[2+] decrease was significantly reduced, on average, by ∼60%. The half-maximal effective concentration of H2O2 on the Mg[2+] decrease was estimated to be between 400 and 425 μM. The Mg[2+] decrease by H2O2 in the absence of Na[+] was inhibited by 200 μM imipramine, a known inhibitor of Na[+]/Mg[2+] exchange. We perfused rat hearts with the Ca[2+]-free Tyrode's solution containing H2O2 (500 μM, 5 min) on the Langendorff apparatus,. H2O2 stimulation increased Mg[2+] concentration in the perfusate, suggesting the H2O2-induced decrease in [Mg[2+]]i was caused by Mg[2+] extrusion. Collectively, these results suggest the existence of a Na[+]-independent Mg[2+] efflux system activated by ROS in cardiomyocytes. The lower [Mg[2+]]i may in part be attributed to ROS-mediated cardiac dysfunction.}, }
@article {pmid36907467, year = {2023}, author = {Wang, Y and Singh, A and Li, G and Yue, S and Hertel, K and Wang, ZJ}, title = {Opioid induces increased DNA damage in prefrontal cortex and nucleus accumbens.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {224}, number = {}, pages = {173535}, pmid = {36907467}, issn = {1873-5177}, support = {DP1 DA056804/DA/NIDA NIH HHS/United States ; K01 DA050908/DA/NIDA NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; }, mesh = {Mice ; Animals ; *Analgesics, Opioid ; *Heroin/pharmacology ; Nucleus Accumbens ; Prefrontal Cortex ; Recurrence ; Self Administration ; }, abstract = {Opioid use disorder (OUD) is a chronic disease characterized by compulsive opioid taking and seeking, affecting millions of people worldwide. The high relapse rate is one of the biggest challenges in treating opioid addiction. However, the cellular and molecular mechanisms underlying relapse to opioid seeking are still unclear. Recent studies have shown that DNA damage and repair processes are implicated in a broad spectrum of neurodegenerative diseases as well as in substance use disorders. In the present study, we hypothesized that DNA damage is related to relapse to heroin seeking. To test our hypothesis, we aim to examine the overall DNA damage level in prefrontal cortex (PFC) and nucleus accumbens (NAc) after heroin exposure, as well as whether manipulating DNA damage levels can alter heroin seeking. First, we observed increased DNA damage in postmortem PFC and NAc tissues from OUD individuals compared to healthy controls. Next, we found significantly increased levels of DNA damage in the dorsomedial PFC (dmPFC) and NAc from mice that underwent heroin self-administration. Moreover, increased accumulation of DNA damage persisted after prolonged abstinence in mouse dmPFC, but not in NAc. This persistent DNA damage was ameliorated by the treatment of reactive oxygen species (ROS) scavenger N-acetylcysteine, along with attenuated heroin-seeking behavior. Furthermore, intra-PFC infusions of topotecan and etoposide during abstinence, which trigger DNA single-strand breaks and double-strand breaks respectively, potentiated heroin-seeking behavior. These findings provide direct evidence that OUD is associated with the accumulation of DNA damage in the brain (especially in the PFC), which may lead to opioid relapse.}, }
@article {pmid36901935, year = {2023}, author = {Hsieh, MJ and Ho, HY and Lo, YS and Lin, CC and Chuang, YC and Abomughaid, MM and Hsieh, MC and Chen, MK}, title = {Semilicoisoflavone B Induces Apoptosis of Oral Cancer Cells by Inducing ROS Production and Downregulating MAPK and Ras/Raf/MEK Signaling.}, journal = {International journal of molecular sciences}, volume = {24}, number = {5}, pages = {}, pmid = {36901935}, issn = {1422-0067}, mesh = {Humans ; Apoptosis/drug effects ; *Carcinoma, Squamous Cell/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Mitogen-Activated Protein Kinase Kinases ; *Mouth Neoplasms/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Mitogen-Activated Protein Kinases/drug effects/metabolism ; ras Proteins/drug effects/metabolism ; Proto-Oncogene Proteins c-raf/drug effects/metabolism ; }, abstract = {Oral squamous cell carcinoma (OSCC) is the sixth most common type of cancer worldwide. Despite advancement in treatment, advanced-stage OSCC is associated with poor prognosis and high mortality. The present study aimed to investigate the anticancer activities of semilicoisoflavone B (SFB), which is a natural phenolic compound isolated from Glycyrrhiza species. The results revealed that SFB reduces OSCC cell viability by targeting cell cycle and apoptosis. The compound caused cell cycle arrest at the G2/M phase and downregulated the expressions of cell cycle regulators including cyclin A and cyclin-dependent kinase (CDK) 2, 6, and 4. Moreover, SFB induced apoptosis by activating poly-ADP-ribose polymerase (PARP) and caspases 3, 8, and 9. It increased the expressions of pro-apoptotic proteins Bax and Bak, reduced the expressions of anti-apoptotic proteins Bcl-2 and Bcl-xL, and increased the expressions of the death receptor pathway protein Fas cell surface death receptor (FAS), Fas-associated death domain protein (FADD), and TNFR1-associated death domain protein (TRADD). SFB was found to mediate oral cancer cell apoptosis by increasing reactive oxygen species (ROS) production. The treatment of the cells with N-acetyl cysteine (NAC) caused a reduction in pro-apoptotic potential of SFB. Regarding upstream signaling, SFB reduced the phosphorylation of AKT, ERK1/2, p38, and JNK1/2 and suppressed the activation of Ras, Raf, and MEK. The human apoptosis array conducted in the study identified that SFB downregulated survivin expression to induce oral cancer cell apoptosis. Taken together, the study identifies SFB as a potent anticancer agent that might be used clinically to manage human OSCC.}, }
@article {pmid36891481, year = {2023}, author = {Schechter, J and Brown, GW and Janda, M}, title = {A preliminary evaluation of N-acetylcysteine's effects on patient adherence to treatment for cocaine use disorder.}, journal = {The mental health clinician}, volume = {13}, number = {1}, pages = {4-10}, pmid = {36891481}, issn = {2168-9709}, abstract = {INTRODUCTION: Cocaine use disorder (CUD) is a disabling disease associated with high rates of relapse and intense cravings. Patients with CUD struggle to adhere to treatment, which contributes to relapse and frequent readmissions to residential rehab (RR) facilities. Preliminary studies suggest that N-acetylcysteine (NAC) attenuates cocaine-induced neuroplasticity and, therefore, may assist with cocaine abstinence and adherence to treatment.<br><br>METHODS: This retrospective cohort study obtained data from 20 RR facilities across Western New York. Eligible subjects were 18 or older, diagnosed with CUD, and were divided based on their exposure to 1200 mg NAC twice daily during RR. The primary outcome was treatment adherence measured by outpatient treatment attendance rates (OTA). Secondary outcomes included length of stay (LOS) in RR and craving severity on a 1 to 100 visual analog scale.<br><br>RESULTS: One hundred eighty-eight (N = 188) patients were included in this investigation: NAC, n = 90; control, n = 98. NAC did not significantly impact OTA (% appointments attended), NAC 68%; control 69%, (P = .89) or craving severity NAC 34 &#xb1; 26; control 30 &#xb1; 27, (P = .38). Subjects treated with NAC had a significantly longer average LOS in RR compared with controls, NAC 86 &#xb1; 30; control 78 &#xb1; 26, (P = .04).<br><br>DISCUSSION: In this study, NAC did not impact treatment adherence but was associated with a significantly longer LOS in RR for patients with CUD. Owing to limitations, these results may not be applicable to the general population. More rigorous studies examining NAC's impact on treatment adherence in CUD are warranted.}, }
@article {pmid36880836, year = {2023}, author = {Tang, Y and Zhang, Z and Liu, S and Yao, Y and Pan, T and Qi, J and Kang, H and Liu, Y and Cai, C and Zhou, M and He, X and Hu, X and Ma, X and Wu, D and Han, Y}, title = {Conditioning therapy with N-acetyl-L-cysteine, decitabine and modified BUCY regimen for myeloid malignancies patients prior to allogeneic hematopoietic stem cell transplantation.}, journal = {American journal of hematology}, volume = {98}, number = {6}, pages = {881-889}, doi = {10.1002/ajh.26903}, pmid = {36880836}, issn = {1096-8652}, mesh = {Humans ; Decitabine ; Acetylcysteine/therapeutic use ; Busulfan ; Prospective Studies ; Reactive Oxygen Species ; *Myeloproliferative Disorders/complications ; *Hematopoietic Stem Cell Transplantation/methods ; Behavior Therapy ; *Neoplasms/complications ; Transplantation Conditioning/adverse effects ; *Leukemia, Myeloid, Acute/therapy ; *Graft vs Host Disease/etiology ; }, abstract = {Conditioning therapy is an essential procedure prior to hematopoietic stem cell transplant (HSCT), imposing a great impact on the outcomes of recipients. We performed a prospective randomized controlled trial to assess the outcome of HSCT recipients with myeloid malignancies after receiving the conditioning therapy consisting of modified BUCY (mBUCY), N-acetyl-L-cysteine (NAC), and decitabine. Enrolled patients were randomly allocated to either Arm A (decitabine, day -12 to -10; NAC, day -9 to +30; mBUCY, day -9 to -2), or Arm B (mBUCY regimen followed by stem cells infusion). Seventy-six patients in Arm A and 78 patients in Arm B were finally evaluated. The results showed platelet recovery accelerate in Arm A, with more patients achieving a platelet count of ≥50 × 10[9] /L than Arm B at day +30 and +60 (p = .004 and .043, respectively). The cumulative incidence of relapse is 11.8% (95% CI 0.06-0.22) in Arm A, and 24.4% (95% CI 0.16-0.35) in Arm B (p = .048). The estimated 3-year overall survival rate was 86.4% (±4.4%) and 79.9% (±4.7%) in 2 arms, respectively (p = .155). EFS at 3 years was 79.2% (±4.9%) in Arm A and 60.0% (±5.9%) in Arm B (p = .007). Intracellular reactive oxygen species (ROS) level was found to be reversely correlated with platelet recovery, and fewer patients in Arm A displayed excessive ROS within hematopoietic progenitor cells compared to Arm B. In conclusion, the addition of decitabine and NAC to mBUCY is a feasible and promising conditioning therapy for myeloid malignancies patients.}, }
@article {pmid36880428, year = {2023}, author = {Shen, J and Kom, MC and Huang, H and Fu, G and Xie, Y and Gao, Y and Tang, Y and Yan, J and Jin, L}, title = {Role of NF-κB signaling pathway in hexavalent chromium-induced hepatotoxicity.}, journal = {Environmental toxicology}, volume = {38}, number = {6}, pages = {1361-1371}, doi = {10.1002/tox.23769}, pmid = {36880428}, issn = {1522-7278}, support = {SXAB202015//Open Fund of Shaoxing Academy of Biomedicine of Zhejiang Sci-Tech University/ ; 2018C37105//Zhejiang Province Science and Technology Project of China/ ; }, mesh = {Mice ; Humans ; Animals ; *NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Inbred C57BL ; Signal Transduction ; Chromium/toxicity ; Acetylcysteine/pharmacology ; *Chemical and Drug Induced Liver Injury ; }, abstract = {Hexavalent chromium Cr (VI) is a primary human carcinogen with damaging toxic effects on multiple organs. Cr (VI) exposure can induce hepatotoxicity through oxidative stress, but its exact mechanism of action was still unclear. In our study, a model of acute Cr (VI) induced liver injury was established by exposing mice to different concentrations (0, 40, 80, and 160 mg/kg) of Cr (VI); RNA-seq was used to characterize changes in liver tissue transcriptome of C57BL/6 mice after exposing to 160 mg/kg Bw of Cr (VI). Changes in liver tissue structures, proteins, and genes were observed by hematoxylin and eosin (H&amp;E), western blot, immunohistochemistry and RT-PCR. After Cr (VI) exposure, abnormal liver tissue structure, hepatocyte injury, and hepatic inflammatory response were observed in mice in a dose-dependent manner. RNA-seq transcriptome results indicated that oxidative stress, apoptosis, and inflammatory response pathways were increased after Cr (VI) exposure; KEGG pathway analysis found that activation of NF-κB signaling pathway was significantly upregulated. Consistent with the RNA-seq results, immunohistochemistry showed that Cr (VI) exposure resulted in infiltrating of Kupffer cells and neutrophils, increasing expression of inflammatory factors (TNF-α, IL-6, IL-1β), and activating of NF-κB signaling pathways (p-IKKα/β and p-p65). However, ROS inhibitor, N-acetyl-L-cysteine (NAC), could reduce infiltration of Kupffer cells and neutrophils and expression of inflammatory factors. Besides, NAC could inhibit NF-κB signaling pathway activation, and alleviate Cr (VI)-induced liver tissue damage. Our findings strongly suggested that inhibition of ROS by NAC might help in the development of new strategies for Cr (VI)-associated liver fibrosis. Our findings revealed for the first time that Cr (VI) induced liver tissue damage through the inflammatory response mediated by the NF-κB signaling pathway, and inhibition of ROS by NAC might help in the development of new strategies for Cr (VI)-associated hepatotoxicity.}, }
@article {pmid36874025, year = {2023}, author = {Tan, J and Xiang, Y and Xiong, Y and Zhang, Y and Qiao, B and Zhang, H}, title = {Crebanine induces ROS-dependent apoptosis in human hepatocellular carcinoma cells via the AKT/FoxO3a signaling pathway.}, journal = {Frontiers in pharmacology}, volume = {14}, number = {}, pages = {1069093}, pmid = {36874025}, issn = {1663-9812}, abstract = {Background: Hepatocellular carcinoma (HCC), as an aggressive cancer with a high mortality rate, needs high-efficiency and low-toxicity drug therapy. Natural products have great potential as candidate lead compounds for the development of new HCC drugs. Crebanine is an isoquinoline alkaloid derived from Stephania with various potential pharmacological effects such as anti-cancer. However, the molecular mechanism underlying crebanine-induced liver cancer cells apoptosis has not been reported. Here, we investigated the effect of crebanine on HCC and identified a potential mechanism of action. Methods: In this paper, we intend to detect the toxic effects of crebanine on hepatocellular carcinoma HepG2 cells through a series of in vitro experiments, including detecting the effects of crebanine on the proliferation of HepG2 cells using the CCK8 method and plate cloning assay, observing the growth status and morphological changes of crebanine on HepG2 cells by inverted microscopy; and using the Transwell method to determine the the effect of crebanine on the migration and invasion ability of HepG2 cells; using Hoechst 33258 assay to stain cancer cells, thus observing the effect of crebanine on the morphology of HepG2 apoptotic cells, and detecting the apoptotic state and level of HepG2 cells by flow cytometry; using ROS kit and JC-1 assay kit to detect the changes of reactive oxygen species and mitochondrial membrane potential of HepG2 The immunofluorescence assay was taken to verify whether crebanine had an effect on the expression of p-FoxO3a in cancer cells; the Wetern blot assay was also used to examine the effect of crebanine on proteins related to the mitochondrial apoptotic pathway and its effect on the regulation of the relative protein expression of AKT/FoxO3a axis; after this, NAC and AKT inhibitor LY294002 were used to cells were pretreated with NAC and AKT inhibitor LY294002, respectively, in order to further validate the inhibitory effect of crebanine. Results: It was shown that crebanine effectively inhibited the growth and capacity of HepG2 cells migration and invasion in a dose-dependent manner. Furthermore, the effect of crebanine on the morphology of HepG2 cells was observed through microscopy. Meanwhile, crebanine induced apoptosis by causing reactive oxygen species (ROS) burst and mitochondrial membrane potential (MMP) disrupt. We found that crebanine could down-regulate Bcl-2 and up-regulate Bax, cleaved-PARP, cleaved-caspase-3 and cleaved-caspase-9, but these effects were overturned by ROS inhibitor N-acetylcysteine (NAC). Crebanine also down-regulated p-AKT and p-FoxO3a, and the PI3K inhibitor LY294002 significantly enhances this effect. We also found that the expression of AKT/FoxO3a signaling pathway was ROS-dependent. As shown by Western blots, NAC could partially attenuate the inhibitory effect of crebanine on AKT and FoxO3a phosphorylation. Conclusion: Based on our results, our results suggest that crebanine, as a compound with potential anticancer activity, has significant cytotoxic effects on hepatocellular carcinoma,and it likely induces apoptosis via ROS in the mitochondrial pathway and simultaneously affects the biological function of HCC via the ROS-AKT-FoxO3a signaling axis.}, }
@article {pmid36873280, year = {2023}, author = {Maghsadi, Z and Azadmehr, A and Moghadamnia, AA and Feizi, F and Hamidi, N}, title = {N-Acetylcysteine attenuated pulmonary fibrosis induced by bleomycin via immunomodulation responses.}, journal = {Research in pharmaceutical sciences}, volume = {18}, number = {2}, pages = {177-184}, pmid = {36873280}, issn = {1735-5362}, abstract = {BACKGROUND AND PURPOSE: Pulmonary fibrosis (PF) is a chronic and life-threatening interstitial lung disease. N-acetyl cysteine (NAC) is an antioxidant pharmaceutically available to reduce endothelial dysfunction, inflammation, and fibrosis, however, the therapeutic effect of NAC on PF has not been clearly identified. This research aimed to investigate the possible therapeutic impact of NAC on PF induced by bleomycin in the rat model.<br><br>EXPERIMENTAL APPROACH: Rats received intraperitoneal injections of NAC at 150, 300, and 600 mg/kg for 28 days before bleomycin, while the positive and negative control groups were treated with bleomycin alone and normal saline, respectively. Then, rats' lung tissues were isolated and leukocyte infiltration and also collagen deposition were evaluated using hematoxylin and eosin and Mallory trichrome stainings, respectively. In addition, the levels of IL-17, and TGF-&#x3b2; cytokines in bronchoalveolar lavage fluid and hydroxyproline in homogenized lung tissues were assayed using the ELISA method.<br><br>FINDINGS/RESULTS: Histological findings indicated that NAC decreased leukocyte infiltration, collagen deposition, and fibrosis score in the bleomycin-induced PF tissue. Moreover, NAC significantly reduced TGF-&#x3b2; and hydroxyproline levels at 300-600 mg/kg, as well as IL-17 cytokine at 600 mg/kg.<br><br>CONCLUSION AND IMPLICATIONS: NAC showed a potential anti-fibrotic effect by reducing hydroxyproline and TGF-&#x3b2; as well as an anti-inflammatory effect by decreasing IL-17 cytokine. So, it may be administered as a prophylactic or therapeutic candidate agent to attenuate PF via immunomodulatory effects. Although, future studies are suggested.}, }
@article {pmid36866174, year = {2023}, author = {Redwan, A and Kiriaev, L and Kueh, S and Morley, JW and Houweling, P and Perry, BD and Head, SI}, title = {Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in MDX mouse dystrophic fast-twitch skeletal muscle.}, journal = {Frontiers in physiology}, volume = {14}, number = {}, pages = {1109587}, pmid = {36866174}, issn = {1664-042X}, abstract = {Introduction: It has been proposed that an increased susceptivity to oxidative stress caused by the absence of the protein dystrophin from the inner surface of the sarcolemma is a trigger of skeletal muscle necrosis in the destructive dystrophin deficient muscular dystrophies. Here we use the mdx mouse model of human Duchenne Muscular Dystrophy to test the hypothesis that adding the antioxidant NAC at 2% to drinking water for six weeks will treat the inflammatory phase of the dystrophic process and reduce pathological muscle fiber branching and splitting resulting in a reduction of mass in mdx fast-twitch EDL muscles. Methods: Animal weight and water intake was recorded during the six weeks when 2% NAC was added to the drinking water. Post NAC treatment animals were euthanised and the EDL muscles dissected out and placed in an organ bath where the muscle was attached to a force transducer to measure contractile properties and susceptibility to force loss from eccentric contractions. After the contractile measurements had been made the EDL muscle was blotted and weighed. In order to assess the degree of pathological fiber branching mdx EDL muscles were treated with collagenase to release single fibers. For counting and morphological analysis single EDL mdx skeletal muscle fibers were viewed under high magnification on an inverted microscope. Results: During the six-week treatment phase NAC reduced body weight gain in three- to nine-week-old mdx and littermate control mice without effecting fluid intake. NAC treatment also significantly reduced the mdx EDL muscle mass and abnormal fiber branching and splitting. Discussion: We propose chronic NAC treatment reduces the inflammatory response and degenerative cycles in the mdx dystrophic EDL muscles resulting in a reduction in the number of complexed branched fibers reported to be responsible for the dystrophic EDL muscle hypertrophy.}, }
@article {pmid36863618, year = {2023}, author = {Xue, Y and Zhang, D and Wei, Y and Guo, C and Song, B and Cui, Y and Zhang, C and Xu, D and Zhang, S and Fang, J}, title = {Polymeric nano-micelle of carbon monoxide donor SMA/CORM2 ameliorates acetaminophen-induced liver injury via suppressing HMGB1/TLR4 signaling pathway.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {184}, number = {}, pages = {106413}, doi = {10.1016/j.ejps.2023.106413}, pmid = {36863618}, issn = {1879-0720}, mesh = {Animals ; Mice ; Acetaminophen ; Anti-Inflammatory Agents/pharmacology ; Carbon Monoxide/metabolism/pharmacology ; *Chemical and Drug Induced Liver Injury/metabolism ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy/metabolism/pathology ; Disease Models, Animal ; *HMGB1 Protein/metabolism ; Liver/metabolism ; Mice, Inbred C57BL ; Micelles ; Signal Transduction ; Toll-Like Receptor 4/metabolism ; }, abstract = {Acetaminophen (APAP) overdose-induced hepatotoxicity is the most common cause of acute liver failure. Excessive generation of reactive oxygen species (ROS) and inflammatory responses are the major causes of necrosis and/or necroptosis of the liver cells. Currently, the treatment options for APAP-induced liver injury are very limited, N-acetylcysteine (NAC) is the only approved drug to treat APAP overdose patients. It is of great necessity to develop new therapeutic strategies. In a previous study, we focused on the anti-oxidative, anti-inflammatory signal molecule carbon monoxide (CO), and developed a nano-micelle encapsulating CO donor, i.e., SMA/CORM2. Administration of SMA/CORM2 to the mice exposed to APAP significantly ameliorated the liver injury and inflammatory process, in which modulating macrophage reprogramming plays a critical role. Along this line, in this study, we investigated the potential effect of SMA/CORM2 on toll-like receptor 4 (TLR4) and high mobility group protein B1 (HMGB1) signaling pathways that are known to be closely involved in many inflammatory responses and necroptosis. In a mouse APAP-induced liver injury model, similar to the previous study, SMA/CORM2 at 10 mg/kg remarkably improved the condition of the liver after injury as evidenced by histological examination and liver function. During the process of liver injury triggered by APAP, TLR4 expression gradually increased over time, and it was significantly upregulated as early as 4 h after APAP exposure, whereas, an increase of HMGB1 was a late-stage event. Notably, SMA/CORM2 treatment suppressed significantly both TLR4 and HMGB1, consequently inhibiting the progression of inflammation and liver injury. Compared to CORM2 without SMA modification (native CORM2) of 1 mg/kg that is equivalent to 10 mg/kg of SMA/CORM2 (the amount of CORM2 in SMA/CORM2 is 10% [w/w]), SMA/CORM2 exhibited a much better therapeutic effect, indicating its superior therapeutic efficacy to native CORM2. These findings revealed that SMA/CORM2 protects against APAP-induced liver injury via mechanisms involving the suppression of TLR4 and HMGB1 signaling pathways. Taking together the results in this study and previous studies, SMA/CORM2 exhibits great therapeutic potential for APAP overdose-induced liver injury, we thus anticipate the clinical application of SMA/CORM2 for the treatment of APAP overdose, as well as other inflammatory diseases.}, }
@article {pmid36860857, year = {2023}, author = {Lee, SH and Han, MS and Lee, TH and Lee, DB and Park, JH and Lee, SH and Kim, TH}, title = {Hydrogen peroxide attenuates rhinovirus-induced anti-viral interferon secretion in sinonasal epithelial cells.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1086381}, pmid = {36860857}, issn = {1664-3224}, mesh = {Humans ; Antiviral Agents/pharmacology ; Hydrogen Peroxide ; Rhinovirus ; *Nasal Polyps ; Toll-Like Receptor 3 ; Epithelial Cells ; Acetylcysteine/pharmacology ; *Interferon Type I ; Antioxidants ; }, abstract = {BACKGROUND: Altered innate defense mechanisms, including an imbalance between oxidants and antioxidants release, have been implicated in the pathogenesis of chronic rhinosinusitis (CRS). The aim of this study is to investigate whether oxidative stress may attenuate the secretion of anti-viral interferons in human sinonasal mucosa.<br><br>METHODS: The levels of H2O2 in nasal secretion were increased in patients with CRS with nasal polyps, compared with that of CRS patients without nasal polyps and control subjects. Normal sinonasal epithelial cells derived from healthy subjects were cultured under an air-liquid interface. The cultured cells were infected with rhinovirus 16 (RV 16) or treated with poly (I: C), TLR3 agonist, after being pretreated with an oxidative stressor, H2O2 or antioxidant, N-acetylcysteine (NAC). Thereafter, the expression levels of type I (IFN-&#x3b2;) and type III (IFN-&#x3bb;1 and &#x3bb;2) interferons and interferon-stimulated genes (ISGs) were evaluated with RT-qPCR, ELISA, and western blot.<br><br>RESULTS: The data showed that the production of type I (IFN-&#x3b2;) and type III (IFN-&#x3bb;1 and &#x3bb;2) interferons and ISGs was upregulated in cells infected with RV 16 or treated with poly (I: C). However, their up-regulated expression was attenuated in cells pretreated with H2O2, but not inhibited in cells pretreated with NAC. In line with these data, the up-regulated expression of TLR3, RIG-1, MDA5, and IRF3 was reduced in cells pretreated with H2O2, but not attenuated in cells treated with NAC. Furthermore, cells transfected with Nrf2 siRNA showed decreased secretion of anti-viral interferons whereas sulforaphane treatment enhanced the secretory capacity of antiviral interferons.<br><br>CONCLUSIONS: These results suggest that the production of RV16-induced antiviral interferons may be attenuated by oxidative stress.}, }
@article {pmid36860082, year = {2023}, author = {Wei, M and Dhanasekaran, S and Ji, Q and Yang, Q and Zhang, H}, title = {Sustainable and efficient method utilizing N-acetyl-L-cysteine for complete and enhanced ochratoxin A clearance by antagonistic yeast.}, journal = {Journal of hazardous materials}, volume = {448}, number = {}, pages = {130975}, doi = {10.1016/j.jhazmat.2023.130975}, pmid = {36860082}, issn = {1873-3336}, mesh = {Humans ; *Saccharomyces cerevisiae ; Acetylcysteine ; *Mycotoxins ; Biodegradation, Environmental ; }, abstract = {With the increasing global climate change, ochratoxin A (OTA) pollution in food and environment has become a serious and potential risk element threatening food safety and human health. Biodegradation of mycotoxin is an eco-friendly and efficient control strategy. Still, research works are warranted to develop low-cost, efficient, and sustainable approaches to enhance the mycotoxin degradation efficiency of microorganisms. In this study, the activities of N-acetyl-L-cysteine (NAC) against OTA toxicity were evidenced, and its positive effects on the OTA degradation efficiency of antagonistic yeast, Cryptococcus podzolicus Y3 were verified. Co-culturing C. podzolicus Y3 with 10 mM NAC improved 100% and 92.6% OTA degradation rate into ochratoxin α (OTα) at 1 d and 2 d. The excellent promotion role of NAC on OTA degradation was observed even at low temperatures and alkaline conditions. C. podzolicus Y3 treated with OTA or OTA+NAC promoted reduced glutathione (GSH) accumulation. GSS and GSR genes were highly expressed after OTA and OTA+NAC treatment, contributing to GSH accumulation. In the early stages of NAC treatment, yeast viability and cell membrane were reduced, but the antioxidant property of NAC prevented lipid peroxidation. Our finding provides a sustainable and efficient new strategy to improve mycotoxin degradation by antagonistic yeasts, which could be applied to mycotoxin clearance.}, }
@article {pmid36855363, year = {2023}, author = {Concessao, PL and Bairy, KL and Raghavendra, AP}, title = {Ameliorating effect of Mucuna pruriens seed extract on sodium arsenite-induced testicular toxicity and hepato-renal histopathology in rats.}, journal = {Veterinary world}, volume = {16}, number = {1}, pages = {82-93}, pmid = {36855363}, issn = {0972-8988}, abstract = {BACKGROUND AND AIM: A significant cause of arsenic poisoning is polluted groundwater. Arsenic poisoning results in the suppression of spermatogenesis and the liver and kidneys are vulnerable to the toxic effects as well. Mucuna pruriens has been identified to have fertility-enhancing and anti-lipid peroxidation properties. Based on these properties of M. pruriens, this study aimed to investigate the efficacy of M. pruriens seed extract in reducing sodium arsenite-induced testicular impairment and hepato-renal histopathology in rats.<br><br>MATERIALS AND METHODS: The study was divided into two groups; short-term (45 days) and long-term (90 days) treatment groups and each group was divided into nine subgroups. Subgroups 1 and 2 served as normal and N-acetyl cysteine (NAC) controls, respectively. Subgroups 3-9 received sodium arsenite in the drinking water (50 mg/L). Subgroup-4 received NAC (210 mg/kg body weight [BW]) orally once daily. Subgroups 5-7 received aqueous seed extract of M. pruriens (350, 530, and 700 mg/kg BW, respectively) orally once daily. Subgroups 8 and 9 received a combination of NAC and aqueous seed extract (350 and 530 mg/kg BW, respectively) orally once daily. Following the treatment, animals were sacrificed and sperm parameters and DNA damage were evaluated. Testis, liver, and kidneys were analyzed for histopathology.<br><br>RESULTS: Sodium arsenite-induced a significant reduction in sperm parameters and increase in the abnormal architecture of spermatozoa. Histology revealed tissue necrosis. The M. pruriens seed extract ameliorated the damaging effects of sodium arsenite with respect to tissue architecture and sperm parameters when coadministered.<br><br>CONCLUSION: Mucuna pruriens has beneficial effects against the deleterious effects of sodium arsenite on various tissues. Thus, M. pruriens (530 and 700 mg/kg BW) supplementation would reduce the adverse changes observed with sodium arsenite exposure.}, }
@article {pmid36854537, year = {2023}, author = {Musa, MA and Kolawole, Q}, title = {7,8-Diacetoxy-3-(4-methylsulfonylphenyl)-4-phenylcoumarin Induces ROS-dependent Cell Death in the A549 Human Lung Cancer Cell Line.}, journal = {Anticancer research}, volume = {43}, number = {3}, pages = {1001-1007}, doi = {10.21873/anticanres.16244}, pmid = {36854537}, issn = {1791-7530}, mesh = {Male ; Humans ; Reactive Oxygen Species ; A549 Cells ; *Lung Neoplasms/drug therapy ; Cell Death ; Coumarins/pharmacology ; Cell Line ; }, abstract = {BACKGROUND/AIM: Coumarins comprise of a very large class of naturally occurring compounds with growing interest in their synthesis and possible applications in the treatment of various diseases. We herein report the in-vitro cytotoxic activity of 3,4-Diarylcoumarins (4a-i) in A549 (lung) and PC-3 (prostate) cancer cell lines.<br><br>MATERIALS AND METHODS: The cytotoxic activity was evaluated using crystal violet dye-binding. The most active compound effect on the cell-cycle phases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production and apoptosis were also evaluated.<br><br>RESULTS: Among the synthesized compounds that were evaluated, 7,8-Diacetoxy-3-(4-(methylsulfonyl)phenyl)-4-phenylcoumrin (4f) showed highest cytotoxicity (CC50=13.5%&#xb1;0.15&#x3bc;M) in A549 cancer cell line. The mechanism of its cytotoxic action indicated significant cell arrest in G1/G0, S and G2 phases of the cell cycle, loss of mitochondrial membrane potential (MMP), increase in reactive oxygen species (ROS) production and induction of apoptotic cell death. The cell viability result of pretreated A549 cells with antioxidant N-acetylcysteine (NAC), followed by compound 4f treatment confirmed ROS-dependent cell death.<br><br>CONCLUSION: The presence of 3-4-methylsulfonyl and 7,8-diacetoxy groups on 3,4-Diarylcoumarin is critical in modulating higher cytotoxic activity and could serve as a valuable template for the development of novel synthetic compounds as potential anticancer agents for lung cancer treatment.}, }
@article {pmid36852734, year = {2023}, author = {Akinlolu, A and Emojevwe, V and Uwejigho, R and Ilesanmi, J and Owolabi, R and Igandan, A}, title = {Neuro-protective potentials of N-acetylcysteine and zinc against di(2-ethylhexyl)-phthalate-induced neuro-histopathology and dys-regulations of Dopamine and Glutamate in rat brain.}, journal = {Journal of environmental science and health. Part A, Toxic/hazardous substances &amp; environmental engineering}, volume = {58}, number = {1}, pages = {81-90}, doi = {10.1080/10934529.2023.2177449}, pmid = {36852734}, issn = {1532-4117}, mesh = {Animals ; Rats ; Rats, Wistar ; Male ; *Diethylhexyl Phthalate/toxicity ; Dopamine/genetics ; Glutamic Acid/genetics ; *Gene Expression Regulation/drug effects ; *Acetylcysteine/pharmacology ; *Zinc/pharmacology ; *Brain/drug effects ; }, abstract = {This study examined neuro-protective potentials of N-acetyl-cysteine (NAC) and Zinc on expression levels of Dopamine and Glutamate in the Cerebrum, Hypothalami and Pituitary Glands in Di(2-ethylhexyl)-phthalate (DEHP)-induced neurotoxicity in rats. Thirty-six adult male Wistar rats were randomly divided into 6 groups (n = 6). Group 1 was control. Groups 2-6 received oral administrations of 100 mg/kg NAC, 0.5 mg/kg Zinc, 750 mg/kg DEHP, DEHP + NAC doses and DEHP + Zinc doses respectively for 21 days. Brain histology (Heamatoxyline and Eosine technique), histochemical and enzyme-linked-immunosorbent assays of Dopamine and Glutamate in homogenates of Cerebrum, Hypothalami and Pituitary Glands were evaluated. Data were statistically analyzed using One-way-ANOVA with Tukey-post-hoc test at p ≤ 0.05. Histo-pathological evaluations of Cerebrum, Hypothalami and Pituitary Glands showed gross histo-alterations and neurodegenerative changes (Group 4), mild histo- and neuro-degenerative changes (Groups 5 and 6) and normal histology (Group 1). Histochemical analyses showed higher Dopamine levels in Hypothalami (Group 5) and Pituitary Glands (Groups 5 and 6), compared with Group 4. Furthermore, results showed lower Glutamate levels in Cerebrum, Hypothalami and Pituitary Glands of Groups 5 and 6, compared with Group 4. Overall, NAC and Zinc conferred neuro-protection and histo-protection against DEHP-induced neuro-toxicity, neuro-histopathology, decreased Dopamine levels and increased Glutamate levels.}, }
@article {pmid36849104, year = {2023}, author = {Wang, H and Banerjee, N and Wang, G and Firoze Khan, M}, title = {Autophagy dysregulation in trichloroethene-mediated inflammation and autoimmune response.}, journal = {Toxicology}, volume = {487}, number = {}, pages = {153468}, pmid = {36849104}, issn = {1879-3185}, support = {P30 ES030285/ES/NIEHS NIH HHS/United States ; R01 ES016302/ES/NIEHS NIH HHS/United States ; R01 ES026887/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Autoimmune Diseases/chemically induced ; Autoimmunity ; Autophagy ; Inflammation/chemically induced ; Solvents/toxicity ; *Trichloroethylene/toxicity ; }, abstract = {Trichloroethene (TCE), an organic solvent extensively used for degreasing metals, can cause inflammatory autoimmune disorders [i.e., systemic lupus erythematosus (SLE) and autoimmune hepatitis] from both environmental and occupational exposure. Autophagy has emerged as a pivotal pathogenic factor in various autoimmune diseases. However, role of autophagy dysregulation in TCE-mediated autoimmunity is largely unknown. Here, we investigate whether autophagy dysregulation contributes to pathogenesis of TCE-mediated autoimmune responses. Using our established mouse model, we observed TCE-treated mice had elevated MDA-protein adducts, microtubule-associated protein light chain 3 conversion (LC3-II/LC3-I), beclin-1, phosphorylation of AMP-activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) phosphorylation in the livers of MRL+ /+ mice. Suppression of oxidative stress with antioxidant N-acetylcysteine (NAC) effectively blocked TCE-mediated induction of autophagy markers. On the other hand, pharmacological autophagy induction with rapamycin significantly reduced TCE-mediated hepatic inflammation (NLRP3, ASC, Caspase1 and IL1-β mRNA levels), systemic cytokines (IL-12 and IL-17) and autoimmune responses (ANA and anti-dsDNA levels). Taken together, these results suggest that autophagy plays a protective role against TCE-mediated hepatic inflammation and autoimmunity in MRL+ /+ mice. These novel findings on the regulation of autophagy could help in designing therapeutic strategies for chemical exposure-mediated autoimmune responses.}, }
@article {pmid36842745, year = {2023}, author = {Liu, YX and Yang, JY and Sun, JL and Wang, AC and Wang, XY and Zhu, LB and Cao, HH and Huang, ZH and Liu, SH and Xu, JP}, title = {Reactive oxygen species-mediated phosphorylation of JNK is involved in the regulation of BmFerHCH on Bombyx mori nucleopolyhedrovirus proliferation.}, journal = {International journal of biological macromolecules}, volume = {235}, number = {}, pages = {123834}, doi = {10.1016/j.ijbiomac.2023.123834}, pmid = {36842745}, issn = {1879-0003}, mesh = {Animals ; Phosphorylation ; *Nucleopolyhedroviruses/physiology ; Reactive Oxygen Species/metabolism ; Apoferritins/metabolism ; MAP Kinase Signaling System ; Cell Proliferation ; *Bombyx/metabolism ; Insect Proteins/metabolism ; }, abstract = {c-Jun N-terminal kinase (JNK) phosphorylation is widely observed during virus infection, modulating various aspects of the virus-host interaction. In our previous research, we have proved that B. mori ferritin heavy-chain homolog (BmFerHCH), an inhibitor of reactive oxygen species (ROS), facilitates B. mori nucleopolyhedrovirus (BmNPV) proliferation. However, one question remains: Which downstream signaling pathways does BmFerHCH regulate by inhibiting ROS? Here, we first determined that silencing BmFerHCH inhibits BmNPV proliferation, and this inhibition depends on ROS. Then, we substantiated that BmNPV infection activates the JNK signaling pathway. Interestingly, the JNK phosphorylation during BmNPV infection is activated by ROS. Further, we found that the enhanced nuclear translocation of phospho-JNK induced by BmNPV infection was dramatically reduced by pretreatment with the antioxidant N-acetylcysteine (NAC), whereas there was more detectable phospho-JNK in the cytoplasm. Next, we investigated how changes in BmFerHCH expression affect JNK phosphorylation. BmFerHCH overexpression suppressed the phosphorylation of JNK and nuclear translocation of phospho-JNK during BmNPV infection, whereas BmFerHCH knockdown facilitated phosphorylation of JNK and nuclear translocation of phospho-JNK. By measuring the viral load, we found the inhibitory effect of BmFerHCH knockdown on BmNPV infection depends on phosphorylated JNK. In addition, the JNK signaling pathway was involved in BmNPV-triggered apoptosis. Hence, we hypothesize that ROS-mediated JNK phosphorylation is involved in the regulation of BmFerHCH on BmNPV proliferation. These results elucidate the molecular mechanisms and signaling pathways of BmFerHCH-mediated response to BmNPV infection.}, }
@article {pmid36840032, year = {2023}, author = {Kim, SH and Jung, DE and Song, JY and Jung, J and Jung, JK and Lee, H and Roh, E and Hong, JT and Han, SB and Kim, Y}, title = {Targeting IKKβ Activity to Limit Sterile Inflammation in Acetaminophen-Induced Hepatotoxicity in Mice.}, journal = {Pharmaceutics}, volume = {15}, number = {2}, pages = {}, pmid = {36840032}, issn = {1999-4923}, abstract = {The kinase activity of inhibitory κB kinase β (IKKβ) acts as a signal transducer in the activating pathway of nuclear factor-κB (NF-κB), a master regulator of inflammation and cell death in the development of numerous hepatocellular injuries. However, the importance of IKKβ activity on acetaminophen (APAP)-induced hepatotoxicity remains to be defined. Here, a derivative of caffeic acid benzylamide (CABA) inhibited the kinase activity of IKKβ, as did IMD-0354 and sulfasalazine which show therapeutic efficacy against inflammatory diseases through a common mechanism: inhibiting IKKβ activity. To understand the importance of IKKβ activity in sterile inflammation during hepatotoxicity, C57BL/6 mice were treated with CABA, IMD-0354, or sulfasalazine after APAP overdose. These small-molecule inhibitors of IKKβ activity protected the APAP-challenged mice from necrotic injury around the centrilobular zone in the liver, and rescued the mice from hepatic damage-associated lethality. From a molecular perspective, IKKβ inhibitors directly interrupted sterile inflammation in the Kupffer cells of APAP-challenged mice, such as damage-associated molecular pattern (DAMP)-induced activation of NF-κB activity via IKKβ, and NF-κB-regulated expression of cytokines and chemokines. However, CABA did not affect the upstream pathogenic events, including oxidative stress with glutathione depletion in hepatocytes after APAP overdose. N-acetyl cysteine (NAC), the only FDA-approved antidote against APAP overdose, replenishes cellular levels of glutathione, but its limited efficacy is concerning in late-presenting patients who have already undergone oxidative stress in the liver. Taken together, we propose a novel hypothesis that chemical inhibition of IKKβ activity in sterile inflammation could mitigate APAP-induced hepatotoxicity in mice, and have the potential to complement NAC treatment in APAP overdoses.}, }
@article {pmid36836353, year = {2023}, author = {Okamoto, M and Nakano, K and Takahashi-Nakaguchi, A and Sasamoto, K and Yamaguchi, M and Teixeira, MC and Chibana, H}, title = {In Candida glabrata, ERMES Component GEM1 Controls Mitochondrial Morphology, mtROS, and Drug Efflux Pump Expression, Resulting in Azole Susceptibility.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {9}, number = {2}, pages = {}, pmid = {36836353}, issn = {2309-608X}, abstract = {Mitochondrial dysfunction or morphological abnormalities in human pathogenic fungi are known to contribute to azole resistance; however, the underlying molecular mechanisms are unknown. In this study, we investigated the link between mitochondrial morphology and azole resistance in Candida glabrata, which is the second most common cause of human candidiasis worldwide. The ER-mitochondrial encounter structure (ERMES) complex is thought to play an important role in the mitochondrial dynamics necessary for mitochondria to maintain their function. Of the five components of the ERMES complex, deletion of GEM1 increased azole resistance. Gem1 is a GTPase that regulates the ERMES complex activity. Point mutations in GEM1 GTPase domains were sufficient to confer azole resistance. The cells lacking GEM1 displayed abnormalities in mitochondrial morphology, increased mtROS levels, and increased expression of azole drug efflux pumps encoded by CDR1 and CDR2. Interestingly, treatment with N-acetylcysteine (NAC), an antioxidant, reduced ROS production and the expression of CDR1 in Δgem1 cells. Altogether, the absence of Gem1 activity caused an increase in mitochondrial ROS concentration, leading to Pdr1-dependent upregulation of the drug efflux pump Cdr1, resulting in azole resistance.}, }
@article {pmid36835209, year = {2023}, author = {Sakai, M and Yu, Z and Taniguchi, M and Picotin, R and Oyama, N and Stellwagen, D and Ono, C and Kikuchi, Y and Matsui, K and Nakanishi, M and Yoshii, H and Furuyashiki, T and Abe, T and Tomita, H}, title = {N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36835209}, issn = {1422-0067}, support = {20dm0107099h0005, JP19dm0107099, JP18ek0109183, JP22gm0910012, and JP22wm0425001//Ministry of Education, Culture, Sports, Science and Technology of Japan, the Strategic Research Program for Brain Sciences, and the Japan Agency for Medical Research and Development/ ; KAKENHI 21390329, 16K07210, 18H05429, 21H04812, and 19K16372//Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; No. 24116007//Grant-in-Aid for Scientific Research on Innovative Areas/ ; }, mesh = {Animals ; Humans ; Mice ; *Acetylcysteine/pharmacology ; *Inflammation/metabolism/pathology ; Lipopolysaccharides/pharmacology ; *Microglia/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; *Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-α-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-α and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-α and NO synthesis, whereas high concentrations (≥30 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-α-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-α remains unclear and merits further mechanistic investigations.}, }
@article {pmid36834536, year = {2023}, author = {Li, F and Liu, H and Wu, X and Song, Z and Tang, H and Gong, M and Liu, L and Li, F}, title = {Tetrathiomolybdate Decreases the Expression of Alkaline Phosphatase in Dermal Papilla Cells by Increasing Mitochondrial ROS Production.}, journal = {International journal of molecular sciences}, volume = {24}, number = {4}, pages = {}, pmid = {36834536}, issn = {1422-0067}, support = {31972594//National Natural Science Foundation of China/ ; CARS-43-B-1//the earmarked fund for CARS/ ; ZR2021MC043//Natural Science Foundation of Shandong Province/ ; ZR2021QC108//Natural Science Foundation of Shandong Province/ ; SDAIT-21-16//Special Economic Animal Industry Technology System of Shandong Province/ ; 2021LZGC002//Agricultural Seed Improvement Project of Shandong Province/ ; }, mesh = {*Hair Follicle/metabolism ; *Dermis ; Cells, Cultured ; Alkaline Phosphatase/metabolism ; Reactive Oxygen Species/metabolism ; Proteomics ; Copper/metabolism ; Cell Proliferation ; }, abstract = {Dermal papilla cells (DPCs) play important roles in hair growth regulation. However, strategies to regrow hair are lacking. Here, global proteomic profiling identified the tetrathiomolybdate (TM)-mediated inactivation of copper (Cu) depletion-dependent mitochondrial cytochrome c oxidase (COX) as the primary metabolic defect in DPCs, leading to decreased Adenosine Triphosphate (ATP) production, mitochondrial membrane potential depolarization, increased total cellular reactive oxygen species (ROS) levels, and reduced expression of the key marker of hair growth in DPCs. By using several known mitochondrial inhibitors, we found that excessive ROS production was responsible for the impairment of DPC function. We therefore subsequently showed that two ROS scavengers, N-acetyl cysteine (NAC) and ascorbic acid (AA), partially prevented the TM- and ROS-mediated inhibition of alkaline phosphatase (ALP). Overall, these findings established a direct link between Cu and the key marker of DPCs, whereby copper depletion strongly impaired the key marker of hair growth in the DPCs by increasing excessive ROS production.}, }
@article {pmid36831011, year = {2023}, author = {Li, H and Li, JJ and Lu, W and Yang, J and Xia, Y and Huang, P}, title = {Targeting Mitochondrial IDH2 Enhances Antitumor Activity of Cisplatin in Lung Cancer via ROS-Mediated Mechanism.}, journal = {Biomedicines}, volume = {11}, number = {2}, pages = {}, pmid = {36831011}, issn = {2227-9059}, support = {(No. 81902323, No. 81972595).//This work was supported in part by grants from the National Natural Science Foundation of China/ ; }, abstract = {Mitochondrial isocitrate dehydrogenase 2 (IDH2) is an important metabolic enzyme in the tricarboxylic acid cycle (TCA) cycle. Our previous study showed that high expression of wild-type IDH2 promotes the proliferation of lung cancer cells. This study aims to test the potential of targeting IDH2 as a therapeutic strategy to inhibit lung cancer in vitro and in vivo. First, we analyzed the available data from the databases gene expression omnibus (GEO) database to evaluate the clinical relevance of IDH2 expression in affecting lung cancer patient survival. We then generated a stable IDH2-knockdown lung cancer cell line using a lentivirus-based method for in vitro and in vivo study. Cell growth, apoptosis, cell viability, and colony formation assays were conducted to test the sensitivity of lung cancer cells with different IDH2 expression status to cisplatin or radiation treatment in vitro. For mechanistic study, Cellular oxygen consumption and extracellular acidification rates were measured using a Seahorse metabolic analyzer, and reactive oxygen species (ROS) generation was analyzed using flow cytometry. An animal study using a xenograft tumor model was performed to further evaluate the in vivo therapeutic effect on tumor growth. We found that high IDH2 expression was associated with poor survival in lung cancer patients undergoing chemotherapy. Inhibition of IDH2 significantly enhanced the anticancer activity of cisplatin and also increased the effect of radiation against lung cancer cells. IDH2 was upregulated in cisplatin-resistant lung cancer cells, which could be sensitized by targeted inhibition of IDH2. Mechanistic study showed that abrogation of IDH2 caused only minimal changes in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in lung cancer cells, but induced a significant increase in ROS, which rendered the cancer cells more sensitive to cisplatin. Pretreatment of lung cancer cells with the ROS scavenger N-acetyl-cysteine could partially rescue cells from the cytotoxic effect of cisplatin and IDH2 inhibition. Importantly, abrogation of IDH2 significantly increased the sensitivity of lung cancer cells to cisplatin in vivo.}, }
@article {pmid36830070, year = {2023}, author = {Abu-Halaka, D and Shpaizer, A and Zeigerman, H and Kanner, J and Tirosh, O}, title = {DMF-Activated Nrf2 Ameliorates Palmitic Acid Toxicity While Potentiates Ferroptosis Mediated Cell Death: Protective Role of the NO-Donor S-Nitroso-N-Acetylcysteine.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {36830070}, issn = {2076-3921}, abstract = {Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease that can develop into an aggressive form called nonalcoholic steatohepatitis (NASH), which ultimately progresses to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure. Currently, the deterioration of NAFLD is attributed to specific lipid toxicity which could be due to lipotoxicity and/or ferroptosis. In the current study, we evaluated the involvement of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf-2), which is a main activator of phase II metabolism in the two types of lipid-induced toxicity in hepatocytes, lipotoxicity by saturated fatty acids, and in ferroptosis, and the effect of NO donor treatment. AML12 cells were exposed to 600 μM palmitic acid to induce lipotoxicity or treated with 20 μM erastin or 5 μM RSL3 for ferroptosis. In SFA-lipotoxicity, pretreatment with the Nrf2 activator dimethyl fumarate (DMF) managed to ameliorate the cells and the oxidative stress level while aggravating ferroptosis due to emptying the thiol pool. On the other hand, the nitric oxide (NO)-donor, S-nitroso-N-acetylcysteine (NAC-SNO) proved to be effective in the prevention of hepatocytes ferroptosis.}, }
@article {pmid36830062, year = {2023}, author = {Shakya, S and McGuffee, RM and Ford, DA}, title = {Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {2}, pages = {}, pmid = {36830062}, issn = {2076-3921}, support = {S10 OD025246/OD/NIH HHS/United States ; S10OD025246/NH/NIH HHS/United States ; R01 GM115553/GM/NIGMS NIH HHS/United States ; R01ES034383/NH/NIH HHS/United States ; R01 ES034383/ES/NIEHS NIH HHS/United States ; R01GM115553/NH/NIH HHS/United States ; }, abstract = {Hypochlorous acid is produced by leukocyte myeloperoxidase activity. 2-Chlorofatty aldehydes (2-ClFALDs) are formed when hypochlorous acid attacks the plasma membrane phospholipid plasmalogen molecular subclass and are thus produced following leukocyte activation as well as in the lungs of mice exposed to chlorine gas. The biological role of 2-ClFALD is largely unknown. Recently, we used an alkyne analog (2-ClHDyA) of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDA), to identify proteins covalently modified by 2-ClHDyA in endothelial cells and epithelial cells. Here, we demonstrate that 2-ClHDA reduces the metabolic activity of RAW 264.7 cells in a dose-dependent manner. 2-ClHDyA localizes to the mitochondria, endoplasmic reticulum and Golgi in RAW 264.7 cells and modifies many proteins. The thiol-containing precursor of glutathione, N-acetyl cysteine (NAC), was shown to produce an adduct with 2-ClHDA with the loss of Cl[-] (HDA-NAC). This adduct was characterized in both positive and negative ion modes using LC-MS/MS and electrospray ionization. NAC treatment of neutrophils reduced the 2-ClFALD levels in PMA-stimulated cells with subsequent increases in HDA-NAC. NAC treatments reduced the 2-ClHDA-elicited loss of metabolic activity in RAW 264.7 cells as well as 2-ClHDA protein modification. These studies demonstrate that 2-ClFALD toxic effects can be reduced by NAC, which reduces protein modification.}, }
@article {pmid36828949, year = {2023}, author = {Dandekar, AA and Vora, D and Yeh, JS and Srivastava, RK and Athar, M and Banga, AK}, title = {Enhanced Transdermal Delivery of N-Acetylcysteine and 4-Phenylbutyric Acid for Potential Use as Antidotes to Lewisite.}, journal = {AAPS PharmSciTech}, volume = {24}, number = {3}, pages = {71}, pmid = {36828949}, issn = {1530-9932}, mesh = {*Skin Absorption ; Acetylcysteine/metabolism ; Antidotes ; Oleic Acid/metabolism ; Dimethyl Sulfoxide/metabolism ; Administration, Cutaneous ; Skin/metabolism ; *Arsenicals/metabolism ; Sodium Dodecyl Sulfate/metabolism ; }, abstract = {Lewisite is a highly toxic chemical warfare agent that leads to cutaneous and systemic damage. N-acetylcysteine (NAC) and 4-phenylbutryic acid (4-PBA) are two novel antidotes developed to treat toxicity caused by lewisite and similar arsenicals. Our in vivo studies demonstrated safety and effectiveness of these agents against skin injury caused by surrogate lewisite (Phenylarsine oxide) proving their potential for the treatment of lewisite injury. We further focused on exploring various enhancement strategies for an enhanced delivery of these agents via skin. NAC did not permeate passively from propylene glycol (PG). Iontophoresis as a physical enhancement technique and chemical enhancers were investigated for transdermal delivery of NAC. Application of cathodal and anodal iontophoresis with the current density of 0.2 mA/cm[2] for 4 h followed by passive diffusion till 24 h significantly enhanced the delivery of NAC with a total delivery of 65.16 ± 1.95 µg/cm[2] and 87.23 ± 7.02 µg/cm[2], respectively. Amongst chemical enhancers, screened oleic acid, oleyl alcohol, sodium lauryl ether sulfate, and dimethyl sulfoxide (DMSO) showed significantly enhanced delivery of NAC with DMSO showing highest delivery of 28,370.2 ± 2355.4 µg/cm[2] in 24 h. Furthermore, 4-PBA permeated passively from PG with total delivery of 1745.8 ± 443.5 µg/cm[2] in 24 h. Amongst the chemical enhancers screened for 4-PBA, oleic acid, oleyl alcohol, and isopropyl myristate showed significantly enhanced delivery with isopropyl myristate showing highest total delivery of 17,788.7 ± 790.2 µg/cm[2]. These studies demonstrate feasibility of delivering these antidotes via skin and will aid in selection of excipients for the development of topical/transdermal delivery systems of these agents.}, }
@article {pmid36827603, year = {2023}, author = {Pitha, I and Kambhampati, S and Sharma, A and Sharma, R and McCrea, L and Mozzer, A and Kannan, RM}, title = {Targeted Microglial Attenuation through Dendrimer-Drug Conjugates Improves Glaucoma Neuroprotection.}, journal = {Biomacromolecules}, volume = {24}, number = {3}, pages = {1355-1365}, pmid = {36827603}, issn = {1526-4602}, support = {P30 EY001765/EY/NEI NIH HHS/United States ; U01 NS103882/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; Microglia ; *Dendrimers ; Neuroprotection ; *Glaucoma ; Disease Models, Animal ; }, abstract = {Retinal microglial/macrophage activation and optic nerve (ON) microglial/macrophage activation are glaucoma biomarkers and potential therapeutic targets for this blinding disease. We report targeting of activated microglia by PAMAM dendrimers in a rat glaucoma model and neuroprotection by N-acetylcysteine-conjugated dendrimer (D-NAC) conjugates in a post-injury rescue experiment. Intravitreally delivered fluorescently labeled dendrimer (D-Cy5) conjugates targeted and were retained in Iba-1-positive cells (90% at 7 days and 55% after 28 days) in the retina following intraocular pressure (IOP) elevation, while systemically delivered D-Cy5 targeted ON cells. A single intravitreal D-NAC dose given 1 week after IOP elevation significantly reduced transcription of pro-inflammatory (IL-6, MCP-1, IL-1β) and A1 astrocyte (Serping1, Fkbp5, Amigo2) markers and increased survival of retinal ganglion cells (39 ± 12%) versus BSS- (20 ± 15%, p = 0.02) and free NAC-treated (26 ± 14%, p = 0.15) eyes. These results highlight the potential of dendrimer-targeted microglia and macrophages for early glaucoma detection and as a neuroprotective therapeutic target.}, }
@article {pmid36827384, year = {2024}, author = {Ebrahimi, F and Zavareh, S and Nasiri, M}, title = {The Combination of Estradiol and N-Acetylcysteine Reduces Ischemia-Reperfusion Injuries of Mice Autografted Ovarian Tissue.}, journal = {Biopreservation and biobanking}, volume = {22}, number = {1}, pages = {29-37}, doi = {10.1089/bio.2022.0184}, pmid = {36827384}, issn = {1947-5543}, mesh = {Animals ; Mice ; *Estradiol/pharmacology ; Acetylcysteine/pharmacology ; Fibroblast Growth Factor 2 ; Interleukin-6 ; Vascular Endothelial Growth Factor A ; Antioxidants/pharmacology/therapeutic use ; *Reperfusion Injury/drug therapy ; Inflammation ; }, abstract = {Ischemia-reperfusion injuries are important issues after ovarian tissue transplantation (OTT). Our study examined the effects of N-acetylcysteine (NAC) and estradiol (E2) on mouse ovarian autografts. Mice (6-8 weeks) were divided into ovarian autograft as follows: Control: fresh OTT; Sham: cryopreserved/warmed OTT; NAC: cryopreserved/warmed OTT with NAC treatment; E2: cryopreserved/warmed OTT with E2 treatment; NAC+E2: cryopreserved/warmed OTT with the treatment of NAC and E2. In all groups, grafts were harvested on days 2, 7, and 28 after transplantation to evaluate histological parameters, inflammation relative to genes expression, and oxidative status. Histological analysis showed that NAC, E2, and a combination of NAC+E2 significantly increased the primordial, preantral, and antral follicular number. When NAC was used, it significantly reduced the expression of Tnf-α and Fgf-2, whereas it increased Il-1β, Il-6, and Vegf expression levels. The levels of Il-6, Fgf-2, and VEGF were dramatically increased in the E2-treated group. The combination of NAC and E2 significantly increased levels of Il-1β, Il-6, Fgf-2, and Vegf. NAC and E2 alone or in combination significantly increased total antioxidant capacity but did not affect the superoxide dismutase and glutathione peroxidase activities. In conclusion, after transplantation, NAC and E2 alone or in combination, could improve follicular development and angiogenesis as well as decline inflammation and ovarian oxidative damage.}, }
@article {pmid36820266, year = {2023}, author = {Kielmann, J and Pucci, L and Xydis, A}, title = {Personalized Nutrition and Lifestyle Interventions in Systemic Lupus Erythematosus: A Case Report.}, journal = {Integrative medicine (Encinitas, Calif.)}, volume = {21}, number = {6}, pages = {22-27}, pmid = {36820266}, issn = {1546-993X}, abstract = {BACKGROUND: A 63-year-old male with a 4-year history of systemic lupus erythematosus (SLE) safely and successfully integrated personalized nutrition and lifestyle modifications to improve the symptomatic outcome of his illness.<br><br>CASE/INTERVENTION: The client presented to our nutritional practice with fatigue, acid reflux, joint pain, brain fog and skin rashes. During the nutritional intervention, he safely used a variety of nutritional interventions and supplementation, including dietary improvements, omega-3 fish oils, N-acetyl cysteine, prebiotics and intermittent fasting, along with stress reduction techniques. His symptoms decreased significantly, or disappeared, over 4 years of using these interventions.<br><br>CONCLUSION: This case demonstrates the safety and potential benefits of personalized nutrition, stress reduction techniques and targeted supplementation in helping to decrease symptoms of SLE. Our client's energy levels and overall performance improved, skin rashes and acid reflux resolved, joint pain and stiffness decreased and brain fog gradually lessened over the 4 years he was in our care.}, }
@article {pmid36816622, year = {2023}, author = {Simasingha, N and Tanasoontrarat, W and Claimon, T and Sethasine, S}, title = {Efficacy of dexamethasone and N-acetylcysteine combination in preventing post-embolization syndrome after transarterial chemoembolization in hepatocellular carcinoma.}, journal = {World journal of gastroenterology}, volume = {29}, number = {5}, pages = {890-903}, pmid = {36816622}, issn = {2219-2840}, mesh = {Humans ; Acetylcysteine ; *Carcinoma, Hepatocellular/pathology ; *Chemoembolization, Therapeutic/adverse effects/methods ; Dexamethasone ; *Liver Neoplasms/pathology ; Nausea/etiology ; Treatment Outcome ; Vomiting/etiology ; Drug Combinations ; }, abstract = {BACKGROUND: Conventional transarterial chemoembolization (cTACE) is the current standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Post-embolization syndrome (PES) is complex clinical syndrome that presents as fever, abdominal pain, nausea, and vomiting. Either dexamethasone (DEXA) or N-acetylcysteine (NAC) is used to prevent PES; however, the synergistic effect of their combined therapy for preventing PES and liver decompensation has not been determined.<br><br>AIM: To evaluate the efficacy of DEXA and NAC combination in preventing PES and liver decompensation after cTACE.<br><br>METHODS: Patients with Barcelona Clinic Liver Cancer stage A or B HCC who were scheduled for TACE were prospectively enrolled. All patients were randomly stratified to receive NAC and DEXA or placebo. The dual therapy (NAC + DEXA) group received intravenous administration of 10 mg DEXA every 12 h, NAC 24 h prior to cTACE (150 mg/kg/h for 1 h followed by 12.5 mg/kg/h for 4 h), and a continuous infusion of 6.25 mg/h NAC plus 4 mg DEXA every 12 h for 48 h after cTACE. The placebo group received an infusion of 5% glucose solution until 48 h after procedure. PES was defined by South West Oncology Group toxicity code grading of more than 2 that was calculated using incidence of fever, nausea, vomiting, and pain.<br><br>RESULTS: One-hundred patients were enrolled with 50 patients in each group. Incidence of PES was significantly lower in the NAC + DEXA group compared with in the placebo group (6% vs 80%; P < 0.001). Multivariate analysis showed that the dual treatment is a protective strategic therapy against PES development [odds ratio (OR) = 0.04; 95% confidence interval (CI): 0.01-0.20; P < 0.001). Seven (14%) patients in the placebo group, but none in the NAC + DEXA group, developed post-TACE liver decompensation. A dynamic change in Albumin-Bilirubin score of more than 0.5 point was found to be a risk factor for post-TACE liver decompensation (OR = 42.77; 95%CI: 1.01-1810; P = 0.049).<br><br>CONCLUSION: Intravenous NAC + DEXA administration ameliorated the occurrence of PES event after cTACE in patients with intermediate-stage HCC.}, }
@article {pmid36813253, year = {2023}, author = {Sasaki, S and Negishi, T and Tsuzuki, T and Yukawa, K}, title = {Methylmercury-induced reactive oxygen species-dependent and independent dysregulation of MAP kinase-related signaling pathway in cultured normal rat cerebellar astrocytes.}, journal = {Toxicology}, volume = {487}, number = {}, pages = {153463}, doi = {10.1016/j.tox.2023.153463}, pmid = {36813253}, issn = {1879-3185}, mesh = {Rats ; Animals ; Reactive Oxygen Species/metabolism ; *Antioxidants/pharmacology/metabolism ; MAP Kinase Signaling System ; *Methylmercury Compounds ; Astrocytes ; Oxidative Stress ; Glutathione/metabolism ; Acetylcysteine/pharmacology/metabolism ; Cells, Cultured ; }, abstract = {Methylmercury (MeHg), a global environmental pollutant, could seriously damage the central nervous system (CNS) and cause neurological disorders such as cerebellar symptoms. Although numerous studies have revealed detailed toxicity mechanisms of MeHg in neurons, toxicity in astrocytes is barely known. Here, we tried to shed light on the toxicity mechanisms of MeHg exposure in cultured normal rat cerebellar astrocytes (NRA), focusing on the involvement of reactive oxygen species (ROS) in MeHg toxicity by assessing the effects of major antioxidants Trolox, a free-radical scavenger, N-acetyl-L-cysteine (NAC), a potent thiol-containing antioxidant, and glutathione (GSH), an endogenous thiol-containing antioxidant. Exposure to MeHg at just approximately 2 µM for 96 h increased cell viability, which was accompanied by the increase in intracellular ROS level and at ≥ 5 µM induced significant cell death and lowered ROS level. Trolox and NAC suppressed 2 µM MeHg-induced increases in cell viability and ROS level corresponding to control, although GSH with 2 µM MeHg induced significant cell death and ROS increase. On the contrary, against 4 µM MeHg-induced cell loss and ROS decrease, NAC inhibited both cell loss and ROS decrease, Trolox inhibited cell loss and further enhanced ROS decrease, and GSH moderately inhibited cell loss and increased ROS level above the control level. MeHg-induced oxidative stress was suggested by increases in the protein expression levels of heme oxygenase-1 (HO-1), Hsp70, and Nrf2, except for the decrease in SOD-1 and no change in catalase. Furthermore, MeHg exposure dose-dependently induced increases in the phosphorylation of MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK) and phosphorylation and/or expression levels of transcription factors (CREB, c-Jun, and c-Fos) in NRA. NAC successfully suppressed 2 µM MeHg-induced alterations in all of the above-mentioned MeHg-responsive factors, whereas Trolox suppressed some MeHg-responsive factors but failed to suppress MeHg-induced increases in the protein expression levels of HO-1 and Hsp70 and increase in p38MAPK phosphorylation. Protein expression analyses in NRA exposed to 2 µM MeHg and GSH were excluded because of devastating cell death. These results suggested that MeHg could induce aberrant NRA activation, and ROS must be substantially involved in the toxicity mechanism of MeHg in NRA; however, other factors should be assumed.}, }
@article {pmid36810107, year = {2023}, author = {Abbasifard, M and Khorramdelazad, H and Rostamian, A and Rezaian, M and Askari, PS and Sharifi, GTK and Parizi, MK and Sharifi, MTK and Najafizadeh, SR}, title = {Effects of N-acetylcysteine on systemic lupus erythematosus disease activity and its associated complications: a randomized double-blind clinical trial study.}, journal = {Trials}, volume = {24}, number = {1}, pages = {129}, pmid = {36810107}, issn = {1745-6215}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Severity of Illness Index ; *Lupus Erythematosus, Systemic/drug therapy ; Kidney ; Double-Blind Method ; Treatment Outcome ; }, abstract = {BACKGROUNDS: N-acetylcysteine (NAC) has broadly been used as an anti-oxidant agent in various types of diseases. This study aimed to assess the effect of NAC on the systemic lupus erythematosus (SLE) disease activity and outcome.<br><br>METHODS: In this randomized, double-blind clinical trial study, 80 SLE patients were recruited that were classified into two groups: 40 patients received NAC (1800 mg/day; 3 times per day with 8-h intervals) for 3 months and 40 patients as the control group received normal therapies. Laboratory measurements and disease activity based on the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index (SLEDAI) were determined before the initiation of treatment and after the study time period.<br><br>RESULTS: A statistically significant decrease in BILAG (P= 0.023) and SLEDAI (P= 0.034) scores after receiving NAC for a 3-month period was observed. BILAG (P= 0.021) and SLEDAI (P= 0.030) scores were significantly lower in NAC-receiving patients compared to the control group after 3 months. The disease activity in each organ based on BILAG score after treatment indicated a significant decrease in the NAC group compared to the baseline level in general (P=0.018), mucocutaneous (P=0.003), neurological (P=0.015), musculoskeletal (P=0.048), cardiorespiratory (P=0.047), renal (P=0.025), and vascular (P=0.048) complications. Analysis indicated a significant increase in CH50 level in the NAC group after treatment compared to the baseline level (P=0.049). No adverse event was reported by the study subjects.<br><br>CONCLUSIONS: It appears that the administration of 1800 mg/day NAC to SLE patients can decrease the SLE disease activity and its complications.}, }
@article {pmid36809299, year = {2023}, author = {Chen, DW and Kang, T and Xu, XZ and Xia, WJ and Ye, X and Wu, YB and Xu, YR and Liu, J and Ren, H and Deng, J and Chen, YK and Ding, HQ and Aslam, M and Zelek, WM and Morgan, BP and Kapur, R and Santoso, S and Fu, YS}, title = {Mechanism and intervention of murine transfusion-related acute lung injury caused by anti-CD36 antibodies.}, journal = {JCI insight}, volume = {8}, number = {6}, pages = {}, pmid = {36809299}, issn = {2379-3708}, mesh = {Mice ; Humans ; Male ; Animals ; *Transfusion-Related Acute Lung Injury/pathology ; Blood Platelets/pathology ; Monocytes/pathology ; Complement System Proteins ; Complement Activation ; }, abstract = {Anti-CD36 Abs have been suggested to induce transfusion-related acute lung injury (TRALI) upon blood transfusion, particularly in Asian populations. However, little is known about the pathological mechanism of anti-CD36 Ab-mediated TRALI, and potential therapies have not yet been identified. Here, we developed a murine model of anti-CD36 Ab-mediated TRALI to address these questions. Administration of mouse mAb against CD36 (mAb GZ1) or human anti-CD36 IgG, but not GZ1 F(ab')2 fragments, induced severe TRALI in Cd36+/+ male mice. Predepletion of recipient monocytes or complement, but not neutrophils or platelets, prevented the development of murine TRALI. Moreover, plasma C5a levels after TRALI induction by anti-CD36 Abs increased more than 3-fold, implying a critical role of complement C5 activation in the mechanism of Fc-dependent anti-CD36-mediated TRALI. Administration of GZ1 F(ab')2, antioxidant (N-acetyl cysteine, NAC), or C5 blocker (mAb BB5.1) before TRALI induction completely protected mice from anti-CD36-mediated TRALI. Although no significant amelioration in TRALI was observed when mice were injected with GZ1 F(ab')2 after TRALI induction, significant improvement was achieved when mice were treated postinduction with NAC or anti-C5. Importantly, anti-C5 treatment completely rescued mice from TRALI, suggesting the potential role of existing anti-C5 drugs in the treatment of patients with TRALI caused by anti-CD36.}, }
@article {pmid36808460, year = {2023}, author = {Dwivedi, SK and Arachchige, DL and Vohs, T and Tang, J and Usimaki, K and Olowolagba, AM and Fritz, DR and Luck, RL and Werner, T and Liu, H}, title = {Near-infrared rhodol dyes bearing salicylaldehyde moieties for ratiometric pH sensing in live cells during mitophagy and under hypoxia conditions.}, journal = {Journal of materials chemistry. B}, volume = {11}, number = {13}, pages = {2852-2861}, pmid = {36808460}, issn = {2050-7518}, support = {R15 GM114751/GM/NIGMS NIH HHS/United States ; R15 GM146206/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; HeLa Cells ; *Mitophagy ; *Hydrogen Peroxide ; Fluorescent Dyes ; Hypoxia ; Hydrogen-Ion Concentration ; }, abstract = {We describe a simple but efficient approach to make fluorescent probes A and B based on rhodol dyes incorporated with salicyaldehyde moiety for monitoring pH changes in mitochondria under oxidative stresses and hypoxia conditions, and for tracking mitophagy processes. Probes A and B possess pKa values (pKa ≈ 6.41 and 6.83 respectively) near physiological pH and exhibit decent mitochondria-targeted capabilities, low cytotoxicity, and useful ratiometric and reversible pH responses, which make the probes appropriate for monitoring pH fluctuations of mitochondria in living cells with built-in calibration feature for quantitative analysis. The probes have been effectively useful for the ratiometric determination of pH variations of mitochondria under the stimuli of carbonyl cyanide-4(trifluoromethoxy)phenylhydrazone (FCCP), hydrogen peroxide (H2O2), and N-acetyl cysteine (NAC), and during mitophagy triggered by cell nutrient deprivation, and under hypoxia conditions with cobalt chloride (CoCl2) treatment in living cells. In addition, probe A was efficient in visualizing pH changes in the larvae of fruit flies.}, }
@article {pmid36807852, year = {2023}, author = {Wei, Y and Geng, W and Zhang, T and He, H and Zhai, J}, title = {N-acetylcysteine rescues meiotic arrest during spermatogenesis in mice exposed to BDE-209.}, journal = {Environmental science and pollution research international}, volume = {30}, number = {17}, pages = {50952-50968}, pmid = {36807852}, issn = {1614-7499}, support = {NO.&#xa0;82273598//the&#xa0;National&#xa0;Natural&#xa0;Science&#xa0;Foundation&#xa0;of&#xa0;China/ ; NO. 2108085MH305//the&#xa0;Nature&#xa0;Science&#xa0;Research&#xa0;Project&#xa0;of&#xa0;Anhui&#xa0;Province&#xa0;/ ; }, mesh = {Mice ; Male ; Animals ; *Acetylcysteine/pharmacology ; *Meiosis ; Semen ; Spermatogenesis ; }, abstract = {Deca-bromodiphenyl ethers (BDE-209) has been widely used in electronic devices and textiles as additives to flame retardants. Growing evidence showed that BDE-209 exposure leads to poorer sperm quality and male reproductive dysfunction. However, the underlying mechanisms of BDE-209 exposure caused a decline in sperm quality remains unclear. This study aimed to evaluate the protective effects of N-acetylcysteine (NAC) on meiotic arrest in spermatocytes and decreased sperm quality in BDE-209-exposed mice. In the study, mice were treated with NAC (150 mg/kg BW) 2 h before administrated with BDE-209 (80 mg/kg BW) for 2 weeks. For the in vitro studies, spermatocyte cell line GC-2spd cells were pretreated with NAC (5 mM) 2 h before treated with BDE-209 (50 μM) for 24 h. We found that pretreatment with NAC attenuated the oxidative stress status induced by BDE-209 in vivo and in vitro. Moreover, pretreatment with NAC rescued the testicular histology impairment and decreased the testicular organ coefficient in BDE-209-exposed mice. In addition, NAC supplement partially promoted meiotic prophase and improved sperm quality in BDE-209-exposed mice. Furthermore, NAC pretreatment effectively improved DNA damage repair by recovering DMC1, RAD51, and MLH1. In conclusion, BDE-209 caused spermatogenesis dysfunction related to the meiotic arrest medicated by oxidative stress, decreasing sperm quality.}, }
@article {pmid36806345, year = {2023}, author = {Zhang, X and Wang, S and Jin, Y and Wang, J and Wang, R and Yang, X and Zhang, S and Yan, T and Jia, Y}, title = {Wei-Tong-Xin ameliorated cisplatin-induced mitophagy and apoptosis in gastric antral mucosa by activating the Nrf2/HO-1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {308}, number = {}, pages = {116253}, doi = {10.1016/j.jep.2023.116253}, pmid = {36806345}, issn = {1872-7573}, mesh = {Mice ; Animals ; *NF-E2-Related Factor 2/metabolism ; *Cisplatin/pharmacology ; Heme Oxygenase-1/metabolism ; Mitophagy ; Pyloric Antrum/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Apoptosis ; Mucous Membrane ; }, abstract = {Wei-Tong-Xin (WTX) originated from the famous ancient Chinese formula "Wan Ying Yuan", recorded in the ancient Chinese medicine book "Zhong Zang Jing" by Hua Tuo. As "Jun" drugs, Dahuang and Muxiang have the effects of clearing heat and expelling fire, reducing food retention, regulating Qi and relieving pain. As "Chen" drug, Qianniuzi has the effect of assisting "Jun" drugs. Zhuyazao and Gancao, as "Zuo-Shi" drugs, can reduce toxicity and modulate the medicinal properties of other herbs.<br><br>AIM OF THE STUDY: The present study aimed to investigate the effect and mechanism of WTX on the oxidative stress of gastric antrum mucosa in mice with cisplatin (CIS)-induced dyspepsia.<br><br>MATERIALS: AND.<br><br>METHODS: A variety of experimental methods, including western blot, qRT-PCR, immunofluorescence and immunohistochemistry were performed in vivo and in vitro.<br><br>RESULTS: In vivo, WTX restored the number and function of interstitial cells of Cajal (ICCs), accompanied by the inhibition of lipid peroxidation. Moreover, WTX inhibited the activation of Parkin-dependent mitophagy and apoptosis. In vitro, WTX activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and inactivated mitophagy in GES-1&#xa0;cells. To explore the role of Nrf2 in WTX's improvement of CIS-induced cell damage, Nrf2 inhibitor ML385 was used in cell experiments. We found that ML385 counteracted the regulation of WTX on mitophagy and apoptosis. Finally, N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, was applied in our experiments, and the results suggested that WTX suppressed the CIS-induced apoptosis via mitochondrial pathway.<br><br>CONCLUSIONS: The above results, for the first time, indicated that WTX inhibited mitophagy and apoptosis of gastric antral mucosal cells induced by CIS through the Nrf2/HO-1 signaling pathway.}, }
@article {pmid36802832, year = {2023}, author = {Turk, T and Liu, C and Fujiwara, E and Straube, S and Hagtvedt, R and Dennett, L and Abba-Aji, A and Dytoc, M}, title = {Pharmacological Interventions for Primary Psychodermatologic Disorders: An Evidence Mapping and Appraisal of Randomized Controlled Trials.}, journal = {Journal of cutaneous medicine and surgery}, volume = {27}, number = {2}, pages = {140-149}, pmid = {36802832}, issn = {1615-7109}, mesh = {Humans ; Sertraline/therapeutic use ; Fluoxetine/therapeutic use ; Clomipramine/therapeutic use ; Olanzapine ; *Antipsychotic Agents/therapeutic use ; Desipramine ; Pimozide ; Randomized Controlled Trials as Topic ; Acetylcysteine/therapeutic use ; *Dermatitis/drug therapy ; }, abstract = {BACKGROUND: The lack of clinical guidelines for the treatment of primary psychodermatologic disorders (PPDs) hinders the delivery of optimal care to patients. The review aimed to identify, appraise, and summarize the currently available evidence about the safety and effectiveness of pharmacological management of PPDs through randomized controlled trials (RCTs).<br><br>METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRIMSA) statement and the Global Evidence Mapping Initiative guidance were followed. Medline, Embase, PsycInfo, Cochrane and Scopus were searched, and two reviewers independently completed article review, data extraction, and quality assessment.<br><br>RESULTS: Among 2618 unique studies, full texts of 83 were reviewed and 21 RCTs were included. Five PDDs were identified: trichotillomania (n = 12), pathologic skin picking (n = 5), nail biting (n = 2), delusional parasitosis (n = 1), and dermatitis from compulsive hand washing (n = 1). Seven different classes of medications were investigated: SSRIs (i.e., fluoxetine, sertraline, and citalopram), tricyclic antidepressants (i.e., clomipramine and desipramine), antipsychotics (i.e., olanzapine and pimozide), anticonvulsant (i.e., lamotrigine), N-acetylcysteine, inositol, and milk thistle. RCT-derived evidence supports the use of antidepressants in trichotillomania (sertraline and clomipramine), pathologic skin picking (fluoxetine), pathologic nail biting and dermatitis from compulsive hand washing (clomipramine or desipramine); antipsychotics in trichotillomania (olanzapine) and delusional parasitosis (pimozide); N-acetyl cysteine in trichotillomania and skin picking.<br><br>CONCLUSION: Few pharmacotherapies for primary psychodermatologic disorders are assessed through controlled trials in the literature. This review serves as a roadmap for researchers and clinicians to reach informed decisions with current evidence, and to build on it to establish guidelines in the future.}, }
@article {pmid36799253, year = {2023}, author = {Xu, K and Ma, J and Lu, R and Shao, X and Zhao, Y and Cui, L and Qiu, Z and Tian, Y and Li, J}, title = {Effective-compound combination of Bufei Yishen formula III combined with ER suppress airway mucus hypersecretion in COPD rats: via EGFR/MAPK signaling.}, journal = {Bioscience reports}, volume = {43}, number = {11}, pages = {}, pmid = {36799253}, issn = {1573-4935}, mesh = {Animals ; Rats ; ErbB Receptors/metabolism ; *Interleukin-6/metabolism ; Lung/pathology ; Mucus/metabolism ; *Pulmonary Disease, Chronic Obstructive/pathology ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: The aim of this study was to explore the combined efficacy ofeffective-component compatibility of Bufei Yishen formula III (ECC-BYF III) and exercise rehabilitation (ER) in inhibiting airway mucus hypersecretion in a chronic obstructive pulmonary disease (COPD) rat model.<br><br>METHODS: A total of 48 SD rats were divided into control, model, acetylcysteine (NAC), ECC-BYF III, ER, and ECC-BYF III + ER groups (n=8). COPD rats were exposed to cigarette smoke and bacteria for 8 weeks and administered various treatments over the next eight weeks. Rats were euthanized at week 17 after pulmonary function testing. Pathological examination of lung tissues was performed. IL-6 and IL-10 levels were measured in bronchoalveolar lavage fluid (BALF) and protein levels of MUC5AC, MUC5B, AQP-5, EGFR, ERK, JNK, and p38 were measured in lung tissues.<br><br>RESULTS: Improved pulmonary function and pathological changes were observed in ECC-BYF III, ECC-BYF III + ER, and NAC groups. ECC-BYF III and ECC-BYF III + ER had greater mean alveolar number (MAN) compared with NAC. Lung inflammation and goblet cell generation were reduced and MUC5AC, MUC5B and AQP-5 expressions were lower in all treatment groups. ECC-BYF III has more significant effect on MUC5AC than ER and NAC. ECC-BYFIII + ER had a greater effect on suppressing IL-6 in BALF compared with other treatments. ECC-BYFIII, ER, and ECC-BYF III + ER reduced EGFR, ERK, JNK, and p38 phosphorylated protein levels. ECC-BYFIII+ER had a greater effect on p-JNK and p-p38 than ECC-BYFIII and NAC.<br><br>CONCLUSION: ECC-BYF III, ER, and ECC-BYF III + ER have efficacy in inhibiting airway mucus hypersecretion with improved pulmonary function and pathological changes. ECC-BYF III had a greater effect in improving MAN and MUC5AC in lung tissue. ECC-BYF III+ER had a greater effect in alleviating pulmonary pathology and inflammation. These effects may be mediated by inhibition of the EGFR/MAPK pathway.}, }
@article {pmid36796651, year = {2023}, author = {Yoo, JY and Lee, YJ and Kim, YJ and Baik, TK and Lee, JH and Lee, MJ and Woo, RS}, title = {Multiple low-dose radiation-induced neuronal cysteine transporter expression and oxidative stress are rescued by N-acetylcysteine in neuronal SH-SY5Y cells.}, journal = {Neurotoxicology}, volume = {95}, number = {}, pages = {205-217}, doi = {10.1016/j.neuro.2023.02.006}, pmid = {36796651}, issn = {1872-9711}, mesh = {Humans ; *Acetylcysteine/pharmacology/metabolism ; Apoptosis ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/metabolism ; Cell Line, Tumor ; *Neuroblastoma/radiotherapy/metabolism ; Oxidative Stress ; Cell Survival ; }, abstract = {Recently, several studies have demonstrated that low-dose radiation (LDR) therapy has positively impacts on the treatment of Alzheimer's disease (AD). LDR suppresses the production of pro-neuroinflammation molecules and improves cognitive function in AD. However, it is unclear whether direct exposure to LDR causes beneficial effects and what mechanism is involved in neuronal cells. In this study, we first determined the effect of high-dose radiation (HDR) alone on C6 cells and SH-SY5Y cells. We found that SH-SY5Y cells were more vulnerable than C6 cells to HDR. Moreover, in neuronal SH-SY5Y cells exposed to single or multiple LDR, N-type cells showed decreased cell viability with increasing radiation exposure time and frequency, but S-type cells were unaffected. Multiple LDR increased proapoptotic molecules such as p53, Bax and cleaved caspase-3, and decreased anti-apoptotic molecule (Bcl2). Multiple LDR also generated free radicals in neuronal SH-SY5Y cells. We detected a change in the expression of the neuronal cysteine transporter EAAC1. Pretreatment with N-acetylcysteine (NAC) rescued the increased in EAAC1 expression and the generation of ROS in neuronal SH-SY5Y cells after multiple LDR. Furthermore, we verified whether the increased in EAAC1 expression induces cell defense or cell death promotion signaling. We showed that transient overexpression of EAAC1 reduced the multiple LDR-induced p53 overexpression in neuronal SH-SY5Y cells. Our results indicate that neuronal cells can be injured by increased production of ROS not only by HDR but also by multiple LDR, which suggests that combination treatment with anti-free radical agents such as NAC may be useful in multiple LDR therapy.}, }
@article {pmid36795483, year = {2023}, author = {Bhardwaj, M and Lee, JJ and Versace, AM and Harper, SL and Goldman, AR and Crissey, MAS and Jain, V and Singh, MP and Vernon, M and Aplin, AE and Lee, S and Morita, M and Winkler, JD and Liu, Q and Speicher, DW and Amaravadi, RK}, title = {Lysosomal lipid peroxidation regulates tumor immunity.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {8}, pages = {}, pmid = {36795483}, issn = {1558-8238}, support = {R01 CA266404/CA/NCI NIH HHS/United States ; P50 CA174523/CA/NCI NIH HHS/United States ; R01 CA256945/CA/NCI NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; S10 OD023586/OD/NIH HHS/United States ; R01 CA238237/CA/NCI NIH HHS/United States ; P30 DK050306/DK/NIDDK NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; P01 CA114046/CA/NCI NIH HHS/United States ; P50 CA261608/CA/NCI NIH HHS/United States ; }, mesh = {Mice ; Animals ; Lipid Peroxidation ; *Apoptosis ; Cell Death ; *Neoplasms/pathology ; Antioxidants/pharmacology ; Lysosomes/metabolism ; }, abstract = {Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naive T cells and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate that LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.}, }
@article {pmid36795166, year = {2023}, author = {Hammerschmidt, TG and Guerreiro, GB and Donida, B and Raabe, M and Kessler, RG and Ferro, MB and Moura, DJ and Giugliani, R and Vargas, CR}, title = {Beneficial in vitro effect of N-acetylcysteine and coenzyme Q10 on DNA damage in neurodegenerative Niemann-Pick type C 1 disease: preliminary results.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {396}, number = {7}, pages = {1563-1569}, pmid = {36795166}, issn = {1432-1912}, support = {2018-0648//Fundo de Incentivo &#xe0; Pesquisa e Eventos (FIPE/HCPA)./ ; 430443/2018-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, mesh = {Humans ; *Niemann-Pick Disease, Type C/drug therapy/genetics/metabolism ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; DNA Damage ; }, abstract = {Niemann-Pick type C1 (NP-C1) is a lysosomal storage disease (LSD) caused by mutations in NPC1 gene that lead to defective synthesis of the respective lysosomal transporter protein and cholesterol accumulation in late endosomes/lysosomes (LE/L) compartments, as well as glycosphingolipids GM2 and GM3 in the central nervous system (CNS). Clinical presentation varies according to the age of onset and includes visceral and neurological symptoms, such as hepatosplenomegaly and psychiatric disorders. Studies have been associating the pathophysiology of NP-C1 with oxidative damage to lipids and proteins, as well as evaluating the benefits of adjuvant therapy with antioxidants for this disease. In this work, we evaluated the DNA damage in fibroblasts culture from patients with NP-C1 treated with miglustat, as well as the in vitro effect of the antioxidant compounds N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10), using the alkaline comet assay. Our preliminary results demonstrate that NP-C1 patients have increased DNA damage compared to healthy individuals and that the treatments with antioxidants can mitigate it. DNA damage may be due to an increase in reactive species since it has been described that NP-C1 patients have increased peripheral markers of damage to other biomolecules. Our study suggests that NP-C1 patients could benefit from the use of adjuvant therapy with NAC and CoQ10, which should be better evaluated in a future clinical trial.}, }
@article {pmid36791995, year = {2023}, author = {Mukherjee, S and Gupta, P and Ghosh, S and Choudhury, S and Das, A and Ahir, M and Adhikary, A and Chattopadhyay, S}, title = {Targeted tumor killing by pomegranate polyphenols: Pro-oxidant role of a classical antioxidant.}, journal = {The Journal of nutritional biochemistry}, volume = {115}, number = {}, pages = {109283}, doi = {10.1016/j.jnutbio.2023.109283}, pmid = {36791995}, issn = {1873-4847}, mesh = {Animals ; Mice ; Antioxidants/pharmacology/therapeutic use/chemistry ; Reactive Oxygen Species/metabolism ; *Pomegranate ; Fruit/chemistry ; Ascites ; Polyphenols/pharmacology/analysis ; Epithelial-Mesenchymal Transition ; Oxidative Stress ; NF-E2-Related Factor 2/metabolism ; *Carcinoma ; NF-kappa B/metabolism ; Apoptosis ; }, abstract = {One of the key biochemical features that distinguish a cancer cell from normal cells is its persistent pro-oxidative state that leads to intrinsic oxidative stress. Malignant cells have evolved sophisticated adaptation systems that involve high dependency on antioxidant functions and upregulation of pro-survival molecules to counteract the deleterious effects of reactive species and to maintain dynamic redox balance. This situation renders them vulnerable to further oxidative challenges by exogenous agents. In the present study, we advocated that pomegranate polyphenols act as pro-oxidants and trigger ROS-mediated apoptosis in cancer cells. With the help of both in vitro and in vivo models, we have established that pomegranate fruit extract (PFE) can cause a significant reduction in tumor proliferation while leaving normal tissues and cells unharmed. Administration of PFE (0.2% v/v) in Erhlich's ascites carcinoma-bearing mice for 3 weeks, inhibited the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element signaling cascade, increased intracellular reactive oxygen species content, altered glutathione cycle thereby activating reactive oxygen species-induced apoptotic pathway in Erhlich's ascites carcinoma cells. Moreover, PFE mitigated epithelial to mesenchymal transition and migration in triple negative breast cancer cells (MDA-MB 231 cells) by down-regulating nuclear factor kappa light-chain-enhancer of activated B cells. Pre-treatment of tumor cells with N-acetyl cysteine protected these cells from undergoing PFE-induced apoptosis while siRNA-mediated silencing of Nuclear factor (erythroid-derived 2)-like 2 and nuclear factor kappa light-chain-enhancer of activated B cells in tumor cells increased the cytotoxic potential and pro-oxidative activity of PFE, indicating a clear role of these transcription factors in orchestrating the anticancer/pro-oxidative properties of PFE. The seminal findings provided may be exploited to develop potential therapeutic targets for selective killing of malignant cells.}, }
@article {pmid36791364, year = {2023}, author = {Hong, MK and Echanique, KA and Hoffman, LF and Kita, AE}, title = {Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model.}, journal = {Otology &amp; neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology}, volume = {44}, number = {4}, pages = {373-381}, pmid = {36791364}, issn = {1537-4505}, support = {K08 DC019957/DC/NIDCD NIH HHS/United States ; }, mesh = {Rats ; Animals ; Cisplatin/toxicity ; *Antineoplastic Agents ; *Ototoxicity ; Acetylcysteine/pharmacology ; Gentamicins/toxicity ; Schwann Cells ; }, abstract = {HYPOTHESIS: The ototoxicity of gentamicin and cisplatin can be evaluated with a Schwann cell model to screen for otoprotective agents that can be encapsulated into poly (lactic-co-glycolic acid) (PLGA) microparticles for drug delivery to the inner ear.<br><br>BACKGROUND: Aminoglycosides and cisplatin are widely prescribed but known to cause ototoxicity. There is strong evidence that compromise to Schwann cells ensheathing inner ear afferent neurons results in inner ear dysfunction mimicking drug-induced ototoxicity. There is a need for a model for ototoxic demyelination to screen medications for protective potential and to subsequently target and tune the delivery of any promising agents.<br><br>METHODS: RT4-D6P2T rat schwannoma cells were used as a Schwann cell model to assess gentamicin and cisplatin toxicity and to screen for protective agents. Cell viability was evaluated with the MTT cell proliferation assay. N -acetylcysteine (NAC) was encapsulated into a PLGA microparticle, and its elution profile was determined.<br><br>RESULTS: The estimated 50% lethal concentration dose for gentamicin was 805.6 &#x3bc;M, which was 46-fold higher than that for cisplatin (17.5 &#x3bc;M). In several trials, cells dosed with NAC and cisplatin demonstrated a 22.6% (p < 0.001) increase in cell viability when compared with cisplatin alone. However, this protective effect was not consistent across all trials. NAC was encapsulated into a PLGA microparticle and elution plateaued at 5 days.<br><br>CONCLUSION: When dosed at their respective therapeutic ranges, cisplatin is more likely than gentamicin to induce damage to the Schwann cell model. Although NAC demonstrates an uncertain role in protecting against cisplatin-induced Schwann cell cytotoxicity, this study establishes a method to screen for other otoprotective medications to encapsulate into a tunable microparticle for localized drug delivery.}, }
@article {pmid36780980, year = {2023}, author = {Siddiqui, SI and Malik, C and Ghosh, S}, title = {Voltage dependent anion channel and its interaction with N-acetyl-L-Cysteine (NAC) under oxidative stress on planar lipid bilayer.}, journal = {Biochimie}, volume = {209}, number = {}, pages = {150-160}, doi = {10.1016/j.biochi.2023.02.005}, pmid = {36780980}, issn = {1638-6183}, mesh = {*Lipid Bilayers ; *Acetylcysteine/pharmacology ; Antioxidants/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Hydrogen Peroxide/pharmacology/metabolism ; Voltage-Dependent Anion Channels/metabolism ; Oxidative Stress ; }, abstract = {Mitochondria are the major source of Hydrogen Peroxide (H2O2), a reactive oxygen species, in the cells. The reactive oxygen species generated by the mitochondria oxidize major proteins including Voltage Dependent Anion Channel (VDAC). We were interested to know how the effect of H2O2 is countered by antioxidants present around the mitochondria. N-Acetyl-l-Cysteine (NAC) is a naturally existing antioxidant in the cells. Keeping this in view, the modulatory effect of antioxidant NAC on H2O2 oxidized VDAC has been investigated through in vitro electrophysiological studies. First, the effect of H2O2 and NAC was studied on independently incorporated single-channel VDAC. It was observed that NAC suppresses VDAC conductance with a half-maximal inhibitory concentration (IC50) of ∼1.04 μM. In contrast, H2O2 enhances VDAC conductance. Later, oxidative stress was induced by H2O2 on VDAC increased conductance with half-maximal effective concentration (EC50) of ∼302 nM. An application of 1 μM NAC on H2O2 treated (300 nM) VDAC reversed the effect of oxidation. In the next step, NAC and H2O2 were added in reverse order. When oxidative stress was induced using H2O2, reduction in conductance by NAC was 4.5 ± 0.404 nS. The change in conductance is nearly 6.3%. However, if antioxidant NAC was incubated first followed by H2O2 treatment, the conductance of VDAC was 3.09 ± 0.27 nS. The change in conductance is near 33%. Both H2O2 and NAC also affected various conducting states of VDAC. In-silico studies indicated the binding of NAC at Lysine and Glutamic acid of VDAC. Hence, NAC was found to be effective in protection of VDAC against H2O2-induced oxidative stress due to its strong binding.}, }
@article {pmid36779633, year = {2023}, author = {Fang, Z and Xu, Y and Liu, G and Shao, Q and Niu, X and Tai, W and Shen, T and Fan, M and Chen, M and Lei, L and Gao, W and Song, Y and Wang, Z and Du, X and Li, X}, title = {Narirutin activates TFEB (transcription factor EB) to protect against Acetaminophen-induced liver injury by targeting PPP3/calcineurin.}, journal = {Autophagy}, volume = {19}, number = {8}, pages = {2240-2256}, pmid = {36779633}, issn = {1554-8635}, mesh = {Mice ; Animals ; *Calcineurin/metabolism ; Acetaminophen ; Autophagy/genetics ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Liver/metabolism ; Glutathione/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Acetaminophen (APAP) overdose is the predominant cause of drug-induced liver injury worldwide. The macroautophagy/autophagy-lysosomal pathway (ALP) is involved in the APAP hepatotoxicity. TFEB (transcription factor EB) promotes the expression of genes related to autophagy and lysosomal biogenesis, thus, pharmacological activation of TFEB-mediated ALP may be an effective therapeutic approach for treating APAP-induced liver injury. We aimed to reveal the effects of narirutin (NR), the main bioactive constituents isolated from citrus peels, on APAP hepatotoxicity and to explore its underlying mechanism. Administration of NR enhanced activities of antioxidant enzymes, improved mitochondrial dysfunction and alleviated liver injury in APAP-treated mice, whereas NR did not affect APAP metabolism and MAPK/JNK activation. NR enhanced TFEB transcriptional activity and activated ALP in an MTOR complex 1 (MTORC1)-independent but PPP3/calcineurin-dependent manner. Moreover, knockout of Tfeb or knockdown of PPP3CB/CNA2 (protein phosphatase 3, catalytic subunit, beta isoform) in the liver abolished the beneficial effects of NR on APAP overdose. Mechanistically, NR bound to PPP3CB via PRO31, LYS61 and PRO347 residues and enhanced PPP3/calcineurin activity, thereby eliciting dephosphorylation of TFEB and promoting ALP, which alleviated APAP-induced oxidative stress and liver injury. Together, NR protects against APAP-induced liver injury by activating a PPP3/calcineurin-TFEB-ALP axis, indicating NR may be a potential agent for treating APAP overdose.Abbreviations: ALP: autophagy-lysosomal pathway; APAP: acetaminophen; APAP-AD: APAP-protein adducts; APAP-Cys: acetaminophen-cysteine adducts; CAT: catalase; CETSA: cellular thermal shift assay; CQ: chloroquine; CYP2E1: cytochrome P450, family 2, subfamily e, polypeptide 1; CYCS/Cyt c: cytochrome c, somatic; DARTS: drug affinity responsive target stability assay; ENGASE/NAG: endo-beta-N-acetylglucosaminidase; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; GSH: glutathione; GPX/GSH-Px: glutathione peroxidase; KD: dissociation constant; Leu: leupeptin; MCOLN1: mucolipin 1; MTORC1: MTOR complex 1; NAC: N-acetylcysteine; NAPQI: N-acetyl-p-benzoquinoneimine; NFAT: nuclear factor of activated T cells; NR: narirutin; OA: okadaic acid; RRAG: Ras related GTP binding; ROS: reactive oxygen species; PPP3CB/CNA2: protein phosphatase 3, catalytic subunit, beta isoform; PPP3R1/CNB1: protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type I); SOD: superoxide dismutase; SPR: surface plasmon resonance analysis; TFEB: transcription factor EB.}, }
@article {pmid36779379, year = {2023}, author = {Zhang, Z and Shen, C and Zhou, F and Zhang, Y}, title = {Shikonin potentiates therapeutic efficacy of oxaliplatin through reactive oxygen species-mediated intrinsic apoptosis and endoplasmic reticulum stress in oxaliplatin-resistant colorectal cancer cells.}, journal = {Drug development research}, volume = {84}, number = {3}, pages = {542-555}, doi = {10.1002/ddr.22044}, pmid = {36779379}, issn = {1098-2299}, mesh = {Animals ; Mice ; Humans ; Oxaliplatin/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Apoptosis ; *Naphthoquinones/pharmacology/therapeutic use ; Cell Line, Tumor ; *Colorectal Neoplasms/drug therapy/metabolism ; Endoplasmic Reticulum Stress ; }, abstract = {Oxaliplatin (OXA) has been recognized as a third-generation platinum-based chemotherapeutic agent with stellar therapeutic efficacy in managing colorectal cancer (CRC). Nevertheless, resistance to OXA in CRC patients hinders its effectiveness. Shikonin (SHI), a natural naphthoquinone derived from Arnebia euchroma (Royle) Johnst., features a broad pharmacological profile and minimal toxicities. To assess the synergism of SHI and OXA towards OXA-resistant CRC cells (HCT116[R]), we employed in vitro and in vivo pharmacological assays. Our experiments provided evidence that SHI, either alone or in combination with OXA, considerably reduced cell proliferation, triggered apoptosis, and induced the generation of reactive oxygen species (ROS) in HCT116[R] cells. Furthermore, the combination of SHI and OXA dramatically curbed the extent of HCT116[R] -initiated xenograft growth in mouse models. Bioinformatics, western blot, and ROS assays highlighted that the mechanisms of SHI against OXA-resistant CRC cells may involve the induction of cellular responses to chemical stress, intrinsic apoptosis, as well as endoplasmic reticulum stress pathways mediated by ROS. Notably, the synergism of SHI+OXA was partially abrogated by an ROS inhibitor N-acetyl cysteine. Our findings imply the potential of SHI to boost the sensitivity of OXA to CRC, offering promising benefits for clinical strategies to combat OXA resistance.}, }
@article {pmid36777598, year = {2023}, author = {Önem, AN and Sözgen Başkan, K and Apak, R}, title = {Voltammetric Measurement of Antioxidant Activity by Prevention of Cu(II)-Induced Oxidative Damage on DNA Bases Using a Modified Electrode.}, journal = {ACS omega}, volume = {8}, number = {5}, pages = {5103-5115}, pmid = {36777598}, issn = {2470-1343}, abstract = {The protective effect of antioxidants using electrochemical techniques can be evaluated by examining the oxidative changes in deoxyribonucleic acid (DNA) nucleobases. In this study, a gold nanoparticle (AuNP)-decorated and multiwalled carbon nanotube (MWCNT)-Nafion-modified glassy carbon electrode (GCE/AuNP/MWCNT-Nafion) was developed to evaluate the preventive ability of antioxidants on oxidative DNA damage. A modified working electrode was prepared and characterized by cyclic voltammetry, electrochemical impedance spectroscopy, and scanning electron microscopy. The developed electrochemical method relies on two phenomena: (i) reactive species (RS) produced by dissolved oxygen in the presence of copper(II) partially damage the DNA immobilized on the electrode surface and (ii) antioxidant compounds prevent this damage by scavenging the formed RS. Changes in guanine, adenine, and cytosine oxidation signals resulting from DNA damage were measured using differential pulse stripping voltammetry before/after the interaction of dsDNA with Cu(II) while antioxidants were absent or present. The DNA protective ability of antioxidants was assessed for a number of antioxidant compounds (i.e., ascorbic acid, gallic acid, epicatechin, catechin, epicatechin gallate, glutathione, chlorogenic acid, N-acetyl cysteine, rosmarinic acid, quercetin, and rutin). Quercetin was found to show the highest antioxidant effect, and its limit of detection was determined as 1 μM. The manufactured biosensor was put in an application for the determination of antioxidant activity of herbal teas.}, }
@article {pmid36775116, year = {2023}, author = {Sharma, JR and Agraval, H and Yadav, UCS}, title = {Cigarette smoke induces epithelial-to-mesenchymal transition, stemness, and metastasis in lung adenocarcinoma cells via upregulated RUNX-2/galectin-3 pathway.}, journal = {Life sciences}, volume = {318}, number = {}, pages = {121480}, doi = {10.1016/j.lfs.2023.121480}, pmid = {36775116}, issn = {1879-0631}, mesh = {Humans ; Epithelial-Mesenchymal Transition ; Galectin 3 ; *Cigarette Smoking ; Reactive Oxygen Species ; *Adenocarcinoma of Lung ; *Lung Neoplasms/pathology ; Transcription Factors ; }, abstract = {AIMS: An elevated level of galectin-3, a carbohydrate-binding lectin implicated in tumorigenesis, metastasis, and epithelial-mesenchymal transition (EMT), has been found in cigarette smokers. However, the regulation of its expression and role in the pathogenesis of CS-induced EMT and lung cancer metastasis is unclear. Here, we have investigated the mechanism of CS-induced and galectin-3-mediated EMT in airway epithelial cells (AECs).<br><br>MAIN METHODS: A549 adenocarcinoma cells and primary small airway epithelial cells cultured on an air-liquid interface (ALI) were exposed to cigarette smoke extract (CSE), and MTT, trypan blue, migration, invasion, tumor spheroid and colony formation assays were performed to assess EMT phenotype. Immunoblotting was performed to assess EMT and stemness markers and other regulatory proteins.<br><br>KEY FINDINGS: CSE exposure affected cell survival and morphology, migration, invasion, and clonogenicity of AECs, which were concomitant with an increase in the expression of EMT markers, galectin-3, and runt-related transcription factor-2 (RUNX-2), an osteogenic transcription factor and upstream regulator of galectin-3. Chemical inhibition or silencing of RUNX-2 downregulated galectin-3 and modulated EMT marker expression, migration, invasion, and clonogenicity in CSE-exposed AECs. Recombinant human galectin-3 also induced EMT and stemness-associated changes in the AECs, and GB1107, a galectin-3 inhibitor, ameliorated these changes. Further, CSE-induced intracellular ROS enabled an increase in RUNX-2 and galectin-3 expression, which were reversed by n-acetyl-cysteine.<br><br>SIGNIFICANCE: These results provide a novel mechanistic insight into CSE-induced EMT via RUNX-2/galectin-3 axis mediated through ROS, which promoted EMT-associated changes, including invasion, migration, and stemness in AECs, which could be implicated in CS-induced lung cancer progression.}, }
@article {pmid36774779, year = {2023}, author = {Kashif, M and Yao, H and Schmidt, S and Chen, X and Truong, M and Tüksammel, E and Liu, Y and Bergo, MO}, title = {ROS-lowering doses of vitamins C and A accelerate malignant melanoma metastasis.}, journal = {Redox biology}, volume = {60}, number = {}, pages = {102619}, pmid = {36774779}, issn = {2213-2317}, mesh = {Animals ; Humans ; Mice ; Acetylcysteine ; *Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; *Melanoma/drug therapy/genetics/pathology ; Reactive Oxygen Species/metabolism ; Vitamins ; Vitamin A/pharmacology ; Melanoma, Cutaneous Malignant ; }, abstract = {Oxidative stress is a barrier of migration and metastasis for malignant melanoma cells. Consequently, reducing oxidative stress with the antioxidant N-acetylcysteine (NAC) stimulates melanoma cell migration in vitro and metastasis in vivo. However, it is not yet known whether the NAC effect is shared with other antioxidants. Here, we screened 104 redox-active compounds and identify 27 that increase migration of human malignant melanoma cells in two doses. Validation experiments in four cell lines and four drug doses resulted in a list of 18 compounds which were ranked based on their ability to increase migration and reduce ROS levels; vitamin C (VitC) ranked as number one, followed by the vitamin E analogue Trolox and several carotenoids and Vitamin A-related compounds. Four diet-relevant compounds from this list-VitC, β-carotene, retinyl palmitate, and canthaxanthin-were selected and found to accelerate metastasis in mice with BRAF[V600E]-driven malignant melanoma. Genomics analyses revealed that the transcription factor BACH1 is activated following antioxidant administration and knockout of Bach1 in mouse melanoma cells reduced lymph node and liver metastasis in xenograft mouse models. We conclude that a broad range of antioxidants accelerate melanoma migration and metastasis and that BACH1 is functionally linked to melanoma metastasis in vivo.}, }
@article {pmid36773561, year = {2023}, author = {Chu, Y and Xu, Y and Yang, W and Chu, K and Li, S and Guo, L}, title = {N-acetylcysteine protects human periodontal ligament fibroblasts from pyroptosis and osteogenic differentiation dysfunction through the SIRT1/NF-κB/Caspase-1 signaling pathway.}, journal = {Archives of oral biology}, volume = {148}, number = {}, pages = {105642}, doi = {10.1016/j.archoralbio.2023.105642}, pmid = {36773561}, issn = {1879-1506}, mesh = {Humans ; *NF-kappa B/metabolism ; *Acetylcysteine/pharmacology ; Osteogenesis ; Caspase 1/metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Periodontal Ligament ; Lipopolysaccharides/pharmacology ; Sirtuin 1/metabolism/pharmacology ; Cells, Cultured ; Signal Transduction ; Cell Differentiation ; Fibroblasts ; Adenosine Triphosphate/metabolism ; }, abstract = {OBJECTIVE: This study was aimed to determine whether N-acetylcysteine (NAC) could inhibit lipopolysaccharides / adenosine triphosphate (ATP)-induced pyroptosis and alleviate the damage of osteogenic differentiation in human periodontal ligament fibroblasts (hPDLFs). Furthermore, this study detected whether NAC acted effectively by modulating the silent information regulator 2 homolog 1 (SIRT1)/ the nuclear factor-κB (NF-κB)/Caspase-1 signaling pathway in hPDLFs.<br><br>DESIGN: Cell Counting Kit-8 assay was employed to determine the appropriate concentration of NAC for the follow-up experiments. To explore the effect and the underlying mechanisms of NAC on pyroptosis and osteogenic differentiation in hPDLFs, intracellular reactive oxygen species levels were detected using 2',7'-Dichlorodihydrofluorescein Diacetate kits. Moreover, SIRT1 inhibitor, SIRT1 activator, NF-&#x3ba;B inhibitor and Caspase-1 inhibitor were applied, the incidence of pyroptosis was detected by flow cytometry, the osteogenic differentiation of hPDLFs was observed using alkaline phosphatase and alizarin red staining, Real-time quantitative polymerase chain reaction and Western Blot were used to detect the expression of relevant factors, the release of interleukin-1&#x3b2;, interleukin-18 and lactate dehydrogenase were detected by Enzyme-linked immunosorbent assay.<br><br>RESULTS: The results demonstrated that NAC protected hPDLFs from lipopolysaccharides/ATP-induced damage, alleviating pyroptosis and osteogenic differentiation dysfunction. Moreover, NAC abrogated the inhibition of SIRT1 activity by scavenging reactive oxygen species, thereby reduced pyroptosis and osteogenic differentiation dysfunction by inhibiting the NF-&#x3ba;B/Caspase-1signaling pathway.<br><br>CONCLUSION: NAC could inhibit pyroptosis and osteogenic differentiation dysfunction of hPDLFs by scavenging reactive oxygen species to regulate the SIRT1/NF-&#x3ba;B/Caspase-1 signaling axis.}, }
@article {pmid36770846, year = {2023}, author = {Eom, JW and Lim, JW and Kim, H}, title = {Lutein Induces Reactive Oxygen Species-Mediated Apoptosis in Gastric Cancer AGS Cells via NADPH Oxidase Activation.}, journal = {Molecules (Basel, Switzerland)}, volume = {28}, number = {3}, pages = {}, pmid = {36770846}, issn = {1420-3049}, support = {no number//BK21 FOUR project, Yonsei University, Republic of Korea./ ; }, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *NF-kappa B/metabolism ; *Stomach Neoplasms/drug therapy ; Lutein/pharmacology ; Antioxidants/pharmacology ; bcl-2-Associated X Protein ; Apoptosis ; Caspases ; NADPH Oxidases/metabolism ; }, abstract = {Disruption of apoptosis leads to cancer cell progression; thus, anticancer agents target apoptosis of cancer cells. Reactive oxygen species (ROS) induce apoptosis by activating caspases and caspase-dependent DNase, leading to DNA fragmentation. ROS increase the expression of apoptotic protein Bax, which is mediated by activation of nuclear factor-κB (NF--κB). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is an important source of endogenous ROS, and its activation is involved in apoptosis. Lutein, an oxygenated carotenoid and known antioxidant, is abundant in leafy dark green vegetables, such as spinach and kale, and in yellow-colored foods, such as corn and egg yolk. High amounts of lutein increase ROS levels and exhibit anticancer activity. However, its anticancer mechanism remains unclear. This study aimed to determine whether lutein activates NADPH oxidase to produce ROS and induce apoptosis in gastric cancer AGS cells. Lutein increased ROS levels and promoted the activation of NADPH oxidase by increasing the translocation of NADPH oxidase subunit p47 [phox] to the cell membrane. It increased NF-κB activation and apoptotic indices, such as Bax, caspase-3 cleavage, and DNA fragmentation, and decreased Bcl-2, cell viability, and colony formation in AGS cells. The specific NADPH oxidase inhibitor ML171, and the known antioxidant N-acetyl cysteine reversed lutein-induced cell death, DNA fragmentation, and NF-κB DNA-binding activity in AGS cells. These results suggest that lutein-induced ROS production is dependent on NADPH oxidase, which mediates NF-κB activation and apoptosis in gastric cancer AGS cells. Therefore, lutein supplementation may be beneficial for increasing ROS-mediated apoptosis in gastric cancer cells.}, }
@article {pmid36769455, year = {2023}, author = {Ito, K and Kise, H and Suzuki, S and Nagai, S and Hachiya, K and Takeda, H and Kawabata, S and Ikeda, D and Takubo, K and Kaneko, S and Fujita, N}, title = {Potential Involvement of Oxidative Stress in Ligamentum Flavum Hypertrophy.}, journal = {Journal of clinical medicine}, volume = {12}, number = {3}, pages = {}, pmid = {36769455}, issn = {2077-0383}, support = {19K09634//JSPS/ ; }, abstract = {Oxidative stress (OS) results in many disorders, of which degenerative musculoskeletal conditions are no exception. However, the interaction between OS and ligamentum flavum (LF) hypertrophy in lumbar spinal canal stenosis is not clearly understood. The first research question was whether OS was involved in LF hypertrophy, and the second was whether the antioxidant N-acetylcysteine (NAC) was effective on LF hypertrophy. In total, 47 LF samples were collected from patients with lumbar spinal disorders. The cross-sectional area of LF was measured on axial magnetic resonance imaging. Immunohistochemistry of 8-OHdG and TNF-α were conducted on human LF samples. A positive association was found between 8-OHdG or TNF-α expression and cross-sectional area of LF. Flow cytometry analysis showed that H2O2, buthionine sulfoximine, and TNF-α treatment significantly increased intracellular reactive oxygen species in primary LF cells. NAC inhibited the induction of LF hypertrophy markers by OS or TNF in a real-time reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Western blotting analysis indicated that p38, Erk, and p65 phosphorylation were involved in intracellular OS signaling in LF cells. In conclusion, our results indicated that OS could be a therapeutic target for LF hypertrophy. Although this study included no in vivo studies to examine the longitudinal efficacy of NAC on LF hypertrophy, NAC may have potential as a therapeutic agent against lumbar spinal canal stenosis.}, }
@article {pmid36764275, year = {2023}, author = {Zhou, Y and Zhang, Y and Wang, H and Zhang, X and Chen, Y and Chen, G}, title = {Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway.}, journal = {International immunopharmacology}, volume = {116}, number = {}, pages = {109725}, doi = {10.1016/j.intimp.2023.109725}, pmid = {36764275}, issn = {1878-1705}, mesh = {Animals ; Mice ; Caspase 1/metabolism ; *Cognitive Dysfunction/chemically induced/metabolism ; Hippocampus/metabolism ; *Inflammasomes/metabolism ; Microglia ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Pyroptosis ; Reactive Oxygen Species/metabolism ; *Sevoflurane/adverse effects ; }, abstract = {BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication with its pathophysiological mechanisms not been fully elucidated. Pyroptosis is a novel type of pro-inflammatory cell death and considered to be associated with cognitive dysfunction. Therefore, our study aimed to examine the effect of pyroptosis on sevoflurane-induced cognitive impairment in aged mice as well as its underlying mechanism.<br><br>METHODS: A mice model of cognitive impairment was established by sevoflurane exposure and the levels of reactive oxygen species (ROS), N-GSDMD, cleaved caspase-1, ASC, IL-1&#x3b2; and IL-18, and NLRP3 in hippocampus was determined. To explore the underlying mechanism, a pyroptosis inhibitor, necrosulfonamide (NSA), and a ROS scavenger, N-acetylcysteine (NAC), were administrated before sevoflurane exposure both in vitro and in vivo. Neurobehavioral tests, western blot, transmission electron microscope (TEM) observation, and immunofluorescence staining were performed.<br><br>RESULTS: Sevoflurane induced hippocampal pyroptosis in the cognitive impairment model. NSA effectively inhibited the pyroptosis and improved cognitive function. Co-labeled immunofluorescence staining suggested sevoflurane induces microglial pyroptosis. Sevoflurane induced pyroptosis accompanied with ROS accumulation in a dose-independent manner in BV2 cells, and NAC effectively reduce the levels of ROS and pyroptosis through NLRP3 inflammasome pathway in both vitro and vivo. Furthermore, NAC could also alleviate sevoflurane-induced cognitive dysfunction.<br><br>CONCLUSIONS: Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway. Both pyroptosis inhibition and ROS scavenging might be potential approaches to ameliorate sevoflurane-induced neurocognitive dysfunction.}, }
@article {pmid36762617, year = {2023}, author = {Zhai, L and Ruan, S and Wang, J and Guan, Q and Zha, L}, title = {NADPH oxidase 4 regulate the glycolytic metabolic reprogramming of microglial cells to promote M1 polarization.}, journal = {Journal of biochemical and molecular toxicology}, volume = {37}, number = {5}, pages = {e23318}, doi = {10.1002/jbt.23318}, pmid = {36762617}, issn = {1099-0461}, mesh = {Animals ; Mice ; *Glycolysis ; Lipopolysaccharides ; *Microglia/metabolism ; *NADPH Oxidase 4/genetics/metabolism ; *Neuroinflammatory Diseases ; Reactive Oxygen Species/metabolism ; }, abstract = {This work aimed to investigate the role and mechanism of NADPH oxidase 4 (NOX4) in the polarization of microglial cells. Microglial cells were transfected with the NOX4 overexpression plasmid (pGL3-NOX4), and later treated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) to induce its M1 polarization. Later, the F4/80 + CD86 + cell proportion was detected by flow cytometry (FCM), the inflammatory factor expression levels were analyzed through enzyme-linked immunosorbent assay (ELISA), while ionized calcium binding adapter molecule 1 (IBA-1) and PKM2 expression were measured by immunofluorescence (IF) staining. In addition, dichlorodihydrofluorescein diacetate probe was utilized to detect the reactive oxygen species (ROS) levels, glucose uptake, and glycolysis, as well as lactic acid level. The expression of glycolytic enzymes PKM2, HK2, and citrate (Si)-synthas (CS) was detected by Western-blot (WB) assay. Moreover, the polarization level of microglial cells was detected after ROS expression was suppressed by the ROS inhibitor N-acetylcysteine (NAC). In mouse experiments, LPS was applied in inducing central neuroinflammation in NOX4 knockdown mouse model (KO) and wild-type mice (WT). Thereafter, the inflammatory factor levels and lactic acid level in mouse tissues were detected; IBA-1 and CD86 expression in mice was measured by IF staining; and the expression of glycolytic enzymes PKM2, HK2, and CS in the central nervous system (CNS) was also detected. After NOX4 overexpression in microglial cells, the M1 polarization level was upregulated, the F4/80 + CD86 + cell proportion increased, and inflammatory factors were upregulated. At the same time, the expression of glycolytic enzymes PKM2, HK2, and CS was upregulated. NAC pretreatment suppressed the effects of NOX4, reduced the F4/80 + CD86 + cell proportion, and suppressed the expression of PKM2, HK2, and CS. In the mouse model, the expression levels of CD86 in KO group decreased, and the inflammatory factors were also downregulated. NOX4 promotes glycolysis of microglial cells via ROS, thus accelerating M1 polarization and inflammatory factor expression. In this regard, NOX4 is promising as a new target for the treatment of neuroinflammation.}, }
@article {pmid36759944, year = {2022}, author = {Tan, R and Black, M and Home, J and Blackwell, J and Clark, I and Wylie, L and Vanhatalo, A and Jones, AM}, title = {Physiological and performance effects of dietary nitrate and N-acetylcysteine supplementation during prolonged heavy-intensity cycling.}, journal = {Journal of sports sciences}, volume = {40}, number = {23}, pages = {2585-2594}, doi = {10.1080/02640414.2023.2176052}, pmid = {36759944}, issn = {1466-447X}, mesh = {Humans ; Male ; *Exercise/physiology ; *Fruit and Vegetable Juices ; *Nitrates/blood ; *Acetylcysteine/administration &amp; dosage ; Antioxidants/administration &amp; dosage ; *Dietary Supplements ; Cross-Over Studies ; Reactive Oxygen Species ; Endurance Training ; Oxygen Consumption/physiology ; Nitrites/blood ; Adult ; *Plant Extracts/pharmacology ; Plant Roots ; }, abstract = {The purpose of this study was to investigate effects of concurrent and independent administration of dietary nitrate (NO3[-]), administered as NO3[-]-rich beetroot juice (BR; ~12.4 mmol of NO3[-]), and N-acetylcysteine (NAC; 70 mg·kg[-1]) on physiological responses during prolonged exercise and subsequent high-intensity exercise tolerance. Sixteen recreationally active males supplemented with NO3[-]-depleted beetroot juice (PL) or BR for 6 days and ingested an acute dose of NAC or maltodextrin (MAL) 1 h prior to performing 1 h of heavy-intensity cycling exercise immediately followed by a severe-intensity time-to-exhaustion (TTE) test in four conditions: 1) PL+MAL, 2) PL+NAC, 3) BR+MAL and 4) BR+NAC. Pre-exercise plasma [NO3[-]] and nitrite ([NO2[-]]) were elevated following BR+NAC and BR+MAL (both P < 0.01) compared with PL+NAC and PL+MAL; plasma [cysteine] was increased in PL+NAC and BR+NAC (both P < 0.01) compared to PL+MAL. Muscle excitability declined over time during the prolonged cycling bout in all conditions but was better preserved in PL+NAC compared to BR+NAC (P < 0.01) and PL+MAL (P < 0.05). There was no effect of supplementation on subsequent TTE . These findings indicate that co-ingestion of BR and NAC does not appreciably alter physiological responses during prolonged heavy-intensity cycling or enhance subsequent exercise tolerance.}, }
@article {pmid36757588, year = {2023}, author = {Gupta, J and Rajamani, P}, title = {Size- and surface functionalization-driven molecular interaction of CdSe quantum dots with jack bean urease: multispectroscopic, thermodynamic, and AFM approach.}, journal = {Environmental science and pollution research international}, volume = {30}, number = {16}, pages = {48300-48322}, pmid = {36757588}, issn = {1614-7499}, support = {UGC ref No.: 3798/ (NET-DEC 2018)//University Grants Commission/ ; }, mesh = {Humans ; *Quantum Dots/chemistry ; Urease/metabolism ; *Cadmium Compounds/chemistry ; *Selenium Compounds/chemistry ; Glutathione ; Acetylcysteine ; Thermodynamics ; *Cysts ; Tumor Microenvironment ; }, abstract = {Quantum dots (QDs) with distinctive optical properties have been extensively researched and developed for usage in solar cells, imaging, drug delivery, cellular targeting, etc. But the inevitable production of QDs can lead to their unavoidable release and increased environmental concentration. Depending on morphological and surface properties, QDs at the nano-bio interface considerably impact the activity and structure of bio-molecules. The present study investigates the interaction of metalloenzyme jack bean urease (JBU) and bi-sized CdSe QDs (2.43 nm and 3.63 nm), surface-functionalized to mercaptopropionic acid (MPA) (-COOH), L-cysteine (CYS), L-glutathione (GSH), N-acetyl L-cysteine (NAC) (-COOH, -NH2), and cysteamine hydrochloride (CYST) (-NH2) to assess any alterations in JBU's binding, microenvironment, structure, exciton lifetime, and activity. JBU catalyzes the hydrolysis of urea to produce ammonia and carbon dioxide; any changes in its properties could threaten the survival of several microbes and plants. Spectroscopy techniques such as UV-Vis, fluorescence, circular dichroism, synchronous, time-resolved fluorescence, atomic force microscopy, and JBU activity assay were studied. Results suggested highly spontaneous and energy-favored interactions, which involved static quenching and hydrophobic forces of varied magnitude, dependent on QDs properties. The size, surface modifications, and dosage of QDs significantly impacted the secondary structure and activity of JBUs. Even though the larger sizes of the relevant modifications demonstrated stronger binding, the smaller sizes had the greatest impact on α-helicity and activity. CYST-capped QDs with an average number of the binding site (n) = 1, reduced α-helicity by 16% and activity by 22-30% at 7 nM concentration. In contrast, MPA-capped QDs with n < 1 had the least effect on α-helical structure and activity. The smaller GSH-capped QDs increased the activity by 9%, via partially restoring JBU's α-helical content. The study thus thoroughly analyzed the impact of varied-size and surface-functionalized QDs on the structure and function of JBU, which can be exploited further for several biomedical applications.}, }
@article {pmid36756299, year = {2023}, author = {Guo, M and Chen, Q and Huang, Y and Wu, Q and Zeng, Y and Tan, X and Teng, F and Ma, X and Pu, Y and Huang, W and Gu, J and Zhang, C and Long, Y and Xu, Y}, title = {High Glucose-Induced Kidney Injury via Activation of Necroptosis in Diabetic Kidney Disease.}, journal = {Oxidative medicine and cellular longevity}, volume = {2023}, number = {}, pages = {2713864}, pmid = {36756299}, issn = {1942-0994}, mesh = {Rats ; Mice ; Animals ; *Diabetic Nephropathies ; Reactive Oxygen Species/metabolism ; Necroptosis ; *Diabetes Mellitus, Experimental/complications ; Kidney/metabolism ; Inflammation ; Glucose/toxicity ; }, abstract = {Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) and is closely associated to programmed cell death. However, the complex mechanisms of necroptosis, an alternative cell death pathway, in DKD pathogenesis are yet to be elucidated. This study indicates that necroptosis is involved in DKD induced by high glucose (HG) both in vivo and in vitro. HG intervention led to the activation of RIPK1/RIPK3/MLKL signaling, resulting in renal tissue necroptosis and proinflammatory activation in streptozotocin/high-fat diet- (STZ/HFD-) induced diabetic mice and HG-induced normal rat kidney tubular cells (NRK-52E). We further found that in HG-induced NRK-52E cell, necroptosis might, at least partly, depend on the levels of reactive oxygen species (ROS). Meanwhile, ROS participated in necroptosis via a positive feedback loop involving the RIPK1/RIPK3 pathway. In addition, blocking RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS generation, could effectively protect the kidney against HG-induced damage, decrease the release of proinflammatory cytokines, and rescue renal function in STZ/HFD-induced diabetic mice. Inhibition of RIPK1 effectively decreased the activation of RIPK1-kinase-/NF-κB-dependent inflammation. Collectively, we demonstrated that high glucose induced DKD via renal tubular epithelium necroptosis, and Nec-1 or NAC treatment downregulated the RIPK1/RIPK3/MLKL pathway and finally reduced necroptosis, oxidative stress, and inflammation. Thus, RIPK1 may be a therapeutic target for DKD.}, }
@article {pmid36756050, year = {2023}, author = {Yu, Q and Shen, C and Wang, X and Wang, Z and Liu, L and Zhang, J}, title = {Graphene Oxide/Gelatin Nanofibrous Scaffolds Loaded with N-Acetyl Cysteine for Promoting Wound Healing.}, journal = {International journal of nanomedicine}, volume = {18}, number = {}, pages = {563-578}, pmid = {36756050}, issn = {1178-2013}, mesh = {Mice ; Animals ; *Acetylcysteine/pharmacology ; Gelatin/pharmacology ; Wound Healing ; Cicatrix ; *Nanofibers/chemistry ; Tissue Scaffolds/chemistry ; }, abstract = {PURPOSE: We aimed to develop an antioxidant dressing material with pro-angiogenic potential that could promote wound healing. Gelatin (Gel) was selected to improve the biocompatibility of the scaffolds, while graphene oxide (GO) was added to enhance their mechanical property. The loaded N-Acetyl cysteine (NAC) was performing the effect of scavenging reactive oxygen species (ROS) at the wound site.<br><br>MATERIALS AND METHODS: The physicochemical and mechanical properties, NAC releases, and biocompatibility of the NAC-GO-Gel scaffolds were evaluated in vitro. The regeneration capability of the scaffolds was systemically investigated in vivo using the excisional wound-splinting model in mice.<br><br>RESULTS: The NAC-GO-Gel scaffold had a stronger mechanical property and sustainer NAC release ability than the single Gel scaffold, which resulted in a better capacity for cell proliferation and migration. Mice wound-splinting models revealed that the NAC-GO-Gel scaffold effectively accelerated wound healing, promoted re-epithelialization, enhanced neovascularization, and reduced scar formation.<br><br>CONCLUSION: The NAC-GO-Gel scaffold not only promotes wound healing but also reduces scar formation, showing a great potential application for the repair of skin defects.}, }
@article {pmid36753335, year = {2023}, author = {Gong, B and Zhang, S and Wang, X and Ran, G and Zhang, X and Xi, J and Gao, Z and Lei, Y and Pan, J and Liu, Y and Luan, Y and Zhang, X and Peng, Y and Li, W and Zheng, J}, title = {Inflammation Intensifies Monocrotaline-Induced Liver Injury.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.2c07939}, pmid = {36753335}, issn = {1520-5118}, abstract = {Pyrrolizidine alkaloids (PAs) are the most common toxins of plant origin, and it is evident that PAs pollute soil, water, nearby plants, and derived foods. Cases of human poisoning due to ingestion of PA-contaminated foods have been reported in several countries. Monocrotaline (MCT) is a pyrrolizidine alkaloid from the plants of Crotalaria genus that causes hepatic and cardiopulmonary toxicities, and the exhibition of the toxicities requires the metabolic activation by CYP3A4 to form electrophilic dehydro-monocrotaline (DHM). The present study demonstrated that myeloperoxidase (MPO) also participated in the bioactivation of MCT. N-Chloromonocrotaline was detected in both HClO/MCT incubations and MPO/H2O2/MgCl2/MCT incubations. DHM-derived N-acetylcysteine (NAC) conjugates were detected in the above incubations fortified with NAC. Lipopolysaccharide-induced inflammation in mice resulted in an elevated level of hepatic MPO activity, increased metabolic activation of MCT, and intensified elevation of serum ALT and AST activity induced by MCT. MPO inhibitor 4-aminobenzoic acid hydrazide was found to reverse these alterations. Mpo-KO mice were resistant to the observed potentiating effect of inflammation on MCT-induced liver injury. In conclusion, inflammation intensified MCT-induced liver injury. MPO participated in the observed potentiating effect of inflammation on the hepatotoxicity induced by MCT.}, }
@article {pmid36749578, year = {2023}, author = {Abedi, B and Tayefi-Nasrabadi, H and Kianifard, D and Basaki, M and Shahbazfar, AA and Piri, A and Dolatyarieslami, M}, title = {The effect of co-administration of artemisinin and N-acetyl cysteine on antioxidant status, spermatological parameters and histopathology of testis in adult male mice.}, journal = {Hormone molecular biology and clinical investigation}, volume = {44}, number = {2}, pages = {207-214}, pmid = {36749578}, issn = {1868-1891}, mesh = {Male ; Mice ; Animals ; *Antioxidants/pharmacology ; Acetylcysteine/pharmacology/metabolism ; Testis/metabolism ; Oxidative Stress ; Semen/metabolism ; Spermatozoa/metabolism ; Glutathione/metabolism ; *Artemisinins/adverse effects/metabolism ; }, abstract = {OBJECTIVES: This in vivo study aimed to evaluate the effect of various concentrations of artemisinin (Art) alone or together with N-acetyl cysteine (NAC) on spermatological indices, antioxidant status, and histopathological parameters of testicular tissue in adult male mice.<br><br>METHODS: Six groups of five healthy male mice (25-30&#xa0;g) were randomly assigned to different experimental groups. These groups received DMSO and corn oil (0.1%) as an Art solvent (Control), 50&#xa0;mg&#xa0;kg[-1] Art (Art-50), 250&#xa0;mg&#xa0;kg[-1] Art (Art-250), 50&#xa0;mg&#xa0;kg[-1] Art&#xa0;+&#xa0;150&#xa0;mg&#xa0;kg[-1] NAC (Art-50+NAC-150), 250&#xa0;mg&#xa0;kg[-1] Art&#xa0;+&#xa0;150&#xa0;mg&#xa0;kg[-1] NAC (Art-250+NAC-150) and 150&#xa0;mg&#xa0;kg[-1] NAC (NAC-150) for a period of 7&#xa0;days. Testes and epididymis were prepared to evaluate the malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), spermatological indices, and histological parameters.<br><br>RESULTS: We showed that the high dose of Art (Art-250) significantly reduced the sperm count, motility, viability, and the activity of CAT and increased the levels of MDA compared to the control group. Also, the overdose of Art caused adverse changes in testicular tissue. Co-administration of NAC with Art (Art-250+NAC-150) corrected the adverse effects of Art.<br><br>CONCLUSIONS: The current study reports that a high dose of Art affects, spermatological parameters, antioxidant/stress oxidative status of the male reproductive system, and NAC is capable neutralize all adverse effects caused by Art.}, }
@article {pmid36740148, year = {2023}, author = {Kandhari, K and Mishra, JPN and Agarwal, R and Singh, RP}, title = {Acacetin induces sustained ERK1/2 activation and RIP1-dependent necroptotic death in breast cancer cells.}, journal = {Toxicology and applied pharmacology}, volume = {462}, number = {}, pages = {116409}, doi = {10.1016/j.taap.2023.116409}, pmid = {36740148}, issn = {1096-0333}, mesh = {Female ; Humans ; Apoptosis ; *Breast Neoplasms/pathology ; Cell Line, Tumor ; MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/pharmacology ; }, abstract = {Acacetin (AC), a naturally occurring flavonoid has shown anticancer potential. Herein, we studied the mechanisms of cell death and growth inhibition by AC in breast carcinoma T-47D and MDA-MB-231 cells. AC (10-40 μM) significantly decreased the levels of G2/M phase cyclins and CDKs, simultaneously increasing the expression of CDK inhibitors including Cip1/p21. A concentration-dependent increase in cell death was noted in both breast cancer cell lines with no such considerable effects on MCF-10A non-tumorigenic breast cells. The cell death-inducing potential of AC was further confirmed using confocal microscopy and flow cytometry analysis. AC resulted in mitochondrial superoxide generation, DNA damage, and ROS generation. N-acetyl cysteine (NAC) pre-treatment inhibited ROS generation and partially reversed ERK1/2 activation as well as cell death by AC. Further, AC enhanced the expression of RIP1 and RIP3, which mediate necroptosis. RIP1-specific inhibitor Necrostatin-1 (NS-1) reversed the AC-induced DNA damage and cell death. Collectively, these findings, for the first time, suggested that AC exerts its antitumor potential through ROS induction and RIP1-dependent necroptosis in breast carcinoma cells.}, }
@article {pmid36738354, year = {2023}, author = {Zhang, Y and Peng, X and Xue, M and Liu, J and Shang, G and Jiang, M and Chen, D and Liu, B and Wang, Y and Jia, X and Xu, J and Zhang, F and Hu, Y}, title = {SARS-COV-2 spike protein promotes RPE cell senescence via the ROS/P53/P21 pathway.}, journal = {Biogerontology}, volume = {24}, number = {5}, pages = {813-827}, pmid = {36738354}, issn = {1573-6768}, mesh = {Animals ; Humans ; *Spike Glycoprotein, Coronavirus/metabolism ; Reactive Oxygen Species/metabolism ; NF-kappa B/metabolism ; Tumor Suppressor Protein p53/metabolism ; Zebrafish ; *COVID-19 ; SARS-CoV-2/metabolism ; Cellular Senescence/physiology ; }, abstract = {SARS-Cov-2 infection, which has caused the COVID-19 global pandemic, triggers cellular senescence. In this study, we investigate the role of the SARS-COV-2 spike protein (S-protein) in regulating the senescence of RPE cells. The results showed that administration or overexpression of S-protein in ARPE-19 decreased cell proliferation with cell cycle arrest at the G1 phase. S-protein increased SA-β-Gal positive ARPE-19 cells with high expression of P53 and P21, senescence-associated inflammatory factors (e.g., IL-1β, IL-6, IL-8, ICAM, and VEGF), and ROS. Elimination of ROS by N-acetyl cysteine (NAC) or knocking down p21 by siRNA diminished S-protein-induced ARPE cell senescence. Both administrated and overexpressed S-protein colocalize with the ER and upregulate ER-stress-associated BIP, CHOP, ATF3, and ATF6 expression. S-protein induced P65 protein nuclear translocation. Inhibition of NF-κB by bay-11-7082 reduced S-protein-mediated expression of senescence-associated factors. Moreover, the intravitreal injection of S-protein upregulates senescence-associated inflammatory factors in the zebrafish retina. In conclusions, the S-protein of SARS-Cov-2 induces cellular senescence of ARPE-19 cells in vitro and the expression of senescence-associated cytokines in zebrafish retina in vivo likely by activating ER stress, ROS, and NF-κb. These results may uncover a potential association between SARS-cov-2 infection and development of AMD.}, }
@article {pmid36736558, year = {2023}, author = {Hao, W and Zhao, C and Li, G and Wang, H and Li, T and Yan, P and Wei, S}, title = {Blue LED light induces cytotoxicity via ROS production and mitochondrial damage in bovine subcutaneous preadipocytes.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {322}, number = {}, pages = {121195}, doi = {10.1016/j.envpol.2023.121195}, pmid = {36736558}, issn = {1873-6424}, mesh = {Animals ; Cattle ; Reactive Oxygen Species/metabolism ; *Oxidative Stress ; *Apoptosis ; Light ; Antioxidants/metabolism ; Autophagy ; }, abstract = {The purpose of this study was to investigate the effect and mechanism of blue light irradiation on bovine subcutaneous preadipocytes. In this study, preadipocytes were divided into dark group (control) and blue light group. Results show that blue light exposure time-dependently reduced the viability of preadipocytes and induced mitochondrial damage, in accompaniment with the accumulation of intracellular reactive oxygen species (ROS). Meanwhile, blue light caused oxidative stress, as evidenced by the increased MDA level, the reduced T-AOC contents, as well as the decreased activities of antioxidant enzymes. Additionally, blue light treatment induced apoptosis and G2/M phase arrest via Bcl-2/Bax/cleaved caspase-3 pathway and P53/GADD45 pathway, respectively. Protein expressions of LC3-II/LC3-I and P62 were up-regulated under blue light exposure, indicating blue light initiated autophagy but impeded autophagic degradation. Moreover, blue light caused an increase in the secretion of pro-inflammatory factors (TNF-α, IL-1β, and IL-6). Pretreatment with N-acetylcysteine (NAC), a potent ROS scavenger, restored the loss of mitochondrial membrane potential (Δψ) and reduced excess ROS. Additionally, the above negative effects of blue light on cells were alleviated after NAC administration. In conclusion, this study demonstrates blue light induces cellular ROS overproduction and Δψ depolarization, resulting in the decrease of cell viability and the activation of apoptosis, autophagy, and inflammation, providing a reference for the application of blue light in the regulation of fat cells in the future.}, }
@article {pmid36728396, year = {2023}, author = {Chen, CH and Hung, KF and Huang, CY and Leong, JL and Chu, YC and Chang, CY and Wang, ML and Chiou, SH and Cheng, YF}, title = {Is N -acetylcysteine effective in treating patients with coronavirus disease 2019? A meta-analysis.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {86}, number = {3}, pages = {274-281}, doi = {10.1097/JCMA.0000000000000869}, pmid = {36728396}, issn = {1728-7731}, mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; Length of Stay ; }, abstract = {BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has brought tremendous challenges to public health and medical systems around the world. The current strategy for drug repurposing has accumulated some evidence on the use of N -acetylcysteine (NAC) in treating patients with COVID-19. However, the evidence remains debated.<br><br>METHODS: We performed the systematic review and meta-analysis that complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Five databases and reference lists were searched from inception to May 14, 2022. Studies evaluating the efficacy of NAC in treating patients with COVID-19 were regarded as eligible. The review was registered prospectively on PROSPERO (CRD42022332791).<br><br>RESULTS: Of 778 records identified from the preliminary search, four studies were enrolled in the final qualitative review and quantitative meta-analysis. A total of 355 patients were allocated into the NAC group and the control group. The evaluated outcomes included intubation rate, improvement, duration of intensive unit stay and hospital stay and mortality. The pooled results showed nonsignificant differences in intubation rate (OR, 0.55; 95% CI, 0.16-1.89; p = 0.34; I2 = 75%), improvement of oxygenation ([MD], 80.84; 95% CI, -38.16 to 199.84; p = 0.18; I2 = 98%), ICU stay (MD, -0.74; 95% CI, -3.19 to 1.71; p = 0.55; I2 = 95%), hospital stay (MD, -1.05; 95% CI, -3.02 to 0.92; p = 0.30; I2 = 90%), and mortality (OR, 0.58; 95% CI, 0.23-1.45; p = 0.24; I2 = 54%). Subsequent trial sequential analysis (TSA) showed conclusive nonsignificant results for mortality, while the TSA for the other outcomes suggested that a larger sample size is essential.<br><br>CONCLUSIONS: The current evidence reveals NAC is not beneficial for treating patients with COVID- 19 with regard to respiratory outcome, mortality, duration of ICU stay and hospital stay.}, }
@article {pmid36723800, year = {2023}, author = {Liu, H and Alhassan, N and Yoon, KT and Almutlaq, L and Lee, SS}, title = {Oxidative stress triggers hyperdynamic circulation via central neural activation in portal hypertensive rats.}, journal = {Hepatology international}, volume = {17}, number = {3}, pages = {689-697}, pmid = {36723800}, issn = {1936-0541}, mesh = {Rats ; Animals ; *Peroxidase/metabolism/pharmacology ; Rats, Sprague-Dawley ; Hydrogen Peroxide/pharmacology ; *Hypertension, Portal ; Hemodynamics ; Portal Vein ; Oxidative Stress ; }, abstract = {BACKGROUND: Hyperdynamic circulation in portal hypertension (PHT) depends on central neural activation. However, the initiating mechanism that signals PHT to the central neural cardiovascular-regulatory centers remains unclear. We aimed to test the hypothesis that oxidative stress in the gut initiates the signal that activates central cardiovascular nuclei in portal hypertensive rats.<br><br>METHODS: Two groups of rats were used. One had portal hypertension produced by partial portal vein ligation, while controls underwent sham operation. Hemodynamics including portal pressure, cardiac output, mean arterial pressure (MAP) and peripheral vascular resistance were measured. Activation of central cardiovascular nuclei was determined by immunohistochemical Fos expression in the paraventricular nucleus (PVN) of the hypothalamus. Myeloperoxidase activity, an oxidative stress marker, was measured in the jejunum. Hydrogen peroxide, the antioxidant N-acetyl-cysteine (NAC) or saline controls were administered for 12-14&#xa0;days by gavage or osmotic minipumps placed in the peritoneal cavity.<br><br>RESULTS: Compared with controls, PHT rats showed increased cardiac output (54.2&#x2009;&#xb1;&#x2009;9.5 vs 33.6&#x2009;&#xb1;&#x2009;2.4&#xa0;ml/min/100&#xa0;g BW, p&#x2009;<&#x2009;0.01), decreased MAP (96.2&#x2009;&#xb1;&#x2009;6.4&#xa0;mmHg vs 103.2&#x2009;&#xb1;&#x2009;7.8, p&#x2009;<&#x2009;0.01) and systemic vascular resistance (1.84&#x2009;&#xb1;&#x2009;0.28 vs 3.14&#x2009;&#xb1;&#x2009;0.19&#xa0;mmHg/min/ml/100&#xa0;g BW, p&#x2009;<&#x2009;0.01). PHT rats had increased jejunal myeloperoxidase and PVN Fos expression. NAC treatment eliminated the hyperdynamic circulation, decreased jejunal myeloperoxidase and PVN Fos expression in PHT rats, but had no effect on sham controls. H2O2 significantly increased PVN Fos expression and decreased MAP.<br><br>CONCLUSION: These results indicate that in PHT, mesenteric oxidative stress is the initial signal that activates chemoreceptors and triggers hyperdynamic circulation by central neural cardiovascular-regulatory centers.}, }
@article {pmid36722116, year = {2023}, author = {Takeuchi, M and Nishisho, T and Toki, S and Kawaguchi, S and Tamaki, S and Oya, T and Uto, Y and Katagiri, T and Sairyo, K}, title = {Blue light induces apoptosis and autophagy by promoting ROS-mediated mitochondrial dysfunction in synovial sarcoma.}, journal = {Cancer medicine}, volume = {12}, number = {8}, pages = {9668-9683}, pmid = {36722116}, issn = {2045-7634}, mesh = {Humans ; Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Sarcoma, Synovial/therapy/pathology ; Apoptosis ; Autophagy ; Mitochondria ; Cell Line, Tumor ; }, abstract = {BACKGROUND: Synovial sarcoma (SS) has limited treatment options and there is an urgent need to develop a novel therapeutic strategy to treat SS. Blue light (BL) has been shown to inhibit the growth of several cancer cells. However, the efficacy of BL in soft tissue sarcomas such as SS has not been demonstrated, and the detailed mechanism underlying the antitumor activity of BL is not fully understood. In this study, we investigated the antitumor effect of BL on SS.<br><br>METHODS: Human SS cell lines were continuously irradiated with BL using light-emitting diodes (LEDs) in an incubator for in vitro analysis. The chicken chorioallantoic membrane (CAM) tumors and xenograft tumors in mice were subjected to daily BL irradiation with LEDs.<br><br>RESULTS: BL caused growth inhibition of SS cells and histological changes in CAM tumors. BL also suppressed the migration and invasion abilities of SS cells. The type of cell death in SS cells was revealed to be apoptosis. Furthermore, BL induced excessive production of reactive oxygen species (ROS) in mitochondria, resulting in oxidative stress and malfunctioned mitochondria. Reducing the production of ROS using N-acetylcysteine (NAC), a ROS scavenger, attenuated the inhibitory effect of BL on SS cells and mitochondrial dysfunction. In addition, BL induced autophagy, which was suppressed by the administration of NAC. The autophagy inhibitor of 3-methyladenine and small interfering RNA against the autophagy marker light chain 3B facilitated apoptotic cell death. Moreover, BL suppressed tumor growth in a mouse xenograft model.<br><br>CONCLUSION: Taken together, our results revealed that BL induced apoptosis via the ROS-mitochondrial signaling pathway, and autophagy was activated in response to the production of ROS, which protected SS cells from apoptosis. Therefore, BL is a promising candidate for the development of an antitumor therapeutic strategy targeting SS.}, }
@article {pmid36716335, year = {2023}, author = {Gaymon, DO and Barndt, R and Stires, H and Riggins, RB and Johnson, MD}, title = {ROS is a master regulator of in vitro matriptase activation.}, journal = {PloS one}, volume = {18}, number = {1}, pages = {e0267492}, pmid = {36716335}, issn = {1932-6203}, support = {R01 CA123223/CA/NCI NIH HHS/United States ; T32 CA009686/CA/NCI NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; }, mesh = {Reactive Oxygen Species/metabolism ; Lapatinib ; Etoposide ; *Phosphatidylinositol 3-Kinases ; *Mitogen-Activated Protein Kinase Kinases ; }, abstract = {Matriptase is a type II transmembrane serine protease that is widely expressed in normal epithelial cells and epithelial cancers. Studies have shown that regulation of matriptase expression and activation becomes deranged in several cancers and is associated with poor disease-free survival. Although the central mechanism of its activation has remained unknown, our lab has previously demonstrated that inflammatory conditions such as intracellular pH decrease strongly induces matriptase activation. In this investigation, we first demonstrate clear matriptase activation following Fulvestrant (ICI) and Tykerb (Lapatinib) treatment in HER2-amplified, estrogen receptor (ER)-positive BT474, MDA-MB-361 and ZR-75-30 or single ER-positive MCF7 cells, respectively. This activation modestly involved Phosphoinositide 3-kinase (PI3K) activation and occurred as quickly as six hours post treatment. We also demonstrate that matriptase activation is not a universal hallmark of stress, with Etoposide treated cells showing a larger degree of matriptase activation than Lapatinib and ICI-treated cells. While etoposide toxicity has been shown to be mediated through reactive oxygen species (ROS) and MAPK/ERK kinase (MEK) activity, MEK activity showed no correlation with matriptase activation. Novelly, we demonstrate that endogenous and exogenous matriptase activation are ROS-mediated in vitro and inhibited by N-acetylcysteine (NAC). Lastly, we demonstrate matriptase-directed NAC treatment results in apoptosis of several breast cancer cell lines either alone or in combination with clinically used therapeutics. These data demonstrate the contribution of ROS-mediated survival, its independence of kinase-mediated survival, and the plausibility of using matriptase activation to indicate the potential success of antioxidant therapy.}, }
@article {pmid36713695, year = {2023}, author = {Mukherjee, S and Sawant, AV and Prassanawar, SS and Panda, D}, title = {Copper-Plumbagin Complex Produces Potent Anticancer Effects by Depolymerizing Microtubules and Inducing Reactive Oxygen Species and DNA Damage.}, journal = {ACS omega}, volume = {8}, number = {3}, pages = {3221-3235}, pmid = {36713695}, issn = {2470-1343}, abstract = {Here, we have synthesized a copper complex of plumbagin (Cu-PLN) and investigated its antiproliferative activities in different cancer cells. The crystal structure of Cu-PLN showed that the complex was square planar with a binding stoichiometry of 1:2 (Cu/Plumbagin). Cu-PLN inhibited the proliferation of human cervical carcinoma (HeLa), human breast cancer (MCF-7), and murine melanoma (B16F10) cells with half-maximal inhibitory concentrations (IC50) of 0.85 ± 0.05, 2.3 ± 0.1, and 1.1 ± 0.1 μM, respectively. Plumbagin inhibited the proliferation of HeLa, MCF-7, and B16F10 cells with IC50 of 7 ± 0.1, 8.2 ± 0.2, and 6.2 ± 0.4 μM, respectively, showing that Cu-PLN is a stronger antiproliferative agent than plumbagin. Interestingly, Cu-PLN showed much stronger toxicity against breast carcinoma and skin melanoma cells than noncancerous breast epithelial and skin fibroblast cells, indicating its specific cytotoxicity toward cancer cells. A short exposure of Cu-PLN triggered microtubule disassembly in cultured cancer cells, and the complex also inhibited the polymerization of purified tubulin much more strongly than plumbagin. Furthermore, Cu-PLN inhibited the binding of colchicine to tubulin. In addition to microtubule depolymerization, the antiproliferative mechanism of Cu-PLN involved induction of reactive oxygen species, reduction of the mitochondrial membrane potential, and DNA damage. Moreover, the cytotoxic effects of Cu-PLN reduced significantly in cells pre-treated with N-acetyl cysteine, suggesting that reactive oxygen species generation is crucial in Cu-PLN's mode of action. Thus, the complexation of plumbagin with copper yields a promising antitumor agent having a stronger antiproliferative activity than cisplatin, a widely used anticancer drug.}, }
@article {pmid36713582, year = {2022}, author = {Brown, K and Jenkins, LMM and Crooks, DR and Surman, DR and Mazur, SJ and Xu, Y and Arimilli, BS and Yang, Y and Lane, AN and Fan, TW and Schrump, DS and Linehan, WM and Ripley, RT and Appella, E}, title = {Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {1094210}, pmid = {36713582}, issn = {2234-943X}, support = {P30 CA177558/CA/NCI NIH HHS/United States ; }, abstract = {TP53 is the most commonly mutated gene in cancer, and gain-of-function mutations have wide-ranging effects. Efforts to reactivate wild-type p53 function and inhibit mutant functions have been complicated by the variety of TP53 mutations. Identified from a screen, the NSC59984 compound has been shown to restore activity to mutant p53 in colorectal cancer cells. Here, we investigated its effects on esophageal adenocarcinoma cells with specific p53 hot-spot mutations. NSC59984 treatment of cells reactivated p53 transcriptional regulation, inducing mitochondrial intrinsic apoptosis. Analysis of its effects on cellular metabolism demonstrated increased utilization of the pentose phosphate pathway and inhibition of glycolysis at the fructose-1,6-bisphosphate to fructose 6-phosphate junction. Furthermore, treatment of cells with NSC59984 increased reactive oxygen species production and decreased glutathione levels; these effects were enhanced by the addition of buthionine sulfoximine and inhibited by N-acetyl cysteine. We found that the effects of NSC59984 were substantially greater in cells harboring the p53 R248W mutation. Overall, these findings demonstrate p53-dependent effects of NSC59984 on cellular metabolism, with increased activity in cells harboring the p53 R248W mutation. This research highlights the importance of defining the mutational status of a particular cancer to create a patient-centric strategy for the treatment of p53-driven cancers.}, }
@article {pmid36708988, year = {2023}, author = {Ono, S and Ogura, J and Sugiura, H and Yamauchi, M and Tanaka, A and Sato, T and Maekawa, M and Yamaguchi, H and Mano, N}, title = {Glutathione depletion results in S-nitrosylation of protein disulfide isomerase in neuroblastoma cells.}, journal = {Life sciences}, volume = {316}, number = {}, pages = {121442}, doi = {10.1016/j.lfs.2023.121442}, pmid = {36708988}, issn = {1879-0631}, mesh = {Humans ; Protein Disulfide-Isomerases/metabolism ; *Alzheimer Disease ; Endoribonucleases ; *Neuroblastoma/pathology ; Protein Serine-Threonine Kinases ; Glutathione ; Glutamates ; }, abstract = {AIMS: Protein disulfide isomerase (PDI) is an essential enzyme involved in oxidative protein folding. PDI is S-nitrosylated in the brains of Alzheimer's disease patients, and S-nitrosylated PDI is considered one of main causes of Alzheimer's disease. However, the mechanisms underlying PDI S-nitrosylation have not yet been elucidated. Because glutathione (GSH) depletion is a pathological feature of Alzheimer's disease, we investigated the effect of GSH depletion on the S-nitrosylation level of PDI.<br><br>MAIN METHODS: SH-SY5Y cells, which is a human derived neuroblastoma cells, were used in this study. Glutamate and buthionine sulfoximine (BSO) were used as GSH depletors. S-nitrosylated PDI was detected by biotin-switch assay.<br><br>KEY FINDINGS: GSH depletion by glutamate, a cystine/glutamate antiporter xCT inhibitor, increased S-nitrosylated PDI at C343 in SH-SY5Y cells, and induced IRE1&#x3b1; phosphorylation. BSO, a &#x3b3;-glutamylcysteine synthetase inhibitor, also increased S-nitrosylated PDI and phosphorylated IRE1&#x3b1; upon GSH depletion. Because S-nitrosylated PDI at C343 is stable in neuro cells, S-nitrosylated PDI by GSH depletion progresses to neurodegeneration by the induction of endoplasmic reticulum stress via phosphorylated IRE1&#x3b1; signaling from the early to late stage. Furthermore, treatment with neohesperidin, but not N-acetylcysteine (NAC), improved PDI S-nitrosylation level in GSH-depleted SH-SY5Y cells because nitrosylated compound of NAC induces PDI S-nitrosylation.<br><br>SIGNIFICANCE: The results of our study provide a new insight into the mechanisms of neurodegeneration, and may be useful for the development of drugs for Alzheimer's diseases.}, }
@article {pmid36708663, year = {2023}, author = {Liu, X and Xi, H and Han, S and Zhang, H and Hu, J}, title = {Zearalenone induces oxidative stress and autophagy in goat Sertoli cells.}, journal = {Ecotoxicology and environmental safety}, volume = {252}, number = {}, pages = {114571}, doi = {10.1016/j.ecoenv.2023.114571}, pmid = {36708663}, issn = {1090-2414}, mesh = {Animals ; Male ; *Zearalenone/toxicity ; Sertoli Cells/metabolism ; Reactive Oxygen Species/metabolism ; Goats/metabolism ; Oxidative Stress ; Apoptosis ; Autophagy ; }, abstract = {Zearalenone (ZEA), one of the non-steroidal estrogen mycotoxin, can cause male reproductive damage and genotoxicity in mammals. Testicular oxidative injury is an important factor causing male sterility. Testicular Sertoli cells are essential for spermatogenesis and male fertility. At present, the mechanism of oxidative injury in dairy goat Sertoli cells after exposure to ZEA remains unclear. This study explored the effects of ZEA on oxidative stress and autophagy in dairy goat Sertoli cells. It was found that treatment of primary Sertoli cells with 25, 50 and 100 μmol/L ZEA for 24 h can promote ROS production, decrease cell viability, antioxidant enzyme activity and mitochondrial membrane potential, induce caspase-dependent cell apoptosis and autophagy activity. ZEA-induced autophagy was confirmed by LC3-I/LC3-II transformation. More importantly, N-acetylcysteine (NAC) pretreatment can remarkably inhibit ZEA-induced oxidative stress, apoptosis and autophagy in Sertoli cells by eliminating ROS. In conclusion, this study indicates that ZEA induces oxidative stress and autophagy in dairy goat Sertoli cells by promoting ROS production.}, }
@article {pmid36708386, year = {2023}, author = {Fernández-Rodríguez, S and Cano-Cebrián, MJ and Esposito-Zapero, C and Pérez, S and Guerri, C and Zornoza, T and Polache, A}, title = {N-Acetylcysteine normalizes brain oxidative stress and neuroinflammation observed after protracted ethanol abstinence: a preclinical study in long-term ethanol-experienced male rats.}, journal = {Psychopharmacology}, volume = {240}, number = {4}, pages = {725-738}, pmid = {36708386}, issn = {1432-2072}, support = {GVA2016-096//Conselleria de Cultura, Educaci&#xf3;n y Ciencia, Generalitat Valenciana/ ; ACIF/2018/039//Conselleria de Cultura, Educaci&#xf3;n y Ciencia, Generalitat Valenciana/ ; UV-INV_AE18-785117//Universitat de Val&#xe8;ncia/ ; }, mesh = {Rats ; Male ; Animals ; *Ethanol ; Rats, Wistar ; *Acetylcysteine/pharmacology ; Alcohol Abstinence ; Neuroinflammatory Diseases ; Brain ; Chronic Disease ; Oxidative Stress ; Glutamates/metabolism ; Alcohol Drinking/drug therapy ; }, abstract = {RATIONALE: Using a preclinical model based on the Alcohol Deprivation Effect (ADE), we have reported that N-Acetylcysteine (NAC) can prevent the relapse-like drinking behaviour in long-term ethanol-experienced male rats.<br><br>OBJECTIVES: To investigate if chronic ethanol intake and protracted abstinence affect several glutamate transporters and whether NAC, administered during the withdrawal period, could restore the ethanol-induced brain potential dysfunctions. Furthermore, the antioxidant and anti-inflammatory effects of NAC during abstinence in rats under the ADE paradigm were also explored.<br><br>METHODS: The expression of GLT1, GLAST and xCT in nucleus accumbens (Nacc) and dorsal striatum (DS) of male Wistar was analysed after water and chronic ethanol intake. We used the model based on the ADE within another cohort of male Wistar rats. During the fourth abstinence period, rats were treated for 9&#xa0;days with vehicle or NAC (60, 100&#xa0;mg/kg; s.c.). The effects of NAC treatment on (i) glutamate transporters expression in the Nacc and DS, (ii) the oxidative status in the hippocampus (Hip) and amygdala (AMG) and (iii) some neuroinflammatory markers in prefrontal cortex (PFC) were tested.<br><br>RESULTS: NAC chronic administration during protracted abstinence restored oxidative stress markers (GSSG and GGSH/GSH) in the Hip. Furthermore, NAC was able to normalize some neuroinflammation markers in PFC without normalizing the observed downregulation of GLT1 and GLAST in Nacc.<br><br>CONCLUSIONS: NAC restores brain oxidative stress and neuroinflammation that we previously observed after protracted ethanol abstinence in long-term ethanol-experienced male rats. This NAC effect could be a plausible mechanism for its anti-relapse effect. Also, brain oxidative stress and neuroinflammation could represent and identify plausible targets for searching new anti-relapse pharmacotherapies.}, }
@article {pmid36708242, year = {2022}, author = {yingBai, Y and meiCheng, Y and Wang, W and Yang, L and Yang, Y}, title = {In vivo and in vitro studies of Alloimperatorin induced autophagy in cervical cancer cells via reactive oxygen species pathway.}, journal = {Bioengineered}, volume = {13}, number = {6}, pages = {14299-14314}, pmid = {36708242}, issn = {2165-5987}, mesh = {Mice ; Animals ; Female ; Humans ; *Uterine Cervical Neoplasms/metabolism ; Reactive Oxygen Species/metabolism ; Mice, Nude ; Autophagy ; Apoptosis ; Cell Line, Tumor ; }, abstract = {Alloimperatorin (Alloi) has been shown to have anti-proliferative effects in our previous studies. we aimed to investigate whether Alloimperatorin induces autophagy through the reactive oxygen species (ROS) pathway and anticancer activity in vivo. The anti-proliferative effect of Alloimperatorin was evaluated using a cell counting kit (CCK-8 kit). Apoptosis was detected using flow cytometry. Confocal microscopy, immunofluorescence, and mRFP-GFP-LC3 lentivirus transfection were used to verify autophagy. Electron microscopy detection of autophagosomes was induced by Alloimperatorin. Western blotting was used to detect autophagy proteins in HeLa and SiHa cells. A xenograft model was used to monitor the inhibitory effect of Alloimperatorin on tumor growth in nude mice. The results showed that Alloimperatorin induced ROS production and inhibited the proliferation of HeLa and SiHa cells. Furthermore, Alloimperatorin increased the apoptosis rate in HeLa and SiHa cells. Confocal microscopy fluorescence indicated that Alloimperatorin increased autophagy fluorescence of HeLa and SiHa cells. mRFP-GFP-LC3 lentivirus transfection and electron microscopy demonstrated that Alloimperatorin increased autophagy in HeLa and SiHa cells. Western blotting showed that Alloimperatorin induced the expression of autophagy proteins in HeLa and SiHa cells. However, N-acetylcysteine reversed the autophagy. These results demonstrate that Alloimperatorin can induce autophagy in HeLa and SiHa cells through the ROS pathway. In vivo xenograft experiments showed that Alloimperatorin could inhibit tumor growth in nude mice. Alloimperatorin is expected to be an effective new drug for cervical cancer treatment.Abbreviations: ROS, reactive oxygen species; Alloi, Alloimperatorin; CCK-8, Cell Counting Kit-8; NAC, N-acetyl-L-cysteine; DCFH-DA, 2,7-dichlorodihydrofluorescein diacetate; OD, optical density; PBS, phosphate buffer solution; BCA, bicinchoninic acid; DAPI, 4,6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide.}, }
@article {pmid36707135, year = {2023}, author = {Sahoo, DK and Chainy, GBN}, title = {Hormone-linked redox status and its modulation by antioxidants.}, journal = {Vitamins and hormones}, volume = {121}, number = {}, pages = {197-246}, doi = {10.1016/bs.vh.2022.10.007}, pmid = {36707135}, issn = {0083-6729}, mesh = {Humans ; Animals ; *Antioxidants/pharmacology/therapeutic use ; Reactive Oxygen Species/pharmacology ; Oxidative Stress/physiology ; Oxidation-Reduction ; *Melatonin/pharmacology ; }, abstract = {Hormones have been considered as key factors involved in the maintenance of the redox status of the body. We are making considerable progress in understanding interactions between the endocrine system, redox status, and oxidative stress with the dynamics of life, which encompasses fertilization, development, growth, aging, and various pathophysiological states. One of the reasons for changes in redox states of vertebrates leading to oxidative stress scenario is the disruption of the endocrine system. Comprehending the dynamics of hormonal status to redox state and oxidative stress in living systems is challenging. It is more difficult to come to a unifying conclusion when some hormones exhibit oxidant properties while others have antioxidant features. There is a very limited approach to correlate alteration in titers of hormones with redox status and oxidative stress with growth, development, aging, and pathophysiological stress. The situation is further complicated when considering various tissues and sexes in vertebrates. This chapter discusses the beneficial impacts of hormones with antioxidative properties, such as melatonin, glucagon, insulin, estrogens, and progesterone, which protect cells from oxidative damage and reduce pathophysiological effects. Additionally, we discuss the protective effects of antioxidants like vitamins A, E, and C, curcumin, tempol, N-acetyl cysteine, α-lipoic acid, date palm pollen extract, resveratrol, and flavonoids on oxidative stress triggered by hormones such as aldosterone, glucocorticoids, thyroid hormones, and catecholamines. Inflammation, pathophysiology, and the aging process can all be controlled by understanding how antioxidants and hormones operate together to maintain cellular redox status. Identifying the hormonal changes and the action of antioxidants may help in developing new therapeutic strategies for hormonal imbalance-related disorders.}, }
@article {pmid36705628, year = {2023}, author = {Zhao, Y and Huang, H and Lv, N and Huang, C and Chen, H and Xing, H and Guo, C and Li, N and Zhao, D and Chen, X and Zhang, Y}, title = {Glutathione S-Transferases Mediate In Vitro and In Vivo Inactivation of Genipin: Implications for an Underlying Detoxification Mechanism.}, journal = {Journal of agricultural and food chemistry}, volume = {71}, number = {5}, pages = {2399-2410}, doi = {10.1021/acs.jafc.2c08175}, pmid = {36705628}, issn = {1520-5118}, mesh = {Rats ; Animals ; *Liver/metabolism ; Glutathione Transferase/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism ; Glutathione/metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {Genipin (GP), the reactive metabolite of geniposide (GE), is responsible for GE-induced hepatotoxicity. As a potential detoxification pathway, the inactivation of GP by glutathione S-transferases (GSTs) has not yet been characterized. In this study, the thiol-GSH conjugates of GP, M532-1 and M532-2 were first identified and the catalytic activities of GSTs were investigated both in vitro and in vivo. GSTA1-1 and GSTA4-4 showed high activity in the formation of both thiol-GSH conjugates, whereas GSTA4-4 specifically catalyzed M532-2 formation in vitro. The active GST isoforms protect against alkylation of N-acetylcysteine (NAC), a classic model nucleophile. GST inhibition attenuated M532-1 formation in rat bile, confirming the in vivo catalytic role of GSTs. In conclusion, this study demonstrated the inactivation of GP by GSTs and implied that interindividual variability of GSTs may be a risk factor for susceptibility to GE-induced hepatotoxicity.}, }
@article {pmid36703750, year = {2022}, author = {Huang, Z and Wang, H and Chun, C and Li, X and Xu, S and Zhao, Y}, title = {Self-assembled FGF21 nanoparticles alleviate drug-induced acute liver injury.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1084799}, pmid = {36703750}, issn = {1663-9812}, abstract = {Acetaminophen (N-acetyl-p-aminophenol, APAP) is a common antipyretic agent and analgesic. An overdose of APAP can result in acute liver injury (ALI). Oxidative stress and inflammation are central to liver injury. N-acetylcysteine (NAC), a precursor of glutathione, is used commonly in clinical settings. However, the window of NAC treatment is limited, and more efficacious alternatives must be found. Endogenous cytokines such as fibroblast growth factor (FGF) 21 can improve mitochondrial function while decreasing intracellular oxidative stress and inflammatory responses, thereby exhibiting antioxidant-like effects. In this study, self-assembled nanoparticles comprising chitosan and heparin (CH) were developed to deliver FGF21 (CH-FGF21) to achieve the sustained release of FGF21 and optimize the in vivo distribution of FGF21. CH-FGF21 attenuated the oxidative damage and intracellular inflammation caused by APAP to hepatocytes effectively. In a murine model of APAP-induced hepatotoxicity, CH-FGF21 could alleviate ALI progression and promote the recovery of liver function. These findings demonstrated that a simple assembly of CH nanoparticles carrying FGF21 could be applied for the treatment of liver diseases.}, }
@article {pmid36700765, year = {2023}, author = {Jiang, X and Li, Y and Fu, D and You, T and Wu, S and Xin, J and Wen, J and Huang, Y and Hu, C}, title = {Caveolin-1 ameliorates acetaminophen-aggravated inflammatory damage and lipid deposition in non-alcoholic fatty liver disease via the ROS/TXNIP/NLRP3 pathway.}, journal = {International immunopharmacology}, volume = {114}, number = {}, pages = {109558}, doi = {10.1016/j.intimp.2022.109558}, pmid = {36700765}, issn = {1878-1705}, mesh = {Mice ; Animals ; *Non-alcoholic Fatty Liver Disease/drug therapy/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Acetaminophen ; Reactive Oxygen Species/metabolism ; Caveolin 1/metabolism ; Inflammasomes/metabolism ; Pyroptosis ; Thioredoxins/genetics/metabolism ; RNA, Small Interfering ; *Chemical and Drug Induced Liver Injury/drug therapy ; Lipids ; Carrier Proteins/genetics ; }, abstract = {The overuse of acetaminophen (APAP) may cause more severe hepatotoxicity in patients with non-alcoholic fatty liver disease (NAFLD). Caveolin-1 (CAV1), is an essential regulator of metabolic function, which can alleviate liver damage by scavenging reactive oxygen species (ROS). Evidence suggests that the NOD-like receptor family pyrin domain-containing 3 (NLRP3) -mediated pyroptosis is involved in the development of NAFLD. Moreover, thioredoxin-interactive protein (TXNIP) activation is a key event linking ROS to NLRP3 inflammasome. However, whether CAV1 alleviates APAP-aggravated hepatotoxicity in NAFLD via the ROS/TXNIP/NLRP3 pathway remains unclear. An in vivo fatty liver model was established by feeding mice a high-fat diet for 56 days. Additionally, using in vitro approach, AML-12 cells were incubated with free fatty acids for 48 h and APAP was added during the last 24 h. We found that the overuse of APAP in NAFLD not only induced oxidative stress, but also increased TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition. In addition to inhibiting ROS generation and lipid deposition, overexpression of CAV1 reduced the elevated levels of TXNIP expression and NLRP3-mediated pyroptosis. However, the effect of CAV1 on TXNIP expression, NLRP3-mediated pyroptosis, and lipid deposition was reversed by CAV1 small interfering RNA (siRNA) intervention. Finally, N-acetyl cysteine (NAC) treatment reduced CAV1 siRNA-mediated changes in TXNIP expression and NLRP3-mediated pyroptosis levels. These results demonstrate that the inhibitory effect of CAV1 on NLRP3-mediated pyroptosis may be mediated through the ROS/TXNIP axis. Moreover, the current study provides novel mechanistic insights into the protective effects of CAV1 on APAP-aggravated hepatotoxicity in NAFLD.}, }
@article {pmid36700727, year = {2023}, author = {Grant, JE and Chamberlain, SR}, title = {Monoamine Oxidase Inhibitors for Trichotillomania: A Case Series.}, journal = {Journal of clinical psychopharmacology}, volume = {43}, number = {2}, pages = {149-151}, doi = {10.1097/JCP.0000000000001654}, pmid = {36700727}, issn = {1533-712X}, mesh = {United States ; Humans ; Monoamine Oxidase Inhibitors/therapeutic use ; *Trichotillomania/drug therapy ; Phenelzine ; *Obsessive-Compulsive Disorder/drug therapy ; Selective Serotonin Reuptake Inhibitors ; }, abstract = {PURPOSE/BACKGROUND: Despite several decades of research, there are no US Food and Drug Administration-approved medications for trichotillomania or medications generally approved in other geographical jurisdictions. Monoamine oxidase inhibitors show efficacy in the treatment of depression and some possible promise for obsessive compulsive disorder.<br><br>METHODS/PROCEDURES: We present new data from a case series collected in a specialty clinical practice over a 4-year period.<br><br>FINDINGS/RESULTS: In 5 treatment-resistant patients whose trichotillomania had not improved with at least 1 course of cognitive behavior therapy and trials of n -acetyl cysteine, an antipsychotic, and a serotonin selective reuptake inhibitor, 2 had marked clinical improvement (>40% improvement) on phenelzine, 1 improved on tranylcypromine, and 2 showed no improvement (<10%) on phenelzine. In 2 of the 3 patients who experienced improvement, there was co-occurring depression.<br><br>IMPLICATIONS/CONCLUSIONS: Monoamine oxidase inhibitors in trichotillomania may deserve large-scale randomized controlled trials, particularly in specialist settings where first-line interventions have proven inadequate to manage severe symptoms.}, }
@article {pmid36700278, year = {2023}, author = {Özdemir, M and Birinci, B and Haberal, B and Ok Atılgan, A and Demirkale, &#x130;}, title = {In vivo study of the role of hyaluronic acid, N-acetyl cysteine, and deproteinized calf serum on injury-induced cartilage degeneration.}, journal = {Joint diseases and related surgery}, volume = {34}, number = {1}, pages = {158-165}, pmid = {36700278}, issn = {2687-4792}, mesh = {Animals ; Rats ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; *Cartilage, Articular/injuries ; *Hyaluronic Acid/pharmacology/therapeutic use ; }, abstract = {OBJECTIVES: The aim of this study was to compare the effects of hyaluronic acid (HA), N-acetyl cysteine (NAC), and deproteinized calf serum on cartilage healing after the creation of traumatic cartilage injury in a rat model.<br><br>MATERIALS AND METHODS: A total of 48 rats, each weighing an average of 350 g, were randomly separated into four groups of 12. An osteochondral defect was created, 2-mm-wide and 3-mm deep in each rat. Injections were made to the knees of the rats as saline solution in Group 1, deproteinized calf serum in Group 2, NAC in Group 3, and HA in Group 4. At the end of 12 weeks, all rats were sacrificed and tissues were evaluated histologically.<br><br>RESULTS: The HA group had a better cell morphology, tissue morphology, surface architecture, and vascularity than the other groups (p<0.001). Matrix staining, chondrocyte clustering, and the assessment scores of the mid, deep, superficial zones, and overall were higher in the HA group than in the other groups (p<0.001). The NAC showed a better tissue morphology, cell morphology, and vascularity than the control group (p=0.003, p<0.001, and p<0.001, respectively).<br><br>CONCLUSION: Hyaluronic acid was the most effective agent in cartilage healing compared to NAC and deproteinized calf serum. In addition, the NAC was more effective compared to the control group.}, }
@article {pmid36689858, year = {2023}, author = {Lin, CL and Yu, CI and Lee, TH and Chuang, JM and Han, KF and Lin, CS and Huang, WP and Chen, JY and Chen, CY and Lin, MY and Lee, CH}, title = {Plumbagin induces the apoptosis of drug-resistant oral cancer in vitro and in vivo through ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {111}, number = {}, pages = {154655}, doi = {10.1016/j.phymed.2023.154655}, pmid = {36689858}, issn = {1618-095X}, mesh = {Animals ; Mice ; Reactive Oxygen Species/metabolism ; *Zebrafish/metabolism ; Apoptosis ; Cell Line, Tumor ; Mitochondria ; *Mouth Neoplasms/drug therapy/metabolism ; Endoplasmic Reticulum Stress ; }, abstract = {BACKGROUND: Oral cancer is one of the leading causes of cancer-related deaths worldwide. Chemotherapy is widely used in the treatment of oral cancer, but its clinical efficacy is limited by drug resistance. Hence, novel compounds capable of overcoming drug-resistance are urgently needed.<br><br>PURPOSE: Plumbagin (PG), a natural compound isolated from Plumbago zeylanica L, has been used to treat various cancers. In this study, we investigated the anticancer effects of PG on drug-resistant oral cancer (CR-SAS) cells, as well as the underlying mechanism.<br><br>METHODS: MTT assays were used to evaluate the effect of PG on the viability of CR-SAS cells. Apoptosis and reactive oxygen species (ROS) production by the cells were determined using flow cytometry. Protein expression levels were detected by western blotting.<br><br>RESULTS: The results show that PG reduces the viability and causes the apoptosis of CR-SAS cells. PG is able to induce intracellular and mitochondrial ROS generation that leads to mitochondrial dysfunction. Furthermore, endoplasmic reticulum (ER) stress was triggered in PG-treated CR-SAS cells. The inhibition of ROS using&#xa0;N-acetylcysteine (NAC) abrogated the PG-induced ER stress and apoptosis, as well as the reduction in cell viability.&#xa0;Meanwhile, similar results were observed both in zebrafish and in murine models of drug-resistant oral cancer.<br><br>CONCLUSION: Our results indicate that PG induces the apoptosis of CR-SAS cells via the ROS-mediated ER stress pathway and mitochondrial dysfunction. It will be interesting to develop the natural compound PG for the treatment of drug-resistant oral cancer.}, }
@article {pmid36687698, year = {2022}, author = {Wang, W and Guan, J and Feng, Y and Nie, L and Xu, Y and Xu, H and Fu, F}, title = {Polystyrene microplastics induced nephrotoxicity associated with oxidative stress, inflammation, and endoplasmic reticulum stress in juvenile rats.}, journal = {Frontiers in nutrition}, volume = {9}, number = {}, pages = {1059660}, pmid = {36687698}, issn = {2296-861X}, abstract = {INTRODUCTION: Unintended intake of microplastic particles has been demonstrated to exert adverse health effects, however, studies on relevant nephrotoxicity in juvenile mammals are lacking.<br><br>METHODS: Therefore, we investigated the potential nephrotoxicity of oral-exposed polystyrene microplastics (PSMPs) (1,000 nm, 2.0 mg/kg/d) for 28 days in juvenile rats. Levels of oxidative stress, inflammation, and endoplasmic reticulum (ER) stress in kidneys were analyzed.<br><br>RESULTS AND DISCUSSION: Results revealed that PSMPs noticeably decreased the growth rate of bodyweight, and organ index of the kidney, cardiac, and ovary. The intestinal injury caused by PSMPs exposure was also observed, which was distinctly alleviated with N-acetyl-cysteine (NAC) and Salubrinal (Sal) treatment compared with the single PSMPs group. PSMPs caused histological lesions of the kidney via disrupting the serum blood urea nitrogen (BUN), creatinine (CRE), and pro-inflammatory mediators IL-1&#x3b2;, IL-6, and TNF-&#x3b1;. Furthermore, PSMPs exposure induced ER stress and inflammation presumably potentially mediated by oxidative stress in kidneys of rats. Eventually, PSMPs also promoted renal cells apoptosis, manifested as an obvious increase in the number of positive cells for the dUTP nick end labeling of Terminal deoxynucleotidyl transferase, which also can be confirmed by the elevated expression of genes associated with apoptosis Bcl-2, Bax, Caspase-12, Caspase-9, Caspase-3, and IHC score of Caspase-12 in the PSMPs group. Supplementation of NAC and Sal not only ameliorated the PSMPs-induced oxidative stress and ER stress but also the inflammation and apoptosis in the kidney. Collectively, this study suggested that PSMPs caused nephrotoxicity in juvenile rats potentially through oxidative damage and ER stress, which call for greater efforts to be taken on regulating the PSMPs ingestion in children.}, }
@article {pmid36686028, year = {2023}, author = {Dalai, MK and Singh, GK and Bairwa, Y and Chauhan, SS and Ingle, M}, title = {Premedication with simethicone and N-acetyl cysteine in esophagogastroduodenoscopy: Is it time to use it in practice?.}, journal = {Endoscopy international open}, volume = {11}, number = {1}, pages = {E81}, pmid = {36686028}, issn = {2364-3722}, }
@article {pmid36678548, year = {2022}, author = {Song, F and Lin, J and Zhang, H and Guo, Y and Mao, Y and Liu, Z and Li, G and Wang, Y}, title = {Long-Term Sleep Deprivation-Induced Myocardial Remodeling and Mitochondrial Dysfunction in Mice Were Attenuated by Lipoic Acid and N-Acetylcysteine.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {16}, number = {1}, pages = {}, pmid = {36678548}, issn = {1424-8247}, support = {82270417;81970283;81870627//National Natural Science Foundation of China/ ; 2018YFA0107304//the National Key R&amp;D Program of China/ ; 20720202013//Fundamental Research Funds for the Central Universities/ ; }, abstract = {The impact of long-term sleep deprivation on the heart and its underlying mechanisms are poorly understood. The present study aimed to investigate the impact of chronic sleep deprivation (CSD) on the heart and mitochondrial function and explore an effective drug for treating CSD-induced heart dysfunction. We used a modified method to induce CSD in mice; lipoic acid (LA) and N-acetylcysteine (NAC) were used to treat CSD mice. Echocardiography, hematoxylin-eosin (H&amp;E) staining, Sirius red staining, and immunohistochemistry were used to determine heart function and cardiac fibrosis. The serum levels of brain natriuretic peptide (BNP), superoxide Dismutase (SOD), micro malondialdehyde (MDA), and glutathione (GSH) were measured to determine cardiovascular and oxidative stress-related damage. Transmission electron microscopy was used to investigate mitochondrial damage. RNA-seq and Western blotting were used to explore related pathways. We found that the left ventricular ejection fraction (LVEF) and fraction shortening (LVFS) values were significantly decreased and myocardial hypertrophy was induced, accompanied by damaged mitochondria, elevated reactive oxygen species (ROS), and reduced SOD levels. RNA-sequence analysis of the heart tissue showed that various differentially expressed genes in the metabolic pathway were enriched. Sirtuin 1 (Sirt1) and Glutathione S-transferase A3 (Gsta3) may be responsible for CSD-induced heart and mitochondrial dysfunction. Pharmacological inhibition of ROS by treating CSD mice with LA and NAC effectively reduced heart damage and mitochondrial dysfunction by regulating Sirt1 and Gsta3 expression. Our data contribute to understanding the pathways of CSD-induced heart dysfunction, and pharmacological targeting to ROS may represent a strategy to prevent CSD-induced heart damage.}, }
@article {pmid36672522, year = {2022}, author = {Teschke, R}, title = {Treatment of Drug-Induced Liver Injury.}, journal = {Biomedicines}, volume = {11}, number = {1}, pages = {}, pmid = {36672522}, issn = {2227-9059}, abstract = {Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.}, }
@article {pmid36672389, year = {2023}, author = {Schlörmann, W and Horlebein, C and Hübner, SM and Wittwer, E and Glei, M}, title = {Potential Role of ROS in Butyrate- and Dietary Fiber-Mediated Growth Inhibition and Modulation of Cell Cycle-, Apoptosis- and Antioxidant-Relevant Proteins in LT97 Colon Adenoma and HT29 Colon Carcinoma Cells.}, journal = {Cancers}, volume = {15}, number = {2}, pages = {}, pmid = {36672389}, issn = {2072-6694}, abstract = {The aim of the present study was to examine whether reactive oxygen species (ROS) contribute to chemopreventive effects of fermentation supernatants (FS) of different dietary fibers (Synergy1[®], oat-, barley-, yeast β-glucan, Curdlan) and butyrate as a fermentation metabolite. LT97 and HT29 cells were treated with butyrate and FS alone or with N-acetyl-cysteine (NAC) and their impact on ROS formation, cell growth, and protein expression (Cyclin D2, p21, PARP, Bid, GPx2) was investigated. Butyrate and FS significantly decreased cell growth. ROS levels were significantly increased, particularly in LT97 cells, while co-treatment with NAC decreased ROS formation and growth inhibitory effects in both cell lines. After treatment with butyrate and FS, Cyclin D2 expression was reduced in LT97 cells and p21 expression was increased in both cell lines. Levels of full-length PARP and Bid were decreased, while levels of cleaved PARP were enhanced. GPx2 expression was significantly reduced by fiber FS in HT29 cells. A notable effect of NAC on butyrate- and FS-modulated protein expression was observed exclusively for PARP and Bid in HT29 cells. From the present results, a contribution of ROS to growth inhibitory and apoptotic effects of butyrate and FS on LT97 and HT29 cells cannot be excluded.}, }
@article {pmid36671018, year = {2023}, author = {Kim, JE and Park, H and Kang, TC}, title = {Peroxiredoxin 6 Regulates Glutathione Peroxidase 1-Medited Glutamine Synthase Preservation in the Hippocampus of Chronic Epilepsy Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36671018}, issn = {2076-3921}, support = {No. 2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; }, abstract = {Clasmatodendrosis (an autophagic astroglial degeneration) plays an important role in the regulation of spontaneous seizure duration but not seizure frequency or behavioral seizure severity in chronic epilepsy rats. Recently, it has been reported that N-acetylcysteine (NAC), a precursor to glutathione (GSH), attenuates clasmatodendritic degeneration and shortens spontaneous seizure duration in chronic epilepsy rats, although the underlying mechanisms of its anti-convulsive effects are not fully understood. To elucidate this, the present study was designed to investigate whether NAC affects astroglial glutamine synthase (GS) expression mediated by GSH peroxidase 1 (GPx1) and/or peroxiredoxin 6 (Prdx6) in the epileptic hippocampus. As compared to control animals, GS and GPx1 expressions were upregulated in reactive CA1 astrocytes of chronic epilepsy rats, while their expressions were significantly decreased in clasmatodendritic CA1 astrocytes and reactive astrocytes within the molecular layer of the dentate gyrus. Prdx6 expression was increased in reactive CA1 astrocytes as well as clasmatodendritic CA1 astrocytes. In the molecular layer of the dentate gyrus, Prdx6 expression levels were similar to those in control animals. NAC ameliorated clasmatodendrosis through the increment of GS and GPx1 expressions, while it abolished Prdx6 upregulation. 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) alleviated clasmatodendrosis by enhancing GPx1 and GS expressions in clasmatodendritic CA1 astrocytes without changing the Prdx6 level. NAC or MJ33 did not affect GS, GPx1 and Prdx6 expression in astrocytes within the molecular layer of the dentate gyrus. These findings indicate that upregulated aiPLA2 activity of Prdx6 may abolish GPx1-mediated GS preservation and lead to clasmatodendrosis in CA1 astrocytes, which would extend spontaneous seizure duration due to impaired glutamate-glutamine conversion regulated by GS. Therefore, the present data suggest that aiPLA2 activity of Prdx6 in astrocytes may be one of the upstream effectors of seizure duration in the epileptic hippocampus.}, }
@article {pmid36671002, year = {2023}, author = {Chhunchha, B and Kubo, E and Krueger, RR and Singh, DP}, title = {Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36671002}, issn = {2076-3921}, support = {EY024589/EY/NEI NIH HHS/United States ; UNMC//UNMC/ ; }, abstract = {A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2's activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders.}, }
@article {pmid36670992, year = {2023}, author = {Mursaleen, L and Chan, SHY and Noble, B and Somavarapu, S and Zariwala, MG}, title = {Curcumin and N-Acetylcysteine Nanocarriers Alone or Combined with Deferoxamine Target the Mitochondria and Protect against Neurotoxicity and Oxidative Stress in a Co-Culture Model of Parkinson's Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36670992}, issn = {2076-3921}, abstract = {As the blood-brain barrier (BBB) prevents most compounds from entering the brain, nanocarrier delivery systems are frequently being explored to potentially enhance the passage of drugs due to their nanometer sizes and functional characteristics. This study aims to investigate whether Pluronic® F68 (P68) and dequalinium (DQA) nanocarriers can improve the ability of curcumin, n-acetylcysteine (NAC) and/or deferoxamine (DFO), to access the brain, specifically target mitochondria and protect against rotenone by evaluating their effects in a combined Transwell® hCMEC/D3 BBB and SH-SY5Y based cellular Parkinson’s disease (PD) model. P68 + DQA nanoformulations enhanced the mean passage across the BBB model of curcumin, NAC and DFO by 49%, 28% and 49%, respectively (p < 0.01, n = 6). Live cell mitochondrial staining analysis showed consistent co-location of the nanocarriers within the mitochondria. P68 + DQA nanocarriers also increased the ability of curcumin and NAC, alone or combined with DFO, to protect against rotenone induced cytotoxicity and oxidative stress by up to 19% and 14% (p < 0.01, n = 6), as measured by the MTT and mitochondrial hydroxyl radical assays respectively. These results indicate that the P68 + DQA nanocarriers were successful at enhancing the protective effects of curcumin, NAC and/or DFO by increasing the brain penetrance and targeted delivery of the associated bioactives to the mitochondria in this model. This study thus emphasises the potential effectiveness of this nanocarrier strategy in fully utilising the therapeutic benefit of these antioxidants and lays the foundation for further studies in more advanced models of PD.}, }
@article {pmid36670939, year = {2022}, author = {Campesi, I and Brunetti, A and Capobianco, G and Galistu, A and Montella, A and Ieri, F and Franconi, F}, title = {Sex Differences in X-ray-Induced Endothelial Damage: Effect of Taurine and N-Acetylcysteine.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36670939}, issn = {2076-3921}, abstract = {Ionizing radiation (IR) can induce some associated pathological conditions due to numerous cell damages. The influence of sex is scarcely known, and even less known is whether the effect of antioxidants is sex-dependent. Given the increased use of IR, we investigated whether male human umbilical vein endothelial cells (MHUVECs) and female human umbilical vein endothelial cells (FHUVECs) respond differently to IR exposure and whether the antioxidants 10 mM taurine (TAU) and 5 mM N-acetylcysteine (NAC) can prevent IR-induced damage in a sex-dependent way. In untreated cells, sex differences were observed only during autophagy, which was higher in FHUVECs. In non-irradiated cells, preincubation with TAU and NAC did not modify viability, lactate dehydrogenase (LDH) release, migration, or autophagy, whereas only NAC increased malondialdehyde (MDA) levels in FHUVECs. X-ray irradiation increased LDH release and reduced viability and migration in a sex-independent manner. TAU and NAC did not affect viability while reduced LDH release in irradiated cells: they have the same protective effect in FHUVECs, while, TAU was more protective than NAC in male cells.. Moreover, TAU and NAC significantly promoted the closure of wounds in both sexes in irradiated cells, but NAC was more effective at doing this in FHUVECs. In irradiated cells, TAU did not change autophagy, while NAC attenuated the differences between the sexes. Finally, NAC significantly decreased MDA in MHUVECs and increased MDA in FHUVECs. In conclusion, FHUVECs appear to be more susceptible to IR damage, and the effects of the two antioxidants present some sex differences, suggesting the need to study the influence of sex in radiation mitigators.}, }
@article {pmid36670915, year = {2022}, author = {Lemminger, AK and Fiorenza, M and Eibye, K and Bangsbo, J and Hostrup, M}, title = {High-Intensity Exercise Training Alters the Effect of N-Acetylcysteine on Exercise-Related Muscle Ionic Shifts in Men.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {12}, number = {1}, pages = {}, pmid = {36670915}, issn = {2076-3921}, abstract = {This study investigated whether high-intensity exercise training alters the effect of N-acetylcysteine (a precursor of antioxidant glutathione) on exercise-related muscle ionic shifts. We assigned 20 recreationally-active men to 6 weeks of high-intensity exercise training, comprising three weekly sessions of 4-10 × 20-s all-out bouts interspersed by 2 min recovery (SET, n = 10), or habitual lifestyle maintenance (n = 10). Before and after SET, we measured ionic shifts across the working muscle, using leg arteriovenous balance technique, during one-legged knee-extensor exercise to exhaustion with and without N-acetylcysteine infusion. Furthermore, we sampled vastus lateralis muscle biopsies for analyses of metabolites, mitochondrial respiratory function, and proteins regulating ion transport and antioxidant defense. SET lowered exercise-related H[+], K[+], lactate[-], and Na[+] shifts and enhanced exercise performance by ≈45%. While N-acetylcysteine did not affect exercise-related ionic shifts before SET, it lowered H[+], HCO3[-], and Na[+] shifts after SET. SET enhanced muscle mitochondrial respiratory capacity and augmented the abundance of Na[+]/K[+]-ATPase subunits (α1 and β1), ATP-sensitive K[+] channel subunit (Kir6.2), and monocarboxylate transporter-1, as well as superoxide dismutase-2 and glutathione peroxidase-1. Collectively, these findings demonstrate that high-intensity exercise training not only induces multiple adaptations that enhance the ability to counter exercise-related ionic shifts but also potentiates the effect of N-acetylcysteine on ionic shifts during exercise.}, }
@article {pmid36670802, year = {2023}, author = {Zhang, Y and Tian, J and Wang, C and Wu, T and Yi, D and Wang, L and Zhao, D and Hou, Y}, title = {N-Acetylcysteine Administration Improves the Redox and Functional Gene Expression Levels in Spleen, Mesenteric Lymph Node and Gastrocnemius Muscle in Piglets Infected with Porcine Epidemic Diarrhea Virus.}, journal = {Animals : an open access journal from MDPI}, volume = {13}, number = {2}, pages = {}, pmid = {36670802}, issn = {2076-2615}, support = {32172763//National Natural Science Foundation of China/ ; 32072762//National Natural Science Foundation of China/ ; }, abstract = {Our previous study reported that N-acetylcysteine (NAC) administration improved the function of intestinal absorption in piglets infected with porcine epidemic diarrhea virus (PEDV). However, the effects of NAC administration on the functions of other tissues and organs in PEDV-infected piglets have not been reported. In this study, the effects of NAC on the liver, spleen, lung, lymph node, and gastrocnemius muscle in PEDV-infected piglets were investigated. Thirty-two 7-day-old piglets with similar body weights were randomly divided into one of four groups: Control group, NAC group, PEDV group, and PEDV+NAC group (eight replicates per group and one pig per replicate). The trial had a 2 × 2 factorial design consisting of oral administration of 0 or 25 mg/kg body weight NAC and oral administration of 0 or 1.0 × 10[4.5] TCID50 PEDV. The trial lasted 12 days. All piglets were fed a milk replacer. On days 5-9 of the trial, piglets in the NAC and PEDV + NAC groups were orally administered NAC once a day; piglets in the control and PEDV groups were orally administered the same volume of saline. On day 9 of trial, piglets in the PEDV and PEDV+NAC groups were orally administrated 1.0 × 10[4.5] TCID50 PEDV, and the piglets in the control and NAC groups were orally administrated the same volume of saline. On day 12 of trial, samples, including of the liver, spleen, lung, lymph node, and gastrocnemius muscle, were collected. PEDV infection significantly increased catalase activity but significantly decreased the mRNA levels of Keap1, Nrf2, HMOX2, IFN-α, MX1, IL-10, TNF-α, S100A12, MMP3, MMP13, TGF-β, and GJA1 in the spleens of piglets. NAC administration ameliorated abnormal changes in measured variables in the spleens of PEDV-infected piglets. In addition, NAC administration also enhanced the antioxidant capacity of the mesenteric lymph nodes and gastrocnemius muscles in PEDV-infected piglets. Collectively, these novel results revealed that NAC administration improved the redox and functional gene expression levels in the spleen, mesenteric lymph nodes, and gastrocnemius muscle in PEDV-infected piglets.}, }
@article {pmid36670547, year = {2023}, author = {Luo, G and Huang, L and Zhang, Z}, title = {The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {248}, number = {5}, pages = {412-424}, pmid = {36670547}, issn = {1535-3699}, mesh = {Humans ; *Acetaminophen/adverse effects ; Oxidative Stress ; *Chemical and Drug Induced Liver Injury/drug therapy ; Acetylcysteine/therapeutic use ; }, abstract = {Acetaminophen (APAP), a widely used antipyretic and analgesic drug in clinics, is relatively safe at therapeutic doses; however, APAP overdose may lead to fatal acute liver injury. Currently, N-acetylcysteine (NAC) is clinically used as the main antidote for APAP poisoning, but its therapeutic effect remains limited owing to rapid disease progression and the general diagnosis of advanced poisoning. As is well known, APAP-induced hepatotoxicity (AIH) is mainly caused by the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), and the toxic mechanisms of AIH are complicated. Several cellular processes are involved in the pathogenesis of AIH, including liver metabolism, mitochondrial oxidative stress and dysfunction, sterile inflammation, endoplasmic reticulum stress, autophagy, and microcirculation dysfunction. Mitochondrial oxidative stress and dysfunction are the major cellular events associated with APAP-induced liver injury. Many biomolecules involved in these biological processes are potential therapeutic targets for AIH. Therefore, there is an urgent need to comprehensively clarify the molecular mechanisms underlying AIH and to explore novel therapeutic strategies. This review summarizes the various cellular events involved in AIH and discusses their potential therapeutic targets, with the aim of providing new ideas for the treatment of AIH.}, }
@article {pmid36662362, year = {2023}, author = {Zhang, Q and Wang, M and Hu, X and Yan, A and Ho, PL and Li, H and Sun, H}, title = {Gold drugs as colistin adjuvants in the fight against MCR-1 producing bacteria.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {28}, number = {2}, pages = {225-234}, pmid = {36662362}, issn = {1432-1327}, support = {R7070-18//Research Grants Council, University Grants Committee/ ; 17308921//Research Grants Council, University Grants Committee/ ; F-HKU704/19//Research Grants Council, University Grants Committee/ ; 2122-7S04//Research Grants Council, University Grants Committee/ ; Norman//The University of Hong Kong/ ; Cecilia Yip Foundation//The University of Hong Kong/ ; CID-HKU-1-13//Health and Medical Research Fund/ ; 18171042//Health and Medical Research Fund/ ; }, mesh = {*Colistin/pharmacology ; Anti-Bacterial Agents/pharmacology ; Bacteria ; Gold/pharmacology ; Drug Resistance, Bacterial/genetics ; Plasmids ; *Escherichia coli Proteins/chemistry ; Microbial Sensitivity Tests ; }, abstract = {The emergence and rapid spread of the mobile colistin resistance gene mcr-1 among bacterial species and hosts significantly challenge the efficacy of "last-line" antibiotic colistin. Previously, we reported silver nitrate and auranofin serve as colistin adjuvants for combating mcr-1-positive bacteria. Herein, we uncovered more gold-based drugs and nanoparticles, and found that they exhibited varying degree of synergisms with colistin on killing mcr-1-positive bacteria. However, pre-activation of the drugs by either glutathione or N-acetyl cysteine, thus releasing and accumulating gold ions, is perquisite for their abilities to substitute zinc cofactor from MCR-1 enzyme. X-ray crystallography and biophysical studies further supported the proposed mechanism. This study not only provides basis for combining gold-based drugs and colistin for combating mcr-1-positive bacterial infections, but also undoubtedly opens a new horizon for metabolism details of gold-based drugs in overcoming antimicrobial resistance.}, }
@article {pmid36652130, year = {2023}, author = {Xu, H and Shen, X and Li, X and Yang, X and Chen, C and Luo, D}, title = {The natural product dehydrocurvularin induces apoptosis of gastric cancer cells by activating PARP-1 and caspase-3.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {28}, number = {3-4}, pages = {525-538}, pmid = {36652130}, issn = {1573-675X}, mesh = {Humans ; Apoptosis ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; *Stomach Neoplasms/drug therapy/genetics ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Caspase 3/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Apoptosis Inducing Factor/genetics/metabolism ; *Antineoplastic Agents/pharmacology ; }, abstract = {The natural product dehydrocurvularin (DSE2) is a fungal-derived macrolide with potent anticancer activity, but the mechanism is still unclear. We found that DSE2 effectively inhibited the growth of gastric cancer cells and induced the apoptosis by activating Poly(ADP-ribose) polymerase 1 (PARP-1) and caspase-3. Pharmacological inhibition and genetic knockdown with PARP-1 or caspase-3 suppressed DSE2-induced apoptosis. PARP-1 was previously reported to be cleaved into fragments during apoptosis. However, PARP-1 was barely cleaved in DSE2-induced apoptosis. DSE2 induced PARP-1 activation as indicated by rapid depletion of NAD[+] and the concomitant formation of poly(ADP-ribosylated) proteins (PARs). Interestingly, the PARP-1 inhibitor (Olaparib) attenuated the cytotoxicity of DSE2. Moreover, the combination of Olaparib and Z-DEVD-FMK (caspase-3 inhibitor) further reduced the cytotoxicity. It has been shown that PARP-1 activation triggers cytoplasm-nucleus translocation of apoptosis-inducing factor (AIF). Caspase-3 inhibitors inhibited PARP-1 activation and suppressed PARP-1-induced AIF nuclear translocation. These results indicated that DSE2-induced caspase-3 activation may occur before PARP-1 activation. The ROS inhibitor, N-acetyl-cysteine, significantly inhibited the activation of caspase-3 and PARP-1, indicating that ROS overproduction contributed to DSE2-induced apoptosis. Using an in vivo approach, we further found that DSE2 significantly inhibited gastric tumor growth and promoted translocation of AIF to the nucleus. In conclusion, DSE2 induces gastric cell apoptosis by activating caspase-3 and PARP-1, and shows potent antitumor activity against human gastric carcinoma in vitro and in vivo.}, }
@article {pmid36651429, year = {2023}, author = {Costa, RIDD and Fischer, JMDS and Rasslan, R and Koike, MK and Utiyama, EM and Montero, EFS}, title = {Effects of N-acetylcysteine on the inflammatory response and bacterial translocation in a model of intestinal obstruction and ischemia in rats.}, journal = {Acta cirurgica brasileira}, volume = {37}, number = {12}, pages = {e371204}, pmid = {36651429}, issn = {1678-2674}, mesh = {Rats ; Animals ; Rats, Wistar ; Interleukin-10 ; Acetylcysteine/pharmacology/therapeutic use ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Bacterial Translocation ; Saline Solution, Hypertonic/pharmacology ; Ischemia ; Inflammation/drug therapy ; *Intestinal Obstruction ; Resuscitation/methods ; *Shock, Hemorrhagic ; }, abstract = {PURPOSE: To evaluate effect of N-acetylcysteine (NAC) associated with Ringer lactate or hypertonic saline in inflammation and bacterial translocation on experimental intestinal obstruction (IO).<br><br>METHODS: Wistar rats was subjected to IO. Six or 24 hours after, rats were subjected to enterectomy and fluid resuscitation: IO, RL (subjected to the same procedures but with fluid resuscitation using Ringer's lactate solution); RLNAC (added NAC to Ringer's solution); and HSNAC (surgical procedure + fluid reposition with 7.5% hypertonic saline and NAC). After 24 h, tissues were collected to cytokines, bacterial translocation, and histological assessments.<br><br>RESULTS: In kidney, interleukin-1beta (IL-1beta) was lower in the groups with fluid resuscitation compared to IO group. The RLNAC showed lower levels compared to the RL. Interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and (IFN-gamma) were lower in the treatment groups than in IO. In lung, IL-1beta and IL-6 were lower in RLNAC compared to IO. IL-10 was lower in RL, RLNAC and HSNAC compared to IO. TNF-alpha was higher in HSNAC compared to both RL and RLNAC. Bacterial translocation was observed in all animals of IO group. In kidneys, inflammation and congestion degrees were lower in HSNAC compared to RL. In lungs, inflammation levels were higher in RLNAC compared with the sham group.<br><br>CONCLUSIONS: The data indicates that NAC associated with RL can promote a decrease in the inflammatory process in the kidneys and lungs in rats, following intestinal obstruction and ischemia in rats.}, }
@article {pmid36647403, year = {2023}, author = {Wakil, A and Niazi, M and Meybodi, MA and Pyrsopoulos, NT}, title = {Emerging Pharmacotherapies in Alcohol-Associated Hepatitis.}, journal = {Journal of clinical and experimental hepatology}, volume = {13}, number = {1}, pages = {116-126}, pmid = {36647403}, issn = {0973-6883}, abstract = {UNLABELLED: The incidence of alcoholic-associated hepatitis (AH) is increasing. The treatment options for severe AH (sAH) are scarce and limited to corticosteroid therapy which showed limited mortality benefit in short-term use only. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH and to improve their high mortality rates.This review article focuses on the current novel therapeutics targeting various mechanisms in the pathogenesis of alcohol-related hepatitis. Anti-inflammatory agents such as IL-1 inhibitor, Pan-caspase inhibitor, Apoptosis signal-regulating kinase-1, and CCL2 inhibitors are under investigation. Other group of agents include gut-liver axis modulators, hepatic regeneration, antioxidants, and Epigenic modulators. We describe the ongoing clinical trials of some of the new agents for alcohol-related hepatitis.<br><br>CONCLUSION: A combination of therapies was investigated, possibly providing a synergistic effect of drugs with different mechanisms. Multiple clinical trials of novel therapies in AH remain ongoing. Their result could potentially make a difference in the clinical course of the disease. DUR-928 and granulocyte colony-stimulating factor had promising results and further trials are ongoing to evaluate their efficacy in the large patient sample.}, }
@article {pmid36647192, year = {2023}, author = {Chen, M and Qian, C and Jin, B and Hu, C and Zhang, L and Wang, M and Zhou, B and Zuo, W and Huang, L and Wang, Y}, title = {Curcumin analog WZ26 induces ROS and cell death via inhibition of STAT3 in cholangiocarcinoma.}, journal = {Cancer biology &amp; therapy}, volume = {24}, number = {1}, pages = {2162807}, pmid = {36647192}, issn = {1555-8576}, mesh = {Humans ; Animals ; Mice ; *Curcumin/pharmacology/therapeutic use ; *Antineoplastic Agents/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Cell Line, Tumor ; Cell Death ; Apoptosis ; *Cholangiocarcinoma/drug therapy ; Cell Proliferation ; G2 Phase Cell Cycle Checkpoints ; Bile Ducts, Intrahepatic/metabolism/pathology ; *Bile Duct Neoplasms/drug therapy/pathology ; }, abstract = {Cholangiocarcinoma (CCA) is an aggressive biliary epithelial tumor with limited therapeutic options and poor prognosis. Curcumin is a promising active natural compound with several anti-cancer properties, though its clinical uses remain hindered due to its poor bioavailability. We recently synthesized curcumin analogs with multifunctional pharmacological and bioactivities with enhanced bioavailability. Among these novel curcumin analogs, WZ26 is a representative molecule. However, the anti-tumor effect of WZ26 against CCA is unclear. In this study, we evaluated the anti-tumor effect of WZ26 in both CCA cells and CCA xenograft mouse model. The underlying molecular anti-cancer mechanism of WZ26 was also studied. Our results show that WZ26 significantly inhibited cell growth and induced mitochondrial apoptosis in CCA cell lines, leading to significant inhibition of tumor growth in xenograft tumor mouse model. Treatment of WZ26 increased reactive oxygen species (ROS) generation, subsequently decreased mitochondrial membrane potential and inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby inducing G2/M cell cycle arrest and cell apoptosis. Pretreatment of N-acetyl cysteine (NAC), an antioxidant agent, could fully reverse the WZ26-induced ROS-mediated changes in CCA cells. Our findings provide experimental evidence that curcumin analog WZ26 could be a potential candidate against CCA via enhancing ROS induction and inhibition of STAT3 activation.}, }
@article {pmid36639145, year = {2023}, author = {Moosa, MS and Russomanno, G and Dorfman, JR and Gunter, H and Patel, C and Costello, E and Carr, D and Maartens, G and Pirmohamed, M and Goldring, C and Cohen, K}, title = {Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury.}, journal = {British journal of clinical pharmacology}, volume = {89}, number = {6}, pages = {1844-1851}, pmid = {36639145}, issn = {1365-2125}, support = {MR/L006758/1/MRC_/Medical Research Council/United Kingdom ; MR/M009114/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {*MicroRNAs/blood ; *Acetylcysteine/administration &amp; dosage ; *Chemical and Drug Induced Liver Injury/drug therapy ; Administration, Intravenous ; *Acetaminophen/adverse effects ; *Antibiotics, Antitubercular/adverse effects ; Alanine Transaminase/blood ; Humans ; Male ; Female ; Adult ; Placebos ; }, abstract = {AIM: Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations.<br><br>METHODS: We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions.<br><br>RESULTS: We included 45 participants; mean age (&#xb1;&#x2009;standard deviation) 38 (&#xb1;10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68&#x2009;h (47-77&#x2009;h). The median pre-infusion ALT and miR-122 concentrations were 420&#x2009;U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's &#x3c1;&#xa0;=&#x2009;.54, P&#xa0;=&#x2009;.0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P&#xa0;=&#x2009;.40 and P&#xa0;=&#x2009;.68 respectively).<br><br>CONCLUSIONS: miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.}, }
@article {pmid36638648, year = {2023}, author = {Silva, BR and Silva, JRV}, title = {Mechanisms of action of non-enzymatic antioxidants to control oxidative stress during in vitro follicle growth, oocyte maturation, and embryo development.}, journal = {Animal reproduction science}, volume = {249}, number = {}, pages = {107186}, doi = {10.1016/j.anireprosci.2022.107186}, pmid = {36638648}, issn = {1873-2232}, mesh = {Animals ; *Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; *Melatonin/pharmacology ; Resveratrol/pharmacology ; Lycopene/pharmacology ; Quercetin/pharmacology ; Cysteamine/metabolism/pharmacology ; Phycocyanin/metabolism/pharmacology ; In Vitro Oocyte Maturation Techniques/veterinary ; Oxidative Stress ; Oocytes/physiology ; Glutathione/pharmacology ; Acetylcysteine/pharmacology ; Carnitine/metabolism/pharmacology ; Ascorbic Acid/pharmacology ; Embryonic Development ; }, abstract = {In vitro follicle growth and oocyte maturation still has a series of limitations, since not all oocytes matured in vitro have the potential to develop in viable embryos. One of the factors associated with low oocyte quality is the generation of reactive oxygen species (ROS) during in vitro culture. Therefore, this review aims to discuss the role of non-enzymatic antioxidants in the control of oxidative stress during in vitro follicular growth, oocyte maturation and embryonic development. A wide variety of non-enzymatic antioxidants (melatonin, resveratrol, L-ascorbic acid, L-carnitine, N-acetyl-cysteine, cysteamine, quercetin, nobiletin, lycopene, acteoside, mogroside V, phycocyanin and laminarin) have been used to supplement culture media. Some of them, like N-acetyl-cysteine, cysteamine, nobiletin and quercetin act by increasing the levels of glutathione (GSH), while melatonin and resveratrol increase the expression of antioxidant enzymes and minimize oocyte oxidative stress. L-ascorbic acid reduces free radicals and reactive oxygen species. Lycopene positively regulates the expression of many antioxidant genes. Additionally, L-carnitine protects DNA against ROS-induced damage, while acteoside and laminarin reduces the expression of proapoptotic genes. Mogrosides increases mitochondrial function and reduces intracellular ROS levels, phycocyanin reduces lipid peroxidation, and lycopene neutralizes the adverse effects of ROS. Thus, it is very important to know their mechanisms of actions, because the combination of two or more antioxidants with different activities has great potential to improve in vitro culture systems.}, }
@article {pmid36636887, year = {2023}, author = {Tanabe, P and Schlenk, D}, title = {Role of Aryl Hydrocarbon Receptor and Oxidative Stress in the Regioselective Toxicities of Hydroxychrysenes in Embryonic Japanese Medaka (Oryzias latipes).}, journal = {Environmental toxicology and chemistry}, volume = {42}, number = {3}, pages = {698-706}, doi = {10.1002/etc.5560}, pmid = {36636887}, issn = {1552-8618}, mesh = {Animals ; Cytochrome P-450 CYP1A1/metabolism ; *Oryzias/metabolism ; Oxidative Stress ; *Polycyclic Aromatic Hydrocarbons/toxicity ; Reactive Oxygen Species ; Receptors, Aryl Hydrocarbon/metabolism ; }, abstract = {Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are environmental contaminants that can be created through oxidation of parent PAHs. Previous studies have found that 2-hydroxychrysene (2-OHCHR) caused anemia in embryonic Japanese medaka whereas 6-hydroxychrysene (6-OHCHR) did not, an example of regioselective toxicity. Anemia was prevented by cytochrome P450 (CYP) inhibition, which reduced the formation of the potential oxidatively active metabolite, 1,2-catechol, from 2-OHCHR. 2-OHCHR has also been found to be a four-fold more potent aryl hydrocarbon receptor (AhR) agonist compared with 6-OHCHR. These findings led us to hypothesize that AhR activation and/or oxidative stress play an important role in 2-OHCHR toxicity. Although treatments with the AhR agonists polychlorinated biphenyl (PCB)126 and 2-methoxychrysene (2-MeOCHR) did not cause significant toxicity, pretreatments with the AhR antagonist, CH-223191, reduced anemia by 97.2 ± 0.84% and mortality by 96.6 ± 0.69%. Aryl hydrocarbon receptor inhibition by the antagonist was confirmed by significant reductions (91.0 ± 9.94%) in induced ethoxyresorufin-O-deethylase activity. Thiobarbituric acid reactive substances concentrations were 32.9 ± 3.56% higher (p < 0.05) in 2-OHCHR treatments at 100 hours postfertilization compared with controls. Staining 2-OHCHR-treated embryos with the reactive oxygen species (ROS) scavenger 2',7'-dichlorofluorescin diacetate revealed 32.6 ± 2.69% of 2-OHCHR-treated embryos exhibiting high concentrations of ROS in caudal tissues, which is a site for embryonic hematopoiesis in medaka. Pretreatment with antioxidants, N-acetylcysteine (NAC) or vitamin E (Vit E) significantly reduced 2-OHCHR-induced anemia (NAC: 80.7 ± 1.12% and Vit E: 99.1 ± 0.43%) and mortality (NAC: 67.1 ± 1.69% and Vit E: 98.9 ± 0.66%). These results indicate that AhR may mediate 2-OHCHR toxicity through canonical signaling by up-regulating CYP1, enhancing the formation of reactive metabolites of 2-OHCHR that generate ROS within caudal hematopoietic tissues, potentially disrupting hematopoiesis, leading to anemia and subsequent mortality. Environ Toxicol Chem 2023;42:698-706. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.}, }
@article {pmid36634885, year = {2023}, author = {Tang, Y and Jin, L and Qi, W and Gao, Y and Xie, Y and Xie, X and Lv, J and Jiang, Z and Jiang, H and Fan, C and Yan, J}, title = {N-acetyl-L-cysteine attenuated the toxicity of ZIF-8 on EA.hy926 endothelial cells by wnt/β-catenin pathway.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {88}, number = {}, pages = {105553}, doi = {10.1016/j.tiv.2023.105553}, pmid = {36634885}, issn = {1879-3177}, mesh = {Humans ; *Acetylcysteine/pharmacology ; *beta Catenin/metabolism ; *Endothelial Cells/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Wnt Signaling Pathway ; }, abstract = {As kinds of porous crystalline compounds, zeolitic imidazolate frameworks (ZIFs) have been developed quickly and attracted considerable attention for use in nano drug delivery systems, which raised concerns about cardiovascular disorders. At the present, the cytotoxic mechanism of ZIFs in cardiovascular disorders was still unclear. Our experiment explored the toxicity of ZIF-8, a typical kind of ZIFs, on human EA.hy926 vascular endothelial cells. The cell viability, ROS formation, apoptosis level, inflammatory response level, wound healing ability and atherosclerosis-related indicators of EA.hy926 endothelial cells were analyzed after ZIF-8 treatment. Meanwhile, we evaluated the ability of antioxidant N-Acetyl-L-cysteine (NAC) to attenuate the toxicity of ZIF-8 on EA.hy926 endothelial cells. As results, NAC attenuated ROS formation, cell apoptosis, LDH formation and endothelial dysfunction caused by ZIF-8. As the Wnt/β-catenin pathway was involved in endothelial cell dysfunction, we also studied the expression level of β-catenin and LEF1 in ZIF-8 and/or NAC treated EA.hy926 cells. As expected, ZIF-8 increased the protein expressions of β-catenin and LEF1in the IC50 group, which was significantly inhibited by co-treatment with NAC. Taken together, this study could help improve our understanding about the mechanism of ZIF-8-induced endothelial cells injury and NAC had therapeutic potential in preventing ZIF-8-associated endothelial dysfunction by wnt/β-catenin pathway.}, }
@article {pmid36627753, year = {2023}, author = {Paraskevas, T and Kantanis, A and Karalis, I and Michailides, C and Karamouzos, V and Koniari, I and Pierrakos, C and Velissaris, D}, title = {N-acetylcysteine efficacy in patients hospitalized with COVID-19 pneumonia: a systematic review and meta-analysis.}, journal = {Romanian journal of internal medicine = Revue roumaine de medecine interne}, volume = {61}, number = {1}, pages = {41-52}, doi = {10.2478/rjim-2023-0001}, pmid = {36627753}, issn = {2501-062X}, mesh = {Humans ; *COVID-19 ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; Hospitalization ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is a mucolytic agents with anti-inflammatory properties that has been suggested as an adjunctive therapy in patients with COVID-19 pneumonia.<br><br>OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate available evidence on the possible beneficial effects of NAC on SARS-CoV-2 infection.<br><br>METHODS: In September 2022, we conducted a comprehensive search on Pubmed/Medline and Embase on randomized controlled trials (RCTs) and observational studies on NAC in patients with COVID-19 pneumonia. Study selection, data extraction and risk of bias assessment was performed by two independent authors. RCTs and observational studies were analyzed separately.<br><br>RESULTS: We included 3 RCTs and 5 non-randomized studies on the efficacy of NAC in patients with COVID-19, enrolling 315 and 20826 patients respectively. Regarding in-hospital mortality, the summary effect of all RCTs was OR: 0.85 (95% CI: 0.43 to 1.67, I[2]=0%) and for non-randomized studies OR: 1.02 (95% CI: 0.47 to 2.23, I[2]=91%). Need for ICU admission was only reported by 1 RCT (OR: 0.86, 95% CI:0.44-1.69, p=0.66), while all included RCTs reported need for invasive ventilation (OR:0.91, 95% CI:0.54 to 1.53, I[2]=0). Risk of bias was low for all included RCTs, but certainty of evidence was very low for all outcomes due to serious imprecision and indirectness.<br><br>CONCLUSION: The certainty of evidence in the included studies was very low, thus recommendations for clinical practice cannot be yet made. For all hard clinical outcomes point estimates in RCTs are close to the line of no effect, while observational studies have a high degree of heterogeneity with some of them suggesting favorable results in patients receiving NAC. More research is warranted to insure that NAC is both effective and safe in patients with COVID-19 pneumonia.}, }
@article {pmid36626340, year = {2023}, author = {Safarinejad, MR and Safarinejad, S}, title = {Expression of Concern: Efficacy of Selenium and/or N-Acetyl-Cysteine for Improving Semen Parameters in Infertile Men: A Double-Blind, Placebo Controlled, Randomized Study.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000003113}, doi = {10.1097/JU.0000000000003113}, pmid = {36626340}, issn = {1527-3792}, }
@article {pmid36619199, year = {2022}, author = {Ma, J and Liu, X and Wei, Y and Lu, R and Xu, K and Tian, Y and Li, J}, title = {Effective Component Compatibility of Bufei Yishen Formula III Which Regulates the Mucus Hypersecretion of COPD Rats via the miR-146a-5p/EGFR/MEK/ERK Pathway.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2022}, number = {}, pages = {9423435}, pmid = {36619199}, issn = {1741-427X}, abstract = {BACKGROUND: The effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) with 5 ingredients (ginsenoside Rh1, astragaloside, icariin, nobiletin, and paeonol) has been shown to protect against chronic obstructive pulmonary disease (COPD). The present study aimed to observe the effects of ECC-BYF III in a COPD rat model and dissect its potential mechanisms in regulating mucus hypersecretion via the miR-146a-5p/epidermal growth factor receptor (EGFR)/MEK/ERK pathway.<br><br>METHODS: COPD model rats were treated with normal saline, ECC-BYF III, or N-acetylcysteine (NAC). Pulmonary function, lung tissue histology with H &amp; E and AB-PAS staining, expression levels of interleukin (IL)-4, IL-6, IL-1&#x3b2;, MUC5AC, MUC5B, and FOXA2 in lung tissues and the mRNA and proteins involved in the miR-146a-5p/EGFR/MEK/ERK pathway were evaluated.<br><br>RESULTS: The COPD rats showed a significant decrease in the pulmonary function and serious pathological damage to the lung tissue. ECC-BYF III and NAC significantly improved the ventilation function and small airway pathological damage in the COPD rats. The goblet cells and the expression levels of IL-1&#x3b2;, IL-6, MUC5AC, and MUC5B were increased in the COPD rats and were significantly decreased after ECC-BYF III or NAC intervention. The expression levels of IL-4 and FOXA2 in the COPD rats were markedly decreased and were improved in the ECC-BYF III and NAC groups. ECC-BYF III appeared to have a potent effect in restoring the reduced expression of miR-146a-5p. The increased phosphorylation levels of EGFR, MEK, and ERK1/2 and the protein expression levels of SPDEF in the lungs of COPD rats could be significantly reduced by ECC-BYF III.<br><br>CONCLUSIONS: ECC-BYF III has a significant effect in improving the airway mucus hypersecretion in COPD model rats, as well as a protective effect against limited pulmonary function and injured lung histopathology. The protective effect of ECC-BYF III in reducing airway mucus hypersecretion in COPD may involve the miR-146a-5p/EGFR/MEK/ERK pathway.}, }
@article {pmid36615764, year = {2022}, author = {Alwadani, AH and Almasri, SA and Aloud, AA and Albadr, NA and Alshammari, GM and Yahya, MA}, title = {The Synergistic Protective Effect of γ-Oryzanol (OZ) and N-Acetylcysteine (NAC) against Experimentally Induced NAFLD in Rats Entails Hypoglycemic, Antioxidant, and PPARα Stimulatory Effects.}, journal = {Nutrients}, volume = {15}, number = {1}, pages = {}, pmid = {36615764}, issn = {2072-6643}, support = {GSR//This research was funded by Deanship of scientific research in King Saud University through the initiative of DSR Graduate Students Research Support/ ; }, mesh = {Rats ; Male ; Animals ; *Non-alcoholic Fatty Liver Disease/drug therapy/etiology/prevention &amp; control ; Antioxidants/metabolism ; Acetylcysteine/metabolism ; PPAR alpha/genetics/metabolism ; Hypoglycemic Agents/pharmacology ; Liver/metabolism ; Diet, High-Fat/adverse effects ; Glucose/metabolism ; }, abstract = {This study estimated that the combined effect of γ-Oryzanol and N-acetylcysteine (NAC) against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats also estimated some of their mechanisms of action. Adult male rats were divided into seven groups (n = 8 each) as control, control + NAC, control + γ-Oryzanol, HFD, HFD + NAC, HFD + γ-Oryzanol, and HFD + NAC + γ-Oryzanol. NAC was administered orally at a final concentration of 200 mg/kg, whereas γ-Oryzanol was added to diets at a concentration of 0.16. All treatments were conducted for 17 weeks and daily. Both NAC and γ-Oryzanol were able to reduce final body weights, fat weights, fasting glucose, fasting insulin, serum, and serum levels of liver function enzymes as well as the inflammatory markers such as tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6), and leptin in HFD-fed rats. They also improved hepatic structure and glucose tolerance, increased adiponectin levels, and reduced serum and hepatic levels of triglycerides (TGs) and cholesterol (CHOL) in these rats. These effects were concomitant with a reduction in the hepatic levels of lipid peroxides (MDA) and serum levels of LDL-C, but also with an increment in the hepatic levels of superoxide dismutase (SOD) and glutathione (GSH). Interestingly, only treatment with γ-Oryzanol stimulated the mRNA levels of proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) in the liver and white adipose tissue (WAT) of rats. Of note, the combination therapy of both drugs resulted in maximum effects and restored almost normal liver structure and basal levels of all the above-mentioned metabolic parameters. In conclusion, a combination therapy of γ-Oryzanol and NAC is an effective therapy to treat NAFLD, which can act via several mechanisms on the liver and adipose tissue.}, }
@article {pmid36611912, year = {2022}, author = {Tam, E and Sung, HK and Lam, NH and You, S and Cho, S and Ahmed, SM and Abdul-Sater, AA and Sweeney, G}, title = {Role of Mitochondrial Iron Overload in Mediating Cell Death in H9c2 Cells.}, journal = {Cells}, volume = {12}, number = {1}, pages = {}, pmid = {36611912}, issn = {2073-4409}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Antioxidants/metabolism ; Cell Death ; Mitochondria/metabolism ; Iron/metabolism ; *Iron Overload/metabolism ; }, abstract = {Iron overload (IO) is associated with cardiovascular diseases, including heart failure. Our study's aim was to examine the mechanism by which IO triggers cell death in H9c2 cells. IO caused accumulation of intracellular and mitochondrial iron as shown by the use of iron-binding fluorescent reporters, FerroOrange and MitoFerroFluor. Expression of cytosolic and mitochondrial isoforms of Ferritin was also induced by IO. IO-induced iron accumulation and cellular ROS was rapid and temporally linked. ROS accumulation was detected in the cytosol and mitochondrial compartments with CellROX, DCF-DA and MitoSOX fluorescent dyes and partly reversed by the general antioxidant N-acetyl cysteine or the mitochondrial antioxidant SkQ1. Antioxidants also reduced the downstream activation of apoptosis and lytic cell death quantified by Caspase 3 cleavage/activation, mitochondrial Cytochrome c release, Annexin V/Propidium iodide staining and LDH release of IO-treated cells. Finally, overexpression of MitoNEET, an outer mitochondrial membrane protein involved in the transfer of Fe-S clusters between mitochondrial and cytosol, was observed to lower iron and ROS accumulation in the mitochondria. These alterations were correlated with reduced IO-induced cell death by apoptosis in MitoNEET-overexpressing cells. In conclusion, IO mediates H9c2 cell death by causing mitochondrial iron accumulation and subsequent general and mitochondrial ROS upregulation.}, }
@article {pmid36611209, year = {2023}, author = {Liu, Y and She, W and Li, Y and Wang, M and Liu, Y and Ning, B and Xu, T and Huang, T and Wei, Y}, title = {Aa-Z2 triggers ROS-induced apoptosis of osteosarcoma by targeting PDK-1.}, journal = {Journal of translational medicine}, volume = {21}, number = {1}, pages = {7}, pmid = {36611209}, issn = {1479-5876}, mesh = {Humans ; Apoptosis ; *Bone Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; *Osteosarcoma/drug therapy/pathology ; Phosphatidylinositol 3-Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism ; }, abstract = {BACKGROUND: Osteosarcoma (OS) is the most frequent cancer derived from bone, and the prognosis of OS is poor. Metabolic alterations have been previously reported to contribute to the development of OS, and arsenic compounds have been suggested to exhibit strong anti-OS effects. However, few studies have described the therapeutic efficiency of arsenic compounds by targeting metabolism in OS.<br><br>METHODS: Here, we presented a novel organo-arsenic compound, Aa-Z2, and its antitumour efficacy against OS both in vitro and in vivo.<br><br>RESULTS: Aa-Z2 induced OS cell apoptosis, G2/M phase arrest, and autophagy through the accumulation of reactive oxygen species (ROS). Elevated ROS functioned by promoting the mitochondrial-dependent caspase cascade and attenuating the PI3K/Akt/mTOR signalling pathway. N-acetylcysteine (NAC), a kind of ROS scavenger, could reverse the effects of Aa-Z2 treatment on 143B and HOS cells. Specifically, by targeting pyruvate dehydrogenase kinase 1 (PDK-1), Aa-Z2 induced changes in mitochondrial membrane potential and alterations in glucose metabolism to accumulate ROS. Overexpression of PDK-1 could partially desensitize OS cells to Aa-Z2 treatment. Importantly, Aa-Z2 suppressed tumour growth in our xenograft osteosarcoma model.<br><br>CONCLUSION: The study provides new insights into the mechanism of Aa-Z2-related metabolic alterations in OS inhibition, as well as pharmacologic evidence supporting the development of metabolism-targeting therapeutics.}, }
@article {pmid36607576, year = {2023}, author = {Wang, W and Li, S and Wang, X and Wang, J and Zhang, Y}, title = {PbO nanoparticles increase the expression of ICAM-1 and VCAM-1 by increasing reactive oxygen species production in choroid plexus.}, journal = {Environmental science and pollution research international}, volume = {30}, number = {14}, pages = {40162-40173}, pmid = {36607576}, issn = {1614-7499}, support = {ZD2020113//Science and Technology Project of Hebei Education Department/ ; H2020209250//Natural Science Foundation of Hebei Province/ ; 82073589//National Natural Science Foundation of China/ ; }, mesh = {*Vascular Cell Adhesion Molecule-1/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Reactive Oxygen Species/metabolism ; Choroid Plexus/metabolism ; Antioxidants/metabolism ; *Nanoparticles ; }, abstract = {PbO nanoparticles (nano-PbO) are widely used in the production of electrode materials, but exposure to them can cause brain damage. The first barrier preventing nano-PbO from entering the brain is the choroid plexus. However, the effect of nano-PbO on the choroid plexus remains unclear. Thus, the purpose of this study was to investigate the effect of nano-PbO exposure on lymphocyte cells infiltration, the adhesion protein of the choroid plexus as well as the role of reactive oxygen species (ROS) during the process. Results showed that nano-PbO exposure increased the percentage of lymphocyte cells in the brain and upregulated the expression of surface adhesion proteins, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in choroid plexus. Meanwhile, nano-PbO treatment also resulted in the increase of intercellular ROS production, and significantly decrease glutathione (GSH) content, glutathione peroxidase (GSH-PX) activity, and superoxide dismutase (SOD) activity in Z310 cells beside the increase of ICAM and VCAM-1 expression. Treatment with ROS inhibitor N-acetylcysteine (NAC) significantly downregulated the expression of ICAM-1 and VCAM-1expression. In conclusion, exposure to nano-PbO increases the expression of ICAM-1 and VCAM-1 through oxidative stress, which may contribute to peripheral lymphocyte cells infiltration into the brain.}, }
@article {pmid36604630, year = {2023}, author = {Lu, K and Zhou, M and Wang, L and Wang, Y and Tang, H and He, G and Wang, H and Tang, C and He, J and Wang, W and Tang, K and Wang, Y and Deng, Z}, title = {N-Acetyl-L-cysteine facilitates tendon repair and promotes the tenogenic differentiation of tendon stem/progenitor cells by enhancing the integrin α5/β1/PI3K/AKT signaling.}, journal = {BMC molecular and cell biology}, volume = {24}, number = {1}, pages = {1}, pmid = {36604630}, issn = {2661-8850}, support = {CQYC2021059825//Chongqing talents funding/ ; CQYC2021059825//Chongqing talents funding/ ; CQYC2021059825//Chongqing talents funding/ ; 4174DH//National Key Research of China/ ; 4174DH//National Key Research of China/ ; 4174DH//National Key Research of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; 82002306//National Science Foundation for Young Scientists of China/ ; cstc2021jcyj-msxmX0137//Chongqing Science &amp; Technology Commission/ ; cstc2021jcyj-msxmX0137//Chongqing Science &amp; Technology Commission/ ; cstc2021jcyj-msxmX0137//Chongqing Science &amp; Technology Commission/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; cstc2020jcyj-cxttX0004//Sports Injury Repair and Reconstruction Research Innovation Group/ ; }, mesh = {Rats ; Animals ; *Phosphatidylinositol 3-Kinases/metabolism ; Integrin alpha5beta1/metabolism ; Acetylcysteine/pharmacology/metabolism ; Integrin alpha5/metabolism/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinase/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Tendons ; Cell Differentiation/genetics ; Stem Cells ; *Tendon Injuries/drug therapy/metabolism ; }, abstract = {BACKGROUND: Tendon injury is associated with oxidative stress, leading to reactive oxygen species (ROS) production and inflammation. N-acetyl-L-cysteine (NAC) is a potent antioxidant. However, how NAC affects the biological functions of tendon stem/progenitor cells (TSPCs) and tendon repair has not been clarified. METHOD: The impacts of NAC on the viability, ROS production, and differentiation of TSPCs were determined with the cell counting kit-8, fluorescence staining, Western blotting, and immunofluorescence. The effect of NAC on gene transcription in TSPCs was analyzed by transcriptomes and bioinformatics and validated by Western blotting. The potential therapeutic effect of NAC on tendon repair was tested in a rat model of Achilles tendon injury.<br><br>RESULTS: Compared with the untreated control, treatment with 500 &#xb5;M NAC greatly promoted the proliferation of TSPCs and significantly mitigated hydrogen peroxide-induced ROS production and cytotoxicity in vitro. NAC treatment significantly increased the relative protein expression of collagen type 1 alpha 1 (COL1A1), tenascin C (TNC), scleraxis (SCX), and tenomodulin (TNMD) in TPSCs. Bioinformatics analyses revealed that NAC modulated transcriptomes, particularly in the integrin-related phosphoinositide 3-kinase (PI3K)/AKT signaling, and Western blotting revealed that NAC enhanced integrin &#x3b1;5&#x3b2;1 expression and PI3K/AKT activation in TSPCs. Finally, NAC treatment mitigated the tendon injury, but enhanced the protein expression of SCX, TNC, TNMD, and COLIA1 in the injured tissue regions of the rats.<br><br>CONCLUSION: NAC treatment promoted the survival and differentiation of TSPCs to facilitate tendon repair after tendon injury in rats. Thus, NAC may be valuable for the treatment of tendon injury.}, }
@article {pmid36601378, year = {2022}, author = {Tamagawa, S and Sakai, D and Schol, J and Sako, K and Nakamura, Y and Matsushita, E and Warita, T and Hazuki, S and Nojiri, H and Sato, M and Ishijima, M and Watanabe, M}, title = {N-acetylcysteine attenuates oxidative stress-mediated cell viability loss induced by dimethyl sulfoxide in cryopreservation of human nucleus pulposus cells: A potential solution for mass production.}, journal = {JOR spine}, volume = {5}, number = {4}, pages = {e1223}, pmid = {36601378}, issn = {2572-1143}, abstract = {BACKGROUND: Cell therapy is considered a promising strategy for intervertebral disc (IVD) regeneration. However, cell products often require long-term cryopreservation, which compromises cell viability and potency, thus potentially hindering commercialization and off-the-shelf availability. Dimethyl sulfoxide (DMSO) is a commonly used cryoprotectant, however, DMSO is associated with cytotoxicity and cell viability loss. This study aimed to investigate the effects of DMSO on human nucleus pulposus cells (NPC) and the role of oxidative stress in DMSO-induced cytotoxicity. Furthermore, we examined the potential of antioxidant N-acetylcysteine (NAC) supplementation to mitigate the negative effects of DMSO.<br><br>METHODS: NPC were exposed to various concentrations of DMSO with or without a freezing cycle. Cell viability, cell apoptosis and necrosis rates, intracellular reactive oxygen species (ROS) levels, and gene expression of major antioxidant enzymes were evaluated. In addition, NAC was added to cryopreservation medium containing 10% DMSO and its effects on ROS levels and cell viability were assessed.<br><br>RESULTS: DMSO concentrations &#x2264;1% for 24&#x2009;h did not significantly affect the NPC viability, whereas exposure to 5 and 10% DMSO (most commonly used concentration) caused cell viability loss (loss of 57% and 68% respectively after 24&#x2009;h) and cell death in a dose- and time-dependent manner. DMSO increased intracellular and mitochondrial ROS (1.9-fold and 3.6-fold respectively after 12&#x2009;h exposure to 10% DMSO) and downregulated gene expression levels of antioxidant enzymes in a dose-dependent manner. Tempering ROS through NAC treatment significantly attenuated DMSO-induced oxidative stress and supported maintenance of cell viability.<br><br>CONCLUSIONS: This study demonstrated dose- and time-dependent cytotoxic effects of DMSO on human NPC. The addition of NAC to the cryopreservation medium ameliorated cell viability loss by reducing DMSO-induced oxidative stress in the freeze-thawing cycle. These findings may be useful for future clinical applications of whole cells and cellular products.}, }
@article {pmid36597797, year = {2023}, author = {Shahveghar Asl, Z and Parastouei, K and Eskandari, E}, title = {The effects of N-acetylcysteine on ovulation and sex hormones profile in women with polycystic ovary syndrome: a systematic review and meta-analysis.}, journal = {The British journal of nutrition}, volume = {130}, number = {2}, pages = {202-210}, doi = {10.1017/S0007114522003270}, pmid = {36597797}, issn = {1475-2662}, mesh = {Humans ; Female ; *Polycystic Ovary Syndrome/drug therapy ; Acetylcysteine/pharmacology/therapeutic use ; Gonadal Steroid Hormones ; Follicle Stimulating Hormone ; Ovulation ; }, abstract = {Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases characterised by unusual levels of sex hormones and dysfunction of the ovaries. The infertility rate is high among patients with PCOS. Unusual hormonal status can lead to the inability of ovaries to release functional and mature follicles. Clinical trials on the effects of N-acetylcysteine (NAC) supplementation on ovulation and sex hormones profile in women with PCOS have been controversial. We performed a systematic review and meta-analysis to evaluate the potential effects of NAC supplementation on ovulation and sex hormones profile. PubMed, Scopus, Embase, Web of Science and Cochrane Central library international databases were searched till September 2021. Meta-analysis was performed using a random-effects approach in case of significant between-study heterogeneity. Eighteen studies, including 2185 participants, were included in the present meta-analysis. NAC significantly reduced total testosterone (TT) levels (standardised mean difference (SMD): −0·25 ng/ml; 95 % CI (−0·39, −0·10); ‘P < 0·001’, I[2] = 53·9 %, P = 0·034) and increased follicle-stimulating hormone (FSH) levels (SMD: 0·39 mg/ml; 95 % CI (0·07, 0·71); P = 0·01, I[2] = 70·9 %, P = 0·002). Oestrogen levels also increased after correcting publication bias. However, no significant effect was observed on the number of follicles, endometrial thickness, progesterone, serum luteinising hormone levels and sex hormone-binding globulin. The results indicated that NAC supplementation decreased TT levels and increased FSH levels. Overall, NAC supplementation might be effective in the improvement of reproductive system function in patients with PCOS.}, }
@article {pmid36593372, year = {2023}, author = {Cepaityte, D and Leivaditis, K and Varouktsi, G and Roumeliotis, A and Roumeliotis, S and Liakopoulos, V}, title = {N-Acetylcysteine: more than preventing contrast-induced nephropathy in uremic patients-focus on the antioxidant and anti-inflammatory properties.}, journal = {International urology and nephrology}, volume = {55}, number = {6}, pages = {1481-1492}, pmid = {36593372}, issn = {1573-2584}, mesh = {Humans ; Antioxidants/therapeutic use/pharmacology ; Acetylcysteine/therapeutic use ; Reactive Oxygen Species ; *Kidney Failure, Chronic/therapy/drug therapy ; Oxidative Stress ; *Renal Insufficiency, Chronic/therapy/drug therapy ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Oxidative stress (OS) has been recognized as a pathophysiologic mechanism underlying the development and progression of chronic kidney disease (CKD). OS, which results from the disturbance of balance among pro-oxidants and antioxidants favoring the pro-oxidants, is present even in early CKD and increases progressively along with deterioration of kidney function to end-stage kidney disease (ESKD). In ESKD, OS is further exacerbated mainly due to dialysis procedures per se and predisposes to increased cardiovascular morbidity and mortality. Therefore, since OS plays a pivotal role in the pathogenesis and progression of atherosclerosis in uremic patients, several strategies aiming to ameliorate OS in these patients have been proposed. Among those, N-acetylcysteine (NAC), a thiol-containing antioxidant agent, has attracted special attention due to its pleiotropic functions and beneficial effect in various OS-related entities including paracetamol overdose and prevention of contrast-induced nephropathy. In this review, we present the currently available literature on the antioxidant and anti-inflammatory properties of NAC in CKD, including hemodialysis and peritoneal dialysis.}, }
@article {pmid36592900, year = {2023}, author = {Wang, YH and Wang, YQ and Yu, XG and Lin, Y and Liu, JX and Wang, WY and Yan, CH}, title = {Chronic environmental inorganic arsenic exposure causes social behavioral changes in juvenile zebrafish (Danio rerio).}, journal = {The Science of the total environment}, volume = {867}, number = {}, pages = {161296}, doi = {10.1016/j.scitotenv.2022.161296}, pmid = {36592900}, issn = {1879-1026}, mesh = {Humans ; Animals ; Zebrafish/metabolism ; *Arsenic/toxicity/metabolism ; *Arsenicals/metabolism ; Oxidative Stress ; Zebrafish Proteins/metabolism ; *Water Pollutants, Chemical/metabolism ; }, abstract = {Arsenic (As) is a metalloid commonly found worldwide. Environmental As exposure may cause potential health hazards and behavioral changes in humans and animals. However, the effects of environmental As concentrations on social behavior, especially during the juvenile stage, are unclear. In this study, we observed behavioral changes in juvenile zebrafish after 28 days of exposure to inorganic As (NaAsO2 100 and 500 ppb) in water, especially anxiety and social deficits. Additionally, the level of oxidative stress in the zebrafish brain after As treatment increased, the content of dopamine (DA) decreased, and the transcription level of genes involved in DA metabolism with the activity of monoamine oxidase (MAO) increased. Oxidative stress is a recognized mechanism of nerve damage induced by As exposure. The zebrafish were exposed to N-acetylcysteine (NAC) to reduce As exposure-induced oxidative stress. The results showed improvements in social behavior, DA content, MAO activity, and gene transcription in zebrafish. In conclusion, environmental As exposure can induce behavioral abnormalities, such as anxiety and social deficits in zebrafish, which may be caused by As-induced oxidative stress altering gene transcription levels, causing an increase in MAO activity and a decrease in DA.}, }
@article {pmid36591540, year = {2022}, author = {LoBianco, FV and Krager, KJ and Johnson, E and Godwin, CO and Allen, AR and Crooks, PA and Compadre, CM and Borrelli, MJ and Aykin-Burns, N}, title = {Parthenolide induces rapid thiol oxidation that leads to ferroptosis in hepatocellular carcinoma cells.}, journal = {Frontiers in toxicology}, volume = {4}, number = {}, pages = {936149}, pmid = {36591540}, issn = {2673-3080}, support = {P20 GM109005/GM/NIGMS NIH HHS/United States ; R01 CA258673/CA/NCI NIH HHS/United States ; T32 GM106999/GM/NIGMS NIH HHS/United States ; }, abstract = {Hepatocellular carcinoma (HCC) is both a devastating and common disease. Every year in the United States, about 24,500 men and 10,000 women are diagnosed with HCC, and more than half of those diagnosed patients die from this disease. Thus far, conventional therapeutics have not been successful for patients with HCC due to various underlying comorbidities. Poor survival rate and high incidence of recurrence after therapy indicate that the differences between the redox environments of normal surrounding liver and HCC are valuable targets to improve treatment efficacy. Parthenolide (PTL) is a naturally found therapeutic with anti-cancer and anti-inflammatory properties. PTL can alter HCC's antioxidant environment through thiol modifications leaving tumor cells sensitive to elevated reactive oxygen species (ROS). Investigating the link between altered thiol mechanism and increased sensitivity to iron-mediated lipid peroxidation will allow for improved treatment of HCC. HepG2 (human) and McARH7777 (rat) HCC cells treated with PTL with increasing concentrations decrease cell viability and clonogenic efficiency in vitro. PTL increases glutathione (GSH) oxidation rescued by the addition of a GSH precursor, N-acetylcysteine (NAC). In addition, this elevation in thiol oxidation results in an overall increase in mitochondrial dysfunction. To elucidate if cell death is through lipid peroxidation, using a lipid peroxidation sensor indicated PTL increases lipid oxidation levels after 6 h. Additionally, western blotting reveals glutathione peroxidase 4 (GPx4) protein levels decrease after treatment with PTL suggesting cells are incapable of preventing lipid peroxidation after exposure to PTL. An elevation in lipid peroxidation will lead to a form of cell death known as ferroptosis. To further establish ferroptosis as a critical mechanism of death for HCC in vitro, the addition of ferrostatin-1 combined with PTL demonstrates a partial recovery in a colony survival assay. This study reveals that PTL can induce tumor cell death through elevations in intracellular oxidation, leaving cells sensitive to ferroptosis.}, }
@article {pmid36590525, year = {2022}, author = {Prylutskyy, Y and Nozdrenko, D and Gonchar, O and Prylutska, S and Bogutska, K and Franskevych, D and Hromovyk, B and Scharff, P and Ritter, U}, title = {C60 fullerene attenuates muscle force reduction in a rat during fatigue development.}, journal = {Heliyon}, volume = {8}, number = {12}, pages = {e12449}, pmid = {36590525}, issn = {2405-8440}, abstract = {C60 fullerene (C60) as a nanocarbon particle, compatible with biological structures, capable of penetrating through cell membranes and effectively scavenging free radicals, is widely used in biomedicine. A protective effect of C60 on the biomechanics of fast (m. gastrocnemius) and slow (m. soleus) muscle contraction in rats and the pro- and antioxidant balance of muscle tissue during the development of muscle fatigue was studied compared to the same effect of the known antioxidant N-acetylcysteine (NAC). C60 and NAC were administered intraperitoneally at doses of 1 and 150 mg kg[-1], respectively, daily for 5 days and 1 h before the start of the experiment. The following quantitative markers of muscle fatigue were used: the force of muscle contraction, the level of accumulation of secondary products of lipid peroxidation (TBARS) and the oxygen metabolite H2O2, the activity of first-line antioxidant defense enzymes (superoxide dismutase (SOD) and catalase (CAT)), and the condition of the glutathione system (reduced glutathione (GSH) content and the activity of the glutathione peroxidase (GPx) enzyme). The analysis of the muscle contraction force dynamics in rats against the background of induced muscle fatigue showed, that the effect of C60, 1 h after drug administration, was (15-17)% more effective on fast muscles than on slow muscles. A further slight increase in the effect of C60 was revealed after 2 h of drug injection, (7-9)% in the case of m. gastrocnemius and (5-6)% in the case of m. soleus. An increase in the effect of using C60 occurred within 4 days (the difference between 4 and 5 days did not exceed (3-5)%) and exceeded the effect of NAC by (32-34)%. The analysis of biochemical parameters in rat muscle tissues showed that long-term application of C60 contributed to their decrease by (10-30)% and (5-20)% in fast and slow muscles, respectively, on the 5th day of the experiment. At the same time, the protective effect of C60 was higher compared to NAC by (28-44)%. The obtained results indicate the prospect of using C60 as a potential protective nano agent to improve the efficiency of skeletal muscle function by modifying the reactive oxygen species-dependent mechanisms that play an important role in the processes of muscle fatigue development.}, }
@article {pmid36589610, year = {2022}, author = {Heo, YR and Son, CN and Baek, WK and Kim, SH}, title = {Grape seed proanthocyanidin extract induces apoptotic and autophagic cell death in rheumatoid arthritis fibroblast-like synoviocytes.}, journal = {Archives of rheumatology}, volume = {37}, number = {3}, pages = {393-403}, pmid = {36589610}, issn = {2618-6500}, abstract = {OBJECTIVES: In this study, we aimed to evaluate the association between grape seed proanthocyanidin extract (GSPE) and rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLSs) and to investigate whether GSPE induces cell death in RA-FLSs.<br><br>MATERIALS AND METHODS: The FLSs were isolated from RA synovial tissues. Cell viability and cell cycle staging were analyzed using a hemocytometer and flow cytometry. Caspase 3 and poly (ADP-ribose) polymerase (PARP) proteins were analyzed using Western blotting with z-VAD-fmk. Protein LC3 and polyubiquitin-binding protein p62 that were degraded by autophagy were evaluated using Western blotting with 3-methyladenine and chloroquine. Reactive oxygen species (ROS) were also evaluated.<br><br>RESULTS: When RA-FLSs were treated with GSPE, cell viability decreased, the number of cells in sub-G1 and G2/M phases increased, and the expression of pro-PARP and pro-caspase 3 proteins decreased in a concentration-dependent manner. This result was offset, when the cells were co-treated with the pan-caspase inhibitor z-VAD-fmk. The reduced cell viability, increased expression of LC3-II protein, and reduced expression of p62 protein with GSPE treatment were offset, when RA-FLSs were co-treated with GSPE and autophagy inhibitors 3-methyladenine and chloroquine. The level of ROS in RA-FLSs treated with GSPE was significantly lower than treatment with N-acetyl-cysteine, a ROS inhibitor.<br><br>CONCLUSION: Our study results show that GSPE induces apoptotic and autophagic cell death and inhibites reactive oxygen species in RA-FLSs.}, }
@article {pmid36587882, year = {2023}, author = {Behera, J and Pitchiah Kumar, M and Ireen Femela, A and Senguttuvan, G and Ramasamy, MS}, title = {miRNA-15/IL-10Rα axis promotes Kabasura Kudineer (Indian traditional Siddha formulation) induced immunomodulation by suppressing oxidative stress.}, journal = {Journal of ethnopharmacology}, volume = {305}, number = {}, pages = {116032}, doi = {10.1016/j.jep.2022.116032}, pmid = {36587882}, issn = {1872-7573}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; Antioxidants/pharmacology/metabolism ; Interleukin-6/metabolism ; Lipopolysaccharides/pharmacology ; Nitric Oxide/metabolism ; Inflammation ; Oxidative Stress ; Anti-Inflammatory Agents/pharmacology ; Glutathione/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Kabasura Kudineer (KK), the traditional Indian medicine of Siddha, effectively manages common respiratory symptoms such as flu, cold, and fever. However, there is no evidence of the immunomodulatory capacity of KK in the cultured Jurkat T-lymphocytes under the LPS insult studied.<br><br>AIM OF THE STUDY: Assess the effect of the traditional Indian medicine of Siddha, Kabasura Kudineer (KK) on immunomodulation by suppressing oxidative damage in cultured Jurkat T cells in vitro. The miRNA activity on anti-inflammatory gene receptors and cellular nitric oxide levels also was studied.<br><br>MATERIALS AND METHODS: Jurkat T cells were exposed to LPS treatment in the presence or absence of KK. Cell viability and nitric oxide (NO) were measured with MTT and Griess assay. Cellular antioxidant systems (glutathione and SOD) were determined using glutathione and SOD assay. Lipid peroxidation was measured using an MDA assay. MiRNA-15a-5p expression was performed using microRNA qPCR Assays. Both inflammatory and anti-inflammatory genes (IL-6, IL-1, IL-10, IL-13) were performed using a qPCR and ELISA assay.<br><br>RESULTS: The data showed that reduced cell proliferation and exaggerated NO production was observed in LPS treated condition compared to the control condition. Further, LPS treatment increased lipid peroxidation and reduced antioxidant enzyme activities (SOD and glutathione) in cultured Jurkat T cells. However, treatment with KK or N-acetyl cysteine (NAC; antioxidant) treatment mitigates the above effect. Mechanistically, LPS-induced oxidative stress upregulated miR- 15-5p expression and suppressed IL-10 Receptor alpha (IL-10R&#x3b1;) by binding to its 3'-UTR region. The deregulated expression of IL-10R&#x3b1; expression leads to increased IL-6 and IL-1&#x3b2; expression in LPS-induced Jurkat T cells; however, treatment with KK or NAC reversed the above effects.<br><br>CONCLUSION: Collectively, our study revealed the previously undefined mechanistic role of Kabasura Kudineer (KK) that alleviates the LPS-induced oxidative damage associated with inflammation by inhibiting the miRNA-15-5p/IL-10R&#x3b1; axis.}, }
@article {pmid38313355, year = {2023}, author = {Hatami, B and Abdi, S and Pourhoseingholi, MA and Eghlimi, H and Rabbani, AH and Masoumi, M and Hajimohammadebrahim-Ketabforoush, M}, title = {The effects of N-acetylcysteine on hepatic, hematologic, and renal parameters in cirrhotic patients: a randomized controlled trial.}, journal = {Gastroenterology and hepatology from bed to bench}, volume = {16}, number = {4}, pages = {432-440}, pmid = {38313355}, issn = {2008-2258}, abstract = {AIM: To evaluate the effects of N-acetylcysteine (NAC) supplementation in cirrhotic patients.<br><br>BACKGROUND: Chronic hepatic inflammation leads to fibrosis and cirrhosis through various mechanisms such as oxidative stress. NAC is one of the intracellular precursors of glutathione that can degrade most reactive oxygen species. Recently, the beneficial effects of NAC in animal and human studies on preventing liver injury progression and improving liver function have been examined. However, more studies on human subjects are still required.<br><br>METHODS: Well-known cirrhotic patients with a specific etiology and aged 18 to 70 years who referred to the gastrointestinal clinic of Ayatollah Taleghani Hospital from December 2018 to December 2019 were enrolled in the present randomized double-blind controlled trial. Patients in the intervention group received NAC tablets at a dose of 600 mg daily, and the control group received a placebo. Demographic data, medical characteristics, and Child-Pugh and MELD scores evaluated at baseline and after 6 months.<br><br>RESULTS: Totally, 60 patients completed the present study (30 patients in the intervention group, and 30 patients in the control group). Hematological and biochemical parameters were normal in both groups with no significant differences at baseline and 6 months after intervention values. Moreover, the renal function indicators including serum creatinine (Cr) and urea (BUN) decreased significantly after intervention. Hepatic parameters also decreased significantly 6 months after intervention. Decreases in the renal and hepatic parameters 6 months after baseline in the control group were not statistically significant.<br><br>CONCLUSION: The results of this study showed that NAC improved hepatic and renal function by decreasing serum urea and creatinine levels but had no significant effect on hematological and biochemical parameters. Furthermore, NAC significantly improved hepatic profiles by decreasing ALT, AST, and ALP in the liver enzymes between the intervention and control groups. Moreover, NAC caused a significant decrease in Child-Pugh and MELD scores.}, }
@article {pmid36586713, year = {2023}, author = {Huang, D and Wang, Y and Xiao, J and Wang, Y and Zhu, X and Xu, B and Wang, M}, title = {Scavenging of reactive oxygen species effectively reduces Pseudomonas aeruginosa biofilms through disrupting policing.}, journal = {Environmental research}, volume = {220}, number = {}, pages = {115182}, doi = {10.1016/j.envres.2022.115182}, pmid = {36586713}, issn = {1096-0953}, mesh = {Reactive Oxygen Species/metabolism ; *Anti-Bacterial Agents/pharmacology ; *Pseudomonas aeruginosa/genetics ; Biofilms ; Drug Resistance, Microbial ; Acetylcysteine/pharmacology ; }, abstract = {Biofilm formation is likely to contribute greatly to antibiotic resistance in bacteria and therefore the efficient removal of bacterial biofilms needs addressing urgently. Here, we reported that the supplement of non-inhibitory concentration of N-acetyl-L-cysteine (NAC), a common reactive oxygen species (ROS) scavenger, can significantly reduce the biomass of mature Pseudomonas aeruginosa biofilms (corroborated by crystal violet assay and laser scanning confocal microscopy). 1 mM NAC increased the cheater (ΔlasR mutant) frequency to 89.4 ± 1.5% in the evolved PAO1 after the 15-day treatment. Scavenging of ROS by NAC induced the collapse of P. aeruginosa biofilms, but it did not alter quorum sensing-regulated genes expression (e.g., hcnC and cioAB) and hydrogen cyanide production. The replenishment of public good protease contributed to the recovery of biofilm biomass, indicating the role of disrupting policing in biofilm inhibition. Furthermore, 7 typical ROS scavengers (e.g., superoxide dismutase, catalase and peroxidase, etc.) also effectively inhibited mature P. aeruginosa biofilms. This study demonstrates that scavenging of ROS can promote the selective control of P. aeruginosa biofilms through policing disruption as a targeted biofilm control strategy in complex water environments.}, }
@article {pmid36582212, year = {2022}, author = {Chen, X and Malaeb, SN and Pan, J and Wang, L and Scafidi, J}, title = {Editorial: Perinatal hypoxic-ischemic brain injury: Mechanisms, pathogenesis, and potential therapeutic strategies.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {1086692}, pmid = {36582212}, issn = {1662-5102}, support = {P50 HD103538/HD/NICHD NIH HHS/United States ; R01 NS099461/NS/NINDS NIH HHS/United States ; R01 NS125653/NS/NINDS NIH HHS/United States ; }, }
@article {pmid36577481, year = {2023}, author = {Mancini, L and Paolantoni, M and Schoubben, A and Ricci, M}, title = {Development of spray-dried N-acetylcysteine dry powder for inhalation.}, journal = {International journal of pharmaceutics}, volume = {631}, number = {}, pages = {122550}, doi = {10.1016/j.ijpharm.2022.122550}, pmid = {36577481}, issn = {1873-3476}, mesh = {*Acetylcysteine ; Powders/chemistry ; Leucine/chemistry ; Administration, Inhalation ; Aerosols/chemistry ; *Mannitol/chemistry ; Particle Size ; Dry Powder Inhalers ; }, abstract = {N-acetylcysteine (NAC) has both antioxidant and immunomodulatory activities and has been used as adjuvant therapy in several viral infections. Recently, NAC attracted attention for its possible role in reducing the affinity of the spike protein receptor binding domain to angiotensin-converting enzyme (ACE2) receptors. Since only NAC solutions are available for inhalation, the purpose of the work was to develop a NAC dry powder for inhalation using mannitol or leucine as excipient. The powder was successfully produced using co-spray-drying with leucine. ATR-FTIR analyses evidenced spectral variations ascribed to the formation of specific interactions between NAC and leucine. This effect on the NAC environment was not evident for NAC-mannitol powders, but mannitol was in a different polymorphic form compared to the supplied material. Both the feedstock concentration and the leucine content have an impact on the powder aerodynamic features. In particular, to maximize the respirable fraction, it is preferable to produce the powder starting from a 0.5 % w/v feedstock solution using 33 to 50 % w/w leucine content. The NAC-leucine powder was stable for ten months maintaining NAC content of 50 % (w/w) and about 200 μg of NAC was able to deposit on a transwell insert, useful for future in vitro studies.}, }
@article {pmid36567856, year = {2022}, author = {Wei, B and Hao, Z and Zheng, H and Qin, Y and Zhao, F and Shi, L}, title = {Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {5888636}, pmid = {36567856}, issn = {1942-0994}, mesh = {Humans ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; *Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxides/metabolism ; *Vascular Endothelial Growth Factor A/metabolism ; *Neovascularization, Pathologic/metabolism ; *Angiogenesis Inhibitors/pharmacology ; }, abstract = {Brevilin A (BA), a sesquiterpene lactone isolated from Centipeda minima herb, has been identified to exhibit potent anticancer activity. However, the potential pharmacological effect and mechanism of BA in regulating endothelial cell (EC) angiogenesis, a key event in tumor growth, is poorly understood. In this study, BA was shown to significantly prevent vascular endothelial growth factor (VEGF) induced EC angiogenic capacities in vitro, ex vivo, and in vivo. Subsequent functional assays revealed that BA dose dependently inhibited VEGF-stimulated survival, proliferation, migration, and triggered apoptosis activity in human umbilical vein endothelial cells (HUVECs), as well as suppressed the expression of antiapoptotic protein Bcl-2, increased the expression of proapoptotic protein caspase-3 and Bax, and suppressed PI3K/AKT pathway. Meanwhile, BA was also able to depolarize mitochondrial membranal permeability (MMP), accelerate mitochondrial superoxide accumulation, induce intracellular reactive oxygen species (ROS) production, and decreased intracellular glutathione (GSH) in HUVECs. Furthermore, both mitochondria-specific superoxide scavenger Mito-TEMPOL and broad-spectrum antioxidant N-acetyl-cysteine (NAC) dramatically abolished BA-induced mitochondrial dysfunction and mitochondrial ROS production, causing the reversion of PI3K/AKT pathway and repression of apoptosis, eventually correcting the impaired endothelial behavior in survival, growth, migration, and angiogenesis. Collectively, our data for the first time identified a new mechanism for antiangiogenic effect of BA in vascular EC, one that is based on the regulation of mitochondrial-dependent ROS overproduction.}, }
@article {pmid36564154, year = {2023}, author = {Wilkinson, MGL and Moulding, D and McDonnell, TCR and Orford, M and Wincup, C and Ting, JYJ and Otto, GW and Restuadi, R and Kelberman, D and Papadopoulou, C and Castellano, S and Eaton, S and Deakin, CT and Rosser, EC and Wedderburn, LR}, title = {Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis.}, journal = {Annals of the rheumatic diseases}, volume = {82}, number = {5}, pages = {658-669}, pmid = {36564154}, issn = {1468-2060}, support = {18DS03/DH_/Department of Health/United Kingdom ; 085860/WT_/Wellcome Trust/United Kingdom ; 22936/DH_/Department of Health/United Kingdom ; MRF_MRF-057-0001-RG-ROSS-C0797/MRF/MRF/United Kingdom ; 21593/VAC_/Versus Arthritis/United Kingdom ; 14518/VAC_/Versus Arthritis/United Kingdom ; MRF_MRF-159-0006-ELP-MCDO-C0954/MRF/MRF/United Kingdom ; 21992/VAC_/Versus Arthritis/United Kingdom ; 20164/VAC_/Versus Arthritis/United Kingdom ; 21552/VAC_/Versus Arthritis/United Kingdom ; GOSH BRC 18IR33/DH_/Department of Health/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/N003322/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Child ; Humans ; *Dermatomyositis ; Leukocytes, Mononuclear/metabolism ; Monocytes/metabolism ; DNA, Mitochondrial ; *Interferon Type I/metabolism ; Nucleotidyltransferases ; }, abstract = {OBJECTIVES: To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM).<br><br>METHODS: RNA-sequencing was performed on CD4[+], CD8[+], CD14[+] and CD19[+] cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by [13]C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-&#x3b1;, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35.<br><br>RESULTS: Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including 'megamitochondria', cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC.<br><br>CONCLUSIONS: These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.}, }
@article {pmid36563924, year = {2023}, author = {Yang, HL and Lin, YA and Pandey, S and Liao, JW and Way, TD and Yeh, YL and Chen, SJ and Hseu, YC}, title = {In vitro and in vivo anti-tumor activity of Antrodia salmonea against twist-overexpressing HNSCC cells: Induction of ROS-mediated autophagic and apoptotic cell death.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {172}, number = {}, pages = {113564}, doi = {10.1016/j.fct.2022.113564}, pmid = {36563924}, issn = {1873-6351}, mesh = {Animals ; Mice ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; Reactive Oxygen Species/metabolism ; Mice, Nude ; *Apoptosis ; Autophagy ; Cell Line, Tumor ; *Head and Neck Neoplasms/drug therapy ; }, abstract = {Head and neck squamous cell carcinoma (HNSCC) is a relatively common malignancy, characterized by lethal morbidity. Herein, we attempted to investigate the autophagy/apoptosis activities of the submerged fermented broths of Antrodia salmonea (AS) in HNSCC Twist-overexpressing (OECM-1 and FaDu-Twist) cells. AS (0-150 μg/mL) effectively reduced cell viability, colony formation, and downregulated Twist expression in OECM-1 and FaDu-Twist cells compared to FaDu cells. AS- induced apoptosis was mainly associated with activation of caspase-3, PARP cleavage, increased expression of VDAC-1 and disproportionation of Bax/Bcl-2. Annexin V/PI staining suggested late apoptosis induction by AS treatment. AS exhibits enhanced autophagy process mediated via LC3-I/II accumulation, increased acidic vesicular organelles (AVOs) formation and p62/SQSTM1 expression feeding into the apoptotic program. However, pre-treatment with autophagy blockers 3-MA and CQ significantly diminished AS-induced cell death. Additionally, suppression of AS-induced ROS release by treatment with antioxidant N-acetylcysteine (NAC) resulted in reduction of apoptotic and autophagic cell death. In vivo studies strengthened the above observations and showed that AS effectively reduced the tumor volume and tumor weight in OECM-1-xenografted nude mice. This study discovered that Antrodia salmonea exhibits a novel anti-cancer mechanism which could be harnessed as a new potent drug for HNSCC treatment.}, }
@article {pmid36563904, year = {2023}, author = {Mohammadi, E and Nikbakht, F and Vazifekhah, S and Babae, JF and Jogataei, MT}, title = {Evaluation the cognition-improvement effects of N-acetyl cysteine in experimental temporal lobe epilepsy in rat.}, journal = {Behavioural brain research}, volume = {440}, number = {}, pages = {114263}, doi = {10.1016/j.bbr.2022.114263}, pmid = {36563904}, issn = {1872-7549}, mesh = {Rats ; Animals ; *Epilepsy, Temporal Lobe/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism ; Maze Learning ; Hippocampus/metabolism ; Cognition ; *Epilepsy/metabolism ; Kainic Acid/pharmacology ; Memory Disorders/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Disease Models, Animal ; }, abstract = {Memory impairment is a critical issue in patients with temporal lobe epilepsy (TLE). Neuronal loss within the hippocampus and recurrent seizures may cause cognitive impairment in TLE. N -acetyl cysteine (NAC) is a sulfur-containing amino acid cysteine that is currently being investigated due to its protective effects on neurodegenerative disorders. NAC was orally administrated at a dose of 100 mg/kg for 8 days (7-day pretreatment and 1-day post-surgery). Neuronal viability, mTOR protein level, and spatial memory were detected in the kainite temporal epilepsy model via Nissl staining, western blot method, and Morris water maze task, respectively. Results showed that NAC delayed seizure activity and ameliorated memory deficit induced by Kainic acid. Histological analysis showed that NAC significantly increased the number of intact neurons in CA3 and hilar areas of the hippocampus following the induction of epilepsy. NAC also modulated the mTOR protein level 5 days after epilepsy compared to the KA-induced group. CONCLUSION: These results suggest that NAC improved memory impairment via anticonvulsant and neuroprotective activity and, in all probability, by lowering the level of mTOR.}, }
@article {pmid36558992, year = {2022}, author = {Zhang, T and Xiu, YH and Xue, H and Li, YN and Cao, JL and Hou, WS and Liu, J and Cui, YH and Xu, T and Wang, Y and Jin, CH}, title = {A Mechanism of Isoorientin-Induced Apoptosis and Migration Inhibition in Gastric Cancer AGS Cells.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {12}, pages = {}, pmid = {36558992}, issn = {1424-8247}, support = {2020YFD1001400//National Key Research and Development Project of China/ ; 2019HTY078//Heilongjiang Touyan Innovation Team Program/ ; 2020GSP16//Central Government Supports Local College Reform and Development Fund Talent Training Projects/ ; }, abstract = {Isoorientin (ISO) is a flavonoid compound containing a luteolin structure, which can induce autophagy in some tumor cells. This study investigated the impact of ISO in gastric cancer AGS cells, and performed an experimental analysis on the main signaling pathways and transduction pathways it regulates. CCK-8 assay results showed that ISO reduced the survival rate of gastric cancer AGS cells, but the toxicity to normal cells was minimal. Hoechst 33342/PI double staining assay results showed that ISO induced apoptosis in gastric cancer AGS cells. Further analysis by flow cytometry and Western blot showed that ISO induced apoptosis via a mitochondria-dependent pathway. In addition, the level of reactive oxygen species (ROS) in gastric cancer AGS cells also increased with the extension of the ISO treatment time. However, cell apoptosis was inhibited by preconditioning cells with N-acetylcysteine (NAC). Moreover, ISO arrested the cell cycle at the G2/M phase by increasing intracellular ROS levels. Cell migration assay results showed that ISO inhibited cell migration by inhibiting the expression of p-AKT, p-GSK-3β, and β-catenin and was also related to the accumulation of ROS. These results suggest that ISO-induced cell apoptosis by ROS-mediated MAPK/STAT3/NF-κB signaling pathways inhibited cell migration by regulating the AKT/GSK-3β/β-catenin signaling pathway in gastric cancer AGS cells.}, }
@article {pmid36557977, year = {2022}, author = {Huang, J and Wang, J and Song, G and Hu, C and Xu, Z and Chen, Z and Xu, C and Yang, D}, title = {Antiproliferative Evaluation of Novel 4-Imidazolidinone Derivatives as Anticancer Agent Which Triggers ROS-Dependent Apoptosis in Colorectal Cancer Cell.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {24}, pages = {}, pmid = {36557977}, issn = {1420-3049}, support = {cstc2020jcyj-msxmX0595//Natural Science Foundation of Chongqing/ ; KJQN201901331//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; KJZD-K202001302//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; P2021YX05//Scientific Research Foundation of the Chongqing University of Arts and Sciences/ ; KJQN202201330//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; }, mesh = {Humans ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Apoptosis ; *Antineoplastic Agents/pharmacology/therapeutic use ; *Colorectal Neoplasms/drug therapy/metabolism ; }, abstract = {Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide, and more therapies are needed to treat CRC. To discover novel CRC chemotherapeutic molecules, we used a series of previously synthesized novel imidazolidin-4-one derivatives to study their anticancer role in several cancer cell lines. Among these compounds, compound 9r exhibited the best anticancer activity in CRC cell lines HCT116 and SW620. We further investigated the anticancer molecular mechanism of compound 9r. We found that compound 9r induced mitochondrial pathway apoptosis in HCT116 and SW620 cells by inducing reactive oxygen species (ROS) production. Moreover, the elevated ROS generation activated the c-Jun N-terminal kinase (JNK) pathway, which further accelerated apoptosis. N-acetylcysteine (NAC), an antioxidant reagent, suppressed compound 9r-induced ROS production, JNK pathway activation, and apoptosis. Collectively, this research synthesized a series of imidazolidin-4-one derivatives, evaluated their anticancer activity, and explored the molecular mechanism of compound 9r-induced apoptosis in CRC cells. The present results suggest that compound 9r has a potential therapeutic role in CRC. Hence, it deserves further exploration as a lead compound for CRC treatment.}, }
@article {pmid36555816, year = {2022}, author = {Kesidou, E and Bitsina, C and Chatzisotiriou, A and Theotokis, P and Dandi, E and Tata, DA and Spandou, E}, title = {N-Acetylcysteine Administration Attenuates Sensorimotor Impairments Following Neonatal Hypoxic-Ischemic Brain Injury in Rats.}, journal = {International journal of molecular sciences}, volume = {23}, number = {24}, pages = {}, pmid = {36555816}, issn = {1422-0067}, mesh = {Animals ; Rats ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; Animals, Newborn ; Rats, Sprague-Dawley ; *Hypoxia-Ischemia, Brain/metabolism ; *Brain Injuries/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use/metabolism ; Brain/metabolism ; }, abstract = {Hypoxic ischemic (HI) brain injury that occurs during neonatal period has been correlated with severe neuronal damage, behavioral deficits and infant mortality. Previous evidence indicates that N-acetylcysteine (NAC), a compound with antioxidant action, exerts a potential neuroprotective effect in various neurological disorders including injury induced by brain ischemia. The aim of the present study was to investigate the role of NAC as a potential therapeutic agent in a rat model of neonatal HI brain injury and explore its long-term behavioral effects. To this end, NAC (50 mg/kg/dose, i.p.) was administered prior to and instantly after HI, in order to evaluate hippocampal and cerebral cortex damage as well as long-term functional outcome. Immunohistochemistry was used to detect inducible nitric oxide synthase (iNOS) expression. The results revealed that NAC significantly alleviated sensorimotor deficits and this effect was maintained up to adulthood. These improvements in functional outcome were associated with a significant decrease in the severity of brain damage. Moreover, NAC decreased the short-term expression of iNOS, a finding implying that iNOS activity may be suppressed and that through this action NAC may exert its therapeutic action against neonatal HI brain injury.}, }
@article {pmid36555541, year = {2022}, author = {Matsuura, T and Komatsu, K and Ogawa, T}, title = {N-Acetyl Cysteine-Mediated Improvements in Dental Restorative Material Biocompatibility.}, journal = {International journal of molecular sciences}, volume = {23}, number = {24}, pages = {}, pmid = {36555541}, issn = {1422-0067}, mesh = {Humans ; *Acetylcysteine/metabolism ; *Antioxidants/pharmacology ; Glutathione/metabolism ; Gingiva/metabolism ; Polymers ; Composite Resins/pharmacology ; Materials Testing ; Dental Materials/pharmacology ; }, abstract = {The fibroblast-rich gingival tissue is usually in contact with or adjacent to cytotoxic polymer-based dental restoration materials. The objective of this study was to determine whether the antioxidant amino acid, N-acetyl cysteine (NAC), reduces the toxicity of dental restorative materials. Human oral fibroblasts were cultured with bis-acrylic, flowable composite, bulk-fill composite, self-curing acrylic, and titanium alloy test specimens. Cellular behavior and function were analyzed on and around the materials. Impregnation of the bulk-fill composite and self-curing acrylic with NAC reduced their toxicity, improving the attachment, growth, and function of human oral fibroblasts on and around the materials. These mitigating effects were NAC dose dependent. However, NAC impregnation of the bis-acrylic and flowable composite was ineffective, with no cells attaching to nor around the materials. Although supplementing the culture medium with NAC also effectively improved fibroblast behaviors, direct impregnation of materials with NAC was more effective than supplementing the cultures. NAC-mediated improvements in fibroblast behavior were associated with reduced production of reactive oxygen species and oxidized glutathione together with increased glutathione reserves, indicating that NAC effectively directly scavenged ROS from materials and reinforced the cellular antioxidant defense system. These results establish a proof of concept of NAC-mediated improvements in biocompatibility in the selected dental restorative materials.}, }
@article {pmid36553574, year = {2022}, author = {Ji, T and Chen, X and Zhang, Y and Fu, K and Zou, Y and Wang, W and Zhao, J}, title = {Effects of N-Acetylcysteine on the Proliferation, Hormone Secretion Level, and Gene Expression Profiles of Goat Ovarian Granulosa Cells.}, journal = {Genes}, volume = {13}, number = {12}, pages = {}, pmid = {36553574}, issn = {2073-4425}, mesh = {Female ; Animals ; Sheep ; *Transcriptome ; *Acetylcysteine/metabolism ; Goats/genetics ; Granulosa Cells/metabolism ; Cell Proliferation ; Hormones ; RNA, Messenger/metabolism ; }, abstract = {The purpose of this paper was to investigate the effects of N-acetylcysteine (NAC) on the proliferation, hormone secretion, and mRNA expression profiles of ovarian granulosa cells (GCs) in vitro. A total of 12 ovaries from 6 follicular-stage goats were collected for granulosa cell extraction. The optimum concentration of NAC addition was determined to be 200 μM via the Cell Counting Kit 8 (CCK-8) method. Next, GCs were cultured in a medium supplemented with 200 μM NAC (200 μM NAC group) and 0 μ M NAC (control group) for 48 h. The effects of 200 μM NAC on the proliferation of granulosa cells and hormones were studied by 5-ethynyl-2'-deoxyuridine (EdU) assay and enzyme-linked immunosorbent assay (ELISA). mRNA expression was analyzed by transcriptome sequencing. The results indicate that 200 μM NAC significantly increased cell viability and the proportion of cells in the S phase but promoted hormone secretion to a lesser degree. Overall, 122 differentially expressed genes (DEGs) were identified. A total of 51 upregulated and 71 downregulated genes were included. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that the most DEGs were enriched in terms of cell growth regulation, cell growth, neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, the cAMP-signaling pathway, and the Wnt-signaling pathway. Seven genes related to granulosa cell proliferation were screened, IGFBP4, HTRA4, SST, SSTR1, WISP1, DAAM2, and RSPO2. The above results provide molecular theoretical support for NAC as a feed additive to improve follicle development and improve reproductive performance in ewes.}, }
@article {pmid36550944, year = {2022}, author = {Lee, JH and Park, HJ and Kim, YA and Lee, DH and Noh, JK and Jung, JG and Yoon, HH and Lee, SK and Lee, S}, title = {Establishment of a Serum-Free Hepatocyte Cryopreservation Process for the Development of an "Off-the-Shelf" Bioartificial Liver System.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {9}, number = {12}, pages = {}, pmid = {36550944}, issn = {2306-5354}, support = {Technology Innovation Program (10078349)//the Ministry of Trade, Industry &amp; Energy (MOTIE; Korea)/ ; SMO1220041//Future Medicine 2030 Project of the Samsung Medical center/ ; }, abstract = {To use hepatocytes immediately when necessary for hepatocyte transplantation and bioartificial liver (BAL) systems, a serum-free cryopreservation protocol ensuring the high survival of hepatocytes and maintenance of their functions should be developed. We established a serum-free protocol for the cryopreservation of primary hepatocytes, hepatocyte spheroids, and hepatocyte spheroid beads in liquid nitrogen. The serum-free cryopreservation solutions showed a significantly higher performance in maintaining enhanced viability and ammonia removal, urea secretion, and the albumin synthesis of hepatocyte spheroids and spheroid beads. The serum-free thawing medium, containing human serum albumin (HSA) and N-acetylcysteine (NAC), was compared with a fetal bovine serum-containing thawing medium for the development of a serum-free thawing medium. Our results show that hepatocyte spheroids and spheroid beads thawed using a serum-free thawing medium containing HSA and NAC exhibited increased hepatocyte viability, ammonia removal, urea secretion, and albumin synthesis compared to those thawed using the serum-containing medium. Finally, we evaluated the liver functions of the cryopreserved BAL system-applied serum-free cryopreservation process compared to the fresh BAL system. The ammonia removal efficiency of the cryopreserved hepatocyte spheroids BAL was lower than or similar to that of the fresh BAL system. Additionally, the urea concentrations in the media of all three BAL systems were not significantly different during BAL system operation. This cryopreserved spheroid-based BAL system using a serum-free process will be a good candidate for the treatment of patients.}, }
@article {pmid36549672, year = {2023}, author = {Kim, NH and Lee, AY}, title = {Growth Factors Upregulated by Uric Acid Affect Guanine Deaminase-Induced Melanogenesis.}, journal = {Biomolecules &amp; therapeutics}, volume = {31}, number = {1}, pages = {89-96}, pmid = {36549672}, issn = {1976-9148}, abstract = {Uric acid produced by guanine deaminase (GDA) is involved in photoaging and hyperpigmentation. Reactive oxygen species (ROS) generated by uric acid plays a role in photoaging. However, the mechanism by which uric acid stimulates melanogenesis in GDA-overexpressing keratinocytes is unclear. Keratinocyte-derived paracrine factors have been identified as important mechanisms of ultraviolet-induced melanogenesis. Therefore, the role of paracrine melanogenic growth factors in GDA-induced hypermelanosis mediated by uric acid was examined. The relationships between ROS and these growth factors were examined. Primary cultured normal keratinocytes overexpressed with wild type or mutant GDA and those treated with xanthine or uric acid in the presence or absence of allopurinol, H2O2, or N-acetylcysteine (NAC) were used in this study. Intracellular and extracellular bFGF and SCF levels were increased in keratinocytes by wild type, but not by loss-of-function mutants of GDA overexpression. Culture supernatants from GDA-overexpressing keratinocytes stimulated melanogenesis, which was restored by anti-bFGF and anti-SCF antibodies. Allopurinol treatment reduced the expression levels of bFGF and SCF in both GDA-overexpressing and normal keratinocytes exposed to exogenous xanthine; the exogenous uric acid increased their expression levels. H2O2-stimulated tyrosinase expression and melanogenesis were restored by NAC pretreatment. However, H2O2 or NAC did not upregulate or downregulate bFGF or SCF, respectively. Overall, uric acid could be involved in melanogenesis induced by GDA overexpression in keratinocytes via bFGF and SCF upregulation not via ROS generation.}, }
@article {pmid36541703, year = {2023}, author = {Demers, ND and Riccio, V and Jo, DS and Bhandari, S and Law, KB and Liao, W and Kim, C and McQuibban, GA and Choe, SK and Cho, DH and Kim, PK}, title = {PEX13 prevents pexophagy by regulating ubiquitinated PEX5 and peroxisomal ROS.}, journal = {Autophagy}, volume = {19}, number = {6}, pages = {1781-1802}, pmid = {36541703}, issn = {1554-8635}, support = {PJT#156196//CIHR/Canada ; }, mesh = {Animals ; Humans ; Mice ; *Macroautophagy ; *Autophagy/physiology ; Reactive Oxygen Species/metabolism ; Leucine/metabolism ; Lysine/metabolism ; Actins/metabolism ; Zebrafish/metabolism ; Fibroblasts/metabolism ; Ubiquitin/metabolism ; Peroxisomes/metabolism ; Amino Acids/metabolism ; Oxygen/metabolism ; Sirolimus ; Membrane Proteins/metabolism ; }, abstract = {Peroxisomes are rapidly degraded during amino acid and oxygen deprivation by a type of selective autophagy called pexophagy. However, how damaged peroxisomes are detected and removed from the cell is poorly understood. Recent studies suggest that the peroxisomal matrix protein import machinery may serve double duty as a quality control machinery, where they are directly involved in activating pexophagy. Here, we explored whether any matrix import factors are required to prevent pexophagy, such that their loss designates peroxisomes for degradation. Using gene editing and quantitative fluorescence microscopy on culture cells and a zebrafish model system, we found that PEX13, a component of the peroxisomal matrix import system, is required to prevent the degradation of otherwise healthy peroxisomes. The loss of PEX13 caused an accumulation of ubiquitinated PEX5 on peroxisomes and an increase in peroxisome-dependent reactive oxygen species that coalesce to induce pexophagy. We also found that PEX13 protein level is downregulated to aid in the induction of pexophagy during amino acid starvation. Together, our study points to PEX13 as a novel pexophagy regulator that is modulated to maintain peroxisome homeostasis.Abbreviations: AAA ATPases: ATPases associated with diverse cellular activities; ABCD3: ATP binding cassette subfamily D member; 3ACOX1: acyl-CoA oxidase; 1ACTA1: actin alpha 1, skeletal muscle; ACTB: actin beta; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; CAT: catalase; CQ: chloroquine; Dpf: days post fertilization: FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; H2O2: hydrogen peroxide; HA - human influenza hemagglutinin; HBSS: Hanks' Balanced Salt Solution; HCQ; hydroxychloroquine; KANL: lysine alanine asparagine leucine; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYC: MYC proto-oncogene, bHLH transcription factor; MZ: maternal and zygotic; NAC: N-acetyl cysteine; NBR1 - NBR1 autophagy cargo receptor; PBD: peroxisome biogenesis disorder; PBS: phosphate-buffered saline; PEX: peroxisomal biogenesis factor; PTS1: peroxisome targeting sequence 1; RFP: red fluorescent protein; ROS: reactive oxygen speciess; iRNA: short interfering RNA; SKL: serine lysine leucine; SLC25A17/PMP34: solute carrier family 25 member 17; Ub: ubiquitin; USP30: ubiquitin specific peptidase 30.}, }
@article {pmid36539667, year = {2023}, author = {Newman, SA and Short, JL and Nicolazzo, JA}, title = {Reduction in ABCG2 mRNA Expression in Human Immortalised Brain Microvascular Endothelial Cells by Ferric Ammonium Citrate is Mediated by Reactive Oxygen Species and Activation of ERK1/2 Signalling.}, journal = {Pharmaceutical research}, volume = {40}, number = {3}, pages = {651-660}, pmid = {36539667}, issn = {1573-904X}, mesh = {Humans ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/metabolism ; ATP-Binding Cassette Transporters/metabolism ; Brain/metabolism ; *Endothelial Cells/metabolism ; *MAP Kinase Signaling System ; Neoplasm Proteins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; RNA, Messenger/genetics/metabolism ; }, abstract = {PURPOSE: The ATP-binding cassette (ABC) transport protein ABCG2 (also known as breast cancer resistance protein (BCRP)) is expressed at the luminal face of the blood-brain barrier (BBB), where it limits the brain uptake of a number of therapeutic drugs. We recently reported that the ABC efflux transporter P-glycoprotein (P-gp) was downregulated in human immortalised brain endothelial (hCMEC/D3) cells treated with ferric ammonium citrate (FAC). The aim of the present study, therefore, was to assess whether BCRP expression is also affected by FAC and identify any signalling mechanisms involved.<br><br>METHODS: ABCG2 mRNA was assessed by RT-qPCR. Protein levels of BCRP, phosphorylated extracellular-regulated kinases 1 and 2 (p-ERK1/2) and total ERK 1/2 were assessed by Western blot. Reactive oxygen species (ROS) levels were determined using 2',7'-dichlorofluorescin diacetate.<br><br>RESULTS: Treatment of hCMEC/D3 cells with FAC (250 &#xb5;M, 72 h) significantly reduced ABCG2 mRNA levels (32.2 &#xb1; 3.7%) without a concomitant reduction in BCRP protein expression. ABCG2 mRNA levels were restored to control levels when co-treated with the antioxidant N-acetylcysteine (NAC), suggesting the effect of FAC was mediated by a ROS-sensitive pathway. We also found that FAC-treatment was associated with increased levels of p-ERK1/2, suggesting involvement of the ERK1/2 signalling pathway in the observed ABCG2 mRNA downregulation. The ERK1/2 signalling pathway inhibitor U0126 restored p-ERK1/2 levels and partially attenuated the FAC-induced reduction in ABCG2 mRNA.<br><br>CONCLUSIONS: This study suggests that FAC-induced downregulation of ABCG2 mRNA is&#xa0;driven by&#xa0;ROS and ERK1/2 signalling, mechanisms which may be exploited to modulate BCRP expression at the BBB.}, }
@article {pmid36533744, year = {2022}, author = {Abdelrazik, E and Hassan, HM and Abdallah, Z and Magdy, A and Farrag, EA}, title = {Renoprotective effect of N-acetylcystein and vitamin E in bisphenol A-induced rat nephrotoxicity; Modulators of Nrf2/ NF-κB and ROS signaling pathway.}, journal = {Acta bio-medica : Atenei Parmensis}, volume = {93}, number = {6}, pages = {e2022301}, pmid = {36533744}, issn = {2531-6745}, mesh = {Animals ; Rats ; Male ; *NF-kappa B/metabolism/pharmacology/therapeutic use ; *NF-E2-Related Factor 2/metabolism/pharmacology/therapeutic use ; Reactive Oxygen Species/adverse effects/metabolism ; Vitamin E/adverse effects ; Oxidative Stress ; Signal Transduction ; Inflammation/drug therapy ; }, abstract = {Bisphenol A (BPA) is a chemical product that is widely used as a plastic precursor. It acts directly on the kidney mitochondria, causing renal dysfunction. N-acetylcysteine is effective in protecting the kidneys from chemical-induced damage. Vitamin E is an antioxidant that protects cells from the damaging effects of free radicals. The aim of this study is to further evaluate and compare NAC and vitamin E to oppose the nephrotoxicity caused by BPA.<br><br>RESEARCH DESIGN AND METHODS: Forty-two adult male rats were divided into 7 groups:&#xa0; control, BPA, NAC, vitamin E, BPA plus NAC, BPA plus vitamin E, and combined BPA, NAC and vitamin E. BPA, NAC, vitamin E were given orally at doses of 50 mg/kg, 200 mg/kg, and 1000 mg/kg respectively, for 5 weeks.<br><br>RESULTS: NAC and vitamin E groups showed improved kidney function tests and alleviated BPA-induced oxidative stress; increased GSH and decreased MDA, NO and iNOS levels. NAC and vitamin E significantly attenuated inflammation; decreased NF-&#x3ba;B and increased IL-4, and Nrf2, in addition there was alleviation of renal histopathology. To some extent, vitamin E administration showed significant improvement. Moreover, combined NAC and vitamin E treatment showed more significance than either NAC or vitamin E separate groups.<br><br>CONCLUSIONS: This study determined the substantial protective effects of NAC and/or vitamin E in BPA-induced nephrotoxicity through modulation of Nrf2 with subsequent improvement of oxidative stress and inflammation. The alleviation was more significant in combined NAC and vitamin E treatment mainly through their synergistic effect on Nrf2.}, }
@article {pmid36528076, year = {2023}, author = {Haugsten Hansen, M and Sadredini, M and Hasic, A and Anderson, ME and Sjaastad, I and Korseberg Stokke, M}, title = {CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor.}, journal = {Journal of molecular and cellular cardiology}, volume = {175}, number = {}, pages = {49-61}, doi = {10.1016/j.yjmcc.2022.12.002}, pmid = {36528076}, issn = {1095-8584}, support = {R35 HL140034/HL/NHLBI NIH HHS/United States ; }, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; *Methionine/metabolism ; Mice, Inbred C57BL ; Arrhythmias, Cardiac/metabolism ; Myocytes, Cardiac/metabolism ; Racemethionine/metabolism ; Reperfusion/adverse effects ; Phosphorylation ; }, abstract = {BACKGROUND: Available evidence suggest that Ca[2+]/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing.<br><br>METHODS: We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKII&#x3b4; by using hearts and cardiomyocytes from mice with CaMKII&#x3b4; resistant to oxidation of methionines 281 and 282 (MMVV).<br><br>RESULTS: Hearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca[2+] waves and Ca[2+] sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca[2+]-handling proteins in MMVV and WT hearts.<br><br>CONCLUSIONS: Although CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.}, }
@article {pmid36526177, year = {2023}, author = {Shi, X and Xu, T and Cui, W and Qi, X and Xu, S}, title = {Combined negative effects of microplastics and plasticizer DEHP: The increased release of Nets delays wound healing in mice.}, journal = {The Science of the total environment}, volume = {862}, number = {}, pages = {160861}, doi = {10.1016/j.scitotenv.2022.160861}, pmid = {36526177}, issn = {1879-1026}, mesh = {Animals ; Mice ; *Diethylhexyl Phthalate/metabolism/toxicity ; Ecosystem ; *Extracellular Traps/metabolism ; Fibrosis ; Microplastics/metabolism ; *Plasticizers/toxicity/metabolism ; Plastics/metabolism ; *Wound Healing ; }, abstract = {Environmental harmful pollutants microplastics (MPs) and di (2-ethyl) hexyl phthalate (DEHP) are widely residual in the environment, which may cause lesion to multiple apparatus by inducing oxidative stress, threatening the health of human and animals. Neutrophil extracellular traps (Nets) are involved in skin wound healing. Most studies focused on the individual effects of different poisons on animals and ecosystems, but there are few studies on the accumulation and interaction of multiple poisons. The purpose of this study is to explore the effect of DEHP and MPs co-exposure on skin wound healing and the formation of Nets. For this purpose, we detected this hypothesis by replicating the DEHP and MPs-exposed skin wound model in mice, as well as the co-culture system of neutrophil and fibroblast. The results displayed that MPs and DEHP exposure delayed skin healing, which was more pronounced in the combined exposure group. In vitro and in vivo experiments confirmed that compared with the DEHP or MPs group, the DEHP+MPs group had more significant oxidative stress, increased Nets release and inflammatory factors, and inhibited the Wnt/β-catenin pathway and fibrosis-related factors. N-acetylcysteine (NAC) attenuated these phenomena. Through the co-culture system, we confirmed that the overproduction of Nets induced fibroblasts to exacerbate inflammatory responses and inhibit Wnt pathway and fibrosis. Overall, DEHP and MPs can produce synergistic toxic injury in mice skin wounds, and the excessive activation of ROS/Nets can aggravate inflammatory and inhibit fibrosis, resulting in delayed wound healing.}, }
@article {pmid36525766, year = {2023}, author = {Xu, H and Du, Y and Wang, Q and Chen, L and Huang, J and Liu, Y and Zhou, C and Du, B}, title = {Comparative efficacy, acceptability, and tolerability of adjunctive anti-inflammatory agents on bipolar disorder: A systemic review and network meta-analysis.}, journal = {Asian journal of psychiatry}, volume = {80}, number = {}, pages = {103394}, doi = {10.1016/j.ajp.2022.103394}, pmid = {36525766}, issn = {1876-2026}, mesh = {Humans ; *Bipolar Disorder/drug therapy ; Network Meta-Analysis ; Anti-Inflammatory Agents/therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal ; Combined Modality Therapy ; }, abstract = {OBJECTIVES: We performed a network meta-analysis (NMA) with up-to-date evidence to compare different anti-inflammatory agents to improve the treatment of bipolar disorder (BD) patients.<br><br>METHODS: Four databases (i.e., the Cochrane Library, Web of Science, PubMed, and Embase) were searched for randomized controlled trials (RCTs) published between 1995 and 2022 on the use of anti-inflammatory agents in the treatment of BD. A systematic review and NMA were conducted.<br><br>RESULTS: Adjunctive N-acetylcysteine (NAC) was superior to placebo for the treatment of BD according to the endpoint scale score (SMD -0.65, 95% confidence interval (CI): -&#xa0;0.99 to -&#xa0;0.31), response rate (odds ratio (OR) 3.42, 95% CI: 1.23-9.52), remission rate (OR 4.94, 95% CI: 1.03-41.38) and surface under the cumulative ranking curve (SUCRA) value of the endpoint scale score (0.84). Adjunctive nonsteroidal anti-inflammatory drugs (NSAIDs) were more favorable than placebo based on the remission rate (OR 3.93, 95% CI: 1.15-13.43) and were significantly more acceptable than other treatments (OR 0.60, 95% CI: 0.36-0.99). Adjunctive coenzyme Q10 (CoQ10) was superior to other agents in terms of the response rate (OR 18.85, 95% CI: 2.63-135.00), with a SUCRA value for the response rate of 0.90 and that for the remission rate of 0.71.<br><br>CONCLUSION: Adjunctive NAC is recommended for the treatment of BD. Adjunctive NSAIDs and CoQ10 are still seen as effective, but more high-quality clinical studies are needed to verify their efficacy. Other anti-inflammatory agents may not be recommended for clinical use at present. All anti-inflammatory agents demonstrated a good safety profile. We call for further research on the combined treatment of BD with different anti-inflammatory agents to be included in future trials.}, }
@article {pmid36521547, year = {2023}, author = {Ma, F and Li, H and Huo, H and Han, Q and Liao, J and Zhang, H and Li, Y and Pan, J and Hu, L and Guo, J and Tang, Z}, title = {N-acetyl-L-cysteine alleviates FUNDC1-mediated mitophagy by regulating mitochondrial dynamics in type 1 diabetic nephropathy canine.}, journal = {Life sciences}, volume = {313}, number = {}, pages = {121278}, doi = {10.1016/j.lfs.2022.121278}, pmid = {36521547}, issn = {1879-0631}, mesh = {Animals ; Dogs ; Acetylcysteine/pharmacology ; *Diabetes Mellitus ; *Diabetic Nephropathies/pathology ; *Insulins/pharmacology ; Mitochondrial Dynamics ; Mitochondrial Proteins/metabolism ; Mitophagy ; }, abstract = {Diabetic nephropathy (DN) is a major complication of type 1 diabetes mellitus, and hyperglycemia and hypertension are the main risk factors for the development of DN. N-Acetyl-Cysteine (NAC) has a variety of effects, interfering with the production and scavenging of free radicals and regulating the metabolic activity of tissue cells. However, the efficacy of NAC on DN treatment is unclear. Thus, this study investigated the protective mechanism of NAC combined with insulin on renal injury in dogs with DN. The forty dogs were selected and divided into control group, DM group, INS group, INS + NAC group and NAC group to establish the model for a trial period of 4 months. The results revealed that INS + NAC was effective in reducing and stabilizing blood glucose levels. Biochemical results showed that INS + NAC treatment significantly regulated the stability of UREA, CREA and fructosamine indicators. Meanwhile, histopathology staining showed significant glomerular wrinkling and fibrosis in the DM group, which could be reversed after INS + NAC treatment. In addition, INS + NAC could restore mitochondria homeostasis by upregulating the levels of mitochondrial fission (MFN1, MFN2 and OPA1) and inhibiting of mitochondrial fusion (DRP1, FIS1 and MFF) related indicators. Further studies revealed that INS + NAC regulated the expression levels of renal BNIP3, NIX and FUNDC1 in the DM group, thereby alleviating mitophagy. Collectively, these results suggested that NAC combined with insulin protects DN by regulating the mitochondrial dynamics and FUNDC1-mediated mitophagy.}, }
@article {pmid36518453, year = {2022}, author = {Henneh, IT and Ahlidja, W and Alake, J and Kwabil, A and Ahmed, MA and Kyei-Asante, B and Adinortey, MB and Ekor, M and Armah, FA}, title = {Ziziphus abyssinica root bark extract ameliorates paracetamol-induced liver toxicity in rats possibly via the attenuation of oxidative stress.}, journal = {Toxicology reports}, volume = {9}, number = {}, pages = {1929-1937}, pmid = {36518453}, issn = {2214-7500}, abstract = {Ziziphus abyssinica root bark is widely used in folk medicine to manage liver diseases, particularly, jaundice but its effect on paracetamol-induced liver toxicity (PILT) has not yet been validated. This study explored the ameliorative effect of ethanolic root bark extract of Ziziphus abyssinica (ZAE) against PILT in rats. The flavonoid and phenolic content of ZAE was evaluated using Folin-Ciocalteau and aluminium trichloride colorimetric methods, respectively. Antioxidant activity of ZAE was determined in vitro by evaluating its ferrous reducing antioxidant capacity (FRAC) as well as DPPH and nitic oxide (NO) radicals scavenging activities. Sprague-Dawley rats were assigned to six groups (n = 6) and administered with normal saline (10 mL/kg, p.o.), N-acetylcysteine (50 mg/kg, i.p.) and ZAE (30, 100, and 300 mg/kg, p.o.) respectively for seven days after which they received paracetamol (PCM, 3000 mg/kg, p.o.). Animals were sacrificed 48 h after paracetamol administration under light anaesthesia and assessed for liver toxicity and oxidative stress. Total flavonoid and phenolic contents of ZAE were 1313.425 µg/mL quercetin equivalence and 268.31 µg/mL gallic acid equivalence respectively. ZAE exhibited marked FRAC as well as DPPH and NO radical scavenging activities with IC50s of 80.41 ± 1.56, 67.56 ± 1.11 and 7.11 ± 1.48 μg/mL respectively. ZAE and N-acetylcysteine significantly (p < 0.05) reduced the paracetamol-mediated elevation of serum total bilirubin, proteins and activity of liver enzymes (AST, ALP, and ALT). Similarly, ZAE increased hepatic glutathione, total thiols and catalase activity of the paracetamol intoxicated rats. Morphological changes associated with the paracetamol hepatotoxicity were also ameliorated by ZAE. Overall, the hepatoprotective effect of ZAE may be related to its antioxidant property.}, }
@article {pmid36517965, year = {2023}, author = {Wang, P and Ma, H and Hou, X and Song, L and Feng, M}, title = {N-acetyl-L-cysteine ameliorates gestational diabetes mellitus by inhibiting oxidative stress.}, journal = {Biotechnology and applied biochemistry}, volume = {70}, number = {3}, pages = {1128-1136}, doi = {10.1002/bab.2426}, pmid = {36517965}, issn = {1470-8744}, mesh = {Pregnancy ; Humans ; Female ; Mice ; Animals ; *Diabetes, Gestational/drug therapy/metabolism ; Acetylcysteine/pharmacology/metabolism/therapeutic use ; Oxidative Stress ; Antioxidants/metabolism ; Inflammation ; }, abstract = {Gestational diabetes mellitus (GDM) is a common pregnant disorder that needs careful medical attention. N-acetyl-L-cysteine (NAC) is a well-recognized antioxidant to treat oxidative stress-induced diseases. Although its role in GDM has been reported, the mechanism remains largely unknown. Therefore, our current study further explored its protective role against GDM. An 8-week-old, db/+, female mice were injected with a single dose of 100 mg/kg streptozotocin (STZ) to induce diabetes. Pregnant mice were randomly treated with 1200 mg/kg NAC or water daily. On gestational day 19, oral glucose tolerance test was performed, and visceral fat tissue and blood samples were collected. After delivery, litter size and weight were recorded. NAC could effectively improve GDM-induced glucose intolerance, hyperlipidemia, activated inflammation, and oxidative stress in GDM mice. Moreover, NAC reduced the litter size and weight of GDM mice. NAC also activated the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in the liver of GDM mice. NAC effectively ameliorated GDM symptoms and the reproductive outcome of GDM mice through inhibiting oxidative stress, inflammation, and hyperlipidemia. Therefore, NAC might serve as a potential candidate drug against GDM.}, }
@article {pmid36517743, year = {2022}, author = {Liu, F and Zhang, Y and Shi, Y and Xiong, K and Wang, F and Yang, J}, title = {Ceramide induces pyroptosis through TXNIP/NLRP3/GSDMD pathway in HUVECs.}, journal = {BMC molecular and cell biology}, volume = {23}, number = {1}, pages = {54}, pmid = {36517743}, issn = {2661-8850}, support = {81400058//Jin Yang/ ; }, mesh = {Humans ; *Pyroptosis/genetics ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Ceramides/pharmacology ; Caspase 1/genetics/metabolism/pharmacology ; Human Umbilical Vein Endothelial Cells ; RNA, Messenger/genetics ; Lactate Dehydrogenases/metabolism ; Carrier Proteins ; Phosphate-Binding Proteins/metabolism/pharmacology ; Pore Forming Cytotoxic Proteins/metabolism ; }, abstract = {BACKGROUND: Pyroptosis of endothelial cells is a new cause of endothelial dysfunction in multiple diseases. Ceramide acts as a potential bioactive mediator of inflammation and increases vascular endothelial permeability in many diseases, whether it can aggravate vascular endothelial injury by inducing cell pyroptosis remains unknown. This study was established to explore the effects of C8-ceramide (C8-Cer) on human umbilical vein vascular endothelial cells (HUVECs) and its possible underlying mechanism.<br><br>METHODS: HUVECs were exposed to various concentrations of C8-Cer for 12&#x2009;h, 24&#x2009;h, 48&#x2009;h. The cell survival rate was measured using the cell counting kit-8 assay. Western blotting and Real-time polymerase chain reaction (RT-PCR) were used to detect the pyroptosis-releated protein and mRNA expressions, respectively. Caspase-1 activity assay was used to detect caspase-1 activity. Hoechst 33342/propidium iodide double staining and flow cytometry were adopted to measure positive staining of cells. Lactate dehydrogenase release assay and enzyme-linked immunosorbent assay were adopted to measure leakage of cellular contents. FITC method was used to detect the permeability of endothelial cells. ROS fluorescence intensity were detected by flow cytometry.<br><br>RESULTS: The viability of HUVECs decreased gradually with the increase in ceramide concentration and time. Ceramide upregulated the expression of thioredoxin interacting protein (TXNIP), NLRP3, GSDMD, GSDMD-NT, caspase-1 and Casp1 p20 at the protein and mRNA level in a dose-dependent manner. It also enhanced the PI uptake in HUVECs and upregulated caspase-1 activity. Moreover, it promoted the release of lactate dehydrogenase, interleukin-1&#x3b2;, and interleukin-18. Meanwhile, we found that ceramide led to increased vascular permeability. The inhibitor of NLRP3 inflammasome assembly, MCC950, was able to disrupt the aforementioned positive loop, thus alleviating vascular endothelial cell damage. Interestingly, inhibition of TXNIP either chemically using verapamil or genetically using small interfering RNA (siRNA) can effectively inhibit ceramide-induced pyroptosis and improved cell permeability. In addition, ceramide stimulated reactive oxygen species (ROS) generation. The pretreatment of antioxidant N-acetylcysteine (NAC), ROS scavenger, blocked the expression of pyroptosis markers induced by C8-cer in HUVECs.<br><br>CONCLUSION: The current study demonstrated that C8-Cer could aggravate vascular endothelial cell damage and increased cell permeability by inducing cell pyroptosis. The results documented that the ROS-dependent TXNIP/NLRP3/GSDMD signalling pathway plays an essential role in the ceramide-induced pyroptosis in HUVECs.}, }
@article {pmid36514019, year = {2022}, author = {Podolanczuk, AJ and Kim, JS and Cooper, CB and Lasky, JA and Murray, S and Oldham, JM and Raghu, G and Flaherty, KR and Spino, C and Noth, I and Martinez, FJ and , }, title = {Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial.}, journal = {BMC pulmonary medicine}, volume = {22}, number = {1}, pages = {475}, pmid = {36514019}, issn = {1471-2466}, support = {UH3 HL145266/HL/NHLBI NIH HHS/United States ; U24 HL145265/HL/NHLBI NIH HHS/United States ; UH3HL145266/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Double-Blind Method ; Genotype ; *Idiopathic Pulmonary Fibrosis/drug therapy/genetics ; Treatment Outcome ; Vital Capacity ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; Clinical Trials, Phase III as Topic ; }, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial.<br><br>METHODS: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600&#xa0;mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC.<br><br>DISCUSSION: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study to use molecularly-focused techniques to identify patients with IPF most likely to benefit from treatment. PRECISIONS has the potential to shift the paradigm in how trials in this condition are designed and executed, and is the first step toward personalized medicine for patients with IPF. Trial Registration ClinicalTrials.gov identifier: NCT04300920. Registered March 9, 2020. https://clinicaltrials.gov/ct2/show/NCT04300920.}, }
@article {pmid36509450, year = {2023}, author = {Ramesh, R and Skog, S and Örkenby, L and Kugelberg, U and Nätt, D and Öst, A}, title = {Dietary Sugar Shifts Mitochondrial Metabolism and Small RNA Biogenesis in Sperm.}, journal = {Antioxidants &amp; redox signaling}, volume = {38}, number = {16-18}, pages = {1167-1183}, pmid = {36509450}, issn = {1557-7716}, mesh = {Male ; Humans ; Animals ; Reactive Oxygen Species/metabolism ; Dietary Sugars/metabolism ; Hydrogen Peroxide/metabolism ; Proteomics ; Semen/metabolism ; Spermatozoa/metabolism ; Mitochondria/metabolism ; *MicroRNAs/genetics/metabolism ; Drosophila/metabolism ; *RNA, Small Untranslated/metabolism ; }, abstract = {Aims: Increasing concentrations of dietary sugar results in a linear accumulation of triglycerides in male Drosophila, while inducing a U-shaped obesity response in their offspring. Here, using a combination of proteomics and small RNA (sRNA) sequencing, we aimed at understanding the molecular underpinning in sperm for such plasticity. Results: Proteomic analysis of seminal vesicles revealed that increasing concentrations of dietary sugar resulted in a bell-shaped induction of proteins involved in metabolic/redox regulation. Using stains and in vivo redox reporter flies, this pattern could be explained by changes in sperm production of reactive oxygen species (ROS), more exactly mitochondria-derived H2O2. By quenching ROS with the antioxidant N-acetyl cysteine and performing sRNA-seq on sperm, we found that sperm miRNA is increased in response to ROS. Moreover, we found sperm mitosRNA to be increased in high-sugar diet conditions (independent of ROS). Reanalyzing our previously published data revealed a similar global upregulation of human sperm mitosRNA in response to a high-sugar diet, suggesting evolutionary conserved mechanisms. Innovation: This work highlights a fast response to dietary sugar in mitochondria-produced H2O2 in Drosophila sperm and identifies redox-sensitive miRNA downstream of this event. Conclusions: Our data support a model where changes in the sperm mitochondria in response to dietary sugar are the primary event, and changes in redox homoeostasis are secondary to mitochondrial ROS production. These data provide multiple candidates for paternal intergenerational metabolic responses as well as potential biomarkers for human male fertility. Antioxid. Redox Signal. 38, 1167-1183.}, }
@article {pmid36506010, year = {2022}, author = {Magalhães, LS and Melo, EV and Damascena, NP and Albuquerque, ACB and Santos, CNO and Rebouças, MC and Bezerra, MO and Louzada da Silva, R and de Oliveira, FA and Santos, PL and da Silva, JS and Lipscomb, MW and da Silva, &#xc2;M and de Jesus, AR and de Almeida, RP}, title = {Use of N-acetylcysteine as treatment adjuvant regulates immune response in visceral leishmaniasis: Pilot clinical trial and in vitro experiments.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {1045668}, pmid = {36506010}, issn = {2235-2988}, mesh = {Humans ; Acetylcysteine/pharmacology/therapeutic use ; Adjuvants, Immunologic/therapeutic use ; Immunity ; Interleukin-10 ; *Leishmania infantum ; *Leishmaniasis, Visceral/drug therapy ; Leukocytes, Mononuclear ; }, abstract = {This investigation aimed to assess the effect of N-acetylcysteine (NAC) as an adjuvant treatment to alleviate visceral leishmaniasis (VL). The present work includes both blinded randomized clinical intervention and experimental in vitro studies. The clinical trial included 60 patients with VL randomly allocated into two groups: a test group (n = 30) treated with meglumine antimoniate plus NAC (SbV + NAC) and a control group (n = 30) treated with meglumine antimoniate only (SbV). The primary outcome was clinical cure (absence of fever, spleen and liver sizes reduction, and hematological improvement) in 180 days. The cure rate did not differ between the groups; both groups had similar results in all readout indices. The immunological parameters of the patients treated with SbV + NAC showed higher sCD40L in sera during treatment, and the levels of sCD40L were negatively correlated with Interleukin-10 (IL-10) serum levels. In addition, data estimation showed a negative correlation between the sCD40L levels and the spleen size in patients with VL. For the in vitro experiments, peripheral blood mononuclear cells (PBMCs) or PBMC-derived macrophages from healthy donors were exposed to soluble Leishmania antigen (SLA) or infected with stationary promastigotes of Leishmania infantum in the presence or absence of NAC. Results revealed that NAC treatment of SLA-stimulated PBMCs reduces the frequency of monocytes producing IL-10 and lowers the frequency of CD4+ and CD8+ T cells expressing (pro-)inflammatory cytokines. Together, these results suggest that NAC treatment may modulate the immune response in patients with VL, thus warranting additional investigations to support its case use as an adjuvant to antimony therapy for VL.}, }
@article {pmid36502431, year = {2023}, author = {Tüfekci, KK and Bakirhan, EG and Terzi, F}, title = {A Maternal High-Fat Diet Causes Anxiety-Related Behaviors by Altering Neuropeptide Y1 Receptor and Hippocampal Volumes in Rat Offspring: the Potential Effect of N-Acetylcysteine.}, journal = {Molecular neurobiology}, volume = {60}, number = {3}, pages = {1499-1514}, pmid = {36502431}, issn = {1559-1182}, support = {KUBAP01/2021-03//Kastamonu &#xdc;niversitesi/ ; }, mesh = {Humans ; Rats ; Animals ; Male ; Female ; Pregnancy ; *Acetylcysteine/pharmacology/therapeutic use ; Diet, High-Fat/adverse effects ; *Obesity, Maternal/metabolism ; Hippocampus/metabolism ; Obesity/complications/drug therapy/metabolism ; Anxiety/complications ; }, abstract = {The children of obese mothers are known to have a high risk of obesity and metabolic disease and are prone to developing cognitive deficits, although the underlying mechanism is not yet fully understood. This study investigated the relationship between neuropeptide Y1 receptor (NPY1R) and anxiety-like behaviors in the hippocampi of male rat offspring exposed to maternal obesity and the potential neuroprotective effects of N-acetylcysteine (NAC). A maternal obesity model was created using a high-fat (60% k/cal) diet. NAC (150 mg/kg) was administered by intragastric gavage for 25 days in both the NAC and obesity + NAC (ObNAC) groups. All male rat offspring were subjected to behavioral testing on postnatal day 28, the end of the experiment. Stereological analysis was performed on hippocampal sections, while NPY1R expression was determined using immunohistochemical methods. Stereological data indicated significant decreases in the total volume of the hippocampus and CA1 and dentate gyrus (DG) regions in the obese (Ob) group (p < 0.01). Decreased NPY1R expression was observed in the Ob group hippocampus (p < 0.01). At behavioral assessments, the Ob group rats exhibited increased anxiety and less social interaction, although the ObNAC group rats exhibited stronger responses than the Ob group (p < 0.01). The study results show that NAC attenuated anxiety-like behaviors and NPY1R expression and also protected hippocampal volume against maternal obesity. The findings indicate that a decrease in NPY1R-positive neurons in the hippocampus of male rats due to maternal conditions may be associated with increased levels of anxiety and a lower hippocampal volume. Additionally, although there is no direct evidence, maintenance of NPY1R expression by NAC may be critical for regulating maternal obesity-induced anxiety-related behaviors and hippocampal structure.}, }
@article {pmid36500398, year = {2022}, author = {Słowiński, D and Świerczyńska, M and Romański, J and Podsiadły, R}, title = {HPLC Study of Product Formed in the Reaction of NBD-Derived Fluorescent Probe with Hydrogen Sulfide, Cysteine, N-acetylcysteine, and Glutathione.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {23}, pages = {}, pmid = {36500398}, issn = {1420-3049}, support = {POWR.03.02.00-00-I029/16//National Center for Research and Development (Warsaw, Poland)/ ; }, mesh = {Humans ; *Cysteine ; Fluorescent Dyes ; *Hydrogen Sulfide ; Acetylcysteine ; Optical Imaging ; Glutathione ; Sulfhydryl Compounds ; Homocysteine ; HeLa Cells ; }, abstract = {Hydrogen sulfide (H2S) and its bioderivatives analogs, such as L-cysteine (L-Cys) and glutathione (GSH), are ubiquitous biological thiols in the physiological and pathological processes of living systems. Their aberrant concentration levels are associated with many diseases. Although several NBD-based fluorescence probes have been developed to detect biological thiols, the HPLC-detection of H2S, GSH, L-Cys, and N-acetylcysteine-specific products has not been described. Herein, a novel NBD-derived pro-coumarin probe has been synthesized and used to develop a new strategy for the triple mode detection of H2S and such thiols as GSH, L-Cys, and NAC. Hydrogen sulfide and those biothiols at physiological pH release fluorescent coumarin from the probe and cause a significant fluorescence enhancement at 473 nm. The appropriate NBD-derived product for H2S, L-Cys, GSH, and NAC has a different color and retention time that allows distinguishing these biological thiols meaning the probe has a great possibility in the biological application. Fluorescent imaging combined with colorimetric and HPLC detection of H2S/biothiol-specific product(s) brings a potential tool for confirming the presence of biological thiols and determining concentrations in various aqueous biological samples.}, }
@article {pmid36499332, year = {2022}, author = {Feriotto, G and Tagliati, F and Brunello, A and Beninati, S and Tabolacci, C and Mischiati, C}, title = {A Central Contribution of TG2 Activity to the Antiproliferative and Pro-Apoptotic Effects of Caffeic Acid in K562 Cells of Human Chronic Myeloid Leukemia.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36499332}, issn = {1422-0067}, mesh = {Humans ; K562 Cells ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics/metabolism ; Imatinib Mesylate/pharmacology/therapeutic use ; Caffeic Acids/pharmacology/therapeutic use ; Apoptosis ; Drug Resistance, Neoplasm ; }, abstract = {Caffeic acid (CA) has shown antitumor activity in numerous solid and blood cancers. We have recently reported that CA is active in reducing proliferation and triggering apoptosis in both Imatinib-sensitive and resistant Chronic Myeloid Leukemia (CML) cells. Tissue transglutaminase type 2 (TG2) enzyme is involved in cell proliferation and apoptosis of numerous types of cancer. However, its activity has different effects depending on the type of tumor. This work investigated the possible involvement of TG2 activation in the triggering of CA-dependent anticancer effects on the K562 cell line, which was studied as a model of CML. CA-dependent changes in TG2 activity were compared with the effects on cell proliferation and apoptosis. The use of N-acetylcysteine (NAC), an antioxidant molecule, suggested that the antiproliferative effect of CA was due to the increase in reactive oxygen species (ROS). The use of a TG2 inhibitor showed that TG2 activity was responsible for the increase in ROS generated by CA and reduced both caspase activation and triggering of CA-dependent apoptosis. The knocking-down of TGM2 transcripts confirmed the crucial involvement of TG2 activation in CML cell death. In conclusion, the data reported, in addition to ascertaining the important role of TG2 activation in the antiproliferative and pro-apoptotic mechanism of CA allowed us to hypothesize a possible therapeutic utility of the molecules capable of triggering the activation pathways of TG2 in the treatment of CML.}, }
@article {pmid36498845, year = {2022}, author = {Milara, J and Martínez-Expósito, F and Montero, P and Roger, I and Bayarri, MA and Ribera, P and Oishi-Konari, MN and Alba-García, JR and Zapater, E and Cortijo, J}, title = {N-acetylcysteine Reduces Inflammasome Activation Induced by SARS-CoV-2 Proteins In Vitro.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36498845}, issn = {1422-0067}, support = {PI20/01363//Instituto de Salud Carlos III/ ; PID2020-114871RB-I00//Instituto de Salud Carlos III/ ; CB06/06/0027//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red/ ; 2017/023/UV//Generalitat Valenciana/ ; }, mesh = {Humans ; *SARS-CoV-2/metabolism ; Inflammasomes/metabolism ; Acetylcysteine/pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *COVID-19 ; Cytokines ; Recombinant Proteins/pharmacology ; }, abstract = {Inflammasome activation is one of the first steps in initiating innate immune responses. In this work, we studied the activation of inflammasomes in the airways of critically ill COVID-19 patients and the effects of N-acetylcysteine (NAC) on inflammasomes. Tracheal biopsies were obtained from critically ill patients without COVID-19 and no respiratory disease (control, n = 32), SARS-CoV-2 B.1 variant (n = 31), and B.1.1.7 VOC alpha variant (n = 20) patients. Gene expression and protein expression were measured by RT-qPCR and immunohistochemistry. Macrophages and bronchial epithelial cells were stimulated with different S, E, M, and N SARS-CoV-2 recombinant proteins in the presence or absence of NAC. NLRP3 inflammasome complex was over-expressed and activated in the COVID-19 B.1.1.7 VOC variant and associated with systemic inflammation and 28-day mortality. TLR2/MyD88 and redox NOX4/Nrf2 ratio were also over-expressed in the COVID-19 B.1.1.7 VOC variant. The combination of S-E-M SARS-CoV-2 recombinant proteins increased cytokine release in macrophages and bronchial epithelial cells through the activation of TLR2. NAC inhibited SARS-CoV-2 mosaic (S-E-M)-induced cytokine release and inflammasome activation. In summary, inflammasome is over-activated in severe COVID-19 and increased in B.1.1.7 VOC variant. In addition, NAC can reduce inflammasome activation induced by SARS-CoV-2 in vitro, which may be of potential translational value in COVID-19 patients.}, }
@article {pmid36498831, year = {2022}, author = {Lee, JW and Cho, JY and Thuy, PX and Moon, EY}, title = {HeLa Cervical Cancer Cells Are Maintained by Nephronophthisis 3-Associated Primary Cilium Formation via ROS-Induced ERK and HIF-1α Activation under Serum-Deprived Normoxic Condition.}, journal = {International journal of molecular sciences}, volume = {23}, number = {23}, pages = {}, pmid = {36498831}, issn = {1422-0067}, support = {Basic Research Program 2021R1A4A5033289//National Research Foundation of Korea/ ; }, mesh = {Female ; Humans ; Cell Hypoxia ; *Cilia/metabolism ; HeLa Cells ; Hydrogen Peroxide/metabolism ; *Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Kinesins/genetics/metabolism ; }, abstract = {The primary cilium (PC) is a microtubule-based antenna-like organelle projecting from the surface of the cell membrane. We previously reported that PC formation could be regulated by nephronophthisis 3 (NPHP3) expression followed by its interaction with thymosin β4. Here, we investigated whether cancer cell viability is regulated by NPHP3-mediated PC formation. The total and viable cell number were reduced by incubating cells under serum deprivation (SD) without fetal bovine serum (-FBS). PC frequency was increased by SD which enhanced NPHP3 expression and hypoxia inducible factor (HIF)-1α. The role of HIF-1α on NPHP3 expression and PC formation was confirmed by the binding of HIF-1α to the NPHP3 promoter and siRNA-based inhibition of HIF-1α (siHIF-1α), respectively. HIF-1α-stabilizing dimethyloxallyl glycine (DMOG) and hypoxic conditions increased NPHP3 expression and PC formation. In addition, as SD elevated the reactive oxygen species (ROS), PC frequency and NPHP3 expression were inhibited by a treatment with N-acetylcysteine (NAC), a ROS scavenger. PC formation was increased by H2O2 treatment, which was inhibited by siHIF-1α. The inhibition of ERK with P98059 decreased the frequency of PC formation and NPHP3 expression. Cell viability was reduced by a treatment with ciliobrevin A (CilioA) to inhibit PC formation, which was re-affirmed by using PC-deficient IFT88[-/-] cells. Taken together, the results imply that PC formation in cancer cells could be controlled by NPHP3 expression through ROS-induced HIF-1α and ERK activation under SD conditions. It suggests that cancer cell viability under SD conditions could be maintained by NPHP3 expression to regulate PC formation.}, }
@article {pmid36497648, year = {2022}, author = {Gorbachev, V and Nikulchev, E and Kosenkov, AN and Sokolov, A and Zavalishin, I and Nikitin, I}, title = {Estimating the Mass of Food Components Necessary for the Utilization of Free Radical Particles in the Human Body.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {23}, pages = {}, pmid = {36497648}, issn = {1660-4601}, mesh = {Humans ; *Human Body ; Free Radicals ; *Diet ; Vitamins ; Ascorbic Acid ; }, abstract = {The article proposes an algorithm for an approximate assessment of the molar volume of free radicals generated in the human body per day. It takes into account the act of breathing, physical activity, food consumption, the influence of unfavorable environmental conditions, exposure to xenobiotics, as well as bad habits (alcohol and tobacco smoking). A calculation of the required set of the most commonly used food products for the disposal of free radicals was made. The calculation is a structure of four blocks with the possibility of adding optional data from human population genetic studies, environmental conditions, etc. In the proposed algorithm, the results of antiradical activity (ARA) of food products are used as input, including the results of predicting antiradical activity using artificial neural networks (ANN), which we published earlier. Based on the accepted values of one equivalent (in terms of the activity of 1 μmol of ascorbic acid), it was shown (for our data) that for the utilization of all free radicals produced in the human body per day, it will take an average of ≈260 to ≈540 g of food components in terms of dry mass (including proteins, fats, carbohydrates, etc.). At the same time, for the utilization of consumed xenobiotics, from 220 mg (in terms of vitamin C) to 260 mg (in terms of acetylcysteine -NAC) of additional plastic components or 11.5-13.0 g of essential amino acids will be required, which must be taken into account when calculating diets. This approach will be useful in the development of new functional foods, as well as in assessing the possible impact of diets on human health. Another applied point of this study is related to the possibility of using these data for better detailing and selection of food products for people working in conditions of increased radiation (in space conditions), in contact with harmful substances (chemical synthesis and production), for people practicing increased physical activity (bodybuilding and sports), and for the purposes of medical nutritional therapy.}, }
@article {pmid36497051, year = {2022}, author = {Liu, B and Ding, C and Tang, W and Zhang, C and Gu, Y and Wang, Z and Yu, T and Li, Z}, title = {Hepatic ROS Mediated Macrophage Activation Is Responsible for Irinotecan Induced Liver Injury.}, journal = {Cells}, volume = {11}, number = {23}, pages = {}, pmid = {36497051}, issn = {2073-4409}, support = {81974458, 82170607//National Natural Science Foundation of China/ ; 2021JJ30463, 2022JJ10037//Hunan Provincial Natural Science Foundation of China/ ; 2019RS1042, 2019TP1035//China Hunan Provincial Science/Technology Department/ ; 2022XKQ0205 and KF2022001//Hunan Normal University/ ; }, mesh = {Mice ; Animals ; Macrophage Activation ; Irinotecan/pharmacology ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Hepatocytes/metabolism ; *Fatty Liver/metabolism ; Acetylcysteine/pharmacology ; }, abstract = {Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice.}, }
@article {pmid36495185, year = {2023}, author = {Panahi, Y and Ghanei, M and Rahimi, M and Samim, A and Vahedian-Azimi, A and Atkin, SL and Sahebkar, A}, title = {Evaluation the efficacy and safety of N-acetylcysteine inhalation spray in controlling the symptoms of patients with COVID-19: An open-label randomized controlled clinical trial.}, journal = {Journal of medical virology}, volume = {95}, number = {1}, pages = {e28393}, pmid = {36495185}, issn = {1096-9071}, mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/adverse effects ; *COVID-19/therapy ; Length of Stay ; SARS-CoV-2 ; Treatment Outcome ; Administration, Inhalation ; *Oral Sprays ; Nebulizers and Vaporizers ; }, abstract = {The aim of this study was to evaluate the effect and safety of N-acetylcysteine (NAC) inhalation spray in the treatment of patients with coronavirus disease 2019 (COVID-19). This randomized controlled clinical trial study was conducted on patients with COVID-19. Eligible patients (n = 250) were randomly allocated into the intervention group (routine treatment + NAC inhaler spray one puff per 12 h, for 7 days) or the control group who received routine treatment alone. Clinical features, hemodynamic, hematological, biochemical parameters and patient outcomes were assessed and compared before and after treatment. The mortality rate was significantly higher in the control group than in the intervention group (39.2% vs. 3.2%, p < 0.001). Significant differences were found between the two groups (intervention and control, respectively) for white blood cell count (6.2 vs. 7.8, p < 0.001), hemoglobin (12.3 vs. 13.3, p = 0.002), C-reactive protein (CRP: 6 vs. 11.5, p < 0.0001) and aspartate aminotransferase (AST: 32 vs. 25.5, p < 0.0001). No differences were seen for hospital length of stay (11.98 ± 3.61 vs. 11.81 ± 3.52, p = 0.814) or the requirement for intensive care unit (ICU) admission (7.2% vs. 11.2%, p = 0.274). NAC was beneficial in reducing the mortality rate in patients with COVID-19 and inflammatory parameters, and a reduction in the development of severe respiratory failure; however, it did not affect the length of hospital stay or the need for ICU admission. Data on the effectiveness of NAC for Severe Acute Respiratory Syndrome Coronavirus-2 is limited and further research is required.}, }
@article {pmid36493885, year = {2023}, author = {Dong, W and Zhang, K and Gong, Z and Luo, T and Li, J and Wang, X and Zou, H and Song, R and Zhu, J and Ma, Y and Liu, G and Liu, Z}, title = {N-acetylcysteine delayed cadmium-induced chronic kidney injury by activating the sirtuin 1-P53 signaling pathway.}, journal = {Chemico-biological interactions}, volume = {369}, number = {}, pages = {110299}, doi = {10.1016/j.cbi.2022.110299}, pmid = {36493885}, issn = {1872-7786}, mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/therapeutic use ; Cadmium/toxicity ; Sirtuin 1/metabolism ; Tumor Suppressor Protein p53/metabolism ; Kidney/metabolism ; *Renal Insufficiency, Chronic/chemically induced/drug therapy ; Signal Transduction ; Fibrosis ; Cellular Senescence ; }, abstract = {With the development of modern industrial civilization, cadmium (Cd), a known nephrotoxic metal, has become a growing public safety issue due to its ability to induce various types of kidney disease. Maladaptive proximal tubule repair is a significant cause of Cd-induced chronic kidney disease (CKD), which is characterized by premature senescence and pro-fibrosis. Previously, we demonstrated that cadmium causes DNA damage and cycle arrest in renal tubular epithelial cells, which may be relevant to premature senescence regulated by sirtuin 1 (SIRT1). In this study, in vivo and in vitro studies were conducted to elucidate the role of SIRT1-mediated premature renal senescence in Cd-induced CKD. As oxidative stress is a significant cause of aging, we evaluated whether N-acetylcysteine (NAC) would inhibit Cd-induced premature aging and dysfunction in rat renal tubular epithelial cells. Cadmium induced premature renal senescence and fibrosis, and NAC inhibited premature renal senescence and fibrosis through the SIRT1-P53 pathway and delayed CKD progression. Overall, the results suggested that the SIRT1-P53 pathway mediates oxidative stress, premature renal senescence, and renal fibrosis during cadmium exposure, which may be a potential therapeutic target for Cd-induced CKD.}, }
@article {pmid36481977, year = {2022}, author = {Ye, Z and Wang, Q and Dai, S and Ji, X and Cao, P and Xu, C and Bao, G}, title = {The Berberis vulgaris L. extract berberine exerts its anti-oxidant effects to ameliorate cholesterol overloading-induced cell apoptosis in the primary mice hepatocytes: an in vitro study.}, journal = {In vitro cellular &amp; developmental biology. Animal}, volume = {58}, number = {10}, pages = {855-866}, pmid = {36481977}, issn = {1543-706X}, support = {202101AY070001-085//Basic Research Program of Yunnan Science and Technology Department/ ; 2018BS006//The Doctoral Research Fund of First Affiliated Hospital of Kunming Medical University/ ; }, mesh = {Animals ; Mice ; *Antioxidants/pharmacology/metabolism ; *Apoptosis/drug effects ; *Berberine/pharmacology/therapeutic use ; *Berberis/metabolism ; Cardiovascular Diseases/drug therapy ; Cholesterol/metabolism/pharmacology ; Hepatocytes/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Cholesterol overloading stress damages normal cellular functions in hepatocytes and induces metabolic disorders to facilitate the development of multiple diseases, including cardiovascular diseases, which seriously degrades the life quality of human beings. Recent data suggest that the Berberis vulgaris L. extract berberine is capable of regulating cholesterol homeostasis, which is deemed as potential therapeutic drug for the treatment of cholesterol overloading-associated diseases, but its detailed functions and molecular mechanisms are still largely unknown. In the present study, we evidenced that berberine suppressed cell apoptosis in high-cholesterol-diet mice liver and cholesterol-overloaded mice hepatocytes. Also, cholesterol overloading promoted reactive oxygen species (ROS) generation to trigger oxidative damages in hepatocytes, which were reversed by co-treating cells with both berberine and the ROS scavenger N-acetylcysteine (NAC). Moreover, the underlying mechanisms were uncovered, and we validated that berberine downregulated Keap1, and upregulated Nrf2 to activate the anti-oxidant Nrf2/HO-1 signaling pathway in cholesterol overloading-treated hepatocytes, and both Keap1 upregulation and Nrf2 downregulation abrogated the suppressing effects of berberine on cell apoptosis in the hepatocytes with cholesterol exposure. Taken together, we concluded that berberine activated the anti-oxidant Keap1/Nrf2/HO-1 pathway to eliminate cholesterol overloading-induced oxidative stress and apoptotic cell death in mice hepatocytes, and those evidences hinted that berberine might be used as putative therapeutic drug for the treatment of cholesterol overloading-associated cardiovascular diseases.}, }
@article {pmid36471531, year = {2023}, author = {Guo, M and Zhang, W and Niu, S and Shang, M and Chang, X and Wu, T and Zhang, T and Tang, M and Xue, Y}, title = {Adaptive regulations of Nrf2 alleviates silver nanoparticles-induced oxidative stress-related liver cells injury.}, journal = {Chemico-biological interactions}, volume = {369}, number = {}, pages = {110287}, doi = {10.1016/j.cbi.2022.110287}, pmid = {36471531}, issn = {1872-7786}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; Silver/toxicity ; NF-E2-Related Factor 2/metabolism ; *Metal Nanoparticles/toxicity ; Oxidative Stress ; Acetylcysteine/pharmacology ; Hep G2 Cells ; *Chemical and Drug Induced Liver Injury ; }, abstract = {Silver nanoparticles (AgNPs) are widely used in various fields such as industry, agriculture, and medical care because of their excellent broad-spectrum antibacterial activity. However, their extensive use has raised concerns about their health risks. Liver is one of the main target organs for the accumulation and action of AgNPs. Therefore, evaluating the toxic effects of AgNPs on liver cells and its mechanisms of action is crucial for the safe application of AgNPs. In the study, polyvinylpyrrolidone (PVP)-coated AgNPs were characterized. The human hepatoma cell line (HepG2) and the normal hepatic cell line (L02) were exposed to different concentrations of AgNPs (20-160 μg/mL) and pretreated with the addition of N-acetylcysteine (NAC) or by Nrf2 siRNA transfection. NAC was able to inhibit the concentration-dependent increase in the level of apoptosis induced by AgNPs in HepG2 cells and L02 cells. Interestingly, HepG2 cells were more sensitive to AgNPs than L02 cells, and this may be related to the different ROS generation and responses to AgNPs by cancer cells and normal cells. In addition, NAC also alleviated the imbalance of antioxidant system and cell cycle arrest, which may be related to AgNPs-induced DNA damage and autophagy. The knockdown of nuclear factor erythroid-derived factor 2-related factor (Nrf2) found that AgNPs-induced ROS and apoptosis levels were further upregulated, but the cell cycle arrest was alleviated. On the whole, Nrf2 exerts a protective role in AgNPs-induced hepatotoxicity. This study complements the hepatotoxicity mechanisms of AgNPs and provides data for a future exploration of AgNPs-related anti-hepatocellular carcinoma drugs.}, }
@article {pmid36467056, year = {2022}, author = {Elsayed, S and Elsaid, KA}, title = {Protein phosphatase 2A regulates xanthine oxidase-derived ROS production in macrophages and influx of inflammatory monocytes in a murine gout model.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {1033520}, pmid = {36467056}, issn = {1663-9812}, abstract = {Background: Gout is a common arthritis, due to deposition of monosodium urate (MSU) crystals which results in IL-1β secretion by tissue-resident macrophages. Xanthine oxidase (XO) catalyzes uric acid (UA) production and in the process, reactive oxygen species (ROS) are generated which contributes to NLRP3 inflammasome activation. Protein phosphatase 2A (PP2A) may be involved in regulating inflammatory pathways in macrophages. The objective of this study was to investigate whether PP2A regulates gout inflammation, mediated by XO activity modulation. We studied UA and ROS generations in MSU stimulated murine bone marrow derived macrophages (BMDMs) in response to fingolimod phosphate, a PP2A activator, and compared its anti-inflammatory efficacy to that of an XO inhibitor, febuxostat. Methods: BMDMs were stimulated with MSU, GM-CSF/IL-1β or nigericin ± fingolimod (2.5 μM) or febuxostat (200 μM) and UA levels, ROS, XO, and PP2A activities, Xdh (XO) expression and secreted IL-1β levels were determined. PP2A activity and IL-1β in MSU stimulated BMDMs ± N-acetylcysteine (NAC) (10 μM) ± okadaic acid (a PP2A inhibitor) were also determined. M1 polarization of BMDMs in response to MSU ± fingolimod treatment was assessed by a combination of iNOS expression and multiplex cytokine assay. The in vivo efficacy of fingolimod was assessed in a murine peritoneal model of acute gout where peritoneal lavages were studied for pro-inflammatory classical monocytes (CMs), anti-inflammatory nonclassical monocytes (NCMs) and neutrophils by flow cytometry and IL-1β by ELISA. Results: Fingolimod reduced intracellular and secreted UA levels (p < 0.05), Xdh expression (p < 0.001), XO activity (p < 0.001), ROS generation (p < 0.0001) and IL-1β secretion (p < 0.0001), whereas febuxostat enhanced PP2A activity (p < 0.05). NAC treatment enhanced PP2A activity and reduced XO activity and PP2A restoration mediated NAC's efficacy as co-treatment with okadaic acid increased IL-1β secretion (p < 0.05). Nigericin activated caspase-1 and reduced PP2A activity (p < 0.001) and fingolimod reduced caspase-1 activity in BMDMs (p < 0.001). Fingolimod reduced iNOS expression (p < 0.0001) and secretion of IL-6 and TNF-α (p < 0.05). Fingolimod reduced CMs (p < 0.0001), neutrophil (p < 0.001) and IL-1β (p < 0.05) lavage levels while increasing NCMs (p < 0.001). Conclusion: Macrophage PP2A is inactivated in acute gout by ROS and a PP2A activator exhibited a broad anti-inflammatory effect in acute gout in vitro and in vivo.}, }
@article {pmid36467051, year = {2022}, author = {Liu, M and Hu, T and Gou, W and Chang, H and Li, Y and Li, Y and Zuo, D and Hou, W and Jiao, S}, title = {Exploring the pharmacological mechanisms of icaritin against nasopharyngeal carcinoma via network pharmacology and experimental validation.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {993022}, pmid = {36467051}, issn = {1663-9812}, abstract = {Background: Icaritin is a natural product with a wide range of anti-tumor effects. However, its anti-tumor mechanism has not been thoroughly studied. This study examined the inhibitory effect of icaritin on nasopharyngeal cancer and its underlying mechanism using network pharmacology along with in vivo and in vitro experiments. Methods: MTT and clone formation assays were used to detect the effects of icaritin on the viability and proliferation of nasopharyngeal carcinoma cells, followed by the construction of a HONE1 xenograft tumor model to evaluate the anti-tumor efficacy of icaritin in vivo. A public database was used to predict prospective targets, built a protein-protein interaction (PPI) network, and analyze gene enrichment and biological processes. Based on network pharmacological data, cell cycle-related proteins were identified using western blotting. Besides, cell cycle distribution, apoptosis, and intracellular reactive oxygen species (ROS) generation were identified using flow cytometry. In addition, SA-β-Gal staining was performed to detect cellular senescence, and western blotting was performed to detect the expression of P53, P21, and other proteins to verify key signaling pathways. Results: Icaritin effectively inhibited the viability and proliferation of nasopharyngeal carcinoma cell lines and showed good anti-tumor activity against HONE1 nasopharyngeal carcinoma cells in vivo. Key protein targets, including AKT1, HSP90AA1, CDK4, CCND1, and EGFR, were screened using PPI network topology analysis. GO and KEGG analysis revealed that the cell cycle, p53 signaling, and cell senescence pathways may be the main regulatory pathways. Flow cytometry and western blot experiments showed that icaritin caused S-phase arrest and promoted an increase in ROS. SA-β-Gal staining showed that icaritin significantly induced cellular senescence, and western blotting showed that the expression of senescence-related proteins p53 and P21 increased significantly. Moreover, inhibition of ROS levels by N-Acetylcysteine (NAC) enhanced cell viability, reversed cellular senescence and reduced cellular senescence-associated protein expression. Conclusion: The results of network pharmacological analysis and in vivo and in vitro experiments showed that icaritin effectively inhibited the growth of nasopharyngeal carcinoma cells, promoted ROS production, induced cellular senescence, and inhibited tumor cells, which are related to the regulation of P53/P21 signal pathway.}, }
@article {pmid36464114, year = {2023}, author = {Abdallah, S and Jampy, A and Moison, D and Wieckowski, M and Messiaen, S and Martini, E and Campalans, A and Radicella, JP and Rouiller-Fabre, V and Livera, G and Guerquin, MJ}, title = {Foetal exposure to the bisphenols BADGE and BPAF impairs meiosis through DNA oxidation in mouse ovaries.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {317}, number = {}, pages = {120791}, doi = {10.1016/j.envpol.2022.120791}, pmid = {36464114}, issn = {1873-6424}, mesh = {Female ; Mice ; Animals ; *Meiosis ; *Ovary ; Benzhydryl Compounds/toxicity ; DNA ; Aneuploidy ; }, abstract = {Many endocrine disruptors have been proven to impair the meiotic process which is required for the production of healthy gametes. Bisphenol A is emblematic of such disruptors, as it impairs meiotic prophase I and causes oocyte aneuploidy following in utero exposure. However, the mechanisms underlying these deleterious effects remain poorly understood. Furthermore, the increasing use of BPA alternatives raises concerns for public health. Here, we investigated the effects of foetal exposure to two BPA alternatives, bisphenol A Diglycidyl Ether (BADGE) and bisphenol AF (BPAF), on oogenesis in mice. These compounds delay meiosis initiation, increase the number of MLH1 foci per cell and induce oocyte aneuploidy. We further demonstrate that these defects are accompanied by changes in gene expression in foetal premeiotic germ cells and aberrant mRNA splicing of meiotic genes. We observed an increase in DNA oxidation after exposure to BPA alternatives. Specific induction of oxidative DNA damage during foetal germ cell differentiation causes similar defects during oogenesis, as observed in 8-oxoguanine DNA Glycosylase (OGG1)-deficient mice or after in utero exposure to potassium bromate (KBrO3), an inducer of oxidative DNA damage. The supplementation of BPA alternatives with N-acetylcysteine (NAC) counteracts the effects of bisphenols on meiosis. Together, our results propose oxidative DNA lesion as an event that negatively impacts female meiosis with major consequences on oocyte quality. This could be a common mechanism of action for numerous environmental pro-oxidant pollutants, and its discovery, could lead to reconsider the adverse effect of bisphenol mixtures that are simultaneously present in our environment.}, }
@article {pmid36459039, year = {2022}, author = {Santus, P and Danzo, F and Zuffi, A and Pini, S and Saad, M and Visconti, A and Radovanovic, D}, title = {Oxidative stress and viral Infections: rationale, experiences, and perspectives on N-acetylcysteine.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {22}, pages = {8582-8590}, doi = {10.26355/eurrev_202211_30395}, pmid = {36459039}, issn = {2284-0729}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Oxidative Stress ; *Virus Diseases/drug therapy ; Inflammation ; }, abstract = {This article explores current evidence on the role of oxidative stress in viral infections, and on the use of antioxidant drugs as adjunctive treatment. MEDLINE/PubMed was searched for appropriate keywords, and preclinical and clinical studies with reviews were retrieved and examined by authors. Old and current evidence shows that GSH content reduction is the main mechanism of redox imbalance in viral-infected cells. Clinical studies found that GSH levels are depleted in patients with viral infections such as HIV and SARS-CoV. Viral infections activate inflammation through different pathways, and several of these mechanisms are related to oxidative stress. NAC is a precursor of GSH, and many of its intracellular effects are mediated by GSH replenishment, but it also activates some anti-inflammatory mechanisms. NAC has an excellent safety profile and better oral and topical bioavailability than GSH. These characteristics make NAC a suitable option as a repurposed drug. Adjunctive antioxidant treatment may improve the outcomes of antiviral therapies. Current evidence supports the rationale for this practice and some clinical experience showed encouraging results.}, }
@article {pmid36458919, year = {2023}, author = {Amar, SK and Donohue, KB and Gust, KA}, title = {Cellular and molecular responses to ethyl-parathion in undifferentiated SH-SY5Y cells provide neurotoxicity pathway indicators for organophosphorus impacts.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {191}, number = {2}, pages = {285-295}, pmid = {36458919}, issn = {1096-0929}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Parathion/toxicity ; Cell Line, Tumor ; *Neuroblastoma/metabolism ; Apoptosis ; *Neurotoxicity Syndromes/etiology ; Cell Survival ; }, abstract = {High-fidelity nonanimal screening methods are needed that can rapidly and accurately characterize organophosphorus compound (OP)-induced neurotoxicity. Herein, the efficacy of human neuroblastoma cell line (SH-SY5Y) to provide molecular and cellular responses characteristic of the OP neurotoxicity pathway was investigated in response to the OP-model compound, ethyl-parathion. Undifferentiated SH-SY5Y cells were exposed to ethyl-parathion for 30 min at 0 (control), 0.5, 2.5, 5, 10, and 25 µg/ml. Dose-responsive reductions in cell viability were observed with significant reductions at ≥10 µg/ml. From these results, ethyl-parathion exposures of 0 (control), 5, and 10 µg/ml were selected to examine bioindicators underlying the OP neurotoxicity pathway including: reactive oxygen species (ROS), cell membrane peroxidation, mitochondrial membrane potential (MMP), and apoptosis. Ethyl-parathion elicited highly significant increases in ROS relative to controls (p < .01) at both exposure concentrations, confirmed using N-acetyl cysteine (NAC) as a ROS quencher which alleviated ROS increases. A response characteristic of increased ROS exposure, cell membrane-lipid peroxidation, significantly increased (p < .05) at the highest ethyl-parathion exposure (10 µg/ml). As a likely consequence of membrane-lipid peroxidation, ethyl-parathion-induced reductions in MMP were observed with significant effects at 10 µg/ml, reducing MMP by 58.2%. As a culmination of these cellular-damage indicators, apoptosis progression was investigated by phosphatidylserine translocation where ethyl-parathion-induced dose-responsive, highly significant (p < .01) increases at both 5 and 10 µg/ml. Overall, the mechanistic responses observed in undifferentiated SH-SY5Y cells corresponded with in vivo mammalian results demonstrating potential for this nonanimal model to provide accurate OP neurotoxicology screening.}, }
@article {pmid36454053, year = {2022}, author = {Palsdottir, A and Snorradottir, AO and Hakonarson, H}, title = {[Did ketogenic diet in past centuries protect against the consequence of the cystatin L68Q mutation in carriers of HCCAA?].}, journal = {Laeknabladid}, volume = {108}, number = {12}, pages = {553-557}, doi = {10.17992/lbl.2022.12.721}, pmid = {36454053}, issn = {1670-4959}, mesh = {Humans ; *Cystatin C/genetics ; *Diet, Ketogenic ; Food ; Glutathione ; Mutation ; *Cerebral Amyloid Angiopathy, Familial/genetics ; }, abstract = {Hereditary cystatin C amyloid angiopathy (HCCAA) is a dominantly inherited disease caused by a mutation (L68Q) in the cystatin C gene, CST3. Mutant cystatin C protein accumulates as amyloid in arterioles in the brain leading to repeated brain hemorrhages and death of young carriers. Recently a possible treatment option was reported for HCCAA carriers involving an oral treatment with N-acetyl-cysteine in order to increase glutathione which was found to dissolve aggregates of mutant cystatin C. An earlier study described how the life span of carriers of the L68Q mutation shortened in the latter half of the 19th century. During the same decades a drastic change occured in the diet in Iceland. In the beginning of the century the diet was simple and low in carbohydrates, which mostly came from milk products. Import of grains and sugar was limited, but increased greatly according to import records. Due to lack of salt, food was preserved in acid whey, but gradually salt replaced whey as means of preserving food. This study aims to explore if changes in the diet of Icelanders during the same decades could possibly affect the amount of glutathione in people.}, }
@article {pmid36453778, year = {2022}, author = {Erol, K and Y Sozmen, E and Küçük, &#xdc; and Kucuk, L}, title = {Effect of pheniramine maleate on rat skeletal muscle ischemia-reperfusion injury.}, journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma &amp; emergency surgery : TJTES}, volume = {28}, number = {12}, pages = {1667-1673}, pmid = {36453778}, issn = {1307-7945}, mesh = {Male ; Animals ; Rats ; *Pheniramine ; Rats, Sprague-Dawley ; Poly(ADP-ribose) Polymerase Inhibitors ; Thiobarbituric Acid Reactive Substances ; *Reperfusion Injury/drug therapy ; Acetylcysteine ; Superoxide Dismutase ; Femoral Artery ; Muscle, Skeletal ; Nitric Oxide ; }, abstract = {BACKGROUND: Skeletal muscle ischemia-reperfusion injury (IRI) is a common clinical problem encountered after tourniquet ap-plication or replantation. This study investigated the effect of pheniramine maleate (Ph), which is frequently used in clinical practice to reduce IRI, and compared its efficacy in IRI with N-acetylcysteine (NAC), a molecule that has been shown to be effective in IRI.<br><br>METHODS: Twenty-eight male Sprague-Dawley rats were randomly divided into four groups (sham, ischemia-reperfusion [IR], IR+Ph, IR+NAC; n=7 rats per group). Ischemia was induced in the lower right extremities of rats for 3 h using a femoral artery clamp and an elastic tourniquet. Ph and NAC were administered intraperitoneally 15 min before ischemia was terminated. At 24 h after reperfusion, levels of thiobarbituric acid reactive substance (TBARS), catalase (CAT), myeloperoxidase (MPO), superoxide dismutase (SOD), polyadenosine diphosphate ribose polymerase (PARP), and neutrophil infiltration were evaluated. Inducible nitric oxide syn-thase (iNOS) density in muscle tissue was evaluated by immunohistochemical methods after 1 week.<br><br>RESULTS: SOD, MPO, PARP, CAT, and TBARS levels in muscle tissue were significantly lower in the sham group compared with the other groups (p<0.001). All parameters except TBARS were lower in the NAC and Ph groups than in the IR group (p<0.001). Neu-trophil infiltration in the muscle tissue samples from the IR group was significantly increased compared with the NAC and Ph groups (p<0.05). iNOS staining was not observed in the sham and NAC groups.<br><br>CONCLUSION: Ph is effective at reducing experimental rat skeletal muscle IRI.}, }
@article {pmid38362235, year = {2022}, author = {Greenberg, NR and Farhadi, F and Kazer, B and Potenza, MN and Angarita, GA}, title = {The Potential of N-acetyl Cysteine in Behavioral Addictions and Related Compulsive and Impulsive Behaviors and Disorders: a Scoping Review.}, journal = {Current addiction reports}, volume = {9}, number = {4}, pages = {660-670}, pmid = {38362235}, issn = {2196-2952}, support = {R01 AT010508/AT/NCCIH NIH HHS/United States ; R01 DA052454/DA/NIDA NIH HHS/United States ; R01 DK121551/DK/NIDDK NIH HHS/United States ; R21 DA043055/DA/NIDA NIH HHS/United States ; }, abstract = {PURPOSE OF REVIEW: Behavioral addictions (also termed disorders due to addictive behaviors) contain impulsive and compulsive features and have been shown to involve glutamate dysregulation. N-acetylcysteine (NAC), a well-tolerated cysteine pro-drug and antioxidant, may reduce addictive behaviors by restoring glutamate homeostasis. The current review details and discusses the use of NAC in behavioral addictions and related impulsive and compulsive behaviors, including gambling disorder, problematic use of the internet, problematic video gaming, compulsive sexual behavior, problematic shopping/buying, problematic stealing, repetitive self-injurious behavior, and binge eating disorder.<br><br>RECENT FINDINGS: Preliminary results have indicated the usefulness of NAC in gambling disorder, self-injurious behaviors, and compulsive sexual behaviors. Preclinical studies indicate that NAC is effective in improving binge eating behavior, but clinical trials are limited to a small open-label trial and case report. Studies are lacking on the efficacy of NAC in problematic use of the internet, problematic video gaming, problematic stealing, and problematic shopping/buying.<br><br>SUMMARY: NAC demonstrates potential for use in behavioral addictions and compulsive behaviors, particularly in gambling disorder and self-injury. However, more studies are needed to assess the effectiveness of NAC in other behavioral addictions and the mechanisms by which NAC improves these conditions.}, }
@article {pmid36450250, year = {2022}, author = {Laoukili, J and van Schelven, S and Küçükköse, E and Verheem, A and Goey, K and Koopman, M and Borel Rinkes, I and Kranenburg, O}, title = {BRAF[V600E] in colorectal cancer reduces sensitivity to oxidative stress and promotes site-specific metastasis by stimulating glutathione synthesis.}, journal = {Cell reports}, volume = {41}, number = {9}, pages = {111728}, doi = {10.1016/j.celrep.2022.111728}, pmid = {36450250}, issn = {2211-1247}, mesh = {Humans ; Proto-Oncogene Proteins B-raf/genetics ; Oxidative Stress ; Glutamate-Cysteine Ligase/genetics ; Glutathione ; *Lung Neoplasms/genetics ; *Colorectal Neoplasms/genetics ; }, abstract = {The presence of BRAF[V600E] in colorectal cancer (CRC) is associated with a higher chance of distant metastasis. Oxidative stress in disseminated tumor cells limits metastatic capacity. To study the relationship between BRAF[V600E], sensitivity to oxidative stress, and metastatic capacity in CRC, we use patient-derived organoids (PDOs) and tissue samples. BRAF[V600E] tumors and PDOs express high levels of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Deletion of GCL in BRAF[V600E] PDOs strongly reduces their capacity to form distant liver and lung metastases but does not affect peritoneal metastasis outgrowth. Vice versa, the glutathione precursor N-acetyl-cysteine promotes organ-site-specific metastasis in the liver and the lungs but not in the peritoneum. BRAF[V600E] confers resistance to pharmacologically induced oxidative stress in vitro, which is partially overcome by treatment with the BRAF-inhibitor vemurafenib. We conclude that GCL-driven glutathione synthesis protects BRAF[V600E]-expressing tumors from oxidative stress during distant metastasis to the liver and the lungs.}, }
@article {pmid36448959, year = {2023}, author = {Padoei, F and Mamsharifi, P and Hazegh, P and Boroumand, H and Ostadmohammady, F and Abbaszadeh-Mashkani, S and Banafshe, HR and Matini, AH and Ghaderi, A and Dehkohneh, SG}, title = {The therapeutic effect of N-acetylcysteine as an add-on to methadone maintenance therapy medication in outpatients with substance use disorders: A randomized, double-blind, placebo-controlled clinical trial.}, journal = {Brain and behavior}, volume = {13}, number = {1}, pages = {e2823}, pmid = {36448959}, issn = {2162-3279}, mesh = {Humans ; Adolescent ; Young Adult ; Adult ; Middle Aged ; *Acetylcysteine/pharmacology/therapeutic use ; Outpatients ; Antioxidants ; Methadone/therapeutic use ; *Substance-Related Disorders ; Double-Blind Method ; }, abstract = {OBJECTIVE: Patients with substance use disorders (SUD) under methadone maintenance therapy (MMT) are susceptible to a number of complications (psychological and metabolic disorders). Evidence studies have shown the roles of the glutamatergic system in addiction. N-Acetylcysteine (NAC) enhances extracellular glutamate, and is effective in the treatment of neuropsychiatric disorders. We assessed oral NAC as an add-on to MMT medication for the treatment of SUD.<br><br>METHODS: In the current randomized, double-blind, placebo-controlled clinical trial, outpatients with SUD under MMT who were 18-60 years old received 2400&#xa0;mg/day NAC (n&#xa0;=&#xa0;30) or placebo (n&#xa0;=&#xa0;30) for 12&#xa0;weeks. Psychological status and metabolic biomarkers were assessed at baseline and the end of the trial.<br><br>RESULTS: Compared with the placebo group, NAC treatment resulted in a significant improvement in depression score (&#x3b2; -2.36; 95% CI, -3.97, -0.76; p&#xa0;=&#xa0;.005), and anxiety score (&#x3b2; -1.82; 95% CI, -3.19, -0.44; p&#xa0;=&#xa0;.01). Furthermore, NAC treatment resulted in a significant elevation in total antioxidant capacity levels (&#x3b2; 72.28&#xa0;mmol/L; 95% CI, 11.36, 133.19; p&#xa0;=&#xa0;.02), total glutathione (GSH) levels (&#x3b2; 81.84&#xa0;&#x3bc;mol/L; 95% CI, 15.40, 148.28; p&#xa0;=&#xa0;.01), and a significant reduction in high-sensitivity C-reactive protein levels (&#x3b2; -0.89&#xa0;mg/L; 95% CI, -1.50, -0.28; p&#xa0;=&#xa0;.005), and homeostasis model of assessment-insulin resistance (&#x3b2; -0.33; 95% CI, -0.65, -0.009; p&#xa0;=&#xa0;.04), compared with the placebo group.<br><br>CONCLUSION: In the current study, improvement in depression and anxiety symptoms as well as some metabolic profiles with NAC treatment for 12&#xa0;weeks in outpatients with SUD under MMT was detected.}, }
@article {pmid36447062, year = {2023}, author = {Hammerschmidt, TG and Donida, B and Raabe, M and Faverzani, JL and de Fátima Lopes, F and Machado, AZ and Kessler, RG and Reinhardt, LS and Poletto, F and Moura, DJ and Vargas, CR}, title = {Evidence of redox imbalance and mitochondrial dysfunction in Niemann-Pick type C 1 patients: the in vitro effect of combined therapy with antioxidants and β-cyclodextrin nanoparticles.}, journal = {Metabolic brain disease}, volume = {38}, number = {2}, pages = {507-518}, pmid = {36447062}, issn = {1573-7365}, support = {430443/2018-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 2018-0648//Fundo de Incentivo &#xe0; Pesquisa e Eventos (FIPE/HCPA)/ ; }, mesh = {Animals ; *Niemann-Pick Disease, Type C/genetics ; Antioxidants/pharmacology/therapeutic use/metabolism ; *beta-Cyclodextrins/pharmacology/therapeutic use/metabolism ; Oxidation-Reduction ; Mitochondria/metabolism ; Cholesterol/metabolism ; }, abstract = {Niemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes: NPC1 or NPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of β-cyclodextrin (β-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated the in vitro therapeutic potential of β-CD to reduce cholesterol in fibroblasts from NPC1 patients. β-CD was used in its free and nanoparticulate form. We also evaluated the β-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitrative stress could contribute to the pathophysiology of NPC1, as the levels of lipoperoxidation and the nitrite and nitrate levels were increased in these patients when compared to healthy individuals, as well as DNA damage. The nanoparticles containing β-CD reduced the cholesterol accumulated in the NPC1 fibroblasts. This result was potentiated by the concomitant use of the nanoparticles with the antioxidants NAC and CoQ10 compared to those presented by healthy individuals cells ́. In addition, treatments combining β-CD nanoparticles and antioxidants could reduce mitochondrial oxidative stress, demonstrating advantages compared to free β-CD. The results obtained are promising regarding the combined use of β-CD loaded nanoparticles and antioxidants in the treatment of NPC1 disease.}, }
@article {pmid36445126, year = {2022}, author = {Llamosí, M and Sempere, J and Coronel, P and Gimeno, M and Yuste, J and Domenech, M}, title = {Combination of Cefditoren and N-acetyl-l-Cysteine Shows a Synergistic Effect against Multidrug-Resistant Streptococcus pneumoniae Biofilms.}, journal = {Microbiology spectrum}, volume = {10}, number = {6}, pages = {e0341522}, pmid = {36445126}, issn = {2165-0497}, mesh = {Humans ; Animals ; Mice ; Streptococcus pneumoniae ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology ; *COVID-19 ; SARS-CoV-2 ; Cephalosporins/pharmacology/therapeutic use ; Biofilms ; Anti-Bacterial Agents/pharmacology/therapeutic use ; *Respiratory Tract Infections/microbiology ; }, abstract = {Biofilm formation by Streptococcus pneumoniae is associated with colonization of the upper respiratory tract, including the carrier state, and with chronic respiratory infections in patients suffering from chronic obstructive pulmonary disease (COPD). The use of antibiotics alone to treat recalcitrant infections caused by biofilms is insufficient in many cases, requiring novel strategies based on a combination of antibiotics with other agents, including antibodies, enzybiotics, and antioxidants. In this work, we demonstrate that the third-generation oral cephalosporin cefditoren (CDN) and the antioxidant N-acetyl-l-cysteine (NAC) are synergistic against pneumococcal biofilms. Additionally, the combination of CDN and NAC resulted in the inhibition of bacterial growth (planktonic and biofilm cells) and destruction of the biofilm biomass. This marked antimicrobial effect was also observed in terms of viability in both inhibition (prevention) and disaggregation (treatment) assays. Moreover, the use of CDN and NAC reduced bacterial adhesion to human lung epithelial cells, confirming that this strategy of combining these two compounds is effective against resistant pneumococcal strains colonizing the lung epithelium. Finally, administration of CDN and NAC in mice suffering acute pneumococcal pneumonia caused by a multidrug-resistant strain was effective in clearing the bacteria from the respiratory tract in comparison to treatment with either compound alone. Overall, these results demonstrate that the combination of oral cephalosporins and antioxidants, such as CDN and NAC, respectively, is a promising strategy against respiratory biofilms caused by S. pneumoniae. IMPORTANCE Streptococcus pneumoniae is one of the deadliest bacterial pathogens, accounting for up to 2 million deaths annually prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccines have decreased the burden of diseases produced by S. pneumoniae, but the rise of antibiotic-resistant strains and nonvaccine serotypes is worrisome. Pneumococcal biofilms are associated with chronic respiratory infections, and treatment is challenging, making the search for new antibiofilm therapies a priority as biofilms become resistant to traditional antibiotics. In this work, we used the combination of an antibiotic (CDN) and an antioxidant (NAC) to treat the pneumococcal biofilms of relevant clinical isolates. We demonstrated a synergy between CDN and NAC that inhibited and treated pneumococcal biofilms, impaired pneumococcal adherence to the lung epithelium, and treated pneumonia in a mouse pneumonia model. We propose the widely used cephalosporin CDN and the repurposed drug NAC as a new antibiofilm therapy against S. pneumoniae biofilms, including those formed by antibiotic-resistant clinical isolates.}, }
@article {pmid36435287, year = {2023}, author = {Zhang, Q and Deng, C and Peng, M and Li, C and Teng, Y and Guo, S and Wu, T and Yi, D and Hou, Y}, title = {Integration of transcriptomic and proteomic analyses reveals protective mechanisms of N-acetylcysteine in indomethacin-stimulated enterocytes.}, journal = {The Journal of nutritional biochemistry}, volume = {112}, number = {}, pages = {109231}, doi = {10.1016/j.jnutbio.2022.109231}, pmid = {36435287}, issn = {1873-4847}, mesh = {Humans ; Animals ; Swine ; *Acetylcysteine/pharmacology ; *Enterocytes/metabolism ; Transcriptome ; Indomethacin/pharmacology ; Proteomics ; Apoptosis ; }, abstract = {Intestinal health is critical for the growth and development of humans and animals. Our previous study has demonstrated that indomethacin (IDMT) could induce intestinal injury in piglets, and N-acetylcysteine (NAC) supplementation contributed to alleviating intestinal injury induced by various stimuli. In this study, we investigated the mechanism of IDMT-induced cell death in IPEC-1 cell lines and explored the role of NAC by using transcriptomic and proteomic analyses. Results showed that cell viability was substantially reduced with the increasing concentrations of IDMT, whereas NAC significantly increased the survival rate of IPEC-1 cells regardless of its addition method. Transcriptomics and proteomics data indicated that terms, such as cell cycle, energy metabolism, and cell proliferation, were significantly enriched by Gene ontology and pathway analyses. Flow cytometer analysis showed that IDMT induced cell cycle arrest at G0/G1 phase. The expression of cell cycle regulatory proteins (CDK1, CCNA2, and CDC45) was decreased by IDMT stimulation. Importantly, NAC treatment repaired IDMT-induced mitochondrial dysfunction by increasing ATP production, decreasing oxygen consumption rate in non-mitochondrial O2 consumption, and increasing the red/green fluorescence ratio. IDMT stimulation significantly increased caspase-3 expression, which was partially reversed by NAC treatment. These results suggest that IDMT-induced cell death may be attributable to disturbance of the cell cycle processes, mitochondria dysfunction and apoptosis, and NAC could confer a protective effect by restoring the mitochondrial function and inhibiting the apoptosis pathway. This study provides a theoretical basis for the pathogenesis of IDMT-induced intestinal injury and guides the clinic application of NAC.}, }
@article {pmid36434296, year = {2022}, author = {Yilmaz, FN and Hacioglu, M and Aldogan, EH}, title = {Impact of N-Acetylcysteine and Antibiotics Against Single and Dual Species Biofilms of Pseudomonas aeruginosa and Achromobacter xylosoxidans.}, journal = {Current microbiology}, volume = {80}, number = {1}, pages = {5}, pmid = {36434296}, issn = {1432-0991}, mesh = {Animals ; Humans ; Pseudomonas aeruginosa ; *Achromobacter denitrificans ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Aztreonam/pharmacology ; *Cystic Fibrosis/microbiology ; Caenorhabditis elegans ; Biofilms ; Tobramycin/pharmacology ; Ciprofloxacin/pharmacology ; }, abstract = {Lungs of cystic fibrosis patients are often colonized or infected with organisms, such as Pseudomonas aeruginosa and other emerging pathogenic bacteria such as Achromobacter xylosoxidans. Further, it is well established that infections of the cystic fibrosis lung airways are caused by polymicrobial infections, although its composition and diversity may change throughout the patient's life. In the present study, we investigated the effects of N-acetylcysteine (NAC) and amikacin, aztreonam, ciprofloxacin, and tobramycin alone and in combination against single- and dual-species biofilms of P. aeruginosa and A. xylosoxidans, in vitro and in the Caenorhabditis elegans infection model. Results showed that tobramycin and ciprofloxacin were the most effective antibiotics, while aztreonam was the least effective antibiotic against both single- and dual-species biofilms of P. aeruginosa and A. xylosoxidans. However, NAC showed little effect on both single- and dual-species, even with a combination of antibiotics. Increased survival was observed in C. elegans when treated with NAC in combination with tobramycin or ciprofloxacin, compared to no treatment or NAC alone. Tobramycin and ciprofloxacin were found effective in biofilms, but more research is needed to better understand the effects of NAC and antibiotics against single- and dual-species biofilms.}, }
@article {pmid36432632, year = {2022}, author = {Petkova, T and Yordanova, A and Milanova, A}, title = {Population Pharmacokinetics of Doxycycline, Administered Alone or with N-Acetylcysteine, in Chickens with Experimental Mycoplasma gallisepticum Infection.}, journal = {Pharmaceutics}, volume = {14}, number = {11}, pages = {}, pmid = {36432632}, issn = {1999-4923}, support = {N/A//TRAKIA UNIVERSITY, PhD program/ ; }, abstract = {Mycoplasmosis is a bacterial infection that significantly affects poultry production, and it is often controlled with antibiotics, including doxycycline. The conducted study aimed to determine population pharmacokinetic (PopPk) parameters of doxycycline in healthy (n = 12) and in Mycoplasma gallisepticum-challenged (n = 20) chickens after its oral administration via drinking water at the registered dose rate of 20 mg/kg b.w./24 h for five days, without or with co-administration of N-acetylcysteine (NAC, a dose of 100 mg/kg b.w./24 h) via the feed. Doxycycline concentrations in plasma were analyzed with the LC-MS/MS method. The values of tvV/F and tvke were 4.73 L × kg−1 and 0.154 h−1, respectively, and they showed low BSV. A high BSV of 93.17% was calculated for the value of tlag of 0.8 h, which reflects the inter-individual differences in the water consumption. PTA was computed after Monte Carlo simulation with the registered dose for doxycycline. The target of %fT > MIC ≥ 80% and 100% can be achieved in 90% of the broiler population, after a correction for protein binding, for bacteria with MIC ≤ 0.5 mg × L−1 and 0.25 mg × L−1, respectively. The applied PopPk model did not reveal significant effect of M. gallisepticum infection and co-administration of NAC on pharmacokinetic parameters of doxycycline.}, }
@article {pmid36428416, year = {2022}, author = {Nascimento, DR and Azevedo, VAN and Barroso, PAA and Barrozo, LG and Silva, BR and Silva, AWB and Donato, MAM and Peixoto, CA and Silva, JRV}, title = {Effects of N-acetylcysteine on Growth, Viability, and Ultrastructure of In Vitro Cultured Bovine Secondary Follicles.}, journal = {Animals : an open access journal from MDPI}, volume = {12}, number = {22}, pages = {}, pmid = {36428416}, issn = {2076-2615}, support = {308737/2018-0//National Council for Scientific and Technological Development/ ; }, abstract = {This study aimed to investigate the effects of different concentrations of N-acetylcysteine (NAC) on the growth, antrum formation, viability, and ultrastructure of bovine secondary follicles cultured in vitro for 18 days. To this end, the follicles were cultured in TCM-199+ medium alone or supplemented with 1.0, 5.0, or 25.0 mM NAC. Follicular growth, antrum formation, viability (calcein-AM and ethidium homodimer-1) and ultrastructure were evaluated at the end of culture period. The results showed that 1.0 mM NAC increased the percentage of growing follicles and the fluorescence intensity for calcein-AM when compared to other treatments (p < 0.05). On the other hand, follicles cultured with 25.0 mM NAC had higher fluorescence intensity for ethidium homodimer-1, which is a sign of degeneration. Ultrastructural analysis showed that oocytes from follicles cultured in control medium alone or with 1 mM NAC had intact zonae pellucidae in close association with oolemmae, but the ooplasm showed mitochondria with a reduced number of cristae. On the other hand, oocytes from follicles cultured with 5 or 25 mM NAC had extremely vacuolated cytoplasm and no recognizable organelles. In conclusion, 1 mM NAC increases cytoplasmic calcein staining and the growth rate in bovine secondary follicles cultured in vitro, but the presence of 5 or 25 mM NAC causes damage in cellular membranes and organelles, as well as reducing the percentages of growing follicles.}, }
@article {pmid36421484, year = {2022}, author = {Mapamba, DA and Sauli, E and Mrema, L and Lalashowi, J and Magombola, D and Buza, J and Olomi, W and Wallis, RS and Ntinginya, NE}, title = {Impact of N-Acetyl Cysteine (NAC) on Tuberculosis (TB) Patients-A Systematic Review.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {11}, pages = {}, pmid = {36421484}, issn = {2076-3921}, support = {LMU-IMPH-TB Sequel-01//TB sequel project by the German Ministry of Education and Research/ ; }, abstract = {Sustained TB infection overproduces reactive oxygen species (ROS) as a host defense mechanism. Research shows ROS is destructive to lung tissue. Glutathione (GSH) neutralizes ROS, although it is consumed. NAC is a precursor of GSH synthesis, and administering an appropriate dose of NAC to patients with respiratory conditions may enhance lung recovery and replenish GSH. The present review searched for articles reporting on the effects of NAC in TB treatment from 1960 to 31 May 2022. The PICO search strategy was used in Google Scholar, PubMed, SciFinder, and Wiley online library databases. The COVIDENCE tool was used to delete inappropriate content. We eventually discovered five clinical trials, one case report, seven reviews, in vitro research, and four experimental animal studies from the twenty-four accepted articles. The use of NAC resulted in increased GSH levels, decreased treatment time, and was safe with minimal adverse events. However, the evidence is currently insufficient to estimate the overall effects of NAC, thus the study warrants more NAC clinical trials to demonstrate its effects in TB treatment.}, }
@article {pmid36421407, year = {2022}, author = {Gençosman, S and Ceylanlı, D and Şehirli, A&#xd6; and Teralı, K and Bölükbaşı, F and Çetinel, &#x15e; and Sayıner, S}, title = {Investigation of the Possible Protective Effect of N-Acetylcysteine (NAC) against Irinotecan (CPT-11)-Induced Toxicity in Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {11}, pages = {}, pmid = {36421407}, issn = {2076-3921}, abstract = {Irinotecan (CPT-11) is a chemotherapeutic agent involved in the treatment regimens for several malignancies such as colorectal cancer. N-acetylcysteine (NAC) is a strong antioxidant and anti-inflammatory agent used in the treatment of several diseases related to oxidative stress and inflammation. This study aimed at investigating whether NAC provides protection against hepatorenal and gastrointestinal tissue damage induced by CPT-11. Thirty-two Wistar albino rats were divided into four groups as control, NAC, CPT-11, and CPT-11+NAC. Following the experimental period, blood, and tissue samples (liver, kidney, stomach, and small intestine) were collected, and biochemical indicators, together with pro-inflammatory cytokines (TNF-α and IL-1β), matrix metalloproteinases (MMPs), malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD) levels were evaluated. Both the biochemical indicators and the pro-inflammatory cytokines, MMP, and MDA levels increased in animals treated with CPT-11, while SOD and GPx activities decreased. Histopathological evaluation revealed structural damage in all examined tissues. With NAC administration, significant improvements were observed, both biochemically and histologically. In conclusion, the results of the present study suggest that NAC treatment together with CPT-11 may have a beneficial effect on reducing CPT-11 toxicity in rats, by modulating inflammation and the oxidant-antioxidant balance. These results strongly promote further investigative studies.}, }
@article {pmid36420805, year = {2022}, author = {Janković, SM}, title = {Acetaminophen toxicity and overdose: current understanding and future directions for NAC dosing regimens.}, journal = {Expert opinion on drug metabolism &amp; toxicology}, volume = {18}, number = {11}, pages = {745-753}, doi = {10.1080/17425255.2022.2151893}, pmid = {36420805}, issn = {1744-7607}, mesh = {Humans ; Acetylcysteine ; Acetaminophen/therapeutic use ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury/drug therapy ; }, abstract = {INTRODUCTION: Although N-acetyl-cysteine (NAC) has long been used for the treatment of acetaminophen poisoning/overdose, the optimal NAC dosing regimen for varying patterns or severity of the poisoning/overdose is still unknown.<br><br>AREAS COVERED: Relevant literature was searched for in the MEDLINE (from 1964 until August 31[st], 2022), SCOPUS (from 2004 until August 31[st], 2022) and GOOGLE SCHOLAR (from 2004 until August 31[st], 2022) databases, without restriction in terms of publication date. The inclusion criteria were: original clinical studies reporting results, and studies investigating efficacy and safety of NAC dosing regimens in case(s) of overdose or poisoning with acetaminophen.<br><br>EXPERT OPINION: For a more effective treatment of acetaminophen poisoning in the future, it will be crucial to advance the technology of measuring acetaminophen, its metabolites and NAC in the serum, preferably with the point-of-care technique, so that in real time it can be continuously assessed whether it is necessary to administer NAC, and further to increase the dose of NAC and extend the duration of its administration, or not.}, }
@article {pmid36418258, year = {2022}, author = {Zhang, YP and Zhang, Q and Deng, F and Chen, B and Zhang, JH and Hu, J}, title = {[Effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its mechanism].}, journal = {Zhonghua shao shang yu chuang mian xiu fu za zhi}, volume = {38}, number = {11}, pages = {1014-1022}, doi = {10.3760/cma.j.cn501225-20220630-00272}, pmid = {36418258}, issn = {2097-1109}, support = {82100889//Youth Science Foundation Project of National Natural Science Foundation of China/ ; CSTB2022BSXM-JCX0022//Chongqing Doctor "Through Train" Project/ ; XZ-2019-505-018//Science and Technology Ability Promotion Project of Army Medical University/ ; }, mesh = {Humans ; RNA, Small Interfering/genetics ; Cell Line ; *Epidermis ; *Glucose/pharmacology ; Epidermal Cells ; }, abstract = {Objective: To investigate the effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its possible molecular mechanism, so as to explore the mechanism of refractory diabetic foot wound healing. Methods: The method of experimental research was used. HaCaT cells in logarithmic growth phase was taken for experiment. The cells were collected and divided into normal control group (culture solution containing glucose with final molarity of 5.5 mmol/L) and high glucose (culture solution containing glucose with final molarity of 30.0 mmol/L) 24 h group, high glucose 48 h group, and high glucose 72 h group according to the random number table (the same grouping method below). The cells in normal control group were routinely cultured for 72 h, cells in high glucose 72 h group were cultured with high glucose for 72 h, cells in high glucose 48 h group were routinely cultured for 24 h then cultured with high glucose for 48 h, cells in high glucose 24 h group were routinely cultured for 48 h then cultured with high glucose for 24 h. Then the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal control group and high glucose group. After being correspondingly cultured for 48 h as before, the protein expression of P62 was detected by immunofluorescence method (indicated as green fluorescence). The cells were collected and divided into negative control small interfering RNA (siRNA) group, P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group, and transfected with the corresponding reagents. At post transfection hour (PTH) 72, the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group. After the corresponding treatment, the protein expression of P62 was detected by Western blotting at PTH 72 h, the cell migration rate was detected and calculated at 24 h after scratching by scratch test, with the number of samples being 9; and the range of cell movement was observed and the trajectory velocity was calculated within 3 h under the living cell workstation, with the number of samples being 76, 75, 80, and 79 in normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group, respectively. The cells were collected and divided into normal glucose+phosphate buffered solution (PBS) group, high glucose+PBS group, and high glucose+N-acetylcysteine (NAC) group. After the corresponding treatment, the protein expression of P62 at 48 h of culture was detected by Western blotting and immunofluorescence method, respectively. Except for scratch test and cell motility experiment, the number of samples was all 3 in the rest experiments. Data were statistically analyzed with one-way analysis of variance and least significant difference test. Results: Compared with the protein expression in normal control group, the protein expressions of P62 of cells in high glucose 24 h group, high glucose 48 h group, and high glucose 72 h group were significantly increased (P<0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose group was stronger than that in normal control group. At PTH 72, compared with the protein expression in negative control siRNA group, the protein expressions of P62 of cells in P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group were significantly decreased (P<0.01). At PTH 72, compared with the protein expression in normal glucose+negative control siRNA group, the protein expression of P62 of cells in normal glucose+P62-siRNA group was significantly decreased (P<0.01), while the protein expression of P62 of cells in high glucose+negative control siRNA group was significantly increased (P<0.01); compared with the protein expression in high glucose+negative control siRNA group, the protein expression of P62 of cells in high glucose+P62-siRNA group was significantly decreased (P<0.01). At 24 h after scratching, compared with (55±7)% in normal glucose+negative control siRNA group, the cell migration rate in normal glucose+P62-siRNA group was significantly increased ((72±14)%, P<0.01), while the cell migration rate in high glucose+negative control siRNA group was significantly decreased ((37±7)%, P<0.01); compared with that in high glucose+negative control siRNA group, the cell migration rate in high glucose+P62-siRNA group was significantly increased ((54±10)%, P<0.01). Within 3 h of observation, the cell movement range in high glucose+negative control siRNA group was smaller than that in normal glucose+negative control siRNA group, while the cell movement range in normal glucose+P62-siRNA group was larger than that in normal glucose+negative control siRNA group, and the cell movement range in high glucose+P62-siRNA group was larger than that in high glucose+negative control siRNA group. Compared with that in normal glucose+negative control siRNA group, the cell trajectory speed in normal glucose+P62-siRNA group was significantly increased (P<0.01), while the cell trajectory speed in high glucose+negative control siRNA group was significantly decreased (P<0.01); compared with that in high glucose+negative control siRNA group, the cell trajectory speed in high glucose+P62-siRNA group was significantly increased (P<0.01). At 48 h of culture, compared with that in normal glucose+PBS group, the protein expression of P62 of cells in high glucose+PBS group was significantly increased (P<0.01); compared with that in high glucose+PBS group, the protein expression of P62 of cells in high glucose+NAC group was significantly decreased (P<0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose+PBS group was stronger than that in normal glucose+PBS group, while the green fluorescence of P62 of cells in high glucose+NAC group was weaker than that in high glucose+PBS group. Conclusions: In HaCaT cells, high glucose microenvironment can promote the protein expression of P62; knockdown of P62 protein can promote the migration and increase the mobility of HaCaT cells; and the increase of reactive oxygen species in high glucose microenvironment may be the underlying mechanism for the increase of P62 expression.}, }
@article {pmid36414340, year = {2022}, author = {Lee, M and McCarron, J and Balinski, A and Bower, R}, title = {Intravenous acetaminophen associated with acute liver failure.}, journal = {BMJ case reports}, volume = {15}, number = {11}, pages = {}, pmid = {36414340}, issn = {1757-790X}, mesh = {Female ; Humans ; Acetaminophen/adverse effects ; *Liver Failure, Acute/etiology ; Acetylcysteine/therapeutic use ; *Drug-Related Side Effects and Adverse Reactions ; *Brain Diseases/complications ; }, abstract = {A woman in her mid-60s, without known liver disease, was admitted to the hospital with a partial malignant colonic obstruction. Over a 6-day course, she received a total of 13 g of intravenous acetaminophen not exceeding 4 g over a 24-hour period. She developed encephalopathy and an international normalised ratio of 6.1 meeting criteria for acute liver failure (ALF). She was treated with intravenous N-acetyl cysteine and other causes of liver failure were excluded. The patient was discharged with subsequent resolution of encephalopathy and improvement of her liver chemistries. Though ALF is rare, in countries where acetaminophen is readily available, almost 50% of ALF cases are acetaminophen-induced hepatotoxicity and most have been documented as oral ingestion of acetaminophen. We present a rare case of intravenous acetaminophen-induced ALF.}, }
@article {pmid36410267, year = {2022}, author = {Izquierdo-Alonso, JL and Pérez-Rial, S and Rivera, CG and Peces-Barba, G}, title = {N-acetylcysteine for prevention and treatment of COVID-19: Current state of evidence and future directions.}, journal = {Journal of infection and public health}, volume = {15}, number = {12}, pages = {1477-1483}, pmid = {36410267}, issn = {1876-035X}, mesh = {Humans ; Acetylcysteine/therapeutic use ; SARS-CoV-2 ; *Respiratory Distress Syndrome ; Immunotherapy ; *COVID-19 Drug Treatment ; }, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes coronavirus disease 2019 (COVID-19) and can be associated with serious complications, including acute respiratory distress syndrome. This condition is accompanied by a massive release of cytokines, also denominated cytokine storm, development of systemic oxidative stress and a prothrombotic state. In this context, it has been proposed a role for acetylcysteine (NAC) in the management of patients with COVID-19. NAC is a molecule classically known for its mucolytic effect, but it also has direct and indirect antioxidant activity as a precursor of reduced glutathione. Other effects of NAC have also been described, such as modulating the immune and inflammatory response, counteracting the thrombotic state, and having an antiviral effect. The pharmacological activities of NAC and its effects on the mechanisms of disease progression make it a potential therapeutic agent for COVID-19. NAC is safe, tolerable, affordable, and easily available. Moreover, the antioxidant effects of the molecule may even prevent infection and play an important role as a complement to vaccination. Although the clinical efficacy and dosing regimens of NAC have been evaluated in the clinical setting with small series of patients, the results are promising. In this article, we review the pathogenesis of SARS-CoV-2 infection and the current knowledge of the mechanisms of action of NAC across disease stages. We also propose NAC posology strategies to manage COVID-19 patients in different clinical scenarios.}, }
@article {pmid36409196, year = {2023}, author = {Lopez-Mejia, IC and Pijuan, J and Navaridas, R and Santacana, M and Gatius, S and Velasco, A and Castellà, G and Panosa, A and Cabiscol, E and Pinyol, M and Coll, L and Bonifaci, N and Peña, LP and Vidal, A and Villanueva, A and Gari, E and Llobet-Navàs, D and Fajas, L and Matias-Guiu, X and Yeramian, A}, title = {Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness.}, journal = {Molecular oncology}, volume = {17}, number = {1}, pages = {98-118}, pmid = {36409196}, issn = {1878-0261}, mesh = {Humans ; *Antioxidants/metabolism ; Cell Line, Tumor ; Cell Movement ; *Cystadenocarcinoma, Serous/drug therapy/pathology ; *Focal Adhesion Kinase 1/metabolism ; Oxidative Stress ; Phosphorylation ; Reactive Oxygen Species ; Tyrosine/metabolism ; Animals ; }, abstract = {Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer (EC), characterized by its high propensity for metastases. In fact, while endometrioid endometrial carcinoma (EEC), which accounts for 85% of EC, presents a good prognosis, USC is the most frequently fatal. Herein, we used for the first time a peptide-based tyrosine-kinase-activity profiling approach to quantify the changes in tyrosine kinase activation between USC and EEC. Among the tyrosine kinases highly activated in USC, we identified focal adhesion kinase (FAK). We conducted mechanistic studies using cellular models. In a USC cell line, targeting FAK either by inhibitors PF-573228 and defactinib (VS-6063) or by gene silencing limits 3D cell growth and reduces cell migration. Moreover, results from our studies suggest that oxidative stress is increased in USC tumors compared to EEC ones. Reactive oxygen species (ROS) induce tyrosine phosphorylation of FAK and a concomitant tyrosine phosphorylation of paxillin, a mediator of FAK signal transduction. Mechanistically, by tracking hundreds of individual cells per condition, we show that ROS increased cell distance and migration velocity, highlighting the role of ROS-FAK-PAX signaling in cell migration. Both defactinib and ROS scavenger N-acetylcysteine (NAC) revert this effect, pointing toward ROS as potential culprits for the increase in USC cell motility. A proof of concept of the role of FAK in controlling cell growth was obtained in in vivo experiments using cancer-tissue-originated spheroids (CTOS) and a patient-derived orthotopic xenograft model (orthoxenograft/PDOX). Defactinib reduces cell proliferation and protein oxidation, supporting a pro-tumoral antioxidant role of FAK, whereas antioxidant NAC reverts FAK inhibitor effects. Overall, our data points to ROS-mediated FAK activation in USC as being responsible for the poor prognosis of this tumor type and emphasize the potential of FAK inhibition for USC treatment.}, }
@article {pmid36407165, year = {2022}, author = {Santosa, Y and Harca, AD and Yuwono, A and Hermanto, A and Oliver, MS and Sukmadja, E and Soewardi, R}, title = {Is It Safe to Do Percutaneous Coronary Intervention in Moderate to Severe Chronic Kidney Disease Patients? A Prospective Cohort Study.}, journal = {Cureus}, volume = {14}, number = {10}, pages = {e30312}, pmid = {36407165}, issn = {2168-8184}, abstract = {INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is a common and potentially serious complication of percutaneous coronary intervention (PCI) procedures, as it induces acute kidney injury (AKI), especially in previously diagnosed chronic kidney disease (CKD) patients, particularly in those who also have diabetes. Adequate hydration and using a minimal volume of contrast media are the recommended measures to decrease CI-AKI in CKD patients. A combination of sodium bicarbonate and N-acetylcysteine (NAC) may be a superior strategy for preventing CI-AKI. This study is aimed to evaluate the safety of PCI in moderate to severe CKD patients.<br><br>METHOD: This was a prospective, single-center study, from 2019 to 2021. We included all chronic kidney disease who undergo PCI procedures. The kidney level was measured on admission and 24 hours after the PCI procedure. The patients received 75 meq/500 mL of sodium bicarbonate one to six hours before procedures, oral acetylcysteine 600 mg bid for three days, and rehydration with 1000 ml of normal saline infusion for eight hours in patients without congestive heart failure. SPSS Version 23.0 (IBM SPSS Statistics for Windows, Version 23.0., IBM Corp., Armonk, NY) was used to input and process the data.<br><br>RESULTS: This study included 118 subjects, with baseline characteristics of age 58.77 &#xb1; 9.08 years, 80.5% male, 47.5% diabetic, 50% hypertension, and 59.5% congestive heart failure. From the coronary angiogram, we found most of our subjects (57.6%) had three-vessel disease, 28.8% had two-vessel disease, and 15.6% had one-vessel disease. About 67.8% of subjects used <50 ml of low molecular contrast. The baseline creatinine level was 2.46 &#xb1; 1.04 mg/dL and the estimated glomerular filtration rate (eGFR) was 30 &#xb1; 12.65 mL/min. There were 19 (16.1%) patients with stage 3A CKD, 45 (38.1%) stage 3B, 41 (34.7%) stage 4, and 41 (34.7%) stage 5. The kidney function test after 24 hours of contrast admission showed a creatinine level of 2.37 &#xb1; 1.20 mg/dL (P<0.05) and the eGFR of 34.74 &#xb1; 16.10 mL/min. There was no significant difference in creatinine levels between stage 3A and stage 5 CKD. There was a significant reduction in creatinine in stage 3B CKD, from 1.917 &#xb1; 0.22 to 1.71 &#xb1; 0.37 mg/dL (P = 0.001); and stage 4 CKD, from 2.77 &#xb1; 0.55 to 2.72 &#xb1; 0.94 mg/dL (P = 0.013).<br><br>DISCUSSION: CKD is a risk factor for developing CI-AKI after PCI, which is a marker of poor long-term outcomes. The development of CI-AKI is a strong predictor of post-PCI bleeding, which aggravates hemodynamic instability. The combination of NAC and NaHCO3 exerts a better antioxidative effect, which reduces the harmful short-term and long-term consequences of contrast media. Previous studies revealed the use of low-to-zero contrast media was safer in CKD patients who had undergone PCI. By applying these measures, our study showed a good outcome of PCI with no worsening renal function in CKD patients.<br><br>CONCLUSION: With good prophylaxis measures, such as using minimal volume contrast media, adequate rehydration, and the combination of sodium bicarbonate and acetylcysteine, it is safe to do PCI in moderate to severe CKD patients.}, }
@article {pmid36406192, year = {2022}, author = {Min, WL and Wang, BF and Liang, BB and Zhang, L and Pan, JY and Huang, Y and Zhao, Y and Lin, S and Zhao, YH and Zhang, SQ and Ma, QY}, title = {A ROS/Akt/NF-κB Signaling Cascade Mediates Epidermal Growth Factor-Induced Epithelial-Mesenchymal Transition and Invasion in Human Breast Cancer Cells.}, journal = {World journal of oncology}, volume = {13}, number = {5}, pages = {289-298}, pmid = {36406192}, issn = {1920-454X}, abstract = {BACKGROUND: As one of the most widely used anti-diabetic drugs for type II diabetes, metformin has been shown to exhibit anti-cancer activity in recent years. Epidermal growth factor (EGF) and its receptor, EGFR, play important roles in cancer metastasis in various tumors, including breast cancer. Epithelial-mesenchymal transition (EMT) is a critical process for cancer invasion and metastasis. In this study, we use EGF as a metastatic inducer to investigate the effect of metformin on cancer cell migration, invasion and EMT.<br><br>METHODS: Human breast cancer MCF-7 cells were exposed to EGF with or without metformin or N-acetyl cysteine (NAC). The effects of metformin on breast cancer cell proliferation were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The production of reactive oxygen species (ROS) was tested using 2,7-dichlorodihydrofluorecein diacetate (DCFH-DA). The migratory and invasive abilities of tumor cells were analyzed using wound healing assay and transwell invasion assay, respectively. The expressions of E-cadherin, N-cadherin and Snail were tested using real-time quantitative polymerase chain reaction (qRT-PCR) and western blotting at mRNA and protein levels. The activation of protein kinase B (Akt) and nuclear factor kappa B (NF-&#x3ba;B) were measured by western blotting.<br><br>RESULTS: Our results showed that metformin inhibited breast cancer cell proliferation in a dose-dependent manner with or without EGF. EGF-induced alterations in cell morphology that are characteristic of EMT were reversed by metformin. Metformin also inhibited the EGF-modulated expression of E-cadherin, N-cadherin and Snail and further suppressed cell invasion and migration. In addition, metformin suppressed EGF-induced phosphorylation of Akt and NF-&#x3ba;B. ROS is involved in EGF-induced cancer invasion and activation of phosphatidylinositol 3-kinase (PI3K)/Akt/NF-&#x3ba;B pathway.<br><br>CONCLUSION: Taken together, these data indicate that metformin suppresses EGF-induced breast cancer cell migration, invasion and EMT through the inhibition of the PI3K/Akt/NF-&#x3ba;B pathway. These results provide a novel mechanism to explain the role of metformin as a potent anti-metastatic agent in breast cancer cells.}, }
@article {pmid36403891, year = {2023}, author = {Wei, Y and Ni, L and Pan, J and Li, X and Deng, Y and Xu, B and Yang, T and Sun, J and Liu, W}, title = {Methylmercury promotes oxidative stress and autophagy in rat cerebral cortex: Involvement of PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways and attenuation by N-acetyl-L-cysteine.}, journal = {Neurotoxicology and teratology}, volume = {95}, number = {}, pages = {107137}, doi = {10.1016/j.ntt.2022.107137}, pmid = {36403891}, issn = {1872-9738}, mesh = {Animals ; Rats ; *Acetylcysteine/pharmacology ; AMP-Activated Protein Kinases/metabolism/pharmacology ; Autophagy ; Cerebral Cortex ; *Methylmercury Compounds/toxicity ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases ; }, abstract = {Methylmercury (MeHg) is a potent neurotoxicant that could induce oxidative stress and autophagy. However, the underlying mechanisms through which MeHg affects the central nervous system have not been fully elucidated, and little has been known of the interaction between oxidative stress and autophagy. Therefore, rats were administrated with different MeHg concentrations to evaluate the neurotoxic effects and autophagy in cerebral cortex. Moreover, we have investigated the neuroprotective role of N-acetyl-L-cysteine (NAC) against MeHg-induced neurotoxicity in order to estimate the regulation effects of oxidative stress on autophagy. A total of 64 rats, 40 of which were randomly divided into control and MeHg-treated (4, 8 and 12 μ mol/kg) groups. The remaining 24 rats were divided into control, NAC control (1 mmol/kg), 12 μ mol/kg MeHg, and NAC pretreatment. Administration of 12 μ mol/kg MeHg significantly increased behavioral and pathological abnormalities, and autophagy levels. In addition, the oxidative stress levels increased, together with abnormal expression of autophagy-related molecules. Pretreatment with NAC significantly prevented MeHg-induced oxidative stress and PI3K/AKT/mTOR or AMPK/TSC2/mTOR-mediated autophagy. In conclusion, the present study suggested that oxidative stress can regulate autophagy through PI3K/AKT/mTOR or AMPK/TSC2/mTOR pathways. This study provides a theoretical basis for the study and treatment of MeHg-induced neurotoxicity.}, }
@article {pmid36402045, year = {2023}, author = {Cao, X and Guo, L and Zhou, C and Huang, C and Li, G and Zhuang, Y and Yang, F and Liu, P and Hu, G and Gao, X and Guo, X}, title = {Effects of N-acetyl-l-cysteine on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets.}, journal = {Poultry science}, volume = {102}, number = {1}, pages = {102274}, pmid = {36402045}, issn = {1525-3171}, mesh = {Animals ; Female ; *Acetylcysteine/pharmacology/metabolism ; *Chickens/physiology ; Ovary/metabolism ; Oxidative Stress ; Antioxidants/metabolism ; Inflammation/veterinary/metabolism ; Heat-Shock Response ; Cytokines/metabolism ; }, abstract = {The aims of this study were to investigate the effects of supplemental N-acetyl-l-cysteine (NAC) on chronic heat stress-induced oxidative stress and inflammation in the ovaries of growing pullets. A total of 120, 12-wk-old, Hy-Line Brown hens were randomly separated into 4 groups with 6 replicates of 5 birds in each group for 21 d. The 4 treatments were as follows: the CON group and CN group were supplemented with basal diet or basal diet with 1 g/kg NAC, respectively; and the HS group and HSN group were heat-stressed groups supplemented with basal diet or basal diet with 1 g/kg NAC, respectively. The results indicated that the ovaries suffered pathological damage due to chronic heat stress and that NAC effectively ameliorated these changes. Compared with the HS group, antioxidant enzyme activities (including SOD, GSH-Px, CAT, and T-AOC) were enhanced, while the MDA contents and the expression levels of HSP70 were decreased in the HSN group. In addition, NAC upregulated the expression levels of HO-1, SOD2, and GST by upregulating the activity of Nrf2 at different time points to mitigate oxidative stress caused by heat exposure. Simultaneously, NAC attenuated chronic heat stress-induced NF-κB pathway activation and decreased the expression levels of the proinflammatory cytokines IL-8, IL-18, TNF-α, IKK-α, and IFN-γ. Cumulatively, our results indicated that NAC could ameliorate chronic heat stress-induced ovarian damage by upregulating the antioxidative capacity and reducing the secretion of proinflammatory cytokines.}, }
@article {pmid36400163, year = {2023}, author = {Suresh, V and Behera, P and Parida, D and Mohapatra, AP and Das, SK and Kumari, S and Avula, K and Mohapatra, A and Syed, GH and Senapati, S}, title = {Therapeutic role of N-acetyl cysteine (NAC) for the treatment and/or management of SARS-CoV-2-induced lung damage in hamster model.}, journal = {European journal of pharmacology}, volume = {938}, number = {}, pages = {175392}, pmid = {36400163}, issn = {1879-0712}, mesh = {Animals ; Cricetinae ; *SARS-CoV-2 ; Acetylcysteine/pharmacology/therapeutic use ; *COVID-19 ; Interleukin-6 ; Reactive Oxygen Species ; Lung ; }, abstract = {Oxidative stress by reactive oxygen species (ROS) has been hypothesized to be the major mediator of SARS-CoV-2-induced pathogenesis. During infection, the redox homeostasis of cells is altered as a consequence of virus-induced cellular stress and inflammation. In such scenario, high levels of ROS bring about the production of pro-inflammatory molecules like IL-6, IL-1β, etc. that are believed to be the mediators of severe COVID-19 pathology. Based on the known antioxidant, anti-inflammatory, mucolytic and antiviral properties of NAC, it has been hypothesized that NAC will have beneficial effects in COVID-19 patients. In the current study efforts have been made to evaluate the protective effect of NAC in combination with remdesivir against SARS-CoV-2 induced lung damage in the hamster model. The SARS-CoV-2 infected animals were administered with high (500 mg/kg/day) and low (150 mg/kg/day) doses of NAC intraperitoneally with and without remdesivir. Lung viral load, pathology score and expression of inflammatory molecules were checked by using standard techniques. The findings of this study show that high doses of NAC alone can significantly suppress the SARS-CoV-2 mediated severe lung damage (2 fold), but on the contrary, it fails to restrict viral load. Moreover, high doses of NAC with and without remdesivir significantly suppressed the expression of pro-inflammatory genes including IL-6 (4.16 fold), IL-1β (1.96 fold), and TNF-α (5.55 fold) in lung tissues. Together, results of this study may guide future preclinical and clinical attempts to evaluate the efficacy of different doses and routes of NAC administration with or without other drugs against SARS-CoV-2 infection.}, }
@article {pmid36399957, year = {2022}, author = {Yin, YL and Chen, Y and Ren, F and Wang, L and Zhu, ML and Lu, JX and Wang, QQ and Lu, CB and Liu, C and Bai, YP and Wang, SX and Wang, JZ and Li, P}, title = {Nitrosative stress induced by homocysteine thiolactone drives vascular cognitive impairments via GTP cyclohydrolase 1 S-nitrosylation in vivo.}, journal = {Redox biology}, volume = {58}, number = {}, pages = {102540}, pmid = {36399957}, issn = {2213-2317}, mesh = {Animals ; Humans ; Mice ; *Cognitive Dysfunction/etiology/metabolism ; Cysteine/metabolism ; Endothelial Cells/metabolism ; GTP Cyclohydrolase ; *Hyperhomocysteinemia/chemically induced/metabolism ; Nitric Oxide/metabolism ; Nitrosative Stress ; }, abstract = {BACKGROUND: s: Hyperhomocysteinemia (HHcy) is one of risk factors for vascular cognitive impairment (VCI). GTP cyclohydrolase 1 (GCH1) deficiency is critical to oxidative stress in vascular dysfunction. The aim of this study was designed to examine whether HHcy induces VCI through GCH1 S-nitrosylation, a redox-related post-translational modification of cysteine.<br><br>METHODS: The VCI model was induced by feeding mice homocysteine thiolactone (HTL) for 16 consecutive weeks. The cognitive functions were evaluated by step-down avoidance test, passive avoidance step-through task test, and Morris water maze (MWM) test. Protein S-nitrosylation was assayed using a biotin-switch method.<br><br>RESULTS: In cell-free system, nitric oxide (NO) donor induced GCH1 protein S-nitrosylation and decreased GCH1 activity. In endothelial cells, HTL increased GCH1 S-nitrosylation, reduced tetrahydrobiopterin, and induced oxidative stress, which were attenuated by N-acetyl-cysteine, L-N6-1-Iminoethyl-lysine, mutant of GCH1 cysteine 141 to alanine (MT-GCH1) or gene deletion of inducible NO synthase (iNOS). Further, HTL incubation or iNOS overexpression promoted endothelial cellular senescence, but abolished by exogenous expression of MT-GCH1 or pharmacological approaches including N-acetyl-cysteine, L-sepiapterin, and tempol. In wildtype mice, long-term administration of HTL induced GCH1 S-nitrosylation and vascular stiffness, decreased cerebral blood flow, and damaged the cognitive functions. However, these abnormalities induced by HTL administration were rescued by enforced expression of MT-GCH1 or gene knockout of iNOS. In human subjects, GCH1 S-nitrosylation was increased and cognitive functions were impaired in patients with HHcy.<br><br>CONCLUSION: The iNOS-mediated nitrosative stress induced by HTL drives GCH1 S-nitrosylation to induce cerebral vascular stiffness and cognitive impairments.}, }
@article {pmid36396003, year = {2023}, author = {Elkin, ER and Su, AL and Dou, JF and Colacino, JA and Bridges, D and Padmanabhan, V and Harris, SM and Boldenow, E and Loch-Caruso, R and Bakulski, KM}, title = {Sexually concordant and dimorphic transcriptional responses to maternal trichloroethylene and/or N-acetyl cysteine exposure in Wistar rat placental tissue.}, journal = {Toxicology}, volume = {483}, number = {}, pages = {153371}, pmid = {36396003}, issn = {1879-3185}, support = {P30 AG053760/AG/NIA NIH HHS/United States ; P42 ES017198/ES/NIEHS NIH HHS/United States ; T32 DK071212/DK/NIDDK NIH HHS/United States ; R01 ES028802/ES/NIEHS NIH HHS/United States ; R01 ES025574/ES/NIEHS NIH HHS/United States ; R01 DK107535/DK/NIDDK NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; R01 ES025531/ES/NIEHS NIH HHS/United States ; R01 AG055406/AG/NIA NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; R01 AG067592/AG/NIA NIH HHS/United States ; }, mesh = {Female ; Male ; Rats ; Pregnancy ; Animals ; *Trichloroethylene/toxicity/metabolism ; Acetylcysteine/pharmacology ; Rats, Wistar ; Antioxidants/pharmacology ; Placenta/metabolism ; }, abstract = {Numerous Superfund sites are contaminated with the volatile organic chemical trichloroethylene (TCE). In women, exposure to TCE in pregnancy is associated with reduced birth weight. Our previous study reported that TCE exposure in pregnant rats decreased fetal weight and elevated oxidative stress biomarkers in placentae, suggesting placental injury as a potential mechanism of TCE-induced adverse birth outcomes. In this study, we investigated if co-exposure with the antioxidant N-acetylcysteine (NAC) attenuates TCE exposure effects on RNA expression. Timed-pregnant Wistar rats were exposed orally to 480 mg TCE/kg/day on gestation days 6-16. Exposure of 200 mg NAC/kg/day alone or as a pre/co-exposure with TCE occurred on gestation days 5-16 to stimulate antioxidant genes prior to TCE exposure. Tissue was collected on gestation day 16. In male and female placentae, we evaluated TCE- and/or NAC-induced changes to gene expression and pathway enrichment analyses using false discovery rate (FDR) and fold-change criteria. In female placentae, exposure to TCE caused significant differential expression 129 genes while the TCE+NAC altered 125 genes, compared with controls (FDR< 0.05 + fold-change >1). In contrast, in male placentae TCE exposure differentially expressed 9 genes and TCE+NAC differentially expressed 35 genes, compared with controls (FDR< 0.05 + fold-change >1). NAC alone did not significantly alter gene expression in either sex. Differentially expressed genes observed with TCE exposure were enriched in mitochondrial biogenesis and oxidative phosphorylation pathways in females whereas immune system pathways and endoplasmic reticulum stress pathways were differentially expressed in both sexes (FDR<0.05). TCE treatment was differentially enriched for genes regulated by the transcription factors ATF6 (both sexes) and ATF4 (males only), indicating a cellular condition triggered by misfolded proteins during endoplasmic reticulum stress. This study demonstrates novel genes and pathways involved in TCE-induced placental injury and showed antioxidant co-treatment largely did not attenuate TCE exposure effects.}, }
@article {pmid36394765, year = {2022}, author = {Alomar, FA}, title = {Methylglyoxal in COVID-19-induced hyperglycemia and new-onset diabetes.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {21}, pages = {8152-8171}, doi = {10.26355/eurrev_202211_30169}, pmid = {36394765}, issn = {2284-0729}, mesh = {Humans ; Pyruvaldehyde ; *COVID-19 ; Magnesium Oxide ; SARS-CoV-2 ; *Hyperglycemia ; *Diabetes Mellitus/drug therapy ; Insulin ; }, abstract = {Elevation in blood glucose is common in COVID-19 patients. There is also a high incidence of new-onset diabetes mellitus (DM) in COVID-19 patients following hospitalization. To date, the underlying cause(s) for the hyperglycemia and new-onset DM post-COVID-19 remain poorly understood. In this narrative review, we suggest that upregulation of the cytotoxic and diffusible glycolytic byproduct methylglyoxal (MGO) arising from increased glycolysis in infected pancreatic islets, macrophages, and peripheral cells/tissues is impairing insulin production, secretion, and signaling. This hypothesis is based on our recent discovery that MGO levels were elevated in the plasma of hospitalized COVID-19 patients without and with DM and even higher in COVID-19 patients that succumb to the disease. In pancreatic islets infected with SARS-CoV-2, elevated MGO will disrupt mitochondrial function, perturb Ca2+ homeostasis, and activate the receptors for advanced glycation end-product (RAGE) and nuclear factor kappa B (NF-kB) resulting in impaired insulin production and secretion. In macrophages, excess MG production can diffuse into the vasculature disrupting endothelial function and triggering micro/macro hemorrhage, ischemia, and tissue fibrosis. In skeletal muscle and liver cells, MGO disruption of insulin signaling can blunt glucose absorption. Metformin and N-acetyl cysteine have recently been shown to decrease morbidity and mortality in COVID-19 patients. Here we propose that these agents may be exerting their beneficial effects by chemically reacting with and lowering MGO levels. Knowledge gained from this review should provide novel mechanistic insights for hyperglycemia in COVID-19 patients and strategies to blunt the development of new-onset of DM in post-COVID patients.}, }
@article {pmid36384314, year = {2023}, author = {Parli, GM and Gales, MA and Gales, BJ}, title = {"N-Acetylcysteine for Obsessive-Compulsive and Related Disorders in Children and Adolescents: A Review".}, journal = {The Annals of pharmacotherapy}, volume = {57}, number = {7}, pages = {847-854}, doi = {10.1177/10600280221138092}, pmid = {36384314}, issn = {1542-6270}, mesh = {Humans ; Adolescent ; Child ; Child, Preschool ; Young Adult ; Adult ; Acetylcysteine/therapeutic use ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Obsessive-Compulsive Disorder/drug therapy/diagnosis/psychology ; *Cognitive Behavioral Therapy ; *Drug-Related Side Effects and Adverse Reactions ; Treatment Outcome ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: To evaluate clinical data using oral n-acetylcysteine (NAC) in obsessive-compulsive and related disorders (OCDRD) treatment.<br><br>DATA SOURCES: PubMed, Ovid MEDLINE (1946-July 2022), and the Cochrane Library database were searched using the terms NAC, children, adolescent, obsessive-compulsive disorder (OCD), trichotillomania (TTM), excoriation, hoarding disorder, and body dysmorphic disorder. Bibliographies were reviewed for relevant trials and case studies.<br><br>English language, clinical trials, or case studies analyzing NAC use in patients aged 3 to 21 years old with OCDRD as determined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition.<br><br>DATA SYNTHESIS: Three randomized double-blind placebo-controlled trials of NAC in children and adolescents studied 121 patients with OCDRD. Trials assessed symptom severity from baseline to 10 to 12 weeks of NAC therapy. Two OCD trials identified statistically significant improvements, with only 1 trial demonstrating a clear clinically relevant difference from placebo. One trial in TTM found no difference between the NAC and placebo. Adverse effects were mild and included nausea, blurred vision, fatigue, tremor, and sweats. N-acetylcysteine titrated to 2400 or 2700 mg/day in divided doses was the most studied regimen.<br><br>Many OCDRD patients fail to completely respond to first-line treatment with cognitive behavioral therapy (CBT) and/or selective serotonin reuptake inhibitors (SSRIs) leaving practitioners with few additional treatment options. Preliminary efficacy and safety data are presented in this review.<br><br>CONCLUSIONS: Limited evidence suggests children and adolescents with OCD refractory to SSRIs or CBT may benefit from NAC augmentation.}, }
@article {pmid36383882, year = {2022}, author = {Alavinejad, P and Tran, NN and Eslami, O and Shaarawy, OE and Hormati, A and Seiedian, SS and Parsi, A and Ahmed, MH and Behl, NS and Abravesh, AA and Tran, QT and Vignesh, S and Salman, S and Sakr, N and Ara, TF and Hajiani, E and Hashemi, SJ and Patai, &#xc1;V and Butt, AS and Lee, SH}, title = {ORAL N-ACETYL CYSTEINE VERSUS RECTAL INDOMETHACIN FOR PREVENTION OF POST ERCP PANCREATITIS: A MULTICENTER MULTINATIONAL RANDOMIZED CONTROLLED TRIAL.}, journal = {Arquivos de gastroenterologia}, volume = {59}, number = {4}, pages = {508-512}, doi = {10.1590/S0004-2803.202204000-90}, pmid = {36383882}, issn = {1678-4219}, abstract = {BACKGROUND: This multicenter multinational RCT designed to compare the efficacy of suppository indomethacin and NAC for prevention of PEP.<br><br>METHODS: During a 6-month period, all of the ERCP cases in seven referral centers were randomly assigned to receive either 1200 mg oral NAC, indomethacin suppository 100 mg, 1200 mg oral NAC plus indomethacin suppository 100 mg or placebo 2 hours before ERCP. The primary outcomes were the rate and severity of any PEP.<br><br>RESULTS: A total of 432 patients included (41.4% male). They were originally citizens of 6 countries (60.87% Caucasian). They were randomly allocated to receive either NAC (group A, 84 cases), rectal indomethacin (group B, 138 cases), NAC + rectal indomethacin (group C, 115 cases) or placebo (group D, 95 cases). The rate of PEP in groups A, B and C in comparison with placebo were 10.7%, 17.4%, 7.8% vs 20% (P=0.08, 0.614 &amp; 0.01 respectively). The NNT for NAC, indomethacin and NAC + indomethacin was 11, 38 and 8 respectively.<br><br>CONCLUSION: Oral NAC is more effective than rectal indomethacin when compared to placebo for prevention of PEP and the combination of NAC and Indomethacin had the lowest incidence of PEP and may have synergistic effect in preventing of PEP (IRCT20201222049798N1; 29/12/2020).}, }
@article {pmid36382021, year = {2022}, author = {Soleymani, M and Masoudkabir, F and Shabani, M and Vasheghani-Farahani, A and Behnoush, AH and Khalaji, A}, title = {Updates on Pharmacologic Management of Microvascular Angina.}, journal = {Cardiovascular therapeutics}, volume = {2022}, number = {}, pages = {6080258}, pmid = {36382021}, issn = {1755-5922}, mesh = {Humans ; Female ; *Microvascular Angina/diagnosis/drug therapy ; *Coronary Artery Disease ; Coronary Angiography ; Angiotensin Receptor Antagonists/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; }, abstract = {Microvascular angina (MVA), historically called cardiac syndrome X, refers to angina with nonobstructive coronary artery disease. This female-predominant cardiovascular disorder adds considerable health-related costs due to repeated diagnostic angiography and frequent hospital admissions. Despite the high prevalence of this diagnosis in patients undergoing coronary angiography, it is still a therapeutic challenge for cardiologists. Unlike obstructive coronary artery disease, with multiple evidence-based therapies and management guidelines, little is known regarding the management of MVA. During the last decade, many therapeutic interventions have been suggested for the treatment of MVA. However, there is a lack of summarization tab and update of current knowledge about pharmacologic management of MVA, mostly due to unclear pathophysiology. In this article, we have reviewed the underlying mechanisms of MVA and the outcomes of various medications in patients with this disease. Contrary to vasospastic angina in which normal angiogram is observed as well, nitrates are not effective in the treatment of MVA. Beta-blockers and calcium channel blockers have the strongest evidence of improving the symptoms. Moreover, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, estrogen, and novel antianginal drugs has had promising outcomes. Investigations are still ongoing for vitamin D, omega-3, incretins, and n-acetyl cysteine, which have resulted in beneficial initial outcomes. We believe that the employment of the available results and results of the future large-scale trials into cardiac care guidelines would help reduce the global cost of cardiac care tremendously.}, }
@article {pmid36374790, year = {2022}, author = {Flores, A and Moyano, P and Sola, E and García, JM and García, J and Anadon, MJ and Frejo, MT and Naval, MV and Fernadez, MC and Pino, JD}, title = {Single and repeated bisphenol A treatment induces ROS, Aβ and hyperphosphorylated-tau accumulation, and insulin pathways disruption, through HDAC2 and PTP1B overexpression, leading to SN56 cholinergic apoptotic cell death.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {170}, number = {}, pages = {113500}, doi = {10.1016/j.fct.2022.113500}, pmid = {36374790}, issn = {1873-6351}, mesh = {*tau Proteins/metabolism ; Reactive Oxygen Species/metabolism ; Histone Deacetylase 2/metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Amyloid beta-Peptides/metabolism ; Cholinergic Neurons/metabolism ; Apoptosis ; Cholinergic Agents/metabolism ; *Insulins/metabolism ; }, abstract = {Bisphenol-A (BPA), a polymer component extensively used, produces memory and learning alterations after acute and long-term exposure. However, the mechanisms are not well known. Cortex and hippocampus neuronal networks control cognitive functions, which are innervated by basal forebrain cholinergic neurons (BFCN), and their neurodegeneration induces cognitive dysfunctions. Wild type or protein tyrosine phosphatase 1B (PTP1B), histone deacetylase 2 (HDAC2), tau or β amyloid precursor protein (βAPP) silenced SN56 cells treated with BPA (0.001 μM-100 μM) with or without N-acetylcysteine (NAC; 1 mM), following 1 and 14 days, were used, as a model of BFCN to determine the insulin pathway dysfunction, oxidative stress (OS) generation and amyloid-β (Aβ) and tau proteins accumulation involvement in the BCFN cell death induction, as a possible mechanism that could produce the cognitive disorders reported. BPA-induced BFCN cell death, after 24 h and 14 days of treatment, through insulin pathway dysfunction, OS generation, mediated by NRF2 pathway downregulation, and Aβ and tau proteins accumulation, which were in turn induced by HDAC2 and PTP1B overexpression. This is relevant information to explain the BFCN neurodegeneration mechanisms that could trigger the neurodegeneration in the rest of the regions innerved by them, leading to cognitive disorders.}, }
@article {pmid36374720, year = {2023}, author = {Hsu, SS and Lin, YS and Chio, LM and Liang, WZ}, title = {Evaluation of the mycotoxin patulin on cytotoxicity and oxidative stress in human glioblastoma cells and investigation of protective effect of the antioxidant N-acetylcysteine (NAC).}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {221}, number = {}, pages = {106957}, doi = {10.1016/j.toxicon.2022.106957}, pmid = {36374720}, issn = {1879-3150}, mesh = {Humans ; *Patulin/toxicity ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology/metabolism ; *Glioblastoma/drug therapy/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Mycotoxins are secondary metabolites produced by various kinds of fungi that can induce disease in humans. The fungal species Penicillium expansum produces patulin (C7H6O4), a polyketide lactone mycotoxin found in fruits. Patulin is classified as noncarcinogen; however, recently, it has been associated with harmful effects on the central nervous system. Patulin's toxic action has been established in various brain models; however, its effect on human glioblastoma remains elusive. This study explores whether patulin induces cytotoxicity through oxidative stress in DBTRG-05MG human glioblastoma cells. This study also evaluates whether the antioxidant N-acetylcysteine (NAC) protects against patulin-induced cytotoxicity. In DBTRG-05MG cells, patulin concentration (10-60 μM) dependently induced cytotoxicity. Concerning oxidative stress, patulin (10 and 20 μM) increased the production of intracellular reactive oxygen species (ROS) but depleted reduced glutathione (GSH) contents and regulated the expressions of antioxidant-related proteins (Nrf2 and HO-1). Furthermore, patulin induced cytotoxicity via modulation of apoptosis-related protein expressions (Bax, cleaved caspase-9, and cleaved caspase-3). These cytotoxic responses were partially reversed via pretreatment with NAC (10 μM). In summary, these data help us understand the toxicology of patulin in human glioblastoma and evaluate whether NAC could clinically reduce patulin-affected brain damage.}, }
@article {pmid36364008, year = {2022}, author = {Zhang, Y and Tang, Y and Tang, X and Wang, Y and Zhang, Z and Yang, H}, title = {Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {21}, pages = {}, pmid = {36364008}, issn = {1420-3049}, support = {2020J01176, 2021J02028 and 2022J01172//Fujian Natural Science Foundation/ ; 2021G02023 and 2022G023//Key Projects of Scientific and Technological Innovation in Fujian Province/ ; 2020L3008//Special Funds of the Central Government Guilding Local Science and Technology Development/ ; I202003009 and I202102008//Innovation and Entrepreneurship Project of Fujian Normal University/ ; }, mesh = {Male ; Humans ; Reactive Oxygen Species/metabolism ; Paclitaxel/pharmacology ; Caspase 3/genetics/pharmacology ; Apoptosis ; *Prostatic Neoplasms/drug therapy/genetics/pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/pharmacology ; *Antineoplastic Agents/pharmacology ; }, abstract = {Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway involved in the function of PTX are poorly understood. In the current study, we employed the CCK-8 assay, revealing that PTX can inhibit the survival and induce the apoptosis of PC3M cells (a human prostate cancer cell line) in a concentration-dependent manner. Reactive oxygen species (ROS), as a metabolic intermediate produced by the mitochondrial respiratory chain, are highly accumulated under the PTX treatment, which results in a sharp decrease of the mitochondrial membrane potential in PC3M cells. Additionally, the migration and invasion of PC3M cells are weakened due to PTX treatment. Further analysis reveals that N-acetylcysteine (NAC), which functions as an antioxidant, not only rescues the decreased mitochondrial membrane potential induced by the abnormal ROS level, but also restores the migration and invasion of PC3M cells. In a subsequent exploration of the detailed mechanism, we found that hypoxia-inducible factor (HIF)-1α works as a downstream gene that can respond to the increased ROS in PC3M cells. Under PTX treatment, the expression levels of HIF-1α mRNA and protein are significantly increased, which stimulate the activation of JNK/caspase-3 signaling and promote the apoptosis of PC3M cells. In summary, we demonstrate that PTX regulates the expression of HIF-1α through increased ROS accumulation, thereby promoting the activation of JNK/caspase-3 pathway to induce the apoptosis of PCa cells. This study provides new insights into the mechanism of antineoplastic action of taxanes and unveils the clinical benefit of the ROS-HIF-1α signaling pathway, which may offer a potential therapeutic target to prevent the development of PCa.}, }
@article {pmid36362692, year = {2022}, author = {Mylonas, KS and Sarantis, P and Kapelouzou, A and Karamouzis, MV and Kapetanakis, EI and Kontzoglou, K and Iliopoulos, DC and Nikiteas, N and Schizas, D}, title = {Mechanosensitive Stem-Cell Genes and Klotho in Atherosclerotic Aortas: Regulating Spatially Deranged Expression Patterns Using Colchicine Regimens.}, journal = {Journal of clinical medicine}, volume = {11}, number = {21}, pages = {}, pmid = {36362692}, issn = {2077-0383}, support = {N/A//Hellenic Atherosclerosis Society/ ; N/A//Hellenic Surgical Society/ ; }, abstract = {AIMS: Inflammatory dysregulation of mechanosensitive developmental genes may be central to atherogenesis. In the present seven-week model, we utilized colchicine regimens to curtail aortic atherogenesis in New Zealand White rabbits. We also explored the effect of colchicine regimens on atheroprotective (Klotho, HOXA5, NOTCH1, and OCT4) and proatherogenic (HIF1a, SOX2, BMP4, and NANOG) genes.<br><br>METHODS: The control (n = 6) and group A (n = 6) received standard and cholesterol-enriched chow, respectively. Groups B (n = 8) and C (n = 8) were fed hypercholesterolemic diet and were treated with colchicine plus fenofibrate or N-acetylcysteine (NAC), respectively.<br><br>RESULTS: Group A developed significantly greater thoracic and abdominal aortic atherosclerosis compared to groups B (p < 0.001) and C (p < 0.001). Combining colchicine with NAC resulted in stronger atheroprotection both in the thoracic and the abdominal aorta. In group A thoracic aortas, Klotho was downregulated compared to controls (95% CI: 1.82-15.76). Both colchicine regimens upregulated Klotho back to baseline levels (p < 0.001). Colchicine/fenofibrate also significantly upregulated thoracic NOTCH1 compared to controls (95% CI: -8.09 to -0.48). Colchicine/NAC significantly reduced thoracic NANOG expression compared to hyperlipidemic diet alone (95% CI: 0.37-8.29). In the abdominal aorta, hypercholesterolemic diet resulted in significant downregulation of HOXA5 (95% CI: 0.03-2.74) which was reversed with colchicine/NAC back to baseline (95% CI: -1.19 to 1.51). Colchicine/fenofibrate downregulated HIF1a compared to baseline (95% CI: 0.83-6.44). No significant differences were noted in terms of BMP4, SOX2, and OCT4.<br><br>CONCLUSIONS: Overall, the aortic expression pattern of mechanosensitive genes seems to be spatially influenced by a hyperlipidemic diet and can be modified using colchicine-based therapy.}, }
@article {pmid36359827, year = {2022}, author = {Kaur, K and Chen, PC and Ko, MW and Mei, A and Chovatiya, N and Huerta-Yepez, S and Ni, W and Mackay, S and Zhou, J and Maharaj, D and Malarkannan, S and Jewett, A}, title = {The Potential Role of Cytotoxic Immune Effectors in Induction, Progression and Pathogenesis of Amyotrophic Lateral Sclerosis (ALS).}, journal = {Cells}, volume = {11}, number = {21}, pages = {}, pmid = {36359827}, issn = {2073-4409}, mesh = {Humans ; *Amyotrophic Lateral Sclerosis/immunology/metabolism/pathology ; *CD8-Positive T-Lymphocytes/metabolism ; Cytokines/metabolism ; Granzymes/metabolism ; Leukocytes, Mononuclear/metabolism ; *T-Lymphocytes, Cytotoxic/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neuron system. The causes of ALS are heterogeneous, and are only partially understood. We studied different aspects of immune pathogenesis in ALS and found several basic mechanisms which are potentially involved in the disease. Our findings demonstrated that ALS patients' peripheral blood contains higher proportions of NK and B cells in comparison to healthy individuals. Significantly increased IFN-γ secretion by anti-CD3/28 mAbs-treated peripheral blood mononuclear cells (PBMCs) were observed in ALS patients, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism for ALS progression. In addition, elevated granzyme B and perforin secretion at a single cell level, and increased cytotoxicity and secretion of IFN-γ by patients' NK cells under specific treatment conditions were also observed. Increased IFN-γ secretion by ALS patients' CD8+ T cells in the absence of IFN-γ receptor expression, and increased CD8+ T cell effector/memory phenotype as well as increased granzyme B at the single cell level points to the CD8+ T cells as potential cells in targeting motor neurons. Along with the hyper-responsiveness of cytotoxic immune cells, significantly higher levels of inflammatory cytokines including IFN-γ was observed in peripheral blood-derived serum of ALS patients. Supernatants obtained from ALS patients' CD8+ T cells induced augmented cell death and differentiation of the epithelial cells. Weekly N-acetyl cysteine (NAC) infusion in patients decreased the levels of many inflammatory cytokines in peripheral blood of ALS patient except IFN-γ, TNF-α, IL-17a and GMCSF which remained elevated. Findings of this study indicated that CD8+ T cells and NK cells are likely culprits in targeting motor neurons and therefore, strategies should be designed to decrease their function, and eliminate the aggressive nature of these cells. Analysis of genetic mutations in ALS patient in comparison to identical twin revealed a number of differences and similarities which may be important in the pathogenesis of the disease.}, }
@article {pmid36359406, year = {2022}, author = {Aiyer, A and Das, T and Whiteley, GS and Glasbey, T and Kriel, FH and Farrell, J and Manos, J}, title = {The Efficacy of an N-Acetylcysteine-Antibiotic Combination Therapy on Achromobacter xylosoxidans in a Cystic Fibrosis Sputum/Lung Cell Model.}, journal = {Biomedicines}, volume = {10}, number = {11}, pages = {}, pmid = {36359406}, issn = {2227-9059}, support = {IMCRC/WLY/08052019.1 and CT20584//This research was funded by COMMERCIAL DEVELOPMENT &amp; INDUSTRY PARTNERSHIP, grant number CT20584-University of Sydney and Whiteley Corporation and DEPARTMENT OF IN-DUSTRY, INNOVATION AND SCIENCE (Innovative Manufacturing CRC Ltd.) and WHITELEY CORPORATION/ ; }, abstract = {Cystic fibrosis (CF) is a disorder causing dysfunctional ion transport resulting in the accumulation of viscous mucus. This environment fosters a chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans, a gram-negative aerobic bacillus, has been increasingly associated with antibiotic resistance and chronic colonisation in CF. In this study, we aimed to create a reproducible model of CF infection using an artificial sputum medium (ASMDM-1) with bronchial (BEAS-2B) and macrophage (THP-1) cells to test A. xylosoxidans infection and treatment toxicity. This study was conducted in three distinct stages. First, the tolerance of BEAS-2B cell lines and two A. xylosoxidans strains against ASMDM-1 was optimised. Secondly, the cytotoxicity of combined therapy (CT) comprising N-acetylcysteine (NAC) and the antibiotics colistin or ciprofloxacin was tested on cells alone in the sputum model in both BEAS-2B and THP-1 cells. Third, the efficacy of CT was assessed in the context of a bacterial infection within the live cell/sputum model. We found that a model using 20% ASMDM-1 in both cell populations tolerated a colistin-NAC-based CT and could significantly reduce bacterial loads in vitro (~2 log10 CFU/mL compared to untreated controls). This pilot study provides the foundation to study other bacterial opportunists that infect the CF lung to observe infection and CT kinetics. This model also acts as a springboard for more complex co-culture models.}, }
@article {pmid36357979, year = {2023}, author = {Li, ZQ and Zhang, C and Fan, S and Wang, LL and Jiang, Y and Li, HJ}, title = {Evidence for exposure biomarkers in dictamnine-induced liver injury resulting from metabolic activation in vitro and in mice.}, journal = {Journal of applied toxicology : JAT}, volume = {43}, number = {5}, pages = {662-679}, doi = {10.1002/jat.4414}, pmid = {36357979}, issn = {1099-1263}, mesh = {Mice ; Animals ; Activation, Metabolic ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Microsomes, Liver/metabolism ; Acetylcysteine ; Glutathione/metabolism ; }, abstract = {Dictamnine (DTN), a furoquinoline alkaloid isolated from Dictamni Cortex, is responsible for the liver injury caused by Dictamni Cortex and the preparations. Discovering new biomarkers with high specificity and sensitivity for diagnosis and tracing the source of DTN-induced liver injury is urgently needed. Considering that metabolic activation of DTN has been suggested as a primary trigger initiating hepatotoxicity, the present study aimed to investigate the bio-activation process of DTN in vitro and in mice and to explore whether the adducts could be developed as exposure biomarkers. When trapping with N-acetyl-cysteine (NAC) and glutathione (GSH) in mouse liver microsomes and CYP3A4 overexpressed L02 cells, two isomers of DTN-NAC adducts were detected in both systems and one DTN-GSH adduct was found in mouse liver microsomes. As expected, one DTN-NAC adduct was also found in plasma and bile of mice with liver injury after DTN exposure. Moreover, mouse liver microsomes were used to simulate the conjugation of serum albumin with metabolically activated DTN. The sole modified peptide [25] DAHKSEVAHR[34] was found, and the oxidative metabolites of DTN might bind to the side chain amino of albumin at Arg34. The above findings not only provided confirmative evidence that DTN was metabolically activated to induce liver injury but also suggested that the adducts had the potential to be developed as exposure biomarkers of DTN-induced liver injury.}, }
@article {pmid36354958, year = {2022}, author = {Kandel, R and Singh, KP}, title = {Higher Concentrations of Folic Acid Cause Oxidative Stress, Acute Cytotoxicity, and Long-Term Fibrogenic Changes in Kidney Epithelial Cells.}, journal = {Chemical research in toxicology}, volume = {35}, number = {11}, pages = {2168-2179}, pmid = {36354958}, issn = {1520-5010}, support = {R15 DK121362/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Animals ; Mice ; *Folic Acid/pharmacology ; *Antioxidants ; Reactive Oxygen Species ; Oxidative Stress ; Kidney ; Acetylcysteine ; Epithelial Cells ; Fibrosis ; }, abstract = {Kidney fibrosis is a common step during chronic kidney disease (CKD), and its incidence has been increasing worldwide. Aberrant recovery after repeated acute kidney injury leads to fibrosis. The mechanism of fibrogenic changes in the kidney is not fully understood. Folic acid-induced kidney fibrosis in mice is an established in vivo model to study kidney fibrosis, but the mechanism is poorly understood. Moreover, the effect of higher concentrations of folic acid on kidney epithelial cells in vitro has not yet been studied. Oxidative stress is a common property of nephrotoxicants. Therefore, this study evaluated the role of folic acid-induced oxidative stress in fibrogenic changes by using the in vitro renal proximal tubular epithelial cell culture model. To obtain comprehensive and robust data, three different cell lines derived from human and mouse kidney epithelium were treated with higher concentrations of folic acid for both acute and long-term durations, and the effects were determined at the cellular and molecular levels. The result of cell viability by the MTT assay and the measurement of reactive oxygen species (ROS) levels by the DCF assay revealed that folic acid caused cytotoxicity and increased levels of ROS in acute exposure. The cotreatment with antioxidant N-acetyl cysteine (NAC) protected the cytotoxic effect, suggesting the role of folic acid-induced oxidative stress in cytotoxicity. In contrast, the long-term exposure to folic acid caused increased growth, DNA damage, and changes in the expression of marker genes for EMT, fibrosis, oxidative stress, and oxidative DNA damage. Some of these changes, particularly the acute effects, were abrogated by cotreatment with antioxidant NAC. In summary, the novel findings of this study suggest that higher concentrations of folic acid-induced oxidative stress act as the driver of cytotoxicity as an acute effect and of fibrotic changes as a long-term effect in kidney epithelial cells.}, }
@article {pmid36352994, year = {2022}, author = {Parvizrad, R and Marghamlki, EG and Nikfar, S and Dermani, SK}, title = {Effects of melatonin and N-acetylcysteine on aluminum phosphide poisoning in rats.}, journal = {Journal of family medicine and primary care}, volume = {11}, number = {8}, pages = {4500-4504}, pmid = {36352994}, issn = {2249-4863}, abstract = {INTRODUCTION: Aluminum phosphide (ALP) poisoning is one of the deadliest types of poisoning in the world. The antioxidant properties of melatonin and N-acetylcysteine and their effects on reducing cell death have been identified. The aim of this study was to evaluate the effects of N-acetylcysteine and melatonin in the treatment of aluminum phosphide poisoning in rats.<br><br>MATERIALS AND METHODS: Fifty male Wistar rats weighing 200-250 g were tested in five groups of ten. The first group was the control group; the second group received (10 mg/kg) of ALP, the third group received (10 mg/kg) of ALP and (10 mg/kg) of melatonin, the fourth group received (10 mg/kg) of ALP and (10 mg/kg) of N-acetylcysteine, and the last group received (10 mg/kg) of ALP and (10 mg/kg) of melatonin and N-acetylcysteine. The plasma of samples was isolated, and the activity of antioxidant enzymes (glutathione S-transferase (GST), Superoxide dismutase (SOD), and catalase (CAT)) was analyzed.<br><br>RESULTS: The concentrations of CAT, GST, Glutathione, GSH were decreased in plasma, liver, and kidneys of mice treated with aluminum phosphide; also, the concentrations of aspartate aminotransferase (AST), ALT, and AlK were increased (P < 0.05), while the activity of SOD did not change significantly (P > 0.05). Treatment with N-acetylcysteine and melatonin led to an increase in the activity of CAT, GST, and GSH in plasma, liver, and kidney. After the administration of N-acetylcysteine and melatonin to mice, the levels of all enzymes were close to normal, and the mice survived for 12-15 hours after administration.<br><br>DISCUSSION: The administration of N-acetylcysteine (NAC) and melatonin at a dose of 10 mg/kg improves hepatic manifestations and prevents liver necrosis; also, they are considered potential therapeutic agents in the treatment of this poisoning.}, }
@article {pmid36345724, year = {2022}, author = {Zalachoras, I and Ramos-Fernández, E and Hollis, F and Trovo, L and Rodrigues, J and Strasser, A and Zanoletti, O and Steiner, P and Preitner, N and Xin, L and Astori, S and Sandi, C}, title = {Glutathione in the nucleus accumbens regulates motivation to exert reward-incentivized effort.}, journal = {eLife}, volume = {11}, number = {}, pages = {}, pmid = {36345724}, issn = {2050-084X}, mesh = {Humans ; Male ; Rats ; Animals ; *Nucleus Accumbens/physiology ; *Motivation ; Antioxidants/metabolism ; Reward ; Glutathione/metabolism ; }, abstract = {Emerging evidence is implicating mitochondrial function and metabolism in the nucleus accumbens in motivated performance. However, the brain is vulnerable to excessive oxidative insults resulting from neurometabolic processes, and whether antioxidant levels in the nucleus accumbens contribute to motivated performance is not known. Here, we identify a critical role for glutathione (GSH), the most important endogenous antioxidant in the brain, in motivation. Using proton magnetic resonance spectroscopy at ultra-high field in both male humans and rodent populations, we establish that higher accumbal GSH levels are highly predictive of better, and particularly, steady performance over time in effort-related tasks. Causality was established in in vivo experiments in rats that, first, showed that downregulating GSH levels through micro-injections of the GSH synthesis inhibitor buthionine sulfoximine in the nucleus accumbens impaired effort-based reward-incentivized performance. In addition, systemic treatment with the GSH precursor N-acetyl-cysteine increased accumbal GSH levels in rats and led to improved performance, potentially mediated by a cell-type-specific shift in glutamatergic inputs to accumbal medium spiny neurons. Our data indicate a close association between accumbal GSH levels and an individual's capacity to exert reward-incentivized effort over time. They also suggest that improvement of accumbal antioxidant function may be a feasible approach to boost motivation.}, }
@article {pmid36344940, year = {2022}, author = {Liao, Y and Wu, Y and Zi, K and Shen, Y and Wang, T and Qin, J and Chen, L and Chen, M and Liu, L and Li, W and Zhou, H and Xiong, S and Wen, F and Chen, J}, title = {The effect of N-acetylcysteine in patients with non-cystic fibrosis bronchiectasis (NINCFB): study protocol for a multicentre, double-blind, randomised, placebo-controlled trial.}, journal = {BMC pulmonary medicine}, volume = {22}, number = {1}, pages = {401}, pmid = {36344940}, issn = {1471-2466}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Quality of Life ; Prospective Studies ; RNA, Ribosomal, 16S ; Anti-Bacterial Agents ; *Bronchiectasis/complications ; Double-Blind Method ; *Cystic Fibrosis/complications ; Fibrosis ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC), which is specifically involved in airway mucus clearance and antioxidation, is recommended by the treatment guideline for non-cystic fibrosis bronchiectasis (NCFB). However, there is little clinical evidence of its long-term efficacy concerning quality of life (QoL) and exacerbation in patients with NCFB. In addition, the influences of NAC on airway bacterial colonization, chronic inflammation and oxidative stress in NCFB are also unclear.<br><br>METHODS: NINCFB is a prospective, multicentre, double-blind, randomised, placebo-controlled trial that will recruit 119 patients with NCFB and randomly divide them into an NAC group (n&#xa0;=&#x2009;79) and a control group (n&#xa0;=&#x2009;40). Participants in the NAC group will receive 600&#x2009;mg oral NAC twice daily for 52&#x2009;weeks, while patients in the control group will receive 600&#x2009;mg placebo twice daily for 52&#x2009;weeks. The information at baseline will be collected once participants are enrolled. The primary endpoints are the changes in St George's Respiratory Questionnaire scores and the number of exacerbations in 52&#x2009;weeks. The secondary endpoints are the 16S rRNA of sputum and the levels of inflammatory factors and oxidative stressors in sputum and serum. Other data related to radiography, lung function tests, number of oral and/or intravenous antibiotic therapies and adverse events (AEs) will also be analysed. Further subgroup analysis distinguished by the severity of disease, severity of lung function, airway bacterial colonization and exacerbation frequency will be performed.<br><br>DISCUSSION: The objective of this study is to determine the long-term efficacy of NAC on QoL and exacerbation of NCFB and to explore the effectiveness of NAC for antibiosis, anti-inflammation and antioxidation in NCFB. The study results will provide high-quality clinical proof for the revision and optimization of treatment guidelines and for expert consensus on NCFB treatment.<br><br>TRIAL REGISTRATION: The trial was registered on the Chinese Clinical Trial Register at April 11, 2020 (chictr.org.cn , ChiCTR2000031817).}, }
@article {pmid36341071, year = {2022}, author = {Akibekov, OS and Syzdykova, AS and Lider, LA and Zhumalin, AK and Baibolin, ZK and Zhagipar, FS and Akanova, ZZ and Ibzhanova, AA and Gajimuradova, AM}, title = {Hematological, biochemical, and serological parameters of experimentally infected rabbits with Trichinella nativa and Trichinella spiralis for early identification of trichinellosis.}, journal = {Veterinary world}, volume = {15}, number = {9}, pages = {2285-2292}, pmid = {36341071}, issn = {0972-8988}, abstract = {BACKGROUND AND AIM: Trichinellosis remains a dangerous disease for humans and animals, which can lead to a lethal outcome. The study of specific body reactions in response to invasion by different types of Trichinella can help in the early diagnosis of the disease. This study aimed to investigate the hematological, biochemical, and serological characteristics of rabbits experimentally infected with trichinellosis, as well as the possibility of using changes in these parameters at various disease stages for early hematological, biochemical, and serological diagnosis of trichinellosis.<br><br>MATERIALS AND METHODS: Three groups of rabbits were orally infected with Trichinella nativa and Trichinella spiralis derived from encysted T. spirtalis larvae in pork muscle samples. The first and second groups were infected with T. nativa and T. spiralis, respectively, while the third group served as control by receiving a physiological solution. An ADVIA 2120i automatic hematology analyzer with a blood smear staining module was used to determine the hematological parameters of rabbits. Antigens were used in an enzyme-linked immunosorbent assay (ELISA) to detect antibodies in the sera of infected rabbits that were supernatants containing excretory-secretory antigens (ES-Ag) and somatic antigen (S-Ag).<br><br>RESULTS: The detection of biochemical responses to the invasion of T. nativa and T. spiralis isolates was detected and hematological parameters were featured in two cases. Trichinella nativa increased the number of erythrocytes, neutrophils, eosinophils, monocytes, basophils, and thrombocytes on day 7 in rabbits. Creatine kinase (CK) is regarded as the most important indicator for the early detection of parasite invasion. Blood biochemistry showed no active response to T. spiralis infection. However, counts of erythrocytes, neutrophils, lymphocytes, and CK rose significantly. In both color indicators, the number of thrombocytes decreased. Enzyme-linked immunosorbent assay with ES-Ag and S-Ag of these isolates demonstrated the ability to detect antibodies as early as 7 days after infection, with a significant increase in the marker up to 70 days.<br><br>CONCLUSION: On the 7[th] day after infection, blood tests of infected animals revealed CK-N-acetyl-cysteine (18.2%) and neutrophils (43%) when infected with T. nativa and neutrophils (26.7%) and lymphocytes (20%) when infected with T. spiralis. These indicators may serve as specific parameters for the early detection of Trichinella spp. invasion.}, }
@article {pmid36338342, year = {2022}, author = {Hsu, YC and Chuang, HC and Tsai, KL and Tu, TY and Shyong, YJ and Kuo, CH and Liu, YF and Shih, SS and Lin, CL}, title = {Administration of N-Acetylcysteine to Regress the Fibrogenic and Proinflammatory Effects of Oxidative Stress in Hypertrophic Ligamentum Flavum Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {1380353}, pmid = {36338342}, issn = {1942-0994}, mesh = {Humans ; *Ligamentum Flavum/metabolism ; Acetylcysteine/pharmacology/metabolism ; Vimentin/metabolism ; Hydrogen Peroxide/metabolism ; Hypertrophy/drug therapy/metabolism ; Transforming Growth Factor beta/metabolism ; Collagen Type I/metabolism ; Oxidative Stress ; }, abstract = {Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal stenosis (LSS). In hypertrophic ligamentum flavum (LF) cells, oxidative stress activates intracellular signaling and induces the expression of inflammatory and fibrotic markers. This study explored whether healthy and hypertrophic LF cells respond differently to oxidative stress, via examining the levels of phosphorylated p38 (p-p38), inducible nitric oxide synthase (iNOS), and α-smooth muscle actin (α-SMA). Furthermore, the efficacy of N-acetylcysteine (NAC), an antioxidant, in reversing the fibrogenic and proinflammatory effects of oxidative stress in hypertrophic LF cells was investigated by assessing the expression levels of p-p38, p-p65, iNOS, TGF-β, α-SMA, vimentin, and collagen I under H2O2 treatment with or without NAC. Under oxidative stress, p-p38 increased significantly in both hypertrophic and healthy LF cells, and iNOS was elevated in only the hypertrophic LF cells. This revealed that oxidative stress negatively affected both hypertrophic and healthy LF cells, with the hypertrophic LF cells exhibiting more active inflammation than did the healthy cells. After H2O2 treatment, p-p38, p-p65, iNOS, TGF-β, vimentin, and collagen I increased significantly, and NAC administration reversed the effects of oxidative stress. These results can form the basis of a novel therapeutic treatment for LFH using antioxidants.}, }
@article {pmid36337710, year = {2022}, author = {Liu, LF and Hu, Y and Liu, YN and Shi, DW and Liu, C and Da, X and Zhu, SH and Zhu, QY and Zhang, JQ and Xu, GH}, title = {Reactive oxygen species contribute to delirium-like behavior by activating CypA/MMP9 signaling and inducing blood-brain barrier impairment in aged mice following anesthesia and surgery.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {1021129}, pmid = {36337710}, issn = {1663-4365}, abstract = {Postoperative delirium (POD) is common in the elderly and is associated with poor clinical outcomes. Reactive oxygen species (ROS) and blood-brain barrier (BBB) damage have been implicated in the development of POD, but the association between these two factors and the potential mechanism is not clear. Cyclophilin A (CypA) is a specifically chemotactic leukocyte factor that can be secreted in response to ROS, which activates matrix metalloproteinase 9 (MMP9) and mediates BBB breakdown. We, therefore, hypothesized that ROS may contribute to anesthesia/surgery-induced BBB damage and delirium-like behavior via the CypA/MMP9 pathway. To test these hypotheses, 16-month-old mice were subjected to laparotomy under 3% sevoflurane anesthesia (anesthesia/surgery) for 3 h. ROS scavenger (N-acetyl-cysteine) and CypA inhibitor (Cyclosporin A) were used 0.5 h before anesthesia/surgery. A battery of behavior tests (buried food test, open field test, and Y maze test) was employed to evaluate behavioral changes at 24 h before and after surgery in the mice. Levels of tight junction proteins, CypA, MMP9, postsynaptic density protein (PSD)-95, and synaptophysin in the prefrontal cortex were assessed by western blotting. The amounts of ROS and IgG in the cortex of mice were observed by fluorescent staining. The concentration of S100β in the serum was detected by ELISA. ROS scavenger prevented the reduction in TJ proteins and restored the permeability of BBB as well as reduced the levels of CypA/MMP9, and further alleviated delirium-like behavior induced by anesthesia/surgery. Furthermore, the CypA inhibitor abolished the increased levels of CypA/MMP, which reversed BBB damage and ameliorated delirium-like behavior caused by ROS accumulation. Our findings demonstrated that ROS may participate in regulating BBB permeability in aged mice with POD via the CypA/MMP9 pathway, suggesting that CypA may be a potential molecular target for preventing POD.}, }
@article {pmid36332383, year = {2023}, author = {Chilvery, S and Yelne, A and Khurana, A and Saifi, MA and Bansod, S and Anchi, P and Godugu, C}, title = {Acetaminophen induced hepatotoxicity: An overview of the promising protective effects of natural products and herbal formulations.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {108}, number = {}, pages = {154510}, doi = {10.1016/j.phymed.2022.154510}, pmid = {36332383}, issn = {1618-095X}, mesh = {Mice ; Animals ; Acetaminophen/adverse effects ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control/metabolism ; *Biological Products/pharmacology ; Mice, Inbred C57BL ; Liver ; Plant Extracts/pharmacology/metabolism ; }, abstract = {BACKGROUND: The liver plays an important role in regulating the metabolic processes and is the most frequently targeted organ by toxic chemicals. Acetaminophen (APAP) is a well-known anti-allergic, anti-pyretic, non-steroidal anti-inflammatory drug (NSAID), which upon overdose leads to hepatotoxicity, the major adverse event of this over-the-counter drug.<br><br>PURPOSE: APAP overdose induced acute liver injury is the second most common cause that often requires liver transplantation worldwide, for which N-acetyl cysteine is the only synthetic drug clinically approved as an antidote. So, it was felt that there is a need for the novel therapeutic approach for the treatment of liver diseases with less adverse effects. This review provides detailed analysis of the different plant extracts; phytochemicals and herbal formulations for the amelioration of APAP-induced liver injury.<br><br>METHOD: The data was collected using different online resources including PubMed, ScienceDirect, Google Scholar, Springer, and Web of Science using keywords given below.<br><br>RESULTS: Over the past decades various reports have revealed that plant-based approaches may be a better treatment choice for the APAP-induced hepatotoxicity in pre-clinical experimental conditions. Moreover, herbal compounds provide several advantages over the synthetic drugs with fewer side effects, easy availability and less cost for the treatment of life-threatening diseases.<br><br>CONCLUSION: The current review summarizes the hepatoprotective effects and therapeutic mechanisms of various plant extracts, active phytoconstituents and herbal formulations with potential application against APAP induced hepatotoxicity as the numbers of hepatoprotective natural products are more without clinical relativity. Further, pre-clinical pharmacological research will contribute to the designing of natural products as medicines with encouraging prospects for clinical application.}, }
@article {pmid36322347, year = {2023}, author = {Albeltagy, RS and Dawood, SM and Mumtaz, F and Abdel Moneim, AE and El-Habit, OH}, title = {Antioxidant capacity of N-acetylcysteine against the molecular and cytotoxic implications of cadmium chloride leading to hepatotoxicity and vital progression.}, journal = {Environmental science and pollution research international}, volume = {30}, number = {9}, pages = {23237-23247}, pmid = {36322347}, issn = {1614-7499}, mesh = {Male ; Rats ; Acetylcysteine/pharmacology ; *Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; bcl-2-Associated X Protein ; Cadmium/pharmacology ; Cadmium Chloride/pharmacology ; *Chemical and Drug Induced Liver Injury ; Glutathione/pharmacology ; Oxidative Stress ; Proto-Oncogene Proteins c-bcl-2 ; Animals ; }, abstract = {Many studies have reported that cadmium (Cd) can induce liver cell injury; however, the toxicity mechanisms of Cd on the liver have not been fully explained. Thirty-two male albino rats were divided into four groups: the control group, the N-acetylcysteine (NAC) group orally as effervescent instant sachets with a concentration of 200 mg dissolved in distilled water and dosage was 200 mg/kg body weight freshly prepared, the cadmium chloride (CdCl2) group (treated with 3 mg/kg orally), and the N-acetylcysteine (NAC) + cadmium chloride group (treated with 200 mg/kg orally post to CdCl2) for 60 days. The NAC alone did not make notable changes in most of the parameters. The CdCl2 alone, compared to control, induced significant alterations in oxidative stress markers (increment in lipid peroxidation (LPO) and nitric oxide (NO)) and antioxidant defense system (decrement in superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx)), which resulted in a downregulation of pro-apoptotic Bcl2-associated X protein (Bax) and caspase-3 and upregulation of anti-apoptotic B-cell leukemia/lymphoma 2 (Bcl2) protein as well as the survival fate of hepatic cells. Post-administration of NAC to CdCl2 resulted in a reduction in oxidative stress markers, shifting of cells from the G2/M phase to the G0/G1 inhibiting signal-regulated kinase activation, and impairment of the anti-apoptotic signaling pathway when compared to the CdCl2 group alone. Accordingly, the Bcl2/Bax ratio was reduced to 1.17-fold change, as an adaptive process to hepatic tissue injury. These findings demonstrated that NAC would attenuate the possibility of oxidative stress and cytotoxicity of hepatic tissue induced by CdCl2.}, }
@article {pmid36321532, year = {2022}, author = {Zhang, Q and Li, P and Li, H and Yi, D and Guo, S and Wang, L and Zhao, D and Wang, C and Wu, T and Hou, Y}, title = {Multifaceted Effects and Mechanisms of N-Acetylcysteine on Intestinal Injury in a Porcine Epidemic Diarrhea Virus-Infected Porcine Model.}, journal = {Molecular nutrition &amp; food research}, volume = {66}, number = {24}, pages = {e2200369}, doi = {10.1002/mnfr.202200369}, pmid = {36321532}, issn = {1613-4133}, mesh = {Animals ; Acetylcysteine/pharmacology ; *Coronavirus Infections/drug therapy/veterinary ; Interferons ; *Porcine epidemic diarrhea virus/genetics ; Proteomics ; Swine ; *Swine Diseases/drug therapy ; }, abstract = {SCOPE: This study investigates the potential effects of N-acetylcysteine (NAC) on intestinal injury in a porcine epidemic diarrhea virus (PEDV)-infected porcine model.<br><br>METHODS AND RESULTS: Thirty-two piglets are randomly assigned to one of four groups: the control, PEDV, NAC, and NAC+PEDV. Piglets in the NAC+PEDV group are orally administrated with NAC (100&#xa0;mg&#xa0;(kg&#xb7;BW)[-1] &#xa0;day[-1]) for 4 consecutive days after 2 days of PEDV infection. The results show that NAC administration decreases the diarrhea rate and improves intestinal morphology. The concentration of diamine oxidase and intestinal fatty-acid binding protein, as well as IL-1&#x3b2;, IL-8, and TNF-&#x3b1; in the plasma, is decreased by NAC. Intriguingly, NAC administration significantly increases the viral load in the jejunum and ileum and down-regulates the expression of interferon-related genes. Microarray and proteomic analyses show that the differentially expressed genes/proteins between NAC+PEDV and PEDV groups are highly enriched in substance transport. Furthermore, aquaporin 8/10 expression is significantly increased by NAC upon PEDV infection.<br><br>CONCLUSION: NAC administration alleviates PEDV-induced intestinal injury by inhibiting inflammatory responses and improving substance transport, but promotes viral replication by inhibiting interferon signaling. These results suggest NAC exhibits multifaceted effects upon PEDV infection, and thus caution is required when using NAC as a dietary supplement to prevent viral infection.}, }
@article {pmid36321244, year = {2022}, author = {Jannatifar, R and Asa, E and Sahraei, SS and Verdi, A and Piroozmanesh, H}, title = {N-acetyl-l-cysteine and alpha lipoic acid are protective supplement on human sperm parameters in cryopreservation of asthenoteratozoospermia patients.}, journal = {Andrologia}, volume = {54}, number = {11}, pages = {e14612}, doi = {10.1111/and.14612}, pmid = {36321244}, issn = {1439-0272}, support = {//Academic Center for Education, Culture and Research/ ; }, mesh = {Humans ; Male ; *Thioctic Acid/pharmacology/therapeutic use ; Sperm Motility ; *Semen Preservation/methods ; Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use/metabolism ; *Asthenozoospermia/drug therapy/metabolism ; NF-E2-Related Factor 2/metabolism ; Cryopreservation/methods ; Spermatozoa/metabolism ; }, abstract = {The aim of this study is to evaluate the beneficial effects of N-acetyl-cysteine (NAC), alpha lipoic acid (ALA) and combination of NAC + ALA supplement in freezing medium on Sperm structural and functional in asthenoteratozoospermia patients. Thirty freshly ejaculated semen samples were cryopreserved with sperm freezing medium (SFM) as control group and three group that SFM supplemented with NAC, ALA and their combination NAC+ ALA. The sperm samples were analysed according to WHO. Mitochondrial membrane potential (MMP), acrosome reaction (AR), antioxidant enzymes and DNA fragmentation were assessed using by Rhodamine123, PSA- FITC ELISA and TUNEL staining respectively. Expression level of NRF2 was assessed by real-time PCR assay. NAC and ALA alone significantly improved sperm motility, viability and DNA fragmentation (p < 0.05). MMP increased in NAC and ALA separately (p < 0.05). While did not affect the amount of sperm morphology and AR (p > 0.05). Antioxidant enzymes significantly difference in NAC and ALA groups (p < 0.05). In addition, NAC and ALA groups showed a significantly higher expression of NRF2 gene compared with other groups (p < 0.05). Our results revealed that the ALA and NAC supplements had a protective effect in cryopreservation process on the structural and functional characteristics of sperm.}, }
@article {pmid36315628, year = {2023}, author = {Zhang, M and Ma, B and Yang, S and Wang, J and Chen, J}, title = {Bisphenol A (BPA) induces apoptosis of mouse Leydig cells via oxidative stress.}, journal = {Environmental toxicology}, volume = {38}, number = {2}, pages = {312-321}, doi = {10.1002/tox.23690}, pmid = {36315628}, issn = {1522-7278}, support = {81660255//National Natural Science Foundation of China/ ; 82060278//National Natural Science Foundation of China/ ; 82171591//National Natural Science Foundation of China/ ; //Major Discipline Academic and Technical Leaders Training Program of Jiangxi Province/ ; 20212ACB206036//Natural Science Foundation of Jiangxi Province/ ; 20204BCJ22031//Natural Science Foundation of Jiangxi Province/ ; }, mesh = {Animals ; Male ; Mice ; Acetylcysteine ; *Apoptosis ; Benzhydryl Compounds/toxicity/metabolism ; *Leydig Cells/metabolism ; *Oxidative Stress ; RNA, Messenger/metabolism ; *Semen/metabolism ; Testis/metabolism ; *Phenols/metabolism/toxicity ; }, abstract = {As one of the most frequently produced synthetic compounds worldwide, bisphenol A (BPA) has been widely used in many kinds of products such as appliances, housewares, and beverage cans. BPA has been shown to cause damage to male reproductive system; however, the potential mechanism remains to be investigated. In the present study, BPA exposure decreased the testis and epididymis coefficient, caused a disintegration of germinal epithelium, decreased the density and motility of sperm in the epididymis tissue, and increased the number of abnormal sperm morphology, which indicated that BPA exposure could cause damage to testis. BPA was also shown to induce apoptosis and oxidative stress in the testis tissue. The serum testosterone concentration was decreased in the BPA-treated group, suggesting that BPA could lead to Leydig cell damage. Subsequently, mouse TM3 cell, a kind of mouse Leydig cell line, was utilized to investigate the potential mechanism. Herein, we showed that BPA exposure could inhibit cell viability and induce apoptosis of TM3 cells. Furthermore, oxidative stress in the cells could also be induced by BPA, while the inhibition of oxidative stress by N-acetyl-L-cysteine (NAC), an oxidative stress scavenger, could reverse the inhibition of cell viability and induction of apoptosis by BPA exposure, indicating that oxidative stress was involved in BPA-induced apoptosis of TM3 cells. Finally, RNA-sequencing and real-time PCR were utilized to screen and validate the potential oxidative stress-related genes involving in BPA-induced apoptosis. We found that BPA exposure increased the mRNA levels of oxidative stress-related genes such as Lonp1, Klf4, Rack1, Egln1, Txn2, Msrb1, Atox1, Mtr, and Atp2a2, as well as decreased the mRNA level of Dhfr gene; while NAC could rescue the expression of these genes. Taken together, oxidative stress was involved in BPA-induced apoptosis of mouse Leydig cells.}, }
@article {pmid36314307, year = {2022}, author = {Oğuz Cumaoğlu, M and Cumaoğlu, B and Tekin, Y and Günay, N}, title = {Therapeutic effect of 6-shogaol on acetaminophen-induced hepatotoxicity in mice: an experimental study.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {20}, pages = {7371-7378}, doi = {10.26355/eurrev_202210_30006}, pmid = {36314307}, issn = {2284-0729}, mesh = {Mice ; Animals ; Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy ; Nitrites/pharmacology ; Nitrates/pharmacology ; Aspartate Aminotransferases ; Alanine Transaminase ; Acetylcysteine/pharmacology ; Liver ; Glutathione ; *Liver Diseases ; }, abstract = {OBJECTIVE: Acetaminophen (APAP) is one of the most commonly used analgesics and antipyretics. It causes serious liver damage when taken in large quantities by adults or children. Also, 6-shogaol is an active compound obtained from ginger with anti-inflammatory and antioxidant properties. This study aimed at examining the therapeutic effect of 6-shogaol in APAP-induced hepatotoxicity.<br><br>MATERIALS AND METHODS: The mice were separated into five groups. After the mice were sacrificed, the levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in the blood, glutathione (GSH) level in the liver tissue homogenate, and levels of induced nitrite oxide synthetase (INOS) and total nitrite/nitrate were measured by spectrophotometric methods.<br><br>RESULTS: APAP administration significantly increased the serum levels of ALT, AST, and ALP, INOS activity in liver tissue, and total nitrite/nitrate levels compared with control and significantly decreased GSH levels. After APAP toxicity, 6-shogaol and N-acetylcysteine (NAC) administration significantly decreased the levels of ALT, AST, INOS, and total nitrite/nitrate levels and significantly increased GSH levels compared with control. Also, 6-shogaol was found to be better than NAC in increasing the GSH level.<br><br>CONCLUSIONS: The study showed that 6-shogaol might have an early therapeutic effect on APAP-induced liver damage.}, }
@article {pmid36313085, year = {2022}, author = {Finnegan, E and Daly, E and Pearce, AJ and Ryan, L}, title = {Nutritional interventions to support acute mTBI recovery.}, journal = {Frontiers in nutrition}, volume = {9}, number = {}, pages = {977728}, pmid = {36313085}, issn = {2296-861X}, abstract = {UNLABELLED: When mild traumatic brain injury (mTBI) occurs following an impact on the head or body, the brain is disrupted leading to a series of metabolic events that may alter the brain's ability to function and repair itself. These changes may place increased nutritional demands on the body. Little is known on whether nutritional interventions are safe for patients to implement post mTBI and whether they may improve recovery outcomes. To address this knowledge gap, we conducted a systematic review to determine what nutritional interventions have been prescribed to humans diagnosed with mTBI during its acute period (<14 days) to support, facilitate, and result in measured recovery outcomes.<br><br>METHODS: Databases CINAHL, PubMed, SPORTDiscus, Web of Science, and the Cochrane Library were searched from inception until January 6, 2021; 4,848 studies were identified. After removing duplicates and applying the inclusion and exclusion criteria, this systematic review included 11 full papers.<br><br>RESULTS: Patients that consumed enough food to meet calorie and macronutrient (protein) needs specific to their injury severity and sex within 96 h post mTBI had a reduced length of stay in hospital. In addition, patients receiving nutrients and non-nutrient support within 24-96 h post mTBI had positive recovery outcomes. These interventions included omega-3 fatty acids (DHA and EPA), vitamin D, mineral magnesium oxide, amino acid derivative N-acetyl cysteine, hyperosmolar sodium lactate, and nootropic cerebrolysin demonstrated positive recovery outcomes, such as symptom resolution, improved cognitive function, and replenished nutrient deficiencies (vitamin D) for patients post mTBI.<br><br>CONCLUSION: Our findings suggest that nutrition plays a positive role during acute mTBI recovery. Following mTBI, patient needs are unique, and this review presents the potential for certain nutritional therapies to support the brain in recovery, specifically omega-3 fatty acids. However, due to the heterogenicity nature of the studies available at present, it is not possible to make definitive recommendations.<br><br>The systematic review conducted following the PRISMA guidelines protocol was registered (CRD42021226819), on Prospero.}, }
@article {pmid36312742, year = {2022}, author = {Nasr, S and Perl, A}, title = {Principles behind SLE treatment with N-acetylcysteine.}, journal = {Immunometabolism (Cobham, Surrey)}, volume = {4}, number = {4}, pages = {e00010}, pmid = {36312742}, issn = {2633-0407}, abstract = {Systemic lupus erythematous (SLE) is a multisystem chronic autoimmune disease in which disrupted molecular pathways lead to multiple clinical manifestations. Currently approved treatments include hydroxychloroquine, some immunosuppressive medications, and some biologics. They all come with a range of side effects. N-acetylcysteine (NAC) is an antioxidant that has shown potential benefits in SLE patients without having major side effects. The following review highlights the molecular mechanisms behind the therapeutic effect of NAC in SLE patients. A higher-than normal mitochondrial transmembrane potential or mitochondrial hyperpolarization (MHP) was found in lymphocytes from SLE patients. MHP is attributed the blocked electron transport, and it is associated with the depletion of ATP and glutathione and the accumulation of oxidative stress-generating mitochondria due to diminished mitophagy. Comprehensive metabolome analyses identified the accumulation of kynurenine as the most predictive metabolic biomarker of lupus over matched healthy subjects. Cysteine is the rate-limiting constituent in the production of reduced glutathione, and it can be replaced by its precursor NAC. Kynurenine accumulation has been reversed by treatment with NAC but not placebo in the setting of a double-blind placebo-controlled clinical trial of 3-month duration. Mitochondrial oxidative stress and its responsiveness to NAC have been linked to systemic inflammation, gut microbiome changes, and organ damage in lupus-prone mice. Given the unique safety of NAC and chronicity of SLE, the clinical trial of longer duration is being pursued.}, }
@article {pmid36312610, year = {2022}, author = {Kumar, S and Bhagat, P and Pandey, S and Pandey, R}, title = {The Role of Antioxidant Agent (N-Acetylcysteine) in Oleic Acid-Induced Acute Lung Injury in a Rat Model.}, journal = {Cureus}, volume = {14}, number = {9}, pages = {e29478}, pmid = {36312610}, issn = {2168-8184}, abstract = {Context Reactive oxygen species (ROS) produced by inflammatory cells play a major role in mediating lung injury in sepsis or hyperoxic lung injury. Aims N-Acetylcysteine (NAC), an antioxidant, was examined in this research to see whether it helps prevent acute lung injury (ALI). Materials and methods Experiments were performed on Charles-Foster strain healthy male adult albino rats. All the animals were randomly divided into one control and two experimental groups. In control/group I, saline was administered, and cardiorespiratory parameters were recorded. Oleic acid (OA) was administered in group II to produce ALI. In group III, OA was administered to NAC-pretreated rats, and cardiorespiratory parameters were recorded to observe the effect of NAC on ALI. This study used analysis of variance (ANOVA) with two factors and a post hoc test (multiple comparisons - least significant difference (LSD) test) for statical analysis. For determining survival time, the Mantel-Cox test and Kaplan-Meier survival curves were used. A P value < 0.05 was considered significant. Results Respiratory arrest, pulmonary edema, and reduced partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio were all indications of OA-induced ALI in rats. The animals in the NAC + OA group had better respiratory and cardiac statistics than those in the OA alone group, and their survival duration was extended. However, NAC pretreatment could not protect the animals against the development of pulmonary edema. Conclusions These observations indicate that NAC (an antioxidant agent) protected rats against ALI in the initial phase and prolonged the survival time but failed to prevent the development of pulmonary edema.}, }
@article {pmid36308430, year = {2023}, author = {Khalid, F and Phan, T and Qiang, M and Maity, P and Lasser, T and Wiese, S and Penzo, M and Alupei, M and Orioli, D and Scharffetter-Kochanek, K and Iben, S}, title = {TFIIH mutations can impact on translational fidelity of the ribosome.}, journal = {Human molecular genetics}, volume = {32}, number = {7}, pages = {1102-1113}, pmid = {36308430}, issn = {1460-2083}, mesh = {Humans ; Transcription Factor TFIIH/genetics/metabolism ; DNA Repair/genetics ; *Xeroderma Pigmentosum/genetics/pathology ; Mutation ; *Trichothiodystrophy Syndromes/genetics/pathology ; Ribosomes/genetics/metabolism ; }, abstract = {TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome. A total of 50% of the TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration.}, }
@article {pmid36306926, year = {2022}, author = {Wang, JX and Wang, XL and Xu, ZQ and Zhang, Y and Xue, D and Zhu, R and Chen, Q and Li, YH and Zhu, GQ and Tan, X}, title = {Chemerin-9 in paraventricular nucleus increases sympathetic outflow and blood pressure via glutamate receptor-mediated ROS generation.}, journal = {European journal of pharmacology}, volume = {936}, number = {}, pages = {175343}, doi = {10.1016/j.ejphar.2022.175343}, pmid = {36306926}, issn = {1879-0712}, mesh = {Animals ; Male ; Rats ; Blood Pressure ; Dizocilpine Maleate/pharmacology ; NADPH Oxidases/metabolism ; *Paraventricular Hypothalamic Nucleus ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Receptors, Chemokine ; Receptors, Glutamate ; *Superoxides ; Sympathetic Nervous System ; Verapamil/pharmacology ; }, abstract = {Chemerin is an adipokine involved in regulating energy homeostasis and reproductive function. Excessive sympathetic activity contributes to hypertension, chronic heart failure and chronic renal disease. Hypothalamic paraventricular nucleus (PVN) is crucial in regulating sympathetic activity and blood pressure. The present study is designed to investigate the roles of chemerin in the PVN in regulating sympathetic activity and blood pressure and underlying mechanisms. Microinjections were performed in the bilateral PVN in male adult rats under anesthesia. Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were continuously recorded. The PVN microinjection of chemerin-9, an active fragment of chemerin, increased RSNA and MAP, which were abolished by chemokine-like receptor 1 (CMKLR1) antagonist α-NETA, a superoxide scavenger tempol, antioxidant N-acetylcysteine (NAC), NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and apocynin. Immunofluorescence analyses showed that N-methyl-D-aspartate (NMDA) receptors existed in most of cells of the PVN, and some of them co-existed with chemerin. The effects of chemerin-9 on RSNA and MAP were prevented by glutamate-binding site antagonist L-phenylalanine, NMDA receptor antagonist MK-801, and calcium channel blocker verapamil or nifedipine, but only attenuated by non-NMDA receptor antagonist CNQX. Moreover, chemerin-9 increased NADPH oxidase activity and superoxide production, which were prevented by α-NETA, MK-801, or verapamil. These results indicate that chemerin-9 in the PVN increases sympathetic activity and blood pressure via CMKLR1-dependent calcium influx, and glutamate receptor-mediated NADPH oxidase activation and subsequent superoxide production.}, }
@article {pmid36305293, year = {2022}, author = {Shakya, R and Park, GH and Joo, SH and Shim, JH and Choi, JS}, title = {Hydroxyzine Induces Cell Death in Triple-Negative Breast Cancer Cells via Mitochondrial Superoxide and Modulation of Jak2/STAT3 Signaling.}, journal = {Biomolecules &amp; therapeutics}, volume = {30}, number = {6}, pages = {585-592}, pmid = {36305293}, issn = {1976-9148}, abstract = {Treatment of triple-negative breast cancer (TNBC) has been limited due to the lack of molecular targets. In this study, we evaluated the cytotoxicity of hydroxyzine, a histamine H1 receptor antagonist in human triple-negative breast cancer BT-20 and HCC-70 cells. Hydroxyzine inhibited the growth of cells in dose- and time-dependent manners. The annexin V/propidium iodide double staining assay showed that hydroxyzine induced apoptosis. The hydroxyzine-induced apoptosis was accompanied down-regulation of cyclins and CDKs, as well as the generation of reactive oxygen species (ROS) without cell cycle arrest. The effect of hydroxyzine on the induction of ROS and apoptosis on TNBC cells was prevented by pre-treatment with ROS scavengers, N-acetyl cysteine or Mito-TEMPO, a mitochondria-targeted antioxidant, indicating that an increase in the generation of ROS mediated the apoptosis induced by hydroxyzine. Western blot analysis showed that hydroxyzine-induced apoptosis was through down-regulation of the phosphorylation of JAK2 and STAT3 by hydroxyzine treatment. In addition, hydroxyzine induced the phosphorylation of JNK and p38 MAPK. Our results indicate that hydroxyzine induced apoptosis via mitochondrial superoxide generation and the suppression of JAK2/STAT3 signaling.}, }
@article {pmid36302499, year = {2022}, author = {Su, Y and Yin, X and Huang, X and Guo, Q and Ma, M and Guo, L}, title = {Astragaloside IV ameliorates sepsis-induced myocardial dysfunction by regulating NOX4/JNK/BAX pathway.}, journal = {Life sciences}, volume = {310}, number = {}, pages = {121123}, doi = {10.1016/j.lfs.2022.121123}, pmid = {36302499}, issn = {1879-0631}, mesh = {Animals ; Rats ; Apoptosis ; bcl-2-Associated X Protein ; Caspase 3 ; Lipopolysaccharides ; Myocytes, Cardiac/metabolism ; NADPH Oxidase 4 ; Rats, Sprague-Dawley ; *Sepsis/complications/drug therapy/metabolism ; *Saponins/therapeutic use ; *Triterpenes/therapeutic use ; }, abstract = {AIMS: Sepsis can induce multiple organ dysfunction, and sepsis-induced myocardial dysfunction (SIMD) is relatively common. The current dilemma might ascribe partly to SIMD's lack of unified molecular mechanisms. Our study aims to assess the function of Astragaloside IV (ASI) in cecal ligation and puncture (CLP)-induced cardiac dysfunction and explore its underlying mechanisms.<br><br>MAIN METHODS: In vivo, ASI (30&#xa0;mg/kg/day), NADPH oxidase 4 (NOX4) inhibitor 4-hydroxy-3-methoxyacetophenone (APO, 30&#xa0;mg/kg/day), reactive oxygen species (ROS) inhibitor N-Acetylcysteine (NAC, 150&#xa0;mg/kg/day) and c-Jun NH2-terminal kinase (JNK) inhibitor (SP600125, 15&#xa0;mg/kg/day) were severally administered to Sprague Dawley rats following the CLP surgery. The cardiac function, cardiac enzyme markers, proinflammatory cytokine, and cell apoptosis-associated proteins were detected. In vitro, cardiomyocyte H9C2 cells were treated with lipopolysaccharide (LPS, 40&#xa0;&#x3bc;g/ml) after the presence of ASI (100&#xa0;&#x3bc;mol/ml), SP600125 (10&#xa0;&#x3bc;mol/ml), APO (10&#xa0;&#x3bc;mol/ml). A series of experiments verified the relationship among NOX4, JNK, and BAX.<br><br>KEY FINDINGS: The results indicated that CLP-induced sepsis increased the secretion of creatine kinase isoenzymes (CKMB), brain natriuretic peptide (BNP), cardiac troponin T (c-TnI), interleukin-1&#x3b2; (IL-1&#x3b2;) and interleukin-18 (IL-18), as well as the protein expression of NOX4 and Caspase-3 in vivo. LPS increased the protein level of NOX4 and Caspase-3, upregulated the rate of p-JNK/JNK, and downregulated the rate of Bcl2/BAX in vitro. ASI can reverse these changes in vivo and has a synergistic effect with APO and SP600125 in vitro.<br><br>SIGNIFICANCE: This study suggested that ASI may ameliorate SIMD, through regulating NOX4/JNK/BAX signaling pathway, which may be a feasible therapeutic strategy.}, }
@article {pmid36300938, year = {2022}, author = {Deng, Z and Sun, R and Han, X and Zhang, Y and Zhou, Y and Shan, Y and Xu, J and Li, X and He, F and Fang, W}, title = {Porcine Circovirus 2 Activates the PERK-Reactive Oxygen Species Axis To Induce p53 Phosphorylation with Subsequent Cell Cycle Arrest at S Phase in Favor of Its Replication.}, journal = {Journal of virology}, volume = {96}, number = {22}, pages = {e0127422}, pmid = {36300938}, issn = {1098-5514}, mesh = {Animals ; Acetylcysteine/pharmacology ; *Cell Cycle Checkpoints ; *Circoviridae Infections/veterinary/virology ; *Circovirus/physiology ; Phosphorylation ; Reactive Oxygen Species/metabolism ; S Phase ; Swine ; *Swine Diseases/virology ; Tumor Suppressor Protein p53/genetics/metabolism ; Virus Replication/genetics ; Endoplasmic Reticulum Stress ; eIF-2 Kinase/metabolism ; }, abstract = {Porcine circovirus type 2 (PCV2), the causative agent of porcine circovirus-associated diseases (PCVAD), is known to induce oxidative stress, activate p53 with induction of cell cycle arrest, and trigger the PERK (protein kinase R-like endoplasmic reticulum kinase) branch of the endoplasmic reticulum (ER) stress pathway. All these cellular responses could enhance PCV2 replication. However, it remains unknown whether PERK activation by PCV2 is involved in p53 signaling with subsequent changes of cell cycle. Here, we demonstrate that PCV2 infection induced cell cycle arrest at S phase to favor its replication via the PERK-reactive oxygen species (ROS)-p53 nexus. PCV2 infection promoted phosphorylation of p53 (p-p53) at Ser15 in porcine alveolar macrophages. Inhibition of PERK by RNA silencing downregulated total p53 (t-p53) and p-p53. Treatment with the MDM2 inhibitor nutlin-3 led to partial recovery of t-p53 in perk-silenced and PCV2-infected cells. perk silencing markedly downregulated ROS production. Scavenging of ROS with N-acetylcysteine (NAC) of PCV2-infected cells downregulated t-p53 and p-p53. Increased accumulation of p-p53 in the nuclei during PCV2 infection could be downregulated by silencing of perk or NAC treatment. Further studies showed that perk silencing or NAC treatment alleviated S phase accumulation and downregulated cyclins E1 and A2 in PCV2-infected cells. These findings indicate that the PCV2-activated PERK-ROS axis promotes p-p53 and contributes to cell cycle accumulation at S phase when more cellular enzymes are available to favor viral DNA synthesis. Overall, our study provides a novel insight into the mechanism how PCV2 manipulates the host PERK-ROS-p53 signaling nexus to benefit its own replication via cell cycle arrest. IMPORTANCE Coinfections or noninfectious triggers have long been considered to potentiate PCV2 infection, leading to manifestation of PCVAD. The triggering mechanisms remain largely unknown. Recent studies have revealed that PERK-mediated ER stress, oxidative stress, and cell cycle arrest during PCV2 infection are conducive to viral replication. However, how PCV2 employs such host cell responses requires further research. Here, we provide a novel mechanism of PCV2-induced ER stress and enhanced viral replication: the PCV2-activated PERK-ROS-p53 nexus increases S phase cell population, a cell cycle period of DNA synthesis favorable for PCV2 replication. The fact that PCV2 deploys the simple ROS molecules to activate p53 to benefit its replication provides novel insights into the triggering factors, that is, certain stimuli or management measures that induce ER stress with subsequent generation of ROS would exacerbate PCVAD. Use of antioxidants is justified on farms where PCVAD is severe.}, }
@article {pmid36299882, year = {2022}, author = {Mesmar, J and Abdallah, R and Hamade, K and Baydoun, S and Al-Thani, N and Shaito, A and Maresca, M and Badran, A and Baydoun, E}, title = {Ethanolic extract of Origanum syriacum L. leaves exhibits potent anti-breast cancer potential and robust antioxidant properties.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {994025}, pmid = {36299882}, issn = {1663-9812}, abstract = {UNLABELLED: Background: Breast cancer (BC) is the second most common cancer overall. In women, BC is the most prevalent cancer and the leading cause of cancer-related mortality. Triple-negative BC (TNBC) is the most aggressive BC, being resistant to hormonal and targeted therapies.<br><br>HYPOTHESIS/PURPOSE: The medicinal plant Origanum syriacum L. is a shrubby plant rich in bioactive compounds and widely used in traditional medicine to treat various diseases. However, its therapeutic potential against BC remains poorly investigated. In the present study, we screened the phytochemical content of an ethanolic extract of O. syriacum (OSEE) and investigated its anticancer effects and possible underlying mechanisms of action against the aggressive and highly metastatic human TNBC cell line MDA-MB-231.<br><br>METHODS: MTT, trans-well migration, and scratch assays were used to assess cell viability, invasion, or migration, respectively. Antioxidant potential was evaluated in vitro using the DPPH radical-scavenging assay and levels of reactive oxygen species (ROS) were assessed in cells in culture using DHE staining. Aggregation assays were used to determine cell-cell adhesion. Flow cytometry was used to analyze cell cycle progression. Protein levels of markers of apoptosis (BCL-2, pro-Caspase3, p53), proliferation (p21, Ki67), cell migration, invasion, or adhesion (FAK, E-cadherin), angiogenesis (iNOS), and cell signaling (STAT3, p38) were determined by immunoblotting. A chorioallantoic Membrane (CAM) assay evaluated in ovo angiogenesis.<br><br>RESULTS: We demonstrated that OSEE had potent radical scavenging activity in vitro and induced the generation of ROS in MDA-MB-231 cells, especially at higher OSEE concentrations. Non-cytotoxic concentrations of OSEE attenuated cell proliferation and induced G0/G1 cell cycle arrest, which was associated with phosphorylation of p38 MAPK, an increase in the levels of tumor suppressor protein p21, and a decrease of proliferation marker protein Ki67. Additionally, only higher concentrations of OSEE were able to attenuate inhibition of proliferation induced by the ROS scavenger N-acetyl cysteine (NAC), indicating that the anti-proliferative effects of OSEE could be ROS-dependent. OSEE stimulated apoptosis and its effector Caspase-3 in MDA-MB-231 cells, in correlation with activation of the STAT3/p53 pathway. Furthermore, the extract reduced the migration and invasive properties of MDA-MB-231 cells through the deactivation of focal adhesion kinase (FAK). OSEE also reduced the production of inducible nitric oxide synthase (iNOS) and inhibited in ovo angiogenesis.<br><br>CONCLUSION: Our findings reveal that OSEE is a rich source of phytochemicals and has robust anti-breast cancer properties that significantly attenuate the malignant phenotype of MD-MB-231 cells, suggesting that O. syriacum may not only act as a rich source of potential TNBC therapeutics but may also provide new avenues for the design of novel TNBC drugs.}, }
@article {pmid36296600, year = {2022}, author = {Kwon, JH and Lee, NG and Kang, AR and Ahn, IH and Choi, IY and Song, JY and Hwang, SG and Um, HD and Choi, JR and Kim, J and Park, JK}, title = {JNC-1043, a Novel Podophyllotoxin Derivative, Exerts Anticancer Drug and Radiosensitizer Effects in Colorectal Cancer Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {20}, pages = {}, pmid = {36296600}, issn = {1420-3049}, support = {505382022//Ministry of Science ICT and Future Planning/ ; 505312022//Ministry of Science ICT and Future Planning/ ; 2021R1F1A1055981//National Research Foundation of Korea/ ; NRF-2020M2D9A2094153//National Research Foundation of Korea/ ; }, mesh = {Humans ; Podophyllotoxin/pharmacology ; Reactive Oxygen Species/metabolism ; Annexin A5 ; Acetylcysteine/pharmacology ; Propidium/pharmacology ; *Radiation-Sensitizing Agents/pharmacology ; Apoptosis ; *Antineoplastic Agents/pharmacology ; Cell Proliferation ; *Colorectal Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; }, abstract = {The objective of this study was to determine whether (5S)-5-(4-benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo [3',4':6,7] naphtho [2,3-d] [1,3]dioxol-6-one (JNC-1043), which is a novel chemical derivative of β-apopicropodophyllin, acts as a novel potential anticancer reagent and radiosensitizer in colorectal cancer (CRC) cells. Firstly, we used MTT assays to assess whether JNC-1043 could inhibit the cell proliferation of HCT116 and DLD-1 cells. The IC50 values of these cell lines were calculated as 114.5 and 157 nM, respectively, at 72 h of treatment. Using doses approximating the IC50 values, we tested whether JNC-1043 had a radiosensitizing effect in the CRC cell lines. Clonogenic assays revealed that the dose-enhancement ratios (DER) of HCT116 and DLD-1 cells were 1.53 and 1.25, respectively. Cell-counting assays showed that the combination of JNC-1043 and γ-ionizing radiation (IR) enhanced cell death. Treatment with JNC-1043 or IR alone induced cell death by 50~60%, whereas the combination of JNC-1043 and IR increased this cell death by more than 20~30%. Annexin V-propidium iodide assays showed that the combination of JNC-1043 and IR increased apoptosis by more 30~40% compared to that induced by JNC-1043 or IR alone. DCFDA- and MitoSOX-based assays revealed that mitochondrial ROS production was enhanced by the combination of JNC-1043 and IR. Finally, we found that suppression of ROS by N-acetylcysteine (NAC) blocked the apoptotic cell death induced by the combination of JNC-1043 and IR. The xenograft model also indicated that the combination of JNC-1043 and IR increased apoptotic cell death in tumor mass. These results collectively suggest that JNC-1043 acts as a radiosensitizer and exerts anticancer effects against CRC cells by promoting apoptosis mediated by mitochondrial ROS.}, }
@article {pmid36293450, year = {2022}, author = {Wang, XL and Wang, JX and Chen, JL and Hao, WY and Xu, WZ and Xu, ZQ and Jiang, YT and Luo, PQ and Chen, Q and Li, YH and Zhu, GQ and Li, XZ}, title = {Asprosin in the Paraventricular Nucleus Induces Sympathetic Activation and Pressor Responses via cAMP-Dependent ROS Production.}, journal = {International journal of molecular sciences}, volume = {23}, number = {20}, pages = {}, pmid = {36293450}, issn = {1422-0067}, support = {31871148 &amp; 32071106//National Natural Science Foundation of China/ ; }, mesh = {Male ; Rats ; Animals ; *Paraventricular Hypothalamic Nucleus/metabolism ; Reactive Oxygen Species/metabolism ; *Superoxides/metabolism ; Adenylyl Cyclases/metabolism ; Antioxidants/pharmacology ; Acetylcysteine/pharmacology ; Rats, Sprague-Dawley ; Sympathetic Nervous System ; Blood Pressure ; NADPH Oxidases/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Adipokines/metabolism ; RNA, Messenger/metabolism ; }, abstract = {Asprosin is a newly discovered adipokine that is involved in regulating metabolism. Sympathetic overactivity contributes to the pathogenesis of several cardiovascular diseases. The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in the regulation of sympathetic outflow and blood pressure. This study was designed to determine the roles and underlying mechanisms of asprosin in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male adult SD rats under anesthesia. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) were recorded, and PVN microinjections were performed bilaterally. Asprosin mRNA and protein expressions were high in the PVN. The high asprosin expression in the PVN was involved in both the parvocellular and magnocellular regions according to immunohistochemical analysis. Microinjection of asprosin into the PVN produced dose-related increases in RSNA, MAP, and HR, which were abolished by superoxide scavenger tempol, antioxidant N-acetylcysteine (NAC), and NADPH oxidase inhibitor apocynin. The asprosin promoted superoxide production and increased NADPH oxidase activity in the PVN. Furthermore, it increased the cAMP level, adenylyl cyclase (AC) activity, and protein kinase A (PKA) activity in the PVN. The roles of asprosin in increasing RSNA, MAP, and HR were prevented by pretreatment with AC inhibitor SQ22536 or PKA inhibitor H89 in the PVN. Microinjection of cAMP analog db-cAMP into the PVN played similar roles with asprosin in increasing the RSNA, MAP, and HR, but failed to further augment the effects of asprosin. Pretreatment with PVN microinjection of SQ22536 or H89 abolished the roles of asprosin in increasing superoxide production and NADPH oxidase activity in the PVN. These results indicated that asprosin in the PVN increased the sympathetic outflow, blood pressure, and heart rate via cAMP-PKA signaling-mediated NADPH oxidase activation and the subsequent superoxide production.}, }
@article {pmid36291336, year = {2022}, author = {Dogaru, IA and Puiu, MG and Manea, M and Dionisie, V}, title = {Current Perspectives on Pharmacological and Non-Pharmacological Interventions for the Inflammatory Mechanism of Unipolar Depression.}, journal = {Brain sciences}, volume = {12}, number = {10}, pages = {}, pmid = {36291336}, issn = {2076-3425}, abstract = {Since depression remains a major public health issue there is a constant need for new and more efficient therapeutic strategies based on the mechanisms involved in the aetiology of depression. Thus, the pathogenic link between depression and inflammation is considered to play a potential key role in the development of such therapies. This review summarizes the results of various pharmacological (non-steroidal anti-inflammatory drugs, aspirin, cyclooxygenase inhibitors, cytokine inhibitors, corticosteroids, statins, minocycline, N-acetyl cysteine, omega-3 fatty acids and probiotics) and non-pharmacological interventions (electroconvulsive therapy, physical exercise and psychological therapy) and outlines their efficacy and discusses potential challenges. Both conventional and non-conventional anti-inflammatory drugs showed promising results according to the specific group of patients. The pre-existing pro-inflammatory status was, in most cases, a predictor for clinical efficacy and, in some cases, a correlation between clinical improvement and changes in various biomarkers was found. Some of the non-pharmacological interventions (physical exercise and electroconvulsive therapy) have also showed beneficial effects for depressive patients with elevated inflammatory markers. Treatments with anti-inflammatory action may improve clinical outcomes in depression, at least for some categories of patients, thus opening the way for a future personalised approach to patients with unipolar depression regarding the inflammation-related mechanism.}, }
@article {pmid36291178, year = {2022}, author = {La Maestra, S and Garibaldi, S and Balansky, R and D'Agostini, F and Micale, RT and De Flora, S}, title = {Inhibition of the Cell Uptake of Delta and Omicron SARS-CoV-2 Pseudoviruses by N-Acetylcysteine Irrespective of the Oxidoreductive Environment.}, journal = {Cells}, volume = {11}, number = {20}, pages = {}, pmid = {36291178}, issn = {2073-4409}, mesh = {Humans ; *Angiotensin-Converting Enzyme 2 ; SARS-CoV-2 ; Acetylcysteine/pharmacology ; Hydrogen Peroxide/pharmacology ; Reactive Oxygen Species ; Antioxidants/pharmacology ; HEK293 Cells ; Peptidyl-Dipeptidase A/metabolism ; Ascorbic Acid/pharmacology ; Oxidants/pharmacology ; Sulfhydryl Compounds/pharmacology ; *COVID-19 Drug Treatment ; }, abstract = {The binding of SARS-CoV-2 spikes to the cell receptor angiotensin-converting enzyme 2 (ACE2) is a crucial target both in the prevention and in the therapy of COVID-19. We explored the involvement of oxidoreductive mechanisms by investigating the effects of oxidants and antioxidants on virus uptake by ACE2-expressing cells of human origin (ACE2-HEK293). The cell uptake of pseudoviruses carrying the envelope of either Delta or Omicron variants of SARS-CoV-2 was evaluated by means of a cytofluorimetric approach. The thiol N-acetyl-L-cysteine (NAC) inhibited the uptake of both variants in a reproducible and dose-dependent fashion. Ascorbic acid showed modest effects. In contrast, neither hydrogen peroxide (H2O2) nor a system-generating reactive oxygen species (ROS), which play an important role in the intracellular alterations produced by SARS-CoV-2, were able to affect the ability of either Delta or Omicron SARS-CoV-2 pseudoviruses to be internalized into ACE2-expressing cells. In addition, neither H2O2 nor the ROS generating system interfered with the ability of NAC to inhibit that mechanism. Moreover, based on previous studies, a preventive pharmacological approach with NAC would have the advantage of decreasing the risk of developing COVID-19, irrespective of its variants, and at the same time other respiratory viral infections and associated comorbidities.}, }
@article {pmid36290795, year = {2022}, author = {Chen, YN and Chan, CK and Yen, CY and Shiau, JP and Chang, MY and Wang, CC and Jeng, JH and Tang, JY and Chang, HW}, title = {Antioral Cancer Effects by the Nitrated [6,6,6]Tricycles Compound (SK1) In Vitro.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290795}, issn = {2076-3921}, support = {MOST 111-2320-B-037-015-MY3; MOST 110-2314-B-037-074-MY3//Ministry of Science and Technology/ ; KMU-DK(A)111008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {A novel nitrated [6,6,6]tricycles-derived compound containing nitro, methoxy, and ispropyloxy groups, namely SK1, was developed in our previous report. However, the anticancer effects of SK1 were not assessed. Moreover, SK1 contains two nitro groups (NO2) and one nitrogen-oxygen (N-O) bond exhibiting the potential for oxidative stress generation, but this was not examined. The present study aimed to evaluate the antiproliferation effects and oxidative stress and its associated responses between oral cancer and normal cells. Based on the MTS assay, SK1 demonstrated more antiproliferation ability in oral cancer cells than normal cells, reversed by N-acetylcysteine. This suggests that SK1 causes antiproliferation effects preferentially in an oxidative stress-dependent manner. The oxidative stress-associated responses were further validated, showing higher ROS/MitoSOX burst, MMP, and GSH depletion in oral cancer cells than in normal cells. Meanwhile, SK1 caused oxidative stress-causing apoptosis, such as caspases 3/8/9, and DNA damages, such as γH2AX and 8-OHdG, to a greater extent in oral cancer cells than in normal cells. Siilar to cell viability, these oxidative stress responses were partially diminished by NAC, indicating that SK1 promoted oxidative stress-dependent responses. In conclusion, SK1 exerts oxidative stress, apoptosis, and DNA damage to a greater extent to oral cancer cells than in normal cells.}, }
@article {pmid36290682, year = {2022}, author = {Georgiou-Siafis, SK and Samiotaki, MK and Demopoulos, VJ and Panayotou, G and Tsiftsoglou, AS}, title = {Glutathione-Hemin/Hematin Adduct Formation to Disintegrate Cytotoxic Oxidant Hemin/Hematin in Human K562 Cells and Red Blood Cells' Hemolysates: Impact of Glutathione on the Hemolytic Disorders and Homeostasis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290682}, issn = {2076-3921}, abstract = {Hemin, an oxidized form of heme, acts as potent oxidant to regulate glutathione (GSH) content in pro-erythroid K562 nucleated cells, via activation of the KEAP1/NRF2 defensive signaling pathway. Moreover, GSH, as an essential metabolite, is involved in the regulation of cell-redox homeostasis and proposed to scavenge cytotoxic free heme, which is released from hemoglobin of damaged red blood cells (RBCs) during different hemolytic disorders. In the present study, we aimed to uncover the molecular mechanism by which GSH inhibits hemin-induced cytotoxicity (HIC) by affecting hemin's structural integrity in K562 cells and in RBC hemolysates. GSH, along with other thiols (cysteine, thioglycolic acid, and mercaptoethanol) altered the spectrum of hemin, while each of them co-added with hemin in cultures of K562 cells prevented HIC and growth arrest and markedly reduced the intracellular level of hemin. In addition, GSH endogenous levels served as a barrier to HIC in K562 cells, as shown by the depletion in GSH. LC-MS/MS analysis of the in vitro reaction between hemin and GSH revealed at least five different isomers of GSH-hemin adducts, as well as hydroxy derivatives as reaction products, which are characterized by unique mass spectra (MS). The latter allowed the detection of adducts in human RBC hemolysates. Based on these findings, we proposed a molecular mechanism via which GSH prevents HIC and structurally disintegrates heme. An analogous reaction was observed in RBC hemolysates via direct inter-reaction between hematin (ferric and hydroxide heme) released from hemoglobin and GSH. Overall, GSH-hematin adducts could be considered as novel entities of the human metabolome of RBCs in hemolytic disorders.}, }
@article {pmid36290612, year = {2022}, author = {Jin, W and Kam, MK and Lee, SW and Park, YH and Lee, HJ and Lee, DS}, title = {Peroxiredoxin 2 Ameliorates AβO-Mediated Autophagy by Inhibiting ROS via the ROS-NRF2-p62 Pathway in N2a-APP Swedish Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290612}, issn = {2076-3921}, support = {2020R1A2B5B01002563//Republic of Korea government/ ; 20009707//the Ministry of Trade, Industry &amp; Energy (MOTIE, Korea)/ ; 2021R1I1A1A01042201//the Ministry of Education/ ; }, abstract = {In Alzheimer's disease, reactive oxygen species (ROS) are generated by the deposition of amyloid-beta oligomers (AβOs), which represent one of the important causes of neuronal cell death. Additionally, AβOs are known to induce autophagy via ROS induction. Previous studies have shown that autophagy upregulation aggravates neuronal cell death. In this study, the effects of peroxiredoxin 2 (Prx2), a member of the peroxidase family of antioxidant enzymes, on regulating AβO-mediated autophagy were investigated. Prx2 decreased AβO-mediated oxidative stress and autophagy in N2a-APPswe cells. Further, we examined the relationship between the neuronal protective effect of Prx2 and a decrease in autophagy. Similar to the effects of N-acetyl cysteine, Prx2 decreased AβO-induced ROS and inhibited p62 protein expression levels by downregulating the activation of NRF2 and its translocation to the nucleus. In addition, treatment with 3-methyladenine, an autophagy inhibitor, ameliorates neuronal cell death. Overall, these results demonstrate that the Prx2-induced decrease in autophagy was associated with the inhibition of ROS via the ROS-NRF2-p62 pathway in N2a-APPswe cells. Therefore, our results revealed that Prx2 is a potential therapeutic target in anti-Alzheimer therapy.}, }
@article {pmid36290607, year = {2022}, author = {Kim, JE and Lee, DS and Kang, TC}, title = {Sp1-Mediated Prdx6 Upregulation Leads to Clasmatodendrosis by Increasing Its aiPLA2 Activity in the CA1 Astrocytes in Chronic Epilepsy Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290607}, issn = {2076-3921}, support = {No. 2021R1A2B5B01001482//National Research Foundation of Korea (NRF)/ ; }, abstract = {Clasmatodendrosis is an autophagic astroglial degeneration (a non-apoptotic (type II) programmed cell death) whose underlying mechanisms are fully understood. Peroxiredoxin-6 (Prdx6), the "non-selenium glutathione peroxidase (NSGPx)", is the only member of the 1-cysteine peroxiredoxin family. Unlike the other Prdx family, Prdx6 has multiple functions as glutathione peroxidase (GPx) and acidic calcium-independent phospholipase (aiPLA2). The present study shows that Prdx6 was upregulated in CA1 astrocytes in chronic epilepsy rats. 2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and N-acetylcysteine (NAC, a precursor of glutathione) ameliorated clasmatodendrosis accompanied by reduced Prdx6 level in CA1 astrocytes. Specificity protein 1 (Sp1) expression was upregulated in CA1 astrocyte, which was inhibited by mithramycin A (MMA). MMA alleviated clasmatodendrosis and Prdx6 upregulation. Sp1 expression was also downregulated by CDDO-Me and NAC. Furthermore, 1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol (MJ33, a selective inhibitor of aiPLA2 activity of Prdx6) attenuated clasmatodendrosis without affecting Prdx6 expression. All chemicals shortened spontaneous seizure duration but not seizure frequency and behavioral seizure severity in chronic epilepsy rats. Therefore, our findings suggest that Sp1 activation may upregulate Prdx6, whose aiPLA2 activity would dominate over GPx activity in CA1 astrocytes and may lead to prolonged seizure activity due to autophagic astroglial degeneration.}, }
@article {pmid36290593, year = {2022}, author = {Rambaud, V and Marzo, A and Chaumette, B}, title = {Oxidative Stress and Emergence of Psychosis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {36290593}, issn = {2076-3921}, abstract = {Treatment and prevention strategies for schizophrenia require knowledge about the mechanisms involved in the psychotic transition. Increasing evidence suggests a redox imbalance in schizophrenia patients. This narrative review presents an overview of the scientific literature regarding blood oxidative stress markers' evolution in the early stages of psychosis and chronic patients. Studies investigating peripheral levels of oxidative stress in schizophrenia patients, first episode of psychosis or UHR individuals were considered. A total of 76 peer-reviewed articles published from 1991 to 2022 on PubMed and EMBASE were included. Schizophrenia patients present with increased levels of oxidative damage to lipids in the blood, and decreased levels of non-enzymatic antioxidants. Genetic studies provide evidence for altered antioxidant functions in patients. Antioxidant blood levels are decreased before psychosis onset and blood levels of oxidative stress correlate with symptoms severity in patients. Finally, adjunct treatment of antipsychotics with the antioxidant N-acetyl cysteine appears to be effective in schizophrenia patients. Further studies are required to assess its efficacy as a prevention strategy. Redox imbalance might contribute to the pathophysiology of emerging psychosis and could serve as a therapeutic target for preventive or adjunctive therapies, as well as biomarkers of disease progression.}, }
@article {pmid36289489, year = {2022}, author = {Li, Y and Yu, H and Lv, M and Li, Q and Zou, K and Lv, S}, title = {Combination therapy with budesonide and N-acetylcysteine ameliorates LPS-induced ALI by attenuating neutrophil recruitment through the miR-196b-5p/Socs3 molecular axis.}, journal = {BMC pulmonary medicine}, volume = {22}, number = {1}, pages = {388}, pmid = {36289489}, issn = {1471-2466}, mesh = {Rats ; Animals ; Lipopolysaccharides ; Acetylcysteine ; Neutrophil Infiltration ; Budesonide/pharmacology ; Eosine Yellowish-(YS)/adverse effects ; Hematoxylin ; *Acute Lung Injury/chemically induced/drug therapy/metabolism ; *MicroRNAs/genetics/metabolism ; RNA, Messenger ; Suppressor of Cytokine Signaling 3 Protein/genetics/metabolism ; }, abstract = {BACKGROUND: Neutrophil infiltration accelerates the inflammatory response and is highly correlated to the development of acute lung injury (ALI). Budesonide (BUD) and N-acetylcysteine (NAC) both inhibit the inflammatory response to alleviate ALI, so we further investigated whether their combination is better for ALI.<br><br>METHODS: In this study, we investigated the effect and mechanism of Combined BUD and NAC therapy on LPS-induced ALI. Rat ALI model and neutrophil abnormal activation model were established by lipopolysaccharide (LPS). BUD and NAC were treated alone or in combination, or cells were transfected with miR-196b-5p mimic or si-Socs3 to evaluate the efficacy and mechanism of BUD and NAC alone or in combination. Histopathological observation of lungs was performed by Hematoxylin Eosin (HE) staining. The quantity of neutrophils and inflammatory factors level in bronchoalveolar lavage fluid (BALF) were determined by Richter-Gimza complex stain and Enzyme-Linked Immunosorbnent Assay (ELISA), respectively. ReverseTranscription-PolymeraseChainReaction (RT-qPCR) was utilized to assess miR-196b-5p and inflammatory factor mRNA levels. The expression level of Socs3 was detected by immunohistochemistry or Western Blot.<br><br>RESULTS: BUD and NAC combined treatment had a better effect on neutrophil recruitment and inflammatory response in LPS-induced ALI than did BUD and NAC alone. Transfection of the miR-196b-5p mimic reversed the effect of combined BUD and NAC. In conclusion, the combination of BUD and NAC is a better treatment for ALI.<br><br>CONCLUSIONS: Combination therapy with BUD and NAC ameliorates LPS-induced ALI by attenuating neutrophil recruitment through the miR-196b-5p/Socs3 molecular axis.}, }
@article {pmid36285551, year = {2022}, author = {Jalalian, R and Maleki, M and Ghafari, R and Habibi, V and Heydari, S and Iranian, M}, title = {Comparing the efficacy of N-acetylcysteine plus carvedilol versus carvedilol in the prevention of atrial fibrillation following coronary artery bypass graft surgery.}, journal = {Journal of cardiac surgery}, volume = {37}, number = {12}, pages = {4698-4704}, doi = {10.1111/jocs.17062}, pmid = {36285551}, issn = {1540-8191}, mesh = {Humans ; Carvedilol/therapeutic use ; *Atrial Fibrillation/epidemiology/etiology/prevention &amp; control ; Acetylcysteine/therapeutic use ; Coronary Artery Bypass/adverse effects ; Adrenergic beta-Antagonists/therapeutic use ; Postoperative Complications/epidemiology/prevention &amp; control ; }, abstract = {BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia following open-heart surgery. Agents with antioxidant properties may reduce postoperative complications like postoperative AF (POAF) in patients undergoing open-heart surgery. This study was conducted to assess the effect of N-acetylcysteine (NAC) in prevention of AF following coronary artery bypass graft (CABG) surgery.<br><br>METHODS: Three hundred patients who underwent CABG surgery were entered in the study. Patients with contraindications for beta-blockers and patients were simultaneously replacing or repairing the valve with open-heart surgery were excluded. The patients were randomly divided into two groups (n&#x2009;=&#x2009;150) and they were received NAC plus carvedilol or carvedilol. The patients were monitored for 5 days after surgery and the incidence of AF during hospitalization was recorded.<br><br>RESULTS: AF was detected in 14 patients in the NAC with Carvedilol group (9.33%) and 23 patients in Carvedilol group (15.33%). There was no significant difference in the incidence of POAF between the two groups (p&#xa0;value&#x2009;=&#x2009;0.112). The result of multivariable regression model represented that although the incidence of POAF was lower in NAC plus carvedilol group, it wasn't statistically significant (p&#xa0;value&#x2009;=&#x2009;0.10).<br><br>CONCLUSIONS: NAC was not associated with a decreased incidence of AF following CABG surgery.}, }
@article {pmid36280140, year = {2023}, author = {Zheng, Z and Xie, J and Ma, L and Hao, Z and Zhang, W and Li, L}, title = {Vitamin D Receptor Activation Targets ROS-Mediated Crosstalk Between Autophagy and Apoptosis in Hepatocytes in Cholestasic Mice.}, journal = {Cellular and molecular gastroenterology and hepatology}, volume = {15}, number = {4}, pages = {887-901}, pmid = {36280140}, issn = {2352-345X}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Receptors, Calcitriol/metabolism ; Hepatocytes/metabolism ; Apoptosis ; Extracellular Signal-Regulated MAP Kinases/metabolism ; *Cholestasis/pathology ; Autophagy/genetics ; Mitogen-Activated Protein Kinase Kinases/metabolism ; RNA, Small Interfering/metabolism ; }, abstract = {BACKGROUND &amp; AIMS: Observational epidemiologic studies have associated vitamin D deficiency with cholestasis. We reported previously that activation of the vitamin D/vitamin D receptor (VDR) axis in cholangiocytes mitigates cholestatic liver injury by remodeling the damaged bile duct. However, the function of VDR in hepatocytes during cholestasis remains unclear.<br><br>METHODS: Paricalcitol (VDR agonist, 200 ng/kg) was injected intraperitoneally into bile duct-ligated mice every other day for 5 days. Primary hepatocytes and HepG2 hepatoma cells were transfected with Vdr short hairpin RNA, control short hairpin RNA, Vdr plasmid, control vector, Atg5 small interfering RNA (siRNA), and control siRNA. Liver histology, cell proliferation, and autophagy were evaluated.<br><br>RESULTS: Treatment with the VDR agonist paricalcitol improved liver injury in bile duct-ligated mice by up-regulating VDR expression in hepatocytes, which in turn reduced hepatocyte apoptosis by inhibiting reactive oxygen species (ROS) generation via suppressing the Ras-related C3 botulinum toxin substrate 1/reduced nicotinamide adenine dinucleotide phosphate oxidase 1 pathway. Mechanistically, upon exposure to an ROS-inducing compound, Vdr siRNA contributed to apoptosis, whereas the Vdr overexpression caused resistance to apoptosis. Interestingly, up-regulated VDR expression also increased the generation of autophagosomes and macroautophagic/autophagic flux, which was the underlying mechanism for reduced apoptosis following VDR activation. Autophagy depletion impaired the positive effects of VDR overexpression, whereas autophagy induction was synergystic with VDR overexpression. Importantly, up-regulation of VDR promoted autophagy activation by suppressing the activation of the extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (p38MAPK) pathway. Thus, a p38MAPK inhibitor abrogated the Vdr siRNA-induced decrease in autophagy and the Vdr siRNA-induced increase in apoptosis. In contrast, a Mitogen-activated protein kinase kinase (MEK)/ERK activator prevented the enhancement of autophagy and decreased apoptosis following Vdr overexpression. Moreover, the ROS inhibitor N-acetylcystein (NAC) blocked Vdr siRNA-enhanced activation of the ERK/p38MAPK pathway.<br><br>CONCLUSIONS: VDR activation mitigated liver cholestatic injury by reducing autophagy-dependent hepatocyte apoptosis and suppressing the activation of the ROS-dependent ERK/p38MAPK pathway. Thus, VDR activation may be a potential target for the treatment of cholestatic liver disease.}, }
@article {pmid36275479, year = {2022}, author = {Xu, Y and Zhao, Y and Liu, S and Lv, S and Chen, L and Wang, W and Feng, Y and Fu, F and Xu, H}, title = {Zinc Oxide Particles Can Cause Ovarian Toxicity by Oxidative Stress in Female Mice Model.}, journal = {International journal of nanomedicine}, volume = {17}, number = {}, pages = {4947-4960}, pmid = {36275479}, issn = {1178-2013}, mesh = {Female ; Mice ; Animals ; *Zinc Oxide/pharmacology ; NF-E2-Related Factor 2/metabolism ; Ovary ; Kelch-Like ECH-Associated Protein 1/metabolism ; Antioxidants/pharmacology ; Eosine Yellowish-(YS)/metabolism/pharmacology ; Hematoxylin/metabolism/pharmacology ; Progesterone ; Oxidative Stress ; *Nanoparticles ; Malondialdehyde/metabolism ; Acetylcysteine/pharmacology ; Superoxide Dismutase/metabolism ; Estradiol/pharmacology ; }, abstract = {INTRODUCTION: Zinc oxide nanoparticles (ZnO NPs) participate in all aspects of our lives, but with their wide application, more and more disadvantages are exposed. The goal of this study was to investigate the toxicity of ZnO NPs in female mice ovaries and explore its potential mechanism.<br><br>METHODS: In this study, adult female mice were orally exposed to 0, 100, 200, and 400 mg/kg ZnO NPs for 7 days. We explored the underlying mechanisms via the intraperitoneal injection of N-acetyl-cysteine (NAC), an inhibitor of oxidative stress, and salubrinal (Sal), an inhibitor of endoplasmic reticulum (ER) stress.<br><br>RESULTS: The results indicated that serum estradiol and progesterone levels declined greatly with increasing ZnO NPs dosage. Hematoxylin and eosin (HE) staining revealed increased atretic follicles and exfoliated follicular granulosa cells. Moreover, at the transcriptional level, antioxidant-related genes such as Keap1 and Nrf2, and ER stress-related genes PERK, eIF2&#x3b1;, and ATF4 were markedly upregulated. In addition, the expression of Caspase12, Caspase9, and Caspase3, which are genes related to apoptosis, was also upregulated in all ZnO NPs treatment groups. Serum malondialdehyde (MDA) content was remarkably up-regulated, whereas superoxide dismutase (SOD) activity was down-regulated. The 400 mg/kg ZnO NPs treatment group suffered the most substantial harm. However, ovarian damage was repaired when NAC and Sal were added to this group.<br><br>CONCLUSION: ZnO NPs had toxic effects on the ovary of female mice, which were due to oxidative stress, ER stress, and the eventual activation of apoptosis.}, }
@article {pmid36273750, year = {2022}, author = {Gregory, EA and Binagia, EM}, title = {Anaphylaxis due to First-Time Intravenous Infusion of N-Acetylcysteine in a Dog.}, journal = {Topics in companion animal medicine}, volume = {51}, number = {}, pages = {100734}, doi = {10.1016/j.tcam.2022.100734}, pmid = {36273750}, issn = {1946-9837}, mesh = {Humans ; Female ; Dogs ; Animals ; Acetylcysteine/therapeutic use ; *Anaphylaxis/chemically induced/drug therapy/veterinary ; Infusions, Intravenous/veterinary ; Diphenhydramine/therapeutic use ; Epinephrine ; *Dog Diseases/chemically induced/drug therapy ; }, abstract = {A 4-year-old female spayed Pomeranian was referred to the emergency service for intermittent trouble breathing and an enlarged liver found on ultrasound. A severe mixed hepatopathy was found on bloodwork, and ultrasound-guided liver aspirates showed marked hepatocellular vacuolar changes and rare neutrophils. An intravenous (IV) loading dose of n-acetylcysteine (NAC) was given for the first time in this patient, and immediately after the infusion the patient collapsed, became hypotensive, hypothermic, tachycardic, and developed gallbladder wall edema. Treatment for anaphylaxis was immediately initiated with IV fluids, an epinephrine bolus and then continuous rate infusion, diphenhydramine, and famotidine. Clinical signs resolved within an hour of treatment with no recurrence. The hepatic enzymopathy improved, and the patient was ultimately diagnosed with a steroid hepatopathy based on laparoscopic liver biopsies. Anaphylaxis caused by first-time administration of IV NAC in a dog has not previously been reported, though it is known to occur in humans. Based on this report, it would be clinically wise to give careful consideration before prescribing NAC in cases where it is not a specific antidote or if other options are available, and to closely monitor the patient during and immediately after administration.}, }
@article {pmid36273620, year = {2022}, author = {Tang, D and Zheng, S and Liu, C and Zuo, N and Yan, R and Wu, C and Ma, J and Wang, C and Chen, B and Liu, S and He, Y}, title = {Kinesin spindle protein inhibitor exacerbates cisplatin-induced hair cell damage.}, journal = {Archives of biochemistry and biophysics}, volume = {731}, number = {}, pages = {109432}, doi = {10.1016/j.abb.2022.109432}, pmid = {36273620}, issn = {1096-0384}, mesh = {Mice ; Animals ; Cisplatin/toxicity ; Kinesins ; *Ototoxicity ; Superoxides ; *Antineoplastic Agents/toxicity ; Reactive Oxygen Species/metabolism ; Cell Survival ; Apoptosis ; }, abstract = {There is emerging evidence indicating that Kinesin family, plays vital roles in influencing the growth of axons, interference with the progression of tumor. However, the function of Kinesin member in the auditory organs remains unknown. SB743921, a kinesin spindle protein (KSP) inhibitor, was applied in mouse organ of Corti and House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line to examine the role of KSP in auditory system with and without cisplatin damage. Cell Counting Kit-8 (CCK-8) and Lactase dehydrogenase (LDH) release assay were conducted to evaluate cell activity and toxicity. Pretreatment with SB743921 increased the sensitivity of HEI-OC1 cells to cisplatin ototoxicity through promoting cell apoptosis and deteriorating superoxide generation mediated damage from cisplatin. SB743921 also enhanced cisplatin induced hair cell damage in explants of mouse cochleae in vitro. Furthermore, the combined N-acetylcysteine (NAC) treatment with cisplatin or with cisplatin and SB743921 both completely rescued the reduced number of hair cells impaired by cisplatin, confirming the strengthening function of superoxide accumulation by SB743921 after cisplatin treatment. Inhibition of kinesin spindle protein enhanced the susceptibility of hair cells to cisplatin induced damage in mouse cochlear explants and HEI-OC1 cells, indicating that kinesin spindle protein might be an unprecedented target to weaken the ototoxicity of platinum medicaments.}, }
@article {pmid36270032, year = {2022}, author = {Mohammadi, E and Nikbakht, F and Barati, M and Roghani, M and Vazifekhah, S and Khanizadeh, AM and Heidari, Z}, title = {Protective effect of N-acetyl cysteine on the mitochondrial dynamic imbalance in temporal lobe epilepsy: Possible role of mTOR.}, journal = {Neuropeptides}, volume = {96}, number = {}, pages = {102294}, doi = {10.1016/j.npep.2022.102294}, pmid = {36270032}, issn = {1532-2785}, mesh = {Animals ; Rats ; *Acetylcysteine/metabolism ; *Epilepsy, Temporal Lobe/drug therapy/chemically induced ; Hippocampus ; Mitochondrial Dynamics ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Understanding the underlying molecular mechanisms involved in epilepsy is critical for the development of more effective therapies. It is believed that mTOR (Mechanistic Target of Rapamycin kinases) activity and the mitochondrial dynamic balance change during epilepsy. mTOR affects mitochondrial fission by stimulating the translation of mitochondrial fission process 1 (MTFP1). In This study, the protective role of N-acetylcysteine was studied in temporal lobe epilepsy (TLE) through the regulation of mTOR and mitochondrial dynamic proteins. Rats received N-acetylcysteine (oral administration) seven days before induction of epilepsy, followed by one day after epilepsy. TLE was induced by microinjection of kainite into the left lateral ventricle. The total mTOR and Drp1 levels in the hippocampus were evaluated by western blotting. MFN1 was assessed using immunohistochemistry, and the expression of Fis.1 and MTFP1 (fission-related proteins) and OPA (fusion-related protein) were detected by real-time PCR. The mitochondrial membrane potential was measured by Rhodamin 123. The results showed that 72 h after induction of epilepsy, the mTOR protein level increased, and the balance of the mitochondrial dynamic was disturbed; however, oral administration of NAC decreased the mTOR protein level and improved the mitochondrial dynamic. These findings indicate that NAC plays a neuroprotective role in temporal lobe epilepsy, probably through decreasing the mTOR protein level, which can improve the imbalance in the mitochondrial dynamic.}, }
@article {pmid36267623, year = {2022}, author = {Li, X and Wang, Z and Wang, H and Xu, H and Sheng, Y and Lian, F}, title = {Role of N-acetylcysteine treatment in women with advanced age undergoing IVF/ICSI cycles: A prospective study.}, journal = {Frontiers in medicine}, volume = {9}, number = {}, pages = {917146}, pmid = {36267623}, issn = {2296-858X}, abstract = {OBJECTIVE: The main objective of this study was to explore the efficacy of a new antioxidant N-acetylcysteine (NAC) supplementation in reproductive outcomes of advanced age women undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET), and the effect on the expression of L-glutathione (GSH) in follicular fluid (FF) and mitochondrial DNA (mtDNA) copy number of granulosa cells.<br><br>METHODS: The present prospective randomized controlled study was conducted in 200 patients with advanced age women undergoing GnRH antagonist protocol. The treatment group (group A) consisted of 100 women who received N-acetylcysteine treatment from the menstrual phase of the previous cycle for about 45 days using the GnRH antagonist protocol. The control group (group B) consisted of 100 women who received the same protocol without N-acetylcysteine. Total gonadotrophin dosage the number of oocyte received, high-quality blastocysts, and pregnancy outcomes were compared between two groups. Pregnancy outcomes included biochemical pregnancy rate, clinical pregnancy rate, embryo implantation rate, ectopic pregnancy rate, multiple pregnancy rate, and ongoing pregnancy rate. Follicular fluid (FF) was collected after oocytes were gathered. The GSH content in the FF was tested with enzyme linked immunosorbent assay (ELISA). The mtDNA copy number of the granulosa cells was measured using real-time PCR techniques.<br><br>RESULTS: Total doses of Gn in the NAC treatment group were less than those in the control group (2385.50 &#xb1; 879.19 vs. 2527.63 &#xb1; 1170.33, P = 0.047). Compared with the control, the number of high-quality blastocysts in NAC treatment increased significantly (1.82 &#xb1; 2.12 vs. 1.43 &#xb1; 1.58, p = 0.014). Clinical pregnancy rates did not differ in both groups (all P > 0.05). At the same time, the GSH content in the FF differed significantly between the two groups (1.88 &#xb1; 1.23 vs. 1.07 &#xb1; 0.70, p = 0.001). There was no significant difference in the mtDNA copy number between the two groups (P = 0.157).<br><br>CONCLUSION: A combination of NAC and Gn treatment is capable of improving the ovarian response to superovulation drugs in assisted reproductive technologies (ARTs) and also in aged populations. The addition of NAC during IVF can improve the quality of blastocysts in advanced age female subjects. However, more clinical trials are required to be designed to confirm this conclusion in future.<br><br>ETHICS AND DISSEMINATION: The experiment solicited approval from the Institutional ethics committee of the Affiliated Reproductive Hospital of Shandong University. All the participants provided written informed consent. This survey was conducted as per the Declaration of Helsinki and relevant amendments.<br><br>TRIAL REGISTRATION NUMBER: www.chictr.org.cn, identifier ChiCTR2100048297.}, }
@article {pmid36263951, year = {2023}, author = {Bian, J and Liang, H and Zhang, M}, title = {Comparison of Clinical Effectiveness Between Ambroxol and N-Acetylcysteine in Surgical Patients: A Retrospective Cohort Study.}, journal = {Journal of clinical pharmacology}, volume = {63}, number = {2}, pages = {172-179}, doi = {10.1002/jcph.2157}, pmid = {36263951}, issn = {1552-4604}, mesh = {Humans ; Adolescent ; Adult ; *Acetylcysteine/therapeutic use ; *Ambroxol/therapeutic use ; Retrospective Studies ; Lung ; Expectorants/therapeutic use ; Postoperative Complications/prevention &amp; control/drug therapy/epidemiology ; Treatment Outcome ; }, abstract = {Postoperative pulmonary complications (PPCs) are a major cause of postoperative morbidity, mortality, and longer hospital stays. Expectorants are widely used during the perioperative period to reduce PPCs. This study aimed to compare the clinical effectiveness between ambroxol (AMB) and N-acetylcysteine (NAC) in patients undergoing surgery. A multicenter, retrospective cohort study was conducted using deidentified medical records from hospital information system. Between July 1, 2015, and November 30, 2017, patients aged ≥18 years, who received intravenous AMB or nebulized NAC as the only expectorant therapy for >3 days during their hospitalization for thoracic, abdominal, and neurosurgery, were included in this study. The clinical outcomes were evaluated, and propensity score matching was used to adjust significant differences between 2 groups. A total of 4025 cases in the AMB group and 2062 in NAC group after propensity score matching were identified. The incidence of PPCs (13.9% vs 11.6%; P = .013), postoperative sputum suction (17.2% vs 8.0%; P < .001), intensive care unit admission after surgery (25.1% vs 22.5%; P = .024), and postoperative mechanical ventilation (22.3% versus 17.5%; P < .001) in the AMB group were all significantly higher than those in the NAC group. This study suggested that patients treated with NAC during the perioperative period had a significantly lower risk of PPCs. However, further prospective study is needed to ensure the replicability of our findings.}, }
@article {pmid36258210, year = {2022}, author = {Zhan, Y and Zhang, Z and Liu, Y and Fang, Y and Xie, Y and Zheng, Y and Li, G and Liang, L and Ding, Y}, title = {NUPR1 contributes to radiation resistance by maintaining ROS homeostasis via AhR/CYP signal axis in hepatocellular carcinoma.}, journal = {BMC medicine}, volume = {20}, number = {1}, pages = {365}, pmid = {36258210}, issn = {1741-7015}, mesh = {Humans ; *Carcinoma, Hepatocellular/metabolism ; Receptors, Aryl Hydrocarbon/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Liver Neoplasms/metabolism ; Nuclear Proteins/metabolism ; Acetylcysteine ; Signal Transduction ; Homeostasis ; Cytochrome P-450 Enzyme System/metabolism ; Cell Line, Tumor ; Apoptosis ; }, abstract = {BACKGROUND: Radiotherapy (RT) is one of the major therapeutic approaches to hepatocellular carcinoma (HCC). Ionizing radiation (IR) inducing the generation of reactive oxygen species (ROS) leads to a promising antitumor effect. However, the dysregulation of the redox system often causes radioresistance and impairs the efficacy of RT. Increasing evidence indicates that nuclear protein 1 (NUPR1) plays a critical role in redox reactions. In this study, we aim to explore the role of NUPR1 in maintaining ROS homeostasis and radioresistance in HCC.<br><br>METHODS: The radioresistant role of NUPR1 was determined by colony formation assay, comet assay in vitro, and xenograft tumor models in vivo. Probes for ROS, apoptosis assay, and lipid peroxidation assay were used to investigate the functional effect of NUPR1 on ROS homeostasis and oxidative stress. RNA sequencing and co-immunoprecipitation assay were performed to clarify the mechanism of NUPR1 inhibiting the AhR/CYP signal axis. Finally, we analyzed clinical specimens to assess the predictive value of NUPR1 and AhR in the radiotherapeutic efficacy of HCC.<br><br>RESULTS: We demonstrated that NUPR1 was upregulated in HCC tissues and verified that NUPR1 increased the radioresistance of HCC in vitro and in vivo. NUPR1 alleviated the generation of ROS and suppressed oxidative stress, including apoptosis and lipid peroxidation by downregulating cytochrome P450 (CYP) upon IR. ROS scavenger N-acetyl-L-cysteine (NAC) and CYP inhibitor alizarin restored the viability of NUPR1-knockdown cells during IR. Mechanistically, the interaction between NUPR1 and aryl hydrocarbon receptor (AhR) promoted the degradation and decreased nuclear translation of AhR via the&#xa0;autophagy-lysosome pathway, followed by being incapable of CYP's transcription. Furthermore, genetically and pharmacologically activating AhR abrogated the radioresistant role of NUPR1. Clinical data suggested that NUPR1 and AhR could serve as novel biomarkers for predicting the radiation response of HCC.<br><br>CONCLUSIONS: Our findings revealed the role of NUPR1 in regulating ROS homeostasis and oxidative stress via the AhR/CYP signal axis upon IR. Strategies targeting the NUPR1/AhR/CYP pathway may have important clinical applications for improving the radiotherapeutic efficacy of HCC.}, }
@article {pmid36255562, year = {2023}, author = {Pan, J and Zhao, J and Feng, L and Xu, X and He, Z and Liang, W}, title = {Inhibition of USP14 Suppresses ROS-dependent Ferroptosis and Alleviates Renal Ischemia/Reperfusion Injury.}, journal = {Cell biochemistry and biophysics}, volume = {81}, number = {1}, pages = {87-96}, pmid = {36255562}, issn = {1559-0283}, mesh = {Mice ; Animals ; Reactive Oxygen Species/metabolism ; *Ferroptosis ; Kidney/metabolism ; *Reperfusion Injury/drug therapy/metabolism ; Ischemia ; *Acute Kidney Injury/drug therapy ; Ubiquitin Thiolesterase ; }, abstract = {The ubiquitin-specific protease 14 (USP14) is a deubiquitinating enzyme, its inhibitor was reported could alleviate the ischemia/reperfusion (I/R)-stimulated cerebral neuronal damage. However, its specific role in I/R-induced acute kidney injury (AKI) remains unclear. We established hypoxia/reoxygenation (H/R)-induced HK-2 cell injury model in vitro and I/R-induced kidney injury mice model in vivo. The expression or activity of USP14 was inhibited by siRNA or IU1, a small molecule inhibitor of USP14. ROS were scavenged by N-acetyl-cysteine (NAC). Biochemical index analysis and hematoxylin &amp; eosin (H&amp;E) staining were performed to evaluate renal injury. The results indicated that USP14 was upregulated in H/R-induced HK-2 cells and kidney tissues of I/R mice. Inhibition of USP14 suppressed the cell death, inflammatory, oxidative stress and reactive oxygen species (ROS)-dependent ferroptosis of H/R-induced HK-2 cells. What's more, IU1 and NAC effectively alleviated renal injury of I/R mice. In summary, this study suggested that inhibition of USP14 protected renal from I/R injury.}, }
@article {pmid36250047, year = {2022}, author = {Singh, A and Zhao, X and Drlica, K}, title = {Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {938032}, pmid = {36250047}, issn = {2235-2988}, mesh = {Animals ; Anti-Bacterial Agents/pharmacology ; Antitubercular Agents/pharmacology/therapeutic use ; Cysteine ; DNA Gyrase/genetics ; *Disinfectants ; *Extensively Drug-Resistant Tuberculosis/drug therapy ; Fluoroquinolones/pharmacology ; Mice ; Microbial Sensitivity Tests ; Moxifloxacin ; *Mycobacterium tuberculosis/genetics/metabolism ; NAD ; Reactive Oxygen Species ; *Tuberculosis, Multidrug-Resistant/drug therapy ; }, abstract = {With tuberculosis, the emergence of fluoroquinolone resistance erodes the ability of treatment to interrupt the progression of MDR-TB to XDR-TB. One way to reduce the emergence of resistance is to identify heteroresistant infections in which subpopulations of resistant mutants are likely to expand and make the infections fully resistant: treatment modification can be instituted to suppress mutant enrichment. Rapid DNA-based detection methods exploit the finding that fluoroquinolone-resistant substitutions occur largely in a few codons of DNA gyrase. A second approach for restricting the emergence of resistance involves understanding fluoroquinolone lethality through studies of antimicrobial tolerance, a condition in which bacteria fail to be killed even though their growth is blocked by lethal agents. Studies with Escherichia coli guide work with Mycobacterium tuberculosis. Lethal action, which is mechanistically distinct from blocking growth, is associated with a surge in respiration and reactive oxygen species (ROS). Mutations in carbohydrate metabolism that attenuate ROS accumulation create pan-tolerance to antimicrobials, disinfectants, and environmental stressors. These observations indicate the existence of a general death pathway with respect to stressors. M. tuberculosis displays a variation on the death pathway idea, as stress-induced ROS is generated by NADH-mediated reductive stress rather than by respiration. A third approach, which emerges from lethality studies, uses a small molecule, N-acetyl cysteine, to artificially increase respiration and additional ROS accumulation. That enhances moxifloxacin lethality with M. tuberculosis in culture, during infection of cultured macrophages, and with infection of mice. Addition of ROS stimulators to fluoroquinolone treatment of tuberculosis constitutes a new direction for suppressing the transition of MDR-TB to XDR-TB.}, }
@article {pmid36249602, year = {2022}, author = {Alsugoor, MH}, title = {Availability of Antidotes for Management of Acute Toxicity Cases at Emergency Departments in Qassim Hospitals: A Retrospective Study.}, journal = {Cureus}, volume = {14}, number = {9}, pages = {e28992}, pmid = {36249602}, issn = {2168-8184}, abstract = {BACKGROUND: Drug overdose is a medico-social issue worldwide that may occur intentionally or unintentionally. It is one of the most common reasons for emergency department visits, and it is also a frequent cause of morbidity and mortality globally. This study aims to determine the occurrence of acute toxicity cases and their management outcomes at the emergency departments in Qassim Province hospitals in Saudi Arabia. In addition, the study aims to investigate the antidote availabilities at those medical centers.<br><br>METHODS: A retrospective hospital record-based study of acute toxicity cases admitted to the emergency department in hospitals in Qassim during the period from January 1, 2020, to December 31, 2020, was conducted. Data were collected based on hospital resources such as gastrointestinal decontamination, stabilization, elimination enhancement resources, and antidotes from Qassim hospitals, and the availability of antidotes as well as the clinical data of the patients with the management outcome.<br><br>RESULTS: A total of 264 patients with acute toxicity were admitted to the emergency departments of 14 hospitals in Qassim Province in 2020. Of the 264 cases, 179 (68%) were males, and 85 (32%) cases were females. Ninety-five percent of the cases were admitted to public hospitals, whereas 5% were admitted to private hospitals. The largest group by age of admitted cases were aged 11-20 years (19.3%). This study showed that 99% received appropriate treatment for their cause of toxicity, whereas 1% did not. The most common causes of toxicity in Qassim were found to be food poisoning (20.5%), followed by intentional suicide attempts with warfarin/enoxaparin/aspirin overdoses (15.9%) and acetaminophen (paracetamol) overdosage seen in 15.5% of admitted cases. Flagyl, in addition to fluids, was used in the management of 16.7% of cases, N-acetyl cysteine was used for 16.3%, and vitamins K and B6 were used for 14.0% of cases. Activated charcoal, atropine, calcium chloride, calcium gluconate, flumazenil, insulin, magnesium, sodium bicarbonate, and vitamin K were available at all the studied hospitals. However, all the hospitals lacked both ethylenediaminetetraacetic acid (EDTA) and a cyanide kit. Methylene blue and leucovorin were available in only one of the studied hospitals.}, }
@article {pmid36247436, year = {2022}, author = {Chen, JJ and Lee, TH and Kuo, G and Huang, YT and Chen, PR and Chen, SW and Yang, HY and Hsu, HH and Hsiao, CC and Yang, CH and Lee, CC and Chen, YC and Chang, CH}, title = {Strategies for post-cardiac surgery acute kidney injury prevention: A network meta-analysis of randomized controlled trials.}, journal = {Frontiers in cardiovascular medicine}, volume = {9}, number = {}, pages = {960581}, pmid = {36247436}, issn = {2297-055X}, abstract = {OBJECTS: Cardiac surgery is associated with acute kidney injury (AKI). However, the effects of various pharmacological and non-pharmacological strategies for AKI prevention have not been thoroughly investigated, and their effectiveness in preventing AKI-related adverse outcomes has not been systematically evaluated.<br><br>METHODS: Studies from PubMed, Embase, and Medline and registered trials from published through December 2021 that evaluated strategies for preventing post-cardiac surgery AKI were identified. The effectiveness of these strategies was assessed through a network meta-analysis (NMA). The secondary outcomes were prevention of dialysis-requiring AKI, mortality, intensive care unit (ICU) length of stay (LOS), and hospital LOS. The interventions were ranked using the P-score method. Confidence in the results of the NMA was assessed using the Confidence in NMA (CINeMA) framework.<br><br>RESULTS: A total of 161 trials (involving 46,619 participants) and 53 strategies were identified. Eight pharmacological strategies {natriuretic peptides [odds ratio (OR): 0.30, 95% confidence interval (CI): 0.19-0.47], nitroprusside [OR: 0.29, 95% CI: 0.12-0.68], fenoldopam [OR: 0.36, 95% CI: 0.17-0.76], tolvaptan [OR: 0.35, 95% CI: 0.14-0.90], N-acetyl cysteine with carvedilol [OR: 0.37, 95% CI: 0.16-0.85], dexmedetomidine [OR: 0.49, 95% CI: 0.32-0.76;], levosimendan [OR: 0.56, 95% CI: 0.37-0.84], and erythropoietin [OR: 0.62, 95% CI: 0.41-0.94]} and one non-pharmacological intervention (remote ischemic preconditioning, OR: 0.76, 95% CI: 0.63-0.92) were associated with a lower incidence of post-cardiac surgery AKI with moderate to low confidence. Among these nine strategies, five (fenoldopam, erythropoietin, natriuretic peptides, levosimendan, and remote ischemic preconditioning) were associated with a shorter ICU LOS, and two (natriuretic peptides [OR: 0.30, 95% CI: 0.15-0.60] and levosimendan [OR: 0.68, 95% CI: 0.49-0.95]) were associated with a lower incidence of dialysis-requiring AKI. Natriuretic peptides were also associated with a lower risk of mortality (OR: 0.50, 95% CI: 0.29-0.86). The results of a sensitivity analysis support the robustness and effectiveness of natriuretic peptides and dexmedetomidine.<br><br>CONCLUSION: Nine potentially effective strategies were identified. Natriuretic peptide therapy was the most effective pharmacological strategy, and remote ischemic preconditioning was the only effective non-pharmacological strategy. Preventive strategies might also help prevent AKI-related adverse outcomes. Additional studies are required to explore the optimal dosages and protocols for potentially effective AKI prevention strategies.}, }
@article {pmid36244131, year = {2022}, author = {Koda, Y and Nagasaki, Y}, title = {Design of cysteine-based self-assembling polymer drugs for anticancer chemotherapy.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {220}, number = {}, pages = {112909}, doi = {10.1016/j.colsurfb.2022.112909}, pmid = {36244131}, issn = {1873-4367}, mesh = {Humans ; Mice ; Animals ; *Micelles ; *Polymers/chemistry ; Cysteine/chemistry ; Polyethylene Glycols/chemistry ; Drug Carriers/chemistry ; }, abstract = {Reactive oxygen species (ROS) play essential roles in the body, such as the production of energy in oxidative phosphorylation and signal transduction for homeostasis. Redox balance in biological systems gradually collapses due to various environmental factors, including aging and disease, and induces oxidative stress in the body. None of the natural or synthetic antioxidants have been approved clinically, owing to their adverse effects. Herein, we developed L-cysteine (Cys)-based polymer micelles as new self-assembling antioxidants to reduce the adverse effects of conventional antioxidants. Poly(ethylene glycol)-block-poly(L-cysteine) (PEG-block-PCys) was synthesized via anionic ring-opening polymerization. Because the free SH groups in the side chains of the PCys segment were protected by disulfide bonds, the obtained block copolymers were amphiphilic and formed polymer micelles (Nano[Cys]s) of tens of nanometers in size in aqueous media. The stability of Nano[Cys]s in the presence of bovine serum albumin (BSA) was increased by increasing the molecular weight (MW) of the PCys segments, which was analyzed using dynamic light scattering (DLS). The size and coagulation tendency of Nano[Cys]s were also analyzed using DLS measurements by changing the pH and NaCl concentration. Nano[Cys]s were confirmed to be less toxic both in vitro and in vivo than N-acetylcysteine (NAC) because of their size and biocompatible PEG surface layer. Intraperitoneal (i.p.) administration of Nano[Cys]s to the tumor xenograft mouse model successfully suppressed tumor growth. Interestingly, this effect depended on the MW of the PCys segments.}, }
@article {pmid36243239, year = {2022}, author = {Chen, Y and Xi, Y and Li, M and Wu, Y and Yan, W and Dai, J and Wu, M and Ding, W and Zhang, J and Zhang, F and Zhou, S and Wang, S}, title = {Maternal exposure to PM2.5 decreases ovarian reserve in neonatal offspring mice through activating PI3K/AKT/FoxO3a pathway and ROS-dependent NF-κB pathway.}, journal = {Toxicology}, volume = {481}, number = {}, pages = {153352}, doi = {10.1016/j.tox.2022.153352}, pmid = {36243239}, issn = {1879-3185}, mesh = {Humans ; Female ; Mice ; Animals ; *Ovarian Reserve/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species ; NF-KappaB Inhibitor alpha/metabolism ; Follicular Atresia ; Maternal Exposure/adverse effects ; Signal Transduction ; Mice, Inbred C57BL ; Particulate Matter/toxicity ; }, abstract = {There is evidence of an association between exposure to ambient fine particulate matter (PM2.5) and female ovarian dysfunction in adults. However, it is not fully clear whether maternal exposure to PM2.5 negatively affects the ovarian function in offspring. The size of primordial follicle pool, definitely assembled during fetal life, determines ovarian reserve and ovarian function. In this study, female C57BL/6 mice were exposed to either ambient PM2.5 (mean daily concentration 49 µg/m[3]) or filtered air through a whole-body exposure system for 4 weeks before mating, and remained exposed until postpartum. We found that maternal exposure to PM2.5 reduces the initial size of primordial follicle pool and impairs its development in offspring mice. The number of primordial follicles and total follicles was decreased in PM2.5-exposed offspring mice on postnatal day 3 (PND3) and postnatal day 7 (PND7). Maternal PM2.5 exposure promoted the activation of primordial follicles and upregulated the level of p-AKT in offspring mice, accelerating the depletion of primordial follicle pool. While LY294002, a specific inhibitor of PI3K, reversed the overactivation of primordial follicles induced by PM2.5. Besides, maternal PM2.5 exposure induced follicular atresia and granulosa cell apoptosis, increased the accumulation of lipid peroxidation products 4-HNE, and elevated the expression of oxidative stress-related genes and p-p65, p-IκBα in offspring mice. While N-acetylcysteine (NAC) pretreatment abolished the increases of apoptosis, reactive oxygen species (ROS), p-p65 and p-IκBα levels in ovarian granulosa COV434 cells induced by PM2.5 exposure. These findings reveal that maternal exposure to PM2.5 decreases the initial size of primordial follicle pool, and impairs ovarian follicular development in offspring mice. Our data suggest that this involves the activation of the PI3K/AKT/FoxO3a pathway and the ROS-dependent NF-κB pathway. Our study implicates a link between maternal PM2.5 exposure and ovarian reserve in offspring, and improves our understanding of the effects of PM2.5 on reproductive health.}, }
@article {pmid36242913, year = {2022}, author = {Kalyanaraman, B}, title = {NAC, NAC, Knockin' on Heaven's door: Interpreting the mechanism of action of N-acetylcysteine in tumor and immune cells.}, journal = {Redox biology}, volume = {57}, number = {}, pages = {102497}, pmid = {36242913}, issn = {2213-2317}, abstract = {N-acetylcysteine (NAC) has been used as a direct scavenger of reactive oxygen species (hydrogen peroxide, in particular) and an antioxidant in cancer biology and immuno-oncology. NAC is the antioxidant drug most frequently employed in studies using tumor cells, immune cells, and preclinical mouse xenografts. Most studies use redox-active fluorescent probes such as dichlorodihydrofluorescein, hydroethidine, mitochondria-targeted hydroethidine, and proprietary kit-based probes (i.e., CellROX Green and CellROX Red) for intracellular detection of superoxide or hydrogen peroxide. Inhibition of fluorescence by NAC was used as a key experimental observation to support the formation of reactive oxygen species and redox mechanisms proposed for ferroptosis, tumor metastasis, and redox signaling in the tumor microenvironment. Reactive oxygen species such as superoxide and hydrogen peroxide stimulate or abrogate tumor cells and immune cells depending on multiple factors. Understanding the mechanism of antioxidants is crucial for interpretation of the results. Because neither NAC nor the fluorescent probes indicated above react directly with hydrogen peroxide, it is critically important to reinterpret the results to advance our understanding of the mechanism of action of NAC and shed additional mechanistic insight on redox-regulated signaling in tumor biology. To this end, this review is focused on how NAC could affect multiple pathways in cancer cells, including iron signaling, ferroptosis, and the glutathione-dependent antioxidant and redox signaling mechanism, and how NAC could inhibit oxidation of the fluorescent probes through multiple mechanisms.}, }
@article {pmid36235607, year = {2022}, author = {Wang, N and Hao, Y and Fu, L}, title = {Trimethylamine-N-Oxide Promotes Osteoclast Differentiation and Bone Loss via Activating ROS-Dependent NF-κB Signaling Pathway.}, journal = {Nutrients}, volume = {14}, number = {19}, pages = {}, pmid = {36235607}, issn = {2072-6643}, support = {82172456//National Natural Science Foundation of China/ ; 20210407//Seeds Fund of Engineering Research Center of Digital Medicine of the Ministry of Education/ ; 2017ZZ01023//Shanghai Clinical Medical Center/ ; shslczdzk06701//Shanghai Municipal Key Clinical Specialty/ ; }, mesh = {Acetylcysteine/metabolism ; Actins/metabolism ; Animals ; *Bone Resorption/metabolism ; Cattle ; Cell Differentiation ; Methylamines ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; NFATC Transcription Factors/genetics/metabolism ; Nitriles ; Osteoclasts/metabolism ; Osteogenesis ; *Osteoporosis/metabolism ; Oxides/metabolism ; Proto-Oncogene Proteins c-fos/genetics/metabolism ; RANK Ligand/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Sulfones ; TNF Receptor-Associated Factor 6/metabolism ; }, abstract = {Trimethylamine-N-oxide (TMAO), an important gut microbiota (GM)-derived metabolite, has been shown to be abnormally increased in osteoporosis. However, the role and underlying mechanism of TMAO in regulating bone loss during osteoporosis have not been fully investigated. In the current study, we found that 100-400 μM TMAO dose-dependently enhanced TRAP-positive osteoclasts, F-actin ring formation, and resorption area on bovine bone slices and up-regulated osteoclast-related gene expression (Calcr, Traf6, Dcstamp, Acp5, C-Fos, and NFATc1). Western blotting validated that TMAO not only activated NF-κB signaling pathway but also stimulated c-Fos and NFATc1 protein expression in a dose-dependent manner. Furthermore, BAY 11-7082, an NF-κB inhibitor, pretreatment markedly suppressed TRAP-positive osteoclast formation and osteoclast-related genes under TMAO treatment. BAY 11-7082 also inhibited p-p65/p65, c-Fos, and NFATc1 protein expression promoted by TMAO. Moreover, TMAO significantly increased ROS production, which was inhibited by N-acetylcysteine (NAC), an ROS antagonist. In addition, we proved that NAC pretreatment could inhibit TMAO-promoted NF-κB activation. NAC also suppressed TRAP-positive osteoclast formation, osteoclast-related gene expression, and protein expression of c-Fos and NFATc1 under TMAO treatment. In vivo studies showed significantly decreased bone mass and increased TRAP-positive osteoclasts in TMAO-treated C57BL/6 mice. Moreover, western-blotting and immunohistochemical staining showed that TMAO administration markedly stimulated NF-κB p65 expression. Additionally, TMAO administration significantly promoted the gene and protein expression of C-Fos and NFATc1. In conclusion, TMAO could promote osteoclast differentiation and induce bone loss in mice by activating the ROS-dependent NF-κB signaling pathway.}, }
@article {pmid36232686, year = {2022}, author = {Yao, Q and Zou, X and Liu, S and Wu, H and Shen, Q and Kang, J}, title = {Oxidative Stress as a Contributor to Insulin Resistance in the Skeletal Muscles of Mice with Polycystic Ovary Syndrome.}, journal = {International journal of molecular sciences}, volume = {23}, number = {19}, pages = {}, pmid = {36232686}, issn = {1422-0067}, support = {82171634//National Natural Science Foundation of China/ ; 31971068//National Natural Science Foundation of China/ ; 81670733//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Biomarkers/metabolism ; Dehydroepiandrosterone ; Female ; Humans ; *Insulin Resistance ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/metabolism ; NADP/metabolism ; Oxidative Stress ; Oxidoreductases/metabolism ; *Polycystic Ovary Syndrome/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Androgen/metabolism ; Testosterone/metabolism ; }, abstract = {Polycystic ovarian syndrome (PCOS) is a reproductive, endocrine, and metabolic disorder. Circulating markers of oxidative stress are abnormal in women with PCOS. There is a close relationship between oxidative stress and insulin resistance (IR). However, little information is available about oxidative stress in the skeletal muscles of those affected by PCOS. In this study, PCOS was induced in prepubertal C57BL/6J mice by injection with dehydroepiandrosterone. Oxidative stress biomarkers were then measured in both serum and skeletal muscles. The underlying mechanisms were investigated in C2C12 myotubes treated with testosterone (T). We discovered increased oxidative biomarkers, increased ROS production, and damaged insulin sensitivity in the skeletal muscles of mice with PCOS. High levels of T caused mitochondrial dysfunction and increased ROS levels through the androgen receptor (AR)-nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) signaling pathway in C2C12 cells. Treatment of C2C12 cells with an antioxidant N-acetylcysteine (NAC) decreased T-induced ROS production, improved mitochondrial function, and reversed IR. Administration of NAC to mice with PCOS improved insulin sensitivity in the skeletal muscles of the animals. Hyperandrogenism caused mitochondrial dysfunction and redox imbalance in the skeletal muscles of mice with PCOS. We discovered that oxidative stress contributed to skeletal muscle IR in PCOS. Reducing ROS levels may improve the insulin sensitivity of skeletal muscles in patients with PCOS.}, }
@article {pmid36230633, year = {2022}, author = {Kim, W and Park, A and Jang, HH and Kim, SE and Park, KS}, title = {Breast Tumor Cell-Stimulated Bone Marrow-Derived Mesenchymal Stem Cells Promote the Sprouting Capacity of Endothelial Cells by Promoting VEGF Expression, Mediated in Part through HIF-1α Increase.}, journal = {Cancers}, volume = {14}, number = {19}, pages = {}, pmid = {36230633}, issn = {2072-6694}, support = {NRF-2022R1F1A1072927//National Research Foundation of Korea/ ; NRF-2017M3A9E4065331//National Research Foundation of Korea/ ; 1415179737, 20018551//Ministry of Trade, Industry and Energy/ ; }, abstract = {Breast tumor cells recruit bone marrow-derived mesenchymal stem cells (BM-MSCs) and alter their cellular characteristics to establish a tumor microenvironment. BM-MSCs enhance tumor angiogenesis through various mechanisms. We investigated the mechanisms by which BM-MSCs promote angiogenesis in response to breast tumor. Conditioned media from MDA-MB-231 (MDA CM) and MCF7 (MCF7 CM) breast tumor cells were used to mimic breast tumor conditions. An in vitro spheroid sprouting assay using human umbilical vein endothelial cells (HUVECs) was conducted to assess the angiogenesis-stimulating potential of BM-MSCs in response to breast tumors. The ROS inhibitor N-acetylcysteine (NAC) and JAK inhibitor ruxolitinib attenuated increased HIF-1α in BM-MSCs in response to MDA CM and MCF7 CM. HIF-1α knockdown or HIF-1β only partially downregulated VEGF expression and, therefore, the sprouting capacity of HUVECs in response to conditioned media from BM-MSCs treated with MDA CM or MCF7 CM. Inactivation of the VEGF receptor using sorafenib completely inhibited the HUVECs' sprouting. Our results suggest that increased HIF-1α expression under normoxia in BM-MSCs in response to breast tumor cells is mediated by ROS and JAK/Stat3, and that both HIF-1α-dependent and -independent mechanisms increase VEGF expression in BM-MSCs to promote the angiogenic sprouting capacity of endothelial cells in a VEGF-dependent manner.}, }
@article {pmid36225391, year = {2022}, author = {Bühner, LM and Kapanaiah, SKT and Kätzel, D}, title = {Chronic N-acetylcysteine treatment improves anhedonia and cognition in a mouse model of the schizophrenia prodrome.}, journal = {Frontiers in behavioral neuroscience}, volume = {16}, number = {}, pages = {1002223}, pmid = {36225391}, issn = {1662-5153}, abstract = {Schizophrenia is a severe psychiatric disorder whose neurodevelopmental pathogenesis includes a prodromal phase before its diagnostically decisive-namely psychotic-symptoms are present. This prodrome is characterized by cognitive and affective deficits, and it may constitute a critical time period for an early therapeutic intervention to improve or even prevent further disease development. N-acetylcysteine (NAC) is an easily repurposable compound that has recently shown promise in improving non-psychotic symptoms in patients with established schizophrenia. Its therapeutic mechanism may involve the amelioration of circuit abnormalities like a hyper-glutamatergic state and oxidative stress in cortex which have been proposed to drive the pathogenesis of this disease. However, it is currently unknown to what extent NAC can actually improve prodromal aberrations. To investigate this preclinically, we deployed the cyclin-D2 knockout mouse model (CD2-KO) that shares physiological and behavioral abnormalities with the schizophrenia prodrome, including a hyperactive CA1 region, and cognitive and affective deficits. Applying NAC chronically in drinking water (0.9 g/l) during development (∼P22-P70), we found that excessive novelty-induced hyperlocomotion was neither ameliorated during (∼P68) nor after (∼P75) treatment; similarly, T-maze working memory (tested after treatment; ∼P84) was unaffected. However, once chronic NAC treatment was resumed (at approximately P134) in those mice that had received it before, working memory, cognitive flexibility (tested under NAC), and anhedonia (sucrose-preference, tested 1 day after NAC-treatment stopped) were improved in CD2-KO mice. This suggests that chronic NAC treatment may be a therapeutic strategy to improve some cognitive and affective dysfunctions in the schizophrenia prodrome.}, }
@article {pmid36222315, year = {2023}, author = {Garcia-Serrano, AM and Vieira, JPP and Fleischhart, V and Duarte, JMN}, title = {Taurine and N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice.}, journal = {Nutritional neuroscience}, volume = {26}, number = {11}, pages = {1090-1102}, doi = {10.1080/1028415X.2022.2131062}, pmid = {36222315}, issn = {1476-8305}, mesh = {Mice ; Animals ; Female ; *Acetylcysteine/therapeutic use/pharmacology ; *Diet, High-Fat/adverse effects ; Creatine/metabolism ; Phosphocreatine/metabolism ; Obesity/metabolism ; Memory Disorders/etiology/prevention &amp; control ; Hippocampus/metabolism ; Lactates/metabolism ; Mice, Inbred C57BL ; }, abstract = {Background: Obesity constitutes a risk factor for cognitive impairment. In rodent models, long-term exposure to obesogenic diets leads to hippocampal taurine accumulation. Since taurine has putative cyto-protective effects, hippocampal taurine accumulation in obese and diabetic models might constitute a counteracting response to metabolic stress. Objective: We tested the hypothesis that treatment with taurine or with N-acetylcysteine (NAC), which provides cysteine for the synthesis of taurine and glutathione, prevent high-fat diet (HFD)-associated hippocampal alterations and memory impairment. Methods: Female mice were fed either a regular diet or HFD. Some mice had access to 3%(w/v) taurine or 3%(w/v) NAC in the drinking water. After 2 months, magnetic resonance spectroscopy (MRS) was used to measure metabolite profiles. Memory was assessed in novel object and novel location recognition tests. Results: HFD feeding caused memory impairment in both tests, and reduced concentration of lactate, phosphocreatine-to-creatine ratio, and the neuronal marker N-acetylaspartate in the hippocampus. Taurine and NAC prevented HFD-induced memory impairment and N-acetylaspartate reduction. NAC, but not taurine, prevented the reduction of lactate and phosphocreatine-to-creatine ratio. MRS revealed NAC/taurine-induced increase of hippocampal glutamate and GABA levels. Conclusion: NAC and taurine can prevent memory impairment, while only NAC prevents alterations of metabolite concentrations in HFD-exposed female mice.}, }
@article {pmid36219247, year = {2022}, author = {Becchi, S and Hood, J and Kendig, MD and Mohammadkhani, A and Shipman, ML and Balleine, BW and Borgland, SL and Corbit, LH}, title = {Food for thought: diet-induced impairments to decision-making and amelioration by N-acetylcysteine in male rats.}, journal = {Psychopharmacology}, volume = {239}, number = {11}, pages = {3495-3506}, pmid = {36219247}, issn = {1432-2072}, support = {401526/CAPMC/CIHR/Canada ; 147473/CAPMC/CIHR/Canada ; 950-232211//Canada Research Chairs/ ; 401526/CAPMC/CIHR/Canada ; 147473/CAPMC/CIHR/Canada ; }, mesh = {Rats ; Male ; Animals ; *Acetylcysteine/pharmacology ; *Corpus Striatum ; Learning ; Glutamic Acid ; Diet ; }, abstract = {RATIONALE: Attempts to lose weight often fail despite knowledge of the health risks associated with obesity and determined efforts. We previously showed that rodents fed an obesogenic diet displayed premature habitual behavioural control and weakened flexible decision-making based on the current value of outcomes produced by their behaviour. Thus, habitual control may contribute to failed attempts to modify eating behaviours.<br><br>OBJECTIVES: To examine the effects of an obesogenic diet on behavioural control and glutamate transmission in dorsal striatum regions and to assess the ability of N-acetylcysteine (NAC) to reverse deficits.<br><br>METHODS: Here, we examined diet-induced changes to decision-making and used in vitro electrophysiology to investigate the effects of diet on glutamate transmission within the dorsomedial (DMS) and dorsolateral (DLS) striatum, areas that control goal-directed and habitual behaviours, respectively. We administered NAC in order to normalize glutamate release and tested whether this would restore goal-directed performance following an obesogenic diet.<br><br>RESULTS: We found that an obesogenic diet reduced sensitivity to outcome devaluation and increased glutamate release in the DMS, but not DLS. Administration of NAC restored goal-directed control and normalized mEPSCs in the DMS. Finally, NAC administered directly to the DMS was sufficient to reinstate sensitivity to outcome devaluation following an obesogenic diet.<br><br>CONCLUSIONS: These data indicate that obesogenic diets alter neural activity in the basal ganglia circuit responsible for goal-directed learning and control which leads to premature habitual control. While the effects of diet are numerous and widespread, normalization of glutamatergic activity in this circuit is sufficient for restoring goal-directed behaviour.}, }
@article {pmid36217638, year = {2022}, author = {Calefi, PHS and de Azevedo Queiroz, I and Alcalde, M and Oliveira, S and Vivan, RR and Weckwerth, PH and Kato, AS and Duarte, MAH}, title = {Comparison of the Physicochemical Properties, Antimicrobial Action, and Cytotoxicity of Ambroxol Hydrochloride, N-acetylcysteine, and Calcium Hydroxide Pastes.}, journal = {European endodontic journal}, volume = {7}, number = {3}, pages = {217-222}, pmid = {36217638}, issn = {2548-0839}, mesh = {Acetylcysteine/pharmacology ; *Ambroxol/pharmacology ; *Anti-Infective Agents/pharmacology ; Calcium Hydroxide/toxicity ; Chemical Phenomena ; Enterococcus faecalis ; Water ; }, abstract = {OBJECTIVE: To evaluate the solubility, pH, antimicrobial action, and cytotoxicity of ambroxol hydrochloride (AMB), N-acetylcysteine (NAC), and calcium hydroxide (CH) pastes for use as intracanal medications.<br><br>METHODS: Solubility was determined by micro-CT, based on the paste volume remaining after immersion in water for 7 days. pH was measured by immersing acrylic tubes containing the pastes in ultrapure water and then measuring pH after 3 hours, 3 days, and 7 days. Antimicrobial action against Enterococcus faecalis was assessed based on the percentage of living cells, using the live/dead staining method under confocal microscopy. Cytotoxicity was assessed based on the cell viability of L929 fibroblast-like cells after 6, 24, and 48 hours. Cytotoxicity data were compared using the ANOVA and Tukey tests, and the antimicrobial data were compared using the Kruskal-Wallis and Dunn tests. The significance level used was 5% (&#x3b1;=0.05).<br><br>RESULTS: The solubility values for all the study groups were significantly different (P<0.05), where the highest values were for NAC, followed by AMB, and then CH. Likewise, the pH levels were all significantly different (P<0.05), where NAC and AMB levels were acidic, and CH levels were alkaline. The antimicrobial action of AMB was significantly higher than that of CH (P<0.05), and that of NAC was also higher than that of CH, albeit not significantly. AMB and NAC were more cytotoxic than CH, and higher dilutions of CH promoted higher cell viability levels than lower dilutions of the same paste (P<0.05).<br><br>CONCLUSION: The NAC and AMB pastes were more soluble and cytotoxic than the CH paste and had acidic pH levels. The AMB paste displayed the highest antimicrobial action against Enterococcus faecalis biofilm.}, }
@article {pmid36216166, year = {2022}, author = {Brites, G and Basso, J and Miranda, M and Miguel Neves, B and Vitorino, C and Cruz, MT}, title = {Development of a new hydrogel for the prevention of allergic contact dermatitis.}, journal = {International journal of pharmaceutics}, volume = {628}, number = {}, pages = {122265}, doi = {10.1016/j.ijpharm.2022.122265}, pmid = {36216166}, issn = {1873-3476}, mesh = {Humans ; *Hydrogels ; *Dermatitis, Allergic Contact/prevention &amp; control ; Allergens ; Skin ; }, abstract = {Allergic contact dermatitis (ACD) is the most prevalent occupational disease and the most common form of immunotoxicity in humans. Preventing exposure to the triggering allergens is the mainstay of treatment. However, avoidance is not always possible in an occupational setting. From a pathophysiological point of view, a variety of events are involved in the development of ACD, including the formation of immunogenic complexes following the stable association of the allergen with skin proteins, which is thought to be the molecular initiating event responsible for the development of ACD. Previously, the team identified molecules that exhibited higher antiallergic potential due to their capacity to block the interaction between allergens and skin proteins. These assumptions were the starting point for the design of this work aiming to develop and characterize a new hydrogel containing the active ingredients lysine and N-acetyl cysteine under the premises of quality- and safety- by design. Two factorial plannings were established envisioning the optimization of the hydrogel in terms of mechanical and rheological properties. In vitro release and permeation studies supported its skin surface barrier effect. In addition, the selected hydrogel proved to be safe without causing human skin irritation or skin sensitization.}, }
@article {pmid36211962, year = {2022}, author = {Ma, C and Wu, X and Zhang, X and Liu, X and Deng, G}, title = {Heme oxygenase-1 modulates ferroptosis by fine-tuning levels of intracellular iron and reactive oxygen species of macrophages in response to Bacillus Calmette-Guerin infection.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {1004148}, pmid = {36211962}, issn = {2235-2988}, support = {P30 DK054759/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antioxidants ; BCG Vaccine ; Cysteine ; Cytokines ; *Ferroptosis ; Heme Oxygenase-1 ; Iron/metabolism ; Macrophages ; Membrane Proteins ; Mice ; *Mycobacterium bovis ; Phospholipid Hydroperoxide Glutathione Peroxidase ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; *Tuberculosis/pathology ; *Tuberculosis, Pulmonary/pathology ; }, abstract = {Macrophages are the host cells and the frontline defense against Mycobacterium tuberculosis (Mtb) infection, and the form of death of infected macrophages plays a pivotal role in the outcome of Mtb infections. Ferroptosis, a programmed necrotic cell death induced by overwhelming lipid peroxidation, was confirmed as one of the mechanisms of Mtb spread following infection and the pathogenesis of tuberculosis (TB). However, the mechanism underlying the macrophage ferroptosis induced by Mtb infection has not yet been fully understood. In the present study, transcriptome analysis revealed the upregulation of heme oxygenase-1 (HMOX1) and pro-ferroptosis cytokines, but downregulation of glutathione peroxidase 4 (GPX4) and other key anti-lipid peroxidation factors in the peripheral blood of both patients with extra-pulmonary tuberculosis (EPTB) and pulmonary tuberculosis (PTB). This finding was further corroborated in mice and RAW264.7 murine macrophage-like cells infected with Bacillus Calmette-Guerin (BCG). A mechanistic study further demonstrated that heme oxygenase-1 protein (HO-1) regulated the production of reactive oxygen species (ROS) and iron metabolism, and ferroptosis in BCG-infected murine macrophages. The knockdown of Hmox1 by siRNA resulted in a significant increase of intracellular ROS, Fe[2+], and iron autophagy-mediated factor Ncoa4, along with the reduction of antioxidant factors Gpx4 and Fsp1 in macrophages infected with BCG. The siRNA-mediated knockdown of Hmox1 also reduced cell survival rate and increased the release of intracellular bacteria in BCG-infected macrophages. By contrast, scavenging ROS by N-acetyl cysteine led to the reduction of intracellular ROS, Fe[2+], and Hmox1 concentrations, and subsequently inhibited ferroptosis and the release of intracellular BCG in RAW264.7 cells infected with BCG. These findings suggest that HO-1 is an essential regulator of Mtb-induced ferroptosis, which regulates ROS production and iron accretion to alter macrophage death against Mtb infections.}, }
@article {pmid36201094, year = {2022}, author = {Ahmed, HM and Shehata, HH and El-Saeed, GSM and Gabal, HHA and El-Daly, SM}, title = {Ameliorative effect of Lactobacillus rhamnosus GG on acetaminophen-induced hepatotoxicity via PKC/Nrf2/PGC-1α pathway.}, journal = {Journal, genetic engineering &amp; biotechnology}, volume = {20}, number = {1}, pages = {142}, pmid = {36201094}, issn = {2090-5920}, abstract = {BACKGROUND: Acetaminophen (APAP) overdose is a common cause of hepatotoxicity. Antioxidants like N-acetyl cysteine are recommended as a therapeutic option; nevertheless, it has limitations. The search for efficient alternatives is ongoing. Probiotics are live microorganisms that maintain a healthy gut microecology. Lactobacillus rhamnosus GG (LGG) is one of the widely used probiotics. Our study aimed to assess the protective and therapeutic effects of probiotic LGG on APAP-induced hepatotoxicity and evaluate the molecular pathways behind this effect.<br><br>METHODS: Wistar Albino male rats were randomly distributed into the following experimental groups: group 1, non-treated rats (vehicle); group 2, rats received oral gavage of suspension of probiotic LGG (5&#x2009;&#xd7;&#x2009;10[10]&#xa0;CFU GG/0.5&#xa0;ml in PBS) daily for 2&#xa0;weeks (probiotic control); group 3, rats received APAP dose of 2&#xa0;g/kg body weight (positive control); group 4, rats received oral gavage of suspension of probiotic LGG for 2&#xa0;weeks followed by a single dose of APAP injection (prophylactic); and group 5, rats received a single dose of APAP and then 24&#xa0;h later treated with oral gavage of probiotic LGG daily for 2&#xa0;weeks (treatment).<br><br>RESULTS: Our study revealed that administration of probiotic LGG (either as prophylactic or treatment) exhibited a remarkable reduction in APAP-induced liver injury as resembled by the decrease in liver enzymes (ALT and AST) and the histopathological features of liver sections. Moreover, the significant reduction in the oxidative marker malondialdehyde, along with the enhancement in glutathione reductase, and the significant reduction in inflammatory markers (nitric oxide and tumor necrosis factor-&#x3b1;) were all indicators of the efficiency of LGG in ameliorating the alterations accompanied with APAP-induced hepatotoxicity. Our findings also demonstrate that LGG administration boosted the expression of Nrf2 and PGC-1 while decreasing the expression of protein kinase C (PKC). As a result, the nuclear abundance of Nrf2 is increased, and the expression of various antioxidants is eventually upregulated.<br><br>CONCLUSION: Our study shows that probiotic LGG supplementation exerts a prophylactic and therapeutic effect against APAP-induced hepatotoxicity through modulating the expression of PKC and the Nrf2/PGC-1&#x3b1; signaling pathway and eventually suppressing oxidative damage from APAP overdose.}, }
@article {pmid36199646, year = {2022}, author = {Singh, A and Singh, G and Singh, S and Kazi, SE and Gill, M}, title = {N-acetylcysteine in the Treatment of Internet Gaming Disorder.}, journal = {Cureus}, volume = {14}, number = {9}, pages = {e28662}, pmid = {36199646}, issn = {2168-8184}, abstract = {Internet gaming disorder (IGD) is the persistent and recurrent use of the internet to engage in video gaming through a single or multiplayer interface that can lead to significant impairment or distress. With technological advancements in the last decade via portable handheld devices, along with their global availability, video games have found a new medium in which they can provide instantaneous access for casual and enthusiastic users alike. Unfortunately, this exponentially increases the possibility of addiction. IGD shares a similar pathophysiological etiology to addiction as drugs or gambling. However, it can be challenging to manage IGD due to the ease of video game access and limited understanding of the newly recognized disorder. This study aims to fill in the knowledge gap concerning the limited research on internet gaming addiction, its consequential effects on human cognitive-behavioral functioning, and pharmacotherapy management as observed in our patient, who developed IGD, starting initially as a casual recreational hobby among peers. This case also highlights the lack of social awareness and seriousness attributed to this disorder. It focuses on using N-acetylcysteine in the management as well as other psychological and psychotropic drugs.}, }
@article {pmid36192693, year = {2022}, author = {Zhang, S and Bei, Y and Huang, Y and Huang, Y and Hou, L and Zheng, XL and Xu, Y and Wu, S and Dai, X}, title = {Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {28}, number = {1}, pages = {121}, pmid = {36192693}, issn = {1528-3658}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Cyclooxygenase 2/metabolism/pharmacology ; Disease Models, Animal ; *Ferroptosis ; Hyperplasia/metabolism ; Iron/metabolism/pharmacology ; Mice ; Muscle, Smooth, Vascular/metabolism ; Myocytes, Smooth Muscle/metabolism ; *Neointima ; Osteopontin/metabolism/pharmacology ; Phenotype ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Smooth Muscle Myosins/metabolism ; }, abstract = {BACKGROUND: Stent implantation-induced neointima formation is a dominant culprit in coronary artery disease treatment failure after percutaneous coronary intervention. Ferroptosis, an iron-dependent regulated cell death, has been associated with various cardiovascular diseases. However, the effect of ferroptosis on neointima formation remains unclear.<br><br>METHODS: The mouse common right carotid arteries were ligated for 16 or 30&#xa0;days, and ligated tissues were collected for further analyses. Primary rat vascular smooth muscle cells (VSMCs) were isolated from the media of aortas of Sprague-Dawley (SD) rats and used for in vitro cell culture experiments.<br><br>RESULTS: Ferroptosis was positively associated with neointima formation. In vivo, RAS-selective lethal 3 (RSL3), a ferroptosis activator, aggravated carotid artery ligation-induced neointima formation and promoted VSMC phenotypic conversion. In contrast, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), showed the opposite effects in mice. In vitro, RSL3 promoted rat VSMC phenotypic switching from a contractile to a synthetic phenotype, evidenced by increased contractile markers (smooth muscle myosin heavy chain and calponin 1), and decreased synthetic marker osteopontin. The induction of ferroptosis by RSL3 was confirmed by the increased expression level of ferroptosis-associated gene prostaglandin-endoperoxide synthase 2 (Ptgs2). The effect of RSL3 on rat VSMC phenotypic switching was abolished by Fer-1. Moreover, N-acetyl-L-cysteine (NAC), the reactive oxygen species inhibitor, counteracted the effect of RSL3 on the phenotypic conversion of rat VSMCs.<br><br>CONCLUSIONS: Ferroptosis induces VSMC phenotypic switching and accelerates ligation-induced neointimal hyperplasia in mice. Our findings suggest inhibition of ferroptosis as an attractive strategy for limiting vascular restenosis.}, }
@article {pmid36191663, year = {2023}, author = {Guan, F and Zhang, S and Fan, L and Sun, Y and Ma, Y and Cao, C and Zhang, Y and He, M and Du, H}, title = {Kunling Wan improves oocyte quality by regulating the PKC/Keap1/Nrf2 pathway to inhibit oxidative damage caused by repeated controlled ovarian hyperstimulation.}, journal = {Journal of ethnopharmacology}, volume = {301}, number = {}, pages = {115777}, doi = {10.1016/j.jep.2022.115777}, pmid = {36191663}, issn = {1872-7573}, mesh = {Animals ; Female ; Mice ; Pregnancy ; Antioxidants/pharmacology/metabolism ; *Hydrogen Peroxide/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; Oocytes/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Kunling Wan (KW) is a traditional Chinese medicine that is principally used for kidney deficiency, qi stagnation, and blood stasis, which are basic syndromes of infertility in China. KW can improve ovarian follicular development, ovarian function, and endometrial receptivity, which lead to improving pregnancy outcomes. Repeated controlled ovarian hyperstimulation (COH) reduces oocyte quality and results in a lower pregnancy rate. Whether KW has the potential to improve oocyte quality reduced by repeated COH has yet to be determined.<br><br>AIMS OF THE STUDY: The aim of this study wwas to evaluate the effect of KW on oocyte quality after damage due to repeated COH, and to investigate the mechanism(s) underlying the antioxidative protection of oocytes by mitochondria.<br><br>MATERIALS AND METHODS: Female Kunming mice were randomly divided into four groups: normal group, model (repeated COH) group, KW group, and N-acetylcysteine (NAC) group. We observed the morphology and quality of mitochondria, level of reactive oxygen species (ROS), and antioxidant enzymes activity of each group. Oocytes were treated with H2O2 and KW-containing serum, and we determined the antioxidant effects of KW on H2O2-treated oocytes and the mechanism involved in the regulation of Nrf2 in reducing oxidative damage.<br><br>RESULTS: Our results revealed that repeated COH caused oxidative damage and impaired oocyte mitochondrial function and structure, resulting in poor oocyte quality. KW pretreatment reduced oxidative damage by inhibiting ROS production and improving mitochondrial structure and function, thereby enhancing overall oocyte quality. In response to H2O2, KW activated the PKC/Keap1/Nrf2-signaling pathway and promoted the translocation of Nrf2 from the cytoplasm to the nucleus, which activated the expression of SOD and GSH-Px, and removed the excess ROS that caused the initial mitochondrial damage.<br><br>CONCLUSIONS: KW improved oocyte quality perturbed by repeated COH via reducing oxidative effects and improving mitochondrial function. The mechanism may be related to regulation of the PKC/Keap1/Nrf2 pathway in removing excess ROS.}, }
@article {pmid36191509, year = {2023}, author = {Vivoli, A and Ghislain, J and Filali-Mouhim, A and Angeles, ZE and Castell, AL and Sladek, R and Poitout, V}, title = {Single-Cell RNA Sequencing Reveals a Role for Reactive Oxygen Species and Peroxiredoxins in Fatty Acid-Induced Rat β-Cell Proliferation.}, journal = {Diabetes}, volume = {72}, number = {1}, pages = {45-58}, pmid = {36191509}, issn = {1939-327X}, support = {R01 DK058096/DK/NIDDK NIH HHS/United States ; MOP 77686//CIHR/Canada ; }, mesh = {Rats ; Animals ; Fatty Acids/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Oleic Acid/pharmacology ; *Diabetes Mellitus, Type 2/metabolism ; Insulin/metabolism ; *Insulin-Secreting Cells/metabolism ; Cell Proliferation ; Palmitates/metabolism ; Glucose/metabolism ; Sequence Analysis, RNA ; *Islets of Langerhans/metabolism ; }, abstract = {The functional mass of insulin-secreting pancreatic β-cells expands to maintain glucose homeostasis in the face of nutrient excess, in part via replication of existing β-cells. Type 2 diabetes appears when these compensatory mechanisms fail. Nutrients including glucose and fatty acids are important contributors to the β-cell compensatory response, but their underlying mechanisms of action remain poorly understood. We investigated the transcriptional mechanisms of β-cell proliferation in response to fatty acids. Isolated rat islets were exposed to 16.7 mmol/L glucose with or without 0.5 mmol/L oleate (C18:1) or palmitate (C16:0) for 48 h. The islet transcriptome was assessed by single-cell RNA sequencing. β-Cell proliferation was measured by flow cytometry. Unsupervised clustering of pooled β-cells identified different subclusters, including proliferating β-cells. β-Cell proliferation increased in response to oleate but not palmitate. Both fatty acids enhanced the expression of genes involved in energy metabolism and mitochondrial activity. Comparison of proliferating versus nonproliferating β-cells and pseudotime ordering suggested the involvement of reactive oxygen species (ROS) and peroxiredoxin signaling. Accordingly, N-acetyl cysteine and the peroxiredoxin inhibitor conoidin A both blocked oleate-induced β-cell proliferation. Our study reveals a key role for ROS signaling through peroxiredoxin activation in oleate-induced β-cell proliferation.}, }
@article {pmid36184612, year = {2023}, author = {Shim, SM and Choi, HR and Kwon, SC and Kim, HY and Sung, KW and Jung, EJ and Mun, SR and Bae, TH and Kim, DH and Son, YS and Jung, CH and Lee, J and Lee, MJ and Park, JW and Kwon, YT}, title = {The Cys-N-degron pathway modulates pexophagy through the N-terminal oxidation and arginylation of ACAD10.}, journal = {Autophagy}, volume = {19}, number = {6}, pages = {1642-1661}, pmid = {36184612}, issn = {1554-8635}, mesh = {Animals ; Mice ; Sequestosome-1 Protein/metabolism ; *Macroautophagy ; *Autophagy/physiology ; Reactive Oxygen Species/metabolism ; Cysteamine ; Cysteine ; Ubiquitin/metabolism ; Arginine/metabolism ; Transferases/metabolism ; }, abstract = {In the N-degron pathway, N-recognins recognize cognate substrates for degradation via the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). We have recently shown that the autophagy receptor SQSTM1/p62 (sequestosome 1) is an N-recognin that binds the N-terminal arginine (Nt-Arg) as an N-degron to modulate autophagic proteolysis. Here, we show that the N-degron pathway mediates pexophagy, in which damaged peroxisomal fragments are degraded by autophagy under normal and oxidative stress conditions. This degradative process initiates when the Nt-Cys of ACAD10 (acyl-CoA dehydrogenase family, member 10), a receptor in pexophagy, is oxidized into Cys sulfinic (Cys[O2]) or sulfonic acid (Cys[O3]) by ADO (2-aminoethanethiol (cysteamine) dioxygenase). Under oxidative stress, the Nt-Cys of ACAD10 is chemically oxidized by reactive oxygen species (ROS). The oxidized Nt-Cys2 is arginylated by ATE1-encoded R-transferases, generating the RC[OX] N-degron. RC[OX]-ACAD10 marks the site of pexophagy via the interaction with PEX5 and binds the ZZ domain of SQSTM1/p62, recruiting LC3[+]-autophagic membranes. In mice, knockout of either Ate1 responsible for Nt-arginylation or Sqstm1/p62 leads to increased levels of peroxisomes. In the cells from patients with peroxisome biogenesis disorders (PBDs), characterized by peroxisomal loss due to uncontrolled pexophagy, inhibition of either ATE1 or SQSTM1/p62 was sufficient to recover the level of peroxisomes. Our results demonstrate that the Cys-N-degron pathway generates an N-degron that regulates the removal of damaged peroxisomal membranes along with their contents. We suggest that tannic acid, a commercially available drug on the market, has a potential to treat PBDs through its activity to inhibit ATE1 R-transferases.Abbreviations: ACAA1, acetyl-Coenzyme A acyltransferase 1; ACAD, acyl-Coenzyme A dehydrogenase; ADO, 2-aminoethanethiol (cysteamine) dioxygenase; ATE1, arginyltransferase 1; CDO1, cysteine dioxygenase type 1; ER, endoplasmic reticulum; LIR, LC3-interacting region; MOXD1, monooxygenase, DBH-like 1; NAC, N-acetyl-cysteine; Nt-Arg, N-terminal arginine; Nt-Cys, N-terminal cysteine; PB1, Phox and Bem1p; PBD, peroxisome biogenesis disorder; PCO, plant cysteine oxidase; PDI, protein disulfide isomerase; PTS, peroxisomal targeting signal; R-COX, Nt-Arg-CysOX; RNS, reactive nitrogen species; ROS, reactive oxygen species; SNP, sodium nitroprusside; UBA, ubiquitin-associated; UPS, ubiquitinproteasome system.}, }
@article {pmid36182795, year = {2022}, author = {Xu, L and He, D and Wu, Y and Shen, L and Wang, Y and Xu, Y}, title = {Tanshinone IIA inhibits cardiomyocyte apoptosis and rescues cardiac function during doxorubicin-induced cardiotoxicity by activating the DAXX/MEK/ERK1/2 pathway.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {107}, number = {}, pages = {154471}, doi = {10.1016/j.phymed.2022.154471}, pmid = {36182795}, issn = {1618-095X}, mesh = {Animals ; Mice ; *Abietanes/pharmacology ; Acetylcysteine/pharmacology ; Apoptosis ; *Cardiotoxicity/drug therapy ; Caspase 3 ; Caspase 8 ; Co-Repressor Proteins ; Doxorubicin/adverse effects ; *MAP Kinase Signaling System ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase Kinases ; Molecular Chaperones/pharmacology ; Myocytes, Cardiac ; RNA ; }, abstract = {BACKGROUND: Heart failure (HF) is a common cardiovascular syndrome. Tanshinone IIA (Tan IIA) is a pharmacologically active monomer that exerts a significant cardioprotective effect in the clinic; however, the specific mechanisms are not fully understood.<br><br>PURPOSE: We mainly investigated the protective effects of Tan IIA on doxorubicin (DOX)-induced HF.<br><br>METHODS: In an in vitro study, H9C2 and HL-1 cells were cultured and treated with DOX and Tan IIA for 24 h, we investigated the mechanism underlying Tan IIA-mediated protection. In an in vivo study, a model of DOX-induced HF was established in C57BL/6 mice that were divided into the six groups randomly: a control group, a DOX group, DOX groups treated with Tan IIA (DOX+Tan IIA) at dosages of 2.5, 5 and 10 mg/kg/day and DOX groups treated with N-acetylcysteine (NAC) at dosages of 200 mg/kg/day.<br><br>RESULT: The results demonstrated that Tan IIA significantly increased cell viability and protected against DOX-induced apoptosis. RNA-sequencing showed that the genes expression associated with the apoptotic signaling pathway was altered by Tan IIA. Among the differentially expressed genes, death-domain associated protein (DAXX), which plays an critical role in apoptotic signaling, exhibited increased expression under Tan IIA treatment. In addition, RNA interference was used to silence the expression of DAXX, which abolished Tan IIA-mediated protection against DOX-induced apoptosis; this effect was associated with extracellular signal-regulated protein kinase 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) expression. In the in vivo study, the echocardiography results revealed that heart function was rescued by Tan IIA, and the histomorphology results showed that Tan IIA prevented myocardial structural alteration and myofibril disruption. Furthermore, Tan IIA induced the expressions of DAXX, p-ERK1/2 and p-MEK. Tan IIA also inhibited apoptosis by suppressing the expression of cleaved caspase-8, p-P38 and cleaved caspase-3.<br><br>CONCLUSION: Our results provide novel interpretations into the important role of DAXX in DOX-induced cardiotoxicity and show that Tan IIA may be a novel agent strategy for HF treatment via activating the DAXX/MEK/ERK1/2 pathway.}, }
@article {pmid36182028, year = {2022}, author = {Schoeps, VA and Graves, JS and Stern, WA and Zhang, L and Nourbakhsh, B and Mowry, EM and Henry, RG and Waubant, E}, title = {N-Acetyl Cysteine as a Neuroprotective Agent in Progressive Multiple Sclerosis (NACPMS) trial: Study protocol for a randomized, double-blind, placebo-controlled add-on phase 2 trial.}, journal = {Contemporary clinical trials}, volume = {122}, number = {}, pages = {106941}, doi = {10.1016/j.cct.2022.106941}, pmid = {36182028}, issn = {1559-2030}, mesh = {Humans ; *Neuroprotective Agents/adverse effects ; *Multiple Sclerosis ; Acetylcysteine/adverse effects ; Disease Progression ; *Multiple Sclerosis, Chronic Progressive/diagnostic imaging/drug therapy ; Double-Blind Method ; Treatment Outcome ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase II as Topic ; }, abstract = {INTRODUCTION: Patients with progressive multiple sclerosis (PMS) experience relentless disability worsening. Current approved therapies have very modest effects on disability progression and purely focus on immunomodulation. While some inflammatory processes exist in non-active PMS, other biological processes such as neuronal injury from oxidative stress are likely more critical. N-acetyl cysteine (NAC) directly scavenges free radicals and restores neuronal glutathione, a major endogenous antioxidant. Our group has recently evaluated the safety of high dose NAC in a pilot trial in PMS with no tolerability concerns. We aim now to assess the safety, tolerability, and effect of NAC on progression of several MRI, clinical and biological markers in PMS patients.<br><br>METHODS: The NACPMS trial is a multi-site, randomized, double-blind, parallel-group, placebo-controlled add-on phase 2 trial. Ninety-eight PMS patients with EDSS 3.0-7.0 and aged 40-70&#xa0;years will be randomized to NAC 1200&#xa0;mg TID or matching placebo (1:1) as an add-on to the standard of care stratified by site and disease type during a 15-month intervention period. It is hypothesized that a reduction in oxidative stress injury will lessen brain atrophy estimated by MRI. The primary outcome analysis will compare the percent change over 12&#xa0;months (Month 15 vs Month 3) between treatment and control arms using multivariable linear regression adjusted by age, sex, and disease duration.<br><br>ETHICS: This study was approved by the Institutional Review Board at the University of California, San Francisco (IRB21-34143), and an Investigational New Drug approval was obtained from the FDA (IND127184).<br><br>TRIAL REGISTRATION: NCT05122559.}, }
@article {pmid36170201, year = {2022}, author = {Andrade, C}, title = {Antipsychotic Augmentation With N-Acetylcysteine for Patients With Schizophrenia.}, journal = {The Journal of clinical psychiatry}, volume = {83}, number = {5}, pages = {}, doi = {10.4088/JCP.22f14664}, pmid = {36170201}, issn = {1555-2101}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; *Antipsychotic Agents/therapeutic use ; *Clozapine/therapeutic use ; Humans ; *Schizophrenia/drug therapy ; }, abstract = {N-acetylcysteine (NAC) augmentation of antipsychotic medication is one of very many antipsychotic augmentation strategies that have been studied in schizophrenia. A recent systematic review and meta-analysis of 6 randomized controlled trials (RCTs) found that NAC (median dose, 2,000 mg/d) improved several clinical outcomes at different time points with medium to large effect sizes; however, many of the significant findings in this meta-analysis are suspect because they appeared to be influenced by 2 short-term (8-week) RCTs with outlying characteristics. Important findings not influenced by the 2 outlying RCTs were significant attenuation by NAC of negative symptom (3 RCTs) and total psychopathology (2 RCTs) ratings at ≥ 24 weeks and improvement in working memory but not processing speed (3 RCTs). Of these findings, reduction in psychopathology ratings, though statistically significant, appeared too small to be clinically meaningful. Finally, a newly published, moderately large RCT of NAC (2,000 mg/d) in schizophrenia patients refractory to clozapine found that 1 year of treatment with NAC did not outperform placebo for any clinical, cognitive, or quality of life outcome. The take-home message is that it is premature to recommend the use of NAC to treat schizophrenia for any target domain in routine clinical practice and that there does not appear to be a role for NAC for any indication in clozapine-refractory schizophrenia. However, it may be worth studying whether NAC, dosed at 2,000 mg/d or higher for 6 months or longer, improves functional outcomes in schizophrenia.}, }
@article {pmid36169181, year = {2022}, author = {Wang, T and Liu, J and Huang, X and Zhang, C and Shangguan, M and Chen, J and Wu, S and Chen, M and Yang, Z and Zhao, S}, title = {Gomisin A enhances the antitumor effect of paclitaxel by suppressing oxidative stress in ovarian cancer.}, journal = {Oncology reports}, volume = {48}, number = {5}, pages = {}, pmid = {36169181}, issn = {1791-2431}, mesh = {Animals ; Carcinoma, Ovarian Epithelial ; Cell Line, Tumor ; Cell Proliferation ; Complex Mixtures/pharmacology ; Cyclin B1/metabolism ; Cyclin-Dependent Kinase 4/metabolism ; Cyclooctanes ; Cysteine/pharmacology ; Dioxoles ; Eosine Yellowish-(YS)/pharmacology/therapeutic use ; Female ; Humans ; Lignans ; Mice ; *Ovarian Neoplasms/pathology ; Oxidative Stress ; *Paclitaxel/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {Gomisin A (GA) is an effective component of Schisandra. The crude extracts of Schisandra chinensis and its active ingredients have been shown to inhibit multidrug resistance in tumour cells. Reactive oxygen species (ROS) have different roles in cancer and may contribute to therapy resistance. The human ovarian cancer (OC) cell lines SKOV3 and A2780, and a mouse model of OC, were used in the present study. MTT assay, colony formation assay, flow cytometry, western blot analysis, and haematoxylin and eosin (H&amp;E) staining were performed to determine the antitumor effect of GA and paclitaxel (PTX) in vitro and in vivo. The ROS inhibitor N‑acetyl cysteine (NAC) was used to assess the mechanism underlying the chemosensitizing effects of GA. Notably, the proliferation of OC cells was inhibited by PTX, which could be enhanced by the ROS inhibitor NAC or GA. Treatment with NAC + PTX or GA + PTX enhanced the cell cycle arrest, but not apoptosis, induced by PTX. Moreover, the molecular mechanism underlying this effect may be that GA decreases the levels of ROS in ovarian cancer cells and inhibits cell cycle progression by downregulating the expression of the cell cycle proteins cyclin‑dependent kinase 4 and cyclin B1. In conclusion, the combination of PTX and the ROS inhibitor GA may be a novel strategy in OC chemotherapy.}, }
@article {pmid36159904, year = {2022}, author = {Bai, X and Wang, M and Niu, X and Yu, H and Yue, JX and Sun, Y}, title = {Effect of N-acetyl-cysteine treatment on sensorineural hearing loss: a meta-analysis.}, journal = {World journal of otorhinolaryngology - head and neck surgery}, volume = {8}, number = {3}, pages = {205-212}, pmid = {36159904}, issn = {2589-1081}, abstract = {N-acetyl-cysteine (NAC) is an efficacious treatment for sensorineural hearing loss in animal models, such as noise-induced hearing loss (NIHL), however previous research into the effect of NAC on patients with hearing loss produced contradictory results. In this study, we investigated the effect of NAC treatment on sensorineural hearing loss. PubMed, Web of Science and Embase databases were searched in their entirety using the key words: hearing loss, NAC, N-acetylcysteine, and sensorineural hearing loss. Studies which included assessment of hearing loss with pure-tone threshold (PTA) data were selected. Eligible studies regarding the effects of NAC treatment on patients with hearing loss were collected by two independent reviewers. A total of 1197 individuals were included from seven published studies. Two studies reported data for a sudden idiopathic sensorineural hearing loss (SISNHL) group. Three studies reported data for a NIHL group. Other studies reported data for drug-induced hearing loss. The meta-analysis demonstrated that the overall effect of NAC treatment on sensorineural hearing loss was invalid. However, NAC treatment was linked with improved patient outcomes of hearing tests in cases of sudden hearing loss, but did not prevent hearing loss induced by noise or ototoxicity. However, there is a need for better-designed studies with larger samples to further prove the correlation between the effect of NAC and hearing loss.}, }
@article {pmid36159825, year = {2022}, author = {Yin, X and Zhuang, X and Luo, W and Liao, M and Huang, L and Cui, Q and Huang, J and Yan, C and Jiang, Z and Liu, Y and Wang, W}, title = {Andrographolide promote the growth and immunity of Litopenaeus vannamei, and protects shrimps against Vibrio alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {990297}, pmid = {36159825}, issn = {1664-3224}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anisomycin ; Anti-Bacterial Agents/pharmacology ; Antioxidants/pharmacology ; Apoptosis ; Diterpenes ; Immunity, Innate ; Inflammation ; Interleukin-1beta/metabolism ; *Penaeidae ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Suppressor Protein p53/genetics ; *Vibrio alginolyticus ; bcl-2-Associated X Protein ; }, abstract = {Vibrio alginolyticus (V. alginolyticus) is one of the major pathogens causing mass mortality of shrimps worldwide, affecting energy metabolism, immune response and development of shrimps. In the context of the prohibition of antibiotics, it is necessary to develop a drug that can protect shrimp from V. alginolyticus. Andrographolide (hereinafter called Andr), a traditional drug used in Chinese medicine, which possesses diverse biological effects including anti-bacteria, antioxidant, immune regulation. In this study, we investigated the effect of Andr on growth, immunity, and resistance to V. alginolyticus infection of Litopenaeus vannamei (L. vannamei) and elucidate the underlying molecular mechanisms. Four diets were formulated by adding Andr at the dosage of 0 g/kg (Control), 0.5 g/kg, 1 g/kg, and 2 g/kg in the basal diet, respectively. Each diet was randomly fed to one group with three replicates of shrimps in a 4-week feeding trial. The results showed that dietary Andr improved the growth performance and non-specific immune function of shrimps. L. vannamei fed with Andr diets showed lower mortality after being challenged by V. alginolyticus. After 6 h of V. alginolyticus infection, reactive oxygen species (ROS) production, tissue injury, apoptosis, expression of inflammatory factors (IL-1 β and TNFα) and apoptosis-related genes (Bax, caspase3 and p53) were increased in hemocytes and hepatopancreas, while feeding diet with 0.5 g/kg Andr could inhibit the increase. Considering that JNK are important mediators of apoptosis, we examined the influence of Andr on JNK activity during V. alginolyticus infection. We found that Andr inhibited JNK activation induced by V. alginolyticus infection on L. vannamei. The ROS scavenger N-acetyl-l-cysteine (NAC) suppressed V. alginolyticus-induced inflammation and apoptosis, suggesting that ROS play an important role in V. alginolyticus-induced inflammation and apoptosis. Treated cells with JNK specific activator anisomycin, the inflammation and apoptosis inhibited by Andr were counteracted. Collectively, Andr promote the growth and immunity of L. vannamei, and protects shrimps against V. alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway. These results improve the understanding of the pathogenesis of V. alginolyticus infection and provide clues to the development of effective drugs against V. alginolyticus.}, }
@article {pmid36158364, year = {2022}, author = {Gautam, A and Singh, H}, title = {Dengue Fever With Fulminant Liver Failure and Fatal Pulmonary Alveolar Hemorrhage: A Case Report.}, journal = {Cureus}, volume = {14}, number = {8}, pages = {e28302}, pmid = {36158364}, issn = {2168-8184}, abstract = {Dengue infection may rarely present with end-organ dysfunction. A 22-year-old male patient presented with a serologically confirmed dengue infection, with clinical manifestations and laboratory pictures suggestive of fulminant hepatitis. The in-hospital disease course was complicated with encephalopathy, recurrent hypoglycemic episodes, coagulopathy, pulmonary alveolar hemorrhage, hypotension, and kidney injury. He was managed with intravenous fresh frozen plasma, platelet concentrate, crystalloids and N-acetyl cysteine (NAC) along with other recommended supportive measures for dengue and fulminant hepatic failure. The patient did not show any improvement in liver function despite therapy and succumbed to his illness on day 6 of hospitalization. In view of the large burden of disease in developing nations and atypical manifestations of dengue infection, research into effective treatment strategies is warranted.}, }
@article {pmid36157143, year = {2022}, author = {Ballester, MP and Sittner, R and Jalan, R}, title = {Alcohol and Acute-on-Chronic Liver Failure.}, journal = {Journal of clinical and experimental hepatology}, volume = {12}, number = {5}, pages = {1360-1370}, pmid = {36157143}, issn = {0973-6883}, abstract = {Acute-on-chronic liver failure (ACLF) is a clinical syndrome that occurs in patients with cirrhosis and is characterised by acute deterioration, organ failure and high short-term mortality. Alcohol is one of the leading causes of ACLF and the most frequently reported aetiology of underlying chronic liver disease. Among patients with alcoholic hepatitis (AH), ACLF is a frequent and severe complication. It is characterised by both immune dysfunction associated to an increased risk of infection and high-grade systemic inflammation that ultimately induce organ failure. Diagnosis and severity of ACLF determine AH prognosis, and therefore, ACLF prognostic scores should be used in severe AH with organ failure. Corticosteroids remain the first-line treatment for severe AH but they seem insufficient when ACLF is associated. Novel therapeutic targets to contain the excessive inflammatory response and reduce infection have been identified and are under investigation. With liver transplantation remaining one of the most effective therapies for severe AH and ACLF, adequate organ allocation represents a growing challenge. Hence, a clear understanding of the pathophysiology, clinical implications and management strategies of ACLF in AH is essential for hepatologists, which is narrated briefly in this review.}, }
@article {pmid36156107, year = {2022}, author = {Tras, B and Eser Faki, H and Ozdemir Kutahya, Z and Bahcivan, E and Dik, B and Uney, K}, title = {The effects of dexamethasone and minocycline alone and combined with N-acetylcysteine and vitamin E on serum matrix metalloproteinase-9 and coenzyme Q10 levels in aflatoxin B1 administered rats.}, journal = {Polish journal of veterinary sciences}, volume = {25}, number = {3}, pages = {419-427}, doi = {10.24425/pjvs.2022.142026}, pmid = {36156107}, issn = {2300-2557}, mesh = {*Acetylcysteine/pharmacology ; *Aflatoxin B1/toxicity ; Animals ; Dexamethasone/pharmacology ; Male ; Matrix Metalloproteinase 9/genetics ; Minocycline/pharmacology ; Rats ; Rats, Wistar ; Reducing Agents ; Ubiquinone/analogs &amp; derivatives ; Vitamin E/pharmacology ; }, abstract = {This study aimed to determine the effects of dexamethasone and minocycline alone and combined treatment with N-acetylcysteine (NAC) and vitamin E on serum coenzyme Q10 (CoQ10) and matrix metalloproteinase-9 (MMP-9) levels in rats administered aflatoxin B1 (AFB1). The study was carried out on 66 male Wistar rats. Following the intraperitoneal (IP) administration of AFB1 at dose of 2 mg/kg, minocycline (45 and 90 mg/kg, IP) and dexamethasone (5 and 20 mg/kg, IP) were administered alone and combined with NAC (200 mg/kg, IP) and vitamin E (600 mg/kg, IP). CoQ10 and MMP-9 levels were analyzed using the HPLC-UV method and a commercial kit by ELISA, respectively. AFB1 increased MMP-9 level and decreased CoQ10 level compared to the control group. After dexamethasone and minocycline administration, there is no increase in CoQ10 level, which is caused by AFB1. However, dexamethasone and minocycline combined with NAC+vitamin E caused significant increases in CoQ10 levels. Dexamethasone and minocycline alone and combined with NAC+vitamin E decreased MMP-9 levels compared to the single AFB1 treated group. The use of MMPs inhibitors and oxidative stress-reducing agents is anticipated to be beneficial in the poisoning with AFB1.}, }
@article {pmid36155419, year = {2022}, author = {Harchegani, AB and Rostami, S and Mohsenifar, Z and Dafchahi, AB and Moghadam, FM and Jaafarzadeh, M and Saraabestan, SS and Ranji, N}, title = {Anti-apoptotic properties of N-Acetyl cysteine and its effects on of Liver X receptor and Sirtuin 1 expression in the liver of rats exposed to Lead.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {74}, number = {}, pages = {127070}, doi = {10.1016/j.jtemb.2022.127070}, pmid = {36155419}, issn = {1878-3252}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Caspase 3/genetics/metabolism ; Lead/metabolism ; Lipids ; Liver/metabolism ; Liver X Receptors/genetics/metabolism ; Rats ; *Sirtuin 1/genetics/metabolism/pharmacology ; bcl-2-Associated X Protein/metabolism/pharmacology ; }, abstract = {BACKGROUND: This study aimed to evaluate the expression of Liver X receptor (Lxr), Sirtuin 1 (Sirt1), apoptotic-related genes, and the protective role of N-acetylcysteine (NAC) in the liver of rats treated with Lead (Pb).<br><br>METHODS: Rats were randomly divided into 5 groups, including G1 (control), G2 (single dose of Pb), G3 (continuous dose of Pb), G4 (single dose of Pb + NAC), and G5 (continuous dose of Pb + NAC). Lipid profiles and liver specific enzymes were assessed. Expression of Lxr, Sirt1, Bax and Caspase-3 genes was considered using RT-PCR.<br><br>RESULTS: Exposure to Pb caused a significant accumulation of Pb in the blood and liver tissue, increase in serum AST, ALT and ALP enzymes, as well as lipid profiles. Chronic exposure to Pb caused a significant decrease in Lxr (3.15-fold; p&#xa0;<&#xa0;0.001) and Sirt1 (2.78-fold; p&#xa0;=&#xa0;0.009), but significant increase in expression of Bax (4.49-fold; p&#xa0;<&#xa0;0.001) and Caspase-3 (4.10-fold; p&#xa0;<&#xa0;0.001) genes when compared to the control. Combined therapy with Pb +&#xa0;NAC in rats caused a significant decrease in AST, ALT and ALP values (28.93%, 20.80% and 28.86%, respectively) in the blood as compared to rats treated with Pb alone. Co-treated with Pb +&#xa0;NAC significantly increased the expression of Lxr (1.72-fold; p&#xa0;=&#xa0;0.043) and Sirt1 (2.45-fold; p&#xa0;=&#xa0;0.008), but decreased the expression of Bax (1.96-fold; p&#xa0;=&#xa0;0.03) and Caspase 3 (2.22-fold; p&#xa0;=&#xa0;0.029) genes when compared to rats treated with Pb alone.<br><br>CONCLUSION: Chronic exposure to Pb is strongly associated with accumulation of Pb in the blood and liver, hepatic cells apoptosis, down-expression of Lxr and Sirt1 genes and consequently liver injury and abnormal lipid profiles. NAC reversed the Pb-induced toxicity on the liver tissue.}, }
@article {pmid36155047, year = {2023}, author = {Wu, Y and Yao, Y and Bai, H and Shimizu, K and Li, R and Zhang, C}, title = {Investigation of pulmonary toxicity evaluation on mice exposed to polystyrene nanoplastics: The potential protective role of the antioxidant N-acetylcysteine.}, journal = {The Science of the total environment}, volume = {855}, number = {}, pages = {158851}, doi = {10.1016/j.scitotenv.2022.158851}, pmid = {36155047}, issn = {1879-1026}, mesh = {Humans ; Animals ; Mice ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Acetylcysteine/pharmacology ; Antioxidants ; Polystyrenes/toxicity ; Microplastics ; }, abstract = {Accumulating evidences show that the hazardous substance atmospheric nanoplastics increase the respiratory risk of individuals, but the inside toxicity mechanisms to lung tissue remain unclear. This study aims at investigating the potential mechanisms of inhaled cationic polystyrene nanoplastics (amine-polystyrene nanoplastics, APS-NPs)-induced pulmonary toxicity on mice. In vivo, the mice intratracheal administrated with APS-NPs suspension (5 mg/kg) were found inflammatory infiltrates in lung tissues through histopathology analysis. Furthermore, transcriptome analysis demonstrated that 1821 differentially expressed mRNA between APS group and control group were dominantly associated with 288 known KEGG pathways, indicating that APS-NPs might cause early inflammatory responses in lung tissue by activating the NLRP3/capase-1/IL-1β signaling pathway. Moreover, in vitro results also showed that NLRP3 inflammasome could be activated to induce pyroptosis in MLE-12 cells after exposure to APS-NPs. And, MH-S cells after exposure to APS-NPs exhibited increased Irg1 proteins, leading to the increasing generation of ROS and inflammatory factors (e.g., tnf-α, il-6, il-1β). In conclusion, these results revealed that Irg1/NF-κB/NLRP3/Caspase-1 signaling pathway was activated significantly after exposing to APS-NPs, leading to pulmonary toxicity on mice. Intriguingly, prior administration of the clinical antioxidant N-acetylcysteine (NAC) could serve as a possible candidate for the prevention and treatment of pulmonary toxicity induced by APS-NPs. The study contributes to a better understanding of the potential risks of environmental nanoplastics to humans and its improvement measure.}, }
@article {pmid36154299, year = {2022}, author = {Zhao, Y and Li, F and Li, S and Ji, J and Qiao, W and Fang, J}, title = {Aluminum chloride induces G0/G1 phase arrest via regulating the reactive oxygen species-depended non-canonical STAT1 pathway in hFOB1.19 cells.}, journal = {Human &amp; experimental toxicology}, volume = {41}, number = {}, pages = {9603271221129846}, doi = {10.1177/09603271221129846}, pmid = {36154299}, issn = {1477-0903}, mesh = {Aluminum Chloride/toxicity ; *Cysteine/pharmacology ; G1 Phase ; Phosphorylation ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; STAT1 Transcription Factor/metabolism ; Serine/metabolism/pharmacology ; *Signal Transduction ; }, abstract = {Treatment with aluminum chloride (AlCl3) suppresses the growth of osteoblastic cells; however, the molecular mechanisms underlying the impact of AlCl3 on cell growth have not been fully characterized. In this study, we observed that exposure of hFOB1.19 cells to AlCl3 arrested cells at G0/G1 phase by inducing p21 expression. Further studies indicated that AlCl3 upregulated the phosphorylation level of signal transducer and activator of transcription 1 (STAT1) at serine 727 site (Ser727). By chromatin immunoprecipitation and electrophoretic mobility shift assay, we found that AlCl3 promoted STAT1/DNA binding activity to p21 promoter, thus resulting in the upregulation of p21. Moreover, siRNA-mediated knockdown of STAT1 attenuated p21 level induced by AlCl3. Notably, using hFOB1.19 cells stably expressing dominant-negative STAT1 (Ser727Ala), we demonstrated that phosphorylation of STAT1 at Ser727 site is required for p21-mediated cycle arrest induced by AlCl3. Mechanism investigation indicated that AlCl3 stimulated the phosphorylation of JNK, and administration of JNK inhibitor SP600125 prevented AlCl3-induced G0/G1 arrest through suppressing the phosphorylation of STAT1. Notably, pretreatment with N-acetyl-cysteine, a reactive oxygen species scavenger, conferred a significantly inhibitory effect on AlCl3-mediated activation of JNK/STAT1 signaling pathway. Taken together, our findings provide the molecular mechanism for G0/G1 arrest induced by AlCl3 in osteoblastic cells.}, }
@article {pmid36148786, year = {2022}, author = {Barrozo, LG and Silva, BR and Paulino, LRFM and Barbalho, EC and Nascimento, DR and Costa, FC and Batista, ALPS and Lopes, EPF and Rodrigues, APR and Silva, JRV}, title = {N-Acetyl cysteine reduces the levels of reactive oxygen species and improves in vitro maturation of oocytes from medium-sized bovine antral follicles.}, journal = {Zygote (Cambridge, England)}, volume = {30}, number = {6}, pages = {882-890}, doi = {10.1017/S0967199422000429}, pmid = {36148786}, issn = {1469-8730}, mesh = {Cattle ; Animals ; *In Vitro Oocyte Maturation Techniques/methods ; Reactive Oxygen Species/metabolism ; *Acetylcysteine/pharmacology/metabolism ; Oocytes ; Meiosis ; Superoxide Dismutase/metabolism ; Glutathione Peroxidase/metabolism ; RNA, Messenger/genetics/metabolism ; }, abstract = {This study aims to evaluate the effects of N-acetylcysteine (NAC) on bovine oocyte maturation, mitochondrial activity and transzonal projections (TZP), as well as on the levels of reactive oxygen species (ROS) and messenger RNA (mRNA) for catalase (CAT) superoxide dismutase (SOD), periredoxin-6 (Prdx6), glutathione peroxidase (GPx), growth and differentiation factor-9 (GDF9), histone H1Foo, cyclin B1 (CCNB1) and c-Mos. Bovine cumulus-oocyte complexes (COC) of medium-sized antral follicles (3.0-6.0 mm) were prematured in TCM-199 for 8 h at 38.5°C in 5% CO2. After prematuration in the presence of forskolin and C-type natriuretic peptide, COCs were matured in TCM-199 alone or with 0.1, 0.5 or 2.5 mM NAC. Then, oocytes were classified according to the stage of chromatin. Furthermore, mitochondrial activity and intracellular levels of ROS and TZP were also evaluated. The levels of mRNAs for CAT, SOD, Prdx6, GPx, GDF9, H1Foo, CCNB1 and c-Mos were evaluated using real-time polymerase chain reaction (RT-PCR). The results showed that NAC significantly increased the percentages of oocytes with resumption of meiosis when compared with those oocytes matured in control medium. Oocytes had homogeneous mitochondrial distribution, and those cultured with 0.1 and 0.5 mM NAC had lower levels of ROS when compared with the control. In addition, 0.5 mM NAC reduced TZP and the levels of mRNA for CCNB1. In contrast, NAC did not influence the expression of CAT, GPx, Prdx6, SOD, GDF9, H1Foo, and c-Mos. In conclusion, 0.5 mM NAC reduced the levels of ROS, TZP and mRNA for CCNB1, and improved in vitro resumption of meiosis in oocytes from medium-sized bovine antral follicles.}, }
@article {pmid36148515, year = {2023}, author = {Hegde, G and Sharma, P and Lekhadia, U and Gopani, S and Kandoi, N}, title = {Entrapped Malecot catheter removal: Our experience.}, journal = {Tropical doctor}, volume = {53}, number = {1}, pages = {146-147}, doi = {10.1177/00494755221125082}, pmid = {36148515}, issn = {1758-1133}, mesh = {Humans ; *Drainage ; Device Removal ; Catheters ; *Liver Abscess ; }, abstract = {Some surgeons use a Malecot catheter for drainage of intra-abdominal or mediastinal collections. These tubes are usually removed after 2-3 weeks. If left later, they may become entrapped due to the ingrowing of tissue, and fibrosis within the flower-like tip of the Malecot's catheter. Its removal then needs careful manipulation to prevent organ damage. We present our experience in ensuring the safe removal of such entrapped Malecot's catheters in liver abscess patients.}, }
@article {pmid36148239, year = {2022}, author = {Liggett, JR and Kang, J and Ranjit, S and Rodriguez, O and Loh, K and Patil, D and Cui, Y and Duttargi, A and Nguyen, S and He, B and Lee, Y and Oza, K and Frank, BS and Kwon, D and Li, HH and Kallakury, B and Libby, A and Levi, M and Robson, SC and Fishbein, TM and Cui, W and Albanese, C and Khan, K and Kroemer, A}, title = {Oral N-acetylcysteine decreases IFN-γ production and ameliorates ischemia-reperfusion injury in steatotic livers.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {898799}, pmid = {36148239}, issn = {1664-3224}, support = {R21 AI130800/AI/NIAID NIH HHS/United States ; T32 DK120521/DK/NIDDK NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; S10 OD025153/OD/NIH HHS/United States ; R01 DK127830/DK/NIDDK NIH HHS/United States ; R01 DK116567/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cytokines ; *Fatty Liver/drug therapy ; Interferon-gamma ; Ligands ; Mice ; Mice, Inbred C57BL ; Peroxisome Proliferator-Activated Receptors ; Phospholipids ; *Reperfusion Injury/etiology ; Triglycerides ; }, abstract = {Type 1 Natural Killer T-cells (NKT1 cells) play a critical role in mediating hepatic ischemia-reperfusion injury (IRI). Although hepatic steatosis is a major risk factor for preservation type injury, how NKT cells impact this is understudied. Given NKT1 cell activation by phospholipid ligands recognized presented by CD1d, we hypothesized that NKT1 cells are key modulators of hepatic IRI because of the increased frequency of activating ligands in the setting of hepatic steatosis. We first demonstrate that IRI is exacerbated by a high-fat diet (HFD) in experimental murine models of warm partial ischemia. This is evident in the evaluation of ALT levels and Phasor-Fluorescence Lifetime (Phasor-FLIM) Imaging for glycolytic stress. Polychromatic flow cytometry identified pronounced increases in CD45+CD3+NK1.1+NKT1 cells in HFD fed mice when compared to mice fed a normal diet (ND). This observation is further extended to IRI, measuring ex vivo cytokine expression in the HFD and ND. Much higher interferon-gamma (IFN-γ) expression is noted in the HFD mice after IRI. We further tested our hypothesis by performing a lipidomic analysis of hepatic tissue and compared this to Phasor-FLIM imaging using "long lifetime species", a byproduct of lipid oxidation. There are higher levels of triacylglycerols and phospholipids in HFD mice. Since N-acetylcysteine (NAC) is able to limit hepatic steatosis, we tested how oral NAC supplementation in HFD mice impacted IRI. Interestingly, oral NAC supplementation in HFD mice results in improved hepatic enhancement using contrast-enhanced magnetic resonance imaging (MRI) compared to HFD control mice and normalization of glycolysis demonstrated by Phasor-FLIM imaging. This correlated with improved biochemical serum levels and a decrease in IFN-γ expression at a tissue level and from CD45+CD3+CD1d+ cells. Lipidomic evaluation of tissue in the HFD+NAC mice demonstrated a drastic decrease in triacylglycerol, suggesting downregulation of the PPAR-γ pathway.}, }
@article {pmid36145638, year = {2022}, author = {Pontremoli, C and Boffito, M and Laurano, R and Iviglia, G and Torre, E and Cassinelli, C and Morra, M and Ciardelli, G and Vitale-Brovarone, C and Fiorilli, S}, title = {Mesoporous Bioactive Glasses Incorporated into an Injectable Thermosensitive Hydrogel for Sustained Co-Release of Sr[2+] Ions and N-Acetylcysteine.}, journal = {Pharmaceutics}, volume = {14}, number = {9}, pages = {}, pmid = {36145638}, issn = {1999-4923}, support = {685872//H2020-NMP-PILOTS-2015/ ; }, abstract = {An injectable delivery platform for promoting delayed bone healing has been developed by combining a thermosensitive polyurethane-based hydrogel with strontium-substituted mesoporous bioactive glasses (MBG_Sr) for the long-term and localized co-delivery of pro-osteogenic Sr[2+] ions and an osteogenesis-enhancing molecule, N-Acetylcysteine (NAC). The incorporation of MBG_Sr microparticles, with a final concentration of 20 mg/mL, did not alter the overall properties of the thermosensitive hydrogel, in terms of sol-to-gel transition at a physiological-like temperature, gelation time, injectability and stability in aqueous environment at 37 °C. In particular, the hydrogel formulations (15% w/v polymer concentration) showed fast gelation in physiological conditions (1 mL underwent complete sol-to-gel transition within 3-5 min at 37 °C) and injectability in a wide range of temperatures (5-37 °C) through different needles (inner diameter in the range 0.4-1.6 mm). In addition, the MBG_Sr embedded into the hydrogel retained their full biocompatibility, and the released concentration of Sr[2+] ions were effective in promoting the overexpression of pro-osteogenic genes from SAOS2 osteoblast-like cells. Finally, when incorporated into the hydrogel, the MBG_Sr loaded with NAC maintained their release properties, showing a sustained ion/drug co-delivery along 7 days, at variance with the MBG particles as such, showing a strong burst release in the first hours of soaking.}, }
@article {pmid36145547, year = {2022}, author = {Coelho, AM and Queiroz, IF and Perucci, LO and Souza, MO and Lima, WG and Talvani, A and Costa, DC}, title = {Piperine as Therapeutic Agent in Paracetamol-Induced Hepatotoxicity in Mice.}, journal = {Pharmaceutics}, volume = {14}, number = {9}, pages = {}, pmid = {36145547}, issn = {1999-4923}, support = {00//Coordena&#xe7;&#xe3;o de Aperfeicoamento de Pessoal de N&#xed;vel Superior/ ; 00//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de Minas Gerais/ ; 00//Universidade Federal de Ouro Preto/ ; }, abstract = {High doses of paracetamol (APAP) can cause irreversible liver damage. Piperine (P) inhibits cytochrome P450, which is involved in the metabolism of various xenobiotics, including paracetamol. We evaluated the hepatoprotective effects of piperine with or without N-acetylcysteine (NAC) in APAP-induced hepatotoxicity. The mice were treated with two doses of piperine (P20 or P40) and/or NAC at 2 h after administration of APAP. The NAC+P20 and NAC+P40 groups showed a reduced area of necrosis, MMP-9 activity, and Casp-1 expression. Furthermore, the NAC+P20 group was the only treatment that reduced alanine aminotransferase (ALT) and increased the levels of sulfhydryl groups (-SH). In the NAC+P40 group, NLRP-3 expression was reduced. Aspartate aminotransferase (AST), thiobarbituric acid-reactive substances (TBARS), and IL-1β expression decreased in the NAC, NAC+P20, and NAC+P40 groups compared to the APAP group. The liver necrosis area, TNF levels, carbonylated protein, and IL-18 expression decreased in the P40, NAC, NAC+P20, and NAC+P40 groups compared to the APAP group. The cytokine IL-6 was reduced in all treatments. Piperine can be used in combination with NAC to treat APAP-induced hepatotoxicity.}, }
@article {pmid36144576, year = {2022}, author = {Shi, Z and Zhao, Y and Liu, S and Wang, Y and Yu, Q}, title = {Size-Dependent Impact of Magnetic Nanoparticles on Growth and Sporulation of Aspergillus niger.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {18}, pages = {}, pmid = {36144576}, issn = {1420-3049}, support = {3217010793//National Natural Science Foundation of China/ ; TSBICIP-KJGG-006//Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project/ ; 2021BEG02002//Natural Foundation of Ningxia Hui Nationality Autonomous Region/ ; }, mesh = {Acetylcysteine ; Aspergillus niger ; Chitin ; DNA ; Iron ; *Magnetite Nanoparticles ; Reactive Oxygen Species ; }, abstract = {Magnetic nanoparticles (MNPs) are becoming important DNA nanocarriers for genetic engineering of industrial fungi. However, the biological effect of MNPs on industrial fungi remains unknown. In this study, we prepared three kinds of magnetic nanoparticles with different sizes (i.e., 10 nm, 20 nm, and 200 nm) to investigate their impact on the growth and sporulation of the important industrial fungus Aspergillus niger. Transmission electron microscopy, X-ray diffraction analysis and Zeta potential analysis revealed that the three kinds of MNPs, including MNP10, MNP20 and MNP200, had uniform size distribution, regular Fe3O4 X-ray diffraction (XRD) patterns and similar Zeta potentials. Interestingly, although the three kinds of MNPs did not obviously inhibit growth of the fungus, the MNP20 at 500 mg/L strongly attenuated sporulation, leading to a remarkable decrease in spore numbers on culturing plates. Further investigation showed that MNP20 at the high concentration led to drastic chitin accumulation in the cell wall, indicating cell wall disruption of the MNP20-treated fungal cells. Moreover, the MNPs did not cause unusual iron dissolution and reactive oxygen species (ROS) accumulation, and the addition of ferrous ion, ferric ion or the reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) had no impact on the sporulation of the fungus, suggesting that both iron dissolution and ROS accumulation did not contribute to attenuated sporulation by MNP20. This study revealed the size-dependent effect of MNPs on fungal sporulation, which was associated with MNP-induced cell wall disruption.}, }
@article {pmid36140239, year = {2022}, author = {Chen, J and Hwang, DW and Chen, YW and Chen, TC and Yadav, NN and Stait-Gardner, T and Price, WS and Zheng, G}, title = {MRI Detection of Hepatic N-Acetylcysteine Uptake in Mice.}, journal = {Biomedicines}, volume = {10}, number = {9}, pages = {}, pmid = {36140239}, issn = {2227-9059}, support = {G2015031594478959//Sigma Xi/ ; MOST 110-2113-M-001-031//MInistry of Science and Technology of the Republic of China (Taiwan)/ ; }, abstract = {This proof-of-concept study looked at the feasibility of using a thiol-water proton exchange (i.e., CEST) MRI contrast to detect in vivo hepatic N-acetylcysteine (NAC) uptake. The feasibility of detecting NAC-induced glutathione (GSH) biosynthesis using CEST MRI was also investigated. The detectability of the GSH amide and NAC thiol CEST effect at B0 = 7 T was determined in phantom experiments and simulations. C57BL/6 mice were injected intravenously (IV) with 50 g L[-1] NAC in PBS (pH 7) during MRI acquisition. The dynamic magnetisation transfer ratio (MTR) and partial Z-spectral data were generated from the acquisition of measurements of the upfield NAC thiol and downfield GSH amide CEST effects in the liver. The [1]H-NMR spectroscopy on aqueous mouse liver extracts, post-NAC-injection, was performed to verify hepatic NAC uptake. The dynamic MTR and partial Z-spectral data revealed a significant attenuation of the mouse liver MR signal when a saturation pulse was applied at -2.7 ppm (i.e., NAC thiol proton resonance) after the IV injection of the NAC solution. The [1]H-NMR data revealed the presence of hepatic NAC, which coincided strongly with the increased upfield MTR in the dynamic CEST data, providing strong evidence that hepatic NAC uptake was detected. However, this MTR enhancement was attributed to a combination of NAC thiol CEST and some other upfield MT-generating mechanism(s) to be identified in future studies. The detection of hepatic GSH via its amide CEST MRI contrast was inconclusive based on the current results.}, }
@article {pmid36139851, year = {2022}, author = {Hsu, YY and Chuang, YT and Yen, CY and Cheng, MY and Chen, CY and Cheng, YB and Chang, HW}, title = {Methanol Extract of Clavularia inflata Exerts Apoptosis and DNA Damage to Oral Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {36139851}, issn = {2076-3921}, support = {MOST 111-2320-B-037-015-MY3; MOST-108-2320-B-110-009-MY3//Ministry of Science and Technology/ ; KMU-DK(A)111008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Antiproliferation effects of Clavularia-derived natural products against cancer cells have been reported on, but most studies have focused on identifying bioactive compounds, lacking a detailed investigation of the molecular mechanism. Crude extracts generally exhibit multiple targeting potentials for anticancer effects, but they have rarely been assessed for methanol extracts of Clavularia inflata (MECI). This investigation aims to evaluate the antiproliferation of MECI and to examine several potential mechanisms between oral cancer and normal cells. A 24 h MTS assay demonstrated that MECI decreased cell viability in several oral cancer cell lines more than in normal cells. N-acetylcysteine (NAC), an oxidative stress inhibitor, recovered these antiproliferation effects. Higher oxidative stress was stimulated by MECI in oral cancer cells than in normal cells, as proven by examining reactive oxygen species and mitochondrial superoxide. This preferential induction of oxidative stress was partly explained by downregulating more cellular antioxidants, such as glutathione, in oral cancer cells than in normal cells. Consequently, the MECI-generated high oxidative stress in oral cancer cells was preferred to trigger more subG1 population, apoptosis expression (annexin V and caspase activation), and DNA damage, reverted by NAC. In conclusion, MECI is a potent marine natural product showing preferential antiproliferation against oral cancer cells.}, }
@article {pmid36139832, year = {2022}, author = {Altomare, AA and Brioschi, M and Eligini, S and Bonomi, A and Zoanni, B and Iezzi, A and Jemos, C and Porro, B and D'Alessandra, Y and Guarino, A and Omodeo Salè, E and Aldini, G and Agostoni, P and Banfi, C}, title = {N-Acetylcysteine Regenerates In Vivo Mercaptoalbumin.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {36139832}, issn = {2076-3921}, support = {Ricerca Corrente 2021, 2764191//Ministero della Salute/ ; }, abstract = {Human serum albumin (HSA) represents the most abundant plasma protein, with relevant antioxidant activity due to the presence of the sulfhydryl group on cysteine at position 34 (Cys34), the latter being one of the major target sites for redox-dependent modifications leading to the formation of mixed disulfide linkages with low molecular weight thiols. Thiolated forms of HSA (Thio-HSA) may be useful as markers of an unbalanced redox state and as a potential therapeutic target. Indeed, we have previously reported that albumin Cys34 can be regenerated in vitro by N-Acetylcysteine (NAC) through a thiol-disulfide breaking mechanism, with a full recovery of the HSA antioxidant and antiplatelet activities. With this case study, we aimed to assess the ability of NAC to regenerate native mercaptoalbumin (HSA-SH) and the plasma antioxidant capacity in subjects with redox unbalance, after oral and intravenous administration. A placebo-controlled crossover study, single-blinded, was performed on six hypertensive subjects, randomized into two groups, on a one-to-one basis with NAC (600 mg/die) or a placebo, orally and intravenously administered. Albumin isoforms, HSA-SH, Thio-HSA, and glutathione levels were evaluated by means of mass spectrometry. The plasma antioxidant activity was assessed by a fluorimetric assay. NAC, orally administered, significantly decreased the Thio-HSA levels in comparison with the pre-treatment conditions (T0), reaching the maximal effect after 60 min (-24.7 ± 8%). The Thio-HSA reduction was accompanied by a concomitant increase in the native HSA-SH levels (+6.4 ± 2%). After intravenous administration of NAC, a significant decrease of the Thio-HSA with respect to the pre-treatment conditions (T0) was observed, with a maximal effect after 30 min (-68.9 ± 10.6%) and remaining significant even after 6 h. Conversely, no effect on the albumin isoforms was detected with either the orally or the intravenously administered placebo treatments. Furthermore, the total antioxidant activity of the plasma significantly increased after NAC infusion with respect to the placebo (p = 0.0089). Interestingly, we did not observe any difference in terms of total glutathione corrected for hemoglobin, ruling out any effect of NAC on the intracellular glutathione and supporting its role as a disulfide-breaking agent. This case study confirms the in vitro experiments and demonstrates for the first time that NAC is able to regenerate mercaptoalbumin in vivo, allowing us to hypothesize that the recovery of Cys34 content can modulate in vivo oxidative stress and, hopefully, have an effect in oxidative-based diseases.}, }
@article {pmid36139457, year = {2022}, author = {Ouyang, J and Xiao, Y and Ren, Q and Huang, J and Zhou, Q and Zhang, S and Li, L and Shi, W and Chen, Z and Wu, L}, title = {7-Ketocholesterol Induces Oxiapoptophagy and Inhibits Osteogenic Differentiation in MC3T3-E1 Cells.}, journal = {Cells}, volume = {11}, number = {18}, pages = {}, pmid = {36139457}, issn = {2073-4409}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Core Binding Factor Alpha 1 Subunit ; Ketocholesterols/pharmacology ; *Osteogenesis ; *Oxysterols/pharmacology ; Superoxide Dismutase ; }, abstract = {7-Ketocholesterol (7KC) is one of the oxysterols produced by the auto-oxidation of cholesterol during the dysregulation of cholesterol metabolism which has been implicated in the pathological development of osteoporosis (OP). Oxiapoptophagy involving oxidative stress, autophagy, and apoptosis can be induced by 7KC. However, whether 7KC produces negative effects on MC3T3-E1 cells by stimulating oxiapoptophagy is still unclear. In the current study, 7KC was found to significantly decrease the cell viability of MC3T3-E1 cells in a concentration-dependent manner. In addition, 7KC decreased ALP staining and mineralization and down-regulated the protein expression of OPN and RUNX2, inhibiting osteogenic differentiation. 7KC significantly stimulated oxidation and induced autophagy and apoptosis in the cultured MC3T3-E1 cells. Pretreatment with the anti-oxidant acetylcysteine (NAC) could effectively decrease NOX4 and MDA production, enhance SOD activity, ameliorate the expression of autophagy-related factors, decrease apoptotic protein expression, and increase ALP, OPN, and RUNX2 expression, compromising 7KC-induced oxiapoptophagy and osteogenic differentiation inhibition in MC3T3-E1 cells. In summary, 7KC may induce oxiapoptophagy and inhibit osteogenic differentiation in the pathological development of OP.}, }
@article {pmid36139298, year = {2022}, author = {Yang, P and Chen, X and Tian, X and Zhou, Z and Zhang, Y and Tang, W and Fu, K and Zhao, J and Ruan, Y}, title = {A Proteomic Study of the Effect of N-acetylcysteine on the Regulation of Early Pregnancy in Goats.}, journal = {Animals : an open access journal from MDPI}, volume = {12}, number = {18}, pages = {}, pmid = {36139298}, issn = {2076-2615}, support = {2021YFD1200403//National Key Research &amp; Development plan/ ; 32060753//National Natural Science Foundation of China/ ; Qian Kehe foundation-ZK [2021] General 151//Science and Technology Project of Guizhou Province/ ; Qian Kehe platform talents [2022]021-1//Guizhou high level Innovative Talents Project/ ; }, abstract = {Dietary supplementation with N-acetyl-L-cysteine (NAC) may support early pregnancy regulation and fertility in female animals. The purpose of this study was to investigate the effect of supplementation with 0.07% NAC on the expression of the uterine keratin gene and protein in Qianbei-pockmarked goats during early pregnancy using tandem mass spectrometry (TMT) relative quantitative proteomics. The results showed that there were significant differences in uterine keratin expression between the experimental group (NAC group) and the control group on day 35 of gestation. A total of 6271 proteins were identified, 6258 of which were quantified by mass spectrometry. There were 125 differentially expressed proteins (DEPs), including 47 upregulated and 78 downregulated proteins, in the NAC group. Bioinformatic analysis showed that these DEPs were mainly involved in the transport and biosynthesis of organic matter and were related to the binding of transition metal ions, DNA and proteins and the catalytic activity of enzymes. They were enriched in the Jak-STAT signalling pathway, RNA monitoring pathway, amino acid biosynthesis, steroid biosynthesis and other pathways that may affect the early pregnancy status of does through different pathways and thus influence early embryonic development. Immunohistochemistry, real-time quantitative PCR and Western blotting were used to verify the expression and localization of glial fibrillary acidic protein (GFAP) and pelota mRNA surveillance and ribosomal rescue factor (PELO) in uterine horn tissue. The results showed that both PELO and GFAP were localized to endometrial and stromal cells, consistent with the mass spectrometry data at the transcriptional and translational levels. Moreover, NAC supplementation increased the levels of the reproductive hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol (E2), progesterone (P4), superoxide dismutase (SOD), glutamate peroxidase (GSH-Px) and nitric oxide (NO) in the serum of does. These findings provide new insight into the mechanism by which NAC regulates early pregnancy and embryonic development in goats.}, }
@article {pmid36139290, year = {2022}, author = {Fu, K and Chen, X and Guo, W and Zhou, Z and Zhang, Y and Ji, T and Yang, P and Tian, X and Wang, W and Zou, Y}, title = {Effects of N Acetylcysteine on the Expression of Genes Associated with Reproductive Performance in the Goat Uterus during Early Gestation.}, journal = {Animals : an open access journal from MDPI}, volume = {12}, number = {18}, pages = {}, pmid = {36139290}, issn = {2076-2615}, support = {2021YFD1200403//the National Key Research and Development plan of China/ ; 32060753//the National Natural Science Foundation of China/ ; Qian Kehe foundation-ZK [2021] General 151//the Science and Technology Project of Guizhou Province/ ; Qian Kehe Platform Talents [2022]021-1//the Guizhou High Level Innovative Talents Project/ ; Qian Jiaohe YJSKYJJ [2021]011//the Guizhou Provincial Education Department Postgraduate Research Fund/ ; }, abstract = {N acetylcysteine (NAC) affects antioxidation and reactive oxygen species scavenging in the body and thereby promotes embryonic development and implantation and inhibits inflammation. The mechanism through which NAC regulates reproductive performance in the uteri of goats during early gestation remains unclear. In this study, the treatment group was fed 0.07% NAC for the first 35 days of gestation, whereas the control group received no NAC supplementation. The regulatory genes and key pathways associated with goat reproductive performance under NAC supplementation were identified by RNA-seq. RT-qPCR was used to verify the sequencing results and subsequently construct tissue expression profiles of the relevant genes. RNA-seq identified 19,796 genes coexpressed in the control and treatment groups and 1318 differentially expressed genes (DEGs), including 787 and 531 DEGs enriched in the treatment and control groups, respectively. A GO analysis revealed that the identified genes mapped to pathways such as cell activation, cytokine production, cell mitotic processes, and angiogenesis, and a KEGG enrichment analysis showed that the DEGs were enriched in pathways associated with reproductive regulation, immune regulation, resistance to oxidative stress, and cell adhesion. The RT-qPCR analysis showed that BDNF and CSF-1 were most highly expressed in the uterus, that WIF1 and ESR2 showed low expression in the uterus, and that CTSS, PTX3, and TGFβ-3 were most highly expressed in the oviduct, which indicated that these genes may be directly or indirectly involved in the modulation of reproduction in early-gestation goats. These findings provide fundamental data for the NAC-mediated modulation of the reproductive performance of goats during early gestation.}, }
@article {pmid36139036, year = {2022}, author = {Bao, M and Hua, X and Mo, H and Sun, Z and Xu, B and Chen, X and Xu, M and Xu, X and Song, J}, title = {N-Acetylcysteine, an ROS Inhibitor, Alleviates the Pathophysiology of Hyperthyroidism-Induced Cardiomyopathy via the ROS/Ca[2+] Pathway.}, journal = {Biomolecules}, volume = {12}, number = {9}, pages = {}, pmid = {36139036}, issn = {2218-273X}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Calpain/pharmacology ; *Cardiomyopathies/drug therapy/etiology ; Caspase 3 ; Fibrosis ; Humans ; *Hyperthyroidism/complications/drug therapy ; NF-kappa B/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species/metabolism ; }, abstract = {Hyperthyroidism is common and can induce cardiomyopathy, but there is no effective therapeutic strategy. The purpose of this study was to investigate the molecular mechanism of hyperthyroidism-induced cardiomyopathy (HTC) and the effect of N-acetylcysteine (NAC), an ROS inhibitor, on the pathophysiology of HTC in vivo and in vitro. Compared with those in the control groups in vivo and in vitro, TT3 and TT4 were significantly increased, the structure of myocardial cells was enlarged and disordered, and interstitial fibrosis and the apoptosis of myocardial cells were markedly increased in the L-Thy group. The ROS and inflammatory response were increased in the hyperthyroidism group. In the NAC group, the contents of TT3 and TT4 were decreased, the myocardial cell structure was slightly disturbed, fibrosis and apoptosis were significantly reduced, and the ROS level and inflammatory response were significantly reduced. Interestingly, L-Thy decreased the viability of fibroblasts and H9c2 cells, suggesting that L-Thy-induced fibrosis was not caused by the proliferation of fibroblasts. The molecular mechanism of HTC could be explained by the fact that L-Thy could cause cardiac hypertrophy, inflammation, and fibrosis by regulating the Ca[2+]/calpain/Rcan1-dependent signalling pathway, the Ca[2+]/Rcan1/NF-κB/p65-dependent signalling pathway, and the Ca[2+]/ROS/Bcl-2/caspase-3-dependent signalling pathway. In conclusion, NAC can alleviate the pathophysiology of hyperthyroidism-induced cardiomyopathy, probably by regulating the ROS/Ca[2+]-dependent pathway.}, }
@article {pmid36138415, year = {2022}, author = {Abdulrab, S and Mostafa, N and Al-Maweri, SA and Abada, H and Halboub, E and Alhadainy, HA}, title = {Correction: Antibacterial and anti-inflammatory efficacy of N-acetyl cysteine in endodontic treatment: a scoping review.}, journal = {BMC oral health}, volume = {22}, number = {1}, pages = {419}, doi = {10.1186/s12903-022-02458-x}, pmid = {36138415}, issn = {1472-6831}, }
@article {pmid36130098, year = {2023}, author = {Hameed, MQ and Hodgson, N and Lee, HHC and Pascual-Leone, A and MacMullin, PC and Jannati, A and Dhamne, SC and Hensch, TK and Rotenberg, A}, title = {N-acetylcysteine treatment mitigates loss of cortical parvalbumin-positive interneuron and perineuronal net integrity resulting from persistent oxidative stress in a rat TBI model.}, journal = {Cerebral cortex (New York, N.Y. : 1991)}, volume = {33}, number = {7}, pages = {4070-4084}, pmid = {36130098}, issn = {1460-2199}, support = {P50 HD105351/HD/NICHD NIH HHS/United States ; R01 NS088583/NS/NINDS NIH HHS/United States ; }, mesh = {Rats ; Animals ; *Acetylcysteine/pharmacology/metabolism ; Parvalbumins/metabolism ; *Brain Injuries, Traumatic/metabolism ; Oxidative Stress/physiology ; Interneurons/metabolism ; }, abstract = {Traumatic brain injury (TBI) increases cerebral reactive oxygen species production, which leads to continuing secondary neuronal injury after the initial insult. Cortical parvalbumin-positive interneurons (PVIs; neurons responsible for maintaining cortical inhibitory tone) are particularly vulnerable to oxidative stress and are thus disproportionately affected by TBI. Systemic N-acetylcysteine (NAC) treatment may restore cerebral glutathione equilibrium, thus preventing post-traumatic cortical PVI loss. We therefore tested whether weeks-long post-traumatic NAC treatment mitigates cortical oxidative stress, and whether such treatment preserves PVI counts and related markers of PVI integrity and prevents pathologic electroencephalographic (EEG) changes, 3 and 6 weeks after fluid percussion injury in rats. We find that moderate TBI results in persistent oxidative stress for at least 6 weeks after injury and leads to the loss of PVIs and the perineuronal net (PNN) that surrounds them as well as of per-cell parvalbumin expression. Prolonged post-TBI NAC treatment normalizes the cortical redox state, mitigates PVI and PNN loss, and - in surviving PVIs - increases per-cell parvalbumin expression. NAC treatment also preserves normal spectral EEG measures after TBI. We cautiously conclude that weeks-long NAC treatment after TBI may be a practical and well-tolerated treatment strategy to preserve cortical inhibitory tone post-TBI.}, }
@article {pmid36129244, year = {2022}, author = {Tan, JL and Stam, J and van den Berg, AP and van Rheenen, PF and Dekkers, BGJ and Touw, DJ}, title = {Amanitin intoxication: effects of therapies on clinical outcomes - a review of 40 years of reported cases.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {11}, pages = {1251-1265}, doi = {10.1080/15563650.2022.2098139}, pmid = {36129244}, issn = {1556-9519}, mesh = {Humans ; *Amanitins ; *Mushroom Poisoning/drug therapy/complications ; Amanita ; Alanine Transaminase ; Acetylcysteine/therapeutic use ; Silybin/therapeutic use ; Penicillin G/therapeutic use ; }, abstract = {BACKGROUND AND AIMS: Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed a systematic review to investigate the effect of the most commonly used therapies: N-acetylcysteine (NAC), benzylpenicillin (PEN), and silibinin (SIL) on patient outcomes. In addition, other factors contributing to patient outcomes are identified.<br><br>METHODS: We searched MEDLINE and Embase for case series and case reports that described patient outcomes after poisoning with amanitin-containing Amanita mushrooms. We extracted clinical characteristics, treatment details, and outcomes. We used the liver item from the Poisoning Severity Score (PSS) to categorize intoxication severity.<br><br>RESULTS: We included 131 publications describing a total of 877 unique cases. The overall survival rate of all patients was 84%. Patients receiving only supportive care had a survival rate of 59%. The use of SIL or PEN was associated with a 90% (OR 6.40 [3.14-13.04]) and 89% (OR 5.24 [2.87-9.56]) survival rate, respectively. NAC/SIL combination therapy was associated with 85% survival rate (OR 3.85 [2.04, 7.25]). NAC/PEN/SIL treatment group had a survival rate of 76% (OR 2.11 [1.25, 3.57]). Due to the limited number of cases, the use of NAC alone could not be evaluated. Additional analyses in 'proven cases' (amanitin detected), 'probable cases' (mushroom identified by mycologist), and 'possible cases' (neither amanitin detected nor mushroom identified) showed comparable results, but the results did not reach statistical significance. Transplantation-free survivors had significantly lower peak values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), and international normalized ratio (INR) compared to liver transplantation survivors and patients with fatal outcomes. Higher peak PSS was associated with increased mortality.<br><br>CONCLUSION: Based on data available, no statistical differences could be observed for the effects of NAC, PEN or SIL in proven poisonings with amanitin-containing mushrooms. However, monotherapy with SIL or PEN and combination therapy with NAC/SIL appear to be associated with higher survival rates compared to supportive care alone. AST, ALT, TSB, and INR values are possible predictors of potentially fatal outcomes.}, }
@article {pmid36121248, year = {2022}, author = {Su, Y and Yin, X and Huang, X and Guo, Q and Ma, M and Guo, L}, title = {The BCL2/BAX/ROS pathway is involved in the inhibitory effect of astragaloside IV on pyroptosis in human umbilical vein endothelial cells.}, journal = {Pharmaceutical biology}, volume = {60}, number = {1}, pages = {1812-1818}, pmid = {36121248}, issn = {1744-5116}, mesh = {Acetylcysteine/pharmacology ; Caspase 1/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Lipopolysaccharides/pharmacology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; *Pyroptosis ; Reactive Oxygen Species/metabolism ; Saponins ; Triterpenes ; bcl-2-Associated X Protein ; }, abstract = {CONTEXT: Astragaloside IV (AS-IV) is extracted from Astragalus membranaceus (Fisch.) Bunge (Fabaceae). However, its effects on endothelial cell injury remain unclear.<br><br>OBJECTIVE: To investigate the mechanisms underlying the effects of AS-IV on lipopolysaccharide (LPS)-induced endothelial injury in&#xa0;vitro.<br><br>MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were pre-treated with AS-IV (100&#xa0;&#xb5;mol/mL), 4-hydroxy-3-methoxyacetophenone (APO, 10&#xa0;&#xb5;mol/mL), N-acetylcysteine (NAC, 50&#xa0;&#xb5;mol/mL) and Ac-YVAD-cmk (AC, 5&#xa0;&#xb5;mol/mL) for 2&#x2009;h before 1&#x2009;&#x3bc;g/mL LPS 24&#x2009;h exposure. Untreated cells cultured without any exposure were used as controls. Cell viability, reactive oxygen species (ROS) and pyroptosis assays were performed. The pyroptosis related proteins were detected by western blot.<br><br>RESULTS: The rate in late pyroptosis (Q2-2) of AS-IV (13.65&#x2009;&#xb1;&#x2009;0.74%), APO (13.69&#x2009;&#xb1;&#x2009;0.67%) and NAC (15.87&#x2009;&#xb1;&#x2009;0.46%) groups was lower than the LPS group (21.89&#x2009;&#xb1;&#x2009;0.66%, p&#x2009;<&#x2009;0.05), while the rate in early pyroptosis (Q2-4) of AS-IV group (12.00&#x2009;&#xb1;&#x2009;0.26%) was lower than other groups (p&#x2009;<&#x2009;0.05). The expression of NOX4, GSDMD, NLRP3, ASC and caspase-1 decreased after AS-IV, NAC or AC intervention (p&#x2009;<&#x2009;0.05). The ROS production in AS-IV (4664&#x2009;&#xb1;&#x2009;153.20), APO (4094&#x2009;&#xb1;&#x2009;78.37), NAC (5103&#x2009;&#xb1;&#x2009;131.10) and AC (3994&#x2009;&#xb1;&#x2009;102.50) groups was lower than the LPS (5986&#x2009;&#xb1;&#x2009;127.30) group, while the mitochondrial BCL2/BAX protein expression ratio increased in AS-IV, APO and NAC groups (p&#x2009;<&#x2009;0.05).<br><br>DISCUSSION AND CONCLUSIONS: AS-IV suppressed pyroptosis in LPS-activated HUVECs by inducing ROS/NLRP3-mediated inhibition of the inflammatory response, providing a scientific basis for clinical applications of AS-IV.}, }
@article {pmid36116068, year = {2022}, author = {Anraku, T}, title = {Anoxia/reoxygenation enhances spontaneous contractile activity via TRPA1 channel and COX2 activation in isolated rat whole bladder.}, journal = {Neurourology and urodynamics}, volume = {41}, number = {8}, pages = {1692-1702}, doi = {10.1002/nau.25045}, pmid = {36116068}, issn = {1520-6777}, mesh = {Rats ; Animals ; TRPA1 Cation Channel ; *Urinary Bladder ; Cyclooxygenase 2 ; *Urinary Bladder Diseases ; Hypoxia/complications ; Ischemia ; }, abstract = {PURPOSE: Bladder ischemia/reperfusion is an important etiologic factor for overactive bladder disease. The occurrence of this disease is closely associated with enhanced spontaneous contractile activity of the bladder. However, the relationship between bladder ischemia/reperfusion and altered spontaneous bladder contractions (SBC) remains poorly studied. Therefore, the present study investigated whether ischemia/reperfusion affects SBC ex vivo.<br><br>METHODS: SBC was measured using isolated whole bladder preparations from rats. The preparations were exposed to anoxia (95% N2) for 0.5-6&#x2009;h, followed by reoxygenation (95% O2) in Krebs medium.<br><br>RESULTS: Anoxia followed by reoxygenation significantly enhanced the amplitude of SBC without affecting its frequency in an anoxic duration-dependent manner. The 5&#x2009;h anoxia/reoxygenation-induced enhancement of SBC amplitude was completely suppressed by an antioxidant combination of L(+)-ascorbate/D, L-&#x3b1;-tocopherol, or N-acetyl cysteine. Additionally, the enhanced SBC amplitude was inhibited in a concentration-dependent manner by the nonselective TRP antagonist ruthenium red, or selective TRPA1 antagonists HC-030031 or AP-18. A similar inhibitory effect was obtained after repeated treatment with the TRPA1 agonist allyl isothiocyanate, as it induced acute desensitization of TRPA1 channels. Further, the enhanced SBC amplitude was significantly diminished by the nonselective cyclooxygenase (COX) inhibitor indomethacin or selective COX2 inhibitor NS-398, but not by the selective COX1 inhibitor SC-560 and 5-lipoxygenase inhibitor MK-886.<br><br>CONCLUSIONS: The study findings reveal that the spontaneous contractile activity of the bladder is significantly enhanced in response to anoxia/reoxygenation, and that oxidative stress and activation of TRPA1 and COX2 (the resulting production of prostaglandins) are involved in the enhanced SBC activity.}, }
@article {pmid36115584, year = {2022}, author = {Hussain, Y and Singh, J and Raza, W and Meena, A and Rajak, S and Sinha, RA and Luqman, S}, title = {Purpurin ameliorates alcohol-induced hepatotoxicity by reducing ROS generation and promoting Nrf2 expression.}, journal = {Life sciences}, volume = {309}, number = {}, pages = {120964}, doi = {10.1016/j.lfs.2022.120964}, pmid = {36115584}, issn = {1879-0631}, mesh = {Animals ; Mice ; Alanine Transaminase/metabolism ; *Anthraquinones/pharmacology ; Antioxidants/pharmacology ; Aspartate Aminotransferases/metabolism ; Buthionine Sulfoximine/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control ; Cysteine/pharmacology ; Cytochrome P-450 CYP2E1/metabolism ; *Ethanol/toxicity ; Glutathione/metabolism ; Ligands ; *NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {INTRODUCTION AND AIM: Purpurin, a naturally occurring anthraquinone isolated from the roots of Rubia cordifolia, exhibits anti-cancer, anti-genotoxic, anti-microbial, neuromodulatory and photodynamic activity. However, purpurin's in vivo and in vitro antioxidant mechanism remains unexplored. The present study explores the anti-oxidative mechanism of purpurin under the influence of alcohol using in vivo and in vitro test systems.<br><br>METHODS: Mice hepatocytes and alcohol-induced liver toxicity model were used to evaluate the effect of purpurin. The non-enzymatic and enzymatic oxidative stress markers were estimated by the colorimetric method. The reactive oxygen species (ROS) were quantified in mitochondria and cells using flow cytometer. Real-time PCR and western blotting were used to quantify cytochrome 450 subtype 2E1 (CYP2E1) and Nrf2 expression in the liver tissue of mice. In silico studies were performed through receptor-ligand binding interaction.<br><br>KEY FINDINGS: Purpurin effectively reduced total cellular and mitochondrial ROS in primary hepatocytes and WRL-68 cells. It prevented alcohol-induced ROS-dependent biochemical and cellular insults observed by analysing the serum glutamic pyruvic transaminase (SGPT), glutamic-oxaloacetic transaminase (SGOT) levels and CYP2E1 expression in liver tissue of alcohol-administered mice. Moreover, it also restored the activity of antioxidant enzymes. Its antioxidant effect was established by glutathione and ROS-dependent mechanisms using buthionine sulfoximine and N-acetyl cysteine. Along with alcohol, purpurin up-regulated Nrf2 expression in hepatocytes.<br><br>SIGNIFICANCE: This work confirmed the ameliorative effect of purpurin for alcohol-induced hepatotoxicity by drabbing free radicals and curbing oxidative stress via activation of antioxidant signalling pathways.}, }
@article {pmid38647894, year = {2022}, author = {Li, N and Zeng, Y and Chen, Y and Shen, Y and Wang, W}, title = {Induction of cellulase production by Sr[2+] in Trichoderma reesei via calcium signaling transduction.}, journal = {Bioresources and bioprocessing}, volume = {9}, number = {1}, pages = {96}, pmid = {38647894}, issn = {2197-4365}, support = {2021-02-08-00-12-F00758//Shanghai Agriculture Applied Technology Development Program, China/ ; 22ZR1417600//Natural Science Foundation of Shanghai/ ; 32000050//National Natural Science Foundation of China/ ; }, abstract = {Trichoderma reesei RUT-C30 is a well-known high-yielding cellulase-producing fungal strain that converts lignocellulose into cellulosic sugar for resource regeneration. Calcium is a ubiquitous secondary messenger that regulates growth and cellulase production in T. reesei. We serendipitously found that adding Sr[2+] to the medium significantly increased cellulase activity in the T. reesei RUT-C30 strain and upregulated the expression of cellulase-related genes. Further studies showed that Sr[2+] supplementation increased the cytosolic calcium concentration and activated the calcium-responsive signal transduction pathway of Ca[2+]-calcineurin-responsive zinc finger transcription factor 1 (CRZ1). Using the plasma membrane Ca[2+] channel blocker, LaCl3, we demonstrated that Sr[2+] induces cellulase production via the calcium signaling pathway. Supplementation with the corresponding concentrations of Sr[2+] also inhibited colony growth. Sr[2+] supplementation led to an increase in intracellular reactive oxygen species (ROS) and upregulated the transcriptional levels of intracellular superoxide dismutase (sod1) and catalase (cat1). We further demonstrated that ROS content was detrimental to cellulase production, which was alleviated by the ROS scavenger N-acetyl cysteine (NAC). This study demonstrated for the first time that Sr[2+] supplementation stimulates cellulase production and upregulates cellulase genes via the calcium signaling transduction pathway. Sr[2+] leads to an increase in intracellular ROS, which is detrimental to cellulase production and can be alleviated by the ROS scavenger NAC. Our results provide insights into the mechanistic study of cellulase synthesis and the discovery of novel inducers of cellulase.}, }
@article {pmid37256553, year = {2022}, author = {Li, Y and Li, M and Ahmed, K and Yang, J and Song, L and Cui, ZG and Hiraku, Y}, title = {Mechanistic Study of Macranthoside B Effects on Apoptotic Cell Death in Human Cervical Adenocarcinoma Cells.}, journal = {Folia biologica}, volume = {68}, number = {5-6}, pages = {189-200}, pmid = {37256553}, issn = {0015-5500}, mesh = {Humans ; Caspase 3/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; HeLa Cells ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism ; Apoptosis ; *Saponins/pharmacology ; *Adenocarcinoma ; Membrane Potential, Mitochondrial ; CCAAT-Enhancer-Binding Proteins/metabolism/pharmacology ; Ubiquitin-Protein Ligases/metabolism/pharmacology ; }, abstract = {Macranthoside B (MB) is a triterpenoid saponin extracted from Lonicera macranthoides, a traditional Chinese medicine. In the current study, we investigated the anticancer potential of MB in various cancer cells and elucidated its underlying mechanisms. MB exposure inhibited cell proliferation, induced mitochondrial membrane potential (MMP) loss, increased sub-G1 accumulation, and resulted in cleavage of caspase-3 and PARP, which are reflective of apoptosis. In HeLa cells, MB induced down-regulation of SOD2 and GPx1, phosphorylation of Akt and PDK1, and thus promoted ROS-mediated apoptosis. This was further supported by the protection of sub-G1 accumulation, MMP loss, cleavage of caspase-3 and PARP in the presence of N-acetylcysteine (NAC). Additionally, MB induced cell death via down-regulation of ubiquitin-like with PHD and ringfinger domains 1 (UHRF1) and Bcl-xL. Taken together, this study provides a new insight into the apoptosis- inducing potential of MB, and its molecular mechanisms are associated with an increase in oxidative stress and inhibition of the PDK1/Akt pathway.}, }
@article {pmid36457967, year = {2022}, author = {Chang, PH and Liu, CW and Hung, SH and Kang, YN}, title = {Effect of N-acetyl-cysteine in prevention of noise-induced hearing loss: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Archives of medical science : AMS}, volume = {18}, number = {6}, pages = {1535-1541}, pmid = {36457967}, issn = {1734-1922}, abstract = {INTRODUCTION: Noise-induced hearing loss is one of the most prevalent causes of hearing impairment and occupational diseases. Although multiple factors lead to noise-induced hearing loss, prevention and protection strategies remain limited. Studies in the past decade have employed antioxidants, especially N-acetyl-cysteine, to prevent noise-induced hearing loss. Therefore, this systematic review and meta-analysis of randomized controlled trials evaluated the effect of N-acetyl-cysteine on the prevention of noise-induced hearing loss.<br><br>MATERIAL AND METHODS: This systematic review and meta-analysis included relevant studies from the Cochrane Library, EMBASE, PubMed, ScienceDirect, Scopus, and Web of Science by using related terms. The study only included randomized controlled trials in meta-analyses and assessed the quality of the identified randomized controlled trials by using the Cochrane Risk of Bias tool. Two authors extracted and calculated data on characteristics and hearing threshold. The results are presented as weighted mean difference (WMD) with 95% confidence interval (CI).<br><br>RESULTS: This study identified five randomized controlled trials that randomized 1,115 patients into N-acetyl-cysteine and control groups. The meta-analysis evidenced that N-acetyl-cysteine has greater protective effects against hearing threshold shifts than the control in the 0 to 4 kHz (WMD = -3.39, 95% CI: -6.56 to -0.22) and 0 to 6 kHz (MD = -3.49, 95% CI: -6.57 to -0.41) subgroups.<br><br>CONCLUSIONS: The present review and meta-analysis recommends that N-acetyl-cysteine may be considered as an option for protective therapy for noise-induced hearing loss. Nonetheless, larger randomized controlled trials are requisite for further investigation and verification.}, }
@article {pmid36704111, year = {2020}, author = {Abu Hasna, A and Khoury, RD and Toia, CC and Gonçalves, GB and de Andrade, FB and Talge Carvalho, CA and Ribeiro Camargo, CH and Carneiro Valera, M}, title = {In vitro Evaluation of the Antimicrobial Effect of N-acetylcysteine and Photodynamic Therapy on Root Canals Infected with Enterococcus faecalis.}, journal = {Iranian endodontic journal}, volume = {15}, number = {4}, pages = {236-245}, pmid = {36704111}, issn = {2008-2746}, abstract = {INTRODUCTION: This study aimed to evaluate the in vitro effectiveness of N-acetylcysteine (NAC), photodynamic therapy (PDT) and NAC with supplemental PDT in optimizing the removal of bacteria from infected dentinal tubules of root canals infected with Enterococcus (E.) faecalis biofilm.<br><br>METHODS AND MATERIALS: Eighty human teeth were randomly divided into 5 groups (n=16) according to the intracanal medication used: saline solution (control); calcium hydroxide (CH); NAC; PDT; NAC+PDT. Ten samples from each group were prepared for microbiological culture analysis (CFU/mL) and were inoculated with E. faecalis suspension for 21 days for biofilm development; the other six samples from each group were prepared for scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) and submitted to a 5-days contamination protocol including eight centrifugation cycles on every other day for dentinal tubules infection. For antimicrobial activity analysis by microbiological culture (CFU/mL), the root canals were contaminated with E. faecalis biofilm, instrumented and then medicated according to the experimental groups. Three samples were collected from the root canals: after 21-days of contamination, immediately after the instrumentation and 14-days after the medication according to the experimental groups. The morphology of E. faecalis biofilm on the root canal walls and bacterial cells viability were assessed by means of SEM and CLSM, respectively. One-way ANOVA and Repeated Measures ANOVA tests were used to analyze the obtained data statistically.<br><br>RESULTS: CFU/mL analysis showed that CH, NAC and NAC+PDT promoted greater antibacterial activity with statistically significant difference compared to saline solution and PDT (P<0.0001). However, saline solution and PDT were statistically similar (P>0.07). Illustrative images by SEM confirmed partially the CFU/mL results. CLSM showed that all groups were effective eliminating E. faecalis except for the saline solution group.<br><br>CONCLUSIONS: Based on this in vitro study NAC was bactericidal against E. faecalis biofilms regardless PDT stimulation, presenting similar antimicrobial activity to CH.}, }
@article {pmid36879587, year = {2019}, author = {Rastegar Khosravi, M and Khonsha, M and Ramazanzadeh, R}, title = {Combined Effect of Levofloxacin and N-Acetylcysteine against Enterococcus faecalis Biofilm for Regenerative Endodontics: An in Vitro Study.}, journal = {Iranian endodontic journal}, volume = {14}, number = {1}, pages = {40-46}, pmid = {36879587}, issn = {2008-2746}, abstract = {INTRODUCTION: Endodontic treatment of necrotic immature teeth poses several clinical challenges. A major problem is the elimination of microorganisms from the root canal system. This study evaluates the in vitro antibacterial efficacy of ciprofloxacin (CIP), levofloxacin (LEV), and their combination with N-acetylcysteine (NAC) in root canals infected with Enterococcus faecalis (E. faecalis).<br><br>METHODS AND MATERIALS: A total of 120 human extracted teeth with single canals were prepared and randomly divided into six groups: Calcium hydroxide (CH), ciprofloxacin (CIP), levofloxacin (LEV), ciprofloxacin and N-acetylcysteine (CIP+NAC), levofloxacin and N-acetylcysteine (LEV+NAC), and normal saline as a positive control. According to the name of the groups, intracanal medicaments were placed into the canals and the teeth were restored with a temporary filling. After one week, intracanal medicament was removed and the final count of bacteria was measured. Antibacterial effect of medicament was assessed by measuring the percentage reduction in the colony counts (RCC) and scanning electron microscopy (SEM). The Mann-Whitney U test and the Kruskal-Wallis test were used to compare the overall antibacterial efficacy of the intracanal medicaments at significance level of 0.05.<br><br>RESULTS: All intracanal medicaments were significantly more effective than calcium hydroxide (P<0.05). The combination of LEV and NAC caused significantly higher reduction in colony count in comparison with other tested medicaments (P=0.001).<br><br>CONCLUSION: The combination of LEV and NAC showed greater antibacterial activity compared with other tested medicaments against biofilm of E. faecalis. Thus, it has the potential to be used in regenerative endodontic treatments.}, }
@article {pmid36115150, year = {2022}, author = {He, YM and Shen, XL and Guo, YN and Liang, SS and Ding, KN and Lu, MH and Tang, LP}, title = {Yinhuang oral liquid protects acetaminophen-induced acute liver injury by regulating the activation of autophagy and Nrf2 signaling.}, journal = {Ecotoxicology and environmental safety}, volume = {244}, number = {}, pages = {114073}, doi = {10.1016/j.ecoenv.2022.114073}, pmid = {36115150}, issn = {1090-2414}, mesh = {Acetaminophen/metabolism/toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/metabolism ; Animals ; Antioxidants/metabolism ; Aspartate Aminotransferases/metabolism ; Autophagy ; Autophagy-Related Protein-1 Homolog/metabolism ; Beclin-1/metabolism ; *Chemical and Drug Induced Liver Injury/etiology/metabolism/prevention &amp; control ; *Chemical and Drug Induced Liver Injury, Chronic/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Liver ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress ; RNA, Messenger/metabolism ; Signal Transduction ; Superoxide Dismutase/metabolism ; TOR Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {This study aimed to investigate the protective effect and potential mechanism of Yinhuang oral liquid (YOL) against acetaminophen (APAP) induced liver injury in mice. C57BL/6 mice were randomly divided into control group, model group (300 mg/kg APAP), NAC group and YOL group. Mice were treated intragastrical with YOL (8 g/kg) and N-Acetylcysteine (NAC, 300 mg/kg) 6 h before and 6 h after the APAP (300 mg/kg) intraperitoneal injection. 12 h after APAP exposure, blood and liver samples were collected for subsequent testing. The results showed that APAP decreased liver index, induced liver pathological injury with hepatocytes swelling, necrosis and apoptosis and inflammatory cell infiltration. APAP exposure significantly increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels to 35 and 6 multiples than their original levels. YOL alleviated liver pathological damage, decreased the serum levels of ALT and AST in APAP exposure mice, and it worked better than NAC. Moreover, APAP promoted oxidative stress by increasing lipid peroxidation (MDA) and decreasing anti-oxidant enzyme activities of SOD and GSH, inhibited the mRNA levels of Nrf2, HO-1, Gclc and Gclm, and decreased the protein levels of Nrf2, HO-1 and Keap1, compared to control group. Furthermore, APAP exposure significantly down-regulated the mRNA and protein levels of autophagy related genes (Beclin-1, LC3-II, LC3-I, Atg4B, Atg5, Atg16L1 and Atg7). However, the gene levels of mTOR and p-mTOR increased, and p-ULK1 protein level decreased in liver of APAP treated mice. Additionally, YOL alleviated the oxidative injury by up-regulating Nrf2 pathway. The gene and protein levels of autophagy-related genes Beclin-1, LC3-II, LC3-I, Atg4B, Atg5, Atg16L1 and Atg7 reached the basal levels after YOL treatment. In conclusion, YOL had a protective and therapeutic role in APAP-induced liver injury in mice by activating Nrf2 signaling pathway and autophagy.}, }
@article {pmid36115081, year = {2022}, author = {Rana, AK and Sharma, S and Upadhyay, D and Chamoli, P and Prasad, S}, title = {Antibiogram guided optimized medical treatment in chronic otitis media: A useful interventional strategy before surgery?.}, journal = {American journal of otolaryngology}, volume = {43}, number = {6}, pages = {103628}, doi = {10.1016/j.amjoto.2022.103628}, pmid = {36115081}, issn = {1532-818X}, mesh = {Humans ; Child ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Cysteine/therapeutic use ; *Otitis Media/drug therapy/surgery ; *Otitis Media, Suppurative/drug therapy/surgery ; Tympanoplasty ; Ciprofloxacin/therapeutic use ; Microbial Sensitivity Tests ; Chronic Disease ; Treatment Outcome ; Mastoid/surgery ; }, abstract = {BACKGROUND: Chronic otitis media is a middle ear cleft disease presenting with tympanic membrane perforation and discharge. Wet ear after tympanoplasty and discharging mastoid cavity are problematic in clinical practice.<br><br>MATERIAL AND METHODS: 1050 patients of age 10 to 50&#xa0;years presenting with active ear discharge and clinically diagnosed with unilateral chronic suppurative otitis media were included in the study. The patients were equally divided into two equal groups, Group ET, and AT. All patients were prescribed topical ciprofloxacin, oral levocetirizine 5&#xa0;mg and n-acetyl cysteine 600&#xa0;mg BD for one week. Swabs of ear discharge were collected in ET groups for antibiogram. Both groups were evaluated on next visit and treatment changed in AT groups and result observed in next visit. Surgical outcome was evaluated at end of 2&#xa0;yrs.<br><br>RESULT: A total of 1158 organisms were isolated in culture out of which, 69.94&#xa0;% were aerobes, 13.47&#xa0;% anaerobes and 16.58&#xa0;% were fungi. On the second visit in group AT, treatment of 85.14&#xa0;% patients was changed in accordance with culture sensitivity report. In patients with mucosal disease, only 46.87&#xa0;% patients of group ET had a favorable outcome in comparison to 90.28&#xa0;% patients of group AT while in patients with squamosal disease, 17.56&#xa0;% patients of group ET and 28.99&#xa0;% patients in group AT had a dry ear. Surgeries in AT group were found to have statistically significant higher success rate as compared to ET group.}, }
@article {pmid36113554, year = {2022}, author = {Matsumoto, T and Kudo, M and Osada, T and Taguchi, K and Kobayashi, T}, title = {Methylglyoxal impairs ATP- and UTP-induced relaxation in the rat carotid arteries.}, journal = {European journal of pharmacology}, volume = {933}, number = {}, pages = {175259}, doi = {10.1016/j.ejphar.2022.175259}, pmid = {36113554}, issn = {1879-0712}, mesh = {*Acetylcholine/pharmacology ; Acetylcysteine ; Adenosine ; Adenosine Triphosphate/pharmacology ; Animals ; Antioxidants/pharmacology ; Arachidonic Acid ; Arginine ; Carotid Arteries ; Cyclooxygenase Inhibitors ; Indomethacin/pharmacology ; Magnesium Oxide ; Nitric Oxide ; Polyphosphates ; Prostaglandin-Endoperoxide Synthases ; Prostaglandins ; *Pyruvaldehyde/pharmacology ; Rats ; Receptors, Purinergic P2Y ; Sodium ; Uridine ; Uridine Triphosphate/pharmacology ; Vasoconstrictor Agents ; }, abstract = {Although methylglyoxal (MGO), a highly reactive dicarbonyl compound, influences the functioning of the vasculature, modulating its effects on vascular reactivity to various substances remains unclear, especially purinoceptor ligands. Therefore, we sought to investigate the direct effects of MGO on relaxation induced by adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) in isolated rat carotid arteries. When carotid arteries were exposed to MGO (420 μM for 1 h), relaxation induced by acetylcholine or sodium nitroprusside was not affected by MGO. However, ATP- and UTP-induced relaxation was impaired by MGO compared with the control. In both ATP- and UTP-induced relaxation, endothelial denudation, incubation with the nitric oxide (NO) synthase inhibitor N[G]-nitro-L-arginine or the selective P2Y purinoceptor 2 (P2Y2) receptor antagonist AR-C118925XX reduced relaxation in both the control and MGO groups, while the differences between the control and MGO groups were eliminated. The cyclooxygenase (COX) inhibitor indomethacin inhibited the differences in ATP/UTP-mediated relaxations between the control and MGO groups. Moreover, N-acetyl-L-cysteine (NAC), an antioxidant, could augment carotid arterial relaxation induced by ATP/UTP in the presence of MGO. MGO increased arachidonic acid-induced contraction, which was suppressed by NAC. Following both ATP/UTP stimulation, MGO increased the release of prostanoids. These results suggest that MGO impaired ATP- and UTP-induced relaxation in carotid arteries, which was caused by suppressed P2Y2 receptor-mediated signaling and reductions in endothelial NO. Moreover, MGO partially contributed to COX-derived vasoconstrictor prostanoids through increased oxidative stress.}, }
@article {pmid36108767, year = {2022}, author = {Li, X and Wu, H and Huo, H and Ma, F and Zhao, M and Han, Q and Hu, L and Li, Y and Zhang, H and Pan, J and Tang, Z and Guo, J}, title = {N-acetylcysteine combined with insulin alleviates the oxidative damage of cerebrum via regulating redox homeostasis in type 1 diabetic mellitus canine.}, journal = {Life sciences}, volume = {308}, number = {}, pages = {120958}, doi = {10.1016/j.lfs.2022.120958}, pmid = {36108767}, issn = {1879-0631}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/pharmacology ; Blood Glucose ; Catalase/metabolism ; *Cerebrum/metabolism ; Claudin-1/metabolism ; *Diabetes Mellitus, Type 1/complications/drug therapy ; Dogs ; Glutathione Disulfide/metabolism/pharmacology ; Homeostasis ; Hydrogen Peroxide/pharmacology ; Insulin/metabolism ; Lipids/pharmacology ; Occludin/metabolism ; Oxidation-Reduction ; Oxidative Stress ; RNA, Messenger/metabolism ; }, abstract = {Neurodegenerative diseases are one of the major complications of type 1 diabetes mellitus (T1DM). The effect of insulin monotherapy on controlling blood glucose and neurodegeneration associated with diabetes is unsatisfactory. It is revealed that oxidative stress is a key element in T1DM. Therefore, N-acetylcysteine (NAC) was used together with insulin to investigate the therapeutic effect on neuronal damage in T1DM in this study. A total of 40 beagles were randomly divided into 5 groups (control group, DM group, insulin monotherapy group, NAC combined with insulin group, and NAC monotherapy group) to explore the effects of NAC on alleviating the oxidative damage in cerebrum. Our results showed that the contents of H2O2, 8-OHdg and MDA were apparently increased in DM group, while DNA and lipid oxidative damage was alleviated by the treatment of NAC and insulin. Histopathology revealed the sparse of neurofibrils and vacuolar degeneration in DM group. Additionally, compared with the control group, the mRNA expression levels of HO-1, nqo1, GCLC and GSTM1 were significantly decreased in DM group, while the opposite trend could be shown under NAC combined with insulin treatment. Meanwhile, the tight junction proteins of ZO-1, occludin and Claudin-1 were up-regulated with the treatment of NAC combined with insulin. Additionally, NAC further alleviated oxidative damage by enhancing the activity of GSH, Trx and TrxR and reducing the activity of catalase, GSSG and Grx to maintain redox homeostasis. These results demonstrated that NAC combined with insulin exerted protective effects against T1DM-induced cerebral injury via maintaining cerebral redox homeostasis.}, }
@article {pmid36100129, year = {2022}, author = {Chen, S and Sun, P and Li, Y and Shen, W and Wang, C and Zhao, P and Cui, H and Xue, JY and Du, GQ}, title = {Melatonin activates the Mst1-Nrf2 signaling to alleviate cardiac hypertrophy in pulmonary arterial hypertension.}, journal = {European journal of pharmacology}, volume = {933}, number = {}, pages = {175262}, doi = {10.1016/j.ejphar.2022.175262}, pmid = {36100129}, issn = {1879-0712}, mesh = {Animals ; Antioxidants/pharmacology/therapeutic use ; Arginine Vasopressin ; Cysteine/therapeutic use ; Disease Models, Animal ; Familial Primary Pulmonary Hypertension ; Hepatocyte Growth Factor/metabolism ; *Hypertension, Pulmonary/chemically induced/complications/drug therapy ; Hypertrophy, Right Ventricular ; Malondialdehyde ; *Melatonin/pharmacology/therapeutic use ; Monocrotaline ; NF-E2-Related Factor 2 ; Proto-Oncogene Proteins/metabolism ; *Pulmonary Arterial Hypertension/drug therapy ; RNA, Small Interfering/therapeutic use ; Rats ; Ventricular Remodeling ; }, abstract = {Among pulmonary arterial hypertension (PAH) patients, right ventricular (RV) functioning has been considered a major determining factor for cardiac capacity and survival. However, despite the recognition of the clinical importance for preserving RV functioning, no effective treatments are currently available for RV failure. This study aims to suggest one such possible treatment, through investigating the cardio-protective capabilities of the anti-oxidant, melatonin (Mel), for treating adverse RV remodeling in PAH, along with its underlying mechanisms. Arginine vasopressin induced neonatal rat cardiomyocyte hypertrophy in vitro; in vivo, PAH was induced in rats through intraperitoneal monocrotaline (MCT) injections, and Mel was administered intraperitoneally 24 h prior to MCT. Mel reduced rat cardiomyocyte hypertrophy and mitochondrial oxidative stress in vitro by activating the Mst1-Nrf2 pathway, which were all reversed upon siRNA knockdown of Mst1. Likewise, in vivo, Mel pre-treatment significantly ameliorated MCT-induced deterioration in cardiac function, RV hypertrophy, fibrosis and dilation. These beneficial effects were also associated with Mst1-Nrf2 pathway up regulation and its associated reduction in oxidative stress, as evidenced by the decrease in RV malondialdehyde content. Notably, results from Mel treatment were similar, or even superior, to those obtained from N-acetyl cysteine (NAC), which has already been-confirmed as an anti-oxidative treatment for PAH. By contrast, co-treatment with the Mst1 inhibitor XMU-MP-1 reversed all of those Mel-associated beneficial effects. Our findings thus identified Mel as a potent cardio-protective agent against the onset of maladaptive RV remodeling, through enhancement of the anti-oxidative response via Mst1-Nrf2 pathway activation.}, }
@article {pmid36096839, year = {2022}, author = {Abdulrab, S and Mostafa, N and Al-Maweri, SA and Abada, H and Halboub, E and Alhadainy, HA}, title = {Antibacterial and anti-inflammatory efficacy of N-acetyl cysteine in endodontic treatment: a scoping review.}, journal = {BMC oral health}, volume = {22}, number = {1}, pages = {398}, pmid = {36096839}, issn = {1472-6831}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Calcium Hydroxide/pharmacology/therapeutic use ; Chlorhexidine ; Humans ; }, abstract = {BACKGROUND: This scoping review systematically summarized the available evidence about the efficacy of N-acetyl cysteine (NAC) as an intracanal antibacterial and/or anti-inflammatory.<br><br>METHODS: PubMed, Scopus, Web of Science, and Google scholar search engines/databases were searched up to February 2022 to retrieve relevant studies. The studies were evaluated for eligibility criteria, and identifying relevant studies.<br><br>RESULTS: Out of 193 studies, 15 fulfilled the inclusion criteria and were processed for data extraction. Thirteen in vitro studies assessed antibacterial/antibiofilm efficacy of NAC, and reported good and promising efficacy: NAC was found as efficacious as the comparators (chlorhexidine, sodium hypochlorite, calcium hydroxide), or even showed higher efficacy. Regarding the anti-inflammatory efficacy of NAC, one in vitro study found it equivalent to, while one clinical trial revealed it more efficacious than calcium hydroxide.<br><br>CONCLUSIONS: There is accumulating evidence on the anti-microbial and anti-inflammatory efficacy of NAC in context of endodontics. However, further clinical trials with robust methodology and objective and reliable clinical, biological and microbial outcomes are warranted to translate its use for clinical practice on humans.}, }
@article {pmid36094079, year = {2022}, author = {Cai, X and Hua, S and Deng, J and Du, Z and Zhang, D and Liu, Z and Khan, NU and Zhou, M and Chen, Z}, title = {Astaxanthin Activated the Nrf2/HO-1 Pathway to Enhance Autophagy and Inhibit Ferroptosis, Ameliorating Acetaminophen-Induced Liver Injury.}, journal = {ACS applied materials &amp; interfaces}, volume = {14}, number = {38}, pages = {42887-42903}, doi = {10.1021/acsami.2c10506}, pmid = {36094079}, issn = {1944-8252}, mesh = {Acetaminophen/metabolism ; Acetylcysteine ; Autophagy ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/prevention &amp; control ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy/metabolism/pathology ; *Ferroptosis ; Heme Oxygenase-1/metabolism ; *Hereditary Sensory and Motor Neuropathy/drug therapy/metabolism/pathology ; Humans ; Liver/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Silicon Dioxide/pharmacology ; Xanthophylls ; }, abstract = {Acetaminophen (APAP)-induced liver injury (AILI) is a common liver disease in clinical practice. Only one clinically approved drug, N-acetylcysteine (NAC), for the treatment of AILI is available in clinics, but novel treatment strategies are still needed due to the complicated pathological changes of AILI and the side effects of NAC. Here, we found that astaxanthin (ASX) can prevent AILI through the Nrf2/HO-1 pathway. After treatment with ASX, there was a positive activation of the Nrf2/HO-1 pathway in AILI models both in vivo and in vitro accompanied by enhanced autophagy and reduced ferroptosis. In APAP-challenged L02 liver cells, ASX reduced autophagy and enhanced apoptosis of the cells. Furthermore, we developed ASX-loaded hollow mesoporous silica nanoparticles (HMSN@ASX) to improve the aqueous solubility of ASX and targeted delivery of ASX to the liver and then significantly improve the therapeutic effects. Taken together, we found that ASX can protect against AILI by activating the Nrf2/HO-1 pathway, which mainly affects oxidative stress, autophagy, and ferroptosis processes, and the HMSN@ASX nanosystem can target the liver to enhance the treatment efficiency of AILI.}, }
@article {pmid36093092, year = {2022}, author = {Schuurman, M and Wallace, M and Sahi, G and Barillaro, M and Zhang, S and Rahman, M and Sawyez, C and Borradaile, N and Wang, R}, title = {N-acetyl-L-cysteine treatment reduces beta-cell oxidative stress and pancreatic stellate cell activity in a high fat diet-induced diabetic mouse model.}, journal = {Frontiers in endocrinology}, volume = {13}, number = {}, pages = {938680}, pmid = {36093092}, issn = {1664-2392}, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; *Diabetes Mellitus, Experimental/complications/drug therapy ; *Diabetes Mellitus, Type 2/metabolism ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/complications/etiology ; Oxidative Stress ; Pancreatic Stellate Cells/metabolism ; }, abstract = {Obesity plays a major role in type II diabetes (T2DM) progression because it applies metabolic and oxidative stress resulting in dysfunctional beta-cells and activation of intra-islet pancreatic stellate cells (PaSCs) which cause islet fibrosis. Administration of antioxidant N-acetyl-L-cysteine (NAC) in vivo improves metabolic outcomes in diet-induced obese diabetic mice, and in vitro inhibits PaSCs activation. However, the effects of NAC on diabetic islets in vivo are unknown. This study examined if dosage and length of NAC treatment in HFD-induced diabetic mice effect metabolic outcomes associated with maintaining healthy beta-cells and quiescent PaSCs, in vivo. Male C57BL/6N mice were fed normal chow (ND) or high-fat (HFD) diet up to 30 weeks. NAC was administered in drinking water to HFD mice in preventative treatment (HFD[pNAC]) for 23 weeks or intervention treatment for 10 (HFD[iNAC]) or 18 (HFD[iNAC+)] weeks, respectively. HFD[pNAC] and HFD[iNAC+], but not HFD[iNAC], mice showed significantly improved glucose tolerance and insulin sensitivity. Hyperinsulinemia led by beta-cell overcompensation in HFD mice was significantly rescued in NAC treated mice. A reduction of beta-cell nuclear Pdx-1 localization in HFD mice was significantly improved in NAC treated islets along with significantly reduced beta-cell oxidative stress. HFD-induced intra-islet PaSCs activation, labeled by αSMA, was significantly diminished in NAC treated mice along with lesser intra-islet collagen deposition. This study determined that efficiency of NAC treatment is beneficial at maintaining healthy beta-cells and quiescent intra-islet PaSCs in HFD-induced obese T2DM mouse model. These findings highlight an adjuvant therapeutic potential in NAC for controlling T2DM progression in humans.}, }
@article {pmid36090543, year = {2022}, author = {Chen, M and Ke, J and Ma, S and Chai, H and Zhang, L and Zhang, L}, title = {Application of Melatonin with N-Acetylcysteine Exceeds Traditional Treatment for Acetaminophen-Induced Hepatotoxicity.}, journal = {Emergency medicine international}, volume = {2022}, number = {}, pages = {2791743}, pmid = {36090543}, issn = {2090-2840}, abstract = {Acetaminophen (APAP) overdose is one of the leading causes of acute liver damage. Given N-acetylcysteine (NAC) and melatonin (MLT) both have an attenuated value for APAP-induced liver toxification, where an optimized integrated treatment has not been well deciphered. Here, by giving a single dose of APAP (500 mg/kg) to wild-type male mice, combined with a single dose of 500 mg/kg NAC or 100 mg/kg MLT separately as the therapeutic method, this study aimed to investigate the effects of NAC and melatonin (MLT) alone or combined on acetaminophen (APAP)-induced liver injury. In this study, NAC and MLT both partially have an alleviated function in APAP-challenged liver injury. However, MLT's add-on role strengthens the hepatoprotective effect of NAC on APAP-induced liver damage and resolute the inflammatory infiltration. Meanwhile, the combination of two reagents attenuates the decreased glutathione (GSH) and activation of the p38/JNK pathway. The combination of MLT and NAC can further ameliorate APAP-induced liver injury, which provides a novel strategy for drug-induced liver injury (DILI).}, }
@article {pmid36086867, year = {2023}, author = {Wu, J and Wang, D and Zhou, J and Li, J and Xie, R and Li, Y and Huang, J and Liu, B and Qiu, J}, title = {Gambogenic acid induces apoptosis and autophagy through ROS-mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells.}, journal = {Phytotherapy research : PTR}, volume = {37}, number = {1}, pages = {310-328}, doi = {10.1002/ptr.7614}, pmid = {36086867}, issn = {1099-1573}, support = {2019A1515010386//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Male ; Humans ; *MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Apoptosis ; Endoplasmic Reticulum Stress ; Autophagy ; Cell Line, Tumor ; Acetylcysteine/metabolism/pharmacology ; *Prostatic Neoplasms/drug therapy ; }, abstract = {Prostate cancer (PCa) is the most common malignant tumor in males, which frequently develops into castration-resistant prostate cancer (CRPC) with limited therapies. Gambogenic acid (GNA), a flavonoids compound isolated from Gamboge, exhibits anti-tumor capacity in various cancers. Our results showed that GNA revealed not only antiproliferative and pro-apoptotic activities but also the induction of autophagy in PCa cells. In addition, autophagy inhibitor chloroquine enhanced the pro-apoptosis effect of GNA. Moreover, the activation of JNK pathway and the induction of apoptosis and autophagy triggered by GNA were attenuated by JNK inhibitor SP600125. We also found that GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. Meanwhile, suppressing ER stress with 4-phenylbutyric acid (4-PBA) markedly blocked the activation of JNK pathway induced by GNA. Further research indicated that ROS scavenger N-acetyl-L-cysteine (NAC) effectively abrogated ER stress and JNK pathway activation induced by GNA. Furthermore, NAC and 4-PBA significantly reversed GNA-triggered apoptosis and autophagy. Finally, GNA remarkably suppressed prostate tumor growth with low toxicity in vivo. In conclusion, the present study revealed that GNA induced apoptosis and autophagy through ROS-mediated ER stress via JNK signaling pathway in PCa cells. Thus, GNA might be a promising therapeutic drug against PCa.}, }
@article {pmid36077566, year = {2022}, author = {Yi, Y and Gao, K and Zhang, L and Lin, P and Wang, A and Jin, Y}, title = {Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway.}, journal = {International journal of molecular sciences}, volume = {23}, number = {17}, pages = {}, pmid = {36077566}, issn = {1422-0067}, support = {31772817//National Natural Science Foundation of China/ ; 2018BBF33001//Key R&amp;D Program of Ningxia Hui Autonomous Region/ ; }, mesh = {Animals ; Calcium/metabolism ; Calcium, Dietary ; Goats/metabolism ; *Necroptosis ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Stromal Cells/metabolism ; *Zearalenone/toxicity ; }, abstract = {Zearalenone (ZEA) is a fungal mycotoxin known to exert strong reproductive toxicity in animals. As a newly identified type of programmed cell death, necroptosis is regulated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like pseudokinase (MLKL). However, the role and mechanism of necroptosis in ZEA toxicity remain unclear. In this study, we confirmed the involvement of necroptosis in ZEA-induced cell death in goat endometrial stromal cells (gESCs). The release of lactate dehydrogenase (LDH) and the production of PI-positive cells markedly increased. At the same time, the expression of RIPK1 and RIPK3 mRNAs and P-RIPK3 and P-MLKL proteins were significantly upregulated in ZEA-treated gESCs. Importantly, the MLKL inhibitor necrosulfonamide (NSA) dramatically attenuated gESCs necroptosis and powerfully blocked ZEA-induced reactive oxygen species (ROS) generation and mitochondrial dysfunction. The reactive oxygen species (ROS) scavengers and N-acetylcysteine (NAC) inhibited ZEA-induced cell death. In addition, the inhibition of MLKL alleviated the intracellular Ca[2+] overload caused by ZEA. The calcium chelator BAPTA-AM markedly suppressed ROS production and mitochondrial damage, thus inhibiting ZEA-induced necroptosis. Therefore, our results revealed the mechanism by which ZEA triggers gESCs necroptosis, which may provide a new therapeutic strategy for ZEA poisoning.}, }
@article {pmid36077493, year = {2022}, author = {Morgan, C and Sáez-Briones, P and Barra, R and Reyes, A and Zepeda-Morales, K and Constandil, L and Ríos, M and Ramírez, P and Burgos, H and Hernández, A}, title = {Prefrontal Cortical Control of Activity in Nucleus Accumbens Core Is Weakened by High-Fat Diet and Prevented by Co-Treatment with N-Acetylcysteine: Implications for the Development of Obesity.}, journal = {International journal of molecular sciences}, volume = {23}, number = {17}, pages = {}, pmid = {36077493}, issn = {1422-0067}, support = {021943HK//Direcci&#xf3;n de Investigaci&#xf3;n Cient&#xed;fica y Tecnol&#xf3;gica (DICYT) of the University of Santiago de Chile/ ; 1181622//FONDECYT/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Diet, High-Fat/adverse effects ; Humans ; Male ; Mice ; *Nucleus Accumbens ; Obesity/drug therapy/etiology/prevention &amp; control ; Prefrontal Cortex ; Weight Gain ; }, abstract = {A loss of neuroplastic control on nucleus accumbens (NAc) neuronal activity exerted by the medial prefrontal cortex (mPFC) through long-term depression (LTD) is involved in triggering drug-seeking behavior and relapse on several substances of abuse due to impaired glutamate homeostasis in tripartite synapses of the nucleus accumbens (NAc) core. To test whether this maladaptive neuroplastic mechanism underlies the addiction-like behavior induced in young mice by a high-fat diet (HFD), we utilized 28-days-old male mice fed HFD ad-libitum over 2 weeks, followed by 5 days of HFD abstinence. Control groups were fed a regular diet. HFD fed mice showed increased ΔFosB levels in the NAc core region, whereas LTD triggered from the mPFC became suppressed. Interestingly, LTD suppression was prevented by an i.p. injection of 100 mg/kg N-acetylcysteine 2.5 h before inducing LTD from the mPFC. In addition, excessive weight gain due to HFD feeding was diminished by adding 2mg/mL N-acetylcysteine in drinking water. Those results show a loss of neuroplastic mPFC control over NAc core activity induced by HFD consumption in young subjects. In conclusion, ad libitum consumption of HFD can lead to neuroplastic changes an addiction-like behavior that can be prevented by N-acetylcysteine, helping to decrease the rate of excessive weight gain.}, }
@article {pmid36076297, year = {2022}, author = {Wang, L and Mao, B and Fan, K and Sun, R and Zhang, J and Liang, H and Liu, Y}, title = {ROS attenuates TET2-dependent ZO-1 epigenetic expression in cerebral vascular endothelial cells.}, journal = {Fluids and barriers of the CNS}, volume = {19}, number = {1}, pages = {73}, pmid = {36076297}, issn = {2045-8118}, support = {2018YFC2000202//the National Key R&amp;D Program of China/ ; }, mesh = {Animals ; Blood-Brain Barrier/metabolism ; DNA-Binding Proteins/metabolism ; *Dioxygenases/metabolism ; *Endothelial Cells/metabolism ; Epigenesis, Genetic ; Humans ; Hydrogen Peroxide/metabolism ; Mice ; Mice, Knockout ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Tight Junction Proteins/metabolism ; Tight Junctions/metabolism ; Zonula Occludens-1 Protein/metabolism ; }, abstract = {AIMS: To investigate whether DNA active demethylase TET regulates the expression of tight junction proteins in endothelial cells of the blood-brain barrier (BBB).<br><br>METHODS: Correlations between TET2 activity (indicated by its catalytic product 5hmC) and the expression of BBB tight junction proteins were examined in Tet2 knockout mice and post-mortem human brain tissues. In cultured endothelial cells, the impact of changes of TET activity on the expression of tight junction protein, ZO-1, was studied. BBB permeability assays were performed in Tet2 knockout mice.<br><br>RESULTS: It was found that the level of 5hmC decreased in brain microvascular endothelial cells of aging mice. In Tet2 knockout mice, the level of 5hmC in endothelial cells was weaker and significantly correlated with the reduced expression of tight junction protein ZO-1. In cultured endothelial cells, H2O2 significantly decreased the expression of 5hmC and ZO-1. Tet2 knock-down using siRNA significantly downregulated the expression of ZO-1 in endothelial cells. hMeChip-PCR showed that H2O2 decreased the level of 5hmC in the ZO-1 promoter region, which was rescued by N-acetyl cysteine (NAC). Consistently, Tet2 knock-down using siRNA significantly downregulated the level of 5hmC in the ZO-1 promoter region. It was also found that the level of 5hmC decreased in endothelial cells of aging human brains compared with that of adult brains, and the level of ZO-1 was positively correlated with that of 5hmC in microvascular endothelial cells.<br><br>CONCLUSIONS: These findings suggest that TET activity is essential in regulating ZO-1 expression of BBB. It might be a potential target for neuroprotection during aging and in diverse neurological conditions.}, }
@article {pmid36076278, year = {2022}, author = {Meng, Z and Liu, J and Feng, Z and Guo, S and Wang, M and Wang, Z and Li, Z and Li, H and Sui, L}, title = {N-acetylcysteine regulates dental follicle stem cell osteogenesis and alveolar bone repair via ROS scavenging.}, journal = {Stem cell research &amp; therapy}, volume = {13}, number = {1}, pages = {466}, pmid = {36076278}, issn = {1757-6512}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Cell Differentiation/physiology ; Cells, Cultured ; Dental Sac/metabolism ; Humans ; *Osteogenesis/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; RNA/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Stem Cells/metabolism ; }, abstract = {BACKGROUND: Dental follicle stem cells (DFSCs) show mesenchymal stem cell properties with the potential for alveolar bone regeneration. Stem cell properties can be impaired by reactive oxygen species (ROS), prompting us to examine the importance of scavenging ROS for stem cell-based tissue regeneration. This study aimed to investigate the effect and mechanism of N-acetylcysteine (NAC), a promising antioxidant, on the properties of DFSCs and DFSC-based alveolar bone regeneration.<br><br>METHODS: DFSCs were cultured in media supplemented with different concentrations of NAC (0-10&#xa0;mM). Cytologic experiments, RNA-sequencing and antioxidant assays were performed in vitro in human DFSCs (hDFSCs). Rat maxillary first molar extraction models were constructed, histological and radiological examinations were performed at day 7 post-surgery to investigate alveolar bone regeneration in tooth extraction sockets after local transplantation of NAC, rat DFSCs (rDFSCs) or NAC-treated rDFSCs.<br><br>RESULTS: 5&#xa0;mM NAC-treated hDFSCs exhibited better proliferation, less senescent rate, higher stem cell-specific marker and immune-related factor expression with the strongest osteogenic differentiation; other concentrations were also beneficial for maintaining stem cell properties. RNA-sequencing identified 803 differentially expressed genes between hDFSCs with and without 5&#xa0;mM NAC. "Developmental process (GO:0032502)" was prominent, bioinformatic analysis of 394 involved genes revealed functional and pathway enrichment of ossification and PI3K/AKT pathway, respectively. Furthermore, after NAC treatment, the reduction of ROS levels (ROS, superoxide, hydrogen peroxide), the induction of antioxidant levels (glutathione, catalase, superoxide dismutase), the upregulation of PI3K/AKT signaling (PI3K-p110, PI3K-p85, AKT, phosphorylated-PI3K-p85, phosphorylated-AKT) and the rebound of ROS level upon PI3K/AKT inhibition were showed. Local transplantation of NAC, rDFSCs or NAC-treated rDFSCs was safe and promoted oral socket bone formation after tooth extraction, with application of NAC-treated rDFSCs possessing the best effect.<br><br>CONCLUSIONS: The proper concentration of NAC enhances DFSC properties, especially osteogenesis, via PI3K/AKT/ROS signaling, and offers clinical potential for stem cell-based alveolar bone regeneration.}, }
@article {pmid36075319, year = {2022}, author = {Fan, C and Tian, Y and Zhang, Y and Teng, J and Zhao, X}, title = {Ceramide induces macrophage migration inhibitory factor -mediated parthanatos in mouse neurons by increasing ROS levels.}, journal = {Neuroscience letters}, volume = {788}, number = {}, pages = {136862}, doi = {10.1016/j.neulet.2022.136862}, pmid = {36075319}, issn = {1872-7972}, mesh = {Animals ; Apoptosis Inducing Factor/metabolism ; Ceramides/metabolism/pharmacology ; *Macrophage Migration-Inhibitory Factors/metabolism ; Mice ; Neurons/metabolism ; *Parthanatos ; Poly(ADP-ribose) Polymerase Inhibitors ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Ceramides, the key component of sphingolipid metabolism and second messengers, have been associated with neurodegenerative diseases progression and pathology, and can induce neuronal apoptosis and necrosis, but the effect of ceramide on parthanatos has not been fully elucidated. In this study, we investigated the ceramide-mediated parthanatos pathway and the role of macrophage inhibitory factor (MIF) in parthanatos. We found that ceramide significantly diminished the viability and induced the death of primary cortical neurons. These effects were not prevented by treatment with the pan-caspase inhibitor Z-VAD-FMK treatment; in contrast, treatment with the poly (ADP ribosyl) polymerase-1 (PARP-1) inhibitor ABT-888 prevented these ceramide-mediated effects. Specifically, ceramide induced PARP-1 overactivation, increased PAR polymer levels, facilitated apoptosis-inducing factor (AIF) and MIF nuclear translocation and induced DNA damage. Knockdown of MIF with an adenovirus carrying a MIF short hairpin RNA (shRNA) inhibited ceramide-induced DNA damage and neuronal death, but nuclear translocation of AIF was unaffected. Furthermore, ceramide increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) significantly inhibited PAR production and neuronal death. These findings suggested that ceramide induced neuronal parthanatos by increasing ROS levels and that MIF might be downstream of AIF in the ceramide-mediated parthanatos pathway. In conclusion, our results suggest that knocking down MIF expression may be a potential therapeutic strategy for nervous system diseases.}, }
@article {pmid36068741, year = {2022}, author = {Liu, N and Li, G and Guan, Y and Wang, R and Ma, Z and Zhao, L and Yao, S}, title = {N-acetylcysteine alleviates pulmonary alveolar proteinosis induced by indium-tin oxide nanoparticles in male rats: involvement of the NF-κB signaling pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {241}, number = {}, pages = {113812}, doi = {10.1016/j.ecoenv.2022.113812}, pmid = {36068741}, issn = {1090-2414}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/metabolism ; Indium/toxicity ; Lung ; *Lung Injury/chemically induced/drug therapy/metabolism ; Male ; NF-kappa B/metabolism ; *Nanoparticles/toxicity ; *Pulmonary Alveolar Proteinosis/chemically induced/metabolism/pathology ; *Pulmonary Fibrosis/chemically induced/drug therapy/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Tin Compounds ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Indium-tin oxide (ITO) was previously found to have a toxic effect on lung tissues, and oxidative stress and the inflammatory response are two important mechanisms of ITO‑induced lung injury. N-acetylcysteine (NAC) has been found to exhibit antioxidant and anti‑inflammatory properties. The current study aimed to evaluate the possible protective effects of NAC against ITO nanoparticle (Nano-ITO)-induced pulmonary alveolar proteinosis (PAP) in adult male Sprague-Dawley rats, especially via modulation of nuclear factor-kappa B (NF-κB) signaling. For this purpose, 50 rats were randomly allocated into five groups (10 rats each) as follows: (1) control group; (2) saline group; (3) NAC (200 mg/kg) group; (4) PAP model group receiving a repeated intratracheal dose of Nano-ITO (6 mg/kg); and (5) PAP model+NF-κB inhibitor (NAC) group pre-treated intraperitoneally with NAC (200 mg/kg) twice per week before the administration of an intratracheal dose of Nano-ITO (6 mg/kg). Rats were then euthanized under anesthesia, and their lungs were removed for histopathological and biochemical investigations. A 6 mg/kg dose of Nano-ITO markedly altered the levels of some oxidative stress biomarkers. The histological examination of Nano-ITO-exposed rats demonstrated diffused alveolar damage that involved PAP, cholesterol crystals, alveolar fibrosis, pulmonary fibrosis, and alveolar emphysema. The immunohistochemical results of Nano-ITO-exposed rats revealed strongly positive NF-κB p65 and inhibitory kappa B kinase (IKK)-β and weakly positive inhibitor of kappa-B subunit alpha (IκB-α) staining reactivity in the nuclei of cells lining the epithelium of the bronchioles and alveoli. Moreover, Nano-ITO activated the NF-κB pathway. However, pre-treatment with NAC significantly attenuated Nano-ITO-evoked alterations in the previously mentioned parameters, highlighting their antioxidant, anti-inflammatory, and anti-apoptotic potential. The results indicated that the degree of pulmonary fibrosis and proteinosis in the NAC‑treated group was improved compared with that in the Nano-ITO-induced PAP model group. The level of malondialdehyde was also decreased overall in the NAC-treated group compared with that in the Nano-ITO-induced model group, indicating that the pulmonary fibrosis degree and oxidation levels were decreased. The present study also demonstrated that NAC increased the activity of antioxidant enzyme superoxide dismutase and total antioxidant capacity, indicating that it could alleviate oxidative stress in the lung tissue of Nano-ITO‑exposed rats. In addition, NAC reduced the production of pro‑inflammatory cytokines interleukin (IL)‑1β, IL‑6, and tumor necrosis factor (TNF)‑α, and increased the levels of anti‑inflammatory factor IL‑10. The current study demonstrated that NAC can effectively attenuate Nano-ITO‑induced lung injury by reducing oxidative damage and the inflammatory response.}, }
@article {pmid36067963, year = {2022}, author = {Jiang, Y and Geng, N and Wang, M and Wu, W and Feng, N and Zhang, X}, title = {5-HMF affects cardiovascular development in zebrafish larvae via reactive oxygen species and Wnt signaling pathways.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {262}, number = {}, pages = {109452}, doi = {10.1016/j.cbpc.2022.109452}, pmid = {36067963}, issn = {1532-0456}, mesh = {Acetylcysteine/metabolism/pharmacology ; Aldehydes/metabolism/pharmacology ; Animals ; Antioxidants/metabolism ; Embryo, Nonmammalian ; Humans ; Larva/metabolism ; Reactive Oxygen Species/metabolism ; *Wnt Signaling Pathway ; *Zebrafish/metabolism ; }, abstract = {5-Hydroxymethylfurfural (5-HMF) is a small molecule aldehyde compound produced by the Maillard reaction. As 5-HMF exists in a variety of foods and drugs and is easily ingested by humans, it has attracted extensive toxicological attention in recent years. Relevant research showed that 5-HMF has cytotoxicity, genotoxicity, and tumor effects. However, the cardiovascular effects of 5-HMF are unknown. To investigate the cardiovascular effects of 5-HMF in zebrafish, wild-type and transgenic embryos were treated with 10, 25, and 50 μg/mL of 5-HMF, followed by toxicological evaluation, histological observation, fluorescence observation, cell apoptosis staining, and gene quantitative analysis. High 5-HMF concentrations led to a significant increase in the heart rate and pericardial edema ratio, larger venous sinus-arterial bulb distance, more apoptosis of cardiac cells, cardiac linearization, defects in angiogenesis and cardiovascular development, and apoptosis-related gene expression disorders in zebrafish larvae. The abnormal phenotype caused by 5-HMF can be rescued by antioxidant N-acetyl-L-cysteine (NAC) and Wnt signaling pathway activator BML-284. It is inferred that high 5-HMF concentrations increased the level of reactive oxygen species, inhibited the transduction of the Wnt signaling pathway, and resulted in abnormal cardiovascular development in zebrafish larvae. This study provides a reference for understanding the mechanism of 5-HMF effects on cardiac development.}, }
@article {pmid36066601, year = {2022}, author = {Güven, D and Özbek, &#x130;}, title = {Characteristics, Treatment, and Prognosis of Elemental Mercury Intoxication in Children: A Single-Center Retrospective Study.}, journal = {Pediatric emergency care}, volume = {38}, number = {10}, pages = {481-488}, doi = {10.1097/PEC.0000000000002834}, pmid = {36066601}, issn = {1535-1815}, mesh = {Acetylcysteine ; Child ; Humans ; *Mercury ; *Mercury Poisoning/diagnosis/drug therapy ; Penicillamine/therapeutic use ; Prognosis ; Retrospective Studies ; Succimer/therapeutic use ; Sulfonic Acids ; }, abstract = {OBJECTIVES: Mercury exposure is common and can be toxic, especially in children. Children are often drawn to elemental mercury because of its density, color, and proclivity to form beads.<br><br>METHODS: We present data on 49 children with mercury intoxication (MI) and 60 children with mercury exposure from Turkey.<br><br>RESULTS: The most common source of mercury was broken thermometer in schools. Inhaling mercury vapor was the most common route of exposure. The median exposure time was 6 (6-16) hours in the MI group, and the time to 1st symptoms was 10 (0-24) hours. In the MI group, the median blood mercury level was 21 &#x3bc;g/L (13-32.3), the median spot urine mercury level was 40 &#x3bc;g/L (7.66-78), and the median 24-hour urine mercury level was 25.8 &#x3bc;g/L (11-64). The most common symptoms in patients with MI were malaise, muscle pain, muscle cramps, abdominal pain, nausea, headache, and decreased appetite. The patients were treated with n-acetyl cysteine, 2,3-dimercaptopropane sulfonic acid, D-penicillamine, and meso 2,3-dimercaptosuccinic acid. A positive correlation was found between exposure time and urinary mercury level in the MI group (r = 0.793, P < 0.001). A positive moderate correlation was found between exposure time and blood level in the mercury exposure group (r = 0.535, P < 0.00). The neurological and systemic examinations of patients were all normal at the 1st follow-up visit 1 month after discharge.<br><br>CONCLUSIONS: Diagnosis, removal of the exposure source, and use of chelation therapy can result in complete resolution of the signs and symptoms of MI.}, }
@article {pmid36063970, year = {2023}, author = {Fredriksson, I and Jayaram-Lindström, N and Kalivas, PW and Melas, PA and Steensland, P}, title = {N-acetylcysteine improves impulse control and attenuates relapse-like alcohol intake in long-term drinking rats.}, journal = {Behavioural brain research}, volume = {436}, number = {}, pages = {114089}, doi = {10.1016/j.bbr.2022.114089}, pmid = {36063970}, issn = {1872-7549}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Alcohol Drinking/drug therapy ; *Alcoholism/drug therapy ; Animals ; Cystine ; Ethanol/pharmacology ; Glutamates/therapeutic use ; Male ; *Prodrugs/therapeutic use ; Rats ; Rats, Wistar ; Recurrence ; Self Administration ; }, abstract = {Increasing evidence suggests that individuals with alcohol use disorder (AUD) present with a disrupted glutamatergic system that underlies core components of addictive disorders, including drug relapse and low impulse control. N-acetylcysteine (NAC) is a cystine prodrug that has been found to promote glutamate homeostasis and drug abstinence. However, no studies to date have evaluated NAC's effect on impulsivity in substance use disorders. Here we determined whether NAC would decrease alcohol-intake behaviors, in addition to improving impulse control, in long-term alcohol drinking male Wistar-Han rats. Before the start of the experiments, all rats were exposed to long-term intermittent access to 20% ethanol for at least seven weeks. Next, in different groups of rats, the effect of NAC (60 and/or 90 mg/kg) was evaluated on (i) voluntary alcohol drinking using a two-bottle free choice paradigm, (ii) the motivation to self-administer alcohol under a progressive ratio schedule of reinforcement, and (iii) relapse-like drinking using the alcohol deprivation effect model. Finally, (iv) NAC's effect on impulse control was evaluated using the five-choice serial reaction time task. Results showed that NAC administration at 90 mg/kg significantly reduced relapse-like drinking and improved impulse control. In contrast, NAC had no effect on levels of alcohol drinking or motivation to drink alcohol. In conclusion, our findings continue to support the use of NAC as an adjuvant treatment for the maintenance of abstinence in AUD. Moreover, we provide evidence for NAC's efficacy in improving impulse control following drinking, which warrants further investigation in substance use settings.}, }
@article {pmid36061354, year = {2022}, author = {Han, L and Hao, Y and Wu, X and Hu, D}, title = {PSMB5 Alleviates Ulcerative Colitis by Inhibiting ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis.}, journal = {Disease markers}, volume = {2022}, number = {}, pages = {2329904}, pmid = {36061354}, issn = {1875-8630}, mesh = {Animals ; Body Weight ; Caspase 1/metabolism/pharmacology ; *Colitis, Ulcerative/chemically induced/drug therapy ; *Inflammasomes/metabolism/pharmacology ; Interleukin-18/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase ; }, abstract = {Ulcerative colitis (UC) is a chronic inflammatory disease. Intestinal mucosal injury is a significant factor in UC. Pyroptosis is a kind of programmed cell death induced by inflammatory caspases. Proteasome 20S subunit beta 5 (PSMB5) promotes cell viability. The purpose of this study was to determine the impact of PSMB5 on intestinal mucosal injury and to elucidate the underlying processes in dextran sulfate sodium- (DSS-) induced UC mice. Kunming (KM) mice received 3% DSS for 5 days to induce UC. We collected clinical symptoms, body weight, colon length, and histological changes. MDA (malondialdehyde) and SOD (superoxide dismutase) levels were determined using an ELISA assay. RT-PCR was used to assess the expression of IL-1β and IL-18. PSMB5 demonstrated a significant effect against UC by increasing body weight and colon length and decreasing DAI (disease activity index), colon macroscopic damage index (CMDI), histological injury scores, and reactive oxygen species (ROS), MDA, and SOD levels, thereby alleviating histopathological changes and inhibiting oxidative stress. HIEC-6 cells were exposed to lipopolysaccharide (LPS) condition with or without PSMB5, along with caspase-1 inhibitor (Z-VAD-FMK), NLRP3 inhibitor (MCC950), and ROS scavenger N-acetylcysteine (NAC). The viability of the cells, the release of lactate dehydrogenase (LDH), and intracellular ROS generation were determined using assay kits. Western blot analysis was used to determine the levels of NLRP3, ASC, cleaved caspase-1 (p20), pro-IL-1β, IL-1β, pro-IL-18, and IL-18. PSMB5 overexpression enhanced the inflammatory damage in LPS-treated HIEC-6 cells by activating the NLRP3 inflammasome and mediating pyroptosis, as demonstrated by increased LDH release and lower cell viability, as well as increased expression of NLRP3, ASC, cleaved caspase-1 (p20), IL-1, and IL-18. Meanwhile, NAC protected HIEC-6 cells from LPS-induced damage by reversing the activation of the NLRP3 inflammasome-mediated pyroptosis. In conclusion, PSMB5 may lower HIEC-6 cell susceptibility to LPS and ameliorate UC-induced HIEC-6 cell damage by decreasing ROS generation and hence inhibiting NLRP3-mediated pyroptosis.}, }
@article {pmid36058431, year = {2022}, author = {Ma, W and Wang, X and Sun, H and Xu, B and Song, R and Tian, Y and Zhao, L and Xu, Y and Zhao, Y and Yang, F and Chen, H and Gong, R and Yu, Y and Li, X and Li, S and Zhang, W and Zhang, T and Ne, J and Cai, B}, title = {Oxidant stress-sensitive circRNA Mdc1 controls cardiomyocyte chromosome stability and cell cycle re-entry during heart regeneration.}, journal = {Pharmacological research}, volume = {184}, number = {}, pages = {106422}, doi = {10.1016/j.phrs.2022.106422}, pmid = {36058431}, issn = {1096-1186}, mesh = {Animals ; Animals, Newborn ; Cell Cycle ; Cell Cycle Proteins/genetics ; Cell Proliferation ; Chromosomal Instability ; Cysteine/metabolism ; Heart/physiology ; Mice ; *Myocardial Infarction/metabolism ; *Myocytes, Cardiac/metabolism ; Oxidants/metabolism ; RNA, Circular/genetics ; Regeneration/physiology ; }, abstract = {Targeting cardiomyocyte plasticity has emerged as a new strategy for promoting heart repair after myocardial infarction. However, the precise mechanistic network underlying heart regeneration is not completely understood. As noncoding RNAs, circular RNAs (circRNAs) play essential roles in regulating cardiac physiology and pathology. The present study aimed to investigate the potential roles of circMdc1 in cardiac repair after injury and elucidate its underlying mechanisms. Here, we identified that circMdc1 levels were upregulated in postnatal mouse hearts but downregulated in the regenerative myocardium. The expression of circMdc1 in cardiomyocytes is sensitive to oxidative stress, which was attenuated by N-acetyl-cysteine. Enforced circMdc1 expression inhibited cardiomyocyte proliferation, while circMdc1 silencing led to cardiomyocyte cell cycle re-entry. In vivo, the cardiac-specific adeno-associated virus-mediated knockdown of circMdc1 promoted cardiac regeneration and heart repair accompanied by improved heart function. Conversely, circMdc1 overexpression blunted the regenerative capacity of neonatal hearts after apex resection. Moreover, circMdc1 was able to block the translation of its host gene Mdc1 specifically by binding to PABP, affecting DNA damage and the chromosome stability of cardiomyocytes. Furthermore, overexpression of Mdc1 caused damaged mouse hearts to regenerate and repair after myocardial infarction in vivo. Oxidative stress-sensitive circMdc1 plays an important role in cardiac regeneration and heart repair after injury by regulating DNA damage and chromosome stability in cardiomyocytes by blocking the translation of the host gene Mdc1.}, }
@article {pmid36058351, year = {2022}, author = {Wang, Y and Cui, J and Zheng, G and Zhao, M and Hao, Z and Lian, H and Li, Y and Wu, W and Zhang, X and Wang, J}, title = {Ochratoxin A induces cytotoxicity through ROS-mediated endoplasmic reticulum stress pathway in human gastric epithelium cells.}, journal = {Toxicology}, volume = {479}, number = {}, pages = {153309}, doi = {10.1016/j.tox.2022.153309}, pmid = {36058351}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Beclin-1 ; *Endoplasmic Reticulum Stress ; Epithelium ; Humans ; *Ochratoxins/toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium species that greatly threatens human health. We previously showed that OTA induced cycle arrest, apoptosis and autophagy in human gastric epithelium cells (GES-1). However, the mechanism underlying these effects is still unclear. Here, we showed that OTA exposure increased the expression of endoplasmic reticulum (ER) stress indicators (GRP78, PERK, ATF6, eIF2α, and CHOP), suggesting the activation of the unfolded protein response pathway. 4-phenylbutyric acid (4-PBA), an ER stress-specific inhibitor, attenuated OTA-induced loss of cell viability and apoptosis in GES-1 cells. It also attenuated the G2 phase arrest and autophagy induced by OTA, as evidenced by upregulated G2 phase-related proteins (Cdc2, Cdc25C, and cyclinB1) and downregulated autophagy markers (LC3B and Beclin-1). Moreover, OTA was found to increase ROS generation, and the inhibition of ROS formation by N-acetylcysteine (NAC), an ROS inhibitor, attenuated OTA-induced ER stress and subsequent apoptosis, cell cycle arrest, and autophagy. Collectively, these results suggest that the ROS-mediated ER stress pathway contributes to the OTA toxin-induced cytotoxicity in GES-1 cells. This study offers new insights into the molecular mechanisms underlying OTA toxicity in gastric cells.}, }
@article {pmid36047304, year = {2022}, author = {Jia, Y and Zhang, J and Zhao, Y and Dong, R and Wang, H and Jiang, X}, title = {Gold nanoparticles bearing a clinically used non-antibiotic drug for combating multi-drug resistant bacteria.}, journal = {Chemical communications (Cambridge, England)}, volume = {58}, number = {75}, pages = {10544-10547}, doi = {10.1039/d2cc03460c}, pmid = {36047304}, issn = {1364-548X}, mesh = {Acetylcysteine ; Anti-Bacterial Agents/pharmacology ; Bacteria ; *Gold/pharmacology ; *Metal Nanoparticles ; Microbial Sensitivity Tests ; }, abstract = {We introduce N-acetyl-L-cysteine (NAC), a clinically used non-antibiotic drug, to the synthesis of antibacterial gold nanoparticles (Au_NAC). Au_NAC shows excellent antibacterial activities against multi-drug resistant (MDR) Gram-negative bacteria and possesses wound healing capabilities. We provide a new direction for antibiotic design and novel uses of known drugs.}, }
@article {pmid36047270, year = {2022}, author = {Lin, R and Pian, Y and Zhang, C and Zhou, L and Ren, X}, title = {[N-acetylcysteine alleviates cadmium-induced testicular interstitial cell apoptosis by activating protein kinase B pathway].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {51}, number = {4}, pages = {632-637}, doi = {10.19813/j.cnki.weishengyanjiu.2022.04.022}, pmid = {36047270}, issn = {1000-8020}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Apoptosis ; *Cadmium/toxicity ; Leydig Cells/metabolism ; Male ; Mice ; Oxidative Stress ; Proto-Oncogene Proteins c-akt/metabolism/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {OBJECTIVE: To investigate the regulation mechanism of N-acetylcysteine(NAC) on cadmium-induced apoptosis of mouse testicular interstitial cells based on protein kinase B pathway(AKT pathway).<br><br>METHODS: Mouse testicular mesenchymal cells(TM3) were divided into fourgroups according to different treatment, control group, cadmium group(Cd, 5, 10, 20, 30, 40 and 50 &#x3bc;mol/L), NAC group(NAC, 500 &#x3bc;mol/L) and NAC+Cd group(500 &#x3bc;mol/L NAC+20 &#x3bc;mol/L Cd). Cells of NAC+Cd group were pretreated with NAC for 30 min, and then combined with cadmium for 24 h. Cell viability was determined by CCK8. Hoechst staining was used to determine cell morphology. Cell apoptosis rate was analyzed by flow cytometry. Malondialdehyde(MDA) and glutathione(GSH) were measured simultaneously. Western blot was used to detect the expression levels of AKT protein, B-cell lymphoma-2(Bcl-2) and Bcl-2 associated X protein(Bax).<br><br>RESULTS: Cadmium inhibited the proliferation of TM3 cells in a dose-effect relationship. Cell morphology observation showed that with the increase of cadmium concentration, the cells shrank, became round and even fell off, and appeared dense nuclear staining. The MDA level in Cd group was(1.56&#xb1;0.11) &#x3bc;mol/mg prot, which was significantly higher than that in control group(P<0.01). Compared to the control group, the level of GSH was significantly decreased to(1.28&#xb1;0.25) &#x3bc;mol/mg prot(P<0.01). NAC pretreatment could reduce the MDA content and increase the GSH level, and the difference was statistically significant compared with the Cd group(P<0.01). Western blot result showed that NAC pretreatment significantly increased levels of phosphorylated AKT and Bcl-2, the levels were 0.65&#xb1;0.05 and 0.45&#xb1;0.03, respectively(P<0.01). The Bax/Bcl-2 ratio was 1.54&#xb1;0.15, which was significantly lower than that of the Cd group(P<0.01).<br><br>CONCLUSION: NAC can inhibit cadmium-mediated TM3 cell damage and apoptosis, which may be related to the improvement of oxidative stress state, activation of TM3 AKT pathway and reduction of Bax/Bcl-2 ratio.}, }
@article {pmid36046596, year = {2022}, author = {Chi, L and Shan, Y and Cui, Z}, title = {N-Acetyl-L-Cysteine Protects Airway Epithelial Cells during Respiratory Syncytial Virus Infection against Mucin Synthesis, Oxidative Stress, and Inflammatory Response and Inhibits HSPA6 Expression.}, journal = {Analytical cellular pathology (Amsterdam)}, volume = {2022}, number = {}, pages = {4846336}, pmid = {36046596}, issn = {2210-7185}, mesh = {Acetylcysteine/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Antiviral Agents/metabolism/pharmacology ; Cell Line ; Epithelial Cells/metabolism ; ErbB Receptors/metabolism ; Glutathione Disulfide/metabolism/pharmacology ; HSP70 Heat-Shock Proteins ; Humans ; Oxidative Stress ; Reactive Oxygen Species/metabolism/pharmacology ; *Respiratory Syncytial Virus Infections/drug therapy/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Objective. Respiratory syncytial virus (RSV) infection is an important cause of hospitalization of children worldwide, leading to significant morbidity and mortality. RSV infection leads to increasing inflammatory and apoptosis events in the airway epithelium through mechanisms involving ROS generation. The antioxidant N-acetyl-L-cysteine (NAC) has been shown to inhibit influenza virus replication and to reduce the secretion of inflammatory and apoptotic mediators during virus infection. The study aims to investigate the effects of NAC on human bronchial epithelial cells BEAS-2B and HSPA6 expression during RSV infection. Methods. CCK-8 assays were performed to evaluate cell survival. The production of proinflammatory factors, TNF-α, IL-6, IL-1β, IL-18, and MUC5AC was examined by quantitative real-time PCR and ELISA. Oxidative stress was determined by reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH)/glutathione disulfide (GSSG) ratio. Immunoblotting analysis of epidermal growth factor receptor (EGFR) and its phosphorylation was performed. The antiviral effect of NAC was assessed by determining viral titers using plaque assay. Results. RSV infection reduced cell survival, promoted the release of proinflammatory factors, increased the ROS production and MDA concentration, and diminished the SOD activity and GSH/GSSG ratio, all which were attenuated by NAC treatment. Accordingly, NAC treatment inhibited the activation of EGFR and MUC5AC in BEAS-2B cells with RSV infection. Furthermore, NAC administration resulted in a marked decrease in RSV-induced HSPA6 expression in BEAS-2B cells. Concomitantly, EPB treatment led to an evident inhibition of RSV fusion gene and viral replication in RSV-infected BEAS-2B cells. Conclusion. This work supports the use of NAC to exert antimucin synthesis, anti-inflammatory, antioxidant, and antiviral effects on airway epithelium during RSV infection.}, }
@article {pmid36041358, year = {2022}, author = {Zhu, Q and Xiao, Y and Jiang, M and Liu, X and Cui, Y and Hao, H and Flaker, GC and Liu, Q and Zhou, S and Liu, Z}, title = {N-acetylcysteine attenuates atherosclerosis progression in aging LDL receptor deficient mice with preserved M2 macrophages and increased CD146.}, journal = {Atherosclerosis}, volume = {357}, number = {}, pages = {41-50}, doi = {10.1016/j.atherosclerosis.2022.08.008}, pmid = {36041358}, issn = {1879-1484}, support = {R01 HL124122/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aging ; Animals ; *Atherosclerosis/drug therapy/genetics/prevention &amp; control ; CD146 Antigen ; Diet, High-Fat ; *Hyperlipidemias/complications/drug therapy/genetics ; Inflammation/pathology ; Macrophages/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Reactive Oxygen Species ; Receptors, LDL/genetics ; }, abstract = {BACKGROUND AND AIMS: Inflammation and reactive oxygen species (ROS) are important to the pathogenesis of atherosclerosis. The effect of antioxidants on atherosclerosis is inconsistent, and sometimes controversial. We aimed to test the hypothesis that attenuation of atherosclerosis by N-acetylcysteine (NAC) depends on NAC treatment timing and duration.<br><br>METHODS: Male LDL receptor deficient (LDLR[-/-]) mice were fed a normal diet (ND) and divided into controls (on ND for 24 months), models 1-2 (at age of 9 months, starting NAC treatment for 3 or 6 months), and model 3 (at age of 18 months, starting NAC treatment for 6 months). To determine if hyperlipidemia compromises NAC treatment outcome, mice were fed a high fat diet (HFD) starting at age of 6 weeks and treated with NAC starting at 9 months of age for 6 months.<br><br>RESULTS: NAC treatment for 6 months, not for 3 months, significantly attenuated atherosclerosis progression, but did not reverse atherosclerotic lesions, in aging LDLR[-/-] mice on ND. NAC had no effect on atherosclerotic lesions in mice on HFD. NAC treatment significantly decreased aortic ROS production, and the levels of inflammatory cytokines in serum and aorta of aging LDLR[-/-] mice with increased CD146 level. Bone marrow transplantation study with GFP-positive bone marrow cells showed that NAC treatment preserved M2 population and M2 polarization in the aorta of LDLR[-/-] mice.<br><br>CONCLUSIONS: Early and adequate NAC treatment could effectively attenuate inflammation and atherosclerosis progression with preserved M2 population and increased CD146 level in aging LDLR[-/-] mice without extreme hyperlipidemia.}, }
@article {pmid36039439, year = {2022}, author = {Ii, H and Taniguchi, K and Yoshiya, T and Nohara, Y and Kageyama, S and Kawauchi, A and Nakata, S}, title = {The γ-Glutamylcyclotransferase Inhibitor Pro-GA Induces an Antiproliferative Effect Through the Generation of Mitochondrial Reactive Oxygen Species.}, journal = {Anticancer research}, volume = {42}, number = {9}, pages = {4311-4317}, doi = {10.21873/anticanres.15931}, pmid = {36039439}, issn = {1791-7530}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Breast Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; MCF-7 Cells ; Mice ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; *gamma-Glutamylcyclotransferase ; }, abstract = {BACKGROUND/AIM: γ-Glutamylcyclotransferase (GGCT) is up-regulated in a broad range of cancers, including breast cancer, and GGCT inhibition has been shown to be a promising strategy for therapy. Herein, we evaluated the efficacy and mechanism of action of pro-GA, a GGCT enzymatic inhibitor, in MCF7 breast cancer cells.<br><br>MATERIALS AND METHODS: Proliferation was evaluated by WST-8 and trypan blue dye exclusion assays. Western blot analysis was conducted to examine the expression of cyclin-dependent kinase inhibitors (CDKI), including p21, p27, and p16. Induction of senescence was assessed by senescence-associated &#x3b2;-galactosidase staining. Generation of mitochondrial superoxide reactive oxygen species (ROS) was assessed using flow cytometry. The effect of N-acetylcysteine (NAC) on pro-GA dependent inhibition of proliferation, ROS generation, and senescence was also studied. The efficacy of systemic administration of pro-GA was evaluated in a MCF7 xenograft mouse model.<br><br>RESULTS: Treatment with pro-GA inhibited proliferation of MCF7 cells, increased CDKI expression and mitochondrial ROS, and induced cellular senescence. We found that cotreatment with NAC restored proliferation in pro-GA treated cells. NAC similarly suppressed CDKI expression, mitochondrial ROS generation, and senescence induced by pro-GA. Furthermore, the systemic administration of pro-GA in an MCF7 xenograft model had significant antitumor effects without toxicity.<br><br>CONCLUSION: Pro-GA may be a promising therapeutic agent for the treatment of breast cancer.}, }
@article {pmid36034775, year = {2022}, author = {Licata, A and Minissale, MG and Stankevičiūtė, S and Sanabria-Cabrera, J and Lucena, MI and Andrade, RJ and Almasio, PL}, title = {N-Acetylcysteine for Preventing Acetaminophen-Induced Liver Injury: A Comprehensive Review.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {828565}, pmid = {36034775}, issn = {1663-9812}, abstract = {Aims: N-Acetylcysteine (NAC) is used as an antidote in acetaminophen (APAP) overdose to prevent and mitigate drug-induced liver injury (DILI). Our objective was to systematically review evidence of the use of NAC as a therapeutic option for APAP overdose and APAP-related DILI in order to define the optimal treatment schedule and timing to start treatment. Methods: Bibliographic databases (PubMed, Web of Science, Embase, and MEDLINE) were searched for retrospective and prospective cohort studies, case series, and clinical trials. The prespecified primary outcomes were DILI-related mortality, hepatotoxicity, and adverse events (AEs). Results: In total, 34 studies of NAC usage in APAP-related DILI cases with 19,580 patients were identified, of which 2,376 patients developed hepatotoxicities. The mortality rate across different studies ranged from 0 to 52%. Large variability of NAC regimens was found, i.e., intravenous (I.V.) (100-150 mg/kg) and oral (70-140 mg/kg), and length of treatment varied-12, 24, or 48 h for I.V. regimen and 72 h for oral administration. The timing of initiation of NAC treatment showed different results in terms of occurrence of hepatotoxicity and mortality; if started within 8 h and no more than 24 h from APAP overdose, either intravenously or orally, NAC administration was efficacious in terms of mortality. The most frequent AEs reported were anaphylactic reactions, followed by cutaneous AEs for the IV route and intestinal AEs for the oral one. Conclusion: NAC improves hepatotoxicity and reduces mortality. Timing of treatment, ranging from 8 to 24 h from APAP overdose, regardless of the regimen or route of administration, is important to prevent or minimize liver damage, particularly in children and in elderly and obese patients.}, }
@article {pmid36033949, year = {2022}, author = {Le, JW and Sun, M and Zhu, JH and Fan, H}, title = {Protective effect of N-acetylcysteine on acute lung injury in septic rats by inhibiting inflammation, oxidation, and apoptosis.}, journal = {Iranian journal of basic medical sciences}, volume = {25}, number = {7}, pages = {859-864}, pmid = {36033949}, issn = {2008-3866}, abstract = {OBJECTIVES: Acute lung injury (ALI) is a common comorbidity in patients with sepsis, and finding drugs that can effectively reduce its mortality is a hot spot in current research. The purpose of this study is to explore the protective mechanism of N-acetylcysteine (NAC) on ALI in septic rats.<br><br>MATERIALS AND METHODS: We used NAC to intervene in septic rats to evaluate the plasma inflammatory factors and lung tissue pathological damage. Biochemical methods were used to determine the levels of oxidases in lung tissue, the expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) proteins, and observed lung tissue cell apoptosis.<br><br>RESULTS: NAC pretreatment decreased the mortality of septic rats, improved lung tissue pathological damage, reduced the levels of tumor necrosis factor-&#x3b1;, interleukin-1&#x3b2;, interleukin-6, interleukin-8, and malondialdehyde, and increased activity of superoxide dismutase, glutathione peroxidase, and catalase. Moreover, NAC pretreatment significantly decreased iNOS protein expression and increased eNOS protein expression in lung tissue. Meanwhile, NAC significantly decreased the number of apoptosis and the levels of Bax and Caspase-3 mRNA and increased the level of Bcl-2 mRNA in the lung tissue of septic rats.<br><br>CONCLUSION: NAC protects ALI in septic rats by inhibiting inflammation, oxidative stress, and apoptosis.}, }
@article {pmid36032833, year = {2022}, author = {İskender Emekli, Z and Şentürk, F and Bahadir, O}, title = {Protective Effects of Curcumin and N-Acetyl Cysteine Against Noise-Induced Sensorineural Hearing Loss: An Experimental Study.}, journal = {Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India}, volume = {74}, number = {Suppl 1}, pages = {467-471}, pmid = {36032833}, issn = {2231-3796}, abstract = {We investigated the effectiveness of N-acetyl cysteine (NAC) and curcumin, which have known antioxidant and anti-inflammatory effects, in reducing acoustic trauma. We randomly divided 40 adult male rats into four groups: a control group (group 1), a curcumin group (group 2), a NAC group (group 3), and an ethyl alcohol group (group 4). The rats were exposed to 110 dB sound at a frequency of 4 kHz for 2 h to simulate acoustic trauma. Group 1, group 2, group 3, and group 4 received 1 ml saline, 200 mg/kg curcumin, 350 mg/kg NAC, or 1 ml ethyl alcohol, respectively, intraperitoneally 30 min before and 24 and 48 h after acoustic trauma. Distortion product otoacoustic emissions (DPOAEs) were recorded before and after the acoustic trauma, and 72 h after drug administration. In group 2, signal-to-noise ratio (SNR) values in frequencies of 1000 Hz, 1500 Hz, and 4000 Hz decreased in the second measurements when compared to the first, and showed improvements in the third measurements in comparison to the second ones. In group 3, SNR values decreased in the second measurements, but only the values at 6000 Hz were found to be statistically significant (p = 0.007). The values in the third measurements were statistically significant when compared to the second ones. There was a statistically significant difference in the third measurements in both groups 2 and 3, possibly due to curcumin and NAC treatment. This study showed that curcumin and NAC may be effective against noise-induced hearing loss.}, }
@article {pmid36029289, year = {2022}, author = {Zhang, F and Wang, F and Li, W and Liang, L and Sang, X}, title = {The toxicity mechanism of glabridin in prostate cancer cells is involved in reactive oxygen species-dependent PI3K/Akt pathway: Integrated utilization of bioinformatic analysis and in vitro test validation.}, journal = {Environmental toxicology}, volume = {37}, number = {12}, pages = {2937-2946}, doi = {10.1002/tox.23649}, pmid = {36029289}, issn = {1522-7278}, mesh = {Male ; Humans ; Reactive Oxygen Species/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Caspase 3/metabolism ; Computational Biology ; Prospective Studies ; Apoptosis ; Cell Proliferation ; *Prostatic Neoplasms ; Acetylcysteine/pharmacology ; In Vitro Techniques ; }, abstract = {Glabridin is a prenylated isoflavonoid with considerable anticancer property. Reactive oxygen species (ROS) have evolved as regulators of many cellular signaling pathways in prostate cancer (PC). However, the role of ROS signaling in the anticancer activity of glabridin has not been investigated. Here, we attempted to evaluate the effect of glabridin on PC and the involvement of ROS signaling. Intracellular ROS and mitochondrial ROS (mitoROS) production in PC cell lines, DU-145 and LNCaP, were measured by H2DCFDA and MitoSOX Red staining, respectively. MTT assay was used to analyze the cellular viability. EdU staining assay was conducted to analyze the cell proliferation. To analyze apoptotic rate, TUNEL assay was performed. Caspase-3 activity was detected to reflect cell apoptosis. Western blot was carried out to detect the expression levels of Akt and p-Akt. We found that intracellular ROS and mitoROS levels were dose-dependently upregulated after glabridin treatment in both DU-145 and LNCaP cells, which was reversed by the treatment of ROS inhibitor, N-acetyl-L-cysteine (NAC). Glabridin inhibited the cell viability and reduced the number of EdU-positive DU-145 and LNCaP cells, which were respectively proved by MTT assay and EdU staining assay. Glabridin promoted cell death with increased apoptotic rate and caspase-3 activity in DU-145 and LNCaP cells. The effects of glabridin on cell proliferation and apoptosis were reversed by NAC. Moreover, glabridin suppressed the ratio of p-Akt/Akt, while NAC mitigated the decreased p-Akt/Akt ratio. In addition, the effects of glabridin on cell proliferation and apoptosis were also attenuated by Akt activator, SC79. Collectively, our results demonstrated that glabridin suppressed proliferation and induced apoptosis in PC cells via regulating ROS-mediated PI3K/Akt pathway. These findings suggested that glabridin might hold a promising prospective as a therapeutic agent against PC.}, }
@article {pmid36028602, year = {2022}, author = {Liu, Q and Wang, Y and Tan, D and Liu, Y and Zhang, P and Ma, L and Liang, M and Chen, Y}, title = {The Prevention and Reversal of a Phenytoin-Resistant Model by N-acetylcysteine Therapy Involves the Nrf2/P-Glycoprotein Pathway at the Blood-Brain Barrier.}, journal = {Journal of molecular neuroscience : MN}, volume = {72}, number = {10}, pages = {2125-2135}, pmid = {36028602}, issn = {1559-1166}, support = {82071458//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Mice ; *Phenytoin/pharmacology/therapeutic use ; Blood-Brain Barrier/metabolism ; Acetylcysteine/pharmacology/therapeutic use/metabolism ; Nimodipine/pharmacology ; Anticonvulsants/pharmacology/therapeutic use ; NF-E2-Related Factor 2/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics/metabolism ; Brain/metabolism ; *Drug Resistant Epilepsy/metabolism ; }, abstract = {The transporter hypothesis is one of the most popular hypotheses of drug-resistant epilepsy (DRE). P-glycoprotein (P-gp), a channel protein at the blood-brain barrier (BBB), plays an important role in the transport of some anti-seizure drugs from brain tissue into vessels, which reduces drug concentrations and diminishes the effects of drug treatment. We performed this study to test whether P-gp is overexpressed in DRE and identify ways to prevent and reverse DRE. In this study, we established a phenytoin (PHT)-resistant mouse model and revealed that P-gp was overexpressed at the BBB in PHT-resistant mice. The P-gp inhibitor nimodipine decreased the resistance of phenytoin. Antioxidative preventive treatment with N-acetylcysteine (NAC) prevented the mice from entering a PHT-resistant state, and NAC therapy tended to reverse PHT resistance into sensitivity. We were also able to induce PHT resistance by activating the Nrf2/P-gp pathway, which indicates that oxidative stress plays an important role in drug resistance. Taken together, these findings suggest that antioxidative therapy may be a promising strategy for overcoming DRE.}, }
@article {pmid36028178, year = {2022}, author = {Zhang, Y and Yang, S and Qiu, Z and Huang, L and Huang, L and Liang, Y and Liu, X and Wang, M and Zhou, B}, title = {Pyrogallol enhances therapeutic effect of human umbilical cord mesenchymal stem cells against LPS-mediated inflammation and lung injury via activation of Nrf2/HO-1 signaling.}, journal = {Free radical biology &amp; medicine}, volume = {191}, number = {}, pages = {66-81}, doi = {10.1016/j.freeradbiomed.2022.08.030}, pmid = {36028178}, issn = {1873-4596}, mesh = {Acetylcysteine/metabolism ; *Acute Lung Injury/drug therapy/therapy ; Animals ; Heme Oxygenase-1/genetics/metabolism ; Humans ; Inflammation/drug therapy/therapy ; Inflammation Mediators/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Lipopolysaccharides ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology ; NF-E2-Related Factor 2/genetics/metabolism ; NF-kappa B/metabolism ; *Pyrogallol/pharmacology ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 4/genetics/metabolism ; Umbilical Cord/cytology ; }, abstract = {The main challenges in clinical applications of mesenchymal stem cells (MSCs) are attributed to their heterogeneity. It is believed that preconditioning of MSCs with active compounds may enhance the expression of potentially therapeutic molecules and thus achieve stable and effective therapeutic outcomes. In the present study, we investigated the mechanism by which pyrogallol increased the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) against LPS-induced acute lung injury (ALI). hUCMSCs with pyrogallol treatment increased expression of HO-1 at both mRNA and protein levels, accompanied by Kelch-Like ECH-Associated Protein 1 (Keap1) degradation, and upregulation of the Nrf2 protein levels as well as nuclear translocation of Nrf2. Moreover, the modulation of Keap1 and Nrf2 as well as HO-1 upregulation by pyrogallol was reversed by pretreatment with N-acetylcysteine (NAC) and a P38 kinase inhibitor (SB203580). Whereas, NAC pretreatment abrogated pyrogallol-mediated activation of P38 kinase, indicating that pyrogallol-derived ROS led to P38 kinase activation, thus promoting Nrf2/HO-1 signaling. Additionally, we found that the induction of p62 by the pyrogallol-mediated ROS/P38/Nrf2 axis interacted with Keap1 and resulted in autophagic degradation of Keap1, which created a positive feedback loop to further release of Nrf2. Furthermore, the increased expression of HO-1 in pyrogallol-pretreated hUCMSCs led to enhanced inhibitory effects on LPS-mediated TLR4/P-P65 signaling in BEAS-2B cells, resulting in increasing suppression of LPS-indued expression of a series of pro-inflammatory mediators. Compared to untreated hUCMSCs, Sprague-Dawley (SD) rats with pyrogallol-primed hUCMSCs transplantation showed enhanced improvements in LPS-mediated lung pathological alterations, the increased lung index (lung/body ratio), apoptosis of epithelial cells, the activation of TLR4/NF-κB signaling as well as the release of pro-inflammatory mediators. Together, these results suggested that hUCMSCs with pyrogallol pretreatment enhanced the therapeutic efficacy of hUCMSCs, which may provide a promising therapeutic strategy to maximize the therapeutic efficacy of hUCMSC-based therapy for treating LPS-associated ALI.}, }
@article {pmid36016767, year = {2022}, author = {Kashi, EA and Salmani, AA and Shafagh, S and Mousavi, GA and Mousavi, N and Heydari, M and Hajian, A}, title = {Effects of oral N-acetyl cysteine on pain and plasma biochemical parameters in fibrocystic breast disorder: A randomized controlled trial.}, journal = {Surgery open science}, volume = {10}, number = {}, pages = {69-73}, pmid = {36016767}, issn = {2589-8450}, abstract = {BACKGROUND: Fibrocystic change is the most common benign lesion in breasts of a woman in her reproductive age. It is an outcome of estrogen excess due to sex hormone imbalance. Cyclical pain as the most common symptom worsens life quality, compels patient to seek health care support continuously, and imposes large amounts of expense to both patient and health system. Current study aims to evaluate effects of N-acetyl cysteine on decreasing pain and changes in plasma biochemistry.<br><br>METHOD: A total of 64 eligible women participated in this double-blinded randomized controlled trial. They were between 18 and 40&#x202f;years. Participants were randomly allocated into oral N-acetyl cysteine and placebo receivers. Intervention and follow-up lasted for, respectively, a 12-week drugs-on and 12-month drugs-off period. Visual analog scaling was applied to measure severity of pain. Peripheral venous plasma was extracted and compared for inflammatory parameters including high-sensitivity C-reactive protein, total antioxidant capacity, malondialdehyde, total plasma glutathione, lipid profile, and fasting blood sugar.<br><br>RESULTS: Oral N-acetyl cysteine significantly decreased feeling of cyclical mastalgia (P&#x202f;<&#x202f;.01) after 12&#x202f;weeks of consumption. In addition to lowering of plasma level of high-sensitivity C-reactive protein (P&#x202f;=&#x202f;.008), total plasma glutathione significantly increased (P&#x202f;=&#x202f;.02) among N-acetyl cysteine receivers. No change in lipid profile and insulin sensitivity was seen.<br><br>CONCLUSION: N-Acetyl cysteine could mitigate cyclical mastalgia. Inflammation as a considered reason for cyclical mastalgia also was halted by N-acetyl cysteine consumption.}, }
@article {pmid36014444, year = {2022}, author = {Cui, XY and Park, SH and Park, WH}, title = {Anti-Cancer Effects of Auranofin in Human Lung Cancer Cells by Increasing Intracellular ROS Levels and Depleting GSH Levels.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {16}, pages = {}, pmid = {36014444}, issn = {1420-3049}, support = {2019R1I1A2A01041209//The Basic Science Research Program through the National Research Foundation of Korea (NRF)/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis ; *Auranofin/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Glutathione/metabolism ; Humans ; *Lung Neoplasms/drug therapy/metabolism ; Membrane Potential, Mitochondrial ; Reactive Oxygen Species/metabolism ; }, abstract = {Auranofin, as a thioredoxin reductase (TrxR) inhibitor, has promising anti-cancer activity in several cancer types. However, little is known about the inhibitory effect of auranofin on lung cancer cell growth. We, therefore, investigated the antigrowth effects of auranofin in various lung cancer cells with respect to cell death, reactive oxygen species (ROS), and glutathione (GSH) levels. Treatment with 0~5 µM auranofin decreased cell proliferation and induced cell death in Calu-6, A549, SK-LU-1, NCI-H460, and NCI-H1299 lung cancer cells at 24 h. In addition, 0~5 µM auranofin increased ROS levels, including O2[•-], and depleted GSH levels in these cells. N-acetyl cysteine (NAC) prevented growth inhibition and mitochondrial membrane potential (MMP, ∆Ψm) loss in 3 and 5 µM auranofin-treated Calu-6 and A549 cells at 24 h, respectively, and decreased ROS levels and GSH depletion in these cells. In contrast, L-buthionine sulfoximine (BSO) enhanced cell death, MMP (∆Ψm) loss, ROS levels, and GSH depletion in auranofin-treated Calu-6 and A549 cells. Treatment with 3 and 5 µM auranofin induced caspase-3 activation and poly (ADP ribose) polymerase (PARP) cleavage in Calu-6 and A549 cells, respectively. Both were prevented by NAC, but enhanced by BSO. Moreover, TrxR activity was reduced in auranofin-treated Calu-6 and A549 cells. That activity was decreased by BSO, but increased by NAC. In conclusion, these findings demonstrate that auranofin-induced cell death is closely related to oxidative stress resulted from increased ROS levels and GSH depletion in lung cancer cells.}, }
@article {pmid36012934, year = {2022}, author = {Wang, J and Wang, Y and Ling, X and Zhang, Z and Deng, Y and Tian, P}, title = {Comparison of Sputum Treated with Power Ultrasound and Routine NALC-NaOH Methods for Mycobacterial Culture: A Prospective Study.}, journal = {Journal of clinical medicine}, volume = {11}, number = {16}, pages = {}, pmid = {36012934}, issn = {2077-0383}, support = {2021SFGC0504//Department of Science and Technology of Shandong Province/ ; 2019WS532.//Health Science and Technology Development Plan of Shandong Province/ ; }, abstract = {Mycobacterial culture remains the gold standard for the diagnosis of active tuberculosis. However, an appropriate digestion and decontamination method is essential for the effective recovery of tubercle bacilli in culture. The study was designed to compare the efficacy of sputum treated with power ultrasound (PU) and routine NALC-NaOH methods for mycobacterial culture from clinically suspected cases of pulmonary tuberculosis. To evaluate the PU and routine NALC-NaOH methods, sputum specimens (n = 597) were studied (culturing on MGIT 960), and the performances were compared. Of the 597 samples, 89 (14.91%) sputum samples treated with the NaOH-NALC method were mycobacterial culture positive, including Mycobacterium tuberculosis (M.TB; n = 77, 12.90%) and nontuberculous mycobacteria (NTM; n = 12, 2.01%). One hundred and ten (18.43%) sputum samples treated with the PU method were culture positive, including M.TB (n = 87, 14.57%) and NTM (n = 23, 3.85%). The PU method detected 10 additional cases of M.TB and 11 additional cases of NTM when compared to the NALC-NaOH method. Statistical analysis showed that a significant difference was found in the culture-positive ratio of M.TB and NTM between the two method groups (p < 0.05). Compared with that of the NALC-NaOH method (8.04%), sputum treated with PU method (4.86%) had a significantly lower contamination rate (p < 0.05). In conclusion, our data indicate that, compared with the NALC-NaOH method, the PU method is a rapid and effective approach for mycobacterial culture when detecting active TB. However, its accurate mechanism has not been well addressed, and further investigation is still required.}, }
@article {pmid36012679, year = {2022}, author = {Lai, CC and Baskaran, R and Tsao, CY and Tuan, LH and Siow, PF and Palani, M and Lee, LJ and Liu, CM and Hwu, HG and Lee, LJ}, title = {Chronic N-Acetylcysteine Treatment Prevents Amphetamine-Induced Hyperactivity in Heterozygous Disc1 Mutant Mice, a Putative Prodromal Schizophrenia Animal Model.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012679}, issn = {1422-0067}, support = {105-2628-B-002-004-MY3//Ministry of Science and Technology of the Republic of China/ ; 108-2320-B-002-066-MY3//Ministry of Science and Technology of the Republic of China/ ; }, mesh = {Acetylcysteine/pharmacology ; *Amphetamine/pharmacology ; Animals ; Disease Models, Animal ; Dopamine/metabolism ; Female ; Glycogen Synthase Kinase 3 ; Humans ; Mice ; Nerve Tissue Proteins ; Pregnancy ; Receptors, Dopamine ; *Schizophrenia/drug therapy/genetics/prevention &amp; control ; }, abstract = {Symptoms of schizophrenia (SZ) typically emerge during adolescence to young adulthood, which gives a window before full-blown psychosis for early intervention. Strategies for preventing the conversion from the prodromal phase to the psychotic phase are warranted. Heterozygous (Het) Disc1 mutant mice are considered a prodromal model of SZ, suitable for studying psychotic conversion. We evaluated the preventive effect of chronic N-acetylcysteine (NAC) administration, covering the prenatal era to adulthood, on the reaction following the Amph challenge, which mimics the outbreak or conversion of psychosis, in adult Het Disc1 mice. Biochemical and morphological features were examined in the striatum of NAC-treated mice. Chronic NAC treatment normalized the Amph-induced activity in the Het Disc1 mice. Furthermore, the striatal phenotypes of Het Disc1 mice were rescued by NAC including dopamine receptors, the expression of GSK3s, MSN dendritic impairments, and striatal PV density. The current study demonstrated a potent preventive effect of chronic NAC treatment in Disc1 Het mice on the acute Amph test, which mimics the outbreak of psychosis. Our findings not only support the benefit of NAC as a dietary supplement for SZ prodromes, but also advance our knowledge of striatal dopamine receptors, PV neurons, and GSK3 signaling pathways as therapeutic targets for treating or preventing the pathogenesis of mental disorders.}, }
@article {pmid36012632, year = {2022}, author = {Luo, Q and Jia, L and Huang, C and Qi, Q and Jahangir, A and Xia, Y and Liu, W and Shi, R and Tang, L and Chen, Z}, title = {Polyphyllin I Promotes Autophagic Cell Death and Apoptosis of Colon Cancer Cells via the ROS-Inhibited AKT/mTOR Pathway.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012632}, issn = {1422-0067}, support = {2020YFH0148//Sichuan international science and technology innovation cooperation project/ ; }, mesh = {Apoptosis ; *Autophagic Cell Death ; Autophagy ; Cell Line, Tumor ; *Colonic Neoplasms/drug therapy ; Diosgenin/analogs &amp; derivatives ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Colon cancer is a common malignant tumor of the digestive tract, and it is considered among the biggest killers. Scientific and reasonable treatments can effectively improve the survival rate of patients if performed in the early stages. Polyphyllin I (PPI), a pennogenyl saponin isolated from Paris polyphylla var. yunnanensis, has exhibited strong anti-cancer activities in previous studies. Here, we report that PPI exhibits a cytotoxic effect on colon cancer cells. PPI suppressed cell viability and induced autophagic cell death in SW480 cells after 12 and 24 h, with the IC50 values 4.9 ± 0.1 μmol/L and 3.5 ± 0.2 μmol/L, respectively. Furthermore, we found PPI induced time-concentration-dependent autophagy and apoptosis in SW480 cells. In addition, down-regulated AKT/mTOR activity was found in PPI-treated SW480 cells. Increased levels of ROS might link to autophagy and apoptosis because reducing the level of ROS by antioxidant N-acetylcysteine (NAC) treatment mitigated PPI-induced autophagy and apoptosis. Although we did not know the molecular mechanism of how PPI induced ROS production, this is the first study to show that PPI induces ROS production and down-regulates the AKT/mTOR pathway, which subsequently promotes the autophagic cell death and apoptosis of colon cancer cells. This present study reports PPI as a potential therapeutic agent for colon cancer and reveals its underlying mechanisms of action.}, }
@article {pmid36012403, year = {2022}, author = {Chen, GS and Chen, SY and Liu, ST and Hsieh, CC and Lee, SP and Huang, SM}, title = {Stabilization of the c-Myc Protein via the Modulation of Threonine 58 and Serine 62 Phosphorylation by the Disulfiram/Copper Complex in Oral Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {23}, number = {16}, pages = {}, pmid = {36012403}, issn = {1422-0067}, support = {MND-MAB-111-094 to S-M Huang//Ministry of National Defense-Medical Affairs Bureau, Taiwan/ ; A1111035 to S-M Huang//Teh-Tzer Study Group for Human Medical Research Foundation, Taiwan/ ; TSGH-E-111200 to S-P Lee//Tri-Service General Hospital, Taiwan/ ; }, mesh = {*Carcinoma, Squamous Cell/drug therapy ; Cell Line, Tumor ; Copper/metabolism/pharmacology ; Disulfiram/pharmacology ; Humans ; *Mouth Neoplasms/drug therapy ; Phosphorylation ; Proto-Oncogene Proteins c-myc/metabolism ; Reactive Oxygen Species/metabolism ; Serine/metabolism ; Threonine/metabolism ; }, abstract = {MYC has a short half-life that is tightly regulated through phosphorylation and proteasomal degradation. Many studies have claimed that treatment with disulfiram (DSF) with or without copper ions can cause cancer cell death in a reactive oxygen species (ROS)-dependent manner in cancer cells. Our previous study showed that the levels of c-Myc protein and the phosphorylation of threonine 58 (T58) and serine 62 (S62) increased in DSF-Cu-complex-treated oral epidermoid carcinoma Meng-1 (OECM-1) cells. These abovementioned patterns were suppressed by pretreatment with an ROS scavenger, N-acetyl cysteine. The overexpression of c-Myc failed to induce hypoxia-inducible factor 1α protein expression, which was stabilized by the DSF-Cu complex. In this study, we further examined the regulatory mechanism behind the induction of the c-Myc of the DSF-Cu complex in an OECM-1 cell compared with a Smulow-Glickman (SG) human normal gingival epithelial cell. Our data showed that the downregulation of c-Myc truncated nick and p62 and the induction of the ratio of H3P/H3 and p-ERK/ERK might not be involved in the increase in the amount of c-Myc via the DSF/copper complexes in OECM-1 cells. Combined with the inhibitors for various signaling pathways and cycloheximde treatment, the increase in the amount of c-Myc with the DSF/copper complexes might be mediated through the increase in the stabilities of c-Myc (T58) and c-Myc (S62) proteins in OECM-1 cells. In SG cells, only the c-Myc (T58) protein was stabilized by the DSF-Cu (I and II) complexes. Hence, our findings could provide novel regulatory insights into the phosphorylation-dependent stability of c-Myc in DSF/copper-complex-treated oral squamous cell carcinoma.}, }
@article {pmid36010550, year = {2022}, author = {Huang, Z and Gan, S and Zhuang, X and Chen, Y and Lu, L and Wang, Y and Qi, X and Feng, Q and Huang, Q and Du, B and Zhang, R and Liu, Z}, title = {Artesunate Inhibits the Cell Growth in Colorectal Cancer by Promoting ROS-Dependent Cell Senescence and Autophagy.}, journal = {Cells}, volume = {11}, number = {16}, pages = {}, pmid = {36010550}, issn = {2073-4409}, mesh = {Animals ; Apoptosis ; Artesunate/pharmacology ; Autophagy ; Cell Line, Tumor ; Cell Proliferation ; Cellular Senescence ; *Colorectal Neoplasms/drug therapy/metabolism ; *Endoribonucleases ; Mice ; Protein Serine-Threonine Kinases ; Reactive Oxygen Species/metabolism ; }, abstract = {Although artesunate has been reported to be a promising candidate for colorectal cancer (CRC) treatment, the underlying mechanisms and molecular targets of artesunate are yet to be explored. Here, we report that artesunate acts as a senescence and autophagy inducer to exert its inhibitory effect on CRC in a reactive oxygen species (ROS)-dependent manner. In SW480 and HCT116 cells, artesunate treatment led to mitochondrial dysfunction, drastically promoted mitochondrial ROS generation, and consequently inhibited cell proliferation by causing cell cycle arrest at G0/G1 phase as well as subsequent p16- and p21-mediated cell senescence. Senescent cells underwent endoplasmic reticulum stress (ERS), and the unfolded protein response (UPR) was activated via IRE1α signaling, with upregulated BIP, IRE1α, phosphorylated IRE1α (p-IRE1α), CHOP, and DR5. Further experiments revealed that autophagy was induced by artesunate treatment due to oxidative stress and ER stress. In contrast, N-Acetylcysteine (NAC, an ROS scavenger) and 3-Methyladenine (3-MA, an autophagy inhibitor) restored cell viability and attenuated autophagy in artesunate-treated cells. Furthermore, cellular free Ca[2+] levels were increased and could be repressed by NAC, 3-MA, and GSK2350168 (an IRE1α inhibitor). In vivo, artesunate administration reduced the growth of CT26 cell-derived tumors in BALB/c mice. Ki67 and cyclin D1 expression was downregulated in tumor tissue, while p16, p21, p-IRE1α, and LC3B expression was upregulated. Taken together, artesunate induces senescence and autophagy to inhibit cell proliferation in colorectal cancer by promoting excessive ROS generation.}, }
@article {pmid36009471, year = {2022}, author = {Petrillo, T and Semprini, E and Tomatis, V and Arnesano, M and Ambrosetti, F and Battipaglia, C and Sponzilli, A and Ricciardiello, F and Genazzani, AR and Genazzani, AD}, title = {Putative Complementary Compounds to Counteract Insulin-Resistance in PCOS Patients.}, journal = {Biomedicines}, volume = {10}, number = {8}, pages = {}, pmid = {36009471}, issn = {2227-9059}, abstract = {Polycystic ovary syndrome (PCOS) is the most frequent endocrine-metabolic disorder among women at reproductive age. The diagnosis is based on the presence of at least two out of three criteria of the Rotterdam criteria (2003). In the last decades, the dysmetabolic aspect of insulin resistance and compensatory hyperinsulinemia have been taken into account as the additional key features in the etiopathology of PCOS, and they have been widely studied. Since PCOS is a complex and multifactorial syndrome with different clinical manifestations, it is difficult to find the gold standard treatment. Therefore, a great variety of integrative treatments have been reported to counteract insulin resistance. PCOS patients need a tailored therapeutic strategy, according to the patient's BMI, the presence or absence of familiar predisposition to diabetes, and the patient's desire to achieve pregnancy or not. The present review analyzes and discloses the main clinical insight of such complementary substances.}, }
@article {pmid36009344, year = {2022}, author = {Lad, A and Hunyadi, J and Connolly, J and Breidenbach, JD and Khalaf, FK and Dube, P and Zhang, S and Kleinhenz, AL and Baliu-Rodriguez, D and Isailovic, D and Hinds, TD and Gatto-Weis, C and Stanoszek, LM and Blomquist, TM and Malhotra, D and Haller, ST and Kennedy, DJ}, title = {Antioxidant Therapy Significantly Attenuates Hepatotoxicity following Low Dose Exposure to Microcystin-LR in a Murine Model of Diet-Induced Non-Alcoholic Fatty Liver Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {36009344}, issn = {2076-3921}, support = {P30 ES020957/NH/NIH HHS/United States ; F31 HL160178/HL/NHLBI NIH HHS/United States ; }, abstract = {We have previously shown in a murine model of Non-alcoholic Fatty Liver Disease (NAFLD) that chronic, low-dose exposure to the Harmful Algal Bloom cyanotoxin microcystin-LR (MC-LR), resulted in significant hepatotoxicity including micro-vesicular lipid accumulation, impaired toxin metabolism as well as dysregulation of the key signaling pathways involved in inflammation, immune response and oxidative stress. On this background we hypothesized that augmentation of hepatic drug metabolism pathways with targeted antioxidant therapies would improve MC-LR metabolism and reduce hepatic injury in NAFLD mice exposed to MC-LR. We chose N-acetylcysteine (NAC, 40 mM), a known antioxidant that augments the glutathione detoxification pathway and a novel peptide (pNaKtide, 25 mg/kg) which is targeted to interrupting a specific Src-kinase mediated pro-oxidant amplification mechanism. Histological analysis showed significant increase in hepatic inflammation in NAFLD mice exposed to MC-LR which was attenuated on treatment with both NAC and pNaKtide (both p ≤ 0.05). Oxidative stress, as measured by 8-OHDG levels in urine and protein carbonylation in liver sections, was also significantly downregulated upon treatment with both antioxidants after MC-LR exposure. Genetic analysis of key drug transporters including Abcb1a, Phase I enzyme-Cyp3a11 and Phase II metabolic enzymes-Pkm (Pyruvate kinase, muscle), Pklr (Pyruvate kinase, liver, and red blood cell) and Gad1 (Glutamic acid decarboxylase) was significantly altered by MC-LR exposure as compared to the non-exposed control group (all p ≤ 0.05). These changes were significantly attenuated with both pNaKtide and NAC treatment. These results suggest that MC-LR metabolism and detoxification is significantly impaired in the setting of NAFLD, and that these pathways can potentially be reversed with targeted antioxidant treatment.}, }
@article {pmid36009205, year = {2022}, author = {Mlejnek, P}, title = {Direct Interaction between N-Acetylcysteine and Cytotoxic Electrophile-An Overlooked In Vitro Mechanism of Protection.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {36009205}, issn = {2076-3921}, support = {IGA_LF_2022_034//Palack&#xfd; University, Olomouc/ ; }, abstract = {In laboratory experiments, many electrophilic cytotoxic agents induce cell death accompanied by reactive oxygen species (ROS) production and/or by glutathione (GSH) depletion. Not surprisingly, millimolar concentrations of N-acetylcysteine (NAC), which is used as a universal ROS scavenger and precursor of GSH biosynthesis, inhibit ROS production, restore GSH levels, and prevent cell death. The protective effect of NAC is generally used as corroborative evidence that cell death induced by a studied cytotoxic agent is mediated by an oxidative stress-related mechanism. However, any simple interpretation of the results of the protective effects of NAC may be misleading because it is unable to interact with superoxide (O2•[-]), the most important biologically relevant ROS, and is a very weak scavenger of H2O2. In addition, NAC is used in concentrations that are unnecessarily high to stimulate GSH synthesis. Unfortunately, the possibility that NAC as a nucleophile can directly interact with cytotoxic electrophiles to form non-cytotoxic NAC-electrophile adduct is rarely considered, although it is a well-known protective mechanism that is much more common than expected. Overall, apropos the possible mechanism of the cytoprotective effect of NAC in vitro, it is appropriate to investigate whether there is a direct interaction between NAC and the cytotoxic electrophile to form a non-cytotoxic NAC-electrophilic adduct(s).}, }
@article {pmid36009056, year = {2022}, author = {Ashar, Y and Teng, Q and Wurpel, JND and Chen, ZS and Reznik, SE}, title = {Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function.}, journal = {Biomolecules}, volume = {12}, number = {8}, pages = {}, pmid = {36009056}, issn = {2218-273X}, support = {R16 GM145586/GM/NIGMS NIH HHS/United States ; 1R16GM145586/NH/NIH HHS/United States ; }, mesh = {Cell Movement/physiology ; Female ; Folic Acid/metabolism ; Humans ; Multidrug Resistance-Associated Proteins ; Palmitic Acid/metabolism/pharmacology ; *Placenta/metabolism ; Pregnancy ; *Trophoblasts/metabolism ; Vascular Remodeling ; }, abstract = {Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid increases MRP1-mediated folate removal from EVTs, thereby interfering with EVTs' role in early placental vascular remodeling. HTR-8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM palmitic acid, respectively, for 72 h. Palmitic acid increased ABCC1 gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions in the cultured cells. Treatment with N-acetylcysteine (NAC) prevented the palmitic acid-mediated upregulation of MRP1 and restored invasion and migration in the EVTs. Finally, in an ABCC1 knockout subline of Swan-71 cells, there was a significant increase in invasion and migration functions. The novel finding in this study that palmitic acid increases MRP1-mediated folate efflux provides a missing link that helps to explain how maternal consumption of saturated fatty acids compromises the in utero environment.}, }
@article {pmid36006894, year = {2022}, author = {Miller, R and Kim, Y and Park, CG and Torres, C and Kim, B and Lee, J and Flaherty, D and Han, HS and Kim, YJ and Kong, H}, title = {Extending the Bioavailability of Hydrophilic Antioxidants for Metal Ion Detoxification via Crystallization with Polysaccharide Dopamine.}, journal = {ACS applied materials &amp; interfaces}, volume = {14}, number = {35}, pages = {39759-39774}, doi = {10.1021/acsami.2c08889}, pmid = {36006894}, issn = {1944-8252}, mesh = {Acetylcysteine ; Adenosine Triphosphate/metabolism ; *Antioxidants/metabolism/pharmacology ; Biological Availability ; Crystallization ; Dihydroxyphenylalanine ; *Dopamine/pharmacology ; Humans ; Ions ; Oxidative Stress ; Polysaccharides/pharmacology ; Reactive Oxygen Species/metabolism ; Silver/toxicity ; }, abstract = {Although metal ions, such as silver and gold, have been shown to have strong antimicrobial properties, their potential to have toxic effects on human and environmental health has gained interest with an improved understanding of their mechanisms to promote oxidative stress. Redox control is a major focus of many drug delivery systems and often incorporates an antioxidant as the active pharmaceutical ingredient (API) to neutralize overproduced reactive oxygen species (ROS). Nevertheless, there are still limitations with bioavailability and extended redox control with regard to antioxidant drug delivery. Herein, this study develops a colloidal antioxidant crystal system that dissolves sustainably through polymer stabilization using sodium hyaluronate conjugated with dopamine (HA-dopa). We explore the role of dopamine incorporation into crystal-stabilizing polymers and quantify the balance between drug-polymer interactions and competing polymer-polymer interactions. We propose that this type of analysis is useful in the engineering of and provides insight into the release behavior of polymer-crystal complexes. In developing our crystal complex, N-acetylcysteine (NAC) was used as the model antioxidant to protect against silver ion toxicity. We found that our optimized HA-dopa-stabilized NAC crystals prolong the release time of NAC 5-fold compared to a polymer-free NAC crystal. Therefore, following sublethal exposure to AgNO3, the extended lifetime of NAC was able to maintain normal intracellular ROS levels, modulate metabolic function, mitigate fluctuations in ATP levels and ATP synthase activity, and preserve contraction frequency in engineered cardiac muscle tissue. Furthermore, the protective effects of the HA-dopa-stabilized NAC crystals were extended to a Daphnia magna model where silver-ion-induced change to both cell-level biochemistry and organ function was alleviated. As such, we propose that the packaging of hydrophilic antioxidants as colloidal crystals drastically extends the lifetime of the API, better maintains ROS homeostasis post metal ion exposure, and therefore preserves both intracellular biochemistry and tissue functionality.}, }
@article {pmid36006112, year = {2022}, author = {Branco, V and Coppo, L and Aschner, M and Carvalho, C}, title = {N-Acetylcysteine or Sodium Selenite Prevent the p38-Mediated Production of Proinflammatory Cytokines by Microglia during Exposure to Mercury (II).}, journal = {Toxics}, volume = {10}, number = {8}, pages = {}, pmid = {36006112}, issn = {2305-6304}, support = {UID/DTP/04138/2019//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; R01 ES007331/ES/NIEHS NIH HHS/United States ; PTDC/MED-FAR/31136/2017//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; DL57/2016/CP1376/CT002//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e Tecnologia/ ; (NIEHS) R01ES07331/ES/NIEHS NIH HHS/United States ; }, abstract = {Mercury (Hg) is known for its neurotoxicity and is reported to activate microglia cells at low exposure levels. Since mercury decreases the activity of the glutathione and thioredoxin systems, we hypothesize that Hg would, in turn, disrupt microglia homeostasis by interfering with redox regulation of signaling pathways. Thus, in this work, we analyzed the effect of exposure to Hg[2+] on nuclear translocation and activation of NF-kB (p50) and p38 and pro-inflammatory gene transcription (IL-1ß; iNOS, TNF-alpha) considering the interaction of Hg with the glutathione system and thioredoxin systems in microglial cells. N9 (mouse) microglia cells were exposed to different concentrations of Hg[2+] and the 24 h EC50 for a reduction in viability was 42.1 ± 3.7 μM. Subsequent experiments showed that at sub-cytotoxic levels of Hg[2+], there was a general increase in ROS (≈40%) accompanied by a significant depletion (60-90%) of glutathione (GSH) and thioredoxin reductase (TrxR) activity. Upon 6 h of exposure to Hg[2+], p38 (but not p50) accumulated in the nucleus (50% higher than in control), which was accompanied by an increase in its phosphorylation. Transcript levels of both IL1-ß and iNOS were increased over two-fold relative to the control. Furthermore, pre-exposure of cells to the p38 inhibitor SB 239063 hindered the activation of cytokine transcription by Hg[2+]. These results show that disruption of redox systems by Hg[2+] prompts the activation of p38 leading to transcription of pro-inflammatory genes in microglia cells. Treatment of N9 cells with NAC or sodium selenite-which caused an increase in basal GSH and TrxR levels, respectively, prevented the activation of p38 and the transcription of pro-inflammatory cytokines. This result demonstrates the importance of an adequate nutritional status to minimize the toxicity resulting from Hg exposure in human populations at risk.}, }
@article {pmid36002994, year = {2022}, author = {Gandhi, VV and Bihani, SC and Phadnis, PP and Kunwar, A}, title = {Diselenide-derivative of 3-pyridinol targets redox enzymes leading to cell cycle deregulation and apoptosis in A549 cells.}, journal = {Biological chemistry}, volume = {403}, number = {10}, pages = {891-905}, doi = {10.1515/hsz-2022-0123}, pmid = {36002994}, issn = {1437-4315}, mesh = {A549 Cells ; *Apoptosis ; Cell Cycle ; *Glutathione/metabolism ; Glutathione Transferase/metabolism/pharmacology ; Humans ; Molecular Docking Simulation ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {The aim of present study was to understand the mechanism of action of 2,2'-diselenobis(3-pyridinol) or DISPOL in human lung cancer (A549) cells. A549 cells were treated with 10 µM (∼IC50) of DISPOL for varying time points to corelate the intracellular redox changes with its cytotoxic effect. The results indicated that DISPOL treatment led to a time dependant decrease in the basal level of reactive oxygen species (ROS). Additionally, DISPOL treatment elevated the ratio of reduced (GSH) and oxidised (GSSG) glutathione by upregulating gamma-glutamylcysteine ligase (γ-GCL) involved in GSH biosynthesis and inhibiting the activities of redox enzymes responsible for GSH utilization and recycling, such as glutathione-S-transferase (GST) and glutathione reductase (GR). Molecular docking analysis suggests putative interactions of DISPOL with GST and GR which could account for its inhibitory effect on these enzymes. Further, DISPOL induced reductive environment preceded G1 arrest and apoptosis as evidenced by decreased expression of cell cycle genes (Cyclin D1 and Cyclin E1) and elevation of p21 and apoptotic markers (cleaved caspase 3 and cleaved PARP). The combinatorial experiments involving DISPOL and redox modulatory agents such as N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) indeed confirmed the role of reductive stress in DISPOL-induced cell death. Finally, Lipinski's rule suggests attributes of drug likeness in DISPOL. Taken together, DISPOL exhibits a novel mechanism of reductive stress-mediated cell death in A549 cells that warrants future exploration as anticancer agent.}, }
@article {pmid35995981, year = {2022}, author = {Zhou, L and Wang, B and Xie, H and Du, C and Tang, J and Tang, W}, title = {Intrauterine exposure to oxidative stress induces caspase-1-dependent enteric nerve cell pyroptosis.}, journal = {Pediatric surgery international}, volume = {38}, number = {11}, pages = {1555-1567}, pmid = {35995981}, issn = {1437-9813}, support = {81801496, 81900460, 81700449//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Caspase 1/metabolism ; Caspase 3/metabolism ; Cathepsin D/metabolism ; Galactose ; Hydrogen Peroxide ; *Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Neurons ; Oxidative Stress ; Propidium ; *Pyroptosis/physiology ; RNA, Small Interfering/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {PURPOSE: This study determined whether oxidative stress causes the developmental abnormalities of the enteric nervous system during the embryonic period.<br><br>METHODS: Using the test results of tissue specimens of children with Hirschsprung disease (HSCR), we established a pregnant rat model of oxidative stress and a cellular oxidative stress model to conduct related molecular, cellular, and histopathological experiments for exploration and validation.<br><br>RESULTS: The results of the quantitative real-time polymerase chain reaction assay indicated overexpression of pyroptosis markers (NLRP3, ASC, and caspase-1) in HSCR lesions and newborn pups in the oxidative stress group (treated with D-galactose). The expression of cathepsin D was significantly decreased in intestinal tissues of newborn pups in the oxidative stress group compared to the control group. Reactive oxygen species scavengers (N-acetyl-cysteine, NAC), the caspase-1 inhibitor (VX-765), and the NLRP3 siRNA could reverse the release of LDH, decrease the number of propidium iodide stained cells, and reduce the percentage of TUNEL/caspase-3 double-positive cells in the H2O2-treated group.<br><br>CONCLUSION: Oxidative stress can induce the death of enteric nerve cells by activating caspase-1-dependent pyroptosis through NLRP3 inflammasomes, which may contribute to abnormal enteric nervous system development.}, }
@article {pmid35994611, year = {2022}, author = {Zhao, Y and Sun, C and Su, M and Shi, J and Hu, Z and Peng, Y and Zheng, J}, title = {Evidence for Metabolic Activation of Omeprazole In Vitro and In Vivo.}, journal = {Chemical research in toxicology}, volume = {35}, number = {9}, pages = {1493-1502}, doi = {10.1021/acs.chemrestox.2c00111}, pmid = {35994611}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic ; Animals ; Benzoquinones/metabolism ; *Cytochrome P-450 CYP3A/metabolism ; Glutathione/metabolism ; Humans ; Imines/metabolism ; Ketoconazole/metabolism ; Microsomes, Liver/metabolism ; *Omeprazole/metabolism/pharmacology ; Proton Pump Inhibitors/metabolism ; Rats ; }, abstract = {Omeprazole (OPZ) is a proton pump inhibitor commonly used for the treatment of gastric acid hypersecretion. Studies have revealed that use of OPZ can induce hepatotoxicity, but the mechanisms by which it induces liver injury are unclear. This study aimed to identify reactive metabolites of OPZ, determine the pathways of the metabolic activation, and define the correlation of the bioactivation with OPZ cytotoxicity. Quinone imine-derived glutathione (GSH), N-acetylcysteine (NAC), and cysteine (Cys) conjugates were detected in OPZ-fortified rat and human liver microsomal incubations captured with GSH, NAC, or Cys. The same GSH conjugates were detected in bile of rats and cultured liver primary cells after exposure to OPZ. Similarly, the same NAC conjugates were detected in urine of OPZ-treated rats. The resulting quinone imine was found to react with Cys residues of hepatic protein. CYP3A4 dominated the metabolic activation of OPZ. Exposure to OPZ resulted in decreased cell survival in cultured primary hepatocytes. Pretreatment with ketoconazole attenuated the susceptibility of hepatocytes to the cytotoxicity of OPZ.}, }
@article {pmid35992575, year = {2022}, author = {du Preez, HN and Aldous, C and Kruger, HG and Johnson, L}, title = {N-Acetylcysteine and Other Sulfur-Donors as a Preventative and Adjunct Therapy for COVID-19.}, journal = {Advances in pharmacological and pharmaceutical sciences}, volume = {2022}, number = {}, pages = {4555490}, pmid = {35992575}, issn = {2633-4690}, abstract = {The airway epithelial glycocalyx plays an important role in preventing severe acute respiratory syndrome coronavirus 2 entry into the epithelial cells, while the endothelial glycocalyx contributes to vascular permeability and tone, as well as modulating immune, inflammatory, and coagulation responses. With ample evidence in the scientific literature that coronavirus disease 2019 (COVID-19) is related to epithelial and endothelial dysfunction, preserving the glycocalyx should be the main focus of any COVID-19 treatment protocol. The most studied functional unit of the glycocalyx is the glycosaminoglycan heparan sulfate, where the degree and position of the sulfate groups determine the biological activity. N-acetylcysteine (NAC) and other sulfur donors contribute to the inorganic sulfate pool, the rate-limiting molecule in sulfation. NAC is not only a precursor to glutathione but also converts to hydrogen sulfide, inorganic sulfate, taurine, Coenzyme A, and albumin. By optimising inorganic sulfate availability, and therefore sulfation, it is proposed that COVID-19 can be prevented or at least most of the symptoms attenuated. A comprehensive COVID-19 treatment protocol is needed to preserve the glycocalyx in both the prevention and treatment of COVID-19. The use of NAC at a dosage of 600 mg bid for the prevention of COVID-19 is proposed, but a higher dosage of NAC (1200 mg bid) should be administered upon the first onset of symptoms. In the severe to critically ill, it is advised that IV NAC should be administered immediately upon hospital admission, and in the late stage of the disease, IV sodium thiosulfate should be considered. Doxycycline as a protease inhibitor will prevent shedding and further degradation of the glycocalyx.}, }
@article {pmid35989889, year = {2021}, author = {Hyppolite, JJ and Hilzenrat, N}, title = {Palbociclib-induced severe hepatitis: A case study and literature review.}, journal = {Canadian liver journal}, volume = {4}, number = {4}, pages = {433-437}, pmid = {35989889}, issn = {2561-4444}, abstract = {Palbociclib is a selective and reversible CDK4/6 inhibitor approved for patients presenting with HR+ HER2- locally advanced or metastatic breast cancer. Its adverse effect (AE) is mainly reported on the occurrence of leukopenia and fatigue. Even though palbociclib has an extensive hepatic metabolism, there are rare reports about significant liver toxicity. We present the case of a 61-year-old female with metastatic breast cancer treated with palbociclib and an aromatase inhibitor (letrozole). The patient developed a rare AE of severe acute drug-induced hepatitis but improved dramatically after stopping the palbociclib and receiving treatment with N-acetylcysteine (NAC). The treatment with NAC may be a proof of concept for the mechanism of palbociclib liver injury.}, }
@article {pmid35987016, year = {2022}, author = {Kwak, AW and Park, JW and Lee, SO and Lee, JY and Seo, JH and Yoon, G and Lee, MH and Choi, JS and Shim, JH}, title = {Isolinderalactone sensitizes oxaliplatin-resistance colorectal cancer cells through JNK/p38 MAPK signaling pathways.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {105}, number = {}, pages = {154383}, doi = {10.1016/j.phymed.2022.154383}, pmid = {35987016}, issn = {1618-095X}, mesh = {Apoptosis ; Caspases ; Cell Line, Tumor ; *Colorectal Neoplasms ; Humans ; JNK Mitogen-Activated Protein Kinases ; MAP Kinase Signaling System ; Oxaliplatin ; Reactive Oxygen Species ; *Sesquiterpenes ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {BACKGROUND: Isolinderalactone (ILL), a sesquiterpene lactone compound, can be extracted from the root of Lindera aggregate. Physiological activities of ILL, including anti-inflammatory and anti-proliferative effects, have been investigated in multiple diseases. Nevertheless, little is known regarding its anti-cancer activities and the mechanism of action of ILL in targeting human CRC cells.<br><br>PURPOSE: To determine ILL-mediated anti-proliferative effects on oxaliplatin (Ox)-sensitive and resistant colorectal cancer (CRC) cells and underlying mechanisms involved in its effects focusing on signal transduction.<br><br>METHODS: Inhibitory effect of ILL on CRC cells was evaluated by analyzing mitochondrial membrane potential (MMP) dysfunction and multi-caspase activity. Apoptosis-regulating proteins and JNK/p38 signaling molecules were monitored by Western blotting. ROS-dependent physiological modifications by ILL were confirmed by pretreatment with N-acetylcysteine (NAC). Moreover, the involvement of JNK/p38 signaling in ROS-mediated apoptosis was verified by treatment with SP600125 (JNK inhibitor) and SB203580 (p38 inhibitor).<br><br>RESULTS: ILL decreased cell viability and colony formation in both CRC Ox-sensitive (HCT116 and HT29) and Ox-resistant (OxR) (HCT116-OxR and HT29-OxR) cells. ILL induced G2/M phase cell cycle arrest, ROS generation, phosphorylated (p)JNK/p38 MAPK activation, mitochondrial membrane potential (MMP) depolarization, and multi-caspase activation, which eventually triggered apoptotic cell death of CRC cells. In addition, combined treatment with ILL and SP600125, SB203580, or pan-caspase inhibitor (Z-VAD-FMK) prevented decreases in cell viability seen after treatment with ILL alone. Pretreatment with NAC attenuated ILL-mediated apoptosis, ROS production, and p-JNK/p38 expression.<br><br>CONCLUSION: Taken together, our results suggest that ILL can exert its anticancer effect in CRC Ox-sensitive and OxR cells by inducing ROS-mediated apoptosis through JNK/p38 MAPK signaling pathways. This is the first study demonstrating that ILL has a potential to improve drug efficacy against resistance mechanisms, providing a new insight into therapeutic strategies targeting drug-resistant CRC.}, }
@article {pmid35986432, year = {2022}, author = {Wang, K and Chen, YS and Chien, HW and Chiou, HL and Yang, SF and Hsieh, YH}, title = {Melatonin inhibits NaIO3-induced ARPE-19 cell apoptosis via suppression of HIF-1α/BNIP3-LC3B/mitophagy signaling.}, journal = {Cell &amp; bioscience}, volume = {12}, number = {1}, pages = {133}, pmid = {35986432}, issn = {2045-3701}, support = {110-2320-B-040-005-MY3//Ministry of Science and Technology, Taiwan/ ; }, abstract = {BACKGROUND: Age-related macular degeneration (AMD) leads to gradual central vision loss and eventual irreversible blindness. Melatonin, an endogenous hormone, exhibits anti-inflammatory and antitumor effects; however, the role it plays in AMD remains unclear. Herein, we investigated the anti-AMD molecular mechanism of melatonin after sodium iodate (NaIO3) treatment of ARPE-19 cells in vitro and in animal models with the goal of improving the therapeutic effect.<br><br>RESULTS: The in vitro results showed that melatonin protected against NaIO3-induced cell viability decline, mitochondrial dysfunction and apoptosis in ARPE-19 cells, and melatonin also alleviated NaIO3-induced reactive oxygen species (ROS) production, mitochondrial dysfunction and mitophagy activation. Melatonin reduced NaIO3-induced mitophagy activation through HIF-1&#x3b1;-targeted BNIP3/LC3B transcription, whereas ROS inhibition realized with N-acetylcysteine (NAC, a ROS inhibitor) combined with melatonin reduced the effect of NaIO3 on mitophagy. An animal model of AMD was established to confirm the in vitro data. Mouse tail vein injection of NaIO3 and melatonin was associated with enhanced repair of retinal layers within 7&#xa0;days, as observed by optical coherence tomography (OCT) and hematoxylin and eosin (H&amp;E) staining. A reduction in BNIP3 and HIF-1&#x3b1; levels, as determined by immunohistochemistry (IHC) assay, was also observed.<br><br>CONCLUSIONS: These results indicate that melatonin attenuated NaIO3-induced mitophagy of ARPE-19 cells via reduction in ROS-mediated HIF-1&#x3b1; targeted BNIP3/LC3B signaling in vitro and in vivo. Melatonin may be a potential therapeutic drug in the treatment of AMD.}, }
@article {pmid35982963, year = {2022}, author = {Nazir, LA and Shahid, NH and Amit, K and Umar, SA and Rajni, S and Bharate, S and Sangwan, PL and Tasduq, SA}, title = {Synthesis and anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid against B16F10 cells via induction of endoplasmic reticulum stress-mediated autophagy through ERK/AKT signaling pathway.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {890299}, pmid = {35982963}, issn = {2234-943X}, abstract = {Melanoma is an aggressive form of cancer with poor prognosis and survival rates and limited therapeutic options. Here, we report the anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid (NPC-402), a derivative of glycyrrhtinic acid, from a reputed medicinal plant Glycyrrhiza glabra against B16F10 cells. We studied the cytotoxic effect of NPC-402 on melanoma cells and investigated the role of mitogen-activated protein (MAP) kinase, AKT axis, and endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated autophagy as the involved signaling cascade by studying specific marker proteins. In this study, 4-phenylbutyric acid (4PBA, a chemical chaperone) and small interference RNA (siRNA) knockdown of C/EBP Homologous Protein (CHOP)/growth arrest- and DNA damage-inducible gene 153(GAD153) blocked NPC-402-mediated autophagy induction, thus confirming the role of ER stress and autophagy in melanoma cell death. NPC-402 induced oxidative stress and apoptosis in melanoma cells, which were effectively mitigated by treatment with N-acetylcysteine (NAC). In vivo studies showed that intraperitoneal (i.p.) injection of NPC-402 at 10 mg/kg (5 days in 1 week) significantly retarded angiogenesis in the Matrigel plug assay and reduced the tumor size and tumor weight without causing any significant toxic manifestation in C57BL/6J mice. We conclude that NPC-402 has a high potential to be developed as a chemotherapeutic drug against melanoma.}, }
@article {pmid35981484, year = {2022}, author = {Feng, Y and Yuan, H and Wang, W and Xu, Y and Zhang, J and Xu, H and Fu, F}, title = {Co-exposure to polystyrene microplastics and lead aggravated ovarian toxicity in female mice via the PERK/eIF2α signaling pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {243}, number = {}, pages = {113966}, doi = {10.1016/j.ecoenv.2022.113966}, pmid = {35981484}, issn = {1090-2414}, mesh = {Animals ; Eukaryotic Initiation Factor-2/metabolism ; Female ; Lead/toxicity ; Mammals/metabolism ; Mice ; Mice, Inbred C57BL ; *Microplastics ; Ovary/metabolism ; Plastics ; *Polystyrenes/metabolism/toxicity ; Signal Transduction ; }, abstract = {Generally, individual microplastics (MPs) or lead (Pb) exposure could initiate ovarian toxicity. However, their combined effects on the ovary and its mechanism in mammals remained unclear. Female C57BL/6 mice were used in this study to investigate the combined ovarian toxicity of polystyrene MPs (PS-MPs, 0.1 mg/d/mouse) and Pb (1 g/L) for 28 days. Results showed that co-exposure to PS-MPs and Pb increased the accumulation of Pb in ovaries, the histopathological damage in ovaries and uterus, the serum malondialdehyde levels and decreased serum superoxide dismutase and sex hormone levels significantly when compared with single PS-MPs and Pb exposure. These observations indicated that co-exposure exerted more severe toxicity to mouse ovaries and uterus. Furthermore, co-exposure to PS-MPs and Pb caused endoplasmic reticulum (ER) stress by activating the PERK/eIF2α signaling pathway in the ovary, which resulted in apoptosis. However, the oxidative and ovarian damage were alleviated, and the mRNA levels of genes related to the PERK/eIF2α signaling pathway were down-regulated to levels of the control mice in the PS-MPs and Pb co-exposed mice administered with ER stress inhibitor (Salubrinal, Sal) or the antioxidant (N-acetyl-cysteine, NAC). In conclusion, our findings suggested that the combination of PS-MPs and Pb aggravated ovarian toxicity in mice by inducing oxidative stress and activating the PERK/eIF2α signaling pathway, thereby providing a basis for future studies into the combined toxic mechanism of PS-MPs and Pb in mammals.}, }
@article {pmid35975988, year = {2022}, author = {Shee, S and Singh, S and Tripathi, A and Thakur, C and Kumar T, A and Das, M and Yadav, V and Kohli, S and Rajmani, RS and Chandra, N and Chakrapani, H and Drlica, K and Singh, A}, title = {Moxifloxacin-Mediated Killing of Mycobacterium tuberculosis Involves Respiratory Downshift, Reductive Stress, and Accumulation of Reactive Oxygen Species.}, journal = {Antimicrobial agents and chemotherapy}, volume = {66}, number = {9}, pages = {e0059222}, pmid = {35975988}, issn = {1098-6596}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {2,2'-Dipyridyl/pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase ; Cysteine ; Iron ; Iron Chelating Agents/pharmacology ; Mice ; Moxifloxacin/pharmacology ; *Mycobacterium tuberculosis ; NAD ; Reactive Oxygen Species/metabolism ; Sulfur/pharmacology ; Thiourea ; *Tuberculosis/microbiology ; }, abstract = {Moxifloxacin is central to treatment of multidrug-resistant tuberculosis. Effects of moxifloxacin on the Mycobacterium tuberculosis redox state were explored to identify strategies for increasing lethality and reducing the prevalence of extensively resistant tuberculosis. A noninvasive redox biosensor and a reactive oxygen species (ROS)-sensitive dye revealed that moxifloxacin induces oxidative stress correlated with M. tuberculosis death. Moxifloxacin lethality was mitigated by supplementing bacterial cultures with an ROS scavenger (thiourea), an iron chelator (bipyridyl), and, after drug removal, an antioxidant enzyme (catalase). Lethality was also reduced by hypoxia and nutrient starvation. Moxifloxacin increased the expression of genes involved in the oxidative stress response, iron-sulfur cluster biogenesis, and DNA repair. Surprisingly, and in contrast with Escherichia coli studies, moxifloxacin decreased expression of genes involved in respiration, suppressed oxygen consumption, increased the NADH/NAD[+] ratio, and increased the labile iron pool in M. tuberculosis. Lowering the NADH/NAD[+] ratio in M. tuberculosis revealed that NADH-reductive stress facilitates an iron-mediated ROS surge and moxifloxacin lethality. Treatment with N-acetyl cysteine (NAC) accelerated respiration and ROS production, increased moxifloxacin lethality, and lowered the mutant prevention concentration. Moxifloxacin induced redox stress in M. tuberculosis inside macrophages, and cotreatment with NAC potentiated the antimycobacterial efficacy of moxifloxacin during nutrient starvation, inside macrophages, and in mice, where NAC restricted the emergence of resistance. Thus, NADH-reductive stress contributes to moxifloxacin-mediated killing of M. tuberculosis, and the respiration stimulator (NAC) enhances lethality and suppresses the emergence of drug resistance.}, }
@article {pmid35975308, year = {2023}, author = {Kumar, P and Liu, C and Suliburk, J and Hsu, JW and Muthupillai, R and Jahoor, F and Minard, CG and Taffet, GE and Sekhar, RV}, title = {Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {78}, number = {1}, pages = {75-89}, pmid = {35975308}, issn = {1758-535X}, support = {R01 AG041782/AG/NIA NIH HHS/United States ; R01AG041782/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; Aged ; *Acetylcysteine/pharmacology/metabolism ; Glycine/metabolism ; Health Promotion ; Oxidative Stress ; Aging/physiology ; Glutathione ; Dietary Supplements ; *Insulin Resistance/physiology ; Inflammation/drug therapy/metabolism ; Mitochondria/metabolism ; }, abstract = {BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.<br><br>METHODS: Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure.<br><br>RESULTS: Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects.<br><br>CONCLUSION: GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.}, }
@article {pmid35972898, year = {2023}, author = {Panwar, A and Vaidyanathan, S and Udupa, ST and Munoli, RN and Praharaj, SK}, title = {Anticraving Effect of N-Acetyl Cysteine in a Patient With Pregabalin and Alcohol Dependence.}, journal = {American journal of therapeutics}, volume = {30}, number = {6}, pages = {e597-e598}, doi = {10.1097/MJT.0000000000001544}, pmid = {35972898}, issn = {1536-3686}, mesh = {Humans ; *Alcoholism/complications/drug therapy ; Pregabalin/therapeutic use ; Acetylcysteine/therapeutic use ; }, }
@article {pmid35968645, year = {2022}, author = {Rjiba-Touati, K and Ayed-Boussema, I and Hamdi, H and Azzebi, A and Abid, S}, title = {Bromuconazole fungicide induces cell cycle arrest and apoptotic cell death in cultured human colon carcinoma cells (HCT116) via oxidative stress process.}, journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals}, volume = {27}, number = {7}, pages = {659-670}, doi = {10.1080/1354750X.2022.2098378}, pmid = {35968645}, issn = {1366-5804}, mesh = {Humans ; *Fungicides, Industrial/toxicity ; Reactive Oxygen Species/metabolism ; Caspase 3/metabolism ; Acetylcysteine/metabolism ; Fluorescein-5-isothiocyanate/metabolism/pharmacology ; Cell Line, Tumor ; Cell Cycle Checkpoints ; Apoptosis ; Triazoles/toxicity ; Oxidative Stress ; Biomarkers/metabolism ; Colon/metabolism ; *Carcinoma/metabolism ; DNA ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND: Bromuconazole, a fungicide belonging to the triazole family, is a plant protection product used to control, repel or destroy fungi that may develop on crops. We investigated the pro-apoptotic effect of bromuconazole and the role of oxidative stress in the death mechanism induced by this fungicide in this study.<br><br>METHODS: The human colon HCT116 cell line was treated with Bromuconazole (IC50/4, IC50/2, and IC50) for 24&#x2009;h. Cells were collected and analysed for biomarkers of apoptotic cell death and oxidative stress as well as for the assessment of genotoxic damage.<br><br>RESULTS: Our study showed that bromuconazole caused a concentration-dependent increase in cell mortality with an IC50 of 180&#x2009;&#xb5;M. Bromuconazole induced cell cycle arrest in the G0/G1 phase and DNA synthesis inhibition. The Comet assay showed that bromuconazole caused DNA damage in a concentration-dependent manner. Bromuconazole-induced apoptosis was observed by, Annexin-V/FITC-PI and BET/AO staining, by mitochondrial membrane depolarisation, and by increased caspase-3 activity. In addition, bromuconazole induced a significant increase in ROS and lipid peroxidation levels and a disruption in SOD and CAT activities. N-acetylcysteine (NAC) strongly prevents cytotoxic and genotoxic damage caused by bromuconazole.<br><br>CONCLUSION: Bromuconazole toxicity was through the oxidative stress process, which causes DNA damage and mitochondrial dysfunction, leading to cell cycle arrest and apoptotic death of HCT116 cells.}, }
@article {pmid35965824, year = {2022}, author = {Zhou, Z and Dun, L and Xu, H and Yu, P and Chen, C and Si, T and An, H and Lu, J and Wei, B and Guo, D and Yang, Q and Zheng, N and Yi, P}, title = {The neuroprotective effect of YaoYi-moxibustion on ischemic stroke by attenuating NK-κB expression in rats.}, journal = {Annals of translational medicine}, volume = {10}, number = {14}, pages = {791}, pmid = {35965824}, issn = {2305-5839}, abstract = {BACKGROUND: Traditional Chinese medicine (TCM) has become a crucial direction for ischemic stroke treatment. This study sought to explore the underlying roles of YaoYi-moxibustion (YY-moxi) in ischemic stroke.<br><br>METHODS: A total of 75 Sprague-Dawley rats were randomly divided into the following 5 groups: (I) the sham-operated group; (II) the middle cerebral artery occlusion model (MCAO) group; (III) the YY-moxi group; (IV) the antioxidant (N-acetylcysteine, NAC) group; and (V) the NAC + YY-moxi group. After the model had been established, the NAC group received intracerebroventricular injections of NAC, the YY-moxi group received YY-moxi, and the NAC + YY-moxi group received a combination of these 2 interventions. The neurological deficit score was confirmed, and the cerebral infarction was examined by triphenyl tetrazolium chloride (TTC) staining. In the ischemia site of stroke, terminal deoxynucleotidyl transferase-mediated Dutp nick end labeling staining was applied to examine the apoptotic cells. Additionally, the apoptosis-associated genes and protein expressions in the ischemic brains were investigated by the reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), immunohistochemistry, and western blot analysis.<br><br>RESULTS: YY-moxi alone and YY-moxi combined with NAC significantly reduced the neurological scores and cerebral infarction area of the MCAO rats. Additionally, YY-moxi alone and the combined application of YY-moxi and NAC improved the pathological status of ischemic brain tissues. Further, we found that YY-moxi alone and YY-moxi in combination with NAC could enhanced the antioxidation ability and reduced the inflammatory response of the MCAO model rats. We also proved that YY-moxi alone and YY-moxi combined with NAC significantly suppressed apoptosis-related proteins in the MCAO model rats.<br><br>CONCLUSIONS: These findings indicate that YY-moxi exerts a protective effect on cerebral ischemic injury by reducing apoptosis. The study suggests that the mechanism may be related to its downregulating the expression of nuclear factor kappa B (NK-&#x3ba;B).}, }
@article {pmid35965681, year = {2022}, author = {Yuan, S and Pan, Y and Xu, T and Zhang, L and Chen, X and Wang, F and Liu, Q and Jia, L}, title = {Daurisoline Inhibits ESCC by Inducing G1 Cell Cycle Arrest and Activating ER Stress to Trigger Noxa-Dependent Intrinsic and CHOP-DR5-Dependent Extrinsic Apoptosis via p-eIF2α-ATF4 Axis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {5382263}, pmid = {35965681}, issn = {1942-0994}, mesh = {Activating Transcription Factor 4/metabolism ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins ; Benzylisoquinolines ; Cell Line, Tumor ; *Esophageal Neoplasms ; *Esophageal Squamous Cell Carcinoma/drug therapy/metabolism ; Eukaryotic Initiation Factor-2/metabolism ; G1 Phase Cell Cycle Checkpoints ; Humans ; Mice ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Esophageal squamous cell carcinoma (ESCC), one of the most malignant human cancers in clinic, requires novel treatment. Daurisoline (DAS) is a component of traditional Chinese herb, which exhibits anti-cancer effects by autophagy inhibition and metastasis suppression. However, the effect and mechanism of DAS on ESCC remain unclear. Here, we found that DAS inhibited cell proliferation and colony formation in both human ESCC cell lines EC1 and ECA109. Mechanistically, DAS induced p21-/p27-dependent G1 phase cell cycle arrest and apoptosis in a dose-dependent manner. The induction of apoptosis by DAS was largely dependent on the activation of the transcription factor ATF4 and its downstream NOXA-dependent intrinsic and CHOP-DR5-dependent extrinsic apoptotic pathway. ATF4 activation induced by DAS was due to the generation of excessive reactive oxygen species (ROS) and the subsequent activation of endoplasmic reticulum (ER) stress through the p-eIF2α-ATF4 signal pathway, which can be largely abrogated by N-acetylcysteine (NAC), a scavenger of ROS. Moreover, DAS treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model by up-regulating key proteins related to cell cycle arrest and apoptotic pathway. Taken together, these findings identified DAS as a novel candidate for the treatment of ESCC.}, }
@article {pmid35963952, year = {2022}, author = {Tandra, HV and Rupakumar, T and Vijayasekharan, K and V R, P and C S, G and T, PK}, title = {A stitch in time saves nine: timely use of N-acetyl cysteine (NAC) for chemotherapy-induced veno-occlusive disease (VOD)-is it a cost-effective alternative?.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {30}, number = {11}, pages = {8611-8614}, pmid = {35963952}, issn = {1433-7339}, mesh = {Child ; Humans ; Polydeoxyribonucleotides/pharmacology ; *Hepatic Veno-Occlusive Disease/therapy/drug therapy ; Cost-Benefit Analysis ; Acetylcysteine/therapeutic use ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Vascular Diseases/drug therapy/etiology ; *Antineoplastic Agents/adverse effects ; }, abstract = {Chemotherapy-induced veno-occlusive disease (VOD) is a rare liver dysfunction seen among pediatric cancer patients which could lead to severe morbidity and mortality. Defibrotide is the commonly used antidote in the management of both stem cell transplant and chemotherapy-associated VOD along with liver supportive measures. Defibrotide is costly and generally not accessible to majority of patients treated at resource poor settings. In this report, we describe the successful management of chemotherapy-induced VOD with timely administration of N-acetyl cysteine.}, }
@article {pmid35956786, year = {2022}, author = {Thalappil, MA and Butturini, E and Carcereri de Prati, A and Bettin, I and Antonini, L and Sapienza, FU and Garzoli, S and Ragno, R and Mariotto, S}, title = {Pinus mugo Essential Oil Impairs STAT3 Activation through Oxidative Stress and Induces Apoptosis in Prostate Cancer Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {15}, pages = {}, pmid = {35956786}, issn = {1420-3049}, support = {RM11916B8876093E, RM120172B8EB30C5, RM12117A89F5B8BB//Sapienza University of Rome/ ; }, mesh = {*Antineoplastic Agents/pharmacology/therapeutic use ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Glutathione/metabolism ; Humans ; Male ; *Oils, Volatile/pharmacology/therapeutic use ; Oxidative Stress ; *Pinus/metabolism ; *Plant Oils/pharmacology/therapeutic use ; *Prostatic Neoplasms/drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *STAT3 Transcription Factor/genetics/metabolism ; }, abstract = {Essential oils (EOs) and their components have been reported to possess anticancer properties and to increase the sensitivity of cancer cells to chemotherapy. The aim of this work was to select EOs able to downregulate STAT3 signaling using Western blot and RT-PCR analyses. The molecular mechanism of anti-STAT3 activity was evaluated through spectrophotometric and fluorometric analyses, and the biological effect of STAT3 inhibition was analyzed by flow cytometry and wound healing assay. Herein, Pinus mugo EO (PMEO) is identified as an inhibitor of constitutive STAT3 phosphorylation in human prostate cancer cells, DU145. The down-modulation of the STAT3 signaling cascade decreased the expression of anti-proliferative as well as anti-apoptotic genes and proteins, leading to the inhibition of cell migration and apoptotic cell death. PMEO treatment induced a rapid drop in glutathione (GSH) levels and an increase in reactive oxygen species (ROS) concentration, resulting in mild oxidative stress. Pretreatment of cells with N-acetyl-cysteine (NAC), a cell-permeable ROS scavenger, reverted the inhibitory action of PMEO on STAT3 phosphorylation. Moreover, combination therapy revealed that PMEO treatment displayed synergism with cisplatin in inducing the cytotoxic effect. Overall, our data highlight the importance of STAT3 signaling in PMEO cytotoxic activity, as well as the possibility of developing adjuvant therapy or sensitizing cancer cells to conventional chemotherapy.}, }
@article {pmid35956498, year = {2022}, author = {Picchi, V and Calzone, A and Gobbi, S and Paccani, S and Lo Scalzo, R and Marti, A and Faoro, F}, title = {Oxidative Stress Mitigation by Chitosan Nanoparticles in Durum Wheat Also Affects Phytochemicals and Technological Quality of Bran and Semolina.}, journal = {Plants (Basel, Switzerland)}, volume = {11}, number = {15}, pages = {}, pmid = {35956498}, issn = {2223-7747}, support = {ID052- Project NA-NOTOX//Ministry of Agricultural, Food and Forestry Policies/ ; }, abstract = {In our previous work, durum wheat cv. Fabulis was grown over two consecutive seasons (2016-2017 and 2017-2018) in an experimental field in the north of Italy. With the aim of mitigating oxidative stress, plants were subjected to four treatments (deionized water, CHT 0.05 mg/mL, CHT-NPs, and CHT-NPs-NAC) three times during the experiment. Chitosan nanoparticles (CHT-NPs) reduced symptom severity on wheat leaves and positively influenced the final grain yield. The present work aimed at investigating whether CHT treatments and particularly N-acetyl cysteine (NAC)-loaded or -unloaded CHT-NPs, while triggering plant defense mechanisms, might also vary the nutritional and technological quality of grains. For this purpose, the grains harvested from the previous experiment were analyzed for their content in phytochemicals and for their technological properties. The results showed that CHT increased the polyphenol and tocopherol content and the reducing capacity of bran and semolina, even if the positive effect of the nano-formulation remained still unclear and slightly varied between the two years of cultivation. The positive effect against oxidative stress induced by the chitosan treatments was more evident in the preservation of both the starch pasting properties and gluten aggregation capacity, indicating that the overall technological quality of semolina was maintained. Our data confirm the role of chitosan as an elicitor of the antioxidant defense system in wheat also at the grain level.}, }
@article {pmid35955744, year = {2022}, author = {Sinha, BK and Tokar, EJ and Bortner, CD}, title = {Molecular Mechanisms of Cytotoxicity of NCX4040, the Non-Steroidal Anti-Inflammatory NO-Donor, in Human Ovarian Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {23}, number = {15}, pages = {}, pmid = {35955744}, issn = {1422-0067}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; *Antineoplastic Agents/pharmacology ; Aspirin/analogs &amp; derivatives ; Carcinoma, Ovarian Epithelial ; Doxorubicin/pharmacology ; Female ; Humans ; Nitro Compounds ; *Ovarian Neoplasms/pathology ; Peroxynitrous Acid ; Reactive Nitrogen Species ; Reactive Oxygen Species ; }, abstract = {NCX4040, the non-steroidal anti-inflammatory-NO donor, is cytotoxic to several human tumors, including ovarian tumor cells. We have found that NCX4040 is also cytotoxic against both OVCAR-8 and its adriamycin resistant (NCI/ADR-RES) tumor cell lines. Here, we have examined mechanism(s) for the cytotoxicity of NCX4040 in OVCAR-8 and NCI/ADR-RES cell lines. We found that NCX4040 induced significant apoptosis in both cell lines. Furthermore, NCX4040 treatment caused significant depletion of cellular glutathione, causing oxidative stress due to the formation of reactive oxygen/nitrogen species (ROS/RNS). Significantly more ROS/RNS were detected in OVCAR-8 cells than in NCI/ADR-RES cells which may have resulted from increased activities of SOD, glutathione peroxidase and transferases expressed in NCI/ADR-RES cells. NCX4040 treatment resulted in the formation of double-strand DNA breaks in both cells; however, more of these DNA breaks were detected in OVCAR-8 cells. RT-PCR studies indicated that NCX4040-induced DNA damage was not repaired as efficiently in NCI/ADR-RES cells as in OVCAR-8 cells which may lead to a differential cell death. Pretreatment of OVCAR-8 cells with N-acetylcysteine (NAC) significantly decreased cytotoxicity of NCX4040 in OVCAR-8 cells; however, NAC had no effects on NCX4040 cytotoxicity in NCI/ADR-RES cells. In contrast, FeTPPS, a peroxynitrite scavenger, completely blocked NCX4040-induced cell death in both cells, suggesting that NCX4040-induced cell death could be mediated by peroxynitrite formed from NCX4040 following cellular metabolism.}, }
@article {pmid35952519, year = {2022}, author = {Blum, AW and Grant, JE}, title = {N-acetylcysteine in the treatment of compulsive sexual behavior disorder: A case series.}, journal = {Journal of psychiatric research}, volume = {154}, number = {}, pages = {203-206}, doi = {10.1016/j.jpsychires.2022.07.066}, pmid = {35952519}, issn = {1879-1379}, mesh = {*Acetylcysteine/therapeutic use ; Compulsive Behavior/drug therapy ; Glutamic Acid ; Humans ; Male ; Sexual Behavior ; *Sexual Dysfunctions, Psychological ; }, abstract = {Although compulsive sexual behavior disorder (CSBD) is a relatively common disorder with an estimated prevalence of at least 3%, clinicians currently have limited evidence and no FDA-approved drugs to guide their treatment of this condition. N-acetylcysteine (NAC), an amino acid that seems to restore extracellular levels of glutamate in the nucleus accumbens, has previously demonstrated efficacy in treating multiple psychiatric disorders, including substance use disorders and putative behavioral addictions. However, no study has assessed the use of NAC (or any other glutamatergic agent, for that matter) in the treatment of CSBD. Here, we present data from a case series of 8 male patients with CSBD treated with NAC in routine clinical practice in a specialty outpatient clinic. Of these 8 patients, all of whom had previously been treated for CSBD with medications, therapy, or both, 5 had marked clinical improvement (>35% improvement on a modified version of Yale-Brown Obsessive Compulsive Scale) on NAC, and 3 showed minimal or no improvement (<15%). These findings suggest that NAC may be a potentially promising, well-tolerated treatment option for patients with CSBD, including those who have failed more traditional therapies.}, }
@article {pmid35948106, year = {2022}, author = {Zhang, M and Chen, J and Jiang, Y and Chen, T}, title = {Fine particulate matter induces heart defects via AHR/ROS-mediated endoplasmic reticulum stress.}, journal = {Chemosphere}, volume = {307}, number = {Pt 2}, pages = {135962}, doi = {10.1016/j.chemosphere.2022.135962}, pmid = {35948106}, issn = {1879-1298}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Butylamines ; Cardiotoxicity ; Endoplasmic Reticulum Stress ; *Heart Defects, Congenital ; *Hydrocarbons, Aromatic/metabolism ; Particulate Matter/pharmacology ; Pharmaceutical Preparations/metabolism ; Reactive Oxygen Species/metabolism ; Zebrafish/metabolism ; }, abstract = {Accumulating body of evidence indicates that exposure to fine particulate matter (PM2.5) is closely associated with congenital heart disease in the offspring, but the underlying molecular mechanisms remain to be elucidated. We previously reported that extractable organic matter (EOM) from PM2.5 induces reactive oxygen species (ROS) overproduction by activating aromatic hydrocarbon receptor (AHR), leading to heart defects in zebrafish embryos. We hypothesized that endoplasmic reticulum (ER) stress might be elicited by the excessive ROS production and thereby contribute to the cardiac developmental toxicity of PM2.5. In this study, we examined the effects of EOM on endoplasmic reticulum (ER) stress, apoptosis, and Wnt signal pathway in zebrafish embryos, and explored their roles in EOM-induced heart defects. Our results showed that 4-Phenylbutyric acid (4-PBA), a pharmaceutical inhibitor of ER stress, significantly attenuated the EOM-elevated heart malformation rates. Moreover, EOM upregulated the expression levels of ER stress marker genes including CHOP and PDI in the heart of zebrafish embryos, which were counteracted by genetic or pharmaceutical inhibition of AHR activity. The ROS scavenger N-Acetyl-l-cysteine (NAC) also abolished the EOM-induced ER stress. We further demonstrated that both 4-PBA and CHOP genetic knockdown rescued the PM2.5-induced ROS overproduction, apoptosis and suppression of Wnt signaling. In conclusion, our results indicate that PM2.5 induces AHR/ROS-mediated ER stress, which leads to apoptosis and Wnt signaling inhibition, ultimately resulting in heart defects.}, }
@article {pmid35946140, year = {2023}, author = {do Amaral, GCLS and Hassan, MA and Sloniak, MC and Pannuti, CM and Romito, GA and Villar, CC}, title = {Effects of antimicrobial mouthwashes on the human oral microbiome: Systematic review of controlled clinical trials.}, journal = {International journal of dental hygiene}, volume = {21}, number = {1}, pages = {128-140}, doi = {10.1111/idh.12617}, pmid = {35946140}, issn = {1601-5037}, mesh = {Adult ; Humans ; *Anti-Infective Agents/pharmacology/therapeutic use ; *Anti-Infective Agents, Local/therapeutic use ; Chlorhexidine/therapeutic use ; *Dental Plaque/drug therapy ; *Microbiota ; Mouthwashes/therapeutic use ; Phylogeny ; Controlled Clinical Trials as Topic ; }, abstract = {OBJECTIVES: This review aimed to assess the impact of mouthwashes on the composition of the human oral microbiome.<br><br>METHOD: An electronic search algorithm was adapted to MEDLINE-PubMed, Scopus, Embase and ISI Web of Science, and reference lists of relevant sources were manually searched. Inclusion criteria were controlled clinical trials published in English whose population were adult individuals who rinse with antimicrobial mouthwashes and that analysed changes in the oral microbiome by metataxonomy, metagenomics or phylogenetic microarray. Identified studies were screened and assessed following the PRISMA guidelines, and results were compiled into qualitative synthesis of the evidence.<br><br>RESULTS: Five controlled clinical studies were included. These studies found associations between the daily use of mouthwashes and changes in the oral microbiome, but the nature of the effect varied according to the mouthwash. Chlorhexidine (CHX) rinses lowered microbial diversity. While 7-day use of CHX led to increases in the abundance of Neisseria, Streptococcus and Granulicatella and a decrease in the abundance of Actinomyces, its prolonged use led to widespread reductions in several genera and species. Cetylpyridinium chloride-containing mouthwashes specifically lowered the abundance of gingivitis-associated genera. In contrast, N-acetyl cysteine-based mouthwashes did not promote changes in the oral microbiome.<br><br>CONCLUSIONS: Despite substantial heterogeneity, we found evidence to support the hypothesis that CHX and CPC mouthwashes promote changes in oral microbial structure and/or reductions in community diversity that favour the resolution of dysbiosis. However, future large population-based studies of adequate duration are needed to fully understand the extent to which antimicrobial mouthwashes modulate the microbiome.}, }
@article {pmid35945549, year = {2022}, author = {Liu, X and Jiang, M and Pang, C and Wang, J and Hu, L}, title = {Sodium selenite inhibits proliferation and metastasis through ROS-mediated NF-κB signaling in renal cell carcinoma.}, journal = {BMC cancer}, volume = {22}, number = {1}, pages = {870}, pmid = {35945549}, issn = {1471-2407}, mesh = {Animals ; Apoptosis ; *Carcinoma, Renal Cell/drug therapy ; Cell Line, Tumor ; Cell Proliferation ; Humans ; *Kidney Neoplasms/drug therapy ; Mice ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Sodium Selenite/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Sodium selenite (SSE) has been reported to exert anti-tumor effects in several cancer cells. However, the underlying mechanisms in renal cancer are yet to be elucidated. The effects of SSE on the proliferation, metastasis, and apoptosis of renal cancer cells, as well as its mechanism, were investigated in this study.<br><br>METHODS: ACHN and 786-O renal cancer cells were treated with different concentrations of SSE, MTT, and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using scratch-wound-healing and transwell-migration assays. The effect of SSE on apoptosis was assessed by AnnexinV-FITC/PI double staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. We also made subcutaneous xenografts in athymic mice to verify the effect of SSE on tumor growth in vivo.<br><br>RESULTS: Our results demonstrated that treatment with SSE resulted in significant inhibition of cell proliferation and migration. Flow cytometry and Western blot confirmed that SSE induced apoptosis via the endogenous apoptotic pathway. We also confirmed that SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-&#x3ba;B (NF-&#x3ba;B) signaling. Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed the effect of SSE on cells. Similarly, subcutaneous xenografts in athymic mice models showed that SSE inhibits tumor growth in vivo.<br><br>CONCLUSION: These results indicate that SSE inhibits proliferation and migration and induces apoptosis via ROS mediated inhibition of NF-&#x3ba;B signaling in renal cancer cells.}, }
@article {pmid35940529, year = {2022}, author = {Pan, T and Qi, J and Tang, Y and Yao, Y and Chen, J and Wang, H and Yang, J and Xu, X and Shi, Q and Liu, Y and He, X and Chen, F and Ma, X and Hu, X and Wu, X and Wu, D and Han, Y}, title = {N-Acetylcysteine as Prophylactic Therapy for Transplantation-Associated Thrombotic Microangiopathy: A Randomized, Placebo-Controlled Trial.}, journal = {Transplantation and cellular therapy}, volume = {28}, number = {11}, pages = {764.e1-764.e7}, doi = {10.1016/j.jtct.2022.07.029}, pmid = {35940529}, issn = {2666-6367}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Prospective Studies ; Retrospective Studies ; *Thrombotic Microangiopathies/drug therapy ; *Hematopoietic Stem Cell Transplantation/adverse effects ; }, abstract = {Transplantation-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication for patients undergoing hematopoietic stem cell transplantation (HSCT). N-acetylcysteine (NAC) has recently been considered as a potential treatment for patients with thrombotic thrombocytopenic purpura. To assess the value of NAC for the prevention of TA-TMA, we conducted a prospective study at the First Affiliated Hospital of Soochow University. This open-label, randomized placebo-controlled trial included 160 patients who were scheduled for allogeneic HSCT. Participants were assigned at random 1:1 to either oral NAC (50 mg/kg/day from 9 days before HSCT to 30 days after HSCT) or placebo treatment. The primary outcome was the incidence of TA-TMA. Overall survival (OS) and event-free survival (EFS) were assessed in the NAC and placebo control groups. The incidence of TA-TMA was 9.1% (95% confidence interval [CI], 2% to 16.2%) in the NAC group, compared with 23% (95% CI, 13.2% to 32.8%) in the control group, with a rate ratio of .34 (95% CI, .123 to .911; P = .039). The median time to the onset of TA-TMA was 60 days (interquartile range [IQR], 42 to 129 days) in the NAC group and 36 days (IQR, 30.5 to 51 days) in the control group (P = .063). The 2-year OS rate was 75.4% (95% CI, 28.65% to 73.53%) in the NAC group and 63.0% (95% CI, 50.8% to 73.5%) in the control group, with a hazard ratio (HR) of .622 (95% CI, .334-1.155; P = .132). The EFS rate was 25.8% in the NAC patients and 8.1% in controls (HR, .254; 95% CI, .094 to .692; P = .024). The median time of EFS was 60 days in the NAC group and 38 days in controls. Our findings suggest that NAC may be a potential treatment to reduce the incidence of TA-TMA.}, }
@article {pmid35938960, year = {2022}, author = {Park, C and Cha, HJ and Lee, H and Jeong, JW and Han, M and Song, KS and Kim, GY and Chang, YC and Leem, SH and Hyun, JW and Kim, HS and Hong, SH and Choi, YH}, title = {Induction of apoptosis through inactivation of ROS-dependent PI3K/Akt signaling pathway by platycodin D in human bladder urothelial carcinoma cells.}, journal = {General physiology and biophysics}, volume = {41}, number = {4}, pages = {263-274}, doi = {10.4149/gpb_2022013}, pmid = {35938960}, issn = {0231-5882}, mesh = {Apoptosis ; *Carcinoma, Transitional Cell ; Humans ; Phosphatidylinositol 3-Kinase/metabolism/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; *Saponins/pharmacology ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; *Triterpenes/pharmacology ; Urinary Bladder/metabolism ; *Urinary Bladder Neoplasms/drug therapy/metabolism/pathology ; }, abstract = {Platycodin D (PD) is a triterpenoid saponin, a major bioactive constituent of the roots of Platycodon grandiflorum, which is well known for possessing various pharmacological properties. However, the anti-cancer mechanism of PD in bladder cancer cells remains poorly understood. In the current study, we investigated the effect of PD on the growth of human bladder urothelial carcinoma cells. PD treatment significantly reduced the cell survival of bladder cancer cells associated with induction of apoptosis and DNA damage. PD inhibited the expression of inhibitor of apoptosis family members, activated caspases, and induced cleavage of poly (ADP-ribose) polymerase. PD also increased the release of cytochrome c into the cytoplasm by disrupting the mitochondrial membrane potential while upregulating the expression ratio of Bax to Bcl-2. The PD-mediated anti-proliferative effect was significantly inhibited by pre-treatment with a pancaspase inhibitor, but not by an inhibitor of necroptosis. Moreover, PD suppressed the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and the apoptosis-inducing effect of PD was further enhanced by a PI3K inhibitor. In addition, PD increased the accumulation of reactive oxygen species (ROS), whereas N-acetyl cysteine (NAC), an ROS inhibitor, significantly attenuated the growth inhibition and inactivation of the PI3K/Akt/mTOR signaling caused by PD. Furthermore, NAC significantly suppressed apoptosis, DNA damage, and decreased cell viability induced by PD treatment. Collectively, our findings indicated that PD blocked the growth of bladder urothelial carcinoma cells by inducing ROS-mediated inactivation of the PI3K/Akt/mTOR signaling.}, }
@article {pmid35938289, year = {2022}, author = {Kelley, RC and Lapierre, SS and Muscato, DR and Hahn, D and Christou, DD and Ferreira, LF}, title = {Cardiac and respiratory muscle responses to dietary N-acetylcysteine in rats consuming a high-saturated fat, high-sucrose diet.}, journal = {Experimental physiology}, volume = {107}, number = {11}, pages = {1312-1325}, pmid = {35938289}, issn = {1469-445X}, support = {T32 HL134621/HL/NHLBI NIH HHS/United States ; R01 HL130318/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Male ; Rats ; *Acetylcysteine/therapeutic use ; Antioxidants/therapeutic use ; Diet, High-Fat ; Fatty Acids ; Obesity ; Rats, Wistar ; Respiratory Muscles ; *Sucrose ; }, abstract = {NEW FINDINGS: What is the central question of this study? This study addresses whether a high-fat, high-sucrose diet causes cardiac and diaphragm muscle abnormalities in male rats and whether supplementation with the antioxidant N-acetylcysteine reverses diet-induced dysfunction. What is the main finding and its importance? N-Acetylcysteine attenuated the effects of high-fat, high-sucrose diet on markers of cardiac hypertrophy and diastolic dysfunction, but neither high-fat, high-sucrose diet nor N-acetylcysteine affected the diaphragm. These results support the use of N-acetylcysteine to attenuate cardiovascular dysfunction induced by a 'Western' diet.<br><br>ABSTRACT: Individuals with overweight or obesity display respiratory and cardiovascular dysfunction, and oxidative stress is a causative factor in the general aetiology of obesity and of skeletal and cardiac muscle pathology. Thus, this preclinical study aimed to define diaphragmatic and cardiac morphological and functional alterations in response to an obesogenic diet in rats and the therapeutic potential of an antioxidant supplement, N-acetylcysteine (NAC). Young male Wistar rats consumed ad libitum a 'lean' or high-saturated fat, high-sucrose (HFHS) diet for &#x223c;22&#xa0;weeks and were randomized to control or NAC (2&#xa0;mg/ml in the drinking water) for the last 8 weeks of the dietary intervention. We then evaluated diaphragmatic and cardiac morphology and function. Neither HFHS diet nor NAC supplementation affected diaphragm-specific force, peak power or morphology. Right ventricular weight normalized to estimated body surface area, left ventricular fractional shortening and posterior wall maximal shortening velocity were higher in HFHS compared with lean control animals and not restored by NAC. In HFHS rats, the elevated deceleration rate of early transmitral diastolic velocity was prevented by NAC. Our data showed that the HFHS diet did not compromise diaphragmatic muscle morphology or in vitro function, suggesting other possible contributors to breathing abnormalities in obesity (e.g., abnormalities of neuromuscular transmission). However, the HFHS diet resulted in cardiac functional and morphological changes suggestive of hypercontractility and diastolic dysfunction. Supplementation with NAC did not affect diaphragm morphology or function but attenuated some of the cardiac abnormalities in the rats receiving the HFHS diet.}, }
@article {pmid35924425, year = {2022}, author = {Ruan, S and Zha, L}, title = {Moronic acid improves intestinal inflammation in mice with chronic colitis by inhibiting intestinal macrophage polarization.}, journal = {Journal of biochemical and molecular toxicology}, volume = {36}, number = {11}, pages = {e23188}, doi = {10.1002/jbt.23188}, pmid = {35924425}, issn = {1099-0461}, support = {82000495//National Natural Science Foundation of China/ ; 2022AD30019//Science and Technology Project of Jiaxing/ ; }, mesh = {Mice ; Animals ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species ; *Colitis/chemically induced/drug therapy/metabolism ; Cytokines/metabolism ; Macrophages/metabolism ; Lipopolysaccharides/toxicity ; *Inflammatory Bowel Diseases ; Inflammation/drug therapy ; }, abstract = {This study focuses on exploring the role and mechanism of moronic acid (MOA), a small triterpenoid molecule, against inflammatory bowel disease (IBD). Intestinal macrophages were cultured in vitro, and their M1 polarization was induced by lipopolysaccharide (LPS) and interferon gamma (IFN-γ). After intervention with MOA, the proportion of M1 macrophages was detected, and the levels of inflammatory cytokines (TNF-α, IL-6, and IL-1β) were examined by ELISA. IFA staining was performed to determine the P50 and CD86 expressions, while DCFH-DA was used to determine the reactive oxygen species (ROS) level, as well as the p-P50 and NLRP3 protein levels. Additionally, we also used N-acetylcysteine, a ROS inhibitor, to further explore the association between MOA and ROS-NF-κB signaling. In murine experimentation, colitis was induced in mice with DSS. After MOA intervention, we assessed the mucosal barrier damage, tissue ROS, as well as protein and inflammatory cytokine levels. MOA could inhibit the M1 polarization of intestinal macrophages, suppress the expressions of inflammatory cytokines, and reduce the level of ROS-NF-κB-NLRP3 signaling. After inhibiting ROS through NAC treatment, the effect of MOA was evidently weakened. Clearly, MOA exerted its activity via ROS. In the murine model, MOA could lower the CD86 level in the intestinal tissues, inhibit the M1 polarization of macrophages, and reduce the tissue levels of inflammatory cytokines. This study finds that MOA can regulate ROS-NF-κB-NLRP3 signaling by inhibiting ROS, thereby suppressing the M1 polarization of intestinal macrophages, which plays a protective role in IBD.}, }
@article {pmid35921555, year = {2023}, author = {Datta, S and Cano, M and Satyanarayana, G and Liu, T and Wang, L and Wang, J and Cheng, J and Itoh, K and Sharma, A and Bhutto, I and Kannan, R and Qian, J and Sinha, D and Handa, JT}, title = {Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity.}, journal = {Autophagy}, volume = {19}, number = {3}, pages = {966-983}, pmid = {35921555}, issn = {1554-8635}, support = {R01 EY031594/EY/NEI NIH HHS/United States ; P30 EY006360/EY/NEI NIH HHS/United States ; K99 EY029010/EY/NEI NIH HHS/United States ; P30 EY001765/EY/NEI NIH HHS/United States ; R01 EY027691/EY/NEI NIH HHS/United States ; R00 EY029010/EY/NEI NIH HHS/United States ; R01 EY033765/EY/NEI NIH HHS/United States ; P30 EY008098/EY/NEI NIH HHS/United States ; }, mesh = {Humans ; Aged ; Mitophagy/genetics ; Autophagy ; Thioredoxin Reductase 1 ; Antioxidants ; Acetylcysteine ; *Dendrimers ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; Retinal Pigment Epithelium ; *Macular Degeneration ; Phosphatidylinositol 3-Kinase ; Basic-Leucine Zipper Transcription Factors ; Amines ; Retinal Pigments ; Serine ; }, abstract = {Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without treatment for early disease. Degenerative retinal pigment epithelial (RPE) cell heterogeneity is a well-recognized but understudied pathogenic factor. Due to the daily phagocytosis of photoreceptor outer segments, unique photo-oxidative stress, and high metabolism for maintaining vision, the RPE has robust macroautophagy/autophagy, and mitochondrial and antioxidant networks. However, the autophagy subtype, mitophagy, in the RPE and AMD is understudied. Here, we found decreased PINK1 (PTEN induced kinase 1) in perifoveal RPE of early AMD eyes. PINK1-deficient RPE have impaired mitophagy and mitochondrial function that triggers death-resistant epithelial-mesenchymal transition (EMT). This reprogramming is mediated by novel retrograde mitochondrial-nuclear signaling (RMNS) through superoxide, NFE2L2 (NFE2 like bZIP transcription factor 2), TXNRD1 (thioredoxin reductase 1), and phosphoinositide 3-kinase (PI3K)-AKT (AKT serine/threonine kinase) that induced canonical transcription factors ZEB1 (zinc finger E-box binding homeobox 1) and SNAI1 (Snail family transcriptional repressor 1) and an EMT transcriptome. NFE2L2 deficiency disrupted RMNS that paradoxically normalized morphology but decreased function and viability. Thus, RPE heterogeneity is defined by the interaction of two cytoprotective pathways that is triggered by mitophagy function. By neutralizing the consequences of impaired mitophagy, an antioxidant dendrimer tropic for the RPE and mitochondria, EMT (a recognized AMD alteration) was abrogated to offer potential therapy for early AMD, a stage without treatment.Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; AMD: age-related macular degeneration; CCCP: cyanide m-chlorophenyl hydrazone; CDH1: cadherin 1; DAVID: Database for Annotation, Visualization and Integrated Discovery; DHE: dihydroethidium; D-NAC: N-acetyl-l-cysteine conjugated to a poly(amido amine) dendrimer; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSEA: Gene Set Enrichment Analysis; HSPD1: heat shock protein family D (Hsp60) member 1; IVT: intravitreal; KD: knockdown; LMNA, lamin A/C; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MMP: mitochondrial membrane potential; NAC: N-acetyl-l-cysteine; NQO1: NAD(P)H quinone dehydrogenase 1; NFE2L2: NFE2 like bZIP transcription factor 2; O2[-]: superoxide anion; OCR: oxygen consumption rate; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; RMNS: retrograde mitochondrial-nuclear signaling; ROS: reactive oxygen species; RPE: retinal pigment epithelium; SNAI1: snail family transcriptional repressor 1; TJP1: tight junction protein 1; TPP-D-NAC: triphenyl phosphinium and N-acetyl-l-cysteine conjugated to a poly(amido amine) dendrimer; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; Trig: trigonelline; TXNRD1: thioredoxin reductase 1; VIM: vimentin; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.}, }
@article {pmid35917249, year = {2022}, author = {Gilli, M and Hollaert, TG and Setbon, HM and des Rieux, A and Leprince, JG}, title = {Quality of Cure in Depth of Commercially Available Bulk-fill Composites: A Layer-by-layer Mechanical and Biological Evaluation.}, journal = {Operative dentistry}, volume = {47}, number = {4}, pages = {437-448}, doi = {10.2341/21-084-L}, pmid = {35917249}, issn = {1559-2863}, mesh = {*Composite Resins/chemistry/therapeutic use ; Culture Media, Conditioned ; *Dental Materials/chemistry ; Humans ; Materials Testing ; Polymerization ; Viscosity ; }, abstract = {Despite their popularity, the use of bulk-fill composites remains controversial, both in terms of their properties and their in-depth development. The objectives of the present work were (1) to provide a more comprehensive evaluation of the quality of cure in depth of commercially available bulk-fill composites by combining various key mechanical and biological characterization methods, (2) to evaluate the inter-material differences when optimally cured, and (3) to evaluate the efficiency of an antioxidant-N-acetyl-cysteine (NAC)-to restrain the adverse effects of the leached components on cell viability. Nine bulk-fill composites (including flowable and high-viscosity materials) were investigated and compared to two conventional resin-based composites, one flowable and one high-viscosity restorative material. The materials were injected or packed into Teflon molds of various configurations, up to 6 mm material thickness. They were then light-cured from the top for 20 seconds with Bluephase G2 (Ivoclar Vivadent, irradiance = 1050 mW/cm2). The following physico-mechanical properties were measured for the upper (0-2 mm), intermediate (2-4 mm), and lower (4-6 mm) layers: degree of conversion using Raman Spectrometry (DC, in %), microhardness using a Vickers micro-indenter before (VHN dry) and after 24 hours of storage in ethanol (VHN EtOH), and flexural strength (in MPa) and flexural modulus (in GPa) using a three-point bend test. Each composite layer and an uncured layer were also stored for one week in a standard cell growth medium to generate conditioned media. Human dental pulp cells were then cultured for 24 hours with the latter and cell viability was measured using an MTS assay. A similar experiment was repeated with conditioned media produced in contact with uncured composites, with and without the addition of 4 mM NAC. The data were subjected to a Shapiro-Wilk test, then one-way ANOVA or Kruskal-Wallis test, followed either by Tukey's test (inter-material comparison) or by Dunnett's or Dunn's test (comparison between layers relative to the upper one). The level of statistical significance was set at 0.05. Some materials (EverX, X-traF, VenusBF, X-traB) did not show any significant differences (p>0.05) for any of the properties considered between the intermediate layers compared to the upper one (considered as reference). Others displayed significant differences, at least for some properties, highlighting the value of combining various key mechanical and biological characterization methods when investigating the quality of cure in depth. Significant inter-material differences (p<0.05) were observed when comparing the properties of their upper layer, considered as "optimally" polymerized. Hence, one needs to consider the absolute property values, not only their relative evolution concerning layer thickness. Finally, the use of NAC appeared as beneficial to reduce the risk of harmful effects to dental pulp cells, especially in case of excessive thickness use, and may therefore be of potential interest as an additive to composites in the future.}, }
@article {pmid35911996, year = {2022}, author = {Li, Y and Yu, H and Zhou, X and Jin, L and Li, W and Li, GL and Shen, X}, title = {Multiple Sevoflurane Exposures During the Neonatal Period Cause Hearing Impairment and Loss of Hair Cell Ribbon Synapses in Adult Mice.}, journal = {Frontiers in neuroscience}, volume = {16}, number = {}, pages = {945277}, pmid = {35911996}, issn = {1662-4548}, abstract = {OBJECTIVES: This study aims to investigate the effects of multiple sevoflurane exposures in neonatal mice on hearing function in the later life and explores the underlying mechanisms and protective strategies.<br><br>MATERIALS AND METHODS: Neonatal Kunming mice were exposed to sevoflurane for 3 days. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) tests, immunofluorescence, patch-clamp recording, and quantitative real-time PCR were performed to observe hearing function, hair cells, ribbon synapses, nerve fibers, spiral ganglion neurons, and oxidative stress.<br><br>RESULTS: Compared to control group, multiple sevoflurane exposures during the neonatal time significantly elevated ABR thresholds at 8 kHz (35.42 &#xb1; 1.57 vs. 41.76 &#xb1; 1.97 dB, P = 0.0256), 16 kHz (23.33 &#xb1; 1.28 vs. 33.53 &#xb1; 2.523 dB, P = 0.0012), 24 kHz (30.00 &#xb1; 2.04 vs. 46.76 &#xb1; 3.93 dB, P = 0.0024), and 32 kHz (41.25 &#xb1; 2.31 vs. 54.41 &#xb1; 2.94 dB, P = 0.0028) on P30, caused ribbon synapse loss on P15 (13.10 &#xb1; 0.43 vs. 10.78 &#xb1; 0.52, P = 0.0039) and P30 (11.24 &#xb1; 0.56 vs. 8.50 &#xb1; 0.84, P = 0.0141), and degenerated spiral ganglion neuron (SGN) nerve fibers on P30 (110.40 &#xb1; 16.23 vs. 55.04 &#xb1; 8.13, P = 0.0073). In addition, the V half of calcium current become more negative (-21.99 &#xb1; 0.70 vs. -27.17 &#xb1; 0.60 mV, P < 0.0001), exocytosis was reduced (105.40 &#xb1; 19.97 vs. 59.79 &#xb1; 10.60 fF, P < 0.0001), and Lpo was upregulated (P = 0.0219) in sevoflurane group than those in control group. N-acetylcysteine (NAC) reversed hearing impairment induced by sevoflurane.<br><br>CONCLUSION: The findings suggest that multiple sevoflurane exposures during neonatal time may cause hearing impairment in adult mice. The study also demonstrated that elevated oxidative stress led to ribbon synapses impairment and SGN nerve fibers degeneration, and the interventions of antioxidants alleviated the sevoflurane-induced hearing impairment.}, }
@article {pmid35910843, year = {2022}, author = {Li, J and Jia, B and Cheng, Y and Song, Y and Li, Q and Luo, C}, title = {Targeting Molecular Mediators of Ferroptosis and Oxidative Stress for Neurological Disorders.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {3999083}, pmid = {35910843}, issn = {1942-0994}, mesh = {*Ferroptosis ; Humans ; Lipid Peroxidation ; *Nervous System Diseases ; Oxidative Stress/physiology ; Reactive Oxygen Species ; }, abstract = {With the acceleration of population aging, nervous system diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), anxiety, depression, stroke, and traumatic brain injury (TBI) have become a huge burden on families and society. The mechanism of neurological disorders is complex, which also lacks effective treatment, so relevant research is required to solve these problems urgently. Given that oxidative stress-induced lipid peroxidation eventually leads to ferroptosis, both oxidative stress and ferroptosis are important mechanisms causing neurological disorders, targeting mediators of oxidative stress and ferroptosis have become a hot research direction at present. Our review provides a current view of the mechanisms underlying ferroptosis and oxidative stress participate in neurological disorders, the potential application of molecular mediators targeting ferroptosis and oxidative stress in neurological disorders. The target of molecular mediators or agents of oxidative stress and ferroptosis associated with neurological disorders, such as reactive oxygen species (ROS), nuclear factor erythroid 2-related factor-antioxidant response element (Nrf2-ARE), n-acetylcysteine (NAC), Fe[2+], NADPH, and its oxidases NOX, has been described in this article. Given that oxidative stress-induced ferroptosis plays a pivotal role in neurological disorders, further research on the mechanisms of ferroptosis caused by oxidative stress will help provide new targets for the treatment of neurological disorders.}, }
@article {pmid35909484, year = {2022}, author = {Baponwa, O and Amang, AP and Mezui, C and Koubala, BB and Siwe, GT and Vandi, VL and Tan, PV}, title = {Antioxidant Mechanism of Renal and Hepatic Failure Prevention Related to Paracetamol Overdose by the Aqueous Extract of Amblygonocarpus andongensis Stem Bark.}, journal = {BioMed research international}, volume = {2022}, number = {}, pages = {1846558}, pmid = {35909484}, issn = {2314-6141}, mesh = {Acetaminophen/pharmacology ; Animals ; *Antioxidants/metabolism ; Kidney/pathology ; Liver/pathology ; *Liver Failure/metabolism ; Oxidative Stress ; Plant Bark/metabolism ; Plant Extracts/therapeutic use ; Rats ; Water/metabolism ; }, abstract = {Paracetamol is a commonly used analgesic/antipyretic whose long-term intake or overdose is associated with renal and hepatic injuries. The aim of this study was to determine the hepatonephroprotective mechanisms of the aqueous extract of Amblygonocarpus andongensis stem bark (AEAASB) on renal and hepatic failure resulting from paracetamol overdose. Forty-five rats were divided into nine groups (n = 5); these were treated once daily for 8 days with 5 ml/kg distilled water (normal, negative, and satellite controls); 0.9% normal saline and 140 mg/kg N-acetyl-cysteine (positive controls); 125, 250, and 500 mg/kg AEAASB (test groups); and 500 mg/kg AEAASB (satellite test). On day 8 after different treatments, hepatonephrotoxicity was induced in all the groups except the normal group by oral administration of a single dose of paracetamol (1000 mg/kg). Urinary, hematological, serum, and oxidative stress parameters and in vitro antioxidant activity of AEAASB were evaluated. Histological sections of the liver and kidney were performed. AEAASB significantly decreased urea, creatinine, transaminases, alkaline phosphatase, and bilirubin (p < 0.001) at 500 mg/kg compared to the negative control. Significant decreases in hepatic (p < 0.01) and renal (p < 0.001) malondialdehyde levels were associated with increases in superoxide dismutase, catalase, and reduced glutathione levels in 500 mg/kg AEAASB compared with the negative control. Histological analysis showed that AEAASB prevented paracetamol-induced renal and liver tissue damage. Furthermore, AEAASB revealed a very strong antioxidant activity (inhibitory concentration 50 = 180 μg/ml, antioxidant activity index = 5.55) with an ability to scavenge 63.03% 2,2-diphenyl-2-picrylhy-drazyl radical and reduced ferric iron by 52.68 mgEqVitC/100 g DM. The hepatonephroprotective effect of AEAASB might result from its ability to improve the antioxidant status through the stimulation of antioxidant factors and the scavenging of free radicals. This property could be ascribed to the presence of some classes of bioactive compounds such as phenolic compounds in great amounts.}, }
@article {pmid35909335, year = {2022}, author = {Wang, X and Zhang, W and Ge, P and Yu, M and Meng, H}, title = {Parthanatos participates in glutamate-mediated HT22 cell injury and hippocampal neuronal death in kainic acid-induced status epilepticus rats.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {28}, number = {12}, pages = {2032-2043}, pmid = {35909335}, issn = {1755-5949}, mesh = {Rats ; Animals ; *Parthanatos ; Kainic Acid ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Glutamic Acid ; Poly (ADP-Ribose) Polymerase-1/metabolism/pharmacology ; Cell Death ; Hippocampus/metabolism ; *Status Epilepticus ; Acetylcysteine/pharmacology ; }, abstract = {AIMS: Epileptic seizures or status epilepticus (SE) can cause hippocampal neuronal death, which has detrimental effects. Parthanatos, a new form of programmed cell death, is characterized by hyperactivation of poly (ADP-ribose) polymerase-1 (PARP-1), excessive synthesis of poly ADP-ribose polymer, mitochondrial depolarization, and nuclear translocation of apoptosis-inducing factor, observed in various neurodegenerative disorders but rarely reported in epilepsy. We aimed to investigate whether parthanatos participates in the mechanism of seizure-induced hippocampal neuronal death.<br><br>METHODS: Glutamate-mediated excitotoxicity cell model was used to study the mechanism of seizure-induced cell injury. Injection of kainic acid into the amygdala was used to establish the epileptic rat model. Corresponding biochemical tests were carried out on hippocampal tissues and HT22 cells following indicated treatments.<br><br>RESULTS: In vitro, glutamate time-dependently induced HT22 cell death, accompanied by parthanatos-related biochemical events. Pretreatment with PJ34 (PARP-1 inhibitor) or small interfering RNA-mediated PARP-1 knockdown effectively protected HT22 cells against glutamate-induced toxic effects and attenuated parthanatos-related biochemical events. Application of the antioxidant N-acetylcysteine (NAC) rescued HT22 cell death and reversed parthanatos-related biochemical events. In vivo, PJ34 and NAC afforded protection against SE-induced hippocampal neuronal damage and inhibited parthanatos-related biochemical events.<br><br>CONCLUSION: Parthanatos participates in glutamate-induced HT22 cell injury and hippocampal neuronal damage in rats following epileptic seizures. ROS might be the initiating factor during parthanatos.}, }
@article {pmid35904459, year = {2022}, author = {Roydhouse, J and Tomko, RL and Gray, KM and Gutman, R}, title = {Assessment of patient perception of treatment assignment and patient-reported outcomes in a cannabis use disorder trial.}, journal = {The American journal of drug and alcohol abuse}, volume = {48}, number = {6}, pages = {651-661}, doi = {10.1080/00952990.2022.2097918}, pmid = {35904459}, issn = {1097-9891}, mesh = {Female ; Humans ; *Marijuana Abuse/drug therapy ; Patient Reported Outcome Measures ; Perception ; }, abstract = {Background: Blinding is a cornerstone of trial methodology. Prior work indicates participant-perceived assignment may be associated with trial outcomes. Less is known about how perception changes over time and if this is associated with outcomes.Objectives: To evaluate if participants change their perception of assignment over time in a blinded trial, and if perception is associated with different types of patient-reported outcomes (PROs).Methods: This was a secondary analysis of data from the Achieving Cannabis Cessation-Evaluating N-Acetylcysteine Treatment (ACCENT) trial, which evaluated the efficacy of N-acetylcysteine (NAC) relative to placebo for treating cannabis use disorder. Participants (N = 234; 164 men, 70 women) were asked at weeks 5 and 9 what treatment (placebo or NAC) they believed they were receiving. We included PROs proximal (cannabis-associated problems, craving) and distal (anxiety) to the intervention. Analysis was by multiple linear regression and mixed models.Results: Approximately 20% of participants in both arms changed their perception over time. Relative to participants who consistently perceived assignment to placebo, participants who consistently perceived assignment to NAC did not always have comparatively better average scores (coefficient -3.3 [95% CI: -7.0, 0.5]). In some analyses, participants who switched to guessing NAC from placebo had comparatively better average scores (coefficient -3.0 [95% CI: -9.3, 3.4]), but this was inconsistent across outcomes or strata defined by actual assignment or guess accuracy.Conclusion: The study suggests that the proportion of individuals who switch their perception over time is modest. However, this group may influence the estimates of intervention effects on some PROs.}, }
@article {pmid35902628, year = {2022}, author = {Czekus, C and Steullet, P and Orero López, A and Bozic, I and Rusterholz, T and Bandarabadi, M and Do, KQ and Gutierrez Herrera, C}, title = {Alterations in TRN-anterodorsal thalamocortical circuits affect sleep architecture and homeostatic processes in oxidative stress vulnerable Gclm[-/-] mice.}, journal = {Molecular psychiatry}, volume = {27}, number = {11}, pages = {4394-4406}, pmid = {35902628}, issn = {1476-5578}, support = {320030_179565 / 1//Swiss Re | Swiss Re Foundation (SwissRe Foundation)/ ; 18.1.2018/25.1.2024//Universit&#xe4;t Bern (University of Bern)/ ; }, mesh = {Mice ; Humans ; Animals ; *Glutamate-Cysteine Ligase ; *Sleep/physiology ; Thalamus ; Thalamic Nuclei ; Oxidative Stress ; Cerebral Cortex ; }, abstract = {Schizophrenia is associated with alterations of sensory integration, cognitive processing and both sleep architecture and sleep oscillations in mouse models and human subjects, possibly through changes in thalamocortical dynamics. Oxidative stress (OxS) damage, including inflammation and the impairment of fast-spiking gamma-aminobutyric acid neurons have been hypothesized as a potential mechanism responsible for the onset and development of schizophrenia. Yet, the link between OxS and perturbation of thalamocortical dynamics and sleep remains unclear. Here, we sought to investigate the effects of OxS on sleep regulation by characterizing the dynamics of thalamocortical networks across sleep-wake states in a mouse model with a genetic deletion of the modifier subunit of glutamate-cysteine ligase (Gclm knockout, KO) using high-density electrophysiology in freely-moving mice. We found that Gcml KO mice exhibited a fragmented sleep architecture and impaired sleep homeostasis responses as revealed by the increased NREM sleep latencies, decreased slow-wave activities and spindle rate after sleep deprivation. These changes were associated with altered bursting activity and firing dynamics of neurons from the thalamic reticularis nucleus, anterior cingulate and anterodorsal thalamus. Administration of N-acetylcysteine (NAC), a clinically relevant antioxidant, rescued the sleep fragmentation and spindle rate through a renormalization of local neuronal dynamics in Gclm KO mice. Collectively, these findings provide novel evidence for a link between OxS and the deficits of frontal TC network dynamics as a possible mechanism underlying sleep abnormalities and impaired homeostatic responses observed in schizophrenia.}, }
@article {pmid35901044, year = {2022}, author = {Li, YX and Hsiao, CH and Chang, YF}, title = {N-acetyl cysteine prevents arecoline-inhibited C2C12 myoblast differentiation through ERK1/2 phosphorylation.}, journal = {PloS one}, volume = {17}, number = {7}, pages = {e0272231}, pmid = {35901044}, issn = {1932-6203}, mesh = {Acetylcysteine/metabolism/pharmacology ; *Arecoline/pharmacology ; Cell Differentiation ; *MAP Kinase Signaling System ; Muscle Development ; Myoblasts/metabolism ; Phosphorylation ; Reactive Oxygen Species/metabolism ; }, abstract = {Arecoline is known to induce reactive oxygen species (ROS). Our previous studies showed that arecoline inhibited myogenic differentiation and acetylcholine receptor cluster formation of C2C12 myoblasts. N-acetyl-cysteine (NAC) is a known ROS scavenger. We hypothesize that NAC scavenges the excess ROS caused by arecoline. In this article we examined the effect of NAC on the inhibited myoblast differentiation by arecoline and related mechanisms. We found that NAC less than 2 mM is non-cytotoxic to C2C12 by viability analysis. We further demonstrated that NAC attenuated the decreased number of myotubes and nuclei in each myotube compared to arecoline treatment by H &amp; E staining. We also showed that NAC prevented the decreased expression level of the myogenic markers, myogenin and MYH caused by arecoline, using immunocytochemistry and western blotting. Finally, we found that NAC restored the decreased expression level of p-ERK1/2 by arecoline. In conclusion, our results indicate that NAC attenuates the damage of the arecoline-inhibited C2C12 myoblast differentiation by the activation/phosphorylation of ERK. This is the first report to demonstrate that NAC has beneficial effects on skeletal muscle myogenesis through ERK1/2 upon arecoline treatment. Since defects of skeletal muscle associates with several diseases, NAC can be a potent drug candidate in diseases related to defects in skeletal muscle myogenesis.}, }
@article {pmid35898618, year = {2022}, author = {Ren, C and Hu, C and Wu, Y and Li, T and Zou, A and Yu, D and Shen, T and Cai, W and Yu, J}, title = {Nicotinamide Mononucleotide Ameliorates Cellular Senescence and Inflammation Caused by Sodium Iodate in RPE.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {5961123}, pmid = {35898618}, issn = {1942-0994}, mesh = {Cellular Senescence ; Humans ; Inflammation/metabolism ; Iodates ; *Macular Degeneration/metabolism ; NAD/metabolism ; Nicotinamide Mononucleotide/metabolism/pharmacology ; Oxidative Stress ; *Retinal Pigment Epithelium/metabolism ; }, abstract = {Senescent cells have been demonstrated to have lower cellular NAD[+] levels and are involved in the development of various age-related diseases, including age-related macular degeneration (AMD). Sodium iodate (NaIO3) has been primarily used as an oxidant to establish a model of dry AMD. Results of previous studies have showed that NaIO3 induced retinal tissue senescence in vivo. However, the role of NaIO3 and the mechanism by which it induces retinal pigment epithelium (RPE) senescence remains unknown. In this study, RPE cell senescence was confirmed to be potentially induced by NaIO3. The results showed that the number of senescence-associated-β-galactosidase (SA-β-gal-)-positive cells and the protein levels of p16 and p21 increased after NaIO3 treatment. Additionally, the senescent RPE cells underwent oxidative stress and NAD[+] depletion. Furthermore, significant DNA damage and mitochondrial dysfunction were also detected in senescent RPE cells. The antioxidant N-acetylcysteine (NAC) could alleviate cellular senescence only by a minimal degree, whereas supplementation with nicotinamide mononucleotide (NMN) strongly ameliorated RPE senescence through the alleviation of DNA damage and the maintenance of mitochondrial function. The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling. Moreover, both the expression of senescence markers of RPE and subretinal inflammatory cell infiltration were decreased by NMN treatment in vivo. Our results indicate that RPE senescence induced by NaIO3 acquired several key features of AMD. More importantly, NMN may potentially be used to treat RPE senescence and senescence-associated pre-AMD changes by restoring the NAD[+] levels in cells and tissues.}, }
@article {pmid35897820, year = {2022}, author = {Wu, MF and Huang, YH and Chiu, LY and Cherng, SH and Sheu, GT and Yang, TY}, title = {Curcumin Induces Apoptosis of Chemoresistant Lung Cancer Cells via ROS-Regulated p38 MAPK Phosphorylation.}, journal = {International journal of molecular sciences}, volume = {23}, number = {15}, pages = {}, pmid = {35897820}, issn = {1422-0067}, support = {CSH-2018-C-024//Chung Shan Medical University Hospital/ ; TCVGH-1103202C//Taichung Veterans General Hospital/ ; }, mesh = {Apoptosis ; *Curcumin/pharmacology ; Eukaryotic Initiation Factor-2/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Lung Neoplasms/drug therapy ; MAP Kinase Signaling System ; Phosphorylation ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {This study aimed to challenge chemoresistance by curcumin (CUR) with drug-selected human lung cancer A549 sublines that continuously proliferate in the present of docetaxel (DOC) and vincristine (VCR). Their sensitivities to CUR were measured by MTT assay and the particular intracellular reactive oxygen species (ROS) was detected by fluorescence activated cell sorting (FACS) analysis. Apoptosis was analyzed by Annexin V assay of the flow cytometry. Inhibitors and RNA interference were used to examine the signaling pathway regulated by the kinases. The obtained data demonstrated that CUR induces chemoresistant cell apoptosis by generating ROS and application of N-acetylcysteine (NAC) blocks ROS production, resulting in apoptosis suppression. Phosphorylation of extracellular regulated kinase (ERK), p38 MAPK, and eIF-2α were increased but c-Jun N-terminal kinase (JNK) did not increase when chemoresistant cells were treated with CUR. Downregulation of ERK and p38 MAPK phosphorylation by their inhibitors had no effect on CUR-induced apoptosis. Interestingly, the knockdown of p38 MAPK with shRNA significantly reduced CUR-induced apoptosis on the chemoresistant sublines. Phosphorylation of the eIF-2α protein was inhibited when p38 MAPK was knocked down in DOC-resistant A549 cells, but a high level of phosphorylated eIF-2α protein remained on the VCR-resistant A549 cells when p38 MAPK was knocked down. These data confirmed that CUR-augmented ROS potently induced apoptosis via upregulated p38 MAPK phosphorylation. Therefore, activated p38 MAPK is considered a pro-apoptotic signal for CUR-induced apoptosis of chemoresistant human lung cancer cells.}, }
@article {pmid35893741, year = {2022}, author = {Yang, CW and Chien, TM and Yen, CH and Wu, WJ and Sheu, JH and Chang, HW}, title = {Antibladder Cancer Effects of Excavatolide C by Inducing Oxidative Stress, Apoptosis, and DNA Damage In Vitro.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {8}, pages = {}, pmid = {35893741}, issn = {1424-8247}, support = {MOST 108-2314-B-037-021-MY3//Ministry of Science and Technology/ ; #NSYSUKMU 111-P20//National Sun Yat-sen University-KMU Joint Research Project/ ; KMU-DK(A)111008//Kaohsiung Medical University/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Excavatolide C (EXCC) is a bioactive compound derived from the gorgonian octocoral Briareum excavatum, and its anticancer effects are rarely addressed, particularly for bladder cancer. This investigation aimed to explore the potential impacts of EXCC on inhibiting the proliferation of three kinds of bladder cancer cells (5637, BFTC905, and T24). EXCC inhibits bladder cancer cell proliferation based on 48 h ATP assay. This antiproliferation function is validated to be oxidative stress dependent. Cellular and mitochondrial oxidative stresses were upregulated by EXCC, accompanied by depleting glutathione and mitochondrial membrane potential. These antiproliferation and oxidative stress events were suppressed by N-acetylcysteine (NAC), indicating that EXCC has an oxidative stress-regulating function for antiproliferation of bladder cancer cells. Oxidative stress-related responses such as apoptosis, caspase activation, and DNA damage were upregulated by EXCC and reverted by NAC. Taken together, the antiproliferation function of EXCC provides a potential treatment against bladder cancer cells via oxidative stress modulation.}, }
@article {pmid35893129, year = {2022}, author = {Sun, T and Zhang, Q and Li, M and Tang, S and Dai, C}, title = {T-2 Toxin Induces Apoptotic Cell Death and Protective Autophagy in Mouse Microglia BV2 Cells.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {8}, number = {8}, pages = {}, pmid = {35893129}, issn = {2309-608X}, support = {31972740//National Natural Science Foundation of China/ ; }, abstract = {T-2 toxin exposure could cause neurotoxicity; however, the precise molecular mechanisms remain unclear. In the present study, we investigated T-2 toxin-induced cytotoxicity and underlying molecular mechanisms using a mouse microglia BV2 cell line. The results show that T-2 toxin treatment-induced cytotoxicity of BV2 cells was dose- and time-dependent. Compared to the control, T-2 toxin treatment at 1.25-5 ng/mL significantly increased reactive oxygen species (ROS) production and triggered oxidative stress. T-2 toxin treatment also caused mitochondrial dysfunction in BV2 cells, which was evidenced by decreased mitochondrial transmembrane potential, upregulated expression of Bax protein, and decreased expression of Bcl-2 protein. Meanwhile, T-2 toxin treatment upregulated the expression of cleaved-caspase-3, cleaved-PARP-1 proteins, and downregulated the expression of HO-1 and nuclear Nrf2 proteins, finally inducing cell apoptosis in BV2 cells. N-acetylcysteine (NAC) supplementation significantly attenuated T-2 toxin-induced cytotoxicity. Moreover, T-2 toxin treatment activated autophagy and upregulated autophagy flux, and the inhibition of autophagy significantly promoted T-2 toxin-induced cell apoptosis. Taken together, our results reveal that T-2 toxin-induced cytotoxicity in BV2 cells involves the production of ROS, the activation of the mitochondrial apoptotic pathway, and the inhibition of the Nrf2/HO-1 pathway. Our study offers new insight into the underlying molecular mechanisms in T-2 toxin-mediated neurotoxicity.}, }
@article {pmid35892873, year = {2022}, author = {Obrador, E and Salvador-Palmer, R and López-Blanch, R and Oriol-Caballo, M and Moreno-Murciano, P and Estrela, JM}, title = {N-Acetylcysteine Promotes Metastatic Spread of Melanoma in Mice.}, journal = {Cancers}, volume = {14}, number = {15}, pages = {}, pmid = {35892873}, issn = {2072-6694}, support = {SBT-001//Scientia BioTech S.L./ ; }, abstract = {N-acetylcysteine (NAC) is a direct Cys donor and a promoter of glutathione (GSH) synthesis. GSH regulates melanoma growth and NAC has been suggested to increase melanoma metastases in mice. We found that high therapeutic doses of NAC do not increase the growth of melanoma xenografts, but can cause metastatic spread and distant metastases. Nevertheless, this is not due to an antioxidant effect since NAC, in fact, increases the generation of reactive oxygen species in the growing metastatic melanoma. Trolox, an antioxidant vitamin E derivative, administered in vivo, decreased metastatic growth. Metastatic cells isolated from NAC-treated mice showed an increase in the nuclear translocation of Nrf2, as compared to controls. Nrf2, a master regulator of the antioxidant response, controls the expression of different antioxidant enzymes and of the γ-glutamylcysteine ligase (the rate-limiting step in GSH synthesis). Cystine uptake through the xCT cystine-glutamate antiporter (generating intracellular Cys) and the γ-glutamylcysteine ligase activity are key to control metastatic growth. This is associated to an increase in the utilization of L-Gln by the metastatic cells, another metastases promoter. Our results demonstrate the potential of NAC as an inducer of melanoma metastases spread, and suggest that caution should be taken when administering GSH promoters to cancer patients.}, }
@article {pmid35889482, year = {2022}, author = {Malkawi, A and Alrabadi, N and Haddad, R and Malkawi, A and Khaled, K and Ovenseri, AC}, title = {Development of Self-Emulsifying Drug Delivery Systems (SEDDSs) Displaying Enhanced Permeation of the Intestinal Mucus Following Sustained Release of Prototype Thiol-Based Mucolytic Agent Load.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {14}, pages = {}, pmid = {35889482}, issn = {1420-3049}, support = {I.u-27-2441//Isra University/ ; }, mesh = {Caco-2 Cells ; Delayed-Action Preparations ; Drug Delivery Systems ; *Emulsifying Agents ; Emulsions ; *Expectorants ; Humans ; Mucus ; Permeability ; Sulfhydryl Compounds ; }, abstract = {In this study, mucoactive self-emulsifying drug delivery systems (SEDDSs) based on sustained release of N-acetylcysteine (NAC) were developed for providing effective intestinal mucopermeation. Polymeric ionic complexes of NAC were formed with polyethyleneimine (PEI), Eudragit E 100, and Eudragit RS 100 and loaded into a novel SEDDS. The SEDDSs exhibited a stable average size of 75 ± 12 nm (polydispersity index (PDI) < 0.3) and showed a rise in the zeta potential from −17.31 mV to −7.72 mV. On Caco-2 cells, SEDDSs at 1−3% were non-cytotoxic. An average of 91.8 ± 5.4% NAC was released from SEDDSs containing Eudragit E 100 (p ≤ 0.05) and Eudragit RS 100 (p ≤ 0.001) complexes at a significantly slower rate within 80 min, whereas the SEDDS containing PEI released NAC in a matter of seconds. Similarly, the SEDDS complexes revealed a time-dependent reduction in mucus dynamic viscosity of 52.6 ± 19.9%. Consequently, as compared with a blank SEDDS, mucodiffusion revealed about 2- and 1.8-fold significantly greater mucopermeation of SEDDSs anchoring Eudragit E 100−NAC and RS 100−NAC complexes (p ≤ 0.05), respectively. The mucoactive SEDDSs, which steadily released NAC while permeating the mucus, were linked to a significantly increased mucopermeation in vitro as a result of optimal mucolytic targeting.}, }
@article {pmid35884757, year = {2022}, author = {Tang, Q and Li, T and Chen, K and Deng, X and Zhang, Q and Tang, H and Shi, Z and Zhu, T and Zhu, J}, title = {PS-NPs Induced Neurotoxic Effects in SHSY-5Y Cells via Autophagy Activation and Mitochondrial Dysfunction.}, journal = {Brain sciences}, volume = {12}, number = {7}, pages = {}, pmid = {35884757}, issn = {2076-3425}, abstract = {Polystyrene nanoparticles (PS-NPs) are organic pollutants that are widely detected in the environment and organisms, posing potential threats to both ecosystems and human health. PS-NPs have been proven to penetrate the blood-brain barrier and increase the incidence of neurodegenerative diseases. However, information relating to the pathogenic molecular mechanism is still unclear. This study investigated the neurotoxicity and regulatory mechanisms of PS-NPs in human neuroblastoma SHSY-5Y cells. The results show that PS-NPs caused obvious mitochondrial damages, as evidenced by inhibited cell proliferation, increased lactate dehydrogenase release, stimulated oxidative stress responses, elevated Ca[2+] level and apoptosis, and reduced mitochondrial membrane potential and adenosine triphosphate levels. The increased release of cytochrome c and the overexpression of apoptosis-related proteins apoptotic protease activating factor-1 (Apaf-1), cysteinyl aspartate specific proteinase-3 (caspase-3), and caspase-9 indicate the activation of the mitochondrial apoptosis pathway. In addition, the upregulation of autophagy markers light chain 3-II (LC3-II), Beclin-1, and autophagy-related protein (Atg) 5/12/16L suggests that PS-NPs could promote autophagy in SHSY-5Y cells. The RNA interference of Beclin-1 confirms the regulatory role of autophagy in PS-NP-induced neurotoxicity. The administration of antioxidant N-acetylcysteine (NAC) significantly attenuated the cytotoxicity and autophagy activation induced by PS-NP exposure. Generally, PS-NPs could induce neurotoxicity in SHSY-5Y cells via autophagy activation and mitochondria dysfunction, which was modulated by mitochondrial oxidative stress. Mitochondrial damages caused by oxidative stress could potentially be involved in the pathological mechanisms for PS-NP-induced neurodegenerative diseases.}, }
@article {pmid35883905, year = {2022}, author = {Zhu, J and Gillissen, B and Dang Tran, DL and May, S and Ulrich, C and Stockfleth, E and Eberle, J}, title = {Inhibition of Cell Proliferation and Cell Viability by Sinecatechins in Cutaneous SCC Cells Is Related to an Imbalance of ROS and Loss of Mitochondrial Membrane Potential.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {35883905}, issn = {2076-3921}, support = {S0251/10015/2020//Deutsches Stiftungszentrum GmbH/ ; }, abstract = {The term sinecatechins designates an extract containing a high percentage of catechins obtained from green tea, which is commercially registered as Veregen or Polyphenon E (PE) and may be considered for treatment of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK). As shown here, treatment of four cSCC cell lines with 200 µg/mL of PE resulted in strong, dose-dependent decrease in cell proliferation (20-30%) as well as strongly decreased cell viability (4-21% of controls, 48 h). Effects correlated with loss of mitochondrial membrane potential, whereas early apoptosis was less pronounced. At the protein level, some activation of caspase-3 and enhanced expression of the CDK inhibitor p21 were found. Loss of MMP and induced cell death were, however, largely independent of caspases and of the proapoptotic Bcl-2 proteins Bax and Bak, suggesting that sinecatechins induce also non-apoptotic, alternative cell death pathways, in addition to apoptosis. Reactive oxygen species (ROS) were downregulated in response to PE at 4 h, followed by an increase at 24 h. The contributory role of initially reduced ROS was supported by the antioxidant N-acetyl cysteine, which in combination with PE further enhanced the negative effects on cell viability. Thus, sinecatechins inhibited cell proliferation and viability of cSCC cells, which could suggest the use of PE for AK treatment. The mechanisms appear as linked to an imbalance of ROS levels.}, }
@article {pmid35883857, year = {2022}, author = {Galli, F and Marcantonini, G and Giustarini, D and Albertini, MC and Migni, A and Zatini, L and Gioiello, A and Rossi, R and Bartolini, D}, title = {How Aging and Oxidative Stress Influence the Cytopathic and Inflammatory Effects of SARS-CoV-2 Infection: The Role of Cellular Glutathione and Cysteine Metabolism.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {35883857}, issn = {2076-3921}, support = {19837 (2020.0522)//Fondazione Cassa di Risparmio di Perugia/ ; 10435 (2019.0320)//Fondazione Cassa di Risparmio di Perugia/ ; 20420 (2021.0339).//Fondazione Cassa di Risparmio di Perugia/ ; }, abstract = {SARS-CoV-2 infection can cause a severe respiratory distress syndrome with inflammatory and thrombotic complications, the severity of which increases with patients' age and presence of comorbidity. The reasons for an age-dependent increase in the risk of severe COVID-19 could be many. These include defects in the homeostatic processes that control the cellular redox and its pivotal role in sustaining the immuno-inflammatory response to the host and the protection against oxidative stress and tissue degeneration. Pathogens may take advantage of such age-dependent abnormalities. Alterations of the thiol redox balance in the lung tissue and lining fluids may influence the risk of infection, and the host capability to respond to pathogens and to avoid severe complications. SARS-CoV-2, likewise other viruses, such as HIV, influenza, and HSV, benefits in its replication cycle of pro-oxidant conditions that the same viral infection seems to induce in the host cell with mechanisms that remain poorly understood. We recently demonstrated that the pro-oxidant effects of SARS-CoV-2 infection are associated with changes in the cellular metabolism and transmembrane fluxes of Cys and GSH. These appear to be the consequence of an increased use of Cys in viral protein synthesis and to ER stress pathway activation that interfere with transcription factors, as Nrf2 and NFkB, important to coordinate the metabolism of GSH with other aspects of the stress response and with the pro-inflammatory effects of this virus in the host cell. This narrative review article describes these cellular and molecular aspects of SARS-CoV-2 infection, and the role that antivirals and cytoprotective agents such as N-acetyl cysteine may have to limit the cytopathic effects of this virus and to recover tissue homeostasis after infection.}, }
@article {pmid35883843, year = {2022}, author = {Yu, TJ and Shiau, JP and Tang, JY and Yen, CH and Hou, MF and Cheng, YB and Shu, CW and Chang, HW}, title = {Physapruin A Induces Reactive Oxygen Species to Trigger Cytoprotective Autophagy of Breast Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {35883843}, issn = {2076-3921}, support = {MOST 108-2320-B-037-015-MY3, MOST 110-2314-B-037-074-MY3, and MOST 108-2320-B-110-008-MY3//Ministry of Science and Technology/ ; NSYSUKMU 111-P20 and NSYSUKMU 111-P11//National Sun Yat-sen University-KMU Joint Research Project/ ; 111-05//NSYSU-KCGMH Joint Research Project/ ; KMUH110-0M39//Kaohsiung Medical University Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Physalis peruviana-derived physapruin A (PHA) is a potent compound that selectively generates reactive oxygen species (ROS) and induces cancer cell death. Autophagy, a cellular self-clearance pathway, can be induced by ROS and plays a dual role in cancer cell death. However, the role of autophagy in PHA-treated cancer cells is not understood. Our study initially showed that autophagy inhibitors such as bafilomycin A1 enhanced the cytotoxic effects of PHA in breast cancer cell lines, including MCF7 and MDA-MB-231. PHA treatment decreased the p62 protein level and increased LC3-II flux. PHA increased the fluorescence intensity of DAPGreen and DALGreen, which are used to reflect the formation of autophagosome/autolysosome and autolysosome, respectively. ROS scavenger N-acetylcysteine (NAC) decreased PHA-elevated autophagy activity, implying that PHA-induced ROS may be required for autophagy induction in breast cancer cells. Moreover, the autophagy inhibitor increased ROS levels and enhanced PHA-elevated ROS levels, while NAC scavenges the produced ROS resulting from PHA and autophagy inhibitor. In addition, the autophagy inhibitor elevated the PHA-induced proportion of annexin V/7-aminoactinmycin D and cleavage of caspase-3/8/9 and poly (ADP-ribose) polymerase. In contrast, NAC and apoptosis inhibitor Z-VAD-FMK blocked the proportion of annexin V/7-aminoactinmycin D and the activation of caspases. Taken together, PHA induced ROS to promote autophagy, which might play an antioxidant and anti-apoptotic role in breast cancer cells.}, }
@article {pmid35882152, year = {2022}, author = {Chen, C and Wang, J and Liang, Z and Li, M and Fu, D and Zhang, L and Yang, X and Guo, Y and Ge, D and Liu, Y and Sun, B}, title = {Monosodium urate crystals with controlled shape and aspect ratio for elucidating the pathological progress of acute gout.}, journal = {Biomaterials advances}, volume = {139}, number = {}, pages = {213005}, doi = {10.1016/j.bioadv.2022.213005}, pmid = {35882152}, issn = {2772-9508}, mesh = {*Arthritis, Gouty/chemically induced ; *Gout/drug therapy ; Humans ; Inflammasomes/adverse effects ; Macrophages/metabolism ; Uric Acid/adverse effects ; }, abstract = {Gout is a self-limiting inflammatory arthritis mediated by the precipitation of monosodium urate (MSU) crystals that further activate the NLRP3 inflammasome and initiate a cascade of inflammatory events. However, the key physicochemical properties of MSU crystals that determine the acute phase of gout have not been fully identified. In this study, a library of engineered MSU crystals with well-controlled size and shape is designed to explore their proinflammatory potentials in mediating the pathological progress of gout. It is demonstrated that medium-sized long aspect ratio MSU crystals induce more prominent IL-1β production in vitro due to enhanced cellular uptake and the production of mitochondrial reactive oxygen species (mtROS). The characteristics of MSU crystals are also correlated with their inflammatory potentials in both acute peritonitis and arthritis models. Furthermore, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is demonstrated to inhibit MSU-induced oxidative burst by removing plasma membrane cholesterol. As a result, it attenuates the inflammatory responses both in vitro and in vivo. Additionally, antioxidant N-acetylcysteine (NAC) is shown to alleviate acute gouty symptom by suppressing oxidative stress. This study identifies the key physicochemical properties of MSU crystals that mediate the pathogenesis of gout, which sheds light on novel design strategies for the intervention of gout.}, }
@article {pmid35878501, year = {2022}, author = {Tang, M and Yang, Z and Liu, J and Zhang, X and Guan, L and Liu, X and Zeng, M}, title = {Combined intervention with N-acetylcysteine and desipramine alleviated silicosis development by regulating the Nrf2/HO-1 and ASMase/ceramide signaling pathways.}, journal = {Ecotoxicology and environmental safety}, volume = {242}, number = {}, pages = {113914}, doi = {10.1016/j.ecoenv.2022.113914}, pmid = {35878501}, issn = {1090-2414}, mesh = {*Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism ; Ceramides/metabolism ; *Desipramine/metabolism/therapeutic use ; Disease Models, Animal ; Drug Therapy, Combination ; Dust ; Fibrosis ; Heme Oxygenase (Decyclizing) ; Lung ; Matrix Metalloproteinase 1/metabolism/toxicity ; NF-E2-Related Factor 2 ; *Pulmonary Fibrosis/chemically induced/drug therapy/metabolism ; Rats ; Rats, Wistar ; Signal Transduction ; Silicon Dioxide/toxicity ; *Silicosis/metabolism ; Sphingomyelin Phosphodiesterase/metabolism/toxicity ; Tissue Inhibitor of Metalloproteinase-1 ; }, abstract = {Silicosis is a systemic disease characterized by diffuse fibrosis of the lung tissue caused by long-term inhalation of large amounts of free silica (SiO2) dust. The pathogenesis of silicosis has not been fully elucidated, and there is a lack of effective treatment methods. N-acetylcysteine (NAC) can potentially treat pulmonary fibrosis by exerting antioxidant effects. Desipramine (DMI) can influence pulmonary fibrosis development by inhibiting acid sphingomyelinase (ASMase) activity and regulating ceramide concentrations. Both can interfere with pulmonary fibrosis through different mechanisms, but the intervention effects of NAC combined with DMI on silicosis fibrosis have not been reported. Therefore, this study established a rat silicosis model using a single tracheal drip of SiO2 dust suspension in Wistar rats to investigate the effect of NAC combined with DMI on SiO2 dust-induced silicosis and its related molecular mechanisms. The histopathological examination of the SiO2 dust-induced silicosis rats suggested that NAC and DMI alone or in combination could decrease the severity of pulmonary fibrosis in rats. The combined intervention had a better effect on reducing fibrosis than the individual interventions. NAC and DMI, alone or in combination, decreased the levels of markers related to pulmonary fibrosis in rats (smooth muscle α-actin (α-SMA), collagen (Col) I, Col III, hydroxyproline (HYP), inflammatory factors (transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α)), and lipid peroxidase malondialdehyde (MDA)). The nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme-oxygenase-1 (HO-1) and ASMase/ceramide pathways were inhibited to some extent by increasing the superoxide dismutase (SOD) levels of antioxidant enzymes and 8-iso-prostaglandin F2α (8-iso-PGF2α) levels of lipid peroxides. The combined intervention and NAC alone inhibited the SiO2 dust-induced elevation of matrix metalloproteinase 1 (MMP-1) and tissue inhibitor matrix metalloproteinase 1 (TIMP-1), but the effect was not significant in the DMI-treated group. Combining DMI and NAC inhibited Col I deposition and reduced HO-1, TIMP-1, and ASMase levels in lung tissues compared to individual treatments. In summary, the SiO2 dust could induce oxidative stress and inflammation in rats, resulting in an imbalance in extracellular matrix (ECM) synthesis/catabolism and ASMase/ceramide signaling pathway activation, leading to silicosis development.The combined intervention of DMI and NAC may synergistically regulate the Nrf2/HO-1 pathway, maintain the anabolic balance of the ECM, inhibit ASMase/ceramide signaling pathway activation by suppressing the inflammatory response and effectively delay silicosis fibrosis progression.}, }
@article {pmid35871676, year = {2022}, author = {San-Martín-Martínez, D and Serrano-Lemus, D and Cornejo, V and Gajardo, AIJ and Rodrigo, R}, title = {Pharmacological Basis for Abrogating Myocardial Reperfusion Injury Through a Multi-Target Combined Antioxidant Therapy.}, journal = {Clinical pharmacokinetics}, volume = {61}, number = {9}, pages = {1203-1218}, pmid = {35871676}, issn = {1179-1926}, mesh = {Antioxidants/pharmacology/therapeutic use ; Humans ; *Myocardial Infarction/drug therapy ; *Myocardial Reperfusion Injury/drug therapy/prevention &amp; control ; }, abstract = {The main goal of the treatment for acute myocardial infarction is to achieve reperfusion of the affected myocardial tissue, with percutaneous coronary angioplasty being the gold standard procedure. However, this strategy has been associated with additional heart damage termed "lethal reperfusion injury," which is responsible for up to half of the final infarct size. Among the possible underlying mechanisms that are likely to explain this damage, studies suggest that oxidative stress plays a key role. Although this has not been translated into clinical benefits in most studies, recent preclinical studies reported promising results and a possible synergy with the combined use of vitamin C (VC), N-acetylcysteine (NAC), and deferoxamine (DFO). However, to implement a combined therapy with these drugs for patients requires further studies to understand their pharmacokinetic properties. Available data of the clinical trials have not been validated by looking into the pharmacokinetics in their design. Therefore, this article presents an update and comparison of the evidence for the efficacy of these administration schemes for each drug in cardioprotection, their pharmacokinetic properties and mechanisms of action for their use against "lethal reperfusion injury." To achieve a cardioprotective effect using a new pharmacological strategy before the onset of reperfusion, it is helpful to consider the pharmacokinetics of each drug. In this regard, to design a fast and short pharmacologic therapeutic strategy, theoretically VC and DFO concentrations could be modeled by a one-compartment model whereas NAC could be modeled by a three-compartment model with an initial short half-life.}, }
@article {pmid35870339, year = {2022}, author = {He, X and Jarrell, ZR and Liang, Y and Ryan Smith, M and Orr, ML and Marts, L and Go, YM and Jones, DP}, title = {Vanadium pentoxide induced oxidative stress and cellular senescence in human lung fibroblasts.}, journal = {Redox biology}, volume = {55}, number = {}, pages = {102409}, pmid = {35870339}, issn = {2213-2317}, support = {RC2 DK118619/DK/NIDDK NIH HHS/United States ; T32 ES012870/ES/NIEHS NIH HHS/United States ; R01 ES031980/ES/NIEHS NIH HHS/United States ; F32 ES033908/ES/NIEHS NIH HHS/United States ; R01 ES032189/ES/NIEHS NIH HHS/United States ; P30 ES019776/ES/NIEHS NIH HHS/United States ; R21 ES031824/ES/NIEHS NIH HHS/United States ; }, abstract = {Both environmental exposure to vanadium pentoxide (V2O5, V[+5] for its ionic counterparts) and fibroblast senescence are associated with pulmonary fibrosis, but whether V[+5] causes fibroblast senescence remains unknown. We found in a dose-response study that 2-40 μM V[+5] caused human lung fibroblasts (HLF) senescence with increased senescence-associated β-galactosidase activity and p16 expression, while cell death occurred at higher concentration (LC50, 82 μM V[+5]). Notably, measures of reactive oxygen species (ROS) production with fluorescence probes showed no association of ROS with V[+5]-dependent senescence. Preloading catalase (polyethylene-conjugated), a H2O2 scavenger, did not alleviate the cellular senescence induced by V[+5]. Analyses of the cellular glutathione (GSH) system showed that V[+5] oxidized GSH, increased GSH biosynthesis, stimulated cellular GSH efflux and increased protein S-glutathionylation, and addition of N-acetyl cysteine inhibited V[+5]-elevated p16 expression, suggesting that thiol oxidation mediates V[+5]-caused senescence. Moreover, strong correlations between GSSG/GSH redox potential (Eh), protein S-glutathionylation, and cellular senescence (R[2] > 0.99, p < 0.05) were present in V[+5]-treated cells. Studies with cell-free and enzyme-free solutions showed that V[+5] directly oxidized GSH with formation of V[+4] and GSSG in the absence of O2. Analyses of V[+5] and V[+4] in HLF and culture media showed that V[+5] was reduced to V[+4] in cells and that a stable V[+4]/V[+5] ratio was rapidly achieved in extracellular media, indicating ongoing release of V[+4] and reoxidation to V[+5]. Together, the results show that V[+5]-dependent fibroblast senescence is associated with a cellular/extracellular redox cycling mechanism involving the GSH system and occurring under conditions that do not cause cell death. These results establish a mechanism by which environmental vanadium from food, dietary supplements or drinking water, can cause or contribute to lung fibrosis in the absence of high-level occupational exposures and cytotoxic cell death.}, }
@article {pmid35861217, year = {2022}, author = {Aksoy, N and Vatansever, C and Zengin Ersoy, G and Adakli Aksoy, B and Fışgın, T}, title = {The effect of biofilm inhibitor N-acetylcysteine on the minimum inhibitory concentration of antibiotics used in Gram-negative bacteria in the biofilm developed on catheters.}, journal = {The International journal of artificial organs}, volume = {45}, number = {10}, pages = {865-870}, doi = {10.1177/03913988221112969}, pmid = {35861217}, issn = {1724-6040}, mesh = {Acetylcysteine/pharmacology ; Amikacin ; *Anti-Bacterial Agents/pharmacology ; Biofilms ; Catheters ; Cefepime/pharmacology ; Ceftazidime/pharmacology ; Child ; *Colistin/pharmacology ; Escherichia coli ; Gram-Negative Bacteria ; Humans ; Meropenem/pharmacology ; Microbial Sensitivity Tests ; Pseudomonas aeruginosa ; }, abstract = {The study determined the effect of N-acetylcysteine (NAC) on the susceptibility of various antibiotics used to treat Gram-negative catheter-related infection in isolates obtained from pediatric patients admitted to the hematology and oncology department of Medical Park Bahçelievler hospital in Istanbul, Turkey. Biofilms were created in vitro utilizing clinical isolates of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas putida, and Proteus mirabilis. 24 h old biofilms were developed on 96-well plate with strains and the minimum biofilm inhibitory concentration (MBIC) of six antibiotics were measured before and after the addition of 75 mg/ml N-acetylcysteine with microplate reader at 450 nm after crystal violet assay. The addition of NAC reduce the MBIC of cefepime, ceftazidime, colistin, meropenem from (16, 16, 8, 4 μg/ml) to (8, 4, 4, 2 μg/ml) respectively in E. coli (isolate 1). In P. aeruginosa (isolate 4), the MBIC of amikacin, ceftazidime, meropenem (64, 32, and 32 μg/ml) reduced to (8, 1, and 0.5 μg/ml) respectively. MBIC of cefepime, colistin, meropenem (32, 16,and 16 μg/ml) reduced to (2, 2,and 0.5 μg/ml) respectively in P. putida (isolate 5). In P. mirabilis (isolate 6), MBIC of amikacin, cefepime, ceftazidime, colisitin and meropenem (64, 128, 32, 4, and 32 μg/ml) reduced to (8, 8, 1, 1, 4 μg/ml). NAC in combination therapy can practically reduce the MBIC of antibiotics used to treat Gram negative bacteria that develop biofilm in medical catheters. As a result, these combinations can be considered as an essential alternative for increasing the antibiotic susceptibility of pathogenic microorganisms and thus increasing treatment success rates.}, }
@article {pmid35858325, year = {2022}, author = {Fernandez, AM and Martinez-Rachadell, L and Navarrete, M and Pose-Utrilla, J and Davila, JC and Pignatelli, J and Diaz-Pacheco, S and Guerra-Cantera, S and Viedma-Moreno, E and Palenzuela, R and Ruiz de Martin Esteban, S and Mostany, R and Garcia-Caceres, C and Tschöp, M and Iglesias, T and de Ceballos, ML and Gutierrez, A and Torres Aleman, I}, title = {Insulin regulates neurovascular coupling through astrocytes.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {119}, number = {29}, pages = {e2204527119}, pmid = {35858325}, issn = {1091-6490}, mesh = {Animals ; *Astrocytes/metabolism ; *Brain/blood supply ; Glial Fibrillary Acidic Protein/genetics ; Glucose/metabolism ; *Insulin/metabolism ; Mice ; Mice, Knockout ; *Neovascularization, Physiologic ; *Neurovascular Coupling ; Reactive Oxygen Species/metabolism ; Receptor, Insulin/genetics ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.}, }
@article {pmid35857752, year = {2022}, author = {Neill, E and Rossell, SL and Yolland, C and Meyer, D and Galletly, C and Harris, A and Siskind, D and Berk, M and Bozaoglu, K and Dark, F and Dean, OM and Francis, PS and Liu, D and Phillipou, A and Sarris, J and Castle, DJ}, title = {N-Acetylcysteine (NAC) in Schizophrenia Resistant to Clozapine: A Double-Blind, Randomized, Placebo-Controlled Trial Targeting Negative Symptoms.}, journal = {Schizophrenia bulletin}, volume = {48}, number = {6}, pages = {1263-1272}, pmid = {35857752}, issn = {1745-1701}, mesh = {Humans ; *Clozapine/adverse effects ; *Schizophrenia/drug therapy/chemically induced ; Acetylcysteine/pharmacology ; Quality of Life/psychology ; Treatment Outcome ; Australia ; *Antipsychotic Agents/adverse effects ; Double-Blind Method ; }, abstract = {BACKGROUND AND HYPOTHESIS: Clozapine is the most effective antipsychotic for treatment-resistant schizophrenia, yet a significant proportion of individuals on clozapine continue to experience disabling symptoms, despite being treated with an adequate dose. There is a need for adjunct treatments to augment clozapine, notably for negative and cognitive symptoms. One such potential agent is the glutathione precursor N-acetylcysteine (NAC).<br><br>STUDY DESIGN: A randomized double-blind, multi-center, placebo-controlled trial for clozapine patients with enduring psychotic symptoms (n = 84) was undertaken to investigate the efficacy of adjunctive NAC (2 g daily) for negative symptoms, cognition and quality of life (QoL). Efficacy was assessed at 8, 24, and 52 weeks.<br><br>STUDY RESULTS: NAC did not significantly improve negative symptoms (P = .62), overall cognition (P = .71) or quality of life (Manchester quality of life: P = .11; Assessment of quality of life: P = .57) at any time point over a 1-year period of treatment. There were no differences in reported side effects between the groups (P = .26).<br><br>CONCLUSIONS: NAC did not significantly improve schizophrenia symptoms, cognition, or quality of life in treatment-resistant patients taking clozapine. This trial was registered with "Australian and New Zealand Clinical Trials" on the 30 May, 2016 (Registration Number: ACTRN12615001273572).}, }
@article {pmid35856379, year = {2022}, author = {Micheletto, C and Izquierdo, JL and Avdeev, SN and Rada Escobar, RA and Pacheco Gallego, MC}, title = {N-acetylcysteine as a therapeutic approach to post-COVID-19 pulmonary fibrosis adjunctive treatment.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {13}, pages = {4872-4880}, doi = {10.26355/eurrev_202207_29212}, pmid = {35856379}, issn = {2284-0729}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Anti-Inflammatory Agents ; Antioxidants/pharmacology ; Glutathione ; Humans ; *Pulmonary Fibrosis/chemically induced/drug therapy ; Quality of Life ; *COVID-19 Drug Treatment ; }, abstract = {OBJECTIVE: Growing interest is directed to the outcomes of COVID-19 in survivors, both in the convalescent period and in the long-term, which are responsible for morbidity and quality of life deterioration. This article aims to describe the mechanisms supporting the possible use of NAC as an adjuvant treatment for post-COVID-19 pulmonary fibrosis.<br><br>MATERIALS AND METHODS: A search was performed in PubMed/MEDLINE.<br><br>RESULTS: Interstitial changes have been observed in the CT scan of COVID-19 pneumonia. In patients with respiratory outcomes in the post-COVID-19 stage, glutathione (GSH) deficiency was found and interpreted as a reaction to the inflammatory cascade caused by the viral infection, while the pathophysiological process of pulmonary fibrosis involves numerous cytokines, such as TGF-&#x3b2;, TNF-&#x3b1;, IL-1, PDGF and VEGF. NAC has a good tolerability profile, is easily administered orally and inexpensively, and has antioxidant and anti-inflammatory effects that may target the pathophysiologic mechanisms involved in pulmonary fibrosis. It may revert GSH deficiency, exerts direct and indirect antioxidant activity, anti-inflammatory activity and improves immune T-cell response.<br><br>CONCLUSIONS: The mechanism of action of NAC suggests a role in the treatment of pulmonary fibrosis induced by COVID-19.}, }
@article {pmid35856373, year = {2022}, author = {Buha, I and Mirić, M and Agić, A and Simić, M and Stjepanović, M and Milenković, B and Nagorni-Obradović, L and Škodrić-Trifunović, V and Ilić, B and Popević, S and Dimic-Janjic, S and Ilić, A}, title = {A randomized, double-blind, placebo-controlled study evaluating the efficacy of propolis and N-acetylcysteine in exacerbations of chronic obstructive pulmonary disease.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {13}, pages = {4809-4815}, doi = {10.26355/eurrev_202207_29206}, pmid = {35856373}, issn = {2284-0729}, mesh = {Acetylcysteine/adverse effects ; Disease Progression ; Double-Blind Method ; Humans ; *Propolis/therapeutic use ; *Pulmonary Disease, Chronic Obstructive ; }, abstract = {OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) accelerate the progressive impairment of lung function and general health. Together with maintenance therapy for chronic obstructive pulmonary disease (COPD), N-acetylcysteine (NAC) and natural propolis have demonstrated pharmacological properties that address crucial pathophysiological processes underlying COPD and may prevent AECOPDs. This study aims at responding to dose-dependent efficacy and safety concerns regarding a propolis-NAC combination for the reduction of COPD exacerbation rates.<br><br>PATIENTS AND METHODS: This was a single-center, randomized, double-blind, phase IV trial with three treatment arms: Placebo and two active substance groups, one (AS-600) received 600 mg of NAC + 80 mg of propolis while the other (AS-1,200) received 1,200 mg of NAC + 160 mg of propolis. Following an AECOPD, frequent-exacerbation phenotype patients (n=46) were assigned a once-daily three-month therapy with the study drug and one year follow-up. The primary endpoint was the COPD exacerbation incidence rate during the follow-up period as a measure of dose-dependent efficacy of NAC-propolis combination compared to placebo.<br><br>RESULTS: There was a statistically significant difference in the AECOPD incidence rate: 52.6% in patients that received placebo, 15.4% that received AS-600 and only 7.1% that received AS-1,200 (Fisher's exact test, p = 0.013). Compared to placebo, AECOPD frequency was significantly lower only in AS-1,200 (p=0.009). Compared to placebo, the relative risk for exacerbation was 0.29 in AS-600 and 0.13 in AS-1,200. No adverse events related to the treatment were reported.<br><br>CONCLUSIONS: Oral combination of natural propolis with NAC confirmed formulation efficiency with a favorable safety profile. Our results need to be confirmed by larger clinical trials.}, }
@article {pmid35851521, year = {2022}, author = {Wu, L and Zeng, W and Ishigaki, Y and Zhang, J and Bai, H and Harimoto, T and Suzuki, T and Ye, D}, title = {A Ratiometric Photoacoustic Probe with a Reversible Response to Hydrogen Sulfide and Hydroxyl Radicals for Dynamic Imaging of Liver Inflammation.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {61}, number = {37}, pages = {e202209248}, doi = {10.1002/anie.202209248}, pmid = {35851521}, issn = {1521-3773}, mesh = {Animals ; Fluorescent Dyes ; *Hydrogen Sulfide ; Hydroxyl Radical ; Liver/diagnostic imaging ; Mice ; Oxidation-Reduction ; *Photoacoustic Techniques/methods ; Spectrum Analysis ; }, abstract = {Reversible imaging probes that allow for the dynamic visualization of the redox cycle between hydroxyl radical (⋅OH) and hydrogen sulfide (H2 S) are vital to probe the redox imbalance-involved pathological process in vivo. Herein, we report a reversible ratiometric photoacoustic (PA) imaging nanoprobe (1-PAIN) for the real-time imaging of ⋅OH/H2 S redox cycle in vivo. 1-PAIN displays a low PA ratio between 690 and 825 nm (PA690 /PA825), which significantly increases by ≈5-fold upon oxidation by ⋅OH, and is switched back to the initially low PA690 /PA825 value upon reduction by H2 S. 1-PAIN could dynamically report on the hepatic ⋅OH production in mice during the lipopolysaccharide (LPS)-induced liver inflammation process, and visualize hepatic H2 S generation during the N-acetyl cysteine (NAC)-induced anti-inflammation process. 1-PAIN can act as a useful tool to probe the redox state in living biology, beneficial for the study of redox imbalance-related diseases.}, }
@article {pmid35850245, year = {2022}, author = {Huo, H and Wu, H and Ma, F and Li, X and Liao, J and Hu, L and Han, Q and Li, Y and Pan, J and Zhang, H and Tang, Z and Guo, J}, title = {N-acetyl-L-cysteine ameliorates hepatocyte pyroptosis of dog type 1 diabetes mellitus via suppression of NLRP3/NF-κB pathway.}, journal = {Life sciences}, volume = {306}, number = {}, pages = {120802}, doi = {10.1016/j.lfs.2022.120802}, pmid = {35850245}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Diabetes Mellitus, Type 1/drug therapy ; Dogs ; Hepatocytes/metabolism ; Insulin/pharmacology ; *NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pyroptosis ; Rats ; Rats, Sprague-Dawley ; Streptozocin/pharmacology ; }, abstract = {Type 1 diabetes mellitus (T1DM) is a chronic and represented by insulin-causing pancreatic β-cell disruption and hyperglycemia. N-Acetyl-Cysteine (NAC) is regarded as facilitating endothelial cell function and angiogenesis and may have treatment effect in the case of diabetes. However, the impact of NAC on T1DM are unknown. Here we reported that inflammatory pathogenesis of canine type 1 diabetes liver disease and the therapeutic effect of NAC combined with insulin. For this purpose, the model was established by intravenous injection of streptozotocin (20 mg/kg). Forty adult dogs were used and divided into 5 groups: control group, DM group, insulin treatment group, NAC combined with insulin therapy, and NAC group, while study lasted for 16 weeks. Results showed that the level of liver function enzyme activity were apparently increased in DM group, while the NAC with insulin treatment remarkable decreased liver function enzyme levels. Histopathology revealed that obvious changes in liver structure of all DM group, as evidenced by hepatocyte disorder and cellular swelling. Liver structure was evaluated by Periodic Acid Schiff (PAS) and Masson staining, the tissues appeared glycogen deposition and collagen deposition, indicating that DM aggravated liver injury. Compared with control group, the protein and mRNA expression of NLRP3, Caspase-1, ASC, and GSDMD were significantly induced in the DM group, while INS and NAC combined with INS treatment reversed the above changes. The levels of NF-κB P65, p-NF-κB, and IFN γ were availably enhanced in the DM group, which decreased through insulin and NAC combined with insulin treatment. This study demonstrated that NAC combined with INS exerted protective effects against STZ-induced liver injury by inhibiting the NLRP3/NF-κB pathway. The findings indicated that NAC combined with INS may serve as a potential candidate therapy for the treatment of T1DM.}, }
@article {pmid35849165, year = {2022}, author = {Abbas, AA and Hamdy, A and Ahmed, AE}, title = {Compromised blood-bile barrier after acetaminophen overdose.}, journal = {Archives of toxicology}, volume = {96}, number = {10}, pages = {2825-2827}, pmid = {35849165}, issn = {1432-0738}, mesh = {Acetaminophen ; Acetylcysteine/pharmacology ; Bile ; Bile Acids and Salts ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; *Drug Overdose ; Humans ; Liver ; }, abstract = {N-acetylcysteine (NAC) is the only approved drug for the treatment of acetaminophen (APAP) intoxication. A limitation of NAC is the short therapeutic time-window as it is only effective within approximately eight hours after APAP ingestion, which is critical since patients seek medical attention often after the onset of symptoms approximately 24 h after overdose. Recently, a so far unknown mechanism was identified by which APAP causes an increase of intracellular bile acid concentrations in hepatocytes to concentrations that exceed cytotoxic thresholds. APAP compromises the tight junctions of bile canaliculi that leads to the leakage of highly concentrated bile acids into the sinusoids. From the sinusoidal blood, a high fraction of the released bile acids is transported back into hepatocytes by basolateral uptake carriers and secreted into bile canaliculi. Repeated leakage from the canaliculi followed by hepatocellular reuptake and canalicular secretion causes an increase of intracellular bile acid concentrations and finally hepatocyte death. Importantly, inhibition of bile acid uptake carriers reduced intracellular bile acid concentrations and strongly ameliorated APAP hepatotoxicity, a finding that could result in a new therapeutic option for APAP-intoxicated patients.}, }
@article {pmid35843301, year = {2022}, author = {Rhana, P and Barros, GM and Santos, VCO and Costa, AD and Santos, DMD and Fernandes-Braga, W and Durço, AO and Santos, MRV and Roman-Campos, D and Vasconcelos, CML and Cruz, JS and Souza, DS}, title = {S-limonene protects the heart in an experimental model of myocardial infarction induced by isoproterenol: Possible involvement of mitochondrial reactive oxygen species.}, journal = {European journal of pharmacology}, volume = {930}, number = {}, pages = {175134}, doi = {10.1016/j.ejphar.2022.175134}, pmid = {35843301}, issn = {1879-0712}, mesh = {Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; *Heart Injuries/metabolism ; Isoproterenol/toxicity ; Limonene/metabolism/pharmacology/therapeutic use ; Models, Theoretical ; *Myocardial Infarction/chemically induced/drug therapy/prevention &amp; control ; Myocardium/metabolism ; Myocytes, Cardiac/metabolism ; Oxidative Stress ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Myocardial infarction (MI) is associated with high mortality rates, despite the fact that there are therapies available. Importantly, excessive oxidative stress may contribute to ischemia/reperfusion injury leading to death related to MI. In this scenario, naturally occurring antioxidant compounds are an important source of possible therapeutic intervention. Thus, this study sought to elucidate the mechanisms of cardioprotection of s-limonene in an isoproterenol-induced MI animal model.<br><br>METHODS: Wistar rats were treated with 1&#xa0;mg/kg s-limonene (SL) or 100&#xa0;mg/kg N-acetylcysteine (NAC, positive control) once, 30&#xa0;min after isoproterenol-induced MI (applied in two doses with a 24&#xa0;h interval). The protective effects of SL in the heart were examined via the serum level of creatine kinase myocardial band (CK-MB), electrocardiographic profile, infarct size and histological parameters. Using isolated cardiomyocytes, we also assessed calcium transient amplitude, cytosolic and mitochondrial oxidative stress and the expression of proteins related to oxidative stress.<br><br>RESULTS: SL at a concentration of 1&#xa0;mg/kg attenuated isoproterenol-induced MI injury, by preventing ST-segment elevation and QTc prolongation in the ECG. SL reduced the infarct size and collagen content in cardiac tissue. At the cellular level, SL prevented increased Ca[2+], associated with attenuation of cytosolic and mitochondrial oxidative stress. These changes resulted in a reduction of the oxidized form of Ca[2+] Calmodulin-Dependent Kinase II (CaMKII) and restored superoxide dismutase and glutathione peroxidase activity.<br><br>CONCLUSION: Our data show that s-limonene promotes cardioprotection against MI injury, probably through inhibition of increased Ca[2+] and attenuation of oxidative stress via CaMKII.}, }
@article {pmid35842931, year = {2022}, author = {Emojevwe, V and Nwangwa, EK and Naiho, AO and Oyovwi, MO and Igiehon, O and Ogunwole, E and Makinde-Taylor, MS and Ayotomide, OA and Akinola, AO and Edesiri, PT and Oghenetega, BO and Ovuakporaye, SI}, title = {Therapeutic efficacy of N-acetylcysteine and zinc sulphate against di-(2-ethylhexyl) phthalate-induced testicular oxido-nitrergic stress in male Wistar rat.}, journal = {Andrologia}, volume = {54}, number = {9}, pages = {e14508}, doi = {10.1111/and.14508}, pmid = {35842931}, issn = {1439-0272}, mesh = {Animals ; Male ; Rats ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; *Diethylhexyl Phthalate/toxicity ; Phthalic Acids ; Rats, Wistar ; *Testis ; Zinc Sulfate/pharmacology ; }, abstract = {The therapeutic efficacy of N-acetylcysteine (NAC) and zinc sulphate on di-(2-ethylhexyl) phthalate (DEHP)-induced testicular oxido-nitrergic stress in rats was investigated in 36 male Wistar rats (170 ± 10 g) randomly assigned into one of six groups (n = 6). Group 1 (control) received 2.5 ml/kg of distilled water for 42 days, while group 2 (vehicle) received 2.5 ml/kg of corn oil for 42 days. Groups 3,4,5, and 6 were administered DEHP (750 mg/kg/day) for 21 days, after which groups 4, 5, and 6 received zinc sulphate (0.5 mg/kg/day), NAC (100 mg/kg/day), and zinc sulphate (0.5 mg/kg/day) + NAC (100 mg/kg/day) for an additional 21 days respectively. After the experimental period, the animals were euthanized by light thiopental sodium, and their testes were carefully dissected out for histological and biochemical assays. The result shows a significant alteration in testicular levels of malondialdehyde, nitric oxide, antioxidant enzymes, total antioxidant capacity, sulphydryl levels, dehydrogenases and testicular architecture following the administration of DEHP. These effects were reversed by coadministration of NAC and zinc sulphate in the study. We therefore concluded that the combined effects of NAC and ZnSO4 effectively improved testicular antioxidant status and reduced testicular nitregic stress, thus improving testicular architecture and functions.}, }
@article {pmid35839558, year = {2022}, author = {Yang, YS and Maddock, RJ and Zhang, H and Lee, J and Hellemann, G and Marder, SR and Green, MF}, title = {N-Acetylcysteine effects on glutathione and glutamate in schizophrenia: A preliminary MRS study.}, journal = {Psychiatry research. Neuroimaging}, volume = {325}, number = {}, pages = {111515}, doi = {10.1016/j.pscychresns.2022.111515}, pmid = {35839558}, issn = {1872-7506}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Glutamic Acid ; Glutathione ; Humans ; *Psychotic Disorders/diagnostic imaging/drug therapy ; *Schizophrenia/diagnostic imaging/drug therapy ; }, abstract = {N-acetylcysteine (NAC) is a commonly used antioxidant that may have beneficial effects for schizophrenia. In this double-blind, randomized, placebo-controlled preliminary study, 40 patients with schizophrenia or schizoaffective disorder were randomized to receive 2400 mg NAC daily or placebo over eight weeks to examine the effects of NAC on prefrontal magnetic resonance spectroscopy levels of glutathione and glutamate. Secondary outcomes included negative symptoms, cognition, and plasma glutathione levels. We found that NAC treatment was associated with increased glutathione (statistically significant) and decreased glutamate (trend-level) compared with placebo in medial prefrontal cortex but not dorsolateral prefrontal cortex. We also observed a baseline association between medial prefrontal cortex levels of glutathione and plasma reduced / oxidized glutathione ratios. No treatment effects on symptoms or cognition were observed. Taken together, these findings indicate that treatment with N-acetylcysteine may increase medial prefrontal cortical levels of glutathione after eight weeks of treatment. These changes in cortical levels of glutathione may serve as an early biomarker of later clinical change and may underlie the cognitive and symptomatic improvements reported in longer-term treatment studies.}, }
@article {pmid35834022, year = {2022}, author = {Temel, A and Erac, B}, title = {Investigating Biofilm Formation and Antibiofilm Activity Using Real Time Cell Analysis Method in Carbapenem Resistant Acinetobacter baumannii Strains.}, journal = {Current microbiology}, volume = {79}, number = {9}, pages = {256}, pmid = {35834022}, issn = {1432-0991}, mesh = {*Acinetobacter Infections/microbiology ; *Acinetobacter baumannii ; Anti-Bacterial Agents/pharmacology ; Biofilms ; Carbapenems/pharmacology ; Humans ; Microbial Sensitivity Tests ; }, abstract = {Acinetobacter baumannii is a significant nosocomial pathogen, with its biofilm forming capacity playing an important role in its pathogenicity. The fast and reliable detection of the biofilm formation and measurement of antibiofilm activity of various molecules are critical for combating A. baumannii infections. In this study, we aimed to detect biofilm formation by real time cell analyses (RTCA) method in clinical A. baumannii isolates and to investigate antibiofilm activities of tigecycline (TGC), N-acetylcysteine (NAC), and acetylsalicylic acid (ASA). The effect of the tested drugs on expressions of biofilm-related genes bap and csuE in clinical A. baumannii strains was also analyzed by real time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Biofilm forming capacities for strong and weak biofilm producer A. baumannii strains were detected within 10 h by RTCA method (P < 0.05). We also observed that sub-minimum inhibitory concentrations of NAC + TGC and ASA + TGC combinations could significantly reduce biofilm formation and expression of biofilm-related genes in A. baumanii strains. No statistically significant activity of the tested drugs was detected against mature biofilms of the bacterial strains with the RTCA method. These results suggest that reproducible results on biofilm production capacity of A. baumannii strains and antibiofilm activities of various compounds can be obtained in a short time using RTCA method. Therefore, RTCA method seems to be a beneficial technique for biofilm detection and can help in combating A. baumannii infections by giving health providers the opportunity of implementing antibiofilm treatment strategies in a timely manner.}, }
@article {pmid35832486, year = {2022}, author = {Li, S and Luo, G and Zeng, R and Lin, L and Zou, X and Yan, Y and Ma, H and Xia, J and Zhao, Y and Zhou, X}, title = {Endoplasmic Reticulum Stress Contributes to Ventilator-Induced Diaphragm Atrophy and Weakness in Rats.}, journal = {Frontiers in physiology}, volume = {13}, number = {}, pages = {897559}, pmid = {35832486}, issn = {1664-042X}, abstract = {Background: Accumulating evidence indicates that endoplasmic reticulum (ER) stress plays a critical role in the regulation of skeletal muscle mass. In recent years, much attention has been given to ventilator-induced diaphragm dysfunction (VIDD) because it strongly impacts the outcomes of critically ill patients. Current evidence suggests that the enhancement of oxidative stress is essential for the development of VIDD, but there are no data on the effects of ER stress on this pathological process. Methods: VIDD was induced by volume-controlled mechanical ventilation (MV) for 12 h; Spontaneous breathing (SB, for 12 h) rats were used as controls. The ER stress inhibitor 4-phenylbutyrate (4-PBA), the antioxidant N-acetylcysteine (NAC), and the ER stress inducer tunicamycin (TUN) were given before the onset of MV or SB. Diaphragm function, oxidative stress, and ER stress in the diaphragms were measured at the end of the experiments. Results: ER stress was markedly increased in diaphragms relative to that in SB after 12 h of MV (all p < 0.001). Inhibition of ER stress by 4-PBA downregulated the expression levels of proteolysis-related genes in skeletal muscle, including Atrogin-1 and MuRF-1, reduced myofiber atrophy, and improved diaphragm force-generating capacity in rats subjected to MV (all p < 0.01). In addition, mitochondrial reactive oxygen species (ROS) production and protein level of 4-HNE (4-hydroxynonenal) were decreased upon 4-PBA treatment in rats during MV (all p < 0.01). Interestingly, the 4-PBA treatment also markedly increased the expression of peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) (p < 0.01), a master regulator for mitochondrial function and a strong antioxidant. However, the antioxidant NAC failed to reduce ER stress in the diaphragm during MV (p > 0.05). Finally, ER stress inducer TUN largely compromised diaphragm dysfunction in the absence of oxidative stress (all p < 0.01). Conclusion: ER stress is induced by MV and the inhibition of ER stress alleviates oxidative stress in the diaphragm during MV. In addition, ER stress is responsible for diaphragm dysfunction in the absence of oxidative stress. Therefore, the inhibition of ER stress may be another promising therapeutic approach for the treatment of VIDD.}, }
@article {pmid35829920, year = {2022}, author = {Tsikas, D and Mikuteit, M}, title = {N-Acetyl-L-cysteine in human rheumatoid arthritis and its effects on nitric oxide (NO) and malondialdehyde (MDA): analytical and clinical considerations.}, journal = {Amino acids}, volume = {54}, number = {9}, pages = {1251-1260}, pmid = {35829920}, issn = {1438-2199}, mesh = {*Acetylcysteine/pharmacology ; *Arthritis, Rheumatoid/drug therapy ; Biomarkers ; Humans ; Malondialdehyde ; Nitric Oxide/metabolism ; Oxidative Stress ; }, abstract = {N-Acetyl-L-cysteine (NAC) is an endogenous cysteine metabolite. The drug is widely used in chronic obstructive pulmonary disease (COPD) and as antidote in acetaminophen (paracetamol) intoxication. Currently, the utility of NAC is investigated in rheumatoid arthritis (RA), which is generally considered associated with inflammation and oxidative stress. Besides clinical laboratory parameters, the effects of NAC are evaluated by measuring in plasma or serum nitrite, nitrate or their sum (NOx) as measures of nitric oxide (NO) synthesis. Malondialdehyde (MDA) and relatives such as 4-hydroxy-nonenal and 15(S)-8-iso-prostaglandin F2α serve as measures of oxidative stress, notably lipid peroxidation. In this work, we review recent clinico-pharmacological studies on NAC in rheumatoid arthritis. We discuss analytical, pre-analytical and clinical issues and their potential impact on the studies outcome. Major issues include analytical inaccuracy due to interfering endogenous substances and artefactual formation of MDA and relatives during storage in long-term studies. Differences in the placebo and NAC groups at baseline with respect to these biomarkers are also a serious concern. Modern applied sciences are based on data generated using commercially available instrumental physico-chemical and immunological technologies and assays. The publication process of scientific work rarely undergoes rigorous peer review of the analytical approaches used in the study in terms of accuracy/trueness. There is pressing need of considering previously reported reference concentration ranges and intervals as well as specific critical issues such as artefactual formation of particular biomarkers during sample storage. The latter especially applies to surrogate biomarkers of oxidative stress, notably MDA and relatives. Reported data on NO, MDA and clinical parameters, including C-reactive protein, interleukins and tumour necrosis factor α, are contradictory in the literature. Furthermore, reported studies do not allow any valid conclusion about utility of NAC in RA. Administration of NAC patients with rheumatoid arthritis is not recommended in current European and American guidelines.}, }
@article {pmid35821597, year = {2023}, author = {Zhou, S and Rao, Z and Xia, Y and Wang, Q and Liu, Z and Wang, P and Cheng, F and Zhou, H}, title = {CCAAT/Enhancer-binding Protein Homologous Protein Promotes ROS-mediated Liver Ischemia and Reperfusion Injury by Inhibiting Mitophagy in Hepatocytes.}, journal = {Transplantation}, volume = {107}, number = {1}, pages = {129-139}, pmid = {35821597}, issn = {1534-6080}, mesh = {Animals ; Mice ; Apoptosis ; Beclin-1/metabolism ; Hepatocytes/metabolism ; Hypoxia/metabolism ; Ischemia ; Liver/metabolism ; *Liver Diseases/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; *Reperfusion Injury/prevention &amp; control/metabolism ; *Transcription Factor CHOP/genetics/metabolism ; }, abstract = {BACKGROUND: Liver ischemia and reperfusion (IR) injury represent a major risk factor in both partial hepatectomy and liver transplantation. CCAAT/enhancer-binding protein homologous protein (CHOP) is a key regulator of cell death, its precise molecular basis in regulating hepatocyte death during liver IR has not been delineated.<br><br>METHODS: Hepatocellular CHOP deficient mice were generated by bone marrow chimera models using global CHOP knockout mice. Liver partial warm ischemia model and hypoxia/reoxygenation model of primary hepatocytes were applied. Liver injury and mitophagy-related signaling pathways were investigated. IR-stressed patient liver tissues and serum samples were analyzed as well.<br><br>RESULTS: Mice with hepatocellular CHOP deficiency exhibited alleviated cell death, decreased reactive oxygen species (ROS) expression, and enhanced mitophagy in hepatocytes after IR, confirmed by in vitro studies of hepatocytes after hypoxia/reoxygenation. Mitochondria ROS scavenge by Mito TEMPO effectively attenuated hepatocyte death and liver IR injury of wild-type mice, whereas no significant effects were observed in hepatocellular CHOP -deficient mice. CHOP depletion upregulated dynamin-related protein 1 and Beclin-1 activation in the mitochondria of hepatocytes leading to enhanced mitophagy. Following IR, increased CHOP expression and impaired mitophagy activation were observed in the livers of patients undergoing hepatectomy. N-acetyl cysteine pretreatment significantly improved the liver function of patients after surgery.<br><br>CONCLUSIONS: IR-induced CHOP activation exacerbates ROS-mediated hepatocyte death by inhibiting dynamin-related protein 1-Beclin-1-dependent mitophagy.}, }
@article {pmid35818509, year = {2022}, author = {Trabattoni, D and Brambilla, M and Canzano, P and Becchetti, A and Teruzzi, G and Porro, B and Fiorelli, S and Muratori, M and Tedesco, CC and Veglia, F and Montorsi, P and Bartorelli, AL and Tremoli, E and Camera, M}, title = {Migraine in Patients Undergoing PFO Closure: Characterization of a Platelet-Associated Pathophysiological Mechanism: The LEARNER Study.}, journal = {JACC. Basic to translational science}, volume = {7}, number = {6}, pages = {525-540}, pmid = {35818509}, issn = {2452-302X}, abstract = {The association between migraine and patent foramen ovale (PFO) has been documented. We aimed to investigate platelet activation, prothrombotic phenotype, and oxidative stress status of migraineurs with PFO on 100 mg/day aspirin, before and 6 months after PFO closure. Data show that, before PFO closure, expression of the classical platelet activation markers is comparable in patients and aspirin-treated healthy subjects. Conversely, MHA-PFO patients display an increased prothrombotic phenotype (higher tissue factor[pos] platelets and microvesicles and thrombin-generation potential), sustained by an altered oxidative stress status. This phenotype, which is more controlled by P2Y12-blockade than by aspirin, reverted after PFO closure together with a complete migraine remission. (pLatelEts And MigRaine iN patEnt foRamen Ovale [LEARNER]; NCT03521193).}, }
@article {pmid35814787, year = {2022}, author = {Zhao, J and Li, M and Tan, C}, title = {Efficacy of N-acetylcysteine in Preventing Acute Kidney Injury and Major Adverse Cardiac Events After Cardiac Surgery: A Meta-Analysis and Trial Sequential Analysis.}, journal = {Frontiers in medicine}, volume = {9}, number = {}, pages = {795839}, pmid = {35814787}, issn = {2296-858X}, abstract = {BACKGROUND: The effect of N-acetylcysteine (NAC), an antioxidant, on preventing acute kidney injury (AKI) and major adverse cardiac events (MACE) remains controversial. Therefore, we conducted this meta-analysis and trial sequential analysis to evaluate its efficacy on cardiac surgery-related adverse events.<br><br>METHODS: PubMed, Embase, and Cochrane Library were searched for relevant studies from inception to June 2021. We selected randomized controlled trials comparing NAC with controls in patients undergoing cardiac surgery.<br><br>RESULTS: Twenty-five studies including 2,444 patients met the inclusion criteria. The pooled results showed that there was no significant difference in the incidence of AKI between the NAC and control groups [relative risk (RR) = 0.91, 95% confidence interval (CI) = 0.77, 1.08, P = 0.28], but the trial sequential analysis (TSA) could not confirm this result. No difference was observed in the need for renal replacement therapy (RRT), all-cause mortality, MACE, length of stay in the intensive care unit (ICU), and length of stay in the hospital. Results of subgroup analysis results showed that intravenous infusion instead of oral NAC could significantly reduce the incidence of AKI and arrhythmia (RR = 0.84, 95% CI = 0.71, 0.99, P = 0.03, I [2] = 3% and RR = 0.74, 95% CI = 0.61, 0.91, P = 0.004, I [2] = 48%, respectively).<br><br>CONCLUSION: Intravenous administration of NAC can reduce the incidence of AKI and arrhythmia in patients after cardiac surgery, but cannot reduce all-cause mortality, AMI, cardiac insufficiency, and the number of patients using RRT. Oral NAC has no significant effect on the outcomes of patients after cardiac surgery.}, }
@article {pmid35814364, year = {2022}, author = {Domingo-Vidal, M and Whitaker-Menezes, D and Mollaee, M and Lin, Z and Tuluc, M and Philp, N and Johnson, JM and Zhan, T and Curry, J and Martinez-Outschoorn, U}, title = {Monocarboxylate Transporter 4 in Cancer-Associated Fibroblasts Is a Driver of Aggressiveness in Aerodigestive Tract Cancers.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {906494}, pmid = {35814364}, issn = {2234-943X}, support = {R37 CA234239/CA/NCI NIH HHS/United States ; }, abstract = {The most common cancers of the aerodigestive tract (ADT) are non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The tumor stroma plays an important role in ADT cancer development and progression, and contributes to the metabolic heterogeneity of tumors. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the tumor stroma of ADT cancers and exert pro-tumorigenic functions. Metabolically, glycolytic CAFs support the energy needs of oxidative (OXPHOS) carcinoma cells. Upregulation of the monocarboxylate transporter 4 (MCT4) and downregulation of isocitrate dehydrogenase 3α (IDH3α) are markers of glycolysis in CAFs, and upregulation of the monocarboxylate transporter 1 (MCT1) and the translocase of the outer mitochondrial membrane 20 (TOMM20) are markers of OXPHOS in carcinoma cells. It is unknown if glycolytic metabolism in CAFs is a driver of ADT cancer aggressiveness. In this study, co-cultures in vitro and co-injections in mice of ADT carcinoma cells with fibroblasts were used as experimental models to study the effects of fibroblasts on metabolic compartmentalization, oxidative stress, carcinoma cell proliferation and apoptosis, and overall tumor growth. Glycolytic metabolism in fibroblasts was modulated using the HIF-1α inhibitor BAY 87-2243, the antioxidant N-acetyl cysteine, and genetic depletion of MCT4. We found that ADT human tumors express markers of metabolic compartmentalization and that co-culture models of ADT cancers recapitulate human metabolic compartmentalization, have high levels of oxidative stress, and promote carcinoma cell proliferation and survival. In these models, BAY 87-2243 rescues IDH3α expression and NAC reduces MCT4 expression in fibroblasts, and these treatments decrease ADT carcinoma cell proliferation and increase cell death. Genetic depletion of fibroblast MCT4 decreases proliferation and survival of ADT carcinoma cells in co-culture. Moreover, co-injection of ADT carcinoma cells with fibroblasts lacking MCT4 reduces tumor growth and decreases the expression of markers of metabolic compartmentalization in tumors. In conclusion, metabolic compartmentalization with high expression of MCT4 in CAFs drives aggressiveness in ADT cancers.}, }
@article {pmid35810264, year = {2022}, author = {Feng, H and Xi, F}, title = {Miltirone Attenuates Reactive Oxygen Species-Dependent Neuronal Apoptosis in MPP[+]-Induced Cell Model of Parkinson's Disease Through Regulating the PI3K/Akt Pathway.}, journal = {Neurochemical research}, volume = {47}, number = {10}, pages = {3137-3149}, pmid = {35810264}, issn = {1573-6903}, mesh = {1-Methyl-4-phenylpyridinium/toxicity ; Apoptosis ; Caspase 3/metabolism ; Cell Line, Tumor ; Humans ; *Neuroblastoma ; *Parkinson Disease/metabolism ; *Phenanthrenes/pharmacology ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Miltirone is a phenanthrene-quinone derived from Salvia miltiorrhiza Bunge with anti-inflammatory and anti-oxidant effects. Our study aimed to explore the protective effect of miltirone on 1-methyl-4-phenylpyridinium (MPP[+])-induced cell model of Parkinson's disease (PD). PharmMapper database was employed to predict the targets of miltirone. PD-related genes were identified using GeneCards database. The overlapping genes between miltirone and PD were screened out using Venn diagram. KEGG analysis was performed using DAVID and KOBAS databases. Cell viability, reactive oxygen species (ROS) generation, apoptosis, and caspase-3 activity were detected by CCK-8 assay, a ROS assay kit, TUNEL, and caspase-3 activity assay, respectively. Effect of miltirone on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway was explored by western blot analysis. A total of 214 targets of miltirone and 372 targets related to PD were attained, including 29 overlapping targets. KEGG analysis demonstrated that the 29 overlapping targets were both significantly enriched in the PI3K/Akt pathway. MPP[+] stimulation reduced the cell viability in SH-SY5Y cells and neuronal primary cultures derived from human brain. Miltirone or N-acetylcysteine (NAC) attenuated MPP[+]-induced reduction in cell viability, ROS production, SOD activity reduction, apoptosis, and increase of caspase-3 activity. Additionally, miltirone recuperated MPP[+]-induced inactivation of the PI3K/Akt pathway. Moreover, treatment with LY294002, an inhibitor of the PI3K/Akt pathway, reversed the inhibitory effect of miltirone on MPP[+]-induced ROS generation and apoptosis in SH-SY5Y cells and neuronal primary cultures. In conclusion, miltirone attenuated ROS-dependent apoptosis in MPP[+]-induced cellular model of PD through activating the PI3K/Akt pathway.}, }
@article {pmid35806270, year = {2022}, author = {Ward, RJ and Dexter, DT and Crichton, RR}, title = {Iron, Neuroinflammation and Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {23}, number = {13}, pages = {}, pmid = {35806270}, issn = {1422-0067}, mesh = {Humans ; Inflammation/metabolism ; *Iron/metabolism ; Iron-Regulatory Proteins/metabolism ; Microglia/metabolism ; *Neuroinflammatory Diseases ; }, abstract = {Disturbance of the brain homeostasis, either directly via the formation of abnormal proteins or cerebral hypo-perfusion, or indirectly via peripheral inflammation, will activate microglia to synthesise a variety of pro-inflammatory agents which may lead to inflammation and cell death. The pro-inflammatory cytokines will induce changes in the iron proteins responsible for maintaining iron homeostasis, such that increased amounts of iron will be deposited in cells in the brain. The generation of reactive oxygen and nitrogen species, which is directly involved in the inflammatory process, can significantly affect iron metabolism via their interaction with iron-regulatory proteins (IRPs). This underlies the importance of ensuring that iron is maintained in a form that can be kept under control; hence, the elegant mechanisms which have become increasingly well understood for regulating iron homeostasis. Therapeutic approaches to minimise the toxicity of iron include N-acetyl cysteine, non-steroidal anti-inflammatory compounds and iron chelation.}, }
@article {pmid35802043, year = {2022}, author = {Behera, J and Ison, J and Voor, MJ and Tyagi, N}, title = {Exercise-Linked Skeletal Irisin Ameliorates Diabetes-Associated Osteoporosis by Inhibiting the Oxidative Damage-Dependent miR-150-FNDC5/Pyroptosis Axis.}, journal = {Diabetes}, volume = {71}, number = {12}, pages = {2777-2792}, pmid = {35802043}, issn = {1939-327X}, support = {R01 AR067667/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; Female ; Mice ; *Diabetes Mellitus, Experimental/genetics/metabolism ; *Diabetes Mellitus, Type 2/complications/genetics/metabolism ; *Fibronectins/metabolism ; *Glucose Intolerance/metabolism ; Mice, Inbred C57BL ; Muscle, Skeletal/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Osteoporosis/genetics/prevention &amp; control ; Oxidative Stress ; Pyroptosis ; X-Ray Microtomography ; MicroRNAs/genetics ; }, abstract = {Recent evidence suggests that physical exercise (EX) promotes skeletal development. However, the impact of EX on the progression of bone loss and deterioration of mechanical strength in mice with type 2 diabetic mellitus (T2DM) remains unexplored. In the current study, we investigated the effect of EX on bone mass and mechanical quality using a diabetic mouse model. The T2DM mouse model was established with a high-fat diet with two streptozotocin injections (50 mg/kg/body wt) in C57BL/6 female mice. The diabetic mice underwent treadmill exercises (5 days/week at 7-11 m/min for 60 min/day) for 8 weeks. The data showed that diabetes upregulated miR-150 expression through oxidative stress and suppressed FNDC5/Irisin by binding to its 3'-untranslated region. The decreased level of irisin further triggers the pyroptosis response in diabetic bone tissue. EX or N-acetyl cysteine or anti-miRNA-150 transfection in T2DM mice restored FNDC5/Irisin expression and bone formation. Furthermore, EX or recombinant irisin administration prevented T2DM-Induced hyperglycemia and improved glucose intolerance in diabetic mice. Furthermore, osteoblastic knockdown of Nlrp3 silencing (si-Nlrp3) or pyroptosis inhibitor (Ac-YVADCMK [AYC]) treatment restores bone mineralization in diabetic mice. Micro-computed tomography scans and mechanical testing revealed that trabecular bone microarchitecture and bone mechanical properties were improved after EX in diabetic mice. Irisin, either induced by skeleton or daily EX or directly administered, prevents bone loss by mitigating inflammasome-associated pyroptosis signaling in diabetic mice. This study demonstrates that EX-induced skeletal irisin ameliorates diabetes-associated glucose intolerance and bone loss and possibly provides a mechanism of its effects on metabolic osteoporosis.}, }
@article {pmid35799894, year = {2022}, author = {Zhu, D and Fan, T and Chen, Y and Huo, X and Li, Y and Liu, D and Cai, Y and Cheung, CW and Tang, J and Cui, J and Xia, Z}, title = {CXCR4/CX43 Regulate Diabetic Neuropathic Pain via Intercellular Interactions between Activated Neurons and Dysfunctional Astrocytes during Late Phase of Diabetes in Rats and the Effects of Antioxidant N-Acetyl-L-Cysteine.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8547563}, pmid = {35799894}, issn = {1942-0994}, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism ; Astrocytes/metabolism ; *Connexin 43/metabolism ; *Diabetes Mellitus, Experimental/metabolism ; *Diabetic Neuropathies/drug therapy/metabolism ; Hyperalgesia/drug therapy/metabolism ; *Neuralgia/drug therapy/metabolism ; Neurons/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Receptors, CXCR4/metabolism ; Receptors, Chemokine/metabolism ; Spinal Cord/metabolism ; }, abstract = {Growing evidence suggests that the interactions between astrocytes and neurons exert important functions in the central sensitization of the spinal cord dorsal horn in rodents with diabetes and neuropathic pain (DNP). However, it still remains unclear how signal transmission occurs in the spinal cord dorsal horn between astrocytes and neurons, especially in subjects with DNP. Chemokine CXC receptor 4 (CXCR4) plays critical roles in DNP, and connexin 43 (CX43), which is also primarily expressed by astrocytes, contributes to the development of neuropathy. We thus postulated that astrocytic and neuronal CXCR4 induces and produces inflammatory factors under persistent peripheral noxious stimulation in DNP, while intercellular CX43 can transmit inflammatory stimulation signals. The results showed that streptozotocin-induced type 1 diabetic rats developed heat hyperalgesia and mechanical allodynia. Diabetes led to persistent neuropathic pain. Diabetic rats developed peripheral sensitization at the early phase (2 weeks) and central sensitization at the late phase (5 weeks) after diabetes induction. Both CXCR4 and CX43, which are localized and coexpressed in neurons and astrocytes, were enhanced significantly in the dorsal horn of spinal cord in rats undergoing DNP during late phase of diabetes, and the CXCR4 antagonist AMD3100 reduced the expression of CX43. The nociceptive behavior was reversed, respectively, by AMD3100 at the early phase and by the antioxidant N-acetyl-L-cysteine (NAC) at the late phase. Furthermore, rats with DNP demonstrated downregulation of glial fibrillary acidic protein (GFAP) as well as upregulation of c-fos in the spinal cord dorsal horn at the late phase compared to the controls, and upregulation of GFAP and downregulation of c-fos were observed upon treatment with NAC. Given that GFAP and c-fos are, respectively, makers of astrocyte and neuronal activation, our findings suggest that CXCR4 as an inflammatory stimulation protein and CX43 as an intercellular signal transmission protein both may induce neurons excitability and astrocytes dysfunction in developing DNP.}, }
@article {pmid35795313, year = {2022}, author = {Zhang, L and Xiong, Y and Du, L}, title = {Efficacy and Safety of N-Acetylcysteine for Chronic Obstructive Pulmonary Disease and Chronic Bronchitis.}, journal = {BioMed research international}, volume = {2022}, number = {}, pages = {9133777}, pmid = {35795313}, issn = {2314-6141}, mesh = {Acetylcysteine/adverse effects ; *Bronchitis, Chronic/chemically induced/drug therapy ; Double-Blind Method ; Humans ; *Pulmonary Disease, Chronic Obstructive ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) and chronic bronchitis are associated with poor clinical outcomes. N-acetylcysteine (NAC) is a widely used therapeutic option for such patients; however, the clinical efficacy of NAC has not been conclusively determined. We hypothesized that high-dose oral NAC can improve the clinical outcomes for patients with concurrent chronic bronchitis and COPD. Objective and Methods. This was a randomized, double-blind, placebo-controlled trial evaluating the efficacy of high-dose NAC for COPD patients with concurrent chronic bronchitis. Study participants were randomized into two groups and administered with NAC (900 mg) twice daily or matching placebo for 3 months. Then, respiratory health status was evaluated using the St. George's Respiratory Questionnaire (SGQR), which was set as the primary end point.<br><br>RESULTS: A total of 143 COPD patients with chronic bronchitis were screened, and as a result, only 100 patients were enrolled in this study (50 participants were randomized to receive placebo, and others were randomized to receive NAC). After treatment, differences in SGQR scores between the placebo and NAC groups were not significant. Moreover, differences in secondary end points between the two groups after treatment were insignificant. Discussion. High-dose NAC has no marked clinical benefits for COPD patients with concurrent chronic bronchitis.}, }
@article {pmid35791005, year = {2022}, author = {Kuruoglu, T and Altun, G and Kuruoglu, E and Turan, DB and Önger, ME}, title = {Actions of N-acetylcysteine, daptomycin, vancomycin, and linezolid on methicillin-resistant Staphylococcus aureus biofilms in the ventriculoperitoneal shunt infections: an experimental study.}, journal = {Chinese neurosurgical journal}, volume = {8}, number = {1}, pages = {15}, pmid = {35791005}, issn = {2057-4967}, abstract = {BACKGROUND: Shunt systems are used to provide cerebrospinal fluid drainage in the treatment of hydrocephalus. Recently, antibiotic-impregnated shunt systems are used to prevent colonization in the ventriculoperitoneal catheters. Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative microorganism of shunt infections. The aim of the study is to investigate effects of several substances on MRSA biofilms in the ventriculoperitoneal catheters.<br><br>METHODS: The present study consists of mainly eight groups (each has two subgroups as antibiotic-impregnated and nonantibiotic-impregnated catheters). In addition, each group contains six molds using MRSA strains. In this study, daptomycin (DAPT) (2&#xa0;mg/ml), vancomycin (VAN) (10&#xa0;mg/ml), linezolid (LIN) (2&#xa0;mg/ml), N-acetylcysteine (NAC) (6&#xa0;mg/ml), and various combinations of these substances were used to evaluate the treatment against MRSA using scanning electron microscope (SEM) images and microbiological enumeration.<br><br>RESULTS: The colony count in the antibiotic-impregnated samples significantly decreased compared to nonantibiotic-impregnated samples in the MRSA, MRSA&#x2009;+&#x2009;DAPT, and MRSA&#x2009;+&#x2009;LIN groups (p&#x2009;<&#x2009;0.01), respectively. Conversely, the colony count in antibiotic-impregnated samples significantly increased compared to nonantibiotic-impregnated samples in NAC&#x2009;+&#x2009;DAPT and NAC&#x2009;+&#x2009;VAN groups (p&#x2009;<&#x2009;0.01), respectively.<br><br>CONCLUSIONS: The results showed that the use of antibiotic-impregnated catheters has a significant impact on the prevention of infection whereas the combination of NAC and DAPT showed better antibiofilm and antibacterial effects than other combinations on the prevention and treatment of nonantibiotic-impregnated catheter infections.}, }
@article {pmid35788981, year = {2022}, author = {Panda, M and Biswal, BK}, title = {Evodiamine inhibits stemness and metastasis by altering the SOX9-β-catenin axis in non-small-cell lung cancer.}, journal = {Journal of cellular biochemistry}, volume = {123}, number = {9}, pages = {1454-1466}, doi = {10.1002/jcb.30304}, pmid = {35788981}, issn = {1097-4644}, support = {1201//Department of Science and Technology, Odisha, India/ ; ECR/2016/000792//Science and Engineering Research Board/ ; }, mesh = {*Alkaloids/pharmacology ; Apoptosis ; Cadherins ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cysteine ; Humans ; *Lung Neoplasms/drug therapy ; Poly(ADP-ribose) Polymerase Inhibitors ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Quinazolines ; Reactive Oxygen Species ; SOX9 Transcription Factor ; Vimentin ; beta Catenin/metabolism ; }, abstract = {Evodiamine (EVO), a natural dietary alkaloid extracted from the roots of the Evodia rutaecarpa, has shown anticancer activities. Here, we have investigated EVO's role in inhibiting cell proliferation and migration in A549 and NCI-H522 lung cancer cells. EVO decreased the cell viability in A549 and NCI-H522 cells in a dose- and time-dependent manner. It also induced apoptosis by downregulating the expression of antiapoptotic Bcl-2 and upregulating the expression of cleaved caspase-3 and PARP. In addition, the treatment of EVO elevated the level of reactive oxygen species (ROS) generation inside the cells to induce the cell death pathways. In contrast, the pretreatment of ROS scavenger, N-acetyl cysteine, reverses the effect of EVO and attenuates cell death. Moreover, excess ROS generation in response to EVO resulted in the depletion of mitochondrial membrane potential. Furthermore, it induced DNA damage and arrested the cell cycle at the G2/M phase in A549 and NCI-H522 cells. Our study also investigated that EVO significantly suppressed tumorigenicity by inhibiting colony formation and tumorsphere formation. However, the treatment of EVO downregulated the cancer stem cell markers CD44 and CD133 in non-small-cell lung cancer. The inhibitory effect of EVO on cell invasion was mediated by altering the expression of E-cadherin, ZO-1, N-cadherin, and Vimentin. Additionally, we have revealed that EVO treatment showed downregulation of SOX9, an upstream component of β-catenin. Lastly, we have demonstrated that EVO targets the SOX9-β-catenin axis by reducing SOX9 and β-catenin expression. These findings suggested that EVO could be a promising agent for treating human lung cancer.}, }
@article {pmid35788669, year = {2022}, author = {Magner, K and Ilin, JV and Clark, EG and Kong, JWY and Davis, A and Hiremath, S}, title = {Meta-analytic Techniques to Assess the Association Between N-acetylcysteine and Acute Kidney Injury After Contrast Administration: A Systematic Review and Meta-analysis.}, journal = {JAMA network open}, volume = {5}, number = {7}, pages = {e2220671}, pmid = {35788669}, issn = {2574-3805}, mesh = {*Acetylcysteine/adverse effects/therapeutic use ; *Acute Kidney Injury/chemically induced/prevention &amp; control ; Humans ; Publication Bias ; Renal Dialysis ; Renal Replacement Therapy ; }, abstract = {IMPORTANCE: The most suitable analytic method to systematically analyze numerous trials with contradictory results is unclear. Multiple trials assessing the use of N-acetylcysteine (NAC) for prevention of contrast-induced acute kidney injury (CI-AKI) have had contradictory results with recent trials confirming a lack of benefit.<br><br>OBJECTIVE: To systematically review the literature on NAC for the prevention of CI-AKI, and to explore the heterogeneity, publication bias, and small-study effect to determine the most suitable analytic method in a setting where the literature is contradictory.<br><br>DATA SOURCES: Medline, Embase, and Cochrane Central Register of Controlled Trials databases were used to find randomized clinical trials (RCTs) comparing NAC with any other prophylactic agent or placebo in adults.<br><br>STUDY SELECTION: The search included studies published in English from database inception to January 2020. Two independent reviewers screened the studies, extracted data, and performed the risk of bias assessment.<br><br>DATA EXTRACTION AND SYNTHESIS: A meta-analysis was conducted about the effect of NAC on CI-AKI, the need for dialysis, and mortality. Fixed and random effects analyses were also performed. Funnel plots and the trim and fill method were used for assessment of publication bias. Metaregression was performed to explore the heterogeneity and subgroup analysis to examine the association between NAC and CI-AKI when studies were categorized according to sample size and number of events.<br><br>RESULTS: A total of 101 trials were included in this meta-analysis. The median sample size was 112 (range, 20 to 4993). Twenty-nine trials had a sample size of 200 or more, and only 3 trials had a sample size of 500 or more. Forty-five trials reported the need for kidney replacement therapy, and 41 trials reported mortality as an outcome. NAC seemed to show a benefit, with a pooled OR of 0.72 (95% CI, 0.63-0.82) using random effects model and a pooled OR of 0.82 (95% CI 0.76-0.90) using a fixed effects model. However, there was significant heterogeneity (I2&#x2009;=&#x2009;37.6; P&#x2009;<&#x2009;.001) and significant publication bias, which was reduced only when restricting to large RCTs (N&#x2009;&#x2265;&#x2009;500). The clinical outcomes (ie, the need for kidney replacement therapy and mortality) revealed little heterogeneity and no publication bias, and each provided a robust neutral summary result.<br><br>CONCLUSIONS AND RELEVANCE: In this meta-analysis, NAC was associated with a benefit in the prevention of CI-AKI. However, because of substantial publication bias and other biases, standard meta-analytic techniques resulted in significant heterogeneity and a spurious, or factitious, association, even when using a random effects model. When the analysis was restricted to RCTs with a large sample size to account for publication bias or restricted to trials with clinical outcomes, this issue was reduced and resulted in more robust and neutral effect sizes.}, }
@article {pmid35783478, year = {2022}, author = {Licks, F and Minuzzo Hartmann, R and Schemitt, E and Raskopf Colares, J and Marques, C and Fillmann, H and Possa Marroni, N}, title = {Synergistic antioxidant and anti-inflammatory action of N-acetylcysteine in portal hypertensive gastropathy in rats.}, journal = {Hepatology forum}, volume = {3}, number = {2}, pages = {51-56}, pmid = {35783478}, issn = {2757-7392}, abstract = {BACKGROUND AND AIM: Portal hypertension (PH) is a syndrome associated with cirrhosis and characterized by a progressive increase in portal pressure, with consequent compensatory vascular dilation. Gastric vascular changes associated with oxidative and nitrosative stress characterize the clinical presentation of portal hypertensive gastropathy (PHG). In addition, the inflammatory process is considered an aggravating factor for severity by contributing to gastric tissue injury. The aim of this study was to investigate the synergistic anti-inflammatory and antioxidant action of N-acetylcysteine (NAC) in the stomach of rats with PH.<br><br>MATERIALS AND METHODS: Eighteen Wistar male rats were used in this experimental protocol and were divided into three groups with six in each group: sham-operated (SO), partial portal vein ligation (PPVL), and PPVL + NAC. Treatment with NAC at a dose of 10 mg/kg (i.p.) was initiated on day 8 after surgery and continued for 7 days. We evaluated the expression of iNOS, NQO-1, HSP-90, and SOD by Western blot, as well as nuclear factor-kappa B (NF-&#x3ba;B) and tumor necrosis factor (TNF)-&#x3b1; staining by immunohistochemistry, in the rat stomach.<br><br>RESULTS: The PPVL group exhibited increased expression of HSP-90, iNOS, SOD, and NQO-1 when compared with controls. NAC reduced the expression of all studied proteins. Similarly, NF-&#x3ba;B and TNF-&#x3b1; staining was increased in PPVL animals versus controls and reduced in PPVL + NAC versus PPVL animals, respectively.<br><br>CONCLUSION: These results suggest the effectiveness of NAC as a dual anti-inflammatory and antioxidant in animals with experimental PHG induced by partial ligation of the portal vein.}, }
@article {pmid35779304, year = {2022}, author = {Motallebzadeh, E and Suliman Maashi, M and Mahmoud, MZ and Aliasgharzedeh, A and Vakili, Z and Talaei, SA and Mohseni, M}, title = {Radioprotective effects of N-acetylcysteine on rats' brainstem following megavoltage X-irradiations.}, journal = {Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine}, volume = {187}, number = {}, pages = {110348}, doi = {10.1016/j.apradiso.2022.110348}, pmid = {35779304}, issn = {1872-9800}, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Antioxidants/metabolism ; *Brain Stem/metabolism/radiation effects ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; *Radiation-Protective Agents/pharmacology ; Rats ; Superoxide Dismutase/metabolism ; X-Rays/adverse effects ; }, abstract = {PURPOSE: This study aimed to determine the radioprotective effect of N-acetylcysteine (NAC) on the radiation-induced oxidative stress (OS) in the rats' brainstem.<br><br>MATERIALS AND METHODS: Eighty rats in four identical groups, including vehicle control (VC), irradiation alone (RAD), irradiation with 1&#xa0;g/kg of NAC treatment (RAN), and NAC treatment without radiation (NAC) were used. Whole-brain irradiation was performed with a single dose of 25&#xa0;Gy. The rats received the treatments via intraperitoneal (IP) injection 1&#xa0;h before the irradiation process. Nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC), and glutathione peroxidase (GPx) were measured in the rats' brainstem and compared between the groups. Furthermore, the pathological study was performed to assess tissue damage after 24&#xa0;h, 72&#xa0;h, and 5 days of irradiation.<br><br>RESULTS: The levels of NO and MDA in the brainstem tissue for the RAD group were 60.37&#xa0;&#xb1;&#xa0;3.35&#xa0;&#x3bc;mol/L and 45.10&#xa0;&#xb1;&#xa0;2.48&#xa0;&#x3bc;M, respectively, which were higher than those of VC group (NO: 30.41&#xa0;&#xb1;&#xa0;1.83&#xa0;&#x3bc;mol/L; MDA: 31.02&#xa0;&#xb1;&#xa0;1.71&#xa0;&#x3bc;M). The level of SOD, CAT, TAC, and GPx declined in the RAD compared to the VC group. Pre-treatment with NAC decreased the level of NO and MDA and also enhanced the antioxidant activities. The greatest pathological changes in the rats' brainstems were seen in RAD animals compared to the VC group at 24&#xa0;h, 72&#xa0;h, and 5 days. Furthermore, the pathological changes were not observed in the NAC group in all the assessed times.<br><br>CONCLUSION: Based on the results, NAC can decrease the irradiation-induced oxidative stress and pathology damages in the rats' brainstem. It can be concluded that NAC can be an appropriate radioprotection candidate for the human brainstem.}, }
@article {pmid35777681, year = {2022}, author = {Zhang, T and Shen, Y and Zhu, R and Shan, W and Li, Y and Yan, M and Zhang, Y}, title = {Benzo[a]pyrene exposure promotes RIP1-mediated necroptotic death of osteocytes and the JNK/IL-18 pathway activation via generation of reactive oxygen species.}, journal = {Toxicology}, volume = {476}, number = {}, pages = {153244}, doi = {10.1016/j.tox.2022.153244}, pmid = {35777681}, issn = {1879-3185}, mesh = {Animals ; *Benzo(a)pyrene/toxicity ; Cell Death ; *Interleukin-18 ; MAP Kinase Kinase 4/metabolism ; Mice ; Osteocytes/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) of environmental pollutants, readily produced during the processing of petroleum and fatty foods. BaP exposure can cause skeletal deformities. However, whether BaP affects osteocytes, making up over 95% of all the bone cells, remains unknown. This study aimed to investigate the effect of BaP on osteocytes in vivo and in vitro, as well as explore the underlying mechanisms. The in vivo data showed that BaP (50 mg/kg) exposure for 12 weeks could cause bone destruction, and increase osteocytes death in mouse cortical femur. Our in vitro results revealed that BaP (25-100 μmol/L) exposure inhibited cell viability of MLO-Y4 cells, and resulted in cell death in a dose-dependent manner. Furthermore, BaP exposure significantly triggered necroptosis of MLO-Y4 cells, as indicated by increased propidium iodide (PI)-positive cells and up-regulation of necroptosis-related protein expressions of receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). This necrotic effect was reversed by the RIP1 inhibitor necrostatin-1 (Nec-1). Simultaneously, BaP activated the downstream c-Jun N-terminal kinase (JNK)/ interleukin (IL)-18 signaling pathway, which was suppressed after the JNK inhibitor SP600125 or Nec-1 treatment. In addition, BaP exposure promoted the production of intracellular reactive oxygen species (ROS), mitochondrial ROS (mtROS), and elevated malondialdehyde (MDA) levels; while BaP decreased superoxide dismutase (SOD) activity and antioxidant enzymes including nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels, leading to oxidative damage. The ROS scavenger N-acetylcysteine (NAC) inhibited this necroptotic death and the JNK/IL-18 pathway activation. Collectively, BaP exposure may cause RIP1-mediated necroptotic death of osteocytes and activate the JNK/IL-18 pathway via ROS generation.}, }
@article {pmid35777452, year = {2022}, author = {Martínez-González, JJ and Ríos-Morales, SL and Guevara-Flores, A and Ramos-Godinez, MDP and López-Saavedra, A and Rendón, JL and Del Arenal Mena, IP}, title = {Evaluating the effect of curcumin on the metacestode of Taenia crassiceps.}, journal = {Experimental parasitology}, volume = {239}, number = {}, pages = {108319}, doi = {10.1016/j.exppara.2022.108319}, pmid = {35777452}, issn = {1090-2449}, mesh = {Animals ; *Anthelmintics/pharmacology ; *Curcumin/pharmacology ; *Cysticercosis/drug therapy ; Cysticercus ; Mice ; Mice, Inbred BALB C ; Oxidative Stress ; *Taenia ; }, abstract = {Curcumin, a curcuminoid present in the rhizome of the plant Curcuma longa has multiple pharmacological effects including anticarcinogenic and anti-inflammatory properties. This work evaluates the anthelmintic effect of the curcumin molecule (98% pure) on Taenia crassiceps cysticerci viability in vitro. Cysticerci incubated in the presence of increasing concentrations of curcumin showed a dose-dependent mortality correlated with a significant increase in the production of reactive oxygen species and a partial inhibition of thioredoxin-glutathione reductase, the only disulfide reductase present in these parasites. At 500 μM curcumin, a 100% of cysticerci lethality was obtained after 2 h of treatment. These results suggest the curcumin-induced oxidative stress could be in the origin of the anthelminthic effect of curcumin. Mice with cysticerci were injected intraperitoneally with 20, 40, or 60 mM curcumin daily for 30 days. A decrease in the burden of cysticerci (46%) was observed with a 60 mM dose of curcumin, supporting this compound as a potential anthelmintic drug.}, }
@article {pmid35777063, year = {2022}, author = {Chen, SL and Ho, CY and Chin, SC}, title = {Effects of oral N-acetylcysteine combined with oral prednisolone on idiopathic sudden sensorineural hearing loss.}, journal = {Medicine}, volume = {101}, number = {26}, pages = {e29792}, pmid = {35777063}, issn = {1536-5964}, mesh = {Acetylcysteine/therapeutic use ; Glucocorticoids/therapeutic use ; *Hearing Loss, Sensorineural/diagnosis/drug therapy ; *Hearing Loss, Sudden/diagnosis/drug therapy ; Humans ; Prednisolone/therapeutic use ; Retrospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: Idiopathic sudden sensorineural hearing loss (ISSNHL) is an acute condition that presents with sudden hearing loss, for which steroids remain the main treatment. N-acetylcysteine (NAC), as a precursor of glutathione, can reduce the production of reactive oxygen species to protect hair cells in the inner ear from damage. However, data regarding the therapeutic outcomes of oral steroid combined with oral NAC for ISSNHL are still limited. This study was performed to investigate this issue.<br><br>METHODS: Between June 2016 and October 2021, 219 patients (219 ears) diagnosed with ISSNHL and treated with oral prednisolone were enrolled in this retrospective study. Oral NAC was prescribed to 94 of these patients (NAC group) but not to the remaining 125 patients (non-NAC group). The clinical and audiological findings were assessed.<br><br>RESULTS: The NAC group showed a mean hearing level gain of 29.5 &#xb1; 21.8 dB, speech reception threshold (SRT) gain of 26.2 &#xb1; 34.4 dB, and speech discrimination score (SDS) gain of 25.5 &#xb1; 30.4%. Although the NAC group had better mean hearing level, SRT, and SDS gains than the non-NAC group, the differences were not statistically significant (all P > .05). The only significant difference between the NAC and non-NAC groups was the posttreatment pure tone audiometry (PTA) thresholds at 8 kHz, which were 54.2 &#xb1; 24.4 and 60.9 &#xb1; 34.1 dB, respectively (P = .046).<br><br>CONCLUSIONS: This study demonstrated the effect of oral steroid combined with oral NAC for ISSNHL. Both the NAC and non-NAC groups showed obvious improvement in all PTA thresholds, as well as mean hearing level, SRT, and SDS gains. The NAC group showed significantly better PTA performance at a high frequency (8 kHz) than the non-NAC group. Therefore, for oral treatment of ISSNHL, we advocate concurrent use of oral prednisolone and oral NAC.}, }
@article {pmid35775164, year = {2022}, author = {Tu, C and Lai, S and Huang, Z and Cai, G and Zhao, K and Gao, J and Wu, Z and Zhong, Z}, title = {Accumulation of advanced oxidation protein products contributes to age-related impairment of gap junction intercellular communication in osteocytes of male mice.}, journal = {Bone &amp; joint research}, volume = {11}, number = {7}, pages = {413-425}, pmid = {35775164}, issn = {2046-3758}, abstract = {AIMS: Gap junction intercellular communication (GJIC) in osteocytes is impaired by oxidative stress, which is associated with age-related bone loss. Ageing is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, it is still unknown whether AOPP accumulation is involved in the impairment of osteocytes' GJIC. This study aims to investigate the effect of AOPP accumulation on osteocytes' GJIC in aged male mice and its mechanism.<br><br>METHODS: Changes in AOPP levels, expression of connexin43 (Cx43), osteocyte network, and bone mass were detected in 18-month-old and three-month-old male mice. Cx43 expression, GJIC function, mitochondria membrane potential, reactive oxygen species (ROS) levels, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation were detected in murine osteocyte-like cells (MLOY4 cells) treated with AOPPs. The Cx43 expression, osteocyte network, bone mass, and mechanical properties were detected in three-month-old mice treated with AOPPs for 12 weeks.<br><br>RESULTS: The AOPP levels were increased in aged mice and correlated with degeneration of osteocyte network, loss of bone mass, and decreased Cx43 expression. AOPP intervention induced NADPH oxidase activation and mitochondrial dysfunction, triggered ROS generation, reduced Cx43 expression, and ultimately impaired osteocytes' GJIC, which were ameliorated by NADPH oxidase inhibitor apocynin, mitochondria-targeted superoxide dismutase mimetic (mito-TEMPO), and ROS scavenger N-acetyl cysteine. Chronic AOPP loading accelerated the degradation of osteocyte networks and decreased Cx43 expression, resulting in deterioration of bone mass and mechanical properties in vivo.<br><br>CONCLUSION: Our study suggests that AOPP accumulation contributes to age-related impairment of GJIC in osteocytes of male mice, which may be part of the pathogenic mechanism responsible for bone loss during ageing. Cite this article: Bone Joint Res&#xa0;2022;11(7):413-425.}, }
@article {pmid35770045, year = {2022}, author = {Xin, Q and Ji, Q and Zhang, Y and Ma, W and Tian, B and Liu, Y and Chen, Y and Wang, F and Zhang, R and Wang, X and Yuan, J}, title = {Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {1112987}, pmid = {35770045}, issn = {1942-0994}, mesh = {*Antineoplastic Agents/pharmacology/therapeutic use ; Apoptosis ; *Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Cell Proliferation ; Cisplatin/pharmacology/therapeutic use ; Drug Resistance, Neoplasm ; Humans ; *Lung Neoplasms/pathology ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Lung cancer has become a global health issue in recent decades. Approximately 80-85% of cases are non-small-cell lung cancer (NSCLC). Despite the high rate of resistance, cisplatin-base chemotherapy is still the main treatment for NSCLC patients. Thus, overcoming cisplatin resistance is urgently needed in NSCLC therapy. In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells. Mechanistically, NRF2 is specifically degraded by the proteasome following its own ubiquitylation in APR-246-treated cisplatin-resistant cells, which in turn decreases NRF2/SLC7A11/GSH axis activity. Our study provides new insights into the biology driving cisplatin resistance of lung cancer and highlights APR-246 as a potential therapeutic reagent for overcoming cisplatin resistance.}, }
@article {pmid35769842, year = {2021}, author = {Mosayebi, S and Soltani, R and Shafiee, F and Assarzadeh, S and Hakamifard, A}, title = {Evaluation of the Effectiveness of N-Acetylcysteine in the Prevention of Colistin-Induced Nephrotoxicity: A Randomized Controlled Clinical Trial.}, journal = {Journal of research in pharmacy practice}, volume = {10}, number = {4}, pages = {159-165}, pmid = {35769842}, issn = {2319-9644}, abstract = {OBJECTIVE: The present study aimed to evaluate the effectiveness of N-Acetylcysteine (NAC), as an antioxidant, in preventing nephrotoxicity in patients receiving colistin.<br><br>METHODS: In a randomized controlled clinical trial, eligible participants receiving colistin were divided into two groups including drug (n = 43) and control (n = 39). In the drug group, 1200 mg of NAC was administered daily for 10 days concurrently with colistin. Patients in the control group received only colistin. The serum creatinine level (SCr), blood urea nitrogen (BUN), and creatinine clearance (CrCl) at baseline and every other day, and the number of cases with acute kidney injury (AKI) during the study were recorded. Before starting treatment and on day 5, the level of urinary neutrophil gelatinase-associated lipocalin (NGAL) was determined. Finally, the values were compared between the groups.<br><br>FINDINGS: There was a significant increase in SCr and BUN and a significant reduction in CrCl in both groups, but there was not any significant difference between the two groups at any time. Changes in the urine NGAL levels were not significantly different between the two groups. Even though the number of cases with AKI in the drug group (8 cases, 18.6%) was less than the control group (11 cases, 28.2%), the difference was not statistically significant (P = 0.303).<br><br>CONCLUSION: Simultaneous administration of NAC with a dose of 1200 mg daily does not have any effect in the prevention of colistin-induced nephrotoxicity.}, }
@article {pmid35769058, year = {2022}, author = {Song, K and Yang, GM and Han, J and Gil, M and Dayem, AA and Kim, K and Lim, KM and Kang, GH and Kim, S and Jang, SB and Vellingiri, B and Cho, SG}, title = {Modulation of Osteogenic Differentiation of Adipose-Derived Stromal Cells by Co-Treatment with 3, 4'-Dihydroxyflavone, U0126, and N-Acetyl Cysteine.}, journal = {International journal of stem cells}, volume = {15}, number = {3}, pages = {334-345}, pmid = {35769058}, issn = {2005-3606}, abstract = {BACKGROUND AND OBJECTIVES: Flavonoids form the largest group of plant phenols and have various biological and pharmacological activities. In this study, we investigated the effect of a flavonoid, 3, 4'-dihydroxyflavone (3, 4'-DHF) on osteogenic differentiation of equine adipose-derived stromal cells (eADSCs).<br><br>METHODS AND RESULTS: Treatment of 3, 4'-DHF led to increased osteogenic differentiation of eADSCs by increasing phosphorylation of ERK and modulating Reactive Oxygen Species (ROS) generation. Although PD98059, an ERK inhibitor, suppressed osteogenic differentiation, another ERK inhibitor, U0126, apparently increased osteogenic differentiation of the 3, 4'-DHF-treated eADSCs, which may indicate that the effect of U0126 on bone morphogenetic protein signaling is involved in the regulation of 3, 4'-DHF in osteogenic differentiation of eADSCs. We revealed that 3, 4'-DHF could induce osteogenic differentiation of eADSCs by suppressing ROS generation and co-treatment of 3, 4'-DHF, U0126, and/or N-acetyl cysteine (NAC) resulted in the additive enhancement of osteogenic differentiation of eADSCs.<br><br>CONCLUSIONS: Our results showed that co-treatment of 3, 4'-DHF, U0126, and/or NAC cumulatively regulated osteogenesis in eADSCs, suggesting that 3, 4'-DHF, a flavonoid, can provide a novel approach to the treatment of osteoporosis and can provide potential therapeutic applications in therapeutics and regenerative medicine for human and companion animals.}, }
@article {pmid35765435, year = {2022}, author = {Madarshahian, S and Enayati, M and Vinyes Parés, G and Ufheil, G and Abbaspourrad, A}, title = {Solid phase wax coating of N-acetylcysteine (NAC) to decrease its solubility profile as a ready to mix supplement.}, journal = {RSC advances}, volume = {12}, number = {27}, pages = {17550-17558}, pmid = {35765435}, issn = {2046-2069}, abstract = {N-Acetylcysteine (NAC) has health benefits attributed to its antioxidant properties and disulfide bond cleavage ability. Unfortunately, solutions of NAC are acidic with an undesirable taste and an unpleasant aftertaste. A method for slowing NAC release in water was developed using a solid phase wax coating. A coating of natural waxes, using food grade corn oil as the solvent and surfactants to facilitate the wax coating on the particles was used to decrease the solubility of NAC powder, crystals, and granules in water. A high NAC loading, between 55 and 91% for NAC granules and NAC crystals, was achieved as measured using LC-MS. The NAC wax-coated particles were fully characterized, and microscopy and SEM images revealed the shape, morphology, and size of the particles. Conductometry was used to study NAC release profile in water from wax-coated particles and the results indicate that solid phase wax coatings slowed the release of NAC into water.}, }
@article {pmid35761113, year = {2023}, author = {Abedini Bajgiran, F and Khazaei Koohpar, Z and Salehzadeh, A}, title = {Effects of N-Acetylcysteine Supplementation on Oxidative Stress and Expression of Apoptosis-Related Genes in Testicular Tissue of Rats Exposed to Lead.}, journal = {Biological trace element research}, volume = {201}, number = {5}, pages = {2407-2415}, pmid = {35761113}, issn = {1559-0720}, mesh = {Rats ; Male ; Animals ; *Antioxidants/pharmacology/metabolism ; *Acetylcysteine/pharmacology ; Lead/metabolism ; Semen/metabolism ; Testis ; Oxidative Stress ; Spermatozoa ; 8-Hydroxy-2'-Deoxyguanosine/metabolism/pharmacology ; Apoptosis ; Dietary Supplements ; }, abstract = {BACKGROUND: Lead occupational exposure is now a main concern in the modern world. Lead is a non-biodegradable element with multi-devastating effects on different organs. Acute or chronic exposure to lead is reported to be one of the most important causes of infertility both in males and females basically by inducing oxidative stress and apoptosis.<br><br>OBJECTIVES: The current study scrutinized the mitigating effects of N-acetylcysteine (NAC) on lead toxicity, oxidative stress, and apoptotic/anti-apoptotic genes in the testis tissues of male rats.<br><br>METHODS: Rats were randomly divided into a control group (G1) and four study groups treated with single and continuous doses of lead with and without NAC administration. Malondialdehyde (MDA), total antioxidant capacity (TAC), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were analyzed as oxidative stress biomarkers and the expression of apoptosis-related genes was studied using RT-PCR.<br><br>RESULTS: Continuous exposure to lead caused a significant decrease in sperm count, motility, viability, and morphology (P&#x2009;<&#x2009;0.001). Number of germinal cells, Leydig cells, spermatocytes, and the diameter of seminiferous tubule were significantly decreased (P&#x2009;<&#x2009;0.001) in G3 group. Continuous exposure to lead significantly decreased TAC content, but increased the levels of MDA and 8-OHdG (P&#x2009;<&#x2009;0.001). Administration of continuous dose of lead dramatically increased expression of Bax, Caspase-3, Caspase-8, Cytochrome-C, MMP2, and MMP9 genes in testicular tissue. NAC treatments not only improved morphological changes and sperm quality, but also enhanced antioxidant balance and modulated apoptosis process in testicular tissue of rats.<br><br>CONCLUSION: Lead exposure strongly motivated testicular cells towards apoptosis, caused an oxidant/antioxidant imbalance, and decreased sperm quality along with morphological changes in testis cells. NAC treatments was associated with protective effects on testicular tissue mainly by rebalancing of the antioxidants capacity, as well as downregulation of apoptosis-related genes.}, }
@article {pmid35756790, year = {2022}, author = {Xi, X and Li, ZX and Zhao, Y and Liu, H and Chen, S and Liu, DX}, title = {N-acetylcysteine promotes cyclic mechanical stress-induced osteogenic differentiation of periodontal ligament stem cells by down-regulating Nrf2 expression.}, journal = {Journal of dental sciences}, volume = {17}, number = {2}, pages = {750-762}, pmid = {35756790}, issn = {2213-8862}, abstract = {BACKGROUND/PURPOSE: Mechanical stress plays a vital role in osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Cyclic mechanical stress may up-regulate reactive oxygen species (ROS) level. N-acetylcysteine (NAC) possesses powerful antioxidant capacity. However, it is undefined the impact of NAC on osteogenic differentiation stimulated by cyclic mechanical stress in PDLSCs. The aim of our research was to study the effect of NAC on PDLSCs during osteogenic differentiation under cyclic mechanical stress.<br><br>MATERIALS AND METHODS: The expression levels of osteogenesis markers were used to examine the osteogenic differentiation of PDLSCs. ROS production were measured by flow cytometry. The levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) were analyzed. We also examined the changes of alveolar bone and periodontal ligament (PDL) tissues in orthodontic rats by micro-computed tomography (micro-CT) system and immunohistochemistry (IHC) staining. The nuclear factor erythroid-2-related factor-2 (Nrf2) expression was examined.<br><br>RESULTS: NAC could enhance the osteogenic differentiation and up-regulate the GSH level as well as the ratio of GSH/GSSG, while down-regulate ROS generation and Nrf2 expression induced by cyclic mechanical stress in PDLSCs. NAC had beneficial effects on the microstructure of alveolar bone and enhanced the expression levels of osteogenesis markers, such as alkaline phosphatase (ALP) and collagen type 1 (COL1) in PDL in orthodontic rats at the tension side.<br><br>CONCLUSION: NAC could improve the osteogenic differentiation stimulated by cyclic mechanical stress in PDLSCs and in orthodontic rats, suggesting a potential therapeutic approach for alveolar bone remodeling in orthodontics.}, }
@article {pmid35755270, year = {2022}, author = {Mendivil-Perez, M and Jimenez-Del-Rio, M and Velez-Pardo, C}, title = {Polycationic peptide R[7]-G-Aβ25-35 selectively induces cell death in leukemia Jurkat T cells through speedy mitochondrial depolarization, and CASPASE-3 -independent mechanism.}, journal = {Biochemistry and biophysics reports}, volume = {31}, number = {}, pages = {101300}, pmid = {35755270}, issn = {2405-5808}, abstract = {BACKGROUND: Acute lymphoblastic leukemia (ALL) is still incurable hematologic neoplasia in an important percentage of patients. Therefore, new therapeutic approaches need to be developed.<br><br>METHODS: To evaluate the cellular effect of cell-penetrating peptides (C-PP) on leukemia cells, Jurkat cells -a model of ALL were exposed to increasing concentration (50-500&#xa0;&#x3bc;M) A&#x3b2;25-35, R[7]-G-A&#x3b2;25-35 and A&#x3b2;25-35-G-R[7] peptide for 24&#xa0;h. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry (FC), and fluorescent microscopy (FM) analysis were used to assess metabolic viability, cell cycle and proliferation, mitochondria functionality, oxidative stress, and cell death markers.<br><br>RESULTS: We report for the first time that the R[7]-G-A&#x3b2;25-35, but not A&#x3b2;25-35 peptide, induced selective cell death in Jurkat cells more efficiently than the A&#x3b2;25-35-G-R[7] peptide. Indeed, R[7]-G-A&#x3b2;25-35 (200&#xa0;&#x3bc;M) altered the metabolic activity (-25%), arrested the cell cycle in the G2/M-phase (15%), and induced a significant reduction of cellular proliferation (i.e., -74% reduction of Ki-67 nuclei reactivity). Moreover, R[7]-G-A&#x3b2;25-35 induced the dissipation of mitochondrial membrane potential (&#x394;&#x3a8;m, 51%) and produced an important amount of reactive oxygen species (ROS, 75% at 8&#xa0;h) in Jurkat cells. The exposure of cells to antioxidant/cytoprotectant N-acetylcysteine (NAC) did not prevent R[7]-G-A&#x3b2;25-35 from a loss of &#x394;&#x3a8;m in Jurkat cells. The peptide was also unable to activate the executer CASPASE-3, thereby preserving the integrity of the cellular DNA corroborated by the fact that the caspase-3 inhibitor NSCI was unable to protect cells from R[7]-G-A&#x3b2;25-35 -induced cell damage. Further analysis showed that the R[7]-G-A&#x3b2;25-35 peptide is specifically localized at the outer mitochondria membrane (OMM) according to colocalization with the protein translocase TOMM20. Additionally, the cytotoxic effect of the poly-R[7] peptide resembles the toxic action of the uncoupler FCCP, mitocan oligomycin, and rotenone in Jurkat cells. Importantly, the R[7]-G-A&#x3b2;25-35 peptide was innocuous to menstrual mesenchymal stromal cells (MenSC) -normal non-leukemia proliferative cells.<br><br>CONCLUSION: Our findings demonstrated that the cationic A&#x3b2; peptide possesses specific anti-leukemia activity against Jurkat cells through oxidative stress (OS)- and CASPASE-3-independent mechanism but fast mitochondria depolarization.}, }
@article {pmid35753672, year = {2022}, author = {Ben Othmène, Y and Monceaux, K and Belhadef, A and Karoui, A and Ben Salem, I and Boussabbeh, M and Abid-Essefi, S and Lemaire, C}, title = {Triazole fungicide tebuconazole induces apoptosis through ROS-mediated endoplasmic reticulum stress pathway.}, journal = {Environmental toxicology and pharmacology}, volume = {94}, number = {}, pages = {103919}, doi = {10.1016/j.etap.2022.103919}, pmid = {35753672}, issn = {1872-7077}, mesh = {Animals ; Apoptosis ; *Endoplasmic Reticulum Stress ; *Fungicides, Industrial/toxicity ; Mammals/metabolism ; Reactive Oxygen Species/metabolism ; Triazoles/toxicity ; }, abstract = {Tebuconazole (TEB) is a common triazole fungicide that has been widely applied in the treatment of fungal diseases. It is reported that TEB could exert harmful effects on mammals' health. However, the molecular mechanism involved in TEB toxicity remain undefined. Our study aimed to investigate the mechanisms of TEB-induced toxicity in intestinal cells. We found that TEB stimulates apoptosis through the mitochondrial pathway. Additionally, TEB triggers endoplasmic reticulum (ER) stress as demonstrated by the activation of the three arms of unfolded protein response (UPR). The incubation with the chemical chaperone 4-phenylbutyrate (4-PBA) alleviated ER stress and reduced TEB-induced apoptosis, suggesting that ER stress plays an important role in mediating TEB-induced toxicity. Furthermore, inhibition of ROS by N-acetylcysteine (NAC) inhibited TEB-induced ER stress and apoptosis. Taken together, these findings suggest that TEB exerts its toxic effects in HCT116 cells by inducing apoptosis through ROS-mediated ER stress and mitochondrial apoptotic pathway.}, }
@article {pmid35753275, year = {2022}, author = {Zhang, Y and Hu, B and Qian, X and Xu, G and Jin, X and Chen, D and Tang, J and Xu, L}, title = {Transcriptomics-based analysis of co-exposure of cadmium (Cd) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) indicates mitochondrial dysfunction induces NLRP3 inflammasome and inflammatory cell death in renal tubular epithelial cells.}, journal = {Ecotoxicology and environmental safety}, volume = {241}, number = {}, pages = {113790}, doi = {10.1016/j.ecoenv.2022.113790}, pmid = {35753275}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cadmium/toxicity ; Caspase 1/metabolism ; Epithelial Cells ; Ether/metabolism/pharmacology ; *Halogenated Diphenyl Ethers/metabolism/toxicity ; Humans ; *Inflammasomes/genetics/metabolism ; Mitochondria/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Transcriptome ; }, abstract = {Environmental pollution often releases multiple contaminants resulting in as yet largely uncharacterized additive toxicities. Cadmium (Cd) is a widespread pollutant that induces nephrotoxicity in animal models and humans. However, the combined effect of Cd in causing nephrotoxicity with 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a typical congener of polybrominated diphenyl ethers (PBDEs), has not been evaluated and mechanisms are not completely clear. Here, we applied transcriptome sequencing analysis to investigate the combined toxicity of Cd and BDE-47 in the renal tubular epithelial cell lines HKCs. Cd or BDE-47 exposure decreased cell viability in a dose-dependent manner, and exhibited cell swelling and rounding similar to necrosis, which was exacerbated by co-exposure. Transcriptomic analysis revealed 2191, 1331 and 3787 differentially-expressed genes following treatment with Cd, BDE-47 and co-exposure, respectively. Interestingly, functional annotation and enrichment analyses showed involvement of pathways for oxidative stress, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and inflammatory cell death for all three treatments. Examination of indices of mitochondrial function and oxidative stress in HKC cells showed that the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and intracellular calcium ion concentration [Ca[2+]]i were elevated, while superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) were decreased. The ratio of apoptotic and necrotic cells and intracellular lactate dehydrogenase (LDH) release were increased by Cd or BDE-47 exposure, and was aggravated by co-exposure, and was attenuated by ROS scavenger N-Acetyl-L-cysteine (NAC). NLRP3 inflammasome and pyroptosis pathway-related genes of NLRP3, adaptor molecule apoptosis-associated speck-like protein (ASC), caspase-1, interleukin-18 (IL-18) and IL-1β were elevated, while gasdermin D (GSDMD) was down-regulated, and protein levels of NLRP3, cleaved caspase-1 and cleaved GSDMD were increased, most of which were relieved by NAC. Our data demonstrate that exposure to Cd and BDE-47 induces mitochondrial dysfunction and triggers NLRP3 inflammasome and GSDMD-dependent pyroptosis leading to nephrotoxicity, and co-exposure exacerbates this effect, which could be attenuated by inhibiting ROS. This study provides a further mechanistic understanding of kidney damage, and co-exposure impact is worthy of concern and should be considered to improve the accuracy of environmental health assessment.}, }
@article {pmid35749991, year = {2022}, author = {Yang, D and Zhu, J and Zhou, X and Pan, D and Nan, S and Yin, R and Lei, Q and Ma, N and Zhu, H and Chen, J and Han, L and Ding, M and Ding, Y}, title = {Polystyrene micro- and nano-particle coexposure injures fetal thalamus by inducing ROS-mediated cell apoptosis.}, journal = {Environment international}, volume = {166}, number = {}, pages = {107362}, doi = {10.1016/j.envint.2022.107362}, pmid = {35749991}, issn = {1873-6750}, mesh = {Pregnancy ; Female ; Humans ; Animals ; Mice ; Polystyrenes/toxicity/metabolism ; Plastics/metabolism ; Reactive Oxygen Species/metabolism ; Tissue Distribution ; Fetus/metabolism ; Apoptosis ; gamma-Aminobutyric Acid/metabolism ; *Nanoparticles/toxicity ; *Water Pollutants, Chemical/toxicity ; }, abstract = {The adverse effects of plastic on adult animal and human health have been receiving increasing attention. However, its potential toxicity to fetuses has not been fully elucidated. Herein, biodistribution of polystyrene (PS) particles was determined after the maternal mice were orally given PS micro- and/or nano-particles with and without surface modifications during gestational days 1 to 17. The results showed that PS microplastics (MPs) and nanoparticles (NPs) mainly emerged in the alimentary tract, brain, uterus, and placenta in maternal mice, and only the latter infiltrated into the fetal thalamus. PS NPs and carboxyl-modified NPs induced differentially expressed genes mainly enriched in oxidative phosphorylation and GABAergic synapse. Maternal administration of PS particles during gestation led to anxiety-like behavior of the progenies and their γ-aminobutyric acid (GABA) reduction in the prefrontal cortex and amygdala at Week 8. N-Acetylcysteine (NAC), an antioxidant, alleviated PS particles-induced oxidative injury in the fetal brain and rescued the anxiety-like behavior of the progenies. Additionally, PS nanoparticles caused excessive ROS and apoptosis in neuronal cell lines, which were prevented by glutathione supplementation. These results suggested that PS particles produced a negative effect on fetuses by inducing oxidative injury and suppressing GABA synthesis in their brain. The findings contribute to estimating the risk for PS particles to human and animal health.}, }
@article {pmid35749822, year = {2022}, author = {Tráj, P and Herrmann, EM and Sebők, C and Vörösházi, J and Mackei, M and Gálfi, P and Kemény, &#xc1; and Neogrády, Z and Mátis, G}, title = {Protective effects of chicoric acid on polyinosinic-polycytidylic acid exposed chicken hepatic cell culture mimicking viral damage and inflammation.}, journal = {Veterinary immunology and immunopathology}, volume = {250}, number = {}, pages = {110427}, doi = {10.1016/j.vetimm.2022.110427}, pmid = {35749822}, issn = {1873-2534}, mesh = {Animals ; Caffeic Acids ; Cell Culture Techniques/veterinary ; *Chickens/metabolism ; Cytokines/genetics ; Hepatocytes/metabolism ; Inflammation/veterinary ; *Poly I-C/pharmacology ; Succinates ; }, abstract = {Virus induced damage triggered by excessive inflammation and free radical production is a major threat in the poultry industry, leading to low productivity even in vaccinated flocks. The purpose of the study was to induce inflammation with the viral double-stranded RNA analog polyinosinic-polycytidylic acid (poly I:C) on chicken primary hepatocyte - non-parenchymal cell co-cultures to investigate the immunomodulatory and cell protectant effects of chicoric acid (CA) in comparison to N-acetylcysteine (NAC). Poly I:C significantly elevated the activity of the cell damage marker, lactate dehydrogenase (LDH) and the concentration of inflammatory cytokines (IL-6, IL-8, IFN-α, IFN-γ and M-CSF) in the culture medium and decreased cellular metabolic activity. CA significantly reduced the elevated LDH and cytokine levels in a dose-dependent manner, moreover, the higher (100 µg/mL) concentration of CA even elevated the level of metabolic activity. In contrast, 10 µg/mL NAC treatment decreased the level of each inflammatory cytokine but did not rectify cell damage or metabolic depression. The results indicate, that CA, present in common plants of the Asteraceae family, proves to be a beneficial hepatoprotective, and along with NAC, an immunomodulatory supplement in vitro under a stimulus mimicking viral infection.}, }
@article {pmid35739993, year = {2022}, author = {Zhu, Q and Liu, X and Zhu, Q and Liu, Z and Yang, C and Wu, H and Zhang, L and Xia, X and Wang, M and Hao, H and Cui, Y and Zhang, G and Hill, MA and Flaker, GC and Zhou, S and Liu, Z}, title = {N-Acetylcysteine Enhances the Recovery of Ischemic Limb in Type-2 Diabetic Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {6}, pages = {}, pmid = {35739993}, issn = {2076-3921}, support = {NIH HL124122/NH/NIH HHS/United States ; }, abstract = {Critical limb ischemia (CLI) is a severe complication of diabetes mellitus that occurs without effective therapy. Excessive reactive oxygen species (ROS) production and oxidative stress play critical roles in the development of diabetic cardiovascular complications. N-acetylcysteine (NAC) reduces ischemia-induced ROS production. The present study aimed to investigate the effect of NAC on the recovery of ischemic limb in an experimental model of type-2 diabetes. TALLYHO/JngJ diabetic and SWR/J non-diabetic mice were used for developing a CLI model. For NAC treatment, mice received NAC (1 mg/mL) in their drinking water for 24 h before initiating CLI, and continuously for the duration of the experiment. Blood flow, mechanical function, histology, expression of antioxidant enzymes including superoxide dismutase (SOD)-1, SOD-3, glutathione peroxidase (Gpx)-1, catalase, and phosphorylated insulin receptor substrate (IRS)-1, Akt, and eNOS in ischemic limb were evaluated in vivo or ex vivo. Body weight, blood glucose, plasma advanced glycation end-products (AGEs), plasma insulin, insulin resistance index, and plasma TNF-a were also evaluated during the experiment. NAC treatment effectively attenuated ROS production with preserved expressions of SOD-1, Gpx-1, catalase, phosphorylated Akt, and eNOS, and enhanced the recovery of blood flow and function of the diabetic ischemic limb. NAC treatment also significantly decreased the levels of phosphorylated IRS-1 (Ser307) expression and plasma TNF-α in diabetic mice without significant changes in blood glucose and AGEs levels. In conclusion, NAC treatment enhanced the recovery of blood flow and mechanical function in ischemic limbs in T2D mice in association with improved tissue redox/inflammatory status and insulin resistance.}, }
@article {pmid35739949, year = {2022}, author = {Iciek, M and Bilska-Wilkosz, A and Kozdrowicki, M and Górny, M}, title = {Reactive Sulfur Compounds in the Fight against COVID-19.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {6}, pages = {}, pmid = {35739949}, issn = {2076-3921}, abstract = {The SARS-CoV-2 coronavirus pandemic outbreak in 2019 resulted in the need to search for an effective and safe strategy for treating infected patients, relieving symptoms, and preventing severe disease. SARS-CoV-2 is an RNA virus that can cause acute respiratory failure and thrombosis, as well as impair circulatory system function. Permanent damage to the heart muscle or other cardiovascular disorders may occur during or after the infection. The severe course of the disease is associated with the release of large amounts of pro-inflammatory cytokines. Due to their documented anti-inflammatory, antioxidant, and antiviral effects, reactive sulfur compounds, including hydrogen sulfide (H2S), lipoic acid (LA), N-acetylcysteine (NAC), glutathione (GSH), and some other lesser-known sulfur compounds, have attracted the interest of scientists for the treatment and prevention of the adverse effects of diseases caused by SARS-CoV-2. This article reviews current knowledge about various endogenous or exogenous reactive sulfur compounds and discusses the possibility, or in some cases the results, of their use in the treatment or prophylaxis of COVID-19.}, }
@article {pmid35739442, year = {2022}, author = {Chen, J and Yao, Y and Wang, Y and Wang, X and Peng, X and Li, T and Liu, Y and Du, J}, title = {Autophagy triggered by the ROS/ERK signaling pathway protects mouse embryonic palatal cells from apoptosis induced by nicotine.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {54}, pages = {81909-81922}, pmid = {35739442}, issn = {1614-7499}, support = {81570940//the National Natural Science Foundation of China/ ; 81873706//the National Natural Science Foundation of China/ ; 82170912//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; Mice ; Reactive Oxygen Species/metabolism ; Nicotine/pharmacology ; MAP Kinase Signaling System ; Acetylcysteine/pharmacology ; *Cleft Lip ; *Electronic Nicotine Delivery Systems ; Osteogenesis ; Teratogens ; *Cleft Palate/chemically induced ; Autophagy ; Apoptosis ; Signal Transduction ; Microtubule-Associated Proteins/metabolism ; Chloroquine/pharmacology ; }, abstract = {Maternal cigarette smoking during pregnancy is a known high-risk factor for having a child with a cleft lip and/or palate (CLP), a common congenital malformation. Nicotine is the major teratogen component of cigarettes and e-cigarettes, and nicotine plays an important role in the development of CLP. However, the mechanism underlying nicotine's effect on CLP remains unclear. Here, we aimed to determine the role and molecular mechanisms of nicotine-induced autophagy, an important process involved in regulating the cellular stress response in mouse embryonic palatal cells (MEPCs). First, we found that nicotine promoted MEPCs proliferation and inhibited their apoptosis from 0 to 12 h. After 12 h, the proliferation was inhibited, and apoptosis was promoted. The migration of MEPCs was also inhibited by nicotine. Simultaneously, long-term nicotine stimulation inhibited the osteogenic differentiation of MEPCs. We then found that nicotine significantly increased autophagy flux in MEPCs at 12 h by increasing the expression of microtubule-associated protein light chain 3 (LC3) and reducing P62 expression levels. After nicotine exposure, intracellular reactive oxygen species (ROS) and extracellular signal-regulated kinase-1/2 (ERK1/2) expression significantly increased, and the expression of ERK1/2 was reversed by the ROS scavenging agent N-acetylcysteine (NAC). Moreover, the autophagy induced by nicotine was reversed by SCH772984, a specific inhibitor of ERK1/2, and the autophagy inhibitor chloroquine (CQ). These results suggest that in the early stage of nicotine exposure, MEPCs may trigger autophagy through the ROS/ERK1/2 signaling pathway to avoid cell damage caused by nicotine.}, }
@article {pmid35738838, year = {2022}, author = {Ok, SH and Ahn, SH and Lee, SH and Kim, HJ and Sim, G and Park, JK and Sohn, JT}, title = {Lipid emulsion attenuates propranolol-induced early apoptosis in rat cardiomyoblasts.}, journal = {Human &amp; experimental toxicology}, volume = {41}, number = {}, pages = {9603271221110852}, doi = {10.1177/09603271221110852}, pmid = {35738838}, issn = {1477-0903}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Caspase 3 ; Emulsions/pharmacology ; Lipids/pharmacology ; *Propranolol/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: Propranolol is used to treat several cardiovascular diseases; however, toxic doses of propranolol cause severe myocardial depression and cardiac arrest. The aim of this study was to examine the effects of lipid emulsion (LE) on cardiotoxicity induced by toxic doses of propranolol in H9C2 rat cardiomyoblast cell line and to elucidate the underlying mechanism.<br><br>METHODS: The experimental groups comprised control, propranolol alone, esmolol alone, or LE followed by propranolol or esmolol treatment, and reactive oxygen species (ROS) inhibitor N-acetyl-L-cysteine (NAC) followed by propranolol treatment. The effects of propranolol, esmolol, NAC, and LE, alone or in combination, on cell viability, apoptosis, and ROS production were examined. Additionally, we investigated the effect of LE on propranolol concentration.<br><br>RESULTS: LE and NAC reversed the inhibition of cell viability induced by propranolol (p < .001). However, LE had no effect on the inhibition of cell viability caused by esmolol. The LE inhibited propranolol-induced expressions of cleaved caspase-3 (p < .001), caspase-9 (p < .001), and Bax (p < .01), but not caspase-8. NAC inhibited the propranolol-induced expression of cleaved caspase-3. LE inhibited propranolol-induced early apoptosis, but had no effect on late apoptosis. Additionally, LE inhibited the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells generated by propranolol. It attenuated propranolol-induced ROS production. However, it had no effect on propranolol concentration.<br><br>CONCLUSION: LE inhibits early apoptosis caused by a toxic dose of propranolol by suppressing the intrinsic apoptotic pathway, via direct inhibition of ROS production.}, }
@article {pmid35735984, year = {2022}, author = {Valzano, F and Boncompagni, SR and Micieli, M and Di Maggio, T and Di Pilato, V and Colombini, L and Santoro, F and Pozzi, G and Rossolini, GM and Pallecchi, L}, title = {Activity of N-Acetylcysteine Alone and in Combination with Colistin against Pseudomonas aeruginosa Biofilms and Transcriptomic Response to N-Acetylcysteine Exposure.}, journal = {Microbiology spectrum}, volume = {10}, number = {4}, pages = {e0100622}, pmid = {35735984}, issn = {2165-0497}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Biofilms ; Colistin/pharmacology/therapeutic use ; *Cystic Fibrosis ; Disease Progression ; Humans ; Microbial Sensitivity Tests ; *Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa/genetics ; Transcriptome ; }, abstract = {Chronic colonization by Pseudomonas aeruginosa is critical in cystic fibrosis (CF) and other chronic lung diseases, contributing to disease progression. Biofilm growth and a propensity to evolve multidrug resistance phenotypes drastically limit the available therapeutic options. In this perspective, there has been growing interest in evaluating combination therapies, especially for drugs that can be administered by nebulization, which allows high drug concentrations to be reached at the site of infections while limiting systemic toxicity. Here, we investigated the potential antibiofilm activity of N-acetylcysteine (NAC) alone and in combination with colistin against a panel of P. aeruginosa strains (most of which are from CF patients) and the transcriptomic response of a P. aeruginosa CF strain to NAC exposure. NAC alone (8,000 mg/L) showed a limited and strain-dependent antibiofilm activity. Nonetheless, a relevant antibiofilm synergism of NAC-colistin combinations (NAC at 8,000 mg/L plus colistin at 2 to 32 mg/L) was observed with all strains. Synergism was also confirmed with the artificial sputum medium model. RNA sequencing of NAC-exposed planktonic cultures revealed that NAC (8,000 mg/L) mainly induced (i) a Zn[2+] starvation response (known to induce attenuation of P. aeruginosa virulence), (ii) downregulation of genes of the denitrification apparatus, and (iii) downregulation of flagellar biosynthesis pathway. NAC-mediated inhibition of P. aeruginosa denitrification pathway and flagellum-mediated motility were confirmed experimentally. These findings suggested that NAC-colistin combinations might contribute to the management of biofilm-associated P. aeruginosa lung infections. NAC might also have a role in reducing P. aeruginosa virulence, which could be relevant in the very early stages of lung colonization. IMPORTANCE Pseudomonas aeruginosa biofilm-related chronic lung colonization contributes to cystic fibrosis (CF) disease progression. Colistin is often a last-resort antibiotic for the treatment of such P. aeruginosa infections, and it has been increasingly used in CF, especially by nebulization. N-acetylcysteine (NAC) is a mucolytic agent with antioxidant activity, commonly administered with antibiotics for the treatment of lower respiratory tract infections. Here, we show that NAC potentiated colistin activity against in vitro biofilms models of P. aeruginosa strains, with both drugs tested at the high concentrations achievable after nebulization. In addition, we report the first transcriptomic data on the P. aeruginosa response to NAC exposure.}, }
@article {pmid35730047, year = {2022}, author = {Sengupta, P and Dutta, S}, title = {N-acetyl cysteine as a potential regulator of SARS-CoV-2-induced male reproductive disruptions.}, journal = {Middle East Fertility Society journal}, volume = {27}, number = {1}, pages = {14}, pmid = {35730047}, issn = {1110-5690}, abstract = {BACKGROUND: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), has shown its persistent pandemic strength. This viral infectivity, kinetics, and the mechanisms of its actions in human body are still not completely understood. In addition, the infectivity and COVID-19 severity reportedly differ with patient's gender with men being more susceptible to the disease. Thus, different studies have also suggested the adverse impact of COVID-19 on male reproductive functions, mainly emphasizing on high expressions of angiotensin-converting enzyme 2 (ACE2) in the testes that allows the viral entry into the cells.<br><br>MAIN BODY: The N-acetylcysteine (NAC), a potent therapeutic agent of COVID-19, may be effective in reducing the impairing impacts of this disease on male reproductive functions. NAC acts as mucolytic agent by reducing sulfide bonds in the cross-linked glycoprotein matrix in mucus owing to its free sulfhydryl group. Since NAC also breaks the viral disulfide bonds required for the host cell invasion, it may help to prevent direct SARS-CoV-2 invasion into the testicular cells as well. NAC also acts as a potent anti-inflammatory and antioxidant, directly scavenging reactive oxygen species (ROS) and regulating the redox state by maintaining the thiol pool being a precursor of cysteine (an essential substrate for glutathione synthesis). Since it is suggested that male reproductive impairment in COVID-19 patient may be caused by secondary immune responses owing to systemic inflammation and OS, the anti-inflammatory and antioxidant properties of NAC explained above may attribute in protecting the male reproduction functions from these COVID-19-mediated damages.<br><br>CONCLUSION: This article explains the mechanisms how NAC treatment for COVID-19 may prevent the infection-mediated disruptions in male reproduction.}, }
@article {pmid35725091, year = {2022}, author = {Ding, S and Wu, M and Xiao, R and Fang, C and Wang, Q and Xu, B and Chu, W}, title = {Evaluation of N-acetylcysteine and glutathione as quenching agents for the analysis of halogenated disinfection by-products.}, journal = {Journal of environmental sciences (China)}, volume = {117}, number = {}, pages = {71-79}, doi = {10.1016/j.jes.2022.01.033}, pmid = {35725091}, issn = {1001-0742}, mesh = {Acetylcysteine/analysis ; *Disinfectants/analysis ; Disinfection/methods ; *Drinking Water/analysis ; Glutathione ; Halogenation ; *Water Pollutants, Chemical/analysis ; *Water Purification/methods ; }, abstract = {Disinfection by-products (DBPs), formed from the reactions of disinfectants with natural organic matter and halides in drinking water, were considered to be cytotoxic and genotoxic, and might trigger various cancers. The relatively low concentration of DBPs in finished water (low µg/L or even ng/L levels) and the interference from water matrix inhibited in situ determination of DBPs. Moreover, the further formation and degradation of DBPs by disinfectants during the holding time (several hours to several days) from sample collection to analysis could adversely affect the determination of DBPs. To obtain accurate, precise and reliable data of DBP occurrence and formation, robust and reliable sample preservation is indispensable. However, the commonly used quenching agents (e.g., sodium sulfite, sodium thiosulfate, and ascorbic acid) for sample preservation can decompose reactive DBPs by reductive dehalogenation. This study evaluated the performance of N-acetylcysteine (NAC) and glutathione (GSH) as quenching agents for the analysis of halogenated DBPs by investigating the stoichiometry of the disinfectant-quenching agent reaction, the formation of DBPs during chlor(am)ination of NAC or GSH, and the effects of NAC or GSH on the stability of 18 individual DBPs and total organic halogen (TOX). Based on the results of this study, NAC and GSH were considered to be ideal quenching agents for the analysis of most DBPs and TOX, except halonitromethanes.}, }
@article {pmid35724513, year = {2022}, author = {Getsy, PM and Baby, SM and May, WJ and Lewis, THJ and Bates, JN and Hsieh, YH and Gaston, B and Lewis, SJ}, title = {L-NAC reverses of the adverse effects of fentanyl infusion on ventilation and blood-gas chemistry.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {153}, number = {}, pages = {113277}, pmid = {35724513}, issn = {1950-6007}, support = {P01 HL101871/HL/NHLBI NIH HHS/United States ; R61 HL154136/HL/NHLBI NIH HHS/United States ; U01 DA051373/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; *Analgesics, Opioid/adverse effects ; Animals ; *Fentanyl/adverse effects ; Humans ; Lysine/analogs &amp; derivatives ; Male ; Pain/chemically induced/drug therapy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {There is an urgent need for development of drugs that are able to reverse the adverse effects of opioids on breathing and arterial blood-gas (ABG) chemistry while preserving opioid analgesia. The present study describes the effects of bolus injections of N-acetyl-L-cysteine (L-NAC, 500 μmol/kg, IV) on ventilatory parameters, ABG chemistry, Alveolar-arterial (A-a) gradient, sedation (righting reflex) and analgesia status (tail-flick latency assay) in unanesthetized adult male Sprague Dawley rats receiving a continuous infusion of fentanyl (1 μg/kg/min, IV). Fentanyl infusion elicited pronounced disturbances in (1) ventilatory parameters (e.g., decreases in frequency of breathing, tidal volume and minute ventilation), (2) ABG chemistry (decreases in pH, pO2, sO2 with increases in pCO2), (3) A-a gradient (increases that were consistent with reduced alveolar gas exchange), and (4) sedation and analgesia. Bolus injections of L-NAC given 60 and 90 min after start of fentanyl infusion elicited rapid and sustained reversal of the deleterious effects of fentanyl infusion on ventilatory parameters and ABG chemistry, whereas they did not affect the sedative or analgesic effects of fentanyl. Systemic L-NAC is approved for human use, and thus our findings raise the possibility that this biologically active thiol may be an effective compound to combat opioid-induced respiratory depression in human subjects.}, }
@article {pmid35723848, year = {2022}, author = {Mamashli, M and Nasseri, S and Mohammadi, Y and Ayati, S and Zarban, A}, title = {Anti-inflammatory effects of N-Acetylcysteine and Elaeagnus angustifolia extract on acute lung injury induced by λ-carrageenan in rat.}, journal = {Inflammopharmacology}, volume = {30}, number = {5}, pages = {1759-1768}, pmid = {35723848}, issn = {1568-5608}, mesh = {Acetylcysteine/pharmacology ; *Acute Lung Injury/chemically induced/drug therapy/pathology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Carrageenan/pharmacology ; Cytokines ; *Elaeagnaceae/chemistry ; Free Radical Scavengers/pharmacology ; Interleukin-6 ; Lung ; Plant Extracts/pharmacology ; Rats ; Rats, Wistar ; Sulfhydryl Compounds/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {N-Acetylcysteine (NAC) is a chemical compound with anti-inflammatory and antioxidant activity and acts as a free radical scavenger. Elaeagnus angustifolia (EA) is a plant native to the western part of Iran, with antioxidant and anti-inflammatory properties. The present study been taken evaluated the protective effect afforded by EA and NAC extracts on carrageenan-induced acute lung injury in Wistar rats. In this study, 42 rats were randomly assigned into seven groups. NAC and EA extracts were orally administered once/day for 21 continuous days. Pulmonary damage was induced by intratracheal injection of 100 μl of 2% λ-Carrageenan on day 21. Twenty-four hours post-surgery, the rats were euthanized and the samples were collected. Pretreatment with NAC and EA extracts reduced the total and differential cell accumulation as well as IL-6, and TNF-α cytokines. Antioxidant indicators demonstrate that in the groups receiving NAC and EA extract, MDA decreased while thiol and antioxidant capacity elevated. Treatment with NAC and EA significantly reduced Carrageenan-induced pathological pulmonary tissue injury. NAC and EA extract has protective effects on acute carrageenan-induced lung injury.}, }
@article {pmid35723751, year = {2023}, author = {Martinho, FC and Corazza, BJM and Khoury, RD and Orozco, EIF and Toia, CC and Machado, FP and Valera, MC}, title = {Impact of N-acetylcysteine (NAC) and calcium hydroxide intracanal medications in primary endodontic infection: a randomized clinical trial.}, journal = {Clinical oral investigations}, volume = {27}, number = {2}, pages = {817-826}, pmid = {35723751}, issn = {1436-3771}, mesh = {Humans ; *Chlorhexidine/pharmacology/therapeutic use ; Calcium Hydroxide/pharmacology/therapeutic use ; Acetylcysteine/pharmacology ; Dental Pulp Cavity/microbiology ; Root Canal Irrigants/pharmacology/therapeutic use ; Bacteria ; *Periapical Periodontitis/drug therapy/microbiology ; Saline Solution ; DNA ; Root Canal Preparation ; }, abstract = {OBJECTIVES: This RCT investigated the impact of N-acetylcysteine (NAC) and calcium hydroxide [Ca(OH)2] intracanal medications (ICMs) in primary endodontic infection with apical periodontitis (PEIAP).<br><br>MATERIALS AND METHODS: Thirty-six teeth with PEIAP were randomly divided into groups according to the ICM: NAC, Ca(OH)2&#x2009;+&#x2009;saline solution (SSL), and Ca(OH)2&#x2009;+&#x2009;2% chlorhexidine-gel (2% CHX-gel) (all, n&#x2009;=&#x2009;12). Root canal samples (RCSs) were collected before (s1) and after instrumentation (s2) and after 14&#xa0;days of ICM (s3). Chemomechanical preparation (CMP) was performed with a Reciproc file and 2.5% NaOCl. Checkerboard DNA-DNA hybridization was used to assess 40 target bacteria species.<br><br>RESULTS: At s1, bacterial DNA was detected in 100% of RCSs (36/36). All 40 bacterial species were found in PEIAP. The mean number of species per RCS was 17.92&#x2009;&#xb1;&#x2009;13.18. The most frequent bacteria were S. mitis (65%), E. nodatum (63%), E. faecalis (63%), F. nucl sp vicentii (58%), T. forsythia (58%), and F. periodonticum (56%). CMP reduced the mean number of species per RCS to 6.8&#x2009;&#xb1;&#x2009;2.36 (p&#x2009;<&#x2009;0.05). At s3, the intragroup analysis revealed a broader antimicrobial activity for Ca (OH)2&#x2009;+&#x2009;2% CHX-gel and NAC than Ca(OH)2&#x2009;+&#x2009;SSL (p&#x2009;<&#x2009;0.05). NAC eliminated 8/12 bacteria species resistant to both Ca (OH)2 ICMs, including P. micra, P. nigrescens, T. denticola, A. israelii, P. endodontalis, P. acnes, C. ochracea, and E. corrodens.<br><br>CONCLUSIONS: Ca (OH)2&#x2009;+&#x2009;2% chlorhexidine gel (2% CHX gel) showed a greater bacterial elimination over the number of bacterial species; however, NAC eliminated 8/12 bacteria species resistant to both Ca (OH)2 ICMs (RBR-3xbnnn).<br><br>CLINICAL RELEVANCE: The use of intracanal medication with a broad antimicrobial activity can optimize root canal disinfection. Ca(OH)2&#x2009;+&#x2009;2% CHX gel and NAC showed a broader antimicrobial activity than Ca(OH)2&#x2009;+&#x2009;SSL against endodontic pathogens in primary root canal infection.<br><br>TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (REBEC), No. RBR-3xbnnn.}, }
@article {pmid35716031, year = {2022}, author = {Cui, Y and Li, B and Du, J and Huo, S and Song, M and Shao, B and Wang, B and Li, Y}, title = {Dibutyl phthalate causes MC3T3-E1 cell damage by increasing ROS to promote the PINK1/Parkin-mediated mitophagy.}, journal = {Environmental toxicology}, volume = {37}, number = {10}, pages = {2341-2353}, doi = {10.1002/tox.23600}, pmid = {35716031}, issn = {1522-7278}, support = {//Jilin Scientific and Technological Development Program/ ; }, mesh = {Acetylcysteine/pharmacology ; *Dibutyl Phthalate/toxicity ; *Mitophagy/genetics ; Protein Kinases/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Ubiquitin-Protein Ligases/genetics/metabolism ; }, abstract = {Dibutyl phthalate (DBP) is a plasticizer widely used in daily production, which causes serious environmental pollution, and damage to brain, liver, kidney, and lung by producing excessive reactive oxygen species (ROS) after entering the body. DBP can also cause skeletal dysplasia, but it is unclear whether ROS is involved. In addition, overproduction of ROS can activate mitophagy, which is an important mechanism for regulating mitochondrial quality and cell homeostasis. In order to investigate whether DBP can damage MC3T3-E1 cells (osteoblast cell line) and whether ROS and mitophagy are involved, DBP toxicity experiment, Parkin gene silencing experiment, and N-acetylcysteine (NAC) intervention experiment were performed on MC3T3-E1 cells in turn. First, we found that DBP caused MC3T3-E1 cell viability decline and osteogenic dysfunction, accompanied by the overproduction of ROS and the activation of mitophagy. Then, we found that silencing Parkin expression alleviated DBP-induced apoptosis and osteogenic dysfunction of MC3T3-E1 cells. In addition, NAC treatment inhibited the PINK1/Parkin-mediated mitophagy and alleviated the apoptosis and osteogenic dysfunction of MC3T3-E1 cells caused by DBP. Our research results showed that DBP could cause MC3T3-E1 cell damage by increasing ROS to promote the PINK1/Parkin-mediated mitophagy.}, }
@article {pmid35715620, year = {2022}, author = {Mizugaki, A and Kato, H and Takeda, T and Inoue, Y and Hasumura, M and Hasegawa, T and Murakami, H}, title = {Cystine reduces mitochondrial dysfunction in C2C12 myotubes under moderate oxidative stress induced by H2O2.}, journal = {Amino acids}, volume = {54}, number = {8}, pages = {1203-1213}, pmid = {35715620}, issn = {1438-2199}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Apoptosis ; *Cystine/pharmacology ; Glutathione/metabolism ; *Hydrogen Peroxide/metabolism/pharmacology ; Mitochondria/metabolism ; Muscle Fibers, Skeletal/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Moderate oxidative stress induces temporal impairment in mitochondrial ATP production. As glutathione (GSH) content is reduced to eliminate oxidative stress by oxidation-reduction reaction, intracellular GSH content is crucial for maintaining mitochondrial function under oxidative stress. GSH precursors such as N-acetyl cysteine (NAC) and cysteine are known to suppress oxidative stress based on the supply of cysteine residues being rate-limiting for GSH synthesis. However, it remains unclear whether cystine (Cys2) can suppress mitochondrial dysfunction under oxidative stress conditions. Therefore, we examined whether Cys2 could attenuate mitochondrial dysfunction under moderate oxidative stress without scavenging reactive oxygen species (ROS) in the medium. C2C12 myotubes were incubated for 120 min in a Cys2-supplemented medium and subsequently exposed to hydrogen peroxide (H2O2). Heme oxygenase-1 (HO-1) gene expression, intracellular cysteine and GSH content, intracellular ATP level, and maximal mitochondrial respiration were assessed. Cys2 treatment significantly increased GSH content in a dose-dependent manner under oxidative stress. Cys2 treatment significantly decreased HO-1 expression induced by H2O2 exposure. In addition, maximal mitochondrial respiration rate was decreased by H2O2 exposure, but improved by Cys2 treatment. In conclusion, Cys2 treatment mitigates oxidative stress-induced mitochondrial dysfunction by maintaining GSH content under moderate oxidative stress without scavenging ROS in the medium.}, }
@article {pmid35714510, year = {2022}, author = {Yue, Q and Zhang, W and Lin, S and Zheng, T and Hou, Y and Zhang, Y and Li, Z and Wang, K and Yue, L and Abay, B and Li, M and Fan, L}, title = {Ejiao ameliorates lipopolysaccharide-induced pulmonary inflammation via inhibition of NFκB regulating NLRP3 inflammasome and mitochondrial ROS.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {152}, number = {}, pages = {113275}, doi = {10.1016/j.biopha.2022.113275}, pmid = {35714510}, issn = {1950-6007}, mesh = {*Acute Lung Injury/chemically induced/drug therapy/metabolism ; Animals ; Caspase 1/metabolism ; Gelatin ; Inflammasomes/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; NF-KappaB Inhibitor alpha ; NF-kappa B ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Pneumonia/chemically induced/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {There is no effective treatment for acute lung injury (ALI) at present. Some studies have reported the anti-inflammatory effect of Ejiao, but no study has addressed the underlying action mechanism. In this study, the CCK8 assay displayed Ejiao had a protective effect against LPS-elicited inflammatory lung epithelial Beas 2B cells (LILEB 2B cells). Beas 2B cells treated with LPS and Ejiao were challenged with NFκB inhibitor Bay11-7082 and ROS scavenger N-acetyl cysteine (NAC) alone and in combination. The results of qRT-PCR, Western blotting and fluorescence labeling experiments using Bay11-7082 and NAC demonstrated Ejiao could significantly decrease the expression of p-p65 and p-IκBα in NFκB signaling pathway and its downstream NLRP3, ASC, Caspase-1 and IL-1β related to pyroptosis of LILEB 2B cells. Moreover, Ejiao reduced the production of mitochondrial ROS and reversed the change of mitochondrial membrane potential of LILEB 2B cells. Then, HE staining demonstrated Ejiao had a protective effect against the LPS-elicited ALI mouse model (LAMM). Ejiao also dramatically decreased the cell amount and the overall protein concentration of bronchoalveolar lavage fluid in LAMM. Immunohistochemical staining showed Ejiao remarkably reduced the expression of p-p65 and p-IκBα in NFκB signaling pathway and its downstream NLRP3, ASC, Caspase-1 and IL-1β. The ELISA of IL-1β revealed Ejiao could dose-dependably decrease the concentration of IL-1β in lung tissues, serum and BALF of LAMM. Finally, fluorescence labeling demonstrated Ejiao significantly reduced the mitochondrial ROS generation in the lung tissue of LAMM. This finding may afford a novel strategy for the precaution and therapy of ALI.}, }
@article {pmid35711363, year = {2022}, author = {Wang, Q and Park, KH and Geng, B and Chen, P and Yang, C and Jiang, Q and Yi, F and Tan, T and Zhou, X and Bian, Z and Ma, J and Zhu, H}, title = {MG53 Inhibits Necroptosis Through Ubiquitination-Dependent RIPK1 Degradation for Cardiac Protection Following Ischemia/Reperfusion Injury.}, journal = {Frontiers in cardiovascular medicine}, volume = {9}, number = {}, pages = {868632}, pmid = {35711363}, issn = {2297-055X}, abstract = {RATIONALE: While reactive oxygen species (ROS) has been recognized as one of the main causes of cardiac injury following myocardial infarction, the clinical application of antioxidants has shown limited effects on protecting hearts against ischemia-reperfusion (I/R) injury. Thus, the precise role of ROS following cardiac injury remains to be fully elucidated.<br><br>OBJECTIVE: We investigated the role of mitsugumin 53 (MG53) in regulating necroptosis following I/R injury to the hearts and the involvement of ROS in MG53-mediated cardioprotection.<br><br>METHODS AND RESULTS: Antioxidants were used to test the role of ROS in MG53-mediated cardioprotection in the mouse model of I/R injury and induced human pluripotent stem cells (hiPSCs)-derived cardiomyocytes subjected to hypoxia or re-oxygenation (H/R) injury. Western blotting and co-immunoprecipitation were used to identify potential cell death pathways that MG53 was involved in. CRISPR/Cas 9-mediated genome editing and mutagenesis assays were performed to further identify specific interaction amino acids between MG53 and its ubiquitin E3 ligase substrate. We found that MG53 could protect myocardial injury via inhibiting the necroptosis pathway. Upon injury, the generation of ROS in the infarct zone of the hearts promoted interaction between MG53 and receptor-interacting protein kinase 1 (RIPK1). As an E3 ubiquitin ligase, MG53 added multiple ubiquitin chains to RIPK1 at the sites of K316, K604, and K627 for proteasome-mediated RIPK1 degradation and inhibited necroptosis. The application of N-acetyl cysteine (NAC) disrupted the interaction between MG53 and RIPK1 and abolished MG53-mediated cardioprotective effects.<br><br>CONCLUSIONS: Taken together, this study provided a molecular mechanism of a potential beneficial role of ROS following acute myocardial infarction. Thus, fine-tuning ROS levels might be critical for cardioprotection.}, }
@article {pmid35710106, year = {2022}, author = {Yang, W and Guo, R and Pi, A and Ding, Q and Hao, L and Song, Q and Chen, L and Dou, X and Na, L and Li, S}, title = {Long non-coding RNA-EN_181 potentially contributes to the protective effects of N-acetylcysteine against non-alcoholic fatty liver disease in mice.}, journal = {The British journal of nutrition}, volume = {}, number = {}, pages = {1-15}, doi = {10.1017/S0007114522001829}, pmid = {35710106}, issn = {1475-2662}, abstract = {N-acetylcysteine (NAC) possesses a strong capability to ameliorate high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in mice, but the underlying mechanism is still unknown. Our study aimed to clarify the involvement of long non-coding RNA (lncRNA) in the beneficial effects of NAC on HFD-induced NAFLD. C57BL/6J mice were fed a normal-fat diet (10 % fat), a HFD (45 % fat) or a HFD plus NAC (2 g/l). After 14-week of intervention, NAC rescued the deleterious alterations induced by HFD, including the changes in body and liver weights, hepatic TAG, plasma alanine aminotransferase, plasma aspartate transaminase and liver histomorphology (haematoxylin and eosin and Oil red O staining). Through whole-transcriptome sequencing, 52 167 (50 758 known and 1409 novel) hepatic lncRNA were detected. Our cross-comparison data revealed the expression of 175 lncRNA was changed by HFD but reversed by NAC. Five of those lncRNA, lncRNA-NONMMUT148902·1 (NO_902·1), lncRNA-XR_001781798·1 (XR_798·1), lncRNA-NONMMUT141720·1 (NO_720·1), lncRNA-XR_869907·1 (XR_907·1), and lncRNA-ENSMUST00000132181 (EN_181), were selected based on an absolute log2 fold change value of greater than 4, P-value < 0·01 and P-adjusted value < 0·01. Further qRT-PCR analysis showed the levels of lncRNA-NO_902·1, lncRNA-XR_798·1, and lncRNA-EN_181 were decreased by HFD but restored by NAC, consistent with the RNA sequencing. Finally, we constructed a ceRNA network containing lncRNA-EN_181, 3 miRNA, and 13 mRNA, which was associated with the NAC-ameliorated NAFLD. Overall, lncRNA-EN_181 might be a potential target in NAC-ameliorated NAFLD. This finding enhanced our understanding of the biological mechanisms underlying the beneficial role of NAC.}, }
@article {pmid35706905, year = {2022}, author = {Chung, H and Lee, SW and Hyun, M and Kim, SY and Cho, HG and Lee, ES and Kang, JS and Chung, CH and Lee, EY}, title = {Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway.}, journal = {Frontiers in cell and developmental biology}, volume = {10}, number = {}, pages = {800574}, pmid = {35706905}, issn = {2296-634X}, abstract = {Podocyte loss is well known to play a critical role in the early progression of diabetic nephropathy. A growing number of studies are paying attention to necroptosis, a programmed form of cell necrosis as a mechanism of podocyte loss. Although necroptosis is a recently established concept, the significance of receptor interacting serine/threonine kinase 3 (RIPK3), a gene that encodes for the homonymous enzyme RIPK3 responsible for the progression of necroptosis, is well studied. Curcumin, a natural hydrophobic polyphenol compound responsible for the yellow color of Curcuma longa, has drawn attention due to its antioxidant and anti-inflammatory effects on cells prone to necroptosis. Nonetheless, effects of curcumin on high glucose-induced podocyte necroptosis have not been reported yet. Therefore, this study investigated RIPK3 expression in high glucose-treated podocytes to identify the involvement of necroptosis via the RIPK3 pathway and the effects of curcumin treatment on RIPK3-dependent podocytopathy in a hyperglycemic environment. The study discovered that increased reactive oxygen species (ROS) in renal podocytes induced by high glucose was improved after curcumin treatment. Curcumin treatment also significantly restored the upregulated levels of VEGF, TGF-β, and CCL2 mRNAs and the downregulated level of nephrin mRNA in cultured podocytes exposed to a high glucose environment. High glucose-induced changes in protein expression of TGF-β, nephrin, and CCL2 were considerably reverted to their original levels after curcumin treatment. Increased expression of RIPK3 in high glucose-stimulated podocytes was alleviated by curcumin treatment as well as N-acetyl cysteine (NAC, an antioxidant) or GSK'872 (a RIPK3 inhibitor). Consistent with this, the increased necroptosis-associated molecules, such as RIPK3, pRIPK3, and pMLKL, were also restored by curcumin in high glucose-treated mesangial cells. DCF-DA assay confirmed that such a result was attributed to the reduction of RIPK3 through the antioxidant effect of curcumin. Further observations of DCF-DA-sensitive intracellular ROS in NAC-treated and GSK'872-treated podocyte groups showed a reciprocal regulatory relationship between ROS and RIPK3. The treatment of curcumin and GSK'872 in podocytes incubated with high glucose protected from excessive intracellular superoxide anion production. Taken together, these results indicate that curcumin treatment can protect against high glucose-induced podocyte injuries by suppressing the abnormal expression of ROS and RIPK3. Thus, curcumin might be a potential therapeutic agent for diabetic nephropathy as an inhibitor of RIPK3.}, }
@article {pmid35704698, year = {2022}, author = {Chaudhari, S and Yazdizadeh Shotorbani, P and Tao, Y and Kasetti, R and Zode, G and Mathis, KW and Ma, R}, title = {Neogenin pathway positively regulates fibronectin production by glomerular mesangial cells.}, journal = {American journal of physiology. Cell physiology}, volume = {323}, number = {1}, pages = {C226-C235}, pmid = {35704698}, issn = {1522-1563}, support = {R01 DK115424/DK/NIDDK NIH HHS/United States ; R01 EY026177/EY/NEI NIH HHS/United States ; R01 EY028616/EY/NEI NIH HHS/United States ; R01 HL153703/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; *Diabetes Mellitus, Experimental/metabolism ; *Diabetic Nephropathies/genetics/metabolism ; Extracellular Matrix Proteins/genetics/metabolism ; Fibronectins/metabolism ; Glucose/metabolism ; *Membrane Proteins/genetics ; Mesangial Cells/metabolism ; Mice ; Transcription Factors/metabolism ; }, abstract = {Neogenin, a transmembrane receptor, was recently found in kidney cells and immune cells. However, the function of neogenin signaling in kidney is not clear. Mesangial cells (MCs) are a major source of extracellular matrix (ECM) proteins in glomerulus. In many kidney diseases, MCs are impaired and manifest myofibroblast phenotype. Overproduction of ECM by the injured MCs promotes renal injury and accelerates the progression of kidney diseases. The present study aimed to determine if neogenin receptor was expressed in MCs and if the receptor signaling regulated ECM protein production by MCs. We showed that neogenin was expressed in the glomerular MCs. Deletion of neogenin using CRISPR/Cas9 lentivirus system significantly reduced the abundance of fibronectin, an ECM protein. Netrin-1, a ligand for neogenin, also significantly decreased fibronectin production by MCs and decreased neogenin protein expression in MCs. Furthermore, treatment of human MCs with high glucose (HG, 25 mM) significantly increased the protein abundance of neogenin as early as 8 h. Consistently, neogenin expression in glomerulus significantly increased in the eNOS[-/-]db/db diabetic mice starting as early as the age of 8 wk and this increase sustained at least to the age of 24 wk. We further found that the HG-induced increase in neogenin abundance was blunted by antioxidant PEG-catalase and N-acetyl cysteine. Taken together, our results suggest a new mechanism of regulation of fibronectin production by MCs. This previously unrecognized neogenin-fibronectin pathway may contribute to glomerular injury responses during the course of diabetic nephropathy.}, }
@article {pmid35703373, year = {2022}, author = {Ahmadi Kahjoogh, H and Yazdanian, N and Behrangi, E and Roohaninasab, M and Hejazi, P and Goodarzi, A}, title = {Efficacy, safety, tolerability, and satisfaction of N-acetylcysteine and pentoxifylline in lichen planopilaris patients under treatment with topical clobetasol: A triple arm blinded randomized controlled trial.}, journal = {Dermatologic therapy}, volume = {35}, number = {8}, pages = {e15639}, doi = {10.1111/dth.15639}, pmid = {35703373}, issn = {1529-8019}, mesh = {Acetylcysteine/adverse effects ; Administration, Topical ; Adult ; Clobetasol/therapeutic use ; Female ; Humans ; *Lichen Planus/drug therapy ; Male ; Middle Aged ; Patient Satisfaction ; *Pentoxifylline/adverse effects ; Personal Satisfaction ; Treatment Outcome ; }, abstract = {Lichen planoplaris (LPP) is one of the most common causes of inflammatory cicatricial alopecias. There is no definitive cure for the disease and most of the available therapeutic options can potentially lead to serious complications following their use for extended durations. In this study, we aimed to evaluate the efficacy, safety and tolerability of N-acetylcysteine (NAC) and pentoxyfillin (PTX), as adjunctive therapies, in the management of LPP. In a randomized, assessor- and analyst-blinded controlled trial, patients with proven LPP were randomly assigned to three groups of 10. Group I (the control group) received clobetasol 0.05%lotion; Group II, a combination of clobetasol 0.05% lotion and oral PTX; Group III, a combination of clobetasol lotion 0.05% and oral NAC. Lichen planopilaris activity index (LPPAI), the possible side effects, tolerability and patients satisfaction were assessed before and two and four months after the initiation of the treatments. Thirty patients, 96.7% women, with a mean age of 46.8 ± 13.3 years old, were included in the study. Four months into the treatments, the overall LPPAI and the severity and/or frequency of most of its determinants significantly decreased in all groups. In a comparison among the groups, patients who received either of the combination therapies showed more decline in their LPPAI than those receiving only clobetasol. The decline was more noticeable and statistically significant only in the NAC group. Three patients in the PTX group developed complications that were not statistically significant when compared with the other groups. There were no substantial differences in the tolerability of the treatments among the study arms. The use of oral NAC and PTX added to the therapeutic efficacy of topical clobetasol in the treatment of LPP, suggesting that they might be beneficial and safe adjuvant therapies and add to the efficacy of topical treatment without any noticeable impact on the adverse effects experienced by patients.}, }
@article {pmid35699521, year = {2022}, author = {Biegański, P and Kovalski, E and Israel, N and Dmitrieva, E and Trzybiński, D and Woźniak, K and Vrček, V and Godel, M and Riganti, C and Kopecka, J and Lang, H and Kowalski, K}, title = {Electronic Coupling in 1,2,3-Triazole Bridged Ferrocenes and Its Impact on Reactive Oxygen Species Generation and Deleterious Activity in Cancer Cells.}, journal = {Inorganic chemistry}, volume = {61}, number = {25}, pages = {9650-9666}, pmid = {35699521}, issn = {1520-510X}, mesh = {*Antineoplastic Agents/chemistry ; *Carcinoma, Non-Small-Cell Lung ; Electronics ; Humans ; *Lung Neoplasms ; Metallocenes ; Reactive Oxygen Species/metabolism ; Triazoles/chemistry ; }, abstract = {Mixed-valence (MV) binuclear ferrocenyl compounds have long been studied as models for testing theories of electron transfer and in attempts to design molecular-scale electronic devices (e.g., molecular wires). In contrary to that, far less attention has been paid to MV binuclear ferrocenes as anticancer agents. Herein, we discuss the synthesis of six 1,2,3-triazole ferrocenyl compounds for combined (spectro)electrochemical, electron paramagnetic resonance (EPR), computational, and anticancer activity studies. Our synthetic approach was based on the copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition reaction and enabled us to obtain in one step compounds bearing either one, two, or three ferrocenyl entities linked to the common 1,2,3-triazole core. Thus, two series of complexes were obtained, which pertain to derivatives of 3'-azido-3'-deoxythymidine (AZT) and 3-azidopropionylferrocene, respectively. Based on the experimental and theoretical data, the two mono-oxidized species corresponding to binuclear AZT and trinuclear 3-azidopropionylferrocene complexes have been categorized as class II mixed-valence according to the classification proposed by Robin and Day. Of importance is the observation that these two compounds are more active against human A549 and H1975 non-small-cell lung cancer cells than their congeners, which do not show MV characteristics. Moreover, the anticancer activity of MV species competes or surpasses, dependent on the cell line, the activity of reference anticancer drugs such as cisplatin, tamoxifen, and 5-fluorouracil. The most active from the entire series of compounds was the binuclear thymidine derivative with the lowest IC50 value of 5 ± 2 μM against lung H1975 cancer cells. The major mechanism of antiproliferative activity for the investigated MV compounds is based on reactive oxygen species generation in cancer cells. This hypothesis was substantiated by EPR spin-trapping experiments and the observation of decreased anticancer activity in the presence of N-acetyl cysteine (NAC) free-radical scavenger.}, }
@article {pmid35698331, year = {2022}, author = {Sheng, Y and Sun, X and Han, J and Hong, W and Feng, J and Xie, S and Li, Y and Yan, F and Li, K and Tian, B}, title = {N-acetylcysteine functionalized chitosan oligosaccharide-palmitic acid conjugate enhances ophthalmic delivery of flurbiprofen and its mechanisms.}, journal = {Carbohydrate polymers}, volume = {291}, number = {}, pages = {119552}, doi = {10.1016/j.carbpol.2022.119552}, pmid = {35698331}, issn = {1879-1344}, mesh = {Acetylcysteine/chemistry/pharmacology ; Animals ; Chickens ; *Chitosan/chemistry ; Cornea/metabolism ; Female ; *Flurbiprofen/pharmacokinetics ; Oligosaccharides/metabolism/pharmacology ; Palmitic Acid ; Particle Size ; Rabbits ; }, abstract = {An N-acetylcysteine functionalized chitosan oligosaccharide-palmitic acid conjugate (NAC-COS-PA) with bioadhesive and permeation promoting properties was synthesized to enhance transocular drug delivery. Flurbiprofen (FB) loaded self-assembled NAC-COS-PA nanomicelles (NAC-COS-PA-FB) were prepared and the drug loading was 7.35 ± 0.32%. Human immortalized corneal epithelial (HCE-T) cell cytotoxicity and hen's egg test-chorioallantoic membrane assays confirmed that the conjugate had good biocompatibility. The transportation efficiency of coumarin-6 (C6) loaded nanomicelles in the HCE-T cell monolayer was approximately 1.97 times higher than that of free C6. Decreased intracellular Ca[2+] concentration and cell membrane potential, increased cell membrane fluidity, and reversible changes in the F-actin cytoskeleton are presumed to be responsible for the enhanced drug permeation. NAC-COS-PA exhibited strong binding capacity with mucin and rabbit eyeball. In vivo pharmacokinetics indicated that the area under the curve (AUC0-6 h) and the maximum concentration (Cmax) of NAC-COS-PA-FB were approximately 1.92 and 2.44 times that of the FB solution, respectively. NAC-COS-PA-FB demonstrated the best in vivo anti-inflammatory efficacy compared to unfunctionalized nanomicelles (COS-PA-FB) and FB solution. Consequently, NAC-COS-PA appears to be a promising bioadhesive carrier for ophthalmic delivery.}, }
@article {pmid35695627, year = {2022}, author = {Amid, R and Alamdari, MI and Kadkhodazadeh, M}, title = {Effect of Enamel Matrix Derivative and N-Acetyl Cysteine on Proliferation and Osteogenic Activity of Dental Pulp Stem Cells.}, journal = {Journal of long-term effects of medical implants}, volume = {32}, number = {2}, pages = {51-59}, doi = {10.1615/JLongTermEffMedImplants.2022040074}, pmid = {35695627}, issn = {1940-4379}, mesh = {*Acetylcysteine/pharmacology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Dental Pulp ; Humans ; *Osteogenesis ; Stem Cells ; }, abstract = {Successful bone regeneration often requires induction by signaling molecules. Enamel matrix derivative (EMD) is said to enhance initial phases of healing. N-acetyl cysteine (NAC) is a molecule assumed to enhance osteogenesis and induce osteoblastic differentiation. This study sought to compare effects of EMD and NAC on proliferation, mineralization, and enzymatic activity of dental pulp mesenchymal stem cells (DPSCs). DPSCs were cultured on mineralized bone allograft (MBA) powder. After 24 hours, EMD in concentrations of 10, 50, and 100 μg/mL and NAC in 5 mM concentration were added. Methyl thiazolyl tetrazolium (MTT) assay was used for cell proliferation assessment at 1, 2, and 3 days. Osteoblastic differentiation of DPSCs was evaluated at 30 days, by alizarin red staining and assessment of alkaline phosphatase (ALP) activity. Both EMD and NAC caused time-dependent reduction of cell proliferation compared with the negative control. Maximum proliferation of DPSCs was observed in the 10 μg/mL EMD group at all time points, whereas NAC caused higher ALP activity and mineralization of DPSCs compared with EMD. In vitro application of NAC, as a signaling molecule, may effectively enhance bone regeneration by the induction of mineralization and enzymatic activity, despite the resultant reduction in cell proliferation rate.}, }
@article {pmid35691282, year = {2022}, author = {Shahreki, E and Kaykhaei, MA and Mosallanezhad, Z and Adineh, Z and Mokhtari, AM and Mohammadi, M and Hosseini, R and Bazi, A}, title = {Effects of Selenium and/or N-Acetyl-Cysteine Supplementation on Nonthyroidal Illness Syndrome in Hemodialysis Patients: A Factorial Randomized Controlled Trial.}, journal = {Pharmacology}, volume = {107}, number = {9-10}, pages = {480-485}, doi = {10.1159/000525094}, pmid = {35691282}, issn = {1423-0313}, mesh = {Acetylcysteine/therapeutic use ; Dietary Supplements ; Humans ; Renal Dialysis/adverse effects ; *Selenium/pharmacology ; Thyrotropin ; }, abstract = {INTRODUCTION: Nonthyroidal illness syndrome (NTIS) is common in hemodialysis patients (HPs). However, limited clinical trials have been conducted in this field. Therefore, the aim of this study was to investigate the effect of Se and/or N-acetyl-cysteine (NAC) on NTIS parameters in HPs.<br><br>METHODS: In this factorial randomized controlled trial, 68 HPs were divided into four groups: group A received placebo of Se and NAC, group B received 600 &#x3bc;g per day of NAC and placebo of Se, group C received 200 &#x3bc;g of Se per day and placebo of NAC and group D received 200 &#x3bc;g of selenium and 600 &#x3bc;g of NAC per day for 12 weeks. Blood samples were taken at baseline and after 12 weeks to assess free tri-iodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), and reverse T3 (rT3) concentrations.<br><br>RESULTS: Our finding demonstrated that rT3 levels were decreased in B, C, and D groups and increased nearly to baseline levels in the A group after 12 weeks, with a marked difference between the groups (p < 0.001) based on ANOVA. Although there were no significant differences in FT3 (p = 0.39), FT4 (p = 0.76), and TSH (p = 0.71) between the groups at the end of the trial.<br><br>CONCLUSION: This trial showed that Se and/or NAC exert beneficial effects on rT3 levels in HPs. However, long-term clinical trials with a larger sample size using more appropriate biomarkers are recommended to evaluate the efficacy and safety of Se and/or NAC in HPs.}, }
@article {pmid35690339, year = {2022}, author = {Marni, R and Kundrapu, DB and Chakraborti, A and Malla, R}, title = {Insight into drug sensitizing effect of diallyl disulfide and diallyl trisulfide from Allium sativum L. on paclitaxel-resistant triple-negative breast cancer cells.}, journal = {Journal of ethnopharmacology}, volume = {296}, number = {}, pages = {115452}, doi = {10.1016/j.jep.2022.115452}, pmid = {35690339}, issn = {1872-7573}, mesh = {Allyl Compounds ; Antioxidants/pharmacology ; Apoptosis ; Cell Line, Tumor ; Disulfides ; *Garlic/chemistry ; Humans ; Paclitaxel/pharmacology ; Reactive Oxygen Species ; Sulfides/pharmacology ; *Triple Negative Breast Neoplasms/drug therapy ; }, abstract = {Ayurvedic practitioners and herbal healers in India and China have extensively used garlic (Allium sativum L.) to treat cancers. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are major volatile organosulfur phytochemical constituents found in garlic.<br><br>AIM OF THE STUDY: To find new insight into the drug sensitizing effect of DADS and DATS on paclitaxel (PTX)-resistant triple-negative breast cancer cells (TNBC/PR).<br><br>MATERIALS AND METHODS: This study estimates the non-toxic concentration of DADS and DATS against normal healthy breast epithelial cell line (MCF-12A) by using a trypan blue viability assay. Also, it evaluates the effect of DADS and DATS on the sensitization of established stable TNBC/PR cell clones (MDA-MB 231&#xa0;PR and MDA-MB 468&#xa0;PR) by MTT, BrdU incorporation, intracellular ROS, cell cycle, and apoptosis assays.<br><br>RESULTS: The results show that DADS and DATS are non-cytotoxicity against MCF-12A cells. Nevertheless, DADS and DATS have shown significantly high cytotoxicity against MDA-MB 231&#xa0;PR and MDA-MB 468&#xa0;PR cells. They also inhibited PTX-resistant cell proliferation by blocking the cell cycle. Further, they induced apoptosis by activation of caspase 3 and 9. N-acetyl cysteine pre-treatment inhibited DADS and DATS-induced intracellular ROS release. In silico study shows that DADS and DATS interact with a large extracellular loop (LEL) of CD151 with a binding energy of -4.0&#xa0;kcal/mol and transmembrane domain (TM) with a binding affinity of 11.7 and 13.6&#xa0;kcal/mol, respectively. They also inhibited the surface expression of CD151 in TNBC/PR cells.<br><br>CONCLUSION: This study implies that DADS and DATS could be considered for sensitizing drug-resistant breast cancers.}, }
@article {pmid35689653, year = {2022}, author = {Yang, X and Yang, P and Zhang, J and Yang, Y and Xiong, M and Shi, F and Li, N and Jin, Y}, title = {Silica nanoparticle exposure inhibits surfactant protein A and B in A549 cells through ROS-mediated JNK/c-Jun signaling pathway.}, journal = {Environmental toxicology}, volume = {37}, number = {9}, pages = {2291-2301}, doi = {10.1002/tox.23596}, pmid = {35689653}, issn = {1522-7278}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Apoptosis ; Genes, jun/genetics ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; *Lung/metabolism ; *Nanoparticles/toxicity ; *Pulmonary Surfactant-Associated Protein A/metabolism ; *Pulmonary Surfactant-Associated Protein B/metabolism ; Pulmonary Surfactants/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Silicon Dioxide/toxicity ; }, abstract = {Exposure to silica nanoparticles (SiNPs) is related to the dysregulation of pulmonary surfactant that maintains lung stability and function. Nevertheless, there are limited studies concerning the interaction and influence between SiNPs and pulmonary surfactant, and the damage and mechanism are still unclear. Herein, we used A549 cells to develop an in vitro model, with which we investigated the effect of SiNPs exposure on the expression of pulmonary surfactant and the potential regulatory mechanism. The results showed that SiNPs were of cytotoxicity in regarding of reduced cell viability and promoted the production of excessive reactive oxygen species (ROS). Additionally, the JNK/c-Jun signaling pathway was activated, and the expression of surfactant protein A (SP-A) and surfactant protein B (SP-B) was decreased. After the cells being treated with N-acetyl-L-cysteine (NAC), we found that the ROS content was effectively downregulated, and the expression of proteins related to JNK and c-Jun signaling pathways was suppressed. In contrast, the expression of SP-A and SP-B was enhanced. Furthermore, we treated the cells with JNK inhibitor and c-Jun-siRNA and found that the expression of protein related to JNK and c-Jun signaling pathways, as well as SP-A and SP-B, changed in line with that of NAC treatment. These findings suggest that SiNPs exposure can upregulate ROS and activate the JNK/c-Jun signaling pathway in A549 cells, thereby inhibiting the expression of SP-A and SP-B proteins.}, }
@article {pmid35684427, year = {2022}, author = {Papavasileiou, K and Tsiasioti, A and Tzanavaras, PD and Zacharis, CK}, title = {HPLC Determination of Colistin in Human Urine Using Alkaline Mobile Phase Combined with Post-Column Derivatization: Validation Using Accuracy Profiles.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {11}, pages = {}, pmid = {35684427}, issn = {1420-3049}, mesh = {Acetylcysteine ; Chromatography, High Pressure Liquid/methods ; *Colistin/urine ; Humans ; o-Phthalaldehyde ; }, abstract = {In this study, the development, validation, and application of a new liquid chromatography post-column derivatization method for the determination of Colistin in human urine samples is demonstrated. Separation of Colistin was performed using a core-shell C18 analytical column in an alkaline medium in order (i) to be compatible with the o-phthalaldehyde-based post-column derivatization reaction and (ii) to obtain better retention of the analyte. The Colistin derivative was detected spectrofluorometrically (λext/λem = 340/460 nm) after post-column derivatization with o-phthalaldehyde and N-acetyl cysteine. The post-column derivatization parameters were optimized using the Box-Behnken experimental design, and the method was validated using the total error concept. The β-expectation tolerance intervals did not exceed the acceptance criteria of ±15%, meaning that 95% of future results would be included in the defined bias limits. The limit of detection of the method was adequate corresponding to 100 nmol·L[-1]. The mean analytical bias (expressed as relative error) in the spiking levels was suitable, being in the range of -2.8 to +2.5% for both compounds with the percentage relative standard deviation lower than 3.4% in all cases. The proposed analytical method was satisfactorily applied to the analysis of the drug in human urine samples.}, }
@article {pmid35682881, year = {2022}, author = {Valent, I and Bednárová, L and Schreiber, I and Bujdák, J and Valachová, K and Šoltés, L}, title = {Reaction of N-Acetylcysteine with Cu[2+]: Appearance of Intermediates with High Free Radical Scavenging Activity: Implications for Anti-/Pro-Oxidant Properties of Thiols.}, journal = {International journal of molecular sciences}, volume = {23}, number = {11}, pages = {}, pmid = {35682881}, issn = {1422-0067}, support = {VEGA 2/0019/19//Scientific Grant Agency of the Ministry of Education of Slovak Republic and of Slovak Academy of Sciences/ ; CA17120//European Cooperation in Science and Technology/ ; }, mesh = {*Acetylcysteine ; Antioxidants ; Copper/chemistry ; Disulfides ; Oxidation-Reduction ; Oxygen/chemistry ; Reactive Oxygen Species ; *Sulfhydryl Compounds ; }, abstract = {We studied the kinetics of the reaction of N-acetyl-l-cysteine (NAC or RSH) with cupric ions at an equimolar ratio of the reactants in aqueous acid solution (pH 1.4−2) using UV/Vis absorption and circular dichroism (CD) spectroscopies. Cu2+ showed a strong catalytic effect on the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical (ABTSr) consumption and autoxidation of NAC. Difference spectra revealed the formation of intermediates with absorption maxima at 233 and 302 nm (ε302/Cu > 8 × 103 M−1 cm−1) and two positive Cotton effects centered at 284 and 302 nm. These intermediates accumulate during the first, O2-independent, phase of the NAC autoxidation. The autocatalytic production of another chiral intermediate, characterized by two positive Cotton effects at 280 and 333 nm and an intense negative one at 305 nm, was observed in the second reaction phase. The intermediates are rapidly oxidized by added ABTSr; otherwise, they are stable for hours in the reaction solution, undergoing a slow pH- and O2-dependent photosensitive decay. The kinetic and spectral data are consistent with proposed structures of the intermediates as disulfide-bridged dicopper(I) complexes of types cis-/trans-CuI2(RS)2(RSSR) and CuI2(RSSR)2. The electronic transitions observed in the UV/Vis and CD spectra are tentatively attributed to Cu(I) → disulfide charge transfer with an interaction of the transition dipole moments (exciton coupling). The catalytic activity of the intermediates as potential O2 activators via Cu(II) peroxo-complexes is discussed. A mechanism for autocatalytic oxidation of Cu(I)−thiolates promoted by a growing electronically coupled −[CuI2(RSSR)]n− polymer is suggested. The obtained results are in line with other reported observations regarding copper-catalyzed autoxidation of thiols and provide new insight into these complicated, not yet fully understood systems. The proposed hypotheses point to the importance of the Cu(I)−disulfide interaction, which may have a profound impact on biological systems.}, }
@article {pmid35681955, year = {2022}, author = {Lee, DK and Lipner, SR}, title = {The Potential of N-Acetylcysteine for Treatment of Trichotillomania, Excoriation Disorder, Onychophagia, and Onychotillomania: An Updated Literature Review.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {11}, pages = {}, pmid = {35681955}, issn = {1660-4601}, mesh = {Acetylcysteine/therapeutic use ; Compulsive Behavior ; Humans ; Nail Biting/therapy ; Retrospective Studies ; *Trichotillomania/drug therapy/psychology ; }, abstract = {BACKGROUND: Trichotillomania (TTM), excoriation disorder, onychophagia, and onychotillomania are categorized as body focused repetitive behavior (BFRB) disorders, causing damage to the skin, hair, and/or nails with clinically significant psychosocial consequences. Currently, there are no standardized treatments for these compulsive, self-induced disorders. Studies on treatment of these disorders using psychotropic drugs (i.e., selective serotonin reuptake inhibitors, tricyclic antidepressants, anticonvulsants) have shown variable efficacy. Recently, there is a growing interest in N-acetylcysteine (NAC) for treating BFRBs. NAC is a glutamate modulator that has shown promise in successfully reducing the compulsive behaviors in BFRB disorders. This article provides an updated review of the literature on the use of NAC in TTM, excoriation disorder, onychophagia, and onychotillomania.<br><br>METHODS: Relevant articles were searched in the PubMed/MEDLINE database.<br><br>RESULTS: Twenty-four clinical trials, retrospective cohort studies, and case reports assessing the efficacy of NAC in TTM, excoriation disorder, and onychophagia were included. No studies for onychotillomania were found in our search.<br><br>CONCLUSIONS: Although NAC has proven successful for treatment of BFRB disorders, data is derived from few clinical trials and case reports assessing small numbers of patients. Larger studies with longer durations are needed to fully establish the efficacy of NAC in these disorders.}, }
@article {pmid35677385, year = {2022}, author = {Wu, Y and Pi, D and Chen, Y and Zuo, Q and Zhou, S and Ouyang, M}, title = {Ginsenoside Rh4 Inhibits Colorectal Cancer Cell Proliferation by Inducing Ferroptosis via Autophagy Activation.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2022}, number = {}, pages = {6177553}, pmid = {35677385}, issn = {1741-427X}, abstract = {Colorectal cancer (CRC) is a severe threat to human health. Ginsenosides such as ginsenoside Rh4 have been widely studied in the antitumor field. Here, we investigated the antiproliferative activity and mechanism of Rh4 against CRC in vivo and in vitro. The CRC xenograft model showed that Rh4 inhibited xenograft tumor growth with few side effects (p < 0.05). As determined by MTT colorimetric assays, Western blotting, and immunohistochemical analysis, Rh4 effectively inhibited CRC cell proliferation through autophagy and ferroptosis (p < 0.05). Rh4 significantly upregulated autophagy and ferroptosis marker expression in CRC cells and xenograft tumor tissues in the present study (p < 0.05). Interestingly, the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed Rh4-induced ferroptosis (p < 0.05). Moreover, the autophagy inhibitor 3-methyladenine (3-MA) also reversed Rh4-induced ferroptosis (p < 0.05). These results indicate that Rh4-induced ferroptosis is regulated via the autophagy pathway. In addition, Rh4 increased reactive oxygen species (ROS) accumulation, leading to the activation of the ROS/p53 signaling pathway (p < 0.05). Transcriptome sequencing also confirmed this (p < 0.05). Moreover, the ROS scavenger N-acetyl-cysteine (NAC) reversed the inhibitory effect of Rh4 on CRC cells (p < 0.05). Therefore, this study proves that Rh4 inhibits cancer cell proliferation by activating the ROS/p53 signaling pathway and activating autophagy to induce ferroptosis, which provides necessary scientific evidence of the great anticancer potential of Rh4.}, }
@article {pmid35674828, year = {2022}, author = {Quinn, KM and Roberts, L and Cox, AJ and Borg, DN and Pennell, EN and McKeating, DR and Fisher, JJ and Perkins, AV and Minahan, C}, title = {Blood oxidative stress biomarkers in women: influence of oral contraception, exercise, and N-acetylcysteine.}, journal = {European journal of applied physiology}, volume = {122}, number = {8}, pages = {1949-1964}, pmid = {35674828}, issn = {1439-6327}, support = {112//Sport Performance Innovation and Knowledge Excellence unit, Queensland Academy of Sport/ ; }, mesh = {*Acetylcysteine/pharmacology ; Biomarkers ; Contraception ; Contraceptives, Oral/pharmacology ; Cross-Over Studies ; Double-Blind Method ; Female ; Humans ; Malondialdehyde ; *Oxidative Stress ; }, abstract = {PURPOSE: To compare physiological responses to submaximal cycling and sprint cycling performance in women using oral contraceptives (WomenOC) and naturally cycling women (WomenNC) and to determine whether N-acetylcysteine (NAC) supplementation mediates these responses.<br><br>METHODS: Twenty recreationally trained women completed five exercise trials (i.e., an incremental cycling test, a familiarisation trial, a baseline performance trial and two double-blind crossover intervention trials). During the intervention trials participants supplemented with NAC or a placebo 1 h before exercise. Cardiopulmonary parameters and blood biochemistry were assessed during 40 min of fixed-intensity cycling at 105% of gas-exchange threshold and after 1-km cycling time-trial.<br><br>RESULTS: WomenOC had higher ventilation (&#x3b2; [95% CI]&#x2009;=&#x2009;0.07 L&#xb7;min[-1] [0.01, 0.14]), malondialdehydes (&#x3b2;&#x2009;=&#x2009;12.00&#xa0;mmol&#xb7;L[-1] [6.82, 17.17]) and C-reactive protein (1.53&#xa0;mg&#xb7;L[-1] [0.76, 2.30]), whereas glutathione peroxidase was lower (&#x3b2;&#x2009;=&#x2009;&#xa0;22.62&#xa0;mU&#xb7;mL[-1] [-&#xa0;41.32, -&#xa0;3.91]) compared to WomenNC during fixed-intensity cycling. Plasma thiols were higher at all timepoints after NAC ingestion compared to placebo, irrespective of group (all p&#x2009;<&#x2009;0.001; d&#x2009;=&#x2009;1.45 to 2.34). For WomenNC but not WomenOC, the exercise-induced increase in malondialdehyde observed in the placebo trial was blunted after NAC ingestion, with lower values at 40&#xa0;min (p&#x2009;=&#x2009;0.018; d&#x2009;=&#x2009;0.73). NAC did not affect cycling time-trial performance.<br><br>CONCLUSIONS: Blood biomarkers relating to oxidative stress and inflammation are elevated in WomenOC during exercise. There may be an increased strain on the endogenous antioxidant system during exercise, since NAC supplementation in WomenOC did not dampen the exercise-induced increase in malondialdehyde. Future investigations should explore the impact of elevated oxidative stress on exercise adaptations or recovery from exercise in WomenOC.}, }
@article {pmid35666067, year = {2022}, author = {Yang, C and Zhang, X and Ge, X and He, C and Liu, S and Yang, S and Huang, C}, title = {N-Acetylcysteine protects against cobalt chloride-induced endothelial dysfunction by enhancing glucose-6-phosphate dehydrogenase activity.}, journal = {FEBS open bio}, volume = {12}, number = {8}, pages = {1475-1488}, pmid = {35666067}, issn = {2211-5463}, mesh = {*Acetylcysteine/pharmacology ; Cobalt ; Glucosephosphate Dehydrogenase/pharmacology ; Human Umbilical Vein Endothelial Cells ; Humans ; Hypoxia ; *Vascular Diseases ; }, abstract = {Hypoxia-induced endothelial dysfunction is known to be involved in the pathogenesis of several vascular diseases. However, it remains unclear whether the pentose phosphate pathway (PPP) is involved in regulating the response of endothelial cells to hypoxia. Here, we established an in vitro model by treating EA.hy926 (a hybrid human umbilical vein cell line) with cobalt chloride (CoCl2 ; a chemical mimic that stabilizes HIF-1α, thereby leading to the development of hypoxia), and used this to investigate the involvement of PPP by examining expression of its key enzyme, glucose-6-phosphate dehydrogenase (G6PD). We report that CoCl2 induces the accumulation of HIF-1α, leading to endothelial cell dysfunction characterized by reduced cell viability, proliferation, tube formation, and activation of cytokine production, accompanied with a significant decrease in G6PD expression and activity. The addition of 6-aminonicotinamide (6-AN) to inhibit PPP directly causes endothelial dysfunction. Additionally, N-Acetylcysteine (NAC), a precursor of glutathione, was further evaluated for its protective effects; NAC displayed a protective effect against CoCl2 -induced cell damage by enhancing G6PD activity, and this was abrogated by 6-AN. The effects of CoCl2 and the involvement of G6PD in endothelial dysfunction have been confirmed in primary human aortic endothelial cells. In summary, G6PD was identified as a novel target of CoCl2 -induced damage, which highlighted the involvement of PPP in regulating the response of endothelial cell CoCl2 . Treatment with NAC may be a potential strategy to treat hypoxia or ischemia, which are widely observed in vascular diseases.}, }
@article {pmid35663445, year = {2022}, author = {Park, C and Choi, EO and Hwangbo, H and Lee, H and Jeong, JW and Han, MH and Moon, SK and Yun, SJ and Kim, WJ and Kim, GY and Hwang, HJ and Choi, YH}, title = {Induction of apoptotic cell death in human bladder cancer cells by ethanol extract of Zanthoxylum schinifolium leaf, through ROS-dependent inactivation of the PI3K/Akt signaling pathway.}, journal = {Nutrition research and practice}, volume = {16}, number = {3}, pages = {330-343}, pmid = {35663445}, issn = {1976-1457}, abstract = {BACKGROUND/OBJECTIVES: Zanthoxylum schinifolium is traditionally used as a spice for cooking in East Asian countries. This study was undertaken to evaluate the anti-proliferative potential of ethanol extracts of Z. schinifolium leaves (EEZS) against human bladder cancer T24 cells.<br><br>MATERIALS/METHODS: Subsequent to measuring the cytotoxicity of EEZS, the anti-cancer activity was measured by assessing apoptosis induction, reactive oxygen species (ROS) generation, and mitochondrial membrane potential (MMP). In addition, we determined the underlying mechanism of EEZS-induced apoptosis through various assays, including Western blot analysis.<br><br>RESULTS: EEZS treatment concentration-dependently inhibited T24 cell survival, which is associated with apoptosis induction. Exposure to EEZS induced the expression of Fas and Fas-ligand, activated caspases, and subsequently resulted to cleavage of poly (ADP-ribose) polymerase. EEZS also enhanced the expression of cytochrome c in the cytoplasm by suppressing MMP, following increase in the ratio of Bax:Bcl-2 expression and truncation of Bid. However, EEZS-mediated growth inhibition and apoptosis were significantly diminished by a pan-caspase inhibitor. Moreover, EEZS inhibited activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, and the apoptosis-inducing potential of EEZS was promoted in the presence of PI3K/Akt inhibitor. In addition, EEZS enhanced the production of ROS, whereas N-acetyl cysteine (NAC), a ROS scavenger, markedly suppressed growth inhibition and inactivation of the PI3K/Akt signaling pathway induced by EEZS. Furthermore, NAC significantly attenuated the EEZS-induced apoptosis and reduction of cell viability.<br><br>CONCLUSIONS: Taken together, our results indicate that exposure to EEZS exhibits anti-cancer activity in T24 bladder cancer cells through ROS-dependent induction of apoptosis and inactivation of the PI3K/Akt signaling pathway.}, }
@article {pmid35661979, year = {2022}, author = {Bhattarai, N and Hytti, M and Reinisalo, M and Kaarniranta, K and Mysore, Y and Kauppinen, A}, title = {Hydroquinone predisposes for retinal pigment epithelial (RPE) cell degeneration in inflammatory conditions.}, journal = {Immunologic research}, volume = {70}, number = {5}, pages = {678-687}, pmid = {35661979}, issn = {1559-0755}, mesh = {*Ammonium Compounds/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Cells, Cultured ; Cysteine/metabolism/pharmacology ; Humans ; Hydroquinones/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/metabolism/pathology ; Retinal Pigments/metabolism/pharmacology ; *Tobacco Smoke Pollution ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {In addition to hypoxia, inflammation is capable of inducing vascular endothelial growth factor (VEGF) expression in human retinal pigment epithelial (RPE) cells. Excessive levels of VEGF promote choroidal neovascularization and thereby contribute to the pathogenesis of wet age-related macular degeneration (AMD). Intravitreal anti-VEGF injections ameliorate pathological vessel neoformation in wet AMD but excessive dampening of VEGF can result in a degeneration of the RPE. In the present study, we induced VEGF production by exposing human ARPE-19 cells to the pro-inflammatory IL-1α and subsequently to hydroquinone, a component of tobacco smoke that is a major environmental risk factor for AMD. Effects were monitored by measuring the levels of VEGF and anti-angiogenic pigment epithelium-derived factor (PEDF) using an enzyme-linked immunosorbent assay (ELISA) technique. In addition, we measured the production of reactive oxygen species (ROS) using the 2',7'-dichlorofluorescin diacetate (H2DCFDA) probe and studied the effects of two anti-oxidants, ammonium pyrrolidinedithiocarbamate (APDC) and N-acetyl-cysteine (NAC), on VEGF production. Cellular and secreted VEGF as well as secreted PEDF levels were reduced at all tested hydroquinone concentrations (10, 50, or 200 µM); these effects were evident prior to any reduction of cell viability evoked by hydroquinone. Cell viability was carefully explored in our previous study and verified by microscoping in the present study. APDC further reduced the VEGF levels, whereas NAC increased them. The 50 μM concentration of hydroquinone increased ROS production in ARPE-19 cells primed with IL-1α. Hydroquinone disturbs the regulatory balance of VEGF and PEDF in inflammatory conditions. These data support the idea that hydroquinone mediates RPE degeneration by reducing VEGF levels and may predispose to dry AMD since VEGF is as well important for retinal integrity.}, }
@article {pmid35661091, year = {2022}, author = {Savran, F and Karabulut, B and Yılmaz, AS and Surmeli, M and Guler, EM and Genc, S and Ihvan, A}, title = {Mucolytic and Antioxidant Effects of Intranasal Acetylcysteine Use on Acute Rhinosinusitis in Rats with an Acute Rhinosinusitis Model.}, journal = {ORL; journal for oto-rhino-laryngology and its related specialties}, volume = {84}, number = {6}, pages = {447-452}, doi = {10.1159/000524869}, pmid = {35661091}, issn = {1423-0275}, mesh = {Rats ; Animals ; Mice ; *Acetylcysteine/pharmacology ; *Antioxidants/pharmacology ; Expectorants/pharmacology ; Oxidative Stress ; Sulfhydryl Compounds/pharmacology ; }, abstract = {INTRODUCTION: The aim of this study was to investigate whether N-acetylcysteine (NAC) is effective in the treatment murine model of acute rhinosinusitis in rats.<br><br>MATERIALS AND METHODS: Twelve rats were included in the study. The left nasal cavity of all rats was infected with Streptococcus pneumoniae. Group 1 was the group in which NAC was administered into the left nasal cavity twice daily. Group 2 was selected as the control group. All rats were then sterilely sacrificed under anesthesia after intracardiac blood sampling. After sacrifice, sterile culture samples were collected from the posterior nasal cavity.<br><br>RESULTS: Total oxidant status and oxidative stress index (OSI), interleukin 1&#x3b2;, interleukin 6, and tumor necrosis factor &#x3b1; levels decreased significantly in the treatment group. Total antioxidant status was significantly increased. There was a statistically significant increase in total serum thiol levels and native thiol levels. Histopathologic evaluation showed a statistically significant decrease in submucosal gland hypertrophy in the treatment group.<br><br>CONCLUSION: According to our study, intranasal application of NAC can decrease the inflammatory findings in murine acute rhinosinusitis.}, }
@article {pmid35660452, year = {2022}, author = {Li, Q and Liao, J and Chen, W and Zhang, K and Li, H and Ma, F and Zhang, H and Han, Q and Guo, J and Li, Y and Hu, L and Pan, J and Tang, Z}, title = {NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway.}, journal = {Free radical biology &amp; medicine}, volume = {187}, number = {}, pages = {158-170}, doi = {10.1016/j.freeradbiomed.2022.05.024}, pmid = {35660452}, issn = {1873-4596}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; *Diabetes Mellitus/metabolism ; *Diabetic Nephropathies/drug therapy/genetics/metabolism ; Dogs ; *Ferroptosis/genetics ; Homeostasis ; *Insulins/metabolism/pharmacology ; Mammals/metabolism ; Mitochondria/metabolism ; Oxidation-Reduction ; *Sirtuin 3/genetics/metabolism ; }, abstract = {Diabetic nephropathy (DN) is known as a major microvascular complication in type 1 diabetes. The effect of insulin treatment alone on controlling blood glucose is unsatisfactory. N-acetylcysteine (NAC), a chemical agent with thiol group, is found to confer a protective effect in renal injury. However, whether NAC combined with insulin treatment can further enhance the therapeutic effect in DN remains unclear. Here, we firstly used large mammal beagle as DN model to explore the effect of NAC combined with insulin treatment on DN during 120 d. Our results showed that NAC further alleviated mitochondrial oxidative damage and ferroptosis by enhancing activity of mitochondria GSH and maintaining mitochondrial redox homeostasis in DN. Additionally, the upregulated acetylation level of SOD2 was further abrogated by NAC treatment. In MDCK cells, NAC reduced high glucose (HG)-caused ferroptosis via activating Gpx4 expression. Of note, inhibition of Gpx4 by FIN56 abolished the protective effects of NAC on HG-induced ferroptosis. More importantly, 3-TYP reversed the effect of NAC on the mitochondria ROS under HG treatment, as well as eliminated its following beneficial effects for ferroptosis against HG-stimulated cells. These results reveal that NAC attenuated ferroptosis in DN via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2-Gpx4 signaling pathway.}, }
@article {pmid35658749, year = {2022}, author = {Jin, S and Zhang, T and Fu, X and Duan, Z and Sun, J and Wang, Y}, title = {Aniline exposure activates receptor-interacting serine/threonineprotein kinase 1 and causes necroptosis of AML12 cells.}, journal = {Toxicology and industrial health}, volume = {38}, number = {8}, pages = {444-454}, doi = {10.1177/07482337221106751}, pmid = {35658749}, issn = {1477-0393}, mesh = {Aniline Compounds/toxicity ; Apoptosis ; *Chemical and Drug Induced Liver Injury ; Humans ; *Necroptosis ; Protein Serine-Threonine Kinases ; Reactive Oxygen Species/metabolism ; Serine ; }, abstract = {With the increased use of aniline, potential impacts on human health cannot be ignored. The hepatotoxicity of aniline is largely unknown and the underlying mechanism remains unclear. Therefore, the aim of the present study was to investigate the hepatotoxicity of aniline and elucidate the underlying mechanism. AML12 cells were exposed to different concentrations of aniline (0, 5, 10, or 20 mM) to observe changes to reactive oxygen species (ROS) production and the expression patterns of necroptosis-related proteins (RIPK1, RIPK3, and MLKL). The potential mechanism underlying aniline-induced hepatotoxicity was explored by knockout of RIPK1. The results showed that aniline induced cytotoxicity in AML12 cells in a dose-dependent manner in addition to the production of ROS and subsequent necroptosis of AML12 cells. Silencing of RIPK1 reversed upregulation of necroptosis-related proteins in AML12 cells exposed to aniline, demonstrating that aniline-induced ROS production was related to necroptosis of AML12. Moreover, aniline promoted intracellular RIPK1 activation, suggesting that the RIPK1/ROS pathway plays an important role in aniline-induced hepatotoxicity. NAC could quench ROS and inhibit necroptosis. These results provide a scientific basis for future studies of aniline-induced hepatotoxicity for the prevention and treatment of aniline-induced cytotoxicity.}, }
@article {pmid35657279, year = {2022}, author = {Choi, SM and Lee, PH and An, MH and Yun-Gi, L and Park, S and Baek, AR and Jang, AS}, title = {N-acetylcysteine decreases lung inflammation and fibrosis by modulating ROS and Nrf2 in mice model exposed to particulate matter.}, journal = {Immunopharmacology and immunotoxicology}, volume = {44}, number = {6}, pages = {832-837}, doi = {10.1080/08923973.2022.2086138}, pmid = {35657279}, issn = {1532-2513}, mesh = {Female ; Mice ; Animals ; Acetylcysteine/pharmacology ; Particulate Matter/toxicity ; *Pulmonary Fibrosis/chemically induced/drug therapy ; Hyperplasia ; *Pneumonia/chemically induced/drug therapy ; *Respiratory Hypersensitivity ; }, abstract = {Background and Objectives: Air pollutants can induce and incite airway diseases such as asthma. N-acetylcysteine (NAC) affects signaling pathways involved in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and the inflammatory response. However, it is not known how NAC change redox-regulated gene expression in asthma mouse model exposed to particulate matter (PM). To investigate the effects of NAC on asthma mice exposed to PM through Reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (Nrf2), and mucin 5 (Muc5).Methods: To investigate the effects of NAC (100 mg/kg) on redox-regulated gene expression and lung fibrosis in a mouse model of asthma exposed to PM. A mice model of asthma induced by ovalbumin (OVA) or OVA plus titanium dioxide (OVA + TiO2) was established using wild-type BALB/c female mice, and the levels of Nrf2 and mucin 5AC (Muc5ac) proteins following NAC treatment were examined by Western blotting and immunostaining. In addition, the protein levels of ROS were checked.Results: Airway hyperresponsiveness and inflammation, goblet cell hyperplasia, and lung fibrosis were higher in OVA, OVA + TiO2 mice than in control mice. NAC diminished OVA + TiO2-induced airway hyperresponsiveness and inflammation, goblet cell hyperplasia, and lung fibrosis. Levels of ROS, Nrf2, and Muc5ac protein were higher in lung tissue from OVA + TiO2 mice than that from control mice and were decreased by treatment with NAC.Conclusions: NAC reduce airway inflammation and responsiveness, goblet cell hyperplasia, and lung fibrosis by modulating ROS and Nrf2.}, }
@article {pmid35656297, year = {2022}, author = {Sanabria-Cabrera, J and Tabbai, S and Niu, H and Alvarez-Alvarez, I and Licata, A and Björnsson, E and Andrade, RJ and Lucena, MI}, title = {N-Acetylcysteine for the Management of Non-Acetaminophen Drug-Induced Liver Injury in Adults: A Systematic Review.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {876868}, pmid = {35656297}, issn = {1663-9812}, abstract = {Introduction: Idiosyncratic drug-induced liver injury (DILI) is a rare adverse reaction to drugs and other xenobiotics. DILI has different grades of severity and may lead to acute liver failure (ALF), for which there is no effective therapy. N-acetylcysteine (NAC) has been occasionally tested for the treatment of non-acetaminophen drug-induced ALF. However, limited evidence for its efficacy and safety is currently available. Our aim was to elucidate the benefit and safety of NAC in DILI and evaluate its hepatoprotective effect. Methods: We conducted a systematic review to evaluate the management and prevention focused on NAC in idiosyncratic DILI. The main outcomes included mortality due to DILI, time to normalization of liver biochemistry, transplant-free survival, and adverse events. We included clinical trials and observational studies, either prospective or retrospective. Results: A total of 11 studies were included after literature screening. All studies had different methodologies, and some of them had important risk of bias that may lead to interpreting their findings with caution. The majority of the studies proved NAC efficacy in a cohort of patients with ALF due to different etiologies, where DILI represented a subgroup. NAC seemed to improve transplant-free survival; however, its benefit was inconclusive in terms of overall survival. With regard to safety, NAC showed an adequate safety profile. In prevention studies, NAC showed a possible hepatoprotective effect; however, this finding is limited by the lack of studies and presence of bias. Conclusion: NAC treatment seems to have some benefit in non-acetaminophen drug-induced liver failure patients with acceptable safety; however, due to the lack of evidence and limitations detected across studies, its benefit must be corroborated in clinical trials with adequate methodology.}, }
@article {pmid35655853, year = {2022}, author = {Wang, S and Liu, G and Jia, T and Wang, C and Lu, X and Tian, L and Yang, Q and Zhu, C}, title = {Protection Against Post-resuscitation Acute Kidney Injury by N-Acetylcysteine via Activation of the Nrf2/HO-1 Pathway.}, journal = {Frontiers in medicine}, volume = {9}, number = {}, pages = {848491}, pmid = {35655853}, issn = {2296-858X}, abstract = {BACKGROUND AND OBJECTIVE: Acute kidney injury (AKI), the common complication after cardiopulmonary resuscitation (CPR), seriously affects the prognosis of cardiac arrest (CA) patients. However, there are limited studies on post-resuscitation AKI. In addition, it has been demonstrated that N-acetylcysteine (N-AC) as an ROS scavenger, has multiorgan-protective effects on systemic and regional ischaemia-reperfusion injuries. However, no studies have reported its protective effects against post-resuscitation AKI and potential mechanisms. This study aimed to clarify the protective effects of N-AC on post-resuscitation AKI and investigate whether its potential mechanism was mediated by activating Nrf-2/HO-1 pathway in the kidney.<br><br>METHODS: We established cardiac arrest models in rats. All animals were divided into four groups: the sham, control, N-AC, and ZnPP groups. Animals in each group except for the ZnPP group were assigned into two subgroups based on the survival time: 6 and 48 h. The rats in the control, N-AC, and ZnPP groups underwent induction of ventricular fibrillation (VF), 8 min untreated VF and cardiopulmonary resuscitation. Renal function indicators, were detected using commercial kits. Renal pathologic changes were assessed by haematoxylin-eosin (HE) staining. Oxidative stress and inflammatory responses were measured using the corresponding indicators. Apoptosis was evaluated using terminal uridine nick-end labeling (TUNEL) staining, and expression of proteins associated with apoptosis and the Nrf-2/HO-1 pathway was measured by western blotting.<br><br>RESULTS: N-AC inhibited post-resuscitation AKI. We observed that N-AC reduced the levels of biomarkers of renal function derangement; improved renal pathological changes; and suppressed apoptosis, oxidative stress, and inflammatory response. Additionally, the production of ROS in the kidneys markedly decreased by N-AC. More importantly, compared with the control group, N-AC further upregulated the expression of nuclear Nrf2 and endogenous HO-1 in N-AC group. However, N-AC-determined protective effects on post-resuscitation AKI were markedly reversed after pretreatment of the HO-1 inhibitor zinc protoporphyrin (ZnPP).<br><br>CONCLUSIONS: N-AC alleviated renal dysfunction and prolonged survival in animal models of CA. N-AC partially exerts beneficial renal protection via activation of the Nrf-2/HO-1 pathway. Altogether, all these findings indicated that N-AC as a common clinical agent, may have the potentially clinical utility to improve patients the outcomes in cardiac arrest.}, }
@article {pmid35647220, year = {2022}, author = {Popova, L and Mancuso, J}, title = {Dramatic Improvement of Trichotillomania with 6 Months of Treatment With N-Acetylcysteine.}, journal = {Global pediatric health}, volume = {9}, number = {}, pages = {2333794X221086576}, pmid = {35647220}, issn = {2333-794X}, abstract = {We present a case of a 17-year-old male with recurrent hair twirling resulting in patchy alopecia, who improved dramatically on N-acetylcysteine (NAC). Trichotillomania is characterized by repetitive hair pulling, twisting, or twirling and can vary from a mild habit to an impulse-control disorder. Standard treatment for pediatric trichotillomania includes cognitive behavioral therapy or medical therapy with selective serotonin reuptake inhibitors. NAC is a more recently utilized, safe, and well-tolerated over-the-counter supplement with some evidence of benefit for habitual skin and hair disorders. For this patient, we recommended 600 mg twice daily, increasing to 1200 mg twice daily as tolerated. After 6 months, our patient reported decreased desire to twirl his hair and his hair had almost completely regrown. Pediatricians who see patients with trichotillomania or other habitual disorders can consider treating these patients with NAC given its potential benefits and favorable side effect profile.}, }
@article {pmid35640855, year = {2022}, author = {Promsan, S and Thongnak, L and Pengrattanachot, N and Phengpol, N and Sutthasupha, P and Lungkaphin, A}, title = {Agomelatine, a structural analog of melatonin, improves kidney dysfunction through regulating the AMPK/mTOR signaling pathway to promote autophagy in obese rats.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {165}, number = {}, pages = {113190}, doi = {10.1016/j.fct.2022.113190}, pmid = {35640855}, issn = {1873-6351}, mesh = {AMP-Activated Protein Kinases/metabolism ; Acetamides ; Animals ; Autophagy ; *Insulin Resistance ; Kidney ; Male ; *Melatonin/pharmacology ; Naphthalenes ; Obesity/metabolism ; Rats ; Rats, Wistar ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {This study aimed to investigate the renoprotective effect of agomelatine on kidney injury in an obese rat model and to understand the underlying mechanisms involving the AMPK-mTOR-autophagy signaling pathway. Male Wistar rats were fed either a normal (ND) or a high-fat diet (HF) for 16 weeks. The HF rats were divided into 4 groups: (1) HF control; (2) AGOM20 receiving agomelatine 20 mg. kg[-1] day[-1]; (3) AGOM40 receiving agomelatine 40 mg. kg[-1] day[-1]; and (4) NAC receiving N-acetylcysteine 100 mg. kg[-1] day[-1] by oral gavage for 4 weeks. HF rats demonstrated insulin resistance, impaired renal function and oxidative stress as evidenced by the elevation of MDA levels and expression of PKCα and NOX4. These alterations correlated with impaired autophagy, renal fibrosis and apoptosis. Agomelatine showed a greater efficacy than NAC treatment with regard to improving insulin resistance, dyslipidemia and renal dysfunction through alleviation of oxidative stress, fibrosis and apoptosis in kidney cells. Impaired autophagy was blunted after agomelatine or NAC administration, as demonstrated by the increased in Beclin-1, LC3B, Atg5, LAMP2, and AMPK, and decreased mTOR and CTSB expression. These data revealed that agomelatine protected against obesity-induced kidney injury via the regulation of ROS and AMPK-mTOR-autophagy signaling pathways.}, }
@article {pmid35636024, year = {2022}, author = {Walker, H and Guthrie, GD and Lambourg, E and Traill, P and Zealley, I and Plumb, A and Bell, S}, title = {Systematic review and meta-analysis of prophylaxis use with intravenous contrast exposure to prevent contrast-induced nephropathy.}, journal = {European journal of radiology}, volume = {153}, number = {}, pages = {110368}, doi = {10.1016/j.ejrad.2022.110368}, pmid = {35636024}, issn = {1872-7727}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Contrast Media/adverse effects ; Humans ; *Kidney Diseases/chemically induced/prevention &amp; control ; *Renal Insufficiency/chemically induced ; Sodium Bicarbonate/adverse effects ; }, abstract = {PURPOSE: Iodinated radiographic contrast media has been associated with an acute deterioration in renal function, termed contrast induced nephropathy (CIN). This review aims to establish the efficacy of prophylaxis interventions used in adult patients prior to intravenous exposure to iodinated contrast to reduce the risk of CIN.<br><br>METHODS: An electronic search for published peer-reviewed articles was performed, supplemented with manual review of references from previous systematic reviews and the National Institute for Health and Care Excellence guidelines. Risk of bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias. Random-effect meta-analyses were used to assess CIN incidence, need for kidney replacement therapy (KRT), mortality, fluid overload and persistent kidney dysfunction.<br><br>RESULTS: 22 studies assessing a range of interventions were included in the qualitative analysis. The incidence of CIN was reduced by the use of N-acetylcysteine compared to a control group of saline (risk difference&#xa0;=&#xa0;-0.07, 95% CI -0.13 to -0.01) but not by sodium bicarbonate compared to control group of saline (risk difference&#xa0;=&#xa0;-0.02, 95% CI -0.04 to 0.01). Published studies give no indication that prophylactic interventions have significant impact on the need for KRT, mortality or persistent renal impairment.<br><br>CONCLUSION: Evidence for prophylaxis against CIN in patients receiving intravenous iodinated contrast is limited. There was an association with the use of NAC with reduced incidence of CIN following intravenous contrast but there was no impact on other clinical outcomes assessed. The clinical significance of these findings remains unclear and further research focusing on these clinical outcomes is required.}, }
@article {pmid35636015, year = {2022}, author = {Liu, W and Zhao, Y and Wang, G and Feng, S and Ge, X and Ye, W and Wang, Z and Zhu, Y and Cai, W and Bai, J and Zhou, X}, title = {TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling.}, journal = {Redox biology}, volume = {53}, number = {}, pages = {102344}, pmid = {35636015}, issn = {2213-2317}, mesh = {AMP-Activated Protein Kinases/genetics/metabolism ; Adolescent ; Autophagy/genetics ; *Bone Neoplasms ; Humans ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Minor Histocompatibility Antigens/pharmacology ; NF-E2-Related Factor 2/genetics/metabolism ; *Osteosarcoma/genetics ; Reactive Oxygen Species/metabolism ; Repressor Proteins/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Tripartite Motif Proteins/genetics/metabolism ; }, abstract = {Osteosarcoma (OS) is a malignant bone tumor that mainly occurs in adolescents. It is accompanied by a high rate of lung metastasis, and high mortality. Recent studies have suggested the important roles of tripartite motif-containing (TRIM) family proteins in regulating various substrates and signaling pathways in different tumors. However, the detailed functional role of TRIM family proteins in the progression of OS is still unknown and requires further investigations. In this study, we found that tripartite motif-containing 22 (TRIM22) was downregulated in OS tissues and was hence associated with better prognosis. In vitro and in vivo functional analysis demonstrated that TRIM22 inhibits proliferation and metastasis of OS cells. Nuclear factor erythroid 2-related factor 2 (NRF2), a redox regulator, was identified as a novel target for TRIM22. TRIM22 interacts with and accelerates the degradation of NRF2 by inducing its ubiquitination dependent on its E3 ligase activity but independent of Kelch-like ECH-associated protein 1 (KEAP1). Further, a series of gain- and loss-of-function experiments showed that knockdown or overexpression of NRF2 reversed the functions of knockdown or overexpression of TRIM22 in OS. Mechanistically, TRIM22 inhibited OS progression through NRF2-mediated intracellular reactive oxygen species (ROS) imbalance. ROS production was significantly promoted and mitochondrial potential was remarkably inhibited when overexpressing TRIM22, thus activating AMPK/mTOR signaling. Moreover, TRIM22 was also found to inhibit Warburg effect in OS cells. Autophagy activation was found in OS cells which were overexpressed TRIM22, thus leading to autophagic cell death. Treatment with N-Acetylcysteine (NAC), a ROS scavenger or the autophagy inhibitor 3-Methyladenine (3-MA) abolished the decreased malignant phenotypes in TRIM22 overexpressing OS cells. In conclusion, our study indicated that TRIM22 inhibits OS progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating ROS/AMPK/mTOR/Autophagy signaling that leads to autophagic cell death in OS. Therefore, our findings indicated that targeting TRIM22/NRF2 could be a promising therapeutic target for treating OS.}, }
@article {pmid35635082, year = {2022}, author = {Sun, Q and Zhen, P and Li, D and Liu, X and Ding, X and Liu, H}, title = {Amentoflavone promotes ferroptosis by regulating reactive oxygen species (ROS) /5'AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) to inhibit the malignant progression of endometrial carcinoma cells.}, journal = {Bioengineered}, volume = {13}, number = {5}, pages = {13269-13279}, pmid = {35635082}, issn = {2165-5987}, mesh = {AMP-Activated Protein Kinases/metabolism ; Biflavonoids ; *Endometrial Neoplasms ; Female ; *Ferroptosis ; Humans ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Thiobarbituric Acid Reactive Substances ; }, abstract = {It was reported that amentoflavone (AF) had anti-tumor ability. Therefore, this study aimed to investigate the role of AF in endometrial cancer as well as to discuss its underlying mechanism. The viability, proliferation, and apoptosis of endometrial carcinoma cells (KLE) with AF administration were detected by methyl tetrazolium (MTT) assay, clone formation, and terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assays. Thiobarbituric acid reactive substance (TBARS) production and Fe[2+] level in AF-treated KLE cells were detected by TBARS assay and Iron assay. The expressions of proliferation- apoptosis-, ferroptosis-, and 5'AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling-related proteins in AF-treated KLE cells were detected by western blot analysis. Reactive oxygen species (ROS) expression in AF-treated KLE cells was determined by ROS assay kit. N-acetyl cysteine (NAC), which is an inhibitor of ROS, was used to confirm whether AF exerted its effects on KLE cells through ROS/AMPK/mTOR signaling. As a result, AF inhibited the viability and proliferation of KLE cells but promoted apoptosis and ferroptosis. The expressions of ROS and AMPK were increased, while mTOR expression was decreased in AF-treated KLE cells. NAC reversed the effects of AF on biological behaviors of KLE cells by inactivating ROS/AMPK/mTOR signaling. In conclusion, AF promoted ferroptosis by activating ROS/AMPK/mTOR to inhibit the viability and proliferation and promoted the apoptosis and ferroptosis of KLE cells.}, }
@article {pmid35631736, year = {2022}, author = {He, W and Zhong, Q and He, B and Wu, B and Mohi Ud Din, A and Han, J and Ding, Y and Liu, Z and Li, W and Jiang, Y and Li, G}, title = {N-Acetylcysteine Priming Alleviates the Transplanting Injury of Machine-Transplanted Rice by Comprehensively Promoting Antioxidant and Photosynthetic Systems.}, journal = {Plants (Basel, Switzerland)}, volume = {11}, number = {10}, pages = {}, pmid = {35631736}, issn = {2223-7747}, support = {BE2021361; BE2019377//Key Research and Development Program of Jiangsu Province/ ; CX (18) 1002//Jiangsu Agriculture Science and Technology Innovation Fund/ ; }, abstract = {The stress of transplanting injury adversely affects rice growth and productivity worldwide. N-acetylcysteine (NAC), the precursor of glutathione, is a potent ROS scavenger with powerful antioxidant activity. Previous studies on the application of NAC in plants mainly focused on alleviating the stress of heavy metals, UV-B, herbicides, etc. However, the role of NAC in alleviating transplanting injury is still not clear. A barrel experiment was carried out to explain the mechanism of NAC regulating the transplanting injury to machine-transplanted rice during the recovery stage. The results showed that NAC priming shortened the time of initiation of tillering and increased the tiller numbers within 3 weeks after transplanting. In addition, NAC priming increased the chlorophyll content, net photosynthetic rate, and sucrose content, thereby improving the dry weight at the recovery stage, especially root dry weight. At the same time, NAC priming significantly increased the activity of ascorbate peroxidase (APX), glutathione reductase (GR), catalase (CAT), and superoxide dismutase (SOD). In addition, it also regulated flavonoids and total phenols contents to reduce hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents, especially at the initial days after transplanting. These results suggest that NAC priming improves the tolerance of rice seedlings against transplanting injury by enhancing photosynthesis and antioxidant systems at initial days after transplanting, thereby promoting the accumulation of dry matter and tillering for higher yield returns.}, }
@article {pmid35629355, year = {2022}, author = {Shih, SP and Lu, MC and El-Shazly, M and Lin, YH and Chen, CL and Yu, SS and Liu, YC}, title = {The Antileukemic and Anti-Prostatic Effect of Aeroplysinin-1 Is Mediated through ROS-Induced Apoptosis via NOX Activation and Inhibition of HIF-1a Activity.}, journal = {Life (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, pmid = {35629355}, issn = {2075-1729}, support = {MOST 110-2320-B-259-001-MY3&#xff1b;110-2314-B-037-083//Ministry of Science and Technology/ ; NHRI-110A1-CACO-03212109//National Health Research Institutes/ ; 111T2560-5//National Dong Hwa University/ ; }, abstract = {Aeroplysinin-1 is a brominated isoxazoline alkaloid that has exhibited a potent antitumor cell effect in previous reports. We evaluated the cytotoxicity of aeroplysinin-1 against leukemia and prostate cancer cells in vitro. This marine alkaloid inhibited the cell proliferation of leukemia Molt-4, K562 cells, and prostate cancer cells Du145 and PC-3 with IC50 values of 0.12 ± 0.002, 0.54 ± 0.085, 0.58 ± 0.109 and 0.33 ± 0.042 µM, respectively, as shown by the MTT assay. Furthermore, in the non-malignant cells, CCD966SK and NR8383, its IC50 values were 1.54 ± 0.138 and 6.77 ± 0.190 μM, respectively. In a cell-free system, the thermal shift assay and Western blot assay verified the binding affinity of aeroplysinin-1 to Hsp90 and Topo IIα, which inhibited their activity. Flow cytometry analysis showed that the cytotoxic effect of aeroplysinin-1 is mediated through mitochondria-dependent apoptosis induced by reactive oxygen species (ROS). ROS interrupted the cellular oxidative balance by activating NOX and inhibiting HIF-1α and HO-1 expression. Pretreatment with N-acetylcysteine (NAC) reduced Apl-1-induced mitochondria-dependent apoptosis and preserved the expression of NOX, HO-1, and HIF-1a. Our findings indicated that aeroplysinin-1 targeted leukemia and prostate cancer cells through multiple pathways, suggesting its potential application as an anti-leukemia and prostate cancer drug lead.}, }
@article {pmid35629096, year = {2022}, author = {Zisis, IE and Georgiadis, G and Docea, AO and Calina, D and Cercelaru, L and Tsiaoussis, J and Lazopoulos, G and Sofikitis, N and Tsatsakis, A and Mamoulakis, C}, title = {Renoprotective Effect of Vardenafil and Avanafil in Contrast-Induced Nephropathy: Emerging Evidence from an Animal Model.}, journal = {Journal of personalized medicine}, volume = {12}, number = {5}, pages = {}, pmid = {35629096}, issn = {2075-4426}, abstract = {The potential renoprotective effects of vardenafil (VAR) have been evaluated in a very limited number of studies using acute kidney injury animal models other than contrast-induced nephropathy (CIN) with promising results, while avanafil (AVA) has not been evaluated in this respect before. The purpose of this study was to evaluate for the first time the potential renoprotective effect of VAR and AVA in a rat model of CIN. Twenty-five male Wistar rats were equally assigned into five groups: control, CIN, CIN+N-acetyl cysteine (NAC) (100 mg/kg/day) as a positive control, CIN+VAR (10 mg/kg/day) and CIN+AVA (50 mg/kg/day). CIN was induced by dehydration, inhibition of prostaglandin and nitric oxide synthesis as well as exposure to the contrast medium (CM). Serum Cr (sCr) levels were measured at 24 and 48 h after CIN induction. At 48 h of CM exposure, animals were sacrificed. Matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, kidney injury molecule 1 (KIM-1) and cystatin-C (Cys-C) were measured on renal tissue. Histopathological findings were evaluated on kidney tissue. All treatment groups had close to normal kidney appearance. sCr levels subsided in all treatment groups compared to CIN group at 48 h following CIN induction. A significant decline in the levels of MMP-2, MMP-9, KIM-1 and Cys-C compared to CIN group was observed. These results provide emerging evidence that VAR and AVA may have the potential to prevent CIN.}, }
@article {pmid35628435, year = {2022}, author = {Lai, KM and Wang, JH and Lin, SC and Wen, Y and Wu, CL and Su, JH and Chen, CC and Lin, CC}, title = {Crassolide Induces G2/M Cell Cycle Arrest, Apoptosis, and Autophagy in Human Lung Cancer Cells via ROS-Mediated ER Stress Pathways.}, journal = {International journal of molecular sciences}, volume = {23}, number = {10}, pages = {}, pmid = {35628435}, issn = {1422-0067}, support = {(MOE-110-S-0023-E//iEGG and Animal Biotechnology Center of the Feature Areas Research Center Program within the framework of the Higher Education Sprout Project by the Taiwan Ministry of Education/ ; TCVGH-1117307C//Taichung Veterans General Hospital/ ; }, mesh = {Apoptosis ; Autophagy ; *Carcinoma, Non-Small-Cell Lung/drug therapy ; Cell Cycle Checkpoints ; Cell Line, Tumor ; *Diterpenes/pharmacology ; G2 Phase Cell Cycle Checkpoints ; Humans ; *Lung Neoplasms/drug therapy ; Reactive Oxygen Species/metabolism ; }, abstract = {Crassolide, a cembranoid diterpene extracted from the soft coral Lobophytum crissum, has been proven to possess antioxidant and immunomodulatory properties. In the present study, we assessed the anticancer effects of crassolide on human H460 non-small-cell lung cancer (NSCLC) cells. We found that crassolide exerted cytotoxic effects on H460 cancer cells in vitro, inducing G2/M phase arrest and apoptosis. In addition, in H460 cells exposed to crassolide, the expression of the autophagy-related proteins LC3-II and beclin was increased, while the expression of p62 was decreased. Moreover, inhibiting autophagy with chloroquine (CQ) suppressed the crassolide-induced G2/M arrest and apoptosis of H460 cells. Moreover, we also found that crassolide induced endoplasmic reticulum (ER) stress in lung cancer cells by increasing the expression of ER stress marker proteins and that the crassolide-induced G2/M arrest, apoptosis, and autophagy were markedly attenuated by the ER stress inhibitor 4-phenylbutyric acid (4-PBA). Furthermore, we found that crassolide promoted reactive oxygen species (ROS) production by H460 cells and that the ROS inhibitor N-acetylcysteine (NAC) decreased the crassolide-induced ER stress, G2/M arrest, apoptosis, and autophagy. In conclusion, our findings show that crassolide inhibits NSCLC cell malignant biological behaviors for the first time, suggesting that this effect may be mechanistically achieved by inducing G2/M arrest, apoptosis, and autophagy through ROS accumulation, which activates the ER stress pathway. As a result of our findings, we now have a better understanding of the molecular mechanism underlying the anticancer effect of crassolide, and we believe crassolide might be a candidate for targeted cancer therapy.}, }
@article {pmid35628239, year = {2022}, author = {Petricca, S and Celenza, G and Luzi, C and Cinque, B and Lizzi, AR and Franceschini, N and Festuccia, C and Iorio, R}, title = {Synergistic Activity of Ketoconazole and Miconazole with Prochloraz in Inducing Oxidative Stress, GSH Depletion, Mitochondrial Dysfunction, and Apoptosis in Mouse Sertoli TM4 Cells.}, journal = {International journal of molecular sciences}, volume = {23}, number = {10}, pages = {}, pmid = {35628239}, issn = {1422-0067}, support = {07-RIA 2021 IORIO ROBERTO//DISCAB GRANT 2021/ ; CUP E11I18000300005//MIUR (Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca, Italy)/ ; }, mesh = {Animals ; Apoptosis ; Glutathione/metabolism ; Imidazoles/metabolism/pharmacology ; *Ketoconazole/pharmacology ; Male ; Mammals/metabolism ; Mice ; *Miconazole/pharmacology ; Mitochondria/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Triazole and imidazole fungicides represent an emerging class of pollutants with endocrine-disrupting properties. Concerning mammalian reproduction, a possible causative role of antifungal compounds in inducing toxicity has been reported, although currently, there is little evidence about potential cooperative toxic effects. Toxicant-induced oxidative stress (OS) may be an important mechanism potentially involved in male reproductive dysfunction. Thus, to clarify the molecular mechanism underlying the effects of azoles on male reproduction, the individual and combined potential of fluconazole (FCZ), prochloraz (PCZ), miconazole (MCZ), and ketoconazole (KCZ) in triggering in vitro toxicity, redox status alterations, and OS in mouse TM4 Sertoli cells (SCs) was investigated. In the present study, we demonstrate that KCZ and MCZ, alone or in synergistic combination with PCZ, strongly impair SC functions, and this event is, at least in part, ascribed to OS. In particular, azoles-induced cytotoxicity is associated with growth inhibitory effects, G0/G1 cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) generation, imbalance of the superoxide dismutase (SOD) specific activity, glutathione (GSH) depletion, and apoptosis. N-acetylcysteine (NAC) inhibits ROS accumulation and rescues SCs from azole-induced apoptosis. PCZ alone exhibits only cytostatic and pro-oxidant properties, while FCZ, either individually or in combination, shows no cytotoxic effects up to 320 µM.}, }
@article {pmid35624761, year = {2022}, author = {Rodríguez-Agudo, R and Goikoetxea-Usandizaga, N and Serrano-Maciá, M and Fernández-Tussy, P and Fernández-Ramos, D and Lachiondo-Ortega, S and González-Recio, I and Gil-Pitarch, C and Mercado-Gómez, M and Morán, L and Bizkarguenaga, M and Lopitz-Otsoa, F and Petrov, P and Bravo, M and Van Liempd, SM and Falcon-Perez, JM and Zabala-Letona, A and Carracedo, A and Castell, JV and Jover, R and Martínez-Cruz, LA and Delgado, TC and Cubero, FJ and Lucena, MI and Andrade, RJ and Mabe, J and Simón, J and Martínez-Chantar, ML}, title = {Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {5}, pages = {}, pmid = {35624761}, issn = {2076-3921}, support = {DTS20/00138//Instituto de Salud Carlos III/ ; RTC2019-007125//Ministerio de Ciencia e Innovaci&#xf3;n/ ; PID2020-117116RB-100//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; RTI2018-096759//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; //BIOEF and AECC/ ; Rare Tumor Calls 2017//Asociaci&#xf3;n Espa&#xf1;ola Contra el C&#xe1;ncer/ ; Umbrella 2018//La Caixa Foundation Program/ ; BFU2015-70067-REDC, BFU2016-77408-R and BES-2017-080435//MINECO/FEDER/ ; FIGHT-CNNM2//EJP RD Joint Transnational Call 2019/ ; }, abstract = {Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.}, }
@article {pmid35624744, year = {2022}, author = {Chen, H and Ma, N and Song, X and Wei, G and Zhang, H and Liu, J and Shen, X and Zhuge, X and Chang, G}, title = {Protective Effects of N-Acetylcysteine on Lipopolysaccharide-Induced Respiratory Inflammation and Oxidative Stress.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {5}, pages = {}, pmid = {35624744}, issn = {2076-3921}, support = {31702301//National Natural Science Foundation of China/ ; 21BEF02019//the National Key R&amp;D Program of Ningxia Hui Autonomous Region of China/ ; 2017YFD0502205//the National Key R&amp;D Program of China/ ; PAPD//the Priority Academic Program Development of Jiangsu Higher Education Institutions/ ; }, abstract = {As the leading cause of bovine respiratory disease (BRD), bacterial pneumonia can result in tremendous losses in the herd farming industry worldwide. N-acetylcysteine (NAC), an acetylated precursor of the amino acid L-cysteine, has been reported to have anti-inflammatory and antioxidant properties. To explore the protective effect and underlying mechanisms of NAC in ALI, we investigated its role in lipopolysaccharide (LPS)-induced bovine embryo tracheal cells (EBTr) and mouse lung injury models. We found that NAC pretreatment attenuated LPS-induced inflammation in EBTr and mouse models. Moreover, LPS suppressed the expression of oxidative-related factors in EBTr and promoted gene expression and the secretion of inflammatory cytokines. Conversely, the pretreatment of NAC alleviated the secretion of inflammatory cytokines and decreased their mRNA levels, maintaining stable levels of antioxidative gene expression. In vivo, NAC helped LPS-induced inflammatory responses and lung injury in ALI mice. The relative protein concentration, total cells, and percentage of neutrophils in BALF; the level of secretion of IL-6, IL-8, TNF-α, and IL-1β; MPO activity; lung injury score; and the expression level of inflammatory-related genes were decreased significantly in the NAC group compared with the LPS group. NAC also ameliorated LPS-induced mRNA level changes in antioxidative genes. In conclusion, our findings suggest that NAC affects the inflammatory and oxidative response, alleviating LPS-induced EBTr inflammation and mouse lung injury, which offers a natural therapeutic strategy for BRD.}, }
@article {pmid35624495, year = {2022}, author = {Zeng, X and Zhang, YD and Ma, RY and Chen, YJ and Xiang, XM and Hou, DY and Li, XH and Huang, H and Li, T and Duan, CY}, title = {Activated Drp1 regulates p62-mediated autophagic flux and aggravates inflammation in cerebral ischemia-reperfusion via the ROS-RIP1/RIP3-exosome axis.}, journal = {Military Medical Research}, volume = {9}, number = {1}, pages = {25}, pmid = {35624495}, issn = {2054-9369}, mesh = {Animals ; *Brain Ischemia ; Cerebral Infarction ; DNA, Mitochondrial ; *Exosomes/metabolism ; Glucose ; Humans ; Inflammation ; Male ; Mice ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Reperfusion ; *Reperfusion Injury ; Tumor Necrosis Factor-alpha ; }, abstract = {BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that can occur when the blood supply to the ischemic brain tissue is restored. However, the mechanism underlying such injury remains elusive.<br><br>METHODS: The 150 male C57 mice underwent middle cerebral artery occlusion (MCAO) for 1&#xa0;h and reperfusion for 24&#xa0;h, Among them, 50 MCAO mice were further treated with Mitochondrial division inhibitor 1 (Mdivi-1) and 50 MCAO mice were further treated with N-acetylcysteine (NAC). SH-SY5Y cells were cultured in a low-glucose culture medium for 4&#xa0;h under hypoxic conditions and then transferred to normal conditions for 12&#xa0;h. Then, cerebral blood flow, mitochondrial structure, mitochondrial DNA (mtDNA) copy number, intracellular and mitochondrial reactive oxygen species (ROS), autophagic flux, aggresome and exosome expression profiles, cardiac tissue structure, mitochondrial length and cristae density, mtDNA and ROS content, as well as the expression of Drp1-Ser616/Drp1, RIP1/RIP3, LC3 II/LC3 I, TNF-&#x3b1;, IL-1&#x3b2;, etc., were detected under normal or Drp1 interference conditions.<br><br>RESULTS: The mtDNA content, ROS levels, and Drp1-Ser616/Drp1 were elevated by 2.2, 1.7 and 2.7 times after CIRI (P&#x2009;<&#x2009;0.05). However, the high cytoplasmic LC3 II/I ratio and increased aggregation of p62 could be reversed by 44% and 88% by Drp1 short hairpin RNA (shRNA) (P&#x2009;<&#x2009;0.05). The low fluorescence intensity of autophagic flux and the increased phosphorylation of RIP3 induced by CIRI could be attenuated by ROS scavenger, NAC (P&#x2009;<&#x2009;0.05). RIP1/RIP3 inhibitor Necrostatin-1 (Nec-1) restored 75% to a low LC3 II/LC3 I ratio and enhanced 2 times to a high RFP-LC3 after Drp1 activation (P&#x2009;<&#x2009;0.05). In addition, although CIRI-induced ROS production caused no considerable accumulation of autophagosomes (P&#x2009;>&#x2009;0.05), it increased the packaging and extracellular secretion of exosomes containing p62 by 4 - 5 times, which could be decreased by Mdivi-1, Drp1 shRNA, and Nec-1 (P&#x2009;<&#x2009;0.05). Furthermore, TNF-&#x3b1; and IL-1&#x3b2; increased in CIRI-derived exosomes could increase RIP3 phosphorylation in normal or oxygen-glucose deprivation/reoxygenation (OGD/R) conditions (P&#x2009;<&#x2009;0.05).<br><br>CONCLUSIONS: CIRI activated Drp1 and accelerated the p62-mediated formation of autophagosomes while inhibiting the transition of autophagosomes to autolysosomes via the RIP1/RIP3 pathway activation. Undegraded autophagosomes were secreted extracellularly in the form of exosomes, leading to inflammatory cascades that further damaged mitochondria, resulting in excessive ROS generation and the blockage of autophagosome degradation, triggering a vicious cycle.}, }
@article {pmid35622622, year = {2022}, author = {Lee, JL and Wang, YC and Hsu, YA and Chen, CS and Weng, RC and Lu, YP and Chuang, CY and Wan, L}, title = {Bisphenol A Coupled with a High-Fat Diet Promotes Hepatosteatosis through Reactive-Oxygen-Species-Induced CD36 Overexpression.}, journal = {Toxics}, volume = {10}, number = {5}, pages = {}, pmid = {35622622}, issn = {2305-6304}, abstract = {Bisphenol A (BPA) is an endocrine-disrupting chemical that affects lipid metabolism and contributes to non-alcoholic fatty liver disease (NAFLD). The mechanism of BPA exposure in hepatic lipid accumulation and its potential effect on NAFLD remain unclear. This study investigated the effect of BPA-exposure-induced hepatic lipid deposition on the pathology of NAFLD and its underlying mechanism in vitro and in vivo. BPA increased intracellular reactive oxygen species (ROS) levels, and promoted fatty acid uptake through upregulation of a free fatty acid uptake transporter, cluster of differentiation 36 (CD36), in HUH-7 cells. Additionally, C57BL/6 mice administered a high-fat/high-cholesterol/high-cholic acid diet (HFCCD) and BPA (50 mg/kg body weight) for 8 weeks developed a steatohepatitis-like phenotype, characterized by alpha-smooth muscle actin (α-SMA, an indicator of hepatic fibrosis) and cleaved caspase 3 (an indicator of apoptosis) in hepatic tissue; moreover, they had a higher oxidative stress index of 8-hydroxydeoxyguanosine (8-OHdG) in liver tissue compared to the control group. Treatment with ROS scavenger n-acetylcysteine (NAC) ameliorated BPA-mediated HFCCD-induced lipid accumulation and steatohepatitis in the livers of treated mice. Our study indicates that BPA acts synergistically to increase hepatic lipid uptake and promote NAFLD development by stimulating ROS-induced CD36 overexpression.}, }
@article {pmid35621139, year = {2022}, author = {Xu, Y and Bu, H and Jiang, Y and Zhuo, X and Hu, K and Si, Z and Chen, Y and Liu, Q and Gong, X and Sun, H and Zhu, Q and Cui, L and Ma, X and Cui, Y}, title = {N‑acetyl cysteine prevents ambient fine particulate matter‑potentiated atherosclerosis via inhibition of reactive oxygen species‑induced oxidized low density lipoprotein elevation and decreased circulating endothelial progenitor cell.}, journal = {Molecular medicine reports}, volume = {26}, number = {1}, pages = {}, pmid = {35621139}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Atherosclerosis/drug therapy ; *Endothelial Progenitor Cells ; Lipoproteins, LDL/pharmacology ; Mice ; Particulate Matter/toxicity ; Reactive Oxygen Species ; }, abstract = {Ambient fine particulate matter (PM) serves an important role in the development of cardiovascular disease, including atherosclerosis. Antioxidant N‑acetyl cysteine (NAC) has protective effects in the cardiovascular system. However, it is unknown if NAC prevents PM‑potentiated atherosclerosis in hyperlipidemia. Low‑density lipoprotein (LDL) receptor knockout mice were pretreated with 1 mg/ml NAC in drinking water for 1 week and continued to receive NAC, high‑fat diet and intranasal instillation of PM for 1 week or 6 months. Blood plasma was collected for lipid profile, oxidized (ox‑)LDL, blood reactive oxygen species (ROS) and inflammatory cytokine (TNF‑α, IL‑1β and IL‑6) measurement. Blood cells were harvested for endothelial progenitor cell (EPC) population and intracellular ROS analysis. Murine aorta was isolated for atherosclerotic plaque ratio calculation. NAC treatment maintained circulating EPC level and significantly decreased blood ox‑LDL and ROS, inflammatory cytokines, mononuclear and EPC intracellular ROS levels as well as aortic plaque ratio. NAC prevented PM‑potentiated atherosclerosis by inhibiting plasma ROS‑induced ox‑LDL elevation, mononuclear cell and EPC intracellular ROS‑induced circulating EPC reduction and inflammatory cytokine production.}, }
@article {pmid35619297, year = {2023}, author = {Li, W and Zhang, H and Chen, J and Tan, Y and Li, A and Guo, L}, title = {N-acetyl Cysteine Inhibits Cell Proliferation and Differentiation of LPSInduced MC3T3-E1 Cells Via Regulating Inflammatory Cytokines.}, journal = {Current pharmaceutical biotechnology}, volume = {24}, number = {3}, pages = {450-459}, doi = {10.2174/1389201023666220520102001}, pmid = {35619297}, issn = {1873-4316}, mesh = {Cell Line ; *Cytokines ; *Acetylcysteine/pharmacology ; Lipopolysaccharides/pharmacology ; Cell Differentiation ; Osteogenesis ; Cell Proliferation ; }, abstract = {BACKGROUND: Peri-implantitis is one of the most common complications in oral implantation and could lead to the loss of the function of bone tissues around implants.<br><br>METHODS: This study used lipopolysaccharide (LPS) as a stimulant for MC3T3-E1 cells and N-acetyl cysteine (NAC) as an inhibitor to inhibit the effect of LPS to investigate the effect of NAC on the expression of bone formation related factors and inflammatory-related factors of osteoblasts under the action of LPS.<br><br>RESULTS: In this study, we found that the cell proliferation and cell differentiation were significantly promoted when NAC concentrations were between 0 ~ 0.5 mM, but were inhibited when the concentration exceeded 0.5 mM. LPS had a slightly promoting effect on the cell proliferation before 20 &#x3bc;g/mL but inhibited the cell proliferation after 20 &#x3bc;g/mL. LPS reduced protein and gene expressions of Runx2, ALP and BGP and increased protein and gene expressions of NF-&#x3ba;B and TNF-&#x3b1;. NAC reversibly regulated the LPS's regulation on the expression of MC3T3-E1 cell cytokine gene and protein.<br><br>CONCLUSION: The optimal NAC concentration for treating MC3T3-E1 cells is 0.5 mM, and the optimal LPS concentration for stimulating MC3T3-E1 cells is 20 &#x3bc;g/mL. NAC plays an active role in regulating the differentiation of MC3T3-E1 cells, and can inhibit LPS to regulate the differentiation of MC3T3-E1 cells. NAC promotes the expression of an osteogenic factor of MC3T3-E1cells and inhibits the expression of inflammatory cytokines.}, }
@article {pmid35615243, year = {2022}, author = {Arshad, MA and Bangash, MN}, title = {Acute liver failure following paracetamol overdose.}, journal = {Journal of the Intensive Care Society}, volume = {23}, number = {2}, pages = {244-251}, pmid = {35615243}, issn = {1751-1437}, abstract = {Acute liver failure is a rare syndrome comprising a coagulopathy of liver origin, jaundice and encephalopathy in a patient with no prior history of liver disease. Paracetamol overdose is the leading cause of acute liver failure in the United Kingdom and often presents with extrahepatic organ dysfunction requiring critical care. Presentation: We present the case of a patient with hyper acute liver failure secondary to paracetamol overdose. Management and discussion: Management focused on ensuring the correct diagnosis had been made, administering N-acetyl cysteine, fluid resuscitation and broad spectrum antimicrobials. Early intubation and transfer to a transplant centre were undertaken following development of hepatic encephalopathy. Neuroprotective measures and hypertonic saline were instituted to reduce the risk of intracranial hypertension. High dose haemofiltration was also started to help reduce ammonia levels. Aggressive critical care therapies with specialised input results in good outcomes for patients admitted with paracetamol induced hyper acute liver failure. Liver transplant is reserved for those patients unlikely to survive with medical treatment alone.}, }
@article {pmid35615146, year = {2022}, author = {Xu, T and Jiang, Y and Yuan, S and Zhang, L and Chen, X and Zhao, W and Cai, L and Xiao, B and Jia, L}, title = {Andrographolide Inhibits ER-Positive Breast Cancer Growth and Enhances Fulvestrant Efficacy via ROS-FOXM1-ER-α Axis.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {899402}, pmid = {35615146}, issn = {2234-943X}, abstract = {Estrogen receptor (ER)-positive breast cancer is the main subtype of breast cancer (BRCA) with high incidence and mortality. Andrographolide (AD), a major active component derived from the traditional Chinese medicine Andrographis paniculate, has substantial anti-cancer effect in various tumors. However, the antitumor efficacy and the underlying molecular mechanisms of AD on ER-positive breast cancer are poorly understood. In the present study, we demonstrated that andrographolide (AD) significantly inhibited the growth of ER-positive breast cancer cells. Mechanistically, AD suppressed estrogen receptor 1 (ESR1, encodes ER-α) transcription to inhibit tumor growth. Further studies revealed that AD induced ROS production to down-regulate FOXM1-ER-α axis. Conversely, inhibiting ROS production with N-acetylcysteine (NAC) elevated AD-decreased ER-α expression, which could be alleviated by FOXM1 knockdown. In addition, AD in combination with fulvestrant (FUL) synergistically down-regulated ER-α expression to inhibit ER-positive breast cancer both in vitro and in vivo. These findings collectively indicate that AD suppresses ESR1 transcription through ROS-FOXM1 axis to inhibit ER-positive breast cancer growth and suggest that AD might be a potential therapeutic agent and fulvestrant sensitizer for ER-positive breast cancer treatment.}, }
@article {pmid35609854, year = {2022}, author = {Kanazawa, J and Kakisaka, K and Suzuki, Y and Yonezawa, T and Abe, H and Wang, T and Takikawa, Y}, title = {Excess fructose enhances oleatic cytotoxicity via reactive oxygen species production and causes necroptosis in hepatocytes.}, journal = {The Journal of nutritional biochemistry}, volume = {107}, number = {}, pages = {109052}, doi = {10.1016/j.jnutbio.2022.109052}, pmid = {35609854}, issn = {1873-4847}, mesh = {Animals ; Diet, High-Fat/adverse effects ; Fructose/adverse effects/metabolism ; Hepatocytes/metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Necroptosis ; *Non-alcoholic Fatty Liver Disease/metabolism ; Oleic Acid/metabolism/toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {Non-alcoholic fatty liver disease (NAFLD), the hepatic phenotype of metabolic syndrome, has been identified as a major health concern as the number of cirrhosis and deaths associated with NAFLD is expected to increase. Although fructose intake has been considered to be a progressive factor in the pathophysiology of NAFLD, it remains unclear how fructose contributes to hepatocellular damage during lipotoxicity. In the present study, we aimed to analyze the hepatotoxicity of fructose in steatosis. Fructose effects on lipotoxicity were evaluated in HepG2 cells, primary mouse hepatocytes, and in mice fed a high-fat diet with or without sucrose (HFDS/HFD). Oleate induced caspase 3-independent cell death in HepG2 cells and primary mouse hepatocytes cultured in fructose-supplemented medium, and induced cleavage of caspase-1 in primary mouse hepatocytes. In addition, the number of cells stained positive for reactive oxygen species (ROS) was significantly increased, and N-acetyl cysteine was found to inhibit ROS production and cell death. Cell death was confirmed to be through necrotic cell death, and phosphorylation of mixed lineage kinase domain-like (MLKL) protein was observed. Taken together, hepatocyte cytotoxicity was due to excess fructose with oleate-induced ROS-mediated necroptosis. HFDS mice showed progressive hepatic fibrosis and inflammation and a higher NAS score than HFD mice or mice fed a control diet. The expression of hemoxygenase-1, phosphorylation of MLKL, cleavage of caspase1, and apoptosis were significantly increased in the livers of mice fed a HFDS. Overall, excess fructose intake induces necroptosis through the production of ROS and enhances the toxicity of oleatic cytotoxicity.}, }
@article {pmid35608368, year = {2022}, author = {Wang, Q and Zhu, B and Han, Y and Yang, X and Xu, Y and Cheng, Y and Liu, T and Wu, J and Li, S and Ding, L and Bai, J and Niu, Y}, title = {Metal ion-mediated carbon dot nanoprobe for fluorescent turn-on sensing of N-acetyl-l-cysteine.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {37}, number = {8}, pages = {1267-1274}, doi = {10.1002/bio.4292}, pmid = {35608368}, issn = {1522-7243}, support = {//Fund for Shanxi '1331' Project/ ; 2021&#x2009;L535//Scientific and Technological Innovation Programmes of Higher Education Institutions in Shanxi/ ; 2020&#x2009;L0654//Scientific and Technological Innovation Programmes of Higher Education Institutions in Shanxi/ ; CSREP2019KJ038//Cultivate Scientific Research Excellence Programmes of Higher Education Institutions in Shanxi/ ; 2020XS02//Project for the Young Academic Leaders of Taiyuan Institute of Technology/ ; 201901D211454//Applied Basic Research Project of Shanxi Province/ ; }, mesh = {Acetylcysteine ; *Carbon ; Fluorescent Dyes ; Humans ; Ions ; *Quantum Dots ; Spectrometry, Fluorescence/methods ; }, abstract = {In this work, carbon dots (CDs) was easily synthesized from aspartic acid through a pyrolysis method. Based on their favourable fluorescence properties, CDs were utilized to design a metal ion-mediated fluorescent probe for N-acetyl-l-cysteine (NAC) detection. The fluorescence intensity of CDs was firstly quenched by manganese ions (Mn[2+]) through static quenching effect and subsequently restored by NAC via the combination with Mn[2+] due to the coordination effect. Therefore, the fluorescent turn-on sensing of NAC was actuated based on the fluorescence quenching stimulated by Mn[2+] and recovery induced by coordination. The fluorescence recovery efficiencies showed a proportional range to the concentration of NAC in the range 0.04-5 mmol L[-1] and the detection limit was 0.03 mmol L[-1] . Furthermore, this metal ion-mediated fluorescent nanoprobe was applied to human urine sample detection and the standard recovery rates were located in the range 97.62-102.34%. This was the first time that Mn[2+] was used to construct a fluorescent nanoprobe for NAC. Compared with other heavy metal ions, Mn[2+] with good biosecurity prevented the risk of application, which made the nanoprobe green and biopractical. The facile synthesis of CDs and novel metal ion-mediated sensing mode made it a promising method for pharmaceutical analysis.}, }
@article {pmid35608150, year = {2023}, author = {Gabriel, FC and Oliveira, M and Bruna De M Martella,  and Berk, M and Brietzke, E and Jacka, FN and Lafer, B}, title = {Nutrition and bipolar disorder: a systematic review.}, journal = {Nutritional neuroscience}, volume = {26}, number = {7}, pages = {637-651}, doi = {10.1080/1028415X.2022.2077031}, pmid = {35608150}, issn = {1476-8305}, mesh = {Humans ; *Bipolar Disorder ; Diet ; Vitamins ; Micronutrients ; *Fatty Acids, Omega-3 ; Acetylcysteine ; }, abstract = {INTRODUCTION: Individuals with bipolar disorder (BD) have higher rates of unhealthy lifestyles and risk for medical comorbidities Research currently suggests that dietary factors may play a role in the development of depression and anxiety. Therefore, nutritional approaches are potential strategies for the treatment of BD. The aim of this review is to summarize the available evidence on nutrition and BD.<br><br>MATERIALS AND METHODS: The paper was developed based on PRISMA 2020 guidelines. The search was conducted in Sep-2021 using PubMed and Cochrane Library, augmented by manually checked references lists. The search found 986 studies, of which 47 were included, combined with 13 from reference lists, totaling 60 studies.<br><br>RESULTS: There were 33 observational trials, of which 15 focused on fatty acids, 9 on micronutrients, 5 on specific foods, 4 on macro and micronutrients. The 27 interventional studies mainly focused on fatty acids, micronutrients and N-acetylcysteine (NAC).<br><br>DISCUSSION: Dietary intake or supplementation of unsaturated fatty acids, mainly Omega-3 seems to be associated with improved BD symptoms, along with seafood, folic acid and zinc. Studies found variable, mainly non-significant impacts of creatine, carnitine, vitamin D, inositol or NAC supplementation on BD. There are promising results associated with Coenzyme Q10 (Coq10) and probiotics. Taken together, these preliminary findings suggest that dietetic approaches might be included as part of BD treatment. Also considering the high risk of metabolic disorders in individuals with BD, they should be encouraged to choose healthy dietary lifestyles, including daily intake of fruits, vegetables, seafood and whole grains.}, }
@article {pmid35603121, year = {2022}, author = {Khan, MSA and Kumar, KV and Kumar, RA and Prasannan, B and Urs, V and Unni, VN}, title = {A Study of Estimated Glomerular Filtration Rate in Patients Undergoing Diagnostic or Interventional Coronary Contrast Procedures.}, journal = {Indian journal of nephrology}, volume = {32}, number = {2}, pages = {132-137}, pmid = {35603121}, issn = {0971-4065}, abstract = {INTRODUCTION: Angiographic procedures are underused in patients with chronic kidney disease (CKD), who present with acute coronary syndromes, due to risk of contrast-induced acute kidney injury (CI-AKI). In this study, we assessed the change in estimated glomerular filtration rate (eGFR) over 3 months following coronary procedures in CKD patients.<br><br>METHODS: This observational study was done from July 2017 to January 2019 in patients undergoing elective coronary procedures with an eGFR <60 mL/min/1.73 m[2]. CKD-EPI equation was used to calculate eGFR pre and post coronary procedure at 24, 48, and 72 hours as well as 30, 90 days. AKI was diagnosed and patients were given prophylaxis for CI-AKI as per KDIGO recommendation (intravenous normal saline and oral N-acetyl cysteine).<br><br>RESULTS: Patients studied were 282 (225 males, 57 females) of which 68.1% were diabetics. Mean eGFR was 42.91 &#xb1; 10.51 mL/min/1.73 m[2] and mean hemoglobin was 12.08 &#xb1; 1.51 gm/dL. Coronary angiogram (CAG) was done in 174; percutaneous transluminal coronary angioplasty (PTCA) was done in 108. Mean contrast volume in CAG was 55.17 &#xb1; 34.45 mL and in PTCA was 156.94&#xb1;&#xb1;47.99 mL. CI-AKI was seen in 66 (23.4%) patients. The incidence of CI-AKI increased with severity of underlying CKD. The variability of eGFR at 1 and 3 months after coronary procedures showed no significant change from baseline, even in the patients who developed CI-AKI.<br><br>CONCLUSIONS: CI-AKI is self-limiting and has no major detrimental effects on eGFR at 1 and 3 months after contrast exposure.}, }
@article {pmid35602237, year = {2022}, author = {Gill, G and Blakley, BW}, title = {Does N-acetylcysteine Improve Established Hearing Loss in Guinea Pigs?.}, journal = {OTO open}, volume = {6}, number = {2}, pages = {2473974X221100545}, pmid = {35602237}, issn = {2473-974X}, abstract = {OBJECTIVE: To assess whether multiple injections of a powerful antioxidant can improve established sensorineural hearing loss in guinea pigs.<br><br>STUDY DESIGN: Animal study.<br><br>SETTING: Animal science laboratory, University of Manitoba.<br><br>METHODS: A total of 16 guinea pigs were used in our study: 8 underwent unilateral intracochlear neomycin injection, and 8 underwent unilateral saline to serve as controls. After a period of 3 weeks for hearing loss to stabilize, 4 guinea pigs from each group received weekly intraperitoneal injections of N-acetylcysteine (NAC) for 4 weeks. Click auditory brainstem response (ABR) testing was conducted at baseline, weekly after the start of NAC injections, and after the last injection. Pure tone ABR tests were conducted prior to intracochlear injections and at completion of the study.<br><br>RESULTS: Click ABR thresholds were significantly worse in ears treated with neomycin (P < .001), as expected, but not significantly different when treated with NAC (P = .664). Thresholds for pure tone ABR were also not statistically different in neomycin-treated ears with or without NAC (P > .99).<br><br>CONCLUSIONS: The aggressive antioxidant therapy performed in this study was not successful in improving established hearing loss via an antioxidant regimen that is known to change the oxidation-reduction potential in the cochlea.}, }
@article {pmid35598440, year = {2022}, author = {Miyashita, L and Shears, R and Foley, G and Semple, S and Kadioglu, A and Grigg, J}, title = {Underground railway particulate matter and susceptibility to pneumococcal infection.}, journal = {EBioMedicine}, volume = {80}, number = {}, pages = {104063}, pmid = {35598440}, issn = {2352-3964}, support = {MR/P011284/1/MRC_/Medical Research Council/United Kingdom ; MR/R002592/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Cell Line ; Cysteine/metabolism ; Humans ; Lung/metabolism ; Mice ; *Particulate Matter/adverse effects/metabolism ; *Pneumococcal Infections ; Streptococcus pneumoniae/metabolism ; }, abstract = {BACKGROUND: Concentrations of particulate matter less than 10 microns (PM10) on underground railways are higher than those near urban roads. Traffic-related PM10 increases pneumococcal infection via increasing the expression of platelet-activating factor receptor (PAFR), a receptor co-opted by pneumococci to adhere to cells. To date, it is unknown whether underground railway PM10 increases pneumococcal infection. This study sought to determine the effect of London Underground (LU) PM10 on; i) pneumococcal adhesion to airway cells, and ii) susceptibility to pneumococcal disease.<br><br>METHODS: A549 cells and human primary airway epithelial cells were cultured with 20 &#xb5;g/mL PM10 from the Bakerloo (B-PM10) and Jubilee (J-PM10) line platforms of Baker Street station. PAFR expression was assessed by flow cytometry, and pneumococcal adhesion by colony forming unit (CFU) counts. Traffic-related PM10 was collected next to a main road near the station's entrance. The PAFR blocker CV3988 and the antioxidant N-acetyl cysteine were used to assess the role of PAFR-mediated pneumococcal adhesion and oxidative stress respectively. Pneumococcal infection of mice was done after exposure to 3&#xd7;80 &#x3bc;g doses of intranasal LU-PM10.<br><br>FINDINGS: In A549 cells, human primary nasal cells, and human primary bronchial epithelial cells, B-PM10 and J-PM10 increased PAFR expression and pneumococcal adhesion. Stimulated adhesion was abrogated by CV3988 and N-acetyl cysteine. Traffic-related PM10 stimulated increased adhesion compared with B-PM10. B-PM10 and J-PM10 increased lung and blood CFU and mortality in mice. Treatment of B-PM10-exposed mice with CV3988 reduced blood CFU.<br><br>INTERPRETATION: LU-PM10 increases pneumococcal adhesion to airway cells and susceptibility to invasive disease in mice.<br><br>FUNDING: The Medical College of Saint Bartholomew's Hospital Trust, and the UK Medical Research Council Programme Grant (MR/P011284/1).}, }
@article {pmid35598122, year = {2022}, author = {Sengupta, P and Biswas, S and Roy, T}, title = {Comparative Study to Evaluate the Effect of Low-Protein Diet Supplementation with Taurine and N-Acetylcysteine, N-Acetylcysteine and Pyridoxamine Dihydrochloride in Preventing the Progression of Chronic Renal Failure in Patients with Non-Diabetic Kidney Disease.}, journal = {The Journal of the Association of Physicians of India}, volume = {70}, number = {5}, pages = {11-12}, pmid = {35598122}, issn = {0004-5772}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Aged ; Diet, Protein-Restricted ; Dietary Supplements ; Disease Progression ; Female ; Humans ; *Kidney Failure, Chronic/prevention &amp; control ; Male ; Middle Aged ; Pyridoxamine/analogs &amp; derivatives/therapeutic use ; *Renal Insufficiency, Chronic/complications/diagnosis/drug therapy ; Taurine/therapeutic use ; }, abstract = {UNLABELLED: Chronic Kidney Disease(CKD) has multifactorial etiology and there are lots of grey zone in understanding its complex pathophysiology. There is no silver bullet for optimal care of CKD. Oxidative stress being well understood and considered as an important common progressive factor for CKD of different etiology. Several research studies focused on reducing oxidative stress and have shown diverse outcomes. In this randomized, open-label, three arms, controlled, single center study we evaluated the role of N acetylcysteine which is a direct scavenger of free radical, in combination with taurine and pyridoxamine in retarding the progression of non-diabetic kidney disease.<br><br>METHODS: 69 non-dialysis, non-diabetic patients diagnosed with chronic renal failure with GFR more than 15 ml/min/1.73m2 and less than 60ml/min/1.73m2 receiving standard of care were enrolled in the study, of which 22 were in the placebo arm, 23 treated with NT (500 mg Taurine + 150 mg NAC) arm and 24 in the NP (300mg NAC+ 50mg pyridoxamine di-hydrochloride) arm. The subjects in the treatment arm received the study drug twice a day along with low protein (0.6gm protein per Kg body weight) isocaloric diet with 25-30 Kcal/Kg/D and were evaluated monthly up to 6 months. Change in eGFR accorss 3 groups over 6 months were compared.<br><br>RESULT: Mean age of the subjects was 57 &#xb1; 13 years of 56.25% were male and 43.75% were female. 69 patients completed the study. The Empirical Distribution Function (EDF) of NP group was dominant over control and NT group indicating a positive effect of NT on non-diabetic CKD at 10% level of significance. In the subgroup analysis a significant effect was observed in the cases of patients receiving NP with baseline eGFR more than 45 ml/min. The mean increase in eGFR readings over six months was 8.15 units higher in the NP group than in the control group. The two-sided p-values of the t-test, the Wilcoxon test and the Kolmogorov-Smirnov test were 0.0496, 0.0316 and 0.0354, respectively. Thus, all the three tests reject the hypothesis of identical changes in eGFR at the 5% level. In subjects with bicarbonate more than 22 mg/dl, the mean increase in eGFR over six months was 10.86 units higher in the NP group than in the control group indicating NP has a positive effect on increasing eGFR over 6 months, in patients without the presence of any metabolic acidosis. The two-sided p-vales of the t-test, the Wilcoxon test and the Kolmogorov-Smirnov test were 0.0325, 0.0205 and 0.1495, respectively. Thus, two of the three tests reject the hypothesis of identical changes in eGFR at the 5% level which clearly indicates that NP had better efficacy than other groups.<br><br>CONCLUSION: N-acetyl cysteine along with pyridoxine may be a useful intervention along with a low protein diet in retarding progression of CKD in the nondiabetic population in early CKD.}, }
@article {pmid35594827, year = {2022}, author = {Lin, CM and Huang, TH and Chi, MC and Guo, SE and Lee, CW and Hwang, SL and Shi, CS}, title = {N-acetylcysteine alleviates fine particulate matter (PM2.5)-induced lung injury by attenuation of ROS-mediated recruitment of neutrophils and Ly6C[high] monocytes and lung inflammation.}, journal = {Ecotoxicology and environmental safety}, volume = {239}, number = {}, pages = {113632}, doi = {10.1016/j.ecoenv.2022.113632}, pmid = {35594827}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Interleukin-6/metabolism ; Lung ; *Lung Injury/chemically induced/drug therapy/metabolism ; Mice ; Mice, Inbred C57BL ; Monocytes ; Neutrophils/metabolism ; Nitrites/metabolism ; Particulate Matter/adverse effects ; *Pneumonia/chemically induced/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {BACKGROUND: Exposure to particulate matter (PM) may contribute to lung inflammation and injury. The therapeutic effect of N-acetylcysteine (NAC), a well-known antioxidant, with regards to the prevention and treatment of fine PM (PM2.5)-induced lung injury is poorly understood. This study aimed to determine the effect of PM2.5 on the recruitment of neutrophils and Ly6C[high] monocytes into lung alveoli and the production of proinflammatory proteins by stimulating the generation of reactive oxygen species (ROS), and to investigate the therapeutic effect of NAC on PM2.5-induced lung injury.<br><br>METHODS: C57BL/6 mice were exposed to a single administration of PM2.5 (200&#xa0;&#x3bc;g/100&#xa0;&#x3bc;l/mouse) or phosphate-buffered saline (control) via intratracheal instillation. The mice were injected intratracheally via a microsprayer aerosolizer with NAC (20 or 40&#xa0;mg/kg) 1&#xa0;h before PM2.5 instillation and 24&#xa0;h after PM2.5 instillation. Total protein, VEGF, IL-6, and TNF-&#x3b1; in bronchoalveolar lavage fluid (BALF) were measured. Oxidative stress was evaluated by determining levels of malondialdehyde (MDA) and nitrite in BALF. Flow cytometric analysis was used to identify and quantify neutrophils and Ly6C[high] and Ly6Clow monocyte subsets.<br><br>RESULTS: Neutrophil count, total protein, and VEGF content in BALF significantly increased after PM2.5 exposure and reached the highest level on day 2. Increased levels of TNF-alpha, IL-6, nitrite, and MDA in BALF were also noted. Flow cytometric analysis showed increased recruitment of neutrophils and Ly6C[high], but not Ly6C[low] monocytes, into lung alveoli. Treatment with NAC via the intratracheal spray significantly attenuated the recruitment of neutrophils and Ly6C[high] monocytes into lung alveoli in PM2.5-treated mice in a dose-dependent manner. Furthermore, NAC significantly attenuated the production of total protein, VEGF, nitrite, and MDA in the mice with PM2.5-induced lung injury in a dose-dependent manner.<br><br>CONCLUSION: PM2.5-induced lung injury caused by the generation of oxidative stress led to the recruitment of neutrophils and Ly6C[high] monocytes, and production of inflammatory proteins. NAC treatment alleviated PM2.5-induced lung injury by attenuating the ROS-mediated recruitment of neutrophils and Ly6C[high] monocytes and lung inflammation.}, }
@article {pmid35594763, year = {2022}, author = {Wołosowicz, M and Dajnowicz-Brzezik, P and Łukaszuk, B and Żebrowska, E and Maciejczyk, M and Zalewska, A and Kasacka, I and Chabowski, A}, title = {Diverse impact of N-acetylcysteine or alpha-lipoic acid supplementation during high-fat diet regime on fatty acid transporters in visceral and subcutaneous adipose tissue.}, journal = {Advances in medical sciences}, volume = {67}, number = {2}, pages = {216-228}, doi = {10.1016/j.advms.2022.05.001}, pmid = {35594763}, issn = {1898-4002}, mesh = {Male ; Rats ; Animals ; *Thioctic Acid/pharmacology/metabolism ; Acetylcysteine/pharmacology/metabolism ; Fatty Acids/metabolism ; Antioxidants/pharmacology/metabolism ; Diet, High-Fat/adverse effects ; Reactive Oxygen Species/metabolism ; Rats, Wistar ; Subcutaneous Fat/metabolism ; Adipose Tissue/metabolism/pathology ; Dietary Supplements ; RNA, Messenger/metabolism ; Carrier Proteins/metabolism ; }, abstract = {PURPOSE: Adipose tissue's (AT) structural changes accompanying obesity may alter lipid transport protein expression and, thus, the fatty acids (FAs) transport and lipid balance of the body. Metabolic abnormalities within AT contribute to the elevated production of reactive oxygen species and increased oxidative/nitrosative stress. Although compounds such as N-acetylcysteine (NAC) and α-lipoic acid (ALA), which restore redox homeostasis, may improve lipid metabolism in AT, the mechanism of action of these antioxidants on lipid metabolism in AT is still unknown. This study aimed to examine the impact of NAC and ALA on the level and FA composition of the lipid fractions, and the expression of FA transporters in the visceral and subcutaneous AT of high-fat diet-fed rats.<br><br>MATERIALS AND METHODS: Male Wistar rats were randomly divided into four groups. The mRNA levels and protein expression of FA transporters were assessed using real-time PCR and Western Blot analyses. The collected samples were subjected to histological evaluation. The level of lipids (FFA, DAG, and TAG) was measured using gas-liquid chromatography.<br><br>RESULTS: We found that antioxidants affect FA transporter expressions at both the transcript and protein levels, and, therefore, they promote changes in AT's lipid pools. One of the most remarkable findings of our research is that different antioxidant molecules may have a varying impact on AT phenotype.<br><br>CONCLUSION: NAC and ALA exert different influences on AT, which is reflected in histopathological images, FA transport proteins expression patterns, or even the lipid storage capacity of adipocytes.}, }
@article {pmid35593216, year = {2022}, author = {Ma, Z and Wang, W and Pan, C and Fan, C and Li, Y and Wang, W and Lan, T and Gong, F and Zhao, C and Zhao, Z and Yu, S and Yuan, M}, title = {N-acetylcysteine improves diabetic associated erectile dysfunction in streptozotocin-induced diabetic mice by inhibiting oxidative stress.}, journal = {Journal of cellular and molecular medicine}, volume = {26}, number = {12}, pages = {3527-3537}, pmid = {35593216}, issn = {1582-4934}, support = {2019SDRX-xx//Rongxiang Regenemiceive Medicine Foundation of Shandong University/ ; 2018YFC1003600//National Health Commission of the People Republic of China/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; *Diabetes Mellitus, Experimental/complications/drug therapy/metabolism ; *Erectile Dysfunction/complications/drug therapy ; Humans ; Male ; Mice ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Streptozocin/pharmacology ; }, abstract = {Oxidative stress appears to play a role in the pathogenesis of diabetes mellitus erectile dysfunction (DMED). This study aimed to investigate the effect of N-acetylcysteine (NAC) on DMED in streptozotocin-induced diabetic mice and to explore potential mechanisms. In the present study, we show that an erectile dysfunction is present in the streptozotocin-induced mouse model of diabetes as indicated by decreases in intracavernous pressure responses to electro-stimulation as well as from results of the apomorphine test of erectile function. After treatment of NAC, the intracavernous pressure was increased. In these DMED mice, oxidative stress and inflammatory responses were significantly reduced within the cavernous microenvironment, while activity of antioxidant enzymes in this cavernous tissue was enhanced after NAC treatment. These changes protected mitochondrial stress damage and a significant decreased in apoptosis within the cavernous tissue of DMED mice. This appears to involve activation of the nuclear factor erythroid 2-like-2 (Nrf2) signalling pathway, as well as suppression of the mitogen-activated protein kinase (MAPK) p38/ NF-κB pathway within cavernous tissue. In conclusion, NAC can improve erectile function through inhibiting oxidative stress via activating Nrf2 pathways and reducing apoptosis in streptozotocin-induced diabetic mice. NAC might provide a promising therapeutic strategy for individuals with DMED.}, }
@article {pmid35588920, year = {2022}, author = {Limansubroto, N and Chung, WO and Johnson, JD and Paranjpe, A}, title = {Immunomodulatory Effects of N-Acetyl Cysteine Treated SCAP.}, journal = {Journal of endodontics}, volume = {48}, number = {8}, pages = {1055-1062}, doi = {10.1016/j.joen.2022.05.005}, pmid = {35588920}, issn = {1878-3554}, mesh = {*Acetylcysteine/pharmacology ; Cell Differentiation ; Cytokines ; Dental Papilla ; Humans ; *Leukocytes, Mononuclear ; Stem Cells ; }, abstract = {INTRODUCTION: Stem cells of the apical papilla (SCAP) play an important role in regenerative endodontic procedures (REPs). Previous studies have shown that during REPs, bacteria can activate the innate immune system and cause indirect stem cell toxicity, leading to the lysis of SCAP. N-acetylcysteine (NAC)-treated cells are resistant to apoptosis and have increased differentiation capabilities. The immunomodulatory properties of NAC-treated SCAP are still unknown. Hence, the aim of this study is to evaluate the interactions of SCAP pretreated with and without NAC with the immune system.<br><br>METHODS: Flow cytometric analysis was performed to assess the effects of NAC on SCAP viability. Human SCAP were then cultured and were either pretreated with NAC or non-treated and co-cultured with human peripheral blood mononuclear cells. A lactate dehydrogenase assay was performed to evaluate the levels of immune cell mediated apoptosis, followed by an enzyme-linked immunosorbent assay (ELISA) to measure levels of proinflammatory cytokines for these co-cultures. Data were analyzed using analysis of variance with post hoc Tukey test.<br><br>RESULTS: Cells treated with NAC had similar levels of viability as the controls. SCAP pretreated with NAC had significantly lower immune cell-mediated cytotoxicity to nonactivated and activated peripheral blood mononuclear cells. The ELISA results showed that SCAP pretreated with NAC induced lower levels of proinflammatory cytokines.<br><br>CONCLUSIONS: SCAP pretreated with NAC have a higher chance of surviving the activated immune system. This information may provide a better insight into the properties of these stem cells and may be the key to making REPs more predictable.}, }
@article {pmid35587328, year = {2022}, author = {Dhillon, T and Kumar, A and Kumar, V}, title = {Neuroprotective Effect of N-acetylcysteine Against Monocrotophos-Induced Oxidative Stress in Different Brain Regions of Rats.}, journal = {Applied biochemistry and biotechnology}, volume = {194}, number = {9}, pages = {4049-4065}, pmid = {35587328}, issn = {1559-0291}, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism/pharmacology ; Brain ; Lipid Peroxidation ; Male ; Mammals/metabolism ; *Monocrotophos/metabolism/toxicity ; *Neuroprotective Agents/metabolism/pharmacology ; Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {Monocrotophos (MCP) is systemic organophosphate insecticide used against crop pests. It is reported to cause mammalian toxicity through both acute and chronic exposure. In the present study, we have shown the protective role of N-acetylcysteine (NAC) against MCP-induced oxidative stress in frontal cortex, corpus striatum and hippocampus brain regions of rats. Male Albino Wistar rats were divided into control, NAC-treated, MCP and NAC + MCP-treated groups. An oral dose of MCP (0.9 mg/kg b.wt) and NAC (200 mg/kg b.wt) was administered for 28 days. Results showed an increase in lipid peroxidation (LPO) and protein oxidation followed by decreased antioxidant enzymes after 28 days of MCP exposure. Histopathological analysis showed that monocrotophos exposure caused neurodegenerative changes as evident by neurons with dystrophic changes in the form of shrunken hyperchromatic nuclei in all the regions of the rat brain. N-acetylcysteine supplementation to MCP-treated rats showed a reduction in oxidative stress and ameliorated cellular alterations in all of the three regions. The results of the study indicate that N-acetylcysteine offers neuroprotection by improving antioxidant response and decreasing oxidative stress in different regions of the rat brain.}, }
@article {pmid35587124, year = {2023}, author = {Sudanagunta, S and Camarena-Michel, A and Pennington, S and Leonard, J and Hoyte, C and Wang, GS}, title = {Comparison of Two-Bag Versus Three-Bag N-Acetylcysteine Regimens for Pediatric Acetaminophen Toxicity.}, journal = {The Annals of pharmacotherapy}, volume = {57}, number = {1}, pages = {36-43}, doi = {10.1177/10600280221097700}, pmid = {35587124}, issn = {1542-6270}, mesh = {Adult ; Child ; Humans ; Adolescent ; Acetylcysteine/therapeutic use ; Acetaminophen/therapeutic use ; Antidotes/therapeutic use ; Cohort Studies ; *Drug-Related Side Effects and Adverse Reactions ; *Drug Overdose/drug therapy ; Retrospective Studies ; *Analgesics, Non-Narcotic/therapeutic use ; }, abstract = {BACKGROUND: Acetaminophen overdose is a leading cause of liver failure, and a leading cause of pediatric poisoning requiring hospital admission. The antidote, N-acetylcysteine (NAC), is traditionally administered as a three-bag intravenous infusion. Despite its efficacy, NAC is associated with high incidence of nonallergic anaphylactoid reactions (NAARs). Adult evidence demonstrates that alternative dosing regimens decrease NAARs and medication errors (MEs).<br><br>OBJECTIVES: To compare NAARs and MEs associated with two- versus three-bag NAC for acetaminophen overdose in a pediatric population.<br><br>METHODS: This is a retrospective observational cohort study comparing pediatric patients who received three- versus two-bag NAC for acetaminophen toxicity. The primary outcome was incidence of NAARs. Secondary outcomes were rates of MEs and relevant hospital outcomes (length of stay [LOS], intensive care unit (ICU) admission, liver transplant, death).<br><br>RESULTS: Two hundred forty-three patients met inclusion criteria (median age of 15 years): 150 (62%) three-bag NAC and 93 (38%) two-bag NAC. There was no difference in overall NAARs (p = 0.54). Fewer cutaneous NAARs were observed in the two-bag group, three-bag: 15 (10%), two-bag: 2 (2%), p = 0.02. MEs were significantly decreased with the two-bag regimen, three-bag: 59 (39%), two-bag: 21 (23%), p = 0.01. No statistical differences were observed in LOS, ICU admissions, transplant, or death.<br><br>CONCLUSION AND RELEVANCE: A significant decrease in cutaneous NAARs and MEs was observed in pediatric patients by combining the first two bags of the traditional three-bag NAC regimen. In pediatric populations, a two-bag NAC regimen for acetaminophen overdose may improve medication tolerance and safety.}, }
@article {pmid35583464, year = {2022}, author = {Zhang, M and Hu, Y and Li, W and Sun, C and Guan, C and Peng, Y and Zheng, J}, title = {In Vitro and In Vivo Metabolic Activation and Hepatotoxicity of Environmental Pollutant 2,6-Dimethylphenol.}, journal = {Chemical research in toxicology}, volume = {35}, number = {6}, pages = {1036-1044}, doi = {10.1021/acs.chemrestox.2c00048}, pmid = {35583464}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic ; Animals ; *Chemical and Drug Induced Liver Injury ; *Environmental Pollutants/toxicity ; Glutathione/metabolism ; Mice ; Xylenes ; }, abstract = {2,6-Dimethylphenol (2,6-DMP) is an environmental pollutant found in industrial wastewater. Exposure to 2,6-DMP is of increasing concern as it endangered reportedly some aquatic animals. In this study, we investigated the metabolic activation and hepatotoxicity of 2,6-DMP. 2,6-DMP was metabolized to an o-quinone methide intermediate in vitro and in vivo. The electrophilic metabolite was reactive to the sulfhydryl groups of glutathione, N-acetyl cysteine, and cysteine. NADPH was required for the formation of the reactive metabolite. The quinone methide intermediate reacted with cysteine residues to form hepatic protein adduction. A single dose of 2,6-DMP induced marked elevation of serum ALT and AST in mice. Both the protein adduction and hepatotoxicity of 2,6-DMP showed dose dependency.}, }
@article {pmid35582415, year = {2022}, author = {Yu, P and Luo, J and Song, H and Qian, T and He, X and Fang, J and Dong, W and Bian, X}, title = {N-acetylcysteine Ameliorates Vancomycin-induced Nephrotoxicity by Inhibiting Oxidative Stress and Apoptosis in the in vivo and in vitro Models.}, journal = {International journal of medical sciences}, volume = {19}, number = {4}, pages = {740-752}, pmid = {35582415}, issn = {1449-1907}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; *Acute Kidney Injury/chemically induced/drug therapy ; Animals ; Anti-Bacterial Agents/adverse effects ; Apoptosis ; Caspase 3/metabolism ; Kidney/pathology ; Lipocalin-2/metabolism/pharmacology ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; *Vancomycin/adverse effects/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Background: Oxidative stress-related apoptosis is considered as the key mechanism implicated in the pathophysiology of nephrotoxicity with vancomycin (VCM) therapy. We evaluated the possible effects of N-acetylcysteine (NAC) on VCM-induced nephrotoxicity and the underlying mechanism. Methods: VCM-induced nephrotoxicity was established using HK-2 cells and SD rats and observed by measuring cell survival, kidney histological changes, renal function and kidney injury related markers (KIM-1 and NGAL). Oxidative stress, renal cell apoptosis and the involved signaling pathways were also evaluated. Results: In model rats, NAC could protect against VCM-induced acute kidney injury with histological damage, renal dysfunction, and increased Cre and BUN levels. In HK-2 cells, VCM-induced decreased cell viability was restored by NAC. In addition, increased expression of caspase-3, KIM-1 and NGAL suffering from VCM was also reversed by NAC in vivo and in vitro. NAC inhibited ROS production, decreased cell apoptosis by decreasing the Bax/Bcl-2 ratio and caspase-3 expression in HK-2 cells and regulated oxidative stress indicators in the kidney by decreasing GSH, SOD and CAT activity and increasing MDA levels. Furthermore, NAC could effectively reverse VCM-associated increased P38 MAPK/JNK phosphorylation. Conclusions: The results demonstrated that NAC had a protective effect against nephrotoxicity from VCM by inhibiting oxidative stress and apoptosis via P38 MAPK/JNK.}, }
@article {pmid35580081, year = {2022}, author = {Moens, C and Muller, CJF and Bouwens, L}, title = {In vitro comparison of various antioxidants and flavonoids from Rooibos as beta cell protectants against lipotoxicity and oxidative stress-induced cell death.}, journal = {PloS one}, volume = {17}, number = {5}, pages = {e0268551}, pmid = {35580081}, issn = {1932-6203}, mesh = {Antioxidants/analysis/pharmacology ; *Aspalathus ; Cell Death ; *Diabetes Mellitus, Type 2/drug therapy ; Exenatide/pharmacology ; Flavonoids/analysis/pharmacology ; *Insulin-Secreting Cells ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 ; Oxidative Stress ; Plant Extracts/pharmacology/therapeutic use ; Protective Agents/pharmacology ; }, abstract = {Oxidative stress and lipotoxicity effects on pancreatic β cells play a major role in the pathogenesis of type 2 diabetes (T2D). Flavonoids and antioxidants are under study for their cytoprotective effects and antidiabetic potential. In this study, we aimed to compare the protective effect of the Rooibos components aspalathin, isoorientin, 3-hydroxyphloretin (3-OH) and green Rooibos extract (GRT) itself, and exendin-4 and N-acetylcysteine (NAC) as reference molecules, against lipotoxicity and oxidative stress. The insulin-producing β cell line INS1E was exposed to hydrogen peroxide or streptozotocin (STZ) to induce oxidative stress, and palmitate to induce lipotoxicity. Cell viability was assessed by a MTS cell viability assay. Antioxidant response and antiapoptotic gene expression was performed by qRT-PCR. Glucose transporter 2 (GLUT 2) transporter inhibition was assessed through 2-NBDG uptake. GRT and the flavonoids aspalathin and 3-hydroxyphloretin offered significant protection against oxidative stress and lipotoxicity. GRT downregulated expression of pro-apoptotic genes Txnip and Ddit3. The flavonoids aspalathin and 3-hydroxyphloretin also downregulated these genes and in addition upregulated expression of antioxidant response genes Hmox1, Nqo1 and Sod1. Isoorientin gave no cytoprotection. Cytoprotection by Rooibos components was significantly higher than by NAC or exendin-4. Rooibos components strongly protect INS1E β cells against diabetogenic stress. Cytoprotection was associated with the upregulation of antioxidant response genes of the NRF2/KEAP1 pathway or suppression of the TXN system. The Rooibos molecules offered better protection against these insults than exendin-4 and NAC, making them interesting candidates as β cell cytoprotectants for therapeutic or nutraceutical applications.}, }
@article {pmid35578630, year = {2022}, author = {Khurana, P and Varshney, R and Gupta, A}, title = {A network-biology led computational drug repurposing strategy to prioritize therapeutic options for COVID-19.}, journal = {Heliyon}, volume = {8}, number = {5}, pages = {e09387}, pmid = {35578630}, issn = {2405-8440}, abstract = {The alarming pandemic situation of novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection, high drug development cost and slow process of drug discovery have made repositioning of existing drugs for therapeutics a popular alternative. It involves the repurposing of existing safe compounds which results in low overall development costs and shorter development timeline. In the present study, a computational network-biology approach has been used for comparing three candidate drugs i.e. quercetin, N-acetyl cysteine (NAC), and 2-deoxy-glucose (2-DG) to be effectively repurposed against COVID-19. For this, the associations between these drugs and genes of Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) diseases were retrieved and a directed drug-gene-gene-disease interaction network was constructed. Further, to quantify the associations between a target gene and a disease gene, the shortest paths from the target gene to the disease genes were identified. A vector DV was calculated to represent the extent to which a disease gene was influenced by these drugs. Quercetin was quantified as the best among the three drugs, suited for repurposing with DV of -70.19, followed by NAC with DV of -39.99 and 2-DG with DV of -13.71. The drugs were also assessed for their safety and efficacy balance (in terms of therapeutic index) using network properties. It was found that quercetin was a forerunner than other two drugs.}, }
@article {pmid35575346, year = {2022}, author = {Li, X and Xing, G and Guo, X and Wang, Y and Hu, Z and Cheng, M and Peng, Y and Zheng, J}, title = {Identification of Metoprolol Tartrate-Derived Reactive Metabolites Possibly Correlated with Its Cytotoxicity.}, journal = {Chemical research in toxicology}, volume = {35}, number = {6}, pages = {1059-1069}, doi = {10.1021/acs.chemrestox.2c00052}, pmid = {35575346}, issn = {1520-5010}, mesh = {Animals ; Rats ; Acetylcysteine/metabolism/pharmacology ; Glutathione/metabolism ; *Metoprolol/metabolism/pharmacology ; *Microsomes, Liver/metabolism ; }, abstract = {As a selective β1-receptor antagonist, metoprolol tartrate (MTA) is commonly used to treat cardiovascular diseases such as hypertension and angina pectoris. There have been cases of liver injury induced by MTA, but the mechanism of hepatotoxicity induced by MTA is not clear. The purposes of this study were to identify the reactive metabolites of MTA, to determine the pathway for the metabolic activation of MTA, and to define a possible correlation between the metabolic activation and cytotoxicity of MTA. Three oxidative metabolites (M1-M3), a glutathione (GSH) conjugate (M4), and an N-acetyl cysteine (NAC) conjugate (M5) were detected in rat liver microsomal incubations containing MTA and GSH or NAC. M4 was also detected in cultured rat primary hepatocytes and bile of rats given MTA, and M5 was detected in the urine of MTA-treated rats. A quinone methide intermediate may be produced from the metabolic activation process in vitro and in vivo. The metabolite was reactive to glutathione and N-acetyl cysteine. MTA induced marked cytotoxicity in cultured rat primary hepatocytes. Pretreatment of aminobenzotriazole, a nonselective P450 enzyme inhibitor, attenuated the susceptibility of hepatocytes to MTA cytotoxicity.}, }
@article {pmid35575100, year = {2023}, author = {Motafeghi, F and Mortazavi, P and Salman Mahiny, AH and Abtahi, MM and Shokrzadeh, M}, title = {The role of ginger's extract and N-acetylcysteine against docetaxel-induced oxidative stress and genetic disorder.}, journal = {Drug and chemical toxicology}, volume = {46}, number = {4}, pages = {617-624}, doi = {10.1080/01480545.2022.2075377}, pmid = {35575100}, issn = {1525-6014}, mesh = {*Acetylcysteine/pharmacology ; *Zingiber officinale ; Docetaxel/toxicity ; Reactive Oxygen Species ; Oxidative Stress ; Plant Extracts/pharmacology ; Antioxidants/pharmacology ; Flavonoids/pharmacology ; Phenols/pharmacology ; }, abstract = {Oxidative stress plays a prominent role in expanding toxicity and various diseases. This study investigated the potential protective effects of ginger (Zingiber officinale) rhizome extract and NAC on docetaxel induced genotoxicity and oxidative stress. The antioxidant power of NAC and ginger extract on the genetic toxicity induced by docetaxel was assessed by micronucleus test. The ROS test with DCFH reagent was used to assess the reactive oxygen species. The thiobarbituric acid method was used to evaluate the amount of MDA produced by docetaxel. The amounts of phenol and flavonoids in the ginger extracts were also evaluated. The amount of phenol in the ginger extract was 0.886 mg of gallic acid per gram of dry extract. The amount of flavonoids were 0.242 mg/mL of quercetin per gram of dry extract. As shown by the micronucleus results, concentrations of 100 and 500 μM NAC and all concentrations of the ginger extract significantly reduced the number of micronuclei produced by docetaxel. On the other hand, the results of oxidative stress tests (ROS and LPO) showed that docetaxel in HGF cells increased the production of ROS and LPO, and the concentrations of ginger extract and NAC decreased oxidative stress in HGF cells in a dose-dependent manner. The results indicate that using these two antioxidants helps inhibit genetic toxicity and oxidative stress caused by docetaxel.}, }
@article {pmid35573789, year = {2022}, author = {Gu, J and Lin, Y and Wang, Z and Pan, Q and Cai, G and He, Q and Xu, X and Cai, X}, title = {Campylobacter jejuni Cytolethal Distending Toxin Induces GSDME-Dependent Pyroptosis in Colonic Epithelial Cells.}, journal = {Frontiers in cellular and infection microbiology}, volume = {12}, number = {}, pages = {853204}, pmid = {35573789}, issn = {2235-2988}, mesh = {Bacterial Toxins ; *Campylobacter jejuni/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Epithelial Cells/metabolism ; Humans ; *Pyroptosis ; Reactive Oxygen Species/metabolism ; Receptors, Estrogen/metabolism ; }, abstract = {BACKGROUND: Cytolethal distending toxin (CDT) is a critical virulence factor of Campylobacter jejuni, and it induces cell death and regulates inflammation response in human epithelial cells. Pyroptosis is an inflammatory form of programmed cell death (PCD), but whether it is involved in CDT-mediated cytotoxicity remains elusive.<br><br>AIMS: This study explores the role and mechanism of pyroptosis in CDT-mediated cytotoxicity.<br><br>METHODS: HCT116 and FHC cell lines were treated with CDT. Cell Counting Kit-8 (CCK-8) assay was used to detect cell viability. Western blotting was used to measure the expression of related proteins in the pathway, and cell morphology observation, annexin V/propidium iodide (PI) staining and lactate dehydrogenase (LDH) release assay were performed to evaluate the occurrence of pyroptosis.<br><br>RESULT: Our results show that C. jejuni CDT effectively induces pyroptosis in a dose- and time- dependent manner in human colonic epithelial cells owing to its DNase activity. Specific pyroptotic features including large bubbles emerging from plasma membrane and LDH release were observed upon CDT treatment. Moreover, CDT-induced pyroptosis involves the caspase-9/caspase-3 axis, which is followed by gasdermin E (GSDME) cleavage rather than gasdermin D (GSDMD). N-acetyl cysteine (NAC), a reactive oxygen species (ROS) inhibitor, attenuates the activation of caspase-9/3, the cleavage of GSDME and pyroptotic characteristic, therefore demonstrating ROS initiates pyroptotic signaling.<br><br>CONCLUSIONS: We first clarify a molecular mechanism that CDT induces pyroptosis via ROS/caspase-9/caspase-3/GSDME signaling. These findings provide a new insight on understanding of CDT-induced pathogenesis at the molecular level.}, }
@article {pmid35571469, year = {2022}, author = {Krishnamurthy, V and Joseph, A and Venkataraman, S and Kurian, G}, title = {Simethicone and N-acetyl cysteine combination as premedication before esophagogastroduodenoscopy: Double-blind randomized controlled trial.}, journal = {Endoscopy international open}, volume = {10}, number = {5}, pages = {E585-E592}, pmid = {35571469}, issn = {2364-3722}, abstract = {Background and study aims Esophagogastroduodenoscopy (EGD), the most common method used for diagnosing upper gastrointestinal diseases, is often limited by the presence of foam and mucous. Thus, this study was designed to detect whether the combination of simethicone with N-acetyl cysteine (NAC) as premedication before EGD improves mucosal visualization. Patients and methods A total of 768 consenting patients were enrolled in this prospective, double-blind, randomized placebo-controlled trial in four groups (A: simethicone + N-acetyl cysteine; B: simethicone alone; C: NAC alone; and D: placebo). After 20 minutes of consuming the corresponding solution, EGD was done and multiple images were obtained from the esophagus, stomach, and duodenum. Based on the various images obtained, the study parameters were calculated. Statistical Analysis Software (SAS) was used to analyze the results using Kruskal-Wallis with the Bonferroni correction method. Results The study population consisted of 57 % men and the mean age was 44.18 years. Each group was randomized with 192 participants. Group A (combination of simethicone + NAC) premedication had the lowest total mucosal visibility score of 8.31, a significantly lower score for mucous/bubbles obscuring the vision, and less time to complete the procedure. Also, 81 % of the participants in group A did not require flushing to clear the mucous/bubbles. There were no side effects due to this premedication in any of the groups. Conclusions Using simethicone and NAC combined for premedication may improve the quality of EGD.}, }
@article {pmid35571453, year = {2022}, author = {Chen, Q and Hou, Y and Li, D and Ding, Z and Xu, X and Hao, B and Xia, Q and Li, M and Fan, L}, title = {Berberine induces non-small cell lung cancer apoptosis via the activation of the ROS/ASK1/JNK pathway.}, journal = {Annals of translational medicine}, volume = {10}, number = {8}, pages = {485}, pmid = {35571453}, issn = {2305-5839}, abstract = {BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Berberine (BBR), an isoquinoline alkaloid, is commonly used in traditional Chinese medicine. Previous studies have shown that BBR has a potential anti-tumor effect. However, the mechanisms of BBR on mitochondrial function in anti-lung cancer remain unknown. The aim of this study was to explore mitochondrial function in anti-tumor mechanisms of BBR in NSCLC.<br><br>METHODS: The NSCLCs were cultured and treated with various doses (40, 80, 120 &#xb5;g/mL) of BBR for 24 and 48 h. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8). Cell apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. Relative protein expression was examined by western blot and immunohistochemical (IHC) analysis.<br><br>RESULTS: BBR potently suppressed NSCLC cells growth by inducing apoptosis in a dose-and time-dependent manner. BBR induced apoptosis in NSCLC cells as evidenced by caspase-3 cleavage, cytochrome c release, and mitochondrial membrane depolarization. BBR-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of c-jun-NH2-kinase (JNK) and the JNK inhibitor (SP600125) significantly suppressed BBR-induced apoptosis, N-acetyl cysteine (NAC), a ROS scavenger, was sufficient to both suppress apoptosis signal-regulating kinase 1 (ASK1) and JNK activation and disrupt apoptotic induction.<br><br>CONCLUSIONS: The results suggest that BBR induces apoptosis of NSCLC cells via ROS-mediated ASK1/JNK activation and the mitochondrial pathway.}, }
@article {pmid35571237, year = {2022}, author = {Zhu, M and Ye, L and Zhu, G and Zeng, Y and Yang, C and Cai, H and Mo, Y and Song, X and Gao, X and Peng, W and Wang, J and Jin, M}, title = {ROS-Responsive miR-150-5p Downregulation Contributes to Cigarette Smoke-Induced COPD via Targeting IRE1α.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {5695005}, pmid = {35571237}, issn = {1942-0994}, mesh = {3' Untranslated Regions ; Animals ; Biomarkers/metabolism ; *Cigarette Smoking/adverse effects ; Down-Regulation ; Endoribonucleases/metabolism ; Humans ; Inositol ; Mice ; *MicroRNAs/genetics/metabolism ; Protein Serine-Threonine Kinases ; *Pulmonary Disease, Chronic Obstructive/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {MicroRNAs (miRNAs) have been reported in human diseases, in which chronic obstructive pulmonary disease (COPD) is included. Herein, we assessed the role along with the possible mechanisms of miR-150-5p in cigarette smoke- (CS-) induced COPD. The plasma miR-150-5p expression was lower in patients with COPD and acute exacerbation of COPD (AECOPD) and was related to disease diagnosis, disease severity, and lung function. Consistently, exposure to CS for 3 months or 3 days reduced miR-150-5p in the plasma and lung tissues of mice, and CS extract (CSE) inhibited miR-150-5p in human bronchial epithelial cells (HBECs) in a concentration along with time-dependent approach. In vitro, miR-150-5p overexpression decreased the contents of inflammatory factors interleukin- (IL-) 6, IL-8 along with cyclooxygenase-2 (COX-2), and endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP) and promoted cell migrate. Mechanistically, miR-150-5p could bind with the 3'-untranslated region (UTR) of inositol requiring enzyme 1α (IRE1α), while IRE1α overexpression obliterated the impacts of miR-150-5p. Besides, N-acetyl-cysteine (NAC) reversed CSE-induced miR-150-5p downregulation and its downstream effects. In vivo, miR-150-5p overexpression counteracted CS-triggered IRE1α upregulation, inflammation, and ER stress in the lung tissues of mice. In conclusion, our findings illustrated that ROS-mediated downregulation of miR-150-5p led to CS-induced COPD by inhibiting IRE1α expression, suggesting to serve as a useful biomarker for diagnosing and treating COPD.}, }
@article {pmid35566133, year = {2022}, author = {Currie, TL and Engler, MM and Olsen, CH and Krauthamer, V and Scott, JM and Deuster, PA and Flagg, TP}, title = {The Effects of Berry Extracts on Oxidative Stress in Cultured Cardiomyocytes and Microglial Cells: A Potential Cardioprotective and Neuroprotective Mechanism.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {9}, pages = {}, pmid = {35566133}, issn = {1420-3049}, mesh = {Anthocyanins/pharmacology ; Antioxidants/pharmacology ; Fruit ; Microglia ; Myocytes, Cardiac ; Oxidative Stress ; Plant Extracts/pharmacology ; *Ribes ; *Vaccinium macrocarpon ; }, abstract = {Oxidative stress is a key underlying factor in cognitive decline and atherosclerosis. Oxidative stress occurs at the cellular level with an imbalance between reactive oxygen species and reactive nitrogen species and a deficiency in antioxidants. Mounting evidence suggests that berry flavonoids may promote cellular health by exerting antioxidant properties. Black currant and various berry extracts were tested in microglia (BV-2) and cardiomyocyte (HL-1) cell lines to study their biological effects. The principal ingredients in black currant and cranberry extract-delphinidin 3-rutinoside (D3R) and cyanidin 3-glucoside (C3G), were also assessed. A menadione-induced oxidative stressor was used, and its output was quantified to detect oxidative stress (CellROX[TM]). Black currant extract had similar antioxidant effects as N-acetylcysteine (NAC) in HL-1 cells with regard to cellular protection, whereas cranberry extract was ineffective. In contrast, cranberry extract was comparable in effectiveness to black currant extract in BV-2 cells. D3R and C3G also reduced oxidative stress similarly to whole berry extracts, which indicates that these ingredients may confer the antioxidant effects of berries. Black currant and cranberry extracts inhibit oxidative stress in microglial and cardiomyocyte cell lines. Black currant extract was more effective in reducing oxidative stress in the HL-1 cells, whereas cranberry extract was comparable in reducing oxidative stress in the BV-2 cells. The results suggest that berry flavonoids exert neuro- and cardioprotective effects.}, }
@article {pmid35564261, year = {2022}, author = {Nozdrenko, D and Prylutska, S and Bogutska, K and Cherepanov, V and Senenko, A and Vygovska, O and Khrapatyi, S and Ritter, U and Prylutskyy, Y and Piosik, J}, title = {Analysis of Biomechanical and Biochemical Markers of Rat Muscle Soleus Fatigue Processes Development during Long-Term Use of C60 Fullerene and N-Acetylcysteine.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {12}, number = {9}, pages = {}, pmid = {35564261}, issn = {2079-4991}, abstract = {The development of an effective therapy aimed at restoring muscle dysfunctions in clinical and sports medicine, as well as optimizing working activity in general remains an urgent task today. Modern nanobiotechnologies are able to solve many clinical and social health problems, in particular, they offer new therapeutic approaches using biocompatible and bioavailable nanostructures with specific bioactivity. Therefore, the nanosized carbon molecule, C60 fullerene, as a powerful antioxidant, is very attractive. In this study, a comparative analysis of the dynamic of muscle soleus fatigue processes in rats was conducted using 50 Hz stimulation for 5 s with three consistent pools after intraperitoneal administration of the following antioxidants: C60 fullerene (a daily dose of 1 mg/kg one hour prior to the start of the experiment) and N-acetylcysteine (NAC; a daily dose of 150 mg/kg one hour prior to the start of the experiment) during five days. Changes in the integrated power of muscle contraction, levels of the maximum and minimum contraction force generation, time of reduction of the contraction force by 50% of its maximum value, achievement of the maximum force response, and delay of the beginning of a single contraction force response were analyzed as biomechanical markers of fatigue processes. Levels of creatinine, creatine phosphokinase, lactate, and lactate dehydrogenase, as well as pro- and antioxidant balance (thiobarbituric acid reactive substances, hydrogen peroxide, reduced glutathione, and catalase activity) in the blood of rats were analyzed as biochemical markers of fatigue processes. The obtained data indicate that applied therapeutic drugs have the most significant effects on the 2nd and especially the 3rd stimulation pools. Thus, the application of C60 fullerene has a (50-80)% stronger effect on the resumption of muscle biomechanics after the beginning of fatigue than NAC on the first day of the experiment. There is a clear trend toward a positive change in all studied biochemical parameters by about (12-15)% after therapeutic administration of NAC and by (20-25)% after using C60 fullerene throughout the experiment. These findings demonstrate the promise of using C60 fullerenes as potential therapeutic nanoagents that can reduce or adjust the pathological conditions of the muscular system that occur during fatigue processes in skeletal muscles.}, }
@article {pmid35563172, year = {2022}, author = {Gao, M and Hu, J and Zhu, Y and Wang, X and Zeng, S and Hong, Y and Zhao, G}, title = {Ferroptosis and Apoptosis Are Involved in the Formation of L-Selenomethionine-Induced Ocular Defects in Zebrafish Embryos.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, pmid = {35563172}, issn = {1422-0067}, support = {2018YFD0901700//National Key R&amp;D Program of China/ ; 2018ACF60014//The Fundamental Research Funds for the Key Scientific and Technological Projects in Jiangxi Province/ ; }, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis ; *Ferroptosis ; *Microphthalmos ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; *Selenium/metabolism ; Selenomethionine ; Zebrafish/genetics ; }, abstract = {Selenium is an essential trace element for humans and other vertebrates, playing an important role in antioxidant defense, neurobiology and reproduction. However, the toxicity of excessive selenium has not been thoroughly evaluated, especially for the visual system of vertebrates. In this study, fertilized zebrafish embryos were treated with 0.5 µM L-selenomethionine to investigate how excessive selenium alters zebrafish eye development. Selenium-stressed zebrafish embryos showed microphthalmia and altered expression of genes required for retinal neurogenesis. Moreover, ectopic proliferation, disrupted mitochondrial morphology, elevated ROS-induced oxidative stress, apoptosis and ferroptosis were observed in selenium-stressed embryos. Two antioxidants-reduced glutathione (GSH) and N-acetylcysteine (NAC)-and the ferroptosis inhibitor ferrostatin (Fer-1) were unable to rescue selenium-induced eye defects, but the ferroptosis and apoptosis activator cisplatin (CDDP) was able to improve microphthalmia and the expression of retina-specific genes in selenium-stressed embryos. In summary, our results reveal that ferroptosis and apoptosis might play a key role in selenium-induced defects of embryonic eye development. The findings not only provide new insights into selenium-induced cellular damage and death, but also important implications for studying the association between excessive selenium and ocular diseases in the future.}, }
@article {pmid35553365, year = {2023}, author = {Kaya, S and Yalçın, T and Boydak, M and Dönmez, HH}, title = {Protective Effect of N-Acetylcysteine Against Aluminum-Induced Kidney Tissue Damage in Rats.}, journal = {Biological trace element research}, volume = {201}, number = {4}, pages = {1806-1815}, pmid = {35553365}, issn = {1559-0720}, mesh = {Rats ; Animals ; Acetylcysteine/pharmacology ; Aluminum/toxicity ; Rats, Wistar ; Kidney ; *Kidney Diseases/chemically induced/prevention &amp; control/pathology ; *Renal Insufficiency/pathology ; Oxidative Stress ; }, abstract = {Aluminum (AL) is an important nephrotoxic agent with a high daily exposure rate and property of accumulation in tissues. This study aimed to investigate the potential protective efficacy of N-acetylcysteine (NAC) against AL exposure-induced nephrotoxicity in rats. Twenty-eight rats were randomly divided into 4 groups as control, N-acetylcysteine group (NC), AL, and AL + NC, with an equal number of rats in each group (n = 7). No application was made to the control group. A total of 150 mg/kg/day NAC was administered to the NC group and 30 mg/kg/day AL was administered to the AL group intraperitoneally (i.p.). The AL + NC group received 30 mg/kg/day AL and 150 mg/kg/day NAC i.p. Biochemical parameters in blood serum and histopathological changes in kidney tissue, oxidative stress parameters, spexin (SPX), and apoptotic protein levels were examined after 15 days. Histopathological changes, biochemical parameters, oxidative stress parameters, and apoptotic protein levels were significantly irregular in the AL group compared to the control group. Moreover, SPX levels increased in the AL group. However, NAC treatment regulated AL exposure-related changes in the AL + NC group. NAC treatment may have a prophylactic effect against nephrotoxicity due to AL exposure. SPX may play a role in AL-induced nephrotoxicity.}, }
@article {pmid35551047, year = {2022}, author = {Liu, H and Li, MJ and Zhang, XN and Wang, S and Li, LX and Guo, FF and Zeng, T}, title = {N,N-dimethylformamide-induced acute liver damage is driven by the activation of NLRP3 inflammasome in liver macrophages of mice.}, journal = {Ecotoxicology and environmental safety}, volume = {238}, number = {}, pages = {113609}, doi = {10.1016/j.ecoenv.2022.113609}, pmid = {35551047}, issn = {1090-2414}, mesh = {Animals ; *Chemical and Drug Induced Liver Injury/etiology ; Dimethylformamide ; Inflammasomes ; Liver ; *Liver Diseases ; Macrophages ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein ; }, abstract = {N,N-dimethylformamide (DMF) is a non-negligible volatile hazardous material in indoor and outdoor environments. Although the hepatotoxicity of DMF has been well recognized, the underlying mechanisms remain unclear and prophylactic medicine is still lacking. Herein, we established a DMF-induced acute liver injury mouse model and investigated the underlying mechanisms focusing on oxidative stress and the nucleotide-binding domain and leucine-rich repeat receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome. DMF was found to induce oxidative stress, evidenced by the elevation of hepatic malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) adducts levels, and the decline of reduced glutathione (GSH) levels. However, neither N-acetyl cysteine (NAC) nor sulforaphane (SF) ameliorated the hepatoxicity induced by DMF in mice. Interestingly, DMF exposure led to focal necrosis of hepatocytes and NLRP3 inflammasome activation before the onset of obvious liver damage. In addition, DMF exposure induced infiltration and proinflammatory/M1 polarization of macrophages in mice livers. Furthermore, the inactivation of hepatic macrophages by GdCl3 significantly suppressed DMF-induced elevation of serum aminotransferase activities, neutrophile infiltration, and activation of NLRP3 inflammasome in mice liver. Collectively, these results suggest that DMF-induced acute hepatotoxicity may be attributed to the activation of NLRP3 inflammasome in liver macrophages, but not oxidative stress.}, }
@article {pmid35550579, year = {2022}, author = {Zhan, Y and Chen, J and Wu, J and Gu, Y and Huang, Q and Deng, Z and Chen, S and Wu, X and Lv, Y and Zeng, Z and Xie, J}, title = {Human epididymis protein 4 aggravates airway inflammation and remodeling in chronic obstructive pulmonary disease.}, journal = {Respiratory research}, volume = {23}, number = {1}, pages = {120}, pmid = {35550579}, issn = {1465-993X}, support = {81800041//National Natural Science Foundation of China/ ; 82170049//National Natural Science Foundation of China/ ; 81973986//National Natural Science Foundation of China,China/ ; WX21Q07//Health Research Fund of Wuhan/ ; WJ2019M116//Health and family planning research project of Hubei/ ; }, mesh = {Airway Remodeling ; Animals ; Cell Line ; Epithelial Cells/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Inflammation/metabolism ; *Interleukin-6/metabolism ; Mice ; *Pulmonary Disease, Chronic Obstructive ; WAP Four-Disulfide Core Domain Protein 2 ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by chronic inflammation and airway remodeling. Human epididymis protein 4 (HE4) plays a critical role in various inflammatory or fibrotic diseases. However, the role of HE4 in COPD remains unidentified.<br><br>METHODS: HE4 expression was determined in the lung tissues from COPD patients and cigarette smoke (CS)-exposed mice using immunohistochemical staining, qPCR, or western blot. The plasma level of HE4 was detected by ELISA. The regulations of HE4 in the expressions of CS extract (CSE)-induced inflammatory cytokines in human bronchial epithelial cells (HBE) were investigated through knockdown or overexpression of HE4. The role of secretory HE4 (sHE4) in the differentiation and proliferation in human pulmonary fibroblast cells (HPF) was explored via qPCR, western blot, CCK8 assay or 5-ethynyl-2'-deoxyuridine (EdU) staining. The probe of related mechanism in CSE-induced HE4 increase in HBE was conducted by administrating N-acetylcysteine (NAC).<br><br>RESULTS: HE4 was up-regulated in both the lung tissue and plasma of COPD patients relative to controls, and the plasma HE4 was negatively associated with lung function in COPD patients. The same enhanced HE4 expression was verified in CS-exposed mice and CSE-induced HBE, but CSE failed to increase HE4 expression in HPF. In vitro experiments showed that reducing HE4 expression in HBE alleviated CSE-induced IL-6 release while overexpressing HE4 facilitated IL-6 expression, mechanistically through affecting phosphorylation of NF&#x3ba;B-p65, whereas intervening HE4 expression had no distinctive influence on IL-8 secretion. Furthermore, we confirmed that sHE4 promoted fibroblast-myofibroblast transition, as indicated by promoting the expression of fibronectin, collagen I and &#x3b1;-SMA via phosphorylation of Smad2. EdU staining and CCK-8 assay demonstrated the pro-proliferative role of sHE4 in HPF, which was further confirmed by enhanced expression of survivin and PCNA. Pretreatment of NAC in CSE or H2O2-induced HBE mitigated HE4 expression.<br><br>CONCLUSIONS: Our study indicates that HE4 may participate in airway inflammation and remodeling of COPD. Cigarette smoke enhances HE4 expression and secretion in bronchial epithelium mediated by oxidative stress. Increased HE4 promotes IL-6 release in HBE via phosphorylation of NF&#x3ba;B-p65, and sHE4 promotes fibroblastic differentiation and proliferation.}, }
@article {pmid35547461, year = {2022}, author = {Arunpriyandan, V and Sundaresan, KT}, title = {Fulminant Hepatic Failure in Dengue Fever Without Plasma Leakage: A Case Report.}, journal = {Cureus}, volume = {14}, number = {4}, pages = {e23964}, pmid = {35547461}, issn = {2168-8184}, abstract = {Dengue is an important arboviral disease in the tropics and subtropics. Although mild to moderate elevation of liver transaminases is a common phenomenon, dengue infection leading to hepatic failure is a rare complication in adults. We present a case of dengue fever in a young adult, leading to the rare complication of acute liver failure, without dengue shock syndrome. We tried evidence-based management with therapeutic plasma exchange, which led to a significant improvement in liver function.}, }
@article {pmid35546602, year = {2022}, author = {Ponnusamy, S and Ali, HH and Dutt, F and Rahman, SU and Salah, AA and Pipalia, M and Baier, RE and Arany, PR}, title = {Redox signaling induces laminin receptor ribosomal protein-SA expression to improve cell adhesion following radiofrequency glow discharge treatments.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {7742}, pmid = {35546602}, issn = {2045-2322}, mesh = {Biocompatible Materials/pharmacology ; Catalase/pharmacology ; Cell Adhesion ; *Laminin/pharmacology ; Oxidation-Reduction ; Porphyromonas gingivalis ; Receptors, Laminin ; Ribosomal Proteins ; *Streptococcus gordonii ; }, abstract = {Current biomaterials effectively replace biological structures but are limited by infections and long-term material failures. This study examined the molecular mechanisms of radio frequency glow discharge treatments (RFGDT) in mediating the disinfection of biomaterial surfaces and concurrently promoting cell attachment and proliferation. Dental biomaterials were subjected to RFGDT, and viability of oral microbial species, namely Streptococcus mutants (SM), Streptococcus gordonii (SG), Moraxella catarrhalis (MC), and Porphyromonas gingivalis (PG), were assessed. Cell attachment and survival of a pre-odontoblast cell line, MDPC-23, was examined. Finally, mechanistic investigations into redox generation and biological signaling were investigated. Based on their compositions, dental biomaterials induced reactive oxygen species (ROS) following dose-dependent RFGDT. Reduced microbial viability was evident following RFGDT in the catalase-negative (SM and SG) species more prominently than catalase-positive (MC and PG) species. Cell adhesion assays noted improved MDPC-23 attachment and survival. Pretreatments with N-acetylcysteine (NAC) and catalase abrogated these responses. Immunoassays noted redox-induced downstream expression of a laminin receptor, Ribosomal Protein SA, following RFGDT. Thus, RFGDT-induced redox mediates antimicrobial and improves cell responses such as adhesion and proliferation. These observations together provide a mechanistic rationale for the clinical utility of RFGDT with dental biomaterials for regenerative clinical applications.}, }
@article {pmid35543385, year = {2022}, author = {Wen, X and Li, S and Zhang, Y and Zhu, L and Xi, X and Zhang, S and Li, Y}, title = {Recombinant human klotho protects against hydrogen peroxide-mediated injury in human retinal pigment epithelial cells via the PI3K/Akt-Nrf2/HO-1 signaling pathway.}, journal = {Bioengineered}, volume = {13}, number = {5}, pages = {11767-11781}, pmid = {35543385}, issn = {2165-5987}, mesh = {Antioxidants/pharmacology ; Apoptosis ; Cell Survival ; Epithelial Cells/metabolism ; *Heme Oxygenase-1/genetics/metabolism ; Humans ; Hydrogen Peroxide/metabolism/toxicity ; *NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Retinal Pigments/metabolism/pharmacology ; Signal Transduction ; }, abstract = {Globally, age-related macular degeneration (AMD) is a common irreversible ophthalmopathy. Oxidative stress of retinal pigment epithelial cells is involved in AMD occurrence and development. Klotho is an anti-aging protein with antioxidant properties. We investigated the protective properties of Klotho on hydrogen peroxide (H2O2)-induced injury of retinal pigment epithelial cells (ARPE-19 cells) and its associated pathomechanisms. We found that Klotho pretreatment for 24 h could up-regulate Bcl-2 levels, decrease the cleaved-caspase-3 and Bax levels, inhibit H2O2-induced ARPE-19 cell apoptosis, and promote cell proliferation. Klotho pretreatment inhibited the H2O2-mediated elevations of reactive oxygen species (ROS) in ARPE-19 cells. It enhanced antioxidant activities of the cells and restored the glutathione peroxidase (GPX), superoxide dismutase (SOD2), catalase (CAT), as well as malondialdehyde (MDA) levels to close to the normal level. N-acetylcysteine (NAC), a reactive oxygen scavenger, could reverse the harmful effects of H2O2 on proliferation, apoptosis, and oxidative stress of ARPE-19 cells. Further, Klotho pretreatment enhanced Akt phosphorylation and expression as well as nuclear translocation of Nrf2 in H2O2-treated ARPE-19 cells. This indicates that Klotho protects cells from oxidative stress by activating phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)-nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) signaling pathway. Klotho is, therefore, a potential preventive or treatment option for AMD.}, }
@article {pmid35535444, year = {2022}, author = {Rafiee, B and Karbalay-Doust, S and Tabei, SMB and Azarpira, N and Alaee, S and Lohrasbi, P and Bahmanpour, S}, title = {Effects of N-acetylcysteine and metformin treatment on the stereopathological characteristics of uterus and ovary.}, journal = {European journal of translational myology}, volume = {32}, number = {2}, pages = {}, pmid = {35535444}, issn = {2037-7452}, abstract = {In this study, the stereo-pathological effect of metformin and N-acetyl cysteine is evaluated on the uterus and ovary of polycystic ovary syndrome (PCOS) mice. 96 mature females (8-weekold, weight of 20-30 gr) BALB/c mice were classified into 6 groups including the control group (n= 16), letrozole-induced PCOS group (n=16), PCOS + metformin (n=16), PCOS+NAC (n=16) and a separate control group for NAC (n=16). Another PCOS group was maintained for a month to make sure that features remain till the end of the study. Testosterone level, vaginal cytology and stereological evaluations were assessed. Vaginal cytology in letrozole-receiving mice showed a diestrus phase continuity. Testosterone level, body weight, uterine weight, endometrial volume, myometrial volume, gland volume, stromal volume, epithelial volume, vessel volume, daughter and conglomerate glands, endometrial thickness, and myometrial thickness exhibited an increasing trend in the uterus of PCOS mice. While normal gland and vessel length decreased in the PCOS group. Ovarian volume, corticomedullary volume, primary follicles, secondary follicles, and ovarian cysts were increased in PCOS ovaries. While corpus luteum, primordial, graafian, and atretic follicles showed a decline in the PCOS group. NAC and metformin, however, managed to restore the condition to normal. Given the prevalence of PCOS and its impact on fertility, the use of noninvasive methods is of crucial significance. NAC can control and treat pathological parameters and help as a harmless drug in the treatment of women with PCOS.}, }
@article {pmid35535093, year = {2022}, author = {Praharaj, DL and Anand, AC and Acharya, SK}, title = {Dosage of N-Acetyl Cysteine in Acute Liver Failure Not Related to Acetaminophen.}, journal = {Journal of clinical and experimental hepatology}, volume = {12}, number = {2}, pages = {726-728}, pmid = {35535093}, issn = {0973-6883}, }
@article {pmid35535082, year = {2022}, author = {Mishra, S}, title = {Dose of N-acetyl Cysteine in INASL Consensus on Acute Liver Failure (Part 2)-Management.}, journal = {Journal of clinical and experimental hepatology}, volume = {12}, number = {2}, pages = {725}, pmid = {35535082}, issn = {0973-6883}, }
@article {pmid35533555, year = {2022}, author = {Wang, L and Ji, T and Yuan, Y and Fu, H and Wang, Y and Tian, S and Hu, J and Wang, L and Wang, Z}, title = {High-fructose corn syrup promotes proinflammatory Macrophage activation via ROS-mediated NF-κB signaling and exacerbates colitis in mice.}, journal = {International immunopharmacology}, volume = {109}, number = {}, pages = {108814}, doi = {10.1016/j.intimp.2022.108814}, pmid = {35533555}, issn = {1878-1705}, mesh = {Animals ; *Colitis/chemically induced ; Dextran Sulfate/pharmacology ; Disease Models, Animal ; Fructose ; *High Fructose Corn Syrup/adverse effects ; *Inflammatory Bowel Diseases ; Macrophage Activation ; Mice ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Zea mays ; }, abstract = {The dramatically increasing incidence and prevalence of inflammatory bowel disease (IBD) are reportedly related to a Western diet, which is characterized by high sugar consumption. Dietary simple sugars aggravate IBD in animal models. However, the mechanisms underlying this effect remain unclear. Given that high-fructose corn syrup (HFCS) is a major added sugar in food and beverages, we focus on HFCS and investigated the effects of HFCS on a dextran sulfate sodium (DSS)-induced murine colitis model and in RAW264.7 macrophages. Our data demonstrate that short-term consumption of HFCS aggravates colitis and upregulates the proportion of macrophages in IBD mice but not in healthy mice. We find that HFCS promotes proinflammatory cytokine production through reactive oxygen species (ROS)-mediated nuclear factor-κB (NF-κB) signaling in RAW264.7 macrophages. Furthermore, N-acetylcysteine (NAC), an ROS scavenger, alleviates HFCS-aggravated colitis in mice and inhibits the ROS-mediated NF-κB signaling pathway in RAW264.7 macrophages. Our work unveils the important role of macrophages in HFCS-induced exacerbation of colitis and reveals the mechanism of how HFCS immunologically aggravates IBD.}, }
@article {pmid35532240, year = {2022}, author = {Wykoff, JA and Shaffer, KM and Araba, KC and Markovetz, MR and Patarin, J and Robert de Saint Vincent, M and Donaldson, SH and Ehre, C}, title = {Rapid Viscoelastic Characterization of Airway Mucus Using a Benchtop Rheometer.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {182}, pages = {}, doi = {10.3791/63876}, pmid = {35532240}, issn = {1940-087X}, mesh = {Humans ; *Mucus ; Reproducibility of Results ; Respiratory System ; Rheology ; Sputum ; Viscosity ; }, abstract = {In muco-obstructive lung diseases (e.g., asthma, chronic obstructive pulmonary disease, cystic fibrosis) and other respiratory conditions (e.g., viral/bacterial infections), mucus biophysical properties are altered by goblet cell hypersecretion, airway dehydration, oxidative stress, and the presence of extracellular DNA. Previous studies showed that sputum viscoelasticity correlated with pulmonary function and that treatments affecting sputum rheology (e.g., mucolytics) can result in remarkable clinical benefits. In general, rheological measurements of non-Newtonian fluids employ elaborate, time-consuming approaches (e.g., parallel/cone-plate rheometers and/or microbead particle tracking) that require extensive training to perform the assay and interpret the data. This study tested the reliability, reproducibility, and sensitivity of Rheomuco, a user-friendly benchtop device that is designed to perform rapid measurements using dynamic oscillation with a shear-strain sweep to provide linear viscoelastic moduli (G', G", G[*], and tan δ) and gel point characteristics (γc and σc) for clinical samples within 5 min. Device performance was validated using different concentrations of a mucus simulant, 8 MDa polyethylene oxide (PEO), and against traditional bulk rheology measurements. A clinical isolate harvested from an intubated patient with status asthmaticus (SA) was then assessed in triplicate measurements and the coefficient of variation between measurements is <10%. Ex vivo use of a potent mucus reducing agent, TCEP, on SA mucus resulted in a five-fold decrease in elastic modulus and a change toward a more "liquid-like" behavior overall (e.g., higher tan δ). Together, these results demonstrate that the tested benchtop rheometer can make reliable measures of mucus viscoelasticity in clinical and research settings. In summary, the described protocol could be used to explore the effects of mucoactive drugs (e.g., rhDNase, N-acetyl cysteine) onsite to adapt treatment on a case-by-case basis, or in preclinical studies of novel compounds.}, }
@article {pmid35527020, year = {2022}, author = {Chen, G and Lu, H}, title = {Oral high-dose acetylcysteine: Effective against the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?.}, journal = {Drug discoveries &amp; therapeutics}, volume = {16}, number = {3}, pages = {139-141}, doi = {10.5582/ddt.2022.01032}, pmid = {35527020}, issn = {1881-784X}, mesh = {*Acetylcysteine/therapeutic use ; Antioxidants/therapeutic use ; Expectorants/therapeutic use ; Glutathione ; Humans ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; }, abstract = {The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a high rate of transmission and it exhibits immune escape characteristics. N-acetyl-L-cysteine (NAC) is a precursor of reduced glutathione (GSH), which can enter cells to play an antioxidant role, so it is better than glutathione. Patients tolerate NAC well, and adverse reactions are rare and mild, so this type of drug with multiple actions is considered to be a mucolytic agent as well as a drug for the prevention/treatment of various diseases, including COVID-19. Previous studies indicated that the clinical effectiveness of NAC is dose-dependent. Low-dose NAC (0.2 g tid for adults) is a mucolytic expectorant, high-dose NAC (0.6 g bid or tid) has expectorant action as well as antioxidant action, and extreme-dose NAC (300 mg/kg.d) is used for detoxification in cases of an acetaminophen overdose. Presumably, orally administered high-dose NAC (0.6 g tid for adults and 10 mg/kg tid for children) could be used as an adjuvant to treat an Omicron infection. It should reduce the time to negative conversion and prevent severe COVID-19, reducing the duration of hospitalization and increasing the bed turnover rate.}, }
@article {pmid35526290, year = {2022}, author = {Rakhtshah, J and Shirkhanloo, H and Dehghani Mobarake, M}, title = {Simultaneously speciation and determination of manganese (II) and (VII) ions in water, food, and vegetable samples based on immobilization of N-acetylcysteine on multi-walled carbon nanotubes.}, journal = {Food chemistry}, volume = {389}, number = {}, pages = {133124}, doi = {10.1016/j.foodchem.2022.133124}, pmid = {35526290}, issn = {1873-7072}, mesh = {Acetylcysteine ; Adsorption ; Hydrogen-Ion Concentration ; Ions ; Limit of Detection ; *Manganese ; *Nanotubes, Carbon ; Solid Phase Extraction/methods ; Vegetables ; Water ; }, abstract = {A novel method based on the immobilization of N-acetylcysteine on chloro-functionalized multi-walled carbon nanotubes (MWCNTs@NAC) was used for the speciation of manganese ions [Mn (II) and Mn(VII)] in water samples. Also, the total manganese (TMn) in vegetables and food samples was determined by the AT-FAAS. By ultrasound-assisted-dispersive ionic liquid trap micro solid-phase extraction (UA-DILT-μ-SPE), the Mn (II)/Mn(VII) ions were extracted in the presence of MWCNTs@NAC for 50 mL of water samples at a pH of 6.5 and 3.0, respectively. The adsorption capacity of MWCNTs@NAC for Mn(II) and Mn(VII) ions was obtained at 146.7 mg g[-1] and 138.8 mg g[-1], respectively. Under the optimized conditions, the detection limits (LOD), linear range (LR), and enrichment factor (EF) for Mn(II) and Mn(VII) ions were obtained (0.12 μg L[-1]; 0.14 μg L[-1]), (0.48-36 μg L[-1]; 0.55-38.1 μg L[-1]) and (100.2; 94.5), respectively. The proposed methodology was successfully validated by the CRM samples.}, }
@article {pmid35523509, year = {2022}, author = {Raghu, K and Berry, MJ}, title = {Acute liver failure secondary to therapeutic paracetamol dosing in an extremely preterm neonate.}, journal = {BMJ case reports}, volume = {15}, number = {5}, pages = {}, pmid = {35523509}, issn = {1757-790X}, mesh = {Acetaminophen/therapeutic use ; *Ductus Arteriosus, Patent ; Humans ; Ibuprofen/therapeutic use ; Infant ; Infant, Extremely Premature ; Infant, Newborn ; *Liver Failure, Acute/chemically induced/drug therapy ; Male ; }, abstract = {We report the first case of standard therapeutic dose paracetamol for patent ductus arteriosus closure causing acute liver failure in an extremely preterm infant. After 5 days of treatment, he presented with jaundice, acute severe hepatitis and coagulopathy. Treatment with N-acetyl cysteine resulted in full recovery.}, }
@article {pmid35517780, year = {2022}, author = {Chen, HC and Chiou, HC and Tsai, ML and Chen, SC and Lin, MH and Chuang, TC and Hung, CH and Kuo, CH}, title = {Effects of Montelukast on Arsenic-Induced Epithelial-Mesenchymal Transition and the Role of Reactive Oxygen Species Production in Human Bronchial Epithelial Cells.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {877125}, pmid = {35517780}, issn = {1663-9812}, abstract = {Background: Epithelial-mesenchymal transition (EMT) of airway lung epithelial cells is considered a major driver of fibrosis and airway remodeling. Arsenic exposure is well known to cause the malignant transformation of cells, including those in the lung. Accumulating studies have shown that arsenic exposure is associated with chronic pulmonary diseases. However, clinical treatment for arsenic-induced pulmonary damage has not been well investigated. Materials and Methods: The therapeutic effects of montelukast and its combination with fluticasone on sodium arsenite-induced EMT changes in normal human bronchial cells were investigated. The cell migration ability was evaluated by Transwell and wound healing assays. EMT marker expression was determined by immunoblotting. Furthermore, the role of reactive oxygen species (ROS) generation in arsenic-induced EMT and the effect of montelukast on this process were determined by ROS inhibitor treatment and ROS measurement, respectively. Results: Montelukast was effective at reducing arsenic-induced cell migration and mesenchymal protein (fibronectin, MMP-2, N-cadherin, β-catenin, and SMAD2/3) expression. Arsenic-induced ROS production was attenuated by pretreatment with montelukast. Treatment with the ROS inhibitor N-acetyl cysteine reduced arsenic-induced NF-kB phosphorylation and the mesenchymal protein expression, indicating that ROS production is critical for arsenic-induced EMT. In addition, combined treatment with montelukast and fluticasone reversed the inhibitory effects of montelukast on cell migration. The expression of fibronectin, MMP-2 induced by arsenic was further enhanced by the combination treatment compared with montelukast treatment only. Conclusion: This study demonstrated that montelukast is effective at reducing arsenic-induced EMT in human bronchial epithelial cells. Through the inhibition of arsenic-induced ROS generation and NF-kB activation, which is critical for arsenic-induced EMT, montelukast inhibited arsenic-induced cell migration and the expression of extracellular matrix proteins and several EMT-regulating transcription factors. The combination of fluticasone with montelukast reversed the inhibitory effect of montelukast on arsenic-induced EMT. This study provides therapeutic strategies and mechanisms for arsenic-induced pulmonary epithelial damage.}, }
@article {pmid35513370, year = {2022}, author = {Fan, L and Guan, F and Ma, Y and Zhang, Y and Li, L and Sun, Y and Cao, C and Du, H and He, M}, title = {N-Acetylcysteine improves oocyte quality through modulating the Nrf2 signaling pathway to ameliorate oxidative stress caused by repeated controlled ovarian hyperstimulation.}, journal = {Reproduction, fertility, and development}, volume = {34}, number = {10}, pages = {736-750}, doi = {10.1071/RD22020}, pmid = {35513370}, issn = {1448-5990}, mesh = {Animals ; Female ; Mice ; *Acetylcysteine/pharmacology ; NF-E2-Related Factor 2/metabolism ; Oocytes/metabolism ; *Ovarian Hyperstimulation Syndrome/metabolism ; Oxidative Stress ; Signal Transduction ; }, abstract = {CONTEXT: N -acetyl-cysteine (NAC) is a potent antioxidant that can be used for many gynecological diseases such as polycystic ovary syndrome and endometriosis. Controlled ovarian hyperstimulation (COH) is a critical step in infertility treatment. Our previous clinical studies have shown that repeated COH led to oxidative stress in follicle fluid and ovarian granulosa cells.<br><br>AIMS: In this study, we investigated whether NAC could inhibit oxidative stress in mice caused by repeated COH and improve the mitochondrial function of oocytes.<br><br>METHODS: Female Institute of Cancer Research (ICR) mice were randomly assigned into three groups: normal group, model (repeated COH) group, NAC group. We examined the morphology, number and quality of mitochondria. The mechanism of regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) by NAC to ameliorate oxidative stress was also investigated.<br><br>KEY RESULTS: Repeated COH caused oxidative damage in ovaries and oocytes and decreased oocyte quality, while NAC prevented oxidative damage and increased oocyte mitochondrial function. In in vitro experiments, it was verified that NAC can promote the nuclear translocation of Nrf2, which transcriptionally activates the expression of superoxide dismutase and glutathione peroxidase, which removed excessive reactive oxygen species that causes mitochondria damage.<br><br>CONCLUSIONS: The results suggest that NAC raises mitochondrial function in oocytes and improves oocyte quality through decreasing oxidative stress in mice with repeated COH. The underlying mechanism is related to the regulation of the Nrf2 signaling pathway.<br><br>IMPLICATION: This study provides a meaningful foundation for the future clinical application of NAC during repeated COH.}, }
@article {pmid35510880, year = {2022}, author = {Filip, AB and Berg, SE and Mullins, ME and Schwarz, ES and , }, title = {Fomepizole as an adjunctive therapy for acetaminophen poisoning: cases reported to the toxicology investigators consortium (ToxIC) database 2015-2020.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {9}, pages = {1006-1011}, doi = {10.1080/15563650.2022.2070071}, pmid = {35510880}, issn = {1556-9519}, mesh = {*Acetaminophen ; Acetylcysteine/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; Databases, Factual ; Fomepizole ; Humans ; }, abstract = {INTRODUCTION: Fomepizole inhibits formation of toxic acetaminophen (APAP) metabolites and may prevent or reverse mitochondrial toxicity. Given these mechanisms, it may be beneficial in patients with severe APAP toxicity. Current patterns of use for this indication are not well-studied.<br><br>METHODS: This is a secondary analysis of patients enrolled in the Toxicology Investigators Consortium (ToxIC) database from January 2015 to July 2020. We queried cases in which APAP was listed as an ingested agent and fomepizole was also administered. We excluded cases in which APAP was not the primary agent, N-acetylcysteine (NAC) was not administered, or fomepizole was explicitly administered for another indication. Additionally, we sent a survey to each ToxIC site that administered fomepizole for APAP toxicity to better understand when, why, and how they were using it for this indication.<br><br>RESULTS: Twenty-five cases of fomepizole administration following an APAP ingestion met our inclusion criteria. There were one to four cases per year between 2015 and 2019 and eight cases in 2020. Seventeen of 25 (68%) cases were for a known acute ingestion. Eighteen of 25 (72%) patients developed hepatotoxicity (AST or ALT > 1000&#x2009;IU/L) and 10 of 25 (40%) developed coagulopathy (PT > 15s). This was an ill patient population, with 18 of 25 (72%) developing metabolic acidosis (pH <7.20), 12 of 25 (48%) were intubated, 9 of 25 (36%) receiving vasopressors, and 6 of 25 (24%) receiving continuous renal replacement therapy. Overall, mortality was 24%.<br><br>CONCLUSION: The use of fomepizole is increasing in frequency in a small subset of critically ill and acutely APAP-poisoned patients.}, }
@article {pmid35505312, year = {2022}, author = {Wozniak, J and DiSalvo, M and Farrell, A and Vaudreuil, C and Uchida, M and Ceranoglu, TA and Joshi, G and Cook, E and Faraone, SV and Biederman, J}, title = {Findings from a pilot open-label trial of N-acetylcysteine for the treatment of pediatric mania and hypomania.}, journal = {BMC psychiatry}, volume = {22}, number = {1}, pages = {314}, pmid = {35505312}, issn = {1471-244X}, mesh = {Acetylcysteine/therapeutic use ; Adolescent ; Antimanic Agents/therapeutic use ; *Bipolar Disorder/complications/drug therapy ; Child ; Child, Preschool ; Humans ; *Mania ; Pilot Projects ; }, abstract = {BACKGROUND: Pediatric bipolar disorder is a highly prevalent and morbid disorder and is considered a prevalent public health concern. Currently approved treatments often pose the risk of serious side effects. Therefore, this study assessed the efficacy and tolerability of N-acetylcysteine (NAC), in children and adolescents with bipolar spectrum disorder.<br><br>METHODS: We conducted a 12-week open-label trial of NAC for treatment of mania and hypomania in children and adolescents ages 5-17 with bipolar spectrum disorder including participants with full and subthreshold manic symptoms, accepting those with and without mixed states with co-occurring depression, and Young Mania Rating Scale scores&#x2009;&#x2265;&#x2009;20 and&#x2009;<&#x2009;40. Symptoms of mania and depression were assessed using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Children's Depression Rating Scale (CDRS), and Clinical Global Impression (CGI) Severity (CGI-S) and Improvement (CGI-I) scales for mania and depression.<br><br>RESULTS: This study had a high drop-out rate with only 53% completing all 12&#xa0;weeks. There was a significant reduction in YMRS, HDRS, and CDRS mean scores from baseline to endpoint. Of the 24 exposed participants, 54% had an anti-manic response measured by a reduction in YMRS&#x2009;&#x2265;&#x2009;30% and 46% had a CGI-I mania score&#x2009;&#x2264;&#x2009;2 at endpoint. Additionally, 62% of participants had an anti-depressive response measured by a reduction in HDRS&#x2009;&#x2265;&#x2009;30%, 31% had an anti-depressive response measured by a reduction in CDRS&#x2009;&#x2265;&#x2009;30%, and 38% had a CGI-I depression score&#x2009;&#x2264;&#x2009;2 at endpoint.<br><br>CONCLUSIONS: These pilot open-label findings in a small sample provide preliminary data supporting the tolerability and safety of NAC in a pediatric population. The findings of this pilot scale study indicating improvement in mania and depression are promising, but require replication with a monotherapy randomized placebo controlled clinical trial and larger sample.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02357290 . First Registration 06/02/2015.}, }
@article {pmid35504863, year = {2022}, author = {Hoang, DV and Thuy, LTT and Hai, H and Hieu, VN and Kimura, K and Oikawa, D and Ikura, Y and Dat, NQ and Hoang, TH and Sato-Matsubara, M and Dong, MP and Hanh, NV and Uchida-Kobayashi, S and Tokunaga, F and Kubo, S and Ohtani, N and Yoshizato, K and Kawada, N}, title = {Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species.}, journal = {Oncogenesis}, volume = {11}, number = {1}, pages = {23}, pmid = {35504863}, issn = {2157-9024}, support = {19H03641//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 19K08428//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; AMED- JP21fk0210050//Japan Agency for Medical Research and Development (AMED)/ ; 21gm1010009h0004//Japan Agency for Medical Research and Development (AMED)/ ; 21gm1010009h0004//Japan Agency for Medical Research and Development (AMED)/ ; FY2019-2021//Gilead Sciences (Gilead)/ ; }, abstract = {Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H2O2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.}, }
@article {pmid35504402, year = {2022}, author = {Jung, YY and Baek, SH and Ha, IJ and Ahn, KS}, title = {Regulation of apoptosis and autophagy by albendazole in human colon adenocarcinoma cells.}, journal = {Biochimie}, volume = {198}, number = {}, pages = {155-166}, doi = {10.1016/j.biochi.2022.04.014}, pmid = {35504402}, issn = {1638-6183}, mesh = {*Adenocarcinoma/drug therapy/metabolism ; Albendazole/pharmacology ; Apoptosis ; Autophagy ; Cell Line, Tumor ; *Colonic Neoplasms/drug therapy ; Humans ; }, abstract = {Albendazole (ABZ) was initially introduced as an anthelmintic, however, many studies have reported with its anticancer effects. We investigated the anti-tumor effects of ABZ in vitro in human colon adenocarcinoma HCT-15, HCT-116, HT-29, and SW480 cell lines in this study. The cytotoxicity of ABZ was analyzed in colon adenocarcinoma cell lines and normal CCD18Co cells. We found that ABZ induced the subG1 arrest during cell cycle progression, increased the late apoptotic cells, shifted of peak TUNEL-labeled cells peak, and induced apoptosis. Then effects on autophagy activation was confirmed by acridine orange (AO), MDC staining, and immunocytochemistry of LC3. It was observed that ABZ can induce the autophagy activation through modulating the levels of LC3, Atg7, and beclin-1. For mechanistic studies, apoptosis blocker (Z-DEVD-FMK) and autophagy inhibitor (3-MA) were used to confirm that whether ABZ has apoptosis and autophagy specific effects, and reversal in both these cell death processes were noted. The effects of ABZ on AMPK, MAPKs, and ULK induction was also evaluated. We noticed that N-acetyl cysteine (NAC), a broad spectrum antioxidant, can effectively inhibit both apoptosis and autophagy. However, ABZ could even recover suppression of apoptosis and autophagy caused by NAC in colon cancer cells. Therefore, ABZ can potentially up-regulate both the apoptosis and autophagy to significantly suppress tumorigenesis in colorectal cancer cell lines.}, }
@article {pmid35504092, year = {2022}, author = {Liao, C and Zhang, L and Jiang, R and Xu, J and Tang, J and Hu, K and Jiang, S and Li, L and Yang, Y and Huang, J and Tang, L and Li, L}, title = {Inhibition of NAD kinase elevates the hepatic NAD[+] pool and alleviates acetaminophen-induced acute liver injury in mice.}, journal = {Biochemical and biophysical research communications}, volume = {612}, number = {}, pages = {70-76}, doi = {10.1016/j.bbrc.2022.04.079}, pmid = {35504092}, issn = {1090-2104}, mesh = {*Acetaminophen/adverse effects ; Animals ; *Chemical and Drug Induced Liver Injury/drug therapy ; Liver ; Mice ; Mice, Inbred C57BL ; NAD ; Phosphotransferases (Alcohol Group Acceptor) ; }, abstract = {Acetaminophen (APAP) overdose induces acute liver injury (ALI), even acute liver failure (ALF). There is a significant unmet need to furtherly elucidate the mechanisms and find new therapeutic target. Recently, emerging evidence indicates that nicotinamide adenine dinucleotide (NAD[+]) plays a crucial role in APAP-induced ALI. Herein, we firstly investigated the protein expression of NAD kinase (NADK), as the rate-limiting enzyme converting NAD[+] to nicotinamide adenine dinucleotide phosphate (NADP[+]), and found it was positively correlated with APAP-induced ALI in a dose- and time-dependent manner. Additionally, supplementation of N-acetylcysteine (NAC), known as an antidote of APAP, mitigated the ALI and downregulated the expression of NADK which was also in a dose-dependent manner. Moreover, pretreatment with methotrexate (MTX), the inhibitor of NADK, attenuated the levels of transaminases, alleviated morphological abnormalities, and improved oxidative stress triggered by APAP overdose, which was attributed to elevated hepatic NAD[+] pool. Subsequently, the increased NAD[+] upregulated the expression of Sirt1, SOD2 and attenuated DNA damage. Collectively, elevated expression of NADK is related to APAP-induced ALI, and inhibition of NADK alleviates the ALI through elevating liver NAD[+] level and improving antioxidant capacity.}, }
@article {pmid35502492, year = {2023}, author = {Gungor, H and Ekici, M and Ates, MB}, title = {Lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on acetaminophen-induced hepatotoxicity in mice.}, journal = {Drug and chemical toxicology}, volume = {46}, number = {3}, pages = {566-574}, doi = {10.1080/01480545.2022.2069256}, pmid = {35502492}, issn = {1525-6014}, mesh = {Mice ; Animals ; *Acetaminophen/toxicity ; Antioxidants/pharmacology/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Interleukin-6 ; *Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control/metabolism ; Anti-Inflammatory Agents/pharmacology ; Liver ; Oxidative Stress ; Acetylcysteine/pharmacology ; Mice, Inbred C57BL ; Lipids ; }, abstract = {Isorhamnetin is a hepatoprotective flavonoid molecule derived from the leaves and fruits of Hippophae rhamnoides L. However, the protective effect of isorhamnetin on acetaminophen (APAP) induced hepatotoxicity is still unknown. Thus, we aimed to investigate the lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on APAP-induced hepatotoxicity in mice. Hepatotoxicity was induced by a single injection of APAP (300 mg/kg, intraperitoneally). Isorhamnetin (50 or 100 mg/kg, orally) and N-acetylcysteine (NAC) (200 mg/kg, orally), or vehicle control, were administered 1 h before the administration of APAP. Total antioxidant status (TAS) and total oxidative status (TOS) of liver tissue and levels of inflammatory factors (TNF-α, IL-1β, and IL-6) were analyzed by ELISA. Lipid profiles and liver function parameters were measured using an autoanalyzer. In addition, liver tissue was examined histopathologically. Isorhamnetin treatment significantly reduced the APAP-induced increase in the liver weight and liver index; it also reduced the APAP-induced increase in serum liver parameters (ALT, AST, ALP, and LDH) (p < 0.05). Isorhamnetin significantly reduced APAP-induced oxidative stress and inflammation by increasing TAS levels and decreasing TOS, TNF-α, IL-1β, and IL-6 levels (p < 0.05). Moreover, isorhamnetin treatment significantly regulated lipid profiles (TG, T-C, LDL-C, and HDL-C levels) that changed in response to APAP administration (p < 0.05). In histopathological examination, liver degeneration observed in the APAP group was significantly reduced in the NAC and isorhamnetin-treated groups (p < 0.05). This study suggests that isorhamnetin has a significant protective effect on APAP-induced hepatotoxicity in mice through its lipid-lowering, antioxidant, and anti-inflammatory effects.}, }
@article {pmid35499714, year = {2022}, author = {Singh, S and Maurya, P and Rani, S and Mishra, N and Nisha, R and Singh, P and Saraf, SA}, title = {Development of doxorubicin hydrochloride-loaded whey protein nanoparticles and its surface modification with N-acetyl cysteine for triple-negative breast cancer.}, journal = {Drug delivery and translational research}, volume = {12}, number = {12}, pages = {3047-3062}, pmid = {35499714}, issn = {2190-3948}, mesh = {Humans ; Mice ; Animals ; Doxorubicin/pharmacology ; *Triple Negative Breast Neoplasms/drug therapy/metabolism ; Whey Proteins/therapeutic use ; Acetylcysteine ; Cell Line, Tumor ; *Nanoparticles ; }, abstract = {Limited targeted therapies are available for triple-negative breast cancer (TNBC). Thus, the current research focused on developing a targeted protein nanoparticle for TNBC. First, the doxorubicin hydrochloride (Dox)-loaded genipin-crosslinked whey protein nanoparticles (WD) were prepared and optimised by the QbD method using BBD. The hydrodynamic diameter of WD was found to be 364.38 ± 49.23 nm, zeta potential -27.59 ± 1.038 mV, entrapment 63.03 ± 3.625% and Dox loading was found to be 1.419 ± 0.422%. The drug recovery after 18 months of storage was 69%. Then, it was incubated with NAC to obtain modified WD (CyWD). WD followed first-order release kinetics, whereas CyWD followed the Higuchi model. Hemagglutination and hemolysis were not found qualitatively in WD and CyWD. Upon injecting the nanoformulations to 4T1-induced mice, the highest efficacy was found to be in CyWD followed by WD and Dox injection. Upon histopathological observance, it was found that the CyWD group gave the most significant damage to the 4T1 tumour tissue. Thus, NAC-modified protein nanoparticles carrying chemotherapeutic agents can be an excellent targeted therapeutic system against TNBC.}, }
@article {pmid35498128, year = {2022}, author = {Li, X and Yin, C and Hu, Q and Wang, J and Nie, H and Liu, B and Tai, Y and Fang, J and Du, J and Shao, X and Fang, J and Liu, B}, title = {Nrf2 Activation Mediates Antiallodynic Effect of Electroacupuncture on a Rat Model of Complex Regional Pain Syndrome Type-I through Reducing Local Oxidative Stress and Inflammation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8035109}, pmid = {35498128}, issn = {1942-0994}, mesh = {Animals ; Rats ; Acetylcysteine/pharmacology ; Antioxidants ; *Chronic Pain ; *Complex Regional Pain Syndromes ; *Electroacupuncture ; Inflammation ; *NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Rats, Sprague-Dawley ; }, abstract = {Complex regional pain syndrome type-I (CRPS-I) represents a type of neurovascular condition featured by severe pain in affected extremities. Few treatments have proven effective for CRPS-I. Electroacupuncture (EA) is an effective therapy for pain relief. We explored the mechanism through which EA ameliorates pain in a rat CRPS-I model. The chronic postischemic pain (CPIP) model was established using Sprague-Dawley rats to mimic CRPS-I. We found that oxidative stress-related biological process was among the predominant biological processes in affected hindpaw of CPIP rats. Oxidative stress occurred primarily in local hindpaw but not in the spinal cord or serum of model rats. Antioxidant N-acetyl cysteine (NAC) attenuated mechanical allodynia and spinal glia overactivation in CPIP model rats, whereas locally increasing oxidative stress is sufficient to induce chronic pain and spinal glia overactivation in naive rats. EA exerted remarkable antiallodynia on CPIP rats by reducing local oxidative stress via enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Pharmacological blocking Nrf2 abolished antioxidative and antiallodynic effects of EA. EA reduced spinal glia overactivation, attenuated the upregulation of inflammatory cytokines, reduced the enhanced TRPA1 channel activity in dorsal root ganglion neurons innervating the hindpaws, and improved blood flow dysfunction in hindpaws of CPIP rats, all of which were mimicked by NAC treatment. Thus, we identified local oxidative injury as an important contributor to pathogenesis of animal CRPS-I model. EA targets local oxidative injury by enhancing endogenous Nrf2-mediated antioxidative mechanism to relieve pain and inflammation. Our study indicates EA can be an alternative option for CRPS-I management.}, }
@article {pmid35489181, year = {2022}, author = {Ezquer, F and Quintanilla, ME and Morales, P and Santapau, D and Munita, JM and Moya-Flores, F and Ezquer, M and Herrera-Marschitz, M and Israel, Y}, title = {A dual treatment blocks alcohol binge-drinking relapse: Microbiota as a new player.}, journal = {Drug and alcohol dependence}, volume = {236}, number = {}, pages = {109466}, doi = {10.1016/j.drugalcdep.2022.109466}, pmid = {35489181}, issn = {1879-0046}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Alcohol Drinking ; *Alcohol-Related Disorders ; *Alcoholism/drug therapy ; Animals ; Aspirin ; Chronic Disease ; Ethanol ; Humans ; Mice ; *Microbiota ; Rats ; Recurrence ; }, abstract = {RATIONALE: Gut microbiota communicates information to the brain. Some animals are born with a gut microbiota that predisposes to high alcohol consumption, and transplantation of fecal material from alcoholics to mice increases animal preference for ethanol. Alcohol-use-disorders are chronic conditions where relapse is the hallmark. A predictive animal model of relapse is the "alcohol deprivation effect" where ethanol re-access is allowed following chronic alcohol intake and a long alcohol deprivation. The present study evaluates the effect of gut microbiota modification on relapse, as an adjunct to N-acetylcysteine + Acetylsalicylic acid administration, which inhibits the alcohol-induced hyper-glutamatergic condition.<br><br>METHODS: Rats bred as heavy alcohol consumers (UChB) were allowed ethanol intake for one month, were deprived of alcohol for two-weeks and subsequently offered re-access to ethanol. Prior to ethanol re-access animals received orally either (i) vehicle-control, (ii) Lactobacillus-rhamnosus-GG after antibiotic treatment (LGG); (iii) N-acetylcysteine+Acetylsalicylic acid (NAC/ASA) or (iv) both treatments: LGG+&#xa0;(NAC/ASA).<br><br>RESULTS: Marked binge drinking (1.75&#xa0;g ethanol/kg in 60&#xa0;min) and blood alcohol levels exceeding 80&#xa0;mg/dl were observed in the control group upon ethanol-re-access. Lactobacillus-GG or (NAC+ASA) treatments inhibited alcohol intake by 66-80%. The combination of both treatments virtually suppressed (inhibition of 90%) the re-access binge-like drinking, showing additive effects. Treatment with NAC+ASA increased the levels of glutamate transporters xCT and GLT-1 in nucleus accumbens, while Lactobacillus-GG administration increased those of the dopamine transporter (DAT).<br><br>CONCLUSIONS: The administration of a well-accepted probiotic may be of value as an adjunct in the treatment of alcohol-use-disorders.}, }
@article {pmid35487270, year = {2022}, author = {Hammerschmidt, TG and Donida, B and Faverzani, JL and Moura, AP and Dos Reis, BG and Machado, AZ and Kessler, RG and Sebastião, FM and Reinhardt, LS and Moura, DJ and Vargas, CR}, title = {Cytokine profile and cholesterol levels in patients with Niemann-Pick type C disease presenting neurological symptoms: in vivo effect of miglustat and in vitro effect of N-acetylcysteine and coenzyme Q10.}, journal = {Experimental cell research}, volume = {416}, number = {2}, pages = {113175}, doi = {10.1016/j.yexcr.2022.113175}, pmid = {35487270}, issn = {1090-2422}, mesh = {1-Deoxynojirimycin/analogs &amp; derivatives ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cholesterol ; Cytokines ; Enzyme Inhibitors/pharmacology/therapeutic use ; Humans ; Inflammation/drug therapy ; *Niemann-Pick Disease, Type C/drug therapy ; Ubiquinone/analogs &amp; derivatives ; }, abstract = {Niemann Pick type C is an inborn error of metabolism (IEM), classified as a lysosomal storage disease (LSD) caused by a dysfunction in NPC transport protein, that leads to intracellular accumulation of non-esterified cholesterol and other lipids. Clinical manifestations are ample, with visceral and neurological symptoms. Miglustat, a molecule that reversibly inhibits glucosylceramide synthase is used as treatment for this disorder. Studies demonstrated the influence of oxidative stress and inflammation in IEM, as well in animal model of NP-C disease. Nonetheless, literature lacks data on patients, so our work aimed to investigate if there is influence of chronic inflammation in the pathophysiology of NP-C disease, and the effect of miglustat, N-acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). We evaluated the plasmatic cytokines in NPC patients at diagnosis and during the treatment with miglustat. Additionally, we performed an in vitro study with antioxidants NAC (1 mM and 2.5 mM) and CoQ10 (5 μM and 10 μM), where we could verify its effect on inflammatory parameters, as well as in cholesterol accumulation. Our results showed that NP-C patients have higher plasmatic levels of pro and anti-inflammatory cytokines (IL-6, IL-8, and IL-10) at diagnosis and the treatment with miglustat was able to restore it. In vitro study showed that treatment with antioxidants in higher concentrations significantly decrease cholesterol accumulation, and NAC at 2.5 mM normalized the level of pro-inflammatory cytokines. Although the mechanism is not completely clear, it can be related to restoration in lipid traffic and decrease in oxidative stress caused by antioxidants.}, }
@article {pmid35478127, year = {2022}, author = {Sun, HN and Xie, DP and Ren, CX and Guo, XY and Zhang, HN and Xiao, WQ and Han, YH and Cui, YD and Kwon, T}, title = {Ethyl β-Carboline-3-Carboxylate Increases Cervical Cancer Cell Apoptosis Through ROS-p38 MAPK Signaling Pathway.}, journal = {In vivo (Athens, Greece)}, volume = {36}, number = {3}, pages = {1178-1187}, pmid = {35478127}, issn = {1791-7549}, mesh = {Apoptosis ; Carbolines/pharmacology ; Female ; Humans ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxide Dismutase/metabolism ; *Uterine Cervical Neoplasms/drug therapy ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {BACKGROUND/AIM: Ethyl β-carboline-3-carboxylate (β-CCE) is one of the effective ingredients of Picrasma quassioides (P. quassioides). As a β-carboline alkaloid, it can antagonize the pharmacological effects of benzodiazepines by regulating neurotransmitter secretion through receptors, thus affecting anxiety and physiology. However, its efficacy in cancer treatment is still unclear.<br><br>MATERIALS AND METHODS: We explored the effect of b-CCE on SiHa cells using MTT assay, western blot, flow cytometry, LDH release, T-AOC, SOD, and MDA assays.<br><br>RESULTS: We investigated the cytotoxicity of &#x3b2;-CCE in SiHa cells and verified that &#x3b2;-CCE could induce cell apoptosis in a time- and concentration-dependent manner. In this process, treatment with &#x3b2;-CCE significantly increased the levels of cytoplasmic and mitochondrial reactive oxygen species (ROS), which disturb the oxidation homeostasis by regulating the total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, and malondialdehyde (MDA) production. Notably, the addition of N-acetylcysteine (NAC) (ROS scavenger) effectively alleviated &#x3b2;-CCE-induced apoptosis in SiHa cells. In addition, &#x3b2;-CCE might activate the p38/MAPK signaling pathway, as the pre-treatment with SB203580 (p38 inhibitor) significantly reduced &#x3b2;-CCE-induced apoptosis in SiHa cells.<br><br>CONCLUSION: &#x3b2;-CCE has an anti-tumor activity. It activates the p38/MAPK signaling pathway by increasing intracellular ROS levels, which subsequently induce SiHa cell apoptosis. Our results provide a novel therapeutic target for treatment of cervical cancer.}, }
@article {pmid35475860, year = {2022}, author = {}, title = {The Potential Role of Efficacy and Safety Evaluation of N-Acetylcysteine Administration During Liver Procurement. The NAC-400 Single Center Randomized Controlled Trial: Erratum.}, journal = {Transplantation}, volume = {106}, number = {5}, pages = {e287}, doi = {10.1097/TP.0000000000004154}, pmid = {35475860}, issn = {1534-6080}, mesh = {*Acetylcysteine/adverse effects ; *Liver ; Treatment Outcome ; }, }
@article {pmid35473933, year = {2022}, author = {Liu, C and Shen, Y and Huang, L and Wang, J}, title = {TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury.}, journal = {Cell death discovery}, volume = {8}, number = {1}, pages = {232}, pmid = {35473933}, issn = {2058-7716}, support = {81470972//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82070709//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81270826//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81470972//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82070708//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81470972//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82070708//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81470972//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82070708//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Acute kidney injury (AKI) is characterized by necroinflammation formed by necrotic tubular epithelial cells (TECs) and interstitial inflammation. In necroinflammation, macrophages are key inflammatory cells and can be activated and polarized into proinflammatory macrophages. Membranous Toll-like receptors (TLRs) can cooperate with intracellular NOD-like receptor protein 3 (NLRP3) to recognize danger signals from necrotic TECs and activate proinflammatory macrophages by assembling NLRP3 inflammasome. However, the cooperation between TLRs and NLRP3 is still unclear. Using conditioned medium from necrotic TECs, we confirmed that necrotic TECs could release danger signals to activate NLRP3 inflammasome in macrophages. We further identified that necrotic TECs-induced NLRP3 inflammasome activation was dependent on ATP secretion via Pannexin-1 (Panx1) channel in macrophages. Next, we verified that TLR2 was required for the activation of Panx1 and NLRP3 in macrophages. Mechanistically, we indicated that caspase-5 mediated TLR2-induced Panx1 activation. In addition, we showed that necrotic TECs-induced activation of TLR2/caspase-5/Panx1 axis could be decreased in macrophages when TECs was protected by N-acetylcysteine (NAC). Overall, we demonstrate that danger signals from necrotic TECs could activate NLRP3 inflammasome in macrophages via TLR2/caspase-5/Panx1 axis during AKI.}, }
@article {pmid35473809, year = {2022}, author = {Wang, Y and Kong, Y and Zhao, HY and Zhang, YY and Wang, YZ and Xu, LP and Zhang, XH and Liu, KY and Huang, XJ}, title = {Prophylactic NAC promoted hematopoietic reconstitution by improving endothelial cells after haploidentical HSCT: a phase 3, open-label randomized trial.}, journal = {BMC medicine}, volume = {20}, number = {1}, pages = {140}, pmid = {35473809}, issn = {1741-7015}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Endothelial Cells ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Thrombocytopenia/etiology ; }, abstract = {BACKGROUND: Poor graft function (PGF) or prolonged isolated thrombocytopenia (PT), which are characterized by pancytopenia or thrombocytopenia, have become serious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous single-arm trial suggests that N-acetyl-L-cysteine (NAC) prophylaxis reduced PGF or PT after allo-HSCT. Therefore, an open-label, randomized, phase 3 trial was performed to investigate the efficacy and tolerability of NAC prophylaxis to reduce PGF or PT after allo-HSCT.<br><br>METHODS: A phase 3, open-label randomized trial was performed. Based on the percentage of CD34[+]VEGFR2 (CD309)[+] endothelial cells (ECs) in bone marrow (BM) detected by flow cytometry at 14 days before conditioning, patients aged 15 to 60 years with acute leukemia undergoing haploidentical HSCT were categorized as low-risk (EC &#x2265; 0.1%) or high-risk (EC < 0.1%); patients at high risk were randomly assigned (2:1) to receive NAC prophylaxis or nonprophylaxis. The primary endpoint was PGF and PT incidence at +60 days post-HSCT.<br><br>RESULTS: Between April 18, 2019, and June 24, 2021, 120 patients with BM EC <0.1% were randomly assigned for NAC (group A, N = 80) or nonprophylaxis (group B, N = 40), and 105 patients with EC&#x2265;0.1% (group C) were also analyzed. The +60 days incidence of PGF and PT was 7.5% (95% CI, 1.7 to 13.3%) and 22.5% (95% CI, 9.1 to 35.9%) in group A and group B (hazard ratio, 0.317; 95% CI, 0.113 to 0.890; P = 0.021) and 11.4% (95% CI, 5.2 to 17.6%) in group C (hazard ratio, 0.643; 95% CI, 0.242 to 1.715; P = 0.373). Consistently, NAC prophylaxis gradually improved BM ECs and CD34[+] cells in group A, whereas reduced their reactive oxygen species (ROS) levels post-HSCT. Within 60 days post-HSCT, the most common grade 3 to 5 adverse events for the NAC and control groups were infections (19/80 [24%] vs. 10/40 [25%]) and gastrointestinal adverse events (16/80 [20%] vs. 7/40 [18%]). There were no treatment-related deaths.<br><br>CONCLUSIONS: N-Acetyl-L-cysteine prophylaxis can prevent the occurrence of poor hematopoietic function and is well tolerated in haploidentical HSCT. It may offer a potential pathogenesis-oriented therapeutic approach for patients with poor hematopoietic function.<br><br>TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov as #NCT03967665.}, }
@article {pmid35470759, year = {2022}, author = {Gan, X and Zhao, J and Chen, Y and Li, Y and Xuan, B and Gu, M and Feng, F and Yang, Y and Yang, D and Sun, X}, title = {Plin5 inhibits proliferation and migration of vascular smooth muscle cell through interacting with PGC-1α following vascular injury.}, journal = {Bioengineered}, volume = {13}, number = {4}, pages = {10665-10678}, pmid = {35470759}, issn = {2165-5987}, mesh = {Animals ; Becaplermin ; Cell Movement/genetics ; Cell Proliferation ; Cells, Cultured ; Hyperplasia/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Muscle, Smooth, Vascular/pathology ; *Neointima/genetics/metabolism/pathology ; Perilipin-5/metabolism ; Reactive Oxygen Species/metabolism ; Transcription Factors/*metabolism ; *Vascular System Injuries/genetics/metabolism/pathology ; }, abstract = {Abnormal proliferation and migration of vascular smooth muscle cell (VSMC) is a hallmark of vascular neointima hyperplasia. Perilipin 5 (Plin5), a regulator of lipid metabolism, is also confirmed to be involved in vascular disorders, such as microvascular endothelial dysfunction and atherosclerosis. To investigate the regulation and function of plin5 in the phenotypic alteration of VSMC, -an animal model of vascular intima hyperplasia was established in C57BL/6 J and Plin5 knockdown (Plin5[±]) mice by wire injure. Immunohistochemical staining was used to analyze neointima hyperplasia in artery. Ki-67, dihydroethidium immunofluorescence staining and wound healing assay were used to measure proliferation, reactive oxygen species (ROS) generation and migration of VSMC, respectively. Plin5 was downregulated in artery subjected to vascular injury and in VSMC subjected to platelet-derived growth factor (PDGF)-BB. Plin5 knockdown led to accelerated neointima hyperplasia, excessive proliferation and migration of VSMC after injury. In vitro, we observed increased ROS content in VSMC isolated from Plin5[±] mice. Antioxidative N-acetylcysteine (NAC) inhibited VSMC proliferation and migration induced by PDGF-BB or plin5 knockdown. More importantly, plin5-peroxlsome proliferator-activated receptor-γ coactivator (PGC)-1α interaction was also attenuated in VSMC after knockdown of plin5. Overexpression of PGC-1α suppressed PDGF-BB-induced ROS generation, proliferation, and migration in VSMC isolated from Plin5[±] mice. These data suggest that plin5 serves as a potent regulator of VSMC proliferation, migration, and neointima hyperplasia by interacting with PGC-1α and affecting ROS generation.}, }
@article {pmid35466412, year = {2022}, author = {Xie, Y and Zhu, X and Liu, P and Liu, Y and Geng, Y and Zhang, L}, title = {Xanthatin inhibits non-small cell lung cancer proliferation by breaking the redox balance.}, journal = {Drug development research}, volume = {83}, number = {5}, pages = {1176-1189}, doi = {10.1002/ddr.21941}, pmid = {35466412}, issn = {1098-2299}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/metabolism ; Apoptosis ; *Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Furans ; Humans ; *Lung Neoplasms/drug therapy/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {Lung cancer is the cancer with the highest mortality, and non-small cell lung cancer (NSCLC) accounts for more than 80%. Tumor cells often have high reactive oxygen species (ROS) and antioxidant capacity. Redox balance is very important for tumor. The decline of antioxidant capacity and excessive ROS will induce the death of tumor cells. Destroying the redox balance of tumor cells is a promising tumor treatment strategy. Xanthatin is an active sesquiterpene lactone isolated from Xanthium strumarium L. We observed that xanthatin induced the up regulation of mitochondrial ROS and mitochondrial damage. Meanwhile, our results showed that xanthatin could inhibit system xc [-] and reduce glutathione (GSH) synthesis. Antioxidant GSH and N-acetyl- l-cysteine (NAC) significantly reversed cell proliferation inhibition and apoptosis induced by xanthatin. β-Mercaptoethanol (β-ME) which can avoid inhibition of system xc [-] can also reverse the inhibition of cell proliferation induced by xanthatin, si-SLC7A11 was the opposite. Based on these results, we believe that the inhibition of xanthatin on the proliferation of NSCLC cells may be related to breaking the intracellular redox balance. Our data suggest that xanthatin is a promising antitumor candidate for the treatment of NSCLC.}, }
@article {pmid35466101, year = {2022}, author = {Russell, SE and Wrobel, AL and Dean, OM and Berk, M and Dodd, S and Ng, CH and Malhi, GS and Cotton, SM and Sarris, J and Turner, A}, title = {Mixed Methods Thematic Analysis of a Randomised Controlled Trial of Adjunctive Mitochondrial Agents for Bipolar Depression.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {20}, number = {2}, pages = {300-310}, pmid = {35466101}, issn = {1738-1088}, abstract = {OBJECTIVE: There is often a shortfall in recovery following treatment for an episode of bipolar disorder (BD). Exploration of participant's experience provides vital information to enhance statistical outcomes for novel therapy trials. This study used mixed-methods to explore participants' experience of a trial testing N -acetyl cysteine (NAC) and mitochondrially active nutraceuticals for BD depression.<br><br>CASE: report forms from a randomised controlled trial (RCT) of BD depression (n = 148) were analysed using a pragmatic adaption of grounded theory and thematic analysis.<br><br>RESULTS: Thematic analysis of 148 study participants indicated numerous changes in participant experience over time. For example, perceived environmental stressors reported by participants decreased over the trial in both treatment groups. Quantitative analysis of the themes revealed more positive theme reports in the combination treatment arm compared to the placebo arm and there were more negative themes identified in the placebo arm, compared to the NAC arm.<br><br>CONCLUSION: This approach revealed additional results not elucidated in the primary quantitative analysis. This emphasises the value of mixed-methods research in capturing participants' experiences in RCTs and detecting possible latent benefits and risks. Such methods can detect latent target signals in novel therapy trials conducted in BD and generate novel hypotheses.}, }
@article {pmid35461321, year = {2022}, author = {Sempere, J and Llamosí, M and Román, F and Lago, D and González-Camacho, F and Pérez-García, C and Yuste, J and Domenech, M}, title = {Clearance of mixed biofilms of Streptococcus pneumoniae and methicillin-susceptible/resistant Staphylococcus aureus by antioxidants N-acetyl-L-cysteine and cysteamine.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {6668}, pmid = {35461321}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/pharmacology ; Antioxidants/pharmacology ; Biofilms ; Cysteamine/pharmacology ; Methicillin/pharmacology ; *Methicillin-Resistant Staphylococcus aureus ; Microbial Sensitivity Tests ; Staphylococcus aureus ; Streptococcus pneumoniae ; }, abstract = {Biofilm-associated infections are of great concern because they are associated with antibiotic resistance and immune evasion. Co-colonization by Staphylococcus aureus and Streptococcus pneumoniae is possible and a threat in clinical practice. We investigated the interaction between S. aureus and S. pneumoniae in mixed biofilms and tested new antibiofilm therapies with antioxidants N-acetyl-L-cysteine (NAC) and cysteamine (Cys). We developed two in vitro S. aureus-S. pneumoniae mixed biofilms in 96-well polystyrene microtiter plates and we treated in vitro biofilms with Cys and NAC analyzing their effect by CV staining and viable plate counting. S. pneumoniae needed a higher proportion of cells in the inoculum and planktonic culture to reach a similar population rate in the mixed biofilm. We demonstrated the effect of Cys in preventing S. aureus biofilms and S. aureus-S. pneumoniae mixed biofilms. Moreover, administration of 5 mg/ml of NAC nearly eradicated the S. pneumoniae population and killed nearly 94% of MSSA cells and 99% of MRSA cells in the mixed biofilms. The methicillin resistance background did not change the antioxidants effect in S. aureus. These results identify NAC and Cys as promising repurposed drug candidates for the prevention and treatment of mixed biofilms by S. pneumoniae and S. aureus.}, }
@article {pmid35458581, year = {2022}, author = {Rotondo, R and Ragucci, S and Castaldo, S and Landi, N and Oliva, MA and Pedone, PV and Di Maro, A and Arcella, A}, title = {Ageritin-The Ribotoxin-like Protein from Poplar Mushroom (Cyclocybe aegerita) Sensitizes Primary Glioblastoma Cells to Conventional Temozolomide Chemotherapy.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {8}, pages = {}, pmid = {35458581}, issn = {1420-3049}, support = {//v:ALERE(VAnviteLli pEr la RicErca)program./ ; //Italian Ministry of Health with Ricerca Corrente/ ; }, mesh = {*Agaricales ; Antineoplastic Agents, Alkylating ; Cell Line, Tumor ; DNA Modification Methylases ; Drug Resistance, Neoplasm ; *Glioblastoma/drug therapy ; Humans ; Ribonucleases ; Temozolomide/pharmacology ; *Toxins, Biological ; }, abstract = {Here, we propose Ageritin, the prototype of the ribotoxin-like protein family, as an adjuvant treatment to control the growth of NULU and ZAR, two primary human glioblastoma cell lines, which exhibit a pharmacoresistance phenotype. Ageritin is able to inhibit NULU and ZAR growth with an IC50 of 0.53 ± 0.29 µM and 0.42 ± 0.49 µM, respectively. In this study, Ageritin treatment highlighted a macroscopic genotoxic response through the formation of micronuclei, which represents the morphological manifestation of genomic chaos induced by this toxin. DNA damage was not associated with either the deregulation of DNA repair enzymes (i.e., ATM and DNA-PK), as demonstrated by quantitative PCR, or reactive oxygen species. Indeed, the pretreatment of the most responsive cell line ZAR with the ROS scavenger N-acetylcysteine (NAC) did not follow the reverse cytotoxic effect of Ageritin, suggesting that this protein is not involved in cellular oxidative stress. Vice versa, Ageritin pretreatment strongly enhanced the sensitivity to temozolomide (TMZ) and inhibited MGMT protein expression, restoring the sensitivity to temozolomide. Overall, Ageritin could be considered as a possible innovative glioblastoma treatment, directly damaging DNA and downregulating the MGMT DNA repair protein. Finally, we verified the proteolysis susceptibility of Ageritin using an in vitro digestion system, and considered the future perspective use of this toxin as a bioconjugate in biomedicine.}, }
@article {pmid35455407, year = {2022}, author = {Muduli, S and Golan-Goldhirsh, A and Gopas, J and Danilenko, M}, title = {Cytotoxicity of Thioalkaloid-Enriched Nuphar lutea Extract and Purified 6,6'-Dihydroxythiobinupharidine in Acute Myeloid Leukemia Cells: The Role of Oxidative Stress and Intracellular Calcium.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {4}, pages = {}, pmid = {35455407}, issn = {1424-8247}, support = {226/16//Israel Science Foundation/ ; 3-0-7374//Israel Ministry of Health/ ; }, abstract = {Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid progenitors. Here, we report the in vitro antileukemic effects of the sesquiterpene thioalkaloid-enriched fraction of the Nuphar lutea leaf extract (NUP) and a purified thioalkaloid 6,6'-dihydroxythiobinupharidine (DTBN). Treatment with 0.3-10 µg/mL NUP caused a dose- and time-dependent reduction in proliferation and viability of human AML cells (KG-1a, HL60 and U937). This was associated with apoptosis induction manifested by annexin-V/propidium iodide binding as well as cleavage of caspases 8, 9, and 3 as well as poly (ADP-ribose) polymerase. Caspase-dependence of the apoptotic effect was confirmed using the pan-caspase inhibitor Q-VD-OPH. NUP induced significant biphasic changes in the cytosolic levels of reactive oxygen species (ROS) compared to untreated cells-a decrease at early time points (2-4 h) and an increase after a longer incubation (24 h). ROS accumulation was accompanied by lowering the cellular glutathione (GSH) levels. In addition, NUP treatment resulted in elevation of the cytosolic Ca[2+] (Ca[2+]cyt) levels. The thiol antioxidant and glutathione precursor N-acetyl cysteine prevented NUP-induced ROS accumulation and markedly inhibited apoptosis. A similar antiapoptotic effect was obtained by Ca[2+]cyt chelating using BAPTA. These data indicate that NUP-induced cell death is mediated, at least in part, by the induction of oxidative stress and Ca[2+]cyt accumulation. However, a substantial apoptotic activity of pure DTBN (0.05-0.25 µg/mL), was found to be independent of cytosolic ROS or Ca[2+], suggesting that alternative mechanisms are involved in DTBN-induced cytotoxicity. Notably, neither NUP nor DTBN treatment significantly induced cell death of normal human peripheral blood mononuclear cells. Our results provide the basis for further investigation of the antileukemic potential of NUP and its active constituents.}, }
@article {pmid35453441, year = {2022}, author = {Kim, JE and Lee, DS and Kim, TH and Kang, TC}, title = {Glutathione Regulates GPx1 Expression during CA1 Neuronal Death and Clasmatodendrosis in the Rat Hippocampus following Status Epilepticus.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {4}, pages = {}, pmid = {35453441}, issn = {2076-3921}, support = {No. 2021R1A2B5B01001482 and 2021R1A2C4002003//National Research Foundation of Korea (NRF)/ ; }, abstract = {Glutathione peroxidase-1 (GPx1) catalyze the reduction of H2O2 by using glutathione (GSH) as a cofactor. However, the profiles of altered GPx1 expression in response to status epilepticus (SE) have not been fully explored. In the present study, GPx1 expression was transiently decreased in dentate granule cells, while it was temporarily enhanced and subsequently reduced in CA1 neurons following SE. GPx1 expression was also transiently declined in CA1 astrocytes (within the stratum radiatum) following SE. However, it was elevated in reactive CA1 astrocytes, but not in clasmatodendritic CA1 astrocytes, in chronic epilepsy rats. Under physiological condition, L-buthionine sulfoximine (BSO, an inducer of GSH depletion) increased GPx1 expression in CA1 neurons but decreased it in CA1 astrocytes. However, N-acetylcysteine (NAC, an inducer of GSH synthesis) did not influence GPx1 expression in these cell populations. Following SE, BSO aggravated CA1 neuronal death, concomitant with reduced GPx1 expression. Further. BSO also lowered GPx1 expression in CA1 astrocytes. NAC effectively prevented neuronal death and GPx1 downregulation in CA1 neurons, and restored GPx1 expression to the control level in CA1 astrocytes. In chronic epilepsy rats, BSO reduced GPx1 intensity and exacerbated clasmatodendritic degeneration in CA1 astrocytes. In contrast, NAC restored GPx1 expression in clasmatodendritic astrocytes and ameliorated this autophagic astroglial death. To the best of our knowledge, our findings report, for the first time, the spatiotemporal profiles of altered GPx1 expression in the rat hippocampus following SE, and suggest GSH-mediated GPx1 regulation, which may affect SE-induced neuronal death and autophagic astroglial degeneration.}, }
@article {pmid35450505, year = {2023}, author = {Angelovski, M and Hadzi-Petrushev, N and Mitrokhin, V and Kamkin, A and Mladenov, M}, title = {Myocardial infarction and oxidative damage in animal models: objective and expectations from the application of cysteine derivatives.}, journal = {Toxicology mechanisms and methods}, volume = {33}, number = {1}, pages = {1-17}, doi = {10.1080/15376516.2022.2069530}, pmid = {35450505}, issn = {1537-6524}, mesh = {Animals ; *Antioxidants/pharmacology/metabolism ; Motivation ; Oxidative Stress ; *Myocardial Infarction/drug therapy/prevention &amp; control ; Glutathione/metabolism ; Acetylcysteine/pharmacology ; }, abstract = {Reactive oxygen species (ROS) and associated oxidative stress are the main contributors to pathophysiological changes following myocardial infarction (MI), which is the principal cause of death from cardiovascular disease. The glutathione (GSH)/glutathione peroxidase (GPx) system appears to be the main and most active cardiac antioxidant mechanism. Hence, enhancement of the myocardial GSH system might have protective effects in the setting of MI. It follows that by increasing antioxidant capacity, the heart will be able to reduce the damage associated with MI and even prevent/weaken the occurrence of oxidative stress, which is highly ranked among the factors responsible for the occurrence of acute MI. For these reasons, the primary goal of future investigations should be to address the effects of different antioxidative compounds and especially cysteine derivatives like N-acetyl cysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid (OTC) as precursors responsible for the enhancement of the GSH-related antioxidant system's capacity. It is assumed that this will lay down the basis for elucidation of the mechanisms throughout which applicable doses of OTC will manifest a potentially positive impact in the reduction of adverse effects of acute MI. The inclusion of OTC in the models for prediction of the distribution of oxygen in infarcted animal hearts can help to upgrade existing computational models. Such a model would be based on computational geometries of the heart, but the inclusion of biochemical redox features in addition to angiogenic therapy, despite improvement of the post-infarcted oxygenated outcome could enhance the accuracy of the predictive values of oxygenation.}, }
@article {pmid35449013, year = {2022}, author = {Ju, S and Lim, L and Ki, YJ and Choi, DH and Song, H}, title = {Oxidative stress generated by polycyclic aromatic hydrocarbons from ambient particulate matter enhance vascular smooth muscle cell migration through MMP upregulation and actin reorganization.}, journal = {Particle and fibre toxicology}, volume = {19}, number = {1}, pages = {29}, pmid = {35449013}, issn = {1743-8977}, mesh = {Actins ; *Air Pollutants/analysis ; *Atherosclerosis ; Cell Movement ; Humans ; Matrix Metalloproteinases ; Muscle, Smooth, Vascular/chemistry ; Oxidative Stress ; Particulate Matter/analysis/toxicity ; *Polycyclic Aromatic Hydrocarbons/analysis/toxicity ; Up-Regulation ; }, abstract = {BACKGROUND: Epidemiological studies have suggested that elevated concentrations of particulate matter (PM) are strongly associated with the incidence of atherosclerosis, however, the underlying cellular and molecular mechanisms of atherosclerosis by PM exposure and the components that are mainly responsible for this adverse effect remain to be established. In this investigation, we evaluated the effects of ambient PM on vascular smooth muscle cell (VSMC) behavior. Furthermore, the effects of polycyclic aromatic hydrocarbons (PAHs), major components of PM, on VSMC migration and the underlying mechanisms were examined.<br><br>RESULTS: VSMC migration was significantly increased by treatment with organic matters extracted from ambient PM. The total amount of PAHs contained in WPM was higher than that in SPM, leading to higher ROS generation and VSMC migration. The increased migration was successfully inhibited by treatment with the anti-oxidant, N-acetyl-cysteine (NAC). The levels of matrix metalloproteinase (MMP) 2 and 9 were significantly increased in ambient PM-treated VSMCs, with MMP9 levels being significantly higher in WPM-treated VSMCs than in those treated with SPM. As expected, migration was significantly increased in all tested PAHs (anthracene, ANT; benz(a)anthracene, BaA) and their oxygenated derivatives (9,10-Anthraquinone, AQ; 7,12-benz(a)anthraquinone, BAQ, respectively). The phosphorylated levels of focal adhesion kinase (FAK) and formation of the focal adhesion complex were significantly increased in ambient PM or PAH-treated VSMCs, and these effects were blocked by administration of NAC or &#x3b1;-NF, an inhibitor of AhR, the receptor that allows PAH uptake. Subsequently, the levels of phosphorylated Src and NRF, the downstream targets of FAK, were altered with a pattern similar to that of p-FAK.<br><br>CONCLUSIONS: PAHs, including oxy-PAHs, in ambient PM may have dual effects that lead to an increase in VSMC migration. One is the generation of oxidative stress followed by MMP upregulation, and the other is actin reorganization that results from the activation of the focal adhesion complex.}, }
@article {pmid35442462, year = {2022}, author = {Žuža, O and Minić, R and Kotur-Stevuljević, J and Žujović, D and Đorđević, B and Ilić, A}, title = {A combination of N-acetyl cysteine and propolis attenuates oxidative-inflammatory parameters during COPD exacerbation.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {7}, pages = {2467-2477}, doi = {10.26355/eurrev_202204_28481}, pmid = {35442462}, issn = {2284-0729}, mesh = {Acetylcysteine/therapeutic use ; Antioxidants/metabolism/therapeutic use ; Aryldialkylphosphatase/metabolism ; Biomarkers/metabolism ; Humans ; Oxidation-Reduction ; Oxidative Stress ; *Propolis/metabolism/therapeutic use ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; Serum Albumin/metabolism ; }, abstract = {OBJECTIVE: The aim of this study was to determine any differences in oxidative stress and inflammation parameters in COPD patients treated with either N-acetyl cysteine (NAC) alone or with NAC in combination with propolis (NACP).<br><br>PATIENTS AND METHODS: Forty COPD patients in the exacerbation phase were enrolled into the study and were treated with either NAC (NAC group; n=20) or NACP (NACP group; n=20) twice daily for one month. Redox status was determined by measuring superoxide anion (O2.-), advanced oxidation protein products (AOPP), total oxidative status (TOS), prooxidative-antioxidant balance (PAB), malondialdehyde (MDA), ischemia modified albumin (IMA) and several other antioxidant markers: superoxide dismutase (SOD), paraoxonase 1 (PON1), total sulfhydryl groups (SHG) and total antioxidant status (TAS). Interleukins 6, 8 and 17 were measured as markers of inflammatory status.<br><br>RESULTS: Both groups had similar socio-demographic and clinical characteristics. After treatment significantly higher SHG [0.446 (0.395-0.516) vs. 0.292 (0.270-0.325), p<0.001] and significantly lower TOS - 50.6 [49.7-53.4 vs. 73.2 (50.9-84.6), p<0.05] - and IMA [0.650 (0.629-0.682) vs. 0.709 (0.667-0.756), p<0.05] - were found in the NACP group compared to the NAC group. Factorial analysis indicated a larger oxidative stress-inflammatory load in the NAC group after treatment.<br><br>CONCLUSIONS: From an oxidative stress and inflammatory status perspective, treatment with NACP was more successful than with NAC. The inclusion of propolis into therapy for COPD patients, especially those in the exacerbation phase, could prove beneficial.}, }
@article {pmid35442037, year = {2022}, author = {Li, J and Shi, J and Jia, C and Li, W and Peng, Y and Zheng, J}, title = {Metabolic Activation and Cytotoxicity of Propafenone Mediated by CYP2D6.}, journal = {Chemical research in toxicology}, volume = {35}, number = {5}, pages = {829-839}, doi = {10.1021/acs.chemrestox.2c00013}, pmid = {35442037}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic ; Animals ; *Chemical and Drug Induced Liver Injury/metabolism ; *Cytochrome P-450 CYP2D6/metabolism ; Glutathione/metabolism ; Microsomes, Liver/metabolism ; Propafenone/metabolism/pharmacology ; Quinones/metabolism ; Rats ; }, abstract = {Propafenone (PPF) is a class IC antidysrhythmic drug, which is commonly used for the treatment of atrial fibrillation and other supraventricular arrhythmias. It is also a β-adrenoceptor antagonist that can cause bradycardia and bronchospasm. Hepatotoxicity is one of the adverse reactions reported, with clinical manifestations including acute cholestasis and hepatocyte necrosis. However, the mechanism of PPF-induced hepatotoxicity remains unclear. The present study was conducted to identify reactive metabolite(s) to determine related metabolic pathways and define the possible association of the bioactivation with PPF cytotoxicity. An O-demethylation phase I metabolite (M1), a further position C5 hydroxylation (para-position of the benzene ring) metabolite (M2), glutathione (GSH) conjugates (M3 and M4), and N-acetylcysteine (NAC) conjugates (M5 and M6) were detected in rat liver microsomal incubations containing PPF and GSH or NAC as trapping agents. The corresponding GSH conjugates and NAC conjugates were found in the bile and urine of rats after PPF administration, respectively. The observed GSH and NAC conjugates indicate that a quinone metabolite was generated in vitro and in vivo. Recombinant P450 enzyme incubations showed that CYP2D6 was the principal enzyme catalyzing this metabolic activation. Quinidine, a selective inhibitor of CYP2D6, attenuated the susceptibility of hepatocytes to the cytotoxicity of PPF. The results suggest that PPF was metabolized to a p-quinone intermediate which may be involved in PPF-induced hepatotoxicity.}, }
@article {pmid35439594, year = {2022}, author = {Wu, X and Ciminieri, C and Bos, IST and Woest, ME and D'Ambrosi, A and Wardenaar, R and Spierings, DCJ and Königshoff, M and Schmidt, M and Kistemaker, LEM and Gosens, R}, title = {Diesel exhaust particles distort lung epithelial progenitors and their fibroblast niche.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {305}, number = {}, pages = {119292}, doi = {10.1016/j.envpol.2022.119292}, pmid = {35439594}, issn = {1873-6424}, mesh = {Epithelial Cells ; Fibroblasts/pathology ; Humans ; Lung/metabolism ; *Pulmonary Disease, Chronic Obstructive/metabolism ; Vehicle Emissions/toxicity ; *beta Catenin/metabolism ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by inflammation and impaired tissue regeneration, and is reported as the fourth leading cause of death worldwide by the Centers for Disease Control and Prevention (CDC). Environmental pollution and specifically motor vehicle emissions are known to play a role in the pathogenesis of COPD, but little is still known about the molecular mechanisms that are altered following diesel exhaust particles (DEP) exposure. Here we used lung organoids derived from co-culture of alveolar epithelial progenitors and fibroblasts to investigate the effect of DEP on the epithelial-mesenchymal signaling niche in the distal lung, which is essential for tissue repair. We found that DEP treatment impaired the number as well as the average diameter of both airway and alveolar type of lung organoids. Bulk RNA-sequencing of re-sorted epithelial cells and fibroblasts following organoid co-culture shows that the Nrf2 pathway, which regulates antioxidants' activity, was upregulated in both cell populations in response to DEP; and WNT/β-catenin signaling, which is essential to promote epithelial repair, was downregulated in DEP-exposed epithelial cells. We show that pharmacological treatment with anti-oxidant agents such as N-acetyl cysteine (NAC) or Mitoquinone mesylate (MitoQ) reversed the effect of DEP on organoids growth. Additionally, a WNT/β-catenin activator (CHIR99021) successfully restored WNT signaling and promoted organoid growth upon DEP exposure. We propose that targeting oxidative stress and specific signaling pathways affected by DEP in the distal lung may represent a strategy to restore tissue repair in COPD.}, }
@article {pmid35434015, year = {2022}, author = {Chen, W and Teng, X and Ding, H and Xie, Z and Cheng, P and Liu, Z and Feng, T and Zhang, X and Huang, W and Geng, D}, title = {Nrf2 protects against cerebral ischemia-reperfusion injury by suppressing programmed necrosis and inflammatory signaling pathways.}, journal = {Annals of translational medicine}, volume = {10}, number = {6}, pages = {285}, pmid = {35434015}, issn = {2305-5839}, abstract = {BACKGROUND: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) -mediated neuroinflammation is linked to neuronal necroptosis in cerebral ischemia-reperfusion (I/R) injury, especially in cerebral ischemic penumbra. This study was designed to investigate the regulation of nuclear factor E2-related factor-2 (Nrf2) on NLRP3 inflammasome in necroptosis signal pathway induced by I/R injury.<br><br>METHODS: We investigated the mechanisms of Nrf2-negative regulation in necroptosis signaling pathway by using middle cerebral artery occlusion (MCAO) with Q-VD-OPH injected intraperitoneally. The protein level of the NLRP3 inflammasome was detected by western blot with Nrf2 knockdown and overexpression. NLRP3 inflammasome activation was Reactive oxygen species (ROS) dependent, and the protein level was regulated when N-acetylcysteine (NAC) and adenosine triphosphate (ATP) were selected as tools for regulating ROS.<br><br>RESULTS: We demonstrated the negative regulation of Nrf2 on NLRP3 inflammasome activation in Q-VD-OPH-induced necroptosis in cerebral artery I/R injury through Lentivirus-mediated RNA Interferenc, which mediated knockdown and overexpression of Nrf2. NLRP3 inflammasome activation was sensitive to both ATP-mediated ROS level increases and NAC-mediated ROS inhibition, suggesting that ROS is associated with the activation of NLRP3 inflammasome in necroptosis. In addition, Nrf2-induced NAD(P)H quinone dehydrogenase 1 (NQO1) was involved in the inhibition of NLRP3 inflammasome activation. These results suggest that Nrf2 regulates NQO1 to attenuate ROS, which negatively regulates NLRP3 inflammasome.<br><br>CONCLUSIONS: Nrf2/NQO1 was an inhibitor of ROS-induced NLRP3 inflammasome activation in Q-VD-OPH-induced necroptosis following cerebral I/R injury. Therefore, NLRP3 inflammasome could be a potential therapeutic target for cerebral ischemia.}, }
@article {pmid35433335, year = {2022}, author = {Kapur, A and Sharma, M and Sageena, G}, title = {Therapeutic potential of N-acetyl cysteine during COVID-19 epoch.}, journal = {World journal of virology}, volume = {11}, number = {2}, pages = {104-106}, pmid = {35433335}, issn = {2220-3249}, abstract = {N-acetyl cysteine (NAC) is a promising drug for prophylaxis and treatment of coronavirus disease 2019 (COVID-19) based on antioxidant and anti-inflammatory mechanisms. Further studies with cautious approach are needed to establish the benefits and risks before considering NAC as an adjuvant treatment for COVID-19.}, }
@article {pmid35430258, year = {2022}, author = {Barzegari, A and Omidi, Y and Landon, R and Gueguen, V and Parvizpour, S and Meddahi-Pellé, A and Anagnostou, F and Pavon-Djavid, G}, title = {The protective effect of N-acetylcysteine on antimycin A-induced respiratory chain deficiency in mesenchymal stem cells.}, journal = {Chemico-biological interactions}, volume = {360}, number = {}, pages = {109937}, doi = {10.1016/j.cbi.2022.109937}, pmid = {35430258}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Antimycin A/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Apoptosis ; Humans ; *Mesenchymal Stem Cells ; *Mitochondrial Diseases/metabolism ; Oxidative Stress ; }, abstract = {Transplantation of mesenchymal stem cells (MSCs) is an effective treatment in tissue injuries though it is limited due to the early death of stem cells within the first few days. The main reason could be a deficiency in the respiratory chain of injured tissues which is linked to the oxidative stress (OS) and disruption of energy metabolism. The disruption in energy metabolism and OS both inhibit the homing of stem cells in the hypoxic micro-environment, however on other hand, the key functions of stem cells are mainly regulated by their cellular redox status and energy metabolism. Because of that, strategies are being developed to improve the bio-functional properties of MSCs, including preconditioning of the stem cells in hypoxic conditions and pretreatment of antioxidants. To achieve this purpose, in this study N-acetylcysteine (NAC) was used for the protection of cells from oxidative stress and the disruption in energy metabolism was induced by Antimycin A (AMA) via blocking the cytochrome C complex. Then several parameters were analyzed, including cell viability/apoptosis, mitochondrial membrane potential, and redox molecular homeostasis. Based on our findings, upon the exposure of the MSCs to the conditions of deficient respiratory chain, the cells failed to scavenge the free radicals, and energy metabolism was disrupted. The use of NAC was found to alleviate the DNA damage, cell apoptosis, and oxidative stress via Nrf2/Sirt3 pathway though without any effect on the mitochondrial membrane potential. It means that antioxidants protect the cells from OS but the problem of ATP metabolism yet remains unresolved in the hypoxic conditions.}, }
@article {pmid35429732, year = {2022}, author = {Berthou, M and Pallotta, A and Beurton, J and Chaigneau, T and Athanassiou, A and Marcic, C and Marchioni, E and Boudier, A and Clarot, I}, title = {Gold nanostructured membranes to concentrate low molecular weight thiols, a proof of concept study.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1198}, number = {}, pages = {123244}, doi = {10.1016/j.jchromb.2022.123244}, pmid = {35429732}, issn = {1873-376X}, mesh = {Acetylcysteine ; Animals ; Glutathione/metabolism ; Gold/chemistry ; *Metal Nanoparticles/chemistry ; Molecular Weight ; Oxidation-Reduction ; Proof of Concept Study ; Rats ; *Sulfhydryl Compounds/chemistry ; }, abstract = {Thiols are very important molecules in the biomedical field involved for example in redox homeostasis. Their detection and quantification remain difficult due to their poor stability (oxidation) linked to their strong reactivity towards other thiols (by the formation of S-S bonds) or other interfering molecules in the medium. Cellulose membranes with immobilized gold nanoparticles (AuNP) were developed to capture and quantify thiols in simple and complex matrices. This device was first optimized and characterized in terms of nanostructuration and thiol adsorption. N-Acetylcysteine (NAC) and reduced glutathione (GSH), chosen as model molecules, were filtered through the device demonstrating a maximal adsorption capacity of 270 and 60 nmol respectively. In a second step, the adsorbed species were subjected to ligand exchange using a more reactive thiol, dithiothreitol. The results showed release rates of approximately 90% for NAC and GSH. Finally, the amount of endogenous GSH in rat plasma was determined without any pretreatment. For the first time to our knowledge, a nanostructured device for the capture, selective and sensitive quantification of thiols is proposed. This device is easy to handle and overcomes matrix effects. Moreover, the very large concentration factor induced by this technology will be a valuable asset to decrease the quantification limits of analytical methods.}, }
@article {pmid35428374, year = {2022}, author = {Erfani, R and Carmichael, C and Sofokleous, T and Wang, Q}, title = {Nanosecond-pulsed DBD plasma treatment on human leukaemia Jurkat cells and monoblastic U937 cells in vitro.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {6270}, pmid = {35428374}, issn = {2045-2322}, mesh = {Apoptosis ; Humans ; Jurkat Cells ; *Leukemia ; *Plasma Gases/pharmacology ; U937 Cells ; }, abstract = {Plasma therapy offers an exciting and novel way of cancer treatment. Specifically, it is shown that Jurkat death rates are closely governed by the plasma treatment time. However, apart from time, alterations to different parameters of treatment process may yield better results. Here, Dielectric barrier discharge (DBD) reactors excited by a nanosecond-pulse energy source are used to investigate cell viability for longer exposure times as well as the effects of polarity of reactor on treatment. Plasma discharge regimes are discussed and assessed using imaging and thermal imaging methods. We found that by changing the polarity of reactor i.e. changing the direction of plasma discharge, the plasma discharge regime changes influencing directly the effectiveness of treatment. Our results showed that ns-DBD- reactor could induce both apoptosis and necrosis of human Jurkat and U937 cells, and this cytotoxic effect of plasma was not completely antagonized by N-acetyl cysteine. It indicates that plasma could induce ROS-independent cell death. Gene expression analyses revealed that p53, BAD, BID and caspase 9 may play vital roles in plasma caused cell death. In addition, our findings demonstrate how different parameters can influence the effectiveness of our reactors. Our assay reveals the custom ability nature of plasma reactors for hematologic cancer therapy and our findings can be used for further development of such reactors using multi-objective optimisation techniques.}, }
@article {pmid35425932, year = {2021}, author = {Lana, JFSD and Lana, AVSD and Rodrigues, QS and Santos, GS and Navani, R and Navani, A and da Fonseca, LF and Azzini, GOM and Setti, T and Mosaner, T and Simplicio, CL and Setti, TM}, title = {Nebulization of glutathione and N-Acetylcysteine as an adjuvant therapy for COVID-19 onset.}, journal = {Advances in redox research}, volume = {3}, number = {}, pages = {100015}, pmid = {35425932}, issn = {2667-1379}, abstract = {Ever since its emergence, the highly transmissible and debilitating coronavirus disease spread at an incredibly fast rate, causing global devastation in a matter of months. SARS-CoV-2, the novel coronavirus responsible for COVID-19, infects hosts after binding to ACE2 receptors present on cells from many structures pertaining to the respiratory, cardiac, hematological, neurological, renal and gastrointestinal systems. COVID-19, however, appears to trigger a severe cytokine storm syndrome in pulmonary structures, resulting in oxidative stress, exacerbated inflammation and alveolar injury. Due to the recent nature of this disease no treatments have shown complete efficacy and safety. More recently, however, researchers have begun to direct some attention towards GSH and NAC. These natural antioxidants play an essential role in several biological processes in the body, especially the maintenance of the redox equilibrium. In fact, many diseases appear to be strongly related to severe oxidative stress and deficiency of endogenous GSH. The high ratios of ROS over GSH, in particular, appear to reflect severity of symptoms and prolonged hospitalization of COVID-19 patients. This imbalance interferes with the body's ability to detoxify the cellular microenvironment, fold proteins, replenish antioxidant levels, maintain healthy immune responses and even modulate apoptotic events. Oral administration of GSH and NAC is convenient and safe, but they are susceptible to degradation in the digestive tract. Considering this drawback, nebulization of GSH and NAC as an adjuvant therapy may therefore be a viable alternative for the management of the early stages of COVID-19.}, }
@article {pmid35422571, year = {2022}, author = {Ripani, U and Bisaccia, M and Meccariello, L}, title = {Dexamethasone and Nutraceutical Therapy Can Reduce the Myalgia Due to COVID-19 - a Systemic Review of the Active Substances that Can Reduce the Expression of Interlukin-6.}, journal = {Medical archives (Sarajevo, Bosnia and Herzegovina)}, volume = {76}, number = {1}, pages = {66-71}, pmid = {35422571}, issn = {1986-5961}, mesh = {Humans ; *COVID-19 Drug Treatment ; Dexamethasone/therapeutic use ; Dietary Supplements ; Inflammation ; Interleukin-6 ; Myalgia/etiology ; SARS-CoV-2 ; }, abstract = {BACKGROUND: Myalgia reflects generalized inflammation and cytokine response and can be the onset symptom of 36% of patients with COVID-19. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) levels in plasma and upper respiratory secretions directly correlate with the magnitude of viral replication, fever, and respiratory and systemic symptoms, including musculoskeletal clinical manifestations.<br><br>OBJECTIVE: The aim of our work is to report literature scientific investigation clinical protocol to reduce the immunomodulation and inflammatory response nutraceutical therapy associated with dexamethasone and how can reduce the expression of Interlukina-6(IL-6) and myalgia due to COVID-19.<br><br>METHODS: We searched in Pubmed and Cochrane the nautriceutical drugs to treat the immune modulation of organism to COVID-19. We put these keywords: immune inflammation, desease descriptions, epidemiology COVID-19; immunomodulations; IL-6; Rheumatic Symptoms; Joint; Musculoskeletal Disorders; dexamethasone; Polydatin; Zinc; Melatonin; N- Acetyl Cysteine; Colostrum; L- Glutamine; Vitamin D3.<br><br>RESULTS: We found 61 papers. All the authors analyze them. After the Analyze we suggest the use of response nutraceutical therapy associated with dexamethasone can reduce the expression of Interlukina-6(IL-6) and myalgia due to COVID-19.<br><br>CONCLUSION: According the scientific literature nutraceutical therapy associated with dexamethasone can reduce the expression of Interlukina-6(IL-6) and myalgia due to COVID-19.}, }
@article {pmid35422124, year = {2022}, author = {Vind, K and Maffioli, S and Fernandez Ciruelos, B and Waschulin, V and Brunati, C and Simone, M and Sosio, M and Donadio, S}, title = {N-Acetyl-Cysteinylated Streptophenazines from Streptomyces.}, journal = {Journal of natural products}, volume = {85}, number = {5}, pages = {1239-1247}, pmid = {35422124}, issn = {1520-6025}, mesh = {Anti-Bacterial Agents/metabolism ; *Biological Products/metabolism ; Metabolomics ; Multigene Family ; *Streptomyces/genetics ; }, abstract = {Here, we describe two N-acetyl-cysteinylated streptophenazines (1 and 2) produced by the soil-derived Streptomyces sp. ID63040 and identified through a metabolomic approach. These metabolites attracted our interest due to their low occurrence frequency in a large library of fermentation broth extracts and their consistent presence in biological replicates of the producer strain. The compounds were found to possess broad-spectrum antibacterial activity while exhibiting low cytotoxicity. The biosynthetic gene cluster from Streptomyces sp. ID63040 was found to be highly similar to the streptophenazine reference cluster in the MIBiG database, which originates from the marine Streptomyces sp. CNB-091. Compounds 1 and 2 were the main streptophenazine products from Streptomyces sp. ID63040 at all cultivation times but were not detected in Streptomyces sp. CNB-091. The lack of obvious candidates for cysteinylation in the Streptomyces sp. ID63040 biosynthetic gene cluster suggests that the N-acetyl-cysteine moiety derives from cellular functions, most likely from mycothiol. Overall, our data represent an interesting example of how to leverage metabolomics for the discovery of new natural products and point out the often-neglected contribution of house-keeping cellular functions to natural product diversification.}, }
@article {pmid35422087, year = {2022}, author = {Zhang, Y and Liu, Z and Wang, X and Jian, H and Xiao, H and Wen, T}, title = {SHMT2 promotes cell viability and inhibits ROS-dependent, mitochondrial-mediated apoptosis via the intrinsic signaling pathway in bladder cancer cells.}, journal = {Cancer gene therapy}, volume = {29}, number = {10}, pages = {1514-1527}, pmid = {35422087}, issn = {1476-5500}, mesh = {Apoptosis/genetics ; Carbon ; Caspase 3/genetics/metabolism ; Cell Line, Tumor ; Cell Survival/genetics ; Cysteine ; Cytochromes c/metabolism ; Formates ; Glutathione Disulfide ; Glycine ; *Glycine Hydroxymethyltransferase/genetics/metabolism ; Humans ; NAD/metabolism ; NADP/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Serine/metabolism ; Signal Transduction ; *Urinary Bladder Neoplasms/genetics ; }, abstract = {Mitochondrial serine hydroxymethyltransferase (SHMT2) catalyzes the conversion of serine to glycine and concomitantly produces one-carbon units to support cell growth and is upregulated in various cancer cells. SHMT2 knockdown triggers cell apoptosis; however, the detailed mechanism of apoptosis induced by SHMT2 inactivation remains unknown. Here, we demonstrate that SHMT2 supports the proliferation of bladder cancer (BC) cells by maintaining redox homeostasis. SHMT2 knockout decreased the pools of purine and one-carbon units and delayed cell cycle progression in a manner that was rescued by formate, demonstrating that SHMT2-mediated one-carbon units are essential for BC cell proliferation. SHMT2 deficiency promoted the accumulation of intracellular reactive oxygen species (ROS) by decreasing the NADH/NAD[+], NADPH/NADP[+], and GSH/GSSG ratios, leading to a loss in mitochondrial membrane potential, release of cytochrome c, translocation of Bcl-2 family protein and activation of caspase-3. Notably, blocking ROS production with the one-carbon donor formate and the ROS scavenger N-acetyl-cysteine (NAC) effectively rescued SHMT2 deficiency-induced cell apoptosis via the intrinsic signaling pathway. Treatment with the SHMT inhibitor SHIN1 resulted in a significant inhibitory effect on cell proliferation and induced cell apoptosis. Formate and NAC rescued SHIN1-induced cell apoptosis. Our findings reveal an important mechanism by which the loss of SHMT2 triggers ROS-dependent, mitochondrial-mediated apoptosis, which gives insight into the link between serine metabolism and cell apoptosis and provides a promising target for BC treatment and drug discovery.}, }
@article {pmid35420738, year = {2022}, author = {Wołosowicz, M and Łukaszuk, B and Kasacka, I and Chabowski, A}, title = {Diverse Impact of N-Acetylcysteine or Alpha-Lipoic Acid Supplementation during High-Fat Diet Regime on Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 in Visceral and Subcutaneous Adipose Tissue.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {56}, number = {2}, pages = {166-179}, doi = {10.33594/000000511}, pmid = {35420738}, issn = {1421-9778}, support = {SUB/1/DN/21/008/1118//Medical University of Bialystok (MUB)/Poland ; }, mesh = {*Acetylcysteine/therapeutic use ; Animals ; Antioxidants/metabolism ; Diet, High-Fat/adverse effects ; Dietary Supplements ; Male ; Matrix Metalloproteinase 2/genetics/metabolism ; Matrix Metalloproteinase 9/genetics/metabolism ; Obesity/drug therapy/etiology/metabolism ; Rats ; Rats, Wistar ; Subcutaneous Fat/metabolism ; *Thioctic Acid/pharmacology/therapeutic use ; }, abstract = {BACKGROUND/AIMS: The high-fat diet (HFD) regime causes obesity and contributes to the development of oxidative stress in the cells by the production of reactive oxygen species and the occurrence and progress of inflammation. Despite years of studies, there is no data explaining the mechanism of action of N-acetylcysteine (NAC) or alpha-lipoic acid (ALA) on matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) in visceral and subcutaneous adipose tissue of HFD-fed rats. Our experiment aimed to evaluate for the first time the influence of chronic antioxidants administration on MMPs biology after an HFD regime as a potential therapeutic strategy for obesity-related complications prevention.<br><br>METHODS: Male Wistar rats were fed a standard rodent chow or an HFD with intragastric administration of NAC or ALA for ten weeks. The collected samples were subjected to pathohistological evaluation. Real-time PCR and western blot approaches were used to check whether NAC or ALA impacts MMP2/9 expression.<br><br>RESULTS: Antioxidant supplementation markedly reduced the number of circulating inflammatory cytokines, and tissue macrophage infiltration. Moreover, NAC and ALA have a divergent impact on MMP2 and MMP9 expression in different adipose tissue localization.<br><br>CONCLUSION: Based on our results, we speculate that NAC and ALA have a prominent effect on the MMP2/9 functions under obesity conditions.}, }
@article {pmid35417724, year = {2022}, author = {Pan, N and Gao, K and Zhang, B and Fan, X and Lu, L and Wang, X}, title = {Inhibitory effects of zinc chloride (ZnCl2), n-acetyl-L-cysteine (NAC), and calcium/calmodulin dependent protein kinase II inhibitor (KN93) on Cd[2+]-induced abnormal cell morphology and membrane permeability.}, journal = {The Science of the total environment}, volume = {833}, number = {}, pages = {155208}, doi = {10.1016/j.scitotenv.2022.155208}, pmid = {35417724}, issn = {1879-1026}, mesh = {*Acetylcysteine/pharmacology ; Benzylamines ; *Cadmium/toxicity ; Calcium ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 ; Cell Membrane Permeability ; Chlorides ; Permeability ; Sulfonamides ; Zinc Compounds ; }, abstract = {Cadmium (Cd) could reduce abnormal cell morphology and membrane permeability, however, there are few studies on the detoxification of Cd-reduced cell membrane toxicity. In the present study, we firstly studied the effects of zinc chloride (ZnCl2), n-acetyl-L-cysteine (NAC), and calcium/calmodulin dependent protein kinase II inhibitor (KN93) on cell membrane permeability, respectively; then, we studied the inhibitory effects of ZnCl2, NAC, and KN93 on Cd[2+]-induced abnormal cell membrane permeability by scanning electrochemical microscopy (SECM) scanning imaging, transverse scanning curve and DPV technology. Our results showed that 10 μmol·L[-1] ZnCl2, 0.5 mmol·L[-1] NAC and 5 μmol·L[-1] KN93 could significantly improve the activity of MCF-7 cells, while did not destroy the cell morphology and membrane permeability. 0.5 mmol·L[-1] NAC and 5 μmol·L[-1] KN93 could significantly inhibit the effects of Cd[2+] on the morphology and membrane permeability of MCF-7 cells (p < 0.01). 10 μmol·L[-1] ZnCl2 could significantly inhibit the effect of Cd on the membrane permeability of MCF-7 cells, however, it cannot completely eliminate the morphological changes of MCF-7 cells caused by Cd[2+]. The results of cell activity experiment showed that 10 μmol·L[-1] ZnCl2, 0.5 mmol·L[-1] NAC and 5 μmol·L[-1] KN93 could inhibit the effect of Cd[2+] on the activity of MCF-7 cells. By comparing the inhibitory effects of ZnCl2, NAC and KN93 on Cd[2+]- induced cytotoxicity, 5 μmol·L[-1] KN93 had the robust effect on the maintenance of MCF-7 cell morphology and cell membrane integrity. Our research provided evidence on Zn supplement, NAC as antioxidant drugs, and KN93 as special inhibitor for the detoxification of Cd[2+]-reduced abnormal cell morphology and membrane permeability.}, }
@article {pmid35413622, year = {2022}, author = {Wang, Y and Chi, H and Xu, F and He, Z and Li, Z and Wu, F and Li, Y and Zhang, G and Peng, X and Yu, S and Yang, J and Zhang, W and Yang, X}, title = {Cadmium chloride-induced apoptosis of HK-2 cells via interfering with mitochondrial respiratory chain.}, journal = {Ecotoxicology and environmental safety}, volume = {236}, number = {}, pages = {113494}, doi = {10.1016/j.ecoenv.2022.113494}, pmid = {35413622}, issn = {1090-2414}, mesh = {*Apoptosis ; Cadmium/toxicity ; *Cadmium Chloride/toxicity ; Electron Transport ; Humans ; Membrane Potential, Mitochondrial ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Cadmium could induce cell apoptosis, probably related to the dysfunction of the mitochondrial respiratory chain. The human renal proximal tubule (HK-2) was used to explore the mechanism of mitochondrial respiratory chain dysfunction during apoptosis induced by cadmium chloride (CdCl2). Cell viability was evaluated by cell proliferation assay and different concentrations of 60, 80 and 100 μM were selected to evaluate the mitochondrial toxicity of CdCl2 respectively. Under the CdCl2 treatment for 24 h, the mitochondrial reactive oxygen species (ROS) of HK-2 cells increased and the superoxide dismutase (SOD) activity was inhibited at the above three concentrations separately. Both ATP content and mitochondrial membrane potential decreased significantly at 100 μM concentration. The levels of procaspase-3 and Bcl-2 had fallen in a concentration-dependent manner and Bax was significantly increased at 60, 80 and 100 μM concentration compared with no CdCl2 treatment respectively, which activated the mitochondrial apoptosis pathway. N-acetyl-cysteine (NAC) could partially resist CdCl2-induced cell apoptosis, while myxothiazol (Myx) promoted the process. Mitochondria relative alterations manifested as inhibition of complex III and V. In addition, both the quantity of mitochondrial coenzyme Q-binding protein CoQ10 homolog B (CoQ10B) and cytochrome c (Cyt c) had decreased significantly. Taken together, CdCl2 induced HK-2 apoptosis due to the mitochondrial respiratory chain dysfunction by reducing the CoQ10B level, offering a novel evaluating indicator for the environmental toxicity of CdCl2.}, }
@article {pmid35408692, year = {2022}, author = {Mostafa, SM and Aly, AA and Bräse, S and Nieger, M and Abdelhafez, SMN and Abdelzaher, WY and Abdelhafez, EMN}, title = {Synthesis, Characterization, and In Vivo Study of Some Novel 3,4,5-Trimethoxybenzylidene-hydrazinecarbothioamides and Thiadiazoles as Anti-Apoptotic Caspase-3 Inhibitors.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {7}, pages = {}, pmid = {35408692}, issn = {1420-3049}, mesh = {Animals ; Apoptosis ; *Caspase 3/metabolism ; *Caspase Inhibitors/chemistry ; Cytochromes c/metabolism ; Molecular Docking Simulation ; Rats ; Structure-Activity Relationship ; *Thiadiazoles/chemistry ; }, abstract = {The present study aims to discover novel derivatives as antiapoptotic agents and their protective effects against renal ischemia/reperfusion. Therefore, a series of new thiadiazole analogues 2a-g was designed and synthesized through cyclization of the corresponding opened hydrazinecarbothioamides 1a-g, followed by confirmation of the structure via spectroscopic tools (NMR, IR and mass spectra) and elemental analyses. The antiapoptotic activity showed alongside decreasing of tissue damage induced by I/R in the kidneys of rats using N-acetylcysteine (NAC) as an antiapoptotic reference. Most of the cyclized thiadiazoles are better antiapoptotic agents than their corresponding opened precursors. Particularly, compounds 2c and 2g were the most active antiapoptotic compounds with significant biomarkers. A preliminary mechanistic study was performed through caspase-3 inhibition. Compound 2c was selected along with its corresponding opened precursor 1c. An assay of cytochrome C revealed that there is an attenuation of cytochrome C level of about 5.5-fold, which was better than 1c with a level of 4.1-fold. In caspases-3, 8 and 9 assays, compound 2c showed more potency and selectivity toward caspase-3 and 9 compared with 1c. The renal histopathological investigation indicated normal renal tissue for most of the compounds, especially 2c and 2g, relative to the control. Finally, a molecular docking study was conducted at the caspase-3 active site to suggest possible binding modes.}, }
@article {pmid35403558, year = {2022}, author = {Singh, J and Phogat, A and Kumar, V and Malik, V}, title = {N-acetylcysteine ameliorates monocrotophos exposure-induced mitochondrial dysfunctions in rat liver.}, journal = {Toxicology mechanisms and methods}, volume = {32}, number = {9}, pages = {686-694}, doi = {10.1080/15376516.2022.2064258}, pmid = {35403558}, issn = {1537-6524}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Liver/metabolism ; Male ; Mammals/metabolism ; Mitochondria/metabolism ; *Monocrotophos/metabolism/toxicity ; Oxidative Stress ; *Pesticides/toxicity ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; }, abstract = {Background: Monocrotophos (MCP) is an organophosphate pesticide with well-known toxicity in mammals. Exposure of MCP is associated with altered molecular physiology at sub-cellular levels. This study investigated the efficacy of N-acetylcysteine (NAC) against MCP exposure mediated mitochondrial dysfunctions in hepatic tissue of rats.Methods: Male Wistar rats were given NAC (200 mg/kg b.wt), MCP (0.9 mg/kg b.wt) and NAC together with MCP, intragastrically for 28 consecutive days. Mitochondrial complexes activities were evaluated using biochemical analysis. mRNA expression of mitochondrial complexes subunits, PGC-1α and its downstream regulators were analyzed using polymerase chain reaction.Results: Exposure of MCP (0.9 mg/kg b.wt, intragastrically, 28 d) decreased mitochondrial complexes activities and gene expression of complexes subunits. The expression of PGC-1α, NRF-1, NRF-2, and Tfam was also reduced significantly. The administration of NAC (200 mg/kg b.wt, intragastrically, 28 d) significantly increased mitochondrial complexes activities and gene expression of complexes subunits. Additionally, NAC also maintained mitochondrial functions, and enhanced the gene expression of PGC-1α and its downstream regulators.Conclusion: The results of this study indicate that NAC prevents hepatic mitochondrial dysfunctions and maintains PGC-1α signaling. In conclusion, NAC might be speculated as a therapeutic agent for mitochondrial dysfunctions following toxic exposures.}, }
@article {pmid35401119, year = {2022}, author = {Wang, X and Han, Y and Chen, F and Wang, M and Xiao, Y and Wang, H and Xu, L and Liu, W}, title = {Glutathione Peroxidase 1 Protects Against Peroxynitrite-Induced Spiral Ganglion Neuron Damage Through Attenuating NF-κB Pathway Activation.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {841731}, pmid = {35401119}, issn = {1662-5102}, abstract = {Glutathione peroxidase 1 (GPX1) is a crucial antioxidant enzyme that prevented the harmful accumulation of intra-cellular hydrogen peroxide. GPX1 might contribute in limiting cochlear damages associated with aging or acoustic overexposure, but the function of GPX1 in the inner ear remains unclear. The present study was designed to investigate the effect of GPX1 on cochlear spiral ganglion neurons (SGNs) against oxidative stress induced by peroxynitrite, a versatile oxidant generated by the reaction of superoxide anion and nitric oxide. Here, we first found that the expression of GPX1 in cultured SGNs was downregulated after peroxynitrite exposure. Then, the GPX1 mimic ebselen and the gpx1 knockout (gpx1 [-/-]) mice were used to investigate the role of GPX1 in SGNs treated with peroxynitrite. The pretreatment with ebselen significantly increased the survived SGN numbers, inhibited the apoptosis, and enhanced the expression of 4-HNE in the cultured SGNs of peroxynitrite + ebselen group compared with the peroxynitrite-only group. On the contrary, remarkably less survived SGNs, more apoptotic SGNs, and the higher expression level of 4-HNE were detected in the peroxynitrite + gpx1 [-/-] group compared with the peroxynitrite-only group. Furthermore, rescue experiments with antioxidant N-acetylcysteine (NAC) showed that the expression of 4-HNE and the apoptosis in SGNs were significantly decreased, while the number of surviving SGNs was increased in peroxynitrite + NAC group compared the peroxynitrite-only group and in peroxynitrite + gpx1 [-/-] + NAC group vs. peroxynitrite + gpx1 [-/-] group. Finally, mechanistic studies showed that the activation of nuclear factor-kappa B (NF-κB) was involved in the SGNs damage caused by peroxynitrite and that GPX1 protected SGNs against peroxynitrite-induced damage, at least in part, via blocking the NF-κB pathway activation. Collectively, our findings suggest that GPX1 might serve as a new target for the prevention of nitrogen radical-induced SGNs damage and hearing loss.}, }
@article {pmid35396503, year = {2022}, author = {Wang, YW and Dong, HZ and Tan, YX and Bao, X and Su, YM and Li, X and Jiang, F and Liang, J and Huang, ZC and Ren, YL and Xu, YL and Su, Q}, title = {HIF-1α-regulated lncRNA-TUG1 promotes mitochondrial dysfunction and pyroptosis by directly binding to FUS in myocardial infarction.}, journal = {Cell death discovery}, volume = {8}, number = {1}, pages = {178}, pmid = {35396503}, issn = {2058-7716}, abstract = {Myocardial infarction (MI) is a fatal heart disease that affects millions of lives worldwide each year. This study investigated the roles of HIF-1α/lncRNA-TUG1 in mitochondrial dysfunction and pyroptosis in MI. CCK-8, DHE, lactate dehydrogenase (LDH) assays, and JC-1 staining were performed to measure proliferation, reactive oxygen species (ROS), LDH leakage, and mitochondrial damage in hypoxia/reoxygenation (H/R)-treated cardiomyocytes. Enzyme-linked immunoassay (ELISA) and flow cytometry were used to detect LDH, creatine kinase (CK), and its isoenzyme (CK-MB) levels and caspase-1 activity. Chromatin immunoprecipitation (ChIP), luciferase assay, and RNA-immunoprecipitation (RIP) were used to assess the interaction between HIF-1α, TUG1, and FUS. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were used to measure HIF-1α, TUG1 and pyroptosis-related molecules. Hematoxylin and eosin (HE), 2,3,5-triphenyltetrazolium chloride (TTC), and terminal deoxynucleotidyl transferase dUTP risk end labelling (TUNEL) staining were employed to examine the morphology, infarction area, and myocardial injury in the MI mouse model. Mitochondrial dysfunction and pyroptosis were induced in H/R-treated cardiomyocytes, accompanied by an increase in the expression of HIF-α and TUG1. HIF-1α promoted TUG1 expression by directly binding to the TUG1 promoter. TUG1 silencing inhibited H/R-induced ROS production, mitochondrial injury and the expression of the pyroptosis-related proteins NLRP3, caspase-1 and GSDMD. Additionally, H/R elevated FUS levels in cardiomyocytes, which were directly inhibited by TUG1 silencing. Fused in sarcoma (FUS) overexpression reversed the effect of TUG1 silencing on mitochondrial damage and caspase-1 activation. However, the ROS inhibitor N-acetylcysteine (NAC) promoted the protective effect of TUG1 knockdown on H/R-induced cardiomyocyte damage. The in vivo MI model showed increased infarction, myocardial injury, ROS levels and pyroptosis, which were inhibited by TUG1 silencing. HIF-1α targeting upregulated TUG1 promotes mitochondrial damage and cardiomyocyte pyroptosis by combining with FUS, thereby promoting the occurrence of MI. HIF-1α/TUG1/FUS may serve as a potential treatment target for MI.}, }
@article {pmid35394351, year = {2022}, author = {Shen, J and Dong, J and Shao, F and Zhao, J and Gong, L and Wang, H and Chen, W and Zhang, Y and Cai, Y}, title = {Graphene oxide induces autophagy and apoptosis via the ROS-dependent AMPK/mTOR/ULK-1 pathway in colorectal cancer cells.}, journal = {Nanomedicine (London, England)}, volume = {17}, number = {9}, pages = {591-605}, doi = {10.2217/nnm-2022-0030}, pmid = {35394351}, issn = {1748-6963}, mesh = {*AMP-Activated Protein Kinases/metabolism/pharmacology ; Apoptosis ; Autophagy ; Cell Line, Tumor ; *Colorectal Neoplasms/drug therapy/metabolism ; Graphite ; Humans ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Aim: To investigate the anticancer effects and action mechanism of graphene oxide (GO) in colorectal cancer (CRC). Materials &amp; methods: Anticancer effects and mechanisms of GO in CRC were investigated both in vivo and in vitro. Results: GO significantly inhibited tumor growth both in vitro and in vivo. GO was able to enter HCT116 cells through endocytosis. GO treatment resulted in cytotoxicity, reactive oxygen species (ROS) production, apoptosis, autophagy and activation of the AMPK/mTOR/ULK1 signal pathway. However, ROS scavenger N-acetylcysteine (NAC) attenuated the above effects and restored the effects of GO on protein expressions related to apoptosis, autophagy and AMPK/mTOR/ULK1 signal pathways. Conclusion: GO exerts anticancer effects against CRC via ROS-dependent AMPK/mTOR/ULK-1 pathway-related autophagy and apoptosis.}, }
@article {pmid35393384, year = {2022}, author = {Mcpherson, RA and Mangram, AJ and Barletta, JF and Dzandu, JK}, title = {N -acetylcysteine is associated with reduction of postconcussive symptoms in elderly patients: A pilot study.}, journal = {The journal of trauma and acute care surgery}, volume = {93}, number = {5}, pages = {644-649}, doi = {10.1097/TA.0000000000003639}, pmid = {35393384}, issn = {2163-0763}, mesh = {Humans ; Aged ; Aged, 80 and over ; Pilot Projects ; Acetylcysteine/therapeutic use ; Prospective Studies ; *Post-Concussion Syndrome/diagnosis/drug therapy/complications ; Glasgow Coma Scale ; *Brain Concussion/complications/psychology ; }, abstract = {INTRODUCTION: N -acetylcysteine (NAC) may be neuroprotective by minimizing postconcussion symptoms after mild traumatic brain injury (TBI), but limited data exist. This study evaluated the effects of NAC on postconcussion symptoms in elderly patients diagnosed with mild TBI.<br><br>METHODS: This prospective, quasirandomized, controlled trial enrolled patients 60 years or older who suffered mild TBI. Patients were excluded if cognitive function could not be assessed within 3-hours postinjury. Patients were allocated to receive NAC plus standard care, or standard care alone, based on the trauma center where they presented. The primary study outcome was the severity of concussive symptoms measured using the Rivermeade Postconcussion Symptoms Questionnaire (RPQ). Symptoms were evaluated on days 0, 7, and 30. The RPQ scores were compared both within and between treatment groups.<br><br>RESULTS: There were 65 patients analyzed (NAC, n = 34; control, n = 31) with an average age of 76 &#xb1; 10 years. Baseline demographics and clinical variables were similar. No group differences in head Abbreviated Injury Scale score or Glasgow Coma Scale score were observed. Baseline RPQ scores (6 [0-20] vs. 11 [4-20], p = 0.300) were indistinguishable. The RPQ scores on day 7 (2 [0-8] vs. 10 [3-18], p = 0.004) and 30 (0 [0-4] vs. 4 [0-13], p = 0.021) were significantly lower in the NAC group. Within-group differences were significantly lower in the NAC (p < 0.001) but not control group (p = 0.319).<br><br>CONCLUSION: N -acetylcysteine was associated with significant improvements in concussion symptoms in elderly patients with mild TBI. These results justify further research into using NAC to treat TBI.<br><br>LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.}, }
@article {pmid35388968, year = {2022}, author = {Bai, G and Zhou, R and Jiang, X and Zou, Y and Shi, B}, title = {Glyphosate-based herbicides induces autophagy in IPEC-J2 cells and the intervention of N-acetylcysteine.}, journal = {Environmental toxicology}, volume = {37}, number = {8}, pages = {1878-1890}, doi = {10.1002/tox.23534}, pmid = {35388968}, issn = {1522-7278}, support = {32072776//National Natural Science Foundation of China/ ; JQ2019C002//Provincial Science Fund for Distinguished Young Scholars/ ; }, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Autophagy ; Cell Line ; Cell Survival ; Epithelial Cells ; Glycine/analogs &amp; derivatives ; *Herbicides/toxicity ; Interleukin-6/metabolism ; RNA, Messenger/metabolism ; Swine ; Glyphosate ; }, abstract = {Glyphosate-based herbicides (GBHs) are the most widely used pesticide in the world, and its extensive use has increased pressures on environmental safety and potential human and livestock health risks. This study investigated the effects of GBHs on antioxidant capacity, inflammatory cytokines, and autophagy of porcine intestinal epithelial cells (IPEC-J2) and its molecular mechanism. Also, the protective effects of N-acetylcysteine (NAC) against the toxicity of GBHs were evaluated. Our results showed that the activities of antioxidant enzymes (SOD, GSH-Px) were decreased by GBHs. GBHs increased inflammatory factors (IL-1β, IL-6, TNF-α) and the mRNA expression of iNOS and COX-2. GBHs induced the up-regulation of Nrf2/HO-1 pathway and the phosphorylation of IκB-α and NFκB p65, up-regulation of LC3-II/LC3-I, and down-regulation of P62, and NFκB inhibitor decreased the mRNA expression of inflammatory cytokines (IL-1β, IL-6, IL-8). Moreover, NAC reduced the cytotoxicity by suppressing ROS levels, and changed the autophagy-related proteins such as the suppression of LC3-II conversion and up-regulation of P62. Our findings unveil a novel mechanism of GBHs effects on IPEC-J2 cells and NAC can reverse cytotoxicity to some extent.}, }
@article {pmid35383148, year = {2022}, author = {Wu, D and Yan, L and Zheng, C and Ren, X and Pan, Y and Huang, S and Pan, L and Li, Z}, title = {Akt-GSK3β-mPTP pathway regulates the mitochondrial dysfunction contributing to odontoblasts apoptosis induced by glucose oxidative stress.}, journal = {Cell death discovery}, volume = {8}, number = {1}, pages = {168}, pmid = {35383148}, issn = {2058-7716}, support = {Y20180704//Wenzhou Municipal Science and Technology Bureau (Wenzhou Municipal Sci - Tech Bureau)/ ; Y20190503//Wenzhou Municipal Science and Technology Bureau (Wenzhou Municipal Sci - Tech Bureau)/ ; 81870757//National Natural Science Foundation of China (National Science Foundation of China)/ ; GF21H140019//Zhejiang Province Public Welfare Technology Application Research Project (Public Welfare Technology Application Research Project of Zhejiang Province)/ ; }, abstract = {Diabetes Mellitus can cause dental pulp cells apoptosis by oxidative stress, and affect the integrity and function of dental pulp tissue. Mitochondria are the main attack targets of oxidative stress and have a critical role in apoptosis. However, whether mitochondria are involved in dental pulp damage caused by diabetes mellitus remains unclear. This study aimed to investigate the role of mitochondria in the apoptosis of odontoblast-like cell line (mDPC6T) induced by glucose oxidative stress, and to explore its possible mechanism. We established an oxidative stress model in vitro using glucose oxidase/glucose to simulate the pathological state under diabetic conditions. We found that the opening of mitochondrial permeability transition pore (mPTP) contributed to the apoptosis of mDPC6T treated with glucose oxidase, as evidenced by enhanced mitochondrial reactive oxygen species (mtROS) and intracellular Ca[2+] disorder, significantly reduced mitochondrial membrane potential (MMP) and ATP production. Antioxidant N-acetylcysteine (NAC) or Cyclosporine A (mPTP inhibitor) blocked the mPTP opening, which significantly attenuated mitochondrial dysfunction and apoptosis induced by glucose oxidative stress. In addition, we found that glucose oxidative stress stimulated mPTP opening may through inhibition of Akt-GSK3β pathway. This study provides a new insight into the mitochondrial mechanism underlying diabetes-associated odontoblast-like cell apoptosis, laying a foundation for the prevention and treatment of diabetes-associated pulp injury.}, }
@article {pmid35372029, year = {2022}, author = {Fan, Y and Wang, J and Fang, Z and Pierce, SR and West, L and Staley, A and Tucker, K and Yin, Y and Sun, W and Kong, W and Prabhu, V and Allen, JE and Zhou, C and Bae-Jump, VL}, title = {Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer.}, journal = {Frontiers in oncology}, volume = {12}, number = {}, pages = {789450}, pmid = {35372029}, issn = {2234-943X}, abstract = {ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP). The present study was to explore the anti-tumor potential effect of ONC201 in ovarian cancer cell lines and in a transgenic mouse model of high grade serous ovarian cancer under obese (high fat diet) and lean (low fat diet) conditions. ONC201 significantly suppressed cell proliferation, induced arrest in G1 phase, and increased cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial-mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial-mesenchymal transition protein expression. Knockdown of ClpP in ovarian cancer cells reduced ONC201 mediated the anti-tumor activity and cellular stress. Diet-induced obesity accelerated ovarian tumor growth in the KpB mouse model. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in obese and lean mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5, as assessed by immunohistochemistry. These results suggest that ONC201 may be a promising therapeutic agent to be explored in future clinical trials in high-grade serous ovarian cancer.}, }
@article {pmid35371352, year = {2022}, author = {Amjad, W and Thuluvath, P and Mansoor, M and Dutta, A and Ali, F and Qureshi, W}, title = {N-acetylcysteine in non-acetaminophen-induced acute liver failure: a systematic review and meta-analysis of prospective studies.}, journal = {Przeglad gastroenterologiczny}, volume = {17}, number = {1}, pages = {9-16}, pmid = {35371352}, issn = {1895-5770}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: There are discordant reports on N-acetylcysteine (NAC) efficacy in non-acetaminophen acute liver failure (ALF).<br><br>AIM: To determine whether NAC is beneficial in non-acetaminophen ALF.<br><br>MATERIAL AND METHODS: We performed a systemic review and meta-analysis of published data to address the question. PubMed and MEDLINE were searched using the terms non-acetylcysteine and ALF due to non-acetaminophen, viral infection, drug-induced or autoimmune hepatitis. The primary outcome was overall mortality. Secondary outcomes were transplant-free survival and length of hospital stay. Risk ratios were calculated using a random model for meta-analysis.<br><br>RESULTS: A total of 672 patients were included in this meta-analysis from 5 prospective studies (NAC group: n = 334; control group: n = 338). Viral hepatitis (45.8% vs. 32.8%) followed by drug-induced liver injury (24.6% vs. 27.5%), indeterminate cause (13.2% vs. 21.6%) and autoimmune hepatitis (6.6% vs. 8.9%) were the most common etiologies of ALF in the treatment group and control group respectively. Treatment with N-acetylcysteine improved the transplant-free survival significantly (55.1% vs. 28.1%; RR = 0.56; 95% CI: 0.33-0.94) whereas the overall survival was not improved with NAC (71% vs. 59.8%; RR = 0.73; 95% CI: 0.48-1.09). The NAC treatment was associated with shorter hospital stay (standard difference in means (SMD) = -1.62; 95% CI: -1.84 to -1.40, p < 0.001).<br><br>CONCLUSIONS: The treatment of patients with acute liver failure with N-acetylcysteine improved transplant-free survival and length of stay.}, }
@article {pmid35368869, year = {2022}, author = {Despotović, A and Mirčić, A and Misirlić-Denčić, S and Harhaji-Trajković, L and Trajković, V and Zogović, N and Tovilović-Kovačević, G}, title = {Combination of Ascorbic Acid and Menadione Induces Cytotoxic Autophagy in Human Glioblastoma Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {2998132}, pmid = {35368869}, issn = {1942-0994}, mesh = {Ascorbic Acid/pharmacology ; Autophagy/physiology ; *Glioblastoma/drug therapy ; Humans ; TOR Serine-Threonine Kinases/metabolism ; *Vitamin K 3/pharmacology ; }, abstract = {We investigated the ability of the ascorbic acid (AA) and menadione (MD) combination, the well-known reactive oxidative species- (ROS-) generating system, to induce autophagy in human U251 glioblastoma cells. A combination of AA and MD (AA+MD), in contrast to single treatments, induced necrosis-like cell death mediated by mitochondrial membrane depolarization and extremely high oxidative stress. AA+MD, and to a lesser extent MD alone, prompted the appearance of autophagy markers such as autophagic vacuoles, autophagosome-associated LC3-II protein, degradation of p62, and increased expression of beclin-1. While both MD and AA+MD increased phosphorylation of AMP-activated protein kinase (AMPK), the well-known autophagy promotor, only the combined treatment affected its downstream targets, mechanistic target of rapamycin complex 1 (mTORC1), Unc 51-like kinase 1 (ULK1), and increased the expression of several autophagy-related genes. Antioxidant N-acetyl cysteine reduced both MD- and AA+MD-induced autophagy, as well as changes in AMPK/mTORC1/ULK1 activity and cell death triggered by the drug combination. Pharmacological and genetic autophagy silencing abolished the toxicity of AA+MD, while autophagy upregulation enhanced the toxicity of both AA+MD and MD. Therefore, by upregulating oxidative stress, inhibiting mTORC1, and activating ULK1, AA converts MD-induced AMPK-dependent autophagy from nontoxic to cytotoxic. These results suggest that AA+MD or MD treatment in combination with autophagy inducers could be further investigated as a novel approach for glioblastoma therapy.}, }
@article {pmid35361640, year = {2022}, author = {Luo, A and Liu, X and Hu, Q and Yang, M and Jiang, H and Liu, W}, title = {Efficacy of N-acetylcysteine on idiopathic or postinfective non-cystic fibrosis bronchiectasis: a systematic review and meta-analysis protocol.}, journal = {BMJ open}, volume = {12}, number = {3}, pages = {e053625}, pmid = {35361640}, issn = {2044-6055}, mesh = {*Acetylcysteine/therapeutic use ; *Bronchiectasis/drug therapy ; Humans ; Meta-Analysis as Topic ; Quality of Life ; Research Design ; Systematic Reviews as Topic ; }, abstract = {INTRODUCTION: Non-cystic fibrosis (non-CF) bronchiectasis is a chronic pulmonary disorder that causes destruction and permanent dilatation of the airways, resulting in excessive sputum production, repeated infection and inflammation. A need for high-quality and specialised care has been highlighted in recent years. N-acetylcysteine (NAC) is a widely used mucolytic agent in respiratory diseases that not only possesses a property to enhance secretion clearance, but also exhibits antioxidant and anti-inflammatory effects. However, the efficacy and safety of NAC are not well described in idiopathic or postinfective non-CF bronchiectasis.<br><br>OBJECTIVE: This study aims to evaluate the efficacy and safety of NAC in patients with idiopathic or postinfective non-CF bronchiectasis.<br><br>METHODS AND ANALYSIS: PubMed/Medline, Embase, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials will be searched from inception to 1 March 2022 for eligible randomised controlled trials that investigating the effects of NAC on exacerbations, health-related quality of life, lung functions, sputum volume and colour, inflammation markers, exercise capacity and adverse events in patients with idiopathic or postinfective non-CF bronchiectasis, with ongoing trials being identified by searches on the websites of Chinese Clinical Trial Registry and ClinicalTrials.gov. Two independent reviewers will identify eligible studies, two will fulfil the data extraction and three will perform the quality appraisal. To generate more accurate analyses, the Grading of Recommendations Assessment, Development and Evaluation will be used to grade the evidence. &#x3c7;[2] test and I[2] statistic will be used to assess heterogeneity. Subgroup analyses and meta-regression will be used to explore potential sources of heterogeneity. The potential publication bias will be examined using funnel plots.<br><br>ETHICS AND DISSEMINATION: No research ethics approval is required in this study because it is a systematic review. The results of this study are expected to be disseminated through peer-reviewed journals and conferences.<br><br>TRIAL REGISTRATION NUMBER: CRD42021239438.}, }
@article {pmid35361025, year = {2023}, author = {Haroun, RA and Abdel-Aziz, N and Saad, S}, title = {The protective effect of N-acetyl cysteine against selenium toxicity and gamma irradiation in rats.}, journal = {Drug and chemical toxicology}, volume = {46}, number = {3}, pages = {482-490}, doi = {10.1080/01480545.2022.2058010}, pmid = {35361025}, issn = {1525-6014}, mesh = {Animals ; Rats ; *Acetylcysteine/metabolism/pharmacology ; Adenosine Triphosphate/metabolism ; *Antioxidants/pharmacology/metabolism ; Cholesterol/metabolism/pharmacology ; Corticosterone/metabolism/pharmacology ; *Liver/drug effects/metabolism/radiation effects ; Oxidative Stress ; *Selenium/toxicity ; *Gamma Rays/adverse effects ; Adrenal Glands/drug effects/metabolism/radiation effects ; }, abstract = {N-acetyl cysteine (NAC) is a nutritional supplement and greatly applied as an antioxidant in vivo and in vitro. Therefore, this study aimed to assess the metabolic and antioxidant protective effect of NAC against selenium (Se) toxicity and gamma irradiation in rats by measuring biochemical and molecular parameters. This study was conducted on sixty rats divided into six equal different groups; control, NAC, Rad, Se, Rad + NAC, and Se + NAC groups. Oxidative/nitrosative makers (LPO, NO, and NOS), antioxidants status markers (GSH, GPx, and SOD), liver metabolic markers (LDH, SDH, and ATP), and plasma metabolic markers (Glucose, total cholesterol, and total proteins) were measured using commercial colorimetric kits while plasma corticosterone concentration was measured using commercial ELISA kit. Also, Levels of NR3C1 and Glut-2 genes expression using reverse transcription-quantitative polymerase chain reaction were done. Our results revealed that Se toxicity and gamma irradiation induced significant increases in oxidative/nitrosative stress markers and a significant decrease in antioxidant status markers in the liver and adrenal tissues. Moreover, metabolic disorders were recorded as manifested by elevation of plasma ALT, Albumin, glucose and cholesterol, and decrease in protein levels associated with a significant increase in corticosterone concentration. This was also accompanied by a significant decrease in SDH activity and ATP production in the hepatic tissue. Molecular analysis showed a marked increase in NR3C1 mRNA and decrease in Glut-2 mRNA in liver tissue. However, NAC supplementation attenuated the changes induced by these toxins. Finally, we could conclude that, oral supplementation of NAC can modulate the metabolic disturbances and has protective effects in rats exposed to Se toxicity and gamma irradiation.}, }
@article {pmid35358610, year = {2022}, author = {Arber Raviv, S and Alyan, M and Egorov, E and Zano, A and Harush, MY and Pieters, C and Korach-Rechtman, H and Saadya, A and Kaneti, G and Nudelman, I and Farkash, S and Flikshtain, OD and Mekies, LN and Koren, L and Gal, Y and Dor, E and Shainsky, J and Shklover, J and Adir, Y and Schroeder, A}, title = {Lung targeted liposomes for treating ARDS.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {346}, number = {}, pages = {421-433}, pmid = {35358610}, issn = {1873-4995}, support = {680242/ERC_/European Research Council/International ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *COVID-19 ; Humans ; Inflammation/drug therapy ; Lipopolysaccharides/pharmacology ; Liposomes/therapeutic use ; Lung ; *Lung Diseases ; Mice ; Mice, Inbred C57BL ; Nanoparticles ; *Respiratory Distress Syndrome/drug therapy ; Tumor Necrosis Factor-alpha ; }, abstract = {Acute Respiratory Distress Syndrome (ARDS), associated with Covid-19 infections, is characterized by diffuse lung damage, inflammation and alveolar collapse that impairs gas exchange, leading to hypoxemia and patient' mortality rates above 40%. Here, we describe the development and assessment of 100-nm liposomes that are tailored for pulmonary delivery for treating ARDS, as a model for lung diseases. The liposomal lipid composition (primarily DPPC) was optimized to mimic the lung surfactant composition, and the drug loading process of both methylprednisolone (MPS), a steroid, and N-acetyl cysteine (NAC), a mucolytic agent, reached an encapsulation efficiency of 98% and 92%, respectively. In vitro, treating lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages with the liposomes decreased TNFα and nitric oxide (NO) secretion, while NAC increased the penetration of nanoparticles through the mucus. In vivo, we used LPS-induced lung inflammation model to assess the accumulation and therapeutic efficacy of the liposomes in C57BL/6 mice, either by intravenous (IV), endotracheal (ET) or IV plus ET nanoparticles administrations. Using both administration methods, liposomes exhibited an increased accumulation profile in the inflamed lungs over 48 h. Interestingly, while IV-administrated liposomes distributed widely throughout the lung, ET liposomes were present in lungs parenchyma but were not detected at some distal regions of the lungs, possibly due to imperfect airflow regimes. Twenty hours after the different treatments, lungs were assessed for markers of inflammation. We found that the nanoparticle treatment had a superior therapeutic effect compared to free drugs in treating ARDS, reducing inflammation and TNFα, IL-6 and IL-1β cytokine secretion in bronchoalveolar lavage (BAL), and that the combined treatment, delivering nanoparticles IV and ET simultaneously, had the best outcome of all treatments. Interestingly, also the DPPC lipid component alone played a therapeutic role in reducing inflammatory markers in the lungs. Collectively, we show that therapeutic nanoparticles accumulate in inflamed lungs holding potential for treating lung disorders. SIGNIFICANCE: In this study we compare intravenous versus intratracheal delivery of nanoparticles for treating lung disorders, specifically, acute respiratory distress syndrome (ARDS). By co-loading two medications into lipid nanoparticles, we were able to reduce both inflammation and mucus secretion in the inflamed lungs. Both modes of delivery resulted in high nanoparticle accumulation in the lungs, intravenously administered nanoparticles reached lung endothelial while endotracheal delivery reached lung epithelial. Combining both delivery approaches simultaneously provided the best ARDS treatment outcome.}, }
@article {pmid35352469, year = {2022}, author = {Yang, Y and Han, C and Sheng, Y and Wang, J and Li, W and Zhou, X and Ruan, S}, title = {Antrodia camphorata polysaccharide improves inflammatory response in liver injury via the ROS/TLR4/NF-κB signal.}, journal = {Journal of cellular and molecular medicine}, volume = {26}, number = {9}, pages = {2706-2716}, pmid = {35352469}, issn = {1582-4934}, support = {LYY20H280005//Natural Science Foundation of Zhejiang Province/ ; }, mesh = {Animals ; *Antrodia/metabolism ; Liver/metabolism ; Mice ; NF-E2-Related Factor 2/metabolism ; *NF-kappa B/metabolism ; Polyporales ; Polysaccharides/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 4/metabolism ; }, abstract = {Antrodia Camphorata Polysaccharide (ACP) refers to a kind of polysaccharide extracted from the natural porous fungus Antrodia camphorata. This study investigated the mechanism of action of ACP in protecting the liver. The results showed that ACP suppressed the LPS-induced KC cell activation, reduced the expression of inflammatory factors, increased the SOD level and suppressed ROS expression. In addition, N-acetylcysteine (NAC) was adopted for pre-treatment to suppress ROS. The results indicated that NAC synergistically exerted its effect with ACP, suggesting that ACP played its role through suppressing ROS. Further detection revealed that ACP activated the Nrf2 signal. It was discovered in the mouse model that, ACP effectively improved liver injury in mice, decreased ALT and AST levels, and suppressed the expression of inflammatory factors. This study suggests that ACP can exert its effect against oxidative stress via the Nrf2-ARE signalling, which further improves the production of ROS and the activation of TLR4-NF-κB signalling, and protects the liver against liver injury.}, }
@article {pmid35350335, year = {2022}, author = {Li, C and He, Q and Xu, Y and Lou, H and Fan, P}, title = {Synthesis of 3-O-Acetyl-11-keto-β-boswellic Acid (AKBA)-Derived Amides and Their Mitochondria-Targeted Antitumor Activities.}, journal = {ACS omega}, volume = {7}, number = {11}, pages = {9853-9866}, pmid = {35350335}, issn = {2470-1343}, abstract = {In this study, we synthesized a series of amide and mitochondria-targeted derivatives with 3-O-acetyl-11-keto-β-boswellic acid (AKBA) as the parent structure and an ethylenediamine moiety as the link chain. Compound 5e, a mitochondrial-targeting potential derivative, showed significantly stronger antitumor activity than that of AKBA, and it could induce vacuolization of A549 cells and stimulate the production of reactive oxygen species (ROS) in a time- and concentration-dependent manner. The antioxidant N-acetylcysteine (NAC) could inhibit the ROS level but could not suppress vacuolization and cell death induced by 5e. Further studies demonstrated that 5e caused abnormal opening of mitochondrial permeability transition pore (MPTP) and a decrease of mitochondrial membrane potential; additionally, it caused cell cycle arrest in G0/G1 but did not induce apoptosis. 5e represented a compound with improved antiproliferative effects for cancer therapy working through new mechanisms.}, }
@article {pmid35346799, year = {2022}, author = {Wang, W and Chen, E and Ding, X and Lu, P and Chen, J and Ma, P and Lu, L}, title = {N-acetylcysteine protect inner hair cells from cisplatin by alleviated celluar oxidative stress and apoptosis.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {81}, number = {}, pages = {105354}, doi = {10.1016/j.tiv.2022.105354}, pmid = {35346799}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Antineoplastic Agents/toxicity ; Apoptosis ; *Cisplatin/toxicity ; Hair Cells, Auditory, Inner ; Humans ; Oxidative Stress ; Rats ; Zebrafish ; }, abstract = {Cisplatin is a well-known platinum-based chemotherapy drug widely used to treat a variety of malignant tumors. However, cisplatin has serious side-effects include nephrotoxicity and ototoxicity, Cisplatin chemotherapy causes permanent hearing loss at least 40% of treated patients. Our results showed that 20 mM N-acetylcysteine (NAC) can completely protect 50 μM cisplatin-induced hair cell loss in rat cochlear culture and protects against cisplatin-induced hair cell loss in zebrafish in vivo. The fluorescence intensity of mitochondrial ROS significantly increased after the cultures were treated with 15 μM cisplatin for 48 h and was decreased in the group treated with 15 μM cisplatin add 20 mM NAC. In addition, the number of TUNEL positive hair cells was increased after the cultures were treated with 15 μM cisplatin for 48 h and there are null in cisplatin and NAC co-treated group.}, }
@article {pmid35345710, year = {2022}, author = {Philipose, J and Suchman, KI and Aronsky, D and Lee, TP}, title = {A Case of Acute Liver Failure in a Patient on Isoniazid Prophylaxis for Latent Tuberculosis.}, journal = {Cureus}, volume = {14}, number = {2}, pages = {e22452}, pmid = {35345710}, issn = {2168-8184}, abstract = {Isoniazid (INH) is widely used for latent Mycobacterium tuberculosis despite the known risk of liver injury, with severe hepatitis occurring in up to 1% of patients. We report a patient who presented with two weeks of anorexia, nausea, and jaundice following six months of INH monotherapy for latent tuberculosis (TB). After other causes of liver injury were ruled out, she underwent a liver biopsy showing submassive necrosis, hepatocellular dropout, and lobular inflammation with no evidence of fibrosis. She was also found to have acute portal hypertension. She was diagnosed with drug-induced liver injury (DILI) and was treated with n-acetyl cysteine (NAC), ursodiol, and vitamin K. She recovered without the need for a liver transplant. This case supports the need for monitoring of liver tests in high-risk individuals on INH therapy to reduce the risk of hepatotoxicity.}, }
@article {pmid35345568, year = {2022}, author = {Shaikh, N and Chanda, AH and Rahman, MA and Nainthramveetil, MM and Kumar, A and Mathias, RM and Nashwan, AJ}, title = {Inhalational injury and use of heparin &amp; N-acetylcysteine nebulization: A case report.}, journal = {Respiratory medicine case reports}, volume = {37}, number = {}, pages = {101640}, pmid = {35345568}, issn = {2213-0071}, abstract = {Inhalational injury to the upper and lower airway occurs due to thermal or chemical irritation causing airway edema, capillary leak, mucin, and fibrin debris forming clots and soot. The use of unfractionated heparin (UFH) nebulization was found to be effective by dissolving airway clots. We report a case of inhalational burn injury where UFH nebulization led to a better outcome. A healthy male was trapped in a residential room during a fire in the building. He sustained facial, neck, upper chest, and left upper extremity burns accounting for 25% of body surface area. He was intubated at the site and started on supportive care. In the surgical intensive care unit, bronchoscopy showed severe tracheobronchial burn injury; a thorough lavage was done, started on UFH and N-acetylcysteine nebulization (NAC). The patient improved, and his trachea was extubated on day 6. In our patient, unfractionated heparin nebulization was beneficial as the patient was extubated early without landing to acute respiratory distress syndrome.}, }
@article {pmid35344072, year = {2022}, author = {Xu, X and Wang, X and Yang, Y and Ares, I and Martínez, M and Lopez-Torres, B and Martínez-Larrañaga, MR and Wang, X and Anadón, A and Martinez, MA}, title = {Neonicotinoids: mechanisms of systemic toxicity based on oxidative stress-mitochondrial damage.}, journal = {Archives of toxicology}, volume = {96}, number = {6}, pages = {1493-1520}, pmid = {35344072}, issn = {1432-0738}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Antidotes/pharmacology ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; *Curcumin ; Glutathione/metabolism ; Mammals/metabolism ; Neonicotinoids ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Resveratrol/pharmacology ; }, abstract = {Neonicotinoids are the most widely used pesticides in the world. However, research studies have shown that it can affect the cognitive abilities and health of non-target bees and other wild pollinators by inducing DNA damage, apoptosis and mitochondrial damage, injure to its central nervous system, and it is even developmentally neurotoxic to mammals and humans, with mitochondria being an important target of neonicotinoids. Therefore, this article reviews the role of mitochondrial morphology, calcium ions (Ca[2+]) homeostasis, respiratory function, apoptosis, and DNA damage in neonicotinoids-induced systemic toxicity. Additionally, it evaluates the protective effects of various active substances including vitamin C, N-acetylcysteine (NAC), curcumin (CUR), glutathione reduced (GSH), caffeic acid phenethyl ester (CAPE), resveratrol, and thymoquinone (TQ) on neonicotinoids-induced toxicity. This review manuscript found that mitochondria are important targets to neonicotinoids. Neonicotinoids can cause DNA damage, apoptosis, protein oxidation, and lipid peroxidation in non-target organisms by altering mitochondrial Ca[2+] homeostasis, inhibiting mitochondrial respiration, and inducing reactive oxygen species (ROS) production. Several active substances (vitamin C, NAC, CUR, GSH, resveratrol, CAPE, and TQ) play a protective role against neonicotinoid-induced systemic toxicity by inhibiting ROS signaling pathways, apoptosis, and lipid peroxidation. This review manuscript emphasizes the importance and urgency of the development of neonicotinoid antidotes, emphasizes the prospect of the application of targeted mitochondrial antidotes, and prospects the development of neonicotinoid antidotes in order to provide some strategies for the prevention of neonicotinoid toxicity.}, }
@article {pmid35342347, year = {2022}, author = {Gao, Z and Yi, W and Tang, J and Sun, Y and Huang, J and Lan, T and Dai, X and Xu, S and Jin, ZG and Wu, X}, title = {Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2.}, journal = {International journal of biological sciences}, volume = {18}, number = {5}, pages = {2146-2162}, pmid = {35342347}, issn = {1449-2288}, mesh = {Animals ; Mice ; *Acetaminophen/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism ; *Coumarins/pharmacology ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Liver/metabolism ; Molecular Docking Simulation ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress ; }, abstract = {Acetaminophen overdose is a leading cause of acute live failure worldwide. N-acetylcysteine (NAC), as the only antidote, is limited due to its narrow therapeutic time window. Here we demonstrated that Urolithin A (UA), a metabolite of ellagitannin natural products in the gastrointestinal flora, protected against acetaminophen-induced liver injury (AILI) and is superior to NAC in terms of dosage and therapeutical time window. Transcriptomics assay revealed that UA promotes mitophagy and activated Nrf2/ARE signaling in the liver. Consistent with that, mitophagy and Nrf2/ARE signaling were activated, with less oxidative stress in UA-treated liver. Subsequently, molecular docking and dynamics simulation study revealed a binding mode between UA and Nrf-2/Keap1 including the hydrogen-bonding network among oxygen atoms in UA with the Nrf-2/Keap1 residues Arg 415, Ser 508 and Ser 602, which in turn trigger Nrf2 nuclear translocation, subsequently leading to activation of Nrf-2 target genes (HO-1, NQO1). Of note, mitophagy inhibition failed to prevent the protection of UA against AILI, which instead was compromised with Nrf2 gene silencing both in vivo and in vitro. Collectively, our data indicate that UA alleviated acetaminophen-induced oxidative stress and hepatic necrosis via activating Nrf2/ARE signaling pathway, highlighting a therapeutical potential of UA for AILI.}, }
@article {pmid35341601, year = {2022}, author = {Schweikl, H and Weissenberger, S and Gallorini, M and Bolay, C and Waha, C and Hiller, KA and Buchalla, W}, title = {Influence of HEMA on LPS- and LTA-stimulated IL-6 release from human dental pulp cells.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {38}, number = {5}, pages = {886-897}, doi = {10.1016/j.dental.2022.03.008}, pmid = {35341601}, issn = {1879-0097}, mesh = {Dental Pulp/metabolism ; Humans ; Interleukin-6 ; *Lipopolysaccharides/pharmacology ; Methacrylates ; *Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVE: Dental pulp cells interact with immunogenic components such as LPS (lipopolysaccharide) or LTA (lipoteichoic acid) released from microorganisms in carious lesions. In the present investigation, the formation of the pro-inflammatory cytokines TNFα and IL-6 in LPS- or LTA-stimulated cells from the dental pulp interface and pulp fibroblasts was analyzed in the presence of the resin monomer 2-hydroxyethyl methacrylate (HEMA) under varying cellular redox conditions.<br><br>METHOD: Human pulp fibroblasts (HPC) or cells from the dental pulp interface expressing an odontoblast phenotype (hOD-1) were exposed to LTA, LPS or HEMA for 1&#xa0;h or 24&#xa0;h. Redox homeostasis was modified by the prooxidant BSO (L-buthionine sulfoximine) or the antioxidant NAC (N-acetyl cysteine). Formation of TNF&#x3b1; or IL-6 was analyzed by ELISA, and cell survival was determined by a crystal violet assay. Statistical analyses were performed using the Mann-Whitney-U-test.<br><br>RESULTS: Secretion of TNF&#x3b1; was not detected in LPS- or LTA-stimulated HPC or hOD-1, and IL-6 was not found after a short exposure (1&#xa0;h). After a 24&#xa0;h exposure, LPS induced a 3-fold increase in IL-6 formation in HPC, while LTA stimulated IL-6 release about 20-fold. Likewise, LTA was more effective than LPS in hOD-1 stimulating IL-6 levels about 50-fold. HEMA inhibited the LPS- and LTA-induced IL-6 release, and this effect was enhanced by BSO but counteracted by NAC in both cell types. IL-6 release was independent of cell survival rates.<br><br>CONCLUSIONS: The protective immune response in odontoblasts and pulp fibroblasts is impaired by monomers such as HEMA through the disturbance of the redox homeostasis.}, }
@article {pmid35339751, year = {2022}, author = {Sapmaz, T and Sevgin, K and Topkaraoglu, S and Tekayev, M and Aktas, S and Coskun, G and Polat, S and Sapmaz, E and Irkorucu, O}, title = {Comparison of melatonin, oxytetracycline, and N-acetylcysteine pre-treatments in autologous intraperitoneal ovarian transplantation in rats.}, journal = {Biochemical and biophysical research communications}, volume = {606}, number = {}, pages = {49-54}, doi = {10.1016/j.bbrc.2022.03.065}, pmid = {35339751}, issn = {1090-2104}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Female ; *Melatonin/pharmacology ; *Ovary/transplantation ; *Oxytetracycline/pharmacology ; Rats ; Rats, Wistar ; bcl-2-Associated X Protein ; }, abstract = {This study was aimed at investigating the effects of melatonin, oxytetracycline and N-acetylcysteine on the ovarian follicle reserves and surface epithelium in autologous intraperitoneal ovarian transplantation in rats. Thirty adult female Wistar Albino were selected and randomly divided into six groups (n = 5). Group 1, which was the control group, only had their abdomens opened and closed while Group 2 underwent ovarian transplantation. Group 3, 4, 5 and 6 received 20 μg/kg/IM melatonin, 10 mg/kg/IM oxytetracycline, 150 mg/kg/IP N-Asetil sistein (NAC) and 1% ethanol respectively 15 min before the ovarian transplantation. Vaginal cytology was performed to monitor the estrus phase and the follicle reserve and changes in the surface epithelium were histopathologically evaluated during the preparations. Moreover, cellular apoptosis in tissues was evaluated with immunofluorescence staining of Bcl-2 and Bax. The Bax/Bcl-2 ratio was then calculated as the mean fluorescence intensity (MFI) of Bax and Bcl-2 MFI. Dysplastic change was found only significantly higher in the transplantation group (G2) (p < 0.01). Histopathologically, it was found that the follicle reserve was preserved significantly in the oxytetracycline and melatonin treated group (G3, G4) (p < 0.01). It was also observed that the oxytetracycline treated group (G4) were able to show better preventive effects against dysplastic changes of the surface epithelium. Moreover, the melatonin treated group depicted a low Bax/Bcl-2 ratio compared to the group that only underwent transplantation (G2) (p < 0.01). This study indicated that oxytetracycline and melatonin might be more effective than N-acetylcysteine in protecting against oxidative stress during ovarian transplantation.}, }
@article {pmid35338924, year = {2022}, author = {Phan, H and Cossutta, M and Houppe, C and Le Cœur, C and Prevost, S and Cascone, I and Courty, J and Penelle, J and Couturaud, B}, title = {Polymerization-Induced Self-Assembly (PISA) for in situ drug encapsulation or drug conjugation in cancer application.}, journal = {Journal of colloid and interface science}, volume = {618}, number = {}, pages = {173-184}, doi = {10.1016/j.jcis.2022.03.044}, pmid = {35338924}, issn = {1095-7103}, mesh = {Doxorubicin/metabolism/pharmacology ; Drug Carriers ; Humans ; Methacrylates ; Micelles ; *Nanoparticles ; *Neoplasms ; Polymerization ; Polymers ; }, abstract = {HYPOTHESIS: We describe the possibility of using the same block copolymer carriers prepared by PISA for in situ drug encapsulation or drug conjugation.<br><br>EXPERIMENTS: Block copolymers containing poly((ethylene glycol) methacrylate)-co-poly(pentafluorophenyl methacrylate)-b-poly(hydroxypropyl methacrylate) (P((PEGMA-co-PFBMA)-b-PHPMA)) were synthesized at 10&#xa0;wt% using PISA. The first approach involved in situ Doxorubicin (DOX) loading during PISA, while the second exhibited surface functionalization of PISA-made vesicles with dual drug therapies, N-acetyl cysteine (NAC) and DOX using para-fluoro-thiol reaction (PFTR) and carbodiimide chemistry, respectively. Cytotoxicity, cell uptake, and cell apoptosis were assessed on MDA-MB-231 cell lines.<br><br>FINDINGS: P((PEGMA-co-PFBMA)-b-PHPMA) nanocarriers were prepared, showing size and shape transformations from spheres, cylinders to raspberry-forming vesicles. DOX was readily loaded into NPs during PISA with relatively high encapsulation efficiency of 70 %, whereas the plain PISA-made vesicles could be functionalized with NAC and DOX at high yields. DOX-free NPs showed biocompatibility, whilst DOX-conjugated NPs imparted a concentration-dependent cytotoxicity, as well as an enhanced cell uptake compared to free DOX. The results demonstrated that the same PISA-derived self-assemblies enabled either in situ drug encapsulation, or post-polymerization surface engineering with useful functionalities upon tuning the macro-CTA block, thus holding promises for future drug delivery and biomedical applications.}, }
@article {pmid35331045, year = {2023}, author = {Chen, B and Raja, K and Pierre-Louis, F and Patel, M and Patel, R and Kang, S and Daniel, N and Attalla, M and Philips, M}, title = {Intravenous N-Acetylcysteine in Management of COVID-19: A Case Series.}, journal = {Journal of pharmacy practice}, volume = {36}, number = {4}, pages = {1008-1014}, pmid = {35331045}, issn = {1531-1937}, mesh = {Humans ; *Acetylcysteine/therapeutic use ; *COVID-19 ; NF-kappa B ; Cytokine Release Syndrome/drug therapy ; Glutathione Reductase ; Retrospective Studies ; Glutathione ; SARS-CoV-2 ; }, abstract = {A novel coronavirus, severe acute respiratory syndrome coronavirus-2, was isolated from patients' lower respiratory tracts in December 2019. As of May 19, 2021, there were over 33 million reported infections and almost 600,000 deaths in the United States. The infection, coronavirus disease-19 (COVID-19), can lead to cytokine storm, with elevations in interleukin-6 (IL-6), IL-10, tumor necrosis factor-α, nuclear factor-kappaB (NF-kappaB), and glutathione reductase. NF-kappaB activation is necessary for further transcription of other pro-inflammatory markers. Glutathione may play a role in modulation of NF-kappaB activation and elevated glutathione reductase may indicate glutathione depletion. Administration of N-acetylcysteine (NAC) may replenish spent glutathione and attenuate over-activation of NF-kappaB. This retrospective case series included 10 patients who were COVID-19 positive and received intravenous NAC in an attempt to attenuate the cytokine storm. Patients' outcomes were graded based on the World Health Organization symptom severity scale from 0, no evidence of infection, to 8, death. Overall, the median WHO Scale prior to NAC was 6.5, and increased by day seven, which indicated clinical worsening. This retrospective case series showed no benefit of NAC; however, further studies are needed to elucidate if differences in drug regimens would lead to positive results.}, }
@article {pmid35328386, year = {2022}, author = {Argaev-Frenkel, L and Rosenzweig, T}, title = {Complexity of NAC Action as an Antidiabetic Agent: Opposing Effects of Oxidative and Reductive Stress on Insulin Secretion and Insulin Signaling.}, journal = {International journal of molecular sciences}, volume = {23}, number = {6}, pages = {}, pmid = {35328386}, issn = {1422-0067}, support = {3-11350//D-Cure/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; *Diabetes Mellitus, Experimental/complications/drug therapy ; *Diabetes Mellitus, Type 2/complications/drug therapy ; Hydrogen Peroxide/pharmacology ; Hypoglycemic Agents/pharmacology/therapeutic use ; Insulin/metabolism ; Insulin Secretion ; Mice ; Oxidation-Reduction ; Oxidative Stress ; }, abstract = {Dysregulated redox balance is involved in the pathogenesis of type 2 diabetes. While the benefit of antioxidants in neutralizing oxidative stress is well characterized, the potential harm of antioxidant-induced reductive stress is unclear. The aim of this study was to investigate the dose-dependent effects of the antioxidant N-acetylcysteine (NAC) on various tissues involved in the regulation of blood glucose and the mechanisms underlying its functions. H2O2 was used as an oxidizing agent in order to compare the outcomes of oxidative and reductive stress on cellular function. Cellular death in pancreatic islets and diminished insulin secretion were facilitated by H2O2-induced oxidative stress but not by NAC. On the other hand, myotubes and adipocytes were negatively affected by NAC-induced reductive stress, as demonstrated by the impaired transmission of insulin signaling and glucose transport, as opposed to H2O2-stimulatory action. This was accompanied by redox balance alteration and thiol modifications of proteins. The NAC-induced deterioration of insulin signaling was also observed in healthy mice, while both insulin secretion and insulin signaling were improved in diabetic mice. This study establishes the tissue-specific effects of NAC and the importance of the delicate maintenance of redox balance, emphasizing the challenge of implementing antioxidant therapy in the clinic.}, }
@article {pmid35326237, year = {2022}, author = {Yu, TJ and Tang, JY and Shiau, JP and Hou, MF and Yen, CH and Ou-Yang, F and Chen, CY and Chang, HW}, title = {Gingerenone A Induces Antiproliferation and Senescence of Breast Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {35326237}, issn = {2076-3921}, support = {MOST 108-2320-B-037-015-MY3; MOST 110-2314-B-037-074-MY3//Ministry of Science and Technology/ ; #NSYSUKMU 111-P20//National Sun Yat-sen University-KMU Joint Research Project/ ; KMUH110-0M39//Kaohsiung Medical University Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Ginger is a popular spice and consists of several bioactive antioxidant compounds. Gingerenone A (Gin A), a novel compound isolated from Zingiber officinale, is rarely investigated for its anti-breast-cancer properties. Some ginger extracts have been reported to initiate senescence, an anticancer strategy. However, the anticancer effects of Gin A on breast cancer cells remain unclear. The present study aims to assess the modulating impact of Gin A acting on proliferation and senescence to breast cancer cells. Gin A diminished the cellular ATP content and decreased the cell viability of the MTS assay in several breast cancer cell lines. It also showed a delayed G2/M response to breast cancer cells (MCF7 and MDA-MB-231). N-acetylcysteine (NAC), an oxidative stress inhibitor, can revert these responses of antiproliferation and G2/M delay. The oxidative stress and senescence responses of Gin A were further validated by increasing reactive oxygen species, mitochondrial superoxide, and β-galactosidase activity, which were reverted by NAC. Gin A also upregulated senescence-associated gene expressions. In addition to oxidative stress, Gin A also induced DNA damage responses by increasing γH2AX level and foci and generating 8-hydroxyl-2'-deoxyguanosine in breast cancer cells, which were reverted by NAC. Therefore, Gin A promotes antiproliferation and senescence of breast cancer cells induced by oxidative stress.}, }
@article {pmid35326096, year = {2022}, author = {Eligini, S and Porro, B and Aldini, G and Colli, S and Banfi, C}, title = {N-Acetylcysteine Inhibits Platelet Function through the Regeneration of the Non-Oxidative Form of Albumin.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {3}, pages = {}, pmid = {35326096}, issn = {2076-3921}, support = {Ricerca Corrente RC 2021 MPP1A ID 2746191.//Italian Ministry of Health Ricerca Corrente RC 2021 MPP1A ID 2746191)./ ; }, abstract = {N-acetylcysteine (NAC) is able to break down protein disulfides, generating free thiols. This mechanism occurs on mixed disulfides of albumin (HSA) to form mercaptoalbumin (HMA), the main antioxidant species in the plasma. Circulating HSA exists in two main forms: the reduced form (HMA), and the oxidized forms, whose predominant modification is cystenylation (HSA-Cys). Increased levels of oxidized HSA have been detected in several diseases associated with oxidative stress. This study showed that NAC inhibits platelet aggregation by restoring HMA. In addition, the regeneration of HMA by NAC inhibits platelet functions such as intracellular calcium mobilization, reactive oxygen species generation, arachidonic acid metabolites synthesis, and adhesion to the collagen matrix. In our conditions, the exposure of platelets to NAC did not increase GSH levels. However, the inhibition of platelet aggregation was also detected following treatment of platelet-rich plasma with GSH, which, similarly to NAC, reduced HSA-Cys levels. Furthermore, this study showed that cysteine, another compound able to restore HMA by reducing the HSA-Cys content, inhibited platelet aggregation to a similar extent as NAC. The results obtained in this study suggest a new mechanism by which NAC can modulate platelet activation and suggest its possible use as an antiplatelet drug in conditions associated with oxidative stress.}, }
@article {pmid35320665, year = {2022}, author = {Hur, J and Rhee, CK and Jo, YS}, title = {Effects of Antioxidant on Oxidative Stress and Autophagy in Bronchial Epithelial Cells Exposed to Particulate Matter and Cigarette Smoke Extract.}, journal = {Tuberculosis and respiratory diseases}, volume = {85}, number = {3}, pages = {237-248}, pmid = {35320665}, issn = {1738-3536}, support = {//The Korean Academy of Tuberculosis and Respiratory Diseases/ ; }, abstract = {BACKGROUND: We evaluated the effect of particulate matter (PM) and cigarette smoke extract (CSE) on bronchial epithelial cell survival, as well as oxidative stress and autophagy levels. Moreover, we aimed to assess the effect of the antioxidant N-acetylcysteine (NAC) on the adverse effects of PM and CSE exposure.<br><br>METHODS: Normal human bronchial epithelial cells (BEAS-2B cells) were exposed to urban PM with or without CSE, after which cytotoxic effects, including oxidative stress and autophagy levels, were measured. After identifying the toxic effects of urban PM and CSE exposure, the effects of NAC treatment on cell damage were evaluated.<br><br>RESULTS: Urban PM significantly decreased cell viability in a concentration-dependent manner, which was further aggravated by simultaneous treatment with CSE. Notably, pretreatment with NAC at 10 mM for 1 hour reversed the cytotoxic effects of PM and CSE co-exposure. Treatment with 1, 5, and 10 mM NAC was shown to decrease reactive oxygen species levels induced by exposure to both PM and CSE. Additionally, the autophagy response assessed via LC3B expression was increased by PM and CSE exposure, and this also attenuated by NAC treatment.<br><br>CONCLUSION: The toxic effects of PM and CSE co-exposure on human bronchial epithelial cells, including decreased cell viability and increased oxidative stress and autophagy levels, could be partly prevented by NAC treatment.}, }
@article {pmid35316693, year = {2022}, author = {Chen, Q and Huang, J and Tong, W and Gui, X and Zheng, J and Hu, G}, title = {The geometry-dependent regulation of hepatic stellate cells by graphene oxide nanomaterials.}, journal = {Biochemical and biophysical research communications}, volume = {604}, number = {}, pages = {179-184}, doi = {10.1016/j.bbrc.2022.03.050}, pmid = {35316693}, issn = {1090-2104}, mesh = {Fibrosis ; *Graphite/pharmacology ; Hepatic Stellate Cells/metabolism ; Humans ; Liver/metabolism ; Liver Cirrhosis/metabolism ; *Nanostructures ; Transforming Growth Factor beta1/metabolism ; }, abstract = {Nanomaterials are widely used in biomedical applications such as drug delivery, bioimaging, and photothermal therapy. For example, graphene oxide (GO) nanomaterials are among the most popular drug delivery vehicles in treating liver diseases due to their tunable chemical/physical properties, and biocompatibility. However, it has been reported that nanomaterials tend to accumulate in livers. The biophysical impact of the accumulation in liver cells remains unclear, and it may cause the liver fibrosis in the long run. The activation of hepatic stellate cells (HSCs) is one of the key initial steps of liver fibrosis. In this paper, we explored the geometric effect (nanosheets vs. quantum dots) of GO nanomaterials on human HSCs, in terms of cell viability, fibrotic degree, mobility and regulation pathways. Our study showed that GO nanosheets could significantly reduce HSCs cell viability and mobility. The protein expression levels of TGFβRⅡ/Smad2/Smad3 decreased, corresponding to a trend of attenuating fibrotic degree. However, the expression level of α-SMA, a maker protein of fibrosis, increased and contradicted with the projection. Further investigation on mitochondria showed that GO nanosheets disrupted mitochondria membrane and membrane potentials. We found that while modulating fibrotic effect through the TGF-β pathway, GO nanosheets induced oxidative stress and activated HSCs through reactive oxygen species(ROS)pathway. This was confirmed by the decreased expression level of α-SMA after co-incubation of GO nanosheets and n-acetyl cysteine (NAC) with HSCs. GO quantum dots decreased α-SMA expression level at 100 mg/l, along with decrease in GAPDH expression level and constant expression level of β-actin. The correlation between GAPDH and α-SMA remains to be explored. Our study suggested that the biophysical impacts of GO nanomaterials on HSCs are geometry-dependent. Both GO nanosheets and quantum dots can be adapted for attenuating liver fibrosis with further investigation on mechanisms.}, }
@article {pmid35316513, year = {2022}, author = {Bradlow, RCJ and Berk, M and Kalivas, PW and Back, SE and Kanaan, RA}, title = {The Potential of N-Acetyl-L-Cysteine (NAC) in the Treatment of Psychiatric Disorders.}, journal = {CNS drugs}, volume = {36}, number = {5}, pages = {451-482}, pmid = {35316513}, issn = {1179-1934}, mesh = {Acetylcysteine/therapeutic use ; Anxiety Disorders/drug therapy ; *Bipolar Disorder/drug therapy ; Humans ; *Obsessive-Compulsive Disorder/drug therapy ; *Schizophrenia/drug therapy ; }, abstract = {N-acetyl-L-cysteine (NAC) is a compound of increasing interest in the treatment of psychiatric disorders. Primarily through its antioxidant, anti-inflammatory, and glutamate modulation activity, NAC has been investigated in the treatment of neurodevelopmental disorders, schizophrenia spectrum disorders, bipolar-related disorders, depressive disorders, anxiety disorders, obsessive compulsive-related disorders, substance-use disorders, neurocognitive disorders, and chronic pain. Whilst there is ample preclinical evidence and theoretical justification for the use of NAC in the treatment of multiple psychiatric disorders, clinical trials in most disorders have yielded mixed results. However, most studies have been underpowered and perhaps too brief, with some evidence of benefit only after months of treatment with NAC. Currently NAC has the most evidence of having a beneficial effect as an adjuvant agent in the negative symptoms of schizophrenia, severe autism, depression, and obsessive compulsive and related disorders. Future research with well-powered studies that are of sufficient length will be critical to better understand the utility of NAC in the treatment of psychiatric disorders.}, }
@article {pmid35316061, year = {2022}, author = {Shi, J and Zhao, M and Li, K and Zhao, Y and Li, W and Peng, Y and Zheng, J}, title = {Metabolic Activation and Cytotoxicity of Fungicide Carbendazim Mediated by CYP1A2.}, journal = {Journal of agricultural and food chemistry}, volume = {70}, number = {13}, pages = {4092-4101}, doi = {10.1021/acs.jafc.1c08144}, pmid = {35316061}, issn = {1520-5118}, mesh = {Activation, Metabolic ; Animals ; Benzimidazoles ; Carbamates/metabolism/toxicity ; *Cytochrome P-450 CYP1A2/metabolism ; Glutathione/metabolism ; Microsomes, Liver/metabolism ; Rats ; *Zebrafish/metabolism ; }, abstract = {Carbendazim (CBZ) is a broad-spectrum fungicide widely used in many nations for foliar spray as well as seed and soil treatment. The resulting contamination and environmental pollution have been drawing public attention. In particular, CBZ was reported to cause liver damage in rats and zebrafish, and the mechanisms of its toxicity have not been clarified. The purposes of this study were to investigate the metabolic activation of CBZ and to determine a possible role of the reactive metabolites in CBZ-induced liver injury reported. One oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetyl cysteine conjugate (M3) were detected in human and rat liver microsomal incubations fortified with glutathione or N-acetyl cysteine after exposure to CBZ. CYP1A2 was the major enzyme responsible for the metabolic activation of CBZ. Biliary M2 and urinary M3 were detected in rats treated with CBZ. CBZ-derived protein adduction was found in cultured rat primary hepatocytes treated with CBZ. The increase of administration concentration intensified not only the cytotoxicity but also protein adduction induced by CBZ, suggesting a correlation of the cytotoxicity with the observed protein modification. The findings facilitate the understanding of the mechanisms of toxic action of CBZ.}, }
@article {pmid35311615, year = {2022}, author = {Sarris, J and Ravindran, A and Yatham, LN and Marx, W and Rucklidge, JJ and McIntyre, RS and Akhondzadeh, S and Benedetti, F and Caneo, C and Cramer, H and Cribb, L and de Manincor, M and Dean, O and Deslandes, AC and Freeman, MP and Gangadhar, B and Harvey, BH and Kasper, S and Lake, J and Lopresti, A and Lu, L and Metri, NJ and Mischoulon, D and Ng, CH and Nishi, D and Rahimi, R and Seedat, S and Sinclair, J and Su, KP and Zhang, ZJ and Berk, M}, title = {Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.}, journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry}, volume = {23}, number = {6}, pages = {424-455}, doi = {10.1080/15622975.2021.2013041}, pmid = {35311615}, issn = {1814-1412}, mesh = {Adolescent ; Humans ; *Biological Psychiatry ; Canada ; *Mental Disorders/drug therapy ; Anxiety ; Dietary Supplements ; *Fatty Acids, Omega-3 ; Vitamin D ; Zinc ; }, abstract = {OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations.<br><br>METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed.<br><br>RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy.<br><br>CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.}, }
@article {pmid35310492, year = {2022}, author = {Wang, R and Chan, JF and Wang, S and Li, H and Zhao, J and Ip, TK and Zuo, Z and Yuen, KY and Yuan, S and Sun, H}, title = {Orally administered bismuth drug together with N-acetyl cysteine as a broad-spectrum anti-coronavirus cocktail therapy.}, journal = {Chemical science}, volume = {13}, number = {8}, pages = {2238-2248}, pmid = {35310492}, issn = {2041-6520}, abstract = {The emergence of SARS-CoV-2 variants of concern compromises vaccine efficacy and emphasizes the need for further development of anti-SARS-CoV-2 therapeutics, in particular orally administered take-home therapies. Cocktail therapy has shown great promise in the treatment of viral infection. Herein, we reported the potent preclinical anti-SARS-CoV-2 efficacy of a cocktail therapy consisting of clinically used drugs, e.g. colloidal bismuth subcitrate (CBS) or bismuth subsalicylate (BSS), and N-acetyl-l-cysteine (NAC). Oral administration of the cocktail reduced viral loads in the lung and ameliorated virus-induced pneumonia in a hamster infection model. The mechanistic studies showed that NAC prevented the hydrolysis of bismuth drugs at gastric pH via the formation of the stable component [Bi(NAC)3], and optimized the pharmacokinetics profile of CBS in vivo. Combination of bismuth drugs with NAC suppressed the replication of a panel of medically important coronaviruses including Middle East respiratory syndrome-related coronavirus (MERS-CoV), Human coronavirus 229E (HCoV-229E) and SARS-CoV-2 Alpha variant (B.1.1.7) with broad-spectrum inhibitory activities towards key viral cysteine enzymes/proteases including papain-like protease (PL[pro]), main protease (M[pro]), helicase (Hel) and angiotensin-converting enzyme 2 (ACE2). Importantly, our study offered a potential at-home treatment for combating SARS-CoV-2 and future coronavirus infections.}, }
@article {pmid35305384, year = {2022}, author = {Zhang, Y and Yan, M and Niu, W and Mao, H and Yang, P and Xu, B and Sun, Y}, title = {Tricalcium phosphate particles promote pyroptotic death of calvaria osteocytes through the ROS/NLRP3/Caspase-1 signaling axis in amouse osteolysis model.}, journal = {International immunopharmacology}, volume = {107}, number = {}, pages = {108699}, doi = {10.1016/j.intimp.2022.108699}, pmid = {35305384}, issn = {1878-1705}, mesh = {Animals ; Calcium Phosphates ; Caspase 1/metabolism ; Inflammasomes/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; NLR Proteins/metabolism ; *Osteocytes ; *Osteolysis/metabolism ; Pyroptosis ; Reactive Oxygen Species/metabolism ; Skull/metabolism ; }, abstract = {Wear particles-induced inflammatory osteolysis, a major factor of aseptic loosening affects the long-term survival of orthopedic prostheses. Increasing observations have demonstrated that osteocytes, making up over 95% of all the bone cells, is involved in wear particle-induced periprosthetic osteolysis, but its mechanism remains unclear. In the present study, we embedded micro-sized tricalcium phosphate (TCP) particles (30 mg) under the periosteum around the middle suture of the mouse calvaria to establish a calvarial osteolysis model and investigated the biological effects of the particles on calvaria osteocytes in vivo. Results showed that TCP particles induced pyroptosis and activated the NLRP3 inflammasome in calvaria osteocytes, which was confirmed by obvious increases in empty lacunae, protein expressions of speck-like protein containing CARD (ASC), NOD-like receptor protein 3 (NLRP3), cleaved caspase-1 (Casp-1 p20) and cleaved gasdermin D (GSDMD-N), and resulted in elevated ratios of Casp-1 p20/Casp-1 and interleukin (IL)-1β/pro-IL-1β. Simultaneously, TCP particles enhanced serum levels of lactate dehydrogenase (LDH) and IL-1β. Furthermore, the pyroptotic effect was reversed by the Casp-1 inhibitor VX765 or the NLRP3 inhibitor MCC950. In addition, TCP particles increased the levels of intracellular reactive oxygen species (ROS) and malonaldehyde (MDA), whereas decreased the antioxidant enzyme nuclear factor E2-related factor 2 (Nrf2) level, leading to oxidative stress in calvaria osteocytes; the ROS scavenger N-acetylcysteine (NAC) attenuated these effects of pyroptotic death and the NLPR3 activation triggered by TCP particles. Collectively, our data suggested that TCP particles promote pyroptotic death of calvaria osteocytes through the ROS/NLRP3/Caspase-1 signaling axis, contributing to osteoclastogenesis and periprosthetic osteolysis.}, }
@article {pmid35304155, year = {2022}, author = {Sarris, J and Byrne, G and Castle, D and Bousman, C and Oliver, G and Cribb, L and Blair-West, S and Brakoulias, V and Camfield, D and Ee, C and Chamoli, S and Boschen, M and Dean, OM and Dowling, N and Menon, R and Murphy, J and Metri, NJ and Nguyen, TP and Wong, A and Jordan, R and Karamacoska, D and Rossell, SL and Berk, M and Ng, CH}, title = {N-acetyl cysteine (NAC) augmentation in the treatment of obsessive-compulsive disorder: A phase III, 20-week, double-blind, randomized, placebo-controlled trial.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {117}, number = {}, pages = {110550}, doi = {10.1016/j.pnpbp.2022.110550}, pmid = {35304155}, issn = {1878-4216}, mesh = {*Acetylcysteine/therapeutic use ; Double-Blind Method ; Humans ; *Obsessive-Compulsive Disorder/therapy ; Quality of Life ; Treatment Outcome ; }, abstract = {OBJECTIVE: Preliminary evidence has suggested that adjunctive N-acetylcysteine (NAC), an antioxidant precursor to glutathione, may reduce symptoms of obsessive-compulsive disorder (OCD). We conducted a 20-week, multi-site, randomized controlled trial to investigate the safety and efficacy of the adjunctive use of NAC in OCD.<br><br>METHODS: The study was a phase III, 20-week, double-blind, randomized controlled trial across multiple sites in Australia investigating 2&#xa0;g to 4&#xa0;g per day of NAC (titrated according to response) in 98 participants with DSM-5 diagnosed OCD. Data were analysed using linear mixed effects models for the 89 participants who attended at least one follow-up visit.<br><br>RESULTS: A modified intention-to-treat analysis of the primary outcome found no evidence that NAC reduced symptoms of OCD measured on the Yale-Brown Obsessive-Compulsive Scale, relative to placebo (mean difference at week 20&#xa0;=&#xa0;0.53, 95% compatibility interval&#xa0;=&#xa0;-2.18, 3.23; p&#xa0;=&#xa0;0.70; favouring placebo). There was also no evidence that NAC, compared to placebo, improved outcomes on the secondary measures including anxiety, depression, quality of life, functioning, or clinician/participant impression. NAC was well-tolerated with only mild gastrointestinal adverse events associated with the treatment.<br><br>CONCLUSION: We found no evidence supporting the efficacy of the adjunctive use of NAC in OCD.}, }
@article {pmid35296207, year = {2022}, author = {Zhao, L and Zhang, R and Zhang, S and Zhang, H and Yang, Q and Xu, Z}, title = {Upregulation of p67[phox] in response to ischemia/reperfusion is cardioprotective by increasing ZIP2 expression via STAT3.}, journal = {Free radical research}, volume = {56}, number = {1}, pages = {115-126}, doi = {10.1080/10715762.2022.2052057}, pmid = {35296207}, issn = {1029-2470}, mesh = {Animals ; Mice ; Cation Transport Proteins ; Ischemia ; NADPH Oxidase 2/genetics/metabolism ; *NADPH Oxidases/metabolism ; Phosphoproteins ; Reactive Oxygen Species/metabolism ; Reperfusion ; *Reperfusion Injury ; STAT3 Transcription Factor ; Up-Regulation ; }, abstract = {While the zinc transporter ZIP2 (Slc39a2) is upregulated via STAT3 as an adaptive response to protect the heart from ischemia/reperfusion (I/R) injury, the precise mechanism underlying its upregulation remains unclear. The purpose of this study was to investigate the role of NADPH oxidase (NOX) isoform NOX2-derived ROS in the regulation of ZIP2 expression, focusing on the role of the NOX2 cytosolic factor p67[phox]. Mouse hearts or H9c2 cells were subjected to I/R. Protein expression was detected with Western blotting. Infarct size was measured with TTC staining. The cardiac-specific p67[phox] conditional knockout mice (p67[phox] cKO) were generated by adopting the CRISPR/Cas9 system. I/R-induced upregulation of STAT3 phosphorylation and ZIP2 expression was reversed by the ROS scavenger N-acetylcysteine (NAC) and the NOX inhibitor diphenyleneiodonium (DPI). p67[phox] but not NOX2 expression was increased 30 min after the onset of reperfusion, and downregulation of p67[phox] by siRNA or cKO invalidated I/R-induced upregulation of STAT3 phosphorylation and ZIP2 expression. Both NAC and DPI prevented upregulation of STAT3 phosphorylation and ZIP2 expression induced by overexpression of p67[phox], whereas the STAT3 inhibitor stattic abrogated upregulation ZIP2 expression, indicating that the increase of p67[phox] at reperfusion is an upstream signaling event responsible for ZIP2 upregulation via STAT3. Experiments also showed that chelation of Zn[2+] markedly enhanced p67[phox] and ZIP2 expression as well as STAT3 phosphorylation, whereas supplementation of Zn[2+] had the opposite effects, indicating that cardiac Zn[2+] loss upon reperfusion triggers p67[phox] upregulation. Furthermore, ischemic preconditioning (IPC) upregulated ZIP2 via p67[phox], and cKO of p67[phox] aggravated cardiac injury after I/R, indicating that p67[phox] upregulation is cardioprotective against I/R injury. In conclusion, an increase of p67[phox] expression in response to Zn[2+] is an intrinsic adaptive response to I/R and leads to cardioprotection against I/R by upregulating ZIP2 via STAT3.}, }
@article {pmid35292969, year = {2022}, author = {}, title = {Editor's Note: Aghaamoo, S., Zandbina, A., Saffarieh, E. and Nassiri, S. (2021), The effect of N-acetyl cysteine on the volume of uterine leiomyoma: A randomized clinical trial. Int J Gynecol Obstet, 154: 521-525. https://doi.org/10.1002/ijgo.13611.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijgo.14124}, pmid = {35292969}, issn = {1879-3479}, }
@article {pmid35292334, year = {2022}, author = {Duan, L and Sanchez-Guerrero, G and Jaeschke, H and Ramachandran, A}, title = {Activation of the adenosine A2B receptor even beyond the therapeutic window of N-acetylcysteine accelerates liver recovery after an acetaminophen overdose.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {163}, number = {}, pages = {112911}, pmid = {35292334}, issn = {1873-6351}, support = {P30 GM103326/GM/NIGMS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Animals ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control ; *Drug Overdose/drug therapy ; Female ; Liver ; Male ; Mice ; Mice, Inbred C57BL ; Receptor, Adenosine A2B/therapeutic use ; }, abstract = {Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the USA. The short therapeutic window of the current antidote, N-acetylcysteine (NAC) highlights the need for novel late acting therapeutics. The neuronal guidance cue netrin-1 provides delayed protection against APAP hepatotoxicity through the adenosine A2B receptor (A2BAR). The clinical relevance of this mechanism was investigated here by administration of the A2BAR agonist BAY 60-6583, after an APAP overdose (300 or 600 mg/kg) in fasted male and female C57BL/6J mice with assessment of liver injury 6 or 24 h after APAP in comparison to NAC. BAY 60-6583 treatment 1.5 h after APAP overdose (600 mg/kg) protected against liver injury at 6 h by preserving mitochondrial function despite JNK activation and its mitochondrial translocation. Gender independent protection was sustained when BAY 60-6583 was given 6 h after APAP overdose (300 mg/kg), when NAC administration did not show benefit. This protection was accompanied by enhanced infiltration of macrophages with the reparative anti-inflammatory phenotype by 24 h, accompanied by a decrease in neutrophil infiltration. Thus, our data emphasize the remarkable therapeutic utility of using an A2BAR agonist, which provides delayed protection long after the standard of care NAC ceased to be effective.}, }
@article {pmid35292112, year = {2022}, author = {Lin, YC and Lin, YC and Tsai, ML and Liao, WT and Hung, CH}, title = {TSLP regulates mitochondrial ROS-induced mitophagy via histone modification in human monocytes.}, journal = {Cell &amp; bioscience}, volume = {12}, number = {1}, pages = {32}, pmid = {35292112}, issn = {2045-3701}, support = {MOST109-2320-B-037-013//Ministry of Science and Technology, Taiwan/ ; MOST108-2314-B-037-071-//Ministry of Science and Technology, Taiwan/ ; 103-CCH-KMU-005//Kaohsiung Medical University/ ; KMU-TC109A01-1//Kaohsiung Medical University/ ; KMUH107-7R86//Kaohsiung Medical University Hospital/ ; S-109-05//Kaohsiung Municipal Siaogang Hospital/ ; I109-02//Kaohsiung Municipal Siaogang Hospital/ ; }, abstract = {BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a Th2-like cytokine involved in asthma pathogenesis. Excessive reactive oxygen species (ROS) production can lead to airway inflammation, hyperresponsiveness and remodeling. Mitophagy, followed by ROS production, is the selective degradation of mitochondria by autophagy and often occurs in defective mitochondria. In the present study, we aimed to examine the effects of TSLP on ROS production and mitophagy in human monocytes and to investigate the underlying mechanisms, including epigenetic regulation.<br><br>RESULTS: TSLP induced ROS generation, and the effects were reversed by the antioxidant N-acetylcysteine (NAC) in THP-1 cells. Transmission electron microscopy images showed donut-shaped mitochondria that lost the cristae ultrastructure after TSLP stimulation. A decrease in mitochondrial membrane potential, decreased MTCO2 expression, and increased mitochondrial DNA release after TSLP stimulation were found. TSLP enhanced mitochondrial complex I and complex II/III activity and increased mitochondrial copy numbers and the expression of the complex II SHDA gene. TSLP-induced SHDA expression was inhibited by the histone acetyltransferase inhibitor anacardic acid (AA) and the histone methyltransferase inhibitor methylthioadenosine (MTA), and chromatin immunoprecipitation assays revealed that TSLP enhanced H3 acetylation, H4 acetylation, and H3K4 and H3K36 trimethylation in the SHDA promoter. Confocal laser microscopy showed that TSLP treatment increased the signals of the mitophagy-related proteins PINK1, LC3, phospho-parkin and phospho-ubiquitin, and pretreatment with AA and MTA reduced TSLP-induced PINK1 and LC3 accumulation in mitochondria. Western blot analysis showed that TSLP significantly increased phosphor-AMPK signal intensity, and the effects were inhibited by the antioxidant NAC. The increased signal intensities of the mitophagy-related proteins PINK1, Parkin and LC3 I/II were decreased by dorsomorphin, an AMPK inhibitor. TSLP decreased M1-related cytokine CXCL-10 production and increased M2-related cytokine CCL-1 and CCL-22 production, which was suppressed by the mitophagy inhibitor Mdivi-1 and PINK1 gene knockdown.<br><br>CONCLUSIONS: Epithelial-derived TSLP regulates ROS production and mitophagy through AMPK activation and histone modification and alters M1/M2 chemokine expression in human monocytes.}, }
@article {pmid35288263, year = {2022}, author = {Cheng, WC and Wen, Y and Chiu, YS and Chou, CH and Lim, CJ and Lin, SH and Chang, JM and Lin, CC}, title = {Pendulone induces apoptosis via the ROS-mediated ER-stress pathway in human non-small cell lung cancer cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {81}, number = {}, pages = {105346}, doi = {10.1016/j.tiv.2022.105346}, pmid = {35288263}, issn = {1879-3177}, mesh = {Apoptosis ; *Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Endoplasmic Reticulum Stress ; Humans ; *Isoflavones/pharmacology ; *Lung Neoplasms/metabolism ; Membrane Potential, Mitochondrial ; Quinones ; Reactive Oxygen Species/metabolism ; }, abstract = {PURPOSE: Pendulone, an isoflavone compound, is known to act against human cancer cells. However, its role in human non-small cell lung cancer (NSCLC) and the exact molecular mechanisms of action have never been reported.<br><br>METHODS: We investigated the effects of pendulone on cell proliferation and apoptosis in human NSCLC H1299 cells. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was employed to evaluate apoptotic indices such as the cell cycle, mitochondrial membrane potential, cytochrome c release, caspase activity, and death receptor expression. The expression of proteins related to the cell cycle and apoptosis were analyzed by Western blot analysis.<br><br>RESULTS: Pendulone significantly decreased H1299 cell viability by inducing endoplasmic reticulum (ER) stress through the accumulation of reactive oxygen species (ROS). Pendulone induced the expression of ER stress-associated proteins, such as ATF4 and CHOP, which promoted the expression of death receptors. Activation of caspase 8 induced extrinsic pathway apoptosis. Pendulone also caused the loss of mitochondrial membrane potential, inhibited the anti-apoptotic proteins BCL-2 and activated the pro-apoptotic protein BAX, which promoted the release of cytochrome c to activate caspase 9. Antioxidant N-acetylcysteine (NAC), with its ROS-suppressive property, reversed pendulone-induced ER stress and cell apoptosis.<br><br>CONCLUSION: Our findings provide evidence that pendulone induces apoptosis by inducing ER stress through ROS accumulation and mitochondrial dysfunction in NSCLC cell lines.}, }
@article {pmid35287541, year = {2022}, author = {Chen, BC and Lin, LJ and Lin, YC and Lee, CF and Hsu, WC}, title = {Optimal N-acetylcysteine concentration for intratympanic injection to prevent cisplatin-induced ototoxicity in guinea pigs.}, journal = {Acta oto-laryngologica}, volume = {142}, number = {2}, pages = {127-131}, doi = {10.1080/00016489.2022.2038796}, pmid = {35287541}, issn = {1651-2251}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; *Cisplatin/toxicity ; Evoked Potentials, Auditory, Brain Stem ; Guinea Pigs ; Injection, Intratympanic ; *Ototoxicity ; }, abstract = {BACKGROUND: Cisplatin is a chemotherapy drug that can induce sensorineural hearing loss. At present, no otoprotective agent is approved for use.<br><br>OBJECTIVES: This study investigated the optimal concentration of intratympanic N-acetylcysteine (NAC) to prevent cisplatin-induced ototoxicity in a guinea pig model.<br><br>MATERIALS AND METHODS: Guinea pigs (n&#x2009;=&#x2009;64) were treated with a single intratympanic injection containing different NAC concentrations or saline (control) 3&#x2009;days prior to intraperitoneal injection with cisplatin. The threshold change in the auditory brainstem response was assessed.<br><br>RESULTS: Four weeks after intraperitoneal cisplatin injection, only the group that received 2% NAC exhibited significant otoprotection (p&#x2009;<&#x2009;.05) compared with the control. Otoprotection was observed at all the frequencies tested (1k, 2k, 4k, and 8k Hz). The 2% NAC group also exhibited significant otoprotection (p&#x2009;<&#x2009;.05) compared with the other NAC groups (at 1k, 2k, 4k, and 8k Hz). The 4% NAC group exhibited significantly reduced hearing capacity (p&#x2009;<&#x2009;.05) in the fourth week compared with controls.<br><br>CONCLUSIONS AND SIGNIFICANCE: Intratympanic NAC administration is an efficient and safe means of preventing cisplatin-induced ototoxicity. In our animal model, the optimal intratympanic NAC concentration was 2%; concentrations of 4% loss of otoprotection.}, }
@article {pmid35287043, year = {2022}, author = {Xu, X and Shao, G and Zhang, X and Hu, Y and Huang, J and Su, Y and Zhang, M and Cai, Y and Zhou, H}, title = {The efficacy of nutritional supplements for the adjunctive treatment of schizophrenia in adults: A systematic review and network meta-analysis.}, journal = {Psychiatry research}, volume = {311}, number = {}, pages = {114500}, doi = {10.1016/j.psychres.2022.114500}, pmid = {35287043}, issn = {1872-7123}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Dietary Supplements ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Humans ; Network Meta-Analysis ; *Schizophrenia/drug therapy ; Vitamin B 12/therapeutic use ; Vitamin D/therapeutic use ; Vitamins ; }, abstract = {Nutritional supplementations have been widely used as adjunctive treatments for schizophrenia. However, among these supplementations, of which the most beneficial is currently unknown. This study aimed to compare and rank the effectiveness of nutritional supplementations in the adjunctive treatments of schizophrenia. The four nutritional supplementations evaluated were: 1) folate acid or vitamin B12; 2) vitamin D; 3) N-acetyl cysteine (NAC); 4) Omega-3 polyunsaturated fatty acid, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). 17 eligible RCTs with 1165 participants were included in this network meta-analysis based on study criteria. NAC supplementation was significantly more efficacious than folic acid or vitamin B12 [MD (95% CI): -6.6 (-10.8, -2.4)] and omega-3 polyunsaturated fatty acid [MD (95% CI): -5.1(-9.9, -0.8)] supplementation in the term of PANSS score changes. There were no significant differences in the PANSS score changes between NAC and vitamin D [MD (95% CI): -5.2 (-10.9, 0.5)] supplementations. The estimated ranking probabilities of treatments showed that NAC might be the most effective adjunctive intervention over all nutritional supplementations. These results indicate that NAC could improve PANSS score and it may be among the most effective nutritional supplementations in schizophrenia patients.}, }
@article {pmid35281576, year = {2022}, author = {Piktel, E and Wnorowska, U and Depciuch, J and Łysik, D and Cieśluk, M and Fiedoruk, K and Mystkowska, J and Parlińska-Wojtan, M and Janmey, PA and Bucki, R}, title = {N-Acetyl-Cysteine Increases Activity of Peanut-Shaped Gold Nanoparticles Against Biofilms Formed by Clinical Strains of Pseudomonas aeruginosa Isolated from Sputum of Cystic Fibrosis Patients.}, journal = {Infection and drug resistance}, volume = {15}, number = {}, pages = {851-871}, pmid = {35281576}, issn = {1178-6973}, abstract = {BACKGROUND: Extracellular polymeric substances (EPS) produced by bacteria, as they form a biofilm, determine the stability and viscoelastic properties of biofilms and prevent antibiotics from penetrating this multicellular structure. To date, studies demonstrated that an appropriate optimization of the chemistry and morphology of nanotherapeutics might provide a favorable approach to control their interaction with EPS and/or diffusion within the biofilm matrix. Targeting the biofilms' EPS, which in certain conditions can adopt liquid crystal structure, was demonstrated to improve the anti-biofilm activity of antibiotics and nanoparticles. A similar effect is achievable by interfering EPS' production by mucoactive agents, such as N-acetyl-cysteine (NAC). In our previous study, we demonstrated the nanogram efficiency of non-spherical gold nanoparticles, which due to their physicochemical features, particularly morphology, were noted to be superior in antimicrobial activity compared to their spherical-shaped counterparts.<br><br>METHODS: To explore the importance of EPS matrix modulation in achieving a suitable efficiency of peanut-shaped gold nanoparticles (AuP NPs) against biofilms produced by Pseudomonas aeruginosa strains isolated from cystic fibrosis patients, fluorescence microscopy, as well as resazurin staining were employed. Rheological parameters of AuP NPs-treated biofilms were investigated by rotational and creep-recovery tests using a rheometer in a plate-plate arrangement.<br><br>RESULTS: We demonstrated that tested nanoparticles significantly inhibit the growth of mono- and mixed-species biofilms, particularly when combined with NAC. Notably, gold nanopeanuts were shown to decrease the viscosity and increase the creep compliance of Pseudomonas biofilm, similarly to EPS-targeting NAC. Synergistic activity of AuP NPs with tobramycin was also observed, and the AuP NPs were able to eradicate bacteria within biofilms formed by tobramycin-resistant isolates.<br><br>CONCLUSION: We propose that peanut-shaped gold nanoparticles should be considered as a potent therapeutic agent against Pseudomonas biofilms.}, }
@article {pmid35280167, year = {2022}, author = {Schiavi, S and La Rosa, P and Petrillo, S and Carbone, E and D'Amico, J and Piemonte, F and Trezza, V}, title = {N-Acetylcysteine Mitigates Social Dysfunction in a Rat Model of Autism Normalizing Glutathione Imbalance and the Altered Expression of Genes Related to Synaptic Function in Specific Brain Areas.}, journal = {Frontiers in psychiatry}, volume = {13}, number = {}, pages = {851679}, pmid = {35280167}, issn = {1664-0640}, abstract = {Prenatal exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD) in humans and it induces autistic-like behaviors in rodents. Imbalances between GABAergic and glutamatergic neurotransmission and increased oxidative stress together with altered glutathione (GSH) metabolism have been hypothesized to play a role in both VPA-induced embriotoxicity and in human ASD. N-acetylcysteine (NAC) is an antioxidant precursor of glutathione and a modulator of glutamatergic neurotransmission that has been tested in ASD, although the clinical studies currently available provided controversial results. Here, we explored the effects of repeated NAC (150 mg/kg) administration on core autistic-like features and altered brain GSH metabolism in the VPA (500 mg/kg) rat model of ASD. Furthermore, we measured the mRNA expression of genes encoding for scaffolding and transcription regulation proteins, as well as the subunits of NMDA and AMPA receptors and metabotropic glutamate receptors mGLUR1 and mGLUR5 in brain areas that are relevant to ASD. NAC administration ameliorated the social deficit displayed by VPA-exposed rats in the three-chamber test, but not their stereotypic behavior in the hole board test. Furthermore, NAC normalized the altered GSH levels displayed by these animals in the hippocampus and nucleus accumbens, and it partially rescued the altered expression of post-synaptic terminal network genes found in VPA-exposed rats, such as NR2a, MGLUR5, GLUR1, and GLUR2 in nucleus accumbens, and CAMK2, NR1, and GLUR2 in cerebellum. These data indicate that NAC treatment selectively mitigates the social dysfunction displayed by VPA-exposed rats normalizing GSH imbalance and reestablishing the expression of genes related to synaptic function in a brain region-specific manner. Taken together, these data contribute to clarify the behavioral impact of NAC in ASD and the molecular mechanisms that underlie its effects.}, }
@article {pmid35278063, year = {2022}, author = {Ek-Eudomsuk, P and Chalermrujinanant, C and Soontrapa, K}, title = {N-acetylcysteine potentiates the tumor cytotoxicity of cytokine-induced killer cells.}, journal = {Asian Pacific journal of allergy and immunology}, volume = {}, number = {}, pages = {}, doi = {10.12932/AP-280921-1245}, pmid = {35278063}, issn = {0125-877X}, abstract = {BACKGROUND: Cytokine-induced killer (CIK) cells are an ex vivo expanded heterogeneous population of natural killer (NK)-like T cells that can exert potent MHC-unrestricted antitumor activity. A number of pre-clinical and clinical studies have demonstrated that CIK cells can serve as a safe and potent immunotherapy of malignant tumors. N-acetylcysteine (NAC) has been demonstrated to enhance the T-cell functions by increasing their proliferation and cytokine production.<br><br>OBJECTIVE: To investigate whether the incorporation of NAC to CIK cell culture could enhance the antitumor activity of CIK cells.<br><br>METHODS: The phenotypes of human CIK cells, including CD3+CD56+, IFN-&#x3b3;, granzyme B, and perforin, were determined by flow cytometry. The cytotoxic activity against the human erythroleukemic cell line (K562) and cholangiocarcinoma cell line (CL6) prelabeled with CFSE was investigated by flow cytometry. The mRNA expression levels of IFNG, PRF1, and GZMB were measured by real-time PCR.<br><br>RESULTS: By adding NAC into CIK cell culture, the percentage of CD3+CD56+ cells along with the expression of Th1 cytokines and cytolytic granules increased significantly, resulting in an improvement of cytotoxicity against the cancer cell lines CL6 and K562.<br><br>CONCLUSIONS: The incorporation of NAC into CIK culture can markedly improve the cytotoxicity against cancer cells due to the significant increase in the major effector population of CIK cells expressing Th1 cytokines and cytolytic granules.}, }
@article {pmid35277478, year = {2022}, author = {Wiesen, T and Atlas, D}, title = {Novel anti-apoptotic L-DOPA precursors SuperDopa and SuperDopamide as potential neuroprotective agents for halting/delaying progression of Parkinson's disease.}, journal = {Cell death &amp; disease}, volume = {13}, number = {3}, pages = {227}, pmid = {35277478}, issn = {2041-4889}, mesh = {Animals ; Antioxidants/metabolism ; Dopaminergic Neurons/metabolism ; HEK293 Cells ; Humans ; Levodopa/metabolism/pharmacology ; *Neuroprotective Agents/metabolism/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy/metabolism ; Rats ; Rotenone/pharmacology ; }, abstract = {Parkinson's disease (PD) is characterized by a gradual degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpC). Levodopa, the standard PD treatment, provides the missing dopamine in SNpC, but ultimately after a honeymoon with levodopa treatment the neurodegenerative process and the progression of the disease continue. Aimed at prolonging the life of dopaminergic cells, we prepared the levodopa precursors SuperDopa (SD) and SueprDopamide (SDA), in which levodopa is merged with the antioxidant N-acetylcysteine (NAC) into a single molecule. Rotenone is a mitochondrial complex inhibitor often used as experimental model of PD. In vivo, SD and SDA treatment show a significant relief of motor disabilities in rotenone-injected rats. SD and SDA also lower rotenone-induced-α-synuclein (α-syn) expression in human SH-SY5Y cells, and α-syn oligomerization in α-syn-overexpressing-HEK293 cells. In the neuronal SH-SY5Y cells, SD and SDA reverse oxidative stress-induced phosphorylation of cJun-N-terminal kinase (JNK) and p38-mitogen-activated kinase (p38[MAPK]). Attenuation of the MAPK-inflammatory/apoptotic pathway in SH-SY5Y cells concurrent with protection of rotenone-triggered motor impairment in rats, is a manifestation of the combined antioxidant/anti-inflammatory activity of SD and SDA together with levodopa release. The concept of joined therapies into a single molecule, where levodopa precursors confer antioxidant activity by enabling NAC delivery across the BBB, provides a potential disease-modifying treatment for slowing PD progression.}, }
@article {pmid35272139, year = {2022}, author = {Coelho Dos Reis, JGA and Ferreira, GM and Lourenço, AA and Ribeiro, &#xc1;L and da Mata, CPDSM and de Melo Oliveira, P and Marques, DPA and Ferreira, LL and Clarindo, FA and da Silva, MF and Filho, HPP and Oliveira, NRR and Sodré, MMD and Gadelha, SR and Albuquerque, GR and Maciel, BM and Mariano, APM and Silva, MM and Fontana, R and Marin, LJ and Carlos, RSA and Lopes, ATS and Ferreira, FB and Dos Santos, UR and Santana, &#xcd;TS and Fehlberg, HF and Rezende, RP and Dias, JCT and Gross, E and Goulart, GAC and Santiago, MG and de Lemos, APML and da Conceição, AO and Romano, CC and de Carvalho, LD and Martins Filho, OA and Quadros, CA and Morris, DL and Valle, SJ}, title = {Ex-vivo mucolytic and anti-inflammatory activity of BromAc in tracheal aspirates from COVID-19.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {148}, number = {}, pages = {112753}, pmid = {35272139}, issn = {1950-6007}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anti-Inflammatory Agents/administration &amp; dosage/pharmacology ; Bromelains/administration &amp; dosage/*pharmacology ; COVID-19/*pathology ; Chemokines/*drug effects ; Cytokine Release Syndrome/pathology ; Cytokines/*drug effects ; Dose-Response Relationship, Drug ; Down-Regulation ; Drug Combinations ; Expectorants/pharmacology ; Female ; Humans ; Inflammation Mediators/metabolism ; Male ; Middle Aged ; Respiration, Artificial ; Rheology ; SARS-CoV-2 ; Sputum/*cytology ; Trachea/pathology ; Young Adult ; }, abstract = {UNLABELLED: COVID-19 is a lethal disease caused by the pandemic SARS-CoV-2, which continues to be a public health threat. COVID-19 is principally a respiratory disease and is often associated with sputum retention and cytokine storm, for which there are limited therapeutic options. In this regard, we evaluated the use of BromAc®, a combination of Bromelain and Acetylcysteine (NAC). Both drugs present mucolytic effect and have been studied to treat COVID-19. Therefore, we sought to examine the mucolytic and anti-inflammatory effect of BromAc® in tracheal aspirate samples from critically ill COVID-19 patients requiring mechanical ventilation.<br><br>METHOD: Tracheal aspirate samples from COVID-19 patients were collected following next of kin consent and mucolysis, rheometry and cytokine analysis using Luminex kit was performed.<br><br>RESULTS: BromAc&#xae; displayed a robust mucolytic effect in a dose dependent manner on COVID-19 sputum ex vivo. BromAc&#xae; showed anti-inflammatory activity, reducing the action of cytokine storm, chemokines including MIP-1alpha, CXCL8, MIP-1b, MCP-1 and IP-10, and regulatory cytokines IL-5, IL-10, IL-13 IL-1Ra and total reduction for IL-9 compared to NAC alone and control. BromAc&#xae; acted on IL-6, demonstrating a reduction in G-CSF and VEGF-D at concentrations of 125 and 250&#xa0;&#xb5;g.<br><br>CONCLUSION: These results indicate robust mucolytic and anti-inflammatory effect of BromAc&#xae; ex vivo in tracheal aspirates from critically ill COVID-19 patients, indicating its potential to be further assessed as pharmacological treatment for COVID-19.}, }
@article {pmid35270019, year = {2022}, author = {Le, AN and Park, SS and Le, MX and Lee, UH and Ko, BK and Lim, HR and Yu, R and Choi, SH and Lee, BJ and Ham, SY and Ha, CM and Park, JW}, title = {DRG2 Depletion Promotes Endothelial Cell Senescence and Vascular Endothelial Dysfunction.}, journal = {International journal of molecular sciences}, volume = {23}, number = {5}, pages = {}, pmid = {35270019}, issn = {1422-0067}, support = {NRF- 2014R1A6A1030318//National Research Foundation of Korea/ ; NRF-2020R1F1A1058459//National Research Foundation of Korea/ ; }, mesh = {Animals ; Cellular Senescence/genetics ; *Endothelial Cells/metabolism ; Mice ; Mice, Knockout ; Reactive Oxygen Species/metabolism ; *Vascular Diseases/metabolism ; }, abstract = {Endothelial cell senescence is involved in endothelial dysfunction and vascular diseases. However, the detailed mechanisms of endothelial senescence are not fully understood. Here, we demonstrated that deficiency of developmentally regulated GTP-binding protein 2 (DRG2) induces senescence and dysfunction of endothelial cells. DRG2 knockout (KO) mice displayed reduced cerebral blood flow in the brain and lung blood vessel density. We also determined, by Matrigel plug assay, aorta ring assay, and in vitro tubule formation of primary lung endothelial cells, that deficiency in DRG2 reduced the angiogenic capability of endothelial cells. Endothelial cells from DRG2 KO mice showed a senescence phenotype with decreased cell growth and enhanced levels of p21 and phosphorylated p53, γH2AX, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence-associated secretory phenotype (SASP) cytokines. DRG2 deficiency in endothelial cells upregulated arginase 2 (Arg2) and generation of reactive oxygen species. Induction of SA-β-gal activity was prevented by the antioxidant N-acetyl cysteine in endothelial cells from DRG2 KO mice. In conclusion, our results suggest that DRG2 is a key regulator of endothelial senescence, and its downregulation is probably involved in vascular dysfunction and diseases.}, }
@article {pmid35270009, year = {2022}, author = {Yang, CY and Liu, SH and Su, CC and Fang, KM and Yang, TY and Liu, JM and Chen, YW and Chang, KC and Chuang, HL and Wu, CT and Lee, KI and Huang, CF}, title = {Methylmercury Induces Mitochondria- and Endoplasmic Reticulum Stress-Dependent Pancreatic β-Cell Apoptosis via an Oxidative Stress-Mediated JNK Signaling Pathway.}, journal = {International journal of molecular sciences}, volume = {23}, number = {5}, pages = {}, pmid = {35270009}, issn = {1422-0067}, support = {MOST 110-2320-B-303-004-//Ministry of Science and Technology, Taiwan/ ; MOST 109-2320-B-039-039//Ministry of Science and Technology, Taiwan/ ; TTCRD 109-13//Buddhist Tzuchi Medical Foundation of the Taichung Tzu chi Hospital, Taiwan/ ; CSH-2015-C-027//Chung Shan Medical University Hospital, Taichung, Taiwan/ ; Grants No. 109018//Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan/ ; CMU110-S-36//China Medical University, Taiwan/ ; }, mesh = {Animals ; Apoptosis ; Caspase 3/metabolism ; *Endoplasmic Reticulum Stress ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Mammals/metabolism ; *Methylmercury Compounds/pharmacology ; Mitochondria/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Methylmercury (MeHg), a long-lasting organic pollutant, is known to induce cytotoxic effects in mammalian cells. Epidemiological studies have suggested that environmental exposure to MeHg is linked to the development of diabetes mellitus (DM). The exact molecular mechanism of MeHg-induced pancreatic β-cell cytotoxicity is still unclear. Here, we found that MeHg (1-4 μM) significantly decreased insulin secretion and cell viability in pancreatic β-cell-derived RIN-m5F cells. A concomitant elevation of mitochondrial-dependent apoptotic events was observed, including decreased mitochondrial membrane potential and increased proapoptotic (Bax, Bak, p53)/antiapoptotic (Bcl-2) mRNA ratio, cytochrome c release, annexin V-Cy3 binding, caspase-3 activity, and caspase-3/-7/-9 activation. Exposure of RIN-m5F cells to MeHg (2 μM) also induced protein expression of endoplasmic reticulum (ER) stress-related signaling molecules, including C/EBP homologous protein (CHOP), X-box binding protein (XBP-1), and caspase-12. Pretreatment with 4-phenylbutyric acid (4-PBA; an ER stress inhibitor) and specific siRNAs for CHOP and XBP-1 significantly inhibited their expression and caspase-3/-12 activation in MeHg-exposed RIN-mF cells. MeHg could also evoke c-Jun N-terminal kinase (JNK) activation and reactive oxygen species (ROS) generation. Antioxidant N-acetylcysteine (NAC; 1mM) or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox; 100 μM) markedly prevented MeH-induced ROS generation and decreased cell viability in RIN-m5F cells. Furthermore, pretreatment of cells with SP600125 (JNK inhibitor; 10 μM) or NAC (1 mM) or transfection with JNK-specific siRNA obviously attenuated the MeHg-induced JNK phosphorylation, CHOP and XBP-1 protein expression, apoptotic events, and insulin secretion dysfunction. NAC significantly inhibited MeHg-activated JNK signaling, but SP600125 could not effectively reduce MeHg-induced ROS generation. Collectively, these findings demonstrate that the induction of ROS-activated JNK signaling is a crucial mechanism underlying MeHg-induced mitochondria- and ER stress-dependent apoptosis, ultimately leading to β-cell death.}, }
@article {pmid35267162, year = {2022}, author = {Liu, X and Li, F and Zhu, Z and Peng, G and Huang, D and Xie, M}, title = {4-[1-Ethyl-1-methylhexy]-phenol induces apoptosis and interrupts Ca[2+] homeostasis via ROS pathway in Sertoli TM4 cells.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {35}, pages = {52665-52674}, pmid = {35267162}, issn = {1614-7499}, support = {81803193//National Natural Science Foundation of China/ ; 2018A030310033//Natural Science Foundation of Guangdong Province/ ; GC300502-33//Research Start-up Funds of DGUT/ ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphatases/metabolism ; *Apoptosis ; *Homeostasis ; Humans ; Male ; *Phenols/pharmacology ; Reactive Oxygen Species/metabolism ; *Sertoli Cells/cytology/drug effects ; }, abstract = {Biological effect of an individual nonylphenol (NP) isomer extremely relies upon the side chain structure. This research was designed to evaluate the impact of NP isomer, 4-[1-ethyl-1-methylhexy]-phenol (NP65), on Sertoli cells in vitro. Sertoli TM4 cells were exposed to various concentration (0, 0.1, 1, 10, or 20 μM) of NP65 for 24 h, and the outcomes indicated that treatment of NP65 induced reactive oxygen species (ROS) generation, oxidative stress, and apoptosis for Sertoli TM4 cells. In addition, it was found that NP65 exposure affected homeostasis of Ca[2+] in Sertoli TM4 cells by increasing cytoplasm [Ca[2+]]i, inhibiting Ca[2+]-ATPase activity and decreasing cyclic adenosine monophosphate (cAMP) concentration. Pretreatment with ROS scavenger, N-acetylcysteine (NAC), attenuated NP65-induced oxidative stress as well as apoptosis for TM4 cells. Furthermore, NAC blocked NP65-induced disorders of Ca[2+] homeostasis by attenuating the growth of intracellular [Ca[2+]]i and the inhibition of Ca[2+]-ATPase and cAMP activities. Thus, we have demonstrated that NP65 induced apoptosis as well as acted as a potent inhibitor of Ca[2+]-ATPase activity and resulted in disorder of Ca[2+] homeostasis in Sertoli TM4 cells; ROS participated in the process. Our results supported the view that oxidative stress acted an essential role within the development of apoptosis and Ca[2+] overload in TM4 cells as a consequence of NP65 stimulation.}, }
@article {pmid35261035, year = {2022}, author = {Nejati, M and Dehghan, P and Jamilian, P and Zarezadeh, M}, title = {The effects of N-acetylcysteine on recovery biomarkers: A systematic review and meta-analysis of controlled trials.}, journal = {Journal of food biochemistry}, volume = {46}, number = {7}, pages = {e14116}, doi = {10.1111/jfbc.14116}, pmid = {35261035}, issn = {1745-4514}, support = {//Tabriz University of Medical Sciences/ ; }, mesh = {*Acetylcysteine ; Antioxidants ; Biomarkers ; *Dietary Supplements ; Humans ; Lactates ; Randomized Controlled Trials as Topic ; }, abstract = {N-acetylcysteine (NAC) is one of the antioxidant supplements which is thought to improve recovery. Existing studies regarding NAC and recovery presented conflicting results. This systematic review and meta-analysis evaluated the existing trials and determined the efficacy of acute and chronic NAC administration on recovery biomarkers. PubMed, Web of Science, and Scopus were searched up to July 2021. The random effects or fixed effects model was applied in the meta-analysis. Sensitivity and subgroup analyses were performed. In case of the presence of publication bias, standard methods were applied. The meta-analysis comprised 37 papers (1,388 participants). All included studies were in English language. Acute NAC administration indicated no significant effects on lactate, pH, VO2 , and CPK-MB ([SMD = -0.06 mmol/L; 95% CI: -0.40, 0.28; p = .714], [SMD = 0.17; 95% CI: -0.28, 0.62; p = .454], [SMD = -0.11 L/min; 95% CI: -0.63, 0.41; p = .686], and [SMD = -0.19 units/L; 95% CI: -0.62, 0.24; p = .395]). Additionally, no evidence of significant influence of chronic NAC administration on lactate, pH, VO2 , and CK was revealed ([SMD = 0.01 mmol/L; 95% CI: -0.25, 0.27; p = .950], [SMD = -0.51; 95% CI: -1.73, 0.70; p = .424], [SMD = -0.18 L/min; 95% CI: -0.56, 0.20; p = .361], and [SMD = -0.04 units/L; 95% CI: -0.36, 0.29; p = .821]). No considerable effect of NAC on recovery was found. PRACTICAL APPLICATIONS: Previous studies on the influence of NAC administration on recovery biomarkers have presented conflicting results. This systematic review and meta-analysis offers a broad range of detailed information on the influence of chronic and acute NAC supplementation outcomes regarding recovery biomarkers. Overall, the results support that NAC supplementation may not be effective in improving recovery biomarkers. However, subgroup analyses based on NAC dosage indicated the meaningful effect of NAC on CK-MB at the dosage of ≥100 mg/kg.}, }
@article {pmid35259475, year = {2022}, author = {Shou, P and Li, J and Zhang, P and Wei, Y and Yan, M and Zhang, M and Feng, K and Lin, N and Zhao, H and Yang, B}, title = {Pharmacophore-probe reaction guided purification to precisely identify electrophilic withanolides from Tubocapsicum anomalum Makino and their anti-TNBC activity.}, journal = {Fitoterapia}, volume = {158}, number = {}, pages = {105169}, doi = {10.1016/j.fitote.2022.105169}, pmid = {35259475}, issn = {1873-6971}, mesh = {Cell Line, Tumor ; Humans ; Molecular Structure ; Signal Transduction ; *Solanaceae/chemistry ; *Triple Negative Breast Neoplasms/metabolism/pathology ; *Withanolides/chemistry/pharmacology ; }, abstract = {Pharmacophore-probe reaction guided purification strategy can reduce the workload of natural product chemistry and raise the probability of obtaining undescribed and high-bioactive target compounds. In this study, a probe of N-acetyl cysteine (NAC) was used to confirm the pharmacophore of Tubocapsicum anomalum (Franch. et Sav.) Makino. Furthermore, a thiol probe named 4-bromothiophenol (BTP) guided the discovery of three undescribed (1-3) and nine known (4-12) electrophilic withanolides (EWs) featured potential anti-triple negative breast cancer (TNBC) pharmacophore. Notably, co-incubation with BTP made the single crystals of EW conjugates much more accessible, which facilitated the absolute configuration determination of EWs. Electrophilic natural products with the potential of thio-alkylation modification and covalent inhibition key proteins in tumor cell signal transduction pathways may display significant antitumor activity. The MTT results indicated that most EWs showed anti-TNBC activity and were expected to develop anti-TNBC candidate drugs with high selectivity and novel mechanism.}, }
@article {pmid35258392, year = {2022}, author = {Magalhaes-Novais, S and Blecha, J and Naraine, R and Mikesova, J and Abaffy, P and Pecinova, A and Milosevic, M and Bohuslavova, R and Prochazka, J and Khan, S and Novotna, E and Sindelka, R and Machan, R and Dewerchin, M and Vlcak, E and Kalucka, J and Stemberkova Hubackova, S and Benda, A and Goveia, J and Mracek, T and Barinka, C and Carmeliet, P and Neuzil, J and Rohlenova, K and Rohlena, J}, title = {Mitochondrial respiration supports autophagy to provide stress resistance during quiescence.}, journal = {Autophagy}, volume = {18}, number = {10}, pages = {2409-2426}, pmid = {35258392}, issn = {1554-8635}, mesh = {AMP-Activated Protein Kinases/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; *Autophagy ; Cysteine/metabolism ; DNA, Mitochondrial/metabolism ; Dextrans/metabolism ; Endothelial Cells/metabolism ; Fibroblasts/metabolism ; Formaldehyde/metabolism ; Humans ; *Inflammatory Bowel Diseases/metabolism ; Isothiocyanates ; Lipopolysaccharides/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Phosphatidylethanolamines/metabolism ; Reactive Oxygen Species/metabolism ; Respiration ; Sirolimus ; }, abstract = {Mitochondrial oxidative phosphorylation (OXPHOS) generates ATP, but OXPHOS also supports biosynthesis during proliferation. In contrast, the role of OXPHOS during quiescence, beyond ATP production, is not well understood. Using mouse models of inducible OXPHOS deficiency in all cell types or specifically in the vascular endothelium that negligibly relies on OXPHOS-derived ATP, we show that selectively during quiescence OXPHOS provides oxidative stress resistance by supporting macroautophagy/autophagy. Mechanistically, OXPHOS constitutively generates low levels of endogenous ROS that induce autophagy via attenuation of ATG4B activity, which provides protection from ROS insult. Physiologically, the OXPHOS-autophagy system (i) protects healthy tissue from toxicity of ROS-based anticancer therapy, and (ii) provides ROS resistance in the endothelium, ameliorating systemic LPS-induced inflammation as well as inflammatory bowel disease. Hence, cells acquired mitochondria during evolution to profit from oxidative metabolism, but also built in an autophagy-based ROS-induced protective mechanism to guard against oxidative stress associated with OXPHOS function during quiescence.Abbreviations: AMPK: AMP-activated protein kinase; AOX: alternative oxidase; Baf A: bafilomycin A1; CI, respiratory complexes I; DCF-DA: 2',7'-dichlordihydrofluorescein diacetate; DHE: dihydroethidium; DSS: dextran sodium sulfate; ΔΨmi: mitochondrial inner membrane potential; EdU: 5-ethynyl-2'-deoxyuridine; ETC: electron transport chain; FA: formaldehyde; HUVEC; human umbilical cord endothelial cells; IBD: inflammatory bowel disease; LC3B: microtubule associated protein 1 light chain 3 beta; LPS: lipopolysaccharide; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; mtDNA: mitochondrial DNA; NAC: N-acetyl cysteine; OXPHOS: oxidative phosphorylation; PCs: proliferating cells; PE: phosphatidylethanolamine; PEITC: phenethyl isothiocyanate; QCs: quiescent cells; ROS: reactive oxygen species; PLA2: phospholipase A2, WB: western blot.}, }
@article {pmid35257042, year = {2022}, author = {Shirakawa, K and Kobayashi, E and Ichihara, G and Kitakata, H and Katsumata, Y and Sugai, K and Hakamata, Y and Sano, M}, title = {H2 Inhibits the Formation of Neutrophil Extracellular Traps.}, journal = {JACC. Basic to translational science}, volume = {7}, number = {2}, pages = {146-161}, pmid = {35257042}, issn = {2452-302X}, abstract = {Neutrophil extracellular traps (NETs) contribute to inflammatory pathogenesis in numerous conditions, including infectious and cardiovascular diseases, and have attracted attention as potential therapeutic targets. H2 acts as an antioxidant and has been clinically and experimentally proven to ameliorate inflammation. This study was performed to investigate whether H2 could inhibit NET formation and excessive neutrophil activation. Neutrophils isolated from the blood of healthy volunteers were stimulated with phorbol-12-myristate-13-acetate (PMA) or the calcium ionophore A23187 in H2-exposed or control media. Compared with control neutrophils, PMA- or A23187-stimulated human neutrophils exposed to H2 exhibited reduced neutrophil aggregation, citrullination of histones, membrane disruption by chromatin complexes, and release of NET components. CXCR4[high] neutrophils are highly prone to NETs, and H2 suppressed Ser-139 phosphorylation in H2AX, a marker of DNA damage, thereby suppressing the induction of CXCR4 expression. H2 suppressed both myeloperoxidase chlorination activity and production of reactive oxygen species to the same degree as N-acetylcysteine and ascorbic acid, while showing a more potent ability to inhibit NET formation than these antioxidants do in PMA-stimulated neutrophils. Although A23187 formed NETs in a reactive oxygen species-independent manner, H2 inhibited A23187-induced NET formation, probably via direct inhibition of peptidyl arginine deiminase 4-mediated histone citrullination. Inhalation of H2 inhibited the formation and release of NET components in the blood and bronchoalveolar lavage fluid in animal models of lipopolysaccharide-induced sepsis (mice and aged mini pigs). Thus, H2 therapy can be a novel therapeutic strategy for NETs associated with excessive neutrophil activation.}, }
@article {pmid35253534, year = {2022}, author = {Wei, AH and Zeng, L and Ruan, JL and Zhou, DN}, title = {Apoptosis induced by DICO, a novel non-aromatic B-ring flavonoid via a ROS-dependent mechanism in human colon cancer cells.}, journal = {Natural product research}, volume = {36}, number = {23}, pages = {6050-6055}, doi = {10.1080/14786419.2022.2042283}, pmid = {35253534}, issn = {1478-6427}, mesh = {Humans ; Reactive Oxygen Species/metabolism ; *Flavonoids/pharmacology/chemistry ; Apoptosis ; STAT3 Transcription Factor/metabolism ; NF-kappa B/metabolism ; *Colonic Neoplasms/drug therapy ; Cell Line, Tumor ; }, abstract = {5,7-Dihydroxy-2-(1,2-isopropyldioxy-4-oxo-cyclohex-5-enyl)-chromen-4-one (DICO) is a novel non-aromatic B-ring flavonoid, isolated mainly from Macrothelypteris viridifrons and has anti-tumour properties. In this study, we investigated the cytotoxicity and underlying biochemical pathways leading to cell death, in response to DICO treatment of a human colon cancer cell line HT-29. Our results indicated that DICO induced apoptosis by elevating the generation of reactive oxygen species, which could be quenched by the antioxidants N-acetyl cysteine. In addition, activation of signal transducer and activator of transcription 3 and suppression of nuclear factor kappa B played a crucial role in DICO-induced apoptosis. Overall, our results provide mechanistic insights into the apoptotic action of a potential anti-tumour drug, DICO.}, }
@article {pmid35249877, year = {2022}, author = {Feng, Y and Yang, D and Zhi, X and Deng, H and Zhang, W and Wang, R and Wu, W}, title = {[Role of interaction between reactive oxygen species and ferroptosis pathway in methylglyoxal-induced injury in mouse embryonic osteoblasts].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {42}, number = {1}, pages = {108-115}, pmid = {35249877}, issn = {1673-4254}, mesh = {Animals ; Cell Survival ; *Ferroptosis ; Mice ; Osteoblasts ; Pyruvaldehyde/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: To explore the interaction between reactive oxygen species (ROS) and ferroptosis in methylglyoxalinduced injury of mouse embryonic osteoblasts (MC3T3-E1 cells).<br><br>METHODS: MC3T3-E1 cells were treated with methylglyoxal to establish a cell model of diabetic osteoporosis. CCK-8 assay was used to detect the viability of MC3T3-E1 cells. Rhodamine 123 staining followed by photofluorography was used to examine mitochondrial membrane potential (MMP). The intracellular ROS level was detected by 2', 7'-dichlorodihydrofluorescein diacetate staining with photofluorograph. Alkaline phosphatase (ALP) activity in the cells was detected using an ALP kit, the number of mineralized nodules was determined with alizarin red S staining, and the level of iron ions was detected using a detection kit. The expression level of glutathione peroxidase 4 (GPX4, a marker protein that inhibits ferroptosis) in the osteoblasts was determined using Western blotting.<br><br>RESULTS: Treatment of MC3T3-E1 cells with 0.6 mmol/L methylglyoxal for 24 h significantly inhibited the expression level of GPX4 (P < 0.001), increased intracellular iron ion concentration, decreased the cell viability, increased the loss of MMP and intracellular ROS level, decreased both ALP activity and the number of mineralized nodules in the cells (P < 0.001). Co-treatment of MC3T3-E1 cells with 2 mmol/L N-acetylcysteine (NAC, a ROS scavenger) and methylglyoxal significantly increased the expression level of GPX4 (P < 0.01); co-treatment with 4 mmo/L FER-1 (a ferroptosis inhibitor) and methylglyoxal obviously decreased the intracellular ROS level (P < 0.001). Co-treatment of the cells either with NAC and methylglyoxal or with FER-1 and methylglyoxal attenuated methylglyoxal-induced injuries in the osteoblasts (P < 0.001).<br><br>CONCLUSION: The interaction between ROS and ferroptosis pathway plays an important role in methylglyoxal-induced injury of mouse embryonic osteoblasts.}, }
@article {pmid35246254, year = {2022}, author = {Wang, P and Cui, Y and Wang, J and Liu, D and Tian, Y and Liu, K and Wang, X and Liu, L and He, Y and Pei, Y and Li, L and Sun, L and Zhu, Z and Chang, D and Jia, J and You, H}, title = {Mesenchymal stem cells protect against acetaminophen hepatotoxicity by secreting regenerative cytokine hepatocyte growth factor.}, journal = {Stem cell research &amp; therapy}, volume = {13}, number = {1}, pages = {94}, pmid = {35246254}, issn = {1757-6512}, mesh = {Acetaminophen/toxicity ; Animals ; *Chemical and Drug Induced Liver Injury/metabolism/therapy ; Hepatocyte Growth Factor/metabolism ; Liver/metabolism ; *Mesenchymal Stem Cells ; Mice ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Acetaminophen (APAP) overdose is a major cause of the morbidity of acute liver failure. The current clinically approved treatment for APAP poisoning, N-acetylcysteine (NAC), has a limited therapeutic window, and prolonged treatment with NAC delays liver regeneration. Mesenchymal stem cells (MSCs) also have therapeutic effects on APAP-induced mouse liver failure, but whether the effects are comparable to those of NAC has not been determined, and the mechanism still needs further exploration.<br><br>METHODS: Fasted C57BL/6 mice that received 500&#xa0;mg/kg APAP were treated intravenously with 300&#xa0;mg/kg NAC or different amounts of MSCs at 2&#xa0;h after APAP to investigate survival, hepatocyte necrosis and neutrophil/macrophage recruitment. In vitro co-culture was performed to study the anti-necrotic effects of MSCs on the APAP-injured hepatocyte cell line L-O2.<br><br>RESULTS: MSCs dose-dependently rescued the C57BL/6J mice from APAP-induced liver failure, with 87.5% of MSCs (1&#x2009;&#xd7;&#x2009;10[6]) surviving similar to that of NAC (90%). MSC has similar effects on reduced hepatocyte necrosis and granulocytic&#xa0;myeloid-derived suppressor cells (MDSC) infiltration but enhanced the proportion of regenerative monocytic&#xa0;MDSC when compared to NAC. Mechanistically, MSCs attenuate hepatocyte necrosis by secreting hepatocyte growth factor (HGF). When HGF was knocked down, the protective effects of MSCs were reduced on APAP-induced hepatocyte necrosis and mouse liver failure.<br><br>CONCLUSIONS: MSCs are comparable to NAC against APAP-induced liver failure by secreting HGF with less regenerative retardation concerns, thus facilitating the application of MSCs in clinical therapy for APAP liver failure.}, }
@article {pmid35245527, year = {2022}, author = {Aggarwal, H and Gupta, S and Sharma, P and Sharma, BM and Sharma, B}, title = {Neurobehavioral and neurobiochemical effect of atomoxetine and N-acetylcysteine in streptozotocin diabetes induced endothelial dysfunction and related dementia.}, journal = {Physiology &amp; behavior}, volume = {249}, number = {}, pages = {113767}, doi = {10.1016/j.physbeh.2022.113767}, pmid = {35245527}, issn = {1873-507X}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Atomoxetine Hydrochloride/pharmacology/therapeutic use ; Body Weight ; Brain/metabolism ; *Dementia, Vascular/drug therapy ; *Diabetes Mellitus, Experimental/complications/drug therapy/metabolism ; Glucose/metabolism ; Male ; Maze Learning ; Oxidative Stress ; Rats ; Streptozocin/toxicity ; }, abstract = {Metabolic conditions like diabetes, is a major risk factor for the development of dementia of vascular origin. This study investigates the efficacy of atomoxetine (ATX) and N-acetylcysteine (NAC) in streptozotocin (STZ) diabetes induced vascular endothelium dysfunction and related dementia. Single dose STZ (50 mg/kg i.p) was administered to Albino Wistar rats (male, 200-250 g) by dissolving in citrate buffer. Morris water maze (MWM) and attentional set shifting tests (ASST) were used to assess the spatial learning, memory, reversal learning, and executive functioning in animals. Body weight, serum glucose, serum nitrite/nitrate, vascular endothelial function, aortic superoxide anion, brains' oxidative markers (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammatory markers (IL-6, IL-10, TNF-α, and myeloperoxidase-MPO), acetylcholinesterase activity-AChE and histopathological changes were also assessed. Atomoxetine - ATX (2 mg kg[-1]/ 4 mg kg[-1]) and N-acetylcysteine- NAC (250 mg kg[-1]/ 500 mg kg[-1]) were used alone as well as in combination, as the treatment drugs. Donepezil (0.5 mg kg-[1]) was used as a positive control. STZ administered rats showed increase in serum glucose levels and decrease in body weight. Rats administered with STZ also showed reduction in learning, memory, reversal learning, executive functioning, impairment in endothelial function, increase in brains' oxidative stress, inflammation, AChE activity and histopathological changes. Administration of ATX and NAC in two different doses as well as in combination, significantly attenuated the STZ induced diabetes induced impairments in the behavioral, endothelial, biochemical parameters and histopathological changes. Co-treatment of ATX and NAC was better in comparison to the doses when given alone. Hence, STZ administration caused diabetes induced dementia of vascular origin which was attenuated by the administration of ATX and NAC. Therefore, these agents may be studied further for the assessment of their full potential in diabetes induced dementia of vascular origin conditions.}, }
@article {pmid35245333, year = {2022}, author = {Pang, Q and Li, G and Cao, F and Liu, H and Wei, W and Jiao, Y}, title = {Clinical efficacy of Chinese herbs for supplementing qi and activating blood circulation combined with N-acetylcysteine in the treatment of idiopathic pulmonary fibrosis: A systematic review and network meta-analysis.}, journal = {PloS one}, volume = {17}, number = {3}, pages = {e0265006}, pmid = {35245333}, issn = {1932-6203}, mesh = {Acetylcysteine/therapeutic use ; Humans ; *Idiopathic Pulmonary Fibrosis/drug therapy ; Network Meta-Analysis ; Oxygen/therapeutic use ; Qi ; Treatment Outcome ; }, abstract = {BACKGROUND: Chinese herbs for supplementing qi and activating blood circulation (CH) combined with N-acetylcysteine (NAC) is widely used for idiopathic pulmonary fibrosis (IPF) in China, but there is a lack of literature to evaluate its efficacy and clinical value.<br><br>PURPOSE: This study compared CH + NAC with other treatments by network meta-analysis to clarify its clinical value.<br><br>METHODS: Cochrane Library, PubMed, Embase, Web of Science, China National Knowledge Infrastructure, WanFang Data, VIP Database, and China Biology Medicine were searched. Outcomes included lung function (DLCO (%), VC (%), FVC (%), FVC (L)), 6-min walking distance (6MWD), score of St George's respiratory questionnaire (SGRQ), blood gas analysis (PaO2, PaCO2). The data were analyzed by Review Manager 5.4, Stata 12.0 and ADDIS 1.16.5.<br><br>RESULTS: 23 studies including 1390 patients (702 in intervention group and 688 in control group) were collected to compare 8 outcome indicators among different treatments involving CH, CH+NAC, CH+PFD, NAC, PFD and PFD+NAC on IPF. Network meta-analysis showed that CH was better than NAC in terms of DLCO (%) (MD = 5.14, 95%CI: 1.01 to 8.68) and 6MWD (MD = 49.17, 95%CI: 25.97 to 71.36) as well as PFD + NAC was better than NAC in terms of FVC (L) (MD = -0.56, 95%CI: -0.83 to -0.31). In rankings results, CH + NAC is the best in terms of FVC (%), SGRQ, PaO2 and PaCO2; CH is the best in terms of DLCO (%), VC (%) and 6MWD; CH + PFD is the best in terms of FVC (L).<br><br>CONCLUSION: CH related treatments may have advantages in the treatment of IPF and CH + NAC may have clinical application value. However, limited by the quality and quantity of researches included, more rational and scientific randomized controlled trials containing large sample sizes need to be conducted to further verify our conclusions.}, }
@article {pmid35244883, year = {2022}, author = {Elshal, M and Abdelmageed, ME}, title = {Diacerein counteracts acetaminophen-induced hepatotoxicity in mice via targeting NLRP3/caspase-1/IL-1β and IL-4/MCP-1 signaling pathways.}, journal = {Archives of pharmacal research}, volume = {45}, number = {3}, pages = {142-158}, pmid = {35244883}, issn = {1976-3786}, mesh = {*Acetaminophen/metabolism/toxicity ; Animals ; Anthraquinones ; Caspase 1/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism/prevention &amp; control ; Interleukin-4/metabolism ; Liver/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidative Stress ; Signal Transduction ; }, abstract = {The current study aims at repurposing the anti-arthritic drug diacerein (DCN) for the treatment of acetaminophen hepatotoxicity and investigating the potential underlying mechanisms. Mice were randomly divided into six groups receiving either no treatment (control group), 20 mg/kg DCN i.p, 400 mg/kg acetaminophen i.p, DCN 4 h before acetaminophen, DCN 2 h after acetaminophen, or 400 mg/kg N-acetylcysteine (NAC) i.p, 2 h after acetaminophen. Biomarkers of liver dysfunction, oxidative stress, and apoptosis were assessed. Hepatic necroinflammatory changes were evaluated along with hepatic expression of NF-κB and caspase-1. The levels of NLRP3, IL-1β, IL-4, MCP-1, and TNF-α in the liver, as well as CYP2E1 mRNA expression, were measured. Diacerein significantly reduced biomarkers of liver dysfunction, oxidative stress, hepatocyte necrosis, and infiltration of neutrophils and macrophages whether administered 4 h before or 2 h after acetaminophen. Further, the effects were comparable to those of NAC. Diacerein also counteracted acetaminophen-induced hepatocellular apoptosis by increasing Bcl-2 and decreasing Bax and caspase-3 expression levels. Moreover, DCN normalized hepatic TNF-α and significantly decreased NF-κB p65 expression. Accordingly, DCN can prevent or reverse acetaminophen hepatotoxicity in mice, suggesting potential utility as a repurposed drug for clinical treatment.}, }
@article {pmid35238867, year = {2022}, author = {Chen, C and Zhang, B and Xue, J and Li, Z and Dou, S and Chen, H and Wang, Q and Qu, M and Wang, H and Zhang, Y and Wan, L and Zhou, Q and Xie, L}, title = {Pathogenic Role of Endoplasmic Reticulum Stress in Diabetic Corneal Endothelial Dysfunction.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {63}, number = {3}, pages = {4}, pmid = {35238867}, issn = {1552-5783}, mesh = {Acetylcysteine/adverse effects ; Animals ; Cells, Cultured ; *Corneal Edema/metabolism ; *Diabetes Mellitus, Experimental/metabolism ; Endoplasmic Reticulum Stress/physiology ; Endothelial Cells/metabolism ; Humans ; *Hyperglycemia/metabolism ; Mice ; }, abstract = {PURPOSE: Progressive corneal edema and endothelial cell loss represent the major corneal complications observed in diabetic patients after intraocular surgery. However, the underlying pathogenesis and potential treatment remain incompletely understood.<br><br>METHODS: We used streptozotocin-induced type 1 diabetic mice and db/db type 2 diabetic mice as diabetic animal models. These mice were treated with the endoplasmic reticulum (ER) stress agonist thapsigargin; 60-mmHg intraocular pressure (IOP) with the ER stress antagonist 4-phenylbutyric acid (4-PBA); mitochondria-targeted antioxidant SkQ1; or reactive oxygen species scavenger N-acetyl-l-cysteine (NAC). Corneal thickness and endothelial cell density were measured before and after treatment. Human corneal endothelial cells were treated with high glucose with or without 4-PBA. The expression of corneal endothelial- and ER stress-related genes was detected by western blot and immunofluorescence staining. Mitochondrial bioenergetics were measured with an Agilent Seahorse XFp Analyzer.<br><br>RESULTS: In diabetic mice, the appearance of ER stress preceded morphological changes in the corneal endothelium. The persistent ER stress directly caused corneal edema and endothelial cell loss in normal mice. Pharmacological inhibition of ER stress was sufficient to mitigate corneal edema and endothelial cell loss in both diabetic mice after high IOP treatment. Mechanistically, inhibiting ER stress ameliorated the hyperglycemia-induced mitochondrial bioenergetic deficits and improved the barrier and pump functional recovery of the corneal endothelium. When compared with NAC, 4-PBA and SkQ1 exhibited better improvement of corneal edema and endothelial cell loss in diabetic mice.<br><br>CONCLUSIONS: Hyperglycemia-induced ER stress contributes to the dysfunction of diabetic corneal endothelium, and inhibiting ER stress may offer therapeutic potential by improving mitochondrial bioenergetics.}, }
@article {pmid35236897, year = {2022}, author = {Saijo, S and Ohno, M and Iwasaki, H and Matsuda, S and Nishi, K and Hiraoka, Y and Ide, N and Kimura, T and Nishi, E}, title = {Nardilysin in adipocytes regulates UCP1 expression and body temperature homeostasis.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {3449}, pmid = {35236897}, issn = {2045-2322}, mesh = {Adipocytes/metabolism ; Adipose Tissue, Brown/metabolism ; Animals ; Body Temperature ; *Body Temperature Regulation/physiology ; *Metalloendopeptidases/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Reactive Oxygen Species/metabolism ; *Thermogenesis/genetics ; *Uncoupling Protein 1/biosynthesis/genetics/metabolism ; }, abstract = {Brown adipose tissue (BAT) dissipates chemical energy as heat through uncoupling protein 1 (UCP1). The induction of mitochondrial reactive oxygen species (ROS) in BAT was recently identified as a mechanism that supports UCP1-dependent thermogenesis. We previously demonstrated that nardilysin (NRDC) plays critical roles in body temperature homeostasis. Global NRDC-deficient (Nrdc[-/-]) mice show hypothermia due to a lower set point for body temperature, whereas BAT thermogenesis at room temperature (RT) is enhanced mainly to compensate for poor thermal insulation. To examine the primary role of NRDC in BAT thermogenesis, we generated adipocyte-specific NRDC-deficient (Adipo-KO) mice by mating Nrdc floxed (Nrdc[flox/flox]) mice with adiponectin-Cre mice. Adipo-KO mice showed hyperthermia at both RT and thermoneutrality. They were also more cold-tolerant than Nrdc[flox/flox] mice. However, UCP1 mRNA levels were significantly lower in Adipo-KO BAT at RT, thermoneutrality, and 4 °C, whereas no significant differences were observed in UCP1 protein levels at RT and 4 °C. We examined the protein stability of UCP1 using the cycloheximide chase assay and found that NRDC negatively regulated its stability via the ubiquitin-proteasome pathway. NRDC may be also involved in ROS-mediated in vivo thermogenesis because the inhibitory effects of N-acetyl cysteine, an ROS scavenger, on β3 agonist-induced thermogenesis were stronger in Adipo-KO mice. Collectively, the present results demonstrate that NRDC in BAT controls adaptive thermogenesis and body temperature homeostasis possibly via the regulation of UCP1 protein stability and ROS levels.}, }
@article {pmid35235429, year = {2022}, author = {Honda, M and Segawa, T and Ishikawa, K and Maeda, M and Saito, Y and Kon, S}, title = {Nephronectin influences EAE development by regulating the Th17/Treg balance via reactive oxygen species.}, journal = {American journal of physiology. Cell physiology}, volume = {322}, number = {4}, pages = {C699-C711}, doi = {10.1152/ajpcell.00376.2021}, pmid = {35235429}, issn = {1522-1563}, mesh = {Animals ; *Encephalomyelitis, Autoimmune, Experimental/immunology ; Extracellular Matrix Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; *T-Lymphocytes, Regulatory ; *Th17 Cells/metabolism ; }, abstract = {Blood levels of the extracellular matrix protein nephronectin (Npnt), a protein critical for kidney development, are elevated in autoimmune experimental autoimmune encephalitis (EAE) mice, which are a model for multiple sclerosis. We found here that treatment with anti-Npnt antibody directed against the α8β1 integrin-binding site (Npnt-blocking antibody) inhibits EAE development. The selenium transporter selenoprotein P (SeP) was identified as a novel Npnt-binding partner. In EAE, Npnt induced SeP and glutathione peroxidase 1 (GPx1) expression, followed by reactive oxygen species (ROS) inhibition in CD4[+] T cells; these changes were disturbed by Npnt-blocking antibody treatment, which also caused suppressed differentiation of interleukin (IL)-17-producing CD4[+] T-helper cells (Th17s) and elevated differentiation of regulatory T cells (Tregs). Treatment of EAE mice with the ROS scavenger N-acetyl cysteine (NAC) blocked the Npnt-blocking antibody-induced decrease in Th17 differentiation and increase in Treg differentiation. In conclusion, the interaction between Npnt and SeP contributes to EAE development by regulating the Th17/Treg balance via the ROS level.}, }
@article {pmid35229943, year = {2022}, author = {Nall, RW and Beloate, LN and Meyerink, ME and Penaloza, T and Doolittle, J and Froeliger, B and Kalivas, PW and Garcia-Keller, C}, title = {Assessing combined effects of varenicline and N-acetylcysteine on reducing nicotine seeking in rats.}, journal = {Addiction biology}, volume = {27}, number = {2}, pages = {e13151}, pmid = {35229943}, issn = {1369-1600}, support = {I01 BX004727/BX/BLRD VA/United States ; K99 DA047426/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; R37 DA003906/DA/NIDA NIH HHS/United States ; R01 DA038700/DA/NIDA NIH HHS/United States ; P50 DA046373/DA/NIDA NIH HHS/United States ; R01 DA012513/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Nicotine/pharmacology ; Rats ; *Smoking Cessation ; *Tobacco Use Disorder/drug therapy/prevention &amp; control ; Varenicline/pharmacology/therapeutic use ; }, abstract = {Nicotine addiction is a chronic relapsing brain disorder, and cigarette smoking is the leading cause of preventable death in the United States. Currently, the most effective pharmacotherapy for smoking cessation is Varenicline (VRN), which reduces both positive and negative reinforcement by nicotine. Clinically, VRN attenuates withdrawal symptoms and promotes abstinence, but >50% of smokers relapse within 3 months following a quit attempt. This may indicate that VRN fails to ameliorate components of nicotine-induced neuroplasticity that promote relapse vulnerability. Animal models reveal that glutamate dysregulation in the nucleus accumbens is associated with nicotine relapse. N-acetylcysteine (NAC) normalizes glutamate transmission and prolongs cocaine abstinence. Thus, combining VRN and NAC may promote and maintain, respectively, nicotine abstinence. In rats, we found that VRN effectively reduced nicotine self-administration and seeking in early abstinence, but not seeking later in abstinence. In contrast, NAC reduced seeking only later in abstinence. Because VRN and NAC are sometimes associated with mild adverse effects, we also evaluated a sequential approach combining subthreshold doses of VRN during self-administration and early abstinence with subthreshold doses of NAC during late abstinence. As expected, subthreshold VRN did not reduce nicotine intake. However, subthreshold VRN and NAC reduced seeking in late abstinence, suggesting a combined effect. Overall, our results suggest that combining subthreshold VRN and NAC is a viable and drug-specific approach to promote abstinence and reduce relapse while minimizing adverse effects. Our data also suggest that different components and time points in addiction engage the different neurocircuits targeted by VRN and NAC.}, }
@article {pmid35229847, year = {2022}, author = {Ding, Q and Guo, R and Pei, L and Lai, S and Li, J and Yin, Y and Xu, T and Yang, W and Song, Q and Han, Q and Dou, X and Li, S}, title = {N-Acetylcysteine alleviates high fat diet-induced hepatic steatosis and liver injury via regulating the intestinal microecology in mice.}, journal = {Food &amp; function}, volume = {13}, number = {6}, pages = {3368-3380}, doi = {10.1039/d1fo03952k}, pmid = {35229847}, issn = {2042-650X}, mesh = {1-Acylglycerol-3-Phosphate O-Acyltransferase ; Acetylcysteine/pharmacology ; Animals ; *Diet, High-Fat/adverse effects ; Liver ; Mice ; Mice, Inbred C57BL ; *Non-alcoholic Fatty Liver Disease/etiology/microbiology ; }, abstract = {N-Acetylcysteine (NAC), a well-accepted antioxidant, has been shown to protect against high fat diet (HFD)-induced obesity-associated non-alcoholic fatty liver disease (NAFLD) in mice. However, the underlying mechanism(s) of the beneficial role of NAC is still not fully understood. Our study aimed to evaluate the protective effect of NAC against NAFLD in terms of gut microbiota homeostasis. Thirty-two C57BL/6 mice were divided into four groups, including chow diet (CHOW), high-fat diet (HFD), CHOW + NAC (2 g L[-1] in the drinking water), and HFD + NAC groups, and fed for 12 weeks. NAC supplementation significantly improved HFD-induced obesity, dyslipidemia, and liver dysfunction in mice. NAC also rescued HFD-caused disorder of the gut microbiota. Intriguingly, removing intestinal microorganisms by antibiotics (ABX) obviously abolished NAC supplementation-rescued hepatic steatosis and liver injury, indicating the involvement of the gut microbiota in the beneficial role of NAC. The profiles of 1145 expressed hepatic mRNAs were analyzed by whole transcriptome sequencing. Among those, 5 up-expressed mRNAs induced by a HFD, including Cidea, CD36, Acnat2, Mogat1, and GPAT3, were reversed by NAC treatment, which was further verified by a quantitative real-time polymerase chain reaction (qRT-PCR). Meanwhile, those 5 mRNAs exhibited a significant (negative or positive) association with bacterial phyla or genera, including phyla Firmicutes and Bacteroidetes and genera norank_f_Erysipelotrichaceae and Lachnoclostridium, by Spearman's correlation analysis. These results suggested that the homeostasis of the gut microbiota plays an important role in NAC-improved NAFLD by affecting the enterohepatic axis.}, }
@article {pmid35225941, year = {2022}, author = {Poli, V and Madduru, R and Aparna, Y and Kandukuri, V and Motireddy, SR}, title = {Amelioration of Cadmium-Induced Oxidative Damage in Wistar Rats by Vitamin C, Zinc and N-Acetylcysteine.}, journal = {Medical sciences (Basel, Switzerland)}, volume = {10}, number = {1}, pages = {}, pmid = {35225941}, issn = {2076-3271}, mesh = {*Acetylcysteine/metabolism/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Ascorbic Acid/pharmacology/therapeutic use ; *Cadmium/toxicity ; Oxidative Stress ; Rats ; Rats, Wistar ; Vitamins/pharmacology ; Zinc/pharmacology/therapeutic use ; }, abstract = {The present study was performed to determine the protective effects of vitamin C, zinc, and N-acetylcysteine, individually or in combination with Cd, to monitor their amelioration capability against Cd-induced oxidative damage in Wistar rats. We investigated and demonstrated that cadmium is a toxic element that damages rat liver and kidney tissues. Vitamin C, zinc, and NAC have been proven to have protective roles against Cd toxic effects. Nine groups of rats were studied as the experimental group. The present experiment was conducted for 45 days. Liver and kidneys were excised for biochemical evaluation by assaying antioxidant enzymes and lipid oxidation products to assess the impact of Cd toxicity and its amelioration by co-administration of vitamin C, zinc, and NAC along with Cd. Basal metabolic rates and tissue respiration rates of liver and kidney were significantly decreased (p < 0.05) during Cd toxicity. Serum biochemical parameters were also found to be significantly altered to cope with Cd toxicity. All the antioxidant enzymes and products were significant inhibited (p < 0.05) or elevated in rat liver and kidney tissues during Cd-induced toxicity. Our results suggest that co-administration of vitamin C, zinc, and NAC to rats ameliorates oxidative damage induced by Cd toxicity. From the results obtained in the present study, all the agents tested had protective effects against Cd-induced oxidative damage.}, }
@article {pmid35217818, year = {2022}, author = {Fu, H and Shen, QR and Zhao, Y and Ni, M and Zhou, CC and Chen, JK and Chi, C and Li, DJ and Liang, G and Shen, FM}, title = {Activating α7nAChR ameliorates abdominal aortic aneurysm through inhibiting pyroptosis mediated by NLRP3 inflammasome.}, journal = {Acta pharmacologica Sinica}, volume = {43}, number = {10}, pages = {2585-2595}, pmid = {35217818}, issn = {1745-7254}, mesh = {Acetylcysteine ; Angiotensin II/metabolism ; Animals ; *Aortic Aneurysm, Abdominal/drug therapy/metabolism/prevention &amp; control ; Apolipoproteins E/metabolism ; Caspase 1/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Elastin ; *Inflammasomes/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pyroptosis ; Tumor Necrosis Factor-alpha/metabolism ; alpha7 Nicotinic Acetylcholine Receptor/metabolism ; }, abstract = {Abdominal aortic aneurysm (AAA) is defined as a dilated aorta in diameter at least 1.5 times of a normal aorta. Our previous studies found that activating α7 nicotinic acetylcholine receptor (α7nAChR) had a protective effect on vascular injury. This work was to investigate whether activating α7nAChR could influence AAA formation and explore its mechanisms. AAA models were established by angiotensin II (Ang II) infusion in ApoE[-][/-] mice or in wild type and α7nAChR[-/-] mice. In vitro mouse aortic smooth muscle (MOVAS) cells were treated with tumor necrosis factor-α (TNF-α). PNU-282987 was chosen to activate α7nAChR. We found that cell pyroptosis effector GSDMD and NLRP3 inflammasome were activated in abdominal aorta, and inflammatory cytokines in serum were elevated in AAA models of ApoE[-/-] mice. Activating α7nAChR reduced maximal aortic diameters, preserved elastin integrity and decreased inflammatory responses in ApoE[-/-] mice with Ang II infusion. While α7nAChR[-/-] mice led to aggravated aortic injury and increased inflammatory cytokines with Ang II infusion when compared with wild type. Moreover, activating α7nAChR inhibited NLRP3/caspase-1/GSDMD pathway in AAA model of ApoE[-/-] mice, while α7nAChR deficiency promoted this pathway. In vitro, N-acetylcysteine (NAC) inhibited NLRP3 inflammasome activation and NLRP3 knockdown reduced GSDMD expression, in MOVAS cells treated with TNF-α. Furthermore, activating α7nAChR inhibited oxidative stress, reduced NLRP3/GSDMD expression, and decreased cell pyroptosis in MOVAS cells with TNF-α. In conclusion, our study found that activating α7nAChR retarded AAA through inhibiting pyroptosis mediated by NLRP3 inflammasome. These suggested that α7nAChR would be a potential pharmacological target for AAA.}, }
@article {pmid35216241, year = {2022}, author = {Rogóż, Z and Kamińska, K and Lech, MA and Lorenc-Koci, E}, title = {N-Acetylcysteine and Aripiprazole Improve Social Behavior and Cognition and Modulate Brain BDNF Levels in a Rat Model of Schizophrenia.}, journal = {International journal of molecular sciences}, volume = {23}, number = {4}, pages = {}, pmid = {35216241}, issn = {1422-0067}, support = {UMO-2016/23/B/NZ7/01280//the National Science Centre of Poland/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antipsychotic Agents/pharmacology ; Aripiprazole/*pharmacology ; Behavior, Animal/drug effects ; Brain-Derived Neurotrophic Factor/*metabolism ; Cognition/*drug effects ; Cognition Disorders/drug therapy/metabolism ; Disease Models, Animal ; Female ; Hippocampus/*drug effects/metabolism ; Prefrontal Cortex/*drug effects/metabolism ; Pregnancy ; Quinolones/pharmacology ; Rats ; Rats, Sprague-Dawley ; Schizophrenia/*drug therapy/metabolism ; Social Behavior ; }, abstract = {Treatment of negative symptoms and cognitive disorders in patients with schizophrenia is still a serious clinical problem. The aim of our study was to compare the efficacy of chronic administration of the atypical antipsychotic drug aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy}-3,4-dihydro-2(1H)-quinolinone; ARI) and the well-known antioxidant N-acetylcysteine (NAC) both in alleviating schizophrenia-like social and cognitive deficits and in reducing the decreases in the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) and hippocampus (HIP) of adult Sprague-Dawley rats, that have been induced by chronic administration of the model compound L-buthionine-(S, R)-sulfoximine (BSO) during the early postnatal development (p5-p16). ARI was administered at doses of 0.1 and 0.3 mg/kg while NAC at doses of 10 and 30 mg/kg, alone or in combination. Administration of higher doses of ARI or NAC alone, or co-treatment with lower, ineffective doses of these drugs significantly improved social and cognitive performance as assessed in behavioral tests. Both doses of NAC and 0.3 mg/kg of ARI increased the expression of BDNF mRNA in the PFC, while all doses of these drugs and their combinations enhanced the levels of BDNF protein in this brain structure. In the HIP, only 0,3 mg/kg ARI increased the levels of both BDNF mRNA and its protein. These data show that in the rat BSO-induced neurodevelopmental model of schizophrenia, ARI and NAC differently modulated BDNF levels in the PFC and HIP.}, }
@article {pmid35215851, year = {2022}, author = {Zeng, W and Ren, J and Li, Z and Jiang, C and Sun, Q and Li, C and Li, W and Li, W and He, Q}, title = {Levistolide A Inhibits PEDV Replication via Inducing ROS Generation.}, journal = {Viruses}, volume = {14}, number = {2}, pages = {}, pmid = {35215851}, issn = {1999-4915}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antiviral Agents/*pharmacology ; Benzofurans/*pharmacology ; Cell Line ; Chlorocebus aethiops ; Endoplasmic Reticulum Stress ; Porcine epidemic diarrhea virus/*drug effects/physiology ; RNA, Viral/metabolism ; Reactive Oxygen Species/*metabolism ; Sus scrofa ; Vero Cells ; Viral Proteins/metabolism ; Virus Replication/drug effects ; }, abstract = {Porcine epidemic diarrhea virus (PEDV) variant strains adversely affect the production of pigs globally. Vaccines derived from PEDV traditional strains impart less protection against the variant strains. Moreover, sequence diversity among different PEDV variant strains is also complicated. This necessitates developing alternative antiviral strategies for defending against PEDV. This study explored a natural product, Levistolide A (LA), to possess antiviral activity against PEDV. LA was found to suppress PEDV replication in a dose-dependent manner. And the inhibitory effect of LA against PEDV was maintained in the course of time. In terms of viral RNA and protein production, LA also showed a strong inhibitory effect. In addition, LA was indicated to inhibit PEDV from attaching to the cellular membrane or penetrating the cells. Further study revealed that LA can induce the generation of reactive oxygen species (ROS), and the corresponding inhibitor, NAC, was found to antagonize the effect of LA on inhibiting PEDV replication. This illustrated that the LA-induced ROS generation played an important role in its anti-PEDV activity. LA was also identified to stimulate ER stress, which is an important consequence of ROS production and was proven to be able to inhibit PEDV replication. To conclude, this study revealed that LA can inhibit PEDV replication via inducing ROS generation.}, }
@article {pmid35215328, year = {2022}, author = {Guerini, M and Condrò, G and Friuli, V and Maggi, L and Perugini, P}, title = {N-acetylcysteine (NAC) and Its Role in Clinical Practice Management of Cystic Fibrosis (CF): A Review.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {15}, number = {2}, pages = {}, pmid = {35215328}, issn = {1424-8247}, abstract = {N-acetylcysteine is the acetylated form of the amino acid L-cysteine and a precursor to glutathione (GSH). It has been known for a long time as a powerful antioxidant and as an antidote for paracetamol overdose. However, other activities related to this molecule have been discovered over the years, making it a promising drug for diseases such as cystic fibrosis (CF). Its antioxidant activity plays a key role in CF airway inflammation and redox imbalance. Furthermore, this molecule appears to play an important role in the prevention and eradication of biofilms resulting from CF airway infections, in particular that of Pseudomonas aeruginosa. The aim of this review is to provide an overview of CF and the role that NAC could play in preventing and eliminating biofilms, as a modulator of inflammation and as an antioxidant, restoring the redox balance within the airways in CF patients. To do this, NAC can act alone, but it can also be used as an adjuvant molecule to known drugs (antibiotics/anti-inflammatories) to increase their activity.}, }
@article {pmid35204298, year = {2022}, author = {Martinez-Banaclocha, M}, title = {N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204298}, issn = {2076-3921}, abstract = {In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of N-acetyl-cysteine, a promising and well-tolerated therapeutic agent suitable for long-term use.}, }
@article {pmid35204201, year = {2022}, author = {Bădilă, AE and Rădulescu, DM and Ilie, A and Niculescu, AG and Grumezescu, AM and Rădulescu, AR}, title = {Bone Regeneration and Oxidative Stress: An Updated Overview.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204201}, issn = {2076-3921}, abstract = {Bone tissue engineering is a complex domain that requires further investigation and benefits from data obtained over past decades. The models are increasing in complexity as they reveal new data from co-culturing and microfluidics applications. The in vitro models now focus on the 3D medium co-culturing of osteoblasts, osteoclasts, and osteocytes utilizing collagen for separation; this type of research allows for controlled medium and in-depth data analysis. Oxidative stress takes a toll on the domain, being beneficial as well as destructive. Reactive oxygen species (ROS) are molecules that influence the differentiation of osteoclasts, but over time their increasing presence can affect patients and aid the appearance of diseases such as osteoporosis. Oxidative stress can be limited by using antioxidants such as vitamin K and N-acetyl cysteine (NAC). Scaffolds and biocompatible coatings such as hydroxyapatite and bioactive glass are required to isolate the implant, protect the zone from the metallic, ionic exchange, and enhance the bone regeneration by mimicking the composition and structure of the body, thus enhancing cell proliferation. The materials can be further functionalized with growth factors that create a better response and higher chances of success for clinical use. This review highlights the vast majority of newly obtained information regarding bone tissue engineering, such as new co-culturing models, implant coatings, scaffolds, biomolecules, and the techniques utilized to obtain them.}, }
@article {pmid35203827, year = {2022}, author = {De Angelis, M and Mascellino, MT and Miele, MC and Al Ismail, D and Colone, M and Stringaro, A and Vullo, V and Venditti, M and Mastroianni, CM and Oliva, A}, title = {High Activity of N-Acetylcysteine in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae and Acinetobacter baumannii.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35203827}, issn = {2079-6382}, abstract = {AIM: The aim of the study was to evaluate the in vitro activity of N-acetylcysteine (NAC), alone or in combination with beta-lactams, against carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Acinetobacter baumannii (CR-Ab).<br><br>METHODS: The antibacterial activity of each compound was tested by broth microdilution and the synergism was evaluated by the checkerboard method. Killing studies of NAC alone and in combination with beta-lactams were performed. Bacterial morphological changes were investigated with scanning electron microscopy (SEM).<br><br>RESULTS: Overall, 30 strains were included (15 CR-Kp and 15 CR-Ab). The NAC Minimal Inhibitory Concentrations (MIC)50/90 were 5/5 and 2.5/5 mg/mL for CR-Kp and CR-Ab, respectively. For both microorganisms, NAC, in addition to beta-lactams (meropenem for CR-Kp, meropenem and ampicillin/sulbactam for CR-Ab, respectively), was able to enhance their activity. The killing studies showed a rapid and concentration-dependent activity of NAC alone; the addition of NAC to meropenem or ampicillin/sulbactam at subinhibitory concentrations induced a fast and lasting bactericidal activity that persisted over time. The SEM analyses showed evident morphological alterations of the bacterial cells following incubation with NAC, alone and in combination with meropenem.<br><br>CONCLUSIONS: NAC demonstrated a high in vitro activity against CR-Kp and CR-Ab and was able to enhance beta-lactams' susceptibility in the tested strains. The preliminary data on the SEM analyses confirmed the in vitro results.}, }
@article {pmid35203350, year = {2022}, author = {Tanwar, J and Saurav, S and Basu, R and Singh, JB and Priya, A and Dutta, M and Santhanam, U and Joshi, M and Madison, S and Singh, A and Nair, N and Gokhale, RS and Motiani, RK}, title = {Mitofusin-2 Negatively Regulates Melanogenesis by Modulating Mitochondrial ROS Generation.}, journal = {Cells}, volume = {11}, number = {4}, pages = {}, pmid = {35203350}, issn = {2073-4409}, support = {IA/I/19/2/504651/WTDBT_/DBT-Wellcome Trust India Alliance/India ; IA/I/19/2/504651//Wellcome Trust/DBT India Alliance/ ; CLP0027//Unilever R and D, India/ ; SRG/2019/000495//Science and Engineering Research Board/ ; }, mesh = {Animals ; Melanins/metabolism ; Melanocytes/metabolism ; *Melanoma, Experimental/metabolism ; *Melanosomes/metabolism ; Mice ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Inter-organellar communication is emerging as one of the most crucial regulators of cellular physiology. One of the key regulators of inter-organellar communication is Mitofusin-2 (MFN2). MFN2 is also involved in mediating mitochondrial fusion-fission dynamics. Further, it facilitates mitochondrial crosstalk with the endoplasmic reticulum, lysosomes and melanosomes, which are lysosome-related organelles specialized in melanin synthesis within melanocytes. However, the role of MFN2 in regulating melanocyte-specific cellular function, i.e., melanogenesis, remains poorly understood. Here, using a B16 mouse melanoma cell line and primary human melanocytes, we report that MFN2 negatively regulates melanogenesis. Both the transient and stable knockdown of MFN2 leads to enhanced melanogenesis, which is associated with an increase in the number of mature (stage III and IV) melanosomes and the augmented expression of key melanogenic enzymes. Further, the ectopic expression of MFN2 in MFN2-silenced cells leads to the complete rescue of the phenotype at the cellular and molecular levels. Mechanistically, MFN2-silencing elevates mitochondrial reactive-oxygen-species (ROS) levels which in turn increases melanogenesis. ROS quenching with the antioxidant N-acetyl cysteine (NAC) reverses the MFN2-knockdown-mediated increase in melanogenesis. Moreover, MFN2 expression is significantly lower in the darkly pigmented primary human melanocytes in comparison to lightly pigmented melanocytes, highlighting a potential contribution of lower MFN2 levels to higher physiological pigmentation. Taken together, our work establishes MFN2 as a novel negative regulator of melanogenesis.}, }
@article {pmid35202279, year = {2022}, author = {Chen, H and Carty, RK and Bautista, AC and Hayakawa, KA and Lein, PJ}, title = {Triiodothyronine or Antioxidants Block the Inhibitory Effects of BDE-47 and BDE-49 on Axonal Growth in Rat Hippocampal Neuron-Glia Co-Cultures.}, journal = {Toxics}, volume = {10}, number = {2}, pages = {}, pmid = {35202279}, issn = {2305-6304}, support = {T32 ES007059/ES/NIEHS NIH HHS/United States ; R01 ES014901/ES/NIEHS NIH HHS/United States ; P30 ES023513/ES/NIEHS NIH HHS/United States ; P42 ES04699/ES/NIEHS NIH HHS/United States ; }, abstract = {We previously demonstrated that polybrominated diphenyl ethers (PBDEs) inhibit the growth of axons in primary rat hippocampal neurons. Here, we test the hypothesis that PBDE effects on axonal morphogenesis are mediated by thyroid hormone and/or reactive oxygen species (ROS)-dependent mechanisms. Axonal growth and ROS were quantified in primary neuronal-glial co-cultures dissociated from neonatal rat hippocampi exposed to nM concentrations of BDE-47 or BDE-49 in the absence or presence of triiodothyronine (T3; 3-30 nM), N-acetyl-cysteine (NAC; 100 µM), or α-tocopherol (100 µM). Co-exposure to T3 or either antioxidant prevented inhibition of axonal growth in hippocampal cultures exposed to BDE-47 or BDE-49. T3 supplementation in cultures not exposed to PBDEs did not alter axonal growth. T3 did, however, prevent PBDE-induced ROS generation and alterations in mitochondrial metabolism. Collectively, our data indicate that PBDEs inhibit axonal growth via ROS-dependent mechanisms, and that T3 protects axonal growth by inhibiting PBDE-induced ROS. These observations suggest that co-exposure to endocrine disruptors that decrease TH signaling in the brain may increase vulnerability to the adverse effects of developmental PBDE exposure on axonal morphogenesis.}, }
@article {pmid35200000, year = {2022}, author = {Ding, Z and Wang, X and Zhang, N and Sun, C and Zhao, G and Peng, Y and Zheng, J}, title = {Metabolic Activation of Perampanel Mediated by CYP1A2.}, journal = {Chemical research in toxicology}, volume = {35}, number = {3}, pages = {490-498}, doi = {10.1021/acs.chemrestox.1c00396}, pmid = {35200000}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic ; Animals ; *Cytochrome P-450 CYP1A2/metabolism ; *Glutathione/metabolism ; Humans ; Microsomes, Liver/metabolism ; Nitriles ; Pyridones ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Perampanel (PRP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist with high selectivity, has been used as a new adjuvant for the treatment of fractional seizures with or without primary generalized tonic-clonic seizures and secondary generalized seizures in epilepsy patients over the age of 12. Adverse events such as liver injury have been reported during the clinical application of PRP. The purpose of the study is to explore the in vitro and in vivo metabolic activation of PRP. Two GSH conjugates were detected in rat liver microsomal incubations containing PRP, GSH, and NADPH. The two GSH conjugates were both obtained from the bile of rats and rat primary hepatocytes after exposure to PRP. Similar microsomal incubations complemented with N-acetylcysteine (NAC) in place of GSH offered two NAC conjugates. As expected, the NAC conjugates were detected in the urine of PRP-treated rats. One of the two NAC conjugates was identified as NAC conjugate 12 verified by chemical synthesis. The individual human recombinant P450 enzyme incubation assay demonstrated that CYP1A2 dominated the catalysis for the metabolic activation of PRP. Pretreatment with α-naphthoflavone (NTF) decreased the formation of PRP-derived GSH conjugates in both livers of rats and cultured primary hepatocytes after being treated with PRP. Additionally, NTF was found to decrease the susceptibility of primary hepatocytes to the cytotoxicity of PRP. The findings indicate that PRP was metabolized to the corresponding epoxide, which could participate in PRP-induced cytotoxicity.}, }
@article {pmid35193023, year = {2022}, author = {Narai-Kanayama, A and Chiku, K and Ono, H and Momoi, T and Hiwatashi-Kanno, M and Kobayashi, A and Matsuda, H and Yoshida, M and Nakayama, T}, title = {Inhibitory effects of thiol compounds on theaflavin browning and structural analysis of the causative substances.}, journal = {Food chemistry}, volume = {384}, number = {}, pages = {132488}, doi = {10.1016/j.foodchem.2022.132488}, pmid = {35193023}, issn = {1873-7072}, mesh = {Acetylcysteine ; Antioxidants/chemistry ; *Biflavonoids/chemistry ; Catechin ; *Cysteine/chemistry ; Glutathione/chemistry ; Oxidation-Reduction ; Sulfhydryl Compounds/chemistry ; }, abstract = {Theaflavin, a polyphenol responsible for the bright orange color and various bioactivities of black tea exudates, is susceptible to autoxidation at neutral and mild alkaline pH, changing its color to brown. In the presence of cysteine (Cys), glutathione (GSH), or N-acetyl cysteine (NAC), the browning of theaflavin solution was inhibited concomitantly with time-dependent decreases in the concentrations of both theaflavin and thiol group. The rank order of the decrease was Cys ≅ GSH > NAC, suggesting the relevance of the nucleophilic property of the thiol group to its reaction with theaflavin. LC-MS analysis of the reaction products indicated formation of novel derivatives that were mono- or di-molecular adducts of thiol compounds. We determined the chemical structures of theaflavin-Cys and theaflavin-GSH adducts by NMR and proposed the reaction mechanisms. It was found that the theaflavin-Cys adduct was not a simple adduct, to which a new cyclic structure was added.}, }
@article {pmid35191764, year = {2022}, author = {Zhang, Z and Zhang, J and Liu, J and Zhao, H and Zhao, Y and Sun, D}, title = {The effect of different drugs on hard metal lung disease in a rat model.}, journal = {Toxicology and industrial health}, volume = {38}, number = {2}, pages = {92-99}, doi = {10.1177/07482337211062973}, pmid = {35191764}, issn = {1477-0393}, mesh = {Alloys ; Animals ; Bronchoalveolar Lavage Fluid ; Cobalt ; Female ; *Lung ; *Lung Diseases ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/metabolism ; Tungsten ; }, abstract = {Hard metal lung disease (HMLD) drugs include dexamethasone sodium phosphate (Dex), methylprednisolone (MP) injection, N-acetylcysteine injection (NAC), and a mix of Dex, MP, and NAC (MIX). In this study, we compared the effects of these drugs on different cytokines of hard metal lung disease in a rat model. Thirty-six adult female Sprague Dawley rats were distributed equally into the control group, hard metal (HM) group, Dex group, MP group, NAC group, and MIX group. HM powder (0.5 mL, 20 mg/mL; one time) was administered by intraperitoneal injection to the HM group through the pulmonary endotracheal tube, while the control group received normal saline (0.5 mL, 20 mg/mL; one time). After 4 weeks, the drugs were administered to the experimental groups (0.5 mL, 20 mg/mL; one time). After 8 weeks, bronchoalveolar lavage fluid (BALF) and serum were examined for cytokine levels. Biochemical analysis indicated that the Dex, MP, NAC, and MIX did not improve TGF-β1, TGF-β2, KL-6, and MMP-1 in the BALF, while MIX increased TIMP-1 in BALF. In addition, the NAC treatment significantly increased the expression levels of TGF-β1, TGF-β2, KL-6, and MMP-1. The MIX treatment significantly increased the expression levels of TGF-β1, TGF-β2, and KL-6. The MP treatment significantly increased the expression levels of KL-6, and MMP-1. The Dex treatment significantly increased the expression levels of TGF-β1, KL-6, and MMP-1. This study demonstrated that administered with NAC and MIX could improve TGF-β1, TGF-β2, and KL-6 in serum of hard metal lung disease in a rat model. Therefore, NAC injection may be considered a useful candidate in the development of a preventive agent against HMLD.}, }
@article {pmid35189496, year = {2022}, author = {Sharma, R and Tikka, SK and Bhute, AR and Bastia, BK}, title = {N-acetyl cysteine in the treatment of cannabis use disorder: A systematic review of clinical trials.}, journal = {Addictive behaviors}, volume = {129}, number = {}, pages = {107283}, doi = {10.1016/j.addbeh.2022.107283}, pmid = {35189496}, issn = {1873-6327}, mesh = {Acetylcysteine/therapeutic use ; *Cannabis ; Humans ; *Marijuana Abuse/therapy ; }, abstract = {BACKGROUND AND AIM: Cannabis is the most consumed illicit drug globally, with a high risk of developing cannabis use disorder (CUD). No approved pharmacological treatment exists for CUD, but N-Acetyl Cysteine (NAC) has shown promising results in different clinical studies. This study aims to conduct a systematic review of NAC clinical trials for the treatment of CUD.<br><br>METHODS: Systematic review of randomized controlled trials (RCTs) was conducted to determine the effect of NAC for the treatment of cannabis dependence/cannabis use disorder (CUD). Articles were electronically searched across different databases using PubMed, Google Scholar, EMBASE, Cochrane Library, Medline and PsycINFO from inception to June 2021. Several study characteristics, including study duration, sample size, study population and age group, intervention, adverse effects, and outcome measure were extracted. A PICO table was used for data extraction.<br><br>RESULTS: We included 08 RCTs in the qualitative analysis. The risk of bias (RoB) was assessed according to Cochrane RoB criteria, and a 5 point grading system according to the Oxford Centre for Evidence-Based Medicine was used to rate the methodological quality (level of evidence) of the included articles. Mild and well-tolerated adverse events were reported in the placebo and NAC group.<br><br>CONCLUSIONS: The studies collectively offer mixed results, although the strength of the evidence available on which to make a recommendation is strong. NAC has shown to be effective in promoting abstinence, medication adherence and reducing cannabis use and craving among cannabis dependent users. This review also suggests recommendations for future research.}, }
@article {pmid35187102, year = {2021}, author = {Huang, M and Yang, Z and Li, Y and Lan, H and Cyganek, L and Yuecel, G and Lang, S and Bieback, K and El-Battrawy, I and Zhou, X and Borggrefe, M and Akin, I}, title = {Dopamine D1/D5 Receptor Signaling Is Involved in Arrhythmogenesis in the Setting of Takotsubo Cardiomyopathy.}, journal = {Frontiers in cardiovascular medicine}, volume = {8}, number = {}, pages = {777463}, pmid = {35187102}, issn = {2297-055X}, abstract = {BACKGROUND: Previous studies suggested involvement of non-ß-adrenoceptors in the pathogenesis of Takotsubo cardiomyopathy (TTC). This study was designed to explore possible roles and underlying mechanisms of dopamine D1/D5 receptor coupled signaling in arrhythmogenesis of TTC.<br><br>METHODS: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were challenged by toxic concentration of epinephrine (Epi, 0.5 mM for 1 h) for mimicking the catecholamine excess in setting of TTC. Specific receptor blockers and activators were used to unveil roles of D1/D5 receptors. Patch clamp, qPCR, and FACS analyses were performed in the study.<br><br>RESULTS: High concentration Epi and two dopamine D1/D5 receptor agonists [(&#xb1;)-SKF 38393 and fenoldopam] reduced the depolarization velocity and prolonged the duration of action potentials (APs) and caused arrhythmic events in iPSC-CMs, suggesting involvement of dopamine D1/D5 receptor signaling in arrhythmogenesis associated with QT interval prolongation in the setting of TTC. (&#xb1;)-SKF 38393 and fenoldopam enhanced the reactive oxygen species (ROS)-production. H2O2 (100 &#x3bc;M) recapitulated the effects of (&#xb1;)-SKF 38393 and fenoldopam on APs and a ROS-blocker N-acetylcysteine (NAC, 1 mM) abolished the effects, suggesting that the ROS-signaling is involved in the dopamine D1/D5 receptor actions. A NADPH oxidases blocker and a PKA- or PKC-blocker suppressed the effects of the dopamine receptor agonist, implying that PKA, NADPH oxidases and PKC participated in dopamine D1/D5 receptor signaling. The abnormal APs resulted from dopamine D1/D5 receptor activation-induced dysfunctions of ion channels including the Na[+] and L-type Ca[2+] and IKr channels.<br><br>CONCLUSIONS: Dopamine D1/D5 receptor signaling plays important roles for arrhythmogenesis of TTC. Dopamine D1/D5 receptor signaling in cardiomyocytes might be a potential target for treating arrhythmias in patients with TTC.}, }
@article {pmid35186974, year = {2021}, author = {Yu, L and Wang, Y and Guo, YH and Wang, L and Yang, Z and Zhai, ZH and Tang, L}, title = {HIF-1α Alleviates High-Glucose-Induced Renal Tubular Cell Injury by Promoting Parkin/PINK1-Mediated Mitophagy.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {803874}, pmid = {35186974}, issn = {2296-858X}, abstract = {It is well-established that mitophagy leads to Diabetic Nephropathy (DN) and renal failure. Mitophagy mediated by a Hypoxia-inducible factor-1α (HIF-1α) plays a beneficial role in many diseases. Nevertheless, the mechanisms underlying HIF-1α-mediated mitophagy in DN remain unclear. This study defines the role of HIF-1α mediated mitophagy in DN. The expression of HIF-1α was upregulated in HK-2 cells in an High-Glucose (HG) environment, and the YC-1 (a specific inhibitor of HIF-1α) further exacerbated the hypoxia-induced mitochondrial dysfunction. Conversely, the HIF-1α-mediated protective effect was strengthened by scavenger N-acetylcysteine (NAC), a type of reactive oxygen species. Moreover, HIF-1α-Parkin/PINK1-mediated mitophagy prevented apoptosis and ROS production in HK-2 cells subjected to HG exposure. In summary, HIF-1α mediated mitophagy on HK-2 cells under HG conditions could alleviate DN, suggesting that it has huge prospects for DN treatment.}, }
@article {pmid35185289, year = {2022}, author = {Pan, T and Qian, Y and Li, T and Zhang, Z and He, Y and Wang, J and Li, L and Hu, Y and Lin, M}, title = {Acetyl l-carnitine protects adipose-derived stem cells against serum-starvation: regulation on the network composed of reactive oxygen species, autophagy, apoptosis and senescence.}, journal = {Cytotechnology}, volume = {74}, number = {1}, pages = {105-121}, pmid = {35185289}, issn = {0920-9069}, abstract = {Adipose-derived stem cells (ADSCs) play an important role in cell therapy and regenerative medicine. However, local nutritional deficiency often limits therapeutical effect of the transplanted cells. Acetyl l-carnitine (ALC) is a common energy metabolism regulator and free radical scavenger. This study investigated the effect of ALC on ADSCs exposed to severe serum-deprivation and explored the relative machanisms. Treating with 1 mM ALC improved proliferation and alleviated senescence of starved cells, accompanied with reduced reactive oxygen species (ROS) and increased protein expression of SOD1 and catalase. In addition, ALC inhibited apoptosis but increased starvation-induced autophagy, which might be related to the regulation of phases of dissociation of Bcl-2-Beclin1 and Bcl-2-Bax complexes. Evidence obtained by replacing ALC with N-acetylcysteine (N-AC) suggested that ROS might be the central inducer of autophagy, apoptosis and senescence. There was a difference between ALC and N-AC in the protection mechanism, that was, compared with N-AC, ALC maintained autophagy well at the same time as anti-oxidation. Inhibition of autophagy by 3-methyladenine (3-MA) partially offset the protective effect of ALC. However, despite low-level ROS and enhanced autophagy, ALC with high concentration (10 mM) markedly aggravated cell apoptosis and senescence, thus losing cytoprotection and even causing damage.}, }
@article {pmid35177589, year = {2022}, author = {Lv, J and Yi, Y and Qi, Y and Yan, C and Jin, W and Meng, L and Zhang, D and Jiang, W}, title = {Mitochondrial homeostasis regulates definitive endoderm differentiation of human pluripotent stem cells.}, journal = {Cell death discovery}, volume = {8}, number = {1}, pages = {69}, pmid = {35177589}, issn = {2058-7716}, support = {31970608//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2019CFA092//Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)/ ; }, abstract = {Cellular organelles play fundamental roles in almost all cell behaviors. Mitochondria have been reported to be functionally linked to various biological processes, including reprogramming and pluripotency maintenance. However, very little about the role of mitochondria has been revealed in human early development and lineage specification. Here, we reported the characteristics and function of mitochondria during human definitive endoderm differentiation. Using a well-established differentiation system, we first investigated the change of mitochondrial morphology by comparing undifferentiated pluripotent stem cells, the intermediate mesendoderm cells, and differentiated endoderm cells, and found that mitochondria were gradually elongated and matured along differentiation. We further analyzed the expression pattern of mitochondria-related genes by RNA-seq, indicating that mitochondria became active during differentiation. Supporting this notion, the production of adenosine triphosphate (ATP) and reactive oxygen species (ROS) was increased as well. Functionally, we utilized chemicals and genome editing techniques, which could interfere with mitochondrial homeostasis, to determine the role of mitochondria in human endoderm differentiation. Treatment with mitochondrial inhibitors, or genetic depletion of mitochondrial transcription factor A (TFAM), significantly reduced the differentiation efficiency of definitive endoderm. In addition, the defect in endoderm differentiation due to dysfunctional mitochondria could be restored to some extent by the addition of ATP. Moreover, the clearance of excessive ROS due to dysfunctional mitochondria by N-acetylcysteine (NAC) improved the differentiation as well. We further found that ATP and NAC could partially replace the growth factor activin A for definitive endoderm differentiation. Our study illustrates the essential role of mitochondria during human endoderm differentiation through providing ATP and regulating ROS levels, which may provide new insight for metabolic regulation of cell fate determination.}, }
@article {pmid35174928, year = {2022}, author = {Hashim, AR and Bashir, DW and Yasin, NAE and Rashad, MM and El-Gharbawy, SM}, title = {Ameliorative effect of N-acetylcysteine on the testicular tissue of adult male albino rats after glyphosate-based herbicide exposure.}, journal = {Journal of biochemical and molecular toxicology}, volume = {36}, number = {4}, pages = {e22997}, doi = {10.1002/jbt.22997}, pmid = {35174928}, issn = {1099-0461}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Glycine/analogs &amp; derivatives ; *Herbicides/toxicity ; Male ; Oxidative Stress ; Rats ; Glyphosate ; }, abstract = {Glyphosate (GLP) is a broad-spectrum herbicide that is frequently used in crop production, but its residues remain in foodstuffs. This, in turn, has led to potential adverse effects on both human and animal health. Recent studies emphasized that GLP induces teratogenic effects and reproductive disorders, but its mechanism of toxicity is highly debated. N-acetylcysteine (NAC) is well known for its potent antioxidant capacity in addition to anti-inflammatory and cytoprotective properties. Therefore, our study aimed to investigate the reproductive toxicity of GLP in mature rats and evaluate the possible ameliorative effect of NAC against this toxicity. To this end, 30 adult male rats were assigned into three groups (10 rats per group) as follows: Group I, negative control; group II, GLP-exposed; 375 mg/kg GLP, orally; group III, NAC-cotreated, 160 mg/kg NAC 1 h before GLP, plus GLP, 375 mg/kg orally for 6 weeks. At the end of the experiment, the testicles were collected for semen analysis and biochemical, histopathological, and immunohistochemical studies. GLP-exposed rats exhibited disturbances in seminal parameters and a significant increase in malondialdehyde levels and expression of apoptotic markers. Several histopathological changes were observed, including strong immunoreactions for caspase-3 and proliferating cell nuclear antigen. Conversely, the administration of NAC before GLP was able to improve seminal parameters, attenuate the induced oxidative stress and apoptosis in addition to the regeneration of testicular damage. In conclusion, NAC can ameliorate the reproductive toxicity induced by GLP to an acceptable degree.}, }
@article {pmid35171079, year = {2022}, author = {Urso, CJ and Zhou, H}, title = {Palmitic acid-induced defects in cell cycle progression and cytokinesis in Neuro-2a cells.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {21}, number = {10}, pages = {1048-1057}, pmid = {35171079}, issn = {1551-4005}, mesh = {Animals ; Apoptosis ; Cell Line, Tumor ; Cytokinesis ; DNA ; Fatty Acids/metabolism/pharmacology ; *Fatty Acids, Nonesterified/metabolism/pharmacology ; Fatty Acids, Unsaturated/metabolism/pharmacology ; G2 Phase Cell Cycle Checkpoints ; Linoleic Acids/pharmacology ; Mice ; Oleic Acids/pharmacology ; *Palmitic Acid/pharmacology ; alpha-Linolenic Acid/pharmacology ; }, abstract = {Obesity is associated with elevated levels of free fatty acids (FFAs). Excessive saturated fatty acids (SFAs) exhibit significant deleterious cytotoxic effects in many types of cells. However, the effects of palmitic acid (PA), the most common circulating SFA, on cell cycle progression in neuronal cells have not been well-examined. The aim of this study was to examine whether PA affects the proliferation and cell cycle progression in mouse neuroblastoma Neuro-2a (N2a) cells. Our studies found that 200 µM PA significantly decreased DNA synthesis and mitotic index in N2a cells as early as 4 h following treatment. 24 h treatment with 200 µM PA significantly decreased the percentage of diploid (2 N) cells while dramatically increasing the percentage of tetraploid (4 N) cells as compared to the BSA control. Moreover, our studies found that 24 h treatment with 200 µM PA increased the percentage of binucleate cells as compared to the BSA control. Our studies also found that unsaturated fatty acids (UFAs), including linoleic acid, oleic acid, α-linolenic acid, and docosahexaenoic acid, were able to abolish PA-induced decrease of 2 N cells, increase of 4 N cells, and accumulation of binucleate cells. Taken together, these results suggest that PA may affect multiple aspects of the cell cycle progression in N2a cells, including decreased DNA synthesis, G2/M arrest, and cytokinetic failure, which could be abolished by UFAs.Abbreviations: 4-PBA, 4-Phenylbutyric Acid; ALA, α-linolenic acid; BrdU, 5-bromo-2'-deoxyuridine; DAPI, 4',6-diamidino-2-phenylindole; ER, endoplasmic reticulum; FFA, free fatty acids; FITC, fluorescein isothiocyanate; LA, linoleic acid; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; N2a, Neuro-2a; NAC, N-acetyl cysteine; OA, oleic acid; PA, palmitic acid; pHH3, Phosphorylation of histone H3; PI, propidium iodide; SFA, saturated fatty acids; PUFA, polyunsaturated fatty acids; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; UFA, unsaturated fatty acids.}, }
@article {pmid35169555, year = {2022}, author = {Hwang, S and Kim, JK}, title = {N-Acetylcysteine Induces Apoptotic, Oxidative and Excitotoxic Neuronal Death in Mouse Cortical Cultures.}, journal = {Chonnam medical journal}, volume = {58}, number = {1}, pages = {18-23}, pmid = {35169555}, issn = {2233-7385}, abstract = {N-acetylcysteine (NAC) has been used as an antioxidant to prevent oxidative cell death. However, we found NAC itself to induce neuronal death in mouse cortical cultures. Therefore, the current study was performed to investigate the mechanism of neuronal death caused by NAC. Cell death was assessed by measuring lactate dehydrogenase efflux to bathing media after 24-48 h exposure to NAC. NAC (0.1-10 mM) induced neuronal death in a concentration- and exposure time-dependent manner. However, NAC did not injure astrocytes even at a concentration of 10 mM. Also, 10 mM NAC markedly attenuated oxidative astrocyte death induced by 0.5 mM diethyl maleate or 0.25 mM H2O2. The NMDA receptor antagonist MK-801 (10 µM) markedly attenuated the neuronal death caused by 10 mM NAC, while NBQX did not affect the neuronal death. Cycloheximide (a protein synthesis inhibitor, 0.1 µg/mL) and z-VAD-FMK (a caspase inhibitor, 100 µM) also significantly attenuated neuronal death. Apoptotic features such as chromatin condensation, nuclear fragmentation, and caspase 3 activation were observed 1 h after the NAC treatment. The neuronal death induced by 1 or 10 mM NAC was significantly attenuated by the treatment with 100 µM Trolox or 1 mM ascorbic acid. NAC induced the generation of intracellular reactive oxygen species (ROS), as measured by the fluorescent dye 2',7'-dichlorofluorescein diacetate. The ROS generation was almost completely abolished by treatment with Trolox or ascorbic acid. These findings demonstrate that NAC can cause oxidative, apoptotic, and excitotoxic neuronal death in mouse neuronal cultures.}, }
@article {pmid35167014, year = {2022}, author = {Tallarico, M and Leo, A and Guarnieri, L and Zito, MC and De Caro, C and Nicoletti, F and Russo, E and Constanti, A and De Sarro, G and Citraro, R}, title = {N-acetylcysteine aggravates seizures while improving depressive-like and cognitive impairment comorbidities in the WAG/Rij rat model of absence epilepsy.}, journal = {Molecular neurobiology}, volume = {59}, number = {5}, pages = {2702-2714}, pmid = {35167014}, issn = {1559-1182}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; *Cognitive Dysfunction ; Disease Models, Animal ; Electroencephalography/methods ; *Epilepsy, Absence/chemically induced/complications/drug therapy ; Humans ; Rats ; Seizures/chemically induced/complications/drug therapy ; }, abstract = {N-acetylcysteine (NAC) is an antioxidant with some demonstrated efficacy in a range of neuropsychiatric disorders. NAC has shown anticonvulsant effects in animal models. NAC effects on absence seizures are still not uncovered, and considering its clinical use as a mucolytic in patients with lung diseases, people with epilepsy are also likely to be exposed to the drug. Therefore, we aimed to study the effects of NAC on absence seizures in the WAG/Rij rat model of absence epilepsy with neuropsychiatric comorbidities. The effects of NAC chronic treatment in WAG/Rij rats were evaluated on: absence seizures at 15 and 30 days by EEG recordings and animal behaviour at 30 days on neuropsychiatric comorbidities. Furthermore, the mechanism of action of NAC was evaluated by analysing brain expression levels of some possible key targets: the excitatory amino acid transporter 2, cystine-glutamate antiporter, metabotropic glutamate receptor 2, the mechanistic target of rapamycin and p70S6K as well as levels of total glutathione. Our results demonstrate that in WAG/Rij rats, NAC treatment significantly increased the number and duration of SWDs, aggravating absence epilepsy while ameliorating neuropsychiatric comorbidities. NAC treatment was linked to an increase in brain mGlu2 receptor expression with this being likely responsible for the observed absence seizure-promoting effects. In conclusion, while confirming the positive effects on animal behaviour induced by NAC also in epileptic animals, we report the aggravating effects of NAC on absence seizures which could have some serious consequences for epilepsy patients with the possible wider use of NAC in clinical therapeutics.}, }
@article {pmid35163042, year = {2022}, author = {Suzuki-Karasaki, M and Ando, T and Ochiai, Y and Kawahara, K and Suzuki-Karasaki, M and Nakayama, H and Suzuki-Karasaki, Y}, title = {Air Plasma-Activated Medium Evokes a Death-Associated Perinuclear Mitochondrial Clustering.}, journal = {International journal of molecular sciences}, volume = {23}, number = {3}, pages = {}, pmid = {35163042}, issn = {1422-0067}, support = {JP21K0927//Japan Society for the Promotion of Science/ ; JP21K10128//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; Bone Neoplasms/*drug therapy/metabolism ; Cell Death ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cluster Analysis ; Humans ; Lipid Peroxides/metabolism ; Male ; Mice ; Mitochondria/drug effects/*metabolism ; Mitochondrial Dynamics/drug effects ; Mouth Neoplasms/*drug therapy/metabolism ; Osteosarcoma/*drug therapy/metabolism ; Plasma Gases/*administration &amp; dosage/pharmacology ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy, which eliminates cancers effectively and safely, is the current clinical choice. Since aggressive tumors are substantially resistant to multidisciplinary therapies that target apoptosis, tumor-specific activation of another cell death modality is a promising avenue for meeting this goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can kill OS and OC by causing a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) based on its characteristic unipolar mitochondrial perinuclear accumulation. The APAM caused apoptotic and nonapoptotic cell death. The APAM increased mitochondrial ROS (mROS) and cell death, and the antioxidants such as N-acetylcysteine (NAC) prevented them. MPMC occurred following mitochondrial fragmentation, which coincided with nuclear damages. MPMC was accompanied by mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC, Ferrostatin-1, and Nocodazole. In contrast, the APAM induced minimal cell death, mROS generation, mLPO accumulation, and MPMC in fibroblasts. These results suggest that MPMC occurs in a tumor-specific manner via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC induction might serve as a promising target for exerting tumor-specific cytotoxicity.}, }
@article {pmid35157342, year = {2022}, author = {Mansouri, MD and Ramanthan, V and Mansouri, DL and Hull, RA}, title = {In vitro activities of N-acetyl cysteine and levofloxacin as a catheter lock therapy against catheter-associated infections.}, journal = {Journal of applied microbiology}, volume = {132}, number = {5}, pages = {3915-3924}, doi = {10.1111/jam.15490}, pmid = {35157342}, issn = {1365-2672}, support = {R21 AI074010/AI/NIAID NIH HHS/United States ; AI074010/NH/NIH HHS/United States ; AI133037/NH/NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/pharmacology/therapeutic use ; *Anti-Infective Agents ; Biofilms ; *Catheter-Related Infections/drug therapy/microbiology/prevention &amp; control ; Catheters/microbiology ; Escherichia coli ; Humans ; Levofloxacin/pharmacology ; *Methicillin-Resistant Staphylococcus aureus ; Staphylococcus aureus ; }, abstract = {AIMS: Since management of catheter-associated infections, which are generally biofilm-based, is attempted in certain patients such as older and frail patients by using a catheter lock solution (CLS), we examined the combination of N-acetyl cysteine (NAC), an antibiofilm agent, and levofloxacin, a broad-spectrum antimicrobial agent, for this purpose.<br><br>METHODS AND RESULTS: Intravascular catheters were colonized with methicillin-resistant Staphylococcus epidermidis, levofloxacin-sensitive/methicillin-resistant Staph. aureus, levofloxacin-resistant/methicillin-resistant Staph. aureus, vancomycin-resistant Enterococcus, Escherichia coli, Klebsiella pneumoniae or Pseudomonas aeruginosa and treated with a CLS containing normal saline, NAC, levofloxacin or NAC plus levofloxacin (NACLEV) and then cultured to assess their antimicrobial activities. We also examined antibiofilm and antimicrobial activities of each CLS by scanning electron microscopy (SEM) and the mechanical integrity of catheters exposed to CLS. Treatment of colonized catheters with NACLEV-CLS significantly reduced colonization (p&#xa0;<&#xa0;0.005) against all pathogens. SEM images also indicate reduction in colonization with NACLEV-CLS with considerable reduction in both visible bacteria and the associated biofilm. Mean tensile strength of catheters exposed to CLS was not significantly different compared to controls (p&#xa0;>&#xa0;0.05).<br><br>CONCLUSIONS: These in vitro results suggest that NACLEV-CLS can significantly reduce all bacterial colonization and potentially help salvage infected catheters without affecting the catheter's mechanical integrity.<br><br>This study presents a novel CLS with a broad spectrum of antimicrobial activity against catheter-associated infections, particularly in long-term catheters.}, }
@article {pmid35156589, year = {2022}, author = {Jouzdani, AF and Ganjirad, Z and Firozian, F and Soleimani-Asl, S and Ranjbar, A}, title = {Protective Effects of N-acetylcysteine Niosome Nanoparticles on Paraquatinduced Nephrotoxicity in Male Rats.}, journal = {Pharmaceutical nanotechnology}, volume = {10}, number = {2}, pages = {137-145}, doi = {10.2174/2211738510666220214102034}, pmid = {35156589}, issn = {2211-7393}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/pharmacology ; Creatinine ; Liposomes ; Male ; *Nanoparticles ; Paraquat/toxicity ; Rats ; Rats, Wistar ; }, abstract = {INTRODUCTION: Paraquat (PQ), as a bipyridyl compound, is widely used as an effective herbicide that produces reactive oxygen species (ROS), affecting the unsaturated lipids of cell membranes leading to cell mortality. N-acetylcysteine (NAC) is a medication that has a beneficial role in reducing the intoxication of kidneys caused by PQ. Niosomes are bilayer vesicles that enhance the bioavailability of drugs. This study aimed to compare the effects of NAC and niosome of NAC (NACNPs) on PQ-induced kidney toxicity concerning its antioxidant activity.<br><br>METHODS: In this experimental study, after formulating NACNP, 30 Wistar male rats weighing 180 to 250 gm were classified into five groups: the control group was treated with normal saline, while the other four groups received 35mg/kg/day of PQ via intraperitoneal route and, was treated with 25mg/kg/day NAC, 25mg/kg/day niosome and 25 mg/kg/day NACNP by gavage, Then, oxidative stress biomarkers such as total antioxidant capacity (TAC), catalase activity (CAT), lipid peroxidation (LPO), and total thiol group (TTG), plus blood urea nitrogen (BUN) and creatinine levels were evaluated in kidney tissue homogenate and examined histopathologically.<br><br>RESULTS: The results revealed that TTG increased significantly in NAC &amp; NACNP groups than in the PQ group. Further, in the PQ group, LPO increased significantly compared with the control, NAC, and NACNP groups, while in the NAC and NACNP group, LPO diminished compared with the PQ group. There was no significant difference in TAC between groups. Blood urea nitrogen (BUN) and creatinine levels dropped in NACNP compared with the PQ group and the NAC. Histological studies also approved PQ-induced damage and the protective effect of NACNP.<br><br>CONCLUSION: The results indicated that NACNP could modulate oxidative stress status and kidney function against PQ toxicity.}, }
@article {pmid35155393, year = {2022}, author = {Liu, Y and Na, Q and Liu, J and Liu, A and Oppong, A and Lee, JY and Chudnovets, A and Lei, J and Sharma, R and Kannan, S and Kannan, RM and Burd, I}, title = {Dendrimer-Based N-Acetyl Cysteine Maternal Therapy Ameliorates Placental Inflammation via Maintenance of M1/M2 Macrophage Recruitment.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {10}, number = {}, pages = {819593}, pmid = {35155393}, issn = {2296-4185}, support = {P50 HD103538/HD/NICHD NIH HHS/United States ; }, abstract = {Intrauterine inflammation (IUI) is the primary cause of spontaneous preterm birth and predisposes neonates to long-term sequelae, including adverse neurological outcomes. N-acetyl-L-cysteine (NAC) is the amino acid L-cysteine derivative and a precursor to the antioxidant glutathione (GSH). NAC is commonly used clinically as an antioxidant with anti-inflammatory properties. Poor bioavailability and high protein binding of NAC necessitates the use of high doses resulting in side effects including nausea, vomiting, and gastric disruptions. Therefore, dendrimer-based therapy can specifically target the drug to the cells involved in inflammation, reducing side effects with efficacy at much lower doses than the free drug. Towards development of the new therapies for the treatment of maternal inflammation, we successfully administered dendrimer-based N-Acetyl Cysteine (DNAC) in an animal model of IUI to reduce preterm birth and perinatal inflammatory response. This study explored the associated immune mechanisms of DNAC treatment on placental macrophages following IUI, especially on M1/M2 type macrophage polarization. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the pro-inflammatory cytokine mRNA of Il1β and Nos2, and decreased CD45[+] leukocyte infiltration in the placenta following IUI. Furthermore, we found that DNAC altered placental immune profile by stimulating macrophages to change to the M2 phenotype while decreasing the M1 phenotype, thus suppressing the inflammatory responses in the placenta. Our study provides evidence for DNAC therapy to alleviate IUI via the maintenance of macrophage M1/M2 imbalance in the placenta.}, }
@article {pmid35154590, year = {2021}, author = {Mahmoodzadeh, Y and Mahmoudi, J and Gorgani-Firuzjaee, S and Mohtavinejad, N and Namvaran, A}, title = {Effects of N-acetylcysteine on Noise Exposure-induced Oxidative Stress and Depressive- and Anxiety-like Behaviors in Adult Male Mice.}, journal = {Basic and clinical neuroscience}, volume = {12}, number = {4}, pages = {499-510}, pmid = {35154590}, issn = {2008-126X}, abstract = {INTRODUCTION: Depression and anxiety are the most common psychiatric disorders. These conditions widely occur in industrial societies and severely affect individuals' lives. N-Acetylcysteine (NAC) is a mucolytic compound with antioxidant and anti-inflammatory effects. This study aimed to investigate the potential therapeutic effects of NAC on chronic noise-induced depression- and anxiety-like behaviors in mice.<br><br>METHODS: Fifty male BALB/c mice were randomly divided into 5 groups, as follows: control, noise90 dB, noise110 dB, noise 90+NAC, and noise 110+NAC groups. Animals in the noise groups were exposed to 90 dB 2 h/day and 110 dB 2 h/day for 30 days. The NAC groups received NAC (325 mg/kg P.O.) 20 min after being exposed to noise. To evaluate depressive- and anxiety-like behaviors, the examined mice were subjected to the Open Field Test (OFT), Sucrose Preference Test (SPT), Tail Suspension Test (TST), and Elevated Plus Maze (EPM) tasks. At the end of the behavioral tests, the study animals were sacrificed. Accordingly, the levels of Malondialdehyde (MDA), Total Antioxidant Capacity (TAC), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GPx) were determined in the Hippocampus (HIP) and the Prefrontal Cortex (PFC).<br><br>RESULTS: The obtained results suggested that noise exposure would induce anxiety- and depressive-like behaviors, being reversed by NAC administration. Moreover, chronic administration of NAC significantly increased antioxidant enzyme activities and reduced lipid peroxidation (MDA levels) in the PFC and HIP of noise-exposed mice.<br><br>CONCLUSION: Our findings revealed that administrating NAC would reduce the adverse effects of noise on the brain and would exert anti-depressant and anxiolytic effects.}, }
@article {pmid35153010, year = {2022}, author = {Jin, Z and Hu, G and Zhao, K}, title = {Mannose-anchored quaternized chitosan/thiolated carboxymethyl chitosan composite NPs as mucoadhesive carrier for drug delivery.}, journal = {Carbohydrate polymers}, volume = {283}, number = {}, pages = {119174}, doi = {10.1016/j.carbpol.2022.119174}, pmid = {35153010}, issn = {1879-1344}, mesh = {Acetylcysteine/chemistry ; Administration, Mucosal ; Chemical Phenomena ; Chitosan/analogs &amp; derivatives/*chemistry ; Drug Carriers/administration &amp; dosage/*chemistry ; Drug Delivery Systems/*methods ; Drug Liberation ; HEK293 Cells ; Humans ; Hydrophobic and Hydrophilic Interactions ; Macrophages/drug effects ; Mannose/*chemistry ; Mucins/metabolism ; Nanoparticles/*chemistry ; Particle Size ; }, abstract = {There are various challenges for the mucosal delivery of drug, which is largely attributed to the absence of effective drug carriers that can make delivery to mucosal sites. In the present study, we aimed to synthesize bifunctional mucoadhesive nanoparticles (NPs) that could be used for mucosal delivery. N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (M-N-2-HACC) was modified with D-mannose, and N-acetyl-L-cysteine (NAC) was immobilized on the carboxymethyl chitosan (N-CMCS). The electrostatic interaction between the two substances was used to produce mannose-modified thiolated chitosan NPs (M-N-2-HACC/N-CMCS NPs). The NPs showed a particle size of 196.72 ± 0.45 nm and zeta potential of 17.12 ± 0.50 mV. Moreover, it demonstrated high hydrophilicity, enduring drug release, stability, safety, and mucosal adhesion, which contributed to the effectiveness of mucosal administration. Additionally, the NPs could be instantly absorbed by macrophages. Collectively, these results suggested that M-N-2-HACC/N-CMCS NPs could be used as a promising candidate for mucosal delivery.}, }
@article {pmid35151835, year = {2022}, author = {Wang, X and He, MJ and Chen, XJ and Bai, YT and Zhou, G}, title = {Glaucocalyxin A impairs tumor growth via amplification of the ATF4/CHOP/CHAC1 cascade in human oral squamous cell carcinoma.}, journal = {Journal of ethnopharmacology}, volume = {290}, number = {}, pages = {115100}, doi = {10.1016/j.jep.2022.115100}, pmid = {35151835}, issn = {1872-7573}, mesh = {Activating Transcription Factor 4/*drug effects ; Animals ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Diterpenes, Kaurane/*pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Isodon ; Male ; Mice ; Mice, Inbred BALB C ; Mitochondria/drug effects ; Mouth Neoplasms/*pathology ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Transcription Factor CHOP/*drug effects ; Xenograft Model Antitumor Assays ; gamma-Glutamylcyclotransferase/*drug effects ; }, abstract = {The natural extract glaucocalyxin A (GLA), purified from the aboveground sections of the Chinese traditional medicinal herb Rabdosia japonica (Burm. f.) Hara var. glaucocalyx (Maxim.) Hara, has various pharmacological benefits, such as anti-bacterial, anti-coagulative, anti-neoplastic, and anti-inflammatory activities. Although GLA has shown anti-tumor activity against various cancers, the therapeutic potential and biological mechanisms of GLA remain to be further explored in oral squamous cell carcinoma (OSCC).<br><br>AIM OF THE STUDY: This study aimed to elucidate the therapeutic potential and regulatory mechanisms of GLA in OSCC.<br><br>MATERIALS AND METHODS: The cell proliferation and apoptosis effects of GLA were analyzed by CCK-8, clone formation, Annexin V/PI staining, and apoptotic protein expression in vitro. An OSCC xenograft model was applied to confirm the anti-neoplastic effect in vivo. Furthermore, the changes of reactive oxygen species (ROS) were determined by DCFH-DA probe and GSH/GSSG assay, and inhibited by the pan-caspase inhibitor Z-VAD(OMe)-FMK and the ROS scavenger N-acetylcysteine (NAC). The modulation of GLA on mitochondria and ER-dependent apoptosis pathways was analyzed by JC-1 probe, quantitative real-time PCR, and Western blot. Finally, public databases, clinical samples, and transfection cells were analyzed to explore the importance of GLA's indirect targeting molecule CHAC1 in OSCC.<br><br>RESULTS: GLA significantly inhibited cell proliferation and induced apoptosis in vitro and in vivo. GLA perturbed the redox homeostasis, and cell apoptosis was totally rescued by Z-VAD(OMe)-FMK and NAC. Furthermore, GLA activated the mitochondrial apoptosis pathway. Simultaneously, the overexpression and knockdown of CHAC1 dramatically affected GLA-mediated apoptosis. The endoplasmic reticulum stress-associated ATF4/CHOP signal was identified to participate in GLA-upregulated CHAC1 expression. Finally, we found that CHAC1 expression was lower in OSCC compared with normal tissues and positively correlated with 4-Hydroxynonenal (4-HNE) level. High CHAC1 expression also indicated better overall survival. Moreover, CHAC1 selectively regulated the viability of oral cancer cells.<br><br>CONCLUSION: GLA is a promising therapeutic agent that activates the ROS-mediated ATF4/CHOP/CHAC1 axis in OSCC patients.}, }
@article {pmid35151470, year = {2022}, author = {Zhang, B and Ma, X and Loor, JJ and Jiang, Q and Guo, H and Zhang, W and Li, M and Lv, X and Yin, Y and Wen, J and Wang, J and Xu, C and Yang, W}, title = {Role of ORAI calcium release-activated calcium modulator 1 (ORAI1) on neutrophil extracellular trap formation in dairy cows with subclinical hypocalcemia.}, journal = {Journal of dairy science}, volume = {105}, number = {4}, pages = {3394-3404}, doi = {10.3168/jds.2021-21044}, pmid = {35151470}, issn = {1525-3198}, mesh = {Animals ; Calcium ; Cattle ; *Cattle Diseases ; *Extracellular Traps/metabolism ; Female ; *Hypocalcemia/veterinary ; Lactation ; Neutrophils/metabolism ; ORAI1 Protein/genetics ; }, abstract = {Hypocalcemia in dairy cows is associated with decreased neutrophil phagocytosis, adhesion capacity, migration, and reactive oxygen species (ROS) production through alterations in ORAI calcium release-activated calcium modulator 1 (ORAI1). Neutrophils can resist the invasion of pathogenic microorganisms by releasing neutrophil extracellular traps (NET). However, the mechanisms controlling NET formation during hypocalcemia are unknown. To address the role of ORAI1 in NET formation, neutrophils were isolated at 2 d postcalving from lactating Holstein dairy cows (n = 10 per group) diagnosed as clinically healthy (control) or with plasma concentrations of Ca[2+] <2.0 mmol/L as a criterion for diagnosing subclinical hypocalcemia (SCH). A series of ex vivo experiments were conducted as follows: first, neutrophils isolated from both groups of cows were treated with phorbol 12-myristate 13-acetate (PMA) to stimulate NET formation; second, neutrophils from control and SCH were pretreated with or without the ROS scavenger N-acetylcysteine (NAC), the sarcoendoplasmic Ca[2+] ATPase inhibitor thapsigargin, or ORAI1 blocker 2APB and then treated with PMA to stimulate NET formation; and third, neutrophils were transfected with small interfering (si)ORAI1 or nontarget siRNA (siNEG) and then stimulated with PMA to induce formation of NET. A one-way ANOVA was used for statistical analysis of individual experiments. In the first experiment, neutrophils from SCH cows formed NET with fewer DNA filaments, more diffused nuclei, and reduced translocation of myeloperoxidase (MPO) and neutrophil elastase (NE) to the nucleus. Neutrophils from SCH cows stimulated with PMA had a lower mitochondrial permeability, the state of mitochondrial permeability transition pore was open, ROS production was lower and there was increased mitochondrial damage. In the second experiment, in both control and SCH-PMA stimulated neutrophils, exogenous NAC decreased NET formation (assessed via Hoechst 33342 dye; Beyotime). Furthermore, following the challenge with PMA, thapsigargin increased NET formation and ROS production, but blocking ORAI1 with 2APB decreased NADPH oxidase activation, ROS production, and NET formation. In the third experiment, neutrophils transfected with siORAI1 before stimulation with PMA had lower intracellular concentrations of Ca[2+], NET formation, and ROS production. Overall, the data indicated that SCH reduces NET formation in neutrophils partly due to damaged mitochondria. The reduction in ORAI1 abundance in neutrophils of dairy cows with hypocalcemia also decreases ROS production.}, }
@article {pmid35148231, year = {2022}, author = {Joyjamras, K and Chaotham, C and Chanvorachote, P}, title = {Response surface optimization of enzymatic hydrolysis and ROS scavenging activity of silk sericin hydrolysates.}, journal = {Pharmaceutical biology}, volume = {60}, number = {1}, pages = {308-318}, pmid = {35148231}, issn = {1744-5116}, mesh = {Antioxidants/*pharmacology ; Cell Line, Tumor ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; HaCaT Cells ; Humans ; Hydrogen-Ion Concentration ; Hydrolysis/drug effects ; Keratinocytes/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Sericins/*pharmacology ; Subtilisins/metabolism ; Temperature ; }, abstract = {CONTEXT: Sericin, a protein found in wastewater from the silk industry, was shown to contain a variety of biological activities, including antioxidant. The enzymatic conditions have been continuously modified to improve antioxidant effect and scavenging capacity against various free radicals of silk sericin protein.<br><br>OBJECTIVE: Variables in enzymatic reactions, including pH, temperature and enzyme/substrate ratio were analysed to discover the optimum conditions for antioxidant activity of sericin hydrolysates.<br><br>MATERIALS AND METHODS: Hydrolysis reaction catalysed by Alcalase[&#xae;] was optimized through response surface methodology (RSM) in order to generate sericin hydrolysates possessing potency for % inhibition on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, ferric-reducing power and peroxyl scavenging capacity. Flow cytometry was performed to evaluate cellular ROS level in human HaCaT keratinocytes and melanin-generating MNT1 cells pre-treated either with 20&#x2009;mg/mL RSM-optimized sericin hydrolysates or 5&#x2009;mM N-acetyl cysteine (NAC) for 60&#x2009;min prior exposure with 1&#x2009;mM hydrogen peroxide (H2O2).<br><br>RESULTS: Among these three variables, response surface plots demonstrate the major role of temperature on scavenging capacity of sericin hydrolysates. Sericin hydrolysates prepared by using Alcalase[&#xae;] at RSM-optimized condition (enzyme/substrate ratio: 1.5, pH: 7.5, temperature: 70&#x2009;&#xb0;C) possessed % inhibition against H2O2 at 99.11&#x2009;&#xb1;&#x2009;0.54% and 73.25&#x2009;&#xb1;&#x2009;8.32% in HaCaT and MNT1 cells, respectively, while pre-treatment with NAC indicated the % inhibition only at 30.26&#x2009;&#xb1;&#x2009;7.62% in HaCaT and 51.05&#x2009;&#xb1;&#x2009;7.14% in MNT1 cells.<br><br>DISCUSSION AND CONCLUSIONS: The acquired RSM information would be of benefit for further developing antioxidant peptide from diverse resources, especially the recycling of waste products from silk industry.}, }
@article {pmid35142656, year = {2022}, author = {Jiang, SX and Hussaini, T and Yoshida, EM}, title = {N-acetylcysteine for non-acetaminophen induced acute liver failure: A review.}, journal = {Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association}, volume = {28}, number = {2}, pages = {85-91}, pmid = {35142656}, issn = {1998-4049}, mesh = {Acetaminophen/adverse effects ; Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/pharmacology/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy ; Humans ; *Liver Failure, Acute/chemically induced/drug therapy ; Mice ; Prospective Studies ; }, abstract = {The use of N-acetylcysteine (NAC) for non-acetaminophen-induced acute liver failure (NAI-ALF) has been increasing despite controversy in its efficacy. National guidelines are in disagreement for NAC use as standard of care; however, many healthcare centers continue to adopt the use of NAC outside of acetaminophen poisoning. While NAC may have multiple mechanisms of action in treatment of ALF, this has not translated to clinical benefit. Murine models have reported antioxidant and anti-inflammatory properties, as well as improvement in liver-specific microcirculation. Multiple case studies and series have reported positive outcomes of NAC treatment for ALF of various etiologies. While prospective studies suggested the benefit of NAC treatment, these studies have methodological and statistical shortcomings that affect the validity of the results. In this review, we aimed to summarize the existing literature on the efficacy of NAC for NAI-ALF including mechanism of action, case studies and series demonstrating outcomes, and prospective studies that have led to its current widespread use, along with the reported rate of adverse events.}, }
@article {pmid35140209, year = {2022}, author = {Kang, D and Lee, J and Jung, J and Carlson, BA and Chang, MJ and Chang, CB and Kang, SB and Lee, BC and Gladyshev, VN and Hatfield, DL and Lee, BJ and Kim, JH}, title = {Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis.}, journal = {Nature communications}, volume = {13}, number = {1}, pages = {779}, pmid = {35140209}, issn = {2041-1723}, mesh = {Aging ; Animals ; Cartilage, Articular/metabolism ; Chondrocytes/metabolism ; Disease Models, Animal ; *Homeostasis ; Male ; Mice ; Mice, Knockout ; Osteoarthritis/*genetics/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Phosphotransferases/*deficiency/*genetics ; Reactive Oxygen Species ; Selenium/metabolism ; Selenoproteins ; Transcriptome ; }, abstract = {Aging and mechanical overload are prominent risk factors for osteoarthritis (OA), which lead to an imbalance in redox homeostasis. The resulting state of oxidative stress drives the pathological transition of chondrocytes during OA development. However, the specific molecular pathways involved in disrupting chondrocyte redox homeostasis remain unclear. Here, we show that selenophosphate synthetase 1 (SEPHS1) expression is downregulated in human and mouse OA cartilage. SEPHS1 downregulation impairs the cellular capacity to synthesize a class of selenoproteins with oxidoreductase functions in chondrocytes, thereby elevating the level of reactive oxygen species (ROS) and facilitating chondrocyte senescence. Cartilage-specific Sephs1 knockout in adult mice causes aging-associated OA, and augments post-traumatic OA, which is rescued by supplementation of N-acetylcysteine (NAC). Selenium-deficient feeding and Sephs1 knockout have synergistic effects in exacerbating OA pathogenesis in mice. Therefore, we propose that SEPHS1 is an essential regulator of selenium metabolism and redox homeostasis, and its dysregulation governs the progression of OA.}, }
@article {pmid35133468, year = {2022}, author = {Esalatmanesh, K and Jamali, A and Esalatmanesh, R and Soleimani, Z and Khabbazi, A and Malek Mahdavi, A}, title = {Effects of N-acetylcysteine supplementation on disease activity, oxidative stress, and inflammatory and metabolic parameters in rheumatoid arthritis patients: a randomized double-blind placebo-controlled trial.}, journal = {Amino acids}, volume = {54}, number = {3}, pages = {433-440}, pmid = {35133468}, issn = {1438-2199}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; *Arthritis, Rheumatoid/drug therapy ; Biomarkers ; C-Reactive Protein ; Dietary Supplements ; Double-Blind Method ; Humans ; Oxidative Stress ; }, abstract = {Considering the importance of inflammation and oxidative stress in the development of rheumatoid arthritis (RA) as well as anti-inflammatory and antioxidant features of N-acetylcysteine (NAC), this study was conducted to evaluate the effect of NAC supplementation on disease activity, oxidative stress, and inflammatory and metabolic parameters in RA patients. In a randomized double-masked placebo-controlled trial, 74 RA subjects were chosen and randomly divided into two groups to take 600 mg of NAC or placebo twice daily for 3 months. Before and after the study, disease activity was assessed via disease activity score-28 (DAS-28), and serum malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (GPX) activity, nitric oxide (NO), high-sensitivity C-reactive protein (hs-CRP), fasting blood sugar (FBS), lipid profile, and erythrocyte sedimentation rate (ESR) were measured. Seventy patients completed the trial. Compared to baseline, NAC significantly reduced morning stiffness (P < 0.001), DAS-28 (P < 0.001), ESR (P = 0.004), MDA (P < 0.001), NO (P < 0.001), hs-CRP (P = 0.006), FBS (P < 0.001), and low-density lipoprotein cholesterol (LDL-C) (P = 0.023) and significantly increased GPx activity (P = 0.015) and high-density lipoprotein cholesterol (HDL-C) level (P = 0.001). After treatment, remarkable differences were only seen between the two groups in serum NO (P = 0.003), FBS (P = 0.010), and HDL-C (P < 0.001) adjusted for baseline measures. There were no significant changes in morning stiffness, DAS-28, ESR, hs-CRP, MDA, TAC, GPx activity, triglyceride, total cholesterol, and LDL-C levels compared to the placebo group. In conclusion, NAC did not improve RA disease activity, but reduced NO and FBS and increased HDL-C levels. It appears that NAC should not be consumed as a replacement for routine medications prescribed in RA therapy, but it can be used as an adjunctive therapy.}, }
@article {pmid35132919, year = {2022}, author = {Hussein, RM and Kandeil, MA and Mohammed, NA and Khallaf, RA}, title = {Evaluation of the hepatoprotective effect of curcumin-loaded solid lipid nanoparticles against paracetamol overdose toxicity: Role of inducible nitric oxide synthase.}, journal = {Journal of liposome research}, volume = {32}, number = {4}, pages = {365-375}, doi = {10.1080/08982104.2022.2032737}, pmid = {35132919}, issn = {1532-2394}, mesh = {Animals ; Rats ; *Curcumin/pharmacology ; Liposomes ; Acetaminophen ; Nitric Oxide Synthase Type II ; Rats, Wistar ; *Nanoparticles ; Acetylcysteine ; }, abstract = {Curcumin (Cur) is a natural compound that exhibited therapeutic effects against various liver injuries however Cur showed poor water solubility and bioavailability. This study aimed to design Cur-loaded solid lipid nanoparticles (SLNs) and to evaluate the hepatoprotective and antioxidant effects in a model of acute hepatotoxicity induced by paracetamol (PCM) overdose compared to the raw Cur and N-acetylcysteine (NAC). SLNs were prepared by emulsion/solvent evaporation method and 3[2] factorial design was employed. Wistar rats were divided into Control, PCM, PCM + NAC, PCM + raw Cur, and PCM + Cur-SLNs groups and treated orally for 14 days before receiving a single PCM dose. The Cur-loaded SLNs showed high entrapment efficiency % ranging between 69.1 and 92.1%, particle size (PS) between 217 and 506 nm, and zeta potential values between -17.9 and -25.5 mV. The in vivo results revealed that the PCM group exhibited deterioration of liver functions, pathological lesions on the liver tissues, severe oxidative stress, and increases in both the serum and hepatic iNOS levels. Remarkably, the PCM + Cur-SLNs group showed significantly better liver functions and tissue integrity compared to the PCM group. Furthermore, higher reduced glutathione and catalase but lower malondialdehyde and iNOS levels were observed. In conclusion, Cur-loaded SLNs effectively prevented the liver damage induced by PCM overdose through alleviating the oxidative stress and inhibiting the serum and hepatic iNOS expression in an effect comparable to NAC and better than raw Cur.}, }
@article {pmid35129469, year = {2022}, author = {Lee, JV and Engel, C and Tay, S and DeSilva, G and Desai, K and Cashin, J and Semenkovich, CF and Zayed, MA}, title = {Impact of N-Acetyl-Cysteine on Ischemic Stumps Following Major Lower Extremity Amputation: A Pilot Randomized Clinical Trial.}, journal = {Annals of surgery}, volume = {276}, number = {5}, pages = {e302-e310}, pmid = {35129469}, issn = {1528-1140}, support = {R01 DK101392/DK/NIDDK NIH HHS/United States ; P30 DK020579/DK/NIDDK NIH HHS/United States ; R01 HL157154/HL/NHLBI NIH HHS/United States ; R01 HL153262/HL/NHLBI NIH HHS/United States ; K08 HL132060/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Amputation, Surgical ; *Amputation Stumps/surgery ; Humans ; Ischemia/etiology/surgery ; Lower Extremity/surgery ; *Peripheral Arterial Disease/surgery ; Pilot Projects ; Risk Factors ; Treatment Outcome ; }, abstract = {OBJECTIVE: To evaluate the impact of N-acetyl-cysteine (NAC) on amputation stump perfusion and healing in patients with critical limb-threatening ischemia (CLTI).<br><br>BACKGROUND: Patients with CLTI are at increased risk of poor amputation site healing leading to increased procedure-associated morbidity.<br><br>METHODS: In a pilot, double-blind, placebo-controlled, randomized controlled trial, patients with CLTI undergoing major elective lower extremity amputation were randomized 1:1 to intravenous NAC (1200 mg twice-daily) or placebo for up to 5 days postoperatively. Primary outcomes were change in stump perfusion at postoperative day 3 (POD3) and POD5, and healing at POD30. Stumps were serially evaluated for wound healing, and tissue perfusion was evaluated using noninvasive laser-assisted fluorescent angiography.<br><br>RESULTS: Thirty-three patients were randomized to NAC (n = 16) or placebo (n = 17). Thirty-one patients were eligible for intent-to-treat analysis (NAC14; placebo17). Twenty patients (NAC7; placebo13) had amputation stump perfusion defects at POD0 and were considered high-risk for poor healing. Intent-to-treat analysis revealed no significant differences between treatment groups. Subgroup analysis of high-risk patients revealed differences in stump perfusion defect size (NAC-0.53-fold, placebo +0.71-fold; 95% confidence interval -2.11 to-0.35; P < 0.05) and healing (NAC [100%], placebo [46%]; P < 0.01) between study treatments.<br><br>CONCLUSIONS: Postoperative NAC administration may improve amputation stump perfusion and healing in patients with CLTI and tissue perfusion defects at the time of amputation. Intraoperative laser-assisted fluorescent angiogra-phy may help surgeons identify high-risk patients with stump perfusion defects and provide early adjunctive interventions. Future studies can further explore the therapeutic benefits of NAC in the healing and perfusion of other surgical operative sites in high-risk individuals.<br><br>TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT03253328.}, }
@article {pmid35128081, year = {2022}, author = {Pfaff, A and Chernatynskaya, A and Vineyard, H and Ercal, N}, title = {Thiol antioxidants protect human lens epithelial (HLE B-3) cells against tert-butyl hydroperoxide-induced oxidative damage and cytotoxicity.}, journal = {Biochemistry and biophysics reports}, volume = {29}, number = {}, pages = {101213}, pmid = {35128081}, issn = {2405-5808}, support = {R15 EY029813/EY/NEI NIH HHS/United States ; }, abstract = {Oxidative damage to lens epithelial cells plays an important role in the development of age-related cataract, and the health of the lens has important implications for overall ocular health. As a result, there is a need for effective therapeutic agents that prevent oxidative damage to the lens. Thiol antioxidants such as tiopronin or N-(2-mercaptopropionyl)glycine (MPG), N-acetylcysteine amide (NACA), N-acetylcysteine (NAC), and exogenous glutathione (GSH) may be promising candidates for this purpose, but their ability to protect lens epithelial cells is not well understood. The effectiveness of these compounds was compared by exposing human lens epithelial cells (HLE B-3) to the chemical oxidant tert-butyl hydroperoxide (tBHP) and treating the cells with each of the antioxidant compounds. MTT cell viability, apoptosis, reactive oxygen species (ROS), and levels of intracellular GSH, the most important antioxidant in the lens, were measured after treatment. All four compounds provided some degree of protection against tBHP-induced oxidative stress and cytotoxicity. Cells treated with NACA exhibited the highest viability after exposure to tBHP, as well as decreased ROS and increased intracellular GSH. Exogenous GSH also preserved viability and increased intracellular GSH levels. MPG scavenged significant amounts of ROS, and NAC increased intracellular GSH levels. Our results suggest that both scavenging ROS and increasing GSH may be necessary for effective protection of lens epithelial cells. Further, the compounds tested may be useful for the development of therapeutic strategies that aim to prevent oxidative damage to the lens.}, }
@article {pmid35125047, year = {2022}, author = {Yurttaş, GN and Özdemir, ZC and Tanrıkut, C and Kar, E and Küskü Kiraz, Z and Alataş, &#xd6; and Dönmez, DB and Bör, &#xd6;}, title = {The effects of N-acetylcysteine on experimentally created l-asparaginase-induced liver and pancreatic damage in rats.}, journal = {Leukemia &amp; lymphoma}, volume = {63}, number = {6}, pages = {1445-1454}, doi = {10.1080/10428194.2022.2030474}, pmid = {35125047}, issn = {1029-2403}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; *Asparaginase/pharmacology ; Glutathione/metabolism/pharmacology ; Humans ; Liver ; Male ; Oxidative Stress ; Pancreas/metabolism ; Rats ; Rats, Wistar ; }, abstract = {In this study, oxidative stress marker (malondialdehyde, MDA) and antioxidant enzymes (glutathione (GSH), catalase (CAT)) levels in the liver and pancreas tissue and the histopathological effects of N-acetylcysteine (NAC) were investigated in l-asparaginase (l-ASP) induced liver and pancreatic damage in rats. Forty male albino rats were divided into four groups. The control group was intraperitoneally injected physiological saline (0.02 mL/g); NAC group was injected NAC (200 mg/kg, five days); l-ASP group was injected single-dose l-ASP (10,000 U/kg), and l-ASP + NAC group was injected NAC for five days following single-dose l-ASP (10,000 U/kg). The surgical operation was performed on all animals on the fifth day. There was no difference between the groups regarding tissue MDA, GSH, and CAT levels (p>.05, for all). In the group receiving NAC after l-ASP, there was a significant improvement in the liver and pancreas damage score than the l-ASP group. NAC was effective in reducing organ damage caused by l-ASP.}, }
@article {pmid35124906, year = {2021}, author = {Ijaz, N and Waheed, A and Tayyab, M and Mumal, S and Iftikhar, R and Rehman, A and Akram, E}, title = {Reno Protective Role Of N Acetyl Cysteine And Aqueous Extract Of Berberis Lycium Royale Root Bark On Rats.}, journal = {Journal of Ayub Medical College, Abbottabad : JAMC}, volume = {33}, number = {4}, pages = {553-557}, pmid = {35124906}, issn = {1819-2718}, mesh = {Acetylcysteine ; Animals ; *Berberis ; Kidney ; *Lycium ; Plant Bark ; Plant Extracts/pharmacology ; Rats ; Rats, Wistar ; Uric Acid ; Water ; }, abstract = {BACKGROUND: N acetyl cysteine and Berberis lycium Royale root bark have been used to treat kidney diseases. Objectives of the study were to evaluate the individual and combined effect of N acetyl cysteine and aqueous extract of Berberis lycium Royale root bark in Gentamicin induced nephrotoxicity in rats. This randomized control trial conducted at Islamic International Medical College, Rawalpindi in collaboration with NIH, Islamabad in 1 month from Sep to Oct 2020.<br><br>METHODS: Fifty Wister albino rats of 10-12 weeks old were divided into five groups with 10 in each group. Group 1 was normal control given food and water only and remaining 40 were in treatment groups. Nephrotoxicity was induced by intraperitoneal injection of Gentamicin (80mg/kg) for 6 days in group 2, 3, 4 and 5. After induction of nephrotoxicity, Group 3 was administered N acetyl cysteine 140mg/kg per oral, Group 4 was given aqueous extract of Berberis lycium Royale root bark 400 mg/kg per oral and Group 5 was given both N acetyl cysteine 140mg/kg per oral and aqueous extract of Berberis lycium Royale root bark 400 mg/kg per oral for 21 days. Serum uric acid was measured in all groups after 30 days to observe the reversal of renal injury.<br><br>RESULTS: The results of this study indicate that Group 3, Group 4 and Group 5 showed a decrease in serum uric acid level as compared to Disease Control Group (Group 2). However, Group 5 significantly reduced uric acid (p-0.05).<br><br>CONCLUSIONS: Combined effect of N acetyl cysteine and aqueous extract of Berberis lycium Royale root bark showed improvement in uric acid level in Gentamicin induced nephrotoxicity in rats.}, }
@article {pmid35123994, year = {2022}, author = {Thompson, B and Davidson, EA and Chen, Y and Orlicky, DJ and Thompson, DC and Vasiliou, V}, title = {Oxidative stress induces inflammation of lens cells and triggers immune surveillance of ocular tissues.}, journal = {Chemico-biological interactions}, volume = {355}, number = {}, pages = {109804}, pmid = {35123994}, issn = {1872-7786}, support = {P30 EY026878/EY/NEI NIH HHS/United States ; TL1 TR001864/TR/NCATS NIH HHS/United States ; K01 AA025093/AA/NIAAA NIH HHS/United States ; R01 EY022313/EY/NEI NIH HHS/United States ; R01 EY017963/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Chemokine CCL7/genetics/metabolism ; Cytokines/genetics/metabolism ; Down-Regulation/drug effects ; Epithelial Cells/cytology/metabolism ; Epithelial-Mesenchymal Transition/genetics ; Eye/*anatomy &amp; histology/metabolism ; Glutamate-Cysteine Ligase/deficiency/genetics ; *Immunity, Innate ; Lens, Crystalline/cytology/*metabolism ; Leukocytes/cytology/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Up-Regulation/drug effects ; }, abstract = {Recent reports have challenged the notion that the lens is immune-privileged. However, these studies have not fully identified the molecular mechanism(s) that promote immune surveillance of the lens. Using a mouse model of targeted glutathione (GSH) deficiency in ocular surface tissues, we have investigated the role of oxidative stress in upregulating cytokine expression and promoting immune surveillance of the eye. RNA-sequencing of lenses from postnatal day (P) 1-aged Gclc[f/f];Le-Cre[Tg/-] (KO) and Gclc[f/f];Le-Cre[-/-] control (CON) mice revealed upregulation of many cytokines (e.g., CCL4, GDF15, CSF1) and immune response genes in the lenses of KO mice. The eyes of KO mice had a greater number of cells in the aqueous and vitreous humors at P1, P20 and P50 than age-matched CON and Gclc[w/w];Le-Cre[Tg/-] (CRE) mice. Histological analyses revealed the presence of innate immune cells (i.e., macrophages, leukocytes) in ocular structures of the KO mice. At P20, the expression of cytokines and ROS content was higher in the lenses of KO mice than in those from age-matched CRE and CON mice, suggesting that oxidative stress may induce cytokine expression. In vitro administration of the oxidant, hydrogen peroxide, and the depletion of GSH (using buthionine sulfoximine (BSO)) in 21EM15 lens epithelial cells induced cytokine expression, an effect that was prevented by co-treatment of the cells with N-acetyl-l-cysteine (NAC), a antioxidant. The in vivo and ex vivo induction of cytokine expression by oxidative stress was associated with the expression of markers of epithelial-to-mesenchymal transition (EMT), α-SMA, in lens cells. Given that EMT of lens epithelial cells causes posterior capsule opacification (PCO), we propose that oxidative stress induces cytokine expression, EMT and the development of PCO in a positive feedback loop. Collectively these data indicate that oxidative stress induces inflammation of lens cells which promotes immune surveillance of ocular structures.}, }
@article {pmid35123993, year = {2022}, author = {Yang, X and Li, C and Yu, G and Sun, L and Guo, S and Sai, L and Bo, C and Xing, C and Shao, H and Peng, C and Jia, Q}, title = {Ligand-independent activation of AhR by hydroquinone mediates benzene-induced hematopoietic toxicity.}, journal = {Chemico-biological interactions}, volume = {355}, number = {}, pages = {109845}, doi = {10.1016/j.cbi.2022.109845}, pmid = {35123993}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Basic Helix-Loop-Helix Transcription Factors/chemistry/genetics/*metabolism ; Benzene/toxicity ; Cell Line ; Cell Survival/drug effects ; Cytochrome P-450 CYP1A1/genetics/metabolism ; DNA Damage/drug effects ; HSP90 Heat-Shock Proteins/genetics/metabolism ; Humans ; Hydroquinones/*pharmacology ; *Ligands ; Lymphocytes/cytology/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/chemistry/genetics/*metabolism ; }, abstract = {Although it has been well recognized that benzene exposure can cause hematopoietic disorders such as aplastic anemia and leukemia, the underlying molecular mechanism remains to be fully understood. Emerging evidence indicated that aryl hydrocarbon receptor (AhR) plays important roles in hematopoietic and immune systems. This study investigated the activation of aryl hydrocarbon receptor (AhR) by hydroquinone (HQ) and its role in HQ-induced DNA damage and apoptosis in cultured human lymphocytes (JHP cells). We also investigated the effect of ROS on AhR activation and functions in JHP cells exposed to HQ with and without regulator including N-acetyl-l-cysteine (NAC), a potent antioxidant, and tert-butylhydroquinone (TBHQ), a Nrf2 activator. Results showed that HQ can cause oxidative stress, DNA damage and apoptosis. Pretreatment of an AhR antagonist (CH223191) can significantly increase the cell survival and mitigate HQ-induced toxicities such as DNA damage and apoptosis. We found that HQ can obviously increase expressions of total protein of AhR and prompt nuclear translocation compared to the control group. Interestingly, NAC can block HQ-induced AhR activation and DNA damage and apoptosis. Conclusively, our results indicated that HQ toxicity is mediated by AhR which is in turn regulated by ROS generated by HQ. The interaction between AhR and ROS drive and amplify the hematopoietic toxicity of HQ. This study provided new insights of mechanism and potential targets for the prevention and treatment to benzene-induced hematopoietic toxicity.}, }
@article {pmid35123263, year = {2022}, author = {Murae, M and Shimizu, Y and Yamamoto, Y and Kobayashi, A and Houri, M and Inoue, T and Irie, T and Gemba, R and Kondo, Y and Nakano, Y and Miyazaki, S and Yamada, D and Saitoh, A and Ishii, I and Onodera, T and Takahashi, Y and Wakita, T and Fukasawa, M and Noguchi, K}, title = {The function of SARS-CoV-2 spike protein is impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive N-acetyl-cysteine and glutathione.}, journal = {Biochemical and biophysical research communications}, volume = {597}, number = {}, pages = {30-36}, pmid = {35123263}, issn = {1090-2104}, abstract = {Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor angiotensin converting enzyme-2 (ACE2) via its receptor-binding domain (RBD). The cysteine residue at position 488, consisting of a disulfide bridge with cysteine 480 is located in an important structural loop at ACE2-binding surface of RBD, and is highly conserved among SARS-related coronaviruses. We showed that the substitution of Cys-488 with alanine impaired pseudotyped SARS-CoV-2 infection, syncytium formation, and cell-cell fusion triggered by SARS-CoV-2 spike expression. Consistently, in vitro binding of RBD and ACE2, spike-mediated cell-cell fusion, and pseudotyped viral infection of VeroE6/TMPRSS2 cells were inhibited by the thiol-reactive compounds N-acetylcysteine (NAC) and a reduced form of glutathione (GSH). Furthermore, we demonstrated that the activity of variant spikes from the SARS-CoV-2 alpha and delta strains were also suppressed by NAC and GSH. Taken together, these data indicate that Cys-488 in spike RBD is required for SARS-CoV-2 spike functions and infectivity, and could be a target of anti-SARS-CoV-2 therapeutics.}, }
@article {pmid35122928, year = {2022}, author = {Ou, YC and Li, JR and Wu, CC and Yu, TM and Chen, WY and Liao, SL and Kuan, YH and Chen, YF and Chen, CJ}, title = {Cadmium induces the expression of Interleukin-6 through Heme Oxygenase-1 in HK-2 cells and Sprague-Dawley rats.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {161}, number = {}, pages = {112846}, doi = {10.1016/j.fct.2022.112846}, pmid = {35122928}, issn = {1873-6351}, mesh = {Acetylcysteine ; Animals ; Antioxidants/pharmacology ; Cadmium Chloride/*toxicity ; Carbazoles ; Cell Line ; Cell Survival/drug effects ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation/*drug effects ; Heme Oxygenase (Decyclizing)/genetics/*metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Interleukin-6/genetics/*metabolism ; Kidney Diseases/chemically induced ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress/drug effects ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Cadmium is toxic to the kidney through mechanisms involving oxidative stress and inflammation. We studied reciprocal crosstalk among the oxidative stress, inflammation, and the nuclear Nrf2 pathway in cadmium-induced nephrotoxicity on HK-2 human renal proximal tubular epithelial cells. Cadmium chloride (CdCl2) caused cell viability loss, Reactive Oxygen Species (ROS) generation, glutathione reduction, and Interleukin-6 (IL-6) expression, accompanied by Nrf2 activation and Heme Oxygenase-1 (HO-1) expression. Pharmacological treatments demonstrated cytotprotective and anti-inflammatory effects of Nrf2 activation. Intriguingly, inhibition of HO-1 activity mitigated cell viability loss and IL-6 expression in CdCl2-treated cells. Parallel attenuation by HO-1 inhibitor was demonstrated in cadmium-induced ROS generation and glutathione reduction. CdCl2-treated cells also increased levels of ferrous iron, cGMP, Mitogen-Activated Protein Kinases phosphorylation, as well as NF-κB DNA-binding activity. These increments were mitigated by antioxidant N-Acetyl Cysteine, HO-1 inhibitor SnPP, and PKG inhibitor KT5823, and were mimicked by the Carbon Monoxide-releasing compound. In the kidney cortex of CdCl2-exposed Sprague-Dawley rats, we found similar renal injury, histological changes, ROS generation, IL-6 expression, and accompanied pro-oxidant and pro-inflammatory changes. These observations indicated that cadmium-induced nephrotoxicity was associated with oxidative stress and inflammation, and HO-1 likely acts as a linking molecule to induce nephrotoxicity-associated IL-6 expression upon cadmium exposure.}, }
@article {pmid35122656, year = {2022}, author = {Chapela, SP and Burgos, HI and Stella, CA}, title = {N-Acetyl cysteine improves cellular growth in respiratory-deficient yeast.}, journal = {Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]}, volume = {53}, number = {2}, pages = {791-794}, pmid = {35122656}, issn = {1678-4405}, mesh = {*Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Oxidative Stress ; Reactive Oxygen Species ; *Saccharomyces cerevisiae/genetics ; }, abstract = {BACKGROUND: Reactive oxygen species (ROS) is a main factor that alters cellular physiology and functionality. Many strategies are used in order to control excessive oxidative stress. One strategy includes the use of antioxidants like N-acetyl cysteine (NAC). The aim of this study was to compare the effect of this antioxidant on ROS production and cellular growth of a wild-type and a respiratory-deficient Saccharomyces cerevisiae strain.<br><br>METHODS: Using a simple system such as yeast allows oxidative stress investigations on which numerous factors are more manageable or circumscribed than in a higher organism. We grew cells in a complex medium and incubated them during 72&#xa0;h. Later, cellular viability and ROS production was evaluated. ROS level was estimated by use of fluorescence signal with 2',7'-dichlorofluorescein diacetate (DCFH-DA).<br><br>RESULTS: As it is found in the present work, a reducing environment exerted by NAC presence during incubation of the cells allows a respiratory-deficient Saccharomyces cerevisiae strain to improve its cellular growth.<br><br>CONCLUSIONS: It seems likely that the energy production or the phenotype which characterizes a deficient strain is incapable of palliating ROS growth inhibition while NAC helps to overcome this limitation.}, }
@article {pmid35120950, year = {2022}, author = {Paithankar, JG and Kushalan, S and S, N and Hegde, S and Kini, S and Sharma, A}, title = {Systematic toxicity assessment of CdTe quantum dots in Drosophila melanogaster.}, journal = {Chemosphere}, volume = {295}, number = {}, pages = {133836}, doi = {10.1016/j.chemosphere.2022.133836}, pmid = {35120950}, issn = {1879-1298}, mesh = {Animals ; *Cadmium Compounds/chemistry/toxicity ; Drosophila melanogaster ; *Quantum Dots/chemistry/toxicity ; Tellurium/chemistry/toxicity ; }, abstract = {The risk assessment of cadmium (Cd)-based quantum dots (QDs) used for biomedical nanotechnology applications has stern toxicity concerns. Despite cytotoxicity studies of cadmium telluride (CdTe) QDs, the systematic in vivo study focusing on its organismal effects are more relevant to public health. Therefore, the present study aims to investigate the effect of chemically synthesized 3-mercapto propionic acid-functionalized CdTe QDs on organisms' survival, development, reproduction, and behaviour using Drosophila melanogaster as a model. The sub-cellular impact on the larval gut was also evaluated. First/third instar larvae or the adult Drosophila were exposed orally to green fluorescence emitting CdTe QDs (0.2-100 μM), and organisms' longevity, emergence, reproductive performance, locomotion, and reactive oxygen species (ROS), and cell death were assessed. Uptake of semiconductor CdTe QDs was observed as green fluorescence in the gut. A significant decline in percentage survivability up to 80% was evident at high CdTe QDs concentrations (25 and 100 μM). The developmental toxicity was marked by delayed and reduced fly emergence after CdTe exposure. The teratogenic effect was evident with significant wing deformities at 25 and 100 μM concentrations. However, at the reproductive level, adult flies' fecundity, fertility, and hatchability were highly affected even at low concentrations (1 μM). Surprisingly, the climbing ability of Drosophila was unaffected at any of the used CdTe QDs concentrations. In addition to organismal toxicity, the ROS level and cell death were elevated in gut cells, confirming the sub-cellular toxicity of CdTe QDs. Furthermore, we observed a significant rescue in CdTe QDs-associated developmental, reproductive, and survival adversities when organisms were co-exposed with N-acetyl-cysteine (NAC, an antioxidant) and CdTe QDs. Overall, our findings indicate that the environmental release of aqueously dispersible CdTe QDs raises a long-lasting health concern on the development, reproduction, and survivability of an organism.}, }
@article {pmid35117973, year = {2022}, author = {Finsterer, J and Scorza, FA and Scorza, CA and Fiorini, AC}, title = {Repurposing the antioxidant and anti-inflammatory agent N-acetyl cysteine for treating COVID-19.}, journal = {World journal of virology}, volume = {11}, number = {1}, pages = {82-84}, pmid = {35117973}, issn = {2220-3249}, abstract = {Although several considerations have been raised suggesting a beneficial effect of N-acetyl cysteine (NAC) for the treatment of severe acute respiratory syndrome coronavirus 2 infection, there is currently no clinical evidence that NAC truly prevents coronavirus disease 2019 (COVID-19), reduces the severity of the disease, or improves the outcome. Appropriately designed clinical trials are warranted to prove or disprove a therapeutic effect of NAC for COVID-19 patients.}, }
@article {pmid35116094, year = {2022}, author = {Jia, F and Liu, Y and Dou, X and Du, C and Mao, T and Liu, X}, title = {Liensinine Inhibits Osteosarcoma Growth by ROS-Mediated Suppression of the JAK2/STAT3 Signaling Pathway.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8245614}, pmid = {35116094}, issn = {1942-0994}, mesh = {Animals ; Apoptosis/drug effects ; Bone Neoplasms/drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Female ; G1 Phase Cell Cycle Checkpoints/drug effects ; Glutathione/metabolism ; Humans ; Isoquinolines/*pharmacology/therapeutic use ; Janus Kinase 2/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Osteosarcoma/drug therapy/metabolism/pathology ; Phenols/*pharmacology/therapeutic use ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/*drug effects ; Transplantation, Heterologous ; }, abstract = {Osteosarcoma (OS) is the most common malignancy of bone. Liensinine exerts antitumor effects on cancers of the colon, breast, and gallbladder. However, its antitumor activity in OS remains unclear. This study is aimed at investigating the efficacy of liensinine against OS and the underlying mechanism of action. Cell proliferation, apoptosis, and cycle arrest in OS were detected using the Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays, respectively. The production of reactive oxygen species (ROS), glutathione (GSH) and glutathione disulfide (GSSG) concentrations, and mitochondrial membrane potential (MMP) of OS cells were measured by flow cytometry, colorimetry, and JC-1 staining. The expressions of factors related to apoptosis, cell cycle, and activation of the JAK2/STAT3 pathway were determined by Western blotting. To examine the potential role of ROS, an antioxidant (N-acetyl cysteine, NAC) was used in combination with liensinine. In vivo, we generated a xenograft mouse model to assess its antitumor efficacy. Tissue level expressions of factors related to apoptosis and activation of the JAK2/STAT3 pathway were assessed by immunohistochemistry or Western blotting. Liensinine inhibited the proliferation and induced G0/G1 phase arrest and apoptosis of OS cells in a dose-dependent manner. Additionally, liensinine promoted intracellular ROS production, enhanced the GSSG/GSH ratio, and induced MMP loss and ROS-mediated suppression of the JAK2/STAT3 pathway. NAC significantly attenuated the liensinine-induced antitumor activities and activated the JAK2/STAT3 pathway. In vivo, liensinine effectively inhibited the OS growth and promoted apoptosis; however, it had no negative effect on the internal organs. In conclusion, liensinine-induced ROS production could suppress the activation of the JAK2/STAT3 pathway and inhibit the OS growth both in vivo and in vitro. Our findings provided a new rationale for subsequent academic and clinical research on OS treatment.}, }
@article {pmid35113447, year = {2022}, author = {Di Marco, F and Foti, G and Corsico, AG}, title = {Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID-19?.}, journal = {European review for medical and pharmacological sciences}, volume = {26}, number = {2}, pages = {715-721}, doi = {10.26355/eurrev_202201_27898}, pmid = {35113447}, issn = {2284-0729}, mesh = {Acetylcysteine/chemistry/*therapeutic use ; Antioxidants/chemistry ; COVID-19/metabolism/virology ; Glutathione/chemistry/metabolism ; Humans ; Oxidative Stress ; Randomized Controlled Trials as Topic ; Reactive Oxygen Species/metabolism ; SARS-CoV-2/isolation &amp; purification ; Virus Diseases/drug therapy/metabolism ; *COVID-19 Drug Treatment ; }, abstract = {OBJECTIVE: As N-acetylcysteine (NAC) is promising as a re-purposed drug for the adjunctive or supportive treatment of serious COVID-19, this article aimed to describe current evidence.<br><br>MATERIALS AND METHODS: A search was performed in PubMed/Medline for "NAC", "viral Infection", COVID-19", oxidative stress", "inflammation", retrieving preclinical and clinical studies.<br><br>RESULTS: NAC is a pleiotropic molecule with a dual antioxidant mechanism; it may neutralize free radicals and acts as a donor of cysteine, restoring the physiological pool of GSH. Serious COVID-19 patients have increased levels of reactive oxygen species (ROS) and free radicals and often present with glutathione depletion, which prompts a cytokine storm. NAC, which acts as a precursor of GSH inside cells, has been currently used in many conditions to restore or protect against GSH depletion and has a wide safety margin. In addition, NAC has anti-inflammatory activity independently of its antioxidant activity.<br><br>CONCLUSIONS: Clinical and experimental data suggest that NAC may act on the mechanisms leading to the prothrombotic state observed in severe COVID-19.}, }
@article {pmid35112077, year = {2022}, author = {Puri, V and Chaudhary, KR and Singh, A and Singh, C}, title = {Inhalation potential of N-Acetylcysteine loaded PLGA nanoparticles for the management of tuberculosis: In vitro lung deposition and efficacy studies.}, journal = {Current research in pharmacology and drug discovery}, volume = {3}, number = {}, pages = {100084}, pmid = {35112077}, issn = {2590-2571}, abstract = {Several studies have stated that mucus is a critical hurdle for drug delivery to the mucosal tissues. As a result, Polymeric nanoparticles that can overcome mucus barriers are gaining popularity for controlled drug delivery into intra-macrophages to attain high intracellular drug concentration. The present study was aimed to fabricate inhalable N-acetylcysteine (NAC) modified PLGA mucus penetrating particles using the double emulsion method (w/o/w) for target delivery to alveolar macrophages and minimize the dose-related adverse effects, efficiently encapsulate hydrophilic drug, sustain the release profile and prolong the retention time for the management of tuberculosis. Among the numerous formulations, the drug/polymer ratio of 1:10 with 0.50% PVA concentration and sonication time for 2 min s was chosen for further research. The formulated nanoparticles had a mean particle size of 307.50 ± 9.54 nm, PDI was 0.136 ± 0.02, zeta potential about -11.3 ± 0.4 mV, decent entrapment efficiency (55.46 ± 2.40%), drug loading (9.05 ± 0.22%), and excellent flowability. FTIR confirmed that NAC and PLGA were compatible with each other. SEM graphs elucidated that the nanoparticles were spherically shaped with a slightly rough surface whereas TEM analysis ensured the nanometer size nanoparticles and coating of lipid over NPs surface. PXRD spectrum concluded the transformation of the drug from crystalline to amorphous state in the formulation. In vitro release pattern was biphasic started with burst release (64.67 ± 1.53% within 12hrs) followed by sustained release over 48hrs thus enabling the prolonged replenishing of NAC. In vitro lung deposition study pronounced that coated NAC-PLGA-MPPs showed favorable results in terms of emitted dose (86.67 ± 2.52%), MMAD value (2.57 ± 0.12 μm), GSD value (1.55 ± 0.11 μm), and FPF of 62.67 ± 2.08% for the deposition and targeting the lungs. Finally, in vitro efficacy studies demonstrated that NAC-PLGA-MPPs presented more prominent antibacterial activity against MTB H37Rv strain as compared to NAC. Hence, PLGA based particles could be a better strategy to deliver the NAC for lung targeting.}, }
@article {pmid35111421, year = {2021}, author = {Khan, Z and Abumedian, M and Ibekwe, M and Musa, K and Mlawa, G}, title = {Acute Renal Impairment in Patients Due to Paracetamol Overdose in the Absence of Hepatic Impairment.}, journal = {Cureus}, volume = {13}, number = {12}, pages = {e20727}, pmid = {35111421}, issn = {2168-8184}, abstract = {In general, paracetamol poisoning is associated with hepatotoxicity and very rarely with renal impairment in the absence of significant hepatic impairment. Paracetamol poisoning associated with renal impairment is rare, and it is mostly associated with hepatotoxicity. Most patients with acute renal impairment show a pattern of acute tubular necrosis or injury based on their blood, clinical presentation, and imaging. The level of injury was found to be associated with the dose of paracetamol taken. We describe a case of a 22-year-old patient presenting to the hospital with abdominal pain, back pain, and two episodes of vomiting after 36 hours of an intentional paracetamol overdose of 60 tablets. His lab results showed raised creatinine levels and C-reactive protein (CRP) despite normal liver function tests. His paracetamol and salicylate levels were not checked on his initial presentation. He was given N-acetyl cysteine (NAC) treatment for paracetamol overdose and had computed tomography of kidneys, ureters, and bladder (CT KUB) the following day, which showed mild, uncomplicated sigmoid diverticula. He was discharged the next day, but was readmitted two days later with severe abdominal pain and worsening renal function. He had an magnetic resonance imaging (MRI) abdomen that showed coronal/axial wedge like areas of relative hypo-intense change in the T2 acquisition. He received intravenous fluids and antibiotics, and his renal function improved. He was discharged home with outpatient follow-up and appeared to be fully recovered.}, }
@article {pmid35110025, year = {2021}, author = {Kumar, R and Bansal, M and Nath, SS and Kumar, V and Malviya, D and Srivastava, D}, title = {N-Acetylcysteine Supplementation for the Prevention of Postoperative Liver Dysfunction after On-Pump Cardiac Surgery.}, journal = {Turkish journal of anaesthesiology and reanimation}, volume = {49}, number = {6}, pages = {460-469}, pmid = {35110025}, issn = {2667-677X}, abstract = {INTRODUCTION: Incidence of postoperative liver dysfunction continues to be high (ranging from 10-35%) in those who underwent cardiac surgeries using cardiopulmonary bypass (CPB) and is associated with considerable morbidity and mortality. Prolonged cardiopulmonary bypass time (CPBT) was found to be an independent predictor of postoperative liver dysfunction. So, the aim of the study was to evaluate the effect of prophylactic use of N-acetylcysteine (NAC) in patients undergoing on-pump cardiac surgery with expected prolonged CPBT in prevention of liver dysfunction.<br><br>METHODS: 60 consenting adult patients undergoing cardiac surgeries using CPB with CPBT more than 120 mins were included in this single-centre, randomized, parallel-group, double blind interventional study. Study group patients received NAC as per protocol. Liver transferases, alkaline phosphatase, serum bilirubin, kidney function tests and coagulation parameters were measured preoperatively, on the day of surgery and for three days postoperatively.<br><br>RESULTS: Values for serum ALT, AST and ALP were significantly raised in the control group compared to the study group, starting from the day of surgery till 3rd postoperative day. Serum bilirubin level (total and direct) were comparable till first postoperative day and were significantly raised on second and third postoperative days in the control group. Duration of mechanical ventilation, total chest tube drainage, duration of ICU and hospital stay were significantly shorter in study group compared to control group.<br><br>CONCLUSION: Prophylactic intravenous NAC has a protective role in preventing postoperative hepatic dysfunction in patients undergoing cardiac surgery with cardiopulmonary bypass.}, }
@article {pmid35105269, year = {2023}, author = {de Souza, GR and De-Oliveira, ACAX and Soares, V and De-Souza, TP and Barbi, NS and Paumgartten, FJR and da Silva, AJR}, title = {Protective effects of a chemically characterized extract from solanum torvum leaves on acetaminophen-induced liver injury.}, journal = {Drug and chemical toxicology}, volume = {46}, number = {1}, pages = {122-135}, doi = {10.1080/01480545.2021.2012905}, pmid = {35105269}, issn = {1525-6014}, mesh = {Mice ; Animals ; Acetaminophen/toxicity ; *Solanum ; Hydrogen Peroxide/toxicity ; *Chemical and Drug Induced Liver Injury, Chronic ; Plant Extracts ; Mice, Inbred C57BL ; Antioxidants/pharmacology/therapeutic use ; Liver ; Phenols/pharmacology ; Flavonoids/pharmacology/analysis ; *Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control/drug therapy ; }, abstract = {Distinct parts of Solanum torvum Swartz. (Solanaceae) are popularly used for a variety of therapeutic purposes. This study determined the phytochemical composition of a phenolic fraction of S. torvum leaf aqueous extract and investigated its antioxidant and liver-protective properties. A phenolic compound-enriched fraction, or phenolic fraction (STLAE-PF) of an infusion (STLAE) of S. torvum leaves, was tested in vitro (antagonism of H2O2 in cytotoxicity and DCF assays with HepG2/C3A cells), and in vivo for antioxidant activity and protective effects against acetaminophen (APAP)-induced liver injury in mice. Thirty-eight compounds (flavonoids, esters of hydroxycinnamic acid, and chlorogenic acid isomers) were tentatively identified (high-performance liquid chromatography coupled to high-resolution electrospray mass spectrometry) in the STLAE-PF fraction. In vitro assays in HepG2/C3A cells showed that STLAE-PF and some flavonoids contained in this phenolic fraction, at noncytotoxic levels, antagonized in a concentration-dependent manner the effects of a powerful oxidant agent (H2O2). In C57BL/6 mice, oral administration of STLAE (600 and 1,200 mg/kg bw) or STLAE-PF (300 mg/kg bw) prevented the rise in serum transaminases (ALT and AST), depletion of reduced glutathione (GSH) and elevation of thiobarbituric acid reactive species (TBARs) levels in the liver caused by APAP (600 mg/kg bw, i.p.). The hepatoprotective effects of STLAE-PF (300 mg/kg bw) against APAP-caused liver injury were comparable to those of N-acetyl-cysteine (NAC 300 or 600 mg/kg bw i.p.). These findings indicate that a phenolic fraction of S. torvum leaf extract (STLAE-PF) is a new phytotherapeutic agent potentially useful for preventing/treating liver injury caused by APAP overdosing.}, }
@article {pmid35099714, year = {2022}, author = {Okuni, N and Honma, Y and Urano, T and Tamura, K}, title = {Romidepsin and tamoxifen cooperatively induce senescence of pancreatic cancer cells through downregulation of FOXM1 expression and induction of reactive oxygen species/lipid peroxidation.}, journal = {Molecular biology reports}, volume = {49}, number = {5}, pages = {3519-3529}, pmid = {35099714}, issn = {1573-4978}, support = {SUIGAN project//Shimane University/ ; }, mesh = {Animals ; Cell Line, Tumor ; Cell Proliferation ; Cysteine/metabolism ; *Depsipeptides/pharmacology ; Down-Regulation ; *Forkhead Box Protein M1/genetics ; Gene Expression Regulation, Neoplastic ; Humans ; Lipid Peroxidation ; *Pancreatic Neoplasms/drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism ; *Tamoxifen/pharmacology ; alpha-Tocopherol/pharmacology ; }, abstract = {BACKGROUND: Although improvement has been made in therapeutic strategies against pancreatic carcinoma, overall survival has not significantly enhanced over the past decade. Thus, the establishment of better therapeutic regimens remains a high priority.<br><br>METHODS: Pancreatic cancer cell lines were incubated with romidepsin, an inhibitor of histone deacetylase, and tamoxifen, and their effects on cell growth, signaling and gene expression were analyzed. Xenografts of human pancreatic cancer CFPAC1 cells were medicated with romidepsin and tamoxifen to evaluate their effects on tumor growth.<br><br>RESULTS: The inhibition of the growth of pancreatic cancer cells induced by romidepsin and tamoxifen was effectively reduced by N-acetyl cysteine and &#x3b1;-tocopherol, respectively. The combined treatment greatly induced reactive oxygen species production and mitochondrial lipid peroxidation, and these effects were prevented by N-acetyl cysteine and &#x3b1;-tocopherol. Tamoxifen enhanced romidepsin-induced cell senescence. FOXM1 expression was markedly downregulated in pancreatic cancer cells treated with romidepsin, and tamoxifen further reduced FOXM1 expression in cells treated with romidepsin. Siomycin A, an inhibitor of FOXM1, induced senescence in pancreatic cancer cells. Similar results were obtained in knockdown of FOXM1 expression by siRNA.<br><br>CONCLUSION: Since FOXM1 is used as a prognostic marker and therapeutic target for pancreatic cancer, a combination of the clinically available drugs romidepsin and tamoxifen might be considered for the treatment of patients with pancreatic cancer.}, }
@article {pmid35098531, year = {2022}, author = {Sandilands, EA and Rees, JMB and Raja, K and Dhaun, N and Morrison, EE and Hickson, K and Wraight, J and Gray, T and Briody, L and Cameron, S and Thompson, AP and Johnston, NR and Uren, N and Goddard, J and Treweeke, A and Rushworth, G and Webb, DJ and Bateman, DN and Norrie, J and Megson, IL and Eddleston, M}, title = {Acetylcysteine has No Mechanistic Effect in Patients at Risk of Contrast-Induced Nephropathy: A Failure of Academic Clinical Science.}, journal = {Clinical pharmacology and therapeutics}, volume = {111}, number = {6}, pages = {1222-1238}, pmid = {35098531}, issn = {1532-6535}, support = {CZB/4/459/CSO_/Chief Scientist Office/United Kingdom ; }, mesh = {Acetylcysteine/therapeutic use ; Antioxidants ; Contrast Media/adverse effects ; Creatinine ; Cross-Over Studies ; Humans ; *Kidney Diseases ; *Renal Insufficiency, Chronic/drug therapy ; Treatment Outcome ; }, abstract = {Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m[2], P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working.}, }
@article {pmid35094812, year = {2022}, author = {Yamamoto, H and Shibuya, K and Fukushima, T and Hashizume, T}, title = {Effects of antioxidant capacity on micronucleus induction by cigarette smoke in mammalian cells.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {873}, number = {}, pages = {503427}, doi = {10.1016/j.mrgentox.2021.503427}, pmid = {35094812}, issn = {1879-3592}, mesh = {Animals ; *Antioxidants/metabolism ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Glutathione ; Micronucleus Tests ; Rats ; Reactive Oxygen Species ; *Smoke/adverse effects ; Sulfhydryl Compounds ; Nicotiana ; }, abstract = {We have compared micronucleus (MN) induction by cigarette smoke in the L5178Y, TK6, and CHL/IU cell lines. The test sample was total particulate matter of 3R4F reference cigarette smoke, suspended in DMSO. After 3-h treatment, with or without a rat liver S9 metabolic activation system, followed by 24-h recovery, dose-dependent MN increases were seen in all cell lines. However, CHL/IU and TK6 cells were more resistant than L5178Y cells (comparison by Benchmark Doses with PROAST software). 3R4F smoke generates reactive oxygen species (ROS). Therefore, we explored the relationship between the sensitivities to 3R4F smoke and the antioxidant capacities of the cell lines. While the total antioxidant capacities were not significantly different among the cell lines, cellular glutathione (GSH) was higher in CHL/IU cells than in L5178Y cells. Pretreatment of CHL/IU cells with a GSH precursor, N-acetylcysteine (NAC), reduced the genotoxicity/cytotoxicity of 3R4F, whereas an inhibitor of GSH biosynthesis, buthionine sulfoximine (BSO), enhanced it. The effects of NAC and BSO were also seen after treatment with allyl isothiocyanate, a ROS-generating chemical, but not with mitomycin C, a ROS-independent genotoxicant. Pretreatment with NAC increased cellular thiol levels. From the present results, the genotoxicity and cytotoxicity of cigarette smoke differs among these cell lines in a manner that may be related to their antioxidant thiol levels.}, }
@article {pmid35090586, year = {2022}, author = {Duelen, R and Costamagna, D and Gilbert, G and De Waele, L and Goemans, N and Desloovere, K and Verfaillie, CM and Sipido, KR and Buyse, GM and Sampaolesi, M}, title = {Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy.}, journal = {Stem cell reports}, volume = {17}, number = {2}, pages = {352-368}, pmid = {35090586}, issn = {2213-6711}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; CRISPR-Cas Systems/genetics ; Cell Differentiation ; Cell Survival/drug effects ; Dystrophin/genetics/metabolism ; Gene Editing ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Mitochondria/drug effects/physiology ; Muscular Dystrophy, Duchenne/genetics/*pathology ; Myocytes, Cardiac/cytology/metabolism ; NADPH Oxidase 4/*metabolism ; Oxadiazoles/pharmacology ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Duchenne muscular dystrophy (DMD) is a progressive muscle disorder caused by mutations in the Dystrophin gene. Cardiomyopathy is a major cause of early death. We used DMD-patient-specific human induced pluripotent stem cells (hiPSCs) to model cardiomyopathic features and unravel novel pathologic insights. Cardiomyocytes (CMs) differentiated from DMD hiPSCs showed enhanced premature cell death due to significantly elevated intracellular reactive oxygen species (ROS) resulting from depolarized mitochondria and increased NADPH oxidase 4 (NOX4). CRISPR-Cas9 correction of Dystrophin restored normal ROS levels. ROS reduction by N-acetyl-L-cysteine (NAC), ataluren (PTC124), and idebenone improved hiPSC-CM survival. We show that oxidative stress in DMD hiPSC-CMs was counteracted by stimulating adenosine triphosphate (ATP) production. ATP can bind to NOX4 and partially inhibit the ROS production. Considering the complexity and the early cellular stress responses in DMD cardiomyopathy, we propose targeting ROS production and preventing detrimental effects of NOX4 on DMD CMs as promising therapeutic strategy.}, }
@article {pmid35089954, year = {2022}, author = {Hans, D and Rengel, A and Hans, J and Bassett, D and Hood, S}, title = {N-Acetylcysteine as a novel rapidly acting anti-suicidal agent: A pilot naturalistic study in the emergency setting.}, journal = {PloS one}, volume = {17}, number = {1}, pages = {e0263149}, pmid = {35089954}, issn = {1932-6203}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; *Emergency Service, Hospital ; Female ; Humans ; Male ; Middle Aged ; Outcome Assessment, Health Care ; Pilot Projects ; Psychiatric Status Rating Scales ; Young Adult ; *Suicide Prevention ; }, abstract = {OBJECTIVE: N-acetylcysteine has a demonstrated role as an adjunctive therapy in psychotic and affective disorders as a treatment to reduce symptoms of Bipolar Affective Disorder, Major Depressive Disorder and Schizophrenia. However, its potential as a rapidly acting anti-suicidal agent has not yet been assessed. This naturalistic study evaluates its effect in thirty patients presenting following intentional medication overdose.<br><br>METHODS: Eighteen patients who ingested toxic doses of paracetamol received NAC whilst twelve other patients with other overdoses received standard supportive treatment in the emergency department setting. Symptoms were measured using the Montgomery-Asberg Depression Rating Scale and Clinical Global Impression scale at time of presentation, 24 hours, and seven days.<br><br>RESULTS: Baseline characteristics between groups were similar. Both groups showed a significant reduction in suicidality, as measured by the suicide item of the MADRS, over time (p < 0.001). However, there was a greater reduction in suicidality in the 'NAC group' compared to the 'no-NAC group' one-week post presentation (p = 0.014). A greater proportion of the 'no-NAC group' still exhibited severe depressive symptoms (MADRS >32) compared to the 'NAC group' (p = 0.044).<br><br>CONCLUSION: This naturalistic study suggests NAC may have potential use as a rapidly acting treatment adjunct in major depressive disorder, warranting further investigation of its effects.}, }
@article {pmid35084258, year = {2022}, author = {Izquierdo, JL and Soriano, JB and González, Y and Lumbreras, S and Ancochea, J and Echeverry, C and Rodríguez, JM}, title = {Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19.}, journal = {Science progress}, volume = {105}, number = {1}, pages = {368504221074574}, pmid = {35084258}, issn = {2047-7163}, mesh = {Acetylcysteine/therapeutic use ; *COVID-19 ; Hospitalization ; Humans ; Male ; Retrospective Studies ; SARS-CoV-2 ; Treatment Outcome ; }, abstract = {Infection by SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) can be associated with serious and life-threatening conditions, including acute respiratory distress syndrome (ARDS). Severity and mortality have been related to a cytokine storm, an imbalance of oxidative stress, and a pro-thrombotic state.We conducted an observational retrospective cohort study from a community-based large population of hospitalized COVID-19 PCR + patients admitted from March 01, 2020, to January 24, 2021, with integrated primary to tertiary care information in Castilla la Mancha, Spain. We explored the potential benefits of the antioxidant, anti-inflammatory and anti-thrombotic drug N-acetylcysteine (NAC) administered orally in high doses (600 mg every 8 h), added to standard of care in COVID-19 patients by using the free text information contained in their electronic health records (EHRs).Out of 19,208 patients with a diagnosis of COVID-19 hospitalized, we studied 2071 (10.8%) users of oral NAC at high doses. COVID-19 patients treated with NAC were older, predominantly male, and with more comorbidities such as hypertension, dyslipidemia, diabetes, and COPD when compared with those not on NAC (all p < 0.05). Despite greater baseline risk, use of NAC in COVID-19 patients was associated with significantly lower mortality (OR 0.56; 95%CI 0.47-0.67), a finding that remained significant in a multivariate analysis adjusting by baseline characteristics and concomitant use of corticosteroids. There were no significant differences with the use of NAC on the mean duration of hospitalization, admission to the intensive care unit or use of invasive mechanical ventilation. The observed association signaling to better relevant outcomes in COVID-19 patients treated with NAC at high doses should be further explored in other settings and populations and in randomized controlled trials.}, }
@article {pmid35079634, year = {2022}, author = {Modi, HR and Wang, Q and Olmstead, SJ and Khoury, ES and Sah, N and Guo, Y and Gharibani, P and Sharma, R and Kannan, RM and Kannan, S and Thakor, NV}, title = {Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.}, journal = {Bioengineering &amp; translational medicine}, volume = {7}, number = {1}, pages = {e10259}, pmid = {35079634}, issn = {2380-6761}, support = {R01 HL071568/HL/NHLBI NIH HHS/United States ; R01 HL139158/HL/NHLBI NIH HHS/United States ; }, abstract = {Cardiac arrest (CA), the sudden cessation of effective cardiac pumping function, is still a major clinical problem with a high rate of early and long-term mortality. Post-cardiac arrest syndrome (PCAS) may be related to an early systemic inflammatory response leading to exaggerated and sustained neuroinflammation. Therefore, early intervention with targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes. Using a clinically relevant asphyxia CA model, we demonstrate that a single (i.p.) dose of dendrimer-N-acetylcysteine conjugate (D-NAC), can target "activated" microglial cells following CA, leading to an improvement in post-CA survival rate compared to saline (86% vs. 45%). D-NAC treatment also significantly improved gross neurological score within 4 h of treatment (p < 0.05) and continued to show improvement at 48 h (p < 0.05). Specifically, there was a substantial impairment in motor responses after CA, which was subsequently improved with D-NAC treatment (p < 0.05). D-NAC also mitigated hippocampal cell density loss seen post-CA in the CA1 and CA3 subregions (p < 0.001). These results demonstrate that early therapeutic intervention even with a single D-NAC bolus results in a robust sustainable improvement in long-term survival, short-term motor deficits, and neurological recovery. Our current work lays the groundwork for a clinically relevant therapeutic approach to treating post-CA syndrome.}, }
@article {pmid35076219, year = {2022}, author = {Wang, X and Ding, Z and Ma, K and Sun, C and Zheng, X and You, Y and Zhang, S and Peng, Y and Zheng, J}, title = {Cysteine-Based Protein Covalent Binding and Hepatotoxicity Induced by Emodin.}, journal = {Chemical research in toxicology}, volume = {35}, number = {2}, pages = {293-302}, doi = {10.1021/acs.chemrestox.1c00358}, pmid = {35076219}, issn = {1520-5010}, mesh = {Animals ; Binding Sites/drug effects ; Cells, Cultured ; Cysteine/chemistry/*toxicity ; Emodin/chemistry/*toxicity ; Fallopia multiflora/chemistry ; Hepatocytes/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred Strains ; Molecular Structure ; Proteins/*chemistry ; }, abstract = {Emodin (EMD) is a major ingredient of Polygonum multiflorum Thunb. (PMT), which has shown adverse liver reactions. Despite multiple pharmacological activities, EMD is reported to show various toxicities. Our early study demonstrated the reactivity of EMD to glutathione. This study aimed to determine the covalent interaction of hepatic protein with EMD and the correlation of the protein modification with hepatotoxicity induced by EMD. EMD-derived protein adduction was detected in an incubation mixture containing mouse liver homogenates and EMD. Such protein adduction was also observed in hepatic protein obtained from mice exposed to EMD. The protein covalent binding occurred in time- and dose-dependent manners. Pre-treatment of l-buthionine-sulfoximine significantly potentiated EMD-induced adduction and hepatotoxicity caused by EMD and lipopolysaccharide co-treatment. As expected, EMD-derived protein modification was observed in mouse primary hepatocytes treated with EMD. The increase in EMD exposure concentration intensified EMD-derived protein adduction and increased EMD-induced cell death. The susceptibility of hepatocytes to EMD cytotoxicity and the intensity of EMD-induced protein adduction were attenuated by the co-treatment of hepatocytes with N-acetyl cysteine. A good association of protein modification with hepatotoxicity induced by EMD was illustrated, which facilitates the understanding of the mechanism of hepatotoxicity induced by EMD.}, }
@article {pmid35068061, year = {2022}, author = {Yaryari, AM and Mousavibahar, SH and Amirhassani, S and Bagheri, M and Mohammadi, Y and Mehrpooya, M}, title = {Men suffering from category III chronic prostatitis may benefit from N-acetylcysteine as an adjunct to alpha-blockers.}, journal = {Lower urinary tract symptoms}, volume = {14}, number = {3}, pages = {199-207}, doi = {10.1111/luts.12425}, pmid = {35068061}, issn = {1757-5672}, mesh = {Acetylcysteine/therapeutic use ; Adrenergic alpha-Antagonists/therapeutic use ; Chronic Disease ; Humans ; Male ; Pelvic Pain/drug therapy ; *Prostatitis/diagnosis/drug therapy ; Quality of Life ; Tamsulosin/therapeutic use ; }, abstract = {OBJECTIVE: We designed this study to investigate the potential use of N-acetylcysteine (NAC) as an adjunct to alpha-blockers in the treatment of category III chronic prostatitis (CP).<br><br>METHODS: Sixty-three men with category III CP with a National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score of 15 or more were randomized to either the NAC treatment group or the placebo treatment group. Besides tamsulosin at a dose of 0.4&#x2009;mg once daily, participants based on their allocation group received NAC or placebo at a dose of 600&#x2009;mg twice daily for 12&#x2009;weeks. The efficacy of the medications was assessed by measuring changes in the NIH-CPSI total score and its subscales, including pain, urinary symptoms, and quality of life.<br><br>RESULTS: Based on the general linear model analysis of the data, over the 12-week treatment, NAC+tamsulosin was statistically superior to placebo+tamsulosin in reducing the total NIH-CPSI score, pain subscore, and quality-of-life subscore (P value <.001). Further, after 12&#x2009;weeks, more patients in the NAC+tamsulosin group than in the placebo+tamsulosin group met the responder criterion, defined as a decrease of at least 6 points in the NIH-CPSI total score (65.6% vs 29.0%). A more favorable outcome was also noted in the NAC+tamsulosin group regarding the number of patients reporting moderate or marked improvement in symptoms (62.5% vs 25.80%). No significant difference was seen between the groups concerning changes in urinary symptoms.<br><br>CONCLUSIONS: Our study provided clinical evidence that men with category III CP might benefit from NAC treatment. Further studies are needed for the validation of these findings.}, }
@article {pmid35065218, year = {2022}, author = {Karlsson, T and Gustafsson, &#xc5; and Ekstrand-Hammarström, B and Elfsmark, L and Jonasson, S}, title = {Chlorine exposure induces Caspase-3 independent cell death in human lung epithelial cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {80}, number = {}, pages = {105317}, doi = {10.1016/j.tiv.2022.105317}, pmid = {35065218}, issn = {1879-3177}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Caspase 3 ; Cell Physiological Phenomena/drug effects ; Chlorine/*toxicity ; Cytokines/metabolism ; Humans ; Lung/*cytology ; Oxidants/*toxicity ; }, abstract = {Chlorine (Cl2) is a common toxic industrial gas and human inhalation exposure causes tissue damage with symptoms ranging from wheezing to more severe symptoms such as lung injury or even death. Because the mechanism behind Cl2-induced cell death is not clearly understood, the present study aimed to study the cellular effects in vitro after Cl2 exposure of human A549 lung epithelial cells. In addition, the possible treatment effects of the anti-inflammatory antioxidant N-acetyl cysteine (NAC) were evaluated. Exposure of A549 cells to Cl2 (100-1000 ppm) in the cell medium induced cell damage and toxicity within 1 h in a dose-dependent manner. The results showed that 250 ppm Cl2 increased cell death and formation of apoptotic-like bodies, while 500 ppm Cl2 exposure resulted in predominantly necrotic death. Pre-treatment with NAC was efficient to prevent cell damage at lower Cl2 concentrations in part by averting the formation of apoptotic-like bodies and increasing the expression of the anti-apoptotic proteins clusterin and phosphorylated tumour protein p53(S46). Analysis showed that Cl2 induced cell death by a possibly caspase-independent mechanism, since no cleavage of caspase-3 could be detected after exposure to 250 ppm. Currently, these results justifies further research into new treatment strategies for Cl2-induced lung injury.}, }
@article {pmid35065167, year = {2022}, author = {Ali, M and Tabassum, H and Alam, MM and Parvez, S}, title = {N-acetyl-L-cysteine ameliorates mitochondrial dysfunction in ischemia/reperfusion injury via attenuating Drp-1 mediated mitochondrial autophagy.}, journal = {Life sciences}, volume = {293}, number = {}, pages = {120338}, doi = {10.1016/j.lfs.2022.120338}, pmid = {35065167}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Autophagy/*drug effects/physiology ; Brain Ischemia/metabolism/pathology/*prevention &amp; control ; Dynamins/*antagonists &amp; inhibitors/metabolism ; Free Radical Scavengers/pharmacology/therapeutic use ; Male ; Mitochondria/*drug effects/metabolism ; Mitochondrial Dynamics/drug effects/physiology ; Rats ; Rats, Wistar ; Reperfusion Injury/metabolism/pathology/*prevention &amp; control ; }, abstract = {BACKGROUND AND PURPOSE: Ischemic reperfusion (I/R) injury causes a wide array of functional and structure alternations of mitochondria, associated with oxidative stress and increased the severity of injury. Despite the previous evidence for N-acetyl-L-cysteine (NAC) provide neuroprotection after I/R injury, it is unknown to evaluate the effect of NAC on altered mitochondrial autophagy forms an essential axis to impaired mitochondrial quality control in cerebral I/R injury.<br><br>METHODS: Male wistar rats subjected to I/R injury were used as transient Middle Cerebral Artery Occlusion (tMCAO) model. After I/R injury, the degree of cerebral tissue injury was detected by infarct volume, H&amp;E staining and behavioral assessment. We also performed mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometry and mitochondrial respiratory complexes to evaluate the mitochondrial dysfunction. Finally, we performed the western blotting analysis to measure the apoptotic and autophagic marker.<br><br>RESULTS: We found that NAC administration significantly ameliorates brain injury, improves neurobehavioral outcome, decreases neuroinflammation and mitochondrial mediated oxidative stress. We evaluated the neuroprotective effect of NAC against neuronal apoptosis by assessing its ability to sustained mitochondrial integrity and function. Further studies revealed that beneficial effects of NAC is through targeting the mitochondrial autophagy via regulating the GSK-3&#x3b2;/Drp1mediated mitochondrial fission and inhibiting the expression of beclin-1 and conversion of LC3, as well as activating the p-Akt pro-survival pathway.<br><br>CONCLUSION: Our results suggest that NAC exerts neuroprotective effects to inhibit the altered mitochondrial changes and cell death in I/R injury via regulation of p-GSK-3&#x3b2; mediated Drp-1 translocation to the mitochondria.}, }
@article {pmid35063860, year = {2022}, author = {Ntamo, Y and Ziqubu, K and Chellan, N and Nkambule, BB and Nyambuya, TM and Mazibuko-Mbeje, SE and Gabuza, KB and Orlando, P and Tiano, L and Dludla, PV}, title = {Clinical use of N-acetyl cysteine during liver transplantation: Implications of oxidative stress and inflammation as therapeutic targets.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {147}, number = {}, pages = {112638}, doi = {10.1016/j.biopha.2022.112638}, pmid = {35063860}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Humans ; Inflammation/*drug therapy/pathology ; Liver Failure/pathology ; Liver Transplantation/*adverse effects ; Oxidative Stress/*drug effects/physiology ; Randomized Controlled Trials as Topic ; Reperfusion Injury/pathology/prevention &amp; control ; }, abstract = {Currently, liver transplantation is considered as the definitive treatment option for individuals with complete liver failure. However, the detrimental effects of oxidative stress and inflammation remain the predominant feature that drives hepatic ischemia-reperfusion injury during liver transplantation. As such, therapeutic drugs that hinder oxidative stress and attenuate inflammation, have become ideal targets to curb liver injuries during transplantation. The current review analyses available clinical evidence on the importance of using N-acetyl cysteine (NAC) during liver transplantation. Thus, prominent online search engines such as PubMed and Google Scholar were accessed to retrieve literature from randomized clinical trials reporting on the use of NAC during liver transplantation. Overwhelming evidence suggests that established therapeutic properties of NAC, through enhancing endogenous antioxidants like glutathione to block oxidative stress and attenuate inflammation, remain essential to improve liver function in patients undergoing liver transportation. However, to the contrary, some clinical studies did not show any beneficial effects in patients receiving NAC during liver transplantation. Thus, such controversies, in addition to discussing the implications of oxidative stress and inflammation in relation to hepatic ischemia-reperfusion injury remain the major subject of the current review.}, }
@article {pmid35057065, year = {2022}, author = {Guerini, M and Condrò, G and Perugini, P}, title = {Evaluation of the Mucoadhesive Properties of Chitosan-Based Microstructured Lipid Carrier (CH-MLC).}, journal = {Pharmaceutics}, volume = {14}, number = {1}, pages = {}, pmid = {35057065}, issn = {1999-4923}, abstract = {Different mucoadhesive systems have been studied in recent years to increase the residence time of the delivery systems and to prolong the release of the drug. The aim of this work was to evaluate the mucoadhesive properties of chitosan-based Microstructured Lipid Carrier (CH-MLC) with a new approach which requires chitosan and mucin to be compacted into a tablet and mucoadhesion to be assessed on a non-mucoadhesive substrate. This type of test showed that chitosan maintains a close bond with mucin even in the presence of a fluid and even encapsulated in microparticles. After this, using a bioreactor, the release of N-acetylcysteine (NAC) from the microparticles (NA-CH-MLC) through a layer of mucus mimicking the pathological conditions of a patient with cystic fibrosis was tested. The release of the active from NAC-CH-MLC demonstrated how the chitosan inside the microparticles acts as a penetration enhancer and how the microparticles can impart a prolonged release over time.}, }
@article {pmid35055458, year = {2022}, author = {Allam, A and Abdeen, A and Devkota, HP and Ibrahim, SS and Youssef, G and Soliman, A and Abdel-Daim, MM and Alzahrani, KJ and Shoghy, K and Ibrahim, SF and Aboubakr, M}, title = {N-Acetylcysteine Alleviated the Deltamethrin-Induced Oxidative Cascade and Apoptosis in Liver and Kidney Tissues.}, journal = {International journal of environmental research and public health}, volume = {19}, number = {2}, pages = {}, pmid = {35055458}, issn = {1660-4601}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis ; *Chickens/metabolism ; Humans ; Kidney ; Liver ; Nitriles ; Oxidative Stress ; Pyrethrins ; }, abstract = {Deltamethrin (DLM) is a synthetic pyrethroid with anti-acaricide and insecticidal properties. It is commonly used in agriculture and veterinary medicine. Humans and animals are exposed to DLM through the ingestion of polluted food and water, resulting in severe health issues. N-acetylcysteine (NAC) is a prodrug of L-cysteine, the precursor to glutathione. It can restore the oxidant-antioxidant balance. Therefore, this research aimed to examine whether NAC may protect broiler chickens against oxidative stress, at the level of biochemical and molecular alterations caused by DLM intoxication. The indicators of liver and kidney injury in the serum of DLM-intoxicated and NAC-treated groups were examined. Furthermore, lipid peroxidation, antioxidant markers, superoxide dismutase activity, and apoptotic gene expressions (caspase-3 and Bcl-2) were investigated. All parameters were significantly altered in the DLM-intoxicated group, suggesting that DLM could induce oxidative damage and apoptosis in hepato-renal tissue. The majority of the changes in the studied parameters were reversed when NAC therapy was used. In conclusion, by virtue of its antioxidant and antiapoptotic properties, NAC enabled the provision of significant protection effects against DLM-induced hepato-renal injury.}, }
@article {pmid35052593, year = {2021}, author = {Singh, J and Phogat, A and Prakash, C and Chhikara, SK and Singh, S and Malik, V and Kumar, V}, title = {N-Acetylcysteine Reverses Monocrotophos Exposure-Induced Hepatic Oxidative Damage via Mitigating Apoptosis, Inflammation and Structural Changes in Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {1}, pages = {}, pmid = {35052593}, issn = {2076-3921}, abstract = {Oxidative stress-mediated tissue damage is primarily involved in hepatic injuries and dysfunctioning. Natural antioxidants have been shown to exert hepatoprotective, anti-inflammatory and antiapoptotic properties. The present study evaluated the effect of N-acetylcysteine (NAC) against monocrotophos (MCP) exposure-induced toxicity in the rat liver. Albino Wistar rats were divided into four groups: (1) control, (2) NAC-treated, (3) MCP-exposure, (4) NAC and MCP-coexposure group. The dose of MCP (0.9 mg/kg b.wt) and NAC (200 mg/kg b.wt) were administered orally for 28 days. Exposure to MCP caused a significant increase in lipid peroxidation, protein oxidation and decreased glutathione content along with the depletion of antioxidant enzyme activities. Further MCP exposure increased pro-inflammatory cytokines levels and upregulated Bax and Caspase-3 expressions. MCP exposure also caused an array of structural alternations in liver tissue, as depicted by the histological and electron microscopic analysis. Thepretreatment of NAC improved glutathione content, restored antioxidant enzyme activities, prevented oxidation of lipids and proteins, decreased pro-inflammatory cytokines levels and normalized apoptotic protein expression. Treatment of NAC also prevented histological and ultrastructural alternations. Thus, the study represents the therapeutic efficacy and antioxidant potential of NAC against MCP exposure in the rat liver.}, }
@article {pmid35044038, year = {2022}, author = {Hu, Q and Zheng, J and Xu, XN and Gu, C and Li, W}, title = {Uranium induces kidney cells apoptosis via reactive oxygen species generation, endoplasmic reticulum stress and inhibition of PI3K/AKT/mTOR signaling in culture.}, journal = {Environmental toxicology}, volume = {37}, number = {4}, pages = {899-909}, doi = {10.1002/tox.23453}, pmid = {35044038}, issn = {1522-7278}, support = {82160627//National Natural Science Foundation of China/ ; 2020GXNFSAA297262//Natural Science Foundation of Guangxi Autonomous Region/ ; }, mesh = {Apoptosis ; *Endoplasmic Reticulum Stress ; Kidney/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; *Uranium/pharmacology ; }, abstract = {Uranium (U) induces generation of excessive intracellular reactive oxygen species (ROS), which is generally considered as a possible mediator of U-triggered kidney tubular cells injury and nephrotoxicity. Our goal is designed to elucidate that the precise molecular mechanism in ROS downstream is association with U-induced NRK-52[E] cells apoptosis. The results show that U intoxication in NRK-52[E] cells reduced cell activity and triggered apoptosis, as demonstrated by flow cytometry and apoptotic marker cleaved Caspase-3 expression. U exposure triggered endoplasmic reticulum (ER) stress, which is involvement of apoptosis determined by marker molecules including GRP78, PERK, IRE1, ATF6, CHOP, cleaved Caspase-12, and Caspase-3. Administration of antioxidant N-acetylcysteine (NAC) effectively blocked U-triggered ROS generation, ER stress, and apoptosis. U contamination evidently decreased the expression of phosphorylation PI3K, AKT, and mTOR and ratios of their respective phosphorylation to the corresponding total proteins. Application of a PI3K activator IGF-1 significantly abolished these adverse effects of U intoxication on PI3K/AKT/mTOR signaling and subsequently abrogated U-triggered apoptosis. NAC also effectively reversed down-regulation of phosphorylated PI3K induced by U exposure. Taken together, these data strongly suggest that U treatment induces NRK-52[E] cells apoptosis through ROS production, ER stress, and down-regulation of PI3K/AKT/mTOR signaling. Targeting ROS formation-, ER stress-, and PI3K/AKT/mTOR pathway-mediated apoptosis could be a novel approach for attenuating U-triggered nephrotoxicity.}, }
@article {pmid35043378, year = {2022}, author = {Lai, L and Wang, Y and Peng, S and Guo, W and Wei, G and Li, L and Xia, Z and Li, F and Xu, S}, title = {Bupivacaine Induces ROS-Dependent Autophagic Damage in DRG Neurons via TUG1/mTOR in a High-Glucose Environment.}, journal = {Neurotoxicity research}, volume = {40}, number = {1}, pages = {111-126}, pmid = {35043378}, issn = {1476-3524}, support = {81501082//National Natural Science Foundation of China/ ; 81771315//National Natural Science Foundation of China/ ; 82171357//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Apoptosis ; Autophagy ; *Bupivacaine/toxicity ; *Ganglia, Spinal/metabolism ; Glucose/metabolism ; Humans ; Mammals/metabolism ; Mice ; Neurons/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Taurine/metabolism ; }, abstract = {Bupivacaine (BP) is a commonly clinically used local anesthetic (LA). Current studies suggest that neurological complications are increased in diabetic patients after LA application, but the molecular mechanism is poorly understood. LA-induced autophagy and neuronal injury have been reported. We hypothesized that a high-glucose environment aggravates BP-induced autophagic damage. Mouse dorsal root ganglion (DRG) neurons were treated with BP in a high-glucose environment, and the results showed that reactive oxygen species (ROS) levels increased, autophagy was activated, autophagy flux was blocked, and cell viability decreased. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) attenuated ROS-mediated autophagy regulation. Moreover, the expression of the long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) increased, and NAC and TUG1 siRNA inhibited the expression of TUG1/mammalian target of rapamycin (mTOR) in DRGs treated with BP in a high-glucose environment. Intriguingly, contrary to previous reports on a positive effect on neurons, we found that rapamycin, an autophagy activator, and chloroquine, an autophagy and lysosome inhibitor, both exacerbated autophagic damage. These data suggest that a high-glucose environment exacerbated BP induced ROS-dependent autophagic damage in DRG neurons through the TUG1/mTOR signaling pathway, which provides a theoretical basis and target for the clinical prevention and treatment of BP neurotoxicity in diabeties.}, }
@article {pmid35039188, year = {2022}, author = {Karaarslan, U and Çolak, M and Topal, S and Atakul, G and Soydan, E and Çağlar, A and Ağın, H}, title = {The association between N-acetylcysteine treatment and hepatic healing in patients with non-acetaminophen-induced liver injury in pediatric intensive care: A single-center retrospective study.}, journal = {Archives de pediatrie : organe officiel de la Societe francaise de pediatrie}, volume = {29}, number = {2}, pages = {140-144}, doi = {10.1016/j.arcped.2021.11.006}, pmid = {35039188}, issn = {1769-664X}, mesh = {Acetaminophen ; Acetylcysteine/*therapeutic use ; Analgesics, Non-Narcotic/therapeutic use ; *Chemical and Drug Induced Liver Injury/etiology ; Child ; Critical Care ; Female ; Humans ; Liver Failure, Acute/*drug therapy/etiology ; Male ; Retrospective Studies ; Transaminases/blood ; Treatment Outcome ; }, abstract = {OBJECTIVE: The aim of this study was to determine the association between the use of intravenous N-acetylcysteine (NAC) and hepatic healing in pediatric intensive care unit (PICU) patients with non-acetaminophen-induced hepatic injury, except for acute liver failure.<br><br>METHODS: The data of patients who received intravenous NAC as adjuvant therapy for transaminase levels more than sixfold normal values during their PICU stay between 2010 and 2014 were retrospectively collected from the medical records database. The patients who did not receive NAC with elevated transaminase levels during their PICU stay between 2014 and 2018 were also collected as the standard of care (SOC) cohort.<br><br>RESULTS: More than 50% of the liver injuries were secondary to acute hypoxia, hypotension, sepsis, and inflammation. The median number of elevated transaminase period (ETP) days of the NAC and SOC groups were 5 (IQR: 4) and 4 (IQR: 4), respectively (p&#xa0;=&#xa0;0.17). There was no significant difference between the groups in terms of minimum and maximum laboratory values during ETP. There was no significant difference in terms of ETP and maximum ALT levels between the NAC and SOC groups in the hypoxia-hypotension subgroup.<br><br>CONCLUSION: This study did not show an association between indirect measures of hepatic healing and post-insult use of NAC in pediatric liver injury in the PICU setting.}, }
@article {pmid35037248, year = {2022}, author = {Saito, N and Mikami, R and Mizutani, K and Takeda, K and Kominato, H and Kido, D and Ikeda, Y and Buranasin, P and Nakagawa, K and Takemura, S and Ueno, T and Hosaka, K and Hanawa, T and Shinomura, T and Iwata, T}, title = {Impaired dental implant osseointegration in rat with streptozotocin-induced diabetes.}, journal = {Journal of periodontal research}, volume = {57}, number = {2}, pages = {412-424}, doi = {10.1111/jre.12972}, pmid = {35037248}, issn = {1600-0765}, support = {//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Dental Implants ; *Diabetes Mellitus, Experimental/metabolism ; Osseointegration ; Osteogenesis ; Rats ; Streptozocin ; Titanium/pharmacology ; }, abstract = {OBJECTIVE: Few studies have reported on the impact of oxidative stress on the dental implant failure. The aim of this study was to investigate the impact of hyperglycemia-induced oxidative stress on dental implant osseointegration in diabetes mellitus (DM).<br><br>METHODS: Acid-treated titanium implants were bilaterally placed in the maxillary alveolar ridge of streptozotocin-induced diabetic (DM group) and control rats after extraction of first molars. Histological analysis and micro-push-out test were performed 4&#xa0;weeks after surgery. Oxidative stress and osteogenic markers in the surrounding bone were quantified by real-time polymerase chain reaction. In the in vitro study, rat bone marrow-derived mesenchymal stem cells (BMMSCs) were cultured on acid-treated titanium discs in a high-glucose (HG) or normal environment. Intracellular reactive oxygen species (ROS), cell proliferation, alkaline phosphatase (ALP) activity, and extracellular calcification were evaluated following antioxidant treatment with N-acetyl-L-cysteine (NAC).<br><br>RESULTS: The implant survival rate was 92.9% and 75.0% in control and DM group, respectively. Bone-implant contact and push-out loads were significantly lower in the DM group. Expression of superoxide dismutase 1 at the mRNA level and on immunohistochemistry was significantly lower in the DM group. In vitro experiments revealed that the HG condition significantly increased ROS expression and suppressed the proliferation and extracellular calcification of BMMSCs, while NAC treatment significantly restored ROS expression, cell proliferation, and calcification. The ALP activity of both groups was not significantly different.<br><br>CONCLUSION: In diabetes, high-glucose-induced oxidative stress downregulates proliferation and calcification of BMMSCs, impairing osseointegration and leading to implant failure.}, }
@article {pmid35035668, year = {2022}, author = {Chen, W and Huang, W and Yang, Y and Li, K}, title = {Methylglyoxal Scavengers Attenuate Angiogenesis Dysfunction Induced by Methylglyoxal and Oxygen-Glucose Deprivation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {8854457}, pmid = {35035668}, issn = {1942-0994}, mesh = {Angiogenesis Inhibitors/pharmacology/*therapeutic use ; Animals ; Chick Embryo ; Glucose/*metabolism ; Humans ; Oxidative Stress/*drug effects ; Oxygen/*metabolism ; Pyruvaldehyde/pharmacology/*therapeutic use ; }, abstract = {Cerebral endothelial cells play an essential role in brain angiogenesis, and their function has been found to be impaired in diabetes. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite of glucose formed mainly during glycolysis, and its levels can be elevated in hyperglycemic conditions. MG is a potent precursor of AGEs (advanced glycation end-products). In this study, we investigated if MG can induce angiogenesis dysfunction and whether MG scavengers can ameliorate angiogenesis dysfunction induced by MG. Here, we used cultured human brain microvascular endothelial cells (HBMECs) treated with MG and oxygen-glucose deprivation (OGD) to mimic diabetic stroke in vitro. We also used the MG challenged chicken embryo chorioallantoic membrane (CAM) to study angiogenesis in vivo. Interestingly, administration of MG significantly impaired cell proliferation, cell migration, and tube formation and decreased protein expression of angiogenesis-related factors, which was rescued by three different MG scavengers, glyoxalase 1 (GLO1), aminoguanidine (AG), and N-acetyl cysteine (NAC). In cultured CAM, MG exposure significantly reduced angiogenesis and the angiogenesis-related dysfunction could be attenuated by pretreatment with AG or NAC. Treatment of cultured HBMECs with MG plus OGD increased cellular apoptosis significantly, which could be prevented by exposure to GLO1, AG, or NAC. We also noted that administration of MG increased cellular oxidative stress as measured by reactive oxygen species (ROS) generation, enhanced AGE accumulation, and receptor for advanced glycation end-product (RAGE) expression in the cultured HBMECs, which were partially reversed by GLO1, AG, or NAC. Taken together, our findings demonstrated that GLO1, AG, or NAC administration can ameliorate MG-induced angiogenesis dysfunction, and this can be mainly attributed to attenuated ROS production, reduced cellular apoptosis, and increased levels of angiogenic factors. Overall, this study suggested that GLO1, AG, or NAC may be promising candidate compounds for the treatment of angiogenesis dysfunction caused by hyperglycemia in diabetic ischemic stroke.}, }
@article {pmid35035661, year = {2022}, author = {Hseu, YC and Tseng, YF and Pandey, S and Shrestha, S and Lin, KY and Lin, CW and Lee, CC and Huang, ST and Yang, HL}, title = {Coenzyme Q0 Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages.}, journal = {Oxidative medicine and cellular longevity}, volume = {2022}, number = {}, pages = {4266214}, pmid = {35035661}, issn = {1942-0994}, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Humans ; Inflammasomes/*drug effects ; Lipopolysaccharides/*metabolism ; Macrophages/*metabolism ; Mice ; Mitophagy/*immunology ; Transfection ; Ubiquinone/pharmacology/*therapeutic use ; }, abstract = {Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-induced inflammation and redox imbalance in murine RAW264.7 macrophages. CoQ0's non- or subcytotoxic concentration suppressed the NLRP3 inflammasome and procaspase-1 activation, followed by downregulation of IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages. Similarly, treatment of CoQ0 led to LC3-I/II accumulation and p62/SQSTM1 activation. An increase in the Beclin-1/Bcl-2 ratio and a decrease in the expression of phosphorylated PI3K/AKT, p70 S6 kinase, and mTOR showed that autophagy was activated. Besides, CoQ0 increased Parkin protein to recruit damaged mitochondria and induced mitophagy in LPS/ATP-stimulated RAW264.7 macrophages. CoQ0 inhibited LPS/ATP-stimulated ROS generation in RAW264.7 macrophages. Notably, when LPS/ATP-stimulated RAW264.7 macrophages were treated with CoQ0, Mito-TEMPO (a mitochondrial ROS inhibitor), or N-acetylcysteine (NAC, a ROS inhibitor), there was a significant reduction of LPS/ATP-stimulated NLRP3 inflammasome activation and IL1β expression. Interestingly, treatment with CoQ0 or Mito-TEMPO, but not NAC, significantly increased LPS/ATP-induced LC3-II accumulation indicating that mitophagy plays a key role in the regulation of CoQ0-inhibited NLRP3 inflammasome activation. Nrf2 knockdown significantly decreased IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ0 inhibited ROS-mediated NLRP3 inflammasome activation and IL1β expression was suppressed due to the Nrf2 activation. Hence, this study showed that CoQ0 might be a promising candidate for the therapeutics of inflammatory disorders due to its effective anti-inflammatory as well as antioxidant properties.}, }
@article {pmid35029525, year = {2022}, author = {Khoshdel, AR and Emami Aleagha, O and Shahriary, A and Aghamollaei, H and Najjar Asiabani, F}, title = {Topical Effects of N-Acetyl Cysteine and Doxycycline on Inflammatory and Angiogenic Factors in the Rat Model of Alkali-Burned Cornea.}, journal = {Journal of interferon &amp; cytokine research : the official journal of the International Society for Interferon and Cytokine Research}, volume = {42}, number = {2}, pages = {82-89}, doi = {10.1089/jir.2021.0150}, pmid = {35029525}, issn = {1557-7465}, mesh = {Acetylcysteine/metabolism/pharmacology ; Alkalies/metabolism/pharmacology ; Angiogenesis Inducing Agents/metabolism/pharmacology ; Animals ; *Burns, Chemical/complications/drug therapy/metabolism ; Cornea/metabolism ; *Corneal Neovascularization/etiology/genetics ; Disease Models, Animal ; Doxycycline/metabolism/pharmacology ; *Eye Burns/chemically induced/complications/drug therapy ; Rats ; Sodium Hydroxide/metabolism/pharmacology ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {The aim of this study was to analyze the single and combined effects of N-acetyl cysteine (NAC) and doxycycline (Dox) on the inflammatory and angiogenic factors in the rat model of alkali-burned cornea. Rats were treated with a single and combined 0.5% NAC and 12.5 μg/mL Dox eye drops and evaluated on days 3, 7, and 28. In the corneas of various groups, the activity of Catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) enzymes was assessed. The expression of inflammatory factors (TNF-α, Rel-a, and CXCL-1) and angiogenic factors (VEGF-a, MMP2, and MMP9) was measured using real-time polymerase chain reaction. The antioxidant enzyme activities decreased substantially 3 days after injury with sodium hydroxide (NaOH). NAC and combined NAC+ Dox topical treatments increased the SOD enzyme activity on day 28 (P < 0.05). The expression of TNF-α and Rel-a genes following single and combined treatment of NAC and Dox decreased significantly on days 7 and 28 (P < 0.05). The mRNA level of angiogenic factors and corneal neovascularization (CNV) level declined in NaOH-injured rats treated with Dox (P < 0.05). The topical treatment of Dox could attenuate inflammation and CNV complications. However, NAC treatment may not reduce the expression of angiogenic genes.}, }
@article {pmid35024307, year = {2021}, author = {Qian, H and Bai, Q and Yang, X and Akakpo, JY and Ji, L and Yang, L and Rülicke, T and Zatloukal, K and Jaeschke, H and Ni, HM and Ding, WX}, title = {Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {12}, pages = {3791-3805}, pmid = {35024307}, issn = {2211-3835}, support = {R01 AA020518/AA/NIAAA NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; R37 AA020518/AA/NIAAA NIH HHS/United States ; U01 AA024733/AA/NIAAA NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; R21 AA017421/AA/NIAAA NIH HHS/United States ; R01 AG072895/AG/NIA NIH HHS/United States ; }, abstract = {Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.}, }
@article {pmid35024303, year = {2021}, author = {Jaeschke, H and Adelusi, OB and Akakpo, JY and Nguyen, NT and Sanchez-Guerrero, G and Umbaugh, DS and Ding, WX and Ramachandran, A}, title = {Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {12}, pages = {3740-3755}, pmid = {35024303}, issn = {2211-3835}, support = {R01 DK070195/DK/NIDDK NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, abstract = {Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, which is safe at therapeutic doses but can cause severe liver injury and even liver failure after overdoses. The mouse model of APAP hepatotoxicity recapitulates closely the human pathophysiology. As a result, this clinically relevant model is frequently used to study mechanisms of drug-induced liver injury and even more so to test potential therapeutic interventions. However, the complexity of the model requires a thorough understanding of the pathophysiology to obtain valid results and mechanistic information that is translatable to the clinic. However, many studies using this model are flawed, which jeopardizes the scientific and clinical relevance. The purpose of this review is to provide a framework of the model where mechanistically sound and clinically relevant data can be obtained. The discussion provides insight into the injury mechanisms and how to study it including the critical roles of drug metabolism, mitochondrial dysfunction, necrotic cell death, autophagy and the sterile inflammatory response. In addition, the most frequently made mistakes when using this model are discussed. Thus, considering these recommendations when studying APAP hepatotoxicity will facilitate the discovery of more clinically relevant interventions.}, }
@article {pmid35024183, year = {2021}, author = {Fatima, K and Masood, N and Ahmad Wani, Z and Meena, A and Luqman, S}, title = {Neomenthol prevents the proliferation of skin cancer cells by restraining tubulin polymerization and hyaluronidase activity.}, journal = {Journal of advanced research}, volume = {34}, number = {}, pages = {93-107}, pmid = {35024183}, issn = {2090-1224}, mesh = {Animals ; Cell Proliferation ; HEK293 Cells ; Humans ; Hyaluronoglucosaminidase ; Mice ; Molecular Docking Simulation ; Polymerization ; *Skin Neoplasms/drug therapy ; *Tubulin ; }, abstract = {INTRODUCTION: Neomenthol, a cyclic monoterpenoid, is a stereoisomer of menthol present in the essential oil of Mentha spp. It is used in food as a flavoring agent, in cosmetics and medicines because of its cooling effects. However, neomenthol has not been much explored for its anticancer potential. Additionally, targeting hyaluronidase, Cathepsin-D, and ODC by phytochemicals is amongst the efficient approach for cancer prevention and/or treatment.<br><br>OBJECTIVES: To investigate the molecular and cell target-based antiproliferative potential of neomenthol on human cancer (A431, PC-3, K562, A549, FaDu, MDA-MB-231, COLO-205, MCF-7, and WRL-68) and normal (HEK-293) cell lines.<br><br>METHODS: The potency of neomenthol was evaluated on human cancer and normal cell line using SRB, NRU and MTT assays. The molecular target based study of neomenthol was carried out in cell-free and cell-based test systems. Further, the potency of neomenthol was confirmed by quantitative real-time PCR analysis and molecular docking studies. The in vivo anticancer potential of neomenthol was performed on mice EAC model and the toxicity examination was accomplished through in silico, ex vivo and in vivo approaches.<br><br>RESULTS: Neomenthol exhibits a promising activity (IC50 17.3&#xa0;&#xb1;&#xa0;6.49&#xa0;&#x3bc;M) against human epidermoid carcinoma (A431) cells by arresting the G2/M phase and increasing the number of sub-diploid cells. It significantly inhibits hyaluronidase activity (IC50 12.81&#xa0;&#xb1;&#xa0;0.01&#xa0;&#x3bc;M) and affects the tubulin polymerization. The expression analysis and molecular docking studies support the in vitro molecular and cell target based results. Neomenthol prevents EAC tumor formation by 58.84% and inhibits hyaluronidase activity up to 10% at 75&#xa0;mg/kg bw, i.p. dose. The oral dose of 1000&#xa0;mg/kg bw was found safe in acute oral toxicity studies.<br><br>CONCLUSION: Neomenthol delayed the growth of skin carcinoma cells by inhibiting the tubulin polymerization and hyaluronidase activity, which are responsible for tumor growth, metastasis, and angiogenesis.}, }
@article {pmid35023144, year = {2022}, author = {Wang, XJ and Ni, XQ and Zhao, S and Zhao, RZ and Wang, XH and Xia, SJ and Sun, XW and Zhuo, J}, title = {ROS-NLRP3 signaling pathway induces sterile inflammation after thulium laser resection of the prostate.}, journal = {Journal of cellular physiology}, volume = {237}, number = {3}, pages = {1923-1935}, doi = {10.1002/jcp.30663}, pmid = {35023144}, issn = {1097-4652}, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspase 1/genetics/metabolism ; Dogs ; Humans ; Inflammasomes/metabolism ; *Inflammation ; Interleukin-18 ; Interleukin-1beta/metabolism ; Lasers ; Male ; *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Prostate/metabolism/surgery ; *Reactive Oxygen Species/metabolism ; Signal Transduction ; Thulium ; }, abstract = {The sterile inflammation (SI) of the urinary tract is a common problem requiring serious consideration after prostatectomy. This study mainly focuses on the role of the reactive oxygen species-NLR family, pyrin domain-containing 3 (ROS-NLRP3) signaling pathway in SI after thulium laser resection of the prostate (TmLRP). Urinary cytokines were determined in patients who received TmLRP, and heat shock protein 70 (HSP70) was detected in the resected tissues. The involvement of ROS signaling in HSP70-induced inflammation was explored in THP-1 cells with or without N-acetyl- l-cysteine (NAC) pretreatment. The function of NLRP3 and Caspase-1 was determined by Western blot analysis, enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction. These phenomena and mechanisms were verified by the beagle models that received TmLRP. Clinical urine samples after TmLRP showed high expression of inflammatory factors and peaked 3-5 days after surgery. The high expression of HSP70 in the resected tissues was observed. After HSP70 stimulation, the expression of ROS, NLRP3, Caspase-1, and interleukin-18 (IL-18) increased significantly and could be reduced by ROS inhibitor NAC. The expression of IL-1β and IL-18 could be inhibited by NLRP3 or Caspase-1 inhibitors. In beagle models that received TmLRP, HSP70, NLRP3, Caspase-1, IL-1β, and IL-18 were highly expressed in the wound tissue or urine, and could also be reduced by NAC pretreatment. Activation of the ROS-NLRP3 signaling pathway induces SI in the wound after prostatectomy. Inhibition of this pathway may be effective for clinical prevention and treatment of SI and related complications after prostatectomy.}, }
@article {pmid35020164, year = {2023}, author = {Çoban, FK and İnce, S and Demirel, HH and İslam, &#x130; and Aytuğ, H}, title = {Acetaminophen-Induced Nephrotoxicity: Suppression of Apoptosis and Endoplasmic Reticulum Stress Using Boric Acid.}, journal = {Biological trace element research}, volume = {201}, number = {1}, pages = {242-249}, pmid = {35020164}, issn = {1559-0720}, mesh = {Rats ; Animals ; *Acetaminophen/toxicity/metabolism ; Boron/pharmacology ; Acetylcysteine/pharmacology ; Apoptosis ; *Kidney Diseases/chemically induced ; Endoplasmic Reticulum Stress ; }, abstract = {Acetaminophen (APAP) is one of the popular and safe pain medications worldwide. However, due its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure. Boron is a bioactive trace element, found naturally as boric acid (BA) and borate. In this study, the effects of boric acid on the acute renal toxicity induced by APAP in rats were researched in comparison with N-acetyl cysteine (NAC). In the study, 7 groups were formed and 2 g/kg dose of paracetamol per rat was prepared by suspending in 1% Carboxy Methyl Cellulose (CMC) solution of phosphate buffer saline (PBS). Boric acid dissolved in saline was administered to experimental animals by gavage at doses of 50, 100, and 200 mg/kg. In this study, ER stress and apoptosis formed by paracetamol-induced nephrotoxicity were investigated. This purpose determined iNOS, PERK, ATF6, NFkB p53, caspases 3, 12, bcl-2, and bcl-xL gene mRNA expression kidney tissue. Also, the levels of kidney injury molecule-1 (KIM-1), Cysteine (Cys), and IL-18 levels, which are mentioned today as kidney damage markers were compared with BUN and creatine levels. The effect of boron on kidney damage was determined by histopathologic. Data were statistically analyzed by using SPSS-20 ANOVA and stated as means and standard deviation. According to the data obtained in our study, we believe that boric acid has a protective effect on the negative effects of paracetamol on the kidney. We believe that our study will provide useful data to the literature on the possibility of a supplement to be used as an active compound in paracetamol for the prophylaxis of boric acid and it can also be converted into a useful product.}, }
@article {pmid35017325, year = {2021}, author = {Alrowaie, FA and Almatham, KI and Alsamadi, F and Bashir, MS and Munshi, HH}, title = {Could Omega 3 fatty acids reduce the risk of contrast-induced nephropathy in patients undergoing coronary angiography? A randomized controlled trial.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {32}, number = {2}, pages = {328-335}, doi = {10.4103/1319-2442.335443}, pmid = {35017325}, issn = {1319-2442}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Acute Kidney Injury/*chemically induced/diagnosis/metabolism ; Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Fatty Acids, Omega-3/administration &amp; dosage/*pharmacology ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Kidney Diseases/*chemically induced/diagnosis/metabolism ; Male ; Middle Aged ; Treatment Outcome ; }, abstract = {Contrast medium-induced nephropathy (CIN) is a leading cause of acquired acute kidney injury and has been associated with prolonged hospitalization and adverse clinical outcomes. This study aimed to determine if omega 3 fatty acids reduce the risk of CIN in patients with chronic kidney disease undergoing coronary angiography. A total of 130 consecutive patients undergoing coronary angiography were randomly assigned to one of two groups as follows: 67 patients were assigned to the N-acetylcysteine (NAC; 1200 mg) and 63 patients were assigned to the omega 3 fatty acid (4 g). Both drugs were administered orally twice per day one day before and on the day of contrast administration. Of the 130 patients enrolled in this study, 10 (7.7%) experienced an increase of at least 0.5 mg/dL (44 μmol/L) in serum creatinine levels 48 h after administration of the contrast agent including 5 of the 67 patients in the NAC group (7.5%) and 5 of the 63 patients in the omega 3 fatty acids group (7.9%; P = 0.919). There were no significant differences in the need for renal replacement therapy (3.0% vs. 9.5%, P = 0.121) or in the mortality rate (3.0% vs. 6.3%, P = 0.361) between the two groups. Short-term prophylactic omega 3 fatty acid treatment with hydration does not reduce the risk of CIN in patients with chronic kidney disease undergoing coronary angiography.}, }
@article {pmid35014505, year = {2021}, author = {Beltrame, JM and Guindani, C and Novy, MG and Felipe, KB and Sayer, C and Pedrosa, RC and Hermes de Araújo, PH}, title = {Covalently Bonded N-Acetylcysteine-polyester Loaded in PCL Scaffolds for Enhanced Interactions with Fibroblasts.}, journal = {ACS applied bio materials}, volume = {4}, number = {2}, pages = {1552-1562}, doi = {10.1021/acsabm.0c01404}, pmid = {35014505}, issn = {2576-6422}, mesh = {Acetylcysteine/*chemistry ; Caproates/*metabolism ; Fibroblasts/*metabolism ; Lactones/*metabolism ; Polyesters/*chemistry ; Tissue Engineering/*methods ; }, abstract = {Poly(ε-caprolactone) (PCL) is commonly used in devices for tissue reconstruction due to its biocompatibility and suitable mechanical properties. However, its high crystallinity and hydrophobicity do not favor cell adhesion and difficult polymer bioresorption. To improve these characteristics, the development of engineered scaffolds for tissue regeneration, based on poly(globalide-co-ε-caprolactone) (PGlCL) covalently bonded with N-acetylcysteine (PGlCL-NAC) was proposed. The scaffolds were obtained from polymer blends of PCL and PGlCL-NAC, using the electrospinning technique. The use of PGlCL-NAC allowed for the modification of the physical and chemical properties of PCL electrospun scaffolds, including an expressive reduction in the fiber's diameter, hydrophobicity, and crystallinity. All electrospun scaffolds showed no cytotoxicity against fibroblasts (McCoy cells). In vitro biocompatibility assays showed that all tested scaffolds provided high cell viability and proliferation in short-term (NRU, MTT, and nuclear morphology assays) and long-term (clonogenic assay) assays. Nevertheless, PGlCL-NAC based scaffolds have favored the survival and proliferation of the cells in comparison to PCL scaffolds. Cell adhesion on the scaffolds assessed by electronic microscopy images confirmed this behavior. These results suggest that the incorporation of PGlCL-NAC in scaffolds for tissue regeneration could be a promising strategy to improve cell-surface interactions and contribute to the development of more efficiently engineered biomedical devices.}, }
@article {pmid35011309, year = {2021}, author = {Liao, CY and Wu, TC and Yang, SF and Chang, JT}, title = {Effects of NAC and Gallic Acid on the Proliferation Inhibition and Induced Death of Lung Cancer Cells with Different Antioxidant Capacities.}, journal = {Molecules (Basel, Switzerland)}, volume = {27}, number = {1}, pages = {}, pmid = {35011309}, issn = {1420-3049}, support = {MOST 108-2320-B-040-004 (Taiwan, R.O.C.)//Ministry of Science and Technology Taiwan, R.O.C./ ; }, mesh = {Acetylcysteine/chemistry/*pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Antioxidants/chemistry/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Gallic Acid/chemistry/*pharmacology ; Humans ; Lung Neoplasms ; Molecular Structure ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {N-acetylcysteine (NAC) is a recognized antioxidant in culture studies and treatments for oxidative stress-related diseases, but in some cases, NAC is a pro-oxidant. To study the effect of NAC on cell proliferation in the presence or absence of ROS stress, we used the stable ROS generator gallic acid (GA) to treat CL1-0 lung cancer cell models with different antioxidant activities. Different antioxidant activities were achieved through the ectopic expression of different PERP-428 single nucleotide polymorphisms. GA increased ROS levels in CL1-0/PERP-428C cells and caused cell death but had no effect on CL1-0/PERP-428G cells within 24 h. We found that 0.1 mM NAC eliminated GA-induced growth inhibition, but 0.5 mM NAC enhanced GA-induced CL1-0/PERP-428C cell death. However, in the absence of GA, NAC exceeding 2 mM inhibited the growth of CL1-0/PERP-428G cells more significantly than that of CL1-0/PERP-428C cells. Without GA, NAC has an antioxidant effect. Under GA-induced ROS stress, NAC may have pro-oxidant effects. Each cell type has a unique range of ROS levels for survival. The levels of ROS in the cell determines the sensitivity of the cell to an antioxidant or pro-oxidant. Cells with different antioxidant capacities were used to show that the intracellular ROS level affects NAC function and provides valuable information for the adjuvant clinical application of NAC.}, }
@article {pmid35008006, year = {2022}, author = {Xu, D and Zhou, X and Chen, J and Li, N and Ruan, S and Zuo, A and Lei, S and Li, L and Guo, Y}, title = {C1q/tumour necrosis factor-related protein-9 aggravates lipopolysaccharide-induced inflammation via promoting NLRP3 inflammasome activation.}, journal = {International immunopharmacology}, volume = {104}, number = {}, pages = {108513}, doi = {10.1016/j.intimp.2021.108513}, pmid = {35008006}, issn = {1878-1705}, mesh = {Adiponectin/genetics/*immunology ; Animals ; Female ; Glycoproteins/genetics/*immunology ; Inflammasomes/genetics/*immunology ; Inflammation/chemically induced/genetics/*immunology ; Interleukin-1beta/blood/genetics/immunology ; Lipopolysaccharides ; Macrophages, Peritoneal/immunology ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidase 2/genetics/immunology ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*immunology ; Pyroptosis ; Reactive Oxygen Species/immunology ; Mice ; }, abstract = {The NLRP3 inflammasome plays a vital role in inflammation by increasing the maturation of interleukin-1β (IL-1β) and promoting pyroptosis. Given that C1q/tumour necrosis factor-related protein-9 (CTRP9) has been shown to be involved in diverse inflammatory diseases, we sought to assess the underlying impact of CTRP9 on NLRP3 inflammasome activation. In vitro, macrophages isolated from murine peritonea were stimulated with exogenous CTRP9, followed by lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP). We demonstrated that CTRP9 markedly augmented the activation of the NLRP3 inflammasome, as shown by increased mature IL-1β secretion, triggering ASC speck formation and promoting pyroptosis. Mechanistically, CTRP9 increased the levels of NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). Suppressing ROS with N-acetylcysteine (NAC) or interfering with NOX2 by small interfering RNA weakened the promoting effect of CTRP9 on the NLRP3 inflammasome. Furthermore, NLRP3 inflammasome activation, pyroptosis and secretion of mature IL-1β were significantly decreased in macrophages from CTRP9-KO mice compared to those from WT mice with the same treatment. In vivo, we established a sepsis model by intraperitoneal injection of LPS into WT and CTRP9-KO mice. CTRP9 knockout improved the survival rates of the septic mice and attenuated NLRP3 inflammasome-mediated inflammation. In conclusion, our study indicates that CTRP9 aggravates LPS-induced inflammation by promoting NLRP3 inflammasome activation via the NOX2/ROS pathway. CTRP9 could be a promising target for NLRP3 inflammasome-driven inflammatory diseases.}, }
@article {pmid35006548, year = {2022}, author = {Baum, RA and Su, MK and Weant, KA}, title = {The Cents of the Dosage Cap in Patients Greater than 100 Kilograms Receiving N-Acetylcysteine for Acetaminophen Toxicity.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {18}, number = {1}, pages = {67-68}, pmid = {35006548}, issn = {1937-6995}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; }, }
@article {pmid35006546, year = {2022}, author = {Berland, NG and Leonard, J and Calello, DP}, title = {Should the Dosage Cap Be Used in Patients Greater than 100 kg Receiving N-acetylcysteine for Acetaminophen Toxicity?.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {18}, number = {1}, pages = {65-66}, pmid = {35006546}, issn = {1937-6995}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; }, }
@article {pmid35000568, year = {2022}, author = {Guo, X and He, J and Zhang, R and Wang, T and Chen, J and Wang, J and Wang, Z and Chang, G and Niu, Y and Niu, Z and Song, J}, title = {N-Acetylcysteine alleviates spinal cord injury in rats after early decompression surgery by regulating inflammation and apoptosis.}, journal = {Neurological research}, volume = {44}, number = {7}, pages = {605-613}, doi = {10.1080/01616412.2021.2024737}, pmid = {35000568}, issn = {1743-1328}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; Apoptosis ; Decompression ; Inflammation/drug therapy/pathology ; Rats ; Recovery of Function ; Spinal Cord/pathology ; *Spinal Cord Injuries/drug therapy/pathology/surgery ; }, abstract = {OBJECTIVE: Decompression surgery in patients with spinal cord injury (SCI) has a neuroprotective effect by alleviating secondary injury and improving neurological outcomes. N-Acetylcysteine (NAC), a drug approved by the United States Food and Drug Administration, has been shown to play neuroprotective roles via attenuation of apoptosis and inflammation. The purpose of the present study was to investigate the effects of early or late decompression surgery in combination with NAC administration on acute SCI, as well as investigate the underlying mechanisms of its actions.<br><br>METHODS: In this study, an acute SCI model was established in rats. The rats were treated with decompression surgery 24/48&#xa0;h post-SCI in combination with or without NAC.<br><br>RESULTS: The results showed that decompression surgery in combination with NAC lead to a better outcome than decompression alone, as demonstrated by the higher Basso, Beattie, and Bresnahan scores. Histopathological examination demonstrated that early decompression surgery in combination with NAC exerted the best therapeutic effect on spinal cord recovery, which was further confirmed by the extent of inflammation and apoptosis. Additionally, we found that NAC might compensate for a lack of late surgery.<br><br>CONCLUSIONS: Collectively, early decompression surgery and NAC could be a promising combination for the treatment of acute SCI, and its therapeutic effects may be associated with the regulation of inflammation and apoptosis.}, }
@article {pmid34995428, year = {2021}, author = {Elsayed, S and Gohar, A and Omar, M}, title = {A Review Article on 5-Oxoproline Induced High Anion Gap Metabolic Acidosis.}, journal = {South Dakota medicine : the journal of the South Dakota State Medical Association}, volume = {74}, number = {10}, pages = {468-470}, pmid = {34995428}, issn = {0038-3317}, mesh = {Acetaminophen ; Acid-Base Equilibrium ; *Acidosis/chemically induced ; Adult ; *Analgesics, Non-Narcotic ; Female ; Humans ; Pyrrolidonecarboxylic Acid/metabolism ; }, abstract = {In 1989, an acquired high anion gap metabolic acidosis due to elevated 5-oxoproline (pyroglutamic acid) was first reported. This is related to chronic acetaminophen use in malnourished patients and women with chronic medical conditions, it could happen even using therapeutic or low doses. The mainstay of treatment is cessation of acetaminophen use along with the administration of intravenous fluids. N-acetyl cysteine might accelerate improvement. The best explanation of the disorder is glutathione depletion and activation of a key enzyme in the γ-glutamyl cycle. This review article aims to highlight the mechanism and management of acquired high anion gap metabolic acidosis caused by 5-oxoproline in the adult population.}, }
@article {pmid34994286, year = {2022}, author = {Asgari, Z and Moini, A and Montazeri, A and Tavoli, Z and Hosseini, L and Hosseini, R and Tehranian, A and Karimi, R}, title = {Comparing the effect of adjunctive N-acetylcysteine plus low dose contraceptive with low dose contraceptive alone on recurrence of ovarian endometrioma and chronic pelvic pain after conservative laparoscopic surgery: a randomised clinical trial study.}, journal = {Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology}, volume = {42}, number = {5}, pages = {1493-1497}, doi = {10.1080/01443615.2021.2006165}, pmid = {34994286}, issn = {1364-6893}, mesh = {Acetylcysteine/therapeutic use ; *Chronic Pain ; Contraceptive Agents ; *Endometriosis/drug therapy/surgery ; Female ; Humans ; *Laparoscopy ; *Ovarian Diseases/surgery ; Pelvic Pain/drug therapy/etiology/surgery ; Recurrence ; }, abstract = {This study aimed to compare the effectiveness of NAC plus low dose contraceptive with low dose contraceptives alone. This was a randomised trial on a sample of women who underwent conservative laparoscopic surgery for ovarian endometrioma. Patients were randomly assigned either to the NAC plus low dose contraceptive group (n = 48) or low dose contraceptive alone (n = 52). To evaluate the recurrence rate transvaginal ultrasound was performed. Pelvic pain was assessed using a visual analogue scale (VAS). All assessments were performed at two points in time: 3 and 6 months post-surgery and compared between the two regimens. The findings indicated that reduction in the recurrence rate of endometrioma and pelvic pain were similar between both groups. The findings showed that adding N-acetylcysteine to low dose contraceptive treatment has a similar effect in reducing the recurrence rate of endometrioma and pelvic pain when compared to low dose contraceptives alone.Impact statementWhat is already known on this subject? Endometriosis is a frequent benign disease-producing inflammatory response with mild to severe symptoms. Although surgical removal of ectopic lesions is the first-line intervention, the recurrence rate of the disease is high. Thus this study aimed to compare the effectiveness of N-acetylcysteine plus low dose contraceptive with low dose contraceptive alone.What do the results of this study add? The findings showed that adding N-acetylcysteine to low dose contraceptive treatment has a similar effect in reducing the recurrence rate of endometrioma and pelvic pain when compared to low dose contraceptives alone.What are the implications of these findings for clinical practice and/or further research? It is recommended to increase the duration of drug administration in future studies.}, }
@article {pmid34993544, year = {2022}, author = {Chen, CA and Chang, JM and Chen, HC and Chang, EE}, title = {Generation of endoplasmic reticulum stress-dependent reactive oxygen species mediates TGF-β1-induced podocyte migration.}, journal = {Journal of biochemistry}, volume = {171}, number = {3}, pages = {305-314}, doi = {10.1093/jb/mvab128}, pmid = {34993544}, issn = {1756-2651}, mesh = {Apoptosis ; Cell Movement ; *Endoplasmic Reticulum Stress ; *Podocytes/metabolism ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/metabolism/pharmacology ; }, abstract = {Podocyte migration results in proteinuria and glomerulonephropathy. Transforming growth factor-β1 (TGF-β1), endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) can mediate podocyte migration; however, the crosstalk between them is unclear. This study determined the relationships between these factors. ER stress biomarkers (GRP78, p-eIF2α or CHOP), intracellular ROS generation, integrin-β3 and cell adhesion and migration were studied in a treatment of experiment using TGF-β1 with and without the ER stress inhibitors: 4-phenylbutyric acid (4-PBA, a chemical chaperone), salubrinal (an eIF2α dephosphorylation inhibitor) and N-acetylcysteine (NAC, an antioxidant). ER stress biomarkers (p-eIF2α/eIF2α and GRP78), ROS generation and intergrin-β3 expression increased after TGF-β1 treatment. NAC down-regulated the expression of GRP78 after TGF-β1 treatment. 4-PBA attenuated TGF-β1-induced p-eIF2α/eIF2α, CHOP, ROS generation and intergrin-β3 expression. However, salubrinal did not inhibit TGF-β1-induced p-eIF2α/eIF2α, CHOP, ROS generation or integrin-β3 expression. NAC abrogated TGF-β1-induced integrin-β3 expression. At 24 h after treatment with TGF-β1, podocyte adhesion and migration increased. Furthermore, NAC, 4-PBA and an anti-interin-β3 antibody attenuated TGF-β1-induced podocyte adhesion and migration. This study demonstrated that TGF-β1-induced ER stress potentiates the generation of intracellular ROS to a high degree through the PERK/eIF2α/CHOP pathway. This intracellular ROS then mediates integrin-β3 expression, which regulates podocyte migration.}, }
@article {pmid34987729, year = {2021}, author = {Khalili, F and Khosravi, MB and Sahmeddini, MA and Eghbal, MH and Kazemi, K and Nikeghbalian, S and Ghazanfar Tehran, S and Khosravi, B}, title = {The Effect of Perioperative N-acetylcysteine on the Short and Long Term Outcomes in Pediatrics Undergoing Living-Donor Liver Transplantation.}, journal = {International journal of organ transplantation medicine}, volume = {12}, number = {1}, pages = {12-20}, pmid = {34987729}, issn = {2008-6482}, abstract = {BACKGROUND: Ischemia-reperfusion injury during transplantation can cause post-operative graft dysfunction.<br><br>OBJECTIVE: To assess the efficacy of N-acetylcysteine in preventing hepatic ischemia-reperfusion injury and post-transplant outcomes.<br><br>METHODS: In this retrospective study on pediatrics undergoing living-donor (from one of their parents) liver transplantation, N-acetylcysteine was administered to one group (n=20) after induction in the donors until graft harvest, and in the recipients during implantation, which was maintained for 19 hours. The second group (n=20) did not receive NAC. Early allograft dysfunction was determined in the presence of alanine aminotransferase or aspartate aminotransferase &#x2265;2000 IU/L and bilirubin &#x2265;10 mg/dL within the first 7 days, and an international normalized ratio &#x2265;1.6 on day 7. Data were collected from a retrospectively maintained database.<br><br>RESULTS: The incidence of post-reperfusion syndrome was lower in N-acetylcysteine group compared with the other group (5% vs. 30%, p=0.037). Serum creatinine level was significantly (p=0.04) different in the N-acetylcysteine group during the second post-operative week (0.14 vs. 0.15 mg/dL). There was no significant difference in the incidence of early allograft dysfunction (21% vs. 14%, p=0.327), and the survival rate (p=0.409).<br><br>CONCLUSION: Peri-operative infusion of N-acetylcysteine in both donor and recipient would effectively prevent post-reperfusion syndrome and renal insufficiency. However, it might not affect the early allograft dysfunction, ICU stay, and mortality. NAC increases the chance of re-operation due to non-surgical bleeding in the first post-operative day.}, }
@article {pmid34984698, year = {2022}, author = {Huang, G and Zhu, Y and Yong, C and Tian, F and Liu, L and Wu, Q and Shu, Y and Yao, M and Tang, C and Wang, X and Chen, W and Zhou, E}, title = {Artemisia capillaris Thunb. water extract attenuates adriamycin-induced renal injury by regulating apoptosis through the ROS/MAPK axis.}, journal = {Journal of food biochemistry}, volume = {46}, number = {2}, pages = {e14065}, doi = {10.1111/jfbc.14065}, pmid = {34984698}, issn = {1745-4514}, mesh = {Animals ; Apoptosis ; *Artemisia ; *Doxorubicin/adverse effects ; Kidney/physiology ; Plant Extracts/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Renal Insufficiency/chemically induced/drug therapy ; Water ; }, abstract = {Artemisia capillaris Thunb. is widely used in the treatment of kidney diseases, but the underlying mechanism remain elusive. Therefore, this study aimed to elucidate the mechanism of Artemisia capillaris Thunb. in alleviating renal injury. And renoprotective effects of freeze-dried powder of Artemisia capillaris Thunb. water extract (WAC) were assessed using adriamycin (ADR)-induced renal injury to the NRK-52E cells and ADR-induced renal injury Sprague-Dawley rats (SD rats) models. The results show that WAC could alleviate ADR-induced renal injury in SD rats and the NRK-52E cell line, improved renal function (BUN 9.73 ± 0.35 vs 7.13 ± 0.15, SCR 80.60 ± 1.68 vs 60.50 ± 1.42, ACR 11.50 ± 0.50 vs 8.526 ± 0.15) or cell viability (IC50 = 1.08 µg/ml (ADR), cell viability increase 36.38% ± 6.74% (added 4 mg/ml WAC)), and reduced the apoptosis. Moreover, WAC inhibited the MAPK signal transduction, increased the expression of superoxide dismutase 1 (SOD1), and decreased the production of ROS. The treatment of N-acetylcysteine (NAC, antioxidant) in vitro showed that NAC inhibited apoptosis and alleviated renal injury by inhibiting oxidative stress and reducing the phosphorylation of proteins related to the MAPK signaling pathway. Therefore, these results suggested that WAC can alleviate ADR-induced renal injury and apoptosis by regulating the ROS/MAPK axis and has potential to be used as a renoprotective drug. PRACTICAL APPLICATIONS: Artemisia capillaris Thunb., which is a medicinal and edible plant, is widely used to treat kidney diseases in traditional Chinese medicine. The present research examined the renal protective effect of Artemisia capillaris Thunb. The results show that Artemisia capillaris Thunb. can effectively reduce renal tubular cell apoptosis through the ROS/MAPK axis in vivo and in vitro. In general, Artemisia capillaris Thunb. can be used as a potential herb to attenuate renal injury and further research can be conducted to explore its renoprotective mechanisms.}, }
@article {pmid34982438, year = {2021}, author = {Spartalis, M and Siasos, G and Mastrogeorgiou, M and Spartalis, E and Kaminiotis, VV and Mylonas, KS and Kapelouzou, A and Kontogiannis, C and Doulamis, IP and Toutouzas, K and Nikiteas, N and Iliopoulos, DC}, title = {The effect of per os colchicine administration in combination with fenofibrate and N-acetylcysteine on triglyceride levels and the development of atherosclerotic lesions in cholesterol-fed rabbits.}, journal = {European review for medical and pharmacological sciences}, volume = {25}, number = {24}, pages = {7765-7776}, doi = {10.26355/eurrev_202112_27623}, pmid = {34982438}, issn = {2284-0729}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage ; Aorta/drug effects/pathology ; Atherosclerosis/blood/*drug therapy/pathology ; C-Reactive Protein/analysis ; Cholesterol/administration &amp; dosage ; Colchicine/*administration &amp; dosage ; Drug Therapy, Combination ; Fenofibrate/*administration &amp; dosage ; Hypolipidemic Agents/*administration &amp; dosage ; Interleukin-6/antagonists &amp; inhibitors/blood ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists &amp; inhibitors ; Rabbits ; Triglycerides/blood ; }, abstract = {OBJECTIVE: Atherosclerosis is a chronic inflammatory disease promoted by pro-inflammatory cytokines produced by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP 3) inflammasome. Colchicine is an anti-inflammatory agent that inhibits inflammasome's action and stabilizes atherosclerotic lesions. N-acetylcysteine (NAC) reduces low-density lipoprotein (LDL) oxidation, metalloproteinase levels, and foam cell count and volume. Fenofibrate also has antioxidant, anti-inflammatory, and anticoagulant properties while also having a beneficial effect on the vasomotor function of the endothelium. The purpose of this study is to investigate the effect of per os colchicine administration in combination with fenofibrate and NAC on triglyceride levels and the development of atherosclerotic lesions in cholesterol-fed rabbits.<br><br>MATERIALS AND METHODS: Twenty-eight male, 2 months old New Zealand White rabbits were separated into four groups and were fed with different types of diet for 7 weeks: standard, cholesterol 1% w/w, cholesterol 1% w/w plus colchicine 2 mg/kg body weight plus 250 mg/kg body weight/day fenofibrate, and cholesterol 1% w/w plus colchicine 2 mg/kg body weight plus 15 mg/kg body weight/day NAC. Blood samples were drawn from all animals. Lipid profiles were assessed, and interleukin 6 (IL-6) measurements were performed using an enzyme-linked immunosorbent assay (ELISA) kit. Histologic examination was performed on aorta specimens stained with eosin and hematoxylin. Aortic intimal thickness was evaluated using image analysis.<br><br>RESULTS: Colchicine administration in combination with fenofibrate or NAC statistically significantly reduced the extent of atherosclerotic lesions in aortic preparations. Co-administration of colchicine with NAC has a stronger anti-atherogenic effect than the colchicine plus fenofibrate regimen. Triglerycide levels were decreased in the colchicine plus fenofibrate group and the colchicine plus NAC group at the end of the experiment (p < 0.05), whereas the Cholesterol group had increased levels. A favorable significant lower concentration of IL-6 was detected in the colchicine plus NAC group vs. the other groups.<br><br>CONCLUSIONS: In an experimental rabbit model, it appears that colchicine statistically significantly reduces the development of atherosclerosis of the aorta, especially in combination with NAC. Colchicine, as an NLRP3 inflammasome inhibitor, and NAC, as an agent that directly targets IL-6 signaling, can reduce the inflammatory risk. Fenofibrate enhances the attenuating role of colchicine on triglyceride levels. Clinical studies should investigate whether similar effects can be observed in humans.}, }
@article {pmid34981600, year = {2022}, author = {Philippot, Q and Kannengiesser, C and Debray, MP and Gauvain, C and Ba, I and Vieri, M and Gondouin, A and Naccache, JM and Reynaud-Gaubert, M and Uzunhan, Y and Bondue, B and Israël-Biet, D and Dieudé, P and Fourrage, C and Lainey, E and Manali, E and Papiris, S and Wemeau, L and Hirschi, S and Mal, H and Nunes, H and Schlemmer, F and Blanchard, E and Beier, F and Cottin, V and Crestani, B and Borie, R and , }, title = {Interstitial lung diseases associated with mutations of poly(A)-specific ribonuclease: A multicentre retrospective study.}, journal = {Respirology (Carlton, Vic.)}, volume = {27}, number = {3}, pages = {226-235}, doi = {10.1111/resp.14195}, pmid = {34981600}, issn = {1440-1843}, mesh = {Exoribonucleases ; Humans ; *Idiopathic Pulmonary Fibrosis/genetics ; *Lung Diseases, Interstitial/genetics ; Mutation/genetics ; Retrospective Studies ; }, abstract = {BACKGROUND AND OBJECTIVE: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations.<br><br>METHODS: We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network.<br><br>RESULTS: We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59&#x2009;years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n&#xa0;=&#xa0;12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n&#xa0;=&#xa0;13), antifibrotic agents (n&#xa0;=&#xa0;11), immunosuppressants (n&#xa0;=&#xa0;5) and N-acetyl cysteine (n&#xa0;=&#xa0;2). The median forced vital capacity decline for the whole sample was 256&#x2009;ml/year (range -363 to -148). After a median follow-up of 32&#x2009;months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54&#x2009;months (95% CI 29 to &#x221e;). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation.<br><br>CONCLUSION: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed.}, }
@article {pmid34981453, year = {2022}, author = {Yamasaki, T and Okada, M and Hiraishi, A and Mori, W and Zhang, Y and Fujinaga, M and Wakizaka, H and Kurihara, Y and Nengaki, N and Zhang, MR}, title = {Upregulation of Striatal Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Rats with Excessive Glutamate Release Induced by N-Acetylcysteine.}, journal = {Neurotoxicity research}, volume = {40}, number = {1}, pages = {26-35}, pmid = {34981453}, issn = {1476-3524}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Glutamic Acid/metabolism ; Rats ; *Receptors, Metabotropic Glutamate ; Up-Regulation ; }, abstract = {The aim of this study is to investigate the changes in expression of metabotropic glutamate (Glu) receptor subtype 1 (mGluR1), a key molecule involved in neuroexcitetoxicity, during excessive Glu release in the brain by PET imaging. An animal model of excessive Glu release in the brain was produced by intraperitoneally implanting an Alzet osmotic pump containing N-acetylcysteine (NAC), an activator of the cysteine/Glu antiporter, into the abdomen of rats. Basal Glu concentration in the brain was measured by microdialysis, which showed that basal Glu concentration in NAC-treated rats (0.31 µM) was higher than that in saline-treated rats (0.17 µM) at day 7 after the implantation of the osmotic pump. Similarly, PET studies with [[11]C]ITDM, a useful radioligand for mGluR1 imaging exhibited that the striatal binding potential (BPND) of [[11]C]ITDM for mGluR1 in PET assessments was increased in NAC-treated animals at day 7 after implantation (2.30) compared with before implantation (1.92). The dynamic changes in striatal BPND during the experimental period were highly correlated with basal Glu concentration. In conclusion, density of mGluR1 is rapidly upregulated by increases in basal Glu concentration, suggesting that mGluR1 might to be a potential biomarker of abnormal conditions in the brain.}, }
@article {pmid34979873, year = {2022}, author = {El-Shal, LM and El-Star, AAA and Azmy, AM and Elnegris, HM}, title = {The possible protective role of N-acetyl cysteine on duodenal mucosa of high fat diet and orlistat treated adult male albino rats and the active role of tumor necrosis factor α (TNFα) and Interleukin 6 (IL6) (histological and biochemical study).}, journal = {Ultrastructural pathology}, volume = {46}, number = {1}, pages = {18-36}, doi = {10.1080/01913123.2021.2007194}, pmid = {34979873}, issn = {1521-0758}, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Diet, High-Fat/adverse effects ; Interleukin-6 ; Male ; Mucous Membrane/drug effects ; Orlistat/adverse effects ; Oxidative Stress ; Rats ; Tumor Necrosis Factor-alpha ; }, abstract = {BACKGROUND: Obesity is a major universal health issue linked to a majority of illness.<br><br>AIM: To evaluate the histological and biochemical changes occurred in the duodenal mucosa of high fat diet HFD and orlistat fed rats and to assess the possible protective role of N-acetyl cysteine NAC supplementation.<br><br>MATERIAL AND METHOD: Sixty male albino rats weighing 180-200&#xa0;g were classified randomly into control group I and three experimental groups (HFD group II, HFD + orlistat group III, and HFD + orlistat + NAC group IV). All experimental groups received HFD alone/and treatment for 6&#xa0;weeks. Group III received orlistat (32 mg/kg/day) before meals and group IV received the same regimen as group III in addition to NAC (230 mg/kg/day) after meals. After completion of the experiment, duodenal sections were processed for histological examination, oxidative stress parameters, and semiqualitative real time PCR for proinflammatory mediators TNF&#x3b1; and IL6 evaluation. Also, plasma lipid parameters were assessed and morphometric duodenal results were analyzed statistically.<br><br>RESULTS: By histological examination of HFD and (HFD + orlistat) groups, we found severe to moderate duodenal structural disturbances, increased goblet cells, collagen fibers, and BAX and iNOS immunostaining. By Biochemical examination, both groups showed increased proinflammatory markers level (TNF&#x3b1; and IL6) with decreased all antioxidant parameters and increased MDA. Moreover, NAC treatment in group IV significantly reduced all structural changes, levels of proinflammatory mediators and increased all antioxidant parameter levels and decreased MDA.<br><br>CONCLUSION: All findings elucidated that NAC could be accounted to be a useful drug for protection of duodenal mucosa of HFD and orlistat treated animals.}, }
@article {pmid34979328, year = {2022}, author = {Qi, J and Hu, S and He, X and Pan, T and Yang, L and Zhang, R and Tang, Y and Wu, D and Han, Y}, title = {N-Acetyl-L-Cysteine Potentially Inhibits Complement Activation in Transplantation-Associated Thrombotic Microangiopathy.}, journal = {Transplantation and cellular therapy}, volume = {28}, number = {4}, pages = {216.e1-216.e5}, doi = {10.1016/j.jtct.2021.12.018}, pmid = {34979328}, issn = {2666-6367}, mesh = {Acetylcysteine/pharmacology ; Adult ; Complement Activation ; Female ; *Hematopoietic Stem Cell Transplantation ; Humans ; *Thrombotic Microangiopathies/drug therapy ; Treatment Outcome ; }, abstract = {Transplant-associated thrombotic microangiopathy (TA-TMA) has a high mortality rate and lacks effective treatments. We searched the GEO database and analyzed RNA-seq data and whole-genome sequencing data from patients' blood samples. We identified N-acetyl-L-cysteine (NAC) as a possible therapeutic target for TA-TMA. In vitro experiments showed that NAC reduced complement activation and VWF multimerization in HUVECs. We also treated a 36-year-old female TA-TMA patient with NAC. Hemoglobin, platelet counts, lactate dehydrogenase levels, and sC5b-9 levels and schistocytes were normalized after using NAC. It shows that NAC may be an effective drug to improve TA-TMA symptoms by inhibiting complement activation.}, }
@article {pmid34978586, year = {2022}, author = {Akakpo, JY and Ramachandran, A and Curry, SC and Rumack, BH and Jaeschke, H}, title = {Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose.}, journal = {Archives of toxicology}, volume = {96}, number = {2}, pages = {453-465}, pmid = {34978586}, issn = {1432-0738}, support = {R01 DK070195/DK/NIDDK NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; GM103549/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; DK102142/DK/NIDDK NIH HHS/United States ; DK120194/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; GM118247/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/pharmacology ; Analgesics, Non-Narcotic/poisoning ; Animals ; Antidotes/*pharmacology ; Chemical and Drug Induced Liver Injury/etiology/*prevention &amp; control ; Drug Overdose ; Fomepizole/pharmacology ; Hepatocytes/drug effects/pathology ; Humans ; Mice ; }, abstract = {Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.}, }
@article {pmid34976966, year = {2021}, author = {Li, X and Xiong, F and Wang, S and Zhang, Z and Dai, J and Chen, H and Wang, J and Wang, Q and Yuan, H}, title = {N-Acetyl-Cysteine-Loaded Biomimetic Nanofibrous Scaffold for Osteogenesis of Induced-Pluripotent-Stem-Cell-Derived Mesenchymal Stem Cells and Bone Regeneration.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {9}, number = {}, pages = {767641}, pmid = {34976966}, issn = {2296-4185}, abstract = {To regenerate bone tissues, we investigated the osteogenic differentiation of induced-pluripotent-stem-cell-derived mesenchymal stem cells (iPSC-MSCs) and bone regeneration capacities using N-acetyl cysteine (NAC)-loaded biomimetic nanofibers of hydroxyapatite/silk fibroin (HAp/SF). The addition of HAp and NAC decreased the diameters of the electrospun fibers and enhanced the mechanical properties of the silk scaffold. The release kinetic curve indicated that NAC was released from NAC/HAp/SF nanofibers in a biphasic pattern, with an initial burst release stage and a later sustained release stage. This pattern of release of NAC encapsulated on the NAC/HAp/SF scaffolds prolonged the release of high concentrations of NAC, thereby largely affecting the osteogenic differentiation of iPSC-MSCs and bone regeneration. Thus, a new silk electrospun scaffold was developed. HAp was used as a separate nanocarrier for recharging the NAC concentration, which demonstrated the promising potential for the use of NAC/HAp/SF for bone tissue engineering.}, }
@article {pmid34976186, year = {2022}, author = {Qi, H and Zhang, X and Liu, H and Han, M and Tang, X and Qu, S and Wang, X and Yang, Y}, title = {Shikonin induced Apoptosis Mediated by Endoplasmic Reticulum Stress in Colorectal Cancer Cells.}, journal = {Journal of Cancer}, volume = {13}, number = {1}, pages = {243-252}, pmid = {34976186}, issn = {1837-9664}, abstract = {Shikonin is a naphthoquinone pigment isolated from the root of Lithospermum erythrorhizon, which has displayed potent anti-tumor properties. However, the effects of shikonin in colorectal cancer cells have not been yet fully investigated. In this study, we demonstrated that shikonin significantly inhibited the activity of colorectal cancer cells in a time- and dose-dependent manner. The flow cytometry and western blot results indicated that shikonin induced cell apoptosis by down-regulating BCL-2 and activating caspase-3/9 and the cleavage of PARP. The expression of BiP and the PERK/elF2α/ATF4/CHOP and IRE1α /JNK signaling pathways were upregulated after shikonin treatment. The pre-treatment with N-acetyl cysteine significantly reduced the cytotoxicity of shikonin. Taken together, shikonin could inhibit proliferation of the colorectal cancer cell through the activation of ROS mediated-ER stress. The in vivo results showed that shikonin effectively inhibited tumor growth in the HCT-116 and HCT-15 xenograft models. In conclusion, shikonin inhibited the proliferation of colorectal cancer cells in vitro and in vivo and warrants future investigation.}, }
@article {pmid34972717, year = {2022}, author = {Lee, EJ and Park, SJ and Lee, C and Yim, GW and Kim, JW and Kim, HS}, title = {Hypoxia-induced Maspin Expression Affects the Prognosis of Ovarian Clear Cell Carcinoma.}, journal = {In vivo (Athens, Greece)}, volume = {36}, number = {1}, pages = {212-220}, pmid = {34972717}, issn = {1791-7549}, mesh = {*Adenocarcinoma, Clear Cell/genetics ; Female ; Humans ; Hypoxia/genetics ; *Ovarian Neoplasms/drug therapy/genetics ; Prognosis ; *Serpins/genetics ; }, abstract = {BACKGROUND/AIM: To investigate the role of the expression of hypoxia-related genes on the prognosis of ovarian clear cell carcinoma (OCCC).<br><br>MATERIALS AND METHODS: Basal mRNA levels of eight hypoxia-related genes were compared. Cell viability was assayed after treating ES-2 cells under hypoxic conditions. The mRNA and protein levels were evaluated after the induction of hypoxia and administration of increased doses of N-acetylcysteine (NAC). Finally, the prognostic role of their expression levels was evaluated in 61 patients with OCCC.<br><br>RESULTS: The mRNA and protein levels of maspin increased gradually with the induction of hypoxia. Maspin protein expression decreased after treatment with paclitaxel and NAC. High expression of maspin was related to poor progression-free and overall survival in patients with OCCC (adjusted hazard ratios, 3.97 and 7.47; 95% confidence intervals=1.34-11.81, and 1.98-28.13).<br><br>CONCLUSION: High expression of maspin induced by hypoxia might be associated with poor prognosis of OCCC.}, }
@article {pmid34970573, year = {2021}, author = {Zhou, X and Dai, Y and Zhai, Z and Hong, J}, title = {WAY-100635 Alleviates Corneal Lesions Through 5-HT1A Receptor-ROS-Autophagy Axis in Dry Eye.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {799949}, pmid = {34970573}, issn = {2296-858X}, abstract = {Purpose: To explore whether 5-HT1A receptors are involved in the dry eye disease (DED) mouse model and reveal its underlying mechanism. Methods: A C57BL/6J mouse DED model was established via the administration of 0.2% benzalkonium chloride twice a day for 14 days. Corneal fluorescein sodium staining score and Schirmer I test were checked before, and on days 7, 14, and 21 after treatment. The experiment was randomly divided into control, DED, 5-HT1A receptor agonist with or without N-acetylcysteine (NAC) and 5-HT1A receptor antagonist with or without NAC groups. The mRNA expression of inflammatory cytokines was measured by reverse transcription-quantitative polymerase chain reaction. Cellular reactive oxygen species (ROS) were detected by 2', 7'-dichlorodihydrofluorescein diacetate assays. Western blot analysis was used to measure the expression levels of autophagic proteins microtubule-associated protein 1 light chain 3 (LC3B-I/II) and autophagy-related gene 5 (ATG5). Results: 5-HT1A receptor agonist (8-OH-DPAT) increased corneal fluorescein sodium staining spots and 5-HT1A receptor antagonist (WAY-100635) decreased them. Treatment with 8-OH-DPAT was associated with the gene expression of more inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) compared with treatment with WAY-100635. An increased expression of LC3B-I/II and ATG5 was observed in corneal epithelial cells in the mouse model of DED. 8-OH-DPAT significantly enhanced the expression of LC3B-I/II and ATG5 by disrupting ROS levels. WAY-100635 alleviates autophagy by inhibiting ROS production. Conclusion: Excessive ROS release through 8-OH-DPAT induction can lead to impaired autophagy and increased inflammatory response in DED. WAY-100635 reduces corneal epithelial defects and inflammation in DED, as well as alleviates autophagy by inhibiting ROS production. The activation of the 5-HT1A receptor-ROS-autophagy axis is critically involved in DED development.}, }
@article {pmid34965485, year = {2022}, author = {Wen, E and Xin, G and Su, W and Li, S and Zhang, Y and Dong, Y and Yang, X and Wan, C and Chen, Z and Yu, X and Zhang, K and Niu, H and Huang, W}, title = {Activation of TLR4 induces severe acute pancreatitis-associated spleen injury via ROS-disrupted mitophagy pathway.}, journal = {Molecular immunology}, volume = {142}, number = {}, pages = {63-75}, doi = {10.1016/j.molimm.2021.12.012}, pmid = {34965485}, issn = {1872-9142}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/physiology ; Immunologic Factors/therapeutic use ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; Mitochondria/pathology ; Mitophagy/*physiology ; Pancreas/pathology ; Pancreatitis/chemically induced/*pathology ; Phosphatidylinositol 3-Kinase/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/physiology ; Spleen/injuries/*pathology ; TOR Serine-Threonine Kinases/metabolism ; Taurocholic Acid/toxicity ; Toll-Like Receptor 4/genetics/*metabolism ; Tuftsin/therapeutic use ; }, abstract = {Severe acute pancreatitis (SAP) is complicated by systemic inflammatory response syndrome and multiple organ dysfunction, the disease will eventually result in death in almost half of the case. The spleen, as the largest immune organ adjacent to the pancreas, is prone to damage in SAP, thereby aggravating the damage of other organs and increasing mortality. However, to date, the research on the mechanism and treatment of spleen injury caused by SAP is still in its infancy. Herein, we investigated the mechanism of spleen injury, and explored the application potential of tuftsin for relieving spleen damage in SAP mice. Firstly, SAP mice model was constructed via the retrograde infusion of 3.5 % sodium taurocholate into the biliopancreatic duct. Then, we proved that the up-regulation of Toll-like receptor 4 (TLR4) in spleen would lead to the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction under SAP conditions. The splenic ROS and mitochondrial dysfunction could be improved by N-acetylcysteine (NAC) treatment or knocking out TLR4 in SAP mice. Meanwhile, we found that NAC treatment could also improve the autophagy of spleen tissue, suggesting that splenic ROS may affect impaired autophagy, causing the accumulation of damaged mitochondria, aggravating spleen damage. Furthermore, we verified the mechanism of spleen injury is caused by splenic ROS affecting PI3K/p-AKT/mTOR pathway-mediated autophagy. In addition, we detected the spleen injury caused by SAP could decrease the concentration of tuftsin in the serum of mice. Whereas, exogenous supplementation of tuftsin ameliorated the pathological damage, ROS accumulation, impaired autophagy, inflammation expression and apoptosis in damaged spleen. In summary, we verified the new mechanism of SAP-caused spleen damage that TLR4-induced ROS provoked mitophagy impairment and mitochondrial dysfunction in spleen via PI3K/p-AKT mTOR signaling, and the application potential of tuftsin in treating spleen injury, which might expand novel ideas and methods for the treatment of pancreatitis.}, }
@article {pmid34964212, year = {2022}, author = {Bhardwaj, JK and Kumar, V and Saraf, P and Panchal, H and Rathee, V and Sachdeva, SN}, title = {Efficacy of N-acetyl- l-cysteine against glyphosate induced oxidative stress and apoptosis in testicular germ cells preventing infertility.}, journal = {Journal of biochemical and molecular toxicology}, volume = {36}, number = {4}, pages = {e22979}, doi = {10.1002/jbt.22979}, pmid = {34964212}, issn = {1099-0461}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Apoptosis ; Germ Cells/metabolism ; Glycine/analogs &amp; derivatives ; Goats/metabolism ; *Infertility/metabolism ; Male ; Oxidative Stress ; Testis/metabolism ; Glyphosate ; }, abstract = {The present era's demand for continuous pesticides' use to increase the agriculture outcome, has caused numerous health effects among which mammalian infertility, owing to reproductive toxicity, is serious. Thus, the present study emphasizes upon glyphosate (GLY) induced toxicity and mitigating effects of N-acetyl cysteine (NAC) in testicular cells of caprine by using various cytotoxic and biochemical parameters. GLY was found to induce several apoptotic attributes such as pyknotic nuclei, tubular degeneration, increased vacuolization, and so on, in testicular cells. GLY also decreased the cell viability and increased the incidence of apoptosis in testicular cells in a dose- and time-dependent manner as revealed by MTT assay and Fluorescence (ethidium bromide/acridine orange) assay, respectively. It also increased the level of oxidative stress as evident with an increase in lipid peroxidation and decline in antioxidant power along with the decreased enzymatic activity of different antioxidant enzymes (SOD, CAT, and GST). However, NAC supplementation showed antagonistic results in GLY-treated testicular tissues with maximum amelioration at the highest dose, thereby decreasing GLY-mediated apoptosis rate and oxidative stress. Maximum amelioration was reported at 10 mM NAC concentration. Reduced GLY toxicity due to NAC will prove NAC to be an excellent approach for dealing with male reproductive toxicity at the cellular level, benefiting the mammalian reproductive status.}, }
@article {pmid34964128, year = {2022}, author = {Bai, X and Lian, Y and Hu, C and Yang, S and Pei, B and Yao, M and Zhu, X and Shang, L and Li, Z}, title = {Cyanidin-3-glucoside protects against high glucose-induced injury in human nucleus pulposus cells by regulating the Nrf2/HO-1 signaling.}, journal = {Journal of applied toxicology : JAT}, volume = {42}, number = {7}, pages = {1137-1145}, doi = {10.1002/jat.4281}, pmid = {34964128}, issn = {1099-1263}, support = {2041ZF092//Baoding Science and Technology Plan Project/ ; }, mesh = {Aggrecans/metabolism/pharmacology ; *Anthocyanins/metabolism/pharmacology ; Apoptosis ; Caspase 3/metabolism ; Glucose/metabolism/toxicity ; Humans ; Matrix Metalloproteinase 13/metabolism/pharmacology ; Matrix Metalloproteinase 3/metabolism/pharmacology ; NF-E2-Related Factor 2/genetics/metabolism ; *Nucleus Pulposus/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Cyanidin-3-glucoside (C3G) is a well-known natural anthocyanin with antioxidant and anti-inflammatory properties. In this study, we explored the role and action mechanism of C3G in high glucose (HG)-induced damage of human nucleus pulposus cells (HNPCs). Cell viability was assessed by CCK-8 assay. TUNEL assay was performed for detecting apoptotic rate. Western blot was performed to determine the expression levels of cl-caspase-3, caspase-3, Bax, Bim, collagen II, aggrecan, MMP-3, MMP-13, and ADAMTS5. Reactive oxygen species (ROS) generation was analyzed using DCFH-DA staining. The Nrf2 was knocked down or overexpressed in HNPCs through transfection with si-Nrf2 or pcDNA3.0-Nrf2. C3G treatment (12.5, 25, and 50 μM) improved cell viability of HNPCs under HG condition. HG-induced cell apoptosis of HNPCs was attenuated by C3G with decreased apoptotic rate and relative levels of cl-caspase-3/caspase-3, Bax, and Bim. C3G treatment caused significant increase in expression levels of collagen II and aggrecan and decrease in the relative levels of MMP-3, MMP-13, and ADAMTS5. After treatment with C3G, ROS generation in HNPCs was markedly reduced. Treatment with N-acetylcysteine (NAC) reversed HG-induced cell apoptosis and extracellular matrix (ECM) degradation. C3G treatment induced the expression of Nrf2 and HO-1 in HG-induced HNPCs. Moreover, knockdown of Nrf2 reversed the inhibitory effect of C3G on ROS production. Summarily, C3G exerted a protective effect on ROS-mediated cellular damage in HNPCs under HG condition, which was attributed to the induction of the Nrf2/HO-1 signaling pathway.}, }
@article {pmid34958912, year = {2022}, author = {Virel, A and Johansson, J and Axelsson, J and Ericsson, M and Laterveer, R and Ögren, M and Orädd, G and Jakobson Mo, S and Af Bjerkén, S}, title = {N-acetylcysteine decreases dopamine transporter availability in the non-lesioned striatum of the 6-OHDA hemiparkinsonian rat.}, journal = {Neuroscience letters}, volume = {770}, number = {}, pages = {136420}, doi = {10.1016/j.neulet.2021.136420}, pmid = {34958912}, issn = {1872-7972}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Corpus Striatum/drug effects/*metabolism ; Dopamine Plasma Membrane Transport Proteins/*metabolism ; Female ; Nortropanes/pharmacokinetics ; Oxidopamine/toxicity ; Parkinson Disease/diagnostic imaging/etiology/*metabolism ; Positron-Emission Tomography ; Radiopharmaceuticals/pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; }, abstract = {This study aimed to explore the beneficial effects of the antioxidant N-acetylcysteine (NAC) on the degenerated dopamine system. The short- and long-term regulatory mechanisms of NAC on the 6-OHDA hemiparkinsonian rat model were longitudinally investigated by performing positron emission tomography (PET) imaging using the specific dopamine transporter (DAT) radioligand [[18]F]FE-PE2I. The results demonstrate that after a unilateral dopamine insult NAC has a strong influence on the non-lesioned hemisphere by decreasing the levels of DAT in the striatum early after the lesion. We interpret this early and short-term decrease of DAT in the healthy striatum of NAC-treated animals as a beneficial compensatory effect induced by NAC.}, }
@article {pmid34958803, year = {2022}, author = {Liu, D and Cheng, Y and Chen, J and Mei, X and Tang, Z and Cao, X and Liu, J}, title = {Exploring the molecular mechanisms of the inhibition of acrolein-induced BEAS-2B cytotoxicity by luteolin using network pharmacology and cell biology technology.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {160}, number = {}, pages = {112779}, doi = {10.1016/j.fct.2021.112779}, pmid = {34958803}, issn = {1873-6351}, mesh = {Acrolein/*toxicity ; Air Pollutants/*toxicity ; Apoptosis/drug effects ; Bronchi/cytology/drug effects/metabolism ; DNA Damage/drug effects ; Epithelial Cells/cytology/*drug effects/metabolism ; Glutathione/metabolism ; Humans ; Luteolin/*pharmacology ; Network Pharmacology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Acrolein is a highly reactive unsaturated hazardous air pollutant, which is extremely irritating to the respiratory tract. Luteolin, an active flavonoid compound, possesses multiple biological activities. The purpose of this study was to evaluate the mechanism of the inhibition of acrolein-induced human bronchial epithelial (BEAS-2B) cells cytotoxicity by luteolin using network pharmacology and cell biology technology. Firstly, network pharmacology results indicated that oxidative stress processes might play an important role in luteolin inhibiting lung injury. Next, it was verified at the cellular level. Reactive oxygen species (ROS) generation increased, glutathione (GSH) level decreased after exposure to acrolein. MAPK signaling pathways were activated, which activated downstream IκBα/NF-κB signaling pathways. Meanwhile, acrolein caused oxidative DNA damage and double-strand breaks, induced DNA damage response (DDR) and apoptosis. These adverse effects were significantly reversed by luteolin, which inhibited the activation of MAPK/IκBα/NF-κB and DDR pathways, and reduced the ratio of Bax/Bcl-2. Moreover, luteolin also had a similar effect to antioxidant N-acetyl cysteine (NAC) in the regulation of signaling transduction mechanisms, which indicated that the regulation of oxidative stress played an important role in the process. These results provide an experimental basis for elucidating the molecular mechanisms of the inhibition of acrolein-induced BEAS-2B cytotoxicity with luteolin.}, }
@article {pmid34957591, year = {2023}, author = {Bateman, DN}, title = {Large paracetamol overdose-Higher dose acetylcysteine is required.}, journal = {British journal of clinical pharmacology}, volume = {89}, number = {1}, pages = {34-38}, doi = {10.1111/bcp.15201}, pmid = {34957591}, issn = {1365-2125}, mesh = {Humans ; Acetylcysteine/therapeutic use ; Acetaminophen ; Antidotes/therapeutic use ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury ; *Drug-Related Side Effects and Adverse Reactions ; *Analgesics, Non-Narcotic ; }, abstract = {Paracetamol poisoning continues to be a worldwide problem and, despite the availability of an effective antidote, acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from high doses of paracetamol, even in those receiving prompt NAC therapy, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.}, }
@article {pmid34954677, year = {2022}, author = {Zhang, Y and Yan, M and Kuang, S and Lou, Y and Wu, S and Li, Y and Wang, Z and Mao, H}, title = {Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO-Y4: Involvement of ROS-mediated mTOR/ULK1 pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {230}, number = {}, pages = {113119}, doi = {10.1016/j.ecoenv.2021.113119}, pmid = {34954677}, issn = {1090-2414}, abstract = {Bisphenol A (BPA) is a widely environmental endocrine disruptor. The accumulated BPA in humans is toxic to osteoblasts and osteoclasts, but few studies focused on the effects of BPA on osteocytes, the most abundant bone cell type, contributing to the development and metabolism of bone. Here, we reported that BPA (50, 100, 200 μmol/L) inhibited the cell viability of osteocytes MLO-Y4, promoted G0/G1 phase arrest and apoptosis in a dose-dependent manner. BPA treatment significantly increased the levels of autophagy-regulated proteins including Beclin-1 and LC3-II along with the decrease of p62, accompanied by the elevation of autophagy flux and the accumulation of acidic vacuoles, which was blocked by the autophagy inhibitor bafilomycin A1 (BafA1). Furthermore, BPA significantly inhibited the mammalian target of rapamycin (mTOR) and activated Unc-51 like autophagy activating kinase 1 (ULK1) signaling, leading to the decreased p-mTOR/mTOR ratio and the increased p-ULK1/ULK1 ratio. The mTOR activator MHY1485 (MHY) or the ULK1 inhibitor SBI-0206965 (SBI) prevented autophagy and enhanced apoptosis caused by BPA, respectively. In addition, BPA increased the levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased antioxidant enzymes nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels, resulting in oxidative stress. The ROS scavenger N-acetylcysteine (NAC) attenuated BPA-induced the mTOR/ULK1 pathway activation, apoptosis and autophagy. Collectively, ROS-mediated mTOR/ULK1 signaling is involved in BPA-induced apoptosis and autophagy in osteocytes MLO-Y4. Our data first provide in vitro evidence that apoptosis and autophagy as cellular mechanisms for the toxic effect of BPA on osteocytes, thereby advancing our understanding of the potential role of osteocytes in the adverse effect of BPA on bone health.}, }
@article {pmid34953289, year = {2022}, author = {Manohar, S and Ding, D and Jiang, H and Li, L and Chen, GD and Kador, P and Salvi, R}, title = {Combined antioxidants and anti-inflammatory therapies fail to attenuate the early and late phases of cyclodextrin-induced cochlear damage and hearing loss.}, journal = {Hearing research}, volume = {414}, number = {}, pages = {108409}, doi = {10.1016/j.heares.2021.108409}, pmid = {34953289}, issn = {1878-5891}, support = {R01 DC014693/DC/NIDCD NIH HHS/United States ; R01 DC014452/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Cochlea ; *Cyclodextrins/pharmacology ; Hair Cells, Auditory, Outer/physiology ; *Hearing Loss/chemically induced/prevention &amp; control ; *Neurodegenerative Diseases ; Otoacoustic Emissions, Spontaneous ; Rats ; }, abstract = {Niemann-Pick C1 (NPC1) is a fatal neurodegenerative disease caused by aberrant cholesterol metabolism. The progression of the disease can be slowed by removing excess cholesterol with high-doses of 2-hyroxypropyl-beta-cyclodextrin (HPβCD). Unfortunately, HPβCD causes hearing loss; the initial first phase involves a rapid destruction of outer hair cells (OHCs) while the second phase, occurring 4-6 weeks later, involves the destruction of inner hair cells (IHCs), pillar cells, collapse of the organ of Corti and spiral ganglion neuron degeneration. To determine whether the first and/or second phase of HPβCD-induced cochlear damage is linked, in part, to excess oxidative stress or neuroinflammation, rats were treated with a single-dose of 3000 mg/kg HPβCD alone or together with one of two combination therapies. Each combination therapy was administered from 2-days before to 6-weeks after the HPβCD treatment. Combination 1 consisted of minocycline, an antibiotic that suppresses neuroinflammation, and HK-2, a multifunctional redox modulator that suppresses oxidative stress. Combination 2 was comprised of minocycline plus N-acetyl cysteine (NAC), which upregulates glutathione, a potent antioxidant. To determine if either combination therapy could prevent HPβCD-induced hearing impairment and cochlear damage, distortion product otoacoustic emissions (DPOAE) were measured to assess OHC function and the cochlear compound action potential (CAP) was measured to assess the function of IHCs and auditory nerve fibers. Cochleograms were prepared to quantify the amount of OHC, IHC and pillar cell (PC) loss. HPβCD significantly reduced DPOAE and CAP amplitudes and caused significant OHC, IHC and OPC losses with losses greater in the high-frequency base of the cochlea than the apex. Neither minocycline + HK-2 (MIN+ HK-2) nor minocycline + NAC (MIN+NAC) prevented the loss of DPOAEs, CAPs, OHCs, IHCs or IPCs caused by HPβCD. These results suggest that oxidative stress and neuroinflammation are unlikely to play major roles in mediating the first or second phase of HPβCD-induced cochlear damage. Thus, HPβCD-induced ototoxicity must be mediated by some other unknown cell-death pathway possibly involving loss of trophic support from damaged support cells or disrupted cholesterol metabolism.}, }
@article {pmid34951044, year = {2023}, author = {Thanacoody, HKR}, title = {Large paracetamol overdose - Higher dose NAC is NOT required.}, journal = {British journal of clinical pharmacology}, volume = {89}, number = {1}, pages = {39-42}, doi = {10.1111/bcp.15199}, pmid = {34951044}, issn = {1365-2125}, mesh = {Humans ; Acetaminophen ; *Analgesics, Non-Narcotic/therapeutic use ; Acetylcysteine/therapeutic use ; *Drug Overdose/drug therapy ; *Chemical and Drug Induced Liver Injury ; *Drug-Related Side Effects and Adverse Reactions ; Retrospective Studies ; }, abstract = {Paracetamol overdose is common in developed countries but less than 10% involve large ingestions exceeding 30 g or 500 mg/kg. High dose acetylcysteine (NAC) has been proposed in patients taking large paracetamol overdoses based on reports of hepatotoxicity despite early initiation of NAC treatment with the commonly used 300 mg/kg intravenous acetylcysteine regimen. The evidence from cohorts of patients treated with the standard NAC regimen after large paracetamol overdoses shows that it is effective in most patients. A small study in patients with paracetamol overdoses of 40 g or more and paracetamol concentrations above the 300 mg/L nomogram line showed that modification of the standard NAC regimen to provide a total of 400-500 mg/kg NAC over 21-22 h may reduce the risk of hepatotoxicity (peak ALT > 1000 IU/L) but the impact on development of hepatic failure, liver transplantation and mortality with this approach is presently unknown. Better risk stratification of patients taking paracetamol overdose may allow higher dose NAC and adjunctive treatments such as CYP2E1 inhibition and extracorporeal removal of paracetamol to be targeted to those patients at the highest risk of hepatotoxicity after a large paracetamol overdose.}, }
@article {pmid34948425, year = {2021}, author = {Gutziet, O and Iluz, R and Ben Asher, H and Segal, L and Ben Zvi, D and Ginsberg, Y and Khatib, N and Zmora, O and Ross, MG and Weiner, Z and Beloosesky, R}, title = {Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model.}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948425}, issn = {1422-0067}, mesh = {Acetylcysteine/*metabolism ; Animals ; Animals, Newborn ; Antioxidants/metabolism ; Asphyxia Neonatorum/*complications ; Brain/*metabolism ; Gene Expression Regulation ; Hypoxia, Brain/etiology/metabolism/*prevention &amp; control ; In Situ Nick-End Labeling ; *Inflammation ; Interleukin-6/genetics ; Nitric Oxide Synthase Type I/genetics ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Transcription Factor RelA/genetics ; Tumor Necrosis Factor-alpha/genetics ; }, abstract = {Perinatal hypoxia is a major cause of infant brain damage, lifelong neurological disability, and infant mortality. N-Acetyl-Cysteine (NAC) is a powerful antioxidant that acts directly as a scavenger of free radicals. We hypothesized that maternal-antenatal and offspring-postnatal NAC can protect offspring brains from hypoxic brain damage.Sixty six newborn rats were randomized into four study groups. Group 1: Control (CON) received no hypoxic intervention. Group 2: Hypoxia (HYP)-received hypoxia protocol. Group 3: Hypoxia-NAC (HYP-NAC). received hypoxia protocol and treated with NAC following each hypoxia episode. Group 4: NAC Hypoxia (NAC-HYP) treated with NAC during pregnancy, pups subject to hypoxia protocol. Each group was evaluated for: neurological function (Righting reflex), serum proinflammatory IL-6 protein levels (ELISA), brain protein levels: NF-κB p65, neuronal nitric oxide synthase (nNOS), TNF-α, and IL-6 (Western blot) and neuronal apoptosis (histology evaluation with TUNEL stain). Hypoxia significantly increased pups brain protein levels compared to controls. NAC administration to dams or offspring demonstrated lower brain NF-κB p65, nNOS, TNF-α and IL-6 protein levels compared to hypoxia alone. Hypoxia significantly increased brain apoptosis as evidenced by higher grade of brain TUNEL reaction. NAC administration to dams or offspring significantly reduce this effect. Hypoxia induced acute sensorimotor dysfunction. NAC treatment to dams significantly attenuated hypoxia-induced acute sensorimotor dysfunction. Prophylactic NAC treatment of dams during pregnancy confers long-term protection to offspring with hypoxia associated brain injury, measured by several pathways of injury and correlated markers with pathology and behavior. This implies we may consider prophylactic NAC treatment for patients at risk for hypoxia during labor.}, }
@article {pmid34948343, year = {2021}, author = {Kim, B and Yoon, H and Kim, T and Lee, S}, title = {Role of Klotho as a Modulator of Oxidative Stress Associated with Ovarian Tissue Cryopreservation.}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948343}, issn = {1422-0067}, support = {NRF-2016R1C1B3015250//The Korean Government/ ; Research Fund//The Catholic University of Korea/ ; }, mesh = {Animals ; Antioxidants/pharmacology ; *Cryopreservation ; Female ; Fertility Preservation/*methods ; Klotho Proteins/*metabolism ; Mice ; Mice, Inbred BALB C ; Ovary/*metabolism ; *Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {Ovarian tissue cryopreservation is the only option for preserving fertility in adult and prepubertal cancer patients who require immediate chemotherapy or do not want ovarian stimulation. However, whether ovarian tissue cryopreservation can ameliorate follicular damage and inhibit the production of reactive oxygen species in cryopreserved ovarian tissue remains unclear. Oxidative stress is caused by several factors, such as UV exposure, obesity, age, oxygen, and cryopreservation, which affect many of the physiological processes involved in reproduction, from maturation to fertilization, embryonic development, and pregnancy. Here, freezing and thawing solutions were pre-treated with N-acetylcysteine (NAC) and klotho protein upon the freezing of ovarian tissue. While both NAC and klotho protein suppressed DNA fragmentation by scavenging reactive oxygen species, NAC induced apoptosis and tissue damage in mouse ovarian tissue. Klotho protein inhibited NAC-induced apoptosis and restored cellular tissue damage, suggesting that klotho protein may be an effective antioxidant for the cryopreservation of ovarian tissue.}, }
@article {pmid34948311, year = {2021}, author = {Kwon, JH and Lee, NG and Kang, AR and Song, JY and Hwang, SG and Um, HD and Kim, J and Park, JK}, title = {Radiosensitizer Effect of β-Apopicropodophyllin against Colorectal Cancer via Induction of Reactive Oxygen Species and Apoptosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {24}, pages = {}, pmid = {34948311}, issn = {1422-0067}, support = {505312021//National Research Foundation of Korea/ ; NRF-2021R1F1A1055981//National Research Foundation of Korea/ ; NRF-2020M2D9A2094153//National Research Foundation of Korea/ ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Colorectal Neoplasms/*drug therapy/metabolism ; HCT116 Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Podophyllin/*pharmacology ; Radiation-Sensitizing Agents/*pharmacology ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays/methods ; }, abstract = {β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an anti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP exerted an anti-cancer effect against the CRC cell lines HCT116, DLD-1, SW480, and COLO320DM, with IC50 values of 7.88 nM, 8.22 nM, 9.84 nM, and 7.757 nM, respectively, for the induction of DNA damage. Clonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either treatment alone, suggesting that APP sensitized CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in the in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.}, }
@article {pmid34944962, year = {2021}, author = {Tian, Y and Riquelme, MA and Tu, C and Quan, Y and Liu, X and Sun, LZ and Jiang, JX}, title = {Osteocytic Connexin Hemichannels Modulate Oxidative Bone Microenvironment and Breast Cancer Growth.}, journal = {Cancers}, volume = {13}, number = {24}, pages = {}, pmid = {34944962}, issn = {2072-6694}, support = {R01 CA196214/CA/NCI NIH HHS/United States ; CA196214/NH/NIH HHS/United States ; BC161273//Department of Defence/ ; AQ-1507//Welch Foundation/ ; }, abstract = {Osteocytes, the most abundant bone cell types embedded in the mineral matrix, express connexin 43 (Cx43) hemichannels that play important roles in bone remodeling and osteocyte survival. Estrogen deficiency decreases osteocytic Cx43 hemichannel activity and causes a loss in osteocytes' resistance to oxidative stress (OS). In this study, we showed that OS reduced the growth of both human (MDA-MB-231) and murine (Py8119) breast cancer cells. However, co-culturing these cells with osteocytes reduced the inhibitory effect of OS on breast cancer cells, and this effect was ablated by the inhibition of Cx43 hemichannels. Py8119 cells were intratibially implanted in the bone marrow of ovariectomized (OVX) mice to determine the role of osteocytic Cx43 hemichannels in breast cancer bone metastasis in response to OS. Two transgenic mice overexpressing dominant-negative Cx43 mutants, R76W and Δ130-136, were adopted for this study; the former inhibits gap junctions while the latter inhibits gap junctions and hemichannels. Under normal conditions, Δ130-136 mice had significantly more tumor growth in bone than that in WT and R76W mice. OVX increased tumor growth in R76W but had no significant effect on WT mice. In contrast, OVX reduced tumor growth in Δ130-136 mice. To confirm the role of OS, WT and Δ130-136 mice were administered the antioxidant N-acetyl cysteine (NAC). NAC increased tumor burden and growth in Δ130-136 mice but not in WT mice. Together, the data suggest that osteocytes and Cx43 hemichannels play pivotal roles in modulating the oxidative microenvironment and breast cancer growth in the bone.}, }
@article {pmid34944701, year = {2021}, author = {Kolomaznik, M and Mikolka, P and Hanusrichterova, J and Kosutova, P and Matasova, K and Mokra, D and Calkovska, A}, title = {N-Acetylcysteine in Mechanically Ventilated Rats with Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: The Effect of Intravenous Dose on Oxidative Damage and Inflammation.}, journal = {Biomedicines}, volume = {9}, number = {12}, pages = {}, pmid = {34944701}, issn = {2227-9059}, support = {APVV-17-0250//Slovak Research and Development Agency/ ; VEGA 1/0055/19//Scientific Grant Agency of the Slovak Republic/ ; VEGA 1/0004/21//Scientific Grant Agency of the Slovak Republic/ ; }, abstract = {Treatment of acute respiratory distress syndrome (ARDS) is challenging due to its multifactorial aetiology. The benefit of antioxidant therapy was not consistently demonstrated by previous studies. We evaluated the effect of two different doses of intravenous (i.v.) N-acetylcysteine (NAC) on oxidative stress, inflammation and lung functions in the animal model of severe LPS-induced lung injury requiring mechanical ventilation. Adult Wistar rats with LPS (500 μg/kg; 2.2 mL/kg) were treated with i.v. NAC 10 mg/kg (NAC10) or 20 mg/kg (NAC20). Controls received saline. Lung functions, lung oedema, total white blood cell (WBC) count and neutrophils count in blood and bronchoalveolar lavage fluid, and tissue damage in homogenized lung were evaluated. NAC significantly improved ventilatory parameters and oxygenation, reduced lung oedema, WBC migration and alleviated oxidative stress and inflammation. NAC20 in comparison to NAC10 was more effective in reduction of oxidative damage of lipids and proteins, and inflammation almost to the baseline. In conclusion, LPS-instilled and mechanically ventilated rats may be a suitable model of ARDS to test the treatment effects at organ, systemic, cellular and molecular levels. The results together with literary data support the potential of NAC in ARDS.}, }
@article {pmid34944641, year = {2021}, author = {Zhou, J and Terluk, MR and Orchard, PJ and Cloyd, JC and Kartha, RV}, title = {N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy.}, journal = {Biomedicines}, volume = {9}, number = {12}, pages = {}, pmid = {34944641}, issn = {2227-9059}, support = {Grant-in Aid of Research, Artistry and Scholarship award//University of Minnesota Office of Vice President of Research/ ; }, abstract = {The accumulation of saturated very long-chain fatty acids (VLCFA, ≥C22:0) due to peroxisomal impairment leads to oxidative stress and neurodegeneration in X-linked adrenoleukodystrophy (ALD). Among the neural supporting cells, myelin-producing oligodendrocytes are the most sensitive to the detrimental effect of VLCFA. Here, we characterized the mitochondrial dysfunction and cell death induced by VLFCA, and examined whether N-acetylcysteine (NAC), an antioxidant, prevents the cytotoxicity. We exposed murine oligodendrocytes (158 N) to hexacosanoic acid (C26:0, 1-100 µM) for 24 h and measured reactive oxygen species (ROS) and cell death. Low concentrations of C26:0 (≤25 µM) induced a mild effect on cell survival with no alterations in ROS or total glutathione (GSH) concentrations. However, analysis of the mitochondrial status of cells treated with C26:0 (25 µM) revealed depletion in mitochondrial GSH (mtGSH) and a decrease in the inner membrane potential. These results indicate that VLCFA disturbs the mitochondrial membrane potential causing ROS accumulation, oxidative stress, and cell death. We further tested whether NAC (500 µM) can prevent the mitochondria-specific effects of VLCFA in C26:0-treated oligodendrocytes. Our results demonstrate that NAC improves mtGSH levels and mitochondrial function in oligodendrocytes, indicating that it has potential use in the treatment of ALD and related disorders.}, }
@article {pmid34943939, year = {2021}, author = {Sønstevold, T and Engedal, N and Torgersen, ML}, title = {Perturbation of Cellular Redox Homeostasis Dictates Divergent Effects of Polybutyl Cyanoacrylate (PBCA) Nanoparticles on Autophagy.}, journal = {Cells}, volume = {10}, number = {12}, pages = {}, pmid = {34943939}, issn = {2073-4409}, support = {274574//The Research Council of Norway/ ; 198016-2018//Norwegian Cancer Society/ ; 2021088//Southern and Eastern Norway Regional Health Authority/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Autophagy/*drug effects/genetics ; Autophagy-Related Protein-1 Homolog/genetics ; Autophagy-Related Proteins/genetics ; Beclin-1/genetics ; Class III Phosphatidylinositol 3-Kinases/genetics ; *Drug Delivery Systems ; Enbucrilate/chemistry/*pharmacology ; Epithelial Cells/drug effects ; Gene Expression Regulation/drug effects ; Homeostasis/drug effects ; Humans ; Hydrogen Peroxide/metabolism/pharmacology ; MAP Kinase Kinase 4/genetics ; Nanoparticles/*chemistry ; Oxidation-Reduction/drug effects ; p38 Mitogen-Activated Protein Kinases/genetics ; }, abstract = {Nanoparticles (NPs) are used in our everyday life, including as drug delivery vehicles. However, the effects of NPs at the cellular level and their impacts on autophagy are poorly understood. Here, we demonstrate that the NP drug delivery vehicle poly(butyl cyanoacrylate) (PBCA) perturbs redox homeostasis in human epithelial cells, and that the degree of redox perturbation dictates divergent effects of PBCA on autophagy. Specifically, PBCA promoted functional autophagy at low concentrations, whereas it inhibited autophagy at high concentrations. Both effects were completely abolished by the antioxidant N-acetyl cysteine (NAC). High concentrations of PBCA inhibited MAP1LC3B/GABARAP lipidation and LC3 flux, and blocked bulk autophagic cargo flux induced by mTOR inhibition. These effects were mimicked by the redox regulator H2O2. In contrast, low concentrations of PBCA enhanced bulk autophagic cargo flux in a Vps34-, ULK1/2- and ATG13-dependent manner, yet interestingly, without an accompanying increase in LC3 lipidation or flux. PBCA activated MAP kinase signaling cascades in a redox-dependent manner, and interference with individual signaling components revealed that the autophagy-stimulating effect of PBCA required the action of the JNK and p38-MK2 pathways, whose activities converged on the pro-autophagic protein Beclin-1. Collectively, our results reveal that PBCA exerts a dual effect on autophagy depending on the severity of the NP insult and the resulting perturbation of redox homeostasis. Such a dual autophagy-modifying effect may be of general relevance for redox-perturbing NPs and have important implications in nanomedicine.}, }
@article {pmid34943083, year = {2021}, author = {Raiteri, T and Zaggia, I and Reano, S and Scircoli, A and Salvadori, L and Prodam, F and Filigheddu, N}, title = {The Atrophic Effect of 1,25(OH)2 Vitamin D3 (Calcitriol) on C2C12 Myotubes Depends on Oxidative Stress.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {12}, pages = {}, pmid = {34943083}, issn = {2076-3921}, support = {N/A//Italian Ministry of University and Research program "Departments of Excellence 2018-2022", AGING Project - Department of Translational Medicine, Universit&#xe0; del Piemonte Orientale./ ; }, abstract = {Dysfunctional mitochondrial metabolism has been linked to skeletal muscle loss in several physio-pathological states. Although it has been reported that vitamin D (VD) supports cellular redox homeostasis by maintaining normal mitochondrial functions, and VD deficiency often occurs in conditions associated with skeletal muscle loss, the efficacy of VD supplementation to overcome muscle wasting is debated. Investigations on the direct effects of VD metabolites on skeletal muscle using C2C12 myotubes have revealed an unexpected pro-atrophic activity of calcitriol (1,25VD), while its upstream metabolites cholecalciferol (VD3) and calcidiol (25VD) have anti-atrophic effects. Here, we investigated if the atrophic effects of 1,25VD on myotubes depend on its activity on mitochondrial metabolism. The impact of 1,25VD and its upstream metabolites VD3 and 25VD on mitochondria dynamics and the activity of C2C12 myotubes was evaluated by measuring mitochondrial content, architecture, metabolism, and reactive oxygen species (ROS) production. We found that 1,25VD induces atrophy through protein kinase C (PKC)-mediated ROS production, mainly of extramitochondrial origin. Consistent with this, cotreatment with the antioxidant N-acetylcysteine (NAC), but not with the mitochondria-specific antioxidant mitoTEMPO, was sufficient to blunt the atrophic activity of 1,25VD. In contrast, VD3 and 25VD have antioxidant properties, suggesting that the efficacy of VD supplementation might result from the balance between atrophic pro-oxidant (1,25VD) and protective antioxidant (VD3 and 25VD) metabolites.}, }
@article {pmid34942984, year = {2021}, author = {Kim, TW and Ko, SG}, title = {The Herbal Formula JI017 Induces ER Stress via Nox4 in Breast Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {12}, pages = {}, pmid = {34942984}, issn = {2076-3921}, support = {2020R1A5A2019413//National Research Foundation of Korea/ ; }, abstract = {Chemotherapy is a powerful anti-tumor therapeutic strategy; however, resistance to treatment remains a serious concern. To overcome chemoresistance, combination therapy with anticancer drugs is a potential strategy. We developed a novel herbal extract, JI017, with lower toxicity and lesser side effects. JI017 induced programmed cell death and excessive unfolded protein response through the release of intracellular reactive oxygen species (ROS) and calcium in breast cancer cells. JI017 treatment increased the expression of endoplasmic reticulum (ER) stress markers, including p-PERK, p-eIF2α, ATF4, and CHOP, via the activation of both exosomal GRP78 and cell lysate GRP78. The ROS inhibitors diphenyleneiodonium and N-acetyl cysteine suppressed apoptosis and excessive ER stress by inhibiting Nox4 in JI017-treated breast cancer cells. Furthermore, in paclitaxel-resistant breast cancer cell lines, MCF-7R and MDA-MB-231R, a combination of JI017 and paclitaxel overcame paclitaxel resistance by blocking epithelial-mesenchymal transition (EMT) processes, such as the downregulation of E-cadherin expression and the upregulation of HIF-1α, vimentin, Snail, and Slug expression. These findings suggested that JI017 exerts a powerful anti-cancer effect in breast cancer and a combination therapy of JI017 and paclitaxel may be a potential cancer therapy for paclitaxel resistant breast cancer.}, }
@article {pmid34939440, year = {2021}, author = {Alduraywish, AA}, title = {Cardiorespiratory and metabolic fitness indicators in novice volleyball trainees: effect of 1-week antioxidant supplementation with N-acetyl-cysteine/zinc/vitamin C.}, journal = {The Journal of international medical research}, volume = {49}, number = {12}, pages = {3000605211067125}, pmid = {34939440}, issn = {1473-2300}, mesh = {Acetylcysteine/pharmacology ; Angiopoietin-Like Protein 8/blood ; *Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Dietary Supplements ; Hepatocyte Growth Factor/blood ; Humans ; Insulin/blood ; Male ; *Sports Nutritional Physiological Phenomena ; *Volleyball ; Zinc/pharmacology ; }, abstract = {OBJECTIVES: This study aimed to determine the effect of 7-day dietary supplementation of N-acetylcysteine (NAC)/zinc/vitamin C on the time-to-exhaustion (TTE), the cardiorespiratory fitness (CRF) index, and metabolic indicators.<br><br>METHODS: This study enrolled volleyball student trainees (n&#x2009;=&#x2009;18 men) who took NAC/zinc/vitamin C (750&#x2009;mg/5&#x2009;mg/100&#x2009;mg) for 7 days at Jouf University, Saudi Arabia. The CRF index and TTE were determined. Serum concentrations of metabolic regulators (insulin, betatrophin, and hepatocyte growth factor), biomarkers of cellular damage/hypoxia, and indicators of lipid and glycemic control were measured.<br><br>RESULTS: Supplementation improved the TTE and CRF index, and lowered cytochrome c, C-reactive protein, hypoxia-inducible factor-1&#x3b1; (HIF-1&#x3b1;), total cholesterol, insulin, and glycated hemoglobin values. Before and after supplementation, the CRF index was negatively correlated with body mass index and positively correlated with the TTE. Before supplementation, the CRF index was positively correlated with betatrophin concentrations, and hepatocyte growth factor concentrations were positively correlated with betatrophin concentrations and negatively correlated with the homeostasis model assessment of insulin resistance index. After supplementation, the CRF index was negatively correlated with HIF-1&#x3b1; concentrations and metabolites. Additionally, the TTE was negatively correlated with HIF-1&#x3b1;, cytochrome c, and triacylglycerol concentrations.<br><br>CONCLUSION: Supplementation of NAC/zinc/vitamin C improves metabolic and CRF performance.}, }
@article {pmid34936178, year = {2022}, author = {Cecire, J and Adams, K and Pham, H and Pang, T and Burnett, D}, title = {Pharmacological prevention of post-operative pancreatitis: systematic review and meta-analysis of randomized controlled trials on animal studies.}, journal = {ANZ journal of surgery}, volume = {92}, number = {6}, pages = {1338-1346}, doi = {10.1111/ans.17417}, pmid = {34936178}, issn = {1445-2197}, mesh = {Amylases ; Animals ; Humans ; *Interleukin-6 ; Necrosis/complications ; *Pancreatitis/etiology/prevention &amp; control ; Postoperative Complications/etiology/prevention &amp; control ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Postoperative pancreatic fistula (POPF) remains a significant complication of pancreatic resection with recent evidence showing a strong association between post-operative pancreatitis and subsequent development of POPF. Incidence and severity of pancreatitis following endoscopic therapy has been effectively reduced with indomethacin prophylaxis, however further agents require evaluation. We present a systematic literature review and meta-analysis of the prophylactic treatment with corticosteroids or n-acetyl cysteine (NAC) of induced pancreatitis in rodent models.<br><br>METHODS: A systematic literature search was conducted using Pubmed, Medline, Embase and Cochrane library to identify eligible randomized control trials (RCT) involving animal models that examined NAC or corticosteroids. The primary outcome was the subsequent effect on serum amylase and IL-6 and the histopathological markers of severity such as pancreatic oedema and necrosis.<br><br>RESULTS: Four RCTs (n&#xa0;=&#xa0;178) met inclusion criteria examining NAC and eight RCTs (n&#xa0;=&#xa0;546) examining corticosteroid agents (dexamethasone, hydrocortisone, methylprednisolone). Prophylactic administration of all corticosteroid agents showed a net effect in favour of reducing markers of severity of pancreatitis. NAC showed a significant reduction in severity of amylase and necrosis.<br><br>CONCLUSION: The RCTs examined suggest that prophylactic administration of corticosteroid agents and NAC can reduce the severity of pancreatitis as indicated by histopathologic markers, serum amylase and IL-6 levels.}, }
@article {pmid34933532, year = {2021}, author = {Rafiee, B and Bagher Tabei, SM}, title = {The effect of N-acetyl cysteine consumption on men with abnormal sperm parameters due to positive history of COVID-19 in the last three months.}, journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica}, volume = {93}, number = {4}, pages = {465-467}, doi = {10.4081/aiua.2021.4.465}, pmid = {34933532}, issn = {2282-4197}, mesh = {Acetylcysteine/therapeutic use ; *COVID-19 ; Female ; Humans ; *Infertility, Male/drug therapy ; Male ; SARS-CoV-2 ; Semen ; Semen Analysis ; Sperm Count ; Sperm Motility ; Spermatozoa ; }, abstract = {Male infertility is an important factor accounting for 40-50% of infertility cases that may be due to disturbance in one of the parameters as concentration, motility and morphology observed in one or two semen analysis with an interval of 1 and 4 weeks. COVID-19 may affect male fertility through virus division, cytotoxic effects on testicular tissue and immunopathological effect. N-acetyl cysteine (NAC) improved sperm concentration and acrosome reaction while reducing reactive oxygen species (ROS) and oxidation of sperm DNA. This interventional study was conducted on 200 men who were referred to private infertility clinics for female factor (their previous semen analysis was normal) and got COVID-19 infection in the last 3 months showing an impairment of the latest semen analysis due to COVID. Men were placed in two groups of control (n = 100) and intervention (NAC consumption). Subjects who got COVID-19 infection had a significant impairment of sperm quality (sperm concentration, sperm motility, and normal sperm morphology) compared to their semen analysis evaluated before the COVID-19 infection. NAC consumption significantly improved sperm total motility, sperm morphology and sperm concentration. COVID-19 infection has a negative effect on sperm parameters. NAC supplementation may have positive effect on sperm parameters.}, }
@article {pmid34929351, year = {2022}, author = {Zhang, Y and Yan, M and Shan, W and Zhang, T and Shen, Y and Zhu, R and Fang, J and Mao, H}, title = {Bisphenol A induces pyroptotic cell death via ROS/NLRP3/Caspase-1 pathway in osteocytes MLO-Y4.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {159}, number = {}, pages = {112772}, doi = {10.1016/j.fct.2021.112772}, pmid = {34929351}, issn = {1873-6351}, mesh = {Animals ; Benzhydryl Compounds/*toxicity ; Caspase 1/metabolism ; Cell Line ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Osteocytes/*drug effects/metabolism ; Phenols/*toxicity ; Pyroptosis/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, is commonly used as a plasticizer to manufacture various food packaging materials. Evidence has demonstrated that BPA disturbed bone health. However, few studies focused on the effect of BPA on osteocytes, making up over 95% of all the bone cells. Here, we reported that BPA inhibited the cell viability of MLO-Y4 cells, and increased apoptosis in a dose-dependent manner. Furthermore, BPA up-regulated protein expressions of speck-like protein containing CARD (ASC), NLRP3, cleaved caspase-1 (Casp-1 p20) and cleaved gasdermin D (GSDMD-N), and increased the ratios of interleukin (IL)-1β/pro-IL-1β and IL-18/pro-IL-18 in MLO-Y4 cells. BPA enhanced levels of lactate dehydrogenase (LDH), IL-1β and IL-18 in culture supernatants. This pyroptotic death and the NLPR3 inflammasome activation were reversed by the caspase-1 inhibitor VX765 or the NLRP3 inflammasome inhibitor MCC950. Furthermore, BPA stimulated the production of intracellular reactive oxygen species (ROS), mitochondrial ROS (mtROS), elevated malondialdehyde (MDA) level and decreased superoxide dismutase (SOD) activity, which led to oxidative damage in MLO-Y4 cells. The ROS scavenger N-acetylcysteine (NAC) or the mitochondrial antioxidant Mito-TEMPO inhibited the NLPR3 inflammasome activation and pyroptotic death induced by BPA. Collectively, our data suggest that BPA causes pyroptotic death of osteocytes via ROS/NLRP3/Caspase-1 pathway.}, }
@article {pmid34926192, year = {2021}, author = {Hwang, SB and Park, JH and Park, JY and Kang, SS and Chung, HS and Lee, H and Kim, JY and Tchah, H}, title = {Anti-inflammatory and anti-apoptotic effects of N-acetylcysteine in diabetic rat corneal epithelium.}, journal = {International journal of ophthalmology}, volume = {14}, number = {12}, pages = {1805-1812}, pmid = {34926192}, issn = {2222-3959}, abstract = {AIM: To characterize the anti-inflammatory and anti-apoptotic effects of N-acetylcysteine (NAC) in streptozotocin (STZ)-induced diabetic rat corneal epithelium and human corneal epithelial cells (HCECs) exposed to a high-glucose environment.<br><br>METHODS: HCECs were incubated in 0, 5, 50 mmol/L glucose medium, or 50 mmol/L glucose medium with NAC for 24h. Diabetes was induced in rats by intraperitoneal injection of 65 mg/kg STZ and some of these rats were topically administered NAC to corneas with 3 mice per group. We characterized receptor for advanced glycation end-products (RAGE) expression using immunofluorescence, and interleukin (IL)-1&#x3b2; and cleaved caspase-3 (CCAP-3) expression using immunohistochemistry. Circulating tumor necrosis factor (TNF)-&#x3b1; concentration was measured by ELISA and cleaved poly-ADP ribose polymerase (PARP) concentration was quantified by Western blotting. Apoptotic cells were detected using TUNEL assay and annexin V and propidium iodide staining.<br><br>RESULTS: Diabetic rats had higher expression of RAGE (2.46&#xb1;0.13 fold), IL-1&#x3b2;, and CCAP-3 in apoptotic cells of their corneas than control rats. The expression of RAGE (1.83&#xb1;0.11 fold), IL-1&#x3b2;, and CCAP-3, and the number of apoptotic cells, were reduced by topical NAC treatment. HCECs incubated in 50 mmol/L glucose medium showed high concentrations of TNF-&#x3b1; (310&#xb1;2.00 pg/mL) and cleaved PARP (7.43&#xb1;0.56 fold), and more extensive apoptosis than cells in 50 mmol/L glucose medium. However, the addition of NAC reduced the concentrations of TNF-&#x3b1; (153.67&#xb1;2.31 pg/mL) and cleaved PARP (5.55&#xb1;0.31 fold) and the number of apoptotic cells.<br><br>CONCLUSION: NAC inhibits inflammation and apoptosis in the corneas of diabetic rats and HCECs maintained in a high-glucose environment.}, }
@article {pmid34924003, year = {2021}, author = {Zhang, VX and Sze, KM and Chan, LK and Ho, DW and Tsui, YM and Chiu, YT and Lee, E and Husain, A and Huang, H and Tian, L and Wong, CC and Ng, IO}, title = {Antioxidant supplements promote tumor formation and growth and confer drug resistance in hepatocellular carcinoma by reducing intracellular ROS and induction of TMBIM1.}, journal = {Cell &amp; bioscience}, volume = {11}, number = {1}, pages = {217}, pmid = {34924003}, issn = {2045-3701}, support = {04152336//Health and Medical Research Fund/ ; T12-704/16-R//Hong Kong Research Grants Council Theme-based Research Scheme/ ; 81872222//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Controversy over the benefits of antioxidants supplements in cancers persists for long. Using hepatocellular carcinoma (HCC) as a model, we investigated the effects of exogenous antioxidants N-acetylcysteine (NAC) and glutathione (GSH) on tumor formation and growth.<br><br>METHODS: Multiple mouse models, including diethylnitrosamine (DEN)-induced and Trp53KO/C-MycOE-induced HCC models, mouse hepatoma cell and human HCC cell xenograft models with subcutaneous or orthotopic injection were used. In vitro assays including ROS assay, colony formation, sphere formation, proliferation, migration and invasion, apoptosis, cell cycle assays were conducted. Western blot was performed for protein expression and RNA-sequencing to identify potential gene targets.<br><br>RESULTS: In these multiple different mouse and cell line models, we observed that NAC and GSH promoted HCC tumor formation and growth, accompanied with significant reduction of intracellular reactive oxygen species (ROS) levels. Moreover, NAC and GSH promoted cancer stemness, and abrogated the tumor-suppressive effects of Sorafenib both in vitro and in vivo. Exogenous supplementation of NAC or GSH reduced the expression of NRF2 and GCLC, suggesting the NRF2/GCLC-related antioxidant production pathway might be desensitized. Using transcriptomic analysis to identify potential gene targets, we found that TMBIM1 was significantly upregulated upon NAC and GSH treatment. Both TCGA and in-house RNA-sequence databases showed that TMBIM1 was overexpressed in HCC tumors. Stable knockdown of TMBIM1 increased the intracellular ROS; it also abolished the promoting effects of the antioxidants in HCC cells. On the other hand, BSO and SSA, inhibitors targeting NAC and GSH metabolism respectively, partially abrogated the pro-oncogenic effects induced by NAC and GSH in vitro and in vivo.<br><br>CONCLUSIONS: Our data implicate that exogenous antioxidants NAC and GSH, by reducing the intracellular ROS levels and inducing TMBIM expression, promoted HCC formation and tumor growth, and counteracted the therapeutic effect of Sorafenib. Our study provides scientific insight regarding the use of exogenous antioxidant supplements in cancers.}, }
@article {pmid34916980, year = {2021}, author = {Palaniyappan, L and Sabesan, P and Li, X and Luo, Q}, title = {Schizophrenia Increases Variability of the Central Antioxidant System: A Meta-Analysis of Variance From MRS Studies of Glutathione.}, journal = {Frontiers in psychiatry}, volume = {12}, number = {}, pages = {796466}, pmid = {34916980}, issn = {1664-0640}, abstract = {Patients with schizophrenia diverge in their clinical trajectories. Such diverge outcomes may result from the resilience provided by antioxidant response system centered on glutathione (GSH). Proton Magnetic Resonance Spectroscopy (1H-MRS) has enabled the precise in vivo measurement of intracortical GSH; but individual studies report highly variable results even when GSH levels are measured from the same brain region. This inconsistency could be due to the presence of distinct subgroups of schizophrenia with varying GSH-levels. At present, we do not know if schizophrenia increases the interindividual variability of intracortical GSH relative to matched healthy individuals. We reviewed all 1H-MRS GSH studies in schizophrenia focused on the Anterior Cingulate Cortex published until August 2021. We estimated the relative variability of ACC GSH levels in patients compared to control groups using the variability ratio (VR) and coefficient of variation ratio (CVR). The presence of schizophrenia significantly increases the variability of intracortical GSH in the ACC (logVR = 0.12; 95% CI: 0.03-0.21; log CVR = 0.15; 95% CI = 0.06-0.23). Insofar as increased within-group variability (heterogeneity) could result from the existence of subtypes, our results call for a careful examination of intracortical GSH distribution in schizophrenia to seek redox-deficient and redox-sufficient subgroups. An increase in GSH variability among patients also indicate that the within-group predictability of adaptive response to oxidative stress may be lower in schizophrenia. Uncovering the origins of this illness-related reduction in the redox system stability may provide novel treatment targets in schizophrenia.}, }
@article {pmid34916780, year = {2021}, author = {Zhang, BH and Liu, H and Yuan, Y and Weng, XD and Du, Y and Chen, H and Chen, ZY and Wang, L and Liu, XH}, title = {Knockdown of TRIM8 Protects HK-2 Cells Against Hypoxia/Reoxygenation-Induced Injury by Inhibiting Oxidative Stress-Mediated Apoptosis and Pyroptosis via PI3K/Akt Signal Pathway.}, journal = {Drug design, development and therapy}, volume = {15}, number = {}, pages = {4973-4983}, pmid = {34916780}, issn = {1177-8881}, mesh = {Acute Kidney Injury/*metabolism ; Apoptosis/drug effects ; Carrier Proteins/*metabolism ; Cell Survival ; Cells, Cultured ; Humans ; Hydrogen Peroxide/metabolism ; Hypoxia ; Nerve Tissue Proteins/*metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Pyroptosis/drug effects ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/*prevention &amp; control ; Signal Transduction ; }, abstract = {BACKGROUND: Acute kidney injury (AKI) emerges as an acute and critical disease. Tripartite motif 8 (TRIM8), one number of the TRIM protein family, is proved to participate in ischemia/reperfusion (I/R) injury. However, whether TRIM8 is involved in renal I/R injury and the associated mechanisms are currently unclear.<br><br>PURPOSE: This study aimed to investigate the precise role of TRIM8 and relevant mechanisms in renal I/R injury.<br><br>MATERIALS AND METHODS: In this study, human renal proximal tubular epithelial cells (HK-2 cells) underwent 12 hours of hypoxia and 2 h, 3 h or 4 h of reoxygenation to establish an in vitro hypoxia/reoxygenation (H/R) model. The siRNAs specific to TRIM8 (si-TRIM8) were transfected into HK-2 cells to knockdown TRIM8. The cell H/R model included various groups including Control, H/R, H/R+DMSO, H/R+NAC, si-NC+H/R, si-TRIM8+H/R and si-TRIM8+LY294002+H/R. The cell viability and levels of reactive oxygen species (ROS), hydrogen peroxide (H2O2), mRNA, apoptotic proteins, pyroptosis-related proteins and PI3K/AKT pathway-associated proteins were assessed.<br><br>RESULTS: In vitro, realtime-quantitative PCR and western-blot analysis showed that the mRNA and protein expression of TRIM8 were obviously upregulated after H/R treatment in HK-2 cells. Compared with the H/R model group, knockdown of TRIM8 significantly increased cell viability and reduced the levels of ROS, H2O2, apoptotic proteins (Cleaved caspasebase-3 and BAX) and pyroptosis-related proteins (NLRP3, ASC, Caspase-1, Caspase-11, IL-1&#x3b2; and GSDMD-N). Western-blot analysis also authenticated that PI3K/AKT pathway was activated after TRIM8 inhibition. The application of 5 mM N-acetyl-cysteine, one highly efficient ROS inhibitor, significantly suppressed the expression of apoptotic proteins and pyroptosis-related proteins. Moreover, the combined treatment of TRIM8 knockdown and LY294002 reversed the effects of inhibiting oxidative stress.<br><br>CONCLUSION: Knockdown of TRIM8 can alleviate H/R-induced oxidative stress by triggering the PI3K/AKT pathway, thus attenuating pyropyosis and apoptosis in vitro.}, }
@article {pmid34912495, year = {2021}, author = {Ntamo, Y and Ziqubu, K and Chellan, N and Nkambule, BB and Nyambuya, TM and Mazibuko-Mbeje, SE and Gabuza, KB and Marcheggiani, F and Tiano, L and Dludla, PV}, title = {Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {3320325}, pmid = {34912495}, issn = {1942-0994}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chemical and Drug Induced Liver Injury/etiology/pathology/*prevention &amp; control ; Free Radical Scavengers/*pharmacology ; Humans ; }, abstract = {Oxidative stress is a key pathological feature implicated in both acute and chronic liver diseases, including drug-induced liver injury (DILI). The latter describes hepatic injury arising as a direct toxic effect of administered drugs or their metabolites. Although still underreported, DILI remains a significant cause of liver failure, especially in developed nations. Currently, it is understood that mitochondrial-generated oxidative stress and abnormalities in phase I/II metabolism, leading to glutathione (GSH) suppression, drive the onset of DILI. N-Acetyl cysteine (NAC) has attracted a lot of interest as a therapeutic agent against DILI because of its strong antioxidant properties, especially in relation to enhancing endogenous GSH content to counteract oxidative stress. Thus, in addition to updating information on the pathophysiological mechanisms implicated in oxidative-induced hepatic injury, the current review critically discusses clinical evidence on the protective effects of NAC against DILI, including the reduction of patient mortality. Besides injury caused by paracetamol, NAC can also improve liver function in relation to other forms of liver injury such as those induced by excessive alcohol intake. The implicated therapeutic mechanisms of NAC extend from enhancing hepatic GSH levels to reducing biomarkers of paracetamol toxicity such as keratin-18 and circulating caspase-cleaved cytokeratin-18. However, there is still lack of evidence confirming the benefits of using NAC in combination with other therapies in patients with DILI.}, }
@article {pmid34907710, year = {2021}, author = {Thida, M and Li, B and Zhang, X and Chen, C and Zhang, X}, title = {Echinacoside alleviates acetaminophen-induced liver injury by attenuating oxidative stress and inflammatory cytokines in mice.}, journal = {Journal of applied biomedicine}, volume = {19}, number = {2}, pages = {105-112}, pmid = {34907710}, issn = {1214-0287}, mesh = {Acetaminophen/adverse effects ; Animals ; Antioxidants/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy ; *Chemical and Drug Induced Liver Injury, Chronic/drug therapy ; Cytochrome P-450 CYP2E1/metabolism ; *Cytokines/drug effects/metabolism ; *Glycosides/pharmacology/therapeutic use ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Malondialdehyde/metabolism ; Mice ; Molecular Docking Simulation ; *Oxidative Stress/drug effects ; Sulfotransferases/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Uridine Diphosphate/metabolism ; }, abstract = {This study evaluates the protective effect of Echinacoside on acute liver toxicity induced by acetaminophen in mice and the mechanism behind it. Echinacoside and N-Acetyl Cysteine were intragastrically administrated for 7 days, and acetaminophen was intraperitoneally injected into mice 1 h after the last treatment on day 7. At the end of the experimental period, histological examination, parameters for the level of oxidative damage, hepatic malondialdehyde, serum pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β), UDP-glucuronosyltransferases, and sulfotransferases changes were examined using enzyme-linked immunosorbent assay and standard biochemical procedures. The expression of cytochrome P450 2E1 protein was assessed by western blot, followed by in silico molecular docking. Acetaminophen treatment obviously increased the levels of ALT and AST, changed hepatic histopathology, promoted oxidative stress, decreased antioxidant enzyme activities, and elevated the pro-inflammatory cytokines. Echinacoside significantly attenuated Acetaminophen-induced liver damage in a dose-dependent manner, with the most effective dose at 100 mg/kg. The pretreatments of Echinacoside in different concentrations altered the Acetaminophen-induced hepatotoxicity levels by decreasing the level of liver enzymes, reducing the liver necrosis with vacuolization, decreasing the hepatic malondialdehyde formation, increasing hepatic antioxidants activities, suppressing the pro-inflammatory cytokines (Tumor Necrosis Factor, Interleukin-6 and Interleukin-1beta), inhibiting Nitric Oxide production, enhancing sulfotransferases and UDP-glucuronosyltransferases activities. Notably, the expression of cytochrome P450 2E1 was inhibited by Echinacoside in a dose-dependent manner and the binding energy was -214.3 MeV. Echinacoside showed a significant protective effect against Acetaminophen-induced hepatotoxicity through the inhibition of oxidative stress, the expression of pro-inflammatory cytokines and cytochrome P450 2E1 protein expression.}, }
@article {pmid34906805, year = {2022}, author = {Yao, Y and Xiong, W and Chen, L and Ju, X and Wang, L}, title = {Synergistic growth-inhibition effect of quercetin and N-Acetyl-L-cysteine against HepG2 cells relying on the improvement of quercetin stability.}, journal = {Food chemistry}, volume = {374}, number = {}, pages = {131729}, doi = {10.1016/j.foodchem.2021.131729}, pmid = {34906805}, issn = {1873-7072}, mesh = {*Acetylcysteine ; Hep G2 Cells ; Humans ; *Quercetin ; }, abstract = {In this study, N-Acetyl-l-cysteine (NAC) as a widely-used antioxidant was first applied to improve the stability of Que in medium. The stability of Que in medium was analyzed, and the growth-inhibition effect of Que and NAC against HepG2 cells was estimated. The results showed NAC could significantly improve the stability of Que in medium (more than 80%), while Que alone in medium was totally degraded within 4 h. Besides, it was found that Que together with NAC could significantly enhance the growth-inhibition effect against HepG2 cells compared with Que alone, with the IC50 value of 40 μM and 200 μM for Que together with NAC and Que alone. Moreover, NAC could inhibit the depletion of GSH induced by Que. The synergistic growth-inhibition effect of Que and NAC against HepG2 cells was attributed to NAC improving Que stability in medium accompanied by NAC inhibiting the depletion of GSH induced by Que. The results showed that NAC could improve the stability of Que and reduce the degradation rate of Que in culture medium. This study can provide a reference for the further study of the mechanism of NAC enhancing the stability of quercetin and the development of broad-spectrum stabilizers.}, }
@article {pmid34901531, year = {2022}, author = {Sun, L and Ouyang, J and Zeng, Z and Zeng, C and Ma, Y and Zeng, F and Wu, S}, title = {Targeted and activatable nanosystem for fluorescent and optoacoustic imaging of immune-mediated inflammatory diseases and therapy via inhibiting NF-κB/NLRP3 pathways.}, journal = {Bioactive materials}, volume = {10}, number = {}, pages = {79-92}, pmid = {34901531}, issn = {2452-199X}, abstract = {Immune-mediated inflammatory diseases (IMIDs) represent a diverse group of diseases and challenges remain for the current medications. Herein, we present an activatable and targeted nanosystem for detecting and imaging IMIDs foci and treating them through blocking NF-κB/NLRP3 pathways. A ROS-activatable prodrug BH-EGCG is synthesized by coupling a near-infrared chromophore with the NF-κB/NLRP3 inhibitor epigallocatechin-3-gallate (EGCG) through boronate bond which serves as both the fluorescence quencher and ROS-responsive moiety. BH-EGCG molecules readily form stable nanoparticles in aqueous medium, which are then coated with macrophage membrane to ensure the actively-targeting capability toward inflammation sites. Additionally, an antioxidant precursor N-acetylcysteine is co-encapsulated into the coated nanoparticles to afford the nanosystem BH-EGCG&amp;NAC@MM to further improve the anti-inflammatory efficacy. Benefiting from the inflammation-homing effect of the macrophage membrane, the nanosystem delivers payloads (diagnostic probe and therapeutic drugs) to inflammatory lesions more efficiently and releases a chromophore and two drugs upon being triggered by the overexpressed in-situ ROS, thus exhibiting better theranostic performance in the autoimmune hepatitis and hind paw edema mouse models, including more salient imaging signals and better therapeutic efficacy via inhibiting NF-κB pathway and suppressing NLRP3 inflammasome activation. This work may provide perceptions for designing other actively-targeting theranostic nanosystems for various inflammatory diseases.}, }
@article {pmid34899969, year = {2021}, author = {Liu, X and Lu, X and Hu, Z}, title = {N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells.}, journal = {Computational and mathematical methods in medicine}, volume = {2021}, number = {}, pages = {7596343}, pmid = {34899969}, issn = {1748-6718}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Animals ; Case-Control Studies ; Computational Biology ; Cytokines/blood ; Disease Models, Animal ; Female ; Humans ; Interferon-gamma/*biosynthesis ; Interleukin-18/antagonists &amp; inhibitors/*biosynthesis ; Killer Cells, Natural/*drug effects/*immunology ; Lung/drug effects/immunology/pathology ; Macrophages/drug effects/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists &amp; inhibitors ; Pulmonary Disease, Chronic Obstructive/*drug therapy/*immunology/pathology ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) had exerted antioxidation and anti-inflammation effects on chronic obstructive pulmonary disease (COPD) patients. However, its effect in regulating interleukin- (IL-) 18 was not fully understood. This study was designed to evaluate the specific mechanism of NAC regulating IL-18.<br><br>MATERIALS AND METHODS: A total of 112 COPD patients and 103 health individuals were recruited in the study. Cytokine level in patients' serum was measured by enzyme-linked immunosorbent assay (ELISA). A COPD mouse model was established by administration of lipopolysaccharide (LPS) and cigarette smoke. The expression of cytokines was measured by ELISA and flow cytometry. Inflammasome-related protein was measured by Western blot.<br><br>RESULT: NAC could effectively improve the immune status of COPD patients as well as the COPD mouse model by downregulating proinflammation and inflammation cytokines including IL-1&#x3b2;, interferon- (IFN-) &#x3b3;, tumor necrosis factor- (TNF-) &#x3b1;, and IL-18. It also had the capability to suppress synthesis of IL-18 in macrophage to inhibit the secretion of IFN-&#x3b3; from natural killer (NK) cells through influencing the inflammasome-related protein in macrophages.<br><br>CONCLUSION: NAC could effectively inhibit the production of IL-18 by suppressing NLRP3 expression in macrophages to reduce the production of IFN-&#x3b3; in NK cells.}, }
@article {pmid34895315, year = {2021}, author = {Gao, FF and Quan, JH and Lee, MA and Ye, W and Yuk, JM and Cha, GH and Choi, IW and Lee, YH}, title = {Trichomonas vaginalis induces apoptosis via ROS and ER stress response through ER-mitochondria crosstalk in SiHa cells.}, journal = {Parasites &amp; vectors}, volume = {14}, number = {1}, pages = {603}, pmid = {34895315}, issn = {1756-3305}, support = {NRF-2019R1A2C1088346//National Research Foundation of Korea/ ; 81771612//National Natural Science Foundation of China/ ; 81971389//National Natural Science Foundation of China/ ; }, mesh = {*Apoptosis ; Cell Line, Tumor ; Endoplasmic Reticulum/metabolism ; *Endoplasmic Reticulum Stress ; Female ; Humans ; Membrane Potential, Mitochondrial ; Mitochondria/metabolism ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; Trichomonas vaginalis/*physiology ; Uterine Cervical Neoplasms/*parasitology ; }, abstract = {BACKGROUND: Trichomonas vaginalis causes lesions on the cervicovaginal mucosa in women; however, its pathogenesis remains unclear. We have investigated the involvement of the endoplasmic reticulum (ER) in the induction of apoptosis by T. vaginalis and its molecular mechanisms in human cervical cancer SiHa cells.<br><br>METHODS: Apoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), ER stress response and Bcl-2 family protein expression were evaluated using immunocytochemistry, flow cytometry, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide dye staining and western blotting.<br><br>RESULTS: Trichomonas vaginalis induced mitochondrial ROS production, apoptosis, the ER stress response and mitochondrial dysfunction, such as MMP depolarization and an imbalance in Bcl-2 family proteins, in SiHa cells in a parasite burden- and infection time-dependent manner. Pretreatment with N-acetyl cysteine (ROS scavenger) or 4-phenylbutyric acid (4-PBA; ER stress inhibitor) significantly alleviated apoptosis, mitochondrial ROS production, mitochondrial dysfunction and ER stress response in a dose-dependent manner. In addition, T. vaginalis induced the phosphorylation of apoptosis signal regulating kinase 1 (ASK1) and c-Jun N-terminal kinases (JNK) in SiHa cells, whereas 4-PBA or SP600125 (JNK inhibitor) pretreatment significantly attenuated ASK1/JNK phosphorylation, mitochondrial dysfunction, apoptosis and ER stress response in SiHa cells, in a dose-dependent manner. Furthermore, T. vaginalis excretory/secretory products also induced mitochondrial ROS production, apoptosis and the ER stress response in SiHa cells, in a time-dependent manner.<br><br>CONCLUSIONS: Trichomonas vaginalis induces apoptosis through mitochondrial ROS and ER stress responses, and also promotes ER stress-mediated mitochondrial apoptosis via the IRE1/ASK1/JNK/Bcl-2 family protein pathways in SiHa cells. These data suggest that T. vaginalis-induced apoptosis is affected by ROS and ER stress response via ER-mitochondria crosstalk.}, }
@article {pmid34887597, year = {2021}, author = {Ielmini, M and Caselli, I and Ceccon, F and Diurni, M and Poloni, N and Callegari, C}, title = {Selective Serotonin Reuptake Inhibitors and Nutraceutical Combination in Major Depression Disorder: A Case-Control Study.}, journal = {Psychopharmacology bulletin}, volume = {51}, number = {4}, pages = {31-39}, pmid = {34887597}, issn = {2472-2448}, mesh = {Adult ; Case-Control Studies ; *Depressive Disorder, Major/drug therapy ; *Dietary Supplements ; Humans ; Quality of Life ; Selective Serotonin Reuptake Inhibitors/*therapeutic use ; }, abstract = {INTRODUCTION: Major depressive disorder (MDD) is a primary cause of disability in adults, affecting daily functioning and decreasing quality of life. The focus on the role of nutraceuticals as adjunctive treatments to improve antidepressant response is paying growing interest. The study aims to compare the antidepressants response in the utilization of selective serotonin reuptake inhibitors (SSRIs) versus a combination of SSRIs and nutraceutical supplements based on S-Adenosyl methionine (SAMe), N-acetylcysteine (NAC) and folate in terms of efficacy and tolerability.<br><br>METHODS: A case-control study was carried out between March 2018 and September 2019. Cases and controls were evaluated through the following scales: Hospital Anxiety Depression Scale (HADS); Clinical Global Impression (CGI); Patient Global Impression of Improvement (PGI-I); Antidepressant Adverse Events checklist (AES).<br><br>RESULTS: A significant difference between the two groups of patients emerged at T1 in the HADS-A (p = 0.004) score and in the CGI score (p = 0.01), due to a major improvement in patients with a nutraceutical co-prescription. At T3 a significant statistical difference emerged, showing a greater improvement at HADS-D in the case group (p = 0.006), confirmed by a higher remission rate in patients taking a nutraceutical co-prescription. No differences in terms of adverse events emerged.<br><br>CONCLUSION: This study shows promising data about the role of nutraceuticals as adjunctive treatment in major depressive disorder to improve SSRIs efficacy, with good tolerability. More data are needed to confirm these results, particularly about the role of nutraceuticals to decrease the latency of SSRIs response.}, }
@article {pmid34885867, year = {2021}, author = {Mushtaq, I and Bashir, Z and Sarwar, M and Arshad, M and Ishtiaq, A and Khan, W and Khan, U and Tabassum, S and Ali, T and Fatima, T and Valadi, H and Nawaz, M and Murtaza, I}, title = {N-Acetyl Cysteine, Selenium, and Ascorbic Acid Rescue Diabetic Cardiac Hypertrophy via Mitochondrial-Associated Redox Regulators.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {23}, pages = {}, pmid = {34885867}, issn = {1420-3049}, support = {2018-2022//Higher Education Commission (HEC) Pakistan (to Iram Murtaza)/ ; 2019-2021//University research fund (URF), Quaid-i-Azam University (to Iram Murtaza)/ ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Ascorbic Acid/*therapeutic use ; Biomarkers/blood ; Blood Glucose/metabolism ; Body Weight/drug effects ; Calcium/blood ; Cardiomegaly/blood/complications/*drug therapy/pathology ; Cardiotonic Agents/pharmacology/therapeutic use ; Cytochromes c/metabolism ; Diabetic Cardiomyopathies/blood/complications/*drug therapy/pathology ; Disease Models, Animal ; Down-Regulation ; GATA4 Transcription Factor/metabolism ; Lipid Peroxidation/drug effects ; Lipids/blood ; Mitochondria, Heart/drug effects/*metabolism ; Myocardium/pathology ; Oxidation-Reduction ; Oxidative Stress ; PPAR alpha/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Selenium/pharmacology/*therapeutic use ; Rats ; }, abstract = {Metabolic disorders often lead to cardiac complications. Metabolic deregulations during diabetic conditions are linked to mitochondrial dysfunctions, which are the key contributing factors in cardiac hypertrophy. However, the underlying mechanisms involved in diabetes-induced cardiac hypertrophy are poorly understood. In the current study, we initially established a diabetic rat model by alloxan-administration, which was validated by peripheral glucose measurement. Diabetic rats displayed myocardial stiffness and fibrosis, changes in heart weight/body weight, heart weight/tibia length ratios, and enhanced size of myocytes, which altogether demonstrated the establishment of diabetic cardiac hypertrophy (DCH). Furthermore, we examined the expression of genes associated with mitochondrial signaling impairment. Our data show that the expression of PGC-1α, cytochrome c, MFN-2, and Drp-1 was deregulated. Mitochondrial-signaling impairment was further validated by redox-system dysregulation, which showed a significant increase in ROS and thiobarbituric acid reactive substances, both in serum and heart tissue, whereas the superoxide dismutase, catalase, and glutathione levels were decreased. Additionally, the expression levels of pro-apoptotic gene PUMA and stress marker GATA-4 genes were elevated, whereas ARC, PPARα, and Bcl-2 expression levels were decreased in the heart tissues of diabetic rats. Importantly, these alloxan-induced impairments were rescued by N-acetyl cysteine, ascorbic acid, and selenium treatment. This was demonstrated by the amelioration of myocardial stiffness, fibrosis, mitochondrial gene expression, lipid profile, restoration of myocyte size, reduced oxidative stress, and the activation of enzymes associated with antioxidant activities. Altogether, these data indicate that the improvement of mitochondrial dysfunction by protective agents such as N-acetyl cysteine, selenium, and ascorbic acid could rescue diabetes-associated cardiac complications, including DCH.}, }
@article {pmid34884459, year = {2021}, author = {Cela-López, JM and Camacho Roldán, CJ and Gómez-Lizarraga, G and Martínez, V}, title = {Effects of Itxasol© Components on Gene Expression in Bacteria Related to Infections of the Urinary Tract and to the Inflammation Process.}, journal = {International journal of molecular sciences}, volume = {22}, number = {23}, pages = {}, pmid = {34884459}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; Arbutin/pharmacology/therapeutic use ; Bacteria/drug effects/*genetics ; Bacterial Proteins/*genetics ; Drug Combinations ; Gene Expression Regulation, Bacterial/drug effects ; Humans ; Molecular Mimicry ; Umbelliferones/pharmacology/therapeutic use ; Urinary Tract Infections/drug therapy/*microbiology ; }, abstract = {Urinary tract infections (UTIs) represent a health problem of the first magnitude since they affect large segments of the population, cause increased mortality and comorbidity, and have a high incidence of relapse. Therefore, UTIs cause a major socioeconomic concern. Current antibiotic treatments have various limitations such as the appearance of resistance to antibiotics, nephrotoxicity, and side effects such as gastrointestinal problems including microbiota alterations that contribute to increasing antibiotic resistance. In this context, Itxasol© has emerged, approved as an adjuvant for the treatment of UTIs. Designed with biomimetic principles, it is composed of arbutin, umbelliferon, and N-acetyl cysteine. In this work, we review the activities of these three compounds concerning the changes they produce in the expression of bacterial genes and those related to inflammation as well as assess how they are capable of affecting the DNA of bacteria and fungi.}, }
@article {pmid34884437, year = {2021}, author = {Mlejnek, P and Dolezel, P and Kriegova, E and Pastvova, N}, title = {N-acetylcysteine Can Induce Massive Oxidative Stress, Resulting in Cell Death with Apoptotic Features in Human Leukemia Cells.}, journal = {International journal of molecular sciences}, volume = {22}, number = {23}, pages = {}, pmid = {34884437}, issn = {1422-0067}, support = {IGA_LF 2021_006//Palack&#xfd; University, Olomouc/ ; }, mesh = {Acetylcysteine/*pharmacology ; Catalase/genetics ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; HL-60 Cells ; Humans ; Leukemia/drug therapy/*genetics/metabolism ; NADPH Oxidase 2/*genetics ; Oxidative Stress/*drug effects ; Peroxidase/*genetics ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*genetics ; U937 Cells ; }, abstract = {N-acetylcysteine (NAC), often used as an antioxidant-scavenging reactive oxygen species (ROS) in vitro, was recently shown to increase the cytotoxicity of other compounds through ROS-dependent and ROS-independent mechanisms. In this study, NAC itself was found to induce extensive ROS production in human leukemia HL-60 and U937 cells. The cytotoxicity depends on ROS-modulating enzyme expression. In HL-60 cells, NAC activated NOX2 to produce superoxide (O2•[-]). Its subsequent conversion into H2O2 by superoxide dismutase 1 and 3 (SOD1, SOD3) and production of ClO[-] from H2O2 by myeloperoxidase (MPO) was necessary for cell death induction. While the addition of extracellular SOD potentiated NAC-induced cell death, extracellular catalase (CAT) prevented cell death in HL-60 cells. The MPO inhibitor partially reduced the number of dying HL-60 cells. In U937 cells, the weak cytotoxicity of NAC is probably caused by lower expression of NOX2, SOD1, SOD3, and by the absence of MOP expression. However, even here, the addition of extracellular SOD induced cell death in U937 cells, and this effect could be reversed by extracellular CAT. NAC-induced cell death exhibited predominantly apoptotic features in both cell lines. Conclusions: NAC itself can induce extensive production of O2•[-] in HL-60 and U937 cell lines. The fate of the cells then depends on the expression of enzymes that control the formation and conversion of ROS: NOX, SOD, and MPO. The mode of cell death in response to NAC treatment bears apoptotic and apoptotic-like features in both cell lines.}, }
@article {pmid34880073, year = {2023}, author = {Dayasiri, K and Rao, S}, title = {Fifteen-minute update: International normalised ratio as the treatment end point in children with acute paracetamol poisoning.}, journal = {Archives of disease in childhood. Education and practice edition}, volume = {108}, number = {3}, pages = {181-183}, doi = {10.1136/archdischild-2020-320190}, pmid = {34880073}, issn = {1743-0593}, mesh = {Humans ; Child ; *Acetaminophen ; International Normalized Ratio ; *Liver Diseases ; Acetylcysteine/therapeutic use ; Vitamin K/therapeutic use ; }, abstract = {Paracetamol is one of the most frequent reasons for poisonings across the UK with an estimated 90,000 patients and 150 deaths annually. International normalised ratio (INR) may be elevated due to hepatocellular damage and is frequently used to monitor progress on N-acetyl cysteine. N-acetyl cysteine is associated with reduced activity of vitamin K dependent clotting factors leading to a benign elevation of INR. In asymptomatic children with normal aspartate transaminase/alanine transaminase, isolated borderline elevation of INR following paracetamol overdose should be reviewed for possible N-acetyl cysteine induced elevation of INR. Due to these factors, in those with borderline persistent elevation of INR, N-acetyl cysteine can be safety stopped if INR is falling on two or more consecutive tests and is <3.0.}, }
@article {pmid34875739, year = {2021}, author = {Ghorbani, F and Nasiri, Z and Koohestanidehaghi, Y and Lorian, K}, title = {The antioxidant roles of L-carnitine and N-acetyl cysteine against oxidative stress on human sperm functional parameters during vitrification.}, journal = {Clinical and experimental reproductive medicine}, volume = {48}, number = {4}, pages = {316-321}, pmid = {34875739}, issn = {2233-8233}, abstract = {OBJECTIVE: Amino acids can protect sperm structure in cryopreservation due to their antioxidant properties. Therefore, the present study aimed to investigate the protective effect of L-carnitine (LC) and N-acetyl cysteine (NAC) on motility parameters, plasma membrane integrity (PMI), mitochondrial membrane potential (MMP), DNA damage, and human sperm intracellular reactive oxygen species (ROS) during vitrification.<br><br>METHODS: Twenty normal human sperm samples were examined. Each sample was divided into six equal groups: LC (1 and 10 mM), NAC (5 and 10 mM), and cryopreserved and fresh control groups.<br><br>RESULTS: The groups treated with LC and NAC showed favorable findings in terms of motility parameters, DNA damage, and MMP. Significantly higher levels of intracellular ROS were observed in all cryopreserved groups than in the fresh group (p&#x2264;0.05). The presence of LC and NAC at both concentrations caused an increase in PMI, MMP, and progressive motility parameters, as well as a significant reduction in intracellular ROS compared to the control group (p&#x2264;0.05). The concentrations of the amino acids did not show any significant effect.<br><br>CONCLUSION: LC and NAC are promising as potential additives in sperm cryopreservation.}, }
@article {pmid34869660, year = {2021}, author = {Khan, SA and Campbell, AM and Lu, Y and An, L and Alpert, JS and Chen, QM}, title = {N-Acetylcysteine for Cardiac Protection During Coronary Artery Reperfusion: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.}, journal = {Frontiers in cardiovascular medicine}, volume = {8}, number = {}, pages = {752939}, pmid = {34869660}, issn = {2297-055X}, support = {R01 GM125212/GM/NIGMS NIH HHS/United States ; R01 GM126165/GM/NIGMS NIH HHS/United States ; }, abstract = {Coronary artery reperfusion is essential for the management of symptoms in the patients with myocardial ischemia. However, the benefit of reperfusion often comes at an expense of paradoxical injury, which contributes to the adverse events, and sometimes heart failure. Reperfusion is known to increase the production of reactive oxygen species (ROS). We address whether N-acetylcysteine (NAC) reduces the ROS and alleviates reperfusion injury by improving the clinical outcomes. A literature search for the randomized controlled trials (RCTs) was carried out in the five biomedical databases for testing the effects of NAC in patients undergoing coronary artery reperfusion by percutaneous coronary intervention, thrombolysis, or coronary artery bypass graft. Of 787 publications reviewed, 28 RCTs were identified, with a summary of 2,174 patients. A meta-analysis using the random effects model indicated that NAC administration during or prior to the reperfusion procedures resulted in a trend toward a reduction in the level of serum cardiac troponin (cTn) [95% CI, standardized mean difference (SMD) -0.80 (-1.75; 0.15), p = 0.088, n = 262 for control, 277 for NAC group], and in the incidence of postoperative atrial fibrillation [95% CI, relative risk (RR) 0.57 (0.30; 1.06), p = 0.071, n = 484 for control, 490 for NAC group]. The left ventricular ejection fraction or the measures of length of stay in intensive care unit (ICU) or in hospital displayed a positive trend that was not statistically significant. Among the nine trials that measured ROS, seven showed a correlation between the reduction of lipid peroxidation and improved clinical outcomes. These lines of evidence support the potential benefit of NAC as an adjuvant therapy for cardiac protection against reperfusion injury.}, }
@article {pmid34868392, year = {2021}, author = {Zhou, J and Xu, J and Sun, S and Guo, M and Li, P and Cheng, A}, title = {N-Acetylcysteine Slows Down Cardiac Pathological Remodeling by Inhibiting Cardiac Fibroblast Proliferation and Collagen Synthesis.}, journal = {Disease markers}, volume = {2021}, number = {}, pages = {3625662}, pmid = {34868392}, issn = {1875-8630}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Collagen/*biosynthesis ; Male ; Myocytes, Cardiac/metabolism/*pathology ; NF-kappa B/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Ventricular Remodeling/*drug effects ; }, abstract = {OBJECTIVE: By observing the effect of N-acetylcysteine (NAC) on the proliferation and collagen synthesis of rat cardiac fibroblasts (CFs) to explore the effect of NAC on cardiac remodeling (CR).<br><br>METHODS: In vivo, first, the Sprague Dawley (SD) rat myocardial hypertrophy model was constructed, and the effect of NAC on cardiac structure and function was detected by echocardiography, serological testing, and Masson staining. Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression level of antioxidant enzymes, and flow cytometry was used to detect the intracellular reactive oxygen species (ROS) content. In vitro, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and 5-ethynyl-2'-deoxyuridine (EdU) staining were used to detect cell proliferation, and the expression level of the NF-&#x3ba;B signaling pathway was detected.<br><br>RESULTS: Compared with the control group, the model group had disordered cardiac structure, reduced cardiac function, and obvious oxidative stress (OS) response. However, after NAC treatment, it could obviously improve the rat cardiac structure and cardiac function and alleviate redox imbalance and cardiology remodeling. At the same time, NAC can inhibit the activation of the NF-&#x3ba;B signaling pathway and reduce the proliferation level of CFs and the amount of [3]H proline incorporated.<br><br>CONCLUSIONS: NAC can inhibit AngII-induced CF proliferation and collagen synthesis through the NF-&#x3ba;B signaling pathway, alleviate the OS response of myocardial tissue, inhibit the fibrosis of myocardial tissue, and thus slow down the pathological remodeling of the heart.}, }
@article {pmid34867200, year = {2021}, author = {Singh-Mallah, G and Kawamura, T and Ardalan, M and Chumak, T and Svedin, P and Arthur, PG and James, C and Hagberg, H and Sandberg, M and Mallard, C}, title = {N-Acetyl Cysteine Restores Sirtuin-6 and Decreases HMGB1 Release Following Lipopolysaccharide-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Mice.}, journal = {Frontiers in cellular neuroscience}, volume = {15}, number = {}, pages = {743093}, pmid = {34867200}, issn = {1662-5102}, abstract = {Inflammation and neonatal hypoxia-ischemia (HI) are important etiological factors of perinatal brain injury. However, underlying mechanisms remain unclear. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases. Sirtuin-6 is thought to regulate inflammatory and oxidative pathways, such as the extracellular release of the alarmin high mobility group box-1 (HMGB1). The expression and role of sirtuin-6 in neonatal brain injury are unknown. In a well-established model of neonatal brain injury, which encompasses inflammation (lipopolysaccharide, LPS) and hypoxia-ischemia (LPS+HI), we investigated the protein expression of sirtuin-6 and HMGB1, as well as thiol oxidation. Furthermore, we assessed the effect of the antioxidant N-acetyl cysteine (NAC) on sirtuin-6 expression, nuclear to cytoplasmic translocation, and release of HMGB1 in the brain and blood thiol oxidation after LPS+HI. We demonstrate reduced expression of sirtuin-6 and increased release of HMGB1 in injured hippocampus after LPS+HI. NAC treatment restored sirtuin-6 protein levels, which was associated with reduced extracellular HMGB1 release and reduced thiol oxidation in the blood. The study suggests that early reduction in sirtuin-6 is associated with HMGB1 release, which may contribute to neonatal brain injury, and that antioxidant treatment is beneficial for the alleviation of these injurious mechanisms.}, }
@article {pmid34856342, year = {2022}, author = {Ghaffarian-Bahraman, A and Arabnezhad, MR and Keshavarzi, M and Davani-Davari, D and Jamshidzadeh, A and Mohammadi-Bardbori, A}, title = {Influence of cellular redox environment on aryl hydrocarbon receptor ligands induced melanogenesis.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {79}, number = {}, pages = {105282}, doi = {10.1016/j.tiv.2021.105282}, pmid = {34856342}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzo(a)pyrene/pharmacology ; Carbazoles/pharmacology ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Ligands ; Melanins/*biosynthesis ; Melanoma/metabolism/*physiopathology ; Mice ; Onium Compounds/pharmacology ; *Oxidation-Reduction ; Oxidative Stress/drug effects ; Receptors, Aryl Hydrocarbon/*drug effects/metabolism ; }, abstract = {Many environmental pollutants, natural compounds, as well as endogenous chemicals exert their biological/toxicological effects by reacting with the aryl hydrocarbon receptor (AhR). Previous evidence shed new light on the role of AhR in skin physiology by regulating melanin production. In this study, we investigated the effect of oxidative imbalance induced by AhR ligands on the melanogenesis process in B16 murine melanoma cells. Exposure to 6-formylindolo[3,2-b] carbazole (FICZ) or benzo-α-pyrene (BαP) led to enhanced expression of CTNNB1, MITF, and TYR genes following increased tyrosinase enzyme activity and melanin content in an AhR-dependent manner. Analysis of the presence of reactive oxygen species (ROS) as well as reduced glutathione (GSH) / oxidized glutathione (GSSG) ratio revealed that treatment with AhR ligands is associated with oxidative stress which can be ameliorated with NAC (N-acetyl cysteine) or diphenyleneiodonium chloride (DPI). On the other hand, NAC and DPI enhanced melanogenesis induced by AhR ligands by reducing the level of ROS. We have shown for the first time that a cellular redox status is a critical event during AhR ligand-induced melanogenesis.}, }
@article {pmid34854886, year = {2021}, author = {Huynh, TPN and Bowater, RP and Bernuzzi, F and Saha, S and Wormstone, IM}, title = {GSH Levels Serve As a Biological Redox Switch Regulating Sulforaphane-Induced Cell Fate in Human Lens Cells.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {62}, number = {15}, pages = {2}, pmid = {34854886}, issn = {1552-5783}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 6/metabolism ; Aged ; Aged, 80 and over ; Anticarcinogenic Agents/*pharmacology ; Apoptosis/drug effects ; Biomarkers/*metabolism ; Cell Line ; Cell Survival ; Chromatography, Liquid ; Epithelial Cells/*drug effects/metabolism/pathology ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Glutathione Reductase/metabolism ; Humans ; Immunoblotting ; Isothiocyanates/*pharmacology ; Lens, Crystalline/*cytology ; Membrane Potential, Mitochondrial/physiology ; Middle Aged ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Sulfoxides/*pharmacology ; Tandem Mass Spectrometry ; }, abstract = {PURPOSE: Sulforaphane (SFN) is a therapeutic phytochemical agent for many health conditions. SFN-induced cytotoxicity is shown to have promise in preventing posterior capsule opacification (PCO). In the current study, we aimed to elucidate key processes and mechanisms linking SFN treatment to lens cell death.<br><br>METHODS: The human lens epithelial cell line FHL124 and central anterior epithelium were used as experimental models. Cell death was assessed by microscopic observation and cell damage/viability assays. Gene or protein levels were assessed by TaqMan RT-PCR or immunoblotting. Mitochondrial networks and DNA damage were assessed by immunofluorescence. Mitochondrial membrane potential, activating transcription factor 6 (ATF6) activity, ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and glutathione reductase (GR) activity were measured using different light reporter assays. SFN metabolites were analyzed by LC-MS/MS.<br><br>RESULTS: Treatment with N-acetylcysteine (NAC), a reactive oxygen species scavenger, prevented SFN-induced cell death in both models. NAC also significantly protected FHL124 cells from SFN-induced mitochondrial dysfunctions, endoplasmic reticulum stress (ERS), DNA damage and autophagy. SFN significantly depleted GSH, the major antioxidant in the eye, and reduced GR activity, despite doubling its protein levels. The most abundant SFN conjugate detected in lens cells following SFN application was SFN-GSH. The addition of GSH protected lens cells from all SFN-induced cellular events.<br><br>CONCLUSIONS: SFN depletes GSH levels in lens cells through conjugation and inhibition of GR activity. This leads to increased reactive oxygen species and oxidative stress that trigger mitochondrial dysfunction, ERS, autophagy, and DNA damage, leading to cell death. In summary, the work presented provides a mechanistic understanding to support the therapeutic application of SFN for PCO and other disorders.}, }
@article {pmid34854203, year = {2022}, author = {Wieting, J and Deest, M and Bleich, S and Frieling, H and Eberlein, C}, title = {N-Acetylcysteine provides limited efficacy as treatment option for skin picking in Prader-Willi syndrome.}, journal = {American journal of medical genetics. Part A}, volume = {188}, number = {3}, pages = {828-835}, doi = {10.1002/ajmg.a.62589}, pmid = {34854203}, issn = {1552-4833}, mesh = {Acetylcysteine/therapeutic use ; Female ; Humans ; Male ; *Mental Disorders ; *Prader-Willi Syndrome/complications/drug therapy/genetics ; Retrospective Studies ; *Self-Injurious Behavior/drug therapy/genetics ; }, abstract = {Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed genes in chromosome region 15q11-13. In addition to typical characteristics such as hyperphagia, PWS is evidenced by a certain behavioral phenotype. Common indicators are repetitive behaviors, temper tantrums, and self-injurious behaviors such as skin- and/or rectal picking. N-Acetylcysteine (NAC) was previously described as a promising therapeutic option for skin picking in PWS. In this case series, we retrospectively investigated the effect of pharmacotherapy with NAC in 14 individuals with PWS suffering from skin- and/or rectal picking. Treatment success was determined using the Clinical Global Impression-Improvement scale (CGI-I). The Clinical Global Impression-Efficacy index (CGI-EI) was used to put treatment success and side effects into perspective. Six of fourteen patients, all of which were female, showed improvement in symptoms (dosage 1800-2400 mg/day), whereas six patients did not show any change during treatment. Moreover, two male patients treated for solitary rectal picking showed new onset of skin picking. Across all cases, a CGI-I of 3 (corresponding to minimal improvement) was seen after 3 months of treatment, with a CGI-EI of 1.6 (corresponding to moderate efficacy). NAC remains a reasonable therapeutic option in certain cases of skin picking in PWS but provides only limited efficacy compared to previous studies on the topic. There was a higher rate of adverse drug reactions than previously reported. The results particularly suggest caution in future treatment in individuals with solitary rectal picking and reduced efficacy when coadministered with neuroleptics.}, }
@article {pmid34850077, year = {2021}, author = {Hu, M and Zhang, Y and Ma, S and Li, J and Wang, X and Liang, M and Sferruzzi-Perri, AN and Wu, X and Ma, H and Brännström, M and Shao, LR and Billig, H}, title = {Suppression of uterine and placental ferroptosis by N-acetylcysteine in a rat model of polycystic ovary syndrome.}, journal = {Molecular human reproduction}, volume = {27}, number = {12}, pages = {}, doi = {10.1093/molehr/gaab067}, pmid = {34850077}, issn = {1460-2407}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Dihydrotestosterone ; Disease Models, Animal ; Female ; Ferroptosis/*drug effects ; Glutathione/metabolism ; Insulin Resistance ; Iron/metabolism ; Male ; Malondialdehyde/metabolism ; Mitochondria/*drug effects/metabolism/ultrastructure ; Oxidative Phosphorylation ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Placenta/*drug effects/metabolism/ultrastructure ; Polycystic Ovary Syndrome/chemically induced/metabolism/pathology/*prevention &amp; control ; Pregnancy ; Rats, Sprague-Dawley ; Signal Transduction ; Uterus/*drug effects/metabolism/ultrastructure ; Rats ; }, abstract = {The mechanisms that link hyperandrogenism and insulin (INS) resistance (HAIR) to the increased miscarriage rate in women with polycystic ovary syndrome (PCOS) remain elusive. Previous studies demonstrate that increased uterine and placental ferroptosis is associated with oxidative stress-induced fetal loss in a pre-clinical PCOS-like rat model. Here, we investigated the efficacy and molecular mechanism of action of the antioxidant N-acetylcysteine (NAC) in reversing gravid uterine and placental ferroptosis in pregnant rats exposed to 5α-dihydrotestosterone (DHT) and INS. Molecular and histological analyses showed that NAC attenuated DHT and INS-induced uterine ferroptosis, including dose-dependent increases in anti-ferroptosis gene content. Changes in other molecular factors after NAC treatment were also observed in the placenta exposed to DHT and INS, such as increased glutathione peroxidase 4 protein level. Furthermore, increased apoptosis-inducing factor mitochondria-associated 2 mRNA expression was seen in the placenta but not in the uterus. Additionally, NAC was not sufficient to rescue DHT + INS-induced mitochondria-morphological abnormalities in the uterus, whereas the same treatment partially reversed such abnormalities in the placenta. Finally, we demonstrated that NAC selectively normalized uterine leukemia inhibitory factor, osteopontin/secreted phosphoprotein 1, progesterone receptor, homeobox A11 mRNA expression and placental estrogen-related receptor beta and trophoblast-specific protein alpha mRNA expression. Collectively, our data provide insight into how NAC exerts beneficial effects on differentially attenuating gravid uterine and placental ferroptosis in a PCOS-like rat model with fetal loss. These results indicate that exogenous administration of NAC represents a potential therapeutic strategy in the treatment of HAIR-induced uterine and placental dysfunction.}, }
@article {pmid34841761, year = {2021}, author = {Ji, LW and Deng, Y and Li, T}, title = {[Effect of Ketone Body β-Hydroxybutyrate to Attenuate Inflammation-Induced Mitochondrial Oxidative Stress in Vascular Endothelial Cells].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {52}, number = {6}, pages = {954-959}, pmid = {34841761}, issn = {1672-173X}, mesh = {3-Hydroxybutyric Acid ; Cells, Cultured ; Human Umbilical Vein Endothelial Cells ; Humans ; *Inflammation ; *Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {OBJECTIVE: To investigate the regulatory function and mechanism of β-hydroxybutyrate (β-OHB), a ketone body, on the mitochondrial oxidative stress of inflammatory human umbilical vein endothelial cells (HUVECs).<br><br>METHODS: Lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were used to induce macrophages to release proinflammatory factors, and the culture supernatant was collected as a macrophage-conditioned medium (MCM) to culture HUVECs. A total of 7 groups of cells were used in the study: &#x2460;control group, or normal cultured HUVECs; &#x2461;MCM group, or the MCM-cultured HUVECs; groups &#x2462; to &#x2466; were all HUVECs co-cultured with different reagents, including &#x2462;MCM+&#x3b2;-OHB group, &#x2463;MCM+N-acetylcysteine (NAC) group, &#x2464;MCM+&#x3b2;-OHB+NAC group, &#x2465;MCM+&#x3b2;-OHB+histone deacetylase agonist ITSA1 group, and &#x2466;MCM+&#x3b2;-OHB+histone deacetylase inhibitor Entinostat group. MitoSOX immunofluorescence staining was conducted to analyzes the mitochondrial superoxide levels, real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) was performed to examine the mRNA expression of antioxidant genes, and Seahorse mitochondrial energy analyzer was used to measure mitochondrial aerobic respiration capacity.<br><br>RESULTS: Compared with the control group, mitochondrial superoxide production was significantly increased in the MCM cultured HUVECs cells, while &#x3b2;-OHB treatment significantly inhibited mitochondrial superoxide production, which was accompanied by an increase in the mRNA expression of antioxidant genes, and significant increase in the basal mitochondrial oxygen consumption rate and respiratory reserve capacity. NAC treatment did not further enhance the protective effect of &#x3b2;-OHB on mitochondrial functions. In addition, ITSA1 treatment could completely offset the antioxidant and mitochondrial protective effects of &#x3b2;-OHB, and these stated effects were still maintained after Entinostat treatment.<br><br>CONCLUSION: The ketone body &#x3b2;-OHB attenuates the mitochondrial oxidative stress of vascular endothelial cells through activating the antioxidant pathway and inhibiting histone deacetylase activity.}, }
@article {pmid34840312, year = {2022}, author = {Laoprasopwattana, K and Khantee, P and Saelim, K and Geater, A}, title = {Mortality Rates of Severe Dengue Viral Infection Before and After Implementation of a Revised Guideline for Severe Dengue.}, journal = {The Pediatric infectious disease journal}, volume = {41}, number = {3}, pages = {211-216}, pmid = {34840312}, issn = {1532-0987}, mesh = {Acute Kidney Injury/etiology/mortality ; Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Liver Failure, Acute/epidemiology/etiology ; Liver Function Tests ; Male ; *Mortality ; Multiple Organ Failure/etiology/mortality ; Respiratory Distress Syndrome/epidemiology/mortality ; Severe Dengue/complications/diagnosis/*mortality/*physiopathology ; Shock/etiology/mortality ; }, abstract = {OBJECTIVES: To compare the mortality rate of severe dengue (SD) before and after implementation of a revised SD guideline.<br><br>METHODS: Medical records of SD patients <15 years of age hospitalized during 1998-2020 were reviewed. The revised SD guidelines were implemented in 2016, including intensive monitoring of vital signs and intra-abdominal pressure, the release of intra-abdominal pressure in cases of abdominal compartment syndrome (ACS) and the use of N-acetyl cysteine in cases of acute liver failure.<br><br>RESULTS: On initial admission, organ failure including severe bleeding, acute respiratory failure, acute kidney injury and acute liver failure was not significantly different between 78 and 23 patients treated in the pre- and postrevised guideline periods, respectively. After hospitalization, the proportions of patients who developed profound shock (68.8% vs. 41.2%), multiorgan failures (60.4% vs. 73.3%), ACS (37.2% vs. 26.1%) and fatal outcome (33.3% vs. 13.0%) were also not significantly different between the pre- and postrevised guideline periods, respectively. In subgroup analysis, the mortality rates in patients with multiorgan failure (44.1% vs. 15.8%), acute respiratory failure and active bleeding (78.1% vs. 37.5%) and ACS (82.8% vs. 33.3%), respectively, were significantly higher in the pre- than the postrevised guideline periods. The durations of time before the liver function tests returned to normal levels, and the mortality rates in acute liver failure patients treated with and without N-acetyl cysteine were not significantly different.<br><br>CONCLUSIONS: Although following the revised guidelines could not prevent organ failure, the mortality rates in patients with multiorgan failure and/or ACS decreased significantly when following the revised guidelines.}, }
@article {pmid34834918, year = {2021}, author = {Mendonça-Vieira, LR and Aníbal-Silva, CE and Menezes-Neto, A and Azevedo, EAN and Zanluqui, NG and Peron, JPS and Franca, RFO}, title = {Reactive Oxygen Species (ROS) Are Not a Key Determinant for Zika Virus-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells.}, journal = {Viruses}, volume = {13}, number = {11}, pages = {}, pmid = {34834918}, issn = {1999-4915}, mesh = {*Apoptosis ; Cell Line, Tumor ; Humans ; Mitochondria/genetics/metabolism ; Neuroblastoma/metabolism/*physiopathology/virology ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Zika Virus/genetics/*physiology ; Zika Virus Infection/metabolism/*physiopathology/virology ; }, abstract = {INTRODUCTION: ZIKV is a highly neurotropic virus that can cause the death of infected neuroprogenitor cells through mitochondrial damage and intrinsic apoptotic signaling. In this context, the role of reactive oxygen species (ROS) in neuronal cell death caused by ZIKV still remains elusive.<br><br>OBJECTIVE: We aimed at evaluating the role of these cellular components in the death of human undifferentiated neuroblastoma cell line infected with ZIKV.<br><br>RESULTS: ZIKV infection resulted in the extensive death of SH-SY5Y cells with the upregulation of several genes involved in survival and apoptotic responses as well as the colocalization of mitochondrial staining with ZIKV Envelope (E) protein. Notably, levels of intracellular reactive oxygen species (ROS) were not altered during ZIKV infection in undifferentiated SH-SY5Y cells, and consistent with these results, the treatment of infected cells with the widely studied ROS scavenger N-acetylcysteine (NAC) did not prevent cell death in these cells.<br><br>CONCLUSION: Altogether, our results suggest that excessive ROS production is not the main trigger of SH-SY5Y cells death in ZIKV infection.}, }
@article {pmid34834129, year = {2021}, author = {Wang, KC and Lu, MC and Hsu, KC and El-Shazly, M and Shih, SP and Lien, ST and Kuo, FW and Yang, SC and Chen, CL and Yang, YSH}, title = {The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {22}, pages = {}, pmid = {34834129}, issn = {1420-3049}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; HSP90 Heat-Shock Proteins/*metabolism ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Mitochondria/drug effects/metabolism ; Quinones/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite suppressed the proliferation of Molt-4, K562, and Sup-T1 cells with IC50 values of 2.95 ± 0.21, 6.22 ± 0.21, and 8.58 ± 0.60 µM, respectively, as demonstrated by MTT assay. In the cell-free system, it inhibited the activity of topoisomerase I (Topo I) and II (Topo II) by 50% after treatment with 0.235 and 0.094 μM, respectively. The flow cytometric analysis indicated that the cytotoxic effect of xestoquinone was mediated through the induction of multiple apoptotic pathways in Molt-4 cells. The pretreatment of Molt-4 cells with N-acetyl cysteine (NAC) diminished the disruption of the mitochondrial membrane potential (MMP) and apoptosis, as well as retaining the expression of both Topo I and II. In the nude mice xenograft model, the administration of xestoquinone (1 μg/g) significantly attenuated tumor growth by 31.2% compared with the solvent control. Molecular docking, Western blotting, and thermal shift assay verified the catalytic inhibitory activity of xestoquinone by high binding affinity to HSP-90 and Topo I/II. Our findings indicated that xestoquinone targeted leukemia cancer cells through multiple pathways, suggesting its potential application as an antileukemic drug lead.}, }
@article {pmid34833436, year = {2021}, author = {Teder, K and Maddison, L and Soeorg, H and Meos, A and Karjagin, J}, title = {The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {57}, number = {11}, pages = {}, pmid = {34833436}, issn = {1648-9144}, support = {DoRa 3//Archimedes Foundation/ ; PUT1197, IUT34-24//Estonian Research Council/ ; }, mesh = {*Acetylcysteine ; Biological Availability ; Critical Illness ; Humans ; Intensive Care Units ; *Pneumonia, Ventilator-Associated/drug therapy/prevention &amp; control ; }, abstract = {Background and Objectives: N-acetylcysteine (NAC) is a mucolytic agent used to prevent ventilator-associated pneumonia in intensive care units. This study aimed to evaluate the oral bioavailability of NAC in critically ill patients with pneumonia, isolated acute brain injury and abdominal sepsis. Materials and Methods: This quantitative and descriptive study compared NAC's pharmacokinetics after intravenous and enteral administration. 600 mg of NAC was administered in both ways, and the blood levels for NAC were measured. Results: 18 patients with pneumonia, 19 patients with brain injury and 17 patients with abdominal sepsis were included in the population pharmacokinetic modelling. A three-compartmental model without lag-time provided the best fit to the data. Oral bioavailability was estimated as 11.6% (95% confidence interval 6.3-16.9%), similar to bioavailability in healthy volunteers and patients with chronic pulmonary diseases. Conclusions: The bioavailability of enteral NAC of ICU patients with different diseases is similar to the published data on healthy volunteers.}, }
@article {pmid34831255, year = {2021}, author = {Wang, Y and Pandak, WM and Lesnefsky, EJ and Hylemon, PB and Ren, S}, title = {25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models.}, journal = {Cells}, volume = {10}, number = {11}, pages = {}, pmid = {34831255}, issn = {2073-4409}, support = {1I01BX003656/VA/VA/United States ; Research aggrement//Durect corporation/ ; }, mesh = {Animals ; Apoptosis/drug effects/genetics ; Chemical and Drug Induced Liver Injury/*drug therapy/genetics/physiopathology ; Cholesterol Esters/pharmacology/*therapeutic use ; CpG Islands/genetics ; DNA Demethylation ; Disease Models, Animal ; Female ; Gene Expression Regulation/drug effects ; Hydroxycholesterols/pharmacology/*therapeutic use ; Liver/drug effects/injuries/metabolism/pathology ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Models, Biological ; Organ Specificity/drug effects ; Oxidants/metabolism ; Mice ; }, abstract = {Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure (ALF). N-acetylcysteine (NAC) is currently being used as part of the standard care in the clinic but its usage has been limited in severe cases, in which liver transplantation becomes the only treatment option. Therefore, there still is a need for a specific and effective therapy for APAP induced ALF. In the current study, we have demonstrated that treatment with 25-Hydroxycholesterol 3-Sulfate (25HC3S) not only significantly reduced mortality but also decreased the plasma levels of liver injury markers, including LDH, AST, and ALT, in APAP overdosed mouse models. 25HC3S also decreased the expression of those genes involved in cell apoptosis, stabilized mitochondrial polarization, and significantly decreased the levels of oxidants, malondialdehyde (MDA), and reactive oxygen species (ROS). Whole genome bisulfite sequencing analysis showed that 25HC3S increased demethylation of [5m]CpG in key promoter regions and thereby increased the expression of those genes involved in MAPK-ERK and PI3K-Akt signaling pathways. We concluded that 25HC3S may alleviate APAP induced liver injury via up-regulating the master signaling pathways and maintaining mitochondrial membrane polarization. The results suggest that 25HC3S treatment facilitates the recovery and significantly decreases the mortality of APAP induced acute liver injury and has a synergistic effect with NAC in propylene glycol (PG) for the injury.}, }
@article {pmid34830394, year = {2021}, author = {Phoo, NLL and Dejkriengkraikul, P and Khaw-On, P and Yodkeeree, S}, title = {Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death.}, journal = {International journal of molecular sciences}, volume = {22}, number = {22}, pages = {}, pmid = {34830394}, issn = {1422-0067}, support = {Grant no. 14/2564//Chiang Mai University, the Center for Research and Development of Natural Products for Health/ ; Grant No. 163/2563//by Faculty of Medicine Research Fund/ ; }, mesh = {20-Hydroxysteroid Dehydrogenases/*genetics ; Aldo-Keto Reductase Family 1 Member C3/*genetics ; Autophagic Cell Death/drug effects/genetics ; Carcinoma, Signet Ring Cell/*drug therapy/genetics/pathology ; Cell Line, Tumor ; Cisplatin/pharmacology ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Stomach Neoplasms/*drug therapy/genetics/pathology ; Transcriptome/drug effects ; }, abstract = {Signet ring cell gastric carcinoma (SRCGC) is a lethal malignancy that has developed drug resistance to cisplatin therapies. The aim of this study was to characterize the acquisition of the cisplatin-resistance SRCGC cell line (KATO/DDP cells) and to understand the molecular mechanisms underlying cisplatin resistance. Transcriptomic and bioinformatic analyses were used to identify the candidate gene. This was confirmed by qPCR and Western blot. Aldoketoreductase1C1 and 1C3 (AKR1C1 and AKR1C3) were the most promising molecules in KATO/DDP cells. A specific inhibitor of AKR1C1 (5PBSA) and AKR1C3 (ASP9521) was used to enhance cisplatin-induced KATO/DPP cell death. Although cisplatin alone induced KATO/DDP apoptosis, a combination treatment of cisplatin and the AKR1C inhibitors had no influence on percent cell apoptosis. In conjunction with the autophagy inhibitor, 3MA, attenuated the effects of 5PBSA or ASP9521 to enhance cisplatin-induced cell death. These results indicated that AKR1C1 and 1C3 regulated cisplatin-induced KATO/DDP cell death via autophagy. Moreover, cisplatin in combination with AKR1C inhibitors and N-acetyl cysteine increased KATO/DDP cells' viability when compared with a combination treatment of cisplatin and the inhibitors. Taken together, our results suggested that AKR1C1 and 1C3 play a crucial role in cisplatin resistance of SRCGC by regulating redox-dependent autophagy.}, }
@article {pmid34830376, year = {2021}, author = {Kang, J and Bishayee, K and Huh, SO}, title = {Azoxystrobin Impairs Neuronal Migration and Induces ROS Dependent Apoptosis in Cortical Neurons.}, journal = {International journal of molecular sciences}, volume = {22}, number = {22}, pages = {}, pmid = {34830376}, issn = {1422-0067}, support = {2019M3C7A1032601//National Research Foundation of Korea/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Autistic Disorder/chemically induced/genetics/pathology ; Cell Movement/drug effects ; Cell Survival/drug effects ; Female ; Fungicides, Industrial/toxicity ; Humans ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mice ; Mitochondria/drug effects ; Neurogenesis/*drug effects ; Neuronal Outgrowth/drug effects ; Neurons/*drug effects/pathology ; Pregnancy ; Prenatal Exposure Delayed Effects ; Pyrimidines/*pharmacology/toxicity ; Reactive Oxygen Species/antagonists &amp; inhibitors ; Strobilurins/*pharmacology/toxicity ; }, abstract = {Fungicides often cause genotoxic stress and neurodevelopmental disorders such as autism (ASD). Fungicide-azoxystrobin (AZOX) showed acute and chronic toxicity to various organisms, and remained a concern for ill effects in developing neurons. We evaluated the neurotoxicity of AZOX in developing mouse brains, and observed prenatal exposure to AZOX reduced neuronal viability, neurite outgrowth, and cortical migration process in developing brains. The 50% inhibitory concentration (IC50) of AZOX for acute (24 h) and chronic (7 days) exposures were 30 and 10 μM, respectively. Loss in viability was due to the accumulation of reactive oxygen species (ROS), and inhibited neurite outgrowth was due to the deactivation of mTORC1 kinase activity. Pretreatment with ROS scavenger- N-acetylcysteine (NAC) reserved the viability loss and forced activation of mTORC1 kinase revived the neurite outgrowth in AZOX treated neurons. Intra-amniotic injection of AZOX coupled with in utero electroporation of GFP-labelled plasmid in E15.5 mouse was performed and 20 mg/kg AZOX inhibited radial neuronal migration. Moreover, the accumulation of mitochondria was significantly reduced in AZOX treated primary neurons, indicative of mitochondrial deactivation and induction of apoptosis, which was quantified by Bcl2/Bax ratio and caspase 3 cleavage assay. This study elucidated the neurotoxicity of AZOX and explained the possible cure from it.}, }
@article {pmid34829701, year = {2021}, author = {Tsai, MF and Chen, SM and Ong, AZ and Chung, YH and Chen, PN and Hsieh, YH and Kang, YT and Hsu, LS}, title = {Shikonin Induced Program Cell Death through Generation of Reactive Oxygen Species in Renal Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {34829701}, issn = {2076-3921}, support = {109-2320-B-040-022-//Ministry of Science and Technology/ ; }, abstract = {Shikonin mitigated tumor cell proliferation by elevating reactive oxygen species (ROS) levels. Herein, we investigated the effects of shikonin on renal cancer cell (RCC) cell proliferation. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that shikonin dose-dependently reduced the proliferation of Caki-1 and ACHN cells. Shikonin remarkably triggered necrosis and apoptosis in Caki-1 and ACHN cells in proportion to its concentration. Moreover, necrostatin-1 recovered cell viability in the presence of shikonin. Elevated ROS levels and mitochondrial dysfunction were also found in shikonin treatment groups. Pretreatment with N-acetyl cysteine remarkably mitigated shikonin-induced cell death and ROS generation. Western blot analysis revealed that shikonin reduced pro-PARP, pro-caspase-3, and Bcl-2 expression and increased cleavage PARP expression. Enhanced autophagy was also found in the shikonin-treated group as evidenced by acridine orange staining. Moreover, light chain 3B (LC3B)-II accumulation and enhanced p62 expression indicated that autophagy occurred in the shikonin-treated group. LC3B knockdown considerably recovered cell viability in the presence of shikonin. Shikonin treatment elevated p38 activity in a dose-dependent manner. In conclusion, our results revealed that shikonin triggered programmed cell death via the elevation of ROS level and p38 activity in different types of RCC cells. These findings suggested that shikonin may be a potential anti-RCC agent.}, }
@article {pmid34829610, year = {2021}, author = {Henry, ML and Velez-Irizarry, D and Pagan, JD and Sordillo, L and Gandy, J and Valberg, SJ}, title = {The Impact of N-Acetyl Cysteine and Coenzyme Q10 Supplementation on Skeletal Muscle Antioxidants and Proteome in Fit Thoroughbred Horses.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {34829610}, issn = {2076-3921}, support = {N/A//McPhail Equine Endowment, Michigan State University/ ; N/A//Kentucky Equine Research, Versailles, KY/ ; N/A//Martha Wolfson Endowment, Michigan State University/ ; }, abstract = {Horses have one of the highest skeletal muscle oxidative capacities amongst mammals, which, combined with a high glycolytic capacity, could perturb redox status during maximal exercise. We determined the effect of 30 d of oral coenzyme Q10 and N-acetyl-cysteine supplementation (NACQ) on muscle glutathione (GSH), cysteine, ROS, and coenzyme Q10 concentrations, and the muscle proteome, in seven maximally exercising Thoroughbred horses using a placebo and randomized cross-over design. Gluteal muscle biopsies were obtained the day before and 1 h after maximal exercise. Concentrations of GSH, cysteine, coenzyme Q10, and ROS were measured, and citrate synthase, glutathione peroxidase, and superoxide dismutase activities analyzed. GSH increased significantly 1 h post-exercise in the NACQ group (p = 0.022), whereas other antioxidant concentrations/activities were unchanged. TMT proteomic analysis revealed 40 differentially expressed proteins with NACQ out of 387 identified, including upregulation of 13 mitochondrial proteins (TCA cycle and NADPH production), 4 Z-disc proteins, and down regulation of 9 glycolytic proteins. NACQ supplementation significantly impacted muscle redox capacity after intense exercise by enhancing muscle glutathione concentrations and increasing expression of proteins involved in the uptake of glutathione into mitochondria and the NAPDH-associated reduction of oxidized glutathione, without any evident detrimental effects on performance.}, }
@article {pmid34826043, year = {2022}, author = {Liu, XD and Song, CY and Kong, CC and Tian, X}, title = {Bufalin Induces Programmed Necroptosis in Triple-Negative Breast Cancer Drug-Resistant Cell Lines through RIP1/ROS-Mediated Pathway.}, journal = {Chinese journal of integrative medicine}, volume = {28}, number = {10}, pages = {900-908}, pmid = {34826043}, issn = {1993-0402}, mesh = {Antioxidants/pharmacology ; Apoptosis ; Bufanolides ; Caspase 3/metabolism ; Cell Line ; Cell Line, Tumor ; Cysteine/pharmacology ; Docetaxel/pharmacology ; Doxorubicin/pharmacology ; Fluorescein-5-isothiocyanate/pharmacology ; Humans ; *Necroptosis ; Propidium/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Tumor Necrosis Factor ; *Triple Negative Breast Neoplasms/drug therapy ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {OBJECTIVE: To explore the effect and mechanism of action of bufalin in triple-negative breast cancer (TNBC) drug-resistant cell lines.<br><br>METHODS: The normal human mammary epithelial cell line, TNBC cell line, TNBC adriamycin-resistant cell line, and TNBC docetaxel-resistant cell line were treated with different doses of bufalin (0-1,000 nmol/L) at different time points (0-72 h). Propidium iodide staining, AV-FITC/PI double staining, Hoechst 33342/PI double staining and transmission electron microscopy (TEM) were used to evaluate the death patterns of the cell lines.<br><br>RESULTS: Bufalin killed the TNBC cell line and its drug-resistant cell lines in a dose/time-dependent manner (all P<0.01). After treatment with bufalin for 24 h, the adriamycin-resistant cell line showed a co-existing pattern of necroptosis and apoptosis. However, at 48 h, necroptosis was the main manifestation. After treatment with bufalin, the expressions of tumor necrosis factor &#x3b1;, phospho-tumor necrosis factor receptor 1, phospho-receptor interacting protein 1 and c-caspase 3 increased (all P<0.01), the killing effect of bufalin could be mostly inhibited by NEC-1, and by z-VAD-fmk (both P<0.01). Besides, the intracellular reactive oxygen species (ROS) levels increased considerably (P<0.01), the antioxidant N-acetyl cysteine or Nec-1 could inhibit the increase of ROS level and the killing effect of bufalin (all P<0.01). The adriamycin-resistant cell line exhibited necroptosis characteristic after 48 h of bufalin treatment under TEM.<br><br>CONCLUSIONS: Bufalin could induce necroptosis through RIP1/ROS-mediated pathway to kill the drug-resistant TNBC cell lines. This finding provides critical experimental data and theoretical basis for the clinical application of bufalin to overcome the difficulties in the treatment of TNBC.}, }
@article {pmid34825328, year = {2022}, author = {Elsayed, A and Elkomy, A and Alkafafy, M and Elkammar, R and El-Shafey, A and Soliman, A and Aboubakr, M}, title = {Testicular toxicity of cisplatin in rats: ameliorative effect of lycopene and N-acetylcysteine.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {16}, pages = {24077-24084}, pmid = {34825328}, issn = {1614-7499}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; *Cisplatin/toxicity ; Lycopene/metabolism/pharmacology ; Male ; Oxidative Stress ; Rats ; Spermatozoa ; Superoxide Dismutase/metabolism ; *Testis ; }, abstract = {Lycopene (LP) and N-acetylcysteine (NAC) protective effects were assessed for testicular toxicity mediated by cisplatin (CP) in rats. Forty-nine rats were divided into 7 groups (n = 7); these groups included the control group (saline, PO), LP (10 mg/kg, PO), NAC (150 mg/kg, PO), CP (7.5 mg/kg, IP) on the 27th day of the study, LP + CP, NAC+CP, and LP + NAC + CP. Serum levels of testosterone were decreased following CP injection. Malondialdehyde (MDA) has been increased with considerable glutathione (GSH), and dismutase superoxide (SOD) and catalase (CAT) decline in the testis tissues after CP injection. CP caused severe alterations in testicular tissues and elevated caspase-3 expression. Besides that, LP and/or NAC administration improved CP-induced testicular toxicity and apoptosis, probably via their antioxidant properties.}, }
@article {pmid34822616, year = {2021}, author = {Petkova, T and Milanova, A}, title = {Absorption of N-acetylcysteine in Healthy and Mycoplasma gallisepticum-Infected Chickens.}, journal = {Veterinary sciences}, volume = {8}, number = {11}, pages = {}, pmid = {34822616}, issn = {2306-7381}, abstract = {N-acetylcysteine (NAC) is widely used as a mucolytic agent in cases with inflammation of the lungs. NAC is applied in poultry with aflatoxin B1 intoxication as an antioxidant, but its pharmacokinetics are not known. The present study was conducted to characterize the population pharmacokinetics of orally administered NAC in broilers. It included 32 chickens, divided into four groups, treated with NAC at a dose rate of 100 mg/kg/day mixed with the feed: healthy broilers (n = 6); chickens infected with Mycoplasma gallisepticum (n = 10); healthy broilers (n = 6); and diseased chickens (n = 10) treated with NAC and doxycycline (via drinking water, 20 mg/kg body weight (b.w.)). Plasma concentrations were analyzed by Liquid Chromatography -Mass Spectrometry (MS)/MS. NAC was absorbed after oral administration in all four groups of chickens. In healthy chickens treated solely with NAC, maximum plasma concentrations of 2.26 ± 0.91 µg mL[-1] were achieved at 2.47 ± 0.45 h after dosing. The value of absorption half-life was 1.04 ± 0.53 h. The population pharmacokinetic analysis showed that dose adjustment of NAC is not required in M. gallisepticum-infected broilers or when it is combined with doxycycline.}, }
@article {pmid34820428, year = {2021}, author = {Zhang, J and Feng, W and Li, M and Chen, P and Ning, X and Ou, C and Chen, M}, title = {Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis.}, journal = {Frontiers in cardiovascular medicine}, volume = {8}, number = {}, pages = {737652}, pmid = {34820428}, issn = {2297-055X}, abstract = {Chronic cadmium (Cd) exposure contributes to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. In this study, we aimed to investigate Cd-mediated AS through macrophage polarization and know the mechanisms of Cd-caused mitochondrial homeostasis imbalance. In vitro, flow cytometry shows that Cd exposure promotes M1-type polarization of macrophages, manifested as the increasing expressions of nuclear Factor kappa-light-chain-enhancer of activated B (NF-kB) and NLR family pyrin domain containing 3 (NLRP3). Mitochondrial homeostasis tests revealed that decreasing mitochondrial membrane potential and mitophage, increasing the mitochondrial superoxide (mROS), and mitochondrial fission are involved in the Cd-induced macrophage polarization. The upregulated expressions of receptor-interacting protein kinase 3 (RIPK3) and pseudokinase-mixed lineage kinase domain-like protein (p-MLKL) were observed. Knocking out RIPK3, followed by decreasing the expression of p-MLKL, improves the mitochondrial homeostasis imbalance which effectively reverses macrophage polarization. In vivo, the oil red O staining showed that Cd with higher blood significantly aggravates AS. Besides, M1-type polarization of macrophages and mitochondrial homeostasis imbalance were observed in the aortic roots of the mice through immunofluorescence and western blot. Knocking out RIPK3 restored the changes above. Finally, the administered N-acetyl cysteine (NAC) or mitochondrial division inhibitor-1 (Mdivi-1), which decreased the mROS or mitochondrial fission, inhibited the expressions of RIPK3 and p-MLKL, attenuating AS and macrophage M1-type polarization in the Cd-treated group. Consequently, the Cd exposure activated the RIPK3 pathway and impaired the mitochondrial homeostasis, resulting in pro-inflammatory macrophage polarization and subsequent AS. Knocking out RIPK3 provided a potential therapeutic target for Cd-caused macrophage polarization and subsequent AS.}, }
@article {pmid34816377, year = {2022}, author = {Jaafarzadeh, M and Mahjoob Khaligh, R and Mohsenifar, Z and Shabani, A and Rezvani Gilkalaei, M and Rajabi Keleshteri, S and Beigi Harchegani, A}, title = {Protecting Effects of N-acetyl Cysteine Supplementation Against Lead and Cadmium-Induced Brain Toxicity in Rat Models.}, journal = {Biological trace element research}, volume = {200}, number = {10}, pages = {4395-4403}, pmid = {34816377}, issn = {1559-0720}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Brain/metabolism ; Cadmium/toxicity ; Dietary Supplements ; Lead/toxicity ; Male ; *Metals, Heavy/pharmacology ; Oxidative Stress ; Rats ; }, abstract = {We aimed to investigate mitigating effects of N-acetylcysteine (NAC) on the oxidative stress, apoptosis and Parkinson's disease (PD)-related genes in the brain tissue of male rats exposed to continuous doses of cadmium and lead. Rats were randomly divided into five groups, including G1 (control), G2 (continuous dose of Cd), G3 (continuous dose of Pb), G4 (continuous dose of Cd + NAC), and G5 (continuous dose of Pb + NAC). Biomarkers of oxidative stress, malondialdehyde (MDA), and total antioxidant capacity (TAC) were measured. Expression of PD- and apoptosis-related genes was considered using RT-PCR. Chronic exposure to these heavy metals was associated with accumulation of Pb and Cd in the brain and blood and caused severe morphological changes in the brain, as well as decreased body and brain weights. Continuous exposure to Cd and Pb significantly decreased TAC content and SOD expression but increased MDA level in the brain tissues (P < 0.001). A significant increase was observed in expression of PD-related genes, Parkin, Pink1, LRRK2, SNCA, and Caspase-3 in the brain tissues following exposure to Cd and Pb. Pb exhibited stronger toxicity on the brain tissue compared to Cd. NAC supplementation not only improved morphological changes, but also compensated antioxidant capacity and expression of apoptosis- and PD-related genes in the brain tissues when compared to rats exposed to Pb and Cd alone. Chronic exposure to Pb and Cd is strongly associated with accumulation of these heavy metals in the brain, morphological changes, antioxidants depletion, oxidative stress, and brain cells apoptosis. Changes in expression of PD-related genes indicate the higher risk of PD among individuals who are chronically exposed to these heavy metals. NAC can protect brain tissue against Pb and Cd toxicity by elevating antioxidants capacity, mitigating oxidative stress, apoptosis, and down-regulating of PD-related genes.}, }
@article {pmid34815794, year = {2021}, author = {Zhang, DY and Tu, T and Younis, MR and Zhu, KS and Liu, H and Lei, S and Qu, J and Lin, J and Huang, P}, title = {Clinically translatable gold nanozymes with broad spectrum antioxidant and anti-inflammatory activity for alleviating acute kidney injury.}, journal = {Theranostics}, volume = {11}, number = {20}, pages = {9904-9917}, pmid = {34815794}, issn = {1838-7640}, mesh = {Acetylcysteine/pharmacology ; Acute Kidney Injury/*drug therapy ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Disease Models, Animal ; Drug Delivery Systems/*methods ; Female ; Gold/chemistry ; HEK293 Cells ; Humans ; Kidney/drug effects ; Male ; Metal Nanoparticles/administration &amp; dosage/chemistry/*therapeutic use ; Mice ; Mice, Inbred BALB C ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Rationale: Acute kidney injury (AKI) is associated with aberrant generation of oxidative species and inflammation, leading to high mortality of in-hospitalized patients. Although N-acetylcysteine (NAC) showed positive effects in alleviating contrast-induced AKI, the clinical applications are strongly restrained due to the low bioavailability, low renal accumulation, short renal retention time, and high dosage-induced toxicity. Methods: We addressed the clinical dilemma of NAC by developing ultrasmall gold nanoclusters (1-2 nm) capped with NAC (denoted as Au NCs-NAC) as a nanozyme-based antioxidant defense system for AKI alleviation. Rhabdomyolysis-induced AKI mice model was developed, and the same dose of free NAC (as a control) and NAC onto Au NCs (Au NCs-NAC) was used for in vivo investigation of AKI restoration. Results: The as-developed gold nanozyme exhibited high bioavailability and good physicochemical stability as compared to NAC. Meanwhile, Au NCs-NAC showed broad-spectrum antioxidant activity of Au NCs-NAC, offering in vitro renoprotective effects, as well as macrophages by relieving inflammation under hydrogen peroxide or lipopolysaccharide stimulation. Notably, owing to the smaller size than kidney threshold (5.5 nm), Au NCs-NAC displayed preferential renal enrichment (< 2 h) and longer retention (> 24 h) in AKI mice as revealed by fluorescence imaging, thereby largely enhancing the restoration of renal function in AKI mice than free NAC by protecting the kidneys from oxidative injury and inflammation without systemic toxicity, as demonstrated by tissues staining, inflammatory cytokines and biomarkers detection, and mice survival rate. Conclusion: Owing to the synergistic anti-inflammatory/antioxidative effects, and enhanced bioavailability and renal accumulation/retention, Au NCs-NAC displayed far superior therapeutic performance than NAC alone. This work will facilitate the development of high-performance antioxidative nanoplatforms, as well as overcome the clinical limitations of small molecular drugs for AKI treatment and other inflammatory diseases.}, }
@article {pmid34814783, year = {2021}, author = {Hada, B and Karmacharya, MB and Park, SR and Choi, BH}, title = {Low-intensity ultrasound (LIUS) differentially modulates mitochondrial reactive oxygen species (mtROS) generation by three different chemicals in PC12 cells.}, journal = {Free radical research}, volume = {55}, number = {11-12}, pages = {1037-1047}, doi = {10.1080/10715762.2021.2010730}, pmid = {34814783}, issn = {1029-2470}, mesh = {Animals ; Glutathione/metabolism ; Ionomycin/metabolism ; *Mitochondria/metabolism ; PC12 Cells ; Rats ; Reactive Oxygen Species/metabolism ; *Rotenone/pharmacology ; }, abstract = {We have previously shown that low-intensity ultrasound (LIUS) can modulate mitochondrial complex I activity and the generation of mitochondrial reactive oxygen species (mtROS) in PC12 cells. This study investigated the mechanism of LIUS by comparing its effect on mitochondrial dysfunction by three different pathways. LIUS was shown to reverse the effects of rotenone, a Q-site blocker, on the complex I inhibition, mtROS generation, and drop of mitochondrial membrane potential (Δψm). In contrast, common antioxidants, N-acetyl cysteine (NAC), and uric acid (UA) blocked rotenone-induced mtROS generation and Δψm drop without recovering the complex I activity, which suggested that Δψm drop is correlated with mtROS generation rather than complex I inhibition itself. Ionomycin, an ionophore for Ca[2+], and L-buthionine-S,R-sulfoximine (BSO), an inhibitor of glutathione (GSH) biosynthesis, induced mtROS generation and Δψm drop without inhibiting complex I activity via different mechanisms. LIUS showed no effect on ionomycin-induced Δψm drop but showed partial inhibition on the other effects of ionomycin and BSO. These results suggest that LIUS might have redundant mechanisms but acted mainly on the complex I activity thereby modulating mtROS and Δψm levels. LIUS appeared to act on the Q-module of complex I because it showed no inhibitory effect on Zn[2+], an inhibitor of the proton transporting P-module of complex I. Interestingly, pretreatment of LIUS for up to an hour in advance blocked the rotenone effect as efficiently as the co-treatment. Further studies are needed to reveal the exact mechanism of LIUS to inhibit complex I activity.}, }
@article {pmid34811378, year = {2021}, author = {Kim, S and Kim, SY and Rho, SJ and Kim, SH and Song, SH and Kim, CH and Lee, H and Kim, SK}, title = {Biocompatible N-acetyl-nanoconstruct alleviates lipopolysaccharide-induced acute lung injury in vivo.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {22662}, pmid = {34811378}, issn = {2045-2322}, support = {2020M3A9I4038197//Ministry of Science and ICT, South Korea/ ; 2020R1A6A3A01098476//Ministry of Education, South Korea/ ; 2E30341//Korea Institute of Science and Technology/ ; }, mesh = {Acute Lung Injury/*drug therapy ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; *Biocompatible Materials ; Biotechnology/methods ; Cytokines/metabolism ; Drug Delivery Systems ; Inflammation ; Lipopolysaccharides/*chemistry ; Lung/metabolism ; Male ; Microscopy, Electron, Transmission ; Nanoparticles ; Nanotechnology/methods ; Nitrogen ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; }, abstract = {Oxidative stress plays important roles in inflammatory responses during acute lung injury (ALI). Recently, nanoconstruct (Nano)-based drug-delivery systems have shown promise in many models of inflammation. In this study, we evaluated the anti-inflammatory effects of N-acetylcysteine (NAC) loaded in a biocompatible Nano using a rat model of ALI. We synthesized a Nano with a good NAC-releasing capacity using porous silica Nano, which was used to produce Nano/NAC complexes. For in vivo experiments, Sprague-Dawley rats were intraperitoneally administered NAC or Nano/NAC 30 min after intratracheal instillation of lipopolysaccharide. After 6 h, bronchoalveolar lavage fluids and lung tissues were collected. The anti-oxidative effect of the Nano/NAC complex was confirmed by demonstrating reduced levels of reactive oxygen species after treatment with the Nano/NAC in vitro. In vivo experiments also showed that the Nano/NAC treatment may protect against LPS-induced ALI thorough anti-oxidative and anti-inflammatory effects, which may be attributed to the inactivation of the NF-κB and MAPK pathways. In addition, the effects of Nano/NAC treatment were shown to be superior to those of NAC alone. We suggest the therapeutic potential of Nano/NAC treatment as an anti-inflammatory agent against ALI. Furthermore, our study can provide basic data for developing nanotechnology-based pharmacotherapeutics for ALI.}, }
@article {pmid34801537, year = {2022}, author = {Jacobsen, J and Adomako-Bonsu, AG and Maser, E}, title = {Induction of carbonyl reductase 1 (CR1) gene expression in Daphnia magna by TNT, but not its key metabolites 2-ADNT and 4-ADNT.}, journal = {Chemico-biological interactions}, volume = {351}, number = {}, pages = {109752}, doi = {10.1016/j.cbi.2021.109752}, pmid = {34801537}, issn = {1872-7786}, mesh = {Aniline Compounds/pharmacology ; Animals ; Biomarkers/metabolism ; Carbonyl Reductase (NADPH)/genetics/*metabolism ; Daphnia/*drug effects ; Trinitrotoluene/*pharmacology ; Up-Regulation/*drug effects ; Water Pollutants, Chemical/*pharmacology ; }, abstract = {2,4,6-trinitrotoluene (TNT) is a known source of reactive oxygen species (ROS), which cause oxidative stress in aquatic ecosystems. Carbonyl reductases (CRs) are one of several possible defense mechanisms induced against ROS products, especially those that result in the 'so-called' carbonyl stress. Daphnia magna, a freshwater organism living in stagnant freshwater bodies, expresses four copies of the CR gene (Dma_CR1, Dma_CR2, Dma_CR3 and Dma_CR4). In this study, induction of all four copies of Dma_CR by 2-amino-4,6-dinitrotoluene (2-ADNT) and 4-amino-2,6-dinitrotoluene (4-ADNT), was investigated. Reverse transcription polymerase chain reaction (RT-PCR) analysis of treated daphnids revealed up-regulation of Dma_CR1 alone in response to TNT, but not 2-ADNT and 4-ADNT (which are key metabolites of TNT). This concentration- and time-dependent up-regulation in mRNA-expression was observed both in the presence and absence of light, in the same magnitude. Moreover, significant change in mRNA-expression could be observed 8 h after treatment with TNT. In the presence of TNT, the antioxidant N-acetylcysteine (NAc) could not reverse TNT-induced up-regulation of Dma_CR1 mRNA-expression. On the other hand, withdrawal of TNT from the culture medium caused a significant reduction in the TNT-induced mRNA-expression of Dma_CR1 within 24 h. These findings highlight the potential of Dma_CR1 as a biomarker for biomonitoring of TNT levels in freshwater bodies.}, }
@article {pmid34801356, year = {2022}, author = {Parpoudi, S and Mantzoros, I and Gkiouliava, A and Kyziridis, D and Makrantonakis, A and Chatzakis, C and Gekas, C and Konstantaras, D and Ioannidis, O and Bitsianis, S and Miliaras, D and Aggelopoulos, S}, title = {Effect of N-acetyl-L-cysteine on inflammation after intraperitoneal mesh placement in a potentially contaminated environment: An experimental study in the rat.}, journal = {Asian journal of surgery}, volume = {45}, number = {11}, pages = {2191-2196}, doi = {10.1016/j.asjsur.2021.11.001}, pmid = {34801356}, issn = {0219-3108}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Ciprofloxacin ; Inflammation/prevention &amp; control ; Interleukin-6 ; Male ; Rats ; Rats, Wistar ; *Surgical Mesh ; Tissue Adhesions/etiology/pathology/prevention &amp; control ; }, abstract = {BACKGROUND: The use of prosthetic meshes in abdominal wall reconstruction is a well-established approach; however, in certain cases where a bowel resection coexists its application is disputed. Any underlying inflammatory process may augment adhesion formation which is a major postoperative complication. In this animal study, our aim was to investigate the effect of N-acetyl-l-cysteine (NAC) on adhesion formation and the expression of inflammatory markers when a mesh was used in a clean or a potentially contaminated environment.<br><br>METHODS: Sixty male Wistar rats were randomly and equally allocated in 3 groups: A, B and C. Animals in all groups underwent laparotomy, a prosthetic mesh was placed and chemoprophylaxis with ciprofloxacin was administered. In groups B and C an enterectomy was also performed. NAC was injected intraperitoneally in group C. Adhesion formation, IL-1a, IL-6, TNF-a and histological data including fibrosis, neutrophils' infiltration and neovascularization were assessed. Mesh samples were sent for cultivation.<br><br>RESULTS: Adhesion formation was significantly less and inflammation markers were also lower in group C compared to group B (p<0.05). Histological findings were significant for greater fibrosis, neutrophils' infiltration and neovascularization in group B compared to both group A and C. Regarding mesh cultures, more specimens were tested positive in group B (p <0.05). Outcomes between group A and C did not differ.<br><br>CONCLUSION: NAC effectively ameliorated adhesion formation and inflammation in a potentially septic environment where a prosthetic mesh was placed.}, }
@article {pmid34793863, year = {2022}, author = {Liu, Y and Yang, Z and Du, Y and Shi, S and Cheng, Y}, title = {Antioxidant interventions in autism spectrum disorders: A meta-analysis.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {113}, number = {}, pages = {110476}, doi = {10.1016/j.pnpbp.2021.110476}, pmid = {34793863}, issn = {1878-4216}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/*therapeutic use ; Autism Spectrum Disorder/*therapy ; Humans ; Oxidative Stress ; Randomized Controlled Trials as Topic ; Stereotyped Behavior ; }, abstract = {BACKGROUND: Autism spectrum disorder (ASD) might be associated with oxidative stress, and antioxidants are commonly used in the treatment of young people with ASD. However, the evidence about the effectiveness of these interventions remains debatable. We performed a meta-analysis to evaluate the effect of antioxidants on the symptoms of patients with autism.<br><br>METHODS: Data sources: PubMed and Web of Science databases.<br><br>STUDY SELECTION: We selected placebo-controlled, double-blind, randomized clinical trials published until February 2021 to evaluate the efficacy of antioxidant interventions on ASD.<br><br>DATA ANALYSIS: Aberrant Behavior Checklist (ABC), Repetitive Behavior Scale-Revised (RBS), Social Responsiveness Scale (SRS), Developmental Behavior Checklist (DBC) and Clinical Global Impressions Severity scale (CGIS) were used to evaluate the 22 different symptom outcomes. The Hedges-adjusted g value was used to estimate the effect of each dietary intervention relative to the placebo.<br><br>RESULTS: In this meta-analysis, we examined 13 double-blind randomized clinical trials, comprising a total of 570 patients with ASD: 293 in the intervention group and 277 in the placebo group. Antioxidants (N-acetylcysteine (NAC), other antioxidants) are more effective than placebos in improving the irritability among symptoms in the ABC and communication disturbance symptoms in the DBC. There was a good trend of improvement in the stereotypic behavior symptoms in the ABC. Treatment with NAC antioxidants showed a good trend of improvement in irritability in the ABC and symptoms of hyperactivity. The effect size was small, and there was a low risk of statistical heterogeneity and publication bias.<br><br>LIMITATIONS: The number of studies in this meta-analysis was small and the sample size was small.<br><br>CONCLUSION: This meta-analysis suggests that antioxidant intervention has a potential role in the management of some symptoms in patients with ASD, and indicates the feasibility of using antioxidants to treat autism in the future.}, }
@article {pmid34785568, year = {2022}, author = {Qin, X and Hakenjos, JM and MacKenzie, KR and Barzi, M and Chavan, H and Nyshadham, P and Wang, J and Jung, SY and Guner, JZ and Chen, S and Guo, L and Krishnamurthy, P and Bissig, KD and Palmer, S and Matzuk, MM and Li, F}, title = {Metabolism of a Selective Serotonin and Norepinephrine Reuptake Inhibitor Duloxetine in Liver Microsomes and Mice.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {50}, number = {2}, pages = {128-139}, pmid = {34785568}, issn = {1521-009X}, support = {P01 HD087157/HD/NICHD NIH HHS/United States ; R61 HD099995/HD/NICHD NIH HHS/United States ; INV-001902/GATES/Bill &amp; Melinda Gates Foundation/United States ; R01 DK121970/DK/NIDDK NIH HHS/United States ; R01 GM115622/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Depressive Disorder, Major/metabolism ; Duloxetine Hydrochloride/metabolism ; Mice ; Microsomes, Liver/metabolism ; Serotonin/metabolism ; *Serotonin and Noradrenaline Reuptake Inhibitors/metabolism ; }, abstract = {Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical roles in drug safety and efficacy. However, the metabolic profile of DLX in mice is not available, although mice serve as commonly used animal models for mechanistic studies of drug-induced adverse effects. Our study revealed 39 DLX metabolites in human/mouse liver microsomes and mice. Of note, 13 metabolites are novel, including five N-acetyl cysteine adducts and one reduced glutathione (GSH) adduct associated with DLX. Additionally, the species differences of certain metabolites were observed between human and mouse liver microsomes. CYP1A2 and CYP2D6 are primary enzymes responsible for the formation of DLX metabolites in liver microsomes, including DLX-GSH adducts. In summary, a total of 39 DLX metabolites were identified, and species differences were noticed in vitro. The roles of CYP450s in DLX metabolite formation were also verified using human recombinant cytochrome P450 (P450) enzymes and corresponding chemical inhibitors. Further studies are warranted to address the exact role of DLX metabolism in its adverse effects in vitro (e.g., human primary hepatocytes) and in vivo (e.g., Cyp1a2-null mice). SIGNIFICANCE STATEMENT: This current study systematically investigated Duloxetine (DLX) metabolism and bioactivation in liver microsomes and mice. This study provided a global view of DLX metabolism and bioactivation in liver microsomes and mice, which are very valuable to further elucidate the mechanistic study of DLX-related adverse effects and drug-drug interaction from metabolic aspects.}, }
@article {pmid34785186, year = {2022}, author = {Pourbagher-Shahri, AM and Schimmel, J and Shirazi, FM and Nakhaee, S and Mehrpour, O}, title = {Use of fomepizole (4-methylpyrazole) for acetaminophen poisoning: A scoping review.}, journal = {Toxicology letters}, volume = {355}, number = {}, pages = {47-61}, doi = {10.1016/j.toxlet.2021.11.005}, pmid = {34785186}, issn = {1879-3169}, mesh = {Acetaminophen/*toxicity ; Antidotes/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy ; Fomepizole/*therapeutic use ; Humans ; }, abstract = {INTRODUCTION: Acetaminophen (paracetamol, APAP) poisoning is a prominent global cause of drug-induced liver injury. While N-acetylcysteine (NAC) is an effective antidote, it has therapeutic limitations in massive overdose or delayed presentation. The objective is to comprehensively review the literature on fomepizole as a potential adjunct antidote for acetaminophen toxicity.<br><br>METHODS: A scoping review was performed using standardized search terms from inception through July 2021.<br><br>RESULTS: Reports on fomepizole as a therapeutic adjunct for APAP toxicity span heterogeneous types of evidence. Eleven preclinical studies (in vitro and animal), fourteen case reports/series, and one human volunteer study were included. Fomepizole's action is mediated by inhibition of CYP2E1 to prevent oxidant stress generation, and inhibition of c-Jun N-terminal kinase (JNK) to decrease amplification of oxidant stress signaling to mitochondria. Studies have shown a reduction in oxidative metabolites likely by shunting metabolism away from CYP2E1 and a resultant decrease in liver injury in animals, independent of CYP2E1 interactions. Fomepizole has been linked to few adverse effects.<br><br>CONCLUSION: Based on in vitro and animal studies, and bolstered by case reports, fomepizole likely offers benefit as an adjunct antidote for APAP toxicity, however this remains to be shown in a human trial. NAC remains the standard of care antidote, but given that fomepizole is approved and generally safe, it may be considered for APAP toxicity as off-label use by experienced clinicians, in rare circumstances associated with increased risk of hepatotoxicity despite standard NAC dosing. The marginal clinical benefit of fomepizole adjunct therapy beyond NAC monotherapy remains to be clearly defined, and routine use for APAP overdose is premature based on current evidence.}, }
@article {pmid34781617, year = {2021}, author = {Singh, K and Bhargava, V and Brar, JE and Bhargava, M and Kaushal, R and Khullar, D}, title = {Contrast Induced Acute Kidney Injury (CI- AKI) - Myths and Realities.}, journal = {The Journal of the Association of Physicians of India}, volume = {69}, number = {11}, pages = {11-12}, pmid = {34781617}, issn = {0004-5772}, mesh = {Acetylcysteine/therapeutic use ; *Acute Kidney Injury/chemically induced ; *Contrast Media/adverse effects ; Humans ; Renal Dialysis ; Risk Factors ; }, abstract = {Contrast Induced Acute Kidney Injury (CI-AKI) is one of the most common causes of acute kidney injury in hospitalized patients. These days, contrast agents are widely being used in both cardiology and radiology procedures. Old age, history of diabetes, heart failure, proteinuria and low blood pressure are some important risk factors in the pathogenesis of CI-AKI. Apart from risk stratification and the use of low and iso-osmolar contrast agents, intravenous fluid hydration with crystalloids is the only recommended strategy for the prevention of CI-AKI. Agents like N-acetylcysteine (NAC), atrial natriuretic peptide, ascorbic acid, theophylline, and fenoldopam have failed to show any proven beneficial role in the prevention of CI-AKI. Though hemodialysis is still being perceived by many clinicians as the modality for contrast removal but prophylactic hemodialysis is now not recommended for the prevention of CI-AKI.}, }
@article {pmid34776986, year = {2021}, author = {Xiang, Y and Chen, X and Wang, W and Zhai, L and Sun, X and Feng, J and Duan, T and Zhang, M and Pan, T and Yan, L and Jin, T and Gao, Q and Wen, C and Ma, W and Liu, W and Wang, D and Wu, Q and Xie, T and Sui, X}, title = {Natural Product Erianin Inhibits Bladder Cancer Cell Growth by Inducing Ferroptosis via NRF2 Inactivation.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {775506}, pmid = {34776986}, issn = {1663-9812}, abstract = {Erianin, a natural product derived from Dendrobium chrysotoxum Lindl, has been proved to play antitumor activity in various cancers. However, the effects and molecular mechanisms of erianin in bladder cancer cells remain unexplored. In this study, we found that erianin triggered cell death and cell cycle arrest in bladder cancer cells. Then we demonstrated that erianin could promote the accumulation of lethal lipid-based reactive oxygen species (ROS) and the depletion of glutathione (GSH), suggesting the induction of ferroptosis. In the further study, the ferroptosis inhibitor deferoxamine (DFO), N-Acetylcysteine (NAC) and GSH but not necrostatin-1, CQ or Z-VAD-FMK rescued erianin-caused cell death, showing ferroptosis played a major role in erianin-caused cell death. In vivo, we also showed that erianin suppressed the tumor growth by inducing ferroptosis. Mechanistically, we demonstrated that nuclear factor E2-related factor 2 (NRF2) inactivation was a key determinant of ferroptosis caused by erianin. In bladder cancer cells, the compound tert-butylhydro-quinone (TBHQ), an activator of NRF2, suppressed erianin-induced ferroptosis. Whereas, NRF2 inhibition used shRNA augmented the ferroptosis response induced by erianin treatment. In conclusion, our data provide the first evidence that erianin can initiate ferroptosis-like cell death and lipid peroxidation in bladder cancer, which will hopefully become a promising anticancer compound for the treatment of bladder cancer.}, }
@article {pmid34775122, year = {2022}, author = {Biswas, DP and Tk, DS}, title = {The efficacy of adjuvant N acetyl cysteine for the eradication of H pylori infections: A systematic review and meta-analysis of randomized clinical trials.}, journal = {Clinics and research in hepatology and gastroenterology}, volume = {46}, number = {3}, pages = {101832}, doi = {10.1016/j.clinre.2021.101832}, pmid = {34775122}, issn = {2210-741X}, mesh = {Adult ; Anti-Bacterial Agents/therapeutic use ; Clarithromycin/therapeutic use ; Cysteine/therapeutic use ; Drug Therapy, Combination ; *Helicobacter Infections/drug therapy ; *Helicobacter pylori ; Humans ; Proton Pump Inhibitors/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Biofilm-producing bacteria are relatively resistant to antibiotics, as the penetration of antibiotics into the endopolysaccharide envelope is incomplete. N Acetyl cysteine (NAC) is known to destabilize the biofilms, as it cleaves the disulfide bonds of mucus glycoproteins, reducing the viscosity and thickness of mucus. This allows NAC to act synergistically with antibiotics for the eradication of H Pylori. The meta-analysis evaluates the evidence of the efficacy of adjuvant N acetyl cysteine (NAC) compared to standard therapies in the eradication of H. Pylori infections.<br><br>METHODS: We searched randomized clinical trials in MEDLINE, Cochrane Central Register of Clinical Trials (CENTRAL), EBSCO, Database of Abstracts of Reviews of Effects (DARE), and Google Scholar. We included trials comparing standard treatment protocols plus adjuvant NAC and the same regimen without NAC. These studies included adults with a diagnosis of Helicobacter pylori infection. Our primary outcome was the successful eradication of H. Pylori. The results were pooled using a random-effects model, and data were analyzed using RevMan 5.0 software. Cochrane collaboration's tool was used to assess the risk of bias. Publication bias and other inconsistencies were assessed. Sensitivity analyses and grading of evidence were performed.<br><br>FINDINGS: Eight studies, comprising 1167 patients, were included in the meta-analysis, the pooled outcomes of patients on adjuvant NAC+ standard eradication therapy noted an eradication rate of 76.1% (n=581) compared to the patients in standard eradication therapy with a rate of 72.18% (n=586), RR 1.17 [95% CI (0.99, 1.39); I2= 64%; p value=0.07]. Moderate to severe heterogeneity was noted. These pooled results show that adjuvant NAC plus standard treatment protocols are not superior to standard treatment protocols for H pylori eradication. Similar results were seen in the use of adjuvant NAC with 'currently used standard treatment protocols' (78.3% versus 76.3%, RR 1.08, [95% CI 0.94 to 1.25]; I2=55%; p=0.28; n= 829 patients], as well as in the treatment of na&#xef;ve patients (79.8% versus 80.9%, RR 1.00[95% CI 0.87 to 1.15]; i2=27%; P=-0.98; n= 775 patients].<br><br>CONCLUSION: Adjuvant NAC plus standard treatment protocols are not superior to standard treatment protocols for H. pylori eradication. These findings are consistent with the use of adjuvant NAC with 'currently used standard treatment protocols' (clarithromycin-based triple therapies) and also with adjuvant NAC used in the treatment of na&#xef;ve patients. We are moderately certain of these findings. Future studies could explore the use of NAC as a pretreatment before using the current standard therapies in the eradication of H. Pylori rather than NAC as adjuvant therapy.<br><br>FUNDING: None.}, }
@article {pmid34771053, year = {2021}, author = {Balaji, K and Vijayakumar, J and Sankaran, PK and Senthilkumar, S and Vijayaraghavan, R and Selvaraj, J and Yuvaraj, MF}, title = {Molecular Studies on the Nephroprotective Potential of Celastrus paniculatus against Lead-Acetate-Induced Nephrotoxicity in Experimental Rats: Role of the PI3K/AKT Signaling Pathway.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {21}, pages = {}, pmid = {34771053}, issn = {1420-3049}, mesh = {Animals ; Biomarkers ; Celastrus/*chemistry ; Female ; Gene Expression ; Immunohistochemistry ; Kidney/*drug effects/*metabolism/pathology/ultrastructure ; Organometallic Compounds/*adverse effects ; Phosphatidylinositol 3-Kinases/metabolism ; Plant Extracts/chemistry/*pharmacology ; Protective Agents/chemistry/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Signal Transduction/drug effects ; }, abstract = {Chemicals can induce nephrotoxicity, with damage to different segments of the nephron and deterioration of renal function. Nephrotoxicity due to exposure to a toxin such as carbon tetrachloride, sodium oxalate, or heavy metals is the most common cause of kidney injury. The current study aimed to evaluate the protective effects of Celastrus paniculatus seed extract against lead-acetate-induced nephrotoxicity by evaluating the histopathology, immunohistochemistry, ultrastructure, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Twenty-four rats were divided into four groups (n = 6 per group): group 1 contained normal animals and served as the control; group 2 received lead acetate (30 mg/kg body weight (b.w.)/day, oral); group 3 received lead acetate and the standard drug N-acetylcysteine (NAC, 200 mg/kg b.w./day, oral); and group 4 received lead acetate and the ethanolic extract of C. paniculatus seed (EECP; 800 mg/kg b.w./day, oral). Treatment was given for 28 consecutive days. The data were analyzed using one-way analysis of variance with SIGMA PLOT 13 using SYSTAT software followed by Newman-Keul's test for comparison between the groups. EECP ameliorated the adverse changes caused by lead acetate. PI3K and AKT messenger RNA (mRNA) levels were diminished in lead-acetate-treated rats. Treatment with EECP inhibited the occurrence of shrunken cells, the atrophy of glomeruli, and degenerative changes in renal tubules caused by lead acetate. Interestingly, the PI3K and AKT mRNA levels were significantly increased in EECP-treated animals. Our results clearly evidence for the first time that C. paniculatus seed extract inhibits lead-acetate-induced detrimental changes in kidneys by regulating PI3K/AKT signaling pathways.}, }
@article {pmid34770989, year = {2021}, author = {Beck, C and Gren, T and Ortiz-López, FJ and Jørgensen, TS and Carretero-Molina, D and Martín Serrano, J and Tormo, JR and Oves-Costales, D and Kontou, EE and Mohite, OS and Mingyar, E and Stegmann, E and Genilloud, O and Weber, T}, title = {Activation and Identification of a Griseusin Cluster in Streptomyces sp. CA-256286 by Employing Transcriptional Regulators and Multi-Omics Methods.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {21}, pages = {}, pmid = {34770989}, issn = {1420-3049}, support = {NNF20CC0035580//Novo Nordisk Foundation/ ; NNF16OC0021746//Novo Nordisk Foundation/ ; 9.818//German Center for Infection Research/ ; 398967434//German Research Foundation (DFG), TRR261/ ; }, mesh = {*Computational Biology ; Molecular Structure ; Naphthoquinones/analysis/metabolism ; Streptomyces/*chemistry/metabolism ; Transcription Factors/genetics/*metabolism ; Transcription, Genetic/genetics ; }, abstract = {Streptomyces are well-known producers of a range of different secondary metabolites, including antibiotics and other bioactive compounds. Recently, it has been demonstrated that "silent" biosynthetic gene clusters (BGCs) can be activated by heterologously expressing transcriptional regulators from other BGCs. Here, we have activated a silent BGC in Streptomyces sp. CA-256286 by overexpression of a set of SARP family transcriptional regulators. The structure of the produced compound was elucidated by NMR and found to be an N-acetyl cysteine adduct of the pyranonaphtoquinone polyketide 3'-O-α-d-forosaminyl-(+)-griseusin A. Employing a combination of multi-omics and metabolic engineering techniques, we identified the responsible BGC. These methods include genome mining, proteomics and transcriptomics analyses, in combination with CRISPR induced gene inactivations and expression of the BGC in a heterologous host strain. This work demonstrates an easy-to-implement workflow of how silent BGCs can be activated, followed by the identification and characterization of the produced compound, the responsible BGC, and hints of its biosynthetic pathway.}, }
@article {pmid34768986, year = {2021}, author = {Ramburrun, P and Kumar, P and Ndobe, E and Choonara, YE}, title = {Gellan-Xanthan Hydrogel Conduits with Intraluminal Electrospun Nanofibers as Physical, Chemical and Therapeutic Cues for Peripheral Nerve Repair.}, journal = {International journal of molecular sciences}, volume = {22}, number = {21}, pages = {}, pmid = {34768986}, issn = {1422-0067}, support = {n/a//National Research Foundation of South Africa/ ; n/a//NRF South African Research Chairs Initiative/ ; n/a//University Research Committee of the University of the Witwatersrand/ ; }, mesh = {Animals ; Axons/drug effects ; Cell Line ; Cues ; Female ; Guided Tissue Regeneration/methods ; Hydrogels/*chemistry ; Male ; Nanofibers/*chemistry ; Nerve Regeneration/*drug effects ; Neurons/drug effects ; Peripheral Nerve Injuries/*drug therapy ; Polysaccharides, Bacterial/*chemistry ; Rats ; Rats, Sprague-Dawley ; Sciatic Nerve/*drug effects ; Tissue Engineering/methods ; Tissue Scaffolds/chemistry ; }, abstract = {Optimal levels of functional recovery in peripheral nerve injuries remain elusive due to the architectural complexity of the neuronal environment. Commercial nerve repair conduits lack essential guidance cues for the regenerating axons. In this study, the regenerative potential of a biosimulated nerve repair system providing three types of regenerative cues was evaluated in a 10 mm sciatic nerve-gap model over 4 weeks. A thermo-ionically crosslinked gellan-xanthan hydrogel conduit loaded with electrospun PHBV-magnesium oleate-N-acetyl-cysteine (PHBV-MgOl-NAC) nanofibers was assessed for mechanical properties, nerve growth factor (NGF) release kinetics and PC12 viability. In vivo functional recovery was based on walking track analysis, gastrocnemius muscle mass and histological analysis. As an intraluminal filler, PHBV-MgOl-NAC nanofibers improved matrix resilience, deformation and fracture of the hydrogel conduit. NGF release was sustained over 4 weeks, governed by Fickian diffusion and Case-II relaxational release for the hollow conduit and the nanofiber-loaded conduit, respectively. The intraluminal fibers supported PC12 proliferation by 49% compared to the control, preserved up to 43% muscle mass and gradually improved functional recovery. The combined elements of physical guidance (nanofibrous scaffolding), chemical cues (N-acetyl-cysteine and magnesium oleate) and therapeutic cues (NGF and diclofenac sodium) offers a promising strategy for the regeneration of severed peripheral nerves.}, }
@article {pmid34768739, year = {2021}, author = {Chlumsky, O and Smith, HJ and Parker, AE and Brileya, K and Wilking, JN and Purkrtova, S and Michova, H and Ulbrich, P and Viktorova, J and Demnerova, K}, title = {Evaluation of the Antimicrobial Efficacy of N-Acetyl-l-Cysteine, Rhamnolipids, and Usnic Acid-Novel Approaches to Fight Food-Borne Pathogens.}, journal = {International journal of molecular sciences}, volume = {22}, number = {21}, pages = {}, pmid = {34768739}, issn = {1422-0067}, support = {No. 17-15936S//Grantov&#xe1; Agentura &#x10c;esk&#xe9; Republiky/ ; DMR-1455247//The National Science Foundation/ ; MSMT No 21-SVV/2020//Ministerstvo &#x160;kolstv&#xed;, Ml&#xe1;de&#x17e;e a T&#x11b;lov&#xfd;chovy/ ; }, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/pharmacology ; Anti-Infective Agents/pharmacology ; Benzofurans/*pharmacology ; Biofilms/drug effects ; Cell Line ; Escherichia coli/drug effects ; Food Contamination/prevention &amp; control ; Food Microbiology/methods ; Foodborne Diseases/*drug therapy/microbiology ; Glycolipids/*pharmacology ; Humans ; Listeria monocytogenes/drug effects ; Microbial Sensitivity Tests ; Salmonella enterica/drug effects ; Staphylococcus aureus/drug effects ; }, abstract = {In the food industry, the increasing antimicrobial resistance of food-borne pathogens to conventional sanitizers poses the risk of food contamination and a decrease in product quality and safety. Therefore, we explored alternative antimicrobials N-Acetyl-l-cysteine (NAC), rhamnolipids (RLs), and usnic acid (UA) as a novel approach to prevent biofilm formation and reduce existing biofilms formed by important food-borne pathogens (three strains of Salmonella enterica and two strains of Escherichia coli, Listeria monocytogenes, Staphylococcus aureus). Their effectiveness was evaluated by determining minimum inhibitory concentrations needed for inhibition of bacterial growth, biofilm formation, metabolic activity, and biofilm reduction. Transmission electron microscopy and confocal scanning laser microscopy followed by image analysis were used to visualize and quantify the impact of tested substances on both planktonic and biofilm-associated cells. The in vitro cytotoxicity of the substances was determined as a half-maximal inhibitory concentration in five different cell lines. The results indicate relatively low cytotoxic effects of NAC in comparison to RLs and UA. In addition, NAC inhibited bacterial growth for all strains, while RLs showed overall lower inhibition and UA inhibited only the growth of Gram-positive bacteria. Even though tested substances did not remove the biofilms, NAC represents a promising tool in biofilm prevention.}, }
@article {pmid34765973, year = {2021}, author = {Yamamoto, M and Sanomachi, T and Suzuki, S and Togashi, K and Sugai, A and Seino, S and Sato, A and Okada, M and Kitanaka, C}, title = {Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax.}, journal = {Neuro-oncology advances}, volume = {3}, number = {1}, pages = {vdab148}, pmid = {34765973}, issn = {2632-2498}, abstract = {BACKGROUND: Malignant meningioma is an aggressive tumor that requires adjuvant radiotherapy after surgery, yet there has been no standard systemic therapy established so far. We recently reported that malignant meningioma cells are highly sensitive to gemcitabine; however, it remains unknown whether or how gemcitabine interacts with ionizing radiation (IR) in malignant meningioma cells.<br><br>METHODS: We examined the radiosensitization effects of gemcitabine using malignant meningioma cell lines and xenografts and explored the underlying mechanisms.<br><br>RESULTS: Gemcitabine sensitized malignant meningioma cells to IR through the induction of senescence both in vitro and in vivo. Gemcitabine augmented the intracellular production of reactive oxygen species (ROS) by IR, which, together with cell growth suppression/senescence induced by this combination, was inhibited by N-acetyl-cysteine, suggesting a pivotal role for ROS in these combinatorial effects. Navitoclax, a senolytic drug that inhibits Bcl-2 proteins, further enhanced the effects of the combination of gemcitabine and IR by strongly inducing apoptotic cell death in senescent cells.<br><br>CONCLUSION: These results not only indicate the potential of gemcitabine as a candidate radiosensitizer for malignant meningioma, but also reveal a novel role for gemcitabine radiosensitization as a means to create a therapeutic vulnerability of senescent meningioma cells to senolytics.}, }
@article {pmid34762917, year = {2021}, author = {Khurana, H and Srivastava, M and Chaudhary, D and Gosain, TP and Kumari, R and Bean, AC and Chugh, S and Maiti, TK and Stephens, CE and Asthana, S and Singh, R}, title = {Identification of diphenyl furan derivatives via high throughput and computational studies as ArgA inhibitors of Mycobacterium tuberculosis.}, journal = {International journal of biological macromolecules}, volume = {193}, number = {Pt B}, pages = {1845-1858}, doi = {10.1016/j.ijbiomac.2021.11.017}, pmid = {34762917}, issn = {1879-0003}, mesh = {*Amino-Acid N-Acetyltransferase/antagonists &amp; inhibitors/chemistry ; Antitubercular Agents/*chemistry/therapeutic use ; *Bacterial Proteins/antagonists &amp; inhibitors/chemistry ; Enzyme Inhibitors/*chemistry/therapeutic use ; Furans ; Mycobacterium bovis/enzymology ; Mycobacterium tuberculosis/*enzymology ; }, abstract = {Microbial amino acid biosynthetic pathways are underexploited for the development of anti-bacterial agents. N-acetyl glutamate synthase (ArgA) catalyses the first committed step in L-arginine biosynthesis and is essential for M. tuberculosis growth. Here, we have purified and optimized assay conditions for the acetylation of l-glutamine by ArgA. Using the optimized conditions, high throughput screening was performed to identify ArgA inhibitors. We identified 2,5-Bis (2-chloro-4-guanidinophenyl) furan, a dicationic diaryl furan derivatives, as ArgA inhibitor, with a MIC99 values of 1.56 μM against M. tuberculosis. The diaryl furan derivative displayed bactericidal killing against both M. bovis BCG and M. tuberculosis. Inhibition of ArgA by the lead compound resulted in transcriptional reprogramming and accumulation of reactive oxygen species. The lead compound and its derivatives showed micromolar binding with ArgA as observed in surface plasmon resonance and tryptophan quenching experiments. Computational and dynamic analysis revealed that these scaffolds share similar binding site residues with L-arginine, however, with slight variations in their interaction pattern. Partial restoration of growth upon supplementation of liquid cultures with either L-arginine or N-acetyl cysteine suggests a multi-target killing mechanism for the lead compound. Taken together, we have identified small molecule inhibitors against ArgA enzyme from M. tuberculosis.}, }
@article {pmid34762904, year = {2021}, author = {Xue, Y and Ren, X and Zhu, Z and Lei, P and Liu, M and Wan, M and Zhong, D and Huang, H and Diao, X}, title = {Site-specific protein modification by 3-n-butylphthalide in primary hepatocytes: Covalent protein adducts diminished by glutathione and N-acetylcysteine.}, journal = {Life sciences}, volume = {287}, number = {}, pages = {120125}, doi = {10.1016/j.lfs.2021.120125}, pmid = {34762904}, issn = {1879-0631}, mesh = {Acetylcysteine/*metabolism ; Animals ; Benzofurans/*metabolism/*toxicity ; Binding Sites/physiology ; Cells, Cultured ; Cytochrome P-450 CYP3A Inducers/metabolism/toxicity ; Dose-Response Relationship, Drug ; Glutathione/*metabolism ; Hepatocytes/drug effects/*metabolism ; Humans ; Protein Structure, Tertiary ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIMS: 3-n-Butylphthalide (NBP) is widely used for the treatment of cerebral ischaemic stroke but can causeliver injury in clinical practice. This study aims to elucidate the underlying mechanisms and propose potential preventive strategies.<br><br>MAIN METHODS: NBP and its four major metabolites, 3-hydroxy-NBP (3-OH-NBP), 10-hydroxy-NBP, 10-keto-NBP and NBP-11-oic acid, were synthesized and evaluated in primary human or rat hepatocytes (PHHs, PRHs). NBP-related substances or amino acid adducts were identified and semi-quantitated by ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). The target proteins and binding sites were identified by shotgun proteomics based on peptide mass fingerprinting coupled with tandem mass spectrometry and verified by molecular docking.<br><br>KEY FINDINGS: The toxicity of NBP and its four major metabolites were compared in both PHHs and PRHs, and 3-OH-NBP was found to be the most toxic metabolite. 3-OH-NBP induced remarkable cell death and oxidative stresses in hepatocytes, which correlated well with the levels of glutathione and N-acetylcysteine adducts (3-GSH-NBP and 3-NAC-NBP) in cell supernatants. Additionally, 3-OH-NBP covalently conjugated with intracellular Cys, Lys and Ser, with preferable binding to Cys sites at Myh9 Cys1380, Prdx4 Cys53, Vdac2 Cys48 and Vdac3 Cys36. Furthermore, we found that CYP3A4 induction by rifampicin augmented NBP-induced cell toxicity and supplementing with GSH or NAC alleviated the oxidative stresses and reactive metabolites caused by 3-OH-NBP.<br><br>SIGNIFICANCE: Our work suggests that glutathione depletion, mitochondrial injury and covalent protein modification are the main causes of NBP-induced hepatotoxicity, which may be prevented by exogenous GSH or NAC supplementation and avoiding concomitant use of CYP3A4 inducers.}, }
@article {pmid34757312, year = {2021}, author = {Arancini, L and Mohebbi, M and Berk, M and Dean, OM and Bortolasci, CC and Spolding, B and Zazula, R and Dodd, S}, title = {A placebo-controlled, randomised pilot trial of N-acetylcysteine or placebo for cessation of tobacco smoking.}, journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology}, volume = {53}, number = {}, pages = {120-126}, doi = {10.1016/j.euroneuro.2021.10.002}, pmid = {34757312}, issn = {1873-7862}, mesh = {*Acetylcysteine/therapeutic use ; Australia ; Humans ; Pilot Projects ; *Smoking Cessation ; Tobacco Smoking ; Treatment Outcome ; }, abstract = {Smoking represents a significant health threat to the population, however there remains a core group of consistent smokers that are largely unable to break the addiction. Novel therapies are required to assist this group with cessation. N-acetylcysteine (NAC) is a nutraceutical supplement that has shown efficacy compared to placebo in previous pilot studies for assisting smokers to quit or reduce their consumption of cigarettes. A double-blind, randomised trial with a treatment period of 16 weeks and a final follow-up at 42 weeks was conducted comparing 1.8g of effervescent NAC per day (n=47) with placebo (n=47) as an aide to smoking cessation. Both study arms received adjunctive online support through the QuitCoach program. Participants reported smoking at each timepoint (baseline and weeks 8, 16 &amp; 42), which was confirmed through salivary cotinine and exhaled carbon monoxide testing. Primary and secondary analyses were undertaken using a modified intent-to-treat basis, including all participants with at least one valid post baseline outcome, regardless of treatment received or their withdrawal from the study. There was no significant difference in smoking outcomes between intervention groups among the 24 participants that competed follow-up. There were no significant differences in age, gender, or body mass index (BMI) between the groups lost to follow-up or recorded at follow-up. This study found no evidence to support NAC as a therapy for smoking cessation. The negative outcome could be the result of lack of treatment efficacy, or alternatively, small sample size, participant retention difficulties, dose, or duration of follow-up. Trial Registration: Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303. Registered on 19 October 2017.}, }
@article {pmid34753902, year = {2021}, author = {Anna, Z and Joanna, K and Sara, Z and Jan, M and Paula, KS and Izabela, S and Robert, &#x141;J and Małgorzata, &#x17b;P and Mateusz, M}, title = {N-acetylcysteine supplementation did not reverse mitochondrial oxidative stress, apoptosis, and inflammation in the salivary glands of hyperglycemic rats.}, journal = {Nutrition &amp; diabetes}, volume = {11}, number = {1}, pages = {35}, pmid = {34753902}, issn = {2044-4052}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Citrate (si)-Synthase/metabolism ; Diet, High-Fat ; Dietary Supplements ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Hyperglycemia/*drug therapy/metabolism ; Inflammation/metabolism ; Male ; Mitochondria/*metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Salivary Glands/drug effects/*metabolism ; }, abstract = {BACKGROUND/OBJECTIVES: Previous studies have shown that N-acetylcysteine (NAC) supplementation with the simultaneous inclusion of HFD prevents salivary glands from oxidative stress and mitochondrial dysfunction. In this experiment, we examined if NAC supplementation could reverse the harmful effect of HFD on mitochondrial function, reduce the severity of apoptosis, and the activity of pro-oxidative enzymes in the salivary glands of rats with confirmed hyperglycemia.<br><br>SUBJECTS/METHODS: Wistar rats were fed the standard or high-fat (HFD) diet for 10 weeks. After 6 weeks of the experiment, HFD rats were diagnosed with hyperglycemia and for the next 4 weeks, the animals were given NAC intragastrically. In the mitochondrial fraction of the parotid (PG) and submandibular salivary glands (SMG), we assessed redox status, inflammation, and apoptosis.<br><br>RESULTS: The inclusion of NAC increased the activity of mitochondrial complexes I and II&#x2009;+&#x2009;III as well as decreased the concentration of interleukin-1&#x3b2;, tumor necrosis factor &#x3b1;, and caspase-3, but only in the parotid glands of rats with hyperglycemia compared to the HFD group. However, N-acetylcysteine supplementation did not reduce the activity of caspase-9 or the Bax/Bcl-2 ratio in PG and SMG mitochondria. In both salivary glands we observed reduced activity of cytochrome c oxidase, NADPH oxidase, and xanthine oxidase, as well as hindered production of ROS and lower ADP/ATP radio, but the levels of these parameters were not comparable to the control group.<br><br>CONCLUSIONS: We demonstrated that NAC supplementation restores the glutathione ratio only in the mitochondria of the submandibular salivary glands. The supply of NAC did not significantly affect the other measured parameters. Our results indicate that NAC supplementation provides little protection against free radicals, apoptosis, and inflammation in the salivary gland mitochondria of HFD rats. Stimulated salivary secretion in hyperglycaemic rats supplemented with NAC seems to be closely related to mitochondrial respiratory capacity and appropriate ATP level.}, }
@article {pmid34753839, year = {2021}, author = {Pawar, M and Pawar, V and Thete, SG and Dutta, SD and Sadan, PP and Maria, R and Kulkarni, D}, title = {Enhancement of Odontoblastic Differentiation of Stem Cells from Exfoliated Deciduous Tooth Using N-acetylcysteine-An In Vitro Study.}, journal = {The journal of contemporary dental practice}, volume = {22}, number = {8}, pages = {882-889}, pmid = {34753839}, issn = {1526-3711}, mesh = {*Acetylcysteine/pharmacology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; *Dental Pulp ; Humans ; Odontoblasts ; Stem Cells ; Tooth, Deciduous ; }, abstract = {AIM AND OBJECTIVE: The study was conducted to evaluate the effects of N-acetylcysteine (NAC) on the propagation and differentiation of stem cells from human exfoliated deciduous teeth(SHED).<br><br>MATERIALS AND METHODS: SHEDs were isolated by explant culture method and characterized for stem cell properties using flow cytometry method. MTT assay and Cell Counting Kit-8 (CCK-8) assay were used to examine the viability and proliferation of the SHEDs. The effects of NAC-induced osteo/odontoblastic differentiation of SHEDs were determined by functional staining for mineralization, and the gene expression of osteo/odontoblastic transcription factors and proteins was evaluated by real-time quantitative reverse transcription-polymerase chain reaction(qRT-PCR) analyses. Protein levels of collagen type 1 (COL1), dentin sialophosphoprotein (DSPP), and dentin matrix acidic phosphoprotein 1(DMP-1) were calculated by the Western blot method to assess the osteo/odontogenic differentiation.<br><br>RESULTS: SHEDs presented mesenchymal stem cell (MSC)-like characteristics on flow cytometric analysis. The cell viability and metabolic activity of SHEDs were increased with an increase in the concentrations of NAC from 0.5 to 10 nM. However, the concentrations of NAC from 0.5 to 2.5 mM did not affect cell proliferation. NAC incorporated at a concentration of 2.5 mM showed higher mineralization and considerably increased gene expression levels of runt-related transcription factor 2 (RUNX2), COL1A1, DSPP, and DMP-1. It significantly increased the protein expression of odontoblast-related matrix proteins like COL1, DSPP, and DMP-1.<br><br>CONCLUSION: NAC regulates the healthy propagation of dental stem cells in vitro. Its effects on the differentiation of dental pulp SHEDs remain unidentified. This study explores that NAC can encourage the mineralization of SHEDs and differentiate them into the odontoblastic lineage.<br><br>CLINICAL SIGNIFICANCE: The results propose that NAC could have a significant pharmacological role in activating and enhancing odontogenic differentiation of dental stem cells and possibly a prospect in regenerative dentistry.}, }
@article {pmid34753573, year = {2021}, author = {Zhan, Z and Chai, L and Lei, Q and Zhou, X and Wang, Y and Deng, H and Lv, Y and Li, W}, title = {Two-photon ratiometric fluorescent probe for imaging of hypochlorous acid in acute lung injury and its remediation effect.}, journal = {Analytica chimica acta}, volume = {1187}, number = {}, pages = {339159}, doi = {10.1016/j.aca.2021.339159}, pmid = {34753573}, issn = {1873-4324}, mesh = {*Acute Lung Injury/diagnostic imaging ; Diagnostic Tests, Routine ; Fluorescent Dyes ; Humans ; *Hypochlorous Acid ; Photons ; }, abstract = {Acute lung injury (ALI) is a pulmonary inflammatory disease with high morbidity and mortality rates. However, owing to the unknown etiology and rapid progression of the disease, the diagnosis of ALI is full of challenges with no effective treatment. Since the inflammatory response and oxidative stress played vital roles in the development of ALI, we herein developed the largest emission cross-shift (△λ = 145 nm) two-photon ratiometric fluorescent probe of TPRS-HOCl with high selectivity and short response time toward hypochlorous acid (HOCl) for exploring the relevance between the degree of ALI and HOCl concentration in the development process of the disease. In addition, the inhibition effect of HOCl during different treatment periods was also evaluated. Moreover, the tendency of imaging results was basically in accordance with that of hematoxylin and eosin (H&amp;E) staining and the treatment effect became better in the early stage when using N-acetylcysteine (NAC), demonstrating the sensitivity of TPRS-HOCl toward ALI response. Thus, TPRS-HOCl has great potential to diagnose ALI in the early stage and guide for effective treatment.}, }
@article {pmid34751803, year = {2021}, author = {Maiti, R and Mishra, A and Mishra, BR and Jena, M}, title = {Comparative efficacy of mitochondrial agents for bipolar disorder during depressive episodes: a network meta-analysis using frequentist and Bayesian approaches.}, journal = {Psychopharmacology}, volume = {238}, number = {12}, pages = {3347-3356}, pmid = {34751803}, issn = {1432-2072}, mesh = {Acetylcarnitine ; Bayes Theorem ; *Bipolar Disorder/drug therapy ; Humans ; Network Meta-Analysis ; Treatment Outcome ; }, abstract = {RATIONALE: Mitochondrial dysfunctions have emerged as new biological hypothesis and therapeutic target for bipolar disorder. This network meta-analysis has been done to evaluate the comparative efficacy of mitochondrial agents in bipolar depression.<br><br>METHODS: After a comprehensive literature search on PubMed/MEDLINE, Cochrane databases, and International Trials Registry Platform, efficacy data were extracted from 15 randomized controlled trials. Random-effects meta-analysis was done following both frequentist and Bayesian approaches to pool the effects across the interventions. A network graph was built, relative effects of interventions in respect to one another and placebo were calculated, and treatments were ranked as per P- and SUCRA scores. Change in depression rating score was the primary outcome. Data was entered in contrast level and arm level for frequentist and Bayesian approaches, respectively.<br><br>RESULTS: Amongst mitochondrial agents, N-acetylcysteine (NAC) was shown to have the highest probability of being the best treatment, followed by coenzyme Q10 and combination therapy of alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) as depicted by P- and SUCRA scores. In the Bayesian approach, none of the treatments had better efficacy than placebo, but in the frequentist approach, NAC (effect estimate:&#x2009;-&#x2009;1.18 (95% CI:&#x2009;-&#x2009;2.05;&#x2009;-&#x2009;0.31)) was significantly better than placebo.<br><br>CONCLUSION: Methodically, there may be a difference of magnitude in frequentist and Bayesian approaches, but the direction of effect and ranking probabilities do not differ. We conclude that none of the existing mitochondrial agents showed better efficacy than placebo in bipolar depression regarding depression rating scores.}, }
@article {pmid34748318, year = {2021}, author = {Lu, K and Li, Y and Cheng, Y and Li, W and Zeng, B and Gu, C and Zeng, R and Song, Y}, title = {Activation of the ROS/CncC and 20-Hydroxyecdysone Signaling Pathways Is Associated with Xanthotoxin-Induced Tolerance to λ-Cyhalothrin in Spodoptera litura.}, journal = {Journal of agricultural and food chemistry}, volume = {69}, number = {45}, pages = {13425-13435}, doi = {10.1021/acs.jafc.1c04519}, pmid = {34748318}, issn = {1520-5118}, mesh = {Animals ; *Ecdysterone ; Insect Proteins/metabolism ; *Insecticides/pharmacology ; Larva/genetics/metabolism ; Methoxsalen ; Nitriles ; Pyrethrins ; Reactive Oxygen Species ; Signal Transduction ; Spodoptera/genetics/metabolism ; }, abstract = {Adaptation to phytochemicals in herbivorous insects can influence tolerance to insecticides. However, it is unclear how insects use phytochemicals as cues to activate their metabolic detoxification systems. In this study, we found that dietary exposure to xanthotoxin enhanced tolerance of Spodoptera litura larvae to λ-cyhalothrin. Xanthotoxin ingestion significantly elevated the mRNA levels of 35 detoxification genes as well as the transcription factors Cap 'n' collar isoform-C (CncC) and its binding factor small muscle aponeurosis fibromatosis isoform-K (MafK). Additionally, xanthotoxin exposure increased the levels of reactive oxygen species (ROS), while ROS inhibitor N-acetylcysteine (NAC) treatment blocked xanthotoxin-induced expression of CncC, MafK, and detoxification genes and also prevented xanthotoxin-enhanced larval tolerance to λ-cyhalothrin. The 20-hydroxyecdysone (20E) signaling pathway was effectively activated by xanthotoxin, while blocking of 20E signaling transduction prevented xanthotoxin-enhanced larval tolerance to λ-cyhalothrin. Application of 20E induced the expression of multiple xanthotoxin-induced detoxification genes and enhanced λ-cyhalothrin tolerance in S. litura. NAC treatment blocked xanthotoxin-induced 20E synthesis, while the CncC agonist curcumin activated the 20E signaling pathway. These results indicate that the ROS/CncC pathway controls the induction of metabolic detoxification upon exposure to xanthotoxin, at least in part, through its regulation of the 20E signaling pathway.}, }
@article {pmid34746455, year = {2021}, author = {Harahap, Y and Nurahman, F and Purwanto, DJ and Yanuar, A}, title = {The correlation between the level of 3-hydroxypropyl mercapturic acid, CYP2B6 polymorphisms, and hematuria occurrences after cyclophosphamide administration and its bioanalytical methods: A systematic review.}, journal = {Heliyon}, volume = {7}, number = {10}, pages = {e08126}, pmid = {34746455}, issn = {2405-8440}, abstract = {BACKGROUND: Cyclophosphamide (CPA) is a cytotoxic prodrug that needs to be metabolized by cytochrome P450 enzymes, like CYP2B6. Unfortunately, CYP2B6 is a very polymorphic enzyme and can cause a change in 3-hydroxypropyl mercapturic acid (3-HPMA), the most found CYP metabolite in urine levels. Change in 3-HPMA levels can also indicate the level change in its precursor, acrolein, which is responsible for the hematuria incidence after CPA administration.This review's purpose is to obtain a conclusion about the optimal 3-HPMA analysis method in urine after the administration of cyclophosphamide using liquid chromatography-tandem mass spectrometry (LC-MS/MS) through literature review from previous studies. Also, this review was written to examine the relationship between levels of 3-HPMA in urine, polymorphisms of CYP2B6 enzymes, and the incidence of hematuria after cyclophosphamide administration in cancer patients.<br><br>METHODS: Major databases, such as Universitas Indonesia's library database ScienceDirect, PubMed/Medline, Frontiers Media, and Google Scholar database, were used to find both published and unpublished studies without a time limit until 2020. Studies on pharmacokinetics, pharmacodynamics, drug therapy monitoring of cyclophosphamide, bioanalysis, and polymerase chain reaction (PCR) published in Indonesian and English were included. Meanwhile, non-related studies or studies written in other languages besides Indonesian and English were excluded. Two independent reviewers screened the titles, abstracts, and full-text manuscripts. Data obtained from eligible sources were used to answer the purpose of this review in a narrative form.<br><br>RESULTS: The authors found 436 related studies from various databases and websites. Then, the authors narrowed it down into 62 pieces of literature by removing the duplicates and reviewing the abstracts and full-text manuscripts. Out of 62 sources, the authors found 30 studies that explained 3-HPMA analysis using LC/MS-MS, CYP2B6 polymorphisms, and hematuria occurrences. The authors used those 30 studies to build a conclusion regarding the purpose of this study. We strengthened the results with some additional information from the other 32 eligible sources.<br><br>CONCLUSIONS: The authors conclude that according to literature searches from previous studies, the optimal 3-HPMA analysis method in urine after cyclophosphamide administration using LC-MS/MS is using triple quadrupole LC-MS/MS; source of positive ion electrospray ionization (ESI); mobile phase combination of 0.1% formic acid in water (A) - 0.1% formic acid in acetonitrile (90:10 v/v) (B); the Acquity&#xae; BEH C18 column (2.1 &#xd7; 100 mm; 1.7 &#x3bc;m); injection volume of 10 &#x3bc;l; flow rate of 0.2 ml/minute; gradient elution method. Detection was carried out using mass spectrometry with m/z ratio of 222.10 > 90 for 3-HPMA and m/z 164.10 > 122 for n-acetylcysteine (NAC). The optimum sample preparation method is acidification and dilution ratio of 1:5 v/v. Also, there is a relationship between 3-HPMA levels, CYP2B6 polymorphisms, and the occurrences of hematuria after the administration of cyclophosphamide, which is a type of CYP2B6 polymorph, namely CYP2B6&#x2217;6, can increase cyclophosphamide hydroxylation so that it can increase the levels of acrolein and 3-HPMA, as its metabolites, and risk of hematuria.<br><br>ETHICS AND DISSEMINATION: This research does not use human participants, human data, or human tissue for being directly studied for the review. Therefore, ethics approval and consent to participate are not applicable.<br><br>REGISTRATION: This research has not been registered yet.}, }
@article {pmid34745415, year = {2021}, author = {Guo, M and Huang, YL and Wu, Q and Chai, L and Jiang, ZZ and Zeng, Y and Wan, SR and Tan, XZ and Long, Y and Gu, JL and Teng, FY and Xu, Y}, title = {Chronic Ethanol Consumption Induces Osteopenia via Activation of Osteoblast Necroptosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {3027954}, pmid = {34745415}, issn = {1942-0994}, mesh = {Alcohol Drinking/*adverse effects ; Animals ; Bone Diseases, Metabolic/etiology/metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; *Necroptosis ; Osteoblasts/*pathology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Chronic high-dose alcohol consumption impairs bone remodeling, reduces bone mass, and increases the risk of osteoporosis and bone fracture. However, the mechanisms underlying alcohol-induced osteoporosis are yet to be elucidated. In this study, we showed that excess intake of ethyl alcohol (EtOH) resulted in osteopenia and osteoblast necroptosis in mice that led to necrotic lesions and reduced osteogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). We found that EtOH treatment led to the activation of the RIPK1/RIPK3/MLKL signaling, resulting in increased osteoblast necroptosis and decreased osteogenic differentiation and bone formation both in vivo and in vitro. We further discovered that excessive EtOH treatment-induced osteoblast necroptosis might partly depend on reactive oxygen species (ROS) generation; concomitantly, ROS contributed to necroptosis of osteoblasts through a positive feedback loop involving RIPK1/RIPK3. In addition, blocking of the RIPK1/RIPK3/MLKL signaling by necrostatin-1 (Nec-1), a key inhibitor of RIPK1 kinase in the necroptosis pathway, or antioxidant N-acetylcysteine (NAC), an inhibitor of ROS, could decrease the activation of osteoblast necroptosis and ameliorate alcohol-induced osteopenia both in vivo and in vitro. Collectively, we demonstrated that chronic high-dose alcohol consumption induced osteopenia via osteoblast necroptosis and revealed that RIPK1 kinase may be a therapeutic target for alcohol-induced osteopenia.}, }
@article {pmid34739934, year = {2021}, author = {Guo, H and Yin, H and Zuo, Z and Yang, Z and Yang, Y and Wei, L and Cui, H and Deng, H and Chen, X and Chen, J and Zhu, Y and Ouyang, P and Geng, Y and Du, Z and Tang, H and Wang, F and Fang, J}, title = {Oxidative stress-mediated apoptosis and autophagy involved in Ni-induced nephrotoxicity in the mice.}, journal = {Ecotoxicology and environmental safety}, volume = {228}, number = {}, pages = {112954}, doi = {10.1016/j.ecoenv.2021.112954}, pmid = {34739934}, issn = {1090-2414}, abstract = {As an extensively environmental pollution, Nickel (Ni) represents a serious hazard to human health. The present study focused on exploring the mechanism of Ni-mediated nephrotoxicity, such as apoptosis, autophagy and oxidative stress. In the current work, NiCl2 treatment could induce kidney damage. Meanwhile, NiCl2 treatment elevated ROS production and MDA content and suppressed the antioxidant activity, which was characterized by reducing T-AOC, CAT, SOD activity and GSH content. For investigating the role of oxidative stress on NiCl2-mediated nephrotoxicity, N-acetyl cysteine (NAC, effective antioxidant and free radical scavenger) was co-treated with NiCl2. The results showed that NAC significantly suppressed the NiCl2-mediated oxidative stress and mitigated NiCl2-induced the kidney damage. Then, whether oxidative stress-induced autophagy and apoptosis were involved in NiCl2-induced nephrotoxicity was explored. The findings demonstrated that NAC relieved NiCl2-induced autophagy and reversed the activation of Akt/AMPK/mTOR pathway. Concurrently, the results indicated that NAC attenuated NiCl2-induced apoptosis, as evidenced by reduction of apoptotic cells and cleaved-caspase-3/- 8/- 9 together with cleaved-PARP protein levels. To sum up, our findings suggested that NiCl2-mediated renal injury was associated with oxidative stress-induced apoptosis and autophagy. This study provides new theoretical basis for excess Ni exposure nephrotoxic researches.}, }
@article {pmid34736541, year = {2021}, author = {Hadi, F and Kashefinejad, S and Kamalzadeh, L and Hoobehfekr, S and Shalbafan, M}, title = {Glutamatergic medications as adjunctive therapy for moderate to severe obsessive-compulsive disorder in adults: a systematic review and meta-analysis.}, journal = {BMC pharmacology &amp; toxicology}, volume = {22}, number = {1}, pages = {69}, pmid = {34736541}, issn = {2050-6511}, mesh = {Adult ; Drug Therapy, Combination ; Excitatory Amino Acid Agents/*therapeutic use ; Humans ; Obsessive-Compulsive Disorder/*drug therapy ; Selective Serotonin Reuptake Inhibitors/*therapeutic use ; }, abstract = {BACKGROUND: Obsessive-compulsive disorder (OCD) is among the most disabling neuropsychiatric conditions characterized by the presence of repetitive intrusive thoughts, impulses, or images (obsessions) and/or ritualized mental or physical acts (compulsions). Serotonergic medications, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), are the first-line treatments for patients with OCD. Recently, dysregulation of glutamatergic system has been proposed to be involved in the etiology of OCD. We designed this systematic review and meta-analysis to evaluate clinical efficacy of glutamatergic medications in patients with OCD, according to the guidelines of Cochrane collaboration.<br><br>METHOD: We searched Medline, Scopus, and Cochrane library without applying any language filter. Two of the authors independently reviewed search results for irrelevant and duplicate studies and extracted data and assessed methodological quality of the studies. We transformed data into a common rubric and calculated a weighted treatment effect across studies using Review Manager.<br><br>RESULTS: We found 476 references in 3 databases, and after exclusion of irrelevant and duplicate studies, 17 studies with total number of 759 patients with OCD were included. In the present review we found evidence for several drugs such as memantine, N-acetylcysteine (NAC), Minocycline, L-carnosine and riluzole. Glutamaterigic drug plus SSRIs were superior to SSRI+ Placebo with regard to Y-BOCS scale [standardized mean difference (SMD&#x2009;=&#x2009;-&#x2009;3.81 95% CI&#x2009;=&#x2009;-&#x2009;4.4, -&#x2009;3.23).<br><br>CONCLUSION: Augmentation of glutamatergic medications with SSRIs are beneficial in obsessive-compulsive patients, no harmful significant differences in any safety outcome were found between the groups.}, }
@article {pmid34733484, year = {2021}, author = {Mohammed, N and Ahmed, SA and Hegazy, NI and Kashishy, K}, title = {Ameliorative effects of hesperidin and N-acetylcysteine against formaldehyde-induced-hemato- and genotoxicity.}, journal = {Toxicology research}, volume = {10}, number = {5}, pages = {992-1002}, pmid = {34733484}, issn = {2045-452X}, abstract = {This study investigated the hemato- and genotoxic effects of formaldehyde (FA) and the possible mitigating role of hesperidin (HP) and N-acetylcysteine (NAC), each alone and in combination. Sixty-four adult male albino rats were divided into eight equal groups; the study was conducted for 8 weeks; Group I (negative control: received no medication), Group II (positive control: received distilled water), Group III (received HP 50 mg/kg/day), Group IV (received NAC 50 mg/kg/day), Group V (received FA 10 mg/kg/day), Group VI (FA + HP), Group VII (FA + NAC), and Group VIII (FA + HP + NAC). Groups VI, VII, VIII received the same previously mentioned doses and for the same duration. All treatments were given by intraperitoneal administration. At the end of the study, complete blood count, oxidative stress, histopathological changes, immunohistochemical staining of inducible nitric oxide synthase, and proliferating cell nuclear antigen and genotoxicity by comet assay in the bone marrow of treated rats were assessed. FA administration caused significant hematotoxicity represented by elevated white blood cell numbers and serum malondialdehyde levels and reduced red blood cell numbers, platelets, and serum superoxide dismutase values. Histologically, it induced an increase in fat cell numbers in bone marrow tissue with a widening of marrow spaces and decreased cellularity of hematopoietic cells, megakaryocytes, and granulocytes. FA exposure significantly decreased immunoreactivity for proliferating cell nuclear antigen, whereas the immunoreactivity for inducible nitric oxide synthase was increased. Genotoxicity, as measured by comet assay, revealed a significant increase in comet% and tail length in FA-treated group when compared with other groups. The cotreatment with HP and NAC revealed their ability to protect against hematological changes, oxidative damage, histopathological, and immunohistochemical changes, and genotoxicity induced by FA.}, }
@article {pmid34732600, year = {2022}, author = {Tan, YK and Luo, H and Kang, GS and Teoh, KL and Kofidis, T}, title = {N-Acetylcysteine's Renoprotective Effect in Cardiac Surgery: A Systematic Review and Meta-Analysis.}, journal = {Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia}, volume = {28}, number = {2}, pages = {138-145}, pmid = {34732600}, issn = {2186-1005}, mesh = {Acetylcysteine/adverse effects ; *Acute Kidney Injury/diagnosis/epidemiology/etiology ; Adult ; *Cardiac Surgical Procedures/adverse effects ; Female ; Humans ; Male ; Odds Ratio ; Treatment Outcome ; }, abstract = {OBJECTIVE: To examine N-acetylcysteine's (NAC's) renoprotective effect in adult cardiac surgeryMethods: PubMed, Ovid Medline, and Embase were searched for randomized controlled trials published between January 1990 and May 2021 that investigated the effect of NAC in preventing acute kidney injury (AKI) in patients undergoing cardiac surgery. The inclusion criterion was studies that assessed the effect of NAC in comparison to placebo by measuring the incidence of AKI.<br><br>RESULTS: Overall meta-analytic estimates of all 10 included trials showed that NAC did not have a significant effect (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.64-1.10) on AKI. Further subgroup analysis did not show a significant benefit of NAC in preventing AKI.<br><br>CONCLUSION: This meta-analysis suggests that NAC does not have a significant effect in reducing the incidence of AKI. However, there is notable heterogeneity among the included studies that could possibly account for the non-significant effect observed. It is worth noting that only one trial administered NAC high dosages perioperatively, and it is the only included trial to show a significant benefit in reducing the incidence of AKI (OR: 0.30, 95% CI: 0.11-0.81). Further studies on this dosage and duration of administration should be conducted to best elucidate the effect of administering NAC.}, }
@article {pmid34729372, year = {2021}, author = {Saeed, H and Osama, H and Abdelrahman, MA and Madney, YM and Harb, HS and Abdelrahim, MEA and Ali, F}, title = {Vitamins and other immune-supportive elements as cofactors for passing the COVID-19 pandemic.}, journal = {Beni-Suef University journal of basic and applied sciences}, volume = {10}, number = {1}, pages = {71}, pmid = {34729372}, issn = {2314-8543}, abstract = {BACKGROUND: Coronavirus disease 2019 (COVID-19) is a viral disease that causes a respiratory disorder, started in December of 2019 in China. Several vitamins and trace elements could help in enhancing host immunity producing antioxidant or anti-inflammatory action. This work aimed to identify the role of different nutrition, vitamins, and trace elements on the immunity status of the infected subject and the possibility of the beneficial role of these elements in the management of COVID-19.<br><br>MAIN BODY: After collecting (PubMed, scholar, OVID, Embase, Cochrane Library) and investigating published articles, testing the effect of these elements on viral infection, it was found that most of these elements have a significant role during viral infection through a different mechanism, like antioxidant, anti-inflammatory, and immunomodulation. Nutritional interventions in COVID-19 infections are very important currently, and it was reported that&#xa0;vitamin C and D reduce the risk of acute respiratory infections. In addition, low vitamin A diets compromise the effectiveness of inactivated bovine coronavirus vaccines. Administration of N-acetyl cysteine showed a beneficial inhibitory effect in viral infections and enhanced glutathione production. The deficiency of selenium on COVID-19 subjects has a significant impact on the clinical outcome of the subjects. In addition, supplementation with vitamins proved to enhance immune response during viral infection. Vitamins and trace elements not only showed a beneficial effect but also Omega 3 fatty acids showed an immunomodulating effect during infections.<br><br>SHORT CONCLUSIONS: Assessment of levels for these trace elements at the baseline and providing supplementation containing different vitamins and elements could result in better control and clinical outcomes in the case of COVID-19.}, }
@article {pmid34727343, year = {2022}, author = {Yazdi, A and Khansari, N and Mehrpooya, M and Mohammadi, Y and Zareie, S}, title = {Oral N-acetylcysteine as an adjunct to standard medical therapy improved heart function in cases with stable class II and III systolic heart failure.}, journal = {Irish journal of medical science}, volume = {191}, number = {5}, pages = {2063-2075}, pmid = {34727343}, issn = {1863-4362}, mesh = {Acetylcysteine/therapeutic use ; *Heart Failure/therapy ; *Heart Failure, Systolic/drug therapy ; Humans ; Iran ; Stroke Volume ; Ventricular Function, Left ; Ventricular Function, Right ; }, abstract = {BACKGROUND: This research attempted to assess whether N-acetylcysteine (NAC) as adjunctive therapy can be useful in the treatment of patients with heart failure (HF).<br><br>METHODS: Fifty-five cases with diagnosed systolic HF and stable symptomatic New York Heart Association (NYHA) functional class II and III and on optimal medical treatment of HF for at least 3&#xa0;months were assigned for receiving oral NAC (600&#xa0;mg twice daily) or placebo for 12&#xa0;weeks. The outcomes were changes in the echocardiographic hemodynamic indices as well as the patients' functional capacity assessed by NYHA classification over a 12-week treatment.<br><br>RESULTS: Compared to placebo, NAC more significantly improved the systolic left ventricular (LV) function expressed as the ejection fraction and Tei index. These changes are accompanied by more improvement in other LV echocardiographic indices including LV end-diastolic volume index and LV global longitudinal strain in the patients receiving NAC in comparison with those receiving placebo. In parallel with the improvement of LV function, right ventricular (RV) function expressed as RV fractional area change and RV Tei-index also got more improvement in those receiving NAC than those receiving placebo. However, the change in RV global longitudinal strain did not show a significant difference between study groups. Additionally, at week 12, the distribution of the NYHA functional class also shifted toward a better outcome in the NAC group in comparison with the placebo group; however, it was not significant.<br><br>CONCLUSIONS: These preliminary data support experimental findings showing that NAC supplementation is able to improve heart function.<br><br>TRIAL REGISTRATION: The registration of the trial was done at the Iranian Registry of Clinical Trials (www.irct.ir). Identifier code: IRCT20120215009014N333. Registration date: 2020-01-11.}, }
@article {pmid34726248, year = {2021}, author = {Shi, W and Men, L and Pi, X and Jiang, T and Peng, D and Huo, S and Luo, P and Wang, M and Guo, J and Jiang, Y and Peng, L and Lin, L and Li, S and Lv, J}, title = {Shikonin suppresses colon cancer cell growth and exerts synergistic effects by regulating ADAM17 and the IL‑6/STAT3 signaling pathway.}, journal = {International journal of oncology}, volume = {59}, number = {6}, pages = {}, pmid = {34726248}, issn = {1791-2423}, mesh = {ADAM17 Protein/genetics/*metabolism ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Apoptosis ; Cell Proliferation ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Interleukin-6/genetics/*metabolism ; Naphthoquinones/*pharmacology ; STAT3 Transcription Factor/genetics/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Signal transducer and activator of transcription 3 (STAT3) activation is associated with drug resistance induced by anti‑epidermal growth factor receptor (anti‑EGFR) therapy in the treatment of colon cancer. Thus, the combined inhibition of EGFR and STAT3 may prove beneficial for this type of cancer. STAT3 has been proven to play a critical role in colon cancer initiation and progression, and is considered the primary downstream effector driven by interleukin‑6 (IL‑6). A disintegrin and metalloproteinase 17 (ADAM17), documented as an oncogene, catalyzes the cleavage of both EGF and IL‑6R, inducing EGFR signaling and enabling IL‑6 trans‑signaling to activate STAT3 in a wide range of cell types to promote inflammation and cancer development. As a natural product, shikonin (SKN) has been found to function as an antitumor agent; however, its role in the regulation of ADAM17 and IL‑6/STAT3 signaling in colon cancer cells remains unknown. In the present study, it was found that SKN inhibited colon cancer cell growth, suppressed both constitutive and IL‑6‑induced STAT3 phosphorylation, and downregulated the expression of ADAM17. ADAM17 expression was not altered in response to STAT3 knockdown, while IL‑6‑induced STAT3 activation did not induce ADAM17 transcripts. Furthermore, it was demonstrated that SKN did not affect the expression of key proteins involved in the maturation and degradation of ADAM17. SKN decreased ADAM17 expression possibly through reactive oxygen species (ROS)‑mediated translational inhibition, as evidenced by the increased ADAM17 mRNA and phosphorylation levels of eukaryotic initiation factor 2α (eIF2α). The expression of ADAM17 and p‑eIF2α was reversed by N‑acetylcysteine (NAC, a ROS scavenger). Taken together, these results indicate that the concurrent inhibition of ADAM17 and IL‑6/STAT3 signaling by SKN may synergistically contribute to the suppression of colon cancer cell growth.}, }
@article {pmid34725845, year = {2022}, author = {Brown, LE and Reyes, G and Albrecht, EA}, title = {Crotalus atrox venom-induced cellular toxicity: Early wound progression involves reactive oxygen species.}, journal = {Journal of applied toxicology : JAT}, volume = {42}, number = {5}, pages = {852-863}, pmid = {34725845}, issn = {1099-1263}, support = {//Kennesaw State University Office of Research/ ; }, mesh = {Animals ; *Crotalid Venoms/chemistry/toxicity ; *Crotalus/physiology ; HEK293 Cells ; Humans ; Reactive Oxygen Species ; }, abstract = {Understanding the mechanisms that produce cellular cytotoxicity is fundamental in the field of toxicology. Cytotoxic stimuli can include organic toxins such as hemorrhagic snake venom, which can lead to secondary complications such as the development of necrotic tissue and profuse scarring. These clinical manifestations mimic cytotoxic responses induce by other organic compounds such as organic acids. We used hemorrhagic snake venom and human embryonic kidney cells (HEK 293T) as a model system to better understand the cellular responses involved in venom induced cytotoxicity. Cells stimulated with Crotalus atrox (CA) (western diamondback) venom for 4 or 10 h demonstrated significant cytotoxicity. Results from 2',7'-Dichlorodihydrofluorescein diacetate (H2 DCF-DA) assays determine CA venom stimulation induces a robust production of reactive oxygen species (ROS) over a 3-h time course. In contrast, pretreatment with polyethylene glycol (PEG)-catalase or N-acetyl cysteine (NAC) prior to CA venom stimulation significantly blunted H2 DCFDA fluorescence fold changes and showed greater cytoprotective effects than cells stimulated with CA venom alone. Pre- incubating HEK293T cells with the NADPH oxidase (NOX) pan-inhibitor VAS2870 prior venom stimulation significantly minimized the venom-induced oxidative burst at early timepoints (≤2 h). Collectively, our experiments show that pre-application of antioxidants reduces CA venom induce cellular toxicity. This result highlights the importance of ROS in the early stages of cytotoxicity and suggests muting ROS production in noxious injuries may increase positive clinical outcomes.}, }
@article {pmid34722507, year = {2021}, author = {Ma, S and Fu, X and Liu, L and Liu, Y and Feng, H and Jiang, H and Liu, X and Liu, R and Liang, Z and Li, M and Tian, Z and Hu, B and Bai, Y and Liang, B and Liu, X}, title = {Iron-Dependent Autophagic Cell Death Induced by Radiation in MDA-MB-231 Breast Cancer Cells.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {723801}, pmid = {34722507}, issn = {2296-634X}, abstract = {In radiation oncology, ionizing radiation is used to kill cancer cells, in other words, the induction of different types of cell death. To investigate this cellular death and the associated iron accumulation, the transfer, release, and participation of iron after radiation treatment was analyzed. We found that radiation-induced cell death varied in different breast cancer cells and autophagy was induced in MDA-MB-231 and BT549 cells (triple negative breast cancer cell line) rather than in MCF-7 and zr-75 cells. Iron chelator deferoxamine (DFO), the autophagy inhibitor 3MA, silencing of the autophagy-related genes ATG5, and Beclin 1 could decrease radiation induced cell death in MDA-MB-231 cells, while inhibitors of apoptosis such as Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1 (Fer-1), and necroptosis inhibitor Necrostatin-1 showed no change. This suggests the occurrence of autophagic cell death. Furthermore, we found that iron accumulation and iron regulatory proteins, including transferrin (Tf), transferrin receptor (CD71), and Ferritin (FTH), increased after radiation treatment, and the silencing of transferrin decreased radiation-induced cell death. In addition, radiation increased lysosomal membrane permeabilization (LMP) and the release of lysosomal iron and cathepsins, while cathepsins silencing failed to change cell viability. Radiation-induced iron accumulation increased Reactive oxygen species (ROS) generation via the Fenton reaction and increased autophagy in a time-dependent manner. DFO, N-acetylcysteine (NAC), and overexpression of superoxide dismutase 2 (SOD2) decreased ROS generation, autophagy, and cell death. To summarize, for the first time, we found that radiation-induced autophagic cell death was iron-dependent in breast cancer MDA-MB-231 cells. These results provide new insights into the cell death process of cancers and might conduce to the development and application of novel therapeutic strategies for patients with apoptosis-resistant breast cancer.}, }
@article {pmid34718251, year = {2021}, author = {Cao, Q and Wang, T and Xiao, M and Bai, L}, title = {Increased endogenous reactive oxygen species normalizes proliferation defects of Bmi1 heterozygous knockout neural stem cells.}, journal = {Neuroreport}, volume = {32}, number = {17}, pages = {1388-1394}, doi = {10.1097/WNR.0000000000001740}, pmid = {34718251}, issn = {1473-558X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Cell Proliferation/drug effects/*genetics ; Free Radical Scavengers/pharmacology ; Heterozygote ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Knockout ; Neural Stem Cells/drug effects/*metabolism ; Oxidants/pharmacology ; Polycomb Repressive Complex 1/*genetics ; Proto-Oncogene Proteins/*genetics ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/drug effects/metabolism ; }, abstract = {OBJECTIVES: The Bmi1gene, one of transcriptional suppressor genes in multi-comb family, maintains proliferation of neural stem cells (NSCs) and redox homeostasis. However, heterozygous deletion of the Bmi1 gene (Bmi1+/-) does not reduce the proliferative ability of NSCs. The aim of the present study was to reveal the underlying mechanism of this phenotype.<br><br>METHODS: NSCs derived from the cortex of newborn Bmi1+/- and wild-type (WT) mice were treated with different concentrations of hydrogen peroxide (H2O2) and antioxidant N-acetyl-L-cysteine (NAC) for 24&#x2009;h followed by analyses of NSC proliferation and oxidative stress-related indexes.<br><br>RESULTS: The levels of reactive oxygen species (ROS) of Bmi1+/--NSCs were slightly higher than that of WT-NSCs at baseline. H2O2 increased ROS and NAC reduced ROS in a concentration-dependent pattern, but the change was significantly greater in Bmi1+/--NSCs than WT-NSCs. The proliferation and self-renewal ability of Bmi1+/--NSCs and WT-NSCs were comparable in a basic state. After 1&#x2009;&#x3bc;M H2O2 treatment, Brdu incorporation ratio, cell viability, total antioxidant capacity (T-AOC) and total superoxide dismutase activity were increased slightly in WT-NSCs, but decreased in Bmi1+/--NSCs. H2O2 at 10&#x2009;&#x3bc;M decreased proliferation and self-renewal ability of both genotype NSCs, with greater effect in Bmi1+/-. After treatment with 1&#x2009;mM NAC, the number and diameter of neurospheres, Brdu incorporation rate, cell viability, T-AOC and total superoxide dismutase activity of Bmi1+/--NSCs were lower than those of WT-NSCs.<br><br>CONCLUSION: These results suggest that Bmi1+/--NSCs exhibit normal proliferation and self-renewal due to a slight increase in ROS, but are more vulnerable to changes in redox status.}, }
@article {pmid34712416, year = {2021}, author = {Tousian, H and Razavi, BM and Hosseinzadeh, H}, title = {In search of elixir: Pharmacological agents against stem cell senescence.}, journal = {Iranian journal of basic medical sciences}, volume = {24}, number = {7}, pages = {868-880}, pmid = {34712416}, issn = {2008-3866}, abstract = {Stem cell senescence causes different complications. In addition to the aging phenomenon, stem cell senescence has been investigated in various concepts such as cancer, adverse drug effects, and as a limiting factor in cell therapy. This manuscript examines protective medicines and supplements which are capable of hindering stem cell senescence. We searched the databases such as EMBASE, PubMed, and Web of Science with the keywords "stem cell," "progenitor cell," "satellite," "senescence" and excluded the keywords "cancer," "tumor," "malignancy" and "carcinoma" until June 2020. Among these results, we chose 47 relevant studies. Our investigation indicates that most of these studies examined endothelial progenitor cells, hematopoietic stem cells, mesenchymal stem cells, adipose-derived stem cells, and a few others were about less-discussed types of stem cells such as cardiac stem cells, myeloblasts, and induced pluripotent stem cells. From another aspect, 17β-Estradiol, melatonin, metformin, rapamycin, coenzyme Q10, N-acetyl cysteine, and vitamin C were the most studied agents, while the main protective mechanism was through telomerase activity enhancement or oxidative damage ablation. Although many of these studies are in vitro, they are still worthwhile. Stem cell senescence in the in vitro expansion stage is an essential concern in clinical procedures of cell therapy. Moreover, in vitro studies are the first step for further in vivo and clinical studies. It is noteworthy to mention the fact that these protective agents have been used in the clinical setting for various purposes for a long time. Given that, we only need to examine their systemic anti-senescence effects and effective dosages.}, }
@article {pmid34711021, year = {2021}, author = {Aala, J and Harchegani, AB and Monsef, HA and Mohsenifar, Z and Ebrahimi, P and Parvizi, MR}, title = {N-Acetyl cysteine mitigates histopathological changes and inflammatory genes expressions in the liver of cadmium exposed rats.}, journal = {Environmental analysis, health and toxicology}, volume = {36}, number = {4}, pages = {e2021024-0}, pmid = {34711021}, issn = {2671-9525}, abstract = {This study aimed to consider the expression of Nrf2, NLRP3 and caspase 1 genes, as well as oxidative stress, and the protective role of N-acetyl cysteine (NAC) in the liver of rats treated with cadmium (Cd). Male rats were randomly divided into five groups including G1 (control), G2 (single dose of Cd), G3 (continuous dose of Cd), G4 (single dose of Cd + NAC), and G5 (continuous dose of Cd + NAC). Levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured. Expression of Nrf2, NLRP3 and caspase 1 genes was considered using RT-PCR. NAC treatments significantly improved TAC, but decreased MDA values in rats that exposed to continuous dose of Cd (p<0.05). Exposure to continuous dose of Cd caused a significant decrease in Nrf2 expression by 2.46-fold (p<0.001), but enhanced expression of NLRP3 and Caspase 1 genes by 3.13-fold and 3.16-fold), respectively (p<0.001). Compared to rats that treated to continuous dose of Cd, NAC supplementation enhanced the expression of Nrf2 by 1.67-fold (p<0.001) and reduced the expression of NLRP3 and Caspase 1 genes by 1.39-fold (p<0.001) and 1.58-fold (p<0.001), respectively. Down-regulation of Nrf2 and overexpression of NLRP3 and caspase 1 seems to be one of the main mechanisms of Cd toxicity on liver tissue. NAC protects liver tissue against Cd-induced oxidative injuries via enhancement of Nrf2 expression and reduction of NLRP3 and caspase 1 genes.}, }
@article {pmid34709101, year = {2022}, author = {Link, SL and Rampon, G and Osmon, S and Scalzo, AJ and Rumack, BH}, title = {Fomepizole as an adjunct in acetylcysteine treated acetaminophen overdose patients: a case series.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {4}, pages = {472-477}, doi = {10.1080/15563650.2021.1996591}, pmid = {34709101}, issn = {1556-9519}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; Antidotes ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; *Drug Overdose/drug therapy ; Fomepizole ; Humans ; }, abstract = {INTRODUCTION: Acetaminophen (N-acetyl-para-aminophenol or APAP) is the leading cause of acute liver failure worldwide. Standard therapy for APAP overdose is with IV N-acetylcysteine (NAC). However, overdose patients treated with NAC can still incur hepatotoxicity in some circumstances. Fomepizole has proven safety in methanol and ethylene glycol poisoning and is a potent CYP2E1 and c-Jun-N-terminal Kinase (JNK) inhibitor that is effective even in the metabolic phase.<br><br>METHODS: We present a prospective case series of 14 consecutive, high-risk patients who had elevated APAP levels after overdose who were treated with fomepizole as an adjunct to standard IV-NAC. The attending toxicologist utilized clinical judgement to determine the use of fomepizole, especially if APAP levels persisted due to altered half-life or risk factors for toxicity.<br><br>RESULTS: There were no unfavorable outcomes in any patient, which were better than expected.<br><br>CONCLUSIONS: This case series has demonstrated the safety of fomepizole in high-risk APAP overdose. The efficacy of fomepizole needs to be further elucidated through controlled clinical trials on a larger scale. In massive APAP overdoses, fomepizole should be considered as an adjunct due to the known failure rate of NAC and the safety profile of fomepizole.}, }
@article {pmid34703944, year = {2021}, author = {Oszajca, K and Szemraj, J}, title = {Assessment of the correlation between oxidative stress and expression of MMP-2, TIMP-1 and COX-2 in human aortic smooth muscle cells.}, journal = {Archives of medical sciences. Atherosclerotic diseases}, volume = {6}, number = {}, pages = {e158-e165}, pmid = {34703944}, issn = {2451-0629}, abstract = {INTRODUCTION: Smooth muscle cells (SMCs) are considered to be the main producer of matrix metalloproteinase-2 (MMP-2) participating primarily in extracellular matrix (ECM) remodeling. Any disturbances in ECM structure may underlie the pathogenesis of many cardiovascular diseases and contribute to angiogenesis, cancer development, invasion or metastasis. The purpose of the study was to examine the effect of oxidative stress on the expression of MMP-2, its tissue inhibitor type 1 (TIMP-1) and cyclooxygenase-2 (COX-2) in human aortic smooth muscle cells (HASMCs).<br><br>MATERIAL AND METHODS: HASMCs were treated with exogenously applied H2O2 or TNF-&#x3b1;. N-acetylcysteine (NAC) was used as an antioxidant. Gene expression levels were measured by real-time PCR and the protein levels were determined using ELISA assay.<br><br>RESULTS: The studies revealed no association between oxidative stress and either mRNA quantity or protein secretion of MMP-2 and TIMP-1. However, we found markedly reduced (p < 0.001) MMP-2 secretion in cells incubated with NAC. HASMCs stimulated with TNF-&#x3b1; demonstrated a significantly increased COX-2 mRNA level as well as enzyme activity. H2O2-induced cells showed lowered COX-2 activity in comparison to untreated cells. MMP-2 and TIMP-1 expression did not change after COX-2 inhibition with DuP-697.<br><br>CONCLUSIONS: We did not find any effect of oxidative stress on expression of MMP-2 and TIMP-1 in HASMCs. However, COX-2 mRNA and protein level were elevated in these conditions. There was no correlation between COX-2 activity and MMP-2 and TIMP-1 mRNA expression or protein secretion.}, }
@article {pmid34703822, year = {2021}, author = {Chung, SA and Lim, JW and Kim, H}, title = {Docosahexaenoic Acid Inhibits Cytokine Expression by Reducing Reactive Oxygen Species in Pancreatic Stellate Cells.}, journal = {Journal of cancer prevention}, volume = {26}, number = {3}, pages = {195-206}, pmid = {34703822}, issn = {2288-3649}, abstract = {Pancreatic stellate cells (PSCs) are activated by inflammatory stimuli, such as TNF-α or viral infection. Activated PSCs play a crucial role in the development of chronic pancreatitis. Polyinosinic-polycytidylic acid (poly (I:C)) is structurally similar to double-stranded RNA and mimics viral infection. Docosahexaenoic acid (DHA) exhibits anti-inflammatory activity. It inhibited fibrotic mediators and reduced NF-κB activity in the pancreas of mice with chronic pancreatitis. The present study aimed to investigate whether DHA could suppress cytokine expression in PSCs isolated from rats. Cells were pre-treated with DHA or the antioxidant N-acetylcysteine (NAC) and stimulated with TNF-α or poly (I:C). Treatment with TNF-α or poly (I:C) increased the expression of monocyte chemoattractant protein 1 (MCP-1) and chemokine C-X3-C motif ligand 1 (CX3CL1), which are known chemoattractants, and enhanced intracellular and mitochondrial reactive oxygen species (ROS) production and NF-κB activity, but reduced mitochondrial membrane potential (MMP). Increased intracellular and mitochondrial ROS accumulation, cytokine expression, MMP disruption, and NF-κB activation were all prevented by DHA in TNF-α- or poly (I:C)-treated PSCs. NAC suppressed TNF-α- or poly (I:C)-induced expression of MCP-1 and CX3CL1. In conclusion, DHA inhibits poly (I:C)- or TNF-α-induced cytokine expression and NF-κB activation by reducing intracellular and mitochondrial ROS in PSCs. Consumption of DHA-rich foods may be beneficial in preventing chronic pancreatitis by inhibiting cytokine expression in PSCs.}, }
@article {pmid34698588, year = {2021}, author = {Bhardwaj, JK and Kumar, V and Panchal, H and Sachdeva, SN}, title = {Transmission electron microscopic analysis of glyphosate induced cytotoxicity and its attenuation by N-acetyl-L-cysteine in caprine testicular germ cells in vitro.}, journal = {Ultrastructural pathology}, volume = {45}, number = {6}, pages = {407-413}, doi = {10.1080/01913123.2021.1993400}, pmid = {34698588}, issn = {1521-0758}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Electrons ; Germ Cells ; Glycine/analogs &amp; derivatives ; *Goats ; Male ; Microscopy, Electron, Transmission ; Oxidative Stress ; Glyphosate ; }, abstract = {The agricultural pesticide poisoning is currently the most thrust area of human health concern. Pesticide-induced cytotoxicity and the corresponding reproductive toxicity in today's scenario is not a concealed reality that has to be considered for the continuation of respective race. Here, the transmission electron microscopy (TEM) technique was employed to investigate the adverse impact of glyphosate (GLY) and its mitigation by N-acetyl-L-cysteine (NAC) in goat testicular germ cells under in vitro conditions. The ultrastructural observations of testicular tissue from GLY-treated groups at different concentrations (0.1 and 4 mg/ml) and exposure durations (8 and 12 h) revealed that this organophosphate herbicide induced different apoptotic characteristics in testicular germ cells in a time- and dose-dependent manner. However, NAC (10 mM), being a potent antioxidant, was found to mitigate GLY-induced cytotoxicity in testicular cells as evidenced by fewer apoptotic characteristics in GLY plus NAC-treated groups, suggesting its beneficial potential in alleviating the GLY-induced gonadotoxicity in males.Abbreviations: GLY (Glyphosate), NAC (N-acetyl-L-cysteine), TEM (Transmission electron microscopic), GE (genetic engineered), Organophosphate (OPs).}, }
@article {pmid34697592, year = {2021}, author = {Abdelhafez, D and Aboelkomsan, E and El Sadik, A and Lasheen, N and Ashur, S and Elshimy, A and Morcos, GNB}, title = {The Role of Mesenchymal Stem Cells with Ascorbic Acid and N-Acetylcysteine on TNF-α, IL 1β, and NF-κβ Expressions in Acute Pancreatitis in Albino Rats.}, journal = {Journal of diabetes research}, volume = {2021}, number = {}, pages = {6229460}, pmid = {34697592}, issn = {2314-6753}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Blood Glucose/drug effects/metabolism ; Body Weight/drug effects ; Caspase 3/drug effects/metabolism ; Cell Proliferation/drug effects ; Ceruletide ; Fluorescent Dyes ; Insulin/metabolism ; Interleukin-1beta/*drug effects/metabolism ; Islets of Langerhans/*drug effects/metabolism/pathology ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells ; NF-kappa B/*drug effects/metabolism ; Organic Chemicals ; Pancreatitis/chemically induced/*metabolism/pathology ; Proliferating Cell Nuclear Antigen/drug effects/metabolism ; Rats ; Regeneration/drug effects ; Tumor Necrosis Factor-alpha/*drug effects/metabolism ; }, abstract = {Severe acute pancreatitis (SAP) is a necrotic pancreatic inflammation associated with high mortality rate (up to 70%). Bone marrow (BM) mesenchymal stem cells (MSCs) have been investigated in pancreatic cellular regeneration, but still their effects are controversial. Therefore, the present study is aimed at examining the enrichment of the stem cells with ascorbic acid (AA) and N-acetylcysteine (NAC) and explore their combined action on the expression of the inflammatory cytokines: interleukin 1β (IL 1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κβ (NF-κβ). A total of twenty adult male Sprague-Dawley albino rats were divided into four groups: the control group, cerulein group (to induce acute pancreatitis), BM-MSCs group, and combined BM-MSCs with AA and NAC group. Homing and proliferation of stem cells were revealed by the appearance of PKH26-labelled BM-MSCs in the islets of Langerhans. AA and NAC combination with BM-MSCs (group IV) was demonstrated to affect the expression of the inflammatory cytokines: IL 1β, TNF-α, and NF-κβ. In addition, improvement of the biochemical and histological parameters is represented in increasing body weight, normal blood glucose, and insulin levels and regeneration of the islet cells. Immunohistochemical studies showed an increase in proliferating cell nuclear antigen (PCNA) and decrease in caspase-3 reactions, detected markedly in group IV, after the marked distortion of the classic pancreatic lobular architecture was induced by cerulein. It could be concluded that treatment with BM-MSCs combined with antioxidants could provide a promising therapy for acute pancreatitis and improve the degeneration, apoptosis, necrosis, and inflammatory processes of the islets of Langerhans. TNF-α, IL 1β, and NF-κβ are essential biomarkers for the evaluation of MSC regenerative effectiveness.}, }
@article {pmid34690806, year = {2021}, author = {Zhu, X and Zhan, Y and Gu, Y and Huang, Q and Wang, T and Deng, Z and Xie, J}, title = {Cigarette Smoke Promotes Interleukin-8 Production in Alveolar Macrophages Through the Reactive Oxygen Species/Stromal Interaction Molecule 1/Ca[2+] Axis.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {733650}, pmid = {34690806}, issn = {1664-042X}, abstract = {Chronic obstructive pulmonary disease (COPD), primarily attributed to cigarette smoke (CS), is characterized by multiple pathophysiological changes, including oxidative stress and inflammation. Stromal interaction molecule 1 (STIM1) is a Ca[2+] sensor that regulates Ca[2+] entry in different types of cells. The present study aimed to explore the relationship between CS-induced oxidative stress and inflammation, as well as the functional role of STIM1 thereinto. Our results showed that the reactive oxygen species (ROS)/STIM1/Ca[2+] axis played a critical role in CS-induced secretion of interleukin (IL)-8 in human alveolar macrophages. Specifically, smokers with COPD (SC) showed higher levels of ROS in the lung tissues compared with healthy non-smokers (HN). STIM1 was upregulated in the lung tissues of COPD patients. The expression of STIM1 was positively associated with ROS levels and negatively correlated with pulmonary function. The expression of STIM1 was also increased in the bronchoalveolar lavage fluid (BALF) macrophages of COPD patients and PMA-differentiated THP-1 macrophages stimulated by cigarette smoke extract (CSE). Additionally, CSE-induced upregulation of STIM1 in PMA-differentiated THP-1 macrophages was inhibited by pretreatment with N-acetylcysteine (NAC), a ROS scavenger. Transfection with small interfering RNA (siRNA) targeting STIM1 and pretreatment with NAC alleviated CSE-induced increase in intracellular Ca[2+] levels and IL-8 expression. Furthermore, pretreatment with SKF-96365 and 2-APB, the inhibitors of Ca[2+] influx, suppressed CSE-induced secretion of IL-8. In conclusion, our study demonstrates that CSE-induced ROS production may increase the expression of STIM1 in macrophages, which further promotes the release of IL-8 by regulating Ca[2+] entry. These data suggest that STIM1 may play a crucial role in CSE-induced ROS production and inflammation, and participate in the pathogenesis of COPD.}, }
@article {pmid34687865, year = {2021}, author = {Wang, XH and Song, TZ and Zheng, HY and Li, YH and Zheng, YT}, title = {Jejunal epithelial barrier disruption triggered by reactive oxygen species in early SIV infected rhesus macaques.}, journal = {Free radical biology &amp; medicine}, volume = {177}, number = {}, pages = {143-155}, doi = {10.1016/j.freeradbiomed.2021.10.026}, pmid = {34687865}, issn = {1873-4596}, mesh = {Animals ; Humans ; Hydrogen Peroxide ; Intestinal Mucosa ; Macaca mulatta ; Reactive Oxygen Species ; *Simian Acquired Immunodeficiency Syndrome ; *Simian Immunodeficiency Virus ; }, abstract = {Intestinal epithelial barrier destruction occurs earlier than mucosal immune dysfunction in the acute stage of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections. At present, however, the cause of compromised gastrointestinal integrity in early SIV infection remains unknown. In the current study, we investigated the effects of SIV infection on epithelial barrier integrity and explored oxidative stress-mediated DNA damage and apoptosis in epithelial cells from early acute SIVmac239-infected Chinese rhesus macaques (Macaca mulatta). Results showed that the sensitive molecular marker of small intestinal barrier dysfunction, i.e., intestinal fatty acid-binding protein (IFABP), was significantly increased in plasma at 14 days post-SIV infection. SIV infection induced a profound decrease in the expression of tight junction proteins, including claudin-1, claudin-3, and zonula occludens (ZO)-1, as well as a significant increase in the active form of caspase-3 level in epithelial cells. RNA sequencing (RNA-seq) analysis suggested that differentially expressed genes between pre- and post-SIV-infected jejuna were enriched in pathways involved in cell redox homeostasis, oxidoreductase activity, and mitochondria. Indeed, a SIV-mediated increase in reactive oxygen species (ROS) in the epithelium and macrophages, as well as an increase in hydrogen peroxide (H2O2) and decrease in glutathione (GSH)/glutathione disulfide (GSSG) antioxidant defense, were observed in SIV-infected jejuna. In addition, the accumulation of mitochondrial dysfunction and DNA oxidative damage led to an increase in senescence-associated β-galactosidase (SA-β-gal) and early apoptosis in intestinal epithelial cells. Furthermore, HIV-1 Tat protein-induced epithelial monolayer disruption in HT-29 cells was rescued by antioxidant N-acetylcysteine (NAC). These results indicate that mitochondrial dysfunction and oxidative stress in jejunal epithelial cells are primary contributors to gut epithelial barrier disruption in early SIV-infected rhesus macaques.}, }
@article {pmid34687363, year = {2021}, author = {Berkel, C and Cacan, E}, title = {A collective analysis of lifespan-extending compounds in diverse model organisms, and of species whose lifespan can be extended the most by the application of compounds.}, journal = {Biogerontology}, volume = {22}, number = {6}, pages = {639-653}, pmid = {34687363}, issn = {1573-6768}, mesh = {Aging ; Animals ; Caenorhabditis elegans ; *Caenorhabditis elegans Proteins ; Drosophila melanogaster ; *Longevity ; Mice ; }, abstract = {Research on aging and lifespan-extending compounds has been carried out using diverse model organisms, including yeast, worms, flies and mice. Many studies reported the identification of novel lifespan-extending compounds in different species, some of which may have the potential to translate to the clinic. However, studies collectively and comparatively analyzing all the data available in these studies are highly limited. Here, by using data from the DrugAge database, we first identified top compounds in terms of their effects on percent change in average lifespan of diverse organisms, collectively (n = 1728). We found that, when data from all organisms studied were combined for each compound, aspirin resulted in the highest percent increase in average lifespan (52.01%), followed by minocycline (27.30%), N-acetyl cysteine (17.93%), nordihydroguaiaretic acid (17.65%) and rapamycin (15.66%), in average. We showed that minocycline led to the highest percent increase in average lifespan among other compounds, in both Drosophila melanogaster (28.09%) and Caenorhabditis elegans (26.67%), followed by curcumin (11.29%) and gluconic acid (5.51%) for D. melanogaster and by metformin (26.56%), resveratrol (15.82%) and quercetin (9.58%) for C. elegans. Moreover, we found that top 5 species whose lifespan can be extended the most by compounds with lifespan-extending properties are Philodina acuticornis, Acheta domesticus, Aeolosoma viride, Mytilina brevispina and Saccharomyces cerevisiae (211.80%, 76%, 70.26%, 55.18% and 45.71% in average, respectively). This study provides novel insights on lifespan extension in model organisms, and highlights the importance of databases with high quality content curated by researchers from multiple resources, in aging research.}, }
@article {pmid34684533, year = {2021}, author = {Quesada-Vázquez, S and Colom-Pellicer, M and Navarro-Masip, &#xc8; and Aragonès, G and Del Bas, JM and Caimari, A and Escoté, X}, title = {Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease, Hepatic Fibrosis, and Insulin Resistance in Mice.}, journal = {Nutrients}, volume = {13}, number = {10}, pages = {}, pmid = {34684533}, issn = {2072-6643}, support = {ACCI&#xd3;-Eurecat//ACCI&#xd3;/ ; CER-20191010//TECNOMIFOOD; Centre for the Development of Industrial Technology (CDTI)/ ; }, mesh = {Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Biomarkers/metabolism ; *Dietary Supplements ; Fatty Acids/metabolism ; Gene Expression Regulation ; *Insulin Resistance ; Lipid Metabolism ; Liver/injuries/pathology ; Liver Cirrhosis/blood/*metabolism ; Male ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/blood/*metabolism ; Oxidation-Reduction ; RNA, Messenger/genetics/metabolism ; Mice ; }, abstract = {Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD[+]) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.}, }
@article {pmid34684414, year = {2021}, author = {Hodun, K and Sztolsztener, K and Chabowski, A}, title = {Antioxidants Supplementation Reduces Ceramide Synthesis Improving the Cardiac Insulin Transduction Pathway in a Rodent Model of Obesity.}, journal = {Nutrients}, volume = {13}, number = {10}, pages = {}, pmid = {34684414}, issn = {2072-6643}, support = {SUB/1/DN/20/004/1118//Uniwersytet Medyczny w Bialymstoku/ ; }, mesh = {Animal Feed ; Animals ; Antioxidants/*pharmacology ; Biomarkers/blood/metabolism ; Body Weight ; Ceramides/*biosynthesis ; Diet, High-Fat ; *Dietary Supplements ; Glucose/metabolism ; Insulin/*metabolism ; Insulin Resistance ; Male ; Metabolic Networks and Pathways ; Models, Animal ; Myocardium/*metabolism ; Obesity/etiology/*metabolism ; Phosphorylation ; Rats ; Rodentia ; Signal Transduction/*drug effects ; Sphingolipids/metabolism ; }, abstract = {Obesity-related disruption in lipid metabolism contributes to cardiovascular dysfunction. Despite numerous studies on lipid metabolism in the left ventricle, there is no data describing the influence of n-acetylcysteine (NAC) and α-lipoic acid (ALA), as glutathione precursors, on sphingolipid metabolism, and insulin resistance (IR) occurrence. The aim of our experiment was to evaluate the influence of chronic antioxidants administration on myocardial sphingolipid state and intracellular insulin signaling as a potential therapeutic strategy for obesity-related cardiovascular IR. The experiment was conducted on male Wistar rats fed a standard rodent chow or a high-fat diet with intragastric administration of NAC or ALA for eight weeks. Cardiac and plasma sphingolipid species were assessed by high-performance liquid chromatography (HPLC). The proteins expressed from sphingolipid and insulin signaling pathways were determined by Western blot. Antioxidant supplementation markedly reduced ceramide accumulation by lowering the expression of selected proteins from the sphingolipid pathway and simultaneously increased the myocardial sphingosine-1-phosphate level. Moreover, NAC and ALA augmented the expression of GLUT4 and the phosphorylation state of Akt (Ser473) and GSK3β (Ser9), which improved the intracellular insulin transduction pathway. Based on our results, we may postulate that NAC and ALA have a beneficial influence on the cardiac ceramidose under IR conditions.}, }
@article {pmid34681725, year = {2021}, author = {Tsymbal, SA and Moiseeva, AA and Agadzhanian, NA and Efimova, SS and Markova, AA and Guk, DA and Krasnovskaya, OO and Alpatova, VM and Zaitsev, AV and Shibaeva, AV and Tatarskiy, VV and Dukhinova, MS and Ol'shevskaya, VA and Ostroumova, OS and Beloglazkina, EK and Shtil, AA}, title = {Copper-Containing Nanoparticles and Organic Complexes: Metal Reduction Triggers Rapid Cell Death via Oxidative Burst.}, journal = {International journal of molecular sciences}, volume = {22}, number = {20}, pages = {}, pmid = {34681725}, issn = {1422-0067}, support = {Project 19-29-08007//Russian Foundation for Basic Research/ ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Coordination Complexes/chemical synthesis/*pharmacology ; Copper/*chemistry ; Drug Resistance, Neoplasm/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Liposomes/chemistry/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/chemistry/*toxicity ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Superoxides/metabolism ; }, abstract = {Copper-containing agents are promising antitumor pharmaceuticals due to the ability of the metal ion to react with biomolecules. In the current study, we demonstrate that inorganic Cu[2+] in the form of oxide nanoparticles (NPs) or salts, as well as Cu ions in the context of organic complexes (oxidation states +1, +1.5 and +2), acquire significant cytotoxic potency (2-3 orders of magnitude determined by IC50 values) in combinations with N-acetylcysteine (NAC), cysteine, or ascorbate. In contrast, other divalent cations (Zn, Fe, Mo, and Co) evoked no cytotoxicity with these combinations. CuO NPs (0.1-1 µg/mL) together with 1 mM NAC triggered the formation of reactive oxygen species (ROS) within 2-6 h concomitantly with perturbation of the plasma membrane and caspase-independent cell death. Furthermore, NAC potently sensitized HCT116 colon carcinoma cells to Cu-organic complexes in which the metal ion coordinated with 5-(2-pyridylmethylene)-2-methylthio-imidazol-4-one or was present in the coordination sphere of the porphyrin macrocycle. The sensitization effect was detectable in a panel of mammalian tumor cell lines including the sublines with the determinants of chemotherapeutic drug resistance. The components of the combination were non-toxic if added separately. Electrochemical studies revealed that Cu cations underwent a stepwise reduction in the presence of NAC or ascorbate. This mechanism explains differential efficacy of individual Cu-organic compounds in cell sensitization depending on the availability of Cu ions for reduction. In the presence of oxygen, Cu[+1] complexes can generate a superoxide anion in a Fenton-like reaction Cu[+1]L + O2 → O2[-.] + Cu[+2]L, where L is the organic ligand. Studies on artificial lipid membranes showed that NAC interacted with negatively charged phospholipids, an effect that can facilitate the penetration of CuO NPs across the membranes. Thus, electrochemical modification of Cu ions and subsequent ROS generation, as well as direct interaction with membranes, represent the mechanisms of irreversible membrane damage and cell death in response to metal reduction in inorganic and organic Cu-containing compounds.}, }
@article {pmid34681647, year = {2021}, author = {Wang, S and Xu, X and Che, D and Fan, R and Gao, M and Cao, Y and Ge, C and Feng, Y and Li, J and Xie, S and Wang, C and Dai, F and Gao, L and Wang, Y}, title = {Reactive Oxygen Species Mediate 6c-Induced Mitochondrial and Lysosomal Dysfunction, Autophagic Cell Death, and DNA Damage in Hepatocellular Carcinoma.}, journal = {International journal of molecular sciences}, volume = {22}, number = {20}, pages = {}, pmid = {34681647}, issn = {1422-0067}, support = {U1904151, 81703004, 32000271 and 81772832//National Natural Science Foundation of China/ ; 2019M652527, 2020M672214//China Postdoctoral Science Foundation Funded Project/ ; 1901009//Start-up Fund of Postdoctoral Research Program of Henan Province/ ; 2019SJGLX081Y//Postgraduate Education Reform Project of Henan Province/ ; }, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Antioxidants/chemistry/pharmacology ; Autophagic Cell Death/*drug effects ; Autophagosomes/metabolism ; Carcinoma, Hepatocellular/metabolism/pathology ; DNA Damage/*drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/metabolism/pathology ; Lysosomes/*metabolism ; Microtubule-Associated Proteins/metabolism ; Mitochondria/*metabolism ; Naphthalimides/chemistry/*pharmacology ; Proteome/analysis ; Proteomics/methods ; Reactive Oxygen Species/*metabolism ; Sequestosome-1 Protein/metabolism ; }, abstract = {Increasing the level of reactive oxygen species (ROS) in cancer cells has been suggested as a viable approach to cancer therapy. Our previous study has demonstrated that mitochondria-targeted flavone-naphthalimide-polyamine conjugate 6c elevates the level of ROS in cancer cells. However, the detailed role of ROS in 6c-treated cancer cells is not clearly stated. The biological effects and in-depth mechanisms of 6c in cancer cells need to be further investigated. In this study, we confirmed that mitochondria are the main source of 6c-induced ROS, as demonstrated by an increase in 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSox fluorescence. Compound 6c-induced mitochondrial ROS caused mitochondrial dysfunction and lysosomal destabilization confirmed by absolute quantitation (iTRAQ)-based comparative proteomics. Compound 6c-induced metabolic pathway dysfunction and lysosomal destabilization was attenuated by N-acetyl-L-cysteine (NAC). iTRAQ-based comparative proteomics showed that ROS regulated the expression of 6c-mediated proteins, and treatment with 6c promoted the formation of autophagosomes depending on ROS. Compound 6c-induced DNA damage was characterized by comet assay, p53 phosphorylation, and γH2A.X, which was diminished by pretreatment with NAC. Compound 6c-induced cell death was partially reversed by 3-methyladenine (3-MA), bafilomycin (BAF) A1, and NAC, respectively. Taken together, the data obtained in our study highlighted the involvement of mitochondrial ROS in 6c-induced autophagic cell death, mitochondrial and lysosomal dysfunction, and DNA damage.}, }
@article {pmid34681610, year = {2021}, author = {Khoi, CS and Lin, YW and Chen, JH and Liu, BH and Lin, TY and Hung, KY and Chiang, CK}, title = {Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells.}, journal = {International journal of molecular sciences}, volume = {22}, number = {20}, pages = {}, pmid = {34681610}, issn = {1422-0067}, support = {108-FTN16//Far-Eastern Memorial Hospital/ ; 108-FTN16//National Taiwan University Hospital/ ; NTUH- 108-S4373//National Taiwan University Hospital/ ; NTUH-UN-109-S4785//National Taiwan University Hospital/ ; NTUH-110-S5074//National Taiwan University Hospital/ ; MOST- 110-2314-B-002 -130//Ministry of Science and Technology, Taiwan/ ; MOST-107-2314-B-002-027-MY3//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line ; Cell Survival/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Endoribonucleases/metabolism ; Epithelial Cells/cytology/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Kidney Tubules, Proximal/cytology/metabolism ; Ochratoxins/*pharmacology ; Oxidative Stress/drug effects ; Protein Serine-Threonine Kinases/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.}, }
@article {pmid34681218, year = {2021}, author = {Yang, KH and Lin, YS and Wang, SC and Lee, MY and Tang, JY and Chang, FR and Chuang, YT and Sheu, JH and Chang, HW}, title = {Soft Coral-Derived Dihydrosinularin Exhibits Antiproliferative Effects Associated with Apoptosis and DNA Damage in Oral Cancer Cells.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {34681218}, issn = {1424-8247}, support = {MOST 108-2320-B-037-015-MY3 and 110-2314-B-037-074-MY3//Ministry of Science and Technology Taiwan/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; KMUH109-9M56//Kaohsiung Medical University Hospital/ ; }, abstract = {Dihydrosinularin (DHS) is an analog of soft coral-derived sinularin; however, the anticancer effects and mechanisms of DHS have seldom been reported. This investigation examined the antiproliferation ability and mechanisms of DHS on oral cancer cells. In a cell viability assay, DHS showed growth inhibition against several types of oral cancer cell lines (Ca9-22, SCC-9, OECM-1, CAL 27, OC-2, and HSC-3) with no cytotoxic side effects on non-malignant oral cells (HGF-1). Ca9-22 and SCC-9 cell lines showing high susceptibility to DHS were selected to explore the antiproliferation mechanisms of DHS. DHS also causes apoptosis as detected by annexin V, pancaspase, and caspase 3 activation. DHS induces oxidative stress, leading to the generation of reactive oxygen species (ROS)/mitochondrial superoxide (MitoSOX) and mitochondrial membrane potential (MitoMP) depletion. DHS also induced DNA damage by probing γH2AX phosphorylation. Pretreatment with the ROS scavenger N-acetylcysteine (NAC) can partly counter these DHS-induced changes. We report that the marine natural product DHS can inhibit the cell growth of oral cancer cells. Exploring the mechanisms of this cancer cell growth inhibition, we demonstrate the prominent role DHS plays in oxidative stress.}, }
@article {pmid34680757, year = {2021}, author = {Aiyer, A and Visser, SK and Bye, P and Britton, WJ and Whiteley, GS and Glasbey, T and Kriel, FH and Farrell, J and Das, T and Manos, J}, title = {Effect of N-Acetylcysteine in Combination with Antibiotics on the Biofilms of Three Cystic Fibrosis Pathogens of Emerging Importance.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {10}, number = {10}, pages = {}, pmid = {34680757}, issn = {2079-6382}, support = {CT20584//University of Sydney and Whiteley Corporation/ ; grant number CT20584//COMMERCIAL DEVELOPMENT &amp; INDUSTRY PARTNERSHIP, grant number CT20584-University of Sydney and Whiteley Corporation/ ; }, abstract = {Cystic fibrosis (CF) is a genetic disorder causing dysfunctional ion transport resulting in accumulation of viscous mucus that fosters chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans and Stenotrophomonas maltophilia are increasingly prevalent CF pathogens and while Burkholderia cencocepacia is slowly decreasing; all are complicated by multidrug resistance that is enhanced by biofilm formation. This study investigates potential synergy between the antibiotics ciprofloxacin (0.5-128 µg/mL), colistin (0.5-128 µg/mL) and tobramycin (0.5-128 µg/mL) when combined with the neutral pH form of N-Acetylcysteine (NACneutral) (0.5-16.3 mg/mL) against 11 cystic fibrosis strains of Burkholderia, Stenotrophomonas and Achromobacter sp. in planktonic and biofilm cultures. We screened for potential synergism using checkerboard assays from which fraction inhibitory concentration indices (FICI) were calculated. Synergistic (FICI ≤ 0.5) and additive (0.5 > FICI ≥ 1) combinations were tested on irreversibly attached bacteria and 48 h mature biofilms via time-course and colony forming units (CFU/mL) assays. This study suggests that planktonic FICI analysis does not necessarily translate to reduction in bacterial loads in a biofilm model. Future directions include refining synergy testing and determining further mechanisms of action of NAC to understand how it may interact with antibiotics to better predict synergy.}, }
@article {pmid34680063, year = {2021}, author = {Moreno-Gómez-Toledano, R and Sánchez-Esteban, S and Cook, A and Mínguez-Moratinos, M and Ramírez-Carracedo, R and Reventún, P and Delgado-Marín, M and Bosch, RJ and Saura, M}, title = {Bisphenol A Induces Accelerated Cell Aging in Murine Endothelium.}, journal = {Biomolecules}, volume = {11}, number = {10}, pages = {}, pmid = {34680063}, issn = {2218-273X}, mesh = {Acetylcysteine/metabolism ; Activating Transcription Factor 4/*genetics ; Aging/drug effects/genetics ; Animals ; Aorta/drug effects ; Apoptosis/drug effects ; Benzhydryl Compounds/pharmacology ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p16/*genetics ; Endothelium/drug effects/pathology ; Mice ; Necroptosis/drug effects/genetics ; Oxidative Stress/drug effects ; Phenols/pharmacology ; Transcription Factor CHOP/genetics ; eIF-2 Kinase/*genetics ; }, abstract = {Bisphenol A (BPA) is a widespread endocrine disruptor affecting many organs and systems. Previous work in our laboratory demonstrated that BPA could induce death due to necroptosis in murine aortic endothelial cells (MAECs). This work aims to evaluate the possible involvement of BPA-induced senescence mechanisms in endothelial cells. The β-Gal assays showed interesting differences in cell senescence at relatively low doses (100 nM and 5 µM). Western blots confirmed that proteins involved in senescence mechanisms, p16 and p21, were overexpressed in the presence of BPA. In addition, the UPR (unfolding protein response) system, which is part of the senescent phenotype, was also explored by Western blot and qPCR, confirming the involvement of the PERK-ATF4-CHOP pathway (related to pathological processes). The endothelium of mice treated with BPA showed an evident increase in the expression of the proteins p16, p21, and CHOP, confirming the results observed in cells. Our results demonstrate that oxidative stress induced by BPA leads to UPR activation and senescence since pretreatment with N-acetylcysteine (NAC) in BPA-treated cells reduced the percentage of senescent cells prevented the overexpression of proteins related to BPA-induced senescence and reduced the activation of the UPR system. The results suggest that BPA participates actively in accelerated cell aging mechanisms, affecting the vascular endothelium and promoting cardiovascular diseases.}, }
@article {pmid34679638, year = {2021}, author = {Lee, HA and Chu, KB and Moon, EK and Quan, FS}, title = {Glutathione Peroxidase 8 Suppression by Histone Deacetylase Inhibitors Enhances Endoplasmic Reticulum Stress and Cell Death by Oxidative Stress in Hepatocellular Carcinoma Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {10}, pages = {}, pmid = {34679638}, issn = {2076-3921}, support = {2018R1A6A1A03025124 and 2020R1I1A1A01066748//National Research Foundation of Korea/ ; HV20C0085 and HV20C0142//the Ministry of Health &amp; Welfare, Republic of Korea/ ; }, abstract = {Histone deacetylase inhibitors (HDACi) are emerging as anti-hepatocellular carcinoma (HCC) agents. However, the molecular mechanisms underlying HDACi-induced sensitization to oxidative stress and cell death of HCC remain elusive. We hypothesized that HDACi reduces the anti-oxidative stress capacity of HCC, rendering it more susceptible to oxidative stress and cell death. Change in the transcriptome of HCC was analyzed by RNA-seq and validated using real-time quantitative polymerase chain reaction (qPCR) and Western blot. Cell death of HCC was analyzed by fluorescence-activated cell sorting (FACS). Protein localization and binding on the target gene promoters were investigated by immunofluorescence (IF) and chromatin immunoprecipitation (ChIP), respectively. Glutathione peroxidase 8 (GPX8) was highly down-regulated in HCC upon oxidative stress and HDACi co-treatment. Oxidative stress and HDACi enhanced the expression and transcriptional activities of ER-stress-related genes. N-acetyl-cysteine (NAC) supplementation reversed the oxidative stress and HDACi-induced apoptosis in HCC. HDACi significantly enhanced the effect of ER stressors on HCC cell death. GPX8 overexpression reversed the activation of ER stress signaling and apoptosis induced by oxidative stress and HDACi. In conclusion, HDACi suppresses the expression of GPX8, which sensitizes HCC to ER stress and apoptosis by oxidative stress.}, }
@article {pmid34672197, year = {2021}, author = {Weng, J and Wang, Y and Zhang, Y and Ye, D}, title = {An Activatable Near-Infrared Fluorescence Probe for in Vivo Imaging of Acute Kidney Injury by Targeting Phosphatidylserine and Caspase-3.}, journal = {Journal of the American Chemical Society}, volume = {143}, number = {43}, pages = {18294-18304}, doi = {10.1021/jacs.1c08898}, pmid = {34672197}, issn = {1520-5126}, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/chemically induced/*diagnostic imaging/drug therapy/metabolism ; Animals ; Apoptosis/physiology ; Biomarkers/metabolism ; Caspase 3/*metabolism ; Cell Line ; Cisplatin ; Coordination Complexes/chemical synthesis/chemistry/radiation effects ; Female ; Fluorescent Dyes/chemical synthesis/*chemistry/radiation effects ; Indoles/chemical synthesis/chemistry/radiation effects ; Infrared Rays ; Mice, Inbred BALB C ; Mice, Nude ; Optical Imaging ; Phosphatidylserines/*metabolism ; Zinc/chemistry ; Mice ; }, abstract = {Renal-clearable and target-responsive near-infrared (NIR) fluorescent imaging probes have been promising for in vivo diagnosis of acute kidney injury (AKI). However, designing an imaging probe that is renal-clearable and concurrently responsive toward multiple molecular targets to facilitate early detection of AKI with improved sensitivity and specificity is challenging. Herein, by leveraging the receptor-mediated binding and retention effect along with enzyme-triggered fluorescence activation, we design and synthesize an activatable small-molecule NIR fluorescent probe (1-DPA2) using a "one-pot sequential click reaction" approach. 1-DPA2 can target both the externalized phosphatidylserine (PS) and active caspase-3 (Casp-3), two essential biomarkers of apoptosis, producing enhanced 808 nm NIR fluorescence and a high signal-to-background ratio (SBR) amenable to detecting the onset of cisplatin-induced AKI in mice as early as 24 h post-treatment with cisplatin. We not only monitor the gradual activation of Casp-3 in the kidney of mice upon AKI progression but also can report on the progressive recovery of kidney functions in AKI mice following N-acetyl-l-cysteine (NAC) therapy via real-time fluorescence imaging by 1-DPA2. This study demonstrates the ability of 1-DPA2 for longitudinal monitoring of renal cell apoptosis by concurrently targeting PS externalization and Casp-3 activation, which is efficient for early diagnosis of AKI and useful for prediction of potential drug nephrotoxicity as well as in vivo screening of anti-AKI drugs' efficacy.}, }
@article {pmid34665895, year = {2022}, author = {El Shehaby, DM and Sayed, SA and Abd El-Kareem, DM and Elsherif, R and Almaz, D}, title = {Trimetazedine with hyperinsulinimea-euoglycemia, N-acetyl cysteine, and vitamin C: A new approach concept for management of aluminum phosphide poisoning.}, journal = {Journal of biochemical and molecular toxicology}, volume = {36}, number = {1}, pages = {e22931}, doi = {10.1002/jbt.22931}, pmid = {34665895}, issn = {1099-0461}, mesh = {Acetylcysteine/*pharmacology ; Aluminum Compounds/*poisoning ; Animals ; Ascorbic Acid/*pharmacology ; *Hyperinsulinism/chemically induced/drug therapy/metabolism ; Male ; Phosphines/*poisoning ; Rabbits ; Trimetazidine/*pharmacology ; }, abstract = {Aluminum phosphide (AlP) is commonly used as a powerful suicidal tool. The exact mechanism of acute toxicity has not been well defined despite high mortality rates as well as its supportive treatment including rapid decontamination and institution of resuscitative measures. The current study aimed to investigate a new combination therapy using trimetazidine, N-acetyl cysteine, vitamin C, and hyperinsulinemia-euglycemia to manage acute AlP poisoning. Acute AlP-induced cardiotoxicity, hemodynamic changes, and hepatotoxicity were evaluated using electrocardiogram, creatinine kinase MB iso-enzyme, troponin-1, blood pressure, random blood glucose level, liver function tests, and histopathological changes in both the heart and liver in a rabbit model of AlP poisoning. The results showed that the new regimen therapy ameliorates the toxic effect of AlP with significant improvement in survival, cardiovascular and hemodynamic parameters in addition to histopathological changes. These results highlight the strong cardioprotective, antioxidant, hepatoprotective effects of the new combined therapy along with correction of hemodynamic changes and hyperglycemia as a potential target in the management of acute AlP poisoning.}, }
@article {pmid34664816, year = {2021}, author = {Jamali, F and Ahmadzadeh, A and Sahraei, Z and Salamzadeh, J}, title = {Study of the Effects of N-acetylcysteine on Inflammatory Biomarkers and Disease Activity Score in Patients with Rheumatoid Arthritis.}, journal = {Iranian journal of allergy, asthma, and immunology}, volume = {20}, number = {5}, pages = {574-583}, doi = {10.18502/ijaai.v20i5.7407}, pmid = {34664816}, issn = {1735-5249}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Arthritis, Rheumatoid/diagnosis/*drug therapy/etiology/*metabolism ; *Biomarkers ; Blood Sedimentation ; C-Reactive Protein ; Cytokines/blood/metabolism ; Disease Management ; Disease Susceptibility ; Humans ; Inflammation Mediators/*metabolism ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {Rheumatoid arthritis (RA) is considered as an autoimmune-related condition in which the overproduction of pro-inflammatory cytokines leads to an inflammatory cascade. N-acetylcysteine (NAC) is a potent anti-inflammatory and anti-oxidant agent. We aimed to explore the impact of oral NAC on cytokines activities and clinical indicators in RA patients. In this placebo-controlled randomized double-blind clinical trial, 41 active RA patients were allocated in either NAC (600 mg, twice a day) or placebo group, as add-on therapy to the routine regimen, for 8 weeks. Disease activity score with an erythrocyte sedimentation rate (DAS28-ESR), and serum concentrations of interleukin (IL)-1β and IL-17 were assessed at baseline and end of the trial for all participants in the test and control groups. The reduction of the DAS28-ESR was higher considerably in the NAC group compared to that of the control group. No statistically significant differences were seen in the reduction of IL-1β and IL-17 cytokines between the NAC and control groups. In addition, improvements in the patient global assessment, number of tender joints, number of swollen joints, and the ESR rates were in favor of the NAC group. Our findings reveal that NAC may have a beneficial effect on all of the clinical features of RA. However, non-significant variations in the IL-1β and IL-17 levels suggest an alternative way of NAC effectiveness without influencing the measured cytokines. Nevertheless, these results need to be confirmed by further investigations.}, }
@article {pmid34660086, year = {2021}, author = {Sandhu, JK and Waqar, A and Jain, A and Joseph, C and Srivastava, K and Ochuba, O and Alkayyali, T and Ruo, SW and Poudel, S}, title = {Oxidative Stress in Polycystic Ovarian Syndrome and the Effect of Antioxidant N-Acetylcysteine on Ovulation and Pregnancy Rate.}, journal = {Cureus}, volume = {13}, number = {9}, pages = {e17887}, pmid = {34660086}, issn = {2168-8184}, abstract = {Polycystic ovarian syndrome (PCOS) is an endocrinological condition that leads to infertility in many females. N-acetylcysteine (NAC), a novel antioxidant, is being used as an adjuvant to treat infertility in females suffering from PCOS. This review aims to evaluate oxidative stress in females suffering from PCOS and assess whether the anti-oxidizing properties of NAC are beneficial in enhancing the rate of ovulation and pregnancy in infertile PCOS females. A literature search was conducted manually on PubMed and Google Scholar databases using the following keywords: "N-Acetylcysteine," "PCOS," "Oxidative stress," "Antioxidants," and "infertility" alone and/or in combination for data collection. The studies were manually screened and, after applying inclusion-exclusion criteria, 32 studies consisting of 2466 females of the reproductive age group are included in this review. Our review revealed that females suffering from PCOS tend to show elevated levels of inflammatory markers and a decrease in antioxidant capacity. When used in combination with clomiphene citrate or letrozole, NAC increases ovulation and pregnancy rate in infertile females suffering from PCOS and positively affects the quality of oocytes and number of follicles ≥18mm. Moreover, its side effect profile is low. It also results in a mild increase in endometrial thickness in some females. Future studies on a large sample size using NAC alone are highly recommended to evaluate its role as a single-drug therapy for treating infertility in females suffering from PCOS.}, }
@article {pmid34658034, year = {2022}, author = {Bourne, LE and Patel, JJ and Davies, BK and Neven, E and Verhulst, A and D'Haese, PC and Wheeler-Jones, CPD and Orriss, IR}, title = {N-acetylcysteine (NAC) differentially affects arterial medial calcification and bone formation: The role of l-cysteine and hydrogen sulphide.}, journal = {Journal of cellular physiology}, volume = {237}, number = {1}, pages = {1070-1086}, doi = {10.1002/jcp.30605}, pmid = {34658034}, issn = {1097-4652}, support = {PG/15/13/31296/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {*Acetylcysteine/pharmacology ; Arteries/metabolism ; Glutathione/metabolism ; *Hydrogen Sulfide/metabolism/pharmacology ; Osteoblasts/metabolism ; Osteogenesis ; }, abstract = {Arterial medial calcification (AMC) is the deposition of calcium phosphate in the arteries. AMC is widely thought to share similarities with physiological bone formation; however, emerging evidence suggests several key differences between these processes. N-acetylcysteine (NAC) displays antioxidant properties and can generate hydrogen sulphide (H2 S) and glutathione (GSH) from its deacetylation to l-cysteine. This study found that NAC exerts divergent effects in vitro, increasing osteoblast differentiation and bone formation by up to 5.5-fold but reducing vascular smooth muscle cell (VSMC) calcification and cell death by up to 80%. In vivo, NAC reduced AMC in a site-specific manner by 25% but had no effect on the bone. The actions of l-cysteine and H2 S mimicked those of NAC; however, the effects of H2 S were much less efficacious than NAC and l-cysteine. Pharmacological inhibition of H2 S-generating enzymes did not alter the actions of NAC or l-cysteine; endogenous production of H2 S was also unaffected. In contrast, NAC and l-cysteine increased GSH levels in calcifying VSMCs and osteoblasts by up to 3-fold. This suggests that the beneficial actions of NAC are likely to be mediated via the breakdown of l-cysteine and the subsequent GSH generation. Together, these data show that while the molecular mechanisms driving the actions of NAC appear similar, the downstream effects on cell function differ significantly between osteoblasts and calcifying VSMCs. The ability of NAC to exert these differential actions further supports the notion that there are differences between the development of pathological AMC and physiological bone formation. NAC could represent a therapeutic option for treating AMC without exerting negative effects on bone.}, }
@article {pmid34653248, year = {2022}, author = {Docampo, MD and da Silva, MB and Lazrak, A and Nichols, KB and Lieberman, SR and Slingerland, AE and Armijo, GK and Shono, Y and Nguyen, C and Monette, S and Dwomoh, E and Lee, N and Geary, CD and Perobelli, SM and Smith, M and Markey, KA and Vardhana, SA and Kousa, AI and Zamir, E and Greenfield, I and Sun, JC and Cross, JR and Peled, JU and Jenq, RR and Stein-Thoeringer, CK and van den Brink, MRM}, title = {Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.}, journal = {Blood}, volume = {139}, number = {15}, pages = {2392-2405}, pmid = {34653248}, issn = {1528-0020}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; P01 CA023766/CA/NCI NIH HHS/United States ; R01 CA228308/CA/NCI NIH HHS/United States ; R01 HL147584/HL/NHLBI NIH HHS/United States ; R01 HL124112/HL/NHLBI NIH HHS/United States ; U01 AI124275/AI/NIAID NIH HHS/United States ; R01 HL125571/HL/NHLBI NIH HHS/United States ; R01 CA228358/CA/NCI NIH HHS/United States ; K08 HL143189/HL/NHLBI NIH HHS/United States ; R01 HL123340/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 AG052359/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Butyrates ; Fatty Acids, Volatile/physiology ; *Graft vs Host Disease ; *Hematopoietic Stem Cell Transplantation ; Mice ; T-Lymphocytes ; }, abstract = {The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a-/- T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.}, }
@article {pmid34652584, year = {2022}, author = {Song, L and Yao, S and Zheng, D and Xuan, Y and Li, W}, title = {Astaxanthin attenuates contrast-induced acute kidney injury in rats via ROS/NLRP3 inflammasome.}, journal = {International urology and nephrology}, volume = {54}, number = {6}, pages = {1355-1364}, pmid = {34652584}, issn = {1573-2584}, support = {2014-YY007//Six Talent Peaks Project in Jiangsu Province/ ; }, mesh = {*Acute Kidney Injury/chemically induced/metabolism/prevention &amp; control ; Animals ; Caspase 1 ; Female ; Humans ; *Inflammasomes/metabolism ; Interleukin-18 ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Xanthophylls ; }, abstract = {OBJECTIVE: To explore the protective effect and mechanism of astaxanthin on the kidney of rats with contrast-induced acute kidney injury.<br><br>METHODS: Forty SD rats were randomly divided into five groups: Control group (CON); Astaxanthin control group (AST); Contrast media group (CM); Astaxanthin pre-treatment group (AST&#x2009;+&#x2009;CM); N-acetylcysteine pre-treatment group (NAC&#x2009;+&#x2009;CM), each group with eight rats. The rats were killed 72&#xa0;h after the modeling, the blood supernatant and kidneys were collected, and then the serum creatinine and blood urea nitrogen levels were measured; HE staining was used to observe the pathological changes in kidney tissue; TUNEL was used to detect apoptosis level in renal tubular epithelial cells; frozen section was used to observe the expression of ROS in renal tissue by reactive oxygen staining; the expression of NLRP3, ASC, caspase-1, IL-1&#x3b2;, IL-18 were detected by immunohistochemistry and western blot.<br><br>RESULTS: The CI-AKI rat model was induced by iohexol. Then the elevated level of ROS activated the inflammatory response mediated by NLRP3 inflammasome (NLRP3, ASC, caspase-1). Subsequently, the increase in renal tubular epithelial cell apoptosis caused the destruction of the pathological structure of the kidney and finally led to renal impairment. While after the pretreatment of astaxanthin, the level of ROS was decreased. The activation level of NLRP3 inflammasome and its mediated inflammatory response were alleviated significantly. Eventually, the level of renal tubular epithelial cell apoptosis and renal damage were significantly mitigated.<br><br>CONCLUSION: Astaxanthin can protect the kidney in CI-AKI by inhibiting the activation of NLRP3 inflammasome-IL-1&#x3b2;/IL-18 through inhibition of the production of ROS.}, }
@article {pmid34652265, year = {2022}, author = {Atilgan, FA and Atescelik, M and Yilmaz, M and Turk, A and Gurger, M and Goktekin, MC and Kuloglu, T}, title = {Effects of N-acetyl cysteine on TRPM2 expression in kidney and liver tissues following malathion intoxication.}, journal = {Biotechnic &amp; histochemistry : official publication of the Biological Stain Commission}, volume = {97}, number = {5}, pages = {340-346}, doi = {10.1080/10520295.2021.1986639}, pmid = {34652265}, issn = {1473-7760}, mesh = {Acetylcysteine/pharmacology ; Animals ; Atropine Derivatives/metabolism/pharmacology ; Kidney/metabolism ; Liver ; *Malathion/metabolism/toxicity ; Male ; Oxidative Stress ; Rats ; Rats, Wistar ; *TRPM Cation Channels/metabolism ; }, abstract = {We investigated the effects of N-acetyl cysteine (NAC) on transient receptor potential melastatin 2 (TRPM2) channel expression in rat kidney and liver tissues following experimental malathion intoxication. We used seven groups of six male Wistar albino rats: control group, NAC, pralidoxime + atropine, malathion, malathion + pralidoxime + atropine, malathion + pralidoxime + atropine + NAC, and malathion + NAC. Single doses of 100 mg/kg N-acetyl cysteine, 40 mg/kg pralidoxime, 2 mg/kg atropine and 1/3 the lethal dose of malathion were administered. No difference in malondialdehyde (MDA) levels, apoptosis or TRPM2 immunoreactivity was found in liver tissue among the groups. In kidney tissue, MDA levels, apoptosis and TRPM2 immunoreactivity were increased significantly in the malathion and malathion + NAC groups compared to the control group. We found that organophosphate intoxication did not affect MDA, apoptosis or TRPM2 immunoreactivity in rat liver during the acute period. By contrast, we found that in kidney tissue, MDA, apoptosis, and TRPM2 immunoreactivity were increased significantly following administration of malathion. Also, NAC given in addition to pralidoxime and atropine reduced MDA to control levels.}, }
@article {pmid34647812, year = {2022}, author = {Crisol, M and Yong, KW and Wu, K and Laouar, L and Elliott, JAW and Jomha, NM}, title = {Effectiveness of Clinical-Grade Chondroitin Sulfate and Ascorbic Acid in Mitigating Cryoprotectant Toxicity in Porcine Articular Cartilage.}, journal = {Biopreservation and biobanking}, volume = {20}, number = {4}, pages = {401-408}, doi = {10.1089/bio.2021.0083}, pmid = {34647812}, issn = {1947-5543}, mesh = {Animals ; Ascorbic Acid/metabolism/pharmacology ; *Cartilage, Articular/metabolism ; Cell Survival ; Chondrocytes/metabolism ; Chondroitin Sulfates/metabolism/pharmacology ; Cryopreservation/methods ; *Cryoprotective Agents/pharmacology ; Humans ; Swine ; }, abstract = {High concentrations of cryoprotective agents (CPAs) are required to achieve successful vitrification of articular cartilage; however, CPA cytotoxicity causes chondrocyte death. To reduce CPA toxicity, supplementation with research-grade additives, in particular chondroitin sulfate (CS) and ascorbic acid (AA), have previously been shown to improve chondrocyte recovery and metabolic function after exposure to CPAs at hypothermic conditions. However, it is necessary to evaluate the pharmaceutical equivalent clinical grade of these additives to facilitate the supplementation of additives into future vitrification protocols, which will be designed for vitrifying human articular cartilage in tissue banks. We sought to investigate the effectiveness of clinical-grade CS, AA, and N-acetylcysteine (NAC) in mitigating toxicity to chondrocytes during CPA exposure and removal, and determine whether a combination of two additives would further improve chondrocyte viability. We hypothesized that clinical-grade additives would exert chondroprotective effects comparable to those of research-grade additives, and that this protective effect would be enhanced if two additives were combined when compared with a single additive. The results indicated that both clinical-grade and research-grade additives significantly improved cell viability (p < 0.10) compared with the negative control (CPA with no additives). CS, AA, and NAC+AA increased cell viability significantly (p < 0.10) compared with the negative control. However, NAC, NAC+CS, and CS+AA did not improve cell viability when compared with the negative control (p > 0.10). We demonstrated that supplementation with clinical-grade CS or AA significantly improved chondrocyte viability in porcine cartilage subjected to high CPA concentrations, whereas supplementation with clinical-grade NAC did not benefit chondrocyte viability. Supplementation with clinical-grade additives in CPA solutions can mitigate CPA toxicity, which will be important in translating previously developed effective protocols for the vitrification of articular cartilage to human tissue banks.}, }
@article {pmid34645105, year = {2021}, author = {Vukovic, R and Selakovic, D and Stankovic, JSK and Kumburovic, I and Jovicic, N and Rosic, G}, title = {Alteration of Oxidative stress and apoptotic markers alterations in the rat prefrontal cortex influence behavioral response induced by cisplatin and N-acetylcysteine in the tail suspension test.}, journal = {Journal of integrative neuroscience}, volume = {20}, number = {3}, pages = {711-718}, doi = {10.31083/j.jin2003076}, pmid = {34645105}, issn = {0219-6352}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Antioxidants/administration &amp; dosage/*pharmacology ; Apoptosis/*drug effects ; Behavior, Animal/*drug effects ; Cisplatin/administration &amp; dosage/*pharmacology ; Male ; Oxidative Stress/*drug effects ; Prefrontal Cortex/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Cisplatin therapy is often accompanied by neurotoxicity manifestation, and since the prefrontal cortex is strongly involved in emotion regulation, the aim of this study was to analyze the alterations in the oxidative and apoptotic status of this brain region, with its behavioral impact in rats, following cisplatin administration, with or without N-acetylcysteine supplementation. Thirty-two male Wistar albino rats were randomly divided into four equal experimental groups: control, cisplatin group (single dose of 7.5 mg/kg, intraperitoneally (i.p.), on the fifth day), N-acetylcysteine group (500 mg/kg i.p., on the first and the fifth day), cisplatin + N-acetylcysteine group. Behavioral testing was performed in the tail suspension test. Oxidative stress and apoptotic markers were determined in the prefrontal cortex tissue samples. Cisplatin administration increased lipid peroxidation and decreased the activity of antioxidant enzymes in the prefrontal cortex. Also, cisplatin induced increase in Bax and decrease in Bcl-2 relative gene expression. Simultaneous application of N-acetylcysteine diminished cisplatin-induced alterations in oxidative stress and apoptotic markers. The results obtained in the tail suspension test that nominally resembles antidepressant action of cisplatin (attenuated by N-acetylcysteine), should be attributed to strong motor expression of anxiogenic response to cisplatin (also reversed by N-acetylcysteine). The antioxidant supplementation with NAC diminished cisplatin-induced oxidative damage and pro-apoptotic action in the prefrontal cortex, and significantly influenced specific behavioral alterations.}, }
@article {pmid34644184, year = {2021}, author = {Mohammadi-Sardoo, M and Mandegary, A and Nematollahi-Mahani, SN and Moballegh Nasery, M and Nabiuni, M and Amirheidari, B}, title = {Cytotoxicity of mancozeb on Sertoli-germ cell co-culture system: Role of MAPK signaling pathway.}, journal = {Toxicology and industrial health}, volume = {37}, number = {11}, pages = {674-684}, doi = {10.1177/07482337211044028}, pmid = {34644184}, issn = {1477-0393}, mesh = {Animals ; Apoptosis/*drug effects ; Germ Cells/drug effects ; Male ; Maneb/*toxicity ; Mice ; Mitogen-Activated Protein Kinases/*pharmacology ; Oxidative Stress/drug effects ; Sertoli Cells/*drug effects ; Zineb/*toxicity ; }, abstract = {Mancozeb (MZB) is a worldwide fungicide for the management of fungal diseases in agriculture and industrial contexts. Human exposure occurs by consuming contaminated plants, drinking water, and occupational exposure. There are reports on MZB's reprotoxicity such as testicular structure damage, sperm abnormalities, and decrease in sperm parameters (number, viability, and motility), but its molecular mechanism on apoptosis in testis remains limited. To investigate the molecular mechanisms involved in male reprotoxicity induced by MZB, we used primary cultures of mouse Sertoli-germ cells. Cells were exposed to MZB (1.5, 2.5, and 3.5 μM) for 3 h to evaluate viability by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, reactive oxygen species (ROS) generation, and oxidative stress parameters (lipid peroxidation). Cell death and mitogen-activated protein kinase (MAPK) signaling were measured in these cells using flow cytometry and western blotting. In addition, some groups were exposed to N-acetylcysteine (NAC, 5 mM) in the form of co-treatment with MZB. Mancozeb reduced viability and increased the level of intracellular ROS, p38 and c-Jun N-terminal kinases (JNK) MAPK proteins phosphorylation, and apoptotic cell death, which could be blocked by NAC as an inhibitor of oxidative stress. The present study indicated for the first time the toxic manifestations of MZB on the Sertoli-germ cell co-culture. Redox imbalance and p38 and JNK signaling pathway activation might play critical roles in MZB-induced apoptosis in the male reproductive system.}, }
@article {pmid34641738, year = {2022}, author = {Khaleel, EF}, title = {l-Thyroxine induces left ventricular remodeling and fibrosis in rats by upregulating miR-21 in a reactive oxygen-dependent mechanism: a protective role of N-acetylcysteine.}, journal = {Drug and chemical toxicology}, volume = {45}, number = {6}, pages = {2758-2768}, doi = {10.1080/01480545.2021.1986251}, pmid = {34641738}, issn = {1525-6014}, mesh = {Rats ; Male ; Animals ; *Ventricular Remodeling ; Transforming Growth Factor beta1/genetics/metabolism ; Acetylcysteine/pharmacology ; NF-kappa B ; Tumor Necrosis Factor-alpha/metabolism ; Interleukin-6 ; Reactive Oxygen Species ; Thyroxine ; Actins ; Rats, Sprague-Dawley ; Antagomirs ; Inflammasomes ; Fibrosis ; Glutathione ; *MicroRNAs/genetics ; Collagen ; RNA, Messenger ; Oxygen ; Mammals/metabolism ; }, abstract = {miR-21 is the most studied pro-fibrotic marker in the majority of mammalian tissues. The precise mechanism by which hyperthyroidism induces left ventricular LV fibrosis and remodeling remains unclear. In this study, we have investigated the role of miR-21 on l-thyroxine (l-Thy)-induced cardiac fibrosis in rats. Adult male Sprague-Dawley rats were divided into four groups as control, l-Thy, l-Thy + miR antagomir (inhibitor), and l-Thy + N-acetylcysteine (NAC/glutathione (GSH) precursor). Administration of l-Thy significantly increased mRNA levels of miR-21 in the LVs of the treated rats. Also, it impaired the LV systolic and diastolic function and increased the production of reactive oxygen species (ROS), the transactivation of NF-κB p65, the expression of NRLP3 inflammasome, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in these LVs. Concomitantly, l-Thy increased the ventricular collagen deposition, and stimulated the expression of collagen 1/3, alpha-smooth actin (α-SMA), transforming growth factor-β1, and Smad3/p-Smad3 but suppressed the expression of Smad7. All these effects were reversed by pre-treatment with miR-21 antagomir or co-administration of NAC. In conclusion, l-Thy-induced LV remodeling and fibrosis include a ROS-dependent upregulation of miR-21 which in turns activates NF-κB/NRLP3 inflammasome and suppresses SMad7.}, }
@article {pmid34638900, year = {2021}, author = {Kyyriäinen, J and Kajevu, N and Bañuelos, I and Lara, L and Lipponen, A and Balosso, S and Hämäläinen, E and Das Gupta, S and Puhakka, N and Natunen, T and Ravizza, T and Vezzani, A and Hiltunen, M and Pitkänen, A}, title = {Targeting Oxidative Stress with Antioxidant Duotherapy after Experimental Traumatic Brain Injury.}, journal = {International journal of molecular sciences}, volume = {22}, number = {19}, pages = {}, pmid = {34638900}, issn = {1422-0067}, support = {272249//Academy of Finland/ ; 273909//Academy of Finland/ ; 2285733-9//Academy of Finland/ ; 307866//Academy of Finland/ ; 0000//Sigrid Jus&#xe9;liuksen S&#xe4;&#xe4;ti&#xf6;/ ; 0000//Strategic Neuroscience Funding of the University of Eastern Finland/ ; 602102//FP7-HEALTH project 602102 (EPITARGET)/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Brain/drug effects/metabolism/pathology ; Brain Injuries, Traumatic/*drug therapy/genetics/metabolism ; Cell Line ; Cell Survival/drug effects ; Cells, Cultured ; Disease Models, Animal ; Gene Expression/drug effects ; Heme Oxygenase-1/genetics/metabolism ; Isothiocyanates/*pharmacology ; Male ; Mice, Inbred C57BL ; Microglia/cytology/*drug effects/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Neurons/cytology/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Rats, Sprague-Dawley ; Sulfoxides/*pharmacology ; Mice ; Rats ; }, abstract = {We assessed the effect of antioxidant therapy using the Food and Drug Administration-approved respiratory drug N-acetylcysteine (NAC) or sulforaphane (SFN) as monotherapies or duotherapy in vitro in neuron-BV2 microglial co-cultures and validated the results in a lateral fluid-percussion model of TBI in rats. As in vitro measures, we assessed neuronal viability by microtubule-associated-protein 2 immunostaining, neuroinflammation by monitoring tumor necrosis factor (TNF) levels, and neurotoxicity by measuring nitrite levels. In vitro, duotherapy with NAC and SFN reduced nitrite levels to 40% (p < 0.001) and neuroinflammation to -29% (p < 0.001) compared with untreated culture. The treatment also improved neuronal viability up to 72% of that in a positive control (p < 0.001). The effect of NAC was negligible, however, compared with SFN. In vivo, antioxidant duotherapy slightly improved performance in the beam walking test. Interestingly, duotherapy treatment decreased the plasma interleukin-6 and TNF levels in sham-operated controls (p < 0.05). After TBI, no treatment effect on HMGB1 or plasma cytokine levels was detected. Also, no treatment effects on the composite neuroscore or cortical lesion area were detected. The robust favorable effect of duotherapy on neuroprotection, neuroinflammation, and oxidative stress in neuron-BV2 microglial co-cultures translated to modest favorable in vivo effects in a severe TBI model.}, }
@article {pmid34638698, year = {2021}, author = {Vanin, AF}, title = {Physico-Chemistry of Dinitrosyl Iron Complexes as a Determinant of Their Biological Activity.}, journal = {International journal of molecular sciences}, volume = {22}, number = {19}, pages = {}, pmid = {34638698}, issn = {1422-0067}, mesh = {Acetylcysteine/chemistry/metabolism ; *Iron/chemistry/metabolism ; *Models, Biological ; *Models, Chemical ; *Nitrogen Oxides/chemistry/metabolism ; Oxidation-Reduction ; }, abstract = {In this article we minutely discuss the so-called "oxidative" mechanism of mononuclear form of dinitrosyl iron complexes (M-DNICs) formations proposed by the author. M-DNICs are proposed to be formed from their building material-neutral NO molecules, Fe[2+] ions and anionic non-thiol (L[-]) and thiol (RS[-]) ligands based on the disproportionation reaction of NO molecules binding with divalent ion irons in pairs. Then a protonated form of nitroxyl anion (NO[-]) appearing in the reaction is released from this group and a neutral NO molecule is included instead. As a result, M-DNICs are produced. Their resonance structure is described as [(L[-])2Fe[2+](NO)(NO[+])], in which nitrosyl ligands are represented by NO molecules and nitrosonium cations in equal proportions. Binding of hydroxyl ions with the latter causes conversion of these cations into nitrite anions at neutral pH values and therefore transformation of DNICs into the corresponding high-spin mononitrosyl iron complexes (MNICs) with the resonance structure described as [(L[-])2Fe[2+](NO)]. In case of replacing L[-] by thiol-containing ligands, which are characterized by high π-donor activity, electron density transferred from sulfur atoms to iron-dinitrosyl groups neutralizes the positive charge on nitrosonium cations, which prevents their hydrolysis, ensuring relatively a high stability of the corresponding M-DNICs with the resonance structure [(RS[-])2Fe[2+] (NO, NO[+])]. Therefore, M-DNICs with thiol-containing ligands, as well as their binuclear analogs (B-DNICs, respective resonance structure [(RS[-])2Fe[2+]2 (NO, NO[+])2]), can serve donors of both NO and NO[+]. Experiments with solutions of B-DNICs with glutathione or N-acetyl-L-cysteine (B-DNIC-GSH or B-DNIC-NAC) showed that these complexes release both NO and NO[+] in case of decomposition in the presence of acid or after oxidation of thiol-containing ligands in them. The level of released NO was measured via optical absorption intensity of NO in the gaseous phase, while the number of released nitrosonium cations was determined based on their inclusion in S-nitrosothiols or their conversion into nitrite anions. Biomedical research showed the ability of DNICs with thiol-containing ligands to be donors of NO and NO[+] and produce various biological effects on living organisms. At the same time, NO molecules released from DNICs usually have a positive and regulatory effect on organisms, while nitrosonium cations have a negative and cytotoxic effect.}, }
@article {pmid34637923, year = {2021}, author = {Seong, JB and Kim, B and Kim, S and Kim, MH and Park, YH and Lee, Y and Lee, HJ and Hong, CW and Lee, DS}, title = {Macrophage peroxiredoxin 5 deficiency promotes lung cancer progression via ROS-dependent M2-like polarization.}, journal = {Free radical biology &amp; medicine}, volume = {176}, number = {}, pages = {322-334}, doi = {10.1016/j.freeradbiomed.2021.10.010}, pmid = {34637923}, issn = {1873-4596}, mesh = {Animals ; Cell Line, Tumor ; Humans ; *Lung Neoplasms/genetics ; Macrophage Activation ; Macrophages ; Mice ; *Peroxiredoxins/genetics ; Reactive Oxygen Species ; Tumor Microenvironment ; }, abstract = {Strategies for cancer treatment have traditionally focused on suppressing cancer cell behavior, but many recent studies have demonstrated that regulating the tumor microenvironment (TME) can also inhibit disease progression. Macrophages are major TME components, and the direction of phenotype polarization is known to regulate tumor behavior, with M2-like polarization promoting progression. It is also known that reactive oxygen species (ROS) in macrophages drive M2 polarization, and M2 polarization promote lung cancer progression. Lung cancer patients with lower expression of the antioxidant enzyme peroxiredoxin 5 (Prx5) demonstrate poorer survival. This study revealed that Prx5 deficiency in macrophages induced M2 macrophage polarization by lung cancer. We report that injection of lung cancer cells produced larger tumors in Prx5-deficit mice than wild-type mice independent of cancer cell Prx5 expression. Through co-culture with lung cancer cell lines, Prx5-deficient macrophages exhibited M2 polarization, and reduced expression levels of the M1-associated inflammatory factors iNOS, TNFα, and Il-1β. Moreover, these Prx5-deficient macrophages promoted the proliferation and migration of co-cultured lung cancer cells. Conversely, suppression of ROS generation by N-acetyl cysteine (NAC) inhibited the M2-like polarization of Prx5-deficient macrophages, increased expression levels of inflammatory factors, inhibited the proliferation and migration of co-cultured lung cancer cells, and suppressed tumor growth in mice. These findings suggest that blocking the M2 polarization of macrophages may promote lung cancer regression.}, }
@article {pmid34627931, year = {2021}, author = {Raut, PK and Lee, HS and Joo, SH and Chun, KS}, title = {Thymoquinone induces oxidative stress-mediated apoptosis through downregulation of Jak2/STAT3 signaling pathway in human melanoma cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {157}, number = {}, pages = {112604}, doi = {10.1016/j.fct.2021.112604}, pmid = {34627931}, issn = {1873-6351}, mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology/therapeutic use ; Blotting, Western ; Cell Line, Tumor ; Down-Regulation/drug effects ; Humans ; Janus Kinase 2/*metabolism ; Melanoma/*drug therapy/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Melanoma is a highly aggressive and treatment-resistant cancer, and the incidence and mortality rates are increasing worldwide. Thymoquinone (TQ) is the active component of Nigella sativa seed extracts and exerts anticancer effects in various cancer cells. However, the anticancer effects of TQ on melanoma and the underlying molecular mechanisms remain elusive. In this study, TQ treatment induced apoptosis in SK-MEL-28 cells. Interestingly, constitutive phosphorylation of Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) was markedly decreased following TQ treatment. Furthermore, TQ treatment downregulated STAT3-dependent genes including cyclin D1, D2, and D3 and survivin. Moreover, inhibition of Jak2/STAT3 using AG490, an inhibitor of Jak2 or genetic ablation of STAT3, abrogated the expression of target genes. TQ increased the levels of reactive oxygen species (ROS), whereas pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, prevented the suppressive effect of TQ on Jak2/STAT3 activation and protected SK-MEL-28 cells from TQ-induced apoptosis. TQ administration further attenuated the growth of SK-MEL-28 tumor xenografts. Taken together, TQ induced apoptosis of SK-MEL-28 by hindering the Jak2/STAT3 signaling pathway through ROS generation. Our results support further development of TQ as a potential anticancer therapeutic agent for treating melanoma.}, }
@article {pmid34619980, year = {2021}, author = {Subrahmanian, S and Varshney, R and Subramani, K and Murphy, B and Woolington, S and Ahamed, J}, title = {N-Acetylcysteine Inhibits Aortic Stenosis Progression in a Murine Model by Blocking Shear-Induced Activation of Platelet Latent Transforming Growth Factor Beta 1.}, journal = {Antioxidants &amp; redox signaling}, volume = {}, number = {}, pages = {}, doi = {10.1089/ars.2021.0037}, pmid = {34619980}, issn = {1557-7716}, support = {P30 GM114731/GM/NIGMS NIH HHS/United States ; R01 HL123605/HL/NHLBI NIH HHS/United States ; R01 HL148123/HL/NHLBI NIH HHS/United States ; }, abstract = {Objective: Aortic stenosis (AS) is characterized by narrowing of the aortic valve opening, resulting in peak blood flow velocity that induces high wall shear stress (WSS) across the valve. Severe AS leads to heart failure and death. There is no treatment available for AS other than valve replacement. Platelet-derived transforming growth factor beta 1 (TGF-β1) partially contributes to AS progression in mice, and WSS is a potent activator of latent TGF-β1. N-acetylcysteine (NAC) inhibits WSS-induced TGF-β1 activation in vitro. We hypothesize that NAC will inhibit AS progression by inhibiting WSS-induced TGF-β1 activation. Approach: We treated a cohort of Ldlr(-/-)Apob(100/100) low density lipoprotein receptor (LDLR) mice fed a high-fat diet with NAC (2% in drinking water) at different stages of disease progression and measured its effect on AS progression and TGF-β1 activation. Results: Short-term NAC treatment inhibited AS progression in mice with moderate and severe AS relative to controls, but not in LDLR mice lacking platelet-derived TGF-β1 (TGF-β1[platlet-KO]-LDLR). NAC treatment reduced TGF-β signaling, p-Smad2 and collagen levels, and mesenchymal transition from isolectin B4 and CD45-positive cells in LDLR mice. Mechanistically, NAC treatment resulted in plasma NAC concentrations ranging from 75.5 to 449.2 ng/mL, which were sufficient to block free thiol labeling of plasma proteins and reduce active TGF-β1 levels without substantially affecting reactive oxygen species-modified products in valvular cells. Conclusions: Short-term treatment with NAC inhibits AS progression by inhibiting WSS-induced TGF-β1 activation in the LDLR mouse model of AS, motivating a clinical trial of NAC and/or other thiol-reactive agent(s) as a potential therapy for AS.}, }
@article {pmid34617640, year = {2022}, author = {Adl, A and Motamedifar, M and Malekzadeh, P and Sedigh-Shams, M}, title = {Disinfection of dentinal tubules with diclofenac sodium and N-Acetylcysteine compared with calcium hydroxide as intracanal medicaments against Enterococcus faecalis.}, journal = {Australian endodontic journal : the journal of the Australian Society of Endodontology Inc}, volume = {48}, number = {3}, pages = {386-391}, doi = {10.1111/aej.12575}, pmid = {34617640}, issn = {1747-4477}, support = {19832//Shiraz University of Medical Sciences/ ; }, mesh = {*Calcium Hydroxide/pharmacology ; *Enterococcus faecalis ; Root Canal Irrigants/pharmacology ; Diclofenac/pharmacology ; Acetylcysteine/pharmacology ; Dentin ; Anti-Bacterial Agents/pharmacology ; Dental Pulp Cavity/microbiology ; }, abstract = {The purpose of this study was to evaluate the disinfection of dentinal tubules with diclofenac sodium (DS), N-acetylcysteine (NAC) and calcium hydroxide (CH). Contaminated dentinal blocks were divided into two control and seven experimental groups (n = 15): CH, DS, NAC, CH + 5% DS, 50% CH + 50% DS, CH + 5% NAC and 50% CH + 50% NAC. After seven days, dentine debris was obtained from two depths of 100 and 200 µm. The bacterial load was assessed by counting the number of colony-forming units (CFUs). Pure DS exhibited maximum antibacterial activity at both depths. At 200 µm, it showed statistically significant differences with all the other groups (P < 0.05). Mixing CH with either 5% or 50% of DS and NAC did not increase the antibacterial efficacy (P > 0.05). Pure DS was most effective in disinfecting dentinal tubules, and mixing CH with DS or NAC is not recommended.}, }
@article {pmid34614473, year = {2021}, author = {Pang, Y and Wu, D and Ma, Y and Cao, Y and Liu, Q and Tang, M and Pu, Y and Zhang, T}, title = {Reactive oxygen species trigger NF-κB-mediated NLRP3 inflammasome activation involvement in low-dose CdTe QDs exposure-induced hepatotoxicity.}, journal = {Redox biology}, volume = {47}, number = {}, pages = {102157}, pmid = {34614473}, issn = {2213-2317}, mesh = {*Cadmium Compounds/toxicity ; *Chemical and Drug Induced Liver Injury/etiology ; Humans ; Inflammasomes ; NF-kappa B ; *NLR Family, Pyrin Domain-Containing 3 Protein ; *Quantum Dots/toxicity ; Reactive Oxygen Species ; Tellurium/toxicity ; }, abstract = {Cadmium telluride (CdTe) quantum dots (QDs) can be employed as imaging and drug delivery tools; however, the toxic effects and mechanisms of low-dose exposure are unclear. Therefore, this pioneering study focused on hepatic macrophages (Kupffer cells, KCs) and explored the potential damage process induced by exposure to low-dose CdTe QDs. In vivo results showed that both 2.5 μM/kg·bw and 10 μM/kg·bw could both activate KCs to cause liver injury, and produce inflammation by disturbing antioxidant levels. Abnormal liver function further verified the risks of low-dose exposure to CdTe QDs. The KC model demonstrated that low-dose CdTe QDs (0 nM, 5 nM and 50 nM) can be absorbed by cells and cause severe reactive oxygen species (ROS) production, oxidative stress, and inflammation. Additionally, the expression of NF-κB, caspase-1, and NLRP3 were decreased after pretreatment with ROS scavenging agent N-acetylcysteine (NAC, 5 mM pretreated for 2 h) and the NF-κB nuclear translocation inhibitor Dehydroxymethylepoxyquinomicin (DHMEQ, 10 μg/mL pretreatment for 4 h) respectively. The results indicate that the activation of the NF-κB pathway by ROS not only directly promotes the expression of inflammatory factors such as pro-IL-1β, TNF-α, and IL-6, but also mediates the assembly of NLRP3 by ROS activation of NF-κB pathway, which indirectly promotes the expression of NLRP3. Finally, a high-degree of overlap between the expression of the NF-κB and NLRP3 and the activated regions of KCs, further support the importance of KCs in inflammation induced by low-dose CdTe QDs.}, }
@article {pmid34608499, year = {2021}, author = {Kim, S and Lee, H and Lim, JW and Kim, H}, title = {Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells.}, journal = {Molecular medicine reports}, volume = {24}, number = {6}, pages = {}, pmid = {34608499}, issn = {1791-3004}, mesh = {Adenocarcinoma/metabolism ; Animals ; Antitubercular Agents/pharmacology ; Apoptosis ; Cell Death ; Cell Line, Tumor ; Epithelial Cells ; Humans ; Imidazoles ; Indoles ; L-Lactate Dehydrogenase/metabolism ; NADPH Oxidases/drug effects/*metabolism ; *Necroptosis ; Protein Kinases/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism ; Stomach Neoplasms/*metabolism ; Xanthophylls/pharmacology ; }, abstract = {Astaxanthin (ASX), a red‑colored xanthophyll carotenoid, functions as an antioxidant or pro‑oxidant. ASX displays anticancer effects by reducing or increasing oxidative stress. Reactive oxygen species (ROS) promote cancer cell death by necroptosis mediated by receptor‑interacting protein kinase 1 (RIP1) and RIP3. NADPH oxidase is a major source of ROS that may promote necroptosis in some cancer cells. The present study aimed to investigate whether ASX induces necroptosis by increasing NADPH oxidase activity and ROS levels in gastric cancer AGS cells. AGS cells were treated with ASX with or without ML171 (NADPH oxidase 1 specific inhibitor), N‑acetyl cysteine (NAC; antioxidant), z‑VAD (pan‑caspase inhibitor) or Necrostatin‑1 (Nec‑1; a specific inhibitor of RIP1). As a result, ASX increased NADPH oxidase activity, ROS levels and cell death, and these effects were suppressed by ML171 and NAC. Furthermore, ASX induced RIP1 and RIP3 activation, ultimately inducing mixed lineage kinase domain‑like protein (MLKL) activation, lactate dehydrogenase (LDH) release and cell death. Moreover, the ASX‑induced decrease in cell viability was reversed by Nec‑1 treatment and RIP1 siRNA transfection, but not by z‑VAD. ASX did not increase the ratio of apoptotic Bax/anti‑apoptotic Bcl‑2, the number of Annexin V‑positive cells, or caspase‑9 activation, which are apoptosis indices. In conclusion, ASX induced necroptotic cell death by increasing NADPH oxidase activity, ROS levels, LDH release and the number of propidium iodide‑positive cells, as well as activating necroptosis‑regulating proteins, RIP1/RIP3/MLKL, in gastric cancer AGS cells. The results of this study demonstrated the necroptotic effect of ASX on gastric cancer AGS cells, which required NADPH oxidase activation and RIP1/RIP3/MLKL signaling in vitro.}, }
@article {pmid34603718, year = {2021}, author = {Katwal, S and Malbul, K and Mandal, SK and Kc, S and Alam, MZ and Karki, P and Pant, C}, title = {Successfully managed aluminum phosphide poisoning: A case report.}, journal = {Annals of medicine and surgery (2012)}, volume = {70}, number = {}, pages = {102868}, pmid = {34603718}, issn = {2049-0801}, abstract = {INTRODUCTION: and Importance: Aluminum phosphide (ALP) is a commonly available pesticide in agricultural countries like Nepal. Upon ingestion, this releases highly toxic phosphine gas in the gastrointestinal tract when it comes in contact with humidity. This leads to refractory shock, metabolic acidosis, cardiac arrhythmia, renal failure, and hepato-biliary impairment.<br><br>CASE PRESENTATION: We present a successfully managed case of a 17-year-old girl who ingested 6&#xa0;g (2 tablets) of ALP tablets with suicidal intent. Although the mortality has been reported as 70-100% with mere ingestion of 150-500 mg of ALP, this case survived even after developing severe metabolic acidosis, acute renal failure, refractory shock, and ventricular tachycardia.<br><br>CLINICAL DISCUSSION: ALP poisoning is most often lethal. However, there is an emerging evidence of successful use of various drugs such as magnesium sulfate, trimetazidine, and other interventions such as intra-aortic balloon pump and extra corporeal membrane oxygenation in case of ALP poisoning.<br><br>CONCLUSION: Owing to the unavailability of an effective antidote of ALP to date, we emphasize early initiation of supportive management, intensive monitoring, and potential role of membrane stabilizers like magnesium sulfate, and cardio-protective agents like trimetazidine, N-Acetyl cysteine, thiamine, vitamin C, and hydrocortisone in decreasing the likelihood of fatal outcome.}, }
@article {pmid34603395, year = {2021}, author = {Rodríguez, E and Grover Thomas, F and Camus, MF and Lane, N}, title = {Mitonuclear Interactions Produce Diverging Responses to Mild Stress in Drosophila Larvae.}, journal = {Frontiers in genetics}, volume = {12}, number = {}, pages = {734255}, pmid = {34603395}, issn = {1664-8021}, abstract = {Mitochondrial function depends on direct interactions between respiratory proteins encoded by genes in two genomes, mitochondrial and nuclear, which evolve in very different ways. Serious incompatibilities between these genomes can have severe effects on development, fitness and viability. The effect of subtle mitonuclear mismatches has received less attention, especially when subject to mild physiological stress. Here, we investigate how two distinct physiological stresses, metabolic stress (high-protein diet) and redox stress [the glutathione precursor N-acetyl cysteine (NAC)], affect development time, egg-to-adult viability, and the mitochondrial physiology of Drosophila larvae with an isogenic nuclear background set against three mitochondrial DNA (mtDNA) haplotypes: one coevolved (WT) and two slightly mismatched (COX and BAR). Larvae fed the high-protein diet developed faster and had greater viability in all haplotypes. The opposite was true of NAC-fed flies, especially those with the COX haplotype. Unexpectedly, the slightly mismatched BAR larvae developed fastest and were the most viable on both treatments, as well as control diets. These changes in larval development were linked to a shift to complex I-driven mitochondrial respiration in all haplotypes on the high-protein diet. In contrast, NAC increased respiration in COX larvae but drove a shift toward oxidation of proline and succinate. The flux of reactive oxygen species was increased in COX larvae treated with NAC and was associated with an increase in mtDNA copy number. Our results support the notion that subtle mitonuclear mismatches can lead to diverging responses to mild physiological stress, undermining fitness in some cases, but surprisingly improving outcomes in other ostensibly mismatched fly lines.}, }
@article {pmid34602622, year = {2021}, author = {Friciu, MM and Monfort, A and Dubé, PA and Leclair, G}, title = {Stability of N-Acetylcysteine 60 mg/mL in Extemporaneously Compounded Injectable Solutions.}, journal = {The Canadian journal of hospital pharmacy}, volume = {74}, number = {4}, pages = {344-349}, pmid = {34602622}, issn = {1920-2903}, abstract = {BACKGROUND: N-Acetylcysteine (NAC) administered by the IV route is the current treatment of choice for acetaminophen overdose. However, the protocol approved by health authorities in most countries has a complex dosing regimen, which leads to dosage errors in one-third of cases. Therefore, the Canadian Antidote Guide in Acute Care Toxicology and individual poison centres have begun to recommend a simplified regimen using continuous IV infusion. Unfortunately, no study has demonstrated the stability of IV solutions of NAC at concentrations above 30 mg/mL or in solutions other than 5% dextrose.<br><br>OBJECTIVE: To evaluate the stability of solutions of NAC 60 mg/mL in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose, stored for up to 72 hours in polyvinyl chloride (PVC) bags at 25&#xb0;C.<br><br>METHODS: Solutions of the desired concentration were prepared from a commercial solution of NAC 200 mg/mL, with dilution in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose, and were then stored at room temperature in PVC bags for up to 72 hours. At predetermined time points (0, 16, 24, 40, 48 and 72 h), samples were collected and analyzed using a stability-indicating high-performance liquid chromatography method. A solution was considered stable if it maintained at least 90.0% of its initial concentration. Particulate matter count was also evaluated to confirm chemical stability. Finally, organoleptic properties, such as odour and colour, were evaluated to assess the stability of the solutions.<br><br>RESULTS: All solutions maintained at least 98.7% of their initial concentration. No obvious changes in odour or colour were observed. Moreover, particle counts remained acceptable throughout the study, according to the criteria specified in United States Pharmacopeia (USP) General Chapter <788>.<br><br>CONCLUSIONS: NAC 60 mg/mL, diluted in 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose and stored in PVC bags at 25&#xb0;C, was chemically and physically stable for a period of at least 72 hours.}, }
@article {pmid34602393, year = {2021}, author = {Shao, Z and Meng, X and Meng, F}, title = {Efficacy and safety of mesenchymal stem cell in Chinese patients with chronic renal failure: A pilot study in Shandong province, China.}, journal = {Pakistan journal of pharmaceutical sciences}, volume = {34}, number = {3(Special)}, pages = {1227-1231}, pmid = {34602393}, issn = {1011-601X}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; China ; Creatinine/metabolism ; Female ; Free Radical Scavengers/*therapeutic use ; Glomerular Filtration Rate ; Humans ; Kidney Failure, Chronic/metabolism/*therapy ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Middle Aged ; Pilot Projects ; Transplantation, Autologous/methods ; Treatment Outcome ; }, abstract = {This study designed to evaluate efficacy and safety profile of Mesenchymal stem cells (MSCs) versus Acetyl cysteine (NACys) in the Chinese patients with Chronic renal failure (CRF). The CRF patients having eGFR less than 60ml per minute per 1.73m2 randomly assigned to MSCs (N=100) or NACys (N=100) (1:1) for 8 weeks. MSCs administered as intravenous infusion of marrow-derived autologous MSCs (1 × 106 to 2 × 106/kg) reperfusion, whereas, another group received NACys 600mg orally twice a day for 8 weeks. The efficacy variables include: creatinine; cystatin C; TGF-β levels; oxidants/reactive oxygen species production induced by TGF-β; collagen levels (type 1 and 4); urinary albumin/creatinine ratio and Glomerular area. Safety was also assesed. Both the treatments significantly decreased creatinine, cystatin C and reactive oxygen species from baseline, however, reduction in creatinine, cystatin C, and reactive oxygen species level from baseline was significantly higher in patient treated with MSCs (N=100) as compared to NACys (N=100). Moreover, improvement in renal and systemic functional parameters from baseline was significantly higher in patient treated with MSCs as compared to NACys. Overall, MSCs offer significantly greater improvement in renal function as compared to NACys in Chinese CRF patients.}, }
@article {pmid34601074, year = {2021}, author = {Zhao, X and Zhao, X and Wang, Z}, title = {Synergistic neuroprotective effects of hyperbaric oxygen and N-acetylcysteine against traumatic spinal cord injury in rat.}, journal = {Journal of chemical neuroanatomy}, volume = {118}, number = {}, pages = {102037}, doi = {10.1016/j.jchemneu.2021.102037}, pmid = {34601074}, issn = {1873-6300}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Count ; Combined Modality Therapy ; Cytokines/metabolism ; Electromyography ; Female ; *Hyperbaric Oxygenation ; Neuroglia/pathology ; Neuroprotective Agents/*therapeutic use ; Rats ; Rats, Wistar ; Spinal Cord/metabolism/pathology ; Spinal Cord Injuries/*drug therapy/metabolism/pathology ; }, abstract = {BACKGROUND: The mitochondrial dysfunction and following oxidative stress, as well as the spread of inflammation plays major roles in the failure to regenerate following severe spinal cord injury (SCI). In this regard, we investigated the neuroprotective effects of hyperbaric oxygen (HBO), as an anti-apoptotic and anti-inflammatory agent, and N-acetylcysteine (NAC), as a mitochondrial enhancer, in SCI.<br><br>MATERIAL AND METHODS: Seventy-five female adult Wistar rats divided into five groups (n&#xa0;=&#xa0;15): laminectomy alone (Sham) group, SCI group, HBO group (underwent SCI and received HBO), NAC group (underwent SCI and received NAC), and HBO+NAC group (underwent SCI and simultaneously received NAC and HBO). At the end of study, spinal cord tissue samples were taken for evaluation of biochemical profiles including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) levels, immunohistochemistry for caspase-3 as well as gene expressions of interleukin (IL)-10, tumor necrosis factor alpha (TNF-&#x3b1;), and IL-1&#x3b2;. Stereological assessments were performed to determine the total volumes, central cavity volumes and as well as numerical density of the neural and glial cells in traumatic area. Moreover, neurological functions were evaluated by the Basso-Beattie-Bresnehan (BBB) and electromyography (EMG).<br><br>RESULTS: Our results showed that the stereological parameters, biochemical profiles (except MDA) and neurological function were significantly higher in each HBO, NAC and HBO+NAC groups compared to the SCI group, and were highest in HBO+NAC ones. The transcript for IL-10 gene was significantly upregulated in all treatment regimens compared to SCI group, and was highest in HBO+NAC ones. While expression of TNF-&#x3b1; and IL-1&#x3b2;, latency, as well as density of apoptosis cells in caspase-3 evaluation significantly more decreased in HBO+NAC group compared to other groups.<br><br>CONCLUSION: Overall, using combined therapy with HBO and NAC has synergistic neuroprotective effects in SCI treatment.}, }
@article {pmid34599149, year = {2021}, author = {Huang, C and Santofimia-Castaño, P and Liu, X and Xia, Y and Peng, L and Gotorbe, C and Neira, JL and Tang, D and Pouyssegur, J and Iovanna, J}, title = {NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner.}, journal = {Cell death discovery}, volume = {7}, number = {1}, pages = {269}, pmid = {34599149}, issn = {2058-7716}, abstract = {Ferroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents. The ferroptotic activity can be improved by inhibiting antioxidant factors in pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells. In addition, ZZW-115-treatment increases the accumulation of hydroperoxided lipids in these cells. We also found that a loss of activity and strong deregulation of key enzymes involved in the GSH- and GPX-dependent antioxidant systems upon ZZW-115 treatment. These results have been validated in xenografts induced with PDAC- and HCC-derived cells in nude mice during the treatment with ZZW-115. More importantly, we demonstrate that ZZW-115-induced mitochondrial morphological changes, compatible with the ferroptotic process, as well as mitochondrial network disorganization and strong mitochondrial metabolic dysfunction, which are rescued by both Fer-1 and N-acetylcysteine (NAC). Of note, the expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. Altogether, these results demonstrate that the mitochondrial cell death mediated by NUPR1 inhibitor ZZW-115 is fully rescued by Fer-1 but also via TFAM complementation. In conclusion, TFAM could be considered as an antagonist of the ferroptotic cell death.}, }
@article {pmid34597721, year = {2021}, author = {Huang, Y and Zhang, J and Tao, Y and Ji, C and Aniagu, S and Jiang, Y and Chen, T}, title = {AHR/ROS-mediated mitochondria apoptosis contributes to benzo[a]pyrene-induced heart defects and the protective effects of resveratrol.}, journal = {Toxicology}, volume = {462}, number = {}, pages = {152965}, doi = {10.1016/j.tox.2021.152965}, pmid = {34597721}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Azo Compounds/pharmacology ; Benzo(a)pyrene/administration &amp; dosage/*toxicity ; Dose-Response Relationship, Drug ; Heart Defects, Congenital/chemically induced/*prevention &amp; control ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Oxidative Stress/drug effects ; Pyrazoles/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/*metabolism ; Resveratrol/*pharmacology ; Zebrafish ; }, abstract = {Benzo[a]pyrene (BaP), a prototypical polycyclic aromatic hydrocarbon, is widely present in the environment. BaP-induced heart defects have been frequently reported, but the underlying molecular mechanisms remain elusive. Here, we found that BaP increased heart malformations in zebrafish embryos in a concentration-dependent manner, which were attenuated by supplementation with either CH223191 (CH), an aryl hydrocarbon receptor (AHR) inhibitor, or N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger. While CH and NAC both inhibited BaP-induced ROS generation, NAC had no effect on BaP-induced AHR activation. We further demonstrated that BaP increased mitochondrial ROS, decreased mitochondrial membrane potential, and caused endogenous apoptosis, with all these effects being counteracted by supplementation with either CH or NAC. Resveratrol (RSV), a natural AHR antagonist and ROS scavenger, also counteracted the heart malformations caused by BaP. Further experiments showed that RSV attenuated BaP-induced oxidative stress, mitochondrial damage and apoptosis, but had no significant effect on AHR activation. In conclusion, our findings show that BaP induces oxidative stress via AHR activation, which causes mitochondria-mediated intrinsic apoptosis, resulting in heart malformations in zebrafish embryos, and that RSV had a protective effect against BaP-induced heart defects mainly by inhibiting oxidative stress rather than through antagonism of AHR activity.}, }
@article {pmid34597422, year = {2021}, author = {Yokoo, K and Yamamoto, Y and Suzuki, T}, title = {Ammonia impairs tight junction barriers by inducing mitochondrial dysfunction in Caco-2 cells.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {35}, number = {11}, pages = {e21854}, doi = {10.1096/fj.202100758R}, pmid = {34597422}, issn = {1530-6860}, mesh = {Adenosine Triphosphate/metabolism ; Ammonia/*pharmacology ; Caco-2 Cells ; Glutathione/metabolism ; Humans ; Interleukin-8/biosynthesis ; Intestinal Mucosa/metabolism ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/*metabolism ; NADP/metabolism ; Oxidative Stress/drug effects ; Permeability/drug effects ; Renal Insufficiency, Chronic/metabolism ; Signal Transduction/*drug effects ; Tight Junction Proteins/*metabolism ; Tight Junctions/*drug effects/*metabolism ; }, abstract = {Ammonia is one of the major metabolites produced by intestinal microorganisms; however, its role in intestinal homeostasis is poorly understood. The present study investigated the regulation of intestinal tight junction (TJ) proteins by ammonia and the underlying mechanisms in human intestinal Caco-2 cells. Ammonia (15, 30, and 60 mM) increased the permeability of the cells in a dose-dependent manner, as indicated by reduced transepithelial electrical resistance and increased dextran flux. Immunoblot and immunofluorescence analyses revealed that the ammonia-induced increase in TJ permeability reduced the membrane localization of TJ proteins such as zonula occludens (ZO)1, ZO2, occludin, claudin-1, and claudin-3. DNA microarray analysis identified a biological pathway "response to reactive oxygen species" enriched by ammonia treatment, indicating the induction of oxidative stress in the cells. Ammonia treatment also increased the malondialdehyde content and decreased the ratio of reduced to oxidized glutathione. Meanwhile, ammonia treatment-induced mitochondrial dysfunction, as indicated by the downregulation of genes associated with the electron transport chain, reduction of the cellular ATP, NADH, and tricarboxylic acid cycle intermediate content, and suppression of the mitochondrial membrane potential. In contrast, N-acetyl cysteine reversed the ammonia-induced impairment of TJ permeability and structure without affecting the mitochondrial parameters. Collectively, ammonia impaired the TJ barrier by increasing oxidative stress in Caco-2 cells. A mitochondrial dysfunction is possibly an event preceding ammonia-induced oxidative stress. The findings of this study could potentially improve our understanding of the interplay between intestinal microorganisms and their hosts.}, }
@article {pmid34592079, year = {2020}, author = {Devi, N and Boya, C and Chhabra, M and Bansal, D}, title = {N-acetyl-cysteine as adjuvant therapy in female infertility: a systematic review and meta-analysis.}, journal = {Journal of basic and clinical physiology and pharmacology}, volume = {32}, number = {5}, pages = {899-910}, doi = {10.1515/jbcpp-2020-0107}, pmid = {34592079}, issn = {2191-0286}, mesh = {*Abortion, Spontaneous/prevention &amp; control ; *Acetylcysteine/therapeutic use ; Female ; Humans ; *Infertility, Female/drug therapy/etiology ; Live Birth ; Ovulation Induction ; *Polycystic Ovary Syndrome/complications ; Pregnancy ; Pregnancy Rate ; }, abstract = {OBJECTIVES: The objective of this study is to explore the efficacy and safety of N-acetyl-cysteine (NAC) as adjuvant therapy in female infertility.<br><br>CONTENT: We performed a systematic literature search of PubMed, Cochrane Library, Embase, and Ovid databases through April 2019 for Randomized Controlled Trials (RCTs) evaluating the effectiveness and safety of NAC as adjuvant therapy in female infertility. The outcomes assessed were rates of ovulation, pregnancy, miscarriage and multiple pregnancy, presented as pooled odds ratio with 95% confidence interval (CI) using the random-effects model. Heterogeneity and inconsistency of the measurements were identified through Cochrane's Q statistic and I2 statistic. We also performed a sensitivity analysis, publication bias (using funnel plot and Begg's test), and subgroup analysis.<br><br>SUMMARY: Fifteen RCTs recruiting 2330 female receiving NAC were included. The pooled estimate showed the statistically insignificant improvement in outcomes; clinical pregnancy rate 1.55 (95% CI 0.98-2.47; I2=68%; p<0.01), ovulation rate 1.77 (95% CI 0.76-4.14; I2=90%; p<0.01), multiple pregnancy rate 0.83 (95% CI 0.34-1.99; I2=10%; p=0.31) and miscarriage rate 0.76 (95% CI= 0.37, 1.53; I2=0%; p=0.69) . NAC was found less efficacious and safe than metformin in all outcomes. Overall, NAC showed statistically insignificant (OR=0.98-2.47).<br><br>OUTLOOK: NAC can be an effective adjuvant in PCOS related and unexplained female infertility. The effect could be more profound in women with high BMI, insulin resistance, and oxidative stress. However, the findings need further confirmation in well-designed randomized controlled trials to examine clinical outcomes such as live birth rate in more extended follow-up periods.}, }
@article {pmid34590731, year = {2022}, author = {Yi, SY and Barnett, BR and Poetzel, MJ and Stowe, NA and Yu, JJ}, title = {Clinical translational neuroimaging of the antioxidant effect of N-acetylcysteine on neural microstructure.}, journal = {Magnetic resonance in medicine}, volume = {87}, number = {2}, pages = {820-836}, pmid = {34590731}, issn = {1522-2594}, support = {U54 AI117924/AI/NIAID NIH HHS/United States ; P30 HD003352/HD/NICHD NIH HHS/United States ; P30 CA014520/CA/NCI NIH HHS/United States ; T32 GM008692/GM/NIGMS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; T32 GM140935/GM/NIGMS NIH HHS/United States ; F30 AG066329/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Antioxidants/pharmacology ; Brain/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; *Diffusion Tensor Imaging ; Female ; Male ; Nerve Tissue Proteins ; Neuroimaging ; Rats ; Rats, Sprague-Dawley ; }, abstract = {PURPOSE: Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness.<br><br>METHODS: Male and female Disc1 sv&#x394;2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 sv&#x394;2 rats exposed to chronic early-life stress to test how gene-environment interactions might alter effectiveness of NAC therapy.<br><br>RESULTS: The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 sv&#x394;2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits.<br><br>CONCLUSION: These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.}, }
@article {pmid34589369, year = {2021}, author = {Orozco, E and Birnbrich, A and Liberman, SR}, title = {The Role of N-acetylcysteine in the Treatment of Accidental Submersion of the Hands in Liquid Nitrogen.}, journal = {Cureus}, volume = {13}, number = {9}, pages = {e18129}, pmid = {34589369}, issn = {2168-8184}, abstract = {N-acetylcysteine (NAC) is a compound with numerous uses, especially in cases which require prevention of cellular damage. To the authors' knowledge, no reports of NAC as treatment for liquid nitrogen (LN2) injuries currently exist. We present a case in which a 40-year-old woman accidentally submerged her hands in LN2 while working in a lab. The patient was treated with NAC, antibiotics, and wound care. Six months post-injury, the patient had full range of motion, full sensation, full function, and no pain. Therefore, NAC, in combination with dressing changes and antibiotics, can be used to successfully treat patients with LN2 burns.}, }
@article {pmid34588976, year = {2021}, author = {Hang, W and Shu, H and Wen, Z and Liu, J and Jin, Z and Shi, Z and Chen, C and Wang, DW}, title = {N-Acetyl Cysteine Ameliorates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease and Intracellular Triglyceride Accumulation by Preserving Mitochondrial Function.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {636204}, pmid = {34588976}, issn = {1663-9812}, abstract = {Rationale: Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic disease characterized by liver steatosis. Excessive reactive oxygen species (ROS) originating from dysfunctional mitochondria is the major pathophysiological contributor in the development of NAFLD and is thought to be a promising therapeutic target. A few reports demonstrate the antioxidative treatments for NAFLD. Methods: Male C57 mice were fed on a normal chow diet (ND) or high-fat diet (HFD) for 8 weeks. PBS or N-acetyl cysteine (NAC) was gavaged to mice. LO2 human liver cell line treated with palmitic acid (PA) was applied as a cellular model. Western blot, immunofluorescence, biochemistry assay, and pathological staining were used to investigate the mechanism of suppressing lipid accumulation of NAC. Results: NAC treatment was able to prevent HFD-induced NAFLD, as evidenced by less hepatic triglyceride accumulation and lipid droplet formation compared with that of mice in the HFD group. NAC could preserve mitochondrial function by inhibiting excessive mitophagy and promoting mitochondria biogenesis to prevent ROS production. NAC also activated Sirt1 and preserved its protein level and subsequently promoted mitochondria biogenesis via deacetylating PGC1a. Conclusion: We demonstrated that NAC may be an effective drug to treat NAFLD, which was related to its antioxidative and mitochondrial protective effect.}, }
@article {pmid34585633, year = {2021}, author = {Peng, M and Liu, Y and Xu, Y and Li, L and Li, Y and Yang, H}, title = {Cathelicidin-WA ameliorates diabetic cardiomyopathy by inhibiting the NLRP3 inflammasome.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {20}, number = {21}, pages = {2278-2290}, pmid = {34585633}, issn = {1551-4005}, mesh = {Animals ; Antimicrobial Cationic Peptides ; Cell Cycle Proteins ; *Diabetes Mellitus ; *Diabetic Cardiomyopathies/metabolism ; Inflammasomes/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Stroke Volume ; Ventricular Function, Left ; Cathelicidins ; }, abstract = {Cathelicidin-WA (CWA) is a novel cathelicidin peptide isolated from snakes that has been suggested to exert anti-inflammatory effects. The aim of our study was to investigate whether cathelicidin-WA (CWA) could protect the heart from diabetic cardiomyopathy (DCM). Streptozotocin (STZ) injection was used to establish a mouse model of DCM. CWA peptide (2 mg/kg or 8 mg/kg) was continuously administered to the mice from 10 weeks to 16 weeks after STZ injection. The mice in the DCM group exhibited cardiac dysfunction, while 8 mg/kg CWA ameliorated this cardiac dysfunction. Cardiac fibrosis, inflammation, and oxidative stress as well as cardiomyocyte apoptosis in the DCM mice were decreased by treatment with 8 mg/kg CWA. We isolated neonatal rat cardiomyocytes and stimulated the cells with high glucose to establish an in vitro model of myocyte cell injury. Consistently, CWA inhibited high glucose-induced cell death, inflammation and oxidative stress in the myocytes. Moreover, CWA reduced the formation of the NLR family pyrin domain-containing 3 (NRLP3) inflammasome by regulating thioredoxin-interacting protein expression and p65 activation. NLRP3 overexpression inhibited the beneficial effects of CWA on the heart during DCM and on high glucose-induced myocyte injury. In summary, CWA attenuates cardiac injury and preserves cardiac function during DCM by targeting the NLRP3 pathway.Abbreviations: AAV9: Adeno associated virus; AGE: Advanced Glycation End products; CWA: Cathelicidin-WA; DCM: diabetic cardiomyopathy; Gpx: glutathione peroxidase; HG: high glucose; IL: Interleukin; NLR: Family Pyrin Domain Containing 3 (NRLP3); TXNIP: Thioredoxin interacting protein; LVEF: left ventricular ejection fraction; MDA: Malondialdehyde; MnSOD: manganese superoxide dismutase; NADPH: Nicotinamide adenine dinucleotide phosphate; NAC: N-acetyl-cysteine; NRCMs: Neonatal rat cardiomyocytes; ROS: reactive oxygen species; STZ: Streptozotocin; TNFa: tumor necrosis factor a.}, }
@article {pmid34581655, year = {2022}, author = {Lewis, JC and Lim, M and Lai, L and Mendoza, E and Albertson, TE and Chenoweth, JA}, title = {Evaluation of N-acetylcysteine dose for the treatment of massive acetaminophen ingestion.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {4}, pages = {507-513}, doi = {10.1080/15563650.2021.1984503}, pmid = {34581655}, issn = {1556-9519}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; *Drug Overdose/drug therapy ; Eating ; Humans ; Retrospective Studies ; }, abstract = {METHODS: The use of N-acetylcysteine (NAC) remains the standard of care for treatment of acetaminophen (APAP) toxicity and overdose. Currently, there is growing evidence to suggest that massive acetaminophen overdose is associated with increased hepatotoxicity despite timely administration of NAC. This raises the question as to whether an increased dose of intravenous (IV) NAC should be used in the setting of massive APAP ingestion. This study aimed to evaluate the rate of hepatotoxicity after massive APAP overdose treated with 3 different NAC treatment regimens.<br><br>METHODS: This was a retrospective cohort study conducted by electronic medical record review of cases reported to a statewide poison control system between 2007 and 2020. Inclusion criteria were single APAP or APAP combination-medication ingestion; acute massive acetaminophen (APAP) ingestion (defined as APAP concentration &#x2265; 2 times above the Rumack-Matthew 150 nomogram); received one of the three NAC regimens: standard dose IV NAC, oral (PO) NAC, or high dose IV NAC. The risk of hepatotoxicity was evaluated using a multivariate logistic regression model with standard dose IV NAC as the base variable for comparison.<br><br>RESULTS: A total of 373 patients met inclusion for the study. Of those, 135 cases were treated with standard dose IV NAC, 121 cases treated with PO NAC, and 117 cases treated with high dose IV NAC. The risk of developing hepatotoxicity was not statistically significant between the high dose IV NAC (OR 1.05, 95% CI 0.52&#x2009;-&#x2009;2.09) or oral NAC (OR 0.69, 95% CI 0.33&#x2009;-&#x2009;1.46) when compared to standard dose IV NAC. When adjusted for APAP combination medications, initial APAP ratio, initial elevated AST/ALT, and treatment within 8&#x2009;h, there remained no difference between treatment regimens.<br><br>CONCLUSION: This study was unable to detect a large absolute reduction in the rate of hepatotoxicity after massive APAP ingestion in patients treated with high dose IV NAC or PO NAC when compared to standard dose IV NAC; even when treatment was initiated within 8&#x2009;h of ingestion.}, }
@article {pmid34576256, year = {2021}, author = {Lacerda-Abreu, MA and Russo-Abrahão, T and Rocco-Machado, N and Cosentino-Gomes, D and Dick, CF and Carvalho-Kelly, LF and Cunha Nascimento, MT and Rocha-Vieira, TC and Meyer-Fernandes, JR}, title = {Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34576256}, issn = {1422-0067}, support = {401134/2014-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 0012017//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; e-26/201.300/2014//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; }, mesh = {Acetylcysteine/pharmacology ; Breast Neoplasms/*drug therapy ; Cell Adhesion ; Cell Line, Tumor ; Cell Movement ; Cell Survival ; Epithelial-Mesenchymal Transition ; Female ; Humans ; Hydrogen Peroxide/*chemistry ; MCF-7 Cells ; Membrane Potential, Mitochondrial ; NADPH Oxidases/metabolism ; Neoplasm Metastasis ; Oxygen Consumption ; *Phosphates ; Protein Kinase C/metabolism ; Reactive Oxygen Species ; }, abstract = {According to the growth rate hypothesis (GRH), tumour cells have high inorganic phosphate (Pi) demands due to accelerated proliferation. Compared to healthy individuals, cancer patients present with a nearly 2.5-fold higher Pi serum concentration. In this work, we show that an increasing concentration of Pi had the opposite effect on Pi-transporters only in MDA-MB-231 when compared to other breast cell lines: MCF-7 or MCF10-A (non-tumoural breast cell line). Here, we show for the first time that high extracellular Pi concentration mediates ROS production in TNBC (MDA-MB-231). After a short-time exposure (1 h), Pi hyperpolarizes the mitochondrial membrane, increases mitochondrial ROS generation, impairs oxygen (O2) consumption and increases PKC activity. However, after 24 h Pi-exposure, the source of H2O2 seems to shift from mitochondria to an NADPH oxidase enzyme (NOX), through activation of PKC by H2O2. Exogenous-added H2O2 modulated Pi-transporters the same way as extracellular high Pi, which could be reversed by the addition of the antioxidant N-acetylcysteine (NAC). NAC was also able to abolish Pi-induced Epithelial-mesenchymal transition (EMT), migration and adhesion of MDA-MB-231. We believe that Pi transporters support part of the energy required for the metastatic processes stimulated by Pi and trigger Pi-induced H2O2 production as a signalling response to promote cell migration and adhesion.}, }
@article {pmid34576128, year = {2021}, author = {Song, Y and Hu, S and Zhang, J and Zhu, L and Zhao, X and Chen, Q and Zhang, J and Bai, Y and Pan, Y and Shao, C}, title = {Fractionated Irradiation of Right Thorax Induces Abscopal Damage on Bone Marrow Cells via TNF-α and SAA.}, journal = {International journal of molecular sciences}, volume = {22}, number = {18}, pages = {}, pmid = {34576128}, issn = {1422-0067}, support = {31770910, 11775052, and 81672985//National Natural Science Foundation of China/ ; 2017YFC0108604//National Key R&amp;D Program of China/ ; 19411950902//Shanghai Science and Technology Commission/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood Proteins/metabolism ; Bone Marrow Cells/*metabolism/*radiation effects ; Cell Cycle/radiation effects ; DNA Damage ; *Dose Fractionation, Radiation ; Free Radical Scavengers/pharmacology ; Lung Injury/pathology ; Male ; Mesenchymal Stem Cells/metabolism/radiation effects ; Mice, Inbred C57BL ; Proteomics ; Reactive Oxygen Species/metabolism ; Serum Amyloid A Protein/*metabolism ; Thorax/*radiation effects ; Tumor Necrosis Factor-alpha/*metabolism ; Mice ; }, abstract = {Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of mice with fractionated doses (8 Gy × 3). It was found that this localized Th-IR increased apoptosis of bone marrow cells and micronucleus formation of bone marrow polychromatic erythrocytes after irradiation. Tandem mass tagging (TMT) analysis and ELISA assay showed that the concentrations of TNF-α and serum amyloid A (SAA) in the mice were significantly increased after Th-IR. An immunohistochemistry assay revealed a robust increase in SAA expression in the liver rather than in the lungs after Th-IR. In vitro experiments demonstrated that TNF-α induced SAA expression in mouse hepatoma Hepa1-6 cells, and these two signaling factors induced DNA damage in bone marrow mesenchymal stem cells (BMSCs) by increasing reactive oxygen species (ROS). On the other hand, injection with TNF-α inhibitor before Th-IR reduced the secretion of SAA and attenuated the abscopal damage in bone marrow. ROS scavenger NAC could also mitigated Th-IR/SAA-induced bone marrow damage in mice. Our findings indicated that Th-IR triggered TNF-α release from lung, which further promoted SAA secretion from liver in a manner of cascade reaction. Consequently, these signaling factors resulted in induction of abscopal damage on bone marrow of mice.}, }
@article {pmid34575651, year = {2021}, author = {Yang, KH and Tang, JY and Chen, YN and Chuang, YT and Tsai, IH and Chiu, CC and Li, LJ and Chien, TM and Cheng, YB and Chang, FR and Yen, CY and Chang, HW}, title = {Nepenthes Extract Induces Selective Killing, Necrosis, and Apoptosis in Oral Cancer Cells.}, journal = {Journal of personalized medicine}, volume = {11}, number = {9}, pages = {}, pmid = {34575651}, issn = {2075-4426}, support = {MOST 108-2314-B-384-002; MOST 108-2320-B-037-015-MY3//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 110-P016//National Sun Yat-sen University-KMU Joint Research Project/ ; KMUH-109-9M56//Kaohsiung Medical University Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; }, abstract = {Ethyl acetate Nepenthes extract (EANT) from Nepenthes thorellii × (ventricosa × maxima) shows antiproliferation and apoptosis but not necrosis in breast cancer cells, but this has not been investigated in oral cancer cells. In the present study, EANT shows no cytotoxicity to normal oral cells but exhibits selective killing to six oral cancer cell lines. They were suppressed by pretreatment of the antioxidant inhibitor N-acetylcysteine (NAC), demonstrating that EANT-induced cell death was mediated by oxidative stress. Concerning high sensitivity to EANT, Ca9-22 and CAL 27 oral cancer cells were chosen for exploring detailed selective killing mechanisms. EANT triggers a mixture of necrosis and apoptosis as determined by annexin V/7-aminoactinmycin D analysis. Still, they show differential switches from necrosis at a low (10 μg/mL) concentration to apoptosis at high (25 μg/mL) concentration of EANT in oral cancer cells. NAC induces necrosis but suppresses annexin V-detected apoptosis in oral cancer cells. Necrostatin 1 (NEC1), a necroptosis inhibitor, moderately suppresses necrosis but induces apoptosis at 10 μg/mL EANT. In contrast, Z-VAD-FMK, a pancaspase inhibitor, slightly causes necrosis but suppresses apoptosis at 10 μg/mL EANT. Furthermore, the flow cytometry-detected pancaspase activity is dose-responsively increased but is suppressed by NAC and ZVAD, although not for NEC1 in oral cancer cells. EANT causes several oxidative stress events such as reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization. In response to oxidative stresses, the mRNA for antioxidant signaling, such as nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), heme oxygenase 1 (HMOX1), and thioredoxin (TXN), are overexpressed in oral cancer cells. Moreover, EANT also triggers DNA damage, as detected by γH2AX and 8-oxo-2'-deoxyguanosine adducts. The dependence of oxidative stress is validated by the evidence that NAC pretreatment reverts the changes of cellular and mitochondrial stress and DNA damage. Therefore, EANT exhibits antiproliferation involving an oxidative stress-dependent necrosis/apoptosis switch and DNA damage in oral cancer cells.}, }
@article {pmid34575034, year = {2021}, author = {Suzuki, S and Yamamoto, M and Sanomachi, T and Togashi, K and Sugai, A and Seino, S and Yoshioka, T and Okada, M and Kitanaka, C}, title = {Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction.}, journal = {Life (Basel, Switzerland)}, volume = {11}, number = {9}, pages = {}, pmid = {34575034}, issn = {2075-1729}, support = {15K18437//Ministry of Education, Culture, Sports, Science and Technology/ ; NA//Takeda Science Foundation/ ; }, abstract = {Cancer stem cells (CSCs) have high tumor-initiating capacity and are resistant to chemotherapeutic reagents; thus eliminating CSCs is essential to improving the prognosis. Recently, we reported that dexamethasone increases the effects of gemcitabine on pancreatic CSCs; however, the mechanism involved remains to be fully elucidated. In this study, we explored the role of reactive oxygen species (ROS) in the dexamethasone-induced chemosensitization of CSCs. Dexamethasone increased the growth-inhibitory effects of gemcitabine and 5-fluorouracil, whereas N-acetyl-cysteine, a ROS scavenger, abolished this effect. Although dexamethasone alone did not increase ROS levels, dexamethasone promoted the increase in ROS levels induced by gemcitabine and 5-fluorouracil. Dexamethasone treatment reduced the expression of NRF2, a key regulator of antioxidant responses, which was attenuated by siRNA-mediated knockdown of the glucocorticoid receptor. Furthermore, brusatol, a suppressor of NRF2, sensitized pancreatic CSCs to gemcitabine and 5-fluorouracil. Of note, essentially, the same mechanism was functional in ovarian and colon CSCs treated by the combination of dexamethasone and chemotherapeutic agents. Our study suggests that dexamethasone can sensitize CSCs to chemotherapeutic agents by promoting chemotherapy-induced ROS production through suppressing NRF2 expression.}, }
@article {pmid34573138, year = {2021}, author = {Song, WJ and Yun, JH and Jeong, MS and Kim, KN and Shin, T and Kim, HC and Wie, MB}, title = {Inhibitors of Lipoxygenase and Cyclooxygenase-2 Attenuate Trimethyltin-Induced Neurotoxicity through Regulating Oxidative Stress and Pro-Inflammatory Cytokines in Human Neuroblastoma SH-SY5Y Cells.}, journal = {Brain sciences}, volume = {11}, number = {9}, pages = {}, pmid = {34573138}, issn = {2076-3425}, support = {520170377//Kangwon National University/ ; }, abstract = {Trimethyltin (TMT) is an environmental neurotoxin that mediates dopaminergic neuronal injury in the brain. In this study, we characterized the toxic mechanism and possible protective compounds against TMT-induced neurotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells. Antioxidants such as melatonin, N-acetylcysteine (NAC), α-tocopherol, and allopurinol alleviated TMT toxicity. Apoptosis induced by TMT was identified by altered expression of cleaved caspase-3, Bax, Bcl-2, and Bcl-xL through Western blot analysis. The iron chelator deferoxamine ameliorated the alteration of apoptosis-related proteins through TMT exposure. TMT also induced delayed ultrastructural necrotic features such as mitochondrial swelling and cytoplasmic membrane rupture; NAC reduced these necrotic injuries. Esculetin, meloxicam, celecoxib, and phenidone decreased TMT toxicity. Elevation of the pro-inflammatory cytokines IL-1β, TNF-α, and NF-ĸB and reduction of the antioxidant enzymes catalase and glutathione peroxidase-1 (GPx-1) were induced by TMT and ameliorated by inhibitors of LOX and COX-2 enzymes. Both NMDA and non-NMDA antagonists attenuated TMT toxicity. The free calcium ion modulators nimodipine and BAPTA/AM contributed to neuronal survival against TMT toxicity. Inhibitors of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway, an autophagy regulator, decreased TMT toxicity. These results imply that TMT neurotoxicity is the chief participant in LOX- and COX-2-mediated apoptosis, partly via necrosis and autophagy in SH-SY5Y cells.}, }
@article {pmid34572976, year = {2021}, author = {Jenkins, DD and Moss, HG and Brown, TR and Yazdani, M and Thayyil, S and Montaldo, P and Vento, M and Kuligowski, J and Wagner, C and Hollis, BW and Wiest, DB}, title = {NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {9}, pages = {}, pmid = {34572976}, issn = {2076-3921}, support = {MR/R001375/1/MRC_/Medical Research Council/United Kingdom ; F31NS108623/NS/NINDS NIH HHS/United States ; P60743//National Institute for Health Research/ ; EC11-246//Spanish Ministry of Health/ ; FISPI14/0433//Instituto Carlos III,/ ; Neuroscience Insitute Discovery Grant//Medical University of South Carolina/ ; }, abstract = {N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24-48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.}, }
@article {pmid34564600, year = {2021}, author = {Liu, J and Liu, Q and Han, J and Feng, J and Guo, T and Li, Z and Min, F and Jin, R and Peng, X}, title = {N-Acetylcysteine Inhibits Patulin-Induced Apoptosis by Affecting ROS-Mediated Oxidative Damage Pathway.}, journal = {Toxins}, volume = {13}, number = {9}, pages = {}, pmid = {34564600}, issn = {2072-6651}, mesh = {Acetylcysteine/*metabolism/*pharmacology ; Apoptosis/*drug effects ; Cells, Cultured/drug effects ; HEK293 Cells/drug effects ; Humans ; Metabolic Networks and Pathways ; Mitochondria/metabolism ; Mycotoxins/toxicity ; Oxidative Phosphorylation/*drug effects ; Oxidative Stress/*drug effects ; Patulin/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Patulin (PAT) belongs to the family of food-borne mycotoxins. Our previous studies revealed that PAT caused cytotoxicity in human embryonic kidney cells (HEK293). In the present research, we systematically explored the detailed mechanism of ROS production and ROS clearance in PAT-induced HEK293 cell apoptosis. Results showed that PAT treatment (2.5, 5, 7.5, 10 μM) for 10 h could regulate the expression of genes and proteins involved in the mitochondrial respiratory chain complex, resulting in dysfunction of mitochondrial oxidative phosphorylation and induction of ROS overproduction. We further investigated the role of N-acetylcysteine (NAC), an ROS scavenger, in promoting the survival of PAT-treated HEK293 cells. NAC improves PAT-induced apoptosis of HEK293 cells by clearing excess ROS, modulating the expression of mitochondrial respiratory chain complex genes and proteins, and maintaining normal mitochondrial function. In addition, NAC protects the activity of antioxidant enzymes, maintains normal GSH content, and relieves oxidative damage. Additionally, 4 mM NAC alleviated 7.5 μM PAT-mediated apoptosis through the caspase pathway in HEK293 cells. In summary, our study demonstrated that ROS is significant in PAT-mediated cytotoxicity, which provides valuable insight into the management of PAT-associated health issues.}, }
@article {pmid34563228, year = {2021}, author = {Zhao, X and Wang, S and Hong, X and Lu, S and Tang, S and Shen, Y and Feng, M and Guo, P and Fang, Y}, title = {A case of trichotillomania with binge eating disorder: combined with N-acetylcysteine synergistic therapy.}, journal = {Annals of general psychiatry}, volume = {20}, number = {1}, pages = {46}, pmid = {34563228}, issn = {1744-859X}, support = {2019KY681//Project of Health Department in Zhejiang Province/ ; 2018GY20//Huzhou Municipal Science and Technology Bureau/ ; 2018GYB16//Huzhou Municipal Science and Technology Bureau/ ; }, abstract = {BACKGROUND: Obsessive-compulsive and related disorders (OCRDs) are a group of intractable and chronic mental disorders. Trichotillomania (TTM) is a common type of OCRDs characterized by repetitive hair pulling, driven by escalating tension before the action and during the attempts to resist it. Binge eating disorder (BED) is a common type of eating disorder characterized by recurrent compulsive episodes of binge eating. Both have common psychological processes (tension or impulsion) and pathological manifestations (out of control), but the pathological mechanisms are still unclear and the current clinical treatments are often unsatisfactory for these two disorders.<br><br>CASE PRESENTATION: A 25-year-old woman with TTM comorbid BED came to our hospital for treatment. She had accepted systematic cognitive behavioral therapy (CBT) and also monotherapy or multidrug therapy with sertraline, fluvoxamine, bupropion, risperidone in full dosage and duration for 2 years, but all of them did not work. We treated this case with N-acetylcysteine (NAC) as a synergist on the basis of recent treatment (fluvoxamine 150&#xa0;mg/day and bupropion 300&#xa0;mg/day). The pathological hair plucking behavior and binge eating symptoms were both significantly and rapidly improved, and the follow-up in next 14&#xa0;weeks showed that the effect was still maintained.<br><br>CONCLUSION: To our knowledge, this may be the first case report of using NAC as a synergist to treat TTM comorbid BED successfully, which suggest that these two disorders may have a common pathophysiological mechanism. Moreover, NAC can be one choice as a synergistic treatment for OCRDs.}, }
@article {pmid34549670, year = {2022}, author = {Shah, KR and Beuhler, MC}, title = {Single bag high dose intravenous N-acetylcysteine associated with decreased hepatotoxicity compared to triple bag intravenous N-acetylcysteine in high-risk acetaminophen ingestions.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {4}, pages = {493-498}, doi = {10.1080/15563650.2021.1979231}, pmid = {34549670}, issn = {1556-9519}, mesh = {Acetaminophen/therapeutic use ; Acetylcysteine/therapeutic use ; Administration, Intravenous ; *Analgesics, Non-Narcotic/therapeutic use ; *Chemical and Drug Induced Liver Injury/drug therapy/etiology ; *Drug Overdose/drug therapy ; Eating ; Humans ; Retrospective Studies ; }, abstract = {INTRODUCTION: There is controversy that the triple bag intravenous (IV) N-acetylcysteine (NAC) regimen may be underdosing the sickest patients in its current, common usage. We hypothesize that a higher dose IV NAC regimen improves some outcomes.<br><br>METHODS: We conducted a poison center based retrospective observational study from January 1, 2016 to December 31, 2017 comparing a single bag higher dose IV NAC regimen (150&#x2009;mg/kg over 1&#x2009;h, 15&#x2009;mg/kg/hour) to the triple bag IV NAC regimen (150&#x2009;mg/kg over 1&#x2009;h, 12.5&#x2009;mg/kg/hour for 4&#x2009;h, 6.25&#x2009;mg/kg/hour). In a high-risk population of patients with acetaminophen ingestion (defined as multiplication product &#x2265; 10,000&#x2009;mg/L IU/L, not acute ingestions receiving NAC within 8&#x2009;h, and not hepatotoxic on first contact), we evaluated the rate of hepatotoxicity, peak transaminase, and rate of laboratory coagulopathy.<br><br>RESULTS: 89 patients met the inclusion criteria. 12 of the 23 patients (52%) who received triple bag NAC became hepatotoxic and 10 (43%) became coagulopathic, while only 19 of 66 patients (29%) who received single bag NAC became hepatotoxic and 15 (23%) became coagulopathic; p&#x2009;=&#x2009;.043 and .057, resp. Mean peak transaminase was 4481&#x2009;IU/L vs 2143&#x2009;IU/L in those receiving triple bag NAC vs single bag NAC, difference of means 2338&#x2009;IU/L; p&#x2009;=&#x2009;.026.<br><br>CONCLUSION: In this exploratory study of a high-risk population of patients with acetaminophen ingestions, the single bag IV NAC regimen was associated with lower peak transaminase and fewer patients becoming hepatotoxic as compared to the triple bag IV NAC regimen.}, }
@article {pmid34549665, year = {2022}, author = {Minhaj, FS and Leonard, JB and Seung, H and Anderson, BD and Klein-Schwartz, W and King, JD}, title = {In vitro analysis of n-acetylcysteine (NAC) interference with the international normalized ratio (INR).}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {4}, pages = {489-492}, doi = {10.1080/15563650.2021.1979232}, pmid = {34549665}, issn = {1556-9519}, mesh = {*Acetaminophen ; *Acetylcysteine/therapeutic use ; Administration, Intravenous ; Adult ; Female ; Humans ; International Normalized Ratio ; Male ; Middle Aged ; Prothrombin Time ; }, abstract = {BACKGROUND: Previous literature suggests a laboratory interference of n-acetylcysteine (NAC) with prothrombin time (PT) and the international normalized ratio (INR). Early publications focused on this interaction in the setting of an acetaminophen overdose and evaluated the INR of patients receiving intravenous NAC. However, there is limited literature describing the concentration-effect relationship of NAC to INR measurement in the absence of acetaminophen-induced hepatotoxicity at therapeutic NAC concentrations. The purpose of the study is to quantify the degree of interference of NAC on INR values at therapeutic concentrations correlating to each infusion of the regimen (ex. bag 1: 550 mcg/mL, bag 2: 200 mcg/mL, bag 3: 35 mcg/mL, double bag 3: 70 mcg/mL) and at supratherapeutic concentrations in vitro.<br><br>METHODS: Blood samples were obtained from study volunteers. Each blood sample was transferred into vials containing 0.3&#x2009;mL buffered sodium citrate 3.2% and spiked with various concentrations of NAC for final concentrations of 0, 35, 70, 200, 550, 1000, 2000, and 4000&#x2009;mcg/mL. The samples were centrifuged and tested to determine PT and INR on two separate machines: Siemens CS-2500 and Stago SN1114559. We would require a sample size of 6 to achieve a power of 80% and a level of significance of 1.7% (two-sided). Differences between INRs at varying concentrations were determined by Friedman's test. For multiple comparisons, post hoc analysis was performed using Wilcoxon signed-rank test with Bonferroni adjustment. Analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC).<br><br>RESULTS: Participants included 11 healthy subjects: 8 males, 3 females, median age 30&#x2009;years (range 25&#x2009;-&#x2009;58). Median and interquartile ranges (IQR) INR for the baseline samples were 1.09 (IQR 1.05, 1.16) for Siemens and 1.03 (IQR 0.99, 1.11) for Stago analyzers. There was a significant difference in INR between the therapeutic concentrations (baseline, 35, 70,200, or 550&#x2009;&#xb5;g/mL) (Siemens p&#x2009;=&#x2009;.0008, Stago p&#x2009;<&#x2009;.0001). The 550&#x2009;&#xb5;g/mL concentration with the Siemens analyzer was the only one compared separately and found to be significantly greater than the baseline (1.07 vs 1.22, p&#x2009;=&#x2009;.02). For the Stago analyzer the 200&#x2009;&#xb5;g/mL and 500&#x2009;&#xb5;g/mL were compared and found to be significantly different from baseline (1.00 vs 1.07 and 1.19, adjusted p&#x2009;=&#x2009;.02 and p&#x2009;=&#x2009;.03, respectively). The largest INR increase seen was in one subject from a baseline of 1.07-1.32 with the 550&#x2009;&#xb5;g/mL concentration. Increases in concentrations to supratherapeutic levels resulted in a statistically significant non-linear increase in INR for all concentrations (Siemens p&#x2009;<&#x2009;.0001, Stago p&#x2009;<&#x2009;.0001). All of these concentrations were found to be significantly different from baseline (all adjusted p&#x2009;<&#x2009;.05).<br><br>CONCLUSION: Although it was found that at therapeutic concentrations the in&#xa0;vitro presence of NAC affects INR measurements on two different machines, the change is of little clinical relevance. Supratherapeutic concentrations of NAC affect INR significantly, but the clinical utility of those results is limited by the rarity of those concentrations being measured.}, }
@article {pmid34544380, year = {2021}, author = {Dissanayake, DMDIB and Gunaratne, WMSN and Kumarihamy, KWMPP and Kularatne, SAM and Kumarasiri, PVR}, title = {Use of intravenous N-acetylcysteine in acute severe hepatitis due to severe dengue infection: a case series.}, journal = {BMC infectious diseases}, volume = {21}, number = {1}, pages = {978}, pmid = {34544380}, issn = {1471-2334}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; Adult ; Animals ; *Hepatitis ; Humans ; Infant, Newborn ; Male ; Retrospective Studies ; *Severe Dengue/drug therapy ; }, abstract = {BACKGROUND: Dengue fever is a common mosquito borne viral infection. Severe dengue fever associated severe hepatitis carries high mortality. Based on the beneficial effect of N-acetylcysteine (NAC) in paracetamol poisoning and non-acetaminophen induced liver failure, it is used in dengue fever associated hepatitis in clinical practice. We aim to study the reversal of liver enzymes with NAC in the setting of severe hepatitis due to severe dengue infection.<br><br>METHODS: A retrospective analysis was conducted on hospitalized 30 adults with severe dengue fever with severe hepatitis. These 30 patients had aspartate transaminase (AST) and alanine transaminases (ALT) more than 500 U/L and/or PT INR (prothrombin time and international normalized ratio) more than 1.5. They were treated with NAC infusion of 100&#xa0;mg/h for 3 to 5&#xa0;days.<br><br>RESULTS: The mean age of the group was 49.9&#x2009;&#xb1;&#x2009;11.46&#xa0;years and 18 (60%) patients were males. Nineteen patients (63%) developed dengue shock. Of them 12 patients (40%) developed hepatic encephalopathy. Median AST on the day of administration of NAC was 1125 U/L interquartile range (IQR) 1653.25 while median ALT was 752 (IQR 459.25). There was a statistically significant reduction of both ALT (p&#x2009;=&#x2009;0.034) and AST (p&#x2009;=&#x2009;0.049) from day 1 to 4 after NAC infusion. Rise of platelet count between day 1 and day 4 also showed statistically significant difference (p&#x2009;=&#x2009;0.011) but the reduction of prothrombin time and international normalized ratio (PT/INR) from 1 to day 4 did not show statistical significance difference. Mean duration of treatment with NAC was 3.61&#x2009;&#xb1;&#x2009;0.75&#xa0;days while mean length of hospital stay was 6.2&#x2009;&#xb1;&#x2009;1.27&#xa0;days. Only one patient died (3.3%). None of the patients reported adverse drug reaction due to NAC.<br><br>CONCLUSION: Majority of patients demonstrated marked clinical and biochemical improvements and they recovered fully. We observed faster and significant recovery of liver enzymes following administration of NAC. Based on the above findings, this study provides preliminary evidence for the beneficial effect of NAC in severe hepatitis in dengue infection with greater survival benefits.}, }
@article {pmid34544266, year = {2021}, author = {Maartens, M and Kruger, MJ and van de Vyver, M}, title = {The Effect of N-Acetylcysteine and Ascorbic Acid-2-Phosphate Supplementation on Mesenchymal Stem Cell Function in B6.C-Lep[ob]/J Type 2 Diabetic Mice.}, journal = {Stem cells and development}, volume = {30}, number = {23}, pages = {1179-1189}, doi = {10.1089/scd.2021.0139}, pmid = {34544266}, issn = {1557-8534}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Ascorbic Acid/pharmacology ; *Diabetes Mellitus, Experimental/metabolism ; *Diabetes Mellitus, Type 2/pathology ; Dietary Supplements ; Humans ; Male ; *Mesenchymal Stem Cells/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Phosphates ; Quality of Life ; }, abstract = {Diabetes is a complex multifactorial disorder associated with hyperglycemia, oxidative stress, and inflammation. The pathological microenvironment impairs mesenchymal stem cell (MSC) viability and dysregulates their proregenerative and immune-modulatory function causing maladaptive tissue damage. Targeting stem cells to protect them against impairment could thus delay the onset of complications and enhance the quality of life in diabetes mellitus patients. The aim of this study was to investigate the efficacy of N-acetylcysteine (NAC) and ascorbic-acid-2-phosphate (AAP) oral supplementation as preventative measure against MSC impairment. Healthy wild-type control (C57BL/6J) (male, n = 24) and obese diabetic (B6.C-Lep[ob]/J) (ob/ob) (male, n = 24) mice received either placebo or antioxidant (NAC/AAP) supplementation for a period of 6 weeks. Metabolic parameters (weight and blood glucose) and the oxidative status (serum total serum antioxidant capacity, malondialdehyde) of animals were assessed. At the end of the 6-week supplementation period, bone marrow MSCs were isolated and their functionality (growth rate, viability, adipogenesis, and osteogenesis) assessed ex vivo. Real time quantitative polymerase chain reaction microarray analysis was also performed to assess the expression of 84 genes related to oxidative stress in MSCs. Despite no change in the metabolic profile, NAC/AAP supplementation improved the antioxidant status of diabetic animals and reduced lipid peroxidation, which is indicative of cellular damage. NAC/AAP also improved the population doubling time of MSCs (first 6-days postisolation) and significantly downregulated the expression of two genes (Nox1 and Rag2) associated with oxidative stress compared to placebo treatment. Taken together, this study has shown reduced oxidative stress and improvements in MSC function following in vivo antioxidant supplementation in healthy control and type 2 diabetic mice.}, }
@article {pmid34541370, year = {2021}, author = {Lewis, JE and Poles, J and Shaw, DP and Karhu, E and Khan, SA and Lyons, AE and Sacco, SB and McDaniel, HR}, title = {The effects of twenty-one nutrients and phytonutrients on cognitive function: A narrative review.}, journal = {Journal of clinical and translational research}, volume = {7}, number = {4}, pages = {575-620}, pmid = {34541370}, issn = {2424-810X}, abstract = {BACKGROUND AND AIM: Brain health is becoming more important to the average person as the number of people with cognitive impairments, such as Alzheimer's disease (AD), is rising significantly. The current Food and Drug Administration-approved pharmacotherapeutics for dementia neither cure nor halt cognitive decline; they just delay the worsening cognitive impairment. This narrative review summarizes the effects of nutrients and phytonutrients on cognitive function.<br><br>METHODS: A comprehensive literature search of PubMed was performed to find clinical trials in humans that assessed the effects of nutrients and phytonutrients on cognitive function published in English between 2000 and 2021. Six independent reviewers evaluated the articles for inclusion in this review.<br><br>RESULTS: Ninety-six articles were summarized in this narrative review. In total 21 categories of nutrients and phytonutrients were included, i.e., &#x3b1;-lipoic acid, Bacopa monnieri, B vitamins, cholinergic precursors, vitamin D, vitamin E, Ginkgo biloba, ginseng, lion's mane mushroom, N-acetyl cysteine, omega-3 fatty acids, aloe polysaccharides, Rhodiola rosea, rosemary, saffron, tart cherries, turmeric, wild yam, Withania somnifera, xanthines, and zinc. Particular noteworthy effects on cognition included memory, recollection, attention, intelligence, vocabulary, recognition, response inhibition, arousal, performance enhancement, planning, creative thinking, reaction time, vigilance, task switching, orientation to time, place, and person, reading, writing, comprehension, accuracy, learning, information processing speed, executive function, mental flexibility, daily functioning, decrease in mental fatigue, and freedom from distractibility. Some nutrients and phytonutrients also improved mood and contentedness and reduced anxiety and the need for caregiving. These effects are not completely consistent or ubiquitous across all patient populations or health statuses. Adverse effects were minimal or nonexistent.<br><br>CONCLUSION: Due to the growing population of people with cognitive impairment and the lack of effective pharmacotherapeutics, it is prudent for those afflicted or their caregivers to find alternative treatments. Our narrative review shows that many of these nutrients and phytonutrients may be promising for treating some aspects of cognitive impairment, especially for people afflicted with AD.<br><br>RELEVANCE FOR PATIENTS: As demonstrated in a number of clinical trials, healthy adults and patients with various health challenges (e.g., AD, mild cognitive impairment, multiple sclerosis, and Parkinson's disease) exhibiting a wide range of severity in cognitive defects would be best served to consider multiple nutrients and phytonutrients to improve aspects of their cognitive function.}, }
@article {pmid34540868, year = {2021}, author = {Fukutsu, K and Murata, M and Kikuchi, K and Yoshida, S and Noda, K and Ishida, S}, title = {ROCK1 Mediates Retinal Glial Cell Migration Promoted by Acrolein.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {717602}, pmid = {34540868}, issn = {2296-858X}, abstract = {Objective: Acrolein is a highly reactive aldehyde that covalently binds to cellular macromolecules and subsequently modulates cellular function. Our previous study demonstrated that acrolein induces glial cell migration, a pathological hallmark of diabetic retinopathy; however, the detailed cellular mechanism remains unclear. The purpose of this study was to investigate the role of acrolein in retinal glial cell migration by focusing on rho-associated coiled-coil-containing protein kinases (ROCKs). Methods: Immunofluorescence staining for ROCK isoforms was performed using sections of fibrovascular tissue obtained from the eyes of patients with proliferative diabetic retinopathy (PDR). Rat retinal Müller glial cell line, TR-MUL5, was stimulated with acrolein and the levels of ROCK1 were evaluated using real-time PCR and western blotting. Phosphorylation of the myosin-binding subunit of myosin light chain phosphatase [myosin phosphatase target subunit 1, (MYPT1)] and myosin light chain 2 (MLC2) was assessed. The cell migration rate of TR-MUL5 cells exposed to acrolein and/or ripasudil, a non-selective ROCK inhibitor, was measured using the Oris cell migration assay. Results: ROCK isoforms, ROCK1 and ROCK2, were positively stained in the cytosol of glial cells in fibrovascular tissues. In TR-MUL5 cells, the mRNA expression level of Rock1, but not Rock2, was increased following acrolein stimulation. In line with the PCR data, western blotting showed increase in ROCK1 and cleaved ROCK1 protein in TR-MUL5 cells stimulated with acrolein. N-acetylcysteine (NAC) suppressed acrolein-associated Rock1 upregulation in TR-MUL5 cells. Acrolein augmented the phosphorylation of MYPT1 and MLC2 and increased the cell migration rate of TR-MUL5 cells, both of which were abrogated by ripasudil. Conclusions: Our study demonstrated that ROCK1 mediates the migration of retinal glial cells promoted by the unsaturated aldehyde acrolein.}, }
@article {pmid34536564, year = {2022}, author = {Li, HY and Tang, ZM and Wang, Z and Lv, JM and Liu, XL and Liang, YL and Cheng, B and Gao, N and Ji, SR and Wu, Y}, title = {C-Reactive Protein Protects Against Acetaminophen-Induced Liver Injury by Preventing Complement Overactivation.}, journal = {Cellular and molecular gastroenterology and hepatology}, volume = {13}, number = {1}, pages = {289-307}, pmid = {34536564}, issn = {2352-345X}, mesh = {Acetaminophen/adverse effects ; Animals ; C-Reactive Protein ; *Chemical and Drug Induced Liver Injury ; *Chemical and Drug Induced Liver Injury, Chronic ; Mice ; Mice, Inbred C57BL ; Rats ; }, abstract = {BACKGROUND AND AIMS: C-reactive protein (CRP) is a hepatocyte-produced marker of inflammation yet with undefined function in liver injury. We aimed to examine the role of CRP in acetaminophen-induced liver injury (AILI).<br><br>METHODS: The effects of CRP in AILI were investigated using CRP knockout mice and rats combined with human CRP rescue. The mechanisms of CRP action were investigated in&#xa0;vitro and in mice with Fc&#x3b3; receptor 2B knockout, C3 knockout, or hepatic expression of CRP mutants defective in complement interaction. The therapeutic potential of CRP was investigated by intraperitoneal administration at 2 or 6 hours post-AILI induction in wild-type mice.<br><br>RESULTS: CRP knockout exacerbated AILI in mice and rats, which could be rescued by genetic knock-in, adeno-associated virus-mediated hepatic expression or direct administration of human CRP. Mechanistically, CRP does not act via its cellular receptor Fc&#x3b3; receptor 2B to inhibit the early phase injury to hepatocytes induced by acetaminophen; instead, CRP acts via factor H to inhibit complement overactivation on already injured hepatocytes, thereby suppressing the late phase amplification of inflammation likely mediated by C3a-dependent actions of neutrophils. Importantly, CRP treatment effectively alleviated AILI with a significantly extended therapeutic time window than that of N-acetyl cysteine.<br><br>CONCLUSION: Our results thus identify CRP as a crucial checkpoint that limits destructive activation of complement in acute liver injury, and we argue that long-term suppression of CRP expression or function might increase the susceptibility to AILI.}, }
@article {pmid34534560, year = {2021}, author = {Gilardoni, M and Léonço, D and Caffin, F and Gros-Désormeaux, F and Eldin, C and Béal, D and Ouzia, S and Junot, C and Fenaille, F and Piérard, C and Douki, T}, title = {Evidence for the systemic diffusion of (2-chloroethyl)-ethyl-sulfide, a sulfur mustard analog, and its deleterious effects in brain.}, journal = {Toxicology}, volume = {462}, number = {}, pages = {152950}, doi = {10.1016/j.tox.2021.152950}, pmid = {34534560}, issn = {1879-3185}, mesh = {Administration, Cutaneous ; Animals ; Brain/*drug effects ; Chemical Warfare Agents/pharmacokinetics/*toxicity ; DNA Damage/*drug effects ; Glutathione/metabolism ; Metabolomics ; Mice ; Mice, Hairless ; Mustard Gas/administration &amp; dosage/*analogs &amp; derivatives/pharmacokinetics/toxicity ; Skin/metabolism ; Time Factors ; Tissue Distribution ; }, abstract = {Sulfur mustard, a chemical warfare agent known to be a vesicant of skin, readily diffuses in the blood stream and reaches internal organs. In the present study, we used the analog (2-chloroethyl)-ethyl-sulfide (CEES) to provide novel data on the systemic diffusion of vesicants and on their ability to induce brain damage, which result in neurological disorders. SKH-1 hairless mice were topically exposed to CEES and sacrificed at different time until 14 days after exposure. A plasma metabolomics study showed a strong systemic impact following a self-protection mechanism to alleviate the injury of CEES exposure. This result was confirmed by the quantification of specific biomarkers in plasma. Those were the conjugates of CEES with glutathione (GSH-CEES), cysteine (Cys-CEES) and N-acetyl-cysteine (NAC-CEES), as well as the guanine adduct (N7Gua-CEES). In brain, N7Gua-CEES could be detected both in DNA and in organ extracts. Similarly, GSH-CEES, Cys-CEES and NAC-CEES were present in the extracts until day14. Altogether, these results, based on novel exposure markers, confirm the ability of vesicants to induce internal damage following dermal exposure. The observation of alkylation damage to glutathione and DNA in brain provides an additional mechanism to the neurological insult of SM.}, }
@article {pmid34531444, year = {2021}, author = {Mukherjee, I and Dhar, R and Singh, S and Sharma, JB and Nag, TC and Mridha, AR and Jaiswal, P and Biswas, S and Karmakar, S}, title = {Oxidative stress-induced impairment of trophoblast function causes preeclampsia through the unfolded protein response pathway.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {18415}, pmid = {34531444}, issn = {2045-2322}, mesh = {Adult ; Biomarkers/metabolism ; Cell Differentiation/drug effects ; Cell Line ; Cell Movement/drug effects ; Endoribonucleases/metabolism ; Female ; Humans ; Hydrogen Peroxide/toxicity ; Models, Biological ; *Oxidative Stress/drug effects ; Pre-Eclampsia/*pathology ; Pregnancy ; Protein Serine-Threonine Kinases/metabolism ; Trophoblasts/drug effects/*pathology/ultrastructure ; *Unfolded Protein Response/drug effects ; X-Box Binding Protein 1/metabolism ; Young Adult ; }, abstract = {Pre-eclampsia (PE) is a pregnancy-specific disorder, characterized by hypertension and proteinuria. In PE, trophoblasts mediated inadequate remodeling of uterine spiral arteries seem to interrupt uteroplacental blood flow, one of the hallmarks in the early onset of PE (EO-PE). This, in turn, results in placental ischemia-reperfusion injury during hypoxia and reoxygenation episodes, leading to the generation of reactive oxygen species (ROS) and oxidative stress (OS). But still it is debatable if OS is a cause or consequence of PE. In this present study, we have investigated the effects of OS on PE placentae and trophoblast cell functions using BeWo and HTR8/SVneo cell lines. PE placental tissues showed abnormal ultrastructure, high level of reactive oxygen species (ROS) with altered unfolded protein responses (UPR) in compare with term placental tissues. Similar to PE placentae, during OS induction, the trophoblast cells showed altered invasion and migration properties with significantly variable expression of differentiation and invasion markers, e.g., syncytin and MMPs. The effect was rescued by antioxidant, N-acetyl cysteine, thereby implying a ROS-specific effect and in the trophoblast cells, OS triggers UPR pathway through IRE1α-XBP1 axis. Taken together, these findings highlight the harmful effect of unfolded protein response, which was induced due to OS on trophoblast cells and deformed invasion and differentiation programme and can be extended further to clinical settings to identify clinically approved antioxidants during pregnancy as a therapeutic measure to reduce the onset of PE.}, }
@article {pmid34530696, year = {2021}, author = {Zhu, QY and Tai, S and Tang, L and Xiao, YC and Tang, JJ and Chen, YQ and Shen, L and He, J and Ouyang, MQ and Zhou, SH}, title = {N-acetyl cysteine ameliorates aortic fibrosis by promoting M2 macrophage polarization in aging mice.}, journal = {Redox report : communications in free radical research}, volume = {26}, number = {1}, pages = {170-175}, pmid = {34530696}, issn = {1743-2928}, mesh = {*Acetylcysteine/pharmacology ; Aging ; Animals ; Aorta ; Fibrosis ; *Macrophages/pathology ; Mice ; Mice, Inbred C57BL ; }, abstract = {Background: Vascular fibrosis is a universal phenomenon associated with aging, and oxidative stress plays an important role in the genesis of vascular damage in line with the aging process. However, whether antioxidants can ameliorate vascular fibrosis remains unclear.Objectives: The present study was to determine antioxidant N-acetylcysteine (NAC) could ameliorates aortic fibrosis in aging wild-type C57BL/6 mice.Methods: The aortas were harvested from both 12-week and 60-week wild-type mice. The 60-week mice were treated with and without the NAC for 12 weeks starting at the age of 48 weeks. Hematoxylin and eosin (H&amp;E) staining and Masson's trichrome staining of aortic samples were performed, and the levels of reactive oxygen species (ROS), RNA expression of GAPDH, TNF-α, MCP-1, IL-6, IL-10, IL-4, SIRT-1, SIRT-3, FOXO-1, and macrophage polarization were determined.Results: There is a positive relationship between collagen deposition and the M1/M2 macrophage ratio in the aortic wall of aged wild-type C57BL/6 mice. The higher collagen area percentage in the aortas of 60-week-old mice than in 12-week-old mice was reversed by NAC. NAC could not impact the total number of macrophages, but partly promoted M2 macrophage polarization. By performing qRT-PCR using aortic samples from these mice, we identified that SIRT-1, SIRT-3, FOXO-1 could be somehow responsible for aging-related fibrosis.Conclusions: NAC ameliorates aortic fibrosis in aging wild type mice partly by promoting M2 macrophage polarization.}, }
@article {pmid34511825, year = {2021}, author = {Allen, BJW and Abu Shanab, AA and Anderson, MR and Fogden, EN}, title = {Recurrent Pyroglutamic Acidosis in the Context of Undiagnosed Liver Cirrhosis-A Case Report.}, journal = {Journal of clinical and experimental hepatology}, volume = {11}, number = {5}, pages = {623-627}, pmid = {34511825}, issn = {0973-6883}, abstract = {Metabolic associated fatty liver disease, previously known as nonalcoholic fatty liver disease, is the most common cause of chronic liver disease across all ethnic groups; however, it remains enormously underestimated.[1] [,] [2] Sepsis, hepatotoxic medications and malnutrition in the acute settings on top of unknown cirrhosis can lead to decompensation and various metabolic complications. Pyroglutamic acidosis is a rarely recognised cause for unexplained high anion gap metabolic acidosis that is felt to be frequently underdiagnosed. Particular patients at risk include women, the elderly, those on regular paracetamol and those suffering with malnourishment or sepsis. Other risk factors include alcohol abuse and chronic liver disease (3). We present the case of a patient with recurrent episodes of pyroglutamic acidosis and encephalopathy in the context of undiagnosed nonalcoholic fatty liver disease with cirrhosis.}, }
@article {pmid34511433, year = {2021}, author = {Tan, T and Fu, X and Qu, J and Zhang, M and Chen, H and Wang, Y and Wang, B and Li, J and Liu, J and Liu, P}, title = {2,5-dimethyl celecoxib induces apoptosis and autophagy via activation of ROS/JNK axis in nasopharyngeal carcinoma cells.}, journal = {Aging}, volume = {13}, number = {17}, pages = {21483-21496}, pmid = {34511433}, issn = {1945-4589}, mesh = {Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Celecoxib ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Nasopharyngeal Carcinoma/*pathology ; Nasopharyngeal Neoplasms/*pathology ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {2,5-dimethyl celecoxib (DMC), a close derivative of celecoxib, has also been reported to have anticancer effects. However, the effects and underlying molecular mechanisms of DMC with respect to nasopharyngeal carcinoma are still largely unknown. In this study, we present that DMC has displayed anticancer potency in nasopharyngeal carcinoma in vitro and in vivo. Mechanistically, we found DMC induced apoptosis and autophagy for anticancer therapy against nasopharyngeal carcinoma. Furthermore, DMC-induced autophagy could remarkably attenuate after the treatment of reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (SP). Taken together, these results suggested DMC induced apoptosis and autophagic death via activation of ROS/JNK axis in NPC cells, which providing us new insights into developing potential therapeutic agents for nasopharyngeal carcinoma patients.}, }
@article {pmid34510229, year = {2021}, author = {Li, Z and Chi, H and Zhu, W and Yang, G and Song, J and Mo, L and Zhang, Y and Deng, Y and Xu, F and Yang, J and He, Z and Yang, X}, title = {Cadmium induces renal inflammation by activating the NLRP3 inflammasome through ROS/MAPK/NF-κB pathway in vitro and in vivo.}, journal = {Archives of toxicology}, volume = {95}, number = {11}, pages = {3497-3513}, pmid = {34510229}, issn = {1432-0738}, support = {2018YFC1603101//national key r&amp;d program of china/ ; 2019B020210002//guangdong key r&amp;d program/ ; 81872642//national natural science foundation of china/ ; 82073599//national natural science foundation of china/ ; }, mesh = {Acute Kidney Injury/*chemically induced ; Animals ; Cadmium/*toxicity/urine ; Cell Line, Transformed ; Female ; Humans ; Inflammasomes ; Inflammation/*etiology ; Kidney/*drug effects/pathology ; Kidney Tubules, Proximal ; Mitogen-Activated Protein Kinase Kinases/metabolism ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Rats ; }, abstract = {Cadmium (Cd) has been reported to induce kidney damage by triggering oxidative stress and inflammation. The NLR family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated a role in the pathogenesis of inflammation. However, the connection between Cd and NLRP3 inflammasome in the development of renal inflammation remains unknown. In this study, in vitro experiments based on the telomerase-immortalized human renal proximal-tubule epithelial cell line (RPTEC/TERT1) were carried out. Results revealed that CdCl2 (2-8 μM) increased ROS production and activated NLRP3, thereby enhancing secretion of IL-1β and IL-18 (P < 0.05). Knock-down of NLRP3 rescued the RPTEC/TERT1 cells from Cd-induced inflammatory damage. Cd activated the MAPK/NF-κB signaling pathway in RPTEC/TERT1 cells (P < 0.05). In addition, treatment with N-acetylcysteine (NAC) improved inflammation and blocked the upregulation of the MAPK/NF-κB signaling pathway. Pre-treatment with MAPK and NF-κB inhibitors also suppressed NLRP3 inflammasome activation (P < 0.05). Moreover, CdCl2 (25-00 mg/L) stimulated the MAPK/NF-κB signaling pathway, activated the NLRP3 inflammasome, and increased inflammatory response (P < 0.05) leading to renal injury in rats. Exposure to cadmium elevated serum levels of NLRP3 and IL-1β in populations (P < 0.05). Further analysis found that serum NLRP3 and IL-1β levels were positively correlated with urine cadmium (UCd) and urine N-acetyl-β-D-glucosaminidase (UNAG). Overall, Cd induced renal inflammation through the ROS/MAPK/NF-κB signaling pathway by activating the NLRP3 inflammasome. Our research thus provides new insights into the molecular mechanism that NLRP3 contributes to Cd-induced kidney damage.}, }
@article {pmid34499870, year = {2021}, author = {Baron, JM and Heaney, DL and John, A and Fantz, CR}, title = {Real evidence to assess clinical testing interference risk (REACTIR): A strategy using real world data to assess the prevalence of interfering substances in patients undergoing clinical laboratory testing.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {523}, number = {}, pages = {178-184}, doi = {10.1016/j.cca.2021.09.001}, pmid = {34499870}, issn = {1873-3492}, mesh = {*Blood Glucose ; Humans ; Laboratories, Clinical ; *Point-of-Care Systems ; Point-of-Care Testing ; Prevalence ; }, abstract = {INTRODUCTION: Laboratory test interferences can cause spurious test results and patient harm. Knowing the frequency of various interfering substances in patient populations likely to be tested with a particular laboratory assay may inform test development, test utilization and strategies to mitigate interference risk.<br><br>METHODS: We developed REACTIR (Real Evidence to Assess Clinical Testing Interference Risk), an approach using real world data to assess the prevalence of various interfering substances in patients tested with a particular type of assay. REACTIR uses administrative real world data to identify and subgroup patient cohorts tested with a particular laboratory test and evaluate interference risk.<br><br>RESULTS: We demonstrate the application REACTIR to point of care (POC) blood glucose testing. We found that exposure to several substances with the potential to interfere in POC blood glucose tests, including N-acetyl cysteine (NAC) and high dose vitamin C was uncommon in most patients undergoing POC glucose tests with several key exceptions, such as burn patients receiving high dose IV-vitamin C or acetaminophen overdose patients receiving NAC.<br><br>CONCLUSIONS: Findings from REACTIR may support risk mitigation strategies including targeted clinician education and clinical decision support. Likewise, adaptations of REACTIR to premarket assay development may inform optimal assay design and assessment.}, }
@article {pmid34495252, year = {2021}, author = {Watanabe, M and Borges, FT and Pessoa, EA and Fonseca, CD and Fernandes, SM and Drew, RC and Volpini, RA and Vattimo, MFF}, title = {Renoprotective effect of N-acetylcysteine depends upon the severity of the ischemia reperfusion injury.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {54}, number = {11}, pages = {e9941}, pmid = {34495252}, issn = {1414-431X}, mesh = {Acetylcysteine/therapeutic use ; *Acute Kidney Injury/prevention &amp; control ; Animals ; Humans ; Kidney ; Oxidative Stress ; Rats ; Rats, Wistar ; *Reperfusion Injury/prevention &amp; control ; }, abstract = {Acute kidney injury (AKI) is a common complication in seriously ill patients, while renal ischemia-reperfusion (I/R) injury is the most frequent event in this oxidative renal injury. N-acetylcysteine (NAC) is a small molecule containing a thiol group that has antioxidant properties, promoting detoxification and acting directly as a free radical scavenger. In this study, the protective effect of NAC was investigated in short-term (30 min) and long-term (45 min) ischemic AKI. This was achieved via clamping of the renal artery for 30 or 45 min in Wistar rats to induce I/R injury. AKI worsened with a longer period of ischemia (45 compared to 30 min) due to probable irreversible damage. Preconditioning with NAC in short-term ischemia improved renal blood flow and increased creatinine clearance by reducing oxidative metabolites and increasing antioxidant capacity. Otherwise, NAC did not change these parameters in the long-term ischemia. Therefore, this study demonstrated that the period of ischemia determines the severity of the AKI, and NAC presented antioxidant effects in short-term ischemia but not in long-term ischemia, confirming that there is a possible therapeutic window for its renoprotective effect.}, }
@article {pmid34486746, year = {2021}, author = {Luo, G and Liu, J and Bian, T and Zhang, Z and Li, M}, title = {The mechanism of N-acetyl-l-cysteine in improving the secretion of porcine follicle-stimulating hormone in Pichia pastoris.}, journal = {Yeast (Chichester, England)}, volume = {38}, number = {11}, pages = {601-611}, doi = {10.1002/yea.3668}, pmid = {34486746}, issn = {1097-0061}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Follicle Stimulating Hormone ; Humans ; Pichia/genetics ; Saccharomycetales ; *Serum Albumin ; Swine ; }, abstract = {Our previous study revealed that N-acetyl-l-cysteine (NAC) could enhance the secretion of recombinant proteins by Pichia pastoris, but the corresponding molecular mechanisms are still unclear. In the present study, we explored whether other thiols have a similar action on the secretion of recombinant human serum albumin and porcine follicle-stimulating hormone fusion protein (HSA-pFSHβ), to reveal the mechanism of NAC on HSA-pFSHβ secretion. Transcriptome analysis showed that genes involved in oxidoreductase activity and oxidation-reduction process were upregulated in cells supplemented with NAC. The other three thiol-reducing regents including dimercaptopropanol (DT), thioglycolic acid, and mercaptolactic acid could improve HSA-pFSHβ production in the culture supernatant. Among them, only DT had similar effect as NAC on HSA-pFSHβ secretion and the increase of GSH content. Moreover, 1-20 mM GSH, 1-10 mM cysteine, or 1-20 mM N-acetyl-d-cysteine supplementation could improve the secretion of HSA-pFSHβ. Furthermore, 0.4-3.2 mM ethacrynic acid, rather than 1-16 mM BSO could inhibit the effect of NAC on the production of HSA-pFSHβ. These results indicated that NAC improved the secretion of HSA-pFSHβ by increasing the intracellular GSH content through its thiol activity rather than as a precursor for GSH synthesis. In conclusion, our results demonstrate, for the first time, that the secretion of recombinant HSA-pFSHβ in Pichia pastoris could be improved through thiol-reducing agent supplementation, and the mechanism of the effect NAC has on HSA-pFSHβ secretion is associated with improving the intracellular GSH content.}, }
@article {pmid34482039, year = {2021}, author = {Darvishi, FZ and Saadat, M}, title = {Morphine treatment is associated with diminished telomere length together with down-regulated TERT and TERF2 mRNA levels.}, journal = {Drug and alcohol dependence}, volume = {227}, number = {}, pages = {108982}, doi = {10.1016/j.drugalcdep.2021.108982}, pmid = {34482039}, issn = {1879-0046}, mesh = {Down-Regulation ; Humans ; Morphine/pharmacology ; RNA, Messenger/genetics ; *Telomerase/genetics/metabolism ; *Telomere/genetics/metabolism ; Telomeric Repeat Binding Protein 2 ; }, abstract = {BACKGROUND: Drug dependence promotes accelerated aging and higher mortality compare with the general population. Telomere length is a biomarker of determination of cellular aging. Telomere attrition has been reported in heroin dependent patients. To investigate whether telomere length is affected by morphine or not, the expressions of hTERT and TERF2 in morphine treated human SH-SY5Y cells were determined and compared with untreated cells.<br><br>METHODS: The SH-SY5Y cells were treated with 1 and 5&#x2009;&#x3bc;M concentrations of morphine for different exposure times (1d, 2d, 3d, 7d and 60 days). The mRNA levels of hTERT and TERF2 were determined using quantitative real-time RCR. The relative telomere length was measured as the ratio of telomere/36B4.<br><br>RESULTS: The hTERT and TERF2 mRNA levels were down regulated in morphine treated cells as a function of exposure duration. These alterations were reversible if morphine was removed from the culture medium. No reduction in the relative expression of hTERT and TERF2 in the cells exposed to N-acetyl cysteine (NAC) plus morphine was observed. In the SH-SY5Y cells treated by 5&#x2009;&#x3bc;M morphine for 60 consecutive days, the hTERT and TERF2 mRNA levels and relative telomere lengths remarkably decreased.<br><br>CONCLUSIONS: Reversible alteration of mRNA levels by removing morphine from culture medium, and effect of NAC in co-treatment of morphine plus NAC, emphasize the role of reactive oxygen species in down-regulation of the expression of hTERT and TERF2 by morphine. Telomere attrition in morphine treated cells is a consequence of down-regulation of the expression of hTERT and TERF2.}, }
@article {pmid34481340, year = {2021}, author = {Hung, SY and Chen, WF and Lee, YC and Su, JH and Juan, YS and Lin, IP and Zhang, YH and Chang, MK and Lin, MY and Chen, CY and Lee, CH}, title = {Rhopaloic acid A induces apoptosis, autophagy and MAPK activation through ROS-mediated signaling in bladder cancer.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {92}, number = {}, pages = {153720}, doi = {10.1016/j.phymed.2021.153720}, pmid = {34481340}, issn = {1618-095X}, mesh = {Animals ; Apoptosis ; Autophagy ; Cell Line, Tumor ; Cell Proliferation ; Humans ; MAP Kinase Signaling System ; Male ; Pyrans ; Reactive Oxygen Species ; *Urinary Bladder Neoplasms/drug therapy ; Zebrafish ; }, abstract = {BACKGROUND: Bladder cancer (BC) is a very common type of malignant cancer in men and new therapeutic strategies are urgently needed to reduce mortality. Several studies have demonstrated that Rhopaloic acid A (RA), a compound isolated from marine sponges, fights cancer but its potential anti-tumor effect on BC is still unknown.<br><br>PURPOSE: The present study was aimed to explore the potential anti-tumor effects of RA against human BC cells and the underlying molecular mechanism.<br><br>METHODS: Cell cytotoxicity was determined using the MTT and colony formation assays. Cell cycle distribution, apoptosis induction and generation of mitochondrial reactive oxygen species (ROS) were analyzed by flow cytometry. Mitochondrial membrane potential, acridine orange&#xa0;staining and intracellular ROS levels were observed using fluorescence microscopy. Levels of various signaling proteins were assessed using Western blotting. Furthermore, a zebrafish BC xenotransplantation model was used to confirm the anti-tumor effect of RA in vivo.<br><br>RESULTS: Treatment with RA significantly suppressed the proliferation of BC cells that resulted from G2/M cycle arrest. Additionally, RA induced mitochondrial-mediated apoptosis and autophagy in BC cells. The death of BC cells induced by RA was rescued by treatment with inhibitors of apoptosis (Z-VAD-FMA) or autophagy (3-MA). RA activated the MAPK pathway and increased the production of cellular and mitochondrial ROS. Treatment with the ROS scavenger N-acetyl cysteine, effectively reversed the induction of apoptosis, autophagy, JNK activation and DNA damage elicited by RA.&#xa0;Finally, RA significantly inhibited tumor growth in a zebrafish BC xenotransplantation model.<br><br>CONCLUSION: Taken together, our findings indicate that RA induces apoptosis and autophagy and activates the MAPK pathway through ROS-mediated signaling in human BC cells. This RA-induced pathway offers insights into the molecular mechanism of its antitumor effect and shows that RA is a promising candidate for the treatment of BC.}, }
@article {pmid34481041, year = {2021}, author = {Atlas, D}, title = {Emerging therapeutic opportunities of novel thiol-amides, NAC-amide (AD4/NACA) and thioredoxin mimetics (TXM-Peptides) for neurodegenerative-related disorders.}, journal = {Free radical biology &amp; medicine}, volume = {176}, number = {}, pages = {120-141}, doi = {10.1016/j.freeradbiomed.2021.08.239}, pmid = {34481041}, issn = {1873-4596}, mesh = {Acetylcysteine/analogs &amp; derivatives ; Amides ; Humans ; *Neurodegenerative Diseases/drug therapy ; Peptides ; *Sulfhydryl Compounds ; Thioredoxins ; }, abstract = {Understanding neurodegenerative diseases have challenged scientists for decades. It has become apparent that a decrease in life span is often correlated with the development of neurodegenerative disorders. Oxidative stress and the subsequent inflammatory damages appear to contribute to the different molecular and biochemical mechanisms associated with neurodegeneration. In this review, I examine the protective properties of novel amino acid based compounds, comprising the AD series (AD1-AD7) in particular N-acetylcysteine amide, AD4, also called NACA, and the series of thioredoxin mimetic (TXM) peptides, TXM-CB3-TXM-CB16. Designed to cross the blood-brain-barrier (BBB) and permeate the cell membrane, these antioxidant/anti-inflammatory compounds may enable effective treatment of neurodegenerative related disorders. The review addresses the molecular mechanism of cellular protection exhibited by these new reagents, focusing on the reversal of oxidative stress, mitochondrial stress, inflammatory damages, and prevention of premature cell death. In addition, it will cover the outlook of the clinical prospects of AD4/NACA and the thioredoxin-mimetic peptides, which are currently in development.}, }
@article {pmid34479835, year = {2021}, author = {Han, S and Lim, JH and Bang, J and Cho, JH}, title = {Use of a combination of N-acetylcysteine and clonazepam to treat burning mouth syndrome.}, journal = {Oral surgery, oral medicine, oral pathology and oral radiology}, volume = {132}, number = {5}, pages = {532-538}, doi = {10.1016/j.oooo.2021.07.016}, pmid = {34479835}, issn = {2212-4411}, mesh = {Acetylcysteine/therapeutic use ; *Burning Mouth Syndrome/drug therapy ; *Clonazepam ; Humans ; Quality of Life ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: This study was intended to evaluate the clinical efficacy of a combination of N-acetylcysteine (NAC) and clonazepam for treatment of burning mouth syndrome (BMS).<br><br>STUDY DESIGN: A total of 160 patients with BMS were divided into 3 groups: group 1 received NAC (400 mg/d), group 2 received clonazepam (0.5 mg/d), and group 3 received both NAC and clonazepam. We evaluated symptom relief after 8 weeks of treatment using a visual analog scale (VAS). To assess oral health-related quality of life, we used the validated Korean version of an oral health impact profile (OHIP-14K).<br><br>RESULTS: The overall response rates of the 3 groups were 60.3%, 51.3%, and 80.0%, respectively. The mean VAS and OHIP-14K scores significantly decreased in all groups after the 8-week treatments. The VAS score changes were -12.2 &#xb1; 19.5, -10.0 &#xb1; 14.1, and -21.0 &#xb1; 24.6, respectively (P&#x202f;=&#x202f;.001), in the 3 groups and the OHIP-14K changes were -2.3 &#xb1; 9.2, -4.4 &#xb1; 6.9, and -8.7 &#xb1; 10.3, respectively (P&#x202f;=&#x202f;.020). Group 3 showed significantly larger differences in VAS and OHIP-14K scores than group 2, before and after treatment.<br><br>CONCLUSIONS: In the treatment of BMS, the NAC/clonazepam combination therapy was more effective than either monotherapy.}, }
@article {pmid34479474, year = {2021}, author = {Zhu, L and Xu, F and Kang, X and Zhou, J and Yao, Q and Lin, Y and Zhang, W}, title = {The antioxidant N-acetylcysteine promotes immune response and inhibits epithelial-mesenchymal transition to alleviate pulmonary fibrosis in chronic obstructive pulmonary disease by suppressing the VWF/p38 MAPK axis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {27}, number = {1}, pages = {97}, pmid = {34479474}, issn = {1528-3658}, mesh = {Antioxidants/*pharmacology ; Biomarkers ; Disease Susceptibility ; Epithelial-Mesenchymal Transition/*drug effects ; Humans ; Immunomodulation/*drug effects ; Pulmonary Disease, Chronic Obstructive/diagnosis/*etiology/*metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/*metabolism ; von Willebrand Factor/*metabolism ; }, abstract = {BACKGROUND/AIM: N-Acetylcysteine (NAC) demonstrates applications in the prevention of exacerbation of chronic obstructive pulmonary disease (COPD). COPD is often characterized by fibrosis of the small airways. This study aims at investigating the physiological mechanisms by which NAC might mediate the pulmonary fibrosis in COPD.<br><br>METHODS: A total of 10 non-smokers without COPD and 10 smokers with COPD were recruited in this study, and COPD rat models were established. Cigarette smoke extract (CSE) cell models were constructed. The gain- or loss-of-function experiments were adopted to determine the expression of VWF and the extent of p38 MAPK phosphorylation, levels of interleukin-6 (IL-6), tumor necrosis factor-&#x3b1; (TNF-&#x3b1;), and immunoglobulins (IgG, IgM and IgA) in the serum of COPD rats and supernatant of alveolar epithelial cells and to detect cell invasion and migration and the ratio of CD3[+], CD4[+], CD8[+] and CD4[+]/CD8[+]T lymphocytes.<br><br>RESULTS: Expression of VWF and the extent of p38 MAPK phosphorylation were increased in COPD. NAC inhibited p38 MAPK phosphorylation by reducing the VWF expression. NAC could inhibit cell migration and invasion, elevate E-cadherin expression, the ratio of CD3[+], CD4[+], CD8[+] and CD4[+]/CD8[+]T lymphocytes, and levels of IgG, IgA, and IgM, and reduce N-cadherin expression and levels of IL-6 and TNF-&#x3b1; in CSE cells and serum of COPD rats. NAC promoted immune response and suppressed epithelial-mesenchymal transformation (EMT) to relieve COPD-induced pulmonary fibrosis in vitro and in vivo by inhibiting the VWF/p38 MAPK axis.<br><br>CONCLUSIONS: Collectively, NAC could ameliorate COPD-induced pulmonary fibrosis by promoting immune response and inhibiting EMT process via the VWF/p38 MAPK axis, therefore providing us with a potential therapeutic target for treating COPD.}, }
@article {pmid34478974, year = {2021}, author = {Yang, X and Liu, P and Zhang, X and Zhang, J and Cui, Y and Song, M and Li, Y}, title = {T-2 toxin causes dysfunction of Sertoli cells by inducing oxidative stress.}, journal = {Ecotoxicology and environmental safety}, volume = {225}, number = {}, pages = {112702}, doi = {10.1016/j.ecoenv.2021.112702}, pmid = {34478974}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Humans ; Leydig Cells ; Male ; Oxidative Stress ; Sertoli Cells ; *T-2 Toxin/toxicity ; }, abstract = {T-2 toxin is an inevitable mycotoxin in food products and feeds. It is a proven toxicant impairing the male reproductive system. However, previous studies have concentrated on the toxic effect of T-2 toxin on Leydig cells, with little attention on the Sertoli cell cytotoxicity. Therefore, this study aimed to establish the toxic mechanism of T-2 toxin on Sertoli cells. The Sertoli cell line (TM4 cell) was cultured and exposed to different concentrations of T-2 toxin with/without N-acetyl-L-cysteine (NAC) for 24 h. A CCK-8 assay then measured the cell viability. In addition, the expression of TM4 cell biomarkers (FSHR and ABP) and functional factors (occludin (Ocln), zonula occluden-1 (ZO-1), Connexin 43 (Cx-43), and N-Cadherin (N-cad)) were measured by qRT-PCR and Western blotting. The oxidative stress status (ROS, MDA, CAT, and SOD) and apoptosis rate, including the caspase-9, 8, and 3 activities in TM4 cells, were analyzed. We established that (1): T-2 toxin decreased TM4 cells viability and the half-maximal inhibitory concentration was 8.10 nM. (2): T-2 toxin-induced oxidative stress, evidenced by increased ROS and MDA contents, and inhibited CAT and SOD activities. (3): T-2 toxin inhibited FSHR, ABP, ocln, ZO-1, Cx-43, and N-Cad expressions. (4): T-2 toxin promoted TM4 cell apoptosis and caspase-9, 8, and 3 activities. (5): N-acetyl-L-cysteine relieved oxidative stress, functional impairment, and apoptosis in TM4 cells treated with T-2 toxin. Thus, T-2 toxin induced TM4 cell dysfunction through ROS-induced apoptosis.}, }
@article {pmid34478011, year = {2021}, author = {Mohammadlou, H and Hamzeloo-Moghadam, M and Mohammadi, MH and Yami, A and Gharehbaghian, A}, title = {Britannin, a sesquiterpene lactone induces ROS-dependent apoptosis in NALM-6, REH, and JURKAT cell lines and produces a synergistic effect with vincristine.}, journal = {Molecular biology reports}, volume = {48}, number = {9}, pages = {6249-6258}, pmid = {34478011}, issn = {1573-4978}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/isolation &amp; purification/*pharmacology ; Apoptosis/*drug effects ; Catharanthus/*chemistry ; Cell Survival/drug effects ; Drug Synergism ; Free Radical Scavengers/pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Inula/*chemistry ; Jurkat Cells ; Lactones/isolation &amp; purification/*pharmacology ; Leukocytes, Mononuclear/drug effects/metabolism ; Phytochemicals/isolation &amp; purification/*pharmacology ; Plant Extracts/isolation &amp; purification/*pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/isolation &amp; purification/*pharmacology ; Signal Transduction/drug effects ; Vincristine/*pharmacology ; }, abstract = {BACKGROUND: Britannin, a Sesquiterpene Lactone isolated from Inula aucheriana, has recently gained attraction in the therapeutic fields due to its anti-tumor properties. This study was designed to evaluate the effect of this agent on Acute Lymphoblastic Leukemia (ALL) cell lines, either as a monotherapy or in combination with Vincristine (VCR).<br><br>METHODS AND RESULTS: To determine the anti-leukemic effects of Britannin on ALL-derived cell lines and suggest a mechanism of action for the agent, we used MTT assay, Annexin-V/PI staining, ROS assay, and real-time PCR analysis. Moreover, by using a combination index (CI), we evaluated the synergistic effect of Britannin on Vincristine. We found that unlike normal Peripheral Blood Mononuclear Cells (PBMCs) and L929 cells, Britannin reduced the viability of NALM-6, REH, and JURKAT cells. Among tested cells, NALM-6 cells had the highest sensitivity to Britannin, and this agent was able to induce p21/p27-mediated G1 cell cycle arrest and Reactive Oxygen Specious (ROS)-mediated apoptotic cell death in this cell line. When NALM-6 cells were treated with Nacetyl-L-Cysteine (NAC), a scavenger of ROS, Britannin could induce neither apoptosis nor reduce the survival of the cells suggesting that the cytotoxic effect of Britannin is induced through ROS-dependent manner. Moreover, we found that a low dose of Britannin enhanced the effect of Vincristine in NALM-6 cells by inducing apoptotic cell death via altering the expression of apoptotic-related genes.<br><br>CONCLUSIONS: Overall, our results proposed a mechanism for the cytotoxic effect of Britannin, either as a single agent or in combination with Vincristine, in NALM-6 cells.}, }
@article {pmid34474340, year = {2021}, author = {Liang, Y and Du, R and Chen, R and Chu, PH and Ip, MSM and Zhang, KYB and Mak, JCW}, title = {Therapeutic potential and mechanism of Dendrobium officinale polysaccharides on cigarette smoke-induced airway inflammation in rat.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {143}, number = {}, pages = {112101}, doi = {10.1016/j.biopha.2021.112101}, pmid = {34474340}, issn = {1950-6007}, mesh = {Animals ; Antioxidants/isolation &amp; purification/*pharmacology ; *Dendrobium/chemistry ; Disease Models, Animal ; Inflammation Mediators/metabolism ; Lung/*drug effects/immunology/metabolism ; Male ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Phosphorylation ; Plant Extracts/isolation &amp; purification/*pharmacology ; Pneumonia/etiology/immunology/metabolism/*prevention &amp; control ; Polysaccharides/isolation &amp; purification/*pharmacology ; Rats, Sprague-Dawley ; Signal Transduction ; Smoke/*adverse effects ; Tobacco Products/*adverse effects ; Rats ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is among the leading causes of death worldwide, and is characterized by persistent respiratory symptoms and airflow limitation due to chronic airway inflammation. Cigarette smoking is a major risk factor for COPD. This study aims to determine the therapeutic effects of polysaccharides extracted from Dendrobium officinale (DOPs), a valuable traditional Chinese Medicinal herb, on cigarette smoke (CS)-induced airway inflammation in a rat passive smoking model. Male Sprague-Dawley rats were exposed to CS or sham air (SA) as control for a 56-day period. On Day 29, rats were subdivided and given water, DOPs or N-acetylcysteine (NAC) via oral gavage on a daily basis for the remaining duration. DOPs reduced CS-induced oxidative stress as evidenced by reducing malondialdehyde (MDA) levels in the lung. DOPs also exerted potent anti-inflammatory properties as evidenced by a reduction in the number of lymphocytes and monocytes in serum, significantly attenuating infiltration of inflammatory cells in lung tissue, as well as pro-inflammatory mediators in serum, bronchoalveolar lavage (BAL) and lung. Additionally, DOPs inhibited the CS-induced activation of ERK, p38 MAPK and NF-κB signaling pathways. These findings suggest that DOPs may have potentially beneficial effects in limiting smoking-related lung oxidative stress, and inflammation mediated via the inhibition of MAPK and NF-κB signaling pathways in smokers, without or with COPD.}, }
@article {pmid34466155, year = {2021}, author = {Jang, JH and Lee, TJ and Sung, EG and Song, IH and Kim, JY}, title = {Pioglitazone mediates apoptosis in Caki cells via downregulating c-FLIP(L) expression and reducing Bcl-2 protein stability.}, journal = {Oncology letters}, volume = {22}, number = {4}, pages = {743}, pmid = {34466155}, issn = {1792-1082}, abstract = {Pioglitazone is an anti-diabetic agent used in the treatment of type 2 diabetes, which belongs to the thiazolidinediones (TZDs) group. TZDs target peroxisome proliferator-activated receptor γ (PPARγ), which functions as a transcription factor of the nuclear hormone receptor. Pioglitazone has antitumor effects in several cancer types and could be a tool for drug therapy in various cancer treatments. Nevertheless, the molecular basis for pioglitazone-induced anticancer effects in renal cancer (RC) has not yet been elucidated. Thus, the aim of the present study was to investigate the detailed signaling pathway underlying pioglitazone-induced apoptosis in Caki cells derived from human clear cell renal cell carcinoma. As a result, it was demonstrated by flow cytometry analysis and Annexin V-propidium iodide staining that pioglitazone treatment induced apoptotic cell death in a dose-dependent manner in Caki cells. The protein expression levels of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP)(L) and Bcl-2, which were determined by western blotting, decreased after pioglitazone treatment in Caki cells. Flow cytometry and western blot analyses demonstrated that pioglitazone-mediated apoptosis was blocked following pretreatment with the pan-caspase inhibitor, z-VAD-fmk, indicating that pioglitazone-induced apoptosis was mediated via a caspase-dependent signaling pathway. However, the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), did not affect pioglitazone-mediated apoptosis and degradation of c-FLIP(L) and Bcl-2 protein. Of note, it was found by western blot analysis that Bcl-2 protein expression was downregulated by the decreased protein stability of Bcl-2 in pioglitazone-treated Caki cells. In conclusion, these findings indicated that pioglitazone-induced apoptosis is regulated through caspase-mediated degradation of FLIP(L) and reduction of Bcl-2 protein stability, suggesting that pioglitazone is a feasible apoptotic agent that could be used in the treatment of human RC.}, }
@article {pmid34464076, year = {2021}, author = {Pinto, RM and Monteiro, C and Costa Lima, SA and Casal, S and Van Dijck, P and Martins, MCL and Nunes, C and Reis, S}, title = {N-Acetyl-l-cysteine-Loaded Nanosystems as a Promising Therapeutic Approach Toward the Eradication of Pseudomonas aeruginosa Biofilms.}, journal = {ACS applied materials &amp; interfaces}, volume = {13}, number = {36}, pages = {42329-42343}, doi = {10.1021/acsami.1c05124}, pmid = {34464076}, issn = {1944-8252}, mesh = {Acetylcysteine/chemistry/toxicity ; Animals ; Anti-Bacterial Agents/chemistry/*pharmacology/toxicity ; Biofilms/*drug effects ; Cell Line ; Drug Carriers/chemistry/*pharmacology/toxicity ; Drug Synergism ; Humans ; Liposomes/*chemistry/toxicity ; Mice ; Microbial Sensitivity Tests ; Moxifloxacin/pharmacology ; Nanoparticles/*chemistry/toxicity ; Palmitates/chemistry/toxicity ; Phosphatidylethanolamines/chemistry/toxicity ; Polyethylene Glycols/chemistry/toxicity ; Pseudomonas aeruginosa/*drug effects/physiology ; }, abstract = {Bacterial biofilms are a major health concern, mainly due to their contribution to increased bacterial resistance to well-known antibiotics. The conventional treatment of biofilms represents a challenge, and frequently, eradication is not achieved with long-lasting administration of antibiotics. In this context, the present work proposes an innovative therapeutic approach that is focused on the encapsulation of N-acetyl-l-cysteine (NAC) into lipid nanoparticles (LNPs) functionalized with d-amino acids to target and disrupt bacterial biofilms. The optimized formulations presented a mean hydrodynamic diameter around 200 nm, a low polydispersity index, and a high loading capacity. These formulations were stable under storage conditions up to 6 months. In vitro biocompatibility studies showed a low cytotoxicity effect in fibroblasts and a low hemolytic activity in human red blood cells. Nevertheless, unloaded LNPs showed a higher hemolytic potential than NAC-loaded LNPs, which suggests a safer profile of the latter. The in vitro antibiofilm efficacy of the developed formulations was tested against Staphylococcus epidermidis (Gram-positive) and Pseudomonas aeruginosa (Gram-negative) mature biofilms. The results showed that the NAC-loaded LNPs were ineffective against S. epidermidis biofilms, while a significant reduction of biofilm biomass and bacterial viability in P. aeruginosa biofilms were observed. In a more complex therapeutic approach, the LNPs were further combined with moxifloxacin, revealing a beneficial effect between the LNPs and the antibiotic against P. aeruginosa biofilms. Both alone and in combination with moxifloxacin, unloaded and NAC-loaded LNPs functionalized with d-amino acids showed a great potential to reduce bacterial viability, with no significant differences in the presence or absence of NAC. However, the presence of NAC in NAC-loaded functionalized LNPs shows a safer profile than the unloaded LNPs, which is beneficial for an in vivo application. Overall, the developed formulations present a potential therapeutic approach against P. aeruginosa biofilms, alone or in combination with antibiotics.}, }
@article {pmid34456713, year = {2021}, author = {Ruiz-Torres, V and Forsythe, N and Pérez-Sánchez, A and Van Schaeybroeck, S and Barrajón-Catalán, E and Micol, V}, title = {A Nudibranch Marine Extract Selectively Chemosensitizes Colorectal Cancer Cells by Inducing ROS-Mediated Endoplasmic Reticulum Stress.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {625946}, pmid = {34456713}, issn = {1663-9812}, abstract = {The present study shows the putative antiproliferative mechanism of action of the previously analytically characterized nudibranch extract (Dolabella auricularia, NB) and its different effects in colon cancer cells vs. nontumor colon cells. NB extract increased the accumulation of reactive oxygen species (ROS) and increased endoplasmic reticulum (ER) stress via stimulation of the unfolded protein response. Stress scavengers, N-acetylcysteine (NAC) and 4-phenylbutyric acid (4-PBA), decreased the stress induced by NB. The results showed that NB extract increased ER stress through overproduction of ROS in superinvasive colon cancer cells, decreased their resistance threshold, and produced a nonreturn level of ER stress, causing DNA damage and cell cycle arrest, which prevented them from achieving hyperproliferative capacity and migrating to and invading other tissues. On the contrary, NB extract had a considerably lower effect on nontumor human colon cells, suggesting a selective effect related to stress balance homeostasis. In conclusion, our results confirm that the growth and malignancy of colon cancer cells can be decreased by marine compounds through the modification of one of the most potent resistance mechanisms present in tumor cells; this characteristic differentiates cancer cells from nontumor cells in terms of stress balance.}, }
@article {pmid34455951, year = {2022}, author = {Rashid, M and Chandran, VP and Nair, S and Muthu, DS and Pappuraj, J and Jacob, KA and Sridhar, B and Mark, K and Hyder, S and Khan, S and Thunga, G}, title = {N-Acetyl Cysteine in Rodenticide Poisoning: A Systematic Review and Meta-Analysis.}, journal = {Current reviews in clinical and experimental pharmacology}, volume = {17}, number = {3}, pages = {192-204}, doi = {10.2174/2772432816666210825102726}, pmid = {34455951}, issn = {2772-4336}, mesh = {Acetylcysteine/therapeutic use ; Humans ; Prospective Studies ; Retrospective Studies ; *Rodenticides ; }, abstract = {BACKGROUND: Treatment with N-Acetyl Cysteine (NAC) in rodenticide poisoning has not been well established due to mixed study results and insufficient evidence. This review aimed to summarize the clinical benefits of NAC in the management of rodenticide poisoning.<br><br>METHODS: This review follows the PICOS framework and the PRISMA guidelines. Pub- Med/MEDLINE, Scopus, and the Cochrane library were searched to identify the published literature from inception to September 2020, and a reference search was performed for additional relevant studies. The English language studies addressing the use of NAC in rodenticide poisoning were considered for the review. We considered all experimental and observational studies due to the insufficient number of interventional studies.<br><br>RESULTS: Ten studies (two RCTs, four observational, and four descriptive) out of 2,178 studies with 492 participants were considered for the review. Only six studies (two RCTs, one prospective, and three retrospective studies) reported recovery and mortality. Pooled results of RCTs (n=2) showed a significant recovery rate (Odds Ratio [OR]: 3.97; 95% Confidence Interval [CI]:1.69-9.30), whereas summary estimates of prospective and retrospective studies recorded a non-significant effect. Metaanalysis of RCTs (OR: 0.25; 95% CI: 0.11-0.59; n=2) and retrospective studies (OR: 0.34; 95% CI: 0.15-0.78; n=3) showed a significant reduction in mortality, whereas pooled analysis of prospective studies recorded a non-significant effect. A significant reduction in intubation or ventilation (OR: 0.25; 95% CI: 0.11-0.60; 2 RCTs) and a non-significant (P=0.41) difference in duration of hospitalization was observed with NAC when compared to the non-NAC treated group. The quality of the included studies appeared to be moderate to high.<br><br>CONCLUSION: Our findings indicate that NAC showed better survival and lower mortality rate when compared to non-NAC treated group; hence NAC can be considered for the management of rodenticide poisoning.}, }
@article {pmid34454534, year = {2021}, author = {Yang, M and Luo, Q and Chen, X and Chen, F}, title = {Bitter melon derived extracellular vesicles enhance the therapeutic effects and reduce the drug resistance of 5-fluorouracil on oral squamous cell carcinoma.}, journal = {Journal of nanobiotechnology}, volume = {19}, number = {1}, pages = {259}, pmid = {34454534}, issn = {1477-3155}, support = {81803088//National Natural Science Foundation of China/ ; 81870762//National Natural Science Foundation of China/ ; 20ZR1431500//Natural Science Foundation of Shanghai/ ; 19YF1427500//Shanghai Sailing Program/ ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*drug therapy ; Cell Cycle ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/*drug effects ; Extracellular Vesicles/*metabolism ; Fluorouracil/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Head and Neck Neoplasms/drug therapy ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Momordica charantia/*metabolism ; Mouth Neoplasms/*drug therapy ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Squamous Cell Carcinoma of Head and Neck/*drug therapy ; }, abstract = {BACKGROUND: Plant-derived extracellular vesicles (PDEVs) have been exploited for cancer treatment with several benefits. Bitter melon is cultivated as a vegetable and folk medicine with anticancer and anti-inflammatory activities. 5-Fluorouracil (5-FU) is widely used for cancer treatment. However, 5-FU-mediated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammation activation induced the resistance of oral squamous cell carcinoma (OSCC) cells to 5-FU. In this study, we explored the potential of bitter melon-derived extracellular vesicles (BMEVs) for enhancing the therapeutic efficacy and reduce the resistance of OSCC to 5-FU.<br><br>RESULTS: Herein, we demonstrate that bitter melon derived extracellular vesicles (BMEVs), in addition to their antitumor activity against OSCC have intrinsic anti-inflammatory functions. BMEVs induced S phase cell cycle arrest and apoptosis. Apoptosis induction was dependent on reactive oxygen species (ROS) production and JUN protein upregulation, since pretreatment with N-acetyl cysteine or catechin hydrate could prevent apoptosis and JUN accumulation, respectively. Surprisingly, BMEVs significantly downregulated NLRP3 expression, although ROS plays a central role in NLRP3 activation. We further assessed the underlying molecular mechanism and proposed that the RNAs of BMEVs, at least in part, mediate anti-inflammatory bioactivity. In our previous studies, NLRP3 activation contributed to the resistance of OSCC cells to 5-FU. Our data clearly indicate that BMEVs could exert a remarkable synergistic therapeutic effect of 5-FU against OSCC both in vitro and in vivo. Most notably, NLRP3 downregulation reduced the resistance of OSCC to 5-FU.<br><br>CONCLUSIONS: Together, our findings demonstrate a novel approach to enhance the therapeutic efficacy and reduce the drug resistance of cancer cells to chemotherapeutic agents, which provides proof-of-concept evidence for the future development of PDEVs-enhanced therapy.}, }
@article {pmid34453856, year = {2022}, author = {Chi, RF and Li, L and Wang, AL and Yang, H and Xi, J and Zhu, ZF and Wang, K and Li, B and Yang, LG and Qin, FZ and Zhang, C}, title = {Enhanced oxidative stress mediates pathological autophagy and necroptosis in cardiac myocytes in pressure overload induced heart failure in rats.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {49}, number = {1}, pages = {60-69}, doi = {10.1111/1440-1681.13583}, pmid = {34453856}, issn = {1440-1681}, support = {//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Autophagy/drug effects ; Blood Pressure ; Echocardiography ; Heart Failure/metabolism/*pathology/physiopathology ; Male ; Myocytes, Cardiac/drug effects/metabolism/*pathology/physiology ; *Necroptosis/drug effects ; *Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Ventricular Dysfunction, Left ; }, abstract = {In cardiac myocytes in vitro, hydrogen peroxide induces autophagic cell death and necroptosis. Oxidative stress, myocyte autophagy and necroptosis coexist in heart failure (HF). In this study, we tested the hypothesis that excessive oxidative stress mediates pathological autophagy and necroptosis in myocytes in pressure overload-induced HF. HF was produced by chronic pressure overload induced by abdominal aortic constriction (AAC) in rats. Rats with AAC or sham operation were randomised to orally receive an antioxidant N-acetylcysteine (NAC) or placebo for 4 weeks. Echocardiography was performed for the assessments of left ventricular (LV) structure and function. AAC rats exhibited decreased LV fractional shortening (FS) at 4 weeks after surgery. NAC treatment attenuated decreased LV FS in AAC rats. In AAC rats, myocardial level of 8-hydroxydeoxyguanosine assessed by immunohistochemical staining, indicative of oxidative stress, was increased, LC3 II protein, a marker of autophagy, Beclin1 protein and Atg4b, Atg5, Atg7 and Atg12 mRNA expression were markedly increased, RIP1, RIP3 and MLKL expression, indicative of necroptosis, was increased, and all of the alterations in AAC rats were prevented by the NAC treatment. NAC treatment also attenuated myocyte cross-sectional area and myocardial fibrosis in AAC rats. In conclusion, NAC treatment prevented the increases in oxidative stress, myocyte autophagy and necroptosis and the decrease in LV systolic function in pressure overload-induced HF. These findings suggest that enhanced oxidative stress mediates pathological autophagy and necroptosis in myocytes, leading to LV systolic dysfunction, and antioxidants may be of value to prevent HF through the inhibition of excessive autophagy and necroptosis.}, }
@article {pmid34448938, year = {2021}, author = {Cazzola, M and Rogliani, P and Salvi, SS and Ora, J and Matera, MG}, title = {Use of Thiols in the Treatment of COVID-19: Current Evidence.}, journal = {Lung}, volume = {199}, number = {4}, pages = {335-343}, pmid = {34448938}, issn = {1432-1750}, mesh = {COVID-19/epidemiology/metabolism ; Humans ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; SARS-CoV-2 ; Sulfhydryl Compounds/*pharmacology ; *COVID-19 Drug Treatment ; }, abstract = {There is a possible role for oxidative stress, a state characterized by an altered balance between the production of free radicals or reactive oxygen species (ROS) and antioxidant defences, in coronavirus disease 2019 (COVID-19), the genesis of which is quite complex. Excessive oxidative stress could be responsible for the alveolar damage, thrombosis, and red blood cell dysregulation observed in COVID-19. Apparently, deficiency of glutathione (GSH), a low-molecular-weight thiol that is the most important non-enzymatic antioxidant molecule and has the potential to keep the cytokine storm in check, is a plausible explanation for the severe manifestations and death in COVID-19 patients. Thiol drugs, which are considered mucolytic, also possess potent antioxidant and anti-inflammatory properties. They exhibit antibacterial activity against a variety of medically important bacteria and may be an effective strategy against influenza virus infection. The importance of oxidative stress during COVID-19 and the various pharmacological characteristics of thiol-based drugs suggest a possible role of thiols in the treatment of COVID-19. Oral and intravenous GSH, as well as GSH precursors such as N-acetylcysteine (NAC), or drugs containing the thiol moiety (erdosteine) may represent a novel therapeutic approach to block NF-kB and address the cytokine storm syndrome and respiratory distress observed in COVID-19 pneumonia patients.}, }
@article {pmid34445365, year = {2021}, author = {Paskal, W and Kopka, M and Stachura, A and Paskal, AM and Pietruski, P and Pełka, K and Woessner, AE and Quinn, KP and Galus, R and Wejman, J and Włodarski, P}, title = {Single Dose of N-Acetylcysteine in Local Anesthesia Increases Expression of HIF1α, MAPK1, TGFβ1 and Growth Factors in Rat Wound Healing.}, journal = {International journal of molecular sciences}, volume = {22}, number = {16}, pages = {}, pmid = {34445365}, issn = {1422-0067}, support = {MNiSW/2019/106/DIR/NN3//Ministerstwo Nauki i Szkolnictwa Wy&#x17c;szego/ ; 1M15/NM1/17//Warszawski Uniwersytet Medyczny/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Anesthesia, Local ; Animals ; Antigens, CD/metabolism ; Antigens, Differentiation, Myelomonocytic/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Hypoxia-Inducible Factor 1, alpha Subunit/*genetics ; Mitogen-Activated Protein Kinase 1/*genetics ; Oxidative Stress/drug effects ; Peroxidase/metabolism ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/*genetics ; Wound Healing/*drug effects ; }, abstract = {In this study, we aimed to investigate the influence of N-acetylcysteine (NAC) on the gene expression profile, neoangiogenesis, neutrophils and macrophages in a rat model of incisional wounds. Before creating wounds on the backs of 24 Sprague-Dawley rats, intradermal injections were made. Lidocaine-epinephrin solutions were supplemented with 0.015%, 0.03% or 0.045% solutions of NAC, or nothing (control group). Scars were harvested on the 3rd, 7th, 14th and 60th day post-surgery. We performed immunohistochemical staining in order to visualize macrophages (anti-CD68), neutrophils (anti-MPO) and newly formed blood vessels (anti-CD31). Additionally, RT-qPCR was used to measure the relative expression of 88 genes involved in the wound healing process. On the 14th day, the number of cells stained with anti-CD68 and anti-CD31 antibodies was significantly larger in the tissues treated with 0.03% NAC compared with the control. Among the selected genes, 52 were upregulated and six were downregulated at different time points. Interestingly, NAC exerted a significant effect on the expression of 45 genes 60 days after its administration. In summation, a 0.03% NAC addition to the pre-incisional anesthetic solution improves neovasculature and increases the macrophages' concentration at the wound site on the 14th day, as well as altering the expression of numerous genes that are responsible for the regenerative processes.}, }
@article {pmid34443480, year = {2021}, author = {Cozma, V and Rosca, I and Radulescu, L and Martu, C and Nastasa, V and Varganici, CD and Ursu, EL and Doroftei, F and Pinteala, M and Racles, C}, title = {Antibacterial Polysiloxane Polymers and Coatings for Cochlear Implants.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {16}, pages = {}, pmid = {34443480}, issn = {1420-3049}, support = {PN-III-P4-ID-PCCF-2016-0050//Ministery of Research and Innovation, CNCS-UEFISCDI/ ; }, mesh = {Acetylcysteine/chemistry/pharmacology/therapeutic use ; Animals ; Anti-Bacterial Agents/*chemistry/pharmacology/therapeutic use ; Bacterial Adhesion/drug effects ; Biofilms/drug effects ; Coated Materials, Biocompatible/*chemistry/pharmacology/therapeutic use ; Cochlear Implants/adverse effects/*microbiology ; Otitis/*drug therapy ; Polymers/*chemistry/pharmacology/therapeutic use ; Rats, Wistar ; Siloxanes/*chemistry/pharmacology/therapeutic use ; Streptococcus pneumoniae/drug effects ; Sulfhydryl Compounds/chemistry ; Surface Properties ; Rats ; }, abstract = {Within this study, new materials were synthesized and characterized based on polysiloxane modified with different ratios of N-acetyl-l-cysteine (NAC) and crosslinked via UV-assisted thiol-ene addition, in order to obtain efficient membranes able to resist bacterial adherence and biofilm formation. These membranes were subjected to in vitro testing for microbial adherence against S. pneumoniae using standardized tests. WISTAR rats were implanted for 4 weeks with crosslinked siloxane samples without and with NAC. A set of physical characterization methods was employed to assess the chemical structure and morphological aspects of the new synthetized materials before and after contact with the microbiological medium.}, }
@article {pmid34441854, year = {2021}, author = {Comino-Sanz, IM and López-Franco, MD and Castro, B and Pancorbo-Hidalgo, PL}, title = {The Role of Antioxidants on Wound Healing: A Review of the Current Evidence.}, journal = {Journal of clinical medicine}, volume = {10}, number = {16}, pages = {}, pmid = {34441854}, issn = {2077-0383}, abstract = {(1) Background: Reactive oxygen species (ROS) play a crucial role in the preparation of the normal wound healing response. Therefore, a correct balance between low or high levels of ROS is essential. Antioxidant dressings that regulate this balance are a target for new therapies. The purpose of this review is to identify the compounds with antioxidant properties that have been tested for wound healing and to summarize the available evidence on their effects. (2) Methods: A literature search was conducted and included any study that evaluated the effects or mechanisms of antioxidants in the healing process (in vitro, animal models or human studies). (3) Results: Seven compounds with antioxidant activity were identified (Curcumin, N-acetyl cysteine, Chitosan, Gallic Acid, Edaravone, Crocin, Safranal and Quercetin) and 46 studies reporting the effects on the healing process of these antioxidants compounds were included. (4) Conclusions: this review offers a map of the research on some of the antioxidant compounds with potential for use as wound therapies and basic research on redox balance and oxidative stress in the healing process. Curcumin, NAC, quercetin and chitosan are the antioxidant compounds that shown some initial evidence of efficacy, but more research in human is needed.}, }
@article {pmid34440609, year = {2021}, author = {Liu, Z and Zhang, L and Liu, Y and Zhang, H and Chen, J and Feng, G and Yang, P and Sha, F and Cui, L and Sun, G}, title = {Identification of Compound CB-2 as a Novel Late-Stage Autophagy Inhibitor Exhibits Inhibitory Potency against A549 Cells.}, journal = {Life (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {34440609}, issn = {2075-1729}, support = {32070742 ;31471296//National Natural Science Foundation of China/ ; 192102310148&#xff1b;182102310270//Research Program for Science and Technology of Henan Province/ ; }, abstract = {Autophagy has been recognized as a stress tolerance mechanism that maintains cell viability, which contributes to tumor progression, dormancy, and treatment resistance. The inhibition of autophagy in cancer has the potential to improve the therapeutic efficacy. It is therefore of great significance to search for new autophagy inhibitors. In the present study, after screening a series of curcumin derivatives synthesized in our laboratory, (E)-3-((E)-4-chlorobenzylidene)-5-((5-methoxy-1H-indol-3-yl)methylene)-1-methylpiperidin-4-one (CB-2) was selected as a candidate for further study. We found that CB-2 increased the LC3B-II and SQSTM1 levels associated with the accumulation of autophagosomes in non-small cell lung cancer (NSCLC) A549 cells. The increased level of LC3B-II induced by CB-2 was neither eliminated when autophagy initiation was suppressed by wortmannin nor further increased when autophagosome degradation was inhibited by chloroquine (CQ). CB-2 enhanced the accumulation of LC3B-II under starvation conditions. Further studies revealed that CB-2 did not affect the levels of the key proteins involved in autophagy induction but significantly blocked the fusion of autophagosomes with lysosomes. High-dose CB-2 induced the apoptosis and necrosis of A549 cells, while a lower dose of CB-2 mainly impaired the migrative capacity of A549 cells, which only slightly induced cell apoptosis. CB-2 increased the levels of mitochondrial-derived reactive oxygen species (ROS) while decreasing the mitochondrial membrane potential (MMP). Scavenging ROS via N-acetylcysteine (NAC) reversed CB-2-induced autophagy inhibition and its inhibitory effect against A549 cells. In conclusion, CB-2 serves as a new late-stage autophagy inhibitor, which has a strong inhibitory potency against A549 cells.}, }
@article {pmid34440602, year = {2021}, author = {Ko, YH and Jeong, M and Jang, DS and Choi, JH}, title = {Gomisin L1, a Lignan Isolated from Schisandra Berries, Induces Apoptosis by Regulating NADPH Oxidase in Human Ovarian Cancer Cells.}, journal = {Life (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {34440602}, issn = {2075-1729}, support = {NRF-2019R1A2C2011213//National Research Foundation of Korea/ ; }, abstract = {The fruits of Schisandra chinensis (Schisandra berries) are used as health food supplements and popular food ingredients in East Asia. Lignans, major and characteristic polyphenol compounds of Schisandra berries, possess various biological activities, including hepatoprotective and anticancer effects. However, the biological activities of gomisin L1, a lignan isolated from Schisandra berries, are less to be investigated. In this study, the antitumor activity of gomisin L1 and its underlying molecular mechanism in human ovarian cancer cells were investigated. Gomisin L1 exhibited potent cytotoxic activity against A2780 and SKOV3 ovarian cancer cells. Flow cytometry analysis revealed that the growth inhibitory effects of gomisin L1 were mediated by the induction of apoptosis. Furthermore, gomisin L1 induced an increase in intracellular reactive oxygen species (ROS) levels, and the antioxidant N-acetyl cysteine significantly negated gomisin L1-induced cell death. Moreover, inhibition of NADPH oxidase (NOX) using an inhibitor and siRNA attenuated gomisin L1-induced death of, and ROS production in, human ovarian cancer cells. Taken together, these data indicate that the lignan gomisin L1 from Schisandra berries induces apoptotic cell death by regulating intracellular ROS production via NOX.}, }
@article {pmid34440143, year = {2021}, author = {Yan, M and Wang, Z and Xia, T and Jin, S and Liu, Y and Hu, H and Chang, Q}, title = {Enhancement of TEX264-Mediated ER-Phagy Contributes to the Therapeutic Effect of Glycycoumarin against APA Hepatotoxicity in Mice.}, journal = {Biomedicines}, volume = {9}, number = {8}, pages = {}, pmid = {34440143}, issn = {2227-9059}, support = {3332020048//Fundamental Research Funds for the Central Universities/ ; }, abstract = {Acetaminophen (APA)-induced hepatotoxicity is coupled with the activation of autophagy. We sought to determine whether selective autophagy of the endoplasmic reticulum (ER), termed ER-phagy, is involved in APA hepatotoxicity and to explore its potential as a therapeutic target for APA-induced liver injury (AILI). APA (300 or 600 mg/kg) was administered to male C57BL/6N mice, with and without rapamycin, glycycoumarin (GCM) and N-acetylcysteine (NAC). The results demonstrated that ER-phagy accompanied with ER stress was activated after APA overdose. The dynamic changes of LC3 and TEX264 revealed that ER-phagy was induced as early as 6 h and peaked at 24 h following the APA injection. A delayed treatment with GCM, but not rapamycin, considerably attenuated a liver injury and, consequently, reduced its mortality. This is probably due to the inhibition of ER stress and the acceleration of liver regeneration via enhanced ER-phagy. Unlike the impaired hepatocyte proliferation and more severe liver injury in mice that received prolonged treatment with NAC, liver recovery is facilitated by repeated treatment with GCM. These findings suggest that TEX264-mediated ER-phagy is a compensatory mechanism against ER stress provoked by an APA overdose. A delayed and prolonged treatment with GCM enhances ER-phagy, thus serving as a potential therapeutic approach for patients presenting at the late stage of AILI.}, }
@article {pmid34439417, year = {2021}, author = {Botto, L and Bulbarelli, A and Lonati, E and Cazzaniga, E and Tassotti, M and Mena, P and Del Rio, D and Palestini, P}, title = {Study of the Antioxidant Effects of Coffee Phenolic Metabolites on C6 Glioma Cells Exposed to Diesel Exhaust Particles.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34439417}, issn = {2076-3921}, support = {ID 225155, CUP E47F17000020009//Regione Lombardia/ ; }, abstract = {The contributing role of environmental factors to the development of neurodegenerative diseases has become increasingly evident. Here, we report that exposure of C6 glioma cells to diesel exhaust particles (DEPs), a major constituent of urban air pollution, causes intracellular reactive oxygen species (ROS) production. In this scenario, we suggest employing the possible protective role that coffee phenolic metabolites may have. Coffee is a commonly consumed hot beverage and a major contributor to the dietary intake of (poly) phenols. Taking into account physiological concentrations, we analysed the effects of two different coffee phenolic metabolites mixes consisting of compounds derived from bacterial metabolization reactions or phase II conjugations, as well as caffeic acid. The results showed that these mixes were able to counteract DEP-induced oxidative stress. The cellular components mediating the downregulation of ROS included extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and uncoupling protein 2 (UCP2). Contrary to coffee phenolic metabolites, the treatment with N-acetylcysteine (NAC), a known antioxidant, was found to be ineffective in preventing the DEP exposure oxidant effect. These results revealed that coffee phenolic metabolites could be promising candidates to protect against some adverse health effects of daily exposure to air pollution.}, }
@article {pmid34439408, year = {2021}, author = {Karmi, O and Sohn, YS and Marjault, HB and Israeli, T and Leibowitz, G and Ioannidis, K and Nahmias, Y and Mittler, R and Cabantchik, IZ and Nechushtai, R}, title = {A Combined Drug Treatment That Reduces Mitochondrial Iron and Reactive Oxygen Levels Recovers Insulin Secretion in NAF-1-Deficient Pancreatic Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34439408}, issn = {2076-3921}, support = {R01 GM111364/GM/NIGMS NIH HHS/United States ; NIDDK DK120986 (K.P.M.), DK101753 (K.P.M.), DK114464 (K.P.M.), and GM111364 (to R.M.)./NH/NIH HHS/United States ; }, abstract = {Decreased insulin secretion, associated with pancreatic β-cell failure, plays a critical role in many human diseases including diabetes, obesity, and cancer. While numerous studies linked β-cell failure with enhanced levels of reactive oxygen species (ROS), the development of diabetes associated with hereditary conditions that result in iron overload, e.g., hemochromatosis, Friedreich's ataxia, and Wolfram syndrome type 2 (WFS-T2; a mutation in CISD2, encoding the [2Fe-2S] protein NAF-1), underscores an additional link between iron metabolism and β-cell failure. Here, using NAF-1-repressed INS-1E pancreatic cells, we observed that NAF-1 repression inhibited insulin secretion, as well as impaired mitochondrial and ER structure and function. Importantly, we found that a combined treatment with the cell permeant iron chelator deferiprone and the glutathione precursor N-acetyl cysteine promoted the structural repair of mitochondria and ER, decreased mitochondrial labile iron and ROS levels, and restored glucose-stimulated insulin secretion. Additionally, treatment with the ferroptosis inhibitor ferrostatin-1 decreased cellular ROS formation and improved cellular growth of NAF-1 repressed pancreatic cells. Our findings reveal that suppressed expression of NAF-1 is associated with the development of ferroptosis-like features in pancreatic cells, and that reducing the levels of mitochondrial iron and ROS levels could be used as a therapeutic avenue for WFS-T2 patients.}, }
@article {pmid34438950, year = {2021}, author = {Manoharan, A and Ognenovska, S and Paino, D and Whiteley, G and Glasbey, T and Kriel, FH and Farrell, J and Moore, KH and Manos, J and Das, T}, title = {N-Acetylcysteine Protects Bladder Epithelial Cells from Bacterial Invasion and Displays Antibiofilm Activity against Urinary Tract Bacterial Pathogens.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {10}, number = {8}, pages = {}, pmid = {34438950}, issn = {2079-6382}, support = {IMCRC/WLY/08052019.1//Innovative Manufacturing CRC/ ; }, abstract = {Introduction: Urinary tract infections (UTIs) affect more than 150 million individuals annually. A strong correlation exists between bladder epithelia invasion by uropathogenic bacteria and patients with recurrent UTIs. Intracellular bacteria often recolonise epithelial cells post-antibiotic treatment. We investigated whether N-acetylcysteine (NAC) could prevent uropathogenic E. coli and E. faecalis bladder cell invasion, in addition to its effect on uropathogens when used alone or in combination with ciprofloxacin. Methods: An invasion assay was performed in which bacteria were added to bladder epithelial cells (BECs) in presence of NAC and invasion was allowed to occur. Cells were washed with gentamicin, lysed, and plated for enumeration of the intracellular bacterial load. Cytotoxicity was evaluated by exposing BECs to various concentrations of NAC and quantifying the metabolic activity using resazurin at different exposure times. The effect of NAC on the preformed biofilms was also investigated by treating 48 h biofilms for 24 h and enumerating colony counts. Bacteria were stained with propidium iodide (PI) to measure membrane damage. Results: NAC completely inhibited BEC invasion by multiple E. coli and E. faecalis clinical strains in a dose-dependent manner (p < 0.01). This was also evident when bacterial invasion was visualised using GFP-tagged E. coli. NAC displayed no cytotoxicity against BECs despite its intrinsic acidity (pH ~2.6), with >90% cellular viability 48 h post-exposure. NAC also prevented biofilm formation by E. coli and E. faecalis and significantly reduced bacterial loads in 48 h biofilms when combined with ciprofloxacin. NAC visibly damaged E. coli and E. faecalis bacterial membranes, with a threefold increase in propidium iodide-stained cells following treatment (p < 0.05). Conclusions: NAC is a non-toxic, antibiofilm agent in vitro and can prevent cell invasion and IBC formation by uropathogens, thus providing a potentially novel and efficacious treatment for UTIs. When combined with an antibiotic, it may disrupt bacterial biofilms and eliminate residual bacteria.}, }
@article {pmid34438354, year = {2021}, author = {Bortolasci, CC and Turner, A and Mohebbi, M and Liu, ZS and Ashton, M and Gray, L and Marx, W and Walker, AJ and Kowalski, GM and Jacka, F and Berk, M and Dean, OM and Walder, K}, title = {Baseline serum amino acid levels predict treatment response to augmentation with N-acetylcysteine (NAC) in a bipolar disorder randomised trial.}, journal = {Journal of psychiatric research}, volume = {142}, number = {}, pages = {376-383}, doi = {10.1016/j.jpsychires.2021.08.034}, pmid = {34438354}, issn = {1879-1379}, mesh = {*Acetylcysteine/therapeutic use ; *Bipolar Disorder/drug therapy ; Depression ; Double-Blind Method ; Drug Therapy, Combination ; Humans ; Treatment Outcome ; }, abstract = {N-acetylcysteine (NAC) acts on glutamatergic and redox systems, two systems implicated in the pathophysiology of bipolar disorder (BD). This has led to the investigation of NAC as a potential candidate for the treatment of BD. The aim of this study was to investigate metabolomic markers to identify predictors of NAC response in a cohort of BD participants. This study is a secondary analysis of a 16-week, multi-site, randomized, double-blinded, parallel-group, placebo-controlled trial in BD participants with a current acute depressive episode. This study included trial participants who received either NAC 2000 mg/day, or placebo. Participants (NAC: n = 31, placebo: n = 29) were assessed at baseline and week 16 using the Montgomery Åsberg Depression Rating Scale (MADRS) and were dichotomised into "responders" (MADRS at week 16 < 50% of MADRS at baseline) and "non-responders" (MADRS at week 16 > 50% at baseline). Untargeted gas chromatography-mass spectrometry analysis was performed to analyse baseline levels of 68 serum metabolites. Of the nine metabolites that differentiated placebo and NAC groups, five were amino acids with lower levels in the NAC responder group compared with the NAC non-responders. Further analysis generated a predictive model of MADRS improvement including glycine, norleucine, threonine, proline, phenylalanine, tyrosine, glutamic acid, lysine and leucine (R[2] = 0.853; adjusted R[2] = 0.733). This prediction model predicted 85% of the variance in MADRS outcome after adjunctive treatment with NAC. BD participants with lower serum levels of free amino acids at baseline may be more likely to respond to adjunctive treatment with NAC.}, }
@article {pmid34434429, year = {2021}, author = {Affas, S and Ayas, MF and Kassab, IA}, title = {Use of N-Acetylcysteine in Amphetamine-Induced Acute Liver Failure.}, journal = {Journal of medical cases}, volume = {12}, number = {2}, pages = {54-56}, pmid = {34434429}, issn = {1923-4155}, abstract = {Acute liver failure (ALF) is a serious complication of many drugs. Amongst recreational drugs, cocaine, amphetamines and ecstasy (methylenedioxymethamphetamine) have been known to cause ALF as a complication. However, the true effects and management on the liver of such cases have not been well reported and treatment of such conditions needs prompt action. N-acetylcysteine (NAC) is a known hepatoprotective agent but remains controversial in the use of recreational drug-induced acute liver injury. We present a case of ALF secondary to amphetamine ingestion, with a rapid recovery after administration of intravenous NAC.}, }
@article {pmid34433910, year = {2021}, author = {Qiu, P and Hou, W and Wang, H and Lei, KKW and Wang, S and Chen, W and Pardeshi, LA and Prothro, K and Shukla, Y and Su, SSM and Schrump, DS and Chen, Q and Deng, CX and Xu, X and Wang, R}, title = {Sirt1 deficiency upregulates glutathione metabolism to prevent hepatocellular carcinoma initiation in mice.}, journal = {Oncogene}, volume = {40}, number = {41}, pages = {6023-6033}, pmid = {34433910}, issn = {1476-5594}, support = {ZIA BC011115/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Glutathione/*metabolism ; Liver Neoplasms, Experimental/*metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Sirtuin 1/*deficiency/metabolism ; Up-Regulation ; }, abstract = {Sirtuin-1 (SIRT1) is involved in various metabolic pathways, including fatty acid synthesis and gluconeogenesis in the liver. However, its role in initiation and progression of liver cancer remains unclear. Studying Sirt1 liver-specific knockout (LKO) mice in combination with diethylnitrosamine (DEN) treatment, we demonstrated that loss of Sirt1 rendered mice resistant to DEN-induced hepatocellular carcinoma (HCC) development. RNA-seq revealed that livers from LKO mice exhibited an enrichment in glutathione metabolism eight months after DEN challenge. Sirt1 deficiency elevated the expression of glutathione-s-transferase family genes by increasing the level of Nrf2, a key regulator of glutathione metabolism. Hence, LKO livers displayed a reductive environment with an increased ratio of GSH to GSSG and an elevated GSH level. Furthermore, using CRISPR knockout techniques, we confirmed that the impairment of HCC formation in LKO mice is mainly dependent on NRF2 signaling. Meanwhile, HCC induced by DEN could be blocked by the administration of N-acetyl cysteine (NAC) when administered one month after DEN challenge. However, NAC treatment starting five months after DEN injection was not able to prevent tumor development. In conclusion, our findings indicate that a reductive environment orchestrated by glutathione metabolism at an early stage can prevent the initiation of HCC.}, }
@article {pmid34431675, year = {2021}, author = {You, Y and Wang, X and Ma, K and Li, J and Peng, Y and Zheng, J}, title = {Metabolic Activation of Atomoxetine Mediated by Cytochrome P450 2D6.}, journal = {Chemical research in toxicology}, volume = {34}, number = {9}, pages = {2135-2144}, doi = {10.1021/acs.chemrestox.1c00216}, pmid = {34431675}, issn = {1520-5010}, mesh = {Activation, Metabolic ; Animals ; Atomoxetine Hydrochloride/analogs &amp; derivatives/analysis/*metabolism ; Cytochrome P-450 CYP2D6/*metabolism ; Glutathione/analogs &amp; derivatives/analysis ; Hydroxylation ; Male ; Microsomes, Liver/metabolism ; Oxidation-Reduction ; Rats, Sprague-Dawley ; Rats ; }, abstract = {Atomoxetine (ATX) is a neurological drug widely used for the treatment of attention deficit-hyperactivity disorder. Liver injury has been documented in patients administered ATX. The mechanism of ATX's toxic action is less clear. This study is aimed to characterize reactive metabolites of ATX in vitro and in vivo to assist our understanding of the mechanisms of ATX hepatotoxicity. A hydroxylated metabolite, along with an O-dealkylation metabolite, was found in ATX-supplemented rat liver microsome incubations. Additionally, two glutathione (GSH) conjugates and two N-acetylcysteine (NAC) conjugates were observed in rat liver microsome incubations containing ATX, NADPH, and GSH or NAC. The corresponding GSH conjugates and NAC conjugates were found in bile and urine of ATX-treated rats, respectively. Recombinant P450 enzyme incubation study demonstrated that CYP2D6 dominated the metabolic activation of ATX. The insights gained from this study may be of assistance to illuminate the mechanisms of ATX-induced hepatotoxicity.}, }
@article {pmid34425836, year = {2021}, author = {Niu, J and Wang, J and Zhang, Q and Zou, Z and Ding, Y}, title = {Cinobufagin-induced DNA damage response activates G2/M checkpoint and apoptosis to cause selective cytotoxicity in cancer cells.}, journal = {Cancer cell international}, volume = {21}, number = {1}, pages = {446}, pmid = {34425836}, issn = {1475-2867}, support = {(20180101237JC//Natural Science Foundation of Jilin Province/ ; }, abstract = {BACKGROUND: Processed extracts from toad skin and parotoid gland have long been used to treat various illnesses including cancer in many Asian countries. Recent studies have uncovered a family of bufadienolides as the responsible pharmacological compounds, and the two major molecules, cinobufagin and bufalin, have been shown to possess robust antitumor activity; however, the underlying mechanisms remain poorly understood.<br><br>METHODS: Intracellular reactive oxygen species (ROS) were measured by DCFH-DA staining and flow cytometry, and DNA damage was analyzed by immunofluorescent staining and the alkaline comet assay. Cytotoxicity was measured by MTT as well as colony formation assays, and cell cycle and apoptosis were analyzed by flow cytometry. In addition, apoptosis was further characterized by TUNEL and mitochondrial membrane potential assays.<br><br>RESULTS: Here we showed that sublethal doses of cinobufagin suppressed the viability of many cancer but not noncancerous cell lines. This tumor-selective cytotoxicity was preceded by a rapid, cancer-specific increase in cellular ROS and was significantly reduced by the ROS inhibitor N-acetyl cysteine (NAC), indicating oxidative stress as the primary source of cinobufagin-induced cancer cell toxicity. Sublethal cinobufagin-induced ROS overload resulted in oxidative DNA damage and intense replication stress in cancer cells, leading to strong DNA damage response (DDR) signaling. Subsequent phosphorylation of CDC25C and stabilization of p53 downstream of DDR resulted in activation of the G2/M checkpoint followed by induction of apoptosis. These data indicate that cinobufagin suppresses cancer cell viability via DDR-mediated G2 arrest and apoptosis.<br><br>CONCLUSION: As elevated oxidative pressure is shared by most cancer cells that renders them sensitive to further oxidative insult, these studies suggest that nontoxic doses of cinobufagin can be used to exploit a cancer vulnerability for induction of cancer-specific cytotoxicity.}, }
@article {pmid34425541, year = {2021}, author = {Li, S and Cao, Y and Pan, Q and Xiao, Y and Wang, Y and Wang, X and Li, X and Li, Q and Tang, X and Ran, B}, title = {Neonicotinoid insecticides triggers mitochondrial bioenergetic dysfunction via manipulating ROS-calcium influx pathway in the liver.}, journal = {Ecotoxicology and environmental safety}, volume = {224}, number = {}, pages = {112690}, doi = {10.1016/j.ecoenv.2021.112690}, pmid = {34425541}, issn = {1090-2414}, abstract = {Extensive use of neonicotinoids insecticides (NNIs) rapidly garnered widespread attention in the toxicology, since they have been found in human samples, including urine, blood, breast milk and hair. However, the precise mechanism is not completely clear regarding the NNIs-induced hepatotoxicity. In this study, we exposed male mice to three neonicotinoids (dinotefuran (DIN), nitenpyram (NIT) and acetamiprid (ACET) for 30 days. Our results showed that NNIs remarkably induced morphological damage in the liver. Simultaneously, we found that three neonicotinoids could activate the store operated Ca[2+] entry (SOCE) in the liver. Further results confirmed that reactive oxide species (ROS) scavenger n-acetylcysteine (NAC) attenuated DIN-induced calcium ion (Ca[2+]) overload and S-phase arrest via restoring protein expression of SOCE and S phase related genes in L02 hepatocytes. Moreover, we found that NAC obviously combated mitochondrial dysfunction caused by DIN via restoring mitochondrial membrane potential. Meanwhile, DIN treatment significantly increased pyruvate content, impaired the activities of tricarboxylic acid (TCA) cycle rate-limiting enzymes and inhibited adenosine triphosphate (ATP) generation, but these effects were reversed by Serca specific activator CDN1163. Collectively, perturbation of redox states can be recognized as the center of S-phase arrest and Ca[2+] overload after NNIs exposure. In this regard, Ca[2+] homeostasis dysregulation is a causative event of mitochondrial bioenergetic dysfunction in the liver. These data provides a new perspective for understanding NNI-induced hepatotoxicity mechanisms.}, }
@article {pmid34425170, year = {2021}, author = {Osman, KA and Ezz El-Din, EM and Ahmed, NS and El-Seedy, AS}, title = {Effect of N-acetylcysteine on attenuation of chlropyrifos and its methyl analogue toxicity in male rats.}, journal = {Toxicology}, volume = {461}, number = {}, pages = {152904}, doi = {10.1016/j.tox.2021.152904}, pmid = {34425170}, issn = {1879-3185}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/metabolism ; Chlorpyrifos/*analogs &amp; derivatives/chemistry/toxicity ; Cholinesterase Inhibitors/chemistry/toxicity ; Chromosome Aberrations/chemically induced ; Cytochromes c/metabolism ; Erythrocytes/drug effects ; Lipid Peroxidation/drug effects ; Male ; Mutagenicity Tests ; Nitric Oxide/blood ; Pesticides/chemistry/*toxicity ; Rats ; }, abstract = {The attenuating effect of 150 mg/kg of N-acetylcysteine (NAC) against the oral administration of 7.88 and 202.07 mg/kg/day for 14 days of either chlropyrifos-ethyl (CPE-E) or chlropyrifos-methyl (CPF-M), respectively, in male rat was investigated using biochemical and genetic markers. Biomarkers such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), paraoxonase (PON), adenosine 5'-triphosphatase (ATP-ase), glutathione-S-transferase (GST), catalase (CAT), glutathione reduced (GSH) in serum showed a significant decline in their levels, while calcium (Ca[+2]), cytochrome C reduction (CYC-R), lipid peroxidation (LPO), nitric oxide (NO) levels showed a significant increase in serum of treated rats. Regarding the genotoxic parameters, when rats are treated either with CPE-E or CPF-M, liver DNA, chromosomal aberration (CA), and micronucleated polychromatic erythrocytes (MnPCE) significantly increased, while the mitotic index (MI) and polychromatic erythrocytes (PCE)/ normochromatic erythrocytes (NCE) ratio were significantly decreased. However, the administration of NAC following the intoxication of CPF-E or CPF-M attenuated the tested biochemical and genotoxic markers. It can be concluded that NAC can be used to ameliorate the toxicity of certain organophosphorus compounds such as CPF-E and CPF-M.}, }
@article {pmid34424746, year = {2021}, author = {Li, J and Navarro, MA and Uzal, FA and McClane, BA}, title = {NanI Sialidase Contributes to the Growth and Adherence of Clostridium perfringens Type F Strain F4969 in the Presence of Adherent Mucus.}, journal = {Infection and immunity}, volume = {89}, number = {11}, pages = {e0025621}, pmid = {34424746}, issn = {1098-5522}, support = {R21 AI140010/AI/NIAID NIH HHS/United States ; R21 AI148911/AI/NIAID NIH HHS/United States ; }, mesh = {Bacterial Adhesion/*physiology ; Caco-2 Cells ; Clostridium perfringens/growth &amp; development/*physiology ; HT29 Cells ; Humans ; Intestines/*microbiology ; Mucus/*physiology ; Neuraminidase/*physiology ; Virulence Factors/physiology ; }, abstract = {Clostridium perfringens type F strains causing nonfoodborne human gastrointestinal diseases (NFD) typically produce NanI sialidase as their major secreted sialidase. Type F NFDs can persist for several weeks, indicating their pathogenesis involves intestinal colonization, including vegetative cell growth and adherence, with subsequent sporulation that fosters enterotoxin production and release. We previously reported that NanI contributes to type F NFD strain adherence and growth using Caco-2 cells. However, Caco-2 cells make minimal amounts of mucus, which is significant because the intestines are coated with adherent mucus. Therefore, it was important to assess if NanI contributes to the growth and adherence of type F NFD strains in the presence of adherent mucus. Consequently, the current study first demonstrated greater growth of nanI-carrying versus non-nanI-carrying type F strains in the presence of HT29-MTX-E12 cells, which produce an adherent mucus layer, versus their parental HT29 cells, which make minimal mucus. Demonstrating the specific importance of NanI for this effect, type F NFD strain F4969 or a complementing strain grew and adhered better than an isogenic nanI null mutant in the presence of HT29-MTX-E12 cells versus HT29 cells. Those effects involved mucus production by HT29-MTX-E12 cells since mucus reduction using N-acetyl cysteine reduced F4969 growth and adherence. Consistent with those in vitro results, NanI contributed to growth of F4969 in the mouse small intestine. By demonstrating a growth and adherence role for NanI in the presence of adherent mucus, these results further support NanI as a potential virulence factor during type F NFDs.}, }
@article {pmid34422872, year = {2021}, author = {Wang, ML and Yin, XJ and Li, XL and Wang, FD and Zhou, J and Tao, YC and Wang, YH and Wu, DB and Chen, EQ}, title = {Retrospective Analysis of the Clinical Efficacy of N-Acetylcysteine in the Treatment of Hepatitis B Virus Related Acute-on-Chronic Liver Failure.}, journal = {Frontiers in medicine}, volume = {8}, number = {}, pages = {724224}, pmid = {34422872}, issn = {2296-858X}, abstract = {Objective: HBV-related acute-on-chronic liver failure (HBV-ACLF) has a high mortality due to severe intrahepatic cholestasis and coagulation dysfunction, thus new treatment measures are urgently needed to improve the therapeutic effect. This study aimed to observe the efficacy of N-acetylcysteine (NAC) in the treatment of HBV-ACLF. Methods: The data of patients with HBV-ACLF admitted to West China Hospital from October 2019 to August 2020 were collected retrospectively, and they were divided into treatment group and control group according to whether they had received additional NAC treatment. The improvement of biochemistry, coagulation function and disease severity score after 14 days of hospitalization were analyzed between two groups. Results: A total of 90 HBV-ACLF patients were included, including 42 patients in treatment group and 48 patients in control group. Compared with baseline, serum TBil, DBil, TBA, GGT and ALP in two groups both decreased significantly, while PTA increased significantly. Interesting, the decrease of serum TBil, DBil and TBA and the increase of PTA in treatment group were all significantly than these in control group. Additionally, more patients in treatment group than control group changed from CTP grade C to grade B. Subgroup analysis of CTP grade C patients showed that the decrease of serum TBil, DBil and TBA and the increase of PTA in treatment group were significantly than these in control group. Conclusion: The NAC treatment may help to improve intrahepatic cholestasis and coagulation dysfunction of HBV-ACLF.}, }
@article {pmid34420083, year = {2021}, author = {Akakpo, JY and Jaeschke, MW and Ramachandran, A and Curry, SC and Rumack, BH and Jaeschke, H}, title = {Delayed administration of N-acetylcysteine blunts recovery after an acetaminophen overdose unlike 4-methylpyrazole.}, journal = {Archives of toxicology}, volume = {95}, number = {10}, pages = {3377-3391}, pmid = {34420083}, issn = {1432-0738}, support = {DK125465/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; GM103549/GM/NIGMS NIH HHS/United States ; F31 DK120194/DK/NIDDK NIH HHS/United States ; DK102142/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; GM118247/GM/NIGMS NIH HHS/United States ; R01 DK125465/DK/NIDDK NIH HHS/United States ; DK1200194/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antidotes/administration &amp; dosage/*pharmacology ; Cell Proliferation/drug effects ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology ; Drug Overdose/drug therapy ; Fomepizole/administration &amp; dosage/*pharmacology ; Hepatocytes/drug effects/pathology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Time Factors ; }, abstract = {N-acetylcysteine (NAC) is the only clinically approved antidote against acetaminophen (APAP) hepatotoxicity. Despite its efficacy in patients treated early after APAP overdose, NAC has been implicated in impairing liver recovery in mice. More recently, 4-methylpyrazole (4MP, Fomepizole) emerged as a potential antidote in the mouse APAP hepatotoxicity model. The objective of this manuscript was to verify the detrimental effect of NAC and its potential mechanism and assess whether 4MP has the same liability. C57BL/6J mice were treated with 300 mg/kg APAP; 9 h after APAP and every 12 h after that, the animals received either 100 mg/kg NAC or 184.5 mg/kg 4MP. At 24 or 48 h after APAP, parameters of liver injury, mitochondrial biogenesis and cell proliferation were evaluated. Delayed NAC treatment had no effect on APAP-induced liver injury at 24 h but reduced the decline of plasma ALT activities and prevented the shrinkage of the areas of necrosis at 48 h. This effect correlated with down-regulation of key activators of mitochondrial biogenesis (AMPK, PGC-1α, Nrf1/2, TFAM) and reduced expression of Tom 20 (mitochondrial mass) and PCNA (cell proliferation). In contrast, 4MP attenuated liver injury at 24 h and promoted recovery at 48 h, which correlated with enhanced mitochondrial biogenesis and hepatocyte proliferation. In human hepatocytes, 4MP demonstrated higher efficacy in preventing cell death compared to NAC when treated at 18 h after APAP. Thus, due to the wider treatment window and lack of detrimental effects on recovery, it appears that at least in preclinical models, 4MP is superior to NAC as an antidote against APAP overdose.}, }
@article {pmid34419099, year = {2021}, author = {Ke, S and Liu, Q and Zhang, X and Yao, Y and Yang, X and Sui, G}, title = {Cytotoxicity analysis of biomass combustion particles in human pulmonary alveolar epithelial cells on an air-liquid interface/dynamic culture platform.}, journal = {Particle and fibre toxicology}, volume = {18}, number = {1}, pages = {31}, pmid = {34419099}, issn = {1743-8977}, support = {R01 AA020401/AA/NIAAA NIH HHS/United States ; }, mesh = {*Air Pollutants ; *Alveolar Epithelial Cells ; Biomass ; Cell Survival ; Epithelial Cells ; Humans ; Lung ; }, abstract = {BACKGROUND: Exposure to indoor air pollution from solid fuel combustion is associated with lung diseases and cancer. This study investigated the cytotoxicity and molecular mechanisms of biomass combustion-derived particles in human pulmonary alveolar epithelial cells (HPAEpiC) using a platform that combines air-liquid interface (ALI) and dynamic culture (DC) systems.<br><br>METHODS: HPAEpiC were cultured on the surface of polycarbonate (PC) membranes on the ALI-DC platform. The cells were sprayed with an aerosolized solution of biomass combustion soluble constituents (BCSCs) and simultaneously nourished with culture medium flowing beneath the permeable PC membranes. The ALI-DC method was compared with the traditional submerged culture approach. BCSC particle morphology and dosages deposited on the chip were determined for particle characterization. Flow cytometry, scanning electron microscopy, and transmission electron microscopy were used to investigate the apoptosis rate of HPAEpiC and changes in the cell ultrastructure induced by BCSCs. Additionally, the underlying apoptotic pathway was examined by determining the protein expression levels by western blotting.<br><br>RESULTS: Scanning electron microscope images demonstrated that the sample processing and delivering approach of the ALI-DC platform were suitable for pollutant exposure. Compared with the submerged culture method, a significant decline in cell viability and increase in apoptosis rate was observed after BCSC exposure on the ALI-DC platform, indicating that the ALI-DC platform is a more sensitive system for investigating cytotoxicity of indoor air pollutants in lung cells. The morphology and ultrastructure of the cells were damaged after exposure to BCSCs, and the p53 pathway was activated. The Bcl-2/Bax ratio was reduced, upregulating caspase-9 and caspase-3 expression and subsequently inducing apoptosis of HPAEpiC. The addition of N-acetyl cysteine antioxidant significantly alleviated the cytotoxicity induced by BCSCs.<br><br>CONCLUSION: A novel ALI-DC platform was developed to study the cytotoxicity of air pollutants on lung cells. Using the platform, we demonstrated that BCSCs could damage the mitochondria, produce reactive oxygen species, and activate p53 in HPAEpiC, ultimately inducing apoptosis.}, }
@article {pmid34417577, year = {2022}, author = {Yang, CB and Liu, J and Tong, BC and Wang, ZY and Zhu, Z and Su, CF and Sreenivasmurthy, SG and Wu, JX and Iyaswamy, A and Krishnamoorthi, S and Huang, SY and Cheung, KH and Song, JX and Tan, JQ and Lu, JH and Li, M}, title = {TFEB, a master regulator of autophagy and biogenesis, unexpectedly promotes apoptosis in response to the cyclopentenone prostaglandin 15d-PGJ2.}, journal = {Acta pharmacologica Sinica}, volume = {43}, number = {5}, pages = {1251-1263}, pmid = {34417577}, issn = {1745-7254}, mesh = {Apoptosis ; Autophagy ; Cyclopentanes ; *Prostaglandin D2/analogs &amp; derivatives/pharmacology ; *Prostaglandins/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Transcriptional factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, is generally regarded as a pro-survival factor. Here, we identify that besides its effect on autophagy induction, TFEB exerts a pro-apoptotic effect in response to the cyclopentenone prostaglandin 15-deoxy-∆-[12,14]-prostaglandin J2 (15d-PGJ2). Specifically, 15d-PGJ2 promotes TFEB translocation from the cytoplasm into the nucleus to induce autophagy and lysosome biogenesis via reactive oxygen species (ROS) production rather than mTORC1 inactivation. Surprisingly, TFEB promotes rather than inhibits apoptosis in response to 15d-PGJ2. Mechanistically, ROS-mediated TFEB translocation into the nucleus transcriptionally upregulates the expression of ATF4, which is required for apoptosis elicited by 15d-PGJ2. Additionally, inhibition of TFEB activation by ROS scavenger N-acetyl cysteine or inhibition of protein synthesis by cycloheximide effectively compromises ATF4 upregulation and apoptosis in response to 15d-PGJ2. Collectively, these results indicate that ROS-induced TFEB activation exerts a novel role in promoting apoptosis besides its role in regulating autophagy in response to 15d-PGJ2. This work not only evidences how TFEB is activated by 15d-PGJ2, but also unveils a previously unexplored role of ROS-dependent activation of TFEB in modulating cell apoptosis in response to 15d-PGJ2.}, }
@article {pmid34416896, year = {2021}, author = {Chen, M and Yi, J and Zhao, Z}, title = {Biocompatible orthodontic cement with antibacterial capability and protein repellency.}, journal = {BMC oral health}, volume = {21}, number = {1}, pages = {412}, pmid = {34416896}, issn = {1472-6831}, mesh = {Anti-Bacterial Agents/pharmacology/therapeutic use ; Biofilms ; *Dental Bonding ; Dental Cements ; Dental Enamel ; Glass Ionomer Cements/pharmacology ; Humans ; Materials Testing ; *Orthodontic Brackets ; Resin Cements ; }, abstract = {BACKGROUND: White spot lesions (WSLs) often occur in orthodontic treatments. The objectives of this study were to develop a novel orthodontic cement using particles of nano silver (NAg), N-acetylcysteine (NAC) and 2-methacryloyloxyethyl phosphorylcholine (MPC), and to investigate the effects on bonding strength, biofilms and biocompatibility.<br><br>METHODS: A commercial resin-modified glass ionomer cement (RMGIC) was modified by adding NAg, NAC and MPC. The unmodified RMGIC served as the control. Enamel bond strength and cytotoxicity of the cements were investigated. The protein repellent behavior of cements was also evaluated. The metabolic assay, lactic acid production assay and colony-forming unit assay of biofilms were used to determine the antibacterial capability of cements.<br><br>RESULTS: The new bioactive cement with NAg, NAC and MPC had clinically acceptable bond strength and biocompatibility. Compared to commercial control, the new cement suppressed metabolic activity and lactic acid production of biofilms by 59.03% and 70.02% respectively (p&#x2009;<&#x2009;0.05), reduced biofilm CFU by 2 logs (p&#x2009;<&#x2009;0.05) and reduced protein adsorption by 76.87% (p&#x2009;<&#x2009;0.05).<br><br>CONCLUSIONS: The new cement with NAg, NAC and MPC had strong antibacterial capability, protein-repellent ability and acceptable biocompatibility. The new cement is promising to protect enamel from demineralization during orthodontic treatments.}, }
@article {pmid34411914, year = {2021}, author = {Rodrigues, ACBDC and Bomfim, LM and Neves, SP and Soares, MBP and Dias, RB and Valverde, LF and Rocha, CAG and Costa, EV and da Silva, FMA and Rocha, WC and Koolen, HHF and Bezerra, DP}, title = {Tingenone and 22-hydroxytingenone target oxidative stress through downregulation of thioredoxin, leading to DNA double-strand break and JNK/p38-mediated apoptosis in acute myeloid leukemia HL-60 cells.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {142}, number = {}, pages = {112034}, doi = {10.1016/j.biopha.2021.112034}, pmid = {34411914}, issn = {1950-6007}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Line ; Cell Line, Tumor ; DNA Breaks, Double-Stranded/drug effects ; Down-Regulation/drug effects ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/genetics ; MAP Kinase Signaling System/drug effects ; Mice ; Oxidative Stress/drug effects ; Salacia/chemistry ; Thioredoxins/*genetics ; Triterpenes/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Acute myeloid leukemia (AML) is the most lethal form of leukemia. Standard anti-AML treatment remains almost unchanged for decades. Tingenone (TG) and 22-hydroxytingenone (22-HTG) are quinonemethide triterpenes found in the Amazonian plant Salacia impressifolia (Celastraceae), with cytotoxic properties in different histological types of cancer cells. In the present work, we investigated the anti-AML action mechanism of TG and 22-HTG in the AML HL-60 cell line. Both compounds exhibited potent cytotoxicity in a panel of cancer cell lines. Mechanistic studies found that TG and 22-HTG reduced cell growth and caused the externalization of phosphatidylserine, the fragmentation of internucleosomal DNA and the loss of mitochondrial transmembrane potential in HL-60 cells. In addition, pre-incubation with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, prevented TG- and 22-HTG-induced apoptosis, indicating cell death by apoptosis via a caspase-dependent pathway. The analysis of the RNA transcripts of several genes indicated the interruption of the cellular antioxidant system, including the downregulation of thioredoxin, as a target for TG and 22-HTG. The application of N-acetyl-cysteine, an antioxidant, completely prevented apoptosis induced by TG and 22-HTG, indicating activation of the apoptosis pathway mediated by oxidative stress. Moreover, TG and 22-HTG induced DNA double-strand break and phosphorylation of JNK2 (T183/Y185) and p38α (T180/Y182), and co-incubation with SP 600125 (JNK/SAPK inhibitor) and PD 169316 (p38 MAPK inhibitor) partially prevented apoptosis induced by TG and 22-HTG. Together, these data indicate that TG and 22-HTG are new candidate for anti-AML therapy targeting thioredoxin.}, }
@article {pmid34402711, year = {2022}, author = {O'Callaghan, C and Graudins, A and Wong, A}, title = {A two-bag acetylcysteine regimen is associated with shorter delays and interruptions in the treatment of paracetamol overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {60}, number = {3}, pages = {319-323}, doi = {10.1080/15563650.2021.1966027}, pmid = {34402711}, issn = {1556-9519}, mesh = {Acetaminophen/therapeutic use ; Acetylcysteine/therapeutic use ; *Analgesics, Non-Narcotic/therapeutic use ; Antidotes/therapeutic use ; Australia ; *Drug Overdose/drug therapy ; *Drug-Related Side Effects and Adverse Reactions/drug therapy ; Humans ; Retrospective Studies ; }, abstract = {BACKGROUND: The three-bag intravenous (IV) acetylcysteine regimen for paracetamol overdose is associated with frequent and long delays during treatment. This has not been previously studied in regard to the two-bag regimen.<br><br>AIMS: Our primary aim was to compare the cumulative duration of delays during IV acetylcysteine infusion between the three-bag and two-bag regimens. Secondary aims were to compare the frequency of delays and to identify causes for delay.<br><br>METHODS: This was a retrospective cohort study of patients receiving IV acetylcysteine for the treatment of paracetamol overdose, conducted at three Australian emergency departments. A cohort of patients treated with the three-bag regimen from October 2009 to October 2013 was compared to patients treated with the two-bag regimen from February 2014 to May 2020. Start times of each infusion were sourced from medical records and delays were calculated by comparing actual infusion time against prescribed time. Evidence of adverse drug reactions - gastrointestinal reactions and cutaneous and systemic non-allergic anaphylactoid reactions (NAARs) - were also recorded.<br><br>RESULTS: The three-bag cohort included 271 cases and the two-bag cohort included 598 cases. Delays were significantly shorter in the two-bag cohort, compared to the three-bag cohort: median delay 35&#x2009;min (IQR: 15, 70) vs 65&#x2009;min (IQR: 40, 105), p&#x2009;<&#x2009;0.01. Delays longer than 1&#x2009;h were less frequent in the two-bag cohort: 31% vs 51%, p&#x2009;<&#x2009;0.01. NAARs were associated with significantly longer delays in both cohorts and were more frequent in the three-bag cohort.<br><br>CONCLUSIONS: The two-bag regimen was associated with significantly fewer and shorter delays. NAARs, which were more frequent in the three-bag cohort, were associated with significantly longer delays.}, }
@article {pmid34402583, year = {2021}, author = {Ghosh, R and Siddarth, M and Kare, PK and Banerjee, BD and Kalra, OP and Tripathi, AK}, title = {β-Endosulfan-mediated induction of pro-fibrotic markers in renal (HK-2) cells in vitro: A new insight in the pathogenesis of chronic kidney disease of unknown etiology.}, journal = {Environmental toxicology}, volume = {36}, number = {11}, pages = {2354-2360}, doi = {10.1002/tox.23349}, pmid = {34402583}, issn = {1522-7278}, support = {//Department of Science and Technology, Ministry of Science and Technology, India/ ; }, mesh = {*Endosulfan/toxicity ; Epithelial Cells/pathology ; Epithelial-Mesenchymal Transition ; Fibrosis ; Humans ; Kidney/pathology ; Kidney Tubules, Proximal/pathology ; *Renal Insufficiency, Chronic/chemically induced/pathology ; Transforming Growth Factor beta1 ; }, abstract = {Chronic kidney disease of unknown etiology (CKDu), manifested clinically as tubulo interstitial fibrosis, has emerged as the second major cause of chronic kidney disease (CKD) in the Indian subcontinent and various agrochemicals have been implicated in its occurance. Among the agrochemicals organochlorine pesticides particularly endosulfan is well known for its toxicity and recent residue analysis have shown its presence in the blood samples of general population. In this present study, we have investigated the consequences of endosulfan exposure at a concentration (0.01 μM) equivalent to their highest reported presence in human blood sample of some CKDu patients, to human renal proximal tubular epithelial (HK-2) cell line with regard to ROS generation and expression of profibrotic and epithelial to mesenchymal (EMT) markers in order to find out endosulfan's ability to induce profibrotic changes in renal cell. We demonstrated a significant increase in intracellular ROS generation and increased expression of TGF-β1 when cells were incubated with β-endosulfan (0.01 μM) indicating occurrence of oxidative stress and fibrotic process. Again, decreased expression of epithelial marker E-cadherin and increase in the expression of mesenchymal marker α-smooth muscle actin (α-SMA) suggest possible onset of EMT process. Pre-treatment with 5 mM concentration of anti-oxidant N-acetyl cysteine partially attenuated the above process. In conclusion, these findings suggest possible involvement of β-endosulfan in the development of CKDu through oxidative stress and profibrotic signaling.}, }
@article {pmid34399087, year = {2021}, author = {Zhan, X and Xie, Y and Sun, L and Si, Q and Shang, H}, title = {Dexamethasone may inhibit placental growth by blocking glucocorticoid receptors via phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin and reactive oxygen species/AMP-activated protein kinase signalling pathways in human placental JEG-3 cells.}, journal = {Reproduction, fertility, and development}, volume = {33}, number = {12}, pages = {700-712}, doi = {10.1071/RD21048}, pmid = {34399087}, issn = {1448-5990}, mesh = {AMP-Activated Protein Kinases/metabolism ; Apoptosis/drug effects ; Cell Line ; Dexamethasone/*pharmacology ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Placenta/*drug effects/metabolism ; Pregnancy ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Glucocorticoid/*metabolism ; Signal Transduction/*drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {This study explored the molecular mechanism underlying the effects of dexamethasone (DEX, 1 µM) on glucose transporters (GLUT) in JEG-3 human placental choriocarcinoma cells. JEG-3 cells were treated with DEX, an expression plasmid encoding human glucocorticoid receptor α (GRα), pcDNA3.1-GRα, GRα short interference (si) RNA, LY294002, xanthine oxidase (XO)/hypoxanthine (HX), rapamycin, insulin-like growth factor (IGF) 1, N-acetylcysteine (NAC) or phosphatidic acid (PA), and cell proliferation, apoptosis, mitochondrial membrane potential (MMP), human chorionic gonadotrophin (hCG) content, human placental lactogen (hPL) content, glucose uptake, reactive oxygen species levels and signalling pathway modulation were evaluated. Treatment of JEG-3 cells with DEX (1 µM), GRα siRNA, LY294002 (50 µM), XO/HX (7.2 µM/36 nM) or rapamycin (80 nM) inhibited cell proliferation, induced apoptosis, significantly decreased MMP and hCG and hPL content and increased ROS levels. In addition, glucose uptake was decreased through downregulation of the mRNA and protein expression of GRα, GLUT1 and GLUT3. Treatment of JEG-3 cells with GRα siRNA, LY294002, XO/HX or rapamycin inhibited phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, glycogen synthase kinase 3 and mammalian target of rapamycin (mTOR) and induced the phosphorylation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex 2. The effects of GRα overexpression and IGF1 (100 nM), NAC (5 nM) or PA (100 µM) treatment on JEG-3 cells contrasted with those of DEX treatment. DEX blocked glucose uptake by downregulating GRα expression, which reduced GLUT1 and GLUT3 mRNA and protein expression, which, in turn, may have inhibited the PI3K/AKT/mTOR pathway and activated the ROS/AMPK pathway.}, }
@article {pmid34397062, year = {2021}, author = {Qu, L and Fu, R and Ma, X and Fan, D}, title = {Hepatoprotective effects of ginsenoside Rk3 in acetaminophen-induced liver injury in mice by activation of autophagy.}, journal = {Food &amp; function}, volume = {12}, number = {19}, pages = {9128-9140}, doi = {10.1039/d1fo02081a}, pmid = {34397062}, issn = {2042-650X}, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; *Autophagy ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology/*prevention &amp; control ; Chloroquine/pharmacology ; Cytokines/metabolism ; Ginsenosides/administration &amp; dosage/*therapeutic use ; Liver/*drug effects/pathology ; Male ; Mice ; Mice, Inbred ICR ; Oxidative Stress ; }, abstract = {Acetaminophen (APAP)-induced acute liver injury (AIALI) is one of the most common causes of acute liver failure. Owing to the limitations of N-acetylcysteine (NAC), which is the only antidote currently used in clinical practice for APAP, there is a need to develop new therapies that can provide extensive protection against AIALI. Ginsenoside Rk3 is a rare ginsenoside extracted from Panax notoginseng and a previous study has reported its excellent hepatoprotective function. In this study, we explored the therapeutic potential of ginsenoside Rk3 in APAP-induced acute liver injury. We found that ginsenoside Rk3 could reduce APAP-induced hepatotoxicity by reducing serum alanine aminotransferase and aspartate aminotransferase activity and pathological damage to the liver. Moreover, ginsenoside Rk3 could inhibit APAP-induced liver inflammation and oxidative stress by inhibiting the production of oxidative molecules, increasing the production of antioxidant molecules, and reducing the infiltration of inflammatory cells and the production of pro-inflammatory cytokines. Further mechanistic investigations revealed that the therapeutic effect of ginsenoside Rk3 was mainly dependent on the continuous activation of autophagy. Chloroquine, an autophagy inhibitor, was found to inhibit these protective effects. Therefore, ginsenoside Rk3 shows potential as a novel hepatoprotective agent to prevent drug-induced liver injury.}, }
@article {pmid34392569, year = {2021}, author = {Morgan, AM and Hassanen, EI and Ogaly, HA and Al Dulmani, SA and Al-Zahrani, FAM and Galal, MK and Kamel, S and Rashad, MM and Ibrahim, MA and Hussien, AM}, title = {The ameliorative effect of N-acetylcysteine against penconazole induced neurodegenerative and neuroinflammatory disorders in rats.}, journal = {Journal of biochemical and molecular toxicology}, volume = {35}, number = {10}, pages = {e22884}, doi = {10.1002/jbt.22884}, pmid = {34392569}, issn = {1099-0461}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Apoptosis/drug effects ; Behavior, Animal/drug effects ; Brain/metabolism/pathology ; Caspase 3/metabolism ; Elevated Plus Maze Test ; Male ; Malondialdehyde/metabolism ; Neurodegenerative Diseases/*chemically induced/*drug therapy/metabolism/psychology ; Neuroinflammatory Diseases/*chemically induced/*drug therapy/metabolism/psychology ; Neuroprotective Agents/*administration &amp; dosage ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Treatment Outcome ; Triazoles/*adverse effects ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Penconazole (PEN) is a widely used systemic fungicide to treat various fungal diseases in plants but it leaves residues in crops and food products causing serious environmental and health problems. N-acetylcysteine (NAC) is a precursor of the antioxidant glutathione in the body and exerts prominent antioxidant and anti-inflammatory effects. The present study aimed to explore the mechanistic way of NAC to ameliorate the PEN neurotoxicity in male rats. Twenty-eight male rats were randomly divided into four groups (n = 7) and given the treated material via oral gavage for 10 days as the following: Group I (distilled water), Group II (50 mg/kg body weight [bwt] PEN), Group III (200 mg/kg bwt NAC), and Group IV (NAC + PEN). After 10 days all rats were subjected to behavioral assessment and then euthanized to collect brain tissues to perform oxidative stress, molecular studies, and pathological examination. Our results revealed that PEN exhibits neurobehavioral toxicity manifested by alteration in the forced swim test, elevated plus maze test, and Y-maze test. There were marked elevations in malondialdehyde levels with reduction in total antioxidant capacity levels, upregulation of messenger RNA levels of bax, caspase 3, and caspase 9 genes with downregulation of bcl2 genes. In addition, brain sections showed marked histopathological alteration in the cerebrum and cerebellum with strong bax and inducible nitric oxide synthetase protein expression. On the contrary, cotreatment of rats with NAC had the ability to improve all the abovementioned neurotoxic parameters. The present study can conclude that NAC has a neuroprotective effect against PEN-induced neurotoxicity via its antioxidant, anti-inflammatory, and antiapoptotic effect. We recommend using NAC as a preventive and therapeutic agent for a wide variety of neurodegenerative and neuroinflammatory disorders.}, }
@article {pmid34390848, year = {2021}, author = {Qiu, X and Yu, Y and Liu, H and Li, X and Sun, W and Wu, W and Liu, C and Miao, L}, title = {Remodeling the periodontitis microenvironment for osteogenesis by using a reactive oxygen species-cleavable nanoplatform.}, journal = {Acta biomaterialia}, volume = {135}, number = {}, pages = {593-605}, doi = {10.1016/j.actbio.2021.08.009}, pmid = {34390848}, issn = {1878-7568}, mesh = {Cell Differentiation ; Cells, Cultured ; Humans ; *Osteogenesis ; Periodontal Ligament ; *Periodontitis/drug therapy ; Reactive Oxygen Species ; }, abstract = {Modestly removing the excessive reactive oxygen species (ROS) plays a crucial role in regulating the microenvironment of periodontitis and provides favorable conditions for osteogenesis. However, the current strategy for scavenging ROS is not controllable, substantially limiting the outcomes in periodontitis. Herein, we introduced a controllable ROS-scavenging nanoplatform by encasing N-acetylcysteine (NAC, (a well-known ROS scavenger) into tailor-made ROS-cleavable amphiphilic polymer nanoparticles (PEG-ss-PCL NPs) as an intracellular delivery carrier. The existing ROS in the inflammatory microenvironment facilitated polymer degradation via breakage of thioketal bonds, and then led to encapsulated NAC release. NAC eliminated all ROS induced by lipopolysaccharide (LPS), while PssL-NAC adjusted the ROS level slightly higher than that of the control group. The percentage of apoptotic cells cultured with NAC and PssL-NAC decreased observably compared with that of cells cultured with 10 µg/ml LPS. The microenvironment regulated by PssL-NAC was highly suitable for osteogenic differentiation based on PCR and Western blot results, which showed higher expression levels of BMP2, Runx2, and PKA. Analysis of ALP activity and Alizarin red S staining showed consistent results. Additionally, the injection of PssL-NAC into the periodontitis area could alleviate the tissue destruction induced by ligation of the maxillary second molar. PssL-NAC showed a better ability to decrease osteoclast activity and inflammation, consequently improving the restoration of destroyed tissue. Our study suggests that ROS-responsive polymer nanoparticles loaded with NAC (PssL-NAC) can be new promising materials for the treatment of periodontitis. STATEMENT OF SIGNIFICANCE: More and more studies indicate that periodontal tissue damage is closely related to the high reactive oxygen species (ROS) environment. Excessive ROS will aggravate periodontal tissue damage and is not conducive to tissue repair. However, as an essential signal molecule in human physiological activities, ROS absence is also useless for tissue repair. In this study, we proposed to improve ROS imbalance in the environment of periodontitis as a strategy to promote periodontal regeneration and successfully synthesized a smart drug-releasing nanoplatform that can respond to ROS. Besides, we validated its ability to regulate the ROS environment and promote osteogenesis through experimental data in vivo and in vitro.}, }
@article {pmid34389427, year = {2021}, author = {Smiley, CE and Saleh, HK and Nimchuk, KE and Garcia-Keller, C and Gass, JT}, title = {Adolescent exposure to delta-9-tetrahydrocannabinol and ethanol heightens sensitivity to fear stimuli.}, journal = {Behavioural brain research}, volume = {415}, number = {}, pages = {113517}, pmid = {34389427}, issn = {1872-7549}, support = {K99 DA047426/DA/NIDA NIH HHS/United States ; R01 AA024526/AA/NIAAA NIH HHS/United States ; T32 AA007474/AA/NIAAA NIH HHS/United States ; }, mesh = {Age Factors ; Animals ; Behavior, Animal/*drug effects ; Cannabinoid Receptor Agonists/administration &amp; dosage/*pharmacology ; Central Nervous System Depressants/administration &amp; dosage/*pharmacology ; Conditioning, Classical/*drug effects ; Dronabinol/administration &amp; dosage/*pharmacology ; Ethanol/administration &amp; dosage/*pharmacology ; Fear/*drug effects ; Male ; Rats ; Rats, Wistar ; }, abstract = {Cannabis use disorder (CUD) has doubled in prevalence over the past decade as a nation-wide trend toward legalization allows for increased drug accessibility. As a result, marijuana has become the most commonly used illicit drug in the United States particularly among the adolescent population. This is especially concerning since there is greater risk for the harmful side effects of drug use during this developmental period due to ongoing brain maturation. Increasing evidence indicates that CUD often occurs along with other debilitating conditions including both alcohol use disorder (AUD) and anxiety disorders such post-traumatic stress disorder (PTSD). Additionally, exposure to cannabis, alcohol, and stress can induce alterations in glutamate regulation and homeostasis in the prefrontal cortex (PFC) that may lead to impairments in neuronal functioning and cognition. Therefore, in order to study the relationship between drug exposure and the development of PTSD, these studies utilized rodent models to determine the impact of adolescent exposure to delta-9-tetrahydrocannabinol (THC) and ethanol on responses to fear stimuli during fear conditioning and used calcium imaging to measure glutamate activity in the prelimbic cortex during this behavioral paradigm. The results from these experiments indicate that adolescent exposure to THC and ethanol leads to enhanced sensitivity to fear stimuli both behaviorally and neuronally. Additionally, these effects were attenuated when animals were treated with the glutamatergic modulator N-acetylcysteine (NAC). In summary, these studies support the hypothesis that adolescent exposure to THC and ethanol leads to alterations in fear stimuli processing through glutamatergic reliant modifications in PFC signaling.}, }
@article {pmid34389161, year = {2021}, author = {Garcia, AA and Koperniku, A and Ferreira, JCB and Mochly-Rosen, D}, title = {Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives.}, journal = {Trends in pharmacological sciences}, volume = {42}, number = {10}, pages = {829-844}, pmid = {34389161}, issn = {1873-3735}, support = {F32 HD008442/HD/NICHD NIH HHS/United States ; R01 HD084422/HD/NICHD NIH HHS/United States ; T32 GM113854/GM/NIGMS NIH HHS/United States ; }, mesh = {*Glucosephosphate Dehydrogenase Deficiency/genetics ; Glutathione/metabolism ; Humans ; Mutation ; Oxidation-Reduction ; Oxidative Stress ; }, abstract = {Glucose-6-phosphate dehydrogenase (G6PD) maintains redox balance in a variety of cell types and is essential for erythrocyte resistance to oxidative stress. G6PD deficiency, caused by mutations in the G6PD gene, is present in ~400 million people worldwide, and can cause acute hemolytic anemia. Currently, there are no therapeutics for G6PD deficiency. We discuss the role of G6PD in hemolytic and nonhemolytic disorders, treatment strategies attempted over the years, and potential reasons for their failure. We also discuss potential pharmacological pathways, including glutathione (GSH) metabolism, compensatory NADPH production routes, transcriptional upregulation of the G6PD gene, highlighting potential drug targets. The needs and opportunities described here may motivate the development of a therapeutic for hematological and other chronic diseases associated with G6PD deficiency.}, }
@article {pmid34387821, year = {2022}, author = {Zhao, H and Fu, L and Xiang, HX and Xiang, Y and Li, MD and Lv, BB and Tan, ZX and Gao, L and Zhang, C and Xu, DX}, title = {N-acetylcysteine alleviates pulmonary inflammatory response during benzo[a]pyrene-evoked acute lung injury.}, journal = {Environmental science and pollution research international}, volume = {29}, number = {3}, pages = {3474-3486}, pmid = {34387821}, issn = {1614-7499}, support = {81670060//National Natural Science Foundation of China/ ; 91743105//National Natural Science Foundation of China/ ; 2020GQFY05//National Natural Science Foundation Incubation Program of the Second Affiliated Hospital of Anhui Medical University/ ; AHWJ2021b091//Scientific Research of Health Commission in Anhui Province/ ; }, mesh = {Acetylcysteine/pharmacology ; *Acute Lung Injury/chemically induced/drug therapy ; Animals ; Benzo(a)pyrene/toxicity ; Lung ; Mice ; NF-kappa B ; *Pneumonia ; }, abstract = {Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon, exists widely in automobile emissions and polluted atmosphere. The current study aimed to describe pulmonary inflammation during BaP-induced acute lung injury (ALI). All mice except controls were intratracheally instilled with a single dose of BaP (90 μg per mouse). The alveolar structure was damaged, accompanied by numerous inflammatory cell infiltration around pulmonary interstitium and small airway. Airway wall area and mean linear intercept were reduced in BaP-exposed mouse lungs. By contrast, airway wall thickness and destructive index were elevated in BaP-exposed mouse lungs. Several inflammatory genes, such as Tnf-α, Il-1β, Il-6, Mip-2, Kc, and Mcp-1, were upregulated in mouse lungs. Phosphorylated IκBα was elevated in BaP-exposed mouse lungs. Nuclear translocation of NF-κB p65 and p50 was accordingly observed in BaP-exposed mouse lungs. Several molecules of the MAPK pathway, including JNK, ERK1/2, and p38, were activated in mouse lungs. Of interest, pretreatment with N-acetylcysteine (NAC), an antioxidant, alleviated BaP-induced ALI. Moreover, NAC attenuated BaP-induced inflammatory cell infiltration in mouse lungs and inflammatory gene upregulation in A549 cells. In addition, NAC attenuated BaP-induced NF-κB activation in A549 cells and mouse lungs. These results suggest that NAC alleviates pulmonary inflammatory response during BaP-evoked ALI.}, }
@article {pmid34387802, year = {2021}, author = {Aboalgasm, H and Ballo, R and Gwanyanya, A}, title = {Organisational alteration of cardiac myofilament proteins by hyperglycaemia in mouse embryonic stem cell-derived cardiomyocytes.}, journal = {Journal of muscle research and cell motility}, volume = {42}, number = {3-4}, pages = {419-428}, pmid = {34387802}, issn = {1573-2657}, mesh = {Actinin ; Animals ; Glucose ; *Hyperglycemia ; Mice ; Mouse Embryonic Stem Cells ; *Myocytes, Cardiac ; Myofibrils ; }, abstract = {The exposure of the developing foetal heart to hyperglycaemia in mothers with diabetes mellitus is a major risk factor for foetal cardiac complications that lead to heart failure. We studied the effects of hyperglycaemia on the layout of cardiac myofilament proteins in stem cell-derived cardiomyocytes and their possible underlying mechanisms. Mouse embryonic stem cells (mESCs) were differentiated into cardiac-like cells and cultured in media containing baseline- or high glucose concentrations. Cellular biomarkers were detected using Western blot analysis, immunocytochemistry, 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay, and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. High glucose decreased the proportion of cardiac troponin T and α-actinin 2 positive mESCs as well as disrupted the α-actinin 2 striated pattern and the distribution of the cardiac myosin heavy chain α- and β isoforms. However, there was no alteration of the cellular EdU uptake nor the expression of the receptor of advanced glycation end-product (RAGE). High glucose also increased the presence of the oxidative stress marker nitrotyrosine as well as the number of TUNEL-stained nuclei in cardiac-like cells. Treatment with the antioxidant N-acetyl cysteine decreased the number of TUNEL-stained cells in high glucose and improved the α-actinin 2 striated pattern. Hyperglycaemia negatively impacted the expression and cellular organisation of cardiac myofilament proteins in mESC-derived cardiomyocytes through oxidative stress. The results add further insights into the pathophysiological mechanisms of cardiac contractile dysfunction in diabetic cardiac developmental disease.}, }
@article {pmid34387415, year = {2021}, author = {Luo, SY and Liu, C and Ding, J and Gao, XM and Wang, JQ and Zhang, YB and Du, C and Hou, CC and Zhu, JQ and Lou, B and Wu, XF and Shen, WL}, title = {Scavenging reactive oxygen species is a potential strategy to protect Larimichthys crocea against environmental hypoxia by mitigating oxidative stress.}, journal = {Zoological research}, volume = {42}, number = {5}, pages = {592-605}, pmid = {34387415}, issn = {2095-8137}, mesh = {Animals ; Antioxidants/*metabolism ; Cell Line ; Cell Survival ; Environment ; Fishes/*metabolism ; Homeostasis ; NADP ; Oxidative Stress/*physiology ; Oxygen/*chemistry/*metabolism ; *Reactive Oxygen Species ; }, abstract = {The large yellow croaker (Larimichthys crocea), which is an economically important mariculture fish in China, is often exposed to environmental hypoxia. Reactive oxygen species (ROS) homeostasis is essential for the maintenance of normal physiological conditions in an organism. Direct evidence that environmental hypoxia leads to ROS overproduction is scarce in marine fish. Furthermore, the sources of ROS overproduction in marine fish under hypoxic stress are poorly known. In this study, we investigated the effects of hypoxia on redox homeostasis in L. crocea and the impact of impaired redox homeostasis on fish. We first confirmed that hypoxia drove ROS production mainly via the mitochondrial electron transport chain and NADPH oxidase complex pathways in L. crocea and its cell line (large yellow croaker fry (LYCF) cells). We subsequently detected a marked increase in the antioxidant systems of the fish. However, imbalance between the pro-oxidation and antioxidation systems ultimately led to excessive ROS and oxidative stress. Cell viability showed a remarkable decrease while oxidative indicators, such as malondialdehyde, protein carbonylation, and 8-hydroxy-2 deoxyguanosine, showed a significant increase after hypoxia, accompanied by tissue damage. N-acetylcysteine (NAC) reduced ROS levels, alleviated oxidative damage, and improved cell viability in vitro. Appropriate uptake of ROS scavengers (e.g., NAC and elamipretide Szeto-Schiller-31) and inhibitors (e.g., apocynin, diphenylene iodonium, and 5-hydroxydecanoate) may be effective at overcoming hypoxic toxicity. Our findings highlight previously unstudied strategies of hypoxic toxicity resistance in marine fish.}, }
@article {pmid34385060, year = {2021}, author = {Guan, M and Tang, S and Chang, H and Chen, Y and Chen, F and Mu, Y and Zhao, D and Fan, W and Tian, H and Darland, DC and Zhang, Y}, title = {Development of alveolar-capillary-exchange (ACE) chip and its application for assessment of PM2.5-induced toxicity.}, journal = {Ecotoxicology and environmental safety}, volume = {223}, number = {}, pages = {112601}, pmid = {34385060}, issn = {1090-2414}, support = {P20 GM104360/GM/NIGMS NIH HHS/United States ; }, mesh = {*Air Pollutants/toxicity ; Alveolar Epithelial Cells ; Endothelial Cells ; Humans ; Lung ; Particulate Matter/toxicity ; }, abstract = {Although standard two-dimensional (2D) cell culture is an effective tool for cell studies, monolayer cultivation can yield imperfect or misleading information about numerous biological functions. In this study, we developed an alveolar-capillary exchange (ACE) chip aiming to simulate the cellular microenvironment at the alveolar-capillary interface. The ACE chip was designed with two chambers for culturing alveolar epithelial cells and vascular endothelial cells separately, which are separated by a microporous polycarbonate film that allows for the exchange of soluble biomolecules. Using this model, we further tested the toxic effects of fine particulate matter (PM2.5), a form of airborne pollutant known to induce adverse effects on human respiratory system. These effects are largely associated with the ability of PM2.5 to penetrate the alveoli, where it negatively affects the pulmonary function. Our results indicate that alveolar epithelial cells cultured in the ACE chip in solo and coculture with vascular endothelial cells underwent oxidative injury-induced apoptosis mediated via the PEAK-eIF2α signaling pathway of endoplasmic reticulum stress. The use of ACE chip in an alveolar epithelial cell-vascular endothelial cell coculture model revealed cellular vulnerability to PM2.5. Therefore, this chip provides a feasible surrogate approach in vitro for investigating and simulating the cellular microenvironment responses associated with ACE in vivo.}, }
@article {pmid34377857, year = {2021}, author = {Shahrampour, S and Heholt, J and Wang, A and Vedaei, F and Mohamed, FB and Alizadeh, M and Wang, Z and Zabrecky, G and Wintering, N and Bazzan, AJ and Leist, TP and Monti, DA and Newberg, AB}, title = {N-acetyl cysteine administration affects cerebral blood flow as measured by arterial spin labeling MRI in patients with multiple sclerosis.}, journal = {Heliyon}, volume = {7}, number = {7}, pages = {e07615}, pmid = {34377857}, issn = {2405-8440}, abstract = {BACKGROUND: The purpose of this study was to explore if administration of N-acetyl-cysteine (NAC) in patients with multiple sclerosis (MS) resulted in altered cerebral blood flow (CBF) based on Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI).<br><br>METHODS: Twenty-three patients with mild to moderate MS, (17 relapsing remitting and 6 primary progressive) were randomized to either NAC plus standard of care (N = 11), or standard of care only (N = 12). The experimental group received NAC intravenously (50 mg/kg) once per week and orally (500mg 2x/day) the other six days. Patients in both groups were evaluated initially and after 2 months (of receiving the NAC or waitlist control) with ASL MRI to measure CBF. Clinical symptom questionnaires were also completed at both time points.<br><br>RESULTS: The CBF data showed significant differences in several brain regions including the pons, midbrain, left temporal and frontal lobe, left thalamus, right middle frontal lobe and right temporal/hippocampus (p < 0.001) in the MS group after treatment with NAC, when compared to the control group. Self-reported scores related to cognition and attention were also significantly improved in the NAC group as compared to the control group.<br><br>CONCLUSIONS: The results of this study suggest that NAC administration alters resting CBF in MS patients, and this is associated with qualitative improvements in cognition and attention. Given these findings, large scale efficacy studies will be of value to determine the potential clinical impact of NAC over the course of illness in patients with MS, as well as the most effective dosages and differential effects across subpopulations.}, }
@article {pmid34371004, year = {2022}, author = {Guo, Q and Fan, X and Zhu, S and Zhao, X and Fang, N and Guo, M and Liu, Z and Han, Y}, title = {Comparing N-acetylcysteine with sodium thiosulfate for relieving symptoms caused by Lugol's iodine chromoendoscopy: a randomized, double-blind trial.}, journal = {Gastrointestinal endoscopy}, volume = {95}, number = {2}, pages = {249-257}, doi = {10.1016/j.gie.2021.07.025}, pmid = {34371004}, issn = {1097-6779}, mesh = {Acetylcysteine/therapeutic use ; Coloring Agents ; *Esophageal Neoplasms ; *Esophageal Squamous Cell Carcinoma ; Esophagoscopy/methods ; Humans ; Iodides/therapeutic use ; Thiosulfates ; }, abstract = {BACKGROUND AND AIMS: Lugol's iodine chromoendoscopy is an important method to detect esophageal squamous cell carcinoma. Sodium thiosulfate solution (STS) has been used to neutralize iodine after Lugol's chromoendoscopy; however, it is not available in many medical centers. The aim of the current study was to assess the efficacy of N-acetylcysteine solution (NAC) for relieving symptoms caused by Lugol's iodine chromoendoscopy.<br><br>METHODS: Patients were randomized to receive either STS or NAC after spraying Lugol's iodine solution on the esophagus. The neutralizing effects for residual iodine in the esophagus and gastric mucous pool were observed. The primary endpoint was the intensity of retrosternal pain and/or heartburn measured by a visual analog scale (VAS) score 30 minutes after chromoendoscopy. Secondary endpoints were the rate of patients with any adverse symptom, rate of moderate to severe retrosternal discomfort occurring, and heart rate variability between time points before and after chromoendoscopy.<br><br>RESULTS: The neutralization rates for residual iodine between the NAC and STS groups were not significantly different (P > .999). The difference of median VAS scores between the NAC and STS groups 30 minutes after chromoendoscopy was .0 (P&#xa0;= .719; 95% confidence interval, .0-.0), and the 95% confidence interval higher limit was .0, which was less than our prespecified margin of .5, concluding an noninferiority of NAC with regard to STS. There was no significant difference between the 2 groups regarding the rate of patients with any adverse symptom, rate of moderate to severe retrosternal discomfort, or heart rate variability at 5 minutes or 30 minutes after chromoendoscopy.<br><br>CONCLUSION: As a very easily accessible reagent in clinical circumstances, NAC can also alleviate mucosal irritation symptoms induced by Lugol's chromoendoscopy at similar efficacy as STS and can be routinely recommended. (Clinical trial registration number: NCT04764643.).}, }
@article {pmid34369229, year = {2021}, author = {Kuttikrishnan, S and Prabhu, KS and Khan, AQ and Alali, FQ and Ahmad, A and Uddin, S}, title = {Thiostrepton inhibits growth and induces apoptosis by targeting FoxM1/SKP2/MTH1 axis in B-precursor acute lymphoblastic leukemia cells.}, journal = {Leukemia &amp; lymphoma}, volume = {62}, number = {13}, pages = {3170-3180}, doi = {10.1080/10428194.2021.1957873}, pmid = {34369229}, issn = {1029-2403}, mesh = {*Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; *Forkhead Box Protein M1/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; *Thiostrepton/pharmacology ; }, abstract = {Forkhead box M1 (FoxM1) is a transcription factor that plays an important role in the etiology of many cancers, however, its role has not been elucidated in B-precursor acute lymphoblastic leukemia (B-pre-ALL). In the current study, we showed that the downregulation of FoxM1 by its inhibitor thiostrepton inhibited cell viability and induced caspase-dependent apoptosis in a panel of B-pre-ALL cell lines. Thiostrepton led downregulation of FoxM1 accompanied by decreased expression of Aurora kinase A, B, matrix metalloproteinases, and oncogene SKP2 as well as MTH1. Downregulation of the FoxM1/SKP2/MTH1 axis led to increase in the Bax/Bcl2 ratio and suppression of antiapoptotic proteins. Thiostrepton-mediated apoptosis was prevented by N-acetyl cysteine, a scavenger of reactive oxygen species. Co-treatment of B-pre-ALL with subtoxic doses of thiostrepton and bortezomib potentiated the proapoptotic action. Altogether, our results suggest that targeting FoxM1expression could be an attractive strategy for the treatment of B-pre-ALL.}, }
@article {pmid34367464, year = {2021}, author = {Zhou, XY and Zhang, J and Li, Y and Chen, YX and Wu, XM and Li, X and Zhang, XF and Ma, LZ and Yang, YZ and Zheng, KM and Liu, YD and Wang, Z and Chen, SL}, title = {Advanced Oxidation Protein Products Induce G1/G0-Phase Arrest in Ovarian Granulosa Cells via the ROS-JNK/p38 MAPK-p21 Pathway in Premature Ovarian Insufficiency.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6634718}, pmid = {34367464}, issn = {1942-0994}, mesh = {Advanced Oxidation Protein Products/genetics/*metabolism ; Animals ; Apoptosis ; *Cell Cycle Checkpoints ; Cell Proliferation ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/genetics/*metabolism ; Female ; G1 Phase ; Gene Expression Regulation ; Granulosa Cells/metabolism/pathology ; Humans ; JNK Mitogen-Activated Protein Kinases/genetics/*metabolism ; Primary Ovarian Insufficiency/genetics/metabolism/*pathology ; Prognosis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Resting Phase, Cell Cycle ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {The mechanism underlying the role of oxidative stress and advanced oxidation protein products (AOPPs) in the aetiology of premature ovarian insufficiency (POI) is poorly understood. Here, we investigated the plasma AOPP level in POI patients and the effects of AOPPs on granulosa cells both in vitro and in vivo. KGN cells were treated with different AOPP doses, and cell cycle distribution, intracellular reactive oxygen species (ROS), and protein expression levels were measured. Sprague-Dawley (SD) rats were treated daily with PBS, rat serum albumin, AOPP, or AOPP+ N-acetylcysteine (NAC) for 12 weeks to explore the effect of AOPPs on ovarian function. Plasma AOPP concentrations were significantly higher in both POI and biochemical POI patients than in controls and negatively correlated with anti-Müllerian hormone and the antral follicle count. KGN cells treated with AOPP exhibited G1/G0-phase arrest. AOPP induced G1/G0-phase arrest in KGN cells by activating the ROS-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK)-p21 pathway. Pretreatment with NAC, SP600125, SB203580, and si-p21 blocked AOPP-induced G1/G0-phase arrest. In SD rats, AOPP treatment increased the proportion of atretic follicles, and NAC attenuated the adverse effects of AOPPs in the ovary. In conclusion, we provide mechanistic evidence that AOPPs may induce cell cycle arrest in granulosa cells via the ROS-JNK/p38 MAPK-p21 pathway and thus may be a novel biomarker of POI.}, }
@article {pmid34366878, year = {2021}, author = {Ningappa, M and Adenuga, M and Ngo, KA and Mohamed, N and Narayanan, T and Prasadan, K and Ashokkumar, C and Das, J and Schmitt, L and Hartman, H and Sehrawat, A and Salgado, CM and Reyes-Mugica, M and Gittes, GK and Lo, CW and Subramaniam, S and Sindhi, R}, title = {Mechanisms of Impaired Lung Development and Ciliation in Mannosidase-1-Alpha-2 (Man1a2) Mutants.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {658518}, pmid = {34366878}, issn = {1664-042X}, support = {R01 DK109365/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Ciliary defects cause heterogenous phenotypes related to mutation burden which lead to impaired development. A previously reported homozygous deletion in the Man1a2 gene causes lethal respiratory failure in newborn pups and decreased lung ciliation compared with wild type (WT) pups. The effects of heterozygous mutation, and the potential for rescue are not known.<br><br>PURPOSE: We hypothesized that survival and lung ciliation, (a) would decrease progressively in Man1a2 [+/-] heterozygous and Man1a2 [-/-] null newborn pups compared with WT, and (b) could be enhanced by gestational treatment with N-Acetyl-cysteine (NAC), an antioxidant.<br><br>METHODS: Man1a2[+/-] adult mice were fed NAC or placebo from a week before breeding through gestation. Survival of newborn pups was monitored for 24 h. Lungs, liver and tails were harvested for morphology, genotyping, and transcriptional profiling.<br><br>RESULTS: Survival (p = 0.0001, Kaplan-Meier) and percent lung ciliation (p = 0.0001, ANOVA) measured by frequency of Arl13b[+] respiratory epithelial cells decreased progressively, as hypothesized. Compared with placebo, gestational NAC treatment enhanced (a) lung ciliation in pups with each genotype, (b) survival in heterozygous pups (p = 0.017) but not in WT or null pups. Whole transcriptome of lung but not liver demonstrated patterns of up- and down-regulated genes that were identical in living heterozygous and WT pups, and completely opposite to those in dead heterozygous and null pups. Systems biology analysis enabled reconstruction of protein interaction networks that yielded functionally relevant modules and their interactions. In these networks, the mutant Man1a2 enzyme contributes to abnormal synthesis of proteins essential for lung development. The associated unfolded protein, hypoxic and oxidative stress responses can be mitigated with NAC. Comparisons with the developing human fetal lung transcriptome show that NAC likely restores normal vascular and epithelial tube morphogenesis in Man1a2 mutant mice.<br><br>CONCLUSION: Survival and lung ciliation in the Man1a2 mutant mouse, and its improvement with N-Acetyl cysteine is genotype-dependent. NAC-mediated rescue depends on the central role for oxidative and hypoxic stress in regulating ciliary function and organogenesis during development.}, }
@article {pmid34363627, year = {2021}, author = {An, J and Yang, J and Wei, Y and Liu, Y and Song, Y and Zhang, Z and Pan, Y}, title = {Identification of the metabolites of rhapontigenin in rat and human by ultra-high-performance liquid chromatography-high-resolution mass spectrometry.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {35}, number = {20}, pages = {e9180}, doi = {10.1002/rcm.9180}, pmid = {34363627}, issn = {1097-0231}, mesh = {Animals ; Chromatography, High Pressure Liquid/methods ; Hepatocytes/chemistry/metabolism ; Humans ; Male ; Microsomes, Liver/chemistry/metabolism ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Electrospray Ionization/methods ; Stilbenes/*chemistry/*metabolism/urine ; }, abstract = {RATIONALE: Rhapontigenin, a stilbene compound isolated from the medicinal plant of rhubarb rhizomes, has shown a variety of biological activities. The purpose of this study was to identify and characterize the metabolites of rhapontigenin in rat liver microsomes, hepatocytes, urine, and human liver microsomes and hepatocytes.<br><br>METHODS: The samples were analyzed by ultra-high-performance liquid chromatography combined with electrospray ionization quadrupole/orbitrap high-resolution mass spectrometry (UPLC-Q/Orbitrap-HRMS). The structures of the metabolites were interpreted by MS, MS/MS data, and elemental compositions.<br><br>RESULTS: A total of 11 metabolites were detected and tentatively identified. M1, identified as piceatannol, was unambiguously identified using reference standard. Our results suggested that rhapontigenin was metabolized through the following pathways: (a) demethylation to produce piceatannol (M1), which further underwent oxidation to form ortho-quinone intermediate. This intermediate was reactive and conjugated with GSH (M10 and M11), which were further converted into N-acetyl-cysteine and excreted in urine. M1 also underwent sulfation (M8) and glucuronidation (M5); (b) direct sulfation, forming M6 and M7; and (c) direct glucuronidation to form M2, M3, and M4. Glucuronidation was a major metabolic pathway in hepatocytes and urine.<br><br>CONCLUSIONS: The current study provides an overview of the metabolism of rhapontigenin, which is of great importance for us to understand the disposition of this compound.}, }
@article {pmid34361723, year = {2021}, author = {Cela-López, JM and Camacho Roldán, CJ and Gómez-Lizarraga, G and Martínez, V}, title = {A Natural Alternative Treatment for Urinary Tract Infections: Itxasol©, the Importance of the Formulation.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {15}, pages = {}, pmid = {34361723}, issn = {1420-3049}, mesh = {Acetylcysteine/chemistry/*therapeutic use ; Anti-Bacterial Agents/chemistry/therapeutic use ; Anti-Inflammatory Agents/chemistry/therapeutic use ; Antifungal Agents/chemistry/therapeutic use ; Arbutin/chemistry/*therapeutic use ; Biofilms/drug effects/growth &amp; development ; Biological Products/chemistry/*therapeutic use ; Biomimetic Materials/chemistry/therapeutic use ; Candida/drug effects/growth &amp; development/pathogenicity ; Drug Combinations ; Female ; Gram-Negative Bacteria/drug effects/growth &amp; development/pathogenicity ; Gram-Positive Bacteria/drug effects/growth &amp; development/pathogenicity ; Humans ; Male ; Microbial Sensitivity Tests ; Umbelliferones/chemistry/*therapeutic use ; Urinary Tract Infections/*drug therapy/microbiology/pathology ; }, abstract = {Genito-urinary tract infections have a high incidence in the general population, being more prevalent among women than men. These diseases are usually treated with antibiotics, but very frequently, they are recurrent and lead to the creation of resistance and are associated with increased morbidity and mortality. For this reason, it is necessary to develop new compounds for their treatment. In this work, our objective is to review the characteristics of the compounds of a new formulation called Itxasol© that is prescribed as an adjuvant for the treatment of UTIs and composed of β-arbutin, umbelliferon and n-acetyl cysteine. This formulation, based on biomimetic principles, makes Itxasol© a broad-spectrum antibiotic with bactericidal, bacteriostatic and antifungal properties that is capable of destroying the biofilm and stopping its formation. It also acts as an anti-inflammatory agent, without the adverse effects associated with the recurrent use of antibiotics that leads to renal nephrotoxicity and other side effects. All these characteristics make Itxasol© an ideal candidate for the treatment of UTIs since it behaves like an antibiotic and with better characteristics than other adjuvants, such as D-mannose and cranberry extracts.}, }
@article {pmid34358106, year = {2021}, author = {Chittasupho, C and Junmahasathien, T and Chalermmongkol, J and Wongjirasakul, R and Leesawat, P and Okonogi, S}, title = {Suppression of Intracellular Reactive Oxygen Species in Human Corneal Epithelial Cells via the Combination of Quercetin Nanoparticles and Epigallocatechin Gallate and In Situ Thermosensitive Gel Formulation for Ocular Drug Delivery.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {7}, pages = {}, pmid = {34358106}, issn = {1424-8247}, support = {JRCMU2564_014//Chiang Mai University/ ; }, abstract = {Oxidative stress can cause several severe ophthalmological diseases. In this study, we developed a thermosensitive gel as a delivery system for two antioxidant substances, namely, quercetin and epigallocatechin gallate. The quercetin was loaded in the PLGA nanoparticles using a solvent displacement method. The physical and chemical stability of the quercetin nanoparticles were evaluated, and the degradation kinetics of the quercetin in the nanoparticles was investigated. The in vitro antioxidant and intracellular reactive oxygen species inhibition of the quercetin nanoparticles, combined with the epigallocatechin gallate (EGCG), were determined using a 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and a 2,7-dichlorodihydrofluorescein fluorescent probes, respectively. The thermosensitive gel loaded with the quercetin nanoparticles and EGCG was formulated. We confirmed that quercetin nanoparticles displayed the desired physical characteristics, release kinetics, and stability. The combination of quercetin nanoparticles and EGCG suggested the additive effect of antioxidant activity. We also demonstrated the superior intracellular ROS inhibition activity of the quercetin nanoparticles and EGCG with n-acetyl cysteine. The thermosensitive gel showed an appropriate gelation temperature and time for ocular drug delivery. Our results provide promising prospects for applying the thermosensitive gel loaded with quercetin nanoparticles and EGCG as an efficient drug delivery system for antioxidant activity in human corneal epithelial cells.}, }
@article {pmid34356340, year = {2021}, author = {Minati, MA and Libert, M and Dahou, H and Jacquemin, P and Assi, M}, title = {N-Acetylcysteine Reduces the Pro-Oxidant and Inflammatory Responses during Pancreatitis and Pancreas Tumorigenesis.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {7}, pages = {}, pmid = {34356340}, issn = {2076-3921}, support = {n&#xb0;1. B.017.19F//Fonds De La Recherche Scientifique - FNRS/ ; #2018-076//Fondation contre le Cancer/ ; #7.8515.18//T&#xe9;l&#xe9;vie/ ; }, abstract = {Pancreatitis, an inflammation of the pancreas, appears to be a main driver of pancreatic cancer when combined with Kras mutations. In this context, the exact redox mechanisms are not clearly elucidated. Herein, we treated mice expressing a Kras[G12D] mutation in pancreatic acinar cells with cerulein to induce acute pancreatitis. In the presence of Kras[G12D], pancreatitis triggered significantly greater redox unbalance and oxidative damages compared to control mice expressing wild-type&amp;nbsp;Kras alleles. Further analyses identified the disruption in glutathione metabolism as the main redox event occurring during pancreatitis. Compared to the wild-type background, Kras[G12D]-bearing mice showed a greater responsiveness to treatment with a thiol-containing compound, N-acetylcysteine (NAC). Notably, NAC treatment increased the pancreatic glutathione pool, reduced systemic markers related to pancreatic and liver damages, limited the extent of pancreatic edema and fibrosis as well as reduced systemic and pancreatic oxidative damages. The protective effects of NAC were, at least, partly due to a decrease in the production of tumor necrosis factor-α (TNF-α) by acinar cells, which was concomitant with the inhibition of NF-κB(p65) nuclear translocation. Our data provide a rationale to use thiol-containing compounds as an adjuvant therapy to alleviate the severity of inflammation during pancreatitis and pancreatic tumorigenesis.}, }
@article {pmid34351926, year = {2021}, author = {Kardos, P and Beeh, KM and Sent, U and Bissmann, G}, title = {Impact of guideline awareness on the counseling of patients with acute cough among general practitioners and pharmacy personnel.}, journal = {PloS one}, volume = {16}, number = {8}, pages = {e0254086}, pmid = {34351926}, issn = {1932-6203}, mesh = {Acute Disease ; Aged ; Cough/*drug therapy ; *Counseling ; Female ; *General Practitioners ; Guideline Adherence ; Humans ; Male ; Middle Aged ; Nonprescription Drugs/*administration &amp; dosage ; *Pharmacies ; }, abstract = {OBJECTIVE: To explore the awareness and knowledge of applicable guidelines on acute cough among general practitioners, pharmacists and pharmacy technicians and to compare their recommendation behavior and clinical decision making to the evidence-based recommendation in the applicable guidelines.<br><br>METHODS: An anonymous online survey was performed among 303 members of an existing panel of healthcare professionals (HCPs). They were presented with a hypothetical case vignette representative of their daily practice and asked for their treatment recommendations. After being shown an excerpt from the applicable guidelines, these questions were repeated.<br><br>RESULTS: Forty-six % of participants reported to seek information on cough and respiratory conditions very often or often. Among 12 non-prescription treatments-commonly used over-the-counter-products for acute cough, HCPs most often recommended various plant extract-based products (phytotherapeutic remedies) for the acute cough case, whereas chemically defined options such as ambroxol or N-acetyl-cysteine were recommended less often. Following presentation of the guidelines excerpt, recommendations of the phytotherapeutic remedies decreased moderately whereas that of the guideline-recommended ambroxol more than doubled. Among stated reasons for the recommendation guideline conformity increased from 5% to 35% among the top-3 reasons.<br><br>CONCLUSIONS: The recommendations for the treatment of acute cough by professionals involved in primary healthcare deviated considerably from the applicable guideline recommendation but changed after presentation of a guidelines excerpt and knowledge thereof. We conclude that dissemination of applicable guideline knowledge is relevant to improve evidence-based healthcare and clinical decision making.}, }
@article {pmid34349610, year = {2021}, author = {Kwak, MS and Lim, JW and Kim, H}, title = {Astaxanthin Inhibits Interleukin-6 Expression in Cerulein/Resistin-Stimulated Pancreatic Acinar Cells.}, journal = {Mediators of inflammation}, volume = {2021}, number = {}, pages = {5587297}, pmid = {34349610}, issn = {1466-1861}, mesh = {Acinar Cells/drug effects/*metabolism ; Adipokines/metabolism ; Animals ; Anti-Inflammatory Agents/chemistry ; Calcium/chemistry/metabolism ; Cell Line ; Ceruletide/*chemistry ; Chelating Agents/chemistry ; Interleukin-6/*metabolism ; NADPH Oxidases/metabolism ; Obesity/metabolism ; Oxidative Stress ; Pancreas/drug effects/*metabolism ; Rats ; Reactive Oxygen Species ; Resistin/*chemistry ; Xanthophylls/pharmacology ; }, abstract = {Acute pancreatitis is a common clinical condition with increasing the proinflammatory mediators, including interleukin-6 (IL-6). Obesity is a negative prognostic factor in acute pancreatitis. Obese patients with acute pancreatitis have a higher systemic inflammatory response rate. Levels of serum resistin, an adipocytokine secreted by fat tissues, increase with obesity. Cerulein, a cholecystokinin analog, induces calcium (Ca[2+]) overload, oxidative stress, and IL-6 expression in pancreatic acinar cells, which are hallmarks of acute pancreatitis. A recent study showed that resistin aggravates the expression of inflammatory cytokines in cerulein-stimulated pancreatic acinar cells. We aimed to investigate whether resistin amplifies cerulein-induced IL-6 expression and whether astaxanthin (ASX), an antioxidant carotenoid with anti-inflammatory properties, inhibits ceruelin/resistin-induced IL-6 expression in pancreatic acinar AR42J cells. We found that resistin enhanced intracellular Ca[2+] levels, NADPH oxidase activity, intracellular reactive oxygen species (ROS) production, NF-κB activity, and IL-6 expression in cerulein-stimulated AR42J cells, which were inhibited by ASX in a dose-dependent manner. The calcium chelator BAPTA-AM inhibited cerulein/resistin-induced NADPH oxidase activation and ROS production. Antioxidant N-acetyl cysteine (NAC) and ML171, a specific NADPH oxidase 1 inhibitor, suppressed cerulein/resistin-induced ROS production, NF-κB activation, and IL-6 expression. In conclusion, ASX inhibits IL-6 expression, by reducing Ca[2+] overload, NADPH oxidase-mediated ROS production, and NF-κB activity in cerulein/resistin-stimulated pancreatic acinar cells. Consumption of ASX-rich foods could be beneficial for preventing or delaying the incidence of obesity-associated acute pancreatitis.}, }
@article {pmid34346781, year = {2021}, author = {Pascoe, CD and Roy, N and Turner-Brannen, E and Schultz, A and Vaghasiya, J and Ravandi, A and Halayko, AJ and West, AR}, title = {Oxidized phosphatidylcholines induce multiple functional defects in airway epithelial cells.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {321}, number = {4}, pages = {L703-L717}, doi = {10.1152/ajplung.00539.2020}, pmid = {34346781}, issn = {1522-1504}, support = {156616//CIHR/Canada ; }, mesh = {Asthma/*pathology ; Cell Line ; Cell Movement/physiology ; DNA/biosynthesis ; Epithelial Cells/*metabolism ; Humans ; Lipid Metabolism/physiology ; Mitochondria/metabolism ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Phosphatidylcholines/*metabolism ; Phospholipids/metabolism ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/cytology/*pathology ; Respiratory System ; Tight Junctions/physiology ; }, abstract = {Oxidative stress is a hallmark of numerous airway diseases, contributing to extensive cell and tissue damage. Cell membranes and the airway mucosal lining are rich in phospholipids that are particularly susceptible to oxidative attack, producing bioactive molecules including oxidized phosphatidylcholines (OxPCs). With the recent discovery of elevated OxPCs in patients with asthma after allergen challenge, we hypothesized that OxPCs directly contribute to disease by inducing airway epithelial cell dysfunction. We found that OxPCs induced concentration-dependent cell stress and loss of viability in BEAS-2B and Calu-3 cell lines and primary human epithelial cells. These responses corresponded with significant epithelial barrier dysfunction, which was further compounded when combining OxPCs with an epithelial wound. OxPCs inhibited DNA synthesis and migration required to reestablish barrier function, but cells recovered if OxPCs were washed off soon after treatment. OxPCs induced generation of reactive oxygen species, lipid peroxidation, and mitochondrial dysfunction, raising the possibility that OxPCs cause pathological lipid metabolism in a self-propagating cycle. The oxidative stress induced by OxPCs could not be abrogated by putative OxPC receptor blockers, but partial recovery of barrier function, proliferation, and lipid peroxidation could be achieved with the antioxidant N-acetyl cysteine. In summary, we have identified OxPCs as a group of bioactive molecules that significantly impair multiple facets of epithelial cell function, consistent with pathological features of asthma. Further characterization of the mechanisms by which OxPCs affect epithelial cells could yield new insights into how oxidative stress contributes to the pathogenesis of airway disease.}, }
@article {pmid34345305, year = {2021}, author = {Hattori, K and Takano, N and Kazama, H and Moriya, S and Miyake, K and Hiramoto, M and Tsukahara, K and Miyazawa, K}, title = {Induction of synergistic non-apoptotic cell death by simultaneously targeting proteasomes with bortezomib and histone deacetylase 6 with ricolinostat in head and neck tumor cells.}, journal = {Oncology letters}, volume = {22}, number = {3}, pages = {680}, pmid = {34345305}, issn = {1792-1082}, abstract = {Following surgery and chemoradiation, ~50% of patients with locally advanced head and neck tumors experience relapse within the first two years, with a poor prognosis. Therefore, a novel therapeutic approach is required. The aim of the present study was to investigate the effect of combination treatment with the proteasome inhibitor bortezomib (BTZ), and ricolinostat (RCS), a specific inhibitor of histone deacetylase 6 (HDAC6), on CAL27 and Detroit562 head and neck cancer cells. BTZ and RCS exhibited cytotoxicity in a dose- and time-dependent manner. Simultaneous treatment with BTZ and RCS resulted in the synergistic enhancement of non-apoptotic cell death and autophagy. The receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor, necrostatin, but not the autophagy inhibitor, 3-methyladenine, attenuated the cytotoxicity of combined BTZ and RCS treatment. Thus, necroptosis [type-III programmed cell death (PCD)], but not autophagic cell death (type-II PCD), appeared to contribute to the pronounced cytotoxicity. However, no phosphorylation of RIPK1 or mixed lineage kinase domain-like protein was detectable in response to BTZ or RCS. Furthermore, RCS induced α-tubulin acetylation and inhibited BTZ-induced aggresome formation along with endoplasmic reticulum stress loading. Combined treatment with BTZ and RCS enhanced the production of reactive oxygen species (ROS). The ROS scavenger, N-acetyl cysteine, abrogated the increase in cytotoxicity. These results suggest the potential therapeutic value of the dual targeting of the proteasome and HDCA6 for head and neck cancers through the induction of necroptosis-like cell death along with ROS generation.}, }
@article {pmid34343907, year = {2021}, author = {Chen, C and Wang, S and Yu, L and Mueller, J and Fortunato, F and Rausch, V and Mueller, S}, title = {H2O2-mediated autophagy during ethanol metabolism.}, journal = {Redox biology}, volume = {46}, number = {}, pages = {102081}, pmid = {34343907}, issn = {2213-2317}, mesh = {Animals ; Autophagy ; Cytochrome P-450 CYP2E1/genetics ; Ethanol/toxicity ; *Hydrogen Peroxide ; *Liver Diseases, Alcoholic/genetics ; Mice ; }, abstract = {BACKGROUND: Alcoholic liver disease (ALD) is the most common liver disease worldwide and its underlying molecular mechanisms are still poorly understood. Moreover, conflicting data have been reported on potentially protective autophagy, the exact role of ethanol-metabolizing enzymes and ROS.<br><br>METHODS: Expression of LC3B, CYP2E1, and NOX4 was studied in a mouse model of acute ethanol exposure by immunoblotting and immunohistochemistry. Autophagy was further studied in primary mouse hepatocytes and huh7 cells in response to ethanol and its major intermediator acetaldehyde. Experiments were carried out in cells overexpressing CYP2E1 and knock down of NOX4 using siRNA. The response to external H2O2 was studied by using the GOX/CAT system. Autophagic flux was monitored using the mRFP-GFP-LC3 plasmid, while rapamycin and chloroquine served as positive and negative controls.<br><br>RESULTS: Acute ethanol exposure of mice over 24&#xa0;h significantly induced autophagy as measured by LC3B expression but also induced the ROS-generating CYP2E1 and NOX4 enzymes. Notably, ethanol but not its downstream metabolite acetaldehyde induced autophagy in primary mouse hepatocytes. In contrast, autophagy could only be induced in huh7 cells in the presence of overexpressed CYP2E1. In addition, overexpression of NOX4 also significantly increased autophagy, which could be blocked by siRNA mediated knock down. The antioxidant N-acetylcysteine (NAC) also efficiently blocked CYP2E1-and NOX4-mediated induction of autophagy. Finally, specific and non-toxic production of H2O2 by the GOX/CAT system as evidenced by elevated peroxiredoxin (Prx-2) also induced LC3B which was efficiently blocked by NAC. H2O2 strongly increased the autophagic flux as measured by mRFP-GFP-LC3 plasmid.<br><br>CONCLUSION: We here provide evidence that short-term ethanol exposure induces autophagy in hepatocytes both in vivo and in vitro through the generation of ROS. These data suggest that suppression of autophagy by ethanol is most likely due to longer alcohol exposure during chronic alcohol consumption with the accumulation of e.g. misfolded proteins.}, }
@article {pmid34340627, year = {2021}, author = {Dawra, S and Kumar, A and Kumar, D and Ari, B and Srivastava, S and Manrai, M}, title = {Rodenticide-induced acute liver failure - Uncommon presentation of commonly available poison.}, journal = {Tropical doctor}, volume = {51}, number = {4}, pages = {561-565}, doi = {10.1177/00494755211031019}, pmid = {34340627}, issn = {1758-1133}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Humans ; *Liver Failure, Acute/chemically induced/diagnosis ; Phosphorus ; *Poisons ; Rats ; *Rodenticides ; }, abstract = {Rodenticide or 'rat poison' is easily available in a predominantly agrarian economy such as India. Metal phosphides or yellow phosphorous are two common rodenticides. Acute liver failure caused by accidental or suicidal poisoning with rodenticides has been infrequently reported in literature. Liver transplantation offers the best chances of survival in severe intoxication. However, the availability of liver transplantation in resource-limited settings presents a challenge. N-acetyl cysteine has been successfully used in paracetamol poisoning. Its use in rodenticide-induced acute liver failure is not so well known. We report three cases of rodenticide-related acute liver failure, one of them being a pregnant lady. All three patients were given N-acetyl cysteine and two patients improved. It is possible that the administration of N-acetyl cysteine contributed to the improvement in these two.}, }
@article {pmid34339721, year = {2022}, author = {Eghtedari, Y and Oh, LJ and Girolamo, ND and Watson, SL}, title = {The role of topical N-acetylcysteine in ocular therapeutics.}, journal = {Survey of ophthalmology}, volume = {67}, number = {2}, pages = {608-622}, doi = {10.1016/j.survophthal.2021.07.008}, pmid = {34339721}, issn = {1879-3304}, mesh = {*Acetylcysteine/administration &amp; dosage/chemistry ; Administration, Topical ; Chitosan ; *Cornea/drug effects ; *Dry Eye Syndromes/drug therapy ; Humans ; }, abstract = {N-acetylcysteine (NAC) was first discovered as a mucolytic agent in 1960. We investigate the role of topical NAC in ocular therapeutics, including its mechanism of action, current applications, and adverse effects. A systematic search of peer-reviewed articles identified 106 references including in vitro, in vivo and clinical studies on the use of NAC in the treatment of ocular diseases. NAC can be synthetically manufactured, and its mechanisms of action include mucolysis, scavenging hydroxyl radicals, and modulation of inflammatory cascades. These unique properties contribute to the diverse applications of NAC, including its steroid-sparing potential. NAC has been used topically in the treatment of corneal wounds, chemical injuries, keratitis, dry eye disease and meibomian gland dysfunction. The clinical benefits of NAC are evident over a wide range of concentrations, the most common being 5-10% topical NAC applied four times daily. Adverse effects such as corneal necrosis are rare, but have been reported with higher doses. NAC also has potential applications in laser epithelial keratomileusis, diabetic eye disease, retinitis pigmentosa, senile nuclear cataracts, macular degeneration, and cigarette smoke-induced corneal damage. Recently, chitosan-NAC has been used as a nanocarrier for the topical administration of medications to the ocular surface. Owing to its potent antioxidant, anti-inflammatory and mucolytic properties, topical NAC has had extensive use in the treatment of ocular pathology.}, }
@article {pmid34336301, year = {2021}, author = {Chiu, MH and Jaworska, N and Li, NL and Yarema, M}, title = {Massive Acetaminophen Overdose Treated Successfully with N-Acetylcysteine, Fomepizole, and Hemodialysis.}, journal = {Case reports in critical care}, volume = {2021}, number = {}, pages = {6695967}, pmid = {34336301}, issn = {2090-6420}, abstract = {Acetaminophen overdose is one of the most common causes of acute hepatic failure in the developed world. There is strong evidence for N-acetylcysteine (NAC) as a safe and effective antidote for acetaminophen toxicity. However, there is less clarity in the management of massive overdoses (acute, single ingestions > 500 mg/kg with 4-hour equivalent concentrations ~6000 μmol/L) which are often associated with metabolic acidosis and multiorgan dysfunction. In such ingestions, the role of adjuvant treatments such as fomepizole and extracorporeal removal is unclear. We present a case of a 20-year-old female presenting with an acute ingestion of over 120 grams (1764.7 mg/kg) and an acetaminophen concentration of 5880 μmol/L who developed refractory shock, decreased level of consciousness, and metabolic acidosis requiring mechanical ventilation and vasopressor support. She was treated with gastric decontamination with activated charcoal, IV NAC, fomepizole, and hemodialysis. The patient had complete clearance of acetaminophen by 32 hours after presentation and normalization of her acid base and hemodynamic status without any organ failure. This case highlights the potential benefit of a triple strategy of NAC, fomepizole, and early hemodialysis in massive acetaminophen overdose, potentially sparing complications of prolonged intubation and ICU hospitalization.}, }
@article {pmid34332981, year = {2021}, author = {Sun, L and Jiang, Y and Yan, X and Dai, X and Huang, C and Chen, L and Li, T and Zhang, Y and Xiao, H and Yang, M and Xiang, L and Zhang, Y and Chen, S and Li, S and Chen, A and He, F and Lian, J}, title = {Dichloroacetate enhances the anti-tumor effect of sorafenib via modulating the ROS-JNK-Mcl-1 pathway in liver cancer cells.}, journal = {Experimental cell research}, volume = {406}, number = {1}, pages = {112755}, doi = {10.1016/j.yexcr.2021.112755}, pmid = {34332981}, issn = {1090-2422}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Antineoplastic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis/drug effects ; Cell Line, Tumor ; Dichloroacetic Acid/*pharmacology ; Drug Resistance, Neoplasm/drug effects/*genetics ; Drug Synergism ; Gene Expression Regulation, Neoplastic ; Hepatocytes/drug effects/metabolism/pathology ; Humans ; Liver Neoplasms/*drug therapy/genetics/metabolism/pathology ; MAP Kinase Kinase 4/antagonists &amp; inhibitors/*genetics/metabolism ; Male ; Mice, Nude ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists &amp; inhibitors/*genetics/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Signal Transduction ; Sorafenib/*pharmacology ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; Mice ; }, abstract = {Liver cancer is one of the most common and high recurrence malignancies. Besides radiotherapy and surgery, chemotherapy also plays an essential role in the treatment of liver cancer. Sorafenib and sorafenib-based combination therapies have been proven efficacy against tumors. However, previous clinical studies have indicated that some patients with liver cancer are resistant to sorafenib treatment and the existing strategies are not satisfactory in the clinic. Therefore, it is urgent to investigate strategies to improve the effectiveness of sorafenib for liver cancer and to explore effective drug combinations. In the present study, we found that dichloroacetate (DCA) could significantly enhance the anti-tumor effect of sorafenib on liver cancer cells, including reduced viability and dramatically promoted apoptosis in liver cancer cells. Moreover, compared to sorafenib alone, the combination of DCA and sorafenib markedly increased the degradation of anti-apoptotic protein Mcl-1 by enhancing its phosphorylation. Overexpression of Mcl-1 could significantly attenuate the synergetic effect of DCA and sorafenib on apoptosis induction in liver cancer cells. Furthermore, we found that the ROS-JNK pathway was obviously activated in the DCA combined sorafenib group. The levels of ROS and p-JNK were dramatically up-regulated in the two drug combination groups. Antioxidant NAC could alleviate the synergetic effects of DCA and sorafenib on ROS generation, JNK activation, Mcl-1 degradation, and cell apoptosis. Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor 'SP'600125. Finally, the synergetic effects of DCA and sorafenib on tumor growth suppression, Mcl-1 degradation and induction of apoptosis were also validated in liver cancer xenograft in vivo. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be beneficial for further clinical application of sorafenib in liver cancer treatment.}, }
@article {pmid34332247, year = {2021}, author = {He, Z and Zhang, Y and Zhang, H and Zhou, C and Ma, Q and Deng, P and Lu, M and Mou, Z and Lin, M and Yang, L and Li, Y and Yue, Y and Pi, H and Lu, Y and He, M and Zhang, L and Chen, C and Zhou, Z and Yu, Z}, title = {NAC antagonizes arsenic-induced neurotoxicity through TMEM179 by inhibiting oxidative stress in Oli-neu cells.}, journal = {Ecotoxicology and environmental safety}, volume = {223}, number = {}, pages = {112554}, doi = {10.1016/j.ecoenv.2021.112554}, pmid = {34332247}, issn = {1090-2414}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Apoptosis ; *Arsenic/metabolism/toxicity ; Mice ; Mitochondria/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Arsenic is one of the most common environmental pollutants. Neurotoxicity induced by arsenic has become a major public health concern. However, the effects of arsenic-induced neurotoxicity in the brain and the underlying molecular mechanisms are not well understood. N-acetyl-cysteine (NAC) is a thiol-based antioxidant that can antagonize heavy metal-induced neurotoxicity by scavenging reactive oxygen species (ROS). Here, we used the mouse oligodendrocyte precursor cell (OPC) line Oli-neu to explore the neurotoxic effects of arsenic and the protective effects of NAC. We found that arsenic exposure decreased cell viability, increased oxidative stress, caused mitochondrial dysfunction, and led to apoptosis of Oli-neu cells. Furthermore, we revealed that NAC treatment reversed these neurotoxic effects of arsenic. TMEM179, a key membrane protein, was found highly expressed in OPCs and to be an important factor in maintaining mitochondrial functions. We found that TMEM179 played a critical role in mediating the neurotoxic effects of arsenic and the protective role of NAC. PKCβ is a downstream factor through which TMEM179 regulates the expression of apoptosis-related proteins. This study improves our understanding of the neurotoxic effects and mechanisms of arsenic exposure and the protective effects of NAC. It also identifies a potential molecular target, TMEM179, for the treatment of arsenic-induced neurotoxicity.}, }
@article {pmid34332028, year = {2021}, author = {Schulte, MHJ and Goudriaan, AE and Boendermaker, WJ and van den Brink, W and Wiers, RW}, title = {The effect of N-acetylcysteine and working memory training on glutamate concentrations in the dACC and rACC in regular cocaine users - A randomized proof of concept study.}, journal = {Neuroscience letters}, volume = {762}, number = {}, pages = {136146}, doi = {10.1016/j.neulet.2021.136146}, pmid = {34332028}, issn = {1872-7972}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Cocaine-Related Disorders/*therapy ; Double-Blind Method ; Glutamic Acid/*drug effects/metabolism ; Gyrus Cinguli/*drug effects/metabolism ; Humans ; *Learning ; Male ; Memory, Short-Term ; Middle Aged ; Proof of Concept Study ; }, abstract = {INTRODUCTION: Current treatments for cocaine use disorder (CUD) are not very effective and better treatments are needed. This study investigates the effectiveness of a combined intervention that targets the assumed underlying glutamate pathology in cocaine users. To this end, the combined effects of N-acetylcysteine (NAC) and working memory (WM) training on glutamate concentrations in the dorsal and rostral ACC were investigated in a randomized, double-blind placebo-controlled design.<br><br>METHODS: In this study, 38 regular cocaine-using men were randomized to either 25-days with 2400&#xa0;mg/day NAC and WM-training or 25&#xa0;days with placebo with WM-training. Cocaine use, impulsivity, and glutamate concentrations in the dACC and rACC using proton Magnetic Resonance Spectroscopy were assessed at baseline and after treatment.<br><br>RESULTS: Twenty-four participants completed the study, of which 9 received NAC and 15 received placebo. There were no baseline correlations of glutamate concentrations in the dACC or rACC with cocaine use measures or impulsivity. Additionally, there were no effects of NAC, WM-training, or the combination thereof on (changes in) glutamate concentrations in the dACC or rACC.<br><br>DISCUSSION: This randomized proof of concept study could not confirm our hypotheses. Possible explanations are insufficient power and the possible absence of deviant baseline glutamate concentrations in the included participants. Future studies should consider larger samples and a non-using control group to confirm baseline deviations in glutamate in cocaine users.}, }
@article {pmid34330957, year = {2021}, author = {Picchi, SC and de Souza E Silva, M and Saldanha, LL and Ferreira, H and Takita, MA and Caldana, C and de Souza, AA}, title = {GC-TOF/MS-based metabolomics analysis to investigate the changes driven by N-Acetylcysteine in the plant-pathogen Xanthomonas citri subsp. citri.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {15558}, pmid = {34330957}, issn = {2045-2322}, mesh = {Acetylcysteine/*metabolism ; Amino Acids/metabolism ; Cell Membrane/metabolism ; Citrus/metabolism ; Gas Chromatography-Mass Spectrometry/*methods ; Glutamine/metabolism ; Metabolomics/*methods ; Xanthomonas/*metabolism ; }, abstract = {N-Acetylcysteine (NAC) is an antioxidant, anti-adhesive, and antimicrobial compound. Even though there is much information regarding the role of NAC as an antioxidant and anti-adhesive agent, little is known about its antimicrobial activity. In order to assess its mode of action in bacterial cells, we investigated the metabolic responses triggered by NAC at neutral pH. As a model organism, we chose the Gram-negative plant pathogen Xanthomonas citri subsp. citri (X. citri), the causal agent of citrus canker disease, due to the potential use of NAC as a sustainable molecule against phytopathogens dissemination in citrus cultivated areas. In presence of NAC, cell proliferation was affected after 4 h, but damages to the cell membrane were observed only after 24 h. Targeted metabolite profiling analysis using GC-MS/TOF unravelled that NAC seems to be metabolized by the cells affecting cysteine metabolism. Intriguingly, glutamine, a marker for nitrogen status, was not detected among the cells treated with NAC. The absence of glutamine was followed by a decrease in the levels of the majority of the proteinogenic amino acids, suggesting that the reduced availability of amino acids affect protein synthesis and consequently cell proliferation.}, }
@article {pmid34329734, year = {2021}, author = {Gaisina, IN and Hushpulian, DM and Gaisin, AM and Kazakov, EH and Ammal Kaidery, N and Ahuja, M and Poloznikov, AA and Gazaryan, IG and Thatcher, GRJ and Thomas, B}, title = {Identification of a potent Nrf2 displacement activator among aspirin-containing prodrugs.}, journal = {Neurochemistry international}, volume = {149}, number = {}, pages = {105148}, pmid = {34329734}, issn = {1872-9754}, support = {R01 NS101967/NS/NINDS NIH HHS/United States ; }, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Aspirin/*pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Humans ; NF-E2-Related Factor 2/agonists/*metabolism ; Prodrugs/*pharmacology ; Protein Structure, Tertiary ; }, abstract = {Aspirin is a desired leaving group in prodrugs aimed at treatment of neurodegeneration and other conditions. A library of aspirin derivatives of various scaffolds potentially activating Nrf2 has been tested in Neh2-luc reporter assay which screens for direct Nrf2 protein stabilizers working via disruption of Nrf2-Keap1 interaction. Most aspirin prodrugs had a pro-alkylating or pro-oxidant motif in the structure and, therefore, were toxic at high concentrations. However, among the active compounds, we identified a molecule resembling a well-known Nrf2 displacement activator, bis-1,4-(4-methoxybenzenesulfonamidyl) naphthalene (NMBSA). The direct comparison of the newly identified compound with NMBSA and its improved analog in the reporter assay showed no quenching with N-acetyl cysteine, thus pointing to Nrf2 stabilization mechanism without cysteine alkylation. The potency of the newly identified compound in the reporter assay was much stronger than NMBSA, despite its inhibitory action in the commercial fluorescence polarization assay was observed only in the millimolar range. Molecular docking predicted that mono-deacetylation of the novel prodrug should generate a potent displacement activator. The time-course of reporter activation with the novel prodrug had a pronounced lag-period pointing to a plausible intracellular transformation leading to an active product. Treatment of the novel prodrug with blood plasma or cell lysate demonstrated stepwise deacetylation as judge by liquid chromatography-mass spectrometry (LC-MS). Hence, the esterase-catalyzed hydrolysis of the prodrug liberates only acetyl groups from aspirin moiety and generates a potent Nrf2 activator. The discovered mechanism of prodrug activation makes the newly identified compound a promising lead for future optimization studies.}, }
@article {pmid34326284, year = {2021}, author = {Keshtkarjahromi, M and Mariscal, J and Dempsey, K and Tonarelli, S}, title = {Treatment of Severe Excoriation Disorder With Mirtazapine: A Case Report.}, journal = {Clinical neuropharmacology}, volume = {44}, number = {5}, pages = {189-190}, doi = {10.1097/WNF.0000000000000467}, pmid = {34326284}, issn = {1537-162X}, mesh = {Antidepressive Agents ; *Antipsychotic Agents/therapeutic use ; Female ; Humans ; *Mental Disorders/drug therapy ; Middle Aged ; Mirtazapine/therapeutic use ; Selective Serotonin Reuptake Inhibitors ; }, abstract = {OBJECTIVE: Excoriation disorder is a disabling behavioral disorder characterized by compulsive and repetitive picking of the skin. Excoriation disorder has a lifetime prevalence of 3% to 5% in the general population, and it is most common in females. Its course is chronic, and it is characterized by fluctuating and frequent periods of exacerbation. Excoriation disorder is commonly comorbid with several psychiatric disorders. The treatment of this disorder is challenging and requires a multidisciplinary approach. Current literature has described an improvement in skin picking when patients are treated with fluoxetine or escitalopram; other studies have involved augmentation strategies using antipsychotics, such as olanzapine and aripiprazole; serotonin norepinephrine reuptake inhibitors; and N-acetyl-cysteine. Other pharmacological therapies include lamotrigine and opioid antagonists. Psychotherapies are additional nonpharmacological treatment modalities to consider in this condition.<br><br>METHODS: We report the case of a 60-year-old Hispanic woman with severe excoriation disorder and several psychiatric comorbidities who responded remarkably to augmentation treatment with mirtazapine.<br><br>CONCLUSION: Mirtazapine is a noradrenergic and specific serotonergic antidepressant, and its antihistaminergic effect can relieve skin itching and pain.}, }
@article {pmid34325504, year = {2021}, author = {Lee, JY and Kim, DA and Choi, E and Lee, YS and Park, SJ and Kim, BJ}, title = {Aldosterone Inhibits In Vitro Myogenesis by Increasing Intracellular Oxidative Stress via Mineralocorticoid Receptor.}, journal = {Endocrinology and metabolism (Seoul, Korea)}, volume = {36}, number = {4}, pages = {865-874}, pmid = {34325504}, issn = {2093-5978}, mesh = {*Aldosterone/metabolism/pharmacology ; Animals ; Humans ; Mice ; Muscle Development/physiology ; Myoblasts/metabolism ; Oxidative Stress/physiology ; *Receptors, Mineralocorticoid/metabolism ; }, abstract = {BACKGROUND: Despite clinical evidence indicating poor muscle health in subjects with primary aldosteronism (PA), it is still unclear whether the role of aldosterone in muscle metabolism is direct or mediated indirectly via factors, such as electrolyte imbalance or impaired glucose uptake. As one approach to clarify this issue, we investigated the effect of aldosterone on in vitro myogenesis and the potential mechanism explaining it.<br><br>METHODS: Myogenesis was induced in mouse C2C12 myoblasts with 2% horse serum. Immunofluorescence, quantitative reversetranscription polymerase chain reaction, Western blot, viability, and migration analyses were performed for experimental research.<br><br>RESULTS: Recombinant aldosterone treatment suppressed muscle differentiation from mouse C2C12 myoblasts in a dose-dependent manner, and consistently reduced the expression of myogenic differentiation markers. Furthermore, aldosterone significantly increased intracellular reactive oxygen species (ROS) levels in myotubes, and treatment with N-acetyl cysteine, a potent biological thiol antioxidant, reversed the decrease of myotube area, myotube area per myotube, nucleus number per myotube, and fusion index due to aldosterone through decreasing oxidative stress. A binding enzyme-linked immunosorbent assay confirmed that mineralocorticoid receptor (MR) interacted with aldosterone in C2C12 myoblasts, while eplerenone, an MR inhibitor, blocked aldosterone-stimulated intracellular ROS generation during myogenesis and markedly attenuated the suppression of in vitro myogenesis by aldosterone.<br><br>CONCLUSION: These findings support the hypothesis that hypersecretion of aldosterone, like PA, directly contributes to muscular deterioration and suggest that antioxidants and/or MR antagonists could be effective therapeutic options to reduce the risk of sarcopenia in these patients.}, }
@article {pmid34325292, year = {2022}, author = {Chen, X and Bi, M and Yang, J and Cai, J and Zhang, H and Zhu, Y and Zheng, Y and Liu, Q and Shi, G and Zhang, Z}, title = {Cadmium exposure triggers oxidative stress, necroptosis, Th1/Th2 imbalance and promotes inflammation through the TNF-α/NF-κB pathway in swine small intestine.}, journal = {Journal of hazardous materials}, volume = {421}, number = {}, pages = {126704}, doi = {10.1016/j.jhazmat.2021.126704}, pmid = {34325292}, issn = {1873-3336}, mesh = {Animals ; Cadmium/toxicity ; Inflammation/chemically induced ; Intestine, Small/metabolism ; *NF-kappa B/genetics/metabolism ; *Necroptosis ; Oxidative Stress ; Swine ; Tumor Necrosis Factor-alpha ; }, abstract = {Cadmium (Cd) is a toxic environmental pollutant and induces toxic effects to organism. Nevertheless, the mechanism of Cd-induced toxicity in swine remains obscure. To explore this, 10 healthy 6-week-old weaned swine were placed into two groups stochastically, the Cd group was treated with a commercial diet containing 20 mg/kg Cd for 40 days. The results of histopathological and ultrastructural observations showed typical necrosis features and inflammatory cell infiltration in Cd group. Excessive Cd suppressed T-AOC and SOD activities, increased MDA content and ROS levels. Cd diet elevated the expression of RIPK1, RIPK3, and MLKL to activate the RIPK3-dependent necroptosis pathway. Results of Th1 and Th2 cytokines indicated that the levels of IL-4, IL-6 and IL10 was increased, while the level of IFN-γ was decreased, illustrating Th1/Th2 immune imbalance leads to aggravate inflammatory responses. Cd activated the TNF-α/NF-κB pathway and induced inflammatory responses via increasing the expression of HO-1, IL-1β, iNOS, COX2. Heat shock proteins were notably elevated in response to inflammatory reactions. And these effects were inhibited by necrostatin-1 (Nec-1) and N-acetyl-cysteine (NAC). Altogether, these data demonstrated that Cd induced necroptosis and inflammation to aggravate small intestine injury in swine by increasing the excessive accumulation of ROS and imbalanced Th1/Th2, respectively.}, }
@article {pmid34315111, year = {2021}, author = {Ho, MH and Yen, CH and Hsieh, TH and Kao, TJ and Chiu, JY and Chiang, YH and Hoffer, BJ and Chang, WC and Chou, SY}, title = {CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury.}, journal = {Redox biology}, volume = {46}, number = {}, pages = {102067}, pmid = {34315111}, issn = {2213-2317}, mesh = {Animals ; *Brain Concussion ; Chemokine CCL5 ; Glutathione Peroxidase/metabolism ; Hippocampus/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Glutathione Peroxidase GPX1 ; }, abstract = {Traumatic brain injury (TBI) is a prevalent head injury worldwide which increases the risk of neurodegenerative diseases. Increased reactive oxygen species (ROS) and inflammatory chemokines after TBI induces secondary effects which damage neurons. Targeting NADPH oxidase or increasing redox systems are ways to reduce ROS and damage. Earlier studies show that C-C motif chemokine ligand 5 (CCL5) has neurotrophic functions such as promoting neurite outgrowth as well as reducing apoptosis. Although CCL5 levels in blood are associated with severity in TBI patients, the function of CCL5 after brain injury is unclear. In the current study, we induced mild brain injury in C57BL/6 (wildtype, WT) mice and CCL5 knockout (CCL5-KO) mice using a weight-drop model. Cognitive and memory functions in mice were analyzed by Novel-object-recognition and Barnes Maze tests. The memory performance of both WT and KO mice were impaired after mild injury. Cognition and memory function in WT mice quickly recovered after 7 days but recovery took more than 14 days in CCL5-KO mice. FJC, NeuN and Hypoxyprobe staining revealed large numbers of neurons damaged by oxidative stress in CCL5-KO mice after mTBI. NADPH oxidase activity show increased ROS generation together with reduced glutathione peroxidase-1 (GPX1) and glutathione (GSH) activity in CCL5-KO mice; this was opposite to that seen in WT mice. CCL5 increased GPX1 expression and reduced intracellular ROS levels which subsequently increased cell survival both in primary neuron cultures and in an overexpression model using SHSY5Y cell. Memory impairment in CCL5-KO mice induced by TBI could be rescued by i.p. injection of the GSH precursor - N-acetylcysteine (NAC) or intranasal delivery of recombinant CCL5 into mice after injury. We conclude that CCL5 is an important molecule for GPX1 antioxidant activation during post-injury day 1-3, and protects hippocampal neurons from ROS as well as improves memory function after trauma.}, }
@article {pmid34310944, year = {2021}, author = {Whitney, K and Nikulina, E and Rahman, SN and Alexis, A and Bergold, PJ}, title = {Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury.}, journal = {Experimental neurology}, volume = {345}, number = {}, pages = {113816}, pmid = {34310944}, issn = {1090-2430}, support = {R01 NS108190/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Brain/*drug effects/metabolism/pathology ; Brain Injuries, Traumatic/*drug therapy/metabolism/pathology ; Drug Administration Schedule ; Drug Therapy, Combination ; Free Radical Scavengers/administration &amp; dosage ; Male ; Memory Disorders/drug therapy/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Minocycline/*administration &amp; dosage ; Neurodegenerative Diseases/drug therapy/metabolism/pathology ; Neuroprotective Agents/*administration &amp; dosage ; Spatial Memory/*drug effects/physiology ; }, abstract = {Multiple drugs to treat traumatic brain injury (TBI) have failed clinical trials. Most drugs lose efficacy as the time interval increases between injury and treatment onset. Insufficient therapeutic time window is a major reason underlying failure in clinical trials. Few drugs have been developed with therapeutic time windows sufficiently long enough to treat TBI because little is known about which brain functions can be targeted if therapy is delayed hours to days after injury. We identified multiple injury parameters that are improved by first initiating treatment with the drug combination minocycline (MINO) plus N-acetylcysteine (NAC) at 72 h after injury (MN72) in a mouse closed head injury (CHI) experimental TBI model. CHI produces spatial memory deficits resulting in impaired performance on Barnes maze, hippocampal neuronal loss, and bilateral damage to hippocampal neurons, dendrites, spines and synapses. MN72 treatment restores Barnes maze acquisition and retention, protects against hippocampal neuronal loss, limits damage to dendrites, spines and synapses, and accelerates recovery of microtubule associated protein 2 (MAP2) expression, a key protein in maintaining proper dendritic architecture and synapse density. These data show that in addition to the structural integrity of the dendritic arbor, spine and synapse density can be successfully targeted with drugs first dosed days after injury. Retention of substantial drug efficacy even when first dosed 72 h after injury makes MINO plus NAC a promising candidate to treat clinical TBI.}, }
@article {pmid34308314, year = {2021}, author = {McKetin, R and Dean, OM and Turner, A and Kelly, PJ and Quinn, B and Lubman, DI and Dietze, P and Carter, G and Higgs, P and Sinclair, B and Reid, D and Baker, AL and Manning, V and Pas, NT and Thomas, T and Bathish, R and Raftery, DK and Wrobel, A and Saunders, L and Arunogiri, S and Cordaro, F and Hill, H and Hall, S and Clare, PJ and Mohebbi, M and Berk, M}, title = {N-acetylcysteine (NAC) for methamphetamine dependence: A randomised controlled trial.}, journal = {EClinicalMedicine}, volume = {38}, number = {}, pages = {101005}, pmid = {34308314}, issn = {2589-5370}, abstract = {BACKGROUND: Methamphetamine dependence is a significant global health concern for which there are no approved medications. The cysteine prodrug, N-acetylcysteine (NAC), has been found to ameliorate glutamate dysregulation in addiction, and to reduce craving for methamphetamine and other drugs. We evaluated the efficacy and safety of NAC as a pharmacotherapy for methamphetamine dependence.<br><br>METHODS: A parallel double-blind randomised placebo-controlled trial of people dependent on methamphetamine recruited from Geelong, Melbourne and Wollongong, Australia, between July 2018 and December 2019. Participants were randomised to receive either 12 weeks of oral NAC (2400&#xa0;mg/day) or matched placebo, delivered as a take-home medication. The primary outcome was methamphetamine use, measured in two ways: (a) change in days of use in the past 4 weeks from baseline to weeks 4, 8 and 12, assessed using the Timeline Followback; and (b) methamphetamine-positive oral fluid samples taken weekly. Analyses were intention-to-treat and based on imputed data. Secondary outcomes were craving, severity of dependence, withdrawal severity and psychiatric symptoms (depression, suicidality, hostility and psychotic symptoms). Significance levels were p&#xa0;<&#xa0;0.025 for primary outcomes and p&#xa0;<&#xa0;0.01 for secondary outcomes. Adverse events were compared between groups by system organ class. The study was prospectively registered, ACTRN12618000366257.<br><br>RESULTS: Participants (N&#xa0;=&#xa0;153; 59% male, mean [SD] age 38 [8]) were randomised to placebo (n&#xa0;=&#xa0;77) or NAC (n&#xa0;=&#xa0;76). Both groups had a median (IQR) of 24 (15-28) days of methamphetamine use in the 4 weeks prior to baseline. Both groups significantly reduced methamphetamine use (mean [SE] reduction of 7.3 [1.2]) days for placebo, 6.8 [1.2] for NAC) but NAC did not reduce days of methamphetamine use more than placebo (group difference of 0.5 days, 97.5% CI -3.4-4.3). There was no significant effect of NAC on methamphetamine-positive oral fluid samples (placebo 79%, NAC 76%; mean difference -2.6, 97.5% CI -12.6-7.4). NAC did not significantly reduce craving, severity of dependence, withdrawal, suicidality, depression, hostility or psychotic symptoms relative to placebo. Adverse events did not differ significantly between placebo and NAC groups.<br><br>INTERPRETATION: These findings suggest that take-home oral NAC has no significant effect on methamphetamine use or most clinically related outcomes amongst people who are dependent on the drug.}, }
@article {pmid34307672, year = {2021}, author = {Dou, Q and Tong, H and Yang, Y and Zhang, H and Gan, H}, title = {PICK1 Deficiency Exacerbates Sepsis-Associated Acute Kidney Injury.}, journal = {BioMed research international}, volume = {2021}, number = {}, pages = {9884297}, pmid = {34307672}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Acute Kidney Injury/*etiology/*metabolism/pathology ; Animals ; Apoptosis ; Carrier Proteins/*metabolism ; Cell Cycle Proteins/antagonists &amp; inhibitors/*deficiency/metabolism ; Cell Line ; Disease Models, Animal ; Epithelial Cells/drug effects/metabolism/pathology ; Humans ; Kidney Tubules, Proximal/pathology ; Lipopolysaccharides ; MAP Kinase Kinase Kinase 5/metabolism ; Male ; Mice, Inbred C57BL ; Nuclear Proteins/*metabolism ; Peroxides/metabolism ; Sepsis/*complications ; p38 Mitogen-Activated Protein Kinases/metabolism ; Mice ; }, abstract = {We performed in vitro and in vivo experiments to explore the role of protein kinase C-binding protein 1 (PICK1), an intracellular transporter involved in oxidative stress-related neuronal diseases, in sepsis-related acute kidney injury (AKI). Firstly, PCR, western blotting, and immunohistochemistry were used to observe the expression of PICK1 after lipopolysaccharide- (LPS-) induced AKI. Secondly, by inhibiting PICK1 in vivo and silencing PICK1 in vitro, we further explored the effect of PICK1 on AKI. Finally, the relationship between PICK1 and oxidative stress and the related mechanisms were explored. We found that the expression of PICK1 was increased in LPS-induced AKI models both in vitro and in vivo. PICK1 silencing significantly aggravated LPS-induced apoptosis, accompanied by ROS production in renal tubular epithelial cells. FSC231, a PICK1-specific inhibitor, aggravated LPS-induced kidney injury. Besides, NAC (N-acetylcysteine), a potent ROS scavenger, significantly inhibited the PICK1-silencing-induced apoptosis. In conclusion, PICK1 might protect renal tubular epithelial cells from LPS-induced apoptosis by reducing excessive ROS, making PICK1 a promising preventive target in LPS-induced AKI.}, }
@article {pmid34306311, year = {2021}, author = {Yu, L and Yang, X and Li, X and Qin, L and Xu, W and Cui, H and Jia, Z and He, Q and Wang, Z}, title = {Pink1/PARK2/mROS-Dependent Mitophagy Initiates the Sensitization of Cancer Cells to Radiation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {5595652}, pmid = {34306311}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Autophagy/drug effects/*physiology ; Humans ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mitochondria/*drug effects/metabolism ; Mitophagy/*drug effects/physiology ; Neoplasms/drug therapy/metabolism ; *Radiation, Ionizing ; Reactive Oxygen Species/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Autophagy plays a double-edged sword for cancer; particularly, mitophagy plays important roles in the selective degradation of damaged mitochondria. However, whether mitophagy is involved in killing effects of tumor cells by ionizing radiation (IR) and its underlying mechanism remain elusive. The purpose is to evaluate the effects of mitochondrial ROS (mROS) on autophagy after IR; furthermore, we hypothesized that KillerRed (KR) targeting mitochondria could induce mROS generation, subsequent mitochondrial depolarization, accumulation of Pink1, and recruitment of PARK2 to promote the mitophagy. Thereby, we would achieve a new strategy to enhance mROS accumulation and clarify the roles and mechanisms of radiosensitization by KR and IR. Our data demonstrated that IR might cause autophagy of both MCF-7 and HeLa cells, which is related to mitochondria and mROS, and the ROS scavenger N-acetylcysteine (NAC) could reduce the effects. Based on the theory, mitochondrial targeting vector sterile α- and HEAT/armadillo motif-containing protein 1- (Sarm1-) mtKR has been successfully constructed, and we found that ROS levels have significantly increased after light exposure. Furthermore, mitochondrial depolarization of HeLa cells was triggered, such as the decrease of Na[+]K[+] ATPase, Ca[2+]Mg[2+] ATPase, and mitochondrial respiratory complex I and III activities, and mitochondrial membrane potential (MMP) has significantly decreased, and voltage-dependent anion channel 1 (VDAC1) protein has significantly increased in the mitochondria. Additionally, HeLa cell proliferation was obviously inhibited, and the cell autophagic rates dramatically increased, which referred to the regulation of the Pink1/PARK2 pathway. These results indicated that mitophagy induced by mROS can initiate the sensitization of cancer cells to IR and might be regulated by the Pink1/PARK2 pathway.}, }
@article {pmid34301364, year = {2021}, author = {Ham, J and Yun, BH and Lim, W and Song, G}, title = {Folpet induces mitochondrial dysfunction and ROS-mediated apoptosis in mouse Sertoli cells.}, journal = {Pesticide biochemistry and physiology}, volume = {177}, number = {}, pages = {104903}, doi = {10.1016/j.pestbp.2021.104903}, pmid = {34301364}, issn = {1095-9939}, mesh = {Animals ; *Apoptosis ; Male ; Mice ; Mitochondria ; Phthalimides/metabolism ; Reactive Oxygen Species/metabolism ; *Sertoli Cells/metabolism ; }, abstract = {Folpet is a phthalimide type of fungicide and has been used to control several crop diseases. Although it has adverse effects on the gastrointestinal tract, its mechanism and toxic effects on testis have not been demonstrated. In the present study, we elucidated the cytotoxic effect of folpet on the mouse Sertoli cell line, TM4. Our results revealed that folpet suppressed viability and proliferative capacity of TM4 cells and further inhibited 3D spheroid formation. Moreover, folpet impeded appropriate cell cycle progression and induced apoptotic cell death in TM4 cells. It disrupted the electrochemical gradient of mitochondria and calcium homeostasis in TM4 cells. Furthermore, endoplasmic reticulum stress-related proteins were activated in folpet-treated TM4 cells, and relative reactive oxygen species (ROS) production was also increased. N-acetylcysteine (NAC) treatment reinstated the folpet-induced ROS generation in TM4 cells. Additionally, NAC restored the proliferative capacity and reduced the apoptotic cells in folpet-treated TM4 cells. Collectively, we demonstrated that folpet causes ROS-mediated apoptotic cell death with mitochondrial dysfunction and calcium dysregulation in TM4 cells.}, }
@article {pmid34299175, year = {2021}, author = {Paskal, W and Paskal, AM and Pietruski, P and Stachura, A and Pełka, K and Woessner, AE and Quinn, KP and Kopka, M and Galus, R and Wejman, J and Włodarski, P}, title = {N-Acetylcysteine Added to Local Anesthesia Reduces Scar Area and Width in Early Wound Healing-An Animal Model Study.}, journal = {International journal of molecular sciences}, volume = {22}, number = {14}, pages = {}, pmid = {34299175}, issn = {1422-0067}, support = {MNiSW/2019/106/DIR/NN3//Ministerstwo Nauki i Szkolnictwa Wy&#x17c;szego/ ; 1M15/NM1/17//Warszawski Uniwersytet Medyczny/ ; }, mesh = {Acetylcysteine/*pharmacology ; Anesthesia, Local/*methods ; Anesthetics, Local/*pharmacology ; Animals ; Cicatrix/*drug therapy/pathology ; *Disease Models, Animal ; Drug Therapy, Combination ; Free Radical Scavengers/*pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Wound Healing/*drug effects ; }, abstract = {The aim of the study was to evaluate if a pre-incisional N-acetylcysteine (NAC) treatment altered the process of wound healing in a rat model. The dorsal skin of 24 Sprague-Dawley rats was incised in six locations. Before the incisions were made, skin was injected either with lidocaine and epinephrine (one side) or with these agents supplemented with 0.015%, 0.03%, or 0.045% NAC (contralaterally). Photographic documentation of the wound healing process was made at 11 time points. Rats were sacrificed 3, 7, 14, or 60 days after incision to excise scars for histological analysis. They included: Abramov scale scoring, histomorphometry analysis, and collagen fiber arrangement assessment. Skin pretreated with 0.03% NAC produced the shortest scars at all analyzed time points, though this result was statistically insignificant. At this NAC concentration the scars had smaller areas on the third day and were narrower on the day 4 compared with all the other groups (p < 0.05). On day 7, at the same concentration of NAC, the scars had a higher superficial concentration index (p = 0.03) and larger dermal proliferation area (p = 0.04). NAC addition to pre-incisional anesthetic solution decreased wound size and width at an early stage of scar formation at all concentrations; however, with optimal results at 0.03% concentration.}, }
@article {pmid34295982, year = {2021}, author = {Jawaid, H and Ali, MM and Khan, MU and Sami, S and Shaikh, MA}, title = {Efficacy and safety of N-acetylcysteine for the treatment of non-acetaminophen-induced acute liver failure: an updated systematic review and meta-analysis.}, journal = {Clinical and experimental hepatology}, volume = {7}, number = {2}, pages = {156-164}, pmid = {34295982}, issn = {2392-1099}, abstract = {AIM OF THE STUDY: N-acetylcysteine (NAC) is the treatment of choice for acetaminophen-induced liver injury. However, recent years have witnessed growing interest in its role in the treatment of acute liver failure (ALF) due to other aetiologies. This study aims to determine both its safety and efficacy by pooling data from multiple studies.<br><br>MATERIAL AND METHODS: A search was conducted for all controlled randomized/non-randomized studies that measured the efficacy and safety of NAC in adult patients with non-acetaminophen-induced acute liver failure (NAI-ALF). Transplant-free survival (TFS) was considered the primary endpoint, while secondary endpoints such as length of hospital stay, and incidence of adverse events during treatment, were included in our analysis. Data were pooled via a random-effects model, I [2] was used as a measure of heterogeneity, and publication bias was assessed via a funnel plot.<br><br>RESULTS: A total of 3 studies [2 randomized controlled trials (RCTs) and 1 non-randomized cohort] were pooled in this meta-analysis. TFS was significantly higher in patients given NAC, when compared to the placebo/control (PBO) group (RR = 1.54, CI = 1.19-1.98, p = 0.01, I [2] = 0.0%). No secondary endpoint was observed to have improved significantly in patients prescribed NAC: length of hospital stay (SMD = -0.405, CI = -1.44-0.63, p = 0.445, I [2] = 91.1%), renal failure (RR = 1.01, CI = 0.65-1.57, p = 0.967, I [2] = 21.3%), infections (RR = 1.18, CI = 0.91-1.52, p = 0.208, I [2] = 2.3%), pulmonary failure (RR = 1.19, CI = 0.57-2.49, p = 0.649, I [2] = 84.6%). Minimal side effects were reported in around 10-14% of the patients prescribed NAC.<br><br>CONCLUSIONS: NAC was shown to significantly improve TFS in adult patients with NAI-ALF, while no significant benefit was observed concerning the secondary endpoints of length of hospital stay and incidence of adverse effects.}, }
@article {pmid34291011, year = {2021}, author = {Ghorbi, M and Rashidi, M and Olapour, A and Javaherforooshzadeh, F and Akhondzadeh, R}, title = {Effect of N-Acetylcysteine on the treatment of acute respiratory distress syndrome in mechanically ventilated patients admitted to the intensive care unit.}, journal = {Medical journal of the Islamic Republic of Iran}, volume = {35}, number = {}, pages = {87}, pmid = {34291011}, issn = {1016-1430}, abstract = {Background: N-acetylcysteine (NAC) is an antioxidant derived from the amino acid cysteine and is one of the drugs used in the treatment of respiratory diseases. The aim of this study was to investigate the effect of NAC on the treatment of acute respiratory distress syndrome in mechanically ventilated patients admitted to the intensive care unit. Methods: This study was a randomized clinical trial. Patients under mechanical ventilation admitted to the intensive care unit were examined. Patients in the intervention group received daily 150 mg/kg of NAC on the first day of admission and then 50 mg/kg up to the fourth day of admission. Patients in the control group received routine care. The vital signs, level of consciousness, and other important variables were recorded. Data were analyzed using statistical tests and SPSS software version 24. Results: There was no significant difference between MAP, heart rate, respiratory rate, O2Sat, APACHE II score, and pulmonary capacity of the patients in the two groups on the first, second, third and fourth days after the intervention (p>0.05). There was no significant difference between the level of consciousness (according to GCS criteria), respiratory index (PAO2/FIO2) and PEEP of patients in the two study groups within 1 to 2 days after the intervention (p>0.05). There was a significant difference between the level of consciousness (based on GCS criteria), respiratory index (PAO2/FIO2) and PEEP of patients in the two study groups within 3 to 4 days after the intervention (p<0.05). There was no significant difference between the duration of hospitalization in the ICU, the time required for mechanical ventilation and the mortality rate of the patients in the two groups (p>0.05). Conclusion: It seems that N-acetylcysteine has a positive effect on the treatment of acute respiratory distress syndrome in mechanically ventilated patients admitted to the intensive care unit.}, }
@article {pmid34290603, year = {2021}, author = {Qing, C and Xinyi, Z and Xuefei, Y and Xindong, X and Jianhua, F}, title = {The Specific Connexin 43-Inhibiting Peptide Gap26 Improved Alveolar Development of Neonatal Rats With Hyperoxia Exposure.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {587267}, pmid = {34290603}, issn = {1663-9812}, abstract = {Bronchopulmonary dysplasia (BPD) is a common devastating pulmonary complication in preterm infants. Alveolar maldevelopment is the crucial pathological change of BPD highly associated with oxidative stress-mediated excessive apoptosis. Cellular injury can be propagated and amplified by gap junction (GJ)-mediated intercellular communication. Connexin 43 (Cx43) is the most ubiquitous and critical GJ protein. Gap26 is a specific Cx43 mimic peptide, playing as a Cx43-GJ inhibitor. We hypothesized that Cx43-GJ was involved in alveolar maldevelopment of BPD via amplifying oxidative stress signaling and inducing excessive apoptosis. Neonatal Sprague Dawley rats were kept in either normoxia (21% O2) or hyperoxia (85% O2) continuously from postnatal day (PN) 1 to 14 in the presence or absence of Gap26. Moreover, RLE-6TN cells (type II alveolar epithelial cells of rats) were cultured in vitro under normoxia (21% O2) or hyperoxia (85% O2). RLE-6TN cells were treated by N-acetyl cysteine (NAC) (a kind of reactive oxygen species (ROS) scavenger) or Gap26. Morphological properties of lung tissue are detected. Markers associated with Cx43 expression, ROS production, the activity of the ASK1-JNK/p38 signaling pathway, and apoptotic level are detected in vivo and in vitro, respectively. In vitro, the ability of GJ-mediated intercellular communication was examined by dye-coupling assay. In vitro, our results demonstrated ROS increased Cx43 expression and GJ-mediated intercellular communication and Gap26 treatment decreased ROS production, inhibited ASK1-JNK/p38 signaling, and decreased apoptosis. In vivo, we found that hyperoxia exposure resulted in increased ROS production and Cx43 expression, activated ASK1-JNK/p38 signaling, and induced excessive apoptosis. However, Gap26 treatment reversed these changes, thus improving alveolar development in neonatal rats with hyperoxia exposure. In summary, oxidative stress increased Cx43 expression and Cx43-GJ-mediated intercellular communication. And Cx43-GJ-mediated intercellular communication amplified oxidative stress signaling, inducing excessive apoptosis via the ASK1-JNK/p38 signaling pathway. The specific connexin 43-inhibiting peptide Gap26 was a novel therapeutic strategy to improve the alveolar development of BPD.}, }
@article {pmid34284670, year = {2023}, author = {Shah, J and Muir, J and Furfaro, D and Beitler, JR and Dzierba, AL}, title = {Use of N-Acetylcysteine for Clozapine-Induced Acute Liver Injury: A Case Report and Literature Review.}, journal = {Journal of pharmacy practice}, volume = {36}, number = {2}, pages = {463-467}, doi = {10.1177/08971900211034007}, pmid = {34284670}, issn = {1531-1937}, mesh = {Humans ; Female ; Middle Aged ; Acetylcysteine/therapeutic use ; *Clozapine/adverse effects ; *Liver Failure, Acute/drug therapy ; *Drug-Related Side Effects and Adverse Reactions/drug therapy ; *Chemical and Drug Induced Liver Injury/diagnosis/drug therapy/etiology ; }, abstract = {Purpose: To report a case of clozapine-induced hepatotoxicity managed with intravenous (IV) N-acetylcysteine (NAC) and summarize the available literature. Summary: A 46-year-old woman with history of bipolar disorder with psychotic features presented to the intensive care unit with asterixis and elevations in liver enzymes. The patient had been initiated on risperidone, clozapine, and lithium approximately 1 month prior to admission. After ruling out other possible non-drug etiologies, clozapine was suspected as the likeliest cause of the acute liver injury. Her acute liver injury was managed with the discontinuation of all antipsychotics, administration of IV NAC, and other standard of care supportive measures. Conclusion: Although clozapine has been associated with hepatitis and acute liver failure, there are no reports of NAC used in the management of clozapine-induced hepatotoxicity. NAC was used in our patient after considering the potential benefit and limited adverse effects. The role of NAC in non-acetaminophen-induced acute liver failure remains promising, but more research is warranted.}, }
@article {pmid34281260, year = {2021}, author = {Liu, X and Xiao, Y and Zhu, Q and Cui, Y and Hao, H and Wang, M and Cowan, PJ and Korthuis, RJ and Li, G and Sun, Q and Liu, Z}, title = {Circulating Endothelial Progenitor Cells Are Preserved in Female Mice Exposed to Ambient Fine Particulate Matter Independent of Estrogen.}, journal = {International journal of molecular sciences}, volume = {22}, number = {13}, pages = {}, pmid = {34281260}, issn = {1422-0067}, support = {R01 ES026200/ES/NIEHS NIH HHS/United States ; ES026200/NH/NIH HHS/United States ; AA022108/NH/NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cardiovascular Diseases/etiology/metabolism ; Cytokines/blood ; Endothelial Progenitor Cells/*drug effects/*metabolism/pathology ; Estrogens/metabolism ; Female ; Inflammation Mediators/blood ; Male ; Mice ; Mice, Inbred C57BL ; Ovariectomy ; Oxidative Stress/drug effects ; Particulate Matter/*toxicity ; Reactive Oxygen Species/metabolism ; Sex Factors ; }, abstract = {Males have a higher risk for cardiovascular diseases (CVDs) than females. Ambient fine particulate matter (PM) exposure increases CVD risk with increased reactive oxygen species (ROS) production and oxidative stress. Endothelial progenitor cells (EPCs) are important to vascular structure and function and can contribute to the development of CVDs. The aims of the present study were to determine if sex differences exist in the effect of PM exposure on circulating EPCs in mice and, if so, whether oxidative stress plays a role. Male and female C57BL/6 mice (8-10 weeks old) were exposed to PM or a vehicle control for six weeks. ELISA analysis showed that PM exposure substantially increased the serum levels of IL-6 and IL-1β in both males and females, but the concentrations were significantly higher in males. PM exposure only increased the serum levels of TNF-α in males. Flow cytometry analysis demonstrated that ROS production was significantly increased by PM treatment in males but not in females. Similarly, the level of circulating EPCs (CD34[+]/CD133[+] and Sca-1[+]/Flk-1[+]) was significantly decreased by PM treatment in males but not in females. Antioxidants N-acetylcysteine (NAC) effectively prevented PM exposure-induced ROS and inflammatory cytokine production and restored circulating EPC levels in male mice. In sharp contrast, circulating EPC levels remained unchanged in female mice with PM exposure, an effect that was not altered by ovariectomy. In conclusion, PM exposure selectively decreased the circulating EPC population in male mice via increased oxidative stress without a significant impact on circulating EPCs in females independent of estrogen.}, }
@article {pmid34278450, year = {2021}, author = {He, Y and Shi, Y and Yang, Y and Huang, H and Feng, Y and Wang, Y and Zhan, L and Wei, B}, title = {Chrysin induces autophagy through the inactivation of the ROS‑mediated Akt/mTOR signaling pathway in endometrial cancer.}, journal = {International journal of molecular medicine}, volume = {48}, number = {3}, pages = {}, pmid = {34278450}, issn = {1791-244X}, mesh = {Antineoplastic Agents/*pharmacology ; Autophagy/*drug effects ; Cell Line, Tumor ; Endometrial Neoplasms/*drug therapy/metabolism ; Female ; Flavonoids/*pharmacology ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Endometrial cancer (EC) is widely known as an aggressive malignancy. Due to the limited therapeutic options and poor prognosis of patients with advanced‑stage EC, there is a need to identify effective alternative treatments. Chrysin is a naturally active flavonoid (5,7‑dihydroxyflavone), which has been demonstrated to exert anticancer effects and may present a novel strategy for EC treatment. However, the role of chrysin in EC remains largely unclear. The aim of the present study was to examine the anticancer effects of chrysin on EC. The results revealed that, in addition to apoptosis, chrysin increased the LC3II expression levels and markedly accelerated the autophagic flux, suggesting that chrysin induced both the autophagy and apoptosis of EC cells. Furthermore, the inhibition of autophagy by chloroquine enhanced the inhibitory effect on cell proliferation and the promotion of the chrysin‑induced apoptosis of EC cells, indicating that chrysin‑induced autophagy was a cytoprotective mechanism. Additionally, chrysin led to the production of intracellular reactive oxygen species (ROS). N‑acetylcysteine (NAC) pretreatment significantly inhibited chrysin‑induced autophagy, suggesting that ROS activated autophagy induced by chrysin in EC cells. Furthermore, the phosphorylated (p‑)Akt and p‑mTOR levels were significantly decreased in a concentration‑dependent manner following treatment with chrysin, while NAC blocked these effects. Taken together, these findings demonstrated that chrysin‑induced autophagy via the inactivation of the ROS‑mediated Akt/mTOR signaling pathway in EC cells.}, }
@article {pmid34276378, year = {2021}, author = {Hang, X and Zhang, Y and Li, J and Li, Z and Zhang, Y and Ye, X and Tang, Q and Sun, W}, title = {Comparative Efficacy and Acceptability of Anti-inflammatory Agents on Major Depressive Disorder: A Network Meta-Analysis.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {691200}, pmid = {34276378}, issn = {1663-9812}, abstract = {Background: With the growing importance of research about the association between neuroinflammation and major depressive disorder (MDD), anti-inflammatory agents have been used as a new antidepressant therapy in clinical practice. We conducted a network meta-analysis (NMA) with up-to-date evidence to compare different anti-inflammatory agents for improving the treatment of MDD patients. Methods: To identify eligible randomized clinical trials, four databases (i.e, the Cochrane Library, Web of Science, PubMed and Embase) were searched from inception date to May 31, 2020. Anti-inflammatory agents were defined as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, cytokine inhibitors, statins, pioglitazone, minocycline, N-acetylcysteine (NAC) and omega-3 fatty acid (Omega-3 FA). The main outcomes of this NMA were efficacy, acceptability and remission rate. Risk ratio (RR) was adopted for dichotomous outcomes, and the confidence interval (CI) was set at 95%. STATA 14.0 and R 3.6.3 were used to conduct the NMA. The study protocol was registered with PROSPERO (CRD42020182531). Results: A total of 39 studies, involving 2871 participants, were included in quantitative data synthesis. For efficacy, NSAIDs (RR=0.50, 95%CI: 0.26-0.73) and pioglitazone (RR=0.45, 95%CI: 0.20-0.84) were more favorable than placebo. With respect to acceptability, NSAIDs were more acceptable than placebo (RR=0.89, 95%CI: 0.77-0.99) and minocycline (RR=1.22, 95%CI: 1.03-1.49). For remission, NSAIDs were more superior than placebo (RR=0.48, 95%CI: 0.27-0.79) and Omega-3 FA (RR=2.01, 95%CI: 1.09-3.90), while NACs were more favorable than placebo (RR=0.39, 95%CI: 0.13-0.99). Based on the surface under the cumulative ranking curve (SUCRA) value, corticosteroids (0.86) were the best anti-inflammatory agent for MDD patients in terms of efficacy, but the head-to-head comparisons for the efficacy of glucocorticoids and other agents were not statistically significant. As for acceptability, NSAIDs (0.81) were much better than other anti-inflammatory agents. Besides, NAC (0.80) was the best anti-inflammatory agent in the terms of remission. Conclusions: In summary, we found that corticosteroids were more superior than other agents in terms of efficacy according to the SUCRA value. However, this result must be interpreted with caution because the head-to-head comparisons for the efficacy of glucocorticoids and other agents did not reach statistical significance. NSAIDs were recommended for acceptability and NAC for remission rate.}, }
@article {pmid34275660, year = {2021}, author = {Pang, KH and Chapple, CR and Chatters, R and Downey, AP and Harding, CK and Hind, D and Watkin, N and Osman, NI}, title = {A Systematic Review and Meta-analysis of Adjuncts to Minimally Invasive Treatment of Urethral Stricture in Men.}, journal = {European urology}, volume = {80}, number = {4}, pages = {467-479}, doi = {10.1016/j.eururo.2021.06.022}, pmid = {34275660}, issn = {1873-7560}, mesh = {Captopril ; Humans ; Injections, Intralesional ; Male ; Mitomycin ; Recurrence ; Tamoxifen ; Triamcinolone ; Urethra ; *Urethral Stricture/surgery ; }, abstract = {CONTEXT: Urethral stricture disease (USD) is initially managed with minimally invasive techniques such as urethrotomy and urethral dilatation. Minimally invasive techniques are associated with a high recurrence rate, especially in recurrent USD. Adjunctive measures, such as local drug injection, have been used in an attempt to reduce recurrence rates.<br><br>OBJECTIVE: To systematically review evidence for the efficacy and safety of adjuncts used alongside minimally invasive treatment of USD.<br><br>EVIDENCE ACQUISITION: A systematic review of the literature published between 1990 and 2020 was conducted in accordance with the PRISMA checklist.<br><br>EVIDENCE SYNTHESIS: A total of 26 studies were included in the systematic review, from which 13 different adjuncts were identified, including intralesional injection (triamcinolone, n&#xa0;=&#xa0;135; prednisolone, n&#xa0;=&#xa0;58; mitomycin C, n&#xa0;=&#xa0;142; steroid-mitomycin C-hyaluronidase, n&#xa0;=&#xa0;103, triamcinolone-mitomycin C-N-acetyl cysteine, n&#xa0;=&#xa0;50; platelet-rich plasma, n&#xa0;=&#xa0;44), intraluminal instillation (mitomycin C, n&#xa0;=&#xa0;20; hyaluronic acid and carboxymethylcellulose, n&#xa0;=&#xa0;70; captopril, n&#xa0;=&#xa0;37; 192-iridium brachytherapy, n&#xa0;=&#xa0;10), application via a lubricated catheter (triamcinolone, n&#xa0;=&#xa0;124), application via a coated balloon (paclitaxel, n&#xa0;=&#xa0;106), and enteral application (tamoxifen, n&#xa0;=&#xa0;30; deflazacort, n&#xa0;=&#xa0;36). Overall, 13 randomised controlled trials were included in the meta-analysis. Use of any adjunct was associated with a lower rate of USD recurrence (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.27-0.50; p&#xa0;<&#xa0; 0.001) compared to no adjunct use. Of all the adjuncts, mitomycin C was associated with the lowest rate of USD recurrence (intralesional injection: OR 0.23, 95% CI 0.11-0.48; p&#xa0;<&#xa0; 0.001; intraluminal injection: OR 0.11, 95% CI 0.02-0.61; p&#xa0;=&#xa0; 0.01). Urinary tract infection (2.9-14%), bleeding (8.8%), and extravasation (5.8%) were associated with steroid injection; pruritis of the urethra (61%) occurred after instillation of captopril; mild gynaecomastia (6.7%) and gastrointestinal side effects (6.7%) were associated with oral tamoxifen.<br><br>CONCLUSIONS: Adjuncts to minimally invasive treatment of USD appear to lower the recurrence rate and are associated with a low adjunct-specific complication rate. However, the studies included were at high risk of bias. Mitomycin C is the adjunct supported by the highest level of evidence.<br><br>PATIENT SUMMARY: We reviewed studies on additional therapies (called adjuncts) to minimally invasive treatments for narrowing of the urethra in men. Adjuncts such as mitomycin C injection result in a lower recurrence rate compared to no adjunct use. The use of adjuncts appeared to be safe and complications are uncommon; however, the studies were small and of low quality.}, }
@article {pmid34275158, year = {2021}, author = {Sahasrabudhe, SA and Kartha, RV and Ng, M and Basso, LM and Mishra, U and Cloyd, JC and Orchard, PJ and Brundage, RC and Coles, LD}, title = {Population Pharmacokinetic Analysis of N-Acetylcysteine in Pediatric Patients With Inherited Metabolic Disorders Undergoing Hematopoietic Stem Cell Transplant.}, journal = {Journal of clinical pharmacology}, volume = {61}, number = {12}, pages = {1638-1645}, doi = {10.1002/jcph.1943}, pmid = {34275158}, issn = {1552-4604}, mesh = {Acetylcysteine/*pharmacokinetics ; Adolescent ; Child ; Child, Preschool ; Female ; Half-Life ; *Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Metabolic Clearance Rate ; Metabolism, Inborn Errors/*metabolism ; Models, Biological ; Prospective Studies ; Time Factors ; Young Adult ; }, abstract = {N-acetylcysteine (NAC) has been used in patients with cerebral adrenoleukodystrophy as an antioxidant agent in association with hematopoietic stem cell transplant (HSCT). However, an understanding of the pharmacokinetic characteristics of intravenous NAC dosing in these patients is limited. If and how NAC pharmacokinetics change following the transplant is unknown. Toward that end, a total of 260 blood samples obtained from 18 pediatric patients with inherited metabolic disorders who underwent HSCT were included in a population pharmacokinetic analysis using nonlinear mixed-effects modeling. NAC clearance (CL) and volume of distribution (V) were explored on 3 occasions: -7, +7, and +21 days relative to transplant. Additionally, the effect of transplant procedure on NAC disposition was explored by accounting for between-occasion variability. The covariate OCC was modeled as a fixed-effect parameter on CL and/or V1. A 2-compartment model adequately described the pharmacokinetics of total NAC. Weight-based allometric scaling on pharmacokinetic parameters was assumed using standard coefficients. Estimates for CL, central (V1), and peripheral volume (V2), and intercompartment clearance were 14.7 L/h, 23.2 L, 17.1 L, 3.99 L/h, respectively, for a 70-kg person. The data only supported between-subject variability in CL (12%) and V1 (41%). Residual variability was estimated to be 16%. HSCT did not change CL and V1 significantly, and analysis across occasions did not reveal any trends. Pharmacokinetic parameter estimates were in general comparable to those reported previously in different populations. These results suggest that dosing of NAC does not need to be altered following HSCT.}, }
@article {pmid34267823, year = {2021}, author = {Jiang, D and Xu, J and Liu, S and Nasser, MI and Wei, W and Mao, T and Liu, X and Zou, X and Li, J and Li, X}, title = {Rosmanol induces breast cancer cells apoptosis by regulating PI3K/AKT and STAT3/JAK2 signaling pathways.}, journal = {Oncology letters}, volume = {22}, number = {2}, pages = {631}, pmid = {34267823}, issn = {1792-1082}, abstract = {Breast cancer is one of the most frequently diagnosed cancers amongst women; however, there is currently no effective treatment. Natural compounds are considered to contribute to cancer prevention and have a pivotal role in modulating apoptosis. Rosmanol is a phenolic diterpene compound with antioxidant and anti-inflammatory properties. In the present study, the effects of Rosmanol on breast cancer cell proliferation/apoptosis were investigated, and it was demonstrated that it inhibited the proliferation of MCF-7 and MDA-MB 231 cells but did not have a significant effect on normal human breast MCF-10A cells. In addition, the apoptotic process was accelerated by Rosmanol, through mitochondrial pathways and reactive oxygen species (ROS) production caused by DNA damage, which function further demonstrated by the attenuation and addition of the ROS inhibitor, N-acetyl-cysteine. It was also demonstrated that Rosmanol accelerated cell apoptosis, and arrested breast cancer cells in the S phase. Moreover, Rosmanol inhibited proliferation and promoted apoptosis of cancer cells via the inhibition of ERK and STAT3 signals, attributable to the increase in p-p38, the overexpression of protein inhibitor of activated STAT3, and the decrease in PI3K/AKT, ERK and JAK2/STAT3.}, }
@article {pmid34267196, year = {2021}, author = {Gusarov, I and Shamovsky, I and Pani, B and Gautier, L and Eremina, S and Katkova-Zhukotskaya, O and Mironov, A and Makarov, A&#x410; and Nudler, E}, title = {Dietary thiols accelerate aging of C. elegans.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {4336}, pmid = {34267196}, issn = {2041-1723}, support = {/HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aging/*drug effects/genetics/physiology ; Animals ; Animals, Genetically Modified ; Caenorhabditis elegans/*drug effects/*physiology ; Caenorhabditis elegans Proteins/genetics ; DNA-Binding Proteins/genetics ; Dietary Supplements ; Escherichia coli ; Female ; Fibroblasts/metabolism ; Gene Expression Regulation/drug effects ; Glutathione/metabolism/*pharmacology ; Humans ; Male ; Paraquat/pharmacology ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; Transcription Factors/genetics ; Unfolded Protein Response/physiology ; }, abstract = {Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS, it follows that GSH and its precursor, N-acetyl cysteine (NAC), are among the most popular dietary supplements. However, the long- term effects of GSH or NAC on healthy animals have not been thoroughly investigated. We employed C. elegans to demonstrate that chronic administration of GSH or NAC to young or aged animals perturbs global gene expression, inhibits skn-1-mediated transcription, and accelerates aging. In contrast, limiting the consumption of dietary thiols, including those naturally derived from the microbiota, extended lifespan. Pharmacological GSH restriction activates the unfolded protein response and increases proteotoxic stress resistance in worms and human cells. It is thus advantageous for healthy individuals to avoid excessive dietary antioxidants and, instead, rely on intrinsic GSH biosynthesis, which is fine-tuned to match the cellular redox status and to promote homeostatic ROS signaling.}, }
@article {pmid34262291, year = {2021}, author = {Xia, Y and Wang, G and Jiang, M and Liu, X and Zhao, Y and Song, Y and Jiang, B and Zhu, D and Hu, L and Zhang, Z and Cao, T and Wang, JM and Hu, J}, title = {A Novel Biological Activity of the STAT3 Inhibitor Stattic in Inhibiting Glutathione Reductase and Suppressing the Tumorigenicity of Human Cervical Cancer Cells via a ROS-Dependent Pathway.}, journal = {OncoTargets and therapy}, volume = {14}, number = {}, pages = {4047-4060}, pmid = {34262291}, issn = {1178-6930}, abstract = {INTRODUCTION: Glutathione reductase (GSR) provides reduced glutathione (GSH) to maintain redox homeostasis. Inhibition of GSR disrupts this balance, resulting in cell damage, which benefits cancer therapy. However, the effect of GSR inhibition on the tumorigenicity of human cervical cancer is not fully understood.<br><br>MATERIALS AND METHODS: Tissue microarray analysis was employed to determine GSR expression in cervical cancer tissues by immunohistochemical staining. Cell death was measured with PI/FITC-annexin V staining. mRNA levels were measured via quantitative RT-PCR. Protein expression was measured by Western blotting and flow cytometry. STAT3 deletion was performed with CRISPR/Cas9 technology. GSR knockdown was achieved by RNA interference. Reactive oxygen species (ROS) levels were measured by DCF staining. GSR enzymatic activity was measured with a GSR assay kit. The effect of GSR inhibition on the growth of tumors formed by cervical cancer cells was investigated using a xenograft model.<br><br>RESULTS: The expression of GSR was increased in human cervical cancer tissues, as shown by immunohistochemical staining. GSR knockdown by RNA interference in human cervical cancer cell lines resulted in cell death, suggesting the ability of GSR to maintain cancer cell survival. The STAT3 inhibitor 6-nitrobenzo[b]thiophene 1,1-dioxide (Stattic) also inhibited the enzymatic activity of GSR and induced the death of cervical cancer cells. More importantly, Stattic decreased the growth of xenograft tumors formed by cervical cancer cells in nude mice. Mechanistically, tumor cell death induced by Stattic-mediated GSR inhibition was ROS-dependent, since the ROS scavengers GSH and N-acetyl cysteine (NAC) reversed the effect of Stattic. In contrast, pharmacological and molecular inhibition of STAT3 did not induce the death of cervical cancer cells, suggesting a STAT3-independent activity of Stattic.<br><br>CONCLUSION: Stattic inhibits the enzymatic activity of GSR and induces STAT3-independent but ROS-dependent death of cervical cancer cells, suggesting its potential application as a therapeutic agent for human cervical cancers.}, }
@article {pmid34262087, year = {2021}, author = {Zhang, T and Ni, C and Li, C and Lu, P and Chen, D and Dong, Y and Whetstine, JR and Zhang, Y and Xie, Z}, title = {Isoflurane impairs oogenesis through germ cell apoptosis in C. elegans.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {14481}, pmid = {34262087}, issn = {2045-2322}, support = {R01GM088801/NH/NIH HHS/United States ; R01 HD086977/HD/NICHD NIH HHS/United States ; P30 CA006927/CA/NCI NIH HHS/United States ; }, mesh = {Anesthetics, Inhalation/toxicity ; Animals ; Apoptosis/*drug effects ; Caenorhabditis elegans/cytology/*drug effects/embryology/genetics ; Caenorhabditis elegans Proteins/genetics ; Caspases/genetics ; Embryo, Nonmammalian/drug effects ; Female ; Hermaphroditic Organisms ; Isoflurane/*toxicity ; Male ; Oogenesis/*drug effects ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-abl/genetics ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/genetics ; }, abstract = {Anesthetic isoflurane has been reported to induce toxicity. However, the effects of isoflurane on fecundity remain largely unknown. We established a system in C. elegans to investigate the effects of isoflurane on oogenesis. Synchronized L4 stage C. elegans were treated with 7% isoflurane for 4 h. Dead cells, ROS, embryos, and unfertilized eggs laid by hermaphrodites were measured by fluorescence imaging and counting. The C. elegans with losses of ced-3, cep-1, abl-1, male C. elegans, and oxidative stress inhibitor N-acetyl-cysteine were used in the interaction studies. We found that isoflurane decreased the numbers of embryos and unfertilized eggs and increased the levels of dead cells and ROS in C. elegans. The isoflurane-induced impairment of oogenesis was associated with abl-1, ced-3, but not cep-1. N-acetyl-cysteine attenuated the isoflurane-induced impairment of oogenesis in C. elegans. Mating with male C. elegans did not attenuate the isoflurane-induced changes in oogenesis. These findings suggest that isoflurane may impair oogenesis through abl-1- and ced-3-associated, but not cep-1-associated, germ cell apoptosis and oxidative stress, pending further investigation. These studies will promote more research to determine the potential effects of anesthesia on fecundity.}, }
@article {pmid34258270, year = {2021}, author = {Liu, X and Hu, Z and Zhou, H}, title = {N-Acetylcysteine Improves Inflammatory Response in COPD Patients by Regulating Th17/Treg Balance through Hypoxia Inducible Factor-1α Pathway.}, journal = {BioMed research international}, volume = {2021}, number = {}, pages = {6372128}, pmid = {34258270}, issn = {2314-6141}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Aged ; Down-Regulation/drug effects ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Inflammation/blood/complications/*pathology ; Interleukin-10/blood ; Interleukin-17/blood ; Lymphocyte Count ; Male ; Pulmonary Disease, Chronic Obstructive/blood/*complications/*immunology ; T-Lymphocytes, Regulatory/drug effects/*immunology ; Th17 Cells/drug effects/*immunology ; Up-Regulation/drug effects ; }, abstract = {INTRODUCTION: This study was aimed to investigate the effects of N-acetylcysteine (NAC) on chronic obstructive pulmonary disease (COPD) and the change of Th17/Treg cytokine imbalance. Material and Methods. A total of 121 patients with stable COPD at the stage of C or D were consecutively enrolled and randomly divided into 2 groups. Patients in the treatment group received NAC granules (0.2 g × 10 bags, 0.4 g each time, 3 times/d) for half a year. The control group was treated with the same amount of placebo therapy. The peripheral blood of the patient was collected and the cytokine, T lymphocyte subsets were detected.<br><br>RESULTS: We found the oral administration of NAC could regulate Th17/Treg balance to resist inflammation in COPD patients. Serum testing showed that the proportion of Treg in CD4+ T cells has increased and the Th17/Treg ratio has decreased during the NAC treatment. In vitro studies, we found that NAC regulated Th17/Treg balance through Hypoxia Inducible Factor-1&#x3b1; pathway.<br><br>CONCLUSIONS: Our result could provide new diagnosis and treatment for elderly patients with COPD from the perspective of immunity ideas.}, }
@article {pmid34257959, year = {2021}, author = {Davoodi, L and Ebrahimi, NR and Izadyar, H and Moradi, S and Razavi, A and Zakariaei, Z and Soleymani, E}, title = {Evaluation of the effectiveness of N-acetylcysteine on accelerating the recovery of renal failure in patients with leptospirosis, a randomized clinical trial study.}, journal = {Annals of medicine and surgery (2012)}, volume = {67}, number = {}, pages = {102518}, pmid = {34257959}, issn = {2049-0801}, abstract = {BACKGROUND: Limited studies have been conducted on patients with renal function recovery regarding severe leptospirosis. The purpose of this study is to evaluate the effectiveness of N-acetylcysteine (NAC) in accelerating the reduction of serum creatinine in patients with leptospirosis.<br><br>PATIENTS AND METHODS: This is a clinical trial study involving 64 patients with leptospirosis, with microscopic agglutination tests used to confirm the diagnosis of acute kidney injury. NAC was given to patients with a glomerular filtration rate of less than 60&#xa0;ml/min at 1200&#xa0;mg every 12&#xa0;h, and it lasted for 48&#xa0;h. Next, 32 patients were measured and the relationship between the length of hospitalization, age, and sex was also examined. Additionally, the two groups of case and control were compared in terms of the rate of decrease in serum creatinine level in three different time periods. The Shapro-Wilk test was used to investigate the distribution of data.<br><br>RESULTS: No significant differences were observed in the decrease in serum creatinine level on the first, third, and seventh days of hospitalization and also in the use of NAC between the case and control groups (P&#xa0;=&#xa0;0.255). In addition, the use of NAC had no significant effect on reducing the length of hospitalization (P&#xa0;=&#xa0;0.067).<br><br>CONCLUSION: Recovery of acute kidney injury following leptospirosis and drugs that accelerate the healing process in these patients require further studies with greater sample size and longer follow-up time.}, }
@article {pmid34256079, year = {2021}, author = {Katebi, SN and Torkaman-Boutorabi, A and Vousooghi, N and Riahi, E and Haghparast, A}, title = {Systemic administration of N-acetylcysteine during the extinction period and on the reinstatement day decreased the maintenance of morphine rewarding properties in the rats.}, journal = {Behavioural brain research}, volume = {413}, number = {}, pages = {113451}, doi = {10.1016/j.bbr.2021.113451}, pmid = {34256079}, issn = {1872-7549}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Behavior, Animal/*drug effects ; Conditioning, Classical ; Disease Models, Animal ; Locomotion/*drug effects ; Morphine/administration &amp; dosage/*pharmacology ; Morphine Dependence/*drug therapy ; Narcotics/administration &amp; dosage/*pharmacology ; Rats ; Rats, Wistar ; *Reinforcement, Psychology ; Reward ; }, abstract = {Many animal studies and early clinical trials suggested that N-acetylcysteine (NAC) may benefit addiction treatment. The present study tried to evaluate whether chronic administration of systemic NAC during the extinction period and acute administration of systemic NAC on the reinstatement day could reduce the maintenance of the morphine rewarding properties in the conditioned place preference (CPP) paradigm in the rats. Ninety-six adult male Wistar rats (190-220 g) were examined with morphine (7 mg/kg; sc) and saline (1 mL/kg; sc) during the 3-day conditioning phase in the CPP paradigm. After the acquisition of morphine CPP, different doses of NAC were daily administered during the extinction period (5, 10, 25, and 50 mg/kg; ip), or 30 min before the CPP test on the reinstatement day (2, 5, 10, 25, and 50 mg/kg; ip). Conditioning score and locomotor activity were recorded by the video tracking system and Ethovision software after acquisition on the post-conditioning day, the extinction period, and reinstatement day. Daily NAC administration in high doses (25 and 50 mg/kg; ip) reduced extinction-responding compared with the vehicle-control group during the extinction period. Although a single injection of NAC in doses 10, 25, 50 mg/kg decreased the reinstatement of morphine-induced CPP, two lower doses (2 and 5 mg/kg) could not significantly reduce the CPP scores. These are the first data suggesting that NAC's application during the extinction period could attenuate the morphine reward-associated behaviors in the rats. Moreover, NAC could inhibit the reinstatement of morphine CPP, which adds to the growing appreciation that the NAC may have potential therapeutic use in combating morphine dependence. It can be consistent with the hypothesis of the involvement of the glutamatergic system in the pathophysiology of addiction.}, }
@article {pmid34254625, year = {2021}, author = {Li, J and Chang, X and Shang, M and Niu, S and Zhang, W and Li, Y and Sun, Z and Wu, T and Kong, L and Zhang, T and Tang, M and Xue, Y}, title = {The crosstalk between DRP1-dependent mitochondrial fission and oxidative stress triggers hepatocyte apoptosis induced by silver nanoparticles.}, journal = {Nanoscale}, volume = {13}, number = {28}, pages = {12356-12369}, doi = {10.1039/d1nr02153b}, pmid = {34254625}, issn = {2040-3372}, mesh = {Animals ; Apoptosis ; Dynamins/metabolism ; Hepatocytes/metabolism ; *Metal Nanoparticles/toxicity ; Mice ; *Mitochondrial Dynamics ; Oxidative Stress ; Silver/toxicity ; }, abstract = {Previous studies have revealed that the liver is the main target organ of deposition for engineered nanoparticles. The hepatotoxicity of silver nanoparticles (AgNPs), the widely used antimicrobial nanoparticles, has been of great interest. However, little is known about the regulatory mechanism of the mitochondria in AgNP-induced hepatotoxicity. In the present study, we found that AgNPs, rather than silver ions, induced mitochondrial dynamics disorders, oxidative stress, and mitochondria-dependent hepatocyte apoptosis in mice. Using human hepatocellular carcinoma (HepG2) cells, we confirmed that the interaction between dynamin-related protein 1 (DRP1)-dependent mitochondrial fission and oxidative stress promoted mitochondrial damage and mitochondria-dependent apoptosis induced by AgNPs, as determined by the elimination of DRP1 or addition of N-acetylcysteine (NAC). Interestingly, the crosstalk between DRP1-dependent mitochondrial fission and oxidative stress also activated mitophagy and autophagy flux blocking. Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene silencing contributed to the aggravation of mitochondrial damage, oxidative stress, and apoptosis. These results revealed that the interplay between mitochondrial fission and oxidative stress induced mitophagy defects and triggered AgNP-induced mitochondria-dependent apoptosis in liver cells both in vivo and in vitro. Our findings provide a perspective for the mechanism of hepatotoxicity induced by exposure to metal NPs.}, }
@article {pmid34252825, year = {2021}, author = {Barrozo, LG and Paulino, LRFM and Silva, BR and Barbalho, EC and Nascimento, DR and Neto, MFL and Silva, JRV}, title = {N-acetyl-cysteine and the control of oxidative stress during in vitro ovarian follicle growth, oocyte maturation, embryo development and cryopreservation.}, journal = {Animal reproduction science}, volume = {231}, number = {}, pages = {106801}, doi = {10.1016/j.anireprosci.2021.106801}, pmid = {34252825}, issn = {1873-2232}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cryopreservation/*veterinary ; Embryo Culture Techniques/*veterinary ; Female ; Humans ; In Vitro Oocyte Maturation Techniques/*veterinary ; Ovarian Follicle/*drug effects/physiology ; Oxidative Stress/*drug effects ; }, abstract = {Oxidative stress is generated by an imbalance between reactive oxygen species (ROS) formation and cellular defense mechanisms. To reduce cellular damage caused by ROS in vivo or in vitro, N-acetyl-cysteine (NAC) is converted into metabolites that have the capacity of stimulating synthesis of glutathione (GSH) which functions directly as free radical scavengers. The NAC antioxidant potential evaluated to the greatest extent is the indirect action of NAC, as a precursor of GSH, with glutathione being the primary antioxidant in cells. During long-term preantral follicle culture, NAC has a synergic action with FSH and an important function in sustaining preantral follicle growth and follicle-cell viability in vitro. The NAC inclusion in in vitro maturation medium for cumulus-oocyte complexes (COC) leads to protection of oocytes from damage induced by heat stress, reductions in ROS, and increases in cumulus cell expansion. Developing embryos are susceptable to oxidative stress because of susceptability to cellular structure damage and not having well-developed defense mechanisms. Results from various indicate there are beneficial effects of NAC on embryonic development by increasing GSH biosynthesis and regulating cell proliferation. In addition, NAC is also an effective antioxidant during cryopreservation of ovarian follicles, oocytes and embryos, because inclusion of NAC in preservation medium leads to improvements in mitochondrial function and cell viability, and reductions in ROS and cellular apoptosis. In this review, there is evaluation of mechanisms of action of NAC and beneficial effects during in vitro culture of preantral follicles, as well as oocyte maturation, embryonic development and cryopreservation.}, }
@article {pmid34250770, year = {2021}, author = {Jaafarzadeh, MM and Ranji, N and Aboutaleb, E}, title = {The effect of N-acetylcysteine on the levels of copper, zinc and expression of matrix metalloproteinases in the liver.}, journal = {Polish journal of veterinary sciences}, volume = {24}, number = {2}, pages = {191-199}, doi = {10.24425/pjvs.2020.135816}, pmid = {34250770}, issn = {2300-2557}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Copper/chemistry/*metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Liver/*enzymology ; Male ; Metalloproteases/genetics/*metabolism ; Rats ; Rats, Wistar ; Zinc/chemistry/*metabolism ; }, abstract = {This study was conducted to consider the effect of cadmium (Cd) on the liver and serum levels of zinc (Zn) and copper (Cu), and the role of N-acetylcysteine (NAC) in preserving cells against Cd toxicity. Rats were randomly divided into five groups, including G1 (control), G2 (single dose of Cd), G3 (continuous administration of Cd), G4 (single dose of Cd + continu- ous administration of NAC), and G5 (continuous administration of Cd + continuous administra- tion of NAC). Rats in G2 and G4 groups were exposed with single dose of Cd on the first day of study. Continuous administration of Cd and NAC was used every day for 4 weeks. Levels of Zn and Cu were measured by atomic absorption spectroscopy. Expression of matrix metallo- proteinases-2 (MMP2) and MMP9 genes was evaluated using RT-PCR. The mean level of Cd in serum and liver tissue of G2 group increased significantly by about 26-27%, whereas in G3 group, it increased significantly by about 50-60%. While NAC treatment significantly raised Zn and Cu values, Cd levels significantly decreased in the serum and tissue samples of rats exposed to single or continuous Cd. Exposure to single and continuous administration of Cd caused a significant increase in MMP2 expression by 10.14-fold (P=0.016) and 27.61-fold (P⟨0.001), respectively. Single and continuous administration of Cd led to a significant increase in MMP9 expression by 3.63-fold (P=0.046) and 43.12-fold (P⟨0.001), respectively. NAC treatments decreased the expression of MMP2 and MMP9 in rats exposed to single or continuous Cd. Cd exposure was strongly associated with Zn and Cu depletion, and overexpression of MMP2 and MMP9. NAC can protect the liver against Cd toxicity by elevating Zn and Cu contents and down-regulating proteolytic enzymes.}, }
@article {pmid34242719, year = {2021}, author = {Liu, M and Wu, X and Cui, Y and Liu, P and Xiao, B and Zhang, X and Zhang, J and Sun, Z and Song, M and Shao, B and Li, Y}, title = {Mitophagy and apoptosis mediated by ROS participate in AlCl3-induced MC3T3-E1 cell dysfunction.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {155}, number = {}, pages = {112388}, doi = {10.1016/j.fct.2021.112388}, pmid = {34242719}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Aluminum Chloride/*toxicity ; Animals ; Apoptosis/*drug effects ; Cell Line ; Mice ; Mitochondria/drug effects ; Mitophagy/*drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Aluminum (Al), as a common environmental pollutant, causes osteoblast (OB) dysfunction and then leads to Al-related bone diseases (ARBD). One of the mechanisms of ARBD is oxidative stress, which leads to an increase in the production of reactive oxygen species (ROS). ROS can induce mitochondrial damage, thereby inducing mitophagy and apoptosis. But whether mitophagy and apoptosis mediated by ROS, and the role of ROS in AlCl3-induced MC3T3-E1 cell dysfunction is still unclear. In this study, MC3T3-E1 cells used 0 mM Al (control group), 2 mM Al (Al group), 5 mM N-acetyl cysteine (NAC) (NAC group), 2 mM Al and 5 mM NAC (Al + NAC group) for 24 h. We found AlCl3-induced MC3T3-E1 cell dysfunction accompanied by oxidative stress, apoptosis, and mitophagy. While NAC, a ROS scavenger treatment, restored cell function and alleviated the mitophagy and apoptosis. These results suggested that mitophagy and apoptosis mediated by ROS participate in AlCl3-induced MC3T3-E1 cell dysfunction.}, }
@article {pmid34239993, year = {2021}, author = {Poles, J and Karhu, E and McGill, M and McDaniel, HR and Lewis, JE}, title = {The effects of twenty-four nutrients and phytonutrients on immune system function and inflammation: A narrative review.}, journal = {Journal of clinical and translational research}, volume = {7}, number = {3}, pages = {333-376}, pmid = {34239993}, issn = {2424-810X}, abstract = {BACKGROUND AND AIM: Recently, optimal immune function has become a primary focus of worldwide attention not only in the prevention of chronic disease but also as one strategy to reduce the severity of acute illness. Inflammation, a process largely controlled by the immune system, has long been studied and recognized for its role in chronic disease. Optimizing immune function or managing inflammation using individual nutrients and phytonutrients is not well understood by the average person. Thus, this narrative literature review summarizes many of the more recent findings about how certain nutrients and phytonutrients affect immune function and inflammation, and how they may best be utilized considering the growing worldwide interest in this topic.<br><br>METHODS: A comprehensive literature search of PubMed was performed to find clinical trials in humans that assessed the effect of nutrients and phytonutrients on immune function and inflammation, in individuals with acute and chronic health conditions, published in English between 2000 and 2020. Two independent reviewers evaluated the articles for their inclusion.<br><br>RESULTS: Eighty-seven articles were summarized in this narrative review. In total 24 nutrients and phytonutrients were included in the study, that is, acetyl-L-carnitine, Aloe vera polysaccharides, beta-glucans, bilberry, black seed oil, coenzyme Q10, curcumin (turmeric), frankincense, garlic, ginger, hydrolyzed rice bran, isoflavones, lipoic acid, mistletoe, N-acetyl cysteine, omega-3 fatty acids, resveratrol, selenium, shiitake mushroom and its derivatives, Vitamin B12, Vitamin C, Vitamin D3 (cholecalciferol), Vitamin E (d-alpha- and gamma-tocopherol), and zinc. Some of the noteworthy immune function and anti-inflammatory responses to these interventions included modulation of nuclear factor-Kappa B, tumor necrosis factor-a, interferon-g, interleukin-6, and CD4+ T cells, among others. These findings are not completely consistent or ubiquitous across all patient populations or health status.<br><br>CONCLUSIONS: Based on this review, many nutrients and phytonutrients are capable of significantly modulating immune function and reducing inflammation, according to multiple biomarkers in clinical trials in different populations of adults with varying health statuses. Thus, dietary supplementation may serve as an adjunct to conventional pharmaceutical or medical therapies, but evaluation of risks and benefits for each person and health status is necessary. Additional larger studies are also needed to investigate the safety and efficacy of nutritional compounds in various health conditions, with emphases on potential drug-supplement interactions and clinical endpoints.<br><br>RELEVANCE FOR PATIENTS: As demonstrated in the reviewed clinical trials, patients of various health challenges with a wide range of severity may benefit from select nutrients and phytonutrients to improve their immune function and reduce inflammation.}, }
@article {pmid34238412, year = {2021}, author = {Liu, JL and Tong, L and Luo, Y and Gao, YJ}, title = {[Cryptotanshinone May Induce Ferroptosis of Human Liver Cancer HepG2 Cells].}, journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae}, volume = {43}, number = {3}, pages = {366-370}, doi = {10.3881/j.issn.1000-503X.13115}, pmid = {34238412}, issn = {1000-503X}, mesh = {*Ferroptosis ; Hep G2 Cells ; Humans ; *Liver Neoplasms ; *Phenanthrenes/pharmacology ; Reactive Oxygen Species ; }, abstract = {Objective To observe the effect of cryptotanshinone on the ferroptosis of human liver cancer HepG2 cells. Methods The viability of the HepG2 cells cultured in vitro was determined using the Cell Counting Kit-8(CCK-8),and the half maximal inhibitory concentration(IC50)was calculated.The cell morphology was observed using an inverted microscope.The reactive oxygen species(ROS)level was detected with the 2',7'-dichlorodihydrofluorescein diacetate(DCFH-DA)probe.The glutathione(GSH)assay kit was used to determine the GSH level.Western blot analysis was employed to detect the expression of cystine/glutamate antiporter system light chain(xCT)and glutathione peroxidase 4(GPX4),two marker proteins in ferroptosis.Additionally,the cell viability,ROS level,GSH level,and the expression levels of xCT and GPX4 were detected for the cells treated with the ferroptosis inhibitor ferrostain-1(Fer-1),the iron chelator deferoxamine(DFO),and the ROS scavenger N-acetylcysteine(NAC).Results Cryptotanshinone significantly inhibited the cell viability of HepG2 cells with an IC50 of 93.73 μmol/L,and caused the morphological changes and death of the cells.It could significantly induce ROS accumulation,reduce GSH level,and down-regulate the expression of xCT and GPX4 in HepG2 cells.Fer-1,DFO,and NAC can remedy the cryptotanshinone-caused decrease in the cell viability of HepG2 cells.Fer-1 could inhibit cryptotanshinone-induced ROS accumulation,restore GSH level,and recover the expression of xCT and GPX4. Conclusion Cryptotanshinone may increase the accumulation of ROS by inhibiting the expression of xCT and GPX4 to induce the ferroptosis of HepG2 cells.}, }
@article {pmid34237968, year = {2021}, author = {Jiang, C and Zou, J and Lv, Q and Yang, Y}, title = {Systematic review and meta-analysis of the efficacy of N-acetylcysteine in the treatment of acute exacerbation of chronic obstructive pulmonary disease.}, journal = {Annals of palliative medicine}, volume = {10}, number = {6}, pages = {6564-6576}, doi = {10.21037/apm-21-1138}, pmid = {34237968}, issn = {2224-5839}, mesh = {*Acetylcysteine/therapeutic use ; Europe ; Forced Expiratory Volume ; Humans ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; Respiratory Function Tests ; }, abstract = {BACKGROUND: Whether N-acetylcysteine (NAC) therapy can promote the improvement of clinical symptoms and lung function in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has not been verified by large-scale randomized controlled trials, only a few small sample studies.<br><br>METHODS: English databases were searched using a combination of the following terms: "chronic obstructive pulmonary disease", "acute exacerbation of chronic obstructive pulmonary disease", and "N-acetylcysteine". Studies examining NAC in the treatment of AECOPD were screened, so as to be a reference for the experimental group. Meta-analysis was performed using RevMan 5.3 software (Cochrane, Northern Europe), with a total of 15 included literatures.<br><br>RESULTS: The heterogeneity test of improvement rate showed Chi2=1.89, df=7, I2=0% <50%, and P=0.97 (>0.01); the risk rate was 1.09, the 95% confidence interval (CI) was (1.04-1.14), Z=3.93, and P<0.0001. The heterogeneity test of forced expiratory volume in the first second (FEV1) showed that Tau2=63.39, Chi2=118.66, df=9, I2=92% >50%, and P=0.88 (<0.0001); the mean difference was 30.63 (95% CI: 25.48-35.78), Z=11.65, and P<0.0001. The results of the heterogeneity test of forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) showed that Tau2=60.03, Chi2=74.09, df=5, I2=93% >50%, and P<0.0001; the mean difference was 30.42 (95% CI: 24.00-36.85), Z=9.28, and P<0.0001. The heterogeneity test for glutathione sulfur transferase (GSH-ST) activity showed that Tau2=4.12, Chi2=58.12, df=5, I2=91% >50%, and P<0.0001; the mean difference was 3.10 (95% CI: 1.38-4.82), Z=3.63, and P=0.0004.<br><br>CONCLUSIONS: Our meta-analysis confirmed that NAC could promote the symptom improvement rate of patients with AECOPD, improve lung function in FEV1 and FEV1/FVC, and enhance the body's antioxidant capacity.}, }
@article {pmid34236028, year = {2021}, author = {Yang, J and Huang, Y and Liu, M and Wang, T and Zhang, Y and Zhou, W and Qu, Z and Chen, X}, title = {[N-acetylcysteine inhibits the proliferation of hydrogen peroxide treated fibroblast-like synoviocytes in rats with adjuvant arthritis (AA) via blocking Nrf2/Keap1 pathway].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {37}, number = {8}, pages = {687-692}, pmid = {34236028}, issn = {1007-8738}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Arthritis, Experimental/drug therapy ; Cell Proliferation ; Fibroblasts/metabolism ; Hydrogen Peroxide ; Kelch-Like ECH-Associated Protein 1/metabolism ; NF-E2-Related Factor 2/metabolism ; Rats ; Rats, Sprague-Dawley ; *Synoviocytes/metabolism ; }, abstract = {Objective To investigate the effect of N-acetylcysteine (NAC) on the proliferation of fibroblast-like synoviocytes (FLS) treated with low concentration of hydrogen peroxide (H2O2) in rats with adjuvant arthritis (AA) and its mechanism. Methods Twenty SD rats were divided into a normal group and a model group (10 rats in each group). The model group was established by subcutaneous injection of Freund's complete adjuvant into the toe of rats, and the rats were sacrificed 28 days later. The contents of serum malondialdehyde (MDA) were detected by thiobarbituric acid method; the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined by hydroxylamine method and colorimetry respectively; and Nrf2 and Keap1 proteins in ankle synovial tissues of AA rats were detected by immunohistochemistry. AA-FLS were isolated, cultured, and identified by digestion of ankle joint slides of AA rats in vitro. The effects of NAC at different concentrations (final concentration 0, 0.3, 0.9, 3, 10, 30, 90, 180 μmol/L) on the activity of AA-FLS treated with H2O2 at low concentration (5 μmol/L) were detected by CCK-8 assay. The content of mitochondrial reactive oxygen species (ROS) in AA-FLS was detected by MitoSOX fluorescent probe. The effects of NAC (final concentration 0, 3, 10, 30 μmol/L) on Nrf2 and Keap1 protein expressions in AA-FLS treated with H2O2 at low concentration were detected by Western blotting. Results Compared with those in the control group, in AA model, the MDA level increased and SOD and GSH-Px levels decreased in serum, and the Nrf2 protein increased and the Keap1 protein decreased in synovial tissue. Immunocytochemical staining confirmed that the isolated and cultured cells were AA-FLS; NAC inhibited the proliferation of AA-FLS treated with H2O2 in a concentration-dependent manner, and the mitochondrial ROS content and the protein expressions of Nrf2 and Keap1 decreased. Conclusion NAC can inhibit the proliferation of AA-FLS treated with H2O2, which may be related to blocking Nrf2/Keap1 pathway.}, }
@article {pmid34234893, year = {2021}, author = {Park, C and Jeong, JW and Han, MH and Lee, H and Kim, GY and Jin, S and Park, JH and Kwon, HJ and Kim, BW and Choi, YH}, title = {The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis.}, journal = {Animal cells and systems}, volume = {25}, number = {2}, pages = {119-127}, pmid = {34234893}, issn = {1976-8354}, abstract = {Although previous studies have shown anti-cancer activity of betulinic acid (BA), a pentacyclic triterpenoid, against various cancer lines, the underlying molecular mechanisms are not well elucidated. In this study, we evaluated the mechanisms involved in the anti-cancer efficacy of BA in U937 human myeloid leukemia cells. BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA. The down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA. In addition, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio. BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase. However, quenching of ROS by N-acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment. Taken together, our results provide a mechanistic rationale that BA exhibits anti-cancer properties in U937 leukemia cells through ROS-dependent induction of cell cycle arrest at G2/M phase and apoptosis.}, }
@article {pmid34234176, year = {2021}, author = {Elsayed, A and Elkomy, A and Elkammar, R and Youssef, G and Abdelhiee, EY and Abdo, W and Fadl, SE and Soliman, A and Aboubakr, M}, title = {Synergistic protective effects of lycopene and N-acetylcysteine against cisplatin-induced hepatorenal toxicity in rats.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {13979}, pmid = {34234176}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents/adverse effects/*pharmacology ; Antioxidants/metabolism ; Biomarkers ; Cisplatin/adverse effects/*pharmacology ; Drug Synergism ; Immunohistochemistry ; Kidney/*drug effects/metabolism ; Kidney Function Tests ; Liver/*drug effects/metabolism ; Liver Function Tests ; Lycopene/*pharmacology ; Male ; Oxidative Stress/drug effects ; Protective Agents/*pharmacology ; Rats ; }, abstract = {Cisplatin (CP) is one of the most frequently used chemotherapy agents. The objective of this design was to determine the ameliorative effect of lycopene (LP) and/or N-acetylcysteine (NAC) in rats with hepatic and renal toxicity induced by CP. Rats were divided randomly into 7 groups (7 rats/group): control vehicle group (saline only), the LP group (10 mg/kg, orally), the NAC group (150 mg/kg, orally), the CP group (7.5 mg/kg, IP on day 27), the LP-CP group, the NAC-CP group, and the LP-NAC-CP group. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (APK), and levels of urea, creatinine, and lipids (cholesterol, triglycerides, and low-density lipoprotein-cholesterol) increased after CP injection in the serum. Moreover, CP decreased levels of protein, albumin, and HDL cholesterol. Meanwhile, malondialdehyde significantly increased with a decrease in reduced glutathione, superoxide dismutase, and catalase in the liver and kidney tissues. CP also induced some pathological lesions and increased the expression of caspase-3 in the liver and kidney tissues. Administration of LP and NAC alone or in combinations ameliorated hepatorenal toxicity and apoptosis induced by CP.}, }
@article {pmid34229024, year = {2021}, author = {Yang, HL and Tsai, CH and Shrestha, S and Lee, CC and Liao, JW and Hseu, YC}, title = {Coenzyme Q0, a novel quinone derivative of Antrodia camphorata, induces ROS-mediated cytotoxic autophagy and apoptosis against human glioblastoma cells in vitro and in vivo.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {155}, number = {}, pages = {112384}, doi = {10.1016/j.fct.2021.112384}, pmid = {34229024}, issn = {1873-6351}, mesh = {Animals ; Antineoplastic Agents/pharmacology/*therapeutic use ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Benzoquinones/pharmacology/*therapeutic use ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Glioblastoma/*drug therapy/metabolism ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; Necrosis/chemically induced ; Polyporales/chemistry ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; Mice ; }, abstract = {Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone) derived from Antrodia camphorata exerts anticancer activities against breast, melanoma, and ovarian carcinoma. Glioblastoma multiforme is a common tumor affecting the central nervous system. This study explored anticancer properties of CoQ0 on human glioblastoma both in vitro and in vivo, and explained the molecular mechanism behind it. CoQ0 treatment retarded the growth and suppressed colony formation in glioblastoma (U87MG and GBM8401) cells. CoQ0 induced apoptosis by activation of caspase-3, cleavage of PARP, and dysregulation of Bax and Bcl-2 in both cell lines. Annexin V/PI staining indicated CoQ0 mediated necrosis and apoptosis. Interestingly, AVOs were increased trough induction of autophagy by CoQ0, LC3-II accumulation, and p62/SQSTM1 expression, leading to death mechanism. Z-VAD-FMK has no effect on CoQ0-induced autophagy but autophagy inhibition by 3-methyladenine (3-MA)/chloroquine (CQ) led to CoQ0-induced apoptosis. N-acetylcysteine (NAC) inhibited CoQ0-mediated ROS production and diminished CoQ0-induced apoptotic and autophagic cell death. Further, CoQ0 inhibited PI3K/AKT/mTOR signaling pathways. CoQ0 reduced the tumor burden in U87MG and GBM8401 xenografted athymic nude mice and significantly modulated tumor xenograft by inducing apoptosis and autophagy. CoQ0 generated ROS-mediated apoptotic and autophagic cell death for effective glioblastoma treatment.}, }
@article {pmid34224820, year = {2021}, author = {Mukherjee, S and Ghosh, S and Choudhury, S and Gupta, P and Adhikary, A and Chattopadhyay, S}, title = {Pomegranate Polyphenols Attenuate Inflammation and Hepatic Damage in Tumor-Bearing Mice: Crucial Role of NF-κB and the Nrf2/GSH Axis.}, journal = {The Journal of nutritional biochemistry}, volume = {97}, number = {}, pages = {108812}, doi = {10.1016/j.jnutbio.2021.108812}, pmid = {34224820}, issn = {1873-4847}, mesh = {Animals ; Antioxidants/metabolism ; Carcinoma, Ehrlich Tumor/*complications/metabolism ; Cytokines/metabolism ; Dietary Supplements ; Female ; Glutathione/*metabolism ; Hepatocytes/physiology ; Inflammation ; Liver/metabolism ; Liver Diseases/etiology/metabolism/pathology/*prevention &amp; control ; Mice ; NF-E2-Related Factor 2/*metabolism ; NF-kappa B/*metabolism ; Oxidative Stress ; Plant Extracts/administration &amp; dosage ; Polyphenols/*administration &amp; dosage ; *Pomegranate ; }, abstract = {It has been widely reported that cancer, along with its treatment regimens, cause severe toxicity in the host. A suitable agent having chemopreventive properties as well as capabilities of ameliorating tumor- and drug-induced toxicities is of imminent need. Pomegranate has been projected as an excellent anti-tumor, anti-inflammatory and anti-oxidant agent. In this study, for the first time, we delineated the exact signaling cascade by which dietary supplementation of pomegranate fruit extract (PFE) protects tumor-bearing mice from tumor-induced hepatotoxicity. Increased activities of serum Alanine transaminase, Aspartate transaminase, Lactate dehydrogenase and Alkaline phosphatase, as well as histological studies confirmed the establishment of a state of hepatic dysfunction in tumor-bearers. Further investigations revealed that increased hepatic reactive oxygen species content and glutathione depletion-initiated apoptosis in these hepatocytes as we observed an alteration in the apoptotic proteins. PFE supplementation in tumor-bearing mice, on the other hand, differentially modulated redox-sensitive transcription factors Nrf2 and NF-κB, ultimately decreasing tumor-induced hepatic oxidative damage and cell death. siRNA-mediated inhibition of Nrf2 and NF-κB completely abolished the hepato-protective activities of PFE while pre-treatment of tumor-conditioned hepatocytes with N-acetyl cysteine augmented the cyto-protective properties of PFE. The present study clearly identified Nrf2/NF-κB/glutathione axis as the key factor behind the hepatoprotective potential of PFE. These findings would add to the existing knowledge about cancer chemoprevention by dietary polyphenols and might lead to the application of pomegranate polyphenols as supplement to escalate the effectiveness of cancer therapy by protecting normal cells from cancer related toxicities.}, }
@article {pmid34221865, year = {2021}, author = {Liu, Y and Song, Z and Liu, Y and Ma, X and Wang, W and Ke, Y and Xu, Y and Yu, D and Liu, H}, title = {Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {6}, pages = {1513-1525}, pmid = {34221865}, issn = {2211-3835}, abstract = {Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, thus stimulating ferroptosis may be a potential strategy for treating gastric cancer, therapeutic agents against which are urgently required. Jiyuan oridonin A (JDA) is a natural compound isolated from Jiyuan Rabdosia rubescens with anti-tumor activity, unclear anti-tumor mechanisms and limited water solubility hamper its clinical application. Here, we showed a2, a new JDA derivative, inhibited the growth of gastric cancer cells. Subsequently, we discovered for the first time that a2 induced ferroptosis. Importantly, compound a2 decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of a2. Furthermore, we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway, prevention of which rescued a2 induced ferrous iron elevation and cell growth inhibition. Moreover, a2 exhibited more potent anti-cancer activity than 5-fluorouracil in gastric cancer cell line-derived xenograft mice models. Patient-derived tumor xenograft models from different patients displayed varied sensitivity to a2, and GPX4 downregulation indicated the sensitivity of tumors to a2. Finally, a2 exhibited well pharmacokinetic characteristics. Overall, our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2, and a2 will hopefully serve as a promising compound for gastric cancer treatment.}, }
@article {pmid34221501, year = {2021}, author = {Schwalfenberg, GK}, title = {N-Acetylcysteine: A Review of Clinical Usefulness (an Old Drug with New Tricks).}, journal = {Journal of nutrition and metabolism}, volume = {2021}, number = {}, pages = {9949453}, pmid = {34221501}, issn = {2090-0724}, abstract = {OBJECTIVE: To review the clinical usefulness of N-acetylcysteine (NAC) as treatment or adjunctive therapy in a number of medical conditions. Use in Tylenol overdose, cystic fibrosis, and chronic obstructive lung disease has been well documented, but there is emerging evidence many other conditions would benefit from this safe, simple, and inexpensive intervention. Quality of Evidence. PubMed, several books, and conference proceedings were searched for articles on NAC and health conditions listed above reviewing supportive evidence. This study uses a traditional integrated review format, and clinically relevant information is assessed using the American Family Physician Evidence-Based Medicine Toolkit. A table summarizing the potential mechanisms of action for N-acetylcysteine in these conditions is presented. Main Message. N-acetylcysteine may be useful as an adjuvant in treating various medical conditions, especially chronic diseases. These conditions include polycystic ovary disease, male infertility, sleep apnea, acquired immune deficiency syndrome, influenza, parkinsonism, multiple sclerosis, peripheral neuropathy, stroke outcomes, diabetic neuropathy, Crohn's disease, ulcerative colitis, schizophrenia, bipolar illness, and obsessive compulsive disorder; it can also be useful as a chelator for heavy metals and nanoparticles. There are also a number of other conditions that may show benefit; however, the evidence is not as robust.<br><br>CONCLUSION: The use of N-acetylcysteine should be considered in a number of conditions as our population ages and levels of glutathione drop. Supplementation may contribute to reducing morbidity and mortality in some chronic conditions as outlined in the article.}, }
@article {pmid34219533, year = {2021}, author = {Ge, X and Zhang, Y and Huang, F and Wu, Y and Pang, J and Li, X and Fan, F and Liu, H and Li, S}, title = {EGFR tyrosine kinase inhibitor Almonertinib induces apoptosis and autophagy mediated by reactive oxygen species in non-small cell lung cancer cells.}, journal = {Human &amp; experimental toxicology}, volume = {40}, number = {12_suppl}, pages = {S49-S62}, doi = {10.1177/09603271211030554}, pmid = {34219533}, issn = {1477-0903}, mesh = {Acetylcysteine/pharmacology ; Acrylamides/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Carcinoma, Non-Small-Cell Lung/metabolism/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; ErbB Receptors/antagonists &amp; inhibitors ; Humans ; Indoles/*pharmacology ; Lung Neoplasms/metabolism/*pathology ; Protein Kinase Inhibitors/*pharmacology ; Pyrimidines/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Almonertinib, a new third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is highly selective to EGFR T790M-mutant non-small cell lung cancer (NSCLC). However, there is no available information on the form and molecular mechanism of Almonertinib-induced death in NSCLC cells. Herein, CCK-8 and colony formation assays, flow cytometry, electron microscopy, and western blots assay showed that Almonertinib inhibited NSCLC cells growth and proliferation by inducing apoptosis and autophagy which can be inhibited by a broad spectrum of caspase inhibitor Z-VAD-fmk or autophagy inhibitor chloroquine. Importantly, Almonertinib-induced autophagy was cytoprotective in NSCLC cells, and the blockade of autophagy improved cell apoptosis. In addition, Almonertinib increased reactive oxygen species (ROS) generation and clearance of ROS through pretreatment with N-acetyl-L-cysteine (NAC) inhibited the decrease of cell viability, apoptosis and increase of LC3-II induced by Almonertinib. The results of Western blot showed that both EGFR activity and downstream signaling pathways were inhibited by Almonertinib. Taken together, these findings indicated that Almonertinib induced apoptosis and autophagy by promoting ROS production in NSCLC cells.}, }
@article {pmid34211630, year = {2021}, author = {Calvo-Alvarez, J and Jimenez-Del-Rio, M and Velez-Pardo, C}, title = {Vitamin E TPGS 1000 Induces Apoptosis in the K562 Cell Line: Implications for Chronic Myeloid Leukemia.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {5580288}, pmid = {34211630}, issn = {1942-0994}, mesh = {Apoptosis/*drug effects ; Cell Line, Tumor ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy ; Vitamin E/*chemistry ; }, abstract = {Chronic myeloid leukemia (CML) is a hematologic malignancy derived from the myeloid lineage molecularly characterized by t(9;22)(q34;q11) resulting in BCR-ABL1 gene fusion, which is known as Philadelphia (Ph) chromosome. Although tyrosine kinase inhibitors (TKIs) have restored and maintained the quality of life of patients with CML, an important minority of patients become resistant to first-and-second-generation TKIs and require an alternative treatment. The K562 cell (Ph+, p53-/-) line was treated with Vit E TPGS 1000 (20-80 μM) only or with other products of interest (e.g., antioxidant N-acetylcysteine (NAC), specific JNK and caspase-3 inhibitor SP600125, and NSCSI, respectively) for 24 h at 37°C. Cells were analyzed by fluorescence microscopy (FM), flow cytometry (FC), and Western blotting (WB) techniques. We show that TPGS induces apoptosis in K562 cells through H2O2 signaling mechanism comprising the activation of a minimal molecular cascade: the kinase JNK>the transcription factor c-JUN>the activation of BCL-only BH3 proapoptotic protein PUMA>loss of mitochondrial membrane potential (ΔΨ m)>activation of caspase-3>chromatin condensation>fragmentation of DNA. Additionally, TPGS oxidizes the stress sensor protein DJ-1-Cys106-SH into DJ-1-Cys106-SO3 and arrested the cell cycle in the S phase. Remarkably, NAC, SP600125, and NSCSI blocked TPGS-induced OS and apoptosis in K562. Since TPGS is safe in mice and humans, it is especially promising for preclinical and clinical CML leukemia research. Our findings support the view that oxidation therapy offers an important opportunity to eliminate CML.}, }
@article {pmid34208683, year = {2021}, author = {Tenório, MCDS and Graciliano, NG and Moura, FA and Oliveira, ACM and Goulart, MOF}, title = {N-Acetylcysteine (NAC): Impacts on Human Health.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {6}, pages = {}, pmid = {34208683}, issn = {2076-3921}, support = {435704/2018-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 23038.011373/2017-31//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; 60030.0000000192/2021//Funda&#xe7;&#xe3;o&#xa0;de&#xa0;Amparo&#xa0;&#xe0;&#xa0;Pesquisa&#xa0;do&#xa0;Estado&#xa0;de&#xa0;Alagoas/ ; }, abstract = {N-acetylcysteine (NAC) is a medicine widely used to treat paracetamol overdose and as a mucolytic compound. It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant and anti-inflammatory capacity is the biochemical basis used to treat several diseases related to oxidative stress and inflammation. The primary role of NAC as an antioxidant stems from its ability to increase the intracellular concentration of glutathione (GSH), which is the most crucial biothiol responsible for cellular redox imbalance. As an anti-inflammatory compound, NAC can reduce levels of tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing the activity of nuclear factor kappa B (NF-κB). Despite NAC's relevant therapeutic potential, in several experimental studies, its effectiveness in clinical trials, addressing different pathological conditions, is still limited. Thus, the purpose of this chapter is to provide an overview of the medicinal effects and applications of NAC to human health based on current therapeutic evidence.}, }
@article {pmid34206987, year = {2021}, author = {Lesnova, EI and Masalova, OV and Permyakova, KY and Kozlov, VV and Nikolaeva, TN and Pronin, AV and Valuev-Elliston, VT and Ivanov, AV and Kushch, AA}, title = {Difluoromethylornithine (DFMO), an Inhibitor of Polyamine Biosynthesis, and Antioxidant N-Acetylcysteine Potentiate Immune Response in Mice to the Recombinant Hepatitis C Virus NS5B Protein.}, journal = {International journal of molecular sciences}, volume = {22}, number = {13}, pages = {}, pmid = {34206987}, issn = {1422-0067}, support = {19-74-10086//Russian Science Foundation/ ; }, mesh = {Acetylcysteine/*pharmacology ; Adjuvants, Immunologic/*pharmacology ; Animals ; Cell Proliferation ; Cells, Cultured ; Eflornithine/*pharmacology ; Female ; Hepatitis C/*immunology ; Immunity, Active/*drug effects ; Immunogenicity, Vaccine/drug effects ; Interferon-gamma/metabolism ; Interleukin-10/metabolism ; Interleukin-12/metabolism ; Mice ; Mice, Inbred DBA ; Myeloid-Derived Suppressor Cells/drug effects/immunology ; Nitric Oxide/metabolism ; Oligodeoxyribonucleotides/pharmacology ; T-Lymphocytes, Regulatory/drug effects/immunology ; Viral Hepatitis Vaccines/immunology ; Viral Nonstructural Proteins/*immunology ; }, abstract = {Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.}, }
@article {pmid34204067, year = {2021}, author = {Bhattarai, N and Korhonen, E and Mysore, Y and Kaarniranta, K and Kauppinen, A}, title = {Hydroquinone Induces NLRP3-Independent IL-18 Release from ARPE-19 Cells.}, journal = {Cells}, volume = {10}, number = {6}, pages = {}, pmid = {34204067}, issn = {2073-4409}, support = {297267, 307341, 328443, 296840 and 333302//Academy of Finland/ ; x//Emil Aaltosen S&#xe4;&#xe4;ti&#xf6;/ ; x//P&#xe4;ivikki ja Sakari Sohlbergin S&#xe4;&#xe4;ti&#xf6;/ ; 5503743//Kuopion Yliopistollinen Sairaala/ ; x//the Finnish Eye Foundation/ ; x//Sigrid Jus&#xe9;liuksen S&#xe4;&#xe4;ti&#xf6;/ ; x//Sokeain yst&#xe4;v&#xe4;t ry/ ; x//Silm&#xe4;- ja Kudospankkis&#xe4;&#xe4;ti&#xf6;/ ; }, mesh = {*DNA Damage ; Humans ; Hydroquinones/*pharmacology ; Inflammasomes/*metabolism ; Interleukin-18/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Retinal Pigment Epithelium/*metabolism ; }, abstract = {Age-related macular degeneration (AMD) is a retinal disease leading to impaired vision. Cigarette smoke increases the risk for developing AMD by causing increased reactive oxygen species (ROS) production and damage in the retinal pigment epithelium (RPE). We have previously shown that the cigarette tar component hydroquinone causes oxidative stress in human RPE cells. In the present study, we investigated the propensity of hydroquinone to induce the secretion of interleukin (IL)-1β and IL-18. The activation of these cytokines is usually regulated by the Nucleotide-binding domain, Leucine-rich repeat, and Pyrin domain 3 (NLRP3) inflammasome. ARPE-19 cells were exposed to hydroquinone, and cell viability was monitored using the lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide salt (MTT) assays. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the levels of proinflammatory cytokines IL-1β and IL-18 as well as NLRP3, caspase-1, and poly (ADP-ribose) polymerase (PARP). Hydroquinone did not change IL-1β release but significantly increased the secretion of IL-18. Cytoplasmic NLRP3 levels increased after the hydroquinone treatment of IL-1α-primed RPE cells, but IL-18 was equally released from primed and nonprimed cells. Hydroquinone reduced the intracellular levels of PARP, which were restored by treatment with the ROS scavenger N-acetyl-cysteine (NAC). NAC concurrently reduced the NLRP3 levels but had no effect on IL-18 release. In contrast, the NADPH oxidase inhibitor ammonium pyrrolidinedithiocarbamate (APDC) reduced the release of IL-18 but had no effect on the NLRP3 levels. Collectively, hydroquinone caused DNA damage seen as reduced intracellular PARP levels and induced NLRP3-independent IL-18 secretion in human RPE cells.}, }
@article {pmid34203104, year = {2021}, author = {Fernández-Rodríguez, S and Esposito-Zapero, C and Zornoza, T and Polache, A and Granero, L and Cano-Cebrián, MJ}, title = {The Effects of N-Acetylcysteine on the Rat Mesocorticolimbic Pathway: Role of mGluR5 Receptors and Interaction with Ethanol.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {34203104}, issn = {1424-8247}, abstract = {N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol use disorder (AUD), although its mechanism of action is already being debated. In this paper, we set out to assess both the potential involvement of the glutamate metabotropic receptors (mGluR) in the possible dual effect of NAC administered at two different doses and NAC's effect on ethanol-induced activation. To this aim, 30 or 120 mg/kg of NAC was intraperitoneally administered to rats with the presence or absence of the negative allosteric modulator of mGluR5 (MTEP 0.1 mg/kg). Thereafter, the cFOS IR-cell expression was analyzed. Secondly, we explored the effect of 120 mg/kg of NAC on the neurochemical and behavioral activation induced by intra-VTA ethanol administration (150 nmol). Our results showed that the high NAC dose stimulated cFOS expression in the NAcc, and that this effect was suppressed in the presence of MTEP, thus suggesting the implication of mGluR5. Additionally, high doses could attenuate the ethanol-induced increase in cFOS-expression in the NAcc, probably due to a phenomenon based on the long-term depression of the MSNs. Additional experiments are required to corroborate our hypothesis.}, }
@article {pmid34202008, year = {2021}, author = {Son, ES and Fei, X and Yoon, JH and Seo, SY and Maeng, HJ and Jeong, SH and Kim, YC}, title = {Comparison of Pharmacokinetics and Anti-Pulmonary Fibrosis-Related Effects of Sulforaphane and Sulforaphane N-acetylcysteine.}, journal = {Pharmaceutics}, volume = {13}, number = {7}, pages = {}, pmid = {34202008}, issn = {1999-4923}, support = {20191A2C2089867, 2019R1F1A1058103//National Research Foundation of Korea/ ; }, abstract = {Sulforaphane (SFN), belonging to the isothiocyanate family, has received attention owing to its beneficial activities, including chemopreventive and antifibrotic effects. As sulforaphane N-acetylcysteine (SFN-NAC), a major sulforaphane metabolite, has presented similar pharmacological activities to those of SFN, it is crucial to simultaneously analyze the pharmacokinetics and activities of SFN and SFN-NAC, to comprehensively elucidate the efficacy of SFN-containing products. Accordingly, the anti-pulmonary fibrotic effects of SFN and SFN-NAC were assessed, with simultaneous evaluation of permeability, metabolic stability, and in vivo pharmacokinetics. Both SFN and SFN-NAC decreased the levels of transforming growth factor-β1-induced fibronectin, alpha-smooth muscle actin, and collagen, which are major mediators of fibrosis, in MRC-5 fibroblast cells. Regarding pharmacokinetics, SFN and SFN-NAC were metabolically unstable, especially in the plasma. SFN-NAC degraded considerably faster than SFN in plasma, with SFN being formed from SFN-NAC. In rats, SFN and SFN-NAC showed a similar clearance when administered intravenously; however, SFN showed markedly superior absorption when administered orally. Although the plasma SFN-NAC concentration was low owing to poor absorption following oral administration, SFN-NAC was converted to SFN in vivo, as in plasma. Collectively, these data suggest that SFN-NAC could benefit a prodrug formulation strategy, possibly avoiding the gastrointestinal side effects of SFN, and with improved SFN-NAC absorption.}, }
@article {pmid34199944, year = {2021}, author = {Jankó, L and Kovács, T and Laczik, M and Sári, Z and Ujlaki, G and Kis, G and Horváth, I and Antal, M and Vígh, L and Bálint, BL and Uray, K and Bai, P}, title = {Silencing of Poly(ADP-Ribose) Polymerase-2 Induces Mitochondrial Reactive Species Production and Mitochondrial Fragmentation.}, journal = {Cells}, volume = {10}, number = {6}, pages = {}, pmid = {34199944}, issn = {2073-4409}, support = {123975//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; GINOP-2.3.2-15-2016-00006//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; EFOP-3.6.2-16-2017-00006//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; NKFIH-1150-6/2019//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; &#xda;NKP-20-4-II-DE-68//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; }, mesh = {*Gene Silencing ; Hep G2 Cells ; Humans ; *Mitochondria/genetics/metabolism ; Mitochondrial Dynamics/*genetics ; *Poly(ADP-ribose) Polymerases/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Sirtuin 1/genetics/metabolism ; }, abstract = {PARP2 is a DNA repair protein. The deletion of PARP2 induces mitochondrial biogenesis and mitochondrial activity by increasing NAD[+] levels and inducing SIRT1 activity. We show that the silencing of PARP2 causes mitochondrial fragmentation in myoblasts. We assessed multiple pathways that can lead to mitochondrial fragmentation and ruled out the involvement of mitophagy, the fusion-fission machinery, SIRT1, and mitochondrial unfolded protein response. Nevertheless, mitochondrial fragmentation was reversed by treatment with strong reductants, such as reduced glutathione (GSH), N-acetyl-cysteine (NAC), and a mitochondria-specific antioxidant MitoTEMPO. The effect of MitoTEMPO on mitochondrial morphology indicates the production of reactive oxygen species of mitochondrial origin. Elimination of reactive oxygen species reversed mitochondrial fragmentation in PARP2-silenced cells.}, }
@article {pmid34198746, year = {2021}, author = {Southam, HM and Williamson, MP and Chapman, JA and Lyon, RL and Trevitt, CR and Henderson, PJF and Poole, RK}, title = {'Carbon-Monoxide-Releasing Molecule-2 (CORM-2)' Is a Misnomer: Ruthenium Toxicity, Not CO Release, Accounts for Its Antimicrobial Effects.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {6}, pages = {}, pmid = {34198746}, issn = {2076-3921}, support = {BB/M0225791/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, abstract = {Carbon monoxide (CO)-releasing molecules (CORMs) are used to deliver CO, a biological 'gasotransmitter', in biological chemistry and biomedicine. CORMs kill bacteria in culture and in animal models, but are reportedly benign towards mammalian cells. CORM-2 (tricarbonyldichlororuthenium(II) dimer, Ru2Cl4(CO)6), the first widely used and commercially available CORM, displays numerous pharmacological, biochemical and microbiological activities, generally attributed to CO release. Here, we investigate the basis of its potent antibacterial activity against Escherichia coli and demonstrate, using three globin CO sensors, that CORM-2 releases negligible CO (<0.1 mol CO per mol CORM-2). A strong negative correlation between viability and cellular ruthenium accumulation implies that ruthenium toxicity underlies biocidal activity. Exogenous amino acids and thiols (especially cysteine, glutathione and N-acetyl cysteine) protected bacteria against inhibition of growth by CORM-2. Bacteria treated with 30 μM CORM-2, with added cysteine and histidine, exhibited no significant loss of viability, but were killed in the absence of these amino acids. Their prevention of toxicity correlates with their CORM-2-binding affinities (Cys, Kd 3 μM; His, Kd 130 μM) as determined by [1]H-NMR. Glutathione is proposed to be an important intracellular target of CORM-2, with CORM-2 having a much higher affinity for reduced glutathione (GSH) than oxidised glutathione (GSSG) (GSH, Kd 2 μM; GSSG, Kd 25,000 μM). The toxicity of low, but potent, levels (15 μM) of CORM-2 was accompanied by cell lysis, as judged by the release of cytoplasmic ATP pools. The biological effects of CORM-2 and related CORMs, and the design of biological experiments, must be re-examined in the light of these data.}, }
@article {pmid34196897, year = {2021}, author = {de Abreu, JSS and Fernandes, J}, title = {The contrast agent 2,3,5-triiodobenzoic acid (TIBA) induces cell death in tumor cells through the generation of reactive oxygen species.}, journal = {Molecular biology reports}, volume = {48}, number = {6}, pages = {5199-5207}, pmid = {34196897}, issn = {1573-4978}, support = {E-26/201.037/2020//Funda&#xe7;&#xe3;o Carlos Chagas Filho de Amparo &#xe0; Pesquisa do Estado do Rio de Janeiro/ ; }, mesh = {Animals ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Chlorocebus aethiops ; Contrast Media/metabolism/pharmacology ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Lung Neoplasms/pathology ; Neoplasms/*drug therapy/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Triiodobenzoic Acids/metabolism/*pharmacology ; Vero Cells ; }, abstract = {The 2,3,5-triiodobenzoic acid (TIBA) is an iodine contrast agent used for visualization of tissue in X-ray techniques. However, TIBA induces physiological complications like increase in oxygen reactive species (ROS), and consequently, contrast-induced nephropathies. TIBA's antitumor activity was demonstrated in lung cancer, but the subcellular mechanisms involving its activity in tumor cells are still unknown. Thus, the objective of this work was evaluate whether the anti-tumor activity of TIBA involves ROS increase, in tumor lines of non-small cell lung cancer (H460), chronic myeloid leukemia (K562), and its cytotoxicity in normal renal epithelial (VERO). The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay was used for evaluation of cell viability, the H2DCFDA (cell-permeant 2',7'-dichlorodihydrofluorescein diacetate) fluorescent probe to evaluate ROS induction, cell cycle analysis was performed using flow cytometry to measure cell death, and immunofluorescence with annexin/7-AAD (7-amino-actinomycin D), to assess the association of cell death with the ROS generation. TIBA decreases cell viability in a dose-dependent manner for the H460 and K562. However, VERO cells showed less response to the drug, with 70% viable cells after 72 h of treatment in the highest concentration of the drug. While the tumor cells with only 20% viable cells. Besides, tumor cells exhibited higher DNA fragmentation, compared to the renal line (VERO with 5% of fragmented DNA, H460 with 26%, and 56% in K562). Finally, TIBA-induced ROS increase and apoptosis in all lines, which is significantly decreased after treatment with the antioxidant N-acetyl-cysteine (NAC). These data demonstrate the relationship between the increased cellular oxidative stress and the anti-tumor action of the TIBA.}, }
@article {pmid34193975, year = {2021}, author = {Zhu, X and Cabungcal, JH and Cuenod, M and Uliana, DL and Do, KQ and Grace, AA}, title = {Thalamic reticular nucleus impairments and abnormal prefrontal control of dopamine system in a developmental model of schizophrenia: prevention by N-acetylcysteine.}, journal = {Molecular psychiatry}, volume = {26}, number = {12}, pages = {7679-7689}, pmid = {34193975}, issn = {1476-5578}, support = {R01 MH057440/MH/NIMH NIH HHS/United States ; R37 MH057440/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Disease Models, Animal ; *Dopamine/pharmacology ; Dopaminergic Neurons/physiology ; Methylazoxymethanol Acetate/pharmacology ; Rats ; *Schizophrenia ; Thalamic Nuclei ; }, abstract = {Recent evidence showed thalamic abnormalities in schizophrenia involving disruptions to the parvalbumin neurons in the thalamic reticular nucleus (TRN). However, their functional consequences, as well as a potential linkage to oxidative stress, are unclear. The TRN is posited to gate prefrontal control of dopamine neuron activity in the ventral tegmental area (VTA). Thus, we hypothesized that schizophrenia-related TRN abnormalities might contribute to dopamine dysregulation, a well-known feature of the disorder. To test this, in adult rats exposed prenatally to methylazoxymethanol acetate (MAM rats), oxidative impairments to the parvalbumin neurons in the anterior TRN were assessed by immunohistochemistry. Using in vivo electrophysiology, we investigated whether inactivation of the prefrontal cortex would produce differential effects on VTA dopamine neurons in MAM rats. We show that MAM rats displayed reduced markers of parvalbumin and wisteria floribunda agglutinin-labeled perineuronal nets, correlating with increased markers of oxidative stress (8-oxo-7, 8-dihydro-20-deoxyguanosine, and 3-nitrotyrosine). Moreover, MAM rats displayed heightened baseline and abnormal prefrontal control of VTA dopamine neuron activity, as tetrodotoxin-induced inactivation of the infralimbic prefrontal cortex decreased the dopamine population activity, contrary to the normal increase in controls. Such dopamine neuron dysregulation was recapitulated by enzymatic perineuronal net digestion in the TRN of normal rats. Furthermore, juvenile (postnatal day 11-25) antioxidant treatment (N-acetyl-cysteine, 900 mg/L drinking water) prevented all these impairments in MAM rats. Our findings suggest that early accumulation of oxidative stress in the TRN may shape the later onset of schizophrenia pathophysiology, highlighting redox regulation as a potential target for early intervention.}, }
@article {pmid34191348, year = {2022}, author = {Yang, L and Brouillette, MJ and Coleman, MC and Kluz, PN and Goetz, JE}, title = {Automated quantification of live articular chondrocyte fluorescent staining using a custom image analysis framework.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {40}, number = {5}, pages = {1203-1212}, doi = {10.1002/jor.25137}, pmid = {34191348}, issn = {1554-527X}, mesh = {Cartilage ; *Cartilage, Articular/diagnostic imaging ; *Chondrocytes/physiology ; Image Processing, Computer-Assisted/methods ; Joints ; Staining and Labeling ; }, abstract = {The goal of this study was to develop, validate, and implement an image analysis framework to automatically analyze chondrocytes in 3D image stacks of cartilage acquired using a fluorescent confocal microscope. Source specimens consist of viable osteochondral tissue co-stained with multiple live-cell dyes. Our framework utilizes a seeded watershed-based algorithm to automatically segment individual chondrocytes in each 2D slice of the confocal image stack. The resulting cell segmentations are colocalized in 3D to eliminate duplicate segmentation of the same cell resulting from the visibility of fluorescence signal in multiple imaging planes, and the 3D cell distribution is used to automatically define the cartilage tissue volume. The algorithm then provides chondrocyte density data, and the associated segmentation can be used as a mask to extract and quantify per cell intensity of a secondary, functional dye co-staining the chondrocytes. The accuracy of the automated chondrocyte segmentation was validated against manual segmentations (average IOU = 0.79). When applied to a cartilage surrogate, this analysis framework estimated chondrocyte density within 10% of the true density and demonstrated a good agreement between framework's counts and manual counts (R[2] = 0.99). In a real application, the framework was able to detect the increased dye signal of monochlorobimane (MCB) in chondrocytes treated with N-acetylcysteine (NAC) after mechanical injury, quantifying intracellular biochemical changes in living cells. This new framework allows for fast and accurate quantification of intracellular activities of chondrocytes, and it can be adapted for broader application in many imaging and treatment modalities, including therapeutic OA research.}, }
@article {pmid34190354, year = {2021}, author = {Zhang, B and Yang, Y and Yi, J and Zhao, Z and Ye, R}, title = {Hyperglycemia modulates M1/M2 macrophage polarization via reactive oxygen species overproduction in ligature-induced periodontitis.}, journal = {Journal of periodontal research}, volume = {56}, number = {5}, pages = {991-1005}, doi = {10.1111/jre.12912}, pmid = {34190354}, issn = {1600-0765}, support = {81400522//National Natural Science Foundation of China/ ; 81771048//National Natural Science Foundation of China/ ; 81801018//National Natural Science Foundation of China/ ; 2020YFS0170//Sichuan Science and Technology Program/ ; }, mesh = {Animals ; *Diabetes Mellitus, Experimental/complications ; Humans ; *Hyperglycemia/complications ; Macrophages ; *Periodontitis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; X-Ray Microtomography ; }, abstract = {BACKGROUND AND OBJECTIVE: Periodontitis in diabetic patients is characterized by enhanced inflammation and aggravated tissue damage in comparison with that in non-diabetic counterparts. The progression of periodontal damage under diabetic condition can be partly ascribed to hyperglycemia-induced disturbance between immune activation and inflammation resolution, where macrophages are capable of participating given their plasticity in response to different stimuli. Herein, we aimed to investigate the changes of macrophage polarization in periodontitis under diabetic condition and the underlying mechanism.<br><br>MATERIALS AND METHODS: Type-1 diabetes was induced by the injection of streptozotocin (STZ, 60&#xa0;mg/kg) in Sprague-Dawley rats. Rats in N-acetyl cysteine (NAC)-treated groups received NAC dissolved in drinking water (200&#xa0;mg/kg/day). Experimental periodontitis was induced by ligating 3-0 silk around left maxillary second molars for 4&#xa0;weeks. Alveolar bone destruction was tested by micro-computed tomography and tartrate-resistant acid phosphatase (TRAP) staining. M1/M2 macrophage polarization in periodontal tissue was detected by immunohistochemistry staining. RAW264.7 were cultured in normal glucose (5.5&#xa0;mM) or high glucose environment (25&#xa0;mM) with or without NAC (8&#xa0;mmol/L). LPS (100&#xa0;ng/ml) and IL-4 (20&#xa0;ng/ml) were used to induce M1&#xa0;macrophages and M2 macrophages, respectively. M1/M2 macrophage polarization was detected by qRT-PCR, immunofluorescent staining, and flow cytometry. Reactive oxygen species (ROS) accumulation was detected by fluorogenic probes. RANKL (100&#xa0;ng/ml) were applied to induce osteoclastogenic differentiation of RAW264.7, and osteoclast formation was examined by TRAP staining.<br><br>RESULTS: Rats with diabetes displayed enhanced macrophages infiltration and M1 macrophage polarization in periodontal lesions compared with vehicle-treated rats. Under LPS or IL-4 stimulation, high glucose culture of RAW264.7 elevated ROS level and increased the expression of M1 macrophage markers (iNOS, TNF-&#x3b1;, and IL-6) whereas decreased the expression of M2 macrophage markers (Arg-1 and CD206). Supernatants of high glucose-treated M1/M2 macrophages enhanced osteoclast formation compared to normal glucose-cultured cells. Decreasing ROS level via NAC partially reversed the effect of high glucose on M1/M2 macrophage polarization. Meanwhile, daily intake of NAC in rodent models inhibited M1 macrophage polarization, which subsequently ameliorated alveolar bone loss and decreased osteoclast numbers in periodontitis in diabetic rats.<br><br>CONCLUSION: These findings demonstrated that hyperglycemia could polarize macrophage toward M1 macrophages via overproducing ROS under inflammatory condition, which might take responsibility for aggravated periodontal damage in periodontitis under diabetic condition. Inhibiting M1 macrophages and restoring M2 macrophages by ROS scavenger is hopefully a potential adjunct treatment strategy for diabetic periodontitis.}, }
@article {pmid34188159, year = {2021}, author = {Girão-Silva, T and Fonseca-Alaniz, MH and Ribeiro-Silva, JC and Lee, J and Patil, NP and Dallan, LA and Baker, AB and Harmsen, MC and Krieger, JE and Miyakawa, AA}, title = {High stretch induces endothelial dysfunction accompanied by oxidative stress and actin remodeling in human saphenous vein endothelial cells.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {13493}, pmid = {34188159}, issn = {2045-2322}, support = {1R21EB024147-01A1/NH/NIH HHS/United States ; R01 HL141761/HL/NHLBI NIH HHS/United States ; 1R21EB023551-01/NH/NIH HHS/United States ; }, mesh = {Actins/*metabolism ; Endothelial Cells/*metabolism ; Humans ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Saphenous Vein/*metabolism ; *Stress, Mechanical ; THP-1 Cells ; }, abstract = {The rate of the remodeling of the arterialized saphenous vein conduit limits the outcomes of coronary artery bypass graft surgery (CABG), which may be influenced by endothelial dysfunction. We tested the hypothesis that high stretch (HS) induces human saphenous vein endothelial cell (hSVEC) dysfunction and examined candidate underlying mechanisms. Our results showed that in vitro HS reduces NO bioavailability, increases inflammatory adhesion molecule expression (E-selectin and VCAM1) and THP-1 cell adhesion. HS decreases F-actin in hSVECs, but not in human arterial endothelial cells, and is accompanied by G-actin and cofilin's nuclear shuttling and increased reactive oxidative species (ROS). Pre-treatment with the broad-acting antioxidant N-acetylcysteine (NAC) supported this observation and diminished stretch-induced actin remodeling and inflammatory adhesive molecule expression. Altogether, we provide evidence that increased oxidative stress and actin cytoskeleton remodeling play a role in HS-induced saphenous vein endothelial cell dysfunction, which may contribute to predisposing saphenous vein graft to failure.}, }
@article {pmid34185202, year = {2021}, author = {Sun, T and Wei, L and Tian, H and Zhan, W and Ma, H and Nie, D and Wang, S and Chen, X and Tang, G}, title = {Novel PET/CT tracers for targeted imaging of membrane receptors to evaluate cardiomyocyte apoptosis and tissue repair process in a rat model of myocardial infarction.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {26}, number = {7-8}, pages = {460-473}, pmid = {34185202}, issn = {1573-675X}, support = {81770505//National Natural Science Foundation of China/ ; 91949121//National Aerospace Science Foundation of China/ ; 81671719//National Aerospace Science Foundation of China/ ; No.123456//Nanfang Hospital of Southern Medical University/ ; 201740060//Research Project of Shanghai Municipal Health and Family Planning Commission/ ; }, mesh = {Animals ; Apoptosis ; *Myocardial Infarction/diagnostic imaging ; Myocytes, Cardiac ; *Positron Emission Tomography Computed Tomography ; Positron-Emission Tomography ; Rats ; Tissue Distribution ; }, abstract = {The purpose of this study was to employ novel tracers PET imaging approach to define the time course and intensity of myocardial repair after apoptosis and to correlate the imaging signal to immunohistochemical staining in myocardial infarction (MI). We designed novel αVβ3-targeted and radio-functionalized tracers for detection of apoptosis in H9C2 cells and myocardial tissue. MI rats were imaged with [[18]F]FDG, [[18]F]ANP-Cin or [[18]F]ANP-RGD2 using a small-animal PET/CT device. Rats were sacrificed, and tissue samples from viable and injured myocardial areas were sectioned for TUNEL assay and histology. The uncorrected radiochemical yield of [[18]F]ANP-Cin and [[18]F]ANP-RGD2 were 41.3 ± 5.4% and 21.17 ± 4.7%, respectively. Two tracers meet many criteria for cardiac imaging, including high stability, high binding, no toxicity, fast renal clearance and excellent biodistribution in rat models. The uptake of [[18]F]ANP-Cin was significantly higher on the 1st and 3rd day than the 7th or 28th day after MI induction, a timeframe associated with increased cardiomyocyte apoptosis. Higher uptake of [[18]F]ANP-Cin was observed in MI rats than in N-acetylcysteine (NAC)-treated rats on the 3rd days. In contrast with [[18]F]ANP-Cin, no hot-spots was observed with [[18]F]ANP-RGD2 on the 1st day and more hot-spots was observed from the 3rd day to the 7th day, then less on the 28th days in the high apoptotic site. There was no uptake of [[18]F]FDG in or around the apoptotic region. On the 7th day the uptake of [[18]F]ANP-RGD2 was higher in NAC-treated rats than MI rats. [[18]F]ANP-Cin and [[18]F]ANP-RGD2 are superior to [[18]F]FDG for PET/CT imaging for evaluation of cardiomyocyte apoptosis and tissue repair processes in the MI rats.}, }
@article {pmid34183702, year = {2021}, author = {Coppersmith, V and Hudgins, S and Stoltzfus, J and Stankewicz, H}, title = {The use of N-acetylcysteine in the prevention of hangover: a randomized trial.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {13397}, pmid = {34183702}, issn = {2045-2322}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Alcohol Drinking/*adverse effects ; Alcoholic Intoxication/*prevention &amp; control ; Beer/adverse effects ; Cross-Over Studies ; Double-Blind Method ; Ethanol/*adverse effects ; Female ; Humans ; Male ; Nausea/chemically induced ; Young Adult ; }, abstract = {Hangovers resulting from alcohol intoxication can lead to adverse effects ranging from generalized discomfort and work-related absenteeism to emergency department visits from patients seeking symptomatic care. The purpose of this study was to evaluate the efficacy of a low dose (600-1800 mg) of N-Acetylcysteine (NAC) vs placebo on mitigating hangover symptoms. This was a randomized, double-blinded, placebo controlled crossover study involving 49 volunteers who consumed beer to obtain a breath alcohol content (BrAC) of 0.1 g/210L. The participants met on two separate occasions at which time they were given either NAC or placebo capsules. Opposing treatments were administered during the second encounter. The morning after the participant's intoxication and treatment, a Hangover Symptom Scale Questionnaire was administered to determine subjective changes in hangover symptoms. Data was analyzed by self-control, comparing the participant's hangover symptom severity when using NAC compared to placebo. No significant difference was found in the general distribution of total hangover scores (P = .45) (NAC = 10; Placebo = 13). There was also no significant difference found in the general distribution of specific hangover symptoms. However, a significant difference was found in the general distribution of total hangover difference scores based on gender (P = .04) (Female - 3.5; Male 2), specifically for nausea (P = .05) and weakness (P = .03). Although no difference was found in the general hangover scale scores, the study was suggestive of gender specific susceptibility with female participants having improved hangover symptoms after NAC use.}, }
@article {pmid34182881, year = {2021}, author = {Assimakopoulos, SF and Aretha, D and Komninos, D and Dimitropoulou, D and Lagadinou, M and Leonidou, L and Oikonomou, I and Mouzaki, A and Marangos, M}, title = {N-acetyl-cysteine reduces the risk for mechanical ventilation and mortality in patients with COVID-19 pneumonia: a two-center retrospective cohort study.}, journal = {Infectious diseases (London, England)}, volume = {53}, number = {11}, pages = {847-854}, doi = {10.1080/23744235.2021.1945675}, pmid = {34182881}, issn = {2374-4243}, mesh = {Acetylcysteine/therapeutic use ; *COVID-19 ; Cohort Studies ; Humans ; Prospective Studies ; *Respiration, Artificial ; Retrospective Studies ; SARS-CoV-2 ; }, abstract = {BACKGROUND: N-acetyl-cysteine (NAC) has been previously shown to exert beneficial effects in diverse respiratory diseases, through antioxidant and anti-inflammatory actions. Our aim was to evaluate NAC potential impact in hospitalised patients with COVID-19 pneumonia, in terms of progression to severe respiratory failure (SRF) and mortality.<br><br>PATIENTS AND METHODS: This retrospective, two-centre cohort study included consecutive patients hospitalised with moderate or severe COVID-19 pneumonia. Patients who received standard of care were compared with patients who additionally received NAC 600&#x2009;mg bid orally for 14&#x2009;days. Patients' clinical course was recorded regarding (i) the development of SRF (PO2/FiO2 <150) requiring mechanical ventilation support and (ii) mortality at 14 and 28&#x2009;days.<br><br>RESULTS: A total of 82 patients were included, 42 in the NAC group and 40 in the control group. Treatment with oral NAC led to significantly lower rates of progression to SRF as compared to the control group (p&#x2009;<&#x2009;.01). Patients in the NAC group presented significantly lower 14- and 28-day mortality as compared to controls (p&#x2009;<&#x2009;.001 and p&#x2009;<&#x2009;.01 respectively). NAC treatment significantly reduced 14- and 28-day mortality in patients with severe disease (p&#x2009;<&#x2009;.001, respectively). NAC improved over time the PO2/FiO2 ratio and decreased the white blood cell, CRP, D-dimers and LDH levels. In the multivariable logistic regression analysis, non-severe illness and NAC administration were independent predictors of 28-days survival.<br><br>CONCLUSION: Oral NAC administration (1200&#x2009;mg/d) in patients with COVID-19 pneumonia reduces the risk for mechanical ventilation and mortality. Our findings need to be confirmed by properly designed prospective clinical trials.}, }
@article {pmid34177609, year = {2021}, author = {Meng, TT and Wang, W and Meng, FL and Wang, SY and Wu, HH and Chen, JM and Zheng, Y and Wang, GX and Zhang, MX and Li, Y and Su, GH}, title = {Nicotine Causes Mitochondrial Dynamics Imbalance and Apoptosis Through ROS Mediated Mitophagy Impairment in Cardiomyocytes.}, journal = {Frontiers in physiology}, volume = {12}, number = {}, pages = {650055}, pmid = {34177609}, issn = {1664-042X}, abstract = {Nicotine contained in traditional cigarettes, hookahs, and e-cigarettes is an important risk factor for cardiovascular disease. Our previous study showed that macroautophagic flux impairment occurred under nicotine stimulation. However, whether nicotine influences mitochondrial dynamics in neonatal rat ventricular myocytes (NRVMs) is unclear. The purpose of this study was to explore the effects and potential mechanism of nicotine on mitophagy, mitochondrial dynamics, apoptosis, and the relationship between these processes in NRVMs. Our results showed that nicotine exposure increased mitochondria-derived superoxide production, decreased mitochondrial membrane potential, and impaired PINK1/Parkin-mediated mitophagic flux in NRVMs. Interestingly, nicotine significantly promoted dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and suppressed mitofusin (MFN)-mediated fusion, which was also observed in the bafilomycin A1-treated group. These results suggest that mitophagic flux impairment may contribute to Drp-1-mediated mitochondrial fission. Finally, nicotine caused excessive mitochondrial fission and contributed to apoptosis, which could be alleviated by mdivi-1, an inhibitor of Drp1. In addition to CTSB, as we previously reported, the enzyme activity of cathepsin L (CTSL) was also decreased in lysosomes after stimulation with nicotine, which may be the main cause of the hindered mitophagic flux induced by nicotine in NRVMs. Pretreatment with Torin 1, which is an inhibitor of mTOR, activated CTSL and ameliorated nicotine-induced mTOR activation and mitophagy impairment, decreased mitochondria-derived superoxide production, and blunted mitochondrial fission and apoptosis. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) or inhibitors of p38 and JNK, which could also alleviate mitophagy impairment, exhibited similar effects as Torin1 on mitochondria. Taken together, our study demonstrated that nicotine treatment may lead to an increase in Drp1-mediated mitochondrial fission by blocking mitophagic flux by weakening the enzyme activity of CTSL and activating the ROS/p38/JNK signaling pathway. Excessive mitochondrial fission induced by nicotine ultimately leads to apoptosis. Torin1 restored the decreased CTSL enzyme activity by removing excessive ROS and alleviated the effects of nicotine on mitophagic flux, mitochondrial dynamics, and apoptosis. These results may provide new evidence on the relationship between mitophagic flux and mitochondrial dynamics and new perspectives on nicotine's effects on mitochondrial dynamics in cardiomyocytes.}, }
@article {pmid34176834, year = {2022}, author = {Nishimura, Y and Kewcharoen, J and Narimasu, T}, title = {Extremely Elevated Procalcitonin in a Case of Acetaminophen Overdose and Acute Liver Injury.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {61}, number = {1}, pages = {115-118}, pmid = {34176834}, issn = {1349-7235}, mesh = {Acetaminophen ; Acetylcysteine ; *Analgesics, Non-Narcotic ; *Chemical and Drug Induced Liver Injury/diagnosis/etiology ; *Drug Overdose/diagnosis ; Humans ; Liver ; Male ; Middle Aged ; Procalcitonin ; }, abstract = {We herein report a 46-year-old man who suffered an intentional acetaminophen overdose. Laboratory results revealed leukocytosis and an elevated procalcitonin level (8.48 ng/mL). Computed tomography showed findings suggesting possible colitis. Due to concerns about sepsis in addition to acetaminophen overdose, oral N-acetyl cysteine and piperacillin/tazobactam were started. His procalcitonin levels further increased; however, the patient remained afebrile, and the C-reactive protein levels were normal. Piperacillin/tazobactam was discontinued, and he remained stable without antibiotics. The present case shows that the toxicokinetics of acetaminophen overdose can cause an elevated procalcitonin level. Furthermore, procalcitonin levels alone should not guide the need for antibiotics in such cases.}, }
@article {pmid34175667, year = {2021}, author = {Sulkshane, P and Ram, J and Thakur, A and Reis, N and Kleifeld, O and Glickman, MH}, title = {Ubiquitination and receptor-mediated mitophagy converge to eliminate oxidation-damaged mitochondria during hypoxia.}, journal = {Redox biology}, volume = {45}, number = {}, pages = {102047}, pmid = {34175667}, issn = {2213-2317}, mesh = {HeLa Cells ; Humans ; Hypoxia/metabolism ; *Mitochondria/metabolism ; *Mitophagy ; Oxidative Stress ; Ubiquitination ; }, abstract = {The contribution of the Ubiquitin-Proteasome System (UPS) to mitophagy has been largely attributed to the E3 ubiquitin ligase Parkin. Here we show that in response to the oxidative stress associated with hypoxia or the hypoxia mimic CoCl2, the damaged and fragmented mitochondria are removed by Parkin-independent mitophagy. Mitochondria isolated from hypoxia or CoCl2-treated cells exhibited extensive ubiquitination, predominantly Lysine 48-linked and involves the degradation of key mitochondrial proteins such as the mitofusins MFN1/2, or the import channel component TOM20. Reflecting the critical role of mitochondrial protein degradation, proteasome inhibition blocked CoCl2-induced mitophagy. The five conserved ubiquitin-binding autophagy receptors (p62, NDP52, Optineurin, NBR1, TAX1BP1) were dispensable for the ensuing mitophagy, suggesting that the mitophagy step itself was independent of ubiquitination. Instead, the expression of two ubiquitin-independent mitophagy receptor proteins BNIP3 and NIX was induced by hypoxia or CoCl2-treatment followed by their recruitment to the oxidation-damaged mitochondria. By employing BNIP3/NIX double knockout and DRP1-null cell lines, we confirmed that mitochondrial clearance relies on DRP1-dependent mitochondrial fragmentation and BNIP3/NIX-mediated mitophagy. General antioxidants such as N-Acetyl Cysteine (NAC) or the mitochondria-specific Mitoquinone prevented HIF-1α stabilization, ameliorated hypoxia-related mitochondrial oxidative stress, and suppressed mitophagy. We conclude that the UPS and receptor-mediated autophagy converge to eliminate oxidation-damaged mitochondria.}, }
@article {pmid34171822, year = {2021}, author = {McClure, EA and Wahlquist, AE and Tomko, RL and Baker, NL and Carpenter, MJ and Bradley, ED and Cato, PA and Gipson, CD and Gray, KM}, title = {Evaluating N-acetylcysteine for early and end-of-treatment abstinence in adult cigarette smokers.}, journal = {Drug and alcohol dependence}, volume = {225}, number = {}, pages = {108815}, pmid = {34171822}, issn = {1879-0046}, support = {K01 DA036739/DA/NIDA NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; R34 DA042228/DA/NIDA NIH HHS/United States ; UG1 DA013727/DA/NIDA NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Adult ; Female ; Humans ; Male ; Middle Aged ; Smokers ; *Smoking Cessation ; *Tobacco Products ; *Tobacco Use Disorder ; Young Adult ; }, abstract = {BACKGROUND: There is robust preclinical literature and preliminary clinical findings supporting the use of N-Acetylcysteine (NAC) to treat substance use disorders, including tobacco use disorder (TUD). However, randomized controlled trials have yielded mixed results and NAC's efficacy for TUD has not been established. The goals of this study were to assess the efficacy of NAC in promoting early and end-of-treatment abstinence and preventing relapse among adult smokers.<br><br>METHODS: This randomized, double-blinded clinical trial enrolled adult, daily smokers (N&#x2009;=&#x2009;114; ages 23-64; 51 % female; 65 % White; 29 % Black/African American; 7% Hispanic/Latinx), who were randomized 1:1 to receive NAC (n&#x2009;=&#x2009;59) or placebo (n&#x2009;=&#x2009;55) (1200&#x2009;mg b.i.d.) for eight weeks. Participants received brief cessation counseling and incentives for abstinence during the first three days of the quit attempt. Primary outcomes: (i) carbon monoxide (CO)-confirmed abstinence during the first three days of the quit attempt.<br><br>SECONDARY OUTCOMES: (ii) time to relapse; (iii) biologically confirmed abstinence at Week 8.<br><br>RESULTS: No differences were found between NAC and placebo groups on measures of early abstinence (3-day quit attempt; 11 % for NAC vs. 15 % for placebo; all p&#x2009;>&#x2009;0.11), time to relapse (p&#x2009;=&#x2009;0.19), and end-of-treatment abstinence (7% for NAC vs. 11 % for placebo; all p&#x2009;>&#x2009;0.40].<br><br>CONCLUSIONS: Results indicate that NAC is a well-tolerated pharmacotherapy but is unlikely to be efficacious as a monotherapy for TUD in adults. Considered in the collective context of other research, NAC may potentially be more useful in a younger population, as a combination pharmacotherapy, or in the presence of more intensive psychosocial treatment.}, }
@article {pmid34171674, year = {2021}, author = {Kim, K and Kim, C and Park, J and Jeon, HJ and Park, YJ and Kim, YH and Yang, JO and Lee, SE}, title = {Transcriptomic evaluation on methyl bromide-induced phytotoxicity in Arabidopsis thaliana and its mode of phytotoxic action via the occurrence of reactive oxygen species and uneven distribution of auxin hormones.}, journal = {Journal of hazardous materials}, volume = {419}, number = {}, pages = {126419}, doi = {10.1016/j.jhazmat.2021.126419}, pmid = {34171674}, issn = {1873-3336}, mesh = {*Arabidopsis/genetics/metabolism ; *Arabidopsis Proteins/genetics ; Gene Expression Regulation, Plant ; Hormones ; Hydrocarbons, Brominated ; Indoleacetic Acids/toxicity ; Reactive Oxygen Species/metabolism ; Transcriptome ; }, abstract = {The increase in worldwide trade has caused the quality maintenance of commercialized agriproducts to be crucial in keeping its economic value. In recent years, methyl bromide (MB) has been used dominantly during quarantine and pre-shipment, despite it being an environmental hazard with global repercussions. Through this study, it was shown that Arabidopsis thaliana's 2 h exposure to the MB treatment displayed no signs of phytotoxicity, whereas its 4 h exposure significantly interfered with growth. The transcriptomic analysis found the molecular modifications in A. thaliana after the MB fumigation with the up-regulation of genes specifically relative to the abiotic and oxidative stress, and the down-regulation of auxin transporter genes. Some important gene expressions were verified by RT-qPCR and their expression patterns were similar. Oxidative stresses via the reactive oxygen species (ROS) in relation to MB phytotoxicity were confirmed with the increased malondialdehyde in MB-4h-treated A. thaliana. Uneven distribution of auxins via lower expression of auxin transporter genes was also determined using UPLC-ESI-QqQ MS. Application of two ROS scavengers such as N-acetyl-cysteine and L-glutathione minimized MB phytotoxic effect in A. thaliana. Therefore, MB caused severe oxidative stress, and alternatives regarding the use of MB should be considered.}, }
@article {pmid34171382, year = {2021}, author = {Lee, MC and Chen, YK and Tsai-Wu, JJ and Hsu, YJ and Lin, BR}, title = {Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines.}, journal = {Life sciences}, volume = {280}, number = {}, pages = {119752}, pmid = {34171382}, issn = {1879-0631}, mesh = {Angiotensin-Converting Enzyme 2/*genetics ; Antiparasitic Agents/*pharmacology ; COVID-19/genetics ; Cell Line ; Down-Regulation/*drug effects ; Drug Repositioning ; Emetine/*pharmacology ; Humans ; Lung/cytology/drug effects/metabolism ; NF-kappa B/*antagonists &amp; inhibitors ; Pyrrolidines/pharmacology ; Thiocarbamates/pharmacology ; Triclabendazole/*pharmacology ; Zinc/*pharmacology ; COVID-19 Drug Treatment ; }, abstract = {AIMS: Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal a role for NF-κB in human lung cell expression of ACE2, and we further explore the potential utility of repurposing NF-κB inhibitors to downregulate ACE2.<br><br>MAIN METHODS: Expression of ACE2 was assessed by Western blotting and RT-qPCR in multiple human lung cell lines with or without NF-&#x3ba;B inhibitor treatment. Surface ACE2 expression and intracellular reactive oxygen species (ROS) levels were measured with flow cytometry. p50 was knocked down with siRNA. Cytotoxicity was monitored by PARP cleavage and MTS assay.<br><br>KEY FINDINGS: Pyrrolidine dithiocarbamate (PDTC), an NF-&#x3ba;B inhibitor, suppressed endogenous ACE2 mRNA and protein expression in H322M and Calu-3 cells. The ROS level in H322M cells was increased after PDTC treatment, and pretreatment with N-acetyl-cysteine (NAC) reversed PDTC-induced ACE2 suppression. Meanwhile, treatment with hydrogen peroxide augmented ACE2 suppression in H322M cells with p50 knockdown. Two repurposed NF-&#x3ba;B inhibitors, the anthelmintic drug triclabendazole and the antiprotozoal drug emetine, also reduced ACE2 mRNA and protein levels. Moreover, zinc supplementation augmented the suppressive effects of triclabendazole and emetine on ACE2 expression in H322M and Calu-3 cells.<br><br>SIGNIFICANCE: These results suggest that ACE2 expression is modulated by ROS and NF-&#x3ba;B signaling in human lung cells, and the combination of zinc with triclabendazole or emetine shows promise for clinical treatment of ACE2-related disease.}, }
@article {pmid34171359, year = {2021}, author = {Ung, TT and Nguyen, TT and Li, S and Han, JY and Jung, YD}, title = {Nicotine stimulates CYP1A1 expression in human hepatocellular carcinoma cells via AP-1, NF-κB, and AhR.}, journal = {Toxicology letters}, volume = {349}, number = {}, pages = {155-164}, doi = {10.1016/j.toxlet.2021.06.013}, pmid = {34171359}, issn = {1879-3169}, mesh = {Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism ; Carcinoma, Hepatocellular/*enzymology/genetics/pathology ; Cell Proliferation/drug effects ; Cytochrome P-450 CYP1A1/*biosynthesis/genetics ; Enzyme Induction ; Hep G2 Cells ; Humans ; Liver Neoplasms/*enzymology/genetics/pathology ; Nicotine/*toxicity ; Nicotinic Agonists/*toxicity ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Aryl Hydrocarbon/genetics/*metabolism ; Signal Transduction ; Transcription Factor AP-1/genetics/*metabolism ; Transcription Factor RelA/genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Cytochrome P450 1A1 (CYP1A1) is a member of a subfamily of enzymes involved in the metabolism of both endogenous and exogenous substrates and the chemical activation of xenobiotics to carcinogenic derivatives. Here, the effects of nicotine, a major psychoactive compound present in cigarette smoke, on CYP1A1 expression and human hepatocellular carcinoma (HepG2) cell proliferation were investigated. Nicotine stimulated CYP1A1 expression via the transcription factors, activator protein 1, nuclear factor-kappa B, and the aryl hydrocarbon receptor (AhR) signaling pathway. Pharmacological inhibition and mutagenesis studies indicated that p38 mitogen-activated protein kinase, as well as RelA (or p65), mediated the upregulation of CYP1A1 of nicotine in HepG2 cells. The antioxidant compound, N-acetyl-cysteine, abrogated nicotine-activated production of reactive oxygen species and inhibited CYP1A1 expression by nicotine. Furthermore, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was inhibited by diphenyleneiodonium (an NADPH oxidase inhibitor). Thus, these results demonstrated that AhR played an important role in nicotine-induced CYP1A1 expression. Additionally, liver hepatocellular carcinoma HepG2 cells treated with nicotine exhibited markedly enhanced proliferation via CYP1A1 expression and Akt activation.}, }
@article {pmid34171332, year = {2021}, author = {Pedre, B and Barayeu, U and Ezeriņa, D and Dick, TP}, title = {The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species.}, journal = {Pharmacology &amp; therapeutics}, volume = {228}, number = {}, pages = {107916}, doi = {10.1016/j.pharmthera.2021.107916}, pmid = {34171332}, issn = {1879-016X}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Humans ; Hydrogen Sulfide ; Sulfur ; }, abstract = {Initially adopted as a mucolytic about 60 years ago, the cysteine prodrug N-acetylcysteine (NAC) is the standard of care to treat paracetamol intoxication, and is included on the World Health Organization's list of essential medicines. Additionally, NAC increasingly became the epitome of an "antioxidant". Arguably, it is the most widely used "antioxidant" in experimental cell and animal biology, as well as clinical studies. Most investigators use and test NAC with the idea that it prevents or attenuates oxidative stress. Conventionally, it is assumed that NAC acts as (i) a reductant of disulfide bonds, (ii) a scavenger of reactive oxygen species and/or (iii) a precursor for glutathione biosynthesis. While these mechanisms may apply under specific circumstances, they cannot be generalized to explain the effects of NAC in a majority of settings and situations. In most cases the mechanism of action has remained unclear and untested. In this review, we discuss the validity of conventional assumptions and the scope of a newly discovered mechanism of action, namely the conversion of NAC into hydrogen sulfide and sulfane sulfur species. The antioxidative and cytoprotective activities of per- and polysulfides may explain many of the effects that have previously been ascribed to NAC or NAC-derived glutathione.}, }
@article {pmid34167418, year = {2021}, author = {Sabzevare, M and Yazdani, F and Karami, A and Haddadi, M and Aghamollaei, H and Shahriary, A}, title = {The effect of N-acetyl cysteine and doxycycline on TNF-α-Rel-a inflammatory pathway and downstream angiogenesis factors in the cornea of rats injured by 2-chloroethyl-ethyl sulfide.}, journal = {Immunopharmacology and immunotoxicology}, volume = {43}, number = {4}, pages = {452-460}, doi = {10.1080/08923973.2021.1939370}, pmid = {34167418}, issn = {1532-2513}, mesh = {Acetylcysteine/*administration &amp; dosage ; Angiogenesis Inducing Agents/metabolism ; Animals ; Cornea/drug effects/*metabolism ; Doxycycline/*administration &amp; dosage ; Inflammation Mediators/antagonists &amp; inhibitors/metabolism ; Male ; Mustard Gas/*analogs &amp; derivatives/toxicity ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Transcription Factor RelA/*biosynthesis ; Tumor Necrosis Factor-alpha/*biosynthesis ; }, abstract = {BACKGROUND: Cornea injury of sulfur mustard (SM) is considered as the most devastating injuries to the eye. This study aimed to evaluate the single and combined effects of N-acetyl cysteine (NAC) and doxycycline on the inflammatory pathway and cornea neovascularization (CNV) in the rat model of SM-injured cornea.<br><br>MATERIALS AND METHODS: The right cornea of male Sprague-Dawley rats was subjected to 2-chloroethyl-ethyl sulfide (CEES). Rats were topically treated with a single and combined of 0.5% NAC and 12.5&#x2009;&#x3bc;g/ml doxycycline and examined at 3rd, 15th, and 21st days. The activity of three antioxidant enzymes was analyzed in the cornea of different groups. Real-time PCR was performed to measure gene expression of inflammatory factors (tnf-&#x3b1;, rel-a &amp; cxcl-1) and angiogenesis factors (vegf-a, mmp2,9) in the cornea lysates. The histological and opacity assessments were also carried out.<br><br>RESULTS: The activity of antioxidant enzymes significantly declined 3&#x2009;days after the CEES damage. NAC eye drop recovered the enzyme activity on the 21st day of treatment (p-value < .05). The expression of tnf-&#x3b1; and rel-a genes significantly increased after CEES cornea exposure, while NAC declined their expression on the 7th and 21st days. The CNV score and angiogenesis factor expression were decreased in the long term by single and combined treatments (p-value < .05), but the infiltration of inflammatory cells was not completely amended.<br><br>CONCLUSION: NAC and doxycycline eye drop could improve the CNV complication. Also, NAC was an effective treatment against the inflammatory pathway involved in CEES-injured cornea.}, }
@article {pmid34165401, year = {2022}, author = {Martinez-Banaclocha, M}, title = {Interfering with the Reactive Cysteine Proteome in COVID-19.}, journal = {Current medicinal chemistry}, volume = {29}, number = {10}, pages = {1657-1663}, doi = {10.2174/0929867328666210623142811}, pmid = {34165401}, issn = {1875-533X}, mesh = {*COVID-19 ; Cysteine ; Humans ; Immunity ; Proteome ; SARS-CoV-2 ; }, abstract = {Although vaccination against SARS-CoV-2 infection has been initiated, effective therapies for severe COVID-19 disease are still needed. A promising therapeutic strategy is using FDA-approved drugs that have the biological potential to interfere with or modify some of the viral proteins capable of changing the disease's course. Recent studies highlight that some clinically safe drugs can suppress the viral life cycle while potentially promoting an adequate host inflammatory/immune response by interfering with the disease's cysteine proteome.}, }
@article {pmid34165060, year = {2022}, author = {Sarris, J and Byrne, GJ and Oliver, G and Cribb, L and Blair-West, S and Castle, D and Dean, OM and Camfield, DA and Brakoulias, V and Bousman, C and Dowling, N and Ee, C and Murphy, J and Menon, R and Berk, M and Chamoli, S and Boschen, M and Ng, CH}, title = {Treatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study.}, journal = {CNS spectrums}, volume = {27}, number = {5}, pages = {588-597}, doi = {10.1017/S1092852921000638}, pmid = {34165060}, issn = {1092-8529}, mesh = {Humans ; Pilot Projects ; Psychiatric Status Rating Scales ; Quality of Life ; Magnesium/therapeutic use ; *Selenium/therapeutic use ; Cysteine/therapeutic use ; Treatment Outcome ; *Obsessive-Compulsive Disorder/drug therapy/diagnosis ; Dietary Supplements ; Zinc/therapeutic use ; Phosphates/therapeutic use ; Pyridoxal/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach.<br><br>OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium.<br><br>METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4&#xa0;weeks.<br><br>RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval&#xa0;=&#xa0;-9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P&#xa0;&#x2264;&#xa0;.001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS &#x2265;35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD.<br><br>CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.}, }
@article {pmid34163181, year = {2021}, author = {McCarty, MF and DiNicolantonio, JJ and Lerner, A}, title = {Review - Nutraceuticals Can Target Asthmatic Bronchoconstriction: NADPH Oxidase-Dependent Oxidative Stress, RhoA and Calcium Dynamics.}, journal = {Journal of asthma and allergy}, volume = {14}, number = {}, pages = {685-701}, pmid = {34163181}, issn = {1178-6965}, abstract = {Activation of various isoforms of NADPH oxidase contributes to the pathogenesis of asthma at multiple levels: promoting hypercontractility, hypertrophy, and proliferation of airway smooth muscle; enabling lung influx of eosinophils via VCAM-1; and mediating allergen-induced mast cell activation. Free bilirubin, which functions physiologically within cells as a feedback inhibitor of NADPH oxidase complexes, has been shown to have a favorable impact on each of these phases of asthma pathogenesis. The spirulina chromophore phycocyanobilin (PhyCB), a homolog of bilirubin's precursor biliverdin, can mimic the inhibitory impact of biliverdin/bilirubin on NADPH oxidase activity, and spirulina's versatile and profound anti-inflammatory activity in rodent studies suggests that PhyCB may have potential as a clinical inhibitor of NADPH oxidase. Hence, spirulina or PhyCB-enriched spirulina extracts merit clinical evaluation in asthma. Promoting biosynthesis of glutathione and increasing the expression and activity of various antioxidant enzymes - as by supplementing with N-acetylcysteine, Phase 2 inducers (eg, lipoic acid), selenium, and zinc - may also blunt the contribution of oxidative stress to asthma pathogenesis. Nitric oxide (NO) and hydrogen sulfide (H2S) work in various ways to oppose pathogenic mechanisms in asthma; supplemental citrulline and high-dose folate may aid NO synthesis, high-dose biotin may mimic and possibly potentiate NO's activating impact on soluble guanylate cyclase, and NAC and taurine may boost H2S synthesis. The amino acid glycine has a hyperpolarizing effect on airway smooth muscle that is bronchodilatory. Insuring optimal intracellular levels of magnesium may modestly blunt the stimulatory impact of intracellular free calcium on bronchoconstriction. Nutraceutical regimens or functional foods incorporating at least several of these agents may have utility as nutraceutical adjuvants to standard clinical management of asthma.}, }
@article {pmid34160077, year = {2021}, author = {}, title = {Editor's Note: Badawy A, State O and Abdelgawad S. N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial. Acta Obstetricia et Gynecologica Scandinavica, 2007;86:218-222.}, journal = {Acta obstetricia et gynecologica Scandinavica}, volume = {}, number = {}, pages = {}, doi = {10.1111/aogs.14194}, pmid = {34160077}, issn = {1600-0412}, }
@article {pmid34156614, year = {2021}, author = {Cao, L and Zhao, J and Xu, J and Zhu, L and Rahman, SU and Feng, S and Li, Y and Wu, J and Wang, X}, title = {N-acetylcysteine ameliorate cytotoxic injury in piglets sertoli cells induced by zearalenone and deoxynivalenol.}, journal = {Environmental science and pollution research international}, volume = {28}, number = {42}, pages = {60276-60289}, pmid = {34156614}, issn = {1614-7499}, support = {No. 31472250//National Natural Science Foundation of China/ ; No. AHCYJSTX-05-07//Anhui Science and Technology Department/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Male ; Sertoli Cells ; Swine ; *Trichothecenes/toxicity ; *Zearalenone/toxicity ; }, abstract = {Zearalenone (ZEA) and Deoxynivalenol (DON) are two mycotoxins highly detected in agricultural products and feed. Both mycotoxins produce reproductive toxicity and pose a serious threat to human and animal health, among which pigs are the most sensitive animals. Sertoli cells (SCs) play an important role in spermatogenesis; however, the combined toxicity of ZEA and DON and the screening of effective protective agents remains to be determined. By studying the effects of N-acetylcysteine (NAC) on the cells exposed to 20 μM of ZEA and 0.6 μM of DON, we explored the protective mechanism of NAC (4 mM) on the cytotoxic injury of piglets SCs induced by both mycotoxins. The results showed that the combination of ZEA and DON destroy organelles and SCs structures, NAC significantly alleviates the damage caused by ZEA and DON. NAC also significantly increased the expression and distribution of zonula occludens 1 (ZO-1), decreased the relative mRNA and protein expression levels of Bax, Bid, caspase-3, and caspase-9, and increased Bcl-2 expression level and inhibited the decrease of mitochondrial membrane potential. Further, NAC also eases the cell cycle arrest and oxidative stress caused by ZEA and DON. In summary, our results show that NAC could alleviate SCs injury via reducing the oxidative damage and apoptosis caused by ZEA and DON.}, }
@article {pmid34151121, year = {2021}, author = {Akhtar, MJ and Ahamed, M and Alhadlaq, H and Alrokayan, S}, title = {Pt-Coated Au Nanoparticle Toxicity Is Preferentially Triggered Via Mitochondrial Nitric Oxide/Reactive Oxygen Species in Human Liver Cancer (HepG2) Cells.}, journal = {ACS omega}, volume = {6}, number = {23}, pages = {15431-15441}, pmid = {34151121}, issn = {2470-1343}, abstract = {Reactive nitrogen species (RNS) that are formed from the reaction of versatile nitric oxide (NO) with reactive oxygen species (ROS) have been less explored in potential cancer therapy. This may be partly due to the fewer available agents that could induce NO in cells. Here, we report platinum-coated gold nanoparticles (Pt-coated Au NPs; 27 ± 20 nm) as a strong inducer of NO (assessed by live-cell imaging under NO-specific DAR-1 probe labeling and indirectly using a Griess reagent) in human liver carcinoma (HepG2) cells. In addition to NO, this study found a critical role of ROS from mitochondrial sources in the mechanism of toxicity caused by Pt-coated Au NPs. Cotreatment with a thiol-replenishing general antioxidant NAC (N-acetyl cysteine) led to significant amelioration of oxidative stress against NP-induced toxicity. However, NAC did not exhibit as much ameliorative potential against NP-induced oxidative stress as the superoxide radical (O[2•-])-scavenging mitochondrial specific antioxidant mito-TEMPO did. The higher protective potential of mito-TEMPO in comparison to NAC reveals mitochondrial ROS as an active mediator of NP-induced toxicity in HepG2 cells. Moreover, the relatively unaltered NP-induced NO concentration under cotreatment of GSH modulators NAC and buthionine sulfoximine (BSO) suggested that NO production due to NP treatment is rather independent of the cellular thiols at least in HepG2 cells. Moreover, toxicity potentiation by exogenous H2O2 again suggested a more direct involvement of ROS/RNS in comparison to the less potentiation of toxicity due to GSH-exhausting BSO. A steeper amelioration in NP-induced NO and ROS and, consequently, cytotoxicity by mito-TEMPO in comparison to NAC reveal a pronounced role of NO and ROS via the mitochondrial pathway in the toxicity of Pt-coated Au NPs in HepG2 cells.}, }
@article {pmid34149008, year = {2021}, author = {Koc, G and Kuskonmaz, SM and Demirel, K and Koca, G and Akbulut, A and Yumusak, N and Senes, M and Kirtil, G and Korkmaz, M and Culha, C}, title = {Ameliorating effects of N-acetyl cysteine against early liver damage of radioiodine in rats.}, journal = {Nuclear medicine communications}, volume = {42}, number = {11}, pages = {1195-1201}, doi = {10.1097/MNM.0000000000001454}, pmid = {34149008}, issn = {1473-5628}, mesh = {*Acetylcysteine ; }, abstract = {OBJECTIVE: The present study was aimed to explore the potential ameliorating effects of N-acetyl cysteine (NAC) against radioiodine (RAI)-induced early liver damage.<br><br>METHODS: Thirty Wistar Albino male rats were arbitrarily allocated into three groups each containing 10 rats: the control group (group 1); the RAI group (group 2), oral 111&#x2009;MBq/kg radioiodine was administered to rats; the RAI&#x2009;+&#x2009;NAC group (group 3), 150&#x2009;mg/kg/day intraperitoneal NAC treatment was initiated 3 days prior to the RAI administration and continued for 10 days. Liver samples were obtained 24&#x2009;h after the last dose of NAC therapy for biochemical and histopathologic evaluation.<br><br>RESULTS: In the RAI&#x2009;+&#x2009;NAC group, the histopathologic damage was found significantly less than in the RAI group for whole parameters except inflammatory cell infiltration (P&#x2009;<&#x2009;0.05). Unlike the RAI group which had marked histopathologic damage, the RAI&#x2009;+&#x2009;NAC group had only mild histologic activity index scores with no granuloma formation observed. Oxidative stress parameters were demonstrated that the NAC treatment significantly decreased the tissue malondialdehyde (MDA) and catalase levels and increased the total sulfhydryl (total sulfhydryl) levels when compared to the RAI group (P&#x2009;<&#x2009;0.01).<br><br>CONCLUSION: The outcomes of the study exhibited that the NAC treatment improved RAI-induced early liver damage. This improving effect considered to be caused by its antioxidant, anti-inflammatory, and likely vasodilator properties of NAC. Having advantages such as inexpensive, easy access, and tolerability, the NAC can be used as a radioprotective agent, especially in patients with liver diseases and requiring RAI treatment.}, }
@article {pmid34146985, year = {2021}, author = {Tang, J and Hu, B and Zheng, H and Qian, X and Zhang, Y and Zhu, J and Xu, G and Chen, D and Jin, X and Li, W and Xu, L}, title = {2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) activates Aryl hydrocarbon receptor (AhR) mediated ROS and NLRP3 inflammasome/p38 MAPK pathway inducing necrosis in cochlear hair cells.}, journal = {Ecotoxicology and environmental safety}, volume = {221}, number = {}, pages = {112423}, doi = {10.1016/j.ecoenv.2021.112423}, pmid = {34146985}, issn = {1090-2414}, mesh = {Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Line ; Cell Survival/drug effects ; Cytokines/metabolism ; Flame Retardants/*toxicity ; Hair Cells, Auditory/*drug effects/metabolism/pathology ; Halogenated Diphenyl Ethers/*toxicity ; Inflammasomes/metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein ; Necrosis/chemically induced/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/metabolism ; Signal Transduction/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Tetrabromodiphenyl ether (BDE-47) is widely used as commercial flame retardants that can be released into the environment and finally enter human body through the food chain. It has been identified to generate neurotoxicity, but little is known about auditory damage and the underlying mechanism following BDE-47 exposure. This study aimed to assess the cell viability with BDE-47 concentration ranging from 0 to 150 μM in mouse organ of Corti-derived cell lines (HEI-OC1). Aryl hydrocarbon receptor (AhR) as an environmental sensor, reactive oxygen species (ROS), NLRP3 inflammasome and p38 MAPK pathways were detected. Results: (1) BDE-47 inhibited the viability in a time- and dose-dependent way in HEI-OC1 cells. Cell cycle was arrested in G1 phase by BDE-47; (2) Elevated intracellular ROS, LDH levels and necrosis were found, which was alleviated by pretreatment with ROS scavenger N-acetylcysteine (NAC); (3) AhR plays an essential role in ligand-regulated transcription factor activation by exogenous environmental compounds. We found increased expression of AhR and decreased downstream targets of CYP 1A1 and CYP 1B1 in BDE-47-treated HEI-OC1 cells, which was reversed by the AhR antagonist CH-223191 for 2 h before BDE-47 exposure. No significant change was detected in CYP 2B; (4) Enhanced expressions of NLRP3 and caspase-1 were induced by BDE-47, with up-regulations of both pro-inflammatory factors for IL-1β, IL-6 and TNF-α, and anti-inflammatory factors for IL-4, IL-10 and IL-13, but down-regulation for IL-1α; (5) Additionally, the p38 MAPK signaling pathway was activated with increased phosphorylation levels of MKK/3/6, p38 MAPK and NF-kB. Overall, our findings illustrate a role of AhR in ROS-induced necrosis of cochlear hair cells by BDE-47 exposure, in which NLRP3 inflammasome and p38 MAPK signaling pathways are activated. The current study first elucidates the sense of hearing damage induced by BDE-47, and cell-specific or mixture exposures in vivo or human studies are needed to confirm this association.}, }
@article {pmid34146943, year = {2021}, author = {Li, L and Chen, M and Li, G and Cai, R}, title = {Raddeanin A induced apoptosis of non-small cell lung cancer cells by promoting ROS-mediated STAT3 inactivation.}, journal = {Tissue &amp; cell}, volume = {71}, number = {}, pages = {101577}, doi = {10.1016/j.tice.2021.101577}, pmid = {34146943}, issn = {1532-3072}, mesh = {A549 Cells ; Apoptosis/*drug effects ; Carcinoma, Non-Small-Cell Lung/drug therapy/*metabolism/pathology ; Humans ; Lung Neoplasms/drug therapy/*metabolism/pathology ; Neoplasm Proteins/*metabolism ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*metabolism ; Saponins/*pharmacology ; }, abstract = {PURPOSE: Non-small cell lung cancer (NSCLC) is a high-risk type of lung cancer. Raddeanin A exerts anti-tumor activity by regulating cell proliferation and apoptosis, but its role in NSCLC remains to be elucidated. This study was to investigate the effect of raddeanin A in NSCLC and its mechanism.<br><br>METHODS: The effect of raddeanin A (2, 4, 8, 10&#x2009;&#x3bc;mol/L) on the viability, proliferation and apoptosis of A549 and H1299 cells was determined by cell counting kit-8, colony formation and flow cytometry assays, respectively. Next, western blot was performed to examine the protein expressions of cleaved caspase-3, Bax, phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and STAT3. Subsequently, the intracellular reactive oxygen species (ROS) generation and mitochondrial membrane potential of NSCLC cells were detected by 2', 7'-dichlorofluorescein-diacetate (DCFH-DA) and JC-1 assay. Lastly, the effect of N-acetylcysteine (NAC) on the apoptosis, ROS generation, and STAT3 was evaluated by the above-mentioned assays again.<br><br>RESULTS: Raddeanin A treatment had no obvious effect on 16HBE cells viability, but it inhibited viability and proliferation of A549 and H1299 cells, promoted the apoptosis, increased the protein expressions of cleaved caspase-3 and Bax, generated intracellular ROS, as well as decreased mitochondrial membrane potential and the expressions of p-STAT3 and STAT3 in A549 and H1299 cells. After cells treated with NAC, the effect of raddeanin A was reversed, as evidenced by the apoptosis and ROS generation were suppressed, and the expression of p-STAT3 was promoted.<br><br>CONCLUSION: Raddeanin A suppressed the proliferation and induced apoptosis of NSCLC cells via promoting the ROS-mediated STAT3 inactivation.}, }
@article {pmid34146190, year = {2021}, author = {Hirota, K and Matsuoka, M}, title = {N-acetylcysteine restores the cadmium toxicity of Caenorhabditis elegans.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {34}, number = {5}, pages = {1207-1216}, pmid = {34146190}, issn = {1572-8773}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Cadmium/toxicity ; *Caenorhabditis elegans/metabolism ; Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {Cadmium is a well-known environmental toxicant. At the cellular level, exposure to cadmium results in cytotoxic effects through the elevation of reactive oxygen species (ROS) production. Although cadmium exposure leads to the dysfunction of various organs, the underlying mechanisms of the toxic effects of cadmium in vivo are still largely unknown. Caenorhabditis elegans (C. elegans) is a useful model animal and exhibits unique biological reactions in response to environmental toxicants. In this study, the toxic mechanisms of cadmium exposure in C. elegans were investigated using N-acetylcysteine (NAC), which has dual functions, i.e., as a chelator of metals and as an antioxidant. NAC did not inhibit the uptake of cadmium into nematodes, suggesting that NAC did not function as a chelator of cadmium under these experimental conditions. Based on this finding, we investigated the effect of NAC as an antioxidant on representative phenotypic traits caused by cadmium exposure-reduced body length, aversion behavior, and shortened lifespan. NAC did not reverse the decreased body size but did clearly restore the aversion behavior and the shortened lifespan. These data suggest that aversion behavior and shortened lifespan are mediated by oxidative stress in C. elegans.}, }
@article {pmid34146182, year = {2021}, author = {Zhu, X and Liu, S and Cao, Z and Yang, L and Lu, F and Li, Y and Hu, L and Bai, X}, title = {Higenamine mitigates interleukin-1β-induced human nucleus pulposus cell apoptosis by ROS-mediated PI3K/Akt signaling.}, journal = {Molecular and cellular biochemistry}, volume = {476}, number = {11}, pages = {3889-3897}, pmid = {34146182}, issn = {1573-4919}, mesh = {Adrenergic beta-Antagonists/pharmacology ; Alkaloids/*pharmacology ; Apoptosis/drug effects ; Cells, Cultured ; Humans ; Interleukin-1beta/*toxicity ; Intervertebral Disc Degeneration/*drug therapy/metabolism/pathology ; Nucleus Pulposus/*drug effects/metabolism/pathology ; Phosphatidylinositol 3-Kinase/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Tetrahydroisoquinolines/*pharmacology ; }, abstract = {Intervertebral disc degeneration (IDD) is a natural problem linked to the inflammation. Higenamine exerts multiple pharmacological properties in inflammation-related disorders. Our study aimed to explore the function of higenamine on interleukin (IL)-1β-caused apoptosis of human nucleus pulposus cells (HNPCs). Cell apoptosis was investigated by TUNEL and flow cytometry. Apoptosis-related biomarkers were determined by qRT-PCR or Western blotting. The protein in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling was measured by Western blotting. We found that higenamine showed little effect on cell apoptosis, but mitigated IL-1β-caused apoptosis in a dose-dependent pattern. Higenamine attenuated IL-1β-induced decrease of Bcl-2 and increase of Bax and cleaved caspase-3. Higenamine did not affect the reactive oxygen species (ROS) level and the PI3K/Akt signaling, but attenuated IL-1β-induced ROS production and inhibition of the PI3K/Akt signaling. IL-1β repressed the activation of the PI3K/Akt pathway, but ROS inhibition using N-acetylcysteine (NAC) rescued this pathway. The PI3K/Akt signaling suppression using LY294002 reversed the inhibitive effect of higenamine on IL-1β-caused apoptosis, and this effect was weakened by ROS inhibition. In conclusion, higenamine attenuates IL-1β-caused apoptosis of HNPCs via ROS-mediated PI3K/Akt pathway.}, }
@article {pmid34136260, year = {2021}, author = {Desdiani, D and Yulianti, N and Basuki, A}, title = {Delayed hypercoagulable state in COVID-19 adolescent patient: a case report.}, journal = {Respirology case reports}, volume = {9}, number = {7}, pages = {e00793}, pmid = {34136260}, issn = {2051-3380}, abstract = {Coronavirus disease 2019 (COVID-19) is a systemic hyperinflammation disease which can cause severe respiratory symptoms and extrapulmonary manifestations. Hypercoagulable state in COVID-19 adolescent patient is a rare case. We present the case of a 16-year-old Indonesian boy with mild COVID-19 symptoms. Initially, the patient was treated with azithromycin, N-acetyl cysteine, etc. After several days of the treatment, there was clinical improvement. However, on day 15, the patient experienced hypercoagulation and stroke-like symptoms. The patient was then subjected to additional drugs, including low-molecular weight heparin (LMWH), and peripheral neuropathy vitamin therapy. On day 20, the clinical symptoms reduced. This case demonstrates the need for further study of the association between COVID-19 and stroke in young population and the use of anticoagulants to prevent thrombotic events.}, }
@article {pmid34130324, year = {2021}, author = {Vogelbacher, LC and Thimme, R}, title = {[Unusual cause of a PCT-elevation].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {146}, number = {12}, pages = {818-820}, doi = {10.1055/a-1442-5519}, pmid = {34130324}, issn = {1439-4413}, mesh = {Abdominal Pain/etiology ; Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Adult ; Diagnosis, Differential ; Female ; Humans ; Nausea/etiology ; *Poisoning/diagnosis/drug therapy/psychology ; Procalcitonin/*blood ; *Suicide, Attempted ; }, abstract = {INTRODUCTION: Procalcitonin (PCT) is an established marker for bacterial infection. Elevation of PCT can occur due to various reasons and is not specific, as we outline in the following case report.<br><br>HISTORY: We report on a 29 year old patient, who was presented by the psychiatric department because of obscure abdominal pain, nausea and vomiting since two days. Taking the patients history did not result in conclusive findings at first.<br><br>FINDINGS AND DIAGNOSIS: The clinical examination did not result in conclusive findings. The patient was afebrile. Blood work showed an elevation of transaminases and a massive elevation of PCT. In ultrasound no abnormalities were shown, serological investigations for viral hepatitis were negative. Blood cultures remained sterile, the search for an infectious focus remained unremarkable.<br><br>THERAPY AND COURSE: In the course of the in-patient stay the patient reported the ingestion of approximately 40&#x200a;g of acetaminophen in suicidal intention two days before. Therapy with N-acetylcysteine (NAC) was initiated. The transaminases and PCT were regressive the next day. Antibiotic therapy was foregone.<br><br>CONCLUSIONS: This case illustrates that PCT-elevation is not specific for a bacterial infection and must be seen in correlation to patient's history and clinical findings.}, }
@article {pmid34122588, year = {2021}, author = {Hon, KL and Hui, WF and Leung, AK}, title = {Antidotes for childhood toxidromes.}, journal = {Drugs in context}, volume = {10}, number = {}, pages = {}, pmid = {34122588}, issn = {1745-1981}, abstract = {BACKGROUND: Poisoning causes significant morbidity and sometimes mortality in children worldwide. The clinical skill of toxidrome recognition followed by the timely administration of an antidote specific for the poison is essential for the management of children with suspected poisoning. This is a narrative review on antidotes for toxidromes in paediatric practice.<br><br>METHODS: A literature search was conducted on PubMed with the keywords "antidote", "poisoning", "intoxication", "children" and "pediatric". The search was customized by applying the appropriate filters (species: humans; age: birth to 18 years) to obtain the most relevant articles for this review article.<br><br>RESULTS: Toxidrome recognition may offer a rapid guide to possible toxicology diagnosis such that the specific antidote can be administered in a timely manner. This article summarizes toxidromes and their respective antidotes in paediatric poisoning, with an emphasis on the symptomatology and source of exposure. The antidote and specific management for each toxidrome are discussed. Antidotes are only available for a limited number of poisons responsible for intoxication. Antidotes for common poisonings include N-acetyl cysteine for paracetamol and sodium thiosulphate for poisoning by cyanide.<br><br>CONCLUSION: Poisoning is a common cause of paediatric injury. Physicians should be familiar with the recognition of common toxidromes and promptly use specific antidotes for the management of childhood toxidromes.}, }
@article {pmid34120018, year = {2021}, author = {Lofthouse, EM and Manousopoulou, A and Cleal, JK and O'Kelly, IM and Poore, KR and Garbis, SD and Lewis, RM}, title = {N-acetylcysteine, xCT and suppression of Maxi-chloride channel activity in human placenta.}, journal = {Placenta}, volume = {110}, number = {}, pages = {46-55}, doi = {10.1016/j.placenta.2021.05.009}, pmid = {34120018}, issn = {1532-3102}, support = {BB/L020823/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Acetylcysteine/metabolism/*pharmacology ; Amino Acid Transport System y+/*genetics/metabolism ; Animals ; Chloride Channels/*antagonists &amp; inhibitors/metabolism ; Chorionic Villi/drug effects/metabolism ; Female ; Gene Expression/drug effects ; Glutamic Acid/drug effects/metabolism ; HEK293 Cells ; Humans ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects/genetics ; *Placenta/drug effects/metabolism ; Pregnancy ; Proteome/drug effects/metabolism ; Xenopus laevis ; }, abstract = {INTRODUCTION: Placental oxidative stress features in pregnancy pathologies but in clinical trials antioxidant supplementation has not improved outcomes. N-acetylcysteine (NAC) stimulates glutathione production and is proposed as a therapeutic agent in pregnancy. However, key elements of N-acetylcysteine biology, including its cellular uptake mechanism, remains unclear. This study explores how the cystine/glutamate transporter xCT may mediate N-acetylcysteine uptake and how N-acetylcysteine alters placental redox status.<br><br>METHODS: The involvement of xCT in NAC uptake by the human placenta was studied in perfused placenta and Xenopus oocytes. The effect of short-term N-acetylcysteine exposure on the placental villous proteome was determined using LC-MS. The effect of N-acetylcysteine on Maxi-chloride channel activity was investigated in perfused placenta, villous fragments and cell culture.<br><br>RESULTS: Maternoplacental N-acetylcysteine administration stimulated intracellular glutamate efflux suggesting a role of the exchange transporter xCT, which was localised to the microvillous membrane of the placental syncytiotrophoblast. Placental exposure to a bolus of N-acetylcysteine inhibited subsequent activation of the redox sensitive Maxi-chloride channel independently of glutathione synthesis. Stable isotope quantitative proteomics of placental villi treated with N-acetylcysteine demonstrated changes in pathways associated with oxidative stress, apoptosis and the acute phase response.<br><br>DISCUSSION: This study suggests that xCT mediates N-acetylcysteine uptake into the placenta and that N-acetylcysteine treatment of placental tissue alters the placental proteome while regulating the redox sensitive Maxi-chloride channel. Interestingly N-acetylcysteine had antioxidant effects independent of the glutathione pathway. Effective placental antioxidant therapy in pregnancy may require maintaining the balance between normalising redox status without inhibiting physiological redox signalling.}, }
@article {pmid34117842, year = {2021}, author = {Birk, SE and Serioli, L and Cavallo, V and Haagensen, JAJ and Molin, S and Nielsen, LH and Zór, K and Boisen, A}, title = {Enhanced Eradication of Mucin-Embedded Bacterial Biofilm by Locally Delivered Antibiotics in Functionalized Microcontainers.}, journal = {Macromolecular bioscience}, volume = {21}, number = {8}, pages = {e2100150}, doi = {10.1002/mabi.202100150}, pmid = {34117842}, issn = {1616-5195}, mesh = {*Anti-Bacterial Agents/pharmacology/therapeutic use ; Biofilms ; Microbial Sensitivity Tests ; *Mucins ; Pseudomonas aeruginosa ; }, abstract = {Bacterial biofilm-related infections are difficult to eradicate and require repeated treatments with high doses of antibiotics. Thus, there is an urgent need for new treatment strategies that minimize the use of antibiotics while enhancing biofilm eradication. Functionalized reservoir-based microdevices, such as, microcontainers (MCs), offer, high drug loading capacity, mucus embedment, and tuneable drug release. Here, MCs are loaded with the antibiotic ciprofloxacin (CIP), and sealed with a lid consisting of chitosan (CHI) and a mucolytic agent, N-acetylcysteine (NAC). It is found that CHI and NAC work synergistically, showing improved mucoadhesive and mucolytic properties. To better mimic the in vivo habitat of Pseudomonas aeruginosa (P. aeruginosa), the biofilm is grown in a mucin-containing medium on a newly developed centrifugal microfluidic system. The CHI/NAC coated MCs improve eradication of biofilm (88.22 ± 2.89%) compared to CHI-coated MCs (72.68 ± 3.73%) or bolus injection (39.86 ± 13.28%). The findings suggest that MCs are significantly more efficient than a bolus treatment. Furthermore, CHI/NAC functionalized MCs kill most of the biomass already after 5 h (80.75 ± 3.50%), mainly due to a fast drug release. This is the first time that CHI/NAC has been combined as a coating to explore mucolytic properties on bacterial biofilms.}, }
@article {pmid34116184, year = {2021}, author = {Aiyer, A and Manoharan, A and Paino, D and Farrell, J and Whiteley, GS and Kriel, FH and Glasbey, TO and Manos, J and Das, T}, title = {Disruption of biofilms and killing of Burkholderia cenocepacia from cystic fibrosis lung using an antioxidant-antibiotic combination therapy.}, journal = {International journal of antimicrobial agents}, volume = {58}, number = {2}, pages = {106372}, doi = {10.1016/j.ijantimicag.2021.106372}, pmid = {34116184}, issn = {1872-7913}, mesh = {Anti-Bacterial Agents/*pharmacokinetics/*therapeutic use ; Biofilms/*drug effects ; Burkholderia Infections/*drug therapy ; Burkholderia cepacia complex/*drug effects ; Cystic Fibrosis/*microbiology ; Humans ; Lung/*microbiology ; }, abstract = {Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The resulting chloride and bicarbonate imbalance produces a thick, static lung mucus. This mucus is not easily expelled from the lung and can be colonised by bacteria, leading to biofilm formation. CF lung infection with Burkholderia cepacia complex (BCC), particularly the subspecies B. cenocepacia, results in higher morbidity and mortality. Patients infected with BCC can rapidly progress to "cepacia syndrome", a fatal necrotising pneumonia. The aim of this study was to identify whether a combination therapy (CT) of selected antioxidants and antibiotics significantly disrupts B. cenocepacia biofilms and to determine the optimum CT level for treatment. Using controlled in vitro spectrophotometry, colony-forming unit and microscopy assays, three antioxidants (N-acetylcysteine [NAC], glutathione and vitamin C) and three antibiotics (ciprofloxacin, ceftazidime and tobramycin) were screened and assessed for their ability to disrupt the early and mature biofilms of six B. cenocepacia CF isolates. A combination of NAC and ciprofloxacin produced a statistically significant biofilm disruption in all strains tested, with growth inhibition (>5-8 log10) observed when exposed to 4890 or 8150 μg/mL NAC in combination with 32 or 64 μg/mL ciprofloxacin. NAC-mediated biofilm disruption may be aided by the acidic pH of NAC at higher concentrations. This study showed that NAC is an effective disruptor that reduces the necessity for high concentrations of antibiotic. Further research will focus on the host toxicity and efficacy in ex vivo CF models.}, }
@article {pmid34116177, year = {2021}, author = {Fang, W and Chen, Q and Cui, K and Chen, Q and Li, X and Xu, N and Mai, K and Ai, Q}, title = {Lipid overload impairs hepatic VLDL secretion via oxidative stress-mediated PKCδ-HNF4α-MTP pathway in large yellow croaker (Larimichthys crocea).}, journal = {Free radical biology &amp; medicine}, volume = {172}, number = {}, pages = {213-225}, doi = {10.1016/j.freeradbiomed.2021.06.001}, pmid = {34116177}, issn = {1873-4596}, mesh = {Animals ; Carrier Proteins ; Hepatocytes/metabolism ; Humans ; *Lipoproteins, VLDL/metabolism ; Liver/metabolism ; Oxidative Stress ; *Perciformes/metabolism ; }, abstract = {Lipid overload-induced hepatic steatosis is a major public health problem worldwide. However, the potential molecular mechanism is not completely understood. Herein, we found that high-fat diet (HFD) or oleic acid (OA) treatment induced oxidative stress which prevented the entry of hepatocyte nuclear factor 4 alpha (HNF4α) into the nucleus by activating protein kinase C delta (PKCδ) in vivo and in vitro in large yellow croaker (Larimichthys crocea). This reduced the level of microsomal triglyceride transfer protein (MTP) transcription, resulting in the impaired secretion of very-low-density lipoprotein (VLDL) and the abnormal accumulation of triglyceride (TG) in hepatocytes. Meanwhile, the detrimental effects induced by lipid overload could be partly alleviated by pretreating hepatocytes with Go6983 (PKCδ inhibitor) or N-acetylcysteine (NAC, reactive oxygen species (ROS) scavenger). In conclusion, for the first time, we revealed that lipid overload impaired hepatic VLDL secretion via oxidative stress-mediated PKCδ-HNF4α-MTP pathway in fish. This study may provide critical insights into potential intervention strategies against lipid overload-induced hepatic steatosis of fish and human beings.}, }
@article {pmid34114203, year = {2021}, author = {Kim, RJ and An, SH and Gwark, JY and Park, HB}, title = {Antioxidant effects on hypoxia-induced oxidative stress and apoptosis in rat rotator cuff fibroblasts.}, journal = {European cells &amp; materials}, volume = {41}, number = {}, pages = {680-693}, doi = {10.22203/eCM.v041a44}, pmid = {34114203}, issn = {1473-2262}, mesh = {Animals ; Antioxidants/*metabolism ; Apoptosis/*physiology ; Cell Line ; Cell Survival/physiology ; Fibroblasts/metabolism/pathology ; Hypoxia/*metabolism/pathology ; Male ; Matrix Metalloproteinase 2/metabolism ; Oxidative Stress/*physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Rotator Cuff/metabolism/pathology ; }, abstract = {Most cells, highly sensitive to oxygen levels, undergo apoptosis under hypoxia. Therefore, the involvement of hypoxia in rotator cuff tendon degeneration has been proposed. While previous studies have reported that hypoxia induces apoptosis in rotator cuff fibroblasts (RCFs), little research has investigated whether antioxidants have cytoprotective effects against RCF apoptosis. The present study aimed at determining whether the antioxidant N-acetylcysteine (NAC) exerted cytoprotective effects against hypoxia-induced RCF apoptosis. Third-passage rat RCFs were divided into normoxia, NAC, hypoxia and NAC-hypoxia groups. The hypoxia inducer was 1,000 µmol/L cobalt chloride (CoCl2); the antioxidant was 20 mmol/L NAC. Expressions of hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1), cell viability, intracellular reactive oxygen species (ROS) production, apoptosis rates as well as expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase-1 (PARP-1), vascular endothelial growth factors-β (VEGF-β) and matrix metalloproteinase-2 (MMP-2) were evaluated. Expression of HIF-1α and HO-1 was significantly higher in the hypoxia group than in the normoxia group (p < 0.001). Cell viability was significantly lower in the hypoxia group than in the normoxia group (p < 0.001). Intracellular ROS production, apoptosis rate and expressions of cleaved caspase-3, cleaved PARP-1, VEGF-β and MMP-2 were significantly higher in the hypoxia group than in the normoxia group (p < 0.001). All these responses were significantly attenuated by pre-treatment with NAC (p ≤ 0.001). ROS were involved in hypoxic RCF apoptosis induced by CoCl2; NAC, an ROS scavenger, inhibited hypoxia-induced RCF apoptosis by inhibiting ROS production.}, }
@article {pmid34114174, year = {2021}, author = {Taher, A and Lashgari, M and Sedighi, L and Rahimi-Bashar, F and Poorolajal, J and Mehrpooya, M}, title = {A pilot study on intravenous N-Acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome.}, journal = {Pharmacological reports : PR}, volume = {73}, number = {6}, pages = {1650-1659}, pmid = {34114174}, issn = {2299-5684}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Administration, Intravenous ; Adult ; Aged ; Aged, 80 and over ; COVID-19/*complications ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Mortality ; Pilot Projects ; Prospective Studies ; Respiratory Distress Syndrome/*drug therapy ; SARS-CoV-2 ; Severity of Illness Index ; Treatment Outcome ; *COVID-19 Drug Treatment ; }, abstract = {BACKGROUND: We designed this single-centre clinical trial to assess the potential benefits of N-Acetylcysteine (NAC) in patients with COVID19-associated acute respiratory distress syndrome (ARDS).<br><br>METHODS: Ninety-two patients with mild-to-moderate COVID19-associated ARDS were allocated to the placebo (45-cases) or NAC groups (47-cases). Besides standard-of-care treatment, the patients received either intravenous NAC at a dose of 40&#xa0;mg/kg/day or the placebo for three consecutive days. The efficacy outcomes were overall mortality over 28-day, clinical status on day 28, based on the WHO Master Protocol, the proportion of patients requiring mechanical ventilation, changes in ARDS-severity (based on the PaO2/FiO2 ratio), and Sequential Organ Failure Assessment (SOFA) scores 48 and 96&#xa0;h after intervention, RESULTS: No differences were found in the 28-day mortality rate between the two groups (25.5% vs. 31.1% in the NAC and placebo groups, respectively). Although the distribution of the clinical status at day 28 shifted towards better outcomes in the NAC-treated group, it did not reach a statistical significance level (p value&#x2009;=&#x2009;0.83). Similar results were achieved in terms of the proportion of patients who required invasive ventilator support (38.3% vs. 44.4%), the number of ventilator-free days (17.4 vs. 16.6), and median time of ICU and hospital stay. Results regarding the change in PaO2/FiO2 ratio and SOFA scores also showed no significant differences between the groups.<br><br>CONCLUSIONS: Our pilot study did not support the potential benefits of intravenous NAC in treating patients with COVID-19-associated ARDS. More studies are needed to determine which COVID-19 patients benefit from the NAC administration.<br><br>TRIAL REGISTRATION: The trial was registered at Clinicaltrials.gov (identifier code: IRCT20120215009014N355). Registration date: 2020-05-18.}, }
@article {pmid34113101, year = {2021}, author = {Liu, J and Hou, J and Liu, S and Li, J and Zhou, M and Sun, J and Wang, R}, title = {Graphene Oxide Functionalized Double-Layered Patch with Anti-Adhesion Ability for Abdominal Wall Defects.}, journal = {International journal of nanomedicine}, volume = {16}, number = {}, pages = {3803-3818}, pmid = {34113101}, issn = {1178-2013}, mesh = {Abdominal Wall/*abnormalities ; Animals ; Chitosan/*chemistry ; Collagen/chemistry ; Graphite/*chemistry ; Hernia/*drug therapy/etiology/pathology ; Male ; Nanofibers/*administration &amp; dosage/chemistry ; Polyesters/*administration &amp; dosage/chemistry ; Rats ; Rats, Sprague-Dawley ; Tissue Adhesions/*drug therapy/etiology/pathology ; }, abstract = {BACKGROUND: Effective repair of full-thickness abdominal wall defects requires a patch with sufficient mechanical strength and anti-adhesion characteristics to avoid the formation of hernias and intra-abdominal complications such as intestinal obstruction and fistula. However, patches made from polymers or bio-derived materials may not meet these requirements and lack the bionic characteristics of the abdominal wall.<br><br>MATERIALS AND METHODS: In this study, we report a consecutive electrospun method for preparing a double-layer structured nanofiber membrane (GO-PCL/CS-PCL) using polycaprolactone (PCL), graphene oxide (GO) and chitosan (CS). To expand the bio-functions (angiogenesis/reducing reactive oxygen species) of the patch (GO-PCL/NAC-CS-PCL), N-acetylcysteine (NAC) was loaded for the repair of full-thickness abdominal wall defects (2&#xd7;1.5cm) in rat model.<br><br>RESULTS: The double-layered patch (GO-PCL/NAC-CS-PCL) showed excellent mechanical strength and biocompatibility. After 2 months, rats treated with the patch exhibited the desired repair effect with no hernia formation, less adhesion (adhesion score: 1.50&#xb1;0.50, P<0.001) and more collagen deposition (percentage of collagen deposition: 34.94%&#xb1;3.31%, P<0.001).<br><br>CONCLUSION: The double-layered nanomembranes presented in this study have good anti-hernia and anti-adhesion effects, as well as improve the microenvironment in vivo. It, therefore, holds good prospects for the repair of abdominal wall defects and provides a promising key as a postoperative anti-adhesion agent.}, }
@article {pmid34110456, year = {2022}, author = {Lorusso, F and Immordino, A and Dispenza, F and Sireci, F and Gallina, S}, title = {A conservative treatment for chronic obstructive sialoadenitis by intraductal instillation of mucolytic, steroids and antibiotic solution.}, journal = {European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery}, volume = {279}, number = {1}, pages = {501-506}, pmid = {34110456}, issn = {1434-4726}, mesh = {Anti-Bacterial Agents ; Conservative Treatment ; Endoscopy ; *Expectorants ; Humans ; Prospective Studies ; *Sialadenitis/diagnosis/drug therapy ; Steroids ; }, abstract = {PURPOSES: Reporting our experience in treating chronic obstructive sialadenitis with a protocol consisting of sialoendoscopy and intraductal instillation of antibiotics, steroids and n-acetyl-cysteine (NAC) solution.<br><br>METHODS: Prospective study of patients with chronic obstructive sialadenitis with no apparent lithiasic obstructions, with recurrent non-lithiasic sialoadenitis and patients with lithiasic sialoadenitis not solved with sialoendoscopy. In all cases, a sialoendoscopy was performed. All the patients affected by lithiasic sialoadenitis where the chronic inflammation was resolved with sialoendoscopy were excluded from the study. The mid-term follow-up was performed at 12&#xa0;months via phone interview, to understand whether patients had developed any further symptoms after the treatment.<br><br>RESULTS: This study included 26 patients. All the patient without sialolithiasis have not reported any symptoms during the follow-up period. Two of those with sialolithiasis have not shown any signs of recurrence. The remaining three patients with non-resolved sialolithiasis had a recurrence of symptoms which were treated again with 1 intraductal administration of betamethasone, gentamicine and NAC, showing immediately a regression of the symptoms.<br><br>CONCLUSIONS: Intraductal administration of gentamicin&#x2009;+&#x2009;NAC&#x2009;+&#x2009;betamethasone seemed effective for the therapy of chronic obstructive sialoadenitis. Our protocol seemed effective also in that cases where it was not possible to remove or detect endoscopically an obstruction. In all these cases we have noticed an increase in the symptom-free time even in cases where it was not possible to remove the stones.}, }
@article {pmid34109428, year = {2021}, author = {Zhang, H and Wang, S and Wang, Y and Lu, A and Hu, C and Yan, C}, title = {DHA ameliorates MeHg‑induced PC12 cell apoptosis by inhibiting the ROS/JNK signaling pathway.}, journal = {Molecular medicine reports}, volume = {24}, number = {2}, pages = {}, pmid = {34109428}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Docosahexaenoic Acids/*pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System/*drug effects ; Methylmercury Compounds/*pharmacology ; PC12 Cells ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Rats ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Recent studies have reported that methylmercury (MeHg) induces neuronal apoptosis, which is accompanied by abnormal neurological development. Despite the important role of docosahexaenoic acid (DHA) in maintaining the structure and function of the brain, as well as improving neuronal apoptosis induced by MeHg, the exact mechanism remains unknown. The present study hypothesized that the reactive oxygen species (ROS)‑mediated JNK signaling pathway may be associated with the protective effect of DHA against MeHg‑induced PC12 cell apoptosis. Cell Counting Kit‑8, TUNEL staining, flow cytometry, ROS detection, PCR and western blot analysis were performed. The results demonstrated that MeHg inhibited the activity of PC12 cells, causing oxidative damage and promoting apoptosis; however, DHA significantly attenuated this effect. Mechanistic studies revealed that MeHg increased intracellular ROS levels and JNK protein phosphorylation, and decreased the expression levels of the anti‑apoptotic protein Bcl‑2, whereas DHA reduced ROS levels and JNK phosphorylation, and increased Bcl‑2 expression. In addition, the ROS inhibitor N‑acetyl‑l‑cysteine (NAC) was used to verify the experimental results. After pretreatment with NAC, expression levels of Bcl‑2, Bax, phosphorylated‑JNK and JNK were assessed. Bcl‑2 protein expression was increased and the Bcl‑2/Bax ratio was increased. Moreover, the high expression levels of phosphorylated‑JNK induced by MeHg were significantly decreased. Based on the aforementioned results, the present study indicated that the effects of DHA against MeHg‑induced PC12 cell apoptosis may be mediated via the ROS/JNK signaling pathway.}, }
@article {pmid34108512, year = {2021}, author = {Yamamoto, K and Opina, A and Sail, D and Blackman, B and Saito, K and Brender, JR and Malinowski, RM and Seki, T and Oshima, N and Crooks, DR and Kishimoto, S and Saida, Y and Otowa, Y and Choyke, PL and Ardenkjær-Larsen, JH and Mitchell, JB and Linehan, WM and Swenson, RE and Krishna, MC}, title = {Real-Time insight into in vivo redox status utilizing hyperpolarized [1-[13]C] N-acetyl cysteine.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {12155}, pmid = {34108512}, issn = {2045-2322}, mesh = {Acetylcysteine/*metabolism ; Animals ; Apoptosis ; Brain/*metabolism ; Carbon Isotopes/*analysis ; Cell Proliferation ; Glutathione/*metabolism ; Humans ; Magnetic Resonance Imaging ; Mice ; Oxidation-Reduction ; Pancreatic Neoplasms/metabolism/*pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {Drastic sensitivity enhancement of dynamic nuclear polarization is becoming an increasingly critical methodology to monitor real-time metabolic and physiological information in chemistry, biochemistry, and biomedicine. However, the limited number of available hyperpolarized [13]C probes, which can effectively interrogate crucial metabolic activities, remains one of the major bottlenecks in this growing field. Here, we demonstrate [1-[13]C] N-acetyl cysteine (NAC) as a novel probe for hyperpolarized [13]C MRI to monitor glutathione redox chemistry, which plays a central part of metabolic chemistry and strongly influences various therapies. NAC forms a disulfide bond in the presence of reduced glutathione, which generates a spectroscopically detectable product that is separated from the main peak by a 1.5 ppm shift. In vivo hyperpolarized MRI in mice revealed that NAC was broadly distributed throughout the body including the brain. Its biochemical transformation in two human pancreatic tumor cells in vitro and as xenografts differed depending on the individual cellular biochemical profile and microenvironment in vivo. Hyperpolarized NAC can be a promising non-invasive biomarker to monitor in vivo redox status and can be potentially translatable to clinical diagnosis.}, }
@article {pmid34103686, year = {2021}, author = {Wang, S and Cao, K and Liao, Y and Zhang, W and Zheng, J and Li, X and Huang, M and Zhong, Y and Hu, X and Chen, D and Wang, Y}, title = {CDCA2 protects against oxidative stress by promoting BRCA1-NRF2 signaling in hepatocellular carcinoma.}, journal = {Oncogene}, volume = {40}, number = {25}, pages = {4368-4383}, pmid = {34103686}, issn = {1476-5594}, mesh = {Animals ; Antioxidants/metabolism ; Apoptosis/physiology ; BRCA1 Protein/*metabolism ; Carcinoma, Hepatocellular/*metabolism/pathology ; Carrier Proteins/*metabolism ; Cell Cycle Proteins/*metabolism ; Cell Line, Tumor ; Cell Proliferation/physiology ; Glutathione/metabolism ; Hep G2 Cells ; Humans ; Liver Neoplasms/*metabolism/pathology ; Male ; Mice ; NF-E2-Related Factor 2/*metabolism ; Nuclear Proteins/*metabolism ; Oxidative Stress/*physiology ; Prognosis ; Reactive Oxygen Species/metabolism ; Signal Transduction/*physiology ; alpha-Fetoproteins/metabolism ; }, abstract = {Hepatocellular carcinoma (HCC) patients mostly suffer from poor survival outcomes. It is necessary to identify effective therapeutic targets to improve prognosis for HCC patients. Here, we report a new factor, CDCA2, in promoting HCC development. CDCA2 amplification is an independent risk factor for the recurrence and survival of HCC patients, which is positively correlated with elevated level of alpha-fetoprotein (AFP), high histological grade, large tumor size, advanced TNM stage, and poor prognosis for HCC patients. In HCC cells, CDCA2 promotes cell growth and inhibits apoptosis. Mechanistically, CDCA2's transcription is activated through the binding of E2F2/E2F8 with its promoter. CDCA2 depletion contributes to the suppression of cell proliferation and induction of apoptosis due to reactive oxygen species (ROS)-mediated stress, which can be reversed by antioxidants N-acetyl cysteine (NAC) and glutathione (GSH). Interestingly, we found that CDCA2 triggers the BRCA1-NRF2 cascade, which elevates antioxidant response and attenuates ROS levels. In response to oxidative stress, CDCA2 promotes BRCA1's chromatin relocalization to NRF2, activating NRF2-driven downstream signaling (HO-1, TXNRD1, and NQO1), which then protects HCC cells against oxidative damage. In conclusion, our results reveal that CDCA2 is a prognostic biomarker for HCC patients, and present the E2F2/E2F8-CDCA2-BRCA1-NRF2-ROS signaling axis that have implications for HCC therapeutics.}, }
@article {pmid34102208, year = {2021}, author = {Liu, X and Liu, H and Lu, X and Zhao, S}, title = {N-acetylcysteine alleviates ocular surface damage in STZ-induced diabetic mice by inhibiting the ROS/NLRP3/Caspase-1/IL-1β signaling pathway.}, journal = {Experimental eye research}, volume = {209}, number = {}, pages = {108654}, doi = {10.1016/j.exer.2021.108654}, pmid = {34102208}, issn = {1096-0007}, mesh = {Animals ; Blotting, Western ; Caspase 1/biosynthesis/*genetics ; Conjunctiva/*metabolism/pathology ; Cornea/*metabolism/pathology ; Diabetes Mellitus, Experimental/*genetics/metabolism ; *Gene Expression Regulation ; Inflammasomes/genetics/metabolism ; Interleukin-1beta/biosynthesis/*genetics ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/biosynthesis/*genetics ; RNA/genetics ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Diabetes mellitus (DM) induces damage to the ocular surface, which leads to vision decline. In the current study, we investigated whether N-acetylcysteine (NAC) plays a protective role in diabetes-induced ocular surface damage. The diabetic mice model was treated with 0.3% NAC topically. Corneal epithelial integrity, tear volume and corneal sensitivity were examined by sodium fluorescein staining, phenol red cotton thread and esthesiometer respectively. The level of reactive oxygen species (ROS) was measured with 2',7-dichlorofluorescein diacetate. The expression of NLRP3, IL-1β and caspase-1 were evaluated by RT-PCR, western blot and immunostaining. The level of SOD1 was assessed by RT-PCR. We found that the expression of NLRP3, IL-1β and caspase-1 were elevated in diabetic cornea and conjunctiva. Treatment with NAC improved corneal epithelial integrity, increased tear production and corneal sensitivity in diabetic mice. Moreover, NAC markedly attenuated ROS accumulation and decreased NLRP3, IL-1β and caspase-1 levels in diabetic cornea and conjunctiva. These results suggest that NAC improves ocular surface damage in STZ-induced diabetic mice, which may be related to the inhibition of the ROS/NLRP3/Caspase-1/IL-1β signaling pathway.}, }
@article {pmid34100091, year = {2021}, author = {Sriphongphankul, H and Liabsuetrakul, T and Osatakul, S}, title = {Clinical Outcomes of Children Diagnosed Dengue-Associated Acute Liver Failure with or without N-Acetylcysteine Treatment: A Retrospective Cohort Study.}, journal = {Journal of tropical pediatrics}, volume = {67}, number = {2}, pages = {}, doi = {10.1093/tropej/fmab039}, pmid = {34100091}, issn = {1465-3664}, mesh = {Acetylcysteine/therapeutic use ; Child ; *Dengue/complications/diagnosis/drug therapy ; Humans ; *Liver Failure, Acute/drug therapy/etiology ; Microcirculation ; Retrospective Studies ; Thailand ; }, abstract = {OBJECTIVES: N-acetylcysteine (NAC) has been shown to prevent hepatic damage and improve microcirculatory blood flow and oxygen delivery to the tissue. Previous studies have proposed the benefit of NAC in dengue-associated acute liver failure (ALF). However, most studies are descriptive and lack comparison between groups. We aimed to compare the ALF resolution rate and mortality rate of those who received and did not receive NAC treatment.<br><br>METHODS: A retrospective cohort study was conducted among children aged <15&#x2009;years who were diagnosed with dengue-associated ALF at a tertiary hospital in Thailand, between January 2002 and July 2019. Demographic and clinical information were collected. Main outcomes were ALF resolution and mortality rate.<br><br>RESULTS: Thirty-three patients were included of which 16 received NAC treatment (48.5%). Mean ages were 8.5&#x2009;years (SD 3.7) and mean onset of ALF was 6.3&#x2009;days (SD 1.6) after onset of fever. The grading of hepatic encephalopathy (HE) and organ failure was not significantly different between the two groups. In the NAC group, 13/16 children were prescribed 100&#x2009;mg/kg/day of NAC until INR <2 without HE or <1.5 with HE. NAC was initiated 1.1&#x2009;days (SD 0.3) after the ALF diagnosis. The NAC group showed a higher rate of ALF resolution (75% vs. 53% in the non-NAC group, p&#x2009;=&#x2009;0.34) with a lower mortality rate (31% vs. 53%, p&#x2009;=&#x2009;0.36). Side effects of NAC were not found.<br><br>CONCLUSION: NAC may be beneficial in dengue-associated pediatric ALF. Further well-designed randomized control trials should be carried out.}, }
@article {pmid34096834, year = {2021}, author = {Han, L and Jia, Y and Zhao, Y and Sun, C and Zhao, M and Peng, Y and Zheng, J}, title = {Metabolic activation of zolmitriptan mediated by CYP2D6.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {51}, number = {11}, pages = {1292-1302}, doi = {10.1080/00498254.2021.1938290}, pmid = {34096834}, issn = {1366-5928}, mesh = {Activation, Metabolic ; Animals ; *Cytochrome P-450 CYP2D6/metabolism ; Glutathione/metabolism ; *Microsomes, Liver/metabolism ; Oxazolidinones ; Rats ; Tryptamines ; }, abstract = {Zolmitriptan (ZOL), a member of triptans, has been used for the treatment of migraine with definite therapeutic effects. However, several cases of liver injury associated with ZOL have been reported and the underlying mechanisms remain unclear.The present study aimed to investigate the metabolic activation of ZOL in vitro and in vivo. ZOL-derived glutathione (GSH) and N-acetyl cysteine (NAC) conjugates were detected in rat liver microsomal incubations. In addition, the GSH and NAC conjugates were also found in bile and urine of rats given ZOL, respectively.ZOL-derived GSH conjugate M1 was also observed in ZOL-treated rat primary hepatocytes, and the formation of M1 was inhibited by pre-cultured with quinidine (a selective inhibitor of CYP2D6). Combining with recombinant P450 enzymes incubations, we found that CYP2D6 was the predominant enzyme responsible for the metabolic activation of ZOL.ZOL can be metabolized to an α,β-unsaturated imine intermediate by CYP2D6. Pre-treatment of primary hepatocytes with quinidine was able to reverse ZOL-induced cytotoxicity. The finding facilitates the understanding of the mechanisms involved in ZOL-associated liver adverse reactions.}, }
@article {pmid34094961, year = {2021}, author = {Cheng, Z and Yu, S and He, W and Li, J and Xu, T and Xue, J and Shi, P and Chen, S and Li, Y and Hong, S and Xiao, H}, title = {Selenite Induces Cell Cycle Arrest and Apoptosis via Reactive Oxygen Species-Dependent Inhibition of the AKT/mTOR Pathway in Thyroid Cancer.}, journal = {Frontiers in oncology}, volume = {11}, number = {}, pages = {668424}, pmid = {34094961}, issn = {2234-943X}, abstract = {Thyroid cancer is the most common endocrine malignancy, and its incidence has increased in the past decades. Selenium has been shown to have therapeutic effects against several tumors. However, its role in thyroid cancer and its underlying molecular mechanism remains to be explored. In the present study, we demonstrated that sodium selenite significantly decreased cell viability and induced G0/G1 cell cycle arrest and apoptosis in thyroid cancer cells in a dose-dependent manner. Transcriptomics revealed that sodium selenite induced intracellular reactive oxygen species (ROS) by promoting oxidative phosphorylation. Increased intracellular ROS levels inhibited the AKT/mTOR signaling pathway and upregulated EIF4EBP3. Intracellular ROS inhibition by N-acetylcysteine (NAC) ameliorated the cellular effects of sodium selenite. The in vitro findings were reproduced in xenograft thyroid tumor models. Our data demonstrated that sodium selenite exhibits strong anticancer effects against thyroid cancer cells, which involved ROS-mediated inhibition of the AKT/mTOR pathway. This suggests that sodium selenite may serve as a therapeutic option for advanced thyroid cancer.}, }
@article {pmid34094467, year = {2020}, author = {Wang, H and Yu, D and Fang, J and Zhou, Y and Li, D and Liu, Z and Ren, J and Qu, X}, title = {Phenol-like group functionalized graphene quantum dots structurally mimicking natural antioxidants for highly efficient acute kidney injury treatment.}, journal = {Chemical science}, volume = {11}, number = {47}, pages = {12721-12730}, pmid = {34094467}, issn = {2041-6520}, abstract = {Acute kidney injury (AKI) is a syndrome characterized by rapid loss of renal excretory function with high in-hospital mortality. The excess generation of reactive oxygen species (ROS) in the kidneys during AKI has been considered a major cause of renal failure. Currently available antioxidants for AKI treatment often lack the required antioxidative efficacy or renal accumulation rate. Herein, inspired by the structure of natural phenolic antioxidants, phenol-like group functionalized graphene quantum dots (h-GQDs) with both high ROS scavenging efficacy and renal specificity are constructed for AKI antioxidative therapy. Similar to natural polyphenols, the abundant phenol-like groups on h-GQDs are demonstrated to be the active components exerting antioxidative effects. Further exhaustive mechanistic investigations indicate that the ultrahigh antioxidative activity of h-GQDs originates not solely from the phenol-like groups, but also from the synergy between adjacent phenol-like groups, as well as the removal of unfavorable carbonyl groups on h-GQDs. In AKI mice, h-GQDs can effectively protect the kidneys from oxidative injury with only a one-sixteenth dose of the clinical antioxidant N-acetylcysteine (NAC) and show no evidence of toxicity. The findings of this study will facilitate development of high-performance carbon-based antioxidative platforms via structure-activity relationships for treating AKI and other ROS-related diseases.}, }
@article {pmid34094429, year = {2020}, author = {Zhou, Y and Li, P and Wang, X and Wu, C and Fan, N and Liu, X and Wu, L and Zhang, W and Zhang, W and Liu, Z and Tang, B}, title = {In situ visualization of peroxisomal viscosity in the liver of mice with non-alcoholic fatty liver disease by near-infrared fluorescence and photoacoustic imaging.}, journal = {Chemical science}, volume = {11}, number = {44}, pages = {12149-12156}, pmid = {34094429}, issn = {2041-6520}, abstract = {Non-alcoholic fatty liver disease (NAFLD) can gradually develop into hepatic failure, and early diagnosis is crucial to improve treatment efficiency. The occurrence of NAFLD is closely related to lipid metabolism. Peroxisomes act as the first and main site for lipid metabolism in the hepatocytes, so abnormal lipid metabolism might directly affect peroxisomal viscosity. Herein, we developed a new near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging probe (PV-1) for the real-time visualization of peroxisomal viscosity in vivo. This PV-1 encompasses the malononitrile group as the rotor, which emits strong NIRF (at 705 nm) and PA (at 680 nm) signals when rotation is hindered as viscosity increases. Through dual-mode imaging, we discovered distinctly higher viscosity in the liver of NAFLD mice for the first time. We further found the remarkable amelioration of NAFLD upon treatment with N-acetylcysteine (NAC). Therefore, we anticipate that the PV-1 imaging method is promising for the early diagnosis and prognostic evaluation of NAFLD.}, }
@article {pmid34091880, year = {2021}, author = {Smaga, I and Frankowska, M and Filip, M}, title = {N-acetylcysteine in substance use disorder: a lesson from preclinical and clinical research.}, journal = {Pharmacological reports : PR}, volume = {73}, number = {5}, pages = {1205-1219}, pmid = {34091880}, issn = {2299-5684}, support = {Statutory funds//Instytut Farmakologii, Polskiej Akademii Nauk/ ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Drug-Seeking Behavior/*drug effects ; Expectorants/*therapeutic use ; Extinction, Psychological/*drug effects ; Humans ; Substance-Related Disorders/*drug therapy ; }, abstract = {Substance use disorder (SUD) is a chronic brain condition, with compulsive and uncontrollable drug-seeking that leads to long-lasting and harmful consequences. The factors contributing to the development of SUD, as well as its treatment settings, are not fully understood. Alterations in brain glutamate homeostasis in humans and animals implicate a key role of this neurotransmitter in SUD, while the modulation of glutamate transporters has been pointed as a new strategy to diminish the excitatory glutamatergic transmission observed after drugs of abuse. N-acetylcysteine (NAC), known as a safe mucolytic agent, is involved in the regulation of this system and may be taken into account as a novel pharmacotherapy for SUD. In this paper, we summarize the current knowledge on the ability of NAC to reduce drug-seeking behavior induced by psychostimulants, opioids, cannabinoids, nicotine, and alcohol in animals and humans. Preclinical studies showed a beneficial effect in animal models of SUD, while the clinical efficacy of NAC has not been fully established. In summary, NAC will be a small add-on to usual treatment and/or psychotherapy for SUD, however, further studies are required.}, }
@article {pmid34090464, year = {2021}, author = {Javaherforooshzadeh, F and Shaker, Z and Rashidi, M and Akhondzadeh, R and Hayati, F}, title = {The effect of N-acetyl cysteine injection on renal function after coronary artery bypass graft surgery: a randomized double blind clinical trial.}, journal = {Journal of cardiothoracic surgery}, volume = {16}, number = {1}, pages = {161}, pmid = {34090464}, issn = {1749-8090}, support = {PAIN-9817//Ahvaz Jundishapur University of Medical Sciences/ ; }, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/diagnosis/epidemiology/etiology/*prevention &amp; control ; Adult ; Aged ; Antioxidants/*therapeutic use ; *Coronary Artery Bypass ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Injections, Intravenous ; Kidney Function Tests ; Male ; Middle Aged ; Perioperative Care/methods ; Postoperative Complications/diagnosis/epidemiology/*prevention &amp; control ; Treatment Outcome ; }, abstract = {BACKGROUND: This study aimed to compare the effects of N-acetyl cysteine on renal function after coronary artery bypass graft surgery.<br><br>METHODS: In this randomized clinical trial conducted in Golestan Hospital, Ahvaz, Iran, 60 candidates for coronary artery bypass graft surgery were selected and divided into two N-acetyl cysteine and control groups (30 people each). Patients received 3 (2 intraoperative and 1 postoperative) doses of IV N-acetyl cysteine (100&#x2009;mg/kg) (n&#x2009;=&#x2009;30) or placebo (n&#x2009;=&#x2009;30) over 24&#x2009;h. Prescription times were as follows: after induction of anesthesia, in the Next 4&#x2009;h, and in the 16&#x2009;h after on. Primary outcomes were serum levels of BUN and Cr, at baseline,4 and 48&#x2009;h after surgery. And also need renal replacement therapy (RRT). Secondary outcomes included the hemodynamic variables, Blood products transfusion.<br><br>RESULTS: There were significant differences in BUN between groups at 4&#x2009;h (P&#x2009;=&#x2009;0.02) and 48&#x2009;h after surgery (P&#x2009;=&#x2009;0.001) There were significant differences in Cr level between groups at 4&#x2009;h (P&#x2009;<&#x2009;0.001) and 48&#x2009;h after surgery (P&#x2009;=&#x2009;0.001). MAP at different times (at 4&#x2009;h p&#x2009;=&#x2009;0.002 and 48&#x2009;h after surgery P&#x2009;<&#x2009;0.001) were significantly different between the two groups. There was a significant difference between the two groups in terms of the unit of Packed cell transfusion (P&#x2009;=&#x2009;0.002) and FFP transfusion (P&#x2009;<&#x2009;0.001).<br><br>CONCLUSION: In the present study, we found that administration of N-acetyl cysteine can reduce the incidence of acute kidney injury in patients undergoing coronary artery bypass graft surgery and improved kidney functions.<br><br>TRIAL REGISTRY: IRCT20190506043492N3 Registered at 2020.06.07.}, }
@article {pmid34081988, year = {2021}, author = {Ulger, O and Kubat, GB and Cicek, Z and Celik, E and Atalay, O and Suvay, S and Ozler, M}, title = {The effects of mitochondrial transplantation in acetaminophen-induced liver toxicity in rats.}, journal = {Life sciences}, volume = {279}, number = {}, pages = {119669}, doi = {10.1016/j.lfs.2021.119669}, pmid = {34081988}, issn = {1879-0631}, mesh = {Acetaminophen/*toxicity ; Analgesics, Non-Narcotic/toxicity ; Animals ; Chemical and Drug Induced Liver Injury/etiology/pathology/*therapy ; Glutathione/*metabolism ; *Lipid Peroxidation ; Male ; Mitochondria/*transplantation ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIMS: Acetaminophen (APAP) toxicity is one of the leading causes of acute liver injury-related death and liver failure worldwide. In many studies, mitochondrial dysfunction has been identified as an important cause of damage in APAP toxicity. Therefore, our study aimed to investigate the possible effects of mitochondrial transplantation on liver damage due to APAP toxicity.<br><br>MAIN METHODS: APAP toxicity model was implemented by administering a toxic dose of APAP. To demonstrate the efficiency of mitochondria transplantation, it was compared with N-acetylcysteine (NAC) application, which is now clinically accepted. Mitochondrial transplantation was carried out by delivering mitochondria to the liver via the portal circulation, which was injected into the spleen. In our study, the rats were randomly divided into 6 groups as Sham, APAP, Control 1, APAP+mito, Control 2, and APAP+NAC. In the end of the experiment, histological and biochemical analysis were performed and the biodistribution of the transplanted mitochondria to target cells were also shown.<br><br>KEY FINDINGS: Successful mitochondrial transplantation was confirmed and mitochondrial transplantation improved the liver histological structure to a similar level with healthy rats. Moreover, plasma ALT levels, apoptotic cells, and total oxidant levels were decreased. It was also observed that NAC treatment increased GSH levels to the highest level among the groups. However, mitochondrial transplantation was more effective than NAC application in terms of histological and functional improvement.<br><br>SIGNIFICANCE: It has been evaluated that mitochondrial transplantation can be used as an important alternative or adjunctive treatment method in liver damage caused by toxic dose APAP intake.}, }
@article {pmid34080409, year = {2021}, author = {Li, Y and Yang, J and Feng, Q and Li, SQ and Lang, Y and Zhang, XF and Ye, C}, title = {High cyclic tensile stress disrupts the extracellular matrix in human chondrocyte by F-actin cytoskeletal polymerization and reactive oxygen species production.}, journal = {Journal of biological regulators and homeostatic agents}, volume = {35}, number = {3}, pages = {965-974}, doi = {10.23812/21-105-A}, pmid = {34080409}, issn = {0393-974X}, mesh = {Actin Cytoskeleton ; *Actins ; Cells, Cultured ; *Chondrocytes ; Extracellular Matrix ; Humans ; Polymerization ; Reactive Oxygen Species ; }, abstract = {This study aims to explore the mechanism of cyclic tensile stress (CTS) on human chondrocytes (CHs) relating to the reactive oxygen species (ROS) generation and extracellular matrix (ECM) stability in vitro. A well-established CTS model with 5%, 10%, or 20% elongation was performed for CHs stretching. After CTS, the cell viability, total ROS level, main ECM components, matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), F-actin density, and some anti-oxidative enzymes were analyzed. Additionally, the antioxidant N-acetylcysteine (NAC) and cytochalasin D were used to suppress the ROS production and F-actin polymerization when the CHs underwent CTS, respectively. The treatment of 20% elongation-CST significantly decreased the CH viability and the expressions of collagen II, aggrecan, anti-oxidative enzymes and TIMP3/4, however, it increased the ROS accumulation, F-actin polymerization, and the expression of collagen I and MMP3/13. In contrast, the application of NAC and cytochalasin D could partly rescue the CHs from the injury caused by the high CTS. Therefore, high CTS disrupts the ECM by remodeling the F-actin cytoskeleton and promoting ROS production. Cytochalasin D and NAC are effective in rejecting F-actin cytoskeleton polymerization, and ROS accumulation through a potential synergetic process, which alleviates the ECM injury caused by High CTS.}, }
@article {pmid34080202, year = {2021}, author = {Shafie, B and Pourahmad, J and Rezaei, M}, title = {N-acetylcysteine is more effective than ellagic acid in preventing acrolein induced dysfunction in mitochondria isolated from rat liver.}, journal = {Journal of food biochemistry}, volume = {45}, number = {7}, pages = {e13775}, doi = {10.1111/jfbc.13775}, pmid = {34080202}, issn = {1745-4514}, mesh = {*Acetylcysteine/pharmacology ; *Acrolein/toxicity ; Animals ; Cell Survival ; Ellagic Acid/pharmacology ; Liver ; Mitochondria ; Rats ; }, abstract = {Acrolein, a common environmental, food, and water pollutant, has been linked to the pathology of several diseases. This toxic substance is an unsaturated aldehyde and a major component of cigarette smoke and also produced during the processing of fat-containing foods. This study aimed to evaluate the protective effect of ellagic acid and N-acetylcysteine (NAC) in acrolein-induced toxicity in mitochondria isolated from the rat liver. The mitochondria were exposed to different concentrations of acrolein for 40 min, then functionality was assessed. Contact with acrolein rapidly and remarkably depleted the intracellular glutathione and antioxidant capacity, because of increased ROS production and lipid peroxidation which may lead to the cell death. Mitochondria were then pre-exposed to different concentrations of ellagic acid, NAC, and IC50 concentration of acrolein. Consistent with the results, acrolein decreased GSH content and increased ROS level and lipid peroxidation, which led to ATP depletion and mitochondrial dysfunction. While ellagic acid has been able to reduce ROS and therefore the permeability of the mitochondrial membrane potential (MMP), presumably via its antioxidant properties, we've not detected its favorable effect on GSH and ATP restoration and also on mitochondrial complex II function. However, NAC strongly decreased ROS, lipid peroxidation and MMP and improved GSH content and complex II activity. These results showed that ellagic acid while reported to possess some cellular protective properties, did not prevent mitochondria from being affected by acrolein during this in vitro study. PRACTICAL APPLICATIONS: Ellagic acid is found in fruits, vegetables, and nuts which are revealed to possess strong antioxidant and protective properties. Mitochondrial dysfunction has been implicated in the pathogenesis of some chronic diseases including cancer, diabetes, liver disease, and neurodegenerative disorders, and presumably, ellagic acid by its mitochondrial protective effects can be helpful in these chronic conditions. Acrolein is an α,β-unsaturated aldehyde that can be produced during cooking at high temperature. By increasing the ROS level and lipid peroxidation and depleting the glutathione content, acrolein induces cellular damage and mitochondrial toxicity. This toxicant is taken into account as a carcinogen and mutagen. In this study, the protective effect of ellagic acid in comparison with N-acetylcysteine has been investigated during the toxicity of acrolein in the rat liver mitochondria to look for evidence of whether it is useful or not through this insult.}, }
@article {pmid34080015, year = {2021}, author = {Dwir, D and Cabungcal, JH and Xin, L and Giangreco, B and Parietti, E and Cleusix, M and Jenni, R and Klauser, P and Conus, P and Cuénod, M and Steullet, P and Do, KQ}, title = {Timely N-Acetyl-Cysteine and Environmental Enrichment Rescue Oxidative Stress-Induced Parvalbumin Interneuron Impairments via MMP9/RAGE Pathway: A Translational Approach for Early Intervention in Psychosis.}, journal = {Schizophrenia bulletin}, volume = {47}, number = {6}, pages = {1782-1794}, pmid = {34080015}, issn = {1745-1701}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Animals ; Combined Modality Therapy ; Disease Models, Animal ; *Exercise Therapy ; Female ; Glutamate-Cysteine Ligase/deficiency ; Humans ; Interneurons/*drug effects/metabolism ; Male ; Matrix Metalloproteinase 9/*drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidative Stress/*drug effects ; Parvalbumins/metabolism ; Psychotic Disorders/drug therapy/metabolism/*therapy ; Receptor for Advanced Glycation End Products/*drug effects ; Signal Transduction/drug effects ; Translational Research, Biomedical ; }, abstract = {Research in schizophrenia (SZ) emphasizes the need for new therapeutic approaches based on antioxidant/anti-inflammatory compounds and psycho-social therapy. A hallmark of SZ is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory/cognitive processing. Oxidative stress and inflammation during early brain development, as observed in SZ, affect PVI maturation. We compared the efficacy of N-acetyl-cysteine (NAC) and/or environmental enrichment (EE) provided during juvenile and/or adolescent periods in rescuing PVI impairments induced by an additional oxidative insult during childhood in a transgenic mouse model with gluthation deficit (Gclm KO), relevant for SZ. We tested whether this rescue was promoted by the inhibition of MMP9/RAGE mechanism, both in the mouse model and in early psychosis (EP) patients, enrolled in a double-blind, randomized, placebo-controlled clinical trial of NAC supplementation for 6 months. We show that a sequential combination of NAC+EE applied after an early-life oxidative insult recovers integrity and function of PVI network in adult Gclm KO, via the inhibition of MMP9/RAGE. Six-month NAC treatment in EP patients reduces plasma sRAGE in association with increased prefrontal GABA, improvement of cognition and clinical symptoms, suggesting similar neuroprotective mechanisms. The sequential combination of NAC+EE reverses long-lasting effects of an early oxidative insult on PVI/perineuronal net (PNN) through the inhibition of MMP9/RAGE mechanism. In analogy, patients vulnerable to early-life insults could benefit from a combined pharmacological and psycho-social therapy.}, }
@article {pmid34079685, year = {2021}, author = {Gadour, E and Mohamed, T and Hassan, Z and Hassan, A}, title = {Meta-Analysis and Systematic Review of Primary Renal Tubular Acidosis in Patients With Autoimmune Hepatitis and Alcoholic Hepatitis.}, journal = {Cureus}, volume = {13}, number = {5}, pages = {e15287}, pmid = {34079685}, issn = {2168-8184}, abstract = {Renal and hepatic functions are often mingled through both the existence of associated primary organ diseases and hemodynamic co-relationship. The primary objective of this study was to sum up the relationship between autoimmune hepatitis (AIH) on renal tubular acidosis (RTA) and the stages of the disease. A systematic review was performed for 24 trials. A total of 3687 patients were included. The incidence of RTA occurring and short-term mortality reduction was seen in two groups; for an overall effect: Z = 2.85 (P = 0.004) a total 95% CI of 0.53 [0.34, 0.82]. Only one patient with alcoholic liver cirrhosis was found to have an incomplete type of RTA. Test for overall effect: Z = 2.28 (P = 0.02) 95% CI of 2.83 [1.16, 6.95]. A reduction in fatal infections with dual therapy of corticosteroid plus N-acetylcysteine (NAC) test for overall effect: Z = 3.07 (P = 0.002) with 95% CI of 0.45 [0.27, 0.75]. Autoimmune diseases are the most frequent underlying cause of secondary RTA in adults. The primary renal disease must be actively excluded in all patients with hepatic failure by aggressive clinical and laboratory evaluations.}, }
@article {pmid34078255, year = {2021}, author = {Huang, Y and Wen, Q and Huang, J and Luo, M and Xiao, Y and Mo, R and Wang, J}, title = {Manganese (II) chloride leads to dopaminergic neurotoxicity by promoting mitophagy through BNIP3-mediated oxidative stress in SH-SY5Y cells.}, journal = {Cellular &amp; molecular biology letters}, volume = {26}, number = {1}, pages = {23}, pmid = {34078255}, issn = {1689-1392}, support = {81460181//National Natural Science Foundation of China/ ; }, mesh = {Cell Line, Tumor ; Chlorides/*adverse effects/metabolism ; Humans ; Manganese Compounds/*adverse effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Membrane Proteins/*metabolism ; Mitophagy/*drug effects ; Neurons/drug effects/metabolism ; Oxidative Stress/*drug effects ; Parkinsonian Disorders/chemically induced/metabolism ; Proto-Oncogene Proteins/*metabolism ; }, abstract = {BACKGROUND: Manganese overexposure can induce neurotoxicity, lead to manganism and result in clinical manifestations similar to those of parkinsonism. However, the underlying molecular mechanism is still unclear. This study demonstrated that MnCl2 induces mitophagy and leads to neurotoxicity by promoting BNIP3-mediated reactive oxygen species (ROS) generation.<br><br>METHODS: Human neuroblastoma SH-SY5Y cells were used throughout our experiments. Cell viability was detected by cell proliferation/toxicity test kits. Mitochondrial membrane potential was measured by flow cytometry. ROS generation was detected using a microplate reader. Protein levels were evaluated by Western blot. Transmission electron microscopy was used to evaluate mitochondrial morphology. Co-immunoprecipitation was used to verify the interaction between BNIP3 and LC3.<br><br>RESULTS: MnCl2 led to loss of mitochondrial membrane potential and apoptosis of SH-SY5Y cells by enhancing expression of BNIP3 and conversion of LC3-I to LC3-II. Moreover, MnCl2 reduced expression of the mitochondrial marker protein TOMM20 and promoted interaction between BNIP3 and LC3. The results also indicated that a decrease in BNIP3 expression reduced the mitochondrial membrane potential loss, attenuated apoptosis and reduced mitochondrial autophagosome formation in SH-SY5Y cells after MnCl2 treatment. Finally, we found that manganese-induced ROS generation could be reversed by the antioxidant N-acetyl cysteine (NAC) or silencing BNIP3 expression.<br><br>CONCLUSIONS: BNIP3 mediates MnCl2-induced mitophagy and neurotoxicity in dopaminergic SH-SY5Y cells through ROS. Thus, BNIP3 contributes to manganese-induced neurotoxicity by functioning as a mitophagy receptor protein.}, }
@article {pmid34074016, year = {2021}, author = {Li, Y and Tang, T and Lee, H and Song, K}, title = {Cold Atmospheric Pressure Plasma-Activated Medium Induces Selective Cell Death in Human Hepatocellular Carcinoma Cells Independently of Singlet Oxygen, Hydrogen Peroxide, Nitric Oxide and Nitrite/Nitrate.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34074016}, issn = {1422-0067}, support = {NRF2020R1A2C1102153//National Research Foundation of Korea/ ; NRF2016M3A9C6918275//National Research Foundation of Korea/ ; }, mesh = {Acetylcysteine/pharmacology ; Aluminum/pharmacology ; Antineoplastic Agents/*pharmacology ; Atmospheric Pressure ; Carcinoma, Hepatocellular/*drug therapy/metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Free Radicals/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Liver Neoplasms/*drug therapy/metabolism ; Neoplastic Stem Cells/drug effects/metabolism ; Nitrates/*pharmacology ; Nitric Oxide/metabolism ; Nitrites/*pharmacology ; Plasma Gases/*pharmacology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Singlet Oxygen/metabolism ; }, abstract = {Cold atmospheric pressure plasma (CAP) and plasma-activated medium (PAM) induce cell death in diverse cancer cells and may function as powerful anti-cancer agents. The main components responsible for the selective anti-cancer effects of CAP and PAM remain elusive. CAP or PAM induces selective cell death in hepatocellular carcinoma cell lines Hep3B and Huh7 containing populations with cancer stem cell markers. Here, we investigated the major component(s) of CAP and PAM for mediating the selective anti-proliferative effect on Hep3B and Huh7 cells. The anti-proliferative effect of CAP was mediated through the medium; however, the reactive oxygen species scavenger N-acetyl cysteine did not suppress PAM-induced cell death. Neither high concentrations of nitrite or nitrite/nitrate nor a low concentration of H2O2 present in the PAM containing sodium pyruvate affected the viability of Hep3B and Huh7 cells. Inhibitors of singlet oxygen, superoxide anions, and nitric oxide retained the capacity of PAM to induce anti-cancer effects. The anti-cancer effect was largely blocked in the PAM prepared by placing an aluminum metal mesh, but not a dielectric PVC mesh, between the plasma source and the medium. Hence, singlet oxygen, hydrogen peroxide, nitric oxide, and nitrite/nitrate are not the main factors responsible for PAM-mediated selective death in Hep3B and Huh7 cells. Other factors, such as charged particles including various ions in CAP and PAM, may induce selective anti-cancer effects in certain cancer cells.}, }
@article {pmid34072255, year = {2021}, author = {Damri, O and Natour, S and Agam, G}, title = {Do Autophagy Enhancers/ROS Scavengers Alleviate Consequences of Mild Mitochondrial Dysfunction Induced in Neuronal-Derived Cells?.}, journal = {International journal of molecular sciences}, volume = {22}, number = {11}, pages = {}, pmid = {34072255}, issn = {1422-0067}, support = {745/15//Israel Science Foundation/ ; }, mesh = {Adenosine Triphosphate/metabolism ; Apoptosis ; *Autophagy ; Cell Line, Tumor ; Cell Survival/drug effects/genetics ; Disease Susceptibility ; Electron Transport Complex I/metabolism ; Humans ; Mitochondria/*genetics/*metabolism ; Neurons/*metabolism ; Oxidative Phosphorylation ; Reactive Oxygen Species/*metabolism ; }, abstract = {Mitochondrial function is at the nexus of pathways regulating synaptic-plasticity and cellular resilience. The involvement of brain mitochondrial dysfunction along with increased reactive oxygen species (ROS) levels, accumulating mtDNA mutations, and attenuated autophagy is implicated in psychiatric and neurodegenerative diseases. We have previously modeled mild mitochondrial dysfunction assumed to occur in bipolar disorder (BPD) using exposure of human neuronal cells (SH-SY5Y) to rotenone (an inhibitor of mitochondrial-respiration complex-I) for 72 and 96 h, which exhibited up- and down-regulation of mitochondrial respiration, respectively. In this study, we aimed to find out whether autophagy enhancers (lithium, trehalose, rapamycin, and resveratrol) and/or ROS scavengers [resveratrol, N-acetylcysteine (NAC), and Mn-Tbap) can ameliorate neuronal mild mitochondrial dysfunction. Only lithium (added for the last 24/48 h of the exposure to rotenone for 72/96 h, respectively) counteracted the effect of rotenone on most of the mitochondrial respiration parameters (measured as oxygen consumption rate (OCR)). Rapamycin, resveratrol, NAC, and Mn-Tbap counteracted most of rotenone's effects on OCR parameters after 72 h, possibly via different mechanisms, which are not necessarily related to their ROS scavenging and/or autophagy enhancement effects. The effect of lithium reversing rotenone's effect on OCR parameters is compatible with lithium's known positive effects on mitochondrial function and is possibly mediated via its effect on autophagy. By-and-large it may be summarized that some autophagy enhancers/ROS scavengers alleviate some rotenone-induced mild mitochondrial changes in SH-SY5Y cells.}, }
@article {pmid34067571, year = {2021}, author = {Chen, J and Chen, Y and Zheng, Y and Zhao, J and Yu, H and Zhu, J and Li, D}, title = {Neuroprotective Effects and Mechanisms of Procyanidins In Vitro and In Vivo.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {10}, pages = {}, pmid = {34067571}, issn = {1420-3049}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidant Response Elements ; Antioxidants/metabolism ; Glutathione Peroxidase/metabolism ; Heme Oxygenase-1/metabolism ; Hydrogen Peroxide/pharmacology ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-E2 Transcription Factor/metabolism ; Neuroprotective Agents/metabolism/pharmacology ; Oxidative Stress/drug effects ; PC12 Cells ; Proanthocyanidins/*metabolism/*pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Zebrafish/metabolism ; }, abstract = {This study evaluated the neuroprotective effects and mechanisms of procyanidins (PCs). In vitro, rat pheochromocytoma cells (PC12 cells) were exposed to PCs (1, 2 or 4 μg/mL) or N-Acetyl-L-cysteine (NAC) (20 μM) for 24 h, and then incubated with 200 μM of H2O2 for 24 h. Compared with H2O2 alone, PCs significantly increased antioxidant activities (e.g., glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT)), decreased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and increased nuclear factor-erythroid 2-related factor 2 (Nrf2) accumulation and increased the expression of quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC). In vivo, zebrafish larvae (AB strain) 3 days post-fertilization (dpf) were exposed to NAC (30 μM) or PCs (4, 8 or 16 μg/mL) in the absence or presence of 300 μM of H2O2 for 4 days. Compared with H2O2 alone, PCs enhanced antioxidant activities (e.g., GSH-Px, CAT, and SOD), decreased levels of ROS and MDA, and enhanced Nrf2/ antioxidant response element (ARE) activation and raised expression levels of NQO1, HO-1, GCLM, and GCLC. In conclusion, these results indicated that PCs exerted neuroprotective effects via activating the Nrf2/ARE pathway and alleviating oxidative damage.}, }
@article {pmid34065411, year = {2021}, author = {Kang, HK and Sarsenova, M and Kim, DH and Kim, MS and Lee, JY and Sung, EA and Kook, MG and Kim, NG and Choi, SW and Ogay, V and Kang, KS}, title = {Establishing a 3D In Vitro Hepatic Model Mimicking Physiologically Relevant to In Vivo State.}, journal = {Cells}, volume = {10}, number = {5}, pages = {}, pmid = {34065411}, issn = {2073-4409}, support = {2020R1A4A4078907//National Research Foundation of Korea/ ; HI18C0421//Ministry of Health &amp; Welfare, Republic of Korea/ ; }, mesh = {Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Analgesics, Non-Narcotic/toxicity ; *Biomimetics ; Bioprinting/*instrumentation ; *Cell Proliferation ; Free Radical Scavengers/pharmacology ; Hep G2 Cells ; Humans ; Hydrogels ; In Vitro Techniques ; Liver/drug effects/*pathology ; *Models, Biological ; Printing, Three-Dimensional/*statistics &amp; numerical data ; *Tissue Engineering ; Tissue Scaffolds/chemistry ; Toxicity Tests ; }, abstract = {Three-dimensional (3D) bioprinting is a promising technology to establish a 3D in vitro hepatic model that holds great potential in toxicological evaluation. However, in current hepatic models, the central area suffers from hypoxic conditions, resulting in slow and weak metabolism of drugs and toxins. It remains challenging to predict accurate drug effects in current bioprinted hepatic models. Here, we constructed a hexagonal bioprinted hepatic construct and incorporated a spinning condition with continuous media stimuli. Under spinning conditions, HepG2 cells in the bioprinted hepatic construct exhibited enhanced proliferation capacity and functionality compared to those under static conditions. Additionally, the number of spheroids that play a role in boosting drug-induced signals and responses increased in the bioprinted hepatic constructs cultured under spinning conditions. Moreover, HepG2 cells under spinning conditions exhibited intensive TGFβ-induced epithelial-to-mesenchymal transition (EMT) and increased susceptibility to acetaminophen (APAP)-induced hepatotoxicity as well as hepatotoxicity prevention by administration of N-acetylcysteine (NAC). Taken together, the results of our study demonstrate that the spinning condition employed during the generation of bioprinted hepatic constructs enables the recapitulation of liver injury and repair phenomena in particular. This simple but effective culture strategy facilitates bioprinted hepatic constructs to improve in vitro modeling for drug effect evaluation.}, }
@article {pmid34060621, year = {2021}, author = {Wang, Q and Zhang, H and Ren, QQ and Ye, TH and Liu, YM and Zheng, CS and Zhou, GF and Xia, XW}, title = {Sublethal hyperthermia enhances anticancer activity of doxorubicin in chronically hypoxic HepG2 cells through ROS-dependent mechanism.}, journal = {Bioscience reports}, volume = {41}, number = {6}, pages = {}, pmid = {34060621}, issn = {1573-4935}, mesh = {*Ablation Techniques ; Antibiotics, Antineoplastic/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/metabolism/pathology/*therapy ; Dose-Response Relationship, Drug ; Doxorubicin/*pharmacology ; Hep G2 Cells ; Humans ; *Hyperthermia, Induced ; Liver Neoplasms/metabolism/pathology/*therapy ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; *Tumor Hypoxia ; }, abstract = {Thermal ablation in combination with transarterial chemoembolization (TACE) has been reported to exert a more powerful antitumor effect than thermal ablation alone in hepatocellular carcinoma patients. However, the underlying mechanisms remain unclear. The purpose of the present study was to evaluate whether sublethal hyperthermia encountered in the periablation zone during thermal ablation enhances the anticancer activity of doxorubicin in chronically hypoxic (encountered in the tumor area after TACE) liver cancer cells and to explore the underlying mechanisms. In the present study, HepG2 cells precultured under chronic hypoxic conditions (1% oxygen) were treated in a 42°C water bath for 15 or 30 min, followed by incubation with doxorubicin. Assays were then performed to determine intracellular uptake of doxorubicin, cell viability, apoptosis, cell cycle, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and total antioxidant capacity. The results confirmed that sublethal hyperthermia enhanced the intracellular uptake of doxorubicin into hypoxic HepG2 cells. Hyperthermia combined with doxorubicin led to a greater inhibition of cell viability and increased apoptosis in hypoxic HepG2 cells as compared with hyperthermia or doxorubicin alone. In addition, the combination induced apoptosis by increasing ROS and causing disruption of MMP. Pretreatment with the ROS scavenger N-acetyl cysteine significantly inhibited the apoptotic response, suggesting that cell death is ROS-dependent. These findings suggested that sublethal hyperthermia enhances the anticancer activity of doxorubicin in hypoxic HepG2 cells via a ROS-dependent mechanism.}, }
@article {pmid34058306, year = {2021}, author = {Jaudoin, C and Carré, F and Gehrke, M and Sogaldi, A and Steinmetz, V and Hue, N and Cailleau, C and Tourrel, G and Nguyen, Y and Ferrary, E and Agnely, F and Bochot, A}, title = {Transtympanic injection of a liposomal gel loaded with N-acetyl-L-cysteine: A relevant strategy to prevent damage induced by cochlear implantation in guinea pigs?.}, journal = {International journal of pharmaceutics}, volume = {604}, number = {}, pages = {120757}, doi = {10.1016/j.ijpharm.2021.120757}, pmid = {34058306}, issn = {1873-3476}, mesh = {Acetylcysteine ; Animals ; Cochlea ; *Cochlear Implantation ; Guinea Pigs ; Humans ; Liposomes ; Perilymph ; }, abstract = {Patients with residual hearing can benefit from cochlear implantation. However, insertion can damage cochlear structures and generate oxidative stress harmful to auditory cells. The antioxidant N-acetyl-L-cysteine (NAC) is a precursor of glutathione (GSH), a powerful endogenous antioxidant. NAC local delivery to the inner ear appeared promising to prevent damage after cochlear implantation in animals. NAC-loaded liposomal gel was specifically designed for transtympanic injection, performed both 3 days before and on the day of surgery. Hearing thresholds were recorded over 30 days in implanted guinea pigs with and without NAC. NAC, GSH, and their degradation products, N,N'-diacetyl-L-cystine (DiNAC) and oxidized glutathione (GSSG) were simultaneously quantified in the perilymph over 15 days in non-implanted guinea pigs. For the first time, endogenous concentrations of GSH and GSSG were determined in the perilymph. Although NAC-loaded liposomal gel sustained NAC release in the perilymph over 15 days, it induced hearing loss in both implanted and non-implanted groups with no perilymphatic GSH increase. Under physiological conditions, NAC appeared poorly stable within liposomes. As DiNAC was quantified at concentrations which were twice as high as NAC in the perilymph, it was hypothesized that DiNAC could be responsible for the adverse effects on hearing.}, }
@article {pmid34056530, year = {2021}, author = {Aljohani, W and Chan, BPH and Yaghoobi, M}, title = {Role of N-Acetylcysteine in the Treatment of Acute Nonacetaminophen, Nonalcoholic and Nonviral Hepatitis: A Meta-analysis.}, journal = {Journal of the Canadian Association of Gastroenterology}, volume = {4}, number = {3}, pages = {125-130}, pmid = {34056530}, issn = {2515-2092}, abstract = {INTRODUCTION: N-acetylcysteine (NAC) has been extensively investigated for the use in acetaminophen and alcoholic hepatitis and is indicated in acetaminophen overdose. Studies assessing the effect of NAC on other forms of acute hepatitis in adult patients are limited and therefore here we aimed at evaluating the effect of NAC on survival in nonacetaminophen, nonalcoholic and nonviral hepatitis in adults.<br><br>METHODS: A comprehensive literature search up to September 2019 was completed for randomized controlled trials (RCTs) comparing NAC to placebo in the management of acute nonacetaminophen, nonalcoholic and nonviral hepatitis. Studies with insufficient data, non-RCT or nonprospective design, paediatric studies and studies with no comparator were excluded. Study selection, quality assessment and data extraction were independently performed by two co-authors. Primary outcome was survival. Secondary outcomes were an increase in infection rate. We used random model Mantel-Haenszel meta-analysis with Cochrane risk of bias to assess the quality of included studies. The recommendation was presented using the GRADE framework.<br><br>RESULTS: Seven out of 42 retrieved studies were included. Study population included patients with post-liver transplant, postsurgical, hypoxia-induced, ischemic and other nonalcoholic hepatitis. There was no difference in overall survival between NAC and placebo (odds ratio [OR] 0.95 [0.55 to 1.62]) in seven studies including 1033 patients. Furthermore, there was no difference in the rate of infection between NAC and placebo (OR 0.87 [0.43 to 1.79]). Random model analysis was used to adjust the effect of statistically significant heterogeneity in both analyses (P = 0.02). Lack of blinding in one study was found as a possible source of heterogeneity.<br><br>CONCLUSIONS: NAC does not improve overall survival or the rate of infection in patients with acute nonacetaminophen, nonalcoholic and nonviral hepatitis as compared to placebo and should not be recommended in such setting which may even delay a transplant evaluation (level of evidence: 2a, GRADE of recommendation: B).}, }
@article {pmid34055976, year = {2021}, author = {Jiang, C and Wang, Y and Guo, M and Long, Y and Chen, J and Fan, F and Tang, S and Xu, Y}, title = {PCB118 Induces Inflammation of Islet Beta Cells via Activating ROS-NLRP3 Inflammasome Signaling.}, journal = {BioMed research international}, volume = {2021}, number = {}, pages = {5522578}, pmid = {34055976}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspase 1/metabolism ; Cell Survival/drug effects ; Cytokines/metabolism ; Diabetes Mellitus ; Inflammasomes/*metabolism ; Inflammation/*chemically induced ; Interleukin-1beta ; Islets of Langerhans/drug effects/*metabolism ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {BACKGROUND: Diabetes mellitus is a clinical syndrome caused by genetic and environmental factors. Growing evidence suggests that exposure to environmental endocrine disruptors and activation of NLRP3 inflammasome signaling play a vital role in diabetes. However, it is unclear how PCB118, a common environmental endocrine disruptor, contributes to the incidence of diabetes, and its specific mechanism of action is unknown. In this study, we explored whether ROS-induced NLRP3 inflammasome priming and activation were related to PCB118 exposure in mouse islet β-TC-6 cells and the mechanisms of diabetes.<br><br>METHODS: Mouse islet &#x3b2;-TC-6 cells were cultured with PCB118 as a stimulating factor and ROS inhibitor N-acetyl cysteine (NAC) as an intervention. Cellular toxicity due to PCB118 was detected using the Cell Counting Kit-8; ROS was measured using DCFH-DA; the expressions of NLRP3, procaspase-1, caspase-1, pro-IL-1&#x3b2;, and IL-1&#x3b2; protein were detected by western blot; and IL-6, IL-18, and C-C chemokine ligand 2 (CCL-2) were measured by ELISA.<br><br>RESULTS: PCB118 caused significant toxicity to the cells when the stimulation concentration was equal to or greater than 80&#x2009;nmol/L at 72 hours (p < 0.05) and increased the levels of ROS, NLRP3, caspase-1, IL-1&#x3b2;, IL-6, IL-18, and CCL-2 (p < 0.05); the expressions of procaspase-1 and pro-IL-1&#x3b2; were downregulated in a dose-dependent manner after PCB118 exposure (p < 0.05), which was prevented by pretreatment with NAC (p < 0.05).<br><br>CONCLUSIONS: PCB118 can activate NLRP3 inflammasome signaling in islet beta cells via the oxidative stress pathway and cause inflammation in islet beta cells. It suggests that environmental endocrine disruptors play an important role in the inflammation of islet beta cells and may contribute to the development of diabetes through NLRP3 inflammatory signaling.}, }
@article {pmid34055194, year = {2021}, author = {Ni, S and Li, D and Wei, H and Miao, KS and Zhuang, C}, title = {PPARγ Attenuates Interleukin-1β-Induced Cell Apoptosis by Inhibiting NOX2/ROS/p38MAPK Activation in Osteoarthritis Chondrocytes.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {5551338}, pmid = {34055194}, issn = {1942-0994}, mesh = {Animals ; Apoptosis ; Chondrocytes/*metabolism ; Humans ; Interleukin-1beta/*metabolism ; Osteoarthritis/*genetics/pathology ; PPAR gamma/*metabolism ; Rats ; Reactive Oxygen Species ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {INTRODUCTION: Reactive oxygen species (ROS) induced by extracellular cytokines trigger the expression of inflammatory mediators in osteoarthritis (OA) chondrocyte. Peroxisome proliferator-activated receptor gamma (PPARγ) exerts an anti-inflammatory effect. The aim of this study was to elucidate the role of PPARγ in interleukin-1β- (IL-1β-) induced cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) expression through ROS generation in OA chondrocytes.<br><br>METHODS: IL-1&#x3b2;-induced ROS generation and chondrocyte apoptosis were determined by flow cytometry. Contents of NADPH oxidase (NOX), caspase-3, and caspase-9 were evaluated by biochemical detection. The involvement of NOX2 and mitogen-activated protein kinases (MAPKs) in IL-1&#x3b2;-induced COX-2 and PGE2 expression was investigated using pharmacologic inhibitors and further analyzed by western blotting. Activation of PPAR&#x3b3; was performed by using a pharmacologic agonist and was analyzed by western blotting.<br><br>RESULTS: IL-1&#x3b2;-induced COX-2 and PGE2 expression was mediated through NOX2 activation/ROS production, which could be attenuated by N-acetylcysteine (NAC; a scavenger of ROS), GW1929 (PPAR&#x3b3; agonist), DPI (diphenyleneiodonium chloride, NOX2 inhibitor), SB203580 (p38MAPK inhibitor), PD98059 (extracellular signal-regulated kinase, ERK inhibitor), and SP600125 (c-Jun N-terminal kinase, JNK inhibitor). ROS activated p38MAPK to enter the nucleus, which was attenuated by PPAR&#x3b3;.<br><br>CONCLUSION: In OA chondrocytes, IL-1&#x3b2; induced COX-2 and PGE2 expression via activation of NOX2, which led to ROS production and MAPK activation. The activation of PPAR&#x3b3; exerted protective roles in the pathogenesis of OA.}, }
@article {pmid34052344, year = {2021}, author = {Shi, L and Ji, Y and Zhao, S and Li, H and Jiang, Y and Mao, J and Chen, Y and Zhang, X and Mao, Y and Sun, X and Wang, P and Ma, J and Huang, S}, title = {Crosstalk between reactive oxygen species and Dynamin-related protein 1 in periodontitis.}, journal = {Free radical biology &amp; medicine}, volume = {172}, number = {}, pages = {19-32}, doi = {10.1016/j.freeradbiomed.2021.05.031}, pmid = {34052344}, issn = {1873-4596}, mesh = {Animals ; Dynamins/genetics ; Humans ; *Hydrogen Peroxide ; Mice ; Mitochondrial Dynamics ; Osteogenesis ; *Periodontitis/genetics ; Reactive Oxygen Species ; }, abstract = {Excessive generation of reactive oxygen species (ROS) have great impacts on the development of periodontitis. Dynamin-related protein 1 (Drp1) mediated mitochondrial fission is the main reason and the result of excessive ROS generation. However, whether Drp1 and crosstalk between ROS and Drp1 contribute to the process of periodontitis remains elusive. We herein investigated the role and functional significance of crosstalk between ROS and Drp1 in periodontitis. Firstly, human periodontal ligament cells (hPDLCs) were treated with hydrogen peroxide (H2O2) and ROS inhibitor N-acetyl-cysteine (NAC) or Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1). Cell viability, apoptosis, osteogenic differentiation, expression of Drp1, and mitochondrial function were investigated. Secondly, mice with periodontitis were treated with NAC or Mdivi-1. Finally, gingival tissues were collected from periodontitis patients and healthy individuals to evaluate ROS and Drp1 levels. H2O2 induced cellular injury and inflammation, excessive ROS production, mitochondrial abnormalities, and increased expression of p-Drp1 and Drp1 in hPDLCs, which could be reversed by NAC and Mdivi-1. Moreover, both NAC and Mdivi-1 ameliorated tissue damage and inflammation, and decreased expression of p-Drp1 and Drp1 in mice with periodontitis. More importantly, patients with periodontitis presented significantly higher levels of ROS-induced oxidative damage and p-Drp1 than that in healthy individuals and correlated with clinical parameters. In summary, ROS-Drp1 crosstalk greatly promotes the development of periodontitis. Pharmacological blockade of this crosstalk might be a novel therapeutic strategy for periodontitis.}, }
@article {pmid34047778, year = {2021}, author = {Pillai, V and Buck, L and Lari, E}, title = {Scavenging of reactive oxygen species mimics the anoxic response in goldfish pyramidal neurons.}, journal = {The Journal of experimental biology}, volume = {224}, number = {10}, pages = {}, doi = {10.1242/jeb.238147}, pmid = {34047778}, issn = {1477-9145}, mesh = {Animals ; *Goldfish ; *Hypoxia ; Oxygen ; Patch-Clamp Techniques ; Pyramidal Cells ; Reactive Oxygen Species ; }, abstract = {Goldfish are one of a few species able to avoid cellular damage during month-long periods in severely hypoxic environments. By suppressing action potentials in excitatory glutamatergic neurons, the goldfish brain decreases its overall energy expenditure. Coincident with reductions in O2 availability is a natural decrease in cellular reactive oxygen species (ROS) generation, which has been proposed to function as part of a low-oxygen signal transduction pathway. Using live-tissue fluorescence microscopy, we found that ROS production decreased by 10% with the onset of anoxia in goldfish telencephalic brain slices. Employing whole-cell patch-clamp recording, we found that, similar to severe hypoxia, the ROS scavengers N-acetyl cysteine (NAC) and MitoTEMPO, added during normoxic periods, depolarized membrane potential (severe hypoxia -73.6 to -61.4 mV, NAC -76.6 to -66.2 mV and MitoTEMPO -71.5 mV to -62.5 mV) and increased whole-cell conductance (severe hypoxia 5.7 nS to 8.0 nS, NAC 6.0 nS to 7.5 nS and MitoTEMPO 6.0 nS to 7.6 nS). Also, in a subset of active pyramidal neurons, these treatments reduced action potential firing frequency (severe hypoxia 0.18 Hz to 0.03 Hz, NAC 0.27 Hz to 0.06 Hz and MitoTEMPO 0.35 Hz to 0.08 Hz). Neither severe hypoxia nor ROS scavenging impacted action potential threshold. The addition of exogenous hydrogen peroxide could reverse the effects of the antioxidants. Taken together, this supports a role for a reduction in [ROS] as a low-oxygen signal in goldfish brain.}, }
@article {pmid34036678, year = {2021}, author = {Mohammadi, H and Daryabor, G and Ghaffarian Bahraman, A and Keshavarzi, M and Kalantar, K and Mohammadi-Bardbori, A}, title = {Aryl hydrocarbon receptor engagement during redox alteration determines the fate of CD4[+] T cells in C57BL/6 mice.}, journal = {Journal of biochemical and molecular toxicology}, volume = {35}, number = {8}, pages = {e22821}, doi = {10.1002/jbt.22821}, pmid = {34036678}, issn = {1099-0461}, support = {95-01-05-12559//Shiraz University of Medical Sciences/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Azo Compounds/pharmacology ; Gene Expression Regulation/drug effects ; Glutamate-Cysteine Ligase/biosynthesis ; Heme Oxygenase-1/biosynthesis ; Membrane Proteins/biosynthesis ; Mice ; NF-E2-Related Factor 2/biosynthesis ; Oxidation-Reduction/drug effects ; Pyrazoles/pharmacology ; *Receptors, Aryl Hydrocarbon/agonists/metabolism ; T-Lymphocytes, Helper-Inducer/*metabolism ; }, abstract = {The preservation of the redox homeostasis is critical for cell survival and functionality. Redox imbalance is an essential inducer of several pathological states. CD4[+] /helper T cells are highly dependent on the redox state of their surrounding milieu. The potential of the aryl hydrocarbon receptor (AhR) engagement in controlling CD4[+] T-cell fate during redox alteration is still challenging. C57BL/6 mice were treated with AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ), AhR antagonist CH223191, an inhibitor of glutathione biosynthesis buthionine sulfoximine (BSO), and the antioxidant N-acetylcysteine (NAC) alone or in combination. Six days later, splenocytes were evaluated for the expression of the redox-related genes and the possible changes in T-cell subsets. FICZ like BSO significantly elevated the expression of HMOX1, GCLC, and GCLM genes but it failed to increase the expression of the Nrf2 gene. Moreover, FICZ + BSO increased while FICZ + CH223191 or NAC decreased the expression of these genes. FICZ also significantly increased Th1 cell numbers but decreased Tregs in a dose-dependent manner. Furthermore, a high dose of FICZ + CH223191 + NAC significantly enhanced Th1, Th17, and Treg cells but its low dose in such a situation increased Th2 and Th17 while decreased Treg cells. AhR engagement during redox alteration can determine the fate of CD4 + T cells, so, AhR agonists or antagonists might be useful in assessing immune responses. However, these results need further verifications in vitro and in animal models of various diseases.}, }
@article {pmid34036177, year = {2021}, author = {Sahasrabudhe, SA and Silamongkol, T and Park, YW and Colette, A and Eberly, LE and Klimes-Dougan, B and Coles, LD and Cloyd, JC and Öz, G and Mueller, BA and Kartha, RV and Cullen, KR}, title = {Identifying Biological Signatures of N-Acetylcysteine for Non-Suicidal Self-Injury in Adolescents and Young Adults.}, journal = {Journal of psychiatry and brain science}, volume = {6}, number = {}, pages = {}, pmid = {34036177}, issn = {2398-385X}, support = {P30 NS076408/NS/NINDS NIH HHS/United States ; P41 EB027061/EB/NIBIB NIH HHS/United States ; R61 AT009995/AT/NCCIH NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; }, abstract = {UNLABELLED: The prevalence of non-suicidal self-injury (NSSI) is high in adolescents and young adults. However, there is a paucity of evidence-based treatments to address this clinical problem. An open-label, pilot study in the target population showed that treatment with oral N-acetylcysteine (NAC), a widely available dietary supplement, was associated with reduction in NSSI frequency. In preparation for a biologically informed design of an efficacy trial, a critical preliminary step is to clarify NAC's biological signatures, or measures of the mechanisms underlying its clinical effects. Toward that end, we propose a 2-stage project to investigate NAC's biological signatures (changes in glutathione (GSH) and/or glutamate (Glu)) in women with NSSI. The first stage; a double-blind randomized placebo-controlled study will focus on identifying the optimal dose to achieve meaningful change in GSH and Glu during short-term (4 weeks) NAC treatment in 36 women aged 16-24 years with NSSI. Go/No-go criteria to determine if the study will progress to the second stage include pre-specified changes in brain and blood measures of GSH. Changes in the brain GSH are measured through magnetic resonance spectroscopy (MRS). The dose for the stage 2 will be selected based on the biological changes and the tolerability observed in the stage 1. The stage 2 will seek to replicate the biological signature findings in an 8-week trial in a new patient cohort, and examine the relationships among biological signatures, NAC pharmacokinetics and clinical response. This 2-stage project is unique as it unifies clinical psychiatric measurements, quantitative MRS and pharmacological approaches in the first placebo-controlled clinical trial of NAC in young women with NSSI.<br><br>TRIAL REGISTRATION: The stage 1 trial protocol has been registered on https://clinicaltrials.gov/ with ClinicalTrials.gov ID "NCT04005053" (Registered on 02 July 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT04005053).}, }
@article {pmid34034074, year = {2021}, author = {Uzunboy, S and Karakaş, &#xd6; and Demirci-Çekiç, S and Apak, R}, title = {Sulfate radical formation by Cr(III) activation of peroxydisulfate - Diphenylcarbazide spectrophotometric determination of sulfate radical and its scavenging activity.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {260}, number = {}, pages = {119941}, doi = {10.1016/j.saa.2021.119941}, pmid = {34034074}, issn = {1873-3557}, abstract = {Even though sulfate anion radical (SO4[-]) is a very reactive oxidant used in advanced oxidation processes, a reliably selective and simple colorimetric method for determining this radical can hardly be found. Peroxydisulfate (S2O8[2-]) or peroxymonosulfate (HSO5[-]) can be activated with transition metal ions to produce SO4[-]. We have discovered that Cr(III) can be an activator for persulfate, generating Cr(VI) along with SO4[-]. By measuring the emerging chromate with diphenyl carbazide (DPC) spectrophotometry at 542 nm, we could measure both the formation of SO4[-] and its scavenging with antioxidant compounds. We could also investigate a number of UV-absorbing SO4[-] scavengers which could not be measured with other UV spectrometric methods. In addition to conventional antioxidants (phenolics such as quercetin, catechin, epicatechin, caffeic acid, thiols like cysteine and N-acetyl cysteine, and ascorbid acid), nitro-aromatics (represented by 2,4,6-trinitrophenol and 2,4-dinitrophenol) used in ammunition formulations could also be measured as scavengers. The presence of scavengers caused a reduction in the amount of Cr(VI) generated, where the difference in absorbance (ΔA) of chromate - with respect to the DPC method - in the absence and presence of scavengers was a linear function of SO4[-] scavenging capacity. Ethanol and tert-butanol were tested as solvents to show the selectivity of the method for SO4[-]. The method was statistically compared to a suitably modified ABTS/persulfate assay. The efficiency order of sulfate radical scavengers was determined and ranked (Spearman's test) using both the proposed method and modified ABTS/persulfate method to reveal a moderate correlation.}, }
@article {pmid34031264, year = {2021}, author = {Yang, HL and Liu, HW and Shrestha, S and Thiyagarajan, V and Huang, HC and Hseu, YC}, title = {Antrodia salmonea induces apoptosis and enhances cytoprotective autophagy in colon cancer cells.}, journal = {Aging}, volume = {13}, number = {12}, pages = {15964-15989}, pmid = {34031264}, issn = {1945-4589}, mesh = {Adenine/analogs &amp; derivatives/pharmacology ; Animals ; *Apoptosis/drug effects ; *Autophagy/drug effects ; Azoxymethane ; Beclin-1/metabolism ; Carcinogenesis/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chloroquine/pharmacology ; Colitis/chemically induced/complications ; Colonic Neoplasms/etiology/*pathology ; *Cytoprotection/drug effects ; Dextran Sulfate ; Disease Progression ; Humans ; Inflammation/pathology ; MAP Kinase Signaling System/drug effects ; Mice, Inbred ICR ; Microtubule-Associated Proteins/metabolism ; Mitochondria/drug effects/metabolism ; NF-kappa B/metabolism ; Organ Size/drug effects ; Polyporales/*chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; bcl-2-Associated X Protein/metabolism ; Mice ; }, abstract = {A traditional Chinese medicinal fungus, Antrodia salmonea (AS), with antioxidant properties is familiar in Taiwan but anti-cancer activity of AS in human colon cancer is ambiguous. Hence, we explored the anti-cancer activity of AS in colon cancer cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that AS showed a remarkable effect on cell viability in colon cancer cells; SW620, HCT116, and HT29. Annexin V/propidium iodide (PI) stained cells indicated that AS induced both early/late apoptosis in SW620 cells. Additionally, cells treated with AS induced caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage, mitochondrial dysfunction, and Bcl-2 associated X (Bax)/B-cell lymphoma (Bcl-2) dysregulation. Microtubule- associated protein 1A/1B-light chain 3B (LC3-II) accumulation, sequestosome 1 (p62/SQSTM1) activation, autophagy related 4B cysteine peptidase (ATG4B) inactivation, acidic vesicular organelles (AVOs) formation, and Beclin-1/Bcl-2 dysregulation revealed that AS-induced autophagy. Interestingly, cells pretreated with 3-methyladenine (3-MA) strengthened AS-induced caspase-3/apoptosis. Suppression of apoptosis by z-Val-Ala-Asp fluoromethyl ketone (Z-VAD-FMK) did not however block AS-induced autophagy, suggesting that autophagy was not attenuated by the AS-induced apoptosis. Application of N-acetylcysteine (NAC) prevented AS-induced cell death, caspase-3 activation, LC3-II accumulation, and AVOs formation, indicating that AS-induced apoptosis and autophagy was mediated by reactive oxygen species (ROS). Furthermore, AS-induced cytoprotective autophagy and apoptosis through extracellular signal-regulated kinase (ERK) signaling cascades. Moreover, in vivo data disclosed that AS inhibited colitis-associated tumorigenesis in azoxymethane (AOM)-dextran sodium sulphate (DSS)-treated mice. For the first time, we report the anti-cancer properties of this potentially advantageous mushroom for the treatment of human colon cancer.}, }
@article {pmid34028895, year = {2021}, author = {Sketriene, D and Battista, D and Perry, CJ and Sumithran, P and Lawrence, AJ and Brown, RM}, title = {N-acetylcysteine reduces addiction-like behaviour towards high-fat high-sugar food in diet-induced obese rats.}, journal = {The European journal of neuroscience}, volume = {54}, number = {3}, pages = {4877-4887}, doi = {10.1111/ejn.15321}, pmid = {34028895}, issn = {1460-9568}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; Diet, High-Fat/adverse effects ; Male ; Obesity/drug therapy ; Rats ; Rats, Sprague-Dawley ; *Sugars ; }, abstract = {Compulsive forms of eating displayed by some obese individuals share similarities with compulsive drug-taking behaviour, a hallmark feature of substance use disorder. This raises the possibility that drug addiction treatments may show utility in the treatment of compulsive overeating. N-Acetylcysteine (NAC) is a cysteine pro-drug which has experienced some success in clinical trials, reducing cocaine, marijuana and cigarette use, as well as compulsive behaviours such as gambling and trichotillomania. We assessed the impact of NAC on addiction-like behaviour towards highly palatable food in a rat model of diet-induced obesity. Adult male Sprague-Dawley rats were placed on a high-fat high-sugar diet for 8 weeks and then assigned to diet-induced obesity-prone (DIO) or diet-induced obesity-resistant (DR) groups based on weight gain. DIO and DR rats were subjected to an operant conditioning paradigm whereby rats could lever press for high-fat high-sugar food pellets. This alternated with periods of signalled reward unavailability. Before treatment DIO rats ate more in their home cage, earned more food pellets in operant sessions, and responded more during periods that signalled reward unavailability (suggestive of compulsive-like food seeking) compared with DR rats. This persistent responding in the absence of reward displayed by DIO rats was ameliorated by daily injections of NAC (100 mg/kg, i.p.) for 14 days. By the end of the treatment period, lever-pressing by NAC-treated DIO rats resembled that of DR rats. These findings suggest that NAC reduces addiction-like behaviour towards food in rats and supports the potential use of this compound in compulsive overeating.}, }
@article {pmid34026559, year = {2021}, author = {Sepehrinezhad, A and Shahbazi, A and Sahab Negah, S and Joghataei, MT and Larsen, FS}, title = {Drug-induced-acute liver failure: A critical appraisal of the thioacetamide model for the study of hepatic encephalopathy.}, journal = {Toxicology reports}, volume = {8}, number = {}, pages = {962-970}, pmid = {34026559}, issn = {2214-7500}, abstract = {Hepatic encephalopathy (HE) following acute and chronic liver failure is defined as a complex of neuropsychiatric abnormalities, such as discrete personal changes, sleep disorder, forgetfulness, confusion, and decreasing the level of consciousness to coma. The use and design of suitable animal models that represent clinical features and pathological changes of HE are valuable to map the molecular mechanisms that result in HE. Among different types of animal models, thioacetamide (TAA) has been used extensively for the induction of acute liver injury and HE. This agent is not directly hepatotoxic but its metabolites induce liver injury through the induction of oxidative stress and produce systemic inflammation similar to that seen in acute HE patients. In this short review article, we shortly review the most important pathological findings in animal models of acute HE following the administration of TAA.}, }
@article {pmid34026460, year = {2021}, author = {Guo, J and Duan, L and He, X and Li, S and Wu, Y and Xiang, G and Bao, F and Yang, L and Shi, H and Gao, M and Zheng, L and Hu, H and Liu, X}, title = {A Combined Model of Human iPSC-Derived Liver Organoids and Hepatocytes Reveals Ferroptosis in DGUOK Mutant mtDNA Depletion Syndrome.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {8}, number = {10}, pages = {2004680}, pmid = {34026460}, issn = {2198-3844}, mesh = {DNA, Mitochondrial/genetics ; Ferritins/metabolism ; Ferroptosis ; Fibroblasts/metabolism/pathology ; Humans ; Induced Pluripotent Stem Cells/metabolism/*pathology ; Iron Overload/physiopathology ; Liver/metabolism/pathology ; Liver Failure/genetics/metabolism/*pathology ; Lysosomes/metabolism ; Mitochondrial Diseases/genetics/metabolism/*pathology ; *Mutation ; Nuclear Receptor Coactivators/genetics/metabolism ; Organoids/metabolism/*pathology ; Respiration Disorders/etiology/metabolism/*pathology ; }, abstract = {Mitochondrial DNA depletion syndrome (MDS) is a group of severe inherited disorders caused by mutations in genes, such as deoxyribonucleoside kinase (DGUOK). A great majority of DGUOK mutant MDS patients develop iron overload progressing to severe liver failure. However, the pathological mechanisms connecting iron overload and hepatic damage remains uncovered. Here, two patients' skin fibroblasts are reprogrammed to induced pluripotent stem cells (iPSCs) and then corrected by CRISPR/Cas9. Patient-specific iPSCs and corrected iPSCs-derived high purity hepatocyte organoids (iHep-Orgs) and hepatocyte-like cells (iHep) are generated as cellular models for studying hepatic pathology. DGUOK mutant iHep and iHep-Orgs, but not control and corrected one, are more sensitive to iron overload-induced ferroptosis, which can be rescued by N-Acetylcysteine (NAC). Mechanically, this ferroptosis is a process mediated by nuclear receptor co-activator 4 (NCOA4)-dependent degradation of ferritin in lysosome and cellular labile iron release. This study reveals the underlying pathological mechanisms and the viable therapeutic strategies of this syndrome, and is the first pure iHep-Orgs model in hereditary liver diseases.}, }
@article {pmid34025345, year = {2021}, author = {Gumeni, S and Vantaggiato, C and Montopoli, M and Orso, G}, title = {Hereditary Spastic Paraplegia and Future Therapeutic Directions: Beneficial Effects of Small Compounds Acting on Cellular Stress.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {660714}, pmid = {34025345}, issn = {1662-4548}, abstract = {Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative conditions that share a characteristic feature of degeneration of the longest axons within the corticospinal tract, which leads to progressive spasticity and weakness of the lower limbs. Mutations of over 70 genes produce defects in various biological pathways: axonal transport, lipid metabolism, endoplasmic reticulum (ER) shaping, mitochondrial function, and endosomal trafficking. HSPs suffer from an adequate therapeutic plan. Currently the treatments foreseen for patients affected by this pathology are physiotherapy, to maintain the outgoing tone, and muscle relaxant therapies for spasticity. Very few clinical studies have been conducted, and it's urgent to implement preclinical animal studies devoted to pharmacological test and screening, to expand the rose of compounds potentially attractive for clinical trials. Small animal models, such as Drosophila melanogaster and zebrafish, have been generated, analyzed, and used as preclinical model for screening of compounds and their effects. In this work, we briefly described the role of HSP-linked proteins in the organization of ER endomembrane system and in the regulation of ER homeostasis and stress as a common pathological mechanism for these HSP forms. We then focused our attention on the pharmacodynamic and pharmacokinetic features of some recently identified molecules with antioxidant property, such as salubrinal, guanabenz, N-acetyl cysteine, methylene blue, rapamycin, and naringenin, and on their potential use in future clinical studies. Expanding the models and the pharmacological screening for HSP disease is necessary to give an opportunity to patients and clinicians to test new molecules.}, }
@article {pmid34025026, year = {2021}, author = {Morita, M and Iizuka-Ohashi, M and Watanabe, M and Narita, T and Kato, C and Kakibuchi, D and Kitano, F and Ouchi, Y and Sakaguchi, K and Taguchi, T}, title = {[Not Available].}, journal = {Journal of clinical biochemistry and nutrition}, volume = {68}, number = {3}, pages = {235-242}, pmid = {34025026}, issn = {0912-0009}, abstract = {Cutaneous side effects are often observed in patients treated with chemotherapeutic agents, including those treated with epidermal growth factor receptor (EGFR) inhibitors. These side effects are not fatal but often require dose reduction of chemotherapies. The mechanisms of epidermal growth factor receptor inhibition-related dermatologic toxicities are unclear, and prophylactic approaches are not well-established. To explore the mechanisms of the cutaneous side effects induced by epidermal growth factor receptor inhibition, we analyzed the metabolome using human keratinocyte cells. We first demonstrated that afatinib and lapatinib induced apoptosis in HaCaT cells. Using liquid chromatography-mass spectrometry, we detected 676 and 482 metabolites and compounds in the cells and media, respectively. We observed diverse metabolic alterations, including glycolysis, TCA metabolism, and polyamine metabolism, and also found a change in glutathione metabolites after epidermal growth factor receptor inhibition, which led to the accumulation of reactive oxygen species. Supplementation of N-acetyl cysteine partly rescued the afatinib-induced apoptosis, suggesting that reactive oxygen species are involved in the cytotoxicity of skin cells. We observed epidermal growth factor receptor inhibitor-associated comprehensive metabolic changes in human keratinocyte cells, suggesting that oxidative stress evokes cutaneous side effects induced by EGFR inhibition.}, }
@article {pmid34017406, year = {2021}, author = {Ye, M and Lin, W and Zheng, J and Lin, S}, title = {N-acetylcysteine for chronic kidney disease: a systematic review and meta-analysis.}, journal = {American journal of translational research}, volume = {13}, number = {4}, pages = {2472-2485}, pmid = {34017406}, issn = {1943-8141}, abstract = {OBJECTIVE: The present study aimed to evaluate the safety and benefits of N-acetylcysteine (NAC) for chronic kidney disease (CKD) through a systematic review and meta-analysis.<br><br>METHODS AND MATERIALS: We performed a literature search until 5 May 2020 in the CENTRAL, MEDLINE, EMBASE, CINAHL, Clinical Trials Registry Platform and CBM. Two reviewers independently identified eligible articles and extract data. The risk of bias and publication bias were evaluated in all included trials and Cochrane Collaboration's RevMan5.3 software was used for data analysis. Fifteen trials (20 articles) involving a total of 768 patients were included.<br><br>RESULTS: The summary results of the studies showed that NAC did reduce cardiovascular events among people with CKD, the RR was 0.60, and the number that needs to be treated (NNT) was 5.29. Pooled date of estimated glomerular filtration rate (eGFR) and serum creatinine (Scr) in the NAC group were better than those in the placebo group. No patients in all studies were terminated due to side effect. Subgroup analysis also showed that inflammatory cytokines and homocysteine were significantly lower in NAC group.<br><br>CONCLUSION: These results suggested that NAC appears to be safe without obvious adverse events, which can also benefit kidney function, relieve inflammation and reduce cardiovascular events among people with CKD.}, }
@article {pmid34016350, year = {2021}, author = {Zhao, Y and Zhuang, Y and Shi, Y and Xu, Z and Zhou, C and Guo, L and Liu, P and Wu, C and Hu, R and Hu, G and Guo, X and Xu, L}, title = {Effects of N-acetyl-l-cysteine on heat stress-induced oxidative stress and inflammation in the hypothalamus of hens.}, journal = {Journal of thermal biology}, volume = {98}, number = {}, pages = {102927}, doi = {10.1016/j.jtherbio.2021.102927}, pmid = {34016350}, issn = {0306-4565}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Avian Proteins/genetics/metabolism ; Chickens ; Cytokines/genetics/metabolism ; Dietary Supplements ; Female ; Heat Stress Disorders/*drug therapy/genetics/metabolism/veterinary ; Heat-Shock Response/drug effects ; Hypothalamus/*drug effects/metabolism/pathology ; I-kappa B Kinase/genetics ; NF-E2-Related Factor 2/genetics/metabolism ; NF-kappa B/genetics/metabolism ; Oxidative Stress/drug effects ; Oxidoreductases/genetics/metabolism ; Poultry Diseases/*drug therapy/genetics/metabolism/pathology ; }, abstract = {The purpose of this study was to discuss the effects of N-acetyl-l-cysteine (NAC) on heat stress-induced oxidative stress and inflammation in the hypothalamus of hens in different periods. A total of 120 Hy-Line variety brown laying hens (12 weeks old) were randomly assigned to 4 groups with 6 replicates. The control group (C group) (22 ± 1 °C) received a basal diet, the NAC-treated group (N group) (22 ± 1 °C) received a basal diet with 1000 mg/kg NAC, and 2 heat-stressed groups (36 ± 1 °C for 10 h per day and 22 ± 1 °C for the remaining time) were fed a basal diet (HS group) or a basal diet with 1000 mg/kg NAC (HS + N group) for 21 consecutive days. The influence of NAC on histologic changes, oxidative stress and proinflammatory cytokine production was measured and analysed in hens with heat stress-induced hypothalamic changes. NAC effectively alleviated the hypothalamic morphological changes induced by heat stress. In addition, NAC attenuated the activity of the Nf-κB pathway activated by heat stress and decreased the expression of the proinflammatory cytokines IL-6, IL-18, TNF-α, IKK, and IFN-γ. In addition, NAC treatment regulated the expression of HO-1, GSH, SOD2 and PRDX3 by regulating the activity of Nrf2 at different time points to resist oxidative stress caused by heat exposure. In summary, dietary NAC may be an effective candidate for the treatment and prevention of heat stress-induced hypothalamus injury by preventing Nf-κB activation and controlling the Nrf2 pathway.}, }
@article {pmid34006821, year = {2021}, author = {Wang, B and Shi, Y and Chen, J and Shao, Z and Ni, L and Lin, Y and Wu, Y and Tian, N and Zhou, Y and Sun, L and Wu, A and Hong, Z and Wang, X and Zhang, X}, title = {High glucose suppresses autophagy through the AMPK pathway while it induces autophagy via oxidative stress in chondrocytes.}, journal = {Cell death &amp; disease}, volume = {12}, number = {6}, pages = {506}, pmid = {34006821}, issn = {2041-4889}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Acetylcysteine/pharmacology/*therapeutic use ; Aminoimidazole Carboxamide/*analogs &amp; derivatives/pharmacology/therapeutic use ; Animals ; Autophagy/*physiology ; Chondrocytes/*metabolism ; Diabetes Complications/*complications ; Diabetes Mellitus/*drug therapy ; Glucose/*metabolism ; Humans ; Hyperglycemia/*complications ; Mice ; Oxidative Stress/*physiology ; Ribonucleotides/pharmacology/*therapeutic use ; }, abstract = {Diabetes (DB) is a risk factor for osteoarthritis progression. High glucose (HG) is one of the key pathological features of DB and has been demonstrated to induce apoptosis and senescence in chondrocytes. Autophagy is an endogenous mechanism that can protect cells against apoptosis and senescence. The effects of HG on autophagy in cells including chondrocytes have been studied; however, the results have been inconsistent. The current study aimed to elucidate the underlying mechanisms, which could be associated with the contrasting outcomes. The present study revealed that HG can induce apoptosis and senescence in chondrocytes, in addition to regulating autophagy dynamically. The present study demonstrated that HG can cause oxidative stress in chondrocytes and suppress the AMPK pathway in a dose-dependent manner. Elimination of oxidative stress by Acetylcysteine, also called N-acetyl cysteine (NAC), downregulated autophagy and alleviated HG-stimulated apoptosis and senescence, while activation of the AMPK signaling pathway by AICAR not only upregulated autophagy but also alleviated HG-stimulated apoptosis and senescence. A combined treatment of NAC and AICAR was superior to treatment with either NAC or AICAR. The study has demonstrated that HG can suppress autophagy through the AMPK pathway and induce autophagy via oxidative stress in chondrocytes.}, }
@article {pmid34006188, year = {2021}, author = {Zheng, X and Wang, X and Ding, Z and Li, W and Peng, Y and Zheng, J}, title = {Metabolic activation of deferiprone mediated by CYP2A6.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {51}, number = {11}, pages = {1282-1291}, doi = {10.1080/00498254.2021.1931729}, pmid = {34006188}, issn = {1366-5928}, mesh = {Activation, Metabolic ; Animals ; Cytochrome P-450 CYP2A6/metabolism ; *Cytochrome P-450 Enzyme System/metabolism ; Deferiprone ; Glutathione/metabolism ; Humans ; *Microsomes, Liver/metabolism ; Rats ; }, abstract = {Deferiprone (DFP) is a metal chelating agent generally used to treat patients with thalassaemia, due to iron overload in clinical settings.Studies have revealed that long-term use of DFP can induce hepatotoxicity, however, mechanisms of its toxic action remain unclear. The present studies are aimed to characterize the reactive metabolite of DFP, to define the metabolic pathway, and to determine the P450 enzymes participating in the bioactivation.A demethylation metabolite (M1) was observed in rat liver microsomal incubations. Additionally, a glutathione (GSH) conjugate (M2) and an N-acetylcysteine (NAC) conjugate (M3) were detected in microsomal incubations fortified with DFP and GSH/NAC.Biliary M2 and urinary M3 were respectively found in animals administered DFP.CYP2A6 enzyme dominated the catalysis to bioactivate DFP.}, }
@article {pmid34004056, year = {2021}, author = {Manček-Keber, M and Hafner-Bratkovič, I and Lainšček, D and Benčina, M and Govednik, T and Orehek, S and Plaper, T and Jazbec, V and Bergant, V and Grass, V and Pichlmair, A and Jerala, R}, title = {Disruption of disulfides within RBD of SARS-CoV-2 spike protein prevents fusion and represents a target for viral entry inhibition by registered drugs.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {35}, number = {6}, pages = {e21651}, pmid = {34004056}, issn = {1530-6860}, support = {V4-2038//Slovenian Research Agency/ ; P4-0176//Slovenian Research Agency/ ; J3-9257//Slovenian Research Agency/ ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Amides/*pharmacology ; Ascorbic Acid/*pharmacology ; Auranofin/*pharmacology ; *COVID-19/metabolism/pathology ; Disulfides/*metabolism ; Esters/*pharmacology ; HEK293 Cells ; Humans ; SARS-CoV-2/*metabolism ; Spike Glycoprotein, Coronavirus/*metabolism ; Sulfhydryl Compounds/*pharmacology ; Virus Internalization/*drug effects ; *COVID-19 Drug Treatment ; }, abstract = {The SARS-CoV-2 pandemic imposed a large burden on health and society. Therapeutics targeting different components and processes of the viral infection replication cycle are being investigated, particularly to repurpose already approved drugs. Spike protein is an important target for both vaccines and therapeutics. Insights into the mechanisms of spike-ACE2 binding and cell fusion could support the identification of compounds with inhibitory effects. Here, we demonstrate that the integrity of disulfide bonds within the receptor-binding domain (RBD) plays an important role in the membrane fusion process although their disruption does not prevent binding of spike protein to ACE2. Several reducing agents and thiol-reactive compounds are able to inhibit viral entry. N-acetyl cysteine amide, L-ascorbic acid, JTT-705, and auranofin prevented syncytia formation, viral entry into cells, and infection in a mouse model, supporting disulfides of the RBD as a therapeutically relevant target.}, }
@article {pmid34003554, year = {2021}, author = {Lee, YJ and Lee, SY}, title = {Maclurin exerts anti-cancer effects in human osteosarcoma cells via prooxidative activity and modulations of PARP, p38, and ERK signaling.}, journal = {IUBMB life}, volume = {73}, number = {8}, pages = {1060-1072}, doi = {10.1002/iub.2506}, pmid = {34003554}, issn = {1521-6551}, mesh = {Antineoplastic Agents, Phytogenic/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Bone Neoplasms/*drug therapy/*metabolism/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Humans ; MAP Kinase Signaling System/drug effects ; Osteosarcoma/*drug therapy/*metabolism/pathology ; Plant Lectins/*pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Maclurin [(3,4-dihydroxyphenyl)-(2,4,6-trihydroxyphenyl) methanone] is a natural compound that can be extracted from white mulberry(Morus alba) and purple mangosteen(Garcinia mangostana). Maclurin is known for its dual-sided effect on reactive oxygen species (ROS). Osteosarcoma is a primary malignant tumor of the bone and is one of the most aggressive cancers. It is common especially in children and young adults and can progress into highly metastatic cancer. In this study, we investigated the anti-cancer effects of maclurin on U2OS human osteosarcoma cells. The results indicated that maclurin exerts prooxidative effects and induces apoptosis via capase-3-independent PARP regulation in U2OS human osteosarcoma cells. Maclurin also inhibits the migration of U2OS human osteosarcoma cells. Maclurin modulates two of the three major mitogen-activated protein kinases that are closely linked with cancer metastasis; that is, it activates p38 and inactivates Extracellular signal-regulated kinase. The apoptosis-inducing effects of maclurin on U2OS osteosarcoma cells were diminished by additional treatment with antioxidant N-acetyl cysteine (NAC), but the migration-inhibiting effect was not affected by NAC treatment. This further suggested the only apoptosis-inducing effect of maclurin may be strongly related to its prooxidative activity. Taken together, these results suggested that maclurin may be a strong candidate molecule as an anti-osteosarcoma agent.}, }
@article {pmid33999540, year = {2021}, author = {Andrade, C}, title = {N-Acetylcysteine Augmentation for Patients With Major Depressive Disorder and Bipolar Depression.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {1}, pages = {}, doi = {10.4088/JCP.21f13891}, pmid = {33999540}, issn = {1555-2101}, mesh = {Acetylcysteine/*pharmacology ; Antidepressive Agents/pharmacology ; Bipolar Disorder/*drug therapy ; Depressive Disorder, Major/*drug therapy ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Meta-Analysis as Topic ; *Outcome Assessment, Health Care ; Tranquilizing Agents/pharmacology ; }, abstract = {Major depressive disorder (MDD) and bipolar depression (BD) can often be difficult to treat. N-acetylcysteine (NAC) is a nutraceutical product that has been trialed in a large number of neuropsychiatric and medical disorders, with mixed results. Many randomized controlled trials (RCTs) have studied NAC augmentation as an intervention in MDD and BD. These RCTs were pooled in 2 recent meta-analyses. One meta-analysis with 7 RCTs (pooled N = 728) conducted in patients with MDD or BD found that NAC was not superior to placebo in the attenuation of depression ratings in either main or sensitivity analyses. The other meta-analysis with 6 RCTs (pooled N = 248) conducted in patients with BD found a small, imprecise effect size for NAC (standardized mean difference, 0.45; 95% confidence interval, 0.06-0.84). The advantage for NAC in this meta-analysis would almost certainly have been lost had the authors excluded from analysis 2 RCTs, both of which had problematic characteristics and findings and both of which also obtained a large and statistically significant advantage for NAC. At present, therefore, evidence does not encourage the use of NAC as an augmentation treatment for patients with MDD or BD. It remains to be seen whether NAC augmentation benefits depressed subpopulations, such as those with higher levels of inflammatory biomarkers at baseline.}, }
@article {pmid33998977, year = {2022}, author = {Ahmad, A and Zafar, A and Zargar, S and Bazgaifan, A and Wani, TA and Ahmad, M}, title = {Protective effects of apigenin against edifenphos-induced genotoxicity and cytotoxicity in rat hepatocytes.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {40}, number = {19}, pages = {9306-9317}, doi = {10.1080/07391102.2021.1926325}, pmid = {33998977}, issn = {1538-0254}, mesh = {Humans ; Rats ; Animals ; *Apigenin/pharmacology ; Caspase 9/metabolism/pharmacology ; Membrane Potential, Mitochondrial ; Reactive Oxygen Species/metabolism ; Organophosphorus Compounds/pharmacology ; *Pesticides ; DNA Damage ; Apoptosis ; }, abstract = {Edifenphos (EDF) is an organophosphorus pesticide with antifungal and anti-insecticidal properties. However, EDF accumulates in various agricultural products and causes potential hazards to human health. Although numerous reports have indicated EDF accumulation in agricultural products, toxic effects on cellular system is poorly understood. In the present study, we investigated the cytotoxicity and genotoxicity of EDF in rat hepatocytes and its amelioration by apigenin (a dietary flavonoid). Results showed that EDF inhibited the cell viability, induced oxidative stress, DNA damage, loss of mitochondrial membrane potential (ΔΨm) and caspase-9/-3 activation in rat hepatocytes. Incubation of hepatocytes with N-acetyl cysteine (ROS scavenger) significantly abrogated the ROS generation and apoptosis caused by EDF. In addition, this study also showed that apigenin significantly suppressed the toxic effects of EDF by quenching ROS production thereby abrogating the caspase-9/-3 and apoptosis activation in hepatocytes. Taken together, the findings of this study demonstrate that EDF induces cytotoxicity and DNA damage in hepatocytes, and apigenin can be considered as an effective dietary anti-oxidant regimen against EDF- induced toxicity in cellular system.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid33994712, year = {2021}, author = {Kedarisetty, CK and Bal, S and Parida, S and Jain, M and Bhadoria, AS and Varghese, J and Venkataraman, J}, title = {Role of N-acetyl Cysteine in Post-transarterial Chemoembolization Transaminitis in Hepatocellular Carcinoma: A Single-center Experience.}, journal = {Journal of clinical and experimental hepatology}, volume = {11}, number = {3}, pages = {299-304}, pmid = {33994712}, issn = {0973-6883}, abstract = {BACKGROUND: Transarterial chemoembolization (TACE) is the most common locoregional therapy for hepatocellular carcinoma (HCC). Postembolization syndrome is not an uncommon complication. At present, there is no specific treatment for management of this complication. We aimed to study the role of N-acetyl cysteine (NAC), an antioxidant, in management of this complication.<br><br>METHODS: In a prospective observational study, consecutive patients with HCC&#xa0;undergoing TACE from January 2016 to January 2017 were included. Patients with postembolization syndrome, defined as an elevation of transaminase levels more than&#x2009;3-4 times the upper limit of normal, were administered intravenous NAC for 72&#xa0;h (150&#xa0;mg/kg for 1&#xa0;h, then 12.5&#xa0;mg/kg/h for 4&#xa0;h, and continuous infusion 6.25&#xa0;mg/h for the remaining 67&#xa0;h). The other group received only supportive standard of care. The primary end point was reduction in post-TACE transaminitis.<br><br>RESULTS: Of 112 patients with HCC, 53 (47.3%) received NAC. The majority were cirrhotics in both the groups. Both groups were well matched in demographic, laboratory, and tumor characteristics. In the NAC group, there was significant reduction in Aspartate transaminase (AST) and Alanine transaminase (ALT) levels from day 1 to day 3 (p&#xa0;= 0.000) compared with the non-NAC group, with no significant change in bilirubin or international normalized ratio levels. The duration of hospital stay was similar in both the groups. None had any major adverse events to NAC.<br><br>CONCLUSION: This is a prospective, single-center experience, showing that early initiation of N-acetyl cysteine in those with post-TACE embolization syndrome&#xa0;reduces the transaminase level significantly.}, }
@article {pmid33991932, year = {2021}, author = {Li, X and He, S and Zhou, J and Yu, X and Li, L and Liu, Y and Li, W}, title = {Cr (VI) induces abnormalities in glucose and lipid metabolism through ROS/Nrf2 signaling.}, journal = {Ecotoxicology and environmental safety}, volume = {219}, number = {}, pages = {112320}, doi = {10.1016/j.ecoenv.2021.112320}, pmid = {33991932}, issn = {1090-2414}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Chromium/*toxicity ; Glucose/*metabolism ; Insulin/metabolism ; Lipid Metabolism/drug effects ; Mice ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {The hexavalent form of chromium, Cr (VI), has been associated with various diseases in humans. In this study, we examined the mechanisms underlying the effect of Cr (VI) on glucose and lipid metabolism in vivo and in vitro. We found that Cr (VI) induced abnormal liver function, increased fasting blood glucose (FBG), as well as glucose and insulin intolerance in mice. Furthermore, Cr (VI) decreased glucose-6-phosphate (G6P) level and glucose transporter-2 (GLUT2) expression, increased the levels of triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), reduced high-density lipoprotein-cholesterol (HDL-C), and increased sterol regulatory element-binding proteins 1 (SREBP1) and fat synthase (FAS) in vitro and in vivo. Moreover, Cr (VI) promoted intracellular ROS production in vitro, and induced reduction of antioxidant enzyme level and Nrf2/HO-1 expression in vitro and in vivo. Also, N-acetyl cysteine (NAC, effective antioxidant and free radical scavenger) pretreatment inhibited the production of intracellular ROS, significantly suppressed Cr (VI)-induced oxidative stress, lipid accumulation, decreased G6P and GLUT2, and improved impaired glucose tolerance and glucose and insulin intolerance caused by Cr (VI) in mice. Dh404 activated expression of Nrf2 decreased ROS level, increased HO-1 expression, ameliorated activity of the antioxidant enzyme, inhibited Cr (VI) increase of SREBP1, FAS level, and reduction of G6P and GLUT2. To sum up, these data suggest that dysregulation of ROS/Nrf2/HO-1 has an important role in Cr (VI)-induced glucose/lipid metabolic disorder.}, }
@article {pmid33986919, year = {2021}, author = {Guarnieri, S and Morabito, C and Bevere, M and Lanuti, P and Mariggiò, MA}, title = {A Protective Strategy to Counteract the Oxidative Stress Induced by Simulated Microgravity on H9C2 Cardiomyocytes.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {9951113}, pmid = {33986919}, issn = {1942-0994}, mesh = {Cell Line, Tumor ; Cell Proliferation ; Humans ; Myocytes, Cardiac/*metabolism ; Oxidative Stress/*physiology ; }, abstract = {Microgravity affects human cardiovascular function inducing heart rhythm disturbances and even cardiac atrophy. The mechanisms triggered by microgravity and the search for protection strategies are difficult to be investigated in vivo. This study is aimed at investigating the effects induced by simulated microgravity on a cardiomyocyte-like phenotype. The Random Positioning Machine (RPM), set in a CO2 incubator, was used to simulate microgravity, and H9C2 cell line was used as the cardiomyocyte-like model. H9C2 cells were exposed to simulated microgravity up to 96 h, showing a slower cell proliferation rate and lower metabolic activity in comparison to cell grown at earth gravity. In exposed cells, these effects were accompanied by increased levels of intracellular reactive oxygen species (ROS), cytosolic Ca[2+], and mitochondrial superoxide anion. Protein carbonyls, markers of protein oxidation, were significantly increased after the first 48 h of exposition in the RPM. In these conditions, the presence of an antioxidant, the N-acetylcysteine (NAC), counteracted the effects induced by the simulated microgravity. In conclusion, these data suggest that simulated microgravity triggers a concomitant increase of intracellular ROS and Ca[2+] levels and affects cell metabolic activity which in turn could be responsible for the slower proliferative rate. Nevertheless, the very low number of detectable dead cells and, more interestingly, the protective effect of NA, demonstrate that simulated microgravity does not have "an irreversible toxic effect" but, affecting the oxidative balance, results in a transient slowdown of proliferation.}, }
@article {pmid33981177, year = {2021}, author = {Khovarnagh, N and Seyedalipour, B}, title = {Antioxidant, histopathological and biochemical outcomes of short-term exposure to acetamiprid in liver and brain of rat: The protective role of N-acetylcysteine and S-methylcysteine.}, journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society}, volume = {29}, number = {3}, pages = {280-289}, pmid = {33981177}, issn = {1319-0164}, abstract = {The present study was conducted to investigate the protective effects of N-Acetyl-L-cysteine (NAC) and S-methyl- L-cysteine (SMC) against hepatic oxidative stress and brain damage induced by acetamiprid (ACP) in rats, which were evaluated by histopathological changes, measuring serum biomarkers and antioxidant defense systems. In this study, 42 rats were randomly divided into 6 groups and administered by intraperitoneally for one week: the control group, the sham group (normal saline), ACP alone (5 mg/kg) (group1), NAC alone (160 mg/kg) (group2), ACP + SMC (100 mg/kg) (group3), ACP + NAC (group 4) and ACP + NAC + SMC (group 5). Our results showed that acetamiprid induces liver injures including infiltration of inflammatory cells, congestion and altered histo-architecture and brain damages including gliosis, hyperemia and necrosis. The biochemical analyses showed that acetamiprid significantly altered the structural and biochemical profiles of liver which may be due to the loss of integrity of cell membranes. Furthermore, antioxidant parameters results of ACP group revealed that glutathione (GSH) and total antioxidant capacity (TAC) levels decreased significantly, while lipid peroxidation (LPO) content and glutathione-S-transferase (GST) and catalase (CAT) activities increased in both tissues (P < 0.05), suggesting tissue oxidative damage, which was also confirmed histopathological. Conversely, administration of NAC and SMC ameliorated LPO, GSH content and antioxidant enzymes system considerably (P < 0.05) in both tissues. Moreover, NAC and SMC administration also improved liver and brain malfunction. These results indicate that both NAC and in to a lesser amount SMC have a potent antioxidant protection in both tissues of rat against ACP-induced oxidative stress.}, }
@article {pmid33978073, year = {2021}, author = {Leite, AA and Reiter, RJ and Brandão, JCM and Sakae, TM and Marinho, M and Camargo, CR and Oliveira-Junior, IS}, title = {Melatonin can be, more effective than N-acetylcysteine, protecting acute lung injury induced by intestinal ischemia-reperfusion in rat model.}, journal = {Clinics (Sao Paulo, Brazil)}, volume = {76}, number = {}, pages = {e2513}, pmid = {33978073}, issn = {1980-5322}, mesh = {Acetylcysteine/therapeutic use ; *Acute Lung Injury/etiology/prevention &amp; control ; Animals ; Ischemia ; *Melatonin/therapeutic use ; Rats ; Rats, Wistar ; Reperfusion ; *Reperfusion Injury/prevention &amp; control ; }, abstract = {OBJECTIVES: The current study compared the impact of pretreatment with melatonin and N-acetylcysteine (NAC) on the prevention of rat lung damage following intestinal ischemia-reperfusion (iIR).<br><br>METHODS: Twenty-eight Wistar rats were subjected to intestinal ischemia induced by a 60 min occlusion of the superior mesenteric artery, followed by reperfusion for 120 min. Animals were divided into the following groups (n=7 per group): sham, only abdominal incision; SS+iIR, pretreated with saline solution and iIR; NAC+iIR, pretreated with NAC (20 mg/kg) and iIR; MEL+iIR, pretreated with melatonin (20 mg/kg) and iIR. Oxidative stress and inflammatory mediators were measured and histological analyses were performed in the lung tissues.<br><br>RESULTS: Data showed a reduction in malondialdehyde (MDA), myeloperoxidase (MPO), and TNF-alpha in the animals pretreated with NAC or MEL when compared to those treated with SS+iIR (p<0.05). An increase in superoxide dismutase (SOD) levels in the NAC- and MEL-pretreated animals as compared to the SS+iIR group (34&#xb1;8 U/g of tissue; p<0.05) was also observed. TNF-&#x3b1; levels were lower in the MEL+iIR group (91&#xb1;5 pg/mL) than in the NAC+iIR group (101&#xb1;6 pg/mL). Histological analysis demonstrated a higher lung lesion score in the SS+iIR group than in the pretreated groups.<br><br>CONCLUSION: Both agents individually provided tissue protective effect against intestinal IR-induced lung injury, but melatonin was more effective in ameliorating the parameters analyzed in this study.}, }
@article {pmid33977080, year = {2021}, author = {Qiao, Q and Liu, X and Yang, T and Cui, K and Kong, L and Yang, C and Zhang, Z}, title = {Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {10}, pages = {3060-3091}, pmid = {33977080}, issn = {2211-3835}, abstract = {Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.}, }
@article {pmid33976000, year = {2021}, author = {Alanli, R and Kucukay, MB and Ozdemir, O}, title = {Successful treatment of amiodarone-induced hepatic injury with n-acetylcysteine: A case report.}, journal = {Indian journal of pharmacology}, volume = {53}, number = {1}, pages = {60-62}, pmid = {33976000}, issn = {1998-3751}, mesh = {Acetylcysteine/*therapeutic use ; Aged, 80 and over ; Amiodarone/*adverse effects ; Anti-Arrhythmia Agents/*adverse effects ; Antioxidants/*therapeutic use ; Arrhythmias, Cardiac/*therapy ; Chemical and Drug Induced Liver Injury/*diagnosis/drug therapy ; *Defibrillators, Implantable ; Diagnosis, Differential ; Female ; Humans ; }, abstract = {Intravenous amiodarone treatment may cause hepatic toxicity. N-acetylcysteine (NAC) is a powerful antioxidant, reduces the level of free radicals by increasing glutathione levels, and is used in acetaminophen intoxication. An 83-year-old female Caucasian patient who had congestive heart failure and implantable cardioverter-defibrillator was admitted to the hospital with palpitations and confusion. After analysis of ICD device, ventricular tachycardia, ventricular fibrillation runs of patient and intervention of ICD device with electric shocks were noticed. Intravenous 1200 mg amiodarone infusion was administered as treatment. Later, her transaminase levels increased dramatically. Hepatic injury due to intravenous administration of amiodarone was diagnosed and 1200 mg/day intravenous NAC was given. After 72 h of NAC treatment, hepatic enzymes were found to be recovering. After parenteral amiodarone administration, patients must be monitored for acute hepatotoxicity. This article accentuates the benefits of NAC treatment in drug-induced liver injury.}, }
@article {pmid33966346, year = {2021}, author = {Ganai, SA and Srinivasan, P and Rajamanikandan, S and Shah, BA and Mohan, S and Gani, M and Padder, BA and Qadri, RA and Bhat, MA and Baba, ZA and Yatoo, MA}, title = {Delineating binding potential, stability of Sulforaphane-N-acetyl-cysteine in the active site of histone deacetylase 2 and testing its cytotoxicity against distinct cancer lines through stringent molecular dynamics, DFT and cell-based assays.}, journal = {Chemical biology &amp; drug design}, volume = {98}, number = {3}, pages = {363-376}, doi = {10.1111/cbdd.13854}, pmid = {33966346}, issn = {1747-0285}, support = {//Self Financed/ ; }, mesh = {Acetylcysteine/*chemistry ; Antineoplastic Agents/*chemistry/metabolism/pharmacology ; Benzamides/pharmacology ; Binding Sites ; Catalytic Domain ; Cell Line, Tumor ; Cell Survival/drug effects ; Density Functional Theory ; Drug Stability ; Histone Deacetylase 2/*antagonists &amp; inhibitors/genetics/metabolism ; Histone Deacetylase Inhibitors/chemistry/metabolism/pharmacology ; Humans ; Hydrogen Bonding ; Isothiocyanates/*chemistry ; Molecular Docking Simulation ; Mutagenesis ; Pyridines/pharmacology ; Sulfoxides/*chemistry ; Thermodynamics ; }, abstract = {Histone deacetylase 2 (HDAC2), an isozyme of Class I HDACs has potent imputations in actuating neurodegenerative signaling. Currently, there are sizeable therapeutic disquiets with the use of synthetic histone deacetylase inhibitors in disease management. This strongly suggests the unfulfilled medical necessity of plant substitutes for therapeutic intervention. Sulforaphane-N-acetyl-cysteine (SFN-N-acetylcysteine or SFN-NAC), a sulforaphane metabolite has shown significantly worthier activity against HDACs under in vitro conditions. However, the atomistic studies of SFN-NAC against HDAC2 are currently lacking. Thus, the present study employed a hybrid strategy including extra-precision (XP) grid-based flexible molecular docking, molecular mechanics generalized born surface area (MM-GBSA), e-Pharmacophores method, and molecular dynamics simulation for exploring the binding strengh, mode of interaction, e-Pharmacophoric features, and stability of SFN-NAC towards HDAC2. Further, the globally acknowledged density functional theory (DFT) study was performed on SFN-NAC and entinostat individually in complex state with HDAC2. Apart from this, these inhibitors were tested against three distinct cancer cell models and one transformed cell line for cytotoxic activity. Moreover, double mutant of HDAC2 was generated and the binding orientation and interaction of SFN-NAC was scrutinized in this state. On the whole, this study unbosomed and explained the comparatively higher binding affinity of entinostat for HDAC2 and its wide spectrum cytotoxicity than SFN-NAC.}, }
@article {pmid33963542, year = {2021}, author = {Teijeira, A and Garasa, S and Ochoa, MDC and Cirella, A and Olivera, I and Glez-Vaz, J and Andueza, MP and Migueliz, I and Alvarez, M and Rodríguez-Ruiz, ME and Rouzaut, A and Berraondo, P and Sanmamed, MF and Perez Gracia, JL and Melero, I}, title = {Differential Interleukin-8 thresholds for chemotaxis and netosis in human neutrophils.}, journal = {European journal of immunology}, volume = {51}, number = {9}, pages = {2274-2280}, doi = {10.1002/eji.202049029}, pmid = {33963542}, issn = {1521-4141}, mesh = {Acetylcysteine/metabolism ; Chemotaxis/*immunology ; Extracellular Traps/*immunology ; Humans ; Interleukin-8/*immunology ; Neutrophils/*immunology ; Reactive Oxygen Species/metabolism ; Receptors, Interleukin-8A/antagonists &amp; inhibitors/metabolism ; Receptors, Interleukin-8B/antagonists &amp; inhibitors/metabolism ; Signal Transduction/immunology ; }, abstract = {In humans, IL-8 (CXCL8) is a key chemokine for chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages when acting on CXCR1 and CXCR2. CXCL8 activity on neutrophils includes chemotaxis and eliciting the extrusion of neutrophil extracellular traps (NETs). In this study, we show that concentrations of IL-8 that induce NETosis surpass in at least one order of magnitude those required to elicit chemoattraction in human neutrophils. IL-8-induced NETosis was less dependent on G-proteins than migration, while extracellular Ca[+2] chelation similarly inhibited both processes. Reactive oxygen species (ROS) were more important for NETosis than for chemotaxis as evidenced by neutralization with N-acetyl -cysteine. Interestingly, selective blockade with anti-CXCR1 mAb inhibited NETosis much more readily than chemotaxis, while pharmacological inhibition of both CXCR1 and CXCR2, or selective inhibition for CXCR2 alone, similarly inhibited both functions. Together, these results propose a model according to which low concentrations of IL-8 in a gradient attract neutrophils to the inflammatory foci, while high receptor-saturating concentrations of IL-8 give rise to NETosis once leukocytes reach the core of the inflammatory insult.}, }
@article {pmid33959604, year = {2021}, author = {Huang, H and Li, P and Ye, X and Zhang, F and Lin, Q and Wu, K and Chen, W}, title = {Isoalantolactone Increases the Sensitivity of Prostate Cancer Cells to Cisplatin Treatment by Inducing Oxidative Stress.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {632779}, pmid = {33959604}, issn = {2296-634X}, abstract = {Prostate cancer is the most common malignancy among men worldwide. Platinum (II)-based chemotherapy has been used to treat a number of malignancies including prostate cancer. However, the potential of cisplatin for treating prostate cancer is restricted owing to its limited efficacy and toxic side effects. Combination therapies have been proposed to increase the efficacy and reduce the toxic side effects. In the present study, we investigated how isoalantolactone (IATL), a sesquiterpene lactone extracted from the medicinal plant Inula helenium L., acts synergistically with cisplatin on human prostate cancer cells. We show that IATL significantly increased cisplatin-induced growth suppression and apoptosis in human prostate cancer cells. Mechanistically, the combined treatment resulted in an excessive accumulation of intracellular reactive oxygen species (ROS), which leads to the activation of endoplasmic reticulum (ER) stress and the JNK signaling pathway in human prostate cancer cells. Pretreatment of cells with the ROS scavenger N-acetylcysteine (NAC) significantly abrogated the combined treatment-induced ROS accumulation and cell apoptosis. In addition, the activation of ER stress and the JNK signaling pathway prompted by IATL and cisplatin was also reversed by NAC pretreatment. In vivo, we found that IATL combined with cisplatin showed the strongest antitumor effects compared with single agents. These results support the notion that IATL and cisplatin combinational treatment may be more effective for treating prostate cancer than cisplatin alone.}, }
@article {pmid33957094, year = {2021}, author = {Sun, H and Ou, T and Hu, J and Yang, Z and Lei, Q and Li, Y and Wang, G and Li, Y and Wu, K and Wang, S and Wu, S}, title = {Nitazoxanide impairs mitophagy flux through ROS-mediated mitophagy initiation and lysosomal dysfunction in bladder cancer.}, journal = {Biochemical pharmacology}, volume = {190}, number = {}, pages = {114588}, doi = {10.1016/j.bcp.2021.114588}, pmid = {33957094}, issn = {1873-2968}, mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Antiparasitic Agents/pharmacology/therapeutic use ; Dose-Response Relationship, Drug ; Female ; HEK293 Cells ; Humans ; Lysosomes/drug effects/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitophagy/*drug effects/physiology ; Nitro Compounds/*pharmacology/therapeutic use ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Thiazoles/*pharmacology/therapeutic use ; Urinary Bladder Neoplasms/drug therapy/*metabolism ; }, abstract = {Bladder cancer is one of the most common malignancy in the urinary tract with high recurrence and drug resistance in clinics. Alternative treatments from existing drugs might be a promising strategy. Nitazoxanide (NTZ), an FDA-approved antiprotozoal drug, has got increasingly noticed because of its favorable safety profile and antitumor potential, yet the effects in bladder cancer and underlying mechanisms remain poorly understood. Herein, we find that NTZ induces mitochondrial damage and mitophagy initiation through PINK1-generated phospho-ubiquitin(pS65-Ub) and autophagy receptor-mediated pathway even in the absence of Atg5/Beclin1. Meanwhile, NTZ inhibits lysosomal degradation activity, leading to mitophagy flux impairment at late stage. Mitochondrial reactive oxygen species (ROS) production is critical in this process, as eliminating ROS with N-acetylcysteine (NAC) efficiently inhibits PINK1 signaling-mediated mitophagy initiation and alleviates lysosomal dysfunction. Co-treatment with NTZ and autophagy inhibitor Chloroquine (CQ) to aggravate mitophagy flux impairment promotes NTZ-induced apoptosis, while alleviation of mitophagy flux impairment with ROS scavenger reduces cell death. Moreover, we also discover a similar signaling response in the 3D bladder tumor spheroid after NTZ exposure. In vivo study reveals a significant inhibition of orthotopic bladder tumors with no obvious systemic toxicity. Together, our results uncover the anti-tumor activities of NTZ with the involvement of ROS-mediated mitophagy modulation at different stages and demonstrate it as a potential drug candidate for fighting against bladder tumors.}, }
@article {pmid33954959, year = {2022}, author = {El Sharouny, SH and Shaaban, MH and Elsayed, RM and Tahef, AW and Abd ElWahed, MK}, title = {N-acetylcysteine protects against cuprizone-induced demyelination: histological and immunohistochemical study.}, journal = {Folia morphologica}, volume = {81}, number = {2}, pages = {280-293}, doi = {10.5603/FM.a2021.0044}, pmid = {33954959}, issn = {1644-3284}, mesh = {Acetylcysteine/pharmacology ; Animals ; Corpus Callosum/pathology ; *Cuprizone/toxicity ; *Demyelinating Diseases/chemically induced/drug therapy/prevention &amp; control ; Myelin Sheath ; Rats ; }, abstract = {BACKGROUND: Myelination is a sequential process that is tightly controlled by a number of intrinsic and extrinsic factors. Any central nervous system disease in which the neuronal myelin sheath is damaged is referred to as demyelinating disease. The present work was designed to study the histopathological, ultrastructural and immunohistochemical changes in rat brain, mainly corpus callosum (CC), following oral administration of cuprizone (CPZ), and the role of N-acetylcysteine (NAC) in reducing these changes.<br><br>MATERIALS AND METHODS: Demyelination was induced by CPZ administration for short (4 weeks) and long (8 weeks) periods. NAC was given concomitantly and sequentially for similar periods. Spontaneous recovery after cessation of CPZ followed by no medication was also investigated. At the end of each experimental period, both cerebral hemispheres were extracted and prepared for light and electron microscopic examination and immuno-histochemical study.<br><br>RESULTS: The obtained results showed a direct proportion between the duration of CPZ administration and the severity of demyelination. The co-administration of CPZ and NAC, had a fair protective impact that was stronger than the sequential administration of the two drugs. Incomplete spontaneous remyelination was observed after cessation of CPZ, being more evident in short than in long period group, indicating that when CPZ administration is prolonged, remyelination is delayed.<br><br>CONCLUSIONS: In the light of the above results, it could be concluded that NAC has neuroprotective effects and has the potential to be a novel therapeutic approach for the treatment of demyelinating diseases such as multiple sclerosis; however, treatment should begin as soon as the disease manifests.}, }
@article {pmid33953834, year = {2021}, author = {Lim, HM and Lee, J and Nam, MJ and Park, SH}, title = {Acetylshikonin Induces Apoptosis in Human Colorectal Cancer HCT-15 and LoVo Cells via Nuclear Translocation of FOXO3 and ROS Level Elevation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6647107}, pmid = {33953834}, issn = {1942-0994}, mesh = {Anthraquinones/pharmacology/*therapeutic use ; Apoptosis ; Cell Cycle Checkpoints/*genetics ; Cell Proliferation ; Colorectal Neoplasms/*drug therapy ; Drugs, Chinese Herbal/pharmacology/*therapeutic use ; Forkhead Box Protein O3/*metabolism ; Humans ; Reactive Oxygen Species ; }, abstract = {Acetylshikonin, a naphthoquinone, is a pigment compound derived from Arnebia sp., which is known for its anti-inflammatory potential. However, its anticarcinogenic effect has not been well investigated. Thus, in this study, we focused on investigating its apoptotic effects against HCT-15 and LoVo cells, which are human colorectal cancer cells. MTT assay, cell counting assay, and colony formation assay have shown acetylshikonin treatment induced cytotoxic and antiproliferative effects against colorectal cancer cells in a dose- and time-dependent manner. DNA fragmentation was observed via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Also, the increase of subG1 phase in cell cycle arrest assay and early/late apoptotic rates in annexin V/propidium iodide (PI) double staining assay was observed, which indicates an apoptotic potential of acetylshikonin against colorectal cancer cells. 2',7'-Dichlorofluorescin diacetate (DCF-DA) staining was used to evaluate reactive oxygen species (ROS) generation in acetylshikonin-treated colorectal cancer cells. Fluorescence-activated cell sorting (FACS) analysis showed that acetylshikonin induced an increase in reactive oxygen species (ROS) levels and apoptotic rate in a dose- and time-dependent manner in HCT-15 and LoVo cells. In contrast, cotreatment with N-acetyl cysteine (NAC) has reduced ROS generation and antiproliferative effects in colorectal cancer cells. Western blotting analysis showed that acetylshikonin treatment induced increase of cleaved PARP, γH2AX, FOXO3, Bax, Bim, Bad, p21, p27, and active forms of caspase-3, caspase-7, caspase-9, caspase-6, and caspase-8 protein levels, while those of inactive forms were decreased. Also, the expressions of pAkt, Bcl-2, Bcl-xL, peroxiredoxin, and thioredoxin 1 were decreased. Furthermore, western blotting analysis of cytoplasmic and nuclear fractionated proteins showed that acetylshikonin treatment induced the nuclear translocation of FOXO3, which might result from DNA damage by the increased intracellular ROS level. This study represents apoptotic potential of acetylshikonin against colorectal cancer cells via translocation of FOXO3 to the nucleus and upregulation of ROS generation.}, }
@article {pmid33952451, year = {2021}, author = {Jinih, M and Wang, JH and Pfirrmann, RW and O'Leary, DP and Corrigan, MA and Redmond, HP}, title = {Evaluation of the Cytotoxic Effects of the Novel Antineoplastic Agent 1,4,5-Oxathiazinane-4,4-dioxide on Triple Negative Breast Cancer Cells.}, journal = {Anticancer research}, volume = {41}, number = {5}, pages = {2247-2256}, doi = {10.21873/anticanres.15001}, pmid = {33952451}, issn = {1791-7530}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/methods ; Humans ; Molecular Structure ; Reactive Oxygen Species/metabolism ; Triple Negative Breast Neoplasms/metabolism/pathology ; }, abstract = {BACKGROUND/AIM: Adjuvant therapeutic options are limited for triple negative breast cancer (TNBC). Thus, we evaluated the cytotoxic effects of the newly synthesized antineoplastic agent 1,4,5-Oxathiazinane-4,4-dioxide (OTD) on TNBC cells as a potential cancer therapeutic strategy.<br><br>MATERIALS AND METHODS: TNBC primary BT-20 and metastatic MDA-MB-231 cell lines were treated with increasing concentrations of OTD for various time periods to assess cell viability. Cell necrosis, apoptosis, necroptosis, autophagy, and ROS generation were evaluated using assay kits or specific inhibitors.<br><br>RESULTS: Treatment with OTD resulted in a dose- and time-dependent cell death of TNBC BT-20 and MDA-MB-231 cells. OTD also dose-dependently arrested TNBC cell proliferation. Notably, treatment with OTD induced both necrosis and apoptosis of TNBC cells, while the pan-caspase inhibitor Z-VAD-FMK partially attenuated OTD-induced cell death. Importantly, abrogated OTD-induced cell death was observed in the presence of the ROS scavenger N-acetylcysteine (NAC), whereas enhanced OTD-induced cell death was observed after the addition of the glutathione synthesis inhibitor BSO, indicating OTD-induced killing of TNBC cells via a reactive oxygen species-dependent mechanism.<br><br>CONCLUSION: OTD is strongly cytotoxic to both primary and metastatic TNBC cells, possibly by inducing multiple cell death pathways.}, }
@article {pmid33951536, year = {2021}, author = {Ghosh, S and Won, SJ and Wang, J and Fong, R and Butler, NJM and Moss, A and Wong, C and Pan, J and Sanchez, J and Huynh, A and Wu, L and Manfredsson, FP and Swanson, RA}, title = {α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism.}, journal = {Progress in neurobiology}, volume = {202}, number = {}, pages = {102070}, pmid = {33951536}, issn = {1873-5118}, support = {I01 BX003249/BX/BLRD VA/United States ; R01 DK108798/DK/NIDDK NIH HHS/United States ; R01 NS105774/NS/NINDS NIH HHS/United States ; TL4 GM118986/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Cysteine ; Dopamine ; Dopaminergic Neurons/metabolism ; Mice ; Oxidation-Reduction ; *Parkinson Disease/drug therapy ; Substantia Nigra/metabolism ; *alpha-Synuclein/metabolism ; }, abstract = {Oxidative stress and α-synuclein aggregation both drive neurodegeneration in Parkinson's disease, and the protein kinase c-Abl provides a potential amplifying link between these pathogenic factors. Suppressing interactions between these factors may thus be a viable therapeutic approach for this disorder. To evaluate this possibility, pre-formed α-synuclein fibrils (PFFs) were used to induce α-synuclein aggregation in neuronal cultures. Exposure to PFFs induced oxidative stress and c-Abl activation in wild-type neurons. By contrast, α-synuclein - deficient neurons, which cannot form α-synuclein aggregates, failed to exhibit either oxidative stress or c-Abl activation. N-acetyl cysteine, a thiol repletion agent that supports neuronal glutathione metabolism, suppressed the PFF - induced redox stress and c-Abl activation in the wild-type neurons, and likewise suppressed α-synuclein aggregation. Parallel findings were observed in mouse brain: PFF-induced α-synuclein aggregation in the substantia nigra was associated with redox stress, c-Abl activation, and dopaminergic neuronal loss, along with microglial activation and motor impairment, all of which were attenuated with oral N-acetyl cysteine. Similar results were obtained using AAV-mediated α-synuclein overexpression as an alternative means of driving α-synuclein aggregation in vivo. These findings show that α-synuclein aggregates induce c-Abl activation by a redox stress mechanism. c-Abl activation in turn promotes α-synuclein aggregation, in a feed-forward interaction. The capacity of N-acetyl cysteine to interrupt this interaction adds mechanistic support its consideration as a therapeutic in Parkinson's disease.}, }
@article {pmid33948974, year = {2021}, author = {Hung, SW and Zhang, R and Tan, Z and Chung, JPW and Zhang, T and Wang, CC}, title = {Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review.}, journal = {Medicinal research reviews}, volume = {41}, number = {4}, pages = {2489-2564}, pmid = {33948974}, issn = {1098-1128}, mesh = {*Endometriosis/drug therapy ; Female ; Humans ; *Pharmaceutical Preparations ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor A ; }, abstract = {Endometriosis (EM) is defined as endometrial tissues found outside the uterus. Growth and development of endometriotic cells in ectopic sites can be promoted via multiple pathways, including MAPK/MEK/ERK, PI3K/Akt/mTOR, NF-κB, Rho/ROCK, reactive oxidative stress, tumor necrosis factor, transforming growth factor-β, Wnt/β-catenin, vascular endothelial growth factor, estrogen, and cytokines. The underlying pathophysiological mechanisms include proliferation, apoptosis, autophagy, migration, invasion, fibrosis, angiogenesis, oxidative stress, inflammation, and immune escape. Current medical treatments for EM are mainly hormonal and symptomatic, and thus the development of new, effective, and safe pharmaceuticals targeting specific molecular and signaling pathways is needed. Here, we systematically reviewed the literature focused on pharmaceuticals that specifically target the molecular and signaling pathways involved in the pathophysiology of EM. Potential drug targets, their upstream and downstream molecules with key aberrant signaling, and the regulatory mechanisms promoting the growth and development of endometriotic cells and tissues were discussed. Hormonal pharmaceuticals, including melatonin, exerts proapoptotic via regulating matrix metallopeptidase activity while nonhormonal pharmaceutical sorafenib exerts antiproliferative effect via MAPK/ERK pathway and antiangiogenesis activity via VEGF/VEGFR pathway. N-acetyl cysteine, curcumin, and ginsenoside exert antioxidant and anti-inflammatory effects via radical scavenging activity. Natural products have high efficacy with minimal side effects; for example, resveratrol and epigallocatechin gallate have multiple targets and provide synergistic efficacy to resolve the complexity of the pathophysiology of EM, showing promising efficacy in treating EM. Although new medical treatments are currently being developed, more detailed pharmacological studies and large sample size clinical trials are needed to confirm the efficacy and safety of these treatments in the near future.}, }
@article {pmid33947399, year = {2021}, author = {Wang, Y and Li, X and Niu, W and Chen, J and Zhang, B and Zhang, X and Wang, Y and Dang, S and Li, Z}, title = {The alveolar epithelial cells are involved in pulmonary vascular remodeling and constriction of hypoxic pulmonary hypertension.}, journal = {Respiratory research}, volume = {22}, number = {1}, pages = {134}, pmid = {33947399}, issn = {1465-993X}, support = {31670328//National Nature Science Foundation of China/ ; 81800046//National Nature Science Foundation of China/ ; 81471816//National Nature Science Foundation of China/ ; 81571839//National Natural Science Foundation of China/ ; 82070054//National Natural Science Foundation of China/ ; 81200036//National Natural Science Foundation of China/ ; 2019SF-008//Shaanxi Provincial Science and Technology Department (CN)/ ; }, mesh = {Alveolar Epithelial Cells/*metabolism/pathology ; Animals ; Catalase/metabolism ; Cells, Cultured ; Coculture Techniques ; Disease Models, Animal ; Hydrogen Peroxide/metabolism ; Hypertension, Pulmonary/etiology/*metabolism/pathology/physiopathology ; Hypoxia/complications ; Male ; Myocytes, Smooth Muscle/metabolism/pathology ; *Paracrine Communication ; Pulmonary Artery/*metabolism/pathology/physiopathology ; Rats, Sprague-Dawley ; Signal Transduction ; Superoxide Dismutase/metabolism ; *Vascular Remodeling ; *Vasoconstriction ; Rats ; }, abstract = {BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a common type of pulmonary hypertension and characterized by pulmonary vascular remodeling and constriction. Alveolar epithelial cells (AECs) primarily sense alveolar hypoxia, but the role of AECs in HPH remains unclear. In this study, we explored whether AECs are involved in pulmonary vascular remodeling and constriction.<br><br>METHODS: In the constructed rat HPH model, hemodynamic and morphological characteristics were measured. By treating AECs with hypoxia, we further detected the levels of superoxide dismutase 2 (SOD2), catalase (CAT), reactive oxygen species (ROS) and hydrogen peroxide (H2O2), respectively. To detect the effects of AECs on pulmonary vascular remodeling and constriction, AECs and pulmonary artery smooth cells (PASMCs) were co-cultured under hypoxia, and PASMCs and isolated pulmonary artery (PA) were treated with AECs hypoxic culture medium. In addition, to explore the mechanism of AECs on pulmonary vascular remodeling and constriction, ROS inhibitor N-acetylcysteine (NAC) was used.<br><br>RESULTS: Hypoxia caused pulmonary vascular remodeling and increased pulmonary artery pressure, but had little effect on non-pulmonary vessels in vivo. Meanwhile, in vitro, hypoxia promoted the imbalance of SOD2 and CAT in AECs, leading to increased ROS and hydrogen peroxide (H2O2) production in the AECs culture medium. In addition, AECs caused the proliferation of co-cultured PASMCs under hypoxia, and the hypoxic culture medium of AECs enhanced the constriction of isolated PA. However, treatment with ROS inhibitor NAC effectively alleviated the above effects.<br><br>CONCLUSION: The findings of present study demonstrated that AECs were involved in pulmonary vascular remodeling and constriction under hypoxia by paracrine H2O2 into the pulmonary vascular microenvironment.}, }
@article {pmid33946939, year = {2021}, author = {Kobroob, A and Peerapanyasut, W and Kumfu, S and Chattipakorn, N and Wongmekiat, O}, title = {Effectiveness of N-Acetylcysteine in the Treatment of Renal Deterioration Caused by Long-Term Exposure to Bisphenol A.}, journal = {Biomolecules}, volume = {11}, number = {5}, pages = {}, pmid = {33946939}, issn = {2218-273X}, support = {029/2562//Faculty of Medicine, Chiang Mai University/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Administration, Oral ; Animals ; Azotemia/chemically induced/*drug therapy ; Benzhydryl Compounds/*adverse effects ; Disease Models, Animal ; Glomerular Filtration Rate/drug effects ; Lipid Peroxidation/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Phenols/*adverse effects ; Proteinuria/chemically induced/*drug therapy ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; }, abstract = {Human health hazards caused by bisphenol A (BPA), a precursor for epoxy resins and polycarbonate-based plastics, are well documented and are closely associated with mitochondrial impairment and oxidative imbalance. This study aimed to assess the therapeutic efficacy of N-acetylcysteine (NAC) on renal deterioration caused by long-term BPA exposure and examine the signaling transduction pathway involved. Male Wistar rats were given vehicle or BPA orally for 12 weeks then the BPA-treated group was subdivided to receive vehicle or NAC concurrently with BPA for a further 4 weeks, while the vehicle-treated normal control group continued to receive vehicle through to the end of experiment. Proteinuria, azotemia, glomerular filtration reduction and histopathological abnormalities caused by chronic BPA exposure were significantly reduced following NAC therapy. NAC also diminished nitric oxide and lipid peroxidation but enhanced renal glutathione levels, and counteracted BPA-induced mitochondrial swelling, increased mitochondrial reactive oxygen species production, and the loss of mitochondrial membrane potential. The benefit of NAC was related to the modulation of signaling proteins in the AMPK-SIRT3-SOD2 axis. The present study shows the potential of NAC to restore mitochondrial integrity and oxidative balance after long-term BPA exposure, and suggests that NAC therapy is an effective approach to tackle renal deterioration in this condition.}, }
@article {pmid33946527, year = {2021}, author = {Kim, SY and Park, C and Kim, MY and Ji, SY and Hwangbo, H and Lee, H and Hong, SH and Han, MH and Jeong, JW and Kim, GY and Son, CG and Cheong, J and Choi, YH}, title = {ROS-Mediated Anti-Tumor Effect of Coptidis Rhizoma against Human Hepatocellular Carcinoma Hep3B Cells and Xenografts.}, journal = {International journal of molecular sciences}, volume = {22}, number = {9}, pages = {}, pmid = {33946527}, issn = {1422-0067}, support = {NRF-2018R1A2B2005705//National Research Foundation of Korea/ ; NRF-2020R1A2C1099910//National Research Foundation of Korea grant/ ; NRF-2020R1A6C101A201//Korea Basic Science Institute grant/ ; }, mesh = {Animals ; Antineoplastic Agents, Phytogenic/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/*drug therapy/metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; Coptis/chemistry ; Coptis chinensis ; Drugs, Chinese Herbal/pharmacology/*therapeutic use ; Female ; Humans ; Liver Neoplasms/*drug therapy/metabolism ; Mice, Nude ; Reactive Oxygen Species/*metabolism ; Rhizome/chemistry ; Signal Transduction/drug effects ; Mice ; }, abstract = {Coptidis Rhizoma is the dried rhizome from the Coptis chinensis Franch. that has been shown to have a number of beneficial pharmacological properties including antioxidant, anti-inflammatory, and anti-cancer effects. However, the anti-cancer effects of Coptidis Rhizoma on hepatocellular carcinoma (HCC) remain unclear. In this study, we investigated the anti-cancer properties of Coptidis Rhizoma ethanol extract (CR) in HCC Hep3B cells and in a xenograft mouse model. Our results showed that the CR significantly inhibited cell growth and induced apoptosis in Hep3B cells through increased expression of Bcl-2 associated x-protein (Bax) and cleavage of poly-ADP ribose polymerase (PARP), reduced expression of Bcl-2, and activated caspases. CR also increased the generation of intracellular reactive oxygen species (ROS), which caused a loss of mitochondrial membrane potential (MMP, ΔΨm) and activation of the mitochondria-mediated intrinsic apoptosis pathway. Moreover, N-acetylcysteine (NAC), a ROS inhibitor, markedly blocked the effects of CR on apoptotic pathways. CR also induced the expression of light chain 3 (LC3)-I/II, a key autophagy regulator, whereas CR-mediated autophagy was significantly suppressed by NAC. In addition, pre-treatment with NAC perfectly attenuated the inhibition of cell invasion and migration of CR-stimulated Hep3B cells. Furthermore, oral administration of CR suppressed Hep3B tumor growth in xenograft mice without toxicity, alterations to body weight, or changes in hematological and biochemical profiles. Taken together, our findings suggest that CR has anti-tumor effects that result from ROS generation, and may be a potential pharmacological intervention for HCC.}, }
@article {pmid33937072, year = {2021}, author = {Wang, M and Wu, X and Yu, L and Hu, ZY and Li, X and Meng, X and Lv, CT and Kim, GY and Choi, YH and Wang, Z and Xu, HW and Jin, CY}, title = {LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells.}, journal = {Frontiers in oncology}, volume = {11}, number = {}, pages = {658608}, pmid = {33937072}, issn = {2234-943X}, abstract = {Gastric cancer is a global health problem. In this study, we investigate the role of a novel Indole derivative, named LCT-3d, in inhibiting the growth of gastric cancer cells by MTT assay. The Western blotting results showed that LCT-3d modulated the mitochondrial-related proteins and Cleaved-Caspases 3/9, to induce cell apoptosis. The up-regulation of Death receptor 5 (DR5) in MGC803 cells was observed with LCT-3d treatment. Knockdown of DR5 on MGC803 cells partially reversed the LCT-3d-induced mitochondrial apoptosis. The level of Reactive Oxygen Species (ROS) in MGC803 cells was increased with LCT-3d treatment and could be blocked with the pretreatment of the ROS inhibitor N-Acetylcysteine (NAC). The results demonstrate that the elevating ROS can up-regulate the expression of DR5, resulting in apoptosis via mitochondrial pathway. Although the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway served an important role in protecting gastric cancer cells against the injury of ROS, it can't reverse LCT-3d-induced cell apoptosis. Taken together, our study showed that LCT-3d induced apoptosis via DR5-mediated mitochondrial apoptotic pathway in gastric cancer cells. LCT-3d could be a novel lead compound for development of anti-cancer activity in gastric cancer.}, }
@article {pmid33936275, year = {2021}, author = {Mu, P and Hu, Y and Ma, X and Shi, J and Zhong, Z and Huang, L}, title = {Total flavonoids of Rhizoma Drynariae combined with calcium attenuate osteoporosis by reducing reactive oxygen species generation.}, journal = {Experimental and therapeutic medicine}, volume = {21}, number = {6}, pages = {618}, pmid = {33936275}, issn = {1792-0981}, abstract = {In the present study, the effects of total flavonoids of Rhizoma Drynariae (TFRD) and calcium carbonate (CaCO3) on osteoporosis (OP) were assessed in a rat model of OP. For this purpose, 36 Sprague-Dawley rats, aged 3 months, were randomly divided into a group undergoing sham surgery (sham-operated group), model group (OP group), CaCO3 group (OP + CaCO3 group), TFRD group (OP + TFRD group), TFRD combined with CaCO3 group (OP + TFRD + CaCO3 group) and TFRD and CaCO3 combined with N-acetyl cysteine group (OP + TFRD + CaCO3 + NAC group). The rat model of OP was established by bilateral ovariectomy. The changes in bone mineral density (BMD), bone volume parameters and bone histopathology in the rats from each group were observed. The levels of serum reactive oxygen species, superoxide dismutase (SOD), malondialdehyde, glutathione peroxidase (GSH-Px), interleukin (IL)-6, IL-1β, TNF-α, and the levels of bone tissue runt-related transcription factor 2 (RUNX2), osteoprotegerin (OPG), osteocalcin (BGP), PI3K, p-PI3K, AKT, p-AKT, mammalian target of rapamycin (mTOR) and p-mTOR were measured in the rats of each group. The induction of OP was associated with a marked decrease in BMD, bone mineral content, bone volume fraction and trabecular thickness, and decreased serum levels of SOD and GSH-Px. Moreover, the expressions of RUNX2, OPG, BGP were downregulated and an upregulation of p-PI3K, p-AKT and p-mTOR were observed in osteoporotic rats. However, treatment with TFRD and CaCO3 restored all the aforementioned parameters to almost normal values. Furthermore, the findings on histopathological evaluation were consistent with the biochemical observations. Taken together, the findings of the present study demonstrated that TFRD and CaCO3 significantly increased the antioxidant capacity in rats with OP, increased BMD and reduced bone mineral loss, and may be useful for the prevention and treatment of OP.}, }
@article {pmid33933708, year = {2021}, author = {Owumi, S and Bello, T and Oyelere, AK}, title = {N-acetyl cysteine abates hepatorenal toxicities induced by perfluorooctanoic acid exposure in male rats.}, journal = {Environmental toxicology and pharmacology}, volume = {86}, number = {}, pages = {103667}, doi = {10.1016/j.etap.2021.103667}, pmid = {33933708}, issn = {1872-7077}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Aspartate Aminotransferases/blood ; Caprylates/*toxicity ; Creatinine/blood ; Fluorocarbons/*toxicity ; Kidney/*drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Liver/*drug effects/metabolism/pathology ; Male ; Oxidative Stress/drug effects ; Oxidoreductases/metabolism ; Rats, Wistar ; Urea/blood ; gamma-Glutamyltransferase/blood ; Rats ; }, abstract = {Ingestion of perfluorooctanoic acid (PFOA) elicits toxicities in the hepatorenal system. We investigated the effect of PFOA and N-acetylcysteine (NAC) on the hepatorenal function of rats treated thus: control, PFOA (5 mg/kg), NAC (50 mg/kg), PFOA + NAC (5 and 25 mg/kg), and PFOA + NAC (5 and 50 mg/kg). We observed that NAC significantly (p < 0.05) reduced PFOA-induced increase in hepatic and renal function biomarkers of toxicities relative to PFOA alone and alleviated (p < 0.05) decreases in antioxidant status. Increases in oxidative stress and lipid peroxidation in PFOA-treated rats were reverted to normal by NAC and abated increased pro-inflammatory mediators, and decreased anti-inflammatory cytokine both in the hepatorenal system PFOA treated rats. Histology of the kidney and liver indicated that NAC, abated the severity of PFOA-induced damage significantly. Our findings affirm further that oxido-inflammatory mediators involved in PFOA-mediated toxicity can be effectively blocked by NAC through its antioxidant activity.}, }
@article {pmid33932069, year = {2021}, author = {Sun, B and Yu, L and Xu, C and Li, YM and Zhao, YR and Cao, MM and Yang, LY}, title = {NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1α signaling in hepatocellular carcinoma.}, journal = {Cancer science}, volume = {112}, number = {7}, pages = {2753-2769}, pmid = {33932069}, issn = {1349-7006}, support = {81773139//National Natural Science Foundation of China/ ; 81330057//Key Project of National Nature Science Foundation of China/ ; 2017ZX10203207-002-003//National Science &amp; Technology Major Project/ ; 20130162130007//Specialized Research Fund for Doctoral Program of Higher Education of China/ ; 2016YFC0902400//National Key R&amp;D Program of China/ ; }, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Carcinoma, Hepatocellular/*metabolism/mortality/secondary ; Cell Movement ; Disease Progression ; Disease-Free Survival ; Down-Regulation ; Epithelial-Mesenchymal Transition ; Female ; Free Radical Scavengers/pharmacology ; Heterografts ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Liver Neoplasms/*metabolism/mortality ; Male ; Mice ; Middle Aged ; NADP/metabolism ; Neoplasm Invasiveness ; Neoplasm Proteins/metabolism ; Neoplasm Transplantation ; Oxidation-Reduction ; Racemases and Epimerases/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Risk Factors ; }, abstract = {Reactive oxygen species (ROS) derived from aberrant tumor metabolism could contribute to tumor invasion and metastasis. NAD(P)HX Epimerase (NAXE), an epimerase that allows the repair of damaged forms of antioxidant NADPH, is a potential cellular ROS scavenger and its role in tumor development is still elusive. Here, we found that NAXE is significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. NAXE downregulation is associated with poor clinicopathological characteristics and is an independent risk factor for overall and disease-free survival of HCC patients after liver resection. In addition, low NAXE expression could identify worse prognosis of HCC patients before vascular invasion or in early stages of disease. In particularly, low NAXE expression in HCC is markedly associated with microvascular invasion (MVI) and its combination with MVI predicts poorer prognosis of HCC patients after liver resection. Furthermore, in vitro and in vivo experiments both showed that knockdown of NAXE expression in HCC cells promoted migration, invasion, and metastasis by inducing epithelial-mesenchymal transition (EMT), whereas NAXE overexpression causes the opposite effects. Mechanistically, low NAXE expression reduced NADPH levels and further caused ROS level increase and hypoxia-inducible factor-1α (HIF-1α) activation, thereby promoting invasion and metastasis of HCC by facilitating EMT. What is more, the tumor-promoting effect of NAXE knockdown in HCC xenograft can be abolished by giving mice N-acetyl-l-cysteine (NAC) in drinking water. Taken together, our findings uncovered a tumor suppressor role for NAXE in HCC by scavenging excessive ROS and inhibiting tumor-promoting signaling pathways, suggesting a new strategy for HCC therapy by targeting redox signaling.}, }
@article {pmid33928830, year = {2021}, author = {Bo, L and Jin, F and Ma, Z and Li, C}, title = {Redox signaling and antioxidant therapies in acute respiratory distress syndrome: a systematic review and meta-analysis.}, journal = {Expert review of respiratory medicine}, volume = {15}, number = {10}, pages = {1355-1365}, doi = {10.1080/17476348.2021.1924681}, pmid = {33928830}, issn = {1747-6356}, mesh = {Acetylcysteine/therapeutic use ; *Acute Lung Injury ; Antioxidants/*therapeutic use ; Humans ; Oxidation-Reduction ; *Respiratory Distress Syndrome/diagnosis/drug therapy ; }, abstract = {Objectives: No pharmacologic treatment that targets the pathophysiologic alterations of acute respiratory distress syndrome (ARDS) has proven effective. Previous studies have revealed overactive oxidative stress as a potential therapeutic target. Thus we conducted this systematic review to assess the efficacyof antioxidant therapy on the clinical outcomes of ARDS patients.Methods: We retrieved clinical trials from electronic databases. Articles and conference abstracts about antioxidant therapies for patients with ARDS were identified in which the overall effect of each antioxidant therapy on the mortality of ARDS patients was summarized.Results: We identified 18 relevant studies that met the inclusion criteria, including 899 patients in the experimental group and 870 patients in the control group. The pooled results indicated that most antioxidant therapies could not improve all-cause mortality and might even be harmful in ARDS patients at low risk of death.Conclusion: Unclassified patients could not benefit from the antioxidant therapies, and thus discretion must be exercised when using these therapies.Abbreviations ARDS: Acute respiratory distress syndrome; ICU: Intensive care unit; NAC: N-acetylcysteine; ROS: Reactive oxygen species; RNS: Reactive nitrogen species; RR: Relative risk; CI: Confidence interval; OTC: L-2-oxothiazolidine-4-carboxylic acid; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; GLA: Gamma-linolenic acid; NA: Not applicable; PaO2/FiO2 ratio: The ratio of partial pressure arterial oxygen and fraction of inspired oxygen; ALI: Acute lung injury.}, }
@article {pmid33925826, year = {2021}, author = {Plano, SA and Baidanoff, FM and Trebucq, LL and Suarez, S&#xc1; and Doctorovich, F and Golombek, DA and Chiesa, JJ}, title = {Redox and Antioxidant Modulation of Circadian Rhythms: Effects of Nitroxyl, N-Acetylcysteine and Glutathione.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {9}, pages = {}, pmid = {33925826}, issn = {1420-3049}, support = {PICT 2099/1745//Agencia Nacional de Promoci&#xf3;n de la Ciencia y la Tecnolog&#xed;a/ ; 1310/19//Universidad Nacional de Quilmes/ ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Antioxidants/metabolism/*pharmacology ; Biosensing Techniques ; Circadian Clocks/drug effects/physiology ; Circadian Rhythm/*drug effects/*physiology ; Electrochemical Techniques ; Glutathione/metabolism/pharmacology ; Nitric Oxide/metabolism ; Nitrites/pharmacology ; Nitrogen Oxides/metabolism/pharmacology ; Oxidation-Reduction/*drug effects ; Photoperiod ; }, abstract = {The circadian clock at the hypothalamic suprachiasmatic nucleus (SCN) entrains output rhythms to 24-h light cycles. To entrain by phase-advances, light signaling at the end of subjective night (circadian time 18, CT18) requires free radical nitric oxide (NO•) binding to soluble guanylate cyclase (sGC) heme group, activating the cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). Phase-delays at CT14 seem to be independent of NO•, whose redox-related species were yet to be investigated. Here, the one-electron reduction of NO• nitroxyl was pharmacologically delivered by Angeli's salt (AS) donor to assess its modulation on phase-resetting of locomotor rhythms in hamsters. Intracerebroventricular AS generated nitroxyl at the SCN, promoting phase-delays at CT14, but potentiated light-induced phase-advances at CT18. Glutathione/glutathione disulfide (GSH/GSSG) couple measured in SCN homogenates showed higher values at CT14 (i.e., more reduced) than at CT18 (oxidized). In addition, administration of antioxidants N-acetylcysteine (NAC) and GSH induced delays per se at CT14 but did not affect light-induced advances at CT18. Thus, the relative of NO• nitroxyl generates phase-delays in a reductive SCN environment, while an oxidative favors photic-advances. These data suggest that circadian phase-locking mechanisms should include redox SCN environment, generating relatives of NO•, as well as coupling with the molecular oscillator.}, }
@article {pmid33923265, year = {2021}, author = {Maharaj, D and Srinivasan, G and Makepeace, S and Hickey, CJ and Gouvea, J}, title = {Clinical Remission Using Personalized Low-Dose Intravenous Infusions of N-acetylcysteine with Minimal Toxicities for Interstitial Cystitis/Bladder Pain Syndrome.}, journal = {Journal of personalized medicine}, volume = {11}, number = {5}, pages = {}, pmid = {33923265}, issn = {2075-4426}, abstract = {Interstitial Cystitis or Bladder Pain Syndrome (IC/BPS) is a heterogeneous condition characterized by elevated levels of inflammatory cytokines, IL-1β, IL-6, IL-8, IL-10, TNF-α, and is associated with debilitating symptoms of pelvic pain and frequent urination. A standard of care for IC/BPS has not been established, and most patients must undergo a series of different treatment options, with potential for severe adverse events. Here, we report a patient with a 26-year history of IC/BPS following treatment with multiple therapies, including low doses of etodolac, amitriptyline and gabapentin, which she was unable to tolerate because of adverse effects, including headaches, blurred vision and cognitive impairment. The patient achieved a complete clinical remission with minimal adverse events after 16 cycles of N-acetylcysteine (NAC) intravenous (IV) infusions over a period of 5 months, and pro-inflammatory cytokine levels were reduced when compared to measurements taken at presentation. Personalized low dose NAC IV infusion therapy represents an effective, safe, anti-inflammatory therapy administered in the outpatient setting for IC/BPS, and warrants further investigation.}, }
@article {pmid33921050, year = {2021}, author = {Chang, SN and Khan, I and Kim, CG and Park, SM and Choi, DK and Lee, H and Hwang, BS and Kang, SC and Park, JG}, title = {Decursinol Angelate Arrest Melanoma Cell Proliferation by Initiating Cell Death and Tumor Shrinkage via Induction of Apoptosis.}, journal = {International journal of molecular sciences}, volume = {22}, number = {8}, pages = {}, pmid = {33921050}, issn = {1422-0067}, support = {(S2983880)//Ministry of SMEs and Startups/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; *Apoptosis/drug effects ; Autophagosomes/drug effects/metabolism ; Benzopyrans/*pharmacology/toxicity ; Butyrates/*pharmacology/toxicity ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; Male ; Melanoma/*pathology ; Melanoma, Experimental/pathology ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/drug effects/metabolism ; Mitochondrial Membranes/drug effects/metabolism ; Models, Biological ; Reactive Oxygen Species/metabolism ; Skin Neoplasms/*pathology ; Mice ; }, abstract = {Melanoma is known to aggressively metastasize and is one of the prominent causes of skin cancer mortality. This study was designed to assess the molecular mechanism of decursinol angelate (DA) against murine melanoma cell line (B16F10 cells). Treatment of DA resulted in growth inhibition and cell cycle arrest at G0/G1 (p < 0.001) phase, evaluated through immunoblotting. Moreover, autophagy-related proteins such as ATG-5 (p < 0.0001), ATG-7 (p < 0.0001), beclin-1 (p < 0.0001) and transition of LC3-I to LC3-II (p < 0.0001) were markedly decreased, indicating autophagosome inhibition. Additionally, DA treatment triggered apoptotic events which were corroborated by the occurrence of distorted nuclei, elevated reactive oxygen species (ROS) levels and reduction in the mitochondrial membrane potential. Subsequently, there was an increase in the expression of pro-apoptotic protein Bax in a dose-dependent manner, with the corresponding downregulation of Bcl-2 expression and cytochrome C expression following 24 h DA treatment in A375.SM and B16F10 cells. We substantiated our results for apoptotic occurrence through flow cytometry in B16F10 cells. Furthermore, we treated B16F10 cells with N-acetyl-L-cysteine (NAC). NAC treatment upregulated ATG-5 (p < 0.0001), beclin-1 (p < 0.0001) and LC3-I to LC3-II (p < 0.0001) conversion, which was inhibited in the DA treatment group. We also noticed a systematic upregulation of important markers for progression of G1 cell phase such as CDK-2 (p < 0.029), CDK-4 (p < 0.036), cyclin D1 (p < 0.0003) and cyclin E (p < 0.020) upon NAC treatment. In addition, we also observed a significant fold reduction (p < 0.05) in ROS fluorescent intensity and the expression of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase-9 (p > 0.010) and cleaved caspase-3 (p < 0.0001). NAC treatment was able to ameliorate DA-induced apoptosis and cell cycle arrest to support our finding. Our in vivo xenograft model also revealed similar findings, such as downregulation of CDK-2 (p < 0.0001) and CDK-4 (p < 0.0142) and upregulation of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase 3 (p < 0.0001) and cleaved caspase 9 (p < 0.0001). In summary, our study revealed that DA is an effective treatment against B16F10 melanoma cells and xenograft mice model.}, }
@article {pmid33918532, year = {2021}, author = {Picchi, V and Gobbi, S and Fattizzo, M and Zefelippo, M and Faoro, F}, title = {Chitosan Nanoparticles Loaded with N-Acetyl Cysteine to Mitigate Ozone and Other Possible Oxidative Stresses in Durum Wheat.}, journal = {Plants (Basel, Switzerland)}, volume = {10}, number = {4}, pages = {}, pmid = {33918532}, issn = {2223-7747}, support = {ID052- Project NANO-TOX//Ministero delle Politiche Agricole Alimentari e Forestali/ ; }, abstract = {Modern durum wheat cultivars are more prone to ozone stress because of their high photosynthetic efficiency and leaf gas exchanges that cause a greater pollutant uptake. This, in turn, generates an increased reactive oxygen species (ROS) production that is a challenge to control by the antioxidant system of the plant, therefore affecting final yield, with a reduction up to 25%. With the aim of mitigating oxidative stress in wheat, we used chitosan nanoparticles (CHT-NPs) either unloaded or loaded with the antioxidant compound N-acetyl cysteine (NAC), on plants grown either in a greenhouse or in an open field. NAC-loaded NPs were prepared by adding 0.5 mg/mL NAC to the CHT solution before ionotropic gelation with tripolyphosphate (TTP). Greenhouse experiments evidenced that CHT-NPs and CHT-NPs-NAC were able to increase the level of the leaf antioxidant pool, particularly ascorbic acid (AsA) content. However, the results of field trials, while confirming the increase in the AsA level, at least in the first phenological stages, were less conclusive. The presence of NAC did not appear to significantly affect the leaf antioxidant pool, although the grain yield was slightly higher in NAC-treated parcels. Furthermore, both NAC-loaded and -unloaded CHT-NPs partially reduced the symptom severity and increased the weight of 1000 seeds, thus showing a moderate mitigation of ozone injury.}, }
@article {pmid33915137, year = {2021}, author = {Leão-Torres, AG and Pires, CV and Ribelato, AC and Zerbinatti, MC and Santarém, CL and Nogueira, RMB and Giometti, IC and Giuffrida, R and Silva, EO and Gerez, JR and Silva, NJ and Rowan, EG and Floriano, RS}, title = {Protective action of N-acetyl-L-cysteine associated with a polyvalent antivenom on the envenomation induced by Lachesis muta muta (South American bushmaster) in rats.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {198}, number = {}, pages = {36-47}, doi = {10.1016/j.toxicon.2021.04.018}, pmid = {33915137}, issn = {1879-3150}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antivenins/therapeutic use ; *Crotalid Venoms/toxicity ; Male ; Rats ; Rats, Wistar ; Viper Venoms/toxicity ; *Viperidae ; }, abstract = {In this study, we examined the potential use of N-acetyl-L-cysteine (NAC) in association with a polyvalent antivenom and as stand-alone therapy to reduce the acute local and systemic effects induced by Lachesis muta muta venom in rats. Male Wistar rats (300-350 g) were exposed to L. m. muta venom (1.5 mg/kg - i.m.) and subsequently treated with anti-Bothrops/Lachesis serum (antivenom:venom ratio 1:3 'v/w' - i.p.) and NAC (150 mg/kg - i.p.) separately or in association; the animals were monitored for 120 min to assess changes in temperature, locomotor activity, local oedema formation and the prevalence of haemorrhaging. After this time, animals were anesthetized in order to collect blood samples through intracardiac puncture and then euthanized for collecting tissue samples; the hematological-biochemical and histopathological analyses were performed through conventional methods. L. m. muta venom produced pronounced local oedema, subcutaneous haemorrhage and myonecrosis, with both antivenom and NAC successfully reducing the extent of the myonecrotic lesion when individually administered; their association also prevented the occurrence of subcutaneous haemorrhage. Venom-induced creatine kinase (CK) release was significantly prevented by NAC alone or in combination with antivenom; NAC alone failed to reduce the release of hepatotoxic (alanine aminotransferase) and nephrotoxic (creatinine) serum biomarkers induced by L. m. muta venom. Venom induced significant increase of leucocytes which was also associated with an increase of neutrophils, eosinophils and monocytes; antivenom and NAC partially reduced these alterations, with NAC alone significantly preventing the increase of eosinophils whereas neither NAC or antivenom prevented the increase in monocytes. Venom did not induce changes in the erythrogram parameters. In the absence of a suitable antivenom, NAC has the potential to reduce a number of local and systemic effects caused by L. m. muta venom.}, }
@article {pmid33911809, year = {2021}, author = {Choi, DI and Park, JH and Choi, JY and Piao, M and Suh, MS and Lee, JB and Yun, SJ and Lee, SC}, title = {Keratinocytes-Derived Reactive Oxygen Species Play an Active Role to Induce Type 2 Inflammation of the Skin: A Pathogenic Role of Reactive Oxygen Species at the Early Phase of Atopic Dermatitis.}, journal = {Annals of dermatology}, volume = {33}, number = {1}, pages = {26-36}, pmid = {33911809}, issn = {2005-3894}, abstract = {BACKGROUND: Atopic dermatitis (AD) is characterized by chronic, relapsing skin inflammation (eczema) with itchy sensation. Keratinocytes, which are located at the outermost part of our body, are supposed to play important roles at the early phase of type 2 inflammation including AD pathogenesis.<br><br>OBJECTIVE: The purpose of this study was to evaluate whether keratinocytes-derived reactive oxygen species (ROS) could be produced by the allergens or non-allergens, and the keratinocytes-derived ROS could modulate a set of biomarkers for type 2 inflammation of the skin.<br><br>METHODS: Normal human epidermal keratinocytes (NHEKs) were treated with an allergen of house dust mites (HDM) or a non-allergen of compound 48/80 (C48/80). Then, biomarkers for type 2 inflammation of the skin including those for neurogenic inflammation were checked by reverse transcriptase-polymerase chain reaction and western immunoblot experiments.<br><br>RESULTS: HDM or C48/80 was found to upregulate expression levels of our tested biomarkers, including type 2 T helper-driving pathway (KLK5, PAR2, and NF&#x3ba;B), epithelial-cell-derived cytokines (thymic stromal lymphopoietin, interleukin [IL]-25, IL-33), and neurogenic inflammation (NGF, CGRP). The HDM- or C-48/80-induced expression levels of the biomarkers could be blocked by an antioxidant treatment with 5 mM N-acetyl-cysteine. In contrast, pro-oxidant treatment with 1 mM H2O2 could upregulate expression levels of the tested biomarkers in NHEKs.<br><br>CONCLUSION: Our results reveal that keratinocytes-derived ROS, irrespective to their origins from allergens or non-allergens, have a potential to induce type 2 inflammation of AD skin.}, }
@article {pmid33908986, year = {2021}, author = {Aghababaei, M and Luek, JL and Ziemkiewicz, PF and Mouser, PJ}, title = {Toxicity of hydraulic fracturing wastewater from black shale natural-gas wells influenced by well maturity and chemical additives.}, journal = {Environmental science. Processes &amp; impacts}, volume = {23}, number = {4}, pages = {621-632}, doi = {10.1039/d1em00023c}, pmid = {33908986}, issn = {2050-7895}, mesh = {*Hydraulic Fracking ; Natural Gas ; Oil and Gas Fields ; Wastewater ; *Water Pollutants, Chemical/analysis/toxicity ; }, abstract = {Hydraulic fracturing of deep shale formations generates large volumes of wastewater that must be managed through treatment, reuse, or disposal. Produced wastewater liberates formation-derived radionuclides and contains previously uncharacterized organohalides thought to be generated within the shale well, both posing unknown toxicity to human and ecological health. Here, we assess the toxicity of 42 input media and produced fluid samples collected from four wells in the Utica formation and Marcellus Shale using two distinct endpoint screening assays. Broad spectrum acute toxicity was assessed using a bioluminescence inhibition assay employing the halotolerant bacterium Aliivibrio fischeri, while predictive mammalian cytotoxicity was evaluated using a N-acetylcysteine (NAC) thiol reactivity assay. The acute toxicity and thiol reactivity of early-stage flowback was higher than later produced fluids, with levels diminishing through time as the natural gas wells matured. Acute toxicity of early stage flowback and drilling muds were on par with the positive control, 3,5-dichlorophenol (6.8 mg L-1). Differences in both acute toxicity and thiol reactivity between paired natural gas well samples were associated with specific chemical additives. Samples from wells containing a larger diversity and concentration of organic additives resulted in higher acute toxicity, while samples from a well applying a higher composition of ammonium persulfate, a strong oxidizer, showed greater thiol reactivity, predictive of higher mammalian toxicity. Both acute toxicity and thiol reactivity are consistently detected in produced waters, in some cases present up to nine months after hydraulic fracturing. These results support that specific chemical additives, the reactions generated by the additives, or the constituents liberated from the formation by the additives contribute to the toxicity of hydraulic fracturing produced waters and reinforces the need for careful consideration of early produced fluid management.}, }
@article {pmid33906513, year = {2021}, author = {Wei, G and Zhou, Z and Cui, Y and Huang, Y and Wan, Z and Che, X and Chai, Y and Zhang, Y}, title = {A Meta-Analysis of the Efficacy of L-Carnitine/L-Acetyl-Carnitine or N-Acetyl-Cysteine in Men With Idiopathic Asthenozoospermia.}, journal = {American journal of men's health}, volume = {15}, number = {2}, pages = {15579883211011371}, pmid = {33906513}, issn = {1557-9891}, mesh = {Acetylcarnitine ; Acetylcysteine ; *Asthenozoospermia/drug therapy ; Carnitine ; Humans ; Male ; Sperm Motility ; }, abstract = {The meta-analysis was performed to access efficacy of L-carnitine/L-acetyl-carnitine (LC/LAC) and N-acetyl-cysteine (NAC) in men with idiopathic asthenozoospermia. We researched PubMed, EMBASE, and Cochrane Library databases and references to related articles. Finally, seven articles including 621 patients were analyzed. The results indicated that LC/LAC and NAC had a considerable improvement in sperm motility (p = .03 and p < .0001, respectively) and normal morphology (p = .006, p = .0002, respectively) compared with the placebo group. Besides, NAC had a significantly greater increase in sperm concentration (p < .00001) and ejaculate volume (p = .002) compared with the placebo group, and there was no significant difference in LC/LAC. For the analysis of serum hormones, NAC had no obvious differences in improving the serum testosterone, luteinizing hormone, follicle-stimulating hormone, and prolactin compared with non-treatment group. Conclusively, LC/LAC and NAC showed a greater improvement in sperm motility and normal morphology. Moreover, NAC has a positive effect on sperm concentration and ejaculate volume, whereas no obvious effect was observed in serum hormones.}, }
@article {pmid33905761, year = {2021}, author = {Li, H and Wang, M and Kang, W and Lin, Z and Gan, F and Huang, K}, title = {Non-cytotoxic dosage of fumonisin B1 aggravates ochratoxin A-induced nephrocytotoxicity and apoptosis via ROS-dependent JNK/MAPK signaling pathway.}, journal = {Toxicology}, volume = {457}, number = {}, pages = {152802}, doi = {10.1016/j.tox.2021.152802}, pmid = {33905761}, issn = {1879-3185}, mesh = {Animals ; Apoptosis/*drug effects/physiology ; Cell Line ; Fumonisins/administration &amp; dosage/*toxicity ; Kidney/*drug effects/metabolism/pathology ; MAP Kinase Signaling System/*drug effects ; Ochratoxins/administration &amp; dosage/*toxicity ; Oxidative Stress/drug effects/physiology ; *Reactive Oxygen Species/metabolism ; Swine ; }, abstract = {Ochratoxin A (OTA) and fumonisin B1 (FB1), two of the most toxicologically important mycotoxins, often coexist in a variety of foodstuff and feed in humans and animals. Because of the low content of FB1 in foodstuff and feed, alone harmfulness of FB1 is often ignored. However, it is unknown whether the lower dosage of FB1 aggravates the toxicity of other mycotoxins. In this article, we aimed to investigate the effects of the lower dosage of FB1 on OTA-induced nephrotoxicity and apoptosis, and its underlying mechanism in porcine kidney cells (PK-15). Our current study showed that the non-cytotoxic concentration of FB1 (8 μM) could enhance OTA(5 μM)-induced nephrocytotoxicity and the expression of pro-apoptosis-associated genes in PK-15 cells. We also observed that the production of reactive oxygen species (ROS) was increased. However, the expression of pro-apoptosis-associated genes were down-regulated when the N-acetylcysteine (NAC), a ROS scavenger, was used in our experiment. Besides, we found that the combined toxins could increase the protein expression of p-JNK instead of p-p38 and p-ERK. Pretreatment with SP600125, a JNK inhibitor, could significantly block the promotion effects of FB1 on OTA-induced nephrocytotoxicity and apoptosis. The protein expression of p-JNK was also inhibited and the promotion effects of FB1 were significantly alleviated when NAC was used. In conclusion, the non-cytotoxic dosage of FB1 could aggravate the nephrocytotoxicity and apoptosis caused by OTA via ROS-dependent JNK/MAPK signaling pathway.}, }
@article {pmid33902598, year = {2021}, author = {Ni, Z and Sun, W and Li, R and Yang, M and Zhang, F and Chang, X and Li, W and Zhou, Z}, title = {Fluorochloridone induces autophagy in TM4 Sertoli cells: involvement of ROS-mediated AKT-mTOR signaling pathway.}, journal = {Reproductive biology and endocrinology : RB&amp;E}, volume = {19}, number = {1}, pages = {64}, pmid = {33902598}, issn = {1477-7827}, support = {81872643//National Natural Science Foundation of China/ ; }, mesh = {Acetates/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Autophagy/*drug effects/physiology ; Benzopyrans/pharmacology ; Cell Shape ; Endocrine Disruptors/*pharmacology ; Herbicides/*pharmacology/toxicity ; Male ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-akt/*physiology ; Pyrrolidinones/*pharmacology/toxicity ; Random Allocation ; Reactive Oxygen Species ; Sertoli Cells/cytology/*drug effects/metabolism ; Signal Transduction/*physiology ; Spermatozoa/drug effects/ultrastructure ; TOR Serine-Threonine Kinases/*physiology ; }, abstract = {BACKGROUND: Fluorochloridone (FLC), a selective pyrrolidone herbicide, has been recognized as a potential endocrine disruptor and reported to induce male reproductive toxicity, but the underlying mechanism is unclear. The aim of this study was to investigate the mechanism of FLC-induced reproductive toxicity on male mice with particular emphasis on the role of autophagy in mice' TM4 Sertoli cells.<br><br>METHODS: Adult C57BL/6 mice were divided into one control group (0.5% sodium carboxymethyl cellulose), and four FLC-treated groups (3,15,75,375&#x2009;mg/kg). The animals (ten mice per group) received gavage for 28&#x2009;days. After treatment, histological analysis, sperm parameters, the microstructure of autophagy and the expression of autophagy-associated proteins in testis were evaluated. Furthermore, to explore the autophagy mechanism, TM4 Sertoli cells were treated with FLC (0,40,80,160&#x2009;&#x3bc;M) in vitro for 24&#x2009;h. Cell activity and cytoskeletal changes were measured by MTT assay and F-actin immunofluorescence staining. The formation of autophagosome, accumulation of reactive oxygen species (ROS), expression of autophagy marker proteins (LC3, Beclin-1 and P62) and AKT-related pathway proteins (AKT, mTOR) were observed. The ROS scavenger N-acetylcysteine (NAC) and AKT agonist (SC79) were used to treat TM4 cells to observe the changes of AKT-mTOR pathway and autophagy.<br><br>RESULTS: In vivo, it showed that FLC exposure caused testicular injuries, abnormality in epididymal sperm. Moreover, FLC increased the formation of autophagosomes, the accumulation of LC3II/LC3I, Beclin-1 and P62 protein, which is related to the degradation of autophagy. In vitro, FLC triggered TM4 cell autophagy by increasing the formation of autophagosomes and upregulating of LC3II/LC3I, Beclin-1 and P62 levels. In addition, FLC induced ROS production and inhibited the activities of AKT and mTOR kinases. The Inhibition of AKT/mTOR signaling pathways and the activation of autophagy induced by FLC could be efficiently reversed by pretreatment of NAC. Additionally, decreased autophagy and increased cell viability were observed in TM4 cells treated with SC79 and FLC, compared with FLC alone, indicating that FLC-induced autophagy may be pro-death.<br><br>CONCLUSION: Taken together, our study provided the evidence that FLC promoted autophagy in TM4 Sertoli cells and that this process may involve ROS-mediated AKT/mTOR signaling pathways.}, }
@article {pmid33901579, year = {2021}, author = {Che, J and Lv, H and Yang, J and Zhao, B and Zhou, S and Yu, T and Shang, P}, title = {Iron overload induces apoptosis of osteoblast cells via eliciting ER stress-mediated mitochondrial dysfunction and p-eIF2α/ATF4/CHOP pathway in vitro.}, journal = {Cellular signalling}, volume = {84}, number = {}, pages = {110024}, doi = {10.1016/j.cellsig.2021.110024}, pmid = {33901579}, issn = {1873-3913}, mesh = {Activating Transcription Factor 4/metabolism ; Animals ; Apoptosis ; Endoplasmic Reticulum Stress ; Eukaryotic Initiation Factor-1 ; *Eukaryotic Initiation Factor-2/metabolism ; Humans ; *Iron Overload/metabolism ; Mice ; Mitochondria/metabolism ; Osteoblasts/metabolism ; Reactive Oxygen Species/metabolism ; Transcription Factor CHOP ; }, abstract = {Iron is an essential element for crucial biological function; whereas excess iron sedimentation impairs the main functions of tissues or organs. Cumulative researches have shown that the disturbances in iron metabolism, especially iron overload is closely concatenating with bone loss. Nevertheless, the specific process of iron overload-induced apoptosis in osteoblasts has not been thoroughly studied. In this study, our purpose is to elucidate the mechanism of osteoblast apoptosis induced by iron overload via the MC3T3-E1 cell line. Ferric ammonium citrate (FAC) was utilized to simulate iron overload conditions in vitro. These results showed that treatment with FAC dose-dependently induced the apoptosis of MC3T3-E1 cells at 48 h, dysfunction of iron metabolism, and increased intracellular reactive oxygen species (ROS) levels. Following, FAC does-dependently caused the calcium dyshomeostasis, decreased the calcium concentration in endoplasmic reticulum (ER), but increased the crosstalk between ER and mitochondria, and calcium concentration in the mitochondria. Moreover, FAC dose-dependently decreased mitochondrial membrane potential (MMP) and enhanced the expression of apoptosis related proteins (Bax, Cyto-C and C-caspase3). We furthermore revealed that FAC treatment activated the ER-mediated cell apoptosis via p-eIF2α/ATF4/CHOP pathway in MC3T3-E1 osteoblasts cells. In addition, pretreatment with the N-acetylcysteine (NAC) or Tauroursodeoxycholate Sodium (TUDC) attenuated cell apoptosis, ROS levels, mitochondria fragmentation and ER stress-related protein expression, and recovered the protein expression related to iron metabolism. In conclusion, our finding suggested that iron overload induced apoptosis via eliciting ER stress, which resulted in mitochondrial dysfunction and activated p-eIF2α/ATF4/CHOP pathway.}, }
@article {pmid33888657, year = {2021}, author = {Chang, CT and Hsieh, PJ and Lee, HC and Lo, CH and Tam, KW and Loh, EW}, title = {Effectiveness of N-acetylcysteine in Treating Clinical Symptoms of Substance Abuse and Dependence: A Meta-analysis of Randomized Controlled Trials.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {19}, number = {2}, pages = {282-293}, pmid = {33888657}, issn = {1738-1088}, abstract = {OBJECTIVE: Treatment with N-acetylcysteine (NAC) is believed to reduce the clinical symptoms among individuals with substance abuse or dependence. We conducted a meta-analysis of randomized controlled trials to evaluate the effectiveness of NAC in treating substance abuse and dependence.<br><br>METHODS: PubMed, EMBASE, ClinicalTrials.gov registry, and the Cochrane Library were searched for trials published before June 2020.<br><br>RESULTS: A total of 16 trials were analyzed. The treatment effectiveness domains assessed in this study were craving and depressive symptoms, withdrawal syndrome, adverse events, and smoking frequency. Standardized mean difference (SMD), weighted mean difference (WMD), and odds ratio (OR) were used for evaluation where appropriate. A significant decrease in craving symptoms was observed in the NAC treatment group compared with the control group (SMD, -0.67; 95% confidence interval [CI], -1.21 to 0.21). When withdrawal and depressive symptoms were considered as a single domain, the NAC treatment group demonstrated a significantly higher overall improvement than the control group (SMD, -0.35; 95% CI, -0.64 to -0.06). No between-group differences in term of the OR of adverse events (OR, 1.18; 95% CI, 0.68 to 2.06) and a non-significant trend toward reduction in smoking frequency was observed in the NAC treatment group compared with the control group (WMD, -3.09; 95% CI, -6.50 to 0.32).<br><br>CONCLUSION: NAC provides certain noticeable benefits in attenuating substance craving and might help alleviate depressive symptoms and withdrawal syndrome. Precautious measures should be considered when using NAC although no difference in adverse effects was found between NAC treatment and control group.}, }
@article {pmid33884558, year = {2021}, author = {Baum, RA and Woolum, JA and Bailey, AM and Howell, MM and Weant, KA and Geraghty, L and Mohan, S and Webb, AN and Su, MK and Akpunonu, P and , }, title = {Evaluation of Dosing Strategies of N-acetylcysteine for Acetaminophen Toxicity in Patients Greater than 100 Kilograms: Should the Dosage Cap Be Used?.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {17}, number = {3}, pages = {241-249}, pmid = {33884558}, issn = {1937-6995}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*therapeutic use ; Adult ; Analgesics, Non-Narcotic/*toxicity ; Chemical and Drug Induced Liver Injury/*drug therapy ; *Dose-Response Relationship, Drug ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; *Obesity ; Retrospective Studies ; }, abstract = {INTRODUCTION: Acetaminophen is a commonly used analgesic and antipyretic, with the potential to cause significant injury when ingested in toxic amounts. Although the antidote n-acetylcysteine (NAC) is available, evidence supporting dose recommendations for patients weighing over 100 kg are lacking. We performed a retrospective, multi-center analysis to determine if a capped NAC dosing scheme is similar to a non-capped dosing scheme in patients weighing over 100 kg.<br><br>METHODS: Between January 2009 and January 2016, we identified patients presenting to 12 different centers who were evaluated for acetaminophen poisoning treatment. Patients must have weighed greater than 100 kg and were evaluated and identified as needing treatment for acetaminophen-related poisoning with NAC. The primary outcome was occurrence of hepatic injury, defined as an AST or ALT &#x2265; 100 IU/L. Secondary endpoints included number of drug-related adverse events, occurrence of hepatotoxicity, cumulative NAC dose, regimen cost, length of hospital and intensive care unit stays, and in-hospital mortality.<br><br>RESULTS: There were 83 patients identified as meeting the pre-specified inclusion and exclusion criteria. A capped NAC dosing scheme resulted in no difference in hepatic injury when compared to a non-capped regimen (49.4% vs 50%, p = 1.000). The capped dosage regimen was associated with a lower cumulative dose (285.2 mg/kg vs 304.6 mg/kg, p < 0.001) and cost. No other statistically significant differences were identified among the secondary endpoints.<br><br>CONCLUSION: A capped NAC dosing scheme was not associated with higher rates of hepatic injury or hepatotoxicity in obese patients in the setting of acetaminophen poisoning when compared to a non-capped regimen. Further research is needed to verify these results.}, }
@article {pmid33884219, year = {2021}, author = {Awasthi, P and Jindal, A and Sharma, Y and Williams, V and Ravikumar, N and Nallasamy, K and Angurana, SK}, title = {Continuous Venovenous Hemofiltration as a Rescue Therapy for Severe Acetaminophen Toxicity in a Toddler.}, journal = {Journal of pediatric intensive care}, volume = {10}, number = {2}, pages = {159-161}, pmid = {33884219}, issn = {2146-4618}, abstract = {Acetaminophen poisoning is one of the common accidental poisoning in children. Accidental administration of mismatched doses of drops for syrups can lead to life-threatening overdose. N-acetylcysteine (NAC) is the specific antidote; however, extracorporeal therapy such as continuous venovenous hemofiltration (CVVH) can be used as a rescue measure when there is no improvement despite adequate NAC therapy and can be lifesaving. We reported an 18-month-old male infant patient who presented with acetaminophen poisoning following accidental ingestion of acetaminophen drops in place of syrup and developed fulminant hepatic failure. Treatment with NAC did not lead to improvement and CVVH was used as a rescue therapy for 24 hours which led to dramatic clinical and biochemical improvement with intact neurological outcome.}, }
@article {pmid33882750, year = {2021}, author = {Ahmed, EA and Abd-Eldayem, AM and Ahmed, E}, title = {Can granulocyte colony stimulating factor (G-CSF) ameliorate acetaminophen-induced hepatotoxicity?.}, journal = {Human &amp; experimental toxicology}, volume = {40}, number = {10}, pages = {1755-1766}, doi = {10.1177/09603271211008522}, pmid = {33882750}, issn = {1477-0903}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Aspartate Aminotransferases/blood ; Catalase/metabolism ; Chemical and Drug Induced Liver Injury/*drug therapy ; Female ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Granulocyte Colony-Stimulating Factor/*pharmacology ; L-Lactate Dehydrogenase/blood ; Malondialdehyde/blood ; Nitric Oxide/blood ; Rats ; Rats, Wistar ; }, abstract = {Acetaminophen (APAP) is often used as an antipyretic and analgesic agent. Overdose hepatotoxicity, which often results in liver cell failure and liver transplantation, is a severe complication of APAP usage. To save the liver and save lives from acute liver damage caused by APAP, the search for new strategies for liver defense is important. Wistar rats have been used for the induction of APAP hepatotoxicity. Elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were evaluated for liver toxicity. In addition, the levels of hepatic tissue oxidative markers such as malondialdehyde (MDA), nitric oxide (NO) increased while glutathione (GSH) was depleted and catalase (CAT) activity was curtailed. The biochemical findings were consistent with the changes in histology that suggested liver damage and inflammation. Treated rats with N-acetylcysteine (N-AC) and granulocyte colony stimulating factor (G-CSF) showed a decrease in serum levels of ALT, AST and LDH, while the level of ALP in the G-CSF group was still high. After administration of APAP, treatment with N-AC or G-CSF substantially reduced the level of MDA and NO while maintaining the GSH content and CAT activity. Treatment with N-AC and G-CSF after administration of APAP has also attenuated inflammation and hepatocytes necrosis. The results of this study showed that G-CSF could be viewed as an alternative hepatoprotective agent against APAP-induced acute liver injury compared to N-AC.}, }
@article {pmid33882647, year = {2021}, author = {Kuyucuklu, G and Kaynak Onurdağ, F and Eryıldız, C}, title = {[Effect of N-acetylcystein on Antibiofilm Efficiency of Antibiotics in Staphylococci Isolates].}, journal = {Mikrobiyoloji bulteni}, volume = {55}, number = {2}, pages = {125-145}, doi = {10.5578/mb.20219902}, pmid = {33882647}, issn = {0374-9096}, mesh = {*Anti-Bacterial Agents/pharmacology ; Biofilms ; Humans ; Microbial Sensitivity Tests ; *Staphylococcal Infections/drug therapy ; Staphylococcus/genetics ; Vancomycin/pharmacology ; }, abstract = {Biofilms are often responsible for the difficulties in the treatment of infectious diseases due to their properties that facilitate escape from antibiotic effect and their antiphagocytic effects. At least 65% of all infectious diseases are associated with biofilm-forming bacteria. As Staphylococcus aureus and Staphylococcus epidermidis are among the most common agents of hospital infections and the infections are mostly biofilm-related, they pose an important problem. In infectious isolates, the minimum biofilm eradication concentration (MBEK) values of biofilm forms are much higher than the minimum inhibition concentration (MIC) values of planktonic forms. This situation requires the use of much higher doses of antibiotics in the treatment of infections and causes an increase in antibiotic resistance. The N-acetylcysteine (NAC) molecule is known to be effective against biofilm by disrupting mature biofilms and reducing the adhesion of bacteria to surfaces. In this study, it was aimed to demonstrate i) the biofilm-forming abilities ii) the change in ampicillin and vancomycin MIC values in the presence of NAC molecules, iii) the change in the MBEK values of these antibiotics in the presence of NAC molecule and iv) the change in the expression levels of genes thought to be related to biofilm formation in the presence of the NAC molecule among S.aureus (n= 38) and S.epidermidis (n= 12) isolates isolated from various clinical specimens in Trakya University Health Research and Application Center. In this study, microplate crystal violet method was used to demonstrate the biofilm formation in staphylococci. Broth microdilution and checkerboard method were used to demonstrate the change in the presence of NAC molecule of the MIC and MBEC values of ampicillin and vancomycin. The effect of NAC on the expression of intercellular binding proteins A and D (icaA, icaD) and Staphylococcus regulatory protein A (sarA) genes, which are the genes involved in biofilm formation in staphylococci, was determined by quantitative real-time Polymerase Chain Reaction (qRt-PCR) method. The Student-t test was used to compare the control and experimental groups (concentrations detected with synergy and additive effect); p˂ 0.05 was accepted as the limit value of significance. In this study, when the NAC molecule was used together with ampicillin and vancomycin, it was determined that this combination lowers the MIC values of staphylococcus isolates and staphylococcal biofilm MBEK values; and also the expression levels of icaA, icaD and sarA which were effective in biofilm formation in staphylococci have not changed and decreased. As a result, in this study, it has been determined that the NAC molecule can be a new alternative for combined drug therapy and is promising in terms of bringing a new approach to treatment. In addition, it is thought that it is possible to use the NAC molecule together with different microorganisms and antimicrobial agents, and the results obtained in this study are considered to be guiding for further studies on this subject.}, }
@article {pmid33880372, year = {2021}, author = {Zeng, HC and Zhu, BQ and Wang, YQ and He, QZ}, title = {ROS-Triggered Autophagy Is Involved in PFOS-Induced Apoptosis of Human Embryo Liver L-02 Cells.}, journal = {BioMed research international}, volume = {2021}, number = {}, pages = {6625952}, pmid = {33880372}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Alkanesulfonic Acids/*pharmacology ; *Apoptosis/drug effects ; *Autophagy/drug effects ; Cadaverine/pharmacology ; Cell Line ; Cell Survival/drug effects ; Cellular Microenvironment/drug effects ; Embryo, Mammalian/*pathology ; Fluorocarbons/*pharmacology ; Humans ; Liver/drug effects/*embryology/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Proteins/metabolism ; Reactive Oxygen Species/*metabolism ; Vacuoles/drug effects/metabolism ; }, abstract = {The liver is the primary target organ for perfluorooctane sulphonate (PFOS), a recently discovered persistent organic pollutant. However, the mechanisms mediating hepatotoxicity remain unclear. Herein, we explored the relationship between reactive oxygen species (ROS) and autophagy and apoptosis induced by PFOS in L-02 cells, which are incubated with different concentrations of PFOS (0, 50, 100, 150, 200, or 250 μmol/L) for 24 or 48 hrs at 37°C. The results indicated that PFOS exposure decreased cell activities, enhanced ROS levels in a concentration-dependent manner, decreased mitochondrial membrane potential (MMP), and induced autophagy and apoptosis. Compared with the control, 200 μmol/L PFOS increased ROS levels; enhanced the expression of Bax, cleaved-caspase-3, and LC3-II; induced autophagy; decreased MMP; and lowered Bcl-2, p62, and Bcl-2/Bax ratio. The antioxidant N-acetyl cysteine (NAC) protected MMP against PFOS-induced changes and diminished apoptosis and autophagy. Compared with 200 μmol/L PFOS treatment, NAC pretreatment reversed the increase in ROS, Bax, and cleaved-caspase-3 protein caused by PFOS, lowered the apoptosis rate increased by PFOS, and increased the levels of MMP and Bcl-2/Bax ratio decreased by PFOS. The autophagy inhibitor 3-methyladenine and chloroquine decreased apoptosis and cleaved-caspase-3 protein level and increased the Bcl-2/Bax ratio. In summary, our results suggest that ROS-triggered autophagy is involved in PFOS-induced apoptosis in L-02 cells.}, }
@article {pmid33879035, year = {2022}, author = {Hashemi, SA and Kyani, A and Bathaie, SZ}, title = {The in silico mechanism of hVKOR interaction with acetaminophen and its metabolite, as well as N-acetyl cysteine: caution on application in COVID-19 patients.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {40}, number = {18}, pages = {8274-8285}, pmid = {33879035}, issn = {1538-0254}, mesh = {*Acetaminophen/adverse effects/metabolism ; Acetylcysteine ; Benzoquinones/chemistry/metabolism ; Humans ; Hydrogen ; Imines/chemistry ; Vitamin K ; Vitamin K Epoxide Reductases ; *COVID-19 Drug Treatment ; }, abstract = {Acetaminophen and N-acetyl cysteine (NAC) are being used as supportive care in patients suffering from coronavirus disease 2019 (COVID-19). The coagulopathy and cerebral hemorrhage have been recently reported in these patients. Prolonged acetaminophen use increases the international normalized ratio (INR) and the risk of bleeding among patients taking anti-coagulants. Inhibition of vitamin K epoxide reductase (VKOR) by acetaminophen and NAC in chronic applications has been reported, however, detailed knowledge of the molecular mechanism and binding sites are not clear. Herein, we built the homology model of human VKOR (hVKOR) using ITASSER server, confirmed, and applied it for docking analysis of its interaction with acetaminophen and its metabolite, N-acetyl-p-benzoquinone imine (NAPQI), and NAC. We also calculated the lipophilicity and predicted the blood-brain-barrier (BBB) permeation of NAPQI by Swiss ADME. Our analysis showed that NAPQI and NAC, but not acetaminophen, bind strongly to the similar sites in hVKOR via both hydrogen and van der Waals bonding; particularly with Cys135. Thus, it interrupted the vitamin K reducing electron transfer pathway. Further, molecular dynamic (MD) simulation study revealed that the interactions of the ligands with hVKOR are stable. In conclusion, our analysis shed a light on the molecular mechanism of acetaminophen-induced coagulopathy previously reported in some clinical cases with chronic acetaminophen use. Furthermore, considering the anti-coagulopathy of NAPQI and NAC but not acetaminophen, the BBB permeation potency of these agents, and the risk of coagulopathy in COVID-19, we suggest a regular prothrombin time (PT) and INR monitoring of these patients taking acetaminophen and/or NAC.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid33871813, year = {2021}, author = {Schmitz, A and Dempewolf, S and Tan, S and Bicker, G and Stern, M}, title = {Developmental Neurotoxicity of Fipronil and Rotenone on a Human Neuronal In Vitro Test System.}, journal = {Neurotoxicity research}, volume = {39}, number = {4}, pages = {1189-1202}, pmid = {33871813}, issn = {1476-3524}, mesh = {Cell Differentiation/drug effects/physiology ; Cell Line ; Cell Movement/drug effects/physiology ; Dose-Response Relationship, Drug ; Humans ; Insecticides/*toxicity ; Neuronal Outgrowth/*drug effects/physiology ; Neurons/*drug effects/metabolism/pathology ; Neurotoxicity Syndromes/metabolism/pathology ; Pyrazoles/*toxicity ; Rotenone/*toxicity ; }, abstract = {Pesticide exposure during in utero and early postnatal development can cause a wide range of neurological defects. However, relatively few insecticides have been recognized as developmental neurotoxicants, so far. Recently, discovery of the insecticide, fipronil, in chicken eggs has raised public concern. The status of fipronil as a potential developmental neurotoxicant is still under debate. Whereas several in vivo and in vitro studies suggest specific toxicity, other in vitro studies could not confirm this concern. Here, we tested fipronil and its main metabolic product, fipronil sulfone both at concentrations between 1.98 and 62.5 µM, alongside with the established developmental neurotoxicant, rotenone (0.004-10 µM) in vitro on the human neuronal precursor cell line NT2. We found that rotenone impaired all three tested DNT endpoints, neurite outgrowth, neuronal differentiation, and precursor cell migration in a dose-dependent manner and clearly separable from general cytotoxicity in the nanomolar range. Fipronil and fipronil sulfone specifically inhibited cell migration and neuronal differentiation, but not neurite outgrowth in the micromolar range. The rho-kinase inhibitor Y-27632 counteracted inhibition of migration for all three compounds (EC50 between 12 and 50 µM). The antioxidant, n-acetyl cysteine, could ameliorate the inhibitory effects of fipronil on all three tested endpoints (EC 50 between 84 and 164 µM), indicating the involvement of oxidative stress. Fipronil sulfone had a stronger effect than fipronil, confirming the importance to test metabolic products alongside original pesticides. We conclude that in vitro fipronil and fipronil sulfone display specific developmental neurotoxicity on developing human model neurons.}, }
@article {pmid33868959, year = {2021}, author = {Cuninghame, S and Lotfy, K and Cameron, P}, title = {Massive acetaminophen overdose with metabolic acidosis refractory to N-acetylcysteine, fomepizole, and renal replacement therapy.}, journal = {Toxicology reports}, volume = {8}, number = {}, pages = {804-807}, pmid = {33868959}, issn = {2214-7500}, abstract = {Massive Acetaminophen (N-acetyl-p-aminophenol; APAP) overdose is a common presentation to emergency departments around the world. While N-acetylcysteine (NAC) remains the cornerstone of treatment for APAP overdose, extracorporeal treatment, in the form of renal replacement therapy with intermittent hemodialysis (IHD) or continuous renal replacement therapy (CRRT) may provide benefit in cases associated with altered mental status and metabolic acidosis. One treatment with IHD is typically sufficient for resolution of acidosis and global improvement clinically. We describe a case of massive APAP overdose presenting with altered mental status and lactic acidosis, refractory to multiple treatments of IHD as well as CRRT and high-dose NAC along with fomepizole. Despite these interventions, fulminant liver failure progressed with cerebral edema, coagulopathy and death. This is the first description of a fatal acetaminophen ingestion refractory to both IHD and prolonged CRRT. This case highlights the need for further investigation in the management of massive APAP overdose, including optimal method and timing of renal replacement therapy.}, }
@article {pmid33868469, year = {2021}, author = {Shao, X and Zhang, F and Gao, X and Xu, F}, title = {Siomycin A induces reactive oxygen species-mediated cytotoxicity in ovarian cancer cells.}, journal = {Oncology letters}, volume = {21}, number = {6}, pages = {431}, pmid = {33868469}, issn = {1792-1074}, abstract = {Ovarian cancer is one of the leading causes of cancer-related death among women worldwide and accounts for 4% of all cancer cases in female patients. To date, ovarian cancer has the poorest prognosis among all types of gynecological cancer; thus, it is necessary to identify prospective therapeutic options. Previous studies have demonstrated the involvement of reactive oxygen species (ROS) in the cytotoxicity of various anticancer drugs against several types of carcinoma, including ovarian cancer. The present study aimed to investigate the anticancer effects of Siomycin A, a thiopeptide antibiotic, on the ovarian cancer cell lines PA1 and OVCAR3. To determine the viability of these cells following exposure to Siomycin A, the MTT assay was used, and apoptosis was determined by ELISA. In addition, mitochondrial membrane potential was determined by JC1 staining, and cellular ROS levels were assessed by dichlorodihydrofluorescein diacetate staining in the presence and absence of antioxidant NAC. The subsequent levels of antioxidant enzymes and glutathione were also determined following Siomycin A treatment in the two cell lines. A combination study with Siomycin A and cisplatin indicated enhanced efficiency of the drugs on ovarian cancer cell viability. The results of the present study also demonstrated that Siomycin A induced ROS production, inhibited the major antioxidant enzymes, including catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and intracellular GSH in PA1 and OVCAR3 cells, and inhibited the cell viability with an IC50 of ~5.0 and 2.5 µM after 72 h respectively compared with the untreated controls. Additionally, the Siomycin A-induced ROS production further targeted apoptotic cell death by impairing the mitochondrial membrane potential and modulating the levels of pro- and antiapoptotic proteins compared with those in the corresponding control groups. The administration of the antioxidant N-acetylcysteine significantly abrogated the cytotoxic effects of Siomycin A. In conclusion, the results of the present study demonstrated the role of ROS in Siomycin A-mediated cytotoxicity in ovarian cancer cells.}, }
@article {pmid33866216, year = {2021}, author = {Fu, L and Zhao, H and Xiang, Y and Xiang, HX and Hu, B and Tan, ZX and Lu, X and Gao, L and Wang, B and Wang, H and Zhang, C and Xu, DX}, title = {Reactive oxygen species-evoked endoplasmic reticulum stress mediates 1-nitropyrene-induced epithelial-mesenchymal transition and pulmonary fibrosis.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {283}, number = {}, pages = {117134}, doi = {10.1016/j.envpol.2021.117134}, pmid = {33866216}, issn = {1873-6424}, mesh = {Animals ; Bleomycin ; Endoplasmic Reticulum Stress ; *Epithelial-Mesenchymal Transition ; Male ; Mice ; *Pulmonary Fibrosis/chemically induced ; Pyrenes ; Reactive Oxygen Species ; }, abstract = {1-Nitropyrene (1-NP) is one component of atmospheric fine particles. Previous report revealed that acute 1-NP exposure induced respiratory inflammation. This study aimed to investigate whether chronic 1-NP exposure induces pulmonary fibrosis. Male C57BL6/J mice were intratracheally instilled to 1-NP (20 μg/mouse/week) for 6 weeks. Diffuse interstitial inflammation, a-smooth muscle actin (a-SMA)-positive cells, a marker of epithelial-mesenchymal transition (EMT), and an extensive collagen deposition, measured by Masson staining, were observed in 1-NP-exposed mouse lungs. Pulmonary function showed that lung dynamic compliance (Cydn-min) was reduced in 1-NP-exposed mice. Conversely, inspiratory resistance (Ri) and expiratory resistance (Re) were elevated in 1-NP-exposed mice. Mechanistically, cell migration and invasion were accelerated in 1-NP-exposed pulmonary epithelial cells. In addition, E-cadherin, an epithelial marker, was downregulated, and vimentin, a-SMA and N-cadherin, three mesenchymal markers, were upregulated in 1-NP-exposed pulmonary epithelial cells. Although TGF-β wasn't altered, phosphorylated Smad2/3 were enhanced in 1-NP-exposed pulmonary epithelial cells. Moreover, reactive oxygen species (ROS) were increased and endoplasmic reticulum (ER) stress was activated in 1-NP-exposed pulmonary epithelial cells. N-Acetylcysteine (NAC), an antioxidant, attenuated 1-NP-evoked excess ROS, ER stress and EMT in pulmonary epithelial cells. Similarly, pretreatment with NAC alleviated 1-NP-caused pulmonary EMT and lung fibrosis in mice. These results demonstrate that ROS-evoked ER stress contributes, at least partially, to 1-NP-induced EMT and pulmonary fibrosis.}, }
@article {pmid33858491, year = {2021}, author = {Feng, H and Moriyama, T and Ohuchida, K and Sheng, N and Iwamoto, C and Shindo, K and Shirahane, K and Ikenaga, N and Nagai, S and Nakata, K and Mizumoto, K and Nakamura, M}, title = {N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {40}, number = {1}, pages = {133}, pmid = {33858491}, issn = {1756-9966}, mesh = {Acetylcysteine/*metabolism ; Animals ; Female ; Humans ; Mice ; Pancreatic Neoplasms/*metabolism ; Pancreatic Stellate Cells/metabolism ; }, abstract = {BACKGROUND: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions.<br><br>METHOD: We evaluated the expression of &#x3b1;-smooth muscle actin (&#x3b1;-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone's combination therapy on subcutaneous tumor formation and splenic xenografted mouse models.<br><br>RESULTS: In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of &#x3b1;-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone's combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level.<br><br>CONCLUSION: NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.}, }
@article {pmid33857627, year = {2021}, author = {Barati, M and Javidi, MA and Darvishi, B and Shariatpanahi, SP and Mesbah Moosavi, ZS and Ghadirian, R and Khani, T and Sanati, H and Simaee, H and Shokrollahi Barough, M and Farahmand, L and Madjid Ansari, A}, title = {Necroptosis triggered by ROS accumulation and Ca[2+] overload, partly explains the inflammatory responses and anti-cancer effects associated with 1Hz, 100 mT ELF-MF in vivo.}, journal = {Free radical biology &amp; medicine}, volume = {169}, number = {}, pages = {84-98}, doi = {10.1016/j.freeradbiomed.2021.04.002}, pmid = {33857627}, issn = {1873-4596}, mesh = {Animals ; Electromagnetic Fields ; Mice ; Mice, Inbred BALB C ; *Necroptosis ; *Neoplasms ; Reactive Oxygen Species ; }, abstract = {Whereas the anti-neoplastic activity of extremely low frequency magnetic fields (ELF-EMF) is well-documented in literature, little is known about its underlying anti-cancer mechanisms and induced types of cell death. Here, for the first time, we reported induction of necroptosis, a specific type of programed necrotic cell death, in MC4-L2 breast cancer cell lines following a 2 h/day exposure to a 100 Hz, 1 mT ELF-EMF for five days. For in vivo assessment, inbred BALB/c mice bearing established MC-4L2 tumors were exposed to 100 mT, 1 Hz ELF-EMF 2 h daily for a period of 28-day, following which tumors were dissected and fixed for evaluation of tumor biomarkers expression and types of cell death induced using TUNEL assay, Immunohistochemistry and H&amp;E staining. Peripheral blood samples were also collected for assessing pro-inflammatory cytokine profile following exposure. An exaggerated proinflammatory response evident form enhancement of IFN-γ (4.8 ± 0.24 folds) and TNF-α (3.1 ± 0.19 folds) and number of tumors infiltrating lymphocytes (TILs), specially CD8[+] Th cells (~20 folds), proposed occurrence of necroptosis in vivo. Meanwhile, exposure could effectively suppress tumor growth and expression of Ki-67, CD31, VEGFR2 and MMP-9. In vitro studies on ELF-EMF exposed MC-4L2 cells demonstrated a meaningful increase in phosphorylation of RIPK1/RIPK3/MLKL proteins and cleavage of caspase-9/caspase-3, confirming occurrence of both necroptosis and apoptosis. Complementary in vitro studies by treating ELF-EMF exposed MC-4L2 cells with verapamil (a calcium channel inhibitor), N-acetyl cysteine (a ROS scavenger) or calcium chloride confirmed the role of elevated intracellular calcium and ROS levels in ELF-EMF induced necroptosis.}, }
@article {pmid33842212, year = {2021}, author = {Gupta, A and Vijayaraghavan, R and Gautam, A}, title = {Combination therapy of N-acetyl-L-cysteine and S-2(2-aminoethylamino) ethylphenyl sulfide for sulfur mustard induced oxidative stress in mice.}, journal = {Toxicology reports}, volume = {8}, number = {}, pages = {599-606}, pmid = {33842212}, issn = {2214-7500}, abstract = {INTRODUCTION: Sulfur mustard (SM) is chemically, bis(2-chloroethyl) sulfide and a strong alkylating agent that causes cytotoxicity and blisters on skin. In laboratory animal models, SM is extremely lethal. Since no specific antidote has been proposed, decontamination upon contact is the recommended procedure. Several antidotes have been screened for SM, and in that sulfanyl compounds, N-acetyl-l-cysteine (NAC) and S-2(2-aminoethylamino) ethylphenyl sulfide (DRDE-07) showed good protection. Since they showed protection at high doses, the aim of this study was to evaluate the efficacy in combination at low dose, for percutaneously administered SM in mice.<br><br>MATERIAL AND METHODS: 4 LD50 of SM (32.4 mg/kg) was administered, and NAC (50 mg/kg), DRDE-07 (25 and 50 mg/kg) and their combinations were evaluated as 30 min pre-treatment by single oral administration.<br><br>RESULT: After 72 h of SM exposure, significant decrease in body weight, decrease in hepatic reduced glutathione, and increase in hepatic malondialdehyde were observed (P < 0.001), showing oxidative stress. The combination of NAC (100 mg/kg) and DRDE-07 (50 mg/kg) showed significant protection (P < 0.01). The severe histopathological lesions induced by SM in liver, spleen and skin were also considerably reduced by the combination.<br><br>CONCLUSION: The combination of NAC and DRDE-07 having sulfanyl groups, will be promising antioxidants and an effective antidote for SM toxicity.}, }
@article {pmid33840960, year = {2020}, author = {Khatami, MR and Nikravan, N and Salarifar, M and Poorhosseini, HR and Sadeghian, S and Haj-Zeinali, AM and Aghajani, H}, title = {Comparison of Oral and Intravenous N-acetyl Cysteine in Preventing Contrast Nephropathy.}, journal = {Indian journal of nephrology}, volume = {30}, number = {6}, pages = {403-408}, pmid = {33840960}, issn = {0971-4065}, abstract = {INTRODUCTION: Despite high rates of morbidity and mortality in patients with contrast-induced nephropathy (CIN), there is no consensus regarding prevention of this well-known complication of contrast media use. One agent that has been widely used in this regard is N-acetyl cysteine (NAC). Nevertheless, its efficacy is still controversial. The aim of this study was to assess the efficacy of NAC, both in the oral and intravenous forms, for the prevention of CIN.<br><br>METHODS: This study is a double-blind randomized placebo controlled clinical trial. We randomized 434 adult patients with chronic kidney disease (constant serum creatinine &#x2265;1.5 mg/dL) who were candidates for coronary angiography/plasty. The patients were categorized into three groups. One group received 1,200 mg NAC intravenously half an hour before the procedure and oral placebo starting 3 days before angiography. The second group received oral NAC 600 mg twice daily for 3 days, starting the day before the intervention and intravenous placebo half an hour before intervention. The third group received both oral and intravenous placebo. CIN was defined as a 25% relative increase in serum creatinine from baseline value, 48 h after use of contrast medium.<br><br>RESULTS: Of the 434 patients, 149 received intravenous NAC, 145 received oral NAC, and the remaining 140 received placebo. The incidence of CIN in the three groups was 6.1%, 7.6%, and 10.8%, respectively (p = 0.34).<br><br>CONCLUSION: In patients with chronic kidney disease, neither intravenous nor oral NAC is superior to placebo for preventing CIN.}, }
@article {pmid33833814, year = {2021}, author = {Ma, B and Guan, G and Lv, Q and Yang, L}, title = {Curcumin Ameliorates Palmitic Acid-Induced Saos-2 Cell Apoptosis Via Inhibiting Oxidative Stress and Autophagy.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2021}, number = {}, pages = {5563660}, pmid = {33833814}, issn = {1741-427X}, abstract = {OBJECTIVES: We aimed to determine the effects of curcumin on palmitic acid- (PA-) induced human osteoblast-like Saos-2 cell apoptosis and to explore the potential molecular mechanisms in vitro level.<br><br>METHODS: Saos-2 cell were cultured with PA with or without curcumin, N-acetylcysteine (NAC, anti-oxidant), 3-methyladenine (3-MA, autophagy inhibitor) AY-22989 (autophagy agonist) or H2O2. Then, the effects of PA alone or combined with curcumin on viability, apoptosis, oxidative stress, and autophagy in were detected by CCK-8, flow cytometry assay and western blot.<br><br>RESULTS: We found that autophagy was induced, oxidative stress was activated, and apoptosis was promoted in PA-induced Saos-2 cells. Curcumin inhibited PA-induced oxidative stress, autophagy, and apoptosis in Saos-2 cells. NAC successfully attenuated oxidative stress and apoptosis, and 3-MA attenuated oxidative stress and apoptosis in palmitate-induced Saos-2 cells. Interestingly, NAC inhibited PA-induced autophagy, but 3-MA had no obvious effects on oxidative stress in PA-treated Saos-2 cells. In addition, curcumin inhibited H2O2 (oxidative stress agonist)-induced oxidative stress, autophagy, and apoptosis, but curcumin had no obvious effect on AY-22989 (autophagy agonist)-induced autophagy and apoptosis.<br><br>CONCLUSION: The present study demonstrated that oxidative stress is an inducer of autophagy and that curcumin can attenuate excess autophagy and cell apoptosis by inhibiting oxidative stress in PA-induced Saos-2 cells.}, }
@article {pmid33833663, year = {2021}, author = {Ghiam, MK and Patel, SD and Hoffer, A and Selman, WR and Hoffer, BJ and Hoffer, ME}, title = {Drug Repurposing in the Treatment of Traumatic Brain Injury.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {635483}, pmid = {33833663}, issn = {1662-4548}, abstract = {Traumatic brain injury (TBI) is the most common cause of morbidity among trauma patients; however, an effective pharmacological treatment has not yet been approved. Individuals with TBI are at greater risk of developing neurological illnesses such as Alzheimer's disease (AD) and Parkinson's disease (PD). The approval process for treatments can be accelerated by repurposing known drugs to treat the growing number of patients with TBI. This review focuses on the repurposing of N-acetyl cysteine (NAC), a drug currently approved to treat hepatotoxic overdose of acetaminophen. NAC also has antioxidant and anti-inflammatory properties that may be suitable for use in therapeutic treatments for TBI. Minocycline (MINO), a tetracycline antibiotic, has been shown to be effective in combination with NAC in preventing oligodendrocyte damage. (-)-phenserine (PHEN), an anti-acetylcholinesterase agent with additional non-cholinergic neuroprotective/neurotrophic properties initially developed to treat AD, has demonstrated efficacy in treating TBI. Recent literature indicates that NAC, MINO, and PHEN may serve as worthwhile repositioned therapeutics in treating TBI.}, }
@article {pmid33829465, year = {2021}, author = {Mohanty, RR and Padhy, BM and Das, S and Meher, BR}, title = {Therapeutic potential of N-acetyl cysteine (NAC) in preventing cytokine storm in COVID-19: review of current evidence.}, journal = {European review for medical and pharmacological sciences}, volume = {25}, number = {6}, pages = {2802-2807}, doi = {10.26355/eurrev_202103_25442}, pmid = {33829465}, issn = {2284-0729}, mesh = {Acetylcysteine/*therapeutic use ; Antiviral Agents/*therapeutic use ; COVID-19/immunology/virology ; Cytokine Release Syndrome/*prevention &amp; control/virology ; Humans ; Prognosis ; SARS-CoV-2/*drug effects ; *COVID-19 Drug Treatment ; }, abstract = {Since November 2019, SARS Coronavirus 2 disease (COVID-19) pandemic has spread through more than 195 nations worldwide. Though the coronavirus infection affects all age and sex groups, the mortality is skewed towards the elderly population and the cause of death is mostly acute respiratory distress syndrome (ARDS). There are data suggesting the role of excessive immune activation and cytokine storm as the cause of lung injury in COVID-19. The excessive immune activation and cytokine storm usually occurs due to an imbalance in redox homeostasis of the individuals. Considering the antioxidant and free radical scavenging action of N acetyl cysteine (NAC), its use might be useful in COVID-19 patients by decreasing the cytokine storm consequently decreasing the disease severity. Therefore, we reviewed all the available resources pertaining to the role of reactive oxygen species (ROS) in cytokine storm and the mechanism of action of NAC in preventing ROS. We also reviewed the use of NAC in COVID-19.}, }
@article {pmid33826673, year = {2021}, author = {Florentino, PTV and Mendes, D and Vitorino, FNL and Martins, DJ and Cunha, JPC and Mortara, RA and Menck, CFM}, title = {DNA damage and oxidative stress in human cells infected by Trypanosoma cruzi.}, journal = {PLoS pathogens}, volume = {17}, number = {4}, pages = {e1009502}, pmid = {33826673}, issn = {1553-7374}, mesh = {Antioxidants/metabolism ; Cell Death ; Cell Line ; Chagas Disease/*parasitology ; *DNA Damage ; DNA Glycosylases/genetics/metabolism ; DNA Repair ; Down-Regulation ; HeLa Cells ; Histones/genetics/metabolism ; *Host-Parasite Interactions ; Humans ; NF-E2-Related Factor 2/genetics/metabolism ; *Oxidative Stress ; Phosphorylation ; Poly (ADP-Ribose) Polymerase-1/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Trypanosoma cruzi/pathogenicity/*physiology ; }, abstract = {Trypanosoma cruzi is the etiologic agent of Chagas' disease. Infected cells with T. cruzi activate several responses that promote unbalance of reactive oxygen species (ROS) that may cause DNA damage that activate cellular responses including DNA repair processes. In this work, HeLa cells and AC16 human cardiomyocyte cell line were infected with T. cruzi to investigate host cell responses at genome level during parasites intracellular life cycle. In fact, alkaline sensitive sites and oxidized DNA bases were detected in the host cell genetic material particularly in early stages of infection. These DNA lesions were accompanied by phosphorylation of the histone H2Ax, inducing γH2Ax, a marker of genotoxic stress. Moreover, Poly [ADP-ribose] polymerase-1 (PARP1) and 8-oxoguanine glycosylase (OGG1) are recruited to host cell nuclei, indicating activation of the DNA repair process. In infected cells, chromatin-associated proteins are carbonylated, as a possible consequence of oxidative stress and the nuclear factor erythroid 2-related factor 2 (NRF2) is induced early after infection, suggesting that the host cell antioxidant defenses are activated. However, at late stages of infection, NRF2 is downregulated. Interestingly, host cells treated with glutathione precursor, N-acetyl cysteine, NRF2 activator (Sulforaphane), and also Benznidonazol (BNZ) reduce parasite burst significantly, and DNA damage. These data indicate that the balance of oxidative stress and DNA damage induction in host cells may play a role during the process of infection itself, and interference in these processes may hamper T. cruzi infection, revealing potential target pathways for the therapy support.}, }
@article {pmid33826406, year = {2021}, author = {Figueroa, EE and Denton, JS}, title = {Zinc pyrithione activates the volume-regulated anion channel through an antioxidant-sensitive mechanism.}, journal = {American journal of physiology. Cell physiology}, volume = {320}, number = {6}, pages = {C1088-C1098}, pmid = {33826406}, issn = {1522-1563}, support = {F31 DK120225/DK/NIDDK NIH HHS/United States ; S10 OD021734/OD/NIH HHS/United States ; 1F31DK120225-01//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; }, mesh = {Anions ; Antioxidants/*metabolism ; Biological Transport/drug effects ; Cell Line ; Cell Line, Tumor ; Cell Size/drug effects ; HCT116 Cells ; HEK293 Cells ; Humans ; Membrane Proteins/metabolism ; Organometallic Compounds/*pharmacology ; Pyridines/*pharmacology ; Reactive Oxygen Species/metabolism ; Voltage-Dependent Anion Channels/*metabolism ; }, abstract = {Leucine-rich repeat-containing 8 (LRRC8) volume-regulated anion channels (VRACs) play important physiological roles in diverse cell types and may represent therapeutic targets for various diseases. To date, however, the pharmacological tools for evaluating the druggability of VRACs have been limited to inhibitors, as no activators of the channel have been reported. We therefore performed a fluorescence-based high-throughput screening (HTS) of 1,184 Food and Drug Administration-approved drugs for compounds that increase VRAC activity. The most potent VRAC potentiator identified was zinc pyrithione (ZPT), which is used commercially as an antifouling agent and for treating dandruff and other skin disorders. In intracellular Yellow Fluorescent Protein YFP(F46L/H148Q/I152L)-quenching assays, ZPT potentiates the rate and extent of swelling-induced iodide influx dose dependently with a half-maximal effective concentration (EC50) of 5.7 µM. Whole cell voltage-clamp experiments revealed that coapplication of hypotonic solution and 30 µM ZPT to human embryonic kidney 293 or human colorectal carcinoma 116 cells increases the rate of swelling-induced VRAC activation by approximately 10-fold. ZPT potentiates swelling-induced VRAC currents after currents have reached a steady state and activates currents in the absence of cell swelling. Neither ZnCl2 nor free pyrithione activated VRAC; however, treating cells with a mixture of ZnCl2 and pyrithione led to robust channel activation. Finally, the effects of ZPT on VRAC were inhibited by reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and NAD(P)H oxidase inhibitor diphenyleneiodonium chloride, suggesting the mechanism of action involves ROS generation. The discovery of ZPT as a potentiator/activator of VRAC demonstrates the utility of HTS for identifying small-molecule modulators of VRAC and adds to a growing repertoire of pharmacological tool compounds for probing the molecular physiology and regulation of this important channel.}, }
@article {pmid33825597, year = {2022}, author = {Song, Q and Zhou, ZJ and Cai, S and Chen, Y and Chen, P}, title = {Oxidative stress links the tumour suppressor p53 with cell apoptosis induced by cigarette smoke.}, journal = {International journal of environmental health research}, volume = {32}, number = {8}, pages = {1745-1755}, doi = {10.1080/09603123.2021.1910211}, pmid = {33825597}, issn = {1369-1619}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants ; Apoptosis/drug effects/genetics ; Caspase 3/metabolism ; *Cigarette Smoking/adverse effects ; Lung/drug effects/metabolism/pathology/physiopathology ; Mice ; *Oxidative Stress/drug effects/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; *Pulmonary Emphysema/etiology/genetics ; Superoxide Dismutase/metabolism ; *Nicotiana/adverse effects ; *Tobacco Smoke Pollution/adverse effects ; *Tumor Suppressor Protein p53/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {This study was to investigate the effects of oxidative stress in cigarette smoke (CS)-induced cell apoptosis in mice with emphysema. Thirty-two mice were divided into four groups: the control group, the CS group, the CS + Pifithrin-α group, and the CS + NAC group. Pathological changes and apoptosis in lung tissue of mice were detected. The activity of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC) were measured using spectrophotometer. The proteins expression of p53, Bcl-2, Bax, and caspase-3 were determined by western blot. The results showed that cell apoptosis, lung structural damage, and the activity of MDA, as well as the expression of apoptosis-related proteins Bax, total caspase-3, and cleaved caspase-3 were increased in CS-treated mice. The activity of SOD, CAT, and T-AOC, as well as the expression of anti-apoptosis protein Bcl-2 were decreased in CS-treated mice when compared with the control group. However, Pifithrin-α (p53 inhibitor) and N-Acetylcysteine (NAC) could reduce cell apoptosis, lung structural damage and oxidative stress, accelerate the expression of Bcl-2, while suppressing the expression of Bax, total caspase-3 and cleaved caspase-3. More importantly, the treatment with NAC even inhibited the expression of p53. In conclusions, oxidative stress linking the p53 is involved in cell apoptosis in CS-treated emphysema mice.}, }
@article {pmid33824697, year = {2021}, author = {Hao, B and Sun, R and Guo, X and Zhang, L and Cui, J and Zhou, Y and Hong, W and Zhang, Y and He, J and Liu, X and Li, B and Ran, P and Chen, J}, title = {NOX4-Derived ROS Promotes Collagen I Deposition in Bronchial Smooth Muscle Cells by Activating Noncanonical p38MAPK/Akt-Mediated TGF-β Signaling.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6668971}, pmid = {33824697}, issn = {1942-0994}, mesh = {Aged ; Animals ; Bronchi/cytology/metabolism ; Cell Differentiation ; Cell Line ; Collagen/*metabolism ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Myocytes, Smooth Muscle/cytology/*metabolism ; NADPH Oxidase 4/genetics/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Pulmonary Disease, Chronic Obstructive/*metabolism ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; Smad3 Protein/metabolism ; Transforming Growth Factor beta/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND: Airway smooth muscle (ASM) remodeling is a hallmark in chronic obstructive pulmonary disease (COPD). NADPH oxidase 4- (NOX4-) mediated reactive oxygen species (ROS) production plays a crucial role in cell differentiation and extracellular matrix (ECM) synthesis in ASM remodeling. However, the precise mechanisms underpinning its pathogenic roles remain elusive.<br><br>METHODS: The expression of NOX4 and TGF-&#x3b2; 1 in the airway of the lung was measured in COPD patients and the control group. Cigarette smoke- (CS-) induced emphysema mice were generated, and the alteration of &#x3b1;-SMA, NOX4, TGF-&#x3b2; 1, and collagen I was accessed. The changes of the expression of ECM markers, NOX4, components of TGF-&#x3b2;/Smad, and MAPK/Akt signaling in human bronchial smooth muscle cells (HBSMCs) were ascertained for delineating mechanisms of NOX4-mediated ROS production on cell differentiation and remodeling in human ASM cells.<br><br>RESULTS: An increased abundance of NOX4 and TGF-&#x3b2; 1 proteins in the epithelial cells and ASM of lung was observed in COPD patients compared with the control group. Additionally, an increased abundance expression of NOX4 and &#x3b1;-SMA was observed in the lungs of the CS-induced emphysema mouse model. TGF-&#x3b2; 1 displayed abilities to increase the oxidative burden and collagen I production, along with enhanced phosphorylation of ERK, p38MAPK, and p-Akt473 in HBSMCs. These effects of TGF-&#x3b2; 1 could be inhibited by the ROS scavenger N-acetylcysteine (NAC), siRNA-mediated knockdown of Smad3 and NOX4, and pharmacological inhibitors SB203580 (p38MAPK inhibitor) and LY294002 (Akt inhibitor).<br><br>CONCLUSIONS: NOX4-mediated ROS production alters TGF-&#x3b2; 1-induced cell differentiation and collagen I protein synthesis in HBSMCs in part through the p38MAPK/Akt signaling pathway in a Smad-dependent manner.}, }
@article {pmid33824674, year = {2020}, author = {Atefi, N and Behrangi, E and Mozafarpoor, S and Seirafianpour, F and Peighambari, S and Goodarzi, A}, title = {N-acetylcysteine and coronavirus disease 2019: May it work as a beneficial preventive and adjuvant therapy? A comprehensive review study.}, journal = {Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences}, volume = {25}, number = {}, pages = {109}, pmid = {33824674}, issn = {1735-1995}, abstract = {BACKGROUND: Coronaviruses are major pathogens of respiratory system causing different disorders, including the common cold, Middle East respiratory syndrome, and severe acute respiratory syndrome. Today's global pandemic coronavirus disease 2019 (COVID-19) has high mortality rate, with an approximate of 20% in some studies, and is 30-60 times more fatal than the common annual influenza, However, there is still no gold standard treatment for it. N-acetylcysteine (NAC) is a well-known multi-potential drug with hypothetically probable acceptable effect on COVID-related consequences, which we completely focused in this comprehensive review.<br><br>MATERIALS AND METHODS: PubMed, Scopus, Science Direct, and Google Scholar have been searched. Study eligibility criteria: efficacy of NAC in various subclasses of pathogenic events which may occur during COVID-19 infection. Efficacy of NAC for managing inflammatory or any symptoms similar to symptoms of COVID-19 was reviewed and symptom improvements were assessed.<br><br>RESULTS: Randomized clinical trials introduced NAC as an antioxidant glutathione analog and detoxifying agent promoted for different medical conditions and pulmonary disorders to alleviate influenza and reduce mortality by 50% in influenza-infected animals. The beneficial effects of NAC on viral disorders, including Epstein-Barr virus, HIV and hepatitis, and well-known vital organ damages were also exist and reported.<br><br>CONCLUSION: We classified the probable effects of NAC as oxidative-regulatory and apoptotic-regulatory roles, antiviral activities, anti-inflammatory roles, preventive and therapeutic roles in lung disorders and better oxygenation functions, supportive roles in intensive care unit admitted patients and in sepsis, positive role in other comorbidities and nonpulmonary end-organ damages or failures and even in primary COVID-associated cutaneous manifestations. Based on different beneficial effects of NAC, it could be administered as a potential adjuvant therapy for COVID-19 considering patient status, contraindications, and possible drug-related adverse events.}, }
@article {pmid33822307, year = {2021}, author = {Rhee, CK and Chang, SY}, title = {Combination photobiomodulation/N-acetyl-L-cysteine treatment appears to mitigate hair cell loss associated with noise-induced hearing loss in rats.}, journal = {Lasers in medical science}, volume = {36}, number = {9}, pages = {1941-1947}, pmid = {33822307}, issn = {1435-604X}, support = {NRF- 2020R1C1C1009695//National Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MSIT)/ ; NRF-2020R1A6A1A03043283//Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; NRF-2019M3D1A1078943//Creative Materials Discovery Program through the National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Auditory Threshold ; Cochlea ; Evoked Potentials, Auditory, Brain Stem ; Hair Cells, Auditory ; *Hearing Loss, Noise-Induced/drug therapy ; Humans ; Rats ; }, abstract = {Sensorineural hearing loss is an intractable disease. Acoustic overstimulation creates hearing loss; many patients exhibit social and emotional dysfunctions. In a model of noise-induced hearing loss (NIHL), low-level laser photobiomodulation (PBM) at a near-infrared wavelength significantly improved auditory brainstem response (ABR) thresholds. In addition, both N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine (ALCAR) attenuated NIHL, reducing the effects of noise trauma in the cochlea and the central auditory system. Here, we combined PBM with antioxidants to explore hearing threshold recovery and morphological hair cell changes after rats were exposed to noise. The average auditory brainstem response thresholds after PBM/NAC combination treatment were reduced from the apex to the basal turn at all of 8, 16, and 32 kHz compared to the noise-only group. The PBM/NAC combination treated group exhibited intact outer hair cells in all turns, and significantly greater hair cell numbers in the middle and basal cochlear turns, than did controls. Thus, PBM/NAC treatment may prevent hearing dysfunction caused by NIHL.}, }
@article {pmid33816510, year = {2021}, author = {Bai, X and Chen, S and Xu, K and Jin, Y and Niu, X and Xie, L and Qiu, Y and Liu, XZ and Sun, Y}, title = {N-Acetylcysteine Combined With Dexamethasone Treatment Improves Sudden Sensorineural Hearing Loss and Attenuates Hair Cell Death Caused by ROS Stress.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {659486}, pmid = {33816510}, issn = {2296-634X}, abstract = {Sudden sensorineural hearing loss (SSNHL) is a common emergency in the world. Increasing evidence of imbalance of oxidant-antioxidant were found in SSNHL patients. Steroids combined with antioxidants may be a potential strategy for the treatment of SSNHL. In cochlear explant experiment, we found that N-acetylcysteine (NAC) combined with dexamethasone can effectively protect hair cells from oxidative stress when they were both at ineffective concentrations alone. A clinic trial was designed to explore whether oral NAC combined with intratympanic dexamethasone (ITD) as a salvage treatment has a better therapeutic effect. 41 patients with SSNHL were randomized to two groups. 23 patients in control group received ITD therapy alone, while 18 patient s in NAC group were treated with oral NAC and ITD. The patients were followed-up on day 1st (initiation of treatment) and day 14th. Overall, there was no statistical difference in final pure-tone threshold average (PTA) improvement between those two groups. However, a significant hearing gain at 8,000 Hz was observed in NAC group. Moreover, the hearing recovery rates of NAC group is much higher than that in control group. These results demonstrated that oral NAC in combination with ITD therapy is a more effective therapy for SSNHL than ITD alone.}, }
@article {pmid33816149, year = {2021}, author = {Dominari, A and Hathaway Iii, D and Kapasi, A and Paul, T and Makkar, SS and Castaneda, V and Gara, S and Singh, BM and Agadi, K and Butt, M and Retnakumar, V and Chittajallu, S and Taugir, R and Sana, MK and Kc, M and Razzack, S and Moallem, N and Alvarez, A and Talalaev, M}, title = {Bottom-up analysis of emergent properties of N-acetylcysteine as an adjuvant therapy for COVID-19.}, journal = {World journal of virology}, volume = {10}, number = {2}, pages = {34-52}, pmid = {33816149}, issn = {2220-3249}, abstract = {N-acetylcysteine (NAC) is an abundantly available antioxidant with a wide range of antidotal properties currently best studied for its use in treating acetaminophen overdose. It has a robustly established safety profile with easily tolerated side effects and presents the Food and Drug Administration's approval for use in treating acetaminophen overdose patients. It has been proven efficacious in off-label uses, such as in respiratory diseases, heart disease, cancer, human immunodeficiency virus infection, and seasonal influenza. Clinical trials have recently shown that NAC's capacity to replenish glutathione stores may significantly improve coronavirus disease 2019 (COVID-19) outcomes, especially in high risk individuals. Interestingly, individuals with glucose 6-phosphate dehydrogenase deficiency have been shown to experience even greater benefit. The same study has concluded that NAC's ability to mitigate the impact of the cytokine storm and prevent elevation of liver enzymes, C-reactive protein, and ferritin is associated with higher success rates weaning from the ventilator and return to normal function in COVID-19 patients. Considering the background knowledge of biochemistry, current uses of NAC in clinical practice, and newly acquired evidence on its potential efficacy against COVID-19, it is worthwhile to investigate further whether this agent can be used as a treatment or adjuvant for COVID-19.}, }
@article {pmid33813038, year = {2021}, author = {Russo, G and Iaccarino, G and Piccolo, M and Ferraro, MG and Vecchione, R and Grumetto, L and Netti, PA and Santamaria, R}, title = {Prolonged activity of a recombinant manganese superoxide dismutase through a formulation of polymeric multi-layer nanoassemblies targeting cancer cells.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {162}, number = {}, pages = {105825}, doi = {10.1016/j.ejps.2021.105825}, pmid = {33813038}, issn = {1879-0720}, mesh = {Antioxidants ; Humans ; *Neoplasms ; Polymers ; Protein Isoforms ; *Superoxide Dismutase ; }, abstract = {A new isoform of human manganese superoxide dismutase (SOD) has been recently isolated and obtained in a synthetic recombinant form and termed rMnSOD. As compared to other SODs, this isoform exhibits a dramatically improved cellular uptake and an intense antioxidant and antitumoral activity. Unfortunately, its use is severely hampered as this active pharmaceutical ingredient (API) in solution suffers from remarkable instability, which realizes as an interplay of unfolding and aggregation phenomena. This leads the API to be ineffective after three weeks only when stored at 4°C. A formulation strategy was undertaken to mitigate this instability. This was based on the incorporation of the API in hyaluronic acid and its layer-by-layer deposition over a chitosan-n-acetyl cysteine- monolayer nanoemulsion (NE) and its subsequent coverage with a further external interface of a chitosan-n-acetyl cysteine. The obtained constructs were tested over a selected panel of healthy and cancerous cell lines. The undertaken formulation strategy enhanced the API's effect in vitro already at time zero, maintaining the efficacy of this anticancer agent until up to 30 weeks when stored at 4°C.}, }
@article {pmid33809388, year = {2021}, author = {Liou, GG and Hsieh, CC and Lee, YJ and Li, PH and Tsai, MS and Li, CT and Wang, SH}, title = {N-Acetyl Cysteine Overdose Inducing Hepatic Steatosis and Systemic Inflammation in Both Propacetamol-Induced Hepatotoxic and Normal Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {3}, pages = {}, pmid = {33809388}, issn = {2076-3921}, support = {MOST 108-2320-13-040-003 and MOST 109-2320-B-040-005//Ministry of Science and Technology of Taiwan/ ; NCHU-CSMU 10802//National Chung Hsing 579 University and Chung Shan Medical University inter-school project/ ; }, abstract = {Acetaminophen (APAP) overdose induces acute liver damage and even death. The standard therapeutic dose of N-acetyl cysteine (NAC) cannot be applied to every patient, especially those with high-dose APAP poisoning. There is insufficient evidence to prove that increasing NAC dose can treat patients who failed in standard treatment. This study explores the toxicity of NAC overdose in both APAP poisoning and normal mice. Two inbred mouse strains with different sensitivities to propacetamol-induced hepatotoxicity (PIH) were treated with different NAC doses. NAC therapy decreased PIH by reducing lipid oxidation, protein nitration and inflammation, and increasing glutathione (GSH) levels and antioxidative enzyme activities. However, the therapeutic effects of NAC on PIH were dose-dependent from 125 (N125) to 275 mg/kg (N275). Elevated doses of NAC (400 and 800 mg/kg, N400 and N800) caused additional deaths in both propacetamol-treated and normal mice. N800 treatments significantly decreased hepatic GSH levels and induced inflammatory cytokines and hepatic microvesicular steatosis in both propacetamol-treated and normal mice. Furthermore, both N275 and N400 treatments decreased serum triglyceride (TG) and induced hepatic TG, whereas N800 treatment significantly increased interleukin-6, hepatic TG, and total cholesterol levels. In conclusion, NAC overdose induces hepatic and systemic inflammations and interferes with fatty acid metabolism.}, }
@article {pmid33807834, year = {2021}, author = {Yu, TJ and Cheng, YB and Lin, LC and Tsai, YH and Yao, BY and Tang, JY and Chang, FR and Yen, CH and Ou-Yang, F and Chang, HW}, title = {Physalis peruviana-Derived Physapruin A (PHA) Inhibits Breast Cancer Cell Proliferation and Induces Oxidative-Stress-Mediated Apoptosis and DNA Damage.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {3}, pages = {}, pmid = {33807834}, issn = {2076-3921}, support = {MOST 108-2320-B-037-015-MY3//Ministry of Science and Technology, Taiwan/ ; MOST 109-2628-B-110-004//Ministry of Science and Technology, Taiwan/ ; MOST 108-2314-B-037-080//Ministry of Science and Technology, Taiwan/ ; MOST 109-2314-B-037-018//Ministry of Science and Technology, Taiwan/ ; MOST 109-2740-B-037-001//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 110-P016//National Sun Yat-sen University-Kaohsiung Medical University (KMU) Joint Research Project/ ; KMUH109-9R35//Kaohsiung Medical University Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; MOHW 109-TDU-B-212-134016//Health and Welfare Surcharge of Tobacco Products, the Ministry of Health and Welfare, Taiwan/ ; }, abstract = {Breast cancer expresses clinically heterogeneous characteristics and requires multipurpose drug development for curing the different tumor subtypes. Many withanolides have been isolated from Physalis species showing anticancer effects, but the anticancer function of physapruin A (PHA) has rarely been investigated. In this study, the anticancer properties of PHA in breast cancer cells were examined by concentration and time-course experiments. In terms of cellular ATP content, PHA inhibited the proliferation of three kinds of breast cancer cells: MCF7 (estrogen receptor (ER)+, progesterone receptor (PR)+/-, human epidermal growth factor receptor 2 (HER2)-), SKBR3 (ER-/PR-/HER2+), and MDA-MB-231 (triple-negative). Moreover, PHA induced G2/M arrest in MCF7 and MDA-MB-231 cells. In terms of flow cytometry, PHA induced the generation of reactive oxygen species (ROS), the generation of mitochondrial superoxide, mitochondrial membrane potential depletion, and γH2AX-detected DNA damage in breast cancer MCF7 and MDA-MB-231 cells, which were suppressed by the ROS inhibitor N-acetylcysteine (NAC). In terms of flow cytometry and Western blotting, PHA induced apoptotic expression (annexin V, and intrinsic and extrinsic apoptotic signaling), which was suppressed by NAC and an apoptosis inhibitor (Z-VAD-FMK), in breast cancer cells. Therefore, PHA is a potential anti-breast-cancer natural product that modulates the oxidative-stress response, cell-cycle disturbance, apoptosis, and γH2AX-detected DNA damage.}, }
@article {pmid33806369, year = {2021}, author = {Kim, D and Kim, EH and Choi, S and Lim, KM and Tie, L and Majid, A and Bae, ON}, title = {A Commonly Used Biocide 2-N-octyl-4-isothiazolin-3-oneInduces Blood-Brain Barrier Dysfunction via Cellular Thiol Modification and Mitochondrial Damage.}, journal = {International journal of molecular sciences}, volume = {22}, number = {5}, pages = {}, pmid = {33806369}, issn = {1422-0067}, support = {2019002490005 1485016231, 2019002490004 1485016253, 2020002970001//Korea Environmental Industry and Technology Institute/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Blood-Brain Barrier/*drug effects/*metabolism/pathology ; Brain/drug effects/metabolism/pathology ; Cell Death/drug effects ; Cell Line ; Disinfectants/antagonists &amp; inhibitors/*toxicity ; Endothelial Cells/drug effects/metabolism/pathology ; Energy Metabolism/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/metabolism/pathology ; Proteolysis/drug effects ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; Thiazoles/antagonists &amp; inhibitors/*toxicity ; Tight Junction Proteins/metabolism ; }, abstract = {Isothiazolinone (IT) biocides are potent antibacterial substances commonly used as preservatives or disinfectants, and 2-n-Octyl-4-isothiazolin-3-one (OIT; octhilinone) is a common IT biocide that is present in leather products, glue, paints, and cleaning products. Although humans are exposed to OIT through personal and industrial use, the potentially deleterious effects of OIT on human health are still unknown. To investigate the effects of OIT on the vascular system, which is continuously exposed to xenobiotics through systemic circulation, we treated brain endothelial cells with OIT. OIT treatment significantly activated caspase-3-mediated apoptosis and reduced the bioenergetic function of mitochondria in a bEnd.3 cell-based in vitro blood-brain barrier (BBB) model. Interestingly, OIT significantly altered the thiol redox status, as evidenced by reduced glutathione levels and protein S-nitrosylation. The endothelial barrier function of bEnd.3 cells was significantly impaired by OIT treatment. OIT affected mitochondrial dynamics through mitophagy and altered mitochondrial morphology in bEnd.3 cells. N-acetyl cysteine significantly reversed the effects of OIT on the metabolic capacity and endothelial function of bEnd.3 cells. Taken together, we demonstrated that the alteration of the thiol redox status and mitochondrial damage contributed to OIT-induced BBB dysfunction, and we hope that our findings will improve our understanding of the potential hazardous health effects of IT biocides.}, }
@article {pmid33805329, year = {2021}, author = {Almalki, AH and Alsaab, HO and Alsanie, WF and Gaber, A and Alkhalifa, T and Almalki, A and Alzahrani, O and Hardy, AMG and Alhadidi, Q and Shah, ZA and Althobaiti, YS}, title = {Potential Benefits of N-Acetylcysteine in Preventing Pregabalin-Induced Seeking-Like Behavior.}, journal = {Healthcare (Basel, Switzerland)}, volume = {9}, number = {4}, pages = {}, pmid = {33805329}, issn = {2227-9032}, support = {1-439-6079.//Taif University/ ; }, abstract = {Substance-use disorder is globally prevalent and responsible for numerous social and medical problems. Pregabalin (Lyrica), typically used to treat diabetic neuropathy, has recently emerged as a drug of abuse. Drug abuse is associated with several neuronal changes, including the downregulation of glutamate transporters such as glutamate transporter 1 and cystine/glutamate antiporter. We investigated the effects of N-acetylcysteine, a glutamate transporter 1 and xCT upregulator, on pregabalin addiction using a conditioned place preference paradigm. Pregabalin (60 mg/kg) was found to induce conditioned place preference when compared to a vehicle. A 100 mg/kg dose of N-acetylcysteine was found to block pregabalin-seeking behaviors. These results support previous findings showing that glutamate transporters play an important role in pregabalin-induced seeking behaviors. N-acetylcysteine may represent a beneficial agent in preventing the abuse potential of pregabalin.}, }
@article {pmid33804757, year = {2021}, author = {Adams, LE and Moss, HG and Lowe, DW and Brown, T and Wiest, DB and Hollis, BW and Singh, I and Jenkins, DD}, title = {NAC and Vitamin D Restore CNS Glutathione in Endotoxin-Sensitized Neonatal Hypoxic-Ischemic Rats.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {3}, pages = {}, pmid = {33804757}, issn = {2076-3921}, support = {BXoo3401//Department of Veteran Affairs/ ; F31NS108623/NH/NIH HHS/United States ; }, abstract = {Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O2), followed by hypothermia alone or with N-acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)2D3, 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.}, }
@article {pmid33800296, year = {2021}, author = {Oliva, A and Bianchi, A and Russo, A and Ceccarelli, G and Cancelli, F and Aloj, F and Alunni Fegatelli, D and Mastroianni, CM and Venditti, M}, title = {Effect of N-Acetylcysteine Administration on 30-Day Mortality in Critically Ill Patients with Septic Shock Caused by Carbapenem-Resistant Klebsiella pneumoniae and Acinetobacter baumannii: A Retrospective Case-Control Study.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {10}, number = {3}, pages = {}, pmid = {33800296}, issn = {2079-6382}, abstract = {Carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Acinetobacter baumannii (CR-Ab) represent important cause of severe infections in intensive care unit (ICU) patients. N-Acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties, showing also in-vitro antibacterial activity. Aim was to evaluate the effect on 30-day mortality of the addition of intravenous NAC to antibiotics in ICU patients with CR-Kp or CR-Ab septic shock. A retrospective, observational case:control study (1:2) in patients with septic shock caused by CR-Kp or CR-Ab hospitalized in two different ICUs was conducted. Cases included patients receiving NAC plus antimicrobials, controls included patients not receiving NAC. Cases and controls were matched for age, SAPS II, causative agent and source of infection. No differences in age, sex, SAPS II score or time to initiate definitive therapy were observed between cases and controls. Pneumonia and bacteremia were the leading infections. Overall, mortality was 48.9% (33.3% vs. 56.7% in cases and controls, p = 0.05). Independent risk factors for mortality were not receiving NAC (p = 0.002) and CR-Ab (p = 0.034) whereas therapy with two in-vitro active antibiotics (p = 0.014) and time to initial definite therapy (p = 0.026) were protective. NAC plus antibiotics might reduce the 30-day mortality rate in ICU patients with CR-Kp and CR-Ab septic shock.}, }
@article {pmid33798617, year = {2021}, author = {Sharma, M and Naura, AS and Singla, SK}, title = {A deleterious interplay between endoplasmic reticulum stress and its functional linkage to mitochondria in nephrolithiasis.}, journal = {Free radical biology &amp; medicine}, volume = {168}, number = {}, pages = {70-80}, doi = {10.1016/j.freeradbiomed.2021.03.031}, pmid = {33798617}, issn = {1873-4596}, mesh = {Animals ; Endoplasmic Reticulum Stress ; *Hyperoxaluria/metabolism ; Mitochondria/metabolism ; *Nephrolithiasis ; Rats ; Unfolded Protein Response ; }, abstract = {Hyperoxaluria is one of the leading causes of calcium oxalate stone formation in the kidney. Since hyperoxaluria produces Endoplasmic Reticulum (ER) stress in the kidney, it is thus likely that the adaptive unfolded protein response might affect the mitochondrial population as ER and mitochondria share close physical and functional interactions mandatory for several biological processes. Thus this work was designed to study the putative effects of endoplasmic reticulum stress on the renal mitochondria during hyperoxaluria-induced nephrolithiasis. The results showed that hyperoxaluria induced an ER stress led to the unfolded protein response in the renal tissue of experimental rats. Hampered mitochondrion functioning was detected with decreased mitochondrial membrane potential and upsurged mitochondria calcium. These changes in the mitochondria function and ER stress are preceded by apoptosis. The expression of Sigma-1 receptor protein found in the Mitochondria associated ER membranes, the connecting link between ER and mitochondria was found to decrease in the hyperoxaluric rats. Inhibition of ER stress by 4-Phenylbutyric acid prevented the decrease in mitochondria membrane potential and increase in mitochondria calcium observed in hyperoxaluric rats. Also, it restored the protein expression of the sigma-1 receptor protein. On the other hand, N-acetyl cysteine had a nominal impact on the reduction of the ER stress-induced mitochondrial dysfunction. In conclusion, our data showed that hyperoxaluria induces renal ER stress which triggers mitochondria dysfunction, might be via alteration in the sigma-1 receptor protein in the mitochondria-associated ER membranes, which leads to apoptosis, renal injury, and calcium oxalate crystal deposition.}, }
@article {pmid33797725, year = {2021}, author = {Hashim, AR and Bashir, DW and Yasin, NAE and Galal, MK and M, ES}, title = {Ameliorative effect of N-acetylcysteine against glyphosate-induced hepatotoxicity in adult male albino rats: histopathological, biochemical, and molecular studies.}, journal = {Environmental science and pollution research international}, volume = {28}, number = {31}, pages = {42275-42289}, pmid = {33797725}, issn = {1614-7499}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism ; *Chemical and Drug Induced Liver Injury/metabolism/prevention &amp; control ; Glycine/analogs &amp; derivatives ; Liver/metabolism ; Male ; Oxidative Stress ; Rats ; Rats, Wistar ; Glyphosate ; }, abstract = {Glyphosate (GLP) is the most commonly used herbicide that presents many hazards to the environment and living organisms. The present study aimed to explore hepatotoxic properties of GLP on adult albino rats, and the ability of N-acetylcysteine (NAC) to ameliorate these toxic effects. Thirty mature male albino rats were distributed into 3 groups (10 rats/group): Group I (C) a negative control, Group II (GLP) orally administered Roundup 0.8503 ml/kg/day which contain GLP (375 mg/kg) (1/10 of LD50) by gavage needle, and Group III (NAC+ GLP) received NAC (160 mg/kg, 1h before Roundup) by gavage needle and Roundup (0.8503 ml/kg) orally for 6 weeks. Blood and liver samples were collected and processed for biochemical, histopathological, ultrastructural, and immunohistochemical investigations. Group II displayed a significant elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) levels, as well as overexpression of apoptotic markers. The total antioxidant capacity "TAC" and mRNA expression of NRF2 were significantly decreased. Concerning the histopathological findings, there were various degenerative changes as the hepatocytes showed hydropic swelling with nuclear pyknosis. These alterations were confirmed ultrastructurally as most of the cytoplasmic organelles were lost and the mitochondria appeared to deteriorate. Immunohistochemical results showed intense immunoreactivity against proliferating cell nuclear antigen (PCNA) and caspase-3. NAC administration before GLP partially ameliorates these alterations. ALT, AST, and MDA levels as well as expression of apoptotic markers were significantly reduced. TAC and mRNA expression of NRF2 were significantly increased. Histopathological alterations were partially improved as the hepatocytes returned normal and ultrastructurally they showed nearly normal cytoplasmic organelles. Additionally, the intense expression of PCNA and caspase-3 was significantly reduced. We concluded that NAC can ameliorate most of the adverse effects of GLP exposure through its antioxidant property and free radicals scavenging capacity.}, }
@article {pmid33797205, year = {2022}, author = {Nery, FG and Tallman, MJ and Cecil, KM and Blom, TJ and Patino, LR and Adler, CM and DelBello, MP}, title = {N-acetylcysteine for depression and glutamate changes in the left prefrontal cortex in adolescents and young adults at risk for bipolar disorder: A pilot study.}, journal = {Early intervention in psychiatry}, volume = {16}, number = {2}, pages = {195-199}, doi = {10.1111/eip.13149}, pmid = {33797205}, issn = {1751-7893}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Adolescent ; *Bipolar Disorder/diagnosis/drug therapy ; Depression/drug therapy ; Glutamic Acid ; Humans ; Pilot Projects ; Prefrontal Cortex ; Young Adult ; }, abstract = {AIMS: To investigate the mechanism of action of N-acetylcysteine (NAC) in depressive symptoms in young individuals at familial risk for bipolar disorder.<br><br>METHODS: We conducted an 8-week open label clinical trial of NAC 2400&#x2009;mg/days in 15-24&#x2009;years old depressed offspring of a bipolar I disorder parent, with baseline and endpoint proton magnetic resonance spectroscopy acquired within the left ventrolateral prefrontal cortex (VLPFC).<br><br>RESULTS: Nine participants were enrolled and finished the study. NAC significantly improved depressive and anxiety symptom scores, and clinical global impression (all p&#xa0;<&#x2009;.001). There was a non-significant reduction in glutamate levels in the left VLPFC. Reduction in depressive symptom scores was positively associated with reduction in glutamate levels in the left VLPFC (p&#xa0;=&#x2009;.007).<br><br>CONCLUSIONS: This pilot study suggests that NAC might be efficacious for depressive symptoms in at-risk youth, and that its mechanism of action involves the modulation of glutamate in the left VLPFC.}, }
@article {pmid33788342, year = {2021}, author = {Abbasi, M and Pourrajab, B and Tokhi, MO}, title = {Protective effects of vitamins/antioxidants on occupational noise-induced hearing loss: A systematic review.}, journal = {Journal of occupational health}, volume = {63}, number = {1}, pages = {e12217}, pmid = {33788342}, issn = {1348-9585}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Female ; Folic Acid/therapeutic use ; Hearing Loss, Noise-Induced/etiology/*prevention &amp; control ; Humans ; Male ; Middle Aged ; Noise, Occupational/adverse effects ; Occupational Diseases/etiology/*prevention &amp; control ; Occupational Exposure/adverse effects ; Protective Agents/*therapeutic use ; Vitamin B 12/therapeutic use ; Vitamins/*therapeutic use ; }, abstract = {OBJECTIVES: Occupational noise-induced hearing loss (NIHL) due to industrial, military, and other job -related noise exposure can cause harmful health issues to occupied workers, but may also be potentially preventable. Vitamins/antioxidant have been studied as therapeutic strategies to prevent and/or delay the risks of human diseases as well as NIHL .So, this study was conducted to systematically review the protective effects of vitamins/antioxidants on occupational NIHL.<br><br>METHODS: Online databases including PubMed/Medline, Scopus, Web of Science, EMBASE, Science Direct, and Google Scholar were systematically searched up to 12 January 2021. Based on 6336 potentially relevant records identified through the initial search in the databases, 12 full-text publications were retrieved, one of which can be viewed as two separate trials, because it has studied the effects of two different antioxidants (ginseng and NAC) on NIHL, separately.<br><br>RESULTS: A review of the studies shows that vitamin B12, folic acid, and N-acetylcysteine (NAC) have a considerable protective effect on NIHL. However, these protective effects are not yet specified in different frequencies. The findings regarding the protective effects of other antioxidants are inconsistent in this field.<br><br>CONCLUSION: Vitamin B12, folic acid, and NAC may have a protective effect as an antioxidant on reducing occupational hearing loss. For a conclusive evidence of vitamin/antioxidant protective therapies, future studies with precise criteria for noise exposure and similar outcome parameters are required.}, }
@article {pmid33783984, year = {2021}, author = {Kumar, P and Liu, C and Hsu, JW and Chacko, S and Minard, C and Jahoor, F and Sekhar, RV}, title = {Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial.}, journal = {Clinical and translational medicine}, volume = {11}, number = {3}, pages = {e372}, pmid = {33783984}, issn = {2001-1326}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Aging ; Cognition/*drug effects ; DNA Damage/drug effects ; Dietary Supplements ; Endothelium/drug effects ; Female ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Geriatric Assessment ; Glutathione/*drug effects ; Glycine/administration &amp; dosage/*pharmacology ; Glycine Agents/administration &amp; dosage/pharmacology ; Humans ; Inflammation/*drug therapy ; Insulin Resistance ; Male ; Mitochondria/drug effects ; Muscle Strength/*drug effects ; Oxidative Stress/*drug effects ; Pilot Projects ; Young Adult ; }, abstract = {BACKGROUND: Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance. This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition.<br><br>METHODS: A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). After all the participants underwent an initial (pre-supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red-blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait-speed, grip-strength, 6-min walk test; cognitive tests; genomic-damage; glucose-production and muscle-protein breakdown rates; and body-composition.<br><br>RESULTS: GlyNAC supplementation for 24 weeks in OA corrected RBC-GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks.<br><br>CONCLUSIONS: GlyNAC supplementation for 24-weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin-resistance and endothelial dysfunction, and genomic-damage, and improved strength, gait-speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.}, }
@article {pmid33781805, year = {2021}, author = {Hong, Z and Minghua, W and Bo, N and Chaoyue, Y and Haiyang, Y and Haiqing, Y and Chunyu, X and Yan, Z and Yuan, Y}, title = {Rosmarinic acid attenuates acrylamide induced apoptosis of BRL-3A cells by inhibiting oxidative stress and endoplasmic reticulum stress.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {151}, number = {}, pages = {112156}, doi = {10.1016/j.fct.2021.112156}, pmid = {33781805}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Acrylamide/*toxicity ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line ; Cinnamates/administration &amp; dosage/*pharmacology ; Depsides/administration &amp; dosage/*pharmacology ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/drug effects ; MAP Kinase Signaling System/drug effects ; Oxidative Stress/drug effects ; Rats ; Staurosporine/pharmacology ; Rosmarinic Acid ; }, abstract = {Acrylamide (AA) is a common endogenous contaminant in food, with a complex toxicity mechanism. The study on liver damage to experimental animals caused by AA has aroused a great attention. Rosmarinic acid (RosA) as a natural antioxidant shows excellent protective effects against AA-induced hepatotoxicity, but the potential mechanism is still unclear. In the current study, the protective effect of RosA on BRL-3A cell damage induced by AA was explored. RosA increased the activity of SOD and GSH, reduced the content of ROS and MDA, and significantly reduced the oxidative stress (OS) damage of BRL-3A cells induced by AA. RosA pretreatment inhibited the MAPK signaling pathway activated by AA, and down-regulated the phosphorylation of JNK, ERK and p38. RosA pretreatment also reduced the production of calcium ions caused by AA. In addition, the key proteins p-IRE1α, XBP-1s, TRAF2 of the IRE1 pathway, and the expression of endoplasmic reticulum stress (ERS) characteristic proteins GRP78, p-ASK1, Caspase-12 and CHOP were also down-regulated by RosA. NAC blocked the activation of the MAPK signaling pathway and inhibited the ERS pathway. RosA reduced the rate of apoptosis and down-regulated the expression of Bax/Bcl-2 and Caspase-3, thereby inhibiting AA-induced apoptosis. In conclusion, RosA reduced the OS and ERS induced by AA in BRL-3A cells, thereby inhibiting cell apoptosis, and it could be used as a potential protective agent against AA toxicity.}, }
@article {pmid33781788, year = {2021}, author = {Xu, J and Wang, Y and Wang, Z and Wang, Y and He, X}, title = {T-17, a spirostanol saponin, inhibits p53-independent proliferation and p53-dependent migration of gastric cancer cells.}, journal = {Steroids}, volume = {170}, number = {}, pages = {108828}, doi = {10.1016/j.steroids.2021.108828}, pmid = {33781788}, issn = {1878-5867}, mesh = {Apoptosis/drug effects ; Autophagy/drug effects ; *Stomach Neoplasms ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {The p53 tumor suppressor gene contributes to a series of life processes of cells. Previously, we have shown that T-17, a spirostanol saponin extracted from Tupistra chinensis induces cell cycle arrest, apoptosis and autophagy in gastric cancer cells. The p53 is essential in the cell cycle arrest induced by T-17, however, the effect of p53 on T-17-induced apoptosis and autophagy is still unclear. Here, our study shows that T-17 has no difference in the sensitivity of gastric cancer cells with different p53 status. By transfecting p53 siRNA into AGS cells (p53 wild type cells) or wild-type p53 into KATO-III cells (p53 deficiency cells), T-17 was found to induce apoptosis and autophagy in gastric cancer cells in a p53-independent manner. Pre-treatment with N-acetylcysteine (NAC, a ROS scavenger) demonstrated that reactive oxygen species (ROS) mediated T-17-induced p53-independent apoptosis. Besides, T-17 induces apoptosis and autophagy in gastric cancer cells by decreasing the expression of HMGB1, also in a p53-independent manner. But when we detected the inhibitory effect of T-17 on gastric cancer cell migration, it was found that p53 is essential. These experimental results showed that T-17 induced apoptosis and autophagy in gastric cancer cells in a p53-independent manner, but inhibited the migration of gastric cancer cells in a p53-dependent manner. Our research indicates that T-17 is a potential candidate for gastric cancer and provides support for better utilization of Tupistra chinensis.}, }
@article {pmid33777674, year = {2021}, author = {Luo, P and Zheng, M and Zhang, R and Zhang, H and Liu, Y and Li, W and Sun, X and Yu, Q and Tipoe, GL and Xiao, J}, title = {S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {3}, pages = {668-679}, pmid = {33777674}, issn = {2211-3835}, abstract = {Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway.}, }
@article {pmid33777670, year = {2021}, author = {Wang, P and Wang, F and Ni, L and Wu, P and Chen, J}, title = {Targeting redox-altered plasticity to reactivate synaptic function: A novel therapeutic strategy for cognitive disorder.}, journal = {Acta pharmaceutica Sinica. B}, volume = {11}, number = {3}, pages = {599-608}, pmid = {33777670}, issn = {2211-3835}, abstract = {Redox-altered plasticity refers to redox-dependent reversible changes in synaptic plasticity via altering functions of key proteins, such as N-methyl-d-aspartate receptor (NMDAR). Age-related cognitive disorders includes Alzheimer's disease (AD), vascular dementia (VD), and age-associated memory impairment (AAMI). Based on the critical role of NMDAR-dependent long-term potentiation (LTP) in memory, the increase of reactive oxygen species in cognitive disorders, and the sensitivity of NMDAR to the redox status, converging lines have suggested the redox-altered NMDAR-dependent plasticity might underlie the synaptic dysfunctions associated with cognitive disorders. In this review, we summarize the involvement of redox-altered plasticity in cognitive disorders by presenting the available evidence. According to reports from our laboratory and other groups, this "redox-altered plasticity" is more similar to functional changes rather than organic injuries, and strategies targeting redox-altered plasticity using pharmacological agents might reverse synaptic dysfunctions and memory abnormalities in the early stage of cognitive disorders. Targeting redox modifications for NMDARs may serve as a novel therapeutic strategy for memory deficits.}, }
@article {pmid33775218, year = {2021}, author = {El-Yamany, MF and Zaki, ES and Shaltout, SA and Saad, MA}, title = {Bone marrow mononuclear cells boosts anti-cytogentical aberration effect of N-acetylcysteine and α-lipoic acid in rat's liver and bone marrow: implication of oxidative and inflammatory pathways.}, journal = {Toxicology mechanisms and methods}, volume = {31}, number = {6}, pages = {437-449}, doi = {10.1080/15376516.2021.1906370}, pmid = {33775218}, issn = {1537-6524}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Bone Marrow ; Carbon Tetrachloride/toxicity ; *Chemical and Drug Induced Liver Injury/etiology/metabolism/prevention &amp; control ; Liver/metabolism ; Oxidative Stress ; Rats ; Thioctic Acid/metabolism ; }, abstract = {This study investigates the hepatoprotective effect of bone marrow mononuclear cells (BM-MNCs) transplantation, N-acetylcysteine (NAC) and α-lipoic acid (ALA). Rats were administrated carbon tetrachloride (CCl4) (1 mg/kg, i.p.) twice/week for 8 weeks for the induction of hepatotoxicity. 7 groups of rats were used as follows: Normal control, CCl4, CCl4 co-administered with BM-MNCs (1 × 10[6] in 0.1 ml PBS, i.v.), or NAC (300 mg/kg, p.o) or ALA (100 mg/kg, p.o) single or combination. Liver function was tested by measuring serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin as well as interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (Gpx), superoxide dismutase (SOD) and catalase (CAT) activities in liver homogenates. Besides that, estimation of DNA damage was performed. In addition to Micronucleus test and histopathological investigation. CCl4 treated rats showed elevation in ALT, AST, TNF-α, IL-6 and MDA accompanied by reduction in ALB, IL-10, SOD, CAT, GPx and TAC and increased the number of DNA breaks in liver tissue, showed many micronucleated polychromatic erythrocytes (MnPCEs) in bone marrow. NAC, ALA, BM-MNCs and their combination caused a reduction of ALT, AST, while, increase albumin, CAT, TAC, GPx, SOD as compared to CCl4 treated groups. Also decrease in MDA, IL-6 and TNF-α concurrently with an increase in IL-10. Moreover, BM-MNCs, NAC, ALA, and their combination decreased DNA tail %, and the count of MnPCEs. BM-MNCs combination with NAC or ALA exerted significant antioxidant, anti-inflammatory and anti-cytogenetical aberrations effect compared to each of them alone.HighlightsCCl4 elevated ALT, AST, TNF-α, IL-6 and MDACCl4 reduced ALB, IL-10, SOD, CAT, GPx and TACCCl4 increased the number of DNA breaks in liverNAC, ALA and BM-MNCs reduced ALT, AST, while, increase albumin, CAT, TAC, GPx, SODNAC, ALA and BM-MNCs decreased in MDA, IL-6 and TNF-α and increased IL-10 [Figure: see text].}, }
@article {pmid33774160, year = {2021}, author = {Kulkarni, P and Rawtani, D and Barot, T}, title = {Design, development and in-vitro/in-vivo evaluation of intranasally delivered Rivastigmine and N-Acetyl Cysteine loaded bifunctional niosomes for applications in combinative treatment of Alzheimer's disease.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {163}, number = {}, pages = {1-15}, doi = {10.1016/j.ejpb.2021.02.015}, pmid = {33774160}, issn = {1873-3441}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics ; Administration, Intranasal ; Alzheimer Disease/*drug therapy/pathology ; Animals ; Brain/pathology ; Cholinesterase Inhibitors/*administration &amp; dosage/pharmacokinetics ; Delayed-Action Preparations/administration &amp; dosage/pharmacokinetics ; Drug Combinations ; Drug Evaluation, Preclinical ; Drug Liberation ; Free Radical Scavengers/*administration &amp; dosage/pharmacokinetics ; Humans ; Liposomes ; Male ; Models, Animal ; Nasal Mucosa/metabolism ; Particle Size ; Rats ; Rivastigmine/*administration &amp; dosage/pharmacokinetics ; Sheep ; }, abstract = {The present investigation explores the potential of novel dual drug-loaded niosomes for nasal delivery of Rivastigmine (RIV) and N-Acetyl Cysteine (NAC) to the brain. The dual niosomes showed a particle size of 162.4 nm and % entrapment efficiencies of 97.7% for RIV and 85.9% for NAC. The niosomes were statistically validated using Box-Behnken experimental design (BBD) with good significance. Ultrastructural and chemical characterization of the niosomes using various analytical techniques like Fourier Transform Infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC), Transmission electron microscopy (TEM) showcased drug-excipient compatibility and robust stability of 6 months in a liquid state at 4-8 °C. The dual drug-loaded niosomes showed a sustained drug release pattern up to 2 days. Acetylcholinesterase (AChE) and DPPH (1, 1-diphenyl-2- picrylhydrazyl) enzyme inhibition assays showed a better combinative effect than the free drug solutions. A 2-day nasal permeation proved the effectiveness and biocompatibility of the niosomes. In-vivo pharmacokinetic and organ biodistribution studies revealed a better drug profile and greater distribution of the niosomes in the brain compared to other organs, thereby indicating a direct nose-to-brain delivery of the niosomes.}, }
@article {pmid33772418, year = {2021}, author = {Azarmehr, Z and Ranji, N and Khazaei Koohpar, Z and Habibollahi, H}, title = {The effect of N-Acetyl cysteine on the expression of Fxr (Nr1h4), LXRα (Nr1h3) and Sirt1 genes, oxidative stress, and apoptosis in the liver of rats exposed to different doses of cadmium.}, journal = {Molecular biology reports}, volume = {48}, number = {3}, pages = {2533-2542}, pmid = {33772418}, issn = {1573-4978}, support = {17/16/4/16035//Islamic Azad University of Rasht Branch (IR)/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects/*genetics ; Cadmium/blood/*toxicity ; Gene Expression Regulation/drug effects ; Liver/drug effects/*metabolism/pathology ; Liver X Receptors/*genetics/metabolism ; Male ; Oxidative Stress/drug effects/*genetics ; Rats, Wistar ; Receptors, Cytoplasmic and Nuclear/*genetics/metabolism ; Sirtuin 1/*genetics/metabolism ; Rats ; }, abstract = {The aim of this study was to consider the expression of farnesoid X receptor (Fxr), liver X receptor (LXRα) and sirtuin 1 (Sirt1), oxidative stress, inflammation, apoptosis, and the protective role of N-acetylcysteine (NAC) in the liver of rats treated with cadmium (Cd). 30 Wistar rats were divided into 5 groups: G1 (control), G2 (single dose of Cd), G3 (continuous dose of Cd), G4 (single dose of Cd + continuous dose of NAC), and G5 (continuous dose of Cd + continuous dose of NAC). The apoptosis of hepatic cells was measured using the TUNEL assay. Levels of malondialdehyde (MDA), IL-10, TNF-α, and total antioxidant capacity (TAC) were measured by specific kits. The expression of Fxr, LXRα, and Sirt1 genes and ratio of Bax/Bcl2 was considered using RT-PCR. While NAC treatment improved TAC and IL-10 values, it decreased MDA and TNF-α levels in the liver of rats exposed to Cd (P < 0.001). NAC decreased Bax/Bcl2 in the liver of G4 and G5 groups (P < 0.001). Exposure to a continuous dose of Cd decreased Fxr, LXRα, and Sirt1 expression by 36.65- (P < 0.001), 12.52- (P < 0.001) and 11.34-fold (P < 0.001) compared to control, respectively. NAC increased Fxr, LXRα, and Sirt1 expression (P < 0.01) and decreased Cd concentrations in both serum and tissue samples in G4 and G5 groups. Our results suggested that NAC protects liver tissue against Cd toxicity by elevating antioxidant capacity, mitigating oxidative stress, inflammation, apoptosis and up-regulation of FXR, LXR, and SIRT1 genes.}, }
@article {pmid33772346, year = {2021}, author = {Verma, N and Pink, M and Schmitz-Spanke, S}, title = {A new perspective on calmodulin-regulated calcium and ROS homeostasis upon carbon black nanoparticle exposure.}, journal = {Archives of toxicology}, volume = {95}, number = {6}, pages = {2007-2018}, pmid = {33772346}, issn = {1432-0738}, mesh = {A549 Cells ; Alveolar Epithelial Cells/*drug effects/pathology ; Antioxidants/pharmacology ; Calcium/metabolism ; Calmodulin/metabolism ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Humans ; Nanoparticles/*toxicity ; Oxidative Stress/*drug effects/genetics ; Reactive Oxygen Species/metabolism ; Soot/administration &amp; dosage/*toxicity ; Time Factors ; }, abstract = {Toxicological studies propose that exposure to carbon black nanoparticles induces organ injuries and inflammatory responses. Besides, current understanding of the molecular mechanisms implies that carbon black nanoparticles (CBNP) exposure induces the production of reactive oxygen species (ROS) causing inflammation, mitochondrial dysfunction or disturbance in calcium homeostasis. However, the precise mechanisms whereby CBNP exert these effects in the lung are still not fully understood. To gain insight into the possible mechanism of CBNP exerted toxicity, human alveolar epithelial cells (A549) were exposed to different concentrations of CBNP and for different timepoints. The reaction of the cells was monitored by the systematic use of cell-based measurements of calcium and ROS, in the presence and absence of calcium (Ca[2+]) pump inhibitors/chelators and antioxidants. Followed by an in-depth PCR analysis of 84 oxidative stress-related genes. The measurements revealed, as compared to the control, that exposure to CBNP nanoparticles leads to the generation of high ROS levels, as well as a disturbance in calcium homeostasis, which remained primarily unchanged even after 24 h of exposure. Nevertheless, in presence of antioxidants N-acetylcysteine (NAC) and Trolox, ROS formation was considerably reduced without affecting the intracellular calcium concentration. On the other hand, Ca[2+] pump inhibitors/chelators, BAPTA (1,2-bis(o-amino phenoxy)ethane-N, N, N', N'-tetraacetic acid) and verapamil not only decreased the Ca[2+] overload, but also further decreased the ROS formation, indicating its role in CBNP-induced oxidative stress. Further, a PCR array analysis of A549 cells in presence and absence of the calmodulin (CaM) antagonist W7, indicated toward nine altered oxidative stress-related genes which further confirmed our cytotoxicity results. Obtained data suggested that CBNP exposure elevates calcium ion concentration, which further contributes to oxidative stress, via the calcium-binding protein CaM. Its inhibition with W7 leads to downregulation in gene expression of nine oxidative stress-related genes, which otherwise, as compared to control, show increased gene expression. The results of the study thus confirm that exposure of lung epithelial cells to CBNP leads to oxidative stress; however, the oxidative stress itself is a result of a disturbance in both calcium and ROS homeostasis, and should be considered while searching for a new strategy for prevention of CBNP-induced lung toxicity.}, }
@article {pmid33763172, year = {2021}, author = {Ding, X and Nie, Z and She, Z and Bai, X and Yang, Q and Wang, F and Wang, F and Geng, X}, title = {The Regulation of ROS- and BECN1-Mediated Autophagy by Human Telomerase Reverse Transcriptase in Glioblastoma.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6636510}, pmid = {33763172}, issn = {1942-0994}, mesh = {*Autophagy ; Beclin-1/*metabolism ; Brain Neoplasms/*metabolism/*pathology ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Glioblastoma/*metabolism/*pathology ; Humans ; Protein Interaction Maps ; Reactive Oxygen Species/*metabolism ; Survival Analysis ; Telomerase/*metabolism ; }, abstract = {Glioblastoma (GBM) is the most common and aggressive malignant brain tumor with high morbidity and mortality. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, is overexpressed in most cancers including GBM. It is well known that hTERT can compensate telomere shortening to immortalize cells. However, in addition to the canonical function, hTERT has the roles beyond canonical telomere maintenance. To further understand the effects of hTERT on glioblastoma progression, we investigated the role of hTERT in regulating autophagy-a conserved pathway, by which cells deliver cellular organic material and impaired organelles to the lysosomes for degradation and recycle these cargos to produce energy under a stressful condition. Our results showed that downregulation of hTERT impaired autophagy levels by suppressing BECN1/beclin-1 and induced an increase of reactive oxygen species (ROS), which resulted in cell death ultimately. On the contrary, overexpression of BECN1 or treating cells with the antioxidant N-acetylcysteine (NAC) could restore the survival of hTERT knockdown cells. Our study will provide an additional basis of telomerase-targeting therapy for future clinical anticancer treatment.}, }
@article {pmid33760228, year = {2021}, author = {Smaga, I and Frankowska, M and Filip, M}, title = {N-acetylcysteine as a new prominent approach for treating psychiatric disorders.}, journal = {British journal of pharmacology}, volume = {178}, number = {13}, pages = {2569-2594}, doi = {10.1111/bph.15456}, pmid = {33760228}, issn = {1476-5381}, support = {//Maj Institute of Pharmacology Polish Academy of Sciences/ ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Anxiety ; Anxiety Disorders ; *Bipolar Disorder ; Humans ; *Obsessive-Compulsive Disorder ; }, abstract = {N-acetylcysteine (NAC) is a well-known and safe mucolytic agent, also used in patients with paracetamol overdose. In addition to these effects, recent preclinical and clinical studies have shown that NAC exerts beneficial effects on different psychiatric disorders. Many potential mechanisms have been proposed to underlie the therapeutic effects of NAC, including the regulation of several neurotransmitters, oxidative homeostasis, and inflammatory mediators. In this paper, we summarize the current knowledge on the ability of NAC to ameliorate symptoms and neuropathologies related to different psychiatric disorders, including attention deficit hyperactivity disorder, anxiety, bipolar disorder, depression, obsessive-compulsive disorder, obsessive-compulsive-related disorder, posttraumatic stress disorder, and schizophrenia. Although preclinical studies have shown a positive effect of NAC on animal models of psychiatric disorders, the clinical efficacy of NAC is not fully established. NAC remains a strong candidate for adjunct treatment for many psychiatric disorders, but additional preclinical and clinical studies are needed.}, }
@article {pmid33760106, year = {2021}, author = {Xu, X and Li, Q and Li, L and Zeng, M and Zhou, X and Cheng, Z}, title = {Endoplasmic reticulum stress/XBP1 promotes airway mucin secretion under the influence of neutrophil elastase.}, journal = {International journal of molecular medicine}, volume = {47}, number = {5}, pages = {}, pmid = {33760106}, issn = {1791-244X}, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 6/metabolism ; Cells, Cultured ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects/*physiology ; Endoribonucleases/genetics ; Epithelial Cells ; Heat-Shock Proteins/metabolism ; Humans ; Leukocyte Elastase/*metabolism/pharmacology ; Mucin 5AC/*genetics/metabolism ; Phenylbutyrates/pharmacology ; Protein Serine-Threonine Kinases/genetics ; Reactive Oxygen Species/metabolism ; X-Box Binding Protein 1/genetics/*metabolism ; }, abstract = {Endoplasmic reticulum (ER) stress is an important reaction of airway epithelial cells in response to various stimuli, and may also be involved in the mucin secretion process. In the present study, the effect of ER stress on neutrophil elastase (NE)‑induced mucin (MUC)5AC production in human airway epithelial cells was explored. 16HBE14o‑airway epithelial cells were cultured and pre‑treated with the reactive oxygen species (ROS) inhibitor, N‑acetylcysteine (NAC), or the ER stress chemical inhibitor, 4‑phenylbutyric acid (4‑PBA), or the cells were transfected with inositol‑requiring kinase 1α (IRE1α) small interfering RNA (siRNA) or X‑box‑binding protein 1 (XBP1) siRNA, respectively, and subsequently incubated with NE. The results obtained revealed that NE increased ROS production in the 16HBE14o‑cells, with marked increases in the levels of ER stress‑associated proteins, such as glucose‑regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), phosphorylated protein kinase R‑like endoplasmic reticulum kinase (pPERK) and phosphorylated (p)IRE1α. The protein and mRNA levels of spliced XBP1 were also increased, and the level of MUC5AC protein was notably increased. The ROS scavenger NAC and ER stress inhibitor 4‑PBA were found to reduce ER stress‑associated protein expression and MUC5AC production and secretion. Further analyses revealed that MUC5AC secretion was also attenuated by IRE1α and XBP1 siRNAs, accompanied by a decreased mRNA expression of spliced XBP1. Taken together, these results demonstrate that NE induces ER stress by promoting ROS production in 16HBE14o‑airway epithelial cells, leading to increases in MUC5AC protein production and secretion via the IRE1α and XBP1 signaling pathways.}, }
@article {pmid33758187, year = {2021}, author = {March, ME and Gutierrez-Uzquiza, A and Snorradottir, AO and Matsuoka, LS and Balvis, NF and Gestsson, T and Nguyen, K and Sleiman, PMA and Kao, C and Isaksson, HJ and Bragason, BT and Olafsson, E and Palsdottir, A and Hakonarson, H}, title = {NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients.}, journal = {Nature communications}, volume = {12}, number = {1}, pages = {1827}, pmid = {33758187}, issn = {2041-1723}, mesh = {Acetylcysteine/administration &amp; dosage/analogs &amp; derivatives/chemistry/*pharmacology ; Amyloidogenic Proteins/chemistry/genetics/*metabolism ; Biopsy ; Cerebral Amyloid Angiopathy, Familial/*diet therapy/drug therapy/genetics ; Cystatin C/chemistry/genetics/*metabolism ; Cystatins/chemistry/genetics/*metabolism ; Gene Expression ; Glutathione/chemistry/pharmacology ; HEK293 Cells ; Humans ; Skin/drug effects/metabolism ; Young Adult ; }, abstract = {Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50-90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.}, }
@article {pmid33753139, year = {2021}, author = {Wellenberg, A and Weides, L and Kurzke, J and Hennecke, T and Bornhorst, J and Crone, B and Karst, U and Brinkmann, V and Fritz, G and Honnen, S}, title = {Use of C. elegans as a 3R-compliant in vivo model for the chemoprevention of cisplatin-induced neurotoxicity.}, journal = {Experimental neurology}, volume = {341}, number = {}, pages = {113705}, doi = {10.1016/j.expneurol.2021.113705}, pmid = {33753139}, issn = {1090-2430}, support = {P40 OD010440/OD/NIH HHS/United States ; }, mesh = {Animals ; Animals, Genetically Modified ; Antineoplastic Agents/*toxicity ; Caenorhabditis elegans ; Chemoprevention/methods ; Cisplatin/*toxicity ; *Disease Models, Animal ; Dose-Response Relationship, Drug ; Mercaptoethylamines/pharmacology/therapeutic use ; Neurotoxicity Syndromes/metabolism/*prevention &amp; control ; Oxidative Stress/drug effects/physiology ; Platinum Compounds/toxicity ; }, abstract = {Anticancer therapeutics can provoke severe side effects that impair the patient's quality of life. A frequent dose-limiting side effect of platinum-based anticancer therapy is neurotoxicity. Its pathophysiology is poorly understood, and effective preventive or therapeutic measures are missing. Therefore, elucidation of the molecular mechanism of platinating drug-induced neurotoxicity and the development of preventive strategies is urgently needed. To this end, we aim to use C. elegans as a 3R-compliant in vivo model. The 3R principles were conceived for animal welfare in science concerning animal experiments, which should be replaced, reduced or refined. We can analytically demonstrate dose-dependent uptake of cisplatin (CisPt) in C. elegans, as well as genotoxic and cytotoxic effects based on DNA adduct formation (i.e., 1,2-GpG intrastrand crosslinks), induction of apoptosis, and developmental toxicity. Measuring the impairment of pharyngeal pumping as a marker of neurotoxicity, we found that especially CisPt reduces the pumping frequency at concentrations where basal and touch-provoked movement were not yet affected. CisPt causes glutathione (GSH) depletion and RNAi-mediated knockdown of the glutamate-cysteine ligase GCS-1 aggravates the CisPt-induced inhibition of pharyngeal pumping. Moreover, N-acetylcysteine (NAC) mitigated CisPt-triggered toxicity, indicating that GSH depletion contributes to the CisPt-induced pharyngeal damage. In addition to NAC, amifostine (WR1065) also protected the pharynx of C. elegans from the toxic effects of CisPt. Measuring pharyngeal activity by the electrophysiological recording of neurotransmission in the pharynx, we confirmed that CisPt is neurotoxic in C. elegans and that NAC is neuroprotective in the nematode. The data support the hypothesis that monitoring the pharyngeal activity of C. elegans is a useful surrogate marker of CisPt-induced neurotoxicity. In addition, a low GSH pool reduces the resistance of neurons to CisPt treatment, and both NAC and WR1065 are capable of attenuating platinum-induced neurotoxicity during post-incubation in C. elegans. Overall, we propose C. elegans as a 3R-compliant in vivo model to study the molecular mechanisms of platinum-induced neurotoxicity and to explore novel neuroprotective therapeutic strategies to alleviate respective side effects of platinum-based cancer therapy.}, }
@article {pmid33752756, year = {2021}, author = {Zhang, J and Lan, T and Han, X and Xu, Y and Liao, L and Xie, L and Yang, B and Tian, W and Guo, W}, title = {Improvement of ECM-based bioroot regeneration via N-acetylcysteine-induced antioxidative effects.}, journal = {Stem cell research &amp; therapy}, volume = {12}, number = {1}, pages = {202}, pmid = {33752756}, issn = {1757-6512}, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Antioxidants/pharmacology ; Extracellular Matrix ; Hydrogen Peroxide/pharmacology ; Oxidative Stress ; Rats ; Stem Cells ; }, abstract = {BACKGROUND: The low survival rate or dysfunction of extracellular matrix (ECM)-based engineered organs caused by the adverse effects of unfavourable local microenvironments on seed cell viability and stemness, especially the effects of excessive reactive oxygen species (ROS), prompted us to examine the importance of controlling oxidative damage for tissue transplantation and regeneration. We sought to improve the tolerance of seed cells to the transplant microenvironment via antioxidant pathways, thus promoting transplant efficiency and achieving better tissue regeneration.<br><br>METHODS: We improved the antioxidative properties of ECM-based bioroots with higher glutathione contents in dental follicle stem cells (DFCs) by pretreating cells or loading scaffolds with the antioxidant NAC. Additionally, we developed an in situ rat alveolar fossa implantation model to evaluate the long-term therapeutic effects of NAC in bioroot transplantation.<br><br>RESULTS: The results showed that NAC decreased H2O2-induced cellular damage and maintained the differentiation potential of DFCs. The transplantation experiments further verified that NAC protected the biological properties of DFCs by repressing replacement resorption or ankylosis, thus facilitating bioroot regeneration.<br><br>CONCLUSIONS: The following findings suggest that NAC could significantly protect stem cell viability and stemness during oxidative stress and exert better and prolonged effects in bioroot intragrafts.}, }
@article {pmid33752649, year = {2021}, author = {Zhang, B and Wang, Y and Wu, C and Qiu, S and Chen, X and Cai, B and Xie, H}, title = {Freeze-thawing impairs the motility, plasma membrane integrity and mitochondria function of boar spermatozoa through generating excessive ROS.}, journal = {BMC veterinary research}, volume = {17}, number = {1}, pages = {127}, pmid = {33752649}, issn = {1746-6148}, mesh = {Animals ; Antioxidants/metabolism ; Cell Membrane/*pathology ; Cryopreservation/*veterinary ; Freezing ; Male ; Mitochondria/metabolism ; Reactive Oxygen Species/*metabolism ; *Semen Preservation ; *Sperm Motility ; Spermatozoa/metabolism/*pathology ; *Swine/metabolism ; }, abstract = {BACKGROUND: Cryopreservation is an efficient way to store spermatozoa and is closely associated with the quality of sperm after the freeze-thaw process. During freeze-thaw cycling, excessive reactive oxygen species (ROS) are produced, and the effects of ROS on boar sperm during cryopreservation have not been identified.<br><br>RESULTS: In this study, we evaluated the quality of boar spermatozoa in different steps of cryopreservation (extension, cooling, and thawing for 30&#x2009;min and 240&#x2009;min) with or without boar-sperm antioxidant (N-acetylcysteine (NAC)). The ROS levels, sperm motility, plasma membrane integrity, mitochondrial activity, sperm chromatin structure, ATP content, and sperm apoptosis were assayed. After thawing, the ROS level and sperm apoptosis were significantly increased, and the sperm motility, plasma membrane integrity, mitochondrial activity, sperm chromatin structure, and ATP content were significantly impaired compared with those at the extension period and cooling period. Moreover, the addition of N-acetyl L-cysteine (NAC) reversed these changes.<br><br>CONCLUSION: The freeze-thawing of boar spermatozoa impaired their motility, plasma membrane, mitochondrial activity, sperm chromatin structure and apoptosis by producing excessive ROS. Thus, the downregulation of ROS level by antioxidants, especially the NAC, is important for manufacturing frozen pig sperm to increase reproductive cells and livestock propagation, as well as to improve the application of frozen semen in pigs worldwide.}, }
@article {pmid33749848, year = {2021}, author = {Soliman, MM and Aldhahrani, A and Gaber, A and Alsanie, WF and Shukry, M and Mohamed, WA and Metwally, MMM}, title = {Impacts of n-acetyl cysteine on gibberellic acid-induced hepatorenal dysfunction through modulation of pro-inflammatory cytokines, antifibrotic and antioxidant activity.}, journal = {Journal of food biochemistry}, volume = {45}, number = {4}, pages = {e13706}, doi = {10.1111/jfbc.13706}, pmid = {33749848}, issn = {1745-4514}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; *Antioxidants/metabolism/pharmacology ; Cytokines/genetics/metabolism ; Gibberellins ; Liver/metabolism ; Oxidative Stress ; Rats ; }, abstract = {The extensive usage of gibberellic acid (GA3) in agriculture and plant growth is generally associated with enormous human and public health hazards. The present research assesses the impact of n-acetyl cysteine (NAC) on the hepatorenal injury persuaded by GA3 for this purpose, After two weeks of adaptation twenty-four rats allocated into four groups (6 rats/group) as follows: control group, supplied with saline only; n-acetyl cysteine (NAC) group, provided with 150 mg/kg/bw by stomach tube (orally) dissolved in saline; Positive GA3 group, received GA3 (55 mg/kg/bw) orally; Protective group received NAC (150 mg/kg/bw) and GA3 (55 mg/kg/bw) as in NAC and GA3 groups. Rats received their treatments for consecutive 3 weeks. On day 22, rats were anesthetized, then euthanized. Blood and tissue samples were obtained for biochemical, antioxidants markers analysis, gene expression, and histopathological examination. Our results revealed significant changes in serum AST, ALT, urea, uric acid, total protein, and albumin levels with a substantial rise of MDA and NO concentration in GA3 treated rats along with a considerable decrease of the GSH and overexpression of the inflammatory hepatic and renal cytokines (IL-10, TNF-α, NOS) and fibrotic gene expression TGF-β1, and α-SMA, with boost expression of nuclear factor-kappa (NFk B). NAC co-administered with GA3 significantly normalized the kidney and liver function and the antioxidant state, besides normal histological structure of both liver and kidney tissue and downregulated expression of the pro-inflammatory cytokines as well as, fibrogenic gene expression. PRACTICAL APPLICATIONS: The current study confirmed that GA3 induced hepto-renal dysfunction that was ameliorated by NAC administration. Moreover, our findings confirmed the antioxidant capability of n-acetyl cysteine and afford robust evidence about the ameliorative effect of the n-acetyl cysteine to attenuate the hepatorenal injury induced by gibberellic acid through modulation of the antioxidant defense system fibrogenic, and pro-inflammatory cytokines expression.}, }
@article {pmid33749526, year = {2021}, author = {Liu, W and Xu, L and Wang, X and Zhang, D and Sun, G and Wang, M and Wang, M and Han, Y and Chai, R and Wang, H}, title = {PRDX1 activates autophagy via the PTEN-AKT signaling pathway to protect against cisplatin-induced spiral ganglion neuron damage.}, journal = {Autophagy}, volume = {17}, number = {12}, pages = {4159-4181}, pmid = {33749526}, issn = {1554-8635}, mesh = {Autophagy/physiology ; *Cisplatin/adverse effects ; Hydrogen Peroxide/pharmacology ; Neurons/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; *Spiral Ganglion ; }, abstract = {Spiral ganglion neurons (SGNs) are auditory neurons that relay sound signals from the inner ear to the brainstem. The ototoxic drug cisplatin can damage SGNs and thus lead to sensorineural hearing loss (SNHL), and there are currently no methods for preventing or treating this. Macroautophagy/autophagy plays a critical role in SGN development, but the effect of autophagy on cisplatin-induced SGN injury is unclear. Here, we first found that autophagic flux was activated in SGNs after cisplatin damage. The SGN apoptosis and related hearing loss induced by cisplatin were alleviated after co-treatment with the autophagy activator rapamycin, whereas these were exacerbated by the autophagy inhibitor 3-methyladenine, indicating that instead of inducing SGN death, autophagy played a neuroprotective role in SGNs treated with cisplatin both in vitro and in vivo. We further demonstrated that autophagy attenuated reactive oxygen species (ROS) accumulation and alleviated cisplatin-induced oxidative stress in SGNs to mediate its protective effects. Notably, the role of the antioxidant enzyme PRDX1 (peroxiredoxin 1) in modulating autophagy in SGNs was first identified. Deficiency in PRDX1 suppressed autophagy and increased SGN loss after cisplatin exposure, while upregulating PRDX1 pharmacologically or by adeno-associated virus activated autophagy and thus inhibited ROS accumulation and apoptosis and attenuated SGN loss induced by cisplatin. Finally, we showed that the underlying mechanism through which PRDX1 triggers autophagy in SGNs was, at least partially, through activation of the PTEN-AKT signaling pathway. These findings suggest potential therapeutic targets for the amelioration of drug-induced SNHL through autophagy activation.Abbreviations: 3-MA: 3-methyladenine; AAV : adeno-associated virus; ABR: auditory brainstem responses; AKT/protein kinase B: thymoma viral proto-oncogene; Baf: bafilomycin A1; CAP: compound action potential; COX4I1: cytochrome c oxidase subunit 4I1; Cys: cysteine; ER: endoplasmic reticulum; H2O2: hydrogen peroxide; HC: hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; NAC: N-acetylcysteine; PRDX1: peroxiredoxin 1; PTEN: phosphatase and tensin homolog; RAP: rapamycin; ROS: reactive oxygen species; SGNs: spiral ganglion neurons; SNHL: sensorineural hearing loss; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling; WT: wild type.}, }
@article {pmid33747349, year = {2021}, author = {Wang, HR and Chen, PH and Tang, JY and Yen, CY and Su, YC and Huang, MY and Chang, HW}, title = {Manoalide Shows Mutual Interaction between Cellular and Mitochondrial Reactive Species with Apoptosis in Oral Cancer Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6667355}, pmid = {33747349}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Ethidium/analogs &amp; derivatives/metabolism ; Fluoresceins/metabolism ; Humans ; Mitochondria/drug effects/*metabolism ; Mouth Neoplasms/*metabolism/*pathology ; Oligopeptides/pharmacology ; Organophosphorus Compounds/pharmacology ; Phenanthridines/metabolism ; Piperidines/pharmacology ; Reactive Oxygen Species/*metabolism ; Terpenes/*pharmacology ; }, abstract = {We previously found that marine sponge-derived manoalide induced antiproliferation and apoptosis of oral cancer cells as well as reactive species generations probed by dichloro-dihydrofluorescein diacetate (DCFH-DA) and MitoSOX Red. However, the sources of cellular and mitochondrial redox stresses and the mutual interacting effects between these redox stresses and apoptosis remain unclear. To address this issue, we examined a panel of reactive species and used the inhibitors of cellular reactive species (N-acetylcysteine (NAC)), mitochondrial reactive species (MitoTEMPO), and apoptosis (Z-VAD-FMK; ZVAD) to explore their interactions in manoalide-treated oral cancer Ca9-22 and CAL 27 cells. Hydroxyl (˙OH), nitrogen dioxide (NO2˙), nitric oxide (˙NO), carbonate radical-anion (CO3 [˙-]), peroxynitrite (ONOO[-]), and superoxide (O2 [˙-]) were increased in oral cancer cells following manoalide treatments in terms of fluorescence staining and flow cytometry. Cellular reactive species (˙OH, NO2 [·], ˙NO, CO3 [˙-], and ONOO[-]) as well as cellular and mitochondrial reactive species (O2 [˙-]) were induced in oral cancer cells following manoalide treatment for 6 h. NAC, MitoTEMPO, and ZVAD inhibit manoalide-induced apoptosis in terms of annexin V and pancaspase activity assays. Moreover, NAC inhibits mitochondrial reactive species and MitoTEMPO inhibits cellular reactive species, suggesting that cellular and mitochondrial reactive species can crosstalk to regulate each other. ZVAD shows suppressing effects on the generation of both cellular and mitochondrial reactive species. In conclusion, manoalide induces reciprocally activation between cellular and mitochondrial reactive species and apoptosis in oral cancer cells.}, }
@article {pmid33745432, year = {2021}, author = {Chalke, SD and Kale, PP}, title = {Combinational Approaches Targeting Neurodegeneration, Oxidative Stress, and Inflammation in the Treatment of Diabetic Retinopathy.}, journal = {Current drug targets}, volume = {22}, number = {16}, pages = {1810-1824}, doi = {10.2174/1389450122666210319113136}, pmid = {33745432}, issn = {1873-5592}, mesh = {*Diabetic Retinopathy/drug therapy/physiopathology ; Drug Therapy, Combination ; Humans ; Inflammation/drug therapy ; Neurodegenerative Diseases/drug therapy ; Oxidative Stress ; }, abstract = {Diabetic Retinopathy (DR) is one of the most severe ocular problems of diabetes. It is a microvascular complication that impairs the vision of diabetic individuals and can cause acquired blindness. Currently, available treatment options like laser therapy, vitrectomy, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and glucocorticoids help to reduce vision loss at advanced stages. In spite of the available therapies, patients with severe vision loss face difficulty in achieving the normal vision. There is a need for the development of newer treatment strategies to address the condition from the early stages. Multiple factors owing to complex pathophysiological events are responsible for this long-term complication. Neurodegeneration, inflammation, and oxidative stress are the three important factors associated with the development of DR. Oxidative stress is a major contributor to the onset and progression of DR. Pathological events like retinal neurodegeneration and inflammation damage the retina in the early stages of DR. Different combinations of treatments targeting these pathological events are discussed in the present review. The first combination discussed is citicoline and resveratrol and the second combination is duloxetine and N-acetyl cysteine (NAC). These combinations may help in the early stages of DR. CD5-2, and angiopoietin-2 inhibitors is the third combination and this combination may help to manage diabetic macular edema. The main purpose of this article is to discuss the link between these pathologies and the three combinational approaches with the objective of considerating newer therapeutic approaches in research related to DR treatment.}, }
@article {pmid33744595, year = {2021}, author = {Chen, L and Feng, D and Qian, Y and Cheng, X and Song, H and Qian, Y and Zhang, X and Wu, Y and Lv, H and Liu, Q and Cheng, G and Yang, B and Gu, M}, title = {Valtrate as a novel therapeutic agent exhibits potent anti-pancreatic cancer activity by inhibiting Stat3 signaling.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {85}, number = {}, pages = {153537}, doi = {10.1016/j.phymed.2021.153537}, pmid = {33744595}, issn = {1618-095X}, mesh = {Animals ; Apoptosis/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin B1/metabolism ; Female ; Humans ; Iridoids/*pharmacology ; Mice ; Mice, Inbred BALB C ; Molecular Docking Simulation ; Pancreatic Neoplasms/*drug therapy/pathology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/*drug effects ; Valerian/chemistry ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND: Valtrate is a novel epoxy iridoid ester isolated from Chinese herbal medicine Valeriana jatamansi Jones with anti-proliferative activity against various human cancer cell lines. However, its efficacy and molecular mechanisms against pancreatic cancer (PC) cells are largely unclear.<br><br>PURPOSE: To investigate the anti-cancer effects of valtrate on PC cell lines and its underlying mechanisms.<br><br>METHODS: MTT assay was first performed to detect the effect of valtrate on cell viability in human PC cell lines and normal pancreatic epithelial cells HPDE. Cell apoptosis and cycle phase assay were detected by flow cytometry. The relative mRNA expressions of Bax, Bcl-2, c-Myc, and CyclinB1 were tested by quantitative PCR (qPCR) assay. The expression of relative proteins was detected by Western blotting (WB). A PANC-1[luc] cells xenograft mouse model in nu/nu female mice was used to elucidate the effect of valtrate on tumor growth in vivo.<br><br>RESULTS: Valtrate significantly inhibited the growth of PC cells without affecting the growth of normal pancreatic epithelial cells HPDE, induced significant apoptosis and cell cycle arrest in G2/M phase. Moreover, valtrate inhibited the tumor growth of PC cell PANC-1 in xenograft mice by 61%. Further mechanism study demonstrated that valtrate could increase the expression level of Bax, suppress Bcl-2 as well as c-Myc and Cyclin B1, inhibit the transcriptional activity of Stat3, while valtrate decreased the expression level of Stat3 and phosphated-Stat3 (Tyr705) and induced the high molecular aggregation of Stat3. Molecular docking analysis predicted that valtrate might interact with Cys712 of Stat3 protein. Valtrate could also induce a transient depleted intracellular glutathione (GSH) level and increased reactive oxygen species (ROS). NAC (N-acetylcysteine), a reducer reversed valtrate-induced the depletion of Stat3, p-Stat3, c-Myc, and Cyclin B1.<br><br>CONCLUSION: Valtrate exerts anti-cancer activity against PC cells by directly targeting Stat3 through a covalent linkage to inhibit Stat3 activity, which causes apoptosis and cell cycle arrest.}, }
@article {pmid33742775, year = {2021}, author = {Dear, JW and Ng, ML and Bateman, DN and Leroy Sivappiragasam, P and Choi, H and Khoo, BBJ and Ibrahim, B and Drum, CL}, title = {A metabolomic analysis of thiol response for standard and modified N-acetyl cysteine treatment regimens in patients with acetaminophen overdose.}, journal = {Clinical and translational science}, volume = {14}, number = {4}, pages = {1476-1489}, pmid = {33742775}, issn = {1752-8062}, support = {//Clinician Scientist Award (CSA)/ ; CSAINV17nov12//National Medical Research Council of the Singapore Ministry of Health/ ; //National Research Foundation/ ; }, mesh = {Acetaminophen/pharmacokinetics/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Adult ; Antidotes/*administration &amp; dosage ; Biomarkers/blood/metabolism ; Chemical and Drug Induced Liver Injury/blood/diagnosis/etiology/*prevention &amp; control ; Drug Administration Schedule ; Drug Monitoring/methods ; Drug Overdose/blood/*drug therapy/etiology ; Female ; Humans ; Infusions, Intravenous ; Male ; Metabolomics ; Middle Aged ; Oxidation-Reduction/drug effects ; ROC Curve ; Sulfhydryl Compounds/blood/metabolism ; }, abstract = {N-acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol-APAP)-induced acute liver injury (ALI). The 3-bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post-start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post-infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP-metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP-metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP-induced ALI.}, }
@article {pmid33740178, year = {2022}, author = {Alizadeh, B and Salehzadeh, A and Ranji, N and Arasteh, A}, title = {Effects of N-Acetyl Cysteine on Genes Expression of c-myc, and Ask-1, Histopathological, Oxidative Stress, Inflammation, and Apoptosis in the Liver of Male Rats Exposed to Cadmium.}, journal = {Biological trace element research}, volume = {200}, number = {2}, pages = {661-668}, pmid = {33740178}, issn = {1559-0720}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis ; *Cadmium/metabolism/toxicity ; Inflammation/chemically induced/genetics/metabolism ; Liver/metabolism ; Male ; Oxidative Stress ; Rats ; }, abstract = {This study aimed to consider the oxidative damage induced by cadmium (Cd) and apoptosis and the role of N-acetylcysteine (NAC) in preserving hepatic cells against Cd toxicity. Male rats were randomly divided into seven groups including G1 (control), G2 (single dose of Cd), G3 (continuous dose of Cd), G4 (single dose of Cd + continuous dose of NAC), and G5 (continuous dose of Cd + continuous dose of NAC). Hepatic cells apoptosis was measured using TUNEL assay method. Levels of malondialdehyde (MDA), TNF-α, IL-10, and total antioxidant capacity (TAC) were measured by specific kits. Expression of c-myc and Ask-1 genes was considered using RT-PCR. NAC treatments significantly improved TAC and IL-10, but decreased MDA and TNF-α values in rats that were exposed to a single and continuous dose of Cd (p < 0.05). Exposure to a single and continuous dose of Cd caused a significant increase in c-myc expression by 3.76-fold (p < 0.001) and 8.17-fold (p < 0.0001), respectively. Single and continuous dose treatment of Cd led to a significant increase in Ask1 expression by 4.38-fold (p < 0.001) and 13.52-fold (p < 0.001), respectively. NAC treatments significantly decreased the expression of c-myc, and Ask-1 in rats exposed to single or continuous Cd. Cd exposure is strongly associated with oxidative stress, inflammation, antioxidant depletion, and liver cells apoptosis. NAC can protect liver tissue against Cd by elevating antioxidants capacity, mitigating oxidative stress and inflammation, as well as down-regulating of apoptotic genes.}, }
@article {pmid33739173, year = {2021}, author = {Genç, F and Peker, EGG}, title = {Does Short-Term and Low-Dose N-Acetylcysteine Affect Oxidative Stress and Inflammation in The Liver Tissues of Diabetic Rats?.}, journal = {Biological research for nursing}, volume = {23}, number = {4}, pages = {568-574}, doi = {10.1177/10998004211003668}, pmid = {33739173}, issn = {1552-4175}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; *Diabetes Mellitus, Experimental/drug therapy ; Glutathione ; Inflammation/drug therapy/metabolism ; Liver/metabolism ; Male ; Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {Diabetes mellitus is a serious chronic disease in which the oxidant-antioxidant balance is impaired, causing many complications, including hepatopathy. In this study, the effects of short-term and low-dose N-acetylcysteine (NAC) administration on the biochemical, proinflammatory, and oxidative stress parameters in the liver tissue of diabetic rats were investigated. Twenty-four adult male Wistar albino rats weighing approximately 250-300 g were divided into 4 groups (n = 6): Control, Streptozotosin (STZ)-induced diabetes (DM), NAC treatment (60 mg/kg), and STZ-induced diabetes treated with NAC (DM+NAC; 60 mg/kg). NAC treatment was administered intraperitoneally as a single daily dose for 7 days. At the end of the experiment (3 weeks), blood and liver samples were collected for biochemical parameter analysis. Lipid peroxidation, antioxidant parameters, and nitric oxide (NOx) levels were determined by spectrophotometric method. Tissue inflammation parameters were evaluated by ELISA. Lipid peroxidation, proinflammatory cytokines, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) values increased significantly with diabetes. NAC treatment significantly decreased serum ALT and AST levels and proinflammatory cytokines in the diabetic group. Liver glutathione (GSH) and NOx levels increased significantly in the DM+NAC group (p < 0.05). While NAC treatment reduced lipid peroxidation in the liver, it improved the inflammatory response and antioxidant status. The beneficial effect of NAC treatment may be due to its antioxidant activity and the resulting increased level of GSH. The results show that low-dose and short-term NAC treatment had a positive effect on oxidative damage and inflammation in liver tissue. NAC can be used as a potential antioxidant in diabetes to prevent hepatopathy.}, }
@article {pmid33738117, year = {2021}, author = {Qian, B and Li, J and Guo, K and Guo, N and Zhong, A and Yang, J and Wang, J and Xiao, P and Sun, J and Xiong, L}, title = {Antioxidant biocompatible composite collagen dressing for diabetic wound healing in rat model.}, journal = {Regenerative biomaterials}, volume = {8}, number = {2}, pages = {rbab003}, pmid = {33738117}, issn = {2056-3418}, abstract = {Associated with persistent oxidative stress, altered inflammatory responses, poor angiogenesis and epithelization, wound healing in diabetic patients is impaired. N-acetylcysteine (NAC) is reported to resist excess reactive oxygen species (ROS) production, prompt angiogenesis and maturation of the epidermis. Studies have revealed that graphene oxide (GO) can regulate cellular behavior and form cross-links with naturally biodegradable polymers such as collagen (COL) to construct composite scaffolds. Here, we reported a COL-based implantable scaffold containing a mixture of GO capable of the sustained delivery of NAC to evaluate the wound healing in diabetic rats. The morphological, physical characteristics, biocompatibility and NAC release profile of the GO-COL-NAC (GCN) scaffold were evaluated in vitro. Wound healing studies were performed on a 20 mm dorsal full-skin defect of streptozotocin (STZ)-induced diabetic rats. The injured skin tissue was removed at the 18th day post-surgery for histological analysis and determination of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) activity. In diabetic rats, we confirmed that the GCN scaffold presented a beneficial effect in enhancing the wound healing process. Additionally, due to the sustained release of NAC, the scaffold may potentially induce the antioxidant defense system, upregulating the expression levels of the antioxidant enzymes in the wound tissue. The findings revealed that the antioxidant biocompatible composite collagen dressing could not only deliver NAC in situ for ROS inhibition but also promote the wound healing process. This scaffold with valuable therapy potential might enrich the approaches for surgeon in diabetic wound treatment in the future.}, }
@article {pmid33726556, year = {2022}, author = {Wu, J and Cui, D and Li, H and Zeng, J}, title = {Protective effects of NAC and salubrinal on apoptosis of retinal pigment epithelial cells induced by all-trans retinoic acid.}, journal = {European journal of ophthalmology}, volume = {32}, number = {1}, pages = {395-401}, doi = {10.1177/11206721211000674}, pmid = {33726556}, issn = {1724-6016}, mesh = {*Acetylcysteine/pharmacology ; *Apoptosis ; Caspase 3 ; Cell Line ; Cinnamates ; Epithelial Cells/*cytology/drug effects ; Humans ; Oxidative Stress ; Retinal Pigment Epithelium/cytology ; Retinal Pigments ; Thiourea/analogs &amp; derivatives ; Transcription Factor CHOP ; *Tretinoin/pharmacology ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {PURPOSE: Accumulation of endogenous all-trans retinoic acid (ATRA) plays a role in the degeneration of photoreceptor cells and retinal pigment epithelium (RPE) cells, contributing to age-related macular degeneration (AMD). This study attempted to investigate the influence of antioxidant N-acetylcysteine (NAC) and selective endoplasmic reticulum stress (ERS) inhibitor salubrinal on apoptosis of ARPE-19 cells induced by ATRA.<br><br>METHODS: The RPE cell line (ARPE-19) was treated with ATRA, ATRA+NAC, ATRA+salubrinal or ATRA+NAC+salubrinal and the control was untreated. After 24&#x2009;h of cell culture, the levels of apoptosis, multicaspase and reactive oxygen species (ROS) were detected by flow cytometry. Western blot analysis was employed to detect the expression of vascular endothelial growth factor-A (VEGF-A), C/EBP homologous protein (CHOP) and cleaved caspase-3 in the groups.<br><br>RESULTS: The results of flow cytometry showed that NAC and salubrinal decreased the levels of apoptosis, ROS and multicaspase. ATRA increased VEGF-A levels associated with neovascularisation. NAC and salubrinal inhibited an increase in VEGF-A, CHOP and caspase-3 caused by ATRA in ARPE-19 cells.<br><br>CONCLUSIONS: In ARPE-19 cells, the levels of ROS and ERS can be increased by ATRA, contributing to apoptosis, which can be effectively inhibited by NAC and salubrinal. Thus, ATRA may play an important role in the prevention, diagnosis and treatment of age-related macular degeneration.}, }
@article {pmid33726506, year = {2021}, author = {Frontera, E and Desimone, MF and Marzi, MC and Guerra, LN}, title = {N-acetylcysteine delivery with silica nanoparticles into 3T3-L1 adipocytes.}, journal = {Therapeutic delivery}, volume = {12}, number = {4}, pages = {287-296}, doi = {10.4155/tde-2020-0093}, pmid = {33726506}, issn = {2041-6008}, support = {DISP CBLUJ 32-18//Universidad Nacional de Lujan/ ; UBACYT 20020160100105BA//Universidad de Buenos Aires/ ; }, mesh = {3T3-L1 Cells ; *Acetylcysteine ; Adipocytes ; Animals ; Mice ; *Nanoparticles ; Silicon Dioxide ; }, abstract = {Background: The addition of 5 mM N-acetylcysteine (NAC) to 3T3-L1 adipocytes culture inhibits the accumulation of triglycerides (Tg) by 50%, but after 48 h uptake was only 16% of total NAC available. Based on these results, the aim of this study is to increase the NAC cellular uptake by encapsulating it in silica nanoparticles (NPs). Materials &amp; methods: Silica NPs, 20 ± 4.5 nm in size, were developed, with an inner cavity loaded with 5 mM NAC. At 48 h after treatment, there was a dose-dependent cytotoxic effect. We attempted to reduce the cytotoxicity of silica NPs by coating them with bovine serum albumin. Results: While we obtained nontoxic bovine serum albumin coated NPs, their effect on Tg cellular accumulation was also reduced.}, }
@article {pmid33724537, year = {2021}, author = {Soliman, MM and Aldhahrani, A and Gaber, A and Alsanie, WF and Shukry, M and Mohamed, WA and Metwally, MMM and Mohamed, AA}, title = {Impacts of n-acetyl cysteine on gibberellic acid-induced testicular dysfunction through regulation of inflammatory cytokines, steroid and antioxidant activity.}, journal = {Andrologia}, volume = {53}, number = {5}, pages = {e14036}, doi = {10.1111/and.14036}, pmid = {33724537}, issn = {1439-0272}, support = {TURSP-2020-09//Taif University/ ; }, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Antioxidants/metabolism/pharmacology ; Cytokines/genetics/metabolism ; Gibberellins ; Male ; Oxidative Stress ; Rats ; Steroids/metabolism ; Testis/metabolism ; }, abstract = {In agriculture, gibberellic acid (GA3) is commonly used with extreme dangers for public health. The current research evaluates the improving effects of n-acetyl cysteine (NAC, 150 mg/kg bw) co-administered with GA3 (55 mg/kg bw) mediated testicular injury. Twenty-four male albino rats were split into 4 groups: Negative control (CNT), NAC group, positive GA3 group and protective group, co-administered NAC plus GA3. On day 21, rats were anesthetised then euthanised by decapitation. Blood samples were collected; testicular samples were taken for semen analysis, serum chemistry, RNA extraction, histological and antioxidants markers examination. Our results revealed a significant decline p < .05 of catalase level and total antioxidant capacity. There was a substantial rise of MDA concentration in GA3-treated rats along with a considerable decrease of the antioxidant markers (SOD, GSH) and serum male reproductive hormones. In GA3-treated rats, an overexpression of the inflammatory cytokines (TNF-α, IL-1β) and anti-inflammatory cytokine IL-10 with boost mRNA expression of nuclear factor-kappa (NFk B) were confirmed. There was downregulation of steroidogenesis genes and decrease in sperm quality and concentration with an increase in sperm abnormalities, all were reported in GA3-treated rats. NAC treatment significantly increased the antioxidant state, testicular function beside structural germ cell and seminiferous tubules histology accompanied by upsurge of steroidogenic mRNA expressions (P450scc and 3β-HSD) and downregulated the pro-inflammatory cytokines mRNA expression (TNF-α, IL-1β). These results confirm the antioxidant capability of NAC and afford robust evidence about the ameliorative effect of the NAC to attenuate the testicular injury induced by GA3 through modulation of the antioxidant defence system, steroidogenic and pro-inflammatory cytokines mRNA expression.}, }
@article {pmid33724533, year = {2022}, author = {Devisscher, L and Van Campenhout, S and Lefere, S and Raevens, S and Tilleman, L and Van Nieuwerburgh, F and Van Eeckhoutte, HP and Hoorens, A and Lynes, MA and Geerts, A and Laukens, D and Van Vlierberghe, H}, title = {Metallothioneins alter macrophage phenotype and represent novel therapeutic targets for acetaminophen-induced liver injury.}, journal = {Journal of leukocyte biology}, volume = {111}, number = {1}, pages = {123-133}, doi = {10.1002/JLB.3A0820-527R}, pmid = {33724533}, issn = {1938-3673}, mesh = {Acetaminophen/*adverse effects ; Analgesics, Non-Narcotic/*adverse effects ; Animals ; Antibodies, Monoclonal/therapeutic use ; Chemical and Drug Induced Liver Injury/drug therapy/*pathology ; Humans ; Macrophages/drug effects/*pathology ; Male ; Metallothionein/*analysis ; Mice ; Mice, Inbred C57BL ; }, abstract = {Acetaminophen (APAP) intoxication is the foremost cause of drug-induced liver failure in developed countries. The only pharmacologic treatment option, N-acetylcysteine (NAC), is not effective for patients who are admitted too late and/or who have excessive liver damage, emphasizing the need for alternative treatment options. APAP intoxication results in hepatocyte death and release of danger signals, which further contribute to liver injury, in part by hepatic monocyte/macrophage infiltration and activation. Metallothionein (MT) 1 and 2 have important danger signaling functions and might represent novel therapeutic targets in APAP overdose. Therefore, we evaluated hepatic MT expression and the effect of anti-MT antibodies on the transcriptional profile of the hepatic macrophage population and liver injury following APAP overdose in mice. Hepatic MT expression was significantly induced in APAP-intoxicated mice and abundantly present in human livers. APAP intoxication in mice resulted in increased serum transaminase levels, extended necrotic regions on liver histology and induced expression of proinflammatory markers, which was significantly less pronounced in mice treated with anti-MT antibodies. Anti-MT antibody therapy attenuated proinflammatory macrophage polarization, as demonstrated by RNA sequencing analyses of isolated liver macrophages and in LPS-stimulated bone marrow-derived macrophages. Importantly, NAC and anti-MT antibodies were equally effective whereas administration of anti-MT antibody in combination with NAC exceeded the efficiency of both monotherapies in APAP-induced liver injury (AILI). We conclude that the neutralization of secreted MTs using a monoclonal antibody is a novel therapeutic strategy as mono- or add-on therapy for AILI. In addition, we provide evidence suggesting that MTs in the extracellular environment are involved in macrophage polarization.}, }
@article {pmid33724529, year = {2021}, author = {Owumi, SE and Akomolafe, AP and Imosemi, IO and Odunola, OA and Oyelere, AK}, title = {N-acetyl cysteine co-treatment abates perfluorooctanoic acid-induced reproductive toxicity in male rats.}, journal = {Andrologia}, volume = {53}, number = {5}, pages = {e14037}, doi = {10.1111/and.14037}, pmid = {33724529}, issn = {1439-0272}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/metabolism/pharmacology ; Caprylates ; *Fluorocarbons/metabolism/toxicity ; Humans ; Male ; Oxidative Stress ; Rats ; Rats, Wistar ; Sperm Motility ; Spermatozoa/metabolism ; Testis/metabolism ; Testosterone/metabolism ; }, abstract = {Perfluorooctanoic acid is a synthetic perfluoroalkyl-persistent in the environment and toxic to humans. N-acetylcysteine is a pro-drug of both amino acid l-cysteine and glutathione-a non-enzymatic antioxidant. N-acetylcysteine serves as an antidote for paracetamol poisoning and alleviates cellular oxidative and inflammatory stressors. We investigated N-acetylcysteine role against reproductive toxicity in male Wistar rats (weight: 140-220 g; 10 weeks old) posed by perfluorooctanoic acid exposure. Randomised rat cohorts were dosed both with perfluorooctanoic acid (5 mg/kg; p.o) or co-dosed with N-acetylcysteine (25 and 50 mg/kg p.o) for 28 days. Sperm physiognomies, biomarkers of testicular function and reproductive hormones, oxidative stress and inflammation were evaluated. Co-treatment with N-acetylcysteine significantly (p < .05) reversed perfluorooctanoic acid-mediated decreases in reproductive enzyme activities, and adverse effect on testosterone, luteinising and follicle-stimulating hormone concentrations. N-acetylcysteine treatment alone, improved sperm motility, count and viability, and reduced total sperm abnormalities. Co-treatment with N-acetylcysteine mitigated perfluorooctanoic acid-induced alterations in sperm function parameters. N-acetylcysteine abated (p < .05) perfluorooctanoic acid-induced oxidative stress in experimental rats testes and epididymis, and generally improved antioxidant enzyme activities and cellular thiol levels. Furthermore, N-acetylcysteine suppressed inflammatory responses and remedied perfluorooctanoic acid-mediated histological injuries in rat. Cooperatively, N-acetylcysteine enhanced reproductive function in perfluorooctanoic acid dosed rats, by lessening oxidative and nitrative stressors and mitigated inflammatory responses in the examined organ.}, }
@article {pmid33722689, year = {2021}, author = {Shrestha, DB and Budhathoki, P and Sedhai, YR and Adhikari, A and Poudel, A and Aryal, B and Baniya, R}, title = {N-acetyl cysteine versus standard of care for non-acetaminophen induced acute liver injury: a systematic review and meta-analysis.}, journal = {Annals of hepatology}, volume = {24}, number = {}, pages = {100340}, doi = {10.1016/j.aohep.2021.100340}, pmid = {33722689}, issn = {1665-2681}, mesh = {Acetylcysteine/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Length of Stay ; Liver Failure, Acute/*chemically induced/*drug therapy/mortality ; Standard of Care ; Survival Rate ; }, abstract = {The role of N-acetylcysteine (NAC) in the treatment of acetaminophen induced acute liver injury (ALI) is well established but its role in non-acetaminophen induced ALI is still elusive. We conducted this meta-analysis to evaluate the role of NAC in non-acetaminophen induced ALI. We searched electronic databases for studies published till Oct 25, 2020. We used RevMan v5.4 software to analyze the data extracted from selected studies by using Covidence systematic review software. Outcome estimation was done using Odds Ratio (OR) with 95% confidence interval (CI). The heterogeneity in various studies was determined using the I[2] test. A total of 11 studies were included in quantitative analysis. Use of NAC in non-acetaminophen induced ALI showed 53% reduction in mortality compared to standard of care (OR, 0.47; CI, 0.29-0.75) and reduced mean duration of hospital stay by 6.52 days (95% CI, -12.91 to -0.13). Similarly, the rate of encephalopathy was 59% lower in the treatment group (OR, 0.41; CI, 0.20-0.83). However, the risk of developing nausea and vomiting (OR, 3.99; CI, 1.42-11.19), and the need for mechanical ventilation (OR 3.88; CI, 1.14-13.29) were significantly higher in the treatment group. These findings conclude use of NAC decreases mortality and hepatic encephalopathy compared to standard of care in patients with non-acetaminophen induced ALI. Although there is an increased risk of nausea and vomiting with the use of NAC, the majority of adverse events are transient and minor.}, }
@article {pmid33720480, year = {2021}, author = {Li, N and Shi, F and Wang, X and Yang, P and Sun, K and Zhang, L and Hao, X and Li, X and Li, J and Jin, Y}, title = {Silica dust exposure induces pulmonary fibrosis through autophagy signaling.}, journal = {Environmental toxicology}, volume = {36}, number = {7}, pages = {1269-1277}, doi = {10.1002/tox.23124}, pmid = {33720480}, issn = {1522-7278}, support = {81202161//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Autophagy ; Dust ; Humans ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; *Pulmonary Fibrosis/chemically induced ; Quality of Life ; Signal Transduction ; *Silicon Dioxide/toxicity ; }, abstract = {Silicosis is a well-acknowledged occupational lung disease caused by inhalation of a large amount of free silica dust during the production period and eventually a considerable negative impact on the patients' quality of life. Autophagy exerts a critical influence on immune and inflammatory responses during the pathogenesis of pulmonary fibrosis. In this study, we sought to determine whether autophagy is involved in silicosis's pathogenesis and how it may affect pulmonary cellular physiology. In the animal experiments, we found persistent activation of autophagy in the development of pulmonary fibrosis, which was also accompanied by tumor necrosis factor and transforming growth factor expression increased. Therefore, the autophagy signaling pathway may regulate the inflammatory response and affect the progression of fibrosis. Further, in vitro experiments, we used LY294002, RAPA, and N-acetylcysteine (NAC) intervened autophagy. Our results showed that PI3K/Akt/mTOR signaling pathway is involved in the autophagy changed mediated by SiO2 exposed, and autophagy might play a protective role in the progression of pulmonary fibrosis. Additionally, NAC's effect is not apparent on SiO2 -mediated autophagy through the PI3K/Akt/mTOR signaling pathway, but it can reduce the inflammatory response on NR8383 cells mediated by SiO2-exposed. Nevertheless, it's interesting that NAC can reduce the inflammatory response on NR8383 cells mediated by SiO2 -exposed. Taken together, our data demonstrated that SiO2 -exposed can induce pulmonary fibrosis along with autophagy both in vivo and in vitro, NAC could alleviate the inflammatory response NR8383 cells by SiO2 -exposed through non PI3K/Akt/mTOR signaling pathway, and the specific mechanism of its action needs further studying.}, }
@article {pmid33719602, year = {2022}, author = {Lyon, ME and Lyon, AW}, title = {N-Acetylcysteine Interference with a Glucose Dehydrogenase Linked Glucose Meter.}, journal = {Journal of diabetes science and technology}, volume = {16}, number = {5}, pages = {1114-1119}, pmid = {33719602}, issn = {1932-2968}, mesh = {*Acetylcysteine ; Blood Glucose ; *Glucose ; Glucose 1-Dehydrogenase ; Hematologic Tests ; Humans ; }, abstract = {BACKGROUND: Our objective was to determine the effect of therapeutic concentrations of N-acetylcysteine, following intravenous infusion, on the measurement of blood glucose using a Roche Diagnostics glucose dehydrogenase-linked glucose meter compared to hospital laboratory methods.<br><br>METHODS: N-acetylcysteine was added to aliquots of blood, with glucose promptly measured by the glucose meter, blood gas analyzer (glucose oxidase comparative method) and following centrifugation, plasma glucose measured with a hexokinase spectrophotometric comparative method. Glucose results were evaluated with linear regression and Bland Altman plots.<br><br>RESULTS: In the presence of NAC, at concentrations greater than 5&#x2009;mg/dL (0.31&#x2009;mmol/L), positively biased glucose meter results were compared to the clinical laboratory results. Multivariate linear regression revealed that NAC-mediated meter results are influenced by NAC and glucose concentrations.<br><br>CONCLUSIONS: The addition of therapeutic concentrations of NAC to blood produces statistically significant positive biases when measured with the glucose dehydrogenase linked glucose meter device.}, }
@article {pmid33717929, year = {2021}, author = {Setti, T and Arab, MGL and Santos, GS and Alkass, N and Andrade, MAP and Lana, JFSD}, title = {The protective role of glutathione in osteoarthritis.}, journal = {Journal of clinical orthopaedics and trauma}, volume = {15}, number = {}, pages = {145-151}, pmid = {33717929}, issn = {0976-5662}, abstract = {UNLABELLED: It is currently understood that osteoarthritis (OA) is a major chronic inflammatory musculoskeletal disease. While this disease has long been attributed to biomechanical trauma, recent evidence establishes a significant correlation between osteoarthritic progression and unbridled oxidative stress, responsible for prolonged inflammation. Research describes this as a disturbance in the balanced production of reactive oxygen species (ROS) and antioxidant defenses, generating macromolecular damage and disrupted redox signaling and control. Since ROS pathways are being considered new targets for OA treatment, the development of antioxidant therapy to counteract exacerbated oxidative stress is being continuously researched and enhanced in order to fortify the cellular defenses. Experiments with glutathione and its precursor molecule, N-acetylcysteine (NAC), have shown interesting results in the literature for the management of OA, where they have demonstrated efficacy in reducing cartilage degradation and inflammation markers as well as significant improvements in pain and functional outcomes. Glutathione remains a safe, effective and overall cheap treatment alternative in comparison to other current therapeutic solutions and, for these reasons, it may prove to be comparably superior under particular circumstances.<br><br>METHODS: Literature was reviewed using PubMed and Google Scholar in order to bring up significant evidence and illustrate the defensive mechanisms of antioxidant compounds against oxidative damage in the onset of musculoskeletal diseases. The investigation included a combination of keywords such as: oxidative stress, oxidative damage, inflammation, osteoarthritis, antioxidant, glutathione, n-acetylcysteine, redox, and cell signaling.<br><br>CONCLUSION: Based on the numerous studies included in this literature review, glutathione and its precursor N-acetylcysteine have demonstrated significant protective effects in events of prolonged, exacerbated oxidative stress as seen in chronic inflammatory musculoskeletal disorders such as osteoarthritis.}, }
@article {pmid33716588, year = {2021}, author = {Huang, Y and Mei, X and Jiang, W and Zhao, H and Yan, Z and Zhang, H and Liu, Y and Hu, X and Zhang, J and Peng, W and Zhang, J and Qi, Q and Chen, N}, title = {Mesenchymal Stem Cell-Conditioned Medium Protects Hippocampal Neurons From Radiation Damage by Suppressing Oxidative Stress and Apoptosis.}, journal = {Dose-response : a publication of International Hormesis Society}, volume = {19}, number = {1}, pages = {1559325820984944}, pmid = {33716588}, issn = {1559-3258}, abstract = {OBJECTIVE: To investigate the effects of mesenchymal stem cell-conditioned medium (MSC-CM) on radiation-induced oxidative stress, survival and apoptosis in hippocampal neurons.<br><br>METHODS: The following groups were defined: Control, radiation treatment (RT), RT+MSC-CM, MSC-CM, RT + N-Acetylcysteine (RT+NAC), and RT + MSC-CM + PI3 K inhibitor (LY294002). A cell Counting Kit-8 (CCK-8) was used to measure cell proliferation. Apoptosis was examined by AnnexinV/PI flow cytometric analyses. Intracellular reactive oxygen species (ROS) were detected by DCFH-DA. Intracellular glutathione (GSH), malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity were detected by colorimetric assays. Protein levels of &#x3b3;-H2AX, PI3K-AKT, P53, cleaved caspase-3, Bax, and BCl-2 were analyzed by Western blotting.<br><br>RESULTS: The proliferation of HT22 cells was significantly inhibited in the RT group, but was significantly preserved in the RT + MSC-CM group (P < 0.01). Apoptosis was significantly higher in the RT group than in the RT+ MSC-CM group (P < 0.01). MSC-CM decreased intracellular ROS and MDA content after irradiation (P < 0.01). GSH level and SOD activity were higher in the RT + MSC-CM group than in the RT group, as was MMP (P < 0.01). MSC-CM decreased expression of &#x3b3;-H2AX, P53, Bax, and cleaved-caspase-3, but increased Bcl-2 expression (P < 0.01).<br><br>CONCLUSION: MSC-CM attenuated radiation-induced hippocampal neuron cell line damage by alleviating oxidative stress and suppressing apoptosis.}, }
@article {pmid33707964, year = {2021}, author = {Shen, R and Yin, P and Yao, H and Chen, L and Chang, X and Li, H and Hou, X}, title = {Punicalin Ameliorates Cell Pyroptosis Induced by LPS/ATP Through Suppression of ROS/NLRP3 Pathway.}, journal = {Journal of inflammation research}, volume = {14}, number = {}, pages = {711-718}, pmid = {33707964}, issn = {1178-7031}, abstract = {PURPOSE: Inflammation is the driving force of many inflammatory and autoimmune diseases, Pyroptosis is a process of cell death in response to excessive inflammation. Punicalin has been reported to have anti-inflammatory effects. However, the anti-pyroptosis is unknown. Hence, this study was aimed to research the inhibition of MG on LPS/ATP-induced pyroptosis in vitro.<br><br>METHODS: Lipopolysaccharide (LPS)/ATP were used to simulate mouse J774A.1 cells to mimic the inflammatory response and the role of punicalin was examined. The secretion of proinflammatory cytokines was analyzed using enzyme-linked immunosorbent assay (ELISA). The expression of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), caspase-1, and GSDMD-N in LPS/ATP-stimulated cells were examined by Western blot. N-acetylcysteine (NAC) was used to validate the role of Punicalin.<br><br>RESULTS: Punicalin significantly blocked the production of endogenous ROS, reduced LPS/ATP-induced activation of NLRP3, caspase 1, ASC and GSDMD-N, IL-1b and IL-18 protein levels. Furthermore, N-acetylcysteine (NAC), an ROS scavenger, inhibited the LPS/ATP-stimulated activation of NLRP3 inflammasome mediated inflammation and pyroptosis.<br><br>CONCLUSION: Punicalin ameliorates LPS/ATP-induced pyroptosis in J774A.1 macrophages, the mechanism may involve downregulation of the ROS/NLRP3 inflammasome signaling pathway.}, }
@article {pmid33689540, year = {2023}, author = {Gómez-Viquez, NL and Balderas-Villalobos, J and Bello-Sánchez, MD and Mayorga-Luna, M and Mailloux-Salinas, P and García-Castañeda, M and Ríos-Pérez, EB and Mártinez-Ávila, MA and Camacho-Castillo, LDC and Bravo, G and Ávila, G and Altamirano, J and Carvajal, K}, title = {Oxidative stress in early metabolic syndrome impairs cardiac RyR2 and SERCA2a activity and modifies the interplay of these proteins during Ca[2+] waves.}, journal = {Archives of physiology and biochemistry}, volume = {129}, number = {5}, pages = {1058-1070}, doi = {10.1080/13813455.2021.1895224}, pmid = {33689540}, issn = {1744-4160}, mesh = {Rats ; Animals ; *Ryanodine Receptor Calcium Release Channel/metabolism/pharmacology ; *Metabolic Syndrome/metabolism ; Myocytes, Cardiac ; Oxidative Stress ; }, abstract = {We investigated how oxidative stress (OS) alters Ca[2+] handling in ventricular myocytes in early metabolic syndrome (MetS) in sucrose-fed rats. The effects of N-acetyl cysteine (NAC) or dl-Dithiothreitol (DTT) on systolic Ca[2+] transients (SCaTs), diastolic Ca[2+] sparks (CaS) and Ca[2+] waves (CaW), recorded by confocal techniques, and L-type Ca[2+] current (ICa), assessed by whole-cell patch clamp, were evaluated in MetS and Control cells. MetS myocytes exhibited decreased SCaTs and CaS frequency but unaffected CaW propagation. In Control cells, NAC/DTT reduced RyR2/SERCA2a activity blunting SCaTs, CaS frequency and CaW propagation, suggesting that basal ROS optimised Ca[2+] signalling by maintaining RyR2/SERCA2a function and that these proteins facilitate CaW propagation. Conversely, NAC/DTT in MetS recovered RyR2/SERCA2a function, improving SCaTs and CaS frequency, but unexpectedly decreasing CaW propagation. We hypothesised that OS decreases RyR2/SERCA2a activity at early MetS, and while decreased SERCA2a favours CaW propagation, diminished RyR2 restrains it.}, }
@article {pmid33680863, year = {2021}, author = {Subramaniyan, V and Chakravarthi, S and Jegasothy, R and Seng, WY and Fuloria, NK and Fuloria, S and Hazarika, I and Das, A}, title = {Alcohol-associated liver disease: A review on its pathophysiology, diagnosis and drug therapy.}, journal = {Toxicology reports}, volume = {8}, number = {}, pages = {376-385}, pmid = {33680863}, issn = {2214-7500}, abstract = {One of the global burdens of health care is an alcohol-associated liver disease (ALD) and liver-related death which is caused due to acute or chronic consumption of alcohol. Chronic consumption of alcohol damage the normal defense mechanism of the liver and likely to disturb the gut barrier system, mucosal immune cells, which leads to decreased nutrient absorption. Therapy of ALD depends upon the spectrum of liver injury that causes fatty liver, hepatitis, and cirrhosis. The foundation of therapy starts with abstinence from alcohol. Corticosteroids are used for the treatment of ALD but due to poor acceptance, continuing mortality, and identification of tumor necrosis factor-alpha as an integral component in pathogenesis, recent studies focus on pentoxifylline and, antitumor necrosis factor antibody to neutralize cytokines in the therapy of severe alcoholic hepatitis. Antioxidants also play a significant role in the treatment but till today there is no universally accepted therapy available for any stage of ALD. The treatment aspects need to restore the gut functions and require nutrient-based treatments to regulate the functions of the gut system and prevent liver injury. The vital action of saturated fatty acids greatly controls the gut barrier. Overall, this review mainly focuses on the mechanism of alcohol-induced metabolic dysfunction, contribution to liver pathogenesis, the effect of pregnancy, and targeted therapy of ALD.}, }
@article {pmid33680348, year = {2021}, author = {Chavarría, AP and Vázquez, RRV and Cherit, JGD and Bello, HH and Suastegui, HC and Moreno-Castañeda, L and Alanís Estrada, G and Hernández, F and González-Marcos, O and Saucedo-Orozco, H and Manzano-Pech, L and Márquez-Velasco, R and Guarner-Lans, V and Pérez-Torres, I and Soto, ME}, title = {Antioxidants and pentoxifylline as coadjuvant measures to standard therapy to improve prognosis of patients with pneumonia by COVID-19.}, journal = {Computational and structural biotechnology journal}, volume = {19}, number = {}, pages = {1379-1390}, pmid = {33680348}, issn = {2001-0370}, abstract = {The type 2 coronavirus causes severe acute respiratory syndrome (SARS-CoV-2) and produces pneumonia with pulmonary alveolar collapse. In some cases it also causes sepsis and septic shock. There is no specific treatment for coronavirus disease 2019 (COVID-19). Vitamin C (Vit C), Vitamin E (Vit E), N-acetylcysteine (NAC) and Melatonin (MT) increase the intracellular content of GSH, kidnap free radicals and protect DNA, proteins in the cytosol and lipids in cell membranes. Pentoxifylline (Px) has anti-inflammatory activities. Here we evaluate the effect of Vit C, Vit E, NAC, and MT plus Px in COVID-19 patients with moderate and severe pneumonia. 110 patients of either sex were included. They were divided into five groups with 22 patients each. Group 1 received Vit C + Px, group 2 Vit E + Px, group 3 NAC + Px, group 4 MT + Px, and group 5 only Px. Oxidative stress (OS) markers such as lipid peroxidation (LPO) levels, total antioxidant capacity (TAC) and nitrites (NO2 [-]) were evaluated in plasma. The antioxidant therapy improved the survival scores including the Sequential Organ Failure Assessment (SOFA), the Acute Physiology and chronic Health Evaluation II (Apache II), the Simplified Acute Physiology Score II (SAPS II), the Critical Illness Risk Score, Launched during COVID-19 crisis (COVIDGRAM) and the Glasgow Coma Scale (GCS). We found that LPO (p≤0.04) and inflammation markers such as interleukin-6 (IL-6, p≤ 0.01), C reactive protein (CRP, p ≤ 0.01) and procalcitonin (PCT, p ≤ 0.05) were elevated. TAC (p ≤ 0.03) and NO2 [-] (p ≤ 0.04) found themselves diminished in diminished in COVID-19 patients upon admission to the hospital. The different antioxidants reversed this alteration at the end of the treatment. The treatment with antioxidant supplements such as Vit C, E, NAC, and MT plus Px could decelerate the aggressive and lethal development of COVID-19. Antioxidant therapy can be effective in this pandemia since it improves the survival scores including SOFA, Apache II, SAPS II, COVIDGRAM, GCS by lowering the LPO, IL-6, CRP, PCT and increasing systemic TAC and NO2 [-].}, }
@article {pmid33677283, year = {2021}, author = {Yi, SJ and Xiong, YW and Zhu, HL and Dai, LM and Cao, XL and Liu, WB and Shi, XT and Zhou, GX and Liu, AY and Zhao, LL and Zhang, C and Gao, L and Xu, DX and Wang, H}, title = {Environmental cadmium exposure during pregnancy causes diabetes-like phenotypes in mouse offspring: Association with oxidative stress in the fetal liver.}, journal = {The Science of the total environment}, volume = {777}, number = {}, pages = {146006}, doi = {10.1016/j.scitotenv.2021.146006}, pmid = {33677283}, issn = {1879-1026}, mesh = {Adult ; Animals ; Cadmium/metabolism/toxicity ; *Diabetes Mellitus/metabolism ; Female ; Humans ; Liver/metabolism ; Mice ; Oxidative Stress ; Phenotype ; Pregnancy ; *Prenatal Exposure Delayed Effects ; }, abstract = {Cadmium (Cd), a noxious heavy metal, is widespread in the living environment. Gestational exposure to Cd at environmental dose has been shown to cause fetal growth restriction (FGR). However, the long-term effects and the mechanisms underlying environmental Cd exposure on glucose metabolism in offspring remain unclear. Here, we established a murine model to study the impacts of gestational exposure to environmental Cd on glucose metabolism at different life stages of offspring. Results demonstrated that the offspring mice developed hyperglycemia in puberty and impaired glucose tolerance in adulthood following maternal Cd exposure during gestation. Further mechanistic investigation showed that Cd exposure upregulated the expression of key proteins in hepatic gluconeogenesis, including p-CREB, PGC-1α and G6PC, in pubertal and adult offspring. In addition, we demonstrated that Cd exposure during pregnancy markedly elevated the level of oxidative stress-related proteins, including NOX2, NOX4 and HO-1, in the fetal liver. The effects of gestational exposure to N-acetylcysteine (NAC), a free-radical scavenging antioxidant, presented that NAC supplementation alleviated hepatic oxidative stress in fetuses, and thereby reversed hyperglycemia and glucose intolerance in mouse offspring. Collectively, our data suggested that gestational exposure to environmental Cd caused diabetes-like phenotypes via enhancing hepatic gluconeogenesis, which is associated with oxidative stress in fetal livers. This work provides new insights into the protective effects of antioxidants on fetal-originated diabetes triggered by environmental toxicants.}, }
@article {pmid33676989, year = {2021}, author = {Chiesa, E and Greco, A and Dorati, R and Conti, B and Bruni, G and Lamprou, D and Genta, I}, title = {Microfluidic-assisted synthesis of multifunctional iodinated contrast agent polymeric nanoplatforms.}, journal = {International journal of pharmaceutics}, volume = {599}, number = {}, pages = {120447}, doi = {10.1016/j.ijpharm.2021.120447}, pmid = {33676989}, issn = {1873-3476}, mesh = {Contrast Media ; Drug Carriers ; Humans ; *Microfluidics ; *Nanoparticles ; Particle Size ; Polyethylene Glycols ; Polylactic Acid-Polyglycolic Acid Copolymer ; Polymers ; }, abstract = {Contrast Induced Nephropathy is the most severe side-effect arising after non-ionic iodinated contrast agents (CAs) intravenous administration. The use of antioxidants (i.e., N-Acetylcysteine; NAC) is one of the attempted prevention approaches. Herein, we describe the microfluidic-assisted synthesis of iodinated polymeric nanoparticles (NPs) as new multifunctional blood pool CA. The aim of this research is to co-encapsulate Iohexol (IOX; iodinated CA) and NAC (preventive agent) into poly-D,L-lactide-co-glycolide (PLGA) and PEGylated-PLGA (PLGA-PEG) NPs to exploit CA diagnostic proprieties and NAC preventing antioxidant activity. A microfluidic-assisted nanoprecipitation protocol has been set-up for PLGA and PLGA-PEG NPs, evaluating the effect of formulation and microfluidic parameters by analysing the size, PDI and IOX and NAC encapsulation efficiency. The optimized NPs (PLGA-PEG, L:G 50:50, 5% PEG, Mw 90 kDa) formulated with a size of 67 ± 2.8 nm with PDI < 0.2, spherical shape, and an IOX and NAC encapsulation efficiency of 38% and 20%, respectively. The IOX and NAC encapsulation was confirmed by FTIR and DSC. In vitro release study showed an IOX retention into the polymeric matrix and NAC sustained release up to 24-48 h stating microfluidics as powerful tool for the formulation of multifunctional nanoplatforms. Finally, the protective effect of NPs and NAC were preliminary assessed on human kidney cells.}, }
@article {pmid33676898, year = {2021}, author = {Gerner, MC and Bileck, A and Janker, L and Ziegler, LS and Öhlinger, T and Raeven, P and Müllner, EW and Salzer, U and Gerner, C and Schmetterer, KG and Baron, DM}, title = {Packed red blood cells inhibit T-cell activation via ROS-dependent signaling pathways.}, journal = {The Journal of biological chemistry}, volume = {296}, number = {}, pages = {100487}, pmid = {33676898}, issn = {1083-351X}, mesh = {Antigens, CD/*immunology/metabolism ; Antigens, Differentiation, T-Lymphocyte/*immunology/metabolism ; Cell Proliferation/physiology ; Cells, Cultured ; Erythrocytes/*immunology/metabolism ; Humans ; Immunomodulation ; Interleukin-2 Receptor alpha Subunit/*immunology/metabolism ; Lectins, C-Type/*immunology/metabolism ; Leukocytes, Mononuclear ; Lymphocyte Activation ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; T-Lymphocytes/*immunology/metabolism ; }, abstract = {Numerous observations indicate that red blood cells (RBCs) affect T-cell activation and proliferation. We have studied effects of packed RBCs (PRBCs) on T-cell receptor (TCR) signaling and the molecular mechanisms whereby (P)RBCs modulate T-cell activation. In line with previous reports, PRBCs attenuated the expression of T-cell activation markers CD25 and CD69 upon costimulation via CD3/CD28. In addition, T-cell proliferation and cytokine expression were markedly reduced when T-cells were stimulated in the presence of PRBCs. Inhibitory activity of PRBCs required direct cell-cell contact and intact PRBCs. The production of activation-induced cellular reactive oxygen species, which act as second messengers in T-cells, was completely abrogated to levels of unstimulated T-cells in the presence of PRBCs. Phosphorylation of the TCR-related zeta chain and thus proximal TCR signal transduction was unaffected by PRBCs, ruling out mechanisms based on secreted factors and steric interaction restrictions. In large part, downstream signaling events requiring reactive oxygen species for full functionality were affected, as confirmed by an untargeted MS-based phosphoproteomics approach. PRBCs inhibited T-cell activation more efficiently than treatment with 1 mM of the antioxidant N-acetyl cysteine. Taken together, our data imply that inflammation-related radical reactions are modulated by PRBCs. These immunomodulating effects may be responsible for clinical observations associated with transfusion of PRBCs.}, }
@article {pmid33675156, year = {2021}, author = {Krysko, KM and Bischof, A and Nourbakhsh, B and Henry, RG and Revirajan, N and Manguinao, M and Nguyen, K and Akula, A and Li, Y and Waubant, E}, title = {A pilot study of oxidative pathways in MS fatigue: randomized trial of N-acetyl cysteine.}, journal = {Annals of clinical and translational neurology}, volume = {8}, number = {4}, pages = {811-824}, pmid = {33675156}, issn = {2328-9503}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*pharmacology ; Adult ; Aged ; Double-Blind Method ; Fatigue/*drug therapy/etiology/*metabolism/physiopathology ; Feasibility Studies ; Female ; Free Radical Scavengers/administration &amp; dosage/adverse effects/*pharmacology ; Humans ; Male ; Middle Aged ; Multiple Sclerosis, Chronic Progressive/complications/*drug therapy/*metabolism/physiopathology ; Outcome Assessment, Health Care ; Oxidative Stress/*drug effects ; Pilot Projects ; }, abstract = {OBJECTIVE: To assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo.<br><br>METHODS: Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4&#xa0;weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced-to-oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes.<br><br>RESULTS: Fifiteen were randomized (10 NAC, 5 placebo; mean age 56.1&#xa0;years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p&#xa0;=&#xa0;0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p&#xa0;=&#xa0;0.33). GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p&#xa0;=&#xa0;0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups.<br><br>INTERPRETATION: NAC was well-tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half-life, or lack of effect. REGISTERED: clinicaltrials.gov NCT02804594.}, }
@article {pmid33667419, year = {2021}, author = {Grabowska, ME and Chun, B and Moya, R and Saucerman, JJ}, title = {Computational model of cardiomyocyte apoptosis identifies mechanisms of tyrosine kinase inhibitor-induced cardiotoxicity.}, journal = {Journal of molecular and cellular cardiology}, volume = {155}, number = {}, pages = {66-77}, pmid = {33667419}, issn = {1095-8584}, support = {R01 HL137100/HL/NHLBI NIH HHS/United States ; R01 HL137755/HL/NHLBI NIH HHS/United States ; U54 HL127624/HL/NHLBI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*adverse effects/pharmacology ; Apoptosis/*drug effects ; Biomarkers ; Cardiotoxicity/*etiology/*metabolism ; Computational Biology/methods ; Disease Susceptibility ; Gene Regulatory Networks ; Humans ; *Models, Biological ; Myocytes, Cardiac/*drug effects/*metabolism ; Protein Kinase Inhibitors/*adverse effects/pharmacology ; Reproducibility of Results ; Signal Transduction ; }, abstract = {Despite clinical observations of cardiotoxicity among cancer patients treated with tyrosine kinase inhibitors (TKIs), the molecular mechanisms by which these drugs affect the heart remain largely unknown. Mechanistic understanding of TKI-induced cardiotoxicity has been limited in part due to the complexity of tyrosine kinase signaling pathways and the multi-targeted nature of many of these drugs. TKI treatment has been associated with reactive oxygen species generation, mitochondrial dysfunction, and apoptosis in cardiomyocytes. To gain insight into the mechanisms mediating TKI-induced cardiotoxicity, this study constructs and validates a computational model of cardiomyocyte apoptosis, integrating intrinsic apoptotic and tyrosine kinase signaling pathways. The model predicts high levels of apoptosis in response to sorafenib, sunitinib, ponatinib, trastuzumab, and gefitinib, and lower levels of apoptosis in response to nilotinib and erlotinib, with the highest level of apoptosis induced by sorafenib. Knockdown simulations identified AP1, ASK1, JNK, MEK47, p53, and ROS as positive functional regulators of sorafenib-induced apoptosis of cardiomyocytes. Overexpression simulations identified Akt, IGF1, PDK1, and PI3K among the negative functional regulators of sorafenib-induced cardiomyocyte apoptosis. A combinatorial screen of the positive and negative regulators of sorafenib-induced apoptosis revealed ROS knockdown coupled with overexpression of FLT3, FGFR, PDGFR, VEGFR, or KIT as a particularly potent combination in reducing sorafenib-induced apoptosis. Network simulations of combinatorial treatment with sorafenib and the antioxidant N-acetyl cysteine (NAC) suggest that NAC may protect cardiomyocytes from sorafenib-induced apoptosis.}, }
@article {pmid33661545, year = {2021}, author = {Jannatifar, R and Cheraghi, E and Nasr-Esfahani, MH and Piroozmanesh, H}, title = {Association of heat shock protein A2 expression and sperm quality after N-acetyl-cysteine supplementation in astheno-terato-zoospermic infertile men.}, journal = {Andrologia}, volume = {53}, number = {5}, pages = {e14024}, doi = {10.1111/and.14024}, pmid = {33661545}, issn = {1439-0272}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Dietary Supplements ; HSP70 Heat-Shock Proteins/genetics ; Heat-Shock Proteins ; Humans ; *Infertility, Male/drug therapy ; Male ; Spermatozoa ; }, abstract = {In infertile men, reduced expression of heat shock protein A2 (HSPA2) is related to reduced sperm quality and function. The present study has aimed to investigate the effects of N-acetyl-cysteine (NAC) supplementation on expression of heat shock protein A2 (HSPA2). In this study in continuation of previous study, semen samples from 50 astheno-terato-zoospermic men who have received NAC (600 mg/day) orally for three months were evaluated for expression HSPA2 using RT-PCR, and Western blot analysis. In addition, semen samples of these individuals were assessed for sperm parameters, DNA fragmentation (TUNEL), protamine deficiency (CMA3), lipid peroxidation index (MDA) and total antioxidant capacity (TCA). All assessment was carried out before and after NAC treatment. In addition to improved sperm parameters and aforementioned functional parameters, the presented results revealed the significant increase in relative expression levels of HSPA2 was obtained after using NAC treatment (p < .05). Correlation analysis also demonstrated that HSPA2 expression is significantly related to most of the assessed parameters. NAC may directly or indecently impose its beneficial effect through increased expression of HSPA2, which plays a potential role in proper folding of element needed to counteract stress condition in infertile individuals.}, }
@article {pmid33660265, year = {2021}, author = {Wang, C and Gaspari, TA and Ferens, D and Spizzo, I and Kemp-Harper, BK and Samuel, CS}, title = {Simultaneous targeting of oxidative stress and fibrosis reverses cardiomyopathy-induced ventricular remodelling and dysfunction.}, journal = {British journal of pharmacology}, volume = {178}, number = {12}, pages = {2424-2442}, doi = {10.1111/bph.15428}, pmid = {33660265}, issn = {1476-5381}, support = {//Monash University/ ; }, mesh = {Animals ; *Cardiomyopathies/drug therapy ; Fibrosis ; Male ; Mice ; Oxidative Stress ; Ventricular Function, Left ; *Ventricular Remodeling ; }, abstract = {BACKGROUND AND PURPOSE: Oxidative stress and fibrosis are hallmarks of cardiomyopathy-induced heart failure yet are not effectively targeted by current frontline therapies. Here, the therapeutic effects of the anti-oxidant, N-acetylcysteine (NAC), were compared and combined with an acute heart failure drug with established anti-fibrotic effects, serelaxin (RLX), in a murine model of cardiomyopathy.<br><br>EXPERIMENTAL APPROACH: Adult male 129sv mice were subjected to repeated isoprenaline (25&#x2009;mg&#xb7;kg[-1])-induced cardiac injury for five consecutive days and then left to undergo fibrotic healing until Day 14. Subgroups of isoprenaline-injured mice were treated with RLX (0.5&#x2009;mg&#xb7;kg[-1] &#xb7;day[-1]), NAC (25&#x2009;mg&#xb7;kg[-1] &#xb7;day[-1]) or both combined, given subcutaneously via osmotic minipumps from Day 7 to 14. Control mice received saline instead of isoprenaline.<br><br>KEY RESULTS: Isoprenaline-injured mice showed increased left ventricular (LV) inflammation (~5-fold), oxidative stress (~1-2.5-fold), cardiomyocyte hypertrophy (~25%), cardiac remodelling, fibrosis (~2-2.5-fold) and dysfunction by Day 14 after injury. NAC alone blocked the cardiomyopathy-induced increase in LV superoxide levels, to a greater extent than RLX. Additionally, either treatment alone only partly reduced several measures of LV inflammation, remodelling and fibrosis. In comparison, the combination of RLX and NAC prevented the cardiomyopathy-induced LV macrophage infiltration, remodelling, fibrosis and cardiomyocyte size, to a greater extent than either treatment alone after 7&#x2009;days. The combination therapy also restored the isoprenaline-induced reduction in LV function, without affecting systolic BP.<br><br>CONCLUSION AND IMPLICATIONS: These findings demonstrated that the simultaneous targeting of oxidative stress and fibrosis is key to treating the pathophysiology and dysfunction induced by cardiomyopathy.}, }
@article {pmid33654365, year = {2021}, author = {Walayat, S and Shoaib, H and Asghar, M and Kim, M and Dhillon, S}, title = {Role of N-acetylcysteine in non-acetaminophen-related acute liver failure: an updated meta-analysis and systematic review.}, journal = {Annals of gastroenterology}, volume = {34}, number = {2}, pages = {235-240}, pmid = {33654365}, issn = {1108-7471}, abstract = {BACKGROUND: The American Association for the Study of Liver Diseases recommends that N-acetylcysteine (NAC) may be beneficial in non-acetaminophen-related drug-induced liver injury. A subsequent review and analysis reported the current evidence to be inconclusive. Herein, we present an updated review and meta-analysis.<br><br>METHODS: We evaluated prospective, retrospective and randomized controlled trials that compared outcomes in patients of all ages with acute liver failure (defined as abnormal liver enzymes along with elevated international normalized ratio >1.5, with or without hepatic encephalopathy) receiving NAC with the outcomes in a control group. The primary outcome was to compare the overall survival in the 2 groups. Secondary outcomes included difference in length of hospital stay, transplant-free survival, and post-transplant survival.<br><br>RESULTS: Seven studies (N=883) that met the inclusion criteria were included in this analysis. The mean age of patients in the NAC group was 21.22 years compared with 23.62 years in the control group. The odds of overall survival were significantly higher in the NAC group than in controls (odds ratio [OR] 1.77, 95% confidence interval [CI] 1.3-2.41). Post-transplant survival (OR 2.44, 95%CI 1.11-5.37) and transplant-free survival were also better in the NAC group than in the control group (OR 2.85, 95%CI 2.11-3.85). Patients in the control group had statistically significant odds of a longer inpatient stay (mean difference 7.79, 95%CI 6.93-8.66).<br><br>CONCLUSION: In patients with non-acetaminophen-related acute liver failure, NAC significantly improves overall survival, post-transplant survival and transplant-free survival while decreasing the overall length of hospital stay.}, }
@article {pmid33652285, year = {2021}, author = {Wang, Y and Xu, L and Peng, L and Fang, C and Qin, Q and Lv, X and Liu, Z and Yang, B and Song, E and Song, Y}, title = {Polybrominated diphenyl ethers quinone-induced intracellular protein oxidative damage triggers ubiquitin-proteasome and autophagy-lysosomal system activation in LO2 cells.}, journal = {Chemosphere}, volume = {275}, number = {}, pages = {130034}, doi = {10.1016/j.chemosphere.2021.130034}, pmid = {33652285}, issn = {1879-1298}, mesh = {Autophagy ; *Flame Retardants/toxicity ; *Halogenated Diphenyl Ethers/toxicity ; Humans ; Lysosomes ; Oxidative Stress ; Proteasome Endopeptidase Complex ; Quinones ; Ubiquitin ; }, abstract = {Polybrominated diphenyl ethers (PBDEs), a kind of flame retardants, were widely used in the furniture, textile and electronics industries. Because of their lipophilic, persistent and bio-accumulative properties, PBDEs were listed on the Stockholm Convention as typical persistent organic pollutants (POPs). We have previously reported that a highly active, quinone-type metabolite of PBDEs (PBDEQ) causes DNA damage and subsequently triggers apoptosis. However, it is remaining unclear whether PBDEQ provokes protein damage and stimulates corresponding signaling cascade. Using human normal liver (LO2) cells as an in vitro model, we demonstrated that PBDEQ causes oxidative protein damage through excess reactive oxygen species (ROS). Consistently, we found PBDEQ exposure causes the depletion of protein thiol group, the appearance of carbonyl group and the accumulation of protein aggregates. Endoplasmic reticulum (ER) stress was involved in the repair of oxidized proteins. Under the scenario of severe damage, LO2 cells degrade oxidized proteins through ubiquitin-proteasome system (UPS) and autophagy. The blockage of these protein degradation pathways aggravates PBDEQ-induced cytotoxicity in LO2 cells, whilst antioxidant N-acetyl-cysteine (NAC) rescues PBDEQ-induced oxidative protein damage conversely. In summary, our current study first demonstrated PBDEQ-induced protein oxidative damage in LO2 cells, which offer a better understanding of the cytotoxicity of PBDEs and corresponding metabolites.}, }
@article {pmid33651295, year = {2021}, author = {Kiss, LV and Sávoly, Z and Ács, A and Seres, A and Nagy, PI}, title = {Toxicity mitigation by N-acetylcysteine and synergistic toxic effect of nano and bulk ZnO to Panagrellus redivivus.}, journal = {Environmental science and pollution research international}, volume = {28}, number = {26}, pages = {34436-34449}, pmid = {33651295}, issn = {1614-7499}, support = {&#xda;NKP-18-3-III-SZIE-7//New National Excellence Program/ ; 2017-1.3.1-VKE-2017-00001//VKE/ ; }, mesh = {Acetylcysteine ; *Metal Nanoparticles/toxicity ; Particle Size ; Reactive Oxygen Species ; Zinc ; *Zinc Oxide/toxicity ; }, abstract = {To better understand the nanosize-relevant toxic effects and underlying mechanisms, N-acetylcysteine (NAC), as a mitigation agent, an ionic form of Zn (ZnCl2), and the binary mixture of ZnO with different particle sizes (15 nm and 140 nm), was used in toxicity assays with the nematode Panagrellus redivivus. The ZnCl2 concentrations were applied to show the amount of dissolved Zn ions present in the test system. Reactive oxygen species (ROS) measuring method was developed to fit the used test system. Our studies have shown that NAC can mitigate the toxic effects of both studied particle sizes. In the applied concentrations, ZnCl2 was less toxic than both of the ZnO particles. This finding indicates that not only ions and ROS produced by the dissolution are behind the toxic effects of the ZnO NPs, but also other particle size-dependent toxic effects, like the spontaneous ROS generation, are also relevant. When the two materials were applied in binary mixtures, the toxic effects increased significantly, and the dissolved zinc content and the ROS generation also increased. It is assumed that the chemical and physical properties of the materials have been mutually reinforcing to form a more reactive mixture that is more toxic to the P. redivivus test organism. Our findings demonstrate the importance of using mitigation agent and mixtures to evaluate the size-dependent toxicity of the ZnO.}, }
@article {pmid33647321, year = {2021}, author = {Bharathi, V and Girdhar, A and Patel, BK}, title = {Role of CNC1 gene in TDP-43 aggregation-induced oxidative stress-mediated cell death in S. cerevisiae model of ALS.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1868}, number = {6}, pages = {118993}, doi = {10.1016/j.bbamcr.2021.118993}, pmid = {33647321}, issn = {1879-2596}, mesh = {Amyotrophic Lateral Sclerosis/chemically induced/*genetics/metabolism ; Cyclins/*genetics/metabolism ; Cytoplasm/metabolism ; DNA-Binding Proteins/*toxicity ; GTP Phosphohydrolases/genetics ; GTP-Binding Proteins/genetics ; *Gene Deletion ; Humans ; Mediator Complex/genetics ; Microbial Viability/drug effects ; Mitochondrial Proteins/genetics ; Oxidative Stress ; Saccharomyces cerevisiae/drug effects/genetics/*growth &amp; development ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; Vesicular Transport Proteins/genetics ; }, abstract = {TDP-43 protein is found deposited as inclusions in the amyotrophic lateral sclerosis (ALS) patient's brain. The mechanism of neuron death in ALS is not fully deciphered but several TDP-43 toxicity mechanisms such as mis-regulation of autophagy, mitochondrial impairment and generation of oxidative stress etc., have been implicated. A predominantly nuclear protein, Cyclin C, can regulate the oxidative stress response via transcription of stress response genes and also by translocation to the cytoplasm for the activation of mitochondrial fragmentation-dependent cell death pathway. Using the well-established yeast TDP-43 proteinopathy model, we examined here whether upon TDP-43 aggregation, cell survival depends on the CNC1 gene that encodes the Cyclin C protein or other genes which encode proteins that function in conjunction with Cyclin C, such as DNM1, FIS1 and MED13. We show that the TDP-43's toxicity is significantly reduced in yeast deleted for CNC1 or DNM1 genes and remains unaltered by deletions of genes, FIS1 and MED13. Importantly, this rescue is observed only in presence of functional mitochondria. Also, deletion of the YBH3 gene involved in the mitochondria-dependent apoptosis pathway reduced the TDP-43 toxicity. Deletion of the VPS1 gene involved in the peroxisomal fission pathway did not mitigate the TDP-43 toxicity. Strikingly, Cyclin C-YFP was observed to relocate to the cytoplasm in response to TDP-43's co-expression which was prevented by addition of an anti-oxidant molecule, N-acetyl cysteine. Overall, the Cyclin C, Dnm1 and Ybh3 proteins are found to be important players in the TDP-43-induced oxidative stress-mediated cell death in the S. cerevisiae model.}, }
@article {pmid33642448, year = {2021}, author = {Nakamura, K and Minamikawa, H and Takahashi, S and Yoshimura, Y and Yawaka, Y}, title = {N-acetylcysteine attenuates PGE2 and ROS production stimulated by 4-META/MMA-based resin in murine osteoblastic cells.}, journal = {Dental materials journal}, volume = {40}, number = {3}, pages = {808-812}, doi = {10.4012/dmj.2020-275}, pmid = {33642448}, issn = {1881-1361}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; *Dinoprostone ; Methacrylates ; Mice ; Reactive Oxygen Species ; }, abstract = {This study examined the effects of N-acetylcysteine (NAC) on the inflammatory reactions of murine osteoblastic cells cultured on the 4-methacryloxyethyl trimellitate anhydride/methyl methacrylate (4-META/MMA)-based resin. Superbond C&amp;B (SB) was used as the 4-META/MMA-based resin and placed in a 48-well cell culture plate. The cells were cultured in αMEM (control) as well as on SB and SB in αMEM with NAC (SB+NAC). They were examined using the WST-1 proliferation assay, real-time PCR, enzyme-linked immunosorbent assay (ELISA), intracellular reactive oxygen species (ROS) measurements, and cellular glutathione (GSH) detection. COX-2 and IL-6 gene expressions were upregulated in SB; however, they were suppressed by NAC. Furthermore, PGE2 production in the culture medium was increased in SB, whereas NAC decreased the PGE2 production. NAC lowered the ROS level in the culture medium and significantly increased the intracellular GSH level. The present in vitro study demonstrated that NAC might be effective for dental material detoxification.}, }
@article {pmid33641435, year = {2021}, author = {Ren, G and Zhou, Q and Lu, M and Wang, H}, title = {Rosuvastatin corrects oxidative stress and inflammation induced by LPS to attenuate cardiac injury by inhibiting the NLRP3/TLR4 pathway.}, journal = {Canadian journal of physiology and pharmacology}, volume = {99}, number = {9}, pages = {964-973}, doi = {10.1139/cjpp-2020-0321}, pmid = {33641435}, issn = {1205-7541}, mesh = {Animals ; Apoptosis/drug effects ; Cells, Cultured ; Heart/*drug effects ; Inflammation/*drug therapy ; Lipopolysaccharides ; Mice ; Mice, Inbred BALB C ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists &amp; inhibitors ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Rosuvastatin Calcium/*pharmacology ; Signal Transduction/drug effects ; Toll-Like Receptor 4/*antagonists &amp; inhibitors ; }, abstract = {Rosuvastatin has been found to possess antioxidant and anti-inflammatory properties. The aim of the current study was to evaluate whether rosuvastatin was effective in attenuating cardiac injury in lipopolysaccharide (LPS) - challenged mice and H9C2 cells and identify the underlying mechanisms, focusing on the nod-like receptor protein 3 (NLRP3)/toll-like receptor 4 (TLR4) pathway. Cardiac injury, cardiac function, apoptosis, oxidative stress, inflammatory response, and the NLRP3/TLR4 pathway were evaluated in both in vivo and in vitro studies. LPS-induced cardiomyocyte injury was markedly attenuated by rosuvastatin treatment, evidenced by increased cell proliferation of H9C2 cells, rescued cardiac function, and improved morphological changes in mice and reduced lactate dehydrogenase (LDH), creatine kinase MB fraction (CK-MB), and troponin I (cTnI) in serum. Apoptosis was clearly ameliorated in myocardial tissue and H9C2 cells co-treated with rosuvastatin. In addition, after LPS challenge, excessive oxidative stress was present, indicated by increases in malondialdehyde (MDA) content, NADPH activity, and reactive oxygen species (ROS) production and decreased superoxide dismutase (SOD) activity. Rosuvastatin improved all the indicators of oxidative stress, with an effect similar to that of N-acetylcysteine (NAC) (an ROS scavenger). Notably, LPS-exposed H9C2 cells and mice showed significant NLRP3 and TLR4/nuclear factor-κB (NF-κB) pathway activation and inflammatory responses. Administration of rosuvastatin reduced the increases in NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase-1, TLR4, and p65 expression and decreased the tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), IL-18, and IL-6 contents, with an effect similar to that of MCC950 (an NLRP3 inhibitor). In conclusion, inhibition of the inflammatory response and oxidative stress contributes to cardioprotective effect of rosuvastatin against cardiac injury induced by LPS, and the effect of rosuvastatin was achieved through inactivation of the NF-κB/NLRP3 pathway.}, }
@article {pmid33641060, year = {2021}, author = {Pittas, S and Theodoridis, X and Haidich, AB and Bozikas, PV and Papazisis, G}, title = {The effect of N-acetylcysteine on bipolar depression: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Psychopharmacology}, volume = {238}, number = {7}, pages = {1729-1736}, pmid = {33641060}, issn = {1432-2072}, mesh = {Acetylcysteine/*therapeutic use ; Bipolar Disorder/diagnosis/*drug therapy/*psychology ; Combined Modality Therapy/methods ; Humans ; Quality of Life/psychology ; Randomized Controlled Trials as Topic/*methods ; Treatment Outcome ; }, abstract = {RATIONALE: The current pharmacotherapy of bipolar depression often presents limited efficacy and increased risk for adverse events. N-acetylcysteine (NAC) has been suggested as potentially effective and well-tolerated adjunctive treatment for bipolar disorder (BD).<br><br>OBJECTIVES: This systematic review and meta-analysis aimed to examine the efficacy of N-acetylcysteine, as an adjunctive therapy, for treating bipolar depression.<br><br>METHODS: PubMed, Cochrane Library, Scopus databases, and grey literature were searched for studies retrieval. Randomized controlled trials including patients with a diagnosed bipolar disorder and a current depressive episode were included in the analysis. The measured variables included symptoms, functioning, and quality of life scales. The mean change in Montgomery-&#xc5;sberg Depression Rating Scale (MADRS) was set as the primary outcome.<br><br>RESULTS: A total of five studies were included in the analysis. A significant improvement was not observed from the addition of NAC to standard therapy in symptomatology [MADRS (MD = -3.32; 95% CI = -12.79 to 6.16), Young Mania Rating Scale (MD&#xa0;=&#xa0;-0.7; 95% CI&#xa0;=&#xa0;-2.15 to 0.75), Bipolar Depression Rating Scale (MD&#xa0;=&#xa0;-3.19; 95% CI&#xa0;=&#xa0;-15.48 to 9.1), and Clinical Global Impression for severity (MD&#xa0;=&#xa0;-0.13; 95% CI&#xa0;=&#xa0;-0.33 to 0.08)], functioning, [Global Assessment of Functioning Scale (MD&#xa0;=&#xa0;3.21; 95% CI&#xa0;=&#xa0;-12.55 to 18.97), Social and Occupational Functioning Assessment Scale (MD&#xa0;=&#xa0;0.47; 95% CI&#xa0;=&#xa0;-4.60 to 5.53), or quality of life [Quality of Life Enjoyment and Satisfaction Questionnaire (MD&#xa0;=&#xa0;2.27; 95% CI&#xa0;=&#xa0;-9.13 to 13.67)].<br><br>CONCLUSIONS: There is no evidence indicating that NAC has beneficial effects as an adjunctive treatment for bipolar depression. Future trials with improved methodological design and efficient sample sizes are required to draw safer conclusions.}, }
@article {pmid33640978, year = {2021}, author = {Guha, S and Mathew, ND and Konkwo, C and Ostrovsky, J and Kwon, YJ and Polyak, E and Seiler, C and Bennett, M and Xiao, R and Zhang, Z and Nakamaru-Ogiso, E and Falk, MJ}, title = {Combinatorial glucose, nicotinic acid and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease.}, journal = {Human molecular genetics}, volume = {30}, number = {7}, pages = {536-551}, pmid = {33640978}, issn = {1460-2083}, support = {R01 GM120762/GM/NIGMS NIH HHS/United States ; R01 HD065858/HD/NICHD NIH HHS/United States ; R35 GM134863/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Caenorhabditis elegans ; *Disease Models, Animal ; Drug Synergism ; Electron Transport Complex I/genetics/*metabolism ; Free Radical Scavengers/pharmacology ; Glucose/*pharmacology ; Humans ; Longevity/drug effects/genetics ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/genetics/metabolism ; Mitochondrial Diseases/genetics/metabolism/*prevention &amp; control ; Mutation ; Niacin/*pharmacology ; Oxidative Stress/drug effects ; Zebrafish ; }, abstract = {Mitochondrial respiratory chain disorders are empirically managed with variable antioxidant, cofactor and vitamin 'cocktails'. However, clinical trial validated and approved compounds, or doses, do not exist for any single or combinatorial mitochondrial disease therapy. Here, we sought to pre-clinically evaluate whether rationally designed mitochondrial medicine combinatorial regimens might synergistically improve survival, health and physiology in translational animal models of respiratory chain complex I disease. Having previously demonstrated that gas-1(fc21) complex I subunit ndufs2-/-C. elegans have short lifespan that can be significantly rescued with 17 different metabolic modifiers, signaling modifiers or antioxidants, here we evaluated 11 random combinations of these three treatment classes on gas-1(fc21) lifespan. Synergistic rescue occurred only with glucose, nicotinic acid and N-acetylcysteine (Glu + NA + NAC), yielding improved mitochondrial membrane potential that reflects integrated respiratory chain function, without exacerbating oxidative stress, and while reducing mitochondrial stress (UPRmt) and improving intermediary metabolic disruptions at the levels of the transcriptome, steady-state metabolites and intermediary metabolic flux. Equimolar Glu + NA + NAC dosing in a zebrafish vertebrate model of rotenone-based complex I inhibition synergistically rescued larval activity, brain death, lactate, ATP and glutathione levels. Overall, these data provide objective preclinical evidence in two evolutionary-divergent animal models of mitochondrial complex I disease to demonstrate that combinatorial Glu + NA + NAC therapy significantly improved animal resiliency, even in the face of stressors that cause severe metabolic deficiency, thereby preventing acute neurologic and biochemical decompensation. Clinical trials are warranted to evaluate the efficacy of this lead combinatorial therapy regimen to improve resiliency and health outcomes in human subjects with mitochondrial disease.}, }
@article {pmid33640759, year = {2021}, author = {Pingali, P and Wu, YJ and Boothello, R and Sharon, C and Li, H and Sistla, S and Sankaranarayanan, NV and Desai, UR and Le, AT and Doebele, RC and Muldoon, LL and Patel, BB and Neuwelt, A}, title = {High dose acetaminophen inhibits STAT3 and has free radical independent anti-cancer stem cell activity.}, journal = {Neoplasia (New York, N.Y.)}, volume = {23}, number = {3}, pages = {348-359}, pmid = {33640759}, issn = {1476-5586}, support = {P30 CA016059/CA/NCI NIH HHS/United States ; P50 CA058187/CA/NCI NIH HHS/United States ; }, mesh = {AC133 Antigen/metabolism ; Acetaminophen/administration &amp; dosage/*pharmacology ; Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Biomarkers, Tumor ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Free Radicals/*metabolism ; Gene Knockdown Techniques ; Humans ; Interleukin-6/antagonists &amp; inhibitors ; Lung Neoplasms ; Neoplastic Stem Cells/*drug effects/*metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {High-dose acetaminophen (AAP) with delayed rescue using n-acetylcysteine (NAC), the FDA-approved antidote to AAP overdose, has demonstrated promising antitumor efficacy in early phase clinical trials. However, the mechanism of action (MOA) of AAP's anticancer effects remains elusive. Using clinically relevant AAP concentrations, we evaluated cancer stem cell (CSC) phenotype in vitro and in vivo in lung cancer and melanoma cells with diverse driver mutations. Associated mechanisms were also studied. Our results demonstrated that AAP inhibited 3D spheroid formation, self-renewal, and expression of CSC markers when human cancer cells were grown in serum-free CSC media. Similarly, anti-CSC activity was demonstrated in vivo in xenograft models - tumor formation following in vitro treatment and ex-vivo spheroid formation following in vivo treatment. Intriguingly, NAC, used to mitigate AAP's liver toxicity, did not rescue cells from AAP's anti-CSC effects, and AAP failed to reduce glutathione levels in tumor xenograft in contrast to mice liver tissue suggesting nonglutathione-related MOA. In fact, AAP mediates its anti-CSC effect via inhibition of STAT3. AAP directly binds to STAT3 with an affinity in the low micromolar range and a high degree of specificity for STAT3 relative to STAT1. These findings have high immediate translational significance concerning advancing AAP with NAC rescue to selectively rescue hepatotoxicity while inhibiting CSCs. The novel mechanism of selective STAT3 inhibition has implications for developing rational anticancer combinations and better patient selection (predictive biomarkers) for clinical studies and developing novel selective STAT3 inhibitors using AAP's molecular scaffold.}, }
@article {pmid33638319, year = {2021}, author = {Rind, L and Ahmad, M and Khan, MI and Badruddeen,  and Akhtar, J and Ahmad, U and Yadav, C and Owais, M}, title = {An insight on safety, efficacy, and molecular docking study reports of N-acetylcysteine and its compound formulations.}, journal = {Journal of basic and clinical physiology and pharmacology}, volume = {33}, number = {3}, pages = {223-233}, doi = {10.1515/jbcpp-2020-0099}, pmid = {33638319}, issn = {2191-0286}, mesh = {*Acetylcysteine/metabolism/therapeutic use ; *Antioxidants/pharmacology/therapeutic use ; Chromatography, High Pressure Liquid ; Drug Compounding ; Molecular Docking Simulation ; }, abstract = {N-acetylcysteine (NAC) is considered as the body's major antioxidant molecules with diverse biological properties. In this review, the pharmacokinetics, safety and efficacy report on both the preclinical and clinical summary of NAC is discussed. Both in vitro and in vivo preclinical studies along with the clinical data have shown that NAC has enormous biological properties. NAC is used in the treatment of acetaminophen poisoning, diabetic nephropathy, Alzheimer's disease, schizophrenia, and ulcerative colitis, etc. Numerous analytical techniques, for instance, UPLC, LC-MS, HPLC, RP-IPC are primarily employed for the estimation of NAC in different single and fixed-dose combinations. The molecular docking studies on NAC demonstrate the binding within Sudlow's site-I hydrogen bonds and formation of NAC and BSA complexes. Various hydrophobic and hydrophilic amino acids generally exist in making contact with NAC as NAC-BSA complexes. Docking studies of NAC with the active site of the urease exposed an O-coordinated bond through nickel 3002 and a hydrogen bond through His-138. NAC and its analogs also made the allosteric pockets that helped to describe almost all favorable pose for the chaperone in a complex through the protein. Thus, we intended to highlight the several health benefits of this antioxidant compound and applications in pharmaceutical product development.}, }
@article {pmid33636336, year = {2021}, author = {Ren, Y and Chen, J and Chen, P and Hao, Q and Cheong, LK and Tang, M and Hong, LL and Hu, XY and Celestial T Yap,  and Bay, BH and Ling, ZQ and Shen, HM}, title = {Oxidative stress-mediated AMPK inactivation determines the high susceptibility of LKB1-mutant NSCLC cells to glucose starvation.}, journal = {Free radical biology &amp; medicine}, volume = {166}, number = {}, pages = {128-139}, doi = {10.1016/j.freeradbiomed.2021.02.018}, pmid = {33636336}, issn = {1873-4596}, mesh = {AMP-Activated Protein Kinases/genetics/metabolism ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics ; Glucose ; Humans ; *Lung Neoplasms/drug therapy/genetics ; Oxidative Stress/genetics ; }, abstract = {The liver kinase B1 (LKB1) is an important tumor suppressor and its loss-of-function mutations are observed in around 16% of non-small cell lung cancer (NSCLC) cases. One of the main functions of LKB1 is to activate AMP-activated protein kinase (AMPK) via direct phosphorylation. Under metabolic or energy stress conditions, the LKB1-AMPK axis inhibits the anabolic pathways and activates the catabolic pathways to maintain metabolic homeostasis for cell survival. In this study, we found that LKB1-mutant NSCLC cells are particularly susceptible to cell death induced by glucose starvation, but not by other forms of starvation such as amino acid starvation or serum starvation. Reconstitution of LKB1 in LKB1-mutant cells or LKB1 knockout in LKB1-wild type cells highlighted the importance of the LKB1-AMPK axis for cell survival under glucose starvation. Mechanistically, in LKB1-mutant cells, glucose starvation elicits oxidative stress, which causes AMPK protein oxidation and inactivation, and eventually cell death. Importantly, this process could be effectively reversed and rescued by 2DG (a glucose analog capable of producing NADPH, a key antioxidant), A769662 (an allosteric AMPK activator), and N-acetyl cysteine (NAC) (a ROS scavenger), indicating the presence of a vicious circle between AMPK inactivation and ROS in LKB1-mutant NSCLC cells under glucose starvation. Our study thus elucidates the critical role of redox balance in determining the susceptibility to cell death under glucose starvation in LKB1-mutant NSCLC cells. The findings from this study reveal important clues in search of novel therapeutic strategies for LKB1-mutant NSCLC by targeting glucose metabolism and redox balance.}, }
@article {pmid33633548, year = {2020}, author = {Quintanilla, ME and Morales, P and Ezquer, F and Ezquer, M and Herrera-Marschitz, M and Israel, Y}, title = {Administration of N-acetylcysteine Plus Acetylsalicylic Acid Markedly Inhibits Nicotine Reinstatement Following Chronic Oral Nicotine Intake in Female Rats.}, journal = {Frontiers in behavioral neuroscience}, volume = {14}, number = {}, pages = {617418}, pmid = {33633548}, issn = {1662-5153}, abstract = {BACKGROUND: Nicotine is the major addictive component of cigarette smoke and the prime culprit of the failure to quit smoking. Common elements perpetuating the use of addictive drugs are (i) cues associated with the setting in which drug was used and (ii) relapse/reinstatement mediated by an increased glutamatergic tone (iii) associated with drug-induced neuroinflammation and oxidative stress.<br><br>AIMS: The present study assessed the effect of the coadministration of the antioxidant N-acetylcysteine (NAC) plus the anti-inflammatory acetylsalicylic acid (ASA) on oral nicotine reinstatement intake following a post-deprivation re-access in female rats that had chronically and voluntarily consumed a nicotine solution orally. The nicotine-induced oxidative stress and neuroinflammation in the hippocampus and its effects on the glutamate transporters GLT-1 and XCT mRNA levels in prefrontal cortex were also analyzed.<br><br>RESULTS: The oral coadministration of NAC (40 mg/kg/day) and ASA (15 mg/kg/day) inhibited by 85% of the oral nicotine reinstatement intake compared to control (vehicle), showing an additive effect of both drugs. Acetylsalicylic acid and N-acetylcysteine normalized hippocampal oxidative stress and blunted the hippocampal neuroinflammation observed upon oral nicotine reinstatement. Nicotine downregulated GLT-1 and xCT gene expression in the prefrontal cortex, an effect reversed by N-acetylcysteine, while acetylsalicylic acid reversed the nicotine-induced downregulation of GLT-1 gene expression. The inhibitory effect of N-acetylcysteine on chronic nicotine intake was blocked by the administration of sulfasalazine, an inhibitor of the xCT transporter.<br><br>CONCLUSION: Nicotine reinstatement, following post-deprivation of chronic oral nicotine intake, downregulates the mRNA levels of GLT-1 and xCT transporters, an effect reversed by the coadministration of N-acetylcysteine and acetylsalicylic acid, leading to a marked inhibition of nicotine intake. The combination of these drugs may constitute a valuable adjunct in the treatment of nicotine-dependent behaviors.}, }
@article {pmid33632046, year = {2022}, author = {Bastin, AR and Nazari-Robati, M and Sadeghi, H and Doustimotlagh, AH and Sadeghi, A}, title = {Trehalose and N-Acetyl Cysteine Alleviate Inflammatory Cytokine Production and Oxidative Stress in LPS-Stimulated Human Peripheral Blood Mononuclear Cells.}, journal = {Immunological investigations}, volume = {51}, number = {4}, pages = {963-979}, doi = {10.1080/08820139.2021.1891095}, pmid = {33632046}, issn = {1532-4311}, mesh = {*Acetylcysteine/pharmacology ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; *Cytokines/metabolism ; Glutathione Peroxidase/metabolism ; Humans ; Inflammation/drug therapy/metabolism ; Interleukin-6/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism/pharmacology ; Leukocytes, Mononuclear/metabolism ; Lipopolysaccharides ; Malondialdehyde/metabolism ; NF-kappa B/metabolism ; *Oxidative Stress ; *Trehalose/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND: Evidence has shown that inflammation and oxidative stress are implicated in the development of a great number of human diseases. Trehalose possesses various biological effects including antioxidant and anti-inflammatory activities. However, there is little data on the effects of trehalose on human cells including peripheral blood mononuclear cells (PBMCs). Here, we aimed to investigate whether trehalose could attenuate oxidative stress and inflammation induced by lipopolysaccharides (LPS) in PBMCs.<br><br>METHODS: The enzyme-linked immunosorbent assay (ELISA) and RT-PCR were used to assess the levels of inflammatory cytokines. To investigate the phosphorylation of c-Jun N-terminal kinase (JNK) and NF-&#x3ba;B, western blot analysis was utilized. Oxidant-antioxidant markers were assessed using ELISA and colorimetric procedures.<br><br>RESULTS: The results revealed that trehalose significantly mitigated the effect of LPS on the phosphorylation of JNK and NF-&#x3ba;B-P65 (p <&#xa0;.00). This mitigation was associated with significantly reduced levels of inflammatory cytokines IL-6, TNF-&#x3b1;, and IL-1&#x3b2; and increased levels of anti-inflammatory cytokine IL-10 (P <&#xa0;.05). The antioxidant N-acetyl cysteine (NAC) also showed similar effects on JNK and NF-&#x3ba;B-P65 phosphorylation and inflammatory cytokines (p <&#xa0;.00). Furthermore, trehalose alleviated oxidative stress in LPS-stimulated PBMCs as it reversed the altered levels of malondialdehyde and total thiols (p &#x2264;&#xa0;.05) and restored the activity of antioxidant enzymes glutathione peroxidase and manganese superoxide dismutase (p <&#xa0;.001).<br><br>CONCLUSION: The results of this study indicated that trehalose prevented inflammation and oxidative stress in the LPS-stimulated PBMCs, providing evidence for the benefits of trehalose as a potential therapeutic agent in inflammatory conditions.<br><br>ABBREVIATIONS: LPS: Lipopolysaccharide; NAC: N-Acetyl cysteine; ROS: Reactive oxygen species; IL-6: Interleukin-6; TNF-&#x3b1;: Tumor necrosis factor-alpha; SOD: Superoxide dismutase; GPx: Glutathione peroxidase; MDA: Malondialdehyde; MAPK: Mitogen-activated protein kinases; JNK: c-Jun N-terminal kinase; NF-&#x3ba;B: Nuclear factor kappa-light-chain-enhancer of activated B cells.}, }
@article {pmid33630932, year = {2021}, author = {Kim, D and Shea, SM and Ku, DN}, title = {Lysis of arterial thrombi by perfusion of N,N'-Diacetyl-L-cystine (DiNAC).}, journal = {PloS one}, volume = {16}, number = {2}, pages = {e0247496}, pmid = {33630932}, issn = {1932-6203}, mesh = {Animals ; Cystine/*analogs &amp; derivatives/pharmacology ; Fibrinolytic Agents/*pharmacology ; Swine ; Thrombolytic Therapy/*methods ; Thrombosis/*drug therapy ; Thrombotic Stroke/*drug therapy ; }, abstract = {The search persists for a safe and effective agent to lyse arterial thrombi in the event of acute heart attacks or strokes due to thrombotic occlusion. The culpable thrombi are composed either primarily of platelets and von Willebrand Factor (VWF), or polymerized fibrin, depending on the mechanism of formation. Current thrombolytics were designed to target red fibrin-rich clots, but may be not be efficacious on white VWF-platelet-rich arterial thrombi. We have developed an in vitro system to study the efficacy of known and proposed thrombolytic agents on white clots formed from whole blood in a stenosis with arterial conditions. The agents and adjuncts tested were tPA, ADAMTS-13, abciximab, N-acetyl cysteine, and N,N'-Diacetyl-L-cystine (DiNAC). Most of the agents, including tPA, had little thrombolytic effect on the white clots. In contrast, perfusion of DiNAC lysed thrombi as quickly as 1.5 min, which ranged up to 30 min at lower concentrations, and resulted in an average reduction in surface area of 71 ± 20%. The clot burden was significantly reduced compared to both tPA and a saline control (p<0.0001). We also tested the efficacy of all agents on red fibrinous clots formed in stagnant conditions. DiNAC did not lyse red clots, whereas tPA significantly lysed red clot over 48 h (p<0.01). These results lead to a novel use for DiNAC as a possible thrombolytic agent against acute arterial occlusions that could mitigate the risk of hyper-fibrinolytic bleeding.}, }
@article {pmid33630121, year = {2021}, author = {Alshogran, OY and Nusair, SD and El-Elimat, T and Alzoubi, KH and Obeidat, A and Sweidan, M}, title = {Evaluation of coenzyme Q10 combined with or without N-acetyl cysteine or atorvastatin for preventing contrast-induced kidney injury in diabetic rats.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {394}, number = {7}, pages = {1403-1410}, pmid = {33630121}, issn = {1432-1912}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/blood/chemically induced/pathology/*prevention &amp; control ; Animals ; Atorvastatin/*administration &amp; dosage ; Contrast Media/*toxicity ; Diabetes Mellitus, Experimental/blood/*drug therapy/pathology ; Drug Evaluation, Preclinical/methods ; Drug Therapy, Combination ; Male ; Rats ; Rats, Sprague-Dawley ; Ubiquinone/administration &amp; dosage/*analogs &amp; derivatives ; }, abstract = {Combined antioxidants effect for prevention of contrast-induced nephropathy (CIN) remains unclear. This study assessed the potential protective effects of coenzyme Q10 (CoQ10) alone or combined with N-acetyl cysteine (NAC) or atorvastatin against CIN in diabetic rats. Animals were randomly divided into five groups, including control and four disease groups with CIN and diabetes. Group 2 included diabetic rats with CIN. Groups 3-5 included diabetic rats that received CoQ10, CoQ10 and NAC, or CoQ10 and atorvastatin, respectively, before CIN induction. Serum, urine, and tissue were collected to evaluate renal protective effects of tested agents. Renal biomarkers, oxidative stress, and histopathological alterations were investigated. Rats with CIN showed significant renal impairment as revealed by the deleterious effects on kidney function and histology. While induction of CIN did not affect the renal levels of catalase, glutathione peroxidase (GPx), and thiobarbituric acid reactive substances, pretreatment of animals with CoQ10/NAC showed significant increase in GPx and catalase levels versus controls. Lastly, pretreatment with CoQ10/atorvastatin showed regenerative effect on distal tubules with mild kidney histology alterations relative to CIN rats. The combined use of CoQ10/atorvastatin could be a potential strategy to prevent CIN. However, future studies are warranted to test different combinations for longer prophylactic periods.}, }
@article {pmid33629414, year = {2021}, author = {Mardani, N and Mozafarpoor, S and Goodarzi, A and Nikkhah, F}, title = {A systematic review of N-acetylcysteine for treatment of acne vulgaris and acne-related associations and consequences: Focus on clinical studies.}, journal = {Dermatologic therapy}, volume = {34}, number = {3}, pages = {e14915}, doi = {10.1111/dth.14915}, pmid = {33629414}, issn = {1529-8019}, mesh = {*Acetylcysteine ; *Acne Vulgaris/diagnosis/drug therapy ; Anti-Bacterial Agents/therapeutic use ; Escherichia coli ; Humans ; Propionibacterium acnes ; Quality of Life ; }, abstract = {Acne vulgaris is one of the most common dermatologic disorders affects people of all races and ethnicities and has many adverse effects on the quality of life. The increased bacterial resistance to antibiotics has reduced the effectiveness of treatment with these agents. There is an increasing focus on the involvement of oxidative stress in the pathophysiology of acne. This study investigates the effect of N-acetylcysteine (NAC) as an antioxidant in the treatment of acne vulgaris. This systematic review was conducted through a search in databases such as Science Direct, PubMed, Scielo, and Medline using keywords including acne vulgaris, anti and NAC, and all the keywords associated with each of the subtitles. The factors affecting the occurrence and expansion of acne include increased sebum synthesis, hyperkeratinization of pilosebaceous units, colonization with Propionibacterium acnes, and increased release of inflammatory mediators and ROS. Studies have shown that glutathione stimulation following the administration of NAC increases glutathione levels for the detoxification of oxygen-free radicals. Moreover, NAC prevents the synthesis and release of inflammatory cytokines such as TNF-α, IL-8, IL-6, MP9, and IL-1β and has shown antibacterial activities against important bacteria including E. coli, S. epidermidis, Pseudomonas, and Klebsiella. This medication has anti-proliferative effects and is also used for excoriation and PCOD. The results of the present study showed the beneficial effects of using NAC in patients with acne vulgaris in terms of the disease complications and comorbidities. Given its diverse functional mechanisms, this medication can be used to treat acne and its consequences.}, }
@article {pmid33626512, year = {2021}, author = {Mao, C and Li, D and Zhou, E and Zhang, J and Wang, C and Xue, C}, title = {Nicotine exacerbates atherosclerosis through a macrophage-mediated endothelial injury pathway.}, journal = {Aging}, volume = {13}, number = {5}, pages = {7627-7643}, pmid = {33626512}, issn = {1945-4589}, mesh = {Animals ; Carrier Proteins/*metabolism ; Chemotaxis ; Coronary Artery Disease/*metabolism ; Female ; Ganglionic Stimulants/pharmacology ; Humans ; Inflammasomes/metabolism ; Interleukin-18/blood ; Interleukin-1beta/blood ; Intracellular Signaling Peptides and Proteins/metabolism ; Macrophages/*drug effects ; Male ; Mice, Knockout ; Middle Aged ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Nicotine/*pharmacology ; Phagocytosis ; Phosphate-Binding Proteins/metabolism ; Pyroptosis/drug effects ; Reactive Oxygen Species/metabolism ; Severity of Illness Index ; Signal Transduction/drug effects ; Mice ; }, abstract = {Evidence suggests that nicotine intake promotes atherosclerosis. We enrolled 100 patients with coronary heart disease (CHD) and found that plaque burden, TXNIP expression, and inflammatory chemokine levels were higher in smokers than non-smokers. Additionally, patients with higher TXNIP expression in peripheral blood mononuclear cells (PBMCs) had a higher Gensini Scores and higher plasma IL-1β and IL-18 levels. Treating bone marrow-derived macrophages (BMDMs) with nicotine in vitro led to enhanced lipid phagocytosis, chemotaxis, and increased production of reactive oxygen species (ROS), which activated TXNIP/NLRP3 inflammasome signaling and promoted pyroptosis, as evidenced by caspase-1 cleavage and increased production of IL-1β, IL-18, and gasdermin D. Nicotine intake by ApoE[(-/-)] mice fed a high-fat diet recapitulated those phenotypes. The effects of nicotine on pyroptotic signaling were reversed by N-acetyl-cysteine, a ROS scavenger. Silencing TXNIP in vivo reversed the effects of nicotine on macrophage invasion and vascular injury. Nicotine also induced pyroptotic macrophages that contributed to the apoptotic death of endothelial cells. These findings suggest that nicotine accelerates atherosclerosis in part by promoting macrophage pyroptosis and endothelial damage. Therefore, targeting the TXNIP/NLRP3-mediated pyroptotic pathway in macrophages may ameliorate nicotine-induced endothelial damage.}, }
@article {pmid33625322, year = {2021}, author = {Rahmani Talatappeh, N and Ranji, N and Beigi Harchegani, A}, title = {The effect of N-acetyl cysteine on oxidative stress and apoptosis in the liver tissue of rats exposed to cadmium.}, journal = {Archives of environmental &amp; occupational health}, volume = {76}, number = {8}, pages = {518-525}, doi = {10.1080/19338244.2021.1887796}, pmid = {33625322}, issn = {2154-4700}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Cadmium/*toxicity ; Caspase 3/genetics ; Caspase 8/genetics ; Gene Expression/drug effects ; Liver/*drug effects/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics ; Rats ; bcl-2-Associated X Protein/genetics ; }, abstract = {We considered the oxidative damage induced by cadmium (Cd) and apoptosis, and the role of N-acetylcysteine (NAC) in preserving cells against Cd toxicity in the liver of male rats. NAC significantly improved total antioxidant capacity (TAC) and decreased malondialdehyde (MDA) in rats exposed to single and continuous dose of Cd. Single and continuous exposure to Cd caused a significant increase in Bax expression (by 1.5-fold and 3.61-fold, respectively) and significant decrease in expression of Bcl2 compared to control (by 9.14-fold and 2.36-fold, respectively). The expression of Caspase 3 and 8 in rats exposed to Cd was significantly higher than control group (P < 0.05). NAC protects liver tissue against Cd by elevating antioxidants capacity, mitigating oxidative stress, as well as down-regulating of apoptotic factors.}, }
@article {pmid33620007, year = {2021}, author = {Downs, JW and Cumpston, KL and Kershner, EK and Troendle, MM and Rose, SR and Wills, BK}, title = {Clinical outcome of massive acetaminophen overdose treated with standard-dose N-acetylcysteine.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {59}, number = {10}, pages = {932-936}, doi = {10.1080/15563650.2021.1887493}, pmid = {33620007}, issn = {1556-9519}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*administration &amp; dosage ; Chemical and Drug Induced Liver Injury/diagnosis/etiology/*prevention &amp; control ; Drug Administration Schedule ; Drug Overdose/diagnosis/*drug therapy ; Female ; Humans ; Infusions, Intravenous ; Male ; Poison Control Centers ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Recent recognition of "massive" acetaminophen (APAP) overdoses has led to the question of whether standard dosing of N-acetylcysteine (NAC) is adequate to prevent hepatoxicity in these patients. The primary aim of this study was to evaluate the clinical outcome for patients with massive APAP overdose who received standard intravenous NAC dosing of 300 mg/kg over 21 h.<br><br>METHODS: This was a single-center retrospective cohort study conducted by chart review of APAP overdoses reported to a regional poison center from 1 January 2010 to 31 December 2019. Massive APAP overdose was defined by single, acute overdose resulting in an APAP concentration exceeding 300&#x2009;mcg/mL at 4&#x2009;h post-ingestion. Standard univariate statistical analysis was conducted to describe the cohort, and a multivariate logistic model was utilized to calculate adjusted odds ratios for risk of hepatoxicity.<br><br>RESULTS: 1425 cases of APAP overdose were reviewed. 104 cases met the inclusion criteria of massive APAP overdose. Overall, 79 cases (76%) had no acute liver injury or hepatotoxicity, and 25 (24%) developed hepatoxicity. Nine percent (n&#x2009;=&#x2009;4) of cases receiving NAC within 8&#x2009;h developed hepatotoxicity. Crude odds for hepatoxicity was 5.5-fold higher for cases who received NAC after 8&#x2009;h.<br><br>CONCLUSIONS: Standard NAC dosing received within 8&#x2009;h prevented hepatoxicity in 91% (n&#x2009;=&#x2009;40) of cases in our series of massive APAP overdoses. Additional data is needed to determine the clinical outcomes of massive APAP overdose using current intravenous NAC dosing.}, }
@article {pmid33619056, year = {2023}, author = {Vilchèze, C and Jacobs, WR}, title = {The promises and limitations of N-acetylcysteine as a potentiator of first-line and second-line tuberculosis drugs.}, journal = {Antimicrobial agents and chemotherapy}, volume = {65}, number = {5}, pages = {}, pmid = {33619056}, issn = {1098-6596}, support = {R37 AI026170/AI/NIAID NIH HHS/United States ; R01 AI026170/AI/NIAID NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; U19 AI111276/AI/NIAID NIH HHS/United States ; R21 AI132940/AI/NIAID NIH HHS/United States ; }, abstract = {N-acetylcysteine (NAC) is most commonly used for the treatment of acetaminophen overdose and acetaminophen-induced liver injury. In patients infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), NAC is given to treat hepatotoxicity induced by TB drugs. We had previously shown that cysteine, a derivative of NAC, potentiated the activity of isoniazid, a first-line TB drug, by preventing the emergence of INH resistance and persistence in M. tuberculosis in vitro. Herein, we demonstrate that in vitro, NAC has the same boosting activity with various combinations of first- and second-line TB drugs against drug-susceptible and multidrug-resistant M. tuberculosis strains. Similar to cysteine, NAC increased M. tuberculosis respiration. However, in M. tuberculosis-infected mice, the addition of NAC did not augment the activity of first- or second-line TB drugs. A comparison of the activity of NAC combined with TB drugs in murine and human macrophage cell lines revealed that studies in mice might not be recapitulated during host infection in vivo.}, }
@article {pmid33617885, year = {2021}, author = {Tras, B and Eser Faki, H and Ozdemir Kutahya, Z and Bahcivan, E and Dik, B and Bozkurt, B and Uney, K}, title = {Treatment and protective effects of metalloproteinase inhibitors alone and in combination with N-Acetyl cysteine plus vitamin E in rats exposed to aflatoxin B1.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {194}, number = {}, pages = {79-85}, doi = {10.1016/j.toxicon.2021.02.012}, pmid = {33617885}, issn = {1879-3150}, mesh = {*Acetylcysteine/pharmacology ; *Aflatoxin B1/toxicity ; Animals ; Liver ; Male ; Metalloproteases/*metabolism ; Protective Agents/*metabolism ; Rats ; Rats, Wistar ; Vitamin E ; }, abstract = {This study was conducted to investigate the effects of matrix metalloproteinase (MMP) inhibitors dexamethasone and minocycline administrations -both single and in combination with N-acetylcysteine (NAC) and vitamin E-on the tissue distribution and lethal dose (LD)50 of aflatoxin (AF)B1 in rats. We performed this study on male Wistar rats (8-10 weeks) in two phases. In the first phase, rats were administered dexamethasone (5 and 20 mg/kg) and minocycline (45 and 90 mg/kg), both as single treatments and in combination with NAC (200 mg/kg) and vitamin E (600 mg/kg); these treatments followed AFB1 administration (2 mg/kg). In the second phase, the therapeutic effect value (TEV) was calculated to determine the treatment effect on the LD50 level of AFB1. The tissue affinity of AFB1 from high to low was liver, kidney, intestine, brain, heart, spleen, lung, testis, and vitreous humor, respectively. Dexamethasone at the 20 mg/kg dose significantly reduced AFB1 concentrations in the plasma and the other tissues, except for the vitreous humor. The effects of minocycline on the plasma and tissue concentrations of AFB1 varied by dose and tissue. The combinations of dexamethasone or minocycline with NAC and vitamin E increased the AFB1 concentrations in the plasma and all tissues, except for vitreous humor and liver. In male rats, the LD50 value of AFB1 was 11.86 mg/kg. The TEV of dexamethasone (20 mg/kg) was calculated to be 1.5. Dexamethasone can be administered in repeated doses at ≥20 mg/kg to increase survival in AFB1 poisoning.}, }
@article {pmid33615065, year = {2021}, author = {Huang, JW and Lahey, B and Clarkin, OJ and Kong, J and Clark, E and Kanji, S and McCudden, C and Akbari, A and J W Chow, B and Shabana, W and Hiremath, S}, title = {A Systematic Review of the Effect of N-Acetylcysteine on Serum Creatinine and Cystatin C Measurements.}, journal = {Kidney international reports}, volume = {6}, number = {2}, pages = {396-403}, pmid = {33615065}, issn = {2468-0249}, abstract = {INTRODUCTION: N-acetylcysteine (NAC) is an antioxidant that can regenerate glutathione and is primarily used for acetaminophen overdose. NAC has been tested and used for preventing iatrogenic acute kidney injury or slowing the progression of chronic kidney disease, with mixed results. There are conflicting reports that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, we conducted a systematic review of the literature to determine whether there is an effect of NAC on kidney function as measured with serum creatinine and cystatin C.<br><br>METHODS: A literature search was conducted to identify all study types reporting a change in serum creatinine after NAC administration. The primary outcome was change in serum creatinine after NAC administration. The secondary outcome was a change in cystatin C after NAC administration. Subgroup analyses were conducted to assess effect of creatinine assay (Jaffe vs. non-Jaffe and intravenous vs. oral).<br><br>RESULTS: Six studies with a total of 199 participants were eligible for the systematic review and meta-analysis. There was a small but significant decrease in serum creatinine after NAC administration overall (weighted mean difference [WMD],&#xa0;-2.80 &#x3bc;mol/L [95% confidence interval {CI}&#xa0;-5.6 to 0.0]; P&#xa0;= 0.05). This was greater with non-Jaffe methods (WMD,&#xa0;-3.24 &#x3bc;mol/L [95% CI&#xa0;-6.29 to&#xa0;-0.28]; P&#xa0;= 0.04) than Jaffe (WMD,&#xa0;-0.51 &#x3bc;mol/L [95% CI&#xa0;-7.56 to 6.53]; P&#xa0;= 0.89) and in particular with intravenous (WMD,&#xa0;-31.10 &#x3bc;mol/L [95% CI&#xa0;-58.37 to&#xa0;-3.83]; P&#xa0;= 0.03) compared with oral NAC (WMD,&#xa0;-2.5 &#x3bc;mol/L [95% CI&#xa0;-5.32 to 0.32]; P&#xa0;= 0.08). There was no change in cystatin C after NAC administration.<br><br>DISCUSSION: NAC causes a decrease in serum creatinine but not in cystatin C, suggesting analytic interference rather than an effect on kidney function. Supporting this, the effect was greater with non-Jaffe methods of creatinine estimation. Future studies of NAC should use the Jaffe method of creatinine estimation when kidney outcomes are being reported. Even in clinical settings, the use of an enzymatic assay when high doses of intravenous NAC are being used may result in underdiagnosis or delayed diagnosis of acute kidney injury.}, }
@article {pmid33613826, year = {2021}, author = {Zhang, Y and Yang, Y and Xu, M and Zheng, J and Xu, Y and Chen, G and Guo, Q and Tian, W and Guo, W}, title = {The Dual Effects of Reactive Oxygen Species on the Mandibular Alveolar Bone Formation in SOD1 Knockout Mice: Promotion or Inhibition.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {8847140}, pmid = {33613826}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Aging/pathology ; Alveolar Process/diagnostic imaging/drug effects/*growth &amp; development/metabolism ; Animals ; Antioxidants/pharmacology ; Jaw/drug effects ; Mandible/diagnostic imaging/drug effects/*growth &amp; development ; Mice, Knockout ; Osteoclasts/drug effects/metabolism ; *Osteogenesis/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase-1/*antagonists &amp; inhibitors/deficiency/*metabolism ; X-Ray Microtomography ; Mice ; }, abstract = {The status of reactive oxygen species (ROS) correlates closely with the normal development of the oral and maxillofacial tissues. Oxidative stress caused by ROS accumulation not only affects the development of enamel and dentin but also causes pathological changes in periodontal tissues (periodontal ligament and alveolar bone) that surround the root of the tooth. Although previous studies have shown that ROS accumulation plays a pathologic role in some oral and maxillofacial tissues, the effects of ROS on alveolar bone development remain unclear. In this study, we focused on mandibular alveolar bone development of mice deficient in superoxide dismutase1 (SOD1). Analyses were performed using microcomputerized tomography (micro-CT), TRAP staining, immunohistochemical (IHC) staining, and enzyme-linked immunosorbent assay (ELISA). We found for the first time that slightly higher ROS in mandibular alveolar bone of SOD1(-/-) mice at early ages (2-4 months) caused a distinct enlargement in bone size and increased bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and expression of alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2), and osteopontin (OPN). With ROS accumulation to oxidative stress level, increased trabecular bone separation (Tb.Sp) and decreased expression of ALP, Runx2, and OPN were found in SOD1(-/-) mice at 6 months. Additionally, dosing with N-acetylcysteine (NAC) effectively mitigated bone loss and normalized expression of ALP, Runx2, and OPN. These results indicate that redox imbalance caused by SOD1 deficiency has dual effects (promotion or inhibition) on mandibular alveolar bone development, which is closely related to the concentration of ROS and the stage of growth. We present a valuable model here for investigating the effects of ROS on mandibular alveolar bone formation and highlight important roles of ROS in regulating tissue development and pathological states, illustrating the complexity of the redox signal.}, }
@article {pmid33613725, year = {2021}, author = {Li, MH and Liao, X and Li, C and Wang, TT and Sun, YS and Yang, K and Jiang, PW and Shi, ST and Zhang, WX and Zhang, K and Li, C and Yang, P}, title = {Lycorine hydrochloride induces reactive oxygen species-mediated apoptosis via the mitochondrial apoptotic pathway and the JNK signaling pathway in the oral squamous cell carcinoma HSC-3 cell line.}, journal = {Oncology letters}, volume = {21}, number = {3}, pages = {236}, pmid = {33613725}, issn = {1792-1074}, abstract = {Poor drug efficacy is a prominent cause of oral squamous cell carcinoma (OSCC) treatment failure. Although increased efforts in developing OSCC therapeutic strategies have been achieved in recent decades, the 5-year survival rate of patients with OSCC remains poor and effective drugs to treat OSCC are lacking. The aim of the present study was to investigate the apoptotic effect caused by lycorine hydrochloride (LH) and to identify its mechanism in the OSCC HSC-3 cell line. The findings demonstrated that LH effectively induced HSC-3 cell apoptosis and cell cycle arrest at the G0/G1 phase, resulting in the inhibition of cell proliferation. Furthermore, it was found that LH increased reactive oxygen species (ROS) production, triggered mitochondrial membrane potential (MMP) disorder, enhanced the protein expression levels of Bax, Bim, cleaved caspase-9, caspase-3 and poly(ADP-ribose) polymerase 1 and decreased Mcl-1 expression. The protein expression levels of important members of the JNK signaling pathway, including phosphorylated (p)-JNK, p-mitogen-activated protein kinase kinase 4 and p-c-Jun, were significantly increased in LH-treated cells, accompanied by an increase in ROS. However, N-acetyl cysteine (NAC), a potent antioxidant, reversed the upregulated mRNA expression of c-Jun, as well as the enhanced ROS production, the disorder of MMP and the apoptosis of HSC-3 cells induced by LH. These results suggested that LH may induce HSC-3 cell apoptosis via the ROS-mediated mitochondrial apoptotic pathway and the JNK signaling pathway, which indicated that LH may be a potential drug candidate for anti-OSCC therapy.}, }
@article {pmid33613521, year = {2020}, author = {Safe, IP and Amaral, EP and Araújo-Pereira, M and Lacerda, MVG and Printes, VS and Souza, AB and Beraldi-Magalhães, F and Monteiro, WM and Sampaio, VS and Barreto-Duarte, B and Andrade, AMS and Spener-Gomes, R and Costa, AG and Cordeiro-Santos, M and Andrade, BB}, title = {Adjunct N-Acetylcysteine Treatment in Hospitalized Patients With HIV-Associated Tuberculosis Dampens the Oxidative Stress in Peripheral Blood: Results From the RIPENACTB Study Trial.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {602589}, pmid = {33613521}, issn = {1664-3224}, support = {U01 AI069923/AI/NIAID NIH HHS/United States ; U01 AI115940/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Female ; *HIV Infections/blood/complications/drug therapy ; *HIV-1 ; *Hospitalization ; Humans ; Lipid Peroxidation/*drug effects ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; *Tuberculosis/blood/drug therapy/etiology ; }, abstract = {Tuberculosis (TB) still causes significant morbidity and mortality worldwide, especially in persons living with human immunodeficiency virus (HIV). This disease is hallmarked by persistent oxidative stress and systemic inflammation. N-acetylcysteine (NAC), a glutathione (GSH) precursor, has been shown in experimental models to limit Mycobacterium tuberculosis infection and disease both by suppression of the host oxidative response and through direct antimicrobial activity. In a recent phase II randomized clinical trial (RIPENACTB study), use of NAC as adjunct therapy during the first two months of anti-TB treatment was safe. Whether adjunct NAC therapy of patients with TB-HIV coinfection in the context of anti-TB treatment could directly affect pro-oxidation and systemic inflammation has not been yet formally demonstrated. To test this hypothesis, we leveraged existing data and biospecimens from the RIPENACTB trial to measure a number of surrogate markers of oxidative stress and of immune activation in peripheral blood of the participants at pre-treatment and at the day 60 of anti-TB treatment. Upon initiation of therapy, we found that the group of patients undertaking NAC exhibited significant increase in GSH levels and in total antioxidant status while displaying substantial reduction in lipid peroxidation compared to the control group. Only small changes in plasma concentrations of cytokines were noted. Pharmacological improvement of the host antioxidant status appears to be a reasonable strategy to reduce TB-associated immunopathology.}, }
@article {pmid33610806, year = {2021}, author = {Seol, D and Coleman, MC and Martin, JA and Song, I and Jaidev, LR and Salem, AK and Lim, TH}, title = {Targeting oxidative stress with amobarbital to prevent intervertebral disc degeneration: Part I. in vitro and ex vivo studies.}, journal = {The spine journal : official journal of the North American Spine Society}, volume = {21}, number = {6}, pages = {1021-1030}, doi = {10.1016/j.spinee.2021.02.008}, pmid = {33610806}, issn = {1878-1632}, support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; }, mesh = {Amobarbital/metabolism ; Apoptosis ; Humans ; *Intervertebral Disc/metabolism ; *Intervertebral Disc Degeneration/drug therapy/metabolism/prevention &amp; control ; *Nucleus Pulposus ; Oxidative Stress ; *Pharmaceutical Preparations/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Mounting evidence that oxidative stress contributes to the pathogenesis of intervertebral disc (IVD) degeneration (IDD) suggests that therapies targeting oxidative stress may slow or prevent disease progression.<br><br>PURPOSE: The objective of this study was to investigate the inhibitory effects of amobarbital (Amo) on the mitochondria of nucleus pulposus (NP) cells under tert-butyl hydrogen peroxide (tBHP)-induced oxidative stress or in NP tissues under oxidative stress from tissue injury as a means of identifying therapeutic targets for IDD.<br><br>STUDY DESIGN/SETTING: We tested the effects inhibiting mitochondria, a major source of oxidants, with Amo in NP cells subjected to two different forms of insult: exposure to tBHP, and physical injury induced by disc transection. N-acetylcysteine (NAC), an antioxidant known to protect NP cells, was compared to the complex I inhibitor, Amo.<br><br>METHODS: NP cells were pre-treated for 2 hours with Amo, NAC, or both, and then exposed to tBHP for 1 hour. Apoptosis, necrosis, and reactive oxygen species (ROS) production were assessed using confocal microscopy and fluorescent probes (Annexin V, propidium iodide, and MitoSox Red, respectively). The activation of mitogen-activated protein kinases (MAPKs) involved in oxidative stress responses were interrogated by confocal imaging of immunofluorescence stains using phospho-specific antibodies to extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38. Mitochondrial function was assessed by imaging JC-1 staining, a probe for membrane potential.<br><br>RESULTS: Amo was modestly more protective than NAC by some measures, while both agents improved mitochondrial function and lowered tBHP-induced apoptosis, necrosis, and ROS production. Activation of MAPK by tBHP was significantly suppressed by both drugs. Physically injured IVDs were treated immediately after transection with Amo or NAC for 24 hours, and then stained with dihydroethidium (DHE), a fluorescent probe for ROS production. Immunofluorescence was used to track the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor that induces the expression of antioxidant genes. Amo and NAC significantly reduced ROS production and increased Nrf2 expression.<br><br>CONCLUSION: These findings suggest that the progression of IDD may be forestalled by Amo via protection of NP cells from oxidative stress following IVD injury.<br><br>CLINICAL SIGNIFICANCE: This study will define the extent to which a novel, minimally invasive procedure targeting oxidative stress in NP cells can augment surgical interventions intended to retard IVD degeneration.}, }
@article {pmid33610567, year = {2021}, author = {Malkawi, A and Kennedy, R and Asim, MH and Arshad, S}, title = {WITHDRAWN: Self-Emulsifying Drug Delivery Systems: Mucolytic Action of N-acetylcysteine (NAC)-Polymer Hydrophobic Complexes for Effective Mucopermeation.}, journal = {Journal of pharmaceutical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.xphs.2021.02.010}, pmid = {33610567}, issn = {1520-6017}, }
@article {pmid33610032, year = {2021}, author = {Zhong, G and Wan, F and Ning, Z and Wu, S and Jiang, X and Tang, Z and Huang, R and Hu, L}, title = {The protective role of autophagy against arsenic trioxide-induced cytotoxicity and ROS-dependent pyroptosis in NCTC-1469 cells.}, journal = {Journal of inorganic biochemistry}, volume = {217}, number = {}, pages = {111396}, doi = {10.1016/j.jinorgbio.2021.111396}, pmid = {33610032}, issn = {1873-3344}, mesh = {Animals ; Mice ; *Arsenic Trioxide/toxicity ; *Autophagy/drug effects/physiology ; Cell Line ; Cell Survival/drug effects ; *Pyroptosis/drug effects/physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Arsenic trioxide (As2O3) is widely used in traditional Chinese medicine to treat tumors. This study investigated the effect of As(III) on pyroptosis in murine hepatocytes in vitro and how this relates to autophagy. NCTC1469-cells were treated with As(III) alone (6, 12 and 18 μM) or in combination with N-acetylcysteine (NAC,1 mM), 3-methyladenine (3-MA, 5 mM) or rapamycin (Rapa,100 nM) for 24 h. The results showed that As(III)-treatment reduced cell viability in a dose-dependent manner, but induced lactic dehydrogenase (LDH) activity. As(III)-treatment also resulted in increased intracellular reactive oxygen species (ROS) levels and decreased mitochondrial membrane potential (MMP), therefore promoting pyroptosis. Moreover, As(III)-treatment upregulated the expression of autophagy and pyroptosis-related genes (LC3-A, LC3-B, P62, Beclin-1, Atg5, Caspase-1, Gasdermin D, IL-18, IL-1β) and downregulated the expression of m-TOR, NLRP3, ASC genes. Meanwhile the accumulation of light chain 3-B/A (LC3B/LC3A), autophagy-related gene 5 (Atg-5), Bcl-2-interacting protein (Beclin-1), Caspase-1, Gasdermin D, interleukin-1β (IL-1β), IL-18 and poptosis-associated speck-like protein (ASC) proteins were upregulated while nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) was downregulated in all As(III)-treatment groups. Furthermore, the inhibition of autophagy by 3-MA aggravated AsIII-induced pyroptosis and cytotoxicity. However, NAC or Rapa markedly alleviated the abovementioned phenomenon under As(III) stress. In addition, we speculate that the protective mechanism of NAC on As(III)-induced pyroptosis in hepatocytes mainly include the elimination of ROS because of the chelation of As(III) in the culture medium. In conclusion, these results provide new insight into the mechanisms underlying AsIII-induced cytotoxicity and pyroptosis in hepatocytes in vitro.}, }
@article {pmid33608902, year = {2021}, author = {Zuo, XS and Liu, Y and Cai, X and Zhan, L and Hu, K}, title = {Association of different Candida species with catheter-related candidemia, and the potential antifungal treatments against their adhesion properties and biofilm-forming capabilities.}, journal = {Journal of clinical laboratory analysis}, volume = {35}, number = {4}, pages = {e23738}, pmid = {33608902}, issn = {1098-2825}, support = {2020YFC0845100//National Key Research and Development Plan for the Emergency Management of Novel Coronavirus Pneumonia/ ; 81801959//National Science Foundation of China/ ; }, mesh = {Antifungal Agents/*pharmacology ; Biofilms/drug effects ; *Candida/drug effects/pathogenicity/physiology ; Candidemia/*microbiology ; Catheter-Related Infections/*microbiology ; Cell Adhesion/*drug effects ; Humans ; }, abstract = {BACKGROUND: To compare the adhesion properties and biofilm-forming capabilities of 27 Candida isolates obtained from catheter-related candidemia patients and to evaluate the inhibitory effects of antifungal agents on different Candida species.<br><br>MATERIAL AND METHODS: Seven C.&#xa0;albicans, six C.&#xa0;parapsilosis, five C.&#xa0;guilliermondii, five C.&#xa0;tropicalis, and four C.&#xa0;glabrata clinical isolates were investigated. We quantified the adherence of these Candida species by flow cytometric method and evaluated the formation of biofilms by XTT reduction and crystal violet methods. Actions of micafungin (MF), fluconazole (FZ), and N-acetylcysteine (NAC) on the adhesion and biofilm formation of different Candida species were determined.<br><br>RESULTS: Non-albicans Candida species were demonstrated to have stronger adhesion abilities compared with C.&#xa0;albicans. The biofilm-forming capabilities of different Candida species were varied considerably, and the degree of biofilm formation might be affected by different assay approaches. Interestingly, C.&#xa0;parapsilosis displayed the highest biofilm formation abilities, while C.&#xa0;glabrata exhibited the lowest total biomass and metabolic activity. Furthermore, the inhibitory activities of MF, FZ, and NAC on fungal adhesion and biofilm formation were evaluated, and the results indicated that MF could reduce the adhesion ability and biofilm metabolism more significantly (p&#xa0;<&#xa0;0.05), and its antifungal activity was elevated in a dose-dependent manner.<br><br>CONCLUSION: Non-albicans Candida species, especially C.&#xa0;guilliermondii, C.&#xa0;tropicalis, and C.&#xa0;parapsilosis, exhibited higher adhesion ability in catheter-related candidemia patients. However, these Candida species had varied biofilm-forming capabilities. MF tended to have stronger inhibitory effects against both adhesion and biofilm formation of different Candida species.}, }
@article {pmid33607929, year = {2021}, author = {Bourgonje, AR and Offringa, AK and van Eijk, LE and Abdulle, AE and Hillebrands, JL and van der Voort, PHJ and van Goor, H and van Hezik, EJ}, title = {N-Acetylcysteine and Hydrogen Sulfide in Coronavirus Disease 2019.}, journal = {Antioxidants &amp; redox signaling}, volume = {35}, number = {14}, pages = {1207-1225}, doi = {10.1089/ars.2020.8247}, pmid = {33607929}, issn = {1557-7716}, mesh = {Acetylcysteine/*metabolism ; COVID-19/*metabolism ; Humans ; Hydrogen Sulfide/*metabolism ; Oxidation-Reduction ; }, abstract = {Significance: Hydrogen sulfide (H2S) is one of the three main gasotransmitters that are endogenously produced in humans and are protective against oxidative stress. Recent findings from studies focusing on coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shifted our attention to a potentially modulatory role of H2S in this viral respiratory disease. Recent Advances: H2S levels at hospital admission may be of importance since this gasotransmitter has been shown to be protective against lung damage through its antiviral, antioxidant, and anti-inflammatory actions. Furthermore, many COVID-19 cases have been described demonstrating remarkable clinical improvement upon administration of high doses of N-acetylcysteine (NAC). NAC is a renowned pharmacological antioxidant substance acting as a source of cysteine, thereby promoting endogenous glutathione (GSH) biosynthesis as well as generation of sulfane sulfur species when desulfurated to H2S. Critical Issues: Combining H2S physiology and currently available knowledge of COVID-19, H2S is hypothesized to target three main vulnerabilities of SARS-CoV-2: (i) cell entry through interfering with functional host receptors, (ii) viral replication through acting on RNA-dependent RNA polymerase (RdRp), and (iii) the escalation of inflammation to a potentially lethal hyperinflammatory cytokine storm (toll-like receptor 4 [TLR4] pathway and NLR family pyrin domain containing 3 [NLRP3] inflammasome). Future Directions: Dissecting the breakdown of NAC reveals the possibility of increasing endogenous H2S levels, which may provide a convenient rationale for the application of H2S-targeted therapeutics. Further randomized-controlled trials are warranted to investigate its definitive role.}, }
@article {pmid33601156, year = {2021}, author = {Chin, S and Lin, XX and Santarra, B and Gruenhagen, JA and Yehl, P and Chen, T}, title = {Multiplexed small molecule impurity monitoring in antibody-based therapeutics by mixed-mode chromatography paired with charged aerosol detection.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {197}, number = {}, pages = {113952}, doi = {10.1016/j.jpba.2021.113952}, pmid = {33601156}, issn = {1873-264X}, mesh = {Aerosols ; *Antibodies ; Chromatography, High Pressure Liquid ; *Chromatography, Reverse-Phase ; Hydrophobic and Hydrophilic Interactions ; }, abstract = {With advanced genetic engineering technologies and better understanding of disease biology, antibody-based therapeutics are emerging as promising new generation biopharmaceuticals. These novel antibody formats are carefully designed to possess desired features such as enhanced selectivity. However, their high level of structural complexity with multiple components often leads to long development and complex multi-step manufacturing processes, through which a variety of potential small molecule impurities can be introduced. In this work, an in-process assay was developed in which mixed-mode chromatography coupled with charged aerosol detection was utilized for multiplexed detection of nine reagents commonly used in development and manufacturing of antibody-based therapeutics: isopropyl β-d-1-thiogalactopyranoside, methionine sulfoximine, ampicillin, guanidine, dehydroascorbic acid, glutathione, tris(2-carboxyethyl)phosphine, N-acetyl cysteine, and arginine. This method utilized a mixed-mode column with ion-exchange properties operated in the hydrophilic interaction chromatography mode. Various parameters were systematically optimized and under optimal conditions, the method demonstrated excellent specificity, sensitivity, linearity, precision, accuracy, and was successfully applied to determine residual impurities in multiple samples from antibody-derived molecules.}, }
@article {pmid33599830, year = {2021}, author = {Su, AL and Lash, LH and Bergin, IL and Bjork, F and Loch-Caruso, R}, title = {N-Acetyl-L-cysteine and aminooxyacetic acid differentially modulate trichloroethylene reproductive toxicity via metabolism in Wistar rats.}, journal = {Archives of toxicology}, volume = {95}, number = {4}, pages = {1303-1321}, pmid = {33599830}, issn = {1432-0738}, support = {P42 ES017198/ES/NIEHS NIH HHS/United States ; T32 HD079342/HD/NICHD NIH HHS/United States ; P30 ES017885/ES/NIEHS NIH HHS/United States ; T32 ES007062/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aminooxyacetic Acid/*pharmacology ; Animals ; Enzyme Inhibitors/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Male ; Oxidative Stress/drug effects ; Placenta/drug effects ; Pregnancy ; Pregnancy Outcome ; Rats ; Rats, Wistar ; Reproduction/*drug effects ; Solvents/metabolism/toxicity ; Trichloroethylene/metabolism/*toxicity ; }, abstract = {Exposure to the industrial solvent trichloroethylene (TCE) has been associated with adverse pregnancy outcomes in humans and decreased fetal weight in rats. TCE kidney toxicity can occur through formation of reactive metabolites via its glutathione (GSH) conjugation metabolic pathway, largely unstudied in the context of pregnancy. To investigate the contribution of the GSH conjugation pathway and oxidative stress to TCE toxicity during pregnancy, we exposed rats orally to 480 mg TCE/kg/day from gestational day (GD) 6 to GD 16 with and without N-acetyl-L-cysteine (NAC) at 200 mg/kg/day or aminooxyacetic acid (AOAA) at 20 mg/kg/day as pre/co-treatments from GD 5-16. NAC is a reactive oxygen species scavenger that modifies the GSH conjugation pathway, and AOAA is an inhibitor of cysteine conjugate β-lyase (CCBL) in the GSH conjugation pathway. TCE decreased fetal weight, and this was prevented by AOAA but not NAC pre/co-treatment to TCE. Although AOAA inhibited CCBL activity in maternal kidney, it did not inhibit CCBL activity in maternal liver and placenta, suggesting that AOAA prevention of TCE-induced decreased fetal weight was due to CCBL activity inhibition in the kidneys but not liver or placenta. Unexpectedly, NAC pre/co-treatment with TCE, relative to TCE treatment alone, altered placental morphology consistent with delayed developmental phenotype. Immunohistochemical staining revealed that the decidua basale, relative to basal and labyrinth zones, expressed the highest abundance of CCBL1, flavin-containing monooxygenase 3, and cleaved caspase-3. Together, the findings show the differential effects of NAC and AOAA on TCE-induced pregnancy outcomes are likely attributable to TCE metabolism modulation.}, }
@article {pmid33596748, year = {2021}, author = {Yalçın, A and Gürel, A}, title = {Effects of N-acetylcysteine on kidney tissue, matrix metalloproteinase-2, irisin and oxidative stress in a diabetes mellitus model.}, journal = {Biotechnic &amp; histochemistry : official publication of the Biological Stain Commission}, volume = {96}, number = {8}, pages = {616-622}, doi = {10.1080/10520295.2021.1883738}, pmid = {33596748}, issn = {1473-7760}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; *Diabetes Mellitus, Experimental/drug therapy ; Kidney ; Matrix Metalloproteinase 2 ; Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {DM mellitus (DM) is a prevalent chronic disease; diabetic nephropathy (DN) is a primary cause of chronic kidney disease. Oxidation, energy imbalance, and enzyme and cytokine changes contribute to the development and progression of DN. We investigated the possible effects of the antioxidant, N-acetylcysteine (NAC), on kidney morphology, apoptosis, matrix metalloproteinase-2 (MMP2) activity, irisin levels and oxidative stress in an experimental DM model. We used four equal groups of Wistar albino male rats: control, DM, DM + NAC and NAC. Kidney tissues were evaluated for oxidation state, MMP-2, irisin, caspase-3 and histopathology. In the DM group, total oxidant status level, MMP-2 and caspase-3 immunoreactivity were increased, irisin immunoreactivity and total antioxidant status (TAS) were decreased and histological damage was evident. In the DM + NAC group, all changes were significantly improved. NAC exhibited protective effects against DN.}, }
@article {pmid33592258, year = {2021}, author = {Zhang, ZD and Yang, YJ and Liu, XW and Qin, Z and Li, SH and Li, JY}, title = {Aspirin eugenol ester ameliorates paraquat-induced oxidative damage through ROS/p38-MAPK-mediated mitochondrial apoptosis pathway.}, journal = {Toxicology}, volume = {453}, number = {}, pages = {152721}, doi = {10.1016/j.tox.2021.152721}, pmid = {33592258}, issn = {1879-3185}, mesh = {A549 Cells ; Animals ; Apoptosis/drug effects/physiology ; Aspirin/*analogs &amp; derivatives/pharmacology ; Cell Survival/drug effects/physiology ; Eugenol/*analogs &amp; derivatives/pharmacology ; Herbicides/toxicity ; Humans ; Male ; Mitochondria/*drug effects/metabolism ; Oxidative Stress/*drug effects/physiology ; Paraquat/*toxicity ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects/physiology ; p38 Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Paraquat (PQ) is an effective and commercially important herbicide that is widely used worldwide. However, PQ is highly toxic and can cause various complications and acute organ damage. Aspirin eugenol ester (AEE) is a potential new compound with anti-inflammatory and antioxidant stress pharmacological activity. The present study was to reveal the therapeutic effects and the protective effect of AEE against PQ-induced acute lung injury (ALI) with the help of PQ-induced oxidative damage in A549 cells and PQ-induced lung injury in rats. AEE might have no significant therapeutic effect on PQ-induced lung injury in rats. However, AEE had a significant protective effect on PQ-induced lung injury in rats. AEE pretreatment significantly reduced the stimulatory effect of PQ on malondialdehyde (MDA), the inhibitory effect of PQ on catalase (CAT) activity, superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, the ratio of GSH/GSSH, the activity of caspase-3 and the overexpression of p38 mitogen-activated protein kinase (MAPK) phosphorylation in vivo. In vitro, A549 cells were treated with 250 μM PQ for 24 h. Incubation of A549 cells with PQ led to apoptosis, and increased the level of superoxide anions, reactive oxygen species (ROS), malondialdehyde and the activity of caspase-3 and up-regulation of phosphorylated p38-MAPK, reduced mitochondrial membrane potential (ΔΨm) and the activity of SOD. However, after 24 h on AEE pretreatment of A549 cells, the above-mentioned adverse reactions caused by PQ were significantly alleviated. In addition, AEE pretreatment reduced p38-MAPK phosphorylation in PQ-treated A549 cells. SB203580, the specific p38-MAPK inhibitor, and p38-MAPK shRNA attenuated the activation of the p38-MAPK signaling pathway. N-acetylcysteine (NAC) reduced the level of phosphorylated p38-MAPK and the production of intracellular ROS and inhibited apoptosis. The results showed that AEE may inhibit PQ-induced cell damage through ROS/p38-MAPK-mediated mitochondrial apoptosis pathway.}, }
@article {pmid33586210, year = {2021}, author = {Silva, RCP and da Silva, RPC and Souto, FO and de Lorena, VMB and Aires, AL and Costa, VMA and Albuquerque, MCPA and de Souza, VMO}, title = {Extract from Ascaris suum and N-acetyl-L-cysteine induces an immunosuppressant effect in model of autoimmune hepatitis.}, journal = {Parasite immunology}, volume = {43}, number = {6}, pages = {e12826}, doi = {10.1111/pim.12826}, pmid = {33586210}, issn = {1365-3024}, mesh = {Acetylcysteine ; Animals ; *Ascaris suum ; *Hepatitis, Autoimmune/drug therapy ; Immunosuppressive Agents ; Mice ; Mice, Inbred BALB C ; Plant Extracts ; T-Lymphocytes, Regulatory ; }, abstract = {BACKGROUND: Extract of adult Ascaris suum (ASC) worms attenuated the liver damage in experimental autoimmune hepatitis (EAH) with induction of Th2 immune response, but fibrosis occurred. N-acetyl-L-cysteine (NAC) has protective effects against liver fibrosis.<br><br>OBJECTIVES: Evaluate the association ASC&#xa0;+&#xa0;NAC on the T- and B-cell activation, inflammation and fibrogenic markers in the liver in EAH.<br><br>METHODS: Experimental autoimmune hepatitis was induced intravenously with concanavalin A in BALB/c mice. EAH&#xa0;+&#xa0;ASC+NAC group received NAC and ASC; EAH&#xa0;+&#xa0;ASC group received ASC;&#xa0;EAH group received PBS. Doubly labelled CD4[+] T (CD28, CTLA-4, CD40L or IL-10) and CD45R[+] B lymphocytes (IL-10) and CD4[+] CD25[+] FoxP3[+] cells were evaluated, along with gene expression of Col1a1, &#x3b1;-SMA, Fizz1, Arg1 and PPAR-&#x3b3; and histomorphometry.<br><br>RESULTS: Experimental autoimmune hepatitis group showed high frequency of CD28[+] and CD40L[+] &#xa0;T lymphocytes, but&#xa0;not the EAH&#xa0;+&#xa0;ASC group. In relation to EAH group, the Fizz1&#xa0;expression was lower&#xa0;in both groups treated, but Arg1&#xa0;expression&#xa0;was lower in only EAH&#xa0;+&#xa0;ASC+NAC group. In the EAH&#xa0;+&#xa0;ASC+NAC&#xa0;group, there were higher frequencies of&#xa0;CD4[+] IL-10[+] and&#xa0;CD4[+] CD25[+] FoxP3[+] cells,&#xa0;but not CD45R[+] IL-10[+] , along with&#xa0;mitigated inflammation and collagen production.<br><br>CONCLUSIONS: Ascaris suum favoured immunosuppression in EAH&#xa0;limiting the T cells activation. However, association ASC and NAC was necessary for&#xa0;attenuating the inflammatory process and&#xa0;collagen production.}, }
@article {pmid33576880, year = {2021}, author = {Sauvage, J and Wikfors, GH and Li, X and Gluis, M and Nevejan, N and Sabbe, K and Joyce, A}, title = {Effect of pluronic block polymers and N-acetylcysteine culture media additives on growth rate and fatty acid composition of six marine microalgae species.}, journal = {Applied microbiology and biotechnology}, volume = {105}, number = {5}, pages = {2139-2156}, pmid = {33576880}, issn = {1432-0614}, support = {(Joyce 2018-05932)//Medicinska Forskningsr&#xe5;det (SE)/ ; }, mesh = {Acetylcysteine ; Biomass ; Culture Media ; Fatty Acids ; *Microalgae ; Poloxamer ; Polymers ; }, abstract = {The efficiency of microalgal biomass production is a determining factor for the economic competitiveness of microalgae-based industries. N-acetylcysteine (NAC) and pluronic block polymers are two compounds of interest as novel culture media constituents because of their respective protective properties against oxidative stress and shear-stress-induced cell damage. Here we quantify the effect of NAC and two pluronic (F127 and F68) culture media additives upon the culture productivity of six marine microalgal species of relevance to the aquaculture industry (four diatoms-Chaetoceros calcitrans, Chaetoceros muelleri, Skeletonema costatum, and Thalassiosira pseudonana; two haptophytes-Tisochrysis lutea and Pavlova salina). Algal culture performance in response to the addition of NAC and pluronic, singly or combined, is dosage- and species-dependent. Combined NAC and pluronic F127 algal culture media additives resulted in specific growth rate increases of 38%, 16%, and 24% for C. calcitrans, C. muelleri, and P. salina, respectively. Enhanced culture productivity for strains belonging to the genus Chaetoceros was paired with an ~27% increase in stationary-phase cell density. For some of the species examined, culture media enrichments with NAC and pluronic resulted in increased omega-3-fatty acid content of the algal biomass. Larval development (i.e., growth and survival) of the Pacific oyster (Crassostrea gigas) was not changed when fed a mixture of microalgae grown in NAC- and F127-supplemented culture medium. Based upon these results, we propose that culture media enrichment with NAC and pluronic F127 is an effective and easily adopted approach to increase algal productivity and enhance the nutritional quality of marine microalgal strains commonly cultured for live-feed applications in aquaculture. KEY POINTS: • Single and combined NAC and pluronic F127 culture media supplementation significantly enhanced the productivity of Chaetoceros calcitrans and Chaetoceros muelleri cultures. • Culture media enrichments with NAC and F127 can increase omega-3-fatty acid content of algal biomass. • Microalgae grown in NAC- and pluronic F127-supplemented culture media are suitable for live-feed applications.}, }
@article {pmid33570605, year = {2021}, author = {Ding, R and Qian, Y and Chen, M and Yi, J and Zhao, Z}, title = {The effect of N-acetylcysteine on the antibacterial capability and biocompatibility of nano silver-containing orthodontic cement.}, journal = {The Angle orthodontist}, volume = {91}, number = {4}, pages = {515-521}, pmid = {33570605}, issn = {1945-7103}, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/pharmacology ; Biofilms ; *Dental Bonding ; Dental Cements ; Glass Ionomer Cements/pharmacology ; Materials Testing ; *Orthodontic Brackets ; Resin Cements ; Shear Strength ; }, abstract = {OBJECTIVES: To determine whether the incorporation of N-acetylcysteine (NAC) improves the antibacterial ability and biocompatibility of nano silver (NAg)-containing orthodontic cement.<br><br>MATERIALS AND METHODS: NAg was synthesized using a sodium citrate reduction method. NAg particles were characterized using transmission electron microscopy and ultraviolet-visible absorption spectra. NAg and NAC were incorporated into a resin-modified glass ionomer cement. Enamel shear bond strength (SBS), antibacterial capability, and cytotoxicity were evaluated.<br><br>RESULTS: Incorporating 0.15% NAg and 20% NAC had no adverse effect on the SBS of orthodontic cement (P > .1). Adding NAC into NAg-containing cement greatly reduced the biofilm metabolic activity and lactic acid production (P < .05) and lowered the colony unit-forming counts by approximately 1 log (P < .05). The cell viability against NAg-containing cement was improved by NAC (P < .05).<br><br>CONCLUSIONS: The incorporation of NAC into NAg-containing cement achieved stronger antibacterial capability and better biocompatibility, without compromising the enamel SBS. The combined use of NAC and NAg is promising to combat caries in orthodontic practice.}, }
@article {pmid33564104, year = {2021}, author = {Maas, DA and Eijsink, VD and van Hulten, JA and Panic, R and De Weerd, P and Homberg, JR and Vallès, A and Nait-Oumesmar, B and Martens, GJM}, title = {Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {46}, number = {6}, pages = {1161-1171}, pmid = {33564104}, issn = {1740-634X}, mesh = {Animals ; Antioxidants/pharmacology ; Cognition ; *Cognitive Dysfunction/drug therapy/etiology ; Prefrontal Cortex ; Rats ; *Schizophrenia/complications/drug therapy ; }, abstract = {Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5-90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.}, }
@article {pmid33563887, year = {2021}, author = {Wang, H and Lu, H and Wu, Y}, title = {Knockdown of Dual Oxidase 1 (DUOX1) Promotes Wound Healing by Regulating Reactive Oxygen Species (ROS) by Activation of Nuclear Kactor kappa B (NF-κB) Signaling.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {27}, number = {}, pages = {e926492}, pmid = {33563887}, issn = {1643-3750}, mesh = {Acetylcysteine/pharmacology ; Adult ; Apoptosis/drug effects/physiology ; Cell Proliferation/drug effects/physiology ; Cells, Cultured ; Dual Oxidases/genetics/*metabolism ; Female ; Fibroblasts ; Gene Knockdown Techniques ; Humans ; Male ; Malondialdehyde/metabolism ; NF-kappa B/*metabolism ; Oxidative Stress/drug effects/physiology ; Primary Cell Culture ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Signal Transduction/drug effects/physiology ; Superoxide Dismutase/metabolism ; Wound Healing/drug effects/*physiology ; }, abstract = {BACKGROUND The aim of this study was to evaluate the potential role of dual oxidase 1 (DUOX1) in wound healing. MATERIAL AND METHODS Primary fibroblasts were isolated from wound granulation tissue. Fibroblasts cell lines were established using DUOX1 overexpression and interference. Cell proliferation and reactive oxygen species (ROS) production were measured and compared among the groups. RESULTS DUOX1 expression was highest in the slow-healing tissues (P<0.05). Knockdown of DUOX1 significantly increased cell proliferation and inhibited ROS production and cell apoptosis (P<0.01). Moreover, expression of malondialdehyde (MDA) was significantly reduced, while expression of superoxide dismutase (SOD) expression was significantly increased (P<0.01). In addition, DUOX1 silencing significantly upregulated collagen I, collagen III, and NF-kappaB protein levels in the cytoplasm, and inhibited the protein levels of P21, P16, and NF-kappaB in the nucleus (P<0.01). Overexpression of DUOX1 caused a reverse reaction mediated by knockdown of DUOX1. When DUOX1-overexpressing cells were treated with the ROS inhibitor N-acetyl-L-cysteine (NAC), the protein levels that were increased by DUOX1 overexpression were reversed. CONCLUSIONS These results suggest that knockdown of DUOX1 significantly benefits wound healing, likely by the regulation of oxidative stress via NF-kappaB pathway activation.}, }
@article {pmid33560443, year = {2021}, author = {Mohiuddin, M and Pivetta, B and Gilron, I and Khan, JS}, title = {Efficacy and Safety of N-Acetylcysteine for the Management of Chronic Pain in Adults: A Systematic Review and Meta-Analysis.}, journal = {Pain medicine (Malden, Mass.)}, volume = {22}, number = {12}, pages = {2896-2907}, doi = {10.1093/pm/pnab042}, pmid = {33560443}, issn = {1526-4637}, mesh = {Acetylcysteine/therapeutic use ; Adolescent ; *Chronic Pain/drug therapy ; Female ; Humans ; *Neuralgia ; Pain Measurement ; }, abstract = {OBJECTIVE: To assess the efficacy and safety of N-acetylcysteine in the treatment of chronic pain.<br><br>METHODS: A systematic search was carried out until April 2020 for clinical studies of N-acetylcysteine in the management of any persistent or recurrent chronic pain condition for adults &#x2265; 18&#x2009;years old. Risk of bias was assessed using the validated risk of bias tools. When appropriate, a meta-analysis using a random-effects model was performed, with a fixed-effect model for sensitivity analysis.<br><br>RESULTS: Nine studies (n&#x2009;=&#x2009;863) were included (five randomized controlled trials [RCTs], two open-label non-comparative studies and two comparative studies), that evaluated patients with sickle cell disease (3), complex regional pain syndrome (1), pelvic pain/endometriosis (2), rheumatoid arthritis (1), diabetic neuropathy (1), and chronic neuropathic pain (1). In the pooled analysis of three RCTs, N-acetylcysteine did not reduce pain intensities (SMD -0.21, 95% confidence interval [CI]: -0.33 to 0.75, random-effects), improve functional outcomes (SMD 0.21, 95% CI -0.33 to 0.75) or quality of life (SMD 0.60, 95% CI: -4.44 to 5.64); however, sensitivity analysis with a fixed effect model demonstrated an effect for pain intensities and function. Due to adverse events being inconsistently reported, no conclusion could be made regarding safety of N-acetylcysteine in chronic pain.<br><br>CONCLUSIONS: While there is some evidence to indicate N-acetylcysteine may provide analgesic efficacy for certain pain conditions, there is insufficient evidence to provide definitive evidence on NAC in chronic pain management. Larger-size RCTs spanning a variety of chronic pain conditions are needed to determine N-acetylcysteine's role, if any, in pain medicine.}, }
@article {pmid33560023, year = {2021}, author = {Germann, M and Brederoo, SG and Sommer, IEC}, title = {Abnormal synaptic pruning during adolescence underlying the development of psychotic disorders.}, journal = {Current opinion in psychiatry}, volume = {34}, number = {3}, pages = {222-227}, pmid = {33560023}, issn = {1473-6578}, mesh = {Adolescent ; Cognition ; Humans ; Microglia ; *Neuronal Plasticity ; Psychotic Disorders/*pathology/*physiopathology ; Schizophrenia/*pathology/*physiopathology ; }, abstract = {PURPOSE OF REVIEW: Excessive synaptic pruning has first been suggested by Irwin Feinberg (1982) as an important pillar in the pathophysiology in schizophrenia (SCZ). This article reviews recent developments highlighting factors implicated in aberrant synaptic pruning and its contribution to disease onset and emergence of cognitive symptoms in SCZ. Unraveling these factors provides new insights for potential prevention and treatment strategies for psychotic disorders.<br><br>RECENT FINDINGS: Increased pruning in SCZ was recently confirmed by a positron emission tomography-study employing the novel tracer [11C]UCB-J, demonstrating the consequential loss of synaptic density. Recent evidence supports the contributing role of astrocytes and increased complement-mediated microglial pruning in disease onset and cognitive symptoms in SCZ. Increased microglial pruning is mediated specifically by C4. Furthermore, environmental factors (e.g., infections and stress) can lead to dysbiosis which was recently linked to microglial activation and pruning in SCZ.<br><br>SUMMARY: Recent findings render the pruning machinery a potential target for early treatment and prevention in individuals at high risk for SCZ. Minocycline can improve cognition in SCZ, probably by reducing excessive pruning. Probiotics might also have beneficial effects on cognition, although recent findings are not encouraging. N-acetyl-cysteine recovers functional connectivity in SCZ both in vitro and in vivo, making it an interesting candidate.}, }
@article {pmid33558775, year = {2020}, author = {Ersoy Çallıoğlu, E and Berçin, S and Başdemir, G and Kiriş, M and Tatar, &#x130; and Tuzuner, A and Oğuzhan, T and Müderris, T and Sargon, MF and Korkmaz, MH}, title = {The effect of N-acetyl cysteine on biofilm layers in an experimental model of chronic otitis media.}, journal = {Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale}, volume = {40}, number = {6}, pages = {457-462}, pmid = {33558775}, issn = {1827-675X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Biofilms ; Humans ; Models, Theoretical ; *Otitis Media/drug therapy ; *Otitis Media, Suppurative ; Rats ; }, abstract = {OBJECTIVE: The aim of this study was to investigate the efficacy of N-acetylcysteine (NAC) on biofilm layers and on the course of disease in chronic otitis media.<br><br>METHODS: Twenty-five rats that were induced with chronic otitis media (COM) were separated into three groups. In Group 1 (N = 18), 0.2% ciprofloxacin + 0.1% dexamethasone sodium phosphate + 0.5 mg/ml NAC solution was locally injected to the right ear of the rats; in Group 2, (N=18) 0.2% ciprofloxacin + 0.1% dexamethasone sodium phosphate was locally injected to the left ear of the rats. No treatment was applied to either ear of rats in Group 3 (N = 5). Histopathological and scanning electron microscope (SEM) evaluations were performed in all groups.<br><br>RESULTS: SEM revealed biofilm formation in all COM induced groups. No significant difference was seen between groups 1 and 2 in terms of suppuration levels, fibrosis, inner ear involvement, infection staging and biofilm formation (p > 0.05).<br><br>CONCLUSIONS: In this study, while histopathological and SEM evaluation revealed no effect of 0.5 mg/ml NAC on the biofilm layer in COM-induced rats, further studies with NAC at different concentrations are still needed on different types of experimental animals.}, }
@article {pmid33557356, year = {2021}, author = {Zou, ZV and Le Gal, K and El Zowalaty, AE and Pehlivanoglu, LE and Garellick, V and Gul, N and Ibrahim, MX and Bergh, PO and Henricsson, M and Wiel, C and Akyürek, LM and Bergo, MO and Sayin, VI and Lindahl, P}, title = {Antioxidants Promote Intestinal Tumor Progression in Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {2}, pages = {}, pmid = {33557356}, issn = {2076-3921}, support = {2018//Vetenskapsr&#xe5;det/ ; 2020//Swedish Cancer Foundation/ ; }, abstract = {Dietary antioxidants and supplements are widely used to protect against cancer, even though it is now clear that antioxidants can promote tumor progression by helping cancer cells to overcome barriers of oxidative stress. Although recent studies have, in great detail, explored the role of antioxidants in lung and skin tumors driven by RAS and RAF mutations, little is known about the impact of antioxidant supplementation on other cancers, including Wnt-driven tumors originating from the gut. Here, we show that supplementation with the antioxidants N-acetylcysteine (NAC) and vitamin E promotes intestinal tumor progression in the ApcMin mouse model for familial adenomatous polyposis, a hereditary form of colorectal cancer, driven by Wnt signaling. Both antioxidants increased tumor size in early neoplasias and tumor grades in more advanced lesions without any impact on tumor initiation. Importantly, NAC treatment accelerated tumor progression at plasma concentrations comparable to those obtained in human subjects after prescription doses of the drug. These results demonstrate that antioxidants play an important role in the progression of intestinal tumors, which may have implications for patients with or predisposed to colorectal cancer.}, }
@article {pmid33553365, year = {2021}, author = {Bai, L and Yu, E}, title = {A narrative review of risk factors and interventions for cancer-related cognitive impairment.}, journal = {Annals of translational medicine}, volume = {9}, number = {1}, pages = {72}, pmid = {33553365}, issn = {2305-5839}, abstract = {Cancer-related cognitive impairment (CRCI) refers to a series of cognitive impairment symptoms associated with alternations in brain structure and function, caused by a non-central nervous system malignant tumor and its related treatment. CRCI may present as memory loss, impaired concentration, difficulty in multitasking and word retrieval, and reduced comprehension speed. CRCI has become one of the prevalent factors that compromise the quality of life for cancer survivors. Different treatments, including surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted drugs, may contribute to CRCI. Meanwhile, patients' factors, including emotional challenges and genetic makeup, also contribute to the development of CRCI. The condition can be treated with using stimulants methylphenidate and modafinil, metabolites of nicotine: cotinine, antidepressants of fluoxetine and fluvoxamine, dementia drug of donepezil, and antioxidants ZnSO4, n-acetyl cysteine, propofol, and Chinese herbal of silver leaf medicine. Psychotherapies, including meditation and relaxation, cognitive rehabilitation training, along with physical therapies, including aerobic exercise, resistance training, balance training, yoga, qigong, tai chi electroencephalogram biofeedback, and acupuncture, are also beneficial in alleviating cancer-related cognitive impairment symptoms. In recent years, researchers have focused on factors related to the condition and on the available interventions. However, most research was conducted independently, and no review has yet summarized the latest findings. This review details and discusses the status of related factors and potential treatments for CRCI. We also supply specific recommendations to facilitate future research and integration in this field.}, }
@article {pmid33551189, year = {2021}, author = {Siemer, K and Husari, A and Vach, K and Tomakidi, P and Hellwig, E and Schulz, SD and Polydorou, O}, title = {N-Acetylcysteine modulates the effects of composites on human gingival keratinocytes.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {37}, number = {4}, pages = {597-611}, doi = {10.1016/j.dental.2021.01.011}, pmid = {33551189}, issn = {1879-0097}, mesh = {*Acetylcysteine/pharmacology ; Apoptosis ; Filaggrin Proteins ; *Gingiva ; Humans ; Keratinocytes ; Proteins ; }, abstract = {OBJECTIVE: The aim of this study was to evaluate, if antioxidants, like N-Acetylcysteine, can modulate effects of composite eluates on human gingival keratinocytes.<br><br>METHODS: Composite samples of ceram.x&#xae; universal, Filtek&#x2122; Supreme XTE, and Admira&#xae; Fusion were stored 72h in cell culture medium to prepare eluates, according to ISO 10993-12:2012. Human gingival keratinocytes were exposed to these eluates with or without 3mM N-Acetylcysteine. Following cell observation by iCELLigence&#xae;, exposure periods were determined at 1d and 4d. Cell morphological analysis combined with live/dead staining was performed. Tissue-specific biomarkers of terminal differentiation, Involucrin and Filaggrin, were analyzed by indirect immunofluorescence (IIF) and Western blot (WB). qPCR profiling was performed on genes encoding for: inflammation, apoptosis, turn-over of extracellular matrix, adhesion, proliferation and differentiation. For statistical analysis one-way Anova was used (p<0.05).<br><br>RESULTS: Cells exposed to N-Acetylcysteine exhibited morphological changes but no cell death. After adding 3mM N-Acetylcysteine to HGK cultures, increased fluorescence intensity and protein amounts of Involucrin and Filaggrin indicated enhanced differentiation (p<0.05). Gene expression was modulated by: (i) composition of the composite eluates, (ii) NAC and (iii) exposure time. Filtek&#x2122; Supreme XTE showed a significant increased gene expression in inflammatory genes (p<0.05), which was amplified by the addition of NAC at 1d. Concerning exposure time, modulated gene expression showed eluate dependency, substantiated by Filtek&#x2122; Supreme XTE modulation at day 1 and Admira&#xae; Fusion at day 4.<br><br>SIGNIFICANCE: N-Acetylcysteine-emerging effects on gingival keratinocytes were threefold: (i) increase of differentiation, (ii) modulation of composite-related effects and (iii) in parts counteraction of eluate-induced effects.}, }
@article {pmid33545736, year = {2021}, author = {Ya, F and Li, K and Chen, H and Tian, Z and Fan, D and Shi, Y and Song, F and Xu, X and Ling, W and Adili, R and Yang, Y}, title = {Protocatechuic Acid Protects Platelets from Apoptosis via Inhibiting Oxidative Stress-Mediated PI3K/Akt/GSK3β Signaling.}, journal = {Thrombosis and haemostasis}, volume = {121}, number = {7}, pages = {931-943}, doi = {10.1055/s-0040-1722621}, pmid = {33545736}, issn = {2567-689X}, support = {Guangzhou Science, Technology, and Innovation Commission//201804020045/ ; Key Project of National Natural Science Foundation of China//81730090/ ; Key Project of National Natural Science Foundation of China//82030098/ ; National Natural Science Foundation of China//81872617/ ; Shenzhen Science and Technology Innovation Commission//201803073000433/ ; }, mesh = {Animals ; Apoptosis/*drug effects ; Blood Platelets/metabolism ; Calcium/metabolism ; Cardiovascular Diseases/*metabolism ; Catalase/metabolism ; Glycogen Synthase Kinase 3 beta/*metabolism ; Humans ; Hydrogen Peroxide ; Hydroxybenzoates/*metabolism ; Membrane Potential, Mitochondrial/*drug effects ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; Phosphatidylinositol 3-Kinases/*metabolism ; Platelet Activation ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species ; Signal Transduction ; }, abstract = {Oxidative stress plays crucial roles in initiating platelet apoptosis that facilitates the progression of cardiovascular diseases (CVDs). Protocatechuic acid (PCA), a major metabolite of anthocyanin cyanidin-3-O-β-glucoside (Cy-3-g), exerts cardioprotective effects. However, underlying mechanisms responsible for such effects remain unclear. Here, we investigate the effect of PCA on platelet apoptosis and the underlying mechanisms in vitro. Isolated human platelets were treated with hydrogen peroxide (H2O2) to induce apoptosis with or without pretreatment with PCA. We found that PCA dose-dependently inhibited H2O2-induced platelet apoptosis by decreasing the dissipation of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and decreasing phosphatidylserine exposure. Additionally, the distributions of Bax, Bcl-xL, and cytochrome c mediated by H2O2 in the mitochondria and the cytosol were also modulated by PCA treatment. Moreover, the inhibitory effects of PCA on platelet caspase-3 cleavage and phosphatidylserine exposure were mainly mediated by downregulating PI3K/Akt/GSK3β signaling. Furthermore, PCA dose-dependently decreased reactive oxygen species (ROS) generation and the intracellular Ca[2+] concentration in platelets in response to H2O2. N-Acetyl cysteine (NAC), a ROS scavenger, markedly abolished H2O2-stimulated PI3K/Akt/GSK3β signaling, caspase-3 activation, and phosphatidylserine exposure. The combination of NAC and PCA did not show significant additive inhibitory effects on PI3K/Akt/GSK3β signaling and platelet apoptosis. Thus, our results suggest that PCA protects platelets from oxidative stress-induced apoptosis through downregulating ROS-mediated PI3K/Akt/GSK3β signaling, which may be responsible for cardioprotective roles of PCA in CVDs.}, }
@article {pmid33545117, year = {2021}, author = {Paganini, C and Gramegna Tota, C and Monti, L and Monti, I and Maurizi, A and Capulli, M and Bourmaud, M and Teti, A and Cohen-Solal, M and Villani, S and Forlino, A and Superti-Furga, A and Rossi, A}, title = {Improvement of the skeletal phenotype in a mouse model of diastrophic dysplasia after postnatal treatment with N-acetylcysteine.}, journal = {Biochemical pharmacology}, volume = {185}, number = {}, pages = {114452}, doi = {10.1016/j.bcp.2021.114452}, pmid = {33545117}, issn = {1873-2968}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics ; Animals ; Animals, Newborn ; Bone Density/*drug effects/physiology ; *Disease Models, Animal ; Dwarfism/diagnostic imaging/*drug therapy/*metabolism ; Free Radical Scavengers/administration &amp; dosage/pharmacokinetics ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Transgenic ; *Phenotype ; }, abstract = {Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in the SLC26A2 gene encoding for a sulfate/chloride transporter. When SLC26A2 is impaired intracellular level of sulfate is reduced leading to the synthesis of undersulfated proteoglycans. In normal chondrocytes, the main source of intracellular sulfate is the extracellular uptake through SLC26A2, but a small amount comes from the catabolism of sulfur-containing amino acids and other thiols. Here N-acetylcysteine (NAC), an extensively used drug, is proposed as alternative source of intracellular sulfate in an animal model of DTD (dtd mouse). Mutant and wild type mice were treated twice a day with hypodermic injections of 250 mg NAC/kg body weight for one week after birth. At the end of the treatment, an improvement trend in cartilage proteoglycan sulfation and in the skeletal phenotype of treated dtd mice were observed. Thus, a longer treatment lasted three weeks starting from birth was performed. Treated mutant mice showed a significant increase of cartilage proteoglycan sulfation and a relevant improvement of the skeletal phenotype based on measurements of several bony elements and bone quality by DEXA and micro CT. Moreover, the amelioration of the overall growth plate morphology in treated dtd mice suggested a partial rescue of the endochondral ossification process. Overall, the results prove that NAC is an effective source of intracellular sulfate for dtd mice in the postnatal period. This finding paves the way for a potential pharmacological treatment of DTD patients taking advantage from a drug repositioning strategy.}, }
@article {pmid33544107, year = {2021}, author = {Shpaizer, A and Kanner, J and Tirosh, O}, title = {S-Nitroso-N-acetylcysteine (NAC-SNO) vs. nitrite as an anti-clostridial additive for meat products.}, journal = {Food &amp; function}, volume = {12}, number = {5}, pages = {2012-2019}, doi = {10.1039/d0fo02839h}, pmid = {33544107}, issn = {2042-650X}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology/toxicity ; Animals ; Anti-Bacterial Agents/pharmacology/toxicity ; Cattle ; Clostridium/*drug effects ; Food Preservation/methods ; Food Preservatives/*pharmacology/toxicity ; Male ; Meat Products/*microbiology ; Mice ; Mice, Inbred C57BL ; Nitrites/*pharmacology/toxicity ; }, abstract = {Nitrite is added to meat products as a preservative and it acts as a bacteriostatic compound against Clostridium botulinum growth. Nitric-oxide (˙NO), myoglobin and S-nitroso-compounds seem to be the main molecules generated from nitrite in meat products, which by decomposition to ˙NO, form the main anti-clostridial factor. The growth of C. sporogenes from activated spores in the presence of 0.5-2.5 mM NAC-SNO was compared to nitrite, both at 37 °C for 5 days and at room temperature for 28 days. The present study demonstrates that NAC-SNO under the same conditions and concentrations, in meat products, acts as an anti-clostridial compound similar to nitrite. In contrast to nitrite which must be activated in meat by heating, NAC-SNO generates the anti-clostridial factor directly, without heating, as was evaluated in an unheated bacteriological medium. The toxic effect of NAC-SNO and nitrite in methaemoglobinaemia and generation of N-nitrosamines in vivo, in mice, were also determined. Mice were gavage fed milk containing 45 mg per kg per bw of nitrite or an equimolar equivalent of NAC-SNO in the presence of 50 mg per kg per bw of N-methylaniline. Nitrite generated methaemoglobinaemia and carcinogenic N-nitrosoamines (N-nitrosomethylaniline); however, NAC-SNO under the same conditions and concentrations generates much less methaemoglobin and no detectable N-nitrosoamines in the blood, in vivo.}, }
@article {pmid33541511, year = {2020}, author = {Zhao, Y and Zhang, S and Zhang, X}, title = {[Progress of the antioxidant effect of N-acetylcysteine in treatment of acute respiratory distress syndrome].}, journal = {Zhonghua wei zhong bing ji jiu yi xue}, volume = {32}, number = {12}, pages = {1530-1532}, doi = {10.3760/cma.j.cn121430-20200709-00503}, pmid = {33541511}, issn = {2095-4352}, mesh = {*Acetylcysteine/therapeutic use ; Animals ; Antioxidants/therapeutic use ; China ; Oxidative Stress ; *Respiratory Distress Syndrome/drug therapy ; }, abstract = {Acute respiratory distress syndrome (ARDS) is a clinically critical illness characterized by hypoxemia caused by intrapulmonary and (or) extrapulmonary reasons. Its pathogenesis is related to the imbalance of oxidative stress. N-acetylcysteine (NAC) has been widely used in the treatment of respiratory diseases as an antioxidant. At present, there is controversy about whether NAC is beneficial in the treatment of ARDS in terms of antioxidant in China and abroad. This review focuses on the molecular mechanism of NAC, animal experiments and clinical research results, and summarizes the research progress of NAC's antioxidant effect in the treatment of ARDS, in order to provide a reference for the treatment of NAC in ARDS.}, }
@article {pmid33534781, year = {2021}, author = {Yang, J and Liu, J and Wang, P and Sun, J and Lv, X and Diao, Y}, title = {Toxic effect of titanium dioxide nanoparticles on corneas in vitro and in vivo.}, journal = {Aging}, volume = {13}, number = {4}, pages = {5020-5033}, pmid = {33534781}, issn = {1945-4589}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Proliferation/drug effects ; Cornea/*drug effects/metabolism ; Endothelial Cells/*drug effects/metabolism ; Glutathione Peroxidase/drug effects/metabolism ; In Vitro Techniques ; Malondialdehyde/metabolism ; Metal Nanoparticles/*toxicity ; Mice ; Mitochondria/drug effects ; NF-E2-Related Factor 2/*drug effects/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/drug effects/metabolism ; Titanium/*toxicity ; }, abstract = {Titanium dioxide nanoparticles (TiO2 NPs) are widely used in a variety of areas. However, TiO2 NPs possess cytotoxicity which involves oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key molecule preventing cells from oxidative stress damage. In the current study, we explored the effect of Nrf2 signaling pathway in TiO2 NPs-induced corneal endothelial cell injury. Firstly, we found TiO2 NPs inhibited proliferation and damaged morphology and mitochondria of mouse primary corneal endothelial cells. Moreover, TiO2 NPs-induced oxidative damage of mouse primary corneal endothelial cells was inhibited by antioxidant NAC by evaluating production of reactive oxygen species (ROS), malondialdehyde (MDA), and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Next, flow cytometry analysis showed TiO2 NPs promoted apoptosis and cell cycle G2/M phase arrest of mouse primary corneal endothelial cells. Further investigation suggested that Nrf2 signaling pathway activation and the downregulation of ZO-1, β-catenin and Na-K-ATPase were involved in TiO2 NPs-induced mouse primary corneal endothelial cell injury. Our research highlighted the toxic effect of TiO2 NPs on corneas in vitro and in vivo, providing an alternative insight into TiO2 NPs-induced corneal endothelial cell injury.}, }
@article {pmid33530839, year = {2021}, author = {Kaya Tektemur, N and Erdem Güzel, E and Gül, M and Tektemur, A and Özcan Yıldırım, S and Kavak Balgetir, M and Ozan Kocamüftüoğlu, G and Yalçın, T and Enver Ozan, &#x130;}, title = {The combination of N-acetylcysteine and cyclosporin A reduces acetaminophen-induced hepatotoxicity in mice.}, journal = {Ultrastructural pathology}, volume = {45}, number = {1}, pages = {19-27}, doi = {10.1080/01913123.2020.1850964}, pmid = {33530839}, issn = {1521-0758}, mesh = {*Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase ; Animals ; *Chemical and Drug Induced Liver Injury/prevention &amp; control ; Cyclosporine/toxicity ; Liver ; Mice ; }, abstract = {Acetaminophen (APAP)-induced hepatotoxicity is the most common cause of acute liver failure in worldwide. N-acetyl cysteine (NAC) is used as the APAP antidote. Cyclosporin A (CsA) is suppressed mitochondrial damage by binding cyclophilin, a mitochondrial pore transport component. The study aimed to evaluate the effects of NAC, CsA, and NAC+CsA treatments on APAP-induced hepatotoxicity in mice. Mice were randomly divided into five groups (n = 6). 400 mg/kg/ip/single dose APAP, 1200 mg/kg/i.p/single dose NAC and 50 mg/kg/i.p/single dose CsA were performed. Light and electron microscopic alterations were investigated in liver samples. Levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and liver glutathione (GSH) were analyzed. 3-nitrotyrosine and cytochrome c immunoreactivities were evaluated in liver tissue. Here, we found that APAP leads to histopathological and ultrastructural changes in mice liver. Also, APAP increased cytochrome c and 3-nitrotyrosine immunopositive staining. Besides, a significant decrease in liver GSH and an increase in serum AST and ALT levels were detected in the APAP group. Interestingly, NAC+CsA treatment improved histological alterations, cytochrome c, and 3-nitrotyrosine immunoreactivities and liver GSH, serum AST/ALT levels caused by APAP. We suggest that the combination of NAC and CsA reduces acetaminophen-induced hepatotoxicity in mice.}, }
@article {pmid33530504, year = {2021}, author = {Crinelli, R and Zara, C and Galluzzi, L and Buffi, G and Ceccarini, C and Smietana, M and Mari, M and Magnani, M and Fraternale, A}, title = {Activation of NRF2 and ATF4 Signaling by the Pro-Glutathione Molecule I-152, a Co-Drug of N-Acetyl-Cysteine and Cysteamine.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {2}, pages = {}, pmid = {33530504}, issn = {2076-3921}, support = {DISB_CRINELLI_PROGETTI_VALORIZZAZIONE_2017/2018; DISB_FRATERNALE_ATENEO_PRIN2015//Universit&#xe0; degli Studi di Urbino Carlo Bo/ ; DISB_CRINELLI_FFABR_CTC//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, abstract = {I-152 combines two pro-glutathione (GSH) molecules, namely N-acetyl-cysteine (NAC) and cysteamine (MEA), to improve their potency. The co-drug efficiently increases/replenishes GSH levels in vitro and in vivo; little is known about its mechanism of action. Here we demonstrate that I-152 not only supplies GSH precursors, but also activates the antioxidant kelch-like ECH-associated protein 1/nuclear factor E2-related factor 2 (KEAP1/NRF2) pathway. The mechanism involves disulfide bond formation between KEAP1 cysteine residues, NRF2 stabilization and enhanced expression of the γ-glutamil cysteine ligase regulatory subunit. Accordingly, a significant increase in GSH levels, not reproduced by treatment with NAC or MEA alone, was found. Compared to its parent compounds, I-152 delivered NAC more efficiently within cells and displayed increased reactivity to KEAP1 compared to MEA. While at all the concentrations tested, I-152 activated the NRF2 pathway; high doses caused co-activation of activating transcription factor 4 (ATF4) and ATF4-dependent gene expression through a mechanism involving Atf4 transcriptional activation rather than preferential mRNA translation. In this case, GSH levels tended to decrease over time, and a reduction in cell proliferation/survival was observed, highlighting that there is a concentration threshold which determines the transition from advantageous to adverse effects. This body of evidence provides a molecular framework for the pro-GSH activity and dose-dependent effects of I-152 and shows how synergism and cross reactivity between different thiol species could be exploited to develop more potent drugs.}, }
@article {pmid34909640, year = {2020}, author = {Abdoli, N and Sadeghian, I and Mousavi, K and Azarpira, N and Ommati, MM and Heidari, R}, title = {Suppression of cirrhosis-related renal injury by N-acetyl cysteine.}, journal = {Current research in pharmacology and drug discovery}, volume = {1}, number = {}, pages = {30-38}, pmid = {34909640}, issn = {2590-2571}, abstract = {Cirrhosis-induced renal injury or cholemic nephropathy (CN) is a serious clinical complication with poor prognosis. CN could finally lead to renal failure and the need for organ transplantation. Unfortunately, there is no specific pharmacological intervention against CN to date. On the other hand, various studies mentioned the role of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to evaluate the potential protective effects of NAC as a thiol-reducing agent and antioxidant in CN. Bile duct ligation (BDL) was used as a reliable animal model of cholestasis. BDL animals received NAC (0.25% and 1% w: v) in drinking water for 28 consecutive days. Finally, urine, blood, and kidney samples were collected and analyzed. Significant elevation in serum biomarkers of renal injury, along with urine markers of kidney damage, was evident in the BDL group. Moreover, markers of oxidative stress, including reactive oxygen species (ROS) formation, lipid peroxidation, protein carbonylation, and increased oxidized glutathione (GSSG) were evident detected in the kidney of cholestatic rats. Renal tissue antioxidant capacity and reduced glutathione (GSH) were also significantly depleted in the BDL group. Significant mitochondrial depolarization, depleted ATP content, and mitochondrial permeabilization was also detected in mitochondria isolated from the kidney of cholestatic animals. Renal histopathological alterations consisted of significant tissue fibrosis, interstitial inflammation, and tubular atrophy. It was found that NAC (0.25 and 1% in drinking water for 28 consecutive days) blunted histopathological changes, decreased markers of oxidative stress, and improved mitochondrial indices in the kidney of cirrhotic rats. Moreover, serum and urine biomarkers of renal injury were also mitigated in upon NAC treatment. These data indicate a potential renoprotective role for NAC in cholestasis. The effects of NAC on cellular redox state and mitochondrial function seem to play a fundamental role in its renoprotective effects during CN.}, }
@article {pmid34752548, year = {2020}, author = {Phelps, MK and Olson, LM and Patel, MAVB and Thompson, MJ and Murphy, CV}, title = {Nebulized Heparin for Adult Patients With Smoke Inhalation Injury: A Review of the Literature.}, journal = {The Journal of pharmacy technology : jPT : official publication of the Association of Pharmacy Technicians}, volume = {36}, number = {4}, pages = {130-140}, pmid = {34752548}, issn = {8755-1225}, abstract = {Objective: To review the clinical effects of nebulized heparin and N-acetylcysteine (NAC) in patients with smoke inhalation injury (IHI) and provide recommendations for use. Data Sources: A search of PubMed, MEDLINE, and Scopus databases was completed from database inception through April 15, 2020, using terms: heparin, acetylcysteine, smoke inhalation injury, and burn injury. Study Selection and Data Extraction: All studies pertaining to efficacy and safety of nebulized heparin and/or NAC for IHI in adult patients were evaluated. Reference lists were reviewed for additional publications. Nonhuman studies, non-English, and case report publications were excluded. Data Synthesis: Eight studies were included. Four demonstrated positive outcomes, 3 demonstrated no benefit or possible harm, and 1 assessed safety. Supporting trials treated patients within 48 hours of injury with 10 000 units of nebulized heparin with NAC for 7 days or until extubation. Two trials with negative findings treated patients within 72 hours, or unspecified, with 5000 units of nebulized heparin with NAC for 7 days, while the third used 25 000 units within 36 hours but was grossly underpowered for analysis. Clinical findings include reduced duration of mechanical ventilation and improved lung function with possible increase risk of pneumonia and no evidence of increased bleeding risk. Conclusions: Nebulized heparin may improve oxygenation and reduce duration of mechanical ventilation in IHI. If nebulized heparin is used, 10 000 units every 4 hours alternating with NAC and albuterol at 4-hour intervals is recommended. Sterile technique should be emphasized. Monitoring for bronchospasm or new-onset pneumonia should be considered.}, }
@article {pmid34909638, year = {2020}, author = {Ommati, MM and Farshad, O and Niknahad, H and Mousavi, K and Moein, M and Azarpira, N and Mohammadi, H and Jamshidzadeh, A and Heidari, R}, title = {Oral administration of thiol-reducing agents mitigates gut barrier disintegrity and bacterial lipopolysaccharide translocation in a rat model of biliary obstruction.}, journal = {Current research in pharmacology and drug discovery}, volume = {1}, number = {}, pages = {10-18}, pmid = {34909638}, issn = {2590-2571}, abstract = {It has been well documented that cirrhosis is associated with the intestinal injury. Intestinal injury in cirrhosis could lead to bacterial lipopolysaccharide (LPS) translocation to the systemic circulation. It has been found that high plasma LPS is connected with higher morbidity and mortality in cirrhotic patients. Therefore, finding therapeutic approaches to mitigate this complication has great clinical value. Several investigations mentioned the pivotal role of oxidative stress in cirrhosis-associated intestinal injury. It has been well-known that the redox balance of enterocytes is disturbed in cirrhotic patients. In the current study, the effects of thiol-reducing agents N-acetylcysteine (NAC) (0.5 and 1% w: v) and dithiothreitol (DTT) (0.5 and 1% w: v) on biomarkers of oxidative stress, tissue histopathological alterations, and LPS translocation is investigated in a rat model of cirrhosis. Bile duct ligation (BDL) surgery was used to induce cirrhosis in male Sprague-Dawley rats. Animals (n = 48; 8 animals/group) were supplemented with NAC and DTT for 28 consecutive days. Significant changes in ileum and colon markers of oxidative stress were evident in BDL rats as judged by increased reactive oxygen species (ROS), lipid peroxidation, oxidized glutathione (GSSG), and protein carbonylation along with decreased antioxidant capacity and glutathione (GSH) content. Blunted villus, decreased villus number, and inflammation was also detected in the intestine of BDL animals. Moreover, serum LPS level was also significantly higher in BDL rats. NAC and DTT administration (0.5 and 1% w: v, gavage) significantly decreased biomarkers of oxidative stress, mitigated intestinal histopathological alterations, and restored tissue antioxidant capacity. Moreover, NAC and/or DTT significantly suppressed LPS translocation to the systemic circulation. The protective effects of thiol reducing agents in the intestine of cirrhotic rats could be attributed to the effect of these chemicals on the cellular redox environment and biomarkers of oxidative stress.}, }
@article {pmid34345835, year = {2020}, author = {Scialis, RJ and Ghanem, CI and Manautou, JE}, title = {The modulation of transcriptional expression and inhibition of multidrug resistance associated protein 4 (MRP4) by analgesics and their primary metabolites.}, journal = {Current research in toxicology}, volume = {1}, number = {}, pages = {34-41}, pmid = {34345835}, issn = {2666-027X}, abstract = {During the course of a toxic challenge, changes in gene expression can manifest such as induction of metabolizing enzymes as a compensatory detoxification response. We currently report that a single 400 mg/kg acetaminophen (APAP) dose to C57BL/6J mice led to an increase in multidrug resistance-associated (Mrp) 4 (Abcc4) mRNA 12 h after administration. Alanine aminotransferase, as a marker of liver injury, was also elevated indicating hepatotoxicity had occurred. Therefore, induction of Mrp4 mRNA was likely attributable to APAP-induced liver injury. Mrp4 has been shown to be upregulated during oxidative stress, and it is well-established that APAP overdose causes oxidative stress due to depletion of glutathione. Given the importance of Mrp4 upregulation as an adaptive response during cholestatic and oxidative liver injury, we next investigated the extent by which human MRP4 can be inhibited by the analgesics, APAP, diclofenac (DCF), and their metabolites. Using an in vitro assay with inside out human MRP4 vesicles, we determined that APAP-cysteine inhibited MRP4-mediated transport of leukotriene C4 with an apparent IC50 of 125 μM. APAP-glutathione also attenuated MRP4 activity though it achieved only 28% inhibition at 300 μM. Diclofenac acyl glucuronide (DCF-AG) inhibited MRP4 transport by 34% at 300 μM. The MRP4 in vitro inhibition occurs at APAP-cysteine and DCF-AG concentrations seen in vivo after toxic doses of APAP or DCF in mice, hence the findings are important given the role that Mrp4 serves as a compensatory response during oxidative stress following toxic challenge.}, }
@article {pmid33906713, year = {2019}, author = {Ping, F and Cao, Q and Lin, H and Han, SZ}, title = {Antagonistic Effects of N-acetylcysteine on Mitogen-activated Protein Kinase Pathway Activation, Oxidative Stress and Inflammatory Responses in Rats with PM2.5 Induced Lung Injuries.}, journal = {Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih}, volume = {34}, number = {4}, pages = {270-276}, doi = {10.24920/003527}, pmid = {33906713}, issn = {1001-9294}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bronchoalveolar Lavage Fluid ; Enzyme Activation/drug effects ; Glutathione Peroxidase/blood/metabolism ; Inflammation/*pathology ; Interleukin-6/blood/metabolism ; Lung/drug effects/pathology ; Lung Injury/blood/*enzymology/*pathology ; Male ; Mitogen-Activated Protein Kinases/*metabolism ; Mucin 5AC/blood/metabolism ; Mucus/metabolism ; *Oxidative Stress/drug effects ; *Particle Size ; Particulate Matter/*toxicity ; Phosphorylation/drug effects ; Rats, Wistar ; }, abstract = {Objective To evaluate the antagonistic effects of N-acetylcysteine (NAC) on mitogen-activated protein kinases (MAPK) pathway activation, oxidative stress and inflammatory responses in rats with lung injury induced by fine particulate matter (PM2.5).Methods Forty eight male Wistar rats were randomly divided into six groups: blank control group (C1), water drip control group (C2), PM2.5 exposed group (P), low-dose NAC treated and PM2.5 exposed group (L), middle-dose NAC treated and PM2.5 exposed group (M), and high-dose NAC treated and PM2.5 exposed group (H). PM2.5 suspension (7.5 mg/kg) was administered tracheally once a week for four times. NAC of 125 mg/kg, 250 mg/kg and 500 mg/kg was delivered intragastrically to L, M and H group respectively by gavage (10 ml/kg) for six days before PM2.5 exposure. The histopathological changes and human mucin 5 subtype AC (MUC5AC) content in lung tissue of rats were evaluated. We investigated IL-6 in serum and bronchoalveolar lavage fluid (BALF) by Enzyme-linked immunosorbent assay (ELISA), MUC5AC in lung tissue homogenate by ELISA, glutathione peroxidase (GSH-PX) in serum and BALF by spectrophotometry, and the expression of p-ERK1/2, p-JNK1/2 and p-p38 proteins by Western blot. All the measurements were analyzed and compared statistically.Results Lung tissue of rats exposed to PM2.5 showed histological destruction and increased mucus secretion of bronchial epithelial cells. Rats receiving NAC treatment showed less histological destruction and mucus secretion. Of P, L, M and H group, MUC5AC in lung tissue, IL-6 in serum and BALF were higher than controls (C1 and C2) (all P<0.05), with the highest levels found in the P group and a decreasing trend with increase of NAC dose. The activity of GSH-PX in serum and BALF of PM2.5 exposed rats (P, L, M and H) was lower than that of controls (all P<0.05), with higher activities found in NAC treated rats (L, M, and H), and an increasing trend with increase of NAC dose. The expressions of p-ERK1/2, p-JNK1/2 and p-p38 proteins in PM2.5 exposed lung tissue (P, L, M and H) was higher than controls (all P<0.05), with decreased levels and dose dependent downregulation found in NAC treated rats.Conclusion NAC can antagonize major MAPK pathway activation, lung oxidative stress and inflammatory injury induced by PM2.5 in rats.}, }
@article {pmid35519466, year = {2019}, author = {Bala Subramaniyan, S and Veerappan, A}, title = {Water soluble cadmium selenide quantum dots for ultrasensitive detection of organic, inorganic and elemental mercury in biological fluids and live cells.}, journal = {RSC advances}, volume = {9}, number = {39}, pages = {22274-22281}, pmid = {35519466}, issn = {2046-2069}, abstract = {Mercury exists in organic, inorganic, and elemental forms; all of them are highly toxic. A sensor which could detect all forms of mercury below the permissible level in environmental and biological samples would be advantageous. A facile method to synthesize N-acetyl cysteine capped cadmium selenide quantum dots (CdSe QDs) with an emission at 554 nm was reported. CdSe QDs showed high sensitivity and selectivity toward Hg in aqueous media as well as biological fluids like simulated cerebrospinal fluid, saliva, and urine, and also in natural fluids like juices of tomato, sugarcane, and lime. The sensing mechanism is attributed to the interactions between Hg and CdSe QDs inducing fluorescence quenching. The limit of detection is 1.62, 0.75, and 1.27 ppb for organic, inorganic and elemental mercury, respectively, which is below WHO guidelines. The suitability of the sensor for estimating Hg in biological fluids was demonstrated by recovery experiments. Besides sensing, a two color cell imaging method was developed employing CdSe QDs and acridine orange. Using this method, the uptake of Hg in living cells was demonstrated.}, }
@article {pmid35517041, year = {2019}, author = {Zhao, K and Pi, B and Zhao, L and Tian, S and Ge, J and Yang, H and Sha, W and Wang, L}, title = {Influence of N-acetyl cysteine (NAC) and 2-methylene-1,3-dioxepane (MDO) on the properties of polymethyl methacrylate (PMMA) bone cement.}, journal = {RSC advances}, volume = {9}, number = {21}, pages = {11833-11841}, pmid = {35517041}, issn = {2046-2069}, abstract = {The properties of polymethyl methacrylate (PMMA) bone cement make it a popular bone filling material. However, its disadvantages, such as lack of biodegradability and osteogenesis, restrict its clinical application. Studies have indicated the osteogenic properties of N-acetyl cysteine (NAC) and the biodegradability of 2-methylene-1,3-dioxepane/methyl methacrylate-based (MDO/MMA) copolymers. In this study, we developed bioactive PMMA cements through modification with fixed concentrations of NAC and different proportions of MDO. The purpose of this study was to compare the mechanical properties, morphology, NAC release, biocompatibility, degradability and mineralization capability of modified bone cements with those of conventional cement. The specific-modified specimens (NAC-p (5% MDO-co-MMA)) exhibited a lower bending modulus but had little effect on compressive strength. This material was morphologically compact and nonporous, similar to conventional PMMA bone cement. NAC could be released from NAC-p (5% MDO-co-MMA) continuously and appropriately. NAC-p (5% MDO-co-MMA) was biologically safe and showed satisfactory tissue compatibility. Ester was introduced into the polymer, which reinforced the degradation properties of NAC-p (5% MDO-co-MMA). NAC-p (5% MDO-co-MMA) enhanced the mineralization capability of osteoblastic cells.}, }
@article {pmid33817118, year = {2018}, author = {Jiang, J and Zhou, N and Ying, P and Zhang, T and Liang, R and Jiang, X}, title = {Emodin Promotes Apoptosis of Human Endometrial Cancer Through Regulating the MAPK and PI3K/ AKT Pathways.}, journal = {Open life sciences}, volume = {13}, number = {}, pages = {489-496}, pmid = {33817118}, issn = {2391-5412}, abstract = {Emodin, a major component of rhubarb, has anti-tumor effects in a variety of cancers, influencing multiple steps of tumor development through modulating several signaling pathways. The aim of this study is to examine the effect of emodin on cell apoptosis and explore the underlying mechanisms in human endometrial cancer cells. Here we report that emodin can inhibit KLE cell proliferation and induce apoptosis in a time- and dose-dependent manner. Western blot assay found that emodin was involved in MAPK and PI3K/Akt signaling pathways. Specifically, emodin significantly suppressed the phosphorylation of AKT, and enhanced the phosphorylation of MAPK pathways. Furthermore, the generation of reactive oxygen species (ROS) was up-regulated in KLE cells upon treatment with emodin, while the anti-oxidant agent N-acetyl cysteine (NAC) can inhibit emodin-induced apoptosis and promote the activation of AKT and Bcl-2. Taken together, we revealed that emodin may induce apoptosis in KLE cells through regulating the PI3K/AKT and MAPK signaling pathways, indicating the importance of emodin as an anti-tumor agent.}, }
@article {pmid35557821, year = {2018}, author = {Yue, Z and Zhang, X and Yu, Q and Liu, L and Zhou, X}, title = {Cytochrome P450-dependent reactive oxygen species (ROS) production contributes to Mn3O4 nanoparticle-caused liver injury.}, journal = {RSC advances}, volume = {8}, number = {65}, pages = {37307-37314}, pmid = {35557821}, issn = {2046-2069}, abstract = {Mn3O4 nanoparticles (NPs) are one of the most important nanomaterials, and have a wide range of applications (i.e., catalysis, solar-electron transformation and molecular adsorption). However, their biological effect remains to be detailed. In this study, we investigated the in vivo toxicity of the synthesized Mn3O4 NPs using a long-term exposure model. After exposure to the Mn3O4 NPs for 60-120 days, rats preferentially accumulated manganese in the livers. Histopathological observation and apoptosis assays revealed that the Mn3O4 NPs caused severe liver injury associated with apoptosis. Transcription profiling analysis, immune histochemistry (IHC) staining and western blotting showed that the NPs significantly up-regulated expression of the cytochrome P450 (CYP1A2). Accordingly, the NP-treated livers exhibited high levels of reactive oxygen species (ROS) and oxidative damage. Moreover, ROS scavenging by N-acetylcysteine (NAC) attenuated Mn3O4 NP-caused liver injury, but had no impact on the expression of CYP1A2. These results indicated that the toxicity of the Mn3O4 NPs was attributed to cytochrome P450-dependent ROS accumulation and consequent oxidative damage. This study uncovers the contribution of cytochrome P450-induced oxidative stress to nanotoxicity.}, }
@article {pmid35547513, year = {2018}, author = {Jaiswal, A and Sabarwal, A and Narayan Mishra, JP and Singh, RP}, title = {Plumbagin induces ROS-mediated apoptosis and cell cycle arrest and inhibits EMT in human cervical carcinoma cells.}, journal = {RSC advances}, volume = {8}, number = {56}, pages = {32022-32037}, pmid = {35547513}, issn = {2046-2069}, abstract = {Plumbagin, an important phytochemical from the roots of the medicinal plant Plumbago zeylanica L. has shown many biological activities. The roots of this plant have been in use in the Indian system of medicine for more than twenty five centuries for treatments of various ailments. It has shown anticancer activities, however, the anticancer and anti-metastatic effects of plumbagin are largely unknown against cervical cancer cells. Herein, we investigated the molecular alterations associated with plumbagin-mediated inhibition of growth, survival and epithelial to mesenchymal transition of human cervical cancer SiHa and HeLa cells. Plumbagin (1-4 μM) caused a significant decrease in the cell viability and increased the cell death in SiHa and Hela cells after 24 and 48 h. Plumbagin also caused strong G2/M and S-G2/M phase cell cycle arrest in SiHa and HeLa cells, respectively which was accompanied by a decrease in the expression of cyclin and CDK levels. The expression levels of both mRNAs and proteins of cyclin B1, A and E2 and CDK 1 and 2 decreased after 24 and 48 h. Plumbagin strongly induced apoptosis along with increased ratio of Bax : Bcl2 and cleavage of caspase 3, 9, and PARP. Plumbagin caused a significant increase in reactive oxygen species generation which mediated cell death as it was attenuated by pre-treatment with N-acetyl cysteine. Additionally, we also report for the first time that plumbagin possesses an anti-metastatic effect at non-cytotoxic doses that was accompanied by the modulation of MMP-2, 9, E-cadherin, N-cadherin, β-catenin and vimentin. Taken together, our findings suggest that plumbagin has strong anticancer and anti-metastatic effects against human cervical cancer cells.}, }
@article {pmid33527928, year = {2021}, author = {Gran, ER and Bertorelle, F and Fakhouri, H and Antoine, R and Perić Bakulić, M and Sanader Maršić, &#x17d; and Bonačić-Koutecký, V and Blain, M and Antel, J and Maysinger, D}, title = {Size and ligand effects of gold nanoclusters in alteration of organellar state and translocation of transcription factors in human primary astrocytes.}, journal = {Nanoscale}, volume = {13}, number = {5}, pages = {3173-3183}, doi = {10.1039/d0nr06401g}, pmid = {33527928}, issn = {2040-3372}, mesh = {Astrocytes ; *Gold ; Humans ; Ligands ; *Metal Nanoparticles ; Transcription Factors ; }, abstract = {Ultra-small gold nanoclusters (AuNCs) with designed sizes and ligands are gaining popularity for biomedical purposes and ultimately for human imaging and therapeutic applications. Human non-tumor brain cells, astrocytes, are of particular interest because they are abundant and play a role in functional regulation of neurons under physiological and pathological conditions. Human primary astrocytes were treated with AuNCs of varying sizes (Au10, Au15, Au18, Au25) and ligand composition (glutathione, polyethylene glycol, N-acetyl cysteine). Concentration and time-dependent studies showed no significant cell loss with AuNC concentrations <10 μM. AuNC treatment caused marked differential astrocytic responses at the organellar and transcription factor level. The effects were exacerbated under severe oxidative stress induced by menadione. Size-dependent effects were most remarkable with the smallest and largest AuNCs (10, 15 Au atoms versus 25 Au atoms) and might be related to the accessibility of biological targets toward the AuNC core, as demonstrated by QM/MM simulations. In summary, these findings suggest that AuNCs are not inert in primary human astrocytes, and that their sizes play a critical role in modulation of organellar and redox-responsive transcription factor homeostasis.}, }
@article {pmid33527858, year = {2021}, author = {McDougall, G and Murphy, NG and Loubani, O}, title = {N-Acetylcysteine treatment of neonatal acetaminophen toxicity caused by transplacental transfer - a case report.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {59}, number = {9}, pages = {840-842}, doi = {10.1080/15563650.2021.1874405}, pmid = {33527858}, issn = {1556-9519}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*therapeutic use ; Adult ; Analgesics, Non-Narcotic/*therapeutic use ; Brain Diseases/*chemically induced/physiopathology ; Chemical and Drug Induced Liver Injury/*drug therapy/physiopathology ; Drug-Related Side Effects and Adverse Reactions/*drug therapy/physiopathology ; Female ; Humans ; Infant, Newborn ; Male ; *Maternal-Fetal Exchange ; Pregnancy ; Risk Factors ; Treatment Outcome ; }, abstract = {We describe a case of maternal acetaminophen toxicity leading to Caesarean section delivery of a pre-term neonate with acetaminophen-induced hepatic injury and encephalopathy at 33 weeks gestational age. Delayed treatment with N-acetylcysteine (NAC) was initiated in the baby 11 h after delivery, with eventual discharge of a healthy baby at 12 days of age. The baby was treated with a standard but extended duration NAC protocol. Post-operatively, liver biopsy of the mother demonstrated acetaminophen-induced hepatic injury overlying mild hepatic steatosis. This was also managed with NAC therapy leading to complete clinical resolution of acetaminophen induced hepatic injury and discharge on post-operative day 10. This case of delayed NAC therapy for the treatment of pre-term neonatal acetaminophen toxicity is one of very few reported in the literature and can be used as a guide in the management of subsequent cases.}, }
@article {pmid33522955, year = {2021}, author = {Lin, Z and Huang, W and He, Q and Li, D and Wang, Z and Feng, Y and Liu, D and Zhang, T and Wang, Y and Xie, M and Ji, X and Sun, M and Tian, D and Xia, L}, title = {FOXC1 promotes HCC proliferation and metastasis by Upregulating DNMT3B to induce DNA Hypermethylation of CTH promoter.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {40}, number = {1}, pages = {50}, pmid = {33522955}, issn = {1756-9966}, support = {81972237//National Natural Science Foundation of China/ ; 81772623//National Natural Science Foundation of China/ ; 81871911//National Natural Science Foundation of China/ ; }, mesh = {Adult ; Aged ; Carcinoma, Hepatocellular/*genetics/*metabolism/pathology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; DNA (Cytosine-5-)-Methyltransferases/*metabolism ; *DNA Methylation ; Female ; Follow-Up Studies ; Forkhead Transcription Factors/*genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Humans ; Immunophenotyping ; Liver Neoplasms/*genetics/*metabolism/pathology ; MAP Kinase Signaling System/drug effects ; Male ; Middle Aged ; Molecular Imaging ; Neoplasm Metastasis ; Neoplasm Staging ; *Promoter Regions, Genetic ; Reactive Oxygen Species/metabolism ; DNA Methyltransferase 3B ; }, abstract = {BACKGROUND: Forkhead box C1 (FOXC1), as a member of the FOX family, is important for promote HCC invasion and metastasis. FOX family protein lays a pivotal role in metabolism. ROS is involved in tumor progression and is associated with the expression of lots of transcription factors. We next explored the mechanism underlying FOXC1 modulating the metabolism and ROS hemostasis in HCC.<br><br>METHODS: We used amino acids arrays to verify which metabolism is involved in FOXC1-induced HCC. The kits were used to detect the ROS levels in HCC cells with over-expression or down-expression of FOXC1. After identified the downstream target genes and candidate pathway which regulated by FOXC1 during HCC progression in vitro and in vivo, we used western blot, immunohistochemistry, bisulfite genomic sequencing, methylation-specific PCR, chromatin immunoprecipitation analysis and luciferase reporter assays to explore the relationship of FOXC1 and downstream genes. Moreover, the correlation between FOXC1 and target genes and the correlation between target genes and the recurrence and overall survival were analyzed in two independent human HCC cohorts.<br><br>RESULTS: Here, we reported that FOXC1 could inhibit the cysteine metabolism and increase reactive oxygen species (ROS) levels by regulating cysteine metabolism-related genes, cystathionine &#x3b3;-lyase (CTH). Overexpression of CTH significantly suppressed FOXC1-induced HCC proliferation, invasion and metastasis, while the reduction in cell proliferation, invasion and metastasis caused by the inhibition of FOXC1 could be reversed by knockdown of CTH. Meanwhile, FOXC1 upregulated de novo DNA methylase 3B (DNMT3B) expression to induce DNA hypermethylation of CTH promoter, which resulted in low expression of CTH in HCC cells. Moreover, low levels of ROS induced by N-acetylcysteine (NAC) which is an antioxidant inhibited the cell proliferation, migration, and invasion abilities mediated by FOXC1 overexpression, whereas high levels of ROS induced by L-Buthionine-sulfoximine (BSO) rescued the suppression results mediated by FOXC1 knockdown. Our study demonstrated that the overexpression of FOXC1 that was induced by the ROS dependent on the extracellular regulated protein kinases 1 and 2 (ERK1/2)- phospho-ETS Transcription Factor 1 (p-ELK1) pathway. In human HCC tissues, FOXC1 expression was positively correlated with oxidative damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG), p-ELK1 and DNMT3B expression, but negatively correlated with CTH expression. HCC patients with positive co-expression of 8-OHdG/FOXC1 or p-ELK1/FOXC1 or FOXC1/DNMT3B had the worst prognosis, whereas HCC patients who had positive FOXC1 and negative CTH expression exhibited the worst prognosis.<br><br>CONCLUSION: In a word, we clarify that the positive feedback loop of ROS-FOXC1-cysteine metabolism-ROS is important for promoting liver cancer proliferation and metastasis, and this pathway may provide a prospective clinical treatment approach for HCC.}, }
@article {pmid33519199, year = {2021}, author = {Gurunathan, S and Kang, MH and Jeyaraj, M and Kim, JH}, title = {Platinum Nanoparticles Enhance Exosome Release in Human Lung Epithelial Adenocarcinoma Cancer Cells (A549): Oxidative Stress and the Ceramide Pathway are Key Players.}, journal = {International journal of nanomedicine}, volume = {16}, number = {}, pages = {515-538}, pmid = {33519199}, issn = {1178-2013}, mesh = {A549 Cells ; Acetylcholinesterase/metabolism ; Acetylcysteine/pharmacology ; Adenocarcinoma of Lung/genetics/*metabolism/pathology ; Aniline Compounds/pharmacology ; Benzylidene Compounds/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Ceramides/*metabolism ; Enzyme Activation/drug effects ; Exosomes/*metabolism/ultrastructure ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Lung Neoplasms/genetics/*metabolism/pathology ; Lutein/pharmacology ; Metal Nanoparticles/*chemistry/ultrastructure ; Neoplasm Proteins/genetics/metabolism ; *Oxidative Stress/drug effects ; Particle Size ; Platinum/*pharmacology ; RNA, Messenger/genetics/metabolism ; Serum ; Sphingomyelin Phosphodiesterase/metabolism ; Static Electricity ; }, abstract = {BACKGROUND: Several studies have demonstrated various molecular mechanisms involved in the biogenesis and release of exosomes. However, how external stimuli, such as platinum nanoparticles (PtNPs), induces the biogenesis and release of exosomes remains unclear. To address this, PtNPs were synthesized using lutein to examine their effect on the biogenesis and release of exosomes in human lung epithelial adenocarcinoma cancer cells (A549).<br><br>METHODS: The size and concentration of isolated exosomes were characterized by dynamic light scattering (DLS) and nanoparticle tracking analysis system (NTA). Morphology and structure of exosomes were examined using scanning electron microscopy and transmission electron microscopy (TEM), respectively. Quantification of exosomes were analyzed by EXOCET[TM] assay and fluorescence polarization (FP). The expression of typical markers of exosomes were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA).<br><br>RESULTS: A549 cells cultured with PtNPs enhance exosome secretion by altering various physiological processes. Interestingly, A549 cells treated with PtNPs increases total protein concentration, biogenesis and release of exosomes associated with PtNPs-induced oxidative stress. GW4869 inhibits PtNPs induced biogenesis and release of exosomes and also acetylcholinesterase (AChE), neutral sphingomyelinase activity (n-SMase), and exosome counts. A549 cells pre-treated with N-acetylcysteine (NAC) significantly inhibited PtNPs induced exosome biogenesis and release. These findings confirmed that PtNPs-induced exosome release was due to the induction of oxidative stress and the ceramide pathway. These factors enhanced exosome biogenesis and release and may be useful in understanding the mechanism of exosome formation, release, and function.<br><br>CONCLUSION: PtNPs provide a promising agent to increase exosome production in A549 cells. These findings offer novel strategies for enhancing exosome release, which can be applied in the treatment and prevention of cancer. Importantly, this is the first study, to our knowledge, showing that PtNPs stimulate exosome biogenesis by inducing oxidative stress and the ceramide pathway.}, }
@article {pmid33515593, year = {2021}, author = {Dong, X and Zuo, Y and Zhou, M and Sun, J and Xu, P and Chen, B}, title = {Bortezomib activation of mTORC1 pathway mediated by NOX2-drived reactive oxygen species results in apoptosis in primary dorsal root ganglion neurons.}, journal = {Experimental cell research}, volume = {400}, number = {2}, pages = {112494}, doi = {10.1016/j.yexcr.2021.112494}, pmid = {33515593}, issn = {1090-2422}, mesh = {Animals ; Antineoplastic Agents/pharmacology ; *Apoptosis ; Bortezomib/*pharmacology ; Ganglia, Spinal/drug effects/metabolism/*pathology ; Gene Expression Regulation ; Male ; Mechanistic Target of Rapamycin Complex 1/genetics/*metabolism ; NADPH Oxidase 2/genetics/*metabolism ; Neurons/drug effects/metabolism/*pathology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Bortezomib (Bort), a chemotherapeutic agent, is widely used for the clinical treatment of cancers. However, Bort-induced peripheral neurotoxicity (BIPN) significantly restricts its clinical application, which is difficult to deal with since the underlying mechanisms of BIPN are unclear. Here, we showed that Bort activates mTORC1 pathway leading to dorsal root ganglion (DRG) neuronal apoptosis. Inhibition of mTORC1 with rapamycin or knockdown of raptor, regulatory-associated protein of mTORC1, with shRNA dramatically rescued the cells from Bort-caused apoptosis. In addition, we found that Bort-activated mTORC1 pathway was attributed to Bort elevation of reactive oxygen species (ROS). This is supported by the evidence that using ROS scavenger N-acetyl cysteine (NAC) significantly alleviated Bort-activated mTORC1 pathway. Furthermore, we revealed that upregulation of NOX2 contributed to Bort-elicited ROS overproduction, leading to mTORC1 pathway-dependent apoptosis in DRG neurons. Inhibition of NOX2 with apocynin remarkably diminished Bort-induced overgeneration of ROS, activation of mTORC1 pathway and apoptosis in the cells. Taken together, these results indicate that Bort activation of mTORC1 pathway mediated by NOX2-drived ROS leads to apoptotic death in DRG neurons. Our findings highlight that manipulation of intracellular ROS level or NOX2 or mTORC1 activity may be exploited for prevention of BIPN.}, }
@article {pmid33515200, year = {2021}, author = {Mahmood, A and Bisoyi, P and Banerjee, R and Yousuf, M and Goswami, SK}, title = {Mitoapocynin, a mitochondria targeted derivative of apocynin induces mitochondrial ROS generation and apoptosis in multiple cell types including cardiac myoblasts: a potential constraint to its therapeutic use.}, journal = {Molecular and cellular biochemistry}, volume = {476}, number = {5}, pages = {2047-2059}, pmid = {33515200}, issn = {1573-4919}, support = {PDF/2017/000439//Science and Engineering Research Board/ ; EMR/2016/001832//Science and Engineering Research Board/ ; BL/17-18/0376//University Grants Commission/ ; IICT/Pubs./2020/196//CSIR - Indian Institute of Chemical technology (IN)/ ; }, mesh = {Acetophenones/*pharmacology ; Animals ; Apoptosis/*drug effects ; HEK293 Cells ; Humans ; MCF-7 Cells ; Mice ; Mitochondria, Heart/*metabolism ; Myoblasts, Cardiac/*metabolism ; NIH 3T3 Cells ; Reactive Oxygen Species/*metabolism ; }, abstract = {Mitoapocynin is a triphenylphosphonium conjugated derivative of apocynin that specifically locates to the mitochondria. It has been developed as a mitochondrially targeted therapeutic antioxidant. We attempted to attenuate the mitochondrial ROS induced in H9c2 cardiac myoblast cells treated with norepinephrine. Mitoapocynin was a poor quencher of total ROS as detected by the fluoroprobe DCFH-DA. Using mitochondrial superoxide specific probe MitoSoxRed, we found that 5-10 µM mitoapocynin itself induces superoxide over and above that is generated by the norepinephrine treatment. A supposedly control molecule to mitoapocynin, the synthetic compound PhC11TPP, having the triphenylphosphonium group and a benzene moiety with C11 aliphatic chain spacer was also found to be a robust inducer of mitochondrial ROS. Subsequent assays with several cell lines viz., NIH3T3, HEK293, Neuro2A, MCF-7 and H9c2, showed that prolonged exposure to mitoapocynin induces cell death by apoptosis that can be partially prevented by the general antioxidant N-acetyl cysteine. Analyses of mitochondrial electron transport complexes by Blue Native Polyacrylamide gel electrophoresis showed that both mitoapocynin and PhC11TPP disrupt the mitochondrial Complex I and V, and in addition, PhC11TPP also damages the Complex IV. Our data thus highlights the limitations of the therapeutic use of mitoapocynin as an antioxidant.}, }
@article {pmid33514017, year = {2021}, author = {Baek, JY and Jung, K and Kim, YM and Kim, HY and Kang, KS and Chin, YW}, title = {Protective Effect of γ-mangostin Isolated from the Peel of Garcinia mangostana against Glutamate-Induced Cytotoxicity in HT22 Hippocampal Neuronal Cells.}, journal = {Biomolecules}, volume = {11}, number = {2}, pages = {}, pmid = {33514017}, issn = {2218-273X}, support = {Not applicable//New Faculty Startup Fund from Seoul National University/ ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; *Apoptosis ; Calcium/metabolism ; Cell Death/drug effects ; Free Radical Scavengers ; Garcinia mangostana/*metabolism ; Glutamic Acid/*chemistry/*metabolism ; Heme Oxygenase-1/*metabolism ; Hippocampus/*metabolism ; MAP Kinase Kinase 4/metabolism ; Membrane Proteins/*metabolism ; Mice ; Neurons/*metabolism ; Neuroprotective Agents/pharmacology ; *Oxidative Stress ; *Reactive Oxygen Species ; Signal Transduction ; Xanthones/isolation &amp; purification/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The aim of the present study was to examine the protective effect of γ-mangostin, a component of the mangosteen shell, against oxidative damage to nerve cells induced by excessive glutamate, a known excitatory neurotransmitter. To investigate the effect of γ-mangostin on apoptosis, 5 mM of glutamate was used to induce apoptotic cell death in mouse hippocampal HT22 cells. In this study, γ-mangostin was found to exert a stronger protection than N-acetyl cysteine against glutamate-induced cell damage. γ-Mangostin showed prevented glutamate-induced apoptosis in HT22 cells by reducing the production of reactive oxygen species and stimulating the expression of heme oxygenase-1 protein. In addition, glutamate significantly induced the accumulation of intracellular calcium ions, whereas treatment with γ-mangostin markedly reduced it. Hoechst 33342 staining showed an improvement in glutamate-induced nuclear condensation following γ-mangostin treatment. Furthermore, the number of annexin V-positive cells was significantly reduced following treatment with γ-mangostin. Western blot analysis showed the inhibition of glutamate-induced mitogen-activated protein kinase phosphorylation by γ-mangostin. γ-mangostin also inhibited the regulation of the intrinsic mitochondrial apoptotic pathway. Thus, the results of this study suggest that γ-mangostin is an active ingredient of mangosteen and exerts neuroprotective activities in HT22 cells.}, }
@article {pmid33511734, year = {2021}, author = {Dillon, KM and Morrison, HA and Powell, CR and Carrazzone, RJ and Ringel-Scaia, VM and Winckler, EW and Council-Troche, RM and Allen, IC and Matson, JB}, title = {Targeted Delivery of Persulfides to the Gut: Effects on the Microbiome.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {60}, number = {11}, pages = {6061-6067}, pmid = {33511734}, issn = {1521-3773}, support = {R01 GM123508/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Anti-Bacterial Agents/chemical synthesis/chemistry/*pharmacology ; Drug Design ; Escherichia coli/drug effects ; Gastrointestinal Microbiome/*drug effects ; Kinetics ; Listeria monocytogenes/drug effects ; Mice ; Microbial Sensitivity Tests ; Molecular Structure ; Prodrugs/chemical synthesis/chemistry/*pharmacology ; Staphylococcus aureus/drug effects ; Sulfides/chemical synthesis/chemistry/*pharmacology ; }, abstract = {Persulfides (R-SSH) have been hypothesized as potent redox modulators and signaling compounds. Reported herein is the synthesis, characterization, and in vivo evaluation of a persulfide donor that releases N-acetyl cysteine persulfide (NAC-SSH) in response to the prokaryote-specific enzyme nitroreductase. The donor, termed NDP-NAC, decomposed in response to E. coli nitroreductase, resulting in release of NAC-SSH. NDP-NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2 S. NDP-NAC induced these effects by the upregulation of beneficial small- and medium-chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. This study reveals the possibility of maintaining gut health or treating microbiome-related diseases by the targeted delivery of reactive sulfur species.}, }
@article {pmid33511620, year = {2021}, author = {Giorgi, VSI and Ferriani, RA and Navarro, PA}, title = {Follicular Fluid from Infertile Women with Mild Endometriosis Impairs In Vitro Bovine Embryo Development: Potential Role of Oxidative Stress.}, journal = {Revista brasileira de ginecologia e obstetricia : revista da Federacao Brasileira das Sociedades de Ginecologia e Obstetricia}, volume = {43}, number = {2}, pages = {119-125}, pmid = {33511620}, issn = {1806-9339}, mesh = {Animals ; Cattle ; Disease Models, Animal ; Embryonic Development ; *Endometriosis ; Female ; Follicular Fluid/*metabolism ; Humans ; *Infertility, Female ; Oocytes ; }, abstract = {OBJECTIVE: To investigate whether follicular fluid (FF) from infertile women with mild endometriosis (ME) alters in vitro bovine embryo development, and whether the antioxidants N-acetyl-cysteine (NAC) and/or L-carnitine (LC) could prevent such damages.<br><br>METHODS: &#x2003;Follicular fluid was obtained from infertile women (11 with ME and 11 control). Bovine oocytes were matured in vitro divided in: No-FF, with 1% of FF from control women (CFF) or ME women (MEFF); with 1.5&#x2009;mM NAC (CFF&#x2009;+&#x2009;NAC, MEFF&#x2009;+&#x2009;NAC), with 0.6&#x2009;mg/mL LC (CFF&#x2009;+&#x2009;LC, MEFF&#x2009;+&#x2009;LC), or both antioxidants (CFF&#x2009;+&#x2009;NAC&#x2009;+&#x2009;LC, MEFF&#x2009;+&#x2009;NAC&#x2009;+&#x2009;LC). After in vitro fertilization, in vitro embryo culture was performed for 9 days.<br><br>RESULTS: &#x2003;A total of 883 presumptive zygotes were cultured in vitro. No differences were observed in cleavage rate (p&#x2009;=&#x2009;0.5376) and blastocyst formation rate (p&#x2009;=&#x2009;0.4249). However, the MEFF group (12.5%) had lower hatching rate than the No-FF (42.1%, p&#x2009;=&#x2009;0.029) and CFF (42.9%, p&#x2009;=&#x2009;0.036) groups. Addition of antioxidants in the group with CFF did not alter hatching rate (p &#x2265; 0.56), and in groups with MEFF, just NAC increased the hatching rate [(MEFF: 12.5% versus MEFF&#x2009;+&#x2009;NAC: 44.4% (p&#x2009;=&#x2009;0.02); vs MEFF&#x2009;+&#x2009;LC: 18.8% (p&#x2009;=&#x2009;0.79); versus MEFF&#x2009;+&#x2009;NAC&#x2009;+&#x2009;LC: 30.8% (p&#x2009;=&#x2009;0.22)].<br><br>CONCLUSION: &#x2003;Therefore, FF from infertile women with ME added to medium of in vitro maturation of bovine oocytes impairs hatching rate, and NAC prevented these damages, suggesting involvement of oxidative stress in worst of oocyte and embryo quality of women with ME.}, }
@article {pmid33511162, year = {2020}, author = {Wu, T and Lyu, Y and Li, X and Wu, M and Yu, K and Li, S and Ji, C and Zhang, Q and Zhang, Y and Zhao, D and Yi, D and Hou, Y}, title = {Impact of N-Acetylcysteine on the Gut Microbiota in the Piglets Infected With Porcine Epidemic Diarrhea Virus.}, journal = {Frontiers in veterinary science}, volume = {7}, number = {}, pages = {582338}, pmid = {33511162}, issn = {2297-1769}, abstract = {This study was to investigate the impact of N-acetylcysteine (NAC) on the gut microbiota in the healthy piglets and the piglets infected with porcine epidemic diarrhea virus (PEDV). Forty seven-day-old piglets were allocated into four groups: control group, NAC group (supplemented with 50 mg/kg body weight NAC), PEDV group (inoculated with 10[4.5] TCID50 PEDV), and PEDV+NAC group (PEDV infection + NAC supplementation). The intestinal content was collected for DNA extraction and Illumina sequencing. The PEDV-infected piglets displayed distinct bacterial communities compared to the healthy piglets. PEDV infection decreased the abundance of Shigella and increased the abundance of Lactobacillus, Odoribacter, Anaerovibrio, Helicobacter, unclassified Lachnospiraceae, and Sutterella; affected several functions associated with metabolism, barrier, and immune. NAC supplementation decreased the abundance of unclassified Rikenellaceae and increased the abundance of Lactobacillus, Streptococcus, and Enterococcus in the healthy piglets, decreased the abundance of Oscillospira and Prevotella and increased the abundance of Lactobacillus in the PEDV-infected piglets; altered multiple functions involving in amino acid metabolism, cell signaling, cellular community, disease-related pathways, endocrine, and excretory system. In conclusion, PEDV infection caused severe dysbiosis of gut microbiome, whereas NAC supplementation played a positive role in regulating the gut microbiome during PEDV infection. Therefore, substances that can regulate gut microbiota could be ideal candidates to prevent or treat PEDV infection.}, }
@article {pmid33510844, year = {2021}, author = {Drygalski, K and Siewko, K and Chomentowski, A and Odrzygóźdź, C and Zalewska, A and Krętowski, A and Maciejczyk, M}, title = {Phloroglucinol Strengthens the Antioxidant Barrier and Reduces Oxidative/Nitrosative Stress in Nonalcoholic Fatty Liver Disease (NAFLD).}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {8872702}, pmid = {33510844}, issn = {1942-0994}, mesh = {Antioxidants/*metabolism ; Hep G2 Cells ; Humans ; Nitrosative Stress/*drug effects ; Non-alcoholic Fatty Liver Disease/drug therapy/*metabolism/pathology ; Phloroglucinol/*pharmacology ; }, abstract = {Nonalcoholic fatty liver disease (NAFLD) is one of the most commonly occurring diseases within western dietary patterns. Usually untreated, it may lead to type 2 diabetes mellitus (T2DM), steatohepatitis (NASH), and hepatocellular carcinoma (HCC). Besides its severe aftermath, up to now, there is no known therapeutic approach to this disease in everyday clinical practice. Most NAFLD patients are encouraged to do physical activities or diet change and remain without pharmacological treatment. In this study, we present phloroglucinol (PHG) as a novel and promising compound in NAFLD treatment. PHG significantly increased the level of enzymatic and nonenzymatic antioxidants both in palmitate and hydrogen peroxide-induced oxidative stress models. Strengthened antioxidative defense reduced the oxidative/nitrosative damage to cell proteins, lipids, and carbohydrates. Furthermore, PHG treatment reduced hepatic steatosis; lowered inflammatory markers, such as NF-κB or HIF-1α; and inhibited cell apoptosis. Moreover, PHG had a more comprehensive effect than other commonly used antioxidants: N-acetylcysteine (NAC) and α-lipoic acid (ALA), suggesting its clinical usability. Therefore, our paper supports the benefits of natural compounds as a therapeutical approach to NAFLD.}, }
@article {pmid33507837, year = {2023}, author = {Abdelhaffez, AS and Abd El-Aziz, EA and Tohamy, MB and Ahmed, AM}, title = {N-acetyl cysteine can blunt metabolic and cardiovascular effects via down-regulation of cardiotrophin-1 in rat model of fructose-induced metabolic syndrome.}, journal = {Archives of physiology and biochemistry}, volume = {129}, number = {4}, pages = {854-869}, doi = {10.1080/13813455.2021.1876735}, pmid = {33507837}, issn = {1744-4160}, mesh = {Animals ; Male ; Rats ; Acetylcysteine/pharmacology ; Aorta ; Down-Regulation ; Fibrosis ; Fructose/adverse effects/metabolism ; *Insulin Resistance ; *Metabolic Syndrome/metabolism ; Oxidative Stress ; Rats, Wistar ; }, abstract = {In this study, we investigated the ability of N-acetyl cysteine (NAC) to alleviate the metabolic disorders in fructose-induced metabolic syndrome (MS) in male rats and to examine its protective effect on aortic and cardiac tissues via its influence on cardiotrophin-1 (CT-1) expression. NAC (20 mg/kg b.w./day) was administered to fructose induced MS animals for 12 weeks. Chronic fructose consumption (20% w/v) increased body weight gain, relative heart weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), insulin resistance (IR), and associated with metabolic alterations. Histological and immunohistochemical examination revealed aortic stiffness and myocardial degeneration and fibrosis together with increased CT-1 expression. Treatment with NAC improved IR, SBP, DBP, and mitigated dyslipidaemia and oxidative stress. Additionally, NAC down-regulated CT-1 expression in the heart and aorta. These findings demonstrated the protective effect of NAC against aortic and myocardial degeneration and fibrosis through down-regulation of CT-1 in fructose induced MS animal model.}, }
@article {pmid33505724, year = {2021}, author = {Zangeneh, AR and Takhshid, MA and Ranjbaran, R and Maleknia, M and Meshkibaf, MH}, title = {Diverse Effect of Vitamin C and N-Acetylcysteine on Aluminum-Induced Eryptosis.}, journal = {Biochemistry research international}, volume = {2021}, number = {}, pages = {6670656}, pmid = {33505724}, issn = {2090-2247}, abstract = {PURPOSE: The role of oxidative stress in Aluminum (Al)-induced apoptotic effects has been investigated and suicidal death of erythrocytes, eryptosis, is characterized by cell shrinkage and phosphatidylserine externalization (PSE) at the surface of the erythrocyte cell membrane. Eryptosis is stimulated by an increase in cytosolic Ca[2+] concentration and reactive oxygen species (ROS). This ex vivo study was conducted to evaluate the effect of well-known antioxidants including vitamin C (vit C) and N-acetylcysteine (NAC), against Al-induced hemolysis and eryptosis.<br><br>METHODS: Isolated erythrocytes from the healthy volunteers were partitioned into various groups (6 replicates/group) and treated by various concentrations of Al (3-100&#x2009;&#xb5;M) in the presence and absence of vit C (0.6&#x2009;mM) and NAC (1&#x2009;mM). After 24&#x2009;hours of treatment, hemolysis was determined from hemoglobin levels in the supernatant. Flowcytometric methods were applied to measure PSE, cell shrinkage, Ca[2+] content, and ROS abundance using annexin V-binding, forward scatter, Fluo3-fluorescence, and DCFDA dependent fluorescence, respectively. Reduced glutathione (GSH) was measured by the ELISA method.<br><br>RESULTS: The results showed that a 24&#x2009;hours' exposure of the erythrocytes to Al (10-100&#x2009;&#xb5;M) significantly increased hemolysis in a dose and Ca[2+]dependent manner. Al also dramatically decreased forward scatter. The percentage of PSE cells, Fluo3-fluorescence, and DCFDA fluorescence were increased by Al. Furthermore, cotreatment with NAC inhibited the effect of Al on hemolysis, eryptosis, and ROS production. Vit C decreased Al-induced ROS production. However, increased Al-induced eryptosis. There were no significant changes in glutathione after the ALCL3 treatment.<br><br>CONCLUSIONS: Al-induced eryptosis and hemolysis through triggering oxidative stress, while NAC could diverse this effect. In contrast, vit C might intensify Al-induced eryptosis at particular doses through a less known mechanism.}, }
@article {pmid33503268, year = {2021}, author = {Weekate, K and Chuenjitkuntaworn, B and Chuveera, P and Vaseenon, S and Chompu-Inwai, P and Ittichaicharoen, J and Chattipakorn, S and Srisuwan, T}, title = {Alterations of mitochondrial dynamics, inflammation and mineralization potential of lipopolysaccharide-induced human dental pulp cells after exposure to N-acetyl cysteine, Biodentine or ProRoot MTA.}, journal = {International endodontic journal}, volume = {54}, number = {6}, pages = {951-965}, doi = {10.1111/iej.13484}, pmid = {33503268}, issn = {1365-2591}, mesh = {Acetylcysteine/pharmacology ; *Aluminum Compounds/toxicity ; Calcium Compounds/toxicity ; Cells, Cultured ; Dental Pulp ; Drug Combinations ; Escherichia coli ; Humans ; Inflammation ; *Lipopolysaccharides/pharmacology ; Mitochondrial Dynamics ; Osteogenesis ; Oxides ; Root Canal Filling Materials ; Silicates/toxicity ; }, abstract = {AIM: To investigate the effects of N-acetyl cysteine (NAC), Biodentine, ProRoot MTA and their combinations, on cell viability, mitochondrial reactive oxygen species (mtROS) production, mineralization and on the expression of genes related to inflammatory cytokine production, mitochondrial dynamics and cell apoptosis of lipopolysaccharide (LPS)-induced human dental pulp cells (hDPCs).<br><br>METHODOLOGY: Isolated hDPCs were exposed to 20&#xa0;&#x3bc;g&#xa0;mL[-1] of Escherichia coli (E. coli) LPS for 24&#xa0;h, before the experiment, except for the control group. Eight experimental groups were assigned: (i) control (hDPCs cultured in regular medium), (ii) +LPS (hDPCs cultured in LPS medium throughout the experiment), (iii) -LPS/Media, (iv) -LPS/BD, (v) -LPS/MTA, (vi) -LPS/NAC, (vii) -LPS/BD&#xa0;+&#xa0;NAC and (viii) -LPS/MTA&#xa0;+&#xa0;NAC. Cell viability was measured using Alamar blue assay at 24 and 48&#xa0;h. Production of mtROS was evaluated at 6 and 24&#xa0;h by MitoSOX Red and MitoTracker Green. The expressions of IL-6, TNF-&#x3b1;, Bcl-2, Bax, Mfn-2 and Drp-1 genes were investigated at 6&#xa0;h using reverse transcriptase-polymerase chain reaction (RT-PCR). For differentiation potential, cells were cultured in the osteogenic differentiation media and stained using Alizarin red assay at 14 and 21&#xa0;days. The Kruskal-Wallis test, Mann-Whitney U test and one-way anova were performed for statistical analysis.<br><br>RESULTS: NAC was associated with significantly greater LPS-induced hDPC viability (P&#xa0;<&#xa0;0.05). Both Biodentine and MTA extracts promoted cell survival, whereas the combination of NAC to these material extracts significantly increased the number of viable cells at 24&#xa0;h (P&#xa0;<&#xa0;0.05). Biodentine, MTA or NAC did not alter the mtROS level (P&#xa0;>&#xa0;0.05). NAC supplementation to the MTA extract significantly reduced the level of IL-6 and TNF-&#x3b1; expression (P&#xa0;<&#xa0;0.05). Regarding mitochondrial dynamics, the use of NAC alone promoted significant Mfn-2/Drp-1 expression (P&#xa0;<&#xa0;0.05). Most of the groups exhibited a level of Bcl-2/Bax gene expression similar to that of the control group. The increases in mineralization productions were observed in most of the groups, except the LPS group (P&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: The antioxidant effect of NAC was not evident under the LPS-induced condition in DPC in vitro. NAC combined either with Biodentine or MTA improved LPS-induced hDPCs survival at 24&#xa0;h. The combination of NAC with MTA promoted mineralization.}, }
@article {pmid33499140, year = {2021}, author = {Domazetovic, V and Falsetti, I and Viglianisi, C and Vasa, K and Aurilia, C and Stio, M and Menichetti, S and Iantomasi, T}, title = {Protective Role of Natural and Semi-Synthetic Tocopherols on TNFα-Induced ROS Production and ICAM-1 and Cl-2 Expression in HT29 Intestinal Epithelial Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {2}, pages = {}, pmid = {33499140}, issn = {2076-3921}, abstract = {Vitamin E, a fat-soluble compound, possesses both antioxidant and non-antioxidant properties. In this study we evaluated, in intestinal HT29 cells, the role of natural tocopherols, α-Toc and δ-Toc, and two semi-synthetic derivatives, namely bis-δ-Toc sulfide (δ-Toc)2S and bis-δ-Toc disulfide (δ-Toc)2S2, on TNFα-induced oxidative stress, and intercellular adhesion molecule-1 (ICAM-1) and claudin-2 (Cl-2) expression. The role of tocopherols was compared to that of N-acetylcysteine (NAC), an antioxidant precursor of glutathione synthesis. The results show that all tocopherol containing derivatives used, prevented TNFα-induced oxidative stress and the increase of ICAM-1 and Cl-2 expression, and that (δ-Toc)2S and (δ-Toc)2S2 are more effective than δ-Toc and α-Toc. The beneficial effects demonstrated were due to tocopherol antioxidant properties, but suppression of TNFα-induced Cl-2 expression seems not only to be related with antioxidant ability. Indeed, while ICAM-1 expression is strongly related to the intracellular redox state, Cl-2 expression is TNFα-up-regulated by both redox and non-redox dependent mechanisms. Since ICAM-1 and Cl-2 increase intestinal bowel diseases, and cause excessive recruitment of immune cells and alteration of the intestinal barrier, natural and, above all, semi-synthetic tocopherols may have a potential role as a therapeutic support against intestinal chronic inflammation, in which TNFα represents an important proinflammatory mediator.}, }
@article {pmid33498875, year = {2021}, author = {Kwon, Y}, title = {Possible Beneficial Effects of N-Acetylcysteine for Treatment of Triple-Negative Breast Cancer.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {2}, pages = {}, pmid = {33498875}, issn = {2076-3921}, support = {2020R1A2C1005730//National Research Foundation of Korea/ ; }, abstract = {N-acetylcysteine (NAC) is a widely used antioxidant with therapeutic potential. However, the cancer-promoting effect of NAC observed in some preclinical studies has raised concerns regarding its clinical use. Reactive oxygen species (ROS) can mediate signaling that results in both cancer-promoting and cancer-suppressing effects. The beneficial effect of NAC may depend on whether the type of cancer relies on ROS signaling for its survival and metastasis. Triple-negative breast cancer (TNBC) has aggressive phenotypes and is currently treated with standard chemotherapy as the main systemic treatment option. Particularly, basal-like TNBC cells characterized by inactivated BRCA1 and mutated TP53 produce high ROS levels and rely on ROS signaling for their survival and malignant progression. In addition, the high ROS levels in TNBC cells can mediate the interplay between cancer cells and the tissue microenvironment (TME) to trigger the recruitment and conversion of stromal cells and induce hypoxic responses, thus leading to the creation of cancer-supportive TMEs and increased cancer aggressiveness. However, NAC treatment effectively reduces the ROS production and ROS-mediated signaling that contribute to cell survival, metastasis, and drug resistance in TNBC cells. Therefore, the inclusion of NAC in standard chemotherapy could probably provide additional benefits for TNBC patients.}, }
@article {pmid33498402, year = {2021}, author = {Blanco Ayala, TB and Ramírez Ortega, DR and Ovalle Rodríguez, PO and Pineda, B and Pérez de la Cruz, GP and González Esquivel, DG and Schwarcz, R and Sathyasaikumar, KV and Jiménez Anguiano, AJ and Pérez de la Cruz, VP}, title = {Subchronic N-acetylcysteine Treatment Decreases Brain Kynurenic Acid Levels and Improves Cognitive Performance in Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {2}, pages = {}, pmid = {33498402}, issn = {2076-3921}, support = {P50 MH103222/MH/NIMH NIH HHS/United States ; 286885//Consejo Nacional de Ciencia y Tecnolog&#xed;a/ ; }, abstract = {The tryptophan (Trp) metabolite kynurenic acid (KYNA) is an α7-nicotinic and N-methyl-d-aspartate receptor antagonist. Elevated brain KYNA levels are commonly seen in psychiatric disorders and neurodegenerative diseases and may be related to cognitive impairments. Recently, we showed that N-acetylcysteine (NAC) inhibits kynurenine aminotransferase II (KAT II), KYNA's key biosynthetic enzyme, and reduces KYNA neosynthesis in rats in vivo. In this study, we examined if repeated systemic administration of NAC influences brain KYNA and cognitive performance in mice. Animals received NAC (100 mg/kg, i.p.) daily for 7 days. Redox markers, KYNA levels, and KAT II activity were determined in the brain. We also assessed the effect of repeated NAC treatment on Trp catabolism using brain tissue slices ex vivo. Finally, learning and memory was evaluated with and without an acute challenge with KYNA's bioprecursor L-kynurenine (Kyn; 100 mg/kg). Subchronic NAC administration protected against an acute pro-oxidant challenge, decreased KYNA levels, and lowered KAT II activity and improved memory both under basal conditions and after acute Kyn treatment. In tissue slices from these mice, KYNA neosynthesis from Trp or Kyn was reduced. Together, our data indicate that prolonged treatment with NAC may enhance memory at least in part by reducing brain KYNA levels.}, }
@article {pmid33496364, year = {2021}, author = {Dutta, RK and Maharjan, Y and Lee, JN and Park, C and Ho, YS and Park, R}, title = {Catalase deficiency induces reactive oxygen species mediated pexophagy and cell death in the liver during prolonged fasting.}, journal = {BioFactors (Oxford, England)}, volume = {47}, number = {1}, pages = {112-125}, doi = {10.1002/biof.1708}, pmid = {33496364}, issn = {1872-8081}, support = {GIST Research Institute (GRI) IIBR grant funded by the GIST in 2020//Gwangju Institute of Science and Technology/ ; 2019R1A2C208608012//National Research Foundation of Korea/ ; 2018R1A5A1024340//National Research Foundation of Korea/ ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Catalase/genetics/*physiology ; Cells, Cultured ; Food Deprivation ; Hepatitis/drug therapy/etiology/metabolism/pathology ; Liver/metabolism/*pathology ; *Macroautophagy ; Mice, Knockout ; *Peroxisomes ; Reactive Oxygen Species/*metabolism ; Mice ; }, abstract = {Peroxisomes are dynamic organelles that participate in a diverse array of cellular processes, including β-oxidation, which produces a considerable amount of reactive oxygen species (ROS). Although we showed that catalase depletion induces ROS-mediated pexophagy in cells, the effect of catalase deficiency during conditions that favor ROS generation remains elusive in mice. In this study, we reported that prolonged fasting in catalase-knockout (KO) mice drastically increased ROS production, which induced liver-specific pexophagy, an autophagic degradation of peroxisomes. In addition, increased ROS generation induced the production of pro-inflammatory cytokines in the liver tissues of catalase-KO mice. Furthermore, there was a significant increase in the levels of aspartate transaminase and alanine transaminase as well as apparent cell death in the liver of catalase-KO mice during prolonged fasting. However, an intra-peritoneal injection of the antioxidant N-acetyl-l-cysteine (NAC) and autophagy inhibitor chloroquine inhibited the inflammatory response, liver damage, and pexophagy in the liver of catalase-KO mice during prolonged fasting. Consistently, genetic ablation of autophagy, Atg5 led to suppression of pexophagy during catalase inhibition by 3-aminotriazole (3AT). Moreover, treatment with chloroquine also ameliorated the inflammatory response and cell death in embryonic fibroblast cells from catalase-KO mice. Taken together, our data suggest that ROS-mediated liver-specific pexophagy observed during prolonged fasting in catalase-KO mice may be responsible for the process associated with hepatic cell death.}, }
@article {pmid33495825, year = {2021}, author = {Fang, X and Liu, L and Zhou, S and Zhu, M and Wang, B}, title = {N‑acetylcysteine inhibits atherosclerosis by correcting glutathione‑dependent methylglyoxal elimination and dicarbonyl/oxidative stress in the aorta of diabetic mice.}, journal = {Molecular medicine reports}, volume = {23}, number = {3}, pages = {}, pmid = {33495825}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta/*metabolism/pathology ; *Atherosclerosis/drug therapy/genetics/metabolism/pathology ; *Diabetes Complications/drug therapy/genetics/metabolism ; *Diabetes Mellitus, Experimental/drug therapy/genetics/metabolism/pathology ; Glutathione/*metabolism ; Male ; Mice ; Mice, Knockout, ApoE ; Oxidative Stress/*drug effects ; Pyruvaldehyde/*metabolism ; }, abstract = {In diabetic animal models, high plasma/tissue levels of methylglyoxal (MG) are implicated in atherosclerosis. N‑acetylcysteine (NAC) is a cysteine prodrug that replenishes intracellular glutathione (GSH) levels, which can increase the elimination of MG in diabetes mellitus (DM). The present study investigated the anti‑atherosclerotic role of NAC in DM and aimed to determine whether the mechanism involved GSH‑dependent MG elimination in the aorta. Apolipoprotein‑E knockdown (ApoE‑/‑) mice injected with streptozotocin for 5 days exhibited enhanced atherosclerotic plaque size in the aortic root; notably, a high‑lipid diet aggravated this alteration. NAC treatment in the drinking water for 12 weeks decreased the size of the atherosclerotic lesion, which was associated with a reduction in MG‑dicarbonyl stress and oxidative stress, as indicated by decreased serum malondialdehyde levels, and increased superoxide dismutase‑1 and glutathione peroxidase‑1 levels in the diabetic aorta. Endothelial damage was also corrected by NAC, as indicated by an increase in the expression levels of phosphorylated (p‑)Akt and p‑endothelial nitric oxide synthase (eNOS) in the aorta, as well as nitric oxide (NO) in the serum. In addition, MG‑treated human umbilical vein endothelial cells (HUVECs) exhibited increased reactive oxygen species and decreased antioxidant enzyme expression levels. NAC treatment corrected the alteration in HUVECs induced by MG, whereas the protective role of NAC was blocked via inhibition of GSH. These findings indicated that the diabetic aorta was more susceptible to atherosclerotic lesions compared with non‑diabetic ApoE‑/‑ mice. Furthermore, NAC may offer protection against atherosclerotic development in DM by altering aortic and systemic responses via correcting GSH‑dependent MG elimination, leading to decreased oxidative stress and restoration of the p‑Akt/p‑eNOS pathway in the aorta.}, }
@article {pmid33495407, year = {2021}, author = {Li, D and Kou, Y and Gao, Y and Liu, S and Yang, P and Hasegawa, T and Su, R and Guo, J and Li, M}, title = {Oxaliplatin induces the PARP1-mediated parthanatos in oral squamous cell carcinoma by increasing production of ROS.}, journal = {Aging}, volume = {13}, number = {3}, pages = {4242-4257}, pmid = {33495407}, issn = {1945-4589}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Cell Line, Tumor ; Glutathione/drug effects/metabolism ; Humans ; Mice ; Mitochondria/*drug effects/metabolism ; Mouth Neoplasms/*metabolism/pathology ; Neoplasm Transplantation ; Oxaliplatin/*pharmacology ; Parthanatos/*drug effects ; Poly (ADP-Ribose) Polymerase-1/*drug effects ; Reactive Oxygen Species/*metabolism ; Squamous Cell Carcinoma of Head and Neck/*metabolism/pathology ; Superoxide Dismutase/drug effects/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide, and its prognosis is still not optimistic. Oxaliplatin is a type of platinum chemotherapeutic agent, but its treatment effects on OSCC and molecular mechanisms have not been fully elucidated. Parthanatos, a unique form of cell death, plays an important role in a variety of physiological and pathological processes. This study aims to investigate whether oxaliplatin inhibits OSCC by inducing parthanatos. Our results showed that oxaliplatin inhibited the proliferation and migration of OSCC cells in vitro, and also inhibited the tumorigenesis in vivo. Further experiments proved that oxaliplatin induced parthanatos in OSCC cells, characterized by depolarization of the mitochondrial membrane potential, up-regulation of PARP1, AIF and MIF in the nucleus, as well as the nuclear translocation of AIF. Meanwhile, PARP1 inhibitor rucaparib and siRNA against PARP1 attenuated oxaliplatin-induced parthanatos in OSCC cells. In addition, we found that oxaliplatin caused oxidative stress in OSCC cells, and antioxidant NAC not only relieved oxaliplatin-induced overproduction of reactive oxygen species (ROS) but also reversed parthanatos caused by oxaliplatin. In conclusion, our results indicate that oxaliplatin inhibits OSCC by activating PARP1-mediated parthanatos through increasing the production of ROS.}, }
@article {pmid33494270, year = {2021}, author = {Devrim-Lanpir, A and Hill, L and Knechtle, B}, title = {How N-Acetylcysteine Supplementation Affects Redox Regulation, Especially at Mitohormesis and Sarcohormesis Level: Current Perspective.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {2}, pages = {}, pmid = {33494270}, issn = {2076-3921}, abstract = {Exercise frequently alters the metabolic processes of oxidative metabolism in athletes, including exposure to extreme reactive oxygen species impairing exercise performance. Therefore, both researchers and athletes have been consistently investigating the possible strategies to improve metabolic adaptations to exercise-induced oxidative stress. N-acetylcysteine (NAC) has been applied as a therapeutic agent in treating many diseases in humans due to its precursory role in the production of hepatic glutathione, a natural antioxidant. Several studies have investigated NAC's possible therapeutic role in oxidative metabolism and adaptive response to exercise in the athletic population. However, still conflicting questions regarding NAC supplementation need to be clarified. This narrative review aims to re-evaluate the metabolic effects of NAC on exercise-induced oxidative stress and adaptive response developed by athletes against the exercise, especially mitohormetic and sarcohormetic response.}, }
@article {pmid33489797, year = {2020}, author = {Huang, S and He, T and Yang, S and Sheng, H and Tang, X and Bao, F and Wang, Y and Lin, X and Yu, W and Cheng, F and Lv, W and Hu, J}, title = {Metformin reverses chemoresistance in non-small cell lung cancer via accelerating ubiquitination-mediated degradation of Nrf2.}, journal = {Translational lung cancer research}, volume = {9}, number = {6}, pages = {2337-2355}, pmid = {33489797}, issn = {2218-6751}, abstract = {BACKGROUND: The therapeutic efficacy of cisplatin-based chemotherapy for non-small cell lung cancer (NSCLC) is limited by drug resistance. In NSCLC, hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) counteracts oxidative stress to promote chemoresistance. Metformin-mediated downregulation of Nrf2 plays a pivotal role in overcoming drug resistance in NSCLC cells. Therefore, a deeper understanding of the molecular mechanisms of combination therapy and the role of Nrf2 in chemotherapeutic response is critical to clinical translation.<br><br>METHODS: The effects of combination therapy with metformin and cisplatin on cell proliferation and apoptosis, intracellular reactive oxygen species (ROS) levels, and xenograft tumor formation were analyzed in NSCLC cells. Co-immunoprecipitation (co-IP) and Phos-tag assays were used to explore the mechanism of metformin-mediated Nrf2 suppression. Immunohistochemical (IHC) staining was performed to detect Nrf2 expression in matched tumor samples before and after neoadjuvant chemotherapy.<br><br>RESULTS: Metformin was observed to synergistically augment cisplatin-induced cytotoxicity by strongly inhibiting the level of Nrf2, thereby weakening the antioxidant system and detoxification ability of Nrf2 and enhancing ROS-mediated apoptosis in NSCLC. The synergistic antitumor effect of combination therapy is blocked by treatment with the ROS scavenger N-acetyl cysteine (NAC) as well as overexpression of Nrf2 and its downstream antioxidant protein. Mechanistically, metformin extensively dephosphorylates Nrf2 by attenuating the interaction between Nrf2 and extracellular signal-regulated kinases 1/2 (ERK1/2), which then restores its polyubiquitination and accelerates its proteasomal degradation. Moreover, for the first time, an association of non-decreased Nrf2 expression in patients after neoadjuvant chemotherapy with poor survival and chemoresistance in NSCLC was revealed.<br><br>CONCLUSIONS: Our findings illustrate the mechanism of metformin-mediated Nrf2 degradation through posttranslational modifications (PTMs), which weakens the ROS defense system in NSCLC. Fluctuations in Nrf2 expression have a strong predictive ability for chemotherapeutic response in neoadjuvant NSCLC patients. Targeting of the Nrf2 pathway could be a therapeutic strategy for overcoming chemoresistance, with metformin as the first choice for this strategy.}, }
@article {pmid33489034, year = {2020}, author = {Seyedian, R and Shabankareh Fard, E and Najafiasl, M and Assadi, M and Zaeri, S}, title = {N-acetylcysteine-loaded electrospun mats improve wound healing in mice and human fibroblast proliferation in vitro: a potential application of nanotechnology in wound care.}, journal = {Iranian journal of basic medical sciences}, volume = {23}, number = {12}, pages = {1590-1602}, pmid = {33489034}, issn = {2008-3866}, abstract = {OBJECTIVES: N-acetylcysteine (NAC) has gained attention recently in dermatology as a unique anti-oxidant. In light of progress in nanotechnological methods, it was hypothesized that loading NAC onto nanofibers would positively affect skin wound healing. The objective of this study was to fabricate NAC-loaded electrospun mats and test their effect on wound healing in vivo and in vitro.<br><br>MATERIALS AND METHODS: Polyvinyl alcohol (PVA)-based mats loaded with NAC at three concentrations were electrospun and characterized in terms of physicochemical properties and drug release profile. Human fibroblast cells (in vitro) and mouse full-thickness skin wounds (in vivo) were treated with mats for 5 and 14 days, respectively. Wound area, tissue histopathology, fibroblast proliferation and cellular oxidative state were evaluated.<br><br>RESULTS: Mats containing 5% PVA/NAC showed thinner fibers with suitable physicochemical properties and a sustained drug release profile. PVA/NAC (5%) mats enhanced fibroblast proliferation and attachment in vitro. The mats resulted in significant wound closure with high levels of re-epithelialization and collagen fiber synthesis on day 14 post-surgery in vivo. The mats also reduced granulation tissue and edematous stroma to a higher extent. These findings were accompanied by a significant decrease in tissue lipid peroxidation and higher superoxide dismutase activity, which may explain how NAC improved wound healing.<br><br>CONCLUSION: We propose an NAC-loaded nanofibrous mat that takes the advantage of a porous nanoscaffold structure to release NAC in a sustained manner. This mat may be a promising candidate for further clinical evaluation.}, }
@article {pmid33488110, year = {2021}, author = {Shi, C and Yue, F and Shi, F and Qin, Q and Wang, L and Wang, G and Mu, L and Liu, D and Li, Y and Yu, T and She, J}, title = {Selenium-Containing Amino Acids Protect Dextran Sulfate Sodium-Induced Colitis via Ameliorating Oxidative Stress and Intestinal Inflammation.}, journal = {Journal of inflammation research}, volume = {14}, number = {}, pages = {85-95}, pmid = {33488110}, issn = {1178-7031}, abstract = {BACKGROUND: Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation of the gastrointestinal tract. Oxidative stress plays a pivotal role in the pathogenesis of IBD. Selenium-containing amino acids reportedly have anti-oxidative and anti-inflammatory properties, but it remains unknown if selenium-containing amino acids can be used to treat IBD. This study aimed to investigate the effects of two selenium-containing amino acids - selenocysteine and selenocystine - on oxidative stress and chronic inflammation in a mouse model of dextran sulfate sodium (DSS)-induced IBD.<br><br>METHODOLOGY: C57BL/6 mice were randomly assigned to the following six groups: control, DSS, DSS+selenocysteine, DSS+selenocystine, DSS+sodium selenite, and DSS+N-acetylcysteine (NAC). IBD was induced by 3% DSS. Pro-inflammatory cytokines [interleukin-1&#x3b2; (IL-1&#x3b2;), monocyte chemotactic protein 1 (MCP-1), IL-6, and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;)] and markers for oxidative and anti-oxidative stress [malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] were measured using immunohistochemical analysis.<br><br>RESULTS: Selenocysteine and selenocystine significantly attenuated IBD-related symptoms, including preventing weight loss, decreasing disease activity index (DAI) scores, and increasing colon length. Selenocysteine and selenocystine significantly ameliorated the DSS-induced oxidative stress, as demonstrated by a reduction in ROS and MDA activity and an increase in SOD and GPx activity. IL-1, MCP-1, IL-6, and TNF-&#x3b1; levels were significantly increased in the IBD mice, while treatment with the selenium-containing amino acids significantly reduced the levels of these pro-inflammatory cytokines. In vivo safety analysis showed minimal side effects of the selenium-containing amino acids.<br><br>CONCLUSION: We found that selenocysteine and selenocystine ameliorated DSS-induced IBD via reducing oxidative stress and intestinal inflammation, indicating that selenium-containing amino acids could be a novel therapeutic option for patients with IBD.}, }
@article {pmid33488104, year = {2021}, author = {Wang, B and Li, Y and You, C}, title = {miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway.}, journal = {Diabetes, metabolic syndrome and obesity : targets and therapy}, volume = {14}, number = {}, pages = {153-163}, pmid = {33488104}, issn = {1178-7007}, abstract = {INTRODUCTION: Glucose fluctuations have an adverse effect on several diabetes-related complications, especially for the nervous system, but the underlying mechanisms are not clear. MicroRNAs are critical regulators of posttranscription in many physiological processes, such as apoptosis. Our study clarified the neuroprotective effects of miR-129-3p targeting mitochondrial calcium uniporter (MCU) in glucose fluctuation-mediated neuronal damage and the specific mechanisms involved.<br><br>METHODS: The expression of MCU and miR-129-3p was examined by real-time PCR and Western blot in the glucose fluctuation cell model. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-129-3p by MCU. Fluorescent probe and assay kit assay was used to determine oxidative stress condition. Mitochondrial-dependent intrinsic apoptotic factors were examined by flow cytometry assay, enzyme-linked immunosorbent assay (ELISA), and gene and protein expression assays.<br><br>RESULTS: We found an upregulation of MCU and downregulation of miR-129-3p in glucose fluctuation-treated primary hippocampal neuronal cells, and miR-129-3p directly targeted MCU. miR-129-3p overexpression produced a dramatic reduction in calcium overload, reactive oxygen species (ROS) generation, GSH-to-GSSG ratio, MMP-2 expression in the mitochondrial-dependent intrinsic apoptosis pathway and an increase in MnSOD activity. Increasing MCU expression rescued the effects of miR-129-3p overexpression. miR-129-3p downregulation produced a significant increase in calcium overload, reactive oxygen species (ROS) generation, MMP-2 expression, cytochrome c release and cell apoptosis, and antioxidant N-acetyl cysteine (NAC) rescued the effects of miR-129-3p downregulation.<br><br>CONCLUSION: Therefore, miR-129-3p suppressed glucose fluctuation-mediated neuronal damage by targeting MCU via a mitochondrial-dependent intrinsic apoptotic pathway. The miR-129-3p/MCU axis may be a promising therapeutic target for glucose fluctuation-mediated neuronal damage.}, }
@article {pmid33486763, year = {2021}, author = {Imam, H and Nguyen, TH and Stafford, I and Liu, S and Heresztyn, T and Chirkov, YY and Horowitz, JD}, title = {Impairment of platelet NO signalling in coronary artery spasm: role of hydrogen sulphide.}, journal = {British journal of pharmacology}, volume = {178}, number = {7}, pages = {1639-1650}, doi = {10.1111/bph.15388}, pmid = {33486763}, issn = {1476-5381}, mesh = {*Blood Platelets ; Coronary Vessels ; Humans ; *Hydrogen Sulfide/pharmacology ; Platelet Aggregation ; Platelet Aggregation Inhibitors/pharmacology ; Spasm ; }, abstract = {BACKGROUND AND PURPOSE: The pathophysiology of coronary artery spasm (CAS), with its associated ischaemic crises, is currently poorly understood and treatment is frequently ineffective. In view of increasing evidence that platelet-based defects may occur in CAS patients, we investigated platelet reactivity in CAS patients and whether symptomatic crises reflect activation of platelet-endothelial interactions.<br><br>EXPERIMENTAL APPROACH: CAS patients were evaluated during acute and/or chronic symptomatic phases and compared with healthy control subjects. Inhibition of ADP-induced platelet aggregation by the NO donor sodium nitroprusside (SNP) and plasma concentrations of syndecan 1 (glycocalyx shedding marker), tryptase (mast cell activation marker) and platelet microparticles were measured.<br><br>KEY RESULTS: Inhibition of platelet aggregation by SNP was diminished in chronic CAS, with further (non-significant) deterioration during symptomatic crises, whereas plasma concentrations of syndecan 1, tryptase and platelet microparticles increased. Treatment of patients with high-dose N-acetylcysteine (NAC) plus glyceryl trinitrate rapidly increased platelet responsiveness to SNP and decreased plasma syndecan 1 concentrations. The effect of NAC on platelet responsiveness to SNP was confirmed in vitro and mimicked by the H2 S donor NaHS. Conversely, inhibition of enzymatic production of H2 S attenuated NAC effect.<br><br>CONCLUSION AND IMPLICATIONS: CAS is associated with substantial impairment of platelet NO signalling. During acute symptomatic exacerbations, platelet resistance to NO is aggravated, together with mast cell activation and damage to both vasculature and platelets. NAC, via release of H2 S, reverses platelet resistance to NO and terminates glycocalyx shedding during symptomatic crises: This suggests that H2 S donors may correct the pathophysiological anomalies underlying CAS.}, }
@article {pmid33486268, year = {2021}, author = {Fan, X and Xie, M and Zhao, F and Li, J and Fan, C and Zheng, H and Wei, Z and Ci, X and Zhang, S}, title = {Daphnetin triggers ROS-induced cell death and induces cytoprotective autophagy by modulating the AMPK/Akt/mTOR pathway in ovarian cancer.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {82}, number = {}, pages = {153465}, doi = {10.1016/j.phymed.2021.153465}, pmid = {33486268}, issn = {1618-095X}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Apoptosis/drug effects ; Autophagy/*drug effects ; Cell Death ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Female ; Humans ; Ovarian Neoplasms/enzymology/metabolism/*pathology ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Umbelliferones/*pharmacology ; }, abstract = {BACKGROUND: Ovarian cancer is one of the most common gynecological malignancies in the world. Daphnetin (Daph) was previously reported to possess antitumor potential, but its potential and molecular mechanisms in ovarian cancer remain poorly understood.<br><br>PURPOSE: In the current study, we aimed to explore the antitumor effect and detailed mechanisms of Daph in ovarian cancer cells.<br><br>METHODS: The cytotoxic effect of Daph on ovarian cells was determined in vitro and in vivo. Cell growth, proliferation, apoptosis and ROS generation were measured by CCK8 assays, colony formation assays and flow cytometry. Western blotting was used to evaluate the related signal proteins. Immunofluorescence and transmission electron microscopy were used to evaluate markers of autophagy and autophagic flux. The antitumor effects were observed in the A2780 xenograft model. Moreover, Daph-induced autophagy was observed by enhanced LC3-II accumulation and endogenous LC3 puncta, and an autophagy inhibitor further enhanced the antitumor efficacy of Daph, which indicated that the cytoprotective role of autophagy in ovarian cancer.<br><br>RESULTS: We found that Daph exhibited antitumor effects by inducing ROS-dependent apoptosis in ovarian cancer, which could be reversed by N-acetyl cysteine (NAC). The AMPK/Akt/mTOR pathway was involved in Daph-mediated cytoprotective autophagy, and when Daph-mediated the expression level of AMPK and autophagy were blocked, there was robust inhibition of cell proliferation and induction of apoptosis. In addition, in the A2780 xenograft model, combined treatment with Daph and an autophagy inhibitor showed obvious synergetic effects on the inhibition of cell viability and promotion of apoptosis, without any side effects.<br><br>CONCLUSION: Our results suggest that Daph triggers ROS-induced cell apoptosis and induces cytoprotective autophagy by modulating the AMPK/Akt/mTOR pathway. Moreover, the combination of Daph and autophagy inhibitor may be a potential therapeutic strategy for ovarian cancer.}, }
@article {pmid33480045, year = {2021}, author = {Aghaamoo, S and Zandbina, A and Saffarieh, E and Nassiri, S}, title = {The effect of N-acetyl cysteine on the volume of uterine leiomyoma: A randomized clinical trial.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {154}, number = {3}, pages = {521-525}, doi = {10.1002/ijgo.13611}, pmid = {33480045}, issn = {1879-3479}, mesh = {Acetylcysteine ; Female ; Humans ; Iran ; *Leiomyoma/drug therapy ; *Uterine Neoplasms/drug therapy ; }, abstract = {OBJECTIVE: To conduct a clinical trial to investigate the effect of N-acetyl cysteine (NAC), a non-hormonal drug, on the volume of leiomyoma, the most common benign tumor in women.<br><br>METHODS: This study is a randomized clinical trial, which was performed in Semnan, Iran. Eligible women who were diagnosed with uterine leiomyoma using vaginal ultrasound were randomly assigned to receive NAC or placebo for 12 weeks. The change in the volume of Leiomyoma was considered to be the main variable in the efficacy evaluation. Reduction in the leiomyoma volume was calculated after intervention and data were entered in SPSS version 23.<br><br>RESULTS: Fifty individuals were enrolled in our study. 25 women received NAC, while 25 women took placebo. The mean volume of leiomyoma in group A was 5.71 cm[3] and in group B was 6.56 cm[3] . The mean rate of volume reduction in the A and B groups was 25.25 % and 1.08 %, respectively, which demonstrated a significant difference between the two groups (P&#xa0;<&#xa0;0.004).<br><br>CONCLUSION: Although this trial recommends the use of NAC as a non-hormonal drug in the treatment of leiomyoma of the uterus, the possibility of treatment failure in controlling abnormal uterine bleeding cannot be ignored. Nevertheless, we can say it is feasible and effective in the reduction of leiomyoma volume.}, }
@article {pmid33478072, year = {2021}, author = {Huang, Z and Hu, H}, title = {Arginine Deiminase Induces Immunogenic Cell Death and Is Enhanced by N-acetylcysteine in Murine MC38 Colorectal Cancer Cells and MDA-MB-231 Human Breast Cancer Cells In Vitro.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {2}, pages = {}, pmid = {33478072}, issn = {1420-3049}, support = {14431904500//Key Projects of Shanghai in Biomedicine/ ; }, mesh = {Acetylcysteine/*chemistry ; Animals ; Apoptosis/drug effects ; Breast Neoplasms/*pathology ; Cell Line, Tumor ; Colorectal Neoplasms/*pathology ; Humans ; Hydrolases/*chemistry/*pharmacology ; Immunogenic Cell Death/*drug effects ; Mice ; Polyethylene Glycols/chemistry ; }, abstract = {The use of arginine deiminase (ADI) for arginine depletion therapy is an attractive anticancer approach. Combination strategies are needed to overcome the resistance of severe types of cancer cells to this monotherapy. In the current study, we report, for the first time, that the antioxidant N-acetylcysteine (NAC), which has been used in therapeutic practices for several decades, is a potent enhancer for targeted therapy that utilizes arginine deiminase. We demonstrated that pegylated arginine deiminase (ADI-PEG 20) induces apoptosis and G0/G1 phase arrest in murine MC38 colorectal cancer cells; ADI-PEG 20 induces Ca[2+] overload and decreases the mitochondrial membrane potential in MC38 cells. ADI-PEG 20 induced the most important immunogenic cell death (ICD)-associated feature: cell surface exposure of calreticulin (CRT). The antioxidant NAC enhanced the antitumor activity of ADI-PEG 20 and strengthened its ICD-associated features including the secretion of high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP). In addition, these regimens resulted in phagocytosis of treated MC38 cancer cells by bone marrow-derived dendritic cells (BMDCs). In conclusion, we describe, for the first time, that NAC in combination with ADI-PEG 20 not only possesses unique cytotoxic anticancer properties but also triggers the hallmarks of immunogenic cell death. Hence, ADI-PEG 20 in combination with NAC may represent a promising approach to treat ADI-sensitive tumors while preventing relapse and metastasis.}, }
@article {pmid33477393, year = {2021}, author = {Guerini, M and Grisoli, P and Pane, C and Perugini, P}, title = {Microstructured Lipid Carriers (MLC) Based on N-Acetylcysteine and Chitosan Preventing Pseudomonas aeruginosa Biofilm.}, journal = {International journal of molecular sciences}, volume = {22}, number = {2}, pages = {}, pmid = {33477393}, issn = {1422-0067}, mesh = {Acetylcysteine/*pharmacology ; Anti-Infective Agents/pharmacology ; Biofilms/drug effects ; Chitosan/*pharmacology ; Drug Delivery Systems/*methods ; Drug Liberation ; Lipids/pharmacology ; Microbial Sensitivity Tests ; Nanoparticles ; Particle Size ; Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa/drug effects/metabolism ; }, abstract = {The aim of this work was the development of microstructured lipid carriers (MLC) based on chitosan (CH) and containing N-acetylcysteine (NAC), a mucolytic and antioxidant agent, to inhibit the formation of Pseudomonas aeruginosa biofilm. MLC were prepared using the high shear homogenization technique. The MLC were characterized for morphology, particle size, Z potential, encapsulation efficiency and drug release. The antioxidant properties of NAC-loaded microstructured carriers were evaluated through an in vitro spectrophotometer assay. Finally, the activity of NAC-CH-MLC on biofilm production by Pseudomonas aeruginosa was also evaluated. Results obtained from this study highlighted that the use of chitosan into the inner aqueous phase permitted to obtain microstructured particles with a narrow size range and with good encapsulation efficiency. NAC-loaded MLC showed higher antioxidant activity than the free molecule, demonstrating how encapsulation increases the antioxidant effect of the molecule. Furthermore, the reduction of biofilm growth resulted extremely high with MLC being 64.74% ± 6.2% and 83.74% ± 9.95%, respectively, at 0.5 mg/mL and 2 mg/mL. In conclusion, this work represents a favorable technological strategy against diseases in which bacterial biofilm is relevant, such as cystic fibrosis.}, }
@article {pmid33473111, year = {2021}, author = {Dupont, AC and Serrière, S and Barantin, L and Vercouillie, J and Tauber, C and Gissot, V and Bodard, S and Chicheri, G and Chalon, S and Bonnet-Brilhault, PF and Santiago-Ribeiro, PM and Arlicot, N}, title = {Study of influence of the glutamatergic concentration of [[18]F]FPEB binding to metabotropic glutamate receptor subtype 5 with N-acetylcysteine challenge in rats and SRM/PET study in human healthy volunteers.}, journal = {Translational psychiatry}, volume = {11}, number = {1}, pages = {66}, pmid = {33473111}, issn = {2158-3188}, mesh = {*Acetylcysteine ; Animals ; Brain/diagnostic imaging/metabolism ; Healthy Volunteers ; Humans ; Positron-Emission Tomography ; Pyridines ; Radiopharmaceuticals ; Rats ; *Receptor, Metabotropic Glutamate 5/metabolism ; }, abstract = {Altered glutamate signaling is thought to be involved in a myriad of psychiatric disorders. Positron emission tomography (PET) imaging with [[18]F]FPEB allows assessing dynamic changes in metabotropic glutamate receptor 5 (mGluR5) availability underlying neuropathological conditions. The influence of endogenous glutamatergic levels into receptor binding has not been well established yet. The purpose of this study was to explore the [[18]F]FPEB binding regarding to physiological fluctuations or acute changes of glutamate synaptic concentrations by a translational approach; a PET/MRS imaging study in 12 healthy human volunteers combined to a PET imaging after an N-acetylcysteine (NAc) pharmacological challenge in rodents. No significant differences were observed with small-animal PET in the test and retest conditions on the one hand and the NAc condition on the other hand for any regions. To test for an interaction of mGuR5 density and glutamatergic concentrations in healthy subjects, we correlated the [[18]F]FPEB BPND with Glu/Cr, Gln/Cr, Glx/Cr ratios in the anterior cingulate cortex VOI; respectively, no significance correlation has been revealed (Glu/Cr: r = 0.51, p = 0.09; Gln/Cr: r = -0.46, p = 0.13; Glx/Cr: r = -0.035, p = 0.92).These data suggest that the in vivo binding of [[18]F]FPEB to an allosteric site of the mGluR5 is not modulated by endogenous glutamate in vivo. Thus, [[18]F]FPEB appears unable to measure acute fluctuations in endogenous levels of glutamate.}, }
@article {pmid33471797, year = {2021}, author = {Wen, LL and Chen, YT and Lee, YG and Ko, TL and Chou, HC and Juan, SH}, title = {Perfluorooctane sulfonate induces autophagy-associated apoptosis through oxidative stress and the activation of extracellular signal-regulated kinases in renal tubular cells.}, journal = {PloS one}, volume = {16}, number = {1}, pages = {e0245442}, pmid = {33471797}, issn = {1932-6203}, mesh = {Alkanesulfonic Acids/*toxicity ; Animals ; Apoptosis/*drug effects ; Autophagy/drug effects ; Cell Line ; Environmental Pollutants/*toxicity ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Fluorocarbons/*toxicity ; Kidney Tubules/cytology/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Rats ; }, abstract = {Perfluorooctane sulfonate (PFOS) is among the most abundant organic pollutants and is widely distributed in the environment, wildlife, and humans. Its toxic effects and biological hazards are associated with its long elimination half-life in humans. However, how it affects renal tubular cells (RTCs) remains unclear. In this study, PFOS was observed to mediate the increase in reactive oxygen species (ROS) generation, followed by the activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway, which induced autophagy in RTCs. Although PFOS treatment induced autophagy after 6 h, prolonged treatment (24 h) reduced the autophagic flux by increasing lysosomal membrane permeability (LMP), leading to increased p62 protein accumulation and subsequent apoptosis. The increase in LMP was visualized through increased green fluorescence with acridine orange staining, and this was attenuated by 3-methyladenine, an autophagy inhibitor. N-acetyl cysteine and an inhibitor of the mitogen-activated protein kinase kinases (U0126) attenuated autophagy and apoptosis. Taken together, these results indicate that ROS activation and ROS-mediated phosphorylated ERK1/2 activation are essential to activate autophagy, resulting in the apoptosis of PFOS-treated RTCs. Our findings provide insight into the mechanism of PFOS-mediated renal toxicity.}, }
@article {pmid33470049, year = {2021}, author = {Qin, Z and Ou, S and Xu, L and Sorensen, K and Zhang, Y and Hu, DP and Yang, Z and Hu, WY and Chen, F and Prins, GS}, title = {Design and synthesis of isothiocyanate-containing hybrid androgen receptor (AR) antagonist to downregulate AR and induce ferroptosis in GSH-Deficient prostate cancer cells.}, journal = {Chemical biology &amp; drug design}, volume = {97}, number = {5}, pages = {1059-1078}, pmid = {33470049}, issn = {1747-0285}, support = {R01 ES028263/ES/NIEHS NIH HHS/United States ; R01 ES028335/ES/NIEHS NIH HHS/United States ; }, mesh = {Androgen Receptor Antagonists/chemical synthesis/metabolism/*pharmacology/therapeutic use ; Binding Sites ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Down-Regulation/*drug effects ; *Drug Design ; Ferroptosis/*drug effects ; Glutathione/metabolism ; Humans ; Isothiocyanates/*chemistry ; Male ; Molecular Docking Simulation ; Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology ; Protein Isoforms/chemistry/genetics/metabolism ; Receptors, Androgen/chemistry/genetics/metabolism ; Transcriptional Activation/drug effects ; }, abstract = {Sustained androgen receptor (AR) signaling and apoptosis evasion are among the main hurdles of castration-resistant prostate cancer (CRPC) treatment. We designed and synthesized isothiocyanate (ITC)-containing hybrid AR antagonist (ITC-ARi) and rationally combined ITC-ARi with GSH synthesis inhibitor buthionine sulfoximine (BSO) to efficiently downregulate AR/AR splice variant and induce ferroptosis in CRPC cells. The representative ITC-ARi 13 is an AR ligand that contains an N-acetyl cysteine-masked ITC moiety and gradually releases parental unconjugated ITC 12b in aqueous solution. The in vitro anti-PCa activities of 13, such as growth inhibition and AR downregulation, are significantly enhanced when combined with BSO. The drug combination caused notable lipid peroxidation and the cell viability was effectively rescued by iron chelator, antioxidants or the inhibitor of heme oxygenase-1, supporting the induction of ferroptosis. 13 and BSO cooperatively downregulate AR and induce ferroptosis likely through increasing the accessibility of 13/12b to cellular targets, escalating free intracellular ferrous iron and attenuating GSH-centered cellular defense and adaptation. Further studies on the combination of ITC-ARi and GSH synthesis inhibitor could result in a new modality against CRPC.}, }
@article {pmid33469619, year = {2020}, author = {Yin, JL and Teo, KS and Philipose, Z}, title = {Normal dose paracetamol in muscular dystrophy patients - is it normal?.}, journal = {The journal of the Royal College of Physicians of Edinburgh}, volume = {50}, number = {4}, pages = {411-413}, doi = {10.4997/JRCPE.2020.413}, pmid = {33469619}, issn = {2042-8189}, mesh = {*Acetaminophen/adverse effects ; Adolescent ; Alanine Transaminase ; *Analgesics, Non-Narcotic/adverse effects ; Humans ; Liver ; Male ; *Muscular Dystrophies/complications/drug therapy ; Risk Factors ; }, abstract = {A 16-year-old male with Becker muscular dystrophy was admitted to hospital with a significant liver injury due to paracetamol. The dosage of paracetamol ingested was within current guidance yet there was sudden derangement of liver function. The patient was treated with five days of N-acetyl cysteine to which he responded, with his alanine aminotransferase improving from 5,599 to 652 and international normalised ratio from 5.0 to 0.9. He had risk factors for paracetamol toxicity as he was malnourished and had muscular dystrophy. The purpose of this case report is to highlight that despite prescribing approved dosages of paracetamol some patients may have toxicity due to altered body composition and pharmacokinetics.}, }
@article {pmid33468168, year = {2021}, author = {Burgum, MJ and Clift, MJD and Evans, SJ and Hondow, N and Tarat, A and Jenkins, GJ and Doak, SH}, title = {Few-layer graphene induces both primary and secondary genotoxicity in epithelial barrier models in vitro.}, journal = {Journal of nanobiotechnology}, volume = {19}, number = {1}, pages = {24}, pmid = {33468168}, issn = {1477-3155}, support = {NC/R001375/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; 80815//European Social Fund/ ; }, mesh = {Alveolar Epithelial Cells ; Animals ; Cell Differentiation ; Cell Line ; Cell Survival/drug effects ; Coculture Techniques ; DNA Damage/*drug effects ; Filaggrin Proteins ; Graphite/*toxicity ; Humans ; Macrophages/drug effects ; Mutagenicity Tests/methods ; Nanostructures/*chemistry ; Oxidative Stress/drug effects ; THP-1 Cells ; }, abstract = {BACKGROUND: Toxicological evaluation of engineered nanomaterials (ENMs) is essential for occupational health and safety, particularly where bulk manufactured ENMs such as few-layer graphene (FLG) are concerned. Additionally, there is a necessity to develop advanced in vitro models when testing ENMs to provide a physiologically relevant alternative to invasive animal experimentation. The aim of this study was to determine the genotoxicity of non-functionalised (neutral), amine- and carboxyl-functionalised FLG upon both human-transformed type-I (TT1) alveolar epithelial cell monocultures, as well as co-cultures of TT1 and differentiated THP-1 monocytes (d.THP-1 (macrophages)).<br><br>RESULTS: In monocultures, TT1 and d.THP-1 macrophages showed a statistically significant (p&#x2009;<&#x2009;0.05) cytotoxic response with each ENM following 24-h exposures. Monoculture genotoxicity measured by the in vitro cytokinesis blocked micronucleus (CBMN) assay revealed significant (p&#x2009;<&#x2009;0.05) micronuclei induction at 8&#xa0;&#xb5;g/ml for amine- and carboxyl-FLG. Transmission electron microscopy (TEM) revealed ENMs were internalised by TT1 cells within membrane-bound vesicles. In the co-cultures, ENMs induced genotoxicity in the absence of cytotoxic effects. Co-cultures pre-exposed to 1.5&#xa0;mM&#xa0;N-acetylcysteine (NAC), showed baseline levels of micronuclei induction, indicating that the genotoxicity observed was driven by oxidative stress.<br><br>CONCLUSIONS: Therefore, FLG genotoxicity when examined in monocultures, results in primary-indirect DNA damage; whereas co-cultured cells reveal secondary mechanisms of DNA damage.}, }
@article {pmid33466457, year = {2021}, author = {Berrino, E and Carradori, S and Angeli, A and Carta, F and Supuran, CT and Guglielmi, P and Coletti, C and Paciotti, R and Schweikl, H and Maestrelli, F and Cerbai, E and Gallorini, M}, title = {Dual Carbonic Anhydrase IX/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {10}, number = {1}, pages = {}, pmid = {33466457}, issn = {2076-3921}, abstract = {Low concentrations of carbon monoxide (CO) were reported to exhibit anti-inflammatory effects when administered in cells by suitable chemotypes such as CO releasing molecules (CO-RMs). In addition, the pH-modulating abilities of specific carbonic anhydrase isoforms played a crucial role in different models of inflammation and neuropathic pain. Herein, we report a series of chemical hybrids consisting of a Carbonic Anhydrase (CA) inhibitor linked to a CO-RM tail (CAI/CO-RMs). All compounds and their precursors were first tested in vitro for their inhibition activity against the human CA I, II, IX, and XII isoforms as well their CO releasing properties, aiming at corroborating the data by means of molecular modelling techniques. Then, their impact on metabolic activity modulation of RAW 264.7 mouse macrophages for 24 and 48 h was assessed with or without lipopolysaccharide (LPS) stimulation. The compounds were shown to counteract the inflammatory stimulus as also indicated by the reduced tumor necrosis factor alpha (TNF-α) release after treatment. All the biological results were compared to those of N-acetylcysteine (NAC) as a reference antioxidant compound. Within the series, two CAI/CO-RM hybrids (1 and 2), bearing both the well-known scaffold able to inhibit CAs (acesulfame) and the cobalt-based CO releasing portion, induced a higher anti-inflammatory effect up to 48 h at concentrations lower than NAC.}, }
@article {pmid33466433, year = {2021}, author = {Pape, VFS and Gaál, A and Szatmári, I and Kucsma, N and Szoboszlai, N and Streli, C and Fülöp, F and Enyedy, &#xc9;A and Szakács, G}, title = {Relation of Metal-Binding Property and Selective Toxicity of 8-Hydroxyquinoline Derived Mannich Bases Targeting Multidrug Resistant Cancer Cells.}, journal = {Cancers}, volume = {13}, number = {1}, pages = {}, pmid = {33466433}, issn = {2072-6694}, support = {Momentum//Magyar Tudom&#xe1;nyos Akad&#xe9;mia/ ; StG-260572/ERC_/European Research Council/International ; ANR 10-1-2011-0401//Nemzeti Kutat&#xe1;si &#xe9;s Technol&#xf3;giai Hivatal/ ; GINOP-2.3.2-15-2016-00038//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; FK 124240//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; FIEK_16-1-2016-0005//Nemzeti Kutat&#xe1;si Fejleszt&#xe9;si &#xe9;s Innov&#xe1;ci&#xf3;s Hivatal/ ; }, abstract = {Resistance to chemotherapeutic agents is a major obstacle in cancer treatment. A recently proposed strategy is to target the collateral sensitivity of multidrug resistant (MDR) cancer. Paradoxically, the toxicity of certain metal chelating agents is increased, rather than decreased, by the function of P-glycoprotein (Pgp), which is known to confer resistance by effluxing chemotherapeutic compounds from cancer cells. We have recently characterized and compared the solution's chemical properties including ligand protonation and the metal binding properties of a set of structurally related 8-hydroxyquinoline derived Mannich bases. Here we characterize the impact of the solution stability and redox activity of their iron(III) and copper(II) complexes on MDR-selective toxicity. Our results show that the MDR-selective anticancer activity of the studied 8-hydroxyquinoline derived Mannich bases is associated with the iron deprivation of MDR cells and the preferential formation of redox-active copper(II) complexes, which undergo intracellular redox-cycling to induce oxidative stress.}, }
@article {pmid33465741, year = {2021}, author = {Kawaguchi, K and Hashimoto, M and Sugimoto, M}, title = {An antioxidant suppressed lung cellular senescence and enhanced pulmonary function in aged mice.}, journal = {Biochemical and biophysical research communications}, volume = {541}, number = {}, pages = {43-49}, doi = {10.1016/j.bbrc.2020.12.112}, pmid = {33465741}, issn = {1090-2104}, mesh = {Acetylcysteine/*pharmacology ; *Aging ; Animals ; Antioxidants/*pharmacology ; Cells, Cultured ; Cellular Senescence/*drug effects/genetics ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Down-Regulation/drug effects/genetics ; Female ; Gene Expression Profiling ; Lung/anatomy &amp; histology/cytology/*drug effects/*physiology ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; }, abstract = {Oxidative stress is one of the major causes of cellular senescence in mammalian cells. The excess amount of reactive oxygen species generated by oxygen metabolism is pathogenic and facilitates tissue aging. Lung tissue is more susceptible to oxidative stress than other organs because it is directly exposed to environmental stresses. The aging of lung tissues increases the risk of chronic diseases. Senescent cells accumulate in tissues during aging and contribute to aging-associated morbidity; however, the roles of cellular senescence in lung aging and diseases have not yet been elucidated in detail. To clarify the physiological role of oxidative stress-induced cellular senescence in aging-associated declines in pulmonary function, we herein investigated the effects of the antioxidant N-acetyl-L-cysteine (NAC) on lung cellular senescence and aging in mice. The administration of NAC to 1-year-old mice reduced the expression of senescence-associated genes in lung tissue. Pulmonary function and lung morphology were partly restored in mice administered NAC. Collectively, these results suggest that oxidative stress is a major inducer of cellular senescence in vivo and that the control of oxidative stress may prevent lung aging and diseases.}, }
@article {pmid33461581, year = {2021}, author = {Zhang, RH and Zhang, HL and Li, PY and Li, CH and Gao, JP and Li, J and Xu, T and Wang, XJ and Wang, CL and Zhang, HC and Xu, MJ and Tian, SF}, title = {Autophagy is involved in the replication of H9N2 influenza virus via the regulation of oxidative stress in alveolar epithelial cells.}, journal = {Virology journal}, volume = {18}, number = {1}, pages = {22}, pmid = {33461581}, issn = {1743-422X}, mesh = {A549 Cells ; Alveolar Epithelial Cells/*virology ; Animals ; Autophagy/*genetics ; *Gene Expression Regulation ; Humans ; Influenza A Virus, H9N2 Subtype/pathogenicity/*physiology ; Orthomyxoviridae Infections/*veterinary ; Oxidative Stress/*genetics ; Signal Transduction ; Swine ; *Virus Replication ; }, abstract = {BACKGROUND: Oxidative stress is an important pathogenic factor in influenza A virus infection. It has been found that reactive oxygen species induced by the H9N2 influenza virus is associated with viral replication. However, the mechanisms involved remain to be elucidated.<br><br>METHODS: In this study, the role of autophagy was investigated in H9N2 influenza virus-induced oxidative stress and viral replication in A549 cells. Autophagy induced by H9N2 was inhibited by an autophagy inhibitor or RNA interference, the autophagy level, viral replication and the presence of oxidative stress were detected by western blot, TCID50 assay, and Real-time PCR. Then autophagy and oxidative stress were regulated, and viral replication was determined. At last, the Akt/TSC2/mTOR signaling pathways was detected by western blot.<br><br>RESULTS: Autophagy was induced by the H9N2 influenza virus and the inhibition of autophagy reduced the viral titer and the expression of nucleoprotein and matrix protein. The blockage of autophagy suppressed the H9N2 virus-induced increase in the presence of oxidative stress, as evidenced by decreased reactive oxygen species production and malonaldehyde generation, and increased superoxide dismutase 1 levels. The changes in the viral titer and NP mRNA level caused by the antioxidant, N-acetyl-cysteine (NAC), and the oxidizing agent, H2O2, confirmed the involvement of oxidative stress in the control of viral replication. NAC plus transfection with Atg5 siRNA significantly reduced the viral titer and oxidative stress compared with NAC treatment alone, which confirmed that autophagy was involved in the replication of H9N2 influenza virus by regulating oxidative stress. Our data also revealed that autophagy was induced by the H9N2 influenza virus through the Akt/TSC2/mTOR pathway. The activation of Akt or the inhibition of TSC2 suppressed the H9N2 virus-induced increase in the level of LC3-II, restored the decrease in the expression of phospho-pAkt, phospho-mTOR and phospho-pS6 caused by H9N2 infection, suppressed the H9N2-induced increase in the presence of oxidative stress, and resulted in a decrease in the viral titer.<br><br>CONCLUSION: Autophagy is involved in H9N2 virus replication by regulating oxidative stress via the Akt/TSC2/mTOR signaling pathway. Thus, autophagy maybe a target which may be used to improve antiviral therapeutics.}, }
@article {pmid33454892, year = {2021}, author = {Albeltagy, RS and Mumtaz, F and Abdel Moneim, AE and El-Habit, OH}, title = {N-Acetylcysteine Reduces miR-146a and NF-κB p65 Inflammatory Signaling Following Cadmium Hepatotoxicity in Rats.}, journal = {Biological trace element research}, volume = {199}, number = {12}, pages = {4657-4665}, pmid = {33454892}, issn = {1559-0720}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cadmium/toxicity ; *Chemical and Drug Induced Liver Injury/drug therapy ; Male ; *MicroRNAs/genetics ; NF-kappa B/metabolism ; Rats ; Signal Transduction ; }, abstract = {We performed a thorough screening and analysis of the impact of cadmium chloride (CdCl2) and N-acetylcysteine (NAC) on the miR146a/NF-κB p65 inflammatory pathway and mitochondrial biogenesis dysfunction in male albino rats. A total of 24 male albino rats were divided into three groups: a control group, a CdCl2-treated group (3 mg/kg, orally), and a CdCl2 + NAC-treated group (200 mg/kg of NAC, 1 h after CdCl2 treatment), for 60 consecutive days. Real-time quantitative PCR was used to analyze the expression of miR146a, Irak1, Traf6, Nrf1, Nfe2l2, Pparg, Prkaa, Stat3, Tfam, Tnfa, and Il1b, whereas tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2 protein levels were assessed using ELISA, and NF-κB p65 was detected using western blotting. A significant restoration of homeostatic inflammatory processes as well as mitochondrial biogenesis was observed after NAC and CdCl2 treatment. Decreased miR146a and NF-κB p65 were also found after treatment with NAC and CdCl2 compared with CdCl2 treatment alone. Collectively, our findings demonstrate that CdCl2 caused mtDNA release because of Tfam loss, leading to NF-κB p65 activation. Co-treatment with NAC could alleviate Cd-induced genotoxicity in liver tissue. We concluded that adding NAC to CdCl2 resulted in a decreased signaling of the NF-κB p65 signaling pathway.}, }
@article {pmid33453249, year = {2021}, author = {Thieme, K and Pereira, BMV and da Silva, KS and Fabre, NT and Catanozi, S and Passarelli, M and Correa-Giannella, ML}, title = {Chronic advanced-glycation end products treatment induces TXNIP expression and epigenetic changes in glomerular podocytes in vivo and in vitro.}, journal = {Life sciences}, volume = {270}, number = {}, pages = {118997}, doi = {10.1016/j.lfs.2020.118997}, pmid = {33453249}, issn = {1879-0631}, mesh = {Animals ; Antioxidants/metabolism ; Cell Cycle Proteins/*genetics/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Diabetic Nephropathies/genetics/*metabolism ; Epigenesis, Genetic/genetics ; Epithelial Cells/metabolism ; Gene Expression/genetics ; Gene Expression Regulation/drug effects ; Glycation End Products, Advanced/metabolism/*pharmacology ; Histones ; Kidney/cytology/metabolism ; Kidney Glomerulus/metabolism ; Male ; Membrane Proteins ; Oxidative Stress ; Podocytes/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {Advanced glycation end products (AGEs) play an important role in oxidative stress and inflammation, processes implicated in the development and progression of kidney dysfunction. In the present study, we investigated the participation of the pro-oxidant protein thioredoxin-interacting protein (TXNIP) and of epigenetic mechanisms on kidney tissue (in vivo, in non-diabetic rats) and on terminally differentiated glomerular podocytes (in vitro) chronically exposed to AGEs. AGEs induced total kidney and glomerular TXNIP expression and decreased H3K27me3 content. Concomitant treatment with the antioxidant N-acetyl-cysteine (NAC) reversed only the increased TXNIP expression. TXNIP expression positively correlated with proteinuria and negatively correlated with H3K27me3 content. In vitro studies in podocytes showed that 72 h exposure to AGEs decreased nephrin expression and increased Txnip, Nox4, Col4a1, and epithelial-to-mesenchymal transition (EMT) markers (Acta2, Snail1, and Tgfb1). Podocytes treatment with NAC reversed Nox4, Col4a1, Acta2, and Tgfb1 increased expression but did not abrogate the reduced expression of nephrin. MiR-29a expression was downregulated by AGEs in vivo, but not in vitro. In conclusion, treatment of non-diabetic rats with AGEs induced TXNIP expression and decreased the contents of the repressive epigenetic mark H3K27me3 and of miR-29a, potentially driving injury to glomerular filtration barrier and podocytes dysfunction.}, }
@article {pmid33447805, year = {2020}, author = {Kundukad, B and Udayakumar, G and Grela, E and Kaur, D and Rice, SA and Kjelleberg, S and Doyle, PS}, title = {Weak acids as an alternative anti-microbial therapy.}, journal = {Biofilm}, volume = {2}, number = {}, pages = {100019}, pmid = {33447805}, issn = {2590-2075}, abstract = {Weak acids such as acetic acid and N-acetyl cysteine (NAC) at pH less than their pKa can effectively eradicate biofilms due to their ability to penetrate the biofilm matrix and the cell membrane. However, the optimum conditions for their activity against drug resistant strains, and safety, need to be understood for their application to treat infections or to inactivate biofilms on hard surfaces. Here, we investigate the efficacy and optimum conditions at which weak acids can eradicate biofilms. We compared the efficacy of various mono and triprotic weak acids such as N-acetyl cysteine (NAC), acetic acid, formic acid and citric acid, in eradicating biofilms. We found that monoprotic weak acids/acid drugs can kill mucoid P. aeruginosa mucA biofilm bacteria provided the pH is less than their pKa, demonstrating that the extracellular biofilm matrix does not protect the bacteria from the activity of the weak acids. Triprotic acids, such as citric acid, kill biofilm bacteria at pH < pKa1. However, at a pH between pKa1 and pKa2, citric acid is effective in killing the bacteria at the core of biofilm microcolonies but does not kill the bacteria on the periphery. The efficacy of a monoprotic weak acid (NAC) and triprotic weak acid (citric acid) were tested on biofilms formed by Klebsiella pneumoniae KP1, Pseudomonas putida OUS82, Staphylococcus aureus 15981, P. aeruginosa DK1-NH57388A, a mucoid cystic fibrosis isolate and P. aeruginosa PA_D25, an antibiotic resistant strain. We showed that weak acids have a broad spectrum of activity against a wide range of bacteria, including antibiotic resistant bacteria. Further, we showed that a weak acid drug, NAC, can kill bacteria without being toxic to human cells, if its pH is maintained close to its pKa. Thus weak acids/weak acid drugs target antibiotic resistant bacteria and eradicate the persister cells in biofilms which are tolerant to other conventional methods of biofilm eradication.}, }
@article {pmid33446631, year = {2021}, author = {Huang, CR and Chang, TW and Lee, CT and Shen, CJ and Chang, WC and Chen, BK}, title = {ARNT deficiency represses pyruvate dehydrogenase kinase 1 to trigger ROS production and melanoma metastasis.}, journal = {Oncogenesis}, volume = {10}, number = {1}, pages = {11}, pmid = {33446631}, issn = {2157-9024}, support = {MOST-108-2320-B-006-031//Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)/ ; }, abstract = {The metabolic changes in melanoma cells that are required for tumor metastasis have not been fully elucidated. In this study, we show that the increase in glucose uptake and mitochondrial oxidative phosphorylation confers metastatic ability as a result of aryl hydrocarbon receptor nuclear translocator (ARNT) deficiency. In clinical tissue specimens, increased ARNT, pyruvate dehydrogenase kinase 1 (PDK1), and NAD(P)H quinine oxidoreductase-1 (NQO1) was observed in benign nevi, whereas lower expression was observed in melanoma. The depletion of ARNT dramatically repressed PDK1 and NQO1 expression, which resulted in an increase of ROS levels. The elimination of ROS using N-acetylcysteine (NAC) and inhibition of oxidative phosphorylation using carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and rotenone inhibited the ARNT and PDK1 deficiency-induced cell migration and invasion. In addition, ARNT deficiency in tumor cells manipulated the glycolytic pathway through enhancement of the glucose uptake rate, which reduced glucose dependence. Intriguingly, CCCP and NAC dramatically inhibited ARNT and PDK1 deficiency-induced tumor cell extravasation in mouse models. Our work demonstrates that downregulation of ARNT and PDK1 expression serves as a prognosticator, which confers metastatic potential as the metastasizing cells depend on metabolic changes.}, }
@article {pmid33441976, year = {2021}, author = {Wang, H and Li, C and Peng, M and Wang, L and Zhao, D and Wu, T and Yi, D and Hou, Y and Wu, G}, title = {N-Acetylcysteine improves intestinal function and attenuates intestinal autophagy in piglets challenged with β-conglycinin.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {1261}, pmid = {33441976}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Allergens/*toxicity ; Animals ; Animals, Newborn ; Antigens, Plant/*toxicity ; Autophagy/*drug effects ; Female ; Globulins/*toxicity ; Intestinal Mucosa/*metabolism/pathology ; Seed Storage Proteins/*toxicity ; Soybean Proteins/*toxicity ; Swine/*metabolism ; }, abstract = {β-Conglycinin (β-CG), an anti-nutritional factor, is a major allergen in soybeans to induce intestinal dysfunction and diarrhea in neonatal animals, including piglets and human infants. This study with a piglet model determined the effects of N-acetylcysteine (NAC) on intestinal function and autophagy in response to β-CG challenge. Twenty-four 12-day-old piglets (3.44 ± 0.28 kg), which had been weaned at 7 days of age and adapted for 5 days after weaning, were randomly allocated to the control, β-CG, and β-CG + NAC groups. Piglets in the control group were fed a liquid diet containing 10% casein, whereas those in the β-CG and β-CG + NAC groups were fed the basal liquid diets containing 9.5% casein and 0.5% β-CG for 2 days. Thereafter, pigs in the β-CG + NAC group were orally administrated with 50 mg (kg BW)[-1] NAC for 3 days, while pigs in the other two groups were orally administrated with the same volume of sterile saline. NAC numerically reduced diarrhea incidence (- 46.2%) and the concentrations of hydrogen peroxide and malondialdehyde, but increased claudin-1 and intestinal fatty-acid binding protein (iFABP) protein abundances and activities of catalase and glutathione peroxidase in the jejunum of β-CG-challenged piglets. Although β-CG challenge decreased the villus height, villus height/crypt depth ratio, and mRNA levels of claudin-1 and occludin, no significant differences were observed in these indices between the control and β-CG + NAC groups, suggesting the positive effects of NAC supplementation on intestinal mucosal barrier function. Moreover, NAC increased the concentrations of citrulline and D-xylose in the plasma, as well as the expression of genes for aquaporin (AQP) 3, AQP4, peptide transporter 1 (PepT1), sodium/glucose co-transporter-1 (SGLT-1), potassium inwardly-rectifying channel, subfamily J, member 13 (KCNJ13), and solute carrier family 1 member 1 (SLC1A1) in the jejunum, demonstrating that NAC augmented intestinal metabolic activity and absorptive function. Remarkably, NAC decreased Atg5 protein abundance and the LC3II/LC3I ratio (an indicator of autophagy) in the jejunum of β-CG-challenged piglets. Taken together, NAC supplementation improved intestinal function and attenuated intestinal autophagy in β-CG-challenged piglets.}, }
@article {pmid33439409, year = {2021}, author = {Coşkun, &#xd6; and Öztopuz, &#xd6; and Büyük, B}, title = {Possible protective activity of n-acetyl cysteine against cisplatin‑induced hepatotoxicity in rats.}, journal = {Molecular biology reports}, volume = {48}, number = {1}, pages = {637-644}, pmid = {33439409}, issn = {1573-4978}, support = {project number: TSA-2017-1108//Bilimsel Ara&#x15f;tirma Projeleri Birimi/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents/adverse effects ; Antioxidants/pharmacology ; Chemical and Drug Induced Liver Injury/*drug therapy/pathology ; Cisplatin/*adverse effects/pharmacology ; Humans ; Inflammation/chemically induced/*drug therapy/pathology ; Liver/drug effects/injuries ; Neoplasms/*complications/drug therapy ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; }, abstract = {CP is one of the most widely used antineoplastic agents. However, its clinical application is very limited due to its severe toxic effects. The present study aimed to reveal the effects of NAC, which exhibits broad biological activities in reducing CP-induced liver damage, in consideration of biochemical, genetic, and histopathological findings. Twenty-eight wistar rats were randomly divided into four groups of seven animals. A dose of saline was administered (i.p.) to the control group for 5 days. One dose of NAC (200 mg/kg) was administered to the NAC group for 5 days (i.p.). To the NAC + CP group, a dose of CP (7.5 mg/kg) was administered on days 2 and 5 of the experiment, a dose of NAC (200 mg/ kg) (i.p.) was administered for 5 day of the experiment. CP (7.5 mg/kg) was administered to the CP group on days 2 and 5 of the experiment. At the end of the experiment, the biochemical, histological, and mRNA expression analyses of the liver tissues isolated from all the rats were performed. A statistically significant decrease was observed in the AST and ALT enzyme activities in Group NAC + CP compared to Control and CP groups. In addition, it was determined that the NAC administration reduced CP-induced inflammation by increasing the level of NF-κB and decreased CP-caused oxidative stress by decreasing the GPx level. Moreover, the histopathological analyses showed that NAC improved liver morphology. It was revealed by Western blotting analysis that NAC promoted Bcl-2 signaling and decreased p53 signaling. The findings herein showed that NAC could help alleviate hepatotoxicity, a serious therapeutic complication, by reducing CP-induced oxidative stress and playing an effective part in the regulation of apoptotic markers.}, }
@article {pmid33435380, year = {2021}, author = {Zhang, W and Zhu, Y and Yu, H and Liu, X and Jiao, B and Lu, X}, title = {Libertellenone H, a Natural Pimarane Diterpenoid, Inhibits Thioredoxin System and Induces ROS-Mediated Apoptosis in Human Pancreatic Cancer Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {2}, pages = {}, pmid = {33435380}, issn = {1420-3049}, support = {2019YFC0312504//National Key Research and Development Project/ ; 20ZR1470600//Natural Science Foundation of Shanghai/ ; 2020PJD082//Shanghai Pujiang Program/ ; }, mesh = {Antineoplastic Agents/chemistry/isolation &amp; purification/*pharmacology ; Apoptosis/*drug effects ; Ascomycota/chemistry ; Biological Products/chemistry/isolation &amp; purification/*pharmacology ; Cell Proliferation/drug effects ; Diterpenes/chemistry/isolation &amp; purification/*pharmacology ; Drug Screening Assays, Antitumor ; Humans ; Pancreatic Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Thioredoxins/*antagonists &amp; inhibitors/metabolism ; Tumor Cells, Cultured ; }, abstract = {Libertellenone H (LH), a marine-derived pimarane diterpenoid isolated from arctic fungus Eutypella sp. D-1, has shown effective cytotoxicity on a range of cancer cells. The present study is to explore the anticancer effect of LH on human pancreatic cancer cells and to investigate the intracellular molecular target and underlying mechanism. As shown, LH exhibited anticancer activity in human pancreatic cancer cells by promoting cell apoptosis. Mechanistic studies suggested that LH-induced reactive oxygen species (ROS) accumulation was responsible for apoptosis as antioxidant N-acetylcysteine (NAC) and antioxidant enzyme superoxide dismutase (SOD) antagonized the inhibitory effect of LH. Zymologic testing demonstrated that LH inhibited Trx system but had little effect on the glutathione reductase and glutaredoxin. Mass spectrometry (MS) analysis revealed that the mechanism of action was based on the direct conjugation of LH to the Cys[32]/Cys[35] residue of Trx1 and Sec[498] of TrxR, leading to a decrease in the cellular level of glutathione (GSH) and activation of downstream ASK1/JNK signaling pathway. Taken together, our findings revealed LH was a marine derived inhibitor of Trx system and an anticancer candidate.}, }
@article {pmid33435325, year = {2021}, author = {Tosi, GM and Giustarini, D and Franci, L and Minetti, A and Imperatore, F and Caldi, E and Fiorenzani, P and Aloisi, AM and Sparatore, A and Rossi, R and Chiariello, M and Orlandini, M and Galvagni, F}, title = {Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage.}, journal = {International journal of molecular sciences}, volume = {22}, number = {2}, pages = {}, pmid = {33435325}, issn = {1422-0067}, support = {prot.2747//I.Ri.Fo.R Onlus (Institute for Research, Training, and Rehabilitation)/ ; "Dipartimento di Eccellenza" 2018-2022//MIUR (Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca)/ ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/*pharmacology ; Animals ; Antioxidants/chemistry/*pharmacology ; Cell Line ; Cysteine/*analogs &amp; derivatives/chemistry/pharmacology ; Humans ; Male ; Oxidative Stress/*drug effects ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/cytology/*drug effects/metabolism ; Rats ; }, abstract = {Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats' eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.}, }
@article {pmid33421550, year = {2021}, author = {Gupta, S and Kamil, S and Sinha, PR and Rodier, JT and Chaurasia, SS and Mohan, RR}, title = {Glutathione is a potential therapeutic target for acrolein toxicity in the cornea.}, journal = {Toxicology letters}, volume = {340}, number = {}, pages = {33-42}, pmid = {33421550}, issn = {1879-3169}, support = {R01 EY030774/EY/NEI NIH HHS/United States ; R21 EY030233/EY/NEI NIH HHS/United States ; IK6 BX005646/BX/BLRD VA/United States ; I01 BX000357/BX/BLRD VA/United States ; R01 EY029795/EY/NEI NIH HHS/United States ; R01 EY017294/EY/NEI NIH HHS/United States ; R21 EY030234/EY/NEI NIH HHS/United States ; }, mesh = {Acrolein/*toxicity ; Caspase 3/genetics/metabolism ; Caspase 7/genetics/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cornea/*cytology ; Cytoprotection/drug effects ; Fibroblasts/*drug effects ; Gene Expression Regulation/drug effects ; Glutathione/*metabolism ; Humans ; Lipid Peroxidation ; Lipids/chemistry ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {Toxic and volatile chemicals are widely used in household products and previously used as warfare agents, causing a public health threat worldwide. This study aimed to evaluate the extent of injury and mechanisms of acrolein toxicity in the cornea. Primary human corneal stromal fibroblasts cultures (hCSFs) from human donor cornea were cultured and exposed to acrolein toxicity with -/+ N-acetylcysteine (NAC) to study the mode of action in the presence of Buthionine sulphoximine (BSO). PrestoBlue and MTT assays were used to optimize acrolein, NAC, and BSO doses for hCSFs. Cell-based assays and qRT-PCR analyses were performed to understand the acrolein toxicity and mechanisms. Acrolein exposure leads to an increased reactive oxygen species (ROS), compromised glutathione (GSH) levels, and mitochondrial dysfunction. The TUNEL and caspase assays showed that acrolein caused cell death in hCSFs. These deleterious effects can be mitigated using NAC in hCSFs, suggesting that GSH can be a potential target for acrolein toxicity in the cornea.}, }
@article {pmid33416129, year = {2021}, author = {Li, X and Liu, Y and Liao, S and Lin, C and Moro, A and Liu, J and Feng, W and Wang, K and Wang, C}, title = {Polyphyllin VII induces apoptosis and autophagy via mediating H2O2 levels and the JNK pathway in human osteosarcoma U2OS cells.}, journal = {Oncology reports}, volume = {45}, number = {1}, pages = {180-190}, pmid = {33416129}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors/*metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System/*drug effects ; Osteosarcoma/*drug therapy/pathology ; Saponins/*pharmacology/therapeutic use ; }, abstract = {Polyphyllin VII, a compound extracted from the rhizomes of Paris polyphylla, has strong antitumor effects on various human tumor cell lines. However, few studies have reported the possible effect of Polyphyllin VII on human osteosarcoma (OS) cell lines. The present study revealed that Polyphyllin VII promoted OS cell apoptosis and inhibited cell proliferation via upregulating the expression of LC3II, Atg5, Atg7 and the Atg12‑Atg5 complex. By contrast, treatment of OS cells with Polyphyllin VII downregulated Atg12 and p62 expression. Following treatment with class III PI 3‑kinase inhibitor (3‑MA; an autophagy inhibitor), the Polyphyllin VII‑mediated apoptotic effect was reversed. These findings indicated that the inhibition of autophagy could attenuate U2OS cell apoptosis in cells treated with high concentrations of Polyphyllin VII. The present study also demonstrated that Polyphyllin VII upregulated the intracellular hydrogen peroxide (H2O2) levels in U2OS cells. However, treatment of U2OS cells with N‑acetyl‑L cysteine (NAC) effectively reversed this effect. The western blot analysis results indicated that the c‑Jun N‑terminal kinase (JNK) signaling pathway was closely associated with Polyphyllin VII‑induced apoptosis and autophagy. In conclusion, the results of the present study demonstrated that Polyphyllin VII could effectively inhibit cell viability and promote autophagy and apoptosis in U2OS cells. In addition, the mechanism underlying these effects could be associated with the intracellular H2O2 levels and the JNK signaling pathway.}, }
@article {pmid33415010, year = {2020}, author = {West, L and Yin, Y and Pierce, SR and Fang, Z and Fan, Y and Sun, W and Tucker, K and Staley, A and Zhou, C and Bae-Jump, V}, title = {Docosahexaenoic acid (DHA), an omega-3 fatty acid, inhibits tumor growth and metastatic potential of ovarian cancer.}, journal = {American journal of cancer research}, volume = {10}, number = {12}, pages = {4450-4463}, pmid = {33415010}, issn = {2156-6976}, support = {R37 CA226969/CA/NCI NIH HHS/United States ; }, abstract = {Omega-3 polyunsaturated fatty acids (PUFAs), such as those found in fish oil, are thought to have anti-tumorigenic effects and may help to treat and prevent cancer, including ovarian cancer. Thus, we aimed to evaluate the potential of docosahexaenoic acid (DHA), an omega-3 PUFA, as a therapeutic agent in ovarian cancer cell lines and a transgenic mouse model of ovarian cancer. DHA significantly inhibited cellular proliferation, induced cell cycle arrest and caused apoptosis in Hey and IGROV-1 cells. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed DHA-induced caspase 3 activity and prevented DHA-reduced cell proliferation. DHA also induced cellular reactive oxygen species (ROS) and inhibited adhesion and invasion in IGROV-1 and Hey cells. Furthermore, treatment with DHA demonstrated anti-tumorigenic and anti-invasive activity in a K18-gT121 [+/-]; p53[fl/fl]; Brca1[fl/fl] mouse model of ovarian cancer including downregulation of Ki67 and VEGF expression. The data provide a preclinical rationale for applying DHA for dietary intervention and therapeutic adjunct in patients with ovarian cancer.}, }
@article {pmid33414397, year = {2021}, author = {Zhao, T and Zheng, T and Yu, H and Hu, BH and Hu, B and Ma, P and Yang, Y and Yang, N and Hu, J and Cao, T and Chen, G and Yan, B and Peshoff, M and Hatzoglou, M and Geng, R and Li, B and Zheng, QY}, title = {Autophagy impairment as a key feature for acetaminophen-induced ototoxicity.}, journal = {Cell death &amp; disease}, volume = {12}, number = {1}, pages = {3}, pmid = {33414397}, issn = {2041-4889}, support = {R01 DK053307/DK/NIDDK NIH HHS/United States ; R37 DK060596/DK/NIDDK NIH HHS/United States ; R01 DK060596/DK/NIDDK NIH HHS/United States ; R01 DC015111/DC/NIDCD NIH HHS/United States ; R21 DC005846/DC/NIDCD NIH HHS/United States ; }, mesh = {Acetaminophen/*adverse effects ; Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line ; Endoplasmic Reticulum Stress/*drug effects ; Mice ; Mice, Inbred C57BL ; *Ototoxicity/metabolism/pathology ; Oxidative Stress/*drug effects ; }, abstract = {Macroautophagy/autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental animals and in humans. APAP also causes ototoxicity. However, the role of autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced autophagy impairment. Inhibition of autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.}, }
@article {pmid33413696, year = {2021}, author = {Nakhaee, S and Dastjerdi, M and Roumi, H and Mehrpour, O and Farrokhfall, K}, title = {N-acetylcysteine dose-dependently improves the analgesic effect of acetaminophen on the rat hot plate test.}, journal = {BMC pharmacology &amp; toxicology}, volume = {22}, number = {1}, pages = {4}, pmid = {33413696}, issn = {2050-6511}, mesh = {Acetaminophen/*administration &amp; dosage ; Acetylcysteine/*administration &amp; dosage ; Analgesics, Non-Narcotic/*administration &amp; dosage ; Animals ; Drug Synergism ; Drug Therapy, Combination ; Hot Temperature/adverse effects ; Male ; Pain/*drug therapy ; Rats, Sprague-Dawley ; Rats ; }, abstract = {BACKGROUND: Acetaminophen (APAP) induced hepatotoxicity is a clinically important problem. Up to now, interventive therapy with n-acetylcysteine (NAC) has been considered as a gold-standard treatment for APAP overdose. However, no study has focused on the efficacy of these drugs' concurrent administration on probable enhancing therapeutic outcomes. Thus, this study was aimed to investigate the analgesic effect of co-administration of NAC and acetaminophen in male rats. The NAC-APAP drug formulation may demonstrate the stranger antinociceptive effect.<br><br>METHODS: Forty-eight male Sprague-Dawley rats (12-14&#x2009;weeks) randomly divided into six equal groups; control, APAP (received 300&#x2009;mg/kg APAP), NAC (received 600&#x2009;mg/kg NAC) and APAP+ NAC groups that received simultaneously 300&#x2009;mg/kg APAP with 200-600&#x2009;mg/kg NAC (AN200, AN400, AN600). All administrations were done orally for once. The antinociceptive effect was recorded by measurement of latency period on a hot plate in 30, 60, and 90&#x2009;min after administrations.<br><br>RESULTS: The results showed that NAC's concurrent administration with APAP, dose-dependently increased APAP analgesic effects (p<&#x2009;0.0001). Moreover, NAC treatment exhibited an antinociceptive effect in 60 and 90&#x2009;min, per se. The treatments had no adverse effect on liver enzymes and oxidative stress.<br><br>CONCLUSION: Co-administration of NAC with APAP can improve the antinociceptive effect of APAP. It is suggested that this compound can enhance analgesic effects of APAP and eventually lead to a reduction in acetaminophen dose. Further studies are needed to evaluate the molecular mechanism of this hyper analgesic effect.}, }
@article {pmid33412942, year = {2021}, author = {Atamanalp, M and Parlak, V and Özgeriş, FB and Çilingir Yeltekin, A and Ucar, A and Keleş, MS and Alak, G}, title = {Treatment of oxidative stress, apoptosis, and DNA injury with N-acetylcysteine at simulative pesticide toxicity in fish.}, journal = {Toxicology mechanisms and methods}, volume = {31}, number = {3}, pages = {224-234}, doi = {10.1080/15376516.2021.1871794}, pmid = {33412942}, issn = {1537-6524}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis ; DNA Damage ; Ecosystem ; *Oncorhynchus mykiss ; Oxidative Stress ; *Pesticides/toxicity ; }, abstract = {Pesticide toxicities are common in aquatic ecosystems and affects aquatic livings negative. Therefore, it is important to strengthen the antioxidant system in aquatic organisms and to protect the organisms against these toxic chemicals. In this study, the simulative toxicity was established to the fish then the healing process was followed. For this purpose, rainbow trout Oncorhynchus mykiss exposed to cypermethrin and left to the recovery process with either N-acetyl cysteine (an antioxidant, 0.5 mM-1.0 mM concentrations) or no intervention (self-healing) for 96 h. In this context, paraoxonase (PON), arylesterase (AR), myeloperoxidase (MPO), antioxidant enzymes (SOD, CAT, GPx), acetylcholinesterase (AChE) activities as well as MDA, caspase-3 and 8-OHdG levels were measured in fish gills, liver and kidney tissues. In addition, trace element tests were performed in the tissues sampled for each group. At the result of pesticide exposure, SOD, CAT, GPx, PON, AR and AChE activities were increased but MDA, MPO, caspase-3 and 8-OHdG levels were decreased in N-acetyl cysteine (NAC) treated groups in all tissues compared to self-healing group (p < 0.05). When the element analysis of the samples was examined, tissue-based differences were observed significantly in all application groups (p < 0.05). Considering the results of the study, it was found that NAC administration at high concentration (1.0 Mm NAC) was more effective on pesticide toxicity. It was concluded that the most sensitive tissue was the kidney.}, }
@article {pmid33411811, year = {2021}, author = {Lu, J and West, MB and Du, X and Cai, Q and Ewert, DL and Cheng, W and Nakmali, D and Li, W and Huang, X and Kopke, RD}, title = {Electrophysiological assessment and pharmacological treatment of blast-induced tinnitus.}, journal = {PloS one}, volume = {16}, number = {1}, pages = {e0243903}, pmid = {33411811}, issn = {1932-6203}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; *Benzenesulfonates/pharmacology/therapeutic use ; Biomarkers/metabolism ; *Disease Models, Animal ; Evoked Potentials, Auditory, Brain Stem/*drug effects ; Hair Cells, Auditory, Inner/*metabolism/pathology ; *Hearing Loss, Noise-Induced/drug therapy/physiopathology ; Male ; Rats ; *Tinnitus/drug therapy/physiopathology ; }, abstract = {Tinnitus, the phantom perception of sound, often occurs as a clinical sequela of auditory traumas. In an effort to develop an objective test and therapeutic approach for tinnitus, the present study was performed in blast-exposed rats and focused on measurements of auditory brainstem responses (ABRs), prepulse inhibition of the acoustic startle response, and presynaptic ribbon densities on cochlear inner hair cells (IHCs). Although the exact mechanism is unknown, the "central gain theory" posits that tinnitus is a perceptual indicator of abnormal increases in the gain (or neural amplification) of the central auditory system to compensate for peripheral loss of sensory input from the cochlea. Our data from vehicle-treated rats supports this rationale; namely, blast-induced cochlear synaptopathy correlated with imbalanced elevations in the ratio of centrally-derived ABR wave V amplitudes to peripherally-derived wave I amplitudes, resulting in behavioral evidence of tinnitus. Logistic regression modeling demonstrated that the ABR wave V/I amplitude ratio served as a reliable metric for objectively identifying tinnitus. Furthermore, histopathological examinations in blast-exposed rats revealed tinnitus-related changes in the expression patterns of key plasticity factors in the central auditory pathway, including chronic loss of Arc/Arg3.1 mobilization. Using a formulation of N-acetylcysteine (NAC) and disodium 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07) as a therapeutic for addressing blast-induced neurodegeneration, we measured a significant treatment effect on preservation or restoration of IHC ribbon synapses, normalization of ABR wave V/I amplitude ratios, and reduced behavioral evidence of tinnitus in blast-exposed rats, all of which accorded with mitigated histopathological evidence of tinnitus-related neuropathy and maladaptive neuroplasticity.}, }
@article {pmid33409946, year = {2020}, author = {Varghese, J and Joshi, V and Bollipalli, MK and Malleeswaran, S and Patcha, R and Nair, H and Vij, V and Sachan, D and Subramanian, P and Jain, M and Venkataraman, J}, title = {Role of therapeutic plasma exchange in acute liver failure due to yellow phosphorus poisoning.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {39}, number = {6}, pages = {544-549}, pmid = {33409946}, issn = {0975-0711}, mesh = {Adult ; Ammonia ; Female ; Humans ; Hypersensitivity/etiology ; Hypotension/etiology ; International Normalized Ratio ; Liver Failure, Acute/*chemically induced/mortality/*therapy ; Liver Transplantation ; Male ; Phosphorus/*poisoning ; Plasma Exchange/adverse effects/*methods/mortality ; Survival Rate ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Therapeutic plasma exchange (TPE) has been utilized in various liver disorders. There is limited data on the efficacy of TPE in patients with acute liver failure (ALF).<br><br>METHODS: Study group consisted of patients who underwent TPE for ALF due to yellow phosphorous poisoning (YPP) between 2015 and 2019. Demographic data and biochemical parameters were recorded before and after TPE. Overall survival and transplant-free survival (based on King's College Hospital Criteria [KCHC]) were analyzed.<br><br>RESULTS: Forty-three patients underwent TPE for ALF due to YPP. Most of them were young males. Overall survival was 34 (79.06%). In our study population, 20 patients fulfilled KCHC (Group&#xa0;A) and 23 did not fulfill KCHC (Group&#xa0;B). Both the groups showed significant improvement in alanine aminotransferase, aspartate aminotransferase, and international normalized ratio (INR) after TPE (p&#xa0;<&#x2009;0.05). In Group B, there was significant improvement in ammonia after TPE (p&#xa0;<&#x2009;0.05) and all 23 patients (100%) survived after TPE. In Group A, 4 underwent liver transplantation (LT), 7 survived without LT, and the remaining 9 died without LT. Mean survival after completing TPE was 41.2&#x2009;&#xb1;&#x2009;44.5&#xa0;days in Group A and 90&#xa0;days in Group B. This difference was statistically significant (p&#xa0;=&#x2009;0.001). There was statistically significant difference in post-TPE values of INR (p&#xa0;=&#x2009;0.012) and ammonia (p&#xa0;=&#x2009;0.011) between non-survivors and survivors. Adverse events such as hypotension (11.62%) and minor allergic reaction (4.65%) were managed conservatively.<br><br>CONCLUSION: TPE is an effective procedure in ALF due to YPP, not fulfilling KCHC for LT. In KCHC fulfilled group, though it shows LT-free survival benefit, there is requirement of prospective, large volume, multi-center study to assess its efficacy.}, }
@article {pmid33405232, year = {2021}, author = {Zhou, Z and Cui, Y and Zhang, X and Zhang, Y}, title = {The role of N-acetyl-cysteine (NAC) orally daily on the sperm parameters and serum hormones in idiopathic infertile men: A systematic review and meta-analysis of randomised controlled trials.}, journal = {Andrologia}, volume = {53}, number = {2}, pages = {e13953}, doi = {10.1111/and.13953}, pmid = {33405232}, issn = {1439-0272}, support = {DFL20190502//Beijing Municipal Administration of Hospitals' Ascent Plan/ ; ZYLX201820//Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support/ ; 81801429//National Nature Science Foundation of China/ ; }, mesh = {*Acetylcysteine ; Humans ; *Infertility, Male/drug therapy ; Male ; Randomized Controlled Trials as Topic ; Sperm Count ; Sperm Motility ; Spermatozoa ; }, abstract = {The meta-analysis was performed to access the role of N-acetyl-cysteine (NAC) orally daily on the sperm parameters and serum hormones in idiopathic infertile men. Randomised controlled trials (RCTs) were retrieved using PubMed, EMBASE and Cochrane register databases. The references of included studies were also searched. Finally, three articles including 431 infertile men were analysed. The results indicated that the NAC group had a considerable improvement in sperm concentration (mean difference [MD], 3.80; p < .00001), ejaculate volume (MD, 0.69; p = .002), sperm motility (MD, 4.69; p < .0001) and normal morphology (MD, 1.68; p = .0002) compared with the placebo group. However, in terms of serum hormones, the NAC group did not show significant difference in increasing the serum levels of testosterone (MD, 1.35; p = .21), luteinising hormone (MD, 0.82; p = .40), follicle-stimulating hormone (MD, -7.48; p = .29) and prolactin (MD, -0.34; p = .32) compared with the placebo group. In conclusion, NAC orally daily produced a greater improvement in sperm concentration, ejaculate volume, sperm motility and normal morphology for idiopathic infertile men, whereas no significant influence in serum hormones, which required more high-quality RCTs with sufficient sample sizes and statistics to prove.}, }
@article {pmid33404763, year = {2021}, author = {Jariyamana, N and Chuveera, P and Dewi, A and Leelapornpisid, W and Ittichaicharoen, J and Chattipakorn, S and Srisuwan, T}, title = {Effects of N-acetyl cysteine on mitochondrial ROS, mitochondrial dynamics, and inflammation on lipopolysaccharide-treated human apical papilla cells.}, journal = {Clinical oral investigations}, volume = {25}, number = {6}, pages = {3919-3928}, pmid = {33404763}, issn = {1436-3771}, mesh = {*Acetylcysteine/pharmacology ; Humans ; Inflammation ; *Lipopolysaccharides/pharmacology ; Mitochondria ; Mitochondrial Dynamics ; Reactive Oxygen Species ; }, abstract = {OBJECTIVES: N-Acetyl cysteine (NAC), a well-known antioxidant molecule, has been used to modulate oxidative stress and inflammation. However, no studies have examined the effect of NAC in regenerative endodontic procedures (REPs). Therefore, the aim of this study was to investigate the effects of NAC on cell survival, mitochondrial reactive oxygen species (mtROS) production, and inflammatory and mitochondria-related gene expression on lipopolysaccharide (LPS)-treated apical papilla cells (APCs).<br><br>MATERIALS AND METHODS: To assess the NAC concentration, 5 and 10&#xa0;mM NAC were administered to LPS-treated APCs. Cell proliferation was measured at 24, 48, and 72&#xa0;h by using AlamarBlue&#xae; assay. The 5-mM concentration was further analyzed using different treatment durations: 10&#xa0;min, 24&#xa0;h, and the entire study period. The mtROS production was quantified using MitoSOX&#x2122; Red and MitoTracker&#x2122; Green. RT-PCR was used to detect the expression of IL-6 and TNF-&#x3b1; inflammatory genes and mitochondrial morphology-related genes (Mfn-2/Drp-1 and Bcl-2/Bax) at 6 and 24&#xa0;h. The statistical significance level was set at 0.05.<br><br>RESULTS: Five-millimolar NAC promoted the highest LPS-treated APC proliferation. The use of 24-h NAC stimulated cell proliferation, whereas the entire-period NAC application (>&#x2009;48&#xa0;h) significantly reduced the cell number. The mtROS levels were slightly altered after NAC induction. Ten-minute NAC treatment downregulated the IL-6 and TNF-&#x3b1; expression, whereas the expression of Bcl-2/Bax and Mfn-2/Drp-1 ratios was upregulated at 6&#xa0;h.<br><br>CONCLUSIONS: Under the LPS-induced inflammatory condition, NAC stimulated APC survival and decreased inflammation. Ten-minute NAC treatment was sufficient to reduce the level of inflammation and maintain the mitochondrial dynamics.<br><br>CLINICAL RELEVANCE: Ten-minute NAC application is sufficient to reduce the level of inflammation and maintain the mitochondrial dynamics. Therefore, NAC may be considered as a potential adjunctive irrigation solution in REPs.}, }
@article {pmid33402471, year = {2021}, author = {Liang, WF and Gong, YX and Li, HF and Sun, FL and Li, WL and Chen, DQ and Xie, DP and Ren, CX and Guo, XY and Wang, ZY and Kwon, T and Sun, HN}, title = {Curcumin Activates ROS Signaling to Promote Pyroptosis in Hepatocellular Carcinoma HepG2 Cells.}, journal = {In vivo (Athens, Greece)}, volume = {35}, number = {1}, pages = {249-257}, pmid = {33402471}, issn = {1791-7549}, mesh = {Apoptosis ; *Carcinoma, Hepatocellular/drug therapy/genetics ; *Curcumin/pharmacology ; Hep G2 Cells ; Humans ; *Liver Neoplasms/drug therapy/genetics ; Pyroptosis ; Reactive Oxygen Species ; }, abstract = {BACKGROUND/AIM: Curcumin is a polyphenol that exerts a variety of pharmacological activities and plays an anti-cancer role in many cancer cells. It was recently reported that gasdermin E (GSDME) is involved in the progression of pyroptosis.<br><br>MATERIALS AND METHODS: HepG2 cells were treated with various concentrations of curcumin and cell viability was examined using MTT assay, apoptosis was analysed using flow cytometry, reactive oxygen species (ROS) levels using dihydroethidium, LDH release using an LDH cytotoxicity assay, and protein expression using western blot.<br><br>RESULTS: Curcumin increased the expression of the GSDME N-terminus and proteins involved in pyrolysis, promoted HspG2 cell pyrolysis and increased intracellular ROS levels. Moreover, inhibition of the production of intracellular ROS with n-acetylcysteine (NAC) improved the degree of apoptosis and pyrolysis induced by curcumin.<br><br>CONCLUSION: Curcumin induces HspG2 cell death by increasing apoptosis and pyroptosis, and ROS play a key role in this process. This study improves our understanding of the potential anti-cancer properties of curcumin in liver cancer.}, }
@article {pmid33401054, year = {2021}, author = {Alam, MM and Kariya, R and Boonnate, P and Kawaguchi, A and Okada, S}, title = {Induction of apoptosis by Shikonin through ROS-mediated intrinsic and extrinsic apoptotic pathways in primary effusion lymphoma.}, journal = {Translational oncology}, volume = {14}, number = {3}, pages = {101006}, pmid = {33401054}, issn = {1936-5233}, abstract = {Primary effusion lymphoma (PEL) is an incurable non-Hodgkin's lymphoma and novel biology-based treatments are urgently needed in clinical settings. Shikonin (SHK), a napthoquinone derivative, has been used for the treatment of solid tumors. Here, we report that SHK is an effective agent for the treatment of PEL. Treatment with SHK results in significant reduction of proliferation in PEL cells and their rapid apoptosis in vitro. SHK-induced apoptosis of PEL cells is accompanied by the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (Δψm), an activation of c-Jun-N-terminal kinase (JNK), p38, as well as caspase-3, -8, and -9. Scavenging of ROS in the presence of N-acetylcysteine (NAC) almost blocks the loss of mitochondrial membrane Δψm, activation of JNK, cleavage of caspase-3, -9, and an induction of apoptosis in SHK treated PEL cells. SP600125, a specific inhibitor of JNK, also rescues a proportion of cells from the apoptotic effect of SHK. In addition, inhibition of caspase activation in the presence of pan-caspase inhibitor, Q-VD-OPh, blocks the SHK-inducing apoptosis, but doesn't completely inhibit SHK-mediated JNK activation. Therefore, ROS is an upstream trigger of SHK-induced caspase dependent apoptosis of PEL cells through disruption of mitochondrial membrane Δψm in an intrinsic pathway and an activation of JNK in an extrinsic pathway. In a PEL xenografted mouse model, SHK treatment suppresses PEL-mediated ascites formation without showing any significant adverse toxicity. These results suggested that SHK could be a potent anti-tumor agent for the treatment of PEL.}, }
@article {pmid33398722, year = {2021}, author = {Nikooie, R and Moflehi, D and Zand, S}, title = {Lactate regulates autophagy through ROS-mediated activation of ERK1/2/m-TOR/p-70S6K pathway in skeletal muscle.}, journal = {Journal of cell communication and signaling}, volume = {15}, number = {1}, pages = {107-123}, pmid = {33398722}, issn = {1873-9601}, abstract = {The role of autophagy and lysosomal degradation pathway in the regulation of skeletal muscle metabolism was previously studied. However, underlying molecular mechanisms are poorly understood. L-lactate which is utilized as an energetic substrate by skeletal muscle can also augment genes expression related to metabolism and up-regulate those being responsive to reactive oxygen species (ROS). Since ROS is the most important regulator of autophagy in skeletal muscle, we tested if there is a link between cellular lactate metabolism and autophagy in differentiated C2C12 myotubes and the gastrocnemius muscle of male wistar rats. C2C12 mouse skeletal muscle was exposed to 2, 6, 10, and 20 mM lactate and evaluated for lactate autophagic effects. Lactate dose-dependently increased autophagy and augmented ROS generation in differentiated C2C12 myotubes. The autophagic effect of lactate deterred in N-acetylcysteine presence (NAC, a ROS scavenger) indicated lactate regulates autophagy with ROS participation. Lactate-induced up-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) through ROS was required to regulate the autophagy by lactate. Further analysis about ERK1/2 up- and downstream indicated that lactate regulates autophagy through ROS-mediated the activation of ERK1/2/mTOR/p70S6K pathway in skeletal muscle. The in vitro effects of lactate on autophagy also occurred in the gastrocnemius muscle of male Wistar rats. In conclusion, we provided the lactate-associated regulation evidence of autophagy in skeletal muscle by activating ROS-mediated ERK1/2/mTOR/p70S6K pathway. Since the increase in cellular lactate concentration is a hallmark of energy deficiency, the results provide insight into a skeletal muscle mechanism to fulfill its enhanced energy requirement.}, }
@article {pmid33394445, year = {2021}, author = {Ahamed, M and Akhtar, MJ and Khan, MAM and Alhadlaq, HA}, title = {Co-exposure of Bi2O3 nanoparticles and bezo[a]pyrene-enhanced in vitro cytotoxicity of mouse spermatogonia cells.}, journal = {Environmental science and pollution research international}, volume = {28}, number = {14}, pages = {17109-17118}, pmid = {33394445}, issn = {1614-7499}, mesh = {Animals ; Benzo(a)pyrene/toxicity ; Male ; Mice ; *Nanoparticles/toxicity ; Oxidative Stress ; Pyrenes ; Reactive Oxygen Species ; *Spermatogonia ; }, abstract = {Recent attention has been focused on reproductive toxicity of nanoscale materials in combination with pre-existing environmental pollutants. Due to its unique characteristics, bismuth (III) oxide (Bi2O3) nanoparticles (BONPs) are being used in diverse fields including cosmetics and biomedicine. Benzo[a]pyrene (BaP) is a known endocrine disruptor that most common sources of BaP exposure to humans are cigarette smoke and well-cooked barbecued meat. Hence, joint exposure of BONPs and BaP in humans is common. There is scarcity of information on toxicity of BONPs in combination with BaP in human reproductive system. In this work, combined effects of BONPs and BaP in mouse spermatogonia (GC-1 spg) cells were assessed. Results showed that combined exposure of BONPs and BaP synergistically induced cell viability reduction, lactate dehydrogenase leakage, induction of caspases (-3 and -9) and mitochondrial membrane potential loss in GC-1 spg cells. Co-exposure of BONPs and BaP also synergistically induced production of pro-oxidants (reactive oxygen species and hydrogen peroxide) and reduction of antioxidants (glutathione and several antioxidant enzymes). Experiments with N-acetyl-cysteine (NAC, a reactive oxygen species scavenger) indicated that oxidative stress was a plausible mechanism of synergistic toxicity of BONPs and BaP in GC-1 spg cells. Present data could be helpful for future in vivo research and risk assessment of human reproductive system co-exposed to BONPs and BaP.}, }
@article {pmid33393705, year = {2021}, author = {Ezhilarasan, D and Raghunandhakumar, S}, title = {Boldine treatment protects acetaminophen-induced liver inflammation and acute hepatic necrosis in mice.}, journal = {Journal of biochemical and molecular toxicology}, volume = {35}, number = {4}, pages = {e22697}, doi = {10.1002/jbt.22697}, pmid = {33393705}, issn = {1099-0461}, mesh = {Acetaminophen/*adverse effects/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Aporphines/*pharmacology ; Chemical and Drug Induced Liver Injury/metabolism/pathology/*prevention &amp; control ; Cytokines/biosynthesis ; Gene Expression Regulation/drug effects ; Liver/*metabolism/pathology ; Male ; Mice ; Necrosis ; }, abstract = {Drug-induced liver injury (DILI) is a frequent cause responsible for acute liver failure (ALF). Acetaminophen (APAP) is a known hepatotoxin predictably causing intrinsic DILI. At high doses, APAP causes acute liver necrosis and responsible for ALF and liver transplant cases in 50% and 20% of patients, respectively, in the United States alone. Oxidative stress and glutathione depletion are implicated in APAP-induced liver necrosis. Boldine, a plant-derived compound is shown to have promising antioxidant potential. Therefore, this study investigates the protective effect of boldine against APAP-induced acute hepatic necrosis in mice. A single toxic dose of APAP (300 mg/kg b.w. p.o.) was administered in overnight-fasted mice to induce acute liver necrosis. Separately, APAP + boldine and APAP + N-acetylcysteine (NAC) simultaneous treatments were also given. Serum transaminases and reduced glutathione, enzymic antioxidants, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and, IL-6 were evaluated in liver tissue. Acute APAP intoxication significantly elevated serum marker enzymes of hepatotoxicity. APAP administration increased lipid peroxidation, TNF-α, IL-1β, and IL-6 protein expressions. The enzymic antioxidants and reduced glutathione levels were decreased in liver tissue of APAP intoxicated mice. Boldine and NAC simultaneous treatments prevented APAP-induced oxidative stress, inflammation, and necrosis. The results of this study suggest the crucial role of boldine to protect against APAP induced hepatotoxicity by virtue of its antioxidant and anti-inflammatory properties.}, }
@article {pmid33390565, year = {2021}, author = {Jiang, SJ and Huang, CH}, title = {The Clinical Efficacy of N-Acetylcysteine in the Treatment of ST Segment Elevation Myocardial Infarction.}, journal = {International heart journal}, volume = {62}, number = {1}, pages = {142-147}, doi = {10.1536/ihj.20-519}, pmid = {33390565}, issn = {1349-3299}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Cardiovascular Diseases/epidemiology/mortality/prevention &amp; control ; Case-Control Studies ; Creatine Kinase, MB Form/metabolism ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Heart Failure/mortality/physiopathology/prevention &amp; control ; Humans ; Male ; Middle Aged ; Myocardial Infarction/*drug therapy/metabolism/mortality/physiopathology ; Percutaneous Coronary Intervention/methods ; Randomized Controlled Trials as Topic ; ST Elevation Myocardial Infarction/*drug therapy/mortality ; Stroke Volume ; Treatment Outcome ; Troponin T/metabolism ; }, abstract = {The aim of this study was to evaluate the clinical efficacy of N-acetylcysteine (NAC) in the treatment of ST segment elevation myocardial infarction (STEMI).PubMed, EMBASE, Cochrane Library, and Web of Science were searched systematically from the establishment of the database to June 2020. Two researchers independently completed literature screening and data extraction and conducted a meta-analysis.Nine articles including 1419 patients were enrolled. Meta-analysis showed that all-cause mortality [RR = 0.56, 95%CI (0.33, 0.93), P = 0.02], occurrence of major adverse cardiovascular events (MACE) [RR = 0.63, 95%CI (0.47, 0.85), P = 0.002], and myocardial enzyme hs-TnT level [SMD = -0.42, 95%CI (-0.71, -0.13), P = 0.005] were significantly lower in patients with STEMI treated with NAC than those in the control group. There was no significant difference between the NAC group and the control group in new congestive heart failure [RR = 0.94, 95%CI (0.48, 1.82), P = 0.84], ejection fraction [MD = 2.00, 95%CI (-0.59, 4.60), P = 0.13], and CK-MB [SMD = -0.18, 95%CI (-0.47, 0.11), P = 0.23]. There was no significant difference in the occurrence of adverse reactions between the NAC group and the control group [RR = 1.04, 95%CI (0.57-1.89), P = 0.90].NAC can reduce the all-cause mortality and MACE cases of STEMI.}, }
@article {pmid33388248, year = {2021}, author = {Handigund, M and Kim, JT and Bae, TW and Lee, J and Cho, YG}, title = {N-acetylcysteine reduce the stress induced by cold storage of platelets: A potential way to extend shelf life of platelets.}, journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis}, volume = {60}, number = {2}, pages = {103039}, doi = {10.1016/j.transci.2020.103039}, pmid = {33388248}, issn = {1473-0502}, mesh = {Acetylcysteine/*metabolism ; Animals ; Blood Platelets/*metabolism ; Cryopreservation/*methods ; Humans ; Mice ; }, abstract = {The room temperature storage used for platelets worldwide leads to platelet storage lesion (PSL) and risk of bacterial growth, limiting platelet shelf life and safety in transfusion. Thus, there is a need for an alternative storage method that can serve as effective temperature storage for platelet concentrates (PCs). In the previous investigation, we have shown that N-acetylcysteine (NAC) is a potential candidate for an additive solution to retain platelet characteristics during cold storage for up to 5 days. However, the study partially describes the efficacy and has drawbacks to address. Here, we used the apheresis platelet product with 50 mM NAC and stored up to 10 days under refrigerated condition (4 ± 1 °C). Stored platelet concentrates were analyzed for critical parameters such as platelet activation, annexin V binding, sialic acid, reactive oxygen species (ROS), neuraminidase activity, and in vivo efficacy using Prkdc[scid] mice. Investigation observations revealed that PCs with NAC showed reduced platelet activation, annexin V binding, ROS production, and sialic acid levels. in vivo recovery of PCs showed similar recovery rates stored PCs irrespective of treatment or storage condition. However, on the tenth day after 24 h, recovery in room temperature stored concentrates was about 32 %, whereas in NAC treated refrigerated concentrates, it stands at 47 %. These observations indicate that NAC addition protects refrigerated concentrates during long-term storage retaining the platelet integrity. The study also suggests that extending PC storage beyond 10 days is practically accomplishable with efficacy similar to room temperature (RT) stored PCs.}, }
@article {pmid33382531, year = {2021}, author = {Choi, YJ and Lee, J and Ha, SH and Lee, HK and Lim, HM and Yu, SH and Lee, CM and Nam, MJ and Yang, YH and Park, K and Choi, YS and Jang, KY and Park, SH}, title = {6,8-Diprenylorobol induces apoptosis in human colon cancer cells via activation of intracellular reactive oxygen species and p53.}, journal = {Environmental toxicology}, volume = {36}, number = {5}, pages = {914-925}, doi = {10.1002/tox.23093}, pmid = {33382531}, issn = {1522-7278}, support = {NRF-2017R1A5A2015061//Medical Research Center Program/ ; //Ministry of Science and ICT/ ; //National Research Foundation of Korea/ ; NRF-2014R1A6A3A04054307//Basic Science Research Program/ ; }, mesh = {Apoptosis ; Cell Line, Tumor ; Cell Survival ; *Colonic Neoplasms/drug therapy ; Humans ; Reactive Oxygen Species/metabolism ; *Tumor Suppressor Protein p53 ; }, abstract = {6,8-Diprenylorobol is a natural compound mainly found in Glycyrrhiza uralensis fisch and Maclura tricuspidata, which has been used traditionally as food and medicine in Asia. So far, the antiproliferative effect of 6,8-diprenylorobol has not been studied yet in colon cancer. In this study, we aimed to evaluate the antiproliferative effects of 6,8-diprenylorobol in LoVo and HCT15, two kinds of human colon cancer cells. 6,8-Diprenylorobol inhibited the proliferation of LoVo and HCT15 cells in a dose- and time-dependent manner. A 40 μM of 6,8-diprenylorobol for 72 h reduced both of cell viability under 50%. After treatment of 6,8-diprenylorobol (40 and 60 μM) for 72 h, late apoptotic cell portion in LoVo and HCT15 cells were 24, 70% and 13, 90%, respectively, which was confirmed by checking DNA fragmentation in both cells. Mechanistically, 6,8-diprenylorobol activated p53 and its phosphorylated form (Ser15, Ser20, and Ser46) expression but suppressed Akt and mitogen-activated protein kinases (MAPKs) phosphorylation in LoVo and HCT15 cells. Interestingly, 6,8-diprenylorobol induced the generation of intracellular reactive oxygen species (ROS), which was attenuated with N-acetyl cysteine (NAC) treatment. Compared to the control, 60 μM of 6,8-diprenylorobol caused to increase ROS level to 210% in LoVo and HCT15, which was reduced into 161% and 124%, respectively with NAC. Furthermore, cell viability and apoptotic cell portion by 6,8-diprenylorobol was recovered by incubation with NAC. Taken together, these results indicate that 6,8-diprenylorobol has the potential antiproliferative effect against LoVo and HCT15 colon cancer cells through activation of p53 and generation of ROS.}, }
@article {pmid33381272, year = {2020}, author = {Li, D and Pei, X and Qin, X and Liu, X and Li, C and Li, L and Dai, C and Xiao, X and Tang, S}, title = {Olaquindox-Induced Liver Damage Involved the Crosstalk of Oxidative Stress and p53 In Vivo and In Vitro.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {8835207}, pmid = {33381272}, issn = {1942-0994}, mesh = {Animals ; Apoptosis/drug effects/genetics ; Cells, Cultured ; *Chemical and Drug Induced Liver Injury/genetics/metabolism/pathology ; HCT116 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects/genetics ; Quinoxalines/*toxicity ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/genetics ; Tumor Suppressor Protein p53/genetics/*physiology ; }, abstract = {Olaquindox (OLA), a member of the quinoxaline-N,N-dioxide family, has been widely used as a growth-promoting feed additive and treatment for bacterial infections. The toxicity has been a major concern, and the precise molecular mechanism remains poorly understood. The present study was aimed at investigating the roles of oxidative stress and p53 in OLA-caused liver damage. In a mouse model, OLA administration could markedly cause liver injury as well as the induction of oxidative stress and activation of p53. Antioxidant N-acetylcysteine (NAC) inhibited OLA-induced oxidative stress and p53 activation in vivo. Furthermore, knockout of the p53 gene could significantly inhibit OLA-induced liver damage by inhibiting oxidative stress and the mitochondria apoptotic pathway, compared to the p53 wild-type liver tissue. The cell model in vitro further demonstrated that p53 knockout or knockdown in the HCT116 cell and L02 cell significantly inhibited cell apoptosis and increased cell viability, presented by suppressing ROS production, oxidative stress, and the Nrf2/HO-1 pathway. Moreover, loss of p53 decreased OLA-induced mitochondrial dysfunction and caspase activations, with the evidence of inhibited activation of phosphorylation- (p-) p38 and p-JNK and upregulated cell autophagy via activation of the LC3 and Beclin1 pathway in HCT116 and L02 cells. Taken together, our findings provided a support that p53 primarily played a proapoptotic role in OLA-induced liver damage against oxidative stress and mitochondrial dysfunction, which were largely dependent on suppression of the JNK/p38 pathway and upregulation of the autophagy pathway via activation of LC3 and Beclin1.}, }
@article {pmid33380301, year = {2021}, author = {Raghu, G and Berk, M and Campochiaro, PA and Jaeschke, H and Marenzi, G and Richeldi, L and Wen, FQ and Nicoletti, F and Calverley, PMA}, title = {The Multifaceted Therapeutic Role of N-Acetylcysteine (NAC) in Disorders Characterized by Oxidative Stress.}, journal = {Current neuropharmacology}, volume = {19}, number = {8}, pages = {1202-1224}, pmid = {33380301}, issn = {1875-6190}, support = {1059660, 1156072//NHMRC Senior Principal Research Fellowship/ ; }, mesh = {*Acetylcysteine/metabolism/therapeutic use ; *Antioxidants/metabolism ; Expectorants/pharmacology ; Glutathione/metabolism ; Oxidative Stress/drug effects ; }, abstract = {Oxidative stress, which results in the damage of diverse biological molecules, is a ubiquitous cellular process implicated in the etiology of many illnesses. The sulfhydryl-containing tripeptide glutathione (GSH), which is synthesized and maintained at high concentrations in all cells, is one of the mechanisms by which cells protect themselves from oxidative stress. N-acetylcysteine (NAC), a synthetic derivative of the endogenous amino acid L-cysteine and a precursor of GSH, has been used for several decades as a mucolytic and as an antidote to acetaminophen (paracetamol) poisoning. As a mucolytic, NAC breaks the disulfide bonds of heavily cross-linked mucins, thereby reducing mucus viscosity. In vitro, NAC has antifibrotic effects on lung fibroblasts. As an antidote to acetaminophen poisoning, NAC restores the hepatic GSH pool depleted in the drug detoxification process. More recently, improved knowledge of the mechanisms by which NAC acts has expanded its clinical applications. In particular, the discovery that NAC can modulate the homeostasis of glutamate has prompted studies of NAC in neuropsychiatric diseases characterized by impaired glutamate homeostasis. This narrative review provides an overview of the most relevant and recent evidence on the clinical application of NAC, with a focus on respiratory diseases, acetaminophen poisoning, disorders of the central nervous system (chronic neuropathic pain, depression, schizophrenia, bipolar disorder, and addiction), cardiovascular disease, contrast-induced nephropathy, and ophthalmology (retinitis pigmentosa).}, }
@article {pmid33378994, year = {2021}, author = {Zhang, J and Cao, L and Tan, Y and Zheng, Y and Gui, Y}, title = {N-acetylcysteine protects neonatal mice from ventricular hypertrophy induced by maternal obesity in a sex-specific manner.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {133}, number = {}, pages = {110989}, doi = {10.1016/j.biopha.2020.110989}, pmid = {33378994}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology ; Animal Nutritional Physiological Phenomena ; Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; Disease Models, Animal ; Female ; Fibrosis ; Heart Ventricles/*drug effects/metabolism/physiopathology ; Hypertrophy, Left Ventricular/etiology/metabolism/physiopathology/*prevention &amp; control ; Male ; Maternal Nutritional Physiological Phenomena ; Mice, Inbred C57BL ; Obesity, Maternal/*complications/physiopathology ; Oxidative Stress/*drug effects ; Pregnancy ; Prenatal Exposure Delayed Effects ; Sex Factors ; Ventricular Function, Left/*drug effects ; Ventricular Remodeling/*drug effects ; Mice ; }, abstract = {BACKGROUND: Maternal obesity induces adverse cardiac programming in offspring, and effective interventions are needed to prevent cardiovascular ill-health. Herein we hypothesized that exposure to maternal obesogenic diet-induced obesity in mice results in left ventricular remodelling and hypertrophy in early childhood, and that maternal N-acetylcysteine (NAC) treatment alleviates these effects in a sex-dependent manner.<br><br>METHODS AND RESULTS: The maternal obesity was induced in mice by the consumption of a Western diet accompanied by a 20 % sucrose solution. To determine the effect of NAC on the cardiac outcomes induced by maternal obesity, obese dams were continuously exposed to the obesogenic diet, with or without the oral NAC treatment during pregnancy. Left ventricular remodelling and hypertrophy occurred as early as 7 days after birth in the male offspring of obese dams (O-OB) compared with controls (O-CO). An over-expression of key genes and markers related to cardiac fibrosis accompanied by more disorganized myofibrils was observed in the hearts of neonatal male O-OB mice. When we next evaluated the level of oxidative stress in the hearts of neonatal mice, the activity of enzymatic antioxidants declined and expression of NOX enzyme complex was up-regulated in O-OB offspring hearts, but was normal in the offspring of NAC treated mice (O-OB/NAC). Maternal obesity also activated cardiac Akt and mammalian target of rapamycin (mTOR) signalling in offspring, and NAC treatment restored offspring cardiac Akt-mTOR signalling to normal irrespective of sex. NAC treatment did not prevent cardiomyocyte hypertrophy but did alleviate increased heart weight, interventricular septal thickness, and collagen content in male O-OB/NAC pups.<br><br>CONCLUSIONS: Collectively, our results indicated that NAC blunted cardiac fibrosis and related ventricular hypertrophy of male neonatal offspring in the setting of maternal obesity, potentially acting by reducing oxidative stress. The present study provides a basis for investigating the role of NAC in nutrition-related cardiac programming.}, }
@article {pmid33375816, year = {2021}, author = {Lin, H and Ba, G and Tang, R and Li, M and Li, Z and Li, D and Ye, H and Zhang, W}, title = {Increased Expression of TXNIP Facilitates Oxidative Stress in Nasal Epithelial Cells of Patients With Chronic Rhinosinusitis With Nasal Polyps.}, journal = {American journal of rhinology &amp; allergy}, volume = {35}, number = {5}, pages = {607-614}, doi = {10.1177/1945892420982411}, pmid = {33375816}, issn = {1945-8932}, mesh = {Carrier Proteins/genetics ; Chronic Disease ; Epithelial Cells ; Humans ; *Nasal Polyps ; Oxidative Stress ; *Rhinitis ; *Sinusitis ; }, abstract = {BACKGROUND: Oxidative stress plays crucial roles in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Thioredoxin-interacting protein (TXNIP) is essential in the process of triggering oxidative stress. However, its role and mechanism in CRSwNP remain unclear. The present study sought to explore the role and mechanism of TXNIP in the pathogenesis of CRSwNP.<br><br>METHODS: Western blotting, real-time PCR and immunohistochemistry (IHC) were employed to assess TXNIP, thioredoxin (TRX) expression in nasal tissue samples from patients with CRSwNP and control subjects. MDA level and SOD activity in nasal tissue homogenates were measured using MDA and SOD Assay Kit. To evaluate the role and mechanism of TXNIP in CRSwNP, human nasal epithelial cells (HNECs) were cultured and stimulated using TXNIP siRNA, with or without N-acetylcysteine (NAC, an ROS scavenger). Western blotting, real-time PCR, ROS detecting dye DCFH-DA, MDA and SOD Assay Kit were performed to assess the effects and mechanisms of stimulators on the cells.<br><br>RESULTS: We found significantly increased levels of TXNIP and decreased levels of TRX protein, mRNA, positive cells, increased MDA level and decreased SOD activity in CRSwNP patients compared with control subjects. In vitro study, significantly altered levels of TXNIP, TRX, MDA, SOD and ROS in HNECs were found following treatment of TXNIP siRNA with or without NAC on HNECs.<br><br>CONCLUSION: TXNIP expression was increased and TRX expression was decreased in CRSwNP at both protein and mRNA levels. MDA levels were increased and SOD activities were decreased in CRSwNP. TXNIP may have negative association with TRX, and then decrease SOD activities and increase MDA levels, resulting in the upregulation of ROS and oxidative stress in HNECs, which may play a pivotal role in the pathogenesis of CRSwNP. Future studies are expected to further explore the role and mechanism of TXNIP in CRSwNP.}, }
@article {pmid33373629, year = {2021}, author = {Chevallier, V and Zoller, M and Kochanowski, N and Andersen, MR and Workman, CT and Malphettes, L}, title = {Use of novel cystine analogs to decrease oxidative stress and control product quality.}, journal = {Journal of biotechnology}, volume = {327}, number = {}, pages = {1-8}, doi = {10.1016/j.jbiotec.2020.12.011}, pmid = {33373629}, issn = {1873-4863}, mesh = {Amino Acids ; Cell Culture Techniques ; Culture Media ; *Cysteine/metabolism ; *Cystine/metabolism ; Glutathione/metabolism ; *Oxidative Stress ; }, abstract = {Continuous improvements of cell culture media are required in order to ensure high yield and product quality. However, some components can be instable and lead to detrimental effects on bioprocess performances. l-cysteine is an essential amino acid commonly used in cell culture media. Despite its beneficial effect on recombinant protein production, in some cases, this component can be responsible for product microheterogeneity. In this context, alternative components have to be found in order to reduce product variants while maintaining high productivity. In this study, we have assessed the performance of different cysteine and cystine analogs : N-acetyl-cysteine, s-sulfocysteine, N,N'-diacetyl-l-cystine and the N,N'-diacetyl-l-cystine dimethylester (DACDM). Replacement of cysteine by cystine analogs, and especially DACDM, has shown positive impact on charge variants level and recombinant protein coloration level. Moreover, this molecule contributed to the increase of the intracellular glutathione pool, which suggests a close relationship with the oxidative stress regulation.}, }
@article {pmid33373322, year = {2022}, author = {Morales-Borges, RH and Gonzalez, MJ and Duconge, J and Minich, DM}, title = {N-Acetyl Cysteine and Glutathione in Health and Cancer-Pharmacogenomics, Research, and Clinical Practice: Hypothesis and Review.}, journal = {Alternative therapies in health and medicine}, volume = {28}, number = {7}, pages = {169-177}, pmid = {33373322}, issn = {1078-6791}, mesh = {Acetylcysteine/therapeutic use ; *Antineoplastic Agents/therapeutic use ; Antioxidants/therapeutic use ; Glutathione/metabolism ; Humans ; *Neoplasms/drug therapy/genetics ; Pharmacogenetics ; Sulfhydryl Compounds/therapeutic use ; }, abstract = {CONTEXT: Glutathione (GSH) is a major intracellular antioxidant capable of scavenging free radicals and detoxifying electrophiles from endogenous and exogenous sources via the free thiol group. GSH plays an important role in a multiple cellular process, including cell differentiation, proliferation, and apoptosis. Pharmacogenomics has demonstrated its important role as a key element in cellular health.<br><br>OBJECTIVE: The study intended to examine the benefits of using GSH pharmacogenomics as a therapy to prevent side effects and interactions with antineoplastic agents in the diagnosis and treatment of malignancies.<br><br>DESIGN: The research team performed a narrative review using the Google scholar and PubMed electronic databases.<br><br>CONCLUSIONS: In summary, the involvement of GSH in the carcinogenesis and drug resistance of tumor cells is clear and well understood, but further studies, aimed at understanding the GSH-driven molecular pathways, might be crucial to designing new therapeutic strategies to fight cancer progression, overcoming chemoresistance, using in combination with immunotherapies, and preventing or minimizing their negative side effects.}, }
@article {pmid33371832, year = {2021}, author = {Zhou, N and Yang, X and Huang, A and Chen, Z}, title = {The Potential Mechanism of N-acetylcysteine in Treating COVID-19.}, journal = {Current pharmaceutical biotechnology}, volume = {22}, number = {12}, pages = {1584-1590}, doi = {10.2174/1389201021999201228212043}, pmid = {33371832}, issn = {1873-4316}, support = {81772094, 81974289//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/therapeutic use ; *Coronavirus Infections ; Humans ; SARS-CoV-2 ; *COVID-19 Drug Treatment ; }, abstract = {N-Acetylcysteine (NAC) has been proposed to be used to treat Coronavirus Disease 2019 (COVID-19). By reviewing the existing pathological studies of COVID-19, it was found that abundant mucus secretion, formation of a hyaline membrane (supportive of acute respiratory distress syndrome), and interstitial fibrous exudation may be important characteristics of COVID-19 and pathological targets of drug therapy. In addition, multiple extrapulmonary organ injuries in COVID- 19 may be associated with cytokine storm. NAC is an important antioxidant and anti-inflammatory drug. NAC has been demonstrated to have mucolytic effects in bronchitis, relieve respiratory failure in acute respiratory distress syndrome, and inhibit fibrous exudation in interstitial lung disease in clinical studies. These findings suggest that NAC may have a therapeutic effect on the pathological targets of COVID-19. Furthermore, NAC decreases TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-17 serum levels in patients with sepsis, severe burns, acute liver failure, or peritoneal dialysis and may also reduce cytokine storm in COVID-19. The antiviral effect of NAC on other respiratory viruses may also benefit COVID-19 patients. Summarizing the potential mechanisms of NAC in treating COVID-19 suggests that the role of NAC in COVID-19 treatment is worthy of further research.}, }
@article {pmid33370509, year = {2021}, author = {Jayakumar, I and Uppuluri, R and Lakshmanan, C and Kumar Gowdhaman, A and Vellaichamy Swaminathan, V and Raj, R}, title = {Risk-adapted therapy for the management of cytokine release syndrome in children undergoing unmanipulated haploidentical stem cell transplantation.}, journal = {Pediatric transplantation}, volume = {25}, number = {5}, pages = {e13964}, doi = {10.1111/petr.13964}, pmid = {33370509}, issn = {1399-3046}, mesh = {Adolescent ; Child ; Child, Preschool ; Combined Modality Therapy ; Cytokine Release Syndrome/diagnosis/etiology/mortality/*therapy ; Female ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Infant ; Male ; Prospective Studies ; Risk Assessment ; Severity of Illness Index ; Transplantation, Haploidentical/*adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND: We aimed to describe an algorithm for the management of cytokine release syndrome (CRS) associated with haploidentical hematopoietic stem cell transplantation (haploSCT).<br><br>PATIENTS AND METHODS: We performed a prospective study where children up to 18&#xa0;years of age undergoing haploSCT with post-transplant cyclophosphamide from September 2014 to March 2020 were included. Supportive care included low-dose adrenaline, high-flow nasal cannula, and N-acetylcysteine (NAC). Methylprednisolone and tocilizumab were administered in the peri-engraftment phase for grade 2 CRS or one-log increase and grade 3 CRS or a two-log increase in ferritin, respectively.<br><br>RESULTS: Data were analyzed in 135/148 children as 13 children died before engraftment due to sepsis. CRS was noted in 97% transplants (grade 1-74.1%, grade 2-15.6%, grade 3-6.7%, grade 4-1.4%). Grade 2 and above CRS was higher in non-malignant conditions (33% vs 13%, P-value .009). The percentage median rise in ferritin was 129%-grade 1, 171%-grade 2, and 344%-grade 3. Seven children received tocilizumab, and two of whom had ferritin values greater than 100&#xa0;000&#xa0;ng/mL with no mortality in this group. Low-dose adrenaline, high-flow nasal cannula, and ventilator support were needed in 13%, 10%, and 4%, respectively. Mortality in our cohort was 3/135 (2.2%), with two deaths due to sepsis and one due to grade 4 CRS.<br><br>CONCLUSIONS: A risk-stratified approach using steroids in grade 2 and tocilizumab in grade 3/4 in the setting of haploSCT with NAC infusion and early use of low-dose adrenaline and HFNC can help provide adequate control of CRS, thereby ensuring optimal outcomes and survival.}, }
@article {pmid33361844, year = {2020}, author = {Korkushko, OV and Gorban, EM and Bondarenko, OV and Antonyuk-Shcheglova, IA and Naskalova, SS and Parshykov, OV and Utko, NO and Gavalko, AV and Shatilo, VB and Duzhak, GV}, title = {APPLICATION OF QUERCETIN FOR CORRECTION OF THE IMPAIRMENT OF THE FUNCTIONAL STATE OF THE ENDOTHELIUS OF VESSELS (CLINICAL AND EXPERIMENTAL STUDY).}, journal = {Problemy radiatsiinoi medytsyny ta radiobiolohii}, volume = {25}, number = {}, pages = {321-337}, doi = {10.33145/2304-8336-2020-25-321-337}, pmid = {33361844}, issn = {2313-4607}, mesh = {Acetylcysteine/pharmacology ; Adipose Tissue/drug effects/metabolism/radiation effects ; Aged ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Animals ; Aorta, Thoracic/*drug effects/metabolism/radiation effects ; Aspirin/therapeutic use ; Blood Flow Velocity/*drug effects/physiology/radiation effects ; Case-Control Studies ; Endothelium, Vascular/*drug effects/metabolism/radiation effects ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Male ; Mesenteric Arteries/*drug effects/metabolism/radiation effects ; Metabolic Syndrome/*drug therapy/metabolism/pathology ; Middle Aged ; NG-Nitroarginine Methyl Ester/pharmacology ; Phenylephrine/pharmacology ; Quercetin/*pharmacology ; Rats ; Tissue Culture Techniques ; X-Rays ; }, abstract = {OBJECTIVE: in the experiment, to investigate the effect of Quercetin on the NO-dependent reactions of isolated vessels involving endothelium and perivascular adipose tissue (PVAT) after a single X-ray irradiation of rats at a sublethal dose. In a clinical study, to investigate the effect of long-term use of Quercetin on the functional state of themicrovascular endothelium in the elderly patients with metabolic syndrome (MS).<br><br>MATERIAL AND METHODS: Experimental studies were performed on vascular fragments obtained from adult male rats(7-8 months) of the control group, in animals exposed to a single R-irradiation at a dose of 7 Gy and animals irradiated in the same dose, which received Quercetin orally for 14 days three times a week based on 10 mg/kg bodyweight. Fragments of the thoracic aorta (TA) and mesenteric artery (MA) were cleaned of perivascular adipose tissue (PVAT-) or left uncleaned (PVAT+), and then were cut into rings (up to 2 mm). The amplitude of the contractionof the rings TA and MA under the influence of phenylephrine (PE, 3 x 10-6 M), the amplitude of the contraction of therings TA and MA in the presence of a competitive blocker of NO-synthase methyl ester of N-nitro-L-arginine(L-NAME, 10-5 M), the amplitude of relaxation of the rings TA and MA in the presence of N-acetylcysteine (NAC, 10-4 M)were measured. The clinical study examined 110 patients with MS criteria in accordance with ATP III (2001).Patients in the main group for 3 months received Quercetin from the same manufacturer, 80 mg three times a day,patients in the control group received placebo.<br><br>RESULTS: Single R-irradiation disrupts the regulation of the contractile function of TA and MA, which is evidenced bychanges in the contractile reactions of isolated fragments of these vessels as a response to the action of vasoactivecompounds. Course use of Quercetin in irradiated rats leads to the normalization of contractile and dilatory vascular responses due to partial correction of NO metabolism in the endothelium and PVAT. For the majority of patients(69 %) who received Quercetin, a post-occlusive hyperemia test showed a statistically significant increase of maximal volumetric velocity of the skin blood flow rate and duration of the recovery period to the baseline, which indicates about improvement of vasomotor vascular endothelial function.<br><br>CONCLUSIONS: Course use of Quercetin improves the functional state of the microvascular endothelium among theelderly people with MS, normalizes contractile and dilatory vascular responses in irradiated rats due to partial correction of NO metabolism in the endothelium and PVAT.}, }
@article {pmid33360915, year = {2021}, author = {Sun, P and Jin, J and Wang, L and Wang, J and Zhou, H and Zhang, Q and Xu, X}, title = {Porcine epidemic diarrhea virus infections induce autophagy in Vero cells via ROS-dependent endoplasmic reticulum stress through PERK and IRE1 pathways.}, journal = {Veterinary microbiology}, volume = {253}, number = {}, pages = {108959}, doi = {10.1016/j.vetmic.2020.108959}, pmid = {33360915}, issn = {1873-2542}, mesh = {Animals ; *Autophagy ; Chlorocebus aethiops ; Endoplasmic Reticulum Stress/*physiology ; Metabolic Networks and Pathways ; Porcine epidemic diarrhea virus/*pathogenicity ; Protein Serine-Threonine Kinases/*physiology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Unfolded Protein Response ; Vero Cells ; Virus Replication ; eIF-2 Kinase/genetics/*physiology ; }, abstract = {Porcine epidemic diarrhea virus (PEDV), the causative agent of PED, belongs to the genus Alphacoronavirus in the family Coronaviridae. Reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy play crucial roles in regulating a variety of cellular processes during viral infection. However, the precise role of autophagy in PEDV-infected Vero cells remains largely elusive. To elucidate how PEDV infection induces autophagy, this study ascertained whether ER stress was present in PEDV-infected Vero cells. The results showed PEDV infection significantly increased the expression of GRP78 and LC3Ⅱ. Treatment with the ER stress inhibitor 4-phenylbutyrate (4-PBA) could significantly inhibit PEDV-induced autophagy. Antioxidants, such as N-acetylcysteine (NAC), could significantly inhibit PEDV-induced ER stress and autophagy, indicating that ROS act as an upstream regulator of ER stress-mediated autophagy. Further research found that activation of ER stress triggered the unfolded protein response (UPR) through PERK, IRE1, and ATF6 pathways during PEDV infection. However, treatment with the PERK inhibitor GSK2606414, IRE1 inhibitor STF-083010 but not ATF6 inhibitor AEBSF reversed PEDV-induced autophagy. Taken together, the results of this study showed that accumulated ROS played an essential role in regulating ER stress-mediated autophagy during PEDV infection. We also found that PERK and IER1 pathways of UPR signalling were involved in PEDV-induced autophagy. Furthermore, PEDV induced autophagy to promote viral replication via PERK and IER1 pathways in Vero cells. These results provide the mechanism of PEDV-induced ROS-dependent ER stress-mediated autophagy in Vero cells through activating PERK and IRE1 pathways.}, }
@article {pmid33359576, year = {2021}, author = {Lu, B and Ran, Y and Wang, S and Li, J and Zhao, Y and Ran, X and Li, R and Hao, Y}, title = {Chronic oral depleted uranium leads to reproductive damage in male rats through the ROS-hnRNP A2/B1-COX-2 signaling pathway.}, journal = {Toxicology}, volume = {449}, number = {}, pages = {152666}, doi = {10.1016/j.tox.2020.152666}, pmid = {33359576}, issn = {1879-3185}, mesh = {Administration, Oral ; Animals ; Cell Line ; Cyclooxygenase 2/*metabolism ; Dose-Response Relationship, Drug ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Reproduction/drug effects/*physiology ; Signal Transduction/*drug effects/physiology ; Uranium/administration &amp; dosage/*toxicity ; }, abstract = {Depleted uranium (DU) is widely used in civil and military activities. The testis is one of the target organs of DU chronic toxicity. In this study, male SD rats were chronically exposed to DU by 3, 30, 300 mg U/kg through oral intake. After 6 months and 12 months of exposure, it was found that DU could lead to increased oxidative stress levels, decreased glutathione S-transferases (GSTs) expression, resulting in testicular injury and decreased serum testosterone (T) level in rats. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) expression increases with the increase of DU exposure dose. After upregulation of hnRNP A2/B1 expression, the GC-1 cell injury caused by DU is aggravated, suggesting that hnRNP A2/B1 may play an important role in the reproductive toxicity of DU. At the same time, 12 months after chronic oral exposure to DU, the expression level of cyclooxygenase-2 (COX-2) and proinflammatory factor prostaglandin E2 (PGE2) in testicular tissue were increased, and the level of hnRNP A2/B1 caused by DU was decreased by reactive oxygen scavenger N-acetylcysteine (NAC). As hnRNP A2/B1 is a COX-2 regulator, DU may lead to the upregulation of hnRNP A2/B1 expression through the increase of oxidative stress level in germ cells, which in turn leads to the increase of COX-2 and PGE2 level, and ultimately result in the reproductive toxicity. In this study, the regulation mechanism of the ROS-hnRNP A2/B1-COX-2 pathway on DU-induced reproductive damage in male rats was hypothesized, providing a new target for the prevention and treatment of chronic poisoning of DU.}, }
@article {pmid33359261, year = {2021}, author = {Ana, Y and Rojas Marquez, JD and Fozzatti, L and Baigorrí, RE and Marin, C and Maletto, BA and Cerbán, FM and Radi, R and Piacenza, L and Stempin, CC}, title = {An exacerbated metabolism and mitochondrial reactive oxygen species contribute to mitochondrial alterations and apoptosis in CD4 T cells during the acute phase of Trypanosoma cruzi infection.}, journal = {Free radical biology &amp; medicine}, volume = {163}, number = {}, pages = {268-280}, doi = {10.1016/j.freeradbiomed.2020.12.009}, pmid = {33359261}, issn = {1873-4596}, mesh = {Animals ; Apoptosis ; CD4-Positive T-Lymphocytes ; *Chagas Disease/genetics ; Mice ; Reactive Oxygen Species ; *Trypanosoma cruzi ; }, abstract = {Chagas disease caused by Trypanosoma cruzi parasite is an endemic infection in America. It is well known that T. cruzi causes a strong immunosuppression during the acute phase of infection. However, it is not clear whether T. cruzi infection is related to metabolic alterations in CD4 T cells that prevent downstream effector function. Here, we evaluated the CD4 T cell metabolic and mitochondrial profiles from non-infected (NI), acute phase (AP) and chronic phase (CP) T. cruzi infected mice. CD4 T cells from all groups showed increased glucose uptake after stimulation. Moreover, the bioenergetic analysis revealed a rise in glycolysis and a higher oxidative metabolism in CD4 T cells from the AP. These cells showed increased proton leak and uncoupling protein 3 (UCP3) expression that correlated with mitochondrial ROS (mROS) accumulation, mitochondrial membrane potential (MMP) depolarization and expression of PD-1. In addition, CD4 T cells with mitochondrial alteration displayed an activated phenotype, and were less functional and more prone to apoptosis. In contrast, mitochondrial alterations were not observed during in vivo activation of CD4 T cells in a model of OVA-immunization. The Mn-superoxide dismutase (SOD2) expression, which is involved in mROS detoxification, was increased during the AP and CP of infection. Remarkably, the apoptosis observed in CD4 T cells with MMP depolarization was prevented by incubation with N-acetyl cysteine (NAC). Thus, our results showed that infection triggered an exacerbated metabolism together with mROS production in CD4 T cells from the AP of infection. However, antioxidant availability may not be sufficient to avoid mitochondrial alterations rendering these cells more susceptible to apoptosis. Our investigation is the first to demonstrate an association between a disturbed metabolism and an impaired CD4 T cell response during T. cruzi infection.}, }
@article {pmid33357221, year = {2020}, author = {Walther, C and Döring, K and Schmidtke, M}, title = {Comparative in vitro analysis of inhibition of rhinovirus and influenza virus replication by mucoactive secretolytic agents and plant extracts.}, journal = {BMC complementary medicine and therapies}, volume = {20}, number = {1}, pages = {380}, pmid = {33357221}, issn = {2662-7671}, mesh = {Acetylcysteine ; Ambroxol ; Animals ; Bromhexine ; Dogs ; HeLa Cells ; Humans ; Influenza A virus/*drug effects ; Madin Darby Canine Kidney Cells ; Microbial Sensitivity Tests ; *Pelargonium ; Phytotherapy ; Plant Extracts/pharmacology/*therapeutic use ; Respiratory Tract Infections/*drug therapy ; Rhinovirus/*drug effects ; Thymus Plant ; Toxicity Tests ; Virus Replication/*drug effects ; }, abstract = {BACKGROUND: Rhinoviruses and influenza viruses cause millions of acute respiratory infections annually. Symptoms of mild acute respiratory infections are commonly treated with over-the-counter products like ambroxol, bromhexine, and N-acetyl cysteine, as well as of thyme and pelargonium extracts today. Because the direct antiviral activity of these over-the-counter products has not been studied in a systematic way, the current study aimed to compare their inhibitory effect against rhinovirus and influenza virus replication in an in vitro setting.<br><br>METHODS: The cytotoxicity of ambroxol, bromhexine, and N-acetyl cysteine, as well as of thyme and pelargonium extracts was analyzed in Madin Darby canine kidney (MDCK) and HeLa Ohio cells. The antiviral effect of these over-the-counter products was compared by analyzing the dose-dependent inhibition (i) of rhinovirus A2- and B14-induced cytopathic effect in HeLa Ohio cells and (ii) of influenza virus A/Hong Kong/68 (subtype H3N2)- and A/Jena/8178/09 (subtype H1N1, pandemic)-induced cytopathic effect in MDCK cells at non-cytotoxic concentrations. To get insights into the mechanism of action of pelargonium extract against influenza virus, we performed time-of-addition assays as well as hemagglutination and neuraminidase inhibition assays.<br><br>RESULTS: N-acetyl cysteine, thyme and pelargonium extract showed no or only marginal cytotoxicity in MDCK and HeLa Ohio cells in the tested concentration range. The 50% cytotoxic concentration of ambroxol and bromhexine was 51.85 and 61.24&#x2009;&#x3bc;M, respectively. No anti-rhinoviral activity was detected at non-cytotoxic concentrations in this in vitro study setting. Ambroxol, bromhexine, and N-acetyl cysteine inhibited the influenza virus-induced cytopathic effect in MDCK cells no or less than 50%. In contrast, a dose-dependent anti-influenza virus activity of thyme and pelargonium extracts was demonstrated. The time-of addition assays revealed an inhibition of early and late steps of influenza virus replication by pelargonium extract whereas zanamivir acted on late steps only. The proven block of viral neuraminidase activity might explain the inhibition of influenza virus replication when added after viral adsorption.<br><br>CONCLUSION: The study results indicate a distinct inhibition of influenza A virus replication by thyme and pelargonium extract which might contribute to the beneficial effects of these plant extracts on acute respiratory infections symptoms.}, }
@article {pmid33356745, year = {2021}, author = {Ma, B and Lou, T and Wang, T and Li, R and Liu, J and Yu, S and Guo, Y and Wang, Z and Wang, J}, title = {Comprehensive metabolism study of swertiamarin in rats using ultra high-performance liquid chromatography coupled with Quadrupole-Exactive Orbitrap mass spectrometry.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {51}, number = {4}, pages = {455-466}, doi = {10.1080/00498254.2020.1869856}, pmid = {33356745}, issn = {1366-5928}, mesh = {Animals ; Chromatography, High Pressure Liquid ; *Iridoid Glucosides ; Pyrones ; Rats ; Rats, Sprague-Dawley ; *Spectrometry, Mass, Electrospray Ionization ; }, abstract = {Swertiamarin, a natural ingredient with potent pharmacological activities in the iridoid glycoside family, had been reported to have significant therapeutic effects on a variety of human diseases.In this study, a systematic and efficient strategy based on UHPLC-Q-Exactive Orbitrap mass spectrometry was established to reveal the metabolic profile of swertiamarin in rat urine, plasma, and faeces.First of all, post-acquisition data-mining methods, including multiple mass defect filters (MMDFs) and high-resolution extracted ion chromatograms (HREICs), were developed to screen the metabolite candidates of swertiamarin from the complete mass scan data sets.Second, according to the diagnostic product ions (DPIs), neutral loss fragments (NLFs), chromatographic retention time, accurate mass measurement and calculated Clog P values, all metabolite candidates were rapidly identified.As a consequence, 49 metabolites altogether, including archetype compound, were preliminarily characterised. The corresponding in vivo biotransformation processes, such as dehydration, dehydrogenation, hydroxylation, hydrogenation, methylation, sulphonation, N-acetylcysteine (NAC) formation, N-heterocyclisation and their composite reactions, were all discovered in the study.In conclusion, our results not only detailedly elucidated many new metabolites and metabolic pathways of swertiamarin, but also provided a reference for further study of its pharmacological mechanism and evaluation of its safety.}, }
@article {pmid33354859, year = {2021}, author = {Nery, FG and Li, W and DelBello, MP and Welge, JA}, title = {N-acetylcysteine as an adjunctive treatment for bipolar depression: A systematic review and meta-analysis of randomized controlled trials.}, journal = {Bipolar disorders}, volume = {23}, number = {7}, pages = {707-714}, doi = {10.1111/bdi.13039}, pmid = {33354859}, issn = {1399-5618}, mesh = {Acetylcysteine/therapeutic use ; *Bipolar Disorder/diagnosis/drug therapy ; Double-Blind Method ; Humans ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {OBJECTIVES: Previous studies and meta-analyses suggested that N-acetylcysteine (NAC) was superior to placebo in improving depression in bipolar disorder. However, more recent data, including two larger trials, found that NAC was no more effective than placebo. We conducted a meta-analysis to appraise the possible efficacy of NAC in treating bipolar depression.<br><br>METHODS: A systematic review and meta-analysis of double-blind, placebo-controlled trials of NAC as a treatment augmentation strategy for bipolar depression was carried out in PubMed (1966-2020). We utilized random-effect analysis to evaluate improvement in depressive symptoms from baseline to endpoint as the primary efficacy measure.<br><br>RESULTS: Six trials including 248 patients were included. Treatment augmentation with NAC showed a moderate effect size favoring NAC over placebo (d&#xa0;=&#xa0;0.45, 95% C.I.: 0.06-0.84). There was substantial heterogeneity (I[2] &#xa0;=&#xa0;49%). Meta-regression analyses did not identify any moderator that might explain variation in heterogeneity, including baseline depressive symptom scores, mean NAC dose, or duration of study.<br><br>CONCLUSIONS: Results from six clinical trials suggest that treatment augmentation with NAC for bipolar depression appears to be superior to placebo, with a moderate effect size, but a large confidence interval. Larger clinical trials, investigating possible moderating factors, such as NAC dose, treatment duration, baseline depression severity, or chronicity of illness, are warranted.}, }
@article {pmid33351590, year = {2021}, author = {Chen, Z and Shi, Q and Wang, W and Jiang, Z and Zhang, GL and Tong, L and Mu, X and Tang, B}, title = {Fabrication of a "Selenium Signature" Chemical Probe-Modified Paper Substrate for Simultaneous and Efficient Determination of Biothiols by Paper Spray Mass Spectrometry.}, journal = {Analytical chemistry}, volume = {93}, number = {3}, pages = {1749-1756}, doi = {10.1021/acs.analchem.0c04457}, pmid = {33351590}, issn = {1520-6882}, mesh = {Acetylcysteine/*analysis ; Biosensing Techniques ; Cysteine/analogs &amp; derivatives/*analysis ; Dipeptides/*analysis ; Fluorescent Dyes/*chemistry ; Glutathione/*analysis ; Humans ; Mass Spectrometry ; *Paper ; Selenium/*chemistry ; }, abstract = {Significant efforts have been made to develop robust and reliable methods for simultaneous biothiols determination in different matrices, but there still exist the problems such as easy oxidation, tedious derivatization, and difficulty in discrimination, which brings unsatisfactory results in their accuracy and fast quantification in biological samples. To overcome these problems, a simultaneous biothiols detection method combining a "selenium signature" chemical probe and paper spray mass spectrometry (PS-MS) was proposed. In the strategy, the modified-paper substrate is used to enhance the analytical performance. Chemical probe Ebselen-NH2 that has a specific response to biothiols was designed and covalently fixed on the surface of an oxidized paper substrate. By the identification of derivatized product with distinctive selenium isotope distribution and employment of the optimized PS-MS method, qualitative and quantitative analysis of five biothiols including glutathione (GSH), cysteine (Cys), cysteinylglycine (CysGly), N-acetylcysteine (Nac), and homocysteine (Hcy) were realized. Biothiols in plasma and cell lysates were measured with satisfactory results. The established method not only provides a novel protocol for simultaneous determination of biothiols, but also is helpful for understanding the biological and clinical roles played by these bioactive small molecules.}, }
@article {pmid33346373, year = {2022}, author = {Navaratnarajah, A and Bhan, A and Alcock, E and Dew, T and Monaghan, M and Shah, AM and Wendler, O and MacCarthy, P and Dworakowski, R}, title = {Systemic inflammation and oxidative stress contribute to acute kidney injury after transcatheter aortic valve implantation.}, journal = {Cardiology journal}, volume = {29}, number = {5}, pages = {824-835}, pmid = {33346373}, issn = {1898-018X}, mesh = {Acetylcysteine ; *Acute Kidney Injury/diagnosis/epidemiology/etiology ; Aortic Valve ; *Aortic Valve Stenosis/surgery ; Biomarkers ; C-Reactive Protein ; Humans ; Inflammation/etiology ; Interleukin-6 ; Oxidative Stress ; Peroxidase ; *Transcatheter Aortic Valve Replacement/adverse effects/methods ; Treatment Outcome ; Tumor Necrosis Factor-alpha ; }, abstract = {BACKGROUND: Acute kidney injury (AKI) is a frequent complication of transcatheter aortic valve implantation (TAVI) and has been linked to preexisting comorbidities, peri-procedural hypotension, and systemic inflammation. The extent of systemic inflammation after TAVI is not fully understood. Our aim was to characterize the inflammatory response after TAVI and evaluate its contribution to the mechanism of post-procedural AKI.<br><br>METHODS: One hundred and five consecutive patients undergoing TAVI at our institution were included. We analyzed the peri-procedural inflammatory and oxidative stress responses by measuring a range of biomarkers (including C-reactive protein [hsCRP], cytokine levels, and myeloperoxidase [MPO]), before TAVI and 6, 24, and 48 hours post-procedure. We correlated this with changes in renal function and patient and procedural characteristics.<br><br>RESULTS: We observed a significant increase in plasma levels of pro-inflammatory cytokines (hsCRP, interleukin 6, tumor necrosis factor alpha receptors) and markers of oxidative stress (MPO) after TAVI. The inflammatory response was significantly greater after transapical (TA) TAVI compared to transfemoral (TF). This was associated with a higher incidence of AKI in the TA cohort compared to TF (44% vs. 8%, respectively, p < 0.0001). The incidence of AKI was significantly lower when N-acetylcysteine (NAC) was given peri-procedurally (12% vs. 38%, p < 0.005). In multivariate analysis, only the TA approach and no use of NAC before the procedure were independent predictors of AKI.<br><br>CONCLUSIONS: TAVI creates a significant post-procedural inflammatory response, more so with the TA approach. Mechanisms of AKI after TAVI are complex. Inflammatory response, hypoperfusion, and oxidative stress may all play a part and are potential therapeutic targets to reduce/prevent AKI.}, }
@article {pmid33346321, year = {2021}, author = {Geraci, G and Palumbo, VD and Fazzotta, S and Raia, V and Damiano, G and Di Vita, G and Lo Monte, AI}, title = {Lumevis ™: a new medical device to prepare patients for esophagogastroduodenoscopy. Experimental clinical study.}, journal = {La Clinica terapeutica}, volume = {171}, number = {1}, pages = {e16-e22}, doi = {10.7417/CT.2021.2275}, pmid = {33346321}, issn = {1972-6007}, mesh = {Acetic Acid/chemistry ; Acetylcysteine/chemistry ; Adult ; Dyspepsia/diagnostic imaging ; Endoscopy, Digestive System/*methods ; Female ; Gastroesophageal Reflux/diagnostic imaging ; Gastrointestinal Diseases/*diagnostic imaging ; Humans ; Male ; Middle Aged ; Premedication/*methods ; Simethicone/chemistry ; Stomach Neoplasms/diagnostic imaging ; }, abstract = {BACKGROUND: Esophagogastroduodenoscopy (EGDS) is the gold standard exam for upper gastrointestinal diseases. EGDS is very important in Early Gastric Cancer diagnosis and treatment but it is an operator-dependent exam and there are lots of factors that reduce its visibility (mucus, bubbles and foam).<br><br>AIM: The aim of our study is to evaluate if the use of Lumevis&#x2122; improves mucosa visualization during EGDS without increasing the examination time and complications' rate and comparing the differences in patients prepared with water or no intervention.<br><br>MATERIALS AND METHODS: we recruited 50 patients from 01/08/2020 to 31/08/2020 who came to our observation for epigastric pain, dyspepsia and gastroesophageal reflux (GERD). For each patient we evaluate the satisfaction of the procedure, vision quality, EGDS duration and the presence of bubbles following the administration of: nothing (group 1); 50 ml of water alone (W) (group 2); W + simethicone (S) 150 mg+N-acetylcysteine (NAC) 250 mg+10% acetic acid 2.5 ml (group 3); W+S 100 mg + NAC 300 mg + 10% acetic acid 2 ml (group 4); W + S 100 mg + NAC 200 mg + 10% acetic acid 1.5 ml (group 5).<br><br>RESULTS: Our results suggest that the lesion detection rate improves with the use of simethicone, acetylcysteine and acetic acid prior to EGDS, although this needs to be studied prospectively.<br><br>CONCLUSIONS: Lumevis&#x2122; is proposed as a new product in the routine preparation of all patients who have to undergo an EGDS, raising the level in the quality of the exam.}, }
@article {pmid33343802, year = {2020}, author = {Yang, CC and Hsiao, LD and Lin, HH and Tseng, HC and Situmorang, JH and Leu, YL and Yang, CM}, title = {Induction of HO-1 by 5, 8-Dihydroxy-4',7-Dimethoxyflavone via Activation of ROS/p38 MAPK/Nrf2 Attenuates Thrombin-Induced Connective Tissue Growth Factor Expression in Human Cardiac Fibroblasts.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {1080168}, pmid = {33343802}, issn = {1942-0994}, mesh = {Cell Line ; Connective Tissue Growth Factor/*biosynthesis/genetics ; Enzyme Induction/drug effects ; Fibroblasts/*metabolism ; Flavones/*pharmacology ; Heme Oxygenase-1/*biosynthesis/genetics ; Humans ; MAP Kinase Signaling System/*drug effects ; Myocardium/*metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Thrombin/*pharmacology ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Heme oxygenase-1 (HO-1) has been shown to exert as an antioxidant and anti-inflammatory enzyme in cardiovascular inflammatory diseases. Flavonoids have been demonstrated to display anti-inflammatory and antioxidant effects through the induction of HO-1. 5,8-Dihydroxy-4',7-dimethoxyflavone (DDF), one of the flavonoid compounds, is isolated from Reevesia formosana. Whether DDF induced HO-1 expression on human cardiac fibroblasts (HCFs) remained unknown. Here, we found that DDF time- and concentration-dependently induced HO-1 protein and mRNA expression, which was attenuated by pretreatment with reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) in HCFs. DDF-enhanced ROS generation was attenuated by NAC, but not by either diphenyleneiodonium chloride (DPI, Nox inhibitor) or MitoTempol (mitochondrial ROS scavenger). Interestingly, pretreatment with glutathione (GSH) inhibited DDF-induced HO-1 expression. The ratio of GSH/GSSG was time-dependently decreased in DDF-treated HCFs. DDF-induced HO-1 expression was attenuated by an inhibitor of p38 MAPK (p38i VIII) or siRNA, but not by MEK1/2 (PD98059) or JNK1/2 (SP600125). DDF-stimulated p38 MAPK phosphorylation was inhibited by GSH or p38i VIII. Moreover, DDF-induced HO-1 expression was mediated through Nrf2 phosphorylation and translocation into the nucleus which was attenuated by NAC or p38 siRNA. DDF also stimulated antioxidant response element (ARE) promoter activity which was inhibited by NAC, GSH, or p38i VIII. Interaction between Nrf2 and the ARE-binding sites on the HO-1 promoter was revealed by chromatin immunoprecipitation assay, which was attenuated by NAC, GSH, or p38i VIII. We further evaluated the functional effect of HO-1 expression on the thrombin-induced fibrotic responses. Our result indicated that the induction of HO-1 by DDF can attenuate the thrombin-induced connective tissue growth factor expression. These results suggested that DDF-induced HO-1 expression is, at least, mediated through the activation of the ROS-dependent p38 MAPK/Nrf2 signaling pathway in HCFs. Thus, the upregulation of HO-1 by DDF could be a candidate for the treatment of heart fibrosis.}, }
@article {pmid33339155, year = {2020}, author = {Dludla, PV and Nkambule, BB and Mazibuko-Mbeje, SE and Nyambuya, TM and Marcheggiani, F and Cirilli, I and Ziqubu, K and Shabalala, SC and Johnson, R and Louw, J and Damiani, E and Tiano, L}, title = {N-Acetyl Cysteine Targets Hepatic Lipid Accumulation to Curb Oxidative Stress and Inflammation in NAFLD: A Comprehensive Analysis of the Literature.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {12}, pages = {}, pmid = {33339155}, issn = {2076-3921}, support = {D43 TW010131/TW/FIC NIH HHS/United States ; }, abstract = {Impaired adipose tissue function and insulin resistance remain instrumental in promoting hepatic lipid accumulation in conditions of metabolic syndrome. In fact, enhanced lipid accumulation together with oxidative stress and an abnormal inflammatory response underpin the development and severity of non-alcoholic fatty liver disease (NAFLD). There are currently no specific protective drugs against NAFLD, and effective interventions involving regular exercise and healthy diets have proved difficult to achieve and maintain. Alternatively, due to its antioxidant and anti-inflammatory properties, there has been growing interest in understanding the therapeutic effects of N-acetyl cysteine (NAC) against metabolic complications, including NAFLD. Here, reviewed evidence suggests that NAC blocks hepatic lipid accumulation in preclinical models of NAFLD. This is in part through the effective regulation of a fatty acid scavenger molecule (CD36) and transcriptional factors such as sterol regulatory element-binding protein (SREBP)-1c/-2 and peroxisome proliferator-activated receptor gamma (PPARγ). Importantly, NAC appears effective in improving liver function by reducing pro-inflammatory markers such as interleukin (IL)-6 IL-1β, tumour necrosis factor alpha (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). This was primarily through the attenuation of lipid peroxidation and enhancements in intracellular response antioxidants, particularly glutathione. Very few clinical studies support the beneficial effects of NAC against NAFLD-related complications, thus well-organized randomized clinical trials are still necessary to confirm its therapeutic potential.}, }
@article {pmid33331125, year = {2021}, author = {Al-Saloum, S and Zaranek, M and Horbatiuk, J and Gopalakrishnan, P and Dumitrescu, A and McAllister, JP and Harris, CA}, title = {Analysis of N-acetyl cysteine modified polydimethylsiloxane shunt for improved treatment of hydrocephalus.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {109}, number = {8}, pages = {1177-1187}, pmid = {33331125}, issn = {1552-4981}, support = {R01 NS094570/NS/NINDS NIH HHS/United States ; R01NS094570/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*chemistry ; *Catheters ; Cerebrospinal Fluid Shunts ; Dimethylpolysiloxanes/*chemistry ; Humans ; Hydrocephalus/*surgery ; }, abstract = {A major cause of hydrocephalus shunt failure is cell adhesion and obstruction of shunt catheter holes. An estimated 50% of pediatric shunts fail in the first 2 years of insertion, decreasing cell attachment and catheter obstruction can prolong the lifetime and effectiveness of the device. From previous studies, it was shown that treatment of the polydimethylsiloxane (PDMS) surface of a standard catheter with an N-acetyl-cysteine (NAC/1-ethyl-3-(3-dimethylanimopropyl)carbodiimide hydrochloride/N-hydroxysuccinimide) layer increases the wettability of the surface and has been shown to decrease cell adhesion. Other studies indicate that NAC's antioxidant behavior induces glutathione and in turn modulates cell inflammatory pathways. The current study explores the longevity of the NAC coating from the surface of the catheter over time and shows its effect on valve function. Using SEM imaging, contact angle testing, and nanodrop spectrophotometry, this release was quantified for shunt samples incubated for 0, 10, 30, 60, and 90 days. Contact angle showed a significant increase in wettability of the surface when shunts were treated with NAC, confirming successful surface modification. Pressure assays determined that if the coating is release it had no detrimental downstream effects, such as on the shunt valve mechanism. SEM imaging revealed slight deformations in surface coating indicative of salt deposition on the modified shunt samples, while nanodrop spectrophotometry and contact angle data trends suggested some discharge of the NAC coating from the catheter surfaces. The effects of NAC on cell activity may transform the way hydrocephalus is treated in the future by increasing the longevity of the shunt to protect from obstruction.}, }
@article {pmid33326056, year = {2021}, author = {Calverley, P and Rogliani, P and Papi, A}, title = {Safety of N-Acetylcysteine at High Doses in Chronic Respiratory Diseases: A Review.}, journal = {Drug safety}, volume = {44}, number = {3}, pages = {273-290}, pmid = {33326056}, issn = {1179-1942}, mesh = {*Acetylcysteine/adverse effects ; Humans ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; }, abstract = {N-Acetylcysteine (NAC) is widely used in respiratory medicine, with a maximum licensed dose in chronic use of 600 mg/day; however, some clinical trials have studied the efficacy of NAC at higher doses. The aim of this review was to evaluate the adverse effects profile of NAC at higher than the standard dose in chronic respiratory diseases to establish a risk-benefit ratio in increasing the daily dose; therefore, studies using NAC at a dose of at least 600 mg/day were selected. Forty-one articles where NAC has been used at 600 mg and above, up to 3000 mg/day, and with a specific report on safety, were considered. Most of the studies used oral NAC and were conducted on patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchiectasis, chronic bronchitis and cystic fibrosis. In general, the safety profile was similar at both the high and standard doses with the oral formulation; gastrointestinal symptoms were reported but they were no more common than in the control group.}, }
@article {pmid33322743, year = {2020}, author = {Rosli, NHM and Yahya, HM and Ibrahim, FW and Shahar, S and Ismail, IS and Azam, AA and Rajab, NF}, title = {Serum Metabolomics Profiling of Commercially Mixed Functional Foods-Effects in Beta-Amyloid Induced Rats Measured Using [1]H NMR Spectroscopy.}, journal = {Nutrients}, volume = {12}, number = {12}, pages = {}, pmid = {33322743}, issn = {2072-6643}, support = {FRGS/1/2014/SG03/UKM/03/1//Ministry of Higher Education, Malaysia/ ; GUP-2018-066//Universiti Kebangsaan Malaysia/ ; }, mesh = {Amyloid beta-Peptides/*administration &amp; dosage ; Animals ; Disease Models, Animal ; *Functional Food ; *Honey ; Magnetic Resonance Spectroscopy/methods ; Male ; Metabolomics/methods ; Neurodegenerative Diseases/*blood/*diet therapy/prevention &amp; control ; Phoeniceae/*metabolism ; Pomegranate/*metabolism ; Rats ; Rats, Wistar ; }, abstract = {Functional foods such as pomegranate, dates and honey were shown by various previous studies to individually have a neuroprotective effect, especially in neurodegenerative disease such as Alzheimer's disease (AD). In this novel and original study, an [1]H NMR spectroscopy tool was used to identify the metabolic neuroprotective mechanism of commercially mixed functional foods (MFF) consisting of pomegranate, dates and honey, in rats injected with amyloid-beta 1-42 (Aβ-42). Forty-five male albino Wistar rats were randomly divided into five groups: NC (0.9% normal saline treatment + phosphate buffer solution (PBS) solution injection), Abeta (0.9% normal saline treatment + 0.2 µg/µL Aβ-42 injection), MFF (4 mL/kg MFF treatment + PBS solution injection), Abeta-MFF (4 mL/kg MFF treatment + 0.2 µg/µL Aβ-42 injection) and Abeta-NAC (150 mg/kg N-acetylcysteine + 0.2 µg/µL Aβ-42 injection). Based on the results, the MFF and NAC treatment improved the spatial memory and learning using Y-maze. In the metabolic analysis, a total of 12 metabolites were identified, for which levels changed significantly among the treatment groups. Systematic metabolic pathway analysis found that the MFF and NAC treatments provided a neuroprotective effect in Aβ-42 injected rats by improving the acid amino and energy metabolisms. Overall, this finding showed that MFF might serve as a potential neuroprotective functional food for the prevention of AD.}, }
@article {pmid33322048, year = {2020}, author = {Rotondo, R and Oliva, MA and Staffieri, S and Castaldo, S and Giangaspero, F and Arcella, A}, title = {Implication of Lactucopicrin in Autophagy, Cell Cycle Arrest and Oxidative Stress to Inhibit U87Mg Glioblastoma Cell Growth.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {24}, pages = {}, pmid = {33322048}, issn = {1420-3049}, support = {not available//Ministero della Salute/ ; }, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Glioblastoma ; Humans ; Lactones/chemistry/*pharmacology ; Molecular Structure ; Oxidative Stress/*drug effects ; Sesquiterpenes/chemistry/*pharmacology ; }, abstract = {In this study, we propose lactucopicrin (LCTP), a natural sesquiterpene lactone from Lactucavirosa, as a molecule able to control the growth of glioblastoma continuous cell line U87Mg. The IC50 of U87Mg against LCTP revealed a strong cytotoxic effect. Daily administration of LCTP showed a dose and time-dependent reduction of GBM cell growth and viability, also confirmed by inhibition of clonogenic potential and mobility of U87Mg cells. LCTP activated autophagy in U87Mg cells and decreased the phosphorylation of proliferative signals pAKT and pERK. LCTP also induced the cell cycle arrest in G2/M phase, confirmed by decrease of CDK2 protein and increase of p53 and p21. LCTP stimulated apoptosis as evidenced by reduction of procaspase 6 and the increase of the cleaved/full-length PARP ratio. The pre-treatment of U87Mg cells with ROS scavenger N-acetylcysteine (NAC), which reversed its cytotoxic effect, showed the involvement of LCTP in oxidative stress. Finally, LCTP strongly enhanced the sensitivity of U87Mg cells to canonical therapy Temozolomide (TMZ) and synergized with this drug. Altogether, the growth inhibition of U87Mg GBM cells induced by LCTP is the result of several synergic mechanisms, which makes LCTP a promising adjuvant therapy for this complex pathology.}, }
@article {pmid33321673, year = {2021}, author = {Chang, MC and Tang, CM and Lin, YH and Liu, HC and Wang, TM and Lan, WC and Cheng, RH and Lin, YR and Chang, HH and Jeng, JH}, title = {Toxic mechanisms of Roth801, Canals, microparticles and nanoparticles of ZnO on MG-63 osteoblasts.}, journal = {Materials science &amp; engineering. C, Materials for biological applications}, volume = {119}, number = {}, pages = {111635}, doi = {10.1016/j.msec.2020.111635}, pmid = {33321673}, issn = {1873-0191}, mesh = {*Nanoparticles ; Osteoblasts ; Phosphorylation ; Signal Transduction ; *Zinc Oxide ; }, abstract = {ZnO eugenol-based materials are widely used for restoration of caries cavity, apical retrograde filling and root canal sealer. Their effects on apical bone healing await investigation. The toxic mechanisms of ZnO particles and nanoparticles to MG-63 osteoblastic cells were studied. We found the different morphology and size of various particles as observed by scanning electron microscope. Particles of Canals and Roth801 were larger than ZnO-205532 microparticles and ZnO-677450 nanoparticles. Four ZnO particles showed cytotoxicity (>25 μg/ml) as analyzed by MTT. Transmission electron microscope found intracellular vacuoles with particle content. Exposure to ZnO particles induced ROS production and cell cycle arrest as studied by DCF and propidium iodide flow cytometry. ZnO particles activated ATM, ATR, Chk1, Chk2, γ-H2AX, ERK and p38 phosphorylation as detected by immunofluorescent staining and western blotting. The protein expression of cdc2, cyclin B1 and cdc25C were decreased, whereas GADD45α and hemeoxygenase-1 (HO-1) were stimulated. ZnO particles' cytotoxicity to MG63 cells was prevented by N-acetylcysteine (NAC), but not CGK733, AZD7762, U0126 and SB203580. ZnO showed little effect on IL-8 and sICAM-1 secretion. These results indicated that ZnO particles are toxic to osteoblasts. ZnO particles' toxicity were related to ROS, and DNA damage responses, checkpoint kinases, cell cycle arrest, ERK and p38 signaling, but not IL-8 and ICAM-1. These results were useful for materials' development and promote apical healing. Dentists should avoid of extruding ZnO-based sealers excessively over root apex and prevent residual ZnO-based retrograde filling materials in apical area during endodontic practice.}, }
@article {pmid33313002, year = {2020}, author = {Raisi, H and Longerich, T and Moreira Assuncao, B and Mueller, S and Schirmacher, P and Seitz, HK}, title = {Propofol-Induced Hepatitis.}, journal = {European journal of case reports in internal medicine}, volume = {7}, number = {12}, pages = {001921}, pmid = {33313002}, issn = {2284-2594}, abstract = {OBJECTIVES: To present a rare case of propofol-induced hepatitis.<br><br>MATERIALS AND METHODS: A 59-year old man was referred to our department because of suspicion of toxic hepatitis after propofol anaesthesia for endoscopic colonoscopy.<br><br>RESULTS: The patient had jaundice, increased transaminases demonstrating liver necrosis, and liver stiffness of 18 kPa. Liver biopsy revealed bridging necrosis and initial post-collapse fibrosis. Following therapy with steroids and N-acetyl cysteine, the patient was discharged on the seventh day after admission in good general condition.<br><br>CONCLUSION: Although propofol is considered safe, it can cause acute hepatitis, the seventh published case of which is reported here. Importantly, treatment with N-acetyl cysteine, a radical scavenger, but especially with steroids resulted in hepatic improvement.<br><br>LEARNING POINTS: Drug-induced hepatitis is a severe illness caused by a large variety of agents, including many considered safe.It can occur in the absence of predisposing liver abnormality or disease.If the condition is correctly identified, clinical and laboratory abnormalities can be reversed with appropriate treatment.}, }
@article {pmid33312377, year = {2020}, author = {Pillai, K and Mekkawy, AH and Akhter, J and Badar, S and Dong, L and Liu, AI and Morris, DL}, title = {Enhancing the potency of chemotherapeutic agents by combination with bromelain and N-acetylcysteine - an in vitro study with pancreatic and hepatic cancer cells.}, journal = {American journal of translational research}, volume = {12}, number = {11}, pages = {7404-7419}, pmid = {33312377}, issn = {1943-8141}, abstract = {Current systemic dosages of chemotherapeutic drugs such as gemcitabine, 5-FU, cisplatin, doxorubicin are administered every 7 days over 4 cycles due to systemic toxicity. An increase in potency of the drugs will result in dosage reduction with more frequent administration and efficacy increase. Hence, we investigated how the drugs potency can be increased by combining with bromelain and N-acetylcysteine. Tumour cells (5,000/well) were seeded into a 96 well plate and treated 24 hrs later with either single agents or in combinations at various concentrations. Cell survival was assessed by the sulforhodamine B assay after 72 hours of exposure. LD 50 was determined for each treatment and the Combination Index (CI) was assessed to determine synergy using Tallarida's method. CI indicated that synergy was dependent on the concentration of the agents used and was cell line specific. For bromelain and N-acetylcysteine, certain ratio of the two agents gave very good synergy that was prevalent in almost all cell lines. Gemcitabine and 5-FU and doxorubicin reacted favourably with most concentrations of bromelain and NAC investigated. Cisplatin and oxaliplatin were not very compatible with NAC. A value of CI <0.5 indicated that the current clinical chemotherapeutic dosage can be dramatically reduced. Bromelain with NAC showed synergy in all tumour cell lines and acting synergistically with chemotherapeutic drugs. Synergistic combinations resulting in considerable dosage reduction of chemotherapeutic agents may enable more frequent treatment with higher efficacy.}, }
@article {pmid33309621, year = {2021}, author = {Li, S and Li, Z and Yin, R and Nie, J and Fu, Y and Ying, R}, title = {Knockdown of dual oxidase 1 suppresses activin A-induced fibrosis in cardiomyocytes via the reactive oxygen species-dependent pyroptotic pathway.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {131}, number = {}, pages = {105902}, doi = {10.1016/j.biocel.2020.105902}, pmid = {33309621}, issn = {1878-5875}, mesh = {Acetylcysteine/pharmacology ; Activins/antagonists &amp; inhibitors/*pharmacology ; Caspase 1/genetics/metabolism ; Coenzyme A Ligases/genetics/metabolism ; Collagen Type I/genetics/metabolism ; Collagen Type III/genetics/metabolism ; Dual Oxidases/antagonists &amp; inhibitors/*genetics/metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation ; Humans ; Interleukin-18/genetics/metabolism ; Interleukin-1beta/genetics/metabolism ; Myocytes, Cardiac/cytology/*drug effects/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Oxidative Stress/drug effects ; Primary Cell Culture ; Pyroptosis/*drug effects/genetics ; RNA, Small Interfering/genetics/metabolism ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/*metabolism ; Signal Transduction ; Smad2 Protein/genetics/metabolism ; Smad3 Protein/genetics/metabolism ; }, abstract = {Fibrotic diseases account for more than 8 million deaths worldwide annually. Reactive oxygen species (ROS) has been shown to activate pyroptosis and promote the production of interleukin (IL)-1β and IL-18, leading to fibrosis development. However, the role of dual oxidase 1 (DUOX1)-induced ROS production and pyroptosis in cardiac fibrosis remains largely unknown. Activin A was used to induce ROS and pyroptosis in cardiomyocytes. ROS level, pyroptosis, and cytokine production were detected using Active Oxygen Detection Kit, flow cytometry, and enzyme-linked immunosorbent assay, respectively. Western blotting analysis was used to measure expression changes of proteins. DUOX1 was silenced or overexpressed to investigate its role in fibrosis. We found that activin A induced ROS production and pyroptosis in cardiomyocytes, which was blocked by the ROS scavenger, N-acetyl-L-cysteine (NAC). Knockdown of DUOX1 reversed activin A-induced ROS production, pyroptosis, cytokine release, and the upregulation of proinflammatory proteins. Overexpression of DUOX1 resulted in opposite effects of knockdown DUOX1. Administration of an ROS scavenger blocked the effect of DUOX1 overexpression. Supplementation of IL-1β and IL-18 caused significant fibrosis in human cardiac fibroblasts (hCFs). The knockdown of DUOX1 protected cardiomyocytes against activin A-induced fibrosis via the inhibition of ROS, cytokine release, and pyroptosis.}, }
@article {pmid33307232, year = {2021}, author = {Xue, J and Gruber, F and Tschachler, E and Zhao, Y}, title = {Crosstalk between oxidative stress, autophagy and apoptosis in hemoporfin photodynamic therapy treated human umbilical vein endothelial cells.}, journal = {Photodiagnosis and photodynamic therapy}, volume = {33}, number = {}, pages = {102137}, doi = {10.1016/j.pdpdt.2020.102137}, pmid = {33307232}, issn = {1873-1597}, mesh = {Apoptosis ; Autophagy ; Hematoporphyrins/pharmacology ; Human Umbilical Vein Endothelial Cells ; Humans ; Oxidative Stress ; *Photochemotherapy/methods ; Photosensitizing Agents/pharmacology ; }, abstract = {BACKGROUND: Photodynamic therapy (PDT) provides a treatment for port-wine stain (PWS) using hemoporfin (hematoporphyrin monomethyl ether, HMME), a novel photosensitizer, reporting better efficacy and lower recurrence rate. This study investigated the effects of HMME-PDT on human umbilical vein endothelial cells (HUVECs) as well as underlying mechanisms.<br><br>METHODS: Cell proliferation ability was measured by CCK8 assay and cell apoptosis was determined by TUNEL assay and Western blot analysis. Confocal fluorescence microscopy monitoring RFP-GFP-LC3 transfected HUVECs and Western blot analysis were used to evaluate autophagy. 3-Methyladenine (3-MA), Z-VAD-FMK, N-acetylcysteine (NAC) were used for inhibitor studies.<br><br>RESULTS: HMME-PDT decreased cell proliferation ability in an HMME concentration and light dose-dependent manner. Oxidative stress played an important role in HMME-PDT induced cell apoptosis and autophagy in HUVECs. Pretreatment with Z-VAD-FMK, the inhibitor of apoptosis, enhanced HMME-PDT induced autophagy. 3-MA, the suppressor of autophagy, significantly increased HMME-PDT induced apoptosis rates.<br><br>CONCLUSIONS: Our study demonstrated that HMME-PDT induced both apoptosis and autophagy in HUVECs via oxidative stress. Our data suggested that HMME-PDT- induced autophagy was able to prevent apoptotic cell death of HUVECs and rendered them more resistant to HMME-PDT induced toxicity.}, }
@article {pmid33303691, year = {2021}, author = {Teng, T and Kamal, M and Iriondo, O and Amzaleg, Y and Luo, C and Thomas, A and Lee, G and Hsu, CJ and Nguyen, JD and Kang, I and Hicks, J and Smith, A and Sposto, R and Yu, M}, title = {N-Acetyl-L-cysteine Promotes Ex Vivo Growth and Expansion of Single Circulating Tumor Cells by Mitigating Cellular Stress Responses.}, journal = {Molecular cancer research : MCR}, volume = {19}, number = {3}, pages = {441-450}, pmid = {33303691}, issn = {1557-3125}, support = {DP2 CA206653/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; T90 DE021982/DE/NIDCR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Breast Neoplasms/blood/pathology ; Cell Growth Processes/drug effects ; DNA Copy Number Variations ; Female ; Heat-Shock Proteins/*metabolism ; Heterografts ; Humans ; Mice ; Neoplastic Cells, Circulating/*drug effects/metabolism/*pathology ; Oxidative Stress/drug effects ; Scavenger Receptors, Class A/*metabolism ; }, abstract = {Circulating tumor cells (CTC) can be isolated via a minimally invasive blood draw and are considered a "liquid biopsy" of their originating solid tumors. CTCs contain a small subset of metastatic precursors that can form metastases in secondary organs and provide a resource to identify mechanisms underlying metastasis-initiating properties. Despite technological advancements that allow for highly sensitive approaches of detection and isolation, CTCs are very rare and often present as single cells, posing an extreme challenge for ex vivo expansion after isolation. Here, using previously established patient-derived CTC lines, we performed a small-molecule drug screen to identify compounds that can improve ex vivo culture efficiency for single CTCs. We found that N-acetyl-L-cysteine (NAC) and other antioxidants can promote ex vivo expansion of single CTCs, by reducing oxidative and other stress particularly at the initial stage of single-cell expansion. RNA-seq analysis of growing clones and nongrowing clones confirmed the effect by NAC, but also indicates that NAC-induced decrease in oxidative stress is insufficient for promoting proliferation of a subset of cells with predominant senescent features. Despite the challenge in expanding all CTCs, NAC treatment led to establishment of single CTC clones that have similar tumorigenic features. IMPLICATIONS: Through a small molecule screen and validation study, we found that NAC could improve the success of ex vivo expansion of single CTCs by mitigating the initial stress, with the potential to facilitate the investigation of functional heterogeneity in CTCs.}, }
@article {pmid33303231, year = {2021}, author = {Schweikl, H and Birke, M and Gallorini, M and Petzel, C and Bolay, C and Waha, C and Hiller, KA and Buchalla, W}, title = {HEMA-induced oxidative stress inhibits NF-κB nuclear translocation and TNF release from LTA- and LPS-stimulated immunocompetent cells.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {37}, number = {1}, pages = {175-190}, doi = {10.1016/j.dental.2020.10.029}, pmid = {33303231}, issn = {1879-0097}, mesh = {Animals ; *Lipopolysaccharides ; Methacrylates ; Mice ; *NF-kappa B ; Oxidative Stress ; RAW 264.7 Cells ; Reactive Oxygen Species ; Tumor Necrosis Factor-alpha ; }, abstract = {OBJECTIVE: The release of inflammatory cytokines from antigen-stimulated cells of the immune system is inhibited by resin monomers such as 2-hydroxyethyl methacrylate (HEMA). Although the formation of oxidative stress in cells exposed to HEMA is firmly established, the mechanism behind the inhibited cytokine secretion is only partly known. The present investigation presents evidence regarding the role of HEMA-induced oxidative stress in the secretion of the pro-inflammatory cytokine TNFα from cells exposed to the antigens LTA (lipoteichoic acid) or LPS (lipopolysaccharide) of cariogenic microorganisms using BSO (L-buthionine sulfoximine) or NAC (N-acetyl cysteine) to inhibit or stabilize the amounts of the antioxidant glutathione.<br><br>METHOD: RAW264.7 mouse macrophages were treated with LTA, LPS or HEMA in the presence of BSO or NAC for 1h or 24h. Secretion of TNF&#x3b1; from cell cultures was analyzed by ELISA, and the formation of reactive oxygen (ROS) or nitrogen species (RNS) was determined by flow cytometry. Protein expression was detected by Western blotting.<br><br>RESULTS: The release of TNF&#x3b1; in both LTA- and LPS-exposed cells was decreased by HEMA, and this concentration-dependent inhibitory effect was amplified by BSO or NAC. LTA- and LPS-stimulated expression of the redox-sensitive transcription factor NF-&#x3b1;B (p65) in cell nuclei decreased in the presence of HEMA because the translocation of p65 from the cytosol was prevented by oxidative stress specifically increased by the monomer.<br><br>CONCLUSIONS: A disturbance of the cellular redox balance, particularly induced by HEMA, is a crucial factor in the inhibition of LTA- and LPS-stimulated signalling pathways leading to TNF&#x3b1; secretion.}, }
@article {pmid33302164, year = {2021}, author = {Ding, H and Yang, Y and Wei, S and Spicer, LJ and Kenéz, &#xc1; and Xu, W and Liu, Y and Feng, T}, title = {Influence of N-acetylcysteine on steroidogenesis and gene expression in porcine placental trophoblast cells.}, journal = {Theriogenology}, volume = {161}, number = {}, pages = {49-56}, doi = {10.1016/j.theriogenology.2020.11.005}, pmid = {33302164}, issn = {1879-3231}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Female ; Gene Expression ; Placenta ; Pregnancy ; Progesterone ; Swine ; *Trophoblasts ; }, abstract = {N-acetylcysteine (NAC) is a widely used anti-inflammatory agent and antioxidant in vivo and in vitro. As a nutritional supplement, NAC can improve production and reproductive performances in animals through enhancing placental function and regulating hormone production. Trophoblast proliferation and steroid hormone production are two major functions in the placenta. We hypothesized that the effects of NAC on placental function is due to its direct and indirect effects on gene expression in placental trophoblast cells (pTr). To evaluate this hypothesis, we investigated the effects of NAC on steroidogenesis, gene expression, and cell proliferation in porcine pTr in vitro. pTr were treated with NAC in serum-free medium for 24 h with different concentrations (0, 0.1 μM, 1.0 μM, 10.0 μM, 0.1 mM, 1.0 mM, and 10.0 mM). Low-dose NAC (1 μM) stimulated pTr proliferation and decreased progesterone production, while increasing estradiol production (P < 0.05). High-dose NAC (10 mM) suppressed cell proliferation (P < 0.05), but had no effect on steroidogenesis. Low-dose NAC increased CCDN1 and decreased CASP3 and CASP8 mRNA levels (P < 0.05), whereas high-dose NAC decreased CDK4 and CCDN1 and increased CASP3 mRNA levels (P < 0.05). NAC had no effect on the mRNA abundance of StAR and HSD3B. Low-dose NAC upregulated CYP19A1 mRNA expression, and high-dose NAC downregulated CYP11A1 mRNA abundance (P < 0.05). Only low-dose NAC increased NOS3 mRNA abundance and tetrahydrobiopterin reduction (BH4/BH2 ratio). We conclude that NAC may act directly and indirectly on pTr with a dose-dependent manner and may regulate placental function by affecting pTr differentiation via regulating pTr steroid synthesis, cell proliferation, and apoptosis in sows.}, }
@article {pmid33292330, year = {2020}, author = {Liu, X and Li, C and Zheng, K and Zhao, X and Xu, X and Yang, A and Yi, M and Tao, H and Xie, B and Qiu, M and Yang, J}, title = {Chromosomal aberration arises during somatic reprogramming to pluripotent stem cells.}, journal = {Cell division}, volume = {15}, number = {1}, pages = {12}, pmid = {33292330}, issn = {1747-1028}, support = {81200961//National Natural Science Foundation of China/ ; 31572224//National Natural Science Foundation of China/ ; 31771621//National Natural Science Foundation of China/ ; LY18H090014//Natural Science Foundation of Zhejiang Province (CN)/ ; }, abstract = {BACKGROUND: Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has opened new therapeutic possibilities. However, karyotypic abnormalities detected in iPSCs compromised their utility, especially chromosomal aberrations found at early passages raised serious safety concerns. The mechanism underlying the chromosomal abnormality in early-passage iPSCs is not known.<br><br>METHODS: Human dermal fibroblasts (HDFs) were stimulated with KMOS (KLF4, cMYC, OCT4 and SOX2) proteins to enhance their proliferative capacity and many vigorous clones were obtained. Clonal reprogramming was carried out by KMOS mRNAs transfection to confirm the 'chromosomal mutagenicity' of reprogramming process. Subculturing was performed to examine karyotypic stability of iPSCs after the re-establishment of stemness. And antioxidant N-acetyl-cysteine (NAC) was added to the culture medium for further confirmming the mutagenicity in the first few days of reprogramming.<br><br>RESULTS: Chromosomal aberrations were found in a small percentage of newly induced iPS clones by reprogramming transcription factors. Clonal reprogramming ruled out the aberrant chromosomes inherited from rare karyotypically abnormal parental cell subpopulation. More importantly, the antioxidant NAC effectively reduced the occurrence of chromosomal aberrations at the early stage of reprogramming. Once iPS cell lines were established, they restored karyotypic stability in subsequent subculturing.<br><br>CONCLUSIONS: Our results provided the first line of evidence for the 'chromosomal mutagenicity' of reprogramming process.}, }
@article {pmid33290342, year = {2021}, author = {Laverde, CF and Morais-Silva, G and Amaral, VCS and Marin, MT}, title = {Effects of N-acetylcysteine treatment on ethanol's rewarding properties and dopaminergic alterations in mesocorticolimbic and nigrostriatal pathways.}, journal = {Behavioural pharmacology}, volume = {32}, number = {2&amp;3}, pages = {239-250}, doi = {10.1097/FBP.0000000000000613}, pmid = {33290342}, issn = {1473-5849}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Brain/metabolism ; Conditioning, Classical/drug effects ; Dopamine/*metabolism ; Dose-Response Relationship, Drug ; Ethanol/*pharmacology ; Male ; Mice ; Nucleus Accumbens/metabolism ; Prefrontal Cortex/metabolism ; *Reward ; }, abstract = {Recent reports have shown that N-acetylcysteine (N-AC) has beneficial effects in the treatment of cocaine and nicotine abuse. Considering the similar neurobiologic mechanisms involved in the development of addiction to different drugs, N-AC treatment could be useful in the treatment of ethanol abuse. The rewarding properties of the drugs of abuse plays an important role in the development of addiction and can be studied using the conditioned place preference (CPP) paradigm. Thus, to study the effects of N-AC treatment in the rewarding effects of ethanol, we investigated the effects of N-AC administration in the ethanol-induced CPP and neurochemical alterations within the mesocorticolimbic and the nigrostriatal dopaminergic pathways. Adult male Swiss mice were pretreated with N-AC (60 or 120 mg/kg intraperitoneal) and tested for the development, expression, or extinction of the ethanol-induced CPP. Another cohort of animals received N-AC (60 or 120 mg/kg intraperitoneal) 2-h before an acute administration of ethanol and had their brains removed for dopamine and its metabolites quantification in the mesocorticolimbic and nigrostriatal pathways. Pretreatment with N-AC (120 mg/kg) blocked the development of ethanol-induced CPP. On the other hand, N-AC at both doses did not alter the expression nor the extinction of ethanol-induced CPP. N-AC increased 3,4-dihydroxyphenylacetic acid content in the medial prefrontal cortex and dopaminergic turnover within the substantia nigra. Besides that, there was an increase in dopamine content in the nucleus accumbens of ethanol-treated animals. In summary, N-AC treatment blocked the development of ethanol CPP, without altering ethanol effects on dopaminergic neurotransmission.}, }
@article {pmid33281629, year = {2020}, author = {Ko, HK and Lin, AH and Perng, DW and Lee, TS and Kou, YR}, title = {Lung Epithelial TRPA1 Mediates Lipopolysaccharide-Induced Lung Inflammation in Bronchial Epithelial Cells and Mice.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {596314}, pmid = {33281629}, issn = {1664-042X}, abstract = {Toll-like receptor (TLR) 4 was originally thought to be the sole pattern recognition receptor for lipopolysaccharide (LPS). Transient receptor potential ankyrin 1 (TRPA1), a Ca[2+]-permeant channel, has been suggested as a non-TLR receptor membrane-bound sensor of LPS. We recently reported that TRPA1 is expressed in lung epithelial cells (LECs) and mediates lung inflammation induced by cigarette smoke. However, the role of TRPA1 in LPS-induced lung inflammation has not been conclusively defined, and its underlying cellular mechanisms remain unclear. In this study, our in vitro results showed that LPS sequentially produced a cascade of events, including the elevation of intracellular Ca[2+], the activation of NADPH oxidase, increase in intracellular reactive oxygen species (ROS), the activation of mitogen-activated protein kinase (MAPK)/nuclear factor-kB (NF-κB) signaling, and the induction of IL-8. The increase in intracellular Ca[2+] was inhibited by HC030031 (a TRPA1 antagonist) but was unaffected by TAK-242 (a TLR-4 inhibitor). The activation of NADPH oxidase was prevented by its inhibitor apocynin, EGTA (an extracellular Ca[2+] chelator), and HC030031. The increase in intracellular ROS was attenuated by apocynin, N-acetyl-cysteine (NAC, a ROS scavenger), EGTA, and HC030031. The activation of the MAPK/NF-κB signaling was halted by NAC, EGTA, and HC030031. IL-8 induction was suppressed by HC030031 and TRPA1 siRNA, and further reduced by the combination of HC030031 and TAK-242. Our in vivo studies showed that trpa1[-/-] mice exhibited a reduced level of LPS-induced lung inflammation compared with wild-type mice as evidenced by the alleviations of increases in vascular permeability, inflammatory cell infiltration, inflammatory cytokine levels, oxidative stress, and MAPK signaling activation. Thus, in LECs, LPS may activate TRPA1 resulting in an increase in Ca[2+] influx. The increased intracellular Ca[2+] leads to NADPH oxidase activation, which causes an increase in intracellular ROS. The intracellular ROS activates the MAPK/NF-κB signaling resulting in IL-8 induction. This mechanism may possibly be at work to induce lung inflammation in mice.}, }
@article {pmid33281067, year = {2020}, author = {Tatli, &#xd6; and Pasli, S and Imamoğlu, M and Cicek, M and Yadigaroglu, M and Sahin, A and Dilaver, I and Yulug, E and Karaca, Y}, title = {Potential therapeutic effects of ethyl pyruvate and N-acetyl cysteine in an experimental rat model of corrosive esophageal.}, journal = {Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology}, volume = {21}, number = {4}, pages = {260-266}, doi = {10.1016/j.ajg.2020.10.001}, pmid = {33281067}, issn = {2090-2387}, mesh = {Acetylcysteine ; Animals ; *Burns, Chemical ; Caustics ; Female ; Pyruvates ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND AND STUDY AIMS: Esophageal burns due to ingestion of corrosive substances are frequently seen in both children and adults. However, there is no standard method of treatment to prevent associated mortality and morbidity. Therefore, this study aimed to evaluate the effects of known antioxidants, namely N-acetyl cysteine and ethyl pyruvate, on esophageal damage due to sodium hydroxide-induced corrosive burns.<br><br>MATERIALS AND METHODS: Thirty-five female rats were randomly assigned to five equal groups. Group 1 was the sham group, while Group 2 was the control group. Group 3 received N-acetyl cysteine, Group 4 received ethyl pyruvate, and Group 5 received both N-acetyl cysteine and ethyl pyruvate. Rats in the "burn" groups were gavage-fed with 0.2mL of 25% NaOH. All esophagi were extracted on day 4 for histopathological evaluation.<br><br>RESULTS: Total histopathological damage scores were evaluated at the end of the study. Groups 3 and 5 were significantly different from the control group in terms of total histopathological scores (p&#xa0;=&#xa0;0.001), while no significant difference was seen with Group 4. Stenosis index results in groups 3 and 5 were similar to those seen with total histopathological scores (p&#xa0;=&#xa0;0.004).<br><br>CONCLUSION: N-acetyl cysteine, alone or in combination with ethyl pyruvate, may be useful in the treatment of esophageal damage associated with corrosive substances and in achieving histopathological improvement in an experimental setting.}, }
@article {pmid33278022, year = {2020}, author = {Thirunavayakalathil, MA and Varghese, CT and Bharathan, VK and Chandran, B and Nair, K and Mallick, S and Mathew, JS and Amma, BSPT and Menon, RN and Gopalakrishnan, U and Balakrishnan, D and Sudheer, OV and Surendran, S}, title = {Double-blind placebo-controlled randomized trial of N-acetylcysteine infusion following live donor liver transplantation.}, journal = {Hepatology international}, volume = {14}, number = {6}, pages = {1075-1082}, pmid = {33278022}, issn = {1936-0541}, mesh = {Acetylcysteine/therapeutic use ; *Acute Kidney Injury ; Double-Blind Method ; Humans ; *Liver Transplantation ; Living Donors ; }, abstract = {BACKGROUND: The role of N-acetylcysteine (NAC) in improving outcomes following live donor liver transplantation (LDLT) is not well established. We designed a randomized double-blind placebo-controlled trial to study the role of NAC infusion in recipients undergoing LDLT.<br><br>METHODS: We assigned 150 patients who underwent LDLT by computer-generated random sequence on 1:1 ratio to either NAC group or placebo group. Patients in the NAC group received NAC infusion which was started at beginning of graft implantation at an initial loading dose of 150&#xa0;mg/kg/h over 1&#xa0;h, followed by 12.5&#xa0;mg/kg/h for 4&#xa0;h and then at 6.25&#xa0;mg/kg/h continued for 91&#xa0;h. Placebo group received normal saline. The primary endpoint was composite occurrence of acute kidney injury (AKI) and early allograft dysfunction (EAD) in the recipient. Secondary endpoints included levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, INR, primary graft non-function, intraoperative bleeding, post-transplant hospital stay and in-hospital mortality.<br><br>RESULTS: The composite endpoint did not show any significant difference between the NAC and placebo group (21.3% vs 29.3%, p&#x2009;=&#x2009;0.35). Peak AST (425.65&#xa0;IU/L vs 702.24&#xa0;IU/L, p&#x2009;=&#x2009;0.02) and peak ALT (406.65&#xa0;IU/L vs 677.99&#xa0;IU/L, p&#x2009;=&#x2009;0.01) levels were significantly lower in the study group. Time to normalization of transaminases was also significantly low in the study group.<br><br>CONCLUSIONS: Perioperative NAC infusion following LDLT resulted in significantly lower postoperative AST and ALT levels. Rapid normalization of transaminases was also observed. This, however, did not translate to improvement in AKI or EAD.}, }
@article {pmid33275860, year = {2021}, author = {Ieque, AL and Carvalho, HC and Baldin, VP and Santos, NCS and Costacurta, GF and Sampiron, EG and Fernandez de Andrade, CMM and Siqueira, VLD and Caleffi Ferracioli, KR and Cardoso, RF and Cortez, DAG and Silva, EL and Scodro, RBL}, title = {Antituberculosis Activities of Lapachol and β-Lapachone in Combination with Other Drugs in Acidic pH.}, journal = {Microbial drug resistance (Larchmont, N.Y.)}, volume = {27}, number = {7}, pages = {924-932}, doi = {10.1089/mdr.2020.0164}, pmid = {33275860}, issn = {1931-8448}, mesh = {Antitubercular Agents/administration &amp; dosage/*pharmacology ; Cell Survival ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Hydrogen-Ion Concentration ; Macrophages/drug effects ; Microbial Sensitivity Tests ; Naphthoquinones/administration &amp; dosage/*pharmacology ; Tuberculosis, Multidrug-Resistant/*drug therapy ; }, abstract = {Background: The treatment of multidrug-resistant tuberculosis (MDR-TB) is a challenge to be overcome. The increase of resistant isolates associated with serious side effects during therapy leads to the search for substances that have anti-TB activity, which make treatment less toxic, and also act in the macrophage acidic environment promoted by the infection. Objective: The aim of this study was to investigate lapachol and β-lapachone activities in combination with other drugs against Mycobacterium tuberculosis at neutral and acidic pH and its cytotoxicity. Design: Inhibitory and bactericidal activities against M. tuberculosis and clinical isolates were determined. Drug combination and cytotoxicity assay were carried out using standard TB drugs and/or N-acetylcysteine (NAC). Results: Both naphthoquinones presented activity against MDR clinical isolates. The combinations with the first-line TB drugs demonstrated an additive effect and β-lapachone+NAC were synergic against H37Rv. Lapachol activity at acidic pH and its association with NAC improved the selectivity index. Lapachol and β-lapachone produced cell morphological changes in bacilli at pH 6.0 and 6.8, respectively. Conclusion: Lapachol revealed promising anti-TB activity, especially associated with NAC.}, }
@article {pmid33274008, year = {2020}, author = {Zalewska, A and Zięba, S and Kostecka-Sochoń, P and Kossakowska, A and Żendzian-Piotrowska, M and Matczuk, J and Maciejczyk, M}, title = {NAC Supplementation of Hyperglycemic Rats Prevents the Development of Insulin Resistance and Improves Antioxidant Status but Only Alleviates General and Salivary Gland Oxidative Stress.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {8831855}, pmid = {33274008}, issn = {1942-0994}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/*pharmacology ; *Hyperglycemia/drug therapy/metabolism/pathology ; *Insulin Resistance ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; *Salivary Glands/metabolism/pathology ; }, abstract = {Previous studies based on animal models demonstrated that N-acetylcysteine (NAC) prevents oxidative stress and improves salivary gland function when the NAC supplementation starts simultaneously with insulin resistance (IR) induction. This study is the first to evaluate the effect of a 4-week NAC supply on the antioxidant barrier and oxidative stress in Wistar rats after six weeks of high-fat diet (HFD) intake. Redox biomarkers were evaluated in the parotid (PG) and submandibular (SMG) salivary glands and stimulated whole saliva (SWS), as well as in the plasma and serum. We demonstrated that the activity of salivary peroxidase and superoxide dismutase and total antioxidant capacity were significantly higher in PG, SMG, and SWS of IR rats treated with NAC. It appears that in PG and SMG of rats fed an HFD, N-acetylcysteine supplementation abolishes oxidative modifications to proteins (evidenced by decreased content of advanced oxidation protein products (AOPP) and advanced glycation end products (AGE)). Simultaneously, it does not reverse oxidative modifications of lipids (as seen in increased concentration of 8-isoprostanes and 4-hydroxynonenal vs. the control), although it reduces the peroxidation of salivary lipids in relation to the group fed a high-fat diet alone. NAC administration increased protein levels in PG and SMG but did not affect saliva secretion, which was significantly lower compared to the controls. To sum up, the inclusion of NAC supplementation after six weeks of HFD feeding was effective in improving the general and salivary gland antioxidant status. Nevertheless, NAC did not eliminate salivary oxidative stress and only partially prevented salivary gland dysfunction.}, }
@article {pmid33273790, year = {2020}, author = {Anupama, PH and Prasad, N and Nzana, VB and Tiwari, JP and Mathew, M and Abraham, G}, title = {Dietary Management in Slowing Down the Progression of CKDu.}, journal = {Indian journal of nephrology}, volume = {30}, number = {4}, pages = {256-260}, pmid = {33273790}, issn = {0971-4065}, abstract = {Chronic kidney disease of unknown etiology (CKDu) is an emerging entity in the South Asian region. This predominately affects the farming community belonging to the lower socioeconomic status. CKDu being a progressive condition often leads to end-stage renal failurerequiring renal replacement therapy (RRT). Due to the high cost and limited availability of RRT in many areas of geographical locations in India and worldwide, there is an unmet need to slow down the progression of CKDu. The intestinal microbiota is different in patients with CKD, with low levels of beneficial bacteria such as Lactobacillus and Bifidobacteria. Prebiotics and probiotics modify the intestinal microbiota and thereby slow down the progression. Soda bicarbonate therapy is cheap and cost-effective in slowing down the progression of CKDu in a subset of patients. There is also evidence of the beneficial effect of N-acetyl cysteine in early stages of CKD and it should benefit CKDu also. Dietary interventions to prevent dehydration, by providing uncontaminated drinking water, sufficient protein containing diet with adequate calories, and tailored salt intake to prevent hypotension, are necessary compared to other causes of CKD. The objective is to prevent malnutrition, and uremic symptoms. Early diagnosis and prompt intervention may delay the progression of CKDu in the early stages.}, }
@article {pmid33268712, year = {2020}, author = {Honma, S and Tani, I and Sakai, M and Soma, I and Toriyabe, K and Yoshida, M}, title = {Effect of N-Acetyl Cysteine on Renal Interstitial Fibrosis in Mice.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {43}, number = {12}, pages = {1940-1944}, doi = {10.1248/bpb.b20-00657}, pmid = {33268712}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/metabolism ; Fibrosis ; Kidney Diseases/*drug therapy/etiology/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Ureteral Obstruction/complications/*drug therapy/metabolism ; }, abstract = {This study examined the effect of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) inhibitor, on renal interstitial fibrosis induced by unilateral ureteral obstruction (UUO) in mice. UUO led to a significant increase in the fibrotic area of obstructed kidneys, which was attenuated by NAC (84.8 mg/kg/d) in the drinking water. Renal expression of type III collagen and tumor necrosis factor (TNF)-α mRNAs was elevated in UUO mice and inhibited by NAC. Extracellular signal-regulated kinase (ERK1/2) phosphorylation was significantly elevated by UUO, and NAC significantly attenuated the elevation. UUO inhibited the activity of glutathione peroxidase, while NAC restored its activity. Together, the results of this study suggest that renal interstitial fibrosis induced by UUO was ameliorated by NAC via several mechanisms including increased glutathione peroxidase activity, reduced phosphorylation of ERK1/2, and reduced expression of TNF-α and type III collagen mRNAs.}, }
@article {pmid33266501, year = {2020}, author = {Ahamed, M and Akhtar, MJ and Khan, MAM and Alhadlaq, HA and Alshamsan, A}, title = {Barium Titanate (BaTiO3) Nanoparticles Exert Cytotoxicity through Oxidative Stress in Human Lung Carcinoma (A549) Cells.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {10}, number = {11}, pages = {}, pmid = {33266501}, issn = {2079-4991}, support = {2020/129//King Saud University/ ; }, abstract = {Barium titanate (BaTiO3) nanoparticles (BT NPs) have shown exceptional characteristics such as high dielectric constant and suitable ferro-, piezo-, and pyro-electric properties. Thus, BT NPs have shown potential to be applied in various fields including electro-optical devices and biomedicine. However, very limited knowledge is available on the interaction of BT NPs with human cells. This work was planned to study the interaction of BT NPs with human lung carcinoma (A549) cells. Results showed that BT NPs decreased cell viability in a dose- and time-dependent manner. Depletion of mitochondrial membrane potential and induction of caspase-3 and -9 enzyme activity were also observed following BT NP exposure. BT NPs further induced oxidative stress indicated by induction of pro-oxidants (reactive oxygen species and hydrogen peroxide) and reduction of antioxidants (glutathione and several antioxidant enzymes). Moreover, BT NP-induced cytotoxicity and oxidative stress were effectively abrogated by N-acetyl-cysteine (an ROS scavenger), suggesting that BT NP-induced cytotoxicity was mediated through oxidative stress. Intriguingly, the underlying mechanism of cytotoxicity of BT NPs was similar to the mode of action of ZnO NPs. At the end, we found that BT NPs did not affect the non-cancerous human lung fibroblasts (IMR-90). Altogether, BT NPs selectively induced cytotoxicity in A549 cells via oxidative stress. This work warrants further research on selective cytotoxicity mechanisms of BT NPs in different types of cancer cells and their normal counterparts.}, }
@article {pmid33262689, year = {2020}, author = {Fan, C and Long, Y and Wang, L and Liu, X and Liu, Z and Lan, T and Li, Y and Yu, SY}, title = {N-Acetylcysteine Rescues Hippocampal Oxidative Stress-Induced Neuronal Injury via Suppression of p38/JNK Signaling in Depressed Rats.}, journal = {Frontiers in cellular neuroscience}, volume = {14}, number = {}, pages = {554613}, pmid = {33262689}, issn = {1662-5102}, abstract = {Progression of neuronal deterioration within specific brain regions is considered as one of the principal bases for the development of major depressive disorders. Therefore, protects and promotes the maintaining of normal structure and function of neurons might be a potential therapeutic strategy in the treatment of depression. Here, we report that the antioxidant, N-acetylcysteine (NAC), inhibited neuronal injury through its capacity to reduce oxidative stress and exerted antidepressant effects. Specifically, we show that antioxidant enzyme activity was significantly decreased in the hippocampal CA1 region of depressive rats, while treatment with NAC (300 mg/kg, i.p.) produced neuroprotective effects against mitochondrial oxidative stress injuries and oxidative DNA damage in CA1 neurons of these rats. Moreover, NAC treatment alleviated neuronal injury resulting from neuroinflammation and apoptosis in depressed rats, effects that were associated with reductions in dendritic spine atrophy, and synapse deficits. These effects appear to involve a down-regulation of p38 mitogen-activated protein kinase (MAPK)-JNK signaling along with an up-regulation of ERK signaling within the hippocampal CA1 region. Moreover, this NAC treatment significantly ameliorated depression-like behaviors as indicated by performance in the sucrose preference and forced swim tests (FST). Taken together, these results reveal the potential involvement of oxidative stress in the generation of depression. And, the antidepressant-like effects exerted by NAC may involve reductions in this oxidative stress that can result in neuronal deterioration. Such neuroprotective effects of NAC may indicate a potential therapeutic strategy for the treatment of stress-related depression.}, }
@article {pmid33259605, year = {2020}, author = {Dural, E and Shah, UK and Pritchard, D and Chapman, KE and Doak, SH and Jenkins, GJS}, title = {The effect of chronic dosing and p53 status on the genotoxicity of pro-oxidant chemicals in vitro.}, journal = {Mutagenesis}, volume = {35}, number = {6}, pages = {479-489}, doi = {10.1093/mutage/geaa024}, pmid = {33259605}, issn = {1464-3804}, support = {NC/R001375/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, mesh = {Cell Line ; Cells, Cultured ; DNA Damage/*drug effects ; Drug Resistance/genetics ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/administration &amp; dosage/toxicity ; Micronucleus Tests/methods ; Mutagenicity Tests/*methods ; Mutagens/*administration &amp; dosage/toxicity ; Oxidants/*administration &amp; dosage/toxicity ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/deficiency/*genetics ; Vitamin K 3/metabolism ; }, abstract = {In this study, we have studied the cytotoxicity and genotoxic potency of 3 pro-oxidants; H2O2, menadione and KBrO3 in different dosing scenarios, namely acute (1-day dosing) and chronic (5-days). For this purpose, relative population doubling (RPD%) and mononucleated micronucleus (MN) test were used. TK6 cells and NH32 were employed in in vitro experiments. In the study, the total acute dose was divided into 5 days for each prooxidant chemicals by dose fractionation (1/5th per day) method. Acute dosing was compared to chronic dosing. The oxidative stress caused by the exposure of cells with pro-oxidant chemicals to the cells was determined by an optimized 2',7'-dichlorofluorescein diacetate (DCFHDA) test method. The antioxidant levels of the cell lines were altered with buthionine sulfoxide (BSO) and N-acetyl cysteine (NAC), and the effect of antioxidant capacity on the MN formation in the cells was observed with this method. In the case of H2O2 and menadione, fractional dosing has been observed to result in lower toxicity and lower genotoxicity. But in the case of KBrO3, unlike the other 2 pro-oxidants, higher MN induction was observed with fractionated doses. DCFHDA test clearly demonstrated ROS induction with H2O2 and menadione but not with KBrO3. Unexpectedly, DCFHDA test demonstrated that KBrO3 did not cause an increase ROS levels in both acute and chronic dosing, suggesting an alternative ROS induction mechanism. It was also observed that, treatment with BSO and NAC, caused increasing and decreasing of MN fold change respectively, allowing further ROS specific mechanisms to be explored. Hence, dose fractionation expectedly caused less MN, cytotoxicity and ROS formation with H2O2 and menadione exposure, but not with KBrO3. This implies a unique mechanism of action for KBrO3 induced genotoxicity. Chronic dosing in vitro may be a valuable approach allowing better understanding of how chemicals damage DNA and pose human hazards.}, }
@article {pmid33259115, year = {2021}, author = {Safi, R and Malek, E and Nemer, G and Sayed, R and Eid, E and Khalil, S and Nasser, N and Abbas, O and Mohsen-Kanson, T and Kurban, M}, title = {Comparative characterization of sun exposed and sun protected skin-derived mesenchymal-like stem cells in variegate porphyria and healthy individuals.}, journal = {Photodermatology, photoimmunology &amp; photomedicine}, volume = {37}, number = {3}, pages = {202-213}, doi = {10.1111/phpp.12635}, pmid = {33259115}, issn = {1600-0781}, support = {//Conseil National de la Recherche Scientifique/ ; //National Council for Scientific Research/ ; }, mesh = {Culture Media, Conditioned ; Humans ; *Mesenchymal Stem Cells ; Osteogenesis ; *Porphyria, Variegate ; *Porphyrias ; *Skin Diseases ; }, abstract = {BACKGROUND AND PURPOSE: We hypothesized that upon sun exposure, a sub-population of primary skin-derived mesenchymal-like cells is deleteriously affected and thus contribute to the chronic inflammatory state in autosomal recessive variegate porphyria patients. The aim of this study was to isolate and characterize the mesenchymal-like stem cells from different areas of the skin in a porphyria patient (sun exposed, SE, and sun protected, SP) and to compare them with cells from a healthy individual.<br><br>METHODS: The proliferation rate and the migration ability of SE and SP cells were evaluated in the presence of an antioxidant compound, N-acetylcysteine. A co-culture of SE-damaged cells with the conditioned medium from the enriched mesenchymal cell-like SP population was performed in order to regenerate the dermal injured tissue after sun exposure in patients.<br><br>RESULTS: Results showed that the percentage of CD105[+] cells varies between 3.9% in SP and 5% in SE of the healthy individual and between 3.6% and 1.4% in SP and SE in the porphyria patient, respectively. The osteogenic differentiation potential was lower in the porphyria patient when compared to the control. Furthermore, the expression of stem cell markers was more pronounced in SE than in SP cells of both control and porphyria. The use of N-acetyl cysteine did not show any beneficial effects on porphyria SE cells. Treatment with SP-conditioned medium slightly increased the expression of stem cell markers in SE of porphyria patient.<br><br>CONCLUSION: In conclusion, the pool of mesenchymal stem-like SE cells is affected in variegate porphyria patient along with modification of their self-renewal and differentiation properties.}, }
@article {pmid33250889, year = {2020}, author = {Nader, E and Romana, M and Guillot, N and Fort, R and Stauffer, E and Lemonne, N and Garnier, Y and Skinner, SC and Etienne-Julan, M and Robert, M and Gauthier, A and Cannas, G and Antoine-Jonville, S and Tressières, B and Hardy-Dessources, MD and Bertrand, Y and Martin, C and Renoux, C and Joly, P and Grau, M and Connes, P}, title = {Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia.}, journal = {Frontiers in immunology}, volume = {11}, number = {}, pages = {551441}, pmid = {33250889}, issn = {1664-3224}, mesh = {Adolescent ; Adult ; Anemia, Sickle Cell/*blood/pathology ; Cell-Derived Microparticles/*metabolism/pathology ; Child ; Child, Preschool ; *Eryptosis ; Erythrocytes, Abnormal/*metabolism/pathology ; Female ; Humans ; Male ; Nitric Oxide/*blood ; *Oxidative Stress ; *Vascular Stiffness ; }, abstract = {Chronic hemolysis, enhanced oxidative stress, and decreased nitric oxide (NO) bioavailability promote vasculopathy in sickle cell anemia (SCA). Oxidative stress and NO are known to modulate eryptosis in healthy red blood cells (RBCs); however, their role in SCA eryptosis and their impact on the genesis of RBC-derived microparticles (RBC-MPs) remains poorly described. RBC-MPs could play a role in vascular dysfunction in SCA. The aims of this study were to evaluate the roles of oxidative stress and NO in eryptosis and RBC-MPs release, and to determine whether RBC-MPs could be involved in vascular dysfunction in SCA. Markers of eryptosis and oxidative stress, plasma RBC-MPs concentration and arterial stiffness were compared between SCA and healthy (AA) individuals. In-vitro experiments were performed to test: 1) the effects of oxidative stress (antioxidant: n-acetylcysteine (NAC); pro-oxidant: cumene hydroperoxide) and NO (NO donor: sodium nitroprusside (SNP); NO-synthase inhibitor (L-NIO)) on eryptosis, RBC deformability and RBC-MP genesis; 2) the effects of SCA/AA-RBC-MPs on human aortic endothelial cell (HAEC) inflammatory phenotype and TLR4 pathway. Eryptosis, RBC-MPs, oxidative stress and arterial stiffness were increased in SCA. NAC increased RBC deformability and decreased eryptosis and RBC-MPs release, while cumene did the opposite. SNP increased RBC deformability and limited eryptosis, but had no effect on RBC-MPs. L-NIO did not affect these parameters. Arterial stiffness was correlated with RBC-MPs concentration in SCA. RBC-MPs isolated directly from SCA blood increased adhesion molecules expression and the production of cytokines by HAEC compared to those isolated from AA blood. TLR4 inhibition alleviated these effects. Our data show that oxidative stress could promote eryptosis and the release of RBC-MPs that are potentially involved in macrovascular dysfunction in SCA.}, }
@article {pmid33247942, year = {2021}, author = {Zmora, O and Gutzeit, O and Segal, L and Boulos, S and Millo, Z and Ginsberg, Y and Khatib, N and Fainaru, O and Ross, MG and Weiner, Z and Beloosesky, R}, title = {Maternal N-acetyl-cysteine prevents neonatal brain injury associated with necrotizing enterocolitis in a rat model.}, journal = {Acta obstetricia et gynecologica Scandinavica}, volume = {100}, number = {5}, pages = {979-987}, doi = {10.1111/aogs.14054}, pmid = {33247942}, issn = {1600-0412}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Animals ; Animals, Newborn ; Anti-Inflammatory Agents/*pharmacology/*therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Apoptosis/drug effects ; Brain Injuries/*drug therapy/etiology ; Caspase 3/metabolism ; Disease Models, Animal ; Enterocolitis, Necrotizing/complications/*drug therapy/prevention &amp; control ; Female ; In Situ Nick-End Labeling ; Inflammation/complications/*drug therapy ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Nitric Oxide Synthase Type I/metabolism ; Oxidative Stress/drug effects ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Transcription Factor RelA/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {INTRODUCTION: Preterm infants with necrotizing enterocolitis (NEC) are at increased risk of cerebral injury and neurodevelopmental dysfunction. N-acetyl-cysteine (NAC) is a known anti-inflammatory and antioxidant agent. Currently, there is no prophylactic treatment in clinical use to prevent NEC and its neurodevelopmental sequelae. We sought to determine whether brain inflammation/apoptosis accompanies NEC systemic inflammation, and whether it can be attenuated by maternal NAC treatment during pregnancy and/or in the neonatal period in a rat model.<br><br>MATERIAL AND METHODS: An established NEC newborn model (hypoxia 5% O2 for 10&#xa0;min and formula feeding thrice daily, beginning on day 1 for 4&#xa0;days) was used in Sprague-Dawley rat pups (n&#xa0;=&#xa0;32). An additional group of pups (n&#xa0;=&#xa0;33) received NAC (300&#xa0;mg/kg intraperitoneal thrice daily) in addition to NEC conditions (NEC-NAC). Control pups (n&#xa0;=&#xa0;33) were nursed and remained with the dam in room air. Two additional groups included pups of dams treated once daily with NAC (300&#xa0;mg/kg intravenous) in the last 3&#xa0;days of pregnancy. After birth, pups were randomized into NAC-NEC (n&#xa0;=&#xa0;33) with NEC conditions and NAC-NEC-NAC (n&#xa0;=&#xa0;36) with additional postnatal NAC treatment. Pups were sacrificed on the fifth day of life. Pup serum interleukin (IL)-6 protein levels, and brain nuclear factor kappa B (NF-&#x3ba;B) p65, neuronal nitric oxide synthase (nNOS), Caspase 3, tumor necrosis factor alpha (TNF-&#x3b1;), IL-6 and IL-1&#x3b2; protein levels were determined by ELISA, western blot and TUNEL staining, and the groups were compared using analysis of variance (ANOVA).<br><br>RESULTS: NEC pups had significantly increased serum IL-6 levels compared with the control group as well as increased neuronal apoptosis and brain protein levels of NF-&#x3ba;B, nNOS, Caspase 3, TNF-&#x3b1;, IL-6 and IL-1&#x3b2; compared with control. In all NAC treatment groups, levels of serum IL-6, neuronal apoptosis and brain NF-&#x3ba;B, nNOS, Caspase 3, TNF-&#x3b1;, IL-6 and IL-1&#x3b2; protein levels were significantly reduced compared with the NEC group. The most pronounced decrease was demonstrated within the NAC-NEC-NAC group.<br><br>CONCLUSIONS: NAC treatment can attenuate newborn inflammatory response syndrome and decrease offspring brain neuroapoptosis and inflammation in a rat model of NEC by inhibition of NF-&#x3ba;B, nNOS and Caspase 3 pathways.}, }
@article {pmid33247722, year = {2021}, author = {Finsen, SH and Hansen, MR and Hansen, PBL and Mortensen, SP}, title = {Aldosterone Induces Vasoconstriction in Individuals with Type 2 Diabetes: Effect of Acute Antioxidant Administration.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {106}, number = {3}, pages = {e1262-e1270}, doi = {10.1210/clinem/dgaa867}, pmid = {33247722}, issn = {1945-7197}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Aldosterone/administration &amp; dosage/blood/*pharmacology ; Antioxidants/administration &amp; dosage/pharmacology ; Case-Control Studies ; Denmark ; Diabetes Mellitus, Type 2/blood/*physiopathology ; Female ; Femoral Artery/drug effects/physiopathology ; Hemodynamics/drug effects ; Humans ; Leg/blood supply ; Male ; Middle Aged ; Regional Blood Flow/drug effects ; Vasoconstriction/*drug effects ; }, abstract = {CONTEXT: Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and cardiovascular disease. Plasma aldosterone could contribute by reactive oxygen species-dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone.<br><br>OBJECTIVE: We aimed to investigate the acute vascular effects of aldosterone in individuals with type 2 diabetes compared with healthy controls and if infusion of an antioxidant (n-acetylcysteine [NAC]) would alter the vascular response.<br><br>METHODS: In a case-control design, 12 participants with type 2 diabetes and 14 healthy controls, recruited from the general community, were studied. Leg hemodynamics were measured before and during aldosterone infusion (0.2 and 5 ng min-1 [L leg volume]-1) for 10 minutes into the femoral artery with and without coinfusion of NAC (125 mg kg-1 hour-1 followed by 25 mg kg-1 hour-1). Leg blood flow and arterial blood pressure was measured, and femoral arterial and venous blood samples were collected.<br><br>RESULTS: Compared with the control group, leg blood flow and vascular conductance decreased during infusion of aldosterone at the high dose in individuals with type 2 diabetes, whereas coinfusion of NAC attenuated this response. Plasma aldosterone increased in both groups during aldosterone infusion and there was no difference between groups at baseline or during the infusions.<br><br>CONCLUSION: These results suggests that type 2 diabetes is associated with a vasoconstrictor response to physiological levels of infused aldosterone and that the antioxidant NAC diminishes this response.}, }
@article {pmid33247486, year = {2021}, author = {Hegde, S and Wellendorf, AM and Zheng, Y and Cancelas, JA}, title = {Antioxidant prevents clearance of hemostatically competent platelets after long-term cold storage.}, journal = {Transfusion}, volume = {61}, number = {2}, pages = {557-567}, pmid = {33247486}, issn = {1537-2995}, support = {R01 HL147536/HL/NHLBI NIH HHS/United States ; R43 HL123103/HL/NHLBI NIH HHS/United States ; //NIH Center for Accelerated Innovations at Cleveland Clinic/ ; //State of Ohio Third Frontier Program/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Aspirin/toxicity ; Bleeding Time ; Blood Platelets/*drug effects/ultrastructure ; Blood Preservation/*methods ; Cell Shape/drug effects ; Cold Temperature ; Fibrinogen/pharmacology ; Humans ; Macrophages/drug effects ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mitochondria/*metabolism ; Oxygen Consumption ; Phagocytosis/drug effects ; Platelet Activation/drug effects ; Platelet Transfusion ; Platelet-Rich Plasma ; Reactive Oxygen Species/analysis ; Thrombocytopenia/chemically induced/therapy ; }, abstract = {BACKGROUND: Cold storage of platelets (PLTs) has the potential advantage of prolonging storage time while reducing posttransfusion infection given the decreased likelihood of bacterial outgrowth during storage and possibly beneficial effects in treating bleeding patients. However, cold storage reduces PLT survival through the induction of complex storage lesions, which are more accentuated when storage is prolonged.<br><br>STUDY DESIGN AND METHODS: Whole blood-derived PLT-rich plasma concentrates from seven PLT pools (n = 5 donors per pool). PLT additive solution was added (67%/33% plasma) and the product was split into 50-mL bags. Split units were stored in the presence or absence of 1&#x2009;mM&#x2009;of N-acetylcysteine (NAC) under agitation for up to 14&#x2009;days at room temperature or in the cold and were analyzed for PLT activation, fibrinogen-dependent spreading, microparticle formation, mitochondrial respiratory activity, reactive oxygen species (ROS) generation, as well as in vivo survival and bleeding time correction in immunodeficient mice.<br><br>RESULTS: Cold storage of PLTs for 7&#x2009;days or longer induces significant PLT activation, cytoskeletal damage, impaired fibrinogen spreading, enhances mitochondrial metabolic decoupling and ROS generation, and increases macrophage-dependent phagocytosis and macrophage-independent clearance. Addition of NAC prevents PLT clearance and allows a correction of the prolonged bleeding time in thrombocytopenic, aspirin-treated, immunodeficient mice.<br><br>CONCLUSIONS: Long-term cold storage induces mitochondrial uncoupling and increased proton leak and ROS generation. The resulting ROS is a crucial contributor to the increased macrophage-dependent and -independent clearance of functional PLTs and can be prevented by the antioxidant NAC in a magnesium-containing additive solution.}, }
@article {pmid33246336, year = {2021}, author = {Olesen, H&#xd8; and Pors, SE and Jensen, LB and Grønning, AP and Lemser, CE and Nguyen Heimbürger, MTH and Mamsen, LS and Getreu, N and Christensen, ST and Andersen, CY and Kristensen, SG}, title = {N-acetylcysteine protects ovarian follicles from ischemia-reperfusion injury in xenotransplanted human ovarian tissue.}, journal = {Human reproduction (Oxford, England)}, volume = {36}, number = {2}, pages = {429-443}, doi = {10.1093/humrep/deaa291}, pmid = {33246336}, issn = {1460-2350}, mesh = {*Acetylcysteine/pharmacology/therapeutic use ; Animals ; Female ; Heterografts ; Humans ; Mice ; *Ovarian Follicle ; *Reperfusion Injury/drug therapy/prevention &amp; control ; }, abstract = {STUDY QUESTION: Can antioxidant treatment with N-acetylcysteine (NAC) protect ovarian follicles from ischemia-reperfusion injury in xenotransplanted human ovarian tissue?<br><br>SUMMARY ANSWER: Daily administration of NAC for 7-12&#x2009;days post-transplantation reduced ischemia-reperfusion injury and increased follicle survival in human ovarian xenografts by upregulating the antioxidant defense system and exerting anti-inflammatory and antiapoptotic effects.<br><br>WHAT IS KNOWN ALREADY: Freezing of human ovarian tissue is performed with high follicular survival rates but up to 70% of follicles appear to be lost due to hypoxia and ischemia-reperfusion injury during ovarian tissue transplantation (OTT). NAC has been demonstrated to possess antioxidant and antiapoptotic properties, and studies in rodents have shown that intraperitoneal administration of NAC reduces ischemia-reperfusion injury and increases follicle survival in autotransplanted murine ovaries.<br><br>STUDY DESIGN, SIZE, DURATION: Pieces of frozen-thawed human ovarian tissue from 28 women aged 23-36&#x2009;years were transplanted to immunodeficient mice in short- and long-term xenograft studies or cultured in vitro. Three short-term xenograft studies (1-week duration) were performed, in which saline or 150&#x2009;mg/kg NAC was administered for 7&#x2009;days post-transplantation (n&#x2009;=&#x2009;12 patients per group). Two long-term xenograft studies (4&#x2009;weeks of duration) were performed. In one of these studies, saline or 150&#x2009;mg/kg NAC was administered for 12&#x2009;days (n&#x2009;=&#x2009;12 patients per group), while in the other study 50, 150 or 300&#x2009;mg/kg NAC was administered for 7&#x2009;days (n&#x2009;=&#x2009;8 patients per group). In addition, human ovarian tissue (n&#x2009;=&#x2009;12 pieces from three patients per group) was cultured with increasing concentrations of NAC (0, 5, 25 and 75&#x2009;mM) for 4&#x2009;days in vitro.<br><br>Donated ovarian tissue was obtained from women who had undergone ovarian tissue cryopreservation for fertility preservation at the University Hospital of Copenhagen. Cortical tissue pieces (5 &#xd7; 5 &#xd7; 1 mm) were transplanted subcutaneously to immunodeficient mice and NAC or saline was injected intraperitoneally. Grafts were retrieved after 1 or 4&#x2009;weeks and follicle density was assessed. Gene expression analysis of antioxidant defense markers (superoxide dismutase; Sod1/SOD1, heme oxygenase-1; Hmox1/HMOX1, catalase; Cat/CAT), proinflammatory cytokines (tumor necrosis factor-alpha; Tnf-&#x3b1;, interleukin-1-beta; Il1-&#x3b2;, interleukin 6; Il6), apoptotic factors (B-cell lymphoma 2; Bcl2/BCL2, Bcl-2-associated X protein; Bax/BAX) and angiogenic factors (vascular endothelial growth factor A; Vegfa/VEGFA, angiopoietin-like 4; Angptl4/ANGPTL4) was performed in 1-week-old human ovarian xenografts and in cultured human ovarian tissue. Grafts retrieved after 4&#x2009;weeks were histologically processed and analyzed for vascularization by CD31 immunohistochemical staining, fibrosis by Masson's Trichrome staining and apoptosis by immunofluorescence using cleaved caspase-3.<br><br>After 1-week grafting, the relative expression of Sod1, Hmox1 and Cat was significantly higher in the group receiving 150&#x2009;mg/kg NAC (NAC150-treated group) compared to controls (P&#x2009;=&#x2009;0.04, P&#x2009;=&#x2009;0.03, and P&#x2009;=&#x2009;0.01, respectively), whereas the expression levels of Tnf-&#x3b1;, Il1-&#x3b2; and Il6 were reduced. The Bax/Bcl2 ratio was also significantly reduced in the NAC150-treated group (P&#x2009;<&#x2009;0.005). In vitro, the relative gene expression of SOD1, HMOX1 and CAT increased significantly in the human ovarian tissue with increasing concentrations of NAC (P&#x2009;<&#x2009;0.001 for all genes). However, the expression of VEGFA and ANGPTL4 as well as the BAX/BCL2 ratio decreased significantly with increasing concentrations of NAC (P&#x2009;<&#x2009;0.02, P&#x2009;<&#x2009;0.001 and P&#x2009;<&#x2009;0.001, respectively). After 4-week grafting, fibrosis measured by collagen content was similar in the NAC150-treated group compared to controls (control: 56.6% &#xb1; 2.2; NAC150: 57.6% &#xb1; 1.8), whereas a statistically significant reduction in the CD31-positive vessel area was found (control: 0.69% &#xb1; 0.08; NAC150: 0.51% &#xb1; 0.07; P&#x2009;<&#x2009;0.02). Furthermore, a reduced immunoreactivity of cleaved caspase-3 was observed in follicles of the NAC150-treated xenografts compared to controls. Follicle density (follicles/mm3, mean &#xb1; SD) was higher in the NAC150-treated group compared to the control group in the 1-week xenografts (control: 19.5&#x2009;&#xb1;&#x2009;26.3; NAC150: 34.2&#x2009;&#xb1;&#x2009;53.5) and 4-week xenografts (control: 9.3&#x2009;&#xb1;&#x2009;11.0; NAC150: 14.4&#x2009;&#xb1;&#x2009;15.0). Overall, a 2-fold increase in follicle density was observed in the NAC150-group after 1-week grafting where fold changes in follicle density were calculated in relation to grafts from the same patient. Around a 5-fold increase in follicle density was observed in the NAC150 and NAC300 groups after 4-week grafting.<br><br>LARGE SCALE DATA: N/A.<br><br>Follicle density in the human ovarian cortex is highly heterogeneous and can vary 100-fold between cortex pieces from the same woman. A high variability in follicle density within and between treatment groups and patients was found in the current study. Thus, solid conclusions cannot be made. While intraperitoneal injections of NAC appeared to reduce ischemia-reperfusion injury in human ovarian xenografts, different administration routes should be investigated in order to optimize NAC for potential clinical use.<br><br>This is the first study to demonstrate the antioxidant, anti-inflammatory and antiapoptotic properties of NAC in xenotransplanted human ovarian tissue. Therefore, NAC appears to be a promising candidate for protecting ovarian follicles from ischemia-reperfusion injury. This provides the initial steps toward clinical application of NAC, which could potentially reduce the loss of ovarian follicles following OTT.<br><br>We are grateful to the Danish Childhood Cancer Foundation, H&#xf8;rslev Foundation, Aase and Einar Danielsen's Foundation (grant number: 10-001999), Dagmar Marshalls Foundation, Else and Mogens Wedell-Wedellsborgs Foundation, Knud and Edith Eriksens Mindefond, and Fabrikant Einar Willumsens Mindelegat for funding this study. None of the authors have any competing interests to declare.}, }
@article {pmid33245701, year = {2020}, author = {Meletis, CD and Wilkes, K}, title = {Immune Competence and Minimizing Susceptibility to COVID-19 and Other Immune System Threats.}, journal = {Alternative therapies in health and medicine}, volume = {26}, number = {S2}, pages = {94-99}, pmid = {33245701}, issn = {1078-6791}, mesh = {*Betacoronavirus ; COVID-19 ; *Coronavirus Infections ; Humans ; *Immune System/physiopathology ; *Immunocompetence ; *Pandemics ; *Pneumonia, Viral ; SARS-CoV-2 ; }, abstract = {Exposure to viruses, bacteria, and other pathogens is unavoidable. Yet, the mere presence of these threats is not enough to automatically predispose to illness. The susceptibility of an individual to viral or bacterial infections is dependent upon immune competence. Many factors can interfere with the functioning of the immune system. Epigenetic alterations in the form of lifestyle or environmental factors can lead to impaired immunity. For example, exposure to air pollution can increase the risk of complications and mortality from COVID-19. Obesity can also exacerbate the damaging effects of air pollution on the lungs and may enhance the association between air pollution and increased COVID-19 severity. Poor sleep is another factor leading to impaired immunity, likely due to the coinciding melatonin depletion. Melatonin has been found to have antiviral and immune-enhancing effects, and it has been proposed that this hormone may be beneficial in COVID-19 patients. Zinc and vitamins D and C have also been well studied for their ability to shorten the duration of upper respiratory infections, and vitamin D has been found to reduce mortality in COVID-19 patients. Cannabidiol can both directly and indirectly improve immunity by enhancing natural killer cell activity, reducing inflammation, and relieving stress. Other dietary supplements backed by solid scientific evidence to show they act as immune enhancers are astragalus, a yeast fermentate (EpiCor®), olive leaf extract, berberine, N-acetyl cysteine, and garlic.}, }
@article {pmid33240522, year = {2020}, author = {McCulloch, A and Sarwar, A and Bate, T and Thompson, D and McDowell, P and Sharif, Q and Sapey, E and Seccombe, A}, title = {Electronic-prescribing tools improve N-acetylcysteine prescription accuracy and timeliness for patients who present following a paracetamol overdose: A digital innovation quality-improvement project.}, journal = {Digital health}, volume = {6}, number = {}, pages = {2055207620965046}, pmid = {33240522}, issn = {2055-2076}, abstract = {OBJECTIVES: Prescription error rates and delays in treatment provision are high for N-acetylcysteine (NAC) when prescribed for paracetamol overdose (POD). We hypothesised that an electronic tool which proposed the complete NAC regimen would reduce prescription errors and improve the timeliness of NAC provision. Error rates and delays in the provision of NAC were assessed following POD, before and after the implementation of an electronic prescribing tool.<br><br>METHODS: The NAC electronic prescribing tool proposed the three NAC infusions (dosed for weight) following entry of the patient's weight. All NAC prescriptions were reviewed during a three-month period prior to and after the tool's implementation. Error rates were divided into dose, infusion volume or infusion rate. Delays in NAC provision were identified using national Emergency Medicine guidelines.<br><br>RESULTS: 108 NAC prescriptions were analysed for all adult patients admitted to the emergency department of a secondary care hospital in the UK between July-September 2017 and August-October 2018, respectively. There were no differences in the demographics of patients or the seniority of the prescribing clinician before or after the introduction of the electronic tool. The electronic prescribing tool was associated with a decrease in prescribing errors (25% to 0%, p&#x2009;<&#x2009;0.0071) and an increase in the provision of NAC within recommended times (11.1% to 47.4%, p&#x2009;=&#x2009;0.029).<br><br>CONCLUSIONS: An electronic prescribing tool improved prescription errors and the timeliness of NAC provision following POD. Further studies will determine the effect of this on length of stay and the benefit of wider implementation in other secondary care hospitals.}, }
@article {pmid33237503, year = {2021}, author = {Jo, HG and Park, C and Lee, H and Kim, GY and Keum, YS and Hyun, JW and Kwon, TK and Choi, YH and Hong, SH}, title = {Inhibition of oxidative stress induced-cytotoxicity by coptisine in V79-4 Chinese hamster lung fibroblasts through the induction of Nrf-2 mediated HO-1 expression.}, journal = {Genes &amp; genomics}, volume = {43}, number = {1}, pages = {17-31}, pmid = {33237503}, issn = {2092-9293}, mesh = {Animals ; Antioxidants/*pharmacology ; Berberine/*analogs &amp; derivatives/pharmacology ; Cell Line ; Cricetinae ; Cricetulus ; Fibroblasts/drug effects/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Hydrogen Peroxide/toxicity ; NF-E2-Related Factor 2/genetics/*metabolism ; *Oxidative Stress ; }, abstract = {BACKGROUND: Coptisine is a natural alkaloid compound and is known to have multiple beneficial effects including antioxidant activity. However, whether it can protect lung fibroblasts from oxidative damage has not been studied yet.<br><br>OBJECTIVES: To investigate the potential inhibitory effect of coptisine against oxidative stress in V79-4 lung fibroblast cells.<br><br>METHODS: V79-4 cells were treated with H2O2 (1&#xa0;mM) in the presence or absence of coptisine (50 &#xb5;g/ml), N-acetyl cysteine (NAC, 10&#xa0;mM) or zinc protoporphyrin IX (ZnPP, 10 &#xb5;M) for the indicated times. The alleviating effects of coptisine on cytotoxicity, cell cycle arrest, apoptosis, reactive oxygen species (ROS) production, DNA damage, mitochondrial dynamics, and inhibition of ATP production against H2O2 were investigated. Western blot analysis was used to analyze the expression levels of specific proteins.<br><br>RESULTS: Coptisine inhibited H2O2-induced cytotoxicity and DNA damage by blocking abnormal ROS generation. H2O2 treatment caused cell cycle arrest at the G2/M phase accompanied by increased expression of cyclin-dependent kinase (Cdk) inhibitor p21[WAF1/CIP1] and decreased expression of cyclin B1 and cyclin A. However, these effects were attenuated in the presence of coptisine or NAC. Coptisine also prevented apoptosis by decreasing the rate of Bax/Bcl-2 expression in H2O2-stimulated cells and suppressing the loss of mitochondrial membrane potential and the cytosolic release of cytochrome c. In addition, the activation of nuclear factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was markedly promoted by coptisine in the presence of H2O2. However, zinc protoporphyrin IX, a potent inhibitor of HO-1, attenuated the ROS scavenging and anti-apoptotic effects of coptisine.<br><br>CONCLUSIONS: Based on current data, we suggest that coptisine can be used as a potential treatment for oxidative stress-related lung disease.}, }
@article {pmid33229761, year = {2020}, author = {Sayed Zeid, AS and Sayed, SS}, title = {A Comparative Study of the Use of Dexamethasone, N-acetyl Cysteine, and Theophylline to Ameliorate Renal Ischemia-Reperfusion Injury in Experimental Rat Models: A Biochemical and Immuno-histochemical Approach.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {31}, number = {5}, pages = {982-997}, doi = {10.4103/1319-2442.301203}, pmid = {33229761}, issn = {1319-2442}, mesh = {Acetylcysteine/*pharmacology ; *Acute Kidney Injury/metabolism/pathology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Creatinine/blood ; Cystatin C/blood/urine ; Dexamethasone/*pharmacology ; Disease Models, Animal ; Inflammation ; Kidney/chemistry/drug effects/pathology ; Male ; Rats ; *Reperfusion Injury/metabolism/pathology ; Theophylline/*pharmacology ; }, abstract = {Renal ischemia-reperfusion injury (IRI) is commonly encountered in clinical practice during renal transplantation. In a trial to find the drug that best safeguards the kidney against IRI, dexamethasone (Dex), N-acetyl cysteine (NAC), and theophylline (Theo) were tested in experimental rat models. This study included 105 adult male albino rats, which were randomly assigned to the following five groups: Group I - sham-operated, n = 5, Group II - IRI n = 25, Group III - IRI + Dex n = 25, Group IV - IRI + NAC n = 25, and Group V -IRI + Theo n = 25. IRI was induced for 40 min followed by reperfusion. Rats were sacrificed 1, 2, 4, 6, and 24 h after reperfusion. This was preceded by blood and urine sampling for biochemical study of serum Cystatin C (Cys C), serum creatinine, and urinary Cys C. Kidneys were processed for histopathological evaluation and immune-histochemical staining for Cys C. The expression of Cys C in the proximal tubular cells was significantly lower in the IRI group compared to that of the sham group. There was a significant rise in the levels of serum and urinary Cys C after 1 h in the IRI group, while the rise in creatinine occurred later. Dex was superior to NAC and Theo 24 h after the IR insult, and the serum levels of creatinine and Cys C were significantly lower in this group than the other two drug groups (P <0.001 in both cases). Our study revealed a clear benefit for the use of Dex to ameliorate IRI over NAC and Theo if used immediately following the insult. The effect is evident 24-h after its use. The role of serum Cys C as an early marker of acute kidney injury compared to serum creatinine is confirmed.}, }
@article {pmid33228213, year = {2020}, author = {Meryk, A and Grasse, M and Balasco, L and Kapferer, W and Grubeck-Loebenstein, B and Pangrazzi, L}, title = {Antioxidants N-Acetylcysteine and Vitamin C Improve T Cell Commitment to Memory and Long-Term Maintenance of Immunological Memory in Old Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {11}, pages = {}, pmid = {33228213}, issn = {2076-3921}, support = {ZAP746006//Tyrolean Science Funds (TWF)/ ; H2020-PHC-2014//EU 2020/ ; }, abstract = {Aging is characterized by reduced immune responses, a process known as immunosenescence. Shortly after their generation, antigen-experienced adaptive immune cells, such as CD8[+] and CD4[+] T cells, migrate into the bone marrow (BM), in which they can be maintained for long periods of time within survival niches. Interestingly, we recently observed how oxidative stress may negatively support the maintenance of immunological memory in the BM in old age. To assess whether the generation and maintenance of immunological memory could be improved by scavenging oxygen radicals, we vaccinated 18-months (old) and 3-weeks (young) mice with alum-OVA, in the presence/absence of antioxidants vitamin C (Vc) and/or N-acetylcysteine (NAC). To monitor the phenotype of the immune cell population, blood was withdrawn at several time-points, and BM and spleen were harvested 91 days after the first alum-OVA dose. Only in old mice, memory T cell commitment was boosted with some antioxidant treatments. In addition, oxidative stress and the expression of pro-inflammatory molecules decreased in old mice. Finally, changes in the phenotype of dendritic cells, important regulators of T cell activation, were additionally observed. Taken together, our data show that the generation and maintenance of memory T cells in old age may be improved by targeting oxidative stress.}, }
@article {pmid33227845, year = {2020}, author = {Hwang, CY and Han, YH and Lee, SM and Cho, SM and Yu, DY and Kwon, KS}, title = {Sestrin2 Attenuates Cellular Senescence by Inhibiting NADPH Oxidase 4 Expression.}, journal = {Annals of geriatric medicine and research}, volume = {24}, number = {4}, pages = {297-304}, pmid = {33227845}, issn = {2508-4909}, abstract = {BACKGROUND: Sestrin2 (Sesn2) is involved in the maintenance of metabolic homeostasis and aging via modulation of the 5' AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway.<br><br>METHODS: Wild-type and Sesn2 knockout (KO) mice of the 129/SvJ background were maintained in a pathogen-free authorized facility under a 12-hour dark/light cycle at 20&#xb0;C-22&#xb0;C and 50%-60% humidity. Mouse embryonic fibroblasts (MEFs) were prepared from 13.5-day-old embryos derived from Sesn2-KO mice mated with each other.<br><br>RESULTS: The MEFs from Sesn2-KO mice showed enlarged and flattened morphologies and senescence-associated &#x3b2;-galactosidase activity, accompanied by an elevated level of reactive oxygen species. These senescence phenotypes recovered following treatment with N-acetyl-cysteine. Notably, the mRNA levels of NADPH oxidase 4 (NOX4) and transforming growth factor (TGF)-&#x3b2; were markedly increased in Sesn2-KO MEFs. Treatment of Sesn2-KO MEFs with the NOX inhibitor diphenyleneiodonium and the TGF-&#x3b2; inhibitor SB431542 restored cell growth inhibited by Sesn2-KO.<br><br>CONCLUSION: Sesn2 attenuates cellular senescence via suppression of TGF-&#x3b2;- and NOX4-induced reactive oxygen species generation and subsequent inhibition of AMPK.}, }
@article {pmid33226166, year = {2021}, author = {Naasri, S and Helali, I and Aouni, M and Mastouri, M and Harizi, H}, title = {N-acetylcysteine reduced the immunotoxicity effects induced in vitro by azoxystrobin and iprodione fungicides in mice.}, journal = {Environmental toxicology}, volume = {36}, number = {4}, pages = {562-571}, doi = {10.1002/tox.23061}, pmid = {33226166}, issn = {1522-7278}, mesh = {Acetylcysteine/*pharmacology ; Aminoimidazole Carboxamide/*analogs &amp; derivatives/toxicity ; Animals ; Cell Proliferation/drug effects ; Cell Survival/drug effects/immunology ; Cells, Cultured ; Cytokines/biosynthesis ; Dose-Response Relationship, Drug ; Environmental Pollutants/*toxicity ; Fungicides, Industrial/*toxicity ; Hydantoins/*toxicity ; *Macrophages, Peritoneal/drug effects/immunology ; Male ; Mice ; Pyrimidines/*toxicity ; Spleen/drug effects/immunology ; Strobilurins/*toxicity ; }, abstract = {Azoxystrobin (AZO) and Iprodione (IPR) fungicides are extensively used worldwide, and therefore, contaminate all environmental compartments. The toxicity and the mechanisms by which they affected immune cells are complex and remain unknown. This study investigated the impact of AZO and IPR on the in vitro function of mice peritoneal macrophages including lysosomal enzyme activity and tumor necrosis factor (TNF)α and nitric oxide (NO) production in response to lipopolysaccharide (LPS) stimulation, the proliferation of mice splenocytes stimulated by concanavalin (Con)A and LPS, and the production of the Th1cytokine interferon-gamma (IFNγ) and the Th2 cytokine interleukin (IL)-4 and IL-10 by ConA-activated splenocytes. This is the first report indicating that AZO and IPR fungicides dose-dependently inhibited mice macrophage lysosomal enzyme activity and LPS-stimulated production of TNFα and NO. Mitogen-induced proliferation of mice splenocytes was also suppressed by AZO and IPR in a dose-dependent manner. More pronounced impact was observed on ConA-induced response. The production of IFNγ by ConA-stimulated splenocytes was dose-dependently inhibited; however, the production of IL-4 and IL-10 increased in the same conditions. These results suggested that AZO and IPR polarized Th1/Th2 cytokine balance towards Th2 response. Overall, marked immunosuppressive effects were observed for AZO. The immunomodulatory effects caused by AZO and IPR were partially reversed by the pharmacological antioxidant N-acetylcysteine (NAC), suggesting that both fungicides exerted their actions through, at least in part, oxidative stress-dependent mechanism. Collectively, our data showed that AZO and IPR fungicides exerted potent immunomodulatory effects in vitro with eventually strong consequences on immune response and immunologically based diseases.}, }
@article {pmid33222771, year = {2020}, author = {Lababidi, N and Montefusco-Pereira, CV and de Souza Carvalho-Wodarz, C and Lehr, CM and Schneider, M}, title = {Spray-dried multidrug particles for pulmonary co-delivery of antibiotics with N-acetylcysteine and curcumin-loaded PLGA-nanoparticles.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {157}, number = {}, pages = {200-210}, doi = {10.1016/j.ejpb.2020.10.010}, pmid = {33222771}, issn = {1873-3441}, mesh = {Acetylcysteine/*administration &amp; dosage/chemistry/metabolism ; Administration, Inhalation ; Anti-Bacterial Agents/*administration &amp; dosage/chemistry/metabolism ; Anti-Inflammatory Agents/*administration &amp; dosage/chemistry/metabolism ; Azithromycin/administration &amp; dosage/chemistry ; Ciprofloxacin/administration &amp; dosage/chemistry ; Curcumin/*administration &amp; dosage/chemistry/metabolism ; Cytokines/metabolism ; *Drug Carriers ; Drug Combinations ; Drug Compounding ; Expectorants/*administration &amp; dosage/chemistry/metabolism ; Freeze Drying ; Humans ; Inflammation Mediators/metabolism ; Macrophages/drug effects/metabolism/microbiology ; Microbial Viability/drug effects ; Mucus/metabolism ; *Nanoparticles ; Permeability ; Polylactic Acid-Polyglycolic Acid Copolymer/*chemistry ; Pseudomonas Infections/*drug therapy/metabolism/microbiology ; Pseudomonas aeruginosa/drug effects/growth &amp; development ; THP-1 Cells ; Tobramycin/administration &amp; dosage/chemistry ; }, abstract = {Nowadays, the resistance of bacterial biofilms towards the available antibiotics is a severe problem. Therefore, many efforts were devoted to develop new formulations using nanotechnology. We have developed an inhalable microparticle formulation using spray-drying combining multiple drugs: an antibiotic (tobramycin, ciprofloxacin or azithromycin), N-acetylcysteine (NAC), and curcumin (Cur). The use of PLGA nanoparticles (NP) also allowed incorporating curcumin to facilitate spray drying and modify the release of some compounds. The aerosolizable microparticles formulations were characterized in terms of size, morphology, and aerodynamic properties. Biocompatibility when tested on macrophage-like cells was acceptable after 20 h exposure for concentrations up to at least 32 µg/mL. Antibacterial activity of free drugs versus drugs in the multiple drug formulations was evaluated on P. aeruginosa in the same range. When co-delivered the efficacy of tobramycin was enhanced compared to the free drug for the 1 µg/mL concentration. The combinations of azithromycin and ciprofloxacin with NAC and Cur did not show an improved antibacterial activity. Bacteria-triggered cytokine release was not inhibited by free antibiotics, except for TNF-α. In contrast, the application of NAC and the addition of curcumin-loaded PLGA NPs showed a higher potential to inhibit TNF-α, IL-8, and IL-1β release. Overall, the approach described here allows simultaneous delivery of antibacterial, mucolytic, and anti-inflammatory compounds in a single inhalable formulation and may therefore pave the way for a more efficient therapy of pulmonary infections.}, }
@article {pmid33218094, year = {2020}, author = {Černá, P and Mitchell, JL and Lodzinska, J and Cazzini, P and Varjonen, K and Gunn-Moore, DA}, title = {Systemic Mycobacterium kansasii Infection in Two Related Cats.}, journal = {Pathogens (Basel, Switzerland)}, volume = {9}, number = {11}, pages = {}, pmid = {33218094}, issn = {2076-0817}, abstract = {Mycobacterial infections are a major concern in veterinary medicine because of the difficulty achieving an etiological diagnosis, the challenges and concerns of treatment, and the potential zoonotic risk. Mycobacterium kansasii, a slow-growing non-tuberculous mycobacteria, causes disease in both humans and animals. While infections have been well described in humans, where it may be misdiagnosed as tuberculosis, there are fewer reports in animals. Only four cases have been reported in the domestic cat. This case report describes systemic M. kansasii infection in two sibling indoor-only cats that presented two and half years apart with cutaneous disease that was found to be associated with osteolytic and pulmonary pathology. Infection with M. kansasii was confirmed in both cats by polymerase chain reaction on fine-needle aspirate of a lumbosacral soft tissue mass in one cat and on a tissue punch biopsy of a skin lesion in the other; interferon-gamma release assay inferred M. avium-complex and M. tuberculosis-complex infection in the two cats, respectively. Both patients made a full recovery following antimicrobial therapy with rifampicin, azithromycin, and pradofloxacin (plus N-acetyl cysteine in cat 2). This report highlights successful treatment of systemic M. kansasii mycobacteriosis in the cat and the challenge of accurately diagnosing this infection.}, }
@article {pmid33217539, year = {2021}, author = {Zhang, C and Huang, C and Yang, P and Li, C and Li, M}, title = {Eldecalcitol induces apoptosis and autophagy in human osteosarcoma MG-63 cells by accumulating ROS to suppress the PI3K/Akt/mTOR signaling pathway.}, journal = {Cellular signalling}, volume = {78}, number = {}, pages = {109841}, doi = {10.1016/j.cellsig.2020.109841}, pmid = {33217539}, issn = {1873-3913}, mesh = {Apoptosis/*drug effects ; Autophagy/*drug effects ; Bone Neoplasms/*metabolism/pathology ; Cell Line, Tumor ; Humans ; Osteosarcoma/*metabolism/pathology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; TOR Serine-Threonine Kinases ; Vitamin D/*analogs &amp; derivatives/pharmacology ; }, abstract = {Eldecalcitol (ED-71) is a new type of vitamin D analog, and vitamin D has been reported to have therapeutic effects in infectious disease, autoimmune disease, and cancer. However, the anti-cancer effect of ED-71 remains unclear. The objective of this study was to explore the anti-cancer effect of ED-71 in human osteosarcoma cells and to identify the related mechanism. The CCK8 assay results showed that ED-71 inhibited MG-63 cell viability in dose and time dependent manners. Cloning and Transwell invasion assays showed that ED-71 inhibited clonal and invasion ability of MG-63 cells. Flow cytometry results showed ED-71 the G2/M cycle arrest rate, apoptosis, and intracellular ROS. Western blot was used to detect cleaved-caspase-3, Bax, Bcl-2, LC3-II/LC3-I, and P62 levels and the mTOR pathway. The increase of LC3-II and P62 indicated that ED-71 induced the formation of autophagosomes and inhibited autophagy flux. Furthermore, ED-71-induced apoptosis was weakened after adding 3-methyladenine and ED-71-induced early autophagy was weakened by caspase-3 inhibitor (Z-VAD-FMK), which indicated the two processes active each other in the presence of ED-71. Furthermore, N-acetylcysteine (NAC) pretreatment reversed the ED-71-treatment outcomes, including increased apoptosis and autophagy and inhibition of the PI3K/Akt/mTOR pathway. In conclusion, our results reveal that ED-71 induced G2/M arrest, apoptosis and autophagy in MG-63 cells by accumulating ROS to suppress the PI3K/Akt/mTOR signaling pathway.}, }
@article {pmid33217537, year = {2020}, author = {Papi, A and Avdeev, S and Calverley, PMA and Cordeiro, CR and Jesenak, M and Koblížek, V and Petkova, D and Rogliani, P and Tarraf, H and Tzanakis, N and Ulmeanu, R and Uzaslan, E and Adir, Y}, title = {Use of mucolytics in COPD: A Delphi consensus study.}, journal = {Respiratory medicine}, volume = {175}, number = {}, pages = {106190}, doi = {10.1016/j.rmed.2020.106190}, pmid = {33217537}, issn = {1532-3064}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Carbocysteine/administration &amp; dosage/adverse effects/*therapeutic use ; *Consensus ; Drug Therapy, Combination ; Expectorants/administration &amp; dosage/adverse effects/*therapeutic use ; Female ; Health Status ; Humans ; Internationality ; Male ; *Practice Guidelines as Topic ; Pulmonary Disease, Chronic Obstructive/*drug therapy ; Surveys and Questionnaires ; *Symptom Flare Up ; Thioglycolates/administration &amp; dosage/adverse effects/*therapeutic use ; Thiophenes/administration &amp; dosage/adverse effects/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: International guidelines recommend mucolytic agents as add-on therapy in selected patients with COPD because they may reduce exacerbations and improve health status. As the evidence varies among mucolytic agents, we used the Delphi method to assess consensus amongst an international panel of COPD experts on mucolytics use in COPD.<br><br>METHODS: 53 COPD experts from 12 countries were asked to complete an online questionnaire and rate their agreement with 15 statements using a 5-point scale. The mucolytic agents evaluated were carbocysteine, erdosteine and N-acetylcysteine (NAC). Data were collected anonymously and consensus presented using descriptive statistics.<br><br>RESULTS: The 47 respondents reached consensus on the statements. They agreed that regular treatment with mucolytic agents effectively reduces the frequency of exacerbations, reduces the duration of mild-to-moderate exacerbations, and can increase the time to first exacerbation and symptom-free time in COPD patients. Consensus was consistently highest for erdosteine. The experts agreed that all three mucolytics display antioxidant and anti-inflammatory activity. Erdosteine and NAC were thought to improve the efficacy of some classes of antibacterial drugs. All three mucolytics were considered effective for the short-term treatment of symptoms of acute exacerbations when added to other drugs. The panel agreed that approved doses of mucolytic agents have favorable side-effect profiles and can be recommended for regular use in patients with a bronchitic phenotype.<br><br>CONCLUSIONS: Consensus findings support the wider use of mucolytic agents as add-on therapy for COPD. However, the differences in pharmacological actions and clinical effectiveness must be considered when deciding which mucolytic to use.}, }
@article {pmid33216196, year = {2021}, author = {Haghpanah, S and Cohan, N and Bordbar, M and Bazrafshan, A and Karimi, M and Zareifar, S and Safaei, S and Aramesh, A and Moghadam, M and Fard, SAZ and Zekavat, OR}, title = {Effects of three months of treatment with vitamin E and N-acetyl cysteine on the oxidative balance in patients with transfusion-dependent β-thalassemia.}, journal = {Annals of hematology}, volume = {100}, number = {3}, pages = {635-644}, pmid = {33216196}, issn = {1432-0584}, support = {1398.457//Vice-Chancellor for Research, Shiraz University of Medical Sciences/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Adolescent ; Adult ; Antioxidants/administration &amp; dosage/analysis/metabolism ; Blood Transfusion ; Dietary Supplements ; Female ; Humans ; Iran ; Male ; Oxidants/blood ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Time Factors ; Vitamin E/*administration &amp; dosage/pharmacology ; Young Adult ; beta-Thalassemia/blood/*drug therapy/therapy ; }, abstract = {Oxidative stress is a major mechanism contributing to the progression of β-thalassemia. To assess the effect of vitamin E and N-acetyl cysteine (NAC) as antioxidant agents on total oxidative stress (TOS) status and total antioxidant capacity (TAC) in patients with transfusion-dependent β-thalassemia (TDT). In this open-label randomized controlled trial, from May to August 2019, 78 eligible patients with TDT over the age of 18 were enrolled. All patients were registered at the Thalassemia Clinic of Shiraz University of Medical Sciences in Southern Iran. Patients were randomly allocated to the NAC group (10 mg/kg/day, orally), vitamin E group (10 U/kg/day, orally), and control group. The duration of the study was 3 months. The mean age of the participants was 28.5 ± 5.1 (range: 18-41) years. At the end of the study, TOS significantly decreased only in the vitamin E group (mean difference (MD), 95% confidence interval (CI): 0.27 (0.03-0.50), P = 0.026). TAC significantly decreased in both supplemented groups at the 3rd month of treatment (NAC group: MD (95% CI): 0.11 (0.04-0.18), P = 0.002 and vitamin E group: 0.09 (0.01-0.16), P = 0.022 respectively). Hemoglobin did not significantly change at the end of the study in each group (P > 0.05). Mild transient adverse events occurred in 4 patients of the NAC group and 5 patients of the vitamin E group with no need to discontinue the treatment. Vitamin E can be a safe and effective supplement in improving oxidative stress in patients with TDT. Moreover, it seems that a longer duration of using antioxidant supplements needs to make clinical hematologic improvement in TDT patients.}, }
@article {pmid33213951, year = {2021}, author = {Inesta-Vaquera, F and Navasumrit, P and Henderson, CJ and Frangova, TG and Honda, T and Dinkova-Kostova, AT and Ruchirawat, M and Wolf, CR}, title = {Application of the in vivo oxidative stress reporter Hmox1 as mechanistic biomarker of arsenic toxicity.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {270}, number = {}, pages = {116053}, doi = {10.1016/j.envpol.2020.116053}, pmid = {33213951}, issn = {1873-6424}, support = {MR/R009848/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Antioxidants ; *Arsenic/toxicity ; *Arsenic Poisoning ; Biomarkers ; Heme Oxygenase-1/genetics ; Membrane Proteins ; Mice ; Oxidative Stress ; }, abstract = {Inorganic arsenic (iAs) is a naturally occurring metalloid present in drinking water and polluted air exposing millions of people globally. Epidemiological studies have linked iAs exposure to the development of numerous diseases including cognitive impairment, cardiovascular failure and cancer. Despite intense research, an effective therapy for chronic arsenicosis has yet to be developed. Laboratory studies have been of great benefit in establishing the pathways involved in iAs toxicity and providing insights into its mechanism of action. However, the in vivo analysis of arsenic toxicity mechanisms has been difficult by the lack of reliable in vivo biomarkers of iAs's effects. To address this issue we have applied the use of our recently developed stress reporter models to study iAs toxicity. The reporter mice Hmox1 (oxidative stress/inflammation; HOTT) and p21 (DNA damage) were exposed to iAs at acute and chronic, environmentally relevant, doses. We observed induction of the oxidative stress reporters in several cell types and tissues, which was largely dependent on the activation of transcription factor NRF2. We propose that our HOTT reporter model can be used as a surrogate biomarker of iAs-induced oxidative stress, and it constitutes a first-in-class platform to develop treatments aimed to counteract the role of oxidative stress in arsenicosis. Indeed, in a proof of concept experiment, the HOTT reporter mice were able to predict the therapeutic utility of the antioxidant N-acetyl cysteine in the prevention of iAs associated toxicity.}, }
@article {pmid33213456, year = {2020}, author = {Noël, A and Hossain, E and Perveen, Z and Zaman, H and Penn, AL}, title = {Sub-ohm vaping increases the levels of carbonyls, is cytotoxic, and alters gene expression in human bronchial epithelial cells exposed at the air-liquid interface.}, journal = {Respiratory research}, volume = {21}, number = {1}, pages = {305}, pmid = {33213456}, issn = {1465-993X}, support = {R03 ES029441/ES/NIEHS NIH HHS/United States ; GBI-BOR#013//Louisiana Governor's Biotechnology Initiative/ ; 1R03ES029441-01/ES/NIEHS NIH HHS/United States ; }, mesh = {Aerosols ; Antioxidants/pharmacology ; Bronchi/cytology/*drug effects/metabolism ; Cell Differentiation/drug effects/physiology ; Cell Line ; Cytotoxins/*toxicity ; *Electronic Nicotine Delivery Systems ; Flavoring Agents/*toxicity ; Gene Expression ; Humans ; Lung/cytology/drug effects/metabolism ; Oxidative Stress/drug effects/physiology ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/*drug effects/metabolism ; Vaping/*adverse effects ; }, abstract = {BACKGROUND: Exposure to electronic-cigarette (e-cig) aerosols induces potentially fatal e-cig or vaping-associated lung injury (EVALI). The cellular and molecular mechanisms underlying these effects, however, are unknown. We used an air-liquid interface (ALI) in vitro model to determine the influence of two design characteristics of third-generation tank-style e-cig devices-resistance and voltage-on (1) e-cig aerosol composition and (2) cellular toxicity.<br><br>METHODS: Human bronchial epithelial cells (H292) were exposed to either butter-flavored or cinnamon-flavored e-cig aerosols at the ALI in a Vitrocell exposure system connected to a third-generation e-cig device. Exposures were conducted following a standard vaping topography profile for 2&#xa0;h per day, for 1 or 3 consecutive days. 24&#xa0;h after ALI exposures cellular and molecular outcomes were assessed.<br><br>RESULTS: We found that butter-flavored e-cig aerosol produced under 'sub-ohm' conditions (<&#x2009;0.5 &#x3a9;) contains high levels of carbonyls (7-15&#xa0;&#x3bc;g/puff), including formaldehyde, acetaldehyde and acrolein. E-cig aerosol produced under regular vaping conditions (resistance&#x2009;>&#x2009;1 &#x3a9; and voltage&#x2009;>&#x2009;4.5&#xa0;V), contains lower carbonyl levels (<&#x2009;2&#xa0;&#x3bc;g/puff). We also found that the levels of carbonyls produced in the cinnamon-flavored e-cig aerosols were much lower than that of the butter-flavored aerosols. H292 cells exposed to butter-flavored or cinnamon-flavored e-cig aerosol at the ALI under 'sub-ohm' conditions for 1 or 3&#xa0;days displayed significant cytotoxicity, decreased tight junction integrity, increased reactive oxygen species production, and dysregulated gene expression related to biotransformation, inflammation and oxidative stress (OS). Additionally, the cinnamon-flavored e-cig aerosol induced pro-oxidant effects as evidenced by increases in 8-hydroxy-2-deoxyguanosine protein levels. Moreover, we confirmed the involvement of OS as a toxicity process for cinnamon-flavored e-cig aerosol by pre-treating the cells with N-acetyl cysteine (NAC), an antioxidant that prevented the cells from the OS-mediated damage induced by the e-cig aerosol.<br><br>CONCLUSION: The production of high levels of carbonyls may be flavor specific. Overall, inhaling e-cig aerosols produced under 'sub-ohm' conditions is detrimental to lung epithelial cells, potentially via mechanisms associated with OS. This information could help policymakers take the necessary steps to prevent the manufacturing of sub-ohm atomizers for e-cig devices.}, }
@article {pmid33213070, year = {2020}, author = {Aisa-Alvarez, A and Soto, ME and Guarner-Lans, V and Camarena-Alejo, G and Franco-Granillo, J and Martínez-Rodríguez, EA and Gamboa Ávila, R and Manzano Pech, L and Pérez-Torres, I}, title = {Usefulness of Antioxidants as Adjuvant Therapy for Septic Shock: A Randomized Clinical Trial.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {56}, number = {11}, pages = {}, pmid = {33213070}, issn = {1648-9144}, mesh = {*Antioxidants/therapeutic use ; Ascorbic Acid/therapeutic use ; Humans ; Lipid Peroxidation ; *Shock, Septic/drug therapy ; Vitamin E/therapeutic use ; }, abstract = {Background and objectives: Oxidative stress (OS) participates in the pathophysiology of septic shock, which leads to multiple organ failure (MOF), ischemia-reperfusion injury, and acute respiratory distress syndrome. Therefore, antioxidants have been proposed as therapy. Here, we evaluated the effect of antioxidant treatments in patients with septic shock with MOF and determined levels OS before and after treatment. This study was a randomized, controlled, triple-masked, and with parallel assignment clinical trial with a control group without treatment. Materials and Methods: It included 97 patients of either sex with septic shock. 5 treatments were used each in an independent group of 18 patients. Group 1 received vitamin C (Vit C), group 2 vitamin E (Vit E), group 3 n-acetylcysteine (NAC), group 4 melatonin (MT), and group 5 served as control. All antioxidants were administered orally or through a nasogastric tube for five days as an adjuvant to the standard therapy. Results: The results showed that all patients presented MOF due to sepsis upon admission and that the treatment decreased it (p = 0.007). The antioxidant treatment with NAC increased the total antioxidant capacity (p < 0.05). The patients that received Vit C had decreased levels of the nitrate and nitrite ratio (p < 0.01) and C-reactive protein levels (p = 0.04). Procalcitonin levels were reduced by Vit E (p = 0.04), NAC (p = 0.001), and MT (p = 0.04). Lipid-peroxidation was reduced in patients that received MT (p = 0.04). Conclusions: In conclusion, antioxidant therapy associated with standard therapy reduces MOF, OS, and inflammation in patients with septic shock.}, }
@article {pmid33212230, year = {2021}, author = {Yoon, N and Kim, S and Sung, HK and Dang, TQ and Jeon, JS and Sweeney, G}, title = {Use of 2-dimensional cell monolayers and 3-dimensional microvascular networks on microfluidic devices shows that iron increases transendothelial adiponectin flux via inducing ROS production.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1865}, number = {2}, pages = {129796}, doi = {10.1016/j.bbagen.2020.129796}, pmid = {33212230}, issn = {1872-8006}, mesh = {Adiponectin/*metabolism ; Capillary Permeability ; Cell Line ; Electric Impedance ; Endothelial Cells/cytology/*metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Iron/*metabolism ; Lab-On-A-Chip Devices ; Microvessels/cytology/*metabolism ; Permeability ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Iron excess is a risk factor for cardiovascular diseases and it is important to understand the effect of iron on vascular permeability, particularly for the transport of large metabolic hormones such as adiponectin.<br><br>METHODS: We used 2-dimensional monolayers of cultured human dermal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells (HUVEC) as well as 3-dimensional microvascular networks to measure transendothelial flux.<br><br>RESULTS: Iron supplementation reduced transendothelial electric resistance (TEER). Flux analysis indicated that under control conditions permeability of 70&#xa0;kDa dextran and oligomeric forms of adiponectin were restricted in comparison with a 3&#xa0;kDa dextran, however upon iron treatment permeability of the larger molecules was increased. The increased permeability and size-dependent trans-endothelial movement in response to iron was also observed in 3-dimensional microvascular networks. Mechanistically, the alteration in barrier functionality was associated with increased oxidative stress in response to iron since alterations in TEER and permeability were rescued when reactive oxygen species production was attenuated by pre-treatment with the antioxidant N-acetyl cysteine.].<br><br>CONCLUSIONS: Iron supplementation induced ROS production resulting in increased transendothelial permeability.<br><br>GENERAL SIGNIFICANCE: Altogether, this suggests that the oxidative stress associated with iron excess could play an important role in the regulation of endothelial functionality, controlling hormone action in peripheral tissues by regulating the first rate-limiting step controlling hormone access to target tissues.}, }
@article {pmid33212217, year = {2021}, author = {Martinez-Banaclocha, M}, title = {Proteomic Complexity in Parkinson's Disease: A Redox Signaling Perspective of the Pathophysiology and Progression.}, journal = {Neuroscience}, volume = {453}, number = {}, pages = {287-300}, doi = {10.1016/j.neuroscience.2020.11.006}, pmid = {33212217}, issn = {1873-7544}, mesh = {Genetic Predisposition to Disease ; Humans ; Mutation ; Oxidation-Reduction ; *Parkinson Disease/genetics ; Proteomics ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Parkinson's disease (PD) is a prevalent age-related neurodegenerative disorder that results in the progressive impairment of motor and cognitive functions. The majority of PD cases are sporadic, and only 5% of patients are associated with mutations in a few genes, which cause the early onset or familial PD. Environmental toxic substances and the individual genetic susceptibility play a role in sporadic cases, but despite significant efforts to treat and prevent the disease, the pathophysiological mechanisms leading to its onset and progress are not fully understood. In the last decade, genomic and proteomic studies have shown an increasing molecular complexity of sporadic PD, suggesting that a broad spectrum of biochemical pathways underlie its progression. Recent investigations and the literature review suggest the potential role of deregulation of the sensitive-cysteine proteome as a convergent pathogenic mechanism that may contribute to this complexity, opening new therapeutic opportunities.}, }
@article {pmid33208818, year = {2020}, author = {Pillay, Y and Nagiah, S and Phulukdaree, A and Krishnan, A and Chuturgoon, AA}, title = {Patulin suppresses α1-adrenergic receptor expression in HEK293 cells.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {20115}, pmid = {33208818}, issn = {2045-2322}, mesh = {AMP-Activated Protein Kinases/chemistry/metabolism ; Adrenergic alpha-1 Receptor Agonists/pharmacology ; Adrenergic alpha-1 Receptor Antagonists/*pharmacology ; Epinephrine/pharmacology ; Gene Expression Regulation/drug effects ; HEK293 Cells ; Humans ; MAP Kinase Signaling System/drug effects ; Metformin/pharmacology ; Molecular Docking Simulation ; Patulin/chemistry/metabolism/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Adrenergic, alpha-1/*genetics/metabolism ; }, abstract = {Patulin (PAT) is a common mycotoxin contaminant of apple products linked to impaired metabolic and kidney function. Adenosine monophosphate activated protein kinase (AMPK), abundantly expressed in the kidney, intercedes metabolic changes and renal injury. The alpha-1-adrenergic receptors (α1-AR) facilitate Epinephrine (Epi)-mediated AMPK activation, linking metabolism and kidney function. Preliminary molecular docking experiments examined potential interactions and AMPK-gamma subunit 3 (PRKAG3). The effect of PAT exposure (0.2-2.5 µM; 24 h) on the AMPK pathway and α1-AR was then investigated in HEK293 human kidney cells. AMPK agonist Epi determined direct effects on the α1-AR, metformin was used as an activator for AMPK, while buthionine sulphoximine (BSO) and N-acetyl cysteine (NAC) assessed GSH inhibition and supplementation respectively. ADRA1A and ADRA1D expression was determined by qPCR. α1-AR, ERK1/2/MAPK and PI3K/Akt protein expression was assessed using western blotting. PAT (1 µM) decreased α1-AR protein and mRNA and altered downstream signalling. This was consistent in cells stimulated with Epi and metformin. BSO potentiated the observed effect on α1-AR while NAC ameliorated these effects. Molecular docking studies performed on Human ADRA1A and PRKAG3 indicated direct interactions with PAT. This study is the first to show PAT modulates the AMPK pathway and α1-AR, supporting a mechanism of kidney injury.}, }
@article {pmid33206415, year = {2021}, author = {Chrétien, B and Fedrizzi, S and Lelong-Boulouard, V and Sassier, M and Alexandre, J and Dolladille, C}, title = {Could N-acetylcysteine improve the safety of clozapine?.}, journal = {Human psychopharmacology}, volume = {36}, number = {2}, pages = {e2769}, doi = {10.1002/hup.2769}, pmid = {33206415}, issn = {1099-1077}, mesh = {Acetylcysteine/therapeutic use ; *Antipsychotic Agents/adverse effects ; *Clozapine/adverse effects ; Humans ; *Schizophrenia/drug therapy ; Schizophrenia, Treatment-Resistant ; }, abstract = {Clozapine is an atypical antipsychotic indicated in patients with treatment-resistant schizophrenia which remains underused due to safety issues. Mechanisms behind these adverse effects are complex and not fully understood. They may involve immune-related mechanisms, direct toxic effects and oxidative stress. Clozapine-induced oxidative stress might indeed notably be involved in the onset of neutropenia, agranulocytosis, myocarditis, sialorrhea, and metabolic alterations. Therefore, the association of N-acetylcysteine (NAC), an easily accessible, low-cost and well tolerated antioxidant drug could be of interest in clozapine-treated patients to improve clozapine safety. Furthermore, according to recent studies NAC could help to improve schizophrenia symptoms. We believe that the use of NAC in the context of clozapine prescribing merits further study, as it could improve clozapine safety which may lead to a wider use and ultimately improve the healthcare of thousands of patients. NAC could also secondarily show positive knock-on effects for the patients by improving clinical symptoms of schizophrenia in synergy with clozapine, and by reducing substance abuse and thus by improving the patient's overall condition. However, given the rarity of clozapine-induced severe adverse effects, only a large volume of data (e.g., National adverse events monitoring) could assess the benefits of NAC on clozapine safety.}, }
@article {pmid33205650, year = {2020}, author = {Sun, J and Charron, CS and Liu, Z and Novotny, JA and Harrington, PB and Ross, SA and Seifried, HE and Chen, P}, title = {Study on Human Urinary Metabolic Profiles after Consumption of Kale and Daikon Radish using a High-resolution Mass Spectrometry-Based Non-targeted and Targeted Metabolomic Approach.}, journal = {Journal of agricultural and food chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.jafc.0c05184}, pmid = {33205650}, issn = {1520-5118}, abstract = {In the present study, urine samples were collected from healthy human volunteers to determine the metabolic fates of phenolic compounds and glucosinolates after a single meal of kale and daikon radish. The major glucosinolates and phenolic compounds in kale and daikon radish were measured. The urinary metabolome after feeding at different time periods was investigated. A targeted metabolite analysis method was developed based on the known metabolic pathways for glucosinolates and phenolic compounds. Using a targeted approach, a total of 18 metabolites were found in urine: 4 from phenolic compounds and 14 from glucosinolates. Among these metabolites, 4-methylsulfinyl-3-butenyl isothiocyanate, 4-methylsulfinyl-3-butenyl isothiocyanate-cysteine, and 4-methylsulfinyl-3-butenylglucosinolate-N-acetyl cysteine were reported for the first time in human urine. The combination of non-targeted and targeted metabolomic approaches can gain a full metabolite profile for human dietary intervention studies.}, }
@article {pmid33204320, year = {2020}, author = {Hu, J and Li, Y and Li, H and Shi, F and Xie, L and Zhao, L and Tang, M and Luo, X and Jia, W and Fan, J and Zhou, J and Gao, Q and Qiu, S and Wu, W and Zhang, X and Liao, W and Bode, AM and Cao, Y}, title = {Targeting Epstein-Barr virus oncoprotein LMP1-mediated high oxidative stress suppresses EBV lytic reactivation and sensitizes tumors to radiation therapy.}, journal = {Theranostics}, volume = {10}, number = {26}, pages = {11921-11937}, pmid = {33204320}, issn = {1838-7640}, mesh = {Acetylcysteine/administration &amp; dosage ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor/blood ; Biopsy ; Cell Line, Tumor ; Chemoradiotherapy/*methods ; DNA, Viral/blood ; Epstein-Barr Virus Infections/blood/mortality/*therapy/virology ; Female ; Follow-Up Studies ; Free Radical Scavengers/*administration &amp; dosage ; Glutathione Disulfide/blood/metabolism ; Herpesvirus 4, Human/genetics/isolation &amp; purification/pathogenicity ; Humans ; Latent Infection/blood/pathology/therapy/virology ; Male ; Middle Aged ; Nasopharyngeal Carcinoma/blood/mortality/*therapy/virology ; Nasopharyngeal Neoplasms/blood/mortality/*therapy/virology ; Nasopharynx/pathology/virology ; Oxidative Stress/drug effects ; Patient Selection ; Prognosis ; Progression-Free Survival ; Radiation Tolerance/drug effects ; Reactive Oxygen Species ; Viral Load ; Viral Matrix Proteins/metabolism ; Virus Activation/drug effects ; Xenograft Model Antitumor Assays ; Young Adult ; }, abstract = {Generating oxidative stress is a critical mechanism by which host cells defend against infection by pathogenic microorganisms. Radiation resistance is a critical problem in radiotherapy against cancer. Epstein-Barr virus (EBV) is a cancer-causing virus and its reactivation plays an important role in the development of EBV-related tumors. This study aimed to explore the inner relationship and regulatory mechanism among oxidative stress, EBV reactivation, and radioresistance and to identify new molecular subtyping models and treatment strategies to improve the therapeutic effects of radiotherapy. Methods: ROS, NADP[+]/NADPH, and GSSG/GSH were detected to evaluate the oxidative stress of cells. 8-OHdG is a reliable oxidative stress marker to evaluate the oxidative stress in patients. Its concentration in serum was detected using an ELISA method and in biopsies was detected using IHC. qPCR array was performed to evaluate the expression of essential oxidative stress genes. qPCR, Western blot, and IHC were used to measure the level of EBV reactivation in vitro and in vivo. A Rta-IgG ELISA kit and EBV DNA detection kit were used to analyze the reactivation of EBV in serum from NPC patients. NPC tumor tissue microarrays was used to investigate the prognostic role of oxidative stress and EBV reactivation. Radiation resistance was evaluated by a colony formation assay. Xenografts were treated with NAC, radiation, or a combination of NAC and radiation. EBV DNA load of tumor tissue was evaluated using an EBV DNA detection kit. Oxidative stress, EBV reactivation, and the apoptosis rate in tumor tissues were detected by using 8-OHdG, EAD, and TUNEL assays, respectively. Results: We found that EBV can induce high oxidative stress, which promotes its reactivation and thus leads to radioresistance. Basically, EBV caused NPC cells to undergo a process of 'Redox Resetting' to acquire a new redox status with higher levels of ROS accumulation and stronger antioxidant systems by increasing the expression of the ROS-producing enzyme, NOX2, and the cellular master antioxidant regulator, Nrf2. Also, EBV encoded driving protein LMP1 promotes EBV reactivation through production of ROS. Furthermore, high oxidative stress and EBV reactivation were positively associated with poor overall survival of patients following radiation therapy and were significant related to NPC patients' recurrence and clinical stage. By decreasing oxidative stress using an FDA approved antioxidant drug, NAC, sensitivity of tumors to radiation was increased. Additionally, 8-OHdG and EBV DNA could be dual prognostic markers for NPC patients. Conclusions: Oxidative stress mediates EBV reactivation and leads to radioresistance. Targeting oxidative stress can provide therapeutic benefits to cancer patients with radiation resistance. Clinically, we, for the first time, generated a molecular subtyping model for NPC relying on 8-OHdG and EBV DNA level. These dual markers could identify patients who are at a high risk of poor outcomes but who might benefit from the sequential therapy of reactive oxygen blockade followed by radiation therapy, which provides novel perspectives for the precise treatment of NPC.}, }
@article {pmid33204285, year = {2020}, author = {Wei, X and Zong, W and Gao, Y and Peng, S and Liu, K and Zheng, Y}, title = {Effects of the Traditional Chinese Medicine Tang Luo Ning on Intestinal Flora and Oxidative Stress in Diabetic Rats.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2020}, number = {}, pages = {3452625}, pmid = {33204285}, issn = {1741-427X}, abstract = {OBJECTIVE: To determine the effects of TLN on glycolipid metabolism, oxidative stress, and intestinal flora in diabetic rat.<br><br>MATERIALS AND METHODS: Thirty-five male Sprague-Dawley (SD) rats (180-200&#x2009;g) were divided into two groups. The normal group was fed a standard-chow diet, whereas, in the model group, diabetes was induced by intraperitoneal administration of streptozotocin (STZ) combined with a high-fat sucrose diet. Then, the model group was randomly allocated to four groups: DM (diabetes model) and TLNH (TLN high dose), TLNL (TLN low dose), and NAC (N-acetylcysteine). Rats in the TLNH, TLNL, and NAC groups were intragastrically administered TLN and NAC for 12 weeks. Subsequently, their weights, fasting glucose levels, serum lipids, serum insulin, serum ROS, and intestinal flora were determined.<br><br>RESULTS: The weight and intestinal flora abundance of the DM group were significantly lower than those of the normal group, whereas their total serum cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), serum reactive oxygen species (ROS), and serum insulin (INS) levels were significantly higher than those of the normal group. TC and LDL-C levels in the TLNL group and DM group were similar, whereas FBG, INS, and ROS levels in the TLNL group were obviously lower than those in the DM group. Compared with the DM group, there was a significant increase in intestinal flora abundance in the TLNL group. At the phylum level, the ratio of Firmicutes to Bacteroidetes (core microbiota) varied in all groups. However, in the DM group, Firmicutes abundance decreased, whereas that of Bacteroidetes increased. An opposite trend was observed in the TLN-treated groups.<br><br>CONCLUSIONS: TLN, which showed a dose-dependent therapeutic effect, can effectively decrease serum lipid, serum insulin, blood glucose, and serum ROS levels. It can also rebalance the ratio of Firmicutes to Bacteroidetes. Furthermore, the low-dose TLN treatment was most efficacious.}, }
@article {pmid33202749, year = {2020}, author = {Choi, HS and Kim, SL and Kim, JH and Ko, YC and Lee, DS}, title = {Plant Volatile, Phenylacetaldehyde Targets Breast Cancer Stem Cell by Induction of ROS and Regulation of Stat3 Signal.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {11}, pages = {}, pmid = {33202749}, issn = {2076-3921}, support = {NRF-2016R1A6A1A03012862 and NRF-2020R1A2C1006316//National Research Foundation of Korea/ ; }, abstract = {Cancer stem cells (CSCs) are undifferentiated cells that give rise to tumor and resistance to chemotherapy. This study reports that phenylacetaldehyde (PAA), a flower flavor, inhibits formation on breast CSCs. PAA showed anti-proliferation and increased apoptosis of breast cancer. PAA also reduced tumor growth in an in vivo mice model. PAA reduced the CD44[+]/CD24[-] and ALDH1-expressing cells, mammosphere formation, and CSC marker genes. PAA preferentially induced reactive oxygen species (ROS) production and combined treatment with PAA and N-acetyl cysteine (NAC) decreased inhibition of mammosphere formation. PAA reduced phosphorylation of nuclear Stat3. PAA inhibited Stat3 signaling through de-phosphorylation of Stat3 and reduced secretory IL-6. Our results suggest that the PAA-induced ROS deregulated Stat3/IL-6 pathway and PAA may be a potential agent targeting breast cancer and CSCs.}, }
@article {pmid33201834, year = {2020}, author = {Li, X and Zhang, H and Sun, F}, title = {CdSe/ZnS quantum dots exhibited nephrotoxicity through mediating oxidative damage and inflammatory response.}, journal = {Aging}, volume = {13}, number = {8}, pages = {12194-12206}, pmid = {33201834}, issn = {1945-4589}, mesh = {Animals ; Apoptosis/drug effects/immunology ; Cadmium Compounds/chemistry/*toxicity ; Cell Line ; Cell Survival/drug effects ; Kelch-Like ECH-Associated Protein 1/metabolism ; Kidney/cytology/*drug effects/immunology/pathology ; Mice ; Models, Animal ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects/immunology ; Quantum Dots/chemistry/*toxicity ; Rats ; Selenium Compounds/chemistry/*toxicity ; Signal Transduction/drug effects ; Sulfides/chemistry/*toxicity ; Toxicity Tests, Subacute ; Zinc Compounds/chemistry/*toxicity ; }, abstract = {OBJECTIVE: This study aimed to the evaluate the nephrotoxicity of CdSe/ZnS QDs in vitro and vivo, as well as investigate the underlying toxicity mechanisms.<br><br>RESULTS: In vitro experiments showed that compared with control cells, CdSe/ZnS QDs treatment significantly inhibited cell viability and promoted cell apoptosis in dose-dependent manner in NRK cells. Notably, CdSe/ZnS QDs treatment increased the contents of MDA and ROS, and decreased the activities of SOD, CAT and GSH-Px; however, the co-treatment of NAC and QDs relieved the oxidative damage of NRK cells. Moreover, in vivo experiments also revealed that CdSe/ZnS QDs treatment obviously increased kidney weight coefficient, damaged the kidney function, as well as induced inflammatory response and inhibited the activation of NRF2/Keap1 pathway in kidney tissues of mice.<br><br>CONCLUSIONS: CdSe/ZnS QDs exhibited obvious nephrotoxicity by mediating oxidative damage and inflammatory response in vitro and in vivo via NRF2/Keap1 pathway.<br><br>METHODS: The characterization of CdSe/ZnS QDs was analyzed by transmission electron microscope, emission spectrum scanning, and dynamic light scattering. Rat kidney cells (NRK) were exposed to different doses of CdSe/ZnS QDs with or without N-acetylcysteine (NAC, antioxidant). Then, cellular uptake of CdSe/ZnS QDs was detected, and in vitro cytotoxicity was evaluated by MTT assay and TUNEL assay.}, }
@article {pmid33201734, year = {2021}, author = {Khalil, SS and Aziz, JA and Ismail, KA and El-Malkey, NF}, title = {Comparative protective effects of N-acetylcysteine and melatonin against obesity-induced testicular dysfunction in rats.}, journal = {Canadian journal of physiology and pharmacology}, volume = {99}, number = {7}, pages = {708-719}, doi = {10.1139/cjpp-2020-0499}, pmid = {33201734}, issn = {1205-7541}, mesh = {*Acetylcysteine ; Animals ; Epididymis ; Male ; *Melatonin ; Oxidative Stress ; Rats ; *Testis ; }, abstract = {N-acetylcysteine (NAC) and melatonin were reported to exert protective effects on testicular tissues. Thus, this study aimed to determine which of these is more efficient against obesity-induced testicular dysfunction in albino rats. A total of 32 adult male rats (195 ± 10 g) were divided into four groups: control, obese rats fed a high-fat diet (HFD), HFD+NAC (150 mg/kg per day, i.p.) and HFD+melatonin (10 mg/kg per day, i.p.), for 5 weeks. Testes and epididymis were weighed. Lipid profile, pituitary-testicular hormones, tumor necrosis factor α (TNFα), epididymal sperm parameters, testicular oxidant-antioxidant system, testicular and the epididymal histopathology and immunohistochemical localization for androgen receptors (AR) and Bax reaction were analyzed. Administration of NAC or melatonin significantly improved the lipid parameters, gonadal hormones, TNFα level, sperm count and abnormal morphology, oxidant-antioxidant system and the absolute testicular and epididymal mass with an enhancement of testicular architecture, AR expression and apoptosis as compared with that in the obese group. Additionally, as compared with the NAC group, the melatonin group had significantly reduced body mass index, total cholesterol, triglyceride, and TNFα and increased testosterone, sperm count, motility, superoxide dismutase activity, mitigated histomorphometrical changes, Bax expression, and increased testicular AR expression. Therefore, melatonin was more efficient than NAC in affording fortification against HFD-induced testicular dysfunction.}, }
@article {pmid33198925, year = {2020}, author = {Bhardwaj, JK and Saraf, P}, title = {N-acetyl-l-cysteine mediated regulation of DNA fragmentation, an apoptotic event, against methoxychlor toxicity in the granulosa cells of ovarian antral follicles.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {858-860}, number = {}, pages = {503222}, doi = {10.1016/j.mrgentox.2020.503222}, pmid = {33198925}, issn = {1879-3592}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Comet Assay ; DNA Fragmentation/*drug effects ; Female ; Follicular Atresia/drug effects ; Free Radical Scavengers/pharmacology ; Goats ; Granulosa Cells/*drug effects ; Insecticides/toxicity ; Methoxychlor/*toxicity ; Ovarian Follicle/cytology ; Single-Cell Analysis/methods ; }, abstract = {Methoxychlor (MXC), an organo-chlorine insecticide, is a reproductive toxicant in females, causing apoptosis-mediated follicular atresia. To elucidate the potentials of Methoxychlor as a geno-toxicant, granulosa cells of healthy antral follicles, exposed to MXC and antioxidant, N-acetyl-l-cysteine, were studied by the terminal deoxynucleotidyltransferase-dUTP nick end-labelling and single-cell gel electrophoresis (comet) assays. MXC caused DNA fragmentation, as revealed by the increased incidence of dark brown condensed TUNEL positive cells in contrast with lightly brown TUNEL negative cells with maximum TUNEL positive cells were observed in 100 μg/mL MXC treated groups. Quantitatively, maximum geno-toxicity was exhibited at highest MXC treatment with percent tail DNA as 17.87 ± 0.85, 41.16 ± 3.94, and 47.73 ± 3.71 in comparison with control (0.65 ± 0.03, 2.91 ± 0.27, and 7.16 ± 1.39) after 24, 48 and 72 h exposure duration, respectively. MXC treated groups exhibited Type 1-Type 3 comets as compared to Type 0 comets in control groups. Supplementation of NAC led to significant (p < 0.05) decline in geno-toxicity in MXC treated groups with maximum amelioration observed at 5 and 10 mM. Consequently, increased DNA damage attributed to the granulosa cells apoptosis in response to Methoxychlor exposure was significantly combated by NAC supplementation, preventing the geno-toxicity induced cyto-toxicity in GCs.}, }
@article {pmid33198336, year = {2020}, author = {Wolfram, T and Schwarz, M and Reuß, M and Lossow, K and Ost, M and Klaus, S and Schwerdtle, T and Kipp, AP}, title = {N-Acetylcysteine as Modulator of the Essential Trace Elements Copper and Zinc.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {11}, pages = {}, pmid = {33198336}, issn = {2076-3921}, support = {FOR 2558 (KI 1590/3-1)//Deutsche Forschungsgemeinschaft/ ; }, abstract = {N-acetylcysteine (NAC) is a frequently prescribed drug and known for its metal chelating capability. However, to date it is not well characterized whether NAC intake affects the homeostasis of essential trace elements. As a precursor of glutathione (GSH), NAC also has the potential to modulate the cellular redox homeostasis. Thus, we aimed to analyze effects of acute and chronic NAC treatment on the homeostasis of copper (Cu) and zinc (Zn) and on the activity of the redox-sensitive transcription factor Nrf2. Cells were exposed to 1 mM NAC and were co-treated with 50 μM Cu or Zn. We showed that NAC treatment reduced the cellular concentration of Zn and Cu. In addition, NAC inhibited the Zn-induced Nrf2 activation and limited the concomitant upregulation of cellular GSH concentrations. In contrast, mice chronically received NAC via drinking water (1 g NAC/100 mL). Cu and Zn concentrations were decreased in liver and spleen. In the duodenum, NQO1, TXNRD, and SOD activities were upregulated by NAC. All of them can be induced by Nrf2, thus indicating a putative Nrf2 activation. Overall, NAC modulates the homeostasis of Cu and Zn both in vitro and in vivo and accordingly affects the cellular redox balance.}, }
@article {pmid33194693, year = {2020}, author = {Zhang, Y and Huang, Y and Yin, Y and Fan, Y and Sun, W and Zhao, X and Tucker, K and Staley, A and Paraghamian, S and Hawkins, G and Prabhu, V and Allen, JE and Zhou, C and Bae-Jump, V}, title = {ONC206, an Imipridone Derivative, Induces Cell Death Through Activation of the Integrated Stress Response in Serous Endometrial Cancer In Vitro.}, journal = {Frontiers in oncology}, volume = {10}, number = {}, pages = {577141}, pmid = {33194693}, issn = {2234-943X}, support = {R37 CA226969/CA/NCI NIH HHS/United States ; }, abstract = {ONC206 (Oncoceutics) is an imipiridone with nanomolar potency and analogue of ONC201, a selective dopamine receptor D2 (DRD2) antagonist currently being investigated in phase II clinical trials for serous endometrial cancer (SEC). This study investigated the anti-proliferative efficacy of ONC206 in SEC cell lines as well as its impact on cellular stress and adhesion/invasion. ONC206 inhibited cellular proliferation in a dose-dependent manner and was more potent than ONC201 in the ARK1 (IC50 = 0.33µM vs. IC50 = 1.59uM) and SPEC-2 (IC50 = 0.24uM vs. IC50 = 0.81uM) cell lines. Treatment with ONC206 resulted in induction of ROS production and reduction of mitochondrial membrane potential, accompanied by an increase in cleaved caspase-3 and caspase-9 activity (p < 0.01). ONC206 also significantly inhibited cellular adhesion and migration in both cell lines (p < 0.01). Pretreatment with the stress inhibitor N-acetylcysteine (NAC) significantly attenuated the efficacy of ONC206 on cell proliferation, ROS production and cellular invasion. ONC206 demonstrates nanomolar potency for the inhibition of proliferation in SEC cells. Specifically, ONC206 utilizes ISR activation as a significant pathway in the propagation of its anti-proliferative and anti-metastatic effects. Thus, ONC206 may be a promising agent in future SEC clinical trials as was its predecessor ONC201.}, }
@article {pmid33194315, year = {2020}, author = {Dillon, KM and Carrazzone, RJ and Wang, Y and Powell, CR and Matson, JB}, title = {Polymeric persulfide prodrugs: Mitigating oxidative stress through controlled delivery of reactive sulfur species.}, journal = {ACS macro letters}, volume = {9}, number = {4}, pages = {606-612}, pmid = {33194315}, issn = {2161-1653}, support = {R01 GM123508/GM/NIGMS NIH HHS/United States ; }, abstract = {Related biologically to the known gasotransmitter hydrogen sulfide (H2S), persulfides (R-SSH) have recently been recognized as native signaling compounds and redox regulators in their own right. Reported here is the synthesis, characterization, and in vitro evaluation of a small molecule persulfide donor and its polymeric counterpart, both of which release N-acetyl cysteine persulfide (NAC-SSH) in response to esterases. The donors, termed EDP-NAC and poly(EDP-NAC), underwent controlled decomposition in response to porcine liver esterase, resulting in pseudo-first-order release half-lives of 1.6 h ± 0.3 h and 36.0 h ± 0.6 h, respectively. In cell experiments, slow-releasing poly(EDP-NAC) rescued H9C2 cardiomyocytes more effectively than EDP-NAC when cells were treated with 5-fluorouricil (5-FU), which induces sustained production of ROS. Neither EDP-NAC nor poly(EDP-NAC) rescued MCF-7 breast cancer cells from 5-FU-induced oxidative stress, suggesting that polymeric persulfide donors could be used as adjuvants to reduce the deleterious cardiotoxic effects of many chemotherapeutics.}, }
@article {pmid33191885, year = {2021}, author = {Tsao, CF and Chang, YH and Shen, FC and Su, YJ and Lin, HY and Chang, CS and Lin, CY and Lian, WS and Chuang, JH and Lin, TK and Liou, CW and Wang, PW and Weng, SW}, title = {Legacy Effect of Antioxidant N-acetylcysteine in Cellular Senescence of Diet-induced Obesity Mice.}, journal = {Current molecular medicine}, volume = {21}, number = {6}, pages = {506-525}, doi = {10.2174/1566524020999201113101738}, pmid = {33191885}, issn = {1875-5666}, support = {CMRPG8H0201//Chang Gung Memorial Hospital/ ; 106-2314-B182A-157//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Acetylcysteine/*pharmacokinetics ; Animals ; Antioxidants/*pharmacology ; Cellular Senescence/*drug effects ; Diet, High-Fat/*adverse effects ; *Insulin Resistance ; Male ; Mice ; *Obesity/chemically induced/drug therapy/metabolism ; }, abstract = {BACKGROUND: Cellular senescence is a state of stable growth arrest triggered by mitogenic and metabolic stressors. Ageing and a high-fat diet (HFD) are proven inducers of senescence in various organs, presenting a challenge for ageing populations worldwide. Our previous study demonstrated that ROS scavenger N-acetylcysteine (NAC) can improve insulin resistance (IR) and chronic inflammation in diet-induced obesity mice, an effect better achieved through early intervention. We, herein, investigate whether NAC can improve cellular senescence in a diet-induced obesity mouse model, and whether a legacy effect is presented with early intervention.<br><br>MATERIALS AND METHODS: For a twelve-month treatment course, all C57B/L6 mice were fed a chow diet (CD), high-fat high-sucrose diet (HFD), CD+NAC[1-12] (NAC intervention 1st-12th month), HFD+NAC[1-12], and HFD+NAC[1-6] (NAC intervention 1st-6th month). Staticalanalysis was used to analyze the different markers of cellular senescence and inflammation.<br><br>RESULTS: Throughout the study, the HFD group exhibited significantly increased body weight (BW) and body fat, markers of senescence, decreased motor activity (MA) and impaired glucose tolerance. Compared to the HFD group, the HFD+NAC[1-12] group exhibited increased MA, decreased BW and body fat, improved glucose tolerance, and decreased senescence markers.The HFD+NAC[1-6] group showed similar effects to the HFD+NAC[1-12] group, despite discontinuing NAC for 6 months. Our study showed that NAC significantly increased MA in both HFD+NAC[1-12] and HFD+NAC[1-6] groups, and improved HFD-induced mitochondrial and intracellular ROS expression, DNA and protein oxidative damage, and adipose tissue inflammation.<br><br>CONCLUSION: Legacy effect was indeed presented in HFD-induced cellular senescence with NAC intervention, with possible mechanisms being persistently increased motor activity and anti-oxidative stress effects.}, }
@article {pmid33184429, year = {2020}, author = {Yang, J and Wang, L and Wu, MX}, title = {830 nm photobiomodulation therapy promotes engraftment of human umbilical cord blood-derived hematopoietic stem cells.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {19671}, pmid = {33184429}, issn = {2045-2322}, support = {HL141016-01/NH/NIH HHS/United States ; }, mesh = {Animals ; Fetal Blood/*cytology ; *Graft Survival ; *Hematopoietic Stem Cell Transplantation ; Humans ; Leukocyte Common Antigens ; *Low-Level Light Therapy ; Mice ; Mice, Inbred NOD ; Mice, SCID ; }, abstract = {Human umbilical cord blood (hUCB)-derived hematopoietic stem cells (HSCs) are an important source for HSCs in allogeneic HSC transplantation, but a limited number and a low efficacy of engraftment greatly restrict their clinical use. Here, we report the ability of photobiomodulation therapy (PBMT) to significantly enhance the engraftment efficacy of hUCB HSCs and progenitor cells (HSPCs). hUCB CD34[+] cells were illuminated at a fluence of 2 J/cm[2] with a near-infrared light (830 nm) transmitted by an array of light-emitting diodes (LED) prior to infusion of NOD/SCID-IL2Rγ[-/-] mice. The pre-treatment resulted in a threefold higher of the mean percentage of human CD45[+] cells in the periphery of the mice compared to sham-treated CD34[+] cells. The enhanced engraftment may result from a PBMT-mediated increase of intracellular reactive oxygen species (ROS) levels and Src protein phosphorylation in CD34[+] cells. The two events were causally related as suggested by the finding that elevation of ROS by hydrogen peroxide increased Src phosphorylation, while ROS reduction by N-acetyl cysteine partially reversed the phosphorylation. The investigation demonstrates that PBMT can promote engraftment of hUCB HPSCs, at least in part, via ROS-mediated Src signaling pathway. PBMT can be potentially a safe, convenient, and cost-effective modality to improve hematological reconstitution in patients.}, }
@article {pmid33183638, year = {2021}, author = {Li, S and Liang, N and Yan, P and Kawashima, Y and Sun, S}, title = {Inclusion complex based on N-acetyl-L-cysteine and arginine modified hydroxypropyl-β-cyclodextrin for oral insulin delivery.}, journal = {Carbohydrate polymers}, volume = {252}, number = {}, pages = {117202}, doi = {10.1016/j.carbpol.2020.117202}, pmid = {33183638}, issn = {1879-1344}, mesh = {2-Hydroxypropyl-beta-cyclodextrin/*chemistry ; Acetylcysteine/*chemistry ; Administration, Oral ; Animals ; Caco-2 Cells ; Diabetes Mellitus, Experimental/*drug therapy ; Drug Carriers/*chemistry ; Excipients/*chemistry ; Humans ; Hypoglycemic Agents/*administration &amp; dosage ; Insulin/*administration &amp; dosage ; Male ; Rats ; Rats, Wistar ; }, abstract = {Insulin is the most effective drug in the treatment of diabetes mellitus. At present, subcutaneous injection is still the common way for insulin delivery. However, oral delivery is considered as the most preferred way for its high patient compliance and the minimal invasiveness. In this study, a novel N-acetyl-L-cysteine and arginine modified hydroxypropyl-β-cyclodextrin (NAC-HP-β-CD-Arg) was successfully synthesized and characterized. The polymer was used as a carrier for oral delivery of insulin by forming NAC-HP-β-CD-Arg@insulin complex. Enzymatic degradation study indicated that the NAC-HP-β-CD-Arg could protect insulin from enzymolysis. Moreover, the polymer exhibited strong binding ability with mucin. The transportation efficiency of NAC-HP-β-CD-Arg@insulin across the Caco-2 cell monolayer was much greater than free insulin. The in vivo study demonstrated that the orally administered NAC-HP-β-CD-Arg@insulin exhibited an excellent and sustained hypoglycemic effect in diabetic rats. It can be concluded that the NAC-HP-β-CD-Arg is a potential carrier for oral delivery of insulin.}, }
@article {pmid33179647, year = {2021}, author = {Gomez-Aparicio, LS and Bernáldez-Sarabia, J and Camacho-Villegas, TA and Lugo-Fabres, PH and Díaz-Martínez, NE and Padilla-Camberos, E and Licea-Navarro, A and Castro-Ceseña, AB}, title = {Improvement of the wound healing properties of hydrogels with N-acetylcysteine through their modification with methacrylate-containing polymers.}, journal = {Biomaterials science}, volume = {9}, number = {3}, pages = {726-744}, doi = {10.1039/d0bm01479f}, pmid = {33179647}, issn = {2047-4849}, mesh = {*Acetylcysteine/pharmacology ; *Hydrogels ; Methacrylates ; Polymers ; Wound Healing ; }, abstract = {Hydrogels with antioxidant activity have shown to significantly improve the standard of care, because they promote efficient wound healing, i.e. regeneration. N-Acetylcysteine (NAC) is an antioxidant amino acid derivative that promotes complete tissue restoration. However, NAC has anticoagulant properties that may also hinder blood coagulation, which is crucial for hydrogels for wound healing applications. To take advantage of the regenerative activity of NAC while avoiding hampering the hemostasis stage during wound healing, we modified gelatin-NAC with the methacrylate-containing polymers 2-hydroxyethyl methacrylate (H) and poly(ethylene glycol) methyl ether methacrylate (P) to produce Gel-HP-NAC. These hydrogels clotted more blood and faster than Gel and Gel-NAC hydrogels, while maintaining fluid absorption properties adequate to promote wound healing. Similarly, there were more viable human skin fibroblasts after 10 days cultured in Gel-HP-NAC compared with Gel and Gel-NAC. A mouse full-thickness skin wound model demonstrated that Gel-HP-NAC hydrogels improved the wound healing process as compared to the untreated group as proved by the increased wound closure rates and re-epithelialization. Histology of the biopsied tissues indicated more organized collagen deposits on the wounds treated with either Gel-HP-NAC or Gel-NAC than untreated wounds. Our results show that modification of NAC-containing hydrogels through methacrylate-containing polymers improved their wound healing properties, including blood-clotting, and demonstrate the potential of Gel-HP-NAC hydrogels for wound treatment and tissue regeneration.}, }
@article {pmid33179364, year = {2021}, author = {Sukhonthamarn, K and Cho, J and Chisari, E and Goswami, K and Arnold, WV and Parvizi, J}, title = {N-acetylcysteine use as an adjuvant to bone cement to fight periprosthetic joint infections: A preliminary in vitro efficacy and biocompatibility study.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {39}, number = {2}, pages = {356-364}, doi = {10.1002/jor.24910}, pmid = {33179364}, issn = {1554-527X}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Antiviral Agents/pharmacology/*therapeutic use ; Arthritis, Infectious/*drug therapy ; Biofilms/*drug effects ; Bone Cements ; Humans ; Microbial Sensitivity Tests ; Polymethyl Methacrylate ; Prosthesis-Related Infections/*drug therapy ; Toxicity Tests ; }, abstract = {When antibiotic laden bone cement is used to manage periprosthetic joint infection (PJI), failure still occurs with its use in up to 30% of cases. Therefore, we designed an in vitro study to assess the bactericidal effect of N-acetylcysteine (NAC), an antibacterial adjuvant, in cement against planktonic and biofilm forms of common PJI pathogens. NAC (10%, 20%, 30%, 40%, and 50% w/v) added to polymethyl methacrylate (PMMA) and incubated in broth at 36°C. PMMA-alone and/or culture bacteria alone were used as a negative control. Aliquots of cement elution from each group were taken at 1 day and 1 week and then were investigated for antimicrobial efficacy against the planktonic-form and the biofilm-form of Staphylococcus aureus and Escherichia coli. The primary outcome was the residual colony-forming unit count. The cytotoxicity and mechanical properties of the NAC-PMMA cement-blocks were also assessed. NAC-PMMA efficacy against the planktonic bacteria was demonstrated at a minimum of 30% at Day 1 and a minimum of 20% at 1 week after (p < .001). NAC-PMMA cement was effective against biofilm at a minimum of 30% of NAC at 1 day and 1 week of cement immersion (p < .001). The PMMA alone group was identified as having the highest cytotoxicity (p < .001). NAC decreased the stiffness (p = .004) and maximum load breaking point of the cement (p = .029). NAC is an effective and biocompatible adjuvant to PMMA in terms of antibacterial activity against Staphylococcus aureus and Escherichia coli. The broad antibacterial spectrum of NAC, its low expense, and minimal cytotoxicity makes it an ideal agent for addition to PMMA cement.}, }
@article {pmid33178010, year = {2020}, author = {Kätzel, D and Wolff, AR and Bygrave, AM and Bannerman, DM}, title = {Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia.}, journal = {Frontiers in pharmacology}, volume = {11}, number = {}, pages = {486811}, pmid = {33178010}, issn = {1663-9812}, support = {098896/WT_/Wellcome Trust/United Kingdom ; }, abstract = {The development of current neuroleptics was largely aiming to decrease excessive dopaminergic signaling in the striatum. However, the notion that abnormal dopamine creates psychotic symptoms by causing an aberrant assignment of salience that drives maladaptive learning chronically during disease development suggests a therapeutic value of early interventions that correct salience-related neural processing. The mesolimbic dopaminergic output is modulated by several interconnected brain-wide circuits centrally involving the hippocampus and key relays like the ventral and associative striatum, ventral pallidum, amygdala, bed nucleus of the stria terminalis, nucleus reuniens, lateral and medial septum, prefrontal and cingulate cortex, among others. Unraveling the causal relationships between these circuits using modern neuroscience techniques holds promise for identifying novel cellular-and ultimately molecular-treatment targets for reducing transition to psychosis and symptoms of schizophrenia. Imaging studies in humans have implicated a hyperactivity of the hippocampus as a robust and early endophenotype in schizophrenia. Experiments in rodents, in turn, suggested that the activity of its output region-the ventral subiculum-may modulate dopamine release from ventral tegmental area (VTA) neurons in the ventral striatum. Even though these observations suggested a novel circuit-level target for anti-psychotic action, no therapy has yet been developed along this rationale. Recently evaluated treatment strategies-at least in part-target excess glutamatergic activity, e.g. N-acetyl-cysteine (NAC), levetiracetam, and mGluR2/3 modulators. We here review the evidence for the central implication of the hippocampus-VTA axis in schizophrenia-related pathology, discuss its symptom-related implications with a particular focus on aberrant assignment of salience, and evaluate some of its short-comings and prospects for drug discovery.}, }
@article {pmid33177895, year = {2020}, author = {Tafere, GG and Wondafrash, DZ and Demoz, FB}, title = {Repurposing of N-Acetylcysteine for the Treatment of Dengue Virus-Induced Acute Liver Failure.}, journal = {Hepatic medicine : evidence and research}, volume = {12}, number = {}, pages = {173-178}, pmid = {33177895}, issn = {1179-1535}, abstract = {The prevalence of dengue infection-induced acute liver damage is increasing from time to time. Since it has no specific antiviral treatment in the world, people in endemic areas suffer more from dengue disorders. Thus, there is a need for searching options for the treatment of dengue-induced acute liver failure. N-acetylcysteine, which is used for the treatment of nasal congestion disorder and paracetamol overdose toxicity, could be used as a definitive therapy for dengue virus-induced acute liver disease. Therefore, this review discusses the therapeutic use of N-acetylcysteine for dengue-induced acute liver disease. Various case reports and case series showed that patients received NAC recovered from their clinical status. Additionally, a preclinical study showed that N-acetylcysteine has anti-dengue virus activity. Thus, N-acetylcysteine could be used as a definitive therapy in dengue virus-induced hepatitis. This might encourage researchers to further investigate the importance of N-acetylcysteine for dengue virus-induced hepatitis.}, }
@article {pmid33177829, year = {2020}, author = {Shi, Z and Puyo, CA}, title = {N-Acetylcysteine to Combat COVID-19: An Evidence Review.}, journal = {Therapeutics and clinical risk management}, volume = {16}, number = {}, pages = {1047-1055}, pmid = {33177829}, issn = {1176-6336}, abstract = {The novel coronavirus disease (COVID-19) is caused by a virus (SARS-Cov-2) and is known for inducing multisystem organ dysfunction associated with significant morbidity and mortality. Current therapeutic strategies for COVID-19 have failed to effectively reduce mortality rate, especially for elderly patients. A newly developed vaccine against SARS-Cov-2 has been reported to induce the production of neutralizing antibodies in young volunteers. However, the vaccine has shown limited benefit in the elderly, suggesting an age-dependent immune response. As a result, exploring new applications of existing medications could potentially provide valuable treatments for COVID-19. N-acetylcysteine (NAC) has been used in clinical practice to treat critically ill septic patients, and more recently for COVID-19 patients. NAC has antioxidant, anti-inflammatory and immune-modulating characteristics that may prove beneficial in the treatment and prevention of SARS-Cov-2. This review offers a thorough analysis of NAC and discusses its potential use for treatment of COVID-19.}, }
@article {pmid33177587, year = {2020}, author = {Alharbi, Y and Kapur, A and Felder, M and Barroilhet, L and Pattnaik, BR and Patankar, MS}, title = {Oxidative stress induced by the anti-cancer agents, plumbagin, and atovaquone, inhibits ion transport through Na[+]/K[+]-ATPase.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {19585}, pmid = {33177587}, issn = {2045-2322}, support = {R01 CA238423/CA/NCI NIH HHS/United States ; P30 CA014520/CA/NCI NIH HHS/United States ; EY024995-BRP/NH/NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Atovaquone/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Inhibitors/pharmacology ; Female ; Humans ; Ion Transport/drug effects ; Mice ; Naphthoquinones/*pharmacology ; Ovarian Neoplasms/*drug therapy/metabolism/pathology ; Oxidative Stress/*drug effects/physiology ; Patch-Clamp Techniques ; Sodium-Potassium-Exchanging ATPase/*metabolism ; }, abstract = {Oxidative stress inhibits Na[+]/K[+]-ATPase (NKA), the ion channel that maintains membrane potential. Here, we investigate the role of oxidative stress-mediated by plumbagin and atovaquone in the inhibition of NKA activity. We confirm that plumbagin and atovaquone inhibit the proliferation of three human (OVCAR-3, SKOV-3, and TYKNu) and one mouse (ID8) ovarian cancer cell lines. The oxygen radical scavenger, N-acetylcysteine (NAC), attenuates the chemotoxicity of plumbagin and atovaquone. Whole-cell patch clamping demonstrates that plumbagin and atovaquone inhibit outward and the inward current flowing through NKA in SKOV-3 and OVCAR-3. Although both drugs decrease cellular ATP; providing exogenous ATP (5 mM) in the pipet solution used during patch clamping did not recover NKA activity in the plumbagin or atovaquone treated SKOV-3 and OVCAR-3 cells. However, pretreatment of the cells with NAC completely abrogated the NKA inhibitory activity of plumbagin and atovaquone. Exposure of the SKOV-3 cells to either drug significantly decreases the expression of NKA. We conclude that oxidative stress caused by plumbagin and atovaquone degrades NKA, resulting in the inability to maintain ion transport. Therefore, when evaluating compounds that induce oxidative stress, it is important to consider the contribution of NKA inhibition to their cytotoxic effects on tumor cells.}, }
@article {pmid33175655, year = {2021}, author = {Qiao, K and Liu, Q and Xia, Y and Zhang, S}, title = {Evaluation of a Small-Molecule Compound, N-Acetylcysteine, for the Management of Bacterial Spot of Tomato Caused by Copper-Resistant Xanthomonas perforans.}, journal = {Plant disease}, volume = {105}, number = {1}, pages = {108-113}, doi = {10.1094/PDIS-05-20-0928-RE}, pmid = {33175655}, issn = {0191-2917}, mesh = {Acetylcysteine/pharmacology ; Copper/pharmacology ; Florida ; *Solanum lycopersicum ; Plant Diseases ; *Xanthomonas ; Xylella ; }, abstract = {Bacterial spot caused by Xanthomonas spp. is one of the major diseases in tomato. Xanthomonas perforans is the main pathogen of bacterial spot on tomato in Florida. Currently, application of copper fungicides is the primary measure used to manage this disease. However, the development of copper resistance in X. perforans and accumulation of copper in the environment are major concerns for excessive use of copper-based products in agriculture. Due to its antibacterial properties and low environmental impact, N-acetylcysteine (NAC), a small molecule commonly used in medicine for human bacterial diseases, has been studied in agriculture for the control of plant bacterial pathogens, including X. citri and Xylella fastidiosa. This study evaluated the effect of NAC alone and in combination with copper on a copper-resistant X. perforans strain in vitro and its ability to control bacterial spot of tomato under greenhouse and field conditions. In vitro, the minimum inhibitory concentration of NAC against the X. perforans strain was 2,048 mg liter[-1]. NAC increased sensitivity of the copper-resistant X. perforans to copper in vitro when application of NAC was followed by copper application after 6 h. In greenhouse assays, NAC applied alone or in combination with copper significantly (P < 0.05) reduced the disease severity of bacterial spot on tomato compared with the untreated control. NAC at 100 mg liter[-1] + copper at 300 mg liter[-1] consistently exhibited synergistic effects against bacterial spot. In the field trials, NAC at 1,000 mg liter[-1] + copper at 150 mg liter[-1] significantly reduced disease severity compared with the untreated control. Results from this study demonstrated that NAC significantly reduced the disease severity of bacterial spot of tomato and enhanced the efficacy of copper against copper-resistant X. perforans, indicating that NAC could be applied for the effective management of bacterial spot of tomato.}, }
@article {pmid33167060, year = {2021}, author = {Ghafarizadeh, A and Malmir, M and Naderi Noreini, S and Faraji, T}, title = {Antioxidant effects of N-acetylcysteine on the male reproductive system: A systematic review.}, journal = {Andrologia}, volume = {53}, number = {1}, pages = {e13898}, doi = {10.1111/and.13898}, pmid = {33167060}, issn = {1439-0272}, mesh = {*Acetylcysteine/pharmacology ; *Antioxidants/pharmacology ; Genitalia, Male ; Humans ; Kidney ; Male ; Spermatogenesis ; }, abstract = {This study aimed to evaluate the effect of N-acetyl cysteine on the male reproductive system and consensus and classification of data found from previous studies. It is undeniable that N-acetyl cysteine as a powerful antioxidant compound can medicate many diseases such as cardiovascular, kidney, liver and reproductive system disorders. With the increasing environmental pollution that has a direct adverse effect on male fertility, the use of this compound is able to positively function on human fertility health. In this study, we have been collected the main data of scientific articles (1994-2020) about N-acetyl cysteine effects. By searching in the scientific databases of PubMed, Google Scholar, Science Direct, Wiley and Web of Science, related articles were extracted. As a result, all observations have confirmed that N-acetyl cysteine can improve and normalise the spermatogenesis in the male reproduction system.}, }
@article {pmid33164812, year = {2021}, author = {Dilly, AK and Honick, BD and Frederick, R and Elapavaluru, A and Velankar, S and Makala, H and Hitchens, TK and Foley, LM and Guo, J and Beumer, JH and Rigatti, LH and Lee, YJ and Bartlett, DL and Choudry, HA}, title = {Improved chemosensitivity following mucolytic therapy in patient-derived models of mucinous appendix cancer.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {229}, number = {}, pages = {100-114}, pmid = {33164812}, issn = {1878-1810}, support = {P30 CA047904/CA/NCI NIH HHS/United States ; R13 EB033695/EB/NIBIB NIH HHS/United States ; R21 CA241004/CA/NCI NIH HHS/United States ; R50 CA211241/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Adenocarcinoma, Mucinous/*drug therapy/pathology ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Appendiceal Neoplasms/*drug therapy/pathology ; Bromelains/administration &amp; dosage/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Humans ; Mice, Nude ; Mucus/*drug effects ; Peritoneal Neoplasms/*drug therapy/pathology ; Rats, Nude ; Tissue Culture Techniques/methods ; Xenograft Model Antitumor Assays ; Mice ; Rats ; }, abstract = {Abundant intraperitoneal (IP) accumulation of extracellular mucus in patients with appendiceal mucinous carcinoma peritonei (MCP) causes compressive organ dysfunction and prevents delivery of chemotherapeutic drugs to cancer cells. We hypothesized that reducing extracellular mucus would decrease tumor-related symptoms and improve chemotherapeutic effect in patient-derived models of MCP. Mucolysis was achieved using a combination of bromelain (BRO) and N-acetylcysteine (NAC). Ex vivo experiments of mucolysis and chemotherapeutic drug delivery/effect were conducted with MCP and non-MCP tissue explants. In vivo experiments were performed in mouse and rat patient-derived xenograft (PDX) models of early and late (advanced) MCP. MCP tumor explants were less chemosensitive than non-MCP explants. Chronic IP administration of BRO + NAC in a mouse PDX model of early MCP and a rat PDX model of late (advanced) MCP converted solid mucinous tumors into mucinous ascites (mucolysis) that could be drained via a percutaneous catheter (rat model only), significantly reduced solid mucinous tumor growth and improved the efficacy of chemotherapeutic drugs. Combination of BRO + NAC efficiently lyses extracellular mucus in clinically relevant models of MCP. Conversion of solid mucinous tumors into mucinous ascites decreases tumor bulk and allows for minimally invasive drainage of liquified tumors. Lysis of extracellular mucus removes the protective mucinous coating surrounding cancer cells and improves chemotherapeutic drug delivery/efficacy in cancer cells. Our data provide a preclinical rationale for the clinical evaluation of BRO + NAC as a therapeutic strategy for MCP.}, }
@article {pmid33163142, year = {2020}, author = {Lu, B and Zhu, Z and Sheng, L and Li, Y and Yang, Y and Chen, Y and Xue, D and Zhou, Y and Cai, W and Chen, C and Wei, C and Xu, D and Yan, M and Lin, S and Yan, G and Yin, W}, title = {SMARCB1 Promotes Ubiquitination and Degradation of NR4A3 via Direct Interaction Driven by ROS in Vascular Endothelial Cell Injury.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {2048210}, pmid = {33163142}, issn = {1942-0994}, mesh = {Animals ; DNA-Binding Proteins/*metabolism ; Endothelium, Vascular/*injuries/metabolism/pathology ; Human Umbilical Vein Endothelial Cells/*metabolism/pathology ; Humans ; Hypoxia/*metabolism ; Lung/*metabolism/pathology ; Macaca fascicularis ; *Proteolysis ; *Reactive Oxygen Species ; Receptors, Steroid/*metabolism ; Receptors, Thyroid Hormone/*metabolism ; SMARCB1 Protein/*metabolism ; *Ubiquitination ; }, abstract = {Nuclear receptor subfamily 4 group A member 3 (NR4A3) protects the vascular endothelial cell (VEC) against hypoxia stress, whose expression is primarily reported to be governed at a transcriptional level. However, the regulation of NR4A3 in the protein level is largely unknown. Here, we report that NR4A3 protein abundance is decreased immensely in VEC injury induced by reoxygenation after oxygen-glucose deprivation (OGD-R), which is significantly blocked by the administration of the antioxidative steroid TRIOL. Moreover, the notable improvement of NR4A3 and the alleviation of pulmonary endothelial barrier hyperpermeability induced by acute hypobaric hypoxia in cynomolgus monkeys are also observed after TRIOL administration. The overproduction of reactive oxygen species (ROS) decreases NR4A3 protein abundance in VEC under OGD-R condition, which is reversed by TRIOL and N-acetylcysteine (NAC). TRIOL dose-dependently increases the NR4A3 protein level by inhibiting ubiquitination and ubiquitin proteasome system- (UPS-) mediated degradation rather than promoting its transcription. Using yeast two-hybrid screening, we further identify the interaction between NR4A3 and SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and the DNA-binding domain of NR4A3 is required for this interaction. Knockdown of SMARCB1 reduces ubiquitination and degradation of NR4A3, suggesting the proubiquitylation effect of this interaction which is enhanced by ROS in VEC injury induced by OGD-R. In summary, our study here for the first time reveals a posttranslational regulation in SMARCB1-mediated NR4A3 protein degradation which is driven by ROS, providing further understanding of the impaired regulation of NR4A3-mediated prosurvival pathways under pathological condition in VEC.}, }
@article {pmid33162896, year = {2020}, author = {Ding, J and Yu, M and Jiang, J and Luo, Y and Zhang, Q and Wang, S and Yang, F and Wang, A and Wang, L and Zhuang, M and Wu, S and Zhang, Q and Xia, Y and Lu, D}, title = {Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT1R Nox/ROS/PP2A Pathway.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {566410}, pmid = {33162896}, issn = {1664-042X}, abstract = {Increasing evidences suggest that angiotensin (Ang) II participates in the pathogenesis of endothelial dysfunction (ED) through multiple signaling pathways, including angiotensin type 1 receptor (AT1R) mediated NADPH oxidase (Nox)/reactive oxygen species (ROS) signal transduction. However, the detailed mechanism is not completely understood. In this study, we reported that AngII/AT1R-mediated activated protein phosphatase 2A (PP2A) downregulated endothelial nitric oxide synthase (eNOS) phosphorylation via Nox/ROS pathway. AngII treatment reduced the levels of phosphorylation of eNOS Ser1177 and nitric oxide (NO) content along with phosphorylation of PP2Ac (PP2A catalytic subunit) Tyr307, meanwhile increased the PP2A activity and ROS production in human umbilical vein endothelial cells (HUVECs). These changes could be impeded by AT1R antagonist candesartan (CAN). The pretreatment of 10[-8] M PP2A inhibitor okadaic acid (OA) reversed the levels of eNOS Ser1177 and NO content. Similar effects of AngII on PP2A and eNOS were also observed in the mesenteric arteries of Sprague-Dawley rats subjected to AngII infusion via osmotic minipumps for 2 weeks. We found that the PP2A activity was increased, but the levels of PP2Ac Tyr307 and eNOS Ser1177 as well as NO content were decreased in the mesenteric arteries. The pretreatments of antioxidant N-acetylcysteine (NAC) and apocynin (APO) abolished the drop of the levels of PP2Ac Tyr307 and eNOS Ser1177 induced by AngII in HUVECs. The knockdown of p22phox by small interfering RNA (siRNA) gave rise to decrement of ROS production and increment of the levels of PP2Ac Tyr307 and eNOS Ser1177. These results indicated that AngII/AT1R pathway activated PP2A by downregulating its catalytic subunit Tyr307 phosphorylation, which relies on the Nox activation and ROS production. In summary, our findings indicate that AngII downregulates PP2A catalytic subunit Tyr307 phosphorylation to activate PP2A via AT1R-mediated Nox/ROS signaling pathway. The activated PP2A further decreases levels of eNOS Ser1177 phosphorylation and NO content leading to endothelial dysfunction.}, }
@article {pmid33161477, year = {2021}, author = {Godoy, JR and Pittrich, S and Slavic, S and Lillig, CH and Hanschmann, EM and Erben, RG}, title = {Thioredoxin 1 is upregulated in the bone and bone marrow following experimental myocardial infarction: evidence for a remote organ response.}, journal = {Histochemistry and cell biology}, volume = {155}, number = {1}, pages = {89-99}, pmid = {33161477}, issn = {1432-119X}, mesh = {Animals ; Bone Marrow/*metabolism/pathology ; Bone and Bones/*metabolism/pathology ; Male ; Myocardial Infarction/*metabolism/pathology ; Rats ; Rats, Inbred F344 ; Thioredoxins/analysis/*metabolism ; *Up-Regulation ; }, abstract = {Ischemia and reperfusion events, such as myocardial infarction (MI), are reported to induce remote organ damage severely compromising patient outcomes. Tissue survival and functional restoration relies on the activation of endogenous redox regulatory systems such as the oxidoreductases of the thioredoxin (Trx) family. Trxs and peroxiredoxins (Prxs) are essential for the redox regulation of protein thiol groups and for the reduction of hydrogen peroxide, respectively. Here, we determined whether experimental MI induces changes in Trxs and Prxs in the heart as well as in secondary organs. Levels and localization of Trx1, TrxR1, Trx2, Prx1, and Prx2 were analyzed in the femur, vertebrae, and kidneys of rats following MI or sham surgery. Trx1 levels were significantly increased in the heart (P = 0.0017) and femur (P < 0.0001) of MI animals. In the femur and lumbar vertebrae, Trx1 upregulation was detected in bone-lining cells, osteoblasts, megakaryocytes, and other hematopoietic cells. Serum levels of Trx1 increased significantly 2 days after MI compared to sham animals (P = 0.0085). Differential regulation of Trx1 in the bone was also detected by immunohistochemistry 1 month after MI. N-Acetyl-cysteine treatment over a period of 1 month induced a significant reduction of Trx1 levels in the bone of MI rats compared to sham and to MI vehicle. This study provides first evidence that MI induces remote organ upregulation of the redox protein Trx1 in the bone, as a response to ischemia-reperfusion injury in the heart.}, }
@article {pmid33161305, year = {2021}, author = {Xu, J and Wang, L and Zhang, L and Zheng, F and Wang, F and Leng, J and Wang, K and Héroux, P and Shen, HM and Wu, Y and Xia, D}, title = {Mono-2-ethylhexyl phthalate drives progression of PINK1-parkin-mediated mitophagy via increasing mitochondrial ROS to exacerbate cytotoxicity.}, journal = {Redox biology}, volume = {38}, number = {}, pages = {101776}, pmid = {33161305}, issn = {2213-2317}, mesh = {Diethylhexyl Phthalate/analogs &amp; derivatives ; Humans ; *Mitochondria ; *Mitophagy ; Phthalic Acids ; *Protein Kinases/genetics ; Reactive Oxygen Species ; *Ubiquitin-Protein Ligases/genetics ; }, abstract = {Phthalate ester plasticizers are used to improve the plasticity and strength of plastics. One of the most widely used and studied, di-2-ethylhexyl phthalate (DEHP), has been labeled as an endocrine disruptor. The major and toxic metabolic derivative of DEHP, mono-2-ethylhexyl phthalate (MEHP), is capable of interfering with mitochondrial function, but its mechanism of action on mitophagy remains elusive. Here, we report that MEHP exacerbates cytotoxicity by amplifying the PINK1-Parkin-mediated mitophagy pathway. First, MEHP exacerbated mitochondrial damage induced by low-dose CCCP via increased reactive oxygen species (ROS) production, decreased mitochondrial membrane potential (MMP), and enhanced fragmentation in mitochondria. Second, co-exposure to MEHP and CCCP ("MEHP-CCCP") induced robust mitophagy. Mechanistically, MEHP-CCCP stabilized PINK1, increased the level of phosphorylated ubiquitin (pSer 65-Ub), and led to Parkin mitochondrial translocation and activation. Third, MEHP-CCCP synergistically caused more cell death, while inhibition of mitophagy, either through chemical or gene silencing, reduced cell death. Finally and importantly, co-treatment with N-acetyl cysteine (NAC) completely counteracted the effects of MEHP-CCCP, suggesting that mitochondrial ROS played a vital role in this process. Our results link mitophagy and MEHP cytotoxicity, providing an insight into the potential roles of endocrine disrupting chemicals (EDCs) in human diseases such as Parkinson's disease.}, }
@article {pmid33157513, year = {2021}, author = {Pi, S and Nie, G and Wei, Z and Yang, F and Wang, C and Xing, C and Hu, G and Zhang, C}, title = {Inhibition of ROS/NLRP3/Caspase-1 mediated pyroptosis alleviates excess molybdenum-induced apoptosis in duck renal tubular epithelial cells.}, journal = {Ecotoxicology and environmental safety}, volume = {208}, number = {}, pages = {111528}, doi = {10.1016/j.ecoenv.2020.111528}, pmid = {33157513}, issn = {1090-2414}, mesh = {Acetylcysteine/metabolism ; Animals ; Apoptosis ; Caspase 1/*metabolism ; Ducks/metabolism/physiology ; Epithelial Cells/metabolism ; Hazardous Substances/*toxicity ; Humans ; Interleukin-1beta ; Molybdenum/*toxicity ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pyroptosis/*physiology ; Reactive Oxygen Species/*metabolism ; }, abstract = {OBJECTIVE: Excess molybdenum (Mo) is harmful to the body, and the kidney is the vital target organ for Mo exposure. This study focused on the impacts of excess Mo on pyroptosis and the relationship between pyroptosis and apoptosis in kidney.<br><br>METHODS: The duck renal tubular epithelial cells were treated with (NH4)6Mo7O24&#xb7;4H2O (0, 480, 720 and 960&#xa0;&#x3bc;M Mo), N-acetyl-L-cysteine (NAC) (100&#xa0;&#x3bc;M), Z-YVAD-fluoromethylketone (YVAD) (10&#xa0;&#x3bc;M) and the combination of Mo and NAC or YVAD for 12&#xa0;h. The LDH release and IL-1&#x3b2;, IL-18 contents of cell supernatant were detected by LDH and ELISA kits. The MMP and ROS level were measured using MMP and ROS kits by flow cytometry. The apoptotic rate of cell was detected by AO/EB counterstaining. Pyroptosis and apoptosis-related factors mRNA and protein levels were assayed by real-time qPCR and western blot, respectively.<br><br>RESULTS: Excessive Mo markedly increased LDH, IL-18, IL-1&#x3b2; releases and induced overproduction of ROS, pyroptosis-related factors mRNA and protein levels. NAC and YVAD dramatically decreased pyroptosis induced by Mo. Simultaneously, YVAD significantly changed apoptosis-related factors mRNA and protein levels, and reduced cell apoptotic rate.<br><br>CONCLUSION: Excessive Mo exposure can induce pyroptosis by the ROS/NLRP3/Caspase-1 pathway in duck renal tubular epithelial cells, and restraining pyroptosis of Caspase-1 dependence might weaken excess Mo-induced apoptosis. The study provides theoretical basis for excess Mo exposure nephrotoxic researches on waterfowl and the interplay between pyroptosis and apoptosis highlights a new sight into the mechanism of Mo-induced nephrotoxicity.}, }
@article {pmid33155636, year = {2020}, author = {Kam, MK and Lee, DG and Kim, B and Huh, JW and Lee, HJ and Park, YH and Lee, DS}, title = {Amyloid-beta oligomers induce Parkin-mediated mitophagy by reducing Miro1.}, journal = {The Biochemical journal}, volume = {477}, number = {23}, pages = {4581-4597}, doi = {10.1042/BCJ20200488}, pmid = {33155636}, issn = {1470-8728}, mesh = {Alzheimer Disease/genetics/*metabolism ; Amyloid beta-Peptides/genetics/*metabolism ; Animals ; Cell Line ; Hippocampus/*metabolism ; Humans ; Mice ; Mice, Transgenic ; Microtubule-Associated Proteins/genetics/metabolism ; *Mitophagy ; Neurons/*metabolism ; Ubiquitin-Protein Ligases/genetics/*metabolism ; rho GTP-Binding Proteins/genetics/*metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease associated with the accumulation of amyloid-beta oligomers (AβO). Recent studies have demonstrated that mitochondria-specific autophagy (mitophagy) contributes to mitochondrial quality control by selectively eliminating the dysfunctional mitochondria. Mitochondria motility, which is regulated by Miro1, is also associated with neuronal cell functions. However, the role played by Miro1 in the mitophagy mechanism, especially relative to AβO and neurodegenerative disorders, remains unknown. In this study, AβO induced mitochondrial dysfunction, enhanced Parkin-mediated mitophagy, and reduced mitochondrial quantities in hippocampal neuronal cells (HT-22 cells). We demonstrated that AβO-induced mitochondrial fragmentation could be rescued to the elongated mitochondrial form and that mitophagy could be mitigated by the stable overexpression of Miro1 or by pretreatment with N-acetylcysteine (NAC)-a reactive oxygen species (ROS) scavenger-as assessed by immunocytochemistry. Moreover, using time-lapse imaging, under live cell-conditions, we verified that mitochondrial motility was rescued by the Miro1 overexpression. Finally, in hippocampus from amyloid precursor protein (APP)/presenilin 1 (PS1)/Tau triple-transgenic mice, we noted that the co-localization between mitochondria and LC3B puncta was increased. Taken together, these results indicated that up-regulated ROS, induced by AβO, increased the degree of mitophagy and decreased the Miro1 expression levels. In contrast, the Miro1 overexpression ameliorated AβO-mediated mitophagy and increased the mitochondrial motility. In AD model mice, AβO induced mitophagy in the hippocampus. Thus, our results would improve our understanding of the role of mitophagy in AD toward facilitating the development of novel therapeutic agents for the treatment of AβO-mediated diseases.}, }
@article {pmid33154380, year = {2020}, author = {Boz, Z and Hu, M and Yu, Y and Huang, XF}, title = {N-acetylcysteine prevents olanzapine-induced oxidative stress in mHypoA-59 hypothalamic neurons.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {19185}, pmid = {33154380}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Antipsychotic Agents/*pharmacology ; Autophagy/drug effects ; Cell Line ; Cell Survival/drug effects ; Hypothalamus/*drug effects/metabolism ; Mice ; Mitochondria/metabolism ; Mitophagy/drug effects ; Neurons/*drug effects/metabolism ; Olanzapine/*pharmacology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain tissue volume loss in rodent and primate studies; however, the underlying mechanism remains unknown. Abnormal autophagy and oxidative stress have been implicated to have a role in AP-induced neurodegeneration, while N-acetylcysteine (NAC) is a potent antioxidant, shown to be beneficial in the treatment of schizophrenia. Here, we investigate the role of olanzapine and NAC on cell viability, oxidative stress, mitochondrial mass and mitophagy in hypothalamic cells. Firstly, cell viability was assessed in mHypoA-59 and mHypoA NPY/GFP cells using an MTS assay and flow cytometric analyses. Olanzapine treated mHypoA-59 cells were then assessed for mitophagy markers and oxidative stress; including quantification of lysosomes, autophagosomes, LC3B-II, p62, superoxide anion (O2[-]) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O2[-], mitochondrial mass and LC3B-II. We found that olanzapine significantly impacted cell viability in mHypoA-59 hypothalamic cells in a dose and time-dependent manner. Olanzapine inhibited mitophagy, instigated oxidative stress and prompted mitochondrial abnormalities. NAC was able to mitigate olanzapine-induced effects. These findings suggest that high doses of olanzapine may cause neurotoxicity of hypothalamic neurons via increased production of reactive oxygen species (ROS), mitochondrial damage and mitophagy inhibition. This could in part explain data suggesting that APs may reduce brain volume.}, }
@article {pmid33153000, year = {2020}, author = {Wei, S and Isagawa, T and Eguchi, M and Sato, D and Tsukano, H and Miyata, K and Oike, Y and Takeda, N and Ikeda, S and Kawano, H and Maemura, K}, title = {Febuxostat, a Xanthine Oxidase Inhibitor, Decreased Macrophage Matrix Metalloproteinase Expression in Hypoxia.}, journal = {Biomedicines}, volume = {8}, number = {11}, pages = {}, pmid = {33153000}, issn = {2227-9059}, support = {19K08542//Ministry of Education, Culture, Sports, Science and Technology/ ; 17K09592//Ministry of Education, Culture, Sports, Science and Technology/ ; }, abstract = {Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1α independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxygen species (ROS). Here, we show that ROS derived from XO increases MMP-3, -10, and -13 expression in murine macrophages. We found that the transcript levels of macrophage MMP-3, -10, and -13 were increased in hypoxic conditions. Hypoxia induced MMP expression in HIF-1α deficient macrophages. N-acetylcysteine (NAC) or febuxostat, an XO inhibitor, suppressed MMP expression in murine macrophages. Febuxostat decreased the incidence of plaque rupture in apolipoprotein-E-deficient mice. Our results indicate that febuxostat stabilized atherosclerotic plaque via suppressing the activities of macrophage MMP-9 and -13. Febuxostat administration is a potential therapeutic option in the management of atherosclerotic patients.}, }
@article {pmid33152917, year = {2020}, author = {Pandey, V and Tripathi, A and Rani, A and Dubey, PK}, title = {Deoxyelephantopin, a novel naturally occurring phytochemical impairs growth, induces G2/M arrest, ROS-mediated apoptosis and modulates lncRNA expression against uterine leiomyoma.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {131}, number = {}, pages = {110751}, doi = {10.1016/j.biopha.2020.110751}, pmid = {33152917}, issn = {1950-6007}, mesh = {Adult ; Apoptosis/*drug effects ; Caspase 3/physiology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Extracellular Matrix/metabolism ; Female ; G2 Phase Cell Cycle Checkpoints/*drug effects ; Humans ; Lactones/*pharmacology/therapeutic use ; Leiomyoma/*drug therapy/metabolism/pathology ; RNA, Long Noncoding/*analysis/physiology ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology/therapeutic use ; Uterine Neoplasms/*drug therapy/metabolism/pathology ; }, abstract = {Deoxyelephantopin (DOE), a phytochemical, extracted and purified from Elephantopus scaber, has been shown to exhibit antitumor activities. Objective of the present study was to investigate anti-tumor and apoptosis-inducing properties of DOE against uterine leiomyoma (UL) and to explore their molecular mechanisms. Primary cell cultures from fresh UL tissue were established and maintained up to 12 passages. The cells exhibited continuous proliferation with 24 -h doubling time until 12 passages and was then subjected to molecular characterization. The growth inhibitory effect of DOE on UL cells was confirmed by colony formation, cellular senescence, AO/PI and DAPI staining. Fluorescent-activated cell sorting (FACS) assay for apoptosis and cell cycle arrest analysis revealed that DOE significantly (p < 0.05) inhibited the UL cell proliferation via cell cycle arrest at G2/M phase and induced apoptosis via ROS production by lowering mitochondrial membrane potential. Subsequently, the DOE induced ROS was markedly attenuated by co-treatment of N-Acetyl-Cysteine (NAC). Our quantitative RT-PCR and western blot results showed up-regulation of Bax, Caspase-3 and down-regulation of Bcl2, P[53], αSMA, COL4A2, VEGF, PCNA, Cyclin B1 and oncogenic lncRNAs (H19, HOTAIR, BANCR and ROR) in DOE treated UL cells which further strengthen our findings. In conclusion, DOE inhibits growth of UL cells via cell cycle arrest at G2/M phase, induces ROS-dependent caspase-3-mediated mitochondrial intrinsic apoptotic pathway and down-regulation of oncogenic lncRNA in UL cells. Our findings suggest that DOE deserves for further systematic investigation in the uterine leiomyoma animal model as a novel apoptosis inducer for potential applications in the prevention or treatment of uterine leiomyoma.}, }
@article {pmid33149614, year = {2020}, author = {Sheng, YN and Luo, YH and Liu, SB and Xu, WT and Zhang, Y and Zhang, T and Xue, H and Zuo, WB and Li, YN and Wang, CY and Jin, CH}, title = {Zeaxanthin Induces Apoptosis via ROS-Regulated MAPK and AKT Signaling Pathway in Human Gastric Cancer Cells.}, journal = {OncoTargets and therapy}, volume = {13}, number = {}, pages = {10995-11006}, pmid = {33149614}, issn = {1178-6930}, abstract = {BACKGROUND: Zeaxanthin, a carotenoid commonly found in plants, has a variety of biological functions including anti-cancer activity.<br><br>PURPOSE: This study aimed to investigate the potential mechanisms of zeaxanthin in human gastric cancer cells.<br><br>METHODS: CCK-8 assay was used to examine the cytotoxic effect of zeaxanthin on human gastric cancer cells. Flow cytometry was used to analyse AGS cell cycle distribution and apoptosis status. Western blot analysis was used to detect the expression levels of cycle-related proteins (Cyclin A, Cyclin B1, CDK1/2, p21, and p27), apoptosis-related proteins (Bcl-2, Bad, caspase-3, PARP), MAPK, AKT, STAT3, and NF-&#x3ba;B.<br><br>RESULTS: CCK-8 assay showed that zeaxanthin has obvious cytotoxic effects on 12 types of human gastric cancer cells, but no obvious toxic effect on normal cells. In addition, flow cytometry and Western blotting results showed that zeaxanthin induces apoptosis by reducing mitochondrial membrane potential; increasing Cytochrome C, Bax, cleaved-caspase-3 (cle-cas-3), and cleaved-PARP (cle-PARP) expression levels; and decreasing Bcl-2, pro-caspase-3 (pro-cas-3), and pro-PARP expression levels. Additionally, zeaxanthin caused cell cycle arrest at the G2/M phase by increasing the levels of p21 and p27 and reduced the levels of AKT, Cyclin A, Cyclin B1, and Cyclin-dependent kinase 1/2 (CDK1/2). Furthermore, after zeaxanthin treatment, the expression levels of reactive oxygen species (ROS), p-JNK, p-p38, and I-&#x3ba;B increased, and the expression levels of p-ERK, p-AKT, STAT3, and NF-&#x3ba;B decreased. However, the ROS scavenger N-acetylcysteine (NAC) and MAPK inhibitors inhibited zeaxanthin-induced apoptosis, and under the action of zeaxanthin, MAPK regulated NF-&#x3ba;B and STAT3, and reduced their protein expression levels.<br><br>CONCLUSION: Zeaxanthin has a potential effect against gastric cancer cells through the ROS-mediated MAPK, AKT, NF-&#x3ba;B, and STAT3 signaling pathways, and it is expected to become a new drug for the treatment of human gastric cancer.}, }
@article {pmid33146843, year = {2021}, author = {Papi, A and Di Stefano, AFD and Radicioni, M}, title = {Pharmacokinetics and Safety of Single and Multiple Doses of Oral N-Acetylcysteine in Healthy Chinese and Caucasian Volunteers: An Open-Label, Phase I Clinical Study.}, journal = {Advances in therapy}, volume = {38}, number = {1}, pages = {468-478}, pmid = {33146843}, issn = {1865-8652}, mesh = {*Acetylcysteine ; Administration, Oral ; Adult ; Area Under Curve ; *Asian People ; China ; Dose-Response Relationship, Drug ; Healthy Volunteers ; Humans ; Male ; }, abstract = {INTRODUCTION: Few studies have evaluated whether the pharmacokinetics of N-acetyl-cysteine (NAC) are different in Chinese and Caucasian individuals.<br><br>METHODS: This single- and multiple-dose, single-centre, open-label, phase I clinical study was conducted in healthy adult volunteers. All participants received oral NAC 600-mg uncoated tablets, which were administered first as a single dose and, following a 48-h wash-out period, twice daily for 3&#xa0;days. Blood and urine were collected after single- and multiple-dose NAC administration. Adverse event (AE) data were collected throughout the study.<br><br>RESULTS: Fifteen Chinese and 15 Caucasian (mostly Italian) individuals (males 66.7%, mean age 36.8&#xa0;years) participated in the study. Pharmacokinetic characteristics of NAC were similar in the two cohorts. Following both single- and multiple-dose administration, plasma concentration of NAC increased rapidly, reaching a peak at approximately 1.0&#xa0;h. Maximum plasma concentration and extent of exposure were higher after multiple doses than after a single dose. The accumulation ratio was relatively consistent in both Chinese (mean&#x2009;&#xb1;&#x2009;standard deviation 1.5&#x2009;&#xb1;&#x2009;0.4) and Caucasian (1.4&#x2009;&#xb1;&#x2009;0.2) participants. The half-life was 15.4&#xa0;h in Chinese and 18.7&#xa0;h in Caucasian participants, and the fraction of NAC excreted in urine in the 36&#xa0;h following administration was 3.7% in Chinese and 3.8% in Caucasian participants. Two Caucasian participants had a total of 3 AEs (headache, presyncope and dysmenorrhoea). No AEs occurred in Chinese participants.<br><br>CONCLUSIONS: The pharmacokinetic characteristics of NAC are similar in healthy Chinese and Caucasian individuals after single and repeated administration. NAC has a favourable tolerability profile.}, }
@article {pmid33146691, year = {2021}, author = {Hampannavar, MS and Roy, A and Singh, V}, title = {N-Acetyl Cysteine in Antitubercular Drug-Induced Liver Injury: In Search of Homogenous Evidence.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {73}, number = {7}, pages = {e1780}, doi = {10.1093/cid/ciaa1683}, pmid = {33146691}, issn = {1537-6591}, mesh = {*Acetylcysteine/therapeutic use ; Antitubercular Agents/adverse effects ; *Chemical and Drug Induced Liver Injury/etiology ; Humans ; Liver ; }, }
@article {pmid33144914, year = {2020}, author = {Chen, R and Liang, Y and Ip, MSM and Zhang, KY and Mak, JCW}, title = {Amelioration of Cigarette Smoke-Induced Mucus Hypersecretion and Viscosity by Dendrobium officinale Polysaccharides In Vitro and In Vivo.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {8217642}, pmid = {33144914}, issn = {1942-0994}, mesh = {Animals ; Cigarette Smoking/*adverse effects ; Dendrobium/*chemistry ; Epithelial Cells/metabolism/pathology/ultrastructure ; ErbB Receptors/metabolism ; Goblet Cells/pathology ; Humans ; Hyperplasia ; Male ; Mucus/*metabolism ; Polysaccharides/*pharmacology ; Rats, Sprague-Dawley ; Trachea/pathology/ultrastructure ; Viscosity ; }, abstract = {Chronic obstructive pulmonary disease (COPD), characterized by oxidative stress and inflammation, is one of the leading causes of death worldwide, in which cigarette smoke (CS) is the major risk factor. Dendrobium officinale polysaccharides (DOPs) are the main active ingredients extracted from Dendrobium officinale, which have been reported to have antioxidant and anti-inflammatory activity as well as inhibition of mucin gene expression. This study is aimed at investigating the effect of DOPs on CS-induced mucus hypersecretion and viscosity in vitro and in vivo. For in vitro study, primary normal human bronchial epithelial cells (HBECs) differentiated at the air-liquid interface (ALI) culture for 28 days were stimulated with cigarette smoke medium (CSM) in the absence or presence of various concentrations of DOPs or N-acetylcysteine (NAC) for 24 hours. For in vivo study, male Sprague-Dawley rats were randomized to sham air (SA) as control group or CS group for 56 days. At day 29, rats were subdivided and given water as control, DOPs, or NAC as positive control as a mucolytic drug via oral gavage for the remaining duration. Samples collected from apical washing, cell lysates, bronchoalveolar lavage (BAL), and lung tissues were evaluated for mucin gene expression, mucus secretion, and viscosity. DOPs ameliorated the CS-induced mucus hypersecretion and viscosity as shown by the downregulation of MUC5AC mRNA, MUC5AC secretary protein, and mucus viscosity via inhibition of mucus secretory granules in both in vitro and in vivo models. DOPs produced its effective effects on the CS-induced mucus hypersecretion and viscosity via the inhibition of the mucus secretory granules. These findings could be a starting point for considering the potential role of DOPs in the management of the smoking-mediated COPD. However, further research is needed.}, }
@article {pmid33144262, year = {2020}, author = {Fritsch, VN and Loi, VV and Busche, T and Tung, QN and Lill, R and Horvatek, P and Wolz, C and Kalinowski, J and Antelmann, H}, title = {The alarmone (p)ppGpp confers tolerance to oxidative stress during the stationary phase by maintenance of redox and iron homeostasis in Staphylococcus aureus.}, journal = {Free radical biology &amp; medicine}, volume = {161}, number = {}, pages = {351-364}, pmid = {33144262}, issn = {1873-4596}, mesh = {Bacterial Proteins/genetics/metabolism ; Gene Expression Regulation, Bacterial ; *Guanosine Pentaphosphate ; Homeostasis ; Hydrogen Peroxide ; Iron/metabolism ; Oxidation-Reduction ; Oxidative Stress ; *Staphylococcus aureus/metabolism ; }, abstract = {Slow growing stationary phase bacteria are often tolerant to multiple stressors and antimicrobials. Here, we show that the pathogen Staphylococcus aureus develops a non-specific tolerance towards oxidative stress during the stationary phase, which is mediated by the nucleotide second messenger (p)ppGpp. The (p)ppGpp[0] mutant was highly susceptible to HOCl stress during the stationary phase. Transcriptome analysis of the (p)ppGpp[0] mutant revealed an increased expression of the PerR, SigB, QsrR, CtsR and HrcA regulons during the stationary phase, indicating an oxidative stress response. The (p)ppGpp[0] mutant showed a slight oxidative shift in the bacillithiol (BSH) redox potential (EBSH) and an impaired H2O2 detoxification due to higher endogenous ROS levels. The increased ROS levels in the (p)ppGpp[0] mutant were shown to be caused by higher respiratory chain activity and elevated total and free iron levels. Consistent with these results, N-acetyl cysteine and the iron-chelator dipyridyl improved the growth and survival of the (p)ppGpp[0] mutant under oxidative stress. Elevated free iron levels caused 8 to 31-fold increased transcription of Fe-storage proteins ferritin (ftnA) and miniferritin (dps) in the (p)ppGpp[0] mutant, while Fur-regulated uptake systems for iron, heme or siderophores (efeOBU, isdABCDEFG, sirABC and sstADBCD) were repressed. Finally, the susceptibility of the (p)ppGpp[0] mutant towards the bactericidal action of the antibiotics ciprofloxacin and tetracycline was abrogated with N-acetyl cysteine and dipyridyl. Taken together, (p)ppGpp confers tolerance to ROS and antibiotics by down-regulation of respiratory chain activity and free iron levels, lowering ROS formation to ensure redox homeostasis in S. aureus.}, }
@article {pmid33143331, year = {2020}, author = {El-Sheref, EM and Aly, AA and Alshammari, MB and Brown, AB and Abdel-Hafez, SMN and Abdelzaher, WY and Bräse, S and Abdelhafez, EMN}, title = {Design, Synthesis, Molecular Docking, Antiapoptotic and Caspase-3 Inhibition of New 1,2,3-Triazole/Bis-2(1H)-Quinolinone Hybrids.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {21}, pages = {}, pmid = {33143331}, issn = {1420-3049}, mesh = {Animals ; Apoptosis/*drug effects ; *Caspase 3/chemistry/metabolism ; *Caspase Inhibitors/chemical synthesis/chemistry/pharmacology ; *Drug Design ; *Molecular Docking Simulation ; *Quinolones/chemical synthesis/chemistry/pharmacology ; Rats ; *Triazoles/chemical synthesis/chemistry/pharmacology ; }, abstract = {A series of novel 1,2,3-triazoles hybridized with two quinolin-2-ones, was designed and synthesized through click reactions. The structures of the synthesized compounds were elucidated by NMR, IR, and mass spectra in addition to elemental analysis. The synthesized compounds were assessed for their antiapoptotic activity in testis, as testicular torsion is the main cause of male infertility. This effect was studied in light of decreasing tissue damage induced by I/R in the testis of rats using N-acetylcysteine (NAC) as an antiapoptotic reference. Compounds 6a-c were the most active antiapoptotic hybrids with significant measurements for malondialdehyde (MDA) and total antioxidant capacity (TAC) and the apoptotic biomarkers (testicular testosterone, TNFα, and caspase-3) in comparison to the reference. A preliminary mechanistic study was performed to improve the antiapoptotic activity through caspase-3 inhibition. A compound assigned as 6-methoxy-4-(4-(((2-oxo-1,2-dihydroquinolin-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one (6c) was selected as a representative of the most active hybrids in comparison to NAC. Assay of cytochrome C for 6c revealed an attenuation of cytochrome C level about 3.54 fold, comparable to NAC (4.13 fold). In caspases-3,8,9 assays, 6c was found to exhibit more potency and selectivity toward caspase-3 than other caspases. The testicular histopathological investigation was carried out on all targeted compounds 6a-g, indicating a significant improvement in the spermatogenesis process for compounds 6a-c if compared to the reference relative to the control. Finally, molecular docking studies were done at the caspase-3 active site to suggest possible binding modes. Hence, it could conceivably be hypothesized that compounds 6a-c could be considered good lead candidate compounds as antiapoptotic agents.}, }
@article {pmid33139125, year = {2021}, author = {Sato-Shirai, I and Ogawa, E and Arisaka, A and Osaka, H and Murayama, K and Kuwajima, M and Watanabe, M and Ichimoto, K and Ohtake, A and Kumada, S}, title = {Valine-restricted diet for patients with ECHS1 deficiency: Divergent clinical outcomes in two Japanese siblings.}, journal = {Brain &amp; development}, volume = {43}, number = {2}, pages = {308-313}, doi = {10.1016/j.braindev.2020.10.003}, pmid = {33139125}, issn = {1872-7131}, mesh = {Acetylcysteine/pharmacology ; Cysteamine/pharmacology ; Diet Therapy/methods ; Enoyl-CoA Hydratase/*deficiency/genetics/metabolism/physiology ; Family ; Female ; Genetic Testing/methods ; Humans ; Infant ; Japan ; Leigh Disease/genetics/prevention &amp; control ; Magnetic Resonance Imaging/methods ; Male ; Mutation/genetics ; Pedigree ; Siblings ; Treatment Outcome ; Valine/deficiency/genetics/*metabolism ; }, abstract = {BACKGROUND: ECHS1 is a key enzyme of the valine catabolic pathway and oxidation of fatty acids. In ECHS1 deficiency (ECHS1D), accumulation of toxic intermediates from the valine induces neurodegeneration, which presents Leigh syndrome (LS). Therefore, valine restriction is suggested as an effective therapy. Further, cysteamine may detoxify the toxic metabolites themselves and N-acetylcysteine (NAC) is a potent antioxidant preventing neurological affect. Herein, we report the therapeutic effects of dietary therapy, cysteamine, and NAC in two siblings with ECHS1D, including their clinical, neuroradiological, and chemical aspects.<br><br>CASE REPORT: The elder sister was the proband and was diagnosed as LS at 13&#xa0;months of age. Gene analysis identified compound heterozygous ECHS1 mutations. Her psychomotor development was regressed, and she became bedridden. At 4&#xa0;years old she started a low protein diet (LPD), but with no obvious neurological change. The younger brother was confirmed early with ECHS1D and received cysteamine and NAC treatment from 5&#xa0;months of age, which could not prevent him developing LS at 7&#xa0;months of age. Thus, we started a LPD at 14&#xa0;months of age, with which he regained his ability to roll over, then we proceeded to a valine-restricted diet. The brain magnetic resonance image hyperintensity was diminished, and the lactate peak on magnetic resonance spectroscopy decreased. His neurological outcome is better than his elder sister. In both cases, excretion of valine metabolites decreased after dietary therapy without obvious adverse effects.<br><br>CONCLUSION: Early initiation of dietary therapy may reduce neurological sequelae in patients with ECHS1D.}, }
@article {pmid33137095, year = {2020}, author = {Hung, WC and Lee, DY and Chiang, EI and Syu, JN and Chao, CY and Yang, MD and Tsai, SY and Tang, FY}, title = {Docosahexaenoic acid inhibits the proliferation of Kras/TP53 double mutant pancreatic ductal adenocarcinoma cells through modulation of glutathione level and suppression of nucleotide synthesis.}, journal = {PloS one}, volume = {15}, number = {11}, pages = {e0241186}, pmid = {33137095}, issn = {1932-6203}, mesh = {Adenocarcinoma/*drug therapy/metabolism ; Animals ; Apoptosis/drug effects ; Carcinoma, Pancreatic Ductal/*drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Docosahexaenoic Acids/*pharmacology ; Fatty Acids, Omega-3/administration &amp; dosage/metabolism ; Fish Oils/administration &amp; dosage ; Glutathione/*metabolism ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Oxidative Stress/drug effects ; Pancreatic Neoplasms/*drug therapy/metabolism ; Proto-Oncogene Proteins p21(ras)/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {The treatment of cancer cells obtained by blocking cellular metabolism has received a lot of attention recently. Previous studies have demonstrated that Kras mutation-mediated abnormal glucose metabolism would lead to an aberrant cell proliferation in human pancreatic ductal adenocarcinoma (PDAC) cells. Previous literature has suggested that consumption of fish oil is associated with lower risk of pancreatic cancer. In this study, we investigated the anti-cancer effects of docosahexaenoic acid (DHA) in human PDAC cells in vitro and in vivo. Omega-3 polyunsaturated fatty acids (PUFAs) such as DHA and eicosapentaenoic acid (EPA) significantly inhibited the proliferation of human PDAC cells. The actions of DHA were evaluated through an induction of cell cycle arrest at G1 phase and noticed a decreased expression of cyclin A, cyclin E and cyclin B proteins in HPAF-II cells. Moreover, it was found that co-treatment of DHA and gemcitabine (GEM) effectively induced oxidative stress and cell death in HPAF-II cells. Interestingly, DHA leads to an increased oxidative glutathione /reduced glutathione (GSSG/GSH) ratio and induced cell apoptosis in HPAF-II cells. The findings in the study showed that supplementation of GSH or N-Acetyl Cysteine (NAC) could reverse DHA-mediated cell death in HPAF-II cells. Additionally, DHA significantly increased cellular level of cysteine, cellular NADP/NADPH ratio and the expression of cystathionase (CTH) and SLCA11/xCT antiporter proteins in HPAF-II cells. The action of DHA was, in part, associated with the inactivation of STAT3 cascade in HPAF-II cells. Treatment with xCT inhibitors, such as erastin or sulfasalazine (SSZ), inhibited the cell survival ability in DHA-treated HPAF-II cells. DHA also inhibited nucleotide synthesis in HPAF-II cells. It was demonstrated in a mouse-xenograft model that consumption of fish oil significantly inhibited the growth of pancreatic adenocarcinoma and decreased cellular nucleotide level in tumor tissues. Furthermore, fish oil consumption induced an increment of GSSG/GSH ratio, an upregulation of xCT and CTH proteins in tumor tissues. In conclusion, DHA significantly inhibited survival of PDAC cells both in vitro and in vivo through its recently identified novel mode of action, including an increment in the ratio of GSSG/GSH and NADP/NADPH respectively, and promoting reduction in the levels of nucleotide synthesis.}, }
@article {pmid33133645, year = {2020}, author = {Coates, JTT and Rodriguez-Berriguete, G and Puliyadi, R and Ashton, T and Prevo, R and Wing, A and Granata, G and Pirovano, G and McKenna, GW and Higgins, GS}, title = {The anti-malarial drug atovaquone potentiates platinum-mediated cancer cell death by increasing oxidative stress.}, journal = {Cell death discovery}, volume = {6}, number = {}, pages = {110}, pmid = {33133645}, issn = {2058-7716}, support = {19590/CRUK_/Cancer Research UK/United Kingdom ; 28736/CRUK_/Cancer Research UK/United Kingdom ; }, abstract = {Platinum chemotherapies are highly effective cytotoxic agents but often induce resistance when used as monotherapies. Combinatorial strategies limit this risk and provide effective treatment options for many cancers. Here, we repurpose atovaquone (ATQ), a well-tolerated &amp; FDA-approved anti-malarial agent by demonstrating that it potentiates cancer cell death of a subset of platinums. We show that ATQ in combination with carboplatin or cisplatin induces striking and repeatable concentration- and time-dependent cell death sensitization in vitro across a variety of cancer cell lines. ATQ induces mitochondrial reactive oxygen species (mROS), depleting intracellular glutathione (GSH) pools in a concentration-dependent manner. The superoxide dismutase mimetic MnTBAP rescues ATQ-induced mROS production and pre-loading cells with the GSH prodrug N-acetyl cysteine (NAC) abrogates the sensitization. Together, these findings implicate ATQ-induced oxidative stress as key mediator of the sensitizing effect. At physiologically achievable concentrations, ATQ and carboplatin furthermore synergistically delay the growth of three-dimensional avascular spheroids. Clinically, ATQ is a safe and specific inhibitor of the electron transport chain (ETC) and is concurrently being repurposed as a candidate tumor hypoxia modifier. Together, these findings suggest that ATQ is deserving of further study as a candidate platinum sensitizing agent.}, }
@article {pmid33133334, year = {2020}, author = {Zhang, W and Tang, R and Ba, G and Li, M and Lin, H}, title = {Anti-allergic and anti-inflammatory effects of resveratrol via inhibiting TXNIP-oxidative stress pathway in a mouse model of allergic rhinitis.}, journal = {The World Allergy Organization journal}, volume = {13}, number = {10}, pages = {100473}, pmid = {33133334}, issn = {1939-4551}, abstract = {BACKGROUND: Allergic rhinitis (AR) is a type I hypersensitivity mediated by IgE in the nose. Thioredoxin-interacting protein (TXNIP) plays a pivotal role in the process of producing reactive oxygen species (ROS). Resveratrol is a TXNIP inhibitor. Nonetheless, its role and mechanism in AR are still undetermined. The present study aimed to explore the effect and mechanism of resveratrol on an ovalbumin (OVA) induced mouse model of AR.<br><br>METHODS: AR murine model was established using OVA and administrated intranasally with resveratrol or N-acetylcysteine (NAC). Hematoxylin and eosin (HE) stain was used for evaluating eosinophils. Immunohistochemistry (IHC) staining and real-time PCR were employed to evaluate immunolabeling and mRNA expression of TXNIP in nasal mucosas of mice. Malondialdehyde (MDA) level and superoxide dismutase (SOD) activity in nasal tissue homogenates were measured using MDA and SOD Assay Kit. Concentrations of OVA-specific IgE and histamines in serum, and OVA-specific IgE, PGD2, LTC4, ECP, IL-4, IL-5, IL-6, IL-33 and TNF-&#x3b1; in nasal lavage fluid (NLF) were assayed by ELISA. In&#xa0;vitro studies, western blotting, real-time PCR, ELISA, ROS detecting dye DCFH-DA, MDA, and SOD Assay Kit were performed to evaluate the effects and mechanisms of OVA, resveratrol or NAC on spleen mononuclear cells.<br><br>RESULTS: We found significant alternations of sneezing, nasal rubbing, inflammatory cytokines, eosinophil numbers, TXNIP, MDA, and SOD levels in resveratrol or NAC treated mice compared with untreated AR mice. In cultured spleen mononuclear cells, TXNIP, MDA, SOD, ROS and inflammatory cytokines levels were altered by OVA but reversed by resveratrol or NAC.<br><br>CONCLUSIONS: Resveratrol could effectively alleviate murine AR by inhibiting TXNIP-oxidative stress pathway.}, }
@article {pmid33131013, year = {2021}, author = {Zhen, J and Jiao, K and Yang, K and Wu, M and Zhou, Q and Yang, B and Xiao, W and Hu, C and Zhou, M and Li, Z}, title = {The 14-3-3η/GSK-3β/β-catenin complex regulates EndMT induced by 27-hydroxycholesterol in HUVECs and promotes the migration of breast cancer cells.}, journal = {Cell biology and toxicology}, volume = {37}, number = {4}, pages = {515-529}, pmid = {33131013}, issn = {1573-6822}, support = {81573183 and 81673205//National Natural Science Foundation of China/ ; }, mesh = {*Breast Neoplasms/genetics ; Epithelial-Mesenchymal Transition ; Female ; Glycogen Synthase Kinase 3 beta ; Humans ; Hydroxycholesterols ; *beta Catenin/genetics ; }, abstract = {Endothelial-mesenchymal transition (EndMT) is the transformation of endothelial cell morphology to mesenchymal cell morphology, accompanied by decline of endothelial function and enhancement of mesenchymal function, which promotes tumor progression and tumor cell invasion and metastasis. 27-Hydroxycholesterol (27-HC) is a cholesterol metabolite, which has a high content in human blood. 27-HC promotes breast cancer cell proliferation, invasion, and migration. We previously showed that 27-HC promotes EndMT; however, the underlying mechanism still needs to be further explored. We studied the role of the 14-3-3η/GSK-3β/β-catenin complex in EndMT. Our results show that 27-HC induces oxidative stress in HUVECs and activates the p38 signaling pathway, thereby inhibiting the binding of 14-3-3η/GSK-3β/β-catenin, promoting the increase of free β-catenin and nuclear translocation, and finally inducing EndMT. Treatment with N-acetylcysteine (NAC) blocked 27-HC-induced ROS generation and p38 signaling pathway activation, prevented β-catenin from release from binding, and inhibited EndMT. Blocking ROS production or p38 signaling or knocking down 14-3-3η inhibited 27-HC-induced EndMT and inhibited breast cancer cell metastasis. These findings indicate 14-3-3η is necessary for interactions between the p38 kinase and the GSK-3β/β-catenin complex and serves as an adaptor to transmit the upstream kinase signal to the downstream signal, thereby promoting EndMT and breast cancer cell migration.}, }
@article {pmid33126376, year = {2020}, author = {Xiao, S and Yu, Y and Xiong, Y and Sun, F and Liu, X and Yan, J and Zhang, S}, title = {Chinese herbal medicines for the treatment of cough in idiopathic pulmonary fibrosis: A protocol for systematic review and meta-analysis.}, journal = {Medicine}, volume = {99}, number = {44}, pages = {e22991}, pmid = {33126376}, issn = {1536-5964}, mesh = {Cough/*drug therapy/etiology ; Drugs, Chinese Herbal/adverse effects/*therapeutic use ; Humans ; Idiopathic Pulmonary Fibrosis/complications/*drug therapy ; Treatment Outcome ; Meta-Analysis as Topic ; Systematic Review as Topic ; }, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and hidden onset, which causes major health problems worldwide. Cough is a typical manifestation of IPF, which is usually characterized by cough without phlegm, and seriously affects the quality of life (QOL) of patients. At present, the treatment of IPF is mainly focused on prolonging survival time and improving lung function, such as pirfenidone, nintedanib, and N-acetylcysteine (NAC), but lack of effective measures to improve the QOL. Chinese herbal medicines (CHMs) is widely used in the clinical treatment of IPF. The adjuvant treatment of CHMs can effectively reduce the clinical symptoms of patients. Therefore, we designed this study to evaluate the role of CHMs in the treatment of cough in IPF.<br><br>METHOD: This systematic review and meta-analysis will extract all randomized controlled trials (RCTs) related to the treatment of IPF from the following electronic database without date or language restrictions: PubMed, EMBASE, Cochrane CENTRAL, CNKI, VIP, CBM, and Wanfang database. The primary outcomes will be cough frequency and QOL, while secondary outcomes will include safety events. The methodologic quality of RCTs will be assessed using the Cochrane risk assessment tool. The I test will be used to identify the extent of heterogeneity, and funnel plot analysis will be used to test the publication deviation (the number of studies included >10). We will use RevMan5.3 software for data synthesis and analysis.<br><br>RESULT: This review evaluates the efficacy and safety of CHMs in combination therapy on cough frequency, the quality of life, adverse reactions and safety incidents in patients with IPF.<br><br>CONCLUSION: This study protocol will be used to evaluate the efficacy and safety of CHMs in combination with conventional therapy in treatment of cough in IPF.<br><br>OSF REGISTRATION DOI: 10.17605/OSF.IO/JKQYV.}, }
@article {pmid33126286, year = {2021}, author = {Nassar, M and Dargham, A and Jamleh, A and Tamura, Y and Hiraishi, N and Tagami, J}, title = {The Hormetic Effect of Arsenic Trioxide on Rat Pulpal Cells: An In Vitro Preliminary Study.}, journal = {European journal of dentistry}, volume = {15}, number = {2}, pages = {222-227}, pmid = {33126286}, issn = {1305-7456}, abstract = {OBJECTIVES: Despite the agreement that there is no longer any indication for arsenic use in modern endodontics, some concerns are surfacing about the minute amount of arsenic trioxide (As2O3) released from Portland cement-based materials. The present study investigated the effect of different concentrations of As2O3 on rat pulpal cells and the efficacy of N-acetylcysteine (NAC) in preventing As2O3-mediated toxicity.<br><br>MATERIALS AND METHODS: &#x2003;Cytotoxicities of 50, 10, or 5 &#xb5;m As2O3 and the effect of cells co-treatment with 50 &#xb5;m As2O3 and 5,000 &#xb5;m NAC or 500 &#xb5;m NAC were tested at 24 hours or 3 days. Cell viability was assessed by means of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and cellular morphological changes were observed under phase contrast microscope.<br><br>STATISTICAL ANALYSIS: &#x2003;Two-way analysis of variance with Tukey's post-hoc test was used to evaluate differences between the groups (&#x3b1; = 0.05).<br><br>RESULTS: &#x2003;At both exposure times, 50 &#xb5;m As2O3 resulted in lower optical density (OD) values when compared with 10 or 5 &#xb5;m As2O3. At 24 hours, 10 &#xb5;m As2O3 resulted in a higher OD value compared with the control; however, at 3 days the difference was statistically insignificant. At each exposure time, the OD value of 5 &#xb5;m As2O3 group was comparable to the control and 10 &#xb5;m As2O3 group. There were no significant differences between 50 &#xb5;m As2O3 group and 500 &#x3bc;m NAC+50 &#x3bc;m As2O3 group; however, these two groups had lower OD values when compared with 5,000 &#x3bc;m NAC+50 &#x3bc;m As2O3 group at 24 hours and 3 days. The latter group showed significantly lower OD value in comparison with the control at 24 hours and 3 days. Control cells were polygonal-shaped while 50 &#xb5;m As2O3-treated cells exhibited contracted and spherical morphology with increased intercellular spaces. At 24 hours, 10 &#x3bc;m and 5 &#xb5;m As2O3-treated cells were slightly hypertrophic. Cells co-treated with NAC and As2O3 showed increased intercellular spaces and lower cellular density compared with the control.<br><br>CONCLUSIONS: &#x2003;As2O3 displayed a hormetic effect on pulpal cells; however, the proliferative effect induced by low As2O3 concentrations should be interpreted with caution. NAC did not prevent As2O3-mediated toxicity; however, it demonstrated potential for ameliorating this toxicity.}, }
@article {pmid33123316, year = {2020}, author = {Mu, LH and Wang, LH and Yu, TF and Wang, YN and Yan, H and Liu, P and Yan, C}, title = {Triterpenoid Saponin AG8 from Ardisia gigantifolia stapf. Induces Triple Negative Breast Cancer Cells Apoptosis through Oxidative Stress Pathway.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {7963212}, pmid = {33123316}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Ardisia/*chemistry/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Glutathione/metabolism ; Humans ; Malondialdehyde/metabolism ; Mitochondria/drug effects/metabolism ; Oncogene Protein v-akt/metabolism ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Saponins/*pharmacology ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; Triple Negative Breast Neoplasms/metabolism/pathology ; Triterpenes/pharmacology ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Triple-negative breast cancers (TNBCs) are associated with poor patient survival because of the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expressions. Our previous studies have shown that the triterpenoid saponin AG8 from Ardisia gigantifolia stapf. inhibits the proliferation of MDA-MB-231 cells. In this study, the effects of AG8 were further analyzed in different TNBC cell types: MDA-MB-231, BT-549, and MDA-MB-157 cells. AG8 inhibited the viability of MDA-MB-231, BT-549, and MDA-MB-157 cells in a dose-dependent manner and showed stronger cytotoxicity to African American (AA) and mesenchymal (M) subtypes than Caucasian (CA) and mesenchymal stem-like (MSL) subtypes, respectively. AG8 impaired the uptake of MitoTracker Red CMXRos by the mitochondria of TNBC cells in a dose-dependent manner, and this was recovered by N-acetyl-l-cysteine (NAC). AG8 affected GSH, SOD, and MDA levels of TNBC cells, but different TNBC subtypes had different sensitivities to AG8 and NAC. In addition, we found that AG8 increased the Bax/Bcl-2 ratio and the levels of cytoplasmic cytochrome c and significantly decreased phosphorylation of ERK and AKT in BT549 and MDA-MB-157 cells. AG8 elicited its anticancer effects through ROS generation, ERK and AKT activation, and by triggering mitochondrial apoptotic pathways in TNBC cells. AG8 had selective cytotoxic effects against the AA and M TNBC subtypes and markedly induced MDA-MB-157 (AA subtype) cell apoptosis through pathways that were not associated with ROS, which was different from the other two subtypes. The underlying mechanisms should be further investigated.}, }
@article {pmid33120805, year = {2020}, author = {Melquist, S and Estepp, K and Aleksandrovich, Y and Lee, A and Beiseker, A and Hamedani, FS and Bassett, J}, title = {COVID-19 presenting as fulminant hepatic failure: A case report.}, journal = {Medicine}, volume = {99}, number = {43}, pages = {e22818}, pmid = {33120805}, issn = {1536-5964}, mesh = {Adult ; *Betacoronavirus ; COVID-19 ; Coronavirus Infections/complications/*diagnosis ; Female ; Humans ; Liver Failure, Acute/diagnosis/*virology ; Pandemics ; Pneumonia, Viral/complications/*diagnosis ; SARS-CoV-2 ; }, abstract = {INTRODUCTION: Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) responsible for the COVID-19 pandemic has spread from Wuhan, China in December, 2019 to 216 countries and territories as of September 10, 2020 with 27.74 million cases and 899,911 confirmed deaths. The spectrum of disease is most commonly seen as a viral pneumonia with high grade fevers, shortness of breath, dry cough, and chest pain with radiologic evidence of bilateral, interstitial, ground glass opacities, and peripheral lung consolidation. Liver chemistries are frequently abnormal, with transaminases shown to be one-two times the upper limit of normal in most instances. The full spectrum of gastrointestinal involvement of the SARS-CoV-2 infection has yet to be fully seen.Patient concerns: We present a case of a young woman with SLE who developed severe abdominal pain, nausea and vomiting, rapidly progressing to acute hepatic failure and tested positive for SARS-CoV-2 infection. She had no respiratory symptoms.<br><br>DIAGNOSIS: A thorough work-up of acute liver failure including liver biopsy confirmed acute hepatitis with viral like changes. Common viral causes of liver failure were ruled out. The patient had no recent travel history.<br><br>INTERVENTIONS: The patient was started on hydroxychloroquine due to SLE, treated with N-Acetyl-Cysteine, and methylprednisolone.<br><br>OUTCOMES: The patient improved with resolution of encephalopathy and normalization of her liver chemistries without any development of respiratory illness.<br><br>CONCLUSION: This case details a unique presentation of likely SARS-CoV-2 infection. Until now, the literature has primarily described a respiratory illness and liver injury with mild transaminase elevations. Significant liver injury progressing to acute liver failure should be considered in those with SARS-CoV-2 infection.}, }
@article {pmid33118390, year = {2021}, author = {Lim, HM and Park, SH and Nam, MJ}, title = {Induction of apoptosis in indole-3-carbinol-treated lung cancer H1299 cells via ROS level elevation.}, journal = {Human &amp; experimental toxicology}, volume = {40}, number = {5}, pages = {812-825}, doi = {10.1177/0960327120969968}, pmid = {33118390}, issn = {1477-0903}, mesh = {Antineoplastic Agents/*therapeutic use ; Apoptosis/*drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy ; Cell Line, Tumor/*drug effects ; Humans ; Indoles/*metabolism/*therapeutic use ; Reactive Oxygen Species/*metabolism ; }, abstract = {This study was focused on investigating the anticancer potential of indole-3-carbinol (I3C) against lung cancer H1299 cells via an increase in ROS levels. To investigate the induction of growth arrest and/or cell death in H1299 cells, a cell cycle arrest assay, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) assay, and reactive oxygen species (ROS) detection assay were performed. Through the TUNEL assay, we detected I3C-induced DNA fragmentation. Fluorescence-activated cell sorting (FACS) analysis showed that I3C induced an increase in ROS levels and apoptotic rate in a dose- and time-dependent manner in H1299 cells. Western blotting demonstrated that activated forms of caspase-3, caspase-7, caspase-9, and poly (ADP-ribose) polymerase (PARP) were increased in I3C-treated H1299 cells following treatment with I3C. Furthermore, protein expression levels of FOXO3, bim, bax, and phosphorylated ERK and JNK were increased, while those of pAkt, Bcl-xL, and Bcl-2 were decreased by I3C treatment of H1299 cells. To confirm the relationship between cell apoptosis and ROS generation, H1299 cells were treated with I3C simultaneously with N-acetylcysteine (NAC), and it was shown that ROS levels decreased and viability increased. Moreover, in western blot analysis, expression of anti-apoptotic proteins (thioredoxin1, peroxiredoxin-1, Bcl-2, and Bcl-xL) in I3C-treated cells was evidently downregulated and pro-apoptotic proteins (active ASK1 and cleaved PARP) were upregulated compared to cells co-treated with NAC. The study showed that I3C induced downregulation of ROS regulator proteins and elevation of ROS, thus activating apoptotic signaling cascades in human lung cancer H1299 cells.}, }
@article {pmid33115390, year = {2020}, author = {Martínez-Banaclocha, M}, title = {N-acetyl-cysteine in Schizophrenia: Potential Role on the Sensitive Cysteine Proteome.}, journal = {Current medicinal chemistry}, volume = {27}, number = {37}, pages = {6424-6439}, doi = {10.2174/0929867326666191015091346}, pmid = {33115390}, issn = {1875-533X}, mesh = {Acetylcysteine/pharmacology ; Antioxidants ; Cysteine/metabolism ; Glutathione/metabolism ; Humans ; Oxidation-Reduction ; Proteome ; *Schizophrenia/drug therapy ; }, abstract = {BACKGROUND: N-acetyl-cysteine (NAC) has shown widespread utility in different psychiatric disorders, including a beneficial role in schizophrenic patients. Although the replenishment of glutathione and the antioxidant activity of NAC have been suggested as the mechanisms that improve such a wide range of disorders, none seems to be sufficiently specific to explain these intriguing effects. A sensitive cysteine proteome is emerging as a functional and structural network of interconnected Sensitive Cysteine-containing Proteins (SCCPs) that together with reactive species and the cysteine/ glutathione cycles can regulate the bioenergetic metabolism, the redox homeostasis and the cellular growth, differentiation and survival, acting through different pathways that are regulated by the same thiol radical in cysteine residues.<br><br>OBJECTIVE: Since this sensitive cysteine network has been implicated in the pathogenesis of Parkinson's and Alzheimer's diseases, I have reviewed if the proteins that play a role in schizophrenia can be classified as SCCPs.<br><br>RESULTS: The results show that the principal proteins playing a role in schizophrenia can be classified as SCCPs, suggesting that the sensitive cysteine proteome (cysteinet) is defective in this type of psychosis.<br><br>CONCLUSION: The present review proposes that there is a deregulation of the sensitive cysteine proteome in schizophrenia as the consequence of a functional imbalance among different SCCPs, which play different functions in neurons and glial cells. In this context, the role of NAC to restore and prevent schizophrenic disorders is discussed.}, }
@article {pmid33109619, year = {2021}, author = {Martinez, R and Huang, W and Samadani, R and Mackowiak, B and Centola, G and Chen, L and Conlon, IL and Hom, K and Kane, MA and Fletcher, S and Shapiro, P}, title = {Mechanistic Analysis of an Extracellular Signal-Regulated Kinase 2-Interacting Compound that Inhibits Mutant BRAF-Expressing Melanoma Cells by Inducing Oxidative Stress.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {376}, number = {1}, pages = {84-97}, pmid = {33109619}, issn = {1521-0103}, support = {T32 GM066706/GM/NIGMS NIH HHS/United States ; R25 GM055036/GM/NIGMS NIH HHS/United States ; R01 CA120215/CA/NCI NIH HHS/United States ; F31 GM100693/GM/NIGMS NIH HHS/United States ; P41 GM111135/GM/NIGMS NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*chemistry/pharmacology ; Catalytic Domain ; Cell Proliferation/drug effects ; HeLa Cells ; Humans ; Jurkat Cells ; MAP Kinase Signaling System/*drug effects ; Melanoma/*metabolism ; Mitogen-Activated Protein Kinase 1/chemistry/*metabolism ; *Oxidative Stress ; Protein Binding ; Proto-Oncogene Mas ; Proto-Oncogene Proteins B-raf/genetics ; }, abstract = {Constitutively active extracellular signal-regulated kinase (ERK) 1/2 signaling promotes cancer cell proliferation and survival. We previously described a class of compounds containing a 1,1-dioxido-2,5-dihydrothiophen-3-yl 4-benzenesulfonate scaffold that targeted ERK2 substrate docking sites and selectively inhibited ERK1/2-dependent functions, including activator protein-1-mediated transcription and growth of cancer cells containing active ERK1/2 due to mutations in Ras G-proteins or BRAF, Proto-oncogene B-RAF (Rapidly Acclerated Fibrosarcoma) kinase. The current study identified chemical features required for biologic activity and global effects on gene and protein levels in A375 melanoma cells containing mutant BRAF (V600E). Saturation transfer difference-NMR and mass spectrometry analyses revealed interactions between a lead compound (SF-3-030) and ERK2, including the formation of a covalent adduct on cysteine 252 that is located near the docking site for ERK/FXF (DEF) motif for substrate recruitment. Cells treated with SF-3-030 showed rapid changes in immediate early gene levels, including DEF motif-containing ERK1/2 substrates in the Fos family. Analysis of transcriptome and proteome changes showed that the SF-3-030 effects overlapped with ATP-competitive or catalytic site inhibitors of MAPK/ERK Kinase 1/2 (MEK1/2) or ERK1/2. Like other ERK1/2 pathway inhibitors, SF-3-030 induced reactive oxygen species (ROS) and genes associated with oxidative stress, including nuclear factor erythroid 2-related factor 2 (NRF2). Whereas the addition of the ROS inhibitor N-acetyl cysteine reversed SF-3-030-induced ROS and inhibition of A375 cell proliferation, the addition of NRF2 inhibitors has little effect on cell proliferation. These studies provide mechanistic information on a novel chemical scaffold that selectively regulates ERK1/2-targeted transcription factors and inhibits the proliferation of A375 melanoma cells through a ROS-dependent mechanism. SIGNIFICANCE STATEMENT: Constitutive activation of the extracellular signal-regulated kinase (ERK1/2) pathway drives the proliferation and survival of many cancer cell types. Given the diversity of cellular functions regulated by ERK1/2, the current studies have examined the mechanism of a novel chemical scaffold that targets ERK2 near a substrate binding site and inhibits select ERK functions. Using transcriptomic and proteomic analyses, we provide a mechanistic basis for how this class of compounds inhibits melanoma cells containing mutated BRAF and active ERK1/2.}, }
@article {pmid33109047, year = {2021}, author = {Luo, P and Liu, Y and Liu, D and Li, J}, title = {Perspectives for the Use of N-acetylcysteine as a Candidate Drug to Treat COVID-19.}, journal = {Mini reviews in medicinal chemistry}, volume = {21}, number = {3}, pages = {268-272}, doi = {10.2174/1389557520666201027160833}, pmid = {33109047}, issn = {1875-5607}, mesh = {Acetylcysteine/*pharmacology ; Antiviral Agents/*pharmacology ; COVID-19/complications ; Drug Design ; Drug Repositioning ; Humans ; Nitric Oxide/metabolism ; Reactive Oxygen Species/metabolism ; SARS-CoV-2/*drug effects ; *COVID-19 Drug Treatment ; }, abstract = {Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndromerelated coronavirus-2 (SARS-CoV-2), has become an ongoing pandemic worldwide. However, there are no vaccines or antiviral drugs with proven clinical efficacy. Therefore, a remedial measure is urgently needed to combat the devastating COVID-19. The pharmacological activities of Nacetylcysteine (NAC) and its potential functions in inhibiting the progression of COVID-19 make it a promising therapeutic agent for the infection. In this mini-review, we discussed the therapeutic potential of NAC in COVID-19 from the perspective of its multisite pharmacological actions.}, }
@article {pmid33103516, year = {2020}, author = {McGill, MR and Hinson, JA}, title = {The development and hepatotoxicity of acetaminophen: reviewing over a century of progress.}, journal = {Drug metabolism reviews}, volume = {52}, number = {4}, pages = {472-500}, pmid = {33103516}, issn = {1097-9883}, support = {R42 DK079387/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/metabolism/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*enzymology/metabolism ; Cytochrome P-450 Enzyme System/metabolism ; Humans ; Liver/*drug effects/enzymology/metabolism ; Oxidative Stress ; }, abstract = {Acetaminophen (APAP) was first synthesized in the 1800s, and came on the market approximately 65 years ago. Since then, it has become one of the most used drugs in the world. However, it is also a major cause of acute liver failure. Early investigations of the mechanisms of toxicity revealed that cytochrome P450 enzymes catalyze formation of a reactive metabolite in the liver that depletes glutathione and covalently binds to proteins. That work led to the introduction of N-acetylcysteine (NAC) as an antidote for APAP overdose. Subsequent studies identified the reactive metabolite N-acetyl-p-benzoquinone imine, specific P450 enzymes involved, the mechanism of P450-mediated oxidation, and major adducted proteins. Significant gaps remain in our understanding of the mechanisms downstream of metabolism, but several events appear critical. These events include development of an initial oxidative stress, reactive nitrogen formation, altered calcium flux, JNK activation and mitochondrial translocation, inhibition of mitochondrial respiration, the mitochondrial permeability transition, and nuclear DNA fragmentation. Additional research is necessary to complete our knowledge of the toxicity, such as the source of the initial oxidative stress, and to greatly improve our understanding of liver regeneration after APAP overdose. A better understanding of these mechanisms may lead to additional treatment options. Even though NAC is an excellent antidote, its effectiveness is limited to the first 16 hours following overdose.}, }
@article {pmid33100351, year = {2020}, author = {Vanin, AF}, title = {Dinitrosyl Iron Complexes with Thiol-Containing Ligands Can Suppress Viral Infections as Donors of the Nitrosonium Cation (Hypothesis).}, journal = {Biophysics}, volume = {65}, number = {4}, pages = {698-702}, pmid = {33100351}, issn = {0006-3509}, abstract = {The appropriateness of verification of the possible antiviral effect of dinitrosyl iron complexes with thiol-containing ligands as donors of nitrosonium cations (NO[+]) is argued. There is reason to hope that treatment of the human respiratory tract and lungs with sprayed solutions of dinitrosyl iron complexes with glutathione or N-acetylcysteine (NAC) as NO[+] donors during COVID-19 infection can initiate S-nitrosylation of cellular proteases and thereby suppress viral infection.}, }
@article {pmid33098382, year = {2020}, author = {Jannatifar, R and Parivar, K and Hayati Roodbari, N and Nasr-Esfahani, MH}, title = {The Effect of N-Acetyl-Cysteine on NRF2 Antioxidant Gene Expression in Asthenoteratozoospermia Men: A Clinical Trial Study.}, journal = {International journal of fertility &amp; sterility}, volume = {14}, number = {3}, pages = {171-175}, pmid = {33098382}, issn = {2008-076X}, abstract = {BACKGROUND: One of the important factor associated with male infertility is high production of reactive oxygen species (ROS). The main function of Nuclear factor erythroid 2-related factor 2 (NRF2) is to activate the cellular antioxidant response by inducing the transcription of a wide array of genes that can combat the harmful effects of factors such as oxidative stress. The purpose of this study was to evaluate the effect of N-acetyl-L-cysteine (NAC), as an antioxidant drug, on NRF2 Gene Expression in Asthenoteratozoospermia Men.<br><br>MATERIALS AND METHODS: In this randomized, blinded clinical trial study, included 50 infertile men with asthenoteratozoospermia, who received NAC (600 mg, three times daily). Sperm parameters analyzed according to the world health organization (WHO; 2010). Sperm DNA fragmentation, relative NRF2 expression, and seminal plasma level of antioxidant enzymes were measured by TUNEL assay, reverse transcription polymerase chain reaction (RT-PCR) and ELISA test, respectively.<br><br>RESULTS: After NAC treatment, findings showed a significant increase in sperm concentration and motility compared to pre-treatment status, whereas the percentage of abnormal morphology and DNA fragmentation was significantly decreased (P<0.05). A significant improvement in expression of NRF2 gene and antioxidant enzyme levels were observed compared to pre-treatment by NAC (P<0.05). Significant correlations were observed between NRF2 mRNA expression level, specific sperm parameters and level of antioxidant enzymes (P<0.05).<br><br>CONCLUSION: The results demonstrated that NAC oral supplementation protected against oxidative stress by enhancing NRF2 expression. This could improve semen parameters quality parameters in asthenoteratozoospermia men (Registration number: IRCT20170830035998N4).}, }
@article {pmid33095436, year = {2021}, author = {Balan, DJ and Rajavel, T and Das, M and Sathya, S and Jeyakumar, M and Devi, KP}, title = {Thymol induces mitochondrial pathway-mediated apoptosis via ROS generation, macromolecular damage and SOD diminution in A549 cells.}, journal = {Pharmacological reports : PR}, volume = {73}, number = {1}, pages = {240-254}, pmid = {33095436}, issn = {2299-5684}, support = {RUSA 2.0 [F. 24-51/2014-U//Government of India/ ; Policy (TN Multi-Gen)//Government of India/ ; }, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Caspase 9/drug effects/metabolism ; Cell Cycle/drug effects ; Computer Simulation ; DNA Damage ; Genes, bcl-2/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Superoxide Dismutase/*metabolism ; Thymol/antagonists &amp; inhibitors/*pharmacology ; bcl-2-Associated X Protein/drug effects/metabolism ; }, abstract = {BACKGROUND: Thymol is a monoterpene phenol found in thyme species plants. The present study was carried out to investigate the effect of thymol and its molecular mechanism on non-small lung cancer (A549) cells.<br><br>METHODS: The cytotoxic effect of thymol on A549&#xa0;cells was&#xa0;assessed via MTT&#xa0;assay. ROS production, macromolecular damage, apoptosis were determined&#xa0;using DCF-DA, PI, AO/EtBr&#xa0;stains, respectively. ROS-dependent effect of thymol was confirmed using NAC. The expression of caspase-9,&#xa0;Bcl-2, Bax and cell cycle profile was analyzed via western blot and FACS, respectively.<br><br>RESULTS: The antiproliferative effect of thymol on A549 cells was found to be both dose and time dependent with IC50 values of 112&#xa0;&#x3bc;g/ml (745&#xa0;&#x3bc;M) at 24&#xa0;h. Thymol treatment favored apoptotic cell death and caused G0/G1 cell cycle arrest. It mediated cellular and nuclear morphological changes, phosphatidylserine translocation, and mitochondrial membrane depolarization. Additionally, upregulation of Bax, downregulation of Bcl-2, and apoptotic fragmented DNA were also observed. Thymol induced ROS by reducing the SOD level which was confirmed via in vitro and in silico analysis.&#xa0;Furthermore, the levels of lipid peroxides and protein carbonyl content were elevated in thymol-treated groups. Notably,&#xa0;N-acetyl cysteine pretreatment reversed the efficacy of thymol on A549 cells. Moreover,&#xa0;thymol-treated human PBMC&#xa0;cells&#xa0;did not show any significant cytotoxicity.<br><br>CONCLUSION: Overall, our results confirmed that thymol can act as a safe and potent&#xa0;therapeutic&#xa0;agent to treat NSCLC.}, }
@article {pmid33092495, year = {2021}, author = {Sbardelotto, AB and Barros-Nepomuceno, FWA and Soares, BM and Cavalcanti, BC and Ramos de Sousa, RW and Costa, MPD and Pessoa, ODL and Pessoa, C and Ferreira, PMP}, title = {Cellular and biochemical antileukemic mechanisms of the meroterpenoid Oncocalyxone A.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {84}, number = {3}, pages = {95-111}, doi = {10.1080/15287394.2020.1835763}, pmid = {33092495}, issn = {1528-7394}, mesh = {Anthraquinones/chemistry/*pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; HL-60 Cells ; Humans ; }, abstract = {Oncocalyxone A, a 1,4-benzoquinone derived from Cordia oncocalyx, exhibits anti-inflammatory, antimicrobial and antidiabetic properties. The aim of this study was to (1) examine the cytotoxic actions of oncocalyxone A on human normal and tumor cell lines and (2) determine mechanistic actions underlying effects upon leukemia cells using cellular and molecular techniques. Antiproliferative studies on cancer cell lines, peripheral blood mononuclear cells, and human erythrocytes were performed using colorimetric assays. To understand cytotoxicity, assessments were performed with HL-60 leukemia cells (8, 16.5, or 33 µM) after 24 hr incubation using light and fluorescence microscopy, trypan blue, flow cytometry, Comet assay, western blot of caspases and poly-ADP-ribose polymerase (PARP), and effects on topoisomerase I and II. Oncocalyxone A exhibited cytotoxic action upon HL-60 cells and dividing leukocytes, but minimal hemolytic action on erythrocytes. Mechanistic investigations demonstrated reduction of cell viability, loss of membrane integrity, cell shrinking, chromatin condensation, blebbings, externalization of phosphatidylserine, caspase activation, PARP cleavage, mitochondrial depolarization, and DNA damage. Pre-treatment with N-acetylcysteine 4 mM significantly reduced DNA damage and prevented membrane integrity loss. Oncocalyxone A displayed free radical dependent antileukemic activity via apoptotic pathways and induced DNA damage in HL-60 cells. Oncocalyxone A possesses structural chemical simplicity enabling it to be a cost-effective alternative. These properties justify further improvements to enhance activity and selectivity and the development of pharmaceutical formulations. Abbreviations Acridine orange, AO; ANOVA, analysis of variance; BSA, bovine serum albumin; DI, Damage Index; DMSO, dimethylsulfoxide; EC50, effective concentration 50%; EDTA, ethylenediamine tetraacetic acid; EB, ethidium bromide; HCT-116, colon carcinoma line; HL-60, promyelocytic leukemia line; IC50, inhibitory concentration 50%; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide; OVCAR-8, ovarian carcinoma line; NAC, N-acetylcysteine, PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; PI, propidium iodide; PARP, poly-ADP-ribose polymerase; RPMI-1640, Roswell Park Memorial Institute medium; SF-295, glioblastoma line; ROS, reactive oxygen species; 7-AAD, 7-amino-actinomycin D; H2-DCF-DA, 7'-dichlorodihydrofluorescein diacetate.}, }
@article {pmid33084735, year = {2020}, author = {Aydin, A and Sunay, MM and Karakan, T and Özcan, S and Hasçiçek, AM and Yardimci, &#x130; and Surer, H and Korkmaz, M and Hücümenoğlu, S and Huri, E}, title = {The examination of the nephroprotective effect of montelukast sodium and N-acetylcysteine ın renal ıschemia with dimercaptosuccinic acid imaging in a placebo-controlled rat model.}, journal = {Acta cirurgica brasileira}, volume = {35}, number = {9}, pages = {e202000905}, pmid = {33084735}, issn = {1678-2674}, mesh = {*Acetates/pharmacology ; *Acetylcysteine/pharmacology ; Animals ; Cyclopropanes ; Kidney/blood supply ; *Quinolines/pharmacology ; Rats ; Rats, Wistar ; *Reperfusion Injury/prevention &amp; control ; Succimer ; Sulfides ; Tomography, X-Ray Computed ; }, abstract = {PURPOSE: To determine the nephroprotective effect of NAC and Montelukast Sodium administration against the development of renal damage associated with long warm renal ischemia.<br><br>METHODS: Twenty-seven rats were randomly divided into 3 study groups, which received NAC, montelukast and placebo, and 3 rats were included in the sham-treated control group. Medications were given 3 days before the procedure. DMSA renal scintigraphy was performed before and after surgery. The right renal pedicle was occluded for 45 min to induce ischemia and then subjected to reperfusion for 6 h (I/R groups).<br><br>RESULTS: On pathological examination, the mean pathological scores of the montelukast and NAC groups were significantly lower than those of the placebo group. (p <0.05). In biochemical examination, significant differences were found in all parameter levels between the placebo group and the montelukast and NAC groups. (p <0.05) When postoperative DMSA renal scintigraphy measurements and renal function levels were compared, significant differences were found between the montelukast and NAC groups and the placebo and sham groups.<br><br>CONCLUSION: The administration of NAC and montelukast sodium was seen to have a nephroprotective effect against the development of renal damage associated with warm renal ischemia.}, }
@article {pmid33081375, year = {2020}, author = {Park, SY and An, JM and Seo, JT and Seo, SR}, title = {Y-27632 Induces Neurite Outgrowth by Activating the NOX1-Mediated AKT and PAK1 Phosphorylation Cascades in PC12 Cells.}, journal = {International journal of molecular sciences}, volume = {21}, number = {20}, pages = {}, pmid = {33081375}, issn = {1422-0067}, support = {2014R1A2A2A01007717//National Research Foundation of Korea/ ; 2018R1A2B6006286//National Research Foundation of Korea/ ; }, mesh = {Acetylcysteine/pharmacology ; Amides/*pharmacology ; Animals ; Chromans/pharmacology ; Free Radical Scavengers/pharmacology ; NADPH Oxidase 1/metabolism ; Neuronal Outgrowth/*drug effects ; Onium Compounds/pharmacology ; PC12 Cells ; Phosphorylation ; Protein Kinase Inhibitors/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Pyridines/*pharmacology ; Rats ; *Signal Transduction ; p21-Activated Kinases/metabolism ; rac1 GTP-Binding Protein/metabolism ; }, abstract = {Y-27632 is known as a selective Rho-associated coiled coil-forming kinase (ROCK) inhibitor. Y-27632 has been shown to induce neurite outgrowth in several neuronal cells. However, the precise molecular mechanisms linking neurite outgrowth to Y-27632 are not completely understood. In this study, we examined the ability of Y-27632 to induce neurite outgrowth in PC12 cells and evaluated the signaling cascade. The effect of Y-27632 on the neurite outgrowth was inhibited by reactive oxygen species (ROS) scavengers such as N-acetyl cysteine (NAC) and trolox. Furthermore, Y-27632-induced neurite outgrowth was not triggered by NADPH oxidase 1 (NOX1) knockdown or diphenyleneiodonium (DPI), a NOX inhibitor. Suppression of the Rho-family GTPase Rac1, which is under the negative control of ROCK, with expression of the dominant negative Rac1 mutant (Rac1N17) prevented Y-27632-induced neurite outgrowth. Moreover, the Rac1 inhibitor NSC23766 prevented Y-27632-induced AKT and p21-activated kinase 1 (PAK1) activation. AKT inhibition with MK2206 suppressed Y-27632-induced PAK1 phosphorylation and neurite outgrowth. In conclusion, our results suggest that Rac1/NOX1-dependent ROS generation and subsequent activation of the AKT/PAK1 cascade contribute to Y-27632-induced neurite outgrowth in PC12 cells.}, }
@article {pmid33080692, year = {2020}, author = {Liu, Y and Wang, M and Luo, G and Qian, X and Wu, C and Zhang, Y and Chen, B and Leung, EL and Tang, Y}, title = {Experience of N-acetylcysteine airway management in the successful treatment of one case of critical condition with COVID-19: A case report.}, journal = {Medicine}, volume = {99}, number = {42}, pages = {e22577}, pmid = {33080692}, issn = {1536-5964}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Inhalation ; Airway Management/*methods ; Anastomosis, Surgical ; Betacoronavirus ; Bronchoalveolar Lavage/*methods ; COVID-19 ; Coronavirus Infections/complications/*therapy ; Humans ; Intubation, Intratracheal/methods ; Length of Stay ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral/complications/*therapy ; Pneumothorax/complications ; Respiration, Artificial ; SARS-CoV-2 ; }, abstract = {RATIONALE: The new coronavirus pneumonia Corona Virus Disease 2019 (COVID-19) has become a global pandemic. Patients with critically COVID-19 usually require invasive respiratory support, and the airway management is particularly important and the prognosis is poor.<br><br>PATIENT CONCERNS: A 64-year-old man with an anastomotic fistula after radical treatment of esophageal cancer and right-side encapsulated pyopneumothorax was admitted with cough and dyspnea.<br><br>DIAGNOSIS: The patient was diagnosed with novel coronavirus pneumonia and right-side encapsulated pyopneumothorax by pharyngeal swab nucleic acid test in combination with chest computed tomography (CT).<br><br>INTERVENTIONS: The patient was treated with antibiotics, antiviral and antibacterial medications, respiratory support, expectorant nebulization, and nutritional support. But he expressed progressive deterioration. Endotracheal intubation and mechanical ventilation were performed since the onset of the type - respiratory failure on the 13th day of admission. The patient had persistent refractory hypercapnia after mechanical ventilation. Based on the treatment mentioned above, combined with repeated bronchoalveolar lavage by using N-acetylcysteine (NAC) inhalation solution, the patients refractory hypercapnia was gradually improved.<br><br>OUTCOMES: The patient was cured and discharged after being given the mechanical ventilation for 26 days as well as 46 days of hospitalization, currently is surviving well.<br><br>LESSONS: Patients with severe conditions of novel coronavirus pneumonia often encounter bacterial infection in their later illness-stages. They may suffer respiratory failure and refractory hypercapnia that is difficult to improve due to excessive mucus secretion leading to small airway obstruction. This study provided a new insight on the proper treatment severe COVID-19 patients. The use of reasonable antibiotics and symptomatic respiratory support and other treatment, timely artificial airway and repeated bronchoalveolar NAC inhalation solution lavage, expectorant and other airway management are essential for such patients.}, }
@article {pmid33080438, year = {2020}, author = {Shin, SK and Cho, HW and Song, SE and Im, SS and Bae, JH and Song, DK}, title = {Oxidative stress resulting from the removal of endogenous catalase induces obesity by promoting hyperplasia and hypertrophy of white adipocytes.}, journal = {Redox biology}, volume = {37}, number = {}, pages = {101749}, pmid = {33080438}, issn = {2213-2317}, mesh = {3T3-L1 Cells ; *Adipocytes, White ; Adipogenesis ; Animals ; Catalase/genetics ; Diet, High-Fat ; Fibroblasts ; *Hydrogen Peroxide ; Hyperplasia ; Hypertrophy ; Mice ; Mice, Inbred C57BL ; Obesity/genetics ; Oxidative Stress ; }, abstract = {Obesity is regarded as an abnormal expansion and excessive accumulation of fat mass in white adipose tissue. The involvement of oxidative stress in the development of obesity is still unclear. Although mainly present in peroxisomes, catalase scavenges intracellular H2O2 at toxic levels. Therefore, we used catalase-knockout (CKO) mice to elucidate the involvement of excessive H2O2 in the development of obesity. CKO mice with C57BL/6J background gained more weight with higher body fat mass with age than age-matched wild-type (WT) mice fed with either chow or high-fat diets. This phenomenon was attenuated by concomitant treatment with the antioxidants, melatonin or N-acetyl cysteine. Moreover, CKO mouse embryonic fibroblasts (MEFs) appeared to differentiate to adipocytes more easily than WT MEFs, showing increased H2O2 concentrations. Using 3T3-L1-derived adipocytes transfected with catalase-small interfering RNA, we confirmed that a more prominent lipogenesis occurred in catalase-deficient cells than in WT cells. Catalase-deficient adipocytes presented increased nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression but decreased adenosine monophosphate-activated protein kinase (AMPK) expression. Treatment with a NOX4 inhibitor or AMPK activator rescued the propensity for obesity of CKO mice. These findings suggest that excessive H2O2 and related oxidative stress increase body fat mass via both adipogenesis and lipogenesis. Manipulating NOX4 and AMPK in white adipocytes may be a therapeutic tool against obesity augmented by oxidative stress.}, }
@article {pmid33079548, year = {2020}, author = {Yang, S and Tran, C and Whiteley, GS and Glasbey, T and Kriel, FH and McKenzie, DR and Manos, J and Das, T}, title = {Covalent Immobilization of N-Acetylcysteine on a Polyvinyl Chloride Substrate Prevents Bacterial Adhesion and Biofilm Formation.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {36}, number = {43}, pages = {13023-13033}, doi = {10.1021/acs.langmuir.0c02414}, pmid = {33079548}, issn = {1520-5827}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Anti-Bacterial Agents/toxicity ; *Bacterial Adhesion ; Biofilms ; Gram-Positive Bacteria ; Humans ; Polyvinyl Chloride ; }, abstract = {Biofilm formation and antimicrobial resistance at surgical implant sites result in high morbidity and mortality. Identifying novel molecules that inhibit biofilm formation to coat surgical biomaterials is essential. One such compound is N-acetylcysteine (NAC), a potent antioxidant precursor for glutathione, necessary in mammalian cells and known to disrupt/prevent biofilms. In this study, NAC was covalently immobilized onto functionalized polyvinyl chloride surfaces using plasma immersion ion implantation (PIII) treatment that achieves covalent binding without the need for linker groups. NAC immobilization was characterized using water contact angles, Fourier-transform infrared, and X-ray photoelectron spectroscopy techniques. Bacterial viability and biofilm formation on NAC surfaces were assessed using resazurin assays, phase contrast microscopy, and colony counting experiments. Effect of NAC on bacterial polysaccharide production and DNA cleaving was investigated using the phenol-sulfuric acid method and the Qubit fluorometer. Surface thermodynamics between the NAC coating and bacterial cells were measured using the Lewis acid-base method. Surface characterization techniques demonstrated superficial changes after PIII treatment and subsequent covalent NAC immobilization. NAC-coated surfaces significantly reduced biofilm viability and the presence of Gram-negative and Gram-positive bacteria. NAC also decreased polysaccharide production and degraded DNA. This led to unfavorable conditions for biofilm formation on NAC-coated surfaces, as demonstrated by surface thermodynamic analysis. NAC-coated surfaces showed no cytotoxicity to human fibroblast cells. This study has successfully utilized NAC as an antibiofilm coating, which may pave the way for improved prophylactic coatings on medical implant devices in the future.}, }
@article {pmid33075405, year = {2021}, author = {Dobi, A and Rosanaly, S and Devin, A and Baret, P and Meilhac, O and Harry, GJ and d'Hellencourt, CL and Rondeau, P}, title = {Advanced glycation end-products disrupt brain microvascular endothelial cell barrier: The role of mitochondria and oxidative stress.}, journal = {Microvascular research}, volume = {133}, number = {}, pages = {104098}, pmid = {33075405}, issn = {1095-9319}, support = {Z01 ES021164/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Brain/*blood supply ; Capillary Permeability/*drug effects ; Cell Line ; Endothelial Cells/*drug effects/metabolism/pathology ; Glycation End Products, Advanced/*toxicity ; Mice ; Microvessels/*drug effects/metabolism/pathology ; Mitochondria/*drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Serum Albumin, Bovine/*toxicity ; }, abstract = {During diabetes mellitus, advanced glycation end-products (AGEs) are major contributors to the development of alterations in cerebral capillaries, leading to the disruption of the blood-brain barrier (BBB). Consequently, this is often associated with an amplified oxidative stress response in microvascular endothelial cells. As a model to mimic brain microvasculature, the bEnd.3 endothelial cell line was used to investigate cell barrier function. Cells were exposed to native bovine serum albumin (BSA) or modified BSA (BSA-AGEs). In the presence or absence of the antioxidant compound, N-acetyl-cysteine, cell permeability was assessed by FITC-dextran exclusion, intracellular free radical formation was monitored with H2DCF-DA probe, and mitochondrial respiratory and redox parameters were analyzed. We report that, in the absence of alterations in cell viability, BSA-AGEs contribute to an increase in endothelial cell barrier permeability and a marked and prolonged oxidative stress response. Decreased mitochondrial oxygen consumption was associated with these alterations and may contribute to reactive oxygen species production. These results suggest the need for further research to explore therapeutic interventions to restore mitochondrial functionality in microvascular endothelial cells to improve brain homeostasis in pathological complications associated with glycation.}, }
@article {pmid33074372, year = {2021}, author = {Do, VQ and Seo, YS and Park, JM and Yu, J and Duong, MTH and Nakai, J and Kim, SK and Ahn, HC and Lee, MY}, title = {A mixture of chloromethylisothiazolinone and methylisothiazolinone impairs rat vascular smooth muscle by depleting thiols and thereby elevating cytosolic Zn[2+] and generating reactive oxygen species.}, journal = {Archives of toxicology}, volume = {95}, number = {2}, pages = {541-556}, pmid = {33074372}, issn = {1432-0738}, mesh = {Animals ; Calcium/metabolism ; Cells, Cultured ; Disinfectants/toxicity ; HEK293 Cells ; Humans ; Humidifiers ; Male ; Muscle, Smooth, Vascular/*drug effects ; Preservatives, Pharmaceutical/toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Republic of Korea ; Sulfhydryl Compounds/*metabolism ; Thiazoles/*toxicity ; Vasoconstriction/drug effects ; Zinc/*metabolism ; }, abstract = {Chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) are biocidal preservatives and the active ingredients in Kathon CG, which contains ca. 1.5% mixture of CMIT and MIT at a ratio of 3:1 (CMIT/MIT). CMIT/MIT was misused as humidifier disinfectant products, which caused serious health problems in Korea. Here, the vascular effects of CMIT/MIT were investigated to evaluate claims of putative cardiovascular toxicity observed in humidifier disinfectant users. CMIT/MIT did not affect the basal tension of the rat thoracic aorta up to 2.5 μg/mL in myograph experiments. Instead, pretreatment with CMIT/MIT impaired phenylephrine- or 5-hydroxytryptamine-induced vasoconstriction in a range of 0.5-2.5 μg/mL, which was largely irreversible and not recovered by washing out the CMIT/MIT. Similarly, the application of CMIT/MIT to pre-contracted aorta caused a gradual loss of tension. In primary cultured vascular smooth muscle cells (VSMCs), CMIT/MIT caused thiol depletion, which in turn led to cytosolic Zn[2+] elevation and reactive oxygen species (ROS) formation. CMIT/MIT-induced shrinkage, detachment, and lysis of VSMCs depending on the concentration and the treatment time. All events induced by CMIT/MIT were prevented by a thiol donor N-acetylcysteine (NAC). Cytolysis could be inhibited by a Zn[2+] chelator TPEN and a superoxide scavenger TEMPOL, whereas they did not affect shrinkage and detachment. In accordance with these results, CMIT/MIT-exposed aortas exhibited dissociation and collapse of tissue in histology analysis. Taken together, CMIT/MIT causes functional impairment and tissue damage to blood vessels by depleting thiol and thereby elevating cytosolic Zn[2+] and generating ROS. Therefore, exposure to CMIT/MIT in consumer products may be a risk factor for cardiovascular disorders.}, }
@article {pmid33073673, year = {2021}, author = {Daussy, CF and Galais, M and Pradel, B and Robert-Hebmann, V and Sagnier, S and Pattingre, S and Biard-Piechaczyk, M and Espert, L}, title = {HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4[+] T cell death.}, journal = {Autophagy}, volume = {17}, number = {9}, pages = {2465-2474}, pmid = {33073673}, issn = {1554-8635}, mesh = {Autophagy ; CD4-Positive T-Lymphocytes ; Cell Death ; *HIV-1 ; Humans ; Macroautophagy ; Oxidative Stress ; T-Lymphocytes ; }, abstract = {The immunodeficiency observed in HIV-1-infected patients is mainly due to uninfected bystander CD4[+] T lymphocyte cell death. The viral envelope glycoproteins (Env), expressed at the surface of infected cells, play a key role in this process. Env triggers macroautophagy/autophagy, a process necessary for subsequent apoptosis, and the production of reactive oxygen species (ROS) in bystander CD4[+] T cells. Here, we demonstrate that Env-induced oxidative stress is responsible for their death by apoptosis. Moreover, we report that peroxisomes, organelles involved in the control of oxidative stress, are targeted by Env-mediated autophagy. Indeed, we observe a selective autophagy-dependent decrease in the expression of peroxisomal proteins, CAT and PEX14, upon Env exposure; the downregulation of either BECN1 or SQSTM1/p62 restores their expression levels. Fluorescence studies allowed us to conclude that Env-mediated autophagy degrades these entire organelles and specifically the mature ones. Together, our results on Env-induced pexophagy provide new clues on HIV-1-induced immunodeficiency.Abbreviations: Ab: antibodies; AF: auranofin; AP: anti-proteases; ART: antiretroviral therapy; BafA1: bafilomycin A1; BECN1: beclin 1; CAT: catalase; CD4: CD4 molecule; CXCR4: C-X-C motif chemokine receptor 4; DHR123: dihydrorhodamine 123; Env: HIV-1 envelope glycoproteins; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GFP-SKL: GFP-serine-lysine-leucine; HEK: human embryonic kidney; HIV-1: type 1 human immunodeficiency virus; HTRF: homogeneous time resolved fluorescence; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NAC: N-acetyl-cysteine; PARP: poly(ADP-ribose) polymerase; PEX: peroxin; ROS: reactive oxygen species; siRNA: small interfering ribonucleic acid; SQSTM1/p62: sequestosome 1.}, }
@article {pmid33072456, year = {2020}, author = {Daid, SS and Toribio, AD and Lakshmanan, S and Sadda, A and Epstein, A}, title = {Spontaneous Intraparenchymal Hepatic Hemorrhage as a Sequela of COVID-19.}, journal = {Cureus}, volume = {12}, number = {9}, pages = {e10447}, pmid = {33072456}, issn = {2168-8184}, abstract = {Patients with coronavirus disease 2019 (COVID-19) have been presenting with varying signs and symptoms. The medical community is being updated with new knowledge about this disease daily. We present a case of intrahepatic hemorrhage in a patient diagnosed with C0VID-19 which we believe was caused by endothelialitis, which is a characteristic feature of COVID-19. Nevertheless, further continued studies are required to validate this point. We aim to educate the medical community about the possible complications by COVID-19 in the liver and highlight that N-acetylcysteine (NAC) may be a useful option in these cases.}, }
@article {pmid33067289, year = {2020}, author = {Guo, Z and Liu, J and Lei, L and Xue, Y and Liu, L and Huang, H and Chen, S and Liu, Y and Lin, Y and Tao, J and Xu, Q and Wu, K and Zhang, L and Chen, JY}, title = {Effect of N-acetylcysteine on prevention of contrast-associated acute kidney injury in patients with STEMI undergoing primary percutaneous coronary intervention: a systematic review and meta-analysis of randomised controlled trials.}, journal = {BMJ open}, volume = {10}, number = {10}, pages = {e039009}, pmid = {33067289}, issn = {2044-6055}, mesh = {Acetylcysteine/therapeutic use ; *Acute Kidney Injury/chemically induced/prevention &amp; control ; Humans ; *Percutaneous Coronary Intervention/adverse effects ; Randomized Controlled Trials as Topic ; Renal Dialysis ; *ST Elevation Myocardial Infarction/surgery ; }, abstract = {OBJECTIVE: Several studies evaluating the preventive effect of N-acetylcysteine (NAC) on contrast-associated acute kidney injury (CA-AKI) among patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) have suggested inconsistent results and that a systematic review and meta-analysis should be performed.<br><br>DESIGN: Systematic review and meta-analysis.<br><br>DATA SOURCES: PubMed, MEDLINE, EMBASE, ClinicalTrials.gov and the Cochrane Central databases were searched from inception to 15 November 2019.<br><br>ELIGIBILITY CRITERIA: Randomised controlled trials assessing use of NAC compared with non-use of NAC (eg, placebo) in preventing CA-AKI in patients with STEMI following PPCI were included.<br><br>DATA SYNTHESIS: Relative risks with 95% CIs were pooled using a random-effects model. Evidence level of conclusions was assessed by Cochrane GRADE measure.<br><br>RESULTS: Seven trials including 1710 patients were identified. Compared with non-use of NAC, use of NAC significantly reduced the incidence of CA-AKI by 49% (risk ratio (RR) 0.51, 95%&#x2009;CI 0.31 to 0.82, p<0.01) and all-cause in-hospital mortality by 63% (RR 0.37, 95%&#x2009;CI 0.17 to 0.79, p=0.01). The estimated effects on the requirement for dialysis (RR 0.61, 95%&#x2009;CI 0.11 to 3.38, p=0.24) were not statistically significant. Trial sequential analysis con&#xfb01;rmed the true positive of NAC in reducing risk of CA-AKI. Subgroup analyses suggested that the administration of NAC had greater benefits in patients with renal dysfunction and in those receiving oral administration and higher dosage of NAC.<br><br>CONCLUSIONS: NAC intake reduces the risk of CA-AKI and all-cause in-hospital mortality in patients with STEMI undergoing PPCI. The estimated potential benefit of NAC in preventing dialysis was ambiguous, and further high-quality studies are needed.<br><br>PROSPERO REGISTRATION NUMBER: CRD42020155265.}, }
@article {pmid33067169, year = {2021}, author = {Masnadi Shirazi, K and Sotoudeh, S and Masnadi Shirazi, A and Moaddab, SY and Nourpanah, Z and Nikniaz, Z}, title = {Effect of N-acetylcysteine on remission maintenance in patients with ulcerative colitis: A randomized, double-blind controlled clinical trial.}, journal = {Clinics and research in hepatology and gastroenterology}, volume = {45}, number = {4}, pages = {101532}, doi = {10.1016/j.clinre.2020.08.010}, pmid = {33067169}, issn = {2210-741X}, mesh = {*Acetylcysteine/therapeutic use ; C-Reactive Protein ; *Colitis, Ulcerative/drug therapy ; Humans ; Leukocyte L1 Antigen Complex ; Neoplasm Recurrence, Local ; }, abstract = {BACKGROUND: The use of antioxidant agents is suggested as a complementary therapy in UC patients for the prevention of flares. Considering the potent antioxidant activity of N-acetylcysteine (NAC), in the present study we aimed to assess the effect of this supplement on remission maintenance in patients with ulcerative colitis (UC).<br><br>METHODS: In the present double-blind randomized controlled clinical trial, 168 volunteer UC patients who were on high dose corticosteroid and Mesalamine for flare-up management, were recruited. The patients received 800&#x202f;mg NAC or placebo for 16 weeks. Simultaneously, the prednisolone dose was tapered. The patients were followed up six more weeks post-intervention. The primary efficacy of the treatment was remaining in remission. The secondary outcomes were the endoscopic relapse, serum level of hs-CRP, hemoglobin, and fecal calprotectin level.<br><br>RESULTS: During 22 weeks follow up, 25 patients experienced relapses, six of them were in the NAC group and 19 of them were in the placebo group. There was a significant difference between the NAC and placebo groups regarding the relapse-free period (P&#x202f;=&#x202f;0.007). Compared with the NAC group, significantly more patients in the placebo group had an endoscopic relapse (p&#x202f;<&#x202f;0.001). At the end of the intervention period (16 weeks) and 6 weeks post-intervention, the mean fecal calprotectin, serum erythrocyte sedimentation rate, and hs-CRP levels were significantly lower in the NAC group compared with the placebo group (p&#x202f;<&#x202f;0.05).<br><br>CONCLUSION: The findings indicated that NAC had a significantly more positive effect on the maintenance of remission compared with placebo in UC patients that were in the steroid-tapering phase of therapy.}, }
@article {pmid33065789, year = {2020}, author = {Zhou, Q and Zhang, L and Sun, Y and Xie, M and Lin, J}, title = {Clinical value of N-acetylcysteine combined with terbutaline sulfate in elderly patients with chronic obstructive pulmonary disease and its effect on apoptosis/anti-apoptosis mechanism.}, journal = {Annals of palliative medicine}, volume = {9}, number = {5}, pages = {3393-3401}, doi = {10.21037/apm-20-1605}, pmid = {33065789}, issn = {2224-5839}, mesh = {*Acetylcysteine/therapeutic use ; Aged ; Apoptosis ; Humans ; Oxidative Stress ; *Pulmonary Disease, Chronic Obstructive/drug therapy ; Terbutaline/therapeutic use ; }, abstract = {BACKGROUND: The pathogenesis of chronic obstructive pulmonary disease (COPD) is complex. Our study aimed to investigate the clinical value of N-acetylcysteine (NAC) combined with terbutaline sulfate in the treatment of COPD in elderly people, and its effect on the apoptosis/anti-apoptosis mechanism.<br><br>METHODS: A total of 126 elderly COPD patients in our hospital from December 2017 to June 2019 were recruited and divided into 3 groups. On the basis of conventional treatment, control group A was treated with NAC, control group B with terbutaline sulfate, and combined group with both drugs. Lung function, apoptosis/anti-apoptosis related indexes, oxidative stress indexes, COPD assessment test (CAT) score, 6-min walk distance (6MWD), blood gas indexes, and adverse reactions were measured.<br><br>RESULTS: The levels of forced vital capacity (FVC), maximum mid-expiratory flow rate (MMF), peak expiratory flow (PEF), oxygenation index (OI), and blood oxygen saturation (SaO2) in 3 groups were increased after treatment, and were the highest in the combined group. The level of carbon dioxide partial pressure (PaCO2) was decreased, and was the lowest in the combined group. After 2 weeks of treatment, the 6MWD had increased in all 3 groups and was longest in the combined group. The CAT score was decreased and the extent of decrease was the highest in the combined group. After treatment, the levels of Fas receptor/apoptosis antigen 1 (Fas/APO-1), soluble Fas (sFas), malondialdehyde (MDA), and reactive oxygen species (ROS) in the three groups were decreased, and their levels were decreased most markedly in the combined group. Meanwhile, the levels of superoxide dismutase (SOD) and glutathione peroxide enzyme (GSH-PX) were increased after treatment, and their levels were the highest in the combined group. The incidence of dizziness, chest tightness, constipation, and nasal congestion in the combination group were not significantly different from the other two groups.<br><br>CONCLUSIONS: The combined use of terbutaline sulfate and NAC in the treatment of elderly patients with COPD can effectively improve their lung function and blood gas status, which can strengthen athletic ability, reduce the oxidative stress response, and regulate apoptotic cytokines.}, }
@article {pmid33065076, year = {2021}, author = {Celorrio, M and Rhodes, J and Vadivelu, S and Davies, M and Friess, SH}, title = {N-acetylcysteine reduces brain injury after delayed hypoxemia following traumatic brain injury.}, journal = {Experimental neurology}, volume = {335}, number = {}, pages = {113507}, pmid = {33065076}, issn = {1090-2430}, support = {R01 NS097721/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Axons/pathology ; Behavior, Animal/drug effects ; Brain Injuries, Traumatic/*drug therapy/psychology ; Fear ; Glutathione/metabolism ; Hippocampus/pathology ; Hypoxia/*drug therapy/psychology ; Male ; Maze Learning ; Mice ; Mice, Inbred C57BL ; Neurons/pathology ; Neuroprotective Agents/*therapeutic use ; Psychomotor Performance ; Social Behavior ; }, abstract = {Preclinical investigations into neuroprotective agents for traumatic brain injury (TBI) have shown promise when administered before or very early after experimental TBI. However clinical trials of therapeutics demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, a lost in translation phenomenon. N-acetylcysteine (NAC) is a potent anti-oxidant with demonstrated efficacy in pre-clinical TBI when administered early after primary injury. Utilizing our clinically relevant mouse model, we hypothesized that NAC administration in a clinically relevant timeframe could improve the brain's resilience to the secondary insult of hypoxemia. NAC or vehicle administered daily starting 2 h prior to hypoxemia (24 h after controlled cortical impact) for 3 doses in male mice reduced short-term axonal injury and hippocampal neuronal loss. Six month behavioral assessments including novel object recognition, socialization, Barnes maze, and fear conditioning did not reveal performance differences between sham controls and injured mice receiving NAC or saline vehicle. At 7 months after injury, NAC administered mice had reduced hippocampal neuronal loss but no reduction in lesion volume. In summary, our preclinical trial to test the neuroprotective efficacy of NAC against a secondary hypoxic insult after TBI demonstrated short and long-term neuropathological evidence of neuroprotection but a lack of detectable differences in long-term behavioral assessments between sham controls and injured mice limits conclusions on its impact on long-term neurobehavioral outcomes.}, }
@article {pmid33063355, year = {2021}, author = {Cano-Cebrián, MJ and Fernández-Rodríguez, S and Hipólito, L and Granero, L and Polache, A and Zornoza, T}, title = {Efficacy of N-acetylcysteine in the prevention of alcohol relapse-like drinking: Study in long-term ethanol-experienced male rats.}, journal = {Journal of neuroscience research}, volume = {99}, number = {2}, pages = {638-648}, doi = {10.1002/jnr.24736}, pmid = {33063355}, issn = {1097-4547}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Alcohol Drinking/*prevention &amp; control ; Alcoholism/*drug therapy ; Animals ; Drug Evaluation, Preclinical ; Ethanol/toxicity ; Infusions, Subcutaneous ; Injections, Subcutaneous ; Male ; Models, Animal ; Random Allocation ; Rats ; Rats, Wistar ; Recurrence ; Substance Withdrawal Syndrome/*drug therapy ; }, abstract = {Alcohol use disorders are chronic and highly relapsing disorders, thus alcoholic patients have a high rate of recidivism for drug use even after long periods of abstinence. The literature points to the potential usefulness of N-acetylcysteine (NAC) in the management of several substance use disorders probably due to its capacity to restore brain homeostasis of the glutamate system disrupted in addiction. However, there is little evidence in the case of alcohol. The aim of this study was to explore the potential anti-relapse efficacy of NAC using the alcohol deprivation effect (ADE) model in long-term experienced rats. Two experiments were performed in male Wistar rats to: (a) test the efficacy of NAC to prevent relapse and (b) discriminate the best administration schedule (intermittent vs. continuous) for NAC. In the first experiment, animals were implanted with mini-osmotic pumps delivering 0 or 1 mg/hr NAC during 14 days. In a second experiment, rats received 0, 60, or 100 mg/kg once daily by subcutaneous injection. The efficacy to prevent ADE was evaluated in both experiments. NAC subcutaneously administered, either by continuous infusion or by intermittent injections regimen, is able to block the ADE. The best results were obtained after using 60 mg/kg NAC dose. Our findings support the hypothesis that NAC may represent a valuable therapy in the management of alcohol relapse.}, }
@article {pmid33062321, year = {2020}, author = {Erol, G and Kartal, H and Comu, FM and Cetin, E and Demirdas, E and Sicim, H and Unal, CS and Gunay, C and Oz, BS and Bolcal, C}, title = {Effects of N-Acetylcysteine and N-Acetylcysteine Amide on Erythrocyte Deformability and Oxidative Stress in a Rat Model of Lower Extremity Ischemia-Reperfusion Injury.}, journal = {Cardiology research and practice}, volume = {2020}, number = {}, pages = {6841835}, pmid = {33062321}, issn = {2090-8016}, abstract = {N-acetylcysteine (NAC) is an antioxidant which works as a free radical scavenger and antiapoptotic agent. N-acetylcysteine-amide (NACA) is a modified form of NAC containing an amide group instead of a carboxyl group of NAC. Our study aims to investigate the effectiveness of these two substances on erythrocyte deformability and oxidative stress in muscle tissue. Materials and Methods. A total of 24 Wistar albino rats were used in our study. The animals were randomly divided into five groups as control (n: 6), ischemia (n: 6), NAC (n: 6), and NACA (n: 6). In the ischemia, NAC, and NACA groups, 120 min of ischemia and 120 min of reperfusion were achieved by placing nontraumatic vascular clamps across the abdominal aorta. The NAC and NACA groups were administered an injection 30 min before ischemia (100 mg/kg NAC; 100 mg/kg NACA; intravenous). Blood samples were taken from the animals at the end of the ischemic period. The lower extremity gastrocnemius muscle was isolated and stored at -80 degrees to assess the total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) values and was analyzed. Results. The erythrocyte deformability index was found to be statistically significantly lower in rats treated with NAC and NACA before ischemia-reperfusion compared to the groups that received only ischemia-reperfusion. In addition, no statistically significant difference was found between the control group and the NAC and NACA groups. The groups receiving NAC and NACA before ischemia exhibited higher total antioxidative status and lower total oxidative status while the oxidative stress index was also lower. Conclusion. The results of our study demonstrated the protective effects of NAC and NACA on erythrocyte deformability and oxidative damage in skeletal muscle in lower extremity ischemia-reperfusion. NAC and NACA exhibited similar protective effects on oxidative damage and erythrocyte deformability.}, }
@article {pmid33062135, year = {2020}, author = {Zhang, Y and Xiao, JF and Yang, HF and Cao, WW and Shi, HM and Cun, JF and Tay, FR and Ping, J and Jiao, Y and Xiao, YH}, title = {Corrigendum to "N-Acetyl Cysteine as a Novel Polymethyl Methacrylate Resin Component: Protection against Cell Apoptosis and Genotoxicity".}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {2768238}, pmid = {33062135}, issn = {1942-0994}, abstract = {[This corrects the article DOI: 10.1155/2019/1301736.].}, }
@article {pmid33061227, year = {2020}, author = {Concessao, P and Bairy, LK and Raghavendra, AP}, title = {Protective effect of Mucuna pruriens against arsenic-induced liver and kidney dysfunction and neurobehavioral alterations in rats.}, journal = {Veterinary world}, volume = {13}, number = {8}, pages = {1555-1566}, pmid = {33061227}, issn = {0972-8988}, abstract = {BACKGROUND AND AIM: Intoxication of arsenic in rats is known to result in neurological effects as well as liver and kidney dysfunction. Mucuna pruriens has been identified for its medicinal properties. The aim of the study was to investigate the protective effect of aqueous seed extract of M. pruriens on sodium arsenite-induced memory impairment, liver, and kidney functions in rats.<br><br>MATERIALS AND METHODS: The experiment was divided into short-term treatment (45 days) and long-term treatment (90 days), with each group divided into nine sub-groups consisting of six animals each. Sub-groups 1 and 2 served as normal, and N-acetylcysteine (NAC) controls, respectively. Sub-groups 3-9 received sodium arsenite in drinking water (50 mg/L). In addition, sub-group 4 received NAC (210 mg/kg b.wt) orally once daily, sub-groups 5-7 received aqueous seed extract of M. pruriens (350 mg/kg b.wt, 530 mg/kg b.wt, and 700 mg/kg b.wt) orally once daily and sub-groups 8 and 9 received a combination of NAC and aqueous seed extract of M. pruriens (350 mg/kg b.wt and 530 mg/kg b.wt) orally once daily. Following the treatment, the blood was drawn retro-orbitally to assess the liver (serum alanine transaminase [ALT], serum aspartate transaminase, and serum alkaline phosphatase) and kidney (serum urea and serum creatinine) functions. Learning and memory were assessed by passive avoidance test. Animals were sacrificed by an overdose of ketamine, and their Nissl stained hippocampal sections were analyzed for alterations in neural cell numbers in CA1 and CA3 regions.<br><br>RESULTS: In the short-term treatment, groups administered with M. pruriens 530 mg/kg b.wt alone and combination of NAC + M. pruriens 350 mg/kg b.wt exhibited a significant improvement in memory retention, less severe neurodegeneration, and decrease in serum ALT levels. In long-term treatment, groups administered with M. pruriens 700 mg/kg b.wt alone and combination of NAC+M. pruriens 350 mg/kg b.wt, respectively, showed better memory retention, decreased neural deficits, and reduced levels of kidney and liver enzymes.<br><br>CONCLUSION: The seed extract of M. pruriens showed significant enhancement in memory and learning. The number of surviving neurons in the CA1 and CA3 regions also increased on treatment with M. pruriens. Serum ALT, serum urea, and serum creatinine levels showed significant improvement on long-term treatment with M. pruriens.}, }
@article {pmid33053749, year = {2020}, author = {Hseu, YC and Chiang, YC and Vudhya Gowrisankar, Y and Lin, KY and Huang, ST and Shrestha, S and Chang, GR and Yang, HL}, title = {The In Vitro and In Vivo Anticancer Properties of Chalcone Flavokawain B through Induction of ROS-Mediated Apoptotic and Autophagic Cell Death in Human Melanoma Cells.}, journal = {Cancers}, volume = {12}, number = {10}, pages = {}, pmid = {33053749}, issn = {2072-6694}, support = {MOST-106-2320-B-039-054-MY3//Ministry of Science and Technology, Taiwan/ ; MOST-107-2320-B-039-013-MY3//Ministry of Science and Technology, Taiwan/ ; CMU107-TU-12//Asia University, Taiwan/ ; CMU108-MF-19//China Medical University, Taiwan/ ; CMU108-MF-80//China Medical University, Taiwan/ ; CMRC-CHM-8//Ministry of Education, Taiwan/ ; }, abstract = {Melanoma is the most prevalent type of skin cancer with high mortality rates. This study demonstrates the in vitro and in vivo anticancer properties of chalcone flavokawain B (FKB) induced ROS-mediated apoptosis and autophagy in human melanoma (human epithelial melanoma cell line A375 and/or human skin lymph node derived melanoma cell line A2058) cells. Cell viability was calculated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the expression patterns of various apoptosis, autophagy-associated proteins were determined by Western blot methods. Annexin V was detected by flow cytometry, whereas acidic vesicular organelles (AVOs) and intracellular ROS levels were measured by fluorescence microscopy. The in vivo anticancer properties of FKB were evaluated by xenografting the A375 cells into nude mice. The results convey that FKB inhibited cell viability, B-Raf proto-oncogene, serine/threonine kinase (BRAF)/extracellular signal-regulated kinase (ERK) expression in human melanoma cells. Caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage pathway, and Bcl2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2) dysregulation were involved in the execution of apoptosis. Moreover, FKB-induced autophagy was observed through increased microtubule-associated protein 1A/1B-light chain 3B (LC3-II) accumulation and AVOs formation, which was also associated with an increase in sequestosome 1 (SQSTM1/p62), decreased protein kinase B (AKT)/mammalian target of rapamycin (mTOR) expressions, and dysregulated Beclin-1/Bcl-2 levels. Autophagy inhibitors [3-methyladenine (3-MA)/chloroquine (CQ)] and LC3 silencing suppressed FKB-induced apoptosis by decreasing caspase-3 in melanoma cells. The antioxidant N-acetylcysteine (NAC) diminished FKB-induced apoptotic and autophagic cell death. However, the inhibition of apoptosis decreased FKB-induced autophagy (LC3-I/II). The in vivo study confirmed that FKB inhibited melanoma growth in A375-xenografted nude mice. This study concluded that FKB is critically associated with the execution and generation of ROS-modulated apoptotic and autophagic cell death of melanoma cells. FKB also repressed tumor growth in xenografted nude mice. Therefore, flavokawain B might be a potential anti-tumor agent in human melanoma treatment.}, }
@article {pmid33051453, year = {2020}, author = {Guo, J and Ren, R and Sun, K and Yao, X and Lin, J and Wang, G and Guo, Z and Xu, T and Guo, F}, title = {PERK controls bone homeostasis through the regulation of osteoclast differentiation and function.}, journal = {Cell death &amp; disease}, volume = {11}, number = {10}, pages = {847}, pmid = {33051453}, issn = {2041-4889}, mesh = {Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Bone and Bones/*cytology/drug effects/metabolism ; Cell Differentiation/physiology ; Down-Regulation/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Female ; Homeostasis ; Humans ; Indoles/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Osteoclasts/*cytology/drug effects/metabolism ; RANK Ligand/antagonists &amp; inhibitors/metabolism ; Random Allocation ; Thapsigargin/pharmacology ; eIF-2 Kinase/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Osteoclasts are multinucleated giant cells with the ability to degrade bone tissue, and are closely related to abnormal bone metabolic diseases. Endoplasmic reticulum (ER) is an organelle responsible for protein modification, quality control, and transportation. The accumulation of unfolded or misfolded proteins in ER cavity induces ER stress. Double-stranded RNA-dependent protein kinase-like ER kinase (PERK) is an ER stress-sensing protein, which is ubiquitous in eukaryotic cells. Systemic PERK knockout mice show severe bone loss, suggesting that PERK is of great significance for maintaining the normal growth and development of bone tissue, but the role of PERK in osteoclastogenesis is still unclear. In this study, we found that PERK was significantly activated during RANKL-induced osteoclast differentiation; knockdown of PERK by siRNA and inhibition of PERK by GSK2606414, respectively, had significant negative regulatory effects on the formation and bone resorption of osteoclasts. PERK inhibitor GSK2606414 down-regulated the mRNA levels and protein expression of osteoclast differentiation marker genes, and inhibited RANKL-induced activation of Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Treatment with PERK inhibitor GSK2606414 in ovariectomized mouse model significantly suppressed bone loss and osteoclast formation. Thapsigargin activated ER stress to enhance autophagy, while GSK2606414 had a significant inhibitory effect on autophagy flux and autophagosome formation. Antioxidant N-acetylcysteine (NAC) could inhibit the expression of PERK phosphorylation, osteoclast-related proteins and autophagy-related proteins, but the use of PERK activator CCT020312 can reverse inhibition effect of NAC. Our findings demonstrate a key role for PERK in osteoclast differentiation and suggest its therapeutic potential.}, }
@article {pmid33050207, year = {2020}, author = {Clemente, LP and Rabenau, M and Tang, S and Stanka, J and Cors, E and Stroh, J and Culmsee, C and von Karstedt, S}, title = {Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration.}, journal = {Cells}, volume = {9}, number = {10}, pages = {}, pmid = {33050207}, issn = {2073-4409}, mesh = {Antioxidants/metabolism ; Apoptosis ; Biological Transport ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Respiration/*drug effects ; Dynamin I/metabolism ; Dynamin II/metabolism ; Ferroptosis/*drug effects/physiology ; Free Radical Scavengers ; Glutathione Peroxidase/metabolism ; Humans ; Hydrazones/metabolism/*pharmacology ; Iron/metabolism ; Lipid Peroxidation/drug effects ; Mitochondria/drug effects/metabolism ; Protective Agents/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Ferroptosis is a form of regulated necrosis characterized by a chain-reaction of detrimental membrane lipid peroxidation following collapse of glutathione peroxidase 4 (Gpx4) activity. This lipid peroxidation is catalyzed by labile ferric iron. Therefore, iron import mediated via transferrin receptors and both, enzymatic and non-enzymatic iron-dependent radical formation are crucial prerequisites for the execution of ferroptosis. Intriguingly, the dynamin inhibitor dynasore, which has been shown to block transferrin receptor endocytosis, can protect from ischemia/reperfusion injury as well as neuronal cell death following spinal cord injury. Yet, it is unknown how dynasore exerts these cell death-protective effects. Using small interfering RNA suppression, lipid reactive oxygen species (ROS), iron tracers and bona fide inducers of ferroptosis, we find that dynasore treatment in lung adenocarcinoma and neuronal cell lines strongly protects these from ferroptosis. Surprisingly, while the dynasore targets dynamin 1 and 2 promote extracellular iron uptake, their silencing was not sufficient to block ferroptosis suggesting that this route of extracellular iron uptake is dispensable for acute induction of ferroptosis and dynasore must have an additional off-target activity mediating full ferroptosis protection. Instead, in intact cells, dynasore inhibited mitochondrial respiration and thereby mitochondrial ROS production which can feed into detrimental lipid peroxidation and ferroptotic cell death in the presence of labile iron. In addition, in cell free systems, dynasore showed radical scavenger properties and acted as a broadly active antioxidant which is superior to N-acetylcysteine (NAC) in blocking ferroptosis. Thus, dynasore can function as a highly active inhibitor of ROS-driven types of cell death via combined modulation of the iron pool and inhibition of general ROS by simultaneously blocking two routes required for ROS and lipid-ROS driven cell death, respectively. These data have important implications for the interpretation of studies observing tissue-protective effects of this dynamin inhibitor as well as raise awareness that off-target ROS scavenging activities of small molecules used to interrogate the ferroptosis pathway should be taken into consideration.}, }
@article {pmid33048478, year = {2020}, author = {Kim, S and Kim, SH and Lee, CE}, title = {SOCS1 Represses Fractionated Ionizing Radiation-Induced EMT Signaling Pathways through the Counter-Regulation of ROS-Scavenging and ROS-Generating Systems.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {54}, number = {5}, pages = {1026-1040}, doi = {10.33594/000000285}, pmid = {33048478}, issn = {1421-9778}, support = {2015R1A2A2A01003291, 2015M2B2A9029226, 2018R1A2B6002201//National Research Foundation of Korea/Republic of Korea ; }, mesh = {Acetylcysteine/*pharmacology ; Colorectal Neoplasms/drug therapy/metabolism/*pathology/radiotherapy ; *Epithelial-Mesenchymal Transition ; Free Radical Scavengers/pharmacology ; *Gene Expression Regulation, Neoplastic ; Humans ; *Radiation, Ionizing ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Suppressor of Cytokine Signaling 1 Protein/genetics/*metabolism ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND/AIMS: Fractionated ionizing radiation (FIR) is an anti-cancer protocol widely applied for the treatment of diverse types of cancers to reduce damage to normal cells. However, cancer cells receiving multiple irradiations at low doses during FIR, often develop resistance to the therapy exhibiting malignant features including epithelial to mesenchymal transition (EMT). The present study has been performed to elucidate the mechanism of FIR-induced EMT signaling pathways and to identify a molecular target for radioresistance modulated by suppressors of cytokine signaling (SOCS)1.<br><br>METHODS: Colorectal cancer cell lines received FIR with a daily dose of 2 Gy for 3 days. Generation of intracellular reactive oxygen species (ROS) and its role in EMT signaling induced by FIR were analyzed in SOCS1 over-expressing and knock-down cells. ROS were measured by DCF fluorescence using flow cytometry. Expression levels of EMT markers and signaling molecules were analyzed by Western blotting and confocal microscopy.<br><br>RESULTS: FIR induced ROS and changes in EMT markers including down-regulation of E-cadherin with up-regulation of Twist and Snail. Pretreatment of anti-oxidant N-acetyl cysteine (NAC) abrogated the FIR-induced ROS generation and EMT response. Mechanistic studies indicated that the FIR-induced ROS-mediated EMT signaling proceeded through Akt&#x2192;Src&#x2192;Erk pathways. In accordance with the anti-ROS function, SOCS1 blocked the FIR-induced EMT and the associated signaling pathways through thioredoxin (Trx1) up-regulation. This is evidenced by the observation that Trx1 ablation in SOCS1 over-expressing cells negated the inhibitory action of SOCS1 by restoring the FIR-induced ROS and EMT markers. In addition, we have obtained data supporting that the FIR-induced ROS is derived from functional mitochondria and NADPH oxidases (Nox), which are both down-regulated by SOCS1.<br><br>CONCLUSION: The results demonstrate that ROS signal acts as a mediator of the FIR-induced EMT. The data also suggest a potential anti-tumor function of SOCS1 by blocking the FIR therapy-induced resistance through the counter-regulation of ROS generating and scavenging systems.}, }
@article {pmid33048324, year = {2020}, author = {Costa, CRM and Seara, FAC and Peixoto, MS and Ramos, IP and Barbosa, RAQ and Carvalho, AB and Fortunato, RS and Silveira, ALB and Olivares, EL}, title = {Progression of heart failure is attenuated by antioxidant therapy with N-acetylcysteine in myocardial infarcted female rats.}, journal = {Molecular biology reports}, volume = {47}, number = {11}, pages = {8645-8656}, pmid = {33048324}, issn = {1573-4978}, mesh = {*Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; *Antioxidants/administration &amp; dosage/pharmacology ; Electrocardiography/*drug effects ; Female ; Heart/*drug effects ; Myocardial Infarction/*drug therapy ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {This study investigated the therapeutic potential of N-acetylcysteine (NAC) in the treatment of heart failure in female rats. Myocardial infarcted (MI) rats were given NAC (250 mg/kg/day p.o.) during 28 days after surgery (MI + NAC) or vehicle (MI + Placebo), and sham-operated rats received the same treatments (Sham + NAC and Sham + Placebo). Electrocardiographic and echocardiographic analyses were performed in the last week of treatment. Cardiac mRNA levels of types I and II superoxide dismutase (SOD), catalase, types I and III glutathione peroxidase (GPX), nerve growth factor (NGF), β1-adrenergic receptor (β1ADR), and type 2 muscarinic receptor (M2R) were assessed. Cardiac levels NADPH oxidase (NOX) activity, total content of reduced thiols, and SOD, GPX, and catalase activity were assessed. Compared to MI + Placebo group, MI + NAC group exhibited decreased NOX activity, increased content of reduced thiols, increased GPX activity, and normalized GPX III mRNA levels (p < 0.05). Heart and lung weights, left ventricular (LV) end-diastolic volume and left atrium/aorta ratio were decreased, while LV posterior wall thickness and ejection fraction were increased in MI + NAC group versus MI + Placebo rats (p < 0.05). Power density of low frequency band was decreased, while power density of high frequency and the root mean square of the successive differences were increased in MI + NAC rats versus MI + Placebo (p < 0.05). These findings indicate that NAC promotes therapeutic effects in the progression of MI-induced heart failure in female rats.}, }
@article {pmid33044432, year = {2021}, author = {Gómez-Gavara, C and Moya-Herraiz, &#xc1; and Hervás, D and Pérez-Rojas, J and LaHoz, A and López-Andújar, R}, title = {The Potential Role of Efficacy and Safety Evaluation of N-Acetylcysteine Administration During Liver Procurement. The NAC-400 Single Center Randomized Controlled Trial.}, journal = {Transplantation}, volume = {105}, number = {10}, pages = {2245-2254}, doi = {10.1097/TP.0000000000003487}, pmid = {33044432}, issn = {1534-6080}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Aged ; Alanine Transaminase/blood ; Antioxidants/*administration &amp; dosage/adverse effects ; Biomarkers/blood ; *Cold Ischemia/adverse effects/mortality ; Female ; Graft Survival/*drug effects ; Humans ; Infusions, Intravenous ; *Liver Transplantation/adverse effects/mortality ; Male ; Middle Aged ; Primary Graft Dysfunction/diagnosis/etiology/mortality/*prevention &amp; control ; Risk Factors ; Spain ; Time Factors ; *Tissue and Organ Harvesting/adverse effects/mortality ; *Tissue and Organ Procurement ; Treatment Outcome ; }, abstract = {BACKGROUND: N-acetylcysteine infusions have been widely used to reduce ischemia/reperfusion damage to the liver; however, convincing evidence of their benefits is lacking.<br><br>OBJECTIVE: To perform the largest randomized controlled trial to compare the impact of N-acetylcysteine infusion during liver procurement on liver transplant outcomes.<br><br>METHODS: Single center, randomized trial with patients recruited from La Fe University Hospital, Spain, from February 2012 to January 2016. A total of 214 grafts were transplanted and randomized to the N-acetylcysteine group (n&#x2009;=&#x2009;113) or to the standard protocol without N-acetylcysteine (n&#x2009;=&#x2009;101). The primary endpoint was allograft dysfunction (Olthoff criteria). Secondary outcomes included metabolomic biomarkers of oxidative stress levels, interactions between cold ischemia time and alanine aminotransferase level and graft and patient survival (ID no. NCT01866644).<br><br>RESULTS: The incidence of primary dysfunction was 34% (31% in the N-acetylcysteine group and 37.4% in the control group [P&#x2009;=&#x2009;0.38]). N-acetylcysteine administration reduced the alanine aminotransferase level when cold ischemia time was longer than 6 h (P&#x2009;=&#x2009;0.0125). Oxidative metabolites (glutathione/oxidized glutathione and ophthalmic acid) were similar in both groups (P&#x2009;>&#x2009;0.05). Graft and patient survival rates at 12 mo and 3 y were similar between groups (P&#x2009;=&#x2009;0.54 and P&#x2009;=&#x2009;0.69, respectively).<br><br>CONCLUSIONS: N-acetylcysteine administration during liver procurement does not improve early allograft dysfunction according to the Olthoff classification. However, when cold ischemia time is longer than 6 h, N-acetylcysteine improves postoperative ALT levels.}, }
@article {pmid33043729, year = {2020}, author = {Singh, AK and Verma, S and Kumar-M, P and Soni, H and Sharma, S and Sharma, S and Patil, A and Sharma, V}, title = {Appropriate chemopreventive strategy for anti-tubercular therapy related liver injury is unsettled: Results from a systematic review and network meta-analysis.}, journal = {Expert review of clinical pharmacology}, volume = {13}, number = {11}, pages = {1253-1262}, doi = {10.1080/17512433.2020.1835468}, pmid = {33043729}, issn = {1751-2441}, mesh = {Acetylcysteine/therapeutic use ; Antitubercular Agents/administration &amp; dosage/*adverse effects ; Bayes Theorem ; Chemical and Drug Induced Liver Injury/etiology/*prevention &amp; control ; Humans ; Randomized Controlled Trials as Topic ; Research Design ; }, abstract = {BACKGROUND: Role of chemoprophylaxis for prevention of antitubercular therapy-related drug-induced liver injury (ATT-DILI) is uncertain.<br><br>METHODS: Electronic databases were searched for randomized trials reporting on chemoprophylaxis agents for prevention of ATT-DILI. We included studies evaluating the role of a drug in comparison to controls/placebo. The primary outcome was the occurrence of ATT-DILI. We performed a Bayesian random-effects network meta-analysis to calculate odds ratios (ORs) and 95% credible intervals (CrI) for those arms where at least two studies were available. Additional comparative studies for these arms were also identified.<br><br>RESULTS: Fourteen studies were identified and seven included in the meta-analysis. The agents used for prevention of ATT-DILI were silymarin/silibinin (4 trials), N-acetylcysteine (NAC) (3 studies), herbal preparations (5 studies) and one study each for cholecalciferol and carnitine. Compared with controls/placebo, the odds of occurrence of hepatotoxicity with NAC was 7 * 10[-17] (95% CrI: 2.8 * 10[-53], 0.0053) and Silymarin was 0.68 (95% CrI: 0.084, 4.6). NAC had the highest probability of rank 1 (0.99) which was followed by Silymarin (0.004).<br><br>CONCLUSION: N-acetyl cysteine, but not Silymarin/Silibinin, appears to be beneficial in prevention of ATT-DILI. However, the results were limited by the possible risk of bias in included studies, variable definitions of ATT-DILI and limited number and category of patients.}, }
@article {pmid33042407, year = {2020}, author = {He, C and Xia, J and Gao, Y and Chen, Z and Wan, X}, title = {Chlorin A-mediated photodynamic therapy induced apoptosis in human cholangiocarcinoma cells via impaired autophagy flux.}, journal = {American journal of translational research}, volume = {12}, number = {9}, pages = {5080-5094}, pmid = {33042407}, issn = {1943-8141}, abstract = {BACKGROUND: Photodynamic therapy (PDT) is a promising strategy for multiple cancers. Chlorin e6 and its derivative 13[1]-[2'-(2-pyridyl)ethylamine] Chlorin e6 (Chlorin A) are effective photosensitizers, although their cytotoxic mechanisms have not yet been fully characterized.<br><br>METHODS: Cell viability and apoptosis were evaluated by CCK8 assay, TUNEL assay, and Annexin V/PI staining. The expression levels of different proteins were analyzed by Western blot analysis and immunofluorescence. The crosstalk between autophagy, endoplasmic reticulum stress (ERS), and mitochondrial dysfunction was investigated using reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), PERK inhibitor GSK2606414, autophagy inhibitor 3-MA, and mitochondrial stabilizer elamipretide. Furthermore, the extent of ROS production, lysosomal damage, autophagy flux, and mitochondrial membrane potential (MMP) were tracked using established probes. An in vivo xenograft model of cholangiocarcinoma (CCA) was established in BALB/c-nude mice by inoculation with EGI-1 cells, and Chlorin A was administered topically or intravenously, followed by light irradiation.<br><br>RESULTS: Chlorin A-PDT decreased the viability of CCA cells and induced apoptosis. Intriguingly, Chlorin A-PDT promoted autophagy via activation of ROS-induced ERS-related PERK/p-eif2&#x3b1;/CHOP axis, and blocked the ensuing autophagy flux by lysosomal damage. The PERK inhibitor GSK2606414 and NAC alleviated apoptosis and autophagy induced by Chlorin A-PDT. Furthermore, mitochondrial dysfunction aggravated ERS, and stabilizing the mitochondria reduced both apoptosis and autophagy. Finally, Chlorin A-PDT significantly reduced tumor growth in vivo.<br><br>CONCLUSIONS: Chlorin A-PDT induced apoptosis in CCA cells by initiating autophagy and impaired the autophagy flux via ROS-mediated ERS and lysosomal damage.}, }
@article {pmid33035499, year = {2020}, author = {Rodrigues, FS and França, AP and Broetto, N and Furian, AF and Oliveira, MS and Santos, ARS and Royes, LFF and Fighera, MR}, title = {Sustained glial reactivity induced by glutaric acid may be the trigger to learning delay in early and late phases of development: Involvement of p75[NTR] receptor and protection by N-acetylcysteine.}, journal = {Brain research}, volume = {1749}, number = {}, pages = {147145}, doi = {10.1016/j.brainres.2020.147145}, pmid = {33035499}, issn = {1872-6240}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Cerebral Cortex/*drug effects/metabolism ; Cognition/drug effects ; Corpus Striatum/*drug effects/metabolism ; Glutarates/*pharmacology ; Lipid Peroxidation/drug effects ; Male ; Maze Learning/*drug effects ; Mice ; Neurons/drug effects/metabolism ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Receptors, Nerve Growth Factor/*metabolism ; }, abstract = {Degeneration of striatal neurons and cortical atrophy are pathological characteristics of glutaric acidemia type I (GA-I), a disease characterized by accumulation of glutaric acid (GA). The mechanisms that lead to neuronal loss and cognitive impairment are still unclear. The purpose of this study was to verify if acute exposure to GA during the neonatal period is sufficient to trigger apoptotic processes and lead to learning delay in early and late period. Besides, whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Pups mice received a dose of GA (2.5 μmol/ g) or saline, 12 hs after birth, and were treated with NAC (250 mg/kg) or saline, up to 21th day of life. Although GA exhibited deficits in the procedural and working memories in 21 and 40-day-old mice, NAC protected against cognitive impairment. In striatum and cortex, NAC prevented glial cells activation (GFAP and Iba-1), decreased NGF, Bcl-2 and NeuN, the increase of lipid peroxidation and PARP induced by GA in both ages. NAC protected against increased p75[NTR] induced by GA, but not in cortex of 21-day-old mice. Thus, we showed that the integrity of striatal and cortical pathways has an important role for learning and suggested that sustained glial reactivity in neonatal period can be an initial trigger for delay of cognitive development. Furthermore, NAC protected against cognitive impairment induced by GA. This work shows that early identification of the alterations induced by GA is important to avoid future clinical complications and suggest that NAC could be an adjuvant treatment for this acidemia.}, }
@article {pmid33030315, year = {2020}, author = {Cam, S and Baba, D and Senoğlu, Y and Yuksel, A and Erdem, H}, title = {The role of N-acetylcysteine in preventing hepatic injury associated with systemic oxidative stress after extracorporeal shock wave treatment.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {29}, number = {10}, pages = {1175-1180}, doi = {10.17219/acem/126294}, pmid = {33030315}, issn = {1899-5276}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Liver/metabolism ; *Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Systemic oxidative stress may cause detrimental consequences for the liver, leading to hepatic fibrogenesis.<br><br>OBJECTIVES: To investigate histopathological changes in liver tissues due to the increased systemic oxidative stress associated with rat extracorporeal shock wave lithotripsy (SWL) model and to document the consequences of N-acetylcysteine (NAC) administration.<br><br>MATERIAL AND METHODS: In this experimental SWL model, 18 Wistar albino rats were randomly assigned into 3 groups. The control group (group I) had no intervention. Group II underwent SWL treatment with intraperitoneal saline injection. Group III also had SWL with intraperitoneal NAC and was divided into short-term (group III-14 days) and long-term (group III-28 days) subgroup. Hepatectomy was performed for histopathological examinations. Histopathological alterations were evaluated with light microscopy. Immunohistological staining for p53 and myeloperoxidase was also performed.<br><br>RESULTS: Blood samples revealed a significant increase in plasma oxidative stress index (OSI) after plasma total antioxidant status (TAS) and total oxidant status (TOS) had been measured. It was shown that this increased systemic oxidative stress adversely affected liver tissues. Predominantly, sinusoidal dilatation was remarkably observed in rats with significantly high OSI values (p = 0.043). Similarly, periportal necrosis significantly increased in rats with high OSI values (p = 0.033). p53 positivity was also remarkable in rats with systemic oxidative stress (p = 0.049). N-acetylcysteine administration provided a significant decrease in OSI. N-acetylcysteine also improved all these alterations, including p53 staining. Particularly, sinusoidal dilatation was significantly protected in the long-term NAC group (group III-28 days).<br><br>CONCLUSIONS: We demonstrated that SWL-induced systemic oxidative stress causes histological alterations in liver tissues. Increased p53 and myeloperoxidase staining as markers of oxidative damage were also detected. N-acetylcysteine may protect from these histological and ultra-structural alterations related to oxidative stress.}, }
@article {pmid33029057, year = {2020}, author = {Anand, AC and Nandi, B and Acharya, SK and Arora, A and Babu, S and Batra, Y and Chawla, YK and Chowdhury, A and Chaoudhuri, A and Eapen, EC and Devarbhavi, H and Dhiman, RK and Datta Gupta, S and Duseja, A and Jothimani, D and Kapoor, D and Kar, P and Khuroo, MS and Kumar, A and Madan, K and Mallick, B and Maiwall, R and Mohan, N and Nagral, A and Nath, P and Panigrahi, SC and Pawar, A and Philips, CA and Prahraj, D and Puri, P and Rastogi, A and Saraswat, VA and Saigal, S and Shalimar,  and Shukla, A and Singh, SP and Verghese, T and Wadhawan, M and , }, title = {Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure.}, journal = {Journal of clinical and experimental hepatology}, volume = {10}, number = {5}, pages = {477-517}, pmid = {33029057}, issn = {0973-6883}, abstract = {Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.}, }
@article {pmid33026257, year = {2021}, author = {Alsabaani, N}, title = {Inhibition of Protein Kinase R by C16 Protects the Retinal Ganglion Cells from Hypoxia-induced Oxidative Stress, Inflammation, and Apoptosis.}, journal = {Current eye research}, volume = {46}, number = {5}, pages = {719-730}, doi = {10.1080/02713683.2020.1826980}, pmid = {33026257}, issn = {1460-2202}, mesh = {Animals ; *Apoptosis ; Blotting, Western ; Cell Survival/physiology ; Cells, Cultured ; Cytokines/metabolism ; DNA, Single-Stranded/metabolism ; Enzyme-Linked Immunosorbent Assay ; Hypoxia/*metabolism ; Indoles/*pharmacology ; Inflammation/*metabolism ; L-Lactate Dehydrogenase/metabolism ; MAP Kinase Kinase 4/metabolism ; NF-kappa B/metabolism ; *Oxidative Stress/physiology ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Retinal Ganglion Cells/*enzymology/pathology ; Thiazoles/*pharmacology ; eIF-2 Kinase/*antagonists &amp; inhibitors ; p38 Mitogen-Activated Protein Kinases/metabolism ; Rats ; }, abstract = {AIM/PURPOSE: Individually, hypoxia and protein kinase R (PKR) induce retinal ganglion cells (RGCs) damage by aggravating reactive oxygen species (ROS), oxidative stress, inflammation, and apoptosis. However, it is still not established in hypoxia mediates such damaging effect by modulating PKR. This study investigated the expression and activation of PKR in hypoxic RGCs and tested if suppression of PKR by C16 is protective.<br><br>MATERIALS AND METHODS: Isolated RGCs were under normoxic or hypoxic conditions for 12&#xa0;h. In some cases, hypoxic cells were pre-treated with C16, a PKR inhibitor, or n-acetyl cysteine (NAC) a glutathione (GSH) precursor for 1&#xa0;h and then exposed to hypoxia for the next 12&#xa0;h.<br><br>RESULTS: Hypoxia increased cell death, lactate dehydrogenase (LDH) levels, and levels of single-stranded DNA (ssDNA). It also increased levels of ROS, the activity of the nuclear factor-kappa beta (NF-&#x3ba;B), JNK, and p38 MAPK, expression of Bax, p53, and cleaved caspase-3, levels of tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) and interleukin-6 (IL-6), and cytoplasmic levels of cytochrome-c. It concomitantly suppressed levels of GSH and Bcl-2. All these events were associated with increased phosphorylation (activation) of PKR and its target eukaryotic initiation factor 2 (eIF2). Pre-incubating the cells with NAC completely prevented all these effects in hypoxic cells. Similar protective effects without affecting levels of ROS and GSH levels were also seen in hypoxic cells pre-treated with C16.<br><br>CONCLUSION: Hypoxia induces oxidative stress, inflammation, and apoptosis in the RGCs mainly by ROS induced activation of PKR, whereas scavenging ROS by NAC or suppressing PKR by C16 is a novel protective mechanism.}, }
@article {pmid33024731, year = {2020}, author = {Cho, KH and Jeong, MH}, title = {Clinical Benefit of Statins in Korean Patients with Acute Myocardial Infarction: Experience of the Korea Acute Myocardial Infarction Registry.}, journal = {Journal of lipid and atherosclerosis}, volume = {9}, number = {3}, pages = {362-379}, pmid = {33024731}, issn = {2287-2892}, abstract = {Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) are among the most important medications for treating patients with acute myocardial infarction (AMI). Herein, we review the clinical benefit and future scope of statin therapy in Korean patients with AMI from the experience of the Korea AMI Registry. Statins are effective and safe in AMI patients, even in those with very low low-density lipoprotein cholesterol (LDL-C). Peri-procedural statin treatment could reduce the incidence of early stent thrombosis in patients with AMI after percutaneous coronary intervention. Reduction of high sensitivity C-reactive protein levels in patients with AMI plays an important role in the beneficial effect of statins on regression and compositional change of coronary plaques. Obtaining ≥50% reduction in LDL-C is associated with better clinical outcomes after AMI, whereas achieving <70 mg/dL LDL-C is not. Statin therapy has positive effects on clinical outcomes in patients with cardiogenic shock, ischemic heart failure, chronic kidney disease, and vasospasm. The combination of high-dose statin plus N-acetyl cysteine is associated with lower incidence of contrast-induced nephropathy in patients who underwent primary percutaneous coronary intervention. Moderate-intensity pitavastatin therapy is associated with a lower incidence of new-onset diabetes mellitus in patients with AMI and has similar clinical outcomes to moderate-intensity atorvastatin and rosuvastatin therapy. Future studies are required to assess the optimal intensity and LDL-C target concerning statin therapy, and the implementation of guidelines based cholesterol lowering practice in Korean patients with AMI.}, }
@article {pmid33024386, year = {2020}, author = {Rao, CC and Himaaldev, GJ}, title = {STEMI in Young Befogged by Aluminum Phosphide Toxicity-Role of ECMO as Salvage Therapy and Trimetazidine and Magnesium to Suppress Arrhythmias.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {24}, number = {8}, pages = {727-730}, pmid = {33024386}, issn = {0972-5229}, abstract = {INTRODUCTION: Aluminum phosphide poisoning (ALP) has a high-mortality rate despite intensive care management, primarily because it causes severe myocardial depression. This case report highlights the subset of ALP patients presenting as ST elevation myocardial infarction (STEMI) with profound myocardial dysfunction and multiorgan failure and successfully treated with extracorporeal membrane oxygenation (ECMO), trimetazidine, and magnesium.<br><br>CASE DESCRIPTION: A 25-year-old man without any comorbidities was brought to emergency department with dyspnea and hypotension. His electrocardiograph (ECG) revealed STEMI with elevated troponin levels, arterial blood gas (ABG) showed severe metabolic acidosis, and echocardiography (echo) revealed ejection fraction 15%. He was initiated on venoarterial (VA) ECMO in view of refractory hypotension. History of consumption of three tabs of celphos was revealed later by the family members. He progressed to cardiogenic shock, arrhythmias, respiratory failure, acute kidney injury with severe lactic acidosis, liver injury, pancreatitis, and disseminated intravascular coagulation (DIC). He was successfully supported by ECMO, hemodialysis, magnesium, trimetazidine, N-acetyl cysteine, inotropes, and blood products. He was weaned off ECMO on day 6 and was discharged home on day 12. Despite his severe and confounding clinical presentation, he had complete normalization of end-organ dysfunction with no neurological sequela. This case demonstrates the high index of suspicion required for ALP, given the potential for rapid progression and severe multiorgan toxicity. This report also highlights the importance of early referral to a tertiary care center with ECMO capability and also the role of magnesium and trimetazidine to suppress arrhythmias.<br><br>CONCLUSION: Aluminum phosphide poisoning can present as STEMI with cardiogenic shock resulting in acute kidney injury, liver injury, pancreatitis, and DIC. Venoarterial ECMO provides an effective means of support until the recovery of organ function. Trimetazidine and magnesium are helpful in suppressing fatal arrhythmias. This report emphasizes that early recognition and early institution of ECMO can save many young lives who succumb to toxic effects of this poison.<br><br>HOW TO CITE THIS ARTICLE: Rao CC, Himaaldev GJ. STEMI in Young Befogged by Aluminum Phosphide Toxicity-Role of ECMO as Salvage Therapy and Trimetazidine and Magnesium to Suppress Arrhythmias. Indian J Crit Care Med 2020;24(8):727-730.}, }
@article {pmid33023018, year = {2020}, author = {Kaufman, G and Skrtic, D}, title = {N-Acetyl Cysteine Modulates the Inflammatory and Oxidative Stress Responses of Rescued Growth-Arrested Dental Pulp Microtissues Exposed to TEGDMA in ECM.}, journal = {International journal of molecular sciences}, volume = {21}, number = {19}, pages = {}, pmid = {33023018}, issn = {1422-0067}, mesh = {Acetylcysteine/*pharmacology ; Cell Proliferation/drug effects ; Composite Resins/pharmacology ; Dental Pulp/*drug effects/growth &amp; development/metabolism ; Drug Evaluation, Preclinical ; Extracellular Matrix/*drug effects/genetics ; Gene Expression Regulation, Developmental/drug effects ; Humans ; Inflammation/chemically induced/*drug therapy/genetics/pathology ; Interleukin-8/genetics ; NF-E2-Related Factor 2/genetics ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics ; Oxidative Stress/drug effects ; Polyethylene Glycols/pharmacology ; Polymethacrylic Acids/pharmacology ; }, abstract = {Dental pulp is exposed to resin monomers leaching from capping materials. Toxic doses of the monomer, triethyleneglycol dimethacrylate (TEGDMA), impact cell growth, enhance inflammatory and oxidative stress responses, and lead to tissue necrosis. A therapeutic agent is required to rescue growth-arrested tissues by continuing their development and modulating the exacerbated responses. The functionality of N-Acetyl Cysteine (NAC) as a treatment was assessed by employing a 3D dental pulp microtissue platform. Immortalized and primary microtissues developed and matured in the extracellular matrix (ECM). TEGDMA was introduced at various concentrations. NAC was administered simultaneously with TEGDMA, before or after monomer addition during the development and after the maturation stages of the microtissue. Spatial growth was validated by confocal microscopy and image processing. Levels of inflammatory (COX2, NLRP3, IL-8) and oxidative stress (GSH, Nrf2) markers were quantified by immunoassays. NAC treatments, in parallel with TEGDMA challenge or post-challenge, resumed the growth of the underdeveloped microtissues and protected mature microtissues from deterioration. Growth recovery correlated with the alleviation of both responses by decreasing significantly the intracellular and extracellular levels of the markers. Our 3D/ECM-based dental pulp platform is an efficient tool for drug rescue screening. NAC supports compromised microtissues development, and immunomodulates and maintains the oxidative balance.}, }
@article {pmid33013393, year = {2020}, author = {Yu, X and Wang, X and Wang, X and Zhou, Y and Li, Y and Wang, A and Wang, T and An, Y and Sun, W and Du, J and Tong, X and Wang, Y}, title = {TEOA Inhibits Proliferation and Induces DNA Damage of Diffuse Large B-Cell Lymphoma Cells Through Activation of the ROS-Dependent p38 MAPK Signaling Pathway.}, journal = {Frontiers in pharmacology}, volume = {11}, number = {}, pages = {554736}, pmid = {33013393}, issn = {1663-9812}, abstract = {Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for approximately 30% to 40% of non-Hodgkin's lymphomas (NHL). The administration of rituximab significantly improved the outcomes of DLBCL; however, the unavoidable development of resistance limits the long-term efficacy. Therefore, a new generation of less toxic drugs with higher chemotherapy response is required to prevent or reverse chemoresistance. TEOA is a pentacyclic triterpenoid compound isolated from the roots of Actinidia eriantha. Studies have confirmed that TEOA has significant cytotoxicity on gastrointestinal cancer cells. However, there are no relevant reports on DLBCL cells. In this study, we investigated the potential molecular mechanism of the anticancer activity of TEOA in DLBCL cells. The results demonstrated that TEOA inhibited proliferation and induced apoptosis in time-and dose-dependent manners. TEOA induced reactive oxygen species (ROS) generation, which was reversed by N-acetyl cysteine (NAC). TEOA induced DNA damage, increased the level of γ-H2AX, and the phosphorylation of CHK1 and CHK2. In addition, TEOA induced the activation of the p38 MAPK pathway and pretreated with p38 inhibitor SB20358 or ROS scavenger could block TEOA-induced DNA damage. Taken together, these results suggest that ROS mediated activation of the p38 MAPK signal pathway plays an important role in initiating TEOA-induced DNA damage.}, }
@article {pmid33007830, year = {2020}, author = {Mahumane, GD and Kumar, P and Pillay, V and Choonara, YE}, title = {Repositioning N-Acetylcysteine (NAC): NAC-Loaded Electrospun Drug Delivery Scaffolding for Potential Neural Tissue Engineering Application.}, journal = {Pharmaceutics}, volume = {12}, number = {10}, pages = {}, pmid = {33007830}, issn = {1999-4923}, support = {SARChI; CSUR//National Research Foundation (NRF) of South Africa/ ; SIR//South African Medical Research Council (SAMRC)/ ; Friedel Sellschop//University of the Witwatersrand, Johannesburg/ ; }, abstract = {Traumatic brain injury (TBI) presents a serious challenge for modern medicine due to the poor regenerative capabilities of the brain, complex pathophysiology, and lack of effective treatment for TBI to date. Tissue-engineered scaffolds have shown some experimental success in vivo; unfortunately, none have yielded consummate results of clinical efficacy. N-acetylcysteine has shown neuroprotective potential. To this end, we developed a N-acetylcysteine (NAC)-loaded poly(lactic-co-glycolic acid) (PLGA) electrospun system for potential neural tissue application for TBI. Scanning electron microscopy showed nanofiber diameters ranging 72-542 nm and 124-592 nm for NAC-free and NAC-loaded PLGA nanofibers, respectively. NAC loading was obtained at 28%, and drug entrapment efficacy was obtained at 84%. A biphasic NAC release pattern that featured an initial burst release (13.9%) stage and a later sustained release stage was noted, thus enabling the prolonged replenishing of NAC and drastically improving cell viability and proliferation. This was evidenced by a significantly higher cell viability and proliferation on NAC-loaded nanofibers for rat pheochromocytoma (PC12) and human glioblastoma multiform (A172) cell lines in comparison to PLGA-only nanofibers. The increased cell viability and cell proliferation on NAC-loaded nanofiber substantiates for the repositioning of NAC as a pharmacological agent in neural tissue regeneration applications.}, }
@article {pmid33002473, year = {2020}, author = {Bairros, AV and Saldanha, GA and Berlato, DG and Moraes, LS and Gündel, AR and Carvalho, JAM and Habib, IA and De Carli, DM and Oliveira, TF and Oliveira, SCWSEF}, title = {Accidental ingestion of methyl ethyl ketone peroxide: N-acetylcysteine treatment and toxicological analysis.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {511}, number = {}, pages = {47-49}, doi = {10.1016/j.cca.2020.09.034}, pmid = {33002473}, issn = {1873-3492}, mesh = {*Acetylcysteine ; Butanones ; Eating ; Free Radicals ; Humans ; Male ; *Peroxides ; }, abstract = {INTRODUCTION: Methyl ethyl ketone peroxide (MEKP) is a highly toxic product which promotes tissue damage by uncontrolled free radical production.<br><br>CASE REPORT: A man accidentally ingested 110&#xa0;ml of MEKP (37%) at his workplace after mistaking it with a bottle of water. A loading dose of N-acetylcysteine (NAC) and subsequent maintenance doses were applied at the hospital for three consecutive days. Biochemical and hematological parameters showed significant alterations. Tracheal intubation, gastric lavage and hemodialysis were not performed. Methyl ethyl ketone (MEK) and MEKP were detected in EDTA-blood samples by GC-FID and LC-QTOF/MS respectively. An endoscopy exam identified tissue damage. The patient was admitted to the hospital for 10&#xa0;days. No sequelae were reported after the MEKP poisoning. Oral administration of NAC was successful as an antidote without another approach.<br><br>CONCLUSIONS: Although NAC treatment was successful, supervision after the hospitalization period was required according to the prognosis. Workplace conditions promoted anosmia, explaining the accident. MEKP and MEK were successfully detected in blood samples even with less-than-ideal storage conditions. Knowledge of MEKP dangerousness and good work practices can prevent accidental MEKP poisoning.}, }
@article {pmid32998228, year = {2020}, author = {Endo, N and Toyama, T and Naganuma, A and Saito, Y and Hwang, GW}, title = {Hydrogen Peroxide Causes Cell Death via Increased Transcription of HOXB13 in Human Lung Epithelial A549 Cells.}, journal = {Toxics}, volume = {8}, number = {4}, pages = {}, pmid = {32998228}, issn = {2305-6304}, support = {15H05714//Japan Society for the Promotion of Science/ ; 19H04276//Japan Society for the Promotion of Science/ ; }, abstract = {Although homeobox protein B13 (HOXB13) is an oncogenic transcription factor, its role in stress response has rarely been examined. We previously reported that knockdown of HOXB13 reduces the cytotoxicity caused by various oxidative stress inducers. Here, we studied the role of HOXB13 in cytotoxicity caused by hydrogen peroxide in human lung epithelial A549 cells. The knockdown of HOXB13 reduced hydrogen peroxide-induced cytotoxicity; however, this phenomenon was largely absent in the presence of antioxidants (Trolox or N-acetyl cysteine (NAC)). This suggests that HOXB13 may be involved in the cytotoxicity caused by hydrogen peroxide via the production of reactive oxygen species (ROS). Hydrogen peroxide also increased both the mRNA and protein levels of HOXB13. However, these increases were rarely observed in the presence of a transcriptional inhibitor, which suggests that hydrogen peroxide increases protein levels via increased transcription of HOXB13. Furthermore, cell death occurred in A549 cells that highly expressed HOXB13. However, this cell death was mostly inhibited by treatment with antioxidants. Taken together, our findings indicate that HOXB13 may be a novel factor involved in the induction of oxidative stress, which causes cell death via intracellular ROS production.}, }
@article {pmid32995849, year = {2021}, author = {Gupta, AK and Roy, S and Das, PK}, title = {Antileishmanial effect of the natural immunomodulator genipin through suppression of host negative regulatory protein UCP2.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {76}, number = {1}, pages = {135-145}, doi = {10.1093/jac/dkaa406}, pmid = {32995849}, issn = {1460-2091}, mesh = {Animals ; Immunologic Factors ; Iridoids ; *Leishmaniasis, Visceral ; Mice ; Mice, Inbred BALB C ; *Pharmaceutical Preparations ; Reactive Oxygen Species/metabolism ; Uncoupling Protein 2 ; }, abstract = {OBJECTIVES: To evaluate the antileishmanial efficacy of genipin, which specifically inhibits uncoupling protein 2 (UCP2) that is induced in leishmaniasis to neutralize reactive oxygen species (ROS).<br><br>METHODS: The effect of genipin was assessed against intracellular parasites in cultured macrophages and in suppressing spleen and liver parasite burdens in a BALB/c mouse model of visceral leishmaniasis by microscopic evaluation of intracellular amastigotes stained with Giemsa. ROS and mitochondrial membrane potential were measured by H2DCFDA- and JC-1-based fluorometric analysis. ELISA was performed for various Th1 and Th2 cytokines in both in vitro and in vivo infected conditions to evaluate the type of immunological responses. The role of UCP2 was assessed by lipofectamine-mediated transfection and overexpression in macrophages and short hairpin RNA-mediated knockdown of UCP2 in infected animals.<br><br>RESULTS: Genipin reduced the infection-induced UCP2 levels in macrophages, with optimum effect at 100&#x2009;&#x3bc;M. Genipin reversed parasite-induced ROS suppression and mitochondrial membrane potential disruption. It has no inhibitory effect on promastigote or axenic amastigote forms, but markedly suppressed amastigote multiplication within macrophages, which was reversed by the ROS scavenger N-acetyl cysteine. Genipin administration (30&#x2009;mg/kg/day) in infected mice showed significant suppression of liver and spleen parasite burdens with an enhanced host-favourable cytokine balance in a ROS-p38 mitogen-activated protein kinase-dependent manner. Co-treatment with genipin plus a sublethal dose of sodium antimony gluconate (SAG50) showed almost a curative reduction in spleen and liver parasite burden.<br><br>CONCLUSIONS: These results suggest the effectiveness of genipin as a synergistic agent for the front-line antileishmanial drug SAG in circumventing the resistance and toxicity problems associated with its high curative dose.}, }
@article {pmid32995712, year = {2020}, author = {Rahim, MN and Miquel, R and Heneghan, MA}, title = {Approach to the patient with acute severe autoimmune hepatitis.}, journal = {JHEP reports : innovation in hepatology}, volume = {2}, number = {6}, pages = {100149}, pmid = {32995712}, issn = {2589-5559}, abstract = {Autoimmune hepatitis is associated with varied clinical presentations and natural history, as well as somewhat unpredictable treatment responses. Understanding how to stratify patients who require further escalation of therapy will help clinicians manage these patients. The presentation of acute severe autoimmune hepatitis (AS-AIH) is relatively uncommon, although its prevalence is potentially greater than currently perceived. Previous studies consist of small retrospective single-centre series and are not directly comparable due to the diversity of presentations, disease definitions and non-standardised treatment regimens. We define AS-AIH as those who present acutely with AIH and are icteric with an international normalised ratio ≥1.5 and no evidence of hepatic encephalopathy. Those with hepatic encephalopathy should be defined as having AS-AIH with acute liver failure. In this review, we provide a structured practical approach for diagnosing and managing this unique group of patients.}, }
@article {pmid32993622, year = {2020}, author = {Cadegiani, FA}, title = {Repurposing existing drugs for COVID-19: an endocrinology perspective.}, journal = {BMC endocrine disorders}, volume = {20}, number = {1}, pages = {149}, pmid = {32993622}, issn = {1472-6823}, mesh = {Anti-Inflammatory Agents/*therapeutic use ; Betacoronavirus/*drug effects/isolation &amp; purification ; COVID-19 ; Coronavirus Infections/*drug therapy/epidemiology/virology ; Dexamethasone/*therapeutic use ; Drug Repositioning/*methods ; *Endocrine System ; Humans ; Pandemics ; Pneumonia, Viral/*drug therapy/epidemiology/virology ; Prognosis ; SARS-CoV-2 ; }, abstract = {BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2.<br><br>MAIN TEXT: While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed.<br><br>CONCLUSION: While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.}, }
@article {pmid32991316, year = {2020}, author = {Misian, M and Baum, E and Breborowicz, A}, title = {N-acetylcysteine modulates effect of the iron isomaltoside on peritoneal mesothelial cells.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {71}, number = {3}, pages = {}, doi = {10.26402/jpp.2020.3.07}, pmid = {32991316}, issn = {1899-1505}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Adult ; Cells, Cultured ; Cytokines/metabolism ; Disaccharides/*administration &amp; dosage/adverse effects ; Epithelial Cells/*drug effects/metabolism ; Ferric Compounds/*administration &amp; dosage/adverse effects ; Fibrinolysis/drug effects ; Humans ; Inflammation Mediators/metabolism ; Infusions, Intravenous ; Male ; Middle Aged ; Oxidative Stress/drug effects ; *Peritoneal Dialysis/adverse effects ; Peritoneum/*drug effects/metabolism ; Phenotype ; Treatment Outcome ; Uremia/blood/diagnosis/*therapy ; }, abstract = {Intravenous (i.v.) iron supplementation is used in patients on chronic peritoneal dialysis (pd). Iron induced intraperitoneal inflammation observed in our previous studies with iron sucrose may deteriorate the function of the peritoneum as the dialysis membrane. We evaluated effect iron compound, iron-isomaltoside-100 (IIS) on the peritoneal mesothelial cells (MC). We studied the effect of iv treatment with IIS ± N-acetylcysteine (NAC) on the dialysate parameters and function of MC. In 7 uremic pd patients IIS 200 mg was infused i.v. ± NAC 600 mg. Afterward, a 4 hours exchange was performed with Dianeal 1.5%. As a control dialysate exchange preceding IIS treatment was used. Inflammatory parameters of the drained dialysates as well as the dialysates and IIS effects on MC were evaluated in ex vivo experiments. Intravenous infusion of IIS resulted in an increase of the dialysate Fe (+147%, P < 0.01). Concentrations of the dialysates inflammatory mediators were increased: interleukin-6 (IL-6) +39%, P < 0.02, monocyte chemoattractant protein-1(MCP1) +50%, P < 0.02, and hyaluronan (HA) +64%, P < 0.02. Simultaneous i.v. infusion of NAC prevented increase of the dialysate inflammatory mediators. Dialysates collected after IIS treatment induced oxidative stress in MC (+29%, P < 0.05) and stimulated IL-6 synthesis (+64%, P < 0.05) in MC; no such effect was seen in dialysates obtained after simultaneous IIS and NAC i.v. treatment. IIS used as the additive to culture medium stimulated synthesis in MC of IL6 (+76%, P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) (28%, P < 0.001) whereas synthesis of tissue plasminogen activator (t-PA) was reduced (-16%, P < 0.001). These changes were prevented in the presence of NAC 1 mmol/L. Intravenous administration of IIS results in the mild stimulation of intraperitoneal inflammation. IIS changes MC phenotype to the inflammatory one with reduced fibrinolytic activity. These effects are prevented by NAC.}, }
@article {pmid32988387, year = {2020}, author = {Zhuang, H and Yao, C and Zhao, X and Chen, X and Yang, Y and Huang, S and Pan, L and Du, A and Yang, Y}, title = {DNA double-strand breaks in the Toxoplasma gondii-infected cells by the action of reactive oxygen species.}, journal = {Parasites &amp; vectors}, volume = {13}, number = {1}, pages = {490}, pmid = {32988387}, issn = {1756-3305}, support = {31672543//National Natural Science Foundation of China/ ; 31472184//National Natural Science Foundation of China/ ; 2020SNLF007//Zhejiang Province "Sannongliufang" Science and Technology Cooperation Project/ ; 2012C12009-2//Science and Technology Department of Zhejiang/ ; }, mesh = {Apoptosis ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Checkpoint Kinase 2/genetics/metabolism ; *DNA Breaks, Double-Stranded ; HEK293 Cells ; HeLa Cells ; Humans ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Toxoplasma/genetics/*physiology ; Toxoplasmosis/*genetics/metabolism/parasitology/physiopathology ; }, abstract = {BACKGROUND: Toxoplasma gondii is an obligate parasite of all warm-blooded animals around the globe. Once infecting a cell, it manipulates the host's DNA damage response that is yet to be elucidated. The objectives of the present study were three-fold: (i) to assess DNA damages in T. gondii-infected cells in vitro; (ii) to ascertain causes of DNA damage in T. gondii-infected cells; and (iii) to investigate activation of DNA damage responses during T. gondii infection.<br><br>METHODS: HeLa, Vero and HEK293 cells were infected with T. gondii at a multiplicity of infection (MOI) of 10:1. Infected cells were analyzed for a biomarker of DNA double-strand breaks (DSBs) &#x3b3;H2AX at 10&#xa0;h, 20&#xa0;h or 30&#xa0;h post-infection using both western blot and immunofluorescence assay. Reactive oxygen species (ROS) levels were measured using 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA), and ROS-induced DNA damage was inhibited by a ROS inhibitor N-acetylcysteine (NAC). Lastly, DNA damage responses were evaluated by detecting the active form of ataxia telangiectasia mutated/checkpoint kinase 2 (ATM/CHK2) by western blot.<br><br>RESULTS: &#x3b3;H2AX levels in the infected HeLa cells were significantly increased over time during T. gondii infection compared to uninfected cells. NAC treatment greatly reduced ROS and concomitantly diminished &#x3b3;H2AX in host cells. The phosphorylated ATM/CHK2 were elevated in T. gondii-infected cells.<br><br>CONCLUSIONS: Toxoplasma gondii infection triggered DNA DSBs with ROS as a major player in host cells in vitro. It also activated DNA damage response pathway ATM/CHK2. Toxoplasma gondii manages to keep a balance between survival and apoptosis of its host cells for the benefit of its own survival.}, }
@article {pmid32988255, year = {2020}, author = {Abdel-Sattar, AR and Abo-Saif, AA and Aboyoussef, AM}, title = {Nicorandil and atorvastatin attenuate carbon tetrachloride - induced liver fibrosis in rats.}, journal = {Immunopharmacology and immunotoxicology}, volume = {42}, number = {6}, pages = {582-593}, doi = {10.1080/08923973.2020.1830104}, pmid = {32988255}, issn = {1532-2513}, mesh = {Animals ; Atorvastatin/*pharmacology ; Biomarkers/blood ; Carbon Tetrachloride ; Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology/*prevention &amp; control ; Inflammation Mediators/blood ; Lipids/blood ; Liver/*drug effects/metabolism/pathology ; Liver Cirrhosis, Experimental/chemically induced/metabolism/pathology/*prevention &amp; control ; Male ; Nicorandil/*pharmacology ; Oxidative Stress/drug effects ; Rats, Wistar ; }, abstract = {PURPOSE: The present study aimed to evaluate the possible hepatoprotective effects of nicorandil and atorvastatin against experimentally induced liver fibrosis.<br><br>MATERIALS AND METHODS: Wistar male rats wereassigned tofivegroups; control group, fibrosis group, the remaining three groups received in addition to CCl4, N-acetyl cysteine (300&#x2009;mg/kg), nicorandil(15&#x2009;mg/kg) and atorvastatin (20&#x2009;mg/kg), respectively. Liver fibrosis was induced by intraperitoneal injection of rats with CCl4 (2&#x2009;ml/kg), twice weekly for five consecutive weeks. All treatments were administered daily starting from the first day of fibrosis induction for five consecutive weeks. By the end of the experiment, fibrosis biomarkers [hepatic transforming growth factor &#x3b2;1 (TGF-&#x3b2;1) and hydroxyproline (HYP)], liver function [serum alanine transaminase (ALT), aspartate transaminase (AST), albumin and total bilirubin] were assessed. Moreover, lipid profile [total cholesterol, serum triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)], inflammatory biomarkers [hepatic myeloperoxidase (MPO), serum tumor necrosis factor alpha (TNF-&#x3b1;)], relative liver weight] and oxidative stress biomarkers [malondialdehyde (MDA), glutathione (GSH) and catalase (CAT)] were evaluated. In support, histopathological and immunohistochemical examination of liver alpha smooth muscle actin (&#x3b1;-SMA) were performed.<br><br>RESULTS: Nicorandil and atorvastatin effectively reduced fibrosis and liver function biomarkers. They both restored serum lipid profile, TNF-&#x3b1;, MPO, relative liver weight, and hepatic MDA content. Alternatively, they markedly elevated albumin, HDL-C and hepatic content of GSH and CAT. Additionally, a marked histopathological and immunohistochemical improvement of &#x3b1;-SMA was observed.<br><br>CONCLUSION: Nicorandil and atorvastatin might be promising protective agents against liver fibrosis through amelioration of liver function, modulation of fibrous formation, anti-inflammatory and antioxidant potentials.}, }
@article {pmid32987256, year = {2020}, author = {Wang, Y and Li, C and Ali, I and Li, L and Wang, G}, title = {N-acetylcysteine modulates non-esterified fatty acid-induced pyroptosis and inflammation in granulosa cells.}, journal = {Molecular immunology}, volume = {127}, number = {}, pages = {157-163}, doi = {10.1016/j.molimm.2020.09.011}, pmid = {32987256}, issn = {1872-9142}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cattle ; Cell Survival/drug effects ; Fatty Acids, Nonesterified/*toxicity ; Female ; Granulosa Cells/drug effects/*pathology ; Inflammation/*pathology ; Inflammation Mediators/metabolism ; Ketosis/pathology ; Models, Biological ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Pyroptosis/*drug effects ; Up-Regulation/drug effects ; }, abstract = {In the perinatal period of dairy cows, negative energy balance (NEB) is likely to occur, which increases the level of non-esterified fatty acids (NEFA) in the follicular fluid, hinders the proliferation of granulosa cells (GCs), and thus endangers the development of oocytes and the fecundity of dairy cows. We found that there were oxidative stress and inflammatory response in the serum of cows with perinatal ketosis. Whether the oxidative stress induced by NEFA is involved in the pyroptosis and inflammation of GCs remains unclear. After NEFA treatment, the expression of NLRP3 and caspase-1 and the release of inflammatory cytokines IL-1β were increased in a dose-dependent manner, indicating that NEFA may contribute to pyroptosis. Besides, NEFA stimulation induced oxidative stress, resulting in the phosphorylation of NF-κB, and increased the production of interleukin (IL)-6 and nitric oxide (NO), indicating that NEFA may induce inflammation in GCs. However, the NEFA-mediated effects were observably reversed when the GCs were pre-treated with antioxidant and radical scavenger, N-acetylcysteine (NAC). Taken together, our results reveal that NEFA can induce pyroptosis and inflammation through NLRP3 inflammasome and TLR4/NF-κB pathway, respectively, and NAC can alleviate these conditions.}, }
@article {pmid32981726, year = {2020}, author = {Zhang, B and Li, M and Yang, W and Loor, JJ and Liang, Y and Wang, S and Zhao, Y and Guo, H and Ma, X and Yu, L and Xu, C}, title = {Mitochondrial dysfunction and endoplasmic reticulum stress in calf hepatocytes are associated with fatty acid-induced ORAI calcium release-activated calcium modulator 1 signaling.}, journal = {Journal of dairy science}, volume = {103}, number = {12}, pages = {11945-11956}, doi = {10.3168/jds.2020-18684}, pmid = {32981726}, issn = {1525-3198}, mesh = {Animals ; Calcium/*metabolism ; Cattle ; Endoplasmic Reticulum/metabolism ; *Endoplasmic Reticulum Stress ; Fatty Acids/*adverse effects ; Female ; Hepatocytes/metabolism ; Lactation ; Lipid Metabolism ; Liver/metabolism ; Mitochondria/metabolism ; ORAI1 Protein/genetics/*metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; }, abstract = {The store-operated Ca[2+] entry (SOCE) moiety ORAI calcium release-activated calcium modulator 1 (ORAI1) located in the endoplasmic reticulum (ER) participates in key cellular functions such as protein folding, transport, and secretion, and lipid metabolism. We used an in vitro approach to test whether exogenous fatty acids alter ORAI1 signaling and to explore potential consequences on mitochondrial dysfunction and ER stress. First, hepatocytes isolated from 4 healthy female calves (1 d old, 40-50 kg) were challenged with a 1.2 mM mixture of oleic, linoleic, palmitic, stearic, and palmitoleic acids for 0.5, 1, 3, 6, 9, and 12 h to measure oxidative stress [intracellular reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and hydrogen peroxide] and ER stress (protein abundance of PERK, IRE, ATF6, and GRP78). Concentrations of GSH and SOD decreased at 0.5 h, and MDA and hydrogen peroxide increased at 1 h; ER stress proteins increased at 6 h. To determine whether ER stress was caused by oxidative stress, primary calf hepatocytes were treated with the same 1.2 mM fatty acid mix or the reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC) for 6 h. We found that NAC prevented an increase in ER stress protein abundance. Next, the role of ORAI1 on ER stress was measured by transfecting hepatocytes with small interfering (si)ORAI1 or the ORAI1 inhibitor BTP2, followed by a challenge with 1.2 mM fatty acids for 3 h. Without inhibiting ORAI1, exogenous fatty acids upregulated ORAI1 mRNA and protein abundance, oxidative stress, ER stress proteins, and protein abundance of marker indicators of an opened mitochondrial permeability transition pore (mPTP). Inhibition with BPT2 or silencing via siORAI1 abrogated oxidative stress, including increased GSH concentration and SOD activity, decreased MDA, hydrogen peroxide, and ROS concentration; ER stress protein abundance was downregulated, and mitochondrial function was restored. Last, changes in markers of mPTP opening were evaluated by culturing hepatocytes for 6 h with the sarcoendoplasmic Ca[2+] ATPase inhibitor thapsigargin or the calcium ionophore ionomycin. We detected an increase in VDAC1, CLPP, and CypD protein abundance, all of which indicated opening of the mPTP. Overall, data from these in vitro studies suggest that ORAI1 mediates ER stress induced by high concentrations of fatty acids, in part through alleviating mitochondrial dysfunction caused by oxidative stress.}, }
@article {pmid32980537, year = {2020}, author = {Sawyer, TW}, title = {N-Acetylcysteine as a treatment for sulphur mustard poisoning.}, journal = {Free radical biology &amp; medicine}, volume = {161}, number = {}, pages = {305-320}, pmid = {32980537}, issn = {1873-4596}, mesh = {Acetylcysteine ; *Chemical Warfare Agents/toxicity ; Glutathione ; Humans ; Iran ; *Mustard Gas/toxicity ; }, abstract = {In the long and intensive search for effective treatments to counteract the toxicity of the chemical warfare (CW) agent sulphur mustard (H; bis(2-chloroethyl) sulphide), the most auspicious and consistent results have been obtained with the drug N-acetylcysteine (NAC), particularly with respect to its therapeutic use against the effects of inhaled H. It is a synthetic cysteine derivative that has been used in a wide variety of clinical applications for decades and a wealth of information exists on its safety and protective properties against a broad range of toxicants and disease states. Its primary mechanism of action is as a pro-drug for the synthesis of the antioxidant glutathione (GSH), particularly in those circumstances where oxidative stress has exhausted intracellular GSH stores. It impacts a number of pathways either directly or through its GSH-related antioxidant and anti-inflammatory properties, which make it a prime candidate as a potential treatment for the wide range of deleterious cellular effects that H is acknowledged to cause in exposed individuals. This report reviews the available literature on the protection afforded by NAC against the toxicity of H in a variety of model systems, including its efficacy in treating the long-term chronic lung effects of H that have been demonstrated in Iranian veterans exposed during the Iran-Iraq War (1980-1988). Although there is overwhelming evidence supporting this drug as a potential medical countermeasure against this CW agent, there is a requirement for carefully controlled clinical trials to determine the safety, efficacy and optimal NAC dosage regimens for the treatment of inhaled H.}, }
@article {pmid32978699, year = {2021}, author = {Shabat, Y and Lichtenstein, Y and Ilan, Y}, title = {Short-Term Cohousing of Sick with Healthy or Treated Mice Alleviates the Inflammatory Response and Liver Damage.}, journal = {Inflammation}, volume = {44}, number = {2}, pages = {518-525}, pmid = {32978699}, issn = {1573-2576}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; Alanine Transaminase/blood ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Aspartate Aminotransferases/blood ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/blood/etiology/pathology/*therapy ; Concanavalin A ; *Coprophagia ; Dexamethasone/therapeutic use ; Ecosystem ; Gastrointestinal Microbiome ; Hepatitis, Autoimmune/blood/etiology/pathology/*therapy ; *Housing, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Treatment Outcome ; }, abstract = {Cohousing of sick with healthy or treated animals is based on the concept of sharing an intestinal ecosystem and coprophagy, the consumption of feces, which includes sharing of the microbiome and of active drug metabolites secreted in the feces or urine. To develop a model for short-term cohousing, enabling the study of the effect of sharing an ecosystem on inflammatory states. To determine the impact of cohousing of sick and healthy mice on the immune-mediated disorders, mice injected with concanavalin A (ConA) were cohoused with healthy or sick mice or with steroid-treated or untreated mice. To determine the effect of cohousing on acetaminophen (APAP)-induced liver damage, APAP-injected mice were cohoused with N-acetyl-cysteine (NAC)-treated or untreated mice. In the ConA-induced immune-mediated hepatitis model, cohousing of sick with healthy mice was associated with the alleviation of liver damage in sick animals. Similarly, a significant decrease in serum ALT was noted in ConA-injected mice kept in the same cage as ConA-injected mice treated with steroids. A trend for reduction in liver enzymes in APAP-injected mice was observed upon cohousing with NAC-treated animals. Cohousing of sick mice with healthy or treated mice ameliorated the immune-mediated inflammatory state induced by ConA and APAP. These models for liver damage can serve as biological systems for determining the effects of alterations in the ecosystem on the immune system.}, }
@article {pmid32978368, year = {2020}, author = {Qin, AC and Jin, H and Song, Y and Gao, Y and Chen, YF and Zhou, LN and Wang, SS and Lu, XS}, title = {The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells.}, journal = {Cell death &amp; disease}, volume = {11}, number = {9}, pages = {805}, pmid = {32978368}, issn = {2041-4889}, mesh = {Animals ; Apoptosis ; Colonic Neoplasms/*genetics ; Female ; Humans ; Mice ; Mice, SCID ; Nuclear Proteins/*metabolism ; Oncogenes ; Transcription Factors/*metabolism ; }, abstract = {A1874 is a novel BRD4-degrading proteolysis targeting chimera (PROTAC). In primary colon cancer cells and established HCT116 cells, A1874 potently inhibited cell viability, proliferation, cell cycle progression, as well as cell migration and invasion. The BRD4-degrading PROTAC was able to induce caspase and apoptosis activation in colon cancer cells. Furthermore, A1874-induced degradation of BRD4 protein and downregulated BRD-dependent genes (c-Myc, Bcl-2, and cyclin D1) in colon cancer cells. Significantly, A1874-induced anti-colon cancer cell activity was more potent than the known BRD4 inhibitors (JQ1, CPI203, and I-BET151). In BRD4-knockout colon cancer cells A1874 remained cytotoxic, indicating the existence of BRD4-independent mechanisms. In addition to BRD4 degradation, A1874 cytotoxicity in colon cancer cells was also associated with p53 protein stabilization and reactive oxygen species production. Importantly, the antioxidant N-acetyl-cysteine and the p53 inhibitor pifithrin-α attenuated A1874-induced cell death and apoptosis in colon cancer cells. In vivo, A1874 oral administration potently inhibited colon cancer xenograft growth in severe combined immuno-deficient mice. BRD4 degradation and p53 protein elevation, as well as apoptosis induction and oxidative stress were detected in A1874-treated colon cancer tissues. Together, A1874 inhibits colon cancer cell growth through both BRD4-dependent and -independent mechanisms.}, }
@article {pmid32970799, year = {2021}, author = {Eshrati, R and Jafari, M and Gudarzi, S and Nazari, A and Samizadeh, E and Ghafourian Hesami, M}, title = {Comparison of ameliorative effects of Taraxacum syriacum and N-acetylcysteine against acetaminophen-induced oxidative stress in rat liver and kidney.}, journal = {Journal of biochemistry}, volume = {169}, number = {3}, pages = {337-350}, doi = {10.1093/jb/mvaa107}, pmid = {32970799}, issn = {1756-2651}, mesh = {Acetaminophen/toxicity ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase/metabolism ; Chemical and Drug Induced Liver Injury/*drug therapy/pathology ; Ethanol/metabolism ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Humans ; Kidney/*drug effects ; Lipid Peroxidation/drug effects ; Liver/drug effects ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Plant Extracts/chemistry/*pharmacology ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Taraxacum/*chemistry ; }, abstract = {Taraxacum syriacum (TS) with natural antioxidant and pharmacological activities may be considered for treatment of oxidative stress induced by acetaminophen (APAP). The aim of this study was to evaluate the ameliorative effects of the ethanol extract of TS root against hepatorenal toxicity induced by APAP in comparison to N-acetylcysteine (NAC) as a standard drug. Thirty male Wistar rats were randomly divided into five groups. Control group; APAP (1 g/kg) group; APAP-NAC (160 mg/kg) group and APAP-TS100 and APAP-TS200 groups: APAP plus 100 and 200 mg/kg of TS extract, respectively. After 7 days treatment, serum and liver and kidney tissues were prepared and evaluated. TS extract ameliorated the increased lipid peroxidation level and decreased antioxidant enzymes activities and glutathione level in liver and kidney of APAP-treated rats. Moreover, treatment with the TS extract caused significant reduction in the histopathological damages and high levels of serum biochemical markers of hepatic and renal functions after APAP treatment. This study suggests that the extract of TS roots has dose-dependent ameliorative effect against APAP-induced oxidative damage in liver and kidney due to its free radical scavenging and antioxidant properties. The overall efficacy of the extract at 200 mg/kg dose is comparable with NAC.}, }
@article {pmid32967581, year = {2020}, author = {Zoppi, A and Bartolilla, A and Longhi, MR and Aiassa, V}, title = {Simultaneous improvement of ketoconazole solubility, antifungal and antibiofilm activity by multicomponent complexation.}, journal = {Therapeutic delivery}, volume = {11}, number = {11}, pages = {701-712}, doi = {10.4155/tde-2020-0053}, pmid = {32967581}, issn = {2041-6008}, support = {PICT-2015-0790 Cat. A (Res. N&#xb0; 240/16)//Fondo para la Investigaci&#xf3;n Cient&#xed;fica y Tecnol&#xf3;gica (FONCyT)/ ; SECYT-UNC. 2018 (Res. N&#xb0; 411/18)//Secretar&#xed;a de Ciencia y Tecnolog&#xed;a, Universidad Nacional de C&#xf3;rdoba/ ; SECYT-UNC. 2018 (Res. N&#xb0; 411/18)//Secretar&#xed;a de Ciencia y Tecnolog&#xed;a, Universidad Nacional de C&#xf3;rdoba./ ; }, mesh = {*Antifungal Agents/pharmacology ; Biofilms ; Calorimetry, Differential Scanning ; *Ketoconazole/pharmacology ; Microscopy, Electron, Scanning ; Solubility ; Spectroscopy, Fourier Transform Infrared ; X-Ray Diffraction ; }, abstract = {Background: A novel multicomponent complex (MC) of ketoconazole (KET) with β-cyclodextrin (β-CD) and N-acetylcysteine (NAC) was developed with the purpose of improving the solubility as well as the antifungal and antibiofilm activity of KET against Candida albicans. Results &amp; methodology: The interactions among the components were studied using nuclear magnetic resonance, thermal analysis, powder x-ray diffraction, infrared spectroscopy and scanning electron microscopy. Phase-solubility studies demonstrated a considerable increase in the solubility of the MC. An enhancement in antibiofilm and antifungal activity of MC was determined against C. albicans by XTT assay and microbiological studies. Conclusion: This MC, with improvements in the drug pharmaceutical performance, might have an important potential in the development of new pharmaceutical formulations of KET.}, }
@article {pmid32964918, year = {2021}, author = {de Alencar, JCG and Moreira, CL and Müller, AD and Chaves, CE and Fukuhara, MA and da Silva, EA and Miyamoto, MFS and Pinto, VB and Bueno, CG and Lazar Neto, F and Gomez Gomez, LM and Menezes, MCS and Marchini, JFM and Marino, LO and Brandão Neto, RA and Souza, HP and , }, title = {Double-blind, Randomized, Placebo-controlled Trial With N-acetylcysteine for Treatment of Severe Acute Respiratory Syndrome Caused by Coronavirus Disease 2019 (COVID-19).}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {72}, number = {11}, pages = {e736-e741}, doi = {10.1093/cid/ciaa1443}, pmid = {32964918}, issn = {1537-6591}, mesh = {Acetylcysteine/therapeutic use ; Brazil ; Double-Blind Method ; Humans ; Respiration, Artificial ; SARS-CoV-2 ; Treatment Outcome ; *COVID-19 Drug Treatment ; }, abstract = {BACKGROUND: A local increase in angiotensin 2 after inactivation of angiotensin-converting enzyme 2 by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce a redox imbalance in alveolar epithelium cells, causing apoptosis, increased inflammation and, consequently, impaired gas exchange. We hypothesized that N-acetylcysteine (NAC) administration could restore this redox homeostasis and suppress unfavorable evolution in patients with coronavirus disease 2019 (COVID-19).<br><br>METHODS: This was a double-blind, randomized, placebo-controlled, single-center trial conducted at the Emergency Department of Hospital das Cl&#xed;nicas, S&#xe3;o Paulo, Brazil, to determine whether NAC in high doses can avoid respiratory failure in patients with COVID-19. We enrolled 135 patients with severe COVID-19 (confirmed or suspected), with an oxyhemoglobin saturation <94% or respiratory rate >24 breaths/minute. Patients were randomized to receive NAC 21 g (~300 mg/kg) for 20 hours or dextrose 5%. The primary endpoint was the need for mechanical ventilation. Secondary endpoints were time of mechanical ventilation, admission to the intensive care unit (ICU), time in ICU, and mortality.<br><br>RESULTS: Baseline characteristics were similar between the 2 groups, with no significant differences in age, sex, comorbidities, medicines taken, and disease severity. Also, groups were similar in laboratory tests and chest computed tomography scan findings. Sixteen patients (23.9%) in the placebo group received endotracheal intubation and mechanical ventilation, compared with 14 patients (20.6%) in the NAC group (P&#x2005;=&#x2005;.675). No difference was observed in secondary endpoints.<br><br>CONCLUSIONS: Administration of NAC in high doses did not affect the evolution of severe COVID-19.<br><br>CLINICAL TRIALS REGISTRATION: Brazilian Registry of Clinical Trials (REBEC): U1111-1250-356 (http://www.ensaiosclinicos.gov.br/rg/RBR-8969zg/).}, }
@article {pmid32964473, year = {2021}, author = {Chen, L and Zhou, T and White, T and O'Brien, A and Chakraborty, S and Liangpunsakul, S and Yang, Z and Kennedy, L and Saxena, R and Wu, C and Meng, F and Huang, Q and Francis, H and Alpini, G and Glaser, S}, title = {The Apelin-Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis.}, journal = {Hepatology (Baltimore, Md.)}, volume = {73}, number = {6}, pages = {2411-2428}, pmid = {32964473}, issn = {1527-3350}, support = {R21 AA025157/AA/NIAAA NIH HHS/United States ; R01 DK062975/DK/NIDDK NIH HHS/United States ; R01 DK058411/DK/NIDDK NIH HHS/United States ; R01 DK107310/DK/NIDDK NIH HHS/United States ; R01 AA025208/AA/NIAAA NIH HHS/United States ; I01 BX000574/BX/BLRD VA/United States ; I01 BX003031/BX/BLRD VA/United States ; IK6 BX004601/BX/BLRD VA/United States ; R01 DK107682/DK/NIDDK NIH HHS/United States ; R01 DK115184/DK/NIDDK NIH HHS/United States ; U01 AA026917/AA/NIAAA NIH HHS/United States ; R01 DK108959/DK/NIDDK NIH HHS/United States ; R01 DK119421/DK/NIDDK NIH HHS/United States ; IK6 BX005226/BX/BLRD VA/United States ; R21 AA025997/AA/NIAAA NIH HHS/United States ; R01 DK110035/DK/NIDDK NIH HHS/United States ; R01 DK054811/DK/NIDDK NIH HHS/United States ; UH2 AA026903/AA/NIAAA NIH HHS/United States ; T32 DK007698/DK/NIDDK NIH HHS/United States ; I01 BX001724/BX/BLRD VA/United States ; R01 DK076898/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apelin/*metabolism ; Apelin Receptors/antagonists &amp; inhibitors/*metabolism ; Cell Proliferation ; Cholangitis, Sclerosing/*metabolism/pathology ; Cholestasis/*metabolism ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; Hepatic Stellate Cells/metabolism ; Humans ; Liver Cirrhosis/*metabolism ; Mice ; NADPH Oxidase 4/metabolism ; Nitrobenzoates/*pharmacology ; Pyrans/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND AND AIMS: Apelin (APLN) is the endogenous ligand of its G protein-coupled receptor, apelin receptor (APJ). APLN serum levels are increased in human liver diseases. We evaluated whether the APLN-APJ axis regulates ductular reaction and liver fibrosis during cholestasis.<br><br>APPROACH AND RESULTS: We measured the expression of APLN and APJ and serum APLN levels in human primary sclerosing cholangitis (PSC) samples. Following bile duct ligation (BDL) or sham surgery, male wild-type (WT) mice were treated with ML221 (APJ antagonist) or saline for 1&#xa0;week. WT and APLN[-/-] mice underwent BDL or sham surgery for 1&#xa0;week. Multidrug resistance gene 2 knockout (Mdr2[-/-]) mice were treated with ML221 for 1&#xa0;week. APLN levels were measured in serum and cholangiocyte supernatants, and cholangiocyte proliferation/senescence and liver inflammation, fibrosis, and angiogenesis were measured in liver tissues. The regulatory mechanisms of APLN-APJ in (1) biliary damage and liver fibrosis were examined in human intrahepatic biliary epithelial cells (HIBEpiCs) treated with APLN and (2) hepatic stellate cell (HSC) activation in APLN-treated human HSC lines (HHSteCs). APLN serum levels and biliary expression of APLN and APJ increased in PSC samples. APLN levels were higher in serum and cholangiocyte supernatants from BDL and Mdr2[-/-] mice. ML221 treatment or APLN[-/-] reduced BDL-induced and Mdr2[-/-] -induced cholangiocyte proliferation/senescence, liver inflammation, fibrosis, and angiogenesis. In vitro, APLN induced HIBEpiC proliferation, increased nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) expression, reactive oxygen species (ROS) generation, and extracellular signal-regulated kinase (ERK) phosphorylation. Pretreatment of HIBEpiCs with ML221, diphenyleneiodonium chloride (Nox4 inhibitor), N-acetyl-cysteine (NAC, ROS inhibitor), or PD98059 (ERK inhibitor) reduced APLN-induced cholangiocyte proliferation. Activation of HHSteCs was induced by APLN but reduced by NAC.<br><br>CONCLUSIONS: The APLN-APJ axis induces cholangiocyte proliferation through Nox4/ROS/ERK-dependent signaling and HSC activation through intracellular ROS. Modulation of the APLN-APJ axis may be important for managing cholangiopathies.}, }
@article {pmid32963939, year = {2020}, author = {Zhang, X and Zhang, P and An, L and Sun, N and Peng, L and Tang, W and Ma, D and Chen, J}, title = {Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis.}, journal = {Acta pharmaceutica Sinica. B}, volume = {10}, number = {8}, pages = {1397-1413}, pmid = {32963939}, issn = {2211-3835}, abstract = {Pyroptosis is a form of programmed cell death, and recently described as a new molecular mechanism of chemotherapy drugs in the treatment of tumors. Miltirone, a derivative of phenanthrene-quinone isolated from the root of Salvia miltiorrhiza Bunge, has been shown to possess anti-cancer activities. Here, we found that miltirone inhibited the cell viability of either HepG2 or Hepa1-6 cells, and induced the proteolytic cleavage of gasdermin E (GSDME) in each hepatocellular carcinoma (HCC) cell line, with concomitant cleavage of caspase 3. Knocking out GSDME switched miltirone-induced cell death from pyroptosis to apoptosis. Additionally, the induction effects of miltirone on GSDME-dependent pyroptosis were attenuated by siRNA-mediated caspase three silencing and the specific caspase three inhibitor Z-DEVD-FMK, respectively. Miltirone effectively elicited intracellular accumulation of reactive oxygen species (ROS), and suppressed phosphorylation of mitogen-activated and extracellular signal-regulated kinase (MEK) and extracellular regulated protein kinases 1/2 (ERK1/2) for pyroptosis induction. Moreover, miltirone significantly inhibited tumor growth and induced pyroptosis in the Hepa1-6 mouse HCC syngeneic model. These results provide a new insight that miltirone is a potential therapeutic agent for the treatment of HCC via GSDME-dependent pyroptosis.}, }
@article {pmid32963203, year = {2021}, author = {Akgun, E and Boyacioglu, M and Kum, S}, title = {The potential protective role of folic acid against acetaminophen-induced hepatotoxicity and nephrotoxicity in rats.}, journal = {Experimental animals}, volume = {70}, number = {1}, pages = {54-62}, pmid = {32963203}, issn = {1881-7122}, mesh = {Acetaminophen/administration &amp; dosage/*adverse effects ; Acetylcysteine/administration &amp; dosage/pharmacology ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Animals ; Chemical and Drug Induced Liver Injury/*etiology/*prevention &amp; control ; Disease Models, Animal ; Female ; Folic Acid/*administration &amp; dosage/*pharmacology ; *Free Radical Scavengers ; Oxidative Stress/drug effects ; Rats, Sprague-Dawley ; Rats ; }, abstract = {Folic acid (FA), is a group B vitamin, has high reactive oxygen radicals quenching ability, resulting in protection against oxidative damage in aerobic cell. Acetaminophen (N-acetyl-p-aminophenol, APAP) is a nonsteroidal anti-inflammatory drug, and can promote oxidative damage in liver and kidney tissues. The aim of this study was to investigate whether folic acid has protective effects on oxidative liver and kidney injury caused by experimental APAP toxication. Forty female Sprague dawley rats were divided into 5 groups; control, APAP, FA, APAP+FA, and APAP+N-acetylcysteine (NAC) groups. APAP toxication was induced by oral gavage (3 g/kg bodyweight). FA (20 mg/kg bodyweight) and NAC (150 mg/kg bodyweight) were given by oral gavage to the specified groups. Oxidant and antioxidant parameter were determined in liver and kidney tissues. In addition, the liver and kidney tissues were histological evaluated. When compared with APAP group, superoxide dismutase (SOD) and catalase activities and glutathione levels were statistically higher, malondialdehyde (MDA) level and myeloperoxidase activity (except liver tissue) were statistically lower in both APAP+FA and APAP+NAC. Liver and kidney MDA level and kidney SOD activity were significantly lower in APAP+NAC group compared with APAP+FA group. Co-administration of NAC with APAP was found to provide protection, but hepatic cords were defective in some places and some glomerular tubules also had dilatation. Necrotic areas was reduced in the liver and the glomerular structure was in good condition in the APAP+FA group. As a result, FA might have a protective effect against APAP-induced hepato-nephrotoxicity and oxidative stress in rat.}, }
@article {pmid32959856, year = {2020}, author = {Bartnicka, JJ and Al-Salemee, F and Firth, G and Blower, PJ}, title = {L-Cysteine-mediated modulation of copper trafficking in prostate cancer cells: an in vitro and in vivo investigation with [64]Cu and [64]Cu-PET.}, journal = {Metallomics : integrated biometal science}, volume = {12}, number = {10}, pages = {1508-1520}, doi = {10.1039/d0mt00161a}, pmid = {32959856}, issn = {1756-591X}, support = {/DH_/Department of Health/United Kingdom ; 16463/CRUK_/Cancer Research UK/United Kingdom ; MR/N013700/1/MRC_/Medical Research Council/United Kingdom ; WT203148/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; C7893/A26233/CRUK_/Cancer Research UK/United Kingdom ; MC_PC_16048/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Biological Transport ; Cell Line, Tumor ; Copper/*metabolism ; Copper Radioisotopes/metabolism ; Cysteine/*metabolism ; Humans ; Male ; PC-3 Cells ; Positron-Emission Tomography ; Prostatic Neoplasms/*metabolism ; }, abstract = {Copper imbalance is implicated in many diseases, including cancer. Copper in blood is mainly transported by carrier proteins but a small fraction is bound to low molecular weight species, possibly amino acids. Their roles in cellular copper delivery are unknown. Our aim was to test whether accumulation of 64Cu into cancer-derived cells can be influenced by copper-binding serum amino acids. In vitro cellular accumulation of 64Cu was measured in Hank's Balanced Salt Solution in the presence of 100 μM l-histidine, l-methionine, l-cysteine and l-threonine. l-Cysteine markedly increased 64Cu accumulation and retention in DU145, PC3 and SK-OV-3 cells, while some other cell lines did not show an effect. This effect was not due to 64Cu delivery in the form of a 64Cu-cysteine complex, nor to reduction of 64Cu(ii) to 64Cu(i) by l-cysteine. Pre-incubation of cells with l-cysteine increased 64Cu accumulation, even if l-cysteine was removed from HBSS before 64Cu was added. The effect of l-cysteine on 64Cu accumulation was not mediated by increased glutathione synthesis. Despite the demonstrable in vitro effect, pre-injection of l-cysteine precursor N-acetyl-cysteine (NAC) in vivo did not enhance 64Cu delivery to DU145 xenografts in mice. Instead, it decreased 64Cu accumulation in the DU145 tumour and in brain, as assessed by PET imaging. We conclude that 64Cu is not delivered to DU145 cancer cells in vitro as a complex with amino acids but its cellular accumulation is enhanced by l-cysteine or NAC influx to cells. The latter effect was not demonstrable in vivo in the DU145 xenograft.}, }
@article {pmid32958257, year = {2020}, author = {Wang, J and Guo, Z and Zhang, R and Han, Z and Huang, Y and Deng, C and Dong, W and Zhuang, G}, title = {Effects of N-acetylcysteine on oxidative stress and inflammation reactions in a rat model of allergic rhinitis after PM2.5 exposure.}, journal = {Biochemical and biophysical research communications}, volume = {533}, number = {3}, pages = {275-281}, doi = {10.1016/j.bbrc.2020.09.022}, pmid = {32958257}, issn = {1090-2104}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Chemokine CCL11/genetics/immunology ; Disease Models, Animal ; Female ; Gene Expression ; Immunoglobulin E/genetics/immunology ; Inflammation ; Interferon-gamma/genetics/immunology ; Interleukins/genetics/immunology ; Malondialdehyde/immunology/metabolism ; Nasal Mucosa/*drug effects/immunology/pathology ; Oxidative Stress/*drug effects/immunology ; Particle Size ; Particulate Matter/administration &amp; dosage ; Polycyclic Aromatic Hydrocarbons/administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; Rhinitis, Allergic/chemically induced/*drug therapy/immunology/pathology ; Superoxide Dismutase/genetics/immunology ; Th1-Th2 Balance/*drug effects ; }, abstract = {Particulate matter 2.5 (PM2.5) exposure can increase the prevalence of allergic rhinitis (AR), the mechanism underlying which may include oxidative stress and inflammatory response. As a ROS quenching agent, N-acetylcysteine (NAC) can attenuate the accumulation of inflammatory cells and hyper-responsiveness in animal asthma models. To explore the effect of NAC on the oxidative stress and inflammatory reactions in AR rats exposed to PM2.5, we analyzed the components of PM2.5 and examined the nasal symptoms, redox level in nasal mucosa, Th1/Th2-related serum cytokines, nasal mucosal histopathology and ultrastructure in AR rat models with NAC intervention after PM2.5 exposure. The results showed that the high concentrations of metal cations and PAHs in PM2.5 could aggravate Th2-dominant allergic inflammation in AR model and cause redox imbalance, accompanied by nasal epithelial cell stripping and eosinophil infiltration, while NAC intervention could alleviate the clinical symptoms of AR model after PM2.5 exposure, correct the redox imbalance, reduce the Th2 cytokines, reduce eosinophil infiltration, and promote the moderate regeneration of epithelial cells. The mechanism of NAC reversing PM2.5-mediated action may be related to its anti-oxidant and anti-inflammatory effects, which may provide some new insights for the prevention of AR exacerbated by exposure to PM2.5.}, }
@article {pmid32955001, year = {2020}, author = {da Silva Souza, B and Sales, ACS and da Silva, FDS and de Souza, TF and de Freitas, CDT and Vasconcelos, DFP and de Oliveira, JS}, title = {Latex Proteins from Plumeria pudica with Therapeutic Potential on Acetaminophen-Induced Liver Injury.}, journal = {Mini reviews in medicinal chemistry}, volume = {20}, number = {19}, pages = {2011-2018}, doi = {10.2174/1389557520666200821121903}, pmid = {32955001}, issn = {1875-5607}, support = {446497/2014-2, 407413/2018-9//National Council for Technological and Scientific Development (CNPq, Brazil)/ ; }, mesh = {Acetaminophen/administration &amp; dosage/adverse effects ; Animals ; Apocynaceae/*metabolism ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology ; Cytokines/metabolism ; Latex/*metabolism ; Liver/drug effects/metabolism ; Plant Extracts/metabolism ; Plant Proteins/isolation &amp; purification/pharmacology/*therapeutic use ; Protective Agents/isolation &amp; purification/pharmacology/therapeutic use ; }, abstract = {Liver disease is global health problem. Paracetamol (APAP) is used as an analgesic drug and is considered safe at therapeutic doses, but at higher doses, it causes acute liver injury. N-acetyl-p- Benzoquinone Imine (NAPQI) is a reactive toxic metabolite produced by biotransformation of APAP. NAPQI damages the liver by oxidative stress and the formation of protein adducts. The glutathione precursor N-acetylcysteine (NAC) is the only approved antidote against APAP hepatotoxicity, but it has limited hepatoprotective effects. The search for new drugs and novel therapeutic intervention strategies increasingly includes testing plant extracts and other natural products. Plumeria pudica (Jacq., 1760) is a plant that produces latex containing molecules with therapeutic potential. Proteins obtained from this latex (LPPp), a well-defined mixture of chitinases, proteinases proteinase inhibitors have shown anti-inflammatory, antinociceptive, antidiarrheal effects as well as a protective effect against ulcerative colitis. These studies have demonstrated that LPPp acts on parameters such as Glutathione (GSH) and Malondialdehyde (MDA) concentration, Superoxide Dismutase (SOD) activity, Myeloperoxidase (MPO) activity, and TNF- α IL1-β levels. Since oxidative stress and inflammation have been reported to affect the initiation and progression of liver injury caused by APAP, it is suggested that LPPp can act on aspects related to paracetamol hepatoxicity. This article brings new insights into the potential of the laticifer proteins extracted from the latex of P. pudica and opens new perspectives for the treatment of this type of liver disease with LPPp.}, }
@article {pmid32954540, year = {2020}, author = {Sun, X and Zhang, H and Xie, L and Qian, C and Ye, Y and Mao, H and Wang, B and Zhang, H and Zhang, Y and He, X and Zhang, S}, title = {Tristetraprolin destabilizes NOX2 mRNA and protects dopaminergic neurons from oxidative damage in Parkinson's disease.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {11}, pages = {15047-15061}, doi = {10.1096/fj.201902967R}, pmid = {32954540}, issn = {1530-6860}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects ; Animals ; Apoptosis ; Dopaminergic Neurons/*drug effects/enzymology/pathology ; Humans ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/enzymology/pathology ; NADPH Oxidase 2/*chemistry/genetics/metabolism ; Neuroblastoma/drug therapy/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Neurotoxins/toxicity ; Oxidative Stress/*drug effects ; Parkinson Disease/*drug therapy/enzymology/etiology/pathology ; RNA, Messenger/*chemistry/genetics/metabolism ; Tristetraprolin/*pharmacology ; }, abstract = {Tristetraprolin (TTP), an RNA-binding protein encoded by the ZFP36 gene, is vital for neural differentiation; however, its involvement in neurodegenerative diseases such as Parkinson's disease (PD) remains unclear. To explore the role of TTP in PD, an in vitro 1-methyl-4-phenylpyridinium (MPP[+]) cell model and an in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) of PD were used. Transfection of small interfering (si)-TTP RNA upregulated pro-oxidative NOX2 expression and ROS formation, downregulated anti-oxidative GSH and SOD activity；si-TTP upregulated pro-apoptotic cleaved-caspase-3 expression, and downregulated antiapoptotic Bcl-2 expression; while overexpression (OE)-TTP lentivirus caused opposite effects. Through database prediction, luciferase experiment, RNA immunoprecipitation (RIP), and mRNA stability analysis, we evaluated the potential binding sites of TTP to 3'-untranslated regions (3'-UTR) of NOX2 mRNA. TTP affected the NOX2 luciferase activity by binding to two sites in the NOX2 3'-UTR. RIP-qPCR confirmed TTP binding to both sites, with a higher affinity for site-2. In addition, TTP reduced the NOX2 mRNA stability. si-NOX2 and antioxidant N-acetyl cysteine (NAC) reversed si-TTP-induced cell apoptosis. In MPTP-treated mice, TTP expression increased and was co-located with dopaminergic neurons. TTP also inhibited NOX2 and decreased the oxidative stress in vivo. In conclusion, TTP protects against dopaminergic oxidative injury by promoting NOX2 mRNA degradation in the MPP[+] /MPTP model of PD, suggesting that TTP could be a potential therapeutic target for regulating the oxidative stress in PD.}, }
@article {pmid32949789, year = {2020}, author = {Takahashi, T and Misawa, S and Suzuki, S and Saeki, N and Shinoda, Y and Tsuneoka, Y and Akimoto, J and Fujiwara, Y}, title = {Possible mechanism of heme oxygenase-1 expression in rat malignant meningioma KMY-J cells subjected to talaporfin sodium-mediated photodynamic therapy.}, journal = {Photodiagnosis and photodynamic therapy}, volume = {32}, number = {}, pages = {102009}, doi = {10.1016/j.pdpdt.2020.102009}, pmid = {32949789}, issn = {1873-1597}, mesh = {Animals ; Heme Oxygenase-1 ; *Meningeal Neoplasms ; *Meningioma/drug therapy ; *Photochemotherapy/methods ; Photosensitizing Agents/pharmacology/therapeutic use ; Porphyrins ; Rats ; }, abstract = {BACKGROUND: We previously demonstrated that heme oxygenase-1 (HO-1) induction may contribute to a protective response against photodynamic therapy (PDT) using talaporfin sodium (TS) in rat malignant meningioma KMY-J cells. In the present study, we examined the mechanism of HO-1 induction by PDT with TS (TS-PDT) in KMY-J cells.<br><br>METHODS: KMY-J cells were incubated with 25 &#x3bc;M TS for 2&#x2009;h and then exposed to 664&#x2009;nm diode laser irradiation at 1&#x2009;J/cm[2]. The gene and protein expression levels of HO-1 and hypoxia-inducible factor-1&#x3b1; (HIF-1&#x3b1;) were determined by real-time RT-PCR and western blot analysis, respectively. Cell viability was measured using the cell counting kit-8 assay.<br><br>RESULTS: mRNA and protein levels of HO-1 in KMY-J cells were increased significantly at 3, 6, and 9&#x2009;h after laser irradiation and the increased mRNA level of HO-1 was decreased by antioxidant N-acetyl cysteine treatment. The protein level of HIF-1&#x3b1;, which mediates transcriptional activation of the HO-1 gene, was increased significantly at 1&#x2009;h after laser irradiation. Additionally, induction of mRNA expression of HO-1 by TS-PDT was diminished by HIF-1&#x3b1; inhibitor echinomycin. We also demonstrated that echinomycin significantly augmented the cytotoxic effect of TS-PDT.<br><br>CONCLUSIONS: Our findings indicate that TS-PDT may induce HO-1 expression via reactive oxygen species production and then HIF-1 pathway activation in KMY-J cells, and the HO-1 induction may cause attenuation of the therapeutic effect of TS-PDT.}, }
@article {pmid32947878, year = {2020}, author = {Yu, TJ and Tang, JY and Lin, LC and Lien, WJ and Cheng, YB and Chang, FR and Ou-Yang, F and Chang, HW}, title = {Withanolide C Inhibits Proliferation of Breast Cancer Cells via Oxidative Stress-Mediated Apoptosis and DNA Damage.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {9}, pages = {}, pmid = {32947878}, issn = {2076-3921}, support = {MOST 108-2320-B-037-015-MY3, MOST 108-2314-B-037-080, MOST 109-2314-B-037-018//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 109-I002//National Sun Yat-sen University-KMU Joint Research Project/ ; 109CM-KMU-007//Chimei-KMU jointed project/ ; KMUH104-4R20//Kaohsiung Medical University Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; MOHW 109-TDU-B-212-134016//Health and welfare surcharge of tobacco products, the Ministry of Health and Welfare, Taiwan, Republic of China/ ; }, abstract = {Some withanolides, particularly the family of steroidal lactones, show anticancer effects, but this is rarely reported for withanolide C (WHC)-especially anti-breast cancer effects. The subject of this study is to evaluate the ability of WHC to regulate the proliferation of breast cancer cells, using both time and concentration in treatment with WHC. In terms of ATP depletion, WHC induced more antiproliferation to three breast cancer cell lines, SKBR3, MCF7, and MDA-MB-231, than to normal breast M10 cell lines. SKBR3 and MCF7 cells showing higher sensitivity to WHC were used to explore the antiproliferation mechanism. Flow cytometric apoptosis analyses showed that subG1 phase and annexin V population were increased in breast cancer cells after WHC treatment. Western blotting showed that cleaved forms of the apoptotic proteins poly (ADP-ribose) polymerase (c-PARP) and cleaved caspase 3 (c-Cas 3) were increased in breast cancer cells. Flow cytometric oxidative stress analyses showed that WHC triggered reactive oxygen species (ROS) and mitochondrial superoxide (MitoSOX) production as well as glutathione depletion. In contrast, normal breast M10 cells showed lower levels of ROS and annexin V expression than breast cancer cells. Flow cytometric DNA damage analyses showed that WHC triggered γH2AX and 8-oxo-2'-deoxyguanosine (8-oxodG) expression in breast cancer cells. Moreover, N-acetylcysteine (NAC) pretreatment reverted oxidative stress-mediated ATP depletion, apoptosis, and DNA damage. Therefore, WHC kills breast cancer cells depending on oxidative stress-associated mechanisms.}, }
@article {pmid32945495, year = {2020}, author = {Wang, X and Jiang, M and He, X and Zhang, B and Peng, W and Guo, L}, title = {N‑acetyl cysteine inhibits the lipopolysaccharide‑induced inflammatory response in bone marrow mesenchymal stem cells by suppressing the TXNIP/NLRP3/IL‑1β signaling pathway.}, journal = {Molecular medicine reports}, volume = {22}, number = {4}, pages = {3299-3306}, pmid = {32945495}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gene Expression Regulation/drug effects ; Interleukin-1beta/genetics/metabolism ; Lipopolysaccharides/*adverse effects ; Mesenchymal Stem Cells/*cytology/drug effects/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Rats ; Signal Transduction/*drug effects ; }, abstract = {N-acetyl cysteine (NAC) has been used to inhibit lipopolysaccharide (LPS)-induced inflammation. However, the molecular mechanism underlying its anti‑inflammatory effects remains to be elucidated. The present study aimed to determine the effect of NAC on the LPS‑induced inflammatory response in bone marrow mesenchymal stem cells (BMSCs) and elucidate the underlying molecular mechanism. First, BMSCs were stimulated by LPS following pretreatment with NAC (0, 0.1, 0.5, 1 or 2 mM). A Cell Counting Kit 8 assay was used to determine the number of viable cells and 1 mM NAC was selected as the experimental concentration. Then, the secretion of inflammatory factors, including interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α was evaluated by enzyme‑linked immunosorbent assay. Finally, the expression levels of mRNA and proteins, including apoptosis‑associated speck‑like protein containing a CARD (ASC), nucleotide‑binding oligomerization domain‑like receptor protein 3 (NLRP3), caspase‑1, thioredoxin‑interacting protein (TXNIP), and thioredoxin (TRX), were evaluated by reverse transcription‑quantitative PCR and western blot analysis, respectively. The results demonstrated that the secretion of inflammatory factors, which was increased by the administration of LPS, was reduced by pretreatment with NAC. Furthermore, NAC reduced the expression of ASC, NLRP3, caspase‑1 and TXNIP, but enhanced that of TRX. To conclude, NAC had anti‑inflammatory effects on LPS‑stimulated BMSCs, which was closely associated with the TXNIP/NLRP3/IL‑1β signaling pathway. Thus, NAC may be a promising treatment to attenuate the inflammatory response in LPS‑induced BMSCs.}, }
@article {pmid32933169, year = {2020}, author = {Hsu, CN and Hou, CY and Chang-Chien, GP and Lin, S and Tain, YL}, title = {Maternal N-Acetylcysteine Therapy Prevents Hypertension in Spontaneously Hypertensive Rat Offspring: Implications of Hydrogen Sulfide-Generating Pathway and Gut Microbiota.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {9}, pages = {}, pmid = {32933169}, issn = {2076-3921}, support = {CORPG8J0121//Chang Gung Memorial Hospital, Kaohsiung, Taiwan./ ; }, abstract = {Hypertension can come from early life. N-acetylcysteine (NAC), a hydrogen sulfide (H2S) precursor as well as an antioxidant, has antihypertensive effect. We investigated whether maternal NAC therapy can protect spontaneously hypertensive rats (SHR) male offspring against hypertension. The pregnant rats were assigned to four groups: SHRs without treatment; Wistar Kyoto (WKY) without treatment; SHR+NAC, SHRs received 1% NAC in drinking water throughout pregnancy and lactation; and, WKY+NAC, WKY rats received 1% NAC in drinking water during pregnancy and lactation. Male offspring (n = 8/group) were killed at 12 weeks of age. Maternal NAC therapy prevented the rise in systolic blood pressure (BP) in male SHR offspring at 12 weeks of age. Renal cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and H2S-releasing activity were increased in the SHR+NAC offspring. Maternal NAC therapy increased fecal H2S and thiosulfate levels in the SHR+NAC group. Additionally, maternal NAC therapy differentially shaped gut microbiota and caused a distinct enterotype in each group. The protective effect of maternal NAC therapy against hypertension in SHR offspring is related to increased phylum Actinobacteria and genera Bifidobacterium and Allobaculum, but decreased phylum Verrucomicrobia, genera Turicibacter, and Akkermansia. Several microbes were identified as microbial markers, including genera Bifidobacterium, Allobaculum, Holdemania, and Turicibacter. Our results indicated that antioxidant therapy by NAC in pregnant SHRs can prevent the developmental programming of hypertension in male adult offspring. Our findings highlight the interrelationships among H2S-generating pathway in the kidneys and gut, gut microbiota, and hypertension. The implications of maternal NAC therapy elicited long-term protective effects on hypertension in later life that still await further clinical translation.}, }
@article {pmid32928514, year = {2020}, author = {Jing, GC and Liu, D and Liu, YQ and Zhang, MR}, title = {Nao-Fu-Cong ameliorates diabetic cognitive dysfunction by inhibition of JNK/CHOP/Bcl2-mediated apoptosis in vivo and in vitro.}, journal = {Chinese journal of natural medicines}, volume = {18}, number = {9}, pages = {704-713}, doi = {10.1016/S1875-5364(20)60009-7}, pmid = {32928514}, issn = {1875-5364}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Cognitive Dysfunction/*drug therapy ; Diabetes Mellitus, Experimental/drug therapy/physiopathology ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal/*pharmacology ; Hippocampus/drug effects ; MAP Kinase Signaling System/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Neurons/drug effects ; Neuroprotective Agents/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/drug effects ; Random Allocation ; Rats ; Transcription Factor CHOP/antagonists &amp; inhibitors ; }, abstract = {Chinese herbal compound Nao-Fu-Cong (NFC) has been mainly used to treat cognitive disorders in Traditional Chinese Medicine (TCM). The present study aimed to investigate whether its neuroprotective effects might be related to the inhibition of JNK/CHOP/Bcl2-mediated apoptosis pathway or not. We randomly assigned STZ (60 mg·kg[-1])-induced diabetic rats into control group, diabetic model group and NFC groups (low-dose, medium-dose and high-dose). The primary culture of hippocampal neurons were transferred into different culture media on the third day. The cells were then divided into control group, high-glucose group, NFC (low-dose, medium-dose and high-dose) groups, CHOP si-RNA intervention group, JNK pathway inhibitor SP600125 group and oxidative stress inhibitor N-acetylcysteine (NAC) group. NFC significantly improved the cognitive function of diabetic rats, and had neuroprotective effect on hippocampal neurons cultured in high glucose. Further research results showed that NFC could reduce the apoptosis of hippocampal neurons in rats with diabetic cognitive dysfunction. NFC had inhibitory effects on CHOP/JNK apoptosis pathway induced by high glucose, and also decreased the levels of ROS and increased the mitochondrial membrane potential. These suggested that the neuroprotective effect of NFC might be related to the inhibition of CHOP and JNK apoptotic signaling pathways, and the cross pathway between oxidative stress and mitochondrial damage pathway.}, }
@article {pmid32923369, year = {2020}, author = {Ersoy, M and Tiranti, V and Zeviani, M}, title = {Ethylmalonic encephalopathy: Clinical course and therapy response in an uncommon mild case with a severe ETHE1 mutation.}, journal = {Molecular genetics and metabolism reports}, volume = {25}, number = {}, pages = {100641}, pmid = {32923369}, issn = {2214-4269}, abstract = {Ethylmalonic encephalopathy (EE) is a rare metabolic disorder caused by dysfunction of ETHE1 protein, a mitochondrial dioxygenase involved in hydrogen sulfide (H2S) detoxification. EE is usually a fatal disease with a severe clinical course mainly associated with developmental delay and regression, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhoea. Treatment includes antioxidants, antibiotics that lower H2S levels and antispastic medications, which are not curative. The mutations causing absence of the ETHE1 protein, as is the case for the described patient, usually entail a severe fatal phenotype. Although there are rare reported cases with mild clinical findings, the mechanism leading to these milder cases is also unclear. Here, we describe an 11-year-old boy with an ETHE1 gene mutation who has no neurocognitive impairment but chronic diarrhoea, which is controlled by oral medical treatment, and progressive spastic paraparesis that responded to Achilles tendon lengthening.}, }
@article {pmid32923330, year = {2020}, author = {Els, JR and Taljaard, L and Strover, B}, title = {Delayed presentation of paracetamol overdose.}, journal = {African journal of emergency medicine : Revue africaine de la medecine d'urgence}, volume = {10}, number = {3}, pages = {170-172}, pmid = {32923330}, issn = {2211-4203}, abstract = {INTRODUCTION: Deliberate self-harm, including intentional self-poisoning, remains a major health concern in South Africa. Increasing number of cases place a significant burden on our Emergency Centres (EC's). Paracetamol remains the most frequent drug ingested in intentional self-poisoning. As an antidote, N-acetylcysteine (NAC) is very effective in the management of acute cases of paracetamol overdose. However, it shows less efficacy in cases of delayed presentation, where both liver transplant and mortality rates are significantly higher.<br><br>CASE REPORT: We present a case of delayed presentation paracetamol overdose. The patient presented in fulminant hepatic failure with encephalopathy, but made a full recovery after being treated with NAC.<br><br>DISCUSSION: This case report highlighted NAC's potential effectiveness in delayed presentations of paracetamol overdose, irrespective of associated fulminant hepatic failure. The effectiveness of NAC in delayed presentations of paracetamol overdose should therefore not be underestimated, and warrants further research.}, }
@article {pmid32922532, year = {2020}, author = {Zhao, S and Fan, S and Shi, Y and Ren, H and Hong, H and Gao, X and Zhang, M and Qin, Q and Li, H}, title = {Propranolol induced apoptosis and autophagy via the ROS/JNK signaling pathway in Human Ovarian Cancer.}, journal = {Journal of Cancer}, volume = {11}, number = {20}, pages = {5900-5910}, pmid = {32922532}, issn = {1837-9664}, abstract = {Propranolol has a significant anti-cancer effect towards various cancers. Our study aimed at investigating the underlying mechanism of Propranolol's therapeutic effect towards ovarian cancer. Specifically, Propranolol significantly reduced the viability of human ovarian cancer cell lines SKOV-3 and A2780 in a dose- and time-dependent manner. Flow cytometry analysis revealed that Propranolol induced the cell cycle arrest at G2/M phase therefore leading to apoptosis. Moreover, autophagy inhibitor 3-MA markedly enhanced the Propranolol-induced apoptosis. In addition, reactive oxygen species (ROS) increased dramatically after Propranolol treatment and Propranolol activated the phosphorylation of JNK. What is more, p38 inhibitor SB203580 and JNK inhibitor SP600125 attenuated the upregulated expression of LC3-II and cleaved-caspase-3 by the effect of Propranolol. ROS exclusive inhibitor antioxidant N-acetyl cysteine (NAC) weakens the phosphorylation of JNK proteins induced by Propranolol. In summary, these results suggested that Propranolol induced cell apoptosis and protective autophagy through the ROS/JNK signaling pathway in human ovarian cancer cells.}, }
@article {pmid32922469, year = {2020}, author = {Modarresi, A and Nafar, M and Sahraei, Z and Salamzadeh, J and Ziaie, S}, title = {Early Graft Function in Deceased Donor Renal Recipients: Role of N-Acetylcysteine.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {19}, number = {1}, pages = {57-67}, pmid = {32922469}, issn = {1735-0328}, abstract = {Reduced graft function (RGF) in donor renal transplant recipients is caused by oxidative damage due to extensive ischemia-reperfusion (I/R) injury during transplantation. Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker to detect tubular injury early after renal transplantation. N-acetylcysteine (NAC) is a potent antioxidant that can reduce I/R injury by improving oxidative damage. The aim of the present study is to assess the efficacy of NAC in improving graft function and reducing renal tubular injury in deceased donor renal transplant recipients. A double-blind, randomized clinical trial was conducted on 50 deceased donor renal transplant recipients. The patients were randomized into two groups, receiving either 600 mg NAC twice daily, or placebo (days 0 to 5). Results were assessed based on the rate of RGF, levels of plasma NGAL (p-NGAL) and the estimated glomerular filtration rate (eGFR). The rate of RGF was significantly lower in the patients receiving NAC vs. placebo (21.4% vs. 50%). The measurement of p-NGAL levels showed that the patients in the NAC group had significantly greater reduction of p-NGAL by both days 1 and 5 post-transplantation than those in the placebo group. A near steady-state eGFR level was reached by week 1 in the NAC group, however, the improvement of eGFR was significantly slower in the placebo group and a near steady-state was only achieved by week 4. NAC has promising potential in reducing tubular injury and improving graft function, evidenced by significant reduction in the rate of RGF and levels of p-NGAL.}, }
@article {pmid32917271, year = {2020}, author = {Tian, H and Zhou, Y and Tang, L and Wu, F and Deng, Z and Lin, B and Huang, P and Wei, S and Zhao, D and Zheng, J and Zhong, N and Ran, P}, title = {High-dose N-acetylcysteine for long-term, regular treatment of early-stage chronic obstructive pulmonary disease (GOLD I-II): study protocol for a multicenter, double-blinded, parallel-group, randomized controlled trial in China.}, journal = {Trials}, volume = {21}, number = {1}, pages = {780}, pmid = {32917271}, issn = {1745-6215}, support = {2016YFC1304101//National Key Technology Research and Development Program of the 13th National 5-Year Development Plan/ ; 201504010018//Science and Technology Project of Guangzhou/ ; 201604020012//Guangzhou Health care collaborative innovation major project/ ; }, mesh = {*Acetylcysteine/adverse effects ; China ; Double-Blind Method ; Forced Expiratory Volume ; Humans ; Multicenter Studies as Topic ; *Pulmonary Disease, Chronic Obstructive/diagnosis/drug therapy ; Randomized Controlled Trials as Topic ; Respiratory Function Tests ; Treatment Outcome ; }, abstract = {INTRODUCTION: The presence of increased oxidative stress and airway inflammation has been proven in subjects with chronic obstructive pulmonary disease (COPD). Several studies have demonstrated that drugs with antioxidant and anti-inflammatory properties such as N-acetylcysteine (NAC) can reduce the rate of exacerbations in patients with COPD. However, the beneficial effects of NAC in early-stage COPD are minimally discussed. We are investigating whether high-dose NAC has therapeutic effects in Chinese patients with early-stage COPD.<br><br>METHOD AND ANALYSIS: A randomized, double-blinded, placebo-controlled, parallel-group, multicenter clinical trial is evaluating the efficacy and safety of NAC for the long-term treatment of patients with early-stage COPD at 24 centers in China. Subjects aged 40-80&#x2009;years and recruited by physicians or researchers with special training will be randomized to either NAC 600&#x2009;mg twice daily group or matching placebo group for 2&#x2009;years. Measurements will include forced expiratory volume in 1&#x2009;s (FEV1), the number of COPD exacerbations, health-related quality, and pharmacoeconomic analysis.<br><br>DISCUSSION: Currently, there are no randomized controlled trials with high-dose N-acetylcysteine (600&#x2009;mg twice daily) for patients with mild-to-moderate COPD (GOLD I-II). We designed this multicenter randomized controlled trial (RCT) to assess the effectiveness, safety, and cost-effectiveness of long-term treatment with high-dose N-acetylcysteine. The results of this trial may guide clinical practice and change the standard of early COPD management.<br><br>TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-IIR-17012604 . Registered on 07 September 2017.}, }
@article {pmid32916895, year = {2020}, author = {Lee, BK and Hyun, SW and Jung, YS}, title = {Yuzu and Hesperidin Ameliorate Blood-Brain Barrier Disruption during Hypoxia via Antioxidant Activity.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {9}, pages = {}, pmid = {32916895}, issn = {2076-3921}, support = {HI18C0920//the Korea Health Technology R&amp;D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare/ ; 2018R1D1A1B07048729//a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; 20201I1A1A01071848//a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; }, abstract = {Yuzu and its main component, hesperidin (HSP), have several health benefits owing to their anti-inflammatory and antioxidant properties. We examined the effects of yuzu and HSP on blood-brain barrier (BBB) dysfunction during ischemia/hypoxia in an in vivo animal model and an in vitro BBB endothelial cell model, and also investigated the underlying mechanisms. In an in vitro BBB endothelial cell model, BBB permeability was determined by measurement of Evans blue extravasation in vivo and in vitro. The expression of tight junction proteins, such as claudin-5 and zonula occludens-1 (ZO-1), was detected by immunochemistry and western blotting, and the reactive oxygen species (ROS) level was measured by 2'7'-dichlorofluorescein diacetate intensity. Yuzu and HSP significantly ameliorated the increase in BBB permeability and the disruption of claudin-5 and ZO-1 in both in vivo and in vitro models. In bEnd.3 cells, yuzu and HSP were shown to inhibit the disruption of claudin-5 and ZO-1 during hypoxia, and the protective effects of yuzu and HSP on claudin-5 degradation seemed to be mediated by Forkhead box O 3a (FoxO3a) and matrix metalloproteinase (MMP)-3/9. In addition, well-known antioxidants, trolox and N-acetyl cysteine, significantly attenuated the BBB permeability increase, disruption of claudin-5 and ZO-1, and FoxO3a activation during hypoxia, suggesting that ROS are important mediators of BBB dysfunction during hypoxia. Collectively, these results indicate that yuzu and HSP protect the BBB against dysfunction via maintaining integrity of claudin-5 and ZO-1, and these effects of yuzu and HSP appear to be a facet of their antioxidant properties. Our findings may contribute to therapeutic strategies for BBB-associated neurodegenerative diseases.}, }
@article {pmid32908624, year = {2020}, author = {Bu, W and Hao, X and Yang, T and Wang, J and Liu, Q and Zhang, X and Li, X and Gong, Y and Shao, C}, title = {Autophagy Contributes to the Maintenance of Genomic Integrity by Reducing Oxidative Stress.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {2015920}, pmid = {32908624}, issn = {1942-0994}, mesh = {Antioxidants/pharmacology ; Autophagy/drug effects/*genetics ; Cell Line, Tumor ; Cellular Senescence/drug effects ; Checkpoint Kinase 1/metabolism ; *Genomic Instability/drug effects ; Humans ; Mesenchymal Stem Cells/drug effects/metabolism ; Micronuclei, Chromosome-Defective ; Mutagens/toxicity ; Oxidative Stress/drug effects/*genetics ; Reactive Oxygen Species/metabolism ; Sirolimus/pharmacology ; }, abstract = {Autophagy has been well documented to play an important role in maintaining genomic stability. However, in addition to directly engulfing and digesting the damaged organelles and chromatin fragments, autophagy can affect many cellular processes including DNA damage response, regulation of redox homeostasis, and cell division; it remains to be determined to what extent each of those processes contributes to the maintenance of genomic stability. We here examined the role of autophagy-dependent redox regulation in the maintenance of genomic stability in two cancer cell lines (HT1080 and U2OS) and mesenchymal stem cells (MSCs) using micronuclei MN, also referred to as cytoplasmic chromatin fragments, as a marker. Our results showed that the spontaneous and genotoxic stress-induced frequencies of MN in cancer cells were significantly reduced by autophagy activators rapamycin and Torin1, and the reduction in MN was accompanied by a reduction in reactive oxygen species (ROS). Increased micronucleation in senescent MSCs, in which autophagic flux is blocked, was also attenuated by rapamycin, together with a reduction in ROS. Inhibition of autophagy by chloroquine (CQ) or ATG5 depletion, on the other hand, resulted in an increased frequency of MN, though a ROS elevation in response to autophagy inhibition was only observed in MSCs. Importantly, the induction of MN by autophagy inhibition in MSCs could be abrogated by antioxidant N-acetylcysteine (NAC). In contrast to the reported impairment of CHK1 activation in Atg7-deficient mouse embryonic fibroblasts, we found that the level of phosphorylated CHK1 was increased by CQ or ATG5 depletion but decreased by rapamycin or Torin1, suggesting that the increased genomic instability by defective autophagy is not caused by insufficient activation of CHK1-homologous recombination cascade. Together, our findings suggest that redox homeostasis regulated by autophagy contributes substantially to the maintenance of genomic stability in certain contexts.}, }
@article {pmid32904480, year = {2020}, author = {Bretti, C and Cardiano, P and Irto, A and Lando, G and Milea, D and Sammartano, S}, title = {Interaction of N-acetyl-l-cysteine with Na[+], Ca[2+], Mg[2+] and Zn[2+]. Thermodynamic aspects, chemical speciation and sequestering ability in natural fluids.}, journal = {Journal of molecular liquids}, volume = {319}, number = {}, pages = {114164}, pmid = {32904480}, issn = {0167-7322}, abstract = {The estimation of thermodynamic parameters of N-Acetyl-L-cysteine (NAC) protonation were determined in NaCl(aq), (CH3)4NCl(aq), (C2H5)4NI(aq), employing various temperature and ionic strengths conditions, by potentiometric measurements. The interaction of NAC with some essential metal cations (e.g., Ca[2+], Mg[2+] and Zn[2+]) was investigated as well at 298.15 K in NaCl(aq) in the ionic strength range 0.1 ≤ I/mol dm[-3] ≤ 1.0. The values of protonation constants at infinite dilution and at T = 298.15 K are: log K 1 [H] = 9.962 ± 0.005 (S-H) and log K 2 [H] = 3.347 ± 0.008 (COO-H). In the presence of a background electrolyte, both log K 1 [H] and log K 2 [H] values followed the trend (C2H5)4NI ≥ (CH3)4NCl ≥ NaCl. The differences in the values of protonation constants among the three ionic media were interpreted in terms of variation of activity coefficients and formation of weak complexes. Accordingly, the determination of the stability of 4 species, namely: NaL[-], NaHL[0] (aq), (CH3)4NL[-], (CH3)4NHL[0] (aq) was assessed. In addition, as regards the interactions of Mg[2+], Ca[2+] and Zn[2+] with NAC, the main species where the ML[0] (aq), ML(OH)[-], and ML2 [2-], that were found to be important in the chemical speciation of NAC in real multicomponent solutions. The whole set of the data collected may be crucial for the development of NAC-based materials for natural fluids selective decontamination from heavy metals.}, }
@article {pmid32899154, year = {2020}, author = {Kim, D and Kim, KA and Kim, JH and Kim, EH and Bae, ON}, title = {Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt/HIF-1α Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {9}, pages = {}, pmid = {32899154}, issn = {2076-3921}, support = {HI14C2284//the Ministry of Health and Welfare of Korea/ ; NRF-2017R1C1B3002626//the National Research Foundation of Korea supported by the Ministry of Science, ICT &amp; Future Planning/ ; }, abstract = {Methylglyoxal (MG) is a dicarbonyl compound, the level of which is increased in the blood of diabetes patients. MG is reported to be involved in the development of cerebrovascular complications in diabetes, but the exact mechanisms need to be elucidated. Here, we investigated the possible roles of oxidative stress and mitophagy in MG-induced functional damage in brain endothelial cells (ECs). Treatment of MG significantly altered metabolic stress as observed by the oxygen-consumption rate and barrier-integrity as found in impaired trans-endothelial electrical resistance in brain ECs. The accumulation of MG adducts and the disturbance of the glyoxalase system, which are major detoxification enzymes of MG, occurred concurrently. Reactive oxygen species (ROS)-triggered oxidative damage was observed with increased mitochondrial ROS production and the suppressed Akt/hypoxia-inducible factor 1 alpha (HIF-1α) pathway. Along with the disturbance of mitochondrial bioenergetic function, parkin-1-mediated mitophagy was increased by MG. Treatment of N-acetyl cysteine significantly reversed mitochondrial damage and mitophagy. Notably, MG induced dysregulation of tight junction proteins including occludin, claudin-5, and zonula occluden-1 in brain ECs. Here, we propose that diabetic metabolite MG-associated oxidative stress may contribute to mitochondrial damage and autophagy in brain ECs, resulting in the dysregulation of tight junction proteins and the impairment of permeability.}, }
@article {pmid32896808, year = {2020}, author = {Ding, Q and Liu, C and Zhao, C and Dong, H and Xu, Q and James Chou, C and Zhang, Y}, title = {Synthesis and biological study of class I selective HDAC inhibitors with NO releasing activity.}, journal = {Bioorganic chemistry}, volume = {104}, number = {}, pages = {104235}, doi = {10.1016/j.bioorg.2020.104235}, pmid = {32896808}, issn = {1090-2120}, mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; HeLa Cells ; Histone Deacetylase Inhibitors/chemical synthesis/chemistry/*pharmacology ; Histone Deacetylases/metabolism ; Humans ; Molecular Structure ; Neoplasms, Experimental/drug therapy/metabolism/pathology ; Nitric Oxide/*antagonists &amp; inhibitors/biosynthesis ; Phenylenediamines/chemical synthesis/chemistry/*pharmacology ; Structure-Activity Relationship ; }, abstract = {Based on the multi-mechanism antitumor strategy and the regulatory effect of nitric oxide (NO) on histone deacetylases (HDACs), a series of N-acyl-o-phenylenediamine-based HDAC inhibitors equipped with the phenylsulfonylfuroxan module as NO donor was designed, synthesized and biologically evaluated. The in vitro HDAC inhibitory assays revealed that compared with the clinical class I selective HDAC inhibitor MS275, compounds 7c, 7d and 7e possessed similar HDAC inhibitory potency and selective profile, which were confirmed by the results of western blot analysis. The western blot analysis also showed that NO scavenger N-acetyl cysteine (NAC) could weaken the intracellular HDAC inhibitory ability of compound 7c, supporting the HDAC inhibitory effect of NO generated by 7c. It is worth noting that compounds 7c, 7d and 7e exhibited more potent in vitro antiproliferative activities than MS275 against all four tested solid tumor cell lines. The promising in vivo antitumor potency of 7c was demonstrated in a HCT116 xenograft model.}, }
@article {pmid32896000, year = {2021}, author = {Corazza, BJM and Martinho, FC and Khoury, RD and Toia, CC and Orozco, EIF and Prado, RF and Machado, FP and Valera, MC}, title = {Clinical influence of calcium hydroxide and N-acetylcysteine on the levels of resolvins E1 and D2 in apical periodontitis.}, journal = {International endodontic journal}, volume = {54}, number = {1}, pages = {61-73}, doi = {10.1111/iej.13403}, pmid = {32896000}, issn = {1365-2591}, support = {2016/26012-3//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2018/01703-9//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; }, mesh = {Acetylcysteine ; *Calcium Hydroxide ; Chlorhexidine ; Dental Pulp Cavity ; Humans ; *Periapical Periodontitis/drug therapy ; Root Canal Irrigants ; Root Canal Preparation ; }, abstract = {AIM: To investigate the presence of resolvins E1 (RvE1) and D2 (RvD2) in teeth with primary endodontic infections and apical periodontitis, and to assess the influence of calcium hydroxide medication [Ca(OH)2 ], in association with 2% chlorhexidine gel (2% CHX gel), and N-acetylcysteine (NAC) on the levels of RvE1 and RvD2 in periapical tissues.<br><br>METHODOLOGY: Thirty-six single-rooted teeth with primary endodontic infections and apical periodontitis were selected and randomly divided into three groups according to the medication: [Ca(OH)2 ]&#xa0;+&#xa0;saline solution (SSL) [Ca(OH)2 &#xa0;+&#xa0;SSL group] (n&#xa0;=&#xa0;12), Ca(OH)2 &#xa0;+&#xa0;2% chlorhexidine gel [Ca(OH)2 &#xa0;+&#xa0;2% CHX gel group] (n&#xa0;=&#xa0;12) and NAC [NAC group] (n&#xa0;=&#xa0;12). Samples were collected from the periapical interstitial fluid at two different sampling times: before (S1) and after 14&#xa0;days of intracanal medications (S2). Resolvins were measured using the enzyme-linked immunosorbent assay. Data were analysed using paired t-test, Wilcoxon test and Kruskal-Wallis test, followed by Dunn's post hoc test; all statistical tests were performed at a significance level of 5%.<br><br>RESULTS: RvE1 and RvD2 were detected in 100% of the samples (36/36) at S1 and S2. Ca(OH)2 medication did not increase the levels of RvE1 or RvD2 (both P&#xa0;>&#xa0;0.05); however, NAC significantly increased the levels of RvE1 and RvD2 after 14&#xa0;days of treatment (P&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: RvE1 and RvD2 were detected in periapical tissues from teeth with root canal infections. Moreover, calcium hydroxide medication did not increase the levels of resolvins in apical periodontitis. In contrast, the use of NAC intracanal medication significantly increased the levels of RvE1 and RvD2 after 14&#xa0;days of treatment.}, }
@article {pmid32890923, year = {2020}, author = {Zhang, D and Yang, XY and Qin, YZ and Wu, GD and Ning, GB and Huo, NR and Tian, WX}, title = {Antagonistic effect of N-acetyl-L-cysteine against cadmium-induced cytotoxicity and abnormal immune response on chicken peritoneal macrophages.}, journal = {Ecotoxicology and environmental safety}, volume = {206}, number = {}, pages = {111185}, doi = {10.1016/j.ecoenv.2020.111185}, pmid = {32890923}, issn = {1090-2414}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cadmium/*toxicity ; Cells, Cultured ; *Chickens ; Cytokines/*metabolism ; Humans ; Inflammation ; Lipopolysaccharides/pharmacology ; Macrophages, Peritoneal/*drug effects/immunology/metabolism/ultrastructure ; Male ; Mitochondria/drug effects ; Oxidative Stress/drug effects ; Phagocytosis/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Cadmium is a highly toxic metal threatening human and animal health. N-acetyl-L-cysteine (NAC) was reported to play a positive role in disease treatment and immune regulation. The present study aimed to explore the effect of NAC administration on Cd-induced cytotoxicity and abnormal immune response on chicken peritoneal macrophages. Peritoneal macrophages isolated from Isa Brown male chickens were exposed to CdCl2 (20 or 50 μM) and/or NAC (500 μM) for different time periods. Results showed that Cd caused dose-dependent damage on chicken peritoneal macrophages characterized by morphologic and ultrastructural alterations, increased cell apoptosis, reactive oxygen species accumulation and mitochondrial injury. Cd exposure inhibited phagocytic activity of chicken peritoneal macrophages, and promoted transcriptional status of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in both unactivated macrophages and cells in response to lipopolysaccharide (LPS) stimuli. Pretreatment with 500 μM NAC did not affect growth of normal chicken peritoneal macrophages, while remarkably inhibiting Cd-caused cell death, oxidative stress, and mitochondrial membrane depolarization. NAC pretreatment significantly prevented intracellular Cd[2+] accumulation in the Cd-exposed macrophages. Inhibitory effects of NAC on Cd-induced ROS accumulation and mitochondrial injury on chicken macrophages were confirmed in HD-11 macrophage cell line. In addition, NAC pretreatment promoted the phagocytic activity of Cd-exposed chicken peritoneal macrophages, and significantly inhibited expression of pro-inflammatory factors (IL-1β, IL-6 and TNF-α) in both Cd-exposed macrophages and Cd-treated cells in response to LPS stimuli. In conclusion, the present study firstly demonstrated the antagonistic effect of NAC against Cd-caused damage and abnormal immune response on chicken peritoneal macrophages. Protective effect of NAC on chicken macrophages was highly related to its suppression on Cd-induced ROS overproduction, pro-inflammatory reaction and intracellular Cd[2+] accumulation.}, }
@article {pmid32890697, year = {2020}, author = {Jeppesen, R and Christensen, RHB and Pedersen, EMJ and Nordentoft, M and Hjorthøj, C and Köhler-Forsberg, O and Benros, ME}, title = {Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders - A comprehensive systematic review and meta-analysis.}, journal = {Brain, behavior, and immunity}, volume = {90}, number = {}, pages = {364-380}, doi = {10.1016/j.bbi.2020.08.028}, pmid = {32890697}, issn = {1090-2139}, mesh = {Anti-Inflammatory Agents/therapeutic use ; *Antipsychotic Agents/adverse effects ; Humans ; *Psychotic Disorders/drug therapy ; *Schizophrenia/drug therapy ; }, abstract = {OBJECTIVE: Antipsychotic effects of immunomodulating drugs have been suggested; however, a thorough, comprehensive meta-analysis on the effect and safety of anti-inflammatory add-on treatment on psychotic disorders is lacking.<br><br>METHOD: Multiple databases were searched up until February 2020. Only double-blinded, randomized, placebo-controlled clinical trials (RCTs) were included. Primary outcomes were change in total psychopathology and adverse events. Secondary outcomes included, amongst others, positive and negative symptoms, general psychopathology and cognitive domains. We performed random-effects meta-analyses estimating mean differences (MD) and standardized mean differences (SMD) for effect sizes.<br><br>RESULTS: Seventy RCTs (N&#xa0;=&#xa0;4104) were included, investigating either primarily anti-inflammatory drugs, i.e. drugs developed for immunomodulation, such as NSAIDs, minocycline and monoclonal antibodies (k&#xa0;=&#xa0;15), or drugs with potential anti-inflammatory properties (k&#xa0;=&#xa0;55), e.g. neurosteroids, N-acetyl cysteine, estrogens, fatty acids, statins, and glitazones. Antipsychotics plus anti-inflammatory treatment, compared to antipsychotics plus placebo, was associated with a PANSS scale MD improvement of -4.57 (95%CI&#xa0;=&#xa0;-5.93 to -3.20) points, corresponding to a SMD effect size of -0.29 (95%CI&#xa0;=&#xa0;-0.40 to -0.19). Trials on schizophrenia (MD&#xa0;=&#xa0;-6.80; 95%CI, -9.08 to -4.52) showed greater improvement (p&#xa0;<&#xa0;0.01) than trials also including other psychotic disorders. However, primarily anti-inflammatory drugs (MD&#xa0;=&#xa0;4.00; 95%CI&#xa0;=&#xa0;-7.19 to -0.80) were not superior (p&#xa0;=&#xa0;0.69) to potential anti-inflammatory drugs (MD&#xa0;=&#xa0;4.71; 95%CI&#xa0;=&#xa0;-6.26 to -3.17). Furthermore, meta-regression found that smaller studies showed significantly larger effect sizes than the larger studies (p&#xa0;=&#xa0;0.0085), and only 2 studies had low risk of bias on all domains. Small but significant effects were found on negative symptoms (MD&#xa0;=&#xa0;-1.29), positive symptoms (MD&#xa0;=&#xa0;-0.53), general psychopathology (MD&#xa0;=&#xa0;-1.50) and working memory (SMD&#xa0;=&#xa0;0.21). No differences were found regarding adverse events, but only 26 studies reported hereon.<br><br>CONCLUSIONS: Anti-inflammatory add-on treatment to antipsychotics showed improvement of psychotic disorders; however, no superiority was found in primarily anti-inflammatory drugs, raising the question of the mechanism behind the effect, and treatment effect might be overestimated due to the large number of small studies.}, }
@article {pmid32888972, year = {2020}, author = {Gibson, AS and Keefe, KA and Furlong, TM}, title = {Accelerated habitual learning resulting from L-dopa exposure in rats is prevented by N-acetylcysteine.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {198}, number = {}, pages = {173033}, doi = {10.1016/j.pbb.2020.173033}, pmid = {32888972}, issn = {1873-5177}, support = {R01 MH094870/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Behavior, Addictive/drug therapy/metabolism ; Behavior, Animal/*drug effects ; Conditioning, Operant/*drug effects ; Dopamine/metabolism ; Dopamine Agents/pharmacology ; Glutamic Acid/metabolism ; Habits ; Levodopa/*pharmacology ; Male ; Motor Activity/drug effects ; Parkinson Disease/drug therapy/metabolism ; Rats ; Rats, Long-Evans ; }, abstract = {Instrumental actions are initially goal-directed and driven by their associated outcome. However, with repeated experience habitual actions develop which are automated and efficient, as they are instead driven by antecedent stimuli. Dopamine is thought to facilitate the transition from goal-directed to habitual actions. This idea has been largely derived from evidence that psychostimulants accelerate the development of habitual actions. In the current study, we examined the impact of L-dopa (levodopa or L-dihydroxyphenylalanine), which also potentiates dopamine activity, on habitual learning. L-dopa was systemically administered prior to training rats to press a lever for a food outcome. When tested, L-dopa exposed animals were insensitive to changes in the value of the food outcome, and hence demonstrated accelerated habitual behavioral control compared to control animals that remained goal directed. We also showed that when N-acetylcysteine (NAC), an antioxidant and regulator of glutamate activity, was co-administered with L-dopa, it prevented the transition to habitual behavior; an effect demonstrated previously for cocaine. Therefore, this study establishes similarities between L-dopa and psychostimulants in both the development and prevention of habitual actions, and supports the notion that excess dopamine potentiates habitual learning. This finding extends the limited existing knowledge of the impact of L-dopa on learning and behavior, and has implications for neurological disorders where L-dopa is the primary treatment.}, }
@article {pmid32882411, year = {2020}, author = {Shiozawa, A and Kajiwara, C and Ishii, Y and Tateda, K}, title = {N-acetyl-cysteine mediates protection against Mycobacterium avium through induction of human β-defensin-2 in a mouse lung infection model.}, journal = {Microbes and infection}, volume = {22}, number = {10}, pages = {567-575}, doi = {10.1016/j.micinf.2020.08.003}, pmid = {32882411}, issn = {1769-714X}, mesh = {A549 Cells ; Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antitubercular Agents/*pharmacology/therapeutic use ; Bacterial Load/drug effects ; Disease Models, Animal ; Humans ; Interleukin-17/metabolism ; Lung/drug effects/microbiology ; Mice ; Mycobacterium avium/*drug effects/growth &amp; development ; Mycobacterium avium-intracellulare Infection/*drug therapy/metabolism/microbiology ; RAW 264.7 Cells ; Signal Transduction ; beta-Defensins/*metabolism ; }, abstract = {Mycobacterium avium complex is a causative organism for refractory diseases. In this study, we examined the effects of N-acetyl-cysteine on M. avium infection in vitro and in vivo. N-acetyl-cysteine treatment suppressed the growth of M. avium in A549 cells in a concentration-dependent manner. This effect was related to the induction of the antibacterial peptide human β-defensin-2. In a mouse model, N-acetyl-cysteine treatment significantly reduced the number of bacteria in the lungs and induced murine β-defensin-3. In interleukin-17-deficient mice, the effects of N-acetyl-cysteine disappeared, indicating that these mechanisms may be mediated by interleukin-17. Moreover, an additional reduction in bacterial load was observed in mice administered N-acetyl-cysteine in combination with clarithromycin. Our findings demonstrate the potent antimycobacterial effects of N-acetyl-cysteine against M. avium by inducing antimicrobial peptide, suggesting that N-acetyl-cysteine may have applications as an alternative to classical treatment regimens.}, }
@article {pmid32872198, year = {2020}, author = {Park, J and Baek, SH}, title = {Combination Therapy with Cinnamaldehyde and Hyperthermia Induces Apoptosis of A549 Non-Small Cell Lung Carcinoma Cells via Regulation of Reactive Oxygen Species and Mitogen-Activated Protein Kinase Family.}, journal = {International journal of molecular sciences}, volume = {21}, number = {17}, pages = {}, pmid = {32872198}, issn = {1422-0067}, support = {NRF-2020R1C1C1009721//National Research Foundation of Korea/ ; NRF-2020R1I1A3063625//National Research Foundation of Korea/ ; }, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Acrolein/*analogs &amp; derivatives/pharmacology ; Carcinoma, Non-Small-Cell Lung/*metabolism/therapy ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Combined Modality Therapy ; Drug Screening Assays, Antitumor ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hyperthermia, Induced/*methods ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Lung Neoplasms/*metabolism/therapy ; MAP Kinase Signaling System/drug effects ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Lung cancer is the largest cause of cancer-induced deaths. Non-small cell lung cancer (NSCLC) is the most frequently observed subtype of lung cancer. Although recent studies have provided many therapeutic options, there is still a need for effective and safe treatments. This paper reports the combined effects of cinnamaldehyde (CNM), a flavonoid from cinnamon, together with hyperthermia, a therapeutic option for cancer treatment, on the A549 NSCLC cell line. A hyperthermia treatment of 43 °C potentiated the cytotoxicity of CNM in A549 cells. This was attributed to an increase in the apoptosis markers and suppression of the survival/protective factors, as confirmed by Western blot assays. Flow cytometry supported this result because the apoptotic profile, cell health profile, and cell cycle profile were regulated by CNM and hyperthermia combination therapy. The changes in reactive oxygen species (ROS) and its downstream target pathway, mitogen-activated protein kinases (MAPK), were evaluated. The CNM and hyperthermia combination increased the generation of ROS and MAPK phosphorylation. N-acetylcysteine (NAC), a ROS inhibitor, abolished the apoptotic events caused by CNM and hyperthermia co-treatment, suggesting that the cytotoxic effect was dependent of ROS signaling. Therefore, we suggest CNM and hyperthermia combination as an effective therapeutic option for the NSCLC treatment.}, }
@article {pmid32871518, year = {2020}, author = {Mantawy, EM and Said, RS and Kassem, DH and Abdel-Aziz, AK and Badr, AM}, title = {Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against ϒ-radiation-induced premature ovarian failure in rats.}, journal = {Ecotoxicology and environmental safety}, volume = {206}, number = {}, pages = {111190}, doi = {10.1016/j.ecoenv.2020.111190}, pmid = {32871518}, issn = {1090-2414}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Disease Models, Animal ; Female ; Gamma Rays/*adverse effects ; Humans ; MAP Kinase Signaling System/drug effects/radiation effects ; NADPH Oxidase 4/metabolism ; Ovary/*drug effects/metabolism/radiation effects/ultrastructure ; Oxidative Stress/drug effects/radiation effects ; Primary Ovarian Insufficiency/etiology/metabolism/pathology/*prevention &amp; control ; Radiation-Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Müllerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bcl2 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.}, }
@article {pmid32868342, year = {2020}, author = {Wang, Q and Zhou, H and Fan, H and Wang, X}, title = {Coinfection with Porcine Circovirus Type 2 (PCV2) and Streptococcus suis Serotype 2 (SS2) Enhances the Survival of SS2 in Swine Tracheal Epithelial Cells by Decreasing Reactive Oxygen Species Production.}, journal = {Infection and immunity}, volume = {88}, number = {11}, pages = {}, pmid = {32868342}, issn = {1098-5522}, mesh = {Animals ; Circoviridae Infections/immunology/metabolism/*virology ; Circovirus/immunology/metabolism ; Coinfection/immunology/metabolism/*microbiology ; Reactive Oxygen Species/*metabolism ; Respiratory Mucosa/immunology/metabolism/*microbiology ; Streptococcal Infections/immunology/metabolism/*microbiology ; Streptococcus suis/immunology/metabolism ; Swine ; Swine Diseases/immunology/metabolism/*microbiology ; Trachea/immunology/metabolism/microbiology ; }, abstract = {Porcine circovirus type 2 (PCV2) and Streptococcus suis serotype 2 (SS2) clinical coinfection cases have been frequently detected. The respiratory epithelium plays a crucial role in host defense against a variety of inhaled pathogens. Reactive oxygen species (ROS) are involved in killing of bacteria and host immune response. The aim of this study is to assess whether PCV2 and SS2 coinfection in swine tracheal epithelial cells (STEC) affects ROS production and investigate the roles of ROS in bacterial survival and the inflammatory response. Compared to SS2 infection, PCV2/SS2 coinfection inhibited the activity of NADPH oxidase, resulting in lower ROS levels. Bacterial intracellular survival experiments showed that coinfection with PCV2 and SS2 enhanced SS2 survival in STEC. Pretreatment of STEC with N-acetylcysteine (NAC) also helps SS2 intracellular survival, indicating that PCV2/SS2 coinfection enhances the survival of SS2 in STEC through a decrease in ROS production. In addition, compared to SS2-infected STEC, PCV2/SS2 coinfection and pretreatment of STEC with NAC prior to SS2 infection both downregulated the expression of the inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and IL-1β. Further research found that activation of p38/MAPK promoted the expression of inflammatory cytokines in SS2-infected STEC; however, PCV2/SS2 coinfection or NAC pretreatment of STEC inhibited p38 phosphorylation, suggesting that coinfection of STEC with PCV2 and SS2 weakens the inflammatory response to SS2 infection through reduced ROS production. Collectively, coinfection of STEC with PCV2 and SS2 enhances the intracellular survival of SS2 and weakens the inflammatory response through decreased ROS production, which might exacerbate SS2 infection in the host.}, }
@article {pmid32866502, year = {2020}, author = {Mrówka, M and Jaszcz, K and Skonieczna, M}, title = {Anticancer activity of functional polysuccinates with N-acetyl-cysteine in side chains.}, journal = {European journal of pharmacology}, volume = {885}, number = {}, pages = {173501}, doi = {10.1016/j.ejphar.2020.173501}, pmid = {32866502}, issn = {1879-0712}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Cell Line ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Fibroblasts/drug effects ; Humans ; Keratinocytes/drug effects ; Polyesters/chemical synthesis/pharmacology ; Reactive Oxygen Species ; Structure-Activity Relationship ; Succinates/chemistry/*pharmacology ; }, abstract = {The synthesis and characteristics of functional polyesters with a potential anticancer activity have been described, followed by a post-modification process of biologically active polymers. First, biodegradable functional polysuccinates possessing pendant allyl groups, that are susceptible to thiol-ene reaction, were obtained by polyaddition of succinic anhydride and allyl glycidyl ether. The functionality of such polyesters was regulated by replacing a part of unsaturated glycidyl ether with saturated ones. Polymers containing 20-100% mers with allyl groups were reacted with N-acetyl-cysteine (NAC). The use of simple click reaction allowed obtaining polyesters containing different amounts of N-acetyl-cysteine in side chains. The thus obtained polymers with a molecular weight of several thousand are characterized by solubility in methanol as opposed to their initial precursors. Modified polyesters show no toxicity to normal human keratinocytes (HaCaT) cells, similar to the NAC in normal human fibroblasts (NHDF), whereas the anticancer activities were observed against squamous carcinoma (SCC-25), and melanoma (Me45) cells. A standard colorimetric assay (MTS), to assessing cells viability and cytotoxicity of tested compounds, was performed against NHDF for NAC, HaCaT, SCC-25, and Me45 cells, within 24-144 h long-term expositions. Neither contact with NAC alone, and tested materials, nor long incubation decreased normal cell viability or induced inflammation. That reassumed the potential of anticancer activities of tested materials, with the tendency to visible selectivity against cancer cell lines in vitro, confirmed with live microscopic imaging against the Me45 cell line.}, }
@article {pmid32864863, year = {2021}, author = {Sritharan, S and Sivalingam, N}, title = {Curcumin induced apoptosis is mediated through oxidative stress in mutated p53 and wild type p53 colon adenocarcinoma cell lines.}, journal = {Journal of biochemical and molecular toxicology}, volume = {35}, number = {1}, pages = {e22616}, doi = {10.1002/jbt.22616}, pmid = {32864863}, issn = {1099-0461}, mesh = {Adenocarcinoma/drug therapy/genetics/*metabolism/pathology ; Apoptosis/*drug effects/genetics ; Colonic Neoplasms/drug therapy/genetics/*metabolism/pathology ; Curcumin/*pharmacology ; HCT116 Cells ; HT29 Cells ; Humans ; *Mutation ; Oxidative Stress/*drug effects/genetics ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {Curcumin has anti-oxidant, anti-cancer and anti-carcinogen property. Our laboratory had previously reported that, curcumin treatment induces reactive oxygen species (ROS) generation in HT-29 cell line, an effect contradictory to its anti-oxidant property. This study evaluates the role of p53 in curcumin mediated ROS generation and cell death. Curcumin induced ROS was determined by 2',7'-dichlorofluorescein and apoptosis by Hoechst33342/PI staining in HT-29 and HCT-116 cell lines. ROS generation occurs within 1 hour of 40 µM curcumin treatment and a reduction was observed by third hour in HCT-116 insinuating p53 involvement. N-acetyl cysteine (NAC) pre-treatment effectively quenched ROS and inhibited membrane potential loss in HT-29, but less effective in HCT-116. Mitochondrial membrane potential loss is evident with 10 and 40 µM curcumin in HCT-116 and at 40 µM curcumin in HT-29. Total p53 protein level increase was observed by 24 hours in HCT-116 upon NAC pre-treatment. Our results indicate that curcumin induces ROS mediated cell death in colon adenocarcinoma cell lines and may be mediated via p53.}, }
@article {pmid32864221, year = {2020}, author = {Zhou, WT and Wang, LB and Yu, H and Zhang, KK and Chen, LJ and Wang, Q and Xie, XL}, title = {N-acetylcysteine alleviates PCB52-induced hepatotoxicity by repressing oxidative stress and inflammatory responses.}, journal = {PeerJ}, volume = {8}, number = {}, pages = {e9720}, pmid = {32864221}, issn = {2167-8359}, abstract = {Polychlorinated biphenyls (PCBs), particularly low chlorinated congeners in our environment, can induce human hepatotoxicity. However, the mechanisms by which PCBs cause hepatotoxicity remain elusive. Moreover, there are no effective treatments for this condition. In this study, 40 μM PCB52 was administered to rat (Brl-3A) and human hepatocytes (L-02) for 48 h following the N-acetylcysteine (NAC)/saline pretreatment. A significant decrease in cell viability was observed in PCB52-treated cells relative to the control. Besides, PCB52 significantly increased reactive oxygen species (ROS) levels and malondialdehyde (MDA) contents, suggesting induction of oxidative stress. The expression of Traf6, MyD88, and Tnf in Brl-3A cells and that of MYD88, TNF, and IL1B in L-02 cells were significantly upregulated by PCB52. Consistently, overexpression of TLR4, MyD88, Traf6, and NF-κB p65 proteins was observed in PCB52-treated cells, indicating activation of inflammatory responses. Nevertheless, no changes in kelch-like ECH-associated protein 1 (keap1), nuclear factor-erythroid 2-related factor (nrf2), and heme oxygenase-1 proteins were observed in PCB52-treated cells, indicating non-activation of the keap1/nrf2 pathway. Pretreatment with NAC significantly ameliorated PCB52 effects on cell viability, ROS levels, MDA contents and expression of inflammatory elements at both RNA and protein levels. However, no changes in keap1, nrf2 and HO-1 protein levels were detected following NAC pretreatment. Taken together, with non-activated keap1/nrf2 pathway, PCB52-induced oxidative stress and inflammatory responses could be responsible for its hepatotoxicity. These effects were effectively attenuated by NAC pretreatment, which scavenges ROS and dampens inflammatory responses. This study might provide novel strategies for the treatment of the PCBs-associated hepatotoxic effects.}, }
@article {pmid32862473, year = {2021}, author = {Babes, A and Kichko, TI and Selescu, T and Manolache, A and Neacsu, C and Gebhardt, L and Reeh, PW}, title = {Psoralens activate and photosensitize Transient Receptor Potential channels Ankyrin type 1 (TRPA1) and Vanilloid type 1 (TRPV1).}, journal = {European journal of pain (London, England)}, volume = {25}, number = {1}, pages = {122-135}, doi = {10.1002/ejp.1654}, pmid = {32862473}, issn = {1532-2149}, mesh = {Animals ; Ankyrins ; *Furocoumarins ; Humans ; Mice ; TRPA1 Cation Channel ; TRPV Cation Channels ; *Transient Receptor Potential Channels ; }, abstract = {BACKGROUND: PUVA (psoralen UVA) therapy is used to treat a variety of skin conditions, such as vitiligo psoriasis, eczema and mycosis fungoides, but it is frequently accompanied by phototoxicity leading to burning pain, itch and erythema.<br><br>METHODS: We used a combination of calcium and reactive oxygen species (ROS) imaging, patch clamp and neuropeptide release measurement to investigate whether certain ion channels involved in pain and itch signalling could be responsible for these adverese effects of PUVA.<br><br>RESULTS: Clinically used psoralen derivatives 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen at physiologically relevant concentrations were able to activate and photosensitize two recombinant thermoTRP (temperature-gated Transient Receptor Potential) ion channels, TRPA1 (Transient Receptor Potential Ankyrin type 1) and TRPV1 (Transient Receptor Potential Vanilloid type 1). 8-MOP enhanced ROS production by UVA light, and the effect of 8-MOP on TRPA1 could be abolished by the antioxidant N-acetyl cysteine and by removal of critical cysteine residues from the N-terminus domain of the channel. Natively expressed mouse TRPA1 and TRPV1 both contribute to photosensitization of cultured primary afferent neurons by 8-MOP, while direct neuronal activation by this psoralen-derivative is mainly dependent on TRPV1. Both TRPA1 and TRPV1 are to a large extent involved in controlling 8-MOP-induced neuropeptide release from mouse trachea.<br><br>CONCLUSIONS: Taken together our results provide a better understanding of the phototoxicity reported by PUVA patients and indicate a possible therapeutic approach to alleviate the adverse effects associated with this therapy.<br><br>SIGNIFICANCE: Our work provides evidence for the involvement of thermoTRP channels TRPA1 and TRPV1 in the activation and photosensitization of peripheral nociceptors during PUVA (Psoralen UVA) therapy.}, }
@article {pmid32859033, year = {2020}, author = {Akhtar, MJ and Ahamed, M and Alhadlaq, H}, title = {Gadolinium Oxide Nanoparticles Induce Toxicity in Human Endothelial HUVECs via Lipid Peroxidation, Mitochondrial Dysfunction and Autophagy Modulation.}, journal = {Nanomaterials (Basel, Switzerland)}, volume = {10}, number = {9}, pages = {}, pmid = {32859033}, issn = {2079-4991}, support = {14-BIO144-02//National Plan for Science, Technology and Innovation/ ; }, abstract = {In spite of the potential preclinical advantage of Gd2O3 nanoparticles (designated here as GO NPs) over gadolinium-based compounds in MRI, recent concerns of gadolinium deposits in various tissues undergoing MRI demands a mechanistic investigation. Hence, we chose human to measure umbilical vein endothelial cells (HUVECs) that line the vasculature and relevant biomarkers due to GO NPs exposure in parallel with the NPs of ZnO as a positive control of toxicity. GO NPs, as measured by TEM, had an average length of 54.8 ± 29 nm and a diameter of 13.7 ± 6 nm suggesting a fiber-like appearance. With not as pronounced toxicity associated with a 24-h exposure, GO NPs induced a concentration-dependent cytotoxicity (IC50 = 304 ± 17 µg/mL) in HUVECs when exposed for 48 h. GO NPs emerged as significant inducer of lipid peroxidation (LPO), reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and autophagic vesicles in comparison to that caused by ZnO NPs at its IC50 for the same exposure time (48 h). While ZnO NPs clearly appeared to induce apoptosis, GO NPs revealed both apoptotic as well as necrotic potentials in HUVECs. Intriguingly, the exogenous antioxidant NAC (N-acetylcysteine) co-treatment significantly attenuated the oxidative imbalance due to NPs preventing cytotoxicity significantly.}, }
@article {pmid32853674, year = {2020}, author = {Fraternale, A and Zara, C and Pierigè, F and Rossi, L and Ligi, D and Amagliani, G and Mannello, F and Smietana, M and Magnani, M and Brandi, G and Schiavano, GF}, title = {Redox homeostasis as a target for new antimycobacterial agents.}, journal = {International journal of antimicrobial agents}, volume = {56}, number = {4}, pages = {106148}, doi = {10.1016/j.ijantimicag.2020.106148}, pmid = {32853674}, issn = {1872-7913}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Anti-Bacterial Agents/*pharmacology ; Cysteamine/*analogs &amp; derivatives/pharmacology ; Cytokines/metabolism ; Glutathione/analogs &amp; derivatives/*pharmacology ; Humans ; Macrophages/metabolism ; Microbial Sensitivity Tests ; Mycobacterium avium/*drug effects ; Oxidation-Reduction/*drug effects ; Oxidative Stress/drug effects ; }, abstract = {Despite early treatment with antimycobacterial combination therapy, drug resistance continues to emerge. Maintenance of redox homeostasis is essential for Mycobacterium avium (M. avium) survival and growth. The aim of the present study was to investigate the antimycobacterial activity of two pro-glutathione (pro-GSH) drugs that are able to induce redox stress in M. avium and to modulate cytokine production by macrophages. Hence, we investigated two molecules shown to possess antiviral and immunomodulatory properties: C4-GSH, an N-butanoyl GSH derivative; and I-152, a prodrug of N-acetyl-cysteine (NAC) and β-mercaptoethylamine (MEA). Both molecules showed activity against replicating M. avium, both in the cell-free model and inside macrophages. Moreover, they were even more effective in reducing the viability of bacteria that had been kept in water for 7 days, proving to be active both against replicating and non-replicating bacteria. By regulating the macrophage redox state, I-152 modulated cytokine production. In particular, higher levels of interferon-gamma (IFN-γ), interleukin 1 beta (IL-1β), IL-18 and IL-12, which are known to be crucial for the control of intracellular pathogens, were found after I-152 treatment. Our results show that C4-GSH and I-152, by inducing perturbation of redox equilibrium, exert bacteriostatic and bactericidal activity against M. avium. Moreover, I-152 can boost the host response by inducing the production of cytokines that serve as key regulators of the Th1 response.}, }
@article {pmid32848840, year = {2020}, author = {Khalaf, M and Scott-Ward, T and Causer, A and Saynor, Z and Shepherd, A and Górecki, D and Lewis, A and Laight, D and Shute, J}, title = {Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Human Lung Microvascular Endothelial Cells Controls Oxidative Stress, Reactive Oxygen-Mediated Cell Signaling and Inflammatory Responses.}, journal = {Frontiers in physiology}, volume = {11}, number = {}, pages = {879}, pmid = {32848840}, issn = {1664-042X}, abstract = {BACKGROUND: Perturbation of endothelial function in people with cystic fibrosis (CF) has been reported, which may be associated with endothelial cell expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Previous reports indicate that CFTR activity upregulates endothelial barrier function, endothelial nitric oxide synthase (eNOS) expression and NO release, while limiting interleukin-8 (IL-8) release, in human umbilical vein endothelial cells (HUVECs) in cell culture. In view of reported microvascular dysfunction in people with CF we investigated the role of CFTR expression and activity in the regulation of oxidative stress, cell signaling and inflammation in human lung microvascular endothelial cells (HLMVECs) in cell culture.<br><br>METHODS: HLMVECs were cultured in the absence and presence of the CFTR inhibitor GlyH-101 and CFTR siRNA. CFTR expression was analyzed using qRT-PCR, immunocytochemistry (IHC) and western blot, and function by membrane potential assay. IL-8 expression was analyzed using qRT-PCR and ELISA. Nrf2 expression, and NF-&#x3ba;B and AP-1 activation were determined using IHC and western blot. The role of the epidermal growth factor receptor (EGFR) in CFTR signaling was investigated using the EGFR tyrosine kinase inhibitor AG1478. Oxidative stress was measured as intracellular ROS and hydrogen peroxide (H2O2) concentration. VEGF and SOD-2 were measured in culture supernatants by ELISA.<br><br>RESULTS: HLMVECs express low levels of CFTR that increase following inhibition of CFTR activity. Inhibition of CFTR, significantly increased intracellular ROS and H2O2 levels over 30 min and significantly decreased Nrf2 expression by 70% while increasing SOD-2 expression over 24 h. CFTR siRNA significantly increased constitutive expression of IL-8 by HLMVECs. CFTR inhibition activated the AP-1 pathway and increased IL-8 expression, without effect on NF-&#x3ba;B activity. Conversely, TNF-&#x3b1; activated the NF-&#x3ba;B pathway and increased IL-8 expression. The effects of TNF-&#x3b1; and GlyH-101 on IL-8 expression were additive and inhibited by AG1478. Inhibition of both CFTR and EGFR in HLMVECs significantly increased VEGF expression. The antioxidant N-acetyl cysteine significantly reduced ROS production and the increase in IL-8 and VEGF expression following CFTR inhibition.<br><br>CONCLUSION: Functional endothelial CFTR limits oxidative stress and contributes to the normal anti-inflammatory state of HLMVECs. Therapeutic strategies to restore endothelial CFTR function in CF are warranted.}, }
@article {pmid32848711, year = {2020}, author = {Wang, X and Wu, T and Zhang, J and Guo, G and He, X and Pei, Z and Liu, Z and Liu, CF and Ross, CA and Smith, WW}, title = {Transmembrane Protein 230 Mediates a Poly(ADP-ribose) Polymerase-1-Linked Apoptosis.}, journal = {Frontiers in aging neuroscience}, volume = {12}, number = {}, pages = {235}, pmid = {32848711}, issn = {1663-4365}, abstract = {Mutations in transmembrane protein 230 (TMEM230) gene are suggested to be associated with the autosomal dominant Parkinson's disease (PD) with typical movement disorders and Lewy body pathology. However, the normal functions and the pathological roles of TMEM230 are not clear. In this study, we used TMEM230 isoform II constructs including wild-type (WT) and four reported PD-linked mutation constructs (Y92C, R141L, 184Wext*5, and 184PGext*5). Ectopic expression of WT and PD-linked mutant TMEM230 variants in cultured cells dramatically induced apoptotic cell death compared with that of vector control cells. Mutant TMEM230 caused cell toxicity at an increased severity than WT TMEM230. Moreover, expression of TMEM230 increased mitochondrial reactive oxygen species (ROS) levels, decreased cellular ATP, activated caspase 3/7, and increased poly(ADP-ribose) polymerase-1 (PARP1) cleavage. Treatment with N-acetylcysteine (NAC; an ROS scavenger) or Z-VAD-FMK (a caspase inhibitor) significantly attenuated TMEM230-induced apoptosis in both cultured cells and primary neurons. Our results indicated that TMEM230 mediated a PARP1-linked apoptotic cell death pathway. These findings not only provide the novel insight into the biological roles of TMEM230 in the PARP1-linked pathway but also provide a TMEM230-induced cell death mechanism underlying PD pathogenesis.}, }
@article {pmid32848653, year = {2020}, author = {Quintanilla, ME and Ezquer, F and Morales, P and Ezquer, M and Olivares, B and Santapau, D and Herrera-Marschitz, M and Israel, Y}, title = {N-Acetylcysteine and Acetylsalicylic Acid Inhibit Alcohol Consumption by Different Mechanisms: Combined Protection.}, journal = {Frontiers in behavioral neuroscience}, volume = {14}, number = {}, pages = {122}, pmid = {32848653}, issn = {1662-5153}, abstract = {Chronic ethanol intake results in brain oxidative stress and neuroinflammation, which have been postulated to perpetuate alcohol intake and to induce alcohol relapse. The present study assessed the mechanisms involved in the inhibition of: (i) oxidative stress; (ii) neuroinflammation; and (iii) ethanol intake that follow the administration of the antioxidant N-acetylcysteine (NAC) and the anti-inflammatory acetylsalicylic acid (ASA) to animals that had consumed ethanol chronically. At doses used clinically, NAC [40 mg/kg per day orally (p.o.)] and ASA (15 mg/kg per day p.o.) significantly inhibited chronic alcohol intake and relapse intake in alcohol-preferring rats. The coadministration of both drugs reduced ethanol intake by 65% to 70%. N-acetylcysteine administration: (a) induced the Nrf2-ARE system, lowering the hippocampal oxidative stress assessed as the ratio of oxidized glutathione (GSSG)/reduced glutathione (GSH); (b) reduced the neuroinflammation assessed by astrocyte and microglial activation by immunofluorescence; and (c) inhibited chronic and relapse ethanol intake. These effects were blocked by sulfasalazine, an inhibitor of the xCT transporter, which incorporates cystine (precursor of GSH) and extrudes extracellular glutamate, an agonist of the inhibitory mGlu2/3 receptor, which lowers the synaptic glutamatergic tone. The inhibitor of mGlu2/3 receptor (LY341495) blocked the NAC-induced inhibition of both relapse ethanol intake and neuroinflammation without affecting the GSSG/GSH ratio. Unlike N-acetylcysteine, ASA inhibited chronic alcohol intake and relapse via lipoxin A4, a strong anti-inflammatory metabolite of arachidonic acid generated following the ASA acetylation of cyclooxygenases. Accordingly, the lipoxin A4 receptor inhibitor, WRW4, blocked the ASA-induced reduction of ethanol intake. Overall, via different mechanisms, NAC and ASA administered in clinically relevant doses combine their effects inhibiting ethanol intake.}, }
@article {pmid32845997, year = {2021}, author = {Moosa, MS and Maartens, G and Gunter, H and Allie, S and Chughlay, MF and Setshedi, M and Wasserman, S and Stead, DF and Hickman, N and Stewart, A and Sonderup, M and Spearman, CW and Cohen, K}, title = {A Randomized Controlled Trial of Intravenous N-Acetylcysteine in the Management of Anti-tuberculosis Drug-Induced Liver Injury.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {73}, number = {9}, pages = {e3377-e3383}, doi = {10.1093/cid/ciaa1255}, pmid = {32845997}, issn = {1537-6591}, support = {//South African Medical Research Council/ ; }, mesh = {Acetaminophen ; *Acetylcysteine/adverse effects ; Administration, Intravenous ; Adult ; *Chemical and Drug Induced Liver Injury/drug therapy ; Double-Blind Method ; Female ; Humans ; }, abstract = {BACKGROUND: Liver injury is a common complication of anti-tuberculosis therapy. N-acetylcysteine (NAC) used in patients with paracetamol toxicity with limited evidence of benefit in liver injury due to other causes.<br><br>METHODS: We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of intravenous NAC in hospitalized adult patients with anti-tuberculosis drug-induced liver injury (AT-DILI). The primary endpoint was time for serum alanine aminotransferase (ALT) to fall below 100 U/L. Secondary endpoints included length of hospital stay, in-hospital mortality, and adverse events.<br><br>RESULTS: Fifty-three participants were randomized to NAC and 49 to placebo. Mean age was 38 (SD&#xb1;10) years, 58 (57%) were female, 89 (87%) were HIV positive. Median (IQR) serum ALT and bilirubin at presentation were 462 (266-790) U/L and 56 (25-100) &#x3bc;mol/L, respectively. Median time to ALT <100 U/L was 7.5 (6-11) days in the NAC arm and 8 (5-13) days in the placebo arm. Median time to hospital discharge was shorter in the NAC arm (9 [6-15] days) than in the placebo arm (18 [10-25] days) (HR, 1.73; 95% CI, 1.13-2.65). Mortality was 14% overall and did not differ by study arm. The study infusion was stopped early due to an adverse reaction in 5 participants receiving NAC (nausea and vomiting [3], anaphylaxis [1], pain at drip site [1]).<br><br>CONCLUSIONS: NAC did not shorten time to ALT <100 U/L in participants with AT-DILI, but significantly reduced length of hospital stay. NAC should be considered in management of AT-DILI.<br><br>CLINICAL TRIALS REGISTRATION: South African National Clinical Trials Registry (SANCTR: DOH-27-0414-4719).}, }
@article {pmid32837898, year = {2020}, author = {Schloss, J and Leach, M and Brown, D and Hannan, N and Kendall-Reed, P and Steel, A}, title = {The effects of N-acetyl cysteine on acute viral respiratory infections in humans: A rapid review.}, journal = {Advances in integrative medicine}, volume = {7}, number = {4}, pages = {232-239}, pmid = {32837898}, issn = {2212-9588}, abstract = {Current evidence suggests that N-Acetyl Cysteine (NAC) administration may help improve outcomes in people with acute respiratory distress syndrome and acute lung injury - conditions that closely resemble the signs and symptoms of COVID-19. Few mild and transient adverse events were reported in published randomised-controlled trials, indicating that NAC may be reasonably safe. These findings suggest that NAC may complement the management of COVID-19 infection, particularly when administered intravenously within an intensive care unit (ICU) environment. Verdict Current evidence suggests that N-Acetyl Cysteine (NAC) administration may help improve outcomes in people with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) - conditions that closely resemble the signs and symptoms of COVID-19. In this rapid review, NAC was predominately administered intravenously to patients with ARDS or ALI, who were at risk of or requiring mechanical ventilation, and were admitted to a hospital intensive care unit. Findings indicated that NAC administration may assist in improving markers of inflammation or oxidation, systemic oxygenation, the need for / duration of ventilation, rate of patient recovery and clinical improvement score. The effects of NAC on patient length of stay, CT/x-ray images, mortality rate and pulmonary complications were inconclusive. Few mild and transient adverse events were noted, indicating that NAC may be safe for use in acute respiratory distress syndrome or acute lung injury. Based on the evidence identified, and the similar symptomatic profiles of ARDS/ALI and COVID-19, the findings suggest that NAC may be used to complement the management of COVID-19 infection within an acute care setting. The safety and efficacy of orally administered NAC for the management of milder forms of COVID-19 infection within the community setting, remains uncertain. The current research evidence suggests NAC warrants further research for acute respiratory viral infections, including COVID-19.}, }
@article {pmid32835780, year = {2020}, author = {Uppuluri, R and Swaminathan, VV and Ramanan, KM and Meena, S and Varla, H and Ramakrishnan, B and Jayakumar, I and Raj, R}, title = {Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Fanconi Anemia: Improving Outcomes with Improved Supportive Care in India.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {26}, number = {12}, pages = {2292-2298}, doi = {10.1016/j.bbmt.2020.08.019}, pmid = {32835780}, issn = {1523-6536}, mesh = {Child ; Cyclophosphamide/therapeutic use ; *Fanconi Anemia/therapy ; Female ; *Graft vs Host Disease/prevention &amp; control ; *Hematopoietic Stem Cell Transplantation ; Humans ; India ; Male ; Retrospective Studies ; Transplantation Conditioning ; }, abstract = {Fanconi anemia is the most common inherited bone marrow failure syndrome, and hematopoietic stem cell transplantation (HSCT) is the only curative option. Post-transplant cyclophosphamide (PTCy) is challenging in this group of children, given their increased sensitivity to chemotherapy. We performed a retrospective analysis of the data on children diagnosed with Fanconi anemia who underwent a haploidentical HSCT with PTCy from January 2014 to December 2019. Nineteen children (male/female, 0.75:1) underwent 21 haplo-HSCTs with PTCy. Fludarabine, low-dose cyclophosphamide, and 200 centi-gray total body irradiation were included in the conditioning regimen with 25 mg/kg PTCy on days +3 and +4. Haplo-graft was from a sibling in 38% and father in 57% of transplants. The source of stem cells was peripheral blood stem cells in 81% and bone marrow in 19% of transplants, with a median CD34 dose of 5.0 × 10[6]/kg. We documented engraftment in 84% and primary graft failure in 10% of transplants. N-acetylcysteine (NAC) was infused concomitantly during cyclophosphamide in 13 children. Grade 2 and 3 mucositis was lower among those who received NAC as compared to those who did not (30% and 15% versus 33% and 50%), while transaminitis was higher among those who did not receive the infusion. The incidence of acute graft-versus-host disease (GVHD) was 68%, and 81% of these were steroid responsive (grade I/II). We documented chronic GVHD in 25% children, predominantly involving the skin and mouth, which responded to low-dose steroids and ruxolitinib. Serum ferritin was monitored twice weekly as a surrogate marker for cytokine release syndrome due to nonavailability of IL-6 levels. A 1- or 2-log increase in the titers of ferritin associated with clinical features guided the early addition of steroids in the periengraftment period. The mean survival was found to be less among those with high serum ferritin (>10,000 ng/dL) in the periengraftment period as compared to those with ferritin <10,000 ng/dL (mean survival of 25 ± 10 months versus 50 ± 6 months, respectively). The overall survival in our cohort was 68.4%, with a mean survival time of 41.5 months (95% confidence interval, 29.3 to 53.8 months), with a statistically significant correlation between inferior outcome and having received over 15 transfusions before HSCT (P = .01). PTCy can be considered a viable option in children with Fanconi anemia, particularly in resource-limited settings given the high costs of HSCTs. Focused interventions in this subset of children help improve survival outcomes. Early identification of cytokine release syndrome and risk-adapted steroid therapy during engraftment helps prevent mortality. The concomitant use of NAC during cyclophosphamide infusion helps reduce oxygen free radical related tissue damage and regimen-related toxicity.}, }
@article {pmid32828741, year = {2020}, author = {Alamdari, DH and Moghaddam, AB and Amini, S and Keramati, MR and Zarmehri, AM and Alamdari, AH and Damsaz, M and Banpour, H and Yarahmadi, A and Koliakos, G}, title = {Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial.}, journal = {European journal of pharmacology}, volume = {885}, number = {}, pages = {173494}, pmid = {32828741}, issn = {1879-0712}, mesh = {Acetylcysteine/*therapeutic use ; Ascorbic Acid/*therapeutic use ; COVID-19 ; *Clinical Trials, Phase I as Topic ; Compassionate Use Trials ; Coronavirus Infections/complications/*drug therapy ; *Critical Illness ; Female ; Humans ; Hypoxia/complications ; Male ; Methylene Blue/*therapeutic use ; Middle Aged ; Pandemics ; Pneumonia, Viral/complications/*drug therapy ; }, abstract = {COVID-19 is a global catastrophic event that causes severe acute respiratory syndrome. The mechanism of the disease remains unclear, and hypoxia is one of the main complications. There is no currently approved protocol for treatment. The microbial threat as induced by COVID-19 causes the activation of macrophages to produce a huge amount of inflammatory molecules and nitric oxide (NO). Activation of macrophages population into a pro-inflammatory phenotype induces a self-reinforcing cycle. Oxidative stress and NO contribute to this cycle, establishing a cascade inflammatory state that can kill the patient. Interrupting this vicious cycle by a simple remedy may save critical patients' lives. Nitrite, nitrate (the metabolites of NO), methemoglobin, and prooxidant-antioxidant-balance levels were measured in 25 ICU COVID-19 patients and 25 healthy individuals. As the last therapeutic option, five patients were administered methylene blue-vitamin C-N-acetyl Cysteine (MCN). Nitrite, nitrate, methemoglobin, and oxidative stress were significantly increased in patients in comparison to healthy individuals. Four of the five patients responded well to treatment. In conclusion, NO, methemoglobin and oxidative stress may play a central role in the pathogenesis of critical COVID-19 disease. MCN treatment seems to increase the survival rate of these patients. Considering the vicious cycle of macrophage activation leading to deadly NO, oxidative stress, and cytokine cascade syndrome; the therapeutic effect of MCN seems to be reasonable. Accordingly, a wider clinical trial has been designed. It should be noted that the protocol is using the low-cost drugs which the FDA approved for other diseases. TRIAL REGISTRATION NUMBER: NCT04370288.}, }
@article {pmid32825703, year = {2020}, author = {Hong, DK and Kho, AR and Lee, SH and Jeong, JH and Kang, BS and Kang, DH and Park, MK and Park, KH and Lim, MS and Choi, BY and Suh, SW}, title = {Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death.}, journal = {International journal of molecular sciences}, volume = {21}, number = {17}, pages = {}, pmid = {32825703}, issn = {1422-0067}, support = {2019R1A6A3A13093671//National Research Foundation of Korea/ ; 2019R1A2C4004912//National Research Foundation of Korea/ ; 2017M3C7A1028937//National Research Foundation of Korea/ ; 2020R1A2C2008480//National Research Foundation of Korea/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain Ischemia/*drug therapy/metabolism/pathology ; Glutathione/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Neuroglia/drug effects/metabolism/pathology ; Neurons/*drug effects/metabolism/pathology ; Rats ; TRPM Cation Channels/antagonists &amp; inhibitors/*metabolism ; Zinc/metabolism ; }, abstract = {A variety of pathogenic mechanisms, such as cytoplasmic calcium/zinc influx, reactive oxygen species production, and ionic imbalance, have been suggested to play a role in cerebral ischemia induced neurodegeneration. During the ischemic state that occurs after stroke or heart attack, it is observed that vesicular zinc can be released into the synaptic cleft, and then translocated into the cytoplasm via various cation channels. Transient receptor potential melastatin 2 (TRPM2) is highly distributed in the central nervous system and has high sensitivity to oxidative damage. Several previous studies have shown that TRPM2 channel activation contributes to neuroinflammation and neurodegeneration cascades. Therefore, we examined whether anti-oxidant treatment, such as with N-acetyl-l-cysteine (NAC), provides neuroprotection via regulation of TRPM2, following global cerebral ischemia (GCI). Experimental animals were then immediately injected with NAC (150 mg/kg/day) for 3 and 7 days, before sacrifice. We demonstrated that NAC administration reduced activation of GCI-induced neuronal death cascades, such as lipid peroxidation, microglia and astroglia activation, free zinc accumulation, and TRPM2 over-activation. Therefore, modulation of the TRPM2 channel can be a potential therapeutic target to prevent ischemia-induced neuronal death.}, }
@article {pmid32825644, year = {2020}, author = {Martinez-Gil, N and Vidal-Gil, L and Flores-Bellver, M and Maisto, R and Sancho-Pelluz, J and Diaz-Llopis, M and M Barcia, J and Romero, FJ}, title = {Ethanol-Induced Oxidative Stress Modifies Inflammation and Angiogenesis Biomarkers in Retinal Pigment Epithelial Cells (ARPE-19): Role of CYP2E1 and its Inhibition by Antioxidants.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {9}, pages = {}, pmid = {32825644}, issn = {2076-3921}, support = {PROMETEO 94/2016//Conselleria de Cultura, Educaci&#xf3;n y Ciencia, Generalitat Valenciana/ ; }, abstract = {The retinal pigment epithelium (RPE) plays a key role in retinal health, being essential for the protection against reactive oxygen species (ROS). Nevertheless, excessive oxidative stress can induce RPE dysfunction, promoting visual loss. Our aim is to clarify the possible implication of CYP2E1 in ethanol (EtOH)-induced oxidative stress in RPE alterations. Despite the increase in the levels of ROS, measured by fluorescence probes, the RPE cells exposed to the lowest EtOH concentrations were able to maintain cell survival, measured by the Cell Proliferation Kit II (XTT). However, EtOH-induced oxidative stress modified inflammation and angiogenesis biomarkers, analyzed by proteome array, ELISA, qPCR and Western blot. The highest EtOH concentration used stimulated a large increase in ROS levels, upregulating the cytochrome P450-2E1 (CYP2E1) and promoting cell death. The use of antioxidants such as N-acetylcysteine (NAC) and diallyl sulfide (DAS), which is also a CYP2E1 inhibitor, reverted cell death and oxidative stress, modulating also the upstream angiogenesis and inflammation regulators. Because oxidative stress plays a central role in most frequent ocular diseases, the results herein support the proposal that CYP2E1 upregulation could aggravate retinal degeneration, especially in those patients with high baseline oxidative stress levels due to their ocular pathology and should be considered as a risk factor.}, }
@article {pmid32821982, year = {2021}, author = {Epperson, LC and Weiss, ST and Cao, DJ}, title = {A Case Report of a Severe, Unusually Delayed Anaphylactoid Reaction to Intravenous N-Acetylcysteine During Treatment of Acute Acetaminophen Toxicity in an Adolescent.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {17}, number = {1}, pages = {75-79}, pmid = {32821982}, issn = {1937-6995}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects ; Adolescent ; Adrenal Cortex Hormones/therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Anaphylaxis/*chemically induced/diagnosis/drug therapy ; Antidotes/administration &amp; dosage/*adverse effects ; Drug Hypersensitivity/diagnosis/drug therapy/*etiology ; Drug Overdose/diagnosis/*drug therapy ; Female ; Histamine Antagonists/therapeutic use ; Humans ; Infusions, Intravenous ; Severity of Illness Index ; Time Factors ; Treatment Outcome ; }, abstract = {INTRODUCTION: Anaphylactoid reactions are well-documented adverse events associated with the intravenous administration of N-acetylcysteine (NAC) in patients with acetaminophen overdose. Most reactions are mild, occurring within the first 1-5 hours of initiation. This report presents the case of an adolescent with a delayed, life-threatening anaphylactoid reaction 24.5 hours after starting NAC, where discontinuing NAC could have resulted in fulminant hepatic failure (FHF) and death.<br><br>CASE REPORT: A 17-year-old previously healthy female presented with nausea, vomiting, and abdominal pain 10&#xa0;hours after an acute acetaminophen ingestion. Her 11-hour serum acetaminophen concentration was above the treatment line (149&#xa0;&#x3bc;g/mL), and she had elevated transaminases (AST&#x2009;=&#x2009;202&#xa0;U/L, ALT&#x2009;=&#x2009;284&#xa0;U/L). She was treated with intravenous NAC, which was suspended for 3&#xa0;hours after she developed an apparent life-threatening anaphylactoid reaction with angioedema and respiratory distress 24.5&#xa0;hours after treatment initiation. Given her high risk of progression to FHF, NAC was resumed at double the previous rate along with scheduled corticosteroids and antihistamines after resolution of her symptoms. Her AST increased to 10,927&#xa0;U/L, and INR peaked at 3.6, but she had no further anaphylactoid symptoms. She was discharged in her normal state of health after 6&#xa0;days.<br><br>DISCUSSION: Discontinuing NAC in this case of severe, delayed anaphylactoid reaction&#xa0;could have&#xa0;resulted in FHF requiring liver transplant. The reason for her&#xa0;reaction is unclear but could be related to patient risk factors or medication error. Guidelines for reinitiation of NAC after development of delayed anaphylactoid reactions are not well-established. &#xa0;Close observation beyond the first 1-5&#xa0;hours of NAC administration is warranted.}, }
@article {pmid32821608, year = {2020}, author = {Stead, TS and Jeong, JY and Ganti, L and Rubero, J}, title = {Massive Acetaminophen Overdose.}, journal = {Cureus}, volume = {12}, number = {7}, pages = {e9262}, pmid = {32821608}, issn = {2168-8184}, abstract = {The authors present a case of a fatal intentional acetaminophen (APAP) overdose and remind the physician how ubiquitous the drug is. This case presentation highlights the clinical presentation and treatment options for APAP overdose in unresponsive patients. In cases of massive APAP overdose (> 300 µg/ml plasma at four hours post-ingestion), prompt administration of N-acetylcysteine (NAC) and early hemodialysis are indicated.}, }
@article {pmid32821287, year = {2020}, author = {Chen, CC and Luo, JC and Fang, YJ and Lee, JY and Kuo, CC and Yang, TH and Chiu, MC and Yu, JJ and Bair, MJ and Chen, PY and Chou, CK and Chen, CY and Chang, CY and Hsu, YC and Tseng, CH and Hsu, WF and Hu, WH and Tsai, MH and Hsieh, CL and Chen, MJ and Shun, CT and Liu, TY and Lee, YC and Liou, JM and Wu, MS and , }, title = {Comparison of the effect of clarithromycin triple therapy with or without N-acetylcysteine in the eradication of Helicobacter pylori: a randomized controlled trial.}, journal = {Therapeutic advances in gastroenterology}, volume = {13}, number = {}, pages = {1756284820927306}, pmid = {32821287}, issn = {1756-283X}, abstract = {BACKGROUND: Whether adjunctive N-acetylcysteine (NAC) may improve the efficacy of triple therapy in the first-line treatment of Helicobacter pylori infection remains unknown. Our aim was to compare the efficacy of 14-day triple therapy with or without NAC for the first-line treatment of H. pylori.<br><br>MATERIAL AND METHODS: Between 1 January 2014 and 30 June 2018, 680 patients with H. pylori infection na&#xef;ve to treatment were enrolled in this multicenter, open-label, randomized trial. Patients were randomly assigned to receive triple therapy with NAC [NAC-T14, dexlansoprazole 60&#x2009;mg four times daily (q.d.); amoxicillin 1&#x2009;g twice daily (b.i.d.), clarithromycin 500&#x2009;mg b.i.d., NAC 600&#x2009;mg b.i.d.] for 14&#x2009;days, or triple therapy alone (T14, dexlansoprazole 60&#x2009;mg q.d.; amoxicillin 1&#x2009;g b.i.d., clarithromycin 500&#x2009;mg b.i.d.) for 14&#x2009;days. Our primary outcome was the eradication rates by intention to treat (ITT). Antibiotic resistance and CYP2C19 gene polymorphism were determined.<br><br>RESULTS: The ITT analysis demonstrated H. pylori eradication rates in NAC-T14 and T14 were 81.7% [276/338, 95% confidence interval (CI): 77.5-85.8%] and 84.3% (285/338, 95% CI 80.4-88.2%), respectively. In 646 participants who adhered to their assigned therapy, the eradication rates were 85.7% and 88.0% with NAC-T14 and T14 therapies, respectively. There were no differences in compliance or adverse effects. The eradication rates in subjects with clarithromycin-resistant, amoxicillin-resistant, or either clarithromycin/amoxicillin resistant strains were 45.2%, 57.9%, and 52.2%, respectively, for NAC-T14, and were 66.7%, 76.9%, and 70.0%, respectively, for T14. The efficacy of NAC-T14 and T14 was not affected by CYP2C19 polymorphism.<br><br>CONCLUSION: Add-on NAC to triple therapy was not superior to triple therapy alone for first-line H. pylori eradication [ClinicalTrials.gov identifier: NCT02249546].}, }
@article {pmid32819581, year = {2020}, author = {Zhou, J and Chen, A and Wang, Z and Zhang, J and Chen, H and Zhang, H and Wang, R and Miao, D and Jin, J}, title = {Bmi-1 determines the stemness of renal stem or progenitor cells.}, journal = {Biochemical and biophysical research communications}, volume = {529}, number = {4}, pages = {1165-1172}, doi = {10.1016/j.bbrc.2020.06.140}, pmid = {32819581}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Self Renewal/drug effects ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Feedback, Physiological ; Gene Deletion ; Humans ; Kidney/*cytology ; Male ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Polycomb Repressive Complex 1/deficiency/*metabolism ; Proto-Oncogene Proteins/deficiency/*metabolism ; Stem Cells/drug effects/*metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Renal stem or progenitor cells (RSCs), labeled with CD24 and CD133, play an important role during the repair of renal injury. Bmi-1 is a critical factor in regulating stemness of adult stem cells or progenitor cells. To investigate whether Bmi-1 determines the stemness of RSCs by inhibiting p16 and p53, and/or maintaining redox balance, RSCs were isolated, cultured and analyzed for stemness characterizations. In RSCs from Bmi-1-deficient (Bmi-1[-/-]) mice and wild type (WT) littermates, self-renewal, stemness, and expressions of molecules for regulating redox balance and cell cycle progression were compared. Self-renewal of RSCs from Bmi-1 and p16 double-knockout (Bmi-1[-/-]p16[-/-]), Bmi-1 and p53 double-knockout (Bmi-1[-/-]p53[-/-]) and N-acetylcysteine (NAC)-treated Bmi-1[-/-] mice were further analyzed for amelioration. Human renal proximal tubular epithelial cells (HK2) were also used for signaling analysis. Our results showed that third-passage RSCs from WT mice had good stemness; Bmi-1 deficiency led to the decreased stemness, and the increased apoptosis for RSCs; NAC treatment or p16/p53 deletion ameliorated the decreased self-renewal of RSCs in Bmi-1 deficiency mice by maintaining redox balance or inhibiting cell cycle arrest respectively; Oxidative stress (OS) could negatively feedback regulate the mRNA expressions of Bmi-1, p16 and p53. In conclusion, Bmi-1 determined the stemness of RSCs through maintaining redox balance and preventing cell cycle arrest. Thus, Bmi-1 signaling molecules would be novel therapeutic targets for maintaining RSCs and hampering the progression of kidney diseases to prevent renal failure.}, }
@article {pmid32818949, year = {2021}, author = {Buhimschi, CS and Bahtiyar, MO and Zhao, G and Abdelghany, O and Schneider, L and Razeq, SA and Dulay, AT and Lipkind, HS and Mieth, S and Rogers, L and Bhandari, V and Buhimschi, IA}, title = {Antenatal N-acetylcysteine to improve outcomes of premature infants with intra-amniotic infection and inflammation (Triple I): randomized clinical trial.}, journal = {Pediatric research}, volume = {89}, number = {1}, pages = {175-184}, pmid = {32818949}, issn = {1530-0447}, support = {R01 HD047321/HD/NICHD NIH HHS/United States ; R01 HD088033/HD/NICHD NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Adult ; Apgar Score ; Bronchopulmonary Dysplasia/etiology/mortality/*prevention &amp; control ; *Chorioamnionitis/diagnosis ; Connecticut ; Drug Administration Schedule ; Female ; Gestational Age ; Hospital Mortality ; Humans ; Infant ; Infant Mortality ; *Infant, Premature ; Infusions, Intravenous ; Pregnancy ; *Pregnancy Complications, Infectious/diagnosis ; Premature Birth/*etiology/mortality ; Risk Assessment ; Risk Factors ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Intrauterine infection and/or inflammation (Triple I) is an important cause of preterm birth (PTB) and adverse newborn outcomes. N-acetylcysteine (NAC) is a Food and Drug Administration (FDA)-approved drug safely administered to pregnant women with acetaminophen toxicity.<br><br>METHODS: We conducted a single-center, quadruple-blind, placebo-controlled trial of pregnant women with impending PTB due to confirmed Triple I. Participants (n&#x2009;=&#x2009;67) were randomized to an intravenous infusion of NAC or placebo mimicking the FDA-approved regimen. Outcomes included clinical measures and mechanistic biomarkers.<br><br>RESULTS: Newborns exposed to NAC (n&#x2009;=&#x2009;33) had significantly improved status at birth and required less intensive resuscitation compared to placebo (n&#x2009;=&#x2009;34). Fewer NAC-exposed newborns developed two or more prematurity-related severe morbidities [NAC: 21% vs. placebo: 47%, relative risk, 0.45; 95% confidence interval (CI) 0.21-0.95] with the strongest protection afforded against bronchopulmonary dysplasia (BPD, NAC: 3% vs. placebo: 32%, relative risk, 0.10; 95% CI: 0.01-0.73). These effects were independent of gestational age, birth weight, sex, or race. Umbilical cord plasma NAC concentration correlated directly with cysteine, but not with plasma or whole blood glutathione. NAC reduced the placental expression of histone deacetylase-2, suggesting that epigenetic mechanisms may be involved.<br><br>CONCLUSIONS: These data provide support for larger studies of intrapartum NAC to reduce prematurity-related morbidity.<br><br>IMPACT: In this randomized clinical trial of 65 women and their infants, maternal intravenous NAC employing the FDA-approved dosing protocol resulted in lower composite neonatal morbidity independent of gestational age, race, sex, and birthweight. Administration of NAC in amniocentesis-confirmed Triple I resulted in a remarkably lower incidence of BPD. As prior studies have not shown a benefit of postnatal NAC in ventilated infants, our trial highlights the critical antenatal timing of NAC administration. Repurposing of NAC for intrapartum administration should be explored in larger clinical trials as a strategy to improve prematurity-related outcomes and decrease the incidence of BPD.}, }
@article {pmid32817784, year = {2020}, author = {Gavali, JT and Carrillo, ED and García, MC and Sánchez, JA}, title = {The mitochondrial K-ATP channel opener diazoxide upregulates STIM1 and Orai1 via ROS and the MAPK pathway in adult rat cardiomyocytes.}, journal = {Cell &amp; bioscience}, volume = {10}, number = {}, pages = {96}, pmid = {32817784}, issn = {2045-3701}, abstract = {BACKGROUND: Openers of mitochondrial adenosine triphosphate-dependent potassium (mKATP) channels like diazoxide increase reactive oxygen species (ROS) production in cardiac cells and reduce Ca[2+] elevations produced by ischemia-reperfusion, protecting the heart from damage. In this study we tested the hypothesis that opening mKATP channels regulates expression of the major components of store-operated Ca[2+] entry (SOCE) STIM1 and Orai1.<br><br>RESULTS: Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot experiments showed that diazoxide increased expression of STIM1 and Orai1 at the mRNA and protein levels, respectively, in adult rat cardiomyocytes. Immunofluorescence analyses revealed that diazoxide also disrupted the striated distribution pattern of STIM1. These effects were prevented by the ROS scavenger N-acetyl cysteine (NAC), the mKATP channel antagonist 5-hydroxydecanoate (5-HD), or the protein synthesis inhibitor cycloheximide (CHX). Confocal microscopy revealed that diazoxide also led to nuclear translocation of the transcription factors c-Fos and NF&#x3ba;B, which was also blocked by NAC or 5-HD. Finally, the MAPK pathway inhibitor UO126 attenuated diazoxide-induced upregulation of STIM1 and Orai1 expression.<br><br>CONCLUSIONS: Our results suggest that opening mitochondrial potassium ATP channels with diazoxide upregulates the expression of STIM1 and Orai1 by de novo synthesis by a mechanism that involves NFkB, c-Fos, and ROS via MAPK/ERK signaling.}, }
@article {pmid32816469, year = {2020}, author = {Wang, J and Dadmohammadi, Y and Jaiswal, A and Abbaspourrad, A}, title = {Investigation of the Interaction between N-Acetyl-l-Cysteine and Ovalbumin by Spectroscopic Studies, Molecular Docking Simulation, and Real-Time Quartz Crystal Microbalance with Dissipation.}, journal = {Journal of agricultural and food chemistry}, volume = {68}, number = {37}, pages = {10184-10190}, doi = {10.1021/acs.jafc.0c03201}, pmid = {32816469}, issn = {1520-5118}, mesh = {Acetylcysteine/*chemistry ; Binding Sites ; Hydrogen Bonding ; Kinetics ; Molecular Docking Simulation ; Ovalbumin/*chemistry ; Protein Binding ; Protein Conformation, alpha-Helical ; Quartz Crystal Microbalance Techniques ; }, abstract = {This study investigated the interaction between N-acetyl-l-cysteine (NAC) and ovalbumin (OVA) using multispectroscopic technology, molecular docking, and quartz crystal microbalance with dissipation (QCM-D). Fluorescence intensity and UV absorption of OVA were decreased substantially upon the addition of NAC. The calculated Kq values were obtained at 298, 304, and 310 K for 13.48, 15.59, and 17.50 (× 10[12] L mol[-1]), respectively, suggesting that the static quenching was dominated. Thermodynamic parameters such as ΔH (-150.58 kJ mol[-1]), ΔS (-433.51 J mol[-1] K[-1]), and ΔG values (-21.39 kJ mol[-1]), combined with molecular docking and QCM-D data, showed that the interaction was spontaneous and van der Waals and hydrogen bonding were identified as the main driving forces. FTIR and CD results showed that the α-helix content of OVA increased from 2.8 to 22.9%, and the β-sheet decreased from 0.2 to 21.9% in the presence of 5 and 10 μM NAC, respectively, compared to the pure OVA, respectively.}, }
@article {pmid32812379, year = {2021}, author = {Luo, J and Ao, Z and Duan, Z and Ao, Y and Wei, S and Chen, W and Chen, X}, title = {Effects of N-Acetylcysteine on the reproductive performance, oxidative stress and RNA sequencing of Nubian goats.}, journal = {Veterinary medicine and science}, volume = {7}, number = {1}, pages = {156-163}, pmid = {32812379}, issn = {2053-1095}, mesh = {Acetylcysteine/administration &amp; dosage/*metabolism ; Animal Feed/analysis ; Animals ; Base Sequence/*drug effects ; Diet/veterinary ; Dietary Supplements/analysis ; Dose-Response Relationship, Drug ; Female ; Free Radical Scavengers/administration &amp; dosage/*metabolism ; Goats/*physiology ; Oxidative Stress/*drug effects ; Random Allocation ; Reproduction/*drug effects ; }, abstract = {N-acetylcysteine (NAC) has been found to enhance the protective ability of cells to counter balance oxidative stress and inflammation. To investigate the effects of dietary NAC supplementation on the reproductive performance of goats, the reproductive performance and endometrial transcriptome of goats fed with diets with NAC (NAC group) and without NAC supplementation (control group) were compared. Results showed that the goats fed with 0.03% and 0.05% NAC had similar litter size, birth weight, nitric oxide (NO), sex hormones and amino acids levels compared with the goats of the control group. However, feeding with 0.07% NAC supplementation from day 0 to day 30 of gestation remarkably increased the litter size of goats. The goats of the 0.07% NAC group presented increased levels of NO relative to the control group, but their sex hormones and amino acids showed no differences. Comparative transcriptome analysis identified 207 differentially expressed genes (DEGs) in the endometrium between the control and the 0.07% NAC groups. These DEGs included 146 upregulated genes and 61 downregulated genes in the 0.07% NAC group. They were primarily involved in the cellular response to toxic substances, oxidoreductase activity, immune receptor activity, signalling receptor binding, cytokine-cytokine receptor interactions, PI3K-Akt signalling pathway and PPAR signalling pathway. In conclusion, results showed that dietary 0.07% NAC supplementation exerted a beneficial effect on the survival of goat embryos at the early pregnancy stage. Such positive outcome might be due to the increased NO production and affected expression of genes involved in the anti-inflammation pathways of the endometrium.}, }
@article {pmid32803054, year = {2020}, author = {Fazary, AE and Awwad, NS and Ibrahium, HA and Shati, AA and Alfaifi, MY and Ju, YH}, title = {Protonation Equilibria of N-Acetylcysteine.}, journal = {ACS omega}, volume = {5}, number = {31}, pages = {19598-19605}, pmid = {32803054}, issn = {2470-1343}, abstract = {The acid base protonation equilibria of N-acetylcysteine (Nac) and its equilibrium constants in water solutions were determined by the Hyperquad 2008 software assessment from the pH potentiometry data, which provides a diversity of statistics presentations. The effect of a number of organic solvents on the acid base protonation processes was also examined. The solution equilibria of N-acetylcysteine (Nac) were studied at T = 298.15 K in water (w 1) + organic liquid mixtures [100 w 2 = 0, 20, 40, 60, and 80%] with an ionic strength of I = 0.16 mol·dm[-3] NaNO3. Also, the organic solvent's influence was studied based on the Kamlet-Taft linear solvation energy relationship. The experimental results were compared with theoretical ones obtained via the Gaussian 09 calculation computer program. The protonation equilibria of Nac were found to be important in the progress of separation systems in aqueous and non-aqueous ionic solutions. Nac showed a likely good metal dibasic chelating bioligand as the DFT calculations proved two binding sites. Spectrophotometry evaluation was also done for N-acetylcysteine bioligands at various pH values in water solutions then its absorbance ratio was measured.}, }
@article {pmid32800945, year = {2020}, author = {Fraternale, A and Zara, C and Di Mambro, T and Manuali, E and Genovese, DA and Galluzzi, L and Diotallevi, A and Pompa, A and De Marchis, F and Ambrogini, P and Cesarini, E and Luchetti, F and Smietana, M and Green, K and Bartoccini, F and Magnani, M and Crinelli, R}, title = {I-152, a supplier of N-acetyl-cysteine and cysteamine, inhibits immunoglobulin secretion and plasma cell maturation in LP-BM5 murine leukemia retrovirus-infected mice by affecting the unfolded protein response.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1866}, number = {12}, pages = {165922}, doi = {10.1016/j.bbadis.2020.165922}, pmid = {32800945}, issn = {1879-260X}, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Animals ; Antiviral Agents/administration &amp; dosage/*pharmacology ; Cysteamine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Disease Models, Animal ; Female ; Immunoglobulins/blood/*metabolism ; Injections, Intraperitoneal ; Leukemia, Experimental/drug therapy/metabolism/virology ; Mice ; Mice, Inbred C57BL ; Plasma Cells/*drug effects/metabolism/virology ; Protein Unfolding/drug effects ; Retroviridae Infections/*drug therapy/metabolism/virology ; Tumor Virus Infections/*drug therapy/metabolism/virology ; Unfolded Protein Response/*drug effects ; }, abstract = {Excessive production of immunoglobulins (Ig) causes endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR). Hypergammaglobulinemia and lymphadenopathy are hallmarks of murine AIDS that develops in mice infected with the LP-BM5 murine leukemia retrovirus complex. In these mice, Th2 polarization and aberrant humoral response have been previously correlated to altered intracellular redox homeostasis. Our goal was to understand the role of the cell's redox state in Ig secretion and plasma cell (PC) maturation. To this aim, LP-BM5-infected mice were treated with I-152, an N-acetyl-cysteine and cysteamine supplier. Intraperitoneal I-152 administration (30 μmol/mouse three times a week for 9 weeks) decreased plasma IgG and increased IgG/Syndecan 1 ratio in the lymph nodes where IgG were in part accumulated within the ER. PC containing cytoplasmic inclusions filled with IgG were present in all animals, with fewer mature PC in those treated with I-152. Infection induced up-regulation of signaling molecules involved in the UPR, i.e. CHAC1, BiP, sXBP-1 and PDI, that were generally unaffected by I-152 treatment except for PDI and sXBP-1, which have a key role in protein folding and PC maturation, respectively. Our data suggest that one of the mechanisms through which I-152 can limit hypergammaglobulinemia in LP-BM5-infected mice is by influencing IgG folding/assembly as well as secretion and affecting PC maturation.}, }
@article {pmid32799012, year = {2020}, author = {Askari, M and Faryabi, R and Mozaffari, H and Darooghegi Mofrad, M}, title = {The effects of N-Acetylcysteine on serum level of inflammatory biomarkers in adults. Findings from a systematic review and meta-analysis of randomized clinical trials.}, journal = {Cytokine}, volume = {135}, number = {}, pages = {155239}, doi = {10.1016/j.cyto.2020.155239}, pmid = {32799012}, issn = {1096-0023}, mesh = {Adult ; Humans ; *Acetylcysteine/pharmacology ; *Biomarkers/blood ; *Inflammation/blood/metabolism ; Randomized Controlled Trials as Topic ; }, abstract = {PURPOSE: Randomized Clinical Trials (RCTs) have provided varied and conflicting findings regarding the effect of N-acetylcysteine (NAC) on inflammatory biomarkers. This study was conducted to review existing literature to determine whether NAC supplementation can affect inflammatory biomarkers in adults.<br><br>METHODS: Bibliographic databases of Scopus, and PubMed were used for relevant papers published until October 2019. Results were reported as weighted mean differences (WMD) with 95% confidence intervals (CI) using multi-level models. Cochrane's Q and I-squared (I[2]) tests were used to determine heterogeneity among studies.<br><br>RESULTS: Twenty-four RCTs which include 1057 sample size were entered to analysis. NAC doses and intervention duration ranged from 400 to 2000&#xa0;mg/d, and 1 to 80&#xa0;weeks, respectively. Oral supplementation of NAC reduced serum level of C-reactive protein (CRP) [WMD: -0.61&#xa0;mg/L, 95% CI: -1.18 to -0.03, P&#xa0;=&#xa0;0.039, I[2]&#xa0;=&#xa0;79.6%], and interleukin-6 (IL-6) [WMD: -0.43&#xa0;pg/mL, 95% CI: -0.69 to -0.17, P&#xa0;=&#xa0;0.001, I[2]&#xa0;=&#xa0;89.3%]. However, the effect of oral NAC supplementation on other inflammatory biomarkers was nonsignificant. Dose-response investigation showed a non-linear association between oral NAC supplementation with CRP.<br><br>CONCLUSION: Oral NAC supplementation reduced serum level of CRP and IL-6, but did not affect other inflammatory biomarkers. Nevertheless, more RCTs seems to be required to explore how NAC in different dosage and different routes of administration can affect inflammatory biomarkers.}, }
@article {pmid32797774, year = {2020}, author = {Caissie, MD and Gartley, CJ and Scholtz, EL and Hewson, J and Johnson, R and Chenier, T}, title = {The Effects of Treatment with N-Acetyl Cysteine on Clinical Signs in Persistent Breeding-Induced Endometritis Susceptible Mares.}, journal = {Journal of equine veterinary science}, volume = {92}, number = {}, pages = {103142}, doi = {10.1016/j.jevs.2020.103142}, pmid = {32797774}, issn = {0737-0806}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Disease Susceptibility/veterinary ; *Endometritis/drug therapy/veterinary ; Endometrium ; Female ; *Horse Diseases/drug therapy ; Horses ; }, abstract = {Persistent breeding-induced endometritis (PBIE) is a major cause of infertility in mares. Endometrial inflammation that persists until embryonic descent ultimately results in early embryonic death. A poor endometrial biopsy grade (IIb or III) has been identified as a risk factor for PBIE. Intrauterine fluid accumulation (>2 cm in depth), pathologic endometrial edema, and elevated intrauterine neutrophil levels are all clinical features of PBIE. Commonly applied treatment options include uterine lavage and oxytocin therapy. N-acetyl cysteine (NAC), a mucolytic used to treat bacterial endometritis in mares, has anti-inflammatory properties and was investigated as a potential treatment for PBIE. A randomized, blinded, cross-over design clinical trial used NAC before breeding in PBIE-susceptible mares (n = 9). Intrauterine infusion of 3.3% NAC was performed 12 hours before insemination, and endometrial cytology and endometrial biopsy samples were obtained at 12 and 60 hours after insemination. Endometrial biopsies were evaluated for the degree of inflammation present. Clinical signs of endometrial edema and intrauterine fluid volumes were assessed by transrectal ultrasound at 12 and then every 24 hours after breeding. Data were analyzed using repeated measures analysis of variance and a Mann Whitney Wilcoxon Test. Treatment with NAC did not improve clinical signs in PBIE-affected mares. However, endometrial biopsies from mares treated with NAC displayed more diffuse and severe neutrophil infiltration than control cycles. Further research using a larger population of mares is required to evaluate the effects of NAC treatment on the endometrium of PBIE-susceptible mares.}, }
@article {pmid32796068, year = {2020}, author = {Teodorof-Diedrich, C and Spector, SA}, title = {Human Immunodeficiency Virus Type 1 and Methamphetamine-Mediated Mitochondrial Damage and Neuronal Degeneration in Human Neurons.}, journal = {Journal of virology}, volume = {94}, number = {20}, pages = {}, pmid = {32796068}, issn = {1098-5514}, support = {P50 DA026306/DA/NIDA NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; R01 NS084912/NS/NINDS NIH HHS/United States ; R01 NS104015/NS/NINDS NIH HHS/United States ; U01 AI069536/AI/NIAID NIH HHS/United States ; UM1 AI106716/AI/NIAID NIH HHS/United States ; UM1 AI069536/AI/NIAID NIH HHS/United States ; R25 MH081482/MH/NIMH NIH HHS/United States ; UM1 AI068632/AI/NIAID NIH HHS/United States ; UM1 AI068616/AI/NIAID NIH HHS/United States ; R24 HD000836/HD/NICHD NIH HHS/United States ; }, mesh = {Cells, Cultured ; Dynamins/genetics/metabolism ; HIV Envelope Protein gp120/genetics/metabolism ; HIV Infections/genetics/*metabolism/pathology ; HIV-1/genetics/*metabolism ; Humans ; Methamphetamine/*adverse effects/pharmacology ; Microtubule-Associated Proteins/genetics/metabolism ; Mitochondria/genetics/*metabolism/pathology ; Neurodegenerative Diseases/chemically induced/genetics/*metabolism/virology ; Neurons/*metabolism/pathology/virology ; Sequestosome-1 Protein/genetics/metabolism ; tat Gene Products, Human Immunodeficiency Virus/genetics/metabolism ; }, abstract = {Methamphetamine, a potent psychostimulant, is a highly addictive drug commonly used by persons living with HIV (PLWH), and its use can result in cognitive impairment and memory deficits long after its use is discontinued. Although the mechanism(s) involved with persistent neurological deficits is not fully known, mitochondrial dysfunction is a key component in methamphetamine neuropathology. Specific mitochondrial autophagy (mitophagy) and mitochondrial fusion and fission are protective quality control mechanisms that can be dysregulated in HIV infection, and the use of methamphetamine can further negatively affect these protective cellular mechanisms. Here, we observed that treatment of human primary neurons (HPNs) with methamphetamine and HIV gp120 and Tat increase dynamin-related protein 1 (DRP1)-dependent mitochondrial fragmentation and neuronal degeneration. Methamphetamine and HIV proteins increased microtubule-associated protein 1 light chain 3 beta-II (LC3B-II) lipidation and induced sequestosome 1 (SQSTM1, p62) translocation to damaged mitochondria. Additionally, the combination inhibited autophagic flux, increased reactive oxygen species (ROS) production and mitochondrial damage, and reduced microtubule-associated protein 2 (MAP2) dendrites in human neurons. N-Acetylcysteine (NAC), a strong antioxidant and ROS scavenger, abrogated DRP1-dependent mitochondrial fragmentation and neurite degeneration. Thus, we show that methamphetamine combined with HIV proteins inhibits mitophagy and induces neuronal damage, and NAC reverses these deleterious effects on mitochondrial function.IMPORTANCE Human and animal studies show that HIV infection, combined with the long-term use of psychostimulants, increases neuronal stress and the occurrence of HIV-associated neurocognitive disorders (HAND). On the cellular level, mitochondrial function is critical for neuronal health. In this study, we show that in human primary neurons, the combination of HIV proteins and methamphetamine increases oxidative stress, DRP1-mediated mitochondrial fragmentation, and neuronal injury manifested by a reduction in neuronal network and connectivity. The use of NAC, a potent antioxidant, reversed the neurotoxic effects of HIV and methamphetamine, suggesting a novel approach to ameliorate the effects of HIV- and methamphetamine-associated cognitive deficits.}, }
@article {pmid32795434, year = {2021}, author = {Kong, X and Hafiz, G and Wehling, D and Akhlaq, A and Campochiaro, PA}, title = {Locus-Level Changes in Macular Sensitivity in Patients with Retinitis Pigmentosa Treated with Oral N-acetylcysteine.}, journal = {American journal of ophthalmology}, volume = {221}, number = {}, pages = {105-114}, pmid = {32795434}, issn = {1879-1891}, support = {R34 EY031429/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics ; Administration, Oral ; Adult ; Aged ; Female ; Free Radical Scavengers/*administration &amp; dosage/pharmacokinetics ; Humans ; Macula Lutea/*physiology ; Male ; Middle Aged ; Prospective Studies ; Retinitis Pigmentosa/*drug therapy/physiopathology ; Retrospective Studies ; Sensitivity and Specificity ; Visual Acuity ; Visual Field Tests ; Visual Fields/physiology ; Young Adult ; }, abstract = {PURPOSE: To identify characteristics of loci associated with locus-level sensitivity loss or improvement during treatment with N-acetylcysteine (NAC) in retinitis pigmentosa (RP).<br><br>DESIGN: Retrospective analysis of prospectively collected data in the FIGHT RP clinical trial.<br><br>METHODS: Patients (n&#xa0;= 30) were treated with 600, 1,200, or 1,800&#xa0;mg of NAC twice daily for 3&#xa0;months and then 3 times/day for 3&#xa0;months. Microperimetry locus-level changes between baseline and month 6 were correlated with baseline characteristics of loci using regression models. The main outcome measurement was locus-level sensitivity change &#x2265;6 dB.<br><br>RESULTS: Baseline mean sensitivity (3,468 loci; 51 evaluable eyes) was 7.7 dB and for foveal, parafoveal, and perifoveal loci were 20.2, 11.8, and 5.8 dB. During treatment, 287 loci (8.28%) increased &#x2265;6 dB, and 119 of 1,613 loci with baseline sensitivity &#x2265;6 dB decreased &#x2265;6 dB (7.38%). A higher dose of NAC was associated with lower likelihood of sensitivity loss &#x2265;6 dB (P&#xa0;= .033). Loci with low baseline sensitivity were more likely to decrease &#x2265;6 dB (P&#xa0;= .034) but also more likely to increase &#x2265;6 dB (P < .001). Foveal versus perifoveal loci (P < .001) and superior versus inferior loci (P&#xa0;= .005) were more likely to increase &#x2265;6 dB.<br><br>CONCLUSIONS: Higher doses of NAC reduced risk of macular loci sensitivity loss in RP. Greater sensitivity depression reversibility in the fovea during treatment suggests that high foveal cone density protects cones from irreversible loss of function in RP making them more likely to show improved function during NAC treatment.}, }
@article {pmid32791144, year = {2020}, author = {Elswefy, SE and Abdallah, FR and Wahba, AS and Hasan, RA and Atteia, HH}, title = {Antifibrotic effect of curcumin, N-acetyl cysteine and propolis extract against bisphenol A-induced hepatotoxicity in rats: Prophylaxis versus co-treatment.}, journal = {Life sciences}, volume = {260}, number = {}, pages = {118245}, doi = {10.1016/j.lfs.2020.118245}, pmid = {32791144}, issn = {1879-0631}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Apoptosis/drug effects ; Benzhydryl Compounds/*toxicity ; Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control ; Curcumin/*administration &amp; dosage/pharmacology ; Drug Therapy, Combination ; Inflammation/blood ; Interleukins/blood ; Liver/drug effects/enzymology/pathology ; Liver Cirrhosis/chemically induced/*prevention &amp; control ; Male ; Phenols/*toxicity ; Propolis/*administration &amp; dosage/pharmacology ; Rats ; Rats, Wistar ; }, abstract = {AIMS: Bisphenol A (BPA) has been shown to induce liver fibrosis in rodents. Therefore, this study examined the protective effect of a triple combination of curcumin (Cur), N-acetyl cysteine (NAC) and propolis (Prp) extract against BPA-induced hepatic fibrosis.<br><br>METHODS: 100 Wistar male rats were equally assigned into 10 groups; one group was designated as control. 10 rats were gavaged with BPA (50&#x202f;mg/kg/day) for 8 wk and left un-treated (BPA group). The remaining 80 rats were divided into 8 groups, distributed in 2 models. Protective model: rats were daily co-treated with BPA and Cur (100&#x202f;mg/kg, p.o) or NAC (150&#x202f;mg/kg, p.o) or Prp (200&#x202f;mg/kg, p.o) or their combination for 8 wk. Preventive model: rats were daily treated with Cur or NAC or Prp or their combination for 4 wk before BPA administration and then in the same manner as protective model.<br><br>KEY FINDINGS: Current treatment interventions significantly alleviated BPA-induced hepatic damage and fibrosis. They also restored pro-oxidant/antioxidant balance, shifted cytokine balance towards the anti-inflammatory side, decreasing interleukin-1&#x3b2;/interleukin-10 ratio. Moreover, these compounds seem to exert anti-apoptotic effects by increasing the immunoexpression of B-cell lymphoma 2 in hepatocytes and decreasing hepatic caspase-3 content. Finally, they ameliorated extracellular matrix turn over through down-regulation of matrix metalloproteinase-9 and up-regulation of tissue inhibitor of matrix metalloproteinase-2 genetic expression.<br><br>SIGNIFICANCE: Current treatments guarded against BPA-induced hepatic fibrosis due to their antioxidant, anti-inflammatory and anti-apoptotic properties, decreasing extracellular matrix turnover. Interestingly, the triple therapy provided hepatoprotection superior to monotherapy. Besides, prophylactic and concurrent treatments seem to be more effective than concurrent treatments.}, }
@article {pmid32786540, year = {2020}, author = {Li, Q and Li, W and Zhao, J and Guo, X and Zou, Q and Yang, Z and Tian, R and Peng, Y and Zheng, J}, title = {Glutathione Conjugation and Protein Adduction by Environmental Pollutant 2,4-Dichlorophenol In Vitro and In Vivo.}, journal = {Chemical research in toxicology}, volume = {33}, number = {9}, pages = {2351-2360}, doi = {10.1021/acs.chemrestox.0c00118}, pmid = {32786540}, issn = {1520-5010}, mesh = {Animals ; Cattle ; Chlorophenols/chemistry/*pharmacology ; Cysteine/antagonists &amp; inhibitors/chemistry ; Environmental Pollutants/chemistry/*pharmacology ; Glutathione/*antagonists &amp; inhibitors/chemistry ; Male ; Mice ; Mice, Inbred Strains ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Serum Albumin, Bovine/*antagonists &amp; inhibitors/chemistry ; }, abstract = {2,4-Dichlorophenol (2,4-DCP), an environmental pollutant, was reported to cause hepatotoxicity. The biochemical mechanisms of 2,4-DCP induced liver injury remain unknown. The present study showed that 2,4-DCP is chemically reactive and spontaneously reacts with GSH and bovine serum albumin to form GSH conjugates and BSA adducts. The observed conjugation/adduction apparently involved the addition of GSH and departure of chloride via the ipso substitution pathway. Two biliary GSH conjugates and one urinary N-acetyl cysteine conjugate were observed in rats given 2,4-DCP. The N-acetyl cysteine conjugate was chemically synthesized and characterized by mass spectrometry and NMR. As expected, 2,4-DCP was found to modify hepatic protein at cysteine residues in vivo by the same chemistry. The observed protein adduction reached its peak at 15 min and revealed dose dependency. The new findings allowed us to better understand the mechanisms of the toxic action of 2,4-DCP.}, }
@article {pmid32783894, year = {2020}, author = {Baek, EJ and Kim, H and Basova, LA and Rosander, A and Kesby, JP and Semenova, S and Marcondes, MCG}, title = {Sex differences and Tat expression affect dopaminergic receptor expression and response to antioxidant treatment in methamphetamine-sensitized HIV Tat transgenic mice.}, journal = {Neuropharmacology}, volume = {178}, number = {}, pages = {108245}, pmid = {32783894}, issn = {1873-7064}, support = {P50 DA026306/DA/NIDA NIH HHS/United States ; R01 DA036164/DA/NIDA NIH HHS/United States ; R01 DA047822/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*pharmacology ; Dopamine Uptake Inhibitors/*pharmacology ; Female ; Gene Expression ; Locomotion/drug effects/physiology ; Male ; Methamphetamine/*pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Receptors, Dopamine/*biosynthesis/genetics ; *Sex Characteristics ; tat Gene Products, Human Immunodeficiency Virus/*biosynthesis/genetics ; }, abstract = {Methamphetamine (Meth) abuse is a common HIV comorbidity. Males and females differ in their patterns of Meth use, associated behaviors, and responses, but the underlying mechanisms and impact of HIV infection are unclear. Transgenic mice with inducible HIV-1 Tat protein in the brain (iTat) replicate many neurological aspects of HIV infection in humans. We previously showed that Tat induction enhances the Meth sensitization response associated with perturbation of the dopaminergic system, in male iTat mice. Here, we used the iTat mouse model to investigate sex differences in individual and interactive effects of Tat and Meth challenge on locomotor sensitization, brain expression of dopamine receptors (DRDs) and regulatory adenosine receptors (ADORAs). Because Meth administration increases the production of reactive oxygen species (ROS), we also determined whether the effects of Meth could be rescued by concomitant treatment with the ROS scavenger N-acetyl cysteine (NAC). After Meth sensitization and a 7-day abstinence period, groups of Tat+ and Tat-male and female mice were challenged with Meth in combination with NAC. We confirmed that Tat expression and Meth challenge suppressed DRD mRNA and protein in males and females' brains, and showed that females were particularly susceptible to the effects of Meth on D1-like and D2-like DRD subtypes and ADORAs. The expression of these markers differed strikingly between males and females, and between females in different phases of the estrous cycle, in a Tat -dependent manner. NAC attenuated Meth-induced locomotor sensitization and preserved DRD expression in all groups except for Tat + females. These data identify complex interactions between sex, Meth use, and HIV infection on addiction responses, with potential implications for the treatment of male and female Meth users in the context of HIV, especially those with cognitive disorders.}, }
@article {pmid32782443, year = {2020}, author = {He, F and Zheng, G and Hou, J and Hu, Q and Ling, Q and Wu, G and Zhao, H and Yang, J and Wang, Y and Jiang, L and Tang, W and Yang, Z}, title = {N-acetylcysteine alleviates post-resuscitation myocardial dysfunction and improves survival outcomes via partly inhibiting NLRP3 inflammasome induced-pyroptosis.}, journal = {Journal of inflammation (London, England)}, volume = {17}, number = {}, pages = {25}, pmid = {32782443}, issn = {1476-9255}, abstract = {BACKGROUND: NOD-like receptor 3 (NLRP3) inflammasome is necessary to initiate acute sterile inflammation. Increasing evidence indicates the activation of NLRP3 inflammasome induced pyroptosis is closely related to reactive oxygen species (ROS) in the sterile inflammatory response triggered by ischemia/reperfusion (I/R) injury. N-acetylcysteine (NAC) is an antioxidant and plays a protective role in local myocardial I/R injury, while its effect on post-resuscitation myocardial dysfunction, as well as its mechanisms, remain elusive. In this study, we aimed to investigate the effect of NAC on post-resuscitation myocardial dysfunction in a cardiac arrest rat model, and whether its underlying mechanism may be linked to ROS and NLRP3 inflammasome-induced pyroptosis.<br><br>METHODS: The rats were randomized into three groups: (1) sham group, (2) cardiopulmonary resuscitation (CPR) group, and (3) CPR&#x2009;+&#x2009;NAC group. CPR group and CPR&#x2009;+&#x2009;NAC group went through the induction of ventricular fibrillation (VF) and resuscitation. After return of spontaneous circulation (ROSC), rats in the CPR and CPR&#x2009;+&#x2009;NAC groups were again randomly divided into two subgroups, ROSC 6&#x2009;h and ROSC 72&#x2009;h, for further analysis. Hemodynamic measurements and myocardial function were measured by echocardiography, and western blot was used to detect the expression of proteins.<br><br>RESULTS: Results showed that after treatment with NAC, there was significantly better myocardial function and survival duration; protein expression levels of NLRP3, adaptor apoptosis-associated speck-like protein (ASC), Cleaved-Caspase-1 and gasdermin D (GSDMD) in myocardial tissues were significantly decreased; and inflammatory cytokines levels were reduced. The marker of oxidative stress malondialdehyde (MDA) decreased and superoxide dismutase (SOD) increased with NAC treatment.<br><br>CONCLUSIONS: NAC improved myocardial dysfunction and prolonged animal survival duration in a rat model of cardiac arrest. Moreover, possibly by partly inhibiting ROS-mediated NLRP3 inflammasome-induced pryoptosis.}, }
@article {pmid32780893, year = {2020}, author = {De Flora, S and Balansky, R and La Maestra, S}, title = {Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {10}, pages = {13185-13193}, pmid = {32780893}, issn = {1530-6860}, mesh = {Acetylcysteine/*therapeutic use ; Angiotensin-Converting Enzyme 2/antagonists &amp; inhibitors/metabolism ; Antioxidants/*therapeutic use ; *COVID-19/metabolism/pathology ; Chemotherapy, Adjuvant ; Humans ; Oxidative Stress/drug effects ; SARS-CoV-2/*metabolism ; Virus Internalization/*drug effects ; *COVID-19 Drug Treatment ; }, abstract = {COVID-19 may cause pneumonia, acute respiratory distress syndrome, cardiovascular alterations, and multiple organ failure, which have been ascribed to a cytokine storm, a systemic inflammatory response, and an attack by the immune system. Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID-19 patients. N- Acetyl-L-cysteine (NAC) is a precursor of reduced glutathione (GSH). Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. At very high doses, NAC is also used as an antidote against paracetamol intoxication. Thiols block the angiotensin-converting enzyme 2 thereby hampering penetration of SARS-CoV-2 into cells. Based on a broad range of antioxidant and anti-inflammatory mechanisms, which are herein reviewed, the oral administration of NAC is likely to attenuate the risk of developing COVID-19, as it was previously demonstrated for influenza and influenza-like illnesses. Moreover, high-dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID-19 cases and in the control of its lethal complications, also including pulmonary and cardiovascular adverse events.}, }
@article {pmid32778089, year = {2020}, author = {Yeh, YT and Liang, CC and Chang, CL and Hsu, CY and Li, PC}, title = {Increased risk of knee osteoarthritis in patients using oral N-acetylcysteine: a nationwide cohort study.}, journal = {BMC musculoskeletal disorders}, volume = {21}, number = {1}, pages = {531}, pmid = {32778089}, issn = {1471-2474}, mesh = {Acetylcysteine/adverse effects ; Cartilage ; Cohort Studies ; Humans ; *Osteoarthritis, Knee/diagnosis/drug therapy/epidemiology ; Retrospective Studies ; }, abstract = {BACKGROUND: Knee osteoarthritis (OA) is known to be a progressive degenerative disorder; however, recent evidence suggests that inflammatory mediators contribute to cartilage degradation. Studies have reported that N-acetylcysteine (NAC) had a promising effect on the reduction of the synthesis of proinflammatory and structural mediators by synovial cells. Given the lack of relevant clinical trials, we conducted this study to determine the relationship between NAC use and risk of knee OA.<br><br>METHODS: We designed a retrospective cohort study from 2000 to 2013. Patients who received oral NAC over 28&#x2009;days within 1 year after the first prescription were defined as the case group, whereas those without NAC use were considered as candidates of the control group. We adopted 1:4 propensity-score matching by age, sex, index year, and comorbidities to obtain the control group. The primary outcome was a new diagnosis of knee OA during the follow-up period.<br><br>RESULTS: Our study sample comprised 12,928 people who used NAC and 51,715 NAC nonusers. NAC users had a significantly higher incidence of osteoarthritis (adjusted hazard ratio: 1.42, P&#x2009;<&#x2009;.001) than did NAC nonusers. Also, in analyses stratified by age group and sex, all subgroups exhibited a significantly higher incidence of knee osteoarthritis (P&#x2009;<&#x2009;.0001) among NAC users than among NAC nonusers. The use of oral NAC was associated with nearly four-fold increased the risk of knee OA in the young age group.<br><br>CONCLUSIONS: Long-term use of oral NAC is associated with a higher risk of knee OA.}, }
@article {pmid32775000, year = {2020}, author = {Chinnapaka, S and Bakthavachalam, V and Munirathinam, G}, title = {Repurposing antidepressant sertraline as a pharmacological drug to target prostate cancer stem cells: dual activation of apoptosis and autophagy signaling by deregulating redox balance.}, journal = {American journal of cancer research}, volume = {10}, number = {7}, pages = {2043-2065}, pmid = {32775000}, issn = {2156-6976}, support = {R03 CA230829/CA/NCI NIH HHS/United States ; }, abstract = {Cancer stem cells play a major role in tumor initiation, progression, and tumor relapse of prostate cancer (PCa). Recent studies suggest that Translationally Controlled Tumor Protein (TCTP) is a critical survival factor of stem cells including cancer stem cells. Here, we aimed to determine whether the TCTP inhibitor sertraline (STL) could target prostate cancer stem cells (PCSC). In colony formation, spheroidogenesis, angiogenesis, and wound healing assays STL showed a robust inhibition of tumorigenic (colony growth), angiogenic (endothelial tube formation) and metastatic (wound healing and migration) potential of PCSC. Interestingly, antioxidants such as N-acetyl cysteine (NAC), Glutathione (GSH) and catalase effectively blocked the cytotoxicity effect of STL on PCSC implicating oxidative stress as the underlying anti-PCSC targeting mechanism. Cell cycle analysis showed a robust G0 arrest in PCSC exposed to STL. Notably, STL induced both apoptosis and autophagy by activating free radical generation, hydrogen peroxide formation (H2O2), lipid peroxidation (LPO) and depleted the levels of glutathione (GSH). Moreover, surface marker expression analysis using confocal revealed that STL significantly down regulates the expression levels of aldehyde dehydrogenase 1 (ALDH1) and cluster of differentiation 44 (CD44) stem cell markers. Furthermore, in western blot analysis, STL treatment applied in a dose-dependent manner, caused a marked decrease in TCTP, phospho TCTP, anti-apoptotic markers survivin and cellular inhibitor of apoptosis protein 1 (cIAP1) expression as well as a significant increase in cleaved caspase3 and cleaved Poly [ADP-ribose] polymerase 1 (PARP-1) expression. Of note, STL also significantly down regulated the stem cell markers (ALDH1 and CD44) and epithelial to mesenchymal transition (EMT) markers such as transcription factor 8 (TCF8) and lymphoid enhancer-binding factor-1 (LEF1) expression levels. Concurrently, STL increased the levels of autophagy markers such as light chain (LC3), Beclin1 and autophagy-related gene (ATG5). Taken together, our study suggests that STL could be an effective therapeutic agent in eliminating prostate cancer stem cells.}, }
@article {pmid32773102, year = {2020}, author = {Schönrich, G and Raftery, MJ and Samstag, Y}, title = {Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression.}, journal = {Advances in biological regulation}, volume = {77}, number = {}, pages = {100741}, pmid = {32773102}, issn = {2212-4934}, mesh = {Acetylcysteine/therapeutic use ; Antioxidants/*therapeutic use ; Ascorbic Acid/therapeutic use ; Betacoronavirus/immunology/pathogenicity ; COVID-19 ; Coronavirus Infections/drug therapy/*epidemiology/immunology/virology ; Cytokines/genetics/immunology ; Extracellular Traps/drug effects/*immunology/metabolism ; Host-Pathogen Interactions/drug effects/genetics/immunology ; Humans ; Immunity, Innate/drug effects ; Lymphopenia/drug therapy/*epidemiology/immunology/virology ; NF-kappa B/genetics/immunology ; Neutrophils/drug effects/*immunology/virology ; Oxidative Stress/drug effects ; *Pandemics ; Pneumonia, Viral/drug therapy/*epidemiology/immunology/virology ; Reactive Oxygen Species/antagonists &amp; inhibitors/immunology/metabolism ; SARS-CoV-2 ; T-Lymphocytes/drug effects/immunology/virology ; }, abstract = {Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the mononuclear phagocyte system (MPS) and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.}, }
@article {pmid32768617, year = {2020}, author = {Blanco-Ayala, T and Sathyasaikumar, KV and Uys, JD and Pérez-de-la-Cruz, V and Pidugu, LS and Schwarcz, R}, title = {N-Acetylcysteine Inhibits Kynurenine Aminotransferase II.}, journal = {Neuroscience}, volume = {444}, number = {}, pages = {160-169}, pmid = {32768617}, issn = {1873-7544}, support = {P50 MH103222/MH/NIMH NIH HHS/United States ; R01 AA024426/AA/NIAAA NIH HHS/United States ; }, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Kynurenic Acid/pharmacology ; Kynurenine ; Rats ; Transaminases ; }, abstract = {The tryptophan metabolite kynurenic acid (KYNA) may play an important role in normal and abnormal cognitive processes, most likely by interfering with α7 nicotinic and NMDA receptor function. KYNA is formed from its immediate precursor kynurenine either by non-enzymatic oxidation or through irreversible transamination by kynurenine aminotransferases. In the mammalian brain, kynurenine aminotransferase II (KAT II) is the principal enzyme responsible for the neosynthesis of rapidly mobilizable KYNA, and therefore constitutes an attractive target for pro-cognitive interventions. N-acetylcysteine (NAC), a brain-penetrant drug with pro-cognitive efficacy in humans, has been proposed to exert its actions by increasing the levels of the anti-oxidant glutathione (GSH) in the brain. We report here that NAC, but not GSH, inhibits KAT II activity in brain tissue homogenates from rats and humans with IC50 values in the high micromolar to low millimolar range. With similar potency, the drug interfered with the de novo formation of KYNA in rat brain slices, and NAC was a competitive inhibitor of recombinant human KAT II (Ki: 450 μM). Furthermore, GSH failed to S-glutathionylate recombinant human KAT II treated with the dithiocarbamate drug disulfiram. Shown by microdialysis in the prefrontal cortex of rats treated with kynurenine (50 mg/kg, i.p.), peripheral administration of NAC (500 mg/kg, i.p., 120 and 60 min before the application of kynurenine) reduced KYNA neosynthesis by ∼50%. Together, these results suggest that NAC exerts its neurobiological effects at least in part by reducing cerebral KYNA formation via KAT II inhibition.}, }
@article {pmid32763460, year = {2020}, author = {Zhang, S and Asghar, S and Yu, F and Hu, Z and Ping, Q and Chen, Z and Shao, F and Xiao, Y}, title = {The enhancement of N-acetylcysteine on intestinal absorption and oral bioavailability of hydrophobic curcumin.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {154}, number = {}, pages = {105506}, doi = {10.1016/j.ejps.2020.105506}, pmid = {32763460}, issn = {1879-0720}, mesh = {Acetylcysteine ; Administration, Oral ; Animals ; Biological Availability ; *Curcumin/pharmacokinetics ; *Drug Carriers ; Intestinal Absorption ; *Nanoparticles ; Rats ; }, abstract = {To solve the low oral bioavailability of curcumin (CUR) due to the limits imposed by gastrointestinal (GI) barrier, we constructed a nano delivery system to evaluate the effect of N-acetyl-L-cysteine (NAC) on intestinal absorption and oral bioavailability of CUR. CUR was first encapsulated in bovine serum albumin nanoparticles (CUR-BSA-NPs), and then was further modified by NAC (CUR-NBSA-NPs). In situ single-pass intestinal perfusion assay demonstrated that CUR-NBSA-NPs displayed excellent permeation and absorption rates in GI tract. Additionally, the distribution study in GI tract revealed that more NBSA-NPs were absorbed by intestinal segments compared to the BSA nanoparticles. Plasma concentration-time curves in rats showed that AUC0-t, Cmax and MRT0-t values of CUR after oral administration of CUR-NBSA-NPs were increased to 3.25-, 4.42-, and 1.43-fold compared with that of CUR suspension. In conclusion, NAC promotes oral absorption of CUR, thereby improving its oral bioavailability.}, }
@article {pmid32762663, year = {2020}, author = {Maier, A and Dharan, A and Oliver, G and Berk, M and Redston, S and Back, SE and Kalivas, P and Ng, C and Kanaan, RA}, title = {A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial to assess the efficacy of adjunctive N-Acetylcysteine for treatment-resistant PTSD: a study protocol.}, journal = {BMC psychiatry}, volume = {20}, number = {1}, pages = {397}, pmid = {32762663}, issn = {1471-244X}, mesh = {*Acetylcysteine/therapeutic use ; Adult ; Double-Blind Method ; Humans ; Pilot Projects ; Quality of Life ; *Stress Disorders, Post-Traumatic/drug therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Most patients with Posttraumatic Stress Disorder (PTSD) suffer residual symptoms following first-line treatment. Oxidative stress has been implicated in the pathophysiology of PTSD. N-acetylcysteine (NAC) is a precursor of the brain's primary antioxidant, glutathione, and may diminish oxidative cellular damage. An 8-week pilot study of NAC in veterans with PTSD found that symptoms were significantly reduced in the NAC group compared to placebo. This study aims to confirm these findings with a larger sample in a double-blind, placebo-controlled trial to further explore the efficacy of NAC as an adjunctive therapy in treatment-resistant PTSD.<br><br>METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adult patients who still meet criteria for PTSD following first-line treatment. The intervention comprises either NAC as a fixed dose regime of 2.7&#x2009;g/day (900&#x2009;mg three times daily) administered orally for 12&#x2009;weeks, or placebo. Standard care for PTSD will continue in addition, including other pharmacotherapies. Detailed clinical data will be collected at randomisation and weeks 4, 8, 12, 16, and 64 post-randomisation, with self-report measures completed weekly from baseline to 16&#x2009;weeks and at 64&#x2009;weeks post-randomisation. Blood-based biomarkers will be collected at baseline and 12&#x2009;weeks to assess the mechanism of effect. The primary outcome measure will be change in Clinician-Administered PTSD Scale for DSM-5 at 12&#x2009;weeks compared with baseline. Secondary outcomes will be change in quality of life, depression, anxiety, substance use and craving, and somatic symptoms. With 126 completed participants (63 per arm), the study is powered at 80% to detect a true difference in the primary outcome measure using a two-tailed analysis with alpha&#x2009;=&#x2009;0.05, beta&#x2009;=&#x2009;0.2.<br><br>DISCUSSION: This is the first multicentre, double blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. NAC has an established safety profile, is readily available and easy to administer, and has a favourable tolerability profile, therefore making it an attractive adjunctive therapy. Inclusion of blood analyses to assess potential target engagement biomarkers of oxidative stress and neuroinflammation may help gauge the biological mechanisms of effect of NAC.<br><br>TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004 .}, }
@article {pmid32762399, year = {2021}, author = {Kataura, T and Tashiro, E and Nishikawa, S and Shibahara, K and Muraoka, Y and Miura, M and Sakai, S and Katoh, N and Totsuka, M and Onodera, M and Shin-Ya, K and Miyamoto, K and Sasazawa, Y and Hattori, N and Saiki, S and Imoto, M}, title = {A chemical genomics-aggrephagy integrated method studying functional analysis of autophagy inducers.}, journal = {Autophagy}, volume = {17}, number = {8}, pages = {1856-1872}, pmid = {32762399}, issn = {1554-8635}, mesh = {AMP-Activated Protein Kinases/metabolism ; Animals ; Autophagy/*drug effects/physiology ; Diphenylamine/*analogs &amp; derivatives/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Endoribonucleases/drug effects/metabolism ; Lysosomes/drug effects/metabolism ; Macroautophagy/*drug effects ; Protein Serine-Threonine Kinases/drug effects ; Rats ; Sulfonamides/*pharmacology ; }, abstract = {Macroautophagy/autophagy plays a critical role in the pathogenesis of various human diseases including neurodegenerative disorders such as Parkinson disease (PD) and Huntington disease (HD). Chemical autophagy inducers are expected to serve as disease-modifying agents by eliminating cytotoxic/damaged proteins. Although many autophagy inducers have been identified, their precise molecular mechanisms are not fully understood because of the complicated crosstalk among signaling pathways. To address this issue, we performed several chemical genomic analyses enabling us to comprehend the dominancy among the autophagy-associated pathways followed by an aggresome-clearance assay. In a first step, more than 400 target-established small molecules were assessed for their ability to activate autophagic flux in neuronal PC12D cells, and we identified 39 compounds as autophagy inducers. We then profiled the autophagy inducers by testing their effect on the induction of autophagy by 200 well-established signal transduction modulators. Our principal component analysis (PCA) and clustering analysis using a dataset of "autophagy profiles" revealed that two Food and Drug Administration (FDA)-approved drugs, memantine and clemastine, activate endoplasmic reticulum (ER) stress responses, which could lead to autophagy induction. We also confirmed that SMK-17, a recently identified autophagy inducer, induced autophagy via the PRKC/PKC-TFEB pathway, as had been predicted from PCA. Finally, we showed that almost all of the autophagy inducers tested in this present work significantly enhanced the clearance of the protein aggregates observed in cellular models of PD and HD. These results, with the combined approach, suggested that autophagy-activating small molecules may improve proteinopathies by eliminating nonfunctional protein aggregates.Abbreviations: ADK: adenosine kinase; AMPK: AMP-activated protein kinase; ATF4: activating transcription factor 4; BECN1: beclin-1; DDIT3/CHOP: DNA damage inducible transcript 3; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2S1/eIF2α: eukaryotic translation initiation factor 2 subunit alpha; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FDA: Food and Drug Administration; GSH: glutathione; HD: Huntington disease; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; HTT: huntingtin; JAK: Janus kinase, MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MAP2K/MEK: mitogen-activated protein kinase kinase; MAP3K8/Tpl2: mitogen-activated protein kinase kinase kinase 8; MAPK: mitogen-activated protein kinase; MPP[+]: 1-methyl-4-phenylpyridinium; MTOR: mechanistic target of rapamycin kinase; MTORC: MTOR complex; NAC: N-acetylcysteine; NGF: nerve growth factor 2; NMDA: N-methyl-D-aspartate; PCA: principal component analysis; PD: Parkinson disease; PDA: pancreatic ductal adenocarcinoma; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PMA: phorbol 12-myristate 13-acetate; PRKC/PKC: protein kinase C; ROCK: Rho-associated coiled-coil protein kinase; RR: ribonucleotide reductase; SIGMAR1: sigma non-opioid intracellular receptor 1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TFEB: Transcription factor EB; TGFB/TGF-β: Transforming growth factor beta; ULK1: unc-51 like autophagy activating kinase 1; XBP1: X-box binding protein 1.}, }
@article {pmid32756347, year = {2020}, author = {Tang, JY and Wu, KH and Wang, YY and Farooqi, AA and Huang, HW and Yuan, SF and Jian, RI and Tsao, LY and Chen, PA and Chang, FR and Cheng, YB and Hu, HC and Chang, HW}, title = {Methanol Extract of Usnea barbata Induces Cell Killing, Apoptosis, and DNA Damage against Oral Cancer Cells through Oxidative Stress.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {8}, pages = {}, pmid = {32756347}, issn = {2076-3921}, support = {MOST 108-2320-B-037-015-MY3, MOST 108-2314-B-037-020, MOST 108-2628-B-037-001//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 109-I002//National Sun Yat-sen University-KMU Joint Research Project/ ; KMUH108-8R67//Kaohsiung Medical University Chung-Ho Memorial Hospital/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; MOHW109-TDU-B-212-134016//Health and welfare surcharge of tobacco products, the Ministry of Health and Welfare, Taiwan, Republic of China/ ; }, abstract = {Some lichens provide the resources of common traditional medicines and show anticancer effects. However, the anticancer effect of Usnproliea barbata (U. barbata) is rarely investigated, especially for oral cancer cells. The aim of this study was to investigate the cell killing function of methanol extracts of U. barbata (MEUB) against oral cancer cells. MEUB shows preferential killing against a number of oral cancer cell lines (Ca9-22, OECM-1, CAL 27, HSC3, and SCC9) but rarely affects normal oral cell lines (HGF-1). Ca9-22 and OECM-1 cells display the highest sensitivity to MEUB and were chosen for concentration effect and time course experiments to address its cytotoxic mechanisms. MEUB induces apoptosis of oral cancer cells in terms of the findings from flow cytometric assays and Western blotting, such as subG1 accumulation, annexin V detection, and pancaspase activation as well as poly (ADP-ribose) polymerase (PARP) cleavage. MEUB induces oxidative stress and DNA damage of oral cancer cells following flow cytometric assays, such as reactive oxygen species (ROS)/mitochondrial superoxide (MitoSOX) production, mitochondrial membrane potential (MMP) depletion as well as overexpression of γH2AX and 8-oxo-2'deoxyguanosine (8-oxodG). All MEUB-induced changes in oral cancer cells were triggered by oxidative stress which was validated by pretreatment with antioxidant N-acetylcysteine (NAC). In conclusion, MEUB causes preferential killing of oral cancer cells and is associated with oxidative stress, apoptosis, and DNA damage.}, }
@article {pmid32755956, year = {2020}, author = {Poonaki, E and Esfandyar, M and Hejazinia, H and Sadat Ebrahimi, SE and Pirali Hamedani, M and Farzaneh, J and Shafiee Ardestani, M}, title = {N-acetylcysteine-PLGA nano-conjugate: effects on cellular toxicity and uptake of gadopentate dimeglumine.}, journal = {IET nanobiotechnology}, volume = {14}, number = {6}, pages = {470-478}, pmid = {32755956}, issn = {1751-875X}, mesh = {*Acetylcysteine/chemistry/toxicity ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Contrast Media/chemistry/pharmacokinetics ; Drug Delivery Systems ; *Gadolinium DTPA/chemistry/pharmacokinetics ; HEK293 Cells ; Humans ; Kidney/cytology/metabolism ; MCF-7 Cells ; Mice ; *Nanoconjugates/chemistry/toxicity ; *Polylactic Acid-Polyglycolic Acid Copolymer/chemistry/toxicity ; }, abstract = {Gadolinium as a contrast agent in MRI technique combined with DTPA causes contrast induced nephropathy (CIN) and nephrogenic systemic fibrosis (NSF) which can reduce by usage of antioxidants such as N-acetyl cysteine by increasing the membrane's permeability leads to lower cytotoxicity. In this study, N-acetyl cysteine-PLGA Nano-conjugate was synthesized according to stoichiometric rules of molar ratios andafter assessment by FTIR, NMR spectroscopy and Atomic Force Microscopy (AFM) imaging was combined with Magnevist® (gadopentetate dimeglumine) and its effects on the renal cells were evaluated. MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] and cellular uptake assays have indicated relatively significant toxicity of magnevist (P < 0.05) on three cell lines including HEK293, MCF7 and L929 compared to other synthesized ligands that shown no toxicity. Moreover, systemic evaluation has shown no notable changes of blood urea nitrogen (BUN) and creatinine in kidney of mice. In consequence, antioxidant effect was increased as well as the renal toxicity of the contrast agent reduced at the cell level. As a result, PLGA-NAC nano-conjugate can be a promising choice for decreasing the magnevist toxicity for treatment and prevention of CIN and will be able to open a new horizon to research on reduction of toxicity of contrast agents by using nanoparticles.}, }
@article {pmid32752099, year = {2020}, author = {Kim, SY and Hwangbo, H and Lee, H and Park, C and Kim, GY and Moon, SK and Yun, SJ and Kim, WJ and Cheong, J and Choi, YH}, title = {Induction of Apoptosis by Coptisine in Hep3B Hepatocellular Carcinoma Cells through Activation of the ROS-Mediated JNK Signaling Pathway.}, journal = {International journal of molecular sciences}, volume = {21}, number = {15}, pages = {}, pmid = {32752099}, issn = {1422-0067}, support = {2018R1A2B2005705//Basic Science Research Program through the National Research Foundation of Korea grant funded by the Korea government/ ; }, mesh = {Apoptosis/drug effects ; Berberine/*analogs &amp; derivatives/pharmacology ; Carcinoma, Hepatocellular/*drug therapy/genetics/pathology ; Caspase 3/genetics ; Cell Line, Tumor ; Humans ; JNK Mitogen-Activated Protein Kinases/genetics ; Liver Neoplasms/*drug therapy/genetics/pathology ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Neoplasm Recurrence, Local/*drug therapy/genetics/pathology ; Proto-Oncogene Proteins c-bcl-2/genetics ; Reactive Oxygen Species/metabolism ; }, abstract = {Hepatocellular carcinoma (HCC) has a high mortality rate worldwide, and treatment is very limited due to its high recurrence and low diagnosis rate, and therefore there is an increasing need to develop more effective drugs to treat HCC. Coptisine is one of the isoquinoline alkaloids, and it has various pharmacological effects. However, the evidence for the molecular mechanism of the anticancer efficacy is still insufficient. Therefore, this study investigated the antiproliferative effect of coptisine on human HCC Hep3B cells and identified the action mechanism. Our results showed that coptisine markedly increased DNA damage and apoptotic cell death, which was associated with induction of death receptor proteins. Coptisine also significantly upregulated expression of proapoptotic Bax protein, downregulated expression of anti-apoptotic Bcl-2 protein, and activated caspase-3, -8, and -9. In addition, coptisine remarkably increased the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and release of cytochrome c into the cytoplasm. However, N-acetylcysteine (NAC), a ROS scavenger, significantly attenuated the apoptosis-inducing effect of coptisine. It is worth noting that coptisine significantly upregulated phosphorylation of ROS-dependent c-Jun N-terminal kinase (JNK), whereas treatment with JNK inhibitor could suppress an apoptosis-related series event. Taken together, our results suggest that coptisine has an anticancer effect in Hep3B cells through ROS-mediated activation of the JNK signaling pathway.}, }
@article {pmid32751344, year = {2020}, author = {Pulze, L and Congiu, T and Brevini, TAL and Grimaldi, A and Tettamanti, G and D'Antona, P and Baranzini, N and Acquati, F and Ferraro, F and de Eguileor, M}, title = {MCF7 Spheroid Development: New Insight about Spatio/Temporal Arrangements of TNTs, Amyloid Fibrils, Cell Connections, and Cellular Bridges.}, journal = {International journal of molecular sciences}, volume = {21}, number = {15}, pages = {}, pmid = {32751344}, issn = {1422-0067}, mesh = {Acetylcysteine/*pharmacology ; Amyloid/*chemistry/drug effects/metabolism ; Biomarkers, Tumor/genetics/metabolism ; Cell Aggregation/drug effects ; Connexin 43/genetics/metabolism ; Free Radical Scavengers/*pharmacology ; Gap Junctions/drug effects/metabolism/*ultrastructure ; Gene Expression ; Homeostasis/*drug effects/genetics ; Humans ; Interleukin-18/genetics/metabolism ; MCF-7 Cells ; Neprilysin/pharmacology ; Oxidation-Reduction ; Phenotype ; Proteolysis ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; SOXB1 Transcription Factors/genetics/metabolism ; Spheroids, Cellular/drug effects/metabolism/*ultrastructure ; Stage-Specific Embryonic Antigens/genetics/metabolism ; Transcription Factors/genetics/metabolism ; gp100 Melanoma Antigen/genetics/metabolism ; }, abstract = {Human breast adenocarcinoma cells (MCF7) grow in three-dimensional culture as spheroids that represent the structural complexity of avascular tumors. Therefore, spheroids offer a powerful tool for studying cancer development, aggressiveness, and drug resistance. Notwithstanding the large amount of data regarding the formation of MCF7 spheroids, a detailed description of the morpho-functional changes during their aggregation and maturation is still lacking. In this study, in addition to the already established role of gap junctions, we show evidence of tunneling nanotube (TNT) formation, amyloid fibril production, and opening of large stable cellular bridges, thus reporting the sequential events leading to MCF7 spheroid formation. The variation in cell phenotypes, sustained by dynamic expression of multiple proteins, leads to complex networking among cells similar to the sequence of morphogenetic steps occurring in embryogenesis/organogenesis. On the basis of the observation that early events in spheroid formation are strictly linked to the redox homeostasis, which in turn regulate amyloidogenesis, we show that the administration of N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger that reduces the capability of cells to produce amyloid fibrils, significantly affects their ability to aggregate. Moreover, cells aggregation events, which exploit the intrinsic adhesiveness of amyloid fibrils, significantly decrease following the administration during the early aggregation phase of neutral endopeptidase (NEP), an amyloid degrading enzyme.}, }
@article {pmid32747719, year = {2021}, author = {Yu, XX and Zhu, MY and Wang, JR and Li, H and Hu, P and Qing, YJ and Wang, XY and Wang, HZ and Wang, ZY and Xu, JY and Guo, QL and Hui, H}, title = {LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2α-ATF4-CHOP axis.}, journal = {Acta pharmacologica Sinica}, volume = {42}, number = {2}, pages = {290-300}, pmid = {32747719}, issn = {1745-7254}, mesh = {Activating Transcription Factor 4/metabolism ; Animals ; Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Eukaryotic Initiation Factor-2/metabolism ; Female ; Flavanones/administration &amp; dosage/chemistry/*pharmacology ; Humans ; Inhibitory Concentration 50 ; Lymphoma, T-Cell, Cutaneous/*drug therapy/pathology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Reactive Oxygen Species/metabolism ; Skin Neoplasms/*drug therapy/pathology ; Transcription Factor CHOP/metabolism ; Xenograft Model Antitumor Assays ; eIF-2 Kinase/metabolism ; }, abstract = {Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1-25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK-eIF2α-ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.}, }
@article {pmid32745521, year = {2020}, author = {Chen, Q and Konrad, C and Sandhu, D and Roychoudhury, D and Schwartz, BI and Cheng, RR and Bredvik, K and Kawamata, H and Calder, EL and Studer, L and Fischer, SM and Manfredi, G and Gross, SS}, title = {Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients.}, journal = {Neurobiology of disease}, volume = {144}, number = {}, pages = {105025}, pmid = {32745521}, issn = {1095-953X}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 NS062055/NS/NINDS NIH HHS/United States ; R01 NS093872/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Amyotrophic Lateral Sclerosis/*metabolism ; Case-Control Studies ; Cells, Cultured ; Cysteine/*metabolism ; Female ; Fibroblasts/*metabolism ; Glucose/*metabolism ; Glutathione/*metabolism ; Humans ; Male ; Metabolic Networks and Pathways ; *Metabolome ; Metabolomics ; Middle Aged ; Serine/metabolism ; Skin/cytology ; }, abstract = {Amyotrophic lateral sclerosis is a disease characterized by progressive paralysis and death. Most ALS-cases are sporadic (sALS) and patient heterogeneity poses challenges for effective therapies. Applying metabolite profiling on 77-sALS patient-derived-fibroblasts and 43-controls, we found ~25% of sALS cases (termed sALS-1) are characterized by transsulfuration pathway upregulation, where methionine-derived-homocysteine is channeled into cysteine for glutathione synthesis. sALS-1 fibroblasts selectively exhibited a growth defect under oxidative conditions, fully-rescued by N-acetylcysteine (NAC). [U[13]C]-glucose tracing showed transsulfuration pathway activation with accelerated glucose flux into the Krebs cycle. We established a four-metabolite support vector machine model predicting sALS-1 metabotype with 97.5% accuracy. Both sALS-1 metabotype and growth phenotype were validated in an independent cohort of sALS cases. Importantly, plasma metabolite profiling identified a system-wide cysteine metabolism perturbation as a hallmark of sALS-1. Findings reveal that sALS patients can be stratified into distinct metabotypes with differential sensitivity to metabolic stress, providing novel insights for personalized therapy.}, }
@article {pmid32745510, year = {2020}, author = {Bi, S and Tang, J and Zhang, L and Huang, L and Chen, J and Wang, Z and Chen, D and Du, L}, title = {Fine particulate matter reduces the pluripotency and proliferation of human embryonic stem cells through ROS induced AKT and ERK signaling pathway.}, journal = {Reproductive toxicology (Elmsford, N.Y.)}, volume = {96}, number = {}, pages = {231-240}, doi = {10.1016/j.reprotox.2020.07.010}, pmid = {32745510}, issn = {1873-1708}, mesh = {Air Pollutants/*toxicity ; Cell Differentiation/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Human Embryonic Stem Cells/cytology/*drug effects/metabolism ; Humans ; MAP Kinase Signaling System/drug effects ; Nanog Homeobox Protein/genetics/metabolism ; Octamer Transcription Factor-3/genetics/metabolism ; Particulate Matter/*toxicity ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Epidemiological investigations have found that air fine particulate matter (PM) exposure not only causes respiratory and cardiovascular diseases in adults and children, but also affects embryonic development during pregnancy, leading to poor pregnancy outcomes. However, its exact molecular mechanism is still unclear. In this study, human embryonic stem cells (hESCs) were treated with PM at different concentrations then the morphology and proliferation capacity were measured. The mRNA and protein expression of NANOG and OCT4 were detected using quantitative PCR, immunofluorescence, western blotting, and flow cytometry. Reactive oxygen species (ROS) generation and AKT/ERK activation were also measured. Meanwhile, changes in ROS, the expression of NANOG, OCT4, and the AKT/ERK pathways were measured in the hESCs with or without pretreatment of ROS scavenger N-acetylcysteine (NAC) prior to PM exposure. After PM exposure, the proliferation capacity and expression of OCT4 and NANOG at the mRNA and protein levels were downregulated. The ROS level in the hESCs increased after PM exposure, but this increase in ROS was attenuated by pretreatment with NAC. Further analysis showed that the levels of phosphorylated AKT and ERK increased after PM exposure. After pretreatment with NAC, the phosphorylation levels of AKT and ERK, which are crucial for regulating the proliferation, pluripotency, and differentiation of hESC, were significantly attenuated compared with the non-NAC pretreated exposure group. These results suggest that PM exposure may reduce the proliferation and pluripotency of hESC through ROS-mediated AKT/ERK pathways, thereby affecting the long-term development of embryos.}, }
@article {pmid32744307, year = {2020}, author = {Russi, M and Martin, E and D'Autréaux, B and Tixier, L and Tricoire, H and Monnier, V}, title = {A Drosophila model of Friedreich ataxia with CRISPR/Cas9 insertion of GAA repeats in the frataxin gene reveals in vivo protection by N-acetyl cysteine.}, journal = {Human molecular genetics}, volume = {29}, number = {17}, pages = {2831-2844}, doi = {10.1093/hmg/ddaa170}, pmid = {32744307}, issn = {1460-2083}, mesh = {Acetylcysteine/*pharmacology ; Animals ; CRISPR-Cas Systems/*genetics ; Disease Models, Animal ; Drosophila melanogaster/genetics ; Friedreich Ataxia/drug therapy/*genetics/pathology ; Humans ; Introns/genetics ; Iron-Binding Proteins/*genetics ; Oxidative Stress/genetics ; RNA-Seq ; Trinucleotide Repeat Expansion/genetics ; Frataxin ; }, abstract = {Friedreich ataxia (FA) is caused by GAA repeat expansions in the first intron of FXN, the gene encoding frataxin, which results in decreased gene expression. Thanks to the high degree of frataxin conservation, the Drosophila melanogaster fruitfly appears as an adequate animal model to study this disease and to evaluate therapeutic interventions. Here, we generated a Drosophila model of FA with CRISPR/Cas9 insertion of approximately 200 GAA in the intron of the fly frataxin gene fh. These flies exhibit a developmental delay and lethality associated with decreased frataxin expression. We were able to bypass preadult lethality using genetic tools to overexpress frataxin only during the developmental period. These frataxin-deficient adults are short-lived and present strong locomotor defects. RNA-Seq analysis identified deregulation of genes involved in amino-acid metabolism and transcriptomic signatures of oxidative stress. In particular, we observed a progressive increase of Tspo expression, fully rescued by adult frataxin expression. Thus, Tspo expression constitutes a molecular marker of the disease progression in our fly model and might be of interest in other animal models or in patients. Finally, in a candidate drug screening, we observed that N-acetyl cysteine improved the survival, locomotor function, resistance to oxidative stress and aconitase activity of frataxin-deficient flies. Therefore, our model provides the opportunity to elucidate in vivo, the protective mechanisms of this molecule of therapeutic potential. This study also highlights the strength of the CRISPR/Cas9 technology to introduce human mutations in endogenous orthologous genes, leading to Drosophila models of human diseases with improved physiological relevance.}, }
@article {pmid32738495, year = {2020}, author = {Chowdhury, A and Nabila, J and Adelusi Temitope, I and Wang, S}, title = {Current etiological comprehension and therapeutic targets of acetaminophen-induced hepatotoxicity.}, journal = {Pharmacological research}, volume = {161}, number = {}, pages = {105102}, doi = {10.1016/j.phrs.2020.105102}, pmid = {32738495}, issn = {1096-1186}, mesh = {*Acetaminophen ; Animals ; Antidotes/*pharmacology ; Antioxidants/pharmacology ; Autophagy/drug effects ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/metabolism/pathology ; Cytochrome P-450 Enzyme Inhibitors/pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Liver/*drug effects/metabolism/pathology ; Liver Regeneration/drug effects ; Molecular Targeted Therapy ; NF-E2-Related Factor 2/agonists/metabolism ; Oxidative Stress/drug effects ; Protein Kinase Inhibitors/pharmacology ; Signal Transduction ; }, abstract = {Acetaminophen (APAP) is the most popular mild analgesic and antipyretic drug used worldwide. APAP overdose leads to drug-induced hepatotoxicity and can cause hepatic failure if treatment delayed. It is adequately comprehended that the metabolism of high-dose APAP by cytochrome P450 enzymes generates N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolite, which leads to glutathione (GSH) depletion, oxidative stress, and activation of various complex molecular pathways that initiate liver injury and downstream hepatic necrosis. Administration of activated charcoal followed by N-acetylcysteine (NAC) is considered the mainstay therapy; however, including side effects and limitation of rescuing for the delayed patients where liver transplantation may be a lifesaving procedure. Many complex signal transduction pathways such as c-Jun NH2-terminal kinase (JNK), mammalian target of rapamycin (mTOR), nuclear factor (NF)-κB, and NF (erythroid-derived 2)- like 2 (Nrf2) are involved in the development of APAP hepatotoxicity, but yet hasn't been comprehensively studied; thus, the search for effective antidotes and better management strategies continues. Here, we reviewed the most current advances to elucidate the etiological factors and therapeutic targets that could provide better strategies for the management of APAP-induced hepatotoxicity.}, }
@article {pmid32738378, year = {2020}, author = {Moyano, P and Sanjuan, J and García, JM and Anadon, MJ and Naval, MV and Sola, E and García, J and Frejo, MT and Pino, JD}, title = {Dysregulation of prostaglandine E2 and BDNF signaling mediated by estrogenic dysfunction induces primary hippocampal neuronal cell death after single and repeated paraquat treatment.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {144}, number = {}, pages = {111611}, doi = {10.1016/j.fct.2020.111611}, pmid = {32738378}, issn = {1873-6351}, mesh = {Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Cell Death/*drug effects ; Cells, Cultured ; Dinoprostone/*metabolism ; Estrogens/*metabolism ; Female ; Herbicides/*pharmacology ; Hippocampus/cytology/*drug effects/metabolism ; Neurons/*drug effects/metabolism ; Oxidative Stress/drug effects ; Paraquat/*pharmacology ; Pregnancy ; Rats ; Rats, Wistar ; *Signal Transduction ; }, abstract = {Paraquat (PQ) produces hippocampal neuronal cell death and cognitive dysfunctions after unique and continued exposure, but the mechanisms are not understood. Primary hippocampal wildtype or βAPP-Tau silenced cells were co-treated with PQ with or without E2, N-acetylcysteine (NAC), NS-398 (cyclooxygenase-2 inhibitor), MF63 (PGES-1 inhibitor) and/or recombinant brain-derived neurotrophic factor (BDNF) during one- and fourteen-days to studied PQ effect on prostaglandin E2 (PGE2) and BDNF signaling and their involvement in hyperphosphorylated Tau (pTau) and amyloid-beta (Aβ) protein formation, and oxidative stress generation, that lead to neuronal cell loss through estrogenic disruption, as a possible mechanism of cognitive dysfunctions produced by PQ. Our results indicate that PQ overexpressed cyclooxygenase-2 that leads to an increase of PGE2 and alters the expression of EP1-3 receptor subtypes. PQ induced also a decrease of proBDNF and mature BDNF levels and altered P75[NTR] and tropomyosin receptor kinase B (TrkB) expression. PQ induced PGE2 and BDNF signaling dysfunction, mediated through estrogenic disruption, leading to Aβ and pTau proteins synthesis, oxidative stress generation and finally to cell death. Our research provides relevant information to explain PQ hippocampal neurotoxic effects, indicating a probable explanation of the cognitive dysfunction observed and suggests new therapeutic strategies to protect against PQ toxic effects.}, }
@article {pmid32736702, year = {2020}, author = {Kim, SJ and Kim, YS and Kim, JH and Jang, HY and Ly, DD and Das, R and Park, KS}, title = {Activation of ERK1/2-mTORC1-NOX4 mediates TGF-β1-induced epithelial-mesenchymal transition and fibrosis in retinal pigment epithelial cells.}, journal = {Biochemical and biophysical research communications}, volume = {529}, number = {3}, pages = {747-752}, doi = {10.1016/j.bbrc.2020.06.034}, pmid = {32736702}, issn = {1090-2104}, mesh = {Cell Line ; Enzyme Activation ; *Epithelial-Mesenchymal Transition ; Fibrosis ; Humans ; *MAP Kinase Signaling System ; Mechanistic Target of Rapamycin Complex 1/*metabolism ; NADPH Oxidase 4/*metabolism ; Retinal Pigment Epithelium/cytology/metabolism/*pathology ; Signal Transduction ; Transforming Growth Factor beta1/*metabolism ; }, abstract = {Transforming growth factor-β (TGF-β) plays a crucial role in the development of epithelial to mesenchymal transition (EMT) and fibrosis, particularly in an ocular disorder such as proliferative vitreoretinopathy (PVR). However, the key molecular mechanism underlying its pathogenesis remains unknown. In the present study, using cultured ARPE-19 cells, we determined that TGF-β initiates a signaling pathway through extracellular signal-regulated kinase (ERK)-mammalian target of rapamycin complex 1 (mTORC1) that stimulates trans-differentiation and fibrosis of retinal pigment epithelium. Blocking this pathway by a TGF-βRI, ERK or mTORC1 inhibitor protected cells from EMT and fibrotic protein expression. TGF-β1 treatment increased reactive oxygen species (ROS) via NOX4 upregulation, which acts downstream of ERK and mTORC1, as the ROS scavenger N-acetylcysteine and a pan-NADPH oxidase (NOX) inhibitor DPI dissipated excess ROS generation. TGF-β1-induced oxidative stress resulted in EMT and fibrotic changes, as NAC and DPI prevented α-SMA, Col4α3 expression and cell migration. All these inhibitors blocked the downstream pathway activation in addition to clearly preventing the activation of its upstream molecules, indicating the presence of a feedback loop system that may boost the upstream events. Furthermore, the FDA-approved drug trametinib (10 nM) blunted TGF-β1-induced mTORC1 activation and downstream pathogenic alterations through ERK1/2 inhibition, which opens a therapeutic avenue for the treatment of PVR in the future.}, }
@article {pmid32736244, year = {2020}, author = {Liu, T and Di, QN and Sun, JH and Zhao, M and Xu, Q and Shen, Y}, title = {Effects of nonylphenol induced oxidative stress on apoptosis and autophagy in rat ovarian granulosa cells.}, journal = {Chemosphere}, volume = {261}, number = {}, pages = {127693}, doi = {10.1016/j.chemosphere.2020.127693}, pmid = {32736244}, issn = {1879-1298}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Endocrine Disruptors/toxicity ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Granulosa Cells/drug effects ; Humans ; Oxidative Stress/drug effects ; Phenols/*toxicity ; Rats ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases ; }, abstract = {Nonylphenol (NP) is a kind of environmental endocrine disruptors which is generally recognized to cause female reproductive toxicity, but its basic mechanism has not been fully elucidated. In this study, granulosa cells (GCs) were treated with 0-70 μM NP for 24 h, the cell viability of GCs was reduced significantly, as well as increased cell apoptosis with G2/M arrest. Furthermore, NP significantly induced autophagy and the production of reactive oxygen species (ROS). However, these phenomenons were inhibited by blocking the production of ROS with N-Acetyl-l-cysteine (NAC) administration. Intriguingly, the inhibition of autophagy with 3-Methyladenine (3-MA) could enhance the apoptosis induced by NP. Moreover, the down regulating of p-Akt/Akt, p-mTOR/mTOR and subsequent up-regulation of p-AMPK/AMPK induced by NP can be rescued by pretreatment of NAC. Our findings suggested that NP promotes rat ovarian GCs apoptosis and autophagy simultaneously, which may involve the activation of ROS-dependent Akt/AMPK/mTOR pathway. Whatever, the activation of autophagy is likely to develop a protective mechanism to improve the apoptosis of rat ovarian GCs induced by NP.}, }
@article {pmid32729123, year = {2020}, author = {Cerit, &#x130; and Pfaff, A and Ercal, N and Demirkol, O}, title = {Postharvest application of thiol compounds affects surface browning and antioxidant activity of fresh-cut potatoes.}, journal = {Journal of food biochemistry}, volume = {}, number = {}, pages = {e13378}, doi = {10.1111/jfbc.13378}, pmid = {32729123}, issn = {1745-4514}, support = {2017-50-02-022//Sakarya University/ ; }, abstract = {The aim of this study was to compare the effects of sodium metabisulphite and the thiol compounds, glutathione (GSH), L-cysteine (CYS), and N-acetylcysteine (NAC), on the enzymatic browning, antioxidant activities, total phenolic, and ascorbic acid content of potatoes after 1, 24, and 48 hr. Three different concentrations (0.5%, 1.0%, and 2.0%) of each thiol compound were tested. While sulphite solution inhibited polyphenol oxidase as expected, NAC and CYS also decreased its activity. CYS-treated samples exhibited the highest residual thiol content, while the amount of residual thiol in GSH-treated samples was the lowest. The 2.0% NAC and 2.0% CYS solutions were the most effective at increasing antioxidant activity and ascorbic acid content; however, the results of total phenolic content assays were complicated. In summary, solutions containing 2.0% NAC, 1.0% CYS, and 2.0% CYS prevented enzymatic browning and increased the residual thiol content, ascorbic acid, and antioxidant activities of fresh-cut potatoes significantly, but GSH did not significantly inhibit browning. PRACTICAL APPLICATIONS: Fresh-cut potatoes are susceptible to enzymatic browning, which significantly reduces their commercial value. In literature, there have been several methods to protect the enzymatic browning of fruits and vegetables. Among these methods, thiols are good inhibitors of enzymatic browning. So, GSH, CYS, and NAC were used in this study. The outcomes of current work may help to inhibit polyphenol oxidase activity and increase the ascorbic acid content, residual thiol content, and antioxidant activity of fresh-cut potatoes. Both CYS and NAC may be useful alternatives to sulphite anti-browning agents, which may have adverse health effects.}, }
@article {pmid32729099, year = {2020}, author = {Desoky, EAE and Sakr, AM and Alhefnawy, M and Omran, M and Abdalla, MMH and Shahin, AS and Ali, MM}, title = {Renal protective effect of N-acetylcysteine with stepwise ramping voltage against extracorporeal shock wave lithotripsy-induced renal injury: a prospective randomized trial.}, journal = {International urology and nephrology}, volume = {52}, number = {12}, pages = {2261-2267}, doi = {10.1007/s11255-020-02580-1}, pmid = {32729099}, issn = {1573-2584}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Female ; Humans ; Kidney/*injuries ; Kidney Calculi/*therapy ; Lithotripsy/*adverse effects/*methods ; Male ; Middle Aged ; Prospective Studies ; Wounds and Injuries/prevention &amp; control ; }, abstract = {PURPOSE: To evaluate the role of combination of N-acetylcysteine with stepwise ramping voltage in renal protection against the ischemic, vascular and oxidative effects of extracorporeal shock wave lithotripsy.<br><br>PATIENTS AND METHODS: A prospective randomized trial on 164 adult patients scheduled for ESWL for single renal stones. Patients with radio-lucent stones, diabetes, hypertension, febrile UTI, and preoperative albuminuria were excluded from the study. Patients were randomized into one of four groups. Group A patients received maximal fixed voltage of ESWL. Group B patients received stepwise ramping voltage of ESWL. Group C patients received fixed maximal voltage with N-acetylcysteine (NAC) 600&#xa0;mg/bid from 48&#xa0;h before to 24&#xa0;h after the procedure. Group D patients received gradual ramping voltage with NAC. Urinary &#x3b2;2-microglobulin, 24&#xa0;h albumin and N-acetyl-&#x3b2;-D-glucosaminidase/creatinine ratio at 1&#xa0;day and 5&#xa0;days post-ESWL and the stone free rate at 2&#xa0;weeks were measured.<br><br>RESULTS: Group D was the only group that showed no significant difference pre and post ESWL in urinary albumin, &#x3b2;2-microglobulin and N-acetyl-&#x3b2;-D-glucosaminidase/creatinine ratio. Post hoc analysis revealed no significant difference between group B and group C in albumin, &#x3b2;2-microglobulin N-acetyl-&#x3b2;-D-glucosaminidase/creatinine ratio, but both of them had significantly lower levels than group A and significantly higher levels than group D. There was no statistically significant difference between all groups in the stone free rate at 2&#xa0;weeks.<br><br>CONCLUSION: N-acetylcysteine protects the kidney against ESWL-induced renal injuries especially if combined with stepwise ramping voltage.}, }
@article {pmid32728627, year = {2020}, author = {Mohammadi, H and Sayad, A and Mohammadi, M and Niknahad, H and Heidari, R}, title = {N-acetyl cysteine treatment preserves mitochondrial indices of functionality in the brain of hyperammonemic mice.}, journal = {Clinical and experimental hepatology}, volume = {6}, number = {2}, pages = {106-115}, pmid = {32728627}, issn = {2392-1099}, abstract = {AIM OF THE STUDY: Acute or chronic live failure could result in hyperammonemia and hepatic encephalopathy (HE). HE is a clinical complication characterized by severe cognitive dysfunction and coma. The ammonium ion (NH4 [+]) is the most suspected toxic molecule involved in the pathogenesis of HE. NH4 [+] is a neurotoxic agent. Different mechanisms, including oxidative/nitrosative stress, inflammatory response, excitotoxicity, and mitochondrial impairment, are proposed for NH4 [+]-induced neurotoxicity. N-acetyl cysteine (NAC) is a well-known thiol-reductant and antioxidant agent. Several investigations also mentioned the positive effects of NAC on mitochondrial function. In the current study, the effect of NAC treatment on brain mitochondrial indices and energy status was investigated in an animal model of HE.<br><br>MATERIAL AND METHODS: Acetaminophen (APAP)-induced acute liver failure was induced by a single dose of the drug (800 mg/kg, i.p.) to C57BL/6J mice. Plasma and brain levels of NH4 [+] were measured. Then, brain mitochondria were isolated, and several indices, including mitochondrial depolarization, ATP level, lipid peroxidation, glutathione content, mitochondrial permeabilization, and dehydrogenase activity, were assessed.<br><br>RESULTS: A significant increase in plasma and brain NH4 [+] was evident in APAP-treated animals. Moreover, mitochondrial indices of functionality were impaired, and mitochondrial oxidative stress biomarkers were significantly increased in APAP-treated mice. It was found that NAC treatment (100, 200, and 400 mg/kg, i.p.) significantly mitigated mitochondrial impairment in the brain of APAP-treated animals.<br><br>CONCLUSIONS: These data suggest the effects of NAC on brain mitochondrial function and energy status as a pivotal mechanism involved in its neuroprotective properties during HE.}, }
@article {pmid32727289, year = {2021}, author = {Rajput, D and Kumar, N and Sharma, P and Roshan, R and Puliyath, N and Gupta, A}, title = {Use of N-acetyl cysteine to retrieve entrapped Malecot catheter in liver: an old agent for a novel application.}, journal = {Tropical doctor}, volume = {51}, number = {2}, pages = {226-228}, doi = {10.1177/0049475520943703}, pmid = {32727289}, issn = {1758-1133}, mesh = {Acetylcysteine/*therapeutic use ; Catheters/*adverse effects ; Device Removal/*methods ; Drainage/adverse effects ; Expectorants/*therapeutic use ; Humans ; Liver Abscess/*therapy ; Male ; Middle Aged ; }, abstract = {Percutaneous catheter drainage is one way of treating large liver abscesses that are partially liquefied or have thick pus. Apart from discomfort, severe pain, inflammation or frank cellulitis at the insertion site, and sometimes catheter dislodgement, failure to retrieve a catheter is unusual. This may occur either due to fibrous tissue securing the catheter or when inspissated secretions prevent the catheter tip from straightening. N-acetyl cysteine is a mucolytic and exerts action in many parts of the body such as the mouth, throat and lungs. We report successful removal of a catheter stuck in the liver using this substance.}, }
@article {pmid32726657, year = {2020}, author = {Faghfouri, AH and Zarezadeh, M and Tavakoli-Rouzbehani, OM and Radkhah, N and Faghfuri, E and Kord-Varkaneh, H and Tan, SC and Ostadrahimi, A}, title = {The effects of N-acetylcysteine on inflammatory and oxidative stress biomarkers: A systematic review and meta-analysis of controlled clinical trials.}, journal = {European journal of pharmacology}, volume = {884}, number = {}, pages = {173368}, doi = {10.1016/j.ejphar.2020.173368}, pmid = {32726657}, issn = {1879-0712}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Aged, 80 and over ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Biomarkers/blood ; Cytokines/blood/*metabolism ; Female ; Humans ; Inflammation/blood/metabolism/*prevention &amp; control ; Inflammation Mediators/blood/*metabolism ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Randomized Controlled Trials as Topic ; Young Adult ; }, abstract = {Prolonged inflammation could be considered as the leading cause of chronic diseases such as cardiovascular disorders, type two diabetes, and obesity. N-acetylcysteine (NAC) is considered an antioxidant. The present meta-analysis aims to determine the efficacy of NAC in alleviating inflammation and oxidative stress. PubMed-Medline, SCOPUS, Web of Science and Embase databases and Google Scholar were searched up to Nov 2019. Random effect analysis was used to perform meta-analysis. Subgroup analyses were carried out to find heterogeneity sources. Meta-regression analysis was used to explore linear relationship between effect size and variables. Trim and fill analysis were performed in case of the presence of publication bias. Quality assessment was performed using Cochrane Collaboration's tool. A total of 28 studies were included in meta-analysis. NAC significantly decreased malondialdehyde (MDA) (SMD = -1.44 μmol/L; 95% CI: -2.05, -0.84; P < 0.001), IL-8 (WMD = -2.56 pg/ml; 95% CI: -3.89, -1.23; P < 0.001) and homocysteine (WMD = -1.45 pg/ml; 95% CI: -2.74, -0.17; P = 0.027) levels. There were no significant effects of NAC supplementation on CRP (SMD = -0.1 g/L; 95% CI: -0.52, 0.32; P = 0.647), TNF- α (WMD = -0.2 pg/ml; 95% CI: -0.65, 0.25; P = 0.378) and IL-6 (WMD = -0.41 pg/ml; 95% CI: -1.15, 0.32; P = 0.270) levels. However, NAC effects were significant in ameliorating TNF-α and IL-6 using sensitivity analysis. NAC significantly decreased MDA, IL-8, and homocysteine levels. The effects of NAC on amending TNF-α and IL-6 levels were significant after sensitivity analysis. No significant change was observed on CRP levels.}, }
@article {pmid32724493, year = {2020}, author = {Sun, H and Jiang, Y and Song, Y and Zhang, X and Wang, J and Zhang, J and Kang, J}, title = {The MUC5B Mucin Is Involved in Paraquat-Induced Lung Inflammation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {7028947}, pmid = {32724493}, issn = {1942-0994}, mesh = {Animals ; Disease Models, Animal ; Humans ; Mice ; Mucin-5B/*adverse effects ; Mucins/*adverse effects ; Paraquat/*adverse effects ; Pneumonia/*chemically induced/pathology ; Transfection ; }, abstract = {OBJECTIVE: Paraquat (PQ), a widely used toxic herbicide, induces lung inflammation through mechanisms that remain incompletely understood. In a previous study, we found that the plasma MUC5B mucin level was implicated in PQ poisoning in patients. Here, we hypothesize that MUC5B is a critical mediator in PQ-induced cell inflammation.<br><br>METHODS: A mouse model of PQ-induced lung injury was used to examine the MUC5B expression level. A549 cells (alveolar epithelial cells line) were exposed to PQ in dose-dependent and time-dependent manners. Cell viability was detected by CCK-8 assays. The expression levels of MUC5B were examined by dot blot enzyme-linked immunosorbent assay (ELISA) and RT-qPCR. Western blotting was used to detect the levels of proteins in the MAPK and NF-&#x3ba;B pathways. Inflammatory factors in the cell culture medium were measured by ELISA. NF-&#x3ba;B and MAPK pathway inhibitors and MUC5B siRNA (siMUC5B) were used to determine the function of MUC5B. Finally, N-acetyl-cysteine (NAC) was added and its regulatory effect on the MAPK-NF-&#x3ba;B-MUC5B pathway was examined in PQ-induced cell inflammation.<br><br>RESULTS: MUC5B was significantly upregulated accompanying the increases in TNF-&#x3b1; and IL-6 secretion following PQ treatment in mouse and also in A549 cells after treatment with 50&#x2009;&#x3bc;M PQ at 24 hours. Furthermore, MAPK and NF-&#x3ba;B pathway inhibitors could dramatically decrease the expression of MUC5B and the secretion of TNF-&#x3b1; and IL-6. Importantly, siMUC5B could significantly attenuate the secretion of TNF-&#x3b1; and IL-6 induced by PQ. As expected, the addition of NAC efficiently suppresses the TNF-&#x3b1; and IL-6 secretion stimulated from PQ and also downregulated ERK, JNK, and p65 phosphorylation (ERK/JNK MAPK and NF-&#x3ba;B pathways) as well as MUC5B expression.<br><br>CONCLUSION: Our findings suggest that MUC5B participates in the process of PQ-induced cell inflammation and is downstream of the NF-&#x3ba;B and MAPK pathways. NAC can attenuate PQ-induced cell inflammation at least in part by suppressing the MAPK-NF-&#x3ba;B-MUC5B pathway. These results nominate MUC5B as a new biomarker and therapeutic target for PQ-induced lung inflammation.}, }
@article {pmid32720162, year = {2020}, author = {Ahn, J and Kim, H and Yang, KM}, title = {ω-hydroxyundec-9-enoic acid induction of breast cancer cells apoptosis through generation of mitochondrial ROS and phosphorylation of AMPK.}, journal = {Archives of pharmacal research}, volume = {43}, number = {7}, pages = {735-743}, doi = {10.1007/s12272-020-01254-x}, pmid = {32720162}, issn = {1976-3786}, support = {ATDH_2019//Apple Tree Dental Hospital/ ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms/*drug therapy/metabolism/pathology ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Mitochondria/drug effects/metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/analysis/*metabolism ; Structure-Activity Relationship ; Tumor Cells, Cultured ; Undecylenic Acids/*pharmacology ; }, abstract = {This study was performed to evaluate the anticancer effect of ω-hydroxyundec-9-enoic acid (ω-HUA), a microbial bio-catalyst product in breast cancer cells, through AMP-activated protein kinase (AMPK) regulation. ω-HUA mediated apoptosis was induced in breast cancer cells by AMPK activation, loss of mitochondrial membrane potential, and reactive oxygen species (ROS) generation. ω-HUA treatment of breast cancer cells increased the AMPK phosphorylation levels, cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP) proteins. In addition, anti-apoptotic members, such as Bcl-2, were downregulated, while Bax, a pro-apoptotic member, was upregulated. ω-HUA decreased the mitochondrial membrane potential while increasing the expression of cytochrome c (cyt c). Treating the cells with compound C, an AMPK inhibitor, reversed the phenomena, leading to an increase in cell viability and a decrease in apoptosis induction. Treating the cells with an ROS scavenger, N-acetyl cysteine (NAC), led to AMPK inactivation and apoptosis inhibition, allowing the recovery of cell health. In conclusion, ω-HUA sequentially caused the production of mitochondrial ROS and the consequent AMPK activation, thereby inducing apoptosis in breast cancer cells. Thus, ω-HUA may prove useful as an anticancer agent that targets AMPK in breast cancer cells.}, }
@article {pmid32718084, year = {2020}, author = {Liu, YC and Peng, BR and Hsu, KC and El-Shazly, M and Shih, SP and Lin, TE and Kuo, FW and Chou, YC and Lin, HY and Lu, MC}, title = {13-Acetoxysarcocrassolide Exhibits Cytotoxic Activity Against Oral Cancer Cells Through the Interruption of the Keap1/Nrf2/p62/SQSTM1 Pathway: The Need to Move Beyond Classical Concepts.}, journal = {Marine drugs}, volume = {18}, number = {8}, pages = {}, pmid = {32718084}, issn = {1660-3397}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Diterpenes/*pharmacology ; HCT116 Cells ; HeLa Cells ; Humans ; Kelch-Like ECH-Associated Protein 1/*metabolism ; MCF-7 Cells ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice, Nude ; Mouth Neoplasms/*drug therapy/enzymology/genetics/pathology ; NF-E2-Related Factor 2/*metabolism ; Reactive Oxygen Species/metabolism ; Sequestosome-1 Protein/genetics/*metabolism ; Signal Transduction ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {13-Acetoxysarcocrassolide (13-AC), a marine cytotoxic product isolated from the alcyonacean coral Lobophytum crassum, exhibited potent antitumor and immunostimulant effects as reported in previous studies. However, the 13-AC antitumor mechanism of action against oral cancer cells remains unclear. The activity of 13-AC against Ca9-22 cancer cells was determined using MTT assay, flow cytometric analysis, immunofluorescence, immunoprecipitation, Western blotting, and siRNA. 13-AC induced apoptosis in oral cancer cells Ca9-22 through the disruption of mitochondrial membrane potential (MMP) and the stimulation of reactive oxygen species (ROS) generation. It increased the expression of apoptosis- and DNA damage-related proteins in a concentration- and time-dependent manner. It exerted potent antitumor effect against oral cancer cells, as demonstrated by the in vivo xenograft animal model. It significantly reduced the tumor volume (55.29%) and tumor weight (90.33%). The pretreatment of Ca9-22 cells with N-acetylcysteine (NAC) inhibited ROS production resulting in the attenuation of the cytotoxic activity of 13-AC. The induction of the Keap1-Nrf2 pathway and the promotion of p62/SQSTM1 were observed in Ca9-22 cells treated with 13-AC. The knockdown of p62 expression by siRNA transfection significantly attenuated the effect of 13-AC on the inhibition of cell viability. Our results indicate that 13-AC exerted its cytotoxic activity through the promotion of ROS generation and the suppression of the antioxidant enzyme activity. The apoptotic effect of 13-AC was found to be mediated through the interruption of the Keap1/Nrf2/p62/SQSTM1 pathway, suggesting its potential future application as an anticancer agent.}, }
@article {pmid32717964, year = {2020}, author = {Zhou, J and Terluk, MR and Basso, L and Mishra, UR and Orchard, PJ and Cloyd, JC and Schröder, H and Kartha, RV}, title = {N-acetylcysteine Provides Cytoprotection in Murine Oligodendrocytes through Heme Oxygenase-1 Activity.}, journal = {Biomedicines}, volume = {8}, number = {8}, pages = {}, pmid = {32717964}, issn = {2227-9059}, support = {FRD #09-18//University of Minnesota Office of Vice President of Research Grant-in-Aid award and the University of Minnesota Academic Health Center Faculty Development Grant./ ; }, abstract = {Oligodendrocytic injury by oxidative stress can lead to demyelination, contributing to neurodegeneration. We investigated the mechanisms by which an antioxidant, N-acetylcysteine (NAC), reduces oxidative stress in murine oligodendrocytes. We used normal 158N and mutant 158JP cells with endogenously high reactive oxygen species (ROS) levels. Oxidative stress was induced in 158N cells using hydrogen peroxide (H2O2, 500 μM), and both cells were treated with NAC (50 µM to 500 µM). ROS production, total glutathione (GSH) and cell survival were measured 24 h after treatment. In normal cells, H2O2 treatment resulted in a ~5.5-fold increase in ROS and ~50% cell death. These deleterious effects of oxidative stress were attenuated by NAC, resulting in improved cell survival. Similarly, NAC treatment resulted in decreased ROS levels in 158JP cells. Characterization of mechanisms underlying cytoprotection in both cell lines revealed an increase in GSH levels by NAC, which was partially blocked by an inhibitor of GSH synthesis. Interestingly, we observed heme oxygenase-1 (HO-1), a cytoprotective enzyme, play a critical role in cytoprotection. Inhibition of HO-1 activity abolished the cytoprotective effect of NAC with a corresponding decrease in total antioxidant capacity. Our results indicate that NAC promotes oligodendrocyte survival in oxidative stress-related conditions through multiple pathways.}, }
@article {pmid32715490, year = {2020}, author = {Murata, T and Kohno, S and Ogawa, K and Ito, C and Itoigawa, M and Ito, M and Hikita, K and Kaneda, N}, title = {Cytotoxic activity of dimeric acridone alkaloids derived from Citrus plants towards human leukaemia HL-60 cells.}, journal = {The Journal of pharmacy and pharmacology}, volume = {72}, number = {10}, pages = {1445-1457}, doi = {10.1111/jphp.13327}, pmid = {32715490}, issn = {2042-7158}, support = {19K07092//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; 16K08252//Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; }, mesh = {Acridones/isolation &amp; purification/pharmacology/*therapeutic use ; Alkaloids/isolation &amp; purification/pharmacology/*therapeutic use ; Antineoplastic Agents, Phytogenic/isolation &amp; purification/pharmacology/*therapeutic use ; Cell Survival/drug effects/physiology ; *Citrus paradisi ; Cytotoxins ; Dose-Response Relationship, Drug ; HL-60 Cells ; Humans ; Leukemia/drug therapy/*metabolism ; Plant Extracts/isolation &amp; purification/pharmacology/*therapeutic use ; }, abstract = {OBJECTIVES: Acridone alkaloids from Citrus and their derivatives show various kinds of biological activity. However, the anticancer activities of dimeric acridone alkaloids with unique structures and the molecular mechanism of these effects are poorly understood.<br><br>METHODS: We investigated the cytotoxicity effects of dimeric acridone alkaloids isolated from Marsh grapefruit on human myeloid leukaemia HL-60 cells.<br><br>KEY FINDINGS: Of the six dimeric acridone alkaloids tested, citbismine-E, the most potent, dose- and time-dependently decreased HL-60 cell viability by inducing apoptosis. The treatment of HL-60 cells with citbismine-E yielded a significant increase in levels of intracellular reactive oxygen species (ROS). Citbismine-E lowered the mitochondrial membrane potential and increased the activities of caspase-9 and -3. In addition, citbismine-E-induced apoptosis, decrease in mitochondrial membrane potential and caspase activation were significantly alleviated by pretreatment of the cells with antioxidant N-acetylcysteine (NAC). Citbismine-E induced intrinsic caspase-dependent apoptosis through ROS-mediated c-Jun N-terminal kinase activation. Citbismine-E-induced production of oxidative stress biomarkers, malondialdehyde and 8-hydroxy-2'-deoxyguanosine was also attenuated by pretreatment with NAC.<br><br>CONCLUSIONS: Citbismine-E is a powerful cytotoxic agent against HL-60 cells that acts by inducing mitochondrial dysfunction-mediated apoptosis through ROS-dependent JNK activation. Citbismine-E also induced oxidative stress damage via ROS-mediated lipid peroxidation and DNA damage in HL-60 cells.}, }
@article {pmid32714477, year = {2020}, author = {Mao, XR and Wang, RC and Li, RJ and Zhou, CR and Chen, XK and Cheng, CC and Yin, XM}, title = {An Observational Study: Is N-Acetylcysteine Helpful in Performance Improvement of Mycoplasma IST2 Testing through Sample Homogenization?.}, journal = {The Canadian journal of infectious diseases &amp; medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale}, volume = {2020}, number = {}, pages = {1391698}, pmid = {32714477}, issn = {1712-9532}, abstract = {BACKGROUND: Culture is still the gold standard for the detection of genital mycoplasma which could cause urogenital infections in humans. Mycoplasma IST2 is a commercial kit widely used for the detection of M. hominis and Ureaplasma species. Its accuracy was partially impaired because clinical specimens are usually mixed with purulent or transparent mucus. We aimed to solve this problem through sample homogenization by N-acetylcysteine (NAC) treatment.<br><br>METHODS: Twenty-two endocervical swab samples were collected from 22 female patients with suspected mycoplasma infection, while 11 of these specimens were with purulent or transparent mucus. Mycoplasma IST2 testing kit was used for mycoplasma culture and AST for the control group and NAC-treated group.<br><br>RESULTS: Genital mycoplasma was detected in 15 of 22 samples for both groups. The colony number in 6 out of 11 purulent specimens (54.5%) was more than 10[4]&#x2009;CFU/ml of genital mycoplasma for the NAC-treated group, while only one of 11 (9.1%) for the control group. For the nonpurulent specimens, no significant difference had been found in colony counting of genital mycoplasma between the control group and NAC-treated group (P > 0.05). The results of antimicrobial susceptibility testing for the NAC-treated group were highly similar to those for the control group.<br><br>CONCLUSIONS: Our results demonstrate that NAC is helpful in sample homogenization and NAC treatment can improve the detection efficiency of mycoplasma with Mycoplasma IST2 testing.}, }
@article {pmid32712193, year = {2020}, author = {Linzner, N and Fritsch, VN and Busche, T and Tung, QN and Loi, VV and Bernhardt, J and Kalinowski, J and Antelmann, H}, title = {The plant-derived naphthoquinone lapachol causes an oxidative stress response in Staphylococcus aureus.}, journal = {Free radical biology &amp; medicine}, volume = {158}, number = {}, pages = {126-136}, doi = {10.1016/j.freeradbiomed.2020.07.025}, pmid = {32712193}, issn = {1873-4596}, mesh = {Humans ; Hydrogen Peroxide ; *Methicillin-Resistant Staphylococcus aureus ; *Naphthoquinones/pharmacology ; Oxidation-Reduction ; Oxidative Stress ; Staphylococcus aureus ; }, abstract = {Staphylococcus aureus is a major human pathogen, which causes life-threatening systemic and chronic infections and rapidly acquires resistance to multiple antibiotics. Thus, new antimicrobial compounds are required to combat infections with drug resistant S. aureus isolates. The 2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone lapachol was previously shown to exert antimicrobial effects. In this study, we investigated the antimicrobial mode of action of lapachol in S. aureus using RNAseq transcriptomics, redox biosensor measurements, S-bacillithiolation assays and phenotype analyses of mutants. In the RNA-seq transcriptome, lapachol caused an oxidative and quinone stress response as well as protein damage as revealed by induction of the PerR, HypR, QsrR, MhqR, CtsR and HrcA regulons. Lapachol treatment further resulted in up-regulation of the SigB and GraRS regulons, which is indicative for cell wall and general stress responses. The redox-cycling mode of action of lapachol was supported by an elevated bacillithiol (BSH) redox potential (EBSH), higher endogenous ROS levels, a faster H2O2 detoxification capacity and increased thiol-oxidation of GapDH and the HypR repressor in vivo. The ROS scavenger N-acetyl cysteine and microaerophilic growth conditions improved the survival of lapachol-treated S. aureus cells. Phenotype analyses revealed an involvement of the catalase KatA and the Brx/BSH/YpdA pathway in protection against lapachol-induced ROS-formation in S. aureus. However, no evidence for irreversible protein alkylation and aggregation was found in lapachol-treated S. aureus cells. Thus, the antimicrobial mode of action of lapachol in S. aureus is mainly caused by ROS formation resulting in an oxidative stress response, an oxidative shift of the EBSH and increased protein thiol-oxidation. As ROS-generating compound, lapachol is an attractive alternative antimicrobial to combat multi-resistant S. aureus isolates.}, }
@article {pmid32710722, year = {2020}, author = {Muniroh, M}, title = {Methylmercury-induced pro-inflammatory cytokines activation and its preventive strategy using anti-inflammation N-acetyl-l-cysteine: a mini-review.}, journal = {Reviews on environmental health}, volume = {35}, number = {3}, pages = {233-238}, doi = {10.1515/reveh-2020-0026}, pmid = {32710722}, issn = {2191-0308}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Brain ; Cytokines/*metabolism ; Humans ; Inflammation/chemically induced/*prevention &amp; control ; Methylmercury Compounds/*adverse effects ; Mice ; Rats ; }, abstract = {The exposure of methylmercury (MeHg) has become a public health concern because of its neurotoxic effect. Various neurological symptoms were detected in Minamata disease patients, who got intoxicated by MeHg, including paresthesia, ataxia, gait disturbance, sensory disturbances, tremors, visual, and hearing impairments, indicating that MeHg could pass the blood-brain barrier (BBB) and cause impairment of neurons and other brain cells. Previous studies have reported some expected mechanisms of MeHg-induced neurotoxicity including the neuroinflammation pathway. It was characterized by the up-regulation of numerous pro-inflammatory cytokines expression. Therefore, the use of anti-inflammatories such as N-acetyl-l-cysteine (NAC) may act as a preventive compound to protect the brain from MeHg harmful effects. This mini-review will explain detailed information on MeHg-induced pro-inflammatory cytokines activation as well as possible preventive strategies using anti-inflammation NAC to protect brain cells, particularly in in vivo and in vitro studies.}, }
@article {pmid32707089, year = {2020}, author = {Ibrahim, H and Perl, A and Smith, D and Lewis, T and Kon, Z and Goldenberg, R and Yarta, K and Staniloae, C and Williams, M}, title = {Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine.}, journal = {Clinical immunology (Orlando, Fla.)}, volume = {219}, number = {}, pages = {108544}, pmid = {32707089}, issn = {1521-7035}, support = {R34 AR068052/AR/NIAMS NIH HHS/United States ; R01 AI122176/AI/NIAID NIH HHS/United States ; R34 AI141304/AI/NIAID NIH HHS/United States ; R01 AI072648/AI/NIAID NIH HHS/United States ; U01 AR076092/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Antirheumatic Agents/therapeutic use ; Betacoronavirus/*pathogenicity ; Biomarkers/blood ; C-Reactive Protein/metabolism ; COVID-19 ; Coronavirus Infections/blood/complications/*drug therapy/virology ; Cytokine Release Syndrome/blood/complications/*drug therapy/virology ; Drug Administration Schedule ; Ferritins/blood ; Fibrin Fibrinogen Degradation Products/metabolism ; Glucosephosphate Dehydrogenase Deficiency/blood/complications/*drug therapy/virology ; Humans ; Hydroxychloroquine/therapeutic use ; Inflammation/prevention &amp; control ; Male ; Pandemics ; Pneumonia, Viral/blood/complications/*drug therapy/virology ; SARS-CoV-2 ; Treatment Outcome ; }, abstract = {Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.}, }
@article {pmid32706497, year = {2020}, author = {Yu, SM and Han, Y and Kim, SJ}, title = {Simvastatin abolishes nitric oxide- and reactive oxygen species-induced cyclooxygenase-2 expression by blocking the nuclear factor κB pathway in rabbit articular chondrocytes.}, journal = {Cell biology international}, volume = {44}, number = {10}, pages = {2153-2162}, doi = {10.1002/cbin.11424}, pmid = {32706497}, issn = {1095-8355}, support = {2015R1C1A2A01055015//National Research Foundation/ ; 2017R1D1A3B03033401//National Research Foundation/ ; 2018R1D1A1B07051064//National Research Foundation/ ; }, mesh = {Animals ; Cells, Cultured ; Chondrocytes ; Cyclooxygenase 2/*metabolism ; Interleukin-1beta/pharmacology ; NF-kappa B/*metabolism ; Nitric Oxide/metabolism ; Nitroprusside/pharmacology ; Osteoarthritis/chemically induced/*drug therapy ; Rabbits ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Simvastatin/*pharmacology ; }, abstract = {Nitric oxide (NO) and reactive oxygen species (ROS) have been shown to be linked with numerous diseases, including osteoarthritis (OA). Our study aimed to examine the effect of simvastatin on NO- or ROS-induced cyclooxygenase-2 (COX-2) expression in OA. Simvastatin has attracted considerable attention since the discovery of its pharmacological effects on different pathogenic processes, including inflammation. Here, we report that simvastatin treatment blocked sodium nitroprusside (SNP)- and interleukin 1 beta (IL-1β)-induced COX-2 production. In addition, simvastatin attenuated SNP-induced NO production and IL-1β-induced ROS generation. Treatment with simvastatin prevented SNP- and IL-1β-induced nuclear factor kappa B (NF-κB) activity. Inhibiting NO production and ROS generation using N-acetylcysteine (NAC) and NG-monomethyl- l-arginine (l-NMMA), respectively, accelerated the influence of simvastatin on NF-κB activity. In addition, NAC blocked SNP and simvastatin-mediated COX-2 production and NF-κB activity but did not alter IL-1β and simvastatin-mediated COX-2 expression. l-NMMA treatment also abolished IL-1β-mediated COX-2 expression and NF-κB activation, whereas SNP and simvastatin-mediated COX-2 expression were not altered compared with the levels in the SNP and simvastatin-treated cells. Our findings suggested that simvastatin blocks COX-2 expression by inhibiting SNP-induced NO production and IL-1β-induced ROS generation by blocking the NF-κB pathway.}, }
@article {pmid32705225, year = {2020}, author = {An, K and Zhang, Y and Liu, Y and Yan, S and Hou, Z and Cao, M and Liu, G and Dong, C and Gao, J and Liu, G}, title = {Neferine induces apoptosis by modulating the ROS‑mediated JNK pathway in esophageal squamous cell carcinoma.}, journal = {Oncology reports}, volume = {44}, number = {3}, pages = {1116-1126}, pmid = {32705225}, issn = {1791-2431}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Benzylisoquinolines/*pharmacology/therapeutic use ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Esophageal Neoplasms/*drug therapy/pathology ; Esophageal Squamous Cell Carcinoma/*drug therapy/pathology ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; MAP Kinase Signaling System/drug effects ; NF-E2-Related Factor 2/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Current treatments for esophageal squamous cell carcinoma (ESCC) have limited efficacy. Therefore, the development of novel therapeutic targets to effectively manage the disease and boost survival rates is imperative Neferine, a natural product extracted from Nelumbo nucifera (lotus) leaves, has been revealed to inhibit the growth of hepatocarcinoma, breast cancer and lung cancer cells. However, its effect on ESCC is unknown. In the present study, it was revealed that neferine exerted anti‑proliferative effects in ESCC. It was also revealed that it triggered arrest of the G2/M phase and enhanced apoptosis of ESCC cell lines. Moreover, its ability to trigger accumulation of reactive oxygen species (ROS) and activate the c‑Jun N‑terminal kinase (JNK) pathway was demonstrated. Further study revealed how N‑acetyl cysteine (NAC), a ROS inhibitor, attenuated these effects, demonstrating that ROS and JNK inhibitors mediated a marked reversal of neferine‑triggered cell cycle arrest and apoptosis in ESCC cells. Finally, it was revealed that neferine was involved in the inhibition of Nrf2, an antioxidant factor. Collectively, these findings demonstrated the antitumor effect of neferine in ESCC, through the ROS‑mediated JNK pathway and inhibition of Nrf2, indicating its potential as a target for development of novel and effective therapeutic agents against ESCC.}, }
@article {pmid32704565, year = {2020}, author = {Moheet, A and Kumar, A and Zhang, Y and Eberly, L and Coles, LD and Seaquist, ER}, title = {Infusion of N-acetyl cysteine during hypoglycaemia in humans does not preserve the counterregulatory response to subsequent hypoglycaemia.}, journal = {Endocrinology, diabetes &amp; metabolism}, volume = {3}, number = {3}, pages = {e00144}, pmid = {32704565}, issn = {2398-9238}, support = {P30 DK020593/DK/NIDDK NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; }, abstract = {AIM: Administration of N-acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans.<br><br>METHODS: This was a randomized double-blind cross over study where humans were given either a 60-minute infusion of NAC (150&#xa0;mg/kg) followed by a 4-hour infusion of NAC (50&#xa0;mg/kg) or saline starting 30&#xa0;minutes before the initiation of a 2-hour hypoglycaemic (HG) clamp at 8&#xa0;am. After rest at euglycaemia for ~2&#xa0;hours, subjects were exposed to a 2nd HG clamp at 2&#xa0;pm and discharged home in euglycaemia. They returned the following day for a 3rd HG clamp at 8&#xa0;am.<br><br>RESULTS: Twenty-two subjects were enrolled. Eighteen subjects completed the entire protocol. The epinephrine response during clamp 3 (171&#xa0;&#xb1;&#xa0;247&#xa0;pg/mL) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (538&#xa0;&#xb1;&#xa0;392&#xa0;pg/mL) (clamp 3 to clamp 1 NAC: P&#xa0;=&#xa0;.0013). The symptom response during clamp 3 (7&#xa0;&#xb1;&#xa0;5) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (16&#xa0;&#xb1;&#xa0;10) (clamp 3 to clamp 1 NAC: P&#xa0;=&#xa0;.0003). Nine subjects experienced rash, pruritus or nausea during NAC infusion.<br><br>CONCLUSION: We found no difference in the hormone and symptom response to experimental hypoglycaemia measured in subjects who were administered NAC as opposed to saline the day before. This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted.}, }
@article {pmid32704009, year = {2020}, author = {Mitchell, EJ and Thomson, DM and Openshaw, RL and Bristow, GC and Dawson, N and Pratt, JA and Morris, BJ}, title = {Drug-responsive autism phenotypes in the 16p11.2 deletion mouse model: a central role for gene-environment interactions.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {12303}, pmid = {32704009}, issn = {2045-2322}, support = {MR/N012704/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Anxiety/genetics ; Autistic Disorder/*drug therapy/*genetics/physiopathology ; *Chromosome Deletion ; Chromosomes, Mammalian/*genetics ; Disease Models, Animal ; *Gene-Environment Interaction ; Humans ; Male ; Mice, Inbred C57BL ; Motor Activity ; Phenotype ; Social Behavior ; Social Interaction ; }, abstract = {There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment.}, }
@article {pmid32703189, year = {2020}, author = {Al-Khayal, K and Vaali-Mohammed, MA and Elwatidy, M and Bin Traiki, T and Al-Obeed, O and Azam, M and Khan, Z and Abdulla, M and Ahmad, R}, title = {A novel coordination complex of platinum (PT) induces cell death in colorectal cancer by altering redox balance and modulating MAPK pathway.}, journal = {BMC cancer}, volume = {20}, number = {1}, pages = {685}, pmid = {32703189}, issn = {1471-2407}, mesh = {Annexin A5/analysis ; Apoptosis/drug effects/genetics ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Cycle/drug effects ; *Cell Death ; Cell Line, Tumor ; Cell Proliferation ; Colorectal Neoplasms/chemistry/*drug therapy/enzymology/pathology ; Cyclins/metabolism ; Down-Regulation ; Glutathione/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinases/*metabolism ; Oxidation-Reduction ; Platinum Compounds/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Stem Cell Assay ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; bcl-X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {BACKGROUND: Colorectal cancer (CRC) is a heterogeneous tumor having various genetic alterations. The current treatment options had limited impact on disease free survival due to therapeutic resistance. Novel anticancer agents are needed to treat CRC specifically metastatic colorectal cancer. A novel coordination complex of platinum, (salicylaldiminato)Pt(II) complex with dimethylpropylene linkage (PT) exhibited potential anti-cancer activity. In this study, we explored the molecular mechanism of PT-induced cell death in colorectal cancer.<br><br>METHODS: Colony formation was evaluated using the clonogenic assay. Apoptosis, cell cycle analysis, reactive oxygen species, mitochondrial membrane potential and caspase-3/-&#x2009;7 were assessed by flow cytometry. Glutathione level was detected by colorimetric assay. PT-induced alteration in pro-apoptotic/ anti-apoptotic proteins and other signaling pathways were investigated using western blotting. P38 downregulation was performed using siRNA.<br><br>RESULTS: In the present study, we explored the molecular mechanism of PT-mediated inhibition of cell proliferation in colorectal cancer cells. PT significantly inhibited the colony formation in human colorectal cancer cell lines (HT-29, SW480 and SW620) by inducing apoptosis and necrosis. This platinum complex was shown to significantly increase the reactive oxygen species (ROS) generation, depletion of glutathione and reduced mitochondrial membrane potential in colorectal cancer cells. Exposure to PT resulted in the downregulation of anti-apoptotic proteins (Bcl2, BclxL, XIAP) and alteration in Cyclins expression. Furthermore, PT increased cytochrome c release into cytosol and enhanced PARP cleavage leading to activation of intrinsic apoptotic pathway. Moreover, pre-treatment with ROS scavenger N-acetylcysteine (NAC) attenuated apoptosis suggesting that PT-induced apoptosis was driven by oxidative stress. Additionally, we show that PT-induced apoptosis was mediated by activating p38 MAPK and inhibiting AKT pathways. This was demonstrated by using chemical inhibitor and siRNA against p38 kinase which blocked the cytochrome c release and apoptosis in colorectal cancer cells.<br><br>CONCLUSION: Collectively, our data demonstrates that the platinum complex (PT) exerts its anti-proliferative effect on CRC by ROS-mediated apoptosis and activating p38 MAPK pathway. Thus, our findings reveal a novel mechanism of action for PT on colorectal cancer cells and may have therapeutic implication.}, }
@article {pmid32699265, year = {2021}, author = {Li, ZJ and Dai, HQ and Huang, XW and Feng, J and Deng, JH and Wang, ZX and Yang, XM and Liu, YJ and Wu, Y and Chen, PH and Shi, H and Wang, JG and Zhou, J and Lu, GD}, title = {Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma.}, journal = {Acta pharmacologica Sinica}, volume = {42}, number = {2}, pages = {301-310}, pmid = {32699265}, issn = {1745-7254}, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/pharmacology ; Artesunate/administration &amp; dosage/*pharmacology ; Carcinoma, Hepatocellular/*drug therapy/pathology ; Cell Line, Tumor ; Drug Synergism ; Ferroptosis/drug effects ; Humans ; Lipid Peroxidation/drug effects ; Liver Neoplasms/*drug therapy/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Oxidative Stress/drug effects ; Sorafenib/administration &amp; dosage/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination strategy to increase sorafenib efficacy. Artesunate is such a preferred candidate, because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms. In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms. We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7, SNU-449, and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice. The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic. Compared with the treatment with artesunate or sorafenib alone, combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis, which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate, but not by inhibitors of other types of cell death (z-VAD, necrostatin-1 and belnacasan). In Huh7 cells, we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy, two essential aspects of ferroptosis. Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in HCC treatment. The combined treatment can be easily translated into clinical applications.}, }
@article {pmid32695685, year = {2020}, author = {Shenoi, SD and Soman, S and Munoli, R and Prabhu, S}, title = {Update on Pharmacotherapy in Psychodermatological Disorders.}, journal = {Indian dermatology online journal}, volume = {11}, number = {3}, pages = {307-318}, pmid = {32695685}, issn = {2229-5178}, abstract = {Psychodermatological (PD) conditions encountered in dermatologic practice include primary psychiatric conditions such as delusions of parasitosis or secondary psychiatric conditions such as anxiety and depression due to dermatologic disease. The psychotropics include antipsychotic agents, anti-anxiety agents, antidepressants, and miscellaneous drugs such as anti convulsants. Anti psychotics are further divided into first-generation and second-generation drugs. Currently, second-generation drugs e.g., risperidone are preferred over first-generation drugs e.g., pimozide in delusional infestation owing to the side effect profile of the latter. Anti-anxiety agents include benzodiazepines used in acute anxiety and buspirone in chronic anxiety disorders. They are frequently prescribed along with antidepressants. Although dependence and necessity of tapering is a problem with benzodiazepines, delayed onset of action is a feature of buspirone. The commonly used antidepressants in dermatology include selective serotonin reuptake inhibitors (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), selective serotonin norepinephrine reuptake inhibitors (venlafaxine, desvenlefaxine, and duloxetine), norepinephrine dopamine reuptake inhibitors (bupropion), tricyclic antidepressants (doxepin, amitriptyline, imipramine, and clomipramine), and tetracyclic antidepressants (mirtazapine). Miscellaneous drugs include anticonvulsants such as gabapentin and pregabalin, naltrexone, and N-acetyl cysteine. The principles of PD treatment are first establish the psychiatric diagnosis, followed by initiating drug treatment. The choice of drugs is dependent on multiple factors such as side-effect profile, drug interactions, and co-morbid conditions. Usually, drugs are started at a low dose and gradually increased. A literature search was done in Pubmed, Google Scholar, and Medline databases, and articles on treatment were analyzed.}, }
@article {pmid32691990, year = {2020}, author = {Zhan, Y and Guo, Z and Zheng, F and Zhang, Z and Li, K and Wang, Q and Wang, L and Cai, Z and Chen, N and Wu, S and Li, H}, title = {Reactive oxygen species regulate miR-17-5p expression via DNA methylation in paraquat-induced nerve cell damage.}, journal = {Environmental toxicology}, volume = {35}, number = {12}, pages = {1364-1373}, doi = {10.1002/tox.23001}, pmid = {32691990}, issn = {1522-7278}, support = {2017Y9105//The Joint Funds for the innovation of science and Technology, Fujian province/ ; 81573195//The National Natural Science Foundation of China/ ; 81903352//The National Natural Science Foundation of China/ ; 81973083//The National Natural Science Foundation of China/ ; 2017J01523//The Provincial Natural Science Foundation in Fujian/ ; //National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Culture Techniques ; Cell Line, Tumor ; DNA Methylation/*drug effects/genetics ; Decitabine/pharmacology ; Dose-Response Relationship, Drug ; Down-Regulation ; Mice ; MicroRNAs/*genetics ; Neurons/*drug effects/metabolism/pathology ; Oxidative Stress/*drug effects/genetics ; Paraquat/*toxicity ; Reactive Oxygen Species/*metabolism ; Up-Regulation ; }, abstract = {There is emerging evidence suggesting that oxidative stress and DNA methylation can alter miRNA expression. However, little is known on the mechanism of miR-17-5p expression changes in paraquat (PQ)-induced nerve cell damage. In the present study, neuro-2a cells were pretreated with antioxidant N-acetylcysteine (NAC) or DNA methylation inhibitor decitabine (DAC), then exposed to different concentrations of PQ, while the expression levels of miR-17-5p were detected by qRT-PCR. Here, it is showed that PQ downregulated the expression of miR-17-5p dose-dependently in neuro-2a cells. The DNA methylation level was upregulated after PQ exposure, while downregulated with the pretreatment of NAC in the above content, detected by 5-mC immunofluorescence technique. The interaction effect of NAC and PQ in alternating DNA methylation level was further confirmed by flow cytometry. NAC and DAC individually had an interaction effect in PQ-induced nerve cell damage. After using NAC, PQ-induced ROS elevation and DNA methylation are reduced, thereby preventing the proapoptotic effect of miR-17-5p. Above all, PQ can induce DNA methylation variations through ROS production, leading to the downregulation of miR-17-5p expression in PQ-induced nerve cell damage.}, }
@article {pmid32687961, year = {2020}, author = {Lee, DC and Choi, H and Oh, JM and Lee, J and Lee, J and Lee, HY and Kang, JY}, title = {Urban particulate matter regulates tight junction proteins by inducing oxidative stress via the Akt signal pathway in human nasal epithelial cells.}, journal = {Toxicology letters}, volume = {333}, number = {}, pages = {33-41}, doi = {10.1016/j.toxlet.2020.07.017}, pmid = {32687961}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Cytokines/genetics/metabolism ; Epithelial Cells/*drug effects/metabolism ; Female ; Gene Expression Regulation/*drug effects ; Humans ; Male ; Middle Aged ; Nasal Mucosa/*drug effects/metabolism ; Oxidative Stress/*drug effects/genetics ; Particulate Matter/*toxicity ; Proto-Oncogene Proteins c-akt/*metabolism ; Signal Transduction ; Tight Junction Proteins/genetics/*metabolism ; Tight Junctions/drug effects/metabolism ; Turbinates/drug effects/metabolism ; Urbanization ; }, abstract = {Recent studies have revealed that increased reactive oxidative stress (ROS) induced by particulate matter (PM) affects tight junction (TJ) functions; however, the molecular mechanisms underlying this effect have not been evaluated fully. Cultured human epithelial cells obtained from inferior turbinate tissues were exposed to an urban PM (UPM) standard reference material (SRM 1648a). Intracellular ROS level and expression of proinflammatory cytokines and TJ proteins were examined. Expression level of phosphorylated (p)-Akt, p38, p65 were compared between exposed and unexposed cells. Cells were pretreated with the ROS scavenger N-acetylcysteine (NAC) or Akt inhibitor MK-2206 before exposure to determine whether the changes in cellular ROS and TJ protein expression could be reversed. Exposure to UPM significantly increased ROS levels and inflammatory cytokine expression levels, and decreased expression of TJ proteins zonula occludins (ZO)-1, occludin, claudin-1, and E-cadherin. UPM exposure increased p-Akt, p-p38, and p65 expression levels, and NAC pretreatment reversed these effects. Akt inhibition decreased UPM-induced ROS formation and p38 and p65 protein phosphorylation, and restored the decreased ZO-1 and E-cadherin expression. Akt inhibition and ROS scavenging may provide targets for maintaining epithelial integrity by restoring decreased TJ protein expression during exposure to UPM.}, }
@article {pmid32684991, year = {2020}, author = {Kale, M and Srivastava, RK and Athar, M and Banga, AK}, title = {Topical delivery of nordihydroguaretic acid for attenuating cutaneous damage caused by arsenicals.}, journal = {Journal of drug delivery science and technology}, volume = {58}, number = {}, pages = {}, pmid = {32684991}, issn = {1773-2247}, support = {P30 CA013148/CA/NCI NIH HHS/United States ; U01 NS095678/NS/NINDS NIH HHS/United States ; }, abstract = {This study evaluated the topical delivery of nordihydroguaretic acid (NDGA), a molecule that can potentially alleviate cutaneous damage caused by exposure to arsenic warfare chemicals. N-acetylcysteine (NAC 0.2% w/v) was added as an antioxidant, preventing the oxidation of NDGA to toxic quinones. A 24 h study was performed to arrive at a minimum concentration of NDGA needed to deliver maximum drug. A solution of 3% w/v delivered the maximum amount of drug at the end of 24 h (37.45 ± 4.32 μg). Short duration studies were carried out to determine the time needed to saturate skin with NDGA. There was no significant difference in the skin concentrations for 24 h and 8 h (14.89 ± 2.36 μg), due to skin saturation. However, there was significant difference in the amount of drug delivered to the epidermis (12.29 ± 1.87 μg) and dermis (2.54 ± 0.56 μg) at the end of 8 h. Solution of NDGA was applied on UV treated skin to assess changes in drug delivery. In vivo studies revealed that 3% NDGA was non-toxic for topical administration.}, }
@article {pmid32684241, year = {2020}, author = {Hwang, S and Kim, S and Kim, K and Yeom, J and Park, S and Kim, I}, title = {Euchromatin histone methyltransferase II (EHMT2) regulates the expression of ras-related GTP binding C (RRAGC) protein.}, journal = {BMB reports}, volume = {53}, number = {11}, pages = {576-581}, pmid = {32684241}, issn = {1976-670X}, mesh = {Apoptosis/genetics ; Azepines/pharmacology ; Carcinoma, Hepatocellular/genetics/metabolism ; Cell Line, Tumor ; Cell Proliferation/genetics ; Chromatin Immunoprecipitation/methods ; Euchromatin/genetics ; Gene Expression/genetics ; Gene Expression Regulation/drug effects/genetics ; Histocompatibility Antigens/*metabolism/physiology ; Histone Methyltransferases/genetics/metabolism ; Histone-Lysine N-Methyltransferase/genetics/*metabolism/physiology ; Histones/genetics/metabolism ; Humans ; Liver Neoplasms/genetics/metabolism ; Monomeric GTP-Binding Proteins/*metabolism/physiology ; Proteomics ; Quinazolines/pharmacology ; Reactive Oxygen Species/metabolism ; Stress, Physiological/genetics ; Transcriptome/genetics ; }, abstract = {Dimethylation of the histone H3 protein at lysine residue 9 (H3K9) is mediated by euchromatin histone methyltransferase II (EHMT2) and results in transcriptional repression of target genes. Recently, chemical inhibition of EHMT2 was shown to induce various physiological outcomes, including endoplasmic reticulum stress-associated genes transcription in cancer cells. To identify genes that are transcriptionally repressed by EHMT2 during apoptosis, and cell stress responses, we screened genes that are upregulated by BIX-01294, a chemical inhibitor of EHMT2. RNA sequencing analyses revealed 77 genes that were upregulated by BIX-01294 in all four hepatic cell carcinoma (HCC) cell lines. These included genes that have been implicated in apoptosis, the unfolded protein response (UPR), and others. Among these genes, the one encoding the stress-response protein Ras-related GTPase C (RRAGC) was upregulated in all BIX-01294-treated HCC cell lines. We confirmed the regulatory roles of EHMT2 in RRAGC expression in HCC cell lines using proteomic analyses, chromatin immune precipitation (ChIP) assay, and small guide RNA-mediated loss-of-function experiments. Upregulation of RRAGC was limited by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), suggesting that ROS are involved in EHMT2-mediated transcriptional regulation of stress-response genes in HCC cells. Finally, combined treatment of cells with BIX-01294 and 5- Aza-cytidine induced greater upregulation of RRAGC protein expression. These findings suggest that EHMT2 suppresses expression of the RRAGC gene in a ROS-dependent manner and imply that EHMT2 is a key regulator of stress-responsive gene expression in liver cancer cells. [BMB Reports 2020; 53(11): 576-581].}, }
@article {pmid32683294, year = {2020}, author = {Liu, Y and Tang, J and Yuan, J and Yao, C and Hosoi, K and Han, Y and Yu, S and Wei, H and Chen, G}, title = {Arsenite-induced downregulation of occludin in mouse lungs and BEAS-2B cells via the ROS/ERK/ELK1/MLCK and ROS/p38 MAPK signaling pathways.}, journal = {Toxicology letters}, volume = {332}, number = {}, pages = {146-154}, doi = {10.1016/j.toxlet.2020.07.010}, pmid = {32683294}, issn = {1879-3169}, mesh = {Animals ; Arsenites/*toxicity ; Cell Line ; Down-Regulation/drug effects ; Glutathione/metabolism ; Humans ; Lung/drug effects/*metabolism ; MAP Kinase Signaling System/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Occludin/*biosynthesis/drug effects ; Oxidative Stress/drug effects ; Peptides/drug effects/metabolism ; Reactive Oxygen Species ; Signal Transduction/*drug effects ; Superoxide Dismutase/metabolism ; p38 Mitogen-Activated Protein Kinases/drug effects ; }, abstract = {Occludin is an important tight junction (TJ) protein in pulmonary epithelial cells. In this study, we identified changes in occludin in arsenic-induced lung injury in vivo and in vitro. Upon intratracheal instillation with arsenic trioxide (As2O3) at a daily dose of 30 μg/kg for 1 week, levels of occludin mRNA and protein expression decreased significantly in mouse lung tissue. Levels of occludin mRNA and protein expression in BEAS-2B cells were reduced upon exposure to As2O3 in a concentration- and time-dependent manner. In addition, exposure to As2O3 significantly increased expression of p-p38, p-ERK1/2, p-ELK1, and MLCK in mouse lung tissue and BEAS-2B cells. Treatment with As2O3 induced oxidative stress in mouse lung tissue and BEAS-2B cells. In BEAS-2B cells, exposure to As2O3 reduced transepithelial resistance, which was partially restored with N-acetyl-cysteine (NAC) treatment. Reduced expression of occludin mRNA and protein induced by As2O3 was entirely restored with NAC and resveratrol. However, SB203580, PD98059, and ML-7 partially blocked As2O3-induced occludin reduction in BEAS-2B cells. These results indicate that As2O3 inhibits occludin expression in vivo and in vitro at least partially via the ROS/ERK/ELK1/MLCK and ROS/p38 MAPK signaling pathways.}, }
@article {pmid32681471, year = {2020}, author = {Shi, L and Liu, BY and Wang, X and Zhu, MJ and Chen, L and Zhou, MY and Gu, YJ and Cheng, L and Wang, Y}, title = {RUNX3-dependent oxidative epithelial-to-mesenchymal transition in methamphetamine-induced chronic lung injury.}, journal = {Cell stress &amp; chaperones}, volume = {25}, number = {5}, pages = {793-802}, pmid = {32681471}, issn = {1466-1268}, mesh = {A549 Cells ; Alveolar Epithelial Cells/*drug effects ; Animals ; Chronic Disease ; Core Binding Factor Alpha 3 Subunit/*physiology ; *Epithelial-Mesenchymal Transition ; Humans ; Lung/metabolism/pathology ; Lung Injury/*chemically induced ; Male ; Methamphetamine/*toxicity ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {Lung toxicity is the main cause of the death from methamphetamine (MA) abuse, but its mechanism has remained unclear. The purpose of our study was to investigate if MA can induce epithelial-to-mesenchymal transition (EMT) and if RUNX3 is involved in oxidative EMT in MA-induced chronic lung injury. The rats were divided into the control group and MA group. Extracted lungs were used for morphological measurements and Western blot. The alveolar epithelial cells were cultured or transfected and then treated with MA or/and N-acetyl cysteine (NAC) followed by flow cytometry, Western blot, and immunohistochemistry. Chronic exposure to MA resulted in the lower growth ratio of weight, increased right ventricular index, thickened alveolar walls, and reduced number of alveolar sacs. Long-term administration with MA caused oxidative stress and pulmonary EMT. NAC increased RUNX3 and alleviated EMT. However, after knockdown of RUNX3, reactive oxygen species (ROS) levels were significantly upregulated, indicating that RUNX3 was closely related to oxidative stress. Knockdown of RUNX3 aggravated MA-induced EMT by activating RUNX3-dependent TGF-β signaling. Therefore, RUNX3 may be the key to oxidative EMT in methamphetamine-induced chronic lung injury.}, }
@article {pmid32676884, year = {2020}, author = {Chunchai, T and Keawtep, P and Arinno, A and Saiyasit, N and Prus, D and Apaijai, N and Pratchayasakul, W and Chattipakorn, N and Chattipakorn, SC}, title = {A combination of an antioxidant with a prebiotic exerts greater efficacy than either as a monotherapy on cognitive improvement in castrated-obese male rats.}, journal = {Metabolic brain disease}, volume = {35}, number = {8}, pages = {1263-1278}, doi = {10.1007/s11011-020-00603-5}, pmid = {32676884}, issn = {1573-7365}, mesh = {Animals ; Antioxidants/*administration &amp; dosage ; Cognitive Dysfunction/blood/*drug therapy/psychology ; Diet, High-Fat/adverse effects ; Drug Therapy, Combination ; Male ; Maze Learning/drug effects/physiology ; Obesity/blood/*drug therapy/psychology ; Orchiectomy/*adverse effects/trends ; Prebiotics/*administration &amp; dosage ; Rats ; Rats, Wistar ; Testosterone/administration &amp; dosage/blood ; Treatment Outcome ; }, abstract = {Previous studies by ourselves and others have demonstrated that both obesity and testosterone deprivation have been related to cognitive decline. We have also shown that a prebiotic and n-acetyl cysteine (NAC) improved cognitive dysfunction in obese rats and castrated-male rats. However, the effects of NAC, a prebiotic (inulin), and a combination of the two on cognition in castrated-obese rats has never been investigated. The hypothesis was that NAC and inulin attenuated cognitive decline in castrated-obese rats by improving gut dysbiosis, and decreasing oxidative stress, glial activation and apoptosis. Male Wistar rats (n = 36) were fed with either a normal diet (ND: n = 6) or a high-fat diet (HFD: n = 30) for twenty-eight weeks. The resultant obese rats had a bilateral orchiectomy (ORX) and were randomly divided into five subgroups (n = 6/ subgroup). Each subgroup was treated with one of five therapies: a vehicle; testosterone replacement (2 mg/kg/day); NAC (100 mg/kg); inulin (10%, w/w), or a combination of the NAC and inulin for four weeks. The results demonstrated that castrated-obese rats developed gut dysbiosis, metabolic disturbance, brain pathologies, and cognitive decline. All of the pathological conditions in the brain were ameliorated to an equal extent by testosterone replacement, NAC, and inulin supplementation. Interestingly, a combination of NAC and inulin had the greatest beneficial effect on cognitive function by synergistically reducing hippocampal inflammation and ameliorating glial dysmorphology. These findings suggest that a combination of NAC and inulin may confer the greatest benefits in improving cognitive function in castrated-obese male rats.}, }
@article {pmid32675293, year = {2020}, author = {Wu, W and Yuan, J and Shen, Y and Yu, Y and Chen, X and Zhang, L and Huang, K and Zhan, J and Dong, GP and Fu, J}, title = {Iron overload is related to elevated blood glucose levels in obese children and aggravates high glucose-induced endothelial cell dysfunction in vitro.}, journal = {BMJ open diabetes research &amp; care}, volume = {8}, number = {1}, pages = {}, pmid = {32675293}, issn = {2052-4897}, mesh = {*Blood Glucose ; Carotid Intima-Media Thickness ; Child ; Endothelial Cells ; Humans ; *Iron Overload ; Obesity ; }, abstract = {INTRODUCTION: This study was performed to investigate the role of iron overload in the early stage of hyperglycemia-induced vascular functional impairment.<br><br>RESEARCH DESIGN AND METHODS: A total of 196 obese children were enrolled, and data regarding ferritin levels, blood glucose levels, intima-media thickness of carotid arteries, liver function and fibrosis index, hemoglobin, blood pressure, blood lipids, and inflammation indicators were collected. Ferritin levels were compared with a control group, which consisted of 148 healthy non-obese children who were age-matched and gender-matched. Endothelial cells were cultured in high glucose medium and supplemented with ferric citrate with or without iron remover (deferoxamine), a reducing agent (N-acetyl-cysteine), or a nuclear factor-&#x3ba;B (NF-&#x3ba;B) inhibitor (BAY 11-7082). Apoptosis, oxidative stress, nitric oxide levels, and endothelin content were evaluated. DNA microarray analysis was performed to analyze the expression of genes in the NF-&#x3ba;B signaling pathway.<br><br>RESULTS: Obese children have significantly higher ferritin levels compared with the control group. Ferritin level was positively correlated with hemoglobin and was related to metabolic disorders, including impaired glucose tolerance, higher blood pressure, dyslipidemia, and impaired hepatic function. Endothelial cells treated with ferric citrate showed a significantly higher rate of apoptosis, higher levels of oxidative stress, and impaired vasomotor function under high glucose conditions. The above effects were rescued by treatment with an iron remover, reducing agent, or NF-&#x3ba;B inhibitor. Further, detection of phosphorylated-p65 distribution in cells confirmed activation of the NF-&#x3ba;B pathway. DNA microarrays and subsequent gene oncology enrichment analyses revealed the main processes activated in cells.<br><br>CONCLUSION: Increased ferritin levels are related to impaired glucose tolerance and other metabolic disorders in obese children. At the cellular level, iron overload aggravated the endothelial cell dysfunction caused by high glucose.}, }
@article {pmid32671705, year = {2020}, author = {Oliveira, VA and de Souza da Costa, N and Mesquita, M and Pedroso, TF and da Luz Fiuza, T and Peixoto, NC and Pereira, ME and Oliveira, CS}, title = {Mercury toxicity in pregnant and lactating rats: zinc and N-acetylcysteine as alternative of prevention.}, journal = {Environmental science and pollution research international}, volume = {27}, number = {32}, pages = {40563-40572}, pmid = {32671705}, issn = {1614-7499}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Female ; Kidney ; Lactation ; Liver ; Mercuric Chloride/toxicity ; *Mercury/toxicity ; Porphobilinogen Synthase ; Pregnancy ; Rats ; Zinc ; }, abstract = {This study evaluated the toxic effects of inorganic mercury (Hg) in pregnant and lactating rats, as well as the possible protective effect of zinc (Zn) and N-acetylcysteine (NAC). Pregnant and lactating rats were pre-treated with ZnCl2 (27 mg/kg) and/or NAC (5 mg/kg) and after 24 h, they were exposed to HgCl2 (10 mg/kg). Animals were sacrificed 24 h after Hg exposure, and biochemical tests and metal determination were performed. Regarding pregnant rats, Hg exposure caused kidney, blood, and placenta δ-aminolevulinic acid dehydratase (δ-ALA-D) activity inhibition, and the pre-treatments showed a tendency of protection. Moreover, all the animals exposed to Hg presented high Hg levels in the kidney, liver, and placenta when compared with control group. Pregnant rats pre-exposed to Zn (Zn-Hg and Zn/NAC-Hg groups) presented an increase in hepatic metallothionein levels. Therefore, lactating rats exposed to Hg presented renal and blood δ-ALA-D inhibition; the pre-treatments showed a tendency to prevent the renal δ-ALA-D inhibition and prevented the blood δ-ALA-D inhibition caused by Hg. Lactating rats exposed to Hg presented high Hg levels in the kidney and liver. These results showed that 10 mg/kg of HgCl2 causes biochemistry alterations in pregnant and lactating rats, and Zn and NAC present promising results against these damages.}, }
@article {pmid32671444, year = {2020}, author = {Yang, D and Guo, Q and Liang, Y and Zhao, Y and Tian, X and Ye, Y and Tian, J and Wu, T and Lu, N}, title = {Wogonin induces cellular senescence in breast cancer via suppressing TXNRD2 expression.}, journal = {Archives of toxicology}, volume = {94}, number = {10}, pages = {3433-3447}, doi = {10.1007/s00204-020-02842-y}, pmid = {32671444}, issn = {1432-0738}, mesh = {Animals ; Breast Neoplasms/*drug therapy ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/*drug effects ; Female ; Flavanones/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; NF-kappa B/metabolism ; Neoplasm Transplantation ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Thioredoxin Reductase 2/*genetics ; }, abstract = {Cellular senescence contributes to tumor regression through both cell autonomous and non-autonomous mechanisms. Drugs inducing cancer cell senescence and modulating senescence-associated secretory phenotype (SASP) render advantage to the cancer treatment. Breast cancer remains the second most cause of female cancer mortality, among which triple-negative breast cancer (TNBC) has a more aggressive clinical course. Our study showed that in TNBC cell lines including MDA-MB-231 and 4T1 cells, moderate concentrations of wogonin (5, 7-dihydroxy-8-methoxy-2-phenyl-4h-1-benzopyran-4-one) (50-100 μM) not only induced permanent proliferation inhibition, but also increased P16 expression, β-galactosidase activity, senescence-associated heterochromatin foci and SASP, which are the typical characteristics of cellular senescence. Moreover, results showed that wogonin-induced senescence was partially attributed to the reactive oxygen species (ROS) accumulation upon wogonin treatment in MDA-MB-231 cells, since elimination of ROS by N-acetylcysteine (NAC) was able to repress wogonin-induced β-galactosidase activity. Mechanistically, wogonin reduced the expression of TXNRD2, an important antioxidant enzyme in controlling the levels of cellular ROS, by altering the histone acetylation at its regulatory region. In addition, senescent MDA-MB-231 cells induced by wogonin exhibited activated NF-κB and suppressed STAT3, which were recognized as regulators of SASP. SASP from these senescent cells suppressed tumor cell growth, promoted macrophage M1 polarization in vitro and increased immune cell infiltration in xenografted tumors in vivo. These results reveal another mechanism for the anti-breast cancer activity of wogonin by inducing cellular senescence, which suppresses tumor progression both autonomously and non-autonomously.}, }
@article {pmid32670550, year = {2020}, author = {Paneerselvam, C and Ganapasam, S}, title = {β-Escin alleviates cobalt chloride-induced hypoxia-mediated apoptotic resistance and invasion via ROS-dependent HIF-1α/TGF-β/MMPs in A549 cells.}, journal = {Toxicology research}, volume = {9}, number = {3}, pages = {191-201}, pmid = {32670550}, issn = {2045-452X}, abstract = {Hypoxia is contributed in various pathophysiological conditions including obesity, cardiovascular diseases, and cancer. In cancer, hypoxia is a salient phenomenon and has been correlated with tumor progression, metastasis, and provoke resistance to therapies in cancer patients, which exert with stabilization of main effector, hypoxia inducible factor-1 alpha (HIF-1α). Therefore, therapeutic targeting of hypoxic responses in cancer is the potential approach to improve the better treatment efficacy. In the present study, we evaluated the effect of β-Escin (β-Es) on hypoxia-induced resistance to apoptosis and metastasis in human non-small-cell lung cancer cells. The MTT assay revealed that β-Es treatment decreased the A549 cells viability under cobalt chloride-induced hypoxia. Apoptotic proteins were analyzed by western blot that showed cancer cells treated with β-Es induced cell death in hypoxia condition as proteins compared with normoxia. Moreover, we observed that cobalt chloride induced hypoxia through the generation of intracellular reactive oxygen species and stabilized the transcriptional factor HIF-1α, which leads to cancer metastasis. This notion was supported by the migration, invasion, and adhesion assays. Furthermore, hypoxia increased the expression of transforming growth factor-β, and the activation of matrix metalloproteinases were suppressed by the treatment of β-Es as well as pretreatment with N-acetylcysteine (NAC). Therefore, we demonstrate that a concurrent activation of HIF-1α, transforming growth factor-β, and matrix metalloproteinases participate in hypoxia-induced metastasis and that β-Es prevent A549 cells metastasis by inhibition of reactive oxygen species.}, }
@article {pmid32664574, year = {2020}, author = {Alves, TFR and Rios, AC and da Silva Pontes, K and Portella, DL and Aranha, N and Severino, P and Souto, EB and Gonsalves, JKM and de Souza Nunes, R and Chaud, MV}, title = {Bilayer Mucoadhesive Buccal Film for Mucosal Ulcers Treatment: Development, Characterization, and Single Study Case.}, journal = {Pharmaceutics}, volume = {12}, number = {7}, pages = {}, pmid = {32664574}, issn = {1999-4923}, support = {2018/11350-6//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2018/13432-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 2011/21219-5//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 425271/2016-1//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, abstract = {The formation of mucosal ulcers is an end result of epithelial damage, and it occurs due to some specific causes, such as trauma, aphthous stomatitis, lichen planus and lichenoid reactions, cytotoxic effects of chemotherapy and radiation, and drug-induced hypersensitivity reactions and malignant settings. This study focused on films for target drug delivery with respect to the treatment of the diseases of the oral mucosa, specifically mucositis. The results of a single clinical study as a pre-experimental design was performed and followed up to the outcome until 30 days. The polymeric film was prepared in a mucoadhesive bilayer structure: the basal layer with lidocaine HCl had a faster release than the apical layer with benzydamine HCl and N-acetyl-cysteine. Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and SEM characterized the physical-chemical and morphological properties. The cell viability and cytotoxicity were evaluated in cell line MCF7. The transport mechanism of the solvent (swelling) and the drugs in the basal or apical layer (drug release) was explained with mathematical models. To evaluate the effect of movement inside the mouth, the folding endurance was determined. The mucoadhesive bilayer film is biologically safe and stimulates cellular proliferation. A single study in vivo demonstrated the therapeutic effect of the mucoadhesive bilayer film in buccal mucositis.}, }
@article {pmid32662599, year = {2020}, author = {Yu, TJ and Hsieh, CY and Tang, JY and Lin, LC and Huang, HW and Wang, HR and Yeh, YC and Chuang, YT and Ou-Yang, F and Chang, HW}, title = {Antimycin A shows selective antiproliferation to oral cancer cells by oxidative stress-mediated apoptosis and DNA damage.}, journal = {Environmental toxicology}, volume = {35}, number = {11}, pages = {1212-1224}, doi = {10.1002/tox.22986}, pmid = {32662599}, issn = {1522-7278}, support = {109CM-KMU-007//Chimei-KMU jointed project/ ; MOHW 109-TDU-B-212-134016//Health and welfare surcharge of tobacco products, the Ministry of Health and Welfare, Taiwan, Republic of China/ ; KMU-TC108A04//Kaohsiung Medical University Research Center/ ; MOST 108-2314-B-037-020//Ministry of Science and Technology, Taiwan/ ; MOST 108-2314-B-037-080//Ministry of Science and Technology, Taiwan/ ; MOST 108-2320-B-037-015-MY3//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 109-I002//National Sun Yat-sen University-KMU Joint Research Project/ ; //Ministry of Health and Welfare, Taiwan/ ; //Kaohsiung Medical University/ ; KMUH104-4R20//Kaohsiung Medical University Hospital/ ; //National Sun Yat-sen University/ ; //Ministry of Science and Technology/ ; }, mesh = {Acetylcysteine/pharmacology ; Antimycin A/metabolism/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; DNA Damage/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; *Mouth Neoplasms ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Plant Extracts/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {The antibiotic antimycin A (AMA) is commonly used as an inhibitor for the electron transport chain but its application in anticancer studies is rare. Recently, the repurposing use of AMA in antiproliferation of several cancer cell types has been reported. However, it is rarely investigated in oral cancer cells. The purpose of this study is to investigate the selective antiproliferation ability of AMA treatment on oral cancer cells. Cell viability, flow cytometry, and western blotting were applied to explore its possible anticancer mechanism in terms of both concentration- and exposure time-effects. AMA shows the higher antiproliferation to two oral cancer CAL 27 and Ca9-22 cell lines than normal oral HGF-1 cell lines. Moreover, AMA induces the production of higher reactive oxygen species (ROS) levels and pan-caspase activation in oral cancer CAL 27 and Ca9-22 cells than in normal oral HGF-1 cells, providing the possible mechanism for its selective antiproliferation effect of AMA. In addition to ROS, AMA induces mitochondrial superoxide (MitoSOX) generation and depletes mitochondrial membrane potential (MitoMP). This further supports the AMA-induced oxidative stress changes in oral cancer CAL 27 and Ca9-22 cells. AMA also shows high expressions of annexin V in CAL 27 and Ca9-22 cells and cleaved forms of poly (ADP-ribose) polymerase (PARP), caspase 9, and caspase 3 in CAL 27 cells, supporting the apoptosis-inducing ability of AMA. Furthermore, AMA induces DNA damage (γH2AX and 8-oxo-2'-deoxyguanosine [8-oxodG]) in CAL 27 and Ca9-22 cells. Notably, the AMA-induced selective antiproliferation, oxidative stress, and DNA damage were partly prevented from N-acetylcysteine (NAC) pretreatments. Taken together, AMA selectively kills oral cancer cells in an oxidative stress-dependent mechanism involving apoptosis and DNA damage.}, }
@article {pmid32660079, year = {2020}, author = {Mursaleen, L and Noble, B and Chan, SHY and Somavarapu, S and Zariwala, MG}, title = {N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson's Disease.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {7}, pages = {}, pmid = {32660079}, issn = {2076-3921}, support = {FST Studentship//University of Westminster/ ; }, abstract = {Oxidative stress is a key mediator in the development and progression of Parkinson's disease (PD). The antioxidant n-acetylcysteine (NAC) has generated interest as a disease-modifying therapy for PD but is limited due to poor bioavailability, a short half-life, and limited access to the brain. The aim of this study was to formulate and utilise mitochondria-targeted nanocarriers for delivery of NAC alone and in combination with the iron chelator deferoxamine (DFO), and assess their ability to protect against oxidative stress in a cellular rotenone PD model. Pluronic F68 (P68) and dequalinium (DQA) nanocarriers were prepared by a modified thin-film hydration method. An MTT assay assessed cell viability and iron status was measured using a ferrozine assay and ferritin immunoassay. For oxidative stress, a modified cellular antioxidant activity assay and the thiobarbituric acid-reactive substances assay and mitochondrial hydroxyl assay were utilised. Overall, this study demonstrates, for the first time, successful formulation of NAC and NAC + DFO into P68 + DQA nanocarriers for neuronal delivery. The results indicate that NAC and NAC + DFO nanocarriers have the potential characteristics to access the brain and that 1000 μM P68 + DQA NAC exhibited the strongest ability to protect against reduced cell viability (p = 0.0001), increased iron (p = 0.0033) and oxidative stress (p ≤ 0.0003). These NAC nanocarriers therefore demonstrate significant potential to be transitioned for further preclinical testing for PD.}, }
@article {pmid32659578, year = {2021}, author = {Liu, H and Lai, W and Liu, X and Yang, H and Fang, Y and Tian, L and Li, K and Nie, H and Zhang, W and Shi, Y and Bian, L and Ding, S and Yan, J and Lin, B and Xi, Z}, title = {Exposure to copper oxide nanoparticles triggers oxidative stress and endoplasmic reticulum (ER)-stress induced toxicology and apoptosis in male rat liver and BRL-3A cell.}, journal = {Journal of hazardous materials}, volume = {401}, number = {}, pages = {123349}, doi = {10.1016/j.jhazmat.2020.123349}, pmid = {32659578}, issn = {1873-3336}, mesh = {Animals ; Apoptosis ; *Copper/toxicity ; Endoplasmic Reticulum ; Liver ; Male ; *Nanoparticles/toxicity ; Oxidative Stress ; Oxides ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; }, abstract = {Copper oxide nanoparticles (Nano-CuO) toxicity has been researched widely in recent years. However, the relationship between oxidative stress and ER-stress and the possible mechanisms induced by Nano-CuO have been rarely studied. Here, the mechanism of hepatotoxicity and apoptosis through oxidative stress and ER-stress induced by Nano-CuO was investigated in vivo and in vitro. In in vivo experiments, male Wistar rats were intranasally instilled 10 μg Nano-CuO/g body weight daily for 60 days, which caused liver function impairment, oxidative stress, inflammatory response, histopathological and ultrastructural damage, ER-stress and apoptosis in liver tissue. in vitro experiments on rat hepatocytes BRL-3A cells showed that exposure to Nano-CuO for 24 h resulted in excess production of reactive oxygen species leading to decrease in mitochondria membrane potential causing cell death by inducing apoptosis. However, administration of n-acetyl cysteine decreased the apoptosis in Nano-cuo treated group. The in vivo and in vitro experiments confirmed that oxidative stress triggered ER-stress pathway, leading to the opening of apoptosis pathways of CHOP, JNK, and Caspase-12. In summary, treatment of Nano Cuo triggered oxidative stress by ROS, which in turn resulted in activation of ER stress pathways causing cell death in liver tissue and BRL-3A cells.}, }
@article {pmid32659471, year = {2020}, author = {Shah, KN and Shah, PN and Mullen, AR and Chen, Q and Southerland, MR and Chirra, B and DeBerardinis, RJ and Cannon, CL}, title = {N-Acetyl cysteine abrogates silver-induced reactive oxygen species in human cells without altering silver-based antimicrobial activity.}, journal = {Toxicology letters}, volume = {332}, number = {}, pages = {118-129}, pmid = {32659471}, issn = {1879-3169}, support = {HHSN268201000046C/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetates/pharmacology ; Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Anti-Bacterial Agents/*pharmacology ; Ascorbic Acid/pharmacology ; Cell Line ; Free Radical Scavengers/*pharmacology ; Gas Chromatography-Mass Spectrometry ; Glutathione/metabolism ; Humans ; Melatonin/pharmacology ; Microbial Sensitivity Tests ; Reactive Oxygen Species/*metabolism ; Silver/*pharmacology/*toxicity ; Silver Compounds/pharmacology ; Superoxides/metabolism ; }, abstract = {Silver-based antimicrobials are widely used topically to treat infections associated with multi-drug resistant (MDR) pathogens. Expanding this topical use to aerosols to treat lung infections requires understanding and preventing silver toxicity in the respiratory tract. A key mechanism resulting in silver-induced toxicity is the production of reactive oxygen species (ROS). In this study, we have verified ROS generation in silver-treated bronchial epithelial cells prompting evaluation of three antioxidants, N-acetyl cysteine (NAC), ascorbic acid, and melatonin, to identify potential prophylactic agents. Among them, NAC was the only candidate that abrogated the ROS generation in response to silver acetate exposure resulting in the rescue of these cells from silver-associated toxicity. Further, this protective effect directly translated to preservation of metabolic activity, as demonstrated by the normal levels of citric acid cycle metabolites in NAC-pretreated silver acetate-exposed cells. Because the citric acid cycle remained functional, silver-exposed cells pre-incubated with NAC demonstrated significantly higher levels of adenosine triphosphate levels compared with NAC-free controls. Moreover, we found that this prodigious capacity of NAC to rescue silver acetate-exposed cells was due not only to its antioxidant activity, but also to its ability to directly bind silver. Despite binding to silver, NAC did not alter the antimicrobial activity of silver acetate.}, }
@article {pmid32658336, year = {2020}, author = {Mansour, HH and Omran, MM and Hasan, HF and El Kiki, SM}, title = {Modulation of bleomycin-induced oxidative stress and pulmonary fibrosis by N-acetylcysteine in rats via AMPK/SIRT1/NF-κβ.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {47}, number = {12}, pages = {1943-1952}, doi = {10.1111/1440-1681.13378}, pmid = {32658336}, issn = {1440-1681}, mesh = {*AMP-Activated Protein Kinases/metabolism ; Acetylcysteine ; Animals ; *Bleomycin ; Lipid Peroxidation ; Lung/drug effects ; Male ; NF-kappa B/metabolism ; *Oxidative Stress/drug effects ; Platelet-Derived Growth Factor/metabolism ; *Pulmonary Fibrosis ; Rats ; *Sirtuin 1/metabolism ; }, abstract = {The efficacy of bleomycin (BLM) as an antineoplastic drug is limited to the development of dose and time-dependent pulmonary fibrosis. This study was intended to investigate the effect of N-acetylcysteine (NAC) on BLM-induced pulmonary fibrosis in rats. Twenty rats were randomly divided to the following four groups: Group one served as control; group two received BLM (15 mg/kg, intraperitoneal (ip)) for five consecutive days; group three received NAC (200 mg/kg, ip) for five consecutive days; and group four received NAC 1 hour before BLM for 5 days. The expression of connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), silent information regulator l (SIRT1), AMP-activated protein kinase (AMPK) were determined by qRT-PCR in lung tissues. The changes in transforming growth factor-beta1 (TGF-β1), tumour necrosis factor-α (TNF-α), interleukin-β1 (IL-β1) and nuclear factor kappa-β (NF-κβ) in serum were measured by ELISA. The tissue antioxidant status was determined biochemically. BLM administration caused pulmonary fibrosis as evidenced by increased levels of inflammatory mediators (TGF-β1, TNF-α, IL-β1 and NF-κβ) in serum (P < .05), elevated lipid peroxidation and nitric oxide and depleted endogenous antioxidants in lung tissue (P < .05). The expression levels of SIRT1 and AMPK were significantly decreased (P < .05), while the expression levels of CTGF and PDGF were increased significantly in the BLM group as compared to the control group (P < .05). These alterations were normalized by NAC intervention. NAC markedly attenuated the lung histopathological changes and reduced collagen deposition. These results suggest that NAC exerted an ameliorative effect against BLM-induced oxidative damage and pulmonary fibrosis via SIRT1/ AMPK/ NF-κβ pathways.}, }
@article {pmid32655795, year = {2020}, author = {Choi, YY and Seok, JI and Hwang, JI and Kim, DS}, title = {Co-administration of everolimus and N-acetylcysteine attenuates hepatic stellate cell activation and hepatic fibrosis.}, journal = {American journal of translational research}, volume = {12}, number = {6}, pages = {2627-2639}, pmid = {32655795}, issn = {1943-8141}, abstract = {The accelerated course of hepatic fibrosis that occurs in some patients after liver transplantation is an important clinical problem. Activation of hepatic stellate cell (HSCs) is the dominant event in hepatic fibrosis. Previous studies have shown that treatment with mammalian target of rapamycin (mTOR) inhibitors was more effective in reducing the progression of fibrosis than treatment with calcineurin inhibitors, suggesting that mTOR could be a crucial target for inhibition of fibrosis. In addition, N-acetylcysteine (NAC) has been shown to effectively suppress HSC activation-dependent expression of alpha-smooth muscle actin in HSCs, suggesting that NAC could be a candidate for the clinical treatment of hepatic fibrosis. Here, we have evaluated the effects of immunosuppressive drugs and NAC in a mice model of hepatic fibrosis and on HSC activation in vitro. We demonstrated that an mTOR inhibitor significantly inhibited fibrogenic genes in cultured HSCs until day 14. In addition, co-administration of NAC with everolimus further reduced the expression of fibrogenic genes and improved the characteristic of HSCs via blockage of HSC activation and up-regulation of fibrolytic gene. Moreover, in vivo studies showed that everolimus inhibited collagen deposition and inflammation in a mouse model of fibrogenesis, as determined by histological analysis, and everolimus treatment, in combination with NAC, significantly decreased extracellular matrix deposition and improved liver histology. These findings indicated that everolimus, combined with NAC, synergistically inhibited hepatic fibrosis and thus may become a valuable option in immunosuppressant therapy.}, }
@article {pmid32655758, year = {2020}, author = {Moazzen, H and Wu, Y and Engineer, A and Lu, X and Aulakh, S and Feng, Q}, title = {NOX2 Is Critical to Endocardial to Mesenchymal Transition and Heart Development.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {1679045}, pmid = {32655758}, issn = {1942-0994}, mesh = {Animals ; Apoptosis ; Cell Proliferation ; Endocardial Cushions/embryology/metabolism/pathology ; Epithelial-Mesenchymal Transition/genetics/*physiology ; Gene Expression Regulation, Developmental ; Heart/*embryology ; Heart Defects, Congenital/genetics/metabolism/*pathology ; Mice ; NADPH Oxidase 2/deficiency/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {NADPH oxidases (NOX) are a major source of reactive oxygen species (ROS) production in the heart. ROS signaling regulates gene expression, cell proliferation, apoptosis, and migration. However, the role of NOX2 in embryonic heart development remains elusive. We hypothesized that deficiency of Nox2 disrupts endocardial to mesenchymal transition (EndMT) and results in congenital septal and valvular defects. Our data show that 34% of Nox2[-/-] neonatal mice had various congenital heart defects (CHDs) including atrial septal defects (ASD), ventricular septal defects (VSD), atrioventricular canal defects (AVCD), and malformation of atrioventricular and aortic valves. Notably, Nox2[-/-] embryonic hearts show abnormal development of the endocardial cushion as evidenced by decreased cell proliferation and an increased rate of apoptosis. Additionally, Nox2 deficiency disrupted EndMT of atrioventricular cushion explants ex vivo. Furthermore, treatment with N-acetylcysteine (NAC) to reduce ROS levels in the wild-type endocardial cushion explants decreased the number of cells undergoing EndMT. Importantly, deficiency of Nox2 was associated with reduced expression of Gata4, Tgfβ2, Bmp2, Bmp4, and Snail1, which are critical to endocardial cushion and valvoseptal development. We conclude that NOX2 is critical to EndMT, endocardial cushion cell proliferation, and normal embryonic heart development.}, }
@article {pmid32655235, year = {2020}, author = {Mallick, S and Nair, K and Thillai, M and Manikandan, K and Sethi, P and Madhusrinivasan, D and Johns, SM and Binoj, ST and Mohammed, Z and Ramachandran, NM and Balakrishnan, D and Unnikrishnan, G and Dhar, P and Sudheer, OV and Sudhindran, S}, title = {Liver Transplant in Acute Liver Failure - Looking Back Over 10 Years.}, journal = {Journal of clinical and experimental hepatology}, volume = {10}, number = {4}, pages = {322-328}, pmid = {32655235}, issn = {0973-6883}, abstract = {BACKGROUND: Acute liver failure (ALF) is the leading cause for emergency liver transplantation (LT) all over the world. We looked at the profile of cases who required LT for ALF from a single centre to identify the possible predictors of poor outcomes.<br><br>METHODOLOGY: During the 10-year period starting from 2007, 320 cases of ALF were treated at our institution, of which 70 (median age 24 years, Male:Female 1:2) underwent LT. Retrospective analyses of these 70 patients were performed.<br><br>RESULTS: Etiology was identifiable in 73% (n&#xa0;=&#xa0;51) of cases (yellow phosphorous [YP] poisoning [n&#xa0;= 16], Hepatitis A virus [HAV] [n&#xa0;= 15], Hepatitis B virus [HBV] [n&#xa0;= 5], Hepatitis E virus [HEV] [n&#xa0;= 1], anti-tubercular therapy [ATT] induced [n&#xa0;=&#xa0;6], acute Wilson's [n&#xa0;= 3], and autoimmune [n&#xa0;= 5]]. Upon meeting King's College Hospital criteria, 69 had live donor LT (61 right lobe grafts, three left lobe grafts, five left&#xa0;lateral segment grafts) and one had deceased donor LT. Among these, there were five auxiliary partial orthotopic grafts and four ABO-incompatible transplants. Overall, 90-day mortality was 35.7% (n&#xa0;= 25), predominantly due to sepsis. Significant risk factors for mortality on multivariate analysis included indeterminate etiology, pre-op renal dysfunction, and Grade IV hepatic encephalopathy (HE). Cumulative 10-year survival of the remaining survivors was 95.6% (n&#xa0;= 45).<br><br>CONCLUSION: LT for ALF carries high perioperative mortality (35.7%) in those presenting with indeterminate etiology, pre-op renal dysfunction, and Grade IV HE. Nevertheless, if they survive the perioperative period, long-term survival is excellent.}, }
@article {pmid32653010, year = {2020}, author = {Penaloza, CG and Cruz, M and Germain, G and Jabeen, S and Javdan, M and Lockshin, RA and Zakeri, Z}, title = {Higher sensitivity of female cells to ethanol: methylation of DNA lowers Cyp2e1, generating more ROS.}, journal = {Cell communication and signaling : CCS}, volume = {18}, number = {1}, pages = {111}, pmid = {32653010}, issn = {1478-811X}, support = {T34 GM070387/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Alcohol Dehydrogenase/genetics/metabolism ; Aldehyde Dehydrogenase/genetics/metabolism ; Animals ; Azacitidine/pharmacology ; Cell Death/drug effects ; Cell Survival/drug effects ; Cytochrome P-450 CYP2E1/genetics/*metabolism ; DNA Methylation/drug effects/*genetics ; Ethanol/*toxicity ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; Male ; Mice ; Models, Biological ; Protein Isoforms/metabolism ; Reactive Oxygen Species/*metabolism ; Sex Characteristics ; Stress, Physiological/drug effects ; Transcription, Genetic/drug effects ; }, abstract = {BACKGROUND: Cells taken from mouse embryos before sex differentiation respond to insults according to their chromosomal sex, a difference traceable to differential methylation. We evaluated the mechanism for this difference in the controlled situation of their response to ethanol.<br><br>METHODS: We evaluated the expression of mRNA for alcohol dehydrogenase (ADH), aldehyde dehyrogenases (ALDH), and a cytochrome P450 isoenzyme (Cyp2e1) in male and female mice, comparing the expressions to toxicity under several experimental conditions evaluating redox and other states.<br><br>RESULTS: Females are more sensitive to ethanol. Disulfiram, which inhibits alcohol dehydrogenase (ADH), increases cell death in males, eliminating the sex dimorphism. The expressions ADH Class 1 to 4 and ALDH Class 1 and 2 do not differ by sex. However, females express approximately 8X more message for Cyp2e1, an enzyme in the non-canonical pathway. Female cells produce approximately 15% more ROS (reactive oxygen species) than male cells, but male cells contain approximately double the concentration of GSH, a ROS scavenger. Scavenging ROS with N-acetyl cysteine reduces cell death and eliminates sex dimorphism. Finally, since many of the differences in gene expression derive from methylation of DNA, we exposed cells to the methyltransferase inhibitor 5-aza- 2-deoxycytidine; blocking methylation eliminates both the difference in expression of Cyp2e1 and cell death.<br><br>CONCLUSION: We conclude that the sex-differential cell death caused by ethanol derives from sex dimorphic methylation of Cyp2e1 gene, resulting in generation of more ROS.}, }
@article {pmid32652199, year = {2020}, author = {Bjørklund, G and Dadar, M and Anderson, G and Chirumbolo, S and Maes, M}, title = {Preventive treatments to slow substantia nigra damage and Parkinson's disease progression: A critical perspective review.}, journal = {Pharmacological research}, volume = {161}, number = {}, pages = {105065}, doi = {10.1016/j.phrs.2020.105065}, pmid = {32652199}, issn = {1096-1186}, mesh = {Animals ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/therapeutic use ; Antiparkinson Agents/*therapeutic use ; Dietary Supplements ; Disease Progression ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors/metabolism ; Nutritional Status ; Oxidative Stress/drug effects ; Parkinson Disease/*drug therapy/metabolism/pathology/physiopathology ; Substantia Nigra/*drug effects/metabolism/physiopathology ; }, abstract = {Restoring the lost physiological functions of the substantia nigra in Parkinson's disease (PD) is an important goal of PD therapy. The present article reviews a) novel drug targets that should be targeted to slow PD progression, and b) clinical and experimental research data reporting new treatments targeting immune-inflammatory and oxidative pathways. A systematic search was performed based on the major databases, i.e., ScienceDirect, Web of Science, PubMed, CABI Direct databases, and Scopus, on relevant studies performed from 1900 to 2020. This review considers the crucial roles of mitochondria and immune-inflammatory and oxidative pathways in the pathophysiology of PD. High levels of oxidative stress in the substantia nigra, as well as modifications in glutathione regulation, contribute to mitochondrial dysfunction, with a decline in complex I of the mitochondrial electron transport chain reported in PD patients. Many papers suggest that targeting antioxidative systems is a crucial aspect of preventive and protective therapies, even justifying the utilization of N-acetylcysteine (NAC) supplementation to fortify the protection afforded by intracellular glutathione. Dietary recommended panels including ketogenetic diet, muscular exercise, nutraceutical supplementation including NAC, glutathione, nicotine, caffeine, melatonin, niacin, and butyrate, besides to nonsteroidal anti-inflammatory drugs (NSAIDs), and memantine treatment are important aspects of PD therapy. The integration of neuro-immune, antioxidant, and nutritional approaches to treatment should afford better neuroprotection, including by attenuating neuroinflammation, nitro-oxidative stress, mitochondrial dysfunction, and neurodegenerative processes. Future research should clarify the efficacy, and interactions, of nicotine receptor agonists, gut microbiome-derived butyrate, melatonin, and NSAIDs in the treatment of PD.}, }
@article {pmid32651842, year = {2020}, author = {Naime, AA and Lopes, MW and Colle, D and Dafré, AL and Suñol, C and da Rocha, JBT and Aschner, M and Leal, RB and Farina, M}, title = {Glutathione in Chlorpyrifos-and Chlorpyrifos-Oxon-Induced Toxicity: a Comparative Study Focused on Non-cholinergic Toxicity in HT22 Cells.}, journal = {Neurotoxicity research}, volume = {38}, number = {3}, pages = {603-610}, doi = {10.1007/s12640-020-00254-5}, pmid = {32651842}, issn = {1476-3524}, support = {300966/2014-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, mesh = {Acetylcholine/pharmacology ; Acetylcholinesterase/metabolism ; Animals ; Atropine/pharmacology ; Cell Survival/drug effects ; Chlorpyrifos/*analogs &amp; derivatives/pharmacology ; Cholinesterase Inhibitors/pharmacology ; Glutathione/metabolism/*pharmacology ; Neurons/*drug effects ; Neurotoxicity Syndromes/*drug therapy ; }, abstract = {Chlorpyrifos (CPF) is a neurotoxic organophosphorus (OP) insecticide widely used for agricultural purposes. CPF-mediated neurotoxicity is mainly associated with its anticholinesterase activity, which may lead to a cholinergic syndrome. CPF metabolism generates chlorpyrifos-oxon (CPF-O), which possesses higher anticholinesterase activity and, consequently, plays a major role in the cholinergic syndrome observed after CPF poisoning. Recent lines of evidence have also reported non-cholinergic endpoints of CPF- and CPF-O-induced neurotoxicities, but comparisons on the non-cholinergic toxic properties of CPF and CPF-O are lacking. In this study, we compared the non-cholinergic toxicities displayed by CPF and CPF-O in cultured neuronal cells, with a particular emphasis on their pro-oxidant properties. Using immortalized cells derived from mouse hippocampus (HT22 line, which does present detectable acetylcholinesterase activity), we observed that CPF-O was 5-fold more potent in decreasing cell viability compared with CPF. Atropine, a muscarinic acetylcholine receptor antagonist, protected against acetylcholine (ACh)-induced toxicity but failed to prevent the CPF- and CPF-O-induced cytotoxicities in HT22 cells. CPF or CPF-O exposures significantly decreased the levels of the antioxidant glutathione (GSH); this event preceded the significant decrease in cell viability. Pretreatment with N-acetylcysteine (NAC, a GSH precursor) protected against the cytotoxicity induced by both CPF and CPF-O. The present study indicates that GSH depletion is a non-cholinergic event involved in CPF and CPF-O toxicities. The study also shows that in addition of being a more potent AChE inhibitor, CPF-O is also a more potent pro-oxidant molecule when compared with CPF, highlighting the role of CPF metabolism (bioactivation to CPF-O) in the ensuing non-cholinergic toxicity.}, }
@article {pmid32648659, year = {2020}, author = {Yang, HJ and Kong, B and Shuai, W and Zhang, JJ and Huang, H}, title = {MD1 deletion exaggerates cardiomyocyte autophagy induced by heart failure with preserved ejection fraction through ROS/MAPK signalling pathway.}, journal = {Journal of cellular and molecular medicine}, volume = {24}, number = {16}, pages = {9300-9312}, pmid = {32648659}, issn = {1582-4934}, mesh = {Animals ; Antigens, Surface/*physiology ; *Autophagy ; Heart Failure/etiology/metabolism/*pathology ; *MAP Kinase Signaling System ; Male ; Membrane Glycoproteins/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocytes, Cardiac/metabolism/pathology ; *Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; *Stroke Volume ; Ventricular Remodeling ; }, abstract = {In our previous studies, we reported that myeloid differentiation protein 1 (MD1) serves as a negative regulator in several cardiovascular diseases. However, the role of MD1 in heart failure with preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain unclear. Eight-week-old MD1-knockout (MD1-KO) and wild-type (WT) mice served as models of HFpEF induced by uninephrectomy, continuous saline or d-aldosterone infusion and a 1.0% sodium chloride treatment in drinking water for 4 weeks to investigate the effect of MD1 on HFpEF in vivo. H9C2 cells were treated with aldosterone to evaluate the role of MD1 KO in vitro. MD1 expression was down-regulated in the HFpEF mice; HFpEF significantly increased the levels of intracellular reactive oxygen species (ROS) and promoted autophagy; and in the MD1-KO mice, the HFpEF-induced intracellular ROS and autophagy effects were significantly exacerbated. Moreover, MD1 loss activated the p38-MAPK pathway both in vivo and in vitro. Aldosterone-mediated cardiomyocyte autophagy was significantly inhibited in cells pre-treated with the ROS scavenger N-acetylcysteine (NAC) or p38 inhibitor SB203580. Furthermore, inhibition with the autophagy inhibitor 3-methyladenine (3-MA) offset the aggravating effect of aldosterone-induced autophagy in the MD1-KO mice and cells both in vivo and in vitro. Our results validate a critical role of MD1 in the pathogenesis of HFpEF. MD1 deletion exaggerates cardiomyocyte autophagy in HFpEF via the activation of the ROS-mediated MAPK signalling pathway.}, }
@article {pmid32643929, year = {2020}, author = {Zhou, S and Li, W and Tian, M and Zhang, N and Yang, X and Li, W and Peng, Y and Zheng, J}, title = {Metabolic Activation of Pirfenidone Mediated by Cytochrome P450s and Sulfotransferases.}, journal = {Journal of medicinal chemistry}, volume = {63}, number = {15}, pages = {8059-8068}, doi = {10.1021/acs.jmedchem.9b02073}, pmid = {32643929}, issn = {1520-4804}, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/chemistry/*metabolism ; Cytochrome P-450 Enzyme System/chemistry/*metabolism ; Male ; Mice ; Microsomes, Liver/drug effects/*metabolism ; Pyridones/chemistry/*metabolism/pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Sulfotransferases/chemistry/*metabolism ; }, abstract = {Pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis. Idiosyncratic drug reactions, due to clinical application of pirfenidone, have been documented, even along with death cases resulting from acute liver failure. The present study aimed at the investigation of metabolic activation of pirfenidone possibly participating in the reported adverse reactions. Pirfenidone-derived glutathione/N-acetylcysteine (GSH/NAC) conjugates were detected in microsomal/primary hepatocyte incubations after exposure to pirfenidone. The GSH/NAC conjugates were also observed in bile and urine of rats given pirfenidone, respectively. The observation of the conjugates suggests the formation of a quinone methide intermediate derived from pirfenidone. The intermediate was possibly generated through two pathways. First, pirfenidone was directly metabolized to the quinone methide intermediate via dehydrogenation; second, pirfenidone was oxidized to 5-hydroxymethyl pirfenidone, followed by sulfation to a benzyl alcohol-sulfate derivative. The findings facilitate the understanding of the mechanisms of pirfenidone-induced idiosyncratic toxicity and assist medicinal chemists to minimize toxicities in the development of new pharmaceutical agents.}, }
@article {pmid32641196, year = {2021}, author = {Naguy, A and Naguy, C}, title = {N-acetyl-cysteine in schizophrenia-there is more than meets the eyes!.}, journal = {CNS spectrums}, volume = {26}, number = {5}, pages = {446-447}, doi = {10.1017/S1092852920001583}, pmid = {32641196}, issn = {1092-8529}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Antipsychotic Agents/administration &amp; dosage/adverse effects/therapeutic use ; Humans ; Schizophrenia/*drug therapy ; }, }
@article {pmid32640352, year = {2020}, author = {Gu, Q and Rodgers, J and Robinson, B and Kanungo, J}, title = {N-acetylcysteine prevents verapamil-induced cardiotoxicity with no effect on the noradrenergic arch-associated neurons in zebrafish.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {144}, number = {}, pages = {111559}, doi = {10.1016/j.fct.2020.111559}, pmid = {32640352}, issn = {1873-6351}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Calcium Channel Blockers/*toxicity ; Cardiotoxicity/*prevention &amp; control ; Cysteine/metabolism ; Dose-Response Relationship, Drug ; Embryo, Nonmammalian/drug effects/metabolism ; Embryonic Development/drug effects ; Heart Rate/drug effects ; Verapamil/*toxicity ; Zebrafish/*embryology ; }, abstract = {There is a strong association between calcium channel blockers (CCBs) and heart failure. CCB toxicity is very common due to overdose and underlying medical conditions. CCBs also have been shown to affect the nervous system. Recently, we demonstrated that the antioxidant N-acetylcysteine (NAC) prevented ketamine-induced cardiotoxicity, developmental toxicity and neurotoxicity. Functionally, we attributed NAC's beneficial effect to its ability to increase cellular calcium. Here, we hypothesized that if there was an involvement of calcium in NAC's preventative effects on ketamine toxicity, NAC might also ameliorate toxicities induced by verapamil, an L-type CCB used to treat hypertension. Using zebrafish embryos, we show that in the absence of NAC, verapamil (up to 100 μM) dose-dependently reduced heart rate and those effects were prevented by NAC co-treatment. Furthermore, a 2-h treatment with NAC rescued reduction of heart rate induced by pre-treatment of 50 and 100 μM of verapamil for 18 h. Verapamil up to 100 μM and NAC up to 1.5 mM did not have any adverse effects on the expression of tyrosine hydroxylase in the noradrenergic neurons of the arch-associated cluster (AAC) located near the heart. NAC did not change cysteine levels in the embryos suggesting that the beneficial effect of NAC on verapamil toxicity may not involve its antioxidant property. In our search for compounds that can prevent CCB toxicity, this study, for the first time, demonstrates protective effects of NAC against verapamil's adverse effects on the heart.}, }
@article {pmid32640348, year = {2020}, author = {Chen, B and Hong, W and Tang, Y and Zhao, Y and Aguilar, ZP and Xu, H}, title = {Protective effect of the NAC and Sal on zinc oxide nanoparticles-induced reproductive and development toxicity in pregnant mice.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {143}, number = {}, pages = {111552}, doi = {10.1016/j.fct.2020.111552}, pmid = {32640348}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cinnamates/*pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Metal Nanoparticles/chemistry/*toxicity ; Mice ; Pregnancy ; Random Allocation ; Thiourea/*analogs &amp; derivatives/pharmacology ; Weight Gain ; Zinc Oxide/chemistry/*toxicity ; }, abstract = {The growing use of zinc oxide nanoparticles (ZnO NPs) in various applications has raised many concerns about the potential risks to human health. In this research, the protective effects of cellular oxidative stress inhibitor N-Acetyl-cysteine (NAC) and endoplasmic reticulum (ER) stress inhibitor Salubrinal (Sal) on reproductive toxicity induced by ZnO NPs were investigated. The results showed that application of these two kinds of cell stress inhibitors after oral ingestion of ZnO NPs could prevent the weight loss of pregnant mice; reduce zinc content in the uterus, placenta and fetus; reduce abnormal development of the offspring; and decrease fetal abortion. Furthermore, RT-qPCR, Western blot and immunofluorescence assay results indicated that NAC restored the expression of Gclc, reduced the expression of ATF4, JNK and Caspase-12, and decreased the expression of eNOS and IGF-1, in the placenta. Sal decreased the expression of ATF4, JNK and Caspase-12, and increased the expression of eNOS and IGF-1caused by the oral ingestion of ZnO NPs. These results indicated that treatment with NAC and Sal after oral exposure could reduce reproductive and development toxicity caused by ZnO NPs which induced reproductive and development toxicity that was probably caused by the activation of oxide stress and ER stress.}, }
@article {pmid32635894, year = {2020}, author = {Alhuthali, HM and Bradshaw, TD and Lim, KH and Kam, TS and Seedhouse, CH}, title = {The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun.}, journal = {BMC cancer}, volume = {20}, number = {1}, pages = {629}, pmid = {32635894}, issn = {1471-2407}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Damage/drug effects ; Drug Screening Assays, Antitumor ; Free Radical Scavengers/pharmacology ; Humans ; Indole Alkaloids/*pharmacology/therapeutic use ; Leukemia, Myeloid, Acute/*drug therapy/pathology ; MAP Kinase Signaling System/drug effects ; Proto-Oncogene Proteins c-jun/*agonists/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous hematological malignancy with poor long-term survival. New drugs which improve the outcome of AML patients are urgently required. In this work, the activity and mechanism of action of the cytotoxic indole alkaloid Jerantinine B (JB), was examined in AML cells.<br><br>METHODS: We used a combination of proliferation and apoptosis assays to assess the effect of JB on AML cell lines and patient samples, with BH3 profiling being performed to identify early effects of the drug (4&#x2009;h). Phosphokinase arrays were adopted to identify potential driver proteins in the cellular response to JB, the results of which were confirmed and extended using western blotting and inhibitor assays and measuring levels of reactive oxygen species.<br><br>RESULTS: AML cell growth was significantly impaired following JB exposure in a dose-dependent manner; potent colony inhibition of primary patient cells was also observed. An apoptotic mode of death was demonstrated using Annexin V and upregulation of apoptotic biomarkers (active caspase 3 and cleaved PARP). Using BH3 profiling, JB was shown to prime cells to apoptosis at an early time point (4&#x2009;h) and phospho-kinase arrays demonstrated this to be associated with a strong upregulation and activation of both total and phosphorylated c-Jun (S63). The mechanism of c-Jun activation was probed and significant induction of reactive oxygen species (ROS) was demonstrated which resulted in an increase in the DNA damage response marker &#x3b3;H2AX. This was further verified by the loss of JB-induced C-Jun activation and maintenance of cell viability when using the ROS scavenger N-acetyl-L-cysteine (NAC).<br><br>CONCLUSIONS: This work provides the first evidence of cytotoxicity of JB against AML cells and identifies ROS-induced c-Jun activation as the major mechanism of action.}, }
@article {pmid32634696, year = {2020}, author = {Liu, M and Zhang, G and Naqvi, S and Zhang, F and Kang, T and Duan, Q and Wang, Z and Xiao, S and Zheng, Y}, title = {Cytotoxicity of Saikosaponin A targets HEKa cell through apoptosis induction by ROS accumulation and inflammation suppression via NF-κB pathway.}, journal = {International immunopharmacology}, volume = {86}, number = {}, pages = {106751}, doi = {10.1016/j.intimp.2020.106751}, pmid = {32634696}, issn = {1878-1705}, mesh = {Acetylcysteine/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Apoptosis ; Cell Line ; Humans ; Imiquimod/metabolism ; Immunosuppression Therapy ; Inflammation/*drug therapy ; Keratinocytes/*immunology ; Mice ; NF-kappa B/*metabolism ; Oleanolic Acid/*analogs &amp; derivatives/metabolism ; Reactive Oxygen Species/metabolism ; Saponins/*metabolism ; Signal Transduction ; }, abstract = {Saikosaponin A (SSA) is a triterpenoid saponin extracted from oriental medicinal plant Radix bupleuri, possessing various biological functions such as anti-inflammatory, immune regulation and anti-virus. This study aimed to explore therapeutic effects of SSA on psoriasis in both vitro and vivo. Our results showed that SSA increased reactive oxygen species (ROS) generation, and decreased mitochondrial membrane potential (MMP) and M5-induced inflammatory cytokines levels in HEKa cells in a dose-dependent manner. In addition, SSA promoted apoptosis and suppressed phosphorylation of NF-κB in vitro, which were restored by the ROS scavenger N-acetylcysteine (NAC). In imiquimod (IMQ)-induced mice, gavage with SSA markedly decreased Psoriasis Area and Severity Index (PASI) score and ameliorated epidermal hyperplasia through inhibition of NF-κB and NLRP3 signaling pathway. In conclusion, our studies demonstrate that SSA induces apoptosis and suppresses inflammation in HEKa cells and ameliorates IMQ-induced psoriasis in mice, making it a therapeutic candidate for psoriasis.}, }
@article {pmid32632359, year = {2020}, author = {Nasi, A and McArdle, S and Gaudernack, G and Westman, G and Melief, C and Rockberg, J and Arens, R and Kouretas, D and Sjölin, J and Mangsbo, S}, title = {Reactive oxygen species as an initiator of toxic innate immune responses in retort to SARS-CoV-2 in an ageing population, consider N-acetylcysteine as early therapeutic intervention.}, journal = {Toxicology reports}, volume = {7}, number = {}, pages = {768-771}, pmid = {32632359}, issn = {2214-7500}, abstract = {During the current COVID-19 pandemic, a need for evaluation of already available drugs for treatment of the disease is crucial. Hereby, based on literature review from the current pandemic and previous outbreaks with corona viruses we analyze the impact of the virus infection on cell stress responses and redox balance. High levels of mortality are noticed in elderly individuals infected with SARS-CoV2 and during the previous SARS-CoV1 outbreak. Elderly individuals maintain a chronic low level of inflammation which is associated with oxidative stress and inflammatory cytokine production, a condition that increases the severity of viral infections in this population. Coronavirus infections can lead to alterations of redox balance in infected cells through modulation of NAD + biosynthesis, PARP function along with altering proteasome and mitochondrial function in the cell thereby leading to enhanced cell stress responses which further exacerbate inflammation. ROS production can increase IL-6 production and lipid peroxidation resulting in cell damage. Therefore, early treatment with anti-oxidants such as NAC during COVID-19 can be a way to bypass the excessive inflammation and cell damage that lead to severe infection, thus early NAC as intervention should be evaluated in a clinical trial setting.}, }
@article {pmid32630312, year = {2020}, author = {Chen, MC and Hsu, LL and Wang, SF and Hsu, CY and Lee, HC and Tseng, LM}, title = {ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation.}, journal = {Cells}, volume = {9}, number = {7}, pages = {}, pmid = {32630312}, issn = {2073-4409}, mesh = {AMP-Activated Protein Kinase Kinases ; Acetylcysteine/pharmacology ; Amino Acid Transport System y+/genetics/*metabolism ; Antineoplastic Agents/*pharmacology ; Antioxidants/*pharmacology ; Breast Neoplasms/genetics/*metabolism ; Cell Death/*drug effects/genetics ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic/*drug effects/genetics ; Gene Knockdown Techniques ; Glucose/*deficiency/metabolism ; Glutamic Acid/metabolism ; Glutathione/metabolism ; Humans ; Ketoglutaric Acids/pharmacology ; Protein Kinases/metabolism ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; Sirtuin 3/genetics/metabolism ; Sulfasalazine/pharmacology ; Up-Regulation ; }, abstract = {xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.}, }
@article {pmid32629850, year = {2020}, author = {Nunes, TSBS and Rosa, LM and Vega-Chacón, Y and Mima, EGO}, title = {Fungistatic Action of N-Acetylcysteine on Candida albicans Biofilms and Its Interaction with Antifungal Agents.}, journal = {Microorganisms}, volume = {8}, number = {7}, pages = {}, pmid = {32629850}, issn = {2076-2607}, support = {2018/02513-9//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; 001//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; 47434//Programa Institucional de Bolsas de Inicia&#xe7;&#xe3;o Cient&#xed;fica e Tecnol&#xf3;gica UNESP (PIBIC)/ ; }, abstract = {Therapies targeted to fungal biofilms, mainly against the matrix, and therapies that do not induce microbial resistance are relevant. N-acetylcysteine (NAC), a mucolytic agent, has shown antimicrobial action. This study evaluated the effect of NAC against fluconazole-susceptible (CaS) and -resistant (CaR) Candida albicans. The susceptibility of planktonic cultures to NAC, the effect of NAC on biofilms and their matrix, the interaction of NAC with antifungal agents, and confocal microscopy were evaluated. Data were analyzed descriptively and by the ANOVA/Welch and Tukey/Gomes-Howell tests. The minimum inhibitory concentration (MIC) of NAC was 25 mg/mL for both strains. NAC significantly reduced the viability of both fungal strains. Concentrations higher than the MIC (100 and 50 mg/mL) reduced the viability and the biomass. NAC at 12.5 mg/mL increased the fungal viability. NAC also reduced the soluble components of the biofilm matrix, and showed synergism with caspofungin against planktonic cultures of CaS, but not against biofilms. Confocal images demonstrated that NAC reduced the biofilm thickness and the fluorescence intensity of most fluorochromes used. High concentrations of NAC had similar fungistatic effects against both strains, while a low concentration showed the opposite result. The antibiofilm action of NAC was due to its fungistatic action.}, }
@article {pmid32627147, year = {2020}, author = {Liu, J and Chen, X and Zhou, J and Ye, L and Yang, D and Song, Y}, title = {Particulate matter exposure promotes Pseudomonas aeruginosa invasion into airway epithelia by upregulating PAFR via the ROS-mediated PI3K pathway.}, journal = {Human cell}, volume = {33}, number = {4}, pages = {963-973}, pmid = {32627147}, issn = {1749-0774}, support = {30772019//National Natural Science Foundation of China/ ; 81570028//National Natural Science Foundation of China/ ; 16ZR1405700//Natural Science Foundation of Shanghai/ ; 2015CB553404//National Basic Research Program of China (973 Program)/ ; }, mesh = {Cell Line ; Epithelial Cells/*microbiology ; Humans ; Particulate Matter/*adverse effects ; Phosphatidylinositol 3-Kinases/*metabolism ; Platelet Membrane Glycoproteins/*metabolism ; Pseudomonas aeruginosa/*pathogenicity ; Reactive Oxygen Species/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Respiratory Mucosa/*microbiology ; Signal Transduction/*drug effects ; Up-Regulation/drug effects/genetics ; }, abstract = {Over exposure to particulate matter (PM) could irritate respiratory tract infection; while, Pseudomonas aeruginosa (P. aeruginosa) is one of the main common pathogens. Our study aims are to define whether PM exposure enhances the invasion of P. aeruginosa into the airway epithelia and to characterize the underlying mechanisms. Human bronchial epithelial cells (BEAS-2B) or BEAS-2B transfected by PAFR siRNA were challenged with PM and pretreated with N-acetylcysteine (NAC), LY294002 (PI3K inhibitor), BAY 11-7082 (NF-κB inhibitor), or CV-3988 (PAFR antagonist). P. aeruginosa invasion was evaluated using colony-forming units assay and confocal microscopy. Real-time RT-PCR, immunofluorescence, flow cytometry and western blotting were used to detect the genes or proteins expression. PM exposure promoted P. aeruginosa invasion into BEAS-2B cells through ROS-mediated PI3K pathway which enhanced the expression of PAFR, which could be alleviated by treatment with NAC, LY294002, and BAY 11-7082. Furthermore, NAC and PAFR siRNA attenuated PM-stimulated activation of PI3K pathway. Treatment with PAFR antagonist and siRNA also alleviated PM exposure-induced P. aeruginosa invasion into BEAS-2B cells. Our results demonstrated that PM exposure increased the PAFR expression and activated the PI3K pathway in a ROS-dependent manner. Upregulated PAFR and activated PI3K pathway formed a positive regulatory loop and promoted the invasion of P. aeruginosa into airway epithelia. These mechanisms may provide a novel approach against P.aeruginosa invasion.}, }
@article {pmid32626938, year = {2020}, author = {Xu, WT and Shen, GN and Li, TZ and Zhang, Y and Zhang, T and Xue, H and Zuo, WB and Li, YN and Zhang, DJ and Jin, CH}, title = {Isoorientin induces the apoptosis and cell cycle arrest of A549 human lung cancer cells via the ROS‑regulated MAPK, STAT3 and NF‑κB signaling pathways.}, journal = {International journal of oncology}, volume = {57}, number = {2}, pages = {550-561}, doi = {10.3892/ijo.2020.5079}, pmid = {32626938}, issn = {1791-2423}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Drug Screening Assays, Antitumor ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Lung Neoplasms/*drug therapy/pathology ; Luteolin/*pharmacology/therapeutic use ; MAP Kinase Signaling System/*drug effects ; NF-kappa B/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; STAT3 Transcription Factor/metabolism ; }, abstract = {Isoorientin (ISO) is a naturally occurring C‑glycosyl flavone that has various pharmacological properties, such as anti‑bacterial and anti‑inflammatory effects. However, its underlying molecular mechanisms in human lung cancer cells remain unknown. In the present study, the effects of ISO on the induction of apoptosis and relative molecular mechanisms in A549 human lung cancer cells were investigated. The results of Cell Counting Kit‑8 assay (CCK‑8) indicated that ISO exerted significant cytotoxic effects on 3 lung cancer cell lines, but had no obvious side‑effects on normal cells. Moreover, flow cytometry and western blot analysis revealed that ISO induced mitochondrial‑dependent apoptosis by reducing mitochondrial membrane potential. ISO also increased the expression levels of Bax, cleaved‑caspase‑3 (cle‑cas‑3) and poly(ADP‑ribose) polymerase (PARP; cle‑PARP), and decreased the expression levels of Bcl‑2 in A549 cells. Furthermore, ISO induced G2/M cell cycle arrest by decreasing the expression levels of cyclin B1 and CDK1/2, and increasing the expression levels of p21 and p27 in A549 cells. As the duration of ISO treatment increased, intracellular reactive oxygen species (ROS) levels in A549 cells also increased. However, pre‑treatment of the cells with the ROS scavenger, N‑acetylcysteine (NAC), inhibited ISO‑induced apoptosis. In addition, ISO increased the expression levels of p‑p38, p‑JNK and IκB‑α; and decreased the expression levels of p‑extracellular signal‑regulated kinase (ERK), p‑signal transducer and activator of transcription (STAT)3, p‑nuclear factor (NF)‑κB, NF‑κB and p‑IκB; these effects were induced by mitogen‑activated protein kinase (MAPK) inhibitors and blocked by NAC. Taken together, the results of the present study indicate that ISO induces the apoptosis of A549 lung cancer cells via the ROS‑mediated MAPK/STAT3/NF‑κB signaling pathway, and thus may be a potential drug for use in the treatment of lung cancer.}, }
@article {pmid32622850, year = {2020}, author = {Iordache, AM and Buga, AM and Albulescu, D and Vasile, RC and Mitrut, R and Georgiadis, G and Zisis, IE and Mamoulakis, C and Tsatsakis, A and Docea, AO and Calina, D}, title = {Phosphodiesterase-5 inhibitors ameliorate structural kidney damage in a rat model of contrast-induced nephropathy.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {143}, number = {}, pages = {111535}, doi = {10.1016/j.fct.2020.111535}, pmid = {32622850}, issn = {1873-6351}, mesh = {Animals ; Contrast Media/*adverse effects ; Kidney Diseases/*chemically induced/prevention &amp; control ; Kidney Tubules/*drug effects/pathology ; Male ; Phosphodiesterase 5 Inhibitors/*pharmacology ; Rats ; Rats, Wistar ; Sildenafil Citrate/*therapeutic use ; Tadalafil/*therapeutic use ; }, abstract = {The aim of the study was to investigate the potential of sildenafil and tadalafil to ameliorate structural kidney damage in contrast-induced nephropathy (CIN). A rat model of CIN was developed by dehydration, administration of a nitric oxide inhibitor and a prostaglandin synthesis inhibitor (L-NAME/indomethacin) and contrast media exposure to iopromide. The effect of pre-treatment with sildenafil, tadalafil or N-acetyl cysteine (NAC) for 7 days prior to CIN induction was investigated. All animals were sacrificed at 24 h after CIN induction and both kidneys were collected. Histopathological examination was performed under light microscopy in serial tissue sections stained with hematoxylin and eosin. CIN group showed hydropic changes of the renal tubules (proximal and distal convoluted tubules and Henle's loop), an increased Bowman space with lobulated glomerulus and alteration of macula densa region of distal convolute tubules. The groups pretreated with sildenafil and tadalafil showed nearly normal histological aspects of renal tissue. The group pretreated with NAC showed similar but less intense histopathologic changes compared to CIN group. Sildenafil and tadalafil pre-treatment ameliorates CIN-related structural kidney damage and the protective potential of these agents is superior to NAC.}, }
@article {pmid32620109, year = {2020}, author = {de Groot, LES and Liu, D and Dierdorp, BS and Fens, N and van de Pol, MA and Sterk, PJ and Kulik, W and Gerlofs-Nijland, ME and Cassee, FR and Pinelli, E and Lutter, R}, title = {Ex vivo innate responses to particulate matter from livestock farms in asthma patients and healthy individuals.}, journal = {Environmental health : a global access science source}, volume = {19}, number = {1}, pages = {78}, pmid = {32620109}, issn = {1476-069X}, support = {4.1.15.002//Lung Foundation Netherlands/International ; S/121012//Rijksinstituut voor Volksgezondheid en Milieu/International ; }, mesh = {Air Pollutants/*adverse effects ; Animals ; Asthma/physiopathology ; Chickens ; Cytokines/*metabolism ; Environmental Health ; *Farms ; Goats ; Leukocytes, Mononuclear/*chemistry ; Livestock ; *Oxidative Stress ; Particulate Matter/*adverse effects ; Sus scrofa ; }, abstract = {BACKGROUND: Asthma patients suffer from periodic acute worsening of symptoms (i.e. loss of asthma control or exacerbations), triggered by a variety of exogenous stimuli. With the growing awareness that air pollutants impact respiratory diseases, we investigated whether particulate matter (PM) derived from various livestock farms (BioPM) differentially affected innate and oxidative stress responses in asthma and health.<br><br>METHODS: Peripheral blood mononuclear cells (PBMCs), collected from patients sequentially before and during loss of asthma control and from healthy individuals, were exposed to BioPM collected from chicken, goat and pig farms (1 and 5&#x2009;&#x3bc;g/ml), with or without pre-treatment with antioxidants. Cytokine release and oxidative stress were assessed.<br><br>RESULTS: PBMCs produced IFN&#x3b3;, IL-1&#x3b2;, IL-10 and TNF&#x3b1; upon stimulation with BioPM, with that from pig farms inducing the highest cytokine levels. Overall, cytokine production was irrespective of the presence or state of disease. However, PBMCs from stable asthma patients upon exposure to the three BioPM showed more extreme TNF&#x3b1; responses than those from healthy subjects. Furthermore, PBMCs obtained during loss of asthma control that were exposed to BioPM from pig farms showed enhanced IFN&#x3b3; release as well as decreased oxidative stress levels upon pre-treatment with N-acetylcysteine (NAC) compared to stable disease. NAC, but not superoxide dismutase and catalase, also counteracted BioPM-induced cytokine release, indicating the importance of intracellular reactive oxygen species in the production of cytokines.<br><br>CONCLUSIONS: BioPM triggered enhanced pro-inflammatory responses by PBMCs from both healthy subjects and asthma patients, with those from patients during loss of asthma control showing increased susceptibility to BioPM from pig farms in particular.}, }
@article {pmid32617902, year = {2020}, author = {Swetha, KL and Sharma, S and Chowdhury, R and Roy, A}, title = {Disulfiram potentiates docetaxel cytotoxicity in breast cancer cells through enhanced ROS and autophagy.}, journal = {Pharmacological reports : PR}, volume = {72}, number = {6}, pages = {1749-1765}, doi = {10.1007/s43440-020-00122-1}, pmid = {32617902}, issn = {2299-5684}, support = {ECR/2016/000566/LS//Science and Engineering Research Board/ ; }, mesh = {Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Breast Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Disulfiram/administration &amp; dosage/*pharmacology ; Docetaxel/administration &amp; dosage/*pharmacology ; Drug Synergism ; Female ; Humans ; MCF-7 Cells ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Recent studies have demonstrated that autophagy plays a critical role in reducing the drug sensitivity of docetaxel (DTX) therapy. Disulfiram (DSF) has exhibited potent autophagy inducing activity in multiple studies. We hypothesized that DSF co-treatment could sensitize breast cancer cells to DTX therapy via autophagy modulation.<br><br>METHODS: Breast cancer cells, MCF7, and 4T1, were treated with DTX and DSF, alone and in combination. The effects were analyzed by evaluating cytotoxicity, induction of apoptosis, induction of autophagy, and reactive oxygen species (ROS) generation. In addition, the consequence of autophagy and ROS inhibition on the DTX&#x2009;+&#x2009;DSF mediated cytotoxicity was also evaluated.<br><br>RESULTS: Significant synergism in cytotoxicity was observed with DTX&#x2009;+&#x2009;DSF combination in breast cancer cells, MCF7, and 4T1. Hyper induction of ROS and autophagy was also found with the combination treatment. ROS inhibition by N-Acetyl Cysteine (NAC), as well as autophagy inhibition by ATG5 silencing significantly reduced the autophagy level as well as cytotoxicity of the DTX&#x2009;+&#x2009;DSF combination, indicating that the induction of autophagy mediated by high ROS generation played a critical role behind the synergistic cytotoxicity.<br><br>CONCLUSIONS: This study indicates that DTX&#x2009;+&#x2009;DSF combination therapy can effectively sensitize cancer cells by hyper inducing autophagy through ROS generation and can be developed as a therapeutic strategy for cancer treatment in the future.}, }
@article {pmid32616191, year = {2020}, author = {Fan, QM and Zhao, WT and Yuan, R and Wang, QQ and Zhang, LF and Gao, HW and Leng, J and Yang, SL}, title = {The ethyl acetate extraction of Pileostegia tomentella (ZLTE) exerts anti-cancer effects on H1299 cells via ROS-induced canonical apoptosis.}, journal = {Chinese journal of natural medicines}, volume = {18}, number = {7}, pages = {508-516}, doi = {10.1016/S1875-5364(20)30061-3}, pmid = {32616191}, issn = {1875-5364}, mesh = {A549 Cells ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy ; Humans ; Lung Neoplasms/*drug therapy ; Plant Extracts/*pharmacology ; Protein-Tyrosine Kinases/*metabolism ; Proto-Oncogene Proteins/*metabolism ; }, abstract = {Lung cancer is the leading cause of cancer death and the most common malignant tumor, the long-term survival of which has stagnated in the past several decades. Pileostegia tomentella Hand. Mazz is a traditional Chinese medicine called "Zhongliuteng" (ZLT) in the pharmacopeia, which has been proved to possess a potent anti-tumor effect on various cancers. In this study, the effects of ZLT N-butanol extraction (ZLTN) and ZLT ethyl acetate extraction (ZLTE) on the viability of non-small cell lung cancer cell (NSCLC) lines H1299 and A549 were evaluated. Here, we firstly reported that ZLTE significantly inhibited H1299 cells growth without affecting the release of lactate dehydrogenase (LDH). In addition, ZLTE induced caspase-dependent apoptosis in a concentration-dependent manner and increased the expression cleaved-PARP and decreased pro-caspase-3, pro-caspase-7, pro-caspase-8, and pro-caspase-9. Moreover, ZLTE increased the level of cellular reactive oxygen species (ROS) in H1299 cells to lead to apoptosis, which was reversed by N-acetyl-cysteine (NAC). Taken together, our results revealed that ZLTE induced caspase-dependent apoptosis via ROS generation, suggesting that ZLTE is a promising herbal medicine for the treatment of NSCLC.}, }
@article {pmid32615411, year = {2020}, author = {Cheng, CY and Vo, TTT and Lin, WN and Huang, HW and Chuang, CC and Chu, PM and Lee, IT}, title = {Nrf2/HO-1 partially regulates cytoprotective effects of carbon monoxide against urban particulate matter-induced inflammatory responses in oral keratinocytes.}, journal = {Cytokine}, volume = {133}, number = {}, pages = {155185}, doi = {10.1016/j.cyto.2020.155185}, pmid = {32615411}, issn = {1096-0023}, mesh = {Anti-Inflammatory Agents/pharmacology ; Carbon Monoxide/*pharmacology ; Cells, Cultured ; Heme Oxygenase-1/*metabolism ; Humans ; Inflammasomes/*drug effects/metabolism ; Inflammation/chemically induced/metabolism ; Keratinocytes/*drug effects/metabolism ; Mitochondria/drug effects/metabolism ; NADPH Oxidases/metabolism ; NF-E2-Related Factor 2/*metabolism ; Organometallic Compounds/pharmacology ; Particulate Matter/*pharmacology ; Protective Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {INTRODUCTION: Exposure to airborne particulate matter (PM) increases the proportion of oral inflammatory diseases. During the formation of inflammatory conditions, the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation plays an important regulator. Carbon monoxide (CO) arising from heme degradation, catalyzed particularly by heme oxygenase-1 (HO-1), has been shown to own cytoprotective effects including anti-inflammation and antioxidant. Here, we determined the novel mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on PM-induced inflammatory responses in human oral keratinocytes (HOKs).<br><br>METHODS: The effects of CORM-2 on the expression of various inflammatory proteins induced by PM were determined by Western blot, real-time PCR, promoter assay, and ELISA. The involvement of signaling molecules in these responses was studied by using the selective pharmacological inhibitors and siRNAs.<br><br>RESULTS: We proved that PM enhanced C-reactive protein (CRP) levels, NLRP3 inflammasome and caspase-1 activation, and IL-1&#x3b2; release, which were reduced by preincubation with CORM-2. Transfection with PKC&#x3b1; siRNA and preincubation with the ROS scavenger (N-acetyl-cysteine, NAC), an inhibitor of NADPH oxidase (diphenyleneiodonium, DPI), or the mitochondria-specific superoxide scavenger (MitoTEMPO) inhibited PM-mediated inflammatory responses. In addition, PM-regulated PKC&#x3b1; and NADPH oxidase activation as well as NADPH oxidase- and mitochondria-derived ROS generation were inhibited by CORM-2, but not inactivate CORM-2 (iCORM-2) pretreatment. At the end, we confirmed that CORM-2 improved PM-induced inflammatory responses via the induction of Nrf2 activation and HO-1 expression.<br><br>CONCLUSION: We suggest that CORM-2 inhibits PM-induced inflammatory responses in HOKs via the inhibition of PKC&#x3b1;/ROS/NLRP3 inflammasome activation combined with the induction of Nrf2/HO-1 expression.}, }
@article {pmid32609548, year = {2020}, author = {Liu, J and Chen, Y and Gao, Y and Walline, JH and Lu, X and Yu, S and Zhao, L and Ge, Z and Li, Y}, title = {N-acetylcysteine as a treatment for amatoxin poisoning: a systematic review.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {58}, number = {11}, pages = {1015-1022}, doi = {10.1080/15563650.2020.1784428}, pmid = {32609548}, issn = {1556-9519}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Acute Kidney Injury/etiology ; Amanitins/*poisoning ; Gastrointestinal Hemorrhage/etiology ; Humans ; Liver/physiopathology ; Liver Transplantation/mortality/statistics &amp; numerical data ; }, abstract = {Introduction: Amatoxin leads to the majority of deaths by mushroom poisoning around the world. Amatoxin causes gastrointestinal disturbances and multiple organ dysfunction, including liver and renal failure. As a potential treatment for amatoxin poisoning, N-acetylcysteine (NAC) has been used for decades but its benefit is still unproven.Objectives: We undertook a systematic review to evaluate the performance and safety of N-acetylcysteine on patients suffering amatoxin intoxication.Methods: We searched Pubmed, EMBASE, CENTRAL and SinoMed databases, from inception to August 31, 2019. Articles were eligible if there were five or more patients with amatoxin poisoning and N-acetylcysteine was included in the therapeutic regimen. Mortality rate including liver transplant cases (MRLTi) was the primary outcome. Mortality rate not including liver transplant cases, liver and renal function, clinical complications, as well as any adverse reactions to intravenous NAC were secondary outcomes.Results: Thirteen studies with a total of 506 patients were included. The MRLTi of amatoxin-poisoning patients with NAC treatment was 11% (57/506), and a MRLTe of 7.9% (40/506) and a liver transplantation rate of 4.3% (22/506). Transaminase concentrations generally peaked around 3 days after ingestion, prothrombin time/International Normalized Ratio (PT/INR) generally worsened during the first 3-4 days after ingestion before returning to normal four to 7 days after ingestion, and Factor V levels normalized in about 4-5 days after ingestion in patients treated with NAC. Renal failure was reported in 3% (3/101) and acute kidney injury was reported in 19% (5/27). Gastrointestinal bleeding occurred in 21% (15/71). Anaphylactoid reactions were the principle adverse reaction to NAC treatment in amatoxin-poisoning patients with an incidence of 5% (4/73).Conclusions: NAC treatment combined with other therapies appears to be beneficial and safe in patients with amatoxin poisoning. Until further data emerge, it is reasonable to use NAC in addition to other treatments for amatoxin poisoning.}, }
@article {pmid32606699, year = {2020}, author = {Yalin, N and Young, AH}, title = {Pharmacological Treatment of Bipolar Depression: What are the Current and Emerging Options?.}, journal = {Neuropsychiatric disease and treatment}, volume = {16}, number = {}, pages = {1459-1472}, pmid = {32606699}, issn = {1176-6328}, abstract = {Depression accounts for the predominant burden associated with bipolar disorder. The identification and management of bipolar depression are challenging, since bipolar depression differs from unipolar depression, responding poorly to traditional antidepressants, which may also induce a switch to hypomania/mania, mixed states and/or cause rapid cycling. Current treatment options for bipolar depression are limited and guidelines vary greatly in their recommendations, reflecting gaps and inconsistencies in the current evidence base. Moreover, some treatment options, such as quetiapine and olanzapine-fluoxetine, although clearly efficacious, may be associated with adverse cardiometabolic side effects, which can be detrimental to the long-term physical health and well-being of patients, increasing the likelihood of treatment non-adherence and relapse. Evidence for some more recent therapeutic options, including lurasidone and cariprazine, suggests that patients' symptoms can be effectively managed without compromising their physical health. In addition, novel agents targeting alternative neurotransmitter pathways and inflammatory processes (such as ketamine and N-acetyl cysteine) are emerging as promising potential options for the treatment of bipolar depression in the future.}, }
@article {pmid32606152, year = {2020}, author = {Gong, YX and Liu, Y and Jin, YH and Jin, MH and Han, YH and Li, J and Shen, GN and Xie, DP and Ren, CX and Yu, LY and Lee, DS and Kim, JS and Jo, YJ and Kwon, J and Lee, J and Park, YH and Kwon, T and Cui, YD and Sun, HN}, title = {Picrasma quassioides Extract Elevates the Cervical Cancer Cell Apoptosis Through ROS-Mitochondrial Axis Activated p38 MAPK Signaling Pathway.}, journal = {In vivo (Athens, Greece)}, volume = {34}, number = {4}, pages = {1823-1833}, pmid = {32606152}, issn = {1791-7549}, mesh = {Apoptosis ; Female ; Humans ; Membrane Potential, Mitochondrial ; Mitochondria/metabolism ; *Picrasma/metabolism ; Reactive Oxygen Species ; Signal Transduction ; *Uterine Cervical Neoplasms/drug therapy/genetics ; p38 Mitogen-Activated Protein Kinases/genetics ; }, abstract = {BACKGROUND/AIM: Picrasma quassioides (P. quassioides) is used in traditional Asian medicine widely for the treatment of anemopyretic cold, eczema, nausea, loss of appetite, diabetes mellitus, hypertension etc. In this study we aimed to understand the effect of P. quassioides ethanol extract on SiHa cervical cancer cell apoptosis.<br><br>MATERIALS AND METHODS: The P. quassioides extract-induced apoptosis was analyzed using the MTT assay, fluorescence microscopy, flow cytometry and western blotting.<br><br>RESULTS: P. quassioides extract induced cellular apoptosis by increasing the accumulation of cellular and mitochondrial reactive oxygen species (ROS) levels and inhibiting ATP synthesis. Pretreatment with N-Acetylcysteine (NAC), a classic antioxidant, decreased the intracellular ROS production and inhibited apoptosis. In addition, the P38 MAPK signaling pathway is a key in the apoptosis of SiHa cells induced by the P. quassioides extract.<br><br>CONCLUSION: The P. quassioides extract exerts its anti-cancer properties on SiHa cells through ROS-mitochondria axis and P38 MAPK signaling. Our data provide a new insight for P. quassioides as a therapeutic strategy for cervical cancer treatment.}, }
@article {pmid32606118, year = {2020}, author = {James, J and Stauss, M and Ponnusamy, A and Myers, M}, title = {False-positive paracetamol levels in a patient with hyperbilirubinaemia: clinical perspectives.}, journal = {BMJ case reports}, volume = {13}, number = {6}, pages = {}, pmid = {32606118}, issn = {1757-790X}, mesh = {*Acetaminophen/administration &amp; dosage/blood ; Acetylcysteine/administration &amp; dosage ; Analgesics, Non-Narcotic/administration &amp; dosage/blood ; Colitis, Ischemic/drug therapy ; Colorimetry/methods ; Dimensional Measurement Accuracy ; *False Positive Reactions ; Free Radical Scavengers/administration &amp; dosage ; Humans ; Hyperbilirubinemia/*blood ; *Liver Failure/blood/chemically induced/diagnosis ; Liver Function Tests/methods ; Male ; Middle Aged ; Reproducibility of Results ; }, abstract = {Serum concentrations of paracetamol are measured to investigate the cause of acute hepatitis, monitor the clearance of paracetamol from the body and to determine if supratherapeutic levels warrant treatment with N-acetylcysteine (NAC). A 49-year-old man treated for ischaemic colitis developed worsening renal and liver function tests. As part of the investigation of hepatorenal failure, paracetamol levels were requested, which were elevated at 14 mg/L (normal <4 mg/L) resulting in treatment with NAC. Despite treatment, levels of paracetamol remained elevated and the link between hyperbilirubinemia and false-positive paracetamol levels was identified. Bilirubin and its by-products have intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum, causing interference in the enzymatic colorimetric assay most commonly used to measure paracetamol concentration, resulting in false-positive paracetamol levels. Laboratories correct for this interference above a predetermined bilirubin concentration, termed the Icteric Index; however, in our case this interference occurred at a lower level of hyperbilirubinaemia than previously identified as significant. This interaction was found to be more significant at lower bilirubin levels when low or no paracetamol levels were present in the serum, resulting in a change to laboratory practice and development of a 'Sliding Scale' approach to analysis. Concurrent bilirubin or Icteric Index measurement is recommended for all laboratories that use the enzymatic colorimetric assay for paracetamol measurement. Lower Icteric Index or bilirubin thresholds are required when low or no paracetamol levels are present in the serum to prevent false-positive paracetamol results. We describe a new 'Sliding Scale' approach to analysis, and highlight an important interaction for clinicians to be aware of.}, }
@article {pmid32603245, year = {2020}, author = {Li, ZG}, title = {Regulative role of calcium signaling on methylglyoxal-improved heat tolerance in maize (Zea mays L) seedlings.}, journal = {Plant signaling &amp; behavior}, volume = {15}, number = {9}, pages = {1788303}, pmid = {32603245}, issn = {1559-2324}, mesh = {Calcium Signaling/genetics/*physiology ; Heat-Shock Response/genetics/physiology ; Pyruvaldehyde/*metabolism ; Seedlings/genetics/*physiology ; Thermotolerance ; Zea mays/genetics/*physiology ; }, abstract = {Nowadays, calcium (Ca[2+]) and methylglyoxal (MG) are all deemed to be second messengers in plants, which participate in various physiological processes, such as seed germination, seedling establishment, plant growth and development, as well as response to environmental stress. However, the Ca[2+]-MG interaction in the development of thermotolerance in maize seedlings remains unclear. Here, using maize seedlings as materials, the crosstalk between Ca[2+] and MG signaling in the acquisition of thermotolerance was explored. The results showed that root-irrigation with Ca[2+] and MG alone or in combination increased the survival rate of maize seedlings under heat stress, mitigated the decrease in the tissue vitality, and reduced the membrane lipid peroxidation (in term of the content of malondialdehyde), indicating that Ca[2+] and MG could improve the thermotolerance in maize seedlings. In addition, MG-improved thermotolerance was impaired by ethylene glycol-bis(b-aminoethylether)-N,N,N΄,N΄-tetraacetic acid (a Ca[2+] chelator), La[3+] (plasma membrane Ca[2+] channel blocker), ruthenium red (a mitochondrial Ca[2+] channel blocker), neomycin (vacuole Ca[2+] channel blocker), caffeine (an endoplasmic reticulum Ca[2+] channel blocker), and calmodulin antagonists (chlorpromazine and trifluoperazine), respectively. Also, MG scavengers (N-acetyl-cysteine, aminoguanidine, and vitamin B6) had no significant effect on Ca[2+]-triggered thermotolerance (in terms of survival rate, malondialdehyde, and tissue vitality) of maize seedlings. The data illustrated that calcium signaling regulated MG-improved thermotolerance in maize seedlings by mobilizing intracellular and extracellular Ca[2+] pools.}, }
@article {pmid32601973, year = {2020}, author = {Khalefa, HG and Shawki, MA and Aboelhassan, R and El Wakeel, LM}, title = {Evaluation of the effect of N-acetylcysteine on the prevention and amelioration of paclitaxel-induced peripheral neuropathy in breast cancer patients: a randomized controlled study.}, journal = {Breast cancer research and treatment}, volume = {183}, number = {1}, pages = {117-125}, doi = {10.1007/s10549-020-05762-8}, pmid = {32601973}, issn = {1573-7217}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Antineoplastic Agents, Phytogenic/administration &amp; dosage/*adverse effects/therapeutic use ; Biomarkers ; Breast Neoplasms/blood/complications/*drug therapy ; Chemotherapy, Adjuvant ; Drug Administration Schedule ; Female ; Humans ; Kaplan-Meier Estimate ; Lipid Peroxidation/drug effects ; Malondialdehyde/blood ; Middle Aged ; Nerve Growth Factor/blood ; Paclitaxel/administration &amp; dosage/*adverse effects/therapeutic use ; Peripheral Nervous System Diseases/blood/chemically induced/drug therapy/*prevention &amp; control ; Prospective Studies ; Quality of Life ; }, abstract = {PURPOSE: The aim of the current study was to evaluate the effect of N-acetylcysteine (NAC) on the incidence and severity of paclitaxel-induced peripheral neuropathy (PIPN) in breast cancer patients.<br><br>METHOD: A prospective randomized controlled open label study was conducted on 75 breast cancer patients receiving adjuvant paclitaxel 80&#xa0;mg/m[2] weekly for 12&#xa0;weeks. Eligible patients were randomized to either the low dose group; 1200&#xa0;mg daily NAC, the high dose group; 1200&#xa0;mg NAC twice daily or the control group; received paclitaxel only. The primary endpoint was the incidence of different grades of PIPN using National Cancer Institute's common toxicity criteria for adverse event (NCI-CTCAE) while secondary endpoints were the severity of PIPN using modified total neuropathy score (mTNS), quality of life (QOL) using Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-NTX) subscale, serum nerve growth factor (NGF), and serum malondialdehyde (MDA).<br><br>RESULTS: At the end of the 12-week period, the incidence of grade (2, 3) peripheral neuropathy was significantly lower in the high dose group (28.6%) compared to the low dose group (61.9%) and the control group (100%), p value&#x2009;<&#x2009;0.001. A significant improvement in the mTNS and QOL scores was observed after 6 and 12&#xa0;weeks in the high dose group and the low dose group compared to the control, p value&#x2009;<&#x2009;0.001. Significantly higher levels of serum NGF in the high dose group and lower level of serum MDA in the high dose and the low dose group were observed.<br><br>CONCLUSION: Oral NAC (1200&#xa0;mg once and twice daily) might reduce the incidence and severity of PIPN and improve the patients' QOL.<br><br>TRIAL REGISTRY: Clinical Trial.gov registration number: NCT03492047.}, }
@article {pmid32600481, year = {2020}, author = {Bortolasci, CC and Voigt, C and Turner, A and Mohebbi, M and Gray, L and Dodd, S and Walder, K and Berk, M and Cotton, SM and Malhi, GS and Ng, CH and Dowling, N and Sarris, J and Dean, OM}, title = {Interleukin-6 and total antioxidant capacity levels following N-acetylcysteine and a combination nutraceutical intervention in a randomised controlled trial for bipolar disorder.}, journal = {Acta neuropsychiatrica}, volume = {32}, number = {6}, pages = {313-320}, doi = {10.1017/neu.2020.25}, pmid = {32600481}, issn = {1601-5215}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Antioxidants/analysis ; Bipolar Disorder/*drug therapy/metabolism/physiopathology ; Case-Control Studies ; Depressive Disorder/drug therapy/metabolism ; Dietary Supplements/*adverse effects ; Double-Blind Method ; Drug Therapy, Combination ; Energy Metabolism/drug effects ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Humans ; Inflammation/metabolism ; Interleukin-6/*blood ; Male ; Mitochondria/drug effects ; Oxidative Stress/*drug effects ; Placebos/administration &amp; dosage ; Treatment Outcome ; }, abstract = {OBJECTIVE: The aims of this study were to evaluate changes in inflammatory and oxidative stress levels following treatment with N-acetylcysteine (NAC) or mitochondrial-enhancing agents (CT), and to assess the how these changes may predict and/or moderate clinical outcomes primarily the Montgomery-Åsberg Depression Rating Scale (MADRS).<br><br>METHODS: This study involved secondary analysis of a placebo-controlled randomised trial (n = 163). Serum samples were collected at baseline and week 16 of the clinical trial to determine changes in Interleukin-6 (IL-6) and total antioxidant capacity (TAC) following adjunctive CT and/or NAC treatment, and to explore the predictability of the outcome or moderator effects of these markers.<br><br>RESULTS: In the NAC-treated group, no difference was observed in serum IL-6 and TAC levels after 16 weeks of treatment with NAC or CT. However, results from a moderator analysis showed that in the CT group, lower IL-6 levels at baseline was a significant moderator of MADRS &#x3c7;2 (df) = 4.90, p = 0.027) and Clinical Global Impression-Improvement (CGI-I, &#x3c7;2 (df) = 6.28 p = 0.012). In addition, IL-6 was a non-specific but significant predictor of functioning (based on the Social and Occupational Functioning Assessment Scale (SOFAS)), indicating that individuals with higher IL-6 levels at baseline had a greater improvement on SOFAS regardless of their treatment (p = 0.023).<br><br>CONCLUSION: Participants with lower IL-6 levels at baseline had a better response to the adjunctive treatment with the mitochondrial-enhancing agents in terms of improvements in MADRS and CGI-I outcomes.}, }
@article {pmid32599978, year = {2020}, author = {Kim, HJ and Kang, SU and Lee, YS and Jang, JY and Kang, H and Kim, CH}, title = {Protective Effects of N-Acetylcysteine against Radiation-Induced Oral Mucositis In Vitro and In Vivo.}, journal = {Cancer research and treatment}, volume = {52}, number = {4}, pages = {1019-1030}, pmid = {32599978}, issn = {2005-9256}, support = {2017M3A9F7079339//National Research Foundation of Korea/ ; 2018R1A2B3009008//Ministry of Science, ICT and Future Planning/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Animals ; Autophagy/drug effects/radiation effects ; Cell Line ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Keratinocytes ; Mouth Mucosa/drug effects/pathology/radiation effects ; Nebulizers and Vaporizers ; Radiation Injuries, Experimental/etiology/pathology/*prevention &amp; control ; Rats ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Stomatitis/etiology/pathology/*prevention &amp; control ; }, abstract = {PURPOSE: Radiation-induced oral mucositis limits delivery of high-dose radiation to targeted cancers. Therefore, it is necessary to develop a treatment strategy to alleviate radiation-induced oral mucositis during radiation therapy. We previously reported that inhibiting reactive oxygen species (ROS) generation suppresses autophagy. Irradiation induces autophagy, suggesting that antioxidant treatment may be used to inhibit radiation-induced oral mucositis.<br><br>MATERIALS AND METHODS: We determined whether treatment with N-acetyl cysteine (NAC) could attenuate radiation-induced buccal mucosa damage in vitro and in vivo. The protective effects of NAC against oral mucositis were confirmed by transmission electron microscopy and immunocytochemistry. mRNA and protein levels of DNA damage and autophagy-related genes were measured by quantitative real-time polymerase chain reaction and western blot analysis, respectively.<br><br>RESULTS: Rats manifesting radiation-induced oral mucositis showed decreased oral intake, loss of body weight, and low survival rate. NAC intake slightly increased oral intake, body weight, and the survival rate without statistical significance. However, histopathologic characteristics were markedly restored in NAC-treated irradiated rats. LC3B staining of rat buccal mucosa revealed that NAC treatment significantly decreased the number of radiation-induced autophagic cells. Further, NAC inhibited radiation-induced ROS generation and autophagy signaling. In vitro, NAC treatment significantly reduced the expression of NRF2, LC3B, p62, and Beclin-1 in keratinocytes compared with that after radiation treatment.<br><br>CONCLUSION: NAC treatment significantly inhibited radiation-induced autophagy in keratinocytes and rat buccal mucosa and may be a potentially safe and effective option for the prevention of radiation-induced buccal mucosa damage.}, }
@article {pmid32596809, year = {2020}, author = {Wang, L and Xu, X and Liu, T and Wang, J and Shen, J and Guo, M and Wu, Y and Zhai, X and Zuo, D}, title = {1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42), a novel ALK inhibitor, induces apoptosis and protective autophagy in H2228 cells.}, journal = {The Journal of pharmacy and pharmacology}, volume = {72}, number = {10}, pages = {1370-1382}, doi = {10.1111/jphp.13315}, pmid = {32596809}, issn = {2042-7158}, support = {81872394//National Natural Science Foundation of China/ ; 81673308//National Natural Science Foundation of China/ ; ZQN2015003//Young and middle age backbone personnel training programme of Shenyang Pharmaceutical University/ ; 2016921065//Liaoning BaiQianWan Talents Program/ ; }, mesh = {A549 Cells ; Anaplastic Lymphoma Kinase/*antagonists &amp; inhibitors/metabolism ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects/physiology ; Autophagy/*drug effects/physiology ; Cytoprotection/*drug effects/physiology ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Protein Kinase Inhibitors/chemistry/*pharmacology ; Protein Structure, Secondary ; }, abstract = {OBJECTIVES: To examine the antiproliferative effects of 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42) on the echinoderm microtubule-associated protein-4/anaplastic lymphoma kinase fusion gene (EML4-ALK) positive lung cancer cell line H2228 and its underlying mechanism.<br><br>METHODS: The MTT assay was used to study the effect of ZX-42 on H2228 cell growth. Propidium iodide (PI) staining and Western blotting were used to investigate the cell cycle changes. ZX-42-induced cell apoptosis was determined using the Annexin V-FITC/PI (AV/PI) apoptotic assay kit, acridine orange/ethidium bromide (AO/EB) and Hoechst 33258 staining, Rhodamine 123 (Rh 123) fluorescence assay and Western blotting. ZX-42-induced reactive oxygen species (ROS) production was examined by ROS assay kit. Transmission electron microscope, monodansylcadaverine (MDC) staining and the AV/PI apoptotic assay kit were used to demonstrate the relationship between autophagy and apoptosis.<br><br>KEY FINDINGS: ZX-42 had good cell viability inhibitory effect on H2228 cells. ZX-42 dramatically inhibited ALK and its downstream pathways. ZX-42 also blocked H2228 cell cycle at G1 phase and then induced apoptosis by activating the mitochondrial pathway. Next, ZX-42 induced the production of ROS, and antioxidant N-acetylcysteine (NAC) reduced ROS production and also decreased apoptotic rates. We also found that ZX-42 induced protective autophagy in H2228 cells.<br><br>CONCLUSIONS: In summary, ZX-42 is a novel ALK inhibitor that significantly inhibits the cell viability of H2228 cells and ultimately induces apoptosis through the mitochondrial pathway, in which autophagy plays a protective role. Therefore, inhibition of autophagy might enhance the anti-cancer effect of ZX-42.}, }
@article {pmid32594840, year = {2020}, author = {Gao, T and Lin, M and Shao, B and Zhou, Q and Wang, Y and Chen, X and Zhao, D and Dai, X and Shen, C and Cheng, H and Yang, S and Li, H and Zheng, B and Zhong, X and Yu, J and Chen, L and Huang, X}, title = {BMI1 promotes steroidogenesis through maintaining redox homeostasis in mouse MLTC-1 and primary Leydig cells.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {19}, number = {15}, pages = {1884-1898}, pmid = {32594840}, issn = {1551-4005}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p19/metabolism ; Heterocyclic Compounds, 2-Ring/pharmacology ; *Homeostasis/drug effects ; Leydig Cells/drug effects/*metabolism ; Male ; Mice ; Models, Biological ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Polycomb Repressive Complex 1/*metabolism ; Proto-Oncogene Proteins/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Steroids/*biosynthesis ; Testis/metabolism ; Testosterone/biosynthesis ; Thiazoles/pharmacology ; }, abstract = {In males, aging is accompanied by decline in serum testosterone levels due to impairment of testicular Leydig cells. The polycomb protein BMI1 has recently been identified as an anti-aging factor. In our previous study, BMI1 null mice showed decreased serum testosterone and Leydig cell population, excessive oxidative stress and p16/p19 signaling activation. However, a cause-and-effect relationship between phenotypes and pathways was not investigated. Here, we used the rescue approach to study the role of oxidative stress or p16/p19 in BMI1-mediated steroidogenesis. Our results revealed that treatment with antioxidant NAC, but not down-regulation of p16/p19, largely rescued cell senescence, DNA damage and steroidogenesis in BMI1-deficient mouse MLTC-1 and primary Leydig cells. Collectively, our study demonstrates that BMI1 orchestrates steroidogenesis mainly through maintaining redox homeostasis, and thus, BMI1 may be a novel and potential therapeutic target for treatment of hypogonadism.}, }
@article {pmid32592216, year = {2020}, author = {Wang, Y and Dillon, KM and Li, Z and Winckler, EW and Matson, JB}, title = {Alleviating Cellular Oxidative Stress through Treatment with Superoxide-Triggered Persulfide Prodrugs.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {59}, number = {38}, pages = {16698-16704}, pmid = {32592216}, issn = {1521-3773}, support = {R01 GM123508/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; Hydrogen Sulfide/chemistry/pharmacology ; Mice ; Molecular Structure ; Optical Imaging ; Oxidative Stress/drug effects ; Prodrugs/chemical synthesis/chemistry/*pharmacology ; RAW 264.7 Cells ; Rats ; Sulfides/chemical synthesis/chemistry/*pharmacology ; Superoxides/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Overproduction of superoxide anion (O2[.-]), the primary cellular reactive oxygen species (ROS), is implicated in various human diseases. To reduce cellular oxidative stress caused by overproduction of superoxide, we developed a compound that reacts with O2[.-] to release a persulfide (RSSH), a type of reactive sulfur species related to the gasotransmitter hydrogen sulfide (H2 S). Termed SOPD-NAC, this persulfide donor reacts specifically with O2[.-] , decomposing to generate N-acetyl cysteine (NAC) persulfide. To enhance persulfide delivery to cells, we conjugated the SOPD motif to a short, self-assembling peptide (Bz-CFFE-NH2) to make a superoxide-responsive, persulfide-donating peptide (SOPD-Pep). Both SOPD-NAC and SOPD-Pep delivered persulfides/H2 S to H9C2 cardiomyocytes and lowered ROS levels as confirmed by quantitative in vitro fluorescence imaging studies. Additional in vitro studies on RAW 264.7 macrophages showed that SOPD-Pep mitigated toxicity induced by phorbol 12-myristate 13-acetate (PMA) more effectively than SOPD-NAC and several control compounds, including common H2 S donors.}, }
@article {pmid32590340, year = {2020}, author = {Lehnen, TE and Marschner, R and Dias, F and Maia, AL and Wajner, SM}, title = {Oxidative remote induction of type 3 deiodinase impacts nonthyroidal illness syndrome.}, journal = {The Journal of endocrinology}, volume = {246}, number = {3}, pages = {237-246}, doi = {10.1530/JOE-19-0574}, pmid = {32590340}, issn = {1479-6805}, mesh = {Acetylcysteine/metabolism ; Animals ; Euthyroid Sick Syndromes/*metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Male ; Oxidative Stress/physiology ; Rats ; Rats, Wistar ; Thioredoxin-Disulfide Reductase/metabolism ; Thyroid Hormones/*metabolism ; }, abstract = {Imbalances in redox status modulate type 3 deiodinase induction in nonthyroidal illness syndrome. However, the underlying mechanisms that lead to D3 dysfunction under redox imbalance are still poorly understood. Here we evaluated D3 induction, redox homeostasis, and their interrelationships in the liver, muscle, and brain in an animal model of NTIS. Male Wistar rats were subjected to left anterior coronary artery occlusion and randomly separated into two groups and treated or not (placebo) with the antioxidant N-acetylcysteine. Sham animals were used as controls. Animals were killed 10 or 28 days post-MI induction and tissues were immediately frozen for biochemical analysis. D3 activity, protein oxidation and antioxidant defenses were measured in liver, muscle, and brain. Compared to those of the sham group, the levels of D3 expression and activity were increased in the liver (P = 0.002), muscle (P = 0.03) and brain (P = 0.01) in the placebo group. All tissues from the placebo animals showed increased carbonyl groups (P < 0.001) and diminished sulfhydryl levels (P < 0.001). Glutathione levels were decreased and glutathione disulfide levels were augmented in all examined tissues. The liver and muscle showed augmented levels of glutathione peroxidase, glutathione reductase and thioredoxin reductase activity (P = 0.001). NAC prevented all the alterations described previously. D3 dysfunction in all tissues correlates with post-MI-induced protein oxidative damage and altered antioxidant defenses. NAC treatment prevents D3 dysfunction, indicating that reversible redox-related remote D3 activation explains, at least in part, the thyroid hormone derangements of NTIS.}, }
@article {pmid32590070, year = {2020}, author = {Tian, J and Mo, J and Xu, L and Zhang, R and Qiao, Y and Liu, B and Jiang, L and Ma, S and Shi, G}, title = {Scoulerine promotes cell viability reduction and apoptosis by activating ROS-dependent endoplasmic reticulum stress in colorectal cancer cells.}, journal = {Chemico-biological interactions}, volume = {327}, number = {}, pages = {109184}, doi = {10.1016/j.cbi.2020.109184}, pmid = {32590070}, issn = {1872-7786}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Berberine Alkaloids/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/*drug effects ; Colorectal Neoplasms/metabolism ; Cytochromes c/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Humans ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Scoulerine, an isoquinoline alkaloid isolated from Corydalis plants, has been reported to possess potent anti-proliferative and pro-apoptotic function in cancer cells. However, the effects and underlying mechanisms of scoulerine on colorectal cancer (CRC) progression remain elusive. CCK-8 and LDH assays were used to evaluate cell viability. Apoptosis was assessed by flow cytometry analysis, caspase-3/7 activity assay, and Western blot analysis of Bax, Bcl-2 and cytochrome c (Cyt C) expression. Oxidative stress level was examined by measuring reactive oxygen species (ROS) and glutathione (GSH) contents and superoxide dismutase (SOD) activity. Endoplasmic reticulum (ER) stress activation was detected by Western blot analysis of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) expression. Results showed that scoulerine dose-dependently suppressed CRC cell viability. Scoulerine induced apoptosis and increased caspase-3/7 activity in CRC cells. Bax and cytosolic Cyt C expression was enhanced while Bcl-2 and mitochondrial Cyt C expression was reduced in scoulerine-treated CRC cells. Additionally, scoulerine induced oxidative damage in CRC cells by increasing ROS generation and reducing GSH content and SOD activity. Scoulerine activated ER stress, as evidenced by the increased GRP78 and CHOP expression in CRC cells. Interestingly, blocking ROS production by ROS scavenger N-acetyl-cysteine (NAC) attenuated scoulerine-induced ER stress. Inhibition of ER stress by 4-phenyl butyric acid (4-PBA) abolished scoulerine-induced ROS generation in CRC cells. Blockage of ROS and ER stress attenuated scoulerine-induced cell viability reduction and apoptosis in CRC cells. In conclusion, scoulerine promoted cell viability reduction and apoptosis by activating ROS-dependent ER stress in CRC cells.}, }
@article {pmid32590068, year = {2020}, author = {Manaloto, E and Gowen, AA and Lesniak, A and He, Z and Casey, A and Cullen, PJ and Curtin, JF}, title = {Cold atmospheric plasma induces silver nanoparticle uptake, oxidative dissolution and enhanced cytotoxicity in glioblastoma multiforme cells.}, journal = {Archives of biochemistry and biophysics}, volume = {689}, number = {}, pages = {108462}, doi = {10.1016/j.abb.2020.108462}, pmid = {32590068}, issn = {1096-0384}, mesh = {Brain Neoplasms/metabolism/*therapy ; Cell Line, Tumor/metabolism ; Cell Survival/drug effects ; Glioblastoma/metabolism/*therapy ; Humans ; Metal Nanoparticles/analysis ; Oxidative Stress/drug effects ; Plasma Gases/*pharmacology ; Reactive Oxygen Species/metabolism ; Silver/pharmacokinetics/*pharmacology ; }, abstract = {Silver nanoparticles (AgNP) emerged as a promising reagent for cancer therapy with oxidative stress implicated in the toxicity. Meanwhile, studies reported cold atmospheric plasma (CAP) generation of reactive oxygen and nitrogen species has selectivity towards cancer cells. Gold nanoparticles display synergistic cytotoxicity when combined with CAP against cancer cells but there is a paucity of information using AgNP, prompting to investigate the combined effects of CAP using dielectric barrier discharge system (voltage of 75 kV, current is 62.5 mA, duty cycle of 7.5kVA and input frequency of 50-60Hz) and 10 nm PVA-coated AgNP using U373MG Glioblastoma Multiforme cells. Cytotoxicity in U373MG cells was >100-fold greater when treated with both CAP and PVA-AgNP compared with either therapy alone (IC50 of 4.30 μg/mL with PVA-AgNP alone compared with 0.07 μg/mL after 25s CAP and 0.01 μg/mL 40s CAP). Combined cytotoxicity was ROS-dependent and was prevented using N-Acetyl Cysteine. A novel darkfield spectral imaging method investigated and quantified AgNP uptake in cells determining significantly enhanced uptake, aggregation and subcellular accumulation following CAP treatment, which was confirmed and quantified using atomic absorption spectroscopy. The results indicate that CAP decreases nanoparticle size, decreases surface charge distribution of AgNP and induces uptake, aggregation and enhanced cytotoxicity in vitro.}, }
@article {pmid32589880, year = {2020}, author = {Bujan, A and Alonso, SDV and Chiaramoni, NS}, title = {Lipopolymers and lipids from lung surfactants in association with N-acetyl-l-cysteine: Characterization and cytotoxicity.}, journal = {Chemistry and physics of lipids}, volume = {231}, number = {}, pages = {104936}, doi = {10.1016/j.chemphyslip.2020.104936}, pmid = {32589880}, issn = {1873-2941}, mesh = {A549 Cells ; Acetylcysteine/*chemistry ; Cell Survival/drug effects ; Cystic Fibrosis/*drug therapy ; Humans ; Hydrophobic and Hydrophilic Interactions ; Lipids/chemistry/*pharmacology ; Particle Size ; Polymers/chemistry/*pharmacology ; Pulmonary Surfactants/*chemistry ; Surface Properties ; }, abstract = {In the present work, we obtained polymeric diacetylene liposomes that can associate N-Acetyl-l-Cysteine (NAC), a broad spectrum mucolytic. The reason for studying these formulations is that they could be applied in the future as NAC delivery systems, with a possible dose reduction but maintaining its effect. Liposomes used herein are obtained by a photopolymerization reaction, thus gaining stability and rigidity. Lipids belonging to lung surfactant were added in different ratios to the formulations in order to maximize its possible interaction with the lung tissue. Because of lipopolymer stability, the oral or nasal route could be appropriated. This formulation could efficiently transport NAC to exert its mucolytic activity and help in diseases such as cystic fibrosis, which has abnormal mucus production. Also, this type of treatment could be useful in other types of diseases, interacting with the mucus layer and making the lung tissue more permeable to other therapies. Formulations so obtained presented high levels of polymerization. Also, they present small hollow fibers structures with a high number of polymeric units. These types of arrangements could present advantages in the field of drug delivery, giving the possibility of a controlled release. Lipopolymers with lipids from lung surfactant associated with NAC are promising complexes in order to treat not only respiratory illnesses. The stability of the formulation would allow its inoculation through other routes such as the oral one, helping the reposition of NAC as an antioxidant drug. Finally, these formulations are non-toxic and easy to produce.}, }
@article {pmid32589648, year = {2020}, author = {Safe, IP and Lacerda, MVG and Printes, VS and Praia Marins, AF and Rebelo Rabelo, AL and Costa, AA and Tavares, MA and Jesus, JS and Souza, AB and Beraldi-Magalhães, F and Neves, CP and Monteiro, WM and Sampaio, VS and Amaral, EP and Gomes, RS and Andrade, BB and Cordeiro-Santos, M}, title = {Safety and efficacy of N-acetylcysteine in hospitalized patients with HIV-associated tuberculosis: An open-label, randomized, phase II trial (RIPENACTB Study).}, journal = {PloS one}, volume = {15}, number = {6}, pages = {e0235381}, pmid = {32589648}, issn = {1932-6203}, mesh = {Acetylcysteine/*adverse effects/*therapeutic use ; Adult ; Female ; HIV Infections/*complications ; *Hospitalization ; Humans ; Male ; Middle Aged ; *Safety ; Tuberculosis/*complications/*drug therapy ; }, abstract = {Despite the availability of effective antimicrobials, tuberculosis (TB) is still a serious health threat. Mortality is even higher in people living with HIV who are diagnosed with TB. New therapies are needed to shorten the time required to cure TB and decrease fatality rates in this population. N-acetylcysteine (NAC) is a glutathione precursor and has shown recently in experimental setting to present in vitro and in vivo anti-mycobacterial activity. We test the hypothesis that NAC is safe, well tolerated and secondarily efficacious as adjunctive anti-TB therapy in hospitalized individuals with HIV-associated TB. Patients were enrolled sequentially in a tertiary care center, in the Brazilian Amazon. We performed a randomized, parallel group, single-center, open study trial of two arms, in hospitalized patients over 18 years of age, with microbiologically confirmed pulmonary TB in HIV: one with rifampicin, isoniazid, pyrazinamide and ethambutol at standard doses (Control Group), and a second in which NAC 600 mg bid for eight weeks was added (NAC Group). A total of 21 and 18 patients were enrolled to the Control Group and NAC Group, respectively. Adverse event rates were similar in the two arms. Our findings suggest that in the more critical population of hospitalized patients with HIV-associated TB, the use of NAC was not unsafe, despite the low sample size, and a potential impact on faster negative cultures needs to be further explored in larger studies.}, }
@article {pmid32585919, year = {2020}, author = {Fiorillo, M and Tóth, F and Brindisi, M and Sotgia, F and Lisanti, MP}, title = {Deferiprone (DFP) Targets Cancer Stem Cell (CSC) Propagation by Inhibiting Mitochondrial Metabolism and Inducing ROS Production.}, journal = {Cells}, volume = {9}, number = {6}, pages = {}, pmid = {32585919}, issn = {2073-4409}, mesh = {Deferiprone/pharmacology/*therapeutic use ; Humans ; Iron Chelating Agents/pharmacology/*therapeutic use ; Mitochondria/*metabolism ; Neoplastic Stem Cells/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Deferiprone (DFP), also known as Ferriprox, is an FDA-approved, orally active, iron chelator that is currently used clinically for the treatment of iron-overload, especially in thalassaemia major. As iron is a critical factor in Fe-S cluster assembly that is absolutely required for the metabolic function of mitochondria, we hypothesized that DFP treatment could be used to selectively target mitochondria in cancer stem cells (CSCs). For this purpose, we used two ER(+) human breast cancer cell lines, namely MCF7 and T47D cells, as model systems. More specifically, a 3D tumorsphere assay was employed as a functional readout of CSC activity which measures anchorage-independent growth under low attachment conditions. Here, we show that DFP dose dependently inhibited the propagation of CSCs, with an IC-50 of ~100 nM for MCF7 and an IC-50 of ~0.5 to 1 μM for T47D cells, making DFP one the most potent FDA-approved drugs that we and others have thus far identified for targeting CSCs. Mechanistically, we show that high concentrations of DFP metabolically targeted both mitochondrial oxygen consumption (OCR) and glycolysis (extracellular acidification rates (ECAR)) in MCF7 and T47D cell monolayers. Most importantly, we demonstrate that DFP also induced a generalized increase in reactive oxygen species (ROS) and mitochondrial superoxide production, and its effects reverted in the presence of N-acetyl-cysteine (NAC). Therefore, we propose that DFP is a new candidate therapeutic for drug repurposing and for Phase II clinical trials aimed at eradicating CSCs.}, }
@article {pmid32585852, year = {2020}, author = {Yuan, L and Mishra, R and Patel, H and Alanazi, S and Wei, X and Ma, Z and Garrett, JT}, title = {BRAF Mutant Melanoma Adjusts to BRAF/MEK Inhibitors via Dependence on Increased Antioxidant SOD2 and Increased Reactive Oxygen Species Levels.}, journal = {Cancers}, volume = {12}, number = {6}, pages = {}, pmid = {32585852}, issn = {2072-6694}, abstract = {B-Rapidly Accelerated Fibrosarcoma (BRAF) mutations are found in about 50% of melanoma patients. Treatment with Food and Drug Administration (FDA)-approved BRAF and MAP/ERK kinase (MEK) inhibitors has improved progression free and overall survival of patients with BRAF mutant melanoma. However, all responders develop resistance typically within 1 year of treatment with these inhibitors. Evidence indicates that reactive oxygen species (ROS) levels are elevated after BRAF pathway inhibition treatment. We aim to decipher the role of mitochondrial antioxidant proteins relative to ROS levels and BRAF pathway inhibitor resistance. We observed BRAF mutant melanoma cells treated with the combination of a MEK inhibitor (trametinib) and a BRAF inhibitor (dabrafenib), exhibited elevated ROS levels, both in in vitro and in vivo melanoma models. We next generated trametinib- and dabrafenib-resistant (TDR) cells and found increased ROS levels after acquisition of resistance. An immunofluorescence experiment showed an increase of DNA damage in TDR cell lines. Furthermore, we observed that TDR cells increased superoxide dismutase 2 (SOD2), an antioxidant, at both mRNA and protein levels, with the upregulation of the transcription factor Nuclear Factor (NF)-κB. Knockdown of SOD2 significantly reduced the growth of BRAF pathway inhibitor-resistant cells. In addition, the results indicate that TDR cells can be re-sensitized to BRAF pathway inhibitors by the ROS scavenger, N-Acetyl Cysteine (NAC). Overall, these data indicate that BRAF pathway inhibitor-resistant cells can compensate for elevated ROS via increased expression of the antioxidant SOD2.}, }
@article {pmid32583744, year = {2020}, author = {Ireland, SC and Huang, H and Zhang, J and Li, J and Wang, Y}, title = {Hydrogen peroxide induces Arl1 degradation and impairs Golgi-mediated trafficking.}, journal = {Molecular biology of the cell}, volume = {31}, number = {17}, pages = {1931-1942}, pmid = {32583744}, issn = {1939-4586}, support = {R01 GM112786/GM/NIGMS NIH HHS/United States ; R35 GM130331/GM/NIGMS NIH HHS/United States ; R56 AG062225/AG/NIA NIH HHS/United States ; }, mesh = {ADP-Ribosylation Factors/drug effects/*metabolism ; Autoantigens/metabolism ; Biological Transport/physiology ; Golgi Apparatus/*metabolism/physiology ; Golgi Matrix Proteins/metabolism ; HeLa Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Intracellular Membranes/metabolism ; Membrane Proteins/drug effects/*metabolism ; Mitochondria/metabolism ; Oxidative Stress/*physiology ; Protein Transport/physiology ; Reactive Oxygen Species/metabolism ; trans-Golgi Network/metabolism ; }, abstract = {Reactive oxygen species (ROS)-induced oxidative stress has been associated with diseases such as amyotrophic lateral sclerosis, stroke, and cancer. While the effect of ROS on mitochondria and endoplasmic reticulum (ER) has been well documented, its consequence on the Golgi apparatus is less well understood. In this study, we characterized the Golgi structure and function in HeLa cells after exposure to hydrogen peroxide (H2O2), a reagent commonly used to introduce ROS to cells. Treatment of cells with 1 mM H2O2 for 10 min resulted in the degradation of Arl1 and dissociation of GRIP domain-containing proteins Golgin-97 and Golgin-245 from the trans-Golgi. This effect could be rescued by treatment of cells with a ROS scavenger N-acetyl cysteine or protease inhibitors. Structurally, H2O2 treatment reduced the number of cisternal membranes per Golgi stack, suggesting a loss of trans-Golgi cisternae. Functionally, H2O2 treatment inhibited both anterograde and retrograde protein transport, consistent with the loss of membrane tethers on the trans-Golgi cisternae. This study revealed membrane tethers at the trans-Golgi as novel specific targets of ROS in cells.}, }
@article {pmid32583517, year = {2020}, author = {Zhang, Q and Li, J and Li, Y and Che, H and Chen, Y and Dong, J and Xian, CJ and Miao, D and Wang, L and Ren, Y}, title = {Bmi deficiency causes oxidative stress and intervertebral disc degeneration which can be alleviated by antioxidant treatment.}, journal = {Journal of cellular and molecular medicine}, volume = {24}, number = {16}, pages = {8950-8961}, pmid = {32583517}, issn = {1582-4934}, mesh = {Acetylcysteine/pharmacology ; Aggrecans/metabolism ; Animals ; Antioxidants/*physiology ; Apoptosis/drug effects ; Collagen/metabolism ; Interleukin-1beta/metabolism ; Intervertebral Disc/drug effects/metabolism ; Intervertebral Disc Degeneration/*drug therapy/*metabolism ; Mice ; Organ Culture Techniques/methods ; Oxidative Stress/*drug effects ; Polycomb Repressive Complex 1/*deficiency ; Proto-Oncogene Proteins/*deficiency ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {The transcriptional repressor Bmi-1 is involved in cell-cycle regulation and cell senescence, the deficiency of which has been shown to cause oxidative stress. This study investigated whether Bmi-1 deficiency plays a role in promoting disc degeneration and the effect of treatment with antioxidant N-acetylcysteine (NAC) on intervertebral disc degeneration. Bmi-1[-/-] mice were treated with the antioxidant NAC, supplied in drinking water (Bmi-1[-/-] +NAC). For in vitro experiments, mouse intervertebral discs were cultured under low oxygen tension and serum-limiting conditions in the presence of tumour necrosis factor α and interleukin 1β in order to mimic degenerative insult. Disc metabolism parameters in these in vitro and in vivo studies were evaluated by histopathological, immunohistochemical and molecular methods. Bmi-1[-/-] mice showed lower collagen Ⅱ and aggrecan levels and higher collagen Ⅹ levels than wild-type and Bmi-1[-/-] +NAC mice. Bmi-1[-/-] mice showed significantly lower superoxide dismutase (SOD)-1, SOD-2, glutathione peroxidase (GPX)-1 and GPX-3 levels than their wild-type littermates and Bmi-1[-/-] + NAC mice. Relative to Bmi-1[-/-] mice, the control and Bmi-1[-/-] +NAC mice showed significantly lower p16, p21, and p53 levels. These results demonstrate that Bmi-1 plays an important role in attenuating intervertebral disc degeneration in mice by inhibiting oxidative stress and cell apoptosis.}, }
@article {pmid32582807, year = {2020}, author = {Shi, C and Wang, P and Airen, S and Brown, C and Liu, Z and Townsend, JH and Wang, J and Jiang, H}, title = {Nutritional and medical food therapies for diabetic retinopathy.}, journal = {Eye and vision (London, England)}, volume = {7}, number = {}, pages = {33}, pmid = {32582807}, issn = {2326-0254}, support = {P30 EY014801/EY/NEI NIH HHS/United States ; R01 NS111115/NS/NINDS NIH HHS/United States ; }, abstract = {Diabetic retinopathy (DR) is a form of microangiopathy. Reducing oxidative stress in the mitochondria and cell membranes decreases ischemic injury and end-organ damage to the retina. New approaches are needed, which reduce the risk and improve the outcomes of DR while complementing current therapeutic approaches. Homocysteine (Hcy) elevation and oxidative stress are potential therapeutic targets in DR. Common genetic polymorphisms such as those of methylenetetrahydrofolate reductase (MTHFR), increase Hcy and DR risk and severity. Patients with DR have high incidences of deficiencies of crucial vitamins, minerals, and related compounds, which also lead to elevation of Hcy and oxidative stress. Addressing the effects of the MTHFR polymorphism and addressing comorbid deficiencies and insufficiencies reduce the impact and severity of the disease. This approach provides safe and simple strategies that support conventional care and improve outcomes. Suboptimal vitamin co-factor availability also impairs the release of neurotrophic and neuroprotective growth factors. Collectively, this accounts for variability in presentation and response of DR to conventional therapy. Fortunately, there are straightforward recommendations for addressing these issues and supporting traditional treatment plans. We have reviewed the literature for nutritional interventions that support conventional therapies to reduce disease risk and severity. Optimal combinations of vitamins B1, B2, B6, L-methylfolate, methylcobalamin (B12), C, D, natural vitamin E complex, lutein, zeaxanthin, alpha-lipoic acid, and n-acetylcysteine are identified for protecting the retina and choroid. Certain medical foods have been successfully used as therapy for retinopathy. Recommendations based on this review and our clinical experience are developed for clinicians to use to support conventional therapy for DR. DR from both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have similar retinal findings and responses to nutritional therapies.}, }
@article {pmid32576206, year = {2020}, author = {Cao, Y and Wang, J and Tian, H and Fu, GH}, title = {Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {39}, number = {1}, pages = {119}, pmid = {32576206}, issn = {1756-9966}, support = {81972581, 81472570//National Natural Science Foundation of China/ ; shslczdzk01303//Shanghai Municipal Key Clinical Specialty/ ; 19ZR1452800//Natural Science Foundation of Shanghai/ ; 201940429//Foundation of Shanghai Municipal Health Commission/ ; }, mesh = {Animals ; *Apoptosis ; *Autophagy ; Biomarkers, Tumor/genetics/metabolism ; Cell Movement ; Cell Proliferation ; Female ; G2 Phase Cell Cycle Checkpoints ; Gene Expression Regulation, Neoplastic ; Humans ; Janus Kinase 2/genetics/*metabolism ; Male ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Middle Aged ; Mitochondria/drug effects/metabolism/*pathology ; Neoplasm Invasiveness ; Pyridines/*pharmacology ; Pyrimidines/*pharmacology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/genetics/*metabolism ; Signal Transduction ; Stomach Neoplasms/drug therapy/genetics/metabolism/*pathology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND: Gastric cancer (GC) is a common form of malignant cancer in worldwide which has a poor prognosis. Despite recent improvements in the treatment of GC, the prognosis is not yet satisfactory for GC patients. CYT997, a novel microtubule-targeting agent, recently has been identified to be a promising anticancer candidate for the treatment of cancers; however, the effects of CYT997 in GC remain largely unknown.<br><br>METHODS: Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry. The mitochondrial ROS were detected by confocal microscope and flow cytometry. Gastric cancer patient-derived xenograft (PDX) model was used to evaluate its antitumor activity of CYT997 in vivo.<br><br>RESULTS: CYT997 inhibited gastric cancer cell proliferation and induced cell apoptosis and triggered autophagy. CYT997 induced apoptosis through triggering intracellular mitochondrial ROS generation in GC cells. ROS scavengers N-acetylcysteine (NAC) and Mitoquinone (MitoQ) distinctly weakened CYT997-induced cell cycle G2/M arrest and apoptosis in GC cells. Pretreatment with autophagy inhibitor 3-MA promoted the effect of CYT997 on cells apoptosis. Mechanistically, CYT997 performed its function through regulation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in GC cells. In addition, CYT997 inhibited growth of gastric cancer patient-derived xenograft (PDX) tumors.<br><br>CONCLUSIONS: CYT997 induces autophagy and apoptosis in gastric cancer by triggering mitochondrial ROS accumulation to silence JAK2/STAT3 pathway. CYT997 might be a potential antitumor drug candidate to treat GC.}, }
@article {pmid32575864, year = {2020}, author = {Sommer, I and Schwebel, H and Adamo, V and Bonnabry, P and Bouchoud, L and Sadeghipour, F}, title = {Stability of N-Acetylcysteine (NAC) in Standardized Pediatric Parenteral Nutrition and Evaluation of N,N-Diacetylcystine (DAC) Formation.}, journal = {Nutrients}, volume = {12}, number = {6}, pages = {}, pmid = {32575864}, issn = {2072-6643}, mesh = {Acetylcysteine/*administration &amp; dosage/metabolism ; Amino Acids/*administration &amp; dosage/metabolism ; Biological Availability ; Cysteine/administration &amp; dosage/metabolism ; Cystine/*analogs &amp; derivatives/metabolism ; Drug Industry ; *Drug Stability ; Drug Storage ; Humans ; Infant Nutritional Physiological Phenomena ; Infant, Newborn ; *Infant, Premature ; Nutritional Requirements ; Oxidation-Reduction ; Oxygen ; *Parenteral Nutrition ; Parenteral Nutrition Solutions/*chemistry ; }, abstract = {The ESPGHAN/ESPEN/ESPR-Guidelines on pediatric parenteral nutrition (PPN) recommend the administration of the semiessential amino acid (AA) cysteine to preterm neonates due to their biochemical immaturity resulting in an inability to sufficiently synthetize endogenous cysteine. The soluble precursor N-acetylcysteine (NAC) is easily converted into bioavailable cysteine. Its dimer N,N-diacetylcystine (DAC) is almost unconvertable to cysteine when given intravenously resulting in a diminished bioavailability of cysteine. This study aims to understand the triggers and oxidation process of NAC to DAC to evaluate possibilities of reducing DAC formation in standardized PPN. Therefore, different air volumes (21% O2) were injected into the AA compartment of a standardized dual-chamber PPN. O2 concentrations were measured in the AA solution and the headspaces of the primary and secondary packaging. NAC and DAC concentrations were analyzed simultaneously. The analysis showed that O2 is principally delivered from the primary headspace. NAC oxidation exclusively delivers DAC, depending on the O2 amount in the solution and the headspaces. The reaction of NAC to DAC being containable by limiting the O2 concentration, the primary headspace must be minimized during manufacturing, and oxygen absorbers must be added into the secondary packaging for a long-term storage of semipermeable containers.}, }
@article {pmid32574682, year = {2020}, author = {Ventura, RD and Chaves, AS and Magalhães, NS and Gonzalez, FB and Pacini, MF and Pérez, AR and Silva, PMR and Martins, MA and Carvalho, VF}, title = {Activation of PPARγ reduces N-acetyl-cysteine -induced hypercorticoidism by down-regulating MC2R expression into adrenal glands.}, journal = {Free radical biology &amp; medicine}, volume = {156}, number = {}, pages = {137-143}, doi = {10.1016/j.freeradbiomed.2020.06.008}, pmid = {32574682}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Adrenal Glands/metabolism ; Animals ; Hypothalamo-Hypophyseal System/metabolism ; Male ; Mice ; *PPAR gamma/genetics/metabolism ; Pituitary-Adrenal System/metabolism ; Receptors, Corticotropin ; *Thiazolidinediones/pharmacology ; }, abstract = {We previously demonstrated that oral supplementation with antioxidants induced hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis, attested by hypercorticoidism, through an up-regulation of adrenocorticotrophic hormone (ACTH) receptors (MC2R) in adrenal. This study analyzed the role of peroxisome proliferator-activated receptor (PPAR)-γ on HPA axis hyperactivity induced by N-acetyl-cysteine (NAC). Male Swiss-Webster mice were orally treated with NAC for 1, 3, 5, 10, 15, or 18 consecutive days. The PPAR-γ agonist rosiglitazone and/or antagonist GW9662 were daily-injected i.p. for 5 consecutive days, starting concomitantly with NAC treatment. Rosiglitazone treatment inhibited NAC-induced adrenal hypertrophy and hypercorticoidism. Rosiglitazone also significantly reversed the NAC-induced increase in the MC2R expression in adrenal, but not steroidogenic acute regulatory protein (StAR). NAC treatment reduces the expression of PPARγ in the adrenals, but rosiglitazone did not restore the expression of this cytoprotective gene. In addition, GW9662 blocked the ability of rosiglitazone to decrease plasma corticosterone levels in NAC-treated mice. In conclusion, our findings showed that antioxidant supplementation induced a state of hypercorticoidism through down-regulation of PPARγ expression in the adrenals, in a mechanism probably related to a down-regulation of ACTH receptor expression.}, }
@article {pmid32572589, year = {2020}, author = {Chakraborty, S and Tripathi, SJ and Raju, TR and Shankaranarayana Rao, BS}, title = {Mechanisms underlying remediation of depression-associated anxiety by chronic N-acetyl cysteine treatment.}, journal = {Psychopharmacology}, volume = {237}, number = {10}, pages = {2967-2981}, doi = {10.1007/s00213-020-05585-x}, pmid = {32572589}, issn = {1432-2072}, support = {3/1/2/74/Neuro/2018-NCD-I//Indian Council of Medical Research/ ; 45/04/2018-ANA-BMS//Indian Council of Medical Research/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Amygdala/drug effects/metabolism ; Animals ; Anti-Anxiety Agents/*administration &amp; dosage ; Antidepressive Agents/*administration &amp; dosage ; Anxiety/*drug therapy/metabolism/psychology ; Corticosterone/metabolism ; Depression/*drug therapy/metabolism/psychology ; Drug Administration Schedule ; Free Radical Scavengers/*administration &amp; dosage ; Hippocampus/drug effects/metabolism ; Hypothalamo-Hypophyseal System/drug effects/metabolism ; Male ; Pituitary-Adrenal System/drug effects/metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Treatment Outcome ; }, abstract = {RATIONALE: Anxiety is one of the most comorbid conditions with major depressive disorder (MDD). Depression-associated anxiety often stems from the dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its altered regulation by the amygdala. Furthermore, MDD is associated with altered glutamatergic processing leading to anxiety and impaired regulation of the HPA axis. Recent studies have demonstrated that N-acetyl cysteine (NAC), a pleiotropic drug, exerts antidepressant-like effect by modulation of hippocampal functions, periterminal release of glutamate, and/or redox systems. However, the effects of NAC on depression-associated anxiety, HPA axis hyperactivity, and amygdalar dysfunctions are relatively unknown.<br><br>OBJECTIVES: Accordingly, we evaluated the effect of NAC on neonatal clomipramine (CLI)-induced adulthood anxiety and accompanying changes in plasma corticosterone levels, amygdalar volumes, neuronal/glial densities, levels of monoamines, and their metabolites in the amygdalar complex.<br><br>RESULTS: We found that chronic treatment with NAC reverses CLI-induced anhedonia and enhanced anxiety. Interestingly, attenuation of CLI-associated anxiety in NAC-treated rats were accompanied by a reversal of adrenal and spleen hypertrophy, and normalization of enhanced plasma corticosterone levels, indicating improved HPA axis functioning. Furthermore, NAC treatment was sufficient to reverse volumetric hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. The effects of NAC in the reversal of CLI-induced impairments were similar to that of fluoxetine (FLX).<br><br>CONCLUSIONS: We suggest that beneficial effects of NAC on antidepressive- and antianxiety-like behaviors are at least in part mediated via restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that NAC might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.}, }
@article {pmid32569876, year = {2020}, author = {Lee, KI and Choi, S and Choi, HG and Kebede, SG and Dang, TB and Back, YW and Park, HS and Kim, HJ}, title = {Recombinant Rv3261 protein of Mycobacterium tuberculosis induces apoptosis through a mitochondrion-dependent pathway in macrophages and inhibits intracellular bacterial growth.}, journal = {Cellular immunology}, volume = {354}, number = {}, pages = {104145}, doi = {10.1016/j.cellimm.2020.104145}, pmid = {32569876}, issn = {1090-2163}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Bacterial Proteins/*metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Growth Processes ; Immune Evasion ; Immunity, Innate ; Intracellular Space ; MAP Kinase Kinase 4/metabolism ; Macrophages/immunology/*microbiology ; Mice ; Mitochondria/*metabolism ; Mycobacterium tuberculosis/*physiology ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Mycobacterium tuberculosis (Mtb) is an intracellular pathogen known to persist in host cells. The apoptotic response of macrophages serves as a defense mechanism to inhibit the growth of intracellular bacteria, the failure of which can favor the spread of the pathogen to new cells. However, the mycobacterial components that regulate cell death and the related underlying mechanisms remain poorly understood. In this study, we investigated protein Rv3261, isolated from an Mtb culture filtrate, for its apoptotic potential using multidimensional fractionation. Rv3261 was found to induce macrophage apoptosis through the caspase-3/-9-dependent pathway. Furthermore, the ROS-dependent JNK activation pathway was found to be critical in Rv3261-mediated apoptosis. Rv3261 inhibited the growth of intracellular Mtb, which was significantly abrogated by pre-treatment with the ROS scavenger N-acetylcysteine (NAC), suggesting that Rv3261-mediated apoptosis may act as a host defense response. These findings suggest that Rv3261 is involved in the apoptotic modulation of Mtb-infected macrophages.}, }
@article {pmid32568328, year = {2020}, author = {Cui, J and Liu, H and Xu, S}, title = {Selenium-deficient diet induces necroptosis in the pig brain by activating TNFR1 via mir-29a-3p.}, journal = {Metallomics : integrated biometal science}, volume = {12}, number = {8}, pages = {1290-1301}, doi = {10.1039/d0mt00032a}, pmid = {32568328}, issn = {1756-591X}, mesh = {Animals ; Apoptosis/genetics/physiology ; MicroRNAs/genetics/*metabolism ; Necroptosis/genetics/*physiology ; Receptors, Tumor Necrosis Factor, Type I/genetics/*metabolism ; Selenium/*metabolism ; Swine ; }, abstract = {Selenium (Se) deficiency is one of the crucial factors related to nervous system disease and necroptosis. MicroRNAs (miRNAs) play vital roles in regulating necroptosis. However, the mechanism of Se deficiency-induced necroptosis in the pig brain tissue and the role that miRNAs play in this process are unclear. Therefore, in this study, in vitro and pig models of Se deficiency were replicated, and electron microscopy, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays were performed. The results showed that brain cells typically undergo necrotic changes, and that Se deficiency suppresses mir-29a-3p, which increases the levels of TNFRSF1A (TNFR1). Subsequently, a distinct increase in the necroptosis markers (RIPK1, RIPK3, and MLKL) and an evident decrease in caspase 8 was observed. And the expression of 10 selenoproteins was decreased. Moreover, the in vitro experiments showed that the expression of mir-29a-3p decreased as the Se content in the medium decreased and the application of an mir-29a-3p inhibitor increased the number of necrotic cells and the accumulation of ROS, and these effects were inhibited by necrostatin-1 (Nec-1) and N-acetyl-cysteine (NAC), respectively. Taken together, we proved that Se deficiency induced necroptosis both in vitro and in vivo through the targeted regulation of TNFR1 by mir-29a-3p in the pig brain.}, }
@article {pmid32566089, year = {2020}, author = {He, M and Zhou, C and Lu, Y and Mao, L and Xi, Y and Mei, X and Wang, X and Zhang, L and Yu, Z and Zhou, Z}, title = {Melatonin Antagonizes Nickel-Induced Aerobic Glycolysis by Blocking ROS-Mediated HIF-1α/miR210/ISCU Axis Activation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {5406284}, pmid = {32566089}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Cell Death/drug effects ; Cell Line ; Glycolysis/*drug effects ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Iron-Sulfur Proteins/*metabolism ; Melatonin/*pharmacology ; MicroRNAs/genetics/*metabolism ; Nickel/*pharmacology ; Prolyl Hydroxylases/metabolism ; Pyruvates/pharmacology ; Reactive Oxygen Species/*metabolism ; *Signal Transduction/drug effects ; Transcription, Genetic/drug effects ; }, abstract = {Nickel and its compounds, which are well-documented carcinogens, induce the Warburg effect in normal cells by stabilizing hypoxia-inducible factor 1α (HIF-1α). Melatonin has shown diverse anticancer properties for its reactive oxygen species- (ROS-) scavenging ability. Our aim was to explore how melatonin antagonized a nickel-induced increment in aerobic glycolysis. In the current work, a normal human bronchial epithelium cell line (BEAS-2B) was exposed to a series of nonlethal doses of NiCl2, with or without 1 mM melatonin. Melatonin attenuated nickel-enhanced aerobic glycolysis. The inhibition effects on aerobic glycolysis were attributed to the capability of melatonin to suppress the regulatory axis comprising HIF-1α, microRNA210 (miR210), and iron-sulfur cluster assembly scaffold protein (ISCU1/2). N-Acetylcysteine (NAC) manifested similar effects as melatonin in scavenging ROS, maintaining prolyl-hydroxylase activity, and mitigating HIF-1α transcriptional activity in nickel-exposed cells. Our results indicated that ROS generation contributed to nickel-caused HIF-1α stabilization and downstream signal activation. Melatonin could antagonize HIF-1α-controlled aerobic glycolysis through ROS scavenging.}, }
@article {pmid32564864, year = {2020}, author = {Netsomboon, K and Jalil, A and Laffleur, F and Hupfauf, A and Gust, R and Bernkop-Schnürch, A}, title = {Thiolated chitosans: Are Cys-Cys ligands key to the next generation?.}, journal = {Carbohydrate polymers}, volume = {242}, number = {}, pages = {116395}, doi = {10.1016/j.carbpol.2020.116395}, pmid = {32564864}, issn = {1879-1344}, mesh = {Chitosan/chemical synthesis/*chemistry ; Dipeptides/*chemistry ; Ligands ; Molecular Structure ; Particle Size ; Sulfhydryl Compounds/*chemistry ; Surface Properties ; }, abstract = {The potential of Cys-Cys ligands for the development of a novel type of S-protected thiomers was evaluated. S-protected thiomers chitosan-N-acetylcysteine-mercaptonicotinamide (CS-NAC-MNA) and chitosan-N-acetylcysteine-N-acetylcysteine (CS-NAC-NAC) were synthesized and characterized. Viscosity of polymers in presence of various concentrations of S-amino acids was monitored. Mucoadhesive properties were evaluated. FT-IR characterization confirmed the covalent attachment of NAC-MNA and NAC-NAC. Attached sulfhydryl groups were found in the range of 550 μmol/g. In the presence of amino acids bearing a free thiol group viscosity of both polymers increased. This increase in viscosity depended on the amount of added free thiols. Maximum force required to detach CS-NAC-MNA and CS-NAC-NAC from porcine intestinal mucosa was 1.4- and 2.7-fold higher than that required for chitosan, respectively. CS-NAC-MNA adhered up to 3 h, whereas CS-NAC-NAC adhered even for 8 h on this mucosa. Accordingly, the Cys-Cys substructure could be identified as highly potent ligand for the design of mucoadhesive polymers.}, }
@article {pmid32562311, year = {2020}, author = {Wan, SS and Pan, YM and Yang, WJ and Rao, ZQ and Yang, YN}, title = {Inhibition of EZH2 alleviates angiogenesis in a model of corneal neovascularization by blocking FoxO3a-mediated oxidative stress.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {8}, pages = {10168-10181}, doi = {10.1096/fj.201902814RRR}, pmid = {32562311}, issn = {1530-6860}, mesh = {Adenosine/*analogs &amp; derivatives/pharmacology ; Animals ; Cells, Cultured ; Corneal Neovascularization/*drug therapy/metabolism ; Disease Models, Animal ; Enhancer of Zeste Homolog 2 Protein/*antagonists &amp; inhibitors/*metabolism ; Forkhead Box Protein O3/*metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Hypoxia/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Neovascularization, Pathologic/*drug therapy/metabolism ; Oxidative Stress/*drug effects/physiology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/physiology ; Transcription, Genetic/drug effects/physiology ; }, abstract = {Enhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a vital role in ophthalmological disease. However, its role in corneal neovascularization (CoNV) remains unclear. In vitro and in vivo models were assessed in hypoxia-stimulated angiogenesis and in a mouse model of alkali burn-induced CoNV. Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxic conditions and different reoxygenation times to identify the molecular mechanisms involved in this process. In this study, we found that EZH2 was positively related to corneal alkali burn-induced injury. Inhibition of EZH2 with 3-Deazaneplanocin A (DZNeP) alleviated corneal injury, including oxidative stress and neovascularization in vivo. Similarly, inhibition of EZH2 with either DZNeP or small interfering RNA (siRNA) exerted an inhibitory effect on hypoxia/reoxygenation (H/R)-induced oxidative stress and angiogenesis in HUVECs. Moreover, our study revealed that ablation of reactive oxygen species (ROS) with N-acetyl-cysteine suppressed angiogenesis in HUVECs exposed to H/R stimulation. Furthermore, Forkhead-box protein O3a (FoxO3a), which was positively associated with ROS production and angiogenesis, was elevated during H/R. This effect could be reversed through the suppression of the transcription activity of EZH2 with DZNeP or siRNA. In addition, the PI3K/Akt pathway, which is the upstream of FoxO3a, was activated in both DZNeP-treated mice and EZH2-inhibited HUVECs. Collectively, our results demonstrated that the inhibition of EZH2 alleviated corneal angiogenesis by inhibiting FoxO3a-dependent ROS production through the PI3K/Akt signaling pathway. These findings indicate that EZH2 may be a valuable therapeutic target for CoNV.}, }
@article {pmid32561319, year = {2020}, author = {Mishra, S and Divakar, A and Srivastava, S and Dewangan, J and Sharma, D and Asthana, S and Chaturvedi, S and Wahajuddin, M and Kumar, S and Rath, SK}, title = {N-acetyl-cysteine in combination with celecoxib inhibits Deoxynivalenol induced skin tumor initiation via induction of autophagic pathways in swiss mice.}, journal = {Free radical biology &amp; medicine}, volume = {156}, number = {}, pages = {70-82}, doi = {10.1016/j.freeradbiomed.2020.06.001}, pmid = {32561319}, issn = {1873-4596}, mesh = {*Acetylcysteine ; Animals ; Autophagy ; Celecoxib/toxicity ; Mice ; *Skin Neoplasms ; Trichothecenes ; }, abstract = {Deoxynivalenol is a trichothecene mycotoxin which naturally contaminates small grain, cereals intended for human and animal consumption. Investigations for dermal toxicity of DON has been needed and highlighted by WHO. Previous studies on dermal toxicity suggest that DON has DNA damaging potential leading to skin tumor initiation in mice skin. However, considering its toxicological manifestations arising after dermal exposure, strategies for its prevention/protection are barely available in literatute. Collectively, our study demonstrated that N-acetylcysteine (NAC), precursor of glutathione, significantly alters the genotoxic potential of DON. Further NAC in combination with Celecoxib (CXB) inhibits tumor growth by altering antioxidant status and increasing autophagy in DON initiated Swiss mice. Despite the broad spectrum use of CXB, its use is limited by the concerns about its adverse effects on the cardiovascular system. Serum parameters and histology analysis revealed that CXB (2 mg) when applied topically for 24 weeks did not impart any cardiovascular toxicity which could be because skin permeation potential of CXB was quite low when analyzed through HPLC analysis. Although the anticancer effects of CXB and NAC have been studied, however, the combination of NAC and CXB has yet not been explored for any cancer treatment. Therefore our observations provide additional insights into the therapeutic effects of combinatorial treatment of CXB and NAC against skin tumor prevention. This approach might form a novel alternative strategy for skin cancer treatment as well as skin associated toxicities caused by mycotoxins such as DON. This combinatorial approach can overcome the limitations associated with the use of CXB for long term as topical application of the same seems to be safe in comparison to the oral mode of administration.}, }
@article {pmid32560255, year = {2020}, author = {García-Campos, P and Báez-Matus, X and Jara-Gutiérrez, C and Paz-Araos, M and Astorga, C and Cea, LA and Rodríguez, V and Bevilacqua, JA and Caviedes, P and Cárdenas, AM}, title = {N-Acetylcysteine Reduces Skeletal Muscles Oxidative Stress and Improves Grip Strength in Dysferlin-Deficient Bla/J Mice.}, journal = {International journal of molecular sciences}, volume = {21}, number = {12}, pages = {}, pmid = {32560255}, issn = {1422-0067}, support = {1160495 (to AMC), 1151383 (to JAB)//Fondo Nacional de Desarrollo Cient&#xed;fico y Tecnol&#xf3;gico/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Antioxidants/*administration &amp; dosage/pharmacology ; Body Mass Index ; Disease Models, Animal ; Humans ; Lipid Peroxidation/drug effects ; Mice ; Muscle Strength/drug effects ; Muscle, Skeletal/*drug effects/metabolism/physiopathology ; Muscular Dystrophies, Limb-Girdle/*diet therapy/metabolism/physiopathology ; Oxidative Stress/drug effects ; Protein Carbonylation/drug effects ; Superoxide Dismutase/metabolism ; Treatment Outcome ; }, abstract = {Dysferlinopathy is an autosomal recessive muscular dystrophy resulting from mutations in the dysferlin gene. Absence of dysferlin in the sarcolemma and progressive muscle wasting are hallmarks of this disease. Signs of oxidative stress have been observed in skeletal muscles of dysferlinopathy patients, as well as in dysferlin-deficient mice. However, the contribution of the redox imbalance to this pathology and the efficacy of antioxidant therapy remain unclear. Here, we evaluated the effect of 10 weeks diet supplementation with the antioxidant agent N-acetylcysteine (NAC, 1%) on measurements of oxidative damage, antioxidant enzymes, grip strength and body mass in 6 months-old dysferlin-deficient Bla/J mice and wild-type (WT) C57 BL/6 mice. We found that quadriceps and gastrocnemius muscles of Bla/J mice exhibit high levels of lipid peroxidation, protein carbonyls and superoxide dismutase and catalase activities, which were significantly reduced by NAC supplementation. By using the Kondziela's inverted screen test, we further demonstrated that NAC improved grip strength in dysferlin deficient animals, as compared with non-treated Bla/J mice, without affecting body mass. Together, these results indicate that this antioxidant agent improves skeletal muscle oxidative balance, as well as muscle strength and/or resistance to fatigue in dysferlin-deficient animals.}, }
@article {pmid32559876, year = {2020}, author = {Chen, X and Guo, J and Huang, Y and Liu, S and Huang, Y and Zhang, Z and Zhang, F and Lu, Z and Li, F and Zheng, JC and Ding, W}, title = {Urban airborne PM2.5-activated microglia mediate neurotoxicity through glutaminase-containing extracellular vesicles in olfactory bulb.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {264}, number = {}, pages = {114716}, pmid = {32559876}, issn = {1873-6424}, support = {R01 NS097195/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; *Extracellular Vesicles ; *Glutaminase ; Male ; Mice ; Mice, Inbred C57BL ; Microglia ; Olfactory Bulb ; Particulate Matter ; Reactive Oxygen Species ; }, abstract = {Emerging evidence has showed that exposure to airborne particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5) is associated with neurodegeneration. Our previous studies in vitro found that PM2.5 exposure causes primary neurons damage through activating microglia. However, the molecular mechanism of microglia-mediated neurotoxicity remains to elucidate. In this study, five groups (N = 13 or 10) of six-week-old male C57BL/6 mice were daily exposed to PM2.5 (0.1 or 1 mg/kg/day body weight), Chelex-treated PM2.5 (1 mg/kg/day body weight), PM2.5 (1 mg/kg/day body weight) plus CB-839 (glutaminase inhibitor), or deionized water by intranasal instillation for 28 days, respectively. Compared with the control groups, We found that PM2.5 triggered reactive oxygen species (ROS) generation and microglia activation evidenced by significant increase of ionized calcium binding adaptor molecule-1 (IBa-1) staining in the mouse olfactory bulbs (OB). Data from transmission electron microscope (TEM) images and Western blot analysis showed that PM2.5 significantly increased extracellular vesicles (EVs) release from OB or murine microglial line BV2 cells, and glutaminase C (GAC) expression and glutamate generation in isolated OB and BV2 cells. However, treatment with N-acetylcysteine (NAC) or CB-839 significantly diminished the number of EVs and the expression of GAC and abolished PM2.5-induced neurotoxicity. These findings provide new insights that PM2.5 induces oxidative stress and microglia activation through its metal contents and glutaminase-containing EVs in OBs, which may serve as a potential pathway/mechanism of excessive glutamate generation in PM2.5-induced neurotoxicity.}, }
@article {pmid32559414, year = {2020}, author = {Cheng, X and Geng, F and Pan, M and Wu, X and Zhong, Y and Wang, C and Tian, Z and Cheng, C and Zhang, R and Puduvalli, V and Horbinski, C and Mo, X and Han, X and Chakravarti, A and Guo, D}, title = {Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress.}, journal = {Cell metabolism}, volume = {32}, number = {2}, pages = {229-242.e8}, pmid = {32559414}, issn = {1932-7420}, support = {R01 CA227874/CA/NCI NIH HHS/United States ; R01 CA240726/CA/NCI NIH HHS/United States ; R01 NS104332/NS/NINDS NIH HHS/United States ; R01 NS112935/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cell Line, Tumor ; Diacylglycerol O-Acyltransferase/*metabolism ; Fats/*metabolism ; Female ; Glioblastoma/*metabolism ; Humans ; Mice ; Mice, Nude ; Oxidative Stress ; }, abstract = {Glioblastoma (GBM), a mostly lethal brain tumor, acquires large amounts of free fatty acids (FAs) to promote cell growth. But how the cancer avoids lipotoxicity is unknown. Here, we identify that GBM upregulates diacylglycerol-acyltransferase 1 (DGAT1) to store excess FAs into triglycerides and lipid droplets. Inhibiting DGAT1 disrupted lipid homeostasis and resulted in excessive FAs moving into mitochondria for oxidation, leading to the generation of high levels of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release, and apoptosis. Adding N-acetyl-cysteine or inhibiting FA shuttling into mitochondria decreased ROS and cell death induced by DGAT1 inhibition. We show in xenograft models that targeting DGAT1 blocked lipid droplet formation, induced tumor cell apoptosis, and markedly suppressed GBM growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating storage of excess FAs. Targeting DGAT1 could be a promising therapeutic approach for GBM.}, }
@article {pmid32555935, year = {2020}, author = {Silvares, SG and Moron, AF and Simões, MJ and Cintra, &#xc1;U and Montero, EFS and Araujo Júnior, E and Martins, JL}, title = {Histological analysis of the intestinal wall of newborn rats submitted to hypoxia and reoxygenation to evaluate the protective effect of N-Acetylcysteine.}, journal = {Acta cirurgica brasileira}, volume = {35}, number = {4}, pages = {e202000401}, pmid = {32555935}, issn = {1678-2674}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Enterocolitis, Necrotizing/*prevention &amp; control ; Female ; Hypoxia/*pathology ; Ileum/*drug effects/*pathology ; Male ; Pregnancy ; Protective Agents/*pharmacology ; Rats, Wistar ; Reference Values ; Reproducibility of Results ; Time Factors ; Treatment Outcome ; }, abstract = {PURPOSE: To evaluate the effect of N-Acetylcysteine (NAC) in newborn rats submitted to hypoxia and reoxygenation (H/R) conditions in an experimental model of necrotizing enterocolitis.<br><br>METHODS: Eight pregnant rats and their 70 cubs were used (5 groups) and exposed to H/R conditions and received NAC at different times. The animals in the H/R groups were placed in a gas chamber (100% CO2) for 10 minutes and then reoxygenated for 10 minutes (100% O2), twice a day for the first three days of life, with a six-hour span between events. On the third day of life, the animals were anesthetized, laparotomized and the intestines were resected.<br><br>RESULTS: The H/R and NAC groups showed changes in the intestinal wall in relation to the number, height and width of the villi when compared to the control group (p<0.0001), but with better preservation of structures in the NAC group. There were no differences between groups regarding the number (%) of mitoses.<br><br>CONCLUSION: The administration of NAC decreased the lesions in the intestinal wall of rats submitted to H/R, therefore suggesting that this drug can be used to prevent the development of necrotizing enterocolitis in newborns.}, }
@article {pmid32554304, year = {2020}, author = {Xu, L and Wu, T and Lu, S and Hao, X and Qin, J and Wang, J and Zhang, X and Liu, Q and Kong, B and Gong, Y and Liu, Z and Shao, C}, title = {Mitochondrial superoxide contributes to oxidative stress exacerbated by DNA damage response in RAD51-depleted ovarian cancer cells.}, journal = {Redox biology}, volume = {36}, number = {}, pages = {101604}, pmid = {32554304}, issn = {2213-2317}, mesh = {Apoptosis ; Cell Line, Tumor ; DNA Damage ; Female ; G2 Phase Cell Cycle Checkpoints ; Humans ; Mitochondria/genetics/metabolism ; *Ovarian Neoplasms/genetics ; Oxidative Stress ; Rad51 Recombinase/genetics/metabolism ; Reactive Oxygen Species ; *Superoxides ; }, abstract = {Ovarian cancer is the most lethal gynecological malignancy. Abnormal homologous recombination repair, high level of reactive oxygen species (ROS) and upregulation of antioxidant genes are characteristic features of ovarian cancer. However, the molecular mechanisms governing the redox homeostasis in ovarian cancer cells remain to be fully elucidated. We here demonstrated a critical role of RAD51, a protein essential for homologous recombination, in the maintenance of redox homeostasis. We found that RAD51 is overexpressed in high grade serous ovarian cancer and is associated with poor prognosis. Depletion or inhibition of RAD51 results in G2/M arrest, increased production of reactive oxygen species and accumulation of oxidative DNA damage. Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation caused by RAD51 depletion. We further demonstrated that RAD51 inhibition or depletion led to elevated production of mitochondrial superoxide and increased accumulation of mitochondria. Moreover, CHK1 activation is required for the G2/M arrest and the generation of mitochondrial stress in response to RAD51 depletion. Together, our results indicate that nuclear DNA damage caused by RAD51 depletion may trigger mitochondria-originated redox dysregulation. Our findings suggest that a vicious cycle of nuclear DNA damage, mitochondrial accumulation and oxidative stress may contribute to the tumor-suppressive effects of RAD51 depletion or inhibition.}, }
@article {pmid32552909, year = {2020}, author = {Dalugama, C and Nanayakkara, M and Rathnayaka, N and Medagama, A}, title = {Atypical case of hantavirus infection in Sri Lanka mimicking leptospirosis: a case report.}, journal = {Journal of medical case reports}, volume = {14}, number = {1}, pages = {71}, pmid = {32552909}, issn = {1752-1947}, mesh = {Acute Kidney Injury/virology ; Adult ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Arthralgia/virology ; Bilirubin/blood ; Diagnosis, Differential ; Dyspnea/virology ; Farmers ; Fever/virology ; Hantavirus Infections/*diagnosis/therapy ; Hepatomegaly/virology ; Humans ; Leptospirosis ; Male ; Muscle Cramp/virology ; Myalgia/virology ; Myocarditis/virology ; Sri Lanka ; Transaminases/blood ; }, abstract = {BACKGROUND: Hantavirus infection is an emerging zoonotic infection which has two characteristic patterns of presentation: hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome. The clinical presentation of hantavirus infection closely mimics leptospirosis.<br><br>CASE PRESENTATION: This case report describes a previously apparently well 36-year-old Sri Lankan Sinhalese man who presented with an acute febrile illness with myalgia, with liver involvement in the form of transaminitis, cardiac involvement in the form of myocarditis, acute kidney injury, and pulmonary involvement. He was initially managed as severe leptospirosis with multiorgan dysfunction with antibiotics, steroids, and N-acetyl cysteine. A diagnosis of acute hantavirus infection was made subsequently. He made an uneventful recovery.<br><br>CONCLUSION: Hantavirus infections need to considered in the differential diagnosis of patients presenting with acute febrile illness with multiorgan involvement. Larger studies are needed to evaluate the seroprevalence of hantavirus in Sri Lanka because it could be an emerging serious public health problem.}, }
@article {pmid32552298, year = {2020}, author = {Rani, M and Aggarwal, R and Vohra, K}, title = {Effect of N-Acetylcysteine on Metabolic Profile in Metabolic Syndrome Patients.}, journal = {Metabolic syndrome and related disorders}, volume = {18}, number = {7}, pages = {341-346}, doi = {10.1089/met.2020.0017}, pmid = {32552298}, issn = {1557-8518}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Administration, Oral ; Adult ; Antioxidants/*administration &amp; dosage/adverse effects ; Biomarkers/blood ; Blood Pressure/drug effects ; Drug Administration Schedule ; Female ; Humans ; Inflammation Mediators/blood ; Insulin Resistance ; Lipids/blood ; Male ; Metabolic Syndrome/blood/diagnosis/*drug therapy ; Middle Aged ; Oxidative Stress/*drug effects ; Pilot Projects ; Time Factors ; Treatment Outcome ; }, abstract = {Background: N-acetylcysteine (NAC), the acetylated variant of amino acid l-cysteine, acts as a free radical scavenger and plays multifunctional roles by suppressing endogenous level of oxidative stress and inflammation and by enhancing nitric oxide bioavailability. Thus, present study aimed to evaluate the efficacy of NAC on various inherent components of metabolic syndrome (MetS). Methods: An open-label pilot study was conducted at diabetes outpatient clinic. Thirty-five patients (aged ≥18 years) fulfilling the NCEP-ATP III diagnostic criteria for MetS were recruited and allocated to NAC tablets as 600 mg (twice a day) along with their ongoing therapeutic regimen. Blood pressure (BP), body mass index, lipid profile, fasting plasma glucose and insulin, insulin resistance estimated by homeostatic model assessment (HOMA-IR), high-sensitivity C-reactive proteins (hsCRP), nitrite, and thiobarbituric acid reactive substances (TBARS) were measured after 6 weeks treatment. Results: HOMA-IR, hsCRP and systolic BP were decreased significantly from 4.74 ± 0.30% to 3.86 ± 0.21%; 5.66 ± 0.27 to 4.92 ± 0.18 mg/L; and 133.2 ± 1.84 to 128.3 ± 1.52 mmHg, respectively. Among dyslipidemic variables, there was decrease in triglycerides from 194.20 ± 5.03 to 188.04 ± 4.93 mg/dL, but increase in HDL from 33.32 ± 0.19 to 36.29 ± 1.16 mg/dL. Nitrite levels were significantly increased from 6.25 ± 0.20 to 7.92 ± 0.18 μmol/L (P = 0.04), while TBARS levels were decreased from 14.65 ± 0.32 to 13.68 ± 0.33 nmol/L (P = 0.05). It was found from correlation analysis that hsCRP was the main culprit, that is, inflammation was perpetuator of endothelial dysfunction, IR, oxidative stress, hypertension, and vice-versa. Conclusion: This study has provided a new approach of management of MetS with NAC beyond controlling the disease with various drug therapies. NAC may reduce the risk burden via multiple antioxidant, anti-inflammatory, and vasodilatory effect.}, }
@article {pmid32551386, year = {2020}, author = {Allameh, A and Ahmadi-Ashtiani, HR and Maleki, N}, title = {Glutathione-related inflammatory signature in hepatocytes differentiated from the progenitor mesenchymal stem cells.}, journal = {Heliyon}, volume = {6}, number = {6}, pages = {e04149}, pmid = {32551386}, issn = {2405-8440}, abstract = {N-acetylcysteine (NAC) as a glutathione inducer is known for its anti-inflammatory effects in inflammatory conditions. The aim of the present study was to know if supplementation of the culture medium with NAC can improve anti-inflammatory activities of hepatocytes during their differentiation from mesenchymal stem cells (MSCs). For this, in vitro hepatic differentiation of MSCs was performed in culture medium supplemented with NAC and selected pro- and anti-inflammatory factors were monitored for two weeks. Treatment of the MSCs undergoing hepatic differentiation with NAC (0.1 and 1.0 mM) caused a significant (~5-fold) increase in proliferation rate of MSCs, whereas the rate of hepatic differentiation was declined in NAC-treated cells as compared to those untreated with NAC. Under these circumstances, NAC caused a significant increase in total glutathione in cell lysate during 2 weeks of differentiation as compared to untreated group. NAC-related increase in glutathione was associated with significant alterations in tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8 and IL-10 levels secreted in the culture medium. A substantial decrease in the IL-6, IL-8 and TNF-α levels in the culture medium supplemented with NAC was obvious in hepatocytes recovered 14 days after differentiation. In contrast, the secretary IL-10 was significantly increased as a result of NAC treatments. These data suggest that NAC supplementation can improve anti-inflammatory activities of the hepatocytes derived from MSCs. NAC function mediated by glutathione synthesis can also help in modulation of proliferation of the stem cells and their differentiation into hepatocyte-like cells.}, }
@article {pmid32549758, year = {2020}, author = {Lu, Q and Ding, Y and Li, Y and Lu, Q}, title = {5-HT receptor agonist Valerenic Acid enhances the innate immunity signal and suppresses glioblastoma cell growth and invasion.}, journal = {International journal of biological sciences}, volume = {16}, number = {12}, pages = {2104-2115}, pmid = {32549758}, issn = {1449-2288}, mesh = {Animals ; Apoptosis ; Autophagy ; Cell Line, Tumor ; Cell Survival ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Glioblastoma ; Humans ; Immunity, Innate/*drug effects ; Indenes/*pharmacology ; Mice ; Mice, Nude ; Neoplasm Invasiveness/prevention &amp; control ; Neoplasms, Experimental ; Reactive Oxygen Species ; Serotonin Receptor Agonists/*pharmacology ; Sesquiterpenes/*pharmacology ; }, abstract = {Glioblastoma multiform (GBM) continues to threaten people's lives due to the limited therapeutic strategies. As a new drug, Valerenic Acid suppresses the progression of GBM, however, the mechanism is largely unknown. Here, we found that Valerenic Acid can inhibit cell proliferation, migration and invasion of GBM cells by increasing innate immune signals such as enhancing ROS levels and activating the AMPK pathway. Inhibition of ROS by N-acetylcysteine (NAC) or attenuation of AMPK by Compound C could block Valerenic Acid-induced cell death. Additionally, the xenograft mouse model also confirmed that Valerenic Acid had anti-tumor effect. Together, our results provide compelling rational to develop Valerenic Acid as an anti-tumor agent against GBM patients.}, }
@article {pmid32549180, year = {2020}, author = {Bodiga, VL and Vemuri, PK and Nimmagadda, G and Bodiga, S}, title = {Zinc-dependent changes in oxidative and endoplasmic reticulum stress during cardiomyocyte hypoxia/reoxygenation.}, journal = {Biological chemistry}, volume = {401}, number = {11}, pages = {1257-1271}, doi = {10.1515/hsz-2020-0167}, pmid = {32549180}, issn = {1437-4315}, mesh = {Animals ; *Cell Hypoxia ; Cell Line ; *Endoplasmic Reticulum Stress ; Myocytes, Cardiac/cytology/*metabolism ; *Oxidative Stress ; Rats ; Receptor, ErbB-2/metabolism ; Unfolded Protein Response ; Zinc/*metabolism ; }, abstract = {Myocardial zinc dyshomeostasis is associated with caspase-3 activation, ErbB2 degradation and apoptosis during hypoxia/reoxygenation. Zinc pyrithione replenishes intracellular zinc, suppresses caspase-3, augments ErbB2 levels and improves cell survival. We hypothesize that zinc is capable of modulating redox and endoplasmic reticulum (ER) stress in the setting of cardiomyocyte hypoxia-reoxygenation. Hypoxia/reoxygenation lowered intracellular zinc, increased ER as well as oxidative stress in H9c2 cells, both of which were effectively attenuated by zinc supplementation. Silencing of gp91phox attenuated oxidative and ER stress, decreased caspase-3 activation and improved cell survival. Mimicking the oxidative insult using 50 μM H2O2 increased the caspase-3 activity that correlated with decreased ErbB2 levels, concomitant with augmented ER stress. N-acetyl cysteine (NAC) administration completely suppressed ER stress as well as caspase-3 activity. Zinc depletion using TPEN also resulted in lowered ErbB2 and increased apoptosis, along with NOX2 mRNA upregulation, increased oxidative and ER stress. Repletion with zinc suppressed NOX2 mRNA, lowered oxidative as well as ER stress and decreased cell death. These results suggest that zinc dyshomeostasis, along with oxidative stress contribute to the unfolded protein response during myocardial H/R and that zinc replenishment corrects zinc homeostasis, alleviates associated stress and improves cardiomyocyte survival.}, }
@article {pmid32548987, year = {2020}, author = {Lin, X and Wei, M and Song, F and Xue, DI and Wang, Y}, title = {N-acetylcysteine (NAC) Attenuating Apoptosis and Autophagy in RAW264.7 Cells in Response to Incubation with Mycolic Acid from Bovine Mycobacterium tuberculosis Complex.}, journal = {Polish journal of microbiology}, volume = {69}, number = {2}, pages = {223-229}, pmid = {32548987}, issn = {2544-4646}, mesh = {AMP-Activated Protein Kinases/genetics ; Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects/genetics ; Autophagy/*drug effects/genetics ; Gene Expression Regulation/*drug effects ; Lung/drug effects/microbiology ; Lung Injury/microbiology ; Mice ; Mycobacterium tuberculosis/*chemistry ; Mycolic Acids/pharmacology ; RAW 264.7 Cells ; TOR Serine-Threonine Kinases/genetics ; }, abstract = {Bovine tuberculosis is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis (MTB) complex. Mycolic acid (MA) is the main lipid component of the cell membrane of MTB. It is non-enzymatically reduced by NAD(P)H and further produces reactive oxygen species (ROS), which can cause oxidative stress in human cells. N-acetylcysteine (NAC) is a synthetic precursor of glutathione (GSH) and exhibits anti-ROS activity. However, the underlying mechanisms of its protective properties remain uncertain. Herein, after pre-incubation of RAW264.7 cells with NAC, the factors associated with apoptosis and autophagy were measured. Mechanistically, NAC could reduce MA-induced expression of pro-apoptotic and pro-autophagy proteins. At the mRNA level, NAC can inhibit AMPK and activate mTOR expression. The results indicate that NAC might regulate autophagy in RAW264.7 cells through the AMPK/mTOR pathway. To further prove the effect of NAC on MA, ICR mice were used to evaluate the lung injury. Hematoxylin-eosin (HE) staining was performed on the lung. The results show that NAC could reduce cell injury induced by MA. In conclusion, our research showed that NAC attenuates apoptosis and autophagy in response to incubation with mycolic acid. Bovine tuberculosis is an airborne infectious disease caused by organisms of the Mycobacterium tuberculosis (MTB) complex. Mycolic acid (MA) is the main lipid component of the cell membrane of MTB. It is non-enzymatically reduced by NAD(P)H and further produces reactive oxygen species (ROS), which can cause oxidative stress in human cells. N-acetylcysteine (NAC) is a synthetic precursor of glutathione (GSH) and exhibits anti-ROS activity. However, the underlying mechanisms of its protective properties remain uncertain. Herein, after pre-incubation of RAW264.7 cells with NAC, the factors associated with apoptosis and autophagy were measured. Mechanistically, NAC could reduce MA-induced expression of pro-apoptotic and pro-autophagy proteins. At the mRNA level, NAC can inhibit AMPK and activate mTOR expression. The results indicate that NAC might regulate autophagy in RAW264.7 cells through the AMPK/mTOR pathway. To further prove the effect of NAC on MA, ICR mice were used to evaluate the lung injury. Hematoxylin-eosin (HE) staining was performed on the lung. The results show that NAC could reduce cell injury induced by MA. In conclusion, our research showed that NAC attenuates apoptosis and autophagy in response to incubation with mycolic acid.}, }
@article {pmid32547310, year = {2020}, author = {Pattanakuhar, S and Phrommintikul, A and Tantiworawit, A and Srichairattanakool, S and Chattipakorn, SC and Chattipakorn, N}, title = {N-acetylcysteine Restored Heart Rate Variability and Prevented Serious Adverse Events in Transfusion-dependent Thalassemia Patients: a Double-blind Single Center Randomized Controlled Trial.}, journal = {International journal of medical sciences}, volume = {17}, number = {9}, pages = {1147-1155}, pmid = {32547310}, issn = {1449-1907}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Cardiac Imaging Techniques ; Dinoprost/analogs &amp; derivatives/blood ; Echocardiography ; Female ; Heart Rate/*drug effects ; Humans ; Interleukin-10/blood ; Magnetic Resonance Imaging ; Male ; Oxidative Stress/*drug effects ; Thalassemia/blood/diagnostic imaging/*drug therapy ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {Regular blood transfusions in transfusion-dependent thalassemia (TDT) patients can lead to iron overload, causing oxidative stress and sympathovagal imbalance, resulting in increased cardiac complications. We hypothesized that administrating of N-acetylcysteine (NAC) prevents serious adverse events including cardiac complications in TDT patients by reducing systemic oxidative stress and balancing cardiac sympathovagal control. This study was double-blind, randomized control trial, investigating in 59 Thai TDT patients. After randomization, the participants were divided into two groups. The control group received standard care of TDT patient plus placebo, whereas the intervention group received 600 mg of NAC orally for six months. Serum 8-isoprostane, TNF-alpha, IL-10, 24-hour ECG monitoring, echocardiograms and the incidence of thalassemia-related complications were collected. At baseline, no significant difference in any parameters between the control and the intervention groups. At the end of intervention, the incidence of serious adverse events (i.e. infection, worsening thalassemia) was significantly higher in the control group when compared with the intervention group (24.1% vs. 3.3%, p=0.019) (Chi-square test; absolute risk reduction=20.8%, number needed to treat=4.8). The control group also had significantly lower time-dependent HRV parameters, compared with the intervention group (p=0.025 and 0.030, independent t-test). Treatment with NAC restored HRV and reduced serious adverse event in TDT patients, however, no difference in cardiac complications could be demonstrated. NAC could prevent serious adverse events in TDT patients. The proposed mechanism might be the balancing of sympathovagal control.}, }
@article {pmid32547098, year = {2020}, author = {Wang, W and Fang, D and Zhang, H and Xue, J and Wangchuk, D and Du, J and Jiang, L}, title = {Sodium Butyrate Selectively Kills Cancer Cells and Inhibits Migration in Colorectal Cancer by Targeting Thioredoxin-1.}, journal = {OncoTargets and therapy}, volume = {13}, number = {}, pages = {4691-4704}, pmid = {32547098}, issn = {1178-6930}, abstract = {BACKGROUND: Sodium butyrate (NaB) is a short-chain fatty acid which is produced by bacterial fermentation of nondigestible dietary fiber and has been reported to exert anti-tumor effects in many tumors including colorectal cancer (CRC). However, the role of thioredoxin-1 (Trx-1) in NaB-induced anti-tumor effect has not been completely clarified.<br><br>MATERIALS AND METHODS: Effects of NaB on the growth of CRC cell lines HT29 and SW480 were detected by the Cell Counting Kit-8 (CCK-8) and colony formation assays. The apoptotic cells were determined by flow cytometry, and cell migration was assessed by a Transwell assay. Western blot analysis was used to test the Trx-1 and epithelial-to-mesenchymal transition (EMT)-related proteins level. Reactive oxygen species (ROS) level was determined and N-acetylcysteine (NAC) recovery experiment was performed in CRC cells. In addition, mice xenograft model was established to test the effect of NaB on CRC growth in vivo. Further, the effects of NaB on CRC cells with overexpression or knockdown were tested by the CCK-8 and Transwell assays.<br><br>RESULTS: NaB treatment significantly inhibited cell growth and decreased Trx-1 protein expression in CRC cells but not in normal colon epithelial cells. NaB also induced apoptosis, inhibited colony formation, migration and EMT in CRC cells. Besides, NaB increased ROS level in CRC cells and NAC reversed NaB-induced inhibition of cell proliferation. Moreover, downregulation of Trx-1 significantly enhanced NaB-induced inhibitory effects on cell growth and migration, whereas overexpression of Trx-1 attenuated NaB-induced inhibitory effects on growth and migration in CRC cells.<br><br>CONCLUSION: These findings indicate that the NaB-mediated anti-tumor effects on CRC cells are related to downregulation of Trx-1.}, }
@article {pmid32547030, year = {2020}, author = {Sabetghadam, M and Mazdeh, M and Abolfathi, P and Mohammadi, Y and Mehrpooya, M}, title = {Evidence for a Beneficial Effect of Oral N-acetylcysteine on Functional Outcomes and Inflammatory Biomarkers in Patients with Acute Ischemic Stroke.}, journal = {Neuropsychiatric disease and treatment}, volume = {16}, number = {}, pages = {1265-1278}, pmid = {32547030}, issn = {1176-6328}, abstract = {PURPOSE: Numerous preclinical studies have demonstrated the potential neuroprotective effects of N-acetylcysteine (NAC) in the treatment of brain ischemia. Accordingly, the present study aimed to assess the potential therapeutic effects of oral NAC in patients with acute ischemic stroke.<br><br>PATIENTS AND METHODS: In a randomized, double-blind, placebo-controlled trial study, 68 patients with acute ischemic stroke with the onset of symptoms less than 24 hours were randomly assigned to either the NAC-treated group or placebo-treated group. NAC and matched placebo were administrated by a 72-hour oral protocol (initially 4 grams loading dose and after on, 4 g in 4 equal divided doses for more 2 days). The primary outcomes were quantification of any neurologic deficit by the use of the National Institute of Health Stroke Scale (NIHSS) score and functional disability by the use of the modified Rankin scale (mRS) at 90 days after stroke. Additionally, serum levels of markers of oxidative stress and inflammation as a main mechanism of its action were assessed at baseline and the end of 3-day treatment protocol.<br><br>RESULTS: NAC-treated patients in comparison with placebo-treated patients showed a significantly lower mean NIHSS scores at day 90 after stroke. A favorable functional outcome which was defined as an mRS score of 0 or 1, also in favor of NAC compared to placebo was noted on day 90 after stroke (57.6% in the NAC-treated group compared with 28.6% in the placebo-treated group). Further, compared to the placebo, NAC treatment significantly decreased serum levels of proinflammatory biomarkers such as interleukin 6 (IL-6), soluble intercellular cell adhesion molecule-1 (sICAM-1), &#xfeff;nitric oxide (NO), &#xfeff;malondialdehyde (MDA), and neuron-specific enolase (NSE) and significantly increased serum levels of anti-oxidant biomarkers such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and total thiol groups (TTG).<br><br>CONCLUSION: The pattern of results suggests that oral NAC administration early after an acute ischemic stroke is associated with a better outcome profile in terms of acute neurological deficit and disability grade compared to placebo. NAC may improve neurological outcomes of patients with stroke at least in part by its antioxidant and anti-inflammatory effects.}, }
@article {pmid32547011, year = {2020}, author = {Yang, J and Zhang, H and Chan, SM and Li, R and Wu, Y and Cai, M and Wang, A and Wang, Y}, title = {TiO2 Nanotubes Alleviate Diabetes-Induced Osteogenetic Inhibition.}, journal = {International journal of nanomedicine}, volume = {15}, number = {}, pages = {3523-3537}, pmid = {32547011}, issn = {1178-2013}, mesh = {Alkaline Phosphatase/metabolism ; Animals ; Apoptosis/drug effects ; Cell Adhesion/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Diabetes Mellitus/*pathology ; Glucose/toxicity ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Nanotubes/*chemistry ; Osteogenesis/*drug effects ; Osteopontin/metabolism ; Prostheses and Implants ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Surface Properties ; Titanium/*pharmacology ; }, abstract = {BACKGROUND: Patients with diabetes mellitus (DM) have a higher failure rate of dental implant treatments. However, whether titanium (Ti) implants with TiO2 nanotubes (TNT) surface can retain their biocompatibility and osteogenetic ability under DM conditions has not been investigated; in addition, their behavior in DM conditions is not well characterized.<br><br>MATERIALS AND METHODS: Pure Ti discs were surface treated into the polishing (mechanically polished,&#xa0;MP), sandblasted and acid-etched (SLA), and TNT groups. Scanning electron microscopy was used to examine the surface morphology. The cell adhesion and proliferation ability on different modified Ti surfaces at various glucose concentrations (5.5, 11, 16.5, and 22 mM) was detected by the&#xa0;CCK-8 assay. The osteogenetic ability on different modified Ti surfaces under high-glucose conditions was evaluated by alkaline phosphatase (ALP), osteopontin (OPN) immunofluorescence, Western blot, and Alizarin &#xfeff;Red staining in vitro. Detection of cell apoptosis and intracellular reactive oxygen species (ROS) was undertaken both before and after N-acetylcysteine (NAC) treatment to assess the oxidative stress associated with different modified Ti surfaces under high-glucose conditions. An in vivo study was conducted in DM rats with different modified Ti femoral implants. The osteogenetic ability of different modified Ti implants in DM rats was assessed using a micro-CT scan.<br><br>RESULTS: High-glucose conditions inhibited cell adhesion, proliferation, and osteogenetic ability of different modified Ti surfaces. High-glucose conditions induced higher apoptosis rate and intracellular ROS level on different modified Ti surfaces; these effects were alleviated by NAC. Compared with the SLA surface, the TNT surface alleviated the osteogenetic inhibition induced by high-glucose states by reversing the overproduction of ROS in vitro. In the in vivo experiment, micro-CT scan analysis further confirmed the best osteogenetic ability of TNT surface in rats with DM.<br><br>CONCLUSION: TNT surface modification alleviates osteogenetic inhibition induced by DM. It may provide a more favorable Ti implant surface for patients with DM.}, }
@article {pmid32546421, year = {2020}, author = {Utzschneider, KM and Johnson, TN and Breymeyer, KL and Bettcher, L and Raftery, D and Newton, KM and Neuhouser, ML}, title = {Small changes in glucose variability induced by low and high glycemic index diets are not associated with changes in β-cell function in adults with pre-diabetes.}, journal = {Journal of diabetes and its complications}, volume = {34}, number = {8}, pages = {107586}, pmid = {32546421}, issn = {1873-460X}, support = {R01 DK092568/DK/NIDDK NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; P30 DK017047/DK/NIDDK NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Adult ; Biomarkers/metabolism ; Blood Glucose/*metabolism ; *Diet ; Female ; Free Radical Scavengers/therapeutic use ; Glucose Tolerance Test ; *Glycemic Index ; Glycemic Load ; Humans ; Insulin-Secreting Cells/*physiology ; Male ; Middle Aged ; Oxidative Stress/*physiology ; Prediabetic State/*blood/physiopathology ; }, abstract = {Oscillating glucose levels can increase oxidative stress and may contribute to β-cell dysfunction. We tested the hypothesis that increased glycemic variability contributes to β-cell dysfunction by experimentally altering glucose variability with controlled diets varying in glycemic index (GI). Fifty-two adults with prediabetes received a 2-week moderate GI (GI = 55-58) control diet followed by randomization to a four-week low GI (LGI: GI < 35) or high GI (HGI HI > 70) diet. Those on the HGI diet were randomized to placebo or the antioxidant N-acetylcysteine (NAC). Participants underwent blinded CGMS, fasting oxidative stress markers and an intravenous glucose tolerance test to estimate β-cell function (disposition index: DI). On the control diet, DI was inversely correlated with SD glucose (r = -0.314, p = 0.03), but neither DI nor glucose variability were associated with oxidative stress markers. The LGI diet decreased SD glucose (Control 0.96 ± 0.08 vs. LGI 0.79 ± 0.06, p = 0.02) while the HGI diet increased it (Control 0.88 ± 0.06 vs. HGI 1.06 ± 0.07, p = 0.03). Neither DI nor oxidative stress markers changed after the LGI or HGI diets. NAC had no effect on DI, glucose variability or oxidative stress markers. We conclude small changes in glucose variability induced by dietary GI in adults with pre-diabetes are unlikely to contribute to β-cell dysfunction.}, }
@article {pmid32546031, year = {2021}, author = {Song, J and Yao, L and Shi, J and Li, J and Xu, C}, title = {Protective effects of N-acetylcysteine on a chemical-induced murine model of asthma.}, journal = {The Journal of asthma : official journal of the Association for the Care of Asthma}, volume = {58}, number = {9}, pages = {1208-1215}, doi = {10.1080/02770903.2020.1781166}, pmid = {32546031}, issn = {1532-4303}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Allergens ; Animals ; Anti-Asthmatic Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Asthma/chemically induced/*drug therapy/immunology/physiopathology ; Bronchoalveolar Lavage Fluid/cytology/immunology ; Disease Models, Animal ; Eosinophils/drug effects ; Glutathione/immunology ; Immunoglobulin E/immunology ; Interleukin-4/immunology ; Interleukin-5/immunology ; Leukocyte Count ; Lung/drug effects/immunology/pathology/physiopathology ; Male ; Mice, Inbred BALB C ; Neutrophils/drug effects ; Superoxide Dismutase/immunology ; Toluene 2,4-Diisocyanate ; Mice ; }, abstract = {INTRODUCTION: Oxidative stress is involved in the pathophysiology of inflammatory airway diseases, including asthma. In this study, we elucidated the possible protective effects of the antioxidant N-acetylcysteine (NAC) on a toluene diisocyanate (TDI)-induced murine asthma model.<br><br>METHODS: Male BALB/c mice were sensitized and challenged with TDI to generate a chemical-induced asthma model. NAC was given intraperitoneally to mice immediately after each TDI challenge. Airway reactivity to methacholine and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology.<br><br>RESULTS: NAC treatment dramatically reduced the increased airway hyperresponsiveness, inflammatory infiltration, and goblet cell metaplasia in TDI-exposed mice. Numbers of total cells, neutrophils, and eosinophils in the bronchoalveolar lavage fluid of TDI-challenged mice were significantly higher than vehicle control, but the administration of NAC decreased these inflammatory cell counts. TDI exposure led to significantly increased levels of interleukin 4 (IL-4) and IL-5, which were also suppressed by NAC. In addition, diminished lung reduced oxidized glutathione ratio and superoxide dismutase activity were observed after TDI challenge, and these changes were attenuated by NAC.<br><br>CONCLUSION: NAC treatment has beneficial effects in TDI-induced asthma.}, }
@article {pmid32545506, year = {2020}, author = {Cleare, LG and Li, KL and Abuzeid, WM and Nacharaju, P and Friedman, JM and Nosanchuk, JD}, title = {NO Candida auris: Nitric Oxide in Nanotherapeutics to Combat Emerging Fungal Pathogen Candida auris.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {6}, number = {2}, pages = {}, pmid = {32545506}, issn = {2309-608X}, abstract = {Candida auris (C. auris) is an emerging pathogenic fungal species that is especially worrisome due to its high mortality rates and widespread antifungal resistance. Previous studies have demonstrated the efficacy of nitric oxide (NO) nanoparticles on Candida species, and, to our knowledge, this is the first study to investigate the antifungal effects of a NO-generating nanoparticle on C. auris. Six C. auris strains were incubated with a nanoparticle (NAC-SNO-np), which releases N-acetylcysteine S-nitrosothiol (NAC-SNO) and N-acetylcysteine (NAC), and generates NO, through colony forming unit (CFU) assays, and confocal laser scanning microscopy. NAC-SNO-np effectively eradicates planktonic and biofilm C. auris. Across all six strains, 10 mg/mL NAC-SNO-np significantly reduced the number of CFUs (p < 0.05) and demonstrated a >70% decrease in biofilm viability (p < 0.05). NAC-SNO-np effectively eradicates planktonic C. auris and significantly reduces C. auris biofilm formation. Hence, this novel NO-releasing nanoparticle shows promise as a future therapeutic.}, }
@article {pmid32536177, year = {2020}, author = {Badri, S and Soltani, R and Sayadi, M and Khorvash, F and Meidani, M and Taheri, S}, title = {Effect of N-acetylcysteine against Vancomycin-Induced Nephrotoxicity: A Randomized Controlled Clinical Trial.}, journal = {Archives of Iranian medicine}, volume = {23}, number = {6}, pages = {397-402}, doi = {10.34172/aim.2020.33}, pmid = {32536177}, issn = {1735-3947}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/chemically induced/*drug therapy/pathology ; Adult ; Aged ; Antioxidants/*therapeutic use ; Blood Urea Nitrogen ; Creatinine/blood ; Female ; Humans ; Male ; Middle Aged ; Reactive Oxygen Species/metabolism ; Vancomycin/*adverse effects ; }, abstract = {BACKGROUND: The proposed mechanism of vancomycin-induced nephrotoxicity (VIN) is indirect production of reactive oxygen species in the kidney tissue. This study aimed to investigate the effectiveness of N-acetylcysteine (NAC), an anti-oxidant agent, in the prevention of VIN.<br><br>METHODS: Patients who received vancomycin for any indication were randomly divided to drug (NAC) and control groups. The patients in the drug group received oral NAC 600 mg every 12 hours for 10 days, starting concurrently with vancomycin. Serum creatinine (SCr) levels and blood urea nitrogen (BUN) as well as creatinine clearance (CrCl) and 12-hour urine volume were recorded at baseline, every other day during the study, and 12 hours after the last dose of vancomycin on the 10th day. Furthermore, the cases of acute kidney injury (AKI; &#x2265; 0.5 mg/dL or at least 50% increase in serum creatinine from baseline) were recorded in the two groups.<br><br>RESULTS: Over the study period, 84 and 95 patients completed the study in drug and control groups, respectively. SCr and CrCl were significantly lower and higher, respectively, at all-time points (except for baseline) in the NAC compared to the control group. Furthermore, although not statistically significant, 12 cases of vancomycin-induced AKI were observed in the control group (12.63%), while 4 cases (4.76%) were reported from drug group (P = 0.066; relative risk [RR] = 0.377, 95% CI: 0.126-1.124).<br><br>CONCLUSION: NAC has the potential for reduction of VIN. However, more studies are necessary to confirm this effect.}, }
@article {pmid32534175, year = {2020}, author = {Horowitz, RI and Freeman, PR}, title = {Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials.}, journal = {Medical hypotheses}, volume = {143}, number = {}, pages = {109851}, pmid = {32534175}, issn = {1532-2777}, mesh = {Acetazolamide/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Anticoagulants/therapeutic use ; COVID-19 ; COVID-19 Testing ; Clinical Laboratory Techniques ; Coronavirus Infections/*diagnosis/drug therapy/*prevention &amp; control/*therapy ; Diet Therapy ; Humans ; Immune System ; Inflammation ; Ivermectin/therapeutic use ; Mass Screening ; NF-E2-Related Factor 2/antagonists &amp; inhibitors ; NF-kappa B/antagonists &amp; inhibitors ; Pandemics/*prevention &amp; control ; Pneumonia, Viral/*diagnosis/*prevention &amp; control/*therapy ; *Randomized Controlled Trials as Topic ; Resource Allocation ; Risk ; Sildenafil Citrate/therapeutic use ; Treatment Outcome ; COVID-19 Drug Treatment ; }, abstract = {PURPOSE: Asymptomatic or minimally symptomatic infection with COVID-19 can result in silent transmission to large numbers of individuals, resulting in expansion of the pandemic with a global increase in morbidity and mortality. New ways of screening the general population for COVID-19 are urgently needed along with novel effective prevention and treatment strategies.<br><br>HYPOTHESIS: A hypothetical three-part prevention, diagnostic, and treatment approach based on an up-to-date scientific literature review for COVID-19 is proposed. Regarding diagnosis, a validated screening questionnaire and digital app for COVID-19 could help identify individuals who are at risk of transmitting the disease, as well as those at highest risk for poor clinical outcomes. Global implementation and online tracking of vital signs and scored questionnaires that are statistically validated would help health authorities properly allocate essential health care resources to test and isolate those at highest risk for transmission and poor outcomes. Second, regarding prevention, no validated protocols except for physical distancing, hand washing, and isolation exist, and recently ivermectin has been published to have anti-viral properties against COVID-19. A randomized trial of ivermectin, and/or nutraceuticals that have been published to support immune function including glutathione, vitamin C, zinc, and immunomodulatory supplements (3,6 Beta glucan) could be beneficial in preventing transmission or lessening symptomatology but requires statistical validation. Third, concerning treatment, COVID-19 induced inflammation and "cytokine storm syndrome" with hemophagocytic lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) have resulted in extreme morbidity and mortality in those with certain comorbidities, secondary to "acute respiratory distress syndrome" (ARDS) and multiorgan dysfunction with disseminated intravascular coagulation (DIC). Deficiency in red blood cell, serum and alveolar glutathione has been published in the medical literature for ARDS, as well as viral and bacterial pneumonias, resulting from increased levels of free radical/oxidative stress. A randomized controlled trial of blocking NF-&#x3ba;B and cytokine formation using glutathione precursors (N-acetyl-cysteine [NAC] and alpha lipoic acid) and PO/IV glutathione with associated anti-viral effects should be performed, along with an evaluation of Nrf2 activators (curcumin, sulforaphane glucosinolate) which have been scientifically proven to lower inflammation. Since high mortality rates from sepsis induced DIC due to COVID-19 infection has also been associated with thrombotic events and elevated levels of D-dimer, randomized controlled trials of using anticoagulant therapy with heparin is urgently required. This is especially important in patients on ventilators who have met certain sepsis induced coagulopathy (SIC) criteria. The use of acetazolamide with or without sildenafil also needs to be explored with or without heparin, since increased oxygen delivery to vital organs through prevention of thrombosis/pulmonary emboli along with carbonic anhydrase inhibition may help increase oxygenation and prevent adverse clinical outcomes.<br><br>CONCLUSION AND IMPLICATIONS: A three-part prevention, diagnostic, and treatment plan is proposed for addressing the severe complications of COVID-19. Digital monitoring of symptoms to clinically diagnose early exposure and response to treatment; prevention with ivermectin as well as nutritional therapies that support a healthy immune response; treatment with anti-inflammatory therapies that block NF-&#x3ba;B and activate Nrf2 pathways, as well as novel therapies that address COVID-19 pneumonia and ARDS with DIC including anticoagulation and/or novel respiratory therapies with or without acetazolamide and sildenafil. These three broad-based interventions urgently need to be subjected to randomized, controlled trials.}, }
@article {pmid32534099, year = {2020}, author = {Chiang, S and Huang, MLH and Richardson, DR}, title = {Treatment of dilated cardiomyopathy in a mouse model of Friedreich's ataxia using N-acetylcysteine and identification of alterations in microRNA expression that could be involved in its pathogenesis.}, journal = {Pharmacological research}, volume = {159}, number = {}, pages = {104994}, doi = {10.1016/j.phrs.2020.104994}, pmid = {32534099}, issn = {1096-1186}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Basic-Leucine Zipper Transcription Factors/metabolism ; Cardiomyopathy, Dilated/*drug therapy/etiology/genetics/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Friedreich Ataxia/*complications/genetics ; Gene Expression Regulation ; Humans ; Iron-Binding Proteins/genetics/metabolism ; Isothiocyanates/pharmacology ; Kelch-Like ECH-Associated Protein 1/metabolism ; Mice, Knockout ; MicroRNAs/genetics/*metabolism ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; NF-E2-Related Factor 2/genetics/metabolism ; Sulfoxides/pharmacology ; Frataxin ; }, abstract = {Deficient expression of the mitochondrial protein, frataxin, leads to a deadly cardiomyopathy. Our laboratory reported the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation after frataxin deletion in the heart. This was due, in part, to a pronounced increase in Keap1. To assess if this can be therapeutically targeted, cells were incubated with N-acetylcysteine (NAC), or buthionine sulfoximine (BSO), which increases or decreases glutathione (GSH), respectively, or the NRF2-inducer, sulforaphane (SFN). While SFN significantly (p < 0.05) induced NRF2, KEAP1 and BACH1, NAC attenuated SFN-induced NRF2, KEAP1 and BACH1. The down-regulation of KEAP1 by NAC was of interest, as Keap1 is markedly increased in the MCK conditional frataxin knockout (MCK KO) mouse model and this could lead to the decreased Nrf2 levels. Considering this, MCK KO mice were treated with i.p. NAC (500- or 1500-mg/kg, 5 days/week for 5-weeks) and demonstrated slightly less (p > 0.05) body weight loss versus the vehicle-treated KO. However, NAC did not rescue the cardiomyopathy. To additionally examine the dys-regulation of Nrf2 upon frataxin deletion, studies assessed the role of microRNA (miRNA) in this process. In MCK KO mice, miR-144 was up-regulated, which down-regulates Nrf2. Furthermore, miRNA screening in MCK KO mice demonstrated 23 miRNAs from 756 screened were significantly (p < 0.05) altered in KOs versus WT littermates. Of these, miR-21*, miR-34c*, and miR-200c, demonstrated marked alterations, with functional clustering analysis showing they regulate genes linked to cardiac hypertrophy, cardiomyopathy, and oxidative stress, respectively.}, }
@article {pmid32526845, year = {2020}, author = {Chaves Cayuela, N and Kiyomi Koike, M and Jacysyn, JF and Rasslan, R and Azevedo Cerqueira, AR and Pereira Costa, SK and Picanço Diniz-Júnior, JA and Massazo Utiyama, E and Frasson de Souza Montero, E}, title = {N-Acetylcysteine Reduced Ischemia and Reperfusion Damage Associated with Steatohepatitis in Mice.}, journal = {International journal of molecular sciences}, volume = {21}, number = {11}, pages = {}, pmid = {32526845}, issn = {1422-0067}, support = {308995/2012-0//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 817757/38860//Programa de Apoio &#xe0; P&#xf3;s-Gradua&#xe7;&#xe3;o - CAPES-PROAP/ ; }, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/metabolism ; Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Aspartate Aminotransferases/metabolism ; Cell Death/drug effects ; Cytokines/metabolism ; Liver/drug effects/enzymology/pathology ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/metabolism ; Non-alcoholic Fatty Liver Disease/*drug therapy/metabolism/physiopathology ; Oxidative Stress/drug effects ; Reperfusion Injury/*drug therapy/metabolism/pathology ; }, abstract = {N-acetylcysteine (NAC) is a pharmacological alternative with great potential for reducing the deleterious effects of surgical procedures on patients with steatohepatitis. We evaluated the effect of NAC on hepatic ischemia/reperfusion (I/R) injury in C57BL/6J mice, 8 weeks-old, weighing 25-30 g, with steatohepatitis induced by a methionine- and choline-deficient (MCD) diet. Groups: MCD group (steatohepatitis), MCD-I/R group (steatohepatitis plus 30 min of 70% liver ischemia and 24 h of reperfusion), MCD-I/R+NAC group (same as MCD-I/R group plus 150 mg/kg NAC 15 min before ischemia), and control group (normal AIN-93M diet). Liver enzymes and histopathology; nitrite and TBARS (thiobarbituric acid reactive substances) levels; pro-inflammatory cytokines; antioxidants enzymes; Nrf2 (nuclear factor erythroid-2-related factor 2) expression; and apoptosis were evaluated. In the group treated with NAC, reductions in inflammatory infiltration; AST (aspartate aminotransferase), nitrite, and TBARS levels; GPx (gutathione peroxidase) activity; cytokines synthesis; and number of apoptotic cells were observed while the GR (glutathione reductase) activity was increased. No differences were observed in Nfr2 expression or in SOD (superoxide dismutase), CAT (catalase), and GST (glutathione S-transferase) activities. Thus, it may be concluded that NAC exerts beneficial effects on mice livers with steatohepatitis submitted to I/R by reducing oxidative stress, inflammatory response, and cell death.}, }
@article {pmid32526201, year = {2020}, author = {Lim, GE and Park, JE and Cho, YH and Lim, DS and Kim, AJ and Moh, SH and Lee, JH and Lee, JS}, title = {Alpha-neoendorphin can reduce UVB-induced skin photoaging by activating cellular autophagy.}, journal = {Archives of biochemistry and biophysics}, volume = {689}, number = {}, pages = {108437}, doi = {10.1016/j.abb.2020.108437}, pmid = {32526201}, issn = {1096-0384}, mesh = {*Autophagy ; Cell Line ; Dermis/cytology/metabolism/radiation effects ; Endorphins/*metabolism ; Fibroblasts/cytology/metabolism/radiation effects ; Humans ; Procollagen/metabolism ; Protein Precursors/*metabolism ; Reactive Oxygen Species/metabolism ; Skin Aging/*radiation effects ; Ultraviolet Rays/*adverse effects ; }, abstract = {Skin aging is influenced by several genetic, physiological, and environmental factors. In particular, ultraviolet (UV) exposure is an important factor involved in inducing skin photoaging. Autophagy controlling homeostatic balance between the synthesis, degradation, and recycling of cellular organelles and proteins plays important regulatory roles in several biological processes, including aging. The opioid neuropeptide α-neoendorphin (named NEP) is an endogenous decapeptide (N-YGGFLRKYPK-C) that activates the kappa opioid receptor and exhibits certain anti-aging and anti-wrinkling effects on skin cells; however, its action mechanism has not yet been elucidated. Therefore, the aim of this study was to determine the effects of NEP on anti-skin aging and autophagy activation in human dermal fibroblast cells. Western blot results showed that NEP down-regulates the production of phospho-mammalian target of rapamycin (p-mTOR), whereas increases the expression of key autophagy-related molecules such as Beclin-1, Atg5-Atg12, and LC3-II. The immunocytochemical analysis performed with anti-LC3-II antibody also showed that the autophagic indicators, autophagosomes are formed by NEP. These results suggest that NEP can activate cellular autophagy through mTOR-Beclin-1-mediated signaling pathway. It was also revealed by CM-H2DCF-DA assay and Western blottings that NEP can reduce the production of ultraviolet B (UVB)-induced reactive oxygen species (ROS) like with N-acetylcysteine (NAC), resulting in decreasing the expression levels of skin aging-related proteins, such as phospho-ERK (p-ERK), phospho-p38 (p-p38), and phospho-JNK (p-JNK). Furthermore, NEP could increase the type I procollagen production, while decreasing MMP-1, MMP-2, and MMP-9 activities. Taken together, the results demonstrate that NEP can reduce UVB-induced photoaging by activating autophagy.}, }
@article {pmid32512147, year = {2020}, author = {Sharma, P and Caldwell, TS and Rivera, MN and Gullapalli, RR}, title = {Cadmium exposure activates Akt/ERK Signaling and pro-inflammatory COX-2 expression in human gallbladder epithelial cells via a ROS dependent mechanism.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {67}, number = {}, pages = {104912}, pmid = {32512147}, issn = {1879-3177}, support = {P20 GM103451/GM/NIGMS NIH HHS/United States ; P20 GM121176/GM/NIGMS NIH HHS/United States ; P42 ES025589/ES/NIEHS NIH HHS/United States ; }, mesh = {Cadmium/*toxicity ; Cell Line ; Cell Survival/drug effects ; Cyclooxygenase 2/*metabolism ; Dinoprostone/metabolism ; Epithelial Cells/*drug effects/metabolism ; Gallbladder/*cytology ; Glutathione/metabolism ; Humans ; MAP Kinase Signaling System/*drug effects ; NF-kappa B/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Gallbladder cancer (GBC) is the commonest biliary tract cancer with an ill-defined etiology. We examined the role of Cd[+2] exposures in a primary human gallbladder (GB) cell line model in this study. Cd[+2] exposures induced decreased cell viability, reactive oxygen species (ROS) generation, altered Akt/ERK signaling pathway activation, PGE2 and COX-2 expression in a human primary gallbladder epithelial cell model. Pharmacological inhibitors were used to determine the key drivers of elevated COX-2 expression due to Cd[+2] exposure. Our results show Cd[+2] causes a dose-dependent reduction in GB cell viability (EC50 value - 18.6 μM). Dose-dependent activation of phospho-Akt and phospho-ERK signaling pathways via increased phosphoprotein expression was observed due to Cd[+2]. Signaling activation of Akt and ERK was prevented by 5 mM N-Acetyl Cysteine (NAC), establishing the role of ROS as a key driver in the activation process. Importantly, we observed Cd[+2] also caused a dose dependent change in the COX-2 and PGE2 expression levels. PI3K-Akt and NF-kB signaling pathways play a key role in Cd[+2] exposure induced COX-2 activation in the gallbladder epithelial cells. In conclusion, our study measures the toxicological effects of Cd[+2] exposures on human GB epithelial cells for the first time and establishes the role of Cd[+2] as a possible driver of the Akt/ERK pathway overactivity and chronic inflammation in gallbladder carcinogenesis.}, }
@article {pmid32512129, year = {2020}, author = {El Shehaby, DM and El-Mahdy, RI and Ahmed, AM and Hosny, A and Abd El-Rady, NM}, title = {Neurobehavioral, testicular and erectile impairments of chronic ketamine administration: Pathogenesis and ameliorating effect of N-acetyl cysteine.}, journal = {Reproductive toxicology (Elmsford, N.Y.)}, volume = {96}, number = {}, pages = {57-66}, doi = {10.1016/j.reprotox.2020.05.016}, pmid = {32512129}, issn = {1873-1708}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Analgesics/*toxicity ; Animals ; Antioxidants/metabolism ; Behavior, Animal/drug effects ; Cognitive Dysfunction/*chemically induced/*drug therapy/metabolism/pathology ; Erectile Dysfunction/*chemically induced/*drug therapy/metabolism/pathology ; Female ; Hippocampus/drug effects/metabolism/pathology ; Ketamine/*toxicity ; Luteinizing Hormone/blood ; Male ; Prefrontal Cortex/drug effects/metabolism/pathology ; Rats ; Sperm Count ; Sperm Motility/drug effects ; Testis/*drug effects/pathology ; Testosterone/blood ; }, abstract = {Ketamine, a dissociative anesthetic, recently has spread as a recreational drug. Its abuse lead to neurobehavioral disturbance in addition to toxic effects on other body organs. To evaluate the toxic effects of chronic administration of low ketamine doses on the memory, testicles, and erection, explore its pathophysiology through oxidative stress mechanism and examine the ameliorating effect of N-acetyl cysteine (NAC). A total of 40 male albino rats were assigned to control, vehicle, ketamine only I.P. (10 mg/kg), and ketamine (10 mg/kg) + NAC (150 mg/kg) groups. Assessment of memory affection and erectile function by Passive Avoidance, Novel Object Recognition, and copulatory tests were performed. Estimation of malondialdehyde (MDA), catalase (CAT), and total antioxidant capacity (TAC) in serum and prefrontal &amp; hippocampal homogenate, and luteinizing hormone (LH), testosterone in serum were done. Prefrontal cortex, hippocampus, and testes were collected for histopathology. Chronic ketamine administration induced significant memory deficits (P < 0.05), reduced erectile function (P < 0.05), severe hypospermatogenesis, increased MDA, reduced CAT, TAC levels in serum, and tissue homogenate (P < 0.05) and reduction of LH, and testosterone (P < 0.05). Treatment with NAC resulted in significant improvement of memory function, improved erectile function, and decrease in oxidative injury in both serum and tissue homogenates. Testosterone and LH levels exhibited significant difference between treatment groups and controls (P < 0.05). NAC reduced the deleterious histopathological changes. These data suggest that long-term ketamine affects short and long memory, induces erectile and testicular dysfunction through oxidative stress. Co-administration with NAC ameliorates these toxic effects.}, }
@article {pmid32512010, year = {2020}, author = {Pal, S and Rao, GN and Pal, A}, title = {High glucose-induced ROS accumulation is a critical regulator of ERK1/2-Akt-tuberin-mTOR signalling in RGC-5 cells.}, journal = {Life sciences}, volume = {256}, number = {}, pages = {117914}, doi = {10.1016/j.lfs.2020.117914}, pmid = {32512010}, issn = {1879-0631}, mesh = {Acetylcysteine/metabolism ; Animals ; DNA, Mitochondrial ; Enzyme Inhibitors/*metabolism ; Gene Expression Regulation ; Glucose/*metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Hyperglycemia/metabolism ; Inflammation/metabolism ; Interferon Regulatory Factor-3/genetics/metabolism ; Membrane Potential, Mitochondrial ; Mice ; Mitochondria/metabolism ; Mitogen-Activated Protein Kinase 3/*metabolism ; NADPH Oxidases/metabolism ; Neurodegenerative Diseases/metabolism ; Oxidative Stress ; Proto-Oncogene Proteins c-akt/*metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Retinal Ganglion Cells/*metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism ; Tuberous Sclerosis Complex 2 Protein/*metabolism ; }, abstract = {Hyperglycemia and oxidative stress are the primary stressors that elicit mitochondria specific cell stress in diabetes. Here we hypothesized that elevated level of ROS in high glucose (HG) environment, trigger mitochondrial stress by damaging mitochondrial DNA (mtDNA), altering inflammatory mediators, and neurodegenerative markers via stress signalling pathway in retinal ganglion cells (RGC-5). Mechanistically, our findings illustrated that the HG environment increases the ROS production in retinal cells leading to the disruption of antioxidant defence mechanism, and altering mitochondrial machinery such as an increase in loss of mitochondrial membrane potential (ΔΨm), increase in mitochondrial mass, and increase in mtDNA fragmentation. Furthermore, fragmented mtDNA escape from mitochondria into the cytosol, where it engaged with cyclic GMP-AMP synthase (cGAS) and stimulator of IFN gene (STING) phosphorylation and activate interferon regulatory factor 3 (IRF3) via ERK1/2-Akt-tuberin-mTOR dependent pathways. Our results further indicate that siRNA-mediated gene silencing of tuberin suppresses the strong downregulation of tuberin-mTOR-IRF3 activation. HG environment resulted in activation of IRF3, coinciding with the increased expression of inflammatory mediators and neurodegenerative markers. Pre-treatment of N-acetyl-l-cysteine (NAC) or ERK1/2 or phosphoinositide3-kinase (PI3-K)/Akt inhibitors in RGC-5 cells significantly reduced the HG-induced IRF3 expression and declined the expression of neurodegenerative markers. Collectively, our results demonstrates that HG-induced over production of ROS, disrupts the antioxidant defence mechanism and mitochondrial dysfunction, leading to alterations of inflammatory mediators and neurodegenerative markers through the ERK1/2-Akt-tuberin-mTOR dependent signalling pathway in RGC-5 cells.}, }
@article {pmid32510264, year = {2021}, author = {Ommati, MM and Amjadinia, A and Mousavi, K and Azarpira, N and Jamshidzadeh, A and Heidari, R}, title = {N-acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats.}, journal = {Stress (Amsterdam, Netherlands)}, volume = {24}, number = {2}, pages = {213-228}, doi = {10.1080/10253890.2020.1777970}, pmid = {32510264}, issn = {1607-8888}, mesh = {*Acetylcysteine/metabolism/pharmacology ; Animals ; Bile Ducts/metabolism/surgery ; Biomarkers/metabolism ; Liver/metabolism ; Oxidative Stress ; Rats ; *Stress, Psychological ; }, abstract = {Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications. N-acetyl cysteine (NAC) is an antioxidant, radical scavenger, and thiol reductant widely investigated for its cytoprotective properties. The current investigation was designed to evaluate the role of NAC treatment on biomarkers of oxidative stress and organ histopathological alterations in a rat model of cholestasis/cirrhosis. BDL animals were supplemented with NAC (100 and 300 mg/kg, i.p, 42 consecutive days). Biomarkers of oxidative stress in the liver, brain, heart, skeletal muscle, lung, serum, and kidney tissue, as well as organ histopathological changes, were monitored. A significant increase in reactive oxygen species, lipid peroxidation, and protein carbonylation were detected in different tissues of BDL rats. Moreover, tissue antioxidant capacity was hampered, glutathione (GSH) reservoirs were depleted, and oxidized glutathione (GSSG) levels were significantly increased in the BDL group. Significant tissue histopathological alterations were evident in cirrhotic animals. It was found that NAC treatment (100 and 300 mg/kg, i.p) significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats. These data represent NAC as a potential protective agent with therapeutic capability in cirrhosis and its associated complications.HIGHLIGHTSCholestasis is a multifaceted clinical complication that affects different organsOxidative stress plays a pivotal role in cholestasis-associated complicationsTissue antioxidant capacity is hampered in different tissues of cholestatic animalsAntioxidant therapy might play a role in the management of cholestasis-induced organ injuryNAC alleviated biomarkers of oxidative stress in cholestatic animalsNAC significantly improved tissues histopathological alterations in cholestatic rats.}, }
@article {pmid32509139, year = {2020}, author = {Zhang, Z and Nian, Q and Chen, G and Cui, S and Han, Y and Zhang, J}, title = {Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK-Regulated Inflammatory Responses and Apoptosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {1854206}, pmid = {32509139}, issn = {1942-0994}, mesh = {A549 Cells ; Acute Lung Injury/*metabolism ; Aging/*physiology ; Animals ; Apoptosis ; Disease Models, Animal ; Glucuronidase/*metabolism ; Humans ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Klotho Proteins ; Lipid Peroxidation ; Male ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Paraquat ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Acute lung injury (ALI) induced by paraquat (PQ) progresses rapidly with high mortality; however, there is no effective treatment, and the specific mechanism is not well understood. The antiaging protein klotho (KL) has multiple functions and exerts significant influences on various pathophysiological processes. This work evaluated the impact of KL on PQ-induced ALI and investigated its underlying mechanisms. As for in vivo research, C57BL/6 mice were treated with PQ (30 mg/kg) intraperitoneal (IP) injection to create a toxicity model of ALI (PQ group). The mice were divided into control group, KL group, PQ group, and PQ+KL group. For in vitro experiment, A549 cells were incubated with or without KL and then treated in the presence or absence of PQ for 24 h. In vivo result indicated that KL reduced the mortality, reduced IL-1β and IL-6 in the bronchoalveolar lavage fluid (BALF), attenuated ALI, and decreased apoptosis in situ. In vitro result revealed that KL significantly improved cell viability, reduced the levels of IL-1β and IL-6 in culture supernatants, suppressed cell apoptosis, inhibited caspase-3 activation, and enhanced mitochondrial membrane potential (ΔΨm) after PQ treatment. Besides, KL effectively abated reactive oxygen species (ROS) production, improved GSH content, and lowered lipid peroxidation in PQ-exposed A549 cells. Further experiments indicated that phosphorylated JNK and P38 MAPK was increased after PQ treatment; however, KL pretreatment could significantly lower the phosphorylation of P38 MAPK. Suppression of P38 MAPK improved cell viability, alleviated inflammatory response, and reduced apoptosis-related signals; however, it had no obvious effect on the production of ROS. Treatment with N-acetylcysteine (NAC), a classic ROS scavenger, could suppress ROS production and P38 MAPK activation. These findings suggested that KL could alleviate PQ-caused ALI via inhibiting ROS/P38 MAPK signaling-regulated inflammatory responses and mitochondria-dependent apoptosis.}, }
@article {pmid32504923, year = {2020}, author = {Poe, FL and Corn, J}, title = {N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2.}, journal = {Medical hypotheses}, volume = {143}, number = {}, pages = {109862}, pmid = {32504923}, issn = {1532-2777}, mesh = {Acetylcysteine/*therapeutic use ; Betacoronavirus ; COVID-19 ; Clinical Trials as Topic ; Coronavirus Infections/*drug therapy ; Free Radicals ; Glutathione ; Humans ; Inflammation ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Pandemics ; Pneumonia, Viral/*drug therapy ; SARS-CoV-2 ; Severe Acute Respiratory Syndrome ; T-Lymphocytes/drug effects/virology ; Tumor Necrosis Factor-alpha/metabolism ; Viral Load ; COVID-19 Drug Treatment ; }, abstract = {COVID-19, a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread across the globe. Predisposing factors such as age, diabetes, cardiovascular disease, and lowered immune function increase the risk of disease severity. T cell exhaustion, high viral load, and high levels of TNF-ɑ, IL1β, IL6, IL10 have been associated with severe SARS-CoV-2. Cytokine and antigen overstimulation are potentially responsible for poor humoral response to the virus. Lower cellular redox status, which leads to pro-inflammatory states mediated by TNF-ɑ is also potentially implicated. In vivo, in vitro, and human clinical trials have demonstrated N-acetylcysteine (NAC) as an effective method of improving redox status, especially when under oxidative stress. In human clinical trials, NAC has been used to replenish glutathione stores and increase the proliferative response of T cells. NAC has also been shown to inhibit the NLRP3 inflammasome pathway (IL1β and IL18) in vitro, and decrease plasma TNF-ɑ in human clinical trials. Mediation of the viral load could occur through NAC's ability to increase cellular redox status via maximizing the rate limiting step of glutathione synthesis, and thereby potentially decreasing the effects of virally induced oxidative stress and cell death. We hypothesize that NAC could act as a potential therapeutic agent in the treatment of COVID-19 through a variety of potential mechanisms, including increasing glutathione, improving T cell response, and modulating inflammation. In this article, we present evidence to support the use of NAC as a potential therapeutic agent in the treatment of COVID-19.}, }
@article {pmid32503814, year = {2020}, author = {Andreou, A and Trantza, S and Filippou, D and Sipsas, N and Tsiodras, S}, title = {COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2.}, journal = {In vivo (Athens, Greece)}, volume = {34}, number = {3 Suppl}, pages = {1567-1588}, pmid = {32503814}, issn = {1791-7549}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Adenosine Monophosphate/administration &amp; dosage/*analogs &amp; derivatives/pharmacology/therapeutic use ; Adjuvants, Immunologic/administration &amp; dosage/therapeutic use ; Alanine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology/therapeutic use ; Anti-Inflammatory Agents/administration &amp; dosage/therapeutic use ; Antiviral Agents/administration &amp; dosage/pharmacology/*therapeutic use ; Autophagy/drug effects ; Betacoronavirus/drug effects/physiology ; COVID-19 ; Colchicine/administration &amp; dosage/pharmacology/*therapeutic use ; Copper/administration &amp; dosage/*therapeutic use ; Coronavirus Infections/*drug therapy/immunology/physiopathology ; Cytidine/analogs &amp; derivatives ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Hydroxylamines ; Inflammation ; Nitric Oxide/administration &amp; dosage/pharmacology/*therapeutic use ; Pandemics ; Pneumonia, Viral/*drug therapy/immunology/physiopathology ; Prodrugs/administration &amp; dosage/therapeutic use ; Ribonucleosides/administration &amp; dosage/pharmacology/*therapeutic use ; SARS-CoV-2 ; Virus Internalization/drug effects ; Virus Replication/drug effects ; }, abstract = {BACKGROUND: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever.<br><br>MATERIALS AND METHODS: The authors carried out a search in PubMed, ClinicalTrials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2.<br><br>RESULTS: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2.<br><br>CONCLUSION: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2.}, }
@article {pmid32499699, year = {2020}, author = {Zong, S and Tang, Y and Li, W and Han, S and Shi, Q and Ruan, X and Hou, F}, title = {A Chinese Herbal Formula Suppresses Colorectal Cancer Migration and Vasculogenic Mimicry Through ROS/HIF-1α/MMP2 Pathway in Hypoxic Microenvironment.}, journal = {Frontiers in pharmacology}, volume = {11}, number = {}, pages = {705}, pmid = {32499699}, issn = {1663-9812}, abstract = {Various malignant tumors, including colorectal cancer, have the ability to form functional blood vessels for tumor growth and metastasis. Vasculogenic mimicry (VM) refers to the ability of highly invasive tumor cells to link each other to form vessels, which is associated with poor cancer prognosis. However, the antitumor VM agents are still lacking in the clinic. Astragalus Atractylodes mixture (AAM), a traditional Chinese medicine, has shown to inhibit VM formation; however the exact mechanism is not completely clarified. In this study, we found that HCT-116 and LoVo could form a VM network. Additionally, hypoxia increases the intracellular reactive oxygen species (ROS) level and accelerates migration, VM formation in colorectal cancer cells, while N-Acetylcysteine (NAC) could reverse these phenomena. Notably, further mechanical exploration confirmed that the matrix metalloprotease 2 (MMP2) induction is ROS dependent under hypoxic condition. On the basis, we found that AAM could effectively inhibit hypoxia-induced ROS generation, migration, VM formation as well as HIF-1α and MMP2 expression. In vivo, AAM significantly inhibits metastasis of colorectal cancer in murine lung-metastasis model. Taken together, these results verified that AAM effectively inhibits migration and VM formation by suppressing ROS/HIF-1α/MMP2 pathway in colorectal cancer under hypoxic condition, suggesting AAM could serve as a therapeutic agent to inhibit VM formation in human colorectal cancer.}, }
@article {pmid32495004, year = {2020}, author = {Tan, X and Li, T and Zhu, S and Zhong, W and Li, F and Wang, Y}, title = {Induction of SPARC on Oxidative Stress, Inflammatory Phenotype Transformation, and Apoptosis of Human Brain Smooth Muscle Cells Via TGF-β1-NOX4 Pathway.}, journal = {Journal of molecular neuroscience : MN}, volume = {70}, number = {11}, pages = {1728-1741}, pmid = {32495004}, issn = {1559-1166}, mesh = {Antioxidants/pharmacology ; *Apoptosis ; Blood Vessels/cytology ; Brain/*blood supply ; Cells, Cultured ; Humans ; Myocytes, Smooth Muscle/drug effects/*metabolism ; NADPH Oxidase 4/genetics/metabolism ; Osteonectin/genetics/*metabolism ; *Oxidative Stress ; Signal Transduction ; Transforming Growth Factor beta/genetics/metabolism ; }, abstract = {Secreted protein acidic and rich in cysteine (SPARC) has a close association with inflammatory response and oxidative stress in tissues and is widely expressed in intracranial aneurysms (IAs), especially in smooth muscle cells. Therefore, it is inferred that SPARC might be involved in the formation and development of IAs through the inflammatory response pathway or oxidative stress pathway. The aim of this study is to investigate the pathological mechanism of SPARC in oxidative stress, inflammation, and apoptosis during the formation of IAs, as well as the involvement of TGF-β1 and NOX4 molecules. Human brain vascular smooth muscle cells (HBVSMCs) were selected as experimental objects. After the cells were stimulated by recombinant human SPARC protein in vitro, the ROS level in the cells was measured using an ID/ROS fluorescence analysis kit combined with fluorescence microscope and flow cytometry. The related protein expression in HBVSMCs was measured using western blotting. The mitochondrial membrane potential change was detected using a mitochondrial membrane potential kit and laser confocal microscope. The mechanism was explored by intervention with reactive oxygen scavengers N-acetylcysteine (NAC), TGF-β1 inhibitor (SD-208), and siRNA knockout. The results showed that SPARC upregulated the expression of NOX4 through the TGF-β1-dependent signaling pathway, leading to oxidative stress and pro-inflammatory matrix behavior and apoptosis in HBVSMCs. These findings demonstrated that SPARC may promote the progression of IAs.}, }
@article {pmid32492379, year = {2020}, author = {Cui, Y and Liu, L and Xiao, Y and Li, X and Zhang, J and Xie, X and Tian, J and Sen, CK and He, X and Hao, H and Liu, Z}, title = {N-acetylcysteine differentially regulates the populations of bone marrow and circulating endothelial progenitor cells in mice with limb ischemia.}, journal = {European journal of pharmacology}, volume = {881}, number = {}, pages = {173233}, pmid = {32492379}, issn = {1879-0712}, support = {R01 ES026200/ES/NIEHS NIH HHS/United States ; R01 HL124122/HL/NHLBI NIH HHS/United States ; R01 HL148196/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Angiogenesis Inducing Agents/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Bone Marrow Cells/*drug effects/metabolism/pathology ; Cell Proliferation/drug effects ; Disease Models, Animal ; Endothelial Progenitor Cells/*drug effects/metabolism/pathology ; Hindlimb ; Ischemia/*drug therapy/metabolism/pathology/physiopathology ; Male ; Mice, Inbred C57BL ; Muscle, Skeletal/*blood supply ; Neovascularization, Physiologic/*drug effects ; Oxidative Stress/drug effects ; Phenotype ; Reactive Oxygen Species/metabolism ; Recovery of Function ; }, abstract = {Endothelial progenitor cells (EPCs) are important to tissue repair and regeneration especially after ischemic injury, and very heterogeneous in phenotypes and biological features. Reactive oxygen species are involved in regulating EPC number and function. N-acetylcysteine (NAC) inhibits ischemia-induced reactive oxygen species formation and promotes ischemic limb recovery. This study was to evaluate the effect of NAC on EPC subpopulations in bone marrow (BM) and blood in mice with limb ischemia. Limb ischemia was induced by femoral artery ligation in male C57BL/6 mice with or without NAC treatment. EPC subpopulations, intracellular reactive oxygen species production, cell proliferation and apoptosis in BM and blood cells were analyzed at baseline, day 3 (acute ischemia) and 21 (chronic) after ligation. c-Kit+/CD31+, Sca-1+/Flk-1+, CD34+/CD133+, and CD34+/Flk-1+ were used to define EPC subpopulations. Limb blood flow, function, muscle structure, and capillary density were evaluated with laser Doppler perfusion imaging, treadmill test, and immunohistochemistry, respectively, at day 3, 7, 14 and 21 post ischemia. Reactive oxygen species production in circulating and BM mononuclear cells and EPCs populations were significantly increased in BM and blood in mice with acute and chronic ischemia. NAC treatment effectively blocked ischemia-induced reactive oxygen species production in circulating and BM mononuclear cells, and selectively increased EPC population in circulation, not BM, with preserved proliferation in mice with chronic ischemia, and enhanced limb blood flow and function recovery, while preventing acute ischemia-induced increase in BM and circulating EPCs. These data demonstrated that NAC selectively enhanced circulating EPC population in mice with chronic limb ischemia.}, }
@article {pmid32486313, year = {2020}, author = {Shahzadi, I and Fürst, A and Akkus-Dagdeviren, ZB and Arshad, S and Kurpiers, M and Matuszczak, B and Bernkop-Schnürch, A}, title = {Less Reactive Thiol Ligands: Key towards Highly Mucoadhesive Drug Delivery Systems.}, journal = {Polymers}, volume = {12}, number = {6}, pages = {}, pmid = {32486313}, issn = {2073-4360}, abstract = {As less reactive s-protected thiomers can likely interpenetrate the mucus gel layer to a higher extent before getting immobilized via disulfide bond formation with mucins, it was the aim of this study to develop a novel type of s-protected thiomer based on the less reactive substructure cysteine-N-acetyl cysteine (Cys-NAC) in order to obtain improved mucoadhesive properties. For this purpose, two types of s-protected thiomers, polyacrylic acid-cysteine-mercaptonicotinic acid (PAA-Cys-MNA) and polyacrylic acid-cysteine-N-acetyl cysteine (PAA-Cys-NAC), were synthesized and characterized by Fourier-transform infrared spectroscopy (FT-IR) and the quantification of attached disulfide ligands. The viscosity of both products was measured in the presence of NAC and mucus. Both thiomers were also evaluated regarding swelling behavior, tensile studies and retention time on the porcine intestinal mucosa. The FT-IR spectra confirmed the successful attachment of Cys-MNA and Cys-NAC ligands to PAA. The number of attached sulfhydryl groups was in the range of 660-683 µmol/g. The viscosity of both s-protected thiomers increased due to the addition of increasing amounts of NAC. The viscosity of the mucus increased in the presence of 1% PAA-Cys-MNA and PAA-Cys-NAC 5.6- and 10.9-fold, respectively, in comparison to only 1% PAA. Both s-protected thiomers showed higher water uptake than unmodified PAA. The maximum detachment force (MDF) and the total work of adhesion (TWA) increased in the case of PAA-Cys-MNA up to 1.4- and 1.6-fold and up to 2.4- and 2.8-fold in the case of PAA-Cys-NAC. The retention of PAA, PAA-Cys-MNA, and PAA-Cys-NAC on porcine intestinal mucosa was 25%, 49%, and 76% within 3 h, respectively. The results of this study provide evidence that less reactive s-protected thiomers exhibit higher mucoadhesive properties than highly reactive s-protected thiomers.}, }
@article {pmid32479520, year = {2020}, author = {Zmora, O and Gutzeit, O and Segal, L and Boulos, S and Millo, Z and Ginsberg, Y and Khatib, N and Dabbah-Assad, F and Fainaru, O and Weiner, Z and Beloosesky, R}, title = {Prophylactic antenatal N-Acetyl Cysteine administration combined with postnatal administration can decrease mortality and injury markers associated with necrotizing enterocolitis in a rat model.}, journal = {PloS one}, volume = {15}, number = {6}, pages = {e0233612}, pmid = {32479520}, issn = {1932-6203}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage/*therapeutic use ; Caspase 3/metabolism ; Enterocolitis, Necrotizing/drug therapy/metabolism/*prevention &amp; control ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Interleukins/metabolism ; Male ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of neonates, especially premature neonates. To date, there is no prophylactic treatment against NEC, except breast milk and slow increase in enteral feeding, and there is no antenatal prophylaxis.<br><br>AIMS: To assess possible protective effects of antenatal N-Acetyl Cysteine (NAC) against the intestinal pathophysiological changes associated with NEC in a rat model of NEC and against its associated mortality.<br><br>METHODS: Newborn Sprague-Dawley rats were divided into 5 groups: control (n = 33); NEC (n = 32)-subjected to hypoxia and formula feeding for 4 days to induce NEC; NEC-NAC (n = 34)-with induced NEC and concomitant postnatal NAC administration; NAC-NEC (n = 33)-born to dams treated with NAC for the last 3 days of pregnancy starting at gestational age of 18 days, and then subjected to induced NEC after birth; NAC-NEC-NAC (n = 36)-subjected to induced NEC with both prenatal and postnatal NAC treatment. At day of life 5, weight and survival of pups in the different groups were examined, and pups were euthanized. Ileal TNF-&#x3b1;, IL-6, IL-1&#x3b2;, IL-10, NFkB p65, iNOS and cleaved caspase 3 protein levels (western blot) and mRNA expression (RT-PCR) were compared between groups.<br><br>RESULTS: Pup mortality was significantly reduced in the NAC-NEC-NAC group compared to NEC (11% vs. 34%, P<0.05). Ileal protein levels and mRNA expression of all injury markers tested except IL-10 were significantly increased in NEC compared to control. These markers were significantly reduced in all NAC treatment groups (NEC-NAC, NAC-NEC, and NAC-NEC-NAC) compared to NEC. The most pronounced decrease was observed in the NAC-NEC NAC group.<br><br>CONCLUSIONS: Antenatal NAC decreases injury markers and mortality associated with NEC in a rat model. Antenatal administration of NAC may present a novel approach for NEC prophylaxis in pregnancies with risk for preterm birth.}, }
@article {pmid32474849, year = {2020}, author = {Ye, XY and Qiu, XM and Sun, YY and Li, ZG}, title = {Interplay between hydrogen sulfide and methylglyoxal initiates thermotolerance in maize seedlings by modulating reactive oxidative species and osmolyte metabolism.}, journal = {Protoplasma}, volume = {257}, number = {5}, pages = {1415-1432}, doi = {10.1007/s00709-020-01516-x}, pmid = {32474849}, issn = {1615-6102}, support = {31760069, 31360057//National Natural Science Foundation of China/ ; }, mesh = {Hydrogen Sulfide/*chemistry ; Reactive Oxygen Species/*metabolism ; Seedlings/*chemistry ; Zea mays/*chemistry ; }, abstract = {Hydrogen sulfide (H2S) and methylglyoxal (MG) were supposed to be novel signaling molecules in plants. However, whether interplay between H2S and MG can initiate thermotolerance in maize seedlings and in relation to metabolism of reactive oxygen species (ROS) and osmolytes is little known. In this study, watering with MG and NaHS (H2S donor) alone or in combination elevated survival and tissue vigor of maize seedlings under heat stress and coped with an increase in the biomembrane injury (as indicated in membrane lipid peroxidation and electrolyte leakage). The above-mentioned effects were separately weakened by MG scavengers (N-acetyl cysteine: NAC; aminoguanidine: AG) and H2S inhibitor (DL-propargylglycine, PAG) and scavenger (hypotaurine, HT). These suggested that the interplay between H2S and MG initiated the thermotolerance in maize seedlings. The further data indicated that, under non-heat stress and heat stress conditions, MG and NaHS alone or in combination modulated ROS metabolism by regulating the activities of antioxidant enzymes (catalase, ascorbate peroxidase, guaiacol peroxidase, glutathione reductase, monodehydroascorbate reductase, and dehydroascorbate reductase) and the contents of non-enzymatic antioxidants (ascorbic acid, glutathione, flavonoids, and carotenoids) in maize seedlings. In addition, MG and NaHS alone or in combination also separately modulated the metabolism of osmolytes (proline, trehalose, glycine betaine, and total soluble sugar), H2S (L-cysteine desulfhydrase and O-acetylserine (thione) lyase), and MG (glyoxalase I, glyoxalase II, and MG reductase). These physiological effects also were separately impaired by NAC, AG, PAG, and HT. The current data illustrated that the interplay between H2S and MG initiated the thermotolerance in maize seedlings by modulating ROS, osmolyte, H2S, and MG metabolism.}, }
@article {pmid32468750, year = {2020}, author = {Sulaiman, S and Hussain, M and Shad, MN and Chiragh, S}, title = {Hepatoprotective Effect Of Prazosin Is Comparable To N-Acetylcysteine In Acetaminophen Induced Hepatotoxicity In Mice.}, journal = {Journal of Ayub Medical College, Abbottabad : JAMC}, volume = {32}, number = {1}, pages = {28-32}, pmid = {32468750}, issn = {1819-2718}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/*therapeutic use ; Adrenergic alpha-1 Receptor Antagonists/*therapeutic use ; Albuterol/therapeutic use ; Analgesics, Non-Narcotic/adverse effects ; Animals ; Chemical and Drug Induced Liver Injury/*drug therapy/pathology ; Disease Models, Animal ; Female ; Free Radical Scavengers/*therapeutic use ; Liver/pathology ; Male ; Mice ; Necrosis ; Prazosin/*therapeutic use ; }, abstract = {BACKGROUND: Autonomic nervous system modulates acetaminophen induced hepatotoxicity. The purpose of the study was to determine the hepatoprotective effect of α1 antagonist (prazosin) and β2 agonist (salbutamol) on acetaminophen induced hepatotoxicity in mice.<br><br>METHODS: This experimental study was conducted at Post Graduate Medical Institute, Lahore in which 50 adult mice were divided in to five groups. With the exception of normal control, hepatotoxicity was induced in all other study groups by giving single intraperitoneal injection of acetaminophen 300 mg/ kg. First and second groups served as normal and toxic control were given distilled water 6 ml/ kg while third, fourth and fifth experimental groups were given N-acetylcysteine (300 mg/ kg), prazosin (0.18 mg/ kg) and salbutamol (0.35 mg/kg) intraperitoneally at 2,4 and 8 hours after acetaminophen injection. Serum liver enzymes were analysed at 0 and 72 hours while histopathological finding were assessed at the end of study by using SPSS-20.<br><br>RESULTS: All the groups treated with toxic dose of acetaminophen showed significant increase in serum ALT, i.e., B (Toxic control 3372%), C (NAC treated 282%), D (Prazosin treated 582%), E(Salbutamol treated 3297%) and AST levels, i.e., B (Toxic control 2750%), C (NAC treated 230%), D (Prazosin treated 280%), E (Salbutamol treated 828%) with p-value &#x2c2;0.001. When this increase was compared between groups, the lowest increase in serum ALT and AST levels was observed in Nacetylcysteine and prazosin group with no significant difference. Similarly, experimental animals receiving prazosin and N-acetylcysteine had the lowest inflammation, degeneration and necrosis scores than the toxic control group in histopathological analysis of the liver with p-value <0.001.<br><br>CONCLUSIONS: The hepatoprotective effect of prazosin is comparable to N- acetylcysteine against acetaminophen induced hepatotoxicity in mice.}, }
@article {pmid32467034, year = {2020}, author = {Singh, G and Pandey, A and Shandilya, G and Gupta, A and Rawat, JD and Wakhlu, A and Kureel, SN}, title = {Evaluation of nebulized N-acetyl cysteine in outcome of esophageal atresia with tracheoesophegeal fistula.}, journal = {Journal of pediatric surgery}, volume = {55}, number = {12}, pages = {2635-2639}, doi = {10.1016/j.jpedsurg.2020.04.013}, pmid = {32467034}, issn = {1531-5037}, mesh = {Acetylcysteine/*therapeutic use ; Esophageal Atresia/complications/*therapy ; Humans ; Prospective Studies ; Tracheoesophageal Fistula/complications/*therapy ; }, abstract = {AIM: To evaluate the role of nebulized N-acetyl cysteine (NAC) in liquefying the airway secretions and improving the outcome of patients of esophageal atresia with tracheoesophageal fistula (EA + TEF).<br><br>METHODS: It was a non-randomized interventional study. Two milliliters of 10% NAC was given in a nebulized form (2:5 dilution, every six hourly) to patients of ET&#x202f;+&#x202f;TEF, along with regular suction of upper esophageal pouch. The group was compared with control, which comprised patients of EA&#x202f;+&#x202f;TEF receiving only saline nebulization. The consistency of the secretions was compared by hand held consistometer in unit of time (seconds) required to cross a predetermined distance along with gravity.<br><br>RESULTS: Sixty patients were assessed. Of these, 30 patients were present in both groups. The study group showed significant (p&#x202f;=&#x202f;0.01-0.0001) decrease in consistency of secretions from the control group after day 2 of NAC nebulization. Patients' discharge was significantly (p&#x202f;=&#x202f;0.01) earlier in cases. There was no significant (p&#x202f;=&#x202f;0.41) difference in mortality between the groups. No specific adverse effects were observed in the study group.<br><br>CONCLUSION: It appears that nebulized NAC decreases the consistency of secretions in EA&#x202f;+&#x202f;TEF patients. It is interesting to note that the group of patients that received NAC was discharged earlier than the control group and had a higher survival rate than the control group. Whether this is directly attributable to the use of NAC is unknown. A prospective double-blinded randomized clinical trial is warranted to confirm these results.<br><br>LEVEL OF EVIDENCE: Level II, prospective comparative study (non-randomized).}, }
@article {pmid32464194, year = {2020}, author = {De Wang, X and Li, T and Li, Y and Yuan, WH and Zhao, YQ}, title = {2-Pyrazine-PPD, a novel dammarane derivative, showed anticancer activity by reactive oxygen species-mediate apoptosis and endoplasmic reticulum stress in gastric cancer cells.}, journal = {European journal of pharmacology}, volume = {881}, number = {}, pages = {173211}, doi = {10.1016/j.ejphar.2020.173211}, pmid = {32464194}, issn = {1879-0712}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Ginsenosides/*pharmacology ; Humans ; Mitochondria/drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Stomach Neoplasms/*drug therapy/metabolism/pathology ; }, abstract = {20 (R)-Dammarane-3β, 12β, 20, 25-tetrol (25-OH-PPD), a ginsenoside, was derived from Panax ginseng (C. A. Meyer) and inhibited growth of several cancer cell lines. To improve the anti-cancer activity, we introduced the pyrazine ring to 25-OH-PPD and obtained the compound 20(R)-[2,3-β]-Pyrazine-dammarane-12β,20,25-triol (2-Pyrazine-PPD). we evaluated the anti-cancer activity of 2-Pyrazine-PPD and investigated the main anti-cancer mechanisms of 2-Pyrazine-PPD in gastric cancer cells. We found that 2-Pyrazine-PPD remarkably suppressed the proliferation of gastric cancer cells in a concentration-dependent, and showed little toxicity to the normal cell (human gastric epithelial cell line-GES-1). Further study indicated that 2-Pyrazine-PPD induced apoptosis by mitochondria pathway in BGC-803 cancer cells, and activated unfolded protein response and the protein kinase RNA-activated (PKR)-like ER kinase (PERK)/Eukaryotic translation initiation factor-2α (eIF-2α)/Activating transcription factor 4 (ATF4) axis, the expression level of the protein C/EBP homologous protein (CHOP), the marker of endoplasmic reticulum stress, and the apoptosis inducing by 2-Pyrazine-PPD can partly be inhibited by siRNA-mediated knockdown of CHOP. Moreover, the production of reactive oxygen species was remarkably up-regulated in BGC-803 cancer cells treated with 2-Pyrazine-PPD. N-acetylcysteine (NAC, a reactive oxygen species scavenger) can attenuate 2-Pyrazine-PPD-induced apoptosis and endoplasmic reticulum stress. Taken together, we suggested that 2-Pyrazine-PPD exhibited remarkable anti-cancer activity by reactive oxygen species-mediate cell apoptosis and endoplasmic reticulum stress in gastric cancer cells. Our results uncovered the mechanism of 2-Pyrazine-PPD as a promising anti-tumor candidate for gastric cancer therapy.}, }
@article {pmid32458633, year = {2020}, author = {Park, C and Lee, H and Hwangbo, H and Ji, SY and Kim, MY and Kim, SY and Hong, SH and Kim, GY and Choi, YH}, title = {Ethanol Extract of Hizikia fusiforme Induces Apoptosis in B16F10 Mouse Melanoma Cells through ROS-Dependent Inhibition of the PI3K/Akt Signaling Pathway.}, journal = {Asian Pacific journal of cancer prevention : APJCP}, volume = {21}, number = {5}, pages = {1275-1282}, pmid = {32458633}, issn = {2476-762X}, mesh = {Animals ; Apoptosis ; Cell Proliferation ; Ethanol/chemistry ; Melanoma, Experimental/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/*drug effects ; Mice ; Phaeophyceae/*chemistry ; Phosphatidylinositol 3-Kinase/*metabolism ; Plant Extracts/*pharmacology ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND: Previous studies have reported that Hizikia fusiforme, an edible brown seaweed, has diverse health-promoting effects; however, evidence for its anti-cancer potential is still lacking. In this study, we examined the effect of ethanol extract of H. fusiforme (EHF) on the proliferation of B16F10 mouse melanoma cells.<br><br>METHODS: Analyses of cell viability and apoptosis were performed to study the actions of EHF on B16F10 cells. Cellular reactive oxygen species (ROS) and mitochondrial membrane potential (&#x394;&#x3a8;m) were measured using a flow cytometer. Western blot analysis was carried out to measure apoptosis and phosphoinositide 3-kinase (PI3K)/Akt signaling related proteins.<br><br>RESULTS: EHF treatment significantly decreased B16F10 cell viability, which was associated with induction of apoptosis. EHF activated caspase-8 and caspase-9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. In addition, EHF destroyed the integrity of mitochondria and increased Bax/Bcl-2 ratio, which contributed to cytosolic release of cytochrome c. EHF further enhanced intracellular levels of ROS and the addition of N-acetyl cysteine (NAC), a ROS inhibitor, significantly diminished EHF-induced mitochondrial dysfunction and growth inhibition. Moreover, EHF inactivated the PI3K/Akt signaling pathway and LY294002, a PI3K/Akt inhibitor, increased the apoptosis-inducing effect of EHF. However, increased apoptosis and reduced cell viability by simultaneous treatment of EHF and LY294002 were significantly attenuated in the presence of NAC.<br><br>CONCLUSION: These results indicate that EHF induces apoptosis through activation of extrinsic and intrinsic apoptotic pathways and ROS-dependent inactivation of PI3K/Akt signaling in B16F10 cells.<br />.}, }
@article {pmid32458477, year = {2020}, author = {Nakashima, D and Fujita, N and Hata, J and Komaki, Y and Suzuki, S and Nagura, T and Fujiyoshi, K and Watanabe, K and Tsuji, T and Okano, H and Jinzaki, M and Matsumoto, M and Nakamura, M}, title = {Quantitative analysis of intervertebral disc degeneration using Q-space imaging in a rat model.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {38}, number = {10}, pages = {2220-2229}, doi = {10.1002/jor.24757}, pmid = {32458477}, issn = {1554-527X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Diffusion Magnetic Resonance Imaging/*methods ; Disease Models, Animal ; Feasibility Studies ; Female ; Free Radical Scavengers/*therapeutic use ; Intervertebral Disc Degeneration/*diagnostic imaging/drug therapy ; Rats, Wistar ; }, abstract = {The degree of intervertebral disc (IVD) degeneration is qualitatively evaluated on T2-weighted imaging (T2WI). However, it is difficult to assess subtle changes in IVD degeneration using T2WI. Q-space imaging (QSI) is a quantitative diffusion-weighted imaging modality used to detect subtle changes in microenvironments. This study aimed to evaluate whether QSI can detect the inhibitory effects of the antioxidant N-acetylcysteine (NAC) in IVD degeneration. We classified female Wistar rats into control, puncture, and NAC groups (n = 5 per group). In the puncture and NAC groups, IVDs were punctured using a needle. The antioxidant NAC, which suppresses the progression of IVD degeneration, was orally administered in the NAC group 1 week prior to puncture. The progression and inhibitory effect of NAC in IVD degeneration were assessed using magnetic resonance imaging (MRI): IVD height, T2 mapping, apparent diffusion coefficient (ADC), and QSI. MRI was performed using a 7-Tesla system with a conventional probe (20 IVDs in each group). QSI parameters that were assessed included Kurtosis, the probability at zero displacement (ZDP), and full width at half maximum (FWHM). IVD degeneration by puncture was confirmed by histology, IVD height, T2 mapping, ADC, and all QSI parameters (P < .001); however, the inhibitory effect of NAC was confirmed only by QSI parameters (Kurtosis and ZDP: both P < .001; FWHM: P < .01). Kurtosis had the largest effect size (Kurtosis: 1.13, ZDP: 1.06, and FWHM: 1.02) when puncture and NAC groups were compared. QSI has a higher sensitivity than conventional quantitative methods for detecting the progressive change and inhibitory effect of NAC in IVD degeneration.}, }
@article {pmid32454937, year = {2020}, author = {Jalili-Nik, M and Sadeghi, MM and Mohtashami, E and Mollazadeh, H and Afshari, AR and Sahebkar, A}, title = {Zerumbone Promotes Cytotoxicity in Human Malignant Glioblastoma Cells through Reactive Oxygen Species (ROS) Generation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {3237983}, pmid = {32454937}, issn = {1942-0994}, mesh = {Cell Cycle Checkpoints/drug effects ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Glioblastoma/genetics/*metabolism/*pathology ; Humans ; Models, Biological ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/chemistry/*pharmacology ; Time Factors ; Transcription Factor RelA/metabolism ; }, abstract = {Glioblastoma multiforme (GBM) is the most hostile tumor in the central nervous system. Unfortunately, the prognosis of GBM patients is poor following surgical interventions, chemotherapy, and radiotherapy. Consequently, more efficient and effective treatment options for the treatment of GBM need to be explored. Zerumbone, as a sesquiterpene derived from Zingiber zerumbet Smith, has substantial cytotoxic and antiproliferative activities in some types of cancer. Here, we show that exposure of GBM cells (U-87 MG) to Zerumbone demonstrated significant growth inhibition in a concentration-dependent manner. Zerumbone also induced apoptosis and caused cell cycle arrest of human GBM U-87 MG cells in the G2/M phase of the cell cycle. In detail, the apoptotic process triggered by Zerumbone involved the upregulation of proapoptotic Bax and the suppression of antiapoptotic Bcl-2 genes expression as determined by qRT-PCR. Moreover, Zerumbone enhanced the generation of reactive oxygen species (ROS), and N-acetyl cysteine (NAC), as an antioxidant, reversed the ROS-induced cytotoxicity of U-87 MG cells. The Western blot analysis suggested that Zerumbone activated the NF-κB p65, which was partly inhibited by NAC treatment. Collectively, our results confirmed that Zerumbone induces cytotoxicity by ROS generation. Thus, the study raises the possibility of Zerumbone as a potential natural agent for treating GBM due to its ability to induce cytotoxicity.}, }
@article {pmid32450865, year = {2020}, author = {Tsai, CC and Chen, YJ and Yu, HR and Huang, LT and Tain, YL and Lin, IC and Sheen, JM and Wang, PW and Tiao, MM}, title = {Long term N-acetylcysteine administration rescues liver steatosis via endoplasmic reticulum stress with unfolded protein response in mice.}, journal = {Lipids in health and disease}, volume = {19}, number = {1}, pages = {105}, pmid = {32450865}, issn = {1476-511X}, support = {CMRPG8H1301, CMRPG8H0261 and CMRPG8J0691//Kaohsiung Chang Gung Memorial Hospital/ ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Activating Transcription Factor 4/genetics ; Animals ; Antioxidants/pharmacology/therapeutic use ; Apoptosis ; Chaperonin 60/genetics ; *Diet, High-Fat ; *Endoplasmic Reticulum Stress ; Enoyl-CoA Hydratase/genetics ; Fatty Liver/drug therapy/metabolism/physiopathology ; Gene Expression Regulation ; HSP70 Heat-Shock Proteins/genetics ; Liver/*drug effects/metabolism/physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondrial Proteins/genetics ; Non-alcoholic Fatty Liver Disease/*drug therapy/metabolism/physiopathology ; *Unfolded Protein Response ; }, abstract = {BACKGROUND: Fat accumulation in the liver contributes to the development of non-alcoholic fatty liver disease (NAFLD). N-acetylcysteine (NAC) is an antioxidant, acting both directly and indirectly via upregulation of cellular antioxidants. We examined the mechanisms of liver steatosis after 12 months high fat (HF) diet and tested the ability of NAC to rescue liver steatosis.<br><br>METHODS: Seven-week-old C57BL/6 (B6) male mice were administered HF diet for 12&#x2009;months (HF group). Two other groups received HF diet for 12&#x2009;months accompanied by NAC for 12&#x2009;months (HFD&#x2009;+&#x2009;NAC(1-12)) or 6&#x2009;months (HFD&#x2009;+&#x2009;NAC(1-6)). The control group was fed regular diet for 12&#x2009;months (CD group).<br><br>RESULTS: Liver steatosis was more pronounced in the HF group than in the CD group after 12&#x2009;month feeding. NAC intake for 6 or 12&#x2009;months decreased liver steatosis in comparison with HF diet (p&#x2009;<&#x2009;0.05). Furthermore, NAC treatment also reduced cellular apoptosis and caspase-3 expression. In the unfolded protein response (UPR) pathway, the expression of ECHS1, HSP60, and HSP70 was decreased in the HFD group (p&#x2009;<&#x2009;0.05) and rescued by NAC therapy. With regards to the endoplasmic reticulum (ER) stress, Phospho-PERK (p-PERK) and ATF4 expression was decreased in the HF group, and only the HFD&#x2009;+&#x2009;NAC(1-12), but not HFD&#x2009;+&#x2009;NAC(1-6) group, showed significant improvement.<br><br>CONCLUSION: HF diet for 12&#x2009;months induces significant liver steatosis via altered ER stress and UPR pathway activity, as well as liver apoptosis. NAC treatment rescues the liver steatosis and apoptosis induced by HF diet.}, }
@article {pmid32450164, year = {2020}, author = {Firozian, F and Karami, S and Ranjbar, A and Azandaryani, MT and Nili-Ahmadabadi, A}, title = {Improvement of therapeutic potential N-acetylcysteine in acetaminophen hepatotoxicity by encapsulation in PEGylated nano-niosomes.}, journal = {Life sciences}, volume = {255}, number = {}, pages = {117832}, doi = {10.1016/j.lfs.2020.117832}, pmid = {32450164}, issn = {1879-0631}, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Acetylcysteine/*administration &amp; dosage/pharmacology ; Administration, Oral ; Analgesics, Non-Narcotic/administration &amp; dosage/*toxicity ; Animals ; Antidotes/administration &amp; dosage/pharmacology ; Chemical and Drug Induced Liver Injury/etiology/*prevention &amp; control ; Drug Delivery Systems ; Liposomes ; Male ; *Nanoparticles ; Particle Size ; Polyethylene Glycols/chemistry ; Rats ; Rats, Wistar ; Surface-Active Agents/chemistry ; }, abstract = {AIMS: N-Acetylcysteine (NAC) is an effective antidote for the treatment of acetaminophen (APAP) poisoning; however, due to its low stability and bioavailability, repeated dosing of NAC is needed. This study investigated the therapeutic efficacy of NAC by niosomal carriers.<br><br>MATERIALS AND METHODS: Niosomes were synthesized using surface active agents film hydration method and their physicochemical properties were characterized. In the in vivo study, in addition to control group, male rats were divided in different groups and challenged with an oral dose of APAP (2000&#xa0;mg/kg); 4&#xa0;h later, rats were administered normal saline, empty niosome (NIO), NAC (25&#xa0;mg/kg) and NAC-loaded niosome (NAC-NIO) respectively, and sacrificed 48&#xa0;h post-APAP overdose.<br><br>KEY FINDINGS: The particle size and zeta potential of NAC-NIO were 242.3&#xa0;&#xb1;&#xa0;18.5&#xa0;nm and -23.9&#xa0;&#xb1;&#xa0;1.6&#xa0;mV. The loading and encapsulation efficiency of niosomes were 1.22%&#xa0;&#xb1;&#xa0;0.02% and 26.76%&#xa0;&#xb1;&#xa0;6.02%. APAP administration leads to hepatic damage as evidenced by increases in serum hepatic enzyme levels and tissue levels of nitric oxide and lipid peroxidation as well as decreases in hepatic levels of reduced glutathione, catalase, superoxide dismutase, and glutathione peroxidase. Treatment of rats with NIO-NAC was remarkably more effective than NAC in improving biochemical changes such as serum hepatic aminotransferases. These findings were correlated well to the histopathological experiments.<br><br>SIGNIFICANCE: Our results suggest that NAC when delivered as a niosomal structure, is potentially more effective than NAC standard, in improving APAP-induced hepatotoxicity.}, }
@article {pmid32445015, year = {2020}, author = {Liu, H and Gambino, F and Algenio, CS and Wu, C and Gao, Y and Bouchard, CS and Qiao, L and Bu, P and Zhao, S}, title = {Inflammation and oxidative stress induced by lipid peroxidation metabolite 4-hydroxynonenal in human corneal epithelial cells.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {258}, number = {8}, pages = {1717-1725}, doi = {10.1007/s00417-020-04647-2}, pmid = {32445015}, issn = {1435-702X}, support = {81770890//Natural Science Foundation of Tianjin Municipal Science and Technology Commission/ ; 2018//the Richard A. Perritt Charitable Foundation/ ; 2018//Illinois Society for the prevention of Blindness/ ; 2018KJ054//Science Foundation of Tianjin/ ; }, mesh = {Aldehydes/*metabolism ; Blotting, Western ; Cells, Cultured ; Dry Eye Syndromes/*metabolism/pathology ; Epithelium, Corneal/*metabolism/pathology ; Humans ; Inflammation/*metabolism/pathology ; Lipid Peroxidation ; *Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {PURPOSE: Oxidative stress is widely known to be a major contributor in the pathogenesis of dry eye disease (DED). 4-Hydroxynonenal (4-HNE), a well-known byproduct frequently measured as an indicator of oxidative stress-induced lipid peroxidation, has been shown to be elevated in both human and murine corneal DED samples. This study aims to investigate if 4-HNE is responsible for the oxidative stress in human corneal epithelial cells (HCECs) and explores the underlying mechanism by which it confers its effects.<br><br>METHODS: SV40-immortalized HCECs were cultured in minimum essential media (MEM) with 1% penicillin/streptomycin and 10% fetal bovine serum. HCECs were exposed to media with or without 4-HNE and cell culture supernatants were collected at 4 and 24&#xa0;h. Cellular reactive oxygen species (ROS) measurement was performed using a 2',7'-dichlorofluorescein diacetate (DCFDA) assay kit according to the manufacturer's instructions. Protein levels of antioxidant enzymes copper/zinc superoxide dismutase 1 (SOD1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were analyzed by Western blot. NF-&#x3ba;B activation and expression of IL-6 and IL-8 were measured using an NF-&#x3ba;B p65 Total SimpleStep ELISA Kit and Proteome Profiler Human Cytokine Array Kit. Cell viability was evaluated by LDH cytotoxicity assay.<br><br>RESULTS: Treatment with 4-HNE decreased cell viability of HCECs. Band intensities corresponding to levels of ROS production showed a significant increase in ROS generation after treatment with 4-HNE. 4-HNE decreased SOD1 levels and upregulated NQO1 expression in HCECs. A significant increase in activation of NF-&#x3ba;B and production of pro-inflammatory cytokines IL-6 and IL-8 was observed after treatment with 4-HNE. Exposure to N-acetylcysteine (NAC), an antioxidant and ROS scavenger, antagonized the oxidative effects of 4-HNE on HCECs.<br><br>CONCLUSION: 4-HNE induces oxidative stress in corneal epithelial cells by increasing levels of ROS generation and modifying the expression of antioxidant enzyme levels, decreasing cell viability of HCECs in vitro. This study demonstrates a potential pathway by which 4-HNE functions to confer its detrimental effects and provides a new therapeutic target for the treatment of DED.}, }
@article {pmid32444367, year = {2020}, author = {Charron, MJ and Williams, L and Seki, Y and Du, XQ and Chaurasia, B and Saghatelian, A and Summers, SA and Katz, EB and Vuguin, PM and Reznik, SE}, title = {Antioxidant Effects of N-Acetylcysteine Prevent Programmed Metabolic Disease in Mice.}, journal = {Diabetes}, volume = {69}, number = {8}, pages = {1650-1661}, pmid = {32444367}, issn = {1939-327X}, support = {R01 DK115824/DK/NIDDK NIH HHS/United States ; R21 DK081194/DK/NIDDK NIH HHS/United States ; F31 DK093332/DK/NIDDK NIH HHS/United States ; P30 DK020541/DK/NIDDK NIH HHS/United States ; R01 DK122001/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adipose Tissue, Brown/drug effects/metabolism ; Adipose Tissue, White/drug effects/metabolism ; Adiposity/drug effects ; Animals ; Antioxidants/metabolism ; Body Temperature ; Calorimetry, Indirect ; Diet, High-Fat/*adverse effects ; Female ; Glucose Tolerance Test ; Inflammation/drug therapy/metabolism ; Injections, Intraperitoneal ; Insulin Resistance ; Male ; Metabolic Diseases/*drug therapy/*metabolism ; Mice ; Weight Gain/drug effects ; }, abstract = {An adverse maternal in utero and lactation environment can program offspring for increased risk for metabolic disease. The aim of this study was to determine whether N-acetylcysteine (NAC), an anti-inflammatory antioxidant, attenuates programmed susceptibility to obesity and insulin resistance in offspring of mothers on a high-fat diet (HFD) during pregnancy. CD1 female mice were acutely fed a standard breeding chow or HFD. NAC was added to the drinking water (1 g/kg) of the treatment cohorts from embryonic day 0.5 until the end of lactation. NAC treatment normalized HFD-induced maternal weight gain and oxidative stress, improved the maternal lipidome, and prevented maternal leptin resistance. These favorable changes in the in utero environment normalized postnatal growth, decreased white adipose tissue (WAT) and hepatic fat, improved glucose and insulin tolerance and antioxidant capacity, reduced leptin and insulin, and increased adiponectin in HFD offspring. The lifelong metabolic improvements in the offspring were accompanied by reductions in proinflammatory gene expression in liver and WAT and increased thermogenic gene expression in brown adipose tissue. These results, for the first time, provide a mechanistic rationale for how NAC can prevent the onset of metabolic disease in the offspring of mothers who consume a typical Western HFD.}, }
@article {pmid32440328, year = {2020}, author = {Kulshrestha, R and Pandey, A and Jaggi, A and Bansal, S}, title = {Beneficial effects of N-acetylcysteine on protease-antiprotease balance in attenuating bleomycin-induced pulmonary fibrosis in rats.}, journal = {Iranian journal of basic medical sciences}, volume = {23}, number = {3}, pages = {396-405}, pmid = {32440328}, issn = {2008-3866}, abstract = {OBJECTIVES: The role of N-acetylcysteine (NAC) as an anti-oxidant in attenuating bleomycin-induced pulmonary fibrosis has been reported. However, its effect on parenchymal remodeling via regulating the protease-antiprotease balance is not fully defined. Therefore, the present study was designed to explore the possible role of matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and transforming growth factor-β1 (TGF-β1) pathway and their modulation by NAC in attenuating bleomycin-induced pulmonary fibrosis in rats.<br><br>MATERIALS AND METHODS: Bleomycin sulphate (7 units/kg) was instilled inside the trachea to induce pulmonary fibrosis. The time course of TGF-&#x3b2;1, MMP-9, TIMP-1,3 mRNA and protein expression, TGF-&#x3b2;1 and hydroxyproline levels were evaluated on days 7, 14, and 28. NAC (0.3 mmol/kg and 3 mmol/kg) was administered in bleomycin-instilled animals.<br><br>RESULTS: NAC treatment significantly attenuated bleomycin-induced histopathological changes by decreasing interstitial inflammation and reducing the deposition of extracellular matrix proteins such as collagen. Moreover, it increased the mRNA and protein expression of MMP-9 and decreased the expression of TIMP-1,3 in alveolar epithelial cells (AECs), interstitial macrophages and inflammatory cells. Indeed, there was decrease in the MMP-9/TIMP ratio in bleomycin-instilled rats, which increased with NAC treatment. Moreover, NAC attenuated bleomycin-induced increased expression of TGF-&#x3b2;1 and total lung collagen levels.<br><br>CONCLUSION: NAC attenuates bleomycin-induced pulmonary fibrosis by normalizing the protease-antiprotease balance and favoring the degradation of collegen to reduce fibrosis.}, }
@article {pmid32439580, year = {2020}, author = {Lan, W and Chen, Z and Chen, Y and Tan, M and Chen, Y and Chen, J and Chi, X and Chen, Y}, title = {Glycochenodeoxycholic acid impairs transcription factor E3 -dependent autophagy-lysosome machinery by disrupting reactive oxygen species homeostasis in L02 cells.}, journal = {Toxicology letters}, volume = {331}, number = {}, pages = {11-21}, doi = {10.1016/j.toxlet.2020.05.017}, pmid = {32439580}, issn = {1879-3169}, mesh = {Autophagy/*drug effects ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/*metabolism ; Bile Acids and Salts/metabolism ; Cell Line ; Gene Expression/drug effects ; Glycochenodeoxycholic Acid/*toxicity ; Hepatocytes/*drug effects/metabolism/pathology ; Homeostasis/*drug effects ; Humans ; Lysosomes/drug effects ; Proteomics ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cholestasis represents pathophysiologic syndromes defined as impaired bile flow from the liver. As an outcome, bile acids accumulate and promote hepatocyte injury, followed by liver cirrhosis and liver failure. Glycochenodeoxycholic acid (GCDCA) is relatively toxic and highly concentrated in bile and serum after cholestasis. However, the mechanism underlying GCDCA-induced hepatotoxicity remains unclear. In this study, we found that GCDCA inhibits autophagosome formation and impairs lysosomal function by inhibiting lysosomal proteolysis and increasing lysosomal pH, contributing to defects in autophagic clearance and subsequently leading to the death of L02 human hepatocyte cells. Notably, through tandem mass tag (TMT)-based quantitative proteomic analysis and database searches, 313 differentially expressed proteins were identified, of which 71 were increased and 242 were decreased in the GCDCA group compared with those in the control group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that GCDCA suppressed the signaling pathway of transcription factor E3 (TFE3), which was the most closely associated with autophagic flux impairment. In contrast, GCDCA-inhibited lysosomal function and autophagic flux were efficiently attenuated by TFE3 overexpression. Specifically, the decreased expression of TFE3 was closely related to the disruption of reactive oxygen species (ROS) homeostasis, which could be prevented by inhibiting intracellular ROS with N-acetyl cysteine (NAC). In summary, our study is the first to demonstrate that manipulation of ROS/TFE3 signaling may be a therapeutic approach for antagonizing GCDCA-induced hepatotoxicity.}, }
@article {pmid32438253, year = {2020}, author = {Zalachoras, I and Hollis, F and Ramos-Fernández, E and Trovo, L and Sonnay, S and Geiser, E and Preitner, N and Steiner, P and Sandi, C and Morató, L}, title = {Therapeutic potential of glutathione-enhancers in stress-related psychopathologies.}, journal = {Neuroscience and biobehavioral reviews}, volume = {114}, number = {}, pages = {134-155}, doi = {10.1016/j.neubiorev.2020.03.015}, pmid = {32438253}, issn = {1873-7528}, mesh = {Animals ; Antioxidants ; *Glutathione/metabolism ; Humans ; *Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {The mammalian brain has high energy demands, which may become higher in response to environmental challenges such as psychogenic stress exposure. Therefore, efficient neutralization of reactive oxygen species that are produced as a by-product of ATP synthesis is crucial for preventing oxidative damage and ensuring normal energy supply and brain function. Glutathione (GSH) is arguably the most important endogenous antioxidant in the brain. In recent years, aberrant GSH levels have been implicated in different psychiatric disorders, including stress-related psychopathologies. In this review, we examine the available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Additionally, we identify several promising compounds that could raise GSH levels in the brain by either increasing the availability of its precursors or the expression of GSH-regulating enzymes through activation of Nuclear factor erythroid-2-related factor 2 (Nrf2). Given the high tolerability and safety profile of these compounds, they may represent attractive new opportunities to complement existing therapeutic manipulations against stress-related psychopathologies.}, }
@article {pmid32438104, year = {2020}, author = {Fan, H and Le, JW and Zhu, JH}, title = {Protective Effect of N-Acetylcysteine Pretreatment on Acute Kidney Injury in Septic Rats.}, journal = {The Journal of surgical research}, volume = {254}, number = {}, pages = {125-134}, doi = {10.1016/j.jss.2020.04.017}, pmid = {32438104}, issn = {1095-8673}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/etiology/pathology/*prevention &amp; control ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage ; Antioxidants/administration &amp; dosage ; Apoptosis ; Cecum/surgery ; Disease Models, Animal ; Kidney/enzymology/pathology ; Ligation ; Male ; Mitochondria/physiology ; Rats ; Rats, Sprague-Dawley ; Sepsis/*complications ; }, abstract = {BACKGROUND: The aim of this study is to investigate the protective effect of N-acetylcysteine (NAC) pretreatment on acute kidney injury in septic rats.<br><br>METHODS: We constructed a septic rat model by cecal ligation and perforation (CLP) and assessed kidney tissue pathologic damage, renal function changes, and inflammatory factor levels. Meanwhile, we also assessed oxide and antioxidant enzyme levels in kidney tissues, observed apoptosis of kidney tissues, and evaluated mitochondrial membrane activity in renal cortical cells.<br><br>RESULTS: Pretreatment of NAC significantly alleviated pathologic damage of kidney tissues in septic rats; decreased the levels of serum creatinine, blood urea nitrogen, plasma neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1; and reduced the expression of tumor necrosis factor a, interleukin [IL]-1&#x3b2;, IL-6, and IL-8. Furthermore, NAC pretreatment reduced the level of protein-nitrotyrosine adducts and malondialdehyde in CLP-induced kidney tissues, while elevated the levels of superoxide dismutase, glutathione peroxidase, and catalase. Moreover, pretreatment of NAC reduced the number of apoptosis in kidney tissues induced by CLP, decreased the mRNA levels of caspase-3, caspase-9, cytochrome c, and poly ADP-ribose polymerase, and increased mitochondrial membrane activity in renal cortical cells (complex I/II/III/IV).<br><br>CONCLUSIONS: NAC pretreatment has protective effects on acute kidney injury induced by CLP, and its mechanism is closely related to anti-inflammatory, antioxidation, antiapoptosis, and regulation of mitochondrial function.}, }
@article {pmid32438077, year = {2020}, author = {Zhou, H and Sun, Y and Wang, Q and Li, Z and Zhong, W and Wang, X and Dai, X and Kong, L}, title = {N-acetylcysteine alleviates liver injury by suppressing macrophage-mediated inflammatory response post microwave ablation.}, journal = {International immunopharmacology}, volume = {85}, number = {}, pages = {106580}, doi = {10.1016/j.intimp.2020.106580}, pmid = {32438077}, issn = {1878-1705}, mesh = {Ablation Techniques/*adverse effects ; Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/immunology/surgery ; Humans ; Inflammation ; Liver/*drug effects/immunology/pathology/surgery ; Liver Diseases ; Liver Neoplasms/immunology/surgery ; Macrophages/immunology ; Male ; Microwaves/*adverse effects ; Peroxidase/blood ; Rats, Sprague-Dawley ; }, abstract = {OBJECT: To investigate N-acetyl-cysteine (NAC) would able to alleviate liver injury and systemic inflammatory response caused by microwave ablation (MWA) in rats.<br><br>MATERIALS AND METHODS: Male Sprague-Dawley rats weighing 150-200&#xa0;g were randomly divided into sham group (only anesthesia and laparotomy except MWA but with intraperitoneal PBS or NAC solution injection according to different situations), control group (intraperitoneal PBS injection for comparation 2&#xa0;h prior to MWA), and NAC-treated group (intraperitoneal N-acetyl-cysteine (300&#xa0;mg/kg) injection 2&#xa0;h prior to MWA). Experimental rats were sacrificed at 4&#xa0;h following operation in line with the liver injury severity curve. Liver tissue and serum samples were collected for determination of pathology, apoptosis, macrophages contents and protein expression.<br><br>RESULTS: The elevated serum level of liver enzymes, Myeloperoxidase (MPO) and inflammatory factors (TNF-&#x3b1; and CXCL1) in MWA-treated rats revealed injurious and pro- inflammatory effect of MVA. Macrophages aggregation was detected in MWA exposure rats similarly. and NAC pre-conditioning mitigate liver damage and hepatocyte apoptosis, besides macrophages accumulation and following inflammatory response in liver tissue.<br><br>CONCLUSION: Our results demonstrated that N-acetyl-cysteine application alleviate macrophages aggregation and inflammatory response in liver suffering microwave ablation, and mitigating liver injury and cell apoptosis.}, }
@article {pmid32433928, year = {2020}, author = {Lin, HD and Wang, FZ and Lee, CY and Nien, CY and Tseng, YK and Yao, CL and Chen, SC}, title = {4-Aminobiphenyl inhibits the DNA homologous recombination repair in human liver cells: The role of miR-630 in downregulating RAD18 and MCM8.}, journal = {Toxicology}, volume = {440}, number = {}, pages = {152441}, doi = {10.1016/j.tox.2020.152441}, pmid = {32433928}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Aminobiphenyl Compounds/*pharmacology ; Cell Line ; Cyclic AMP Response Element-Binding Protein/biosynthesis ; DNA Breaks, Double-Stranded/drug effects ; DNA-Binding Proteins/*antagonists &amp; inhibitors ; Free Radical Scavengers/pharmacology ; Homologous Recombination ; Humans ; Liver/drug effects/*metabolism ; MicroRNAs/*metabolism ; Minichromosome Maintenance Proteins/*antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; Recombinational DNA Repair/*drug effects ; Ubiquitin-Protein Ligases/*antagonists &amp; inhibitors ; }, abstract = {4-Aminobiphenyl (4-ABP), a well-known human carcinogen, has been shown to cause oxidative DNA damage and induce miR-630 expression in HepG2 cells treated with 18.75 μM-300 μM for 24 h. However, the underlying mechanism regarding the epigenetic regulation of miR-630 on DNA damage repair in liver cells is still not understood and needs to be investigated. In present study, our results showed that miR-630 was upregulated, resulting in mediating a decrease of DNA homologous recombination (HR) repair in L-02, HepG2 or Hep3B cells. Results from a luciferase reporting experiment showed that RAD18 and MCM8 were the potential targets of miR-630 during DNA damage induction. The downregulation of RAD18 or MCM8 by miR-630 was accompanied by inhibition of HR repair. Conversely, inhibiting miR-630 enhanced the expression of RAD18 and MCM8, and rescued HR repair. Additionally, we proved that the transcription factor CREB was related to miR-630 biogenesis in liver cells. Moreover, the levels of CREB, miR-630 expression, and double-strand breaks (DSBs) were attenuated by 5 mM N-acetyl-L-cysteine (NAC) pretreatment, indicating that reactive oxygen species (ROS)-dependent CREB-miR-630 was involved in DSB repair. These findings indicated that the ROS/CREB/-miR-630 axis plays a relevant role in the regulation of RAD18 and MCM8 in HR repair, which may facilitate our understanding of molecular mechanisms regarding the role of miR-630 downregulating DNA damage repair in liver cells.}, }
@article {pmid32432042, year = {2020}, author = {Chirillo, R and Aversa, I and Di Vito, A and Salatino, A and Battaglia, AM and Sacco, A and Di Sanzo, MA and Faniello, MC and Quaresima, B and Palmieri, C and Biamonte, F and Costanzo, F}, title = {FtH-Mediated ROS Dysregulation Promotes CXCL12/CXCR4 Axis Activation and EMT-Like Trans-Differentiation in Erythroleukemia K562 Cells.}, journal = {Frontiers in oncology}, volume = {10}, number = {}, pages = {698}, pmid = {32432042}, issn = {2234-943X}, abstract = {The cell-microenvironment communication is essential for homing of hematopoietic stem cells in stromal niches. Recent evidences support the involvement of epithelial-to-mesenchymal (EMT) process in hematopoietic stem cell homeostasis as well as in leukemia cells invasiveness and migration capability. Here, we demonstrate that the alteration of iron homeostasis and the consequent increase of redox metabolism, mediated by the stable knock down of ferritin heavy chain (FtH), enhances the expression of CXCR4 in K562 erythroleukemia cells, thus promoting CXCL12-mediated motility. Indeed, addition of the CXCR4 receptor antagonist AMD3100 reverts this effect. Upon FtH knock down K562 cells also acquire an "EMT-like" phenotype, characterized by the increase of Snail, Slug and Vimentin with the parallel loss of E-cadherin. By using fibronectin as substrate, the cell adhesion assay further shows a reduction of cell adhesion capability in FtH-silenced K562 cells. Accordingly, confocal microscopy shows that adherent K562 control cells display a variety of protrusions while FtH-silenced K562 cells remain roundish. These phenomena are largely due to the reactive oxygen species (ROS)-mediated up-regulation of HIF-1α/CXCR4 axis which, in turn, promotes the activation of NF-κB and the enhancement of EMT features. These data are confirmed by treatments with either N-acetylcysteine (NAC) or AMD3100 or NF-κB inhibitor IκB-alpha which revert the FtH-silenced K562 invasive phenotype. Overall, our findings demonstrate the existence of a direct relationship among iron metabolism, redox homeostasis and EMT in the hematological malignancies. The effects of FtH dysregulation on CXCR4/CXCL12-mediated K562 cell motility extend the meaning of iron homeostasis in the leukemia cell microenvironment.}, }
@article {pmid32430958, year = {2020}, author = {Yi, C and Li, X and Chen, S and Liu, M and Lu, W and Ye, X}, title = {Natural product corynoline suppresses melanoma cell growth through inducing oxidative stress.}, journal = {Phytotherapy research : PTR}, volume = {34}, number = {10}, pages = {2766-2777}, doi = {10.1002/ptr.6719}, pmid = {32430958}, issn = {1099-1573}, support = {011//ECNU Multifunctional Platform for Innovation/ ; 2017-01-07-00-05-E00011//Innovation Program of Shanghai Municipal Education Commission/ ; 2018YFA0507001//National Key R&amp;D Program of China/ ; 81972828//National Natural Science Foundation of China/ ; 18431900500//Shanghai Committee of Science and Technology/ ; 19ZR1473500//Shanghai Committee of Science and Technology/ ; }, mesh = {Berberine Alkaloids/pharmacology/*therapeutic use ; Biological Products/*chemistry ; Humans ; Medicine, Chinese Traditional/*methods ; Melanoma/*drug therapy ; Oxidative Stress/*drug effects ; }, abstract = {Natural product corynoline is a unique isoquinoline alkaloid extracted from traditional Chinese medicine Corydalis bungeana Turcz, whereas its anticancer properties have not been investigated. In this study, we found that corynoline potently impairs the growth of melanoma cells, B16F10, and A375 in a concentration-dependent manner. Treatment of melanoma cells with corynoline results in G2 cell arrest accompanied by reduced cdc2 activation. Furthermore, corynoline triggers apoptosis of melanoma cells, which is associated with increased expression of Bax and cleaved caspase-3. Mechanistic study indicates that corynoline strongly induces reactive oxygen species (ROS) generation and subsequent DNA damage as evidenced by γ-H2AX accumulation. Notably, the effect of corynoline on melanoma cell cycle and apoptosis is abolished by a ROS scavenger N-acetyl cysteine (NAC), indicating a ROS-dependent mechanism. Finally, corynoline significantly inhibits in vivo B16F10 melanoma tumor growth accompanied by reduced expression of Ki-67 in tumor tissue. Taken together, our data suggest that corynoline suppresses melanoma cell growth in vitro and in vivo by inducing oxidative stress and represents a potential therapeutic agent for melanoma patients.}, }
@article {pmid32429564, year = {2020}, author = {Yu, TJ and Tang, JY and Ou-Yang, F and Wang, YY and Yuan, SF and Tseng, K and Lin, LC and Chang, HW}, title = {Low Concentration of Withaferin a Inhibits Oxidative Stress-Mediated Migration and Invasion in Oral Cancer Cells.}, journal = {Biomolecules}, volume = {10}, number = {5}, pages = {}, pmid = {32429564}, issn = {2218-273X}, support = {MOST 108-2320-B-037-015-MY3; MOST 108-2314-B-037-020, MOST 108-2314-B-037-080//Ministry of Science and Technology, Taiwan/International ; #NSYSUKMU 109-I002//National Sun Yat-sen University-KMU Joint Research Project/International ; 108CM-KMU-11//Chimei-KMU jointed project/International ; KMU-TC108A04//Kaohsiung Medical University Research Center/International ; MOHW 108-TDU-B-212-124016//Health and welfare surcharge of tobacco products, the Ministry of Health and Welfare, Taiwan, Republic of China/International ; }, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Line, Tumor ; Cell Movement/*drug effects ; Cell Proliferation/drug effects ; Glutathione Reductase/genetics/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Humans ; MAP Kinase Signaling System ; Matrix Metalloproteinase 2/genetics/metabolism ; Matrix Metalloproteinase 9/genetics/metabolism ; Mouth Neoplasms/*metabolism ; NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; *Oxidative Stress ; Withanolides/*pharmacology ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Withaferin A (WFA) has been reported to inhibit cancer cell proliferation based on high cytotoxic concentrations. However, the low cytotoxic effect of WFA in regulating cancer cell migration is rarely investigated. The purpose of this study is to investigate the changes in migration and mechanisms of oral cancer Ca9-22 cells after low concentrations of WFA treatment. WFA under 0.5 μM at 24 h treatment shows no cytotoxicity to oral cancer Ca9-22 cells (~95% viability). Under this condition, WFA triggers reactive oxygen species (ROS) production and inhibits 2D (wound healing) and 3D cell migration (transwell) and Matrigel invasion. Mechanically, WFA inhibits matrix metalloproteinase (MMP)-2 and MMP-9 activities but induces mRNA expression for a group of antioxidant genes, such as nuclear factor, erythroid 2-like 2 (NFE2L2), heme oxygenase 1 (HMOX1), glutathione-disulfide reductase (GSR), and NAD(P)H quinone dehydrogenase 1 (NQO1)) in Ca9-22 cells. Moreover, WFA induces mild phosphorylation of the mitogen-activated protein kinase (MAPK) family, including extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 expression. All WFA-induced changes were suppressed by the presence of ROS scavenger N-acetylcysteine (NAC). Therefore, these results suggest that low concentration of WFA retains potent ROS-mediated anti-migration and -invasion abilities for oral cancer cells.}, }
@article {pmid32424535, year = {2020}, author = {Pietruski, P and Paskal, W and Paluch, &#x141; and Paskal, AM and Nitek, &#x17b; and Włodarski, P and Walecki, J and Noszczyk, B}, title = {The Impact of N-Acetylcysteine on Autologous Fat Graft: First-in-Human Pilot Study.}, journal = {Aesthetic plastic surgery}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00266-020-01730-1}, pmid = {32424535}, issn = {1432-5241}, support = {501-1-06-09-17//Medical Centre for Postgraduate Education/ ; }, abstract = {BACKGROUND: Our goal was to determine whether N-acetylcysteine (NAC) administered to the tumescent solution can reduce oxidative stress and increase autologous fat graft (AFG) viability.<br><br>METHODS: The study included 15 women with a mean age of 31.8&#xa0;years (range 23-39&#xa0;years) who underwent breast asymmetry correction with AFG harvested from both thighs. One thigh was infiltrated with a standard tumescent fluid (control graft) and other with a NAC-enriched tumescent fluid (NAC-treated graft). Each participant had breast MRI imaging before and 6&#xa0;months after the procedure. Also, adipose tissue samples from each graft were subjected to biochemical analysis, flow cytometric assay and qRT-PCR to determine the markers of oxidative stress, angiogenesis and adipogenesis.<br><br>RESULTS: Concentration and activity of superoxide dismutase in the NAC-treated grafts turned out to be significantly higher than in the control grafts, in both fresh (p&#x2009;=&#x2009;0.041 and p&#x2009;=&#x2009;0.023, respectively) and frozen samples (p&#x2009;=&#x2009;0.004 and p&#x2009;=&#x2009;0.003, respectively). The level of nitric oxide in frozen samples from the control grafts was significantly higher than in the NAC-treated grafts (p&#x2009;=&#x2009;0.009). iNOS was the only qRT-PCR target showing significant intergroup differences, with higher transcription levels observed in the control grafts (p&#x2009;=&#x2009;0.027). Breast volumetric analysis demonstrated that the NAC-treated group had a 12.19% lower resorption rate than the control group, although it was found to be statistically insignificant (p&#x2009;=&#x2009;0.149). No postoperative complications were observed during a 6-month follow-up.<br><br>CONCLUSIONS: Some results of this study are promising. Further studies on larger groups are needed to determine NAC impact on AFG.<br><br>TRIAL REGISTRY NAME: The Impact of N-Acetylcysteine on Volumetric Retention of Autologous Fat Graft for Breast Asymmetry Correction.<br><br>NCT03197103. URL FOR THE REGISTRY: https://clinicaltrials.gov/ct2/show/NCT03197103?term=acetylcysteine&amp;rank=6 LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.}, }
@article {pmid32418903, year = {2020}, author = {Sharma, A and Vaghasiya, K and Gupta, P and Singh, AK and Gupta, UD and Verma, RK}, title = {Dynamic mucus penetrating microspheres for efficient pulmonary delivery and enhanced efficacy of host defence peptide (HDP) in experimental tuberculosis.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {324}, number = {}, pages = {17-33}, doi = {10.1016/j.jconrel.2020.05.013}, pmid = {32418903}, issn = {1873-4995}, mesh = {Administration, Inhalation ; Animals ; Drug Delivery Systems ; Lung ; Mice ; Microspheres ; Mucus ; Particle Size ; *Tuberculosis/drug therapy ; }, abstract = {Pulmonary drug delivery system is increasingly gaining popularity for several lung diseases including tuberculosis(TB) due to its ability to attain high drug concentrations at the site of infection and to minimize systemic toxicity. In TB therapy, the efficacy of the antibiotics decreases and bacteria becomes resistant in course of time due to the formation of several barriers like lung-mucus and biofilms around the microorganism. The conventional inhalable microparticles(MP) are majorly trapped in dense mucin mess network and quickly cleared by mucocilliary clearance. In this study, we determined whether the anti-TB activity of drug-loaded inhalable polymeric microparticles could be synergized with the mucus-penetrating and biofilm disrupting properties. Mucus-penetrating-microparticles(NAC/PLGA-MPP) were developed combining the benefits of anti-TB drug with host defence peptides(HDP). IDR-1018 peptide was encapsulated with/without an anti-TB drug in N-acetyl cysteine(NAC) decorated porous PLGA microspheres. Aerodynamic parameters(MMAD-3.79 ± 1.04 μm, FPF-52.9 ± 5.11%) were optimized for the finest deposition and targeting inside the lungs. The multiple-tracking-technique(MPT) results indicate that the coating of NAC on porous PLGA-MS dramatically increased (4.1fold) the particle transit through the mucus barrier. Designed inhalable NAC/PLGA-MPP do not adhere to lung mucus, disrupt the bacterial biofilm and provide uniform drug delivery to lungs after pulmonary delivery. The formulation was evaluated for activity against M.tb in macrophage cultures and in mice model infected with a low-dose bacterial (~100 CFU) aerosol. The inhalation of NAC/PLGA-MPP encapsulated with IDR-1018 significantly reduced (p < .05) bacterial load (up to ~3.02LogCFU/ml) and inflammation in lungs in a mouse model of TB compared to untreated and blank treated animals in 6 weeks of daily dose. The histopathological results validate the compelling chemotherapeutic outcome of inhaled formulations. This data supports the harnessing potential of mucus penetrating inhalable drug delivery systems as a vehicle for targeted lung delivery. This "value-added" inhalable formulation could be beneficial for resistant TB therapeutics when used as an "adjunct" to existing DOTS (Directly observed treatment, short-course) therapy.}, }
@article {pmid32418119, year = {2020}, author = {Singh, P and Kacena, MA and Orschell, CM and Pelus, LM}, title = {Aging-Related Reduced Expression of CXCR4 on Bone Marrow Mesenchymal Stromal Cells Contributes to Hematopoietic Stem and Progenitor Cell Defects.}, journal = {Stem cell reviews and reports}, volume = {16}, number = {4}, pages = {684-692}, pmid = {32418119}, issn = {2629-3277}, support = {R01 AG046246/AG/NIA NIH HHS/United States ; R01 HL096305/HL/NHLBI NIH HHS/United States ; P30 CA082709/CA/NCI NIH HHS/United States ; UH3 AI128894/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aging/*metabolism ; Animals ; Cell Count ; Cell Cycle/drug effects ; Cells, Cultured ; Clone Cells ; Colony-Forming Units Assay ; Free Radical Scavengers/pharmacology ; Hematopoietic Stem Cells/drug effects/*metabolism ; Mesenchymal Stem Cells/drug effects/*metabolism ; Mice, Inbred C57BL ; Phenotype ; Reactive Oxygen Species/metabolism ; Receptors, CXCR4/deficiency/*metabolism ; }, abstract = {Aging impairs the regenerative potential of hematopoietic stem cells (HSC) and skews differentiation towards the myeloid lineage. The bone marrow (BM) microenvironment has recently been suggested to influence HSC aging, however the mechanisms whereby BM stromal cells mediate this effect is unknown. Here we show that aging-associated decreased expression of CXCR4 expression on BM mesenchymal stem cells (MSC) plays a crucial role in the development of the hematopoietic stem and progenitor cells (HSPC) aging phenotype. The BM MSC from old mice was sufficient to drive a premature aging phenotype of young HSPC when cultured together ex vivo. The impaired ability of old MSC to support HSPC function is associated with reduced expression of CXCR4 on BM MSC of old mice. Deletion of the CXCR4 gene in young MSC accelerates an aging phenotype in these cells characterized by increased production of reactive oxygen species (ROS), DNA damage, senescence, and reduced proliferation. Culture of HSPC from young mice with CXCR4 deficient MSC also from young mice led to a premature aging phenotype in the young HSPC, as evidenced by reduced hematopoietic regeneration and enhanced myeloid differentiation. Mechanistically, CXCR4 signaling prevents BM MSC dysfunction by suppressing oxidative stress, as treatment of old or CXCR4 deficient MSC with N-acetyl-L-cysteine (NAC), improved their niche supporting activity, and attenuated the HSPC aging phenotype. Our studies suggest that age-associated reduction in CXCR4 expression on BM MSC impairs hematopoietic niche activity with increased ROS production, driving an HSC aging phenotype. Thus, modulation of the SDF-1/CXCR4 axis in MSC may lead to novel interventions to alleviate the age-associated decline in immune/hematopoietic function.}, }
@article {pmid32413425, year = {2020}, author = {Schomberg, J and Wang, Z and Farhat, A and Guo, KL and Xie, J and Zhou, Z and Liu, J and Kovacs, B and Liu-Smith, F}, title = {Luteolin inhibits melanoma growth in vitro and in vivo via regulating ECM and oncogenic pathways but not ROS.}, journal = {Biochemical pharmacology}, volume = {177}, number = {}, pages = {114025}, doi = {10.1016/j.bcp.2020.114025}, pmid = {32413425}, issn = {1873-2968}, support = {P30 CA062203/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Antioxidants/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Extracellular Matrix/*drug effects/genetics/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Luteolin/*pharmacology ; Melanoma/*drug therapy/genetics/metabolism/pathology ; Metabolic Networks and Pathways/drug effects/genetics ; Mice, Nude ; Oncogenes/drug effects ; Oxidative Stress/drug effects/genetics ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Luteolin inhibited growth of several cancer cells in vitro in previous studies, with limited in vivo studies, and no comprehensive understanding of molecular mechanisms at genomics level. This study identified luteolin as an effective agent to inhibit melanoma cell growth in vitro and in vivo. Molecular studies and genomic profiling were used to identify the mechanism of action of luteolin in melanoma cells. As a ROS (reactive oxygen species) scavenger, luteolin unexpectedly induced ROS; but co-treatment with antioxidants NAC or mito-TEMPO did not rescue cell growth inhibition, although the levels of ROS levels were reduced. Next, we profiled luteolin-induced differentially expressed genes (DEGs) in 4 melanoma cell lines using RNA-Seq, and performed pathway analysis using a combination of bioinformatics software including PharmetRx which was especially effective in discovering pharmacological pathways for potential drugs. Our results show that luteolin induces changes in three main aspects: the cell-cell interacting pathway (extracellular matrix, ECM), the oncogenic pathway and the immune response signaling pathway. Based on these results, we further validated that luteolin was especially effective in inhibiting cell proliferation when cells were seeded at low density, concomitantly with down-regulation of fibronectin accumulation. In conclusion, through extensive DEG profiling in a total of 4 melanoma cell lines, we found that luteolin-mediated growth inhibition in melanoma cells was perhaps not through ROS induction, but likely through simultaneously acting on multiple pathways including the ECM (extracellular matrix) pathway, the oncogenic signaling and the immune response pathways. Further investigations on the mechanisms of this promising compound are warranted and likely result in application to cancer patients as its safety pharmacology has been validated in autism patients.}, }
@article {pmid32411699, year = {2020}, author = {Li, Y and Ding, H and Liu, L and Song, Y and Du, X and Feng, S and Wang, X and Li, X and Wang, Z and Li, X and Li, J and Wu, J and Liu, G}, title = {Non-esterified Fatty Acid Induce Dairy Cow Hepatocytes Apoptosis via the Mitochondria-Mediated ROS-JNK/ERK Signaling Pathway.}, journal = {Frontiers in cell and developmental biology}, volume = {8}, number = {}, pages = {245}, pmid = {32411699}, issn = {2296-634X}, abstract = {Elevated plasma non-esterified fatty acid (NEFA) levels and hepatocytes damage are characteristics of ketosis in dairy cows. Oxidative stress is associated with the pathogenesis of NEFA-induced liver damage. However, the exact mechanism by which oxidative stress mediates NEFA-induced hepatocytes apoptosis and liver injury remains poorly understood. The results of the present study demonstrated that NEFA contribute to reactive oxygen species (ROS) generation, resulting in an imbalance between oxidative and antioxidant species, transcriptional activation of p53, transcriptional inhibition of nuclear factor E2-related factor 2 (Nrf2), loss of mitochondria membrane potential (MMP) and release of apoptosis-inducing factor (AIF) and cytochrome c (cyt c) into the cytosol, leading to hepatocytes apoptosis. Besides, NEFA triggered apoptosis in dairy cow hepatocytes via the regulation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), Bcl-2-associated X protein (Bax), B-cell lymphoma gene 2 (Bcl-2), caspase 9 and poly (ADP-ribose) polymerase (PARP). Pretreatment with the inhibitor SP600125 or PD98059 or the antioxidant N-acetylcysteine (NAC) revealed that NEFA-ROS-JNK/ERK-mediated mitochondrial signaling pathway plays a crucial role in NEFA-induced hepatocytes apoptosis. Moreover, the results suggested that the transcription factors p53 and Nrf2 function downstream of this NEFA-ROS-JNK/ERK pathway and are involved in NEFA-induced hepatocytes apoptosis. In conclusion, these findings indicate that the NEFA-ROS-JNK/ERK-mediated mitochondrial pathway plays an important role in NEFA-induced dairy cow hepatocytes apoptosis and strongly suggests that the inhibitors SP600125 and PD98059 and the antioxidant NAC may be developed as therapeutics to prevent hyperlipidemia-induced apoptotic damage in ketotic dairy cows.}, }
@article {pmid32411461, year = {2020}, author = {Ejigu, DA and Abay, SM}, title = {N-Acetyl Cysteine as an Adjunct in the Treatment of Tuberculosis.}, journal = {Tuberculosis research and treatment}, volume = {2020}, number = {}, pages = {5907839}, pmid = {32411461}, issn = {2090-150X}, abstract = {Oxidative stress is a common feature of tuberculosis (TB), and persons with reduced antioxidants are at more risk of TB. TB patients with relatively severe oxidative stress had also more advanced disease as measured by the Karnofsky performance index. Since adverse effects from anti-TB drugs are also mediated by free radicals, TB patients are prone to side effects, such as hearing loss. In previous articles, researchers appealed for clinical trials aiming at evaluating N-acetyl cysteine (NAC) in attenuating the dreaded hearing loss during multidrug-resistant TB (MDR-TB) treatment. However, before embarking on such trials, considerations of NAC's overall impact on TB treatment are crucial. Unfortunately, such a comprehensive report on NAC is missing in the literature and this manuscript reviews the broader effect of NAC on TB treatment. This paper discusses NAC's effect on mycobacterial clearance, hearing loss, drug-induced liver injury, and its interaction with anti-TB drugs. Based on the evidence accrued to date, NAC appears to have various beneficial effects on TB treatment. However, despite the favorable interaction between NAC and first-line anti-TB drugs, the interaction between the antioxidant and some of the second-line anti-TB drugs needs further investigations.}, }
@article {pmid32411331, year = {2020}, author = {Kosuge, Y and Nango, H and Kasai, H and Yanagi, T and Mawatari, T and Nishiyama, K and Miyagishi, H and Ishige, K and Ito, Y}, title = {Generation of Cellular Reactive Oxygen Species by Activation of the EP2 Receptor Contributes to Prostaglandin E2-Induced Cytotoxicity in Motor Neuron-Like NSC-34 Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {6101838}, pmid = {32411331}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Differentiation/drug effects ; Cell Line ; Cyclic AMP/metabolism ; Dinoprostone/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Mice ; Motor Neurons/drug effects/metabolism/*pathology ; Protein Isoforms/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Prostaglandin E, EP2 Subtype/agonists/*metabolism ; Receptors, Prostaglandin E, EP3 Subtype/genetics/metabolism ; }, abstract = {Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by progressive degeneration of motor neurons in the central nervous system. Prostaglandin E2 (PGE2) plays a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. We have shown previously that PGE2 directly induces neuronal death through activation of the E-prostanoid (EP) 2 receptor in differentiated NSC-34 cells, a motor neuron-like cell line. In the present study, to clarify the mechanisms underlying PGE2-induced neurotoxicity, we focused on generation of intracellular reactive oxygen species (ROS) and examined the effects of N-acetylcysteine (NAC), a cell-permeable antioxidant, on PGE2-induced cell death in differentiated NSC-34 cells. Dichlorofluorescein (DCF) fluorescence analysis of PGE2-treated cells showed that intracellular ROS levels increased markedly with time, and that this effect was antagonized by a selective EP2 antagonist (PF-04418948) but not a selective EP3 antagonist (L-798,106). Although an EP2-selective agonist, butaprost, mimicked the effect of PGE2, an EP1/EP3 agonist, sulprostone, transiently but significantly decreased the level of intracellular ROS in these cells. MTT reduction assay and lactate dehydrogenase release assay revealed that PGE2- and butaprost-induced cell death were each suppressed by pretreatment with NAC in a concentration-dependent manner. Western blot analysis revealed that the active form of caspase-3 was markedly increased in the PGE2- and butaprost-treated cells. These increases in caspase-3 protein expression were suppressed by pretreatment with NAC. Moreover, dibutyryl-cAMP treatment of differentiated NSC-34 cells caused intracellular ROS generation and cell death. Our data reveal the existence of a PGE2-EP2 signaling-dependent intracellular ROS generation pathway, with subsequent activation of the caspase-3 cascade, in differentiated NSC-34 cells, suggesting that PGE2 is likely a key molecule linking inflammation to oxidative stress in motor neuron-like NSC-34 cells.}, }
@article {pmid32409143, year = {2020}, author = {Ko, WC and Shieh, JM and Wu, WB}, title = {P38 MAPK and Nrf2 Activation Mediated Naked Gold Nanoparticle Induced Heme Oxygenase-1 Expression in Rat Aortic Vascular Smooth Muscle Cells.}, journal = {Archives of medical research}, volume = {51}, number = {5}, pages = {388-396}, doi = {10.1016/j.arcmed.2020.04.015}, pmid = {32409143}, issn = {1873-5487}, mesh = {Animals ; Aorta/*metabolism ; Gold/*chemistry ; Heme Oxygenase-1/*metabolism ; Humans ; Metal Nanoparticles/*chemistry ; Muscle, Smooth, Vascular/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Rats ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {BACKGROUND AND AIMS: Heme oxygenase 1 (HO-1) is mainly regulated by the redox-sensitive transcription factor, namely nuclear factor erythroid 2-related factor 2 (Nrf2). We previously found a physically-made gold nanoparticle (GNP) can affect migration, adhesion, and proliferation of rat aortic vascular smooth muscle cells (VSMCs). This study was sought to investigate whether the GNP can affect HO-1 expression level in VSMCs.<br><br>METHODS: Cellular fractionation, Western blotting, and immunofluorescence microscopy were used to determine Nrf2 translocation and phosphorylation. SiRNA interference was used to examine role of Nrf2 in GNP-induced HO-1 expression.<br><br>RESULTS: The GNP concentration- and time-dependently enhanced HO-1 protein and mRNA expression; however, the mRNA induction was declined after 16&#xa0;h treatment. The GNP treatment caused Nrf2 expression level and phosphorylation. In addition, it induced cytosolic Nrf2 translocation into nucleus. The HO-1 induction was inhibited by a ROS scavenger N-acetylcysteine (NAC), thiol-containing antioxidants (glutathione [GSH] and dithiothreitol [DTT]), JNK and p38 MAPK inhibitors, and nuclear transport inhibitor leptomycin. Meanwhile, the GNP-induced Nrf2 translocation (activation) was also reduced by NAC, JNK and p38 MAPK inhibitors, and nuclear transport inhibitor. Intriguingly, the GNP only enhanced activation of p38 MAPK but not JNK1/2. Finally, introduction of Nrf2 siRNA to cells to knockdown Nrf2 expression significantly inhibited GNP-induced HO-1 protein expression.<br><br>CONCLUSIONS: This study elucidates the action mechanism that the naked physically-made GNP can enhance HO-1 expression in rat aortic VSMCs by inducing Nrf2 expression and phosphorylation and translocation into nucleus. The Nrf2 activation is mediated through a redox-related reaction and p38 MAPK activation.}, }
@article {pmid32409092, year = {2020}, author = {Tseng, SJ and Huang, ST and Wu, CC and Cheng, CH and Lin, JC}, title = {Studies of proliferation and chondrogenic differentiation of rat adipose stem cells using an anti-oxidative polyurethane scaffold combined with cyclic compression culture.}, journal = {Materials science &amp; engineering. C, Materials for biological applications}, volume = {112}, number = {}, pages = {110964}, doi = {10.1016/j.msec.2020.110964}, pmid = {32409092}, issn = {1873-0191}, mesh = {Acetylcysteine/*chemistry ; Adipose Tissue/cytology ; Aggrecans/genetics/metabolism ; Animals ; Biocompatible Materials/*chemistry/pharmacology ; Cell Adhesion/drug effects ; Cell Culture Techniques/methods ; Cell Differentiation/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Chondrocytes/cytology/metabolism ; Chondrogenesis/drug effects ; Gene Expression/drug effects ; Iridoids/chemistry ; Polyurethanes/*chemistry ; Rats ; SOX9 Transcription Factor/genetics/metabolism ; Stem Cells/cytology/metabolism ; }, abstract = {The adipose stem cell is a potential candidate for the autologous chondrocytes repairing approach because of the abundance of fat in the animal body and its versatile differentiation capability. In this study, rat adipose stem cells (rASCs) were seeded into anti-oxidative N-acetylcysteine (NAC) grafted polyurethane (PU) scaffold and then combined with short dynamic compressive stimulation (24 h) to induce rASCs chondrogenesis differentiation in vitro. The inner pore surface of the PU scaffold was first modified via alginate and type I collagen to promote rASCs adherence. The modified layers crosslinked by genipin showed outstanding stability after ultrasonic treatment, indicating the modified layers were stable and can keep the cells adhesion well during dynamic compressive stimulation. After inner pore surface modification and 10 mM NAC grafting, the PU scaffold-A-C-G (graft 10 mM NAC) has shown the best proliferation efficiency with homogeneous cell distribution after 72hr static culture. After short term dynamic compressive stimulation, significant gene expression in chondrogenic markers, Sox-9, and Aggrecan, were noted in both PU scaffold-A-C-G and PU scaffold-A-C-G (graft 10 mM NAC). Considering the cell proliferation efficiency and gene expression, the anti-oxidative NAC grafted PU scaffold combined with short term dynamic compressive stimulation could be useful for cell culturing in stem cell therapy.}, }
@article {pmid32408577, year = {2020}, author = {Li, S and Ung, TT and Nguyen, TT and Sah, DK and Park, SY and Jung, YD}, title = {Cholic Acid Stimulates MMP-9 in Human Colon Cancer Cells via Activation of MAPK, AP-1, and NF-κB Activity.}, journal = {International journal of molecular sciences}, volume = {21}, number = {10}, pages = {}, pmid = {32408577}, issn = {1422-0067}, support = {2018R1D1A1B07049918//National Research Foundation of Korea/ ; }, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cholic Acid/*pharmacology ; Colonic Neoplasms/enzymology/genetics/metabolism/pathology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; HT29 Cells ; Humans ; Matrix Metalloproteinase 9/genetics/*metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; NF-kappa B/*metabolism ; Onium Compounds/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Transcription Factor AP-1/*metabolism ; }, abstract = {Matrix metalloproteinase-9 (MMP-9) plays a crucial role in cell invasion and cancer metastasis. In this study, we showed that cholic acid (CA), a major primary bile acid, can induce MMP-9 expression in colon cancer HT29 and SW620 cells. CA increased reactive oxygen species (ROS) production and also activated phosphorylation of ERK1/2, JNK, and p38 MAPK. Specific inhibitors and mutagenesis studies showed that ERK1/2 and JNK functioned as upstream signals in the activation of AP-1, and p38 MAPK functioned as an upstream signal in the activation of NF-κB. N-acetyl-L-cysteine (NAC, an ROS scavenger) and diphenyleneiodonium chloride (DPI, an NADPH oxidase inhibitor) inhibited CA-induced activation of ERK1/2, JNK, and p38 MAPK, indicating that ROS production by NADPH oxidase could be the furthest upstream signal in MMP-9 expression. Colon cancer cells pretreated with CA showed remarkably enhanced invasiveness. Such enhancement was partially abrogated by MMP-9-neutralizing antibodies. These results demonstrate that CA could induce MMP-9 expression via ROS-dependent ERK1/2, JNK-activated AP-1, and p38-MAPK-activated NF-κB signaling pathways, which in turn stimulate cell invasion in human colon cancer cells.}, }
@article {pmid32408210, year = {2020}, author = {Gu, J and Wang, H and Zhou, L and Fan, D and Shi, L and Ji, G and Gu, A}, title = {Oxidative stress in bisphenol AF-induced cardiotoxicity in zebrafish and the protective role of N-acetyl N-cysteine.}, journal = {The Science of the total environment}, volume = {731}, number = {}, pages = {139190}, doi = {10.1016/j.scitotenv.2020.139190}, pmid = {32408210}, issn = {1879-1026}, mesh = {*Acetylcysteine ; Animals ; Benzhydryl Compounds ; Cardiotoxicity ; Humans ; Oxidative Stress ; Phenols ; *Zebrafish ; }, abstract = {Research has shown that there is a relationship between bisphenol A (BPA) exposure and the incidence of cardiovascular diseases. However, the effect of bisphenol AF (BPAF), a main substitute for BPA, on heart development remains unclear. In this study, the cardiotoxicity of BPAF was evaluated in zebrafish in vivo and in human cardiac myocytes (HCMs) in vitro. Our results showed that BPAF at a concentration of 200 μg/L results in cardiotoxicity, including a reduced number of cardiomyocytes and endocardial cells in the heart, and reduced heart size in two transgenic zebrafish models (myl7:: dsred2-nuc and fli1a::nGFP). An increase in apoptosis was observed along with antioxidant enzyme inhibition and lipid peroxidation. In addition, the mRNA expression levels of several key genes involved in cardiac development were suppressed by BPAF treatment. In the HCM cell model, BPAF at 2 mg/L induced reactive oxygen species generation, antioxidant enzyme inhibition, mitochondrial dysfunction and oxidative DNA damage. These adverse outcomes can be attenuated by the antioxidant N-acetyl-L-cysteine (NAC), suggesting that oxidative stress is involved in BPAF-induced cardiotoxicity. These data indicated that BPAF exposure increased oxidative stress and apoptosis and that it suppressed the expression of genes involved in cardiac development, which may play crucial roles in the mechanisms of BPAF-induced cardiotoxicity.}, }
@article {pmid32407842, year = {2020}, author = {Luan, X and Yan, Y and Zheng, Q and Wang, M and Chen, W and Yu, J and Fang, J}, title = {Excessive reactive oxygen species induce apoptosis via the APPL1-Nrf2/HO-1 antioxidant signalling pathway in trophoblasts with missed abortion.}, journal = {Life sciences}, volume = {254}, number = {}, pages = {117781}, doi = {10.1016/j.lfs.2020.117781}, pmid = {32407842}, issn = {1879-0631}, mesh = {Abortion, Missed/*metabolism ; Adaptor Proteins, Signal Transducing/genetics/*metabolism ; Apoptosis/*physiology ; Cell Survival/drug effects ; Cells, Cultured ; Female ; Gene Knockdown Techniques ; Heme Oxygenase-1/*metabolism ; Humans ; NF-E2-Related Factor 2/*metabolism ; Pregnancy ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*physiology ; Superoxide Dismutase/metabolism ; Trophoblasts/metabolism ; }, abstract = {AIMS: Previous evidence has demonstrated that oxidative stress is related to the pathogenesis of missed abortion (MA), but the specific mechanism remains obscure. The adaptor protein APPL1 is one of the differential proteins in chorionic trophoblasts. Thus, this study aimed to assess the potential influence of APPL1 on oxidative stress responses as well the possible molecular mechanisms involving in MA.<br><br>MAIN METHODS: In the present study, the chorionic trophoblasts and the HTR-8/SVneo cell line were researched in vitro. Small interfering RNA (siRNA) was used to suppress the expression of APPL1. The fluorescent probes DHE and DCFH-DA were used to assess the intracellular reactive oxidative species (ROS). The activity of superoxide dismutase (SOD) was determined. Apoptosis was detected by TUNEL and flow cytometry. Cell viability was determined using Cell Counting Kit-8. Protein expression was detected by immunohistochemistry, western blotting, and reverse transcription-quantitative PCR.<br><br>KEY FINDINGS: The application of oxidant in normal chorionic trophoblasts induced cell death and overproduction of ROS, which was consistent with MA. In addition, knockdown of APPL1 in HTR-8/SVneo cells resulted in increased ROS and apoptosis, which could be rescued by pretreatment with antioxidants. Mechanistically, we report that overproduction of ROS in trophoblasts and disturbed SOD, APPL1 and Nrf2/HO-1 antioxidant responses constitute important contributors to apoptosis.<br><br>SIGNIFICANCE: Our results suggest that APPL1 has antioxidant properties that suppress oxidative stress and apoptosis via the Nrf2/HO-1 pathway. Moreover, antioxidant N-acetylcysteine (NAC) effectively restored the impaired antioxidative defense system elicited by excess ROS, as a potential therapeutic reagent for MA.}, }
@article {pmid32406252, year = {2021}, author = {Terlizzi, M and Colarusso, C and Di Maio, U and Pinto, A and Sorrentino, R}, title = {The combination of N-Acetyl-L-Cysteine, Pelargonium sidoides and Justicia adhatoda (NAXX) exerts bacteriostatic activity against S. aureus and E. coli.}, journal = {Natural product research}, volume = {35}, number = {23}, pages = {5360-5363}, doi = {10.1080/14786419.2020.1761359}, pmid = {32406252}, issn = {1478-6427}, mesh = {Acetylcysteine/pharmacology ; Escherichia coli ; *Justicia ; *Methicillin-Resistant Staphylococcus aureus ; *Pelargonium ; Plant Extracts/pharmacology ; Staphylococcus aureus ; }, abstract = {Many herbal agents and medicinal plants have provided clinical interest due to their therapeutic properties, availability and lower side effects. The aim of this study was to understand the anti-bacterial activity of the combination of Pelargonium sidoides (PEL), Justicia adhatoda (ADH) and N-Acetyl-L-Cysteine (NAC) (NAXX). We found that NAXX had strong and long-term bacteriostatic activity, which was related to its anti-oxidant activity. Our data demonstrate that NAXX is an innovative medicinal plant-derived strategy to manage of oxidative stress- and microbial-based diseases.}, }
@article {pmid32402895, year = {2020}, author = {Dash, M and Dey, A and Chattopadhyay, S}, title = {Mitigation of arsenic driven utero-ovarian malfunction and changes of apoptotic gene expression by dietary NAC.}, journal = {Ecotoxicology and environmental safety}, volume = {199}, number = {}, pages = {110675}, doi = {10.1016/j.ecoenv.2020.110675}, pmid = {32402895}, issn = {1090-2414}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Antioxidants/metabolism ; Apoptosis/*drug effects/genetics ; Arsenites/*toxicity ; Dietary Supplements ; Female ; Gene Expression/*drug effects ; Male ; Ovary/*drug effects/metabolism/pathology/physiopathology ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Uterus/*drug effects/metabolism/pathology/physiopathology ; }, abstract = {An oral painless dietary therapy is also indispensable in the management of arsenic toxicity despite of its conventional painful therapeutic management. The present study focused on the management of arsenic mediated female reproductive dysfunctions by dietary therapy of N-acetyl cysteine (NAC). Here, sodium arsenite was given at the dose of 10 mg/kg body weight orally for the first 8 day. Day 9 onwards up to day 16 these arsenicated rats were provided with NAC (250 mg/kg body weight) enriched basal diet once daily. Arsenic intoxicated group exhibited a comparable inactivation of antioxidant enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) due to oxidative stress in reproductive organs along with a simultaneous elevation of lipid peroxidation state and decline in non-protein soluble thiols (NPSH) level in female reproductive organs. Arsenic intoxication also accomplished with the up-regulation of inflammatory markers tumour necrosis factor (TNF α) and nuclear factor κB (NF κB). Pro-apoptotic Bax gene and p53 gene expressions were also raised due to arsenic intoxication while anti-apoptotic Bcl-2 gene expression was suppressed. In fact, arsenication decreased the circulating level of vitamin B12 and folic acid. Dietary NAC supplementation significantly reversed back the activity of antioxidant enzymes in arsenite fed rats towards normalcy and also sustained the normal reproductive cyclicity, utero-ovarian histo-morphology and estradiol receptor α (ER-α) expression in these reproductive organs. Dietary NAC exerted its positive action against arsenic intoxication by up-regulation of Bcl-2 gene expression along with the suppression of pro-apoptotic Bax gene and p53 gene. Thus, dietary NAC also plays anti-apoptotic, anti-inflammatory, and anti-oxidative role against arsenic toxicity. NAC also regulates the components (vitamin B12 and folic acid) of S-adenosylmethionine pool in the way of probable removal of arsenic from the system.}, }
@article {pmid32400335, year = {2021}, author = {Mark, K and Hyder, S and Rashid, M and Chandran, VP and Seshadri, S and Seshadri, S and Nair, S and Thunga, G}, title = {Survival Benefits of N-Acetylcysteine in Rodenticide Poisoning: Retrospective Evidence from an Indian Tertiary Care Setting.}, journal = {Current reviews in clinical and experimental pharmacology}, volume = {16}, number = {2}, pages = {201-208}, doi = {10.2174/1574884715666200513090634}, pmid = {32400335}, issn = {2772-4336}, mesh = {*Acetylcysteine/therapeutic use ; Adolescent ; Adult ; Humans ; Middle Aged ; Prospective Studies ; Retrospective Studies ; *Rodenticides ; Tertiary Healthcare ; Young Adult ; }, abstract = {RATIONALE &amp; OBJECTIVE: Rodenticide poisoning, either accidental or intentional, is very common in rural India. The absence of a definite antidote made it a major concern with a high mortality rate. Therefore, this study aimed to assess the effectiveness of N-Acetyl Cysteine (NAC) in rodenticide poisoning as there are recent positive shreds of evidence on it.<br><br>METHODOLOGY: A retrospective study was conducted in a tertiary care teaching hospital on patients admitted with rodenticide poisoning during a period of 2012-2017. The Fischer's exact test and relative risk were measured to analyze the outcome of treatment and risk factors, respectively.<br><br>RESULTS: A total of 229 patients were enrolled in the study with a mean age of 30.04 &#xb1; 15.67 years. The suicidal attack was the major (86.0%) reason for poison consumption. The survival rate was significantly (p &#x2264; 0.03) higher in the NAC treatment group compared to the non-NAC group. Moreover, the majority (93.4%) of participants did not experience any adverse effects. The mean oral loading dose and maintenance dose was 7580.95 &#xb1; 2204.29 mg and 3694.53 &#xb1; 2322.58 mg, respectively. Yellow Phosphorus poisoning (Relative Risk [RR] 2.888 (1.179-7.079); p=0.020) and Time lag of &#x2265; 24 hours (RR 3.479 (1.137-10.645); p=0.029) were the significant risk factors for mortality.<br><br>CONCLUSION: NAC is shown to have a significant survival benefit with a good safety profile among rodenticide poisoners. Further adequately powered prospective researches with more emphasis on dosing parameters are warranted for better quantification in different settings and for clinical implementation.}, }
@article {pmid32398966, year = {2020}, author = {Wang, SY and Ni, X and Hu, KQ and Meng, FL and Li, M and Ma, XL and Meng, TT and Wu, HH and Ge, D and Zhao, J and Li, Y and Su, GH}, title = {Cilostazol alleviate nicotine induced cardiomyocytes hypertrophy through modulation of autophagy by CTSB/ROS/p38MAPK/JNK feedback loop.}, journal = {International journal of biological sciences}, volume = {16}, number = {11}, pages = {2001-2013}, pmid = {32398966}, issn = {1449-2288}, mesh = {Animals ; Bronchodilator Agents/pharmacology ; Cathepsin B/genetics/*metabolism ; Cilostazol/*pharmacology ; Gene Expression Regulation/drug effects ; MAP Kinase Kinase 4/genetics/metabolism ; Myocytes, Cardiac/*drug effects ; Nicotine/*toxicity ; Nicotinic Agonists/toxicity ; Proto-Oncogene Proteins/genetics/*metabolism ; Rats ; Receptor Protein-Tyrosine Kinases/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Nicotine is proved to be an important factor for cardiac hypertrophy. Autophagy is important cell recycling system involved in the regulation of cardiac hypertrophy. Cilostazol, which is often used in the management of peripheral vascular disease. However, the effects of cilostazol on nicotine induced autophagy and cardiac hypertrophy are unclear. Here, we aim to determine the role and molecular mechanism of cilostazol in alleviating nicotine-induced cardiomyocytes hypertrophy through modulating autophagy and the underlying mechanisms. Our results clarified that nicotine stimulation caused cardiomyocytes hypertrophy and autophagy flux impairment significantly in neonatal rat ventricular myocytes (NRVMs), which were evidenced by augments of LC3-II and p62 levels, and impaired autophagosomes clearance. Interestingly, cathepsin B (CTSB) activity decreased dramatically after stimulation with nicotine in NRVMs, which was crucial for substrate degradation in the late stage of autophagy process, and cilostazol could reverse this effect dramatically. Intracellular ROS levels were increased significantly after nicotine exposure. Meanwhile, p38MAPK and JNK were activated after nicotine treatment. By using ROS scavenger N-acetyl-cysteine (NAC) could reverse the effects of nicotine by down-regulation the phosphorylation of p38MAPK and JNK pathways, and pretreatment of specific inhibitors of p38MAPK and JNK could restore the autophagy impairment and cardiomyocytes hypertrophy induced by nicotine. Moreover, CTSB activity of lysosome regained after the treatment with cilostazol. Cilostazol also inhibited the ROS accumulation and the activation of p38MAPK and JNK, which providing novel connection between lysosome CTSB and ROS/p38MAPK/JNK related oxidative stress pathway. This is the first demonstration that cilostazol could alleviate nicotine induced cardiomyocytes hypertrophy through restoration of autophagy flux by activation of CTSB and inhibiting ROS/p38/JNK pathway, exhibiting a feedback loop on regulation of autophagy and cardiomyocytes hypertrophy.}, }
@article {pmid32394901, year = {2021}, author = {Ma, M and Wu, CJ and Zhang, P and Li, T and Wei, SZ and Yu, BT and Qin, F and Yuan, JH}, title = {N-acetylcysteine maintains penile length and erectile function in bilateral cavernous nerve crush rat model by reducing penile fibrosis.}, journal = {Asian journal of andrology}, volume = {23}, number = {2}, pages = {215-221}, pmid = {32394901}, issn = {1745-7262}, mesh = {Acetylcysteine/*pharmacology ; Actins/drug effects/metabolism ; Animals ; Collagen/drug effects/metabolism ; Crush Injuries/*metabolism/pathology/physiopathology ; Disease Models, Animal ; Erectile Dysfunction/prevention &amp; control ; Fibrosis ; Free Radical Scavengers/*pharmacology ; Glutathione/drug effects/metabolism ; Glutathione Peroxidase/drug effects/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Nitric Oxide Synthase Type III/drug effects/metabolism ; Organ Size ; Penile Erection/*drug effects ; Penis/*drug effects/innervation/pathology ; Peripheral Nerve Injuries/*metabolism/pathology/physiopathology ; Postoperative Complications/prevention &amp; control ; Prostatectomy ; Prostatic Neoplasms/surgery ; Protein-Lysine 6-Oxidase/drug effects/metabolism ; Rats ; Transforming Growth Factor beta1/drug effects/metabolism ; Glutathione Peroxidase GPX1 ; }, abstract = {Penile length shortening and erectile dysfunction are common complications after radical prostatectomy. Various methods have been used to maintain erectile function, but less attention has been paid to preserving penis length. N-acetylcysteine (NAC) has the effect of antioxidation and antifibrotic, which may be beneficial to improve those postoperative complications. This study investigated the effect of NAC on maintaining the penile length and the erectile function after bilateral cavernous nerve crush (BCNC) and its underlying mechanism. Twenty-four male rats were randomly divided into three groups: control group, BCNC group, and BCNC + NAC group. NAC or equal volume of saline was daily administrated by intragastric gavage for 4 weeks. The initial and end penile lengths were measured. Intracavernosal pressure/mean arterial pressure (ICP/MAP) ratio was calculated to assess erectile function. Hematoxylin-eosin staining, Masson's trichrome staining, immunohistochemistry, and Western blot were performed to explore cellular and molecular changes of the penis. Compared to the BCNC group, the penile length, ICP/MAP ratio and smooth muscle/collagen ratio in the BCNC + NAC group were improved significantly (all P < 0.05), and the expressions of endothelial nitric oxide synthase, α-smooth muscle actin, glutathione, and glutathione peroxidase 1 were significantly increased after NAC treated (all P < 0.05), along with the decreased expressions of hypoxia-inducible factor-1α, transforming growth factor-β1, collagen I, collagen III, collagen IV, malonaldehyde, and lysine oxidase (all P < 0.05). This study demonstrated that NAC could maintain penile length and partly improve erectile function. Possible mechanism is directly and/or indirectly related to antihypoxic and antifibrosis.}, }
@article {pmid32392918, year = {2020}, author = {Jun, S and Kim, SW and Kim, B and Chang, IY and Park, SJ}, title = {Oncogenic Ras downregulates mdr1b expression through generation of reactive oxygen species.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {24}, number = {3}, pages = {267-276}, pmid = {32392918}, issn = {1226-4512}, abstract = {In the present study, we investigated the effect of oncogenic H-Ras on rat mdr1b expression in NIH3T3 cells. The constitutive expression of H-Ras[V12] was found to downregulate the mdr1b promoter activity and mdr1b mRNA expression. The doxorubicin-induced mdr1b promoter activity of the H-Ras[V12] expressing NIH3T3 cells was markedly lower than that of control NIH3T3 cells. Additionally, there is a positive correlation between the level of H-Ras[V12] expression and a sensitivity to doxorubicin toxicity. To examine the detailed mechanism of H-Ras[V12]-mediated down-regulation of mdr1b expression, antioxidant N-acetylcysteine (NAC) and NADPH oxidase inhibitor diphenylene iodonium (DPI) were used. Pretreating cells with either NAC or DPI significantly enhanced the oncogenic H-Ras-mediated down-regulation of mdr1b expression and markedly prevented doxorubicin-induced cell death. Moreover, NAC and DPI treatment led to a decrease in ERK activity, and the ERK inhibitors PD98059 or U0126 enhanced the mdr1b-Luc activity of H-Ras[V12]-NIH3T3 and reduced doxorubicin-induced apoptosis. These data suggest that Ras[V12] expression could downregulate mdr1b expression through intracellular reactive oxygen species (ROS) production, and ERK activation induced by ROS, is at least in part, contributed to the downregulation of mdr1b expression.}, }
@article {pmid32390631, year = {2020}, author = {Andrade, V and Cortés, N and Pastor, G and Gonzalez, A and Ramos-Escobar, N and Pastene, E and Rojo, LE and Maccioni, RB}, title = {N-Acetyl Cysteine and Catechin-Derived Polyphenols: A Path Toward Multi-Target Compounds Against Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {75}, number = {4}, pages = {1219-1227}, doi = {10.3233/JAD-200067}, pmid = {32390631}, issn = {1875-8908}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Animals ; Catechin/*administration &amp; dosage ; Cell Line, Tumor ; Cysteine/*administration &amp; dosage ; Drug Discovery ; Mice ; Neurons/*drug effects/*metabolism ; Polyphenols/*administration &amp; dosage ; tau Proteins/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial disease, that involves neuroinflammatory processes in which microglial cells respond to "damage signals". The latter includes oligomeric tau, iron, oxidative free radicals, and other molecules that promotes neuroinflammation in the brain, promoting neuronal death and cognitive impairment. Since AD is the first cause of dementia in the elderly, and its pharmacotherapy has limited efficacy, novel treatments are critical to improve the quality of life of AD patients. Multitarget therapy based on nutraceuticals has been proposed as a promising intervention based on evidence from clinical trials. Several studies have shown that epicatechin-derived polyphenols from tea improve cognitive performance; also, the polyphenol molecule N-acetylcysteine (NAC) promotes neuroprotection.<br><br>OBJECTIVE: To develop an approach for a rational design of leading compounds against AD, based on specific semisynthetic epicatechin and catechin derivatives.<br><br>METHODS: We evaluated tau aggregation in vitro and neuritogenesis by confocal microscopy in mouse neuroblastoma cells (N2a), after exposing cells to either epicatechin-pyrogallol (EPIC-PYR), catechin-pyrogallol (CAT-PYR), catechin-phloroglucinol (CAT-PhG), and NAC.<br><br>RESULTS: We found that EPIC-PYR, CAT-PYR, and CAT-PhG inhibit human tau aggregation and significantly increase neuritogenesis in a dose-dependent manner. Interestingly, modification with a phloroglucinol group yielded the most potent molecule of those evaluated, suggesting that the phloroglucinol group may enhance neuroprotective activity of the catechin-derived compounds. Also, as observed with cathechins, NAC promotes neuritogenesis and inhibits tau self-aggregation, possibly through a different pathway.<br><br>CONCLUSION: EPIC-PYR, CAT-PYR, CAT-PhG, and NAC increased the number of neurites in Na2 cell line and inhibits tau-self aggregation in vitro.}, }
@article {pmid32380989, year = {2020}, author = {Shi, H and Yin, D and Bonella, F and Kreuter, M and Oltmanns, U and Li, X and Peng, S and Wei, L}, title = {Efficacy, safety, and tolerability of combined pirfenidone and N-acetylcysteine therapy: a systematic review and meta-analysis.}, journal = {BMC pulmonary medicine}, volume = {20}, number = {1}, pages = {128}, pmid = {32380989}, issn = {1471-2466}, support = {NO.15JCZDJC3500//Natural Science Foundation of Tianjin City/ ; }, mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/adverse effects ; Administration, Inhalation ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage ; Carbon Monoxide/blood ; Drug Therapy, Combination ; Free Radical Scavengers/administration &amp; dosage ; *Idiopathic Pulmonary Fibrosis/drug therapy/physiopathology ; *Pyridones/administration &amp; dosage/adverse effects ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND: While antifibrotic drugs significantly decrease lung function decline in idiopathic pulmonary fibrosis (IPF), there is still an unmet need to halt disease progression. Antioxidative therapy with N-acetylcysteine (NAC) is considered a potential additional therapy that can be combined with antifibrotics in some patients in clinical practice. However, data on the efficacy, tolerability, and safety of this combination are scarce. We performed a systematic review and meta-analysis to appraise the safety, tolerability, and efficacy of the combination compared to treatment with pirfenidone alone.<br><br>METHODS: We systematically reviewed all the published studies with combined pirfenidone (PFD) and NAC (PFD&#x2009;+&#x2009;NAC) treatment in IPF patients. The primary outcomes referred to decline in pulmonary function tests (PFTs) and the rates of IPF patients with side effects.<br><br>RESULTS: In the meta-analysis, 6 studies with 319 total IPF patients were included. The PFD&#x2009;+&#x2009;NAC group was comparable to the PFD alone group in terms of the predicted forced vital capacity (FVC%) and predicted diffusion capacity for carbon monoxide (DLco%) from treatment start to week 24. Side effects and treatment discontinuation rates were also comparable in both groups.<br><br>CONCLUSION: This systematic review and meta-analysis suggests that combination with NAC does not alter the efficacy, safety, or tolerability of PFD in comparison to PFD alone in IPF patients.}, }
@article {pmid32380695, year = {2020}, author = {Hsu, SM and Yang, CH and Teng, YT and Tsai, HY and Lin, CY and Lin, CJ and Shieh, CC and Chen, SH}, title = {Suppression of the Reactive Oxygen Response Alleviates Experimental Autoimmune Uveitis in Mice.}, journal = {International journal of molecular sciences}, volume = {21}, number = {9}, pages = {}, pmid = {32380695}, issn = {1422-0067}, support = {NCKUH-10103009, NCKUH-10203017, NCKUH-10408004//National Cheng Kung University Hospital/ ; }, mesh = {Animals ; Autoimmune Diseases/genetics/*immunology/*metabolism/pathology ; Biomarkers ; Cytokines/metabolism ; Disease Models, Animal ; Disease Susceptibility ; Gene Expression ; Inflammation Mediators/metabolism ; Mice ; Mice, Knockout ; NADPH Oxidases/genetics/metabolism ; NF-kappa B/metabolism ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Retina/immunology/metabolism ; Spleen/immunology/metabolism ; Uveitis/*etiology/*metabolism/pathology ; }, abstract = {Reactive oxygen species (ROS) are produced by host phagocytes and play an important role in antimicrobial actions against various pathogens. Autoimmune uveitis causes blindness and severe visual impairment in humans at all ages worldwide. However, the role of ROS in autoimmune uveitis remains unclear. We used ROS-deficient (Ncf1[-/-]) mice to investigate the role of ROS in experimental autoimmune uveitis (EAU). Besides, we also used the antioxidant N-acetylcysteine (NAC) treatment to evaluate the effect of suppression of ROS on EAU in mice. The EAU disease scores of Ncf1[-/-] mice were significantly lower than those of wild-type mice. EAU induction increased the levels of cytokines (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-12, IL-17, and tumor necrosis factor (TNF)-α) and chemokines (monocyte chemoattractant protein (MCP)-1) in the retinas of wild-type mice but not in those of Ncf1[-/-] mice. EAU induction enhanced the level of NF-κB activity in wild-type mice. However, the level of NF-κB activity in Ncf1[-/-] mice with EAU induction was low. Treatment with the antioxidant NAC also decreased the severity of EAU in mice with reduced levels of oxidative stress, inflammatory mediators, and NF-κB activation in the retina. We successfully revealed a novel role of ROS in the pathogenesis of EAU and suggest a potential antioxidant role for the treatment of autoimmune uveitis in the future.}, }
@article {pmid32376314, year = {2020}, author = {Rabaça, A and Ferreira, C and Bernardino, R and Alves, M and Oliveira, P and Viana, P and Barros, A and Sousa, M and Sá, R}, title = {Use of antioxidant could ameliorate the negative impact of etoposide on human sperm DNA during chemotherapy.}, journal = {Reproductive biomedicine online}, volume = {40}, number = {6}, pages = {856-866}, doi = {10.1016/j.rbmo.2020.01.029}, pmid = {32376314}, issn = {1472-6491}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/*pharmacology ; *DNA ; DNA Damage/*drug effects ; DNA Fragmentation/drug effects ; Etoposide/*pharmacology ; Humans ; Male ; Oxidative Stress/*drug effects ; Semen Analysis ; Semen Preservation ; Spermatozoa/*drug effects ; }, abstract = {RESEARCH QUESTION: A previous study showed that N-acetylcysteine (NAC), used after in-vitro exposure to the gonadotoxic chemotherapeutic drug etoposide, has the ability to decrease DNA damage in human spermatozoa; however, it showed no benefit when used before exposure. This study aimed to evaluate the impact of the NAC on the preservation of sperm quality during in-vitro exposure to etoposide.<br><br>DESIGN: Twenty semen samples were submitted to four experimental conditions: control, NAC-only incubation, etoposide-only incubation, and concomitant etoposide and NAC incubation. After in-vitro incubation, semen parameters, sperm chromatin condensation, sperm DNA fragmentation, sperm oxidative stress and sperm metabolism were used to evaluate the role of NAC in protecting human spermatozoa from etoposide.<br><br>RESULTS: Etoposide did not affect semen parameters, nor did it cause sperm oxidative damage or alterations in glycolytic profile. However, it induced chromatin decondensation and DNA fragmentation, which were fully prevented by NAC.<br><br>CONCLUSIONS: NAC was able to protect sperm DNA integrity during etoposide treatment in vitro, suggesting that NAC may be useful as an adjuvant agent in preserving male fertility during chemotherapy treatments.}, }
@article {pmid32372158, year = {2020}, author = {Efendioglu, M and Basaran, R and Akca, M and Ceman, D and Demirtas, C and Yildirim, M}, title = {Combination Therapy of Gabapentin and N-Acetylcysteine Against Posttraumatic Epilepsy in Rats.}, journal = {Neurochemical research}, volume = {45}, number = {8}, pages = {1802-1812}, doi = {10.1007/s11064-020-03042-x}, pmid = {32372158}, issn = {1573-6903}, mesh = {Acetylcysteine/*therapeutic use ; Adjuvants, Pharmaceutic/therapeutic use ; Animals ; Anticonvulsants/*therapeutic use ; Antioxidants/therapeutic use ; Brain Concussion/complications/*drug therapy ; Drug Combinations ; Epilepsy, Post-Traumatic/*drug therapy/epidemiology ; Gabapentin/*therapeutic use ; Levetiracetam/therapeutic use ; Male ; Rats, Sprague-Dawley ; }, abstract = {Traumatic brain injury (TBI) is a major public health problem worldwide that is associated with increased mortality and morbidity. Posttraumatic epilepsy (PTE) is one of the sequelae of TBI. The aim of this study was to investigate the role of N-acetylcysteine (NAC) as an adjuvant on the efficacy of levetiracetam (LEV) and gabapentin (GBP) in PTE model encouraged by pentylenetetrazol (PTZ) after mild-TBI in male Sprague-Dawley rats. Mild-TBI was performed by the weight-drop method in male Sprague-Dawley rats. PTE model was developed by injecting PTZ (30+15+15 mg/kg, 30 min intervals, i.p.) 7 days after head trauma. After the development of posttraumatic seizures, the rats were treated with NAC (100 mg/kg), LEV (50 mg/kg), GBP (100 mg/kg), NAC+LEV and NAC+GBP intraperitoneally for 14 days. Seizures related to PTE were scored by video-EEG recording. Motor performance of the animals was also evaluated in the rotarod test. 50 mg/kg LEV and 100 mg/kg GBP reduced seizures related to PTE. LEV alone (p = 0.009), but the administration of GBP+NAC (p = 0.015) was more effective on PTE-related seizure control. However, GBP+NAC application adversely affected the fall latency in the rotarod test. In terms of trauma-related seizure control, there was no statistically significant difference between the use of prophylactic LEV and symptomatic LEV. LEV alone or the combination of GBP with NAC provides more effective seizure control in the PTE facilitated by PTZ. On the other hand, the use of prophylactic LEV did not have any extra effect on posttraumatic seizure development and control.}, }
@article {pmid32365393, year = {2020}, author = {Lang, X and Zhang, X and Wang, D and Zhou, W}, title = {In Vitro and In Vivo Metabolic Activation of Obacunone, A Bioactive and Potentially Hepatotoxic Constituent of Dictamni Cortex.}, journal = {Planta medica}, volume = {86}, number = {10}, pages = {686-695}, doi = {10.1055/a-1152-8169}, pmid = {32365393}, issn = {1439-0221}, support = {National Natural Science Foundation of China//Grant No.&#x2009;81573214/ ; }, mesh = {Activation, Metabolic ; *Aldehydes ; Animals ; Benzoxepins ; China ; Chromatography, High Pressure Liquid ; Glutathione ; Humans ; Limonins ; *Microsomes, Liver ; Rats ; }, abstract = {Obacunone is one of the major bioactive constituents from Dictamni cortex, a traditional Chinese medicine widely used in China. Oral administration of obacunone or Dictamni cortex extract has been shown to cause liver injury in rats. Given that obacunone contains a furan ring, which is a structural alert, metabolic activation might be responsible for obacunone-induced liver injury. In this study, bioactivation pathways of obacunone in rat and human liver microsomes were investigated. Obacunone was first metabolized into cis-butene-1,4-dial, and then cis-butene-1,4-dial was captured by glutathione, N-acetyl-cysteine, and N-acetyl-lysine in the microsomal incubation system. A total of 13 adducts derived from the reaction of cis-butene-1,4-dial with glutathione and/or N-acetyl-lysine were detected and structurally identified by liquid chromatography coupled to high-resolution tandem mass spectrometry. The major metabolite (M7) was identified to be the cyclic mono-glutathione conjugate of cis-butene-1,4-dial, which was detected in bile and urine of obacunone-treated rats. M9 and M10, obacunone-derived glutathione-cis-butene-1,4-dial-NAL conjugates, were detected in the microsomal incubations of obacunone fortified with glutathione and N-acetyl-lysine as trapping agents. M3 and M4, pyrroline-2-one derivatives, were also detected in microsomal incubations. Further phenotyping studies indicated that ketoconazole showed a strong inhibitory effect on the production of cis-butene-1,4-dial in a concentration-dependent manner. CYP3A4 was demonstrated to be the primary enzyme responsible for the bioactivation of obacunone by using individual recombinant human CYP450 enzymes. The current study provides an overview of CYP450-dominated bioactivation of obacunone and contributes to the understanding of the role of bioactivation in obacunone-induced liver injury.}, }
@article {pmid32365223, year = {2020}, author = {Namdeo, M and Kandel, R and Thakur, PK and Mohan, A and Dey, AB and Mitra, DK}, title = {Old age-associated enrichment of peripheral T regulatory cells and altered redox status in pulmonary tuberculosis patients.}, journal = {European journal of immunology}, volume = {50}, number = {8}, pages = {1195-1208}, doi = {10.1002/eji.201948261}, pmid = {32365223}, issn = {1521-4141}, support = {5/8/5/26/2011-ECD//Indian Council of Medical Research/International ; 3/1/3/JRF-2009/MPD-103//Indian Council of Medical Research/International ; }, mesh = {Acetylcysteine/pharmacology ; Adolescent ; Adult ; Age Factors ; Aged ; Cytokines/analysis/physiology ; Female ; Humans ; Male ; Middle Aged ; Oxidation-Reduction ; Oxidative Stress ; Programmed Cell Death 1 Receptor/physiology ; T-Lymphocytes, Regulatory/*immunology ; Th1 Cells/immunology ; Transforming Growth Factor beta/physiology ; Tuberculosis, Pulmonary/*immunology/metabolism ; Young Adult ; }, abstract = {Aging influences the susceptibility and prognosis to various infectious diseases including tuberculosis (TB). Despite the impairment of T-cell function and immunity in older individuals, the mechanism for the higher incidence of TB in the elderly remains largely unknown. Here, we evaluated the age-associated immune alterations, particularly in effector and Treg responses in pulmonary TB patients. We also evaluated the impact of redox status and its modulation with N-acetyl-cysteine (NAC) in elderly TB. Higher frequency of Treg cells and reduced IFN-γ positive T cells were observed among older TB patients. The elevated number of Treg cells correlated tightly with bacillary load (i.e. disease severity); which declined significantly in response to successful anti-tubercular treatment. We could rescue Myobacterium tuberculosis-specific effector T cell (Th1) responses through various in vitro approaches, for example, Treg cell depletion and co-culture experiments, blocking experiments using antibodies against IL-10, TGF-β, and programmed death-1 (PD-1) as well as NAC supplementation. We report old age-associated enrichment of Treg cells and suppression of M. tuberculosis-specific effector T (Th1) cell immune responses. Monitoring these immune imbalances in older patients may assist in immune potentiation through selectively targeting Treg cells and/or optimizing redox status by NAC supplementation.}, }
@article {pmid32364634, year = {2020}, author = {Dasari, S and Bakthavachalam, V and Chinnapaka, S and Venkatesan, R and Samy, ALPA and Munirathinam, G}, title = {Neferine, an alkaloid from lotus seed embryo targets HeLa and SiHa cervical cancer cells via pro-oxidant anticancer mechanism.}, journal = {Phytotherapy research : PTR}, volume = {34}, number = {9}, pages = {2366-2384}, pmid = {32364634}, issn = {1099-1573}, support = {P50 AT000155/AT/NCCIH NIH HHS/United States ; R03 CA212890/CA/NCI NIH HHS/United States ; R03 CA230829/CA/NCI NIH HHS/United States ; R03 CA212890-01A1//National Institute of Health/ ; R03 CA227218/CA/NCI NIH HHS/United States ; R03 CA227218//National Institute of Health/ ; R03 CA230829//National Institute of Health/ ; P50 AT 000155//UIC-NIH Botanical Center Pilot/ ; }, mesh = {Apoptosis/*drug effects ; Benzylisoquinolines/*chemistry ; Biological Products/*chemistry ; Cell Line, Tumor ; Female ; HeLa Cells/*drug effects ; Humans ; Lotus/*chemistry ; Seeds/*chemistry ; Transfection ; Tumor Protein, Translationally-Controlled 1 ; Uterine Cervical Neoplasms/*drug therapy ; }, abstract = {Apoptosis and autophagy are important processes that control cellular homeostasis and have been highlighted as promising targets for novel anticancer drugs. This study aims to investigate the inhibitory effects and mechanisms of Neferine (Nef), an alkaloid from the lotus seed embryos of Nelumbo nucifera (N. nucifera), as a dual inducer of apoptosis and autophagy through the reactive oxygen species (ROS) activation in cervical cancer cells. Nef and N. nucifera extract suppressed the cell viability of HeLa and SiHa cells in a dose-dependent manner. Importantly, Nef showed minimal toxicity to normal cells. Furthermore, Nef inhibited anchorage-independent growth, colony formation and migration ability of cervical cancer cells. Nef induces mitochondrial apoptosis by increasing pro-apoptotic protein bax, cytochrome-c, cleaved caspase-3 and caspase-9, poly-ADP ribose polymerase (PARP) cleavage, DNA damage (pH2 AX) while downregulating Bcl-2, procaspase-3 and procaspase-9, and TCTP. Of note, apoptotic effect by Nef was significantly attenuated in the presence of N-acetylcysteine (NAC), suggesting pro-oxidant activity of this compound. Nef also promoted autophagy induction through increasing beclin-1, atg-4, atg-5 and atg-12, LC-3 activation, and P 62/SQSTM1 as determined by western blot analysis. Collectively, these results demonstrate that Nef is a potent anticancer compound against cervical cancer cells through inducing apoptosis and autophagic pathway involving ROS.}, }
@article {pmid32363384, year = {2020}, author = {Manoharan, A and Das, T and Whiteley, GS and Glasbey, T and Kriel, FH and Manos, J}, title = {The effect of N-acetylcysteine in a combined antibiofilm treatment against antibiotic-resistant Staphylococcus aureus.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {75}, number = {7}, pages = {1787-1798}, doi = {10.1093/jac/dkaa093}, pmid = {32363384}, issn = {1460-2091}, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/pharmacology ; Australia ; Biofilms ; *Methicillin-Resistant Staphylococcus aureus ; Microbial Sensitivity Tests ; *Staphylococcus aureus ; }, abstract = {BACKGROUND: The WHO declared Staphylococcus aureus as a 'pathogen of high importance' in 2017. One-fifth of all bloodstream-related infections in Australia and 12 000 cases of bacteraemia in the UK (2017-18) were caused by the MRSA variant. To address the need for novel therapies, we investigated several permutations of an innovative combination therapy containing N-acetylcysteine (NAC), an antibiotic and an enzyme of choice in eradicating MRSA and MSSA biofilms.<br><br>METHODS: Biofilm viability (resazurin assay) and colony count methods were used to investigate the effect of NAC, antibiotics and enzymes on S. aureus biofilm disruption and killing. The effects of NAC and enzymes on the polysaccharide content of biofilm matrices were analysed using the phenol/sulphuric acid method and the effect of NAC on DNA cleavage was determined using the Qubit fluorometer technique. Changes in biofilm architecture when subjected to NAC and enzymes were visualized using confocal laser scanning microscopy (CLSM).<br><br>RESULTS: NAC alone displayed bacteriostatic effects when tested on planktonic bacterial growth. Combination treatments containing 30&#x2009;mM NAC resulted in &#x2265;90% disruption of biofilms across all MRSA and MSSA strains with a 2-3 log10 decrease in cfu/mL in treated biofilms. CLSM showed that NAC treatment drastically disrupted S. aureus biofilm architecture. There was also reduced polysaccharide production in MRSA biofilms in the presence of NAC.<br><br>CONCLUSIONS: Our results indicate that inclusion of NAC in a combination treatment is a promising strategy for S. aureus biofilm eradication. The intrinsic acidity of NAC was identified as key to maximum biofilm disruption and degradation of matrix components.}, }
@article {pmid32362998, year = {2020}, author = {Kyakulaga, AH and Aqil, F and Munagala, R and Gupta, RC}, title = {Synergistic combinations of paclitaxel and withaferin A against human non-small cell lung cancer cells.}, journal = {Oncotarget}, volume = {11}, number = {16}, pages = {1399-1416}, pmid = {32362998}, issn = {1949-2553}, abstract = {Platinum-taxane combination chemotherapy still represents the standard of care for advanced non-small cell lung cancer (NSCLC) with no targetable driver mutations. However, the efficacy of these drugs has plateaued at 10-14 months primarily due to dose-limiting toxicity, chemoresistance, and metastasis. Here, we explored the effects of withaferin A (WFA) alone and in combination with paclitaxel (PAC) on the growth, proliferation, migration, and invasion of human NSCLC cells. We show that the sensitivity of H1299 and A549 cells to concomitant treatment with PAC and WFA was greater than that of either PAC or WFA alone. Using the combination index and dose-reduction index, we demonstrated that various combinations (1:40, 1:20, 1:10) of PAC to WFA, respectively, were highly synergistic. In addition, PAC+WFA co-treatment synergistically inhibited colony formation, migration, invasion and increased the induction of apoptosis in H1299 and A549 cells. Interestingly, the synergism of PAC and WFA was not schedule-dependent but was enhanced when cells were pretreated with WFA indicating a chemo-sensitizing effect. Importantly, WFA was active against both PAC-sensitive (TS-A549) and PAC-resistant (TR-A549) cells both in vitro and in vivo. Mechanistically, WFA inhibits the proliferation of NSCLC cells via thiol oxidation. The effects of WFA were inhibited in the presence of N-acetyl cysteine and other thiol donors. Taken together, our results demonstrate the efficacy of WFA alone or alongside PAC on NSCLC cells and provide a strong rationale for further detailed testing in clinically relevant models for the development of PAC+WFA combination as an alternative therapeutic strategy for advanced NSCLC.}, }
@article {pmid32362877, year = {2020}, author = {Žiemytė, M and Rodríguez-Díaz, JC and Ventero, MP and Mira, A and Ferrer, MD}, title = {Effect of Dalbavancin on Staphylococcal Biofilms When Administered Alone or in Combination With Biofilm-Detaching Compounds.}, journal = {Frontiers in microbiology}, volume = {11}, number = {}, pages = {553}, pmid = {32362877}, issn = {1664-302X}, abstract = {Microorganisms grown in biofilms are more resistant to antimicrobial treatment and immune system attacks compared to their planktonic forms. In fact, infections caused by biofilm-forming Staphylococcus aureus and Staphylococcus epidermidis are a large threat for public health, including patients with medical devices. The aim of the current manuscript was to test the effect of dalbavancin, a recently developed lipoglycopeptide antibiotic, alone or in combination with compounds contributing to bacterial cell disaggregation, on staphylococcal biofilm formation and elimination. We used real-time impedance measurements in microtiter plates to study biofilm growth dynamics of S. aureus and S. epidermidis strains, in the absence or presence of dalbavancin, linezolid, vancomycin, cloxacillin, and rifampicin. Further experiments were undertaken to check whether biofilm-detaching compounds such as N-acetylcysteine (NAC) and ficin could enhance dalbavancin efficiency. Real-time dose-response experiments showed that dalbavancin is a highly effective antimicrobial, preventing staphylococcal biofilm formation at low concentrations. Minimum biofilm inhibitory concentrations were up to 22 higher compared to standard E-test values. Dalbavancin was the only antimicrobial that could halt new biofilm formation on established biofilms compared to the other four antibiotics. The addition of NAC decreased dalbavancin efficacy while the combination of dalbavancin with ficin was more efficient than antibiotic alone in preventing growth once the biofilm was established. Results were confirmed by classical biofilm quantification methods such as crystal violet (CV) staining and viable colony counting. Thus, our data support the use of dalbavancin as a promising antimicrobial to treat biofilm-related infections. Our data also highlight that synergistic and antagonistic effects between antibiotics and biofilm-detaching compounds should be carefully tested in order to achieve an efficient treatment that could prevent both biofilm formation and disruption.}, }
@article {pmid32361974, year = {2020}, author = {Sun, S and Ji, Z and Fu, J and Wang, XF and Zhang, LS}, title = {Endosulfan induces endothelial inflammation and dysfunction via IRE1α/NF-κB signaling pathway.}, journal = {Environmental science and pollution research international}, volume = {27}, number = {21}, pages = {26163-26171}, doi = {10.1007/s11356-020-09023-5}, pmid = {32361974}, issn = {1614-7499}, mesh = {Endoplasmic Reticulum Chaperone BiP ; Endoribonucleases ; *Endosulfan ; Humans ; Inflammation ; Inositol ; *NF-kappa B ; Protein Serine-Threonine Kinases ; Reactive Oxygen Species ; Signal Transduction ; Tumor Necrosis Factor-alpha ; }, abstract = {Cardiovascular diseases are related to vascular endothelial cell injury; our previous studies showed that endosulfan could cause hypercoagulation of blood by inducing endothelial cell injury. To clarify the mechanism of it, we treated human umbilical vein endothelial cells (HUVECs) with 0, 1, 5, and 10 μg/mL endosulfan, while in the inhibition groups, reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC, 3 mmol) and endoplasmic reticulum (ER) stress inhibitor (STF-083010, 10 μmol) were incubated prior to endosulfan. The results showed that endosulfan could induce inflammatory response and dysfunction by increasing the release of inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and endothelin-1 (ET-1), and inducing ROS production in HUVECs. We also found that endosulfan could cause ER damage, remarkably increase the expressions of inositol-requiring enzyme 1α (IRE1α), phosphorylated IRE1α (p-IRE1α), GRP78, XBP1, nuclear factor-kappa B (NF-κB), and phosphorylated NF-κB (p-NF-κB) in HUVECs. The presence of NAC antagonized the ROS production, expressions of IRE1α and p-IRE1α; however, STF-083010 could decrease the expression levels of GRP78, XBP1, NF-κB, and p-NF-κB and attenuate IL-1β, IL-6, TNF-α, VCAM-1, and ET-1 release induced by endosulfan. These results demonstrated that endosulfan-induced endothelial inflammation and dysfunction through the IRE1α/NF-κB signaling pathway may be triggered by oxidative stress. The study provided experimental basis for the correlation between environmental pollutants (endosulfan) and cardiovascular diseases.}, }
@article {pmid32361680, year = {2020}, author = {Rajasekaran, NS and Shelar, SB and Jones, DP and Hoidal, JR}, title = {Reductive stress impairs myogenic differentiation.}, journal = {Redox biology}, volume = {34}, number = {}, pages = {101492}, pmid = {32361680}, issn = {2213-2317}, support = {R01 HL118067/HL/NHLBI NIH HHS/United States ; R03 AG042860/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cell Differentiation ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Mice ; *Muscle Development ; Muscle, Skeletal/metabolism ; *NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Myo-satellite cells regenerate and differentiate into skeletal muscle (SM) after acute or chronic injury. Changes in the redox milieu towards the oxidative arm at the wound site are known to compromise SM regeneration. Recently, we reported that abrogation of Nrf2/antioxidant signaling promotes oxidative stress and impairs SM regeneration in C57/Bl6 mice. Here, we investigated whether the activation of intracellular Nrf2 signaling favors antioxidant transcription and promotes myoblast differentiation. Satellite cell-like C2C12 myoblasts were treated with sulforaphane (SF; 1.0 &amp; 5.0 μM) to activate Nrf2/antioxidant signaling during proliferation and differentiation (i.e. formation of myotubes/myofibers). SF-mediated Nrf2 activation resulted in increased expression of Nrf2-antioxidants (e.g. GCLC and G6PD) and augmented the production of reduced glutathione (GSH) leading to a reductive redox state. Surprisingly, this resulted in significant inhibition of myoblast differentiation, as observed from morphological changes and reduced expression of MyoD, Pax7, and Myh2, due to reductive stress (RS). Furthermore, supplementation of N-acetyl-cysteine (NAC) or GSH-ester or genetic knock-down of Keap1 (using siRNA) also resulted in RS-driven inhibition of differentiation. Interestingly, withdrawing Nrf2 activation rescued differentiation potential and formation of myotubes/myofibers from C2C12 myoblasts. Thus, abrogation of physiological ROS signaling through over-activation of Nrf2 (i.e. RS) and developing RS hampers differentiation of muscle satellite cells.}, }
@article {pmid32360615, year = {2020}, author = {Aparicio-Trejo, OE and Avila-Rojas, SH and Tapia, E and Rojas-Morales, P and León-Contreras, JC and Martínez-Klimova, E and Hernández-Pando, R and Sánchez-Lozada, LG and Pedraza-Chaverri, J}, title = {Chronic impairment of mitochondrial bioenergetics and β-oxidation promotes experimental AKI-to-CKD transition induced by folic acid.}, journal = {Free radical biology &amp; medicine}, volume = {154}, number = {}, pages = {18-32}, doi = {10.1016/j.freeradbiomed.2020.04.016}, pmid = {32360615}, issn = {1873-4596}, mesh = {*Acute Kidney Injury/chemically induced/drug therapy/prevention &amp; control ; Disease Progression ; Energy Metabolism ; Folic Acid ; Humans ; Mitochondria/metabolism ; Oxidation-Reduction ; *Renal Insufficiency, Chronic/chemically induced/drug therapy/metabolism ; }, abstract = {Recent studies suggest that mitochondrial bioenergetics and oxidative stress alterations may be common mechanisms involved in the progression of renal damage. However, the evolution of the mitochondrial alterations over time and the possible effects that their prevention could have in the progression of renal damage are not clear. Folic acid (FA)-induced kidney damage is a widely used experimental model to induce acute kidney injury (AKI), which can evolve to chronic kidney disease (CKD). Therefore, it has been extensively applied to study the mechanisms involved in AKI-to-CKD transition. We previously demonstrated that one day after FA administration, N-acetyl-cysteine (NAC) pre-administration prevented the development of AKI induced by FA. Such therapeutic effect was related to mitochondrial preservation. In the present study, we characterized the temporal course of mitochondrial bioenergetics and redox state alterations along the progression of renal damage induced by FA. Mitochondrial function was studied at different time points and showed a sustained impairment in oxidative phosphorylation capacity and a decrease in β-oxidation, decoupling, mitochondrial membrane potential depolarization and a pro-oxidative state, attributed to the reduction in activity of complexes I and III and mitochondrial cristae effacement, thus favoring the transition from AKI to CKD. Furthermore, the mitochondrial protection by NAC administration before AKI prevented not only the long-term deterioration of mitochondrial function at the chronic stage, but also CKD development. Taken together, our results support the idea that the prevention of mitochondrial dysfunction during an AKI event can be a useful strategy to prevent the transition to CKD.}, }
@article {pmid32354002, year = {2020}, author = {Altomare, A and Baron, G and Brioschi, M and Longoni, M and Butti, R and Valvassori, E and Tremoli, E and Carini, M and Agostoni, P and Vistoli, G and Banfi, C and Aldini, G}, title = {N-Acetyl-Cysteine Regenerates Albumin Cys34 by a Thiol-Disulfide Breaking Mechanism: An Explanation of Its Extracellular Antioxidant Activity.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {5}, pages = {}, pmid = {32354002}, issn = {2076-3921}, support = {Ricerca Corrente 2017 BIO 18, ID 2631209//Ministry of Health, Rome, Italy/ ; CTE_NAZPR19GALDI_02//Zambon Company S.p.A. (Bresso, Milan, Italy)/ ; }, abstract = {In the present paper, the extracellular antioxidant activity of N-acetyl-cysteine (NAC) is explained by considering its ability to regenerate the free form of albumin Cys34 by breaking the disulfide bond of the cysteinylated form (HSA-Cys). NAC's capability to regenerate albumin Cys34 (HSA-SH) was studied by MS intact protein analysis in human plasma and in a concentration range of NAC easily achievable after oral and i.v. administration (5-50 µg/mL). NAC dose-dependently broke the HSA-Cys bond to form the dimer NAC-Cys thus regenerating Cys34, whose reduced state was maintained for at least 120 min. Cys was faster in restoring Cys34, according to the reaction constant determined with the glutathione disulfide (GSSG) reaction, but after 60 min the mixed disulfide HSA-Cys turned back due to the reaction of the dimer Cys-Cys with Cys34. The explanation for the different rate exchanges between Cys-Cys and Cys-NAC with Cys34 was given by molecular modeling studies. Finally, the Cys34 regenerating effect of NAC was related to its ability to improve the total antioxidant capacity of plasma (TRAP assay). The results well indicate that NAC greatly increases the plasma antioxidant activity and this effect is not reached by a direct effect but through the regenerating effect of Cys34.}, }
@article {pmid32353430, year = {2020}, author = {Gao, Y and Cui, X and Wang, M and Zhang, Y and He, Y and Li, L and Li, H and Zhang, X and Cheng, M}, title = {Oscillatory shear stress induces the transition of EPCs into mesenchymal cells through ROS/PKCζ/p53 pathway.}, journal = {Life sciences}, volume = {253}, number = {}, pages = {117728}, doi = {10.1016/j.lfs.2020.117728}, pmid = {32353430}, issn = {1879-0631}, mesh = {Acetanilides/pharmacology ; Animals ; Cell Differentiation/physiology ; Cell Transdifferentiation/physiology ; Cells, Cultured ; Endothelial Progenitor Cells/*cytology ; Male ; Mesenchymal Stem Cells/*cytology ; Protein Kinase C/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; *Stress, Mechanical ; Thiourea/analogs &amp; derivatives/pharmacology ; Time Factors ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {AIMS: Studies indicate that the pattern of shear stress determines the direction of endothelial progenitor cells (EPCs) differentiation. However, the mechanism remains largely unknown. Herein, we try to identify the role of oscillatory shear stress (OSS) in the transdifferentiation of EPCs into mesenchymal cells and the mechanism involved.<br><br>MATERIALS AND METHODS: OSS was applied to EPCs using the flow chamber system in vitro. Matrigel, Boyden chamber, and healing assay were used to observe the changes in EPCs function. Further, 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe and/or western blot were performed to detect the expression of reactive oxygen species (ROS), p53 and PKC&#x3b6; in EPCs. EPCs transduced with Lentivirus carrying Tp53 were implanted into the arterial vessel in the balloon injured rat model, and neointimal thickening was verified by HE staining.<br><br>KEY FINDINGS: OSS enhanced the expression of mesenchymal cell markers alpha-smooth muscle actin (&#x3b1;-SMA) and smooth muscle 22 alpha (SM22&#x3b1;) on EPCs. In the meantime, OSS time-dependently decreased p53 expression in EPCs, which was partially abolished by treatment with ROS scavenger N-acetylcysteine (NAC) or protein kinase C zeta (PKC&#x3b6;) inhibitor Go6983. Moreover, the p53 agonist tenovin-1 attenuated the changes of OSS-mediated the mesenchymal cell markers and EPCs function. Besides, we also found that transplanting EPCs transfected with LV-Tp53 significantly inhibited neointimal thickening and promoted reendothelialization in vivo.<br><br>SIGNIFICANCE: This study demonstrates OSS-induced EPC transdifferentiation into mesenchymal cells and ROS/PKC&#x3b6;/p53 pathway play an essential role in it. It may serve as a promising therapeutic target for cardiovascular disease in the future.}, }
@article {pmid32349551, year = {2021}, author = {Crow, EM and Spyres, MB and Boley, SP and Levine, M and Stellpflug, SJ}, title = {Delayed peaks of acetaminophen in overdose patients with concomitant abdominal trauma.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {59}, number = {1}, pages = {65-68}, doi = {10.1080/15563650.2020.1749278}, pmid = {32349551}, issn = {1556-9519}, mesh = {Abdominal Injuries/*complications/therapy ; Acetaminophen/pharmacokinetics/*poisoning ; Acetylcysteine/therapeutic use ; Adult ; Analgesics, Non-Narcotic/pharmacology/*poisoning ; Antidotes/therapeutic use ; Drug Overdose/blood/*complications/diagnosis/drug therapy ; Fatal Outcome ; Female ; Humans ; *Suicide, Attempted ; Treatment Outcome ; Wounds, Nonpenetrating/*complications/therapy ; Wounds, Stab/*complications/therapy ; }, abstract = {OBJECTIVE: To present two cases of delayed acetaminophen absorption in abdominal trauma patients with concomitant acetaminophen overdose.<br><br>CASES: Case 1. A 25-year-old female arrived to the emergency department with multiple stab wounds. She had ingested an unknown amount of acetaminophen and was then stabbed by her boyfriend in a suicide pact. Initial acetaminophen concentration was 211.7&#x2009;mcg/mL and the patient was started on N-Acetylcysteine (NAC) therapy. She was found to have injuries and was taken for operative repair. Acetaminophen concentrations were down trending and nearly undetectable until 58&#x2009;h post-presentation when concentrations began to rise again.<br><br>CASE 2: A 41-year-old female ingested approximately 500 tablets of acetaminophen prior to jumping from a four-story building in a suicide attempt. She was found to have multiple traumatic injuries as well as an initial acetaminophen concentration of 225&#x2009;mcg/mL and was started on NAC therapy. The patient underwent multiple interventions to treat her traumatic injuries. Despite receiving no acetaminophen while inpatient, the patient's acetaminophen concentrations peaked a second time on her third hospital day.<br><br>CONCLUSIONS: In this case series, two patients with abdominal trauma and coexistent massive acetaminophen ingestions were described. Both cases demonstrated a delayed rise in serum acetaminophen concentrations and required extended NAC therapy.}, }
@article {pmid32348402, year = {2020}, author = {Damasceno, AVBS and Barros, CAV and Percario, S and Ribeiro Junior, RFG and Monteiro, AM and Gouveia, EHH and Henriques, HYB}, title = {Remote ischemic conditioning protects against testicular ischemia∕reperfusion injury in rats.}, journal = {Acta cirurgica brasileira}, volume = {35}, number = {2}, pages = {e202000203}, pmid = {32348402}, issn = {1678-2674}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Drug Evaluation, Preclinical ; Free Radical Scavengers/*pharmacology ; Ischemic Preconditioning/*methods ; Male ; Oxidative Stress/*drug effects ; Oxygen Radical Absorbance Capacity ; Random Allocation ; Rats ; Rats, Wistar ; *Reperfusion Injury ; Testis/*blood supply/drug effects ; }, abstract = {Purpose To evaluate the effect of remote ischemic conditioning associated to N-acetylcysteine (NAC) on testicular ischemia∕reperfusion (I∕R) injury in rats. Methods Twenty-five adult male Wistar rats were randomly distributed into five experimental groups (n=5), as follows: Sham, I∕R, Perconditioning (PER), NAC and PER+NAC. Two-hour ischemia was induced by rotating the left testis 720° to clockwise direction, followed by 4 hours of reperfusion. Perconditioning was performed by three I/R cycles of 10 min each on the left limb, 30 min before reperfusion. N-acetylcysteine (150 mg∕kg) was administered 30 min before reperfusion. Results Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was statistical difference between PER and Sham, and PER+ NAC groups (p<0.05) in plasma. Conclusions The protective effect of perconditioning isolated in the reduction of lipid peroxidation related to oxidative stress was demonstrated. However, when Perconditioning was associated with NAC, there was no protective effect against testicular injury of ischemia and reperfusion.}, }
@article {pmid32347295, year = {2020}, author = {Li, W and Li, W and Leng, Y and Xiong, Y and Xue, R and Chen, R and Xia, Z}, title = {Mechanism of N-acetylcysteine in alleviating diabetic myocardial ischemia reperfusion injury by regulating PTEN/Akt pathway through promoting DJ-1.}, journal = {Bioscience reports}, volume = {40}, number = {6}, pages = {}, pmid = {32347295}, issn = {1573-4935}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Cell Line ; Diabetic Cardiomyopathies/enzymology/genetics/pathology/*prevention &amp; control ; Disease Models, Animal ; Male ; Myocardial Reperfusion Injury/enzymology/genetics/pathology/*prevention &amp; control ; Myocytes, Cardiac/*drug effects/enzymology/pathology ; Oxidative Stress/*drug effects ; PTEN Phosphohydrolase/*metabolism ; Protein Deglycase DJ-1/genetics/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; }, abstract = {Ischemic heart disease is the main cardiovascular complication of diabetes patients which is mainly caused by oxidative stress. DJ-1 is the key regulator for myocardial protection through inhibiting phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and activating Akt (also known as PKB or protein kinase B). This research is to investigate whether the antioxidant N-acetylcysteine (NAC) could alleviate diabetic myocardial ischemia/reperfusion (I/R) injury by the protective molecule DJ-1. DJ-1 in rat myocardial H9c2 cells and cardiac tissue was respectively knocked down by siRNA and adeno-associated virus (AAV). From the present study, it could be found that compared with high glucose (HG)-normal (N)/DM group, hypoxia/reoxygenation (H/R) or I/R injury can aggravate oxidative stress injury and apoptosis rate of myocardial cells, inhibit the expression of Bcl-2, activate the BAX and cleaved caspase-3 (c-caspase-3) protein and PTEN/Akt pathway. However, in the groups of HG-N, DM, HG-N+I/R and DM+I/R, NAC can significantly reduce oxidative stress injury and apoptosis rate of myocytes, promote the Bcl-2 and DJ-1 molecules, inhibit BAX and c-caspase-3 protein and PTEN/Akt pathway. Compared with HG-N+I/R+NAC and DM+I/R+NAC groups, the oxidative stress injury, apoptosis rate of myocardial cells and heart tissues increased after the knockdown of DJ-1, the expression of Bcl-2 and DJ-1 were inhibited, the BAX and c-caspase-3 expression was increased, and PTEN/Akt pathway was activated. Taken together, the findings suggest that NAC can reduce I/R injury in diabetic myocardium by up-regulating the PTEN/Akt pathway through the level of DJ-1.}, }
@article {pmid32346941, year = {2020}, author = {Choi, BY and Hong, DK and Jeong, JH and Lee, BE and Koh, JY and Suh, SW}, title = {Zinc transporter 3 modulates cell proliferation and neuronal differentiation in the adult hippocampus.}, journal = {Stem cells (Dayton, Ohio)}, volume = {38}, number = {8}, pages = {994-1006}, pmid = {32346941}, issn = {1549-4918}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cation Transport Proteins/*metabolism ; Cell Differentiation/drug effects/physiology ; Cell Proliferation/drug effects/physiology ; Chlorides/pharmacology ; Hippocampus/*cytology/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurogenesis/drug effects ; Neurons/cytology/metabolism ; Zinc Compounds/pharmacology ; }, abstract = {The subgranular zone of the dentate gyrus is a subregion of the hippocampus that has two uniquely defining features; it is one of the most active sites of adult neurogenesis as well as the location where the highest concentrations of synaptic zinc are found, the mossy fiber terminals. Therefore, we sought to investigate the idea that vesicular zinc plays a role as a modulator of hippocampal adult neurogenesis. Here, we used ZnT3[-/-] mice, which are depleted of synaptic-vesicle zinc, to test the effect of targeted deletion of this transporter on adult neurogenesis. We found that this manipulation reduced progenitor cell turnover as well as led to a marked defect in the maturation of newborn cells that survive in the DG toward a neuronal phenotype. We also investigated the effects of zinc (ZnCl2), n-acetyl cysteine (NAC), and ZnCl2 plus 2NAC (ZN) supplement on adult hippocampal neurogenesis. Compared with ZnCl2 or NAC, administration of ZN resulted in an increase in proliferation of progenitor cells and neuroblast. ZN also rescued the ZnT3 loss-associated reduction of neurogenesis via elevation of insulin-like growth factor-1 and ERK/CREB activation. Together, these findings reveal that ZnT3 plays a highly important role in maintaining adult hippocampal neurogenesis and supplementation by ZN has a beneficial effect on hippocampal neurogenesis, as well as providing a therapeutic target for enhanced neuroprotection and repair after injury as demonstrated by its ability to prevent aging-dependent cognitive decline in ZnT3[-/-] mice. Therefore, the present study suggests that ZnT3 and vesicular zinc are essential for adult hippocampal neurogenesis.}, }
@article {pmid32346830, year = {2020}, author = {Dong, W and Wang, R and Gong, X and Liang, W and Fan, L and Song, S and Dong, C}, title = {A ratiometric and far-red fluorescence "off-on" sensor for sequential determination of copper(II) and L-histidine based on FRET system between N-acetyl-L-cysteine-capped AuNCs and N,S,P co-doped carbon dots.}, journal = {Mikrochimica acta}, volume = {187}, number = {5}, pages = {299}, pmid = {32346830}, issn = {1436-5073}, support = {21705101//National Natural Science Foundation of China/International ; 201801D121040//Natural Science Foundation of Shanxi Province/International ; 201903D121109//Shanxi Provincial Key Research and Development Project (CN)/International ; 2018M642969//Postdoctoral Research Foundation of China/International ; }, mesh = {Acetylcysteine/*chemistry ; Carbon/chemistry ; Copper/*analysis ; *Fluorescence ; *Fluorescence Resonance Energy Transfer ; Fluorescent Dyes/*chemistry ; Gold/chemistry ; Histidine/*analysis ; Metal Nanoparticles/chemistry ; Quantum Dots/chemistry ; Spectrometry, Fluorescence ; }, abstract = {A far-red fluorescence "off-on" sensing strategy is described for sequential ratiometric determination of Cu[2+] and L-histidine (L-His) based on fluorescence resonance energy transfer (FRET) system. N,S,P co-doped carbon dots (N,S,P-CDs) and N-acetyl-L-cysteine functionalized gold nanoclusters (NAC-AuNCs) are used in the FRET system, which serve as energy donor and acceptor, respectively. After adding NAC-AuNCs into the solution of N,S,P-CDs, the fluorescence of N,S,P-CDs is effectively quenched, while the far-red fluorescence of NAC-AuNCs appears. Cu[2+] can decrease fluorescence of NAC-AuNCs, and then L-His can effectively recover the fluorescence of NAC-AuNCs. The possible reason is that the stronger affinity between Cu[2+] and L-His can pull Cu[2+] away from the surface of NAC-AuNCs. Through it all, the emission intensity of N,S,P-CDs remains nearly constant, so the ratio of fluorescence intensities at 485 and 625 nm exhibits a linear correlation to the Cu[2+] and L-His concentration, respectively. The sensing platform shows good selectivity towards Cu[2+] and L-His with a linear range of 0.65-26.58 μM and 3.13-56.25 μM and determination limits of 0.50 μM and 0.374 μM, respectively. The proposed method has been successfully used for Cu[2+] and L-His determination in real samples with satisfying results. Graphical abstract.}, }
@article {pmid32346587, year = {2020}, author = {D'Ambrosi, R and Ursino, N}, title = {N-Acetyl-Cysteine Reduces Blood Chromium and Cobalt Levels in Metal-on-Metal Hip Arthroplasty.}, journal = {Arthroplasty today}, volume = {6}, number = {2}, pages = {149-152}, pmid = {32346587}, issn = {2352-3441}, abstract = {The most common reasons for revision of metal-on-metal hip arthroplasty are aseptic loosening and metal reaction. Failure of a metal-on-metal implant due to the aggressive destruction of periprosthetic tissues may require extensive reconstruction procedures. The aim of this case report is to describe the treatment in an asymptomatic patient with high levels of chromium and cobalt, using chelation therapy. The rational use of N-acetyl-cysteine (NAC) involves thiol groups to chelate sites for metals. More than 10 years after the metal-on-metal hip arthroplasty, the patient did not have to undergo revision surgery; the levels of the ions in the blood were considerably lowered (chromium from 4.51 mcg/L to 1.85 mcg/L; cobalt from 7.78 UG/L to 0.8 UG/L) after using NAC without adverse effects.}, }
@article {pmid32346167, year = {2020}, author = {Ammar, MA and Abdou, AMH}, title = {Benefits of N-acetylcysteine on liver functions in living donor hepatectomy.}, journal = {Indian journal of anaesthesia}, volume = {64}, number = {3}, pages = {204-209}, pmid = {32346167}, issn = {0019-5049}, abstract = {BACKGROUND AND AIMS: The proportion of patients undergoing living donor liver transplantation is high especially in countries without or with limited cadaver organ sharing programs. The aim of this study was to evaluate the post-hepatectomy effect of using N-Acetylcysteine (NAC) infusion in living donors undergoing donor hepatectomy.<br><br>METHODS: In a prospective randomised non-blinded study, 50 healthy donors were enrolled; following hepatectomy patients were randomised into 2 groups: Group NC receiving NAC 150 mg/kg diluted in 100 ml glucose 5% over 40 minutes, followed by NAC 12.5 mg/kg in 500 ml glucose 5% over 4 hours. This was followed by NAC 6.25 mg/kg for 2 post-operative days, Group C (Control group) received ringer acetate infusion at same rate for 2 days. The primary outcome was serum lactate levels. Secondary outcomes were liver function tests, serum creatinine and urine output on intensive care unit (ICU) admission (0 hr.), after 24 hours and 48 hours, length of ICU stay.<br><br>RESULTS: Our study revealed significant reduction in serum lactate in Group NC at 0, 24 and 48 hours compared to C group (P = 0.017, 0.002, 0.014). INR values showed significant reduction after 48 hours in Group NC compared to Group C (P = 0.049). Total Bilirubin, ALT, and Creatinine, urine output and ICU stay showed no statistical difference between the 2 groups.<br><br>CONCLUSION: The NAC protocol is a safe, cost-effective tool for improvement of post hepatectomy liver function and early stabilisation of the metabolic profile.}, }
@article {pmid32345254, year = {2020}, author = {Keach, JW and Stanislawski, MA and Barón, AE and Plomondon, ME and Langner, P and Amin, A and Gilmartin, HM and Waldo, S and Maddox, TM}, title = {Variation in contrast-associated acute kidney injury prophylaxis for percutaneous coronary intervention: insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) program.}, journal = {BMC nephrology}, volume = {21}, number = {1}, pages = {150}, pmid = {32345254}, issn = {1471-2369}, support = {IK2 HX002567/HX/HSRD VA/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/etiology/*prevention &amp; control ; Aged ; Contrast Media/administration &amp; dosage/*adverse effects ; Coronary Angiography ; Female ; Fluid Therapy/standards/*statistics &amp; numerical data/trends ; Free Radical Scavengers/therapeutic use ; Glomerular Filtration Rate ; Heart Failure/complications ; Humans ; Male ; Middle Aged ; Percutaneous Coronary Intervention/adverse effects/statistics &amp; numerical data ; Perioperative Care/standards/*statistics &amp; numerical data/trends ; Postoperative Complications/etiology/prevention &amp; control ; Practice Guidelines as Topic ; Renal Insufficiency, Chronic/*complications/physiopathology ; Saline Solution/therapeutic use ; Sodium Bicarbonate/therapeutic use ; United States ; Veterans Health Services/*statistics &amp; numerical data ; }, abstract = {BACKGROUND: Contrast-Associated Acute Kidney Injury (CA-AKI) is a serious complication associated with percutaneous coronary intervention (PCI). Patients with chronic kidney disease (CKD) have an elevated risk for developing this complication. Although CA-AKI prophylactic measures are available, the supporting literature is variable and inconsistent for periprocedural hydration and N-acetylcysteine (NAC), but is stronger for contrast minimization.<br><br>METHODS: We assessed the prevalence and variability of CA-AKI prophylaxis among CKD patients undergoing PCI between October 2007 and September 2015 in any cardiac catheterization laboratory in the VA Healthcare System. Prophylaxis included periprocedural hydration with normal saline or sodium bicarbonate, NAC, and contrast minimization (contrast volume to glomerular filtration rate ratio&#x2009;&#x2264;&#x2009;3). Multivariable hierarchical logistic regression models quantified site-specific prophylaxis variability. As secondary analyses, we also assessed CA-AKI prophylaxis measures in all PCI patients regardless of kidney function, periprocedural hydration in patients with comorbid CHF, and temporal trends in CA-AKI prophylaxis.<br><br>RESULTS: From 2007 to 2015, 15,729 patients with CKD underwent PCI. 6928 (44.0%) received periprocedural hydration (practice-level median rate 45.3%, interquartile range (IQR) 35.5-56.7), 5107 (32.5%) received NAC (practice-level median rate 28.3%, IQR 22.8-36.9), and 4656 (36.0%) received contrast minimization (practice-level median rate 34.5, IQR 22.6-53.9). After adjustment for patient characteristics, there was significant site variability with a median odds ratio (MOR) of 1.80 (CI 1.56-2.08) for periprocedural hydration, 1.95 (CI 1.66-2.29) for periprocedural hydration or NAC, and 2.68 (CI 2.23-3.15) for contrast minimization. These trends were similar among all patients (with and without CKD) undergoing PCI. Among patients with comorbid CHF (n&#x2009;=&#x2009;5893), 2629 (44.6%) received periprocedural hydration, and overall had less variability in hydration (MOR of 1.56 (CI 1.38-1.76)) compared to patients without comorbid CHF (1.89 (CI 1.65-2.18)). Temporal trend analysis showed a significant and clinically relevant decrease in NAC use (64.1% of cases in 2008 (N&#x2009;=&#x2009;1059), 6.2% of cases in 2015 (N&#x2009;=&#x2009;128, p&#x2009;=&#x2009;<&#x2009;0.0001)) and no significant change in contrast-minimization (p&#x2009;=&#x2009;0.3907).<br><br>CONCLUSIONS: Among patients with CKD undergoing PCI, there was low utilization and significant site-level variability for periprocedural hydration and NAC independent of patient-specific risk. This low utilization and high variability, however, was also present for contrast minimization, a well-established measure. These findings suggest that a standardized approach to CA-AKI prophylaxis, along with continued development of the evidence base, is needed.}, }
@article {pmid32344315, year = {2020}, author = {Assimakopoulos, SF and Marangos, M}, title = {N-acetyl-cysteine may prevent COVID-19-associated cytokine storm and acute respiratory distress syndrome.}, journal = {Medical hypotheses}, volume = {140}, number = {}, pages = {109778}, pmid = {32344315}, issn = {1532-2777}, }
@article {pmid32337855, year = {2020}, author = {Zhang, C and Bjornson, E and Arif, M and Tebani, A and Lovric, A and Benfeitas, R and Ozcan, M and Juszczak, K and Kim, W and Kim, JT and Bidkhori, G and Ståhlman, M and Bergh, PO and Adiels, M and Turkez, H and Taskinen, MR and Bosley, J and Marschall, HU and Nielsen, J and Uhlén, M and Borén, J and Mardinoglu, A}, title = {The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease.}, journal = {Molecular systems biology}, volume = {16}, number = {4}, pages = {e9495}, pmid = {32337855}, issn = {1744-4292}, mesh = {Acetylcysteine/*administration &amp; dosage/blood ; Adult ; Animals ; Carnitine/*administration &amp; dosage/blood ; Dietary Supplements ; Drug Therapy, Combination ; Healthy Volunteers ; Humans ; Male ; Metabolomics/*methods ; Models, Animal ; Niacinamide/administration &amp; dosage/*analogs &amp; derivatives/blood ; Non-alcoholic Fatty Liver Disease/diet therapy ; Precision Medicine ; Pyridinium Compounds ; Rats ; Serine/*administration &amp; dosage/blood ; }, abstract = {The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.}, }
@article {pmid32337800, year = {2020}, author = {Xiao, Y and Zhu, Q and Liu, X and Jiang, M and Hao, H and Zhu, H and Cowan, PJ and He, X and Liu, Q and Zhou, S and Liu, Z}, title = {High-fat diet selectively decreases bone marrow lin[-] /CD117[+] cell population in aging mice through increased ROS production.}, journal = {Journal of tissue engineering and regenerative medicine}, volume = {14}, number = {6}, pages = {884-892}, pmid = {32337800}, issn = {1932-7005}, support = {R01 HL124122/HL/NHLBI NIH HHS/United States ; NIH HL124122//NIH Clinical Center/International ; R01 ES026200/ES/NIEHS NIH HHS/United States ; }, mesh = {Aging/genetics/*metabolism ; Animals ; Bone Marrow Cells/*metabolism ; Diet, High-Fat/*adverse effects ; Male ; Mice ; Mice, Transgenic ; Proto-Oncogene Proteins c-kit/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Bone marrow (BM) stem cells (BMSCs) are an important source for cell therapy. The outcome of cell therapy could be ultimately associated with the number and function of donor BMSCs. The present study was to evaluate the effect of long-term high-fat diet (HFD) on the population of BMSCs and the role of reactive oxygen species (ROS) in aging mice. Forty-week-old male C57BL/6 mice were fed with HFD for 3 months with regular diet as control. Experiments were repeated when ROS production was reduced in mice treated with N-acetylcysteine (NAC) or using mice overexpressing antioxidant enzyme network (AON) of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase. BM and blood cells were analyzed with flowcytometry for lineage negative (lin[-]) and Sca-1[+] , or lin[-] /CD117[+] , or lin[-] /CD133[+] cells. Lin[-] /CD117[+] cell population was significantly decreased with increased intracellular ROS and apoptosis and decreased proliferation in BM, not in blood, in HFD-treated mice without change for Sca-1[+] or CD133[+] cell populations in BM or blood. NAC treatment or AON overexpression effectively prevented HFD-induced intracellular ROS production and reduction of BM lin[-] /CD117[+] population. These data suggested that long-term HFD selectively decreased BM lin[-] /CD117[+] cell population in aging mice through increased ROS production.}, }
@article {pmid32334464, year = {2020}, author = {Rajendran, S and Lakshminarayanan, A and Ramanathan, G and Subramanian Shanmugam, SK}, title = {Antioxidant Antagonises Chemotherapeutic Drug Effect in Lung Cancer Cell Line A549.}, journal = {Asian Pacific journal of cancer prevention : APJCP}, volume = {21}, number = {4}, pages = {1019-1023}, pmid = {32334464}, issn = {2476-762X}, mesh = {Acetylcysteine/*pharmacology ; Antimetabolites, Antineoplastic/pharmacology ; Antioxidants/*pharmacology ; Apoptosis ; Cell Proliferation ; Drug Therapy, Combination ; Free Radical Scavengers/pharmacology ; Humans ; Lung Neoplasms/*drug therapy/pathology ; Thioguanine/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {OBJECTIVE: This study aimed to find whether antioxidants increase or decrease the effect of chemotherapeutic drug in the in vitro model.<br><br>METHODS: Small lung Cancer cell line (A549) was treated with anticancer drug 6-Thioguanine (6-TG) at different concentration viz., 1, 10, 50 and 100&#x3bc;M and the proliferation was measured using MTT assay. The antioxidant N-Acetyl Cysteine (NAC) in different ratios viz., 1mM, 5mM and 10mM were assayed for their effect in proliferation on the A549 cells alone and in combination with 6-TG.<br><br>RESULTS: Our experiment proves that anticancer drug 6-TG decreases the proliferation and the antioxidant NAC enhances the proliferation of A549 cells. Strikingly when co-treated with 6-TG, the antioxidant NAC diminished the proliferation reduction action of 6-TG on A549 cells.<br><br>CONCLUSION: Our results suggest that antioxidants in fact benefit the tumor cell growth when treated alone and when in combination with anticancer drug, it severely impair the activity of the drug. We propose that extreme care should be taken when prescribing antioxidants alone or in combination with chemotherapeutics.}, }
@article {pmid32329019, year = {2020}, author = {Capella-Peris, C and Cosgrove, MM and Chrismer, IC and Razaqyar, MS and Elliott, JS and Kuo, A and Emile-Backer, M and Meilleur, KG}, title = {Understanding Symptoms in RYR1-Related Myopathies: A Mixed-Methods Analysis Based on Participants' Experience.}, journal = {The patient}, volume = {13}, number = {4}, pages = {423-434}, pmid = {32329019}, issn = {1178-1661}, support = {ZIA NR000026/ImNIH/Intramural NIH HHS/United States ; Bench to Bedside Award [10-2013/Office of Rare Disease/NINR]/NR/NINR NIH HHS/United States ; Intramural Research Program/NR/NINR NIH HHS/United States ; Intramural Research Program/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Adaptation, Psychological ; Adult ; Child ; Double-Blind Method ; Fatigue/drug therapy/physiopathology ; Female ; Humans ; Interviews as Topic ; Male ; Middle Aged ; Muscular Diseases/*drug therapy/*genetics/*physiopathology/psychology ; Pain/drug therapy/physiopathology ; Quality of Life ; Ryanodine Receptor Calcium Release Channel/*genetics ; Socioeconomic Factors ; }, abstract = {BACKGROUND: In rare diseases such as ryanodine receptor 1-related myopathies (RYR1-RM), health-related quality of life (HRQoL) measures are critically important so clinicians and researchers can better understand what symptoms are most important to participants, with the ultimate goal of finding tangible solutions for them.<br><br>OBJECTIVES: The main objective of this study was to characterize symptoms in individuals with RYR1-RM to inform future research. A secondary objective of this study was to analyze positive and negative sentiments regarding symptoms and treatment effects post N-acetylcysteine (NAC) administration in individuals with RYR1-RM.<br><br>METHODS: The study used a mixed-methods design applying methodological triangulation. Qualitative data were collected via semi-structured interviews at three visits to characterize symptoms in individuals with RYR1-RM and to analyze treatment effects. Qualitative data were then transformed into quantitative results to measure the frequency with which each symptom was mentioned by participants.<br><br>RESULTS: A total of 12 symptoms were identified as areas of interest to participants with RYR1-RM, highlighting fatigue and weakness as key symptoms. Data transformation categorized more than 1000 citations, reporting a greater number of positive comments for postintervention interviews than for baseline and preintervention visits and that NAC group participants stated more positive comments regarding treatment effect than did the placebo group.<br><br>CONCLUSIONS: We present a comprehensive characterization of symptoms in RYR1-RM and how those symptoms influence HRQoL. Furthermore, the introduction of mixed methods may be a valuable way to better understand patient-centered data in rare diseases to support affected individuals in coping with their symptoms.}, }
@article {pmid32328640, year = {2020}, author = {Cruz-Garcia, D and Brouwers, N and Malhotra, V and Curwin, AJ}, title = {Reactive oxygen species triggers unconventional secretion of antioxidants and Acb1.}, journal = {The Journal of cell biology}, volume = {219}, number = {4}, pages = {}, pmid = {32328640}, issn = {1540-8140}, mesh = {Antioxidants/*metabolism ; Carrier Proteins/*metabolism ; Reactive Oxygen Species/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; }, abstract = {Nutrient deprivation triggers the release of signal-sequence-lacking Acb1 and the antioxidant superoxide dismutase 1 (SOD1). We now report that secreted SOD1 is functionally active and accompanied by export of other antioxidant enzymes such as thioredoxins (Trx1 and Trx2) and peroxiredoxin Ahp1 in a Grh1-dependent manner. Our data reveal that starvation leads to production of nontoxic levels of reactive oxygen species (ROS). Treatment of cells with N-acetylcysteine (NAC), which sequesters ROS, prevents antioxidants and Acb1 secretion. Starved cells lacking Grh1 are metabolically active, but defective in their ability to regrow upon return to growth conditions. Treatment with NAC restored the Grh1-dependent effect of starvation on cell growth. In sum, starvation triggers ROS production and cells respond by secreting antioxidants and the lipogenic signaling protein Acb1. We suggest that starvation-specific unconventional secretion of antioxidants and Acb1-like activities maintain cells in a form necessary for growth upon their eventual return to normal conditions.}, }
@article {pmid32322478, year = {2020}, author = {Horowitz, RI and Freeman, PR and Bruzzese, J}, title = {Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases.}, journal = {Respiratory medicine case reports}, volume = {30}, number = {}, pages = {101063}, pmid = {32322478}, issn = {2213-0071}, abstract = {PURPOSE: Infection with COVID-19 potentially can result in severe outcomes and death from "cytokine storm syndrome", resulting in novel coronavirus pneumonia (NCP) with severe dyspnea, acute respiratory distress syndrome (ARDS), fulminant myocarditis and multiorgan dysfunction with or without disseminated intravascular coagulation. No published treatment to date has been shown to adequately control the inflammation and respiratory symptoms associated with COVID-19, apart from oxygen therapy and assisted ventilation. We evaluated the effects of using high dose oral and/or IV glutathione in the treatment of 2 patients with dyspnea secondary to COVID-19 pneumonia.<br><br>METHODS: Two patients living in New York City (NYC) with a history of Lyme and tick-borne co-infections experienced a cough and dyspnea and demonstrated radiological findings consistent with novel coronavirus pneumonia (NCP). A trial of 2&#xa0;g of PO or IV glutathione was used in both patients and improved their dyspnea within 1&#xa0;h of use. Repeated use of both 2000 mg of PO and IV glutathione was effective in further relieving respiratory symptoms.<br><br>CONCLUSION: Oral and IV glutathione, glutathione precursors (N-acetyl-cysteine) and alpha lipoic acid may represent a novel treatment approach for blocking NF-&#x3ba;B and addressing "cytokine storm syndrome" and respiratory distress in patients with COVID-19 pneumonia.}, }
@article {pmid32322336, year = {2020}, author = {Chen, W and Yuan, C and Lu, Y and Zhu, Q and Ma, X and Xiao, W and Gong, W and Huang, W and Xia, Q and Lu, G and Li, W}, title = {Tanshinone IIA Protects against Acute Pancreatitis in Mice by Inhibiting Oxidative Stress via the Nrf2/ROS Pathway.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {5390482}, pmid = {32322336}, issn = {1942-0994}, mesh = {Abietanes/pharmacology/*therapeutic use ; Animals ; Anti-Infective Agents/pharmacology/*therapeutic use ; Disease Models, Animal ; Humans ; Male ; Medicine, Chinese Traditional/*methods ; Mice ; Mice, Knockout ; Microscopy, Electron, Transmission/*methods ; NF-E2-Related Factor 2/*metabolism ; Pancreatitis/*drug therapy ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Danshen (Salvia miltiorrhiza Bunge) and its main active component Tanshinone IIA (TSA) are clinically used in China. However, the effects of TSA on acute pancreatitis (AP) and its potential mechanism have not been investigated. In this study, our objective was to investigate the protective effects of TSA against AP via three classic mouse models.<br><br>METHODS: Mouse models of AP were established by caerulein, sodium taurocholate, and L-arginine, separately. Pancreatic and pulmonary histopathological characteristics and serum amylase and lipase levels were evaluated, and changes in oxidative stress injury and the ultrastructure of acinar cells were observed. The reactive oxygen species (ROS) inhibitor N-Acetylcysteine (NAC) and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice were applied to clarify the protective mechanism of the drug.<br><br>RESULTS: In the caerulein-induced AP model, TSA administration reduced serum amylase and lipase levels and ameliorated the histopathological manifestations of AP in pancreatic tissue. Additionally, TSA appreciably decreased ROS release, protected the structures of mitochondria and the endoplasmic reticulum, and increased the protein expression of Nrf2 and heme oxygenase 1 of pancreatic tissue. In addition, the protective effects of TSA against AP were counteracted by blocking the oxidative stress (NAC administration and Nrf2 knockout in mice). Furthermore, we found that TSA protects pancreatic tissue from damage and pancreatitis-associated lung injury in two additional mouse models induced by sodium taurocholate and by L-arginine.<br><br>CONCLUSION: Our data confirmed the protective effects of TSA against AP in mice by inhibiting oxidative stress via the Nrf2/ROS pathway.}, }
@article {pmid32319746, year = {2020}, author = {Tian, X and de Vries, MP and Visscher, SWJ and Permentier, HP and Bischoff, R}, title = {Selective Maleylation-Directed Isobaric Peptide Termini Labeling for Accurate Proteome Quantification.}, journal = {Analytical chemistry}, volume = {92}, number = {11}, pages = {7836-7844}, pmid = {32319746}, issn = {1520-6882}, mesh = {Animals ; Cattle ; *Isotope Labeling ; Peptides/*chemistry ; Proteome/*analysis ; Saccharomyces cerevisiae Proteins/*analysis ; Serum Albumin, Bovine/*analysis ; }, abstract = {Isobaric peptide termini labeling (IPTL) is an attractive protein quantification method because it provides more accurate and reliable quantification information than traditional isobaric labeling methods (e.g., TMT and iTRAQ) by making use of the entire fragment-ion series instead of only a single reporter ion. The multiplexing capacity of published IPTL implementations is, however, limited to three. Here, we present a selective maleylation-directed isobaric peptide termini labeling (SMD-IPTL) approach for quantitative proteomics of LysC protein digestion. SMD-IPTL extends the multiplexing capacity to 4-plex with the potential for higher levels of multiplexing using commercially available [13]C/[15]N labeled amino acids. SMD-IPTL is achieved in a one-pot reaction in three consecutive steps: (1) selective maleylation at the N-terminus; (2) labeling at the ε-NH2 group of the C-terminal Lys with isotopically labeled acetyl-alanine; (3) thiol Michael addition of an isotopically labeled acetyl-cysteine at the maleylated N-terminus. The isobarically labeled peptides are fragmented into sets of b- and y-ion clusters upon LC-MS/MS, which convey not only sequence information but also quantitative information for every labeling channel and avoid the issue of ratio distortion observed with reporter-ion-based approaches. We demonstrate the SMD-IPTL approach with a 4-plex labeled sample of bovine serum albumin (BSA) and yeast lysates mixed at different ratios. With the use of SMD-IPTL for labeling and a narrow precursor isolation window of 0.8 Th with an offset of -0.2 Th, accurate ratios were measured across a 10-fold mixing range of BSA in a background of yeast proteome. With the yeast proteins mixed at ratios of 1:5:1:5, BSA was detected at ratios of 0.94:2.46:4.70:9.92 when spiked at 1:2:5:10 ratios with an average standard deviation of peptide ratios of 0.34.}, }
@article {pmid32319656, year = {2020}, author = {Liu, X and Li, Z and Li, M and Chai, J and He, S and Wu, J and Xu, J}, title = {Icariside II overcomes BRAF inhibitor resistance in melanoma by inducing ROS production and inhibiting MITF.}, journal = {Oncology reports}, volume = {44}, number = {1}, pages = {360-370}, doi = {10.3892/or.2020.7582}, pmid = {32319656}, issn = {1791-2431}, mesh = {Cell Line, Tumor ; Cell Survival/drug effects ; Down-Regulation ; Drug Resistance, Neoplasm/drug effects ; Drug Synergism ; Flavonoids/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Melanoma/drug therapy/*genetics/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Microphthalmia-Associated Transcription Factor/*genetics ; Proto-Oncogene Proteins B-raf/*genetics ; Proto-Oncogene Proteins c-met/genetics ; Reactive Oxygen Species/*metabolism ; Vemurafenib/*pharmacology ; }, abstract = {Metastatic melanoma is the most aggressive skin cancer. Although BRAF inhibitor treatment has achieved great success in melanoma, resistance develops within 12 months. Icariside II (IS), a natural compound extracted from Herba Epimedii, exerts anticancer properties. In the present study, we determined by MTT, flow cytometry and western blotting, respectively that IS potentiated the PLX4032‑induced downregulation of cell viability and increase in apoptosis and autophagy in BRAF inhibitor‑resistant melanoma. In addition, we also revealed by flow cytometry and western blotting, respectively, that IS combined with PLX4032 increased mitochondrial and intracellular reactive oxygen species (ROS) generation and subsequently promoted depolarization of mitochondria and release of apoptotic proteins. N‑acetyl cysteine (NAC) and glutathione (GSH), ROS scavengers, reversed the IS‑induced enhancement of the response to PLX4032. Microphthalmia‑associated transcription factor (MITF) and tyrosine‑protein kinase Met (c‑Met) are well‑known factors that contribute to BRAF inhibitor resistance. Furthermore, c‑Met is a direct transcriptional target of MITF in melanocytes and melanoma cells. It was also revealed that IS markedly inhibited MITF and c‑Met expression partially by increasing ROS production in BRAF inhibitor‑resistant melanoma cells.}, }
@article {pmid32316268, year = {2020}, author = {Park, H and Kim, JE}, title = {Deletion of P2X7 Receptor Decreases Basal Glutathione Level by Changing Glutamate-Glutamine Cycle and Neutral Amino Acid Transporters.}, journal = {Cells}, volume = {9}, number = {4}, pages = {}, pmid = {32316268}, issn = {2073-4409}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Transport System ASC/metabolism ; Amino Acid Transport Systems, Neutral/*metabolism ; Animals ; Gene Deletion ; Glutamate-Ammonia Ligase/metabolism ; Glutamic Acid/*metabolism ; Glutamine/*metabolism ; Glutathione/*metabolism ; Hippocampus/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Minor Histocompatibility Antigens/metabolism ; Molsidomine/analogs &amp; derivatives/pharmacology ; Receptors, Purinergic P2X7/genetics/*metabolism ; }, abstract = {Glutathione (GSH) is an endogenous tripeptide antioxidant that consists of glutamate-cysteine-glycine. GSH content is limited by the availability of glutamate and cysteine. Furthermore, glutamine is involved in the regulation of GSH synthesis via the glutamate-glutamine cycle. P2X7 receptor (P2X7R) is one of the cation-permeable ATP ligand-gated ion channels, which is involved in neuronal excitability, neuroinflammation and astroglial functions. In addition, P2X7R activation decreases glutamate uptake and glutamine synthase (GS) expression/activity. In the present study, we found that P2X7R deletion decreased the basal GSH level without altering GSH synthetic enzyme expressions in the mouse hippocampus. P2X7R deletion also increased expressions of GS and ASCT2 (a glutamine:cysteine exchanger), but diminished the efficacy of N-acetylcysteine (NAC, a GSH precursor) in the GSH level. SIN-1 (500 μM, a generator nitric oxide, superoxide and peroxynitrite), which facilitates the cystine-cysteine shuttle mediated by xCT (a glutamate/cystein:cystine/NAC antiporter), did not affect basal GSH concentration in WT and P2X7R knockout (KO) mice. However, SIN-1 effectively reduced the efficacy of NAC in GSH synthesis in WT mice, but not in P2X7R KO mice. Therefore, our findings indicate that P2X7R may be involved in the maintenance of basal GSH levels by regulating the glutamate-glutamine cycle and neutral amino acid transports under physiological conditions, which may be the defense mechanism against oxidative stress during P2X7R activation.}, }
@article {pmid32313093, year = {2020}, author = {Shi, D and Guo, L and Sun, X and Shang, M and Meng, D and Zhou, X and Liu, X and Zhao, Y and Li, J}, title = {UTMD inhibit EMT of breast cancer through the ROS/miR-200c/ZEB1 axis.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {6657}, pmid = {32313093}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects/radiation effects ; Cell Proliferation/drug effects/radiation effects ; Epithelial-Mesenchymal Transition/drug effects/*genetics/radiation effects ; Female ; Free Radical Scavengers/pharmacology ; *Gene Expression Regulation, Neoplastic ; Gene Transfer Techniques ; Humans ; Mammary Glands, Human/metabolism/pathology ; MicroRNAs/agonists/antagonists &amp; inhibitors/*genetics/metabolism ; Microbubbles ; Oxidative Stress ; RNA, Small Interfering/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Ultrasonic Waves ; Vimentin/antagonists &amp; inhibitors/*genetics/metabolism ; Zinc Finger E-box-Binding Homeobox 1/antagonists &amp; inhibitors/*genetics/metabolism ; }, abstract = {As a potential drug/gene delivery system, the ultrasound-targeted microbubble destruction (UTMD) system can be used as a vehicle as well as increasing the permeability of biological barriers to enhance the effect of tumor treatment. However, the effect of UTMD in the tumor EMT process is unknown. In this study, we aimed to investigate the potential and mechanism of UTMD induced oxidative stress in inhibiting EMT of breast cancer. Human breast MDA231 cells were treated with microbubble (MB), ultrasound (US) and UTMD, respectively. The generation of oxidative stress, the levels of miR-200c, ZEB1 and vimentin, and the numbers of migratory cells were evaluated quantitatively and qualitatively by the measurement of intracellular reactive oxygen species (ROS), qRT-PCR, western blot assay, and transwell assay. Then, to evaluate the role of UTMD-induced oxidative stress and miR-200c in the epithelial-mesenchymal transition (EMT) inhibition, the ROS scavenger N-acetyl-L-cysteine (NAC) and miR-200c inhibitor were used before UTMD treatment. We found that UTMD induced oxidative stress, upregulated the expression of miR-200c, downregulated the expression of ZEB1 and vimentin and suppressed the MDA231 cell migration. The addition of NAC and miR-200c inhibitor had an opposite impact on the expression of miR-200c and ZEB1, thus hindered the effects of UTMD on MDA231 cells EMT. In conclusion, UTMD can inhibit the EMT characteristics of MDA231 cells. The mechanism may be related to the regulation of the miR-200c/ZEB1 axis through the generation of ROS induced by UTMD, which may provide a new strategy to prevent the tumor cells EMT under UTMD treatment.}, }
@article {pmid32309634, year = {2019}, author = {Ahonen, MJR and Hill, DB and Schoenfisch, MH}, title = {Nitric oxide-releasing alginates as mucolytic agents.}, journal = {ACS biomaterials science &amp; engineering}, volume = {5}, number = {7}, pages = {3409-3418}, pmid = {32309634}, issn = {2373-9878}, support = {P30 DK065988/DK/NIDDK NIH HHS/United States ; R21 AI112029/AI/NIAID NIH HHS/United States ; }, abstract = {The excessive production of thick, viscous mucus in severe respiratory diseases leads to obstruction of the airways and provides a suitable environment for the colonization of pathogenic bacteria. The effect of nitric oxide (NO)-releasing alginates with varying NO release kinetics on the viscoelastic properties of human bronchial epithelial (HBE) mucus was evaluated as a function of the NO-release kinetics using parallel plate rheology. Low molecular weight (~5 kDa) alginates with high NO flux (~4000 ppb/mg) and sustained release (half-life ~0.3 h) proved to be most effective in reducing both mucus elasticity and viscosity (≥60% reduction for both). The efficacy of the NO-releasing alginates was shown to be dose-dependent, with high concentrations of NO-releasing alginates (~80 mg•mL[-1]) resulting in greater reduction of the viscosity and elasticity of the mucus samples. Greater reduction in mucus rheology was also achieved with NO-releasing alginates at lower concentrations when compared to both NO-releasing chitosan, a similarly biocompatible cationic polymer, and N-acetyl cysteine (NAC), a conventional mucolytic agent.}, }
@article {pmid32305647, year = {2020}, author = {Yoo, S and Bae, JY and Moon, J and Koh, G}, title = {System χc- overexpression prevents 2-deoxy-d-ribose-induced β-cell damage.}, journal = {Free radical biology &amp; medicine}, volume = {153}, number = {}, pages = {17-25}, doi = {10.1016/j.freeradbiomed.2020.04.012}, pmid = {32305647}, issn = {1873-4596}, mesh = {Amino Acid Transport System y+/genetics/metabolism ; Animals ; Cystine/metabolism ; Deoxyribose/metabolism ; *Diabetes Mellitus, Type 2/metabolism ; Glutathione/metabolism ; *Insulin-Secreting Cells/metabolism ; Oxidative Stress ; Rats ; Ribose/metabolism ; }, abstract = {Pancreatic β-cells are vulnerable to oxidative stress, which promotes β-cell failure in type 2 diabetes. System χc- is a sodium-independent, cystine/glutamate antiporter that mediates the exchange of extracellular l-cystine and intracellular l-glutamate. The import of l-cystine through this transporter is the rate-limiting step in the glutathione (GSH) biosynthesis pathway that plays a significant role in antioxidative defense. Previously, we reported that 2-deoxy-d-ribose (dRib) induces oxidative damage through GSH depletion in pancreatic β-cells. In the current study, we elucidated the mechanism underlying the oxidative stress-induced β-cell damage. We measured the intracellular l-[[14]C]cystine uptake, GSH content, reactive oxygen species (ROS) levels, cytotoxicity, and apoptosis in rat insulinoma cell line, RINm5F. Treatment of dRib decreased the intracellular l-[[14]C]cystine uptake and GSH content and increased the intracellular ROS levels, cytotoxicity, and apoptosis in a time- and dose-dependent manner. Conversely, 2-mercaptoethanol (2-ME), a cystine uptake enhancer, recovered the dRib-induced decrease in l-[[14]C]cystine uptake, GSH content, and cell viability in a Na[+]-independent manner. In the case of isolated islets, dRib dose-dependently decreased the intracellular l-[[14]C]cystine uptake and cell viability; however, dRib-induced cytotoxicity was completely recovered by adding N-acetyl cysteine (NAC). To confirm that system χc- mediates the oxidative stress-induced β-cell damage, we overexpressed xCT (the substrate-specific subunit of system χc-) using a lentiviral vector in RINm5F cells. Overexpression of xCT fully recovered the dRib-induced decrease in l-[[14]C]cystine uptake and GSH content and prevented the dRib-induced increase in ROS levels, cytotoxicity, and apoptosis. The overexpression of xCT showed a protective effect against dRib-induced oxidative damage in RINm5F cells. Our study showed that dRib depletes intracellular GSH content through inhibition of cystine transport via system χc- in β-cells.}, }
@article {pmid32305626, year = {2020}, author = {Ścibior, A and Pietrzyk, &#x141; and Plewa, Z and Skiba, A}, title = {Vanadium: Risks and possible benefits in the light of a comprehensive overview of its pharmacotoxicological mechanisms and multi-applications with a summary of further research trends.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {61}, number = {}, pages = {126508}, pmid = {32305626}, issn = {1878-3252}, mesh = {Animals ; Anti-Infective Agents/adverse effects/pharmacology ; Anticholesteremic Agents/adverse effects/pharmacology ; Antineoplastic Agents/adverse effects/pharmacology ; Cardiotonic Agents/adverse effects/pharmacology ; Humans ; Hypoglycemic Agents/adverse effects/pharmacology ; Neuroprotective Agents/adverse effects/pharmacology ; Organometallic Compounds/adverse effects/*pharmacology ; Vanadium/adverse effects/*pharmacology ; }, abstract = {BACKGROUND: Vanadium (V) is an element with a wide range of effects on the mammalian organism. The ability of this metal to form organometallic compounds has contributed to the increase in the number of studies on the multidirectional biological activity of its various organic complexes in view of their application in medicine.<br><br>OBJECTIVE: This review aims at summarizing the current state of knowledge of the pharmacological potential of V and the mechanisms underlying its anti-viral, anti-bacterial, anti-parasitic, anti-fungal, anti-cancer, anti-diabetic, anti-hypercholesterolemic, cardioprotective, and neuroprotective activity as well as the mechanisms of appetite regulation related to the possibility of using this element in the treatment of obesity. The toxicological potential of V and the mechanisms of its toxic action, which have not been sufficiently recognized yet, as well as key information about the essentiality of this metal, its physiological role, and metabolism with certain aspects on the timeline is collected as well. The report also aims to review the use of V in the implantology and industrial sectors emphasizing the human health hazard as well as collect data on the directions of further research on V and its interactions with Mg along with their character.<br><br>RESULTS AND CONCLUSIONS: Multidirectional studies on V have shown that further analyses are still required for this element to be used as a metallodrug in the fight against certain life-threatening diseases. Studies on interactions of V with Mg, which showed that both elements are able to modulate the response in an interactive manner are needed as well, as the results of such investigations may help not only in recognizing new markers of V toxicity and clarify the underlying interactive mechanism between them, thus improving the medical application of the metals against modern-age diseases, but also they may help in development of principles of effective protection of humans against environmental/occupational V exposure.}, }
@article {pmid32303987, year = {2020}, author = {Jiang, M and Liu, Y and Wu, H and Ma, Z and Gu, X}, title = {High Estrogen Level Modifies Postoperative Hyperalgesia via GPR30 and MMP-9 in Dorsal Root Ganglia Neurons.}, journal = {Neurochemical research}, volume = {45}, number = {7}, pages = {1661-1673}, doi = {10.1007/s11064-020-03032-z}, pmid = {32303987}, issn = {1573-6903}, support = {81500955//National Natural Science Foundation of China/ ; 81600958//National Natural Science Foundation of China/ ; 81771142//National Natural Science Foundation of China/ ; 81671087//National Natural Science Foundation of China/ ; 81870871//National Natural Science Foundation of China/ ; 1701022B//Jiangsu Planned Projects for Postdoctoral Research Funds, China/ ; QRX17053//Nanjing Medical Science and Technique Development Foundation/ ; QRX17138//Nanjing Medical Science and Technique Development Foundation/ ; }, mesh = {Animals ; Benzodioxoles/pharmacology ; Estrogens/*metabolism ; Female ; Ganglia, Spinal/*metabolism ; Hyperalgesia/etiology/*metabolism/prevention &amp; control ; Matrix Metalloproteinase 9/*metabolism ; Ovariectomy/adverse effects ; Pain, Postoperative/etiology/*metabolism/prevention &amp; control ; Quinolines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The cycling of sex hormones is one of the factors affecting pain in females, and the mechanisms are not fully understood. G-protein coupled estrogen receptor 30 (GPR30) is the estrogen receptor known to be involved in mechanical hyperalgesia. Studies have demonstrated that matrix metalloproteinase-9 (MMP-9) is a critical component in peripheral/central nervous system hypersensitivity and neuroinflammation, both of which participate in hyperalgesia. Here, ovariectomized rats were treated with low or high dose estrogen replacement, and then plantar incisions were made. Subsequently, mechanical allodynia was evaluated by determining the paw withdrawal mechanical threshold before and after the incision. In rats with incisions, high estrogen levels induced postoperative hyperalgesia and upregulation of GPR30 and MMP-9 in dorsal root ganglia (DRGs). MMP-9 was expressed primarily in DRG neurons co-expressing GPR30, and led to the activation of IL-1β. After intrathecal injection of the GPR30 agonist G1, female rats with low estrogen and plantar incisions continued to exhibit significant hyperalgesia until 48 h post-incision. In high estrogen level rats with plantar incisions, intrathecal injection of GPR30 antagonist G15 significantly attenuated postoperative hyperalgesia. Intraperitoneal injection of N-acetyl-cysteine, a source of cysteine that prevents the oxidation of cysteine residues on MMP-9, significantly relieved high estrogen-induced postoperative hyperalgesia via suppression of MMP-9 and IL-1β activation in DRGs. These results demonstrate that high estrogen level in rats with incisions elicit GPR30 and MMP-9 upregulation in DRGs and subsequently activate IL-1β, leading to induced postoperative hyperalgesia.}, }
@article {pmid32301102, year = {2021}, author = {Mohey Issa, N and Al-Gholam, MA}, title = {The effect of N-acetylcysteine on the sensory retina of male albino rats exposed prenatally to cypermethrin.}, journal = {Folia morphologica}, volume = {80}, number = {1}, pages = {140-148}, doi = {10.5603/FM.a2020.0043}, pmid = {32301102}, issn = {1644-3284}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Female ; Male ; Placenta ; Pregnancy ; *Pyrethrins/toxicity ; Rats ; Retina ; }, abstract = {BACKGROUND: Cypermethrin (CYP), a pyrethroid that is globally used in the field and house to fight the pests. CYP can induce cellular toxicity and cross the placental barrier. N-acetylcysteine (NAC) can fight the prenatal exposure to the inflammation. This work aimed to study, for the first time, the effects of NAC on the sensory retina of male albino rats exposed prenatally to cypermethrin.<br><br>MATERIALS AND METHODS: Twenty-four sexually mature female albino rats and 12 male albino rats were allowed for mating and divided equally into the following groups: group I (control group): kept without treatment; group II (NAC group): received 1 g/kg/day NAC diluted in distilled water orally by gastric tube from the 7th day of gestation till delivery; group III (CYP group): received 12 mg/kg/day of cypermethrin orally by gastric tube from the 7th day of gestation till delivery; group IV (CYP and NAC group): received 12 mg/kg/day of cypermethrin and 1 g/kg/day of NAC. The ten male offspring of each group were divided into subgroups a and b that were sacrificed at the age of 7th and 14th days postnatal, respectively. At the end of the experiment, the eye samples were subjected to histological, immunohistochemical and morphometric studies.<br><br>RESULTS: Concerning the different previous studies, the sensory retina of CYP subgroups showed vacuolation of the inner and outer plexiform layers, dilated congested blood vessels, hyalinisation and disorganisation of the photoreceptor layer. Also, the expression of collagen IV and caspase 3 (a marker of apoptosis) was up-regulated in the CYP subgroups.<br><br>CONCLUSIONS: N-acetylcysteine significantly protected the sensory retina from the damaging effects of CYP. NAC could be considered as a good protective agent against the damaging effect of CYP on the sensory retina.}, }
@article {pmid32299733, year = {2020}, author = {Gardner, DK and Kuramoto, T and Tanaka, M and Mitzumoto, S and Montag, M and Yoshida, A}, title = {Prospective randomized multicentre comparison on sibling oocytes comparing G-Series media system with antioxidants versus standard G-Series media system.}, journal = {Reproductive biomedicine online}, volume = {40}, number = {5}, pages = {637-644}, doi = {10.1016/j.rbmo.2020.01.026}, pmid = {32299733}, issn = {1472-6491}, mesh = {Acetylcarnitine/analysis ; Acetylcysteine/analysis ; Adult ; Antioxidants/*analysis ; Culture Media/*chemistry ; Embryo Culture Techniques/*methods ; Embryo Transfer/methods ; Embryonic Development/*physiology ; Female ; Fertilization in Vitro/*methods ; Humans ; *Oocytes ; Pregnancy ; Pregnancy Rate ; Prospective Studies ; Thioctic Acid/analysis ; }, abstract = {RESEARCH QUESTION: Does the inclusion of three antioxidants (A3), acetyl-l-carnitine (ALC), N-acetyl-l-cysteine (NAC) and alpha-lipoic acid (ALA) improve human embryo development and pregnancy potential?<br><br>DESIGN: Prospective randomized multicentre comparison of sibling oocytes. A total of 1563 metaphase II oocytes from 133 patients in two IVF centres. Day 3 embryo and day 5/6 blastocyst quality were assessed. Good embryo quality on day 3 was defined as 8 to 10 cells with even cells and low fragmentation; good quality blastocysts as 3BB or greater. Clinical outcome was assessed on transfers of fresh or vitrified-warmed blastocyst on day 5.<br><br>RESULTS: Of the two-pronuclei, 40.7% (G-Series) and 50.2% (G-Series with A3 group) resulted in good quality embryos on day 3 (P < 0.05). The implantation rate by fetal sac was 39.2% and 50.6%, and by fetal heartbeat was 37.8% and 47.1% for the G-Series and G-Series with A3 group, respectively. When stratified by female patient age, patients 35-40 years had an implantation rate by fetal sac and heart of 23.5% in the G-Series compared with 57.5% (P < 0.05) and 50.0% (P < 0.05) in the A3 group. The ongoing pregnancies in patients 35-40 years were significantly higher in the A3 group (50%) compared with the control (25.8%) (P < 0.05).<br><br>CONCLUSIONS: The presence of antioxidants during IVF and embryo culture for patients 35-40 years resulted in a significant increase in implantation and pregnancy rate. Supplementation of antioxidants to IVF and culture media may therefore improve the viability of human embryos in assisted reproductive technologies, plausibly through the reduction of oxidative stress.}, }
@article {pmid32293491, year = {2020}, author = {Wang, DP and Wang, ZJ and Zhao, R and Lin, CX and Sun, QY and Yan, CP and Zhou, X and Cao, JM}, title = {Silica nanomaterials induce organ injuries by Ca[2+]-ROS-initiated disruption of the endothelial barrier and triggering intravascular coagulation.}, journal = {Particle and fibre toxicology}, volume = {17}, number = {1}, pages = {12}, pmid = {32293491}, issn = {1743-8977}, mesh = {Animals ; Aorta/drug effects/metabolism/pathology ; Calcium Signaling/*drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*drug effects/metabolism/pathology ; Erythrocyte Aggregation/*drug effects ; Heart/*drug effects ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism/pathology ; Humans ; Mice, Inbred BALB C ; Nanoparticles/*toxicity ; Organ Specificity ; Particle Size ; Reactive Oxygen Species/*metabolism ; Silicon Dioxide/*toxicity ; Surface Properties ; }, abstract = {BACKGROUND: The growing use of silica nanoparticles (SiNPs) in many fields raises human toxicity concerns. We studied the toxicity of SiNP-20 (particle diameter 20 nm) and SiNP-100 (100 nm) and the underlying mechanisms with a focus on the endothelium both in vitro and in vivo.<br><br>METHODS: The study was conducted in cultured human umbilical vein endothelial cells (HUVECs) and adult female Balb/c mice using several techniques.<br><br>RESULTS: In vitro, both SiNP-20 and SiNP-100 decreased the viability and damaged the plasma membrane of cultured HUVECs. The nanoparticles also inhibited HUVECs migration and tube formation in a concentration-dependent manner. Both SiNPs induced significant calcium mobilization and generation of reactive oxygen species (ROS), increased the phosphorylation of vascular endothelial (VE)-cadherin at the site of tyrosine 731 residue (pY731-VEC), decreased the expression of VE-cadherin expression, disrupted the junctional VE-cadherin continuity and induced F-actin re-assembly in HUVECs. The injuries were reversed by blocking Ca[2+] release activated Ca[2+] (CRAC) channels with YM58483 or by eliminating ROS with N-acetyl cysteine (NAC). In vivo, both SiNP-20 and SiNP-100 (i.v.) induced multiple organ injuries of Balb/c mice in a dose (range 7-35&#x2009;mg/kg), particle size, and exposure time (4-72&#x2009;h)-dependent manner. Heart injuries included coronary endothelial damage, erythrocyte adhesion to coronary intima and coronary coagulation. Abdominal aorta injury exhibited intimal neoplasm formation. Lung injuries were smaller pulmonary vein coagulation, bronchiolar epithelial edema and lumen oozing and narrowing. Liver injuries included multifocal necrosis and smaller hepatic vein congestion and coagulation. Kidney injuries involved glomerular congestion and swelling. Macrophage infiltration occurred in all of the observed organ tissues after SiNPs exposure. SiNPs also decreased VE-cadherin expression and altered VE-cadherin spatial distribution in multiple organ tissues in vivo. The largest SiNP (SiNP-100) and longest exposure time exerted the greatest toxicity both in vitro and in vivo.<br><br>CONCLUSIONS: SiNPs, administrated in vivo, induced multiple organ injuries, including endothelial damage, intravascular coagulation, and secondary inflammation. The injuries are likely caused by upstream Ca[2+]-ROS signaling and downstream VE-cadherin phosphorylation and destruction and F-actin remodeling. These changes led to endothelial barrier disruption and triggering of the contact coagulation pathway.}, }
@article {pmid32290715, year = {2020}, author = {Triggs, T and Kumar, S and Mitchell, M}, title = {Experimental drugs for the inhibition of preterm labor.}, journal = {Expert opinion on investigational drugs}, volume = {29}, number = {5}, pages = {507-523}, doi = {10.1080/13543784.2020.1752661}, pmid = {32290715}, issn = {1744-7658}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Drug Development ; Drugs, Investigational/*pharmacology ; Female ; Humans ; Infant, Newborn ; Obstetric Labor, Premature/*drug therapy/physiopathology ; Pregnancy ; Premature Birth/*prevention &amp; control ; }, abstract = {INTRODUCTION: Preterm birth is the leading cause of neonatal morbidity and mortality globally and poses a substantial economic burden. Consequently, there is a need for the identification of therapeutic targets and novel experimental drugs for the inhibition of preterm labor to improve neonatal outcomes.<br><br>AREAS COVERED: The authors review the pathophysiology of labor and the inflammatory pathways underpinning it. The interruption of these pathways forms the basis of therapeutic targets to inhibit preterm labor. Current drugs available for the treatment of preterm labor are reviewed, followed by experimental drugs including toll-like receptor 4 (TLR-4) antagonists, cytokine suppressive anti-inflammatory drugs (CSAIDs), N-acetyl cysteine (NAC), Sulfasalazine (SSZ), tumor necrosis factor-alpha (TNF-&#x3b1;) antagonists, interleukin-1 receptor (IL-1) inhibitors, omega-3 polyunsaturated fatty acids and lipid metabolites, and the polyphenols.<br><br>EXPERT OPINION: A number of new therapeutic strategies for the prevention of preterm labor are being investigated. These have the potential to improve neurodevelopmental outcomes and survival in babies born preterm, reducing the economic and healthcare costs of caring for the complex needs of these children in the immediate and long term. It is likely that over the next decade there will be a new treatment option that targets the pathological inflammatory processes involved in preterm labor.}, }
@article {pmid32285913, year = {2020}, author = {Liu, P and Chen, T and Tan, F and Tian, J and Zheng, L and Deng, Y and Chen, J and Chi, X}, title = {Dexmedetomidine alleviated neuropathic pain in dorsal root ganglion neurons by inhibition of anaerobic glycolysis activity and enhancement of ROS tolerance.}, journal = {Bioscience reports}, volume = {40}, number = {5}, pages = {}, pmid = {32285913}, issn = {1573-4935}, mesh = {Acetylcysteine/pharmacology ; Anaerobiosis/drug effects ; Animals ; Apoptosis/drug effects ; Cells, Cultured ; Dexmedetomidine/*pharmacology/therapeutic use ; Disease Models, Animal ; Ganglia, Spinal/cytology ; Glucose/analysis/metabolism ; Glycolysis/*drug effects ; Humans ; Hydrogen Peroxide/toxicity ; Neuralgia/chemically induced/*drug therapy/pathology ; Neurons/*drug effects/pathology ; Primary Cell Culture ; Rats ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Neuropathic pain is a kind of chronic pain that is triggered or caused primarily by damage to the nervous system and neurological dysfunction. It's known that dexmedetomidine is a new type of highly selective alpha2-adrenoceptor agonist with sedation, anti-anxiety, analgesic and other effects. However, the function and mechanism of dexmedetomidine on neuropathic pain are not clear. Rat DRG neurons were isolated and identified using immunofluorescence assay. Following treatment with H2O2, dexmedetomidine or ROS inhibitor (NAC), the apoptosis and ROS levels were examined by flow cytometery; apoptosis- and anaerobic glycolysis-related proteins were determined by Western blot assay; glucose consumption, pyruvic acid, lactic acid and ATP/ADP ratios were also measured. The results revealed that dexmedetomidine inhibited H2O2-induced apoptosis and reactive oxygen species (ROS) in rat DRG neurons and in addition, dexmedetomidine down-regulated the expression levels of anaerobic glycolysis-related proteins, significantly reduced glucose, pyruvic acid and lactic acid levels. It also increased the ATP/ADP ratio in H2O2-treated rat dorsal root ganglion (DRG) neurons. Moreover, we also demonstrated that ROS inhibitor (NAC) also inhibited H2O2-induced apoptosis and anaerobic glycolysis in rat DRG neurons. In conclusion, dexmedetomidine suppressed H2O2-induced apoptosis and anaerobic glycolysis activity by inhibiting ROS, in rat DRG neurons. Therefore, dexmedetomidine might play a pivotal role in neuropathic pain by the inhibition of ROS.}, }
@article {pmid32283380, year = {2020}, author = {Xie, C and Ge, M and Jin, J and Xu, H and Mao, L and Geng, S and Wu, J and Zhu, J and Li, X and Zhong, C}, title = {Mechanism investigation on Bisphenol S-induced oxidative stress and inflammation in murine RAW264.7 cells: The role of NLRP3 inflammasome, TLR4, Nrf2 and MAPK.}, journal = {Journal of hazardous materials}, volume = {394}, number = {}, pages = {122549}, doi = {10.1016/j.jhazmat.2020.122549}, pmid = {32283380}, issn = {1873-3336}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Cell Survival/drug effects ; Free Radical Scavengers/pharmacology ; Inflammasomes/*drug effects ; Inflammation/*chemically induced ; MAP Kinase Signaling System/*drug effects ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; NF-E2-Related Factor 2/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidative Stress/*drug effects ; Phenols/*toxicity ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; Sulfones/*toxicity ; Toll-Like Receptor 4/metabolism ; }, abstract = {Bisphenol S is considered as a safer alternative to bisphenol A. In the present study, we used murine macrophages to investigate the effects of BPS exposure on oxidative stress and inflammatory response as well as the underlying mechanism. Cells were exposed to BPS at various concentrations for short period of times. Results showed that 10[-8] M BPS triggered oxidative stress by increasing ROS/RNS production, increased the levels of oxidant enzyme NOX1/2, and decreased the levels of antioxidant enzymes SOD1/2, CAT and GSH-Px. 10[-8] M BPS exposure significantly induced the production of proinflammatory mediators. Activation of the NLRP3 inflammasome, TLR4, and MAPK pathways was involved in this process. Furthermore, we illustrated that NAC pretreatment diminished these effects triggered by BPS exposure. Collectively, our data suggested that BPS at a dose relevant to human serum concentration induced oxidative stress and inflammatory response in macrophages. These novel findings shed light on the concerns regarding the potential adverse effects of BPS exposure that requires further careful attention.}, }
@article {pmid32281194, year = {2020}, author = {Mehrbani Azar, Y and Niesler, CU and van de Vyver, M}, title = {Ex vivo antioxidant preconditioning improves the survival rate of bone marrow stem cells in the presence of wound fluid.}, journal = {Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society}, volume = {28}, number = {4}, pages = {506-516}, doi = {10.1111/wrr.12815}, pmid = {32281194}, issn = {1524-475X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*analogs &amp; derivatives/pharmacology ; Case-Control Studies ; Cell Movement/*drug effects ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Diabetes Mellitus/metabolism ; Exudates and Transudates ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*drug effects ; Mice ; Mice, Obese ; Osteogenesis ; Prediabetic State/*metabolism ; Transplantation, Autologous ; Wounds and Injuries/*metabolism ; }, abstract = {The advancement of autologous mesenchymal stem cell (MSC) therapy for the treatment of non-healing diabetic wounds is hampered by endogenous MSC dysfunction and limited viability of cells post-transplantation into the pathological wound environment. The development of effective strategies to restore the functional capabilities of these impaired MSCs prior to transplantation may be a key to their ultimate success as wound repair mediators. The current study therefore investigated whether antioxidant preconditioning [7.5 mM N-acetylcysteine (NAC) + 0.6 mM ascorbic 2-phosphate (AAP)] could restore the growth rate, migration ability and viability of impaired MSCs and whether this restored state is maintained in the presence of diabetic wound fluid (DWF). Healthy control (source: wild type, C57BL/6J mice) (n = 12) and impaired/diabetic MSCs (source: obese prediabetic, B6.Cg-Lepob/J mice) (n = 12) were isolated from the bone marrow of mice. Treatment groups post-isolation were as follow: (a) No treatment (baseline phenotype): MSCs expanded in standard growth media (SGM) (±8 days) and only exposed to growth media. (b) DWF (baseline response): MSCs expanded in SGM (±8 days) followed by exposure to DWF (24 hours, 48 hours, 96 hours). (c) Antioxidant preconditioning (preconditioned phenotype): MSCs expanded in the presence of NAC/AAP (±8 days). (d) Antioxidant preconditioning + DWF (preconditioned response): MSCs expanded in the presence of NAC/AAP (±8 days) followed by exposure to DWF (24 hours, 48 hours, 96 hours). The results demonstrated that expansion of MSCs (both healthy control and impaired diabetic) in the presence of combined NAC/AAP treatment improved ex vivo MSC viability and protected MSCs in the presence of DWF. Despite improved viability, AAP/NAC could however not rescue the reduced proliferation and migration capacity of impaired diabetic MSCs. The protective effect of NAC/AAP preconditioning against the toxicity of DWF could however be a potential strategy to improve cell number post-transplantation.}, }
@article {pmid32279039, year = {2020}, author = {Purroy, R and Medina-Carbonero, M and Ros, J and Tamarit, J}, title = {Frataxin-deficient cardiomyocytes present an altered thiol-redox state which targets actin and pyruvate dehydrogenase.}, journal = {Redox biology}, volume = {32}, number = {}, pages = {101520}, pmid = {32279039}, issn = {2213-2317}, mesh = {Actins/metabolism ; Animals ; *Friedreich Ataxia/genetics/metabolism ; Iron-Binding Proteins ; *Myocytes, Cardiac/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Oxidoreductases/metabolism ; Pyruvates/metabolism ; Rats ; Sulfhydryl Compounds/metabolism ; Frataxin ; }, abstract = {Friedreich ataxia (FA) is a cardioneurodegenerative disease caused by deficient frataxin expression. This mitochondrial protein has been related to iron homeostasis, energy metabolism, and oxidative stress. Previously, we set up a cardiac cellular model of FA based on neonatal rat cardiac myocytes (NRVM) and lentivirus-mediated frataxin RNA interference. These frataxin-deficient NRVMs presented lipid droplet accumulation, mitochondrial swelling and signs of oxidative stress. Therefore, we decided to explore the presence of protein thiol modifications in this model. With this purpose, reduced glutathione (GSH) levels were measured and the presence of glutathionylated proteins was analyzed. We observed decreased GSH content and increased presence of glutahionylated actin in frataxin-deficient NRVMs. Moreover, the presence of oxidized cysteine residues was investigated using the thiol-reactive fluorescent probe iodoacetamide-Bodipy and 2D-gel electrophoresis. With this approach, we identified two proteins with altered redox status in frataxin-deficient NRVMs: electron transfer flavoprotein-ubiquinone oxidoreductase and dihydrolipoyl dehydrogenase (DLDH). As DLDH is involved in protein-bound lipoic acid redox cycling, we analyzed the redox state of this cofactor and we observed that lipoic acid from pyruvate dehydrogenase was more oxidized in frataxin-deficient cells. Also, by targeted proteomics, we observed a decreased content on the PDH A1 subunit from pyruvate dehydrogenase. Finally, we analyzed the consequences of supplementing frataxin-deficient NRVMs with the PDH cofactors thiamine and lipoic acid, the PDH activator dichloroacetate and the antioxidants N-acetyl cysteine and Tiron. Both dichloroacetate and Tiron were able to partially prevent lipid droplet accumulation in these cells. Overall, these results indicate that frataxin-deficient NRVMs present an altered thiol-redox state which could contribute to the cardiac pathology.}, }
@article {pmid32269708, year = {2020}, author = {Zhou, X and Wang, Z and Ni, Y and Yu, Y and Wang, G and Chen, L}, title = {Suppression effect of N-acetylcysteine on bone loss in ovariectomized mice.}, journal = {American journal of translational research}, volume = {12}, number = {3}, pages = {731-742}, pmid = {32269708}, issn = {1943-8141}, abstract = {Oxidative stress can trigger DNA damage response and activation of cellular senescence. Accumulating studies have demonstrated that senescent cells can produce senescence-associated secretory phenotype that leads to increased bone resorption and decreased bone formation. And elimination of senescent cells or inhibition of SASP secretion has been shown to prevent bone loss in mice. N-acetylcysteine (NAC) is a strong antioxidant. However, it is unclear whether reversed estrogen deficiency-induced bone loss by antioxidant NAC was associated with the inhibition of oxidative stress, DNA damage, osteocyte senescence and SASP. In this study, OVX mice were supplemented with/without E2 or NAC, and were compared with each other. Our results showed that oxidative stress, DNA damage, osteocyte senescence and the secretion of senescence-associated inflammatory cytokines were increased in OVX mice compared with sham-operated mice. However, these parameters were obviously rescued in OVX mice supplemented with E2 or NAC. Data from this study suggest that NAC can prevent OVX-induced bone loss by inhibiting oxidative stress, DNA damage, cell senescence and the secretion of the senescence-associated secretory phenotype.}, }
@article {pmid32264788, year = {2022}, author = {Shahat, AS and Hassan, WA and El-Sayed, WM}, title = {N-Acetylcysteine and Safranal prevented the brain damage induced by hyperthyroidism in adult male rats.}, journal = {Nutritional neuroscience}, volume = {25}, number = {2}, pages = {231-245}, doi = {10.1080/1028415X.2020.1743917}, pmid = {32264788}, issn = {1476-8305}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Brain/metabolism ; Cyclohexenes/adverse effects ; *Hyperthyroidism/chemically induced/complications/pathology ; Male ; Oxidative Stress ; Rats ; Terpenes ; }, abstract = {Background: Hyperthyroidism is associated with impairment in the neurotransmission and severe tissue damage in the brain. The present study explored the potential deleterious effects of experimentally-induced hyperthyroidism on the neurotransmitters, oxidative homeostasis, apoptosis and DNA fragmentation in cerebral cortex, thalamus &amp; hypothalamus, and hippocampus in rats.Methods and Results: The ameliorative effects of N-acetylcysteine (NAC; 50 mg/kg, oral) and safranal (50 mg/kg, intraperitoneal) against hyperthyroidism (L-T4 500 µg/kg, subcutaneous) were investigated. All treatments continued daily over three weeks. Hyperthyroidism was manifested by significant elevations in serum fT3 and fT4 levels and a decline in serum TSH level and body weight. It was also characterized by significant elevations in the levels of dopamine, serotonin, and 5-hydroxyindole acetic acid, and monoamine oxidase activity to varying degrees in the brain regions examined and a significant reduction in norepinephrine in hippocampus only. Hyperthyroidism resulted in a significant oxidative stress in brain typified by elevations in malondialdehyde and nitric oxide content and reductions in glutathione level and SOD and catalase activities. This led to elevations in Caspases 9 and 3 and a reduction in Bcl2 resulting in DNA damage and confirmed by the histopathology of brain tissue. The administration of NAC or safranal with L-T4 prevented these deleterious effects by reducing the oxidative load and improving the brain antioxidant status.Conclusions: Hyperthyroidism disrupted the neurotransmitters in the brain which aggravated the oxidative stress and resulted in apoptosis. N-Acetylcysteine and safranal prevented these deleterious effects by enhancing the poor antioxidant milieu of the brain.}, }
@article {pmid32259323, year = {2020}, author = {Wei, D and Yang, Y and Ricketts, CJ and Vocke, CD and Ball, MW and Sourbier, C and Wangsa, D and Wangsa, D and Guha, R and Zhang, X and Wilson, K and Chen, L and Meltzer, PS and Ried, T and Thomas, CJ and Merino, MJ and Linehan, WM}, title = {Novel renal medullary carcinoma cell lines, UOK353 and UOK360, provide preclinical tools to identify new therapeutic treatments.}, journal = {Genes, chromosomes &amp; cancer}, volume = {59}, number = {8}, pages = {472-483}, pmid = {32259323}, issn = {1098-2264}, support = {ZIA BC011089//Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research/International ; ZIA BC011028/ImNIH/Intramural NIH HHS/United States ; ZIA BC011038/ImNIH/Intramural NIH HHS/United States ; ZIC BC011044/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/pharmacology/therapeutic use ; Bortezomib/pharmacology/therapeutic use ; Carcinoma, Medullary/drug therapy/genetics/*pathology ; Cell Line Authentication/methods ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cisplatin/pharmacology/therapeutic use ; Enhancer of Zeste Homolog 2 Protein/genetics/metabolism ; Humans ; Kidney Neoplasms/drug therapy/genetics/*pathology ; Mice ; Mice, Nude ; Primary Cell Culture/*methods ; SMARCB1 Protein/genetics/metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays/*methods ; }, abstract = {Renal medullary carcinoma (RMC) is a rare, aggressive disease that predominantly afflicts individuals of African or Mediterranean descent with sickle cell trait. RMC comprises 1% of all renal cell carcinoma diagnoses with a median overall survival of 13 months. Patients are typically young (median age-22) and male (male:female ratio of 2:1) and tumors are characterized by complete loss of expression of the SMARCB1 tumor suppressor protein. Due to the low incidence of RMC and the disease's aggressiveness, treatment decisions are often based on case reports. Thus, it is critical to develop preclinical models of RMC to better understand the pathogenesis of this disease and to identify effective forms of therapy. Two novel cell line models, UOK353 and UOK360, were derived from primary RMCs that both demonstrated the characteristic SMARCB1 loss. Both cell lines overexpressed EZH2 and other members of the polycomb repressive complex and EZH2 inhibition in RMC tumor spheroids resulted in decreased viability. High throughput drug screening of both cell lines revealed several additional candidate compounds, including bortezomib that had both in vitro and in vivo antitumor activity. The activity of bortezomib was shown to be partially dependent on increased oxidative stress as addition of the N-acetyl cysteine antioxidant reduced the effect on cell proliferation. Combining bortezomib and cisplatin further decreased cell viability both in vitro and in vivo that single agent bortezomib treatment. The UOK353 and UOK360 cell lines represent novel preclinical models for the development of effective forms of therapy for RMC patients.}, }
@article {pmid32257694, year = {2020}, author = {Parvataneni, S and Vemuri-Reddy, S}, title = {N-acetyl Cysteine Use in the Treatment of Shock Liver.}, journal = {Cureus}, volume = {12}, number = {2}, pages = {e7149}, pmid = {32257694}, issn = {2168-8184}, abstract = {Acute liver failure is a rare, life-threatening illness accounting for about 7% of all liver-related deaths. Patients with acute liver failure are managed with supportive care initially, and if supportive care fails, liver transplantation is the definitive option for eligible candidates in liver failure. N-acetyl cysteine (NAC) has a well-established role in acetaminophen-induced liver failure and has been reported to reduce mortality in these patients. It has also been reported to provide benefit in non-acetaminophen-induced liver failure secondary to infection, drugs, and toxins. Here we report an interesting case of NAC use in an elderly patient with shock liver secondary to severe sepsis in whom liver transplantation was not an option.}, }
@article {pmid32256822, year = {2020}, author = {Yao, H and Fan, M and He, X}, title = {Autophagy suppresses resveratrol-induced apoptosis in renal cell carcinoma 786-O cells.}, journal = {Oncology letters}, volume = {19}, number = {4}, pages = {3269-3277}, pmid = {32256822}, issn = {1792-1074}, abstract = {As a polyphenolic compound, resveratrol (Res) is widely distributed in a variety of plants. Previous studies have demonstrated that Res can inhibit various different types of tumor growth. However, its role in renal cell carcinoma (RCC) remains largely unknown. The present study first demonstrated that Res inhibited cell viability and induced apoptosis in RCC 786-O cells. Further experiments revealed that Res damaged the mitochondria and activated caspase 3. In contrast, Z-VAD-FMK, a pan-caspase inhibitor, suppressed Res-induced apoptosis. Reactive oxygen species (ROS) were involved in the process of Res-induced apoptosis, and antioxidant N-acetyl cysteine could significantly attenuate this. Furthermore, Res activated c-Jun N-terminal kinase via ROS to induce autophagy, whereas inhibition of autophagy with chloroquine or Beclin 1 small interfering RNA aggravated Res-induced apoptosis, indicating that autophagy served as a pro-survival mechanism to protect 786-O cells from Res-induced apoptosis. Therefore, a combination of Res and autophagy inhibitors could enhance the inhibitory effect of Res on RCC.}, }
@article {pmid32250212, year = {2020}, author = {di Michele, F and Talamo, A and Niolu, C and Siracusano, A}, title = {Vitamin D and N-Acetyl Cysteine Supplementation in Treatment-Resistant Depressive Disorder Patients: A General Review.}, journal = {Current pharmaceutical design}, volume = {26}, number = {21}, pages = {2442-2459}, doi = {10.2174/1381612826666200406090051}, pmid = {32250212}, issn = {1873-4286}, mesh = {Acetylcysteine ; Aged ; *Depressive Disorder, Major/drug therapy ; *Depressive Disorder, Treatment-Resistant ; Dietary Supplements ; Humans ; Vitamin D ; }, abstract = {Major Depressive Disorder (MDD) is often a lifetime disabling mental illness as individuals with MDD might not benefit from standard-therapy, including both pharmacological and psychosocial interventions. Novel therapies are, therefore, required. It was shown by recent preclinical and clinical studies that the dysfunction of glutamatergic neurotransmission might be involved in the pathophysiology of MDD. Furthermore, neuroimmune alterations could have a significant role in the pathogenesis of MDD. Vitamin D is a neurosteroid hormone essential for several metabolic processes, immune responses, and for regulating neurotrophic-neuroprotective processes, neurotransmission and synaptic plasticity. Recent studies have also shown Vitamin D deficiency in patients with severe psychiatric disorders, including MDD. Lately, clinical studies have shown the neuroprotective action of N-acetyl cysteine (NAC) through the modulation of inflammatory pathways and via the modulation of synaptic release of glutamate in cortico-subcortical brain regions; the cysteine-glutamate antiporter. This paper reviews the therapeutic use of Vitamin D and NAC and among individuals with refractory MDD to the first- line pharmacological interventions, reviewing the clinical studies published in the last decade. A detailed summary of the current evidence in this area aims to better inform psychiatrists and general practitioners on the potential benefits of Vitamin D and NAC supplementation for this disorder. Nutraceutical supplementation with Vitamin D and NAC in treatment-resistant MDD patients may be important not only for improving depressive clinical manifestations but also for their safety and tolerability profile. This is of great interest, especially considering the need for treating special populations affected by MDD, such as youngsters and elders. Finally, the nutraceutical approach represents a good choice, considering its better compliance by the patients compared to traditional psychopharmacological treatment.}, }
@article {pmid32247160, year = {2020}, author = {Balhara, A and Ladumor, M and Singh, DK and Praneetha, P and Preethi, J and Pokharkar, S and Deshpande, AY and Giri, S and Singh, S}, title = {In vitro evaluation of reactive nature of E- and Z-guggulsterones and their metabolites in human liver microsomes using UHPLC-Orbitrap mass spectrometer.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {186}, number = {}, pages = {113275}, doi = {10.1016/j.jpba.2020.113275}, pmid = {32247160}, issn = {1873-264X}, mesh = {Acetylcysteine/chemistry ; Biotransformation ; Chromatography, High Pressure Liquid ; Commiphora ; Computer Simulation ; Drug Eruptions ; Glutathione/chemistry ; Humans ; Isomerism ; Mass Spectrometry ; Microsomes, Liver/*metabolism ; Plant Extracts/adverse effects/analysis/toxicity ; Plant Gums/adverse effects/analysis/toxicity ; Pregnenediones/*metabolism/pharmacokinetics/toxicity ; }, abstract = {Guggulipid is known to be useful for hypercholesterolemia, arthritis, acne, and obesity. These activities are attributed to its two principal isomeric active constituents, viz., E- and Z-guggulsterones. There are several side effects reported for guggulipid, which include widespread erythematous papules in a morbilliform pattern and macules localized to the arms; swelling and erythema of the face with burning sensation; pruritis; and bullous lesions on the lower legs with associated headaches, myalgia and itching. We hypothesized that one probable reason for these toxic reactions could be the formation of electrophilic reactive metabolites (RMs) of guggulsterones and their subsequent reaction with cellular proteins. Unfortunately, no report exists in the literature highlighting detection of RMs of guggulsterone isomers. Accordingly, the present study was undertaken to investigate the potential of E- and Z-guggulsterones to form RMs in human liver microsomes (HLM) using glutathione (GSH) and N-acetylcysteine (NAC) as trapping agents. The generated samples were analysed using ultra-high performance liquid chromatography (UHPLC) coupled to an Orbitrap mass spectrometer. The analysis of incubations with trapping agents highlighted that hydroxylated metabolites of guggulsterone isomers showed adduction with GSH and NAC. Even direct adducts of guggulsterone isomers were observed with both the trapping agents. The in silico toxicity potential of E- and Z-guggulsterones and their RMs was predicted using ADMET Predictor™ software and comparison was made against reported toxicities of guggulipid.}, }
@article {pmid32244726, year = {2020}, author = {Gorwood, J and Ejlalmanesh, T and Bourgeois, C and Mantecon, M and Rose, C and Atlan, M and Desjardins, D and Le Grand, R and Fève, B and Lambotte, O and Capeau, J and Béréziat, V and Lagathu, C}, title = {SIV Infection and the HIV Proteins Tat and Nef Induce Senescence in Adipose Tissue and Human Adipose Stem Cells, Resulting in Adipocyte Dysfunction.}, journal = {Cells}, volume = {9}, number = {4}, pages = {}, pmid = {32244726}, issn = {2073-4409}, mesh = {Acetylcysteine/pharmacology ; Adipocytes/drug effects/pathology/*virology ; Adipogenesis/drug effects ; Adipose Tissue/*pathology ; Animals ; *Cellular Senescence/drug effects ; Humans ; Insulin Resistance ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Macaca fascicularis ; Mitochondria/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Simian Acquired Immunodeficiency Syndrome/*virology ; Simian Immunodeficiency Virus/drug effects/*physiology ; Stem Cells/drug effects/pathology/*virology ; nef Gene Products, Human Immunodeficiency Virus/*metabolism ; tat Gene Products, Human Immunodeficiency Virus/*metabolism ; }, abstract = {BACKGROUND: Aging is characterized by adipose tissue senescence, inflammation, and fibrosis, with trunk fat accumulation. Aging HIV-infected patients have a higher risk of trunk fat accumulation than uninfected individuals-suggesting that viral infection has a role in adipose tissue aging. We previously demonstrated that HIV/SIV infection and the Tat and Nef viral proteins were responsible for adipose tissue fibrosis and impaired adipogenesis. We hypothesized that SIV/HIV infection and viral proteins could induce adipose tissue senescence and thus lead to adipocyte dysfunctions.<br><br>METHODS: Features of tissue senescence were evaluated in subcutaneous and visceral adipose tissues of SIV-infected macaques and in human adipose stem cells (ASCs) exposed to Tat or Nef for up to 30 days.<br><br>RESULTS: p16 expression and p53 activation were higher in adipose tissue of SIV-infected macaques than in control macaques, indicating adipose tissue senescence. Tat and Nef induced higher senescence in ASCs, characterized by higher levels of senescence-associated beta-galactosidase activity, p16 expression, and p53 activation vs. control cells. Treatment with Tat and Nef also induced oxidative stress and mitochondrial dysfunction. Prevention of oxidative stress (using N-acetyl-cysteine) reduced senescence in ASCs. Adipocytes having differentiated from Nef-treated ASCs displayed alterations in adipogenesis with lower levels of triglyceride accumulation and adipocyte marker expression and secretion, and insulin resistance.<br><br>CONCLUSION: HIV/SIV promotes adipose tissue senescence, which in turn may alter adipocyte function and contribute to insulin resistance.}, }
@article {pmid32244335, year = {2020}, author = {Sugita, Y and Okubo, T and Saita, M and Ishijima, M and Torii, Y and Tanaka, M and Iwasaki, C and Sekiya, T and Tabuchi, M and Mohammadzadeh Rezaei, N and Taniyama, T and Sato, N and Saruta, J and Hasegawa, M and Hirota, M and Park, W and Lee, MC and Maeda, H and Ogawa, T}, title = {Novel Osteogenic Behaviors around Hydrophilic and Radical-Free 4-META/MMA-TBB: Implications of an Osseointegrating Bone Cement.}, journal = {International journal of molecular sciences}, volume = {21}, number = {7}, pages = {}, pmid = {32244335}, issn = {1422-0067}, mesh = {Animals ; Arthroplasty, Replacement, Hip ; Biocompatible Materials/chemistry/pharmacology ; Bone Cements/chemistry/*pharmacology ; Bone Marrow Cells/drug effects ; Bone Regeneration/drug effects ; Bone and Bones/drug effects/pathology ; Boranes ; Boron Compounds/chemistry/*pharmacology ; Calcification, Physiologic/drug effects ; Cell Line ; Cell Survival/drug effects ; Free Radicals/chemistry/*pharmacology ; Hydrophobic and Hydrophilic Interactions ; Male ; Materials Testing ; Methacrylates/chemistry/*pharmacology ; Methylmethacrylate/chemistry ; Methylmethacrylates/chemistry/*pharmacology ; Osteoblasts/drug effects/pathology ; Osteogenesis/*drug effects/genetics ; Phenotype ; Polymerization ; Polymethyl Methacrylate/chemistry/pharmacology ; Prostheses and Implants ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Poly(methyl methacrylate) (PMMA)-based bone cement, which is widely used to affix orthopedic metallic implants, is considered bio-tolerant but lacks osteoconductivity and is cytotoxic. Implant loosening and toxic complications are significant and recognized problems. Here we devised two strategies to improve PMMA-based bone cement: (1) adding 4-methacryloyloxylethyl trimellitate anhydride (4-META) to MMA monomer to render it hydrophilic; and (2) using tri-n-butyl borane (TBB) as a polymerization initiator instead of benzoyl peroxide (BPO) to reduce free radical production. Rat bone marrow-derived osteoblasts were cultured on PMMA-BPO, common bone cement ingredients, and 4-META/MMA-TBB, newly formulated ingredients. After 24 h of incubation, more cells survived on 4-META/MMA-TBB than on PMMA-BPO. The mineralized area was 20-times greater on 4-META/MMA-TBB than PMMA-BPO at the later culture stage and was accompanied by upregulated osteogenic gene expression. The strength of bone-to-cement integration in rat femurs was 4- and 7-times greater for 4-META/MMA-TBB than PMMA-BPO during early- and late-stage healing, respectively. MicroCT and histomorphometric analyses revealed contact osteogenesis exclusively around 4-META/MMA-TBB, with minimal soft tissue interposition. Hydrophilicity of 4-META/MMA-TBB was sustained for 24 h, particularly under wet conditions, whereas PMMA-BPO was hydrophobic immediately after mixing and was unaffected by time or condition. Electron spin resonance (ESR) spectroscopy revealed that the free radical production for 4-META/MMA-TBB was 1/10 to 1/20 that of PMMA-BPO within 24 h, and the substantial difference persisted for at least 10 days. The compromised ability of PMMA-BPO in recruiting cells was substantially alleviated by adding free radical-scavenging amino-acid N-acetyl cysteine (NAC) into the material, whereas adding NAC did not affect the ability of 4-META/MMA-TBB. These results suggest that 4-META/MMA-TBB shows significantly reduced cytotoxicity compared to PMMA-BPO and induces osteoconductivity due to uniquely created hydrophilic and radical-free interface. Further pre-clinical and clinical validations are warranted.}, }
@article {pmid32241444, year = {2020}, author = {Asim, MH and Silberhumer, S and Shahzadi, I and Jalil, A and Matuszczak, B and Bernkop-Schnürch, A}, title = {S-protected thiolated hyaluronic acid: In-situ crosslinking hydrogels for 3D cell culture scaffold.}, journal = {Carbohydrate polymers}, volume = {237}, number = {}, pages = {116092}, doi = {10.1016/j.carbpol.2020.116092}, pmid = {32241444}, issn = {1879-1344}, mesh = {Animals ; Caco-2 Cells ; *Cell Culture Techniques ; Cell Proliferation ; Cysteine/*analogs &amp; derivatives ; Humans ; Hyaluronic Acid/*analogs &amp; derivatives ; Hydrogels/*chemical synthesis ; Mice ; NIH 3T3 Cells ; Rheology ; *Tissue Engineering ; Viscosity ; }, abstract = {The purpose of this study was to synthesize S-protected thiolated hyaluronic acid (HA) and to evaluate its potential for 3D cell culture scaffold. S-protected thiolated HA was synthesized by the covalent attachment of N-acetyl-S-((3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)thio)cysteine hydrazide ligand to the HA. Hydrogels were characterized for texture, swelling behavior and rheological properties. Furthermore, the potential of S-protected thiolated HA hydrogels as a scaffold for tissue engineering was evaluated by cell proliferation studies with Caco-2 and NIH 3T3 cells. It showed enhanced cohesion upon addition of N-acetyl cysteine (NAC). Dynamic viscosity of S-protected thiolated HA hydrogel was increased up to 19.5-fold by addition of NAC and 10.1-fold after mixing with mucus. Furthermore, Caco-2 and NIH 3T3 cells encapsulated into hydrogels proliferated in-vitro. As this novel S-protected thiolated HA is stable towards oxidation and forms highly cohesive gels when getting into contact with endogenous thiols due to disulfide-crosslinking, it is a promising tool for 3D cell culture scaffold.}, }
@article {pmid32239919, year = {2020}, author = {Caroselli, S and Zwergel, C and Pirolli, A and Sabatino, M and Xu, Z and Kirsch, G and Mai, A and Colotti, G and Altieri, F and Canipari, R and Valente, S and Ragno, R}, title = {Discovery of the First Human Arylsulfatase A Reversible Inhibitor Impairing Mouse Oocyte Fertilization.}, journal = {ACS chemical biology}, volume = {15}, number = {6}, pages = {1349-1357}, doi = {10.1021/acschembio.9b00999}, pmid = {32239919}, issn = {1554-8937}, mesh = {Animals ; Arylsulfatases/*antagonists &amp; inhibitors/metabolism ; Cell Line, Tumor ; Coumarins/chemistry/*pharmacology ; Drug Discovery ; Enzyme Inhibitors/chemistry/*pharmacology ; Female ; Fertilization/*drug effects ; Humans ; Male ; Mice ; Molecular Docking Simulation ; Oocytes/*drug effects/physiology ; Sperm Motility/drug effects ; Spermatozoa/drug effects/physiology ; }, abstract = {Arylsulfatase A (ARSA) plays a crucial role in the reproduction of mammals due to its involvement in the specific gamete interaction preceding sperm and egg fusion leading to fertilization. Recently, it has been shown that zona pellucida (ZP) sperm binding and in vivo fertilization in mice are markedly hampered by using a specific anti-ARSA antibody. Herein, the design and discovery of the first ARSA small molecule inhibitor based on a coumarin-containing polycycle are presented. Through a structure-based approach applied on our in-house library, compound 1r was identified as an ARSA reversible inhibitor (ARSAi); then its activity was validated through both surface plasmon resonance and biochemical inhibition experiments, the first providing a KD value of 21 μM and the latter an IC50 value of 13.2 μM. Further investigations highlighted that compound 1r induced 20% sperm death at 25 μM and also impaired sperm motility; nevertheless both the effects were mediated by ROS production, since they were rescued by the cotreatment of 1r and N-acetyl cysteine (NAC). Interestingly, while 1r was not able to hamper the ZP/sperm binding, it markedly decreased the in vitro oocyte fertilization by mouse sperm up to 60%. Notably, this effect was not hampered by 1r/NAC coadministration, hence allowing the ruling out of an ROS-dependent mechanism. In conclusion, herein is reported the first ever hit of ARSAi as a chemical tool that will enable better exploration of ARSA's biological role in fertilization as well as provide a starting point for developing 1r structure optimization aimed at increasing enzyme inhibition potency but also providing a deeper understanding of the involvement of ARSA in the fertilization pathway mechanism.}, }
@article {pmid32239424, year = {2020}, author = {Eroglu, N and Erduran, E and Reis, GP and Bahadır, A}, title = {Therapeutic effect of N-acetylcysteine on chemotherapy-induced liver injury.}, journal = {Irish journal of medical science}, volume = {189}, number = {4}, pages = {1189-1194}, doi = {10.1007/s11845-020-02219-1}, pmid = {32239424}, issn = {1863-4362}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adolescent ; Animals ; Chemical and Drug Induced Liver Injury/*drug therapy ; Child ; Child, Preschool ; Disease Models, Animal ; Female ; Humans ; Liver/*injuries ; Male ; Retrospective Studies ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) may be useful in the management of chemotherapy-induced liver injury.<br><br>AIMS: The present study evaluates the possible therapeutic effects of NAC on chemotherapy-induced hepatotoxicity.<br><br>METHODS: A total of 102 patients' files who were diagnosed with cancer between 2015 and 2019 were evaluated retrospectively. Two patient groups with and without NAC were selected. NAC was administered in a 3-&#x3bc;g/kg IV dose in a 24-h infusion to 70 patients when any alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) values reached three times the normal levels. The other group consisted of 32 patients who were not treated with NAC. Alanine aminotransferase and GGT values were recorded at pretreatment, and on the 1st, 3rd, 5th, and 7th days in both the NAC and non-NAC groups from files.<br><br>RESULTS: In the NAC group, ALT and GGT values on day 1, 3, 5, and 7 differed from each other, decreasing from day 1 to day 7. A statistically significant difference was noted between the values in the NAC group (p&#x2009;<&#x2009;0.001). In the non-NAC group, the ALT values on day 7 were lower than the ALT values on day 1. A comparison of the ALT and GGT values in the NAC and non-NAC groups found that the values in the NAC group decreased earlier than in the non-NAC group.<br><br>CONCLUSIONS: This study shows that NAC has a therapeutic effect on hepatotoxicity in children being treated with chemotherapeutic agents due to underlying malign diseases. The early reduction in the results of liver function tests is important for the continuation of chemotherapy.}, }
@article {pmid32235559, year = {2020}, author = {Beltran, C and Pardo, R and Bou-Teen, D and Ruiz-Meana, M and Villena, JA and Ferreira-González, I and Barba, I}, title = {Enhancing Glycolysis Protects against Ischemia-Reperfusion Injury by Reducing ROS Production.}, journal = {Metabolites}, volume = {10}, number = {4}, pages = {}, pmid = {32235559}, issn = {2218-1989}, support = {PI14/01431 and PI17/01397//Instituto de Salud Carlos III/ ; BFU2015-64462R//Ministerio de Economia y Competitividad/ ; HR17-00627//La Caixa Fundation/ ; }, abstract = {After myocardial ischemia-reperfusion, fatty acid oxidation shows fast recovery while glucose oxidation rates remain depressed. A metabolic shift aimed at increasing glucose oxidation has shown to be beneficial in models of myocardial ischemia-reperfusion. However, strategies aimed at increasing glucose consumption in the clinic have provided mixed results and have not yet reached routine clinical practice. A better understanding of the mechanisms underlying the protection afforded by increased glucose oxidation may facilitate the transfer to the clinic. The purpose of this study was to evaluate if the modulation of reactive oxygen species (ROS) was involved in the protection afforded by increased glucose oxidation. Firstly, we characterized an H9C2 cellular model in which the use of glucose or galactose as substrates can modulate glycolysis and oxidative phosphorylation pathways. In this model, there were no differences in morphology, cell number, or ATP and PCr levels. However, galactose-grown cells consumed more oxygen and had an increased Krebs cycle turnover, while cells grown in glucose had increased aerobic glycolysis rate as demonstrated by higher lactate and alanine production. Increased aerobic glycolysis was associated with reduced ROS levels and protected the cells against simulated ischemia-reperfusion injury. Furthermore, ROS scavenger N-acetyl cysteine (NAC) was able to reduce the amount of ROS and to prevent cell death. Lastly, cells grown in galactose showed higher activation of mTOR/Akt signaling pathways. In conclusion, our results provide evidence indicating that metabolic shift towards increased glycolysis reduces mitochondrial ROS production and prevents cell death during ischemia-reperfusion injury.}, }
@article {pmid32234235, year = {2020}, author = {Otsu, W and Ishida, K and Nakamura, S and Shimazawa, M and Tsusaki, H and Hara, H}, title = {Blue light-emitting diode irradiation promotes transcription factor EB-mediated lysosome biogenesis and lysosomal cell death in murine photoreceptor-derived cells.}, journal = {Biochemical and biophysical research communications}, volume = {526}, number = {2}, pages = {479-484}, doi = {10.1016/j.bbrc.2020.03.118}, pmid = {32234235}, issn = {1090-2104}, mesh = {Active Transport, Cell Nucleus/radiation effects ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*metabolism ; Cell Death/*radiation effects ; Cell Line ; Light/*adverse effects ; Lysosomes/metabolism/*radiation effects ; Mice ; Oxidative Stress/radiation effects ; Photoreceptor Cells, Vertebrate/metabolism/*radiation effects ; }, abstract = {Exposure to blue light from light-emitting diodes (LEDs) is a source of damage for human eyes in today's modern life. Although it is well known that blue light can cause cellular damage and death, the molecular mechanism underlying this is still not fully understood. Here, we demonstrated that exposure to blue LED light increased lysosome levels and perinuclear cluster formation in 661W murine photoreceptor-derived cells. Irradiation with blue LED light promoted the nuclear transport of transcription factor EB (TFEB) and a subsequent increase in lysosomal-related gene expression. Moreover, blue LED light induced morphological changes in lysosomal structure and lysosomal membrane permeabilization (LMP). These effects were suppressed by an antioxidant, N-acetylcysteine (NAC). Finally, a calcium ion chelator, BAPTA-AM, attenuated blue LED light-induced lysosomal biogenesis and cell death. Taken together, these findings suggest that oxidative stress under blue LED light increases lysosome levels via the TFEB pathway in a calcium-dependent manner, resulting in the accumulation of damaged lysosomes and subsequently lysosomal cell death. Our results imply that lysosomal homeostasis plays a key role in the maintenance of eye function and the progression of retinal diseases.}, }
@article {pmid32233142, year = {2020}, author = {Kang, HG and Kim, JW}, title = {Effect of Minoxidil on Trabecular Outflow via the Paracellular Pathway.}, journal = {Korean journal of ophthalmology : KJO}, volume = {34}, number = {2}, pages = {97-105}, pmid = {32233142}, issn = {2092-9382}, mesh = {Blotting, Western ; Cells, Cultured ; Humans ; Minoxidil/*pharmacology ; Nitric Oxide/metabolism ; Permeability/drug effects ; Reactive Oxygen Species/*metabolism ; Trabecular Meshwork/cytology/*drug effects/metabolism ; Vasodilator Agents/pharmacology ; }, abstract = {PURPOSE: To investigate the pathway and effects of minoxidil on trabecular outflow in cultured human trabecular meshwork (TM) cells.<br><br>METHODS: After exposing primarily cultured TM cells to 0, 10, 50, or 100 &#x3bc;M minoxidil sulfate (MS), trabecular outflow was assessed by measuring TM cell monolayer permeability to carboxyfluorescein and transepithelial electrical resistance. To assess the pathway of permeability changes, caveolin-1, occludin, and claudin-5 levels were measured via western blot. Generation of reactive oxygen species (ROS) was measured using the dichlorofluorescein diacetate assay. To assess the involvement of nitric oxide (NO) in minoxidil-induced permeability increase, the degrees of endothelial nitric oxide synthase mRNA expression and NO production were measured with reverse transcription polymerase chain reaction and Griess assays, respectively. Permeability was also measured with co-exposure to 50 &#x3bc;M N-acetyl cysteine.<br><br>RESULTS: MS significantly increased TM cell monolayer permeability (p < 0.05) and decreased transepithelial electrical resistance (p < 0.05). MS decreased the degree of endothelial nitric oxide synthase mRNA expression but did not affect NO production. MS decreased occludin and claudin-5 levels but did not affect caveolin-1 level. MS at 100 &#x3bc;M increased the generation of ROS, and MS-induced permeability increase was attenuated after co-exposure to 50 &#x3bc;M N-acetyl cysteine.<br><br>CONCLUSIONS: Minoxidil may preferentially increase trabecular permeability via a paracellular pathway by downregulation of tight junction proteins. This minoxidil-induced permeability through the TM may be mediated by generation of ROS.}, }
@article {pmid32231783, year = {2020}, author = {Suganthan, N and Sakthilingham, G and Kumanan, T}, title = {Dengue fever complicated with acute liver failure: A case report of expanded dengue syndrome and literature review.}, journal = {SAGE open medical case reports}, volume = {8}, number = {}, pages = {2050313X20913428}, pmid = {32231783}, issn = {2050-313X}, abstract = {Dengue is the most common arboviral disease, the presentation of which ranges from asymptomatic illness to dengue shock syndrome. Liver is the most common organ affected in dengue, and liver involvement is asymptomatic in majority. Dengue fever is a rare, but a leading cause for acute liver failure in endemic regions. Here, we report a case of a 34-year-old male ethanol user (16 units per week), presented with typical features of dengue infection, which was confirmed serologically, complicated with acute liver failure without clinical, radiological or laboratory evidence of plasma leakage. He was managed with intravenous fresh frozen plasma and N-acetyl cysteine along with other recommended supportive therapies for acute hepatic failure. He made an uneventful recovery.}, }
@article {pmid32229256, year = {2020}, author = {Kularatne, RN and Bulumulla, C and Catchpole, T and Takacs, A and Christie, A and Stefan, MC and Csaky, KG}, title = {Protection of human retinal pigment epithelial cells from oxidative damage using cysteine prodrugs.}, journal = {Free radical biology &amp; medicine}, volume = {152}, number = {}, pages = {386-394}, doi = {10.1016/j.freeradbiomed.2020.03.024}, pmid = {32229256}, issn = {1873-4596}, mesh = {Aged ; Epithelial Cells ; Humans ; Oxidative Stress ; *Prodrugs/pharmacology ; Retinal Pigment Epithelium ; Retinal Pigments ; }, abstract = {Age-related macular degeneration (AMD) is one of the major causes of vision loss in the elderly in most developed countries. Among other causes, oxidative stress in the retinal pigment epithelium (RPE) has been hypothesized to be a major driving force of AMD pathology. Oxidative stress could be treated by antioxidant administration into the RPE cells. However, to achieve high in-vivo efficacy of an antioxidant, it is imperative that the agent be able to penetrate the tissues and cells. Evidence suggests that lipophilicity governs cellular penetrance. Out of many antioxidant candidates, N-acetyl-L-cysteine (a prodrug of L-cysteine) (NAC) is a potent antioxidant as the bioavailability of the parent drug, L-cysteine, determines the production of glutathione; the universal antioxidant that regulates ROS. To increase the lipophilicity, four ester derivatives of N-acetylcysteine: N-acetylcysteine methyl ester, N-acetylcysteine ethyl ester, N-acetylcysteine propyl ester, and N-acetylcysteine butyl ester were synthesized. To mimic in vitro AMD conditions, hydroquinone, a component of cigarette smoke, was used as the oxidative insult. Cytosolic and mitochondrial protection against oxidative stress were tested using cytosolic and mitochondrial specific assays. The results provide evidence that these lipophilic cysteine prodrugs provide increased protection against oxidative stress in human RPE cells compared with NAC.}, }
@article {pmid32227122, year = {2020}, author = {Huang, Y and Li, Y and Lou, A and Wang, GZ and Hu, Y and Zhang, Y and Huang, W and Wang, J and Li, Y and Zhu, X and Chen, T and Lin, J and Meng, Y and Li, X}, title = {Alamandine attenuates hepatic fibrosis by regulating autophagy induced by NOX4-dependent ROS.}, journal = {Clinical science (London, England : 1979)}, volume = {134}, number = {7}, pages = {853-869}, doi = {10.1042/CS20191235}, pmid = {32227122}, issn = {1470-8736}, mesh = {Angiotensin-Converting Enzyme 2 ; Animals ; Antioxidants/*pharmacology ; Autophagy/*drug effects ; Carbon Tetrachloride ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/enzymology/etiology/pathology/*prevention &amp; control ; Collagen/metabolism ; Hepatic Stellate Cells/*drug effects/enzymology/ultrastructure ; Hydrogen Peroxide/*metabolism ; Liver/*drug effects/enzymology/ultrastructure ; Liver Cirrhosis, Experimental/chemically induced/enzymology/pathology/*prevention &amp; control ; Male ; NADPH Oxidase 4/*metabolism ; Nerve Tissue Proteins/drug effects/metabolism ; Oligopeptides/*pharmacology ; Oxidative Stress/drug effects ; Peptidyl-Dipeptidase A/metabolism ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled/drug effects/metabolism ; Renin-Angiotensin System/drug effects ; Signal Transduction ; }, abstract = {Angiotensin II (Ang II) has been reported to aggravate hepatic fibrosis by inducing NADPH oxidase (NOX)-dependent oxidative stress. Alamandine (ALA) protects against fibrosis by counteracting Ang II via the MAS-related G-protein coupled (MrgD) receptor, though the effects of alamandine on hepatic fibrosis remain unknown. Autophagy activated by reactive oxygen species (ROS) is a novel mechanism of hepatic fibrosis. However, whether autophagy is involved in the regulation of Ang II-induced hepatic fibrosis still requires investigation. We explored the effect of alamandine on hepatic fibrosis via regulation of autophagy by redox balance modulation. In vivo, alamandine reduced CCl4-induced hepatic fibrosis, hydrogen peroxide (H2O2) content, protein levels of NOX4 and autophagy impairment. In vitro, Ang II treatment elevated NOX4 protein expression and ROS production along with up-regulation of the angiotensin converting enzyme (ACE)/Ang II/Ang II type 1 receptor (AT1R) axis. These changes resulted in the accumulation of impaired autophagosomes in hepatic stellate cells (HSCs). Treatment with NOX4 inhibitor VAS2870, ROS scavenger N-acetylcysteine (NAC), and NOX4 small interfering RNA (siRNA) inhibited Ang II-induced autophagy and collagen synthesis. Alamandine shifted the balance of renin-angiotensin system (RAS) toward the angiotensin converting enzyme 2 (ACE2)/alamandine/MrgD axis, and inhibited both Ang II-induced ROS and autophagy activation, leading to attenuation of HSCs migration or collagen synthesis. In summary, alamandine attenuated liver fibrosis by regulating autophagy induced by NOX4-dependent ROS.}, }
@article {pmid32222530, year = {2020}, author = {Zhang, P and Zhao, S and Lu, X and Shi, Z and Liu, H and Zhu, B}, title = {Metformin enhances the sensitivity of colorectal cancer cells to cisplatin through ROS-mediated PI3K/Akt signaling pathway.}, journal = {Gene}, volume = {745}, number = {}, pages = {144623}, doi = {10.1016/j.gene.2020.144623}, pmid = {32222530}, issn = {1879-0038}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use ; Cell Survival/drug effects ; Cisplatin/*pharmacology/therapeutic use ; Colorectal Neoplasms/*drug therapy/pathology ; Drug Resistance, Neoplasm/drug effects ; HCT116 Cells ; Humans ; Metformin/*pharmacology/therapeutic use ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Signal Transduction/*drug effects ; }, abstract = {Metformin and cisplatin have been widely studied as antitumor agents. However, the effect of metformin combined with cisplatin has not been investigated in colorectal cancer (CRC) cells. This study was aimed to explore the effect of metformin or/and cisplatin on cell viability, apoptosis, and the related signaling pathways in CRC SW480 and SW620 cells. We found that metformin or cisplatin inhibited cell viability of SW480 and SW620 cells in a concentration- and time-dependent manner. Furthermore, metformin combined with cisplatin obviously inhibited cell viability, decreased colony formation, induced apoptosis, mediated cleavage of caspase-9, caspase-3 and PARP, activated mitochondrial membrane potential, downregulated Mcl-1 and Bcl-2 expression, upregulated Bak and Bax expression, and increased reactive oxygen species (ROS) production, compared to the individual agent in SW480 and SW620 cells, which were attenuated by N-acetyl-L-cysteine (NAC), a ROS scavenger. Moreover, NAC could recover the downregulation of p-PI3K and p-Akt treated with combination of metformin and cisplatin, which subsequently activated the PI3K/Akt signaling pathway. Taken together, our results demonstrated that metformin enhanced the sensitivity of CRC cells to cisplatin through ROS-mediated PI3K/Akt signaling pathway.}, }
@article {pmid32222495, year = {2020}, author = {Georgiou-Siafis, SK and Samiotaki, MK and Demopoulos, VJ and Panayotou, G and Tsiftsoglou, AS}, title = {Formation of novel N-acetylcysteine-hemin adducts abrogates hemin-induced cytotoxicity and suppresses the NRF2-driven stress response in human pro-erythroid K562 cells.}, journal = {European journal of pharmacology}, volume = {880}, number = {}, pages = {173077}, doi = {10.1016/j.ejphar.2020.173077}, pmid = {32222495}, issn = {1879-0712}, mesh = {Acetylcysteine/*pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Hemin/*pharmacology ; Humans ; K562 Cells ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress/drug effects ; Protective Agents/*pharmacology ; }, abstract = {Heme (iron protoporphyrin IX), as the prosthetic group in hemoproteins, regulates vital cellular functions in human tissues. However, free heme released during hemolysis events promotes severe complications to millions of people worldwide. Over the years, thiols like glutathione (GSH) were known to antagonize heme toxicity. In this study, we have uncovered the underlying molecular mechanism by which N-acetylcysteine (NAC), a well-known thiol prevents hemin-induced cytotoxicity (HIC). Hemin-responsive human pro-erythroid K562 cells were employed to assess hemin intracellular accumulation and cytotoxicity at concentrations ≥50 μΜ, in cultures exposed only to hemin and/or both hemin and NAC. NAC inhibited the intracellular accumulation of hemin and prevented hemin-induced cell growth inhibition, cell death, oxidative stress, and accumulation of ubiquitinated proteins. Meanwhile, the activation of the NF-E2-related factor-2 (NRF2)-driven stress gene activation, a key element involved in HIC, was suppressed by NAC. A refined mechanism of the chemical reaction between NAC and hemin leading to adduct formation via a nucleophilic attack on hemin was uncovered for the first time by tandem mass spectrometry analysis (LC-MS/MS). Such thiol-hemin adducts acted as intermediates to mitigate HIC and to suppress hemin-induced NRF2-driven gene activation. Our findings support the concept that NAC-hemin adduct formation is the major novel molecular mechanism rather than the reactive oxygen species-scavenging capacity of thiols to protect cells from HIC. Our results imply that thiols and their derivatives can be of potential therapeutic value in hemolytic disorders.}, }
@article {pmid32221675, year = {2021}, author = {Pietruski, P and Paskal, W and Paluch, &#x141; and Paskal, AM and Nitek, &#x17b; and Włodarski, P and Walecki, J and Noszczyk, B}, title = {The Impact of N-Acetylcysteine on Autologous Fat Graft: First-in-Human Pilot Study.}, journal = {Aesthetic plastic surgery}, volume = {45}, number = {5}, pages = {2397-2405}, pmid = {32221675}, issn = {1432-5241}, support = {501-1-06-09-17//Medical Centre for Postgraduate Education/ ; }, mesh = {*Acetylcysteine/pharmacology ; Adipose Tissue ; Adult ; Female ; Humans ; *Mammaplasty ; Pilot Projects ; Retrospective Studies ; Transplantation, Autologous ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Our goal was to determine whether N-acetylcysteine (NAC) administered to the tumescent solution can reduce oxidative stress and increase autologous fat graft (AFG) viability.<br><br>METHODS: The study included 15 women with a mean age of 31.8&#xa0;years (range 23-39&#xa0;years) who underwent breast asymmetry correction with AFG harvested from both thighs. One thigh was infiltrated with a standard tumescent fluid (control graft) and other with a NAC-enriched tumescent fluid (NAC-treated graft). Each participant had breast MRI imaging before and 6&#xa0;months after the procedure. Also, adipose tissue samples from each graft were subjected to biochemical analysis, flow cytometric assay and qRT-PCR to determine the markers of oxidative stress, angiogenesis and adipogenesis.<br><br>RESULTS: Concentration and activity of superoxide dismutase in the NAC-treated grafts turned out to be significantly higher than in the control grafts, in both fresh (p&#x2009;=&#x2009;0.041 and p&#x2009;=&#x2009;0.023, respectively) and frozen samples (p&#x2009;=&#x2009;0.004 and p&#x2009;=&#x2009;0.003, respectively). The level of nitric oxide in frozen samples from the control grafts was significantly higher than in the NAC-treated grafts (p&#x2009;=&#x2009;0.009). iNOS was the only qRT-PCR target showing significant intergroup differences, with higher transcription levels observed in the control grafts (p&#x2009;=&#x2009;0.027). Breast volumetric analysis demonstrated that the NAC-treated group had a 12.19% lower resorption rate than the control group, although it was found to be statistically insignificant (p&#x2009;=&#x2009;0.149). No postoperative complications were observed during a 6-month follow-up.<br><br>CONCLUSIONS: Some results of this study are promising. Further studies on larger groups are needed to determine NAC impact on AFG.<br><br>LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .<br><br>TRIAL REGISTRY NAME: The Impact of N-Acetylcysteine on Volumetric Retention of Autologous Fat Graft for Breast Asymmetry Correction.<br><br>NCT03197103. URL FOR THE REGISTRY: https://clinicaltrials.gov/ct2/show/NCT03197103?term=acetylcysteine&amp;rank=6.}, }
@article {pmid32218738, year = {2020}, author = {Chang, L and Xu, D and Zhu, J and Ge, G and Kong, X and Zhou, Y}, title = {Herbal Therapy for the Treatment of Acetaminophen-Associated Liver Injury: Recent Advances and Future Perspectives.}, journal = {Frontiers in pharmacology}, volume = {11}, number = {}, pages = {313}, pmid = {32218738}, issn = {1663-9812}, abstract = {Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury worldwide, and mitochondrial oxidative stress is considered the major event responsible for APAP-associated liver injury (ALI). Despite the identification of N-acetyl cysteine, a reactive oxygen species scavenger that is regarded as an effective clinical treatment, therapeutic effectiveness remains limited due to rapid disease progression and diagnosis at a late phase, which leads to the need to explore various therapeutic approaches. Since the early 1990s, a number of natural products and herbs have been found to have hepatoprotective effects against APAP-induced hepatotoxicity in terms of acute liver failure prevention and therapeutic amelioration of ALI. In this review, we summarize the hepatoprotective effects and mechanisms of medicinal plants, including herbs and fruit extracts, along with future perspectives that may provide guidance to improve the current status of herbal therapy against ALI.}, }
@article {pmid32215361, year = {2020}, author = {Kuygun Karcı, C and Gül Celik, G}, title = {Nutritional and herbal supplements in the treatment of obsessive compulsive disorder.}, journal = {General psychiatry}, volume = {33}, number = {2}, pages = {e100159}, pmid = {32215361}, issn = {2517-729X}, abstract = {Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder that is characterised by obsessions and compulsions. The recommended treatments for OCD are cognitive- behavioural therapy using exposure and response prevention and/or pharmacotherapy. On the other hand, some nutritional and herbal supplements may be effective in the treatment of OCD. Nutritional and herbal supplements in OCD treatment will be reviewed in this paper. PubMed (Medline), Cochrane Library and Google Scholar databases were reviewed for the topic. There are some supplements that have been researched in OCD treatment studies such as vitamin D, vitamin B12, folic acid, homocysteine, trace elements, N-acetyl cysteine, glycine, myoinositol, St John's wort, milk thistle, valerian root, curcumin and borage. The effectiveness of herbal and nutritional supplements in the treatment of OCD should be supported with more conclusive evidence.}, }
@article {pmid32214827, year = {2020}, author = {Liu, W and Chai, Y and Hu, L and Wang, J and Pan, X and Yuan, H and Zhao, Z and Song, Y and Zhang, Y}, title = {Polyphyllin VI Induces Apoptosis and Autophagy via Reactive Oxygen Species Mediated JNK and P38 Activation in Glioma.}, journal = {OncoTargets and therapy}, volume = {13}, number = {}, pages = {2275-2288}, pmid = {32214827}, issn = {1178-6930}, abstract = {BACKGROUND: Polyphyllin VI (PPVI), a bioactive component derived from a traditional Chinese herb Paris polyphylla, exhibits potential antitumor activity against hepatocellular carcinoma, as well as breast and lung cancers. However, its effect on glioma remains unknown.<br><br>METHODS: Five glioma cell lines (U251, U343, LN229, U87 and HEB) and an animal model were employed in the study. Anti-proliferation effects of PPVI were first determined using CCK-8 cell proliferation and clone formation assays, then reactive oxygen species (ROS), cell cycle progression and apoptosis effects measured by flow cytometry. The effect of PPVI on protein expression was quantified by Western blot analysis.<br><br>RESULTS: Data showed that PPVI inhibited the proliferation of glioma cell lines by modulating the G2/M phase. Additionally, incubation of cells with PPVI promoted apoptosis, autophagy, increased accumulation of ROS and activated ROS-modulated JNK and p38 pathways. On the other hand, N-acetyl cysteine, a ROS inhibitor, attenuated PPVI-triggered effects. Furthermore, JNK and p38 inhibitors ameliorated PPVI-triggered autophagy and apoptosis in glioma cells. In vivo assays showed that PPVI inhibited tumor growth of U87 cell line in nude mice.<br><br>CONCLUSION: Overall, these data suggested that PPVI might be an effective therapeutic agent for glioma.}, }
@article {pmid32212237, year = {2021}, author = {Woodcock, EA and Lundahl, LH and Khatib, D and Stanley, JA and Greenwald, MK}, title = {N-acetylcysteine reduces cocaine-seeking behavior and anterior cingulate glutamate/glutamine levels among cocaine-dependent individuals.}, journal = {Addiction biology}, volume = {26}, number = {2}, pages = {e12900}, pmid = {32212237}, issn = {1369-1600}, support = {F31 DA040369/DA/NIDA NIH HHS/United States ; K99 DA048125/DA/NIDA NIH HHS/United States ; R00 DA048125/DA/NIDA NIH HHS/United States ; R01 DA026861/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Cocaine-Related Disorders/*drug therapy ; Cross-Over Studies ; Double-Blind Method ; Drug-Seeking Behavior/*drug effects ; Female ; Glutamic Acid/*drug effects ; Glutamine/*drug effects ; Gyrus Cinguli/*drug effects ; Humans ; Male ; Middle Aged ; Proton Magnetic Resonance Spectroscopy ; Reward ; }, abstract = {N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm[3]). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.}, }
@article {pmid32212044, year = {2020}, author = {Elizabeth, MA and Samson, P and Itohan, OR}, title = {Histomorphological evaluations on the frontal cortex extrapyramidal cell layer following administration of N-Acetyl cysteine in aluminum induced neurodegeneration rat model.}, journal = {Metabolic brain disease}, volume = {35}, number = {5}, pages = {829-839}, pmid = {32212044}, issn = {1573-7365}, mesh = {Acetylcysteine/*therapeutic use ; *Aluminum ; Aluminum Chloride/toxicity ; Alzheimer Disease/chemically induced/drug therapy ; Animals ; Antioxidants/*therapeutic use ; Astrocytes/metabolism/pathology ; Extrapyramidal Tracts/*pathology ; Glial Fibrillary Acidic Protein/metabolism ; Gliosis/drug therapy/pathology ; Male ; Necrosis ; Neurodegenerative Diseases/*chemically induced/*drug therapy ; Neurons/pathology ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/drug effects ; Prefrontal Cortex/*pathology ; Rats ; Rats, Wistar ; }, abstract = {Aluminum is a potent neurotoxin used in animal models of neurodegenerative diseases like Alzheimer's disease (AD), in which oxidative stress mediates tissue pathogenesis in vivo. N-acetyl cysteine (NAC) is a glutathione precursor with reported antioxidant and neuroprotective potentials. Recent therapy for combating AD is known to provide only symptomatic relief thus necessitating the discovery of new drugs and their mechanism of action. This study was aimed to demonstrate the in vivo neuroprotective effect of NAC against aluminum (Al[3+])-induced neuro-degeneration in rats (a model for AD). Twenty- five (25) adult male Wistar rats used for this study were divided into 5 groups: Group A = Control, B = Aluminum chloride (200 mg/kg), C = 1000 mg/kg of NAC + Aluminum chloride (200 mg/kg), D = 1000 mg/kg of NAC, E = Aluminum chloride (200 mg/kg) was orally administered daily for 3 weeks and discontinued for one week. Frontal Cortex harvested for histological analysis using Haematoxylin and Eosin stain, Cresyl Fast Violet stain for Nissl granules and Glial fibrillary acidic protein immunohistochemistry specific for astrocytes. Aluminum significantly induced oxidative stress, coupled with marked neurons necrosis, chromatolysis and gliosis in the frontal cortex, upon NAC administration, there was neuro anti-inflammatory response as seen in the significant reduction in astrocytes expression, neuronal cell death and Nissl body aggregation which attenuates neuropathological deficits induced by Al[3+]. It was shown that aluminum is a neurotoxin mediating AD-like oxidative stress, NAC has a therapeutic potential associated with its potent in vivo interaction with astrocytes in response to Al[3+] neuro-inflammation seen in positive expression of Nissl granules and glial cells in addition to possibility of endogenous glutathione neuroprotection after withdrawal of stress mediator in neurodegeneration. Graphical abstract.}, }
@article {pmid32205843, year = {2020}, author = {Lee, DG and Kam, MK and Lee, SR and Lee, HJ and Lee, DS}, title = {Peroxiredoxin 5 deficiency exacerbates iron overload-induced neuronal death via ER-mediated mitochondrial fission in mouse hippocampus.}, journal = {Cell death &amp; disease}, volume = {11}, number = {3}, pages = {204}, pmid = {32205843}, issn = {2041-4889}, mesh = {Animals ; Cell Death/physiology ; Endoplasmic Reticulum/metabolism/pathology ; Endoplasmic Reticulum Stress ; Female ; Hippocampus/*metabolism/pathology ; Iron Overload/*metabolism ; Mice ; Mice, Inbred C57BL ; Mitochondrial Dynamics/*physiology ; Neurons/*metabolism/pathology ; Peroxiredoxins/*deficiency/genetics ; Pregnancy ; Signal Transduction ; }, abstract = {Iron is an essential element for cellular functions, including those of neuronal cells. However, an imbalance of iron homeostasis, such as iron overload, has been observed in several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Iron overload causes neuronal toxicity through mitochondrial fission, dysregulation of Ca[2+], ER-stress, and ROS production. Nevertheless, the precise mechanisms between iron-induced oxidative stress and iron toxicity related to mitochondria and endoplasmic reticulum (ER) in vivo are not fully understood. Here, we demonstrate the role of peroxiredoxin 5 (Prx5) in iron overload-induced neurotoxicity using Prx5-deficient mice. Iron concentrations and ROS levels in mice fed a high iron diet were significantly higher in Prx5[-/-] mice than wildtype (WT) mice. Prx5 deficiency also exacerbated ER-stress and ER-mediated mitochondrial fission via Ca[2+]/calcineurin-mediated dephosphorylation of Drp1 at Serine 637. Moreover, immunoreactive levels of cleaved caspase3 in the CA3 region of the hippocampus were higher in iron-loaded Prx5[-/-] mice than WT mice. Furthermore, treatment with N-acetyl-cysteine, a reactive oxygen species (ROS) scavenger, attenuated iron overload-induced hippocampal damage by inhibiting ROS production, ER-stress, and mitochondrial fission in iron-loaded Prx5[-/-] mice. Therefore, we suggest that iron overload-induced oxidative stress and ER-mediated mitochondrial fission may be essential for understanding iron-mediated neuronal cell death in the hippocampus and that Prx5 may be useful as a novel therapeutic target in the treatment of iron overload-mediated diseases and neurodegenerative diseases.}, }
@article {pmid32203558, year = {2020}, author = {Allen, MR and Wallace, J and McNerney, E and Nyman, J and Avin, K and Chen, N and Moe, S}, title = {N-acetylcysteine (NAC), an anti-oxidant, does not improve bone mechanical properties in a rat model of progressive chronic kidney disease-mineral bone disorder.}, journal = {PloS one}, volume = {15}, number = {3}, pages = {e0230379}, pmid = {32203558}, issn = {1932-6203}, support = {I01 BX001471/BX/BLRD VA/United States ; P30 AR072581/AR/NIAMS NIH HHS/United States ; K08 DK110429/DK/NIDDK NIH HHS/United States ; R01 DK110871/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/*administration &amp; dosage ; Caseins/administration &amp; dosage/adverse effects ; Chronic Kidney Disease-Mineral and Bone Disorder/blood/*drug therapy/etiology/pathology ; Disease Models, Animal ; Disease Progression ; Glycation End Products, Advanced/analysis ; Humans ; Kidney/drug effects/physiopathology ; Lipid Peroxidation/drug effects ; Male ; Mutation ; Nuclear Proteins/genetics ; Oxidative Stress/drug effects ; Parathyroid Hormone/blood ; Rats ; Tibia/chemistry/diagnostic imaging/*drug effects/pathology ; X-Ray Microtomography ; }, abstract = {Individuals with chronic kidney disease have elevated levels of oxidative stress and are at a significantly higher risk of skeletal fracture. Advanced glycation end products (AGEs), which accumulate in bone and compromise mechanical properties, are known to be driven in part by oxidative stress. The goal of this study was to study effects of N-acetylcysteine (NAC) on reducing oxidative stress and improving various bone parameters, most specifically mechanical properties, in an animal model of progressive CKD. Male Cy/+ (CKD) rats and unaffected littermates were untreated (controls) or treated with NAC (80 mg/kg, IP) from 30 to 35 weeks of age. Endpoint measures included serum biochemistries, assessments of systemic oxidative stress, bone morphology, and mechanical properties, and AGE levels in the bone. CKD rats had the expected phenotype that included low kidney function, elevated parathyroid hormone, higher cortical porosity, and compromised mechanical properties. NAC treatment had mixed effects on oxidative stress markers, significantly reducing TBARS (a measure of lipid peroxidation) while not affecting 8-OHdG (a marker of DNA oxidation) levels. AGE levels in the bone were elevated in CKD animals and were reduced with NAC although this did not translate to a benefit in bone mechanical properties. In conclusion, NAC failed to significantly improve bone architecture/geometry/mechanical properties in our rat model of progressive CKD.}, }
@article {pmid32203083, year = {2020}, author = {Bi, WK and Shao, SS and Li, ZW and Ruan, YW and Luan, SS and Dong, ZH and Wang, J and Wu, SS and Guo, T and Ma, SZ and Gao, L and Zhao, JJ and He, Z}, title = {FSHR ablation induces depression-like behaviors.}, journal = {Acta pharmacologica Sinica}, volume = {41}, number = {8}, pages = {1033-1040}, pmid = {32203083}, issn = {1745-7254}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line, Tumor ; Depression/genetics/*metabolism ; Female ; Menopause/genetics/*metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidative Stress/drug effects/physiology ; Pentose Phosphate Pathway/physiology ; Receptors, FSH/*deficiency/genetics ; }, abstract = {Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice (Fshr[-/-]). We found that Fshr[-/-] mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg[-1] · d[-1], i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr[-/-] mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.}, }
@article {pmid32194416, year = {2020}, author = {Mai, W and Xu, Y and Xu, J and Zhao, D and Ye, L and Yu, G and Wang, Z and Lu, Q and Lin, J and Yang, T and Gu, C and Liu, S and Zhong, Y and Yang, H}, title = {Berberine Inhibits Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation and Pyroptosis in Nonalcoholic Steatohepatitis via the ROS/TXNIP Axis.}, journal = {Frontiers in pharmacology}, volume = {11}, number = {}, pages = {185}, pmid = {32194416}, issn = {1663-9812}, abstract = {Berberine (BBR), an isoquinoline alkaloid originating from herbal plants, has been deemed beneficial for non-alcoholic fatty liver disease. Increasing evidence has demonstrated that Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and the subsequent pyroptosis contribute to the progression of non-alcoholic steatohepatitis (NASH). However, whether BBR impacts NLRP3 inflammasome activation and pyroptosis in NASH and the potential mechanism remains unclear. In the current study, we found that BBR significantly decreased lipid accumulation, ameliorated reactive oxygen species (ROS) and lipid peroxides, Tumor necrosis factor alpha (TNF-α) expression, and phosphorylation of Nuclear factor kappa B (NF-κB) p65 both in vivo and in vitro. In particular, BBR significantly inhibited NLRP3 expression, caspase-1 activity, and the pyroptosis executor, GSDMD-N, expression. In addition, BBR displayed similar inhibitory effects on NLRP3 inflammasome and pyroptosis with a decrease in ROS levels and TXNIP expression as N-acetyl-cysteine, a ROS scavenger, did. Whereas, the inhibitory effect of BBR on ROS, TXNIP expression, NLRP3 inflammasome activation and pyroptosis could be reversed by H2O2 in AML12 cells. This study demonstrates that BBR's inhibitory effect on NLRP3 inflammasome activation and pyroptosis may be mediated by ROS/TXNIP axis in vitro for the first time. Our findings suggest BBR is a potential candidate for the treatment of NASH.}, }
@article {pmid32193566, year = {2020}, author = {Rodrigues, DF and Pires das Neves, R and Carvalho, ATP and Lourdes Bastos, M and Costa, VM and Carvalho, F}, title = {In vitro mechanistic studies on α-amanitin and its putative antidotes.}, journal = {Archives of toxicology}, volume = {94}, number = {6}, pages = {2061-2078}, pmid = {32193566}, issn = {1432-0738}, mesh = {Adenosine Triphosphate/metabolism ; Alpha-Amanitin/*toxicity ; Antidotes/*pharmacology/toxicity ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; HeLa Cells ; Hep G2 Cells ; Hepatocytes/*drug effects/metabolism/pathology ; Humans ; Lysosomes/drug effects/metabolism/pathology ; Mitochondria, Liver/drug effects/metabolism/pathology ; Mushroom Poisoning/*drug therapy/metabolism/pathology ; RNA/biosynthesis ; RNA Polymerase II/metabolism ; Time Factors ; }, abstract = {α-Amanitin plays a key role in Amanita phalloides intoxications. The liver is a major target of α-amanitin toxicity, and while RNA polymerase II (RNA Pol II) transcription inhibition is a well-acknowledged mechanism of α-amanitin toxicity, other possible toxicological pathways remain to be elucidated. This study aimed to assess the mechanisms of α-amanitin hepatotoxicity in HepG2 cells. The putative protective effects of postulated antidotes were also tested in this cell model and in permeabilized HeLa cells. α-Amanitin (0.1-20 µM) displayed time- and concentration-dependent cytotoxicity, when evaluated through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction and neutral red uptake assays. Additionally, α-amanitin decreased nascent RNA synthesis in a concentration- and time-dependent manner. While α-amanitin did not induce changes in mitochondrial membrane potential, it caused a significant increase in intracellular ATP levels, which was not prevented by incubation with oligomycin, an ATP synthetase inhibitor. Concerning the cell redox status, α-amanitin did not increase reactive species production, but caused a significant increase in total and reduced glutathione, which was abolished by pre-incubation with the inhibitor of gamma-glutamylcysteine synthase, buthionine sulfoximine. None of the tested antidotes [N-acetyl cysteine, silibinin, benzylpenicillin, and polymyxin B (PolB)] conferred any protection against α-amanitin-induced cytotoxicity in HepG2 cells or reversed the inhibition of nascent RNA caused by the toxin in permeabilized HeLa cells. Still, PolB interfered with RNA Pol II activity at high concentrations, though not impacting on α-amanitin observed cytotoxicity. New hepatotoxic mechanisms of α-amanitin were described herein, but the lack of protection observed in clinically used antidotes may reflect the lack of knowledge on their true protection mechanisms and may explain their relatively low clinical efficacy.}, }
@article {pmid32192228, year = {2020}, author = {Bhattarai, N and Korhonen, E and Toppila, M and Koskela, A and Kaarniranta, K and Mysore, Y and Kauppinen, A}, title = {Resvega Alleviates Hydroquinone-Induced Oxidative Stress in ARPE-19 Cells.}, journal = {International journal of molecular sciences}, volume = {21}, number = {6}, pages = {}, pmid = {32192228}, issn = {1422-0067}, support = {297267, 307341, 328443, and 296840//Academy of Finland/ ; -//Emil Aaltosen S&#xe4;&#xe4;ti&#xf6;/ ; -//P&#xe4;ivikki ja Sakari Sohlberg Foundation/ ; -//Finnish Eye Foundation/ ; -//Sigrid Jus&#xe9;liuksen S&#xe4;&#xe4;ti&#xf6;/ ; -//Sokeain Yst&#xe4;v&#xe4;t ry/ ; -//Silm&#xe4;- ja kudospankkis&#xe4;&#xe4;ti&#xf6;/ ; }, mesh = {Antioxidants/pharmacology ; Biomarkers ; Cell Survival/drug effects ; Cytokines/metabolism ; Epithelial Cells/drug effects/metabolism ; Humans ; Hydroquinones/*pharmacology ; Inflammation Mediators/metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/cytology/metabolism ; }, abstract = {Retinal pigment epithelial (RPE) cells maintain homeostasis at the retina and they are under continuous oxidative stress. Cigarette smoke is a prominent environmental risk factor for age-related macular degeneration (AMD), which further increases the oxidant load in retinal tissues. In this study, we measured oxidative stress and inflammatory markers upon cigarette smoke-derived hydroquinone exposure on human ARPE-19 cells. In addition, we studied the effects of commercial Resvega product on hydroquinone-induced oxidative stress. Previously, it was observed that Resvega induces autophagy during impaired protein clearance in ARPE-19 cells, for which it has the potential to alleviate pro-inflammatory pathways. Cell viability was determined while using the lactate dehydrogenase (LDH) and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the cytokine levels were measured using the enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) production were measured using the 2',7'-dichlorofluorescin diacetate (H2DCFDA) probe. Hydroquinone compromised the cell viability and increased ROS production in ARPE-19 cells. Resvega significantly improved cell viability upon hydroquinone exposure and reduced the release of interleukin (IL)-8 and monocytic chemoattractant protein (MCP)-1 from RPE cells. Resvega, N-acetyl-cysteine (NAC) and aminopyrrolidine-2,4-dicarboxylic acid (APDC) alleviated hydroquinone-induced ROS production in RPE cells. Collectively, our results indicate that hydroquinone induces cytotoxicity and increases oxidative stress through NADPH oxidase activity in RPE cells, and resveratrol-containing Resvega products prevent those adverse effects.}, }
@article {pmid32190930, year = {2020}, author = {Korhonen, E and Piippo, N and Hytti, M and Hyttinen, JMT and Kaarniranta, K and Kauppinen, A}, title = {Only IL-1β release is inflammasome-dependent upon ultraviolet B irradiation although IL-18 is also secreted.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {5}, pages = {6437-6448}, doi = {10.1096/fj.201902355RR}, pmid = {32190930}, issn = {1530-6860}, mesh = {DNA Damage ; DNA Repair ; Humans ; Inflammasomes/immunology/*metabolism/radiation effects ; Interleukin-18/*metabolism ; Interleukin-1beta/*metabolism ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/immunology/*metabolism/radiation effects ; Signal Transduction ; *Ultraviolet Rays ; }, abstract = {DNA damage accumulates in aged postmitotic retinal pigment epithelium (RPE) cells, a phenomenon associated with the development of age-related macular degeneration. In this study, we have experimentally induced DNA damage by ultraviolet B (UVB) irradiation in interleukin-1α (IL-1α)-primed ARPE-19 cells and examined inflammasome-mediated signaling. To reveal the mechanisms of inflammasome activation, cells were additionally exposed to high levels of extracellular potassium chloride, n-acetyl-cysteine, or mitochondria-targeted antioxidant MitoTEMPO, prior to UVB irradiation. Levels of interleukin-18 (IL-18) and IL-1β mRNAs were detected with qRT-PCR and secreted amounts of IL-1β, IL-18, and caspase-1 were measured with ELISA. The role of nucleotide-binding domain and leucine-rich repeat pyrin containing protein 3 (NLRP3) in UVB-induced inflammasome activation was verified by using the NLRP3-specific siRNA. Reactive oxygen species (ROS) levels were measured immediately after UVB exposure using the cell-permeant 2',7'-dichlorodihydrofluorescein diacetate (H2 DCFDA) indicator, the levels of cyclobutane pyrimidine dimers were assayed by cell-based ELISA, and the extracellular levels of adenosine triphosphate (ATP) determined using a commercial bioluminescence assay. We found that pro-IL-18 was constitutively expressed by ARPE-19 cells, whereas the expression of pro-IL-1β was inducible by IL-1α priming. UVB induced the release of mature IL-18 and IL-1β but NLRP3 contributed only to the secretion of IL-1β. At the mechanistic level, the release of IL-1β was regulated by K[+] efflux, whereas the secretion of IL-18 was dependent on ROS production. As well as K[+] efflux, the cells released ATP following UVB exposure. Collectively, our data suggest that UVB clearly stimulates the secretion of mature IL-18 as a result of ROS induction, and this response is associated with DNA damage. Moreover, in human RPE cells, K[+] efflux mediates the UVB-activated NLRP3 inflammasome signaling, leading to the processing of IL-1β.}, }
@article {pmid32190510, year = {2020}, author = {Karaca, O and Ertaşkın, A}, title = {Epidemiology of Self-poisoning with Drug in the Central Anatolian Region in Turkey.}, journal = {Cureus}, volume = {12}, number = {2}, pages = {e6962}, pmid = {32190510}, issn = {2168-8184}, abstract = {AIM: Deliberate self-poisoning (DSP) is a common cause of intensive care hospitalization among young adults and a serious health problem worldwide. Demographic data vary according to geographical and sociocultural characteristics of the regions. In recent years, studies investigating epidemiological features and prognosis of these patients have increased. In our study, we retrospectively examined patients who committed suicide with drugs and were treated in the ICU of our hospital.<br><br>MATERIALS AND METHODS: The files of 148 patients who took drugs or substances for committing suicide and who were hospitalized in the ICU of Aksaray Training and Research Hospital between 2015 and 2019 were examined. Demographic data of the patients, type of the agent used in the suicide, time to reach hospital, treatment methods applied, length of hospital stay, vital signs, complications, need for intubation, and mortality rates were recorded.<br><br>RESULTS: Mean age of the 148 patients who took drugs for suicide was 26.7. Female rate was 73%. The most frequently used drug for suicide was paracetamol (34.4%). Antidepressants took the second place and were followed by drugs in the NSAID group. The duration of admission in the hospital after taking the medicine ranged from 1 to 6 h, while it was less than 3 h in 68.2% of the patients. In most suicide patients, the treatment method was in the form of intravenous fluid and supportive therapy (95%). N-acetyl cysteine (paracetamol intoxication) was used in 7% of the patients, an intubation requirement developed in 2.7%, and three patients taking organophosphate died.<br><br>CONCLUSION: In studies conducted in developing countries such as Turkey, female sex (63%-71%) and 25 years of age have been found to be the proportion of the patients (56%-63%), whereas our study found even higher ratios compared to those (73%-66%). In studies conducted in developed countries, most commonly used agents for suicide were benzodiazepines and tricyclic antidepressants, while the most common suicide agent was paracetamol in our study. We believe that the reason for this could be the possibility of accessing the agent without a prescription.}, }
@article {pmid32188759, year = {2020}, author = {Gilljam, KM and Holm, KL and Zahoor, M and Centonze, FG and Farhan, H and Blomhoff, HK}, title = {Differential Effects of Reactive Oxygen Species on IgG versus IgM Levels in TLR-Stimulated B Cells.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {204}, number = {8}, pages = {2133-2142}, doi = {10.4049/jimmunol.1901131}, pmid = {32188759}, issn = {1550-6606}, mesh = {Acetylcysteine/pharmacology ; B-Lymphocytes/*immunology ; Benzoxazoles/pharmacology ; Humans ; Immunoglobulin G/*immunology ; Immunoglobulin M/*immunology ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Toll-Like Receptors/*immunology ; Triazoles/pharmacology ; }, abstract = {It is becoming increasingly evident that reactive oxygen species (ROS) have critical roles as "second messengers" in cell signaling. In B cells, ROS can be generated either as a byproduct of mitochondrial respiration, as a result of the endoplasmic reticulum stress response induced by high production of Igs, or by the activation of NADPH oxidase (NOX) complexes. Having previously shown that costimulation of B cells via TLR 9 and the TLR-related receptor RP105 drives maturation of human peripheral blood B cells into Ig-producing cells, we aimed to study the role of ROS generated during this vital process. To this end, the ROS levels were either reduced by the NOX inhibitor VAS2870 or by the ROS scavenger N-acetyl cysteine (NAC). We revealed that TLR9/RP105-mediated stimulation of human B cells involved a rapid activation of NOX. Moreover, VAS2870 blocked the TLR9/RP105-induced B cell activation and thereby all Ig production. Importantly, we showed that ROS targeted by NAC was selectively required for IgG but not for IgM production. The endoplasmic reticulum stress response in the TLR9/RP105-stimulated cells was higher in IgG[+] than in IgG[-] cells and was reduced by NAC in IgG[+] cells only. Of note, we revealed that substantially higher levels of IgG than IgM were produced per cell and that IgG[+] cells produced significantly higher ROS levels than IgG[-] cells. Taken together, our results imply that NAC-targeted ROS may be particularly important for sustaining the high Ig production in IgG[+] B cells.}, }
@article {pmid32188725, year = {2020}, author = {Arnold, K and Xu, Y and Sparkenbaugh, EM and Li, M and Han, X and Zhang, X and Xia, K and Piegore, M and Zhang, F and Zhang, X and Henderson, M and Pagadala, V and Su, G and Tan, L and Park, PW and Stravitz, RT and Key, NS and Linhardt, RJ and Pawlinski, R and Xu, D and Liu, J}, title = {Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure.}, journal = {Science translational medicine}, volume = {12}, number = {535}, pages = {}, pmid = {32188725}, issn = {1946-6242}, support = {R44 GM134738/GM/NIGMS NIH HHS/United States ; R01 DK111958/DK/NIDDK NIH HHS/United States ; R01 HL125371/HL/NHLBI NIH HHS/United States ; R01 HL142604/HL/NHLBI NIH HHS/United States ; R01 HL094463/HL/NHLBI NIH HHS/United States ; R44 HL139187/HL/NHLBI NIH HHS/United States ; R42 GM128484/GM/NIGMS NIH HHS/United States ; R01 AR070179/AR/NIAMS NIH HHS/United States ; R41 GM123792/GM/NIGMS NIH HHS/United States ; R01 HL144970/HL/NHLBI NIH HHS/United States ; U01 GM102137/GM/NIGMS NIH HHS/United States ; R41 HL139187/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetaminophen/toxicity ; Animals ; Anti-Inflammatory Agents ; *Chemical and Drug Induced Liver Injury/drug therapy/prevention &amp; control ; Europe ; Heparitin Sulfate ; Humans ; Liver ; *Liver Failure, Acute/chemically induced/drug therapy/prevention &amp; control ; Mice ; Mice, Inbred C57BL ; }, abstract = {Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and N-acetyl cysteine, which is the standard of care to treat APAP overdose. We demonstrated that 18-mer-HP administered 3 hours after a lethal dose of APAP is fully protective; however, the treatment of N-acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over N-acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF.}, }
@article {pmid32184590, year = {2020}, author = {Hou, J and Chen, L and Zhou, M and Li, J and Liu, J and Fang, H and Zeng, Y and Sun, J and Wang, Z}, title = {Multi-Layered Polyamide/Collagen Scaffolds with Topical Sustained Release of N-Acetylcysteine for Promoting Wound Healing.}, journal = {International journal of nanomedicine}, volume = {15}, number = {}, pages = {1349-1361}, pmid = {32184590}, issn = {1178-2013}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Collagen/*chemistry ; Delayed-Action Preparations ; Free Radical Scavengers/*pharmacology ; Male ; Nanofibers/chemistry ; Nylons/*chemistry ; Rats ; Rats, Sprague-Dawley ; Re-Epithelialization/*drug effects ; Reactive Oxygen Species/metabolism ; Tissue Scaffolds/*chemistry ; Wound Healing/*drug effects ; }, abstract = {BACKGROUND: Impaired wound healing might be associated with many issues, especially overactive of reactive oxygen species (ROS), deficiency of blood vessels and immature of epidermis. N-acetylcysteine (NAC), as an antioxidant, could solve these problems by inhibiting overreactive of ROS, promoting revascularization and accelerating re-epithelialization. How to deliver NAC in situ with a controllable releasing speed still remain a challenge.<br><br>MATERIALS AND METHODS: In this study, we combined collagen (Col) with N-acetylcysteine to perform the characteristics of sustained release and chemically crosslinked Col/NAC composite with polyamide (PA) nanofibers to enhance the mechanical property of collagen and fabricated this multi-layered scaffold (PA-Col/NAC scaffold). The physical properties of the scaffolds such as surface characteristics, water absorption and tensile modulus were tested. Meanwhile, the ability to promote wound healing in vitro and in vivo were investigated.<br><br>RESULTS: These scaffolds were porous and performed great water absorption. The PA-Col/NAC scaffold could sustainably release NAC for at least 14 days. After cell implantation, PA-Col/NAC scaffold showed better cell proliferation and cell migration than the other groups. In vivo, PA-Col/NAC scaffolds could promote wound healing best among all the groups.<br><br>CONCLUSION: The multi-layered scaffolds could obviously accelerate the process of wound healing and exert better and prolonged effects.}, }
@article {pmid32184133, year = {2020}, author = {Mishra, S and Kumar, G and Chhabra, A and Sethy, NK and Jain, N and Meena, RN and Tulsawani, R and Prasad, DN and Kumar, B and Sharma, M}, title = {Cysteine becomes conditionally essential during hypobaric hypoxia and regulates adaptive neuro-physiological responses through CBS/H2S pathway.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1866}, number = {7}, pages = {165769}, doi = {10.1016/j.bbadis.2020.165769}, pmid = {32184133}, issn = {1879-260X}, mesh = {Acetylcysteine/pharmacology ; Adaptation, Physiological ; Adult ; Altitude Sickness/drug therapy/genetics/*metabolism/pathology ; Animals ; Brain/*metabolism/pathology ; Cerebrovascular Circulation/drug effects/genetics ; Cystathionine beta-Synthase/*genetics/metabolism ; Cysteine/*metabolism ; Disease Models, Animal ; Energy Metabolism/genetics ; Humans ; Hydrogen Sulfide/*metabolism ; Hypoxia/drug therapy/genetics/metabolism ; Male ; Oxygen Consumption/genetics ; Prodrugs/pharmacology ; Rats ; Young Adult ; }, abstract = {Brain is well known for its disproportionate oxygen consumption and high energy-budget for optimal functioning. The decrease in oxygen supply to brain, thus, necessitates rapid activation of adaptive pathways - the absence of which manifest into vivid pathological conditions. Amongst these, oxygen sensing in glio-vascular milieu and H2S-dependent compensatory increase in cerebral blood flow (CBF) is a major adaptive response. We had recently demonstrated that the levels of H2S were significantly decreased during chronic hypobaric hypoxia (HH)-induced neuro-pathological effects. The mechanistic basis of this phenomenon, however, remained to be deciphered. We, here, describe experimental evidence for marked limitation of cysteine during HH - both in animal model as well as human volunteers ascending to high altitude. We show that the preservation of brain cysteine level, employing cysteine pro-drug (N-acetyl-L-cysteine, NAC), markedly curtailed effects of HH - not only on endogenous H2S levels but also, impairment of spatial reference memory in our animal model. We, further, present multiple lines of experimental evidence that the limitation of cysteine was causally governed by physiological propensity of brain to utilize cysteine, in cystathionine beta synthase (CBS)-dependent manner, past its endogenous replenishment potential. Notably, decrease in the levels of brain cysteine manifested despite positive effect (up-regulation) of HH on endogenous cysteine maintenance pathways and thus, qualifying cysteine as a conditionally essential nutrient (CEN) during HH. In brief, our data supports an adaptive, physiological role of CBS-mediated cysteine-utilization pathway - activated to increase endogenous levels of H2S - for optimal responses of brain to hypobaric hypoxia.}, }
@article {pmid32183232, year = {2020}, author = {Michlin, M and Argaev-Frenkel, L and Weinstein-Fudim, L and Ornoy, A and Rosenzweig, T}, title = {Maternal N-Acetyl Cysteine Intake Improved Glucose Tolerance in Obese Mice Offspring.}, journal = {International journal of molecular sciences}, volume = {21}, number = {6}, pages = {}, pmid = {32183232}, issn = {1422-0067}, support = {3-11350//D-CURE/ ; }, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/pharmacology/*therapeutic use ; Cells, Cultured ; Diet, High-Fat/adverse effects ; Female ; Glucose Intolerance/drug therapy/etiology/*prevention &amp; control ; Insulin-Secreting Cells/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Obesity, Maternal/*etiology ; Pregnancy ; Prenatal Exposure Delayed Effects/drug therapy/etiology/*prevention &amp; control ; }, abstract = {Exposure to certain environmental factors during the early stages of development was found to affect health in adulthood. Among other environmental factors, oxidative stress has been suggested to be involved in fetal programming, leading to elevated risk for metabolic disorders, including type 2 diabetes; however, the possibility that antioxidant consumption during early life may affect the development of diabetes has scarcely been studied. The aim of this study was to investigate the effects of N-acetyl-l-cysteine (NAC) given during pregnancy and lactation on the susceptibility of offspring to develop glucose intolerance at adulthood. C57bl6/J mice were given NAC during pregnancy and lactation. High fat diet (HFD) was given to offspring at an age of 6 weeks for an additional 9 weeks, till the end of the study. Isolated islets of NAC-treated offspring (6 weeks old, before HFD feeding) had an increased efficacy of glucose-stimulated insulin secretion and a higher resistance to oxidative damage. Following HFD feeding, glucose tolerance and insulin sensitivity of NAC-treated offspring were improved. In addition, islet diameter was lower in male offspring of NAC-treated mice compared to their HFD-fed littermates. NAC consumption during early life improves glucose tolerance in adulthood in mice.}, }
@article {pmid32182833, year = {2020}, author = {Khan, AQ and Mohamed, EAN and Hakeem, I and Nazeer, A and Kuttikrishnan, S and Prabhu, KS and Siveen, KS and Nawaz, Z and Ahmad, A and Zayed, H and Uddin, S}, title = {Sanguinarine Induces Apoptosis in Papillary Thyroid Cancer Cells via Generation of Reactive Oxygen Species.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {5}, pages = {}, pmid = {32182833}, issn = {1420-3049}, mesh = {Apoptosis/*drug effects ; Autophagy/drug effects ; Benzophenanthridines/*pharmacology ; Caspase 3/genetics ; Caspase 8/genetics ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Cisplatin/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Isoquinolines/*pharmacology ; Neoplastic Stem Cells ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/genetics ; Signal Transduction/drug effects ; Thyroid Cancer, Papillary/*drug therapy/genetics ; }, abstract = {Sanguinarine (SNG), a natural compound with an array of pharmacological activities, has promising therapeutic potential against a number of pathological conditions, including malignancies. In the present study, we have investigated the antiproliferative potential of SNG against two well-characterized papillary thyroid cancer (PTC) cell lines, BCPAP and TPC-1. SNG significantly inhibited cell proliferation of PTC cells in a dose and time-dependent manner. Western blot analysis revealed that SNG markedly attenuated deregulated expression of p-STAT3, without affecting total STAT3, and inhibited growth of PTC via activation of apoptotic and autophagy signaling cascade, as SNG treatment of PTC cells led to the activation of caspase-3 and caspase-8; cleavage of PARP and activation of autophagy markers. Further, SNG-mediated anticancer effects in PTC cells involved the generation of reactive oxygen species (ROS) as N-acetyl cysteine (NAC), an inhibitor of ROS, prevented SNG-mediated antiproliferative, apoptosis and autophagy inducing action. Interestingly, SNG also sensitized PTC cells to chemotherapeutic drug cisplatin, which was inhibited by NAC. Finally, SNG suppressed the growth of PTC thyrospheres and downregulated stemness markers ALDH2 and SOX2. Altogether, the findings of the current study suggest that SNG has anticancer potential against PTC cells as well its derived cancer stem-like cells, most likely via inactivation of STAT3 and its associated signaling molecules.}, }
@article {pmid32180463, year = {2021}, author = {Li, Z and Wang, J and Deng, X and Huang, D and Shao, Z and Ma, K}, title = {Compression stress induces nucleus pulposus cell autophagy by inhibition of the PI3K/AKT/mTOR pathway and activation of the JNK pathway.}, journal = {Connective tissue research}, volume = {62}, number = {3}, pages = {337-349}, doi = {10.1080/03008207.2020.1736578}, pmid = {32180463}, issn = {1607-8438}, mesh = {Animals ; Apoptosis ; Autophagy ; *Intervertebral Disc Degeneration/drug therapy/metabolism ; MAP Kinase Signaling System ; *Nucleus Pulposus/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Purpose: Reactive oxygen species (ROS) are related to compression stress-induced nucleus pulposus (NP) cell autophagy, but the specific mechanism is unknown in compression stress-induced intervertebral disc degeneration (IVDD). Here, we discuss the specific molecular mechanism and explore whether ROS scavengers could be employed as specific drugs to inhibit compression stress-induced IVDD.Methods: Rat NP cells were exposed to 1.0 MPa compression and pretreatment with the ROS scavenger N-acetylcysteine (NAC) or the JNK-selective inhibitor SP600125 not. Intracellular ROS production was monitored by confocal microscopy. Autophagy was detected by observing the NP cell ultrastructural features using TEM and examining autophagic vacuoles by flow cytometry. The levels of autophagy-associated molecules, the JNK pathway and the PI3K/AKT/mTOR pathway were analyzed by western blotting.Results: Compression-mediated autophagy in rat NP cells was implicated in ROS generation. The ROS scavenger NAC could protect compression-induced NP cell injures by inhibiting ROS production. And SP600125, a JNK inhibitor, attenuated compression-induced NP cell autophagy. Additionally, this is the first report showing that compression induces autophagy in rat NP cells by impeding the compression-induced ROS dependent PI3K/AKT/mTOR pathway and the ROS independent activation of JNK pathway. And the involvement of JNK pathway was in different mechanism of action that when inhibited leaded to increased cell death, increased generation of ROS but decreased autophagy.Conclusions: These results show a new regulatory mechanism involving ROS-mediated autophagy in rat NP cells, which may provide ideas for drug development to improve compression stress-induced IVDD and help avoid eventual surgical treatment of IVD herniation.}, }
@article {pmid32179427, year = {2020}, author = {Zhang, L and Hou, L and Liu, Z and Huang, S and Meng, Z and Liang, L}, title = {A mitophagic response to iron overload-induced oxidative damage associated with the PINK1/Parkin pathway in pancreatic beta cells.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {60}, number = {}, pages = {126493}, doi = {10.1016/j.jtemb.2020.126493}, pmid = {32179427}, issn = {1878-3252}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Ferric Compounds/pharmacology ; Insulin-Secreting Cells/drug effects/*metabolism ; Iron Overload/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Oxidative Stress/*drug effects ; Protein Kinases/*metabolism ; Quaternary Ammonium Compounds/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {BACKGROUND: Iron overload can result in a disorder in glucose metabolism. However, the underlining mechanism through which iron overload induces beta cell death remains unknown.<br><br>METHODS: According to the concentration of ferric ammonium citrate (FAC) and N-acetylcysteine, INS-1 cells were randomly divided into four groups: normal control (FAC 0 &#x3bc;M) group, FAC 80 &#x3bc;M group, FAC 160 &#x3bc;M group, FAC 160&#x3bc;M + NAC group. Cell proliferation was assessed by Cell Counting Kit-8. Reactive oxygen species (ROS) level was further evaluated using flow cytometer with a fluorescent probe. The mitochondrial membrane potential was detected by JC-1 kit, and transmission electron microscopy was used to observe the mitochondrial changes. The related protein expressions were detected by western bolt to evaluate mitophagy status.<br><br>RESULTS: It was shown that FAC treatment decreased INS-1 cell viability in vitro, resulted in a decline in mitochondrial membrane potential, increased oxidative stress level and suppressed mitophagy. Furthermore, these effects could be alleviated by the ROS scavenger.<br><br>CONCLUSIONS: We proved that increased iron overload primarily increased oxidative stress and further suppressed mitophagy via PTEN-induced putative kinase 1/Parkin pathway, resulting in cytotoxicity in INS-1 cells.}, }
@article {pmid32176452, year = {2020}, author = {Abedi, M and Rahgozar, S and Esmaeili, A}, title = {Iron protects childhood acute lymphoblastic leukemia cells from methotrexate cytotoxicity.}, journal = {Cancer medicine}, volume = {9}, number = {10}, pages = {3537-3550}, pmid = {32176452}, issn = {2045-7634}, mesh = {Acetylcysteine/pharmacology ; Bone Marrow/metabolism ; Cell Line, Tumor ; Cell Survival ; Child ; Child, Preschool ; Deferasirox/pharmacology ; Drug Resistance, Neoplasm/*drug effects/physiology ; Female ; Ferric Compounds/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Infant ; Inhibitory Concentration 50 ; Iron/*metabolism ; Iron Chelating Agents/pharmacology ; Male ; Methotrexate/*pharmacology ; Multidrug Resistance-Associated Proteins/genetics ; NF-E2-Related Factor 2/genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Quaternary Ammonium Compounds/*pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species ; Superoxide Dismutase/genetics ; Transcriptome ; Up-Regulation ; }, abstract = {Drug resistance is a fundamental clinical concern in pediatric acute lymphoblastic leukemia (pALL), and methotrexate (MTX) is an essential chemotherapy drug administered for the treatment. In the current study, the effect of iron in response to methotrexate and its underlying mechanisms were investigated in pALL cells. CCRF-CEM and Nalm6 cell lines were selected as T and B-ALL subtypes. Cells were pretreated with ferric ammonium citrate, exposed to the IC50 concentration of MTX and cell viability was assessed using MTT, colony formation, and flow cytometry assays. Iron-loaded cells were strongly resistant to MTX cytotoxicity. The inhibitory effect of N-acetyl cysteine to reverse the acquired MTX resistance was greater than that of the iron chelator, deferasirox, highlighting the importance of iron-mediated ROS in MTX resistance. Subsequently, the upregulation of BCL2, SOD2, NRF2, and MRP1 was confirmed using quantitative RT-PCR. Moreover, a positive correlation was demonstrated between the MRP1 expression levels and bone marrow iron storage in pALL patients. Further supporting our findings were the hematoxylin and eosin-stained histological sections showing that iron-treated nude mice xenografts demonstrated significantly more liver damage than those unexposed to iron. Overall, iron is introduced as a player with a novel role contributing to methotrexate resistance in pALL. Our findings suggest that the patients' bone marrow iron stores are necessary to be assessed during the chemotherapy, and transfusions should be carefully administrated.}, }
@article {pmid32173672, year = {2020}, author = {Zhang, S and Lu, Y and Li, H and Ji, Y and Fang, F and Tang, H and Qiu, P}, title = {A steroidal saponin form Paris vietnamensis (Takht.) reverses temozolomide resistance in glioblastoma cells via inducing apoptosis through ROS/PI3K/Akt pathway.}, journal = {Bioscience trends}, volume = {14}, number = {2}, pages = {123-133}, doi = {10.5582/bst.2020.01005}, pmid = {32173672}, issn = {1881-7823}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Brain Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/drug effects ; Free Radical Scavengers/pharmacology/therapeutic use ; Glioblastoma/*drug therapy/pathology ; Humans ; Melanthiaceae/*chemistry ; Phosphatidylinositol 3-Kinases/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Rhizome/chemistry ; Saponins/*pharmacology/therapeutic use ; Signal Transduction/drug effects ; Temozolomide/pharmacology/therapeutic use ; }, abstract = {Glioblastoma is one of the most difficult cancers to treat with a 5-year overall survival rate less than 5%. Temozolomide (TMZ) is an effective drug for prolonging the overall survival time of patients, while drug-resistance is an important clinical problem at present. Pennogenin-3-α-L-rhamnopyranosyl-(1→4)-[α-Lrhamno-pyranosyl-(1→2)]- β-D-glucopyranoside (N45), a steroidal saponin, was isolated from the rhizomes of Paris vietnamensis (Takht.), which is used as a Traditional Chinese Medicine and has been reported to possess preclinical anticancer efficacy in various cancer types. However, the mechanism of the inhibition of N45 on glioblastoma cells and its possible application in the treatment of chemotherapy-resistant glioblastoma cells are still unknown. In this study, we use cellular methodological experiments including cell counting kit-8 (CCK-8) assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining assay, flow cytometry assay, transmission electron microscopy (TEM) and Western blot. The results show that N45 significantly suppresses the proliferation of glioblastoma cells and TMZ-resistant glioblastoma cells (U87R) by inducing mitochondrial apoptosis through reactive oxygen species (ROS)/phosphoinositide 3-kinase (PI3K)/Akt signal pathway, and the N-acetyl-L-cysteine (NAC) combined with N45 effectively reduced N45-mediated apoptosis and reversed the inhibition of PI3K/Akt signal pathway. In addition, N45 decreased the drug-resistance by down-regulation of nuclear factor kappa-B p65 (NF-κB p65) to attenuate O[6]-methylguanine-DNA methyltransferase (MGMT) in TMZ-resistant glioblastoma cells (U87R). Our findings proved that N45 might be a potential therapeutic agent against glioblastoma and TMZ-resistant glioblastoma, promising to be a potential agent to reduce drug resistance.}, }
@article {pmid32169084, year = {2020}, author = {Zhao, G and Sun, H and Zhang, T and Liu, JX}, title = {Copper induce zebrafish retinal developmental defects via triggering stresses and apoptosis.}, journal = {Cell communication and signaling : CCS}, volume = {18}, number = {1}, pages = {45}, pmid = {32169084}, issn = {1478-811X}, mesh = {Animals ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Copper/*toxicity ; Endoplasmic Reticulum/drug effects/metabolism ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; *Retina/abnormalities/drug effects/pathology ; Unfolded Protein Response/drug effects ; *Zebrafish/embryology/metabolism ; }, abstract = {BACKGROUND: The disorder of copper homeostasis is linked with disease and developmental defects, and excess copper_nanoparticles (CuNPs) and ion (Cu[2+]) will induce developmental malformation and disease in organisms. However, little knowledge is available regarding its potential regulation mechanisms, and little study links excess copper with retinal developmental malformation and disease.<br><br>METHODS: Embryos were stressed with copper (CuNPs and Cu[2+]), and cell proliferation and apoptosis assays, reactive oxygen species (ROS) and endoplasmic reticulum (ER) signaling detections, and genetic mutants cox17[-/-] and atp7a[-/-] application, were used to evaluate copper induced retinal developmental malformation and the underlying genetic and biological regulating mechanisms.<br><br>RESULTS: Copper reduced retinal cells and down-regulated expression of retinal genes, damaged the structures of ER and mitochondria in retinal cells, up-regulated unfold protein responses (UPR) and ROS, and increased apoptosis in copper-stressed retinal cells. The copper induced retinal defects could be significantly neutralized by ROS scavengers reduced Glutathione (GSH) &amp; N-acetylcysteine (NAC) and ER stress inhibitor 4- phenylbutyric acid (PBA). Blocking the transportation of copper to mitochondria, or to trans-Golgi network and to be exported into plasma, by deleting gene cox17 or atp7a, could alleviate retinal developmental defects in embryos under copper stresses.<br><br>CONCLUSIONS: This is probably the first report to reveal that copper nanoparticles and ions induce retinal developmental defects via upregulating UPR and ROS, leading to apoptosis in zebrafish embryonic retinal cells. Integrated function of copper transporter (Cox17 and Atp7a) is necessary for copper induced retinal defects.}, }
@article {pmid32166299, year = {2020}, author = {Choe, J and Chen, P and Falk, JA and Nguyen, L and Ng, D and Parimon, T and Ghandehari, S}, title = {A Case Series of Vaping-Associated Lung Injury Requiring Mechanical Ventilation.}, journal = {Critical care explorations}, volume = {2}, number = {1}, pages = {e0079}, pmid = {32166299}, issn = {2639-8028}, abstract = {OBJECTIVES: Vaping-associated lung injury has rapidly become a nationwide epidemic and a threat to public health. In this case series, we describe unique clinical features of severe vaping-associated lung injury, defined as respiratory failure due to vaping that requires mechanical ventilation.<br><br>DATA SOURCES: Clinical observation of four patients.<br><br>STUDY SELECTION: Case series.<br><br>DATA EXTRACTION: Data and images were extract from medical records after approval was obtained from the institutional review board.<br><br>DATA SYNTHESIS: Four patients were admitted to the ICU with severe manifestation of vaping-associated lung injury. Although every case required mechanical ventilatory support (venovenous extracorporeal membrane oxygenation in one patient), all patients survived and were discharged without supplemental oxygen. Systemic corticosteroids were administered in three patients and N-acetyl cysteine in one. A postdischarge pulmonary function test in one patient was normal except for mildly decreased diffusing capacity.<br><br>CONCLUSIONS: Based on our experience, prognosis of severe vaping-associated lung injury appears favorable with aggressive supportive care, although there is evidence from existing literature that mortality rate might rise with increasing disease severity. Underlying mechanism of lung injury might be similar between vaping-associated lung injury and amiodarone pneumonitis. Foamy or lipid-laden macrophages, seen in both conditions, might be a marker of cytotoxicity from substances contained in e-cigarettes, such as vitamin E acetate. Systemic corticosteroids, and possibly N-acetyl cysteine, could be considered as therapeutic adjuncts in vaping-associated lung injury. Serial pulmonary function tests should be obtained in these patients to monitor for potential long-term complications. The primary limitations of this case series are its small sample and lack of longitudinal follow-up data.}, }
@article {pmid32165235, year = {2020}, author = {Chae, IG and Song, NY and Kim, DH and Lee, MY and Park, JM and Chun, KS}, title = {Thymoquinone induces apoptosis of human renal carcinoma Caki-1 cells by inhibiting JAK2/STAT3 through pro-oxidant effect.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {139}, number = {}, pages = {111253}, doi = {10.1016/j.fct.2020.111253}, pmid = {32165235}, issn = {1873-6351}, mesh = {Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology ; Carcinoma, Renal Cell/*drug therapy ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cuminum/chemistry ; Cyclin D1/genetics/metabolism ; Cyclin D2/genetics/metabolism ; Humans ; Janus Kinase 2/genetics/metabolism ; Kidney Neoplasms/drug therapy ; Male ; Mice ; Mice, Nude ; Phytochemicals/pharmacology ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/genetics/metabolism ; Seeds/chemistry ; Signal Transduction ; Survivin/genetics/metabolism ; Xenograft Model Antitumor Assays ; bcl-X Protein/genetics/metabolism ; }, abstract = {Currently, there are limited effective treatment options for renal cell carcinoma (RCC), due to its poor responses to conventional therapies. Instead of using extrinsic anti-cancer drugs, cancer cell-intrinsic reactive oxygen species (ROS) can be a weapon of RCC treatment. In the present study, we found that the phytochemical thymoquinone (TQ), a bioactive natural product obtained from the black cumin seeds of Nigella sativa, generates intracellular ROS in human renal cancer Caki-1 cells. Treatment of Caki-1 cells with high concentration of TQ up-regulated pro-apoptotic p53 and Bax expression, while downregulated anti-apoptotic Bcl-2 and Bcl-xl expression. Simultaneously, TQ suppressed the pro-oncogenic JAK2/STAT3 pathway, resulting in decreased expression of Bcl-2, Bcl-xl, cyclin D1, cyclin D2, and survivin. Thus, TQ can integrate between apoptosis and the pro-survival JAK2/STAT3 pathway through the Bcl family members, collectively magnifying Caki-1 cell apoptosis. However, treatment with the ROS scavenger N-acetyl cysteine significantly blocked TQ-induced apoptosis as well as incorporated signaling pathways, supporting that its pro-oxidant property is crucial for Caki-1 cell apoptosis. Moreover, TQ reduced the tumor xenograft growth of Caki-1 cells in nude mice. Taken together, these data suggest that TQ is a prominent anti-cancer drug to treat human RCC by enhancing apoptosis through its pro-oxidant nature.}, }
@article {pmid32164484, year = {2021}, author = {Kim, HJ and Kim, SY and Kim, DH and Park, JS and Jeong, SH and Choi, YW and Kim, CH}, title = {Crosstalk between HSPA5 arginylation and sequential ubiquitination leads to AKT degradation through autophagy flux.}, journal = {Autophagy}, volume = {17}, number = {4}, pages = {961-979}, pmid = {32164484}, issn = {1554-8635}, mesh = {Animals ; Arginine/*metabolism ; Autophagosomes/drug effects/metabolism ; *Autophagy/drug effects ; Bortezomib/pharmacology ; Cell Line, Tumor ; Endoplasmic Reticulum Chaperone BiP ; Heat-Shock Proteins/*metabolism ; Humans ; Lysine/metabolism ; Lysosomes/drug effects/metabolism ; Mice ; Models, Biological ; Proteasome Inhibitors/pharmacology ; *Proteolysis/drug effects ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-akt/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Specific Peptidase 7/metabolism ; *Ubiquitination/drug effects ; }, abstract = {AKT/PKB is downregulated by the ubiquitin-proteasome system (UPS), which plays a key role in cell survival and tumor progression in various types of cancer. The objective of this study was to determine the relationship between the sequential ubiquitination of lysine residues K284 to K214 in AKT and R-HSPA5 (the arginylated form of HSPA5), which contribute to the autophagic/lysosomal degradation of AKT when impaired proteasomal activity induces cellular stress. Results show that proteasome inhibitors (PIs) increased ATE1 (arginyltransferase 1)-mediated R-HSPA5 levels in a reactive oxygen species (ROS)-dependent manner. Further, binding of fully ubiquitinated AKT with R-HSPA5 induced AKT degradation via the autophagy-lysosome pathway. Specifically, the K48 (Lys48)-linked ubiquitinated form of AKT was selectively degraded in the lysosome with R-HSPA5. The deubiquitinase, USP7 (ubiquitin specific peptidase 7), prevented AKT degradation by inhibiting AKT ubiquitination via interaction with AKT. MUL1 (mitochondrial ubiquitin ligase activator of NFKB 1) also played a vital role in the lysosomal degradation of AKT by sequentially ubiquitinating AKT residues K284 to K214 for R-HSPA5-mediated autophagy. Consistent with this finding, despite HSPA5 arginylation, AKT was not degraded in mul1 KO cells. These results suggest that MUL1-mediated sequential ubiquitination of K284 to K214 may serve as a novel mechanism by which AKT is designated for lysosomal degradation. Moreover, binding of R-HSPA5 with fully ubiquitinated AKT is required for the autophagic/lysosomal degradation of AKT. Thus, modulating the MUL1-mediated non-proteasomal proteolysis mechanisms, such as sequential ubiquitination, may prove to be a novel therapeutic approach for cancer treatment.Abbreviations: AKT1: thymoma viral proto-oncogene 1; ATE1: arginyltransferase 1; ATG5: autophagy related 5; CASP3: caspase 3; EGFP: enhanced green fluorescent protein; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSK3B; glycogen synthase kinase 3 beta; HA: hemagglutinin; HSPA5/GRP78/BIP: heat shock protein 5; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; MUL1: mitochondrial ubiquitin ligase activator of NFKB1; NAC: N-acetylcysteine; NEK2: NIMA (never in mitosis gene a)-related expressed kinase 2; NH4Cl: ammonium chloride; PARP1: poly(ADP-ribose) polymerase family, member 1; PI: proteasome inhibitor; R-HSPA5: arginylated HSPA5; ROS: reactive oxygen species; SQSTM1: sequestome 1; Ub: ubiquitin; USP7: ubiquitin specific peptidase 7.}, }
@article {pmid32156620, year = {2020}, author = {Cai, T and Tamanini, I and Mattevi, D and Verze, P and Palmieri, A and Malossini, G and Mirone, V and Novelli, A and Tascini, C and Johansen, TEB}, title = {Fosfomycin trometamol and N-acetyl-L-cysteine as combined oral therapy of difficult-to-treat chronic bacterial prostatitis: Results of a pilot study.}, journal = {International journal of antimicrobial agents}, volume = {56}, number = {1}, pages = {105935}, doi = {10.1016/j.ijantimicag.2020.105935}, pmid = {32156620}, issn = {1872-7913}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Anti-Bacterial Agents/*therapeutic use ; Drug Resistance, Multiple, Bacterial ; Drug Therapy, Combination ; Escherichia coli/drug effects ; Fosfomycin/*therapeutic use ; Humans ; Klebsiella oxytoca/drug effects ; Male ; Middle Aged ; Pilot Projects ; Prostatitis/*drug therapy/microbiology ; Quality of Life ; Surveys and Questionnaires ; Treatment Outcome ; Young Adult ; }, abstract = {This paper presents the results of a pilot study of difficult-to-treat patients (exhibiting several previous treatment failures or detection of extended-spectrum beta-lactamase [ESBL] strains) with chronic bacterial prostatitis (CBP) who underwent treatment with fosfomycin trometamol (FT) and N-acetyl-L-cysteine (NAC). Twenty-eight patients with clinically- and microbiologically-confirmed CBP who attended a single urological institution between January 2018 and March 2019 were treated with oral administration of 3 g FT once a day for 2 days, followed by a dose of 3 g every 48 h for 2 weeks, in combination with oral administration of NAC 600 mg once a day for 2 weeks. Clinical and microbiological analyses were carried out at the time of admission (T0) and during follow-up at 1 month (T1) and 6 months (T2) after the end of treatment. Symptoms were assessed by the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and International Prostatic Symptom Score (IPSS), and quality of life was assessed by Quality of Well-Being (QoL) questionnaires. Isolated strains were Escherichia coli (23 patients), Enterococcus spp. (3 patients), and Klebsiella oxytoca (2 patients). ESBL strain was found in 19 (67.8%) patients. Microbiological eradication was documented in 21 (75%) patients at the second follow-up visit and clinical cure was achieved in 20 (71.4%) patients. Significant changes on questionnaires were recorded between baseline and follow-up visits. Fifteen of 19 patients (78.9%) with ESBL strains were cured. No significant side effects were reported. FT in combination with NAC is a promising alternative therapy in difficult-to-treat CBP patients.}, }
@article {pmid32155788, year = {2020}, author = {Eshraghi, AA and Shahal, D and Davies, C and Mittal, J and Shah, V and Bulut, E and Garnham, C and Sinha, P and Mishra, D and Marwede, H and Mittal, R}, title = {Evaluating the Efficacy of L-N-acetylcysteine and Dexamethasone in Combination to Provide Otoprotection for Electrode Insertion Trauma.}, journal = {Journal of clinical medicine}, volume = {9}, number = {3}, pages = {}, pmid = {32155788}, issn = {2077-0383}, support = {Not Applicable//MED-EL Corporation/ ; }, abstract = {BACKGROUND: Electrode insertion trauma (EIT) during cochlear implantation (CI) can cause loss of residual hearing. L-N-acetylcysteine (L-NAC) and dexamethasone (Dex) have been individually shown to provide otoprotection albeit at higher concentrations that may be associated with adverse effects. Objective/Aims: The aim of this study is to determine whether L-NAC and Dex could be combined to decrease their effective dosage.<br><br>MATERIALS AND METHODS: The organ of Corti (OC) explants were divided into various groups: 1) control; 2) EIT; 3) EIT treated with different concentrations of Dex; 4) EIT treated with different concentrations of L-NAC; 5) EIT treated with L-NAC and Dex in combination. Hair cell (HC) density, levels of oxidative stress, proinflammatory cytokines and nitric oxide (NO) was determined.<br><br>RESULTS: There was a significant loss of HCs in explants subjected to EIT compared to the control group. L-NAC and Dex in combination was able to provide significant otoprotection at lower concentrations compared to individual drugs.<br><br>CONCLUSIONS AND SIGNIFICANCE: A combination containing L-NAC and Dex is effective in protecting sensory cells at lower protective doses than each compound separately. These compounds can be combined allowing a decrease of potential side effects of each compound and providing significant otoprotection for EIT.}, }
@article {pmid32155190, year = {2020}, author = {Hamada, Y and Furumoto, Y and Izutani, A and Taniuchi, S and Miyake, M and Oyadomari, M and Teranishi, K and Shimomura, N and Oyadomari, S}, title = {Nanosecond pulsed electric fields induce the integrated stress response via reactive oxygen species-mediated heme-regulated inhibitor (HRI) activation.}, journal = {PloS one}, volume = {15}, number = {3}, pages = {e0229948}, pmid = {32155190}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Electricity/*adverse effects ; Fibroblasts/*metabolism ; Gene Knockout Techniques ; Mice ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Stress, Physiological/drug effects/*physiology ; eIF-2 Kinase/genetics ; }, abstract = {The integrated stress response (ISR) is one of the most important cytoprotective mechanisms and is integrated by phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α). Four eIF2α kinases, heme-regulated inhibitor (HRI), double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), and general control nonderepressible 2 (GCN2), are activated in response to several stress conditions. We previously reported that nanosecond pulsed electric fields (nsPEFs) are a potential therapeutic tool for ISR activation. In this study, we examined which eIF2α kinase is activated by nsPEF treatment. To assess the responsible eIF2α kinase, we used previously established eIF2α kinase quadruple knockout (4KO) and single eIF2α kinase-rescued 4KO mouse embryonic fibroblast (MEF) cells. nsPEFs 70 ns in duration with 30 kV/cm electric fields caused eIF2α phosphorylation in wild-type (WT) MEF cells. On the other hand, nsPEF-induced eIF2α phosphorylation was completely abolished in 4KO MEF cells and was recovered by HRI overexpression. CM-H2DCFDA staining showed that nsPEFs generated reactive oxygen species (ROS), which activated HRI. nsPEF-induced eIF2α phosphorylation was blocked by treatment with the ROS scavenger N-acetyl-L-cysteine (NAC). Our results indicate that the eIF2α kinase HRI is responsible for nsPEF-induced ISR activation and is activated by nsPEF-generated ROS.}, }
@article {pmid32151871, year = {2020}, author = {Yan, Y and Wang, G and Huang, J and Zhang, Y and Cheng, X and Chuai, M and Brand-Saberi, B and Chen, G and Jiang, X and Yang, X}, title = {Zinc oxide nanoparticles exposure-induced oxidative stress restricts cranial neural crest development during chicken embryogenesis.}, journal = {Ecotoxicology and environmental safety}, volume = {194}, number = {}, pages = {110415}, doi = {10.1016/j.ecoenv.2020.110415}, pmid = {32151871}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Survival/drug effects ; Chick Embryo ; Embryonic Development/*drug effects ; Female ; HEK293 Cells ; Humans ; Mitochondria/drug effects ; NF-kappa B/metabolism ; Nanoparticles/chemistry/*toxicity ; Neural Crest/*drug effects/embryology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Zinc Oxide/chemistry/*toxicity ; }, abstract = {Zinc oxide Nanoparticles (ZnO NPs) are widely used as emerging materials in agricultural and food-related fields, which exists potential safety hazards to public health and environment while bringing an added level of convenience to our original life. It has been proved that ZnO NPs could be taken up by pregnant women and passed through human placental barrier. However, the toxic potential for embryo development remains largely unanswered. In this study, we discovered that ZnO NPs caused the cytotoxicity in vitro. Inhibition of free Zn[2+] ions in solution by EDTA or inhibition of Zn[2+] ions absorption by CaCl2 could partially eliminate ZnO NPs-mediated cell toxicity, though not redeem completely. This indicated that both nanoparticles and the release of Zn[2+] ions were involved in ZnO NPs-mediated cytotoxicity. In addition, we also found that both nanoparticles and Zn[2+] ion release triggered reactive oxygen species (ROS) production, which further induced cell toxicity, inflammation and apoptosis, which are mediated by NF-κB signaling cascades and the mitochondria dysfunction, respectively. Eventually, these events lead to the suppressed production and migration of cranial neural crest cells (CNCCs), which subsequently prompts the craniofacial defects in chicken embryos. The application of the antioxidant N-Acetyl-L-cysteine (NAC) rescued the ZnO NPs-induced cell toxicity and malformation of the CNCCs, which further verified our hypothesis. Our results revealed the relevant mechanism of ZnO NPs exposure-inhibited the development of CNCCs, which absolutely contribute to assess the risk of nanoparticles application.}, }
@article {pmid32147432, year = {2020}, author = {Toma, L and Sanda, GM and Raileanu, M and Stancu, CS and Niculescu, LS and Sima, AV}, title = {Ninjurin-1 upregulated by TNFα receptor 1 stimulates monocyte adhesion to human TNFα-activated endothelial cells; benefic effects of amlodipine.}, journal = {Life sciences}, volume = {249}, number = {}, pages = {117518}, doi = {10.1016/j.lfs.2020.117518}, pmid = {32147432}, issn = {1879-0631}, mesh = {Amlodipine/*pharmacology ; Cell Adhesion/*physiology ; Cell Adhesion Molecules, Neuronal/*physiology ; Endoplasmic Reticulum Stress/drug effects ; Gene Silencing ; Human Umbilical Vein Endothelial Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Monocytes/*cytology ; NADPH Oxidases/metabolism ; NF-kappa B/metabolism ; Nerve Growth Factors/*physiology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Receptors, Tumor Necrosis Factor, Type I/genetics/*physiology ; Tumor Necrosis Factor-alpha/*physiology ; *Up-Regulation ; Vasodilator Agents/*pharmacology ; }, abstract = {AIMS: The objectives of the present study were to investigate the mechanisms of Ninj-1 regulation in TNFα-activated human endothelial cells (HEC), and to test if Amlodipine (AML) ameliorates the inflammatory stress by decreasing Ninj-1 expression.<br><br>MAIN METHODS: TNF&#x3b1;-activated HEC with/without AML (0.1&#xa0;&#x3bc;M and 1&#xa0;&#x3bc;M) were used. TNF&#x3b1;-receptor 1 (TNFR1) was silenced and inhibitors for oxidative stress (N-acetyl cysteine), endoplasmic reticulum stress (salubrinal, 4-phenyl butyric acid), or NF-kB (Bay 11-7085) and p38 MAPK (SB203580) were used. Levels of Ninj-1, TNFR1, monocyte adhesion, endoplasmic reticulum stress (ERS) sensors, NADPH oxidase- and mitochondria-derived oxidative species were evaluated.<br><br>KEY FINDINGS: The novel findings that we report here are: (i) silencing the endothelial TNFR1 leads to decreased Ninj-1 expression and diminished monocyte adhesion; (ii) increased oxidative stress, ERS and NF-kB activation enhance Ninj-1 expression and monocyte adhesion; (iii) up-regulation of endothelial Ninj-1 expression stimulates monocytes adhesion to TNF&#x3b1; - activated HEC; (iv) AML diminishes monocyte adhesion by reducing Ninj-1 expression through mechanisms involving the decrease of NADPH oxidase and mitochondria-dependent oxidative stress, ERS and NF-kB. In addition, AML alleviates apoptosis by reducing the pro-apoptotic CHOP expression and re-establishing the mitochondrial transmembrane potential.<br><br>SIGNIFICANCE: The results of the present study suggest that Ninj-1 and the proteins involved in its regulation can be considered therapeutic targets for the alleviation of inflammation- dependent disorders. In addition, we demonstrate that some of the benefic effects of AML can be achieved through regulation of Ninj-1.}, }
@article {pmid32146648, year = {2020}, author = {Kommalapati, VK and Kumar, D and Tangutur, AD}, title = {Inhibition of JNJ-26481585-mediated autophagy induces apoptosis via ROS activation and mitochondrial membrane potential disruption in neuroblastoma cells.}, journal = {Molecular and cellular biochemistry}, volume = {468}, number = {1-2}, pages = {21-34}, pmid = {32146648}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chloroquine/*pharmacology ; Drug Synergism ; Free Radical Scavengers/pharmacology ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Hydroxamic Acids/*pharmacology ; Membrane Potential, Mitochondrial/*drug effects ; Mitochondria/drug effects/metabolism ; Neuroblastoma/*drug therapy/genetics/metabolism ; Peripheral Nervous System Neoplasms/*drug therapy/genetics/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Neuroblastoma (NB) is the common pediatric tumor of the sympathetic nervous system characterized by poor prognosis. Owing to the challenges such as high tumor heterogeneity, multidrug resistance, minimal residual disease, etc., there is an immediate need for exploring new therapeutic strategies and effective treatments for NB. Herein, in the current study, we explored the unexplored response of NB cells to the second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585(JNJ) and the lysosomotropic agent, Chloroquine (CQ) alone and upon JNJ/CQ treatment as a plausible therapeutic. We identify that while JNJ alone induced autophagy in NB cells, JNJ/CQ treatment decreased the viability and proliferation of NB cells in vitro by switching from autophagy to apoptosis. Further we found that autophagy inhibition by CQ pre-treatment led to the generation of ROS and a decrease in the mitochondrial membrane potential (MMP) that subsequently caused caspase-3-mediated apoptotic cell death in NB cells. Corroborating the above observations, we found that the ROS scavenger N-acetylcysteine (NAC) countered caspase-3 activity and the cells were rescued from apoptosis. Finally, these observations establish that JNJ/CQ treatment resulted in cell death in NB cells by triggering the formation of ROS and disruption of MMP, suggesting that modulation of JNJ-induced autophagy by CQ represents a promising new therapeutic approach in NB.}, }
@article {pmid32138578, year = {2021}, author = {Li, D and Shao, R and Wang, N and Zhou, N and Du, K and Shi, J and Wang, Y and Zhao, Z and Ye, X and Zhang, X and Xu, H}, title = {Sulforaphane Activates a lysosome-dependent transcriptional program to mitigate oxidative stress.}, journal = {Autophagy}, volume = {17}, number = {4}, pages = {872-887}, pmid = {32138578}, issn = {1554-8635}, support = {R01 DK115474/DK/NIDDK NIH HHS/United States ; R01 NS062792/NS/NINDS NIH HHS/United States ; }, mesh = {Autophagy/drug effects/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Calcineurin/metabolism ; Calcium/metabolism ; Cell Nucleus/drug effects/metabolism ; Gene Expression Regulation/drug effects ; HEK293 Cells ; HeLa Cells ; Humans ; Isothiocyanates/chemistry/*pharmacology ; Lysosomes/drug effects/*metabolism ; Mitochondria/drug effects/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; *Oxidative Stress/drug effects/genetics ; Phosphorylation/drug effects ; Protein Transport/drug effects ; Reactive Oxygen Species/metabolism ; Sulfoxides/chemistry/*pharmacology ; *Transcription, Genetic/drug effects ; }, abstract = {Oxidative stress underlies a number of pathological conditions, including cancer, neurodegeneration, and aging. Antioxidant-rich foods help maintain cellular redox homeostasis and mitigate oxidative stress, but the underlying mechanisms are not clear. For example, sulforaphane (SFN), an electrophilic compound that is enriched in cruciferous vegetables such as broccoli, is a potent inducer of cellular antioxidant responses. NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2), a transcriptional factor that controls the expression of multiple detoxifying enzymes through antioxidant response elements (AREs), is a proposed target of SFN. NFE2L2/NRF2 is a target gene of TFEB (transcription factor EB), a master regulator of autophagic and lysosomal functions, which we show here to be potently activated by SFN. SFN induces TFEB nuclear translocation via a Ca[2+]-dependent but MTOR (mechanistic target of rapamycin kinase)-independent mechanism through a moderate increase in reactive oxygen species (ROS). Activated TFEB then boosts the expression of genes required for autophagosome and lysosome biogenesis, which are known to facilitate the clearance of damaged mitochondria. Notably, TFEB activity is required for SFN-induced protection against both acute oxidant bursts and chronic oxidative stress. Hence, by simultaneously activating macroautophagy/autophagy and detoxifying pathways, natural compound SFN may trigger a self-defense cellular mechanism that can effectively mitigate oxidative stress commonly associated with many metabolic and age-related diseases.Abbreviations: ANOVA: analyzes of variance; AREs: antioxidant response elements; Baf-A1: bafilomycin A1; BHA: butylhydroxyanisole; CAT: catechin hydrate; CCCP: carbonyl cyanide m- chlorophenylhydrazone; CLEAR: coordinated lysosomal expression and regulation; DCFH-DA: 2',7'-dichlorofluorescin diacetate; FBS: fetal bovine serum; GFP: green fluorescent protein; HMOX1/HO-1: heme oxygenase 1; KD: knockdown; KEAP1: kelch like ECH associated protein 1; KO: knockout; LAMP1: lysosomal associated membrane protein 1; MCOLN1/TRPML1: mucolipin 1; ML-SA1: mucolipin-specific synthetic agonist 1; ML-SI3: mucolipin-specific synthetic inhibitor 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: nuclear factor: erythroid 2 like 2; NPC: Niemann-Pick type C; PBS: phosphate-buffered saline; PPP2/PP2A: protein phosphatase 2; Q-PCR: real time polymerase chain reaction; ROS: reactive oxygen species; RPS6KB1/S6K1/p70S6K: ribosomal protein S6 kinase B1; SFN: sulforaphane; TFEB: transcription factor EB; WT, wild-type.}, }
@article {pmid32131874, year = {2020}, author = {Kanai, T and Kondo, N and Okada, M and Sano, H and Okumura, G and Kijima, Y and Ogose, A and Kawashima, H and Endo, N}, title = {The JNK pathway represents a novel target in the treatment of rheumatoid arthritis through the suppression of MMP-3.}, journal = {Journal of orthopaedic surgery and research}, volume = {15}, number = {1}, pages = {87}, pmid = {32131874}, issn = {1749-799X}, support = {18K09057//Ministry of Education, Culture, Sports, Science and Technology/ ; 18K09098//Ministry of Education, Culture, Sports, Science and Technology/ ; 17K10960//Ministry of Education, Culture, Sports, Science and Technology/ ; 17K17739//Ministry of Education, Culture, Sports, Science and Technology/ ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Adult ; Aged, 80 and over ; Antioxidants/*administration &amp; dosage ; Arthritis, Rheumatoid/drug therapy/*enzymology/pathology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Drug Delivery Systems/*methods ; Female ; Humans ; MAP Kinase Signaling System/drug effects/*physiology ; Matrix Metalloproteinase 3/*metabolism ; Middle Aged ; Synoviocytes/drug effects/enzymology ; Treatment Outcome ; }, abstract = {BACKGROUND AND AIM: The pathophysiology of rheumatoid arthritis (RA) is characterized by excess production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) by neutrophils and macrophages in synovium. Additionally, these cytokines promote the production of reactive oxygen species (ROS), and increased production of matrix metalloproteinases (MMPs), including MMP-3, in synoviocytes that result in joint destruction. There is limited information on how proteolytic enzymes such as MMP-3 can be regulated. We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on RA and identified the relationship between the c-Jun N terminal kinase (JNK) pathway and MMP-3. We hypothesized that elucidating this relationship would lead to novel therapeutic approaches to RA treatment and management.<br><br>METHODS: We investigated the effect of administering a low dose (1000 &#x3bc;M or less) of an antioxidant (NAC) to human rheumatoid fibroblast-like synoviocytes (MH7A cells). We also investigated the response of antioxidant genes such as nuclear factor erythroid -derived&#xa0;2-related factor 2 (Nrf2) and Sequestosome 1 (p62). The influence of MMP-3 expression on the JNK pathway leading to joint destruction and the mechanisms underlying this relationship were investigated through primary dispersion culture cells collected from the synovial membranes of RA patients, consisting of rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS).<br><br>RESULTS: Low-dose NAC (1000 &#x3bc;M) increased the expression of Nrf2 and phospho-p62 in MH7A cells, activating antioxidant genes, suppressing the expression of MMP-3, and inhibiting the phosphorylation of JNK. ROS, MMP-3 expression, and IL-6 was suppressed by administering 30 &#x3bc;M of SP600125 (a JNK inhibitor) in MH7A cells. Furthermore, the administration of SP600125 (30 &#x3bc;M) to RA-FLS suppressed MMP-3.<br><br>CONCLUSIONS: We demonstrated the existence of an MMP-3 suppression mechanism that utilizes the JNK pathway in RA-FLS. We consider that the JNK pathway could be a target for future RA therapies.}, }
@article {pmid32127457, year = {2020}, author = {Tyagi, P and Pal, VK and Agrawal, R and Singh, S and Srinivasan, S and Singh, A}, title = {Mycobacterium tuberculosis Reactivates HIV-1 via Exosome-Mediated Resetting of Cellular Redox Potential and Bioenergetics.}, journal = {mBio}, volume = {11}, number = {2}, pages = {}, pmid = {32127457}, issn = {2150-7511}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Bystander Effect ; Cell Line ; *Coinfection ; Disease Models, Animal ; Energy Metabolism ; *Exosomes ; HIV Infections/genetics/*metabolism/*virology ; Humans ; Macrophages/immunology/metabolism ; Mice ; Models, Biological ; Mycobacterium tuberculosis/*physiology ; *Oxidation-Reduction ; Oxidative Phosphorylation ; Oxidative Stress ; Proteome ; Proteomics ; Tuberculosis/genetics/*metabolism/*microbiology ; }, abstract = {The synergy between Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) interferes with therapy and facilitates the pathogenesis of both human pathogens. Fundamental mechanisms by which M. tuberculosis exacerbates HIV-1 infection are not clear. Here, we show that exosomes secreted by macrophages infected with M. tuberculosis, including drug-resistant clinical strains, reactivated HIV-1 by inducing oxidative stress. Mechanistically, M. tuberculosis-specific exosomes realigned mitochondrial and nonmitochondrial oxygen consumption rates (OCR) and modulated the expression of host genes mediating oxidative stress response, inflammation, and HIV-1 transactivation. Proteomics analyses revealed the enrichment of several host factors (e.g., HIF-1α, galectins, and Hsp90) known to promote HIV-1 reactivation in M. tuberculosis-specific exosomes. Treatment with a known antioxidant-N-acetyl cysteine (NAC)-or with inhibitors of host factors-galectins and Hsp90-attenuated HIV-1 reactivation by M. tuberculosis-specific exosomes. Our findings uncover new paradigms for understanding the redox and bioenergetics bases of HIV-M. tuberculosis coinfection, which will enable the design of effective therapeutic strategies.IMPORTANCE Globally, individuals coinfected with the AIDS virus (HIV-1) and with M. tuberculosis (causative agent of tuberculosis [TB]) pose major obstacles in the clinical management of both diseases. At the heart of this issue is the apparent synergy between the two human pathogens. On the one hand, mechanisms induced by HIV-1 for reactivation of TB in AIDS patients are well characterized. On the other hand, while clinical findings clearly identified TB as a risk factor for HIV-1 reactivation and associated mortality, basic mechanisms by which M. tuberculosis exacerbates HIV-1 replication and infection remain poorly characterized. The significance of our research is in identifying the role of fundamental mechanisms such as redox and energy metabolism in catalyzing HIV-M. tuberculosis synergy. The quantification of redox and respiratory parameters affected by M. tuberculosis in stimulating HIV-1 will greatly enhance our understanding of HIV-M. tuberculosis coinfection, leading to a wider impact on the biomedical research community and creating new translational opportunities.}, }
@article {pmid32127289, year = {2020}, author = {Mason, SA and Trewin, AJ and Parker, L and Wadley, GD}, title = {Antioxidant supplements and endurance exercise: Current evidence and mechanistic insights.}, journal = {Redox biology}, volume = {35}, number = {}, pages = {101471}, pmid = {32127289}, issn = {2213-2317}, mesh = {Adaptation, Physiological ; *Antioxidants ; Dietary Supplements ; *Exercise ; Humans ; Muscle, Skeletal ; }, abstract = {Antioxidant supplements are commonly consumed by endurance athletes to minimize exercise-induced oxidative stress, with the intention of enhancing recovery and improving performance. There are numerous commercially available nutritional supplements that are targeted to athletes and health enthusiasts that allegedly possess antioxidant properties. However, most of these compounds are poorly investigated with respect to their in vivo redox activity and efficacy in humans. Therefore, this review will firstly provide a background to endurance exercise-related redox signalling and the subsequent adaptations in skeletal muscle and vascular function. The review will then discuss commonly available compounds with purported antioxidant effects for use by athletes. N-acetyl cysteine may be of benefit over the days prior to an endurance event; while chronic intake of combined 1000 mg vitamin C + vitamin E is not recommended during periods of heavy training associated with adaptations in skeletal muscle. Melatonin, vitamin E and α-lipoic acid appear effective at decreasing markers of exercise-induced oxidative stress. However, evidence on their effects on endurance performance are either lacking or not supportive. Catechins, anthocyanins, coenzyme Q10 and vitamin C may improve vascular function, however, evidence is either limited to specific sub-populations and/or does not translate to improved performance. Finally, additional research should clarify the potential benefits of curcumin in improving muscle recovery post intensive exercise; and the potential hampering effects of astaxanthin, selenium and vitamin A on skeletal muscle adaptations to endurance training. Overall, we highlight the lack of supportive evidence for most antioxidant compounds to recommend to athletes.}, }
@article {pmid32127147, year = {2020}, author = {Lu, H and Hu, H and Yang, Y and Li, S}, title = {The inhibition of reactive oxygen species (ROS) by antioxidants inhibits the release of an autophagy marker in ectopic endometrial cells.}, journal = {Taiwanese journal of obstetrics &amp; gynecology}, volume = {59}, number = {2}, pages = {256-261}, doi = {10.1016/j.tjog.2020.01.014}, pmid = {32127147}, issn = {1875-6263}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Autophagy/*drug effects ; Beclin-1/drug effects ; Blotting, Western ; Catalase/*pharmacology ; Disease Models, Animal ; Female ; In Situ Hybridization, Fluorescence ; Microtubule-Associated Proteins/drug effects ; Rats ; Reactive Oxygen Species/*antagonists &amp; inhibitors ; }, abstract = {OBJECTIVE: The aim of this study was to evaluate the role of oxidative stress and reactive oxygen species (ROS) in the pathogenesis of endometriosis (EMs) and to investigate the role of antioxidant therapy on autophagy and the outcome of EMs.<br><br>MATERIALS AND METHODS: Experimental rats were given an peritoneal perfusion of N-acetyl-l-cysteine (NAC, 200&#xa0;mg/kg) or catalase (CAT, 2000&#xa0;U/mL). Immunofluorescence was then used to detect microtubule-associated protein light chain 3 (LC3). Western blotting was used to determine the levels of Beclin-1 protein while enzyme-linked immunosorbent assays (ELISAs) were used to measure ROS levels after treatment.<br><br>RESULTS: Fluorescent in situ hybridization showed that NAC and CAT influenced the levels of LC3, an autophagy marker; there were significantly lower levels of LC3 fluorescence in the EMs group (surgical group) of rats compared with controls (p&#xa0;<&#xa0;0.05). Western blot analysis revealed a downregulation of Beclin-1 protein in both the NAC and CAT groups (p&#xa0;<&#xa0;0.05) while ELISA revealed significantly lower levels of ROS in the NAC and CAT groups (p&#xa0;<&#xa0;0.05).<br><br>CONCLUSION: The antioxidants NAC and CAT significantly reduced levels of the autophagy marker LC3 and caused levels of Beclin-1 to significantly decrease. Consequently, antioxidant therapy shows potential for the future treatment of EMs.}, }
@article {pmid32119997, year = {2020}, author = {Youl, ENH and Husson, C and El Khattabi, C and El Mere, S and Declèves, AE and Pochet, S and Nortier, J and Antoine, MH}, title = {Characterization of cytotoxic effects of aristolochic acids on the vascular endothelium.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {65}, number = {}, pages = {104811}, doi = {10.1016/j.tiv.2020.104811}, pmid = {32119997}, issn = {1879-3177}, mesh = {AMP-Activated Protein Kinases/genetics ; Animals ; Aorta, Thoracic/drug effects/physiology ; Aristolochic Acids/*pharmacology ; Calcium/metabolism ; Cell Line ; Endothelial Cells/*drug effects/metabolism/pathology ; Endothelium, Vascular/*drug effects/metabolism/physiology ; Humans ; Male ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Aristolochic acid nephropathy (AAN) is characterized by interstitial fibrosis, proximal tubular atrophy, and hypoxia. A correlation between a reduced peritubular capillary density and the severity of fibrosis has been demonstrated. As calcium, redox and energetic homeostasis are crucial in maintaining endothelial cell function and survival, we aimed to investigate AA-induced disturbances involved in endothelial cell injury. Our results showed a cytotoxic effect of AA on EAhy926 endothelial cells. Exposure of aortic rings to AA impaired vascular relaxation to Acetylcholine (ACh). Increased levels of intracellular reactive oxygen species (ROS) were observed in cells exposed to AA. Pre-treatment with antioxidant N-acetyl cysteine inhibited AA-induced cell death. Superoxide dismutase resulted in restoring ACh-induced relaxation. An increase in intracellular calcium level ([Ca[2+]]i) was observed on endothelial cells. Calcium chelators BAPTA-AM or APB, a specific inhibitor of IP3R, improved cell viability. Moreover, AA exposure led to reduced AMP-activated protein kinase (AMPK) expression. AICAR, an activator of AMPK, improved the viability of AA-intoxicated cells and inhibited the rise of cytosolic [Ca[2+]]i levels. This study provides evidence that AA exposure increases ROS generation, disrupts calcium homeostasis and decreases AMPK activity. It also suggests that significant damage observed in endothelial cells may enhance microcirculation defects, worsening hypoxia and tubulointerstitial lesions.}, }
@article {pmid32117038, year = {2020}, author = {Monti, DA and Zabrecky, G and Leist, TP and Wintering, N and Bazzan, AJ and Zhan, T and Newberg, AB}, title = {N-acetyl Cysteine Administration Is Associated With Increased Cerebral Glucose Metabolism in Patients With Multiple Sclerosis: An Exploratory Study.}, journal = {Frontiers in neurology}, volume = {11}, number = {}, pages = {88}, pmid = {32117038}, issn = {1664-2295}, abstract = {Background: Multiple Sclerosis (MS) is an autoimmune disease marked by progressive neurocognitive injury. Treatment options affording neuroprotective effects remain largely experimental. The purpose of this proof of concept study was to explore the effects of N-acetyl-cysteine (NAC) on cerebral glucose metabolism (CMRGlu) and symptoms in patients with multiple sclerosis (MS). Methods: Twenty-four patients with MS were randomized to either NAC plus standard of care, or standard of care only (waitlist control). The experimental group received NAC intravenously once per week and orally the other 6 days. Patients in both groups were evaluated at baseline and after 2 months (of receiving the NAC or waitlist control period) with an integrated Position Emission Tomography (PET)/ Magnetic Resonance Imaging (MRI) scanner, using 18F Fluorodeoxyglucose (FDG) to measure cerebral glucose metabolism. Following imaging evaluation at 2 months, subjects initially attributed to the standard of care arm were eligible for treatment with NAC. Clinical and symptom questionnaires were also completed initially and after 2 months. Results: The FDG PET data showed significantly increased cerebral glucose metabolism in several brain regions including the caudate, inferior frontal gyrus, lateral temporal gyrus, and middle temporal gyrus (p < 0.05) in the MS group treated with NAC, as compared to the control group. Self-reported scores related to cognition and attention were also significantly improved in the NAC group as compared to the control group. Conclusions: The results of this study suggest that NAC positively affects cerebral glucose metabolism in MS patients, which is associated with qualitative, patient reported improvements in cognition and attention. Larger scale studies may help to determine the clinical impact of NAC on measures of functioning over the course of illness, as well as the most effective dosage and dosage regimen.}, }
@article {pmid32109512, year = {2020}, author = {Hu, J and Lemasters, JJ}, title = {Suppression of iron mobilization from lysosomes to mitochondria attenuates liver injury after acetaminophen overdose in vivo in mice: Protection by minocycline.}, journal = {Toxicology and applied pharmacology}, volume = {392}, number = {}, pages = {114930}, pmid = {32109512}, issn = {1096-0333}, support = {S10 OD018113/OD/NIH HHS/United States ; P30 DK123704/DK/NIDDK NIH HHS/United States ; R01 AA021191/AA/NIAAA NIH HHS/United States ; T32 DK083262/DK/NIDDK NIH HHS/United States ; R56 DK037034/DK/NIDDK NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; R01 AA025379/AA/NIAAA NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; R37 DK037034/DK/NIDDK NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P20 GM103542/GM/NIGMS NIH HHS/United States ; R01 DK037034/DK/NIDDK NIH HHS/United States ; R01 DK073336/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Analgesics, Non-Narcotic/administration &amp; dosage/toxicity ; Animals ; Anti-Bacterial Agents/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/*metabolism ; Drug Overdose ; Hepatocytes/drug effects ; Humans ; Iron/*metabolism ; Lysosomes/*drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Minocycline/*pharmacology ; Mitochondria/*metabolism ; }, abstract = {Acetaminophen (APAP) overdose causes hepatotoxicity involving mitochondrial dysfunction. Previous studies showed that translocation of Fe[2+] from lysosomes into mitochondria by the mitochondrial Ca[2+] uniporter (MCU) promotes the mitochondrial permeability transition (MPT) after APAP. Here, our Aim was to assess protection by iron chelation and MCU inhibition against APAP hepatotoxicity in mice. C57BL/6 mice and hepatocytes were administered toxic doses of APAP with and without starch-desferal (an iron chelator), minocycline (MCU inhibitor), or N-acetylcysteine (NAC). In mice, starch-desferal and minocycline pretreatment decreased ALT and liver necrosis after APAP by >60%. At 24 h after APAP, loss of fluorescence of mitochondrial rhodamine 123 occurred in pericentral hepatocytes often accompanied by propidium iodide labeling, indicating mitochondrial depolarization and cell death. Starch-desferal and minocycline pretreatment decreased mitochondrial depolarization and cell death by more than half. In cultured hepatocytes, cell killing at 10 h after APAP decreased from 83% to 49%, 35% and 27%, respectively, by 1 h posttreatment with minocycline, NAC, and minocycline plus NAC. With 4 h posttreatment in vivo, minocycline and minocycline plus NAC decreased ALT and necrosis by ~20% and ~50%, respectively, but NAC alone was not effective. In conclusion, minocycline and starch-desferal decrease mitochondrial dysfunction and severe liver injury after APAP overdose, suggesting that the MPT is likely triggered by iron uptake into mitochondria through MCU. In vivo, minocycline and minocycline plus NAC posttreatment after APAP protect at later time points than NAC alone, indicating that minocycline has a longer window of efficacy than NAC.}, }
@article {pmid32106875, year = {2020}, author = {Hu, C and Zhao, L and Wu, Z and Li, L}, title = {Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury.}, journal = {Stem cell research &amp; therapy}, volume = {11}, number = {1}, pages = {88}, pmid = {32106875}, issn = {1757-6512}, mesh = {Acetaminophen/toxicity ; Animals ; *Chemical and Drug Induced Liver Injury/therapy ; *Chemical and Drug Induced Liver Injury, Chronic ; Humans ; Liver ; Liver Regeneration ; *Liver Transplantation ; Living Donors ; *Mesenchymal Stem Cells ; Microcirculation ; }, abstract = {Acetaminophen (APAP)-induced injury is a common clinical phenomenon that not only occurs in a dose-dependent manner but also occurs in some idiosyncratic individuals in a dose-independent manner. APAP overdose generally results in acute liver injury via the initiation of oxidative stress, endoplasmic reticulum (ER) stress, autophagy, liver inflammation, and microcirculatory dysfunction. Liver transplantation is the only effective strategy for treating APAP-induced liver failure, but liver transplantation is inhibited by scarce availability of donor liver grafts, acute graft rejection, lifelong immunosuppression, and unbearable costs. Currently, N-acetylcysteine (NAC) effectively restores liver functions early after APAP intake, but it does not protect against APAP-induced injury at the late stage. An increasing number of animal studies have demonstrated that mesenchymal stem cells (MSCs) significantly attenuate acute liver injury through their migratory capacity, hepatogenic differentiation, immunoregulatory capacity, and paracrine effects in acute liver failure (ALF). In this review, we comprehensively discuss the mechanisms of APAP overdose-induced liver injury and current therapies for treating APAP-induced liver injury. We then comprehensively summarize recent studies about transplantation of MSC and MSC derivatives for treating APAP-induced liver injury. We firmly believe that MSCs and their derivatives will effectively promote liver regeneration and liver injury repair in APAP overdose-treated animals and patients. To this end, MSC-based therapies may serve as an effective strategy for patients who are waiting for liver transplantation during the early and late stages of APAP-induced ALF in the near future.}, }
@article {pmid32103436, year = {2020}, author = {Yan, G and Guo, Y and Guo, J and Wang, Q and Wang, C and Wang, X}, title = {N-Acetylcysteine Attenuates Lipopolysaccharide-Induced Osteolysis by Restoring Bone Remodeling Balance via Reduction of Reactive Oxygen Species Formation During Osteoclastogenesis.}, journal = {Inflammation}, volume = {43}, number = {4}, pages = {1279-1292}, pmid = {32103436}, issn = {1573-2576}, support = {2019-ZD-0793//Natural foundation planned project of Liaoning Province/ ; NO. RC170541//Supported project for young technological innovation-talents in Shenyang/ ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Bone Remodeling/*drug effects/physiology ; Cells, Cultured ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Lipopolysaccharides/toxicity ; Male ; Mice ; Mice, Inbred C57BL ; Osteoclasts/*drug effects/metabolism ; Osteogenesis/*drug effects/physiology ; Osteolysis/chemically induced/metabolism/*prevention &amp; control ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Chronic inflammatory diseases affect bone and teeth health tremendously. Characterized by osteolytic lesion and hyperactive osteoclastogenesis, inflammatory bone diseases are short of effective therapeutics and therefore highlight the importance of understanding pathogenesis and developing ideal medications. Reactive oxygen species (ROS) play a prominent role in the innate immune response of activated macrophages, as well as in the physiological signaling of osteoclasts (OCs) differentiation. N-acetylcysteine (NAC) is a potent ROS scavenger and a potential option for treating diseases characterized by excessive ROS generation. However, whether NAC can protect physiological bone remodeling from in vivo inflammatory conditions is largely undefined. We applied NAC treatment on lipopolysaccharide (LPS)-induced inflammatory osteolysis mice model and found that NAC could attenuate bone erosion and protect mice against LPS-induced osteolysis, due to the suppressive effect on osteoclastogenesis and stimulated effect on osteogenesis. Moreover, in vitro study demonstrated that, in OC precursors (pre-OCs), LPS-stimulated expressions of OC marker genes, such as tartrate-resistant acid phosphatase type 5 (Acp5), cathepsin K (Ctsk), OC stimulatory transmembrane protein (Oc-stamp), dendritic cell-specific transmembrane protein (Dc-stamp), and nuclear factor of activated T cells 1 (NFATc1), were all reduced because of the NAC pretreatment, thereby adversely affecting OC function including F-actin ring formation and bone resorption. Further mechanism study showed that NAC blocked LPS-induced ROS formation in both macrophages and pre-OCs, cutting off the LPS-stimulated autocrine/paracrine mechanism during inflammatory osteolysis. Our findings reveal that NAC attenuates inflammatory osteolysis via the elimination of ROS formation during LPS-stimulated osteoclastogenesis, and provide a potential therapeutic approach to treat inflammatory bone disease.}, }
@article {pmid32099348, year = {2020}, author = {Ellingsen, J and Johansson, G and Larsson, K and Lisspers, K and Malinovschi, A and Ställberg, B and Thuresson, M and Janson, C}, title = {Impact of Comorbidities and Commonly Used Drugs on Mortality in COPD - Real-World Data from a Primary Care Setting.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {15}, number = {}, pages = {235-245}, pmid = {32099348}, issn = {1178-2005}, mesh = {Aged ; Aged, 80 and over ; Comorbidity ; Electronic Health Records ; Female ; Heart Failure/mortality ; Humans ; Life Expectancy ; Male ; Middle Aged ; Myocardial Infarction/mortality ; *Primary Health Care ; Pulmonary Disease, Chronic Obstructive/diagnosis/*drug therapy/*mortality ; Registries ; Respiratory System Agents/*administration &amp; dosage/adverse effects ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Stroke/mortality ; Sweden/epidemiology ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Life expectancy is significantly shorter for patients with chronic obstructive pulmonary disease (COPD) than the general population. Concurrent diseases are known to infer an increased mortality risk in those with COPD, but the effects of pharmacological treatments on survival are less established. This study aimed to examine any associations between commonly used drugs, comorbidities and mortality in Swedish real-world primary care COPD patients.<br><br>METHODS: Patients with physician-diagnosed COPD from a large primary care population were observed retrospectively, utilizing primary care records and mandatory Swedish national registers. The time to all-cause death was assessed in a stepwise multiple Cox proportional hazards regression model including demography, socioeconomic factors, exacerbations, comorbidities and medication.<br><br>RESULTS: During the observation period (1999-2009) 5776 (32.5%) of 17,745 included COPD patients died. Heart failure (hazard ratio [HR]: 1.88, 95% confidence interval [CI]: 1.74-2.04), stroke (HR: 1.52, 95% CI: 1.40-1.64) and myocardial infarction (HR: 1.40, 95% CI: 1.24-1.58) were associated with an increased risk of death. Use of inhaled corticosteroids (ICS; HR: 0.79, 95% CI: 0.66-0.94), beta-blockers (HR: 0.86, 95% CI: 0.76-0.97) and acetylsalicylic acid (ASA; HR: 0.87, 95% CI: 0.77-0.98) was dose-dependently associated with a decreased risk of death, whereas use of long-acting muscarinic antagonists (LAMA; HR: 1.33, 95% CI: 1.14-1.55) and N-acetylcysteine (NAC; HR: 1.26, 95% CI: 1.08-1.48) were dose-dependently associated with an increased risk of death in COPD patients.<br><br>CONCLUSION: This large, retrospective, observational study of Swedish real-world primary care COPD patients indicates that coexisting heart failure, stroke and myocardial infarction were the strongest predictors of death, underscoring the importance of timely recognition and treatment of comorbidities. A decreased risk of death associated with the use of ICS, beta-blockers and ASA, and an increased risk associated with the use of LAMA and NAC, was also found.}, }
@article {pmid32098455, year = {2020}, author = {Lee, PH and Hong, J and Jang, AS}, title = {N-acetylcysteine decreases airway inflammation and responsiveness in asthma by modulating claudin 18 expression.}, journal = {The Korean journal of internal medicine}, volume = {35}, number = {5}, pages = {1229-1237}, pmid = {32098455}, issn = {2005-6648}, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Asthma/drug therapy ; Bronchoalveolar Lavage Fluid ; Claudins/genetics ; Disease Models, Animal ; Female ; Humans ; Inflammation ; Lung ; Mice ; Mice, Inbred BALB C ; Ovalbumin ; }, abstract = {BACKGROUND/AIMS: N-acetylcysteine (NAC) affects signaling pathways involved in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and the inflammatory response. However, it is not known how the signal mechanism for tight junctional protein claudin (CLDN) 18 is regulated in asthma patients.<br><br>METHODS: To investigate the effects of NAC on CLDN18 expression in a mouse model of asthma, and to assess plasma levels of CLDN18 in asthma patients. A murine model of asthma induced by ovalbumin (OVA) was established using wild-type BALB/c female mice, and the levels of CLDNs, phosphorylated-pyruvate dehydrogenase kinase 1 (p-PDK1), and protein kinase B (Akt) pathway proteins following NAC treatment were examined by Western blotting and immunohistochemistry. In addition, the plasma levels of CLDN18 were evaluated in asthmatic patients and control subjects.<br><br>RESULTS: NAC diminished OVA-induced airway hyper-responsiveness and inflammation. Levels of CLDN18 protein were higher in lung tissue from OVA mice than tissue from control mice, and were increased by treatment with NAC or dexamethasone. Treatment with NAC or dexamethasone decreased the OVA-induced increase in interleukin-1&#x3b1; protein levels. Although treatment with NAC increased OVA-induced p-PDK1 protein levels, it decreased phosphorylated Akt (pAkt)/Akt levels. Soluble CLDN18 levels were lower in patients with asthma than in controls and were correlated with the percentage of neutrophils, forced expiratory volume in 1 second (FEV1)/forced vital capacity % (FVC%) and FEV1%.<br><br>CONCLUSION: CLDN18 plays a role in the pathogenesis of asthma and NAC diminishes airway inflammation and responsiveness by modulating CLDN18 expression.}, }
@article {pmid32098428, year = {2020}, author = {Takac, P and Kello, M and Vilkova, M and Vaskova, J and Michalkova, R and Mojzisova, G and Mojzis, J}, title = {Antiproliferative Effect of Acridine Chalcone Is Mediated by Induction of Oxidative Stress.}, journal = {Biomolecules}, volume = {10}, number = {2}, pages = {}, pmid = {32098428}, issn = {2218-273X}, mesh = {Acridines/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Death/drug effects ; Cell Line, Tumor ; Chalcone/metabolism/*pharmacology ; Chalcones/pharmacology ; Humans ; Oxidative Stress/*drug effects/physiology ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Chalcones are naturally occurring phytochemicals with diverse biological activities including antioxidant, antiproliferative, and anticancer effects. Some studies indicate that the antiproliferative effect of chalcones may be associated with their pro-oxidant effect. In the present study, we evaluated contribution of oxidative stress in the antiproliferative effect of acridine chalcone 1C ((2 E)-3-(acridin-9-yl)-1-(2,6-dimethoxyphenyl)prop-2-en-1-one) in human colorectal HCT116 cells. We demonstrated that chalcone 1C induced oxidative stress via increased reactive oxygen/nitrogen species (ROS/RNS) and superoxide production with a simultaneous weak adaptive activation of the cellular antioxidant defence mechanism. Furthermore, we also showed chalcone-induced mitochondrial dysfunction, DNA damage, and apoptosis induction. Moreover, activation of mitogen activated phosphokinase (MAPK) signalling pathway in 1C-treated cancer cells was also observed. On the other hand, co-treatment of cells with strong antioxidant, N-acetyl cysteine (NAC), significantly attenuated all of the above-mentioned effects of chalcone 1C, that is, decreased oxidant production, prevent mitochondrial dysfunction, DNA damage, and induction of apoptosis, as well as partially preventing the activation of MAPK signalling. Taken together, we documented the role of ROS in the antiproliferative/pro-apoptotic effects of acridine chalcone 1C. Moreover, these data suggest that this chalcone may be useful as a promising anti-cancer agent for treating colon cancer.}, }
@article {pmid32092686, year = {2020}, author = {Fontecha-Barriuso, M and Martín-Sanchez, D and Martinez-Moreno, JM and Cardenas-Villacres, D and Carrasco, S and Sanchez-Niño, MD and Ruiz-Ortega, M and Ortiz, A and Sanz, AB}, title = {Molecular pathways driving omeprazole nephrotoxicity.}, journal = {Redox biology}, volume = {32}, number = {}, pages = {101464}, pmid = {32092686}, issn = {2213-2317}, mesh = {Animals ; Apoptosis ; Cell Death ; Humans ; *Kidney ; Mice ; Necrosis ; *Omeprazole/pharmacology ; Oxidative Stress ; }, abstract = {Omeprazole, a proton pump inhibitor used to treat peptic ulcer and gastroesophageal reflux disease, has been associated to chronic kidney disease and acute interstitial nephritis. However, whether omeprazole is toxic to renal cells is unknown. Omeprazole has a lethal effect over some cancer cells, and cell death is a key process in kidney disease. Thus, we evaluated the potential lethal effect of omeprazole over tubular cells. Omeprazole induced dose-dependent cell death in human and murine proximal tubular cell lines and in human primary proximal tubular cell cultures. Increased cell death was observed at the high concentrations used in cancer cell studies and also at lower concentrations similar to those in peptic ulcer patient serum. Cell death induced by omeprazole had features of necrosis such as annexin V/7-AAD staining, LDH release, vacuolization and irregular chromatin condensation. Weak activation of caspase-3 was observed but inhibitors of caspases (zVAD), necroptosis (Necrostatin-1) or ferroptosis (Ferrostatin-1) did not prevent omeprazole-induced death. However, omeprazole promoted a strong oxidative stress response affecting mitochondria and lysosomes and the antioxidant N-acetyl-cysteine reduced oxidative stress and cell death. By contrast, iron overload increased cell death. An adaptive increase in the antiapoptotic protein BclxL failed to protect cells. In mice, parenteral omeprazole increased tubular cell death and the expression of NGAL and HO-1, markers of renal injury and oxidative stress, respectively. In conclusion, omeprazole nephrotoxicity may be related to induction of oxidative stress and renal tubular cell death.}, }
@article {pmid32092105, year = {2020}, author = {Walker, OS and Ragos, R and Wong, MK and Adam, M and Cheung, A and Raha, S}, title = {Reactive oxygen species from mitochondria impacts trophoblast fusion and the production of endocrine hormones by syncytiotrophoblasts.}, journal = {PloS one}, volume = {15}, number = {2}, pages = {e0229332}, pmid = {32092105}, issn = {1932-6203}, mesh = {Cell Fusion ; Cells, Cultured ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mitochondria/*metabolism ; Oxidative Stress/drug effects/physiology ; Placental Hormones/*metabolism ; Pregnancy ; Reactive Oxygen Species/*metabolism/pharmacology ; Rotenone/pharmacology ; Signal Transduction/drug effects ; Trophoblasts/drug effects/*metabolism ; }, abstract = {The placenta, a tissue that is metabolically active and rich in mitochondria, forms a critical interface between the mother and developing fetus. Oxidative stress within this tissue, derived from the dysregulation of reactive oxygen species (ROS), has been linked to a number of adverse fetal outcomes. While such outcomes have been associated with mitochondrial dysfunction, the causal role of mitochondrial dysfunction and mitochondrially generated ROS in altering the process of placentation remains unclear. In this study, mitochondrial complex I activity was attenuated using 10 nM rotenone to induce cellular oxidative stress by increasing mitochondrial ROS production in the BeWo choriocarcinoma cell line. Increased mitochondrial ROS resulted in a significant decrease in the transcripts which encode for proteins associated with fusion (GCM1, ERVW-1, and ERVFRD-1) resulting in a 5-fold decrease in the percentage of BeWo fusion. This outcome was associated with increased indicators of mitochondrial fragmentation, as determined by decreased expression of MFN2 and OPA1 along with an increase in a marker of mitochondrial fission (DRP1). Importantly, increased mitochondrial ROS also resulted in a 5.0-fold reduction of human placental lactogen (PL) and a 4.4-fold reduction of insulin like growth factor 2 (IGF2) transcripts; hormones which play an important role in regulating fetal growth. The pre-treatment of rotenone-exposed cells with 5 mM N-acetyl cysteine (NAC) resulted in the prevention of these ROS mediated changes in BeWo function and supports a central role for mitochondrial ROS signaling in the maintenance and function of the materno-fetal interface.}, }
@article {pmid32087337, year = {2020}, author = {Back, SE and Gray, K and Santa Ana, E and Jones, JL and Jarnecke, AM and Joseph, JE and Prisciandaro, J and Killeen, T and Brown, DG and Taimina, L and Compean, E and Malcolm, R and Flanagan, JC and Kalivas, PW}, title = {N-acetylcysteine for the treatment of comorbid alcohol use disorder and posttraumatic stress disorder: Design and methodology of a randomized clinical trial.}, journal = {Contemporary clinical trials}, volume = {91}, number = {}, pages = {105961}, pmid = {32087337}, issn = {1559-2030}, support = {T32 AA007474/AA/NIAAA NIH HHS/United States ; R01 AA025086/AA/NIAAA NIH HHS/United States ; R01 AA025365/AA/NIAAA NIH HHS/United States ; R25 DA020537/DA/NIDA NIH HHS/United States ; K23 AA020842/AA/NIAAA NIH HHS/United States ; K02 DA039229/DA/NIDA NIH HHS/United States ; I01 BX004727/BX/BLRD VA/United States ; T32 DA007288/DA/NIDA NIH HHS/United States ; K23 AA023845/AA/NIAAA NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Acetylcysteine/administration &amp; dosage/adverse effects/therapeutic use ; Age Factors ; *Alcoholism/drug therapy/epidemiology/therapy ; Cognitive Behavioral Therapy/methods ; Combined Modality Therapy ; Double-Blind Method ; Magnetic Resonance Imaging ; Patient Satisfaction ; Randomized Controlled Trials as Topic ; Sex Factors ; Socioeconomic Factors ; *Stress Disorders, Post-Traumatic/drug therapy/epidemiology/therapy ; Veterans ; Clinical Trials, Phase II as Topic ; }, abstract = {Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are two prevalent psychiatric conditions in the U.S. The co-occurrence of AUD and PTSD is also common, and associated with a more severe clinical presentation and worse treatment outcomes across the biopsychosocial spectrum (e.g., social and vocational functioning, physical health) as compared to either disorder alone. Despite the high co-occurrence and negative outcomes, research on effective medications for AUD/PTSD is sparse and there is little empirical evidence to guide treatment decisions. The study described in this paper addresses this knowledge gap by testing the efficacy of N-acetylcysteine (NAC) in reducing alcohol use and PTSD symptoms. Animal studies and prior clinical research suggest a role for NAC in the treatment of substance use disorders and PTSD via glutamate modulation. NAC is a cysteine pro-drug that stimulates the cystine-glutamate exchanger, normalizes glial glutamate transporters, and restores glutamatergic tone on presynaptic receptors in reward regions of the brain. Moreover, NAC is available over-the-counter, has a long-established safety record, and does not require titration to achieve the target dose. This paper describes the rationale, study design, and methodology of a 12-week, randomized, double-blind, placebo-controlled trial of NAC (2400 mg/day) among adults with co-occurring AUD and PTSD. Functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy ([1]H-MRS) are utilized to investigate the neural circuitry and neurochemistry underlying comorbid AUD/PTSD and identify predictors of treatment outcome. This study is designed to determine the efficacy of NAC in the treatment of co-occurring AUD/PTSD and provide new information regarding mechanisms of action implicated in co-occurring AUD/PTSD.}, }
@article {pmid32086430, year = {2020}, author = {Krauskopf, J and Gosink, MM and Schomaker, S and Caiment, F and Warner, R and Johnson, K and Kleinjans, J and Aubrecht, J}, title = {The MicroRNA-based Liquid Biopsy Improves Early Assessment of Lethal Acetaminophen Poisoning: A Case Report.}, journal = {The American journal of case reports}, volume = {21}, number = {}, pages = {e919289}, pmid = {32086430}, issn = {1941-5923}, mesh = {Acetaminophen/*poisoning ; Adult ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/*blood/diagnosis ; Drug Overdose/*blood/diagnosis ; Fatal Outcome ; Female ; Humans ; *Liquid Biopsy ; MicroRNAs/*blood ; }, abstract = {BACKGROUND Acetaminophen overdose is the most common cause of acute liver failure. Nevertheless, new biomarker approaches enabling early prediction of the outcome of the acetaminophen overdose are needed. Recently, using next-generation sequencing analysis of serum from human study participants we uncovered injury-specific signatures of circulating microRNAs (miRNAs) that represented underlying molecular mechanisms of toxicity. This case study is first to show the application of miRNA profiling to assess prognosis of acetaminophen poisoning. CASE REPORT The patient was admitted to the hospital following supra therapeutic acetaminophen ingestion. The patient showed elevated levels of biomarkers of hepatocellular injury alanine aminotransferase, aspartate transaminase, and glutamate dehydrogenase. Even though treatment with N-acetyl cysteine was initiated 24 hours post-ingestion, levels of alanine-aminotransferase and aspartate transaminase peaked at about 40 hours post ingestion of acetaminophen. We analyzed global circulating miRNA levels from 24 consecutive serum samples from this study participant covering the period from admission to time of death. CONCLUSIONS The resulting global miRNA profiles were compared with profiles from study participants with non-lethal acetaminophen poisoning and healthy controls. At the admission, the miRNA profiles of both lethal and non-lethal acetaminophen poisoning showed induction of cellular stress and oxidative damage. Later, the miRNA profiles of the lethal poisoning featured fibrosis and coagulation pathways while profiles of non-lethal cases resembled those of healthy study participants. Although additional confirmatory studies are needed, our case study is first to indicate that global miRNA profiles to be used as liquid biopsies have potential to facilitate the assessment of acetaminophen poisoning.}, }
@article {pmid32084513, year = {2020}, author = {Wartenberg, M and Andrault, PM and Saidi, A and Bigot, P and Nadal-Desbarats, L and Lecaille, F and Lalmanach, G}, title = {Oxidation of cathepsin S by major chemicals of cigarette smoke.}, journal = {Free radical biology &amp; medicine}, volume = {150}, number = {}, pages = {53-65}, doi = {10.1016/j.freeradbiomed.2020.02.013}, pmid = {32084513}, issn = {1873-4596}, mesh = {Cathepsins ; Oxidation-Reduction ; *Smoke ; Smoking ; *Nicotiana ; }, abstract = {Lung cysteine cathepsin S (CatS) that is a potent elastase plays a deleterious role in alveolar remodeling during smoke-induced emphysema. Despite the presence of a reactive nucleophilic cysteine (Cys25) within its active site, most of its elastinolytic activity is preserved after exposure to cigarette smoke extract (CSE), a major source of sulfhydryl oxidants. This result led us to decipher CatS resistance to major and representative CSE oxidants: hydrogen peroxide, formaldehyde, acrolein and peroxynitrite. CatS was inactivated by hydrogen peroxide, peroxynitrite and acrolein in a time- and dose-dependent manner, while formaldehyde was a weaker oxidant. Hydrogen peroxide, but not CSE, formaldehyde, and peroxynitrite impaired the autocatalytic maturation of pro-CatS, whereas acrolein prevented the formation of mature CatS without hindering the initial step of the two-step autocatalytic process. Far-UV CD spectra analysis supported that oxidation by CSE and hydrogen peroxide did not led to a structural alteration of CatS, despite a notable increase of protein carbonylation, a major hallmark of oxidative damage. Evaluation of the oxidation status of Cys25 by specific biotinylated redox sensing probes suggested the formation of sulfenic acid followed by a slower conversion to sulfinic acid after incubation with hydrogen peroxide. Addition of reducing reagents (dithiothreitol, glutathione and N-acetyl cysteine) led to a partial recovery of CatS activity following incubation with CSE, hydrogen peroxide and peroxynitrite. Current results provide some mechanistic evidence of CatS stability and activity in the presence of CSE, supporting its harmful contribution to the pathophysiology of emphysema.}, }
@article {pmid32083136, year = {2020}, author = {Li, X and Kim, J and Wu, J and Ahamed, AI and Wang, Y and Martins-Green, M}, title = {N-Acetyl-cysteine and Mechanisms Involved in Resolution of Chronic Wound Biofilm.}, journal = {Journal of diabetes research}, volume = {2020}, number = {}, pages = {9589507}, pmid = {32083136}, issn = {2314-6753}, support = {R21 AI138188/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biofilms/*drug effects ; Chronic Disease ; DNA, Bacterial/analysis/drug effects ; *Diabetes Mellitus ; Disease Models, Animal ; Extracellular Polymeric Substance Matrix/*drug effects ; Free Radical Scavengers/*pharmacology ; Hydrogen-Ion Concentration ; In Vitro Techniques ; Mice ; Mice, Obese ; Microbial Viability/drug effects ; Microscopy, Confocal ; Microscopy, Fluorescence ; Oxidative Stress/drug effects ; Protein Biosynthesis/drug effects ; *Pseudomonas Infections ; Pseudomonas aeruginosa/*drug effects/metabolism/ultrastructure ; *Wound Infection ; Wounds and Injuries ; }, abstract = {Chronic wounds are a major global health problem with the presence of biofilm significantly contributing to wound chronicity. Current treatments are ineffective in resolving biofilm and simultaneously killing the bacteria; therefore, effective biofilm-resolving drugs are needed. We have previously shown that, together with α-tocopherol, N-acetyl-cysteine (NAC) significantly improves the healing of biofilm-containing chronic wounds, in a diabetic mouse model we developed, by causing disappearance of the bacteria and breakdown of the extracellular polymeric substance (EPS). We hypothesize that NAC creates a microenvironment that affects bacterial survival and EPS integrity. To test this hypothesis, we developed an in vitro biofilm system using microbiome taken directly from diabetic mouse chronic wounds. For these studies, we chose mice in which chronic wound microbiome was rich in Pseudomonas aeruginosa (97%). We show that NAC at concentrations with pH < pKa causes bacterial cell death and breakdown of EPS. When used before biofilm is formed, NAC leads to bacterial cell death whereas treatment after the biofilm is established NAC causes biofilm dismantling accompanied by bacterial cell death. Mechanistically, we show that NAC can penetrate the bacterial membrane, increase oxidative stress, and halt protein synthesis. We also show that low pH is important for the actions of NAC and that bacterial death occurs independently of the presence of biofilm. In addition, we show that both the acetyl and carboxylic groups play key roles in NAC functions. The results presented here provide insight into the mechanisms by which NAC dismantles biofilm and how it could be used to treat chronic wounds after debridement (NAC applied at the start of culture) or without debridement (NAC applied when biofilm is already formed). This approach can be taken to develop biofilm from microbiome taken directly from human chronic wounds to test molecules that could be effective for the treatment of specific biofilm compositions.}, }
@article {pmid32082074, year = {2019}, author = {Zhang, Y and Tang, HM and Liu, CF and Yuan, XF and Wang, XY and Ma, N and Xu, GF and Wang, SP and Deng, J and Wang, X}, title = {TGF-β3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway.}, journal = {Mediators of inflammation}, volume = {2019}, number = {}, pages = {3153240}, pmid = {32082074}, issn = {1466-1861}, mesh = {Acetylcysteine/pharmacology ; Animals ; Autophagy/*drug effects ; Blotting, Western ; Cell Line ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Microscopy, Confocal ; Mucin 5AC/metabolism ; NADPH Oxidase 4/genetics/*metabolism ; NADPH Oxidases/metabolism ; Pyroglyphidae/immunology ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction/drug effects ; Transforming Growth Factor beta3/*metabolism ; }, abstract = {Higher concentrations of reactive oxygen species (ROS) have been associated with epithelial cell damage, cell shedding, and airway hyperresponsiveness. Previous studies have indicated that transforming growth factor-beta (TGF-β) mediates ROS production and NADPH oxidase (NOX) activity. In our previous study, we also observed that TGF-β3 increases mucus secretion in airway epithelial cells in an autophagy-dependent fashion. Although it is well known that the relationship between ROS and autophagy is cell context-dependent, the exact mechanism of action remains unclear. The following study examined whether ROS act as upstream of autophagy activation in response to TGF-β3 induction. Using an allergic inflammation mouse model induced by house dust mite (HDM), we observed elevated lung amounts of TGF-β3 accompanied by increased ROS levels. And we found that ROS levels were elevated and NOX4 expression was increased in TGF-β3-induced epithelial cells, while the lack of NOX4 in the epithelial cells could reduce ROS generation and autophagy-dependent MUC5AC expression treated with TGF-β3. Furthermore, our studies demonstrated that the Smad2/3 pathway was involved in TGF-β3-induced ROS generation by promoting NOX4 expression. The inhibition of ROS generation by N-Acetyl-L-cysteine (NAC) resulted in a decrease in mucus expression and autophagy activity in vivo as well as in vitro. Finally, TGF-β3-neutralizing antibody significantly reduced the ROS generation, mucus expression, and autophagy activity and also decreased the phosphorylation of Smad2 and Smad3. Taken together, the obtained results revealed that persistent TGF-β3 activation increased ROS levels in a NOX4-dependent pathway and subsequently induced autophagy as well as MUC5AC expression in the epithelial cells.}, }
@article {pmid32081630, year = {2020}, author = {Petri, L and Ábrányi-Balogh, P and Varga, PR and Imre, T and Keserű, GM}, title = {Comparative reactivity analysis of small-molecule thiol surrogates.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {28}, number = {7}, pages = {115357}, doi = {10.1016/j.bmc.2020.115357}, pmid = {32081630}, issn = {1464-3391}, mesh = {Chromatography, High Pressure Liquid ; Drug Discovery ; Glutathione ; Humans ; Kinetics ; Molecular Probes/*chemical synthesis/chemistry ; Molecular Structure ; Small Molecule Libraries ; Sulfhydryl Compounds/*chemistry ; }, abstract = {Targeted covalent inhibitors represent an increasingly popular approach to modulate challenging drug targets. Since covalent and non-covalent interactions are both contributing to the affinity of these compounds, evaluation of their reactivity is a key-step to find feasible warheads. There are well-established HPLC- and NMR-based kinetic assays to tackle this task, however, they use a variety of cysteine-surrogates including cysteamine, cysteine or acetyl-cysteine and GSH. The diverse nature of the thiol sources often makes the results incomparable that prevents compiling a comprehensive knowledge base for the design of covalent inhibitors. To evaluate kinetic measurements from different sources we performed a comparative analysis of the different thiol surrogates against a designed set of electrophilic fragments equipped with a range of warheads. Our study included seven different thiol models and 13 warheads resulting in a reactivity matrix analysed thoroughly. We found that the reactivity profile might be significantly different for various thiol models. Comparing the different warheads, we concluded that - in addition to its human relevance - glutathione (GSH) provided the best estimate of reactivity with highest number of true positives identified.}, }
@article {pmid32079909, year = {2020}, author = {Harahap, Y and Yanuar, A and Muhammad, C and Melhan, M and Purwanto, DJ}, title = {Quantification of 3-Hydroxypropyl Mercapturic Acid in the Urine of Patients with Breast Cancer to Monitor Cyclophosphamide Toxicity.}, journal = {Therapeutic drug monitoring}, volume = {42}, number = {4}, pages = {548-553}, doi = {10.1097/FTD.0000000000000737}, pmid = {32079909}, issn = {1536-3694}, mesh = {Acetylcysteine/*analogs &amp; derivatives/urine ; Acrolein/metabolism ; Adult ; Alkylating Agents/metabolism/therapeutic use/toxicity ; Biomarkers/urine ; Breast Neoplasms/*drug therapy/*urine ; Chromatography, Liquid/methods ; Cyclophosphamide/metabolism/*therapeutic use/*toxicity ; Female ; Hematuria/chemically induced ; Humans ; Middle Aged ; Spectrometry, Mass, Electrospray Ionization/methods ; Tandem Mass Spectrometry/methods ; }, abstract = {BACKGROUND: The alkylating agent cyclophosphamide is used in chemotherapy regimens for various type of cancer. However, cyclophosphamide may lead to toxic side effects on the bladder, namely hemorrhagic cystitis, which can cause hematuria, and, potentially, bladder cancer. These effects are caused by acrolein, a byproduct of cyclophosphamide metabolism. In this study, a method to quantify 3-hydroxypropyl mercapturic acid (3-HPMA) in urine was developed. 3-HPMA is a stable metabolite of acrolein that serves as biomarker of acrolein.<br><br>METHODS: Urine samples were collected 4 hours after cyclophosphamide administration and analyzed to determine the risk of hematuria. 3-HPMA was analyzed by reverse-phase LC-MS/MS using a triple quadrupole electrospray ionization mass spectrometer in the positive-ion mode. The mobile phase was a 90:10 (vol/vol) mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Multiple reaction monitoring mode was used, with m/z 222.10 &#x2192; 90.97 for 3-HPMA and 164.10 &#x2192; 122.02 for the internal standard N-acetyl cysteine (NAC). Samples were prepared by acidification and dilution.<br><br>RESULTS: The analytical method produced a linear response within the concentration range of 40-10,000 ng/mL. The method was validated in accordance with 2018 FDA guidelines and applied to quantify 3-HPMA in the urine of 40 patients with breast cancer. The measured concentrations ranged from 820.3 to 5596.1 ng/mg creatinine. Seven patients identified with hematuria had low 3-HPMA concentrations of 4445.824 &#xb1; 411.17 ng/mg creatinine, and 33 patients without hematuria had low 3-HPMA concentrations of 2419.4 &#xb1; 1171.8 ng/mg creatinine.<br><br>CONCLUSIONS: The method was applicable for the quantification of 3-HPMA in human urine. Large variations in 3-HPMA concentrations were found in 40 patients with breast cancer treated with cyclophosphamide, with a significant difference (P < 0.05) observed between patients with hematuria and those without hematuria.}, }
@article {pmid32078434, year = {2020}, author = {Zheng, H and Liu, Y and Xu, D and Liu, P and Yang, X and Li, B and Cao, Z and Liu, Y and Zheng, X}, title = {Inhibition of Gap Junction-Mediated Intercellular Communication by Poly(I:C) in Cultured Human Corneal Fibroblasts.}, journal = {Current eye research}, volume = {45}, number = {9}, pages = {1043-1050}, doi = {10.1080/02713683.2020.1716986}, pmid = {32078434}, issn = {1460-2202}, mesh = {Acetylcysteine/pharmacology ; Antiviral Agents/*pharmacology ; Cell Communication/*drug effects ; Cells, Cultured ; Connexin 43/genetics/*metabolism ; Corneal Keratocytes/*drug effects/metabolism ; Down-Regulation ; Fluorescent Antibody Technique ; Gap Junctions/*drug effects ; Humans ; Immunoblotting ; Malondialdehyde/metabolism ; Poly I-C/*pharmacology ; Protein Kinase Inhibitors/pharmacology ; Real-Time Polymerase Chain Reaction ; Superoxide Dismutase/metabolism ; }, abstract = {PURPOSE/AIM: Corneal stromal fibroblasts are connected to each other via gap junctions, which contribute to maintenance of corneal homeostasis. Viral infection of the corneal stroma can result in inflammation and scarring. The effects of polyinosinic-polycytidylic acid [poly(I:C)], an analog of viral double-stranded RNA, on gap junctional intercellular communication (GJIC) in cultured human corneal fibroblasts (HCFs) were examined.<br><br>MATERIALS AND METHODS: Cultured HCFs were exposed to poly(I:C) in the absence or presence of inhibitors of mitogen-activated protein kinase (MAPK) signaling or the antioxidant N-acetyl-L-cysteine (NAC). Expression of the gap junction protein connexin 43 (Cx43) was examined by immunoblot and immunofluorescence analyses. The level of Cx43 mRNA or microRNA-21 or -130a was determined by quantitative reverse transcription-polymerase chain reaction analysis. GJIC was measured with a dye coupling assay. The amount of malondialdehyde and the activity of superoxide dismutase (SOD) were measured with assay kits.<br><br>RESULTS: Exposure of HCFs to poly(I:C) resulted in down-regulation of Cx43 expression and GJIC activity as well as in up-regulation of microRNA-21 expression. Poly(I:C) increased the amount of malondialdehyde and reduced the activity of SOD in the cells, and these effects were prevented by NAC. The inhibitory effects of poly(I:C) on both Cx43 expression and GJIC activity were attenuated by NAC and by c-Jun NH2-terminal kinase (JNK) inhibitor II.<br><br>CONCLUSIONS: Poly(I:C) inhibited Cx43 expression and GJIC in cultured HCFs, possibly as a result of the associated up-regulation of microRNA-21. Poly(I:C) also increased oxidative stress in these cells, and such stress together with signaling by the MAPK JNK was implicated in the effects of poly(I:C) on Cx43 expression and GJIC activity. Down-regulation of GJIC activity among corneal fibroblasts by double-stranded RNA may thus contribute to the disruption of stromal homeostasis during viral infection of the cornea.}, }
@article {pmid32077040, year = {2019}, author = {Sardar, D and Mathews, N and Mammen, J and Nair, SC and Jacob, S and Patel, L and Thomas, A and Jhanwar, S and Sharma, A and Sen, M and Vijayalekshmi, B and Balasubramanian, KA and Subramani, K and Thomas, L and Abhilash, KPP and Zachariah, U and Elias, E and Goel, A and Eapen, CE}, title = {Rodenticidal hepatotoxicity: Raised plasma Von Willebrand factor levels predict in-hospital survival and preliminary report of the outcome of Von Willebrand factor reducing management protocol.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {38}, number = {6}, pages = {527-533}, pmid = {32077040}, issn = {0975-0711}, support = {11592//Fluid Research Fund, Christian Medical College/International ; }, mesh = {Adolescent ; Adult ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/*blood/mortality ; Child ; Clinical Protocols ; Female ; Hospital Mortality ; Humans ; Liver Failure, Acute/*blood/chemically induced/mortality ; Male ; Multiple Organ Failure/blood/chemically induced/mortality ; Predictive Value of Tests ; Prospective Studies ; Retrospective Studies ; Risk Factors ; Rodenticides/*poisoning ; Survival Rate ; Treatment Outcome ; Young Adult ; von Willebrand Diseases/chemically induced/*mortality/therapy ; von Willebrand Factor/*analysis ; }, abstract = {BACKGROUND: High Von Willebrand factor (VWF) levels may predispose to multi-organ failure in acute liver failure (ALF). In rodenticide-induced hepatotoxicity patients, we analyzed if plasma VWF levels predicted survival and also the outcome of VWF lowering by N-acetyl cysteine (NAC), fresh frozen plasma (FFP) infusions, and plasma exchange (PLEX).<br><br>METHODS: We retrospectively analyzed prospectively collected data. Hepatotoxicity was classified as uncomplicated acute hepatitis (UAH), acute liver injury (ALI), and ALF. ALF patients, if not opting for liver transplantation, had PLEX and NAC; ALI patients received NAC &#xb1; FFP (PLEX, if worsening); UAH patients had NAC. Plasma VWF antigen was measured (normal, 50% to 150%). In-hospital survival was analyzed as discharged alive or died/discharged in a terminal condition (poor outcome).<br><br>RESULTS: Twenty-four consecutive rodenticide-induced hepatotoxicity patients (UAH in 1, ALI in 20, ALF in 3) from December 2017 to January 2019 were studied. Baseline VWF levels were 153%, 423 (146-890)% median (range), and 448 (414-555)% in UAH, ALI, ALF patients; model for end-stage liver disease (MELD) scores were 11, 24 (12-38), 36 (32-37) and in-hospital survival rates were 100%, 85%, 67%, respectively. VWF levels were higher in patients with poor outcome (555 [512-890]%) than in those discharged alive (414 [146-617]%) (p-value&#x2009;=&#x2009;0.04). The area under the receiver operating curve of the VWF level, MELD score, and sequential organ failure assessment score to predict survival was 0.92, 0.84, and 0.66, respectively. Of 4 patients meeting criteria for liver transplantation (none had transplantation), 3 (75%) survived.<br><br>CONCLUSIONS: High VWF levels predict poor outcome in rodenticide-induced hepatotoxicity. VWF reduction may be useful in such patients.}, }
@article {pmid32074330, year = {2020}, author = {Yosef, B and Zhou, Y and Mouschouris, K and Poteracki, J and Soker, S and Criswell, T}, title = {N-Acetyl-L-Cysteine Reduces Fibrosis and Improves Muscle Function After Acute Compartment Syndrome Injury.}, journal = {Military medicine}, volume = {185}, number = {Suppl 1}, pages = {25-34}, pmid = {32074330}, issn = {1930-613X}, support = {T32 EB014836/EB/NIBIB NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Analysis of Variance ; Animals ; Compartment Syndromes/*complications/drug therapy/physiopathology ; Disease Models, Animal ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Muscle, Skeletal/*drug effects/pathology/physiopathology ; *Protective Factors ; Rats, Inbred Lew ; Real-Time Polymerase Chain Reaction/methods ; }, abstract = {INTRODUCTION: Upon injury, skeletal muscle undergoes a multiphase process beginning with degeneration of the damaged tissue, which is accompanied by inflammation and finally regeneration. One consequence of an injured microenvironment is excessive production of reactive oxygen species, which results in attenuated regeneration and recovery of function ultimately leading to fibrosis and disability. The objective of this research was to test the potential of the antioxidant, N-Acetyl-L-Cysteine (NAC), as a mediator of reactive oxygen species damage that results from traumatic muscle injury in order to support repair and regeneration of wounded muscle tissue and improve function recovery.<br><br>MATERIALS AND METHODS: Adult female Lewis rats were subjected to compartment syndrome injury as previously published by our group. Rats received intramuscular injections of NAC or vehicle at 24, 48, and 72&#xa0;hours postinjury. Muscle function, tissue fibrosis, and the expression of myogenic and angiogenic markers were measured.<br><br>RESULTS: Muscle function was significantly improved, and tissue fibrosis was significantly decreased in NAC-treated muscles.<br><br>CONCLUSIONS: These results suggest that NAC treatment of skeletal muscle after injury may be a viable option for the prevention of long-term fibrosis and scar formation, facilitating recovery of muscle function.}, }
@article {pmid32072435, year = {2020}, author = {Amjad, W and Alukal, J and Doycheva, I and Zhang, T and Maheshwari, A and Yoo, H and Thuluvath, PJ}, title = {A Combination of N-Acetylcysteine and Prednisone Has No Benefit Over Prednisone Alone in Severe Alcoholic Hepatitis: A Retrospective Analysis.}, journal = {Digestive diseases and sciences}, volume = {65}, number = {12}, pages = {3726-3733}, pmid = {32072435}, issn = {1573-2568}, mesh = {*Acetylcysteine/administration &amp; dosage/adverse effects ; Adult ; Anti-Inflammatory Agents/administration &amp; dosage/adverse effects ; Drug Monitoring/methods ; Drug Therapy, Combination/methods ; Female ; Free Radical Scavengers/administration &amp; dosage/adverse effects ; *Hepatitis, Alcoholic/complications/diagnosis/drug therapy/mortality ; Humans ; *Liver Cirrhosis/diagnosis/etiology ; Male ; Outcome and Process Assessment, Health Care ; *Prednisone/administration &amp; dosage/adverse effects ; Renal Insufficiency/diagnosis/etiology ; Survival Analysis ; United States/epidemiology ; }, abstract = {INTRODUCTION: In this study, we assessed whether there were any survival advantages with a combination treatment of intravenous N-acetylcysteine (NAC) and prednisone over prednisone alone in those with severe alcoholic hepatitis [discriminant function (DF) ≥ 32].<br><br>PATIENTS AND METHODS: Between January 1, 2013, and February 28, 2019, we identified 68 patients (mean age 47.2&#xa0;years&#x2009;&#xb1;&#x2009;10.1, 57% women, 65% cirrhosis, MELD score 28.1&#x2009;&#xb1;&#x2009;6.6) with alcoholic hepatitis, and of those, 21 (31%) received prednisone and 47 (69%) received prednisone&#x2009;+&#x2009;NAC. Lille score&#x2009;&#x2265;&#x2009;0.45 was considered a poor response. Renal insufficiency was defined as GFR&#x2009;<&#x2009;60&#xa0;ml/min/1.73m[2] calculated on two separate occasions.<br><br>RESULTS: DF (74.2&#x2009;&#xb1;&#x2009;33.6 vs. 56.9&#x2009;&#xb1;&#x2009;15.9, p&#x2009;=&#x2009;0.09) was similar, but MELD (29.2&#x2009;&#xb1;&#x2009;6.3 vs. 25.5&#x2009;&#xb1;&#x2009;6.4, p&#x2009;=&#x2009;0.03) scores were higher in the combination group. The overall 30-day and 90-day mortality was 13.2% (9/68) and 20.6% (14/68), respectively. Women were more likely (OR 4.86, 95% CI 1.62-14.59) to respond to treatment based on Lille score compared to men, but the type of treatment regimen had no effect on Lille score (OR 0.84, 95% CI 0.25-2.78). Treatment regimen had no effect on both adjusted and&#xa0;unadjusted survivals. Multivariate analysis, after adjusting for confounding variables, confirmed these observations. DF&#x2009;+&#x2009;renal insufficiency had the highest AUROC (0.86) to predict mortality.<br><br>CONCLUSION: The combination treatment of NAC&#x2009;+&#x2009;prednisone is not better than prednisone alone in patients with severe alcoholic hepatitis.}, }
@article {pmid32071590, year = {2020}, author = {Pesko, MJ and Burbige, EM and Sannar, EM and Beresford, C and Rogers, C and Ariefdjohan, M and Stutzman, D}, title = {The Use of N-acetylcysteine Supplementation to Decrease Irritability in Four Youths With Autism Spectrum Disorders.}, journal = {The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG}, volume = {25}, number = {2}, pages = {149-154}, pmid = {32071590}, issn = {1551-6776}, abstract = {Children and adolescents with autism spectrum disorder (ASD) often experience high levels of irritability, which adversely affects their functioning and behaviors. N-acetylcysteine (NAC), an antioxidant precursor to glutathione, has recently been studied for a variety of neuropsychiatric disorders. There is growing evidence to support its use to decrease irritability and self-injurious behaviors in youth with ASD. However, previous studies were limited to outpatient youth with mild symptoms of irritability, maintained on stable medication regimens, who do not meet criteria for higher levels of care. We describe the use of NAC among 4 youths (14-17 years) with ASD who had Aberrant Behavior Checklist-Irritability (ABC-I) scores of ≥ 20 and other psychotropic medication trials prior to treatment with NAC. In all of the cases, NAC appeared to be well tolerated. There was a reduction of symptoms of irritability and/or antipsychotic medication dosages in these cases; despite this, the authors cannot know whether use of NAC or other medication or behavioral strategies were responsible for such changes because this study was not a controlled trial.}, }
@article {pmid32071301, year = {2020}, author = {Fan, J and Ren, D and Wang, J and Liu, X and Zhang, H and Wu, M and Yang, G}, title = {Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo.}, journal = {Cell death &amp; disease}, volume = {11}, number = {2}, pages = {126}, pmid = {32071301}, issn = {2041-4889}, mesh = {A549 Cells ; Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Proliferation/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Female ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Lung Neoplasms/*drug therapy/enzymology/pathology ; MAP Kinase Signaling System/*drug effects ; Mice, Inbred BALB C ; Mice, Nude ; Phosphorylation ; Quassins/*pharmacology ; Reactive Oxygen Species/*metabolism ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {Worldwide, lung cancer remains a leading cause of cancer mortality. Bruceine D (BD) has been shown to induce pancreatic cancer cell death via several different mechanisms. In this study, we demonstrated that BD inhibited lung cancer cell proliferation. Apoptosis and autophagy were the most important mechanisms involved in BD-induced lung cancer cell death, and complete autophagic flux was observed in A549 and NCI-H292 cells. In addition, BD significantly improved intracellular reactive oxygen species (ROS) levels. BD-mediated cell apoptosis and autophagy were almost inhibited in cells pretreated with N-acetylcysteine (NAC), an ROS scavenger. Furthermore, MAPK signaling pathway activation contributed to BD-induced cell proliferation inhibition and NAC could eliminate p-ERK and p-JNK upregulation. Finally, an in vivo study indicated that BD inhibited the growth of lung cancer xenografts. Overall, BD is a promising candidate for the treatment of lung cancer owing to its multiple mechanisms and low toxicity.}, }
@article {pmid32070920, year = {2020}, author = {Mo, M and Li, S and Dong, Z and Li, C and Sun, Y and Li, A and Zhao, Z}, title = {S-allylmercaptocysteine ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting inflammation and oxidative stress via nuclear factor kappa B and Keap1/Nrf2 pathways.}, journal = {International immunopharmacology}, volume = {81}, number = {}, pages = {106273}, doi = {10.1016/j.intimp.2020.106273}, pmid = {32070920}, issn = {1878-1705}, mesh = {Acute Lung Injury/*drug therapy ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Cysteine/*analogs &amp; derivatives/therapeutic use ; Cytokines/metabolism ; Humans ; Inflammation/*drug therapy ; Inflammation Mediators/metabolism ; Kelch-Like ECH-Associated Protein 1/metabolism ; Lipopolysaccharides/immunology ; Male ; Mice ; Mice, Inbred BALB C ; NF-E2-Related Factor 2/*metabolism ; NF-kappa B/*metabolism ; Oxidative Stress ; Signal Transduction ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {The garlic-derived organosulfur compound S-allylmercaptocysteine (SAMC) has been reported to exhibit anti-inflammatory and anti-oxidative activities, whereas its potential therapeutic effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is unknown. In this study, we focused on exploring the therapeutic effects of SAMC on LPS-induced ALI mice and the involvement of underlying molecular mechanisms. BalB/c mice were treated with SAMC (10, 30 and 60 mg/kg) or positive control N-acetylcysteine (NAC, 500 mg/kg) by gavage after intratracheal instillation of LPS for 30 min and were sacrificed 24 h after LPS administration. Our results indicate that the treatment with SAMC not only ameliorated the histological changes but also decreased LPS-triggered lung edema. Moreover, SAMC displayed an anti-inflammatory effect through reducing inflammatory cells infiltration, myeloperoxidase (MPO) formation and inhibiting pro-inflammatory cytokines/mediator production including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) via suppressing the activation of nuclear factor-kappaB (NF-κB) signaling pathway. Furthermore, SAMC attenuated oxidative stress evoked by LPS via diminishing malondialdehyde (MDA) formation and reversing glutathione (GSH) and superoxide dismutase (SOD) depletion. Meanwhile, SAMC up-regulated expressions of endogenous antioxidant/detoxifying proteins including heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1(NQO1) through reversing the suppression of Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway. Our results demonstrate that SAMC effectively attenuated LPS-induced ALI which was largely dependent upon inhibition of inflammation and oxidative stress via NF-κB and Keap1/Nrf2 signaling pathways.}, }
@article {pmid32070059, year = {2020}, author = {Langston-Cox, A and Anderson, D and Creek, DJ and Palmer, K and Wallace, EM and Marshall, SA}, title = {Measuring Sulforaphane and Its Metabolites in Human Plasma: A High Throughput Method.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {4}, pages = {}, pmid = {32070059}, issn = {1420-3049}, support = {1113902//National Health and Medical Research Council/ ; N/A//Norman Beischer Medical Research Foundation/ ; }, mesh = {Chromatography, Liquid/methods ; Humans ; Isothiocyanates/*blood/pharmacokinetics ; Mass Spectrometry/methods ; Reproducibility of Results ; Sulfoxides ; }, abstract = {(1) Background: There is increasing understanding of the potential health benefits of cruciferous vegetables. In particular sulforaphane (SFN), found in broccoli, and its metabolites sulforaphane-glutathione (SFN-GSH), sulforaphane-cysteine (SFN-Cys), sulforaphane cysteine-glycine (SFN-CG) and sulforaphane-N-acetyl-cysteine (SFN-NAC) have potent antioxidant effects that may offer therapeutic value. Clinical investigation of sulforaphane as a therapeutic antioxidant requires a sensitive and high throughput process for quantification of sulforaphane and metabolites; (2) Methods: We collected plasma samples from healthy human volunteers before and for eight hours after consumption of a commercial broccoli extract supplement rich in sulforaphane. A rapid and sensitive method for quantification of sulforaphane and its metabolites in human plasma using Liquid Chromatography-Mass Spectrometry (LC-MS) has been developed; (3) Results: The LC-MS analytical method was validated at concentrations ranging between 3.9 nM and 1000 nM for SFN-GSH, SFN-CG, SFN-Cys and SFN-NAC and between 7.8 nM and 1000 nM in human plasma for SFN. The method displayed good accuracy (1.85%-14.8% bias) and reproducibility (below 9.53 %RSD) including low concentrations 3.9 nM and 7.8 nM. Four SFN metabolites quantitation was achieved using external standard calibration and in SFN quantitation, SFN-d8 internal standardization was used. The reported method can accurately quantify sulforaphane and its metabolites at low concentrations in plasma; (4) Conclusions: We have established a time- and cost-efficient method of measuring sulforaphane and its metabolites in human plasma suitable for high throughput application to clinical trials.}, }
@article {pmid32068662, year = {2020}, author = {Jamerson, EC and Elhusseiny, AM and ElSheikh, RH and Eleiwa, TK and El Sayed, YM}, title = {Role of Matrix Metalloproteinase 9 in Ocular Surface Disorders.}, journal = {Eye &amp; contact lens}, volume = {46 Suppl 2}, number = {}, pages = {S57-S63}, doi = {10.1097/ICL.0000000000000668}, pmid = {32068662}, issn = {1542-233X}, mesh = {Biomarkers/metabolism ; Eye Diseases/*enzymology ; Humans ; Matrix Metalloproteinase 9/*metabolism ; Signal Transduction ; }, abstract = {OBJECTIVES: (1) To explore the role and significance of Matrix Metalloproteinase 9 (MMP-9), a proteolytic enzyme, in various ocular surface diseases of inflammatory, infectious, and traumatic etiology (2), to further elucidate the molecular mechanisms responsible for its overexpression in ocular surface disease states, and (3) to discuss possible targets of therapeutic intervention.<br><br>METHODS: A literature review was conducted of primary sources from 1995 onward using search results populated from the US National Library of Medicine search database.<br><br>RESULTS: MMP-9 overexpression has been found in in vitro and in vivo models of dry eye disease (DED), corneal ulceration, microbial keratitis, corneal neovascularization, ultraviolet light-induced radiation, and a host of additional surface pathologies. MMP-9 is involved in an intricate signal transduction cascade that includes induction by many proinflammatory molecules including interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-a), nuclear factor kappa light chain enhancer of activated B cells (NF-kB), platelet-activating factor, activator protein 1 (AP-1), and transforming growth factor beta (TGF-B). MMP-9 expression is blunted by a diverse array of molecular factors, such as tissue inhibitors of metalloproteinases, cyclosporine A (CyA), PES_103, epigalloccatechin-3-gallate (EGCG), N-acetylcysteine (NaC), ascorbate, tetracyclines, and corticosteroids. Inhibition of MMP-9 frequently led to improvement of ocular surface disease.<br><br>CONCLUSIONS: Novel insights into the mechanistic action of MMP-9 provide potential for new therapeutic modulations of ocular surface diseases mediated by its overexpression.}, }
@article {pmid32067910, year = {2020}, author = {Liu, Y and Tian, X and Liu, S and Liu, D and Li, Y and Liu, M and Zhang, X and Yan, C and Han, Y}, title = {DNA hypermethylation: A novel mechanism of CREG gene suppression and atherosclerogenic endothelial dysfunction.}, journal = {Redox biology}, volume = {32}, number = {}, pages = {101444}, pmid = {32067910}, issn = {2213-2317}, mesh = {*Atherosclerosis/genetics ; DNA ; *DNA Methylation ; Epigenesis, Genetic ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Lipoproteins, LDL/metabolism ; Repressor Proteins ; }, abstract = {OBJECTIVE: Cellular repressor of E1A-stimulated genes (CREG), a vasculoprotective molecule, is significantly downregulated in atherosclerotic vessels through unclear mechanisms. While epigenetic regulation is involved in atherosclerosis development, it is not known if the CREG gene is epigenetically regulated. The aim of this study was to assess the potential role of CREG methylation in contributing to atherosclerosis.<br><br>APPROACH AND RESULTS: Overexpression of DNA methyltransferase (DNMT)3B significantly inhibited CREG expression in human umbilical vein endothelial cells (HUVECs) and human coronary aortic endothelial cells (HCAECs).Conversely, inhibition of DNA methylation with 5-aza-2'-deoxycytidine (5-aza-dC) dose-dependently increased CREG expression. A CREG promoter analysis identified +168 to +255 bp as a key regulatory region and the CG site at +201/+202 bp as a key methylation site. The transcription factor GR-&#x3b1; could bind to the +201/+202 bp CG site promoting CREG transcription, a process significantly inhibited by DNMT3B overexpression. Treatment of cells with oxidized low-density lipoprotein (ox-LDL), a critical atherosclerogenic factor, significantly increased DNMT3B expression, increasing CREG promotor methylation, blocking GR-&#x3b1; binding, and inhibiting CREG expression. Consistently, CG sites in the CREG promoter fragment were hyper-methylated in human atherosclerotic arteries, and CREG expression was significantly reduced. A negative correlation between DNMT3B and CREG expression levels was observed in human atherosclerotic arteries. Finally, Ox-LDL-induced endothelium dysfunction was significantly attenuated by both 5-aza-dC and an anti-oxidative molecular N-acetylcysteine (NAC) administration through rescue the expression of CREG and activation of the p-eNOS/NO pathway.<br><br>CONCLUSIONS: Our study provides the first direct evidence that DNMT3B-mediated CREG gene hypermethylation is a novel mechanism that contributes to endothelial dysfunction and atherosclerosis development. Blocking CREG methylation may represent a novel therapeutic approach to treat ox-LDL-induced atherosclerosis.}, }
@article {pmid32066777, year = {2020}, author = {Yamamoto, N and Oyaizu, T and Enomoto, M and Horie, M and Yuasa, M and Okawa, A and Yagishita, K}, title = {VEGF and bFGF induction by nitric oxide is associated with hyperbaric oxygen-induced angiogenesis and muscle regeneration.}, journal = {Scientific reports}, volume = {10}, number = {1}, pages = {2744}, pmid = {32066777}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Angiogenesis Inducing Agents ; Animals ; Contusions/genetics/metabolism/pathology/*therapy ; Endothelial Cells/cytology/drug effects/metabolism ; Fibroblast Growth Factor 2/genetics/metabolism ; Gene Expression Regulation ; Hyperbaric Oxygenation/*methods ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Male ; Muscle, Skeletal/*drug effects/metabolism/pathology ; NG-Nitroarginine Methyl Ester/pharmacology ; Neovascularization, Physiologic/*drug effects ; Nitric Oxide/agonists/*biosynthesis ; Nitric Oxide Synthase Type III/antagonists &amp; inhibitors/genetics/metabolism ; Oxygen/*pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/metabolism ; Regeneration/drug effects ; Treatment Outcome ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Hyperbaric oxygen (HBO) treatment promotes early recovery from muscle injury. Reactive oxygen species (ROS) upregulation is a key mechanism of HBO, which produces high O2 content in tissues through increased dissolution of oxygen at high pressure. Nitric oxide (NO), a type of ROS, generally stabilizes hypoxia-inducible factor (HIF) 1α and stimulates secretion of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) from endothelial cells and macrophages, which then induces angiogenesis. The purpose of the present study was to investigate whether HBO could promote angiogenesis via induction of NO and induce muscle regeneration in contused rat skeletal muscles. The HBO protocol consisted of 2.5 atmospheres absolute (ATA) 100% oxygen for 120 minutes, once a day for 5 consecutive days. We also evaluated the effects of a ROS inhibitor (NAC) or NOS-specific inhibitor (L-NAME) on HBO. HBO significantly increased NO3[-], VEGF, and bFGF levels and stabilized HIF1α within 1 day. HBO promoted blood vessel formation at 3-7 days and muscle healing at 5-7 days after contusion. Administration of both NAC and L-NAME before HBO suppressed angiogenesis and muscle regeneration even after HBO. HBO thus promoted angiogenesis and muscle regeneration mainly through generation of NO in the early phase after muscle contusion injury.}, }
@article {pmid32064022, year = {2020}, author = {Liu, Y and Xu, X and Zhang, Y and Li, M and Guo, J and Yan, C and Wang, F and Li, Y and Ding, Y and Li, B and Fan, P}, title = {Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {3690123}, pmid = {32064022}, issn = {1942-0994}, mesh = {Action Potentials/*drug effects/physiology ; Animals ; Benzylamines/pharmacology ; Calcium/metabolism ; Calcium Channels, L-Type/*metabolism/physiology ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists &amp; inhibitors/metabolism ; Cardiotoxicity/*metabolism ; Endoplasmic Reticulum Stress/*drug effects/genetics ; Ether-A-Go-Go Potassium Channels/*metabolism/physiology ; HEK293 Cells ; HSP70 Heat-Shock Proteins/metabolism ; Heart Ventricles/drug effects/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Male ; Mice ; Myocytes, Cardiac/drug effects ; Proteasome Endopeptidase Complex/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Sulfonamides/pharmacology ; Thioridazine/*toxicity ; Ubiquitination ; }, abstract = {Thioridazine (THIO) is a phenothiazine derivative that is mainly used for the treatment of psychotic disorders. However, cardiac arrhythmias especially QT interval prolongation associated with the application of this compound have received serious attention after its introduction into clinical practice, and the mechanisms underlying the cardiotoxicity induced by THIO have not been well defined. The present study was aimed at exploring the long-term effects of THIO on the hERG and L-type calcium channels, both of which are relevant to the development of QT prolongation. The hERG current (I hERG) and the calcium current (I Ca-L) were measured by patch clamp techniques. Protein levels were analyzed by Western blot, and channel-chaperone interactions were determined by coimmunoprecipitation. Reactive oxygen species (ROS) were determined by flow cytometry and laser scanning confocal microscopy. Our results demonstrated that THIO induced hERG channel deficiency but did not alter channel kinetics. THIO promoted ROS production and stimulated endoplasmic reticulum (ER) stress and the related proteins. The ROS scavenger N-acetyl cysteine (NAC) significantly attenuated hERG reduction induced by THIO and abolished the upregulation of ER stress marker proteins. Meanwhile, THIO increased the degradation of hERG channels via disrupting hERG-Hsp70 interactions. The disordered hERG proteins were degraded in proteasomes after ubiquitin modification. On the other hand, THIO increased I Ca-L density and intracellular Ca[2+] ([Ca[2+]]i) in neonatal rat ventricular cardiomyocytes (NRVMs). The specific CaMKII inhibitor KN-93 attenuated the intracellular Ca[2+] overload, indicating that ROS-mediated CaMKII activation promoted calcium channel activation induced by THIO. Optical mapping analysis demonstrated the slowing effects of THIO on cardiac repolarization in mouse hearts. THIO significantly prolonged APD50 and APD90 and increased the incidence of early afterdepolarizations (EADs). In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), THIO also resulted in APD prolongation. In conclusion, dysfunction of hERG channel proteins and activation of L-type calcium channels via ROS production might be the ionic mechanisms for QT prolongation induced by THIO.}, }
@article {pmid32061800, year = {2020}, author = {Fu, SC and Liu, JM and Lee, KI and Tang, FC and Fang, KM and Yang, CY and Su, CC and Chen, HH and Hsu, RJ and Chen, YW}, title = {Cr(VI) induces ROS-mediated mitochondrial-dependent apoptosis in neuronal cells via the activation of Akt/ERK/AMPK signaling pathway.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {65}, number = {}, pages = {104795}, doi = {10.1016/j.tiv.2020.104795}, pmid = {32061800}, issn = {1879-3177}, mesh = {AMP-Activated Protein Kinases/metabolism ; Apoptosis/drug effects ; Cell Line, Tumor ; Chromium/*toxicity ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism/physiology ; Neurons/*drug effects/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Hexavalent chromium (Cr(VI)), a well-known toxic industrial and environmental pollutant, has been shown to cause serious toxic and health effects. However, limited information is available on Cr(VI)-induced neurotoxic potential, with the underlying toxicological mechanisms remain mostly unclear. The present study demonstrated that the mitochondria-dependent apoptosis pathway was involved in Cr(VI)-induced SH-SY5Y cell (the human neuroblastoma cell line) death, which was accompanied by the appearance of cell shrinkage, increased mitochondrial membrane potential (MMP) depolarization and cytochrome c release, and the activation of caspase cascades and poly (ADP-ribose) polymerase (PARP). Cr(VI) treatment also increased the generation of intracellular reactive oxygen species (ROS). Pretreatment of SH-SY5Y cells with antioxidant N-acetylcysteine (NAC) effectively attenuated ROS production and reversed these Cr(VI)-induced cytotoxicity and apoptotic responses. Furthermore, exposure to Cr(VI) significantly increased the phosphorylation levels of Akt, extracellular regulated kinase (ERK)1/2, and AMP-activated protein kinase (AMPK)α. NAC and the pharmacological inhibitor of Akt (LY294002), ERK1/2 (PD980590), and AMPKα (Compound C) markedly abrogated the Cr(VI)-induced activation of Akt, ERK1/2, and AMPKα signal, respectively, with the concomitant inhibition of mitochondrial dysfunction and caspase activation. Additionally, all these inhibitors suppressed Cr(VI)-induced phosphorylation of Akt, ERK1/2, and AMPKα and of each other. Collectively, these results suggest that Cr(VI) exerts its cytotoxicity on neuronal cells by inducing mitochondria-dependent apoptosis through the interdependent activation of Akt, ERK1/2, and AMPKα, which are mainly mediated by ROS generation.}, }
@article {pmid32060981, year = {2020}, author = {Gupta, G and Gliga, A and Hedberg, J and Serra, A and Greco, D and Odnevall Wallinder, I and Fadeel, B}, title = {Cobalt nanoparticles trigger ferroptosis-like cell death (oxytosis) in neuronal cells: Potential implications for neurodegenerative disease.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {4}, pages = {5262-5281}, doi = {10.1096/fj.201902191RR}, pmid = {32060981}, issn = {1530-6860}, mesh = {*Cell Differentiation ; Cells, Cultured ; Cobalt/*chemistry ; Dopaminergic Neurons/metabolism/*pathology ; *Ferroptosis ; Glutathione/metabolism ; Humans ; Metal Nanoparticles/administration &amp; dosage/chemistry/*toxicity ; Neurodegenerative Diseases/chemically induced/*pathology ; }, abstract = {The neurotoxicity of hard metal-based nanoparticles (NPs) remains poorly understood. Here, we deployed the human neuroblastoma cell line SH-SY5Y differentiated or not into dopaminergic- and cholinergic-like neurons to study the impact of tungsten carbide (WC) NPs, WC NPs sintered with cobalt (Co), or Co NPs versus soluble CoCl2 . Co NPs and Co salt triggered a dose-dependent cytotoxicity with an increase in cytosolic calcium, lipid peroxidation, and depletion of glutathione (GSH). Co NPs and Co salt also suppressed glutathione peroxidase 4 (GPX4) mRNA and protein expression. Co-exposed cells were rescued by N-acetylcysteine (NAC), a precursor of GSH, and partially by liproxstatin-1, an inhibitor of lipid peroxidation. Furthermore, in silico analyses predicted a significant correlation, based on similarities in gene expression profiles, between Co-containing NPs and Parkinson's disease, and changes in the expression of selected genes were validated by RT-PCR. Finally, experiments using primary human dopaminergic neurons demonstrated cytotoxicity and GSH depletion in response to Co NPs and CoCl2 with loss of axonal integrity. Overall, these data point to a marked neurotoxic potential of Co-based but not WC NPs and show that neuronal cell death may occur through a ferroptosis-like mechanism.}, }
@article {pmid32059375, year = {2020}, author = {Zalewska, A and Szarmach, I and Żendzian-Piotrowska, M and Maciejczyk, M}, title = {The Effect of N-Acetylcysteine on Respiratory Enzymes, ADP/ATP Ratio, Glutathione Metabolism, and Nitrosative Stress in the Salivary Gland Mitochondria of Insulin Resistant Rats.}, journal = {Nutrients}, volume = {12}, number = {2}, pages = {}, pmid = {32059375}, issn = {2072-6643}, support = {SUB/1/DN/20/002/1209; SUB/1/DN/20/002/3330//Uniwersytet Medyczny w Bialymstoku/ ; }, mesh = {Acetylcysteine/*pharmacology ; Adenosine Diphosphate/*metabolism ; Adenosine Triphosphate/*metabolism ; Animals ; Apoptosis/drug effects ; Cytokines/metabolism ; Diet, High-Fat/adverse effects ; Electron Transport Complex IV/metabolism ; Energy Metabolism/drug effects ; Glutathione/*metabolism ; Hydrogen Peroxide/metabolism ; *Insulin Resistance ; Male ; Mitochondria/*metabolism ; Nitrosative Stress/*drug effects ; Rats, Wistar ; Salivary Glands/*metabolism/pathology ; }, abstract = {This is the first study to assess the effect of N-acetylcysteine (NAC) on the mitochondrial respiratory system, as well as free radical production, glutathione metabolism, nitrosative stress, and apoptosis in the salivary gland mitochondria of rats with high-fat diet (HFD)-induced insulin resistance (IR). The study was conducted on male Wistar rats divided into four groups of 10 animals each: C (control, rats fed a standard diet containing 10.3% fat), C + NAC (rats fed a standard diet, receiving NAC intragastrically), HFD (rats fed a high-fat diet containing 59.8% fat), and HFD + NAC (rats fed HFD diet, receiving NAC intragastrically). We confirmed that 8 weeks of HFD induces systemic IR as well as disturbances in mitochondrial complexes of the parotid and submandibular glands of rats. NAC supplementation leads to a significant increase in the activity of complex I, II + III and cytochrome c oxidase (COX), and also reduces the ADP/ATP ratio compared to HFD rats. Furthermore, NAC reduces the hydrogen peroxide production/activity of pro-oxidant enzymes, increases the pool of mitochondrial glutathione, and prevents cytokine formation, apoptosis, and nitrosative damage to the mitochondria in both aforementioned salivary glands of HFD rats. To sum up, NAC supplementation enhances energy metabolism in the salivary glands of IR rats, and prevents inflammation, apoptosis, and nitrosative stress.}, }
@article {pmid32058163, year = {2020}, author = {Ren, X and Wang, S and Zhang, C and Hu, X and Zhou, L and Li, Y and Xu, L}, title = {Selenium ameliorates cadmium-induced mouse leydig TM3 cell apoptosis via inhibiting the ROS/JNK /c-jun signaling pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {192}, number = {}, pages = {110266}, doi = {10.1016/j.ecoenv.2020.110266}, pmid = {32058163}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cadmium/*toxicity ; Cell Line ; Cell Survival/drug effects ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Leydig Cells/*drug effects/metabolism/pathology ; MAP Kinase Signaling System/drug effects ; Male ; Mice ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Selenium/*pharmacology ; Signal Transduction/drug effects ; }, abstract = {Despite the well-known acknowledgement of both the toxicity of cadmium (Cd) and the ameliorative effect of selenium (Se), the mechanism of the protective effect of selenium on cadmium-induced Mouse Leydig (TM3) cell apoptosis remains unknown. In this study, we hypothesized that the reactive oxygen species (ROS)-mediated c-jun N-terminal kinase (JNK) signaling pathway is involved in anti-apoptosis of selenium against cadmium in TM3 cells. We found that exposure to cadmium caused evident cytotoxicity, in which cell viability was inhibited, followed by inducement of apoptosis. Moreover, the level of ROS generation was elevated, leading to the phosphorylation of JNK. In addition, following cadmium exposure, the nuclear transcription factor c-jun was significantly activated, which led to increased expression of downstream gene c-jun, resulting in downstream activation of the apoptosis-related protein Caspase3 and upregulation of Cleaved-PARP, as well as inhibition of the anti-apoptosis protein Bcl-2. However, pretreatment with selenium remarkably suppressed cadmium-induced TM3 cell apoptosis. Furthermore, the level of ROS declined, and the JNK signaling pathway was blocked. Following this, the gene expression of c-jun decreased while Bcl-2 increased, which was consistent with the effects on proteins, that Caspase3 activity and Cleaved-PARP were inhibited while Bcl-2 level was restored. In order to explain the relationship between molecules of the signaling pathway, N-acetyl-L-cysteine (NAC), the ROS inhibitor, and JNK1/2 siRNA were administered, which further indicated the mediatory role of the ROS/JNK/c-jun signaling pathway in regulating anti-apoptosis of selenium against cadmium-induced TM3 cell apoptosis.}, }
@article {pmid32057768, year = {2020}, author = {Luo, ML and Jiao, Y and Gong, WP and Li, Y and Niu, LN and Tay, FR and Chen, JH}, title = {Macrophages enhance mesenchymal stem cell osteogenesis via down-regulation of reactive oxygen species.}, journal = {Journal of dentistry}, volume = {94}, number = {}, pages = {103297}, doi = {10.1016/j.jdent.2020.103297}, pmid = {32057768}, issn = {1879-176X}, mesh = {Animals ; Cell Differentiation ; Cells, Cultured ; Down-Regulation ; Macrophages ; *Mesenchymal Stem Cells ; Mice ; *Osteogenesis ; *Reactive Oxygen Species ; }, abstract = {OBJECTIVES: The role played by macrophages in regulating the differentiation of mesenchymal stem cells (MSCs) during wound healing and bone regeneration is increasingly being recognized. The present study compared the pro-osteogenic effects of three co-culture methods, conditioned medium generated by macrophages (CM), indirect culture (IC) or direct culture (DC) with macrophages, on bone marrow MSCs (BMMSCs).<br><br>METHODS: Primary BMMSCs were isolated, characterized and co-cultured with RAW264.7 mouse macrophages. Cell morphology and intracellular reactive oxygen species (ROS) levels were determined by scanning electron microscopy (SEM) and flow cytometry, respectively. Alkaline phosphatase (ALP) staining and assay, Alizarin red staining (ARS) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to evaluate osteogenic differentiation.<br><br>RESULTS: Inclusion of macrophages in any of the three co-culture methods resulted in improvement in osteogenic differentiation and mineralization of BMMSCs (DC&#x202f;>&#x202f;IC&#x202f;>&#x202f;CM), as measured by ALP staining and activity, ARS and osteoblastic gene expression (Runx2, Alp, Ocn and Bmp2). The enhanced osteogenesis was reversed with hydrogen peroxide. Macrophages reduced the increased levels of intracellular ROS generated by BMMSCs during osteogenic differentiation in a manner similar to the use of an antioxidant, N-acetyl cysteine.<br><br>CONCLUSIONS: Macrophages exert an osteogenesis-enhancing effect to accelerate BMMSC osteogenesis via ROS downregulation.<br><br>CLINICAL SIGNIFICANCE: The present findings suggest that targeting MSC-macrophage interaction is an effective strategy for regulating stem cell fate and facilitating bone regeneration.}, }
@article {pmid32054204, year = {2020}, author = {Li, C and Peng, M and Liao, M and Guo, S and Hou, Y and Ding, B and Wu, T and Yi, D}, title = {Effects of N-acetylcysteine on the energy status and antioxidant capacity in heart and liver of cold-stressed broilers.}, journal = {Asian-Australasian journal of animal sciences}, volume = {33}, number = {9}, pages = {1444-1454}, pmid = {32054204}, issn = {1011-2367}, support = {2017CFB237//Natural Science Foundation of Hubei Province/ ; Q20171701//Hubei Provincial Department of Education/ ; }, abstract = {OBJECTIVE: Cold stress induces oxidative damage and impairs energy status of broilers. N-acetylcysteine (NAC) exhibits antioxidant properties and modulates energy metabolism of animals. This study was conducted to investigate the effects of NAC on energy status and antioxidant capacity of heart and liver in the cold-stressed broilers.<br><br>METHODS: The experiment consisted of 4 treatments in a 2&#xd7;2 factorial arrangement with two diets (basal diet or plus 0.1% NAC) and two ambient temperatures (thermoneutral [conventional ambient temperature] or cold stress [10&#xb0;C&#xb1;1&#xb0;C during days 15 to 42]).<br><br>RESULTS: No ascites were seen in cold-stressed broilers. NAC did not attenuate the impaired growth performance of stressed birds. However, NAC decreased plasma asparagine but increased aspartate levels in cold-stressed birds (p<0.05). NAC reduced hepatic adenosine triphosphate (ATP) but elevated adenosine diphosphate contents in unstressed birds (p< 0.05). The hepatic ratio of adenosine monophosphate (AMP) to ATP was increased in birds fed NAC (p<0.05). NAC decreased plasma malondialdehyde (MDA) level and cardiac total superoxide dismutase (T-SOD) activity in unstressed birds, but increased hepatic activities of T-SOD, catalase and glutathione peroxidase in stressed birds (p<0.05). NAC down-regulated hepatic AMP-activated protein kinase but up-regulated cardiac heme-oxigenase mRNA expression in stressed birds, and decreased expression of hepatic peroxisome proliferatoractivated receptor coactivator-1&#x3b1; as well as hypoxia-inducible factor-1&#x3b1; in liver and heart of birds.<br><br>CONCLUSION: Dietary NAC did not affect energy status but enhanced the hepatic antioxidant capacity by increasing the activities of antioxidant enzymes in cold-stressed broilers.}, }
@article {pmid32050475, year = {2020}, author = {Nova, Z and Skovierova, H and Strnadel, J and Halasova, E and Calkovska, A}, title = {Short-Term versus Long-Term Culture of A549 Cells for Evaluating the Effects of Lipopolysaccharide on Oxidative Stress, Surfactant Proteins and Cathelicidin LL-37.}, journal = {International journal of molecular sciences}, volume = {21}, number = {3}, pages = {}, pmid = {32050475}, issn = {1422-0067}, mesh = {A549 Cells ; Alveolar Epithelial Cells/cytology/*metabolism ; Antimicrobial Cationic Peptides/*metabolism ; Cell Culture Techniques ; Cell Survival ; Humans ; Lipopolysaccharides/*metabolism ; *Oxidative Stress ; Pulmonary Surfactant-Associated Proteins/*metabolism ; Cathelicidins ; }, abstract = {Alveolar epithelial type II (ATII) cells and their proper function are essential for maintaining lung integrity and homeostasis. However, they can be damaged by lipopolysaccharide (LPS) during Gram-negative bacterial infection. Thus, this study evaluated and compared the effects of LPS on short and long-term cultures of A549 cells by determining the cell viability, levels of oxidative stress and antimicrobial peptide cathelicidin LL-37 and changes in the expression of surfactant proteins (SPs). Moreover, we compared A549 cell response to LPS in the presence of different serum concentrations. Additionally, the effect of N-acetylcysteine (NAC) on LPS-induced oxidative stress as a possible treatment was determined. Our results indicate that A549 cells are relatively resistant to LPS and able to maintain integrity even at high LPS concentrations. Their response to endotoxin is partially dependent on serum concentration. NAC failed to lower LPS-induced oxidative stress in A549 cells. Finally, LPS modulates SP gene expression in A549 cells in a time dependent manner and differences between short and long-term cultures were present. Our results support the idea that long-term cultivation of A549 cells could promote a more ATII-like phenotype and thus could be a more suitable model for ATII cells, especially for in vitro studies dealing with surfactant production.}, }
@article {pmid32048131, year = {2020}, author = {Maiwall, R and Kumar, A and Bhadoria, AS and Jindal, A and Kumar, G and Bhardwaj, A and Maras, JS and Sharma, MK and Sharma, BC and Sarin, SK}, title = {Utility of N-acetylcysteine in ischemic hepatitis in cirrhotics with acute variceal bleed: a randomized controlled trial.}, journal = {Hepatology international}, volume = {14}, number = {4}, pages = {577-586}, doi = {10.1007/s12072-020-10013-5}, pmid = {32048131}, issn = {1936-0541}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Antioxidants/administration &amp; dosage/*therapeutic use ; Esophageal and Gastric Varices/*drug therapy ; Female ; Gastrointestinal Hemorrhage/*drug therapy ; Gastroscopy ; *Hepatitis ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND AND AIMS: Ischemic hepatitis (IH) following acute variceal bleed (AVB) carries an ominous prognosis. N-Acetylcysteine (NAC), a potent anti-oxidant, may prevent IH by improving tissue oxygen delivery and improving hepatic hypoxia.<br><br>METHODS: Consecutive cirrhotics with AVB were prospectively randomized to receive either standard of care (SOC) plus NAC intravenously for 72&#xa0;h(at 150&#xa0;mg/kg/h for 1&#xa0;h followed by 12.5&#xa0;mg/kg/h for 4&#xa0;h, followed by 6.25&#xa0;mg/kg for 67&#xa0;h) (Group A, n&#x2009;=&#x2009;107) or SOC alone (Group B, n&#x2009;=&#x2009;107).<br><br>RESULTS: Baseline characteristics were comparable. IH developed more frequently in Gr.B 25(23%) than A-15(14%); p&#x2009;=&#x2009;0.08). Incidence of IH increased with severity of liver disease. Binary logistic regression analysis showed reduced incidence of IH in Gr.A than B [odds ratio (OR) 0.33, 0.11-0.93] patients after controlling for other significant factors. The incidence of acute kidney injury (AKI) was also reduced in Gr.A [OR 0.34, 0.15-0.75]. Development of IH was significantly associated with increased deaths due to liver failure at 6&#xa0;weeks [subdistribution hazard ratio (SHR) 21.6, 7.4-62.8]. On multivariate competing risk analysis, significantly lower deaths due to liver failure (SHR 0.33, 0.11-0.97) were noted in Gr.A than B.<br><br>CONCLUSIONS: One in five patients with acute variceal bleed develops ischemic hepatitis which is associated with worse outcomes. NAC therapy averts deaths due to liver failure by preventing IH and reduces AKI and is, therefore, recommended for cirrhotics with acute variceal bleed.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov no: NCT02015403.}, }
@article {pmid32045382, year = {2020}, author = {Poisson, J and Tanguy, M and Davy, H and Camara, F and El Mdawar, MB and Kheloufi, M and Dagher, T and Devue, C and Lasselin, J and Plessier, A and Merchant, S and Blanc-Brude, O and Souyri, M and Mougenot, N and Dingli, F and Loew, D and Hatem, SN and James, C and Villeval, JL and Boulanger, CM and Rautou, PE}, title = {Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm.}, journal = {The Journal of clinical investigation}, volume = {130}, number = {5}, pages = {2630-2643}, pmid = {32045382}, issn = {1558-8238}, mesh = {Animals ; Antioxidants/pharmacology ; Aorta, Thoracic/drug effects/physiopathology ; Cardiovascular Diseases/etiology/genetics/physiopathology ; Cell-Derived Microparticles/physiology ; Erythrocytes/*physiology ; Femoral Artery/drug effects/physiopathology ; *Gain of Function Mutation ; Humans ; In Vitro Techniques ; Janus Kinase 2/*genetics/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myeloproliferative Disorders/complications/*genetics/*physiopathology ; Oxidative Stress ; Simvastatin/pharmacology ; Vasoconstriction/drug effects/physiology ; }, abstract = {Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.}, }
@article {pmid32041914, year = {2019}, author = {Wasyanto, T and Yasa', A and Jalaludinsyah, A}, title = {Effect of Oral N-Acetylcysteine Supplementation on the Immunity System in Patients with Acute Myocardial Infarction.}, journal = {Acta medica Indonesiana}, volume = {51}, number = {4}, pages = {311-317}, pmid = {32041914}, issn = {0125-9326}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Disease ; Administration, Oral ; Aged ; Biomarkers/blood ; C-Reactive Protein/analysis ; Drug Therapy, Combination ; Female ; Galectin 3/blood ; Humans ; Immune System/*drug effects ; Indonesia ; Male ; Middle Aged ; Peroxidase/blood ; ST Elevation Myocardial Infarction/blood/*drug therapy/immunology ; Single-Blind Method ; Treatment Outcome ; }, abstract = {BACKGROUND: inflammation, oxidative stress, and fibrosis play important roles after an acute myocardial infarction (AMI) event. The most studied inflammatory biomarker in cardiovascular disease is C-reactive protein (CRP). It has been demonstrated that myeloperoxidase (MPO) and Galectin-3 (Gal-3) have some essential roles on immune system when an AMI event occurs. We aimed to determine the effect of oral N-acetylcysteine (NAC) supplementation at the dose of 600 mg 3 times daily for 3 consecutive days on the immune system of AMI patients.<br><br>METHODS: our randomized single-blinded experimental study using pre- and post-treatment evaluations was performed at Dr. Moewardi Hospital, Indonesia, from May to August 2018. Thirty-two patients with AMI and ST segment elevation (STEMI) who received fibrinolytic therapy were included. There were 17 patients received standard therapy plus 600 mg oral NAC supplementation every 8 h for 3 days and 15 patients received standard therapy, which served as the control group. High-sensitivity C-reactive protein (HsCRP), MPO, and Gal-3 levels of both groups were evaluated at admission and after 72 h receiving treatment.<br><br>RESULTS: HsCRP, MPO, and Gal-3 levels between NAC and control groups at admission were not significantly different; while intergroup differences after 72 h of NAC supplementation were significant (p values of HsCRP, MPO, and Gal-3 levels were 0.0001, 0.001, and 0.017, respectively). Furthermore, in the NAC group, HsCRP, MPO, and Gal-3 levels at 72 h after treatment were significantly different from the corresponding levels at admission (p values: 0.0001, 0.0001, and 0.0001, respectively); the control group did not show these differences. There were also significant intergroup differences between the NAC and control groups regarding HsCRP, MPO, and Gal-3 levels (p values: 0.011, 0.022, and 0.014, respectively).<br><br>CONCLUSION: oral supplementation of 600 mg NAC every 8 h for 72 h can reduce HsCRP, MPO, and Gal-3 levels in AMI patients receiving fibrinolytic therapy. Results of our study will provide more options for supplementation therapy to improve management of IMA patients.}, }
@article {pmid32041019, year = {2020}, author = {Wang, B and Xu, S and Lu, X and Ma, L and Gao, L and Zhang, SY and Li, R and Fu, L and Wang, H and Sun, GP and Xu, DX}, title = {Reactive oxygen species-mediated cellular genotoxic stress is involved in 1-nitropyrene-induced trophoblast cycle arrest and fetal growth restriction.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {260}, number = {}, pages = {113984}, doi = {10.1016/j.envpol.2020.113984}, pmid = {32041019}, issn = {1873-6424}, mesh = {Animals ; Cell Cycle/drug effects ; DNA Damage ; Female ; *Fetal Growth Retardation ; Humans ; Mice ; Mutagens/*toxicity ; Placenta ; Pregnancy ; Pyrenes/chemistry/*toxicity ; Reactive Oxygen Species/metabolism ; *Trophoblasts ; }, abstract = {1-nitropyrene (1-NP) is a key component of diesel exhaust-sourced fine particulate matter (PM2.5). Our recent study demonstrated that gestational 1-NP exposure caused placental proliferation inhibition and fetal intrauterine growth restriction (IUGR). This study aimed to investigate the role of genotoxic stress on 1-NP-induced placental proliferation inhibition and fetal IUGR. Human trophoblasts were exposed to 1-NP (10 μM). Growth index was reduced and PCNA was downregulated in 1-NP-exposed placental trophoblasts. More than 90% of 1-NP-exposed trophoblasts were arrested in either G0/G1 or G2/M phases. CDK1 and cyclin B, two G2/M cycle-related proteins, and CDK2, a G0/G1 cycle-related protein, were reduced in 1-NP-exposed trophoblasts. Phosphorylated Rb, a downstream molecule of CDK2, was inhibited in 1-NP-exposed trophoblasts. Moreover, DNA double-strand break was observed and γ-H2AX, another indicator of DNA double-strand break, was upregulated in 1-NP-exposed trophoblasts. Phosphorylated ATM, a key molecule of genotoxic stress, and its downstream molecule Chk2 were elevated. By contrast, Cdc25A, a downstream target of Chk2, was reduced in 1-NP-exposed trophoblasts. Phenyl-N-t-butylnitrone (PBN), a free radical scavenger, inhibited 1-NP-induced genotoxic stress and trophoblast cycle arrest. Animal experiment showed that N-acetylcysteine (NAC), an antioxidant, rescued 1-NP-induced placental proliferation inhibition and fetal IUGR in mice. These results provide evidence that reactive oxygen species (ROS)-mediated cellular genotoxic stress partially contributes to 1-NP-induced placental proliferation inhibition and fetal IUGR.}, }
@article {pmid32040762, year = {2020}, author = {Muniroh, M and Gumay, AR and Indraswari, DA and Bahtiar, Y and Hardian, H and Bakri, S and Maharani, N and Karlowee, V and Koriyama, C and Yamamoto, M}, title = {Activation of MIP-2 and MCP-5 Expression in Methylmercury-Exposed Mice and Their Suppression by N-Acetyl-L-Cysteine.}, journal = {Neurotoxicity research}, volume = {37}, number = {4}, pages = {827-834}, pmid = {32040762}, issn = {1476-3524}, support = {38/UN.7.3.4/HK/2017//Universitas Diponegoro/ ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Brain/drug effects/metabolism ; Chemokine CXCL2/*biosynthesis/genetics ; Gene Expression ; Male ; Methylmercury Compounds/*toxicity ; Mice ; Mice, Inbred BALB C ; Monocyte Chemoattractant Proteins/*biosynthesis/genetics ; Neurotoxicity Syndromes/*drug therapy/*metabolism ; Random Allocation ; }, abstract = {Methylmercury (MeHg) is a well-known neurotoxin of the central nervous system (CNS). Neuroinflammation is one of the main pathways of MeHg-induced CNS impairment. This study aims to investigate the expressions of IL-6, MIP-2, and MCP-5, as biomarkers in relation with MeHg-induced CNS impairment and N-acetyl-L-cysteine (NAC) treatment in mice, as well as histopathological changes of brain tissue and clinical symptom such as ataxia. Twenty male Balb/c mice, aged 8-9 weeks, were divided into 4 groups and treated with saline (control), NAC [150 mg/kg body weight (BW) day], MeHg (4 mg Hg/kg BW), or a combination of MeHg and NAC for 17 days. MeHg induced the expression of IL-6, MIP-2, and MCP-5 in the serum, with median values (those in controls) of 55.06 (9.44), 15.94 (9.30), and 458.91 (239.91) mg/dl, respectively, and a statistical significance was observed only in IL-6 expression (p < 0.05). MIP-2 and MCP-5 expressions tended to increase in the cerebrum of MeHg-treated group compared with controls; however, the difference was not statistically significant. MeHg treatment also increased IL-6 expression in the cerebellum (7.73 and 4.81 mg/dl in MeHg-treated group and controls, respectively), with a marginal significance. NAC significantly suppressed MeHg-induced IL-6 and MIP-2 expressions in the serum (p < 0.05 for both), and slightly reduced MCP-5 expression in the cerebrum. Ataxia was observed in all MeHg-treated mice after 9-day exposure as well as the decrease of intact Purkinje cells in brain tissue (p < 0.05). These findings suggest that MeHg induced neurotoxicity by elevating the expression of IL-6, MIP-2, and MCP-5 and causing ataxia symptoms, and NAC reduced MeHg-mediated effects on the CNS.}, }
@article {pmid32040747, year = {2020}, author = {Capella-Peris, C and Cosgrove, MM and Chrismer, IC and Emile-Backer, M and Razaqyar, MS and Elliott, JS and Kuo, A and Wakim, PG and Meilleur, KG}, title = {Mixed methods analysis of Health-Related Quality of Life in ambulant individuals affected with RYR1-related myopathies pre-post-N-acetylcysteine therapy.}, journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation}, volume = {29}, number = {6}, pages = {1641-1653}, pmid = {32040747}, issn = {1573-2649}, support = {10-2013/Office of Rare Disease/NINR//Bench to Bedside Award/ ; Intramural Program//NIH Clinical Center/ ; Intramural Program/NR/NINR NIH HHS/United States ; Intramural Program/NS/NINDS NIH HHS/United States ; ZIA NR000026/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adaptation, Psychological ; Adult ; Fatigue/diagnosis ; Female ; Health Status ; Humans ; Muscular Diseases/*psychology ; Quality of Life/*psychology ; Ryanodine Receptor Calcium Release Channel/*metabolism ; }, abstract = {PURPOSE: To characterize Health-Related Quality of Life (HRQoL) in ambulant individuals with RYR1-RM and to determine if a qualitative PRO tool (subjective self-assessment) complements PROMIS and Neuro-QoL scales to detect changes in HRQoL in ambulant individuals with RYR1-RM post N-acetylcysteine (NAC) treatment.<br><br>METHODS: The study used a mixed methods research (MMR) design applying methodological triangulation. Qualitative data were collected via semi-structured interviews using open-ended questions. Quantitative data were gathered through PROMIS and Neuro-QoL instruments. Additionally, qualitative data were transformed into quantitative data for subjective self-assessment and frequency analyses.<br><br>RESULTS: Qualitative results identified five domains and 33 subdomains as areas of interest. The most valuable were the importance of social impacts, the development of several coping strategies, both physical and psychological, and the identification of fatigue and weakness as key symptoms. Data transformation then categorized more than 3100 citations on frequency analyses, globally and by domain, visit, and participant. Regarding quantitative results, there was no clear evidence that any of the three PRO tools captured positive changes as a result of NAC treatment.<br><br>CONCLUSION: Qualitative results showed a comprehensive characterization of HRQoL in this population based on a symptom/patient-centered approach. These findings will inform future studies. Furthermore, given the similar findings across our multiple methods and endpoints, the introduction of MMR may be a valuable, complementary approach to clinical trials. MMR may be especially useful to incorporate in order to address and follow the FDA's guidance and prioritization on the inclusion of affected individuals' perspectives in clinical trials.}, }
@article {pmid32040381, year = {2020}, author = {Famitafreshi, H and Karimian, M}, title = {Reduction of anxiety level is associated with an oxidative-stress imbalance in the hippocampus in morphine administration period in male rats.}, journal = {Journal of addictive diseases}, volume = {38}, number = {1}, pages = {64-70}, doi = {10.1080/10550887.2020.1717281}, pmid = {32040381}, issn = {1545-0848}, mesh = {Animals ; Anxiety/*drug therapy ; Glutathione/analysis ; Hippocampus/*drug effects ; Male ; Malondialdehyde/analysis ; Morphine/*pharmacology ; Narcotics/*pharmacology ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Hippocampus is a region of the brain that is famous for its role in memory. However recently it has been given great importance for a region that regulates emotion and anxiety. Alternation of anxiety level has been observed in drug abusers as a comorbid disorder. The aim of this study is to show that morphine by altering oxidative stress in the hippocampus causes anxiety level alternation. In this study 32 male Sprague-Dawley rats divided into four groups: Control, N-acetyl-cysteine-treated, morphine-treated and N-acetyl-cysteine + morphine-treated. After 14 days of morphine administration (5 mg/kg/rat/i.p.) and N-acetyl-cysteine administration (100 mg/kg/rat/i.p.), Anxiety was assessed with Elevated Plus Maze (EPM) after 14 days in all groups. Then rats were euthanized and the hippocampus was removed for assessing oxidative stress for malondialdehyde (MDA), glutathione and nitrite/nitrate. Our data showed that oxidative stress was disturbed in the hippocampus in morphine-treated rats. Malondialdehyde (MDA) increased and glutathione and nitrite/nitrate were reduced in morphine-treated rats compared to control and N-acetyl-cysteine-treated rats. N-Acetylcysteine treatment improved oxidative stress (OS) markers and anxiety. The anxiety that was assessed with Elevated Plus Maze, morphine-treated rats showed less anxiety level compared to N-acetyl-cysteine -treated and control rats. Morphine reduced the anxiety level. The reduction of anxiety level was associated with oxidative stress imbalance in the hippocampus. Thus, hippocampus can alter anxiety level.}, }
@article {pmid32038274, year = {2019}, author = {Liu, M and Deng, M and Luo, Q and Dou, X and Jia, Z}, title = {High-Salt Loading Downregulates Nrf2 Expression in a Sodium-Dependent Manner in Renal Collecting Duct Cells.}, journal = {Frontiers in physiology}, volume = {10}, number = {}, pages = {1565}, pmid = {32038274}, issn = {1664-042X}, abstract = {BACKGROUND: High salt intake is associated with both oxidative stress and chronic kidney disease (CKD) progression. Nuclear factor E2-related factor 2 (Nrf2) is a transcriptional factor regulating the antioxidant and detoxifying genes to potently antagonize oxidative stress. This study examined the effect of high salt loading on the expression of Nrf2 in kidney.<br><br>METHODS: Mice were treated with acute salt loading, and Nrf2 expression in the kidney was detected by Western blotting and immunostaining. Reactive oxygen species (ROS) levels in the kidney were measured using dihydroethidium (DHE) staining. In vitro, mpkCCD cells were cultured in high osmolality medium by adding sodium chloride (NaCl), sodium gluconate (Na-Glu), choline chloride (Choline-Cl), or mannitol. Then, Nrf2 and its target genes were measured.<br><br>RESULTS: Nrf2 protein in renal cortex and medulla tissue lysates was significantly downregulated after acute salt loading. Immunofluorescence data showed that Nrf2 was mainly located in collecting duct principal cells evidenced by co-staining of Nrf2 with AQP2. Contrasting to the reduced Nrf2 expression, ROS levels in the kidney were significantly increased after salt loading. In vitro, the Nrf2 protein level was downregulated in mpkCCD cells after NaCl treatment for 24 h. Interestingly, sodium gluconate had a similar effect on downregulating Nrf2 expression as NaCl, whereas neither Choline-Cl nor mannitol changed Nrf2 expression. Meanwhile, the mRNA levels of Nrf2 target genes were downregulated by NaCl and/or sodium gluconate, while some of them were also regulated by Choline-Cl, indicating a more complex regulation of these genes under a high salt condition. Finally, we found that the downregulation of Nrf2 caused by NaCl was not affected by N-acetylcysteine (NAC), spironolactone, or NS-398, suggesting other mechanisms mediating Nrf2 downregulation caused by high salt challenge.<br><br>CONCLUSION: High salt downregulated Nrf2 mainly via a sodium-dependent manner in kidney collecting duct cells, which might contribute to the excessive renal oxidative stress and CKD progression.}, }
@article {pmid32036895, year = {2020}, author = {Gao, X and Li, X and Ho, CT and Lin, X and Zhang, Y and Li, B and Chen, Z}, title = {Cocoa tea (Camellia ptilophylla) induces mitochondria-dependent apoptosis in HCT116 cells via ROS generation and PI3K/Akt signaling pathway.}, journal = {Food research international (Ottawa, Ont.)}, volume = {129}, number = {}, pages = {108854}, doi = {10.1016/j.foodres.2019.108854}, pmid = {32036895}, issn = {1873-7145}, mesh = {Animals ; Apoptosis/*drug effects ; Beverages/analysis ; Camellia/*classification ; Cell Survival/drug effects ; Gene Expression Regulation/drug effects ; HCT116 Cells ; Humans ; Male ; Mice ; Mice, Nude ; Mitochondria/*metabolism ; Neoplasms, Experimental/drug therapy ; Phosphatidylinositol 3-Kinases/genetics/*metabolism ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cocoa tea (Camellia ptilophylla), a natural gallocatechin gallate (GCG)-rich and low caffeine-containing tea species, has been recently reported to possess various bioactivities. However, the anti-colon cancer effects of Cocoa tea and its underlying mechanisms remain virtually unknown. This study aimed to assess the anti-proliferative and pro-apoptotic effects of water extract of Cocoa tea (CWE) on human colon cancer HCT116 cells compared with Yunnan Daye tea (YWE). Primarily, CWE showed stronger anti-proliferation and apoptosis induction than YWE. Moreover, reduction of mitochondrial membrane potential (MMP), up-regulation of Bax/Bcl-2 ratio, release of cytochrome c, activation of caspase-9 and -3, and cleavage of poly (ADP-ribose) polymerase (PARP) were observed, suggesting that mitochondrial apoptotic pathway was activated by CWE. Furthermore, CWE-induced apoptosis in HCT116 cells was dependent on the generation of intracellular reactive oxygen species (ROS) and down-regulation of phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Pretreatment with ROS scavenger N-acetyl cysteine (NAC) attenuated the impact of CWE on mitochondria-related apoptosis proteins, and partially recovered the inhibition of Akt phosphorylation. These results indicated that ROS generation mediated mitochondrial dysfunction and inactivation of PI3K/Akt pathway in CWE-induced HCT116 cell apoptosis. Additionally, CWE significantly inhibited tumor growth in HCT116 tumor-bearing mice, suggesting that Cocoa tea could act as a potential functional beverage to prevent or treat colorectal cancer.}, }
@article {pmid32035990, year = {2020}, author = {Lapenna, D and Ciofani, G and Lelli Chiesa, P and Porreca, E}, title = {Evidence for oxidative and not reductive stress in the aged rabbit heart.}, journal = {Experimental gerontology}, volume = {134}, number = {}, pages = {110871}, doi = {10.1016/j.exger.2020.110871}, pmid = {32035990}, issn = {1873-6815}, abstract = {Reductive stress, which is due to a paradoxical excess of antioxidants such as reduced glutathione (GSH) and GSH-related enzymes associated with decreased oxidant levels, has emerged as a pathogenetic mechanism of myocardial damage in pathological conditions such as protein aggregation cardiomyopathy. Notably, in the aged heart a cardiomyopathy-like pathology occurs leading to myocardial dysfunction. Whether reductive stress, or instead its counterpart oxidative stress, is operative in the aged mammalian heart needs to be elucidated also for the different therapeutic implications of such redox stress conditions. In the present investigation, we assessed GSH and the specific enzymatic activities of γ-glutamylcysteine synthetase (γ-GCS), glutathione reductase (GSSG-Red) and selenium-dependent glutathione peroxidase (GSH-Px) as endogenous antioxidants, together with oxidized glutathione (GSSG) and the glutathione redox ratio (GSH/GSSG), in the aerobically perfused hearts of aged rabbits (about 4.5 years old) and young adult control rabbits (3-4 months old). We also assessed in the aged and control hearts H2O2 and catalytically active low molecular weight iron (LMWI) as oxidant forces, as well as fluorescent damage products of lipid peroxidation (FDPL) and protein carbonyls (PC) as biomarkers of lipid and protein oxidation. Moreover, the effects of 4.5 mM N-acetylcysteine (NAC) as reducing thiol antioxidant were studied on hemodynamic parameters and lipid peroxidation in the perfused hearts of the aged and control rabbits. The levels of GSH and of the GSH/GSSG ratio were lower, and those of GSSG higher, in the aged than in the control hearts. The aged hearts were also characterized by decreased activities of the antioxidant enzymes γ-GCS, GSSG-Red and GSH-Px, as well as by heightened levels of H2O2, LMWI, FDPL and PC, highlighting the occurrence of aging-dependent oxidative stress. Associated with such biochemical alterations, hemodynamic dysfunction occurred in the aged rabbit hearts, as evidenced by lowered developed pressure (DP) and enhanced end-diastolic pressure (EDP) with decreased coronary flow (CF). Remarkably, NAC administration significantly improved DP and EDP, and lowered lipid peroxidation, electively in the aged hearts. In conclusion, oxidative and not reductive stress is operative in the aged rabbit heart, whose hemodynamic dysfunction is improved by NAC together with reduction in myocardial lipid peroxidation.}, }
@article {pmid32033264, year = {2020}, author = {Alnahdi, A and John, A and Raza, H}, title = {Mitigation of Glucolipotoxicity-Induced Apoptosis, Mitochondrial Dysfunction, and Metabolic Stress by N-Acetyl Cysteine in Pancreatic β-Cells.}, journal = {Biomolecules}, volume = {10}, number = {2}, pages = {}, pmid = {32033264}, issn = {2218-273X}, support = {HR-31M377; MRG-18/2013-2014//This research was funded by the Sheikh Hamdan Medical Research Award () and the Research Committee, College of Medicine and Health Sciences, UAE University, Al Ain, UAE (HR- 31M377)./International ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; *Apoptosis ; Autophagy/drug effects ; Cell Line ; DNA Damage ; DNA Fragmentation ; Fatty Acids/metabolism ; Glucose/*pharmacology ; Inflammation ; Insulin-Secreting Cells/*metabolism ; Membrane Potential, Mitochondrial ; Mitochondria/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Palmitic Acid/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Glucolipotoxicity caused by hyperglycemia and hyperlipidemia are the common features of diabetes-induced complications. Metabolic adaptation, particularly in energy metabolism; mitochondrial dysfunction; and increased inflammatory and oxidative stress responses are considered to be the main characteristics of diabetes and metabolic syndrome. However, due to various fluctuating endogenous and exogenous stimuli, the precise role of these factors under in vivo conditions is not clearly understood. In the present study, we used pancreatic β-cells, Rin-5F, to elucidate the molecular and metabolic changes in glucolipotoxicity. Cells treated with high glucose (25 mM) and high palmitic acid (up to 0.3 mM) for 24 h exhibited increased caspase/poly-ADP ribose polymerase (PARP)-dependent apoptosis followed by DNA fragmentation, alterations in mitochondrial membrane permeability, and bioenergetics, accompanied by alterations in glycolytic and mitochondrial energy metabolism. Our results also demonstrated alterations in the expression of mammalian target of rapamycin (mTOR)/5' adenosine monophosphate-activated protein kinase (AMPK)-dependent apoptotic and autophagy markers. Furthermore, pre-treatment of cells with 10 mM N-acetyl cysteine attenuated the deleterious effects of high glucose and high palmitic acid with improved cellular functions and survival. These results suggest that the presence of high energy metabolites enhance mitochondrial dysfunction and apoptosis by suppressing autophagy and adapting energy metabolism, mediated, at least in part, via enhanced oxidative DNA damage and mTOR/AMPK-dependent cell signaling.}, }
@article {pmid32023790, year = {2020}, author = {Jang, JW and Lee, JW and Yoon, YD and Kang, JS and Moon, EY}, title = {Bisphenol A and its substitutes regulate human B cell survival via Nrf2 expression.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {259}, number = {}, pages = {113907}, doi = {10.1016/j.envpol.2019.113907}, pmid = {32023790}, issn = {1873-6424}, mesh = {*B-Lymphocytes/cytology/drug effects ; *Benzhydryl Compounds/chemistry/toxicity ; Cell Survival/drug effects ; *Gene Expression Regulation/drug effects ; Humans ; *Hydrogen Peroxide ; *NF-E2-Related Factor 2/genetics ; Oxidative Stress/drug effects ; Oxidoreductases/genetics ; *Phenols/chemistry/toxicity ; Reactive Oxygen Species ; }, abstract = {B cells contribute to produce inflammatory cytokines and antibodies, to present autoantigens, and to interact with T cells, which lead to body defense and disease control. Nuclear factor (erythroid-derived 2)-like 2(Nrf2) is responsible for gene expression of antioxidant enzymes to protect cells from oxidative stress by reactive oxygen species(ROS) production. Bisphenol A(BPA) may not be safe due to the effect on body's physiological functions. The chemicals that substitute for BPA may still have similar effects in the body. Tritan™ copolyester is a novel plastic form using BPA substitutes, 1,4-cyclohexanedimethanol(CHDM), dimethyl terephthalate(DMT), and 2,2,4,4-tetramethyl-1,3-cyclobutanediol(TMCD). Isosorbide(ISO) was also used as a substitute for TMCD and DMT. Here, we investigated whether B cell viability is influenced by BPA and its substitutes via Nrf2 induction using WiL2-NS human B lymphoblast cells. When cytotoxicity was measured by using assays with MTT, CellTiter-Glo, trypan blue and propidium iodide, cytotoxicity by BPA was higher than that by substitutes. BPA and its substitutes showed significant cytotoxicity and ROS production, which were attenuated by the treatment with N-acetylcysteine(NAC), a ROS scavenger. In addition, BPA treatment enhanced gene expression of antioxidant enzymes, heme oxygenase(HO)-1, catalase, superoxide dismutase(SOD) 1 and 2. As H2O2 treatment induced cell death and Nrf2 amount in WiL2-NS cells, BPA treatment increased Nrf2. Cell death by H2O2 was increased in doxycycline-inducible Nrf2-knockdown(KD) cells. In Cytotoxicity by the treatment with BPA or its substitutes was also enhanced in Nrf2-KD cells but that was reduced by Nrf2 overexpression compared to control cells. Taken together, these results implicate that B cell cytotoxicity by substitutes should be lower than BPA and Nrf2 can prevent B cells from BPA- or BPA substitutes-induced cytotoxicity via ROS production. Data suggest that the comprehensive studies or evaluation could be necessary to replace BPA in manufacture by other substitutes.}, }
@article {pmid32020997, year = {2019}, author = {Chacko, B and Peter, JV}, title = {Antidotes in Poisoning.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {23}, number = {Suppl 4}, pages = {S241-S249}, pmid = {32020997}, issn = {0972-5229}, abstract = {INTRODUCTION: Antidotes are agents that negate the effect of a poison or toxin. Antidotes mediate its effect either by preventing the absorption of the toxin, by binding and neutralizing the poison, antagonizing its end-organ effect, or by inhibition of conversion of the toxin to more toxic metabolites. Antidote administration may not only result in the reduction of free or active toxin level, but also in the mitigation of end-organ effects of the toxin by mechanisms that include competitive inhibition, receptor blockade or direct antagonism of the toxin.<br><br>Reduction in free toxin level can be achieved by specific and non-specific agents that bind to the toxin. The most commonly used non-specific binding agent is activated charcoal. Specific binders include chelating agents, bioscavenger therapy and immunotherapy. In some situations, enhanced elimination can be achieved by urinary alkalization or hemadsorption. Competitive inhibition of enzymes (e.g. ethanol for methanol poisoning), enhancement of enzyme function (e.g. oximes for organophosphorus poisoning) and competitive receptor blockade (e.g. naloxone, flumazenil) are other mechanisms by which antidotes act. Drugs such as N-acetyl cysteine and sodium thiocyanate reduce the formation of toxic metabolites in paracetamol and cyanide poisoning respectively. Drugs such as atropine and magnesium are used to counteract the end-organ effects in organophosphorus poisoning. Vitamins such as vitamin K, folic acid and pyridoxine are used to antagonise the effects of warfarin, methotrexate and INH respectively in the setting of toxicity or overdose. This review provides an overview of the role of antidotes in poisoning.<br><br>HOW TO CITE THIS ARTICLE: Chacko B, Peter JV. Antidotes in Poisoning. Indian J Crit Care Med 2019;23(Suppl 4):S241-S249.}, }
@article {pmid32018221, year = {2020}, author = {Xi, X and Yang, Y and Ma, J and Chen, Q and Zeng, Y and Li, J and Chen, L and Li, Y}, title = {MiR-130a alleviated high-glucose induced retinal pigment epithelium (RPE) death by modulating TNF-α/SOD1/ROS cascade mediated pyroptosis.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {125}, number = {}, pages = {109924}, doi = {10.1016/j.biopha.2020.109924}, pmid = {32018221}, issn = {1950-6007}, mesh = {Apoptosis/physiology ; Cell Line ; Cell Proliferation/physiology ; Gene Knockdown Techniques ; Glucose/*metabolism ; Humans ; MicroRNAs/*genetics ; Oxidative Stress/physiology ; Pyroptosis/*physiology ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/*pathology ; Superoxide Dismutase-1/metabolism ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation ; }, abstract = {High-glucose induced retinal pigment epithelium (RPE) death by triggering oxidative stress, however, the underlying mechanisms are still not fully delineated. In this study, the RPE cell line ARPE-19 were treated with different concentrations of glucose, the results showed that high-glucose (50 mM) inhibited cell proliferation, promoted cell apoptosis and reactive oxygen species (ROS) production in a time-dependent manner. Notably, we found that high-glucose (50 mM) increased the expression levels of Caspase-1, Gasdermin D, NLRP3, IL-1β and IL-18 in ARPE-19 cells, which indicated that high-glucose triggered pyroptotic cell death. Further results validated that both ROS scavenger N-acetyl cysteine (NAC) and pyroptosis inhibitor necrosulfonamide (NSA) reversed the effects of high-glucose (50 mM) on ARPE-19 cell proliferation, apoptosis and pyroptosis. In addition, high-glucose (50 mM) significantly decreased the levels of miR-130a and superoxide dismutase (SOD) 1, and promoted tumor necrosis factor (TNF)-α expressions in ARPE-19 cells. Interestingly, upregulation of miR-130a increased SOD1 levels in a TNF-α dependent manner. Furthermore, overexpression of miR-130a abrogated the effects of high-glucose (50 mM) on the above cell functions, which were all reversed by either upregulating TNF-α or knocking down SOD1 in ARPE-19 cells. Taken together, upregulation of miR-130a alleviated the cytotoxic effects of high-glucose (50 mM) on ARPE-19 cells by regulating TNF-α/SOD1/ROS axis mediated pyroptotic cell death.}, }
@article {pmid32016570, year = {2020}, author = {Russo, MST and Napylov, A and Paquet, A and Vuckovic, D}, title = {Comparison of N-ethyl maleimide and N-(1-phenylethyl) maleimide for derivatization of biological thiols using liquid chromatography-mass spectrometry.}, journal = {Analytical and bioanalytical chemistry}, volume = {412}, number = {7}, pages = {1639-1652}, doi = {10.1007/s00216-020-02398-x}, pmid = {32016570}, issn = {1618-2650}, support = {RGPIN 435814-20013//Natural Sciences and Engineering Research Council of Canada/ ; Grant J00126//Concordia University/ ; }, mesh = {Chromatography, Liquid/*methods ; Cyclization ; Ethylmaleimide/*chemistry ; Hydrogen-Ion Concentration ; Spectrometry, Mass, Electrospray Ionization/*methods ; Sulfhydryl Compounds/*chemistry ; }, abstract = {The ratio between reduced and oxidized thiols, mainly glutathione and oxidized glutathione, is one of the biomarkers for the evaluation of oxidative stress. The accurate measurement of thiol concentrations is challenging because reduced thiols are easily oxidized during sample manipulation. Derivatization is commonly used to protect thiols from oxidation. The objective of this work was to systematically compare two cell-permeable derivatizing agents: N-ethyl maleimide (NEM) and (R)-(+)-N-(1-phenylethyl)maleimide (NPEM) in terms of derivatization efficiency, ionization enhancement, side product formation, reaction selectivity for thiols, pH dependence of the reaction, and derivative stability. All thiol measurements and the characterization of side products were performed using a biphenyl reversed phase liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Four thiols, cysteine (CYS), homocysteine, N-acetylcysteine (NAC), and glutathione (GSH), were used for the evaluation. Using 1:10 ratio of thiol:derivatizing agent, complete derivatization was obtained within 30 min for both agents tested with the exception of CYS-NEM, where 97% efficiency was obtained. The more hydrophobic NPEM provided better ionization of the thiols, with enhancement ranging from 2.1x for GSH to 5.7x for CYS in comparison to NEM. NPEM derivatization led to more extensive side reactions, such as double derivatization and ring opening, which hindered the accurate measurement of the thiol concentrations. Both NEM and NPEM also showed poor stability of CYS derivative due to its time-dependent conversion to cyclic cysteine-maleimide derivative. Both reagents also showed significant reactivity with amine-containing metabolites depending on the pH used during derivatization, but overall NEM was found to be more selective towards thiol group than NPEM. Taking into account all evaluation criteria, NEM was selected as a more suitable reagent for the thiol protection and derivatization, but strict control of pH 7.0 is recommended to minimize the side reactions. This work illustrates the importance of the characterization of side products and derivative stability during the evaluation of thiol derivatizing agents and contributes fundamental understanding to improve the accuracy of thiol determinations. The key sources of errors during maleimide derivatization include the derivatization of amine-containing metabolites, poor derivative stability of certain thiols (CYS and NAC), and the side reactions especially if ring opening of the reagent is not minimized. Graphical abstract.}, }
@article {pmid32016519, year = {2021}, author = {Mahawongkajit, P and Kanlerd, A}, title = {A prospective randomized controlled trial comparing simethicone, N-acetylcysteine, sodium bicarbonate and peppermint for visualization in upper gastrointestinal endoscopy.}, journal = {Surgical endoscopy}, volume = {35}, number = {1}, pages = {303-308}, pmid = {32016519}, issn = {1432-2218}, mesh = {Acetylcysteine/*metabolism ; Endoscopy, Gastrointestinal/*methods ; Female ; Humans ; Male ; Mentha piperita/*metabolism ; Middle Aged ; Prospective Studies ; Quality of Life ; Simethicone/*metabolism ; Sodium Bicarbonate/*metabolism ; }, abstract = {OBJECTIVES: Early cancer detection is crucial in improving the patients' quality of life and upper gastrointestinal endoscopy (EGD) plays a key role in this detection. Many clearing mechanisms may be applied to create good endoscopic visualizations for the upper gastrointestinal tract using mucolytic agents, antifoaming agents, proteolytic enzymes and neutralizers. The aim of this study is to compare the effects of simethicone, N-acetylcysteine (NAC), sodium bicarbonate and peppermint as pre-medications for visualization of esophagogastroduodenoscopy (EGD).<br><br>METHODS: This study was a single center prospective randomized controlled trial. The patients were randomly allocated to one of four treatment groups. Group A: water; Group B: water with simethicone; Group C: water with simethicone plus NAC 600&#xa0;mg; Group D: water with simethicone, NAC, sodium bicarbonate and peppermint.<br><br>RESULTS: A total of 128 patients were enrolled and evaluated in this study. Total visibility score (TVS) of Groups A, B, C, and D were 13.4&#x2009;&#xb1;&#x2009;1.86, 10.5&#x2009;&#xb1;&#x2009;1.45, 7.15&#x2009;&#xb1;&#x2009;0.98 and 6.4&#x2009;&#xb1;&#x2009;1.43, respectively. Group D showed lower TVS than other groups. The procedural durations of Groups C and D were significantly shorter than Group A. The volume of solution for mucosal cleansing of Groups C and D was significantly lower than Groups A and B.<br><br>CONCLUSIONS: The application of simethicone plus NAC is safe, improves endoscopic visualization and requires a minimal amount of mucosal cleansing solution. The addition of sodium bicarbonate and peppermint further improved visualization for the upper and lower gastric body. Thai Clinical Trials Registry (TCTR) with a reference number; TCTR20190501002.}, }
@article {pmid32014764, year = {2020}, author = {Mendonça, MCP and de Jesus, MB and van Gestel, CAM}, title = {Protective effect of N-acetylcysteine on the toxicity of silver nanoparticles: Bioavailability and toxicokinetics in Enchytraeus crypticus.}, journal = {The Science of the total environment}, volume = {715}, number = {}, pages = {136797}, doi = {10.1016/j.scitotenv.2020.136797}, pmid = {32014764}, issn = {1879-1026}, mesh = {Acetylcysteine ; Animals ; Biological Availability ; *Metal Nanoparticles ; *Oligochaeta ; Silver ; Soil ; Soil Pollutants ; Toxicokinetics ; }, abstract = {We previously demonstrated that N-acetylcysteine (NAC) could reduce the toxicity of silver (Ag) materials (nanoparticles (NPs) and Ag nitrate) to the soil invertebrate Enchytraeus crypticus (Oligochaeta). It remains however, unclear whether the antitoxic mechanism of NAC was caused by NAC-Ag binding in the soil or inside the organisms. This study aimed at determining the bioavailability of Ag in the soil in a 21-day toxicity test as well as the Ag uptake and elimination kinetics in E. crypticus exposed to AgNPs in LUFA 2.2 standard soil amended with low (100 mg/kg dry soil) and high (600 mg/kg dry soil) NAC concentrations. The addition of NAC to the soil alleviated the toxicity of AgNPs by decreasing the internal Ag concentration of E. crypticus in a dose-dependent manner. Indeed, NAC reduced the binding of Ag to the soil, which probably was due to the formation of soluble but biologically unavailable Ag-cysteine complexes. The reduced Ag uptake in the enchytraeids was explained from an increased elimination at high NAC levels. These findings reinforce the view that metal complexing-compounds like NAC play a key role in the modulation of AgNP toxicity and bioavailability in terrestrial environments. Further, it may inform on the potential of NAC as a remediation solution for Ag or other metal-contaminated soils.}, }
@article {pmid32009631, year = {2019}, author = {Dobrek, L and Nalik-Iwaniak, K and Kopanska, M and Arent, Z and Thor, PJ}, title = {Evaluation of selected protein biomarkers of renal function in rats with an experimental model of acute cyclophosphamide-induced cystitis treated with N-acetylcysteine.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {70}, number = {5}, pages = {}, doi = {10.26402/jpp.2019.5.14}, pmid = {32009631}, issn = {1899-1505}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers/*metabolism ; Cyclophosphamide/*pharmacology ; Cystitis/chemically induced/*drug therapy/*metabolism ; Disease Models, Animal ; Female ; Glomerular Filtration Rate/drug effects ; Kidney Diseases/chemically induced/drug therapy/metabolism ; Kidney Tubules/*drug effects/*metabolism ; Male ; Rats ; Rats, Wistar ; Urinary Bladder/drug effects/metabolism ; }, abstract = {The administration of cyclophosphamide (CP) is associated with the risk of developing cystitis as well as kidney injury. The aim of the study was to verify the uroprotective effect of N-acetylcysteine (NAC), as well as the evaluation of renal function in the experimental model of acute CP-induced cystitis. Rats from group 1 received intraperitoneally only a single dose of 200 mg/kg b.w. of CP. Individuals from groups 2 and 3 additionally received a single dose of 200 mg/kg b.w. of NAC, respectively, orally (p.o.) and intraperitoneally (i.p.). After the administration of the drugs, animals were subject to individual monitoring in metabolic cages to assess 24-hour diuresis and basic vital signs, and then finally sacrificed for the purpose of collecting blood and organs for histopathological analysis. Classic renal parameters (creatinine, urea, uric acid, electrolytes) as well as new markers reflecting renal function, within the filtration-resorption range - cystatin C (CysC), renal tubular integrity - kidney injury molecule-1 (KIM-1) and the condition of the glomerular filtration barrier (nephrin) were determined in the obtained serum and urine samples. In group 1 histopathological development of cystitis was confirmed with the absence of significant pathomorphological disorders of the kidneys, and the initial results of the parameters determined were obtained. In both groups 2 and 3, a decrease of inflammatory changes in urinary bladder was observed, while there were still no morphological disturbances in kidneys. The administration of NAC in both groups 2 and 3 also resulted in a decrease of concentrations in urine and a reduction in 24-hour excretion with urine of all assessed proteins (CysC, KIM-1 and nephrin). NAC, thus exhibited a uroprotective effect, which was accompanied by a functional nephroprotective effect (more accentuated during intraperitoneal administration of this compound), manifested by the reduction of urinary excretion of proteins indicative of developing renal dysfunction.}, }
@article {pmid32007528, year = {2020}, author = {Niu, T and Tian, Y and Wang, G and Guo, G and Tong, Y and Shi, Y}, title = {Inhibition of ROS-NF-κB-dependent autophagy enhances Hypocrellin A united LED red light-induced apoptosis in squamous carcinoma A431 cells.}, journal = {Cellular signalling}, volume = {69}, number = {}, pages = {109550}, doi = {10.1016/j.cellsig.2020.109550}, pmid = {32007528}, issn = {1873-3913}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Carcinoma, Squamous Cell/*therapy ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; NF-kappa B/metabolism ; Perylene/*analogs &amp; derivatives/pharmacology ; Phenol/*pharmacology ; Photochemotherapy ; Photosensitizing Agents/*pharmacology ; Quinones/*pharmacology ; Reactive Oxygen Species/metabolism ; Skin Neoplasms ; }, abstract = {Cutaneous squamous cell carcinoma (cSCC) is a type of malignant skin tumor derived from epidermal Malpighian cells. Photodynamic therapy is regarded as a crucial method in oncology. Hypocrellin A (HA), an efficient natural photosensitizer, has been reported to exert excellent light induced antiviral, antimicrobial and anticancer activity through mediating multiple signaling pathways. The purpose of the present study is to examine the effects of HA united red light irradiation on human squamous carcinoma A431 cells and further reveal the underlying regulatory mechanisms. The results showed that synergistic treatment of HA and red light irradiation inhibited cell proliferation and induced cell apoptosis and autophagy. Moreover, HA united red light irradiation caused a significant accumulation of reactive oxygen species (ROS), and induced the activation of c-Jun NH 2 terminal kinases (JNKs) which was inhibited by the antioxidant N-Acetyl-cysteine (NAC). Furthermore, HA united red light irradiation activated the nuclear factor-kappa B (NF-κB) pathway, and inhibition of NF-κB activity exacerbated HA united red light irradiation-induced apoptosis but suppressed cell autophagy. In addition, the inhibition of autophagy promoted HA united red light irradiation-induced apoptosis and facilitated the NF-κB activity. Over all, our results revealed that HA united red light irradiation could inhibit A431 cell proliferation by inducing apoptosis and autophagy via the activation of the ROS mediated JNK and NF-κB pathways, providing prospective for HA as a potential therapeutic for the treatment of cSCC.}, }
@article {pmid32007101, year = {2020}, author = {Lindsay, A and Baumann, CW and Rebbeck, RT and Yuen, SL and Southern, WM and Hodges, JS and Cornea, RL and Thomas, DD and Ervasti, JM and Lowe, DA}, title = {Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators.}, journal = {Skeletal muscle}, volume = {10}, number = {1}, pages = {3}, pmid = {32007101}, issn = {2044-5040}, support = {R01 HL138539/HL/NHLBI NIH HHS/United States ; T32 AR007612/AR/NIAMS NIH HHS/United States ; R01 AR032961/AR/NIAMS NIH HHS/United States ; R01 HL139065/HL/NHLBI NIH HHS/United States ; R01 AR049899/AR/NIAMS NIH HHS/United States ; R01 AG026160/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aminoquinolines/pharmacology ; Animals ; Antioxidants/pharmacology ; Benzamides/pharmacology ; Calcium/metabolism ; Calcium Channel Agonists/pharmacology ; Calcium Channel Blockers/pharmacology ; Chloroquinolinols/pharmacology ; Flavonoids/pharmacology ; Male ; Mice ; Mice, Inbred mdx ; *Muscle Contraction ; *Muscle Strength ; Muscle, Skeletal/drug effects/*metabolism/physiology ; Muscular Dystrophy, Duchenne/*metabolism ; Ryanodine Receptor Calcium Release Channel/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Stress, Mechanical ; }, abstract = {BACKGROUND: Dystrophin deficiency sensitizes skeletal muscle of mice to eccentric contraction (ECC)-induced strength loss. ECC protocols distinguish dystrophin-deficient from healthy, wild type muscle, and test the efficacy of therapeutics for Duchenne muscular dystrophy (DMD). However, given the large lab-to-lab variability in ECC-induced strength loss of dystrophin-deficient mouse skeletal muscle (10-95%), mechanical factors of the contraction likely impact the degree of loss. Therefore, the purpose of this study was to evaluate the extent to which mechanical variables impact sensitivity of dystrophin-deficient mouse skeletal muscle to ECC.<br><br>METHODS: We completed ex vivo and in vivo muscle preparations of the dystrophin-deficient mdx mouse and designed ECC protocols within physiological ranges of contractile parameters (length change, velocity, contraction duration, and stimulation frequencies). To determine whether these contractile parameters affected known factors associated with ECC-induced strength loss, we measured sarcolemmal damage after ECC as well as strength loss in the presence of the antioxidant N-acetylcysteine (NAC) and small molecule calcium modulators that increase SERCA activity (DS-11966966 and CDN1163) or lower calcium leak from the ryanodine receptor (Chloroxine and Myricetin).<br><br>RESULTS: The magnitude of length change, work, and stimulation duration ex vivo and in vivo of an ECC were the most important determinants of strength loss in mdx muscle. Passive lengthening and submaximal stimulations did not induce strength loss. We further showed that sarcolemmal permeability was associated with muscle length change, but it only accounted for a minimal fraction (21%) of the total strength loss (70%). The magnitude of length change also significantly influenced the degree to which NAC and small molecule calcium modulators protected against ECC-induced strength loss.<br><br>CONCLUSIONS: These results indicate that ECC-induced strength loss of mdx skeletal muscle is dependent on the mechanical properties of the contraction and that mdx muscle is insensitive to ECC at submaximal stimulation frequencies. Rigorous design of ECC protocols is critical for effective use of strength loss as a readout in evaluating potential therapeutics for muscular dystrophy.}, }
@article {pmid32006234, year = {2020}, author = {Yamamoto, Y and Koma, H and Yagami, T}, title = {The Anti-Neuron-Specific Enolase Antibody Induced Neuronal Cell Death in a Novel Fashion.}, journal = {Molecular neurobiology}, volume = {57}, number = {5}, pages = {2265-2278}, pmid = {32006234}, issn = {1559-1182}, support = {Grant-in-Aid 17K08327//the Ministry of Education, Culture, Sports, Science, and Technology of Japan/ ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/pharmacology ; Calcium Signaling ; Caspase 1/metabolism ; Caspase 3/*drug effects ; Cell Death/*drug effects ; Cerebral Cortex/cytology ; Chromatin/ultrastructure ; Enzyme Activation/drug effects ; Female ; Glutathione/pharmacology ; Goats/immunology ; HSP70 Heat-Shock Proteins/metabolism ; Immunoglobulin G/immunology/*pharmacology ; MAP Kinase Signaling System/drug effects ; Neurites/drug effects ; Neurons/cytology/*drug effects ; Phosphopyruvate Hydratase/*immunology/physiology ; Pregnancy ; Prostaglandin D2/analogs &amp; derivatives/physiology ; Proteasome Endopeptidase Complex/*metabolism ; Protein Processing, Post-Translational/drug effects ; Rabbits/immunology ; Rats ; Rats, Wistar ; Species Specificity ; Ubiquitin/*metabolism ; Ubiquitination/drug effects ; }, abstract = {Suppression of ubiquitin proteasome pathway (UPP) and stimulation of caspase-3 are involved in neurodegeneration. Can UPP activators and caspase-3 inhibitors ameliorate neurodegeneration? Here, we found a novel neuronal cell death accompanied with UPP activation and caspase-3 inhibition. Recently, plasmalemmal neuron-specific enolase (NSE) has been identified as one of membrane targets of 15-deoxy-Δ[12,14]-prostaglandin J2 (15d-PGJ2). 15d-PGJ2 induces neuronal apoptosis via activating caspase-3 and inactivating UPP, whereas the anti-NSE antibody inactivated caspase-3, activated UPP, and caused neuronal cell death. The anti-NSE antibody activated caspase-1 (pyroptosis marker), but not condense chromatin (apoptosis marker). The anti-NSE antibody declined intracellular level of ATP, which is not altered in pyroptosis. The intracellular level of calcium is elevated in necrosis and pyroptosis, but its chelator did not ameliorate the neurotoxicity of anti-NSE. Thiol antioxidants such as N-acetyl cysteine and glutathione reduced the neurotoxicity of 15d-PGJ2 but enhanced that of the anti-NSE antibody. The anti-NSE antibody incorporated propidium iodide into neurons through the disrupted plasma membrane, which are not observed in ferroptosis and autophagic cell death. Thus, the anti-NSE antibody induced neuronal cell death in a novel fashion distinguished from necrosis, necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagic cell death.}, }
@article {pmid32005121, year = {2020}, author = {Oono, K and Ohtake, K and Watanabe, C and Shiba, S and Sekiya, T and Kasono, K}, title = {Contribution of Pyk2 pathway and reactive oxygen species (ROS) to the anti-cancer effects of eicosapentaenoic acid (EPA) in PC3 prostate cancer cells.}, journal = {Lipids in health and disease}, volume = {19}, number = {1}, pages = {15}, pmid = {32005121}, issn = {1476-511X}, support = {JP26350904//JSPS KAKENHI/ ; }, mesh = {Blotting, Western ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Eicosapentaenoic Acid/*pharmacology ; Focal Adhesion Kinase 2/*metabolism ; Humans ; Male ; PC-3 Cells ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: n-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are thought to exert protective effects in cardiovascular diseases. In addition, n-3 PUFAs have demonstrated anti-cancer effects in vitro and in vivo.<br><br>OBJECTIVE: We investigated the anti-cancer effects and mechanism of action of EPA on PC3 prostate cancer cells in vitro.<br><br>METHODS: PC3 cells were treated with various concentrations of EPA, and cell survival and the abilities of migration and invasion were evaluated. The time course of the growth inhibitory effect of EPA on PC3 cells was also assessed. The mechanism underlying the anti-cancer effects of EPA was investigated by human phosphokinase and human apoptosis antibody arrays, and confirmed by western blot analysis. We also examined the contribution of reactive oxygen species (ROS) to the effects of EPA using the ROS inhibitor N-acetyl cysteine.<br><br>RESULTS: EPA decreased the survival of PC3 cells in a dose-dependent manner within 3&#x2009;h of application, with an effective concentration of 500&#x2009;&#x3bc;mol/L. EPA inhibited proline-rich tyrosine kinase (Pyk)2 and extracellular signal-regulated kinase 1/2 phosphorylation as determined by western blotting and the antibody arrays. The growth of PC3 cells was inhibited by EPA, which was dependent on ROS induction, while EPA inhibited Pyk2 phosphorylation independent of ROS production.<br><br>CONCLUSIONS: Inhibition of Pyk2 phosphorylation and ROS production contribute to the anticancer effects of EPA on PC3 cells.}, }
@article {pmid32002811, year = {2020}, author = {Thakkar, D and Kate, AS}, title = {1-(Benzo[b]thiophen-4-yl)piperazine Ring Induced Bioactivation of Brexpiprazole in Liver Microsomes: Identification and Characterization of Reactive Conjugates Using Ultra-High-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry.}, journal = {European journal of drug metabolism and pharmacokinetics}, volume = {45}, number = {3}, pages = {393-403}, doi = {10.1007/s13318-020-00606-8}, pmid = {32002811}, issn = {2107-0180}, mesh = {Animals ; Antipsychotic Agents/chemistry/*pharmacokinetics ; Chromatography, High Pressure Liquid ; Cystine/analogs &amp; derivatives/metabolism ; Glutathione/metabolism ; Humans ; Male ; Microsomes, Liver/*metabolism ; Quinolones/chemistry/*pharmacokinetics ; Rats ; Tandem Mass Spectrometry ; Thiophenes/chemistry/*pharmacokinetics ; }, abstract = {BACKGROUND AND OBJECTIVES: Brexpiprazole is an atypical antipsychotic approved for the treatment of schizophrenia and major depressive disorders in adults. The structure of brexpiprazole contains well-known structural alerts like a thiophene ring, piperazine ring and quinolinone motifs. Additionally, the literature reveals that its structural analog, aripiprazole, could generate reactive intermediates. However, the bioactivation potential of brexpiprazole is yet unknown. Therefore, this study was planned to identify and characterize reactive adducts of brexpiprazole and its metabolites.<br><br>METHODS: Based on the reactivity, the potential atomic sites for a reactive intermediate generation were predicted by a xenosite web predictor tool for glutathione, cyanide, protein and DNA. To study the metabolic activation of brexpiprazole, the drug was individually incubated for 2&#xa0;h at 37&#xa0;&#xb0;C with pooled male rat liver microsomes and human liver microsomes in microcentrifuge tubes fortified with glutathione/N-acetyl cysteine. Nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt was used as a co-factor.<br><br>RESULTS: A total of six glutathione and N-acetyl cysteine conjugates of brexpiprazole metabolites were identified and characterized using ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry. Reactive metabolite 1 (RM1), RM3, RM4 and RM6 reactive conjugates were formed due to reactive quinone-imine or quinone intermediates, while RM2 and RM5 reactive adducts were generated because of a thiophene-S-oxide intermediate.<br><br>CONCLUSION: Brexpirazole is bioactivated due to the presence of a 1-(benzo[b]thiophen-4-yl)piperazine ring in its structure. In contrast to aripiprazole, the quinolinone motif was found latent towards bioactivation&#xa0;in brexpiprazole.}, }
@article {pmid31999475, year = {2020}, author = {Sun, Y and Rong, X and Li, D and Lu, Y and Ji, Y}, title = {NF-κB/Cartilage Acidic Protein 1 Promotes Ultraviolet B Irradiation-Induced Apoptosis of Human Lens Epithelial Cells.}, journal = {DNA and cell biology}, volume = {39}, number = {4}, pages = {513-521}, doi = {10.1089/dna.2019.5086}, pmid = {31999475}, issn = {1557-7430}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*physiology ; Calcium-Binding Proteins/genetics/*metabolism ; Cataract/*pathology ; Cells, Cultured ; Epithelial Cells/pathology ; Humans ; Lens, Crystalline/cytology/*pathology ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/metabolism ; Thiocarbamates/pharmacology ; Transcription Factor RelA/*metabolism ; Ultraviolet Rays ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {The apoptosis of human lens epithelial cells (HLECs) is a characteristic change that occurs during the development of cataracts. Ultraviolet B (UVB) is known to induce the generation of reactive oxygen species (ROS) and apoptosis in HLECs, and thus cause cataracts. Previously, we reported the functions of cartilage acidic protein 1 (CRTAC1) in UVB-treated HLECs. However, the underlying mechanism was not known. In this study, we found that CRTAC1 expression and nuclear factor-kappa B (NF-κB) p65 nuclear translocation were elevated in capsule tissues of cataract patients in comparison with normal controls. The NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), alleviated UVB-induced apoptosis in HLECs; while activation of NF-κB suppressed the effects of the ROS inhibitor, N-acetyl-L-cysteine (NAC), on UVB-treated HLECs. The expression and promoter activity of CRTAC1 was inhibited by PDTC and NAC. Moreover, the suppressed effects of CRTAC1 knockdown on UVB-induced ROS generation, cell apoptosis, nuclear translocation of NF-κB p65, and p38 phosphorylation were attenuated by a p38 agonist. In contrast, the p38 inhibitor abolished the promotional effects of CRTAC1 overexpression on HLECs. Taken together, our results for the first time show that NF-κB is a potential transcription factor for CRTAC1. The regulatory network involving NF-κB, CRTAC1, and p38 may therefore play an important role in cataract formation.}, }
@article {pmid31998443, year = {2020}, author = {Mileo, AM and Di Venere, D and Mardente, S and Miccadei, S}, title = {Artichoke Polyphenols Sensitize Human Breast Cancer Cells to Chemotherapeutic Drugs via a ROS-Mediated Downregulation of Flap Endonuclease 1.}, journal = {Oxidative medicine and cellular longevity}, volume = {2020}, number = {}, pages = {7965435}, pmid = {31998443}, issn = {1942-0994}, mesh = {*Breast Neoplasms/drug therapy/metabolism/pathology ; Cynara scolymus/*chemistry ; Down-Regulation/*drug effects ; Female ; Flap Endonucleases/*biosynthesis ; Gene Expression Regulation, Enzymologic/*drug effects ; Humans ; MAP Kinase Signaling System/drug effects ; MCF-7 Cells ; Paclitaxel/*pharmacology ; Polyphenols/chemistry/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Combined treatment of several natural polyphenols and chemotherapeutic agents is more effective comparing to the drug alone in inhibiting cancer cell growth. Polyphenolic artichoke extracts (AEs) have been shown to have anticancer properties by triggering apoptosis or reactive oxygen species- (ROS-) mediated senescence when used at high or low doses, respectively. Our aim was to explore the chemosensitizing potential of AEs in order to enhance the efficacy of conventional chemotherapy in breast cancer cells. We employed breast cancer cell lines to assess the potential synergistic effect of a combined treatment of AEs/paclitaxel (PTX) or AEs/adriamycin (ADR) and to determine the underlying mechanisms correlated to this potential therapeutic approach. Our data shows that AEs/PTX reduced cell proliferation by increasing DNA damage response (DDR) mediated by Flap endonuclease 1 (FEN1) downregulation that results into enhanced breast cancer cell sensitivity to chemotherapeutic drugs. We demonstrated that ROS/Nrf2 and p-ERK pathways are two molecular mechanisms involved in the synergistic effect of AEs plus PTX treatment. To highlight the role of ROS herein, we report that the addition of antioxidant N-acetylcysteine (NAC) significantly decreased the antiproliferative effect of the combined treatment. A combined therapy could be able to reduce the dose of chemotherapeutic drugs, minimizing toxicity and side effects. Our results suggest the use of artichoke polyphenols as ROS-mediated sensitizers of chemotherapy paving the way for innovative and promising natural compound-based therapeutic strategies in oncology.}, }
@article {pmid31995555, year = {2020}, author = {Lu, CH and Kuo, YY and Lin, GB and Chen, WT and Chao, CY}, title = {Application of non-invasive low-intensity pulsed electric field with thermal cycling-hyperthermia for synergistically enhanced anticancer effect of chlorogenic acid on PANC-1 cells.}, journal = {PloS one}, volume = {15}, number = {1}, pages = {e0222126}, pmid = {31995555}, issn = {1932-6203}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Chlorogenic Acid/*pharmacology ; Electromagnetic Radiation ; Humans ; Hyperthermia, Induced/methods ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Pancreatic Neoplasms/pathology/*therapy ; Reactive Oxygen Species/metabolism ; }, abstract = {Most existing cancer treatments involve high-cost chemotherapy and radiotherapy, with major side effects, prompting effort to develop alternative treatment modalities. It was reported that the combination of thermal-cycling hyperthermia (TC-HT) and phenolic compound exhibited a moderate cytotoxic effect against human pancreatic cancer PANC-1 cells. In this study, we investigate the efficacy of triple combination in PANC-1 cancer cells by adopting low-intensity pulsed electric field (LIPEF) to couple with TC-HT and CGA (chlorogenic acid). The study finds that this triple combination can significantly impede the proliferation of PANC-1 cells, with only about 20% viable cells left after 24h, whereas being non-toxic to normal cells. The synergistic activity against the PANC-1 cells was achieved by inducing G2/M phase arrest and apoptosis, which were associated with up-regulation of p53 and coupled with increased expression of downstream proteins p21 and Bax. Further mechanism investigations revealed that the cytotoxic activity could be related to mitochondrial apoptosis, characterized by the reduced level of Bcl-2, mitochondrial dysfunction, and sequential activation of caspase-9 and PARP. Also, we found that the triple treatment led to the increase of intracellular reactive oxygen species (ROS) production. Notably, the triple treatment-induced cytotoxic effects and the elevated expression of p53 and p21 proteins as well as the increased Bax/Bcl-2 ratio, all could be alleviated by the ROS scavenger, N-acetyl-cysteine (NAC). These findings indicate that the combination of CGA, TC-HT, and LIPEF may be a promising modality for cancer treatment, as it can induce p53-dependent cell cycle arrest and apoptosis through accumulation of ROS in PANC-1 cells.}, }
@article {pmid31993909, year = {2020}, author = {Al-Quraishy, S and Dkhil, MA and Abdel-Gaber, R and Zrieq, R and Hafez, TA and Mubaraki, MA and Abdel Moneim, AE}, title = {Myristica fragrans seed extract reverses scopolamine-induced cortical injury via stimulation of HO-1 expression in male rats.}, journal = {Environmental science and pollution research international}, volume = {27}, number = {11}, pages = {12395-12404}, pmid = {31993909}, issn = {1614-7499}, mesh = {Animals ; Antioxidants ; Male ; *Myristica ; Oxidative Stress ; Plant Extracts ; Rats ; Scopolamine ; Seeds ; }, abstract = {Myristica fragrans, commonly known as nutmeg, belongs to the Myristicaceae family and is used as a spice and for its medicinal properties. The purpose of this study was to assess the neuroprotective effect of M. fragrans seed methanolic extract (MFE) on scopolamine-induced oxidative damage, inflammation, and apoptosis in male rat cortical tissue. MFE or N-acetylcysteine (NAC), a standard antioxidant drug, was administered 7 days before treatment with scopolamine resulted in high levels of malondialdehyde and nitric oxide (oxidative stress biomarkers), tumor necrosis factor-alpha and interleukin-1 beta (inflammatory mediators), and Bax and caspase-3 pro-apoptotic proteins. Additionally, scopolamine significantly depleted levels of glutathione (an antioxidant marker), Bcl-2 and c-FLIP (anti-apoptotic proteins), and antioxidant enzymes activity in cortical tissue. Scopolamine also enhanced acetylcholinesterase activity. MFE treatment protected the cortex of rats from the effects of scopolamine by reversing the effects on these toxicity markers. Interestingly, the neuroprotective effect of MFE was comparable to that exerted by the reference antioxidant NAC. Thus, our findings show that MFE has antioxidant, anti-inflammatory, and anti-apoptotic effects. The beneficial effects of MFE on scopolamine were partially mediated by promoting heme oxygenase 1 (Hmox1) expression and preserving cortical tissue structure.}, }
@article {pmid31990607, year = {2020}, author = {Barlaz Us, S and Vezir, O and Yildirim, M and Bayrak, G and Yalin, S and Balli, E and Yalin, AE and Çömelekoğlu, &#xdc;}, title = {Protective effect of N-acetyl cysteine against radiotherapy-induced cardiac damage.}, journal = {International journal of radiation biology}, volume = {96}, number = {5}, pages = {661-670}, doi = {10.1080/09553002.2020.1721605}, pmid = {31990607}, issn = {1362-3095}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cytokines/analysis ; Electrocardiography/radiation effects ; Female ; Heart/*radiation effects ; Myocardium/metabolism/pathology ; Oxidative Stress/drug effects ; Radiation-Protective Agents/*pharmacology ; Radiotherapy/adverse effects ; Rats ; Rats, Wistar ; }, abstract = {Purpose: Although radiotherapy (RT) is an important component of cancer treatment, it induces adverse tissue reactions in the around of cancer tissue. Therefore, radioprotectives are needed to protect normal tissues. The aim of this study was to investigate the radioprotective effect of N-acetylcysteine (NAC) on RT-induced cardiac damage in rats for the acute term.Materials and methods: The animals were divided into four groups. The rats in control group were injected with saline for 7 d; the rats in NAC group were injected NAC at dose of 240 mg/kg d for 7 d; the rats in RT group were injected with saline for 7 d plus was irradiated 1 h after the last injection and the rats in NAC + RT group were injected with NAC for 7 d and irradiated 1 h after the last NAC dose. The electrocardiogram was recorded and evaluated PR interval, QRS duration, QT interval, T wave alterations and heart rate. Serum interleukin-4, interleukin-6, tumor necrosis factor-alpha, interleukin 1 beta, galectin-3 levels and creatine kinase and creatine kinase isoenzyme-MB activities were determined in all groups. Also, tissue malondialdehyde (MDA) and nitric oxide levels, superoxide dismutase, catalase and glutathione peroxidase activities were determined. In addition, histological changes of heart were evaluated. All measurements were performed 24 h after RT.Results: In the RT group, findings supporting cardiac injury were observed in the electrocardiogram. Also, cytokine levels and oxidative stress were significantly increased. Pretreatment of rats with NAC ameliorated cardiac injury induced by RT.Conclusions: Our findings suggested that NAC may be a potential radioprotector which is capable of preventing cardiac damage.}, }
@article {pmid31986930, year = {2020}, author = {Pijls, BG and Sanders, IMJG and Kuijper, EJ and Nelissen, RGHH}, title = {Synergy between induction heating, antibiotics, and N-acetylcysteine eradicates Staphylococcus aureus from biofilm.}, journal = {International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group}, volume = {37}, number = {1}, pages = {130-136}, doi = {10.1080/02656736.2019.1710269}, pmid = {31986930}, issn = {1464-5157}, mesh = {Acetylcysteine/*metabolism ; Anti-Bacterial Agents/pharmacology/*therapeutic use ; Biofilms/*drug effects ; Heating/*methods ; Humans ; Staphylococcus aureus/*drug effects ; }, abstract = {Background: Non-contact induction heating (NCIH) is a noninvasive treatment modality that can be used to cause thermal damage to bacterial biofilms on a metal implant surface in the context of a prosthetic joint infection. The purpose of this study was (1) to determine the effectiveness of NCIH on killing Staphylococcus aureus from biofilm and (2) to determine the possible synergistic effect of NCIH and cocktails of antibiotics and N-acetylcysteine (NAC).Methods:Staphylococcus aureus biofilms were grown on titanium alloy (Ti6Al4V) coupons. These coupons were heated to 50 °C, 60 °C, 70 °C, 80 °C, and 90 °C for 3.5 min and subsequently exposed to cocktails of vancomycin, rifampicin and NAC at clinically relevant concentrations over 24 h.Results: In the control group without induction heating, 2.2*10[7] colony forming units (CFU)/cm[2] were observed. At 50 °C, 60 °C, 70 °C, 80 °C, and 90 °C, a reduction of 0.3-log, 3.9-log, 4.2-log, 4.3-log, and 6.6-log CFU/cm[2] were observed, respectively. There was synergy between antibiotics and induction heating that resulted in less than 100 CFU/cm[2] remaining after 3.5 min at 60 °C, and exposure to vancomycin and rifampicin. Total eradication was observed at 80 °C. Total eradication was also observed at 60 °C and a cocktail of antibiotics with NAC.Conclusion: Induction heating of titanium alloy coupons is effective for the reduction of bacterial load in vitro in S. aureus biofilms. Induction heating and cocktails of antibiotics and NAC have a synergistic effect that results in the total eradication of the biofilm at 60 °C and higher for clinically relevant concentrations of vancomycin, rifampicin and NAC.}, }
@article {pmid31981738, year = {2020}, author = {Riegger, J and Huber-Lang, M and Brenner, RE}, title = {Crucial role of the terminal complement complex in chondrocyte death and hypertrophy after cartilage trauma.}, journal = {Osteoarthritis and cartilage}, volume = {28}, number = {5}, pages = {685-697}, doi = {10.1016/j.joca.2020.01.004}, pmid = {31981738}, issn = {1522-9653}, mesh = {Acetylcysteine/pharmacology ; Aged ; Aged, 80 and over ; Aurintricarboxylic Acid/pharmacology ; Cartilage, Articular/cytology ; Cell Death/drug effects/*genetics ; Cellular Senescence/drug effects/genetics ; Chondrocytes/drug effects/*metabolism/pathology ; Clusterin/pharmacology ; Complement Membrane Attack Complex/antagonists &amp; inhibitors/drug effects/*genetics/metabolism ; Enzyme Inhibitors/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Hypertrophy/*genetics ; Imidazoles/pharmacology ; Immunity, Innate/genetics ; Indoles/pharmacology ; Male ; Middle Aged ; Oligopeptides/pharmacology ; Osteoarthritis/etiology/*genetics/metabolism/pathology ; RNA, Messenger/drug effects/metabolism ; Wounds, Nonpenetrating/complications/*genetics/metabolism ; }, abstract = {OBJECTIVE: Innate immune response and particularly terminal complement complex (TCC) deposition are thought to be involved in the pathogenesis of posttraumatic osteoarthritis. However, the possible role of TCC in regulated cell death as well as chondrocyte hypertrophy and senescence has not been unraveled so far and was first addressed using an ex vivo human cartilage trauma-model.<br><br>DESIGN: Cartilage explants were subjected to blunt impact (0.59&#xa0;J) and exposed to human serum (HS) and cartilage homogenate (HG) with or without different potential therapeutics: RIPK1-inhibitor Necrostatin-1 (Nec), caspase-inhibitor zVAD, antioxidant N-acetyl cysteine (NAC) and TCC-inhibitors aurintricarboxylic acid (ATA) and clusterin (CLU). Cell death and hypertrophy/senescence-associated markers were evaluated on mRNA and protein level.<br><br>RESULTS: Addition of HS resulted in significantly enhanced TCC deposition on chondrocytes and decrease of cell viability after trauma. This effect was potentiated by HG and was associated with expression of RIPK3, MLKL and CASP8. Cytotoxicity of HS could be prevented by heat-inactivation or specific inhibitors, whereby combination of Nec and zVAD as well as ATA exhibited highest cell protection. Moreover, HS+HG exposition enhanced the gene expression of CXCL1, IL-8, RUNX2 and VEGFA as well as secretion of IL-6 after cartilage trauma.<br><br>CONCLUSIONS: Our findings imply crucial involvement of the complement system and primarily TCC in regulated cell death and phenotypic changes of chondrocytes after cartilage trauma. Inhibition of TCC formation or downstream signaling largely modified serum-induced pathophysiologic effects and might therefore represent a therapeutic target to maintain the survival and chondrogenic character of cartilage cells.}, }
@article {pmid31978215, year = {2020}, author = {Craver, BM and Ramanathan, G and Hoang, S and Chang, X and Mendez Luque, LF and Brooks, S and Lai, HY and Fleischman, AG}, title = {N-acetylcysteine inhibits thrombosis in a murine model of myeloproliferative neoplasm.}, journal = {Blood advances}, volume = {4}, number = {2}, pages = {312-321}, pmid = {31978215}, issn = {2473-9537}, support = {T32 CA009054/CA/NCI NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Humans ; Male ; Mice ; Myeloproliferative Disorders/*drug therapy ; Thrombosis/*drug therapy ; }, abstract = {Thrombosis is a major cause of mortality in patients with myeloproliferative neoplasms (MPNs), though there is currently little to offer patients with MPN beyond aspirin and cytoreductive therapies such as hydroxyurea for primary prevention. Thrombogenesis in MPN involves multiple cellular mechanisms, including platelet activation and neutrophil-extracellular trap formation; therefore, an antithrombotic agent that targets one or more of these processes would be of therapeutic benefit in MPN. Here, we treated the JAK2V617F knockin mouse model of polycythemia vera with N-acetylcysteine (NAC), a sulfhydryl-containing compound with broad effects on glutathione replenishment, free radical scavenging, and reducing disulfide bonds, to investigate its antithrombotic effects in the context of MPN. Strikingly, NAC treatment extended the lifespan of JAK2V617F mice without impacting blood counts or splenomegaly. Using an acute pulmonary thrombosis model in vivo, we found that NAC reduced thrombus formation to a similar extent as the irreversible platelet inhibitor aspirin. In vitro analysis of platelet activation revealed that NAC reduced thrombin-induced platelet-leukocyte aggregate formation in JAK2V617F mice. Furthermore, NAC reduced neutrophil extracellular trap formation in primary human neutrophils from patients with MPN as well as healthy controls. These results provide evidence that N-acetylcysteine inhibits thrombosis in JAK2V617F mice and provide a pre-clinical rationale for investigating NAC as a therapeutic to reduce thrombotic risk in MPN.}, }
@article {pmid31975626, year = {2020}, author = {Sampilvanjil, A and Karasawa, T and Yamada, N and Komada, T and Higashi, T and Baatarjav, C and Watanabe, S and Kamata, R and Ohno, N and Takahashi, M}, title = {Cigarette smoke extract induces ferroptosis in vascular smooth muscle cells.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {318}, number = {3}, pages = {H508-H518}, doi = {10.1152/ajpheart.00559.2019}, pmid = {31975626}, issn = {1522-1539}, mesh = {Animals ; Cell Death/drug effects ; Cell Line ; Cyclohexylamines/pharmacology ; Deferoxamine/pharmacology ; Endothelial Cells/drug effects/metabolism ; Ferroptosis/*drug effects ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Muscle, Smooth, Vascular/*metabolism ; Myocytes, Smooth Muscle/drug effects/*metabolism ; NADPH Oxidases/metabolism ; Phenylenediamines/pharmacology ; Quinoxalines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Siderophores/pharmacology ; *Smoke ; Spiro Compounds/pharmacology ; Tissue Inhibitor of Metalloproteinase-1/metabolism ; }, abstract = {Cigarette smoking is a major risk factor for aortic aneurysm and dissection; however, no causative link between smoking and these aortic disorders has been proven. In the present study, we investigated the mechanism by which cigarette smoke affects vascular wall cells and found that cigarette smoke extract (CSE) induced a novel form of regulated cell death termed ferroptosis in vascular smooth muscle cells (VSMCs). CSE markedly induced cell death in A7r5 cells and primary rat VSMCs, but not in endothelial cells, which was completely inhibited by specific ferroptosis inhibitors [ferrostatin-1 (Fer-1) and Liproxstatin-1] and an iron chelator (deferoxamine). CSE-induced VSMC death was partially inhibited by a GSH precursor (N-acetyl cysteine) and an NADPH oxidase inhibitor [diphenyleneiodonium chloride (DPI)], but not by inhibitors of pan-caspases (Z-VAD), caspase-1 (Z-YVAD), or necroptosis (necrostatin-1). CSE also upregulated IL-1β, IL-6, TNF-α, matrix metalloproteinase (MMP)-2, MMP-9, and TIMP-1 (tissue inhibitor of metalloproteinase)in A7r5 cells, which was inhibited by Fer-1. Furthermore, CSE induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. VSMC ferroptosis was induced by acrolein and methyl vinyl ketone, major constituents of CSE. Furthermore, CSE caused medial VSMC loss in ex vivo aortas. Electron microscopy analysis showed mitochondrial damage and fragmentation in medial VSMCs of CSE-treated aortas. All of these manifestations were partially restored by Fer-1. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death and suggest that ferroptosis is a potential therapeutic target for preventing aortic aneurysm and dissection.NEW &amp; NOTEWORTHY Cigarette smoke extract (CSE)-induced cell death in rat vascular smooth muscle cells (VSMCs) was completely inhibited by specific ferroptosis inhibitors and an iron chelator. CSE also induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. CSE caused medial VSMC loss in ex vivo aortas. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death.}, }
@article {pmid31967638, year = {2019}, author = {Zhu, J and Wu, F and Yue, S and Chen, C and Song, S and Wang, H and Zhao, M}, title = {Functions of reactive oxygen species in apoptosis and ganoderic acid biosynthesis in Ganoderma lucidum.}, journal = {FEMS microbiology letters}, volume = {366}, number = {23}, pages = {}, doi = {10.1093/femsle/fnaa015}, pmid = {31967638}, issn = {1574-6968}, mesh = {Apoptosis/*physiology ; Fungal Proteins/genetics ; Gene Silencing ; In Situ Nick-End Labeling ; Reactive Oxygen Species/*metabolism ; Reishi/cytology/*physiology ; Triterpenes/*metabolism ; }, abstract = {Ganoderma lucidum is a medicinal fungus that is widely used in traditional medicine. Fungal PacC is recognized as an important transcription factor that functions during adaptation to environmental pH, fungal development and secondary metabolism. Previous studies have revealed that GlPacC plays important roles in mycelial growth, fruiting body development and ganoderic acid (GA) biosynthesis. In this study, using a terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay, we found that the apoptosis level was increased when PacC was silenced. The transcript and activity levels of caspase-like proteins were significantly increased in the PacC-silenced (PacCi) strains compared with the control strains. Silencing PacC also resulted in an increased reactive oxygen species (ROS) levels (∼2-fold) and decreased activity levels of enzymes involved in the antioxidant system. Further, we found that the intracellular ROS levels contributed to apoptosis and GA biosynthesis. Adding N-acetyl-cysteine and vitamin C decreased intracellular ROS and resulted in the inhibition of apoptosis in the PacCi strains. Additionally, the GA biosynthesis was different between the control strains and the PacCi strains after intracellular ROS was eliminated. Taken together, the findings showed that silencing PacC can result in an intracellular ROS burst, which increases cell apoptosis and GA biosynthesis levels. Our study provides novel insight into the functions of PacC in filamentous fungi.}, }
@article {pmid31964279, year = {2020}, author = {Jongthun, R and Hemachudha, P and Wacharapluesadee, S and Hemachudha, T}, title = {Low-cost management of mushroom poisoning in a limited-resource area: a 12-year retrospective study.}, journal = {Tropical doctor}, volume = {50}, number = {2}, pages = {135-138}, doi = {10.1177/0049475519897704}, pmid = {31964279}, issn = {1758-1133}, mesh = {Acetylcysteine/therapeutic use ; Amanitins/poisoning ; Female ; Gastroenteritis/diagnosis/etiology/therapy ; Humans ; Male ; Mushroom Poisoning/*diagnosis/etiology/*therapy ; Retrospective Studies ; Thailand/epidemiology ; Treatment Outcome ; }, abstract = {Amatoxin poisoning is the main cause of death from accidental ingestion of poisonous mushrooms and a mortality rate of 27.3% has been reported in Thailand. Symptoms of mushroom ingestion are often confused with food poisoning; thus, gastroenteritis is not recognised as the first phase of poisoning. Our study assessed the efficacy of N-acetylcysteine (NAC) as a treatment for amatoxin poisoning. We retrospectively analysed 74 medical records over 12 years. The majority (70/74) were treated successfully with NAC; death in the remaining 4 (5.4%) patients was attributed to late presentation in three and advanced alcoholic cirrhosis in one.}, }
@article {pmid31963881, year = {2020}, author = {Akter, M and Jangra, A and Choi, SA and Choi, EH and Han, I}, title = {Non-Thermal Atmospheric Pressure Bio-Compatible Plasma Stimulates Apoptosis via p38/MAPK Mechanism in U87 Malignant Glioblastoma.}, journal = {Cancers}, volume = {12}, number = {1}, pages = {}, pmid = {31963881}, issn = {2072-6694}, support = {NRF- 2016K1A4A3914113//Ministry of Science, ICT and Future Planning/ ; 2019R1H1A2101686//Ministry of Science ICT/ ; }, abstract = {Nonthermal plasma is a promising novel therapy for the alteration of biological and clinical functions of cells and tissues, including apoptosis and inhibition of tumor progression. This therapy generates reactive oxygen and nitrogen species (RONS), which play a major role in anticancer effects. Previous research has verified that plasma jets can selectively induce apoptosis in various cancer cells, suggesting that it could be a potentially effective novel therapy in combination with or as an alternative to conventional therapeutic methods. In this study, we determined the effects of nonthermal air soft plasma jets on a U87 MG brain cancer cell line, including the dose- and time-dependent effects and the physicochemical and biological correlation between the RONS cascade and p38/mitogen-activated protein kinase (MAPK) signaling pathway, which contribute to apoptosis. The results indicated that soft plasma jets efficiently inhibit cell proliferation and induce apoptosis in U87 MG cells but have minimal effects on astrocytes. These findings revealed that soft plasma jets produce a potent cytotoxic effect via the initiation of cell cycle arrest and apoptosis. The production of reactive oxygen species (ROS) in cells was tested, and an intracellular ROS scavenger, N-acetyl cysteine (NAC), was examined. Our results suggested that soft plasma jets could potentially be used as an effective approach for anticancer therapy.}, }
@article {pmid31963523, year = {2020}, author = {Lee, JH and Subedi, L and Kim, SY}, title = {Effect of Cysteine on Methylglyoxal-Induced Renal Damage in Mesangial Cells.}, journal = {Cells}, volume = {9}, number = {1}, pages = {}, pmid = {31963523}, issn = {2073-4409}, mesh = {Acetylcysteine/chemistry/metabolism/pharmacology ; Animals ; Apoptosis/drug effects/genetics ; Cell Line ; Cell Survival/drug effects ; Cysteine/chemistry/metabolism/*pharmacology ; Guanidines/pharmacology ; Humans ; L-Lactate Dehydrogenase/metabolism ; Lactic Acid/metabolism ; Lactoylglutathione Lyase/metabolism ; MAP Kinase Signaling System/drug effects/genetics ; Mesangial Cells/cytology/*drug effects ; Mice ; Pyruvaldehyde/metabolism/*toxicity ; Reactive Oxygen Species/metabolism ; Sirtuin 1/metabolism ; }, abstract = {Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a key precursor of the formation of advanced glycation end products (AGEs). MGO and MGO-AGEs were reportedly increased in patients with diabetic dysfunction, including diabetic nephropathy. The activation of glyoxalase-I (GLO-I) increases MGO and MGO-AGE detoxification. MGO-mediated glucotoxicity can also be ameliorated by MGO scavengers such as N-acetylcysteine (NAC), aminoguanidine (AG), and metformin. In this study, we noted that l-cysteine demonstrated protective effects against MGO-induced glucotoxicity in renal mesangial cells. l-cysteine prevented MGO-induced apoptosis and necrosis, together with a reduction of reactive oxygen species (ROS) production in MES13 cells. Interestingly, l-cysteine significantly reduced MGO-AGE formation and also acted as an MGO-AGE crosslink breaker. Furthermore, l-cysteine treatment accelerated MGO catabolism to D-lactate via the upregulation of GLO-I. The reduction of AGE formation and induction of AGE breakdown, following l-cysteine treatment, further supports the potential use of l-cysteine as an alternative for the therapeutic control of MGO-induced renal complications in diabetes, especially against diabetic nephropathy.}, }
@article {pmid31962155, year = {2020}, author = {Ågren, L and Elfsmark, L and Akfur, C and Hägglund, L and Ekstrand-Hammarström, B and Jonasson, S}, title = {N-acetyl cysteine protects against chlorine-induced tissue damage in an ex vivo model.}, journal = {Toxicology letters}, volume = {322}, number = {}, pages = {58-65}, doi = {10.1016/j.toxlet.2020.01.006}, pmid = {31962155}, issn = {1879-3169}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Chemokine CXCL1/metabolism ; Chlorine/*toxicity ; Cytoprotection ; Dose-Response Relationship, Drug ; Female ; In Vitro Techniques ; Inflammation Mediators/*metabolism ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Lung/*drug effects/metabolism/pathology/physiopathology ; Lung Injury/chemically induced/metabolism/pathology/*prevention &amp; control ; Rats, Sprague-Dawley ; }, abstract = {High-level concentrations of chlorine (Cl2) can cause life-threatening lung injuries and the objective in this study was to understand the pathogenesis of short-term sequelae of Cl2-induced lung injury and to evaluate whether pre-treatment with the antioxidant N-acetyl cysteine (NAC) could counteract these injuries using Cl2-exposed precision-cut lung slices (PCLS). The lungs of Sprague-Dawley rats were filled with agarose solution and cut into 250 μm-thick slices that were exposed to Cl2 (20-600 ppm) and incubated for 30 min. The tissue slices were pre-treated with NAC (5-25 mM) before exposure to Cl2. Toxicological responses were analyzed after 5 h by measurement of LDH, WST-1 and inflammatory mediators (IL-1β, IL-6 and CINC-1) in medium or lung tissue homogenate. Exposure to Cl2 induced a concentration-dependent cytotoxicity (LDH/WST-1) and IL-1β release in medium. Similar cytokine response was detected in tissue homogenate. Contraction of larger airways was measured using electric-field-stimulation method, 200 ppm and control slices had similar contraction level (39 ± 5%) but in the 400 ppm Cl2 group, the evoked contraction was smaller (7 ± 3%) possibly due to tissue damage. NAC-treatment improved cell viability and reduced tissue damage and the contraction was similar to control levels (50 ± 11%) in the NAC treated Cl2-exposed slices. In conclusion, Cl2 induced a concentration-dependent lung tissue damage that was effectively prevented with pre-treatment with NAC. There is a great need to improve the medical treatment of acute lung injury and this PCLS method offers a way to identify and to test new concepts of treatment of Cl2-induced lung injuries.}, }
@article {pmid31959867, year = {2020}, author = {Chen, H and Chen, H and Liang, J and Gu, X and Zhou, J and Xie, C and Lv, X and Wang, R and Li, Q and Mao, Z and Sun, H and Zuo, G and Miao, D and Jin, J}, title = {TGF-β1/IL-11/MEK/ERK signaling mediates senescence-associated pulmonary fibrosis in a stress-induced premature senescence model of Bmi-1 deficiency.}, journal = {Experimental &amp; molecular medicine}, volume = {52}, number = {1}, pages = {130-151}, pmid = {31959867}, issn = {2092-6413}, mesh = {Animals ; Cells, Cultured ; Cellular Senescence/*physiology ; DNA Damage/physiology ; Disease Models, Animal ; Fibroblasts/metabolism/pathology ; Fibrosis/*metabolism/pathology ; Humans ; Interleukin-11/metabolism ; Lung/*metabolism/pathology ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Oxidative Stress/physiology ; Polycomb Repressive Complex 1/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Proto-Oncogene Proteins/*metabolism ; Signal Transduction/*physiology ; Transforming Growth Factor beta1/metabolism ; Ubiquitin/metabolism ; }, abstract = {To study whether TGF-β1/IL-11/MEK/ERK (TIME) signaling mediates senescence-associated pulmonary fibrosis (SAPF) in Bmi-1-deficient (Bmi-1[-/-]) mice and determines the major downstream mediator of Bmi-1 and crosstalk between p16[INK4a] and reactive oxygen species that regulates SAPF, phenotypes were compared among 7-week-old p16[INK4a] and Bmi-1 double-knockout, N-acetylcysteine (NAC)-treated Bmi-1[-/-], Bmi-1[-/-], and wild-type mice. Pulmonary fibroblasts and alveolar type II epithelial (AT2) cells were used for experiments. Human pulmonary tissues were tested for type Ι collagen, α-smooth muscle actin (α-SMA), p16[INK4a], p53, p21, and TIME signaling by using enzyme-linked immunosorbent assay (ELISA). Our results demonstrated that Bmi-1 deficiency resulted in a shortened lifespan, ventilatory resistance, poor ventilatory compliance, and SAPF, including cell senescence, DNA damage, a senescence-associated secretory phenotype and collagen overdeposition that was mediated by the upregulation of TIME signaling. The signaling stimulated cell senescence, senescence-related secretion of TGF-β1 and IL-11 and production of collagen 1 by pulmonary fibroblasts and the epithelial-to-mesenchymal transition of AT2 cells. These processes were inhibited by anti-IL-11 or the MEK inhibitor PD98059. NAC treatment prolonged the lifespan and ameliorated pulmonary dysfunction and SAPF by downregulating TIME signaling more than p16[INK4a] deletion by inhibiting oxidative stress and DNA damage and promoting ubiquitin-proteasome degradation of p16[INK4a] and p53. Cytoplasmic p16[INK4a] accumulation upregulated MEK/ERK signaling by inhibiting the translocation of pERK1/2 (Thr202/Tyr204) from the cytoplasm to the nucleus in senescent fibroblasts. The accumulation of collagen 1 and α-SMA in human lungs accompanied by cell senescence may be mediated by TIME signaling. Thus, this signaling in aging fibroblasts or AT2 cells could be a therapeutic target for preventing SAPF.}, }
@article {pmid31955671, year = {2020}, author = {Albertson, TE and Chenoweth, JA and Pearson, SJ and Murin, S}, title = {The pharmacological management of asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS).}, journal = {Expert opinion on pharmacotherapy}, volume = {21}, number = {2}, pages = {213-231}, doi = {10.1080/14656566.2019.1701656}, pmid = {31955671}, issn = {1744-7666}, mesh = {Administration, Inhalation ; Adrenal Cortex Hormones/therapeutic use ; Adrenergic beta-2 Receptor Agonists/therapeutic use ; Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome/*drug therapy ; Bronchodilator Agents/*therapeutic use ; Forced Expiratory Volume ; Humans ; Muscarinic Antagonists/therapeutic use ; Nebulizers and Vaporizers ; Vital Capacity ; }, abstract = {Introduction: Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is a disease phenotype that shares T helper lymphocyte cell Th1/neutrophilic/non-Type-2 Inflammation pathways thought to be key in COPD and Th2/eosinophilic/Type-2 inflammatory pathways of asthma. The pharmacology of treating ACOS is challenging in severe circumstances.Areas covered: This review evaluates the stepwise treatment of ACOS using pharmacological treatments used in both COPD and asthma. The most common medications involve the same inhalers used to treat COPD and asthma patients. Advanced stepwise therapies for ACOS patients are based on patient characteristics and biomarkers. Very few clinical trials exist that focus specifically on ACOS patients.Expert opinion: After inhalers, advanced therapies including phosphodiesterase inhibitors, macrolides, N-acetylcysteine and statin therapy for those ACOS patients with a COPD appearance and exacerbations are available. In atopic ACOS patients with exacerbations, advanced asthma therapies (leukotriene receptor antagonists and synthesis blocking agents.) are used. ACOS patients with elevated blood eosinophil/IgE levels are considered for immunotherapy or therapeutic monoclonal antibodies blocking specific Th2/Type-2 interleukins or IgE. Symptom control, stabilization/improvement in pulmonary function and reduced exacerbations are the metrics of success. More pharmacological trials of ACOS patients are needed to better understand which patients benefit from specific treatments.Abbreviations: 5-LOi: 5-lipoxygenase inhibitor; ACOS: asthma - COPD overlap syndrome; B2AR: Beta2 adrenergic receptors; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; CI: confidence interval; COPD: chronic obstructive pulmonary disease; CRS : chronic rhinosinusitis; cys-LT: cysteinyl leukotrienes; DPI: dry powder inhaler; EMA: European Medicines Agency; FDA: US Food and Drug Administration; FDC: fixed-dose combination; FeNO: exhaled nitric oxide; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; GM-CSF: granulocyte-macrophage colony-stimulating factor; ICS : inhaled corticosteroids; IL: interleukin; ILC2: Type 2 innate lymphoid cells; IP3: Inositol triphosphate; IRR: incidence rate ratio; KOLD: Korean Obstructive Lung Disease; LABA: long-acting B2 adrenergic receptor agonist; LAMA: long-acting muscarinic receptor antagonist; LRA: leukotriene receptor antagonist; LT: leukotrienes; MDI: metered-dose inhalers; MN: M-subtype muscarinic receptors; MRA: muscarinic receptor antagonist; NAC: N-acetylcysteine; NEB: nebulization; OR: odds ratio; PDE: phosphodiesterase; PEFR: peak expiratory flow rate; PGD2: prostaglandin D2; PRN: as needed; RR: risk ratio; SABA: short-acting B2 adrenergic receptor agonist; SAMA: short-acting muscarinic receptor antagonist; SDMI: spring-driven mist inhaler; Th1: T helper cell 1 lymphocyte; Th2: T helper cell 2 lymphocytes; TNF-α: tumor necrosis factor alpha; US : United States.}, }
@article {pmid31955440, year = {2020}, author = {Millington, KR and Marsh, JM}, title = {UV damage to hair and the effect of antioxidants and metal chelators.}, journal = {International journal of cosmetic science}, volume = {42}, number = {2}, pages = {174-184}, doi = {10.1111/ics.12601}, pmid = {31955440}, issn = {1468-2494}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Chelating Agents/*pharmacology ; Electron Spin Resonance Spectroscopy ; Fluorescent Dyes/chemistry ; Free Radicals/chemistry ; Hair/*drug effects/*radiation effects ; Hair Color ; Humans ; Metals/*chemistry ; *Ultraviolet Rays ; }, abstract = {OBJECTIVE: To study the effects of addition of a redox metal, copper, antioxidants and metal chelators on the formation of free radicals in natural white Caucasian hair subsequently exposed to UV light. Three different methods, electron paramagnetic resonance (EPR), a fluorescent probe for hydroxyl radical formation (terephthalate) and free radical photoyellowing, were used. These methods utilized different UV sources and reaction conditions, and so can give insights into the different mechanisms of action occurring during UV oxidation of hair. In addition, this study demonstrates how antioxidants and chelators can be screened to determine whether they can protect hair from UV damage.<br><br>RESULTS: The three methods gave somewhat different results, illustrating the importance of reaction conditions and wavelength on the photochemical mechanisms, and the efficacy of additives to influence these reactions. EPR results showed that N-acetylcysteine (NAC) pre-treatment eliminated the intensity of the signal because of sulphur and carbon free radicals in white hair both before and after exposure to UVB radiation. Doping the hair with copper ions had no effect on the intensity of the EPR signal under dry conditions. Terephthalate fluorescent probe data showed that under wet conditions, irradiation of white hair with UVA produced significant amounts of hydroxyl radicals. Pre-treatment of hair with NAC reduced the number of &#x2022;OH radicals produced by natural white hair compared to an untreated control. In contrast to the EPR result, white hair doped with copper ions produced significantly higher levels of &#x2022;OH radicals under wet conditions. It appears that the ability of copper ions to catalyse the photogeneration free radicals in hair is highly dependent on water content. Photoyellowing data showed a benefit for oxalic acid but no difference for NAC and an increase in yellowing for EDTA.<br><br>CONCLUSION: The micro-EPR and terephthalate fluorescent probe methods are both effective techniques to study production of free radicals by hair exposed to UV light under wet and dry conditions, respectively. Both assays are simple methods for determining the effectiveness of potential protective hair treatments against UV damage, but because they assess free radical damage under dry vs wet conditions, the chemistry created on UV exposure is different. This gives insights into mechanism of action, but results may not be consistent between the two methods for actives added for reduction of UV damage. NAC pre-treatment did reduce free radical generation in UV-exposed hair under both wet and dry conditions. Photoyellowing data are more complicated as it is a less direct measure of UV damage and is highly dependent on irradiation source. Using UVB irradiation is experimentally convenient but may not be appropriate, because UVB wavelengths comprise only 0.3% of terrestrial sunlight. The photochemistry of hair exposed to sunlight involves concurrent photobleaching and photoyellowing processes and is far more complex. Under UVB irradiation conditions, oxalic acid showed a yellowing benefit.}, }
@article {pmid31952904, year = {2020}, author = {Eghtedardoost, M and Ghazanfari, T and Sadeghipour, A and Hassan, ZM and Ghanei, M and Ghavami, S}, title = {Delayed effects of sulfur mustard on autophagy suppression in chemically-injured lung tissue.}, journal = {International immunopharmacology}, volume = {80}, number = {}, pages = {105896}, doi = {10.1016/j.intimp.2019.105896}, pmid = {31952904}, issn = {1878-1705}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Adult ; Albuterol/pharmacology/therapeutic use ; Armed Conflicts ; Autophagy/*drug effects ; Beclin-1/metabolism ; Case-Control Studies ; Chemical Warfare Agents/*toxicity ; Down-Regulation/drug effects/immunology ; Female ; Humans ; Iran ; Lung/immunology/pathology ; Lung Injury/chemically induced/drug therapy/*immunology/pathology ; Male ; Microtubule-Associated Proteins/metabolism ; Middle Aged ; Military Personnel ; Mustard Gas/*toxicity ; Oxidative Stress/drug effects/immunology ; Time Factors ; }, abstract = {BACKGROUND: Autophagy is an intracellular hemostasis mechanism, responding to extracellular or intracellular stresses. Sulfur mustard (SM) induces cellular stress. Iranian soldiers exposed to SM gas, during the Iraq-Iran war, suffer from delayed complications even 30 years after exposure. In this study, for exploring the SM effect on autophagy pathway, gene and protein expression of autophagy markers are evaluated in the lung of SM-exposed people.<br><br>METHODS: 52 FFPE lung tissues of SM-exposed people and 33 lung paraffin blocks of non-exposed patients to SM were selected. LC3 and Beclin-1 mRNA expressions were evaluated by QRT-PCR. LC3-B protein and LC3II/LC3I proteins ratio were detected by Immunohistochemistry and immunoblotting method. The collected data were analyzed in SPSS, and P value&#x202f;&#x2264;&#x202f;0.05 was considered significant.<br><br>RESULTS: LC3 gene expression in SM-exposed subjects (median CT value&#x202f;=&#x202f;4.97) increased about 4 fold compared with the control group (median CT value&#x202f;=&#x202f;0.46, P&#x202f;=&#x202f;0.025). Beclin-1 mRNA expression had not significant difference between two groups. After adjusting the confounding variables such as drug usage, LC3-B protein (P&#x202f;=&#x202f;0.041) and LC3II/LC3I ratio (P&#x202f;=&#x202f;0.044) were found significantly lower in the lung cells of SM-exposed group.<br><br>CONCLUSION: Upon exposure to SM gas, the lung cells are affected by acute cellular stress such as oxidative stress. The study results show that LC3 mRNA level increases in these patients, but, surprisingly, LC3-B protein via unknown mechanism has been down-regulated. N-acetyl cysteine and salbutamol drugs could induce the autophagy, and help to reduce the SM effects and improve the clinical condition of SM-injured patients.}, }
@article {pmid31950131, year = {2020}, author = {Lim, J and Ali, S and Liao, LS and Nguyen, ES and Ortiz, L and Reshel, S and Luderer, U}, title = {Antioxidant supplementation partially rescues accelerated ovarian follicle loss, but not oocyte quality, of glutathione-deficient mice†.}, journal = {Biology of reproduction}, volume = {102}, number = {5}, pages = {1065-1079}, pmid = {31950131}, issn = {1529-7268}, support = {R01 ES020454/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Diet ; Dietary Supplements ; Estrous Cycle ; Female ; Genotype ; Glutamate-Cysteine Ligase/genetics/*metabolism ; Glutathione/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Knockout ; Oocytes ; Ovarian Follicle/*physiology ; Thioctic Acid/administration &amp; dosage/*pharmacology ; }, abstract = {The tripeptide thiol antioxidant glutathione (GSH) has multiple physiological functions. Female mice lacking the modifier subunit of glutamate cysteine ligase (GCLM), the rate-limiting enzyme in GSH synthesis, have decreased GSH concentrations, ovarian oxidative stress, preimplantation embryonic mortality, and accelerated age-related decline in ovarian follicles. We hypothesized that supplementation with thiol antioxidants, N-acetyl cysteine (NAC), or α-lipoic acid (ALA) will rescue this phenotype. Gclm-/- and Gclm+/+ females received 0 or 80 mM NAC in drinking water from postnatal day (PND) 21-30; follicle growth was induced with equine chorionic gonadotropin (eCG) on PND 27, followed by an ovulatory dose of human CG and mating with a wild type male on PND 29 and zygote harvest 20 h after hCG. N-acetyl cysteine supplementation failed to rescue the low rate of second pronucleus formation in zygotes from Gclm-/- versus Gclm+/+ females. In the second study, Gclm-/- and Gclm+/+ females received diet containing 0, 150, or 600 mg/kg ALA beginning at weaning and were mated with wild type males from 8 to 20 weeks of age. α-Lipoic acid failed to rescue the decreased offspring production of Gclm-/- females. However, 150 mg/kg diet ALA partially rescued the accelerated decline in primordial follicles, as well as the increased recruitment of follicles into the growing pool and the increased percentages of follicles with γH2AX positive oocytes or granulosa cells of Gclm-/- females. We conclude that ovarian oxidative stress is the cause of accelerated primordial follicle decline, while GSH deficiency per se may be responsible for preimplantation embryonic mortality in Gclm-/- females.}, }
@article {pmid31948545, year = {2020}, author = {Pilipow, K and Scamardella, E and Lugli, E}, title = {Generating stem-like memory T cells with antioxidants for adoptive cell transfer immunotherapy of cancer.}, journal = {Methods in enzymology}, volume = {631}, number = {}, pages = {137-158}, doi = {10.1016/bs.mie.2019.08.016}, pmid = {31948545}, issn = {1557-7988}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; CD8-Positive T-Lymphocytes/drug effects/*immunology/metabolism ; Cytotoxicity Tests, Immunologic/*methods ; Humans ; *Immunologic Memory ; Immunotherapy, Adoptive/*methods ; Neoplasms/*therapy ; Stem Cells ; }, abstract = {Among the multiple factors that are responsible for the success of adoptive cell transfer (ACT) immunotherapy for cancer, the differentiation status of the in vitro expanded T cell product at the time of transfer seems to play a major role. In particular, less differentiated memory CD8[+] T cells endowed with self-renewing capacity and multipotency exert the most potent antitumor activity. To this aim, expansion protocols that generate sufficient numbers of tumor-specific CD8[+] T cells with superior capacity to persist in vivo following ACT are needed. We describe a procedure for the differentiation of TCF-1[+] stem-like CD8[+] memory T cells from peripheral blood naïve precursors that takes advantage of the use of antioxidants, in particular N-acetylcysteine (NAC), in combination with T cell receptor stimulation and proinflammatory cytokines. We additionally describe how to conduct in vitro assays to test the stem-like features of the generated cells at the phenotypic, functional and metabolic level. Balancing the oxidative metabolism by the addition of antioxidants during in vitro manipulation of CD8[+] T cells results in the generation of cell products with potent antitumor characteristics following ACT.}, }
@article {pmid31945496, year = {2020}, author = {Tyagi, M and Bauri, AK and Chattopadhyay, S and Patro, BS}, title = {Thiol antioxidants sensitize malabaricone C induced cancer cell death via reprogramming redox sensitive p53 and NF-κB proteins in vitro and in vivo.}, journal = {Free radical biology &amp; medicine}, volume = {148}, number = {}, pages = {182-199}, doi = {10.1016/j.freeradbiomed.2020.01.011}, pmid = {31945496}, issn = {1873-4596}, mesh = {Animals ; *Antioxidants/pharmacology ; Apoptosis ; Cell Death ; Humans ; Mice ; NF-kappa B/genetics ; *Neoplasms ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Resorcinols ; Sulfhydryl Compounds ; Tumor Suppressor Protein p53/genetics ; }, abstract = {Specific focus on "redox cancer therapy" by targeting drugs to redox homeostasis of the cancer cells is growing rapidly. Recent clinical studies showed that N-acetyl cysteine (NAC) treatment significantly decreased the metabolic heterogeneity and reduced Ki67 (a proliferation marker) with simultaneous enhancement in apoptosis of tumor cells in patients. However, it is not yet precisely known how thiol antioxidants enhance killing of cancer cells in a context dependent manner. To this end, we showed that a dietary compound, malabaricone C (mal C) generated copious amounts of reactive oxygen species (ROS) and also reduced GSH level in lung cancer cells. Paradoxically, although antioxidants supplementation reduced mal C-induced ROS, thiol-antioxidants (NAC/GSH) restored intracellular GSH level but enhanced DNA DSBs and apoptotic cell death induced by mal C. Our results unraveled two tightly coupled biochemical mechanisms attributing this sensitization process by thiol antioxidants. Firstly, thiol antioxidants enable the "catechol-quinone redox cycle" of mal C and ameliorate ROS generation and bio-molecular damage (DNA and protein). Secondly, thiol antioxidants cause rapid glutathionylation of transcription factors [p53, p65 (NF-κB) etc.], oxidized by mal C, and abrogates their nuclear sequestration and transcription of the anti-apoptotic genes. Furthermore, analyses of the mitochondrial fractions of p53 expressing and silenced cells revealed that cytoplasmic accumulation of glutathionylated p53 (p53-SSG) triggers a robust mitochondrial death process. Interestingly, mutation of redox sensitive cysteine residues at 124, 141 and 182 position in p53 significantly reduces mal C plus NAC mediated sensitization of cancer cells. The preclinical results, in two different tumor models in mice, provides further support our conclusion that NAC is able to sensitize mal C induced suppression of tumor growth in vivo.}, }
@article {pmid31943177, year = {2020}, author = {Chen, A and Jiang, P and Zeb, F and Wu, X and Xu, C and Chen, L and Feng, Q}, title = {EGCG regulates CTR1 expression through its pro-oxidative property in non-small-cell lung cancer cells.}, journal = {Journal of cellular physiology}, volume = {235}, number = {11}, pages = {7970-7981}, doi = {10.1002/jcp.29451}, pmid = {31943177}, issn = {1097-4652}, mesh = {Animals ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line, Tumor ; Cisplatin/pharmacology ; Copper Transporter 1/*genetics ; Female ; Humans ; MAP Kinase Signaling System/drug effects ; Mice ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; RNA, Long Noncoding/*genetics ; Reactive Oxygen Species/metabolism ; Tea/chemistry ; Xenograft Model Antitumor Assays ; }, abstract = {Copper transporter 1 (CTR1) plays an important role in increasing cisplatin intake. Our previous studies showed that CTR1 expression was upregulated by (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol, therefore enhanced cisplatin sensitivity in ovary cancer and non-small-cell lung cancer (NSCLC) cells. In the current study in the non-small-cell lung cancer cells, we uncovered a potential mechanism of EGCG-induced CTR1 through its pro-oxidative property. We found that EGCG increased reactive oxygen species (ROS) generation, while in the presence of ROS scavenger N-acetyl-cysteine (NAC), ROS production was eliminated. Changes of CTR1 expression were consistent with the ROS level. Simultaneously, EGCG downregulated ERK1/2 while upregulated lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) through ROS to induce CTR1 expression. Besides, in a nude mouse xenografts model, EGCG treatment raised ROS level, expression of CTR1 and NEAT1 in tumor tissue. Also, ERK1/2 and p-ERK1/2 were suppressed as well. Taken together, these results suggested a novel mechanism that EGCG mediated ROS to regulate CTR1 expression through the ERK1/2/NEAT1 signaling pathway, which provided more possibilities for EGCG as a natural agent in adjuvant therapy of lung cancer.}, }
@article {pmid31941795, year = {2020}, author = {Todd, JJ and Lawal, TA and Witherspoon, JW and Chrismer, IC and Razaqyar, MS and Punjabi, M and Elliott, JS and Tounkara, F and Kuo, A and Shelton, MO and Allen, C and Cosgrove, MM and Linton, M and Michael, D and Jain, MS and Waite, M and Drinkard, B and Wakim, PG and Dowling, JJ and Bönnemann, CG and Emile-Backer, M and Meilleur, KG}, title = {Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies.}, journal = {Neurology}, volume = {94}, number = {13}, pages = {e1434-e1444}, pmid = {31941795}, issn = {1526-632X}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Child ; Dinoprost/analogs &amp; derivatives/urine ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Muscular Diseases/*drug therapy/genetics/urine ; Oxidative Stress/*drug effects ; Ryanodine Receptor Calcium Release Channel/genetics ; Treatment Outcome ; Walk Test ; Young Adult ; }, abstract = {OBJECTIVE: To investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM).<br><br>METHODS: In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance.<br><br>RESULTS: When compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean &#xb1; SD 3.2 &#xb1; 1.5 vs 1.1 &#xb1; 1.7 ng/mg creatinine and 468 &#xb1; 134 vs 600 &#xb1; 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] -1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI -5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study.<br><br>CONCLUSION: In ambulatory RYR1-RM-affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane.<br><br>CLINICALTRIALSGOV IDENTIFIER: NCT02362425.}, }
@article {pmid31940946, year = {2020}, author = {Khurana, N and Chandra, PK and Kim, H and Abdel-Mageed, AB and Mondal, D and Sikka, SC}, title = {Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {9}, number = {1}, pages = {}, pmid = {31940946}, issn = {2076-3921}, support = {n/a//Tulane University/ ; }, abstract = {Androgen receptor (AR) signaling is fundamental to prostate cancer (PC) progression, and hence, androgen deprivation therapy (ADT) remains a mainstay of treatment. However, augmented AR signaling via both full length AR (AR-FL) and constitutively active AR splice variants, especially AR-V7, is associated with the recurrence of castration resistant prostate cancer (CRPC). Oxidative stress also plays a crucial role in anti-androgen resistance and CRPC outgrowth. We examined whether a triterpenoid antioxidant drug, Bardoxolone-methyl, known as CDDO-Me or RTA 402, can decrease AR-FL and AR-V7 expression in PC cells. Nanomolar (nM) concentrations of CDDO-Me rapidly downregulated AR-FL in LNCaP and C4-2B cells, and both AR-FL and AR-V7 in CWR22Rv1 (22Rv1) cells. The AR-suppressive effect of CDDO-Me was evident at both the mRNA and protein levels. Mechanistically, acute exposure (2 h) to CDDO-Me increased and long-term exposure (24 h) decreased reactive oxygen species (ROS) levels in cells. This was concomitant with an increase in the anti-oxidant transcription factor, Nrf2. The anti-oxidant N-acetyl cysteine (NAC) could overcome this AR-suppressive effect of CDDO-Me. Co-exposure of PC cells to CDDO-Me enhanced the efficacy of a clinically approved anti-androgen, enzalutamide (ENZ), as evident by decreased cell-viability along with migration and colony forming ability of PC cells. Thus, CDDO-Me which is in several late-stage clinical trials, may be used as an adjunct to ADT in PC patients.}, }
@article {pmid31939054, year = {2020}, author = {Wong, A and Heard, K and Graudins, A and Dart, R and Sivilotti, MLA}, title = {Adducts Post Acetaminophen Overdose Treated with a 12-Hour vs 20-Hour Acetylcysteine Infusion.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {16}, number = {2}, pages = {188-194}, pmid = {31939054}, issn = {1937-6995}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Analgesics, Non-Narcotic/blood/*poisoning ; Antidotes/*administration &amp; dosage ; Controlled Clinical Trials as Topic ; Drug Overdose/blood/diagnosis/*drug therapy ; Female ; Humans ; Infusions, Parenteral ; Liver Function Tests ; Male ; Protein Binding ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION: Acetaminophen protein adducts in the circulation are a specific biomarker of acetaminophen oxidation, and may be a more sensitive measure of impending hepatic injury following overdose than alanine transaminase (ALT). We performed an exploratory analytical substudy of adducts during a clinical trial (NACSTOP) of abbreviated (12-hour) versus control (20-hour) acetylcysteine to identify any signal of diminished antidotal effectiveness with shortened therapy.<br><br>METHODS: We measured adducts at 0, 12, and 20&#xa0;hours from a convenience sample of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-hour ("abbreviated"; 200&#xa0;mg/kg over 4&#xa0;hours, 50&#xa0;mg/kg over 8&#xa0;hours) vs 20-hour acetylcysteine regimen ("control"; 200&#xa0;mg/kg over 4&#xa0;hours, 100&#xa0;mg/kg over 16&#xa0;hours). Adducts were assayed using high-performance liquid chromatography/mass spectrometry.<br><br>RESULTS: Median ALT 20&#xa0;hours after the initiation of acetylcysteine was 12&#xa0;U/L (IQR 8,14) in the abbreviated 12-hour regimen group (N&#x2009;=&#x2009;8), compared with the control group 16&#xa0;U/L (IQR 11,21; N&#x2009;=&#x2009;21) (p&#x2009;=&#x2009;0.46). Adduct concentrations were similarly low in both groups: abbreviated [(0.005&#xa0;&#x3bc;mol/L, IQR (0,0.14)] and control [(0.005&#xa0;&#x3bc;mol/L, IQR (0,0.05)] (p&#x2009;=&#x2009;0.61).<br><br>CONCLUSIONS: There were minimal to no acetaminophen protein adducts detected. These findings further support discontinuing acetylcysteine when acetaminophen concentrations are low and liver function tests normal after 12&#xa0;hours of treatment.}, }
@article {pmid31936021, year = {2020}, author = {Matsuo, H and Hanamure, Y and Miyano, R and Takahashi, Y and Ōmura, S and Nakashima, T}, title = {Screening for Sulfur Compounds by Molybdenum-Catalyzed Oxidation Combined with Liquid Chromatography-Mass Spectrometry.}, journal = {Molecules (Basel, Switzerland)}, volume = {25}, number = {2}, pages = {}, pmid = {31936021}, issn = {1420-3049}, support = {2019-3025//The Japan Science Society/ ; JP19K15758//Japan Society for the Promotion of Science/ ; 0352//Kitasato University/ ; }, mesh = {Acetylcysteine/chemistry ; Actinobacteria/chemistry/growth &amp; development/*metabolism ; Catalysis ; Chromatography, Liquid ; Fermentation ; Mass Spectrometry ; Molybdenum/*chemistry ; Oxidation-Reduction ; Sulfides/chemistry ; Sulfones/*chemistry ; Sulfur/chemistry ; Sulfur Compounds/*chemistry ; }, abstract = {The molybdenum (Mo)-catalyzed oxidation of sulfide under neutral conditions yields sulfone. This reaction proceeds more smoothly than olefin epoxidation and primary or secondary alcohol oxidation. In this study, Mo-catalyzed oxidation was used to screen for sulfur compounds (named "MoS-screening") in microbial broths by liquid chromatography-mass spectrometry (LC/MS). To demonstrate proof-of-concept, known sulfur microbial compounds were successfully identified from a mixture of non-sulfur microbial compounds as sulfinyl or sulfonyl products of Mo-catalyzed oxidation. Then our MoS-screening method was used to screen 300 samples of microbial broth for sulfur compounds. One of the identified compounds was a kitasetaline-containing N-acetyl cysteine moiety produced by an actinomycete strain. These results demonstrate the potential of MoS-screening in the search for new sulfur compounds from microbial sources.}, }
@article {pmid31935808, year = {2020}, author = {Won, DH and Park, H and Ha, ES and Kim, YM and Hwang, HD and Jang, SW and Kim, MS}, title = {Effect of Formulation Factors and Oxygen Levels on the Stability of Aqueous Injectable Solution Containing Pemetrexed.}, journal = {Pharmaceutics}, volume = {12}, number = {1}, pages = {}, pmid = {31935808}, issn = {1999-4923}, support = {NRF- 2017R1C1B1006483//National Research Foundation of Korea/ ; }, abstract = {The aim of this study was to investigate the effects of various parameters at each control strategy in drug product degradation on the stability of pemetrexed in injectable aqueous solution. A forced degradation study confirmed that oxidation is the main mechanism responsible for the degradation of pemetrexed in aqueous solutions. As control strategies, the antioxidant levels, drug concentration, pH of the control formulation, dissolved oxygen (DO) levels in the control process, and headspace oxygen levels in the control packaging were varied, and their effects on the stability of pemetrexed were evaluated. Sodium sulfite was found to be particularly effective in preventing the color change, and N-acetylcysteine (NAC) had a significant effect in preventing chemical degradation. The sulfite and NAC were found to stabilize pemetrexed in the aqueous solution by acting as sacrificial reductants. A pH below 6 caused significant degradation. The stability of pemetrexed in the solution increased as the concentration of the drug increased from 12.5 to 50 mg/mL. In addition, the DO levels in the solution were controlled by nitrogen purging, and the oxygen levels in headspace were controlled by nitrogen headspace, which also had significant positive effects in improving the stability of the pemetrexed solution; thus, it was confirmed that molecular oxygen is involved in the rate-limiting oxidation step. Based on these results obtained by observing the effects of various control strategies, the optimal formulation of an injectable solution of pemetrexed is suggested as follows: sodium sulfite at 0.06 mg/mL, as an antioxidant for prevention of color change; NAC at 1.63 mg/mL, as an antioxidant for prevention of chemical degradation; pH range 7-8; DO levels below 1 ppm; and headspace oxygen levels below 1%. In conclusion, it can be suggested that this study, which includes well-designed control strategies, can lead to a better understanding of the complex degradation mechanism of pemetrexed; thus, it can lead to the development of an injectable solution formulation of pemetrexed, with improved stability.}, }
@article {pmid31935745, year = {2020}, author = {Ward, P and Moss, HG and Brown, TR and Kalivas, P and Jenkins, DD}, title = {N-acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats.}, journal = {Pediatric research}, volume = {88}, number = {1}, pages = {77-84}, pmid = {31935745}, issn = {1530-0447}, support = {F31 NS108623/NS/NINDS NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Analgesics, Opioid/*metabolism ; Animals ; Animals, Newborn ; Behavior, Animal ; Central Nervous System/metabolism ; Female ; Glutamic Acid/metabolism ; Glutathione/metabolism ; Magnetic Resonance Spectroscopy ; Maternal Exposure ; Naloxone/pharmacology ; Neonatal Abstinence Syndrome/*drug therapy ; Osmosis ; Oxidative Stress/*drug effects ; Pregnancy ; Pregnancy, Animal ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Neonatal abstinence syndrome (NAS) is a significant problem. Opioid withdrawal induces oxidative stress and disrupts glutamate and glutathione homeostasis. We hypothesized that N-acetylcysteine (NAC) administered during acute opioid withdrawal in neonatal rats would decrease withdrawal behaviors and normalize CNS glutathione and glutamate.<br><br>METHODS: Osmotic minipumps with methadone (opioid dependent, OD) and saline (Sham) were implanted into Sprague Dawley dams 7 days prior to delivery. Pups were randomized to receive either naloxone plus saline or NAC (50-100&#x2009;mg/kg), administered on postnatal day (PND) 7. We performed MR spectroscopy on PND6-7 before, 30&#x2009;min, and 120&#x2009;min after withdrawal. On PND7, we assessed withdrawal behaviors for 90&#x2009;min after naloxone administration and summed scores during peak withdrawal period.<br><br>RESULTS: Mean summed behavioral scores were significantly different between groups (&#x3c7;[2] (2)&#x2009;=&#x2009;10.49, p&#x2009;=&#x2009;0.005) but not different between NAC/NAL/OD and Sham (p&#x2009;=&#x2009;0.14): SAL/NAL/OD&#x2009;=&#x2009;17.2&#x2009;&#xb1;&#x2009;4.2 (n&#x2009;=&#x2009;10); NAC/NAL/OD&#x2009;=&#x2009;11.3&#x2009;&#xb1;&#x2009;5.6 (n&#x2009;=&#x2009;9); Sham&#x2009;=&#x2009;6.5&#x2009;&#xb1;&#x2009;0.6 (n&#x2009;=&#x2009;4). SAL/NAL/OD pups had decreased glutathione at 120&#x2009;min (p&#x2009;=&#x2009;0.01), while NAC/NAL/OD pups maintained pre-withdrawal glutathione (p&#x2009;=&#x2009;0.26).<br><br>CONCLUSION: In antenatal OD, NAC maintains CNS glutathione and mitigates acute opioid withdrawal in neonatal rats. This is the first study to demonstrate acute opioid withdrawal neurochemical changes in vivo in neonatal OD. NAC is a potential novel treatment for NAS.}, }
@article {pmid31935421, year = {2020}, author = {Gomez, SD and Bustos, PS and Sánchez, VG and Ortega, MG and Guiñazú, N}, title = {Trophoblast toxicity of the neonicotinoid insecticide acetamiprid and an acetamiprid-based formulation.}, journal = {Toxicology}, volume = {431}, number = {}, pages = {152363}, doi = {10.1016/j.tox.2020.152363}, pmid = {31935421}, issn = {1879-3185}, mesh = {Acetylcysteine/metabolism ; Adult ; Antioxidants/metabolism/pharmacology ; Cell Line ; Cell Survival/drug effects ; DNA Damage ; Drug Compounding ; Female ; Humans ; Insecticides/*toxicity ; Neonicotinoids/*toxicity ; Oxidative Stress ; Pregnancy ; Reactive Oxygen Species/metabolism ; Receptors, Nicotinic/drug effects ; Trophoblasts/*drug effects ; }, abstract = {The neonicotinoid (Neo) insecticide family is a relatively new class of pesticides of growing use. There is an increasing concern that human exposure to environmental pollutants in utero may be associated with diseases in adulthood. A functional placenta and trophoblasts are a requisite for a healthy pregnancy. The aim of this study was to investigate whether the Neo Acetamiprid (Ace) and one of its commercial formulations (Ace CF) display toxic features to a human first trimester trophoblast cell line. HTR-8/SVneo cells were cultured in the presence of Ace or Ace CF (0.1-100 μM) for 4 and 24 h, and changes in cell viability, reactive oxygen species, antioxidant system and macromolecule damage levels were evaluated. Ace and Ace CF are cytotoxic for HTR-8/SVneo trophoblasts. Cell viability loss and oxidative imbalance were triggered by Ace and Ace CF treatments. Impact in the antioxidant enzymes catalase, superoxide dismutase and gluthatione S-transferase activities were observed after 24 h exposure to Ace CF. Moreover, Ace CF caused oxidative damage in proteins, lipids and DNA, whereas Ace only damaged proteins. To test oxidative stress as a toxicity mechanism, cells were pre-incubated with the antioxidant N-acetyl-l-cysteine (NAC), prior Neo treatment. NAC protected trophoblasts from cell death and prevented oxidative damage. Results demonstrate that Ace (as active principle or CF) is cytotoxic for human trophoblasts, and oxidative stress is a toxicity mechanism. Ace CF exhibited a more toxic effect than the active principle, in an identical exposure scenario.}, }
@article {pmid31934469, year = {2019}, author = {Bauerlein, DK and Akbar, HN and von Rosenvinge, EC and Loughry, ND and John, PR}, title = {Benefit of N-Acetylcysteine in Postoperative Hepatic Dysfunction: Case Report and Review of Literature.}, journal = {Case reports in hepatology}, volume = {2019}, number = {}, pages = {4730381}, pmid = {31934469}, issn = {2090-6587}, abstract = {N-Acetylcysteine (NAC) is reported to have multiple clinical applications in addition to being the specific antidote for acetaminophen toxicity. NAC stimulates glutathione biosynthesis, promotes detoxification, and acts directly as a scavenger of free radicals. It is a powerful antioxidant and a potential treatment option for diseases characterized by the generation of free oxygen radicals. We present a case of postoperative hepatic dysfunction of multifactorial etiology in a patient with therapeutic acetaminophen levels, where hepatic function improved considerably following administration of intravenous NAC. This case suggests that NAC should be considered for treatment of acute liver dysfunction in the postoperative setting, even in the absence of elevated acetaminophen levels.}, }
@article {pmid31934265, year = {2019}, author = {Dong, G and Huang, X and Jiang, S and Ni, L and Chen, S}, title = {Simvastatin Mitigates Apoptosis and Transforming Growth Factor-Beta Upregulation in Stretch-Induced Endothelial Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {6026051}, pmid = {31934265}, issn = {1942-0994}, mesh = {Apoptosis/drug effects ; Cell Line ; Endothelium, Vascular/drug effects/pathology/*physiology ; Humans ; Hypertension, Portal/*drug therapy ; Hypolipidemic Agents/*therapeutic use ; Mitochondria/*metabolism ; NADPH Oxidase 2/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Simvastatin/*therapeutic use ; Stress, Mechanical ; Transforming Growth Factor beta/metabolism ; Up-Regulation ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Portal hypertension is a common clinical symptom of digestive disorders. With an increase in portal pressure, the portal vein will continue to dilate. We aimed to determine whether continuous stretch induced by portal hypertension may impair the function of endothelial cells (ECs) in the portal vein and aggravate the progress of portal hypertension and explore its mechanism. ECs were cultured on an elastic silicone membrane and subjected to continuous uniaxial stretch. Apoptosis and expression of TGF-β in ECs under stretch were measured. We found that sustained stretch induced the apoptosis of ECs in a stretch length-dependent manner. Compared with the control, continuous stretch increased the nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression and damaged the mitochondria, resulting in an evident increase in reactive oxygen species (ROS) levels; pretreatment with gp91ds-tat or MitoTEMPO decreased the ROS level in the intracellular levels. N-acetyl-cysteine (NAC) treatment before stretch not only reduced ROS levels but also mitigated the apoptosis of ECs; simvastatin had similar effects through targeting NOX2 and mitochondria. During the stretch, the phosphorylation of p38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB) was obviously increased; pretreatment with P38MAPK or JNK inhibitors decreased the phosphorylation of NF-κB and TGF-β expression. Pyrrolidine dithiocarbamate (PDTC) treatment before stretch also reduced TGF-β expression. After pretreatment with NAC, the phosphorylation of P38MAPK, JNK, and NF-κB and TGF-β expressions in ECs under stretch was suppressed; similar results were observed in simvastatin-treated ECs. This study demonstrated that simvastatin could mitigate EC apoptosis and TGF-β upregulation induced by continuous stretch by reducing the level of ROS.}, }
@article {pmid31931804, year = {2020}, author = {Crupi, R and Gugliandolo, E and Siracusa, R and Impellizzeri, D and Cordaro, M and Di Paola, R and Britti, D and Cuzzocrea, S}, title = {N-acetyl-L-cysteine reduces Leishmania amazonensis-induced inflammation in BALB/c mice.}, journal = {BMC veterinary research}, volume = {16}, number = {1}, pages = {13}, pmid = {31931804}, issn = {1746-6148}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cytokines/metabolism ; Hyperalgesia/drug therapy ; Inflammation/*drug therapy ; Leishmania mexicana/drug effects ; Leishmaniasis, Cutaneous/*drug therapy/pathology ; Male ; Mastocytosis/drug therapy ; Mice, Inbred BALB C ; Oxidative Stress/drug effects ; }, abstract = {BACKGROUND: Leishmaniasis is a emergent disease characterized by different clinical manifestations in both humans and dogs. Predominant clinical features of cutaneous leishmaniasis are ulcerative painless skin lesions. Several data reported that pain is associated with human and dog leishmaniasis, out with areas of painless ulcerative lesions per se. Actually, current medications used for leishmaniasis management are characterized by several side effects and, in addition, some cases of the disease are refractory to the treatment. On this background it is mandatory the identification of new and safe candidates for designing less toxic and low-cost remedies. Therefore, the search for new leishmanicidal compounds is indispensable.<br><br>METHODS: In the present paper we investigated the effect of orally N-acetyl-L-cysteine (NAC) supplementation at dose of 200&#x2009;mg/Kg for 10&#x2009;weeks, in subcutaneous Leishmania (L). amazonensis infected BALB/c mice. And evaluating the effect of NAC on inflammatory response such as TNF-&#x3b1;, IL-6, IL-1&#x3b2; levels, and on thermal and mechanical hyperalgesia.<br><br>RESULTS: In the present paper we showed how NAC supplementation affected parameters of oxidative stress (GSH, MDA, SOD), inflammation such as cytokines levels (IL-1&#x3b2;, IL-6, TNF&#x3b1;) and mast cell activation and consequently on induced pain, during leishmaniosis in BALB\c mice.<br><br>CONCLUSIONS: The findings of our study provided the scientific data demonstrating that L. amazonensis infection induces inflammation and pain in BALB/c mice that are reversed by administration of NAC.}, }
@article {pmid31928237, year = {2020}, author = {Abdel Hamid, OI and Ibrahim, EM and Hussien, MH and ElKhateeb, SA}, title = {The molecular mechanisms of lithium-induced cardiotoxicity in male rats and its amelioration by N-acetyl cysteine.}, journal = {Human &amp; experimental toxicology}, volume = {39}, number = {5}, pages = {696-711}, doi = {10.1177/0960327119897759}, pmid = {31928237}, issn = {1477-0903}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antimanic Agents/*toxicity ; Antioxidants/pharmacology/*therapeutic use ; Cardiotonic Agents/pharmacology/*therapeutic use ; Cardiotoxicity/blood/drug therapy/*etiology/genetics ; Creatine Kinase, MB Form/blood ; Lithium Carbonate/*toxicity ; Male ; MicroRNAs ; Myocardium/pathology ; Rats, Wistar ; Troponin I/blood ; }, abstract = {Lithium is one of the most powerful and commonly used medications for the treatment of various psychiatric diseases, especially bipolar disorder. However, it has a narrow therapeutic index with toxic effects on various organs. There are several case reports of lithium-induced arrhythmia and ischemia. The current work aimed to study the toxic effects of lithium on the heart of adult albino rats and its molecular mechanisms and the ameliorating effect of N-acetyl cysteine (NAC). Sixty adult male Wistar albino rats were classified into four groups; control, NAC-treated received NAC 500 mg/kg/week dissolved in 1 ml 0.9% sodium chloride intraperitoneal, lithium-treated received 52.5 mg/kg/day of lithium carbonate dissolved in 1 ml 0.9% sodium chloride orally by gavage, and lithium-and-NAC-treated (group IV) received lithium and NAC in the previous doses. After 12 weeks, the rats of group III showed a significant accumulation of ascites and a decrease in the mean arterial blood pressure and electrocardiographic (ECG) findings of ischemia and arrhythmia. In addition, there was an elevation in cardiac biomarkers creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and several histological lesions with a significant increase in the area % of Van Gieson, endothelial nitric oxide synthase (eNOS), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunoreaction. There was significant upregulation of microRNA-1, microRNA-21 (miRNA-21), and microRNA-29 (miRNA-29). MiRNA-21 was strongly positively correlated to the area % of 8-OHdG, while miRNA-29 was strongly positively correlated to the area % of Van Gieson staining. NAC significantly improved the cardiotoxic effects of lithium. Being a nontoxic and safe antioxidant, NAC can be used to ameliorate lithium-induced cardiac injury.}, }
@article {pmid31926629, year = {2020}, author = {Wu, F and Xiong, H and Sha, S}, title = {Noise-induced loss of sensory hair cells is mediated by ROS/AMPKα pathway.}, journal = {Redox biology}, volume = {29}, number = {}, pages = {101406}, pmid = {31926629}, issn = {2213-2317}, support = {R01 DC009222/DC/NIDCD NIH HHS/United States ; C06 RR014516/RR/NCRR NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Hair Cells, Auditory, Outer ; *Hearing Loss, Noise-Induced/drug therapy ; *Hydrogen Peroxide ; Mice ; Mice, Inbred CBA ; Reactive Oxygen Species ; }, abstract = {The formation of reactive oxygen species (ROS) is a well-documented process in noise-induced hearing loss (NIHL). We have also previously shown that activation of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPKα) at its catalytic residue T172 is one of the key reactions triggering noise-induced outer hair cell (OHC) death. In this study, we are addressing the link between ROS formation and activation of AMPKα in OHCs after noise exposure. In-vivo treatment of CBA/J mice with the antioxidant N-acetyl cysteine (NAC) reduced noise-induced ROS formation (as assessed by the relative levels of 4-hydroxynonenal and 3-nitrotyrosine) and activation of AMPKα in OHCs. Forskolin, an activator of adenylyl cyclase (AC) and an antioxidant, significantly increased cyclic adenosine monophosphate (cAMP) and decreased ROS formation and noise-induced activation of AMPKα. Consequently, treatment with forskolin attenuated noise-induced losses of OHCs and NIHL. In HEI-OC1 cells, H2O2-induced activation of AMPKα and cell death were inhibited by the application of forskolin. The sum of our data indicates that noise activates AMPKα in OHCs through formation of ROS and that noise-exposure-induced OHC death is mediated by a ROS/AMPKα-dependent pathway. Forskolin may serve as a potential compound for prevention of NIHL.}, }
@article {pmid31926003, year = {2020}, author = {Jaeschke, H and Akakpo, JY and Umbaugh, DS and Ramachandran, A}, title = {Novel Therapeutic Approaches Against Acetaminophen-induced Liver Injury and Acute Liver Failure.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {174}, number = {2}, pages = {159-167}, pmid = {31926003}, issn = {1096-0929}, support = {F31 DK120194/DK/NIDDK NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*adverse effects ; Analgesics, Non-Narcotic/*adverse effects ; Animals ; Chemical and Drug Induced Liver Injury/diagnosis/*drug therapy/etiology/metabolism ; Disease Models, Animal ; *Drug Repositioning ; Humans ; Liver/*drug effects/metabolism/pathology ; Liver Failure, Acute/chemically induced/diagnosis/*drug therapy/metabolism ; Protective Agents/adverse effects/*therapeutic use ; }, abstract = {Liver injury and acute liver failure caused by acetaminophen (APAP, N-acetyl-p-aminophenol, paracetamol) overdose is a significant clinical problem in most western countries. The only clinically approved antidote is N-acetylcysteine (NAC), which promotes the recovery of hepatic GSH. If administered during the metabolism phase, GSH scavenges the reactive metabolite N-acetyl-p-benzoquinone imine. More recently, it was shown that NAC can also reconstitute mitochondrial GSH levels and scavenge reactive oxygen/peroxynitrite and can support mitochondrial bioenergetics. However, NAC has side effects and may not be efficacious after high overdoses. Repurposing of additional drugs based on their alternate mechanisms of action could be a promising approach. 4-Methylpyrazole (4MP) was shown to be highly effective against APAP toxicity by inhibiting cytochrome P450 enzymes in mice and humans. In addition, 4MP is a potent c-Jun N-terminal kinase inhibitor expanding its therapeutic window. Calmangafodipir (CMFP) is a SOD mimetic, which is well tolerated in patients and has the potential to be effective after severe overdoses. Other drugs approved for humans such as metformin and methylene blue were shown to be protective in mice at high doses or at human therapeutic doses, respectively. Additional protective strategies such as enhancing antioxidant activities, Nrf2-dependent gene induction and autophagy activation by herbal medicine components are being evaluated. However, at this point, their mechanistic insight is limited, and the doses used are high. More rigorous mechanistic studies are needed to advance these herbal compounds. Nevertheless, based on recent studies, 4-methylpyrazole and calmangafodipir have realistic prospects to become complimentary or even alternative antidotes to NAC for APAP overdose.}, }
@article {pmid31921893, year = {2019}, author = {Liu, Y and Afzal, J and Vakrou, S and Greenland, GV and Talbot, CC and Hebl, VB and Guan, Y and Karmali, R and Tardiff, JC and Leinwand, LA and Olgin, JE and Das, S and Fukunaga, R and Abraham, MR}, title = {Differences in microRNA-29 and Pro-fibrotic Gene Expression in Mouse and Human Hypertrophic Cardiomyopathy.}, journal = {Frontiers in cardiovascular medicine}, volume = {6}, number = {}, pages = {170}, pmid = {31921893}, issn = {2297-055X}, support = {R01 GM029090/GM/NIGMS NIH HHS/United States ; R01 GM116841/GM/NIGMS NIH HHS/United States ; R01 HL075619/HL/NHLBI NIH HHS/United States ; }, abstract = {Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocyte hypertrophy and fibrosis. Studies in two mouse models (R92W-TnT/R403Q-MyHC) at early HCM stage revealed upregulation of endothelin (ET1) signaling in both mutants, but TGFβ signaling only in TnT mutants. Dysregulation of miR-29 expression has been implicated in cardiac fibrosis. But it is unknown whether expression of miR-29a/b/c and profibrotic genes is commonly regulated in mouse and human HCM. Methods: In order to understand mechanisms underlying fibrosis in HCM, and examine similarities/differences in expression of miR-29a/b/c and several profibrotic genes in mouse and human HCM, we performed parallel studies in rat cardiac myocyte/fibroblast cultures, examined gene expression in two mouse models of (non-obstructive) HCM (R92W-TnT, R403Q-MyHC)/controls at early (5 weeks) and established (24 weeks) disease stage, and analyzed publicly available mRNA/miRNA expression data from obstructive-HCM patients undergoing septal myectomy/controls (unused donor hearts). Results: Myocyte cultures: ET1 increased superoxide/H2O2, stimulated TGFβ expression/secretion, and suppressed miR-29a expression in myocytes. The effect of ET1 on miR-29 and TGFβ expression/secretion was antagonized by N-acetyl-cysteine, a reactive oxygen species scavenger. Fibroblast cultures: ET1 had no effect on pro-fibrotic gene expression in fibroblasts. TGFβ1/TGFβ2 suppressed miR-29a and increased collagen expression, which was abolished by miR-29a overexpression. Mouse and human HCM: Expression of miR-29a/b/c was lower, and TGFB1/collagen gene expression was higher in TnT mutant-LV at 5 and 24 weeks; no difference was observed in expression of these genes in MyHC mutant-LV and in human myectomy tissue. TGFB2 expression was higher in LV of both mutant mice and human myectomy tissue. ACE2, a negative regulator of the renin-angiotensin-aldosterone system, was the most upregulated transcript in human myectomy tissue. Pathway analysis predicted upregulation of the anti-hypertrophic/anti-fibrotic liver X receptor/retinoid X receptor (LXR/RXR) pathway only in human myectomy tissue. Conclusions: Our in vitro studies suggest that activation of ET1 signaling in cardiac myocytes increases reactive oxygen species and stimulates TGFβ secretion, which downregulates miR-29a and increases collagen in fibroblasts, thus contributing to fibrosis. Our gene expression studies in mouse and human HCM reveal allele-specific differences in miR-29 family/profibrotic gene expression in mouse HCM, and activation of anti-hypertrophic/anti-fibrotic genes and pathways in human HCM.}, }
@article {pmid31920904, year = {2019}, author = {Witherspoon, JW and Rekant, JS and Wakim, PG and Vasavada, R and Waite, M and Chrismer, I and Shelton, MO and Jain, MS and Meilleur, KG}, title = {Use of Fatigue Index as a Measure of Local Muscle Fatigability in Ryanodine Receptor Isoform-1-Related Myopathies.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {1234}, pmid = {31920904}, issn = {1664-2295}, abstract = {Introduction: Individuals affected with ryanodine receptor isoform-1-related myopathies (RYR1-RM) commonly experience fatigability in the quadriceps, which may limit physical function and potentially diminish quality of life. Fatigability, in RYR1-RM, results from skeletal muscle injury secondary to dysfunction of the major skeletal muscle Ca[++] channel. However, during fatigability testing, affected individuals did not always reach the point of local muscle fatigue as defined by a fatigue index (FATI) at 50% of peak torque. Surakka et al. compared three versions of FATI equations, which vary by the area under the force curve (AUC). By performing this comparison, they were able to determine the optimal equation in individuals with Multiple Sclerosis. Purpose: Using a similar comparison, we sought to identify the optimal FATI equation in the RYR1-RM population. Secondly, because local muscle fatigability might have an impact on independent living, this study also assessed change in local muscle fatigability over a 6-month time frame. Methods: Thirty participants were analyzed from the RYR1-RM natural history study and double-blind, placebo-controlled N-acetylcysteine (NAC) trial, NCT02362425. Twenty-seven had fatigability data, from isometric knee extension and flexion fatigability tests, available for the purpose of establishing a method for predicting FATI at 50% peak torque. For the natural history study, 30 participants were used to assess disease progression of local muscle fatigability achieved during the knee extension fatigability test, and 29 participants for the knee flexion fatigability test. Results: Surakka's equation 1, using the prediction approach, led to the smallest median error, the smallest square-root of uncorrected sum of squares, and the smallest average of the absolute value of the differences. No difference was observed in FATI at 50% peak torque between month 0 and month 6 for extension (p = 0.606) and flexion (p = 0.740). Conclusion: Surakka's equation 1, with the prediction approach, was found to be the most accurate for imputing values when fatigue was not reached during a sustained knee isometric fatigability test in RYR1-RM. Furthermore, when used to assess fatigability-based disease stability, local muscle fatigability, in this RYR1-RM population remained stable.}, }
@article {pmid31919505, year = {2020}, author = {Magalhães, TFF and Costa, MC and Holanda, RA and Ferreira, GF and Carvalho, VSD and Freitas, GJC and Ribeiro, NQ and Emídio, ECP and Carmo, PHF and de Brito, CB and de Souza, DG and Rocha, CEV and Paixão, TA and de Resende-Stoianoff, MA and Santos, DA}, title = {N-acetylcysteine reduces amphotericin B deoxycholate nephrotoxicity and improves the outcome of murine cryptococcosis.}, journal = {Medical mycology}, volume = {58}, number = {6}, pages = {835-844}, doi = {10.1093/mmy/myz129}, pmid = {31919505}, issn = {1460-2709}, mesh = {Acetylcysteine/*therapeutic use ; Amphotericin B/pharmacology/therapeutic use/*toxicity ; Animals ; Antifungal Agents/pharmacology/*therapeutic use/toxicity ; Brain/drug effects/microbiology ; Creatinine/blood ; Cryptococcosis/*drug therapy/microbiology ; Cryptococcus/drug effects ; Deoxycholic Acid/pharmacology/therapeutic use/*toxicity ; Disease Models, Animal ; Drug Combinations ; Drug Repositioning ; Female ; Kidney/*drug effects/microbiology ; Lung/drug effects/microbiology ; Macrophages/drug effects/microbiology ; Mice ; Mice, Inbred C57BL ; Microbial Sensitivity Tests ; Reactive Oxygen Species ; }, abstract = {Cryptococcosis is a life-threatening fungal infection, and its current treatment is toxic and subject to resistance. Drug repurposing represents an interesting approach to find drugs to reduce the toxicity of antifungals. In this study, we evaluated the combination of N-acetylcysteine (NAC) with amphotericin B (AMB) for the treatment of cryptococcosis. We examined the effects of NAC on fungal morphophysiology and on the macrophage fungicidal activity 3 and 24 hours post inoculation. The therapeutic effects of NAC combination with AMB were investigated in a murine model with daily treatments regimens. NAC alone reduced the oxidative burst generated by AMB in yeast cells, but did not inhibit fungal growth. The combination NAC + AMB decreased capsule size, zeta potential, superoxide dismutase activity and lipid peroxidation. In macrophage assays, NAC + AMB did not influence the phagocytosis, but induced fungal killing with different levels of oxidative bursts when compared to AMB alone: there was an increased reactive oxygen species (ROS) after 3 hours and reduced levels after 24 hours. By contrast, ROS remained elevated when AMB was tested alone, demonstrating that NAC reduced AMB oxidative effects without influencing its antifungal activity. Uninfected mice treated with NAC + AMB had lower concentrations of serum creatinine and glutamate-pyruvate transaminase in comparison to AMB. The combination of NAC + AMB was far better than AMB alone in increasing survival and reducing morbidity in murine-induced cryptococcosis, leading to reduced fungal burden in lungs and brain and also lower concentrations of pro-inflammatory cytokines in the lungs. In conclusion, NAC + AMB may represent an alternative adjuvant for the treatment of cryptococcosis.}, }
@article {pmid31914694, year = {2020}, author = {Liu, H and Chen, Z and Weng, X and Chen, H and Du, Y and Diao, C and Liu, X and Wang, L}, title = {Enhancer of zeste homolog 2 modulates oxidative stress-mediated pyroptosis in vitro and in a mouse kidney ischemia-reperfusion injury model.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {34}, number = {1}, pages = {835-852}, doi = {10.1096/fj.201901816R}, pmid = {31914694}, issn = {1530-6860}, mesh = {Animals ; Disease Models, Animal ; Enhancer of Zeste Homolog 2 Protein/*metabolism ; Epithelial Cells/*metabolism ; Kidney/metabolism ; Kidney Diseases/metabolism ; Male ; Mice, Inbred C57BL ; Pyroptosis/*physiology ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/*metabolism ; Signal Transduction/physiology ; }, abstract = {Enhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a crucial role in several kidney disease models. However, its role in renal ischemia/reperfusion (I/R) injury still remains unclear. In this study, we found that EZH2 was positively related to renal I/R injury and inhibition of EZH2 with DZNeP alleviated I/R injury and blocked the activation of oxidative stress and pyroptosis in vivo. Similarly, inhibition of EZH2 with either DZNeP or si-RNA also exerted an inhibitory effect on hypoxia/reoxygenation (H/R)-induced oxidative stress and pyroptosis in vitro. Moreover, further study revealed that ablation of reactive oxygen species (ROS) with N-acetyl-cysteine (NAC) suppressed pyroptosis in human renal proximal tubular epithelial cell line cells exposed to H/R stimulation. Furthermore, Nox4, which was positively related to the generation of ROS, was upregulated during H/R process, while it could be reversed by EZH2 inhibition. Consistently, Nox4-mediated ROS generation was attenuated upon inhibition of EZH2 with DZNeP or si-RNA. Additionally, the transcriptional activity of Nox4 was enhanced by the activation of ALK5/Smad2/3 signaling pathway, which was abolished by ALK5 knockdown in vitro. Finally, EZH2 inhibition blocked H/R and I/R-activated ALK5/Smad2/3 pathway and also resulted in an obvious decrease in the transcriptional activity and protein expression levels of Nox4. In conclusion, our results proved that EZH2 inhibition alleviated renal pyroptosis by blocking Nox4-dependent ROS generation through ALK5/Smad2/3 signaling pathway, indicating that EZH2 could be a potential therapeutic target for renal I/R injury.}, }
@article {pmid31913681, year = {2020}, author = {Kim, J and Nguyen, TTT and Li, Y and Zhang, CO and Cha, B and Ke, Y and Mazzeffi, MA and Tanaka, KA and Birukova, AA and Birukov, KG}, title = {Contrasting effects of stored allogeneic red blood cells and their supernatants on permeability and inflammatory responses in human pulmonary endothelial cells.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {318}, number = {3}, pages = {L533-L548}, pmid = {31913681}, issn = {1522-1504}, support = {R01 HL107920/HL/NHLBI NIH HHS/United States ; R01 HL076259/HL/NHLBI NIH HHS/United States ; R01 GM122940/GM/NIGMS NIH HHS/United States ; R01 HL130431/HL/NHLBI NIH HHS/United States ; R01 HL146829/HL/NHLBI NIH HHS/United States ; R01 HL087823/HL/NHLBI NIH HHS/United States ; }, mesh = {Allogeneic Cells ; Blood Component Removal/methods ; Blood Preservation/*adverse effects ; *Cell Membrane Permeability ; Endothelium, Vascular/immunology/*pathology ; Erythrocyte Transfusion/adverse effects ; Erythrocytes/*pathology ; Humans ; Inflammation/etiology/immunology/*pathology ; Lung/immunology/*pathology ; }, abstract = {Transfusion of red blood cells (RBCs) is a common life-saving clinical practice in severely anemic or hemorrhagic patients; however, it may result in serious pathological complications such as transfusion-related acute lung injury. The factors mediating the deleterious effects of RBC transfusion remain unclear. In this study, we tested the effects of washed long-term (RBC-O; >28 days) versus short-term (RBC-F; <14 days) stored RBCs and their supernatants on lung endothelial (EC) permeability under control and inflammatory conditions. RBCs enhanced basal EC barrier function as evidenced by an increase in transendothelial electrical resistance and decrease in permeability for macromolecules. RBCs also attenuated EC hyperpermeability and suppressed secretion of EC adhesion molecule ICAM-1 and proinflammatory cytokine IL-8 in response to LPS or TNF-α. In both settings, RBC-F had slightly higher barrier protective effects as compared with RBC-O. In contrast, supernatants from both RBC-F and RBC-O disrupted the EC barrier. The early phase of EC permeability response caused by RBC supernatants was partially suppressed by antioxidant N-acetyl cysteine and inhibitor of Src kinase family PP2, while addition of heme blocker and inhibition of NOD-like receptor family pyrin domain containing protein 3 (NLRP3), stress MAP kinases, receptor for advanced glycation end-products (RAGE), or Toll-like receptor-4 (TLR4) signaling were without effect. Morphological analysis revealed that RBC supernatants increased LPS- and TNF-α-induced breakdown of intercellular junctions and formation of paracellular gaps. RBC supernatants augmented LPS- and TNF-α-induced EC inflammation reflected by increased production of IL-6, IL-8, and soluble ICAM-1. These findings demonstrate the deleterious effects of RBC supernatants on EC function, which may have a major impact in pathological consequences associated with RBC transfusion.}, }
@article {pmid31905757, year = {2019}, author = {Shin, JH and Ryu, CM and Ju, H and Yu, HY and Song, S and Shin, DM and Choo, MS}, title = {Synergistic Effects of N-Acetylcysteine and Mesenchymal Stem Cell in a Lipopolysaccharide-Induced Interstitial Cystitis Rat Model.}, journal = {Cells}, volume = {9}, number = {1}, pages = {}, pmid = {31905757}, issn = {2073-4409}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers ; Combined Modality Therapy ; Cystitis, Interstitial/*etiology/metabolism/pathology/*therapy ; Disease Models, Animal ; Disease Susceptibility ; Female ; Immunohistochemistry ; Lipopolysaccharides/*adverse effects ; *Mesenchymal Stem Cell Transplantation/adverse effects/methods ; Mesenchymal Stem Cells/*cytology/metabolism ; Rats ; Treatment Outcome ; }, abstract = {The purpose of this study was to reduce the amount of stem cells used in treating preclinical interstitial cystitis (IC model) by investigating the synergistic effects of multipotent mesenchymal stem cells (M-MSCs; human embryonic stem cell-derived) and N-acetylcysteine (NAC). Eight-week-old female Sprague-Dawley rats were divided into seven groups, i.e., sham (n = 10), lipopolysaccharide/protamine sulfate (LPS/PS; n = 10), LPS/PS + NAC (n = 10), LPS/PS with 25K MSC (n = 10), LPS/PS with 50K MSC (n = 10) LPS/PS + 25K MSC + NAC (n = 10), and LPS/PS + 50K MSC + NAC (n = 10). To induce the IC rat model, protamine sulfate (10 mg, 45 min) and LPS (750 μg, 30 min) were instilled once a week for five consecutive weeks via a transurethral PE-50 catheter. Phosphate-buffered saline (PBS) was used in the sham group. One week after the final instillation, M-MSCs with two suboptimal dosages (i.e., 2.5 or 5.0 × 10[4] cells) were directly transplanted into the outer-layer of the bladder. Simultaneously, 200 mg/kg of NAC or PBS was intraperitoneally injected daily for five days. The therapeutic outcome was evaluated one week after M-MSC or PBS injection by awake cystometry and histological analysis. Functionally, LPS/PS insult led to irregular micturition, decreased intercontraction intervals, and decreased micturition volume. Both monotherapy and combination therapy significantly increased contraction intervals, increased urination volume, and reduced the residual volume, thereby improving the urination parameters compared to those of the LPS group. In particular, a combination of NAC dramatically reduced the amount of M-MSCs used for significant restoration in histological damage, including inflammation and apoptosis. Both M-MSCs and NAC-based therapy had a beneficial effect on improving voiding dysfunction, regenerating denudated urothelium, and relieving tissue inflammation in the LPS-induced IC/BPS rat model. The combination of M-MSC and NAC was superior to MSC or NAC monotherapy, with therapeutic efficacy that was comparable to that of previously optimized cell dosage (1000K) without compromised therapeutic efficacy.}, }
@article {pmid31905258, year = {2020}, author = {Wu, Z and Liu, Q and Zhu, K and Liu, Y and Chen, L and Guo, H and Zhou, N and Li, Y and Shi, B}, title = {Cigarette smoke induces the pyroptosis of urothelial cells through ROS/NLRP3/caspase-1 signaling pathway.}, journal = {Neurourology and urodynamics}, volume = {39}, number = {2}, pages = {613-624}, doi = {10.1002/nau.24271}, pmid = {31905258}, issn = {1520-6777}, mesh = {Animals ; Caspase 1/*metabolism ; Cell Line ; Epithelial Cells/cytology/*metabolism ; Humans ; Inflammasomes/metabolism ; Male ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Oxidative Stress/physiology ; Pyroptosis/*physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*physiology ; Smoke ; Urothelium/cytology/*metabolism ; }, abstract = {AIMS: Cell death and inflammation are involved in the development of bladder dysfunction. Pyroptosis is programmed cell death, causing cytotoxic effects and local inflammation. As one of the biggest health threats in the world, smoking is also closely related to urinary system diseases. The aims of this study were to investigate the role of NLRP3 inflammasome-mediated pyroptosis in the bladder after cigarette smoke exposure.<br><br>METHODS: The expression of NLRP3 inflammasome and the activity of caspase-1 in bladder tissue was investigated after cigarette smoke exposure. In vitro, bladder urothelial cells were stimulated by cigarette smoke extract and then the activity of caspase-1 and the expression of NLRP3 inflammasome were measured. The role of oxidative stress was also assessed.<br><br>RESULTS: The activity of caspase-1 in bladder tissue increased by 50% after cigarette smoke exposure. Cigarette smoke caused oxidative stress injury and the activation of NLRP3 inflammasome. In addition, reactive oxygen species (ROS) inhibitor N-acetyl-cysteine alleviated the pyroptosis of urothelial cells.<br><br>CONCLUSIONS: Cigarette smoke-induced pyroptosis of bladder tissue by activating ROS/NLRP3/caspase-1 signaling pathway. Inhibition of bladder urothelial cell pyroptosis may be a new approach to alleviate bladder damage caused by smoking.}, }
@article {pmid31898286, year = {2020}, author = {Ding, YY and Luan, JJ and Fan, Y and Olatunji, OJ and Song, J and Zuo, J}, title = {α-Mangostin reduced the viability of A594 cells in vitro by provoking ROS production through downregulation of NAMPT/NAD.}, journal = {Cell stress &amp; chaperones}, volume = {25}, number = {1}, pages = {163-172}, pmid = {31898286}, issn = {1466-1268}, mesh = {A549 Cells ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cytokines/*drug effects ; Down-Regulation ; Humans ; NAD/metabolism ; Nicotinamide Phosphoribosyltransferase/*drug effects/metabolism ; Oxidation-Reduction/*drug effects ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Xanthones/*pharmacology ; }, abstract = {α-Mangostin (MAN) is a bioactive compound isolated from the inedible pericarp of a tropical fruit mangosteen (Garcinia mangostana Linn). It exhibits notable therapeutic potentials on lung cancers, but the underlying mechanisms are still largely unknown. This study was designed to further explore the mechanisms involved in cytotoxicity of MAN on A549 cells. Apoptosis and cell cycle distribution were analyzed by flow cytometry methods. The fluorescent probes DCFH-DA and JC-1 were used to assess the intracellular reactive oxidative species (ROS) and mitochondrial membrane potential statuses, respectively. The regulation of MAN on relevant pathways was investigated by immunoblotting assays. The results obtained indicated that MAN caused significant apoptosis and cell cycle arrest in A549 cells, which eventually resulted in inhibition on cell proliferation in vitro. All these phenomena were synchronized with escalated oxidative stress and downregulation of nicotinamide phosphoribosyltransferase/nicotinamide adenine dinucleotide (NAMPT/NAD). Supplementation with nicotinamide mononucleotide (NMN) and N-acetylcysteine (NAC) efficiently eased MAN-induced ROS accumulation, and potently antagonized MAN-elicited apoptosis and cell cycle arrest. The pro-apoptotic effect of MAN was further confirmed by increased expressions of cleaved caspase 3, 6, 7, and 9, and its effect on cell cycle progression was validated by the altered expressions of p-p38, p-p53, CDK4, and cyclin D1. The immunoblotting assays also demonstrated that NAC/NMN effectively restored these molecular changes elicited by MAN treatment. Collectively, this study revealed a unique anti-tumor mechanism of MAN by provoking ROS production through downregulation of NAMPT/NAD signaling and further validated MAN as a potential therapeutic reagent for lung cancer treatment.}, }
@article {pmid31898254, year = {2020}, author = {Chung, IY and Kim, BO and Jang, HJ and Cho, YH}, title = {Repositioning of a mucolytic drug to a selective antibacterial against Vibrio cholerae.}, journal = {Journal of microbiology (Seoul, Korea)}, volume = {58}, number = {1}, pages = {61-66}, pmid = {31898254}, issn = {1976-3794}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; *Cholera/drug therapy/microbiology ; *Drug Repositioning ; *Vibrio cholerae/drug effects/pathogenicity ; Virulence/*drug effects ; }, abstract = {Drug repositioning, the approach to explore existing drugs for use in new therapeutic indications, has emerged as an alternative drug development strategy. In this study, we found that a mucolytic drug, N-acetylcysteine (NAC) showed antibacterial activity against Vibrio cholerae. NAC can provide acid stress that selectively inhibited the growth of V. cholerae among other bacterial pathogens. To address the antibacterial mechanism of NAC against V. cholerae, six acr (acetylcys-teine-resistant) mutants were isolated from 3,118 random transposon insertion clones. The transposon insertion sites of the six mutants were mapped at the five genes. All these mutants did not display NAC resistance under acidic conditions, despite their resistance to NAC under alkaline conditions, indicating that the NAC resistance directed by the acr mutations was independent of the unusual pH-sensitivity of V. cholerae. Furthermore, all these mutants displayed attenuated virulence and reduced biofilm formation, suggesting that the acr genes are required for pathogenesis of V. cholerae. This study validates the relevance of drug repositioning for antibacterials with new modes of action and will provide an insight into a novel antibacterial therapy for V. cholerae infections to minimize side effects and resistance emergence.}, }
@article {pmid31896473, year = {2020}, author = {Xie, X and Deng, T and Duan, J and Xie, J and Yuan, J and Chen, M}, title = {Exposure to polystyrene microplastics causes reproductive toxicity through oxidative stress and activation of the p38 MAPK signaling pathway.}, journal = {Ecotoxicology and environmental safety}, volume = {190}, number = {}, pages = {110133}, doi = {10.1016/j.ecoenv.2019.110133}, pmid = {31896473}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Animals ; MAP Kinase Signaling System/physiology ; Male ; Mice ; Microplastics/*toxicity ; Oxidative Stress/*physiology ; Plastics ; Polystyrenes/*toxicity ; Reproduction/drug effects ; Signal Transduction/drug effects ; Spermatozoa/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Microplastics (MP) are receiving increased attention as a harmful environmental pollutant, however information on the reproduction toxicity of MP in terrestrial animals, especially mammals, is limited. In this experiment, we investigated the impact of polystyrene microplastics (micro-PS) on the reproductive system of male mice. Healthy Balb/c mice were exposed to saline or to different doses of micro-PS for 6 weeks. The results showed that micro-PS exposure resulted in a significant decrease in the number and motility of sperm, and a significant increase in sperm deformity rate. We also detected a decrease in the activity of the sperm metabolism-related enzymes, succinate dehydrogenase (SDH) and lactate dehydrogenase (LDH), and a decrease in the serum testosterone content in the micro-PS exposure group. We found that micro-PS exposure caused oxidative stress and activated JNK and p38 MAPK. In addition, we found that when N-acetylcysteine (NAC) scavenges ROS, and when the p38 MAPK-specific inhibitor SB203580 inhibits p38MAPK, the micro-PS-induced sperm damage is alleviated and testosterone secretion improves. In conclusion, our findings suggest that micro-PS induces reproductive toxicity in mice through oxidative stress and activation of the p38 MAPK signaling pathways.}, }
@article {pmid31894323, year = {2020}, author = {Lu, W and Ma, YY and Shao, QQ and Liang, J and Qi, TT and Huang, Y and Wang, QJ}, title = {ROS/p53/miR‑335‑5p/Sp1 axis modulates the migration and epithelial to mesenchymal transition of JEG‑3 cells.}, journal = {Molecular medicine reports}, volume = {21}, number = {3}, pages = {1208-1216}, pmid = {31894323}, issn = {1791-3004}, mesh = {Apoptosis/genetics ; Cell Line, Tumor ; Cell Movement/genetics ; Epithelial-Mesenchymal Transition/*genetics ; Humans ; MicroRNAs/*genetics ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Transcription Factor AP-1/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Differential expression of microRNA (miR)‑335‑5p, a key tumor suppressor, has been detected in pre‑eclampsia (PE) placentas. However, the role of miR‑335‑5p in the pathogenesis of PE and the factor modulating its aberrant expression remain unknown. The present study used JEG‑3 cells in vitro to investigate these mechanisms. The role of miR‑335‑5p in proliferation, apoptosis and migration of JEG‑3 cells was investigated using MTT, Annexin V‑FITC/PI, Transwell migration and wound healing assays, respectively. miR‑335‑5p expression levels were analyzed using reverse transcription‑quantitative PCR. The expression levels of E‑cadherin, N‑cadherin, Snail, specificity protein 1 (Sp1) and p53 were assessed using western blot analysis. Cell viability analysis was performed using the Cell Counting Kit‑8 assay. The intracellular reactive oxygen species (ROS) levels were detected using a 2,7‑dichlorodihydrofluorescein diacetate assay. The present results suggested that miR‑335‑5p did not affect the proliferation or apoptotic rate of JEG‑3 cells. Overexpression of miR‑335‑5p significantly inhibited the migration of JEG‑3 cells, decreased the expression levels of Sp1, N‑cadherin and Snail, and increased E‑cadherin expression. Sp1 silencing produced similar results in JEG‑3 cells. H2O2 significantly increased the intracellular ROS levels and miR‑335‑5p expression, whereas N‑acetyl‑cysteine pretreatment prior to H2O2 treatment reversed the increases in miR‑335‑5p expression. Knockdown of p53 significantly decreased the expression levels of miR‑335‑5p in JEG‑3 cells and in H2O2‑treated cells. The present results suggested that miR‑335‑5p expression levels in trophoblast cells could be increased by ROS in a p53‑dependent manner, leading to the downregulation of Sp1 and subsequent inhibition of epithelial to mesenchymal transition and cell migration. The present results may provide novel evidence on the etiology of PE.}, }
@article {pmid31891230, year = {2020}, author = {Li, J and Wang, XH and Hu, J and Shi, M and Zhang, L and Chen, H}, title = {Combined treatment with N-acetylcysteine and gefitinib overcomes drug resistance to gefitinib in NSCLC cell line.}, journal = {Cancer medicine}, volume = {9}, number = {4}, pages = {1495-1502}, pmid = {31891230}, issn = {2045-7634}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use ; Apoptosis/drug effects/genetics ; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects/genetics ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/*drug effects/genetics ; Drug Screening Assays, Antitumor ; Drug Synergism ; ErbB Receptors/antagonists &amp; inhibitors/genetics ; Gefitinib/*pharmacology/therapeutic use ; Humans ; Lung Neoplasms/*drug therapy/genetics/pathology ; Mutation ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; }, abstract = {We aimed to explore the molecular substrate underlying EGFR-TKI resistance and investigate the effects of N-acetylcysteine (NAC) on reversing EGFR-TKI resistance. In the current research, the effects of NAC in combination with gefitinib on reversing gefitinib resistance were examined using CCK-8 assay, combination index (CI) method, matrigel invasion assay, wound-healing assay, flow cytometry, western blot, and quantitative real-time PCR (qRT-PCR). CCK8 assay showed that NAC plus gefitinib combination overcame EGFR-TKI resistance in non-small cell lung cancer (NSCLC) cells by lowering the value of half maximal inhibitory concentration (IC50). CI calculations demonstrated a synergistic effect between the two drugs (CI < 1). Matrigel invasion assay and wound healing assay demonstrated a decrease in migration and invasion ability of PC-9/GR cells after NAC and gefitinib treatment. Flow cytometry displayed enhanced apoptosis in the combination group. Western blot and qRT-PCR revealed that increased E-cadherin and decreased vimentin in the combination group. When PP2 was administered with gefitinib, the same effects were seen. Our findings suggest that NAC could restore the sensitivity of gefitinib-resistant NSCLC cells to gefitinib via suppressing Src activation and reversing epithelial-mesenchymal transition.}, }
@article {pmid31885794, year = {2019}, author = {Yu, LM and Zhang, WH and Han, XX and Li, YY and Lu, Y and Pan, J and Mao, JQ and Zhu, LY and Deng, JJ and Huang, W and Liu, YH}, title = {Hypoxia-Induced ROS Contribute to Myoblast Pyroptosis during Obstructive Sleep Apnea via the NF-κB/HIF-1α Signaling Pathway.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {4596368}, pmid = {31885794}, issn = {1942-0994}, mesh = {Animals ; Cell Hypoxia/*genetics ; Humans ; Mice ; Myoblasts/*metabolism ; NF-kappa B/*metabolism ; Pyroptosis/*physiology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Sleep Apnea, Obstructive/*genetics ; }, abstract = {Tissue hypoxia caused by upper airway collapse is a main cause of excessive oxidative stress and systemic inflammation in obstructive sleep apnea (OSA) patients. Increased reactive oxygen species (ROS) and inflammatory responses affect cell survival and ultimately contribute to tissue injury. In the present study, we proposed that the induction of ROS by hypoxia, as an intrinsic stress, activates myoblast pyroptosis in OSA. We found increased cell death and abnormal expression of pyroptosis markers in the skeletal muscle of OSA mice. In vitro studies showed hypoxia-induced pyroptotic death of C2C12 myoblasts, as evidenced by the activation of caspase-1 and gasdermin D (GSDMD). Hypoxia induced ROS overproduction and accumulation in myoblasts. More importantly, applying N-acetylcysteine (NAC), an ROS scavenger, rescued cell swelling, downregulated the inflammatory response, and prevented pyroptotic death in hypoxia-cultured myoblasts. Hypoxia stimulation promoted NF-κB P65 phosphorylation and HIF-1α nuclear translocation. Moreover, hypoxia increased the nuclear level of cleaved caspase-1 and GSDMD. NAC inhibited hypoxia-induced variations in the HIF-1α and NF-κB signaling pathway. Taken together, our results determined that hypoxia-induced ROS contribute to myoblast pyroptosis. Therefore, our findings suggest that ROS may be a potential therapeutic target for ameliorating hypoxia-induced cell death and tissue injury, especially in OSA and hypoxia-related diseases.}, }
@article {pmid31885780, year = {2019}, author = {Zhao, Y and Jin, L and Chi, Y and Yang, J and Zhen, Q and Wu, H}, title = {Fine Particulate Matter Leads to Unfolded Protein Response and Shortened Lifespan by Inducing Oxidative Stress in C. elegans.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {2492368}, pmid = {31885780}, issn = {1942-0994}, mesh = {Animals ; Caenorhabditis elegans/*pathogenicity ; Cell Line ; Longevity/*drug effects ; Oxidative Stress ; Particulate Matter/*metabolism ; Reactive Oxygen Species ; Unfolded Protein Response/*physiology ; }, abstract = {Oxidative stress has been proven as one of the most critical regulatory mechanisms involved in fine Particulate Matter- (PM2.5-) mediated toxicity. For a better understanding of the underlying mechanisms that enable oxidative stress to participate in PM2.5-induced toxic effects, the current study explored the effects of oxidative stress induced by PM2.5 on UPR and lifespan in C. elegans. The results implicated that PM2.5 exposure induced oxidative stress response, enhanced metabolic enzyme activity, activated UPR, and shortened the lifespan of C. elegans. Antioxidant N-acetylcysteine (NAC) could suppress the UPR through reducing the oxidative stress; both the antioxidant NAC and UPR inhibitor 4-phenylbutyric acid (4-PBA) could rescue the lifespan attenuation caused by PM2.5, indicating that the antioxidant and moderate proteostasis contribute to the homeostasis and adaptation to oxidative stress induced by PM2.5.}, }
@article {pmid31883977, year = {2020}, author = {Manuel, AM and Walla, MD and Dorn, MT and Tanis, RM and Piroli, GG and Frizzell, N}, title = {Fumarate and oxidative stress synergize to promote stability of C/EBP homologous protein in the adipocyte.}, journal = {Free radical biology &amp; medicine}, volume = {148}, number = {}, pages = {70-82}, pmid = {31883977}, issn = {1873-4596}, support = {F31 DK108559/DK/NIDDK NIH HHS/United States ; R01 NS092938/NS/NINDS NIH HHS/United States ; R03 HD077187/HD/NICHD NIH HHS/United States ; R56 DK105087/DK/NIDDK NIH HHS/United States ; }, mesh = {Adipocytes/metabolism ; Apoptosis ; Endoplasmic Reticulum Stress ; *Fumarates ; Kelch-Like ECH-Associated Protein 1/genetics ; *NF-E2-Related Factor 2 ; Oxidative Stress ; Transcription Factor CHOP/genetics/metabolism ; }, abstract = {C/EBP homologous protein (CHOP) is a transcription factor that is elevated in adipose tissue across many models of diabetes and metabolic stress. Although increased CHOP levels are associated with the terminal response to endoplasmic reticulum stress and apoptosis, there is no evidence for CHOP mediated apoptosis in the adipose tissue during diabetes. CHOP protein levels increase in parallel with protein succination, a fumarate derived cysteine modification, in the adipocyte during metabolic stress. We investigated the factors contributing to sustained CHOP proteins levels in the adipocyte, with an emphasis on the regulation of CHOP protein turnover by metabolite-driven modification of Keap1 cysteines. CHOP protein stability was investigated in conditions of nutrient stress due to high glucose or elevated fumarate (fumarase knockdown model); where cysteine succination is specifically elevated. CHOP protein turnover is significantly reduced in models of elevated glucose and fumarate with a ~30% increase in CHOP stability (p > 0.01), in part due to decreased CHOP phosphorylation. Sustained CHOP levels occur in parallel with elevated heme-oxygenase-1, a production of increased Nrf2 transcriptional activity and Keap1 modification. While Keap1 is directly succinated in the presence of excess fumarate derived from genetic knockdown of fumarase (fumarate levels are elevated >20-fold), it is the oxidative modification of Keap1 that predominates in adipocytes matured in high glucose (fumarate increases 4-5 fold). Elevated fumarate indirectly regulates CHOP stability through the induction of oxidative stress. The antioxidant N-acetylcysteine (NAC) reduces fumarate levels, protein succination and CHOP levels in adipocytes matured in high glucose. Elevated CHOP does not contribute elevated apoptosis in adipocytes, but plays a redox-dependent role in decreasing the adipocyte secretion of interleukin-13, an anti-inflammatory chemokine. NAC treatment restores adipocyte IL-13 secretion, confirming the redox-dependent regulation of a potent anti-inflammatory eotaxin. This study demonstrates that physiological increases in the metabolite fumarate during high glucose exposure contributes to the presence of oxidative stress and sustained CHOP levels in the adipocyte during diabetes. The results reveal a novel metabolic link between mitochondrial metabolic stress and reduced anti-inflammatory adipocyte signaling as a consequence of reduced CHOP protein turnover.}, }
@article {pmid31883973, year = {2020}, author = {Cacciottolo, M and Morgan, TE and Saffari, AA and Shirmohammadi, F and Forman, HJ and Sioutas, C and Finch, CE}, title = {Traffic-related air pollutants (TRAP-PM) promote neuronal amyloidogenesis through oxidative damage to lipid rafts.}, journal = {Free radical biology &amp; medicine}, volume = {147}, number = {}, pages = {242-251}, pmid = {31883973}, issn = {1873-4596}, support = {P30 ES007048/ES/NIEHS NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R21 AG050201/AG/NIA NIH HHS/United States ; R01 ES023864/ES/NIEHS NIH HHS/United States ; RF1 AG051521/AG/NIA NIH HHS/United States ; P01 AG055367/AG/NIA NIH HHS/United States ; R56 ES023864/ES/NIEHS NIH HHS/United States ; }, mesh = {*Air Pollutants/toxicity ; *Alzheimer Disease/chemically induced/metabolism ; Amyloid beta-Peptides/metabolism/toxicity ; Amyloid beta-Protein Precursor/genetics/metabolism ; Animals ; Membrane Microdomains/metabolism ; Mice ; Mice, Transgenic ; Oxidative Stress ; Particulate Matter/metabolism/toxicity ; Vehicle Emissions/toxicity ; }, abstract = {Traffic-related air pollution particulate matter (TRAP-PM) is associated with increased risk of Alzheimer Disease (AD). Rodent models respond to nano-sized TRAP-PM (nPM) with increased production of amyloid Aβ peptides, concurrently with oxidative damage. Because pro-Aβ processing of the amyloid precursor protein (APP) occurs on subcellular lipid rafts, we hypothesized that oxidative stress from nPM exposure would alter lipid rafts to favor Aβ production. This hypothesis was tested with J20 mice and N2a cells transgenic for hAPPswe (familial AD). Exposure of J20-APPswe mice to nPM for 150 h caused increased lipid oxidation (4-HNE) and increased the pro-amyloidogenic processing of APP in lipid raft fractions in cerebral cortex; the absence of these changes in cerebellum parallels the AD brain region selectivity for Aβ deposits. In vitro, nPM induced similar oxidative responses in N2a-APPswe cells, with dose-dependent production of NO, oxidative damage (4-HNE, 3NT), and lipid raft alterations of APP with increased Aβ peptides. The antioxidant N-acetyl-cysteine (NAC) attenuated nPM-induced oxidative damage and lipid raft alterations of APP processing. These findings identify neuronal lipid rafts as novel targets of oxidative damage in the pro-amyloidogenic effects of air pollution.}, }
@article {pmid31883926, year = {2020}, author = {Wang, Y and Zhao, S and Chen, Y and Wang, Y and Wang, T and Wo, X and Dong, Y and Zhang, J and Xu, W and Qu, C and Feng, X and Wu, X and Wang, Y and Zhong, Z and Zhao, W}, title = {N-Acetyl cysteine effectively alleviates Coxsackievirus B-Induced myocarditis through suppressing viral replication and inflammatory response.}, journal = {Antiviral research}, volume = {179}, number = {}, pages = {104699}, doi = {10.1016/j.antiviral.2019.104699}, pmid = {31883926}, issn = {1872-9096}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Animals, Newborn ; Antiviral Agents/*therapeutic use ; Caspase Inhibitors/therapeutic use ; Coxsackievirus Infections/complications/*drug therapy ; Enterovirus B, Human/drug effects/physiology ; HeLa Cells ; Humans ; Inflammation/drug therapy/virology ; Mice, Inbred BALB C ; Myocarditis/*drug therapy/virology ; Proteasome Endopeptidase Complex/metabolism ; Specific Pathogen-Free Organisms ; Virus Replication/*drug effects ; }, abstract = {Viral myocarditis caused by Coxsackievirus B (CVB) infection is a severe inflammatory disease of the myocardium, which may develop to cardiomyopathy and heart failure. No effective specific treatment is available. Our previous study demonstrated that suppression of proinflammatory caspase-1 activation effectively inhibited CVB replication. N-acetyl cysteine (NAC) is a widely used antioxidant. In this study, we found that NAC significantly alleviated the myocardial injury caused by CVB type 3 (CVB3) under in vivo condition. Importantly, NAC treatment simultaneously suppressed viral replication and inflammatory response in both myocardium and cell culture. The antiviral and anti-inflammation mechanism of NAC, while independent of its antioxidant property, relies on its inhibition on caspase-1 activation. Moreover, NAC promotes procaspase-1 degradation via ubiquitin proteasome system, which further contributes to caspase-1 down-regulation. NAC also inhibits the activity of viral proteases. Taken together, this study shows that NAC exerts potent anti-CVB and anti-inflammation effect through targeting caspase-1. Given that NAC is a clinically approved medicine, we recommend NAC as a valuable therapeutic agent for viral myocarditis caused by CVB.}, }
@article {pmid31882389, year = {2020}, author = {Tangül, SU and Çakmak, AM and Çağlayan, O and Bozdoğan, &#xd6;}, title = {Prevention of the harmful effects of free oxygen radicals by using N-acetylcysteine in testicular torsion.}, journal = {Journal of pediatric urology}, volume = {16}, number = {1}, pages = {42.e1-42.e8}, doi = {10.1016/j.jpurol.2019.10.028}, pmid = {31882389}, issn = {1873-4898}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Free Radical Scavengers/*therapeutic use ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*adverse effects/*metabolism ; Reperfusion Injury/*etiology/*prevention &amp; control ; Spermatic Cord Torsion/*complications/*metabolism ; }, abstract = {INTRODUCTION: Testicular torsion is a urological emergency both in childhood and in adult life. Many studies on experimental testicular torsion have demonstrated biochemical and pathological ischemia-reperfusion injury and the efficacy of some drugs have been investigated to prevent this damage. N-acetylcysteine (NAC) promotes glutathione synthesis and acts as a glutathione precursor because of the fact that it increases the glutathione-reductase activity by transporting sulfhydryl groups.<br><br>AIM: In this experimental study, the authors aimed to investigate the effectiveness of NAC in preventing ischemia-reperfusion injury following testicular torsion and detorsion.<br><br>STUDY DESIGN: For this experimental study, 36 albino Wistar-male rats were used. The rats were randomly divided into 4 groups: sham (n&#xa0;=&#xa0;8), ischemia-reperfusion&#xa0;(n&#xa0;=&#xa0;8), ischemia-NAC -reperfusion (n&#xa0;=&#xa0;10), and ischemia-NAC-reperfusion-NAC&#xa0;(n&#xa0;=&#xa0;10) groups. Two hours of torsion and 4&#xa0;h of detorsion were created in the left testis. After 4&#xa0;h of detorsion, the rats were sacrificed. Each tissue was divided into two sections for biochemical and pathological examinations.<br><br>RESULTS: There was a statistically significant difference between the study groups in terms of the total-sulfhydryl level, nitric oxide level, and the malondialdehyde values. Histopathological examination revealed that NAC was effective in preventing reperfusion injury in the testis&#xa0;but ineffective in preventing the reduction in the spermatid count.<br><br>DISCUSSION: The results of this experimental study support that NAC can histopathologically maintain the structure of seminiferous tubules against ischemis reperfusion injury and prevent damage to the germinative cells. However, it was unable to prevent the reduction in spermatid count. There was no significant difference in the prevention of ischemia-reperfusion injury between NAC administration during the first hour of ischemia and NAC administration during reperfusion. Although NAC can prevent tissue damage from ischemia reperfusion injury, it is not effective against the reduction in the spermatid count.<br><br>CONCLUSION: N-acetylcysteine may be biochemically effective in preventing ischemia-reperfusion injury after testicular torsion and detorsion. NAC is a readily available and easy to use agent that can be used during testicular ischemia.}, }
@article {pmid31881190, year = {2020}, author = {Sadaf, S and Awasthi, D and Singh, AK and Nagarkoti, S and Kumar, S and Barthwal, MK and Dikshit, M}, title = {Pyroptotic and apoptotic cell death in iNOS and nNOS overexpressing K562 cells: A mechanistic insight.}, journal = {Biochemical pharmacology}, volume = {176}, number = {}, pages = {113779}, doi = {10.1016/j.bcp.2019.113779}, pmid = {31881190}, issn = {1873-2968}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/genetics/*physiology ; Caspase 1/genetics/metabolism ; Caspase 3/genetics/metabolism ; Cell Cycle/genetics/physiology ; Cell Survival/drug effects/genetics/physiology ; Free Radical Scavengers/pharmacology ; Humans ; K562 Cells ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type I/genetics/*metabolism ; Nitric Oxide Synthase Type II/genetics/*metabolism ; Pyroptosis/genetics/*physiology ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects/genetics ; }, abstract = {Previous studies from this lab and others have demonstrated that nitric oxide (NO) in a concentration dependent manner, modulated neutrophil and leukemic cell survival. Subsequent studies delineated importance of iNOS in neutrophil differentiation and leukemic cell death. On the contrary, role of nNOS in survival of these cells remains least understood. Present study was therefore undertaken to assess and compare the role of iNOS and nNOS in the survival of NOS overexpressing myelocytic K562 cells. Cells with almost similar iNOS and nNOS activities displayed comparable cell cycle perturbation, Annexin V positivity, mitochondrial dysfunction, augmented DCF fluorescence, and also attenuated expression of antioxidants. Moreover, induction in cell death was also accompanied by the activation of pJNK/p38MAPK/Erk1/2 and reduction in PI3K/Akt/mTOR signaling. Treatment of NOS isoform overexpressing K562 cells with NAC, a potent free radical scavenger prevented cell death and also the modulations in the signaling proteins. In addition, enhanced expression of CASP1 and CASP4 genes, along with increased Caspase-1 cleavage and increased IL-1β release were significantly more in K562[iNOS] cells, which indicate priming of these cells for pyroptotic cell death. On the other hand, K562[nNOS] cells, displayed much enhanced CASP3 gene expression, Caspase-3 cleavage and Caspase-3 activity. Results obtained indicate that similar level of iNOS or nNOS activation in K562 cells, preferred pyroptotic and apoptotic cell death respectively.}, }
@article {pmid31880113, year = {2019}, author = {Chen, S and Wang, X and Qiu, CM and Hou, JN and Wei, XY and Xiang, CX and Tang, MY and Zhang, R and Pei, HF}, title = {[Study of the Role and Mechanism of Asprosin/Spartin Pathway in Cardiac Microvascular Endothelial Injury Induced by Diabete Mellitus].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {50}, number = {6}, pages = {827-834}, pmid = {31880113}, issn = {1672-173X}, mesh = {Animals ; Apoptosis ; Cells, Cultured ; *Diabetes Mellitus, Experimental ; *Endothelial Cells ; Mice ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; }, abstract = {OBJECTIVE: To detect the effects and mechanism of asprosin (Asp) and spartin on the injury of mice cardiac microvascular endothelial cells (CMECs) induced by high glucose.<br><br>METHODS: The cultured CMECs were divided into 2 groups, one group is normal group (5.5 mmol/L glucose in the medium) and another is HG group (30 mmol/L glucose in the medium). Real-time PCR (qRT-PCR) and Western blot were respectively used to detect the mRNA level of spastic paraplegia 20 (SPG20) and protein expression of spartin in CMECs. Upregulation or downregulation of the expression of spartin was achieved via transfection with adenovirus (Ad) or small interfering RNA (siRNA) respectively. CMECs with downregulation of spartin expression were firstly treated with anti-oxidant N-acetylcysteine (NAC) or Asp respectively for 48 h, and then were interfered with 30 mmol/L glucose for 24 h afterward. The apoptosis of cell was detected by flow cytometry. Nitric oxide (NO) production was detected by NO probe and ELISA kit. The intracellular reactive oxygen species (ROS) levels were tested by DHE staining and ELISA kit. Type 2 diabetic model mice were established and then divided into T2DM group and T2DM+Asp group. After the model mice were established successfully (random blood glucose was more than 16.7 mmol/L), Asp (1 &#x3bc;g/g) was intraperitoneally injected once a day. After 2 weeks, mice echocardiography was performed to test cardiac diastolic function. The integrity of the microvascular endothelium was observed by scanning electron microscopy.<br><br>RESULTS: Compared with the normal group, the mRNA level of SPG20 and protein expression of spartin in mice CMECs of HG group were significantly reduced (P < 0.05). Under the condition of high glucose, Ad transfection induced significant decrease of the intracellular ROS level and the apoptosis level of the CMECs (P < 0.05), while NO increased after Ad transfection. In contrast, siRNA intervention resulted in opposite effect. In addition, the antioxidant NAC partly reversed the above changes caused by downregulating spartin. Asp upregulated the level of SPG20 mRNA and spartin protein expression in CMECs, reduced ROS production, reduced apoptosis and increased NO production. However, intervention effects of Asp, such as decreasing of ROS production, inhibiting apoptosis of CMECs and increasing of NO production, were partly reversed in spartin downregulated cells. In vivo, we found that Asp can improve cardiac function and increase the integrity and smoothness of cardiac microvascular endothelium in type 2 diabetic mice.<br><br>CONCLUSION: Asp can inhibit oxidative stress in mice CMECs through upregulating spartin signaling pathway, thereby alleviating the damage of microvascular endothelium in diabetic heart.}, }
@article {pmid31877368, year = {2020}, author = {Patra, S and Panda, PK and Naik, PP and Panigrahi, DP and Praharaj, PP and Bhol, CS and Mahapatra, KK and Padhi, P and Jena, M and Patil, S and Patra, SK and Bhutia, SK}, title = {Terminalia bellirica extract induces anticancer activity through modulation of apoptosis and autophagy in oral squamous cell carcinoma.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {136}, number = {}, pages = {111073}, doi = {10.1016/j.fct.2019.111073}, pmid = {31877368}, issn = {1873-6351}, mesh = {Antineoplastic Agents, Alkylating/analysis/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Carcinoma, Squamous Cell ; Cell Line, Tumor ; DNA Damage/drug effects ; Humans ; Mouth Neoplasms/drug therapy/metabolism/*physiopathology ; Plant Extracts/analysis/*pharmacology ; Reactive Oxygen Species/metabolism ; Terminalia/*chemistry ; }, abstract = {Terminalia bellirica (TB) has been used in traditional Indian medical system, Ayurveda. However, the mechanism underlying the efficacy of the TB extract against oral squamous cell carcinoma (OSCC) is yet to be explored. The present study established a connecting link between the TB extract induced apoptosis and autophagy in relation to reactive oxygen species (ROS). Our study revealed, that gallic acid in the TB extract possess a strong free radical scavenging capacity contributing towards the selective anti-proliferative activity. Furthermore, TB extract markedly enhanced the accumulation of ROS that facilitated mitochondrial apoptosis through DNA damage, indicating ROS as the vital component in regulation of apoptosis. This effect was effectively reversed by the use of a ROS scavenger, N-acetyl cysteine (NAC). Moreover, it was observed to induce autophagy; however, it attenuated the autophagosome-lysosome fusion in Cal33 cells without altering the lysosomal activity. Pharmacological inhibitors of autophagy, namely, 3-methyladenine and chloroquine, were demonstarated to regulate the stage-specific progression of autophagy post treatment with the TB extract, favouring subsequent activation of apoptosis. These findings revealed, presence of gallic acid in TB extract below NOAEL value causes oxidative upset in oral cancer cells and promote programmed cell death which has a potential therapeutic value against oral squamous cell carcinoma.}, }
@article {pmid31874367, year = {2020}, author = {Li, C and Sun, X and Li, A and Mo, M and Zhao, Z}, title = {S-Allylmercaptocysteine attenuates Bleomycin-induced pulmonary fibrosis in mice via suppressing TGF-β1/Smad and oxidative stress pathways.}, journal = {International immunopharmacology}, volume = {79}, number = {}, pages = {106110}, doi = {10.1016/j.intimp.2019.106110}, pmid = {31874367}, issn = {1878-1705}, mesh = {Animals ; Antioxidants/*therapeutic use ; Bleomycin ; Bronchoalveolar Lavage Fluid/immunology ; Cysteine/*analogs &amp; derivatives/therapeutic use ; Disease Models, Animal ; Female ; Humans ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Pulmonary Fibrosis/*drug therapy ; Signal Transduction ; Smad Proteins/metabolism ; Transforming Growth Factor beta1/metabolism ; }, abstract = {Pulmonary fibrosis (PF) is a disease characterized by diffusing alveolar inflammation and alveolar structural disorders that ultimately lead to pulmonary interstitial fibrosis. S-allylmercaptocysteine (SAMC) as a water-soluble organosulfur garlic derivative exhibits efficient anti-inflammatory and anti-oxidative activities. In this study, we attempted to explore the function of SAMC in inhibiting bleomycin (BLM)-induced pulmonary fibrosis in mice. 0.035 U/g of BLM was intraperitoneally injected into mice twice per week for 4 weeks to induce fibrosis. SAMC (25 and 50 mg/kg) and N-acetylcysteine (NAC, 600 mg/kg) were given to mice for 28 days. The results indicate that SAMC could significantly ameliorate the pathological structure, and decrease inflammatory cell infiltration and pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) in BLM-induced pulmonary fibrosis mice. SAMC showed an anti-fibrosis effect by increasing anti-oxidants like HO-1, GSH and SOD as well as decreasing hydroxyproline (HYP) in BLM-induced mice. Mechanistic studies suggested that SAMC alleviated oxidative stress probably by impacting the Nox4/Nrf2 pathways, and played an anti-fibrosis role with decreasing the expression of α-SMA, collagen III, collagen I by suppressing the TGF-β1/Smad pathway. These findings indicate that SAMC may be partially responsible for the therapeutic effect on PF patients.}, }
@article {pmid31874349, year = {2020}, author = {Martínez, MA and Rodríguez, JL and Lopez-Torres, B and Martínez, M and Martínez-Larrañaga, MR and Maximiliano, JE and Anadón, A and Ares, I}, title = {Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways.}, journal = {Environment international}, volume = {135}, number = {}, pages = {105414}, doi = {10.1016/j.envint.2019.105414}, pmid = {31874349}, issn = {1873-6750}, mesh = {Cell Death ; Cell Line, Tumor ; Cell Survival ; Glycine/analogs &amp; derivatives ; Humans ; *Neuroblastoma ; *Oxidative Stress ; Reactive Oxygen Species ; Glyphosate ; }, abstract = {Glyphosate-containing herbicides are the most used agrochemicals in the world. Their indiscriminate application raises some concerns regarding the possible health and environmental hazards. In this study, we investigated in human neuroblastoma cell line SH-SY5Y if oxidative stress, altered neurodevelopment and cell death pathways are involved in response to glyphosate and its metabolite aminomethylphosphonic acid (AMPA) exposures. MTT and LDH assays were carried out to assess the glyphosate and AMPA cytotoxicity. Lipid peroxides measured as malondialdehyde (MDA), nitric oxide (NO) and reactive oxygen species (ROS) production, and caspase-Glo 3/7 activity were evaluated. The neuroprotective role of melatonin (MEL), Trolox, N-acetylcysteine (NAC) and Sylibin against glyphosate- and AMPA-induced oxidative stress was examined. Glyphosate and AMPA effects on neuronal development related gene transcriptions, and gene expression profiling of cell death pathways by Real-Time PCR array were also investigated. Glyphosate (5 mM) and AMPA (10 mM) induced a significant increase in MDA levels, NO and ROS production and caspase 3/7 activity. Glyphosate exposure induced up-regulation of Wnt3a, Wnt5a, Wnt7a, CAMK2A, CAMK2B and down-regulation of GAP43 and TUBB3 mRNA expression involved in normal neural cell development. In relation to gene expression profiling of cell death pathways, of the 84 genes examined in cells a greater than 2-fold change was observed for APAF1, BAX, BCL2, CASP3, CASP7, CASP9, SYCP2, TNF, TP53, CTSB, NFκB1, PIK3C3, SNCA, SQSTMT, HSPBAP1 and KCNIPI mRNA expression for glyphosate and AMPA exposures. These gene expression data can help to define neurotoxic mechanisms of glyphosate and AMPA. Our results demonstrated that glyphosate and AMPA induced cytotoxic effects on neuronal development, oxidative stress and cell death via apoptotic, autophagy and necrotic pathways and confirmed that glyphosate environmental exposure becomes a concern. This study demonstrates that SH-SY5Y cell line could be considered an in vitro system for pesticide screening.}, }
@article {pmid31868975, year = {2020}, author = {Contreras, MJ and Treulen, F and Arias, ME and Silva, M and Fuentes, F and Cabrera, P and Felmer, R}, title = {Cryopreservation of stallion semen: Effect of adding antioxidants to the freezing medium on sperm physiology.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {55}, number = {2}, pages = {229-239}, doi = {10.1111/rda.13611}, pmid = {31868975}, issn = {1439-0531}, support = {1160467//Consejo Nacional de Innovaci&#xf3;n, Ciencia y Tecnolog&#xed;a/ ; 21181068,//CONICYT/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Membrane/drug effects ; Cryopreservation/methods/*veterinary ; Cryoprotective Agents/*pharmacology ; DNA Fragmentation ; Horses ; Male ; Membrane Lipids ; Membrane Potential, Mitochondrial/drug effects ; Metalloporphyrins/pharmacology ; Oxidative Stress ; Semen Preservation/methods/*veterinary ; Sperm Motility/drug effects ; Zona Pellucida/physiology ; }, abstract = {Cryopreservation of stallion semen has not reached the level of efficiency and positive results described in other species. This is mainly due to the greater sensitivity of stallion sperm to the freezing process, showing higher rates of oxidative stress and plasma membrane damage, which trigger the activation of several cell damage pathways that ultimately culminate in DNA fragmentation and cell death. Therefore, finding molecules that improve the efficiency of this technique in stallion by preventing oxidative stress and cell damage is required. Thus, the aim of the present study was to evaluate the effect of adding three antioxidants (MnTBAP, NAC and FeTPPS) to the freezing medium on the quality and functional parameters of stallion sperm. Semen samples from three stallions frozen with the antioxidants were evaluated in two conditions: (a) adding the antioxidants before freezing, and (b) before and after freezing. Plasma membrane integrity, mitochondrial membrane potential, lipid peroxidation, intracellular ROS levels, membrane lipid disorder, DNA damage, sperm motility and binding to the zona pellucida were assessed. The results showed that MnTBAP was the antioxidant treatment that best controlled the oxidative stress process and post-thaw cell damage, showing higher plasma membrane integrity, mitochondrial membrane potential, sperm motility, number of spermatozoa bound to the zona pellucida of bovine oocytes and lower lipid disorder. Additionally, it was determined that a second post-thaw application of antioxidants is detrimental since induced higher cell damage and lower sperm motility, without showing any beneficial effect on the spermatozoa.}, }
@article {pmid31863459, year = {2020}, author = {Taniguchi, N and Osaki, M and Onuma, K and Ishikawa, M and Ryoke, K and Kodani, I and Okada, F}, title = {Bisphosphonate-induced reactive oxygen species inhibit proliferation and migration of oral fibroblasts: A pathogenesis of bisphosphonate-related osteonecrosis of the jaw.}, journal = {Journal of periodontology}, volume = {91}, number = {7}, pages = {947-955}, doi = {10.1002/JPER.19-0385}, pmid = {31863459}, issn = {1943-3670}, mesh = {Animals ; *Bisphosphonate-Associated Osteonecrosis of the Jaw ; *Bone Density Conservation Agents ; Cell Proliferation ; Diphosphonates ; Fibroblasts ; Humans ; Mice ; Mice, Inbred C57BL ; Reactive Oxygen Species ; Zoledronic Acid ; }, abstract = {BACKGROUND: The onset mechanism for bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been reported, with a focus on bone remodeling, biofilm formation, and epithelial cell proliferation and migration. However, the involvement of stromal cells, especially fibroblasts, in the oral cavity is unclear. Therefore, this study was focused on how bisphosphonates (BPs) affect orthotopic periodontal ligament fibroblasts from the viewpoint of oxidative stress compared with ectopically obtained fibroblasts.<br><br>METHODS: Normal human periodontal ligament fibroblasts (HPdLFs) and normal human dermal fibroblasts (NHDFs) were used to gain insight into the functional differences in sensitivity and reactions to BPs. Cell growth assay, measurement of reactive oxygen species (ROS) and nitric oxide (NO) production, and wound-healing assay in vitro were performed. Maxillary first molars were extracted in C57BL/6 mice and either BP, N-acetyl-cysteine (NAC), and BP or saline were administered.<br><br>RESULTS: BP-induced IC50 values were significantly lower in HPdLFs (30.6 &#xb5;M) than in NHDFs (109.7 &#xb5;M). BP resulted in an increase in ROS, but not NO generation in HPdLFs. BPs also inhibited proliferation and migration of HPdLFs but not NHDFs, while the addition of a ROS inhibitor, NAC, reversed those inhibitions. A BRONJ mouse model in which BP was administered and then the tooth was extracted, impaired wound healing of the socket was observed. When NAC was administered before tooth extraction, wound healing was significantly improved.<br><br>CONCLUSION: These results suggest that BP causes fibroblasts obtained from the oral cavity but not from skin to generate ROS and that the subsequent ROS-mediated inhibition of fibroblast growth and migration definitely delays wound healing, thereby contributing to BRONJ pathogenesis.}, }
@article {pmid31861240, year = {2019}, author = {Vukovic, R and Kumburovic, I and Joksimovic Jovic, J and Jovicic, N and Katanic Stankovic, JS and Mihailovic, V and Djuric, M and Velickovic, S and Arnaut, A and Selakovic, D and Rosic, G}, title = {N-Acetylcysteine Protects against the Anxiogenic Response to Cisplatin in Rats.}, journal = {Biomolecules}, volume = {9}, number = {12}, pages = {}, pmid = {31861240}, issn = {2218-273X}, mesh = {Acetylcysteine/administration &amp; dosage/chemistry/*pharmacology ; Animals ; Anti-Anxiety Agents/administration &amp; dosage/chemistry/*pharmacology ; Antineoplastic Agents/administration &amp; dosage ; Antioxidants/administration &amp; dosage ; Anxiety/*chemically induced/*drug therapy ; Behavior, Animal/drug effects ; Cisplatin/administration &amp; dosage/*adverse effects ; Male ; Oxidative Stress/drug effects ; Protective Agents/administration &amp; dosage/chemistry/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {Since cisplatin therapy is usually accompanied with numerous toxicities, including neurotoxicity, that involve tissue oxidative damage, the aim of this study was to evaluate the possible protective effect of N-acetylcysteine (NAC) on the anxiogenic response to cisplatin (CIS). Thirty-two male Wistar albino rats divided into four groups (control, cisplatin, NAC, and CIS + NAC). All treatments were delivered intraperitoneally. On day one, the control and cisplatin groups received saline while the NAC and CIS + NAC groups were administered with NAC (500 mg/kg). On the fifth day, the control group received saline while the CIS group was treated with cisplatin (7.5 mg/kg), the NAC group again received NAC (500 mg/kg), and the CIS + NAC group was simultaneously treated with cisplatin and NAC (7.5 and 500 mg/kg, respectively). Behavioral testing, performed on the tenth day in the open field (OF) and elevated plus maze (EPM) tests, revealed the anxiogenic effect of cisplatin that was significantly attenuated by NAC. The hippocampal sections evaluation showed increased oxidative stress (increased lipid peroxidation and decline in antioxidant enzymes activity) and proapoptotic action (predominantly by diminished antiapoptotic gene expression) following a single dose of cisplatin. NAC supplementation along with cisplatin administration reversed the prooxidative and proapoptotic effects of cisplatin. In conclusion, the results obtained in this study confirmed that antioxidant supplementation with NAC may attenuate the cisplatin-induced anxiety. The mechanism of anxiolytic effect achieved by NAC may include the decline in oxidative damage that down regulates increased apoptosis and reverses the anxiogenic action of cisplatin.}, }
@article {pmid31860682, year = {2019}, author = {Alnahdi, A and John, A and Raza, H}, title = {N-acetyl cysteine attenuates oxidative stress and glutathione-dependent redox imbalance caused by high glucose/high palmitic acid treatment in pancreatic Rin-5F cells.}, journal = {PloS one}, volume = {14}, number = {12}, pages = {e0226696}, pmid = {31860682}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Catalase/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytokines/metabolism ; Glucose/*pharmacology ; Glutathione/*metabolism ; Insulin-Secreting Cells/*metabolism ; NF-kappa B/metabolism ; Nitric Oxide/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Palmitic Acid/*pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; }, abstract = {Elevated levels of glucose and fatty acids are the main characteristics of diabetes, obesity and other metabolic disorders, associated with increased oxidative stress, mitochondrial dysfunction and inflammation. Once the primary pathogenesis of diabetes is established, which is potentially linked to both genetic and environmental factors, hyperglycemia and hyperlipidemia exert further destructive and/or toxic effects on β-cells. The concept of glucolipotoxicity has arisen from the combination of deleterious effects of chronic elevation of glucose and fatty acid levels on pancreatic β- cell function and/or survival. Though numerous studies have been conducted in this field, the exact molecular mechanisms and causative factors still need to be established. The aim of the present work was to elucidate the molecular mechanisms of oxidative stress, and inflammatory/antioxidant responses in the presence of high concentrations of glucose/fatty acids in a cell-culture system using an insulin-secreting pancreatic β-cell line (Rin-5F) and to study the effects of the antioxidant, N-acetyl cysteine (NAC) on β-cell toxicity. In our study, we investigated the molecular mechanism of cytotoxicity in the presence of high glucose (up to 25 mM) and high palmitic acid (up to 0.3 mM) on Rin-5F cells. Our results suggest that the cellular and molecular mechanisms underlying β-cell toxicity are mediated by increased oxidative stress, imbalance of redox homeostasis, glutathione (GSH) metabolism and alterations in inflammatory responses. Pre-treatment with NAC attenuated oxidative stress and alterations in GSH metabolism associated with β-cells cytotoxicity.}, }
@article {pmid31857147, year = {2020}, author = {Yeh, LC and Shyu, HW and Jin, YR and Chiou, YH and Lin, KH and Chou, MC and Huang, MH and Wang, YF}, title = {Epigallocatechin-3-gallate downregulates PDHA1 interfering the metabolic pathways in human herpesvirus 8 harboring primary effusion lymphoma cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {65}, number = {}, pages = {104753}, doi = {10.1016/j.tiv.2019.104753}, pmid = {31857147}, issn = {1879-3177}, mesh = {Catechin/*analogs &amp; derivatives/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Down-Regulation/drug effects ; Glutarates/metabolism ; *Herpesvirus 8, Human ; Humans ; Lymphoma, Primary Effusion/genetics/*metabolism/virology ; Metabolic Networks and Pathways/*drug effects ; Pyruvate Dehydrogenase (Lipoamide)/*genetics ; }, abstract = {Primary effusion lymphoma (PEL) is an aggressive neoplasm correlated with human herpesvirus 8 (HHV8). Metabolic reprogramming is a hallmark of cancers. The alterations in cellular metabolism are important to the survival of HHV8 latently infected cells. Pyruvate dehydrogenase (PDH) controls the flux of metabolites between glycolysis and the tricarboxylic acid cycle (TCA cycle) and is a key enzyme in cancer metabolic reprogramming. Glutaminolysis is required for the survival of PEL cells. Glutamate dehydrogenase 1 (GDH1) converts glutamate into α-ketoglutarate supplying the TCA cycle with intermediates to support anaplerosis. Previously we have observed that epigallocatechin-3-gallate (EGCG) can induce PEL cell death and N-acetyl cysteine (NAC) attenuates EGCG induced PEL cell death. In this study, results showed that EGCG upregulated the expression of glucose transporter GLUT3, and reduced the expression of pyruvate dehydrogenase E1-alpha (PDHA1), the major regulator of PDH, and GDH1. NAC could partially reverse the effects of EGCG in PEL cells. Overexpression of PDHA1 in PEL cells or supplement of α-ketoglutarate attenuated EGCG induced cell death. EGCG also reduced the levels of oncometabolite D-2-hydroxyglutarate (D2HG). These results suggest that EGCG may modulate the metabolism of PEL cells leading to cell death.}, }
@article {pmid31854983, year = {2020}, author = {Deng, HH and Huang, KY and He, SB and Xue, LP and Peng, HP and Zha, DJ and Sun, WM and Xia, XH and Chen, W}, title = {Rational Design of High-Performance Donor-Linker-Acceptor Hybrids Using a Schiff Base for Enabling Photoinduced Electron Transfer.}, journal = {Analytical chemistry}, volume = {92}, number = {2}, pages = {2019-2026}, doi = {10.1021/acs.analchem.9b04434}, pmid = {31854983}, issn = {1520-6882}, mesh = {Acetylcysteine/chemistry/*metabolism ; Cysteamine/chemistry/*metabolism ; Density Functional Theory ; Electron Transport ; Gold/chemistry/*metabolism ; Metal Nanoparticles/*chemistry ; Particle Size ; Photochemical Processes ; Pyridoxal Phosphate/chemistry/*metabolism ; Schiff Bases/chemistry/metabolism ; Surface Properties ; }, abstract = {Donor-linker-acceptor (D-L-A)-based photoinduced electron transfer (PET) has been frequently used for the construction of versatile fluorescent chemo/biosensors. However, sophisticated and tedious processes are generally required for the synthesis of these probes, which leads to poor design flexibility. In this work, by exploiting a Schiff base as a linker unit, a covalently bound D-L-A system was established and subsequently utilized for the development of a PET sensor. Cysteamine (Cys) and N-acetyl-l-cysteine (NAC) costabilized gold nanoclusters (Cys/NAC-AuNCs) were synthesized and adopted as an electron acceptor, and pyridoxal phosphate (PLP) was selected as an electron donor. PLP can form a Schiff base (an aldimine) with the primary amino group of Cys/NAC-AuNC through its aldehyde group and thereby suppresses the fluorescence of Cys/NAC-AuNC. The Rehm-Weller formula results and a HOMO-LUMO orbital study revealed that a reductive PET mechanism is responsible for the observed fluorescence quenching. Since the pyridoxal (PL) produced by the acid phosphatase (ACP)-catalyzed cleavage of PLP has a weak interaction with Cys/NAC-AuNC, a novel turn-on fluorescent method for selective detection of ACP was successfully realized. To the best of our knowledge, this is the first example of the development of a covalently bound D-L-A system for fluorescent PET sensing of enzyme activity based on AuNC nanoprobes using a Schiff base.}, }
@article {pmid31853976, year = {2020}, author = {Fulas, OA and Laferriere, A and Stein, RS and Bohle, DS and Coderre, TJ}, title = {Topical combination of meldonium and N-acetyl cysteine relieves allodynia in rat models of CRPS-1 and peripheral neuropathic pain by enhancing NO-mediated tissue oxygenation.}, journal = {Journal of neurochemistry}, volume = {152}, number = {5}, pages = {570-584}, doi = {10.1111/jnc.14943}, pmid = {31853976}, issn = {1471-4159}, support = {//CIHR/Canada ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Topical ; Animals ; Disease Models, Animal ; Hyperalgesia/metabolism ; Male ; Methylhydrazines/*administration &amp; dosage ; Neuralgia/*metabolism ; Nitric Oxide/*metabolism ; Rats ; Rats, Long-Evans ; Rats, Sprague-Dawley ; Reflex Sympathetic Dystrophy/*metabolism ; }, abstract = {Local microvascular dysfunction and consequent tissue ischemia/hypoxia contribute to the symptoms of complex regional pain syndrome (CRPS) and peripheral neuropathic pain. As nitric oxide (NO) is a key regulator of microvascular blood flow, compounds that increase it are potentially therapeutic for these pain conditions. This led us to hypothesize that the topical administration of drugs that modulate local tissue NO levels can alleviate the pain of CRPS and peripheral neuropathic pain. We investigated the anti-allodynic effect of a combination of two NO-modulating drugs: meldonium and N-acetylcysteine (NAC). An equimolar topical formulation of the two drugs was tested on chronic post-ischemic pain (CPIP), a rat model of CRPS, as well as chronic constriction injury (CCI) of the sciatic nerve and chemotherapy-induced painful neuropathy (CIPN), rat models of peripheral neuropathic pain. Topical meldonium-NAC produced significant anti-allodynia in CPIP, CCI, and CIPN rats. Moreover repeated application of topical meldonium-NAC produced an increase in the duration of anti-allodynia in the CPIP and CCI rats. While pre-treatment with an NO synthase inhibitor attenuated the anti-allodynic effects of meldonium-NAC, 30-min hyperbaric oxygen treatment combined with a non-effective dose of meldonium-NAC produced significant anti-allodynic effects in CPIP rats. Both experiments implicated NO in the drug combination's anti-allodynic effects. To ascertain the role played by changes in local tissue NO, we performed a quantification of plantar muscle NO in CPIP rats after hind paw topical treatment with meldonium-NAC and revealed significantly increased plantar muscle NO levels in drug-treated rats. The drug combination also reversed the reduction in tissue oxygenation normally observed in CPIP hind paws. In addition to introducing a novel topical treatment for mechanical allodynia in CRPS and peripheral neuropathic pain, this work showcases the analgesic potential of locally targeting microvascular dysfunction and tissue ischemia/hypoxia in these conditions, with emphasis on the role of NO.}, }
@article {pmid31852820, year = {2020}, author = {Liu, C and Miyajima, T and Melangath, G and Miyai, T and Vasanth, S and Deshpande, N and Kumar, V and Ong Tone, S and Gupta, R and Zhu, S and Vojnovic, D and Chen, Y and Rogan, EG and Mondal, B and Zahid, M and Jurkunas, UV}, title = {Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be more affected.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {117}, number = {1}, pages = {573-583}, pmid = {31852820}, issn = {1091-6490}, support = {K99 EY031339/EY/NEI NIH HHS/United States ; P30 EY003790/EY/NEI NIH HHS/United States ; R01 EY020581/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Aqueous Humor/drug effects/metabolism/radiation effects ; Cytochrome P-450 CYP1B1/*metabolism ; DNA Adducts/metabolism/*radiation effects ; DNA Damage/drug effects/*radiation effects ; DNA, Mitochondrial/metabolism/radiation effects ; Disease Models, Animal ; Endothelium, Corneal/drug effects/pathology/radiation effects ; Estrogens/*metabolism ; Female ; Free Radical Scavengers/administration &amp; dosage ; Fuchs' Endothelial Dystrophy/diagnosis/drug therapy/*etiology/pathology ; Humans ; Male ; Mice ; Oxidative Stress/radiation effects ; Reactive Oxygen Species/metabolism ; Severity of Illness Index ; Ultraviolet Rays/*adverse effects ; }, abstract = {Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation of N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development.}, }
@article {pmid31848062, year = {2021}, author = {Jo, YS and Choi, IS and So, YK}, title = {The Use of Inhaled N-Acetylcysteine for Laryngopharyngeal Reflux Disease: A Randomized Controlled Trial.}, journal = {Journal of voice : official journal of the Voice Foundation}, volume = {35}, number = {4}, pages = {618-624}, doi = {10.1016/j.jvoice.2019.11.017}, pmid = {31848062}, issn = {1873-4588}, mesh = {*Acetylcysteine/adverse effects ; Humans ; *Laryngopharyngeal Reflux/diagnosis/drug therapy ; Prospective Studies ; Proton Pump Inhibitors/adverse effects ; Treatment Outcome ; }, abstract = {OBJECTIVES: Proton pump inhibitors (PPIs) are the mainstay of the medical treatment for laryngopharyngeal reflux disease (LPRD). However, extraesophageal symptoms of LPRD, such as globus, are often refractory to PPI treatment. Many kinds of adjunctive medications have been attempted to address those refractory cases. We aimed to study whether inhaled N-acetylcysteine (NAC), a mucolytic agent, has additive effects for the treatment of LPRD when used in conjunction with PPIs.<br><br>METHODS: Patients with reflux symptom index (RSI) greater than 13 and reflux finding scores (RFS) greater than 7 were prospectively enrolled and were randomly assigned to control or study group. Patients were treated with oral rabeprazole in the control group and with oral rabeprazole and inhaled NAC in the study group. Patients were followed once a month for 2 months with questionnaires and stroboscopic examination. At every follow-up, RSI and RFS were checked. The extent of improvements of RSI and RFS were evaluated and compared between two groups.<br><br>RESULTS: With treatment, the mean RSI changed from 21.0 to 7.6 (P < 0.001) in control group and from 19.7 to 4.5 (P < 0.001) in study group. The mean RFS also changed from 12.9 to 7.1 (P < 0.001) in control group and from 13.5 to 6.9 (P < 0.001) in study group. For both RSI and RFS, the extents of improvement were not significantly different between two groups. In patients whose RSI improved less than nine at the first follow-up (poor early responders), RSI became significantly lower in the study group (4.6 &#xb1; 2.0) than in the control group (9.5 &#xb1; 4.6) at second follow-up (P&#xa0;=&#xa0;0.019). In good early responders, however, RSI was not significantly different between the two groups in the second follow-up.<br><br>CONCLUSIONS: In this study, there were no significant differences in the overall outcome between patients treated with inhaled NAC and PPI and those with PPI alone. Interestingly, some additional therapeutic effect of NAC appeared late for the patients with poor early response. Further studies are required to investigate the underlying mechanism for this.}, }
@article {pmid31843961, year = {2020}, author = {Lensmire, JM and Dodson, JP and Hsueh, BY and Wischer, MR and Delekta, PC and Shook, JC and Ottosen, EN and Kies, PJ and Ravi, J and Hammer, ND}, title = {The Staphylococcus aureus Cystine Transporters TcyABC and TcyP Facilitate Nutrient Sulfur Acquisition during Infection.}, journal = {Infection and immunity}, volume = {88}, number = {3}, pages = {}, pmid = {31843961}, issn = {1098-5522}, support = {R01 AI139074/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Cystine/*metabolism ; Membrane Transport Proteins/*physiology ; Mice ; Staphylococcal Infections/*metabolism ; Staphylococcus aureus/*physiology ; Sulfur/*metabolism ; }, abstract = {Staphylococcus aureus is a significant human pathogen due to its capacity to cause a multitude of diseases. As such, S. aureus efficiently pillages vital nutrients from the host; however, the molecular mechanisms that support sulfur acquisition during infection have not been established. One of the most abundant extracellular sulfur-containing metabolites within the host is cysteine, which acts as the major redox buffer in the blood by transitioning between reduced and oxidized (cystine) forms. We therefore hypothesized that S. aureus acquires host-derived cysteine and cystine as sources of nutrient sulfur during systemic infection. To test this hypothesis, we used the toxic cystine analogue selenocystine to initially characterize S. aureus homologues of the Bacillus subtilis cystine transporters TcyABC and TcyP. We found that genetic inactivation of both TcyA and TcyP induced selenocystine resistance. The double mutant also failed to proliferate in medium supplemented with cystine, cysteine, or N-acetyl cysteine as the sole sulfur source. However, only TcyABC was necessary for proliferation in defined medium containing homocystine as the sulfur source. Using a murine model of systemic infection, we observed tcyP-dependent competitive defects in the liver and heart, indicating that this sulfur acquisition strategy supports proliferation of S. aureus in these organs. Phylogenetic analyses identified TcyP homologues in many pathogenic species, implying that this sulfur procurement strategy is conserved. In total, this study is the first to experimentally validate sulfur acquisition systems in S. aureus and establish their importance during pathogenesis.}, }
@article {pmid31842349, year = {2019}, author = {Yu, G and Luo, H and Zhang, N and Wang, Y and Li, Y and Huang, H and Liu, Y and Hu, Y and Liu, H and Zhang, J and Tang, Y and Huang, Y}, title = {Loss of p53 Sensitizes Cells to Palmitic Acid-Induced Apoptosis by Reactive Oxygen Species Accumulation.}, journal = {International journal of molecular sciences}, volume = {20}, number = {24}, pages = {}, pmid = {31842349}, issn = {1422-0067}, support = {31501322//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Apoptosis/*drug effects/*genetics ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Resistance/*genetics ; Fibroblasts ; Gene Deletion ; HCT116 Cells ; Humans ; Mice ; Palmitic Acid/*pharmacology ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/*deficiency ; }, abstract = {Palmitic acid, the most common saturated free fatty acid, can lead to lipotoxicity and apoptosis when overloaded in non-fat cells. Palmitic acid accumulation can induce pancreatic β-cell dysfunction and cardiac myocyte apoptosis. Under various cellular stresses, the activation of p53 signaling can lead to cell cycle arrest, DNA repair, senescence, or apoptosis, depending on the severity/type of stress. Nonetheless, the precise role of p53 in lipotoxicity induced by palmitic acid is not clear. Here, our results show that palmitic acid induces p53 activation in a dose- and time-dependent manner. Furthermore, loss of p53 makes cells sensitive to palmitic acid-induced apoptosis. These results were demonstrated in human colon carcinoma cells (HCT116) and primary mouse embryo fibroblasts (MEF) through analysis of DNA fragmentation, flow cytometry, colony formation, and Western blots. In the HCT116 p53[-/-] cell line, palmitic acid induced greater reactive oxygen species formation compared to the p53[+/+] cell line. The reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and reduced glutathione (GSH) partially attenuated apoptosis in the HCT116 p53[-/-] cell line but had no obvious effect on the p53[+/+] cell line. Furthermore, p53 induced the expression of its downstream target genes, p21 and Sesn2, in response to ROS induced by palmitic acid. Loss of p21 also leads to more palmitic acid-induced cell apoptosis in the HCT116 cell line compared with HCT116 p53[+/+] and HCT116 p53[-/-]. In a mouse model of obesity, glucose tolerance test assays showed higher glucose levels in p53[-/-] mice that received a high fat diet compared to wild type mice that received the same diet. There were no obvious differences between p53[-/-] and p53[+/+] mice that received a regular diet. We conclude that p53 may provide some protection against palmitic acid- induced apoptosis in cells by targeting its downstream genes in response to this stress.}, }
@article {pmid31841237, year = {2020}, author = {Raevens, S and Van Campenhout, S and Debacker, PJ and Lefere, S and Verhelst, X and Geerts, A and Van Vlierberghe, H and Colle, I and Devisscher, L}, title = {Combination of sivelestat and N-acetylcysteine alleviates the inflammatory response and exceeds standard treatment for acetaminophen-induced liver injury.}, journal = {Journal of leukocyte biology}, volume = {107}, number = {2}, pages = {341-355}, doi = {10.1002/JLB.5A1119-279R}, pmid = {31841237}, issn = {1938-3673}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/pathology ; Drug Therapy, Combination ; Free Radical Scavengers/pharmacology ; Glycine/*analogs &amp; derivatives/pharmacology ; Inflammation/etiology/pathology/*prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Serine Proteinase Inhibitors/pharmacology ; Sulfonamides/*pharmacology ; }, abstract = {Hepatocyte death during acetaminophen (APAP) intoxication elicits a reactive inflammatory response, with hepatic recruitment of neutrophils and monocytes, which further aggravates liver injury. Neutrophil elastase (NE), secreted by activated neutrophils, carries degradative and cytotoxic functions and maintains a proinflammatory state. We investigated NE as a therapeutic target in acetaminophen-induced liver injury (AILI). C57BL/6 mice were administered a toxic dose of APAP, 2 h prior to receiving the NE inhibitor sivelestat, N-acetylcysteine (NAC), or a combination therapy, and were euthanized after 24 and 48 h. Upon APAP overdose, neutrophils and monocytes infiltrate the injured liver, accompanied by increased levels of NE. Combination therapy of NAC and sivelestat significantly limits liver damage, as evidenced by lower serum transaminase levels and less hepatic necrosis compared to mice that received APAP only, and this to a greater extent than NAC monotherapy. Lower hepatic expression of proinflammatory markers was observed in the combination treatment group, and flow cytometry revealed significantly less monocyte influx in livers from mice treated with the combination therapy, compared to untreated mice and mice treated with NAC only. The potential of NE to induce leukocyte migration was confirmed in vitro. Importantly, sivelestat did not impair hepatic repair. In conclusion, combination of NE inhibition with sivelestat and NAC dampens the inflammatory response and reduces liver damage following APAP overdose. This strategy exceeds the standard of care and might represent a novel therapeutic option for AILI.}, }
@article {pmid31839216, year = {2020}, author = {Yamamura, H and Suzuki, Y and Asai, K and Imaizumi, Y and Yamamura, H}, title = {Oxidative stress facilitates cell death by inhibiting Orai1-mediated Ca[2+] entry in brain capillary endothelial cells.}, journal = {Biochemical and biophysical research communications}, volume = {523}, number = {1}, pages = {153-158}, doi = {10.1016/j.bbrc.2019.12.035}, pmid = {31839216}, issn = {1090-2104}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood-Brain Barrier/drug effects/metabolism ; Calcium/*metabolism ; Cattle ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Endothelial Cells/*drug effects/metabolism ; Hydrogen Peroxide/antagonists &amp; inhibitors/pharmacology ; ORAI1 Protein/*antagonists &amp; inhibitors/metabolism ; *Oxidative Stress/drug effects ; }, abstract = {Brain capillary endothelial cells (BCECs) form the blood-brain barrier (BBB) and play an essential role in the regulation of its functions. Oxidative stress accumulates excessive reactive oxygen species (ROS) and facilitates the death of BCECs, leading to a dysfunctional BBB. However, the mechanisms underlying the death of BCECs under oxidative stress remain unclear. In the present study, the effects of oxidative stress on cell viability, ROS production, intracellular Ca[2+] concentration, and protein expression were examined using a cell line derived from bovine BCECs, t-BBEC117. When t-BBEC117 cells were exposed to oxidative stress induced by hydrogen peroxide (H2O2, 10-100 μM), cell growth was inhibited in a dose-dependent manner. Oxidative stress by 30 μM H2O2 increased the production of ROS and its effects were blocked by the ROS scavenger, 10 mM N-acetyl-l-cysteine (NAC). In addition, oxidative stress reduced store-operated Ca[2+] entry (SOCE) and this decrease was recovered by NAC or the Orai channel activator, 5 μM 2-aminoethyl diphenylborinate (2-APB). The siRNA knockdown of Orai1 revealed that Orai1 was mainly responsible for SOCE channels and its activity was decreased by oxidative stress. However, the protein expression of Orai1 and STIM1 was not affected by oxidative stress. Oxidative stress-induced cell death was rescued by 2-APB, NAC, or the STIM-Orai activating region. In conclusion, oxidative stress reduces Orai1-mediated SOCE and, thus, facilitates the death of BCECs.}, }
@article {pmid31838118, year = {2020}, author = {Keshk, WA and Ibrahim, MA and Shalaby, SM and Zalat, ZA and Elseady, WS}, title = {Redox status, inflammation, necroptosis and inflammasome as indispensable contributors to high fat diet (HFD)-induced neurodegeneration; Effect of N-acetylcysteine (NAC).}, journal = {Archives of biochemistry and biophysics}, volume = {680}, number = {}, pages = {108227}, doi = {10.1016/j.abb.2019.108227}, pmid = {31838118}, issn = {1096-0384}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Diet, High-Fat/adverse effects ; Inflammasomes/drug effects/metabolism ; Inflammation/etiology/metabolism/*prevention &amp; control ; Male ; Necroptosis/*drug effects ; Neurodegenerative Diseases/etiology/metabolism/*prevention &amp; control ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Rats, Wistar ; }, abstract = {Adequate dietary intake has a crucial effect on brain health. High fat diet (HFD) rich in saturated fatty acids is linked to obesity and its complications as neurodegeneration via inducing oxidative stress and inflammation. The present study aimed to evaluate the effect of HFD on cerebral cortex in addition to shedding the light on the modulatory role of N-acetylcytsteine (NAC) and its possible underlying biochemical and molecular mechanisms. Twenty eight male Wistar rats were equally and randomly divided into four groups. Group III, and group IV were fed on HFD (45% kcal from fat) for 10 weeks. Group II and group IV were treated with NAC in a dose of 150 mg/kg body weight via intraperitoneal route. Body weight, blood glucose, serum insulin, insulin resistance index, cerebral cortex redox and inflammatory status were evaluated. Cerebral cortex receptor-interacting serine/threonine-protein kinase3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), nod like receptor protein 3 (NLRP3), interleukin (IL)-18 levels were determined by immunoassay. In addition, apoptosis-associated speck-like proteins (ASC) expression by real-time PCR; inducible nitric oxide synthase (iNOS), glial fibrillary activating protein (GFAP) and matrix metalloproteinase-9 (MMP-9) expression by immunohistochemistry were evaluated. NAC supplementation protected against HFD-induced gain of weights, hyperglycemia, and insulin resistance. Furthermore, NAC improved redox and inflammatory status; decreased levels of RIPK3, MLKL, NLRP3, IL-18; down-regulated ASC, iNOS, GFAP and MMP-9 expression; and decreased myeloperoxidase activity in cerebral cortex. NAC could protect against HFD-induced neurodegeneration via improving glycemic status and peripheral insulin resistance, disrupting oxidative stress/neuroinflammation/necroptosis/inflammasome activation axis in cerebral cortex. NAC may represent a promising strategy for conserving brain health against metabolic diseases-induced neurodegeneration.}, }
@article {pmid31832291, year = {2019}, author = {Ansari, SF and Memon, M and Brohi, N and Tahir, A}, title = {N-acetylcysteine in the Management of Acute Exacerbation of Chronic Obstructive Pulmonary Disease.}, journal = {Cureus}, volume = {11}, number = {11}, pages = {e6073}, pmid = {31832291}, issn = {2168-8184}, abstract = {Introduction Chronic obstructive pulmonary disease (COPD) is a preventable disease of the airways characterized by limited airflow. Acute exacerbations of COPD (AECOPD) may be precipitated by noxious stimuli. N-acetylcysteine (NAC) has mucolytic, antioxidant, and anti-inflammatory activity. We conducted this study to evaluate the effect of adding high-dose NAC to the protocol treatment of AECOPD. Methods In this single-center, prospective, interventional study, patients admitted with AECOPD, airflow obstruction on spirometry, and who were current smokers with 10 or more packs per year were included after attaining informed consent. NAC granules 600 mg twice daily orally (high dose) were included in the regimen of 25 randomly selected patients and the other 25 were managed without NAC. An improvement in clinical and biochemical markers was observed on day three and day seven. For statistical analysis, SPSS for Windows version 21.0 (IBM Corp., Armonk, NY) was utilized. Results The study was completed by 21 patients in the NAC group and 19 in the non-NAC group. In the NAC group, there was a significant improvement in the mean partial pressure of oxygen (PaO2) both on day three (p=0.03) and day seven (p=0.01). The mean partial pressure of carbon dioxide (PaCO2) was at the borderline in the two groups on day three; however, on day seven, the NAC group showed significantly improved PaCO2 as compared to the non-NAC group (p=0.007). There were significant improvements in oxygen saturation of the NAC group on day seven (p=0.02). There were significant improvements in clinical signs, including wheezing and dyspnea and the need for nasal oxygen support (p≤0.05). Conclusion The addition of 600 mg twice daily NAC (high dose) to the protocol treatment of patients with acute exacerbation of COPD may have beneficial outcomes. In the future, the role of high-dose NAC in AECOPD must be studied through multicenter, double-blinded, placebo-controlled trials with larger sample sizes in order to either establish or invalidate this association.}, }
@article {pmid31831341, year = {2020}, author = {Monzon, B and Hegarty, K and Rech, MA}, title = {A knack for "NAC": Treatment for heat stroke induced acute liver injury.}, journal = {The American journal of emergency medicine}, volume = {38}, number = {4}, pages = {853.e1-853.e3}, doi = {10.1016/j.ajem.2019.11.029}, pmid = {31831341}, issn = {1532-8171}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Emergency Service, Hospital ; Heat Stroke/*complications ; Humans ; Infusions, Intravenous ; Liver Failure, Acute/drug therapy/*etiology/therapy ; Male ; Young Adult ; }, abstract = {INTRODUCTION: Heat stroke occurs when the body's core temperature becomes elevated above 40 °C, which may impact multiple organ systems. We present a case of heat stroke resulting in acute liver injury (ALI) successfully treated with intravenous N-acetylcysteine (NAC).<br><br>CASE PRESENTATION: A 24-year-old unresponsive male without significant past medical history presented to the emergency department with heat stroke; his initial temperature was 107.4&#xa0;&#xb0;F. During his hospital course, he developed ALI with significant elevation in aspartate aminotransferase, alanine aminotransferase, and total bilirubin. These laboratory findings peaked by hospital day two, but improved prior to discharge on hospital day five and throughout his follow up clinic visits. His treatment course included cooling measures, supportive care, supplemental oxygen and airway management, seizure control, and intravenous NAC therapy.<br><br>CONCLUSION: Hepatocellular injury is one of the most serious complications of heat stroke. We discuss the incidence and outcomes for patients who develop acute liver injury secondary to heat stroke and the use of NAC as an early potential therapeutic option.}, }
@article {pmid31831176, year = {2020}, author = {Song, S and Lee, J and Park, S and Choi, S}, title = {Fear renewal requires nitric oxide signaling in the lateral amygdala.}, journal = {Biochemical and biophysical research communications}, volume = {523}, number = {1}, pages = {86-90}, doi = {10.1016/j.bbrc.2019.12.038}, pmid = {31831176}, issn = {1090-2104}, mesh = {Amygdala/*metabolism ; Animals ; Fear/*physiology ; Male ; Nitric Oxide/*metabolism ; Rats ; Rats, Sprague-Dawley ; *Signal Transduction ; }, abstract = {Fear renewal is defined as return of the conditioned fear responses after extinction when a conditioned stimulus (CS) is given outside of the extinction context. Previously, we have suggested that extinction induces S-nitrosylation of GluA1 in the lateral amygdala (LA), and that the extinction-induced S-nitrosylation of GluA1 lowers the threshold of GluA1 phosphorylation (at Ser 831) which is required for fear renewal. This fits nicely with the fact that fear renewal is induced by weak stimuli. However, it has not been tested whether S-nitrosylation of GluA1 in the LA is indeed required for fear renewal. In the present study, we used three different chemicals to impede protein S-nitrosylation via distinct mechanisms. Fear renewal was inhibited by microinjection of 7-Nitroindazole (nNOS inhibitor), and ZL006 (a blocker of PSD-95-nNOS interaction) before fear renewal. Furthermore, fear renewal was also attenuated by microinjection of a strong antioxidant (N-acetyl cysteine), which scavenges reactive oxygen including nitric oxide, into the LA before each extinction training. These findings suggest that protein S-nitrosylation is required for fear renewal.}, }
@article {pmid31830885, year = {2020}, author = {Mehrabi, S and Moradi, MM and Khodamoradi, Z and Nazarinia, MA}, title = {Effects of N-acetylcysteine on Pulmonary Functions in Patients with Systemic Sclerosis: A Randomized Double Blind, Placebo Controlled Study.}, journal = {Current rheumatology reviews}, volume = {16}, number = {2}, pages = {149-157}, doi = {10.2174/1573397115666191212092608}, pmid = {31830885}, issn = {1875-6360}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Lung/*drug effects/physiopathology ; Lung Diseases, Interstitial/*drug therapy/physiopathology ; Male ; Middle Aged ; Respiratory Function Tests ; Scleroderma, Systemic/*drug therapy/physiopathology ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Systemic sclerosis (SSc) is a systematic and rare autoimmune disease that affects many organs. N-acetylcysteine (NAC), thiol-containing compound, can act both as the precursor of reduced glutathione and direct scavenger of reactive oxygen species.<br><br>OBJECTIVE: We assessed the clinical effect of NAC on the pulmonary function test of patients with diffuse scleroderma.<br><br>METHODS: This study is a randomized double-blind clinical trial that was done on 25 patients with diffuse SSc without lung involvement on primary chest high-resolution computed tomography. Placebo was administered for 13 patients and 1200 milligram NAC for 12 patients. Body plethysmography parameters were assessed at the beginning of the study and after 24 weeks.<br><br>RESULTS: Patients in the two groups were matched in the basic demographic data like age, duration of disease, and modified Rodnan skin score. The analysis showed no significant differences in parameters of plethysmography between the two groups. After importing the data of 2 patients in the placebo-treated group, who developed interstitial lung disease, DLCO in the placebo-treated group was 90.69 &#xb1; 21.29 milliliter at the end of the study, which significantly decreased compared with the beginning of the study (102.30 &#xb1; 13.83 ml). Also, changes of DLCO between the two groups were significantly different.<br><br>CONCLUSION: In this trial, the sensitivity of DLCO as the first marker in the evaluation of pulmonary function in patients with SSc was confirmed. On the other hand, NAC had no effect versus placebo in a period of 24 weeks.}, }
@article {pmid31827678, year = {2019}, author = {Hu, L and Zhang, Y and Miao, W and Cheng, T}, title = {Reactive Oxygen Species and Nrf2: Functional and Transcriptional Regulators of Hematopoiesis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {5153268}, pmid = {31827678}, issn = {1942-0994}, mesh = {Animals ; Antioxidants/chemistry/metabolism ; Bone Marrow Transplantation ; Hematopoiesis ; Hematopoietic Stem Cells/cytology/metabolism ; Humans ; NADPH Oxidases/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidoreductases/metabolism ; Reactive Oxygen Species/chemistry/*metabolism ; }, abstract = {Hematopoietic stem cells (HSCs) are characterized by self-renewal and multilineage differentiation potentials. Although they play a central role in hematopoietic homeostasis and bone marrow (BM) transplantation, they are affected by multiple environmental factors in the BM. Here, we review the effects of reactive oxygen species (ROS) and Nrf2 on HSC function and BM transplantation. HSCs reside in the hypoxic microenvironment of BM, and ROS play an important role in HSPC regulation. Recently, an extraphysiologic oxygen shock/stress phenomenon was identified in human cord blood HSCs collected under ambient air conditions. Moreover, Nrf2 has been recently recognized as a master transcriptional factor that regulates multiple antioxidant enzymes. Since several years, the role of Nrf2 in hematopoiesis has been extensively studied, which has functional similarities of cellular oxygen sensor hypoxia-inducible factor-1 as transcriptional factors. Increasing evidence has revealed that abnormally elevated ROS production due to factors such as genetic defects, aging, and ionizing radiation unexceptionally resulted in lethal impairment of HSC function and hematopoiesis. Both experimental and clinical studies have identified elevated ROS levels as a major culprit of ineffective BM transplantation. Lastly, we discuss the possibility of using small molecule antioxidants, such as N-acetyl cysteine, resveratrol, and curcumin, to augment HSC function and improve the therapeutic efficacy of BM transplantation. Further research on the function of ROS levels and improving the efficacy of BM transplantation may have a great potential for broad clinical applications of HSCs.}, }
@article {pmid31825855, year = {2020}, author = {Iordache, AM and Docea, AO and Buga, AM and Zlatian, O and Ciurea, ME and Rogoveanu, OC and Burada, F and Sosoi, S and Mitrut, R and Mamoulakis, C and Albulescu, D and Vasile, RC and Tsatsakis, A and Calina, D}, title = {Sildenafil and tadalafil reduce the risk of contrast-induced nephropathy by modulating the oxidant/antioxidant balance in a murine model.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {135}, number = {}, pages = {111038}, doi = {10.1016/j.fct.2019.111038}, pmid = {31825855}, issn = {1873-6351}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antioxidants/*metabolism ; Catalase/metabolism ; Contrast Media/*adverse effects ; Disease Models, Animal ; Glutathione/metabolism ; Kidney Diseases/*chemically induced/enzymology/metabolism/*prevention &amp; control ; Male ; Mice ; Oxidants/*metabolism ; Oxidative Stress ; Phosphodiesterase 5 Inhibitors/*pharmacology ; Rats ; Rats, Wistar ; Sildenafil Citrate/*pharmacology ; Tadalafil/*pharmacology ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The aim of the study was to evaluate the potential protective role of sildenafil and tadalafil in contrast-induced nephropathy (CIN) by modulating oxidative stress. Thirty Wistar male rats were equally assigned into five groups: sham, CIN, CIN + sildenafil (10 mg/kg bw/day), CIN + tadalafil (5 mg/kg bw/day) and CIN + N-Acetyl Cysteine (NAC) (100 mg/kg bw/day) as a positive control. CIN was induced by 12 h dehydration and administration of indomethacin (10 mg/kg bw), N-ω- nitro-L-arginine methyl ester (10 mg/kg bw), and iopromide (3 g/kg bw iodine). Blood was drawn prior to and 24 h after CIN induction for evaluating renal function and oxidative stress. In the CIN group, total antioxidant capacity (TAC), reduced glutathione (GSH) and catalase (CAT) levels were significantly decreased; and protein carbonyl (PROTC) and thiobarbituric reactive species (TBARS) were significantly increased compared to the sham group. Pre- Sildenafil and tadalafil pre-treatment reduced CIN risk and reversed oxidative stress almost to the sham group levels. These results suggest that PDE5Is can be good candidates for preventing CIN based on their ability to modulate the oxidant/antioxidant balance.}, }
@article {pmid31825807, year = {2020}, author = {Tropeano, CV and Aleo, SJ and Zanna, C and Roberti, M and Scandiffio, L and Loguercio Polosa, P and Fiori, J and Porru, E and Roda, A and Carelli, V and Steimle, S and Daldal, F and Rugolo, M and Ghelli, A}, title = {Fine-tuning of the respiratory complexes stability and supercomplexes assembly in cells defective of complex III.}, journal = {Biochimica et biophysica acta. Bioenergetics}, volume = {1861}, number = {2}, pages = {148133}, pmid = {31825807}, issn = {1879-2650}, support = {R01 GM038237/GM/NIGMS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Electron Transport Complex I/genetics/metabolism ; Electron Transport Complex III/*deficiency ; Electron Transport Complex IV/genetics/metabolism ; Gene Deletion ; Mitochondria/*enzymology/genetics ; Mitochondrial Membranes/*enzymology ; Oxidation-Reduction ; *Oxygen Consumption ; Rotenone/pharmacology ; }, abstract = {The respiratory complexes are organized in supramolecular assemblies called supercomplexes thought to optimize cellular metabolism under physiological and pathological conditions. In this study, we used genetically and biochemically well characterized cells bearing the pathogenic microdeletion m.15,649-15,666 (ΔI300-P305) in MT-CYB gene, to investigate the effects of an assembly-hampered CIII on the re-organization of supercomplexes. First, we found that this mutation also affects the stability of both CI and CIV, and evidences the occurrence of a preferential structural interaction between CI and CIII2, yielding a small amount of active CI+CIII2 supercomplex. Indeed, a residual CI+CIII combined redox activity, and a low but detectable ATP synthesis driven by CI substrates are detectable, suggesting that the assembly of CIII into the CI+CIII2 supercomplex mitigates the detrimental effects of MT-CYB deletion. Second, measurements of oxygen consumption and ATP synthesis driven by NADH-linked and FADH2-linked substrates alone, or in combination, indicate a common ubiquinone pool for the two respiratory pathways. Finally, we report that prolonged incubation with rotenone enhances the amount of CI and CIII2, but reduces CIV assembly. Conversely, the antioxidant N-acetylcysteine increases CIII2 and CIV2 and partially restores respirasome formation. Accordingly, after NAC treatment, the rate of ATP synthesis increases by two-fold compared with untreated cell, while the succinate level, which is enhanced by the homoplasmic mutation, markedly decreases. Overall, our findings show that fine-tuning the supercomplexes stability improves the energetic efficiency of cells with the MT-CYB microdeletion.}, }
@article {pmid31823347, year = {2020}, author = {Monti, DA and Newberg, AB}, title = {Response to "Potential Role of N-Acetyl Cysteine in the Cysteine Proteome in Parkinson's Disease?".}, journal = {Clinical pharmacology and therapeutics}, volume = {107}, number = {5}, pages = {1056}, doi = {10.1002/cpt.1713}, pmid = {31823347}, issn = {1532-6535}, mesh = {Acetylcysteine ; Dopamine ; Humans ; Oxidative Stress ; *Parkinson Disease/drug therapy ; *Proteome ; }, }
@article {pmid31823343, year = {2020}, author = {Martinez-Banaclocha, MA}, title = {Potential Role of N-Acetyl-Cysteine in the Cysteine Proteome in Parkinson's Disease?.}, journal = {Clinical pharmacology and therapeutics}, volume = {107}, number = {5}, pages = {1055}, doi = {10.1002/cpt.1709}, pmid = {31823343}, issn = {1532-6535}, mesh = {Acetylcysteine ; Dopamine ; Humans ; *Parkinson Disease/drug therapy ; *Proteome ; }, }
@article {pmid31822750, year = {2019}, author = {Kaneko, Y and Tanigawa, N and Sato, Y and Kobayashi, T and Nakamura, S and Ito, E and Soma, T and Miyamoto, K and Kobayashi, S and Harato, K and Matsumoto, M and Nakamura, M and Niki, Y and Miyamoto, T}, title = {Oral administration of N-acetyl cysteine prevents osteoarthritis development and progression in a rat model.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {18741}, pmid = {31822750}, issn = {2045-2322}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Animals ; Apoptosis/drug effects ; Arthritis, Experimental/drug therapy/immunology/pathology/*prevention &amp; control ; Cartilage, Articular/cytology/pathology ; Cells, Cultured ; Chondrocytes/drug effects/immunology/pathology ; Collagen Type II/metabolism ; Cytokines/immunology/metabolism ; Disease Progression ; Drug Evaluation, Preclinical ; Humans ; Male ; Matrix Metalloproteinase 13/metabolism ; Osteoarthritis, Knee/drug therapy/immunology/pathology/*prevention &amp; control ; Primary Cell Culture ; Rats ; Reactive Oxygen Species/metabolism ; Stress, Mechanical ; }, abstract = {The number of osteoarthritis patients is increasing with the rise in the number of elderly people in developed countries. Osteoarthritis, which causes joint pain and deformity leading to loss of activities of daily living, is often treated surgically. Here we show that mechanical stress promotes accumulation of reactive oxygen species (ROS) in chondrocytes in vivo, resulting in chondrocyte apoptosis and leading to osteoarthritis development in a rat model. We demonstrate that mechanical stress induces ROS accumulation and inflammatory cytokine expression in cultured chondrocytes in vitro and that both are inhibited by treatment with the anti-oxidant N-acetyl cysteine (NAC). In vivo, osteoarthritis development in a rat osteoarthritis model was also significantly inhibited by oral administration of NAC. MMP13 expression and down-regulation of type II collagen in chondrocytes, both of which indicate osteoarthritis, as well as chondrocyte apoptosis in osteoarthritis rats were inhibited by NAC. Interestingly, osteoarthritis development in sham-operated control sides, likely due to disruption of normal weight-bearing activity on the control side, was also significantly inhibited by NAC. We conclude that osteoarthritis development in rats is significantly antagonized by oral NAC administration. Currently, no oral medication is available to prevent osteoarthritis development. Our work suggests that NAC may represent such a reagent and serve as osteoarthritis treatment.}, }
@article {pmid31819864, year = {2019}, author = {Harper, SN and Leidig, PD and Hughes, FM and Jin, H and Purves, JT}, title = {Calcium Pyrophosphate And Monosodium Urate Activate The NLRP3 Inflammasome Within Bladder Urothelium Via Reactive Oxygen Species And TXNIP.}, journal = {Research and reports in urology}, volume = {11}, number = {}, pages = {319-325}, pmid = {31819864}, issn = {2253-2447}, support = {R01 DK103534/DK/NIDDK NIH HHS/United States ; R01 DK117890/DK/NIDDK NIH HHS/United States ; }, abstract = {OBJECTIVE: To investigate the in vitro activation of the NLRP3 inflammasome within bladder urothelium by stone-forming components. Further, to describe the contributions of reactive oxygen species (ROS) and thioredoxin-interacting protein (TXNIP), an important structural component of the inflammasome, to this activation.<br><br>METHODS: Urothelial cells were harvested and incubated overnight. For agonist studies, cells were treated with varying concentrations of calcium pyrophosphate (CPPD) and monosodium urate (MSU). For inhibitor studies, cells were treated with either N-acetylcysteine (NAC) (1 hr) or Verapamil (4 hrs) prior to incubation with either CPPD (62.5 ug/mL) or MSU (1.25 ug/mL) for 24 hrs. Untreated controls were incubated with ATP (1.25 mM) for 1 hr to maximally stimulate NLRP3 inflammasome activity (measured as caspase-1 cleavage of the fluorogenic substrate Ac-YVAD-AFC). Results are reported as a percentage of maximum ATP response.<br><br>RESULTS: CPPD and MSU activate caspase-1 in urothelial cells in a dose-dependent manner, reaching ~50% and ~25% of the ATP response, respectively. Pre-treatment with the general ROS scavenger NAC reduces this activation in a dose-dependent manner. Additionally, activation was suppressed through treatment with Verapamil, a known downregulator of TXNIP expression.<br><br>CONCLUSION: The stone components CPPD and MSU activate NLRP3 in an ROS and TXNIP-dependent manner in bladder urothelium. These findings demonstrate the importance of ROS and TXNIP, and suggest that targeting either may be a way to decrease stone-dependent NLRP3 inflammation within the bladder.}, }
@article {pmid31819842, year = {2019}, author = {Kuan, KK and Lim, HC and Goh, G and Arciaga, GS and Goh, PL and Mong, R and Chow, WL and Tan, HH}, title = {Cost Savings and Efficacy in Management of Paracetamol Poisoning in a 23-hours Emergency Department Observation Unit: A Comparison to Inpatient Care.}, journal = {Cureus}, volume = {11}, number = {12}, pages = {e6294}, pmid = {31819842}, issn = {2168-8184}, abstract = {Introduction Emergency department observation units (EDOU) have been shown to be effective in decreasing hospitalization rates and length of stay (LOS) for various conditions. However, cost savings and efficacy in the management of poisoning in EDOU have not been widely studied. The objective of our study is to compare the costs and effectiveness of managing paracetamol poisoned patients in the EDOU with those treated in the inpatient wards. Methods We conducted a historical controlled observational study comparing paracetamol-poisoned patients (who received at least 21 hours of IV N-acetylcysteine [NAC]) admitted to the EDOU during 2013-2014 with similar patients admitted to inpatient ward during 2011, 2013-2014. Results We found 136 patients admitted to the inpatient ward and 95 to our EDOU due to paracetamol poisoning but only 78 and 39 patients respectively fulfilled the inclusion criteria. Between the EDOU and inpatient ward groups, we found similar demographics, poisoning presentation, treatment, and adverse event profiles. There were no fatalities and only two patients (one from each group) developed hepatotoxicity. The "medical" length of stay was 31.9 hours shorter in the EDOU group compared to the inpatient ward group (23.3 versus 55.2 hours). EDOU patients have statistically significant savings (comparing bill size) of S$784 per patient. Conclusions Admission to the EDOU resulted in significant cost savings and 58% decreased LOS when compared to inpatient wards. The EDOU is a cost-effective and safe alternative for the management of selected paracetamol poisonings requiring NAC. Further studies would be needed to verify these results.}, }
@article {pmid31819599, year = {2019}, author = {Heidari, N and Sajedi, F and Mohammadi, Y and Mirjalili, M and Mehrpooya, M}, title = {Ameliorative Effects Of N-Acetylcysteine As Adjunct Therapy On Symptoms Of Painful Diabetic Neuropathy.}, journal = {Journal of pain research}, volume = {12}, number = {}, pages = {3147-3159}, pmid = {31819599}, issn = {1178-7090}, abstract = {PURPOSE: Painful diabetic neuropathy (PDN) is a variant of diabetic peripheral neuropathy which is highly prevalent and distressing in diabetic patients. Despite its high burden, the optimal treatment of PDN has remained a clinical challenge. To explain the emergence and maintenance of PDN, increasing attention has been focused on dimensions of inflammation and oxidative toxic stress (OTS). Accordingly, the aim of this study was to investigate the effects of oral N-acetylcysteine (NAC), an agent with known anti-oxidant and anti-inflammatory effects, as an adjunct therapy in patients suffering from PDN.<br><br>PATIENTS AND METHODS: 113 eligible patients with type 2 diabetes suffering from PDN were randomly assigned to either the pregabalin + placebo or pregabalin + NAC group for 8 weeks (pregabalin at a dose of 150 mg per day, NAC and matched placebo at doses of 600 mg twice a day). Mean pain score was evaluated at baseline, week 1, 2, 4, 6, and 8 of the study based on the mean 24 hr average pain score, using an 11-point numeric rating scale (NRS). As secondary efficacy measures, mean sleep interference score (SIS) resulting from PDN, responder rates, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety were also assessed. Additionally, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.<br><br>RESULTS: Ninety patients completed the eight-week course of the study. The decrease in mean pain scores and mean sleep interference score in pregabalin + NAC group was greater in comparison with pregabalin + placebo group (p value<0.001 in both conditions). Moreover, more responders (defined as &#x2265;50% reduction in mean pain score from baseline to end-point) were observed in the pregabalin + NAC group, in comparison with pregabalin + placebo group (72.1% vs 46.8%). More improvement in PGIC and CGIC from baseline to the end of the study was reported in pregabalin + NAC group. Oral NAC had minimal adverse effects and was well tolerated in almost all patients. Furthermore, in respect to OTS biomarkers, adjuvant NAC significantly decreased serum level of MDA and significantly increased serum levels of SOD, GPx, TAC, and TTG.<br><br>CONCLUSION: The pattern of results suggests that compared to placebo and over a time period of 8 weeks, adjuvant NAC is more efficacious in improving neuropathic pain associated with diabetic neuropathy than placebo. Ameliorative effects of NAC on OTS biomarkers demonstrated that NAC may alleviate painful symptoms of diabetic neuropathy, at least in part by its antioxidant effects.}, }
@article {pmid31817370, year = {2019}, author = {Cattò, C and De Vincenti, L and Cappitelli, F and D'Attoma, G and Saponari, M and Villa, F and Forlani, F}, title = {Non-Lethal Effects of N-Acetylcysteine on Xylella fastidiosa Strain De Donno Biofilm Formation and Detachment.}, journal = {Microorganisms}, volume = {7}, number = {12}, pages = {}, pmid = {31817370}, issn = {2076-2607}, support = {2017-0977//Fondazione Cariplo/ ; DD n. 495 del 14/10/2015 and n. 279 del 9/8/2016, Progetto di ricerca Linea B - STIPXYT//Regione Puglia/ ; }, abstract = {This study investigated in-vitro the non-lethal effects of N-acetylcysteine (NAC) on Xylella fastidiosa subspecies pauca strain De Donno (Xf-DD) biofilm. This strain was isolated from the olive trees affected by the olive quick decline syndrome in southern Italy. Xf-DD was first exposed to non-lethal concentrations of NAC from 0.05 to 1000 µM. Cell surface adhesion was dramatically reduced at 500 µM NAC (-47%), hence, this concentration was selected for investigating the effects of pre-, post- and co-treatments on biofilm physiology and structural development, oxidative homeostasis, and biofilm detachment. Even though 500 µM NAC reduced bacterial attachment to surfaces, compared to the control samples, it promoted Xf-DD biofilm formation by increasing: (i) biofilm biomass by up to 78% in the co-treatment, (ii) matrix polysaccharides production by up to 72% in the pre-treatment, and (iii) reactive oxygen species levels by 3.5-fold in the co-treatment. Xf-DD biofilm detachment without and with NAC was also investigated. The NAC treatment did not increase biofilm detachment, compared to the control samples. All these findings suggested that, at 500 µM, NAC diversified the phenotypes in Xf-DD biofilm, promoting biofilm formation (hyper-biofilm-forming phenotype) and discouraging biofilm detachment (hyper-attachment phenotype), while increasing oxidative stress level in the biofilm.}, }
@article {pmid31817202, year = {2019}, author = {Yeh, CC and Wu, JY and Lee, GL and Wen, HT and Lin, P and Kuo, CC}, title = {Vanadium Derivative Exposure Promotes Functional Alterations of VSMCs and Consequent Atherosclerosis via ROS/p38/NF-κB-Mediated IL-6 Production.}, journal = {International journal of molecular sciences}, volume = {20}, number = {24}, pages = {}, pmid = {31817202}, issn = {1422-0067}, support = {CS-107-PP-11 and CS-108-PP-11//National Health Research Institutes/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Aorta/pathology ; Apolipoproteins E/deficiency/genetics ; Atherosclerosis/chemically induced/pathology/veterinary ; Cell Differentiation/*drug effects ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Interleukin-6/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microfilament Proteins/metabolism ; Muscle Proteins/metabolism ; Muscle, Smooth, Vascular/cytology/metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Vanadates/*toxicity ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Vanadium is a transition metal widely distributed in the Earth's crust, and is a major contaminant in fossil fuels. Its pathological effect and regulation in atherosclerosis remain unclear. We found that intranasal administration of the vanadium derivative NaVO3 significantly increased plasma and urinary vanadium levels and induced arterial lipid accumulation and atherosclerotic lesions in apolipoprotein E-deficient knockout mice (ApoE[-/-]) murine aorta compared to those in vehicle-exposed mice. This was accompanied by an increase in plasma reactive oxygen species (ROS) and interleukin 6 (IL-6) levels and a decrease in the vascular smooth muscle cell (VSMC) differentiation marker protein SM22α in the atherosclerotic lesions. Furthermore, exposure to NaVO3 or VOSO4 induced cytosolic ROS generation and IL-6 production in VSMCs and promoted VSMC synthetic differentiation, migration, and proliferation. The anti-oxidant N-acetylcysteine (NAC) not only suppresses IL-6 production and VSMC pathological responses including migration and proliferation but also prevents atherosclerosis in ApoE[-/-] mice. Inhibition experiments with NAC and pharmacological inhibitors demonstrated that NaVO3-induced IL-6 production is signaled by ROS-triggered p38-mediated NF-κB-dependent pathways. Neutralizing anti-IL-6 antibodies impaired NaVO3-mediated VSMC migration and proliferation. We concluded that NaVO3 exposure activates the ROS-triggering p38 signaling to selectively induce NF-κB-mediated IL-6 production. These signaling pathways induce VSMC synthetic differentiation, migration, and proliferation, leading to lipid accumulation and atherosclerosis.}, }
@article {pmid31817161, year = {2019}, author = {Chiu, CF and Chin, HK and Huang, WJ and Bai, LY and Huang, HY and Weng, JR}, title = {Induction of Apoptosis and Autophagy in Breast Cancer Cells by a Novel HDAC8 Inhibitor.}, journal = {Biomolecules}, volume = {9}, number = {12}, pages = {}, pmid = {31817161}, issn = {2218-273X}, mesh = {Autophagy/drug effects ; Breast Neoplasms/drug therapy/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cinnamates/chemistry/*pharmacology ; Down-Regulation ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Histone Deacetylase Inhibitors/chemistry/*pharmacology ; Histone Deacetylases ; Humans ; MCF-7 Cells ; Repressor Proteins/*antagonists &amp; inhibitors ; }, abstract = {: Epigenetic therapy has been demonstrated to be a viable strategy for breast cancer treatment. In this study, we report the anti-tumor activity of a hydroxamate-based histone deacetylase (HDAC)8-selective inhibitor, HMC, in breast cancer cells. MTT assays showed that HMC inhibited cell viability of MCF-7 and MDA-MB-231 cells with IC50 values of 7.7 μM and 9.5 μM, respectively. HMC induced caspase-dependent apoptosis in MCF-7 cells, which was associated with its ability to modulate a series of cell survival-related signaling effectors, including Akt, mTOR, Bax, Mcl-1, and Bcl-2. Additionally, HMC was capable of activating PPARγ, which was accompanied by reduced expression of PPARγ target gene products, such as cyclin D1 and CDK6. HMC increased the production of ROS in MCF-7 cells, which could be partially reversed by the cotreatment with a ROS scavenger (N-acetylcysteine or glutathione). Furthermore, HMC induced autophagy, as characterized by the formation of acidic vesicular organelles and autophagic biomarkers including LC3B-II and Atg5. Notably, pharmacological blockade of autophagy by 3-MA or CQ could attenuate HMC-induced apoptosis, suggesting that autophagy played a self-protective role in HMC-induced cell death. Together, these data suggest the translational potential of HMC to be developed into a potential therapeutic agent for breast cancer therapy.}, }
@article {pmid31816696, year = {2020}, author = {Akyüz, E and Şen, FB and Bener, M and Başkan, KS and Apak, R}, title = {A novel gold nanocluster-based fluorometric biosensor for measuring prooxidant activity with a large Stokes shift.}, journal = {Talanta}, volume = {208}, number = {}, pages = {120425}, doi = {10.1016/j.talanta.2019.120425}, pmid = {31816696}, issn = {1873-3573}, mesh = {Acids, Carbocyclic/chemistry ; Antioxidants/chemistry ; Bilirubin/chemistry ; *Biosensing Techniques ; Blueberry Plants ; Copper/chemistry ; Egg Proteins/chemistry ; Flavonoids/chemistry ; Fluorometry ; Fruit and Vegetable Juices ; Gold/*chemistry ; Malus ; Nanostructures/*chemistry ; Oxidants/*chemistry ; Oxidation-Reduction ; Plant Extracts ; Resveratrol/chemistry ; Sulfhydryl Compounds/chemistry ; Tea ; Wine ; }, abstract = {A chicken egg white protein-protected gold nanocluster (CEW-AuNC) based fluorogenic biosensor, where protein was used as both reducing and protecting agent, was developed to determine the Cu(II)-induced prooxidant activity of natural antioxidants abundant in food and biological samples. Gold nanoclusters, prepared using egg white proteins, exhibited strong fluorescence. The prooxidant activity of the tested antioxidants was indirectly measured by their reducing action on Cu(II) to Cu(I), and the reduced cuprous ion was bound to the thiol groups in the CEW-AuNC structure, causing a decrease in fluorescence intensity. Epicatechin, catechin, epigallocatechin gallate, morin, rutin, quercetin, gallic, chlorogenic, and rosmarinic acids, glutathione, cysteine, N-acetyl cysteine, bilirubin, resveratrol, and α-tocopherol were studied as natural antioxidants. A fluorometric method showing a large Stokes shift with excitation/emission maxima at 360∕640 nm was developed to sensitively measure the decrease in the fluorescence of CEW-AuNC associated with the binding of copper(I) to the protein structure. Total prooxidant activities of the binary, ternary, and quaternary synthetic mixtures and of some food and synthetic serum samples were determined. The biosensor response was statistically compared to that of its spectrophotometric counterpart. This method can be used for the control of the oxidative stability of foods with a prolonged shelf life.}, }
@article {pmid31815636, year = {2019}, author = {Su, SH and Wu, YF and Lin, Q and Wang, DP and Hai, J}, title = {URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion.}, journal = {Journal of neuroinflammation}, volume = {16}, number = {1}, pages = {260}, pmid = {31815636}, issn = {1742-2094}, support = {81601146//National Natural Science Foundation of China/ ; 81771410//National Natural Science Foundation of China/ ; 2017ZZ02020//Priority of Shanghai key discipline of medicine/ ; }, mesh = {Animals ; Autophagy/drug effects/*physiology ; Benzamides/pharmacology/*therapeutic use ; Brain Ischemia/*metabolism/prevention &amp; control ; Carbamates/pharmacology/*therapeutic use ; *Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Inflammasomes/antagonists &amp; inhibitors/*metabolism ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists &amp; inhibitors/*metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Previous studies reported that URB597 (URB) had therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced neuroinflammation and autophagy dysfunction. However, the interaction mechanisms underlying the CCH-induced abnormal excessive autophagy and neuroinflammation remain unknown. In this study, we investigated the roles of impaired autophagy in nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing (NLRP) 3 inflammasome activation in the rat hippocampus and the underlying mechanisms under the condition of induced CCH as well as the effect of URB treatment.<br><br>METHODS: The CCH rat model was established by bilateral common carotid artery occlusion (BCCAo), and rats were randomly divided into 11 groups as follows: (1) sham-operated, (2) BCCAo; (3) BCCAo+autophagy inhibitor 3-methyladenine (3-MA), (4) BCCAo+lysosome inhibitor chloroquine (CQ), (5) BCCAo+microglial activation inhibitor minocycline, (6) BCCAo+ROS scavenger N-acetylcysteine (NAC), (7) BCCAo+URB, (8) BCCAo+URB+3-MA, (9) BCCAo+URB+CQ, (10) BCCAo+URB+minocycline, (11) BCCAo+URB+NAC. The cell localizations of LC3, p62, LAMP1, TOM20 and NLRP3 were assessed by immunofluorescence staining. The levels of autophagy-related proteins (LC3, p62, LAMP1, BNIP3 and parkin), NLRP3 inflammasome-related proteins (NLRP3, CASP1 and IL-1&#x3b2;), microglial marker (OX-42) and proinflammatory cytokines (iNOS and COX-2) were evaluated by western blotting, and proinflammatory cytokines (IL-1&#x3b2; and TNF-a) were determined by ELISA. Reactive oxygen species (ROS) were assessed by dihydroethidium staining. The mitochondrial ultrastructural changes were examined by electron microscopy.<br><br>RESULTS: CCH induced microglial overactivation and ROS accumulation, promoting the activation of the NLRP3 inflammasome and the release of IL-1&#x3b2;. Blocked autophagy and mitophagy flux enhanced the activation of the NLRP3-CASP1 inflammasome pathway. However, URB alleviated impaired autophagy and mitophagy by decreasing mitochondrial ROS and microglial overactivation as well as restoring lysosomal function, which would further inhibit the activation of the NLRP3-CASP1 inflammasome pathway.<br><br>CONCLUSION: These findings extended previous studies indicating the function of URB in the mitigation of chronic ischemic injury of the brain.}, }
@article {pmid31811499, year = {2020}, author = {Xavier, MR and Santos, MMS and Queiroz, MG and de Lima Silva, MS and Goes, AJS and De Morais, MA}, title = {Lawsone, a 2-hydroxy-1,4-naphthoquinone from Lawsonia inermis (henna), produces mitochondrial dysfunctions and triggers mitophagy in Saccharomyces cerevisiae.}, journal = {Molecular biology reports}, volume = {47}, number = {2}, pages = {1173-1185}, pmid = {31811499}, issn = {1573-4978}, support = {APQ-1452-2.01/10//FACEPE/ ; 472533/2013-4//CNPq/ ; }, mesh = {Dose-Response Relationship, Drug ; Gene Expression ; Genes, Reporter ; Lawsonia Plant/*chemistry ; Microbial Sensitivity Tests ; Mitochondria/*drug effects ; Mitophagy/*drug effects ; Molecular Structure ; Naphthoquinones/chemistry/*pharmacology ; Oxidative Stress/drug effects ; Plant Extracts/chemistry/*pharmacology ; Saccharomyces cerevisiae/*drug effects/*metabolism ; }, abstract = {Lawsone is a natural naphthoquinone present in the henna leaf extract with several cytotoxic activities and used as precursor for synthesis of various pharmaceutical compounds. Its biological activities are thought to be the result of oxidative stress generated, although the hydroxy group at position C-2 in its structure tends to reduce its electrophilic potential. In view of lack of knowledge on its activity, the present work aimed to elucidate the biological effect of lawsone using the yeast Saccharomyces cerevisiae. In the model strain BY4741 it was defined 229 mmol/L as the minimal inhibitory concentration (MIC). Using 172 mmol/L as sub-MIC value it was observed that yap1 deletion mutant was sensitive to lawsone independent the presence of oxygen. Lawsone affected yeast growth in glycerol, indicating interference in the respiratory metabolism. Intracellular content of thiol groups did not indicate intensive oxidative stress and the presence of the anti-oxidant N-acetylcysteine (NAC) exacerbated lawsone toxicity. By analysing the sensitivity of atg mutant strains and the localization of GFP-Atg8 fusion protein, it was concluded that lawsone primarily produces mitochondrial malfunctioning, leading to indirect oxidative stress. It triggers the autophagic response that ultimately induces mitophagy.}, }
@article {pmid31805012, year = {2020}, author = {Campochiaro, PA and Iftikhar, M and Hafiz, G and Akhlaq, A and Tsai, G and Wehling, D and Lu, L and Wall, GM and Singh, MS and Kong, X}, title = {Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial.}, journal = {The Journal of clinical investigation}, volume = {130}, number = {3}, pages = {1527-1541}, pmid = {31805012}, issn = {1558-8238}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Administration, Oral ; Adult ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Retinal Cone Photoreceptor Cells/*metabolism ; Retinitis Pigmentosa/*drug therapy/metabolism/pathology/physiopathology ; Visual Acuity/*drug effects ; }, abstract = {BACKGROUNDIn retinitis pigmentosa (RP), rod photoreceptors degenerate from 1 of many mutations, after which cones are compromised by oxidative stress. N-acetylcysteine (NAC) reduces oxidative damage and increases cone function/survival in RP models. We tested the safety, tolerability, and visual function effects of oral NAC in RP patients.METHODSSubjects (n = 10 per cohort) received 600 mg (cohort 1), 1200 mg (cohort 2), or 1800 mg (cohort 3) NAC bid for 12 weeks and then tid for 12 weeks. Best-corrected visual acuity (BCVA), macular sensitivity, ellipsoid zone (EZ) width, and aqueous NAC were measured. Linear mixed-effects models were used to estimate the rates of changes during the treatment period.RESULTSThere were 9 drug-related gastrointestinal adverse events that resolved spontaneously or with dose reduction (maximum tolerated dose 1800 mg bid). During the 24-week treatment period, mean BCVA significantly improved at 0.4 (95% CI: 0.2-0.6, P < 0.001), 0.5 (95% CI: 0.3-0.7, P < 0.001), and 0.2 (95% CI: 0.02-0.4, P = 0.03) letters/month in cohorts 1, 2, and 3, respectively. There was no significant improvement in mean sensitivity over time in cohorts 1 and 2, but there was in cohort 3 (0.15 dB/month, 95% CI: 0.04-0.26). There was no significant change in mean EZ width in any cohort.CONCLUSIONOral NAC is safe and well tolerated in patients with moderately advanced RP and may improve suboptimally functioning macular cones. A randomized, placebo-controlled trial is needed to determine if oral NAC can provide long-term stabilization and/or improvement in visual function in patients with RP.TRIAL REGISTRATIONNCT03063021.FUNDINGMr. and Mrs. Robert Wallace, Mr. and Mrs. Jonathan Wallace, Rami and Eitan Armon, Marc Sumerlin, Cassandra Hanley, and Nacuity Pharmaceuticals, Inc.}, }
@article {pmid31800306, year = {2020}, author = {Li, F and Welling, MC and Johnson, JA and Coughlin, C and Mulqueen, J and Jakubovski, E and Coury, S and Landeros-Weisenberger, A and Bloch, MH}, title = {N-Acetylcysteine for Pediatric Obsessive-Compulsive Disorder: A Small Pilot Study.}, journal = {Journal of child and adolescent psychopharmacology}, volume = {30}, number = {1}, pages = {32-37}, pmid = {31800306}, issn = {1557-8992}, support = {R25 MH077823/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Child ; Double-Blind Method ; Female ; Humans ; Male ; Obsessive-Compulsive Disorder/*drug therapy ; Pilot Projects ; Psychiatric Status Rating Scales ; }, abstract = {Background: Many children and adults with Obsessive-Compulsive Disorder (OCD) fail to respond to first-line pharmacological and behavioral treatments. Glutamate dysfunction may contribute to the development of OCD. N-acetylcysteine (NAC), a glutamate modulating drug, has shown to be a promising agent in adults with OCD. Methods: We conducted a double-blind, placebo-controlled clinical trial from July 2012 to January 2017. Children ages 8 to 17 years with OCD were assigned to receive NAC (up to 2700 mg/day) or the matching placebo for a period of 12 weeks. Children were required to be on stable psychiatric treatment (both medication and therapy) but were not required to be treatment-refractory. The primary outcome was OCD symptom severity as measured by the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). We used linear mixed models to analyze the effect of NAC compared to placebo. Results: Due to poor recruitment and eventual expiration of the study medication, enrollment was stopped at 11 children out of a planned sample size of 40. Nonetheless, NAC was associated with significant reduction in CY-BOCS total score compared to placebo (Satterthwaite's test: t (37) = 2.36, p = 0.024) with effects separating from placebo beginning at week 8. Mean CY-BOCS total score decreased in the NAC group from 21.4 ± 4.65 at baseline to 14.4 ± 5.55 at week 12. In the placebo group, mean CY-BOCS total score remained unchanged (21.3 ± 4.65). In the NAC group, 1 out of 5 participants achieved >35% improvement in CY-BOCS total score, while none of the six patients in placebo group reached this improvement level. NAC and placebo were well tolerated. One mild adverse event was reported in each group. Conclusions: Our trial suggests that there may be some initial improvement in OCD symptom severity with NAC treatment. NAC was well tolerated in the study population. Future trials should employ multiple sites and have a larger study population to further confirm any benefits of NAC.}, }
@article {pmid31799124, year = {2019}, author = {Dludla, PV and Orlando, P and Silvestri, S and Mazibuko-Mbeje, SE and Johnson, R and Marcheggiani, F and Cirilli, I and Muller, CJF and Louw, J and Obonye, N and Nyawo, T and Nkambule, BB and Tiano, L}, title = {N-Acetyl cysteine ameliorates hyperglycemia-induced cardiomyocyte toxicity by improving mitochondrial energetics and enhancing endogenous Coenzyme Q9/10 levels.}, journal = {Toxicology reports}, volume = {6}, number = {}, pages = {1240-1245}, pmid = {31799124}, issn = {2214-7500}, abstract = {The diabetic heart has been linked with reduced endogenous levels of coenzyme Q9/10 (CoQ), an important antioxidant and component of the electron transport chain. Although CoQ has displayed cardioprotective potential in experimental models of diabetes, the impact of N-acetyl cysteine (NAC) on mitochondrial energetics and endogenous levels of CoQ remains to be clarified. To explore these effects, high glucose-exposed H9c2 cardiomyocytes were used as an experimental model of hyperglycemia-induced cardiac injury. The results showed that high glucose exposure caused an increased production of reactive oxygen species (ROS), which was associated with impaired mitochondrial energetics as confirmed by a reduction of maximal respiration rate and depleted ATP levels. These detrimental effects were consistent with significantly reduced endogenous CoQ levels and accelerated cell toxicity. Although metformin demonstrated similar effects on mitochondrial energetics and cell viability, NAC demonstrated a more pronounced effect in ameliorating cytosolic and mitochondrial ROS production. Interestingly, the ameliorative effects of NAC against hyperglycemia-induced injury were linked with its capability to enhance endogenous CoQ levels. Although such data are to be confirmed in other models, especially in vivo studies, the overall findings provide additional evidence on the therapeutic mechanisms by which NAC protects against diabetes-induced cardiac injury.}, }
@article {pmid31790703, year = {2020}, author = {Ren, J and Su, D and Li, L and Cai, H and Zhang, M and Zhai, J and Li, M and Wu, X and Hu, K}, title = {Anti-inflammatory effects of Aureusidin in LPS-stimulated RAW264.7 macrophages via suppressing NF-κB and activating ROS- and MAPKs-dependent Nrf2/HO-1 signaling pathways.}, journal = {Toxicology and applied pharmacology}, volume = {387}, number = {}, pages = {114846}, doi = {10.1016/j.taap.2019.114846}, pmid = {31790703}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Benzofurans/*pharmacology/therapeutic use ; Heme Oxygenase-1 ; Humans ; Inflammation/*drug therapy/immunology ; Lipopolysaccharides/immunology ; MAP Kinase Signaling System/*drug effects/immunology ; Membrane Proteins ; Mice ; Molecular Docking Simulation ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/*antagonists &amp; inhibitors/metabolism ; Phosphorylation/drug effects/immunology ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; }, abstract = {Aureusidin, a naturally-occurring flavonoid, is found in various plants of Cyperaceae such as Heleocharis dulcis (Burm. f.) Trin., but its pharmacological effect and active mechanism are rarely reported. This study aimed to investigate the anti-inflammatory effect and action mechanism of Aureusidin in LPS-induced mouse macrophage RAW264.7 cells. The results suggested that lipopolysaccharide (LPS)-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) production were obviously inhibited by Aureusidin. Moreover, Aureusidin also significantly decreased the mRNA expression of various inflammatory factors in LPS-stimulated RAW264.7 cells. Furthermore, mechanistic studies showed that Aureusidin significantly inhibited nuclear transfer of nuclear factor-κB (NF-κB), while increasing the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) as well as expression of Nrf2 target genes such as heme oxygenase (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), but the addition of the HO-1 inhibitor Sn-protoporphyrin (Snpp) significantly abolished the anti-inflammatory effect of Aureusidin in LPS-stimulated RAW264.7 cells, confirming the view that HO-1 was involved in the anti-inflammatory effect. In addition, Aureusidin increased the levels of reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) phosphorylation in RAW264.7 cells. Antioxidant N-acetylcysteine (NAC) or three MAPK inhibitors blocked the nuclear translocation of Nrf2 and HO-1 expression induced by Aureusidin, indicating that Aureusidin activated the Nrf2/HO-1 signaling pathway through ROS and MAPKs pathways. At the same time, co-treatment with the NAC blocked the phosphorylation of MAPKs. Results from molecular docking indicated that Aureusidin inhibited the NF-κB pathway by covalently binding to NF-κB. Thus, Aureusidin exerted the anti-inflammatory activity through blocking the NF-κB signaling pathways and activating the MAPKs and Nrf2/HO-1 signaling pathways. Based on the above results, Aureusidin may be an attractive therapeutic candidate for the inflammation-related diseases.}, }
@article {pmid31790652, year = {2020}, author = {Yoshioka, Y and Sugino, Y and Shibagaki, F and Yamamuro, A and Ishimaru, Y and Maeda, S}, title = {Dopamine attenuates lipopolysaccharide-induced expression of proinflammatory cytokines by inhibiting the nuclear translocation of NF-κB p65 through the formation of dopamine quinone in microglia.}, journal = {European journal of pharmacology}, volume = {866}, number = {}, pages = {172826}, doi = {10.1016/j.ejphar.2019.172826}, pmid = {31790652}, issn = {1879-0712}, mesh = {Active Transport, Cell Nucleus/drug effects ; Animals ; Cell Line ; Cell Nucleus/*drug effects/*metabolism ; Cytokines/*metabolism ; Dopamine/*analogs &amp; derivatives/biosynthesis/*pharmacology ; Gene Expression Regulation/drug effects ; Lipopolysaccharides/pharmacology ; Mice ; Microglia/cytology/*drug effects/metabolism ; Transcription Factor RelA/*metabolism ; }, abstract = {Many reports have indicated that dopamine has immunomodulatory effects on peripheral immune cells. The purpose of this study was to reveal the immunomodulatory effect of dopamine on the expression of proinflammatory cytokines in microglial cells, which are the immune cells of the central nervous system. In murine microglial cell line BV-2 cells, pretreatment with dopamine for 24 h attenuated the lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines such as tumor-necrosis factor-α, interleukin-1β, and interleukin-6. Neither (5R)-8-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol; hydrochloride (SCH-23390) nor sulpiride, which are dopamine D1-like and D2-like receptor antagonists, respectively, affected the attenuation of LPS-induced expression of cytokines by dopamine. In addition, pretreatment with neither (-)-(6aR,12bR)-4,6,6a,7,8,12b-Hexahydro-7-methylindolo[4,3-a]phenanthridin (CY208-243) nor bromocriptine, dopamine D1-like and D2-like receptor agonists, respectively, was effective in doing so. However, N-acetylcysteine (NAC), which inhibits dopamine oxidation to dopamine quinone, did inhibit this attenuated expression. Dopamine increased the level of quinoproteins, and this increase was inhibited by NAC. Western blot and immunocytochemical analyses revealed that dopamine inhibited LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB) p65. Dopamine also attenuated the expression of cytokines and the nuclear translocation of NF-κB p65 induced by LPS in mouse microglial cells in primary culture. These results suggest that dopamine attenuated LPS-induced expression of cytokines by inhibiting the nuclear translocation of NF-κB p65 through the formation of dopamine quinone in microglial cells.}, }
@article {pmid31790150, year = {2019}, author = {Vyas, A and Duvvuri, U and Kiselyov, K}, title = {Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity.}, journal = {The Biochemical journal}, volume = {476}, number = {24}, pages = {3705-3719}, pmid = {31790150}, issn = {1470-8728}, support = {I01 BX003456/BX/BLRD VA/United States ; R01 DE028343/DE/NIDCR NIH HHS/United States ; }, mesh = {Anoctamin-1/genetics/*metabolism ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cisplatin/*pharmacology ; Copper-Transporting ATPases/genetics/*metabolism ; Drug Resistance, Neoplasm/*genetics ; Gene Expression Regulation, Enzymologic/drug effects ; Gene Expression Regulation, Neoplastic/*drug effects ; Head and Neck Neoplasms/*drug therapy ; Humans ; Neoplasm Proteins/genetics/*metabolism ; Up-Regulation ; }, abstract = {Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors' platinum resistance identifies novel approach to treating these tumors.}, }
@article {pmid31788473, year = {2019}, author = {Bora, P and Thamodaran, V and Šušor, A and Bruce, AW}, title = {p38-Mitogen Activated Kinases Mediate a Developmental Regulatory Response to Amino Acid Depletion and Associated Oxidative Stress in Mouse Blastocyst Embryos.}, journal = {Frontiers in cell and developmental biology}, volume = {7}, number = {}, pages = {276}, pmid = {31788473}, issn = {2296-634X}, abstract = {Maternal starvation coincident with preimplantation development has profound consequences for placental-fetal development, with various identified pathologies persisting/manifest in adulthood; the 'Developmental Origin of Health and Disease' (DOHaD) hypothesis/model. Despite evidence describing DOHaD-related incidence, supporting mechanistic and molecular data relating to preimplantation embryos themselves are comparatively meager. We recently identified the classically recognized stress-related p38-mitogen activated kinases (p38-MAPK) as regulating formation of the extraembryonic primitive endoderm (PrE) lineage within mouse blastocyst inner cell mass (ICM). Thus, we wanted to assay if PrE differentiation is sensitive to amino acid availability, in a manner regulated by p38-MAPK. Although blastocysts appropriately mature, without developmental/morphological or cell fate defects, irrespective of amino acid supplementation status, we found the extent of p38-MAPK inhibition induced phenotypes was more severe in the absence of amino acid supplementation. Specifically, both PrE and epiblast (EPI) ICM progenitor populations remained unspecified and there were fewer cells and smaller blastocyst cavities. Such phenotypes could be ameliorated, to resemble those observed in groups supplemented with amino acids, by addition of the anti-oxidant NAC (N-acetyl-cysteine), although PrE differentiation deficits remained. Therefore, p38-MAPK performs a hitherto unrecognized homeostatic early developmental regulatory role (in addition to direct specification of PrE), by buffering blastocyst cell number and ICM cell lineage specification (relating to EPI) in response to amino acid availability, partly by counteracting induced oxidative stress; with clear implications for the DOHaD model.}, }
@article {pmid31787716, year = {2019}, author = {Park, D}, title = {Metformin Induces Oxidative Stress-Mediated Apoptosis without the Blockade of Glycolysis in H4IIE Hepatocellular Carcinoma Cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {42}, number = {12}, pages = {2002-2008}, doi = {10.1248/bpb.b19-00474}, pmid = {31787716}, issn = {1347-5215}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Glucose/metabolism ; Glycolysis/drug effects ; Humans ; Hypoglycemic Agents/*pharmacology ; Lactic Acid/metabolism ; Liver Neoplasms/*metabolism ; Metformin/*pharmacology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Metformin, a widely prescribed anti-diabetic drug, also exerts anti-cancer effects in different types of cancers. Although a number of molecular mechanisms have been suggested, the metabolic features underlying metformin's anti-cancer activity is not fully understood enough. Because cancer cells have been known to prefer inefficient aerobic glycolysis to support their proliferation, it is important to clarify by which metformin affects metabolism to suppress the proliferation of cancer cells. Here, we report the metabolic changes induced by metformin and its relevance to the induction of apoptosis in H4II rat hepatocellular carcinoma cells. H4IIE cells were treated with metformin and other reagents in culture media with various nutritional compositions. Glutamine as well as pyruvate enhanced the viability of H4IIE cells in glucose-deprived conditions. Protective effects of glucose and pyruvate were comparable at same concentrations (5 mM). Metformin induced apoptosis irrespective of any nutritional conditions. Glucose consumption and lactate production were stimulated by metformin. Inhibition of glycolysis by 2-deoxyglucose suppressed the metformin-induced lactate production but additively enhanced metformin's pro-apoptotic effect. These results indicate that metformin does not interfere but accelerate glycolysis. Unexpectedly, the production of reactive oxygen species (ROS) was markedly stimulated by metformin. A potent antioxidant, N-acetylcysteine (NAC) suppressed all pro-apoptotic changes as well as ROS generation induced by metformin. Taken together, metformin does not interfere with glycolysis but promotes apoptosis by enhancing oxidative stress.}, }
@article {pmid31786651, year = {2020}, author = {McQueen, G and Lay, A and Lally, J and Gabay, AS and Collier, T and Lythgoe, DJ and Barker, GJ and Stone, JM and McGuire, P and MacCabe, JH and Egerton, A}, title = {Effect of single dose N-acetylcysteine administration on resting state functional connectivity in schizophrenia.}, journal = {Psychopharmacology}, volume = {237}, number = {2}, pages = {443-451}, pmid = {31786651}, issn = {1432-2072}, support = {MR/L003988/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Brain/*diagnostic imaging/drug effects/metabolism ; Cross-Over Studies ; Double-Blind Method ; Female ; Gyrus Cinguli/diagnostic imaging/drug effects/metabolism ; Humans ; Magnetic Resonance Imaging/*methods ; Male ; Middle Aged ; Nerve Net/*diagnostic imaging/drug effects/metabolism ; Proton Magnetic Resonance Spectroscopy/methods ; Rest/*physiology ; Schizophrenia/*diagnostic imaging/drug therapy/metabolism ; }, abstract = {RATIONALE: There is interest in employing N-acetylcysteine (NAC) in the treatment of schizophrenia, but investigations of the functional signatures of its pharmacological action are scarce.<br><br>OBJECTIVES: The aim of this study was to identify the changes in resting-state functional connectivity (rs-FC) that occur following administration of a single dose of NAC in patients with schizophrenia. A secondary aim was to examine whether differences in rs-FC between conditions were mediated by glutamate metabolites in the anterior cingulate cortex (ACC).<br><br>METHODS: In a double-blind, placebo-controlled crossover design, 20 patients with schizophrenia had two MRI scans administered 7 days apart, following oral administration of either 2400 mg NAC or placebo. Resting state functional fMRI (rsfMRI) assessed the effect of NAC on rs-FC within the default mode network (DMN) and the salience network (SN). Proton magnetic resonance spectroscopy was used to measure Glx/Cr (glutamate plus glutamine, in ratio to creatine) levels in the ACC during the same scanning sessions.<br><br>RESULTS: Compared to the placebo condition, the NAC condition was associated with reduced within the DMN and SN, specifically between the medial pre-frontal cortex to mid frontal gyrus, and ACC to frontal pole (all p < 0.04). There were no significant correlations between ACC Glx/Cr and rs-FC in either condition (p > 0.6).<br><br>CONCLUSIONS: These findings provide preliminary evidence that NAC can reduce medial frontal rs-FC in schizophrenia. Future studies assessing the effects of NAC on rs-FC in early psychosis and on repeated administration in relation to efficacy would be of interest.}, }
@article {pmid31785979, year = {2020}, author = {Shah, KR and Beuhler, MC}, title = {Fomepizole as an Adjunctive Treatment in Severe Acetaminophen Toxicity.}, journal = {The American journal of emergency medicine}, volume = {38}, number = {2}, pages = {410.e5-410.e6}, doi = {10.1016/j.ajem.2019.09.005}, pmid = {31785979}, issn = {1532-8171}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology ; Drug Overdose/*drug therapy ; Fomepizole/*administration &amp; dosage ; Humans ; Male ; Treatment Outcome ; }, abstract = {A 33-year-old male presented to the emergency department with a chief complaint of abdominal pain after taking #50 500 mg acetaminophen tablets over the preceding two days. He was tachycardic and tachypneic, and the initial labs were notable for acetaminophen level, 337 mg/L; AST, 137 IU/L; ALT, 194 IU/L; ABG pH, 7.24; and lactate, 4.1 mmol/L. The patient was started on IV N-Acetylcysteine (NAC) as well as given a single dose of 15 mg/kg fomepizole. The patient did remarkably well, with a peak AST of 198 IU/L, peak ALT of 301 IU/L, and peak INR of 3.1. Biochemical and animal data support fomepizole having hepatoprotective effects in acetaminophen poisoning. To our knowledge, this is the first human case of an intentional dual NAC/fomepizole regimen for severe acetaminophen toxicity.}, }
@article {pmid31784542, year = {2019}, author = {Verma, SS and Rai, V and Awasthee, N and Dhasmana, A and Rajalaksmi, DS and Nair, MS and Gupta, SC}, title = {Isodeoxyelephantopin, a Sesquiterpene Lactone Induces ROS Generation, Suppresses NF-κB Activation, Modulates LncRNA Expression and Exhibit Activities Against Breast Cancer.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {17980}, pmid = {31784542}, issn = {2045-2322}, mesh = {Antineoplastic Agents, Phytogenic/chemistry/*pharmacology/therapeutic use ; Asteraceae/chemistry ; Breast Neoplasms/*drug therapy/genetics/pathology ; Cell Proliferation/genetics ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Lactones/chemistry/*pharmacology/therapeutic use ; Membrane Potential, Mitochondrial/drug effects ; RNA, Long Noncoding/metabolism ; Reactive Oxygen Species/metabolism ; Sesquiterpenes/chemistry/*pharmacology/therapeutic use ; Signal Transduction/*drug effects/genetics ; Stereoisomerism ; Transcription Factor RelA/metabolism ; }, abstract = {The sesquiterpene lactones, Isodeoxyelephantopin (IDET) and Deoxyelephantopin (DET) are known to exhibit activities against some cancer types. The activities of these lactones against breast cancer and the molecular bases is not known. We examined the efficacy of lactones in breast cancer preclinical model. Although both lactones exhibited drug like properties, IDET was relatively effective in comparison to DET. IDET suppressed the proliferation of both invasive and non-invasive breast cancer cell lines. IDET also suppressed the colony formation and migration of breast cancer cells. The assays for Acridine Orange (AO)/Propidium Iodide (PI) staining, cell cycle distribution, phosphatidylserine externalization and DNA laddering suggested the apoptosis inducing potential of IDET. The treatment with IDET also induced an accumulation of cells in the sub-G1 and G2/M phases. The exposure of breast cancer cells to the lactone was associated with a depolarization in mitochondrial membrane potential, and cleavage of caspase and PARP. The lactone induced reactive oxygen species (ROS) generation in breast cancer cells. Further, the use of N-acetyl cysteine (NAC) suppressed IDET induced ROS generation and apoptosis. The NF-κB-p65 nuclear translocation induced by okadaic acid (OA) was suppressed by the sesquiterpene. IDET also suppressed the expression of NF-κB regulated tumorigenic proteins, and induced the expression of proapoptotic gene (Bax) in cancer cells. While the expression of oncogenic lncRNAs was suppressed, the tumor suppressor lncRNAs were induced by the sesquiterpene. Collectively, the modulation of multiple cell signaling molecules by IDET may contribute to its activities in breast cancer cells.}, }
@article {pmid31779696, year = {2019}, author = {Cotton, SM and Berk, M and Watson, A and Wood, S and Allott, K and Bartholomeusz, CF and Bortolasci, CC and Walder, K and O'Donoghue, B and Dean, OM and Chanen, A and Amminger, GP and McGorry, PD and Burnside, A and Uren, J and Ratheesh, A and Dodd, S}, title = {ENACT: a protocol for a randomised placebo-controlled trial investigating the efficacy and mechanisms of action of adjunctive N-acetylcysteine for first-episode psychosis.}, journal = {Trials}, volume = {20}, number = {1}, pages = {658}, pmid = {31779696}, issn = {1745-6215}, support = {APP1125778//National Health and Medical Research Council/ ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Humans ; Outcome Assessment, Health Care ; Psychotic Disorders/*drug therapy/psychology ; Quality of Life ; *Randomized Controlled Trials as Topic ; Young Adult ; }, abstract = {BACKGROUND: First-episode psychosis (FEP) may lead to a progressive, potentially disabling and lifelong chronic illness; however, evidence suggests that the illness course can be improved if appropriate treatments are given at the early stages. Nonetheless, the efficacy of antipsychotic medications is suboptimal, particularly for negative and cognitive symptoms, and more efficacious and benign treatments are needed. Previous studies have shown that the antioxidant amino acid N-acetylcysteine (NAC) reduces negative symptoms and improves functioning in chronic schizophrenia and bipolar disorder. Research is scarce as to whether NAC is beneficial earlier in the course of illness. The primary aim of this study is to determine the efficacy of treatment with adjunctive NAC (2 g/day for 26 weeks) compared with placebo to improve psychiatric symptoms in young people experiencing FEP. Secondary aims are to explore the neurobiological mechanisms underpinning NAC and how they relate to various clinical and functional outcomes at 26- and 52-week follow-ups.<br><br>METHODS/DESIGN: ENACT is a 26-week, randomised controlled trial of adjunctive NAC versus placebo, with a 26-week non-treatment follow-up period, for FEP. We will be recruiting 162 young people aged 15-25&#x2009;years who have recently presented to, and are being treated at, the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. The primary outcome is the Total Score on the Positive and Negative Syndrome Scale which will be administered at baseline, and weeks 4, 8, 12, 26 (primary endpoint), and 52 (end of study). Secondary outcomes include: symptomatology, functioning, quality of life, neurocognition, blood-derived measures of: inflammation, oxidative and nitrosative stress, and magnetic resonance spectroscopy measures of glutathione concentration.<br><br>DISCUSSION: Targeted drug development for FEP to date has generally not involved the exploration of neuroprotective agents. This study has the potential to offer a new, safe, and efficacious treatment for people with FEP, leading to better treatment outcomes. Additionally, the neuroprotective dimension of this study may lead to a better long-term prognosis for people with FEP. It has the potential to uncover a novel treatment that targets the neurobiological mechanisms of FEP and, if successful, will be a major advance for psychiatry.<br><br>TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ID: ACTRN12618000413224. Registered on 21 March 2018.}, }
@article {pmid31777419, year = {2019}, author = {Nyui, M and Shoji, Y and Ueno, M and Nakanishi, I and Matsumoto, KI}, title = {Reduction of molecular oxygen by redox active thiols: comparison of glutathione, N-acetylcysteine, cysteine, and homocysteine.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {65}, number = {3}, pages = {185-192}, pmid = {31777419}, issn = {0912-0009}, abstract = {The reaction properties of the thiol compounds, cysteine (Cys), N-acetyl-l-cysteine (NAC), the reduced form glutathione (GSH), and homocysteine (HCS) were compared. The main purpose of this study was to find a thiol-based anti-oxidant suitable for biological experiments and to provide clear reasoning for its selection. The availability of thiol compounds to generate superoxide by reducing molecular oxygen (O2) at a hyperthermal temperature was discussed. An oxidative atmosphere, i.e., superoxide generation by the hypoxanthine-xanthine oxidase reaction, hydroxyl radical generation by X-ray irradiation, or direct one-electron oxidation by ferricyanide, was prepared in a reaction mixture containing 0.1 mM TEMPOL and 1 mM test compound, and the EPR signal decay of TEMPOL was observed. A reaction mixture containing 0.1 mM TEMPOL and 1 mM thiol compound was incubated at 44°C, and the EPR signal decay of TEMPOL was observed. Thiols could function as H-donors to the oxoammonium cation and produce the hydroxylamine form of TEMPOL in an oxidative atmosphere. Thiols could also irreversibly react with the oxoammonium cation. GSH and Cys could reduce O2 to form superoxide/hydroperoxyl radical at hyperthermal temperatures, but HCS and NAC could not reduce O2. GSH and Cys may cause reductive stress, whereas NAC is a simple tractable antioxidant.}, }
@article {pmid31771272, year = {2019}, author = {Burns, DP and Drummond, SE and Bolger, D and Coiscaud, A and Murphy, KH and Edge, D and O'Halloran, KD}, title = {N-acetylcysteine Decreases Fibrosis and Increases Force-Generating Capacity of mdx Diaphragm.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {8}, number = {12}, pages = {}, pmid = {31771272}, issn = {2076-3921}, support = {Research Grant to DE//The Physiological Society/ ; }, abstract = {Respiratory muscle weakness occurs due to dystrophin deficiency in Duchenne muscular dystrophy (DMD). The mdx mouse model of DMD shows evidence of impaired respiratory muscle performance with attendant inflammation and oxidative stress. We examined the effects of N-acetylcysteine (NAC) supplementation on respiratory system performance in mdx mice. Eight-week-old male wild type (n = 10) and mdx (n = 20) mice were studied; a subset of mdx (n = 10) received 1% NAC in the drinking water for 14 days. We assessed breathing, diaphragm, and external intercostal electromyogram (EMG) activities and inspiratory pressure during ventilatory and non-ventilatory behaviours. Diaphragm muscle structure and function, cytokine concentrations, glutathione status, and mRNA expression were determined. Diaphragm force-generating capacity was impaired in mdx compared with wild type. Diaphragm muscle remodelling was observed in mdx, characterized by increased muscle fibrosis, immune cell infiltration, and central myonucleation. NAC supplementation rescued mdx diaphragm function. Collagen content and immune cell infiltration were decreased in mdx + NAC compared with mdx diaphragms. The cytokines IL-1β, IL-6 and KC/GRO were increased in mdx plasma and diaphragm compared with wild type; NAC decreased systemic IL-1β and KC/GRO concentrations in mdx mice. We reveal that NAC treatment improved mdx diaphragm force-generating capacity associated with beneficial anti-inflammatory and anti-fibrotic effects. These data support the potential use of NAC as an adjunctive therapy in human dystrophinopathies.}, }
@article {pmid31770553, year = {2020}, author = {Hamedinasab, H and Rezayan, AH and Mellat, M and Mashreghi, M and Jaafari, MR}, title = {Development of chitosan-coated liposome for pulmonary delivery of N-acetylcysteine.}, journal = {International journal of biological macromolecules}, volume = {156}, number = {}, pages = {1455-1463}, doi = {10.1016/j.ijbiomac.2019.11.190}, pmid = {31770553}, issn = {1879-0003}, mesh = {Acetylcysteine/*administration &amp; dosage/chemistry/metabolism ; Chitosan/*chemistry ; Cholesterol/chemistry ; Humans ; Liposomes/*chemistry ; Lung/*metabolism ; Phosphatidylglycerols/chemistry ; Surface Properties ; }, abstract = {The purpose of the present investigation was to formulate NAC (N-acetylcysteine)-loaded chitosan (CH)-coated liposome aiming at obtaining an effective formulation able to ensure a prolonged and controlled release of NAC to the lung by inhalation. Empty liposomes [(DPPG/Chol/DPPG with different molar percentages of DPPG) (0, 1, 2.5, 5)] were prepared and coated with CH at different CH/Lipid ratio (0.5, 1, 1.5,2, 2.5, W/W) to reach optimum coating of CH. TEM and SEM indicated that morphology of CH-coated and -uncoated liposomes were spherical. FTIR analysis indicated attachment of CH on liposome surface. The drug release experiment in the simulated lung fluid showed that the CH-uncoated and -coated liposomes released 51% and 38% of NAC during 9 h, respectively. The results showed that coating of liposome with CH resulted in the prolonged release of NAC from CH-coated liposome. The results of flow cytometry indicated the effective uptake of CH-coated liposome compared with the CH-uncoated liposome in epithelial cells. In vivo experiment indicated good deposition and retention of CH-coated liposome in lung in comparison with CH-uncoated liposome. The results of the present study demonstrated that CH-coated liposome may represent a promising carrier for the delivery of NAC to the lungs by inhalation therapy.}, }
@article {pmid31769880, year = {2020}, author = {Oaks, Z and Jimah, J and Grossman, CC and Beckford, M and Kelly, R and Banerjee, S and Niland, B and Miklossy, G and Kuloglu, Z and Kansu, A and Lee, W and Szonyi, L and Banki, K and Perl, A}, title = {Transaldolase haploinsufficiency in subjects with acetaminophen-induced liver failure.}, journal = {Journal of inherited metabolic disease}, volume = {43}, number = {3}, pages = {496-506}, pmid = {31769880}, issn = {1573-2665}, support = {R01 DK058369/DK/NIDDK NIH HHS/United States ; R01 AI072648/AI/NIAID NIH HHS/United States ; U01 AR076092/AR/NIAMS NIH HHS/United States ; R01 AI122176/AI/NIAID NIH HHS/United States ; U01 DK058369/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Animals ; Carcinoma, Hepatocellular/genetics/pathology ; Female ; Haploinsufficiency/*drug effects ; Humans ; Liver Cirrhosis/pathology/prevention &amp; control ; Liver Failure/*chemically induced ; Liver Neoplasms/genetics/pathology/prevention &amp; control ; Male ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; Oxidative Stress/drug effects ; Pentose Phosphate Pathway ; Transaldolase/*deficiency/metabolism ; Young Adult ; }, abstract = {Transaldolase (TAL) is an enzyme in the pentose phosphate pathway (PPP) that generates NADPH for protection against oxidative stress. While deficiency of other PPP enzymes, such as transketolase (TKT), are incompatible with mammalian cell survival, mice lacking TAL are viable and develop progressive liver disease attributed to oxidative stress. Mice with homozygous or heterozygous TAL deficiency are predisposed to cirrhosis, hepatocellular carcinoma (HCC) and acetaminophen (APAP)-induced liver failure. Both mice and humans with complete TAL deficiency accumulate sedoheptulose 7-phosphate (S7P). Previous human studies relied on screening patients with S7P accumulation, thus excluding potentially pathogenic haploinsufficiency. Of note, mice with TAL haploinsufficiency are also predisposed to HCC and APAP-induced liver failure which are preventable with oral N-acetylcysteine (NAC) administration. Based on TALDO1 DNA sequencing, we detected functional TAL deficiency due to novel, heterozygous variations in two of 94 healthy adults and four of 27 subjects with APAP-induced liver failure (P = .022). The functional consequences of these variations were individually validated by site-directed mutagenesis of normal cDNA and loss of activity by recombinant enzyme. All four patients with TAL haplo-insufficiency with APAP-induced liver failure were successfully treated with NAC. We also document two novel variations in two of 15 children with previously unexplained liver cirrhosis. Examination of the National Center for Biotechnology Information databases revealed 274 coding region variations have been documented in 1125 TALDO1 sequences relative to 25 variations in 2870 TKT sequences (P < .0001). These findings suggest an unexpected prevalence and variety of genetic changes in human TALDO1 with relevance for liver injury that may be preventable by treatment with NAC.}, }
@article {pmid31768573, year = {2020}, author = {Reis, CG and Mocelin, R and Benvenutti, R and Marcon, M and Sachett, A and Herrmann, AP and Elisabetsky, E and Piato, A}, title = {Effects of N-acetylcysteine amide on anxiety and stress behavior in zebrafish.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {393}, number = {4}, pages = {591-601}, pmid = {31768573}, issn = {1432-1912}, mesh = {Acetylcysteine/*analogs &amp; derivatives/therapeutic use ; Animals ; Anti-Anxiety Agents/*therapeutic use ; Anxiety/*drug therapy ; Behavior, Animal/drug effects ; Female ; Male ; Oxidative Stress/drug effects ; Stress, Psychological/*drug therapy ; Zebrafish ; }, abstract = {Anxiety disorders are highly prevalent and a leading cause of disability worldwide. Their etiology is related to stress, an adaptive response of the organism to restore homeostasis, in which oxidative stress and glutamatergic hyperactivity are involved. N-Acetylcysteine (NAC) is a multitarget approved drug proved to be beneficial in the treatment of various mental disorders. Nevertheless, NAC has low membrane permeability and poor bioavailability and its limited delivery to the brain may explain inconsistencies in the literature. N-Acetylcysteine amide (AD4) is a synthetic derivative of NAC in which the carboxyl group was modified to an amide. The amidation of AD4 improved lipophilicity and blood-brain barrier permeability and enhanced its antioxidant properties. The purpose of this study was to investigate the effects of AD4 on behavioral and biochemical parameters in zebrafish anxiety models. Neither AD4 nor NAC induced effects on locomotion and anxiety-related parameters in the novel tank test. However, in the light/dark test, AD4 (0.001 mg/L) increased the time spent in the lit side in a concentration 100 times lower than NAC (0.1 mg/L). In the acute restraint stress protocol, NAC and AD4 (0.001 mg/L) showed anxiolytic properties without meaningful effects on oxidative status. The study suggests that AD4 has anxiolytic effects in zebrafish with higher potency than the parent compound. Additional studies are warranted to characterize the anxiolytic profile of AD4 and its potential in the management of anxiety disorders.}, }
@article {pmid31766382, year = {2019}, author = {Johnson, R and Sangweni, NF and Mabhida, SE and Dludla, PV and Mabasa, L and Riedel, S and Chapman, C and Mosa, RA and Kappo, AP and Louw, J and Muller, CJF}, title = {An In Vitro Study on the Combination Effect of Metformin and N-Acetyl Cysteine against Hyperglycaemia-Induced Cardiac Damage.}, journal = {Nutrients}, volume = {11}, number = {12}, pages = {}, pmid = {31766382}, issn = {2072-6643}, support = {10726//Rabia Johnson/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Cardiotonic Agents/*pharmacology ; Cell Line ; Glucose/*metabolism ; Hyperglycemia ; Lipid Peroxidation/drug effects ; Metformin/*pharmacology ; Models, Biological ; Myocytes, Cardiac/drug effects ; Oxidative Stress/*drug effects ; Rats ; }, abstract = {Chronic hyperglycaemia is a major risk factor for diabetes-induced cardiovascular dysfunction. In a hyperglycaemic state, excess production of reactive oxygen species (ROS), coupled with decreased levels of glutathione, contribute to increased lipid peroxidation and subsequent myocardial apoptosis. N-acetylcysteine (NAC) is a thiol-containing antioxidant known to protect against hyperglycaemic-induced oxidative stress by promoting the production of glutathione. While the role of NAC against oxidative stress-related cardiac dysfunction has been documented, to date data is lacking on its beneficial effect when used with glucose lowering therapies, such as metformin (MET). Thus, the aim of the study was to better understand the cardioprotective effect of NAC plus MET against hyperglycaemia-induced cardiac damage in an H9c2 cardiomyoblast model. H9c2 cardiomyoblasts were exposed to chronic high glucose concentrations for 24 h. Thereafter, cells were treated with MET, NAC or a combination of MET and NAC for an additional 24 h. The combination treatment mitigated high glucose-induced oxidative stress by improving metabolic activity i.e. ATP activity, glucose uptake (GU) and reducing lipid accumulation. The combination treatment was as effective as MET in diminishing oxidative stress, lipid peroxidation and apoptosis. We observed that the combination treatment prevented hyperglycaemic-induced cardiac damage by increasing GLUT4 expression and mitigating lipid accumulation via phosphorylation of both AMPK and AKT, while decreasing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), as well as protein kinase C (PKC), a known activator of insulin receptor substrate-1 (IRS-1), via phosphorylation at Ser307. On this basis, the current results support the notion that the combination of NAC and MET can shield the diabetic heart against impaired glucose utilization and therefore its long-term protective effect warrants further investigation.}, }
@article {pmid31756435, year = {2020}, author = {Gu, SH and Chen, CH}, title = {Reactive oxygen species-mediated bombyxin signaling in Bombyx mori.}, journal = {Insect biochemistry and molecular biology}, volume = {117}, number = {}, pages = {103279}, doi = {10.1016/j.ibmb.2019.103279}, pmid = {31756435}, issn = {1879-0240}, mesh = {Animals ; Bombyx/growth &amp; development/*metabolism ; Insect Proteins/*metabolism ; Larva/growth &amp; development/metabolism ; Neuropeptides/*metabolism ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; }, abstract = {In the present study, we demonstrated that bombyxin, an insect insulin-like peptide, modulated ecdysteroidogenesis in Bombyx mori prothoracic glands (PGs) through redox signaling. Our results showed that bombyxin treatment resulted in a transient increase in intracellular reactive oxygen species (ROS) concentration, as measured using 2',7'-dichlorofluorescin diacetate (DCFDA), an oxidation-sensitive fluorescent probe. The antioxidant N-acetylcysteine (NAC) abolished the bombyxin-induced increase in fluorescence in Bombyx PGs. Furthermore, bombyxin-induced ROS production was inhibited by mitochondrial oxidative phosphorylation inhibitors (rotenone and antimycin A), indicating mitochondria-mediated ROS production. The stimulation of ROS production in response to bombyxin appears to undergo development-specific changes. We further investigated the action mechanism of bombyxin-stimulated ROS signaling. Results showed that in the presence of either NAC, rotenone, or antimycin A, bombyxin-stimulated phosphorylation of insulin receptor, Akt, and 4E-binding protein (4E-BP) was blocked and bombyxin-stimulated ecdysteroidogenesis in PGs was greatly inhibited. From these results, we conclude that ROS signaling appears to be involved in bombyxin-stimulated ecdysteroidogenesis of PGs in B. mori by modulating the phosphorylation of insulin receptor, Akt, and 4E-BP. To our knowledge, this is the first demonstration of redox regulation in insulin signaling in an insect system.}, }
@article {pmid31756327, year = {2020}, author = {Sunilkumar, D and Drishya, G and Chandrasekharan, A and Shaji, SK and Bose, C and Jossart, J and Perry, JJP and Mishra, N and Kumar, GB and Nair, BG}, title = {Oxyresveratrol drives caspase-independent apoptosis-like cell death in MDA-MB-231 breast cancer cells through the induction of ROS.}, journal = {Biochemical pharmacology}, volume = {173}, number = {}, pages = {113724}, doi = {10.1016/j.bcp.2019.113724}, pmid = {31756327}, issn = {1873-2968}, mesh = {Antineoplastic Agents/chemistry/metabolism/pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms/*metabolism/pathology ; Caspase 3/chemistry/metabolism ; Caspases/chemistry/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Molecular Docking Simulation ; Plant Extracts/chemistry/metabolism/*pharmacology ; Protein Binding ; Reactive Oxygen Species/*metabolism ; Stilbenes/chemistry/metabolism/*pharmacology ; }, abstract = {Earlier studies from our laboratory have demonstrated that Oxyresveratrol (OXY), a hydroxyl-substituted stilbene, exhibits potent inhibition of human melanoma cell proliferation. The present study defines a cytotoxic effect of OXY on the highly chemo-resistant, triple-negative human breast cancer cell line MDA-MB-231. OXY-mediated cell death resulted in accumulation of cells at the sub-G1 phase of the cell cycle, induced chromatin condensation, DNA fragmentation, phosphatidylserine externalization and PARP cleavage, indicative of apoptosis. Interestingly, morphology and cell viability studies with the pan-caspase inhibitor, QVD-OPH revealed that OXY-induced cell death was caspase-independent. Docking studies also showed that OXY can bind to the S1 site of caspase-3, and could also exert an inhibitory effect on this executioner caspase. The immunoblot analysis demonstrating the absence of caspase cleavage during cell death further confirmed these findings. OXY was also observed to induce the production of reactive oxygen species, which caused the depolarization of the mitochondrial membrane resulting in translocation of Apoptosis Inducing Factor (AIF) into the nucleus. Pretreatment of the cells with N-Acetyl Cysteine antioxidant prevented cell death resulting from OXY treatment. Thus, OXY initiates ROS-mediated, apoptosis-like cell death, involving mitochondrial membrane depolarization, translocation of AIF into the nucleus, and DNA fragmentation, resulting in caspase-independent cell death in MDA-MB-231 cells. The cytotoxicity manifested by OXY was also observed in 3D cell culture models and primary cells, thereby providing a basis for the utilization of OXY as a novel template for the future design of anticancer therapeutics.}, }
@article {pmid31754457, year = {2019}, author = {Cho, CS and Kowalsky, AH and Namkoong, S and Park, SR and Wu, S and Kim, B and James, A and Gu, B and Semple, IA and Tohamy, MA and Solanki, S and Cho, US and Greenson, JK and Shah, YM and Kim, M and Lee, JH}, title = {Concurrent activation of growth factor and nutrient arms of mTORC1 induces oxidative liver injury.}, journal = {Cell discovery}, volume = {5}, number = {}, pages = {60}, pmid = {31754457}, issn = {2056-5968}, support = {R01 DK114131/DK/NIDDK NIH HHS/United States ; T32 AG000114/AG/NIA NIH HHS/United States ; R01 DK111465/DK/NIDDK NIH HHS/United States ; R01 DK102850/DK/NIDDK NIH HHS/United States ; F31 DK117610/DK/NIDDK NIH HHS/United States ; P30 CA046592/CA/NCI NIH HHS/United States ; P30 AG024824/AG/NIA NIH HHS/United States ; K01 AG061236/AG/NIA NIH HHS/United States ; P30 DK089503/DK/NIDDK NIH HHS/United States ; T32 GM008322/GM/NIGMS NIH HHS/United States ; P30 DK034933/DK/NIDDK NIH HHS/United States ; P30 AR069620/AR/NIAMS NIH HHS/United States ; }, abstract = {mTORC1 is a protein kinase important for metabolism and is regulated by growth factor and nutrient signaling pathways, mediated by the Rheb and Rag GTPases, respectively. Here we provide the first animal model in which both pathways were upregulated through concurrent mutations in their GTPase-activating proteins, Tsc1 and Depdc5. Unlike former models that induced limited mTORC1 upregulation, hepatic deletion of both Tsc1 and Depdc5 (DKO) produced strong, synergistic activation of the mTORC1 pathway and provoked pronounced and widespread hepatocyte damage, leading to externally visible liver failure phenotypes, such as jaundice and systemic growth defects. The transcriptome profile of DKO was different from single knockout mutants but similar to those of diseased human livers with severe hepatitis and mouse livers challenged with oxidative stress-inducing chemicals. In addition, DKO liver cells exhibited prominent molecular pathologies associated with excessive endoplasmic reticulum (ER) stress, oxidative stress, DNA damage and inflammation. Although DKO liver pathologies were ameliorated by mTORC1 inhibition, ER stress suppression unexpectedly aggravated them, suggesting that ER stress signaling is not the major conduit of how hyperactive mTORC1 produces liver damage. Interestingly, superoxide scavengers N-acetylcysteine (NAC) and Tempol, chemicals that reduce oxidative stress, were able to recover liver phenotypes, indicating that mTORC1 hyperactivation induced liver damage mainly through oxidative stress pathways. Our study provides a new model of unregulated mTORC1 activation through concomitant upregulation of growth factor and nutrient signaling axes and shows that mTORC1 hyperactivation alone can provoke oxidative tissue injury.}, }
@article {pmid31751620, year = {2020}, author = {Chakraborty, S and Tripathi, SJ and Srikumar, BN and Raju, TR and Shankaranarayana Rao, BS}, title = {N-acetyl cysteine ameliorates depression-induced cognitive deficits by restoring the volumes of hippocampal subfields and associated neurochemical changes.}, journal = {Neurochemistry international}, volume = {132}, number = {}, pages = {104605}, doi = {10.1016/j.neuint.2019.104605}, pmid = {31751620}, issn = {1872-9754}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Cognitive Dysfunction/chemically induced/*drug therapy/metabolism ; Depression/chemically induced/*drug therapy/metabolism ; Hippocampus/*chemistry/*drug effects/metabolism ; Male ; Organ Size ; Random Allocation ; Rats ; Rats, Wistar ; Selective Serotonin Reuptake Inhibitors/toxicity ; }, abstract = {Depression is highly comorbid with anxiety disorders and associated with profound cognitive impairment. Moreover, cognitive deficits associated with hippocampal dysfunction are central in depression and anxiety disorders. Furthermore, depression is accompanied by glutamatergic dysfunction which can further impair the functioning of the hippocampus. Recent studies have shown that N-acetyl cysteine (NAC), a glutamate modulator produces an antidepressant-like effect by normalization of the periterminal release of glutamate and/or antioxidant effects. However, the effects of repeated NAC treatment on depression-induced anxiety, cognitive deficits, and associated neurochemical and structural alterations are relatively unknown. Accordingly, we investigated whether chronic NAC treatment could reverse cognitive deficits, and associated hippocampal volume loss and monoaminergic alterations in the neonatal clomipramine (CLI) model of depression. We found that chronic NAC treatment produces antidepressive and antianhedonic-like effects. NAC treatment also reversed CLI-induced anxiety. Interestingly, repeated NAC treatment improved the performance of CLI rats in rewarded alternation task in T-maze. The antidepressive-like and procognitive effects of NAC was associated with normalization of volume loss in CA1, dentate gyrus (DG) and hilar subfields of the hippocampus. Furthermore, NAC restored CLI-induced decrease in levels of monoamines and normalized enhanced metabolism in the hippocampus. Taken together, chronic NAC treatment ameliorates depressive and anxiety-like behavior, spatial learning deficits, and reverses CLI-induced pathological alterations at structural and neurochemical levels in the hippocampus. Our findings might help in evolving NAC as a viable pharmacotherapy for reversal of cognitive deficits in depression and associated disorders.}, }
@article {pmid31751619, year = {2020}, author = {Mohamed, DI and Khairy, E and Khedr, SA and Habib, EK and Elayat, WM and El-Kharashi, OA}, title = {N-acetylcysteine (NAC) alleviates the peripheral neuropathy associated with liver cirrhosis via modulation of neural MEG3/PAR2/ NF-ҡB axis.}, journal = {Neurochemistry international}, volume = {132}, number = {}, pages = {104602}, doi = {10.1016/j.neuint.2019.104602}, pmid = {31751619}, issn = {1872-9754}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Free Radical Scavengers/pharmacology/therapeutic use ; Liver Cirrhosis/*drug therapy/metabolism/pathology ; Male ; NF-kappa B/*antagonists &amp; inhibitors/metabolism ; Peripheral Nervous System Diseases/*drug therapy/metabolism/pathology ; RNA, Long Noncoding/*antagonists &amp; inhibitors/metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Receptor, PAR-2/*antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {BACKGROUND AND AIM: Oxidative stress (OS) is accused in pathogenesis of many diseases, including liver cirrhosis by many mechanisms. One of them is the disturbance of long non coding maternally expressed 3 (MEG3)/protease activated receptor 2 (PAR2) downstream pathway. We aimed to investigate the role of this axis in cirrhotic neuropathy and whether an antioxidant compound such as N-acetylcysteine (NAC) could improve the peripheral nerve function through repression of MEG3/PAR2.<br><br>METHODS: Thirty Wistar rats were used and divided into 5 groups; naive, thiacetamide (TAA) (200&#xa0;mg/kg 3 times/week. i.p. for 8 weeks) and TAA+NAC (50 or 100 or 200&#xa0;mg/kg/day) groups. Von Frey (VF) test for mechanical nociceptive responses, hepatic&amp; neural MEG3, NF-&#x4a1;B and neural PAR2 expression by PCR, histological studies for liver and sciatic nerve together with the dorsopedal skin thickness were done.<br><br>RESULTS: TAA induced significant decrease in liver function, negative VF test, an increase in the expression of hepatic&amp; neural MEG3, NF-&#x4a1;B and neural PAR2. The histological studies showed cirrhotic changes with atrophy of the sciatic nerve and the dorsal skin. NAC improved the liver function together with reversal of the neural: functional, biochemical and histological changes in a dose dependent manner.<br><br>CONCLUSIONS: NAC could improve the peripheral neuropathy in cirrhotic rat through suppression of MEG3/PAR2 expression.}, }
@article {pmid31749887, year = {2019}, author = {Kavala, AA and Kuserli, Y and Turkyilmaz, S}, title = {Effect of N-acetylcysteine on intimal hyperplasia and endothelial proliferation in rabbit carotid artery anastomosis.}, journal = {Archives of medical science : AMS}, volume = {15}, number = {6}, pages = {1576-1581}, pmid = {31749887}, issn = {1734-1922}, abstract = {INTRODUCTION: Neointimal hyperplasia due to smooth muscle cell migration and proliferation, as well as extracellular matrix accumulation, plays an important role in stenosis and restenosis that develop after reconstructive vascular interventions. Various agents are being tested to reduce neointimal hyperplasia and to prevent lumen stenosis. In the present study, the effect of N-acetylcysteine (NAC) on intimal hyperplasia and endothelial hyperplasia after carotid anastomosis was investigated in a rabbit model.<br><br>MATERIAL AND METHODS: In the course of the study, rabbits were divided into two groups. The control group (n = 7) underwent right carotid artery anastomosis and received no medication. The NAC group (n = 7) underwent right carotid artery anastomosis and received NAC for 21 days following surgery. NAC was administered at a dose of 150 mg/kg/day just after the surgery. The carotid artery underwent anastomosis, and the histological examination findings of anastomosed and opposite non-anastomosed carotid arteries were compared in two experimental groups that either received NAC or did not.<br><br>RESULTS: Compared with the control group, the reduction in the lumen area and diameter after anastomosis was significantly recovered in the NAC group (p = 0.018; p = 0.612). Increases in the intima and media areas and the intima/media ratio were smaller in the NAC group after anastomosis than in the control group, but the differences were not significant.<br><br>CONCLUSIONS: We believe that vascular anastomosis and post-intervention NAC administration will prolong vascular patency by reducing intimal hyperplasia and providing vascular remodeling.}, }
@article {pmid31749393, year = {2020}, author = {Song, Y and Wang, H and Huang, H and Zhu, Z}, title = {Comparison of the efficacy between NAC and metformin in treating PCOS patients: a meta-analysis.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {36}, number = {3}, pages = {204-210}, doi = {10.1080/09513590.2019.1689553}, pmid = {31749393}, issn = {1473-0766}, mesh = {Acetylcysteine/*therapeutic use ; Body Mass Index ; Female ; Follicle Stimulating Hormone/blood ; Free Radical Scavengers/*therapeutic use ; Humans ; Hypoglycemic Agents/*therapeutic use ; Insulin/blood ; Luteinizing Hormone/blood ; Metformin/*therapeutic use ; Polycystic Ovary Syndrome/blood/*drug therapy ; Pregnancy ; Pregnancy Rate ; Testosterone/blood ; Treatment Outcome ; }, abstract = {Our aim is to evaluate the clinical effectiveness and safety by comparing N-acetyl-cysteine (NAC) with metformin administrated by polycystic ovary syndrome (PCOS) patients. Systematic review and meta-analysis of randomized clinical trials (RCTs). MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure were searched for studies. 10 studies were considered eligible for inclusion. NAC significantly reduced BMI and total testosterone, there was no significant difference in pregnancy rate, serum LH level, fasting insulin, and LH/FSH ratio. In conclusions, NAC may be considered as an alternative supplement to metformin, but large-scale randomized controlled trials are needed to assess the efficacy and safety of NAC in PCOS patients.}, }
@article {pmid31743234, year = {2020}, author = {Uzun, &#xd6; and Bolu, A and Çelik, C}, title = {Effect of N-acetylcysteine on clozapine-induced sialorrhea in schizophrenic patients: a case series.}, journal = {International clinical psychopharmacology}, volume = {35}, number = {4}, pages = {229-231}, doi = {10.1097/YIC.0000000000000297}, pmid = {31743234}, issn = {1473-5857}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Clozapine/*adverse effects/therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Schizophrenia/drug therapy ; Sialorrhea/chemically induced/*drug therapy ; }, abstract = {Clozapine is an atypical antipsychotic demonstrated to be superior in the treatment of refractory schizophrenia. Despite all this effectiveness, it has side effects that can be serious and bothersome. Sialorrhea is the most common adverse drug reaction that occurs during clozapine treatment. It is usually persistent, may impair the patient's quality of life and reduce treatment compliance. However, there is limited evidence to guide possible treatment strategies for sialorrhea. N-Acetylcysteine (NAC) is a powerful antioxidant. It acts directly as a scavenger of free radicals, in particular oxygen radicals. The antioxidant NAC also modulates glutamatergic, neurotrophic and inflammatory pathways. The first time we examined and reported the effect of NAC (1200-2400 mg/day) on clozapine-induced sialorrhea in a patient group of five patients. After four weeks of follow-up, the severity of sialorrhea decreased significantly with NAC augmentation. There were no significant side effects of NAC as measured by the UKU scale.}, }
@article {pmid31742908, year = {2020}, author = {Li, X and Jiang, M and Tan, T and Narasimhulu, CA and Xiao, Y and Hao, H and Cui, Y and Zhang, J and Liu, L and Yang, C and Li, Y and Ma, J and Verfaillie, CM and Parthasarathy, S and Zhu, H and Liu, Z}, title = {N-acetylcysteine prevents oxidized low-density lipoprotein-induced reduction of MG53 and enhances MG53 protective effect on bone marrow stem cells.}, journal = {Journal of cellular and molecular medicine}, volume = {24}, number = {1}, pages = {886-898}, pmid = {31742908}, issn = {1582-4934}, support = {R01 HL124122/HL/NHLBI NIH HHS/United States ; R01 ES026200/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Bone Marrow Cells/*drug effects/metabolism/pathology ; Cell Cycle ; Cell Proliferation ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/*drug effects ; Lipoproteins, LDL/*toxicity ; Male ; Membrane Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Multipotent Stem Cells/*drug effects/metabolism/pathology ; *Protective Factors ; Rats ; }, abstract = {MG53 is an important membrane repair protein and partially protects bone marrow multipotent adult progenitor cells (MAPCs) against oxidized low-density lipoprotein (ox-LDL). The present study was to test the hypothesis that the limited protective effect of MG53 on MAPCs was due to ox-LDL-induced reduction of MG53. MAPCs were cultured with and without ox-LDL (0-20 μg/mL) for up to 48 hours with or without MG53 and antioxidant N-acetylcysteine (NAC). Serum MG53 level was measured in ox-LDL-treated mice with or without NAC treatment. Ox-LDL induced significant membrane damage and substantially impaired MAPC survival with selective inhibition of Akt phosphorylation. NAC treatment effectively prevented ox-LDL-induced reduction of Akt phosphorylation without protecting MAPCs against ox-LDL. While having no effect on Akt phosphorylation, MG53 significantly decreased ox-LDL-induced membrane damage and partially improved the survival, proliferation and apoptosis of MAPCs in vitro. Ox-LDL significantly decreased MG53 level in vitro and serum MG53 level in vivo without changing MG53 clearance. NAC treatment prevented ox-LDL-induced MG53 reduction both in vitro and in vivo. Combined NAC and MG53 treatment significantly improved MAPC survival against ox-LDL. These data suggested that NAC enhanced the protective effect of MG53 on MAPCs against ox-LDL through preventing ox-LDL-induced reduction of MG53.}, }
@article {pmid31740426, year = {2020}, author = {Ong, GJ and Nguyen, TH and Stansborough, J and Surikow, S and Mahadavan, G and Worthley, M and Horowitz, J}, title = {The N-AcetylCysteine and RAMipril in Takotsubo Syndrome Trial (NACRAM): Rationale and design of a randomised controlled trial of sequential N-Acetylcysteine and ramipril for the management of Takotsubo Syndrome.}, journal = {Contemporary clinical trials}, volume = {90}, number = {}, pages = {105894}, doi = {10.1016/j.cct.2019.105894}, pmid = {31740426}, issn = {1559-2030}, mesh = {Humans ; *Acetylcysteine/administration &amp; dosage/therapeutic use ; *Angiotensin-Converting Enzyme Inhibitors/administration &amp; dosage/therapeutic use ; Carrier Proteins/drug effects ; Double-Blind Method ; *Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Inflammasomes/drug effects ; Prospective Studies ; Quality of Life ; *Ramipril/administration &amp; dosage/therapeutic use ; Randomized Controlled Trials as Topic ; *Takotsubo Cardiomyopathy/drug therapy/physiopathology ; Multicenter Studies as Topic ; }, abstract = {BACKGROUND: Takotsubo Syndrome(TTS), contrary to historical reports, is now increasingly recognised to be associated with substantial mortality and morbidity, both in the short- and long-term. Although TTS is often precipitated by a catecholamine "pulse", in-hospital hypotension is a common occurrence, increasing the risk of mortality. Furthermore, despite the transient catecholamine stimulus, there is increasing evidence that there are significant long term sequelae, including persistently impaired left ventricular(LV) systolic dysfunction, myocardial oedema with fibrosis, as well as persistent impairment of quality of life. A definitive therapeutic option to limit the extent of initial myocardial injury, and to accelerate recovery in TTS is therefore justified. However to date, there has been a lack of prospective studies in this area.<br><br>DESIGN AND RATIONALE: NACRAM is a multi-centre, randomised, placebo-controlled trial, sequentially testing early use of intravenous N-acetylcysteine(NAC), followed by/or oral ramipril for 12&#x202f;weeks. The rationale for utilising these agents is related to their effects on limiting nitrosative stress and expression of the inflammasome activator thioredoxin interacting protein(TXNIP); both processes fundamental to the pathogenesis of TTS.<br><br>END POINTS: NACRAM is assessing resolution of myocardial oedema on cardiac magnetic resonance imaging(CMR), improvements in LV systolic function as measured by global longitudinal strain(GLS) on echocardiography, quality of life, and inflammatory markers.<br><br>DISCUSSION: To the best of our knowledge, NACRAM will be the first prospective study to help definitively evaluate a therapeutic option in acute attacks of TTS.}, }
@article {pmid31740394, year = {2020}, author = {He, R and Zheng, W and Ginman, T and Ottosson, H and Norgren, S and Zhao, Y and Hassan, M}, title = {Pharmacokinetic profile of N-acetylcysteine amide and its main metabolite in mice using new analytical method.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {143}, number = {}, pages = {105158}, doi = {10.1016/j.ejps.2019.105158}, pmid = {31740394}, issn = {1879-0720}, mesh = {Acetylcysteine/*analogs &amp; derivatives/blood/pharmacokinetics ; Animals ; Biological Availability ; Female ; Glutathione/metabolism ; Humans ; Mice, Inbred BALB C ; Prodrugs/*pharmacokinetics ; Sulfhydryl Compounds/chemistry ; }, abstract = {N-acetylcysteine amide (NACA) is the amide derivative of N-acetylcysteine (NAC) that is rapidly converted to NAC after systemic administration. It has emerged as a promising thiol antioxidant for multiple indications; however, the pharmacokinetic property is yet unclear due to lack of an accurate quantification method. The present investigation aimed to develop an analytical method for simultaneous quantification of NACA and NAC in plasma. A new reagent (2-(methylsulfonyl)-5-phenyl-1,3,4-oxadiazole, MPOZ) was introduced for thiol stabilization during sample processing and storage. Further, we utilized tris (2-carboxyethyl) phosphine (TCEP) to reduce the oxidized forms of NACA and NAC. After derivatization, NACA-MPOZ and NAC-MPOZ were quantified using liquid chromatography-mass spectrometry (LC-MS). The new method was validated and found to have high specificity, linearity, accuracy, precision, and recovery for the quantification of NACA and NAC in plasma. Furthermore, the formed derivatives of NACA and NAC were stable for 48 h under different conditions. The method was utilized in pharmacokinetic study which showed that the bioavailability of NACA is significantly higher than NAC (67% and 15%, respectively). The pharmacokinetic of NACA obeyed a two-compartment open model. The glutathione (GSH)-replenishing capacity was found to be three to four-fold higher after the administration of NACA compared to that observed after the administration of NAC. In conclusion, the present method is simple, robust and reproducible, and can be utilized in both experimental and clinical studies. NACA might be considered as a prodrug for NAC. Furthermore, this is the first report describing the pharmacokinetics and bioavailability of NACA in mouse.}, }
@article {pmid31739178, year = {2020}, author = {Kishore, S and Gupta, SK and Arava, SK and Mridha, AR and Jaiswal, AK and Sikary, AK and Bharti, DR and Behera, C}, title = {Biochemical findings in sudden unexpected death in epilepsy: Hospital based case-control study.}, journal = {Journal of forensic and legal medicine}, volume = {69}, number = {}, pages = {101884}, doi = {10.1016/j.jflm.2019.101884}, pmid = {31739178}, issn = {1878-7487}, mesh = {Acetylcysteine/pharmacology ; Adolescent ; Adult ; Aged ; Biomarkers/analysis ; Calcium/analysis ; Case-Control Studies ; Child ; Creatine Kinase/analysis ; Female ; Forensic Medicine ; Glucose/analysis ; Humans ; Male ; Middle Aged ; Pericardial Fluid/chemistry ; Potassium/analysis ; Sodium/analysis ; *Sudden Unexpected Death in Epilepsy ; Vitreous Body/chemistry ; Young Adult ; }, abstract = {PURPOSE: A review study on the biochemistry of epilepsy showed that in epileptic patients, serum glucose and cholesterol concentrations are low, sodium is unaffected, potassium increases, glucose is high and mild hypocalcemia. We have conducted a biochemical study on sudden unexpected death in epilepsy (SUDEP) cases in an attempt to establish the characteristic biochemical values to diagnose these deaths.<br><br>METHODS: This was a hospital based case-control study done at All India Institute of Medical Sciences, New Delhi for one year. Twenty SUDEP cases and 20 age- and sex-matched controls were included in the study. Femoral blood, cerebrospinal fluid, vitreous humor, and pericardial fluid were biochemically analyzed for sodium, potassium, calcium, glucose, N-acetyl- cysteine activated creatine kinase (CK-NAC) and isoenzyme CK-MB.<br><br>RESULT: Serum sodium, CK-MB and CK-NAC level was found significantly increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. Likewise, in CSF, sodium and CK-NAC was found increased and potassium level was found decreased in SUDEP cases. In vitreous humor, sodium and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths. In pericardial fluid, sodium, CK-NAC and CK-MB level was found increased and potassium level was found decreased in SUDEP cases in comparison to non-epileptic deaths.<br><br>CONCLUSION: It concludes that high sodium level and low potassium level could be associated with SUDEP. However, this is a small size study, a larger study is needed to verify the findings. Furthermore, it is difficult to conclude whether these findings are exclusive to SUDEP.}, }
@article {pmid31739113, year = {2020}, author = {Meier-Menches, SM and Aikman, B and Döllerer, D and Klooster, WT and Coles, SJ and Santi, N and Luk, L and Casini, A and Bonsignore, R}, title = {Comparative biological evaluation and G-quadruplex interaction studies of two new families of organometallic gold(I) complexes featuring N-heterocyclic carbene and alkynyl ligands.}, journal = {Journal of inorganic biochemistry}, volume = {202}, number = {}, pages = {110844}, doi = {10.1016/j.jinorgbio.2019.110844}, pmid = {31739113}, issn = {1873-3344}, mesh = {*Antineoplastic Agents/chemical synthesis/chemistry/pharmacology ; Drug Screening Assays, Antitumor ; *G-Quadruplexes ; Humans ; Ligands ; MCF-7 Cells ; Methane/analogs &amp; derivatives/chemistry ; *Neoplasms/drug therapy/metabolism/pathology ; *Organogold Compounds/chemical synthesis/chemistry/pharmacology ; }, abstract = {Experimental organometallic gold(I) compounds hold promise for anticancer therapy. This study reports the synthesis of two novel families of gold(I) complexes, including N1-substituted bis-N-heterocyclic carbene (NHC) complexes of general formula [Au(N1-TBM)2]BF4 (N1-TBM = N1-substituted 9-methyltheobromin-8-ylidene) and mixed gold(I) NHC-alkynyl complexes, [Au(N1-TBM)alkynyl]. The compounds were fully characterised for their structure and stability in aqueous environment and in the presence of N-acetyl cysteine by nuclear magnetic resonance (NMR) spectroscopy. The structures of bis(1-ethyl-3,7,9-trimethylxanthin-8-ylidene)gold(I), (4-ethynylpyridine)(1,9-dimethyltheobromine-8-ylidene)gold(I) and of (2,8-Diethyl-10-(4-ethynylphenyl)-5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ[4],5λ[4]-dipyrrolo[1,2-c:2',1'-f][1,3,2]diazaborinine)(1,3,7,9-tetramethylxanthin-8-ylidene)gold(I) were also confirmed by X-ray diffraction analysis. The compounds were studied for their properties as DNA G-quadruplex (G4 s) stabilizers by fluorescence resonance energy transfer (FRET) DNA melting. Only the cationic [Au(N1-TBM)2]BF4 family showed moderate G4 stabilization properties with respect to the previously reported benchmark compound [Au(9-methylcaffein-8-ylidene)2][+] (AuTMX2). However, the compounds also showed marked selectivity for binding to G4 structures with respect to duplex DNA in competition experiments. For selected complexes, the interactions with G4 s were also confirmed by circular dichroism (CD) studies. Furthermore, the gold(I) complexes were assessed for their antiproliferative effects in human cancer cells in vitro, displaying moderate activity. Of note, among the mixed gold(I) NHC-alkynyl compounds, one features a fluorescent boron-dipyrromethene (BODIPY) moiety which allowed determining its uptake into the cytoplasm of cancer cells by fluorescence microscopy.}, }
@article {pmid31737700, year = {2019}, author = {Zhang, X and Burroughs, S and Farooq, A and Bashir, MR and Muir, AJ and Patel, YA}, title = {N-Acetylcysteine in the Management of Acute Liver Failure From Sickle Cell Hepatic Crisis.}, journal = {ACG case reports journal}, volume = {6}, number = {8}, pages = {e00161}, pmid = {31737700}, issn = {2326-3253}, abstract = {N-acetylcysteine (NAC) has been well studied in the treatment of acetaminophen-induced and select non-acetaminophen-induced liver failure. However, its role in the management of sickle cell hepatic crisis resulting in acute liver failure (ALF) is unknown. We describe and discuss the novel and beneficial use of NAC in a 25-year-old man with ALF due to sickle cell hepatic crisis. We further review ALF in sickle cell disease and NAC in the treatment of non-acetaminophen-induced liver failure. Our case highlights the promising role of NAC in sickle cell-related liver injury.}, }
@article {pmid31737162, year = {2019}, author = {You, L and Yang, C and Du, Y and Liu, Y and Chen, G and Sai, N and Dong, X and Yin, X and Ni, J}, title = {Matrine Exerts Hepatotoxic Effects via the ROS-Dependent Mitochondrial Apoptosis Pathway and Inhibition of Nrf2-Mediated Antioxidant Response.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {1045345}, pmid = {31737162}, issn = {1942-0994}, mesh = {Alkaloids/*pharmacology ; Antioxidants/metabolism ; Apoptosis ; Cell Cycle/drug effects ; Cell Line, Tumor ; Heme Oxygenase-1/genetics/metabolism ; Hepatocytes/*drug effects/physiology ; Humans ; Kelch-Like ECH-Associated Protein 1/metabolism ; Mitochondria/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress ; Quinolizines/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Sophora ; Matrines ; }, abstract = {Matrine, an alkaloid isolated from Sophora flavescens, possesses a wide range of pharmacological properties. However, the use of matrine in clinical practice is limited due to its toxic effects. The present study investigated the roles of mitochondria and reactive oxygen species (ROS) in matrine-induced liver injury. Our results showed that treatment of HL-7702 cells with matrine led to significant and concentration- and time-dependent reductions in their viability, as well as significant and concentration-dependent increases in the number of apoptotic cells and supernatant lactate dehydrogenase (LDH) activity. The treatment led to significant increases in the population of cells in S phase and significant reduction of cell proportion in G0/G1 and G2/M phases. It also significantly and concentration-dependently increased the levels of ROS and malondialdehyde (MDA) but significantly and concentration-dependently reduced superoxide dismutase (SOD) activity, level of reduced glutathione (GSH), and mitochondrial membrane potential (MMP). Matrine treatment significantly and concentration-dependently upregulated the expressions of Bax, p53, p-p53, p21, cyclin E, Fas, cleaved caspase-3, caspase-8, and caspase-9 proteins and downregulated the expressions of Bcl-2, cyclin-dependent kinase 2 (CDK2), and cyclin A. It also significantly promoted the cleavage of poly(ADP-ribose)polymerase (PARP), upregulated Kelch-like ECH-associated protein 1 (Keap1) expression, and downregulated the expressions of cellular total and nuclear Nrf2. Matrine significantly inhibited the expressions of downstream oxidoreductases (Heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductases 1 (NQO-1)) and enhanced the formation of Keap1/Nrf2 protein complex. These results show that the hepatotoxic effect of matrine is exerted via inhibition of Nrf2 pathway, activation of ROS-mediated mitochondrial apoptosis pathway, and cell cycle arrest at S phase. Pretreatment with N-acetyl cysteine (NAC) partially reversed matrine-induced hepatotoxicity.}, }
@article {pmid31735020, year = {2019}, author = {Park, JA and Na, HH and Jin, HO and Kim, KC}, title = {Increased Expression of FosB through Reactive Oxygen Species Accumulation Functions as Pro-Apoptotic Protein in Piperlongumine Treated MCF7 Breast Cancer Cells.}, journal = {Molecules and cells}, volume = {42}, number = {12}, pages = {884-892}, pmid = {31735020}, issn = {0219-1032}, mesh = {A549 Cells ; Antineoplastic Agents/*pharmacology ; Apoptosis Regulatory Proteins/*genetics ; Breast Neoplasms/pathology ; Cell Death/drug effects ; Dioxolanes/*pharmacology ; Gene Expression ; Gene Expression Regulation, Neoplastic/drug effects ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; MCF-7 Cells ; Proto-Oncogene Proteins c-fos/*genetics ; RNA, Small Interfering ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Piperlongumine (PL), a natural alkaloid compound isolated from long pepper (Piper longum), can selectively kill cancer cells, but not normal cells, by accumulation of reactive oxygen species (ROS). The objective of this study was to investigate functional roles of expression of SETDB1 and FosB during PL treatment in MCF7 breast cancer cells. PL downregulates SETDB1 expression, and decreased SETDB1 expression enhanced caspase 9 dependent-PARP cleavage during PL-induced cell death. PL treatment generated ROS. ROS inhibitor NAC (N-acetyl cysteine) recovered SETDB1 expression decreased by PL. Decreased SETDB1 expression induced transcriptional activity of FosB during PL treatment. PARP cleavage and positive annexin V level were increased during PL treatment with FosB overexpression whereas PARP cleavage and positive annexin V level were decreased during PL treatment with siFosB transfection, implying that FosB might be a pro-apoptotic protein for induction of cell death in PL-treated MCF7 breast cancer cells. PL induced cell death in A549 lung cancer cells, but molecular changes involved in the induction of these cell deaths might be different. These results suggest that SETDB1 mediated FosB expression may induce cell death in PL-treated MCF7 breast cancer cells.}, }
@article {pmid31730865, year = {2019}, author = {Soliman, E and Behairy, SF and El-Maraghy, NN and Elshazly, SM}, title = {PPAR-γ agonist, pioglitazone, reduced oxidative and endoplasmic reticulum stress associated with L-NAME-induced hypertension in rats.}, journal = {Life sciences}, volume = {239}, number = {}, pages = {117047}, doi = {10.1016/j.lfs.2019.117047}, pmid = {31730865}, issn = {1879-0631}, mesh = {Animals ; Antioxidants/pharmacology ; Aorta/metabolism ; Blood Pressure/drug effects ; Catalase/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Glutathione/metabolism ; Heart/physiology ; Hypertension/*drug therapy/metabolism ; Male ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Oxidation-Reduction ; Oxidative Stress/drug effects ; PPAR gamma/agonists/*metabolism ; Pioglitazone/metabolism/*pharmacology ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, pioglitazone, is used clinically to improve the glycemic state in patients with type-2 diabetes mellitus. Independent of its blood glucose-lowering properties, pioglitazone ameliorates different cardiovascular disorders. The aim of the present study was to investigate the effect of pioglitazone on cardiovascular complications of N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension and to determine the role of oxidative and endoplasmic reticulum (ER) stress in its activity. Nitric oxide (NO) deficiency induced by chronic L-NAME administration was associated with high blood pressure (BP) and cardiac hypertrophy. L-NAME induced oxidative stress as indicated by reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase activities as well as increased malondialdehyde (MDA) levels. Furthermore, L-NAME increased the expression of ER stress markers, activating transcription factor-4 (ATF-4) and C/EPBα-homologous protein-10 (CHOP-10) in both heart and aorta of hypertensive rats. Activation of PPAR-γ by pioglitazone reduced BP, restored the blunted NO levels, increased endothelial NO synthase (eNOS) expression, and restored the antioxidant status of L-NAME-induced hypertensive rats. Moreover, the antihypertensive activity of pioglitazone was associated with a reduction in ER stress and this effect was PPAR-γ dependent. Interestingly, the effect of ER stress inhibitor, 4-phenylbutyric acid (4-PBA) and antioxidant, N-acetylcysteine (NAC), on BP, NO availability, oxidative stress and ER stress mimics the activity of pioglitazone. Taken together, our data suggests that PPAR-γ is a potential target to inhibit vascular complications and cardiac damage associated with NO-deficient HTN and puts more emphasis on the importance of ER stress in regulating PPAR-γ activity.}, }
@article {pmid31725283, year = {2019}, author = {Guo, X and Jia, Y and Han, L and Zhao, Y and Li, W and Zhang, Z and Peng, Y and Zheng, J}, title = {Metabolic Activation of Tofacitinib Mediated by Myeloperoxidase in Vitro.}, journal = {Chemical research in toxicology}, volume = {32}, number = {12}, pages = {2459-2465}, doi = {10.1021/acs.chemrestox.9b00280}, pmid = {31725283}, issn = {1520-5010}, mesh = {Acetylcysteine/chemistry ; Activation, Metabolic/physiology ; Animals ; Antirheumatic Agents/chemistry/metabolism/*toxicity ; Hypochlorous Acid/chemistry ; Leukocytes/*drug effects/metabolism ; Leukopenia/*etiology ; Peroxidase/*metabolism ; Piperidines/chemistry/metabolism/*toxicity ; Pyrimidines/chemistry/metabolism/*toxicity ; Pyrroles/chemistry/metabolism/*toxicity ; Rats, Sprague-Dawley ; }, abstract = {Tofacitinib (TFT) is used for the treatment of moderately and severely active rheumatoid arthritis. Unfortunately, TFT was reported to induce leukopenia, and the underlying mechanisms remain unclear. The present study demonstrated that TFT was oxidized to a chemically reactive nitrenium ion by myeloperoxidase (MPO) occurring in neutrophils. The electrophilic ion showed chemical reactivity toward N-acetyl-cysteine (NAC) to produce two TFT-NAC conjugates (M1 and M2) in incubation of TFT with leucocytes in the presence of NAC. The generation of the nitrenium ion was verified by HClO-mediated oxidation of TFT. In addition, the nitrenium ion was found to react with sulfhydryl groups of cysteine residues of cellular protein in leucocytes after exposure to TFT. The study facilitates the understanding of the mechanisms of TFT toxic action.}, }
@article {pmid31722253, year = {2020}, author = {Lee, YH and Lee, SR}, title = {Neuroprotective effects of N-acetylcysteine via inhibition of matrix metalloproteinase in a mouse model of transient global cerebral ischemia.}, journal = {Brain research bulletin}, volume = {154}, number = {}, pages = {142-150}, doi = {10.1016/j.brainresbull.2019.10.004}, pmid = {31722253}, issn = {1873-2747}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Brain/drug effects/metabolism ; Brain Ischemia/*drug therapy/physiopathology ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Injections, Intraperitoneal ; Ischemic Attack, Transient ; Male ; Matrix Metalloproteinase 9/drug effects/*metabolism ; Matrix Metalloproteinases/drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Neuroprotective Agents/pharmacology ; }, abstract = {N-acetylcysteine (NAC) is known to serve many biological functions including acting as an antioxidant, and electing antiinflammatory effects. Previous reports have revealed that NAC may have neuroprotective effects against the deleterious effects of brain ischemia. Despite of this, the mechanism by which NAC prevents neuronal damage after brain ischemia remains unclear. The current study aimed to investigate this mechanism in a mouse model of transient global brain ischemia. In the present study, mice were subjected to 20 min of transient global brain ischemia, proceeded by intraperitoneal administration of NAC (150 mg/kg) in one group. The mice were then euthanized 72 h after this ischemic insult for collection of experimental tissues. The effect of NAC on neuronal damage and matrix metalloproteinase (MMP)-9 activity were assessed and immunofluorescence, and hippocampal terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay experiments were conducted and results compared between NAC- and vehicle-treated groups. Neuronal damage was primarily observed in the hippocampal CA1 and CA2 regions. In NAC-treated mice, neuronal damage was significantly reduced after ischemia when compared to vehicle-treated animals. NAC also inhibited increased MMP-9 activity after global brain ischemia. NAC increased laminin and NeuN expression and inhibited increases in TUNEL-positive cells, all in the hippocampus. These results suggest that NAC reduces hippocampal neuronal damage following transient global ischemia, potentially via reductions in MMP-9 activity.}, }
@article {pmid31721616, year = {2020}, author = {Townsend, LK and Weber, AJ and Barbeau, PA and Holloway, GP and Wright, DC}, title = {Reactive oxygen species-dependent regulation of pyruvate dehydrogenase kinase-4 in white adipose tissue.}, journal = {American journal of physiology. Cell physiology}, volume = {318}, number = {1}, pages = {C137-C149}, pmid = {31721616}, issn = {1522-1563}, mesh = {Adipocytes/drug effects/*enzymology ; Adipogenesis ; Adipose Tissue, White/drug effects/*enzymology ; Adrenergic beta-3 Receptor Agonists/pharmacology ; Animals ; Antioxidants ; Catalase/genetics/metabolism ; *Energy Metabolism/drug effects ; Gene Expression Regulation, Enzymologic ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/drug effects/*enzymology ; Oxidants/pharmacology ; Oxidation-Reduction ; Phosphoenolpyruvate Carboxykinase (GTP)/genetics/metabolism ; Physical Exertion ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Time Factors ; Tissue Culture Techniques ; }, abstract = {Reactive oxygen species (ROS) are important signaling molecules mediating the exercise-induced adaptations in skeletal muscle. Acute exercise also drives the expression of genes involved in reesterification and glyceroneogenesis in white adipose tissue (WAT), but whether ROS play any role in this effect has not been explored. We speculated that exercise-induced ROS would regulate acute exercise-induced responses in WAT. To address this question, we utilized various models to alter redox signaling in WAT. We examined basal and exercise-induced gene expression in a genetically modified mouse model of reduced mitochondrial ROS emission [mitochondrial catalase overexpression (MCAT)]. Additionally, H2O2, various antioxidants, and the β3-adrenergic receptor agonist CL316243 were used to assess gene expression in white adipose tissue culture. MCAT mice have reduced ROS emission from WAT, enlarged WAT depots and adipocytes, and greater pyruvate dehydrogenase kinase-4 (Pdk4) gene expression. In WAT culture, H2O2 reduced glyceroneogenic gene expression. In wild-type mice, acute exercise induced dramatic but transient increases in Pdk4 and phosphoenolpyruvate carboxykinase (Pck1) mRNA in both subcutaneous inguinal WAT and epididymal WAT depots, which was almost completely absent in MCAT mice. Furthermore, the induction of Pdk4 and Pck1 in WAT culture by CL316243 was markedly reduced in the presence of antioxidants N-acetyl-cysteine or vitamin E. Genetic and nutritional approaches that attenuate redox signaling prevent exercise- and β-agonist-induced gene expression within WAT. Combined, these data suggest that ROS represent important mediators of gene expression within WAT.}, }
@article {pmid31719906, year = {2019}, author = {Tangtrongsup, S and Kisiday, JD}, title = {Differential Effects of the Antioxidants N-Acetylcysteine and Pyrrolidine Dithiocarbamate on Mesenchymal Stem Cell Chondrogenesis.}, journal = {Cellular and molecular bioengineering}, volume = {12}, number = {2}, pages = {153-163}, pmid = {31719906}, issn = {1865-5025}, abstract = {INTRODUCTION: Mesenchymal stem cell (MSC) chondrogenesis is associated with increases in intracellular reactive oxygen species (ROS), which may result in oxidative stress that is detrimental to cartilage regeneration. This study evaluated the ability of the antioxidants N-acetylcysteine (NAC) or pyrrolidine dithiocarbamate (PDTC) to reduce intracellular ROS, and their effect on MSC chondrogenesis and maturation of cartilage-like extracellular matrix.<br><br>METHODS: Equine bone marrow MSCs were cultured in serum-supplemented chondrogenic medium with or without NAC or PDTC. ROS was quantified in monolayer after 8 and 72&#xa0;h of culture. MSCs were seeded into agarose, cultured for 15&#xa0;days, and analyzed for viable cell density, glycosaminoglycan (GAG) and hydroxyproline accumulation, and collagen gene expression. PDTC cultures were evaluated for oxidative damage by protein carbonylation, and mechanical properties via compressive testing.<br><br>RESULTS: NAC significantly lowered levels of ROS after 8 but not 72&#xa0;h, and suppressed GAG accumulation (70%). In secondary experiments using serum-free medium, NAC significantly increased levels of ROS at 72&#xa0;h, and lowered cell viability and extracellular matrix accumulation. PDTC significantly reduced levels of ROS (~&#x2009;30%) and protein carbonylation (27%), and enhanced GAG accumulation (20%). However, the compressive modulus for PDTC-treated samples was significantly lower (40%) than controls. Gene expression was largely unaffected by the antioxidants.<br><br>CONCLUSIONS: NAC demonstrated a limited ability to reduce intracellular ROS in chondrogenic culture, and generally suppressed accumulation of extracellular matrix. Conversely, PDTC was an effective antioxidant that enhanced GAG accumulation, although the concomitant reduction in compressive properties is a significant limitation for cartilage repair.}, }
@article {pmid31719902, year = {2019}, author = {Wang, YX and Liu, HB and Li, PS and Yuan, WX and Liu, B and Liu, ST and Qin, KR}, title = {ROS and NO Dynamics in Endothelial Cells Exposed to Exercise-Induced Wall Shear Stress.}, journal = {Cellular and molecular bioengineering}, volume = {12}, number = {1}, pages = {107-120}, pmid = {31719902}, issn = {1865-5025}, abstract = {INTRODUCTION: Intracellular reactive oxygen species (ROS) and nitric oxide (NO) levels are associated with vascular homeostasis and diseases. Exercise can modulate ROS and NO production through increasing frequency and magnitude of wall shear stress (WSS). However, the details of ROS and NO production in endothelial cells and their interplay under WSS induced by exercise at different intensities remain unclear.<br><br>METHODS: In this study, we developed an in vitro multicomponent nonrectangular flow chamber system to simulate pulsatile WSS waveforms induced by moderate and high intensity exercise. Furthermore, the dynamic responses of ROS and NO in endothelial cells and the relationship between ROS and NO were investigated under the WSS induced by different intensity exercise.<br><br>RESULTS: After exposing to WSS induced by moderate intensity exercise, endothelial cells produced more NO than those under high intensity exercise-induced WSS. In this process, ROS was found to play a dual role in the generation of intracellular NO. Under WSS induced by moderate intensity exercise, modest elevated ROS promoted NO production, whereas excessive ROS in endothelial cells exposed to WSS induced by high intensity exercise attenuated NO bioavailability. Interestingly, antioxidant N-acetylcysteine (NAC) could increase NO production under WSS induced by high intensity exercise.<br><br>CONCLUSIONS: Our results provide some cues for selecting appropriate exercise intensities and elevating benefits of exercise on endothelial function. Additionally, owing to the consistency of our results and some in vivo phenomena, this flow chamber system may serve as an in vitro exercise model of arterial vessel for future studies.}, }
@article {pmid31717651, year = {2019}, author = {Nakamae, I and Morimoto, T and Shima, H and Shionyu, M and Fujiki, H and Yoneda-Kato, N and Yokoyama, T and Kanaya, S and Kakiuchi, K and Shirai, T and Meiyanto, E and Kato, JY}, title = {Curcumin Derivatives Verify the Essentiality of ROS Upregulation in Tumor Suppression.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {22}, pages = {}, pmid = {31717651}, issn = {1420-3049}, mesh = {Animals ; Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival ; Chemistry Techniques, Synthetic ; Curcumin/analogs &amp; derivatives/chemical synthesis/chemistry/*pharmacology ; Disease Models, Animal ; Drug Design ; Humans ; Mice ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Oxidation-Reduction/*drug effects ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND: Curcumin has been shown to exert pleiotropic biological effects, including anti-tumorigenic activity. We previously showed that curcumin controls reactive oxygen species (ROS) levels through the ROS metabolic enzymes, to prevent tumor cell growth. In this study, we synthesized 39 novel curcumin derivatives and examined their anti-proliferative and anti-tumorigenic properties.<br><br>METHODS AND RESULTS: Thirty-nine derivatives exhibited anti-proliferative activity toward human cancer cell lines, including CML-derived K562 leukemic cells, in a manner sensitive to an antioxidant, N-acetyl-cysteine (NAC). Some compounds exhibited lower GI50 values than curcumin, some efficiently induced cell senescence, and others markedly increased ROS levels, efficiently induced cell death and suppressed tumor formation in a xenograft mouse model, without any detectable side effects. A clustering analysis of the selected compounds and their measurement variables revealed that anti-tumorigenic activity was most well-correlated with an increase in ROS levels. Pulldown assays and a molecular docking analysis showed that curcumin derivatives competed with co-enzymes to bind to the respective ROS metabolic enzymes and inhibited their enzymatic activities.<br><br>CONCLUSIONS: The analysis of novel curcumin derivatives established the importance of ROS upregulation in suppression of tumorigenesis, and these compounds are potentially useful for the development of an anti-cancer drug with few side effects.}, }
@article {pmid31715134, year = {2020}, author = {Kumar, K and Mishra, JPN and Singh, RP}, title = {Usnic acid induces apoptosis in human gastric cancer cells through ROS generation and DNA damage and causes up-regulation of DNA-PKcs and γ-H2A.X phosphorylation.}, journal = {Chemico-biological interactions}, volume = {315}, number = {}, pages = {108898}, doi = {10.1016/j.cbi.2019.108898}, pmid = {31715134}, issn = {1872-7786}, mesh = {Animals ; Apoptosis/*drug effects ; Benzofurans/*pharmacology ; Cell Line ; Cell Line, Tumor ; DNA Damage/*drug effects ; DNA-Activated Protein Kinase/*metabolism ; DNA-Binding Proteins/*metabolism ; Female ; HEK293 Cells ; Histones/*metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Stomach Neoplasms/*drug therapy/metabolism ; Up-Regulation/drug effects ; }, abstract = {Usnic acid, a dibenzofuran derivative found in many lichen species, is reported to have anticancer activity against human gastric cancer. We investigated the molecular alterations associated with anticancer effects of usnic acid against human gastric adenocarcinoma AGS and gastric carcinoma SNU-1 cells. Usnic acid (10-25 μM) treatment to these cells caused a significant increase in mitochondrial membrane depolarization and apoptotic cells. Apoptosis induction was accompanied by an increase in the ratio of Bax:Bcl-2 expression and cleaved-PARP. Usnic acid increased the comet tail length and tail DNA in alkaline comet assay indicating DNA double-strand breaks which was also evidenced by an increase in γH2A.X (Ser139) phosphorylation. The expression of DNA damage response proteins including DNA-PKcs, pATM (Ser1981), Chk-2 and p53 were increased. Further, N-acetyl cysteine, a known reactive oxygen species (ROS) scavenger, reversed the effects of usnic acid on expression of DNA damage response proteins and γH2A.X (Ser139) phosphorylation. This reversal was also observed in comet assay in a time and dose-dependent manner suggesting that usnic acid-induced DNA damage was caused by ROS. In addition, the non-toxic concentrations (1-10 μM) of usnic acid inhibited colony forming potential of AGS cells indicating its anti-proliferation activity. More importantly, the concentration of usnic acid that caused significant death in gastric cancer cells, did not show any considerable toxicity to normal human embryonic kidney HEK293 cells, human keratinocyte HaCaT cells and mouse primary gastric cells. Collectively, these results for the first time demonstrated the selective apoptotic effect of usnic acid (10-25 μM) through ROS generation and DNA damage on human gastric cancer cells accompanied with upregulation of γH2A.X (Ser139) phosphorylation, DNA-PKcs and p53.}, }
@article {pmid31714069, year = {2019}, author = {Man, S and Wang, H and Zhou, J and Lu, Y and Su, Y and Ma, L}, title = {Cardiac Glycoside Compound Isolated from Helleborus thibetanus Franch Displays Potent Toxicity against HeLa Cervical Carcinoma Cells through ROS-Independent Autophagy.}, journal = {Chemical research in toxicology}, volume = {32}, number = {12}, pages = {2479-2487}, doi = {10.1021/acs.chemrestox.9b00318}, pmid = {31714069}, issn = {1520-5010}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Autophagy/*drug effects ; Cardiac Glycosides/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Helleborus/*chemistry ; Humans ; Macrolides/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {The current study aimed to examine the anticancer activity of HTF-1, a cardiac glycoside (CG) isolated from Helleborus thibetanus Franch, using a cell-based model and to discover the underlying mechanisms with specific focus on autophagy. We found that HTF-1 was able to potently decrease the viability of several cancer cell lines especially for HeLa cervical carcinoma cells. It was discovered that HTF-1 dose dependently induced overproduction of ROS in HeLa cells, and the cell viability can be rescued when adding ROS scavenger N-acetyl-l-cysteine (NAC). More, we found that HTF-1 induced ROS-independent autophagy in concentration- and time-dependent manners in HeLa cells. This can be collectively verified by LC3-II and p62 abundance and also eGFP-LC3 puncta assay, bafilomycin clamp experiment, and acidotropic dye fluorescent labeling experiment. Additionally, TEM examination showed more autophagic vacuoles for HTF-1-treated HeLa cells. In HeLa cells, pretreatment with wortmannin (an inhibitor of the initial stages of autophagy to block autophagosome formation, thus, it should weaken the autophagy induction effect of HTF-1) decreased the autophagic flux and partially antagonized cell death induced by HTF-1, indicating that autophagy induced by HTF-1 played a cancer-suppressing role. Furthermore, coadministration of BAF (as a distal inhibitor of autophagy) with HTF-1 demonstrated a synergistic anticancer effect against HeLa cells. We believe that our work will enrich the understanding of CGs and especially anticarcinoma activity, also, pave the way for natural-product-based anticancer drug development.}, }
@article {pmid31712969, year = {2020}, author = {Tomko, RL and Baker, NL and Hood, CO and Gilmore, AK and McClure, EA and Squeglia, LM and McRae-Clark, AL and Sonne, SC and Gray, KM}, title = {Depressive symptoms and cannabis use in a placebo-controlled trial of N-Acetylcysteine for adult cannabis use disorder.}, journal = {Psychopharmacology}, volume = {237}, number = {2}, pages = {479-490}, pmid = {31712969}, issn = {1432-2072}, support = {UG1DA020024/DA/NIDA NIH HHS/United States ; UG1DA013714/DA/NIDA NIH HHS/United States ; HHSN271201200017C/DA/NIDA NIH HHS/United States ; K23AA025399/AA/NIAAA NIH HHS/United States ; K01DA036739/DA/NIDA NIH HHS/United States ; K23 AA025399/AA/NIAAA NIH HHS/United States ; UG1 DA013714/DA/NIDA NIH HHS/United States ; K23 DA042935/DA/NIDA NIH HHS/United States ; T32 DA035200/DA/NIDA NIH HHS/United States ; HHSN271201200017C/HH/HHS/United States ; R25 DA020537/DA/NIDA NIH HHS/United States ; K12 HD055885/HD/NICHD NIH HHS/United States ; U10 DA013045/DA/NIDA NIH HHS/United States ; UG1 DA020024/DA/NIDA NIH HHS/United States ; K24DA038240/DA/NIDA NIH HHS/United States ; K01 DA036739/DA/NIDA NIH HHS/United States ; U10DA013045/DA/NIDA NIH HHS/United States ; K24 DA038240/DA/NIDA NIH HHS/United States ; UG1DA015831/DA/NIDA NIH HHS/United States ; UG1 DA013727/DA/NIDA NIH HHS/United States ; UG1DA013727/DA/NIDA NIH HHS/United States ; UG1 DA015831/DA/NIDA NIH HHS/United States ; T32DA035200/DA/NIDA NIH HHS/United States ; K12HD055885//National Institute of Child Health and Human Development/ ; K23DA042935/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Cannabis ; Comorbidity ; Depression/*drug therapy/epidemiology/*psychology ; Double-Blind Method ; Dronabinol/therapeutic use ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Humans ; Male ; Marijuana Abuse/*drug therapy/epidemiology/*psychology ; Motivation/drug effects/physiology ; Treatment Outcome ; Young Adult ; }, abstract = {RATIONALE: Depression is common among individuals with cannabis use disorder (CUD), particularly individuals who present to CUD treatment. Treatments that consider this comorbidity are essential.<br><br>OBJECTIVES: The goal of this secondary analysis was to examine whether N-acetylcysteine (NAC) reduced depressive symptoms among adults (age 18-50) with CUD (N&#x2009;=&#x2009;302) and whether the effect of NAC on cannabis cessation varied as a result of baseline levels of depression. Bidirectional associations between cannabis use amount and depression were also examined.<br><br>METHODS: Data for this secondary analysis were from a National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) multi-site clinical trial for CUD. Adults with CUD (N&#x2009;=&#x2009;302) were randomized to receive 2400&#xa0;mg of NAC daily or matched placebo for 12&#xa0;weeks. All participants received abstinence-based contingency management. Cannabis quantity was measured by self-report, and weekly urinary cannabinoid levels (11-nor-9-carboxy-&#x394;9-tetrahydrocannabinol) confirmed abstinence. Depressive symptoms were measured by the Hospital Anxiety and Depression Scale.<br><br>RESULTS: Depressive symptoms did not differ between the NAC and placebo groups during treatment. There was no significant interaction between treatment and baseline depression predicting cannabis abstinence during treatment. Higher baseline depression was associated with decreased abstinence throughout treatment and a significant gender interaction suggested that this may be particularly true for females. Cross-lagged panel models suggested that depressive symptoms preceded increased cannabis use amounts (in grams) during the subsequent month. The reverse pathway was not significant (i.e., greater cannabis use preceding depressive symptoms).<br><br>CONCLUSIONS: Results from this study suggest that depression may be a risk factor for poor CUD treatment outcome and therefore should be addressed in the context of treatment. However, results do not support the use of NAC to concurrently treat co-occurring depressive symptoms and CUD in adults.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov: NCT01675661.}, }
@article {pmid31712630, year = {2019}, author = {Faria, M and Prats, E and Gómez-Canela, C and Hsu, CY and Arick, MA and Bedrossiantz, J and Orozco, M and Garcia-Reyero, N and Ziv, T and Ben-Lulu, S and Admon, A and Gómez-Oliván, LM and Raldúa, D}, title = {Therapeutic potential of N-acetylcysteine in acrylamide acute neurotoxicity in adult zebrafish.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {16467}, pmid = {31712630}, issn = {2045-2322}, support = {P20 GM103476/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Acrylamide/*toxicity ; Acylation ; Animals ; Antioxidants/pharmacology ; Blood-Brain Barrier/drug effects ; Cell Membrane Permeability ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Neurotoxicity Syndromes/etiology/metabolism/pathology/*prevention &amp; control ; Oxidative Stress/*drug effects ; Proteome/drug effects ; Transcriptome/drug effects ; Zebrafish/*growth &amp; development/metabolism ; }, abstract = {Two essential key events in acrylamide (ACR) acute neurotoxicity are the formation of adducts with nucleophilic sulfhydryl groups on cysteine residues of selected proteins in the synaptic terminals and the depletion of the glutathione (GSx) stores in neural tissue. The use of N-acetylcysteine (NAC) has been recently proposed as a potential antidote against ACR neurotoxicity, as this chemical is not only a well-known precursor of the reduced form of glutathione (GSH), but also is an scavenger of soft electrophiles such as ACR. In this study, the suitability of 0.3 and 0.75 mM NAC to protect against the neurotoxic effect of 0.75 mM ACR has been tested in vivo in adult zebrafish. NAC provided only a mild to negligible protection against the changes induced by ACR in the motor function, behavior, transcriptome and proteome. The permeability of NAC to cross blood-brain barrier (BBB) was assessed, as well as the ACR-scavenging activity and the gamma-glutamyl-cysteine ligase (γ-GCL) and acylase I activities. The results show that ACR not only depletes GSx levels but also inhibits it synthesis from NAC/cysteine, having a dramatic effect over the glutathione system. Moreover, results indicate a very low NAC uptake to the brain, probably by a combination of low BBB permeability and high deacylation of NAC during the intestinal absorption. These results strongly suggest that the use of NAC is not indicated in ACR acute neurotoxicity treatment.}, }
@article {pmid31710159, year = {2020}, author = {Chan, WY and Hickey, EE and Khazandi, M and Page, SW and Trott, DJ and Hill, PB}, title = {In vitro antimicrobial activity of narasin and monensin in combination with adjuvants against pathogens associated with canine otitis externa.}, journal = {Veterinary dermatology}, volume = {31}, number = {2}, pages = {138-145}, doi = {10.1111/vde.12803}, pmid = {31710159}, issn = {1365-3164}, support = {LP130100736//ARC Linkage Grant/ ; }, mesh = {Adjuvants, Pharmaceutic/*pharmacology ; Animals ; Anti-Bacterial Agents/*pharmacology ; Bacteria/drug effects/pathogenicity ; Biofilms/drug effects ; Dog Diseases/*drug therapy/microbiology ; Dogs ; Drug Synergism ; Ionophores/pharmacology ; Microbial Sensitivity Tests ; Monensin/*pharmacology ; Otitis Externa/drug therapy/microbiology/*veterinary ; Proteus mirabilis/drug effects ; Pseudomonas aeruginosa/drug effects ; Pyrans/*pharmacology ; Staphylococcus aureus/drug effects ; }, abstract = {BACKGROUND: The emergence of antimicrobial resistance represents a serious human and animal health risk. Good antimicrobial stewardship is essential to prolong the lifespan of existing antibiotics, and new strategies are required to combat infections in man and animals.<br><br>HYPOTHESIS/OBJECTIVES: To determine the in vitro interaction of ionophores (narasin or monensin) with antimicrobial adjuvants (N-acetylcysteine (NAC), Tris-EDTA or disodium EDTA) against bacterial strains representing pathogens associated with canine otitis externa (OE).<br><br>ANIMAL/ISOLATES: American Type Culture Collection (ATCC) strains Staphylococcus aureus 29213, Pseudomonas aeruginosa 27853 and P.&#xa0;aeruginosa biofilm producer PAO1, and a clinical isolate of Proteus mirabilis from a case of canine OE were tested.<br><br>METHODS AND MATERIALS: A 2D microdilution checkerboard method was used, allowing calculation of fractional inhibitory concentration index (FICI), dose reduction index (DRI) and plotting of isobolograms.<br><br>RESULTS: The combination of narasin with either Tris-EDTA or disodium EDTA produced additive effects (FICI&#xa0;=&#xa0;0.75) against P.&#xa0;aeruginosa ATCC 27853 and P.&#xa0;aeruginosa biofilm producer ATCC PAO1. An additive effect (FICI&#xa0;=&#xa0;0.53-0.75) was found against S.&#xa0;aureus ATCC 29213 when narasin or monensin were combined with NAC. The highest DRI (32-fold) was found with monensin/NAC where the MIC of monensin&#xa0;was reduced from 4 to 0.125&#xa0;&#x3bc;g/mL.<br><br>The combination of narasin with Tris-EDTA or disodium EDTA is a promising strategy to inhibit the intrinsic resistance elements of Gram-negative bacteria. These novel combinations potentially could be useful as a multimodal approach to treat mixed infections in canine OE.}, }
@article {pmid31707450, year = {2020}, author = {Khin, PP and Po, WW and Thein, W and Sohn, UD}, title = {Apoptotic effect of fluoxetine through the endoplasmic reticulum stress pathway in the human gastric cancer cell line AGS.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {393}, number = {4}, pages = {537-549}, pmid = {31707450}, issn = {1432-1912}, mesh = {Antidepressive Agents/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Fluoxetine/*pharmacology ; Humans ; Reactive Oxygen Species/metabolism ; Selective Serotonin Reuptake Inhibitors/*pharmacology ; Stomach Neoplasms/*drug therapy/metabolism ; }, abstract = {Gastric cancer is the fourth most common cancer in the world. Fluoxetine (FLX), a selective serotonin reuptake inhibitor, can inhibit the growth of cancer cells by inducing apoptotic cell death through various signaling pathways. This study was aimed to determine the mechanism of apoptotic cell death induced by FLX in AGS cells. MTT assay for cell viability test and colony forming assay was performed for detection of cell proliferation. Western blot analysis was conducted for protein expression. Increased fluorescence intensity and chromatin condensation were observed using DAPI staining. Production of reactive oxygen species (ROS) was measured by DCFDA assay. AGS cell proliferation was remarkedly inhibited by FLX in a dose-dependent manner starting at a concentration of 20 μM. The expression of death receptors was increased, which resulted in elevated expression of activated caspases and cleaved PARP, leading to FLX-induced apoptosis. Moreover, FLX significantly increased production of ROS, and N-acetyl cysteine, which scavenges ROS, attenuated the cytotoxic effects of FLX. In addition, treatment with FLX increased the expression of the endoplasmic reticulum (ER) stress marker, CHOP. P53 protein expression in AGS cells also decreased significantly with FLX treatment. Inhibition of ER stress significantly decreased the expressions of death receptor 5 (DR5), cleaved caspase 3, and cleaved PARP, but not to control levels. FLX-induced apoptosis in AGS involved upregulation of death receptors, ROS generation, and activation of ER stress.}, }
@article {pmid31707348, year = {2020}, author = {Zhu, W and Wu, RD and Lv, YG and Liu, YM and Huang, H and Xu, JQ}, title = {BRD4 blockage alleviates pathological cardiac hypertrophy through the suppression of fibrosis and inflammation via reducing ROS generation.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {121}, number = {}, pages = {109368}, doi = {10.1016/j.biopha.2019.109368}, pmid = {31707348}, issn = {1950-6007}, mesh = {Angiotensin II/pharmacology ; Animals ; Cardiomegaly/drug therapy/*metabolism ; Cell Line ; Fibrosis/drug therapy/*metabolism ; Heart/drug effects ; Heme Oxygenase-1/metabolism ; Humans ; Inflammation/drug therapy/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Myocardium/metabolism ; Myocytes, Cardiac/drug effects/metabolism ; NF-kappa B/metabolism ; Nuclear Proteins/*antagonists &amp; inhibitors ; Oxidative Stress/drug effects ; Protective Agents/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Transcription Factors/*antagonists &amp; inhibitors ; Transforming Growth Factor beta1/metabolism ; Up-Regulation/drug effects ; }, abstract = {Hypertension is an essential regulator of cardiac injury and remodeling. However, the pathogenesis that contributes to cardiac hypertrophy remains to be fully explored. BRD4, as a bromodomain and extra-terminal (BET) family member, plays an important role in critical biological processes. In the study, our results showed that BRD4 expression was up-regulated in human and mouse hypertrophied hearts, and importantly these effects were modulated by reactive oxygen species (ROS) generation. In angiotensin II (Ang II)-treated cardiomyocytes, BRD4 decrease markedly blunted the prohypertrophic effect, which was further promoted by the combinational treatment of ROS scavenger (N-acetyl-cysteine, NAC). In addition, NAC pre-treatment markedly elevated the anti-fibrotic role of BRD4 suppression in Ang II-incubated cardiomyocytes by repressing transforming growth factor β1 (TGF-β1)/SMADs signaling pathway. NAC combined with BRD4 reduction further alleviated inflammation and oxidative stress in Ang II-exposed cardiomyocytes, which was partly through inhibiting nuclear factor-κB (NF-κB) signaling and improving nuclear erythroid factor 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) pathway, respectively. Furthermore, the in vivo results confirmed the protective effects of BRD4 suppression on mice against aortic banding (AB)-induced cardiac hypertrophy, as evidenced by the reduced cross sectional area and fibrotic area using H&amp;E and Masson trichrome staining. What's more, the degree of cardiac hypertrophy (ANP and BNP), the expression of pro-fibrotic genes (TGF-β1, Collagen I, Collagen III and CTGF), the levels of inflammation and oxidative stress were all significantly attenuated by the blockage of BRD4 in AB-operated mice. Taken together, repressing BRD4 expression was found to confer a protective effect against experimental cardiac hypertrophy in mice, demonstrating its potential as an effective therapeutic target for pathological cardiac hypertrophy.}, }
@article {pmid31707343, year = {2020}, author = {Jiang, BW and Zhang, WJ and Wang, Y and Tan, LP and Bao, YL and Song, ZB and Yu, CL and Wang, SY and Liu, L and Li, YX}, title = {Convallatoxin induces HaCaT cell necroptosis and ameliorates skin lesions in psoriasis-like mouse models.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {121}, number = {}, pages = {109615}, doi = {10.1016/j.biopha.2019.109615}, pmid = {31707343}, issn = {1950-6007}, mesh = {Animals ; Disease Models, Animal ; Female ; HaCaT Cells ; Humans ; Imiquimod/toxicity ; Keratinocytes/*drug effects/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; Necroptosis/*drug effects ; Protein Kinases/metabolism ; Psoriasis/*drug therapy/pathology ; Reactive Oxygen Species/metabolism ; Skin/*drug effects/pathology ; Strophanthins/*pharmacology/therapeutic use ; }, abstract = {Psoriasis is considered an immune-mediated inflammatory skin disorder that affects the quality of life of nearly four percent of the world population. Considering the side effects of existing therapeutic drugs and the urgent need for new drug development, we screened more than 250 traditional Chinese medicine compounds to identify drugs that significantly reduced the viability of human HaCaT keratinocytes, a psoriasis-related model cell line. Convallatoxin (CNT) was found to be a highly effective inhibitor of HaCaT cell viability. Subsequent mechanistic studies revealed that CNT induced HaCaT cell death by necroptosis rather than by apoptosis. CNT destroyed the membrane integrity of HaCaT cells, as detected by nuclear propidium iodide (PI) staining and lactate dehydrogenase (LDH) release. Additionally, the intercellular levels of adenosine triphosphate (ATP) were lower in HaCaT cells treated with CNT than in control HaCaT cells, and typical necroptosis-associated characteristics were observed by electron microscopy in cells treated with CNT. Furthermore, compared with control HaCaT cells, CNT-treated HaCaT cells produced more reactive oxygen species (ROS), but this effect was inhibited by the antioxidants N-acetyl-cysteine (NAC), diphenyleneiodonium chloride (DPI), and apocynin and the necroptosis inhibitor Nec-1. In addition, antioxidant treatment attenuated necroptotic cell death, suggesting that CNT-induced HaCaT necroptosis is mediated by oxidative stress. More importantly, CNT ameliorated skin lesions and inflammation in imiquimod (IMQ)- and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced psoriasis-like mouse models. In conclusion, our results demonstrate that CNT is cytotoxic against HaCaT cells in vitro and exerts antipsoriatic activities in two mouse models of psoriasis in vivo, making CNT a potential promising candidate drug for future research.}, }
@article {pmid31704823, year = {2019}, author = {Toda, Y and Yoshimura, R and Itahara, M and Imai, Y and Yamada, K and Uno, T and Nakata, S and Hosogi, S and Takata, K and Ashihara, E}, title = {DJ-1 Contributes to Self-renewal of Stem Cells in the U87-MG Glioblastoma Cell Line.}, journal = {Anticancer research}, volume = {39}, number = {11}, pages = {5983-5990}, doi = {10.21873/anticanres.13803}, pmid = {31704823}, issn = {1791-7530}, mesh = {Animals ; Apoptosis ; Biomarkers, Tumor/genetics/*metabolism ; Brain Neoplasms/genetics/metabolism/*pathology ; Cell Proliferation ; *Cell Self Renewal ; Gene Expression Regulation, Neoplastic ; Glioblastoma/genetics/metabolism/*pathology ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplastic Stem Cells/metabolism/*pathology ; Prognosis ; Protein Deglycase DJ-1/antagonists &amp; inhibitors/genetics/*metabolism ; RNA, Small Interfering/genetics ; Survival Rate ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND/AIM: DJ-1, an oncogenic molecule, helps to maintain somatic stem cells by reducing the intracellular level of reactive oxygen species (ROS). This study investigated the role of DJ-1 in glioma stem cells (GSCs).<br><br>MATERIALS AND METHODS: U87-MG (U87) and U251-MG (U251) glioblastoma cell lines that express wild-type and mutant p53, respectively, were used. These were cultured with DJ-1-targeting siRNA and subjected to a variety of in vitro experiments or intracranial transplantation into nude mice.<br><br>RESULTS: Knockdown of DJ-1 reduced clonogenicity only in U87 cells, which was rescued by p53 depletion. ROS accumulated in DJ-1-depleted cells, although treatment with N-acetyl cysteine, which quenches ROS, did not affect exhaustion of CSCs among U87 cells by DJ-1 knockdown. In a serial transplantation study, DJ-1 knockdown prolonged the survival of mice in secondary transplantation.<br><br>CONCLUSION: DJ-1 plays a pivotal role in maintenance of stem cell self-renewal in the U87 cell line.}, }
@article {pmid31699484, year = {2020}, author = {Jin, H and Ji, C and Ren, F and Aniagu, S and Tong, J and Jiang, Y and Chen, T}, title = {AHR-mediated oxidative stress contributes to the cardiac developmental toxicity of trichloroethylene in zebrafish embryos.}, journal = {Journal of hazardous materials}, volume = {385}, number = {}, pages = {121521}, doi = {10.1016/j.jhazmat.2019.121521}, pmid = {31699484}, issn = {1873-3336}, mesh = {Acetylcysteine/pharmacology ; Animals ; Azo Compounds/pharmacology ; Cardiotoxicity/embryology ; DNA Damage/drug effects ; Embryo, Nonmammalian/*drug effects ; Embryonic Development/*drug effects ; Heart/embryology ; Heart Defects, Congenital/chemically induced/*embryology/prevention &amp; control ; Oxidative Stress/drug effects ; Purines/pharmacology ; Pyrazoles/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/antagonists &amp; inhibitors/*metabolism ; Trichloroethylene/*toxicity ; Zebrafish ; Zebrafish Proteins/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Trichloroethylene (TCE), a widely used chlorinated solvent, is a common environmental pollutant. Current evidence shows that TCE could induce heart defects during embryonic development, but the underlining mechanism(s) remain unclear. Since activation of the aryl hydrocarbon receptor (AHR) could induce oxidative stress, we hypothesized that AHR-mediated oxidative stress may play a role in the cardiac developmental toxicity of TCE. In this study, we found that the reactive oxygen species (ROS) scavenger, N-Acetyl-L-cysteine (NAC), and AHR inhibitors, CH223191 (CH) and StemRegenin 1, significantly counteracted the TCE-induced heart malformations in zebrafish embryos. Moreover, both CH and NAC suppressed TCE-induced ROS and 8-OHdG (8-hydroxy-2' -deoxyguanosine). TCE did not affect ahr2 and cyp1a expression, but increased cyp1b1 expression, which was restored by CH supplementation. CH also attenuated the TCE-induced mRNA expression changes of Nrf2 signalling genes (nrf2b, gstp2, sod2, ho1, nqo1) and cardiac differentiation genes (gata4, hand2, c-fos, sox9b). In addition, the TCE enhanced SOD activity was attenuated by CH. Morpholino knockdown confirmed that AHR mediated the TCE-induced ROS and 8-OHdG generation in the heart of zebrafish embryos. In conclusion, our results suggest that AHR mediates TCE-induced oxidative stress, leading to DNA damage and heart malformations in zebrafish embryos.}, }
@article {pmid31699387, year = {2020}, author = {Aly, AA and Sayed, SM and Abdelhafez, EMN and Abdelhafez, SMN and Abdelzaher, WY and Raslan, MA and Ahmed, AE and Thabet, K and El-Reedy, AAM and Brown, AB and Bräse, S}, title = {New quinoline-2-one/pyrazole derivatives; design, synthesis, molecular docking, anti-apoptotic evaluation, and caspase-3 inhibition assay.}, journal = {Bioorganic chemistry}, volume = {94}, number = {}, pages = {103348}, doi = {10.1016/j.bioorg.2019.103348}, pmid = {31699387}, issn = {1090-2120}, mesh = {Animals ; Apoptosis/*drug effects ; Caspase 3/*drug effects ; Drug Design ; Molecular Docking Simulation ; Pyrazoles/*chemistry/*pharmacology ; Quinolines/chemical synthesis/*chemistry/*pharmacology ; Rats ; }, abstract = {We report the synthesis of new quinoline-2-one/pyrazole hybrids and their antiapoptotic activity. This effect was studied in sight of decreasing tissue damage induced by I/R in colon of rats using N-acetylcysteine (NAC) as anti-apoptotic reference. Compounds 6a, 6c and 6f showed significant improvement for oxidative stress parameters MDA, SOD, GSH and NOx in comparison with model group and greater than the reference NAC (N-acetylcysteine), whereas compounds 6d and 6e exhibited weaker antioxidant activity when compared with the reference NAC. Moreover, compounds 6a, 6c and 6f showed significant decrease in inflammatory mediators TNFα and CRB greater than NAC when compared to the model group especially compound 6c whose found CRB conc 1.90 (mg/dL) in comparison to NAC of conc 2.13 mg/dL. Additionally, colonic histopathological investigation was performed to all targeted compounds that indicates H&amp;E sections of compounds 6a and 6f revealed apparent normal colonic cells while compound 6e showed dilated blood vessels with more apoptotic cells if compared with NAC. Caspase-3 inhibition assay revealed that compounds 6a, 6b and 6d weaken caspase-3 expression to an extent higher than NAC (1.063, 0.430, 0.731 and 1.115, respectively). Docking studies with caspase-3 revealed that most of the tested compounds showed good binding with the enzyme especially for compound 6d make several interactions better than that of the reference NAC.}, }
@article {pmid31699096, year = {2019}, author = {Hu, H and Fan, X and Guo, Q and Wei, X and Yang, D and Zhang, B and Liu, J and Wu, Q and Oh, Y and Feng, Y and Chen, K and Hou, L and Gu, N}, title = {Silicon dioxide nanoparticles induce insulin resistance through endoplasmic reticulum stress and generation of reactive oxygen species.}, journal = {Particle and fibre toxicology}, volume = {16}, number = {1}, pages = {41}, pmid = {31699096}, issn = {1743-8977}, mesh = {Administration, Oral ; Animals ; Blood Glucose/analysis ; Cytokines/genetics ; Endocrine Disruptors/pharmacokinetics/*toxicity ; Endoplasmic Reticulum Stress/*drug effects/genetics ; Gene Expression/drug effects ; Glucose Tolerance Test ; Insulin Receptor Substrate Proteins/metabolism ; *Insulin Resistance/genetics ; Liver/drug effects/metabolism ; Male ; Mice, Inbred ICR ; NF-kappa B/metabolism ; Nanoparticles/*toxicity ; Pancreas/drug effects/metabolism ; Particle Size ; Reactive Oxygen Species/metabolism ; Silicon Dioxide/pharmacokinetics/*toxicity ; }, abstract = {BACKGROUND: Silicon dioxide nanoparticles (SiO2 NPs) are one of the most widely utilized NPs in various food sectors. However, the potential endocrine toxicity of SiO2 NPs has not been characterized.<br><br>RESULTS: In the present study, mice were orally administered a series of doses of SiO2 NPs. All doses of SiO2 NPs were absorbed into the blood, liver, and pancreas of the mice. Administration of 100&#x2009;mg/kg bw (body weight) of SiO2 NPs significantly increased blood glucose levels in mice. However, the same dose of SiO2 fine-particles (FPs) did not result in altered blood glucose. Whole-genome analysis showed that SiO2 NPs affected the expression of genes associated with reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress. In addition, we showed that SiO2 NPs activated xenobiotic metabolism, resulting in ER stress. Endoplasmic reticulum stress resulted in increased ROS production, which activated the NF-&#x3ba;B pathway leading to expression of inflammatory cytokines. Increased inflammatory cytokine expression resulted in serine phosphorylation of IRS1, which induced insulin resistance (IR). Furthermore these inflammatory cytokines activated the MAPK pathway, which further promoted the serine phosphorylation of IRS1. Insulin resistance resulted in elevated blood glucose. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) inhibited SiO2 NP-induced ROS production. The ROS scavenger N-acetylcysteine (NAC) did not affect SiO2 NP-induced ER stress, but inhibited SiO2 NP-induced activation of the NF-&#x3ba;B and MAPK pathways, expression of inflammatory cytokines, SiO2 NP-induced serine phosphorylation of IRS1, and SiO2 NP-induced elevations of blood glucose.<br><br>CONCLUSION: Silicon dioxide NPs induced IR through ER stress and generation of ROS, but SiO2 FPs did not. Therefore, lifelong exposure of humans to SiO2 NPs may result in detrimental effects on blood glucose. The results of this study strongly suggested that non-nanoformed SiO2 should be used as food additives.}, }
@article {pmid31698002, year = {2020}, author = {Hu, X and Cheng, L and Wang, X and Luo, G and Zhao, T and Tian, J and An, L}, title = {N-acetyl-l-cysteine protects porcine oocytes undergoing meiotic resumption from heat stress.}, journal = {Reproductive toxicology (Elmsford, N.Y.)}, volume = {91}, number = {}, pages = {27-34}, doi = {10.1016/j.reprotox.2019.10.006}, pmid = {31698002}, issn = {1873-1708}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Female ; *Heat-Shock Response ; In Vitro Oocyte Maturation Techniques ; *Meiosis ; Oocytes/cytology/*drug effects/metabolism ; Oxidative Stress ; Protective Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; Swine ; }, abstract = {Heat stress (HS) is a notable risk factor for female reproductive performance. In particular, impaired oocyte maturation was thought to contribute largely to the HS-induced reproductive dysfunctions. In this study, we confirmed that oocytes undergoing GVBD were much susceptible to HS, and thus compromising subsequent embryonic development. Using N-acetyl-l-cysteine (NAC), we found supplementation of a relatively high dose NAC during in vitro maturation, can protect oocytes from HS-induced complications, and thus rescuing impaired embryonic development. Further analysis indicated that mechanisms responsible for protecting GVBD oocytes from HS by NAC may include: (1) reversing disorganized spindle assembly and inhibited extracellular signal-regulated kinase (ERK) signaling; (2) correcting erroneous H3K27me3 modification and dysregulated expression of imprinted genes; (3) alleviating increased intraoocyte reactive oxygen species accumulation and apoptosis initiation. Our study, focusing on the oocyte meiotic maturation, may provide a safe and promising strategy for protecting reproductive sows under environmental hyperthermal conditions.}, }
@article {pmid31693801, year = {2020}, author = {Shin, JM and Park, JH and Yang, HW and Lee, HM and Park, IH}, title = {Cigarette smoke extract inhibits cell migration and contraction via the reactive oxygen species/adenosine monophosphate-activated protein kinase pathway in nasal fibroblasts.}, journal = {International forum of allergy &amp; rhinology}, volume = {10}, number = {3}, pages = {356-363}, doi = {10.1002/alr.22479}, pmid = {31693801}, issn = {2042-6984}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Adult ; Cell Movement/*drug effects ; Cells, Cultured ; Collagen/metabolism ; Female ; Fibroblasts/*drug effects/metabolism/pathology ; Humans ; Male ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Smoke/*adverse effects ; *Nicotiana/chemistry ; Turbinates/pathology/surgery ; }, abstract = {BACKGROUND: Fibroblast migration plays a significant role in wound healing after endoscopic sinonasal surgery. Cigarette smoke extract (CSE) is a potent inhibitor of fibroblast functions including cell proliferation and migration. The purpose of the study was to determine the influence of CSE on migration and collagen gel contraction in nasal fibroblasts and investigate its underlying mechanisms.<br><br>METHODS: Fibroblast migration was evaluated using wound healing assay and transwell migration assay. Contractile activity was assessed by collagen gel contraction assay. Reactive oxygen species (ROS) were quantified by 2',7'-dichlorofluorescein diacetate. Fibroblasts were treated with CSE and N-acetylcysteine (NAC), metformin, compound C, or transfected with small interfering RNA (siRNA) to suppress adenosine monophosphate-activated protein kinase (AMPK) expression. AMPK activation was determined by Western blot.<br><br>RESULTS: CSE and metformin were found to significantly reduce the migration and collagen gel contraction activity of nasal fibroblasts. Conversely, pretreatment with NAC and compound C significantly enhanced the migration and collagen gel contraction activity of fibroblasts. ROS production and AMPK phosphorylation were found to be significantly induced by CSE treatment, whereas the activity was inhibited on treatment with NAC, metformin, compound C, or AMPK siRNA. Silencing of AMPK expression was found to significantly reverse the suppressive effect of CSE in nasal fibroblasts.<br><br>CONCLUSION: CSE has an inhibitory effect on cell migration and collagen gel contraction activity via the ROS/AMPK signaling pathway in nasal fibroblasts.}, }
@article {pmid31691492, year = {2020}, author = {Yuan, L and Liu, H and Liu, X and Zhang, X and Wu, J and Wang, Y and Du, X and Wang, R and Ma, Y and Chen, X and Petlulu, P and Cheng, X and Zhuang, D and Guo, H and Zhang, H}, title = {Epigenetic modification of H3K4 and oxidative stress are involved in MC-LR-induced apoptosis in testicular cells of SD rats.}, journal = {Environmental toxicology}, volume = {35}, number = {2}, pages = {277-291}, doi = {10.1002/tox.22865}, pmid = {31691492}, issn = {1522-7278}, support = {81472948//the National Nature Science Foundation of China/ ; 81773384//the National Nature Science Foundation of China/ ; 142102310344//the Scienti&#xfb01;c and Technological Project of Henan Province/ ; }, mesh = {Animals ; Apoptosis/*drug effects ; *Epigenesis, Genetic ; Histones/*genetics ; Humans ; Male ; Marine Toxins ; Membrane Potential, Mitochondrial/drug effects ; Microcystins/*toxicity ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sertoli Cells/drug effects/metabolism ; Testis/*drug effects ; }, abstract = {Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide, produced by aquatic cyanobacteria such as microcystis, with strong reproductive toxicity which poses greater threat to the reproductive abilities of humans and animals. By exploring the role of trimethylation of histone H3 at lysine 4 (H3K4me3) and the role of oxidative stress in MC-LR-induced apoptosis in testicular Sertoli cells in Sprague-Dawley (SD) rats, this study indicated that MC-LR increased the expression levels of apoptosis-related genes by raising the levels of H3K4me3. 5'-Deoxy-5'-methylthioadenosine (MTA), the inhibitor of H3K4me3, reduced apoptosis, indicating for the first time that epigenetic modification is closely related to the testicular reproductive toxicity induced by MC-LR. MC-LR also induced oxidative stress by stimulating the generation of reactive oxygen species (ROS), and subsequently triggering mitochondria-mediated apoptotic pathway by decreasing mitochondrial membrane potential and increasing the levels of Bax, Bcl-2, Caspase-3, and so on. MC-LR-induced apoptosis of testicular cells could be decreased after pretreatment with oxidative stress inhibitor N-acetyl-cysteine (NAC). Furthermore, the pathological damage to mitochondria and testes were observed in SD rats. These results show that MC-LR can induce apoptosis by raising the levels of H3K4me3, and pretreatment with MTA can ameliorate the MC-LR-induced apoptosis of cocultured cells by lowering the levels of H3K4me3. Furthermore, NAC has a protective effect on MC-LR-induced apoptosis of testicular cells in SD rats by inhibiting the oxidative stress.}, }
@article {pmid31682891, year = {2020}, author = {Cullen, KR and Schreiner, MW and Klimes-Dougan, B and Eberly, LE and LaRiviere, LL and Lim, KO and Camchong, J and Mueller, BA}, title = {Neural correlates of clinical improvement in response to N-acetylcysteine in adolescents with non-suicidal self-injury.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {99}, number = {}, pages = {109778}, pmid = {31682891}, issn = {1878-4216}, support = {R21 MH094558/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adolescent ; Amygdala/*diagnostic imaging/drug effects ; Female ; Functional Neuroimaging/methods ; Humans ; Nucleus Accumbens/*diagnostic imaging/drug effects ; Self-Injurious Behavior/*diagnostic imaging/*drug therapy ; Young Adult ; }, abstract = {Non-suicidal self-injury (NSSI) is a serious clinical problem that is common in adolescents. Novel, biologically-informed approaches for treating NSSI in adolescents are needed to prevent negative outcomes such as chronic NSSI and future suicide attempts. N-acetylcysteine (NAC) has been used successfully to address other conditions that involve repetitive maladaptive behaviors and may have utility in addressing NSSI. This study explored neural circuit changes following an open-label, 8-week trial of NAC in female adolescents with NSSI. We measured whole-brain resting-state functional connectivity (RSFC) of the amygdala and the nucleus accumbens before and after treatment using resting-state functional neuroimaging. Usable neuroimaging data from both pre- and post-treatment were available for 18 participants. Reduction in NSSI frequency was associated with a decrease in left amygdala RSFC with right supplementary motor area (SMA), but with an increase in right amygdala RSFC with right inferior frontal cortex. For nucleus accumbens, a reduction in NSSI frequency was associated with a decrease in connectivity between right nucleus accumbens and left superior medial frontal cortex. We also report change in similar circuits accompanying clinical improvement in depression and global psychopathology measures. These preliminary findings suggest amygdala and nucleus accumbens-based circuits as potential treatment targets, and set the stage for future research designed to confirm these neural targets using randomized, placebo-controlled designs to confirm clinical efficacy and mechanisms of effect.}, }
@article {pmid31681692, year = {2019}, author = {Yadav, P and Yadav, S and Pathak, S}, title = {Warfarin: A double-edged sword.}, journal = {Journal of family medicine and primary care}, volume = {8}, number = {9}, pages = {3045-3047}, pmid = {31681692}, issn = {2249-4863}, abstract = {Warfarin is the commonest anticoagulant used in today's practice; it has a very narrow therapeutics window. Under and overdosing results in various life-threatening complications. Warfarin-related nephropathy (WRN) is a rare cause of acute kidney injury (AKI) in patients on long-term anticoagulation, as a result of supratherapeutic anticoagulation. Warfarin causes AKI by inducing glomerular hemorrhage with subsequent tubular obstruction by red blood cell (RBC) casts. WRN has been associated with irreversible kidney injury and increased risk of mortality. Despite a better understanding of pathophysiology and histopathology of WRN, its preventive measures and clinical outcome are not well known. We report here the case of a 62-year-old male, who was on a long-term warfarin therapy due to chronic atrial fibrillation with a history of old ischemic stroke and dilated cardiomyopathy. He was presented with AKI and his renal biopsy was suggestive of WRN. He was managed by withholding warfarin for a few days until the therapeutic range of international normalized ratio was achieved and steroids and N-acetylcysteine (NAC) recovered. WRN is a diagnosis of exclusion; other causes of AKI must be ruled out. Renal biopsy is the gold standard for diagnosis. Patients on chronic anticoagulant therapy should be monitored periodically for the therapeutic range of anticoagulants, deterioration of renal function, and hematuria.}, }
@article {pmid31680400, year = {2020}, author = {Zacharis, CK and Tzanavaras, PD}, title = {Trace analysis of rimantadine in human urine after dispersive liquid liquid microextraction followed by liquid chromatography-post column derivatization.}, journal = {Journal of separation science}, volume = {43}, number = {3}, pages = {631-638}, doi = {10.1002/jssc.201900903}, pmid = {31680400}, issn = {1615-9314}, mesh = {Chromatography, High Pressure Liquid/instrumentation ; Healthy Volunteers ; Humans ; *Liquid Phase Microextraction/instrumentation ; Rimantadine/*urine ; }, abstract = {The first dispersive liquid liquid microextraction scheme followed by liquid chromatography-post column derivatization for the determination of the antiviral drug rimantadine in urine samples is demonstrated. The effect of the type and volume of organic extraction solvent, type and volume of disperser solvent, sample pH, ionic strength, extraction time, and centrifugation speed on the extraction efficiency were studied. Rimantadine and the internal standard (amantadine) were chromatographed using a reversed phase monolithic stationary phase with a mixture of equal volumes of methanol and phosphate buffer (pH = 3) as mobile phase. On-line post-column derivatization of the analyte was performed using a "two-stream" manifold with o-phthalaldehyde and N-acetyl-cysteine at alkaline medium. Under the optimized extraction conditions, the enrichment factor of rimantadine was 58. The linear range was 5-100 µg/L with correlation coefficient r of 0.9984 while the limit of detection achieved was 0.5 µg/L. The within-day and between-day precision for the tested concentration levels were less than 14.3% and the mean recoveries obtained from the spiked samples were ranged between 87.5 and 113.9%. The main advantages of the proposed method are the simplicity of operation, rapidity, low cost, and low limit of detection of the analyte.}, }
@article {pmid31679408, year = {2021}, author = {Halboub, E and Alkadasi, B and Alakhali, M and AlKhairat, A and Mdabesh, H and Alkahsah, S and Abdulrab, S}, title = {N-acetylcysteine versus chlorhexidine in treatment of aphthous ulcers: a preliminary clinical trial.}, journal = {The Journal of dermatological treatment}, volume = {32}, number = {6}, pages = {649-653}, doi = {10.1080/09546634.2019.1688231}, pmid = {31679408}, issn = {1471-1753}, mesh = {Acetylcysteine/therapeutic use ; Chlorhexidine/therapeutic use ; Female ; Humans ; Mouthwashes ; *Stomatitis, Aphthous/drug therapy ; Treatment Outcome ; Ulcer ; }, abstract = {INTRODUCTION: This study sought to assess the efficacy of N-acetyl cysteine (NAC) in the treatment of recurrent aphthous stomatitis (RAS).<br><br>METHODS: Fifty-eight patients, aged 28&#x2009;&#xb1;&#x2009;9.7&#x2009;years, presented with clinically diagnosed RAS to two oral medicine centers. They were assigned randomly to a single application of either NAC (200&#x2009;mg dissolved in water, n&#x2009;=&#x2009;38) or 0.12% chlorhexidine digluconate (CHX, n&#x2009;=&#x2009;20) mouthwashes for 30&#x2009;seconds. Pain was measured using a Visual Analog Scale (VAS). The size of the ulcer was measured through its greatest dimension using a periodontal probe. These two measurements were taken pre-application (day 1) and 2nd, 4th, and 6th day post-application. Average time (in days) until complete healing was assessed.<br><br>RESULTS: Of all participants, 33 (57%) were females; 34 (59%) married; 29 (50%) reported a family history of aphthae; and 51 (88%) were affected with minor RAS. There were greater improvement in pain from day 1 with NAC on the second day (-3.0&#x2009;&#xb1;&#x2009;2.0 versus -1.8&#x2009;&#xb1;&#x2009;1.9; p&#x2009;=&#x2009;.028) and on the fourth day (-5.0&#x2009;&#xb1;&#x2009;2.6 versus -3.4&#x2009;&#xb1;&#x2009;2.7; p&#x2009;=&#x2009;.041). The differences with regard to the change in ulcer size and average healing time were not significant between NAC and CHX.<br><br>CONCLUSION: Single application of NAC results in a clinically significant reduction of RAS-associated pain within one day of application and is more effective than CHX.}, }
@article {pmid31677872, year = {2020}, author = {Mendonça, MCP and Rodrigues, NP and Scott-Fordsmand, JJ and Jesus, MB and Amorim, MJB}, title = {The toxicity of silver nanomaterials (NM 300K) is reduced when combined with N-Acetylcysteine: Hazard assessment on Enchytraeus crypticus.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {256}, number = {}, pages = {113484}, doi = {10.1016/j.envpol.2019.113484}, pmid = {31677872}, issn = {1873-6424}, mesh = {Acetylcysteine/metabolism ; Animals ; Nanostructures/*toxicity ; Oligochaeta/drug effects/*physiology ; Reproduction/drug effects ; Sewage ; Silver/*toxicity ; Silver Nitrate/toxicity ; Soil ; Soil Pollutants/analysis/*toxicity ; }, abstract = {The widespread production and use of silver nanomaterials (AgNMs) in consumer and medical products have been raising environmental concerns. Once in the environment, the soil is one of the major sinks of AgNMs due to e.g. sewage sludge applications, and invertebrates are directly exposed. In this study, we investigate the potential of N-acetylcysteine (NAC) to reduce the toxic effects of Ag NM300 K (and AgNO3) on the soil invertebrate Enchytraeus crypticus. Ag NM300 K induces mortality, reproduction impairment, and avoidance. The addition of NAC to the soil showed a remarkable reduction in the toxicity of Ag, indicating that NAC can act as a detoxifying agent for terrestrial organisms exposed to Ag materials. That the reduction in toxicity likely is caused by thiol groups, was confirmed by GSH and GSSH studies. Identifying the mechanisms and hence alternatives that allow the recovery of contaminated soils is an important mitigation measure to promote environmental safety and reduce the associated risks to human health. Further, it may inform on strategies to implement in safe-by-design industry development.}, }
@article {pmid31672158, year = {2019}, author = {Córdoba-Jover, B and Arce-Cerezo, A and Ribera, J and Pauta, M and Oró, D and Casals, G and Fernández-Varo, G and Casals, E and Puntes, V and Jiménez, W and Morales-Ruiz, M}, title = {Cerium oxide nanoparticles improve liver regeneration after acetaminophen-induced liver injury and partial hepatectomy in rats.}, journal = {Journal of nanobiotechnology}, volume = {17}, number = {1}, pages = {112}, pmid = {31672158}, issn = {1477-3155}, support = {SAF2016-75358-R//Ministerio de Ciencia Innovaci&#xf3;n y Universidades/ ; PI15/00777//Ministerio de Sanidad, Consumo y Bienestar Social/ ; Marat&#xf3; 120930//Fundaci&#xf3; la Marat&#xf3; de TV3/ ; 2018TP010//Wuyi University/ ; 2017KSYS010//Department of Education of Guangdong Province/ ; }, mesh = {*Acetaminophen ; Animals ; Antioxidants/*therapeutic use ; Cerium/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/physiopathology ; Hep G2 Cells ; Hepatectomy ; Humans ; Liver/drug effects/physiopathology ; Liver Regeneration/*drug effects ; Male ; Nanoparticles/*therapeutic use ; Rats, Wistar ; }, abstract = {BACKGROUND AND AIMS: Cerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases. Consequently, we aimed to investigate the effect of these nanoparticles on hepatic regeneration after liver injury by partial hepatectomy and acetaminophen overdose.<br><br>METHODS: All the in vitro experiments were performed in HepG2 cells. For the acetaminophen and partial hepatectomy experimental models, male Wistar rats were divided into three groups: (1) nanoparticles group, which received 0.1&#xa0;mg/kg cerium nanoparticles i.v. twice a week for 2&#xa0;weeks before 1&#xa0;g/kg acetaminophen treatment, (2) N-acetyl-cysteine group, which received 300&#xa0;mg/kg of N-acetyl-cysteine i.p. 1&#xa0;h after APAP treatment and (3) partial hepatectomy group, which received the same nanoparticles treatment before partial hepatectomy. Each group was matched with vehicle-controlled rats.<br><br>RESULTS: In the partial hepatectomy model, rats treated with cerium oxide nanoparticles showed a significant increase in liver regeneration, compared with control rats. In the acetaminophen experimental model, nanoparticles and N-acetyl-cysteine treatments decreased early liver damage in hepatic tissue. However, only the effect of cerium oxide nanoparticles was associated with a significant increment in hepatocellular proliferation. This treatment also reduced stress markers and increased cell cycle progression in hepatocytes and the activation of the transcription factor NF-&#x3ba;B in vitro and in vivo.<br><br>CONCLUSIONS: Our results demonstrate that the nanomaterial cerium oxide, besides their known antioxidant capacities, can enhance hepatocellular proliferation in experimental models of liver regeneration and drug-induced hepatotoxicity.}, }
@article {pmid31670428, year = {2019}, author = {May, ER and Ratliff, BE and Bemis, DA}, title = {Antibacterial effect of N-acetylcysteine in combination with antimicrobials on common canine otitis externa bacterial isolates.}, journal = {Veterinary dermatology}, volume = {30}, number = {6}, pages = {531-e161}, doi = {10.1111/vde.12795}, pmid = {31670428}, issn = {1365-3164}, support = {//Department of Small Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Bacterial Agents/*pharmacology ; Bacteria/*drug effects ; Dog Diseases/*microbiology ; Dogs ; Drug Synergism ; Microbial Sensitivity Tests ; Otitis Externa/microbiology/*veterinary ; }, abstract = {BACKGROUND: Approved treatments for canine otitis externa are limited in variety and may contain ototoxic ingredients. With bacterial resistance an ongoing concern, it would be ideal if non-ototoxic agents combined with antibiotics resulted in a synergistic effect, requiring lower antibiotic concentrations to treat infections. Evidence of synergism and antagonism between N-acetylcysteine (NAC) and various antibiotic classes has been reported; the present research group was interested in examining these interactions.<br><br>HYPOTHESIS/OBJECTIVES: To determine if NAC, an otoprotective and antimicrobial compound, has synergistic activity when combined with enrofloxacin or gentamicin in vitro against bacterial isolates causing canine otitis externa.<br><br>ANIMALS: Twenty-two isolates from canine clinical cases of otitis externa were identified and tested, including seven Staphylococcus pseudintermedius, 12 Pseudomonas aeruginosa and three Corynebacterium spp. isolates.<br><br>METHODS AND MATERIALS: Each isolate was grown on blood agar for 24&#xa0;h and transferred to Mueller-Hinton broth (MHB), with a final concentration of 5&#xa0;&#xd7;&#xa0;10[5] cfu/mL. Each well was inoculated with 50&#xa0;&#x3bc;L of bacterial suspension. N-acetylcysteine was diluted in MHB to a starting concentration of 160&#xa0;mg/mL. Enrofloxacin and gentamicin were diluted to 64&#xa0;&#x3bc;g/mL. Individual and checkerboard serial microdilution assays were performed in triplicate with negative controls for all isolates tested.<br><br>RESULTS: Interactions observed for NAC and enrofloxacin were synergistic (4.5%), indifferent (77.3%) or antagonistic (18.2%). Interactions observed for NAC and gentamicin were synergistic (4.5%), indifferent (45.5%) or antagonistic (50%).<br><br>Most interactions between NAC and enrofloxacin or gentamicin were indifferent or antagonistic at the concentrations tested in vitro.}, }
@article {pmid31670121, year = {2020}, author = {Sun, J and Charron, CS and Novotny, JA and Peng, B and Yu, L and Chen, P}, title = {Profiling glucosinolate metabolites in human urine and plasma after broccoli consumption using non-targeted and targeted metabolomic analyses.}, journal = {Food chemistry}, volume = {309}, number = {}, pages = {125660}, pmid = {31670121}, issn = {1873-7072}, support = {Y01 OD001298-01/OD/NIH HHS/United States ; }, mesh = {Adult ; Aged ; Brassica/chemistry/*metabolism ; Female ; Glucosinolates/blood/chemistry/metabolism/*urine ; Humans ; Imidoesters/chemistry/metabolism ; Indoles/chemistry ; Limit of Detection ; Male ; Mass Spectrometry ; Metabolomics/*methods ; Middle Aged ; Oximes ; Principal Component Analysis ; Sulfoxides ; }, abstract = {Broccoli is a popular brassica vegetable and its consumption may decrease the occurrence of cancer in certain populations. To gain insight into the metabolites that may induce physiological responses to broccoli intake, a non-targeted metabolomic approach and a targeted approach for analysis of glucosinolate metabolites were developed using high resolution accurate mass spectrometry. A human study was conducted in which 6 subjects consumed a single meal of 200 g of uncooked broccoli florets. The metabolomic analysis revealed changes in endogenous metabolites and a decrease in hippuric acid after broccoli consumption. Targeted analysis using high-resolution, accurate mass-mass spectrometry (HRAM-MS) enabled detection of low concentrations (nM) of glucosinolate metabolites in human urine and plasma. Glucosinolate metabolites were found in human urine (13) and plasma (8), respectively. Metabolites from methoxyl-indole glucosinolates, arising from broccoli consumption, are reported for the first time. Most glucosinolate metabolites reached their peak concentration in urine 2-4 h after consumption while, in plasma, peak maxima were achieved 2 h after intake. The results suggest that glucoraphanin metabolites (sulforaphane, sulforaphane cysteine, sulforaphane N-acetyl cysteine) and indole metabolites (ascorbigen and methoxyl ascorbigen from indole glucosinolates) may serve as marker compounds for the intake of broccoli.}, }
@article {pmid31668653, year = {2020}, author = {Acer-Demir, T and Mammadov, M and Öcbe, P and Çoruhlu, A and Coşkun, D and Nazik, Y and Tüfekçi, I and Güney, LH and Hiçsönmez, A}, title = {The long term effects of intrascrotal low dose and high dose N-acetylcysteine on testis damage in rat model of testicular torsion.}, journal = {Journal of pediatric surgery}, volume = {55}, number = {4}, pages = {672-680}, doi = {10.1016/j.jpedsurg.2019.09.028}, pmid = {31668653}, issn = {1531-5037}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Case-Control Studies ; Male ; Models, Animal ; Rats ; Rats, Wistar ; Reperfusion Injury/*drug therapy ; Spermatic Cord Torsion/*drug therapy ; Testis/*drug effects/pathology ; }, abstract = {BACKGROUND/PURPOSE: During testicular torsion, the testes face oxidative damage owing to ischemia/reperfusion. We studied the long term effects of the intrascrotal administration of N-acetylcysteine (NAC) during detorsion procedure in a rat model of testicular torsion.<br><br>METHODS: Twenty-eight rats were divided into 4 groups: (1) Control group: No procedure was done (2): Torsion-detorsion group: Testis torsion applied for 3&#x202f;h (3): Low Dose Group: After testis torsion-detorsion (for 3&#x202f;h) 10&#x202f;mg/kg NAC was given into tunica vaginalis (4): High Dose Group: After testis torsion-detorsion (for 3&#x202f;h) 100&#x202f;mg/kg NAC was given into tunica vaginalis. We measured dimensions of the testes and examined pathological findings and Johnsen and Cosantino Scores.<br><br>RESULTS: For testes height and volume, high dose NAC group had better results than the torsion-detorsion group (p&#x202f;=&#x202f;0.019, p&#x202f;=&#x202f;0.049). Testes weight showed no difference (p&#x202f;=&#x202f;0.204). Sertoli cell number per tubule in the high dose NAC group was statistically different than the torsion-detorsion group (p&#x202f;=&#x202f;0.017).<br><br>CONCLUSIONS: When NAC was given intrascrotally at a dose of 100&#x202f;mg/kg, it decreased the loss of testis volume and height, and Sertoli cell number per tubule was similar to the control group. These results suggest that the higher dose intrascrotal NAC administered during detorsion may have a protective effect.}, }
@article {pmid31668008, year = {2020}, author = {Jackson, A and Little, M}, title = {Electronic intravenous N-acetyl cysteine ordering tool: A retrospective review.}, journal = {Emergency medicine Australasia : EMA}, volume = {32}, number = {2}, pages = {267-270}, doi = {10.1111/1742-6723.13404}, pmid = {31668008}, issn = {1742-6723}, mesh = {*Acetaminophen/therapeutic use ; Acetylcysteine/therapeutic use ; *Drug Overdose/drug therapy ; Electronics ; Humans ; Retrospective Studies ; }, abstract = {OBJECTIVES: To examine if the electronic N-acetyl cysteine (NAC) order reduced prescribing errors.<br><br>METHODS: This was a retrospective chart review of all patients presenting over 2&#x2009;years to Cairns Hospital ED with a discharge diagnosis of 'paracetamol overdose'. Data were collected for any patient who received i.v. NAC. Any error, and a description of the error such as dose, volume of fluid, time of infusion and incorrect patient weight was recorded.<br><br>RESULTS: There were 172 presentations with paracetamol poisoning with 86 receiving i.v. NAC. In the 75 (87%) where the electronic NAC order was used, there were no errors in dose of NAC, volume of i.v. fluid and length of time of infusion. In the 11 presentations where the manual NAC order was used, there were multiple errors identified.<br><br>CONCLUSION: The use of this electronic NAC order removed errors in NAC prescription and should be considered for prescribing and administering i.v. NAC.}, }
@article {pmid31655538, year = {2019}, author = {Güntürk, I and Yazici, C and Köse, SK and Dağli, F and Yücel, B and Yay, AH}, title = {The effect of N-acetylcysteine on inflammation and oxidative stress in cisplatin-induced nephrotoxicity: a rat model.}, journal = {Turkish journal of medical sciences}, volume = {49}, number = {6}, pages = {1789-1799}, pmid = {31655538}, issn = {1303-6165}, support = {TDK.2014-5056//Research Fund of Erciyes University/International ; }, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*chemically induced/drug therapy ; Animals ; Antineoplastic Agents/*toxicity ; Blood Urea Nitrogen ; Cisplatin/*toxicity ; Creatinine/blood ; Inflammation/chemically induced/*drug therapy ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Treatment Outcome ; }, abstract = {BACKGROUND/AIM: Cisplatin is a highly effective chemotherapeutic agent used in the treatment of solid organ cancers. Besides its chemotherapeutic effectiveness, cisplatin administration is associated with numerous side effects. Of those, the most clinically significant and common effect is nephrotoxicity. Recent studies reported that oxidative stress and inflammation are probably the most important mechanisms that contribute to the nephrotoxicity. N-acetylcysteine (NAC) is an antioxidant and antiinflammatory agent. In the present study, the effects of NAC on cisplatin-induced nephrotoxicity were investigated.<br><br>MATERIALS AND METHODS: Rats were divided into four groups each including eight rats: CONT, NAC-250, CP, and CP+NAC. Rats in experimental groups were treated intraperitoneally (i.p.) with a single dose of cisplatin (10 mg/kg body weight) and i.p. with NAC (250 mg/kg body weight) for three consecutive days. Nephrotoxicity was determined by plasma BUN and creatinine levels. In tissue samples, myeloperoxidase (MPO), nuclear factor-kappa B (NF-kB), high mobility group box-1 (HMGB-1), total oxidant status (TOS), and total antioxidant status (TAS) levels were measured. Kidneys were analyzed histopathologically as well.<br><br>RESULTS: It was revealed that cisplatin was not effective on MPO, HMGB-1 and NF-kB levels but did increase TOS levels and decrease TAS levels in tissue samples. Interestingly, NAC elevated MPO and HMGB-1 levels significantly. Nevertheless, NAC ameliorated histological and functional changes in kidney tissues.<br><br>CONCLUSION: It is suggested that inflammation has a limited effect on cisplatin nephrotoxicity in this experimental design, and, as reflected by decreased BUN and creatinine levels, NAC can be used as an additional therapeutic agent in standard cisplatin treatment protocols.}, }
@article {pmid31654686, year = {2019}, author = {Lababidi, N and Ofosu Kissi, E and Elgaher, WAM and Sigal, V and Haupenthal, J and Schwarz, BC and Hirsch, AKH and Rades, T and Schneider, M}, title = {Spray-drying of inhalable, multifunctional formulations for the treatment of biofilms formed in cystic fibrosis.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {314}, number = {}, pages = {62-71}, doi = {10.1016/j.jconrel.2019.10.038}, pmid = {31654686}, issn = {1873-4995}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Administration, Inhalation ; Animals ; Anti-Bacterial Agents/*administration &amp; dosage/pharmacology ; Azithromycin/administration &amp; dosage/pharmacology ; Biofilms/*drug effects ; Ciprofloxacin/administration &amp; dosage/pharmacology ; Cystic Fibrosis/complications/*drug therapy ; Drug Stability ; Drug Storage ; Expectorants/administration &amp; dosage/pharmacology ; Horses ; Mucus/microbiology ; Particle Size ; Pseudomonas Infections/drug therapy/microbiology ; Pseudomonas aeruginosa/*drug effects/physiology ; Tobramycin/administration &amp; dosage/pharmacology ; }, abstract = {Cystic fibrosis (CF) is a serious lung disease, commonly susceptible to Pseudomonas aeruginosa colonization. The dense mucus together with biofilm formation limit drug permeability and prevent the drug from reaching the site of action, causing treatment failure of the bacterial infection. Besides the use of antibiotics, the mucolytic agent N-acetylcysteine (NAC) is recommended to be co-administered in the treatment of CF. Although several formulations have been developed for inhalation therapy to improve the pulmonary condition in CF patients, there is still no comprehensive study on a combined multifunctional dry powder formulation of antibiotics with NAC. In this work, we developed an innovative multifunctional dry powder inhaler (DPI) formulation based on salt formation between NAC and antibiotics and characterized their solid state properties and physical stability. NAC could be spray dried together with three different antibiotics, azithromycin (Azi), tobramycin (Tobra) and ciprofloxacin (Cipro), without the use of organic solvents to form Azi/NAC, Tobra/NAC and Cipro/NAC DPI formulations. Solid-state characterization of these DPI formulations showed that they were amorphous after spray drying. Azi/NAC and Tobra/NAC form co-amorphous salt systems that were physically stable under storage at stress conditions. For particle characterization, the obtained mass median aerodynamic diameters were in a suitable range for inhalation (< 5.0μm). The multifunctional antibiotic/NAC formulations conserved or improved the antibiotic susceptibility and showed promising results regarding the inhibition of P. aeruginosa PA14 biofilm formation.}, }
@article {pmid31653089, year = {2019}, author = {Lee, SR and Lee, D and Eom, HJ and Rischer, M and Ko, YJ and Kang, KS and Kim, CS and Beemelmanns, C and Kim, KH}, title = {Hybrid Polyketides from a Hydractinia-Associated Cladosporium sphaerospermum SW67 and Their Putative Biosynthetic Origin.}, journal = {Marine drugs}, volume = {17}, number = {11}, pages = {}, pmid = {31653089}, issn = {1660-3397}, support = {2018R1A2B2006879//National Research Foundation of Korea/ ; }, mesh = {Animals ; Antineoplastic Agents/adverse effects ; Cell Survival/drug effects ; Cisplatin/adverse effects ; Cladosporium/chemistry/*genetics ; LLC-PK1 Cells ; Molecular Structure ; Nuclear Magnetic Resonance, Biomolecular ; Phylogeny ; Polyketides/*chemistry/isolation &amp; purification/*pharmacology ; Pyrrolidinones/*chemistry/*pharmacology ; Swine ; }, abstract = {Five hybrid polyketides (1a, 1b, and 2-4) containing tetramic acid core including a new hybrid polyketide, cladosin L (1), were isolated from the marine fungus Cladosporium sphaerospermum SW67, which was isolated from the marine hydroid polyp of Hydractinia echinata. The hybrid polyketides were isolated as a pair of interconverting geometric isomers. The structure of 1 was determined based on 1D and 2D NMR spectroscopic and HR-ESIMS analyses. Its absolute configuration was established by quantum chemical electronic circular dichroism (ECD) calculations and modified Mosher's method. Tetramic acid-containing compounds are reported to be derived from a hybrid PKS-NRPS, which was also proved by analyzing our [13]C-labeling data. We investigated whether compounds 1-4 could prevent cell damage induced by cisplatin, a platinum-based anticancer drug, in LLC-PK1 cells. Co-treatment with 2 and 3 ameliorated the damage of LLC-PK1 cells induced by 25 μM of cisplatin. In particular, the effect of compound 2 at 100 μM (cell viability, 90.68 ± 0.81%) was similar to the recovered cell viability of 88.23 ± 0.25% with 500 μM N-acetylcysteine (NAC), a positive control.}, }
@article {pmid31652494, year = {2019}, author = {Chen, SY and Liu, ST and Lin, WR and Lin, CK and Huang, SM}, title = {The Mechanisms Underlying the Cytotoxic Effects of Copper Via Differentiated Embryonic Chondrocyte Gene 1.}, journal = {International journal of molecular sciences}, volume = {20}, number = {20}, pages = {}, pmid = {31652494}, issn = {1422-0067}, support = {MAB-108-019//The Ministry of National Defense-Medical Affairs Bureau, Taiwan, ROC/ ; C108-118//The Tri-Service General Hospital, Taiwan, ROC/ ; }, mesh = {Activating Transcription Factor 3/genetics/metabolism ; Cell Survival/drug effects ; Copper Sulfate/pharmacology/*toxicity ; HEK293 Cells ; HeLa Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; MAP Kinase Signaling System ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; }, abstract = {Copper is an essential trace element within cells, but it also exerts cytotoxic effects through induction of reactive oxygen species (ROS) production. To determine the mechanisms underlying copper-induced ROS production, we examined the effects of copper sulfate in HeLa cells. Exposure to copper sulfate led to dose-dependent decreases in HeLa cell viability, along with increases in the subG1 and G2/M populations and corresponding decreases in the G1 population. Copper sulfate also increased the levels of apoptosis, senescence, mitochondrial dysfunction, autophagy, ROS, and the expression of several stress proteins, including ATF3, c-Fos, DEC1 (differentiated embryonic chondrocyte gene 1), p21, p53, and HIF-1α (hypoxia-inducible factor 1 alpha). The suppression of copper-induced ROS generation by the ROS scavenger N-acetyl cysteine verified copper's functional role, while the suppression of copper's effects by the copper chelator disulfiram, confirmed its specificity. Selective induction of HIF-1α, p53, and phosphorylated ERK proteins by copper was blocked by the knockdown of the transcription factor DEC1, suggesting copper's effects are mediated by DEC1. In addition to HeLa cells, copper also exerted cytotoxic effects in human endometrial (HEC-1-A) and lung (A549) adenocarcinoma cells, but not in normal human kidney (HEK293) or bronchial (Beas-2B) epithelial cells. These findings shed new light on the functional roles of copper within cells.}, }
@article {pmid31649499, year = {2019}, author = {Yumnamcha, T and Devi, TS and Singh, LP}, title = {Auranofin Mediates Mitochondrial Dysregulation and Inflammatory Cell Death in Human Retinal Pigment Epithelial Cells: Implications of Retinal Neurodegenerative Diseases.}, journal = {Frontiers in neuroscience}, volume = {13}, number = {}, pages = {1065}, pmid = {31649499}, issn = {1662-4548}, support = {P30 EY004068/EY/NEI NIH HHS/United States ; R01 EY023992/EY/NEI NIH HHS/United States ; }, abstract = {PURPOSE: Photoreceptor degeneration occurs in various retinal diseases including age-related macular degeneration (AMD), Retinitis pigmentosa (RP), and diabetic retinopathy (DR). However, molecular mechanisms are not fully understood yet. The retinal pigment epithelium (RPE) forms the outer blood retinal barrier (oBRB) and supplies glucose, oxygen and nutrients from the fenestrated choriocapillaris to photoreceptors for visual function. Therefore, RPE dysfunction leads to photoreceptor injury/death and progression of blinding eye diseases. This study aims to understand the role of the thioredoxin (Trx) and its reductase (TrxR) redox signaling in human RPE dysfunction and cell death mechanism(s) in an in vitro system.<br><br>METHODS: A human RPE cell line (APRE-19) was cultured in DMEM/F12 medium and treated with auranofin (AF - 4 &#x3bc;M, an inhibitor of TrxR) for 4 and 24 h. Mitochondrial and lysosomal function, cellular oxidative stress and NLRP3 inflammasome activity were measured using cell assays, Western blotting, and confocal microscopy. Antioxidants and anti-inflammatory compounds were tested for blocking AF effects on RPE damage. Cell death mechanisms (LDH release to culture media) were determined using necroptosis, ferroptosis and pyroptosis inhibitors. P < 0.05 was considered significant in statistical analysis.<br><br>RESULTS: Auranofin causes mitochondrial dysfunction (&#x394;&#x3c8;m&#x2193; and ATP&#x2193;), oxidative stress (H2O2&#x2191;) and mitophagic flux to lysosomes. Furthermore, the lysosomal enzyme (cathepsin L) activity is reduced while that of pro-inflammatory caspase-1 (NLRP3 inflammasome) is enhanced in ARPE-19. These effects of AF on ARPE-19 are inhibited by antioxidant N-acetylcysteine (5 mM, NAC) and significantly by a combination of SS31 (mitochondrial antioxidant) and anti-inflammatory drugs (amlexanox and tranilast). AF also causes cell death as measured by cytosolic LDH release/leakage, which is not inhibited by either ferrostatin-1 or necrostatin-1 (ferroptosis and necroptosis inhibitors, respectively). Conversely, AF-induced LDH release is significantly reduced by MCC950 and Ac-YVAD-cmk (NLRP3 and Caspase-1 inhibitors, respectively), suggesting a pro-inflammatory cell death by pyroptosis.<br><br>CONCLUSION: The Trx/TrxR redox system is critical for RPE function and viability. We previously showed that thioredoxin-interacting protein (TXNIP) is strongly induced in DR inhibiting the Trx/TrxR system and RPE dysfunction. Therefore, our results suggest that the TXNIP-Trx-TrxR redox pathway may participate in RPE dysfunction in DR and other retinal neurodegenerative diseases.}, }
@article {pmid31640182, year = {2019}, author = {Peerapanyasut, W and Kobroob, A and Palee, S and Chattipakorn, N and Wongmekiat, O}, title = {N-Acetylcysteine Attenuates the Increasing Severity of Distant Organ Liver Dysfunction after Acute Kidney Injury in Rats Exposed to Bisphenol A.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {8}, number = {10}, pages = {}, pmid = {31640182}, issn = {2076-3921}, support = {114/2561 and 129/2561//Faculty of Medicine, Chiang Mai University/ ; 0154/2558//Royal Golden Jubilee PhD Program, Thailand Research Fund/ ; NSTDA Research Chair Grant//National Science and Technology Development Agency/ ; }, abstract = {Distant organ liver damage after acute kidney injury (AKI) remains a serious clinical setting with high mortality. This undesirable outcome may be due to some hidden factors that can intensify the consequences of AKI. Exposure to bisphenol A (BPA), a universal chemical used in plastics industry, is currently unavoidable and can be harmful to the liver. This study explored whether BPA exposure could be a causative factor that increase severity of remote liver injury after AKI and examined the preventive benefit by N-acetylcysteine (NAC) in this complex condition. Male Wistar rats were given vehicle, BPA, or BPA + NAC for 5 weeks then underwent 45 min renal ischemia followed by 24 h reperfusion (RIR), a group of vehicle-sham-control was also included. RIR not only induced AKI but produced liver injury, triggered systemic oxidative stress as well as inflammation, which increasing severity upon exposure to BPA. Given NAC to BPA-exposed rats diminished the added-on effects of BPA on liver functional impairment, oxidative stress, inflammation, and apoptosis caused by AKI. NAC also mitigated the abnormalities in mitochondrial functions, dynamics, mitophagy, and ultrastructure of the liver by improving the mitochondrial homeostasis regulatory signaling AMPK-PGC-1α-SIRT3. The study demonstrates that NAC is an effective adjunct for preserving mitochondrial homeostasis and reducing remote effects of AKI in environments where BPA exposure is vulnerable.}, }
@article {pmid31639156, year = {2019}, author = {Mukunoki, A and Takeo, T and Nakagata, N}, title = {N-acetyl cysteine restores the fertility of vitrified-warmed mouse oocytes derived through ultrasuperovulation.}, journal = {PloS one}, volume = {14}, number = {10}, pages = {e0224087}, pmid = {31639156}, issn = {1932-6203}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cryopreservation ; Embryo Transfer ; Female ; Fertility Preservation/*methods ; Fertilization in Vitro/*methods ; Free Radical Scavengers/administration &amp; dosage ; In Vitro Oocyte Maturation Techniques ; Male ; Mice ; Mice, Inbred C57BL ; Oocytes/cytology/*physiology ; Pregnancy ; *Pregnancy Rate ; *Superovulation ; Vitrification/*drug effects ; }, abstract = {Oocyte cryopreservation is useful for preserving fertility and storing genetic resources. However, the small number of oocytes acquired using conventional treatment to induce superovulation and the reduction of fertility due to cryopreservation represent significant problems. Herein, we vitrified the oocytes derived through high-yield superovulation using inhibin antiserum and equine chorionic gonadotropin (IAS + eCG: IASe) and examined the yield of cryopreserved oocytes and survival rates relative to those of vitrified-warmed mouse oocytes derived through conventional superovulation using equine chorionic gonadotropin (eCG). Furthermore, we investigated the effects of N-acetyl cysteine on the fertility and developmental potential of vitrified-warmed oocytes derived using IASe. Compared with eCG, IASe increased the yield of cryopreserved oocytes and achieved equivalent survival rates. N-acetyl cysteine (0.5 mM) increased the fertilization rate of vitrified-warmed oocytes derived using IASe. Vitrification decreased thiol levels in the zona pellucida (ZP), while warming followed by N-acetyl cysteine treatment increased free thiol levels in ZP. Moreover, N-acetyl cysteine treatment recovered zona hardening by cleaving disulfide bonds and promoting the expansion of ZP. Two-cell embryos derived via in vitro fertilization using N-acetyl cysteine developed into normal pups through embryo transfer. Therefore, we developed an efficient technique for the production of cryopreserved oocytes using IASe through superovulation and found that N-acetyl cysteine improves the fertility of vitrified-warmed oocytes by cleaving the disulfide bonds and promoting the expansion of ZP.}, }
@article {pmid31636802, year = {2019}, author = {Zhang, Y and Xiao, JF and Yang, HF and Jiao, Y and Cao, WW and Shi, HM and Cun, JF and Tay, FR and Ping, J and Xiao, YH}, title = {N-Acetyl Cysteine as a Novel Polymethyl Methacrylate Resin Component: Protection against Cell Apoptosis and Genotoxicity.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {1301736}, pmid = {31636802}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adolescent ; Adult ; Apoptosis/*drug effects ; Humans ; Mutagenicity Tests/*methods ; Young Adult ; }, abstract = {The present study investigated the antiapoptotic and antigenotoxic capabilities of N-acetyl cysteine- (NAC-) containing polymethyl methacrylate (PMMA) resin. An in vitro Transwell insert model was used to mimic the clinical provisional restorations placed on vital teeth. Various parameters associated with cell apoptosis and genotoxicity were investigated to obtain a deeper insight into the underlying mechanisms. The exposure of human dental pulp cell (hDPC) cultures to the PMMA resin (Unifast Trad™) resulted in a rapid increase in reactive oxygen species (ROS) level beginning at 1 h, which was followed by time-dependent cell detachment and overt death. The formation of γ-H2AX and cell cycle G1 phase arrest indicated that oxidative DNA damage occurred as a result of the interactions between DNA bases and ROS, beyond the capacities of cellular redox regulation. Such oxidative DNA damage triggers the activation of p53 via the ataxia telangiectasia mutated (ATM) signaling pathway and the induction of intrinsic mitochondrial apoptosis. Oxidative stress, cell apoptosis, and DNA damage induced by the PMMA resin were recovered to almost the level of untreated controls by the incorporation of NAC. The results indicate that the PMMA resin induced the intrinsic mitochondrial apoptosis as a consequence of p53 activation via the ATM pathway in response to oxidative DNA damage. More importantly, the incorporation of NAC as a novel component into the Unifast Trad™ PMMA resin offers protective effects against cell apoptosis and genotoxicity. This procedure represents a beneficial strategy for developing more biocompatible PMMA-based resin materials.}, }
@article {pmid31635184, year = {2019}, author = {Yamada, M and Watanabe, J and Ueno, T and Ogawa, T and Egusa, H}, title = {Cytoprotective Preconditioning of Osteoblast-Like Cells with N-Acetyl-L-Cysteine for Bone Regeneration in Cell Therapy.}, journal = {International journal of molecular sciences}, volume = {20}, number = {20}, pages = {}, pmid = {31635184}, issn = {1422-0067}, support = {17H04387//Grant-in-Aids for Scienti&#xfb01;c Research/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bone Regeneration/*drug effects ; Cell Survival ; *Cell- and Tissue-Based Therapy ; Cells, Cultured ; *Cytoprotection ; Free Radical Scavengers/pharmacology ; Osteoblasts/*cytology/drug effects/*transplantation ; Osteogenesis/*drug effects ; Oxidation-Reduction ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Oxidative stress hinders tissue regeneration in cell therapy by inducing apoptosis and dysfunction in transplanted cells. N-acetyl-L-cysteine (NAC) reinforces cellular antioxidant capabilities by increasing a major cellular endogenous antioxidant molecule, glutathione, and promotes osteogenic differentiation. This study investigates the effects of pretreatment of osteoblast-like cells with NAC on oxidative stress-induced apoptosis and dysfunction and bone regeneration in local transplants. Rat femur bone marrow-derived osteoblast-like cells preincubated for 3 h with and without 5 mM NAC were cultured in a NAC-free osteogenic differentiation medium with continuous exposure to 50 μM hydrogen peroxide to induce oxidative stress. NAC preincubation prevented disruption of intracellular redox balance and alleviated apoptosis and negative impact on osteogenic differentiation, even under oxidative stress. Autologous osteoblast-like cells with and without NAC pretreatment in a collagen sponge vehicle were implanted in critical-size defects in rat femurs. In the third week, NAC-pretreated cells yielded complete defect closure with significantly matured lamellar bone tissue in contrast with poor bone healing by cells without pretreatment. Cell-tracking analysis demonstrated direct bone deposition by transplanted cells pretreated with NAC. Pretreatment of osteoblast-like cells with NAC enhances bone regeneration in local transplantation by preventing oxidative stress-induced apoptosis and dysfunction at the transplanted site.}, }
@article {pmid31634424, year = {2020}, author = {Sundarraj, K and Raghunath, A and Panneerselvam, L and Perumal, E}, title = {Fisetin, a phytopolyphenol, targets apoptotic and necroptotic cell death in HepG2 cells.}, journal = {BioFactors (Oxford, England)}, volume = {46}, number = {1}, pages = {118-135}, doi = {10.1002/biof.1577}, pmid = {31634424}, issn = {1872-8081}, support = {SB/EMEQ-246/2014//Department of Science and Technology, Science and Engineering Board, New Delhi/ ; }, mesh = {Apoptosis/*drug effects ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Flavonoids/*pharmacology ; Flavonols ; Hep G2 Cells ; Humans ; Signal Transduction/drug effects ; }, abstract = {Fisetin (3,7,3',4'-tetrahydroxyflavone), a bioactive dietary flavonoid, intrigued scientists for its anticancer potential against various cancer types. We investigated the fisetin-induced inhibition of growth and survival of human hepatocellular carcinoma. Fisetin decreased cell viability and proliferation of HepG2 cells as revealed from MTT and clonogenicity assays. Cell cycle arrest in the G2/M phase was observed. Annexin V/propidium iodide (PI) staining followed by flow cytometry revealed that fisetin induced both apoptosis and necroptosis in HepG2 cells. Apoptotic cells were significantly increased on fisetin treatment as observed in morphological evaluations and 4',6-diamidino-2-phenylindole and Acridine orange staining. Flow cytometry, fluorescence imaging, and 2', 7'-dichlorofluorescein diacetate analyses showed an increase in reactive oxygen species (ROS) generation on fisetin treatment. Pretreatment with N-acetyl cysteine inhibited ROS production and also rescued mitochondrial membrane potential in HepG2 cells. The underlying mechanisms of apoptosis and necroptosis were determined by analysis of their respective signaling molecules using qRT-PCR and Western blotting. Fisetin showed a marked increase in the expression of TNFα and IKκB with a decrease in NF-κB, pNF-κB and pIKκB expression. Fisetin reduced the expression of Bcl2, and elevated levels of Bax, caspase-3, and PARP and thus induced apoptosis in HepG2 cells. zVAD suppressed the fisetin-induced expression of caspase-8, RIPK1, RIPK3, and MLKL as opposed to fisetin treatment. Nec-1 + fisetin could not completely block necroptosis, which warrants further investigation. Taken together, our findings demonstrate that the fisetin exhibited anti-proliferative effects on HepG2 cells through apoptosis and necroptosis via multiple signaling pathways. Fiestin has potential as a therapeutic agent against hepatocellular carcinoma.}, }
@article {pmid31632331, year = {2019}, author = {Dechandt, CRP and Ferrari, GD and Dos Santos, JR and de Oliveira, JAC and da Silva-Jr, RMP and Cunha, AOS and Garcia-Cairasco, N and Alberici, LC}, title = {Energy Metabolism and Redox State in Brains of Wistar Audiogenic Rats, a Genetic Model of Epilepsy.}, journal = {Frontiers in neurology}, volume = {10}, number = {}, pages = {1007}, pmid = {31632331}, issn = {1664-2295}, abstract = {The Wistar Audiogenic Rat (WAR) strain is a genetic model of epilepsy, specifically brainstem-dependent tonic-clonic seizures, triggered by acute auditory stimulation. Chronic audiogenic seizures (audiogenic kindling) mimic temporal lobe epilepsy, with significant participation of the hippocampus, amygdala, and cortex. The objective of the present study was to characterize the mitochondrial energy metabolism in hippocampus and cortex of WAR and verify its relationship with seizure severity. Hippocampus of WAR naïve (no seizures) presented higher oxygen consumption in respiratory states related to the maximum capacities of phosphorylation and electron transfer system, elevated mitochondrial density, lower GSH/GSSG and catalase activity, and higher protein carbonyl and lactate contents, compared with their Wistar counterparts. Audiogenic kindling had no adding functional effect in WAR, but in Wistar, it induced the same alterations observed in the audiogenic strain. In the cortex, WAR naïve presented elevated mitochondrial density, lower GSH/GSSG and catalase activity, and higher protein carbonyl levels. Chronic acoustic stimulation in Wistar induced the same alterations in cortex and hippocampus. Mainly in the hippocampus, WAR naïve presented elevated mRNA expression of glucose, lactate and excitatory amino acids transporters, several glycolytic enzymes, lactate dehydrogenase, and Na[+]/K[+] ATPase in neurons and in astrocytes. In vivo treatment with mitochondrial uncoupler 2,4-dinitrophenol (DNP) or N-acetylcysteine (NAC) in WAR had no effect on mitochondrial metabolism, but lowered oxidative stress. Unlike DNP, NAC downregulated all enzyme genes involved in glucose and lactate uptake, and metabolism in neurons and astrocytes. Additionally, it was able to reduce brainstem seizure severity in WAR. In conclusion, in WAR naïve animals, both cerebral cortex and hippocampus display elevated mitochondrial density and/or activity associated with oxidative damage, glucose and lactate metabolism pathways upregulation, and increased Na[+]/K[+] ATPase mRNA expression. Only in vivo treatment with NAC was able to reduce seizure severity of kindled WARs, possibly via down regulation of glucose/lactate metabolism. Taken together, our results are a clear contribution to the field of mitochondrial metabolism associated to epileptic seizures.}, }
@article {pmid31631367, year = {2020}, author = {Song, Q and Lin, L and Chen, L and Cheng, L and Zhong, W}, title = {Co-administration of N-acetylcysteine and dexmedetomidine plays a synergistic effect on protection of LPS-induced acute lung injury via correcting Th1/Th2/Th17 cytokines imbalance.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {47}, number = {2}, pages = {294-301}, doi = {10.1111/1440-1681.13196}, pmid = {31631367}, issn = {1440-1681}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Lung Injury/chemically induced/*metabolism/prevention &amp; control ; Adrenergic alpha-2 Receptor Agonists/administration &amp; dosage ; Animals ; Basic Helix-Loop-Helix Transcription Factors/antagonists &amp; inhibitors/metabolism ; Cytokines/antagonists &amp; inhibitors/metabolism ; Dexmedetomidine/*administration &amp; dosage ; Drug Synergism ; Drug Therapy, Combination ; Free Radical Scavengers/administration &amp; dosage ; Lipopolysaccharides/toxicity ; Male ; Mice ; Mice, Inbred C57BL ; Th1 Cells/drug effects/*metabolism ; Th17 Cells/drug effects/*metabolism ; Th2 Cells/drug effects/*metabolism ; }, abstract = {Recently both N-acetylcysteine (NAC) and Dexmedetomidine (DEX) have shown emerging roles in protection of acute lung injury (ALI). However, how their protective roles work and whether they can provide synergistic effects in ALI remain unknown. Here we explored it from the hot research viewpoint of Th1/Th2/Th17 cytokines balance. Lipopolysaccharide (LPS)-induced ALI was established and treated with NAC and/or DEX. Mice were divided into Sham group, ALI group, NAC group, DEX group and NAC+DEX group. Mice were sampled at 6, 12 and 24 hours after the model construction. Histopathology, wet to dry ratio and myeloperoxidase (MPO) activity were assessed in lung tissues. Protein concentration and cell count were assessed in bronchoalveolar lavage fluid (BALF). Th1/Th2/Th17 cytokines were assessed in plasma, BALF and lung homogenate. ALI-induced lung morphological damage, edema and aberrant MPO activity can be attenuated by NAC or DEX and mostly by NAC+DEX. NAC with DEX significantly reduced ALI-induced protein leakage and cell infiltration in BALF. Th1/Th2/Th17 cytokines imbalance aggravated with ALI progression. NAC, DEX and especially NAC+DEX can effectively correct these unbalanced cytokines. Galectin-9 and Tim-3 were transcriptionally up-regulated in ALI. Combination of NAC with DEX obtained a maximum effect on decreasing Galectin-9/Tim-3 expression. In summary, Th1/Th2/Th17 cytokines imbalance is newly found to participate in LPS-induced ALI. NAC or DEX administration can attenuate ALI by rebalancing Th1/Th2/Th17 cytokines. Their protective roles can be enhanced when co-administration, because DEX may relieve the Galectin-9/Tim-3 axis-mediated immune suppression.}, }
@article {pmid31629901, year = {2020}, author = {Wang, CM and Huo, X and Chen, J and Liu, JW and Yang, TY and Mi, XQ and Meng, Y and Zhou, L and Lin, CJ and Liu, J}, title = {An acute lytic cell death induced by xanthohumol obstructed ROS detecting in HL-60 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {62}, number = {}, pages = {104667}, doi = {10.1016/j.tiv.2019.104667}, pmid = {31629901}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Death/drug effects ; Flavonoids/*toxicity ; HL-60 Cells ; Humans ; Interleukin-1beta/metabolism ; L-Lactate Dehydrogenase/metabolism ; Propiophenones/*toxicity ; Reactive Oxygen Species/*metabolism ; Serum ; }, abstract = {Serum is an important component in cell culture medium. It also possesses potent antioxidant properties. Therefore, the conventional protocols for detecting reactive oxygen species (ROS) in cultured cells with fluorescent probes include washing and suspending cells with serum-free buffers, such as PBS. This transient serum deprivation is essential for the ROS detecting. Unfortunately, it may also cause unexpected results, which push us to choose more optimal experiment conditions. In the present study, we found an acute lytic cell death induced by xanthohumol (XN), which obstructed ROS detecting in human leukemia cell line HL-60 cells. XN induced ROS burst, caused cell swelling, membrane permeability increase, LDH release, and ultimately an acute lytic cell death and cell rupture. These effects could be alleviated by the antioxidant N-Acetyl-L-cysteine (NAC). Apoptosis, pyroptosis or necroptosis were not observed in this process. Results also indicated that 2% serum addition had already completely scavenged ROS induced by 10 μM XN. Taken together, it is strongly suggested to detecting ROS in a serum-free medium when studying where and how ROS generated in cells. The concentration at the ROS maximum point (10 μM XN in this study) can be selected as the optimal concentration.}, }
@article {pmid31627175, year = {2019}, author = {Uchihara, Y and Ohe, T and Mashino, T and Kidokoro, T and Tago, K and Tamura, H and Funakoshi-Tago, M}, title = {N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties.}, journal = {Pharmacological reports : PR}, volume = {71}, number = {6}, pages = {1067-1078}, doi = {10.1016/j.pharep.2019.05.021}, pmid = {31627175}, issn = {2299-5684}, mesh = {Acetylcysteine/*pharmacology ; Aminosalicylic Acids/chemistry/*pharmacology ; Anthraquinones/chemistry/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclic S-Oxides/chemistry/*pharmacology ; Humans ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/*metabolism ; Signal Transduction ; Sulfonamides/chemistry/*pharmacology ; }, abstract = {BACKGROUND: Inhibitors for signal transducer and activator of transcription 3 (STAT3), Stattic, BP-1-102, and LLL12 significantly induce apoptosis in transformed Ba/F3 cells expressing an oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that induces the activation of STAT3. We found that the antioxidant reagent, N-acetyl cysteine (NAC) prevented the abilities of Stattic and BP-1-102, but not LLL12 to induce apoptosis in transformed cells expressing NPM-ALK, providing a novel problem in use of STAT3 inhibitors. We herein investigated the mechanisms how NAC prevented the effects of Sttatic and BP-1-102.<br><br>METHODS: Ba/F3 cells expressing NPM-ALK and SUDHL-1 cells were treated with antioxidants such as NAC, Trolox or edaravone in combination with STAT3 inhibitors. Phosphorylation of STAT3, cell proliferation rate, cell viability, cell cycle, internucleosomal DNA fragmentation and the intracellular accumulation of reactive oxygen species (ROS) was investigated. The binding of STAT3 inhibitors and NAC was analyzed by LC-MS.<br><br>RESULTS: NAC but not Trolox and edaravone diminished the abilities of Stattic and BP-1-102 to induce apoptosis in cells expressing NPM-ALK. The ROS levels in cells expressing NPM-ALK were not markedly affected by the treatments with Stattic and BP-1-102 in combination with NAC, suggesting that NAC inhibited the activity of Stattic and BP-1-102 independent of its antioxidant activity. LC-MS analysis revealed that NAC directly bound to Stattic and BP-1-102. Furthermore, these NAC adducts exhibited no cytotoxicity, and failed to affect the activity of STAT3.<br><br>CONCLUSIONS: NAC antagonizes the activities of Stattic and BP-1-102, which inhibit STAT3 activation by interacting with cysteine residues in STAT3.}, }
@article {pmid31626537, year = {2019}, author = {Du, Z and Liu, J and Zhang, H and Wu, X and Zhang, B and Chen, Y and Liu, B and Ding, L and Xiao, H and Zhang, T}, title = {N-Acetyl-l-cysteine/l-Cysteine-Functionalized Chitosan-β-Lactoglobulin Self-Assembly Nanoparticles: A Promising Way for Oral Delivery of Hydrophilic and Hydrophobic Bioactive Compounds.}, journal = {Journal of agricultural and food chemistry}, volume = {67}, number = {45}, pages = {12511-12519}, doi = {10.1021/acs.jafc.9b05219}, pmid = {31626537}, issn = {1520-5118}, mesh = {Acetylcysteine/*chemistry ; Caco-2 Cells ; Chitosan/*chemistry ; Curcumin/*chemistry/metabolism ; Cysteine/*chemistry ; Drug Carriers/chemistry ; Drug Delivery Systems/*methods ; Humans ; Hydrophobic and Hydrophilic Interactions ; Lactoglobulins/*chemistry ; Molecular Docking Simulation ; Nanoparticles/chemistry ; Particle Size ; Peptides/chemistry ; }, abstract = {Self-assembled and cross-linked hybrid hydrogels for entrapment and delivery of hydrophilic and hydrophobic bioactive compounds were developed based on N-acetyl-l-cysteine (NAC)- or l-cysteine (CYS)-functionalized chitosan-β-lactoglobulin nanoparticles (NPs). In both the systems, amphiphilic protein β-lactoglobulin (β-lg) was self-assembled by using glutaraldehyde for affinity binding with egg white-derived peptides (EWDP) and curcumin and then coated with NAC- or CYS-functionalized chitosan (CS) by electrostatic interaction. The resulting NPs were characterized in terms of size, polydispersity, and surface charge by dynamic light scattering. Results corroborated pH-sensitive properties of NAC-CS-β-lg NPs and CYS-CS-β-lg NPs with the particle size as small as 118 and 48 nm, respectively. The two kinds of NPs also showed excellent entrapment of EWDP and curcumin with the entrapment efficiency (EE) of EWDP and curcumin ranging from 51 to 89% and 42 to 57% in NAC-CS-β-lg NPs, as well as 50-81% and 41-57% in CYS-CS-β-lg NPs under different pH values. Fourier transform infrared and molecular docking studies provided support for the interaction mechanism of NAC/CYS-CS with β-lg as well as the NPs with EWDP and curcumin. Strikingly, the in vitro release kinetics of EWDP and curcumin exhibited the controlled and sustained release properties up to 58 and 70 h from the NPs, respectively. Note that the permeability of QIGLF (pentapeptide, isolated from EWDP) and curcumin passing through Caco-2 cell monolayers were all improved after the entrapment in the NPs. This work offers promising methods for effective entrapment and oral delivery of both hydrophilic and hydrophobic bioactive compounds.}, }
@article {pmid31623295, year = {2019}, author = {Mezzetta, A and Poderelli, L and D'Andrea, F and Pomelli, CS and Chiappe, C and Guazzelli, L}, title = {Unexpected Intrinsic Lability of Thiol-Functionalized Carboxylate Imidazolium Ionic Liquids.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {19}, pages = {}, pmid = {31623295}, issn = {1420-3049}, mesh = {Carboxylic Acids/*chemistry ; Density Functional Theory ; Imidazoles/*chemistry ; Ionic Liquids/*chemistry ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Structure ; Oxidation-Reduction ; Sulfhydryl Compounds/*chemistry ; }, abstract = {New thiol-functionalized carboxylate ionic liquids (ILs), varying both for the cation and for the anion structures, have been prepared as new potential redox switching systems by reacting either 3-mercapto propionic acid (3-MPA) or N-acetyl-cysteine (NAC) with commercially available methyl carbonate ILs. Different ratios of thiol/disulfide ILs were obtained depending both on the acid employed in the neutralization reaction and on the reaction conditions used. Surprisingly, the imidazolium ILs displayed limited thermal stability which resulted in the formation of an imidazole 2-thione and a new sulfide ionic liquid. Conversely, the formation of the imidazole 2-thione was not observed when phosphonium disulfide ILs were heated, thus confirming the involvement of the imidazolium ring in an unexpected side reaction. An insight into the mechanism of the decomposition has been provided by means of DFT calculations.}, }
@article {pmid31622892, year = {2020}, author = {Albano, GD and Moscato, M and Montalbano, AM and Anzalone, G and Gagliardo, R and Bonanno, A and Giacomazza, D and Barone, R and Drago, G and Cibella, F and Profita, M}, title = {Can PBDEs affect the pathophysiologic complex of epithelium in lung diseases?.}, journal = {Chemosphere}, volume = {241}, number = {}, pages = {125087}, doi = {10.1016/j.chemosphere.2019.125087}, pmid = {31622892}, issn = {1879-1298}, mesh = {A549 Cells ; Aged ; Bronchi/*cytology ; Electric Impedance ; Epithelial Cells/drug effects ; Flame Retardants/toxicity ; Halogenated Diphenyl Ethers/*toxicity ; Humans ; Interleukin-8/genetics/metabolism ; Lung Diseases/*chemically induced/physiopathology ; Mucin 5AC/genetics/metabolism ; Mucin-5B/genetics/metabolism ; NADPH Oxidase 4/genetics/metabolism ; Oxidative Stress/drug effects ; Tight Junctions/drug effects/physiology ; }, abstract = {Brominated flame-retardant (BFRs) exposure promotes multiple adverse health outcomes involved in oxidative stress, inflammation, and tissues damage. We investigated BFR effects, known as polybrominated diphenyl ethers (PBDEs) (47, 99 and 209) in an air-liquid-interface (ALI) airway tissue derived from A549 cell line, and compared with ALI culture of primary human bronchial epithelial cells (pHBEC). The cells, exposed to PBDEs (47, 99 and 209) (0.01-1 μM) for 24 h, were studied for IL-8, Muc5AC and Muc5B (mRNAs and proteins) production, as well as NOX-4 (mRNA) expression. Furthermore, we evaluated tight junction (TJ) integrity by Trans-Epithelial Electrical Resistance (TEER) measurements, and zonula occludens-1 (ZO-1) expression in the cells, and pH variations and rheological properties (elastic G', and viscous G″, moduli) in apical washes of ALI cultures. N-acetylcysteine (NAC) (10 mM) effects were tested in our experimental model of A549 cells. PBDEs (47, 99 and 209) exposure decreased TEER, ZO-1 and pH values, and increased IL-8, Muc5AC, Muc5B (mRNAs and proteins), NOX-4 (mRNA), and rheological parameters (G', G″) in ALI cultures of A549 cell line and pHBEC. NAC inhibited PBDE effects in A549 cells. PBDE inhalation might impairs human health of the lungs inducing oxidative stress, inflammatory response, loss of barrier integrity, unchecked mucus production, as well as altered physicochemical and biological properties of the fluids in airway epithelium. The treatment with anti-oxidants restored the negative effects of PBDEs in epithelial cells.}, }
@article {pmid31622878, year = {2019}, author = {Zhang, Y and Ma, Y and Liang, N and Liang, Y and Lu, C and Xiao, F}, title = {Blockage of ROS-ERK-DLP1 signaling and mitochondrial fission alleviates Cr(VI)-induced mitochondrial dysfunction in L02 hepatocytes.}, journal = {Ecotoxicology and environmental safety}, volume = {186}, number = {}, pages = {109749}, doi = {10.1016/j.ecoenv.2019.109749}, pmid = {31622878}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Carcinogens, Environmental ; Chromium/*toxicity ; Dynamins/metabolism/*pharmacology ; Flavonoids/pharmacology ; Hepatocytes/drug effects/physiology ; Humans ; Liver/cytology/*drug effects/metabolism/physiopathology ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/physiology ; Mitochondrial Dynamics/drug effects ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Hexavalent chromium [Cr(VI)] is a common heavy metal pollutant widely used in various industrial fields. It is well known that mitochondria are the most vulnerable targets of heavy metals, but the key molecule/event that directly mediated mitochondrial dysfunction after Cr(VI) exposure is still unclear. The present study was aimed to explore whether Cr(VI) exposure could affect the mitochondrial fission/fusion process, and whether the related abnormal mitochondrial dynamics have been implicated in Cr(VI)-induced mitochondrial dysfunction. We found that the mitochondrial dysfunction caused by Cr(VI) exposure was characterized by decreased mitochondrial respiratory chain complex (MRCC) I/II activities and levels, collapsed mitochondrial membrane potential (MMP), depleted ATP, and increased reactive oxygen species (ROS) level. Cr(VI) induced abnormal mitochondrial fission/fusion events, the antioxidant Nacetyl-L-cysteine (NAC) restored the abnormal mitochondrial function as well as the fission/fusion dynamics. ROS was the up-stream regulator of extracellular regulated protein kinases (ERK) signaling, and the application of a specific ERK1/2 inhibitor PD98059 confirmed that activation of ERK1/2 signaling was associated with the abnormal mitochondrial fission/fusion and mitochondrial dysfunction. We also demonstrated that treatment with dynamic-like protein 1 (DLP1)-siRNA rescued mitochondrial dysfunction in Cr(VI)-exposed L02 hepatocytes. We reached the conclusion that blockage of ROS-ERK-DLP1 signaling and mitochondrial fission alleviates Cr(VI)-induced mitochondrial dysfunction in L02 hepatocytes, which may provide the new avenue for developing effective strategies to protect against Cr(VI)-induced hepatotoxicity.}, }
@article {pmid31622021, year = {2019}, author = {Zhao, Q and Yang, H and Liu, F and Luo, J and Zhao, Q and Li, X and Yang, Y}, title = {Naringenin Exerts Cardiovascular Protective Effect in a Palmitate-Induced Human Umbilical Vein Endothelial Cell Injury Model via Autophagy Flux Improvement.}, journal = {Molecular nutrition &amp; food research}, volume = {63}, number = {24}, pages = {e1900601}, doi = {10.1002/mnfr.201900601}, pmid = {31622021}, issn = {1613-4133}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects/physiology ; Cardiotonic Agents/*pharmacology ; Chloroquine/pharmacology ; Endothelium, Vascular/drug effects/pathology ; Flavanones/*pharmacology ; Human Umbilical Vein Endothelial Cells ; Humans ; Imidazoles/pharmacology ; MAP Kinase Signaling System/drug effects ; Nitric Oxide/metabolism ; Palmitates/*toxicity ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {SCOPE: Palmitic acid (PA) contributes to the pathogenesis of cardiovascular disease by promoting endothelial dysfunction, while naringenin, most abundant in oranges, has been shown to exert multiple beneficial effects on the human cardiovascular system. This study explores whether naringenin prevents PA-induced apoptosis in human umbilical vein endothelial cells (HUVECs).<br><br>METHODS AND RESULTS: Treatment of PA for at least 24 h causes observable decrease in levels of cell viability, oxidative stress, disorder of autophagy flux, and apoptosis in HUVECs. Naringenin enhances the viability of the PA-treated HUVECs and, additionally, effectively decreases oxidative stress by scavenging ROS, and increasing the SOD2 level and GPx activity. Autophagy flux is protected by naringenin, as evidenced by the decreases in the ratio of LC3B-II/I, expression level of p62 and number of autophagosomes, and the increase in the number of autolysosomes in the PA-induced HUVECs. These effects are confirmed by the oxidative stress inhibitor N-acetyl-cysteine and autophagy inhibitor chloroquine. The molecular data indicate that the protective effects of naringenin on autophagy flux may also be regulated via the JNK pathway, as verified via the application of JNK inhibitor SP600125.<br><br>CONCLUSION: These findings provide a possible mechanism by which naringenin prevents endothelial dysfunction and cardiovascular diseases.}, }
@article {pmid31617221, year = {2020}, author = {Lu, Z and Zhou, H and Zhang, S and Dai, W and Zhang, Y and Hong, L and Chen, F and Cao, J}, title = {Activation of reactive oxygen species-mediated mitogen-activated protein kinases pathway regulates both extrinsic and intrinsic apoptosis induced by arctigenin in Hep G2.}, journal = {The Journal of pharmacy and pharmacology}, volume = {72}, number = {1}, pages = {29-43}, doi = {10.1111/jphp.13180}, pmid = {31617221}, issn = {2042-7158}, support = {31602105//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Carcinoma, Hepatocellular/*drug therapy/enzymology/pathology ; Enzyme Activation ; Furans/*pharmacology ; Hep G2 Cells ; Humans ; Lignans/*pharmacology ; Liver Neoplasms/*drug therapy/enzymology/pathology ; Mice, Inbred BALB C ; Mice, Nude ; Mitogen-Activated Protein Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {OBJECTIVES: Arctigenin (ARG) has been proved to inhibit the viability of hepatocellular carcinoma (HCC) via inducing apoptosis. However, the precise mechanism remains unknown. The present study was aimed to further investigate the mechanism of ARG against HCC in vitro and in vivo.<br><br>METHODS: Arctigenin was applied in vitro and in vivo. Western blotting, immunohistochemistry, etc., were used to investigate the mechanisms.<br><br>KEY FINDINGS: The time-dependent enhancement of Bax/Bcl-2 ratio, cytochrome c release, Fas and FasL levels, caspase cascade activation and the loss in the mitochondrial out membrane potential indicated that both intrinsic and extrinsic apoptotic pathways were triggered by ARG. Moreover, Jun NH2-terminal kinase (JNK) and p38 phosphorylated time-dependently. And inhibition of the phosphorylation of either p38 or JNK led to a significant reduction in HepG2 apoptosis, owing to the crucial roles of p38 and JNK played in regulating the apoptosis pathways. In addition, ARG increased the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N-acetyl cysteine almost reversed ARG-induced JNK and p38 activation, and dramatically decreased cell apoptosis. In vivo, ARG increased the cell apoptosis in tumour tissues, and p-p38, p-JNK and Bax were significantly upregulated.<br><br>CONCLUSIONS: Our findings demonstrated that ARG induced apoptosis in HCC via ROS-mediated mitogen-activated protein kinases apoptosis pathway.}, }
@article {pmid31617161, year = {2020}, author = {Zheng, Z and Luo, G and Shi, X and Long, Y and Shen, W and Li, Z and Zhang, X}, title = {The Xc[-] inhibitor sulfasalazine improves the anti-cancer effect of pharmacological vitamin C in prostate cancer cells via a glutathione-dependent mechanism.}, journal = {Cellular oncology (Dordrecht)}, volume = {43}, number = {1}, pages = {95-106}, pmid = {31617161}, issn = {2211-3436}, support = {2017B020210001//Science and Technology Planning Project of Guangdong Province grant/ ; 201607010353//Science and Technology Program of Guangzhou grant/ ; 17ykjc10//Training program of the Major Research Plan of Sun Yat-Sen University grant/ ; 2016B030307003//cience and Technology Planning Project of Guangdong Province/ ; 2017B020210001//Science and Technology Planning Project of Guangdong Province/ ; 81501509//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/pharmacology ; Amino Acid Transport System y+/antagonists &amp; inhibitors ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Ascorbic Acid/metabolism/pharmacology/*therapeutic use ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Synergism ; Glutathione/*metabolism ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Prostatic Neoplasms/*drug therapy/enzymology/metabolism ; Reactive Oxygen Species/metabolism ; Sulfasalazine/pharmacology/*therapeutic use ; Transplantation, Heterologous ; }, abstract = {PURPOSE: Traditional treatment regimens for advanced prostate cancer, especially castration-resistant prostate cancer, result in low survival times with severe side effects. Therefore, new treatment options are required. Vitamin C (VC) has been identified as a promising anti-cancer agent of which the effects depend on the accumulation of H2O2 that is produced through autoxidation. Sulfasalazine (SAS), a cystine transporter (Xc[-]) inhibitor, is known to suppress cellular glutathione (GSH) biosynthesis. Here, we hypothesized that targeting the Xc[-] transporter via SAS may improve the anti-cancer activity of VC through regulating GSH biosynthesis, which in turn may result in the accumulation of reactive oxygen species (ROS).<br><br>METHODS: The anti-cancer effect of VC and/or SAS on prostate cancer cells was assessed using WST-8, colony formation and annexin V-FITC/PI FACS assays. Changes in cellular ROS and GSH levels were determined to verify our hypothesis. Finally, BALB/c nude mice bearing prostate cancer xenografts were used to assess the anti-cancer effects of single or combined VC and SAS therapies.<br><br>RESULTS: We found that SAS could potentiate the short- and long-term cytotoxicity of VC in prostate cancer cells. We also found that the synergistic effect of SAS and VC led to significant cellular GSH depletion, resulting in increased ROS accumulation. This synergistic effect could be reversed by the antioxidant N-acetyl-L-cysteine (NAC). The synergistic effect of SAS and VC was also noted in prostate cancer xenografts and correlated with immunohistochemistry results.<br><br>CONCLUSIONS: Our results strongly indicate that SAS, a relatively non-toxic drug that targets cystine transporters, in combination with VC may be superior to their single applications in the treatment of prostate cancer.}, }
@article {pmid31614178, year = {2019}, author = {Raut, GK and Chakrabarti, M and Pamarthy, D and Bhadra, MP}, title = {Glucose starvation-induced oxidative stress causes mitochondrial dysfunction and apoptosis via Prohibitin 1 upregulation in human breast cancer cells.}, journal = {Free radical biology &amp; medicine}, volume = {145}, number = {}, pages = {428-441}, doi = {10.1016/j.freeradbiomed.2019.09.020}, pmid = {31614178}, issn = {1873-4596}, mesh = {Animals ; Apoptosis/genetics ; Breast Neoplasms/etiology/*genetics/metabolism/pathology ; Cell Survival/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Glucose/*metabolism/pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/genetics/metabolism/pathology ; Oxidative Stress/*genetics ; Prohibitins ; Reactive Oxygen Species/metabolism ; Repressor Proteins/*genetics ; Starvation/complications ; Xenograft Model Antitumor Assays ; }, abstract = {In recent years there has been an upsurge in research focusing on reprogramming cancer cells through understanding of their metabolic signatures. Alterations in mitochondrial bioenergetics and impaired mitochondrial function may serve as effective targeting strategies especially in triple-negative breast cancers (TNBCs) where hormone receptors and endocrine therapy are absent. Glucose starvation (GS) of MDA-MB-231 and MCF-7 breast cancer cells showed decrease in mitochondrial Oxygen Consumption Rate (OCR), which was rescuable to control level through addition of exogenous antioxidant N-Acetyl Cysteine (NAC). Mechanistically, GS led to increase in mitochondrial ROS and upregulation of the pleiotropic protein, Prohibitin 1 (PHB1), leading to its dissociation from Dynamin-related protein 1 (DRP1), perturbance of mitochondrial membrane potential (MMP) and triggering of the apoptosis cascade. PHB1 also reduced the invasive and migratory potential of both cell lines. We emphasize that glucose starvation remarkably sensitized the highly glycolytic metastatic TNBC cell line, MDA-MB-231 to apoptosis and decreased its migratory potential. Based on our findings, additional TNBC cell lines can be evaluated and a nutritional paradigm be proposed for anticancer therapy.}, }
@article {pmid31611741, year = {2019}, author = {Afshari, AR and Jalili-Nik, M and Soukhtanloo, M and Ghorbani, A and Sadeghnia, HR and Mollazadeh, H and Karimi Roshan, M and Rahmani, F and Sabri, H and Vahedi, MM and Mousavi, SH}, title = {Auraptene-induced cytotoxicity mechanisms in human malignant glioblastoma (U87) cells: role of reactive oxygen species (ROS).}, journal = {EXCLI journal}, volume = {18}, number = {}, pages = {576-590}, pmid = {31611741}, issn = {1611-2156}, abstract = {Glioblastoma multiforme (GBM), like the devastating type of astrocytic tumors, is one of the most challenging cancers to treat owing to its aggressive nature. Auraptene, as a prenyloxy coumarin from citrus species, represents antioxidant and antitumor activities; however, the underlying antitumor mechanisms of auraptene against GBM remain unclear. The present study aimed to evaluate the cytotoxic and apoptogenic effects of auraptene, as a promising natural product, and the possible signaling pathways affected in human malignant GBM (U87) cells. Reactive oxygen species (ROS) production significantly decreased in the first 2, and 6 hours after treatment with auraptene however, ROS levels increased in other incubation times (8 and 24 hours), dramatically. N-acetyl-cysteine (NAC) markedly attenuated auraptene-induced ROS production, and consequently reversed auraptene-induced cytotoxicity in 8 and 24 hours after treatment, as well. Induction of apoptosis occurred in the first 24- and 48-hours concentration-dependently. The qRT-PCR showed an up-regulation in p21, CXCL3, and a down-regulation in Cyclin D1 genes expression. Western blot analysis confirmed the up-regulation of the Bax/Bcl-2 ratio protein levels concentration-dependently. Hence, this study collectively revealed that the increase in ROS level is at least one of the mechanisms associated with auraptene-induced GBM cell toxicity as well as the induction of apoptosis through Bax/Bcl-2 modulation and genes expression involved that contribute to the cytotoxicity of auraptene in U87 cells. So, auraptene might be utilized as a potential novel anti-GBM agent after further studies.}, }
@article {pmid31610888, year = {2019}, author = {Camargo, CHR and Gomes, LCL and França, MCM and Bittencourt, TS and Valera, MC and Camargo, SEA and Bottino, MC}, title = {Incorporating N-acetylcysteine and tricalcium phosphate into epoxy resin-based sealer improved its biocompatibility and adhesiveness to radicular dentine.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {35}, number = {12}, pages = {1750-1756}, doi = {10.1016/j.dental.2019.09.001}, pmid = {31610888}, issn = {1879-0097}, mesh = {Acetylcysteine ; Adhesiveness ; Calcium Phosphates ; *Dental Bonding ; Dental Pulp Cavity ; Dentin ; Epoxy Resins ; Humans ; Materials Testing ; *Root Canal Filling Materials ; }, abstract = {OBJECTIVE: This in vitro study was designed to evaluate the biocompatibility, adhesiveness, and antimicrobial activity of epoxy resin-based sealer associated with N-Acetylcysteine (NAC) or beta-tricalcium phosphate nanoparticles (β-TCP) as an experimental retro-filling material.<br><br>METHODS: Cytotoxicity was assessed using 2,3-Bis-(Methoxy-4-Nitro-5-Sulphophenyl)-2H-Tetrazolium-5-Carboxanilide (XTT) and Sulforhodamine B (SRB) assays after exposing human periodontal ligament fibroblasts to extracts of the materials for 1, 3, or 7 days. For the adhesive resistance test, root canals (48 single-root teeth) were instrumented with Reciproc #40 files (VDW GmbH, Germany) and obturated. After 7 days, the apices were sectioned and a retrograde cavity prepared and filled with the experimental materials (Mineral trioxide aggregate, Epoxy sealer, Epoxy sealer+NAC, and Epoxy sealer+&#x3b2;-TCP). For the push-out test, one 2-mm thick slice was obtained from the apical third of each specimen. Antimicrobial activity was performed using agar diffusion method. Biofilms were grown in microplates and exposed to the extracts of retro-filled materials, followed by analysis of growth inhibition on agar plates.<br><br>RESULTS: Epoxy sealer in association with &#x3b2;-TCP or NAC showed better bond strength while Mineral trioxide aggregate allowed for the lowest adhesion. Mineral trioxide aggregate, Epoxy sealer+&#x3b2;-TCP, and Epoxy sealer+NAC showed low cytotoxicity. Epoxy sealer was the most cytotoxic. In antimicrobial activity assays, all materials had no effect on Candida albicans. Addition of NAC improved the antimicrobial property of Epoxy sealer against Enterococcus faecalis compared to unmodified Epoxy sealer (P<0.05).<br><br>SIGNIFICANCE: Incorporating &#x3b2;-TCP or NAC with Epoxy sealer could improve the adhesiveness and biocompatibility for better use in endodontic therapy.}, }
@article {pmid31610661, year = {2019}, author = {Datta, S and Das, A and Chowdhury, AR and Datta, P}, title = {Bioink formulations to ameliorate bioprinting-induced loss of cellular viability.}, journal = {Biointerphases}, volume = {14}, number = {5}, pages = {051006}, doi = {10.1116/1.5111392}, pmid = {31610661}, issn = {1559-4106}, mesh = {Alginates/*chemistry ; Animals ; *Bioprinting ; Cell Line ; Cell Survival ; Mice ; Tissue Scaffolds/*chemistry ; }, abstract = {Extrusion bioprinting, the most affordable and convenient bioprinting modality, is also associated with high process-induced cell deaths. Mechanical stresses on the cells during pneumatic or piston extrusion generate excessive reactive oxygen species and activate apoptosis, inflammatory pathways in the cells. In this study, a bioink formulation is augmented with an antioxidant, N-acetyl cysteine (NAC) as a possible solution to abrogate the effect of bioprinting-associated cell survival losses. The NAC addition to bioinks did not affect the bioprinting process, shape fidelity, or the mechanical properties of the constructs to any large extent. However, the bioprinting process conducted at 0.30 MPa pressure and 410 μm nozzle inner diameter with bioinks of 3% w/v alginate, 10[5] cells/ml resulted in survival losses of up to 25% for MC3T3 cells. In contrast, NAC bioinks showed a significant (p < 0.01) improvement in day 1 cell survival (91%), while the enhancement in day 3 cell viability was still greater. It was further observed that the reactive oxygen species (ROS) load of bioprinted constructs was approximately 1.4 times higher compared to control, whereas NAC containing constructs reduced the ROS load at levels comparable to control samples. The effect on apoptosis and inflammation markers showed that NAC had a greater role in modulating apoptosis. It is concluded that the presented approach to preserve cell viability and functionality would be advantageous over other contemporary methods (like alterations in extrusion pressure, nozzle diameter, polymer concentration, etc.) as viability can be preserved without compromising the fabrication time or the resolution/mechanical properties of the constructs with this bioink formulation approach.}, }
@article {pmid31606392, year = {2019}, author = {Xin, R and Pan, YL and Wang, Y and Wang, SY and Wang, R and Xia, B and Qin, RN and Fu, Y and Wu, YH}, title = {Nickel-refining fumes induce NLRP3 activation dependent on mitochondrial damage and ROS production in Beas-2B cells.}, journal = {Archives of biochemistry and biophysics}, volume = {676}, number = {}, pages = {108148}, doi = {10.1016/j.abb.2019.108148}, pmid = {31606392}, issn = {1096-0384}, mesh = {Cell Line ; Cytokines/metabolism ; Dose-Response Relationship, Drug ; Humans ; Mitochondria/*drug effects/metabolism/*pathology ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Nickel/chemistry/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Nickel (Ni) is a silver-white transition metal that is widely used in the production field due to its unique physical and chemical properties. As a toxicant, long-term exposure to Ni can cause rhinitis, pneumonia and other respiratory inflammation. In the present study, we investigated the effect of particles extracted from Ni-refining fumes on cell viability, inflammation-related proteins and mitochondrial damage in human lung epithelial Beas-2B cells. The cells were exposed to Ni-refining fume particles for 24 h at concentrations of 0, 6.25, 12.50 and 25.00 μg/mL. The expression levels of the NACHT-LRR-PYD domains-containing protein 3 (NLRP3), caspase-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin (IL)-1β and tumor necrosis factor (TNF)-α protein in Beas-2B cells exposed to Ni-refining fume particles increased significantly. Downregulation of NLRP3 expression by siRNA decreased the content of IL-1β. During activation of NLRP3, the mitochondrial membrane potential (MMP) decreased, the opening rate of mitochondrial permeability transition pore (MPTP) increased, and the content of reactive oxygen species (ROS) increased. Using lipopolysaccharide (LPS) intervention as the positive control group, N-acetylcysteine (NAC, an effective ROS remover) acted as an inhibitor. After NAC reduced the level of ROS, activation of the NLRP3 inflammasome was significantly inhibited. Ni-refining fumes caused significant cytotoxicity, inflammation and mitochondrial damage in Beas-2B cells. The present study thus provides experimental support for the hypothesis that Ni-refining fumes cause inflammation by inducing ROS production in Beas-2B cells.}, }
@article {pmid31602264, year = {2019}, author = {Ma, Q and Meng, XY and Wu, KR and Cao, JZ and Yu, R and Yan, ZJ}, title = {Sinularin exerts anti-tumor effects against human renal cancer cells relies on the generation of ROS.}, journal = {Journal of Cancer}, volume = {10}, number = {21}, pages = {5114-5123}, pmid = {31602264}, issn = {1837-9664}, abstract = {Sinularin, a soft corals-derived natural product, exerts anti-tumorigenic activity in various types of human cancer cells. However, the action of Sinularin and its mechanism in renal carcinoma is not well understood. In the current study, we demonstrated that Sinularin inhibited the viability of human renal cancer cells 786-O and ACHN in a dose- and time-dependent manner, but did not show significant toxicity against non-malignant HRCEpic cells. Cell cycle analysis revealed that Sinularin induced G2/M arrest significantly. In addition, Sinularin could induce apoptosis in cells along with caspase-3/-9 activation, release of mitochondrial proteins, up-regulation of pro-apoptotic Bcl-2 family proteins and inhibition of anti-apoptotic Bcl-2 family proteins. Sinularin could also repress the activation of PI3K/Akt/mTOR signaling pathway. Moreover, Sinularin triggered the activation of MAPKs and p38 activation was essential for the anti-tumor effect of Sinularin. The generation of ROS (reactive oxygen species) was critical for Sinularin-induced apoptosis since ROS scavenger NAC (N-acetyl cysteine) could block the Sinularin-triggered apoptosis. In conclusion, all the results indicated that Sinularin may be applied as a therapeutic natural agent for human renal cancer.}, }
@article {pmid31601129, year = {2020}, author = {Daoud, A and Dalhoff, KP and Christensen, MB and Bøgevig, S and Petersen, TS}, title = {Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {58}, number = {7}, pages = {698-704}, doi = {10.1080/15563650.2019.1675886}, pmid = {31601129}, issn = {1556-9519}, mesh = {Acetaminophen/pharmacokinetics/*poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects ; Administration, Intravenous ; Adolescent ; Adult ; Analgesics, Non-Narcotic/pharmacokinetics/poisoning ; Anaphylaxis/chemically induced/*prevention &amp; control ; Antidotes/administration &amp; dosage/*adverse effects ; Child ; Cohort Studies ; Drug Overdose/drug therapy ; Female ; Histamine Antagonists/*administration &amp; dosage ; Humans ; Incidence ; Male ; Middle Aged ; Retrospective Studies ; Young Adult ; }, abstract = {Context:N-acetylcysteine (NAC) is used worldwide to prevent liver injury after paracetamol overdoses. Anaphylactoid reactions to NAC occur frequently and often lead to treatment interruptions or discontinuations. In Denmark in 2013, the NAC treatment regimen was simplified from a three-bag to a two-bag NAC regimen. Factors of importance for the development of anaphylactoid reaction to this new regimen are poorly explored. Previous studies have suggested a protective effect of high plasma levels of paracetamol on the development of anaphylactoid reactions. Likewise, exposure to antihistamines prior to NAC treatment may protect against these reactions.Methods: This is a retrospective cohort study of patients treated with NAC and with at least one plasma paracetamol sample performed in the Capital Region of Denmark from 2010 to 2017. The primary outcome was the incidence of anaphylactoid reactions to NAC requiring intravenous treatment with antihistamines and/or glucocorticoids. Logistic regression analyses were carried out to identify the risk of developing an anaphylactoid reaction to NAC affected by influencing factors.Results: Of 4315 admissions included in the study, 259 (6.0%) developed an anaphylactoid reaction to NAC. The two-bag regimen (adjusted OR 0.44 [95%CI: 0.32-0.60]), increasing age (adjusted OR 0.84 [95%CI: 0.78-0.90] per 10-year increase) or children <10 years (adjusted OR 0.14 [95%CI: 0.04-0.36]) and antihistamine co-ingestion in overdose (adjusted OR 0.17 [95%CI: 0.02-0.64]) were associated with significantly fewer anaphylactoid reactions. High plasma paracetamol concentrations protected against development of anaphylactoid reactions during the two-bag regimen (adjusted OR 0.59 [95%CI: 0.47-0.71] and three-bag regimen 0.82 [95%CI: 0.72-0.94] per doubling of paracetamol concentration). The effect differed between the two regimens (p = .004 for interaction).Conclusion: In this retrospective cohort, a high peak plasma paracetamol concentration, age, antihistamine co-ingestion and use of the two-bag NAC regimen were associated with fewer anaphylactoid reactions to NAC.}, }
@article {pmid31598901, year = {2019}, author = {Wei, J and Pang, CS and Han, J and Yan, H}, title = {Effect of Orally Administered N-Acetylcysteine on Chronic Bronchitis: A Meta-analysis.}, journal = {Advances in therapy}, volume = {36}, number = {12}, pages = {3356-3367}, doi = {10.1007/s12325-019-01111-4}, pmid = {31598901}, issn = {1865-8652}, support = {2015SZ0111//Sichuan Province Science and Technology Support Program/International ; }, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Bronchitis, Chronic/*drug therapy ; Chronic Disease ; Dose-Response Relationship, Drug ; Double-Blind Method ; Humans ; Randomized Controlled Trials as Topic ; Risk ; }, abstract = {INTRODUCTION: The effect of N-acetylcysteine (NAC) treatment for patients with chronic bronchitis (CB) is controversial. To better understand the role of NAC in CB treatment, we performed a meta-analysis to provide a more accurate estimation of the importance of NAC treatment.<br><br>METHODS: PubMed, Embase, and CNKI were systematically searched. The pooled relative risk (RR) and 95% confidence intervals (CI) were calculated using either fixed-effect model or random-effect model based on heterogeneity examination. Statistical analyses were performed using the STATA 12.0 and RevMan 5.2.<br><br>RESULTS: A total of 11 publications with 775 patients who were taking NAC and 789 controls who were taking placebo were judged eligible regarding inclusion criteria. The pooled analysis demonstrated significant evidence that NAC reduced the frequency of CB exacerbations (RR&#x2009;=&#x2009;0.81, 95% CI 0.69-0.93, P&#x2009;=&#x2009;0.004). Patients treated with NAC had significant symptom improvement compared with controls (RR&#x2009;=&#x2009;1.68, 95% CI 1.13-2.52, P&#x2009;=&#x2009;0.01). NAC did not significantly increase the risk of adverse effects compared with placebo (RR 0.86, 95% CI 0.67-1.09, P&#x2009;=&#x2009;0.22). Subgroup analysis was carried out to assess the stability of results. No publication bias was detected during analyses.<br><br>CONCLUSION: There is a role for NAC treatment in the management of CB by reducing symptoms and exacerbations compared with placebo, without increasing the risk of adverse effects. A regular treatment of low dosage (<&#x2009;1200&#xa0;mg per day) and a duration of at least 3&#xa0;months seems to be effective.}, }
@article {pmid31598736, year = {2019}, author = {Mills, KA and Chess-Williams, R and McDermott, C}, title = {Novel insights into the mechanism of cyclophosphamide-induced bladder toxicity: chloroacetaldehyde's contribution to urothelial dysfunction in vitro.}, journal = {Archives of toxicology}, volume = {93}, number = {11}, pages = {3291-3303}, doi = {10.1007/s00204-019-02589-1}, pmid = {31598736}, issn = {1432-0738}, support = {1032032//Cancer Council Queensland/International ; }, mesh = {Acetaldehyde/*analogs &amp; derivatives/metabolism/toxicity ; Acrolein/metabolism/*toxicity ; Antineoplastic Agents, Alkylating/metabolism/*toxicity ; Cell Culture Techniques ; Cell Line ; Cell Survival/drug effects ; Cyclophosphamide/metabolism/*toxicity ; Epithelial Cells/*drug effects/metabolism/pathology ; Humans ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Urinary Bladder/*drug effects/metabolism/pathology ; Urothelium/*drug effects/metabolism/pathology ; }, abstract = {The clinical use of cyclophosphamide and ifosfamide is limited by a resultant bladder toxicity which has been attributed to the metabolite acrolein. Another metabolite chloroacetaldehyde (CAA) associated with nephrotoxicity, has not been investigated for toxicity in the bladder and this study investigates the effects of acrolein and CAA on human urothelial cells in vitro. Human urothelial cells (RT4 and T24) were treated with acrolein or CAA and changes in cell viability, reactive oxygen species, caspase-3 activity and release of urothelial mediators ATP, acetylcholine, PGE2 were measured. The protective effects of N-acetyl cysteine (NAC) were also assessed. Both metabolites were toxic to human urothelial cells, however, CAA significantly decreased cell viability at a ten-fold lower concentration (10 µM) than acrolein (100 µM). This was associated with increased ROS production and caspase-3 activity. NAC protected cells from these changes. In RT4 cells 100 µM acrolein caused a significant increase in basal and stretch-induced ATP, Ach and PGE2 release. In T24 cells chloroacetaldehyde (10 µM) increased basal and stimulated ATP and PGE2 levels. Again, NAC protected against changes in urothelial mediator release following acrolein or CAA. This study is the first to report that CAA in addition to acrolein contributes to the urotoxicity of cyclophosphamide and ifosfamide. Both metabolites altered urothelial mediator levels which could contribute to the sensory and functional bladder changes experienced by patients after treatment with cyclophosphamide or ifosfamide. Alterations in urothelial cell viability and mediator release may be causally linked to oxidative stress, with NAC providing protection against these changes.}, }
@article {pmid31594390, year = {2020}, author = {Petronilho, F and Tenfen, L and Della Giustina, A and Joaquim, L and Novochadlo, M and de Oliveira Junior, AN and Bagio, E and Goldim, MPS and de Carli, RJ and Bonfante, SRSA and Metzker, KLL and Muttini, S and Dos Santos, TM and de Oliveira, MP and Engel, NA and Rezin, GT and Kanis, LA and Barichello, T}, title = {Gold nanoparticles potentiates N-acetylcysteine effects on neurochemicals alterations in rats after polymicrobial sepsis.}, journal = {Journal of drug targeting}, volume = {28}, number = {4}, pages = {428-436}, doi = {10.1080/1061186X.2019.1678168}, pmid = {31594390}, issn = {1029-2330}, mesh = {Acetylcysteine/*metabolism ; Animals ; Antioxidants/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Gold/*pharmacology ; Hippocampus/drug effects/metabolism ; Inflammation/drug therapy/metabolism ; Male ; Metal Nanoparticles/*administration &amp; dosage ; Mitochondria/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Sepsis/*drug therapy/metabolism ; }, abstract = {Herein, we report the effect of gold nanoparticles (AuNP) and n-acetylcysteine (NAC) isolated or in association as important anti-inflammatory and antioxidant compounds on brain dysfunction in septic rats. Male Wistar rats after sham operation or caecal ligation and perforation (CLP) were treated with subcutaneously injection of AuNP (50 mg/kg) and/or NAC (20 mg/kg) or saline immediately and 12 h after surgery. Twenty-four hours after CLP, hippocampus and prefrontal cortex were obtained and assayed for myeloperoxidase (MPO) activity, cytokines, lipid peroxidation, protein carbonyls formation, mitochondrial respiratory chain, and CK activity. AuNP + NAC association decreased MPO activity and pro-inflammatory cytokines production, being more effective than NAC or AuNP isolated treatment. AuNP + NAC association and NAC isolated treatment decreased oxidative stress to lipids in both brain structures, while protein oxidation decreased only in the hippocampus of AuNP + NAC association-treated animals. Complex I activity was increased with AuNP + NAC association and NAC isolated in the hippocampus. Regarding CK activity, AuNP and AuNP + NAC association increased this marker in both brain structures after CLP. Our data provide the first experimental demonstration that AuNP and NAC association was able to reduce sepsis-induced brain dysfunction in rats by decreasing neuroinflammation, oxidative stress parameters, mitochondrial dysfunction and CK activity.}, }
@article {pmid31593144, year = {2019}, author = {Mărginean, CO and Meliţ, LE and Mărginean, MO}, title = {Mushroom intoxication, a fatal condition in Romanian children: Two case reports.}, journal = {Medicine}, volume = {98}, number = {41}, pages = {e17574}, pmid = {31593144}, issn = {1536-5964}, mesh = {Abdominal Pain/diagnosis/etiology ; Agaricales/classification ; Ascites/diagnostic imaging ; Child ; Child, Preschool ; Diarrhea/diagnosis/etiology ; Eating ; Fatal Outcome ; Female ; Hepatomegaly/diagnostic imaging ; Hepatorenal Syndrome/*etiology ; Humans ; Male ; Mushroom Poisoning/*complications/*diagnosis/pathology/therapy ; Plasma Exchange/methods ; Romania/epidemiology ; Ultrasonography ; Vomiting/diagnosis/etiology ; }, abstract = {RATIONALE: Approximately 5000 species of wild mushroom are reported worldwide, of which 100 are documented as poisonous and <10 are fatal. The clinical picture of patients with wild mushroom intoxication depends mostly on the type of ingested mushroom, ranging from mild gastrointestinal symptoms to organ failure and death.<br><br>PATIENT CONCERNS: We report 2 children, sister and brother admitted in our clinic for gastrointestinal symptoms: abdominal pain, nausea, vomiting, and diarrhea after wild mushroom ingestion.<br><br>DIAGNOSIS: The laboratory tests revealed hepatic cytolysis syndrome, hyperbilirubinemia, impaired coagulation status, hypoalbuminemia, hypoglycemia, and electrolytic unbalances in both cases. Abdominal ultrasound showed hepatomegaly and ascites.<br><br>INTERVENTION: After admission, both cases received penicillin by vein, activated charcoal, liver protectors, glucose, and electrolytes perfusions. Nevertheless, their status worsened and required the transfer to the pediatric intensive care unit for appropriate supportive measure. Therefore, therapeutic plasma exchange was initiated along with N-acetyl cysteine and hemostatic drugs.<br><br>OUTCOMES: Despite all these therapeutic interventions, both cases developed hepatorenal syndrome and died after a couple of days from ingestion.<br><br>LESSONS: Mushroom poisoning remains a public health problem in developing countries. Preventable strategies and education regarding the consumption of wild type mushrooms are essential for decreasing the morbidity and mortality rates in these areas.}, }
@article {pmid31588915, year = {2019}, author = {Choi, YH}, title = {Isorhamnetin induces ROS-dependent cycle arrest at G2/M phase and apoptosis in human hepatocarcinoma Hep3B cells.}, journal = {General physiology and biophysics}, volume = {38}, number = {6}, pages = {473-484}, doi = {10.4149/gpb_2019038}, pmid = {31588915}, issn = {0231-5882}, mesh = {*Apoptosis ; Cell Division ; Cell Line, Tumor ; G2 Phase Cell Cycle Checkpoints ; Humans ; *Liver Neoplasms ; Quercetin/analogs &amp; derivatives ; Reactive Oxygen Species ; }, abstract = {Isorhamnetin is a 3'-O-methylated metabolite of quercetin that is found predominantly in a variety of medicinal plants. Although many previous studies have reported that this flavonol has diverse health-promoting effects, evidence for the underlying molecular mechanism of anti-cancer efficacy is still lacking. In this study, it was examined the anti-proliferative effect of isorhamnetin on human hepatocarcinoma Hep3B cells, and found that isorhamnetin induced cell cycle arrest at G2/M phase and apoptosis. Isorhamnetin-induced G2/M arrest was associated with decreased expression of proliferating cell nuclear antigen as well as cyclin A and cyclin B1. However, isorhamnetin increased expression of p21WAF1/CIP1, a cyclin-dependent kinase (Cdk) inhibitor, and increased p21 complexed with Cdk2 and Cdc2. In addition, Isorhamnetin-induced apoptosis was associated with increased expression of Fas/Fas ligand, reduced ratio of Bcl-2/Bax expression, truncation of Bid, cytosolic release of cytochrome c, and activation of caspase-8, -9 and -3. Isorhamnetin also enhanced intracellular levels of reactive oxygen species (ROS), while the addition of N-acetyl cysteine (NAC), a ROS inhibitor, significantly diminished isorhamnetin-induced mitochondrial dysfunction. Furthermore, the interruption of ROS generation using NAC significantly attenuated isorhamnetin-mediated G2/M arrest and apoptosis. Collectively, this is the first report to show that isorhamnetin inhibited the proliferation of human hepatocarcinoma cells by ROS-dependent arrest of the cell cycle at the G2/M phase and induction of apoptosis.}, }
@article {pmid31588368, year = {2019}, author = {Kisby, B and Jarrell, JT and Agar, ME and Cohen, DS and Rosin, ER and Cahill, CM and Rogers, JT and Huang, X}, title = {Alzheimer's Disease and Its Potential Alternative Therapeutics.}, journal = {Journal of Alzheimer's disease &amp; Parkinsonism}, volume = {9}, number = {5}, pages = {}, pmid = {31588368}, issn = {2161-0460}, support = {R01 AG056614/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's Disease (AD) is a chronic neurodegenerative disease that affects over 5 million individuals in the United States alone. Currently, there are only two kinds of pharmacological interventions available for symptomatic relief of AD; Acetyl Cholinesterase Inhibitors (AChEI) and N-methyl-D-aspartic Acid (NMDA) receptor antagonists and these drugs do not slow down or stop the progression of the disease. Several molecular targets have been implicated in the pathophysiology of AD, such as the tau (τ) protein, Amyloid-beta (Aβ), the Amyloid Precursor Protein (APP) and more and several responses have also been observed in the advancement of the disease, such as reduced neurogenesis, neuroinflammation, oxidative stress and iron overload. In this review, we discuss general features of AD and several small molecules across different experimental AD drug classes that have been studied for their effects in the context of the molecular targets and responses associated with the AD progression. These drugs include: Paroxetine, Desferrioxamine (DFO), N-acetylcysteine (NAC), Posiphen/-(-)Phenserine, JTR-009, Carvedilol, LY450139, Intravenous immunoglobulin G 10%, Indomethacin and Lithium Carbonate (Li2CO3).}, }
@article {pmid31588060, year = {2019}, author = {Nishiyama, T and Hayashi, N and Yanagita, H and Ohnuma, T and Ogura, K and Hiratsuka, A}, title = {4-(Hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide has the potential to form 2'-deoxyguanosine and N-acetylcysteine adducts.}, journal = {The Journal of toxicological sciences}, volume = {44}, number = {10}, pages = {693-699}, doi = {10.2131/jts.44.693}, pmid = {31588060}, issn = {1880-3989}, mesh = {Acetylcysteine/*metabolism ; Animals ; Carcinogens/*toxicity ; *DNA Adducts ; Deoxyguanosine/*metabolism ; Esterases/metabolism ; Glucuronides/*toxicity ; Liver/metabolism ; Mice ; Nitrosamines/*toxicity ; }, abstract = {Cigarette smoking is a risk factor for the development of various cancers, such as lung, nasal, liver and bladder cancers. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, is implicated in human lung cancer. NNK-induced DNA adducts are found in target tissues for NNK carcinogenesis. NNK is activated by cytochrome P450 dependent α-hydroxylation at either the methylene carbon or methyl carbon adjacent to the N-nitroso group. The former leads to the formation of the methylating agent, and the latter produce the pyridyloxobutylating agent. NNK and some of its metabolites are further metabolized by UDP-glucuronosyltransferases (UGTs). Glucuronides generally are much less active than the parent aglycon therefore the glucuronides of NNK-related metabolites are thought to be inactive. However, 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide (HO-methyl NNK glucuronide) can be transported to the target organs of NNK carcinogenesis where subsequent hydrolysis causes the release of the reactive intermediate. Regeneration of HO-methyl NNK could play an important role in the tissue-specific carcinogenicity of NNK. In the present study, we investigated the reactivity of HO-methyl NNK glucuronide toward 2'-deoxyguanosine (dGuo) and N-acetylcysteine (NAC; used as a models for thiol groups on proteins). The reaction mixtures of HO-methyl NNK glucuronide and dGuo or NAC were analyzed by LCMS-IT-TOF-MS. We also employed 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone, a pyridyloxobutylating agent, to confirm the formation of pyridyloxobutylated adducts. Thus, we determined the production of pyridyloxobutylated dGuo and NAC adducts. Our results suggest HO-methyl NNK glucuronide could generate a reactive intermediate in the tissues and then form adducts with proteins and DNA.}, }
@article {pmid31587481, year = {2020}, author = {Peerapanyasut, W and Kobroob, A and Palee, S and Chattipakorn, N and Wongmekiat, O}, title = {Bisphenol A aggravates renal ischemia-reperfusion injury by disrupting mitochondrial homeostasis and N-acetylcysteine mitigates the injurious outcomes.}, journal = {IUBMB life}, volume = {72}, number = {4}, pages = {758-770}, doi = {10.1002/iub.2175}, pmid = {31587481}, issn = {1521-6551}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Benzhydryl Compounds/*toxicity ; Homeostasis/drug effects ; Kidney/blood supply/*drug effects/metabolism ; Kidney Diseases/chemically induced/drug therapy ; Male ; Mitochondria/drug effects/metabolism ; Oxidative Stress/drug effects ; Phenols/*toxicity ; Rats, Wistar ; Reperfusion Injury/chemically induced/*drug therapy ; Sirtuins/metabolism ; }, abstract = {Exposure to bisphenol A (BPA), a chemical generally used in consumer products, becomes a global public health concern, as humans are increasingly exposed through their daily consuming activities. Renal ischemia-reperfusion (RIR) is the major cause of acute kidney injury with high prevalence and increased long-term risks for multiple comorbidities and mortality. As the kidney is susceptible to these conditions, we explored whether the outcomes following the RIR episode could be influenced by BPA exposure, and investigated the therapeutic possibility by N-acetylcysteine (NAC) including the mechanisms involved. Three groups of male Wistar rats were fed with vehicle, BPA 5, and 50 mg/kg, respectively, for five consecutive weeks then underwent the sham operation. Three other groups with identical treatment underwent bilateral renal IR induction (45-min ischemia followed by 24-hr reperfusion). An additional RIR group was treated with BPA 50 plus NAC 100 mg/kg. BPA-exposed rats that encountered RIR episode showed dose-dependent worsening of RIR injury as evidenced by augmentations of renal dysfunction and histopathological abnormalities, oxidative stress, apoptosis, mitochondrial functional impairment, mitochondrial dynamic, and mitophagy disproportion compared with the vehicle-exposed RIR group. The NAC therapy considerably attenuated the exacerbated effects of BPA, which was associated with increased AMP-activated protein kinase (AMPK), PGC-1α, silent information regulator 3 or sirtuin 3 (SIRT3), and mitofusin 2 (MFN2) expressions but decreased Phosphorylated dynamin-related protein 1 (p-DRP1)/Dynamin-related protein 1 (DRP1), PTEN-induced putative kinase (PINK), and PARKIN expressions. These findings reveal the detrimental effect of repeated BPA exposure on the renal outcomes following the IR episode, and further demonstrate the protective efficacy of NAC by maintaining mitochondrial homeostasis, which is, partly, mediated through the AMPK-PGC-1α-SIRT3 axis.}, }
@article {pmid31585350, year = {2020}, author = {Feng, T and Niu, J and Pi, B and Lu, Y and Wang, J and Zhang, W and Li, B and Yang, H and Zhu, X}, title = {Osteogenesis enhancement of silk fibroin/ α-TCP cement by N-acetyl cysteine through Wnt/β-catenin signaling pathway in vivo and vitro.}, journal = {Journal of the mechanical behavior of biomedical materials}, volume = {101}, number = {}, pages = {103451}, doi = {10.1016/j.jmbbm.2019.103451}, pmid = {31585350}, issn = {1878-0180}, mesh = {Acetylcysteine/*chemistry ; Animals ; Calcium Phosphates/*chemistry ; Femur/drug effects/physiology ; Fibroins/*chemistry/*pharmacology ; Osteogenesis/*drug effects ; Rats ; Up-Regulation/drug effects ; Wnt Signaling Pathway/*drug effects ; }, abstract = {High brittleness and lack osteogenesis are two major limitations of calcium phosphate cement (CPC) in application in bone defect reconstruction. Here we prepared a composite calcium phosphate cement by mixing N-acetyl cysteine loaded silk fibroin solution with α-tricalcium phosphate. In vitro cytology experiment revealed that SF-NAC/α-TCP could significantly increase the activity of exocrine ALP and up-regulated expression of bone-related genes. However, NAC up-regulated gene expression could be significantly suppressed by DKK1. We propose that NAC functioning as osteogenic factor by activating the Wnt/β-catenin signaling pathway may be the possible mechanism of up-regulation of osteogenic genes. Bone regeneration in vivo shown in a rat femur defect was enhanced by the addition of NAC in SF/α-TCP. In addition, the combination intensity of cement-bone interface was improved. The combination SF-NAC/α-TCP might be developed into a promising tool for bone tissue repair in the clinic.}, }
@article {pmid31583053, year = {2019}, author = {Lei, S and Su, W and Xia, ZY and Wang, Y and Zhou, L and Qiao, S and Zhao, B and Xia, Z and Irwin, MG}, title = {Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {9836302}, pmid = {31583053}, issn = {1942-0994}, mesh = {Analgesics, Opioid/pharmacology/*therapeutic use ; Animals ; Cardiotonic Agents/pharmacology/*therapeutic use ; Caveolin 3 ; Humans ; Hyperglycemia ; Janus Kinase 2 ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Sprague-Dawley ; Remifentanil/pharmacology/*therapeutic use ; STAT3 Transcription Factor ; }, abstract = {Diabetic hearts are more vulnerable to ischemia/reperfusion (I/R) injury and less responsive to remifentanil preconditioning (RPC), but the underlying mechanisms are incompletely understood. Caveolin-3 (Cav-3), the dominant isoform of cardiomyocyte caveolae, is reduced in diabetic hearts in which oxidative stress is increased. This study determined whether the compromised RPC in diabetes was an independent manifestation of hyperglycemia-induced oxidative stress or linked to impaired Cav-3 expression with associated signaling abnormality. RPC significantly attenuated postischemic infarction, cardiac dysfunction, myocardial apoptosis, and 15-F2t-isoprostane production (a specific marker of oxidative stress), accompanied with increased Cav-3 expression and enhanced Akt and STAT3 activation in control but not in diabetic rats. Pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated hyperglycemia-induced reduction of Cav-3 expression and Akt and STAT3 activation and restored RPC-mediated cardioprotection in diabetes, which was abolished by cardiac-specific knockdown of Cav-3 by AAV9-shRNA-Cav-3, PI3K/Akt inhibitor wortmannin, or JAK2/STAT3 inhibitor AG490, respectively. Similarly, NAC could restore RPC protection from high glucose and hypoxia/reoxygenation-induced injury evidenced by decreased levels of LDH release, 15-F2t-isoprostane, O2 [-], and JC-1 monomeric cells, which were reversed by caveolae disrupter methyl-β-cyclodextrin, wortmannin, or AG490 in isolated primary cardiomyocytes or siRNAs of Cav-3, Akt, or STAT3 in H9C2 cells. Either methyl-β-cyclodextrin or Cav-3 knockdown reduced Akt and STAT3 activation. Further, the inhibition of Akt activation by a selective inhibitor or siRNA reduced STAT3 activation and vice versa, but they had no effects on Cav-3 expression. Thus, hyperglycemia-induced oxidative stress abrogates RPC cardioprotection by impairing Cav-3-modulated PI3K/Akt and JAK2/STAT3 signaling. Antioxidant treatment with NAC could restore RPC-induced cardioprotection in diabetes by improving Cav-3-dependent Akt and STAT3 activation and by facilitating the cross talk between PI3K/Akt and JAK2/STAT3 signaling pathways.}, }
@article {pmid31580490, year = {2019}, author = {Ciofu, O and Smith, S and Lykkesfeldt, J}, title = {Antioxidant supplementation for lung disease in cystic fibrosis.}, journal = {The Cochrane database of systematic reviews}, volume = {10}, number = {10}, pages = {CD007020}, pmid = {31580490}, issn = {1469-493X}, abstract = {BACKGROUND: Airway infection leads to progressive damage of the lungs in cystic fibrosis (CF) and oxidative stress has been implicated in the etiology. Supplementation of antioxidant micronutrients (vitamin E, vitamin C, beta-carotene and selenium) or N-acetylcysteine (NAC) as a source of glutathione, may therefore potentially help maintain an oxidant-antioxidant balance. Glutathione or NAC can also be inhaled and if administered in this way can also have a mucolytic effect besides the antioxidant effect. Current literature suggests a relationship between oxidative status and lung function. This is an update of a previously published review.<br><br>OBJECTIVES: To synthesise existing knowledge on the effect of antioxidants such as vitamin C, vitamin E, beta-carotene, selenium and glutathione (or NAC as precursor of glutathione) on lung function through inflammatory and oxidative stress markers in people with CF.<br><br>SEARCH METHODS: The Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and PubMed were searched using detailed search strategies. We contacted authors of included studies and checked reference lists of these studies for additional, potentially relevant studies. We also searched online trials registries.Last search of Cystic Fibrosis Trials Register: 08 January 2019.<br><br>SELECTION CRITERIA: Randomised and quasi-randomised controlled studies comparing antioxidants as listed above (individually or in combination) in more than a single administration to placebo or standard care in people with CF.<br><br>DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed the risk of bias in the included studies. We contacted study investigators to obtain missing information. If meta-analysed, studies were subgrouped according to supplement, method of administration and the duration of supplementation. We assessed the quality of the evidence using GRADE.<br><br>MAIN RESULTS: One quasi-randomised and 19 randomised controlled studies (924 children and adults) were included; 16 studies (n = 639) analysed oral antioxidant supplementation and four analysed inhaled supplements (n = 285). Only one of the 20 included studies was judged to be free of bias.Oral supplements versus controlThe change from baseline in forced expiratory volume in one second (FEV1) % predicted at three months and six months was only reported for the comparison of NAC to control. Four studies (125 participants) reported at three months; we are uncertain whether NAC improved FEV1 % predicted as the quality of the evidence was very low, mean difference (MD) 2.83% (95% confidence interval (CI) -2.16 to 7.83). However, at six months two studies (109 participants) showed that NAC probably increased FEV1 % predicted from baseline (moderate-quality evidence), MD 4.38% (95% CI 0.89 to 7.87). A study of a combined vitamin and selenium supplement (46 participants) reported a greater change from baseline in FEV1 % predicted in the control group at two months, MD -4.30% (95% CI -5.64 to -2.96). One study (61 participants) found that NAC probably makes little or no difference in the change from baseline in quality of life (QoL) at six months (moderate-quality evidence), standardised mean difference (SMD) -0.03 (95% CI -0.53 to 0.47), but the two-month combined vitamin and selenium study reported a small difference in QoL in favour of the control group, SMD -0.66 (95% CI -1.26 to -0.07). The NAC study reported on the change from baseline in body mass index (BMI) (62 participants) and similarly found that NAC probably made no difference between groups (moderate-quality evidence). One study (69 participants) found that a mixed vitamin and mineral supplement may lead to a slightly lower risk of pulmonary exacerbation at six months than a multivitamin supplement (low-quality evidence). Nine studies (366 participants) provided information on adverse events, but did not find any clear and consistent evidence of differences between treatment or control groups with the quality of the evidence ranging from low to moderate. Studies of &#x3b2;-carotene and vitamin E consistently reported greater plasma levels of the respective antioxidants.Inhaled supplements versus controlTwo studies (258 participants) showed inhaled glutathione probably improves FEV1 % predicted at three months, MD 3.50% (95% CI 1.38 to 5.62), but not at six months compared to placebo, MD 2.30% (95% CI -0.12 to 4.71) (moderate-quality evidence). The same studies additionally reported an improvement in FEV1 L in the treated group compared to placebo at both three and six months. One study (153 participants) reported inhaled glutathione probably made little or no difference to the change in QoL from baseline, MD 0.80 (95% CI -1.63 to 3.23) (moderate-quality evidence). No study reported on the change from baseline in BMI at six months, but one study (16 participants) reported at two months and a further study (105 participants) at 12 months; neither study found any difference at either time point. One study (153 participants) reported no difference in the time to the first pulmonary exacerbation at six months. Two studies (223 participants) reported treatment may make little or no difference in adverse events (low-quality evidence), a further study (153 participants) reported that the number of serious adverse events were similar across groups.<br><br>AUTHORS' CONCLUSIONS: With regards to micronutrients, there does not appear to be a positive treatment effect of antioxidant micronutrients on clinical end-points; however, oral supplementation with glutathione showed some benefit to lung function and nutritional status. Based on the available evidence, inhaled and oral glutathione appear to improve lung function, while oral administration decreases oxidative stress; however, due to the very intensive antibiotic treatment and other concurrent treatments that people with CF take, the beneficial effect of antioxidants remains difficult to assess in those with chronic infection without a very large population sample and a long-term study period. Further studies, especially in very young children, using outcome measures such as lung clearance index and the bronchiectasis scores derived from chest scans, with improved focus on study design variables (such as dose levels and timing), and elucidating clear biological pathways by which oxidative stress is involved in CF, are necessary before a firm conclusion regarding effects of antioxidants supplementation can be drawn. The benefit of antioxidants in people with CF who receive CFTR modulators therapies should also be assessed in the future.}, }
@article {pmid31579951, year = {2020}, author = {Yu, JH and Lu, JX and Smollin, C and Cheng, HT and Seak, CJ and Chen, HY}, title = {N-acetylcysteine and ascorbic acid therapy for acute hepatic injury after hexavalent chromium ingestion.}, journal = {Journal of clinical pharmacy and therapeutics}, volume = {45}, number = {1}, pages = {208-210}, doi = {10.1111/jcpt.13044}, pmid = {31579951}, issn = {1365-2710}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Antioxidants/administration &amp; dosage/pharmacology ; Ascorbic Acid/*administration &amp; dosage/pharmacology ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology ; Chromium/*poisoning ; Drug Therapy, Combination ; Humans ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Treatment Outcome ; }, abstract = {WHAT IS KNOWN AND OBJECTIVE: Hexavalent (VI) chromium is a powerful oxidant that can produce cellular oxidative stress and multi-organ system dysfunction. The role of antioxidants such as N-acetylcysteine (NAC) and ascorbic acid in alleviating organ damage in humans remains unclear.<br><br>CASE DESCRIPTION: We present a 47-year-old male who ingested 30&#xa0;mL of plating solution and developed hepatic injury. He was treated with NAC and ascorbic acid with improvement in hepatic function. However, his clinical conditions and jaundice worsened again after discontinuing these therapies.<br><br>WHAT IS NEW AND CONCLUSION: Our findings suggest a potential role for antioxidant therapy for acute hexavalent chromium poisoning.}, }
@article {pmid31579619, year = {2019}, author = {Martinez-Torres, AC and Gomez-Morales, L and Martinez-Loria, AB and Uscanga-Palomeque, AC and Vazquez-Guillen, JM and Rodriguez-Padilla, C}, title = {Cytotoxic activity of IMMUNEPOTENT CRP against non-small cell lung cancer cell lines.}, journal = {PeerJ}, volume = {7}, number = {}, pages = {e7759}, pmid = {31579619}, issn = {2167-8359}, abstract = {BACKGROUND: IMMUNEPOTENT-CRP® (I-CRP) is a bovine dialyzable leukocyte extract containing transfer factor. It is a cost-effective, unspecific active immunotherapy that has been used in patients with non-small cell lung cancer (NSCLC) as an adjuvant to reduce the side-effects of chemotherapy and radiotherapy, and has shown cytotoxic activity in vitro on different cancer cell lines. However, its mechanism of action against lung cancer cells has not been assessed. Therefore, the objective of this work was to assess the cytotoxic mechanism of I-CRP on lung cancer cell lines.<br><br>METHODS: We assessed cell viability through MTT assay on the NSCLC cell lines A549, A427, Calu-1, and INER-51 after treatment with I-CRP. To further understand the mechanisms of cell viability diminution we used fluorescence-activated cell sorting to evaluate cell death (annexin-V and propidium iodide [PI] staining), cell cycle and DNA degradation (PI staining), mitochondrial alterations (TMRE staining), and reactive oxygen species (ROS) production (DCFDA staining). Additionally, we evaluated caspase and ROS dependence of cell death by pretreating the cells with the pan-caspase inhibitor Q-VD-OPH and the antioxidant N-acetylcysteine (NAC), respectively.<br><br>RESULTS: Our data shows that I-CRP is cytotoxic to NSCLC cell lines in a dose and time dependent manner, without substantial differences between the four cell lines tested (A549, A427, Calu-1, and INER-51). Cytotoxicity is induced through regulated cell death and cell cycle arrest induction. I-CRP-induced cell death in NSCLC cell lines is characterized by DNA degradation, mitochondrial damage, and ROS production. Moreover, cell death is independent of caspases but relies on ROS production, as it is abrogated with NAC.<br><br>CONCLUSION: Altogether, these results improve the knowledge about the cytotoxic activity of I-CRP on NSCLC cells, indicating that cell death, cell cycle arrest, DNA degradation and mitochondrial damage are important features, while ROS play the main role for I-CRP mediated cytotoxicity in lung cancer cells.}, }
@article {pmid31578313, year = {2019}, author = {Lu, H and Lu, Y and Xie, Y and Qiu, S and Li, X and Fan, Z}, title = {Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma.}, journal = {JCI insight}, volume = {4}, number = {19}, pages = {}, pmid = {31578313}, issn = {2379-3708}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA179015/CA/NCI NIH HHS/United States ; R21 DE021883/DE/NIDCR NIH HHS/United States ; }, mesh = {Amino Acid Transport System ASC/genetics/metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cetuximab/*pharmacology ; Dichloroacetic Acid/antagonists &amp; inhibitors ; Drug Resistance, Neoplasm/*drug effects/genetics ; ErbB Receptors/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Male ; Mice, Nude ; Minor Histocompatibility Antigens/genetics/metabolism ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase/drug effects/*genetics/*metabolism ; Signal Transduction ; Squamous Cell Carcinoma of Head and Neck/drug therapy/*genetics/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Cetuximab, an EGFR-blocking antibody, is currently approved for treatment of metastatic head and neck squamous cell carcinoma (HNSCC), but its response rate is limited. In addition to blocking EGFR-stimulated cell signaling, cetuximab can induce endocytosis of ASCT2, a glutamine transporter associated with EGFR in a complex, leading to glutathione biosynthesis inhibition and cellular sensitization to ROS. Pyruvate dehydrogenase kinase-1 (PDK1), a key mitochondrial enzyme overexpressed in cancer cells, redirects glucose metabolism from oxidative phosphorylation toward aerobic glycolysis. In this study, we tested the hypothesis that targeting PDK1 is a rational approach to synergize with cetuximab through ROS overproduction. We found that combination of PDK1 knockdown or inhibition by dichloroacetic acid (DCA) with ASCT2 knockdown or with cetuximab treatment induced ROS overproduction and apoptosis in HNSCC cells, and this effect was independent of effective inhibition of EGFR downstream pathways but could be lessened by N-acetyl cysteine, an anti-oxidative agent. In several cetuximab-resistant HNSCC xenograft models, DCA plus cetuximab induced marked tumor regression, whereas either agent alone failed to induce tumor regression. Our findings call for potentially novel clinical trials of combining cetuximab and DCA in patients with cetuximab-sensitive EGFR-overexpressing tumors and patients with cetuximab-resistant EGFR-overexpressing tumors.}, }
@article {pmid31578304, year = {2019}, author = {Breau, M and Houssaini, A and Lipskaia, L and Abid, S and Born, E and Marcos, E and Czibik, G and Attwe, A and Beaulieu, D and Palazzo, A and Flaman, JM and Bourachot, B and Collin, G and Tran Van Nhieu, J and Bernard, D and Mechta-Grigoriou, F and Adnot, S}, title = {The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice.}, journal = {JCI insight}, volume = {4}, number = {19}, pages = {}, pmid = {31578304}, issn = {2379-3708}, mesh = {Acetylcysteine/*adverse effects/*pharmacology ; Adenocarcinoma of Lung/*chemically induced/pathology ; Animals ; Antioxidants/*adverse effects/*pharmacology ; Disease Models, Animal ; Female ; Humans ; Lung/pathology ; Lung Diseases/pathology ; Lung Neoplasms ; Male ; Mice ; Mice, Knockout ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-jun/genetics ; Pulmonary Emphysema/*drug therapy/pathology ; Reactive Oxygen Species ; }, abstract = {Oxidative stress is a major contributor to chronic lung diseases. Antioxidants such as N-acetylcysteine (NAC) are broadly viewed as protective molecules that prevent the mutagenic effects of reactive oxygen species. Antioxidants may, however, increase the risk of some forms of cancer and accelerate lung cancer progression in murine models. Here, we investigated chronic NAC treatment in aging mice displaying lung oxidative stress and cell senescence due to inactivation of the transcription factor JunD, which is downregulated in diseased human lungs. NAC treatment decreased lung oxidative damage and cell senescence and protected from lung emphysema but concomitantly induced the development of lung adenocarcinoma in 50% of JunD-deficient mice and 10% of aged control mice. This finding constitutes the first evidence to our knowledge of a carcinogenic effect of antioxidant therapy in the lungs of aged mice with chronic lung oxidative stress and warrants the utmost caution when considering the therapeutic use of antioxidants.}, }
@article {pmid31577702, year = {2019}, author = {Zheng, R and Tan, Y and Gu, M and Kang, T and Zhang, H and Guo, L}, title = {N-acetyl cysteine inhibits lipopolysaccharide-mediated synthesis of interleukin-1β and tumor necrosis factor-α in human periodontal ligament fibroblast cells through nuclear factor-kappa B signaling.}, journal = {Medicine}, volume = {98}, number = {40}, pages = {e17126}, pmid = {31577702}, issn = {1536-5964}, mesh = {Acetylcysteine/*pharmacology ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts/*drug effects/metabolism ; Humans ; Interleukin-1beta/biosynthesis/*drug effects ; Lipopolysaccharides/pharmacology ; NF-kappa B/*drug effects/metabolism ; Periodontal Ligament ; RNA, Messenger/metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/*drug effects/metabolism ; }, abstract = {BACKGROUND: The aim of this study was to investigate the role of n-acetyl cysteine (NAC) in the lipopolysaccharide (LPS)-mediated induction of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) synthesis by human periodontal ligament fibroblast cells (hPDLFs). In addition, we aimed to determine the involvement of the nuclear factor-kappa B (NF-κB) pathway in any changes in IL-1β and TNF-α expression observed in response to LPS and NAC.<br><br>METHODS: HPDLFs were obtained by primary culture. The culture medium used in this experiment was Dulbecco's Modified Eagle Medium (DMEM low-glucose). Cells were stimulated with various concentrations of NAC or LPS. Cell proliferation was measured at various time-points with the cell Counting Kit 8 (CCK-8) assay. mRNA levels of IL-1&#x3b2; and TNF-&#x3b1; were determined by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Protein levels of IL-1&#x3b2; and TNF-&#x3b1; were measured by enzyme-linked immunosorbent assay (ELISA). Protein and mRNA expression levels of NF-&#x3ba;B were measured by western blot and RT-qPCR.<br><br>RESULTS: The results showed that LPS treatment in hPDLFs induced mRNA and protein expression of IL-1&#x3b2;, TNF-&#x3b1;, and NF-&#x3ba;B. However, these effects were eliminated by pretreatment with NAC. Pretreatment with both NAC (1&#x200a;mmol/L) and BAY11-7082 (10&#x200a;&#x3bc;mol/L) significantly inhibited the NF-&#x3ba;B activity induced by LPS.<br><br>CONCLUSION: NAC inhibits the LPS-mediated synthesis of tumor TNF-&#x3b1; and IL-1&#x3b2; in hPDLFs, through the NF-&#x3ba;B pathway.}, }
@article {pmid31576778, year = {2019}, author = {Etemad, L and Moshiri, M and Balali-Mood, M}, title = {Advances in treatment of acute sulfur mustard poisoning - a critical review.}, journal = {Critical reviews in toxicology}, volume = {49}, number = {3}, pages = {191-214}, doi = {10.1080/10408444.2019.1579779}, pmid = {31576778}, issn = {1547-6898}, mesh = {Chemical Warfare Agents/*poisoning ; Humans ; Mustard Gas/*poisoning ; Respiratory Tract Diseases/therapy ; }, abstract = {Sulfur mustard (SM) is a blistering chemical warfare agent that was used during the World War I and in the Iraq-Iran conflict. The aim of this paper is to discuss and critically review the published results of experiments on the treatment of SM poisoning based on our clinical and research experience. The victims must remove from the contaminated zone immediately. The best solution for decontamination is large amounts of water, using neutral soap and 0.5% sodium hypochlorite. Severely intoxicated patients should be treated according to advanced life support protocols and intensive care therapy for respiratory disorders and the chemical burn. Sodium thiosulfate infusion (100-500 mg/kg/min) should be started up to 60 min after SM exposure. However, N-acetyle cysteine (NAC) is recommended, none of them acts as specific or effective antidote. The important protective and conservative treatment of SM-induced pulmonary injuries include humidified oxygen, bronchodilators, NAC as muculytic, rehydration, mechanical ventilation, appropriate antibiotics and respiratory physiotherapy as clinically indicated. Treatment of acute SM ocular lesions start with topical antibiotics; preferably sulfacetamide eye drop, continue with lubricants, and artificial tears. Treatment for cutaneous injuries include: moist dressing; preferably with silver sulfadiazine cream, analgesic, anti-pruritic, physically debridement, debridase, Laser debridement, followed by skin autologous split-thickness therapy as clinically indicated. The new suggested medications and therapeutic approaches include: anti-inflammatory agents, Niacinamide, Silibinin, Calmodulin antagonists, Clobetasol, full-thickness skin grafting for skin injuries; Doxycycline; Bevacizumab, and Colchicine for ocular injuries. Recommended compounds based on animal studies include Niacinamide, Aprotinin, des-aspartate-angiotensin-I, Gamma-glutamyltransferase, vitamin E, and vitamin D. In vitro studies revealed that Dimethylthiourea, L-nitroarginine, Methyl-ester, Sodium pyruvate, Butylated hydroxyanisole, ethacrynic acid, and macrolide antibiotics are effective. However, none of them, except macrolide antibiotics have been proved clinically. Avoidance of inappropriate polypharmacy is advisable.}, }
@article {pmid31575771, year = {2019}, author = {Bandyopadhaya, A and Tzika, AA and Rahme, LG}, title = {Pseudomonas aeruginosa Quorum Sensing Molecule Alters Skeletal Muscle Protein Homeostasis by Perturbing the Antioxidant Defense System.}, journal = {mBio}, volume = {10}, number = {5}, pages = {}, pmid = {31575771}, issn = {2150-7511}, support = {R01 AI134857/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants ; Cells, Cultured ; Male ; Mice ; Muscle Fibers, Skeletal/metabolism ; Muscle Proteins/metabolism ; Muscle, Skeletal/enzymology/*metabolism ; NADP/metabolism ; Pseudomonas Infections/metabolism/*microbiology ; Pseudomonas aeruginosa/*physiology ; *Quorum Sensing ; Reactive Oxygen Species/metabolism ; Transcription Factors/metabolism ; Uncoupling Protein 3/metabolism ; Xanthine Oxidase/metabolism ; }, abstract = {Skeletal muscle function is compromised in many illnesses, including chronic infections. The Pseudomonas aeruginosa quorum sensing (QS) signal, 2-amino acetophenone (2-AA), is produced during acute and chronic infections and excreted in human tissues, including the lungs of cystic fibrosis patients. We have shown that 2-AA facilitates pathogen persistence, likely via its ability to promote the formation of bacterial persister cells, and that it acts as an interkingdom immunomodulatory signal that epigenetically reprograms innate immune functions. Moreover, 2-AA compromises muscle contractility and impacts the expression of genes involved in reactive oxygen species (ROS) homeostasis in skeletal muscle and in mitochondrial functions. Here, we elucidate the molecular mechanisms of 2-AA's impairment of skeletal muscle function and ROS homeostasis. Murine in vivo and differentiated C2C12 myotube cell studies showed that 2-AA promotes ROS generation in skeletal muscle via the modulation of xanthine oxidase (XO) activity, NAD(P)H oxidase2 (NOX2) protein level, and the activity of antioxidant enzymes. ROS accumulation triggers the activity of AMP-activated protein kinase (AMPK), likely upstream of the observed locations of induction of ubiquitin ligases Muscle RING Finger 1 (MuRF1) and Muscle Atrophy F-box (MAFbx), and induces autophagy-related proteins. The protein-level perturbation in skeletal muscle of silent mating type information regulation 2 homolog 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), and uncoupling protein 3 (UCP3) is rescued by the antioxidant N-acetyl-l-cysteine (NAC). Together, these results unveil a novel form of action of a QS bacterial molecule and provide molecular insights into the 2-AA-mediated skeletal muscle dysfunction caused by P. aeruginosaIMPORTANCEPseudomonas aeruginosa, a bacterium that is resistant to treatment, causes serious acute, persistent, and relapsing infections in humans. There is increasing evidence that bacterial excreted small molecules play a critical role during infection. We have shown that a quorum sensing (QS)-regulated excreted small molecule, 2-AA, which is abundantly produced by P. aeruginosa, promotes persistent infections, dampens host inflammation, and triggers mitochondrial dysfunction in skeletal muscle. QS is a cell-to-cell communication system utilized by bacteria to promote collective behaviors. The significance of our study in identifying a mechanism that leads to skeletal muscle dysfunction, via the action of a QS molecule, is that it may open new avenues in the control of muscle loss as a result of infection and sepsis. Given that QS is a common characteristic of prokaryotes, it is possible that 2-AA-like molecules promoting similar effects may exist in other pathogens.}, }
@article {pmid31570981, year = {2019}, author = {Dai, C and Xiao, X and Sun, F and Zhang, Y and Hoyer, D and Shen, J and Tang, S and Velkov, T}, title = {T-2 toxin neurotoxicity: role of oxidative stress and mitochondrial dysfunction.}, journal = {Archives of toxicology}, volume = {93}, number = {11}, pages = {3041-3056}, doi = {10.1007/s00204-019-02577-5}, pmid = {31570981}, issn = {1432-0738}, support = {2015BAD11B03//National Science and Technology Program during the Twelfth Five-year Plan Period/International ; }, mesh = {Antioxidants/metabolism/pharmacology ; Autophagy/drug effects ; Cell Line ; Cell Survival/drug effects ; Humans ; Male ; Mitochondria/*drug effects/metabolism ; Neurons/*drug effects/metabolism/pathology ; Neurotoxicity Syndromes/*etiology/metabolism/pathology/prevention &amp; control ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction ; T-2 Toxin/metabolism/*toxicity ; }, abstract = {Mycotoxins are highly diverse secondary metabolites produced in nature by a wide variety of fungi. Mycotoxins cause animal feed and food contamination, resulting in mycotoxicosis. T-2 toxin is one of the most common and toxic trichothecene mycotoxins. For the last decade, it has garnered considerable attention due to its potent neurotoxicity. Worryingly, T-2 toxin can cross the blood-brain barrier and accumulate in the central nervous system (CNS) to cause neurotoxicity. This review covers the current knowledge base on the molecular mechanisms of T-2 toxin-induced oxidative stress and mitochondrial dysfunction in the CNS. In vitro and animal data have shown that induction of reactive oxygen species (ROS) and oxidative stress plays a critical role during T-2 toxin-induced neurotoxicity. Mitochondrial dysfunction and cascade signaling pathways including p53, MAPK, Akt/mTOR, PKA/CREB and NF-κB contribute to T-2 toxin-induced neuronal cell death. T-2 toxin exposure can also result in perturbations of mitochondrial respiratory chain complex and mitochondrial biogenesis. T-2 toxin exposure decreases the mitochondria unfolded protein response and dampens mitochondrial energy metabolism. Antioxidants such as N-acetylcysteine (NAC), activation of Nrf2/HO-1 and autophagy have been shown to provide a protective effect against these detrimental effects. Clearly, translational research and the discovery of effective treatment strategies are urgently required against this common food-borne threat to human health and livestock.}, }
@article {pmid31569917, year = {2019}, author = {Elberry, AA and Sharkawi, SMZ and Wahba, MR}, title = {Antinociceptive and anti-inflammatory effects of N-acetylcysteine and verapamil in Wistar rats.}, journal = {The Korean journal of pain}, volume = {32}, number = {4}, pages = {256-263}, pmid = {31569917}, issn = {2005-9159}, abstract = {BACKGROUND: Antinociceptive anti-inflammatory drugs have many adverse effects. The goal of this investigation is to study the probable anti-inflammatory and analgesic effects of verapamil and N-acetylcysteine (NAC) in experimental rats.<br><br>METHODS: Adult male Wistar rats were randomly divided into 4 groups in the antinociceptive study, each containing 6 rats; the normal control group, which received saline (1 mL/kg); the diclofenac group, which received diclofenac sodium (5 mg/kg); the NAC group, which received NAC (125 mg/kg); and the verapamil group, which received verapamil (8 mg/kg). In the anti-inflammatory study, 5 groups were used, the 4 previous groups with the addition of an edema control group, received saline and were subjected to formalin test. Hot plate latency time was recorded for antinociceptive evaluation. Paw edema thickness and biochemical parameters were recorded for anti-inflammatory evaluation.<br><br>RESULTS: Administration of NAC showed significant prolongation of hot plate latency time at 1 hour when compared to the control group while verapamil showed a significant prolongation of hot plate latency time at 1 and 2 hours when compared to the control group and NAC group values. Administration of NAC and verapamil significantly decreased paw edema thickness at 2, 4, and 8 hours when compared to edema control values. Regarding biochemical markers, NAC and verapamil significantly decreased serum nitric oxide synthase, C-reactive protein, and cyclooxygenase- 2 levels compared to the edema control value. In accordance, a marked improvement of histopathological findings was observed with both drugs.<br><br>CONCLUSIONS: NAC and verapamil have antinociceptive and anti-inflammatory effects comparable to diclofenac sodium.}, }
@article {pmid31569821, year = {2019}, author = {Duval, AP and Troquier, L and de Souza Silva, O and Demartines, N and Dormond, O}, title = {Diclofenac Potentiates Sorafenib-Based Treatments of Hepatocellular Carcinoma by Enhancing Oxidative Stress.}, journal = {Cancers}, volume = {11}, number = {10}, pages = {}, pmid = {31569821}, issn = {2072-6694}, support = {164212//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung/ ; }, abstract = {Sorafenib is the first developed systemic treatment for advanced forms of hepatocellular carcinoma, which constitutes the most frequent form of primary liver cancers and is a major global health burden. Although statistically significant, the positive effect of sorafenib on median survival remains modest, highlighting the need to develop novel therapeutic approaches. In this report, we introduce diclofenac, a nonsteroidal anti-inflammatory drug, as a potent catalyzer of sorafenib anticancer efficacy. Treatment of three different hepatocellular cancer cells (Huh-7, HepG2, and PLC-PRF-5) with sorafenib (5 µM, 24 h) and diclofenac (100 µM, 24 h) significantly increased cancer cell death compared to sorafenib or diclofenac alone. Anti-oxidant compounds, including N-acetyl-cysteine and ascorbic acid, reversed the deleterious effects of diclofenac/sorafenib co-therapy, suggesting that the generation of toxic levels of oxidative stress was responsible for cell death. Accordingly, whereas diclofenac increased production of mitochondrial oxygen reactive species, sorafenib decreased concentrations of glutathione. We further show that tumor burden was significantly diminished in mice bearing tumor xenografts following sorafenib/diclofenac co-therapy when compared to sorafenib or diclofenac alone. Taken together, these results highlight the anticancer benefits of sorafenib/diclofenac co-therapy in hepatocellular carcinoma. They further indicate that combining sorafenib with compounds that increase oxidative stress represents a valuable treatment strategy in hepatocellular carcinoma.}, }
@article {pmid31568154, year = {2019}, author = {Huber, LA and Lee, T and LeDrew, RL and Dodge, ME and Brunton, JA and Bertolo, RF}, title = {Photoprotection But Not N-acetylcysteine Improves Intestinal Blood Flow and Oxidation Status in Parenterally Fed Piglets.}, journal = {Journal of pediatric gastroenterology and nutrition}, volume = {69}, number = {6}, pages = {719-725}, doi = {10.1097/MPG.0000000000002498}, pmid = {31568154}, issn = {1536-4801}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Animals, Newborn ; Disease Models, Animal ; Female ; Humans ; Intestines/blood supply ; Light/*adverse effects ; Male ; Mesenteric Arteries/physiology ; Oxidation-Reduction ; Parenteral Nutrition, Total/*methods ; Random Allocation ; Swine ; }, abstract = {OBJECTIVES: The purpose of the present study was to determine if protecting parenteral nutrition solutions from ambient light and supplementing with N-acetylcysteine (NAC) improves mesenteric blood flow, gut morphology, and oxidative status of parenterally fed neonates.<br><br>METHODS: Neonatal Yucatan miniature piglets (n&#x200a;=&#x200a;23, 7-11 days old) were surgically fitted with central venous catheters and an ultrasonic blood flow probe around the superior mesenteric artery. Piglets were fed continuously for 7 days either light-protected (LP) or light-exposed (LE) complete parenteral nutrition that was enriched with either NAC or alanine (ALA).<br><br>RESULTS: There were no differences in body weight or overall gut morphology among groups after 7 days. Plasma concentrations of NAC were greater and total homocysteine lower in NAC- versus ALA-supplemented pigs on day 7 (N-acetylcysteine: 94 vs 7&#x200a;&#x3bc;mol/L; P&#x200a;<&#x200a;0.001; homocysteine: 14 versus 21&#x200a;&#x3bc;mol/L; P&#x200a;<&#x200a;0.005); plasma total glutathione was not affected. Hepatic lipid peroxidation was reduced by 25% in piglets that received LP parenteral nutrition (P&#x200a;<&#x200a;0.05). The mesenteric artery blood flow decreased in all pigs between days 2 and 6 (P&#x200a;<&#x200a;0.001) because of parenteral feeding. Photoprotection alone (LP-ALA) attenuated the decrease in mesenteric blood flow to 66% of baseline on day 6 compared with LE-ALA (37%; P&#x200a;<&#x200a;0.05) and LP-NAC pigs (43%; P&#x200a;=&#x200a;0.062); LE-NAC piglets had intermediate reductions in blood flow (55%).<br><br>CONCLUSIONS: Photoprotection of parenteral nutrition solutions is a simple, effective method to attenuate decline in blood flow to the gut and hepatic lipid peroxidation, which are both commonly associated with parenteral feeding.}, }
@article {pmid31567653, year = {2019}, author = {Guo, DW and Wang, CY and Shih, HC}, title = {N-acetylcysteine and atorvastatin alleviates lung injury due to ischemia-reperfusion injury in rats.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {82}, number = {12}, pages = {909-914}, doi = {10.1097/JCMA.0000000000000193}, pmid = {31567653}, issn = {1728-7731}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Atorvastatin/*therapeutic use ; Cytokines/analysis ; Lung Injury/*drug therapy ; Male ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*complications ; }, abstract = {BACKGROUND: Acute lung injury is a major cause of death following severe injury and ischemia-reperfusion (IR). We investigated the protective effect of pretreatment with N-acetylcysteine (NAC) and atorvastatin (ATOR) in a mesenteric IR rat model.<br><br>METHODS: Male rats were randomly divided into five experimental groups: sham; mesenteric IR; and ATOR, NAC, ATOR + NAC (A + N) pretreatment followed by IR. Blood gas and cytokine levels, biochemistry, and cell count were analyzed. Lung injury was evaluated through histopathology and by using the wet-to-dry lung weight (W/D) ratio.<br><br>RESULTS: Following IR, significant changes were noted in biochemistry, cytokine, and lung injury. Compared with those in the IR group, neutrophil-to-lymphocyte ratio, lactate and alanine aminotransferase (ALT) levels were lower in all pretreatment groups, and creatinine and alkaline phosphatase (ALKP) levels were lower only in the A + N group. Blood pH and base excess (BE) were higher, and partial pressure of carbon dioxide in venous blood (PvCO2) lowered significantly in the ATOR and A + N groups than those in the IR group, and bicarbonate (HCO3-) levels increased only in the A + N group. Lung injury scores and W/D indicated significant attenuation in the A + N group. Compared with those in the IR group, tissue tumor necrosis factor-&#x3b1; levels were significantly lower in all the pretreatment groups and interleukin-1&#x3b2; levels were lower in the A + N group.<br><br>CONCLUSION: NAC and ATOR decreased inflammation and lung injury following mesenteric IR in rats. NAC and ATOR may alleviate lung injury more efficiently in combination than individually.}, }
@article {pmid31565639, year = {2019}, author = {Rajakumaran, A and Ramesh, H and Ashok, R and Balaji, L and Ganesh, A}, title = {Smear Layer Removal and Microhardness Alteration Potential of a Naturally Occurring Antioxidant - An In Vitro Study.}, journal = {Cureus}, volume = {11}, number = {7}, pages = {e5241}, pmid = {31565639}, issn = {2168-8184}, abstract = {INTRODUCTION: It is well-known in the field of endodontics that the presence of a smear layer in the root canals can harbor bacteria and limit the penetration of irrigating solutions and intracanal medications into the dentinal tubules which, in turn, causes the failure of endodontic treatment. Removing the entire smear layer throughout the root canal is essential for the success of endodontic treatment and these chemical agents that facilitate the removal of the smear layer are called chelating agents. Ethylenediaminetetraacetic acid (EDTA), being the most widely used chelating agent, brings about increased reduction in the microhardness of the root dentin, thereby making it friable. N-acetyl cysteine (NAC) is naturally occurring antioxidant that has various beneficial properties for the human being. Several studies have been done in determining the antimicrobial efficacy of NAC against various endodontic pathogens and concluded NAC to be advantageous. The chelating property of NAC has been utilized in heavy metal detoxification, where it binds to the metal ion and removes them from the human system. However, this chelating property has not been explored in the field of endodontics.<br><br>AIM: This study was aimed to compare the ability of N-acetyl cysteine with the conventional chelating agent in the removal of the smear layer and in altering the microhardness of root dentin.<br><br>MATERIALS AND METHODOLOGY: A total of 84 single-rooted human mandibular premolars with relatively similar dimension and morphology, freshly extracted with closed apices, were collected from adult patients. The crowns of all specimens were cut transversally at the cementoenamel junction (CEJ) with the double-faced diamond disc at low speed, with water coolant, to obtain a 12 mm root length. The root canals were randomly divided into three equal groups according to the final irrigation solutions: Group I: 17% EDTA, Group II: 20% NAC, and Group III: distilled water (control). They were then randomly divided into two parts: scanning electron microscope (SEM) analysis for the extent of smear layer removal and microhardness evaluation using the Vicker's hardness test.<br><br>RESULTS: The smear layer removal ability of EDTA and NAC were more effective in the coronal and middle thirds of the root canal. However, both groups showed less smear layer removal in the apical region. Specimens treated with distilled water showed the least reduction in the smear layer throughout the length of the root canals. Regarding the evaluation of microhardness, both EDTA and NAC had a significant reduction in root dentin microhardness. However, the percentage of dentin microhardness reduction was significantly more in the EDTA group (p < 0.05) than N-acetyl cysteine in the coronal, middle, and apical third of the root canals.<br><br>CONCLUSION: The chelating property of NAC is equally effective to that of EDTA in the smear layer from the root canal, and it induced a significantly lesser reduction in microhardness of root dentin than EDTA.}, }
@article {pmid31562333, year = {2019}, author = {Saxena, S and Vekaria, H and Sullivan, PG and Seifert, AW}, title = {Connective tissue fibroblasts from highly regenerative mammals are refractory to ROS-induced cellular senescence.}, journal = {Nature communications}, volume = {10}, number = {1}, pages = {4400}, pmid = {31562333}, issn = {2041-1723}, support = {R01 AR070313/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; *Cellular Senescence ; Connective Tissue/metabolism ; Fibroblasts/cytology/drug effects/*metabolism ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; Murinae ; Oxidants/pharmacology ; Rabbits ; Rats ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {A surveillance system in mammals constantly monitors cell activity to protect against aberrant proliferation in response to damage, injury and oncogenic stress. Here we isolate and culture connective tissue fibroblasts from highly regenerative mammals (Acomys and Oryctolagus) to determine how these cells interpret signals that normally induce cellular senescence in non-regenerating mammals (Mus and Rattus). While H2O2 exposure substantially decreases cell proliferation and increases p53, p21, p16, and p19 in cells from mice and rats, cells from spiny mice and rabbits are highly resistant to H2O2. Quantifying oxygen consumption and mitochondrial stability, we demonstrate that increased intracellular H2O2 is rapidly detoxified in regenerating species, but overwhelms antioxidant scavenging in cells from non-regenerative mammals. However, pretreatment with N-acetylcysteine (NAC) protects mouse and rat cells from ROS-induced cellular senescence. Collectively, our results show that intrinsic cellular differences in stress-sensing mechanisms partially explain interspecific variation in regenerative ability.}, }
@article {pmid31560470, year = {2019}, author = {Shahzamani, S and Jahandideh, AR and Abedi, G and Akbarzadeh, A and Hesaraki, S}, title = {Effect of N-acetyl-cysteine nanoparticles on intra-abdominal adhesion after laparotomy in rats.}, journal = {Polish journal of veterinary sciences}, volume = {22}, number = {3}, pages = {581-588}, doi = {10.24425/pjvs.2019.129967}, pmid = {31560470}, issn = {2300-2557}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Laparotomy/*veterinary ; *Nanoparticles ; *Postoperative Complications ; Rats ; Tissue Adhesions/*drug therapy ; }, abstract = {Postoperative adhesion (POA) is a common and well-known complication with an estimated risk of 50-100%. The antioxidant effect of n-acetyl-cysteine (NAC) can increase intracellular glutathione levels, thereby reducing adhesion. This study was conducted to compare the outcomes of NAC nanoparticles (Nano-NAC) on intra-abdominal adhesion (IAA) after laparotomy in rat. A total of 25 male Wistar rats were randomized into five groups: 50 mg/kg Nano-NAC, 75 mg/kg Nano-NAC, 150 mg/kg Nano-NAC, NAC and control. During the surgical procedure, some sections (2×2cm) were collected through abdominal midline incision to ensure the infliction of peritoneal damage by a standard adhesion. Macroscopic evaluation was performed on the 14th and 28th day and blood samples were collected to evaluate the inflammatory factor (C-reactive protein) on days 0, 14 and 28. According to the serologic results (CRP test), C-reactive protein was at highest level in 150 mg/kg Nano-NAC and control groups and at lowest level in 50 mg/kg Nano-NAC and 75 mg/kg Nano-NAC groups (p⟨0.001). The macroscopic evaluation results showed that frequency of adhesion bands was significantly lower in 50 mg/kg Nano-NAC group than the control at the intervals. Results showed that the intraperitoneal administration of lower Nano-NAC dosages (50 and 75 mg/kg) had a major role in the management of postoperative inflammation. Nano-NAC administration was proved feasible, safe and effective in reduction of the C-reactive protein level.}, }
@article {pmid31556775, year = {2020}, author = {Monte, AS and da Silva, FER and Lima, CNC and Vasconcelos, GS and Gomes, NS and Miyajima, F and Vasconcelos, SMM and Gama, CS and Seeman, MV and de Lucena, DF and Macedo, DS}, title = {Sex influences in the preventive effects of N-acetylcysteine in a two-hit animal model of schizophrenia.}, journal = {Journal of psychopharmacology (Oxford, England)}, volume = {34}, number = {1}, pages = {125-136}, doi = {10.1177/0269881119875979}, pmid = {31556775}, issn = {1461-7285}, mesh = {Acetylcysteine/*pharmacology ; Age Factors ; Animals ; Corpus Striatum/metabolism ; Female ; Glutathione/metabolism ; Hippocampus/metabolism ; Lipid Peroxidation ; Locomotion/drug effects ; Male ; Memory, Short-Term/drug effects ; Nitrites/metabolism ; Parvalbumins/biosynthesis ; Poly I-C ; Prefrontal Cortex/metabolism ; Rats ; Receptors, G-Protein-Coupled/biosynthesis ; Schizophrenia/chemically induced/complications/*prevention &amp; control ; Sensory Gating/drug effects ; *Sex Characteristics ; Social Interaction/drug effects ; Stress, Psychological/complications ; alpha7 Nicotinic Acetylcholine Receptor/biosynthesis ; }, abstract = {BACKGROUND: Schizophrenia (SCZ) is a neurodevelopmental disorder influenced by patient sex. Mechanisms underlying sex differences in SCZ remain unknown. A two-hit model of SCZ combines the exposure to perinatal infection (first-hit) with peripubertal unpredictable stress (PUS, second-hit). N-acetylcysteine (NAC) has been tested in SCZ because of the involvement of glutathione mechanisms in its neurobiology.<br><br>AIMS: We aim to investigate whether NAC administration to peripubertal rats of both sexes could prevent behavioral and neurochemical changes induced by the two-hit model.<br><br>METHODS: Wistar rats were exposed to polyinosinic:polycytidylic acid (a viral mimetic) or saline on postnatal days (PND) 5-7. On PND30-59 they received saline or NAC 220&#x2009;mg/kg and between PND40-48 were subjected to PUS or left undisturbed. On PND60 behavioral and oxidative alterations were evaluated in the prefrontal cortex (PFC) and striatum. Mechanisms of hippocampal memory regulation such as immune expression of G protein-coupled estrogen receptor 1 (GPER), &#x3b1;7-nAChR and parvalbumin were also evaluated.<br><br>RESULTS: NAC prevented sensorimotor gating deficits only in females, while it prevented alterations in social interaction, working memory and locomotor activity in both sexes. Again, in rats of both sexes, NAC prevented the following neurochemical alterations: glutathione (GSH) and nitrite levels in the PFC and lipid peroxidation in the PFC and striatum. Striatal oxidative alterations in GSH and nitrite were observed in females and prevented by NAC. Two-hit induced hippocampal alterations in females, namely expression of GPER-1, &#x3b1;7-nAChR and parvalbumin, were prevented by NAC.<br><br>CONCLUSION: Our results highlights the influences of sex in NAC preventive effects in rats exposed to a two-hit schizophrenia model.}, }
@article {pmid31555026, year = {2019}, author = {Verma, AS and Mallick, P and Dwivedi, PD and Singh, A}, title = {Exogenous supplementation of N-acetylcysteine Can Reduce Hepatotoxicity Induced by Ascites Fluid (Cell-Free) Adsorbed Over Protein-A-Containing Staphylococcus aureus Cowan-I Without Compromising Its Antitumor Effect.}, journal = {Journal of pharmacy &amp; bioallied sciences}, volume = {11}, number = {3}, pages = {205-215}, pmid = {31555026}, issn = {0976-4879}, abstract = {INTRODUCTION: Hepatotoxicity along with enhanced mortality has remained a major concern during the development of antitumor therapy with the use of cell-free ascites fluid adsorbed (ad-AF) over Protein-A-containing Staphylococcus aureus Cowan I (SAC). Major issue with ad-AF inoculation is the significant depletion of hepatic glutathione (GSH). Exogenous supplementation of -SH contents to the host has offered an encouraging hope to explore the possibilities to use ad-AF as a therapeutic material due to its antitumor effects. GSH and l-cysteine have shown a promise with the recovery of -SH contents as well as the recovery of phase I and phase II biotransformation enzymes. Aforementioned observations prompted us to try other -SH donors.<br><br>MATERIALS AND METHODS: Therefore, in this study, N-acetylcysteine (NAC) was used as an exogenous source to provide -SH contents to reduce hepatotoxicity and mortality induced by ad-AF treatment.<br><br>RESULTS: Exogenous supplementation of NAC along with ad-AF treatment to ascites tumor bearers has shown a significant protection against hepatotoxicity and mortality caused by ad-AF. NAC substitution along with ad-AF has significantly enhanced the mean survival time (MST), without altering the antitumor effect of ad-AF as evident from tumor cell counts and viability.<br><br>DISCUSSION: NAC supplementation has been successful to recover hepatic -SH contents along with the significant recovery of phase I and phase II biotransformation enzymes. Marker enzymes for liver injury have also given clear-cut indications for the recovery of tumor bearers from hepatotoxicity induced by ad-AF.<br><br>CONCLUSION: This study has shown that exogenous supplementation of NAC protects the host from the enhanced mortality and hepatotoxicity induced by ad-AF. These observations offer a hope to develop ad-AF as one of the probable treatment strategies for ascites tumors at least at experimental levels.}, }
@article {pmid31553952, year = {2019}, author = {Liu, J and Yao, L and Zhang, M and Jiang, J and Yang, M and Wang, Y}, title = {Downregulation of LncRNA-XIST inhibited development of non-small cell lung cancer by activating miR-335/SOD2/ROS signal pathway mediated pyroptotic cell death.}, journal = {Aging}, volume = {11}, number = {18}, pages = {7830-7846}, pmid = {31553952}, issn = {1945-4589}, mesh = {Acrylamides/pharmacology ; Apoptosis/drug effects/physiology ; Carcinoma, Non-Small-Cell Lung/*genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects/genetics ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Inflammasomes/metabolism ; Lung/metabolism/pathology ; Lung Neoplasms/*genetics/metabolism/pathology ; MicroRNAs/*metabolism ; Pyroptosis/drug effects/*physiology ; RNA, Long Noncoding/*genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/*physiology ; Sulfonamides/pharmacology ; Superoxide Dismutase/*metabolism ; }, abstract = {LncRNA-XIST participated in the regulation of Non-small cell lung cancer (NSCLC) progression, but the underlying mechanisms are still unclear. This study showed that LncRNA-XIST aberrantly overexpressed in either NSCLC tissues or cell lines comparing to their paired control groups. Knock-down of LncRNA-XIST promoted NSCLC cell apoptosis and inhibited cell proliferation, which were reversed by synergistically treating cells with pyroptosis inhibitor Necrosulfonamide (NSA). In addition, knock-down of LncRNA-XIST also promoted reactive oxygen species (ROS) production and NLRP3 inflammasome activation. In parallel, ROS scavenger N-acetyl cysteine (NAC) abrogated the effects of downregulated LncRNA-XIST on NSCLC cell pyroptosis. Furthermore, miR-335 was the downstream target of LncRNA-XIST and overexpressed LncRNA-XIST increased SOD2 expression levels by sponging miR-335. Mechanistically, miR-335 inhibitor reversed the effects of downregulated LncRNA-XIST on ROS levels and cell pyroptosis, which were abrogated by synergistically knocking down SOD2. Taken together, knock-down of LncRNA-XIST inhibited NSCLC progression by triggering miR-335/SOD2/ROS signal pathway mediated pyroptotic cell death.}, }
@article {pmid31553887, year = {2019}, author = {Ko, J and Kang, HJ and Kim, DA and Kim, MJ and Ryu, ES and Lee, S and Ryu, JH and Roncal, C and Johnson, RJ and Kang, DH}, title = {Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {33}, number = {12}, pages = {13334-13345}, doi = {10.1096/fj.201901148R}, pmid = {31553887}, issn = {1530-6860}, mesh = {Allopurinol/toxicity ; Animals ; Cells, Cultured ; Endothelium, Vascular/drug effects/metabolism/*pathology ; Glycocalyx/metabolism/*pathology ; Gout Suppressants/toxicity ; Hyperuricemia/chemically induced/metabolism/*pathology ; Kidney Diseases/chemically induced/metabolism/*pathology ; Male ; Oxidative Stress/*drug effects ; Phenotype ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Uric Acid/*toxicity ; }, abstract = {Recent data suggested a causative role of uric acid (UA) in the development of renal disease, in which endothelial dysfunction is regarded as the key mechanism. Endothelial-to-mesenchymal transition (EndoMT) and shedding of the glycocalyx are early changes of endothelial dysfunction. We investigated whether UA induced EndoMT in HUVECs and an animal model of hyperuricemia fed with 2% oxonic acid for 4 wk. UA induced EndoMT in HUVECs with a generation of reactive oxygen species via the activation of membranous NADPH oxidase (from 15 min) and mitochondria (from 6 h) along with glycocalyx shedding (from 6 h), which were blocked by probenecid. GM6001, an inhibitor of matrix metalloproteinase, alleviated UA-induced glycocalyx shedding and EndoMT. Antioxidants including N-acetyl cysteine, apocynin, and mitotempo ameliorated EndoMT; however, they did not change glycocalyx shedding in HUVECs. In the kidney of hyperuricemic rats, endothelial staining in peritubular capillaries (PTCs) was substantially decreased with a de novo expression of α-smooth muscle actin in PTCs. Plasma level of syndecan-1 was increased in hyperuricemic rats, which was ameliorated by allopurinol. UA caused a phenotypic transition of endothelial cells via induction of oxidative stress with glycocalyx shedding, which could be one of the mechanisms of UA-induced endothelial dysfunction and kidney disease.-Ko, J., Kang, H.-J., Kim, D.-A., Kim, M.-J., Ryu, E.-S., Lee, S., Ryu, J.-H., Roncal, C., Johnson, R. J., Kang, D.-H. Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding.}, }
@article {pmid31552884, year = {2020}, author = {Liu, Y and Wang, H}, title = {Peripheral nerve injury induced changes in the spinal cord and strategies to counteract/enhance the changes to promote nerve regeneration.}, journal = {Neural regeneration research}, volume = {15}, number = {2}, pages = {189-198}, pmid = {31552884}, issn = {1673-5374}, abstract = {Peripheral nerve injury leads to morphological, molecular and gene expression changes in the spinal cord and dorsal root ganglia, some of which have positive impact on the survival of neurons and nerve regeneration, while the effect of others is the opposite. It is crucial to take prompt measures to capitalize on the positive effects of these reactions and counteract the negative impact after peripheral nerve injury at the level of spinal cord, especially for peripheral nerve injuries that are severe, located close to the cell body, involve long distance for axons to regrow and happen in immature individuals. Early nerve repair, exogenous supply of neurotrophic factors and Schwann cells can sustain the regeneration inductive environment and enhance the positive changes in neurons. Administration of neurotrophic factors, acetyl-L-carnitine, N-acetyl-cysteine, and N-methyl-D-aspartate receptor antagonist MK-801 can help counteract axotomy-induced neuronal loss and promote regeneration, which are all time-dependent. Sustaining and reactivation of Schwann cells after denervation provides another effective strategy. FK506 can be used to accelerate axonal regeneration of neurons, especially after chronic axotomy. Exploring the axotomy-induced changes after peripheral nerve injury and applying protective and promotional measures in the spinal cord which help to retain a positive functional status for neuron cell bodies will inevitably benefit regeneration of the peripheral nerve and improve functional outcomes.}, }
@article {pmid31550530, year = {2019}, author = {Khurana, H and Hazari, PP and Mishra, AK}, title = {Radioprotective efficacy of GSH based peptidomimetic complex of manganese against radiation induced damage: DT(GS)2Mn(II).}, journal = {Free radical biology &amp; medicine}, volume = {145}, number = {}, pages = {161-174}, doi = {10.1016/j.freeradbiomed.2019.09.023}, pmid = {31550530}, issn = {1873-4596}, mesh = {Abnormalities, Radiation-Induced/*drug therapy/metabolism/pathology ; Acetylcysteine/metabolism ; Animals ; Cell Survival/drug effects/radiation effects ; DNA Damage/drug effects/radiation effects ; DNA Repair/drug effects/radiation effects ; Glutathione/chemistry/*pharmacology ; Humans ; Manganese/chemistry/metabolism ; Mice ; Oxidative Stress/drug effects/radiation effects ; Peptidomimetics/chemistry/*pharmacology ; Radiation, Ionizing ; Radiation-Protective Agents/chemistry/*pharmacology ; }, abstract = {The adverse effects of ionizing radiation (IR) on biological tissues are mediated via increased production of reactive oxygen species (ROS) often resulting in life-threatening injuries. The effects of ionizing radiation on cells include the formation of ROS, DNA single-strand breaks, double-strand breaks, and extensive base modifications inducing the complex DNA damage. The capacity to endure the radiation insult lies in the biochemical mechanisms and structural properties in many bacterial species such as Deinococcus radiodurans and Thermococcus radiotolerans. In addition, a mechanistic link has established between the presence and accumulation of short peptides and Mn[2+] in the protection of bacteria (Deinococcus radiodurans) from the harmful ionizing radiation. This paradigm has opened up novel avenues of radioprotection in diverse settings and systems for human application. We hereby report a new bifunctional system that comprises of thiol groups in the form of Glutathione (GSH), and manganese to mimic the above system for radioprotection. The present study, therefore, adopts a novel approach to use GSH complexed Mn, and this conjugated system is complying with the prerequisite for radioprotection as seen in the above mechanism. This unique conjugate DT(GS)2Mn(II) was evaluated for its efficacy invitro and invivo. Radioprotective efficacy of DT(GS)2Mn(II) on NIH/3T3 cells revealed that compound could significantly protect cells against radiation-induced toxicity as compared to the standard compound N-acetyl cysteine. Pre-treatment of DT(GS)2Mn(II) increased the survival of mice by 50% compared to radiation alone treatment group. A significant decrease in cytochrome c levels in the group pre-treated with test compound (0.50 ± 0.14) compared to radiation alone group (1.60 ± 0.07) was observed. DT(GS)2Mn(II) attenuated radiation induced apoptosis by promoted expression of anti-apoptotic Bcl-2 along with suppression of cyt-c release and augmented cell survival following irradiation. A distinct improvement in villi length was observed in the group treated with DT(GS)2Mn(II) with an average of 1546 ± 61 μm versus 763 ± 154 μm for radiation alone group. The present findings suggested DT(GS)2Mn(II) is a promising radioprotective agent and exerts it protective effect both invitro and invivo systems by decreasing radiation induced cytotoxicity.}, }
@article {pmid31545445, year = {2019}, author = {Zhang, Z and Xiong, T and Zheng, R and Huang, J and Guo, L}, title = {N‑acetyl cysteine protects HUVECs against lipopolysaccharide‑mediated inflammatory reaction by blocking the NF‑κB signaling pathway.}, journal = {Molecular medicine reports}, volume = {20}, number = {5}, pages = {4349-4357}, doi = {10.3892/mmr.2019.10678}, pmid = {31545445}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Biomarkers ; Cell Survival/drug effects ; Cytokines/metabolism ; Human Umbilical Vein Endothelial Cells/*drug effects/*metabolism ; Humans ; Inflammation/etiology/metabolism ; Inflammation Mediators/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Lipopolysaccharides/adverse effects ; NF-kappa B/*metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Signal Transduction/*drug effects ; }, abstract = {The purpose of the study was to explore the potential protective effects of N‑acetylcysteine (NAC) against lipopolysaccharide (LPS)‑induced inflammatory injury to human umbilical vein endothelial cells (HUVECs). It was also assessed whether the underlying mechanism of this protective effect is mediated via suppression of the nuclear factor‑kappa B (NF‑κB) signaling pathway. Cell viability of HUVECs treated with different concentrations of NAC was assessed using Cell Counting Kit‑8 (CCK‑8) assay. The mRNA expression of inflammatory factors [interleukin‑8 (IL‑8), tumor necrosis factor α (TNF‑α), inducible nitric oxide synthase (iNOS), and intercellular cell adhesive molecule 1 (ICAM‑1)] were assessed using real time semi‑quantitative polymerase chain reaction. Protein expression levels of TNF‑α and IL‑8 were assessed using enzyme‑linked immunosorbent assay. Protein expression levels of ICAM‑1 and the NF‑κB signaling pathway were assessed using western blotting. Nitric reductase method was used to quantify nitric oxide (NO) and iNOS. LPS stimulated the production of TNF‑α, IL‑8, NO, and ICAM‑1 by HUVECs. Moreover, LPS induced activation of the NF‑κB signaling pathway and increased the protein expression of phosphorylated p65. However, pretreatment of HUVECs with NAC significantly attenuated the increase in the expression of inflammatory factors and the level of phosphorylated p65; this indicated that NAC prevented the activation of the NF‑κB signaling pathway. The present findings indicated that NAC protects HUVECs against LPS‑mediated inflammatory reaction and alleviates inflammation. The underlying mechanism is related to the NF‑κB signaling pathway. NAC appears to be a promising agent for prevention and treatment of inflammatory diseases.}, }
@article {pmid31545211, year = {2020}, author = {Zhang, H and Yang, X and Li, X and Cheng, Y and Zhang, H and Chang, L and Sun, M and Zhang, Z and Wang, Z and Niu, Q and Wang, T}, title = {Oxidative and nitrosative stress in the neurotoxicity of polybrominated diphenyl ether-153: possible mechanism and potential targeted intervention.}, journal = {Chemosphere}, volume = {238}, number = {}, pages = {124602}, doi = {10.1016/j.chemosphere.2019.124602}, pmid = {31545211}, issn = {1879-1298}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cerebral Cortex/drug effects/*pathology ; Glutathione/metabolism ; Halogenated Diphenyl Ethers/metabolism/*toxicity ; Male ; Malondialdehyde/metabolism ; Nerve Growth Factors/metabolism ; Neurons/drug effects ; Neurotoxicity Syndromes/*pathology ; Neurotrophin 3/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type I/metabolism ; Nitrosative Stress/*drug effects/physiology ; Oxidative Stress/*drug effects/physiology ; Polybrominated Biphenyls/*toxicity ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; }, abstract = {Polybrominated diphenyl ethers (PBDEs) have been known to exhibit neurotoxicity in rats; however, the underlying mechanism remains unknown and there is no available intervention. In this study, we aimed to investigate the role of oxidative and nitrosative stress in the neurotoxicity in the cerebral cortex and primary neurons in rats following the BDE-153 treatment. Compared to the untreated group, BDE-153 treatment significantly induced the neurotoxic effects in rats, as manifested by the increased lactate dehydrogenase (LDH) activities and cell apoptosis rates, and the decreased neurotrophic factor contents and cholinergic enzyme activities in rats' cerebral cortices and primary neurons. When compared to the untreated group, the oxidative and nitrosative stress had occurred in the cerebral cortex or primary neurons in rats following the BDE-153 treatment, as manifested by the increments in levels of reactive oxygenspecies (ROS), malondialdehyde (MDA), nitric oxide (NO), and neuronal nitric oxide synthase (nNOS) mRNA and protein expressions, along with the decline in levels of superoxide dismutase (SOD) activity, glutathione (GSH) content, and peroxiredoxin I (Prx I) and Prx II mRNA and protein expressions. In addition, the ROS scavenger N-acetyl-l-cysteine (NAC) or NO scavenger NG-Nitro-l-arginine (L-NNA) significantly rescued the LDH leakage and cell survival, reversed the neurotrophin contents and cholinergic enzymes, mainly via regaining balance between oxidation/nitrosation and antioxidation. Overall, our findings suggested that oxidative and nitrosative stresses are involved in the neurotoxicity induced by BDE-153, and that the antioxidation is a potential targeted intervention.}, }
@article {pmid31542421, year = {2019}, author = {Sumneang, N and Kumfu, S and Khamseekaew, J and Siri-Angkul, N and Fucharoen, S and Chattipakorn, SC and Chattipakorn, N}, title = {Combined iron chelator with N-acetylcysteine exerts the greatest effect on improving cardiac calcium homeostasis in iron-overloaded thalassemic mice.}, journal = {Toxicology}, volume = {427}, number = {}, pages = {152289}, doi = {10.1016/j.tox.2019.152289}, pmid = {31542421}, issn = {1879-3185}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/*metabolism ; Deferiprone/*pharmacology ; Heart/drug effects ; Homeostasis ; Iron Chelating Agents/*pharmacology ; Iron Overload/*metabolism ; Mice, Inbred C57BL ; Myocardium/*metabolism ; Myocytes, Cardiac/drug effects/metabolism ; Thalassemia/*metabolism ; Ventricular Function, Left/drug effects ; }, abstract = {The morbidity and mortality in thalassemia patients are predominantly caused by iron overload cardiomyopathy (IOC). Iron-induced cardiac intracellular Ca[2+] ([Ca[2+]]i) dysregulation is among the core pathophysiological processes in IOC-related heart failure. Although cardioprotective roles of deferiprone (DFP) and N-acetylcysteine (NAC) have been reported, their effect on cardiac [Ca[2+]]i transients and Ca[2+]-regulatory protein expression in thalassemic mice is unknown. In the present study, iron overload condition was induced in wild-type (WT) and heterozygous β-thalassemic (HT) mice by a high-iron diet. The iron-overloaded mice subsequently received a vehicle, DFP, NAC, or DFP plus NAC co-therapy. In both WT and HT iron-overloaded mice, DFP and NAC had similar efficacy in decreasing plasma non-transferrin-bound iron, decreasing cardiac iron concentration (CIC) and relieving systolic dysfunction. DFP plus NAC co-therapy, however, was better than the monotherapy in reducing CIC and restoring cardiac [Ca[2+]]i transient amplitude and rising rate. All regimens produced no change in cardiac Ca[2+]-regulatory protein expression. We provided the first evidence regarding the synergistic effect of combined iron chelator-antioxidant therapy on cardiac [Ca[2+]]i homeostasis in iron-overloaded thalassemic mice, with consistent improvement of cardiac contractility.}, }
@article {pmid31539536, year = {2019}, author = {Song, Q and Feng, YB and Wang, L and Shen, J and Li, Y and Fan, C and Wang, P and Yu, SY}, title = {COX-2 inhibition rescues depression-like behaviors via suppressing glial activation, oxidative stress and neuronal apoptosis in rats.}, journal = {Neuropharmacology}, volume = {160}, number = {}, pages = {107779}, doi = {10.1016/j.neuropharm.2019.107779}, pmid = {31539536}, issn = {1873-7064}, mesh = {Animals ; Antidepressive Agents/administration &amp; dosage/pharmacology ; Apoptosis/*drug effects ; Celecoxib/administration &amp; dosage/*pharmacokinetics ; Cyclooxygenase 2/metabolism ; Cyclooxygenase 2 Inhibitors/administration &amp; dosage/*pharmacology ; Depression/*drug therapy/physiopathology ; Disease Models, Animal ; Inflammation/drug therapy ; Male ; Neuroglia/drug effects ; Neurons/*drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Stress, Psychological ; }, abstract = {Depression is considered a neuropsychiatric condition which is associated with neuronal injury within specific brain regions. We previously reported that cyclo-oxygenase (COX)-2, a rate-limiting enzyme for prostaglandin E2 (PGE2) synthesis, significantly enhanced depressive-like disorders induced by chronic stress in rats. However, the underlying molecular mechanisms and identification of potential therapeutic targets for preventing neuronal injury associated with depression remain largely uncharacterized. Here, we show that COX-2 inhibition by celecoxib protects against neuronal injury through suppression of oxidative stress and, in this way, mediates its antidepressant effects. COX-2 is highly expressed in the hippocampal dentate gyrus (DG) of rat depression model and its activity is responsible for depression-like behaviors as demonstrated in two independent rat models of depression. Inhibition of COX-2 exerts neuroprotective actions in DG regions, including suppressing neuroinflammatory response, against oxidative stress and neuronal apoptosis, which are the critical risk factors for neuronal injury and pathophysiology of depression. Moreover, the antioxidant, N-acetylcysteine (NAC), significantly attenuates oxidative stress levels and dendritic spine deficiencies resulting from COX-2 overexpression; and, suppression of oxidative stress by NAC also significantly ameliorates depressive behaviors in rats. These findings suggest that selective inhibition of COX-2 ameliorates depression-like behaviors in rat models of depression. This selective inhibition of COX-2 appears to be protective against oxidative stress and neuronal deterioration resulting from chronic stress. Taken together, these findings have potentially important clinical implications with regard to the development of novel therapeutic approaches in the treatment of neuropsychiatric conditions like depression.}, }
@article {pmid31534523, year = {2019}, author = {Li, J and Zhou, C and Luo, C and Qian, B and Liu, S and Zeng, Y and Hou, J and Deng, B and Sun, Y and Yang, J and Yuan, Q and Zhong, A and Wang, J and Sun, J and Wang, Z}, title = {N-acetyl cysteine-loaded graphene oxide-collagen hybrid membrane for scarless wound healing.}, journal = {Theranostics}, volume = {9}, number = {20}, pages = {5839-5853}, pmid = {31534523}, issn = {1838-7640}, mesh = {Acetylcysteine/*chemistry/therapeutic use ; Animals ; Cell Movement/drug effects ; Collagen/*chemistry ; Elastic Modulus ; Graphite/*chemistry ; Male ; Mice ; Microscopy, Electron, Scanning ; NIH 3T3 Cells ; Porosity ; Rats ; Reactive Oxygen Species/metabolism ; Wound Healing/drug effects ; X-Ray Diffraction ; }, abstract = {Wound dressings composed of natural polymers, such as type I collagen, possess good biocompatibility, water holding capacity, air permeability, and degradability, and can be used in wound repair. However, due to the persistent oxidative stress in the wound area, the migration and proliferation of fibroblasts might be suppressed, leading to poor healing. Thus, collagen-containing scaffolds are not suitable for accelerated wound healing. Antioxidant N-acetyl cysteine (NAC) is known to reduce the reactive oxygen species (ROS) and has been widely used in the clinic. Theoretically, the carboxyl group of NAC allows loading of graphene oxide (GO) for sustained release and may also enhance the mechanical properties of the collagen scaffold, making it a better wound-dressing material. Herein, we demonstrated an innovative approach for a potential skin-regenerating hybrid membrane using GO incorporated with collagen I and NAC (N-Col-GO) capable of continuously releasing antioxidant NAC. Methods: The mechanical stability, water holding capacity, and biocompatibility of the N-Col-GO hybrid membrane were measured in vitro. A 20 mm rat full-skin defect model was created to evaluate the repair efficiency of the N-Col-GO hybrid membrane. The vascularization and scar-related genes in the wound area were also examined. Results: Compared to the Col only scaffold, N-Col-GO hybrid membrane exhibited a better mechanical property, stronger water retention capacity, and slower NAC release ability, which likely promote fibroblast migration and proliferation. Treatment with the N-Col-GO hybrid membrane in the rat wound model showed complete healing 14 days after application which was 22% faster than the control group. HE and Masson staining confirmed faster collagen deposition and better epithelization, while CD31 staining revealed a noticeable increase of vascularization. Furthermore, Rt-PCR demonstrated decreased mRNA expression of profibrotic and overexpression of anti-fibrotic factors indicative of the anti-scar effect. Conclusion: These findings suggest that N-Col-GO drug release hybrid membrane serves as a better platform for scarless skin regeneration.}, }
@article {pmid31531084, year = {2019}, author = {Barzi, F and Miri, R and Sadeghi, R and Sistanizad, M and Sadeghi, M and Mahjoob, MP and Chehrazi, M}, title = {A Randomized Double Blind Placebo Controlled Trial Examining the Effects of Pentoxifylline on Contrast Induced Nephropathy Reduction after Percutaneous Coronary Intervention in High Risk Candidates.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {18}, number = {2}, pages = {1040-1046}, pmid = {31531084}, issn = {1735-0328}, abstract = {Contrast-induced nephropathy (CIN) (known as contrast-induced acute kidney injury) occurs as a result of acute worsening of renal function following a procedure with administration of iodine contrasts agent and remains a substantial concern in clinical practices. The purpose of this study is to investigate the preventive effect of Pentoxifylline supplementation on reduction of CIN occurrence after percutaneous coronary intervention among patients who were high risk of CIN according to Mehran score. In randomized, double-blind clinical trial patients who undergo coronary angiography with Mehran Score ≥ 11 consisted of our population. Patients in a ratio 1:1, divided into two groups received saline 0.9% plus N-acetyl cysteine and Pentoxifylline 400 mg three times per day 24 h before angiography until 48 h after angiography. In control group, the patients received placebo instead of PTX in a same manner as the control group. The endpoint was the incidence of CIN defined as creatinine increase of 0.5 mg/dL within 2 days after contrast. There were no significant differences in baseline characteristics. CIN occurred in 3 (5.5%) and 4 (7.3%) patients of the both groups (Pentoxifylline and control), respectively (p = 0.69; incidence odds ratio 1.36; 95% CI 0.29-6.38). No significant differences were seen in secondary outcome measures and changes in the level of creatinine (p = 0.54). In high-risk patients undergoing coronary angiography pentoxifylline supplementation had protection effect against contrast-induced nephropathy greater than placebo based hydration, but, not supported by our data.}, }
@article {pmid31530743, year = {2019}, author = {Ramburrun, P and Kumar, P and Choonara, YE and du Toit, LC and Pillay, V}, title = {Design and characterisation of PHBV-magnesium oleate directional nanofibers for neurosupport.}, journal = {Biomedical materials (Bristol, England)}, volume = {14}, number = {6}, pages = {065015}, doi = {10.1088/1748-605X/ab453c}, pmid = {31530743}, issn = {1748-605X}, mesh = {Acetylcysteine/chemistry ; Animals ; Axons/metabolism ; Biocompatible Materials/chemistry ; *Biomimetics ; Cell Proliferation ; Magnesium/*chemistry ; Nanofibers/chemistry ; Nerve Regeneration/drug effects ; Nerve Tissue ; Neurons/cytology ; Oleic Acid/*chemistry ; PC12 Cells ; Polyesters/*chemistry ; Rats ; Regenerative Medicine/*methods ; Tensile Strength ; Tissue Engineering ; Tissue Scaffolds/chemistry ; Water/chemistry ; }, abstract = {The focus of significance in neuronal repair strategies is the design of scaffold systems capable of promoting neuronal regeneration and directional guidance via provision of a biomimetic environment resemblance of native neural tissue. The purpose of this study was to synthesize triple-cue electrospun aligned nanofibrous films (physical cue) of poly(3-hyroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV) blended with magnesium-oleate (MgOl) (chemical cue) and N-acetyl-L-cysteine (NAC) (therapeutic cue) with potential incorporation into hollow nerve guidance conduits for an enhanced regenerative strategy. A Box-Behnken experimental design of 15 formulations, were analysed for crystallinity, textural properties and in vitro water-uptake, erosion, NAC-release and PC12 cell viability. Nucleating effects of MgOl provided tuning of PHBV electrospinning-induced crystallinity and mechanical properties. Tensile strengths and deformation moduli of ±12 MPa and ±7 MP, respectively, were attainable, thereby matching native nerve mechanics. Crystallinity changes ascribed differing release kinetics to NAC over 30 d: diffusion-based (42%-58% crystallinity with 33%-47% fractional release) and polymer-relaxational (59%-65% crystallinity with 60%-82% fractional release). The synergistic activity of MgOl and NAC increased PC12 proliferation by 32.6% compared to the control. MgOl produced dual actions as non-toxic plasticiser and PC12 cell proliferation-promoter via nucleation and neurotrophic-like effects, respectively. Controlled release of NAC imparted neuro-protectant effects on PC12 cells and promoted neurite extension, thus, making electrospun PHBV-MgOl nanofibrous films a versatile and promising approach for axonal guidance in peripheral nerve repair strategies.}, }
@article {pmid31530262, year = {2019}, author = {Abrigo, J and Marín, T and Aguirre, F and Tacchi, F and Vilos, C and Simon, F and Arrese, M and Cabrera, D and Cabello-Verrugio, C}, title = {N-Acetyl Cysteine Attenuates the Sarcopenia and Muscle Apoptosis Induced by Chronic Liver Disease.}, journal = {Current molecular medicine}, volume = {20}, number = {1}, pages = {60-71}, doi = {10.2174/1566524019666190917124636}, pmid = {31530262}, issn = {1875-5666}, mesh = {Acetylcysteine/*pharmacology ; Aging/drug effects/metabolism/pathology ; Animals ; Apoptosis/drug effects ; Disease Models, Animal ; End Stage Liver Disease/chemically induced/complications/*drug therapy/pathology ; Humans ; Mice ; Muscle Fibers, Skeletal/drug effects/pathology ; Muscular Atrophy/*drug therapy/etiology/metabolism/pathology ; Oxidative Stress/drug effects ; Pyridines/toxicity ; Sarcopenia/*drug therapy/etiology/metabolism/pathology ; }, abstract = {BACKGROUND: Sarcopenia is characterized by the loss of muscle mass and strength (muscle atrophy) because of aging or chronic diseases, such as chronic liver disease (CLD). Different mechanisms are involved in skeletal muscle atrophy, including decreased muscle fibre diameter and myosin heavy chain levels and increased ubiquitin-proteasome pathway activity, oxidative stress and myonuclear apoptosis. We recently found that all these mechanisms, except myonuclear apoptosis, which was not evaluated in the previous study, were involved in muscle atrophy associated with hepatotoxin 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced CLD.<br><br>OBJECTIVE: In the present study, we evaluated the involvement of myonuclear apoptosis in CLD-associated sarcopenia and the effect of N-acetyl cysteine (NAC) treatment on muscle strength and apoptosis, using a DDC-supplemented diet-fed mouse model.<br><br>METHODS: Four-month-old male C57BL6 mice were fed with a standard or DDCsupplemented diet for six weeks in the absence or presence of NAC treatment.<br><br>RESULTS: Our results showed that NAC attenuated the decrease in muscle fibre diameter and muscle strength associated with CLD-induced muscle wasting in gastrocnemius (GA) muscle of DDC-supplemented diet-fed mice. In addition, in GA muscle of the mice fed with DDC-supplemented diet-induced CLD showed increased myonuclear apoptosis compared with the GA muscle of the control diet-fed mice, as evidenced by increased apoptotic nuclei number, caspase-8 and caspase-9 expression, enzymatic activity of caspase-3 and BAX/BCL-2 ratio. NAC treatment inhibited all the mechanisms associated with myonuclear apoptosis in the GA muscle.<br><br>CONCLUSION: To our knowledge, this is the first study which reports the redox regulation of muscle strength and myonuclear apoptosis in CLD-induced sarcopenia.}, }
@article {pmid31527329, year = {2019}, author = {Kim, SO and Cha, HJ and Park, C and Lee, H and Hong, SH and Jeong, SJ and Park, SH and Kim, GY and Leem, SH and Jin, CY and Hwang, EJ and Choi, YH}, title = {Cordycepin induces apoptosis in human bladder cancer T24 cells through ROS-dependent inhibition of the PI3K/Akt signaling pathway.}, journal = {Bioscience trends}, volume = {13}, number = {4}, pages = {324-333}, doi = {10.5582/bst.2019.01214}, pmid = {31527329}, issn = {1881-7823}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Chromones/pharmacology ; Deoxyadenosines/*pharmacology/therapeutic use ; Drug Evaluation, Preclinical ; Humans ; Morpholines/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Signal Transduction/*drug effects ; Urinary Bladder Neoplasms/*drug therapy/pathology ; }, abstract = {Cordycepin, a derivative of nucleoside adenosine, is one of the active ingredients extracted from the fungi of genus Cordyceps, which have been used for traditional herbal remedies. In this study, we examined the effect of cordycepin on the proliferation and apoptosis of human bladder cancer T24 cells and its mechanism of action. Cordycepin treatment significantly reduced the cell survival rate of T24 cells in a concentration-dependent manner, which was associated with the induction of apoptosis. Cordycepin activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, cordycepin increased the Bax/Bcl-2 ratio and truncation of Bid, and destroyed the integrity of mitochondria, which contributed to the cytosolic release of cytochrome c. Moreover, cordycepin effectively inactivated the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, while LY294002, a PI3K/Akt inhibitor, increased the apoptosis-inducing effect of cordycepin. Cordycepin further enhanced the intracellular levels of reactive oxygen species (ROS), while the addition of N-acetyl cysteine (NAC), a ROS inhibitor, significantly diminished cordycepin-induced mitochondrial dysfunction and growth inhibition, and also blocked the inactivation of PI3K/Akt signaling pathway. Furthermore, the presence of NAC significantly attenuated the enhanced apoptotic cell death and reduction of cell viability by treatment with cordycepin and LY294002. Collectively, the data indicate that cordycepin induces apoptosis through the activation of extrinsic and intrinsic apoptosis pathways and the ROS-dependent inactivation of PI3K/Akt signaling in human bladder cancer T24 cells.}, }
@article {pmid31524245, year = {2019}, author = {Xiong, T and Zhang, Z and Zheng, R and Huang, J and Guo, L}, title = {N‑acetyl cysteine inhibits lipopolysaccharide‑induced apoptosis of human umbilical vein endothelial cells via the p38MAPK signaling pathway.}, journal = {Molecular medicine reports}, volume = {20}, number = {3}, pages = {2945-2953}, doi = {10.3892/mmr.2019.10526}, pmid = {31524245}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Biomarkers ; Cell Survival/drug effects ; Human Umbilical Vein Endothelial Cells/*drug effects/*metabolism ; Humans ; Lipopolysaccharides/*pharmacology ; MAP Kinase Signaling System/*drug effects ; Nitric Oxide/metabolism ; Phosphorylation/drug effects ; }, abstract = {Lipopolysaccharide (LPS) can regulate the expression of apoptotic factors, including caspase‑3, Bcl‑2 and Bcl‑2‑associated X protein (Bax). Nitric oxide (NO) plays an important role in apoptosis. N‑acetyl cysteine (NAC) has been shown to exhibit antioxidant effects in vitro. However, the effects of NAC on LPS‑induced apoptosis of human umbilical vein endothelial cells (HUVECs) and the associated mechanisms are not well characterized. The present study explored the effect of NAC on LPS‑induced apoptosis of HUVECs and determined the participation of the p38 mitogen‑activated protein kinase (MAPK) pathway in the process of apoptosis. Cell viability was assessed using the Cell Counting Kit‑8 (CCK‑8) assay. The expression of caspase‑3, Bax, Bcl‑2, phosphorylated (p)‑p38MAPK/total (t‑)p38MAPK and p‑endothelial e nitric oxide synthase (eNOS)/t‑eNOS proteins were determined by western blotting. The expression levels of caspase‑3, Bax and Bcl‑2 mRNA were determined using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The rate of apoptosis was determined using flow cytometry. An NO detection kit (nitric reductase method) was used to determine NO concentration. The results of CCK‑8 and flow cytometric analyses showed that pretreatment of HUVECs with NAC or p38MAPK inhibitor (SB203580) attenuated LPS‑induced decrease in cell viability and increase in cell apoptosis. RT‑qPCR and western blotting showed that LPS promoted caspase‑3 and Bax expression, but inhibited that of Bcl‑2 in HUVECs; however, these effects were attenuated by pretreatment with NAC or SB203580. LPS stimulation significantly enhanced the expression of p‑p38MAPK protein and reduced the expression of p‑eNOS protein; however, these effects were attenuated by pretreatment with NAC or SB203580. NAC pretreatment attenuated LPS‑induced inhibition of NO synthesis, which was consistent with the effects of SB203580. The results demonstrated that NAC pretreatment alleviated LPS‑induced apoptosis and inhibition of NO production in HUVECs. Furthermore, these effects were proposed to be mediated via the p38MAPK signaling pathway.}, }
@article {pmid31521245, year = {2019}, author = {Wang, X and Bian, Y and Zhang, R and Liu, X and Ni, L and Ma, B and Zeng, R and Zhao, Z and Song, X and Liu, C}, title = {Melatonin alleviates cigarette smoke-induced endothelial cell pyroptosis through inhibiting ROS/NLRP3 axis.}, journal = {Biochemical and biophysical research communications}, volume = {519}, number = {2}, pages = {402-408}, doi = {10.1016/j.bbrc.2019.09.005}, pmid = {31521245}, issn = {1090-2104}, mesh = {Animals ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Cigarette Smoking/adverse effects ; Endothelial Cells/drug effects/metabolism ; Humans ; Melatonin/*pharmacology ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists &amp; inhibitors/metabolism ; Oxidative Stress/drug effects ; Pyroptosis/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Endothelial dysfunction (ED) is a crucial and initial stage for the development of cardiovascular diseases. Accumulated evidence has demonstrated causative links between cigarette smoke (CS) and ED. However, the underlying mechanisms remain largely unknown. Pyroptosis is a unique form of inflammatory cell death. In this study, we found that cigarette smoke extract (CSE) increased pyroptosis in endothelial cells (ECs) as evidenced by increasing lactate dehydrogenase release and the number of propidium iodide (PI) positive cells. A specific NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inhibitor (MCC950) pretreatment dramatically reduced CSE-induced pyroptosis. Additionally, we also observed that N-Acetylcysteine (NAC, a ROS scavenger) pretreatment inhibited NLRP3 inflammasome activation as evidenced by suppressing the upregulation of NLRP3, ASC, cleaved-caspase-1, GSDMD-N, IL-1β and IL-18 protein levels in CSE-treated ECs. Meanwhile, NAC pretreatment also remarkably inhibited CSE-induced EC pyroptosis. Melatonin is a hormone synthesized and secreted by mammalian pineal gland and plays a protective role in various cardiovascular diseases through its powerful anti-inflammatory and antioxidant properties. In this study, melatonin was observed to inhibit ROS production, NLRP3 inflammasome activation and pyroptosis in CSE-treated ECs. Moreover, oxidative stress and NLRP3 inflammasome activation in carotid arteries of smoking rats was also inhibited by melatonin. In conclusion, our study generated two novel findings, (i) CS activates ROS/NLRP3 axis and induces EC pyroptosis; (ii) melatonin attenuates CS-induced EC pyroptosis by inhibiting ROS/NLRP3 axis.}, }
@article {pmid31519249, year = {2019}, author = {Firouzian, F and Pourshoja, P and Nili-Ahmadabadi, A and Ranjbar, A}, title = {Hepatoprotective effect of N-acetylcystein loaded niosomes on liver function in paraquat-induced acute poisoning.}, journal = {Pesticide biochemistry and physiology}, volume = {160}, number = {}, pages = {146-153}, doi = {10.1016/j.pestbp.2019.08.001}, pmid = {31519249}, issn = {1095-9939}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Herbicides/*poisoning ; Liver/*drug effects ; Male ; Nanoparticles/*chemistry ; Paraquat/*poisoning ; Rats ; Rats, Wistar ; }, abstract = {Paraquat (PQ) is widely used as a herbicide around the world. PQ intoxication causes liver disease mainly in mammals. N-acetyl cysteine (NAC) is a medication that has positive effects in reducing the liver intoxication caused by PQ. Here, after formulating a NAC noisome nanoparticle (NACNP), we compared the niosomes and NAC on liver toxicity caused by PQ. Thirty male rats were divided into 5 groups and were treated intraperitoneally with PQ and NAC and NACNP for 24 h. PQ group received 35 mg/kg/day of PQ, while NAC and NACNP groups were administered with 25 mg/kg/day of NAC and NACNP, respectively. In addition, 6 rats receiving saline solution were considered as control group. Serum and liver tissue samples were collected from all rats. Alanine (AST) and aspartate (ALT) aminotransferase levels, and oxidative stress biomarkers including total antioxidant capacity (TAC), lipid peroxidation (LPO), and total thiol groups (TTG) levels were determined. Histological samples were also analyzed using hematoxylin and eosin staining slides. PQ administration resulted in hepatic injury as evidenced by increases in serum AST and ALT levels (p < .001). NACNP decreased LPO, TAC, and TTG levels compered to PQ group in liver tissue. Treatment of animals with NACNP was significantly more effective than free NAC in reducing PQ-induced hepatotoxicity (p < .05). Histological evaluation showed that PQ caused tissue inflammation, which was reduced by NAC treatment. This reduction was stronger for NACNP. Given these results, the use of NACNP, compared to NAC, was more protective against the development of the PQ-induced liver toxicity.}, }
@article {pmid31513294, year = {2020}, author = {Dagnino, S and Bodinier, B and Grigoryan, H and Rappaport, SM and Karimi, M and Guida, F and Polidoro, S and Edmands, WB and Naccarati, A and Fiorito, G and Sacerdote, C and Krogh, V and Vermeulen, R and Vineis, P and Chadeau-Hyam, M}, title = {Agnostic Cys34-albumin adductomics and DNA methylation: Implication of N-acetylcysteine in lung carcinogenesis years before diagnosis.}, journal = {International journal of cancer}, volume = {146}, number = {12}, pages = {3294-3303}, doi = {10.1002/ijc.32680}, pmid = {31513294}, issn = {1097-0215}, support = {Mechanomics/22184/CRUK_/Cancer Research UK/United Kingdom ; 22184/CRUK_/Cancer Research UK/United Kingdom ; Pump priming/MR/L019744/1/MRC_/Medical Research Council/United Kingdom ; R33CA191159/CA/NCI NIH HHS/United States ; MR/S019669/1/MRC_/Medical Research Council/United Kingdom ; 001/WHO_/World Health Organization/International ; }, mesh = {Acetylcysteine/*metabolism ; Biomarkers, Tumor/blood/genetics/metabolism ; Carcinogenesis/*genetics ; Case-Control Studies ; CpG Islands/genetics ; DNA Adducts/*blood/genetics/metabolism ; DNA Methylation ; Epigenomics/methods ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms/blood/*epidemiology/genetics ; Male ; Middle Aged ; Oxidation-Reduction ; Prospective Studies ; Risk Assessment/methods ; Smoking/*adverse effects/blood/genetics ; }, abstract = {Although smoking and oxidative stress are known contributors to lung carcinogenesis, their mechanisms of action remain poorly understood. To shed light into these mechanisms, we applied a novel approach using Cys34-adductomics in a lung cancer nested case-control study (n = 212). Adductomics profiles were integrated with DNA-methylation data at established smoking-related CpG sites measured in the same individuals. Our analysis identified 42 Cys34-albumin adducts, of which 2 were significantly differentially abundant in cases and controls: adduct of N-acetylcysteine (NAC, p = 4.15 × 10[-3]) and of cysteinyl-glycine (p = 7.89 × 10[-3]). Blood levels of the former were found associated to the methylation levels at 11 smoking-related CpG sites. We detect, for the first time in prospective blood samples, and irrespective of time to diagnosis, decreased levels of NAC adduct in lung cancer cases. Altogether, our results highlight the potential role of these adducts in the oxidative stress response contributing to lung carcinogenesis years before diagnosis.}, }
@article {pmid31512726, year = {2020}, author = {Chou, CH and Chen, SU and Chen, CD and Shun, CT and Wen, WF and Tu, YA and Yang, JH}, title = {Mitochondrial Dysfunction Induced by High Estradiol Concentrations in Endometrial Epithelial Cells.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {105}, number = {1}, pages = {}, doi = {10.1210/clinem/dgz015}, pmid = {31512726}, issn = {1945-7197}, mesh = {Animals ; Apoptosis ; Cells, Cultured ; Endometrium/drug effects/metabolism/*pathology ; Epithelial Cells/drug effects/metabolism/*pathology ; Estradiol/*pharmacology ; Estrogens/*pharmacology ; Female ; Humans ; Mice ; Mice, Inbred ICR ; Mitochondria/drug effects/metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; }, abstract = {CONTEXT: A supraphysiological estradiol (E2) concentration after ovarian stimulation is known to result in lower embryo implantation rates in in vitro fertilization. Endometrial epithelial cell (EEC) apoptosis occurs after the stimulation with high E2 concentrations, and mitochondria play important roles in cell apoptosis.<br><br>OBJECTIVE: To investigate the mitochondrial function in EECs after the stimulation with high E2 concentrations.<br><br>MATERIALS AND METHODS: Human EECs were purified and cultured with different E2 concentrations (10-10, 10-9, 10-8, 10-7 M) in vitro, in which 10-7 M is supraphysiologically high. Eight-week-old female mouse endometrium was obtained 5.5 days after the injection of 1.25 IU or 20 IU equine chorionic gonadotropin, roughly during the embryo implantation window, to examine the in vivo effects of high E2 concentrations on mouse EECs.<br><br>RESULTS: In vivo and in vitro experiments demonstrated decreased mitochondrial DNA contents and ATP formation after EECs were stimulated with supraphysiologically high E2 concentrations than those stimulated with a physiologic E2 concentration. Less prominent immunofluorescence mitochondrial staining, fewer mitochondria numbers under electron microscopy, lower 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide aggregate/monomer ratio, and greater reactive oxygen species (ROS) production were found after EECs were stimulated with supraphysiologically high E2 concentrations. The high E2-induced ROS production was reduced when EECs were pretreated with N-acetyl-cysteine in vitro, but remained unchanged after the pretreatment with coenzyme Q10.<br><br>CONCLUSION: High E2 concentrations increase extramitochondrial ROS production in EECs and subsequently result in mitochondrial dysfunction.}, }
@article {pmid31510052, year = {2019}, author = {Tsai, IJ and Lin, WC and Yang, YH and Tseng, YL and Lin, YH and Chou, CH and Tsau, YK}, title = {High Concentration of C5a-Induced Mitochondria-Dependent Apoptosis in Murine Kidney Endothelial Cells.}, journal = {International journal of molecular sciences}, volume = {20}, number = {18}, pages = {}, pmid = {31510052}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology ; Aniline Compounds/pharmacology ; Animals ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Complement C5a/genetics/*pharmacology ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Endothelial Cells/*drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Humans ; Kidney/cytology ; Mice ; Mitochondria/*metabolism ; Reactive Oxygen Species/metabolism ; Receptor, Anaphylatoxin C5a/antagonists &amp; inhibitors/metabolism ; Recombinant Proteins/*pharmacology ; Tetrahydronaphthalenes/pharmacology ; }, abstract = {Patients with a relapse of idiopathic nephrotic syndrome have significantly increased levels of serum complement component 5a (C5a), and proteinuria has been noted in mice treated with C5a via changes in permeability of kidney endothelial cells (KECs) in established animal models. However, the apoptosis of KECs treated with high concentrations of C5a has also been observed. As mitochondrial damage is known to be important in cell apoptosis, the aim of this study was to examine the association between C5a-induced mouse KEC apoptosis and mitochondrial damage. Mouse KECs were isolated and treated with different concentrations of C5a. Cell viability assays showed that a high-concentration mouse recombinant protein C5a (rmC5a) treatment reduced mouse KEC growth. Cell cycle phase analysis, including apoptosis (sub-G1 phase) showed an increased percentage of the subG1 phase with a high-concentration rmC5a treatment. Cytochrome c and caspase 3/9 activities were significantly induced in the mouse KECs after a high-dose rmC5a (50 ng/mL) treatment, and this was rescued by pretreatment with the C5a receptor (C5aR) inhibitor (W-54011) and N-acetylcysteine (NAC). Reactive oxygen species (ROS) formation was detected in C5a-treated mouse KECs; however, W-54011 or NAC pretreatment inhibited high-dose rmC5a-induced ROS formation and also reduced cytochrome c release, apoptotic cell formation, and apoptotic DNA fragmentation. These factors determined the apoptosis of mouse KECs treated with high-dose C5a through C5aR and subsequently led to apoptosis via ROS regeneration and cytochrome c release. The results showed that high concentrations of C5a induced mouse KEC apoptosis via a C5aR/ROS/mitochondria-dependent pathway. These findings may shed light on the potential mechanism of glomerular sclerosis, a process in idiopathic nephrotic syndrome causing renal function impairment.}, }
@article {pmid31509891, year = {2020}, author = {Pajuelo, D and Gonzalez-Juarbe, N and Niederweis, M}, title = {NAD hydrolysis by the tuberculosis necrotizing toxin induces lethal oxidative stress in macrophages.}, journal = {Cellular microbiology}, volume = {22}, number = {1}, pages = {e13115}, pmid = {31509891}, issn = {1462-5822}, support = {R01 AI121354/AI/NIAID NIH HHS/United States ; }, mesh = {Bacterial Toxins/*metabolism ; Humans ; Hydrolysis ; Jurkat Cells ; Macrophages/*microbiology/*pathology ; Mycobacterium tuberculosis/enzymology/*pathogenicity ; NAD/*metabolism ; NAD+ Nucleosidase/metabolism ; Necroptosis ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; THP-1 Cells ; }, abstract = {Mycobacterium tuberculosis (Mtb) kills infected macrophages through necroptosis, a programmed cell death that enhances mycobacterial replication and dissemination. The tuberculosis necrotizing toxin (TNT) is the major cytotoxicity factor of Mtb in macrophages and induces necroptosis by NAD[+] hydrolysis. Here, we show that the catalytic activity of TNT triggers the production of reactive oxygen species (ROS) in Mtb-infected macrophages causing cell death and promoting mycobacterial replication. TNT induces ROS formation both by activating necroptosis and by a necroptosis-independent mechanism. Most of the detected ROS originate in mitochondria as a consequence of opening the mitochondrial permeability transition pore. However, a significant part of ROS is produced by mechanisms independent of TNT and necroptosis. Expressing only the tnt gene in Jurkat T-cells also induces lethal ROS formation indicating that these molecular mechanisms are not restricted to macrophages. Both the antioxidant N-acetyl-cysteine and replenishment of NAD[+] by providing nicotinamide reduce ROS levels in Mtb-infected macrophages, protect them from cell death, and restrict mycobacterial replication. Our results indicate that a host-directed therapy combining replenishment of NAD[+] with inhibition of necroptosis and/or antioxidants might improve the health status of TB patients and augment antibacterial TB chemotherapy.}, }
@article {pmid31507114, year = {2019}, author = {Mevorach, T and Stern, B and Fennig, S and Apter, A and Benaroya Milshtein, N}, title = {[EXCORIATION (SKIN-PICKING) DISORDER].}, journal = {Harefuah}, volume = {158}, number = {9}, pages = {607-611}, pmid = {31507114}, issn = {0017-7768}, mesh = {Diagnostic and Statistical Manual of Mental Disorders ; Humans ; *Obsessive-Compulsive Disorder ; Prevalence ; *Self-Injurious Behavior ; Selective Serotonin Reuptake Inhibitors ; }, abstract = {Excoriation (Skin-Picking) disorder is a clinically recognized condition which was recently included in the Diagnostic and Statistical manual of the American Psychiatric Association (DSM) - fifth edition, as OCD (obsessive compulsive disorder) related disorder. The disorder's official status has been achieved due to its high frequency and unique clinical picture involving both mental and physical impairment. In this article, we would like to present a concise review of the literature together with an illustrative case. Epidemiological surveys show a prevalence of 3% to 5% for the general population, with heterogeneous gender and age distribution. In recent years the disorder has been categorized under the family of BFRB's (Body Focused Repetitive Behaviours). However, there are some elements associated with movement suppression and tic disorders, as well as disorders belonging to obsessive-compulsive spectrum. The treatment of this disorder may be pharmacological and/or psychological. There is some evidence for the benefit of some SSRI (Selective Serotonin Reuptake Inhibitors) agents as well as for N-Acetyl-Cysteine. Various psychological treatments have been investigated and some of them have proven to be effective. These include cognitive behavioural protocols, some of which have been developed specifically for this disorder.}, }
@article {pmid31506575, year = {2019}, author = {Martino, E and Vuoso, DC and D'Angelo, S and Mele, L and D'Onofrio, N and Porcelli, M and Cacciapuoti, G}, title = {Annurca apple polyphenol extract selectively kills MDA-MB-231 cells through ROS generation, sustained JNK activation and cell growth and survival inhibition.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {13045}, pmid = {31506575}, issn = {2045-2322}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/metabolism ; Apoptosis ; Autophagy ; Biomarkers ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chlorogenic Acid/*pharmacology ; Female ; Flavonoids/*pharmacology ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; MAP Kinase Signaling System ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tannins/*pharmacology ; Triple Negative Breast Neoplasms/metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Polyphenols represent the most studied class of nutraceuticals that can be therapeutics for a large spectrum of diseases, including cancer. In this study, we investigated for the first time the antitumor activities of polyphenol extract from Annurca apple (APE) in MDA-MB-231 triple negative breast cancer cells, and we explored the underlying mechanisms. APE selectively inhibited MDA-MB-231 cell viability and caused G2/M phase arrest associated with p27 and phospho-cdc25C upregulation and with p21 downregulation. APE promoted reactive oxygen species (ROS) generation in MDA-MB-231 cells while it acted as antioxidant in non-tumorigenic MCF10A cells. We demonstrated that ROS generation represented the primary step of APE antitumor activity as pretreatment with antioxidant N-acetylcysteine (NAC) prevented APE-induced G2/M phase arrest, apoptosis, and autophagy. APE downregulated Dusp-1 and induced a significant increase in JNK/c-Jun phosphorylation that were both prevented by NAC. Moreover, downregulation of JNK by its specific inhibitor SP600125 significantly diminished the anticancer activity of APE indicating that ROS generation and sustained JNK activation represented the main underlying mechanism of APE-induced cell death. APE also inhibited AKT activation and downregulated several oncoproteins, such as NF-kB, c-myc, and β-catenin. In light of these results, APE may be an attractive candidate for drug development against triple negative breast cancer.}, }
@article {pmid31503362, year = {2019}, author = {Chan, WY and Hickey, EE and Page, SW and Trott, DJ and Hill, PB}, title = {Biofilm production by pathogens associated with canine otitis externa, and the antibiofilm activity of ionophores and antimicrobial adjuvants.}, journal = {Journal of veterinary pharmacology and therapeutics}, volume = {42}, number = {6}, pages = {682-692}, doi = {10.1111/jvp.12811}, pmid = {31503362}, issn = {1365-2885}, support = {LP130100736//ARC Linkage Grant/ ; //Ministry of Higher Education/ ; //Universiti Putra Malaysia/ ; }, mesh = {Acetylcysteine ; Animals ; Anti-Infective Agents/*pharmacology ; Bacteria/*drug effects ; Biofilms/drug effects/*growth &amp; development ; Dog Diseases/*microbiology ; Dogs ; Edetic Acid ; Enrofloxacin ; Ionophores/*pharmacology ; Microbial Sensitivity Tests ; Monensin/pharmacology ; Otitis Externa/microbiology/*veterinary ; Pyrans/pharmacology ; }, abstract = {Otitis externa (OE) is a frequently reported disorder in dogs associated with secondary infections by Staphylococcus, Pseudomonas and yeast pathogens. The presence of biofilms may play an important role in the resistance of otic pathogens to antimicrobial agents. Biofilm production of twenty Staphylococcus pseudintermedius and twenty Pseudomonas aeruginosa canine otic isolates was determined quantitatively using a microtiter plate assay, and each isolate was classified as a strong, moderate, weak or nonbiofilm producer. Minimum biofilm eradication concentration (MBEC) of two ionophores (narasin and monensin) and three adjuvants (N-acetylcysteine (NAC), Tris-EDTA and disodium EDTA) were investigated spectrophotometrically (OD570nm) and quantitatively (CFU/ml) against selected Staphylococcus and Pseudomonas biofilm cultures. Concurrently, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of planktonic cultures were assessed. 16/20 of the S. pseudintermedius clinical isolates were weak biofilm producers. 19/20 P. aeruginosa clinical isolates produced biofilms and were distributed almost equally as weak, moderate and strong biofilm producers. While significant antibiofilm activity was observed, no MBEC was achieved with narasin or monensin. The MBEC for NAC ranged from 5,000-10,000 µg/ml and from 20,000-80,000 µg/ml against S. pseudintermedius and P. aeruginosa, respectively. Tris-EDTA eradicated P. aeruginosa biofilms at concentrations ranging from 6,000/1,900 to 12,000/3,800 µg/ml. The MBEC was up to 16-fold and eightfold higher than the MIC/MBC of NAC and Tris-EDTA, respectively. Disodium EDTA reduced biofilm growth of both strains at concentrations of 470 µg/ml and higher. It can be concluded that biofilm production is common in pathogens associated with canine OE. NAC and Tris-EDTA are effective antibiofilm agents in vitro that could be considered for the treatment of biofilm-associated OE in dogs.}, }
@article {pmid31501154, year = {2019}, author = {Burt, R and Dey, A and Aref, S and Aguiar, M and Akarca, A and Bailey, K and Day, W and Hooper, S and Kirkwood, A and Kirschner, K and Lee, SW and Lo Celso, C and Manji, J and Mansour, MR and Marafioti, T and Mitchell, RJ and Muirhead, RC and Cheuk Yan Ng, K and Pospori, C and Puccio, I and Zuborne-Alapi, K and Sahai, E and Fielding, AK}, title = {Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress.}, journal = {Blood}, volume = {134}, number = {17}, pages = {1415-1429}, pmid = {31501154}, issn = {1528-0020}, support = {9609/CRUK_/Cancer Research UK/United Kingdom ; 26770/CRUK_/Cancer Research UK/United Kingdom ; C27995/A21019/CRUK_/Cancer Research UK/United Kingdom ; A20937/CRUK_/Cancer Research UK/United Kingdom ; 21019/CRUK_/Cancer Research UK/United Kingdom ; CRUK/09/006/CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {Adult ; Aged ; Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Cell Line, Tumor ; Cells, Cultured ; Coculture Techniques ; Cytarabine/pharmacology/therapeutic use ; Daunorubicin/pharmacology/therapeutic use ; Female ; Humans ; Male ; Mesenchymal Stem Cells/*drug effects/metabolism ; Mice ; Middle Aged ; Mitochondria/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/metabolism ; Young Adult ; }, abstract = {We investigated and modeled the mesenchymal stromal cell (MSC) niche in adult acute lymphoblastic leukemia (ALL). We used gene expression profiling, cytokine/chemokine quantification, flow cytometry, and a variety of imaging techniques to show that MSCs, directly isolated from the primary bone marrow specimens of patients with ALL, frequently adopted an activated, cancer-associated fibroblast phenotype. Normal, primary human MSCs and the MSC cell line HS27a both were activated de novo, when exposed to the reactive oxygen species (ROS)-inducing chemotherapy agents cytarabine (AraC) and daunorubicin (DNR), a phenomenon blocked by the antioxidant N-acetyl cysteine. Chemotherapy-activated HS27a cells were functionally evaluated in a coculture model with ALL targets. Activated MSCs prevented therapy-induced apoptosis and death in ALL targets, via mitochondrial transfer through tunneling nanotubes (TNTs). Reduction of mitochondrial transfer by selective mitochondrial depletion or interference with TNT formation by microtubule inhibitors, such as vincristine (VCR), prevented the "rescue" function of activated MSCs. Corticosteroids, also a mainstay of ALL therapy, prevented the activation of MSCs. We also demonstrated that AraC (but not VCR) induced activation of MSCs, mitochondrial transfer, and mitochondrial mass increase in a murine NSG model of disseminated SEM cell-derived ALL, wherein CD19+ cells closely associated with nestin+ MSCs after AraC, but not in the other conditions. Our data propose a readily clinically exploitable mechanism for improving treatment of ALL, in which traditional ROS-inducing chemotherapies are often ineffective at eradicating residual disease, despite efficiently killing the bulk population.}, }
@article {pmid31500670, year = {2019}, author = {Arancini, L and Bortolasci, CC and Dodd, S and Dean, OM and Berk, M}, title = {N-acetylcysteine for cessation of tobacco smoking: rationale and study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {20}, number = {1}, pages = {555}, pmid = {31500670}, issn = {1745-6215}, mesh = {Acetylcysteine/*therapeutic use ; Double-Blind Method ; Humans ; *Randomized Controlled Trials as Topic ; Smoking Cessation/*methods ; }, abstract = {BACKGROUND: Tobacco smoking is a highly prevalent, addictive behaviour and a key public health priority. However available cessation therapies have low quit and high relapse rates, indicating an urgent need for more effective treatments. Predicated on promising preclinical and pilot clinical data, this paper presents a rationale and protocol for the trial of N-acetylcysteine (NAC) as a novel anti-craving smoking cessation aid.<br><br>METHODS: Current smokers (n&#x2009;=&#x2009;120) of at least 10 cigarettes a day are recruited through online advertisements, print publications and dissemination of flyers. Participants are randomised on a 1:1 ratio to receive either 16-week treatment of 1.8&#x2009;g/day of NAC or placebo with all participants receiving quit support from the online QuitCoach tool. Participants are attending visits at baseline, 8 and 16&#x2009;weeks with a 42-week post-discontinuation follow-up. The primary outcome measure is sustained abstinence at six&#x2009;months after treatment based on self-reported rating scales and confirmed by exhaled carbon monoxide and salivary cotinine levels. Secondary outcomes are timing of the first lapse and relapse, between-group cigarette consumption, withdrawal symptoms, general wellbeing and mood/anxiety symptoms. Between-group differences in adverse events and subgroup analyses for variables including gender and Diagnostic Statistics Manual 5 diagnostics will also be investigated.<br><br>DISCUSSION: The planned trial addresses an issue of major importance to human health and, if an effect is shown, may result in substantial changes to the management of smoking and nicotine addiction with overt public health implications.<br><br>TRIAL REGISTRATION: Australian New Zealand Clinical Trials registry (ANZCTR), ACTRN12617001478303 . Registered on 19 October 2017.}, }
@article {pmid31497434, year = {2019}, author = {Saleem, M and Iftikhar, H}, title = {A Rare Case of Acetaminophen Toxicity Leading to Severe Kidney Injury.}, journal = {Cureus}, volume = {11}, number = {6}, pages = {e5003}, pmid = {31497434}, issn = {2168-8184}, abstract = {Acetaminophen is one of the most common analgesic medications available over the counter. Acetaminophen overdose can cause both hepatic and renal injuries. The literature suggests the incidence of acute kidney injury is around 2% - 10% in those with acetaminophen overdose. We report a case of acute kidney injury from acetaminophen overdose requiring hemodialysis.}, }
@article {pmid31496247, year = {2019}, author = {Kanner, J and Shpaizer, A and Nelgas, L and Tirosh, O}, title = {S-Nitroso-N-acetylcysteine (NAC-SNO) as an Antioxidant in Cured Meat and Stomach Medium.}, journal = {Journal of agricultural and food chemistry}, volume = {67}, number = {39}, pages = {10930-10936}, doi = {10.1021/acs.jafc.9b03741}, pmid = {31496247}, issn = {1520-5118}, mesh = {Acetylcysteine/*analogs &amp; derivatives/analysis/metabolism ; Animals ; Antioxidants/*analysis/metabolism ; Food Preservatives/*analysis/metabolism ; Gastric Mucosa/*metabolism ; Hot Temperature ; Lipid Peroxidation ; Meat Products/*analysis ; Nitrites/analysis ; Oxidation-Reduction ; Turkeys ; }, abstract = {The stability of lipids in meat products depends on the initial concentration of hydroperoxides, the catalytic involvement of metal ions and myoglobin, endogenous antioxidants, and biological and technological factors. Ground meat was treated with additives, sealed in vacuum bags, heated to 75 °C, and stored opened to air at 4 °C. S-Nitroso-N-acetylcysteine (NAC-SNO) at concentration like nitrite used by the industry prevents lipid peroxidation in the product, even after storage for 1 month at 4 °C. The same simulated treatments at different concentrations of both compounds show that NAC-SNO acts as an antioxidant ∼4-fold better than nitrite at pH 6.2 or 3.0. Ascorbic acid significantly improves nitrite antioxidant effect. NAC-SNO was found to prevent, much better than nitrite, accumulation of reactive aldehydes and hydroxynonenal protein modification. In condition like those used by the industry for meat products processing, NAC-SNO acts better than nitrite to provide antioxidant protection without the side effect of N-nitrosation, oxidation, and the loss of nutrient generated by nitrite.}, }
@article {pmid31496224, year = {2019}, author = {Chaves-Filho, AB and Yoshinaga, MY and Dantas, LS and Diniz, LR and Pinto, IFD and Miyamoto, S}, title = {Mass Spectrometry Characterization of Thiol Conjugates Linked to Polyoxygenated Polyunsaturated Fatty Acid Species.}, journal = {Chemical research in toxicology}, volume = {32}, number = {10}, pages = {2028-2041}, doi = {10.1021/acs.chemrestox.9b00199}, pmid = {31496224}, issn = {1520-5010}, mesh = {Animals ; Chromatography, Liquid ; Fatty Acids, Unsaturated/*chemistry/metabolism ; Glutathione/*chemistry/isolation &amp; purification/metabolism ; Liver/chemistry/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Structure ; Oxidation-Reduction ; Peroxides/chemistry/metabolism ; Tandem Mass Spectrometry ; }, abstract = {Radical mediated oxidation of polyunsaturated fatty acids (PUFA) is known to generate a series of polyoxygenated cyclic products (PUFA-On, n ≥ 3). Here, we describe the characterization of glutathione (GSH) conjugates bound to polyoxygenated docosahexaenoic (DHA-On, n = 3-9), arachidonic (ARA-On, n = 3-7), α-linolenic (ALA-O3), and linoleic (LA-O3) acid species. Similar conjugates were also characterized for N-acetylcysteine (NAC) and Cu,Zn-superoxide dismutase (SOD1). Extensive LC-MS/MS characterization using a synthetic α-linolenic hydroxy-endoperoxide (ALA-O3) derivative revealed at least two types of mechanisms leading to thiol adduction: a mechanism involving the nucleophilic attack by thiolate anion on 1,2-dioxolane to form a sulfenate ester-bonded conjugate and a mechanism involving cleavage of the dioxolane to form a α,β-unsaturated carbonyl followed by the Michael addition reaction. Finally, we detected a GSH conjugate with hydroxy-endoperoxide derived from linoleic acid (LA-O3) in mice liver. In summary, our study reveals the formation of a series of thiol conjugates that are bound to highly oxygenated PUFA species. GSH conjugates described in our study may potentially play relevant roles in redox and inflammatory processes, especially under high oxygen tension conditions.}, }
@article {pmid31491945, year = {2019}, author = {Hong, JM and Kim, JH and Kim, H and Lee, WJ and Hwang, YI}, title = {SB365, Pulsatilla Saponin D Induces Caspase-Independent Cell Death and Augments the Anticancer Effect of Temozolomide in Glioblastoma Multiforme Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {18}, pages = {}, pmid = {31491945}, issn = {1420-3049}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/chemistry/*pharmacology ; Apoptosis/drug effects ; Autophagy/drug effects ; Biomarkers ; Caspases/*metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Disease Models, Animal ; Glioblastoma/metabolism ; Humans ; Matrix Metalloproteinases ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Pulsatilla/*chemistry ; Reactive Oxygen Species/metabolism ; Saponins/chemistry/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {SB365, a saponin D extracted from the roots of Pulsatilla koreana, has been reported to show cytotoxicity in several cancer cell lines. We investigated the effects of SB365 on U87-MG and T98G glioblastoma multiforme (GBM) cells, and its efficacy in combination with temozolomide for treating GBM. SB365 exerted a cytotoxic effect on GBM cells not by inducing apoptosis, as in other cancer cell lines, but by triggering caspase-independent cell death. Inhibition of autophagic flux and neutralization of the lysosomal pH occurred rapidly after application of SB365, followed by deterioration of mitochondrial membrane potential. A cathepsin B inhibitor and N-acetyl cysteine, an antioxidant, partially recovered cell death induced by SB365. SB365 in combination with temozolomide exerted an additive cytotoxic effect in vitro and in vivo. In conclusion, SB365 inhibits autophagic flux and induces caspase-independent cell death in GBM cells in a manner involving cathepsin B and mainly reactive oxygen species, and its use in combination with temozolomide shows promise for the treatment of GBM.}, }
@article {pmid31487907, year = {2019}, author = {Wang, HR and Tang, JY and Wang, YY and Farooqi, AA and Yen, CY and Yuan, SF and Huang, HW and Chang, HW}, title = {Manoalide Preferentially Provides Antiproliferation of Oral Cancer Cells by Oxidative Stress-Mediated Apoptosis and DNA Damage.}, journal = {Cancers}, volume = {11}, number = {9}, pages = {}, pmid = {31487907}, issn = {2072-6694}, support = {MOST 107-2320-B-037-016//Ministry of Science and Technology, Taiwan/ ; MOST 107-2314-B-037-048//Ministry of Science and Technology, Taiwan/ ; MOST 107-2311-B-214-003//Ministry of Science and Technology, Taiwan/ ; #NSYSUKMU 108-P001//National Sun Yat-sen University-KMU Joint Research Project/ ; 108CM-KMU-11//Chimei-KMU jointed project/ ; KMUH107-7R74//Kaohsiung Medical University Hospital/ ; MOHW 108-TDU-B-212-124016//Health and welfare surcharge of tobacco products, the Ministry of Health and Welfare, Taiwan, Republic of China/ ; }, abstract = {Marine sponge-derived manoalide has a potent anti-inflammatory effect, but its potential application as an anti-cancer drug has not yet been extensively investigated. The purpose of this study is to evaluate the antiproliferative effects of manoalide on oral cancer cells. MTS assay at 24 h showed that manoalide inhibited the proliferation of six types of oral cancer cell lines (SCC9, HSC3, OC2, OECM-1, Ca9-22, and CAL 27) but did not affect the proliferation of normal oral cell line (human gingival fibroblasts (HGF-1)). Manoalide also inhibits the ATP production from 3D sphere formation of Ca9-22 and CAL 27 cells. Mechanically, manoalide induces subG1 accumulation in oral cancer cells. Manoalide also induces more annexin V expression in oral cancer Ca9-22 and CAL 27 cells than that of HGF-1 cells. Manoalide induces activation of caspase 3 (Cas 3), which is a hallmark of apoptosis in oral cancer cells, Ca9-22 and CAL 27. Inhibitors of Cas 8 and Cas 9 suppress manoalide-induced Cas 3 activation. Manoalide induces higher reactive oxygen species (ROS) productions in Ca9-22 and CAL 27 cells than in HGF-1 cells. This oxidative stress induction by manoalide is further supported by mitochondrial superoxide (MitoSOX) production and mitochondrial membrane potential (MitoMP) destruction in oral cancer cells. Subsequently, manoalide-induced oxidative stress leads to DNA damages, such as γH2AX and 8-oxo-2'-deoxyguanosine (8-oxodG), in oral cancer cells. Effects, such as enhanced antiproliferation, apoptosis, oxidative stress, and DNA damage, in manoalide-treated oral cancer cells were suppressed by inhibitors of oxidative stress or apoptosis, or both, such as N-acetylcysteine (NAC) and Z-VAD-FMK (Z-VAD). Moreover, mitochondria-targeted superoxide inhibitor MitoTEMPO suppresses manoalide-induced MitoSOX generation and γH2AX/8-oxodG DNA damages. This study validates the preferential antiproliferation effect of manoalide and explores the oxidative stress-dependent mechanisms in anti-oral cancer treatment.}, }
@article {pmid31485293, year = {2019}, author = {Terluk, MR and Ebeling, MC and Fisher, CR and Kapphahn, RJ and Yuan, C and Kartha, RV and Montezuma, SR and Ferrington, DA}, title = {N-Acetyl-L-cysteine Protects Human Retinal Pigment Epithelial Cells from Oxidative Damage: Implications for Age-Related Macular Degeneration.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {5174957}, pmid = {31485293}, issn = {1942-0994}, support = {R01 EY028554/EY/NEI NIH HHS/United States ; T32 AG029796/AG/NIA NIH HHS/United States ; T32 EY025187/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Epithelial Cells/*metabolism ; Humans ; Macular Degeneration/*genetics/pathology ; Retinal Pigment Epithelium/*metabolism ; }, abstract = {Age-related macular degeneration (AMD) involves the loss of retinal pigment epithelium (RPE) and photoreceptors and is one of the leading causes of blindness in the elderly. Oxidative damage to proteins, lipids, and DNA has been associated with RPE dysfunction and AMD. In this study, we evaluated oxidative stress in AMD and the efficacy of antioxidant, N-acetyl-L-cysteine (NAC), in protecting RPE from oxidative damage. To test this idea, primary cultures of RPE from human donors with AMD (n = 32) or without AMD (No AMD, n = 21) were examined for expression of NADPH oxidase (NOX) genes, a source of reactive oxygen species (ROS). Additionally, the cells were pretreated with NAC for 2 hours and then treated with either hydrogen peroxide (H2O2) or tert-butyl hydroperoxide (t-BHP) to induce cellular oxidation. Twenty-four hours after treatment, ROS production, cell survival, the content of glutathione (GSH) and adenosine triphosphate (ATP), and cellular bioenergetics were measured. We found increased expression of p22phox, a NOX regulator, in AMD cells compared to No AMD cells (p = 0.02). In both AMD and No AMD cells, NAC pretreatment reduced t-BHP-induced ROS production and protected from H2O2-induced cell death and ATP depletion. In the absence of oxidation, NAC treatment improved mitochondrial function in both groups (p < 0.01). Conversely, the protective response exhibited by NAC was disease-dependent for some parameters. In the absence of oxidation, NAC significantly reduced ROS production (p < 0.001) and increased GSH content (p = 0.02) only in RPE from AMD donors. Additionally, NAC-mediated protection from H2O2-induced GSH depletion (p = 0.04) and mitochondrial dysfunction (p < 0.05) was more pronounced in AMD cells compared with No AMD cells. These results demonstrate the therapeutic benefit of NAC by mitigating oxidative damage in RPE. Additionally, the favorable outcomes observed for AMD RPE support NAC's relevance and the potential therapeutic value in treating AMD.}, }
@article {pmid31484617, year = {2019}, author = {Yan, Y}, title = {[Effect of N-acetylcysteine on Cognitive Function and Nuclear Factor Erythroid 2 Related Factor 2/Heme Oxygenase-1 Pathway in Mouse Models of Postoperative Cognitive Dysfunction].}, journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae}, volume = {41}, number = {4}, pages = {529-535}, doi = {10.3881/j.issn.1000-503X.11600}, pmid = {31484617}, issn = {1000-503X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cognition/*drug effects ; Cognitive Dysfunction/*drug therapy/etiology ; Heme Oxygenase-1/*metabolism ; Male ; Membrane Proteins/*metabolism ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/*metabolism ; Postoperative Complications ; Random Allocation ; }, abstract = {To investigate the effect of N-acetylcysteine(NAC)on cognitive function and nuclear factor erythroid 2 related factor 2/ heme oxygenase-1(Nrf2/HO-1)pathway in mouse models of postoperative cognitive dysfunction. Methods Fifty-four male C57BL/6J mice(3-4 months old)were randomly divided into control group,surgery group,and surgery+NAC group by block randomization.The intramedullary fixation for left tibial fracture surgery was performed to establish postoperative cognitive dysfunction models.NAC(150 mg/kg)was administered intraperitoneally in group surgery+NAC 30 minutes before and 3 hours,6 hours after surgery,while saline was given in control group and surgery group.Six mice in each group were selected randomly underwent Morris water maze test on the third day after surgery.Animals were sacrificed at the first and third postoperative days,and the hippocampus was harvested.Enzyme-linked immunosorbent assay was used to quantify the levels of interleukin-6(IL-6)and malondialdehyde(MDA)in hippocampus.Western blot and real-time polymerase chain reaction were used to measure the expressions of Nrf2 and HO-1 in hippocampus. Results There was no significant difference in swimming speed among three groups(F=2.135,P=0.114).Compared with control group and surgery+NAC group,the surgery group had prolonged escape latency(P<0.01),reduced platform crossing times(P<0.01),and shortened time spent in the target quadrant(P<0.01).Compared with the control group,the surgery group and the surgery+NAC group had significantly increased levels of IL-6 and MDA in hippocampus at the first postoperative day(all P=0.000).On the third postoperative day,there was no significant difference in the levels of IL-6(P=0.251)and MDA(P=0.103)between control group and surgery+NAC group.The protein expressions of Nrf2 and HO-1 in hippocampus were significantly higher in surgery group and surgery+NAC group than in control group and significantly higher in surgery+NAC group than in surgery group(all P=0.000).The mRNA expressions of Nrf2 and HO-1 in hippocampus were significantly higher in surgery group and surgery+NAC group than in control group and significantly higher in surgery+NAC group than in surgery group (all P=0.000). Conclusions NAC pretreatment may reduce oxidative stress and inflammatory response in hippocampus and improve cognitive function.Such effect may be relate to the activation of Nrf2/HO-1 pathway.}, }
@article {pmid31482411, year = {2020}, author = {Schwenck, J and Mehling, R and Thaiss, WM and Kramer, D and Menendez, IG and Öz, HH and Hartl, D and Schulze-Osthoff, K and Hailfinger, S and Ghoreschi, K and Quintanilla-Martinez, L and Carlsen, H and Röcken, M and Pichler, BJ and Kneilling, M}, title = {Temporal Dynamics of Reactive Oxygen and Nitrogen Species and NF-κB Activation During Acute and Chronic T Cell-Driven Inflammation.}, journal = {Molecular imaging and biology}, volume = {22}, number = {3}, pages = {504-514}, pmid = {31482411}, issn = {1860-2002}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Female ; Free Radical Scavengers/pharmacology ; Inflammation/diagnostic imaging/drug therapy/*immunology/*pathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; NF-kappa B/*immunology ; Optical Imaging/*methods ; Picryl Chloride/pharmacology ; Reactive Nitrogen Species/*immunology ; Reactive Oxygen Species/*immunology ; Signal Transduction ; T-Lymphocytes/drug effects/*immunology/metabolism ; }, abstract = {PURPOSE: Reactive oxygen and nitrogen species (ROS/RNS) production and the NF-κB activation are critically involved in inflammatory responses, but knowledge about the temporal dynamics during acute and chronic inflammation is limited. Here, we present a comparative longitudinal in vivo study of both parameters in an experimental model of acute and chronic T cell-driven delayed-type hypersensitivity reaction (DTHR) using noninvasive optical imaging.<br><br>PROCEDURES: Trinitrochlorobenzene (TNCB)-sensitized NF-&#x3ba;B-luciferase-reporter and wild-type mice were TNCB challenged on the right ear to elicit acute DTHR and then repetitively challenged (up to five times) to induce chronic DTHR. Mice were treated with the ROS-scavenging and NF-&#x3ba;B inhibiting molecule N-acetylcysteine (NAC) or underwent sham treatment. ROS/RNS production was noninvasively analyzed in vivo using the ROS-/RNS-sensitive chemiluminescent probe L-012, and NF-&#x3ba;B activation was measured using NF-&#x3ba;B-luciferase-reporter mice. H&amp;E staining, CD3 and myeloperoxidase (MPO) immunohistochemistry (IHC), and quantitative PCR (qPCR) analyses were employed to investigate immune cell infiltration and expression of NF-&#x3ba;B- and ROS-/RNS-driven genes.<br><br>RESULTS: In acute DTHR, we found strongly elevated ROS/RNS production and NF-&#x3ba;B activation 12&#xa0;h after the 1st TNCB ear challenge, peaking at 24&#xa0;h after the challenge. In chronic DTHR, ROS production peaked as early as 4&#xa0;h after the 5th TNCB challenge, whereas NF-&#x3ba;B activity peaked after 12&#xa0;h. The increase in ROS/RNS production in acute DTHR was higher than the increase in NF-&#x3ba;B activity but the relationship was inverse in chronic DTHR. Treatment with the ROS scavenger NAC had differential effects on ROS/RNS production and NF-&#x3ba;B activation during acute and chronic DTHR. Ex vivo cross-validation by histopathology and qPCR analysis correlated closely with the in vivo imaging results.<br><br>CONCLUSIONS: Noninvasive in vivo imaging is capable of assessing the temporal dynamics of ROS/RNS production and NF-&#x3ba;B activation during progression from acute to chronic DTHR and enables monitoring of anti-inflammatory treatment responses.}, }
@article {pmid31481850, year = {2019}, author = {Gerald, CL and McClendon, CJ and Ranabhat, RS and Waterman, JT and Kloc, LL and Conklin, DR and Barton, KT and Khatiwada, JR and Williams, LL}, title = {Sorrel Extract Reduces Oxidant Production in Airway Epithelial Cells Exposed to Swine Barn Dust Extract In Vitro.}, journal = {Mediators of inflammation}, volume = {2019}, number = {}, pages = {7420468}, pmid = {31481850}, issn = {1466-1861}, support = {K12 GM102778/GM/NIGMS NIH HHS/United States ; UL1 TR001111/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Dust ; Epithelial Cells/*drug effects/*metabolism ; Hibiscus/*chemistry ; Hydrogen Peroxide/metabolism ; Oxidative Stress/drug effects ; Plant Extracts/*chemistry/*pharmacology ; Reactive Oxygen Species/metabolism ; Swine ; }, abstract = {Exposure to hog barn organic dust contributes to occupational lung diseases, which are mediated by inflammatory and oxidative stress pathways. Isoprostanes-a family of eicosanoids produced by oxidation of phospholipids by oxygen radicals-are biomarkers of pulmonary oxidative stress. Importantly, 8-isoprostane has been implicated as a key biomarker and mediator of oxidative stress because it is a potent pulmonary vasoconstrictor. Antioxidants found in fruits and vegetables hold promise for preventing or reducing effects of oxidative stress-related diseases including chronic bronchitis and chronic obstructive pulmonary disease (COPD). Here, we investigated 8-isoP and oxidant production by organic dust-exposed airway epithelial cells and the inhibitory effects of an extract from calyces of the sorrel plant, Hibiscus sabdariffa, on oxidant-producing pathways. Confluent cultures of normal human tracheobronchial epithelial cells were pretreated or not with 1% sorrel extract prior to 5% dust extract (DE) exposure. Following DE treatments, live cells, cell-free supernatants, or cell extracts were evaluated for the presence of 8-isoprostane, superoxide, hydrogen peroxide, nitric oxide, hydroxyl radical, peroxynitrite, and catalase activity to evaluate sorrel's inhibitory effect on oxidative stress. The well-known radical scavenging antioxidant, N-acetyl cysteine (NAC), was used for comparisons with sorrel. DE exposure augmented the production of all radicals measured including 8-isoprostane (p value < 0.001), which could be inhibited by NAC or sorrel. Among reactive oxygen and nitrogen species generated in response to DE exposure, sorrel had no effect on H2O2 production and NAC had no significant effect on NO[·] production. The observations reported here suggest a possible role for sorrel in preventing 8-isoprostane and oxidant-mediated stress responses in bronchial epithelial cells exposed to hog barn dust. These findings suggest a potential role for oxidative stress pathways in mediating occupational lung diseases and antioxidants within sorrel and NAC in reducing dust-mediated oxidative stress within the airways of exposed workers.}, }
@article {pmid31479873, year = {2020}, author = {Sadeghi, A and Shabani, M and Alizadeh, S and Meshkani, R}, title = {Interplay between oxidative stress and autophagy function and its role in inflammatory cytokine expression induced by palmitate in skeletal muscle cells.}, journal = {Cytokine}, volume = {125}, number = {}, pages = {154835}, doi = {10.1016/j.cyto.2019.154835}, pmid = {31479873}, issn = {1096-0023}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Autophagy/*drug effects/genetics ; Cell Line ; Chloroquine/pharmacology ; Cytokines/*metabolism ; Free Radical Scavengers/pharmacology ; Inflammation/metabolism ; Interleukin-6/metabolism ; Mice ; Microtubule-Associated Proteins/*metabolism ; Muscle, Skeletal/drug effects/*metabolism ; Oxidative Stress ; Palmitates/*pharmacology ; Reactive Oxygen Species/metabolism ; Sequestosome-1 Protein/metabolism ; Sirolimus/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Autophagy is a cellular process activated in response to various stresses such as starvation, hypoxia, and oxidative stress. Autophagy was reported to modulate the inflammatory pathways. However, whether autophagy is involved in regulation of palmitate-induced inflammation of skeletal muscle C2C12 cells is still unknown. The present study aimed to investigate the autophagic pathway in C2C12 cells treated with 0.5 mM palmitate. The results showed that the protein levels of LC3BII and P62 were increased in C2C12 cells after 12 h palmitate treatment. Besides, inhibition of autophagy by chloroquine or 3-methyladenin and its activation by rapamycin were associated with elevated mRNA and protein levels of IL-6 and TNF-α inflammatory cytokines in C2C12 cells. To study the mechanism by which autophagy impairment leads to activation of inflammatory responses, reactive oxygen species (ROS) levels in palmitate-treated cells were measured. The results showed that while palmitate stimulates ROS production, pretreatment of the cells with N-acetyl cysteine (NAC), a ROS scavenger, reduced inflammatory responses and also improved LC3-BII and P62 protein in the C2C12 cells exposed to palmitate. These findings suggest that palmitate-induced defect of autophagic flux leads to elevated inflammatory cytokine expression in the skeletal muscle cells by regulating the oxidative stress process.}, }
@article {pmid31472964, year = {2019}, author = {Shin, JH and Cho, DH}, title = {TMP21 regulates autophagy by modulating ROS production and mTOR activation.}, journal = {Biochemical and biophysical research communications}, volume = {518}, number = {4}, pages = {746-751}, doi = {10.1016/j.bbrc.2019.08.125}, pmid = {31472964}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Autophagy/*genetics ; Autophagy-Related Protein 5/genetics/metabolism ; Autophagy-Related Protein 7/genetics/metabolism ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Knockout Techniques ; HeLa Cells ; Humans ; Membrane Proteins/*genetics/metabolism ; Naphthyridines/pharmacology ; Nucleocytoplasmic Transport Proteins ; RNA Interference ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/*genetics/metabolism ; }, abstract = {Autophagy is a catabolic cellular response to stress that has been liked to various human diseases. However, the precise involvement of autophagy in health and disease remains unclear. To explore the molecular mechanisms of autophagy, we investigated the effect of TMP21. We found that the down-regulation of TMP21 induced autophagy in SH-SY5Y cells. In addition, the enhanced autophagy observed upon TMP21 depletion was almost completely blocked in ATG5 knockout (KO) or ATG7-KO HeLa cells. Silencing of TMP21 in SH-SY5Y cells also increased the production of cellular reactive oxygen species (ROS). Accordingly, treatment with the ROS scavenger NAC suppressed autophagy activation as well as ROS production in TMP21-depleted cells. In addition, the inhibition of mTOR by treatment with Torin1 was mitigated in TMP21 overexpressing cells compared with that in control cells. Taken together, these results indicated that TMP21 could regulate autophagy by modulating ROS production and mTOR activation.}, }
@article {pmid31471533, year = {2019}, author = {Xu, J and Li, H and Yang, K and Guo, S and Wang, J and Feng, C and Chen, H}, title = {Hyper-osmolarity environment-induced oxidative stress injury promotes nucleus pulposus cell senescence in vitro.}, journal = {Bioscience reports}, volume = {39}, number = {9}, pages = {}, pmid = {31471533}, issn = {1573-4935}, mesh = {Acetylcysteine/pharmacology ; Aggrecans/genetics ; Animals ; Cell Proliferation/*genetics ; Cellular Senescence/*genetics ; Collagen/genetics ; Gene Expression Regulation/drug effects ; Intervertebral Disc Degeneration/genetics/metabolism/pathology ; NF-kappa B/genetics ; Nucleus Pulposus/drug effects/*metabolism ; Osmolar Concentration ; Oxidative Stress/*genetics ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Nucleus pulposus (NP) cell senescence is involved in disc degeneration. The in situ osmolarity within the NP region is an important regulator of disc cell's biology. However, its effects on NP cell senescence remain unclear. The present study was aimed to investigate the effects and mechanism of hyper-osmolarity on NP cell senescence. Rat NP cells were cultured in the in situ-osmolarity medium and hyper-osmolarity medium. The reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) was added along with the medium to investigate the role of oxidative injury. Cell cycle, cell proliferation, senescence associated β-galactosidase (SA-β-Gal) activity, telomerase activity, expression of senescence markers (p16 and p53) and matrix molecules (aggrecan and collagen II) were tested to assess NP cell senescence. Compared with the in situ-osmolarity culture, hyper-osmolarity culture significantly decreased cell proliferation and telomerase activity, increased SA-β-Gal activity and cell fraction in the G0/G1 phase, up-regulated expression of senescence markers (p16 and p53) and down-regulated expression of matrix molecules (aggrecan and collagen II), and increased intracellular ROS accumulation. However, addition of NAC partly reversed these effects of hyper-osmolarity culture on cellular senescence and decreased ROS content in NP cells. In conclusion, a hyper-osmolarity culture promotes NP cell senescence through inducing oxidative stress injury. The present study provides new knowledge on NP cell senescence and helps us to better understand the mechanism of disc degeneration.}, }
@article {pmid31468387, year = {2019}, author = {Shen, Y and Lau-Cam, CA}, title = {Taurine Enhances the Protective Actions of Fish Oil Against D-Galactosamine-Induced Metabolic Changes and Hepatic Lipid Accumulation and Injury in the Rat.}, journal = {Advances in experimental medicine and biology}, volume = {1155}, number = {}, pages = {71-85}, doi = {10.1007/978-981-13-8023-5_7}, pmid = {31468387}, issn = {0065-2598}, mesh = {Animals ; Fish Oils/*pharmacology ; Galactosamine/*adverse effects ; *Lipid Metabolism ; Liver/*drug effects/metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Taurine/*pharmacology ; }, abstract = {This study has evaluated the effects of a supplementation with taurine (TAU) on the actions of fish oil (FO) against the hypoglycemia, hypoproteinemia, and hepatic accumulation of lipids and liver damage caused by D-galactosamine (GAL) in the rat. To this end, male Sprague-Dawley rats (200-225 g), in groups of 6, were orally treated with physiological saline (2.5 mL, control group), FO (60 mg/kg), TAU (2.4 mmol/kg) or FO-TAU for three consecutive days and before a single oral dose of GAL (400 mg/kg) given on day 3. In parallel, rats receiving only GAL on day 3 or N-acetylcysteine (NAC, 2.4 mmol/kg) for 3 days before GAL served as controls. On day 4 blood samples were collected by cardiac puncture and used to either measure glucose (GLC) or to obtain plasma fractions. Immediately thereafter, the livers were excised, made into a homogenate in phosphate buffered saline pH 7.4, and centrifuged to obtain clear supernatant. Plasma samples were assayed for their total protein (TP), triglycerides (TG), cholesterol (CHOL), phospholipids (PLP), free fatty acids (FFA) and total bilirubin (TB) and direct bilirubin (DB) contents, and for the activities of alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP). The liver homogenates were used to measure TG, CHOL, PLP and total lipids (TL) contents. Without exceptions, GAL was found to markedly affect (p < 0.001) all of the experimental parameters examined, with increases occurring in all instances except for the values of the plasma GLC, TP and PLP which were decreased. A pretreatment with either FO or TAU led to significant attenuation of the effects of GAL and which, in most cases, were of similar magnitude. On the other hand, a combined pretreatment with FO plus TAU usually resulted in a greater protection than with either agent alone (p ≤ 0.05). NAC, serving as a reference treatment, was, in most instances, equipotent with FO alone and. in addition, was the only agent that significantly attenuated the increases in both liver weight and liver weight to body weight ratio caused by GAL.}, }
@article {pmid31466266, year = {2019}, author = {Yeh, IJ and Wang, TY and Lin, JC and Lin, TJ and Chang, JS and Yen, MC and Liu, YH and Wu, PL and Chen, FW and Shih, YL and Peng, CY}, title = {Optimal Regimen of N-Acetylcysteine on Chromium-Induced Renal Cell Damage.}, journal = {Metabolites}, volume = {9}, number = {9}, pages = {}, pmid = {31466266}, issn = {2218-1989}, support = {KMUH103-3M52//Kaohsiung Medical University Chung-Ho Memorial Hospital/ ; }, abstract = {Chromium (Cr) is a well-known heavy metal that can cause renal damage. The production of reactive oxygen species (ROS) due to chromium-induced toxicity induces cell dysfunction, apoptosis, and death. N-acetylcysteine (NAC) is an antioxidant used as an antidote for chromium-induced toxicity. However, the optimal regimen and protective mechanisms of NAC are not fully understood in human renal cells. Our results showed that exposure to 10 μM K2Cr2O7, a toxic Cr(VI) compound, induced apoptosis and production of intracellular ROS in the human proximal tubular epithelial cell line HK-2. Supplements of 600 or 1000 µg/mL NAC inhibited intracellular ROS in HK-2 cells exposed to Cr(VI) and significantly increased cell viability within 2 h of Cr(VI)-induced cytotoxicity. Moreover, Cr(VI) induced the expression of apoptosis markers, including cleaved-caspase-3, cleaved-poly (ADP-ribose) polymerase, cleaved-caspase 8, and cleaved-caspase 9, and altered the expression ratio of Bax/Bcl-xL. Expression of apoptosis markers within 2 h of Cr(VI)-induced cytotoxicity in cells treated with 600 µg/mL NAC was significantly suppressed. However, delayed treatment with NAC at 4 h and 8 h after exposure to Cr did not suppress the activation of apoptotic pathways. In summary, our study reports the optimum timing and dose of NAC for the protection of human renal proximal tubular cells from Cr(VI)-induced cell death. The NAC treatment strategy described could be applied in clinical practice to suppress renal cell apoptosis, which in turn could rescue renal function.}, }
@article {pmid31465783, year = {2019}, author = {Ait Abderrahim, L and Taïbi, K and Abderrahim, NA and Alomery, AM and Abdellah, F and Alhazmi, AS and Aljassabi, S}, title = {Protective effects of melatonin and N-acetyl cysteine against oxidative stress induced by microcystin-LR on cardiac muscle tissue.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {169}, number = {}, pages = {38-44}, doi = {10.1016/j.toxicon.2019.08.005}, pmid = {31465783}, issn = {1879-3150}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Heart/*drug effects ; Male ; Marine Toxins ; Melatonin/*pharmacology ; Mice ; Mice, Inbred BALB C ; Microcystins/*toxicity ; Microcystis/*chemistry ; Myocardium/pathology ; Oxidative Stress/drug effects ; Protective Agents/*pharmacology ; Toxicity Tests ; }, abstract = {Microcystin Leucine-Arginine (MC-LR) is a toxin produced by the cyanobacteria Microcystis aeruginosa. It is the most encountered and toxic type of cyanotoxins. Oxidative stress was shown to play a role in the pathogenesis of microcystin LR by the induction of intracellular reactive oxygen species (ROS) formation that oxidize and damage cellular macromolecules. In the present study we examined the effect of acute MC-LR dose on the cardiac muscle of BALB/c mice. Afterwards, melatonin and N-acetyl cysteine (NAC) were assayed and evaluated as potential protective and antioxidant agents against damages generated by MC-LR. For this purpose, thirty mice were assigned into six groups of five mice each. The effect of MC-LR was first compared to the control group supplied with distilled water, then compared to the other groups supplied with melatonin and NAC. The experiment lasted 10 days after which animals were euthanized. Biomarkers of toxicity such as alkaline phosphatase activity, lipid peroxidation, protein carbonyl content, reduced glutathione content, serum lactate dehydrogenase and serum sorbitol dehydrogenase were assayed. Results showed that toxin treated mice have experienced significant oxidative damage in their myocardial tissue as revealed by noticeable levels of oxidative stress biomarkers and by the reduction in alkaline phosphatase activity. Whereas, melatonin and NAC treated mice manifested lesser oxidative damages. Our findings suggest a potential therapeutic use of melatonin and N-acetyl cysteine as antioxidant protective agents against oxidative damage induced by MC-LR.}, }
@article {pmid31465111, year = {2020}, author = {Gu, H and Wang, C and Li, J and Yang, Y and Sun, W and Jiang, C and Li, Y and Ni, M and Liu, WT and Cheng, Z and Hu, L}, title = {High mobility group box-1-toll-like receptor 4-phosphatidylinositol 3-kinase/protein kinase B-mediated generation of matrix metalloproteinase-9 in the dorsal root ganglion promotes chemotherapy-induced peripheral neuropathy.}, journal = {International journal of cancer}, volume = {146}, number = {10}, pages = {2810-2821}, doi = {10.1002/ijc.32652}, pmid = {31465111}, issn = {1097-0215}, mesh = {Animals ; Antineoplastic Agents/*toxicity ; Ganglia, Spinal/drug effects/*metabolism ; HMGB1 Protein/drug effects/metabolism ; Macrophages/drug effects/metabolism ; Matrix Metalloproteinase 9/drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Oxaliplatin/toxicity ; Peripheral Nervous System Diseases/*chemically induced/*metabolism ; Phosphatidylinositol 3-Kinases/drug effects/metabolism ; Proto-Oncogene Proteins c-akt/drug effects/metabolism ; RAW 264.7 Cells ; Signal Transduction/*drug effects/physiology ; Toll-Like Receptor 4/drug effects/metabolism ; }, abstract = {Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of chemotherapeutics. The mechanisms of CIPN remain substantially unidentified, although inflammation-induced peripheral sensitization has been indicated as an important factor. Here, we aimed to illustrate the role of the matrix metalloproteinase (MMP)-9-related signaling pathway in the process of CIPN. Oxaliplatin (L-OHP) was administered to mice to establish the CIPN model. Gelatin zymography was used to measure MMP-9/2 activities. Western blotting and immunohistochemistry were used to measure the expression of high-mobility group box-1 (HMGB-1), calcitonin gene-related peptide and ionized calcium-binding adapter molecule 1. Mechanical withdrawal was measured by von Frey hairs testing. Raw 264.7 cells and SH-SY5Y cells were cultured to investigate cell signaling in vitro. Here, we report that L-OHP-induced mechanical pain in mice with significant MMP-9/2 activation in dorsal root ganglion (DRG) neurons. MMP-9 inhibition or knockout alleviated the occurrence of CIPN directly. MMP-9/2 were released from macrophages and neurons in the DRG via the HMGB-1-toll-like receptor 4 (TLR4)-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) axis, because MMP-9/2 activities could be reduced by macrophage scavengers or PI3Kγ knockout in CIPN mice. The in vitro data revealed that induced MMP-9 activity by recombinant HMGB-1 could be abolished by TLR4, PI3K or Akt inhibitors. Finally, it was shown that N-acetyl-cysteine (NAC) could reduce MMP-9/2 activities and attenuate CIPN effectively and safely. The HMGB-1-TLR4-PI3K/Akt-MMP-9 axis is involved in the crosstalk between macrophages and neurons in the pathological process of CIPN in mice. Direct inhibition of MMP-9 by NAC may be a potential therapeutic regimen for CIPN treatment.}, }
@article {pmid31464322, year = {2019}, author = {Yang, Y and Zhang, L and Jiang, G and Lei, A and Yu, Q and Xie, J and Chen, Y}, title = {Evaluation of the protective effects of Ganoderma atrum polysaccharide on acrylamide-induced injury in small intestine tissue of rats.}, journal = {Food &amp; function}, volume = {10}, number = {9}, pages = {5863-5872}, doi = {10.1039/c9fo01452g}, pmid = {31464322}, issn = {2042-650X}, mesh = {Acrylamide/*adverse effects ; Animals ; Catalase/genetics/metabolism ; Cytokines/genetics/metabolism ; Drug Evaluation, Preclinical ; Ganoderma/*chemistry ; Glutathione/metabolism ; Humans ; Intestinal Diseases/chemically induced/*drug therapy/genetics/metabolism ; Intestine, Small/*drug effects/injuries ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Plant Extracts/*administration &amp; dosage ; Polysaccharides/*administration &amp; dosage/chemistry ; Protective Agents/*administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {This research investigated the protective effects of Ganoderma atrum polysaccharide (PSG-1) on acrylamide (AA) induced intestinal injury in rats. Our results showed that PSG-1 pretreatment effectively reduced the levels of malondialdehyde (MDA), but increased the activity of catalase (CAT), superoxide dismutase (SOD), glutathione (GSH) and the total glutathione (T-GSH), and significantly reduced oxidative stress in AA treated rats. Furthermore, PSG-1 pretreatment down-regulated pro-inflammatory cytokines i.e. interleukin 2 (IL-2), interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) and increased the amounts of anti-inflammatory cytokines i.e. interleukin 4 (IL-4) and interleukin 10 (IL-10), significantly reducing an inflammatory response in the intestines of rats. In AA induced intestinal injury, the tissue uric acid (UA) level and alkaline phosphatase (ALP) activity and the serum level of d-lactic acid (d-lactate), nitric oxide (NO) and endothelin-1 (ET-1) decreased significantly after treatment with PSG-1 and N-acetylcysteine (NAC). Histological observations of the small intestine confirmed the protective effects of different doses of PSG-1. These findings suggested that PSG-1 pretreatment could alleviate AA-induced oxidative stress, reduce inflammatory response, and inhibit AA absorption by protecting the intestinal barrier. Therefore, Ganoderma atrum polysaccharide has the potential to be a dietary supplement ingredient that provides protection against AA-induced gut injury.}, }
@article {pmid31460584, year = {2019}, author = {Oliveira, CP and Cotrim, HP and Stefano, JT and Siqueira, ACG and Salgado, ALA and Parise, ER}, title = {N-ACETYLCYSTEINE AND/OR URSODEOXYCHOLIC ACID ASSOCIATED WITH METFORMIN IN NON-ALCOHOLIC STEATOHEPATITIS: AN OPEN-LABEL MULTICENTER RANDOMIZED CONTROLLED TRIAL.}, journal = {Arquivos de gastroenterologia}, volume = {56}, number = {2}, pages = {184-190}, doi = {10.1590/S0004-2803.201900000-36}, pmid = {31460584}, issn = {1678-4219}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Aged ; Drug Therapy, Combination ; Female ; Humans ; Male ; Metformin/*administration &amp; dosage ; Middle Aged ; Non-alcoholic Fatty Liver Disease/*drug therapy ; Treatment Outcome ; Ursodeoxycholic Acid/*administration &amp; dosage ; Young Adult ; }, abstract = {BACKGROUND: Nowadays, pharmacological treatment of non-alcoholic fatty liver disease (NAFLD) is still limited and it is based on the treatment of conditions associated comorbities. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis.<br><br>OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) and/or ursodeoxycholic acid (UDCA) for treatment of non-alcoholic steatohepatitis (NASH).<br><br>METHODS: Open-label multicenter randomized trial was conducted for 48 weeks. It included patients with biopsy-proven NASH. The patients were randomized into three groups: NAC (1.2 g) + UDCA (15 mg/kg) + MTF (850-1500 mg/day) (n=26); UDCA (20 mg/kg) + MTF (850-1500 mg/day) (n=13); NAC (1.2g) + MTF (850-1500 mg/day) (n=14) for 48 weeks. Clinical, laboratory and the second liver biopsies were performed after 48 weeks.<br><br>RESULTS: A total of 53 patients were evaluated; 17 (32.1%) were males; median age &#xb1;54 (IQR=15, 21-71) years. In the baseline, no difference was seen between groups according clinical and histological parameters. The groups differed only in cholesterol, LDL and triglycerides. No significant differences in biochemical and histologic parameters were found between these the three groups after 48 weeks of treatment. In the intragroup analysis (intention-to-treat) comparing histological and biochemical features, there were significant improvements in the steatosis degree (P=0.014), ballooning (0.027) and, consequently, in the NAFLD Activity Score (NAS) (P=0.005), and in the ALT levels at the end of the treatment only in the NAC + MTF group. No significant evidence of modification in the liver fibrosis could be observed in any of the groups.<br><br>CONCLUSION: This multicenter study suggests that the association of NAC + MTF could reduce the liver disease activity in patients with NASH. These data stimulate further controlled studies with this therapy for these patients.}, }
@article {pmid31456939, year = {2019}, author = {Alsamri, H and El Hasasna, H and Al Dhaheri, Y and Eid, AH and Attoub, S and Iratni, R}, title = {Carnosol, a Natural Polyphenol, Inhibits Migration, Metastasis, and Tumor Growth of Breast Cancer via a ROS-Dependent Proteasome Degradation of STAT3.}, journal = {Frontiers in oncology}, volume = {9}, number = {}, pages = {743}, pmid = {31456939}, issn = {2234-943X}, abstract = {We have previously demonstrated that carnosol, a naturally occurring diterpene, inhibited in vitro cell viability and colony growth, as well as induced cell cycle arrest, autophagy and apoptosis in human triple negative breast cancer (TNBC) cells. In the present study, we evaluated the ability of carnosol to inhibit tumor growth and metastasis in vivo. We found that non-cytotoxic concentrations of carnosol inhibited the migration and invasion of MDA-MB-231 cells in wound healing and matrigel invasion assays. Furthermore, gelatin zymography, ELISA, and RT-PCR assays revealed that carnosol inhibited the activity and downregulation the expression of MMP-9. Mechanistically, we demonstrated that carnosol suppressed the activation of STAT3 signaling pathway through a ROS-dependent targeting of STAT3 to proteasome-degradation in breast cancer cells (MDA-MB-231, Hs578T, MCF-7, and T47D). We show that blockade of proteasome activity, by MG-132 and bortezomib, or ROS accumulation, by N-acetylcysteine (NAC), restored the level of STAT3 protein. In addition, using chick embryo tumor growth assay, we showed that carnosol significantly and markedly suppressed tumor growth and metastasis of breast cancer xenografts. To the best of our knowledge, this is the first report which shows that carnosol specifically targets signal transducer and activator of transcription 3 (STAT3) for proteasome degradation in breast cancer. Our study further provide evidence that carnosol may represent a promising therapeutic candidate that canmodulate breast cancer growth and metastasis.}, }
@article {pmid31447555, year = {2019}, author = {Shen, Y and Gong, S and Li, J and Wang, Y and Zhang, X and Zheng, H and Zhang, Q and You, J and Huang, Z and Chen, Y}, title = {Co-loading antioxidant N-acetylcysteine attenuates cytotoxicity of iron oxide nanoparticles in hypoxia/reoxygenation cardiomyocytes.}, journal = {International journal of nanomedicine}, volume = {14}, number = {}, pages = {6103-6115}, pmid = {31447555}, issn = {1178-2013}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Autophagy/drug effects ; Cell Hypoxia/drug effects ; Cell Survival/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Ferric Compounds/*toxicity ; Magnetite Nanoparticles/*toxicity/ultrastructure ; Membrane Potential, Mitochondrial/drug effects ; Myocytes, Cardiac/drug effects/*pathology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Oxygen/*pharmacology ; Porosity ; Rats ; Reactive Oxygen Species/metabolism ; Silicon Dioxide/toxicity ; }, abstract = {PURPOSE: Myocardial delivery of magnetic iron oxide nanoparticles (MNPs) might produce iron overload-induced myocardial injury, and the oxidative stress was regarded as the main mechanism. Therefore, we speculated antioxidant modification might be a reasonable strategy to mitigate the toxicity of MNPs.<br><br>METHODS AND RESULTS: Antioxidant N-acetylcysteine (NAC) was loaded into magnetic mesoporous silica coated Fe3O4 nanoparticles. Neonatal rat hypoxia/reoxygenation (H/R) cardiomyocytes were incubated with nanoparticles for 24 hrs. NAC can effectively mitigate iron-induced oxidative injury of cardiomyocytes, evidenced by reduced production of MDA, 8-iso-PGF2&#x3b1;, and 8-OHDG and maintained concentrations of SOD, CAT, GSH-Px, and GSH in ELISA and biochemical tests; downregulated expression of CHOP, GRP78, p62, and LC3-II proteins in Western Blot, and less cardiomyocytes apoptosis in flow cytometric analysis.<br><br>CONCLUSIONS: NAC modifying could suppress the toxic effects of Fe3O4 nanoparticles in H/R cardiomyocytes model in vitro, indicating a promising strategy to improve the safety of iron oxide nanoparticles.}, }
@article {pmid31444827, year = {2019}, author = {Nwankwo, CO and Jafferany, M}, title = {N-Acetylcysteine in psychodermatological disorders.}, journal = {Dermatologic therapy}, volume = {32}, number = {5}, pages = {e13073}, doi = {10.1111/dth.13073}, pmid = {31444827}, issn = {1529-8019}, mesh = {Acetylcysteine/*therapeutic use ; Dermatology/methods ; Female ; Humans ; Male ; Nail Biting/psychology/therapy ; Obsessive-Compulsive Disorder/diagnosis/*drug therapy ; Prognosis ; Projective Techniques ; Severity of Illness Index ; Skin Diseases ; Treatment Outcome ; Trichotillomania/*drug therapy/psychology ; }, abstract = {Treatment of psychodermatological conditions, particularly body-focused repetitive behavior disorders, is often unsatisfactory. Various psychopharmacological and non-pharmacological treatments have been used to ameliorate the symptoms of these disorders. N-Acetylcysteine (NAC) is a newer modality in the treatment of these disorders. This short review focuses on pharmacology, mode of action, and use of NAC in common body-focused repetitive disorders such as trichotillomania, skin-picking disorders, and onychotillomania (nail biting). Current research and literature review have been evaluated and will be discussed.}, }
@article {pmid31442540, year = {2019}, author = {Wang, C and Ning, Z and Wan, F and Huang, R and Chao, L and Kang, Z and Yang, F and Zhong, G and Li, Y and Pan, J and Tang, Z and Hu, L}, title = {Characterization of the cellular effects and mechanism of arsenic trioxide-induced hepatotoxicity in broiler chickens.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {61}, number = {}, pages = {104629}, doi = {10.1016/j.tiv.2019.104629}, pmid = {31442540}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Arsenic Trioxide/*toxicity ; Cells, Cultured ; *Chemical and Drug Induced Liver Injury ; Chickens ; Hepatocytes/*drug effects/metabolism ; Methionine Sulfoxide Reductases/genetics/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {To characterize the cellular effects and mechanism of arsenic trioxide (ATO)-induced hepatotoxicity in broiler chickens, increasing concentrations of ATO (0, 0.6, 1.2, 2.4, and 4.8 μM) were added to chicken hepatocyte cultures in vitro. The changes in hepatocyte morphology, oxidative stress and apoptosis were evaluated using fluorescence microscopy and flow cytometry. The effects of ATO on mRNA or protein expression of antioxidant enzymes, especially methionine sulfoxide reductase (Msr), were analyzed using qRT-PCR and western blotting assays. Increased apoptosis were concomitant with increased reactive oxygen species (ROS) accumulation and upregulation of antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) with increasing ATO concentrations. Moreover, G1 phase arrest and dysregulation of the balance between antiapoptotic versus proapoptotic factors were noted. Furthermore, upregulation of HO-1, SOD-1, and TRX in the ATO groups were consistent with ATO-induced oxidative damage. High Msr, SOD-1, TRX, Bak1, Bax, and p53 protein levels in the ATO groups indicate that these proteins may have accumulated to counter ATO-induced oxidative stress. ROS scavenger N-acetyl-l-cysteine (NAC) could reverse ATO-induced oxidative damage and restore hepatocyte viability, even with compromised Msr function. Our findings suggest that Msr can protect broiler hepatocytes against ATO-induced oxidative stress. Furthermore, NAC-mediated reversal of oxidative damage may represent a strategy to mitigate potential economic losses associated with arsenic poisoning in the poultry industry.}, }
@article {pmid31439071, year = {2019}, author = {Çakici, N and van Beveren, NJM and Judge-Hundal, G and Koola, MM and Sommer, IEC}, title = {An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis.}, journal = {Psychological medicine}, volume = {49}, number = {14}, pages = {2307-2319}, pmid = {31439071}, issn = {1469-8978}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Humans ; Schizophrenia/*drug therapy ; }, abstract = {BACKGROUND: Accumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs).<br><br>METHODS: PubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes.<br><br>RESULTS: Our search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect.<br><br>CONCLUSIONS: Some, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.}, }
@article {pmid31438633, year = {2019}, author = {Park, C and Cha, HJ and Lee, H and Hwang-Bo, H and Ji, SY and Kim, MY and Hong, SH and Jeong, JW and Han, MH and Choi, SH and Jin, CY and Kim, GY and Choi, YH}, title = {Induction of G2/M Cell Cycle Arrest and Apoptosis by Genistein in Human Bladder Cancer T24 Cells through Inhibition of the ROS-Dependent PI3k/Akt Signal Transduction Pathway.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {8}, number = {9}, pages = {}, pmid = {31438633}, issn = {2076-3921}, abstract = {We examined the anti-cancer effect of genistein, a soy-derived isoflavone, in human bladder transitional cell carcinoma T24 cells. According to our data, genistein induced G2/M phase arrest of the cell cycle and apoptosis. Genistein down-regulated the levels of cyclin A and cyclin B1, but up-regulated the levels of p21WAF1/CIP1, cyclin-dependent kinase (Cdk) inhibitor, that was complexed with Cdc2 and Cdk2. Furthermore, genistein induced the activation of caspases (caspase-3, -8 and -9), and cleavage of poly (ADP-ribose) polymerase cleavage. However, genistein-induced apoptosis was significantly inhibited by a pan-caspase inhibitor, indicating that the induction of apoptosis by genestein was caspase-dependent. In addition, genistein increased the cytosolic release of cytochrome c by increasing the Bax/Bcl-2 ratio and destroying mitochondria integrity. Moreover, genistein inactivated the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, while LY294002, a PI3K/Akt inhibitor, increased the apoptosis-inducing effect of genistein. Genistein further increased the accumulation of reactive oxygen species (ROS), which was significantly suppressed by N-acetyl cysteine (NAC), a ROS scavenger, and in particular, NAC prevented genistein-mediated inactivation of PI3K/Akt signaling, G2/M arrest and apoptosis. Therefore, the present results indicated that genistein promoted apoptosis induction in human bladder cancer T24 cells, which was associated with G2/M phase cell cycle arrest via regulation of ROS-dependent PI3K/Akt signaling pathway.}, }
@article {pmid31433961, year = {2019}, author = {Park, JE and Kim, DH and Ha, E and Choi, SM and Choi, JS and Chun, KS and Joo, SH}, title = {Thymoquinone induces apoptosis of human epidermoid carcinoma A431 cells through ROS-mediated suppression of STAT3.}, journal = {Chemico-biological interactions}, volume = {312}, number = {}, pages = {108799}, doi = {10.1016/j.cbi.2019.108799}, pmid = {31433961}, issn = {1872-7786}, mesh = {Animals ; Antineoplastic Agents/*pharmacokinetics/therapeutic use ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology/therapeutic use ; Carcinoma, Squamous Cell/drug therapy/metabolism/pathology ; Cell Line, Tumor ; Down-Regulation/*drug effects ; Humans ; Mice ; Mice, Inbred NOD ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*metabolism ; Transplantation, Heterologous ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {Black seed (Nigella sativa) oil has been used in various dermatological applications, and its major constituent, thymoquinone (TQ) has been shown to exhibit antiproliferative activity against various cancer cells. In this study, we tried to provide a mechanistic basis of apoptosis induced by TQ. Skin squamous carcinoma A431 cells were treated with TQ to monitor the apoptosis induced by TQ. Western blot analysis was performed to detect expression of apoptotic or anti-apoptotic proteins. Cell viability and apoptosis were measured by using the MTT test and FACS analysis, respectively. The induction of intracellular reactive oxygen species (ROS) by TQ was evaluated by 2',7'-dichlorofluorescein diacetate staining. In vivo xenograft study was followed to confirm the antiproliferative effect of TQ. Treatment of A431 cells with TQ-induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, and activation of caspase-9, -7, and -3. TQ inhibited the constitutive phosphorylation and DNA binding activity of signal transducer and activator of transcription-3 (STAT3) in A431 cells by blocking the phosphorylation of the upstream kinase, Src. Moreover, the expression of STAT3 target gene products, cyclin D1 and survivin, was attenuated by TQ treatment. The generation of ROS was increased during TQ-induced apoptosis, and the pretreatment of N-acetyl cysteine, a ROS scavenger, reversed the apoptotic effect of TQ. In vivo study with NOD scid gamma (NSG) mice confirmed the inhibitory effect of TQ on the growth of A431 cells. Our results provide the first demonstration that TQ induces the apoptosis of A431 cells through generation of ROS and inhibition of STAT3 signaling.}, }
@article {pmid31432102, year = {2019}, author = {Chu, L and Xiao, L and Xu, B and Xu, J}, title = {Dissociation of HKII in retinal epithelial cells induces oxidative stress injury in the retina.}, journal = {International journal of molecular medicine}, volume = {44}, number = {4}, pages = {1377-1387}, pmid = {31432102}, issn = {1791-244X}, mesh = {Amyloid beta-Peptides/metabolism/pharmacology ; Apoptosis ; Biomarkers ; Cell Line ; Cell Survival/drug effects ; Epithelial Cells/drug effects/metabolism ; Gene Knockout Techniques ; Hexokinase/*genetics/metabolism ; Humans ; Mitochondria ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Retinal Diseases/*etiology/*metabolism/pathology ; Retinal Pigment Epithelium/drug effects/*metabolism ; }, abstract = {The retina is sensitive to injury resulting from oxidative stress (OS) due to its high oxygen consumption. Patients with retinitis pigmentosa suffer from excessive OS. N‑acetylcysteine (NAC) is used as a mucolytic agent for the clinical treatment of disorders, such as chronic bronchitis and other pulmonary diseases. The aim of the present study was to investigate the role of hexokinase 2 (HKII) in retinal OS injury. Amyloid β (Aβ)1‑40 was used to establish a cellular model of OS. Cell viability was measured with a Cell Counting Kit‑8 assay, and the apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) of cells were analyzed via flow cytometry with corresponding kits. The mRNA and protein levels were detected by reverse transcription‑quantitative PCR and western blot analyses, respectively. It was observed that Aβ1‑40 reduced the expression of HKII in the mitochondria of retinal pigment epithelial ARPE cells and impaired mitochondrial antioxidant functions. Additionally, knockdown of HKII promoted apoptosis, and increased ROS levels and the MMP. NAC attenuated the inhibition of mitochondrial functions induced by Aβ1‑40. The knockdown of HKII was revealed to decrease the levels of Bcl‑2, manganese superoxide dismutase (SOD) and copper‑zinc‑SOD, and increase the levels of cleaved caspase‑3, Bax and cytochrome c. The present findings suggested that the dissociation of HKII induced by OS induces apoptosis and mitochondrial damage. This study provided improved understanding of the mechanisms underlying the effects of OS on retinal epithelial cells.}, }
@article {pmid31430466, year = {2019}, author = {Williams, L and Burgos, ES and Vuguin, PM and Manuel, CR and Pekson, R and Munnangi, S and Reznik, SE and Charron, MJ}, title = {N-Acetylcysteine Resolves Placental Inflammatory-Vasculopathic Changes in Mice Consuming a High-Fat Diet.}, journal = {The American journal of pathology}, volume = {189}, number = {11}, pages = {2246-2257}, pmid = {31430466}, issn = {1525-2191}, support = {F31 DK093332/DK/NIDDK NIH HHS/United States ; R01 NS069577/NS/NINDS NIH HHS/United States ; R21 DK081194/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Diet, High-Fat/*adverse effects ; Disease Models, Animal ; Female ; Inflammation/complications/pathology/*prevention &amp; control ; Male ; Maternal Nutritional Physiological Phenomena/physiology ; Mice ; Mice, Transgenic ; Placenta/*drug effects/pathology ; Pregnancy ; Pregnancy Complications/etiology/*prevention &amp; control ; Vascular Diseases/complications/pathology/*prevention &amp; control ; }, abstract = {The mechanism by which poor maternal nutrition can affect the long-term health of offspring is poorly understood. In mice, we previously found that maternal high-fat diet (HFD) exposure results in reduced fetal growth regardless of maternal genotype. We tested our hypothesis that maternal HFD-induced inflammation contributes to metabolic disease susceptibility of the offspring via alterations in the placenta. The effect of maternal genotype, diet, and treatment with the anti-inflammatory compound N-acetylcysteine (NAC) on placental morphologic features was investigated. Placentas from wild-type dams maintained on a HFD but not those heterozygous (+/-) for Glut4 (Slc2a4) on the same diet had an increase in decidual inflammation and vasculopathy occurring together. NAC administration resulted in amelioration of HFD-induced decidual vasculopathy independent of offspring genotype and sex. Consistent with these morphologic improvements, placentas from HFD dams treated with NAC had decreased mRNA and immunostaining of IL-1β and monocyte chemoattractant protein-1, decreased mRNA of inflammatory genes, and increased mRNA of Vegfa. These results strongly suggest consumption of an HFD results in vascular changes in placenta reflected by alterations in expression of pivotal vascular developmental markers and inflammatory genes all of which are ameliorated by NAC. These placental changes play a key role in the increased programed metabolic disease of HFD-exposed offspring.}, }
@article {pmid31425734, year = {2019}, author = {Chen, T and Zhu, J and Wang, YH and Hang, CH}, title = {ROS-Mediated Mitochondrial Dysfunction and ER Stress Contribute to Compression-Induced Neuronal Injury.}, journal = {Neuroscience}, volume = {416}, number = {}, pages = {268-280}, doi = {10.1016/j.neuroscience.2019.08.007}, pmid = {31425734}, issn = {1873-7544}, mesh = {Animals ; Apoptosis/drug effects/physiology ; Calcium/metabolism ; Endoplasmic Reticulum Stress/*physiology ; Mitochondria/drug effects/*metabolism ; Neurons/*metabolism ; Oxidative Stress/*physiology ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Intracranial hypertension (IH) is a medical or surgical emergency that can be the common ending of various neurological disorders, such as traumatic brain injury, cerebral vascular diseases and brain tumors. However, the molecular mechanisms underlying IH-induced neuronal apoptosis have not been fully determined, and the treatments are symptomatic, insufficient and complicated by side-effects. In this study, a cellular model induced by compressed gas treatment in primary cultured rat cortical neurons was performed to mimic IH-induced neuronal injury in vitro. We found that compression induced cytotoxicity and apoptosis in cortical neurons in a dose- and time-dependent manner. Compression resulted in oxidative stress, which could be prevented by the ROS scavenger N-acetylcysteine (NAC). Compression produced mitochondrial oxidative stress, ATP loss and mitochondrial fragmentation. The results of western blot showed that compression differently regulated the expression of mitochondrial dynamic proteins, and the Drp1 inhibitor mdivi-1 partially reversed the compression-induced cytotoxicity. Compression significantly increased the expression of ER stress-associated factors in a time-dependent manner. The results of calcium imaging showed that compression induced intracellular calcium overload via promoting ER calcium release. Furthermore, the results using inhibitors of each signaling pathway demonstrated that ROS mediated the compression-induced ER stress and mitochondrial dysfunction in cortical neurons. In conclusion, our results demonstrated that compression induced apoptosis in primary cultured cortical neurons, which was associated with ROS mediated ER stress and mitochondrial dysfunction. Pharmacological compounds or agents targeting mitochondrial dysfunction and ER stress associated oxidative stress might be ideal candidates for the treatment of IH-related neurological diseases.}, }
@article {pmid31425726, year = {2019}, author = {Ninh, VK and El Hajj, EC and Ronis, MJ and Gardner, JD}, title = {N-Acetylcysteine prevents the decreases in cardiac collagen I/III ratio and systolic function in neonatal mice with prenatal alcohol exposure.}, journal = {Toxicology letters}, volume = {315}, number = {}, pages = {87-95}, pmid = {31425726}, issn = {1879-3169}, support = {F31 HL134263/HL/NHLBI NIH HHS/United States ; T32 AA007577/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Alcoholism/*physiopathology ; Animals ; Animals, Newborn ; Cell Proliferation/*drug effects ; Collagen Type I/*metabolism ; Coronary Vessels/*chemistry ; Disease Models, Animal ; Ethanol/*toxicity ; Female ; Fibroblasts/*drug effects ; Mice ; Pregnancy ; Prenatal Exposure Delayed Effects/*chemically induced ; }, abstract = {Prenatal alcohol exposure (PAE) is often associated with congenital heart defects, most commonly septal, valvular, and great vessel defects. However, there have been no known studies on whether PAE affects the resulting fibroblast population after development, and whether this has any consequences in the postnatal period. Our previous study focused on the effects of PAE on the postnatal fibroblast population, which translated into changes in cardiac extracellular matrix (ECM) composition and cardiac function in the neonatal heart. Moreover, our lab has previously demonstrated that alcohol-induced fibrosis is mediated by oxidative stress mechanisms in adult rat hearts following chronic alcohol exposure. Thus, we hypothesize that PAE alters cardiac ECM composition that persists into the postnatal period, leading to cardiac dysfunction, and these effects are prevented by antioxidant treatment. To investigate these effects, pregnant mice were intraperitoneally injected with 2.9 g EtOH/kg body weight on gestation days 6.75 and 7.25. Controls were injected with vehicle saline. Randomly selected dams in both groups were then treated with 100 mg/kg body weight of the antioxidant N-acetylcysteine (NAC) immediately after EtOH or vehicle administration. Left ventricular (LV) chamber dimension and function were assessed in sedated animals on neonatal day 5 using echocardiography. Ejection fraction decreased in the PAE group. NAC treatment prevented this depression of systolic function in PAE neonates. Hearts were analyzed for expression of fibroblast activation markers. Alpha smooth muscle actin (α-SMA) increased in PAE neonatal hearts, and this increase was prevented by NAC treatment. In PAE pups, collagen I decreased, but collagen III expression increased compared to saline animals; the overall collagen I/III ratio significantly decreased. When PAE mice were treated with NAC, collagen I/III ratio did not change. Overall, our data demonstrate that prenatal alcohol exposure produces changes in collagen subtype in neonatal cardiac ECM and a decline in systolic function, and these adverse effects were prevented by NAC treatment.}, }
@article {pmid31423251, year = {2019}, author = {Dong, G and Lin, XH and Liu, HH and Gao, DM and Cui, JF and Ren, ZG and Chen, RX}, title = {Intermittent hypoxia alleviates increased VEGF and pro-angiogenic potential in liver cancer cells.}, journal = {Oncology letters}, volume = {18}, number = {2}, pages = {1831-1839}, pmid = {31423251}, issn = {1792-1074}, abstract = {Vascular endothelial growth factor (VEGF) is an important angiogenic factor. The VEGF rebound induced by hypoxia following transarterial embolization/chemoembolization for primary liver cancer is associated with treatment failure and poor survival rates in patients. The present study investigated the ability of intermittent hypoxia to alleviate the acute hypoxia-induced increase of VEGF and decrease the pro-angiogenic potential of liver cancer cells. The liver cancer cells were exposed to normoxia, or acute or intermittent hypoxia, and the expression of VEGF was determined using reverse transcription-quantitative polymerase chain reaction analysis and western blotting. The pro-angiogenic effects of acute or intermittent hypoxia-exposed liver cancer cells on endothelial cells were assessed in vitro and in vivo. The expression of VEGF in the liver cancer cells exposed to intermittent hypoxia was significantly lower than that in cells exposed to acute hypoxia. Compared with conditioned medium (CM) from acute hypoxia-exposed liver cancer cells, the CM from intermittent hypoxia-exposed liver cancer cells showed markedly less promotion of proliferation and tube formation in endothelial cells. Activation of the reactive oxygen species (ROS)/NF-κB/hypoxia-inducible factor-1α/VEGF signaling pathway was increased in the liver cancer cells exposed to acute hypoxia. Exposure to ROS scavenger N-acetyl-cysteine or NF-κB inhibitor PDTC inhibited the activation of the above pathway and the expression of VEGF induced by acute hypoxia. The in vivo pro-angiogenic effects of intermittent hypoxia-exposed liver cancer cells on endothelial cells were significantly reduced compared with those of acute hypoxia-exposed liver cancer cells. Intermittent hypoxia may alleviate the acute hypoxia-induced increase of VEGF and decrease the pro-angiogenic potential of liver cancer cells, suggesting a novel treatment strategy.}, }
@article {pmid31422047, year = {2019}, author = {Lejay, A and Charles, AL and Georg, I and Goupilleau, F and Delay, C and Talha, S and Thaveau, F and Chakfé, N and Geny, B}, title = {Critical Limb Ischaemia Exacerbates Mitochondrial Dysfunction in ApoE-/- Mice Compared with ApoE+/+ Mice, but N-acetyl Cysteine still Confers Protection.}, journal = {European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery}, volume = {58}, number = {4}, pages = {576-582}, doi = {10.1016/j.ejvs.2019.03.028}, pmid = {31422047}, issn = {1532-2165}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Calcium/metabolism ; Critical Illness ; Disease Models, Animal ; Hyperlipidemias/*complications/genetics/metabolism ; Ischemia/*drug therapy/etiology/metabolism/pathology ; Mice, Knockout, ApoE ; Mitochondria, Muscle/*drug effects/metabolism/pathology ; Muscle, Skeletal/*drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Peripheral Arterial Disease/*drug therapy/etiology/metabolism/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVES: The current study was performed in order to determine the influence of hypercholesterolaemia on critical limb ischaemia (CLI) and whether targeting oxidative stress by antioxidant therapies such as N-acetyl cysteine (NAC), considered to be a direct scavenger of reactive oxygen species, could confer muscle protection.<br><br>METHODS: Apolipoprotein E (ApoE)-/- mice (n&#xa0;=&#xa0;9, 29 weeks old) and their genetic controls ApoE+/+ mice (n&#xa0;=&#xa0;9, 29 weeks old) were submitted to sequential right femoral and iliac ligations; the left limb served as control. ApoE+/+ mice were divided into two groups: Group 1 (n&#xa0;=&#xa0;4) and Group 2 (n&#xa0;=&#xa0;5); as well as ApoE-/- mice: Group 3 (n&#xa0;=&#xa0;3), and Group 4 (n&#xa0;=&#xa0;6). NAC treatment was administered to Groups 2 and 4 in drinking water. Mice were sacrificed on Day 40 and gastrocnemius muscles were harvested to study mitochondrial respiration by oxygraphy, calcium retention capacity by spectrofluorometry, and production of reactive oxygen species by electron paramagnetic resonance.<br><br>RESULTS: CLI associated with ApoE deficiency resulted in more severe mitochondrial dysfunction: maximum oxidative capacity and calcium retention capacity were decreased (-42.9% vs.&#xa0;-25.1%, p&#xa0;=&#xa0;.010; and&#xa0;-73.1% vs.&#xa0;-40.3%, p&#xa0;=&#xa0;.003 respectively) and production of reactive oxygen species was enhanced (+63.6% vs.&#xa0;+41.4%, p&#xa0;=&#xa0;.03) in ApoE-/- mice compared with ApoE+/+ mice respectively. Antioxidant treatment restored oxidative capacity, calcium retention capacity and decreased production of reactive oxygen species in both mice strands.<br><br>CONCLUSIONS: In this small murine study, hypercholesterolaemia exacerbated mitochondrial dysfunction, as clinically expected; but antioxidant therapy appeared protective, which is counter to clinical experience. Further work is clearly needed.}, }
@article {pmid31421008, year = {2019}, author = {Singh, S and Hynan, LS and Rule, JA and Lee, WM}, title = {Changes in alpha-foetoprotein and Gc-globulin in relation to outcomes in non-acetaminophen acute liver failure.}, journal = {Liver international : official journal of the International Association for the Study of the Liver}, volume = {39}, number = {12}, pages = {2368-2373}, doi = {10.1111/liv.14216}, pmid = {31421008}, issn = {1478-3231}, support = {FD-R-001661//U.S. Food and Drug Administration/International ; R-01-DK58369/DK/NIDDK NIH HHS/United States ; R-01-DK58369/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Biomarkers/blood ; Female ; Humans ; Liver Failure, Acute/blood/*drug therapy ; Male ; Middle Aged ; Retrospective Studies ; Vitamin D-Binding Protein/*blood ; Young Adult ; alpha-Fetoproteins/*metabolism ; }, abstract = {BACKGROUND: Changes in Gc-globulin (Gc) and in alpha-foetoprotein (AFP) have been shown to be related to outcome in patients with acute liver failure (ALF). Gc is a serum protein that complexes with intravascular actin released during cellular necrosis. AFP, also made by hepatocytes, is associated with hepatocellular growth and regeneration. Previously, low absolute levels or decreases over time in either AFP or Gc portended to be a poor outcome.<br><br>METHODS: In a retrospective analysis of the double-blind trial of intravenous N-acetylcysteine (NAC) for ALF not because of acetaminophen, sera on days 1 and 3 or days 2 and 4 following admission were available to measure AFP in 70 patients and Gc in 66 patients. Mann-Whitney U tests were performed on the admission values, the absolute change and the fractional change of AFP and Gc to compare TFS (transplant-free survival) and non-TFS (death or transplantation). Logistic regression and receiver operating characteristic (ROC) analyses were performed to evaluate the markers in comparison and in addition to King's College Criteria (KCC).<br><br>RESULTS: Transplant-free survival patients were characterized by increases in AFP, whereas non-TFS had significantly different (negative) absolute and fractional changes (P&#xa0;<&#xa0;.01). The addition of declining AFP levels to KCC improved the area under the curve in predicting non-TFS (AUC >70%). Gc globulin values did not differ between TFS and non-TFS in the 2-day intervals studied (P>&#xa0;.2).<br><br>CONCLUSION: In this comparison of two prognostic markers in patients with non-acetaminophen-induced ALF, rising AFP but not rising Gc levels was associated with TFS.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov number NCT00004467.}, }
@article {pmid31419506, year = {2019}, author = {Zhuang, J and Nie, G and Yang, F and Dai, X and Cao, H and Xing, C and Hu, G and Zhang, C}, title = {Cadmium induces cytotoxicity through oxidative stress-mediated apoptosis pathway in duck renal tubular epithelial cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {61}, number = {}, pages = {104625}, doi = {10.1016/j.tiv.2019.104625}, pmid = {31419506}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cadmium/*toxicity ; Cells, Cultured ; Ducks ; Epithelial Cells/*drug effects/metabolism ; Kidney Tubules/*cytology ; Oxidative Stress/*drug effects ; }, abstract = {Cadmium (Cd) is a well studied nephrotoxic metal element. To investigate the effects of Cd-induced cytotoxicity on oxidative stress-mediated apoptosis in primary renal tubular epithelial cells of duck. Shaoxing duck (Anas platyrhyncha) renal tubular epithelial cells were cultured in medium in absence and presence of 3CdSO4·8H2O (1.25, 2.5, 5.0 μM Cd), in N-acetyl-l-cysteine (NAC) (100 μM), and the combination of Cd and NAC for 12 h. After 12 h exposure, morphologic observation and function, reactive oxygen species (ROS) level, antioxidant indices, the activity of ATPase, intracellular pH and [Ca[2+]]i, mitochondrial membrane potential (MMP), and apoptosis-related genes mRNA were determined. The results showed that Cd exposure could induce release of intracellular lactate dehydrogenase (LDH), simultaneously, enhance the ROS generation, acidification, malondialdehyde (MDA) and [Ca[2+]]i, decrease glutathione (GSH), Na[+], K[+]-ATPase, Ca[2+]-ATPase, catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) activities as well as MMP, upregulated Bak-1, Bax and Caspase-3 mRNA expression, inhibited Bcl-2 mRNA expression, and induced cell apoptosis. The toxicity of Cd to cells showed a dose-dependent manner. Antioxidant NAC could efficiently alleviate Cd-induced the cytotoxicity. Taken together, these results suggest that Cd exposure cause cytotoxicity through oxidative stress-mediated apoptosis pathway in duck renal tubular epithelial cells.}, }
@article {pmid31419475, year = {2019}, author = {Wang, H and Wang, G and Liang, Y and Du, X and Boor, PJ and Sun, J and Khan, MF}, title = {Redox regulation of hepatic NLRP3 inflammasome activation and immune dysregulation in trichloroethene-mediated autoimmunity.}, journal = {Free radical biology &amp; medicine}, volume = {143}, number = {}, pages = {223-231}, pmid = {31419475}, issn = {1873-4596}, support = {R01 ES016302/ES/NIEHS NIH HHS/United States ; R01 ES026887/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anesthetics, Inhalation/toxicity ; Animals ; Autoimmune Diseases/chemically induced/*immunology/metabolism/pathology ; Female ; Free Radical Scavengers/pharmacology ; Inflammasomes/drug effects/*immunology/metabolism ; Inflammation/chemically induced/*immunology/metabolism/pathology ; Liver/drug effects/*immunology/metabolism ; Mice ; Mice, Inbred Strains ; NLR Family, Pyrin Domain-Containing 3 Protein/*immunology ; Oxidative Stress/*drug effects ; Trichloroethylene/*toxicity ; }, abstract = {Trichloroethene (TCE) exposure is associated with the development of various autoimmune diseases (ADs), including autoimmune hepatitis (AIH) and systemic lupus erythematosus (SLE), potentially through the generation of excessive reactive oxygen and nitrogen species (RONS; oxidative stress). However, the mechanisms by which oxidative stress contributes to these TCE-mediated ADs are not fully understood, and are the focus of current investigation. Female MRL+/+ mice were treated with TCE along with or without antioxidant N-acetylcysteine (NAC) for 6 weeks (TCE, 10 mmol/kg, i. p., every 4th day; NAC, 250 mg/kg/day via drinking water). TCE-treated mice had elevated antinuclear antibodies (ANA) and 4-hydroxynonenal (HNE)-specific circulating immune complexes, suggesting the association of TCE-induced oxidative stress with autoimmune response. In addition, TCE exposure led to prominent lobular inflammation with sinusoid dilation, increased sinusoidal cellularity and increased staining for proliferating cell nuclear antigen (PCNA), confirming inflammatory and hepatocellular cell proliferation. Importantly, TCE exposure resulted in the activation of hepatic inflammasome (NLRP3 and caspase-1) and up-regulation of pro-inflammatory cytokine IL-1β, and these changes were attenuated by NAC supplementation. TCE treatment also led to dysregulation of hepatic immune response as evident from markedly increased hepatic lymphocyte infiltration (especially B cells) and imbalance between Tregs (decreased) and Th17 cells (increased). Interestingly, TCE-mediated dysregulation of various hepatic and splenic immune cells was also effectively attenuated by NAC. Taken together, our findings provide evidence for TCE-mediated inflammasome activation, infiltration of various immune cells, and skewed balance of Treg and Th17 cells in the liver. The attenuation of TCE-mediated hepatic inflammasome activation and immune responses by NAC further supports a critical role of oxidative stress in TCE-mediated inflammation and autoimmunity. These novel findings could help in designing therapeutic strategies for such ADs.}, }
@article {pmid31410096, year = {2019}, author = {Akbay, E and Erdem, B and Ünlü, A and Durukan, AB and Onur, MA}, title = {Effects of N-acetyl cysteine, vitamin E and vitamin C on liver glutathione levels following amiodarone treatment in rats.}, journal = {Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery}, volume = {16}, number = {2}, pages = {88-92}, pmid = {31410096}, issn = {1731-5530}, abstract = {INTRODUCTION: Amiodarone, a pharmaceutical extensively used to suppress atrial and ventricular tachyarrhythmias, is also known to cause many side effects on many tissues. N-acetyl-cysteine (NAC), vitamin E and vitamin C are known as antioxidants for their ability to minimize oxidative stress. In the peer-reviewed literature, there is no study reporting on the protective effects of these antioxidant agents against its hepatotoxicity.<br><br>AIM: We investigated the oxidative effects of NAC, vitamins E and C on liver tissue after amiodarone treatment.<br><br>MATERIAL AND METHODS: Rats were randomly assigned to: control; amiodarone group; amiodarone + NAC treated group; amiodarone + Vit. E group and amiodarone + Vit. C group. Liver tissues were isolated from animals and total glutathione levels were measured.<br><br>RESULTS: In all time intervals, the level of glutathione increased. When all time intervals were compared, the amiodarone group revealed the lowest levels. The antioxidant co-administered group was studied; the glutathione levels were statistically significantly higher than the sole amiodarone group. When vitamins E, C or N-acetyl cysteine were examined, there was no statistically significant difference among them.<br><br>CONCLUSIONS: In this study we found that hepatotoxicity capacity of amiodarone may be reduced by taking up antioxidants. In addition, the effect documented here may be reproducible and may be applied to clinical settings.}, }
@article {pmid31409904, year = {2019}, author = {Han, Y and Kim, B and Cho, U and Park, IS and Kim, SI and Dhanasekaran, DN and Tsang, BK and Song, YS}, title = {Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells.}, journal = {Oncogene}, volume = {38}, number = {45}, pages = {7089-7105}, pmid = {31409904}, issn = {1476-5594}, mesh = {Antineoplastic Agents/pharmacology ; Apoptosis ; Cell Proliferation ; Cisplatin/*pharmacology ; Drug Resistance, Neoplasm/*drug effects ; Female ; Humans ; Hypoxia/*physiopathology ; Mitochondria/drug effects/metabolism/*pathology ; *Mitochondrial Dynamics ; Mitochondrial Proteins/genetics/metabolism ; Ovarian Neoplasms/drug therapy/genetics/metabolism/*pathology ; Quinazolinones/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Tumor Cells, Cultured ; Tumor Microenvironment ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {Mitochondria undergo fission and fusion continually for survival through the course of cellular adaption processes in response to changes in the surrounding environment. Dysregulated mitochondrial dynamics has been reported in various diseases including cancer. Under hypoxic conditions (<1% O2), the relationship between mitochondrial dynamics and sensitivity to cisplatin (CDDP) was examined in ovarian cancer cells. We found that hypoxia promoted mitochondrial fission and CDDP resistance in ovarian cancer cells. Hypoxia-induced reactive oxygen species (ROS) caused an increase in mitochondrial fission, a response abolished by free radical scavenging with N-acetylcysteine (NAC) and Trolox. Also, treatment of hydrogen peroxide (H2O2) decreased inhibitory p-Drp1 (Ser637) content and increased mitochondrial fission. Suppression of mitochondrial fission enhanced the CDDP sensitivity of hypoxic ovarian cancer cells. Lastly, in tumor spheroids from malignant ascites or tissues of patients with advanced-stage ovarian cancer, pretreatment with Mdivi-1 increased the CDDP sensitivity. Taken together, our results implicate that hypoxia-induced ROS trigger mitochondrial fission and CDDP resistance through downregulation of p-Drp1 (Ser637) and Mfn1 in ovarian cancer cells. Inhibition of Drp1 by Mdivi-1 treatment or si-Drp1 transfection increased CDDP sensitivity of ovarian cancer cells under hypoxia. Therefore, mitochondrial dynamics of cancer cells adapting to the hypoxic tumor microenvironment could be a potential target for anticancer therapy.}, }
@article {pmid31406447, year = {2019}, author = {Senthilkumaran, S and Benita, F and Nath Jena, N and Sasikumar, S and Thirumalaikolundusubramanian, P}, title = {5-oxoprolinuria (Pyroglutamic Aciduria) and Metabolic Acidosis: Unraveling the Mystery.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {23}, number = {7}, pages = {342-343}, pmid = {31406447}, issn = {0972-5229}, abstract = {UNLABELLED: A case of high anion gap metabolic acidosis (HAGMA) and high level of 5-oxoprolinuria were noticed in an elderly female of 66 years who had multiple risk/precipitating factors and recovered well with N-acetyl cysteine infusion. This is reported in view of its rarity and to create awareness of this entity among medical students and practicing physicians who handles such cases in emergency room or critical care unit. Moreover they have to remember and investigate the cases of metabolic acidosis for 5-oxoprolinuia especially in susceptible individuals who are on paracetamol with or without other precipitating factors.<br><br>HOW TO CITE THIS ARTICLE: Senthilkumaran S, Benita F, Jena NN, Sasikumar S, Thirumalaikolundusubramanian P. 5-oxoprolinuria (Pyroglutamic Aciduria) and Metabolic Acidosis: Unraveling the Mystery. Indian J Crit Care Med 2019;23(7):342-343.}, }
@article {pmid31404783, year = {2019}, author = {Jun, Y and Youn, CK and Jo, ER and Cho, SI}, title = {In vitro inhibitory activity of N-acetylcysteine on tympanostomy tube biofilms from methicillin-resistant Staphylococcus aureus and quinolone-resistant Pseudomonas aeruginosa.}, journal = {International journal of pediatric otorhinolaryngology}, volume = {126}, number = {}, pages = {109622}, doi = {10.1016/j.ijporl.2019.109622}, pmid = {31404783}, issn = {1872-8464}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; Biofilms/*drug effects ; Drug Resistance, Bacterial/drug effects ; Humans ; In Vitro Techniques ; Methicillin-Resistant Staphylococcus aureus/*drug effects ; Microbial Sensitivity Tests ; Microscopy, Electrochemical, Scanning ; Middle Ear Ventilation/*adverse effects ; Prostheses and Implants/*microbiology ; Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa/*drug effects ; Quinolones/*pharmacology/therapeutic use ; Staphylococcal Infections/drug therapy ; }, abstract = {OBJECTIVES: Biofilm formation in tympanostomy tubes causes persistent and refractory otorrhea. In the present study, we investigated the in vitro antibiofilm activity of N-acetylcysteine (NAC) against biofilm formation by methicillin-resistant Staphylococcus aureus (MRSA) and quinolone-resistant Pseudomonas aeruginosa (QRPA).<br><br>METHODS: We examined the antibiofilm activity of NAC against biofilms produced by MRSA and QRPA strains using in vitro biofilm formation assay, adhesion assay, and biofilm eradication assay. Additionally, the antibiofilm activity of different concentrations of NAC against tympanostomy-tube biofilms from MRSA and QRPA strains was compared using a scanning electron microscope.<br><br>RESULTS: The adhesion of MRSA and QRPA strains decreased significantly in a concentration-dependent manner after treatment with varying amounts of NAC. Treatment with NAC inhibited biofilm formation of both MRSA and QRPA strains and increased eradication of preformed mature biofilm produced by MRSA and QRPA. Besides, NAC exhibited significant eradication-activity against tympanostomy-tube biofilms produced by MRSA and QRPA strains.<br><br>CONCLUSIONS: Our results show potent inhibition of MRSA and QRPA biofilm after treatment with NAC. NAC shows potential for the treatment of biofilms and refractory post-tympanostomy tube otorrhea resulting from MRSA and QRPA infection.}, }
@article {pmid31401317, year = {2019}, author = {Hassan, MS and Morgan, AM and Mekawy, MM and Zeineb, MA}, title = {Molecular mechanisms of Cisplatin- induced placental toxicity and teratogenicity in rats and the ameliorating role of N-acetyl-cysteine.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {115}, number = {}, pages = {105579}, doi = {10.1016/j.biocel.2019.105579}, pmid = {31401317}, issn = {1878-5875}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cisplatin/*toxicity ; Cytoprotection/drug effects ; Dose-Response Relationship, Drug ; Female ; Placenta/*drug effects/physiopathology ; Pregnancy ; Rats ; Reproduction/drug effects ; Teratogenesis/*drug effects ; }, abstract = {The aim of the present study is to investigate the molecular mechanisms of Cisplatin- induced placental toxicity and teratogenicity in rats and the ameliorating role of N-acetyl-cysteine (NAC). Cisplatin was administrated intraperitoneally at 5 mg/kg.b.wt as a single dose on the 12[th] day of gestation while NAC was administered orally throughout gestation either alone or in concomitant injection of Cisplatin at 200 mg/kg.b.wt. Cisplatin + NAC group showed reduction in the elevated morphological, visceral and skeletal abnormalities as well as the morphological and histopathological changes in placenta compared to Cisplatin - treated rats. Importantly, NAC attenuated Cisplatin-induced placental apoptosis through down-regulation of Fas and Caspase-3 genes expression. In conclusion, induction of placental apoptosis by overexpression of Fas and Caspase-3 genes gives a new insight into the mechanism of Cisplatin teratogenicity. The protective role of NAC, on the other hand, was characterized by attenuation of Fas and Caspase-3 genes- mediated apoptosis.}, }
@article {pmid31401057, year = {2019}, author = {Sun, P and Gu, L and Luo, J and Qin, Y and Sun, L and Jiang, S}, title = {ROS-mediated JNK pathway critically contributes to PFOS-triggered apoptosis in SH-SY5Y cells.}, journal = {Neurotoxicology and teratology}, volume = {75}, number = {}, pages = {106821}, doi = {10.1016/j.ntt.2019.106821}, pmid = {31401057}, issn = {1872-9738}, mesh = {Acetylcysteine/pharmacology ; Alkanesulfonic Acids/*toxicity ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Nucleus/drug effects ; Cytoplasm/drug effects ; Fluorocarbons/*toxicity ; Free Radical Scavengers/pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mitochondria/drug effects/metabolism ; Neurons/drug effects ; Neurotoxicity Syndromes/*pathology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Recent studies have indicated that perfluorooctane sulfonate (PFOS) and its derivatives can lead to neurotoxicity. In the present study, we showed that PFOS may trigger neuronal apoptosis through a c-Jun N-terminal kinase (JNK)-related mechanism. We revealed that c-Jun N-terminal kinase (JNK) was robustly activated in PFOS-exposed neuronal cells. The doses of PFOS that initiates JNK activation coincides with that inducing neuronal apoptosis, as confirmed by western blot and Annexin V-PE/7-AAD analyses. In addition, we found that reactive oxidative species (ROS) accumulation plays a casual role in PFOS-initiated JNK activation, as treatment with ROS scavenger N-acetyl-l-cysteine (NAC) abrogated PFOS-induced mitochondrial and nuclear translocation of phosphorylated JNK (p-JNK). In keeping with this notion, the expression of JNK downstream pro-apoptotic target Bim was increased following PFOS exposure in JNK- and ROS-dependent manners. Finally, Annexin V-PE/7-AAD analysis uncovered that treatment with NAC or SP600125 could significantly impair PFOS-induced neuronal apoptosis. These findings implicate that JNK signaling is critically involved in PFOS-induced neuronal death by virtue of mitochondrial translocation and the transcription of pro-apoptotic genes.}, }
@article {pmid31400773, year = {2019}, author = {Lu, K and Cheng, Y and Li, W and Ni, H and Chen, X and Li, Y and Tang, B and Li, Y and Chen, D and Zeng, R and Song, Y}, title = {Copper-induced H2O2 accumulation confers larval tolerance to xanthotoxin by modulating CYP6B50 expression in Spodoptera litura.}, journal = {Pesticide biochemistry and physiology}, volume = {159}, number = {}, pages = {118-126}, doi = {10.1016/j.pestbp.2019.06.004}, pmid = {31400773}, issn = {1095-9939}, mesh = {Animals ; Antioxidant Response Elements/genetics/physiology ; Copper/*pharmacology ; Cytochrome P-450 Enzyme System/metabolism ; Hydrogen Peroxide/*metabolism ; Methoxsalen/*pharmacology ; Peroxidase/genetics/metabolism ; RNA Interference ; Spodoptera/*drug effects/*metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {In the plant-insect arms race, plants synthesize toxic compounds to defend against herbivorous insects, whereas insects employ cytochrome P450 monooxygenases (P450s) to detoxify these phytotoxins. As ubiquitous environmental contaminants, heavy metals can be easily absorbed by plants and further accumulated in herbivorous insects through the food chains, resulting in tangible consequences for plant-insect interactions. However, whether heavy metals can influence P450 activities and thereby cause further effects on larval tolerance to phytotoxins remains unknown. In this study, we shown that prior exposure to copper (Cu) enhanced larval tolerance to xanthotoxin in Spodoptera litura, a major polyphagous pest of agriculture. P450 activities were induced in larvae exposed to Cu or xanthotoxin, and a midgut specific expressed P450 gene, CYP6B50 was cross-induced after exposure to these two toxic xenobiotics. Knocking down CYP6B50 by RNA interference (RNAi) rendered the larvae more sensitive to xanthotoxin. As defense against oxidative stress following metal exposure has been demonstrated to affect insecticide resistance, the reactive oxygen species (ROS) generation and antioxidant enzyme activities were assessed. Cu exposure caused the accumulation of hydrogen peroxide (H2O2) and enhanced the activities of superoxide dismutase (SOD) and peroxidase (POD) in larval midgut. In addition, two antioxidant response elements (AREs) were identified from the CYP6B50 promoter, indicating that Cu-induced CYP6B50 expression may be related to the ROS burst. Application of ROS scavenger N-acetylcysteine (NAC) effectively suppressed CYP6B50 expression, inhibited P450 activities and impaired larval tolerance to xanthotoxin that had been induced by Cu. These results indicate that the increase in CYP6B50 expression regulated by Cu-induced H2O2 generation contributed to the enhancement of larval tolerance to xanthotoxin in S. litura. Ingestion of heavy metals from their host plants can inadvertently boost the counter-defense system of herbivorous insects to protect themselves against plant defensive toxins.}, }
@article {pmid31398338, year = {2019}, author = {Sanghvi, VR and Leibold, J and Mina, M and Mohan, P and Berishaj, M and Li, Z and Miele, MM and Lailler, N and Zhao, C and de Stanchina, E and Viale, A and Akkari, L and Lowe, SW and Ciriello, G and Hendrickson, RC and Wendel, HG}, title = {The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.}, journal = {Cell}, volume = {178}, number = {4}, pages = {807-819.e21}, pmid = {31398338}, issn = {1097-4172}, support = {U54 OD020355/OD/NIH HHS/United States ; R01 CA190384/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; S10 OD010598/OD/NIH HHS/United States ; R01 CA207217/CA/NCI NIH HHS/United States ; P01 CA013106/CA/NCI NIH HHS/United States ; R01 CA183876/CA/NCI NIH HHS/United States ; P50 CA192937/CA/NCI NIH HHS/United States ; P50 CA217694/CA/NCI NIH HHS/United States ; R01 CA142798/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Carcinoma, Hepatocellular/*metabolism/pathology ; Female ; Gene Knockdown Techniques ; Glucose/metabolism ; Glycosylation ; HEK293 Cells ; Hep G2 Cells ; Heterografts ; Humans ; Kelch-Like ECH-Associated Protein 1/metabolism ; Liver Neoplasms/*metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; NF-E2-Related Factor 2/*metabolism ; Phosphotransferases (Alcohol Group Acceptor)/genetics/*metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Transduction, Genetic ; }, abstract = {The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.}, }
@article {pmid31396402, year = {2019}, author = {Zhao, Q and Liu, Y and Zhong, J and Bi, Y and Liu, Y and Ren, Z and Li, X and Jia, J and Yu, M and Yu, X}, title = {Pristimerin induces apoptosis and autophagy via activation of ROS/ASK1/JNK pathway in human breast cancer in vitro and in vivo.}, journal = {Cell death discovery}, volume = {5}, number = {}, pages = {125}, pmid = {31396402}, issn = {2058-7716}, abstract = {Breast cancer is the most common malignant tumor in women, and progress toward long-term survival has stagnated. Pristimerin, a natural quinonemethide triterpenoid, exhibits potential anti-tumor effects on various cancers. However, the underlying mechanism remains poorly understood. In this study, we found that pristimerin reduced the viability of breast cancer cells in vitro and the growth of xenografts in vivo, and these reductions were accompanied by thioredoxin-1 (Trx-1) inhibition and ASK1 and JNK activation. The results showed that pristimerin inhibited cell cycle progression and triggered cell apoptosis and autophagy. Furthermore, we found that the generation of reactive oxygen species (ROS) was a critical mediator in pristimerin-induced cell death. Enhanced ROS generation by pristimerin activated the ASK1/JNK signaling pathway. Inhibition of ROS with N-acetyl cysteine (NAC) significantly decreased pristimerin-induced cell death by inhibiting the phosphorylation of ASK1 and JNK. Taken together, these results suggest a critical role for the ROS/ASK1/JNK pathway in the anticancer activity of pristimerin.}, }
@article {pmid31396339, year = {2019}, author = {Chen, L and Wang, G and Wang, Q and Liu, Q and Sun, Q and Chen, L}, title = {N-acetylcysteine prevents orchiectomy-induced osteoporosis by inhibiting oxidative stress and osteocyte senescence.}, journal = {American journal of translational research}, volume = {11}, number = {7}, pages = {4337-4347}, pmid = {31396339}, issn = {1943-8141}, abstract = {Oxidative stress is associated with many diseases and has been found to induce DNA damage and cellular senescence. Numerous evidences support the detrimental effects of oxidative stress or cellular senescence on skeletal homeostasis. N-acetylcysteine (NAC) is a powerful antioxidant. However, it is unclear whether NAC can suppress orchiectomy (ORX)-induced osteoporosis by inhibiting oxidative stress and osteocyte senescence. In this study, ORX mice were supplemented with/without NAC, and were compared with each other and with sham-operated mice. Our results showed that NAC could prevent ORX-induced osteoporosis by inhibiting oxidative stress, DNA damage, osteocyte senescence and senescence-associated secretory phenotype (SASP), subsequently stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption. The results from this study suggest that NAC could be considered as a potential therapeutic agent for prevention and treatment of osteoporosis caused by testosterone deficiency.}, }
@article {pmid31394209, year = {2019}, author = {Wang, P and Feng, YB and Wang, L and Li, Y and Fan, C and Song, Q and Yu, SY}, title = {Interleukin-6: Its role and mechanisms in rescuing depression-like behaviors in rat models of depression.}, journal = {Brain, behavior, and immunity}, volume = {82}, number = {}, pages = {106-121}, doi = {10.1016/j.bbi.2019.08.002}, pmid = {31394209}, issn = {1090-2139}, mesh = {Animals ; Antidepressive Agents/therapeutic use ; Apoptosis/drug effects ; Autophagy/drug effects ; CA1 Region, Hippocampal/metabolism/physiology ; Depression/immunology/*metabolism/physiopathology ; Depressive Disorder/drug therapy/metabolism ; Disease Models, Animal ; Hippocampus/metabolism ; Interleukin-6/*metabolism/pharmacology ; Male ; Neurons/drug effects ; Neuroprotection ; Oxidative Stress/physiology ; Rats ; Rats, Wistar ; Stress, Psychological/physiopathology ; }, abstract = {Neuronal injury within specific brain regions is considered a critical risk factor in the pathophysiology of depression. However, the underlying mechanisms of this process, and thus the potential for development of novel therapeutic strategies in the treatment of depression, remain largely unknown. Here, we report that Il-6 protects against neuronal anomalies related with depression, in part, by suppressing oxidative stress and consequent autophagic and apoptotic hyperactivity. Specifically, we show that IL-6 is downregulated within the CA1 hippocampus in two animal models of depression and upregulated by antidepressants. Increasing levels of IL-6 in the CA1 region result in pleiotropic protective actions including reductions in oxidative stress and modulation of autophagy, anti-immuno-inflammatory activation and anti-apoptotic effects in CA1 neurons, all of which are associated with the rescue of depression-like behaviors. In contrast, IL-6 downregulation exacerbates neuronal anomalies within the CA1 region and facilitates the genesis of depression phenotypes in rats. Interestingly, in addition to attenuating oxidative damage, the antioxidant, N-acetylcysteine (NAC), is also associated with significantly decreased neuronal deficits and the display of depressive behaviors in rats. These results suggest that IL-6 may exert neuroprotection within CA1 neurons via pleiotropic mechanisms and may serve as a potential therapeutic target for the treatment of depression.}, }
@article {pmid31393045, year = {2020}, author = {Kong, W and Li, C and Qi, Q and Shen, J and Chang, K}, title = {Cardamonin induces G2/M arrest and apoptosis via activation of the JNK-FOXO3a pathway in breast cancer cells.}, journal = {Cell biology international}, volume = {44}, number = {1}, pages = {177-188}, doi = {10.1002/cbin.11217}, pmid = {31393045}, issn = {1095-8355}, support = {81801750//National Natural Science Foundation of China/ ; }, abstract = {Cardamonin (CD), a naturally occurring chalcone isolated from large black cardamom, was previously reported to suppress the proliferation of breast cancer cells. However, its precise molecular anti-tumor mechanisms have not been well elucidated. In this study, we found that CD markedly inhibited the proliferation of MDA-MB 231 and MCF-7 breast cancer cells through the induction of G2/M arrest and apoptosis. Reactive oxygen species (ROS) plays a pivotal role in the inhibition of CD-induced cell proliferation. Treatment with N-acetyl-cysteine (NAC), an ROS scavenger, blocked CD-induced G2/M arrest and apoptosis in this study. Quenching of ROS by overexpression of catalase also blocked CD-induced cell cycle arrest and apoptosis. We showed that CD enhanced the expression and nuclear translocation of Forkhead box O3 (FOXO3a) via upstream c-Jun N-terminal kinase, inducing the expression of FOXO3a and its target genes, including p21, p27, and Bim. This process led to the reduction of cyclin D1 and enhancement of activated caspase-3 expression. The addition of NAC markedly reversed these effects, knockdown of FOXO3a using small interfering RNA also decreased CD-induced G2/M arrest and apoptosis. In vivo, CD efficiently suppressed the growth of MDA-MB 231 breast cancer xenograft tumors. Taken together, our data provide a molecular mechanistic rationale for CD-induced cell cycle arrest and apoptosis in breast cancer cells.}, }
@article {pmid31392779, year = {2019}, author = {Rasheduzzaman, M and Yin, H and Park, SY}, title = {Cardiac glycoside sensitized hepatocellular carcinoma cells to TRAIL via ROS generation, p38MAPK, mitochondrial transition, and autophagy mediation.}, journal = {Molecular carcinogenesis}, volume = {58}, number = {11}, pages = {2040-2051}, doi = {10.1002/mc.23096}, pmid = {31392779}, issn = {1098-2744}, mesh = {Apoptosis/drug effects ; Autophagy/*drug effects ; Carcinoma, Hepatocellular/*genetics/pathology ; Cardiac Glycosides/*pharmacology ; Cell Proliferation/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/*genetics/pathology ; Membrane Potential, Mitochondrial/genetics ; Mitochondria/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics ; Reactive Oxygen Species/metabolism ; TNF-Related Apoptosis-Inducing Ligand ; p38 Mitogen-Activated Protein Kinases/genetics ; }, abstract = {A major concern in the clinical application of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) in tumors is the development of resistance. Therefore, agents that can potentially restore TRAIL sensitivity are important therapeutic targets for cancer treatment. Herein, we evaluated lanatoside c and digoxin, both of which are widely used cardiac glycosides (CGs), for their ability to sensitize human hepatocellular carcinoma cells (Huh-7 and HepG2) through TRAIL-induced apoptosis. CGs functionalize TRAIL as shown by its effect on intracellular reactive oxygen species (ROS) generation, which damages mitochondrial integrity and thereby confers intrinsic apoptotic caspase cascade during combined treatment. Caspase activation is dependent on ROS as shown by the ability of CGs to generate ROS and the ROS-N-acetylcysteine (NAC) relationship, which inhibits apoptosis during cotreatment by preventing the formation of caspase-8 and -3. Furthermore, CGs triggered p38MAPK phosphorylation and NAC pre-exposure blocked p38MAPK phosphorylation, which demonstrated that p38MAPK was dependent upon ROS generation. Additionally, CGs were found to be potent inducers of AMPK-mediated protective autophagy as pharmacological and genetic autophagy inhibition reached the higher threshold of TRAIL-mediated apoptosis. Finally, CGs downregulated the expression of the antiapoptotic protein Bcl-2 and increased the translocation of proapoptotic protein cytochrome c, thereby inducing apoptosis. Collectively, these results indicate that CGs potentiate the enhanced cytotoxic capacity to TRAIL through ROS generation, p38MAPK phosphorylation, cell survival protein downregulation, and protective autophagy inhibition.}, }
@article {pmid31392607, year = {2019}, author = {Mercantepe, T and Topcu, A and Rakici, S and Tumkaya, L and Yilmaz, A and Mercantepe, F}, title = {The radioprotective effect of N-acetylcysteine against x-radiation-induced renal injury in rats.}, journal = {Environmental science and pollution research international}, volume = {26}, number = {28}, pages = {29085-29094}, pmid = {31392607}, issn = {1614-7499}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Caspase 3 ; Kidney/drug effects ; Male ; Oxidative Stress/drug effects ; *Radiation Protection ; Rats ; *X-Rays ; }, abstract = {The purpose of this study was therefore to investigate the effects of radiotherapy on the kidney and the potential use of agents such as N-acetylcysteine (NAC) in developing a future therapeutic protocol for radiation-induced nephrotoxicity at the histopathological and biochemical levels. Our study consisted of three groups: control (oral saline solution only; group 1), irradiation (IR; group 2), and NAC + IR (group 3). The irradiation groups received a single dose of whole-body 6-Gy x-irradiation. The NAC group received 300 mg/kg by the oral route for 7 days, from 5 days before irradiation to 2 days after. All subjects were sacrificed under anesthesia 2 days after irradiation. IR increased tubular necrosis scores (TNS), MDA, and caspase-3 expression, while reducing renal tissue GSH levels. We also observed dilation in renal corpuscles and tubules. Capillary congestion was present in the intertubular spaces. NAC reduced the levels of TNS, MDA, and caspase-3 expression, but increased the levels of renal tissue GSH. ROS-scavenging antioxidants may represent a promising means of preventing renal injury in patients undergoing radiotherapy.}, }
@article {pmid31386788, year = {2019}, author = {Go, D and Lee, J and Choi, JA and Cho, SN and Kim, SH and Son, SH and Song, CH}, title = {Reactive oxygen species-mediated endoplasmic reticulum stress response induces apoptosis of Mycobacterium avium-infected macrophages by activating regulated IRE1-dependent decay pathway.}, journal = {Cellular microbiology}, volume = {21}, number = {12}, pages = {e13094}, pmid = {31386788}, issn = {1462-5822}, support = {//Chungnam National University / The Brain Korea 21 PLUS Project for Medical Science, Chungnam National University/International ; }, mesh = {Animals ; Apoptosis/*physiology ; Cell Line ; Endoplasmic Reticulum Stress/*physiology ; Macrophages/*metabolism/*microbiology ; Membrane Proteins/*metabolism ; Mice ; Mycobacterium avium/pathogenicity ; Protein Serine-Threonine Kinases/*metabolism ; RAW 264.7 Cells ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*physiology ; Tuberculosis, Avian/metabolism/microbiology ; }, abstract = {Mycobacterium avium, a slow-growing nontuberculous mycobacterium, causes fever, diarrhoea, loss of appetite, and weight loss in immunocompromised people. We have proposed that endoplasmic reticulum (ER) stress-mediated apoptosis plays a critical role in removing intracellular mycobacteria. In the present study, we investigated the role of the regulated IRE1-dependent decay (RIDD) pathway in macrophages during M. avium infection based on its role in the regulation of gene expression. The inositol-requiring enzyme 1 (IRE1)/apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) signalling pathway was activated in macrophages after infection with M. avium. The expression of RIDD-associated genes, such as Bloc1s1 and St3gal5, was decreased in M. avium-infected macrophages. Interestingly, M. avium-induced apoptosis was significantly suppressed by pretreatment with irestatin (inhibitor of IRE1α) and 4μ8c (RIDD blocker). Macrophages pretreated with N-acetyl cysteine (NAC) showed decreased levels of reactive oxygen species (ROS), IRE1α, and apoptosis after M. avium infection. The expression of Bloc1s1 and St3gal5 was increased in NAC-pretreated macrophages following infection with M. avium. Growth of M. avium was significantly increased in irestatin-, 4μ8c-, and NAC-treated macrophages compared with the control. The data indicate that the ROS-mediated ER stress response induces apoptosis of M. avium-infected macrophages by activating IRE1α-RIDD. Thus, activation of IRE1α suppresses the intracellular survival of M. avium in macrophages.}, }
@article {pmid31382676, year = {2019}, author = {Zuhra, K and Tomé, CS and Masi, L and Giardina, G and Paulini, G and Malagrinò, F and Forte, E and Vicente, JB and Giuffrè, A}, title = {N-Acetylcysteine Serves as Substrate of 3-Mercaptopyruvate Sulfurtransferase and Stimulates Sulfide Metabolism in Colon Cancer Cells.}, journal = {Cells}, volume = {8}, number = {8}, pages = {}, pmid = {31382676}, issn = {2073-4409}, mesh = {Acetylcysteine/*pharmacology ; Cell Line, Tumor ; Colonic Neoplasms/*metabolism ; Energy Metabolism ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen Sulfide/*metabolism ; Mitochondria/*metabolism ; Oxidoreductases Acting on Sulfur Group Donors/*metabolism ; Sulfurtransferases/*metabolism ; }, abstract = {Hydrogen sulfide (H2S) is an endogenously produced signaling molecule. The enzymes 3-mercaptopyruvate sulfurtransferase (MST), partly localized in mitochondria, and the inner mitochondrial membrane-associated sulfide:quinone oxidoreductase (SQR), besides being respectively involved in the synthesis and catabolism of H2S, generate sulfane sulfur species such as persulfides and polysulfides, currently recognized as mediating some of the H2S biological effects. Reprogramming of H2S metabolism was reported to support cellular proliferation and energy metabolism in cancer cells. As oxidative stress is a cancer hallmark and N-acetylcysteine (NAC) was recently suggested to act as an antioxidant by increasing intracellular levels of sulfane sulfur species, here we evaluated the effect of prolonged exposure to NAC on the H2S metabolism of SW480 colon cancer cells. Cells exposed to NAC for 24 h displayed increased expression and activity of MST and SQR. Furthermore, NAC was shown to: (i) persist at detectable levels inside the cells exposed to the drug for up to 24 h and (ii) sustain H2S synthesis by human MST more effectively than cysteine, as shown working on the isolated recombinant enzyme. We conclude that prolonged exposure of colon cancer cells to NAC stimulates H2S metabolism and that NAC can serve as a substrate for human MST.}, }
@article {pmid31381934, year = {2019}, author = {Cui, S and Nian, Q and Chen, G and Wang, X and Zhang, J and Qiu, J and Zhang, Z}, title = {Ghrelin ameliorates A549 cell apoptosis caused by paraquat via p38-MAPK regulated mitochondrial apoptotic pathway.}, journal = {Toxicology}, volume = {426}, number = {}, pages = {152267}, doi = {10.1016/j.tox.2019.152267}, pmid = {31381934}, issn = {1879-3185}, mesh = {A549 Cells ; Apoptosis/*drug effects ; Caspase 3/biosynthesis/drug effects ; Cell Survival/drug effects ; Ghrelin/*pharmacology ; Herbicides/*toxicity ; Humans ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects ; Oxidative Stress/drug effects ; Paraquat/*antagonists &amp; inhibitors/*toxicity ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/drug effects/*metabolism ; }, abstract = {Paraquat has relatively strong detrimental effects on humans and animals and can cause acute lung injury with high mortality. Ghrelin is a brain-gut peptide which plays important roles in regulating various physiological processes. This study investigated whether ghrelin could inhibit paraquat-induced lung injuries and attempted to elucidate the possible molecular mechanisms. A549 cells were preincubated with different concentrations of ghrelin and then treated with 200 μM of PQ for 24 h. Then cell survival, apoptosis, cellular oxidative stress and lipid peroxidation of A549 cells were detected after different treatments. Subsequently, we analyzed the mitochondrial membrane potential (ΔΨm) and measured caspase-3 activation in A549 cells. In addition, we investigated the activation of the MAPKs pathway and the function of p38-MAPK within mitochondrial apoptosis. Our study indicated that ghrelin administration improved cell viability and reduced apoptosis of PQ-treated A549 cells dose-dependently. Ghrelin treatment reduced the elevation of ROS and MDA, while improved GSH content in A549 cells after paraquat exposure. Moreover, we found that ghrelin dose-dependently increased ΔΨm and decreased caspase-3 activity. The phosphorylated p38 MAPK and JNK levels elevated following PQ exposure, while the phosphorylation of p38 MAPK decreased following ghrelin pretreatment. p38 MAPK siRNA or SB203580 pretreatment ameliorated PQ-caused cell injury and apoptosis related signals, however, the intracellular ROS production was not affected. N-Acetylcysteine (NAC), a classic antioxidant pretreatment decreased the phosphorylated p38 MAPK level and intracellular ROS production, alleviated cell injury, and inhibited apoptosis. The results showed that p38-MAPK pathway plays an important role in PQ-caused alveolar epithelial cell insult, and ghrelin might attenuate PQ-induced cell injury by inhibiting ROS-induced p38-MAPK modulated mitochondrial apoptotic pathway.}, }
@article {pmid31381933, year = {2019}, author = {Li, SJ and Chen, P and Peres, TV and Villahoz, BF and Zhang, Z and Miah, MR and Aschner, M}, title = {Triclosan induces PC12 cells injury is accompanied by inhibition of AKT/mTOR and activation of p38 pathway.}, journal = {Neurotoxicology}, volume = {74}, number = {}, pages = {221-229}, pmid = {31381933}, issn = {1872-9711}, support = {R21 ES025415/ES/NIEHS NIH HHS/United States ; R21 ES028960/ES/NIEHS NIH HHS/United States ; R01 ES020852/ES/NIEHS NIH HHS/United States ; R01 ES007331/ES/NIEHS NIH HHS/United States ; R01 ES010563/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Anti-Infective Agents, Local/*toxicity ; Apoptosis Regulatory Proteins/biosynthesis/drug effects/genetics ; Cell Survival/drug effects ; L-Lactate Dehydrogenase/metabolism ; Metabolic Networks and Pathways/*drug effects ; Oncogene Protein v-akt/*drug effects ; Oxidative Stress/drug effects ; PC12 Cells ; Phosphorylation ; Rats ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/*drug effects ; Triclosan/*toxicity ; p38 Mitogen-Activated Protein Kinases/*drug effects ; }, abstract = {Triclosan (TCS) has been widely used as a disinfectant and antiseptic in multiple consumer and healthcare products due to its clinical effectiveness against various bacteria, fungi and protozoa. Recently, several studies have reported the adverse effects of TCS on various nerve cells, arousing concerns about its potential neurotoxicity. The present study aimed to investigate the neurotoxicity of TCS in rat pheochromocytoma PC12 cells. After differentiation, the stabilized PC12 cells were treated with 1, 10, 50 μM TCS for 12 h. At the end of the treatment, the generation of reactive oxygen species (ROS), protein expression of apoptotic-related genes, AMPK-AKT/mTOR, as well as p38 in PC12 cells were determined. The concentrations were chosen based on the results of cell viability and lactic dehydrogenase (LDH) assays in response to TCS treatment (ranging from 0.001 to 100 μM) for varied time periods. The results showed that TCS is cytotoxic to PC12 cells, causing decreased cell viability accompanied by increased LDH release. TCS treatment at 10 and 50 μM for 12 h increased the mRNA and protein expression of the pro-apoptotic gene Bax, while Bcl-2 levels remained unchanged. Moreover, an increase in the generation of reactive oxygen species (ROS) was found in TCS-treated PC12 cells at the concentrations of 1 and 10 μM. Pretreatment with 100 μM N-acetyl cysteine (NAC- ROS scavenger) for 1 h normalized the ROS generations in TCS-treated PC12 cells. Additionally, the suppression of the phosphorylation of Akt and mTOR was observed in TCS-treated PC12 cells at 10 and 50 μM for 12 h, concomitant with the activation of p38 MAPK pathway at 50 μM TCS. However, there were no effects of TCS on the phosphorylation of AMPK in these cells. Taken together, these results suggest that TCS may cause adverse effects and oxidative stress in PC12 cells accompanied by inhibition of Akt/mTOR and activation of p38.}, }
@article {pmid31381364, year = {2019}, author = {Hamamsy, ME and Bondok, R and Shaheen, S and Eladly, GH}, title = {Safety and efficacy of adding intravenous N-acetylcysteine to parenteral L-alanyl-L-glutamine in hospitalized patients undergoing surgery of the colon: a randomized controlled trial.}, journal = {Annals of Saudi medicine}, volume = {39}, number = {4}, pages = {251-257}, pmid = {31381364}, issn = {0975-4466}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Administration, Intravenous ; Adult ; Aged ; Antioxidants/*administration &amp; dosage/adverse effects ; Colonic Diseases/*surgery ; Dipeptides/*administration &amp; dosage/adverse effects ; Double-Blind Method ; Egypt ; Female ; Humans ; Intensive Care Units ; Male ; Middle Aged ; Postoperative Complications/epidemiology/prevention &amp; control ; Preoperative Care/methods ; Prospective Studies ; Systemic Inflammatory Response Syndrome/epidemiology/*prevention &amp; control ; }, abstract = {BACKGROUND: Colon surgery can cause systemic inflammatory response syndrome (SIRS). There is a recent trend towards the use of antioxidant agents in the prevention or alleviation of the severity of postoperative SIRS, but its use is controversial as studies have shown conflicting results.<br><br>OBJECTIVES: Investigate the efficacy and tolerability of perioperative intravenous administration of N-acetylcysteine (NAC) as an antioxidant and anti-inflammatory agent in patients undergoing colon surgery.<br><br>DESIGN: Randomized, double-blinded, and controlled clinical trial.<br><br>SETTING: Surgical critical care unit in Egypt.<br><br>PATIENTS AND METHODS: Sixty patients who required admission to the ICU following colon surgery were enrolled in the study between July 2015 and October 2016. Eligibility included the need for parenteral nutrition for at least 5 days due to failure of or contraindication to enteral nutrition. Patients were randomly allocated using a computer-generated list to a loading dose of NAC followed by continuous infusion started one hour prior to induction, and continued over 48 hours, or to the control group, who received the same volume of dextrose 5%. Allocation was concealed using opaque, sealed envelopes under pharmacy control. The researcher, the anesthesiologist, the surgeon, and patients were blinded to the treatment allocation.<br><br>MAIN OUTCOME MEASURES: Clinical and laboratory evaluation for manifestations of SIRS, serum levels of tumor necrosis factor alpha and malondialdehyde, and occurrence of side effects in the study group.<br><br>SAMPLE SIZE: 60 patients with mean (SD) ages of 56 (15.1) years in the study group (n=30) and 57.7 (12.3) years in the control group (n=30).<br><br>RESULTS: There was a significant difference in the mean serum level of ALT (22.6 (9.9) U/L in the study group vs. 31.1 (17.8) U/L in the control group, P=.028) after treatment with NAC, but differences between the groups in the serum level of tumor necrosis factor alpha and malondialdehyde after treatment were not significant. Serum levels of malondialdehyde increased in both groups after treatment P<.001. There was no statistically significant difference from baseline or between the groups after treatment in other clinical data and laboratory parameters following NAC administration, and only 6.6% of the patients in the study group experienced mild side effects.<br><br>CONCLUSIONS: Preoperative administration of NAC is safe, but its efficacy as an antioxidant and anti-inflammatory agent was not statistically significant and requires further investigation in a larger sample.<br><br>LIMITATIONS: Single-center study, small sample size, and short duration of NAC administration.<br><br>CLINICAL TRIALS REGISTRY: NCT03589495.<br><br>CONFLICT OF INTEREST: None.}, }
@article {pmid31379162, year = {2019}, author = {Zhang, S and Asghar, S and Yu, F and Chen, Z and Hu, Z and Ping, Q and Shao, F and Xiao, Y}, title = {BSA Nanoparticles Modified with N-Acetylcysteine for Improving the Stability and Mucoadhesion of Curcumin in the Gastrointestinal Tract.}, journal = {Journal of agricultural and food chemistry}, volume = {67}, number = {33}, pages = {9371-9381}, doi = {10.1021/acs.jafc.9b02272}, pmid = {31379162}, issn = {1520-5118}, mesh = {Acetylcysteine/*chemistry ; Animals ; Caco-2 Cells ; Cattle ; Curcumin/*chemistry/metabolism ; Drug Carriers/*chemistry ; Drug Delivery Systems/*instrumentation ; Drug Stability ; Gastrointestinal Tract/*metabolism ; Humans ; Nanoparticles/*chemistry ; Particle Size ; Serum Albumin, Bovine/*chemistry ; }, abstract = {A major obstacle to the clinical use of curcumin (CUR) is its reduced bioavailability because of the drug's hydrophobic nature, low intestinal absorption, and rapid metabolism. In this study, a novel oral drug delivery system was constructed for improving the stability and enhancing mucoadhesion of CUR in the gastrointestinal (GI) tract. First, CUR was encapsulated in the bovine serum albumin nanoparticles (CUR-BSA-NPs). Then, N-acetyl cysteine (NAC)-modified CUR-BSA-NPs (CUR-NBSA-NPs) were obtained. The average particle size and zeta potential of CUR-NBSA-NPs were 251.6 nm and -30.66 mV, respectively; encapsulation efficiency and drug loading were 85.79 and 10.9%, respectively. CUR-NBSA-NPs exhibited a sustained release property and prominently enhanced stability in simulated GI conditions. Additionally, enhanced mucoadhesion of CUR-NBSA-NPs was also observed. An MTT study showed that the CUR-NBSA-NPs were safe for oral administration. Overall, NAC-modified BSA-NPs may potentially serve as an oral vehicle for improving CUR stability in the GI tract and enhancing mucoadhesion.}, }
@article {pmid31377610, year = {2019}, author = {Soheyli, E and Azad, D and Sahraei, R and Hatamnia, AA and Rostamzad, A and Alinazari, M}, title = {Synthesis and optimization of emission characteristics of water-dispersible ag-in-s quantum dots and their bactericidal activity.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {182}, number = {}, pages = {110389}, doi = {10.1016/j.colsurfb.2019.110389}, pmid = {31377610}, issn = {1873-4367}, mesh = {Acetylcysteine/chemistry ; Anti-Bacterial Agents/*administration &amp; dosage/chemical synthesis/chemistry ; Bacillus subtilis/drug effects ; Bacteria/classification/*drug effects ; Escherichia coli/drug effects ; Microbial Sensitivity Tests/methods ; Microscopy, Electron, Transmission ; Quantum Dots/*administration &amp; dosage/chemistry/ultrastructure ; Salmonella enterica/drug effects ; Silver/*chemistry ; Solubility ; Species Specificity ; Spectrum Analysis ; Staphylococcus aureus/drug effects ; Water/*chemistry ; X-Ray Diffraction ; }, abstract = {Developing novel aqueous-soluble quantum dots (QDs) can create new opportunities for better biological utilization. In the present work, novel, high emissive and biocompatible N-acetyl-L-cysteine-capped Ag-In-S QDs (as an I-III-VI structure) were prepared in a facile and straightforward way. The dominance of the strong confinement regime was observed due to the very small size of nanoparticles, which was smaller than their excitonic Bohr radius. To prepare reproducible Ag-In-S QDs, their emission characteristics were improved by optimizing the experimental variables which resulted in the enhancement of their emission quantum yield to near 32% at 615 nm. The absorption and emission results support the contribution of band edge-independent radiative recombination pathways for charge carriers in the prepared Ag-In-S QDs. The possible mechanisms for such donor-acceptor recombination were also discussed. To explore the antibacterial ability of the Ag-In-S QDs, their bactericidal activity was evaluated against different types of Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Escherichia coli and Salmonella enterica) bacteria. Precise measurements confirmed a remarkable bactericidal activity of Ag-In-S QDs against the different pathogenic bacteria even at low concentration of QDs (15 μg/mL). It was found that the QDs are more effective on Gram-negative bacteria. While the preparation method was simple and cost-effective, the as-synthesized QDs were highly emissive and stable with significant antibacterial activity. This demonstrates the great potential of present Ag-In-S QDs for future hygienic and medical purposes.}, }
@article {pmid31377469, year = {2019}, author = {Condello, M and Pellegrini, E and Spugnini, EP and Baldi, A and Amadio, B and Vincenzi, B and Occhionero, G and Delfine, S and Mastrodonato, F and Meschini, S}, title = {Anticancer activity of "Trigno M", extract of Prunus spinosa drupes, against in vitro 3D and in vivo colon cancer models.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {118}, number = {}, pages = {109281}, doi = {10.1016/j.biopha.2019.109281}, pmid = {31377469}, issn = {1950-6007}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Colonic Neoplasms/*drug therapy/pathology/ultrastructure ; Female ; Fluorouracil/pharmacology ; HCT116 Cells ; Humans ; Mice, SCID ; *Models, Biological ; Plant Extracts/*therapeutic use ; Prunus/*chemistry ; Spheroids, Cellular/drug effects/pathology ; Tumor Stem Cell Assay ; Xenograft Model Antitumor Assays ; }, abstract = {In 2018 there were over 1.8 million new cases worldwide of colorectal cancer and relapses after clinical treatments. Many studies ascribe the risk of the appearance of this cancer to the Western life style : a sedentary life, obesity, and low -fiber, high -fat diets can promote the onset of disease. Several studies have shown supplement phytochemicals to have an inhibiting effect on the growth of various cancers through the activation of apoptosis. Our goal was to prove the effectiveness of a natural compound in the combined therapy of colorectal cancer. Trigno M supplement was an optimal candidate as anticancer product for its high concentrations of phenolic acids, flavonoids and anthocyanins. Our work showed the antitumor activity of Trigno M, extract of Prunus spinosa drupes combined with the nutraceutical activator complex (NAC), in 2D, 3D and in vivo colorectal cancer models. The cellular model we used both in vitro and in vivo was the HCT116 cell line, particularly suitable for engraftment after inoculation in mice. Trigno M inhibited the growth and colony formation of HCT116 cells (35%) as compared to the chemotherapy treatment with 5-fluorouracil (80%) used in clinical therapy. The reduction of the morphological dimensions in the spheroid cells after Trigno M, was compared with 5-fluorouracil demonstrating the efficacy of the Trigno M compound also in 3D models. Flow cytometric analysis on 3D cells showed a significant increase in the apoptotic cell fraction after Trigno M treatment (44.8%) and a low level of necrotic fraction (6.7%) as compared with control cells. Trigno M and 5-fluorouracil induced the apoptosis in a comparable percentage. Monotherapy with Trigno M in severely immunodeficient mice, carrying colon rectal cancer xenografts, significantly reduced tumor growth. The histopatological analysis of the ectopic tumors showed a lower level of necrosis after Trigno M treatment compared with the control. We conclude that Trigno M is well tolerated by mice, delays colorectal cancer growth in these animals and should be weighed up for integration of the current multi-drug protocols in the treatment of colon carcinoma.}, }
@article {pmid31374947, year = {2019}, author = {Young, M and Ozcan, A and Lee, B and Maxwell, T and Andl, T and Rajasekaran, P and Beazley, MJ and Tetard, L and Santra, S}, title = {N-acetyl Cysteine Coated Gallium Particles Demonstrate High Potency against Pseudomonas aeruginosa PAO1.}, journal = {Pathogens (Basel, Switzerland)}, volume = {8}, number = {3}, pages = {}, pmid = {31374947}, issn = {2076-0817}, abstract = {Nosocomial infections pose serious health concerns with over 2 million reported annually in the United States. Many of these infections are associated with bacterial resistance to antibiotics and hence, alternative treatments are critically needed. The objective of this study was to assess the antimicrobial efficacy of a gallium (Ga)-based particle coated with N-Acetyl Cysteine (Ga-NAC) against Pseudomonas aeruginosa PAO1. Our studies showed the Minimum Inhibitory Concentration (MIC) of PAO1 treated with Ga-NAC was 1 µg/mL. Cytotoxicity of Ga-NAC against multiple cell lines was determined with no cytotoxicity observed up to concentrations of 2000 µg/mL (metal concentration), indicating a high therapeutic window. To elucidate potential antibacterial modes of action, Inductively Coupled Plasma-Mass Spectrometry (ICP-MS), infrared spectroscopy, and atomic force microscopy (AFM) were used. The results suggest improved Ga[3+] interaction with PAO1 through Ga-NAC particles. No significant change in cell membrane chemistry or roughening was detected. As cell membrane integrity remained intact, the antimicrobial mode of action was linked to cellular internalization of Ga and subsequent iron metabolic disruption. Furthermore, Ga-NAC inhibited and disrupted biofilms seen with crystal violet assay and microscopy. Our findings suggest the Ga-NAC particle can potentially be used as an alternative to antibiotics for treatment of Pseudomonas aeruginosa infections.}, }
@article {pmid31372298, year = {2019}, author = {Liu, J and Chen, X and Dou, M and He, H and Ju, M and Ji, S and Zhou, J and Chen, C and Zhang, D and Miao, C and Song, Y}, title = {Particulate matter disrupts airway epithelial barrier via oxidative stress to promote Pseudomonas aeruginosa infection.}, journal = {Journal of thoracic disease}, volume = {11}, number = {6}, pages = {2617-2627}, pmid = {31372298}, issn = {2072-1439}, abstract = {BACKGROUND: Airborne particulate matter (PM) is associated with increasing susceptibility to respiratory bacterial infection. Tight junctions (TJs) are protein complexes that form airway epithelial barrier against infection. This study aimed to investigate the effects of PM on the airway TJs in response to infection.<br><br>METHODS: The cytotoxicity of PM to BEAS-2B was evaluated. The reactive oxygen species (ROS) production was measured by the flow cytometry. Colony forming units (CFUs) assay and confocal microscopy were utilized to evaluate the number of bacteria. Immunofluorescence and western blot assay were conducted to detect the expressions of TJs proteins. Animal models were used to investigate the role of TJs in PM-induced lung injury upon bacterial infection.<br><br>RESULTS: In vitro, PM decreased cell viability, increased ROS production, and increased the number of intracellular bacteria accompanying by the degradation of TJs. N-acetylcysteine (NAC) significantly reversed the PM-induced bacterial invasion and PM-induced disruption of TJs. In vivo, PM increases bacteria-infected lung injury, lung bacteria burden and blood bacterial dissemination, which was closely correlated to the degradation of TJs.<br><br>CONCLUSIONS: PM disrupts TJs via oxidative stress to promote bacterial infection.}, }
@article {pmid31371943, year = {2019}, author = {Daems, N and Penninckx, S and Nelissen, I and Van Hoecke, K and Cardinaels, T and Baatout, S and Michiels, C and Lucas, S and Aerts, A}, title = {Gold nanoparticles affect the antioxidant status in selected normal human cells.}, journal = {International journal of nanomedicine}, volume = {14}, number = {}, pages = {4991-5015}, pmid = {31371943}, issn = {1178-2013}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*metabolism ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cetuximab/pharmacology ; Endocytosis/drug effects ; Glutathione Reductase/metabolism ; Gold/*chemistry ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/*chemistry/ultrastructure ; Mitochondria/drug effects/metabolism ; Particle Size ; Polyamines/chemistry ; Protective Agents/pharmacology ; Static Electricity ; Thioredoxin-Disulfide Reductase/metabolism ; }, abstract = {Purpose: This study evaluates the cytotoxicity of AuNPs coated with polyallylamine (AuNPs-PAA) and conjugated or not to the epidermal growth factor receptor (EGFR)-targeting antibody Cetuximab (AuNPs-PAA-Ctxb) in normal human kidney (HK-2), liver (THLE-2) and microvascular endothelial (TIME) cells, and compares it with two cancer cell lines that are EGFR-overexpressing (A431) or EGFR-negative (MDA-MB-453). Results: Conjugation of Cetuximab to AuNPs-PAA increased the AuNPs-PAA-Ctxb interactions with cells, but reduced their cytotoxicity. TIME cells exhibited the strongest reduction in viability after exposure to AuNPs-PAA(±Ctxb), followed by THLE-2, MDA-MB-453, HK-2 and A431 cells. This cell type-dependent sensitivity was strongly correlated to the inhibition of thioredoxin reductase (TrxR) and glutathione reductase (GR), and to the depolarization of the mitochondrial membrane potential. Both are suggested to initiate apoptosis, which was indeed detected in a concentration- and time-dependent manner. The role of oxidative stress in AuNPs-PAA(±Ctxb)-induced cytotoxicity was demonstrated by co-incubation of the cells with N-acetyl L-cysteine (NAC), which significantly decreased apoptosis and mitochondrial membrane depolarization. Conclusion: This study helps to identify the cells and tissues that could be sensitive to AuNPs and deepens the understanding of the risks associated with the use of AuNPs in vivo.}, }
@article {pmid31371783, year = {2019}, author = {Yokosawa, T and Yamada, M and Noguchi, T and Suzuki, S and Hirata, Y and Matsuzawa, A}, title = {Pro-caspase-3 protects cells from polymyxin B-induced cytotoxicity by preventing ROS accumulation.}, journal = {The Journal of antibiotics}, volume = {72}, number = {11}, pages = {848-852}, doi = {10.1038/s41429-019-0216-6}, pmid = {31371783}, issn = {1881-1469}, mesh = {Acetylcysteine ; Animals ; Anti-Bacterial Agents/pharmacology/*toxicity ; Caspase 3/*metabolism ; Cell Line ; Cell Survival/drug effects ; Fas Ligand Protein/pharmacology ; Gene Deletion ; Gene Expression Regulation/drug effects ; Humans ; Mice ; Polymyxin B/pharmacology/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Polymyxin B (PMB), a last-line antibiotic used against antibiotic-resistant superbugs, causes undesirable cytotoxic side effects. However, its mechanisms remain unknown. In this study, we unexpectedly found that caspase-3, a main executor of apoptosis, plays a protective role in PMB-induced cytotoxicity. Caspase-3 knockout (KO) cells exhibited higher susceptibility to PMB-induced cytotoxicity compared with wild-type (WT) cells, accompanied by increased levels of reactive oxygen species (ROS). Interestingly, co-treatment with the antioxidant N-acetylcysteine (NAC) rescued cell viability to a similar extent as WT cells. Furthermore, PMB failed to facilitate the processing of inactive caspase-3 (pro-caspase-3) into active forms, suggesting that pro-caspase-3 nonenzymatically suppresses PMB-driven ROS accumulation and its cytotoxicity. Thus, our findings that demonstrate the potential ability of PMB to stimulate ROS generation, but which is normally masked by pro-caspase-3-dependent mechanisms, may provide novel insights into the mechanisms of PMB-induced side effects.}, }
@article {pmid31368586, year = {2019}, author = {Xiong, G and Zhao, L and Yan, M and Wang, X and Zhou, Z and Chang, X}, title = {N-acetylcysteine alleviated paraquat-induced mitochondrial fragmentation and autophagy in primary murine neural progenitor cells.}, journal = {Journal of applied toxicology : JAT}, volume = {39}, number = {11}, pages = {1557-1567}, doi = {10.1002/jat.3839}, pmid = {31368586}, issn = {1099-1263}, support = {NSFC 81472996//National Natural Science Foundation of China/International ; NSFC 81773472//National Natural Science Foundation of China/International ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Lateral Ventricles/drug effects/pathology ; Mice ; Mice, Inbred C57BL ; Mitochondria/*drug effects/ultrastructure ; Neural Stem Cells/*drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Paraquat/*toxicity ; Primary Cell Culture ; Reactive Oxygen Species/metabolism ; }, abstract = {The developing brain is uniquely vulnerable to toxic chemical exposures. Studies indicate that neural stem cell (NSC) self-renewal is susceptible to oxidative stress caused by xenobiotics. However, the impact of antioxidants on NSC self-renewal and the potential mechanisms remain elusive. In this study, primary murine neural progenitor cells (mNPCs) from the subventricular zone were used as a research model. In addition, paraquat (PQ) was used to elicit oxidative stress and N-acetylcysteine (NAC) was used as a powerful antioxidant. mNPCs were treated with 80 μm PQ for 24 hours with or without 4 hours of NAC pretreatment. Our results showed that PQ treatment increased intracellular reactive oxygen species production, decreased cell viability and DNA synthesis, and promoted cell apoptosis. Meanwhile, pretreatment with NAC alleviated PQ-induced cytotoxicity in mNPCs. To elucidate the mechanisms further, we found that NAC pretreatment prevented PQ-induced reactive oxygen species production, mitochondrial fragmentation and autophagy in mNPCs. NAC-pretreated cells showed increased anti-apoptotic protein Bcl-2 and decreased pro-apoptotic protein Bax expression. Similarly, NAC pretreatment increased p-mTOR and decreased LC3B-II protein expression. Moreover, NAC decreased mitophagy related mRNA Pink1 and Parkin expression. Taken together, our results suggested that the antioxidant NAC treatment significantly attenuated PQ-induced mNPC self-renewal disruption through decreasing autophagy and salvaging mitochondrial morphology. These findings revealed a potential mechanism for neurological treatment relating to antioxidant and suggested potentially relevant implications for PQ-related neurodegenerative disorders. Thus, our study also provided insight into therapeutic strategies for the neurotoxic effects of oxidative stress-associated toxicants.}, }
@article {pmid31368551, year = {2019}, author = {Nouri, A and Heidarian, E}, title = {Ameliorative effects of N-acetyl cysteine on diclofenac-induced renal injury in male rats based on serum biochemical parameters, oxidative biomarkers, and histopathological study.}, journal = {Journal of food biochemistry}, volume = {43}, number = {8}, pages = {e12950}, doi = {10.1111/jfbc.12950}, pmid = {31368551}, issn = {1745-4514}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*drug therapy/etiology/genetics/metabolism ; Animals ; Biomarkers/blood ; Creatinine/blood ; Diclofenac/*adverse effects ; Humans ; Kidney/drug effects/injuries/metabolism ; Male ; Malondialdehyde/blood ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/genetics/metabolism ; Uric Acid/blood ; }, abstract = {Diclofenac (DIC) can cause nephrotoxicity in humans. In this study, we evaluated the protective effects of N-acetyl cysteine (NAC) on DIC-induced nephrotoxicity. Rats were assigned to four groups. Group 1 was control group; group 2 administrated with DIC only; group 3 administrated with DIC plus NAC and group 4 was treated with DIC and silymarin. Then, the oxidative biomarkers in serum and kidney were evaluated. In group 2, DIC caused a remarkable elevation (p < 0.05) in the levels of serum uric acid, TNF-α, creatinine, urea, GOT, and GPT, protein carbonyl, malondialdehyde (MDA), and renal TNF-α gene expression, relative to control group. In treated groups with NAC and silymarin, a noticeable reduction (p < 0.05) was seen in mentioned levels of biochemical parameters. NAC showed that it could reduce the abnormality of biochemical parameters and histopathological changes which is induced by DIC. PRACTICAL APPLICATIONS: N-acetyl cysteine (NAC) has a potential to ameliorate renal histopathological changes and improving renal activity of antioxidant enzymes in nephrotoxicity by diclofenac. Also, NAC has a potential to reduce inflammatory gene expression in the diclofenac-induced nephrotoxicity. Additionally, NAC can be considered as an antioxidant which reduces renal MDA and serum protein carbonyl due to nephrotoxicity by diclofenac.}, }
@article {pmid31368246, year = {2019}, author = {Praneetha, P and Balhara, A and Ladumor, MK and Singh, DK and Patil, A and Preethi, J and Pokharkar, S and Deshpande, AY and Giri, S and Singh, S}, title = {Characterization of stable and reactive metabolites of piperine formed on incubation with human liver microsomes.}, journal = {Journal of mass spectrometry : JMS}, volume = {54}, number = {9}, pages = {738-749}, doi = {10.1002/jms.4424}, pmid = {31368246}, issn = {1096-9888}, mesh = {Acetylcysteine/chemistry ; Alkaloids/*analysis/*metabolism ; Benzodioxoles/*analysis/*metabolism ; Chromatography, High Pressure Liquid ; Glutathione/chemistry ; Humans ; Isomerism ; Microsomes, Liver/*metabolism ; Piperidines/*analysis/*metabolism ; Polyunsaturated Alkamides/*analysis/*metabolism ; Tandem Mass Spectrometry ; }, abstract = {Black pepper, though commonly employed as a spice, has many medicinal properties. It consists of volatile oils, alkaloids, pungent resins, etc., of which piperine is a major constituent. Though safe at low doses, piperine causes alteration in the activity of drug metabolising enzymes and transporters at high dose and is known to precipitate liver toxicity. It has a potential to form reactive metabolite(s) (RM) owing to the presence of structural alerts, such as methylenedioxyphenyl (MDP), α, β-unsaturated carbonyl group (Michael acceptor), and piperidine. The present study was designed to detect and characterize stable and RM(s) of piperine formed on in vitro incubation with human liver microsomes. The investigation of RMs was done with the aid of trapping agents, viz, glutathione (GSH) and N-acetylcysteine (NAC). The samples were analysed by ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC-HRMS) using Thermo Scientific Q Exactive Plus Orbitrap. Full scan MS followed by data-dependent MS[2] (Full MS-ddMS[2]) mode was used to establish mass spectrometric fragmentation pathways of protonated piperine and its metabolites. In total, four stable metabolites and their isomers (M1a-c, M2a-b, M3a-c, and M4a-b) were detected. Their formation involved removal of carbon (3, M1a-c), hydroxylation (2, M2a-b), hydroxylation with hydrogenation (3, M3a-c), and dehydrogenation (2, M4a-b). Out of these metabolites, M1, M2, and M3 are reported earlier in the literature, but their isomers and two M4 variants are novel. In addition, six novel conjugates of RMs, including three GSH conjugates of m/z 579 and three NAC conjugates of m/z 435, were also observed.}, }
@article {pmid31367603, year = {2019}, author = {Salas-Callo, CI and Pirmez, R}, title = {Trichoteiromania: Good Response to Treatment with N-Acetylcysteine.}, journal = {Skin appendage disorders}, volume = {5}, number = {4}, pages = {242-245}, pmid = {31367603}, issn = {2296-9195}, abstract = {Lichen simplex chronicus on the scalp, also known as trichoteiromania, can be difficult to manage, as the therapeutic options are limited to topical or intralesional glucocorticoids. We describe a patient with trichoteiromania, presenting three lichenified pruriginous plaques on different regions of the scalp, associated with fracture and loss of hair shafts. Prior treatment with potent topical glucocorticoids was ineffective. However, treatment with oral N-acetylcysteine (NAC) 1,200 mg/day resulted in complete hair regrowth within 16 weeks. NAC is a safe drug with a good tolerance profile that could be a therapeutic option for patients with trichoteiromania. The potential of NAC has not been completely elucidated, thus more studies will be necessary to confirm its efficacy in the long term for some psychodermatological conditions.}, }
@article {pmid31364730, year = {2019}, author = {Ahmad, R and Vaali-Mohammed, MA and Elwatidy, M and Al-Obeed, O and Al-Khayal, K and Eldehna, WM and Abdel-Aziz, HA and Alafeefy, A and Abdulla, M}, title = {Induction of ROS‑mediated cell death and activation of the JNK pathway by a sulfonamide derivative.}, journal = {International journal of molecular medicine}, volume = {44}, number = {4}, pages = {1552-1562}, doi = {10.3892/ijmm.2019.4284}, pmid = {31364730}, issn = {1791-244X}, mesh = {Apoptosis/*drug effects ; Biomarkers ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Humans ; Immunophenotyping ; MAP Kinase Signaling System/*drug effects ; Reactive Oxygen Species/*metabolism ; Sulfonamides/*pharmacology ; }, abstract = {The emergence of colorectal cancer in developed nations can be attributed to dietary habits, smoking, a sedentary lifestyle and obesity. Several treatment regimens are available for primary and metastatic colorectal cancer; however, these treatment options have had limited impact on cure and disease‑free survival, and novel agents need to be developed for treating colorectal cancer. Thus, the objective of this study was to explore the anticancer mechanism of a benzo(1,3)dioxol‑based derivative of sulfonamide. The compound's inhibitory effect on cell proliferation was determined using the MTT assay and the xCelligence RTDP machine. Alternations in the expression of Bcl‑2 and inhibitor of apoptosis protein families were detected by western blotting. Apoptotic marker protein expression, including cytochrome c and cleaved poly(ADP‑ribose)polymerase was measured in the cytosolic extract of cells. Apoptosis and necrosis were detected by flow cytometry and immunofluorescence. Reactive oxygen species (ROS), and activation of caspase‑3 and caspase‑7 were measured using flow cytometry. Activation of the JNK pathway was detected by western blotting. We investigated the molecular mechanism of action of the sulfonamide derivative on colorectal cancer cells and found that the compound possesses a potent anticancer effect, which is primarily exerted by inducing apoptosis and necrosis. Interestingly, this compound exhibited little antiproliferative effect against the normal colonic epithelial cell line FHC. Furthermore, our results showed that the compound could significantly increase ROS production. Apoptosis induction could be attenuated by the free oxygen radical scavenger N‑acetyl cysteine (NAC), indicating that the antiproliferative effect of this compound on colorectal cancer cells is at least partially dependent on the redox balance. In addition, JNK signaling was activated by treatment with this derivative, which led to the induction of apoptosis. On the contrary, a JNK inhibitor could suppress the cell death induced by this compound. Our findings thus suggested a novel anticancer mechanism of a benzo(1,3)dioxol‑based derivative of sulfonamide for colorectal cancer cells and may have therapeutic potential for the treatment of colorectal cancer; however, further investigation is required.}, }
@article {pmid31364146, year = {2019}, author = {Varone, F and Gibiino, G and Gasbarrini, A and Richeldi, L}, title = {Evaluation of the lung microbiome as a therapeutic target in the management of idiopathic pulmonary fibrosis: role of antioxidant/antibiotic combination therapy.}, journal = {European review for medical and pharmacological sciences}, volume = {23}, number = {14}, pages = {6379-6386}, doi = {10.26355/eurrev_201907_18463}, pmid = {31364146}, issn = {2284-0729}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Anti-Bacterial Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Colistin/pharmacology/therapeutic use ; Disease Progression ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/metabolism/microbiology ; Lung/drug effects/*microbiology ; Microbiota/drug effects ; }, abstract = {OBJECTIVE: Changes in the composition of the lung microbiome influence many lung diseases, including idiopathic pulmonary fibrosis (IPF), with a demonstrated association between the progression of IPF and the assessed pulmonary microbial community. A hypothesis to explain the pathogenesis of IPF is that an oxidant-antioxidant imbalance causes repeated epithelial cell injury and endogenous and exogenous antioxidants/redox modulators influence fibrogenesis, protect the lung against fibrosis, and prevent its progression.<br><br>MATERIALS AND METHODS: The present article is focused on Lung Microbiome in Idiopathic Pulmonary Fibrosis and the role of Antioxidant/Antibiotic Combination Therapy.<br><br>RESULTS: N-Acetylcysteine (NAC) at concentrations possibly achievable by nebulization showed an in vitro synergy with colistin against S. maltophilia isolates (a common coloniser of the respiratory tract of patients with chronic lung disease). Combined NAC plus colistin seems to have a beneficial role in restoring oxidant injury which may be related to its antioxidant effect. Progress has been made in the identification of the lung microbiome and the possible causal role of bacteria in the IPF pathogenesis. Recent studies suggest that antibacterial therapy in combination with antioxidant therapy may be a promising avenue for the treatment of this untreatable disease. Novel routes of administration are also an important area of research and studies assessing the use of inhaled NAC in patients with IPF could be considered.}, }
@article {pmid31360107, year = {2019}, author = {Di, S and Fan, C and Ma, Z and Li, M and Guo, K and Han, D and Li, X and Mu, D and Yan, X}, title = {PERK/eIF-2α/CHOP Pathway Dependent ROS Generation Mediates Butein-induced Non-small-cell Lung Cancer Apoptosis and G2/M Phase Arrest.}, journal = {International journal of biological sciences}, volume = {15}, number = {8}, pages = {1637-1653}, pmid = {31360107}, issn = {1449-2288}, mesh = {A549 Cells ; Acetylcysteine/metabolism ; Animals ; Apoptosis/genetics/physiology ; Butylamines/metabolism ; Cell Adhesion/genetics/physiology ; Cell Cycle/genetics/physiology ; Cell Movement/genetics/physiology ; Cell Survival/genetics/physiology ; Endoplasmic Reticulum Stress/genetics/physiology ; Eukaryotic Initiation Factor-2/metabolism ; Humans ; In Situ Nick-End Labeling ; Male ; Membrane Potential, Mitochondrial/genetics/physiology ; Mice, Nude ; Oxidative Stress/genetics/*physiology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/physiology ; Transcription Factor CHOP/metabolism ; eIF-2 Kinase/metabolism ; }, abstract = {Butein, a member of the chalcone family, is a potent anticarcinogen against multiple cancers, but its specific anti-NSCLC mechanism remains unknown. The present study examined the effects of butein treatment on NSCLC cell lines and NSCLC xenografts. Butein markedly decreased NSCLC cell viability; inhibited cell adhesion, migration, invasion, and colony forming ability; and induced cell apoptosis and G2/M phase arrest in NSCLC cells. Moreover, butein significantly inhibited PC-9 xenograft growth. Both in vivo and in vitro studies verified that butein exerted anti-NSCLC effect through activating endoplasmic reticulum (ER) stress-dependent reactive oxygen species (ROS) generation. These pro-apoptotic effects were reversed by the use of 4- phenylbutyric acid (4-PBA), CHOP siRNA, N-acetyl-L-cysteine (NAC) and Z-VAD-FMK (z-VAD) in vitro. Moreover, inhibition of ER stress markedly reduced ROS generation. In addition, in vivo studies further confirmed that inhibition of ER stress or oxidative stress partially abolished the butein-induced inhibition of tumor growth. Therefore, butein is a potential therapeutic agent for NSCLC, and its anticarcinogenic action might be mediated by ER stress-dependent ROS generation and the apoptosis pathway.}, }
@article {pmid31359699, year = {2019}, author = {Su, WQ and Wei, TX and Jing, J and Meng, ZP and Chen, XY and Wu, XX and Zhu, HX and Fu, TM}, title = {[Effect of N-acetyl-L-cysteine on bioavailability and brain distribution of curcumin by nasal delivery].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {44}, number = {13}, pages = {2841-2848}, doi = {10.19540/j.cnki.cjcmm.20190426.501}, pmid = {31359699}, issn = {1001-5302}, mesh = {Acetylcysteine/*pharmacology ; Administration, Intranasal ; Animals ; Biological Availability ; Brain ; *Brain Chemistry ; Chromatography, Liquid ; Curcumin/*pharmacokinetics ; Rats ; Tandem Mass Spectrometry ; Tissue Distribution ; }, abstract = {Curcumin(Cur) is a natural active substance extracted from the roots or tubers of traditional Chinese medicinal materials. It has anti-inflammatory and anti-tumor activities on brain diseases. Due to the poor stability,low solubility,poor absorption and low bioavailability of curcumin,N-acetyl-L-cysteine(NAC) was used as an absorption enhancer and mixed with curcumin to improve the absorption of curcumin in the body. In this paper,curcumin was smashed by airflow pulverization,and Cur-NAC mixtures were prepared by being grinded with liquid. Then,the raw material and the product were analyzed by differential scanning calorimetry(DSC),X-ray diffraction(XRD) for structural characterization. The dissolution was determined by high performance liquid chromatography(HPLC) analysis. The characteristic peaks of the samples prepared by grinding method were similar to those of the raw materials,while the melting temperature and the accumulated dissolution degree were not significantly changed. The crystal forms of the products were not changed,and no new crystal form was formed after grinding. After the administration of intranasal powder,blood samples were collected from the orbit,while the whole brain tissues were removed from the skull and dissected into 10 anatomical regions. The concentrations of curcumin in these samples were determined by UPLC-MS/MS. The concentrations of curcumin in plasma and brain were compared at different time points. After intranasal administration of two drugs,it was found that the concentration of curcumin after sniffing up the mixtures in plasma was high,and the concentration of the drug in the olfactory bulb,hippocampus,and pons was increased significantly. Within 0. 083-0. 5 h,the olfactory bulb,piriform lobe and hippocampus remained high concentrations,the endodermis,striatum,hypothalamus and midbrain reached high concentrations within 1-3 h; and the cerebellum,pons and brain extension maintained relatively high concentrations within 3-7 h. The experiment showed that nasal administration of Cur-NAC mixtures can significantly improve the bioavailability of curcumin,and lead to significant differences in brain tissue distribution.}, }
@article {pmid31357564, year = {2019}, author = {Mo, C and Shetti, D and Wei, K}, title = {Erianin Inhibits Proliferation and Induces Apoptosis of HaCaT Cells via ROS-Mediated JNK/c-Jun and AKT/mTOR Signaling Pathways.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {15}, pages = {}, pmid = {31357564}, issn = {1420-3049}, support = {2015A050502013//International Cooperation Projects of Guangdong Provincial Science and Technology/ ; }, mesh = {Apoptosis/*drug effects ; Bibenzyls/chemistry/*pharmacology ; Cell Line, Tumor ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; MAP Kinase Signaling System/drug effects ; Phenol ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Psoriasis is a recurrent skin disease described as keratinocyte hyperproliferation and aberrant differentiation. Erianin, a bibenzyl compound extracted from Dendrobium chrysotoxum, has displayed antitumor and anti-angiogenesis effects. However, the effects of erianin on a human keratinocyte cell line (HaCaT) are not fully understood. In the present study, we explored the effect of erianin on proliferation and apoptosis in HaCaT cells. Our results indicated that treatment with erianin ranging from 12.5 nM to 50 nM inhibited proliferation and induced apoptosis of HaCaT cells. In addition, erianin-induced apoptosis was accompanied by elevated reactive oxygen species (ROS). The ROS scavenger N-acetyl-cysteine (NAC) attenuated this elevation. Moreover, treatment with erianin induced activation of the c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway and suppressed the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, while pretreatment with NAC also reversed these effects. Collectively, these data demonstrated that erianin inhibited proliferation and induced apoptosis of HaCaT cells through ROS-mediated JNK/c-Jun and AKT/mTOR signaling pathways. Erianin could be recognized as a potential anti-psoriasis drug.}, }
@article {pmid31357343, year = {2019}, author = {Bayarsaikhan, G and Avan, AN and Çekiç, SD and Apak, R}, title = {Use of modified CUPRAC and dinitrophenylhydrazine colorimetric methods for simultaneous measurement of oxidative protein damage and antioxidant defense against oxidation.}, journal = {Talanta}, volume = {204}, number = {}, pages = {613-625}, doi = {10.1016/j.talanta.2019.06.049}, pmid = {31357343}, issn = {1873-3573}, mesh = {Animals ; Antioxidants/chemistry ; Blood Proteins/*analysis/chemistry ; Cattle ; Citrus sinensis ; Colorimetry/methods ; Copper/chemistry ; Egg Proteins/*analysis/chemistry ; Fruit and Vegetable Juices ; Hydrazines/chemistry ; Phenanthrolines/chemistry ; Poultry ; *Protein Carbonylation ; Serum Albumin, Bovine/*analysis/chemistry ; }, abstract = {A modified CUPRAC (cupric reducing antioxidant capacity) method was developed for the simultaneous estimation of protein oxidation and counteracting antioxidant defense, and the results were compared with those of a modified 2,4-dinitrophenylhydrazine (DNPH) carbonyl assay. The alkaline carbonyl method was cleared off interferences by solvent extraction using a cationic surfactant. Both solution and Nafion membrane sensor CUPRAC methods were used to measure the oxidative hazard in protein solutions. Bovine serum albumin, fetal bovine serum and egg white were used as protein probes, exposed to oxidation by Fe(II)-induced Fenton reaction in the absence and presence of selected antioxidants (ascorbic acid, cysteine, gallic acid, glutathione, and N-acetyl cysteine). Protein probes were initially unreactive toward the CUPRAC and DNPH reagents, but produced colored products upon Fenton oxidation which were bleached by antioxidants, enabling an indirect measurement of antioxidant activity (AOA) by difference. Spearman's rank test for antioxidants demonstrated that there was a strong correlation (+0.7 to +0.9) between the modified CUPRAC and carbonyl assays. There was also a strong correlation between the results of the solution phase and optical sensing CUPRAC methods (R[2] > 0.95). As opposed to conventional antioxidant assays not using biologically relevant probes, this work utilizes protein probes for AOA assessment.}, }
@article {pmid31355497, year = {2019}, author = {Ghosh, I and Mukherjee, A and Mukherjee, A}, title = {Nanoscale zerovalent iron particles induce differential cytotoxicity, genotoxicity, oxidative stress and hemolytic responses in human lymphocytes and erythrocytes in vitro.}, journal = {Journal of applied toxicology : JAT}, volume = {39}, number = {12}, pages = {1623-1639}, doi = {10.1002/jat.3843}, pmid = {31355497}, issn = {1099-1263}, mesh = {Antioxidants/metabolism ; Cell Culture Techniques ; Cell Survival/drug effects ; Cells, Cultured ; *DNA Damage ; Dose-Response Relationship, Drug ; Erythrocytes/*drug effects/metabolism/pathology ; Healthy Volunteers ; Hemolysis/*drug effects ; Humans ; Iron/chemistry/*toxicity ; Lymphocytes/*drug effects/metabolism/pathology ; Male ; Metal Nanoparticles/chemistry/*toxicity ; Oxidative Stress/*drug effects ; Particle Size ; Reactive Oxygen Species/metabolism ; }, abstract = {The growing usage of nanoscale zerovalent iron particles (nZVI) in the remediation of soil, ground/surface water has elicited large-scale environmental release triggering human exposure. The size of nanomaterials is a key regulator of toxicity. However, the effect of a variable size of nZVI on genotoxicity is unexplored in human cells. To the best of our knowledge, in this study, the cytotoxic, genotoxic and hemolytic potential of nZVI-1 (15 nm) and nZVI-2 (50 nm) at concentrations of 5, 10 and 20 μg/mL was evaluated for the first time in human lymphocytes and erythrocytes treated for 3 hours. In erythrocytes, spherocytosis and echinocytosis occurred upon exposure to nZVI-1 and nZVI-2, respectively, leading to hemolysis. Lymphocytes treated with 20 μg/mL nZVI-2 and 10 μg/mL nZVI-1, incurred maximum DNA damage, although nZVI-2 induced higher cyto-genotoxicity than nZVI-1. This can be attributed to higher Fe ion dissolution and time/concentration-dependent colloidal destabilization (lower zeta potential) of nZVI-2. Although nZVI-1 showed higher uptake, its lower genotoxicity can be due to lesser Fe content, Fe ion dissolution and superior colloidal stability (higher zeta potential) compared with nZVI-2. Substantial accumulation of Ca[2+] , superoxide anions, hydroxyl radicals and H2 O2 leading to mitochondrial impairment and altered antioxidant enzyme activity was noted at the same concentrations. Pre-treatment with N-acetyl-cysteine modulated these parameters indicating the indirect action of reactive oxygen species in nZVI-induced DNA damage. The morphology of diffused nuclei implied the possible onset of apoptotic cell death. These results validate the synergistic role of size, ion dissolution, colloidal stability and reactive oxygen species on cyto-genotoxicity of nZVI and unlock further prospects in its environmental nano-safety evaluation.}, }
@article {pmid31352431, year = {2020}, author = {Ehrenfeld, V and Fulda, S}, title = {Thioredoxin inhibitor PX-12 induces mitochondria-mediated apoptosis in acute lymphoblastic leukemia cells.}, journal = {Biological chemistry}, volume = {401}, number = {2}, pages = {273-283}, doi = {10.1515/hsz-2019-0160}, pmid = {31352431}, issn = {1437-4315}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Disulfides/*pharmacology ; Drug Screening Assays, Antitumor ; Humans ; Imidazoles/*pharmacology ; Mitochondria/*drug effects/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, abstract = {Imbalances in redox homeostasis have been described to be involved in the development, progression and relapse of leukemia. As the thioredoxin (Trx) system, one of the major cellular antioxidant networks, has been implicated in acute lymphoblastic leukemia (ALL), we investigated the therapeutic potential of Trx inhibition in ALL. Here, we show that the Trx inhibitor PX-12 reduced cell viability and induced cell death in a dose- and time-dependent manner in different ALL cell lines. This antileukemic activity was accompanied by an increase in reactive oxygen species (ROS) levels and enhanced PRDX3 dimerization. Pre-treatment with the thiol-containing ROS scavenger N-acetylcysteine (NAC), but not with non-thiol-containing scavengers α-tocopherol (α-Toc) or Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP), significantly rescued PX-12-induced cell death. Furthermore, PX-12 triggered activation of BAK. Importantly, knockdown of BAK reduced PX-12-stimulated ROS production and cell death. Similarly, silencing of NOXA provided significant protection from PX-12-mediated cell death. The relevance of mitochondria-mediated, caspase-dependent apoptosis was further supported by data showing that PX-12 triggered cleavage of caspase-3 and that addition of the broad-range caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (zVAD.fmk) potently blocked cell death upon PX-12 treatment. This study provides novel insights into the mechanisms of PX-12-induced cell death in ALL and further highlights the therapeutic potential of redox-active compounds in ALL.}, }
@article {pmid31350739, year = {2019}, author = {Weidenbusch, M and Wörnle, M and Kazmierczak, P and Ricke, J and Fischereder, M}, title = {[Prevention of "contrast-induced" acute kidney injury - practical considerations].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {144}, number = {15}, pages = {1009-1013}, doi = {10.1055/a-0840-7315}, pmid = {31350739}, issn = {1439-4413}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; *Acute Kidney Injury/chemically induced/drug therapy/prevention &amp; control ; Clinical Trials as Topic ; Contrast Media/*adverse effects ; Epidemiologic Studies ; Humans ; Tomography, X-Ray Computed/adverse effects ; }, abstract = {Acute kidney injury (AKI) episodes after iodine radiocontrast application are decreasing since non-ionic agents are routinely used. Retrospective studies (in total comprising more than 100 000 patients) DO NOT show increased AKI rates after CT scans with the application of radiocontrast (vs. uncontrasted CT scans). AKI rates are generally higher after intra-arterial (i. a.) compared with intra-venous (i. v.) radiocontrast application - cholesterol embolism due to catheter manipulation does play a role in this setting. Because of the multifactorial pathogenesis the term "contrast-associated AKI" (CA-AKI) should be used preferentially. The AMACING trial, which prospectively evaluated the use of i. v. volume administration before contrast application to prevent CA-AKI, DID NOT show a benefit for volume therapy. Instead, the trial found a significant increase in symptomatic heart failure episodes in patients after volume administrastion. "Hydration" before (emergency) contrasted CT scans therefore can put patients at risk through both volume overload and diagnostic delay. The PRESERVE trial prospectively evaluated the use of volume administration and N-acetyl cysteine (NAC) before i. a. contrast application to prevent CA-AKI. While NAC, which was placebo controlled, did not show any benefit (and therefore should not be used anymore), all patients in the PRESERVE trial received i. v. volume (either sodium chloride or sodium bicarbonate). Interestingly, the incidence of CA-AKI in both groups was below 5 % and hence almost half of what was expected based on previous trials. If the baseline volume status is checked in order to avoid overload, volume administration in patients with i. a. contrast application can be safely performed until definitive data are available. The type of solution can be pragmatically guided by the patient's acid base status. While preventive measures to avoid CA-AKI are limited, the clinical relevance of (any) AKI remains - new data showing increased morbidity and mortality with creatinine increments of onl 0.3 mg/dl. In order to distinguish CA-AKI from other, potentially treatably forms of AKI (e. g. pre- or post-renal AKI), early consultation of a nephrologist seems favorable.}, }
@article {pmid31349560, year = {2019}, author = {Ciacci, N and Boncompagni, S and Valzano, F and Cariani, L and Aliberti, S and Blasi, F and Pollini, S and Rossolini, GM and Pallecchi, L}, title = {In Vitro Synergism of Colistin and N-acetylcysteine against Stenotrophomonas maltophilia.}, journal = {Antibiotics (Basel, Switzerland)}, volume = {8}, number = {3}, pages = {}, pmid = {31349560}, issn = {2079-6382}, support = {Rep. m. 609/2016 Prot. n. 12193-III/19 in date 01.04.2016//ZAMBON S.P.A./ ; }, abstract = {Stenotrophomonas maltophilia is an emerging global opportunistic pathogen, responsible for a wide range of human infections, including respiratory tract infections. Intrinsic multidrug resistance and propensity to form biofilms make S. maltophilia infections recalcitrant to treatment. Colistin is among the second-line options in case of difficult-to-treat S. maltophilia infections, with the advantage of being also administrable by nebulization. We investigated the potential synergism of colistin in combination with N-acetylcysteine (NAC) (a mucolytic agent with antioxidant and anti-inflammatory properties) against S. maltophilia grown in planktonic phase and biofilm. Eighteen S. maltophilia clinical isolates (comprising three isolates from cystic fibrosis (CF) and two trimethoprim-sulfamethoxazole (SXT)-resistant strains) were included. Checkerboard assays showed a synergism of colistin/NAC combinations against the strains with colistin Minimum Inhibitory Concentration (MIC) >2 µg/mL (n = 13), suggesting that NAC could antagonize the mechanisms involved in colistin resistance. Nonetheless, time-kill assays revealed that NAC might potentiate colistin activity also in case of lower colistin MICs. A dose-dependent potentiation of colistin activity by NAC was also clearly observed against S. maltophilia biofilms, also at sub-MIC concentrations. Colistin/NAC combinations, at concentrations likely achievable by topical administration, might represent a valid option for the treatment of S. maltophilia respiratory infections and should be examined further.}, }
@article {pmid31345961, year = {2019}, author = {Ni, T and Yang, W and Xing, Y}, title = {Protective effects of delphinidin against H2O2-induced oxidative injuries in human retinal pigment epithelial cells.}, journal = {Bioscience reports}, volume = {39}, number = {8}, pages = {}, pmid = {31345961}, issn = {1573-4935}, mesh = {Anthocyanins/*pharmacology ; Cell Line ; Epithelial Cells/*metabolism/pathology ; Humans ; Hydrogen Peroxide/*pharmacology ; Oxidative Stress/*drug effects ; Retinal Pigment Epithelium/*injuries/*metabolism/pathology ; }, abstract = {Age-related macular degeneration (AMD) is now one of the leading causes of blindness in the elderly population and oxidative stress-induced damage to retinal pigment epithelial (RPE) cells occurs as part of the pathogenesis of AMD. In the present study, we evaluated the protective effect of delphinidin (2-(3,4,5-trihydroxyphenyl) chromenylium-3,5,7-triol) against hydrogen peroxide (H2O2)-induced toxicity in human ARPE-19 cells and its molecular mechanism. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and flow cytometry demonstrated that pretreatment of ARPE-19 cells with delphinidin (25, 50, and 100 μg/ml) significantly increased cell viability and reduced the apoptosis from H2O2 (0.5 mM)-induced oxidative stress in a concentration-dependent manner, which was achieved by the inhibition of Bax, cytochrome c, and caspase-3 protein expression and enhancement of Bcl-2 protein. The same tendency was observed in ARPE-19 cells pre-treated with 15 mM of N-acetylcysteine (NAC) before the addition of H2O2 Furthermore, pre-incubation of ARPE-19 cells with delphinidin markedly inhibited the intracellular reactive oxygen species (ROS) generation and Nox1 protein expression induced by H2O2 Moreover, the decreased antioxidant enzymes activities of superoxide dismutase (SOD), catalase (CAT), and glutathione-peroxidase (GSH-PX) and elevated (MDA) level in H2O2-treated cells were reversed to the normal standard by the addition of delphinidin, which was regulated by increasing nuclear Nrf2 protein expression in ARPE-19 cells. Our results suggest that delphinidin effectively protects human ARPE-19 cells from H2O2-induced oxidative damage via anti-apoptotic and antioxidant effects.}, }
@article {pmid31345384, year = {2019}, author = {Zhong, LM and Liu, ZG and Zhou, X and Song, SH and Weng, GY and Wen, Y and Liu, FB and Cao, DL and Liu, YF}, title = {Expansion of PMN-myeloid derived suppressor cells and their clinical relevance in patients with oral squamous cell carcinoma.}, journal = {Oral oncology}, volume = {95}, number = {}, pages = {157-163}, doi = {10.1016/j.oraloncology.2019.06.004}, pmid = {31345384}, issn = {1879-0593}, mesh = {Acetylcysteine/pharmacology ; Adult ; Aged ; Case-Control Studies ; Cell Proliferation/drug effects ; Cell Separation ; Cells, Cultured ; Coculture Techniques ; Female ; Flow Cytometry ; Healthy Volunteers ; Humans ; Lymphocyte Activation/drug effects ; Male ; Middle Aged ; Mouth Neoplasms/blood/*immunology/pathology ; Myeloid-Derived Suppressor Cells/*immunology/metabolism ; Primary Cell Culture ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; STAT3 Transcription Factor/antagonists &amp; inhibitors/metabolism ; Squamous Cell Carcinoma of Head and Neck/blood/*immunology/pathology ; T-Lymphocytes/*immunology/metabolism ; Triterpenes/pharmacology ; Young Adult ; }, abstract = {OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy worldwide, with a high mortality. The prognosis of OSCC remains unsatisfactory; the dysregulated immune system plays an important role in the pathogenesis of OSCC. Myeloid-derived suppressor cells (MDSCs) have been identified as immune-suppressive cells in multiple tumor types. The aim of this study was to clarify the underlying immunoregulatory mechanism of MDSC in patients with OSCC.<br><br>MATERIALS AND METHODS: Flow cytometry was used to analyze the phenotype of MDSC among peripheral blood mononuclear cells (PBMCs) from patients with OSCC and healthy control subjects. The correlation between MDSC frequency and the disease index of patients with OSCC was evaluated. T cell proliferation experiment was used to evaluate the immunosuppressive function of MDSC.<br><br>RESULTS: Patients with OSCC exhibited significantly higher levels of PMN-MDSCs than did healthy controls. In the co-culture assay, T cell proliferation and IFN-&#x3b3; production were abrogated by the addition of PMN-MDSCs in a dose-dependent manner. The levels of reactive oxygen species were higher for PMN-MDSCs derived from patients with OSCC than for those from normal individuals. p-STAT3 levels, a key activator of MDSCs, was higher in OSCC-related PMN-MDSCs than in those from healthy controls. Both of these effects were reversed by NAC (an ROS inhibitor) and JSI-124 (a p-STAT3 inhibitor). Finally, PMN-MDSC levels were positively related to histological differentiation, nodal metastasis, and recurrence.<br><br>CONCLUSION: PMN-MDSCs were elevated in OSCC patients, with strong immune-suppressive effects via p-STAT3/reactive oxygen species, providing a new direction for therapeutic strategies.}, }
@article {pmid31342735, year = {2019}, author = {Elshiekh, M and Kadkhodaee, M and Seifi, B and Ranjbaran, M}, title = {Additional effects of erythropoietin pretreatment, ischemic preconditioning, and N-acetylcysteine posttreatment in rat kidney reperfusion injury.}, journal = {Turkish journal of medical sciences}, volume = {49}, number = {4}, pages = {1249-1255}, pmid = {31342735}, issn = {1303-6165}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Urea Nitrogen ; Creatinine/blood ; Cytokines/blood ; Disease Models, Animal ; Erythropoietin/*pharmacology ; Ischemic Preconditioning/*methods ; *Kidney/drug effects/injuries/physiopathology ; Kidney Diseases/metabolism/physiopathology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; *Reperfusion Injury/metabolism/physiopathology ; }, abstract = {BACKGROUND/AIM: Since the nature of ischemia/reperfusion (IR)-induced tissue damage is multifactorial and complex, in the current study, the effects of multiple treatment strategies via concomitant administration of erythropoietin (EPO) and N-acetylcysteine (NAC) with an ischemic preconditioning (IPC) regimen on renal IR injury were examined.<br><br>MATERIALS AND METHODS: Thirty male Wistar rats were subjected to bilateral occlusion of the renal pedicles for 50 min followed by reperfusion. EPO (1000 IU/kg) was administered for 3 days, as well as IPC before the IR and NAC (150 mg/kg) administration for 4 days after IR. The animals were randomly allocated into 6 groups (n = 5): sham, IR, EPO+IR, IPC+IR, NAC+IR, and EPO+IPC+NAC+IR. Kidney tissues and blood samples were obtained for oxidative stress, proinflammatory cytokines, and renal functional evaluations.<br><br>RESULTS: IR caused significant inflammatory response, oxidative stress, and reduced renal function. Treatment with EPO, IPC, and NAC or a combination of two of them attenuated renal dysfunction and reduced the oxidative stress and inflammatory markers. Rats treated with the combination of EPO, IPC, and NAC showed a higher degree of protection compared to the other groups.<br><br>CONCLUSION: These results showed that concomitant administration of EPO and IPC along with posttreatment NAC may have additive beneficial effects on kidney IR injury during IR-induced acute renal failure.}, }
@article {pmid31341611, year = {2019}, author = {Bateman, DN and Dear, JW}, title = {Acetylcysteine in paracetamol poisoning: a perspective of 45 years of use.}, journal = {Toxicology research}, volume = {8}, number = {4}, pages = {489-498}, pmid = {31341611}, issn = {2045-452X}, abstract = {Paracetamol poisoning was first reported in 1966. The development of antidotes followed within 10 years, and by 1980 acetylcysteine (NAC) was acknowledged as the optimal therapy available. This article examines the history of the development of NAC and recent developments in its use. We offer suggestions for improvements in the way NAC may be administered and outline new developments that should have major impacts on the way we manage paracetamol poisoning in the near future.}, }
@article {pmid31339623, year = {2019}, author = {Akhter, MS and Uddin, MA and Barabutis, N}, title = {Unfolded protein response regulates P53 expression in the pulmonary endothelium.}, journal = {Journal of biochemical and molecular toxicology}, volume = {33}, number = {10}, pages = {e22380}, pmid = {31339623}, issn = {1099-0461}, support = {P20 GM103424/GM/NIGMS NIH HHS/United States ; (LEQSF(2019-22)-RD-A-26)//R&amp;D, Research Competitiveness Subprogram (RCS) of the Louisiana Board of Regents through the Board of Regents Support Fund/ ; (5P20GM103424-15//National Institute of General Medical Sciences of the National Institute of Health/ ; 3P20GM103424-15S1)//National Institute of General Medical Sciences of the National Institute of Health/ ; }, mesh = {Acetylcysteine/pharmacology ; Alkaloids/pharmacology ; Animals ; Brefeldin A/pharmacology ; Cattle ; Cells, Cultured ; Dithiothreitol/pharmacology ; Endothelium/drug effects/metabolism ; *Genes, p53 ; Pulmonary Artery/cytology/drug effects/*metabolism ; Thapsigargin/pharmacology ; *Unfolded Protein Response/drug effects ; }, abstract = {Lung endothelial barrier dysfunction leads to severe pathologies, including the lethal Acute Respiratory Distress Syndrome. P53 has been associated with anti-inflammatory activities. The current study employs a variety of unfolded protein response (UPR) activators and inhibitors to investigate the regulation of P53 by UPR in lung cells. The bovine cells that were exposed to the UPR inductors brefeldin A, dithiothreitol, and thapsigargin; demonstrated elevated expression levels of P53 compared to the vehicle-treated cells. On the contrary, the UPR inhibitors N-acetyl cysteine, kifunensine, and ATP-competitive IRE1α kinase-inhibiting RNase attenuator; produced the opposite effects. The outcomes of the present study reveal a positive regulation between UPR and P53. Since it has been shown that a mild induction of the unfolded protein response opposes inflammation, we suggest that P53 is involved in those protective activities in the lung.}, }
@article {pmid31336784, year = {2019}, author = {Wang, K and Chen, B and Yin, T and Zhan, Y and Lu, Y and Zhang, Y and Chen, J and Wu, W and Zhou, S and Mao, W and Tan, Y and Du, B and Liu, X and Ho, HI and Xiao, J}, title = {N-Methylparoxetine Blocked Autophagic Flux and Induced Apoptosis by Activating ROS-MAPK Pathway in Non-Small Cell Lung Cancer Cells.}, journal = {International journal of molecular sciences}, volume = {20}, number = {14}, pages = {}, pmid = {31336784}, issn = {1422-0067}, support = {81773953//the National Natural Science Foundation of China/ ; 81873146//the National Natural Science Foundation of China/ ; 2017A030313477//the Guangdong Natural Science Foundation/ ; S201910572047//the National Undergraduate Training Programs for Innovation and Entrepreneurship/ ; }, mesh = {Apoptosis/*drug effects ; Autophagy/*drug effects ; Carcinoma, Non-Small-Cell Lung/*metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lung Neoplasms/*metabolism ; Lysosomes/metabolism ; MAP Kinase Signaling System/*drug effects ; Mitochondria/drug effects/metabolism ; Molecular Structure ; Paroxetine/analogs &amp; derivatives/chemistry/*pharmacology ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The main mechanistic function of most chemotherapeutic drugs is mediated by inducing mitochondria-dependent apoptosis. Tumor cells usually respond to upregulate autophagy to eliminate impaired mitochondria for survival. Hypothetically, inhibiting autophagy might promote mitochondria-dependent apoptosis, thus enhancing the efficacy of chemotherapeutic therapies. We previously identified N-methylparoxetine (NMP) as an inducer of mitochondrial fragmentation with subsequent apoptosis in non-small cell lung cancer (NSCLC) cells. We discovered that ROS was accumulated in NMP-treated NSCLC cells, followed by c-Jun N-terminal kinase (JNK) and p38 MAP kinase (p38) activation. This was reversed by the application of a reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), leading to a reduction in apoptosis. Our data suggested that NMP induced apoptosis in NSCLC cells by activating mitogen-activated protein kinase (MAPK) pathway. We further speculated that the remarkable increase of ROS in NMP-treated NSCLC cells might result from an inhibition of autophagy. Our current data confirmed that NMP blocked autophagy flux at late stage wherein lysosomal acidification was inhibited. Taken together, this study demonstrated that NMP could exert dual apoptotic functions-mitochondria impairment and, concomitantly, autophagy inhibition. NMP-related excessive ROS accumulation induced apoptosis by activating the MAPK pathway in NSCLC cells.}, }
@article {pmid31336238, year = {2019}, author = {Tang, Q and Huang, K and Liu, J and Wu, S and Shen, D and Dai, P and Li, C}, title = {Fine particulate matter from pig house induced immune response by activating TLR4/MAPK/NF-κB pathway and NLRP3 inflammasome in alveolar macrophages.}, journal = {Chemosphere}, volume = {236}, number = {}, pages = {124373}, doi = {10.1016/j.chemosphere.2019.124373}, pmid = {31336238}, issn = {1879-1298}, mesh = {Animals ; Inflammasomes/*metabolism ; Macrophages, Alveolar/*metabolism ; NF-kappa B/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Particulate Matter/*chemistry ; Swine ; Toll-Like Receptor 4/*metabolism ; }, abstract = {Fine particulate matter (PM2.5) from livestock houses is harmful not only to the health and welfare of animals but also to the farmers working inside. As an important pollution source in the atmosphere environment, PM2.5 can threaten public health. PM2.5 collected from nursery pig house was studied. It included particulates of various morphologies, and the concentration of endotoxin was as high as to 681.80 EU/mg. To investigate the ability of PM2.5 from the nursery pig house to induce an immune response, porcine alveolar macrophages 3D4/21 cells were studied. The results showed that PM2.5 can induce cell death, ROS production and inflammatory cytokines release (IL-1β, IL-18, TNF-α and COX-2) by activating TLR4/MyD88 pathway and NLRP3 inflammasome. Furthermore, the downstream signaling pathways of TLR4/MyD88, MAPK and NF-κB, participated in NLRP3 inflammasome activation. To further study the role of endotoxin present in PM2.5 and the oxidative stress induced by PM2.5, polymyxin B (PMB) and N-acetylcysteine (NAC) were used to neutralize the effect of the endotoxin and inhibit the production of ROS, respectively. The results showed endotoxin and ROS played important roles in PM2.5-induced immune response. This study suggests that PM2.5 from pig house is a significant risk for immune response in alveolar macrophages.}, }
@article {pmid31331389, year = {2019}, author = {Li, Q and Zhao, Z}, title = {Influence of N-acetyl-L-cysteine against bisphenol a on the maturation of mouse oocytes and embryo development: in vitro study.}, journal = {BMC pharmacology &amp; toxicology}, volume = {20}, number = {1}, pages = {43}, pmid = {31331389}, issn = {2050-6511}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Benzhydryl Compounds/*toxicity ; Embryonic Development/*drug effects ; Endocrine Disruptors/*toxicity ; Female ; Fertilization in Vitro ; Glutathione/metabolism ; Mice ; Oocytes/*drug effects/physiology ; Oxidative Stress/drug effects ; Phenols/*toxicity ; Pregnancy ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Bisphenol A (BPA), an endocrine disruptor, is a widely used chemical that has adverse effects on animal development and reproduction. The current research aimed to evaluate the effect of BPA on the in vitro maturation (IVM) and subsequent embryo development of mouse oocytes following in vitro fertilization (IVF).<br><br>METHODS: IVM was performed in the presence of different concentrations (0, 20, 50, or 100&#x2009;&#x3bc;g/mL) of BPA. Nuclear maturation, IVF efficiency and embryonic development were determined. The levels of reactive oxygen species (ROS) and glutathione (GSH) in the BPA (50&#x2009;&#x3bc;g/mL) group were evaluated. We explored the ability of N-acetyl-L-cysteine (NAC) in the IVM medium to rescue the BPA-induced damage by examining changes in nuclear maturation, IVF rate, blastocyst formation, ROS levels and GSH content.<br><br>RESULTS: Compared with the control, BPA (50&#x2009;&#x3bc;g/mL) supplementation during oocyte IVM significantly inhibited nuclear maturation and decreased fertilization and blastocyst formation rates. In addition, BPA exposure increased ROS levels and decreased GSH content in oocytes. The addition of NAC weakened the BPA-induced suppression of nuclear maturation, relieved the BPA-induced downregulation of the fertilization and blastocyst formation rates, and mitigated the increased ROS levels and decreased GSH content.<br><br>CONCLUSION: BPA affects mouse oocyte maturation and subsequent early embryonic developmental competence following IVF by increasing intracytoplasmic oxidative stress in mature oocytes. NAC can reduce these harmful effects to a certain extent.}, }
@article {pmid31330570, year = {2020}, author = {Namba, MD and Kupchik, YM and Spencer, SM and Garcia-Keller, C and Goenaga, JG and Powell, GL and Vicino, IA and Hogue, IB and Gipson, CD}, title = {Accumbens neuroimmune signaling and dysregulation of astrocytic glutamate transport underlie conditioned nicotine-seeking behavior.}, journal = {Addiction biology}, volume = {25}, number = {5}, pages = {e12797}, pmid = {31330570}, issn = {1369-1600}, support = {K99 DA047426/DA/NIDA NIH HHS/United States ; R21 DA044479/DA/NIDA NIH HHS/United States ; R01 DA046526/DA/NIDA NIH HHS/United States ; R00 DA036569/DA/NIDA NIH HHS/United States ; K99 DA036569/DA/NIDA NIH HHS/United States ; K22 AI123159/AI/NIAID NIH HHS/United States ; R03 DA045881/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Astrocytes/*metabolism ; Conditioning, Psychological ; Disease Models, Animal ; Drug-Seeking Behavior/drug effects ; Glial Fibrillary Acidic Protein/metabolism ; Glutamic Acid/*metabolism ; Male ; Nicotine/administration &amp; dosage/*pharmacology ; Nucleus Accumbens/*drug effects ; Rats ; Rats, Sprague-Dawley ; Self Administration ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Nicotine self-administration is associated with decreased expression of the glial glutamate transporter (GLT-1) and the cystine-glutamate exchange protein xCT within the nucleus accumbens core (NAcore). N-acetylcysteine (NAC) has been shown to restore these proteins in a rodent model of drug addiction and relapse. However, the specific molecular mechanisms driving its inhibitory effects on cue-induced nicotine reinstatement are unknown. Here, we confirm that extinction of nicotine-seeking behavior is associated with impaired NAcore GLT-1 function and expression and demonstrates that reinstatement of nicotine seeking rapidly enhances membrane fraction GLT-1 expression. Extinction and cue-induced reinstatement of nicotine seeking was also associated with increased tumor necrosis factor alpha (TNFα) and decreased glial fibrillary acidic protein (GFAP) expression in the NAcore. NAC treatment (100 mg/kg/day, i.p., for 5 d) inhibited cue-induced nicotine seeking and suppressed AMPA to NMDA current ratios, suggesting that NAC reduces NAcore postsynaptic excitability. In separate experiments, rats received NAC and an antisense vivo-morpholino to selectively suppress GLT-1 expression in the NAcore during extinction and were subsequently tested for cue-induced reinstatement of nicotine seeking. NAC treatment rescued NAcore GLT-1 expression and attenuated cue-induced nicotine seeking, which was blocked by GLT-1 antisense. NAC also reduced TNFα expression in the NAcore. Viral manipulation of the NF-κB pathway, which is downstream of TNFα, revealed that cue-induced nicotine seeking is regulated by NF-κB pathway signaling in the NAcore independent of GLT-1 expression. Ultimately, these results are the first to show that immunomodulatory mechanisms may regulate known nicotine-induced alterations in glutamatergic plasticity that mediate cue-induced nicotine-seeking behavior.}, }
@article {pmid31330490, year = {2019}, author = {Martínez, MA and Rodríguez, JL and Lopez-Torres, B and Martínez, M and Martínez-Larrañaga, MR and Anadón, A and Ares, I}, title = {Oxidative stress and related gene expression effects of cyfluthrin in human neuroblastoma SH-SY5Y cells: Protective effect of melatonin.}, journal = {Environmental research}, volume = {177}, number = {}, pages = {108579}, doi = {10.1016/j.envres.2019.108579}, pmid = {31330490}, issn = {1096-0953}, mesh = {Apoptosis ; Cell Line, Tumor ; Cell Survival ; Dual Oxidases ; Gene Expression ; Humans ; Insecticides/*toxicity ; Melatonin/metabolism ; Neuroblastoma ; Nitriles/*toxicity ; Oxidative Stress/*physiology ; Protective Agents/*metabolism ; Pyrethrins/*toxicity ; Reactive Oxygen Species ; }, abstract = {This study was designed to assess oxidative stress induction in human neuroblastoma SH-SY5Y cells in response to cyfluthrin exposure. Cell viability MTT assay was carried out to assess cyfluthrin cytotoxicity; IC30 and IC50 values for cyfluthrin were calculated to be 4.81 ± 0.92 μM and 19.39 ± 3.44 μM, respectively. Cyfluthrin induced a significant increase in ROS generation, lipid peroxides measured as malondialdehyde (MDA) and nitric oxide (NO) production and a significant decrease in NQO1 activity. The antioxidant activity of melatonin (MEL), Trolox, N-acetylcysteine (NAC) and Sylibin against cyfluthrin-induced oxidative stress was examined. Cyfluthrin increased significantly gene expressions of apoptosis, proinflammation and oxidative stress (Bax, Bcl-2, Casp-3, BNIP3, AKT1, p53, APAF1, NFκB1, TNFα and Nrf2) mediators. In the most genes, the mRNA levels induced by cyfluthrin were partially reduced by MEL (1 μM). Cyfluthrin effects on gene expression profiling of oxidative stress pathway by Real-Time PCR array analysis showed that of the 84 genes examined, (fold change > 1.5) changes in mRNA levels were detected in 31 genes: 13 upregulated and 18 down-regulated. A fold change >3.0 fold was observed on upregulated CYBB, DUOX1, DUOX2, AOX1, BNIP3, HSPA1A, NOS2, and NQO1 genes. The greater fold change reversion (2.5 fold) by MEL (1 μM) was observed on cyfluthrin-upregulated CYBB, AOX1, BNIP3 and NOS2 genes. These results demonstrated that oxidative stress is a key element in cyfluthrin induced neurotoxicity as well as MEL may play a role in reducing cyfluthrin-induced oxidative stress.}, }
@article {pmid31330229, year = {2019}, author = {Chung, YP and Yen, CC and Tang, FC and Lee, KI and Liu, SH and Wu, CC and Hsieh, SS and Su, CC and Kuo, CY and Chen, YW}, title = {Methylmercury exposure induces ROS/Akt inactivation-triggered endoplasmic reticulum stress-regulated neuronal cell apoptosis.}, journal = {Toxicology}, volume = {425}, number = {}, pages = {152245}, doi = {10.1016/j.tox.2019.152245}, pmid = {31330229}, issn = {1879-3185}, mesh = {Animals ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Cell Line, Tumor ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Methylmercury Compounds/*toxicity ; Mice ; Neurons/*drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; }, abstract = {Epidemiological studies have positively linked mercury exposure and neurodegenerative diseases (ND). Methylmercury (MeHg), an organic form of mercury, is a ubiquitous and potent environmental neurotoxicant that easily crosses the blood-brain barrier and causes irreversible injury to the central nervous system (CNS). However, the molecular mechanisms underlying MeHg-induced neurotoxicity remain unclear. Here, the present study found that Neuro-2a cells underwent apoptosis in response to MeHg (1-5 μM), which was accompanied by increased phosphatidylserine (PS) exposure on the outer cellular membrane leaflets, caspase-3 activity, and the activation of caspase cascades and poly (ADP-ribose) polymerase (PARP). Exposure of Neuro-2a cells to MeHg also triggered endoplasmic reticulum (ER) stress, which was identified via several key molecules (including: glucose-regulated protein (GRP)78, GRP94, C/EBP homologous protein (CHOP) X-box binding protein(XBP)-1, protein kinase R-like ER kinase (PERK), eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme(IRE)-1, activation transcription factor(AFT)4, and ATF6. Transfection with GRP78-, GRP94-, CHOP-, and XBP-1-specific small interfering (si)RNA significantly suppressed the expression of these proteins, and attenuated cytotoxicity and caspase-12, -7, and -3 activation in MeHg-exposed cells. Furthermore, MeHg dramatically decreased Akt phosphorylation, and the overexpression of activation of Akt1 (myr-Akt1) could significantly prevent MeHg-induced Akt inactivation, as well as apoptotic and ER stress-related signals. Pretreatment with the antioxidant N-acetylcysteine (NAC) effectively prevented MeHg-induced neuronal cell reactive oxygen species (ROS) generation, apoptotic and ER stress-related signals, and Akt inactivation. Collectively, these results indicate that MeHg exerts its cytotoxicity in neurons by inducing ROS-mediated Akt inactivation up-regulated ER stress, which induces apoptosis and ultimately leads to cell death.}, }
@article {pmid31330211, year = {2019}, author = {Zhang, M and Asghar, S and Jin, X and Hu, Z and Ping, Q and Chen, Z and Shao, F and Xiao, Y}, title = {The enhancing effect of N-acetylcysteine modified hyaluronic acid-octadecylamine micelles on the oral absorption of paclitaxel.}, journal = {International journal of biological macromolecules}, volume = {138}, number = {}, pages = {636-647}, doi = {10.1016/j.ijbiomac.2019.07.114}, pmid = {31330211}, issn = {1879-0003}, mesh = {Acetylcysteine/*chemistry ; Administration, Oral ; Amines/*chemistry ; Animals ; Cell Line, Tumor ; Drug Carriers ; Drug Delivery Systems ; Humans ; Hyaluronic Acid/*chemistry ; Male ; *Micelles ; Paclitaxel/*administration &amp; dosage/*pharmacokinetics ; Rats ; Tissue Distribution ; }, abstract = {A micelle system based on hyaluronic acid (HA)-octadecylamine (OA) conjugate (HOA) functionalized with N-acetylcysteine (NAC) was constructed to yield NAC modified HOA conjugate (NHOA) for improving oral paclitaxel (PTX) delivery (PTX-NHOA). The average size of spherical PTX-NHOA micelles was 162.7 nm with a zeta potential of -27.6 mv. The encapsulation efficiency (EE) and drug loading (DL) of PTX-NHOA micelles were 92.64% and 6.96%, respectively. Additionally, NHOA micelles exihibited significantly higher cellular uptake in comparison with HOA micelles by caveolin-mediated and clathrin-mediated endocytosis. Higher permeation ability of NHOA micelles (2.75-fold and 1.32-fold, respectively) through cell monolayers of Caco-2/HT29 cells than that of Taxol and HOA micelles were also observed. The intestinal biodistribution result showed that NAC-modified micelles could enhance its adhesion to the intestinal surface and permeate deeply within the intestinal villi. The NHOA micelles were better absorbed in the duodenum, followed by the jejunum and the ileum. In vivo pharmacokinetic studies showed that AUC0-t value of PTX-NHOA micelles was about 5.92-fold and 2.47-fold higher compared to that of Taxol and PTX-HOA micelles, respectively. In a word, NHOA micelles is a promising drug delivery system in improving the oral absorption of insoluble drugs.}, }
@article {pmid31323271, year = {2019}, author = {Nie, Q and Zhu, L and Zhang, L and Leng, B and Wang, H}, title = {Astragaloside IV protects against hyperglycemia-induced vascular endothelial dysfunction by inhibiting oxidative stress and Calpain-1 activation.}, journal = {Life sciences}, volume = {232}, number = {}, pages = {116662}, doi = {10.1016/j.lfs.2019.116662}, pmid = {31323271}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aorta, Thoracic/drug effects/metabolism ; Biomarkers/metabolism ; Calpain/*metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; Diabetes Mellitus, Experimental/metabolism ; Dipeptides/pharmacology ; Endothelium, Vascular/*drug effects/metabolism/pathology ; Human Umbilical Vein Endothelial Cells ; Humans ; Hyperglycemia/metabolism/*pathology ; Male ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Saponins/*pharmacology ; Streptozocin ; Triterpenes/*pharmacology ; Vasodilation/drug effects ; }, abstract = {AIMS: Vascular endothelial cells act as a selective barrier between circulating blood and vessel wall and play an important role in the occurrence and development of cardiovascular diseases. Astragaloside IV (As-IV) has a protective effect on vascular endothelial cells, but its underlying mechanism remains unclear. This study is aimed at investigating the effect of As-IV on endothelial dysfunction (ED).<br><br>METHODS: Male Sprague-Dawley (SD) were injected intraperitoneally with 65&#x202f;mg/kg streptozotocin (STZ) to induce diabetes and then administered orally with As-IV (40, 80&#x202f;mg/kg) for 8&#x202f;weeks. Vascular function was evaluated by vascular reactivity in vivo and in vitro. The expression of calpain-1 and eNOS in the aorta of diabetic rats was examined by western blot. NO production was measured using nitrate reductase method. Oxidative stress was determined by measuring SOD, GSH-px and ROS.<br><br>RESULTS: Our results showed that As-IV administration significantly improved diabetes associated ED in vivo, and both NAC (an antioxidant) and MDL-28170 (calpain-1 inhibitor) significantly attenuated hyperglycemia-induced ED in vitro. Meanwhile, pretreatment with the inhibitor l-NAME nearly abolished vasodilation to ACh in all groups of rats. Furthermore, As-IV increased NO production and the expression of eNOS in the thoracic aorta of diabetic rats. In addition, the levels of ROS were significantly increased, and the activity of SOD and GSH-px were decreased in diabetic rats, while As-IV administration reversed this change in a concentration-dependent manner.<br><br>CONCLUSION: These results suggest that As-IV improves endothelial dysfunction in thoracic aortas from diabetic rats by reducing oxidative stress and calpain-1.}, }
@article {pmid31322268, year = {2019}, author = {Zada, S and Hwang, JS and Ahmed, M and Lai, TH and Pham, TM and Kim, DH and Kim, DR}, title = {Protein kinase A activation by β‑Lapachone is associated with apoptotic cell death in NQO1‑overexpressing breast cancer cells.}, journal = {Oncology reports}, volume = {42}, number = {4}, pages = {1621-1630}, doi = {10.3892/or.2019.7243}, pmid = {31322268}, issn = {1791-2431}, mesh = {Apoptosis/drug effects ; Breast Neoplasms/*drug therapy/enzymology/pathology ; Cell Line, Tumor ; Cyclic AMP-Dependent Protein Kinases/*metabolism ; Enzyme Activation/drug effects ; Female ; Humans ; NAD(P)H Dehydrogenase (Quinone)/*biosynthesis ; Naphthoquinones/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {One million females are diagnosed worldwide every year with breast cancer, and the mortality rate of these patients remains high. Several treatments, including surgery, are available for breast cancer. β‑Lapachone (β‑Lap), a natural quinone compound, has been developed for cancer treatment due to its strong cytotoxic effect through its action on NAD(P)H:quinone oxidoreductase 1 (NQO1)‑dependent activity. However, the mechanism in regards to how β‑Lap induces cytotoxicity in breast cancer cells is still elusive. In the present study, we showed that β‑Lap induced apoptotic cell death via activation of protein kinase A (PKA) in NQO1‑overexpressing MDA‑MB‑231 human breast cancer cells. This PKA‑dependent cell death was observed solely in NQO1‑overexpressing 231 cells via the high production of reactive oxygen species (ROS). Cell survival of antioxidant [N‑acetylcysteine (NAC)]‑treated NQO1‑overexpressing 231 cells was significantly recovered, and NQO1‑negative 231 cells did not respond to β‑Lap. Antiapoptotic proteins such as Bcl2 and Bcl‑xL were decreased, while proapoptotic proteins, including cytochrome c, activation of caspase‑3, and cleavage of PARP were increased after β‑Lap treatment of NQO1‑overexpressing 231 cells. Furthermore, PKA activators, forskolin or dibutyryl‑cAMP, an analog of cAMP, aggravated the β‑Lap‑induced apoptotic cell death by decreasing antiapoptotic proteins and further activating proapoptotic proteins in NQO1‑positive 231 cells. Treatment with a PKA inhibiter, H89, significantly increased cell viability even in NQO1‑overexpressing cells treated with β‑Lap. These data showed that β‑Lap activated PKA via ROS accumulation, subsequently leading to apoptotic cell death in NQO1‑positive breast cancer cells.}, }
@article {pmid31317129, year = {2019}, author = {Pettie, JM and Caparrotta, TM and Hunter, RW and Morrison, EE and Wood, DM and Dargan, PI and Thanacoody, RH and Thomas, SHL and Elamin, MEMO and Francis, B and Webb, DJ and Sandilands, EA and Eddleston, M and Dear, JW}, title = {Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose.}, journal = {EClinicalMedicine}, volume = {11}, number = {}, pages = {11-17}, pmid = {31317129}, issn = {2589-5370}, support = {209562/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; }, abstract = {BACKGROUND: Acetylcysteine (NAC) is effective at preventing liver injury after paracetamol overdose. The Scottish and Newcastle Anti-emetic Pre-treatment for Paracetamol Poisoning (SNAP) Study demonstrated that a 12 h NAC regimen was associated with fewer adverse drug reactions compared with the standard 21 h regimen. Here, we describe the clinical effectiveness of the SNAP NAC regimen.<br><br>METHODS: The SNAP regimen, consisting of intravenous NAC 100&#x202f;mg/kg over 2&#x202f;h then 200&#x202f;mg/kg over 10&#x202f;h, was introduced to treat all paracetamol overdose patients at the Royal Infirmary of Edinburgh, the Royal Victoria Infirmary, Newcastle and St Thomas' Hospital, London. Patient data were prospectively and systematically collected before and after the change in treatment (total patients N&#x202f;=&#x202f;3340, 21&#x202f;h&#x202f;N&#x202f;=&#x202f;1488, SNAP N&#x202f;=&#x202f;1852). Health record linkage was used to determine patient outcome after hospital discharge.<br><br>FINDINGS: There was no difference in liver injury or liver synthetic dysfunction between regimens. Hepatotoxicity (peak ALT&#x202f;>&#x202f;1000&#x202f;U/L) occurred in 64 (4.3%) and 67 (3.6%) patients, respectively, in the 21&#x202f;h and SNAP groups (absolute difference -&#xa0;0.7%, 95% CI -&#xa0;2.1 to 0.6). Multivariable logistic regression did not identify treatment regimen as an outcome-associated factor. No patients were readmitted to hospital with, or died from, liver failure within 30&#x202f;days of discharge. Anti-histamine treatment (for NAC anaphylactoid drug reactions) was prescribed for 163 (11.0%) patients with the 21&#x202f;h regimen and 37 (2.0%) patients with the SNAP regimen (absolute difference 9.0% (95% CI 7.3 to 10.7)).<br><br>INTERPRETATION: In clinical use the SNAP regimen has similar efficacy as standard therapy for preventing liver injury and produces fewer adverse reactions.}, }
@article {pmid31316665, year = {2019}, author = {Yusuf, SYM and Ismail, IA and Hamid, RA and Jamil, NA and Yasin, MM}, title = {Isolated Bilateral Pinna Swelling: A Rare Initial Presentation of Leprosy.}, journal = {Open access Macedonian journal of medical sciences}, volume = {7}, number = {11}, pages = {1815-1817}, pmid = {31316665}, issn = {1857-9655}, abstract = {BACKGROUND: Leprosy or Hansen disease is a chronic infectious disease that causes social stigma due to its deforming bodily appearance and physical disability. It has a wide spectrum of presentation affecting diagnosis.<br><br>CASE REPORT: A 21-year-old man who presented with chronic isolated bilateral pinna swelling as a result of leprosy is reported. The bilateral pinna swelling started as multiple shiny papules with an erythematous background and progressively became hyperpigmented and lobular over two years. This rare presentation of leprosy poses initial diagnostic difficulties, leading to misdiagnoses by various health care professionals. Diagnoses ascribed include eczema, insect bite and perichondritis. A suspicion of leprosy was raised when hyperaesthetic hypopigmentation of skin started to appear on the body after two years, with worsening of the pinna swellings. This was confirmed by identification of Mycobacterium leprae in slit skin smear test and skin biopsy.<br><br>CONCLUSION: Isolated involvement of pinna in a patient without lesions in other body parts is an unusual initial presentation of leprosy. However, leprosy should be kept as a rare differential diagnosis of isolated lesions on the ear in patients not responding to conventional treatment.}, }
@article {pmid31316651, year = {2019}, author = {Al-Jawad, FH and Al-Attar, Z and Abbood, MS}, title = {The Protective Effect of Nitroglycerin, N-Acetyl Cysteine and Metoprolol in CCL4 Induced Animal Model of Acute Liver Injury.}, journal = {Open access Macedonian journal of medical sciences}, volume = {7}, number = {11}, pages = {1739-1743}, pmid = {31316651}, issn = {1857-9655}, abstract = {OBJECTIVE: The current study was designed to determine the hepatoprotective effect of well-known drugs. Nitroglycerin, N-acetyl cysteine and Metoprolol in acute liver injury induced by CCL4. The antioxidant effects of b-blockers, especially carvedilol, have been described by several investigators. However, for metoprolol, the effect is a bit query as there is only one in-vitro study showing a little hepatoprotective effect. Thus, it is worthy to re-study the hepatoprotective effect of metoprolol.<br><br>AIM: To explore the possible hepatoprotective effect of Nitroglycerin, N-acetyl cysteine and Metoprolol Tartrate.<br><br>MATERIAL AND METHODS: The normal serum values of ALP, AST, ALT, TSB and TSP were determined in 35 healthy rabbits allocated to 5 groups before CCL4 induction and at three occasions 24, 72, 120 hrs after induction by CCL4 and treatment with the tested drugs: Nitroglycerin, N-acetyl cysteine and Metoprolol for five successive days.<br><br>RESULTS: Showed significant decrease in serum levels of ALP, AST, ALT and TSB with a significant increase in TSP level of all the tested drugs measured at 120 hrs compared with the control and their levels measured at 24, 72 hrs.<br><br>CONCLUSION: All the tested drugs proved in having a hepatoprotective effect when they are given orally to animals. The histopathological sections of the liver tissue supported the real effect of these drugs in the management of ALI.}, }
@article {pmid31311721, year = {2019}, author = {Morrison, EE and Oatey, K and Gallagher, B and Grahamslaw, J and O'Brien, R and Black, P and Oosthuyzen, W and Lee, RJ and Weir, CJ and Henriksen, D and Dear, JW and , }, title = {Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12 h regimen of N-acetylcysteine for paracetamol overdose (POP trial).}, journal = {EBioMedicine}, volume = {46}, number = {}, pages = {423-430}, pmid = {31311721}, issn = {2352-3964}, support = {MC_PC_12014/MRC_/Medical Research Council/United Kingdom ; RE/08/001/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Acetaminophen/*administration &amp; dosage/*adverse effects ; Acetylcysteine/*therapeutic use ; Adult ; Biomarkers ; Chemical and Drug Induced Liver Injury/*drug therapy/*etiology/metabolism ; Drug Interactions ; Drug Overdose ; Edetic Acid/*analogs &amp; derivatives/therapeutic use ; Female ; Humans ; Male ; Protective Agents/*therapeutic use ; Pyridoxal Phosphate/*analogs &amp; derivatives/therapeutic use ; Time Factors ; Young Adult ; }, abstract = {BACKGROUND: The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose.<br><br>METHODS: Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24&#x202f;h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n&#x202f;=&#x202f;6) or NAC alone (n&#x202f;=&#x202f;2). Calmangafodipir doses were 2, 5, or 10&#x202f;&#x3bc;mol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395).<br><br>FINDINGS: All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced &#x2265;1 adverse event (AE), most commonly gastrointestinal. Patients experiencing &#x2265;1 serious adverse event (SAE): NAC alone, 2/6; NAC&#x202f;+&#x202f;calmangafodipir (2&#x202f;&#x3bc;mol/kg), 4/6; NAC&#x202f;+&#x202f;calmangafodipir (5 &#x3bc;mol/kg), 2/6; NAC&#x202f;+&#x202f;calmangafodipir (10&#x202f;&#x3bc;mol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT&#x202f;>&#x202f;100&#x202f;U/L; with NAC&#x202f;+&#x202f;calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20&#x202f;h fold change, NAC&#x202f;+&#x202f;calmangafodipir (5&#x202f;&#x3bc;mol/kg) compared to NAC alone: 0.48 (95%CI 0.28-0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected.<br><br>INTERPRETATION: Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.}, }
@article {pmid31310363, year = {2019}, author = {Yi, Z and Jiang, L and Zhao, L and Zhou, M and Ni, Y and Yang, Y and Yang, H and Yang, L and Zhang, Q and Kuang, Y and Deng, M and Zhu, Y}, title = {Glutathione peroxidase 3 (GPX3) suppresses the growth of melanoma cells through reactive oxygen species (ROS)-dependent stabilization of hypoxia-inducible factor 1-α and 2-α.}, journal = {Journal of cellular biochemistry}, volume = {120}, number = {11}, pages = {19124-19136}, doi = {10.1002/jcb.29240}, pmid = {31310363}, issn = {1097-4644}, mesh = {Aged ; Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism ; Cell Line, Tumor ; Female ; Glutathione Peroxidase/genetics/*metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Male ; Melanoma/genetics/*metabolism/pathology ; Mice ; Mice, Nude ; Middle Aged ; Neoplasm Proteins/genetics/*metabolism ; Protein Stability ; Reactive Oxygen Species/*metabolism ; }, abstract = {In this study, we aimed to explore the mechanism of glutathione peroxidase 3 (GPX3) in the growth of malignant melanoma (MM) cells by hypoxia-inducible factor-1α (HIF1-α) and HIF2-α regulating the metabolism through reactive oxygen species (ROS). The messenger RNA and protein expression of GPX3, HIF1-α, HIF2-α in tissues, and cell lines were measured by reverse transcription-quantitative PCR and Western blot analysis. A375 cells were transfected with GPX3 overexpression plasmid, small interfering RNA (siRNA) targeting GPX3, or siRNA targeting HIF1-α/HIF2-α to upregulate or downregulate the expression of GPX3 or HIF1-α/HIF2-α. The effects of H2 O2 and N-acetylcysteine (NAC) on the levels of HIF1-α and HIF2-α after overexpression of GPX3 were studied. The cell viability was detected by Cell Counting Kit-8. The levels of ROS, glucose uptake and lactic acid production, oxidative phosphorylation, and glycolysis of cells were measured for assessment of cellular metabolism. The expression of GPX3 decreased, while ROS, HIF1-α, and HIF2-α increased in MM tissues and cells. Overexpression of GPX3 inhibited the viability of MM cells and the growth of melanoma xenografts. The overexpression of GPX3 reduced the glucose uptake, extracellular lactic acid content, and extracellular acidification rate and increased the oxygen consumption rate level. Overexpression of GPX3 could reduce the levels of HIF1-α and HIF2-α, which could regulate metabolic levels. GPX3 reduced ROS level in MM to inhibit HIF1-α and HIF2-α. The addition of H2 O2 increased while NAC reduced the protein levels of HIF1-α and HIF2-α in the cells overexpressing GPX3. Our study demonstrates that GPX3 inhibits the growth of MM cells through its inhibitory effect on cell metabolic disorder by inhibiting HIF1-α via regulating ROS.}, }
@article {pmid31308694, year = {2019}, author = {Tang, JY and Yu, TJ and Lin, LC and Peng, SY and Wang, CL and Ou-Yang, F and Cheng, YB and Chang, HW}, title = {Ethyl acetate extracts of Nepenthes ventricosa x sibuyanensis leaves cause growth inhibition against oral cancer cells via oxidative stress.}, journal = {OncoTargets and therapy}, volume = {12}, number = {}, pages = {5227-5239}, pmid = {31308694}, issn = {1178-6930}, abstract = {Introduction: The genus Nepenthes of the pitcher plants contains several natural and hybrid species that are commonly used in herbal medicine in several countries, but its possible use in cancer applications remains unknown as yet. Methods: In this study, we investigated the antioral cancer properties using ethyl acetate extracts of the Nepenthes hybrid (Nepenthes ventricosa x sibuyanensis), namely EANS. The bioactivity was detected by a MTS-based cell proliferation assay and flow cytometric or Western blot analysis for apoptosis, oxidative stress, and DNA damage. Results: Treatment for 24 hrs of EANS inhibited all three types of oral cancer cells that were tested (Ca9-22, CAL 27, and SCC9), with just a small difference to normal oral cells (HGF-1). This antiproliferation was inhibited by pretreatments with the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC), and the apoptosis inhibitor (Z-VAD). EANS treatment increased the subG1 population and it also dose- and time-dependently induced annexin V- and pancaspase-detected apoptosis as well as cleaved caspases 3 and 9 overexpressions in the oral cancer cells (Ca9-22). After EANS treatment of Ca9-22 cells, intracellular ROS and mitochondrial superoxide (MitoSOX) were overexpressed and mitochondrial membrane potential (MMP) was disrupted. Moreover, DNA damages such as γH2AX and 8-oxo-2'-deoxyguanosine (8-oxodG) were increased after EANS treatment to Ca9-22 cells. The EANS-induced effects (namely, oxidative stress, apoptosis, and DNA damage) were suppressed by ROS scavenger. Conclusion: Our findings demonstrated that EANS inhibits ROS-mediated proliferation against oral cancer cells.}, }
@article {pmid31307590, year = {2019}, author = {Fisher, ES and Curry, SC}, title = {Evaluation and treatment of acetaminophen toxicity.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {85}, number = {}, pages = {263-272}, doi = {10.1016/bs.apha.2018.12.004}, pmid = {31307590}, issn = {1557-8925}, mesh = {Acetaminophen/administration &amp; dosage/*adverse effects ; Acute Disease ; Animals ; Chemical and Drug Induced Liver Injury/*diagnosis/*therapy ; Disease Progression ; Humans ; Liver/drug effects ; Risk Factors ; }, abstract = {A review of the typical clinical course, diagnosis and treatment of acetaminophen toxicity is provided. For an acute overdose, most adults must ingest about 12g or more acetaminophen (APAP) before risk of serious hepatotoxicity is of concern. A nomogram of serum APAP concentration vs hours post-ingestion can assist in determining risk of liver injury and need for treatment. However, histories concerning the time of ingestion and the amount of drug ingested are usually unreliable. Peak serum transaminase activities usually occur 48-96h after acute ingestion. It is possible for patients to present in liver failure days after ingestion with undetectable serum APAP concentrations. Patients who have chronically ingested excessive APAP doses and develop hepatotoxicity usually present with such, and renal failure is more common in this population. Current treatment centers on administration of N-acetylcysteine (NAC) to prevent hepatotoxicity, though NAC also improves outcomes in patients who present with acute liver failure. When given early after APAP ingestion, NAC's main mechanism of action is to maintain intracellular glutathione stores so to detoxify the electrophilic APAP metabolite, NAPQI. NAC is generally well-tolerated when given intravenously, with the main concern being anaphylactoid reactions. These reactions usually occur during loading doses and are easily treated with discontinuation of the NAC infusion, administration of antihistamines, and then restarting the loading dose at a slower infusion rate. There is concern that current NAC dosing is not large enough to adequately treat large APAP ingestions. Patients with acute liver failure may be candidates for orthotopic liver transplantation.}, }
@article {pmid31306752, year = {2019}, author = {Roos, C and Dahlgren, D and Sjögren, E and Sjöblom, M and Hedeland, M and Lennernäs, H}, title = {Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {142}, number = {}, pages = {387-395}, doi = {10.1016/j.ejpb.2019.07.012}, pmid = {31306752}, issn = {1873-3441}, mesh = {Administration, Oral ; Animals ; Biological Availability ; Body Fluids/metabolism ; Excipients/*chemistry ; Fasting/*metabolism ; Intestinal Absorption/*drug effects ; Intestinal Mucosa/metabolism ; Intestines/physiology ; Jejunum/*metabolism ; Male ; Permeability/drug effects ; Pharmaceutical Preparations/*chemistry/*metabolism ; Rats ; Rats, Wistar ; Sodium Dodecyl Sulfate/chemistry ; Solubility/drug effects ; }, abstract = {Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.}, }
@article {pmid31302316, year = {2019}, author = {Chan, LP and Tseng, YP and Ding, HY and Pan, SM and Chiang, FY and Wang, LF and Chou, TH and Lien, PJ and Liu, C and Kuo, PL and Liang, CH}, title = {Tris(8-Hydroxyquinoline)iron induces apoptotic cell death via oxidative stress and by activating death receptor signaling pathway in human head and neck carcinoma cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {63}, number = {}, pages = {153005}, doi = {10.1016/j.phymed.2019.153005}, pmid = {31302316}, issn = {1618-095X}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects/physiology ; Caspases/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Coordination Complexes/*pharmacology ; Cytochromes c/metabolism ; Fas Ligand Protein/metabolism ; Glutathione/metabolism ; Head and Neck Neoplasms/*drug therapy/metabolism/pathology ; Humans ; Hydroxyquinolines/*pharmacology ; Iron/*chemistry ; Iron Compounds/*pharmacology/therapeutic use ; Mitochondria/drug effects/metabolism ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Quinolines/*pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Receptors, Death Domain/metabolism ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND: 8-Hydroxyquinoline derivatives have highly sensitive fluorescent chemosensors for metal ions, which are associated with anti-oxidant, anti-tumor and anti-HIV-1 properties. Head and neck squamous cell carcinoma (HNSCC) is associated with a high rate of mortality and novel anti-HNSCC drugs must be developed. Therefore, effective chemotherapy agents are required to address this public health issue.<br><br>HYPOTHESIS/PURPOSE: The aim of this study was to investigate the inhibitory effect of tris(8-hydroxyquinoline)iron (Feq3) on the HNSCC and the underlying mechanism.<br><br>STUDY DESIGN/METHODS: A novel 8-hydroxyquinoline derivative, Feq3, was synthesized. The cell viabilities were analyzed using MTT reagent. Apoptosis and the cell cycle distributions were determined by flow cytometer. Reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, western blot, MitoSOX and CellROX stain assay were used to study the mechanism of Feq3. Feq3 combined with antioxidants NAC (N-acetylcysteine) and BSO (buthionine sulfoximine) measured the cell viability and intracellular ROS.<br><br>RESULTS: Feq3 induced the death of HNSCC cells and caused them to exhibit the morphological features of apoptosis. Feq3 also induced apoptosis of SCC9 cells by cell cycle arrest during the G2/M phase and the induced arrest of SCC25 cells in the G0/G1 and G2/M phases, which was associated with decreased cyclin B1/cdc2 and cyclin D/cdk4 expressions. Feq3 increases reactive oxygen species (ROS) and reduces glutathione (GSH) levels, and responds to increased p53 and p21 expressions. Feq3 induced apoptosis by mitochondria-mediated Bax and cytochrome c up-expression and down-expression Bcl-2. Feq3 also up-regulated tBid, which interacts with the mitochondrial pathway and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;)/TNF-Rs, FasL/Fas, and TNF-related apoptosis inducing ligand receptors (TRAIL-Rs)/TRAIL-dependent caspases apoptotic signaling pathway in HNSCC cells. However, Feq3 activates Fas but not FasL in SCC25 cells. Feq3 arrests the growth of HNSCC cells and is involved in the mitochondria- and death receptor (DR)-mediated caspases apoptotic pathway.<br><br>CONCLUSION: This study is the first to suggest that apoptosis mediates the anti-HNSCC of Feq3. Feq3 has potential as a cancer therapeutic agent against HNSCC.}, }
@article {pmid31298161, year = {2019}, author = {Bala, A and Panditharadyula, SS}, title = {Role of Nuclear Factor Erythroid 2-Related Factor 2 (NRF-2) Mediated Antioxidant Response on the Synergistic Antitumor Effect of L-Arginine and 5-Fluro Uracil (5FU) in Breast Adenocarcinoma.}, journal = {Current pharmaceutical design}, volume = {25}, number = {14}, pages = {1643-1652}, doi = {10.2174/1381612825666190705205155}, pmid = {31298161}, issn = {1873-4286}, mesh = {Adenocarcinoma/*drug therapy/metabolism ; Animals ; Antioxidants/*metabolism ; Arginine/*pharmacology ; Breast Neoplasms/*drug therapy/metabolism ; Fluorouracil/*pharmacology ; Humans ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Breast adenocarcinoma (BAC) in glandular tissue cells have excessive metastasis and invasion capability. The major challenges for the chemotherapy used for the management of BAC include chemoresistance and auto-immunosuppression in BAC. The 5-fluro uracil (5-FU) based therapy promotes the immune activation in BAC by targeting the regulatory T cells and myeloid-derived suppressor cells (MDSC). The beneficial effect of the combination of L-Arginine with 5-FU strives to be established in different pre-clinical and clinical conditions and explored in the scientific literature. L-Arginine induces NO production and potentiates the anticancer effect of 5-FU. NO-mediated signaling is regulated by nuclear factor erythroid 2-related factor 2 (NRF-2) mediated antioxidant response. NRF-2 mediated antioxidant mechanism always suppresses the formation of superoxide (O2-) as well as other reactive oxygen species (ROS). Thus the utilization of NO by O2- will be minimum in this combination therapy. The regulatory role of NRF-2 in regulation to Antioxidant Response Element (ARE) mediated cytoprotective gene expression in BAC remains unexplored. The present review summarizes the role of NRF-2 mediated antioxidant response on the synergistic antitumor effect of L-Arginine and 5-FU in BAC. This review brought new insight into the management of BAC and in the same context, a hypothesis is raised on the use of reduced glutathione (GSH) or N-Acetyl Cysteine as it may be an added adjuvant in the combination of 5- FU and L-Arginine for management of BAC.}, }
@article {pmid31949616, year = {2018}, author = {Wang, F and Liu, S and Zhuang, R and Bao, J and Shen, Y and Xi, J and Sun, J and Fang, H}, title = {N,N'-diacetylcystine ameliorates inflammation in experimental non-alcoholic steatohepatitis by regulating nuclear transcription factor kappa B activation.}, journal = {International journal of clinical and experimental pathology}, volume = {11}, number = {11}, pages = {5351-5358}, pmid = {31949616}, issn = {1936-2625}, abstract = {Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases worldwide that has been continuously increasing recently. NAFLD embraces a spectrum of liver histological alterations, ranging from simple steatosis (NAFL) to severe non-alcoholic steatohepatitis (NASH), that is characterized by fat accumulation, lobular inflammation, and ballooning degeneration in the hepatocytes in the absence of alcohol abuse. The innate immune system has an important role in NASH pathogenesis. Among the components of innate immunity, the nuclear factor kappa B (NF-κB) has been closely associated with NASH. N,N'-diacetylcystine (DiNAC), the disulfide dimer of N-acetylcysteine (NAC), is a potent modulator of the immune system. Previous research has confirmed that DiNAC has beneficial effects in liver injury. In this study, we aimed to investigate the effects of DiNAC on high fat diet (HFD)-induced NASH in rats. Male Sprague-Dawley rats were fed with HFD to produce the NASH model and treated with or without DiNAC for 8 weeks. We assessed serum levels of alanine-aminotransferase (ALT), aspartate aminotransferase (AST), inflammatory cytokines, liver histology, and the expression of NF-κB genes in the liver. The results showed that the levels of ALT and AST were significantly increased in the HFD rat model. DiNAC treatment also resulted in a statistically significant reduction of the levels of ALT and AST. Hematoxylin and eosin (H&amp;E) staining revealed that DiNAC alleviated histological injury. Moreover, DiNAC strongly reduced the generation of inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), through NF-κB downregulation. Taken together, these results indicate that DiNAC treatment effectively delayed the progression of NASH by suppressing the expression of NF-κB mRNA in the liver. Our data suggest that DiNAC protects liver injury in HFD-treated NASH rats, which might be a promising drug for the treatment of NASH.}, }
@article {pmid31304253, year = {2018}, author = {Yamada, H and Ono, S and Wada, S and Aoi, W and Park, EY and Nakamura, Y and Sato, K}, title = {Statuses of food-derived glutathione in intestine, blood, and liver of rat.}, journal = {NPJ science of food}, volume = {2}, number = {}, pages = {3}, pmid = {31304253}, issn = {2396-8370}, abstract = {Oral administration of glutathione has been demonstrated to reduce exercise-induced fatigue and improve liver function, although glutathione can be synthesized in the liver. However, little is known about the underlying mechanism of this effect. To address this, the status of food-derived glutathione in the intestine, blood, and liver was examined. Glutathione-1-[13]C or N-acetyl-cysteine-1-[13]C (NAC) was orally administered to rats (50 mg/kg). Food-derived glutathione contents within tissues were estimated by subtracting endogenous glutathione-1-[13]C from the total glutathione-1-[13]C. Food-derived glutathione was present in rat intestines and livers (approximately 60 and 300 μmol/kg, respectively, 120 min after ingestion) in electrochemically reduced form, while all food-derived glutathione in the blood plasma was conjugated with proteins and low-molecular-weight thiol compounds. However, no significant amounts of NAC-derived glutathione were detected in the blood plasma. These findings indicate that food-derived glutathione is directly absorbed in its electrochemically reduced form in the intestine, is then transported in the blood in bound forms, and is finally deposited into the liver in reduced form. Therefore, upon entering the bloodstream, food-derived glutathione binds to thiol compounds and releases hydrogen atom; subsequently, it does the reverse upon incorporation into the liver, which might impact the physiological redox condition. With respect to food-derived glutathione and cysteine-containing peptides, this study provides new insights on their modes of transportation and mechanisms of action.}, }
@article {pmid32634177, year = {2018}, author = {Leon, M and Sawmiller, D and Shytle, RD and Tan, J}, title = {Therapeutic Cocktail Approach for Treatment of Hyperhomocysteinemia in Alzheimer's Disease.}, journal = {Cell medicine}, volume = {10}, number = {}, pages = {2155179017722280}, pmid = {32634177}, issn = {2155-1790}, abstract = {In the United States, Alzheimer's disease (AD) is the most common cause of dementia, accompanied by substantial economic and emotional costs. During 2015, more than 15 million family members who provided care to AD patients had an estimated total cost of 221 billion dollars. Recent studies have shown that elevated total plasma levels of homocysteine (tHcy), a condition known as hyperhomocysteinemia (HHcy), is a risk factor for AD. HHcy is associated with cognitive decline, brain atrophy, and dementia; enhances the vulnerability of neurons to oxidative injury; and damages the blood-brain barrier. Many therapeutic supplements containing vitamin B12 and folate have been studied to help decrease tHcy to a certain degree. However, a therapeutic cocktail approach with 5-methyltetrahydrofolate, methyl B12, betaine, and N-acetylcysteine (NAC) have not been studied. This novel approach may help target multiple pathways simultaneously to decrease tHcy and its toxicity substantially.}, }
@article {pmid31618189, year = {2017}, author = {Bozkurt, I and Sharma, A and Esen, S}, title = {Colistin-induced nephrotoxicity and the role of N-acetylcysteine: a retrospective cohort study.}, journal = {Journal of infection in developing countries}, volume = {11}, number = {11}, pages = {895-899}, doi = {10.3855/jidc.9459}, pmid = {31618189}, issn = {1972-2680}, abstract = {INTRODUCTION: Colistin is associated with dose-dependent nephrotoxicity. N-acetylcycteine (NAC) may reduce the risk of concomitant acute kidney injury (AKI) due to its antioxidant properties. We report a retrospective cohort study evaluating the role of N-acetylcysteine (NAC) in the development of colistin (COL) associated nephrotoxicity.<br><br>METHODOLOGY: A single centre retrospective cohort study was conducted in a university hospital between January 2014 and June 2015. Nephrotoxicity was defined and staged per the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria. We evaluated the association between NAC use and COL-related nephrotoxicity by comparing the incidence of nephrotoxicity in patients receiving colistin with or without adjunctive NAC.<br><br>RESULTS: Forty-six patients received intravenous (IV) COL and 46 patients received IV NAC+COL. The cumulative COL doses did not differ between the two groups (p = 0.802). The initial creatinine value doubled in 29 (63%) patients undergoing NAC+COL therapy and in 27 (58.7%) patients in the COL group (p = 0.669). The median doubling time of baseline creatinine was 6 and 7 days in the NAC+COL and COL groups, respectively. The mean hospital stay, potentially nephrotoxic agent use, and mortality rates were statistically higher for the patients receiving NAC+COL (p < 0.005).<br><br>CONCLUSIONS: The present study was not able to reveal any beneficial effect of NAC for patients undergoing COL therapy. The NAC+COL group had a higher baseline risk for development of AKI. However, the incidence of AKI was comparable between the groups. The results of the study would not solely exhibit the protective effect of adjunctive NAC therapy.}, }
@article {pmid31966503, year = {2017}, author = {Wang, Y and Xie, Y and Ma, J and Gong, R and Yan, Z and Wang, W and Wang, Y and Xu, B and Li, X}, title = {Lovastatin induces apoptosis of HepG-2 cells by activating ROS-dependent mitochondrial and ER stress pathways.}, journal = {International journal of clinical and experimental pathology}, volume = {10}, number = {12}, pages = {11480-11488}, pmid = {31966503}, issn = {1936-2625}, abstract = {BACKGROUND: Statins can reduce the malignancies through stimulating apoptosis. We aimed to elucidate the role of lovastatin in HepG-2 cells.<br><br>METHODS: HepG-2 and non-tumor L-O2 cells were used as the cell models. CCK-8, flow cytometric analysis and carboxy fluorescein diacetate succinimidyl ester (CFDA-SE) labeling were performed to monitor the viability, apoptosis and proliferation.<br><br>RESULTS: We found that lovastatin exerted the most tumor suppressing effects on liver cancer cells among the three tested statins. Lovastatin treatment significantly reduced cell viability and proliferation, and induced apoptosis in HepG-2. However, drug resistance effects were observed in the non-tumor L-O2 cells. The apoptosis triggered by lovastatin was accompanied by high intracellular levels of ROS. Pretreatment with the ROS blocker N-acetyl-cysteine (NAC) could mitigate the lovastatin-induced cytotoxicity in HepG-2 cells. Mechanistically, lovastatin increased HepG-2 cell apoptosis by triggering mitochondrial and endoplasmic reticulum (ER) stress pathways through ROS accumulation.<br><br>CONCLUSIONS: Lovastatin significantly induced cell apoptosis by activating ROS-dependent mitochondrial and ER stress pathways in HepG-2 cells.}, }
@article {pmid32625481, year = {2017}, author = {,  and Turck, D and Bresson, JL and Burlingame, B and Dean, T and Fairweather-Tait, S and Heinonen, M and Hirsch-Ernst, KI and Mangelsdorf, I and McArdle, HJ and Naska, A and Neuhäuser-Berthold, M and Nowicka, G and Pentieva, K and Sanz, Y and Sjödin, A and Stern, M and Tomé, D and Van Loveren, H and Vinceti, M and Willatts, P and Martin, A and Strain, JJ and Siani, A}, title = {Condensyl[®] and decreases sperm DNA damage which is a risk factor for male infertility: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006.}, journal = {EFSA journal. European Food Safety Authority}, volume = {15}, number = {5}, pages = {e04775}, pmid = {32625481}, issn = {1831-4732}, abstract = {Following an application from Laboratoire Nurilia submitted for authorisation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006 via the Competent Authority of France, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to 'Condensyl[®] and decreases sperm DNA damage. High sperm DNA damage is a risk factor for male subfertility/infertility'. Condensyl[®] is a fixed combination of opuntia fruit dry extract, N-acetyl cysteine, zinc, nicotinamide, vitamins B2, B6, B12 and E, and folic acid. The Panel considers that Condensyl[®] is sufficiently characterised. The Panel assumes that the disease that is the subject of the application is male infertility and that the target population for the claim includes males wishing to increase their fertility but excludes males with clinical infertility. The Panel considers that the reduction of DNA sperm damage is a beneficial physiological effect in the context of reducing the risk of male infertility. The applicant provided four human intervention studies conducted in males with clinical infertility, from which no conclusions could be drawn for the scientific substantiation of the claim. The Panel concludes that a cause and effect relationship has not been established between the consumption of Condensyl[®] and reduction of DNA sperm damage in the context of reducing the risk of male infertility.}, }
@article {pmid31719857, year = {2017}, author = {Plein, T and Thiebes, AL and Finocchiaro, N and Hesselmann, F and Schmitz-Rode, T and Jockenhoevel, S and Cornelissen, CG}, title = {Towards a Biohybrid Lung Assist Device: N-Acetylcysteine Reduces Oxygen Toxicity and Changes Endothelial Cells' Morphology.}, journal = {Cellular and molecular bioengineering}, volume = {10}, number = {2}, pages = {153-161}, pmid = {31719857}, issn = {1865-5025}, support = {P30 DK020595/DK/NIDDK NIH HHS/United States ; }, abstract = {The development of an endothelialized membrane oxygenator requires solution strategies combining the knowledge of oxygenators with endothelial cells' biology. Since it is well known that exposing cells towards pure oxygen causes oxidative stress, this aspect has to be taken into account in the development of a biohybrid oxygenator system. N-Acetylcysteine (NAC) is known for its antioxidant properties in cells. We tested its applicability for the development of an endothelialized oxygenator model. Cultivating human umbilical vein derived endothelial cells (HUVEC) up to 6 days with increasing concentrations of NAC from 1 to 30 mM revealed NAC toxicity at concentrations from 20 mM. Cell density clearly decreased after radical oxygen species exposure in non-NAC pretreated cells compared to 20 mM NAC precultured HUVEC after 3 and 6 days. Also the survival rate after ROS treatment could be restored by incubation with NAC from 15 to 25 mM for all time points. NAC treated cells changed their morphology from typical endothelial cells' cobblestone pattern to a fusiform, elongated configuration. Transformed cells were still positive for typical endothelial cell markers. Our present results show the potential of NAC for the protection of an endothelial cell layer in an endothelialized membrane oxygenator due to its antioxidative properties. Moreover, NAC induces a morphological change in HUVEC similar to dynamic cultivation procedures.}, }
@article {pmid32262475, year = {2015}, author = {Zhu, L and Zhang, J and Xiao, L and Liu, S and Yu, J and Chen, W and Zhang, X and Peng, B}, title = {Autophagy in resin monomer-initiated toxicity of dental mesenchymal cells: a novel therapeutic target of N-acetyl cysteine.}, journal = {Journal of materials chemistry. B}, volume = {3}, number = {33}, pages = {6820-6836}, doi = {10.1039/c5tb00894h}, pmid = {32262475}, issn = {2050-7518}, abstract = {Dental restorative biomaterials are commonly used to restore the teeth impaired by caries, erosion, or fracture. Resin monomers released from polymerized restorative composite materials could disturb cell viability and cause toxicity of oral eukaryotic cells, which remains a medical challenge. However, the intracellular processes or underlying mechanisms of resin monomer-mediated toxicity and the potential preventive/therapeutic strategy are still far from clear. The present study aimed to determine the role of autophagy in resin monomer triethylene glycol dimethacrylate (TEGDMA)-induced cytotoxicity and explore autophagy as a potential therapeutic target of anti-oxidant N-acetyl cysteine (NAC) in vitro and ex vivo. The results showed that TEGDMA exposure resulted in several specific features of autophagy in human dental mesenchymal cells (DMCs), including the formation of acidic vesicular organelles, appearance of autophagic vacuoles, and LC3-II accumulation. By pharmacological and genetic approaches, the inhibition of autophagy significantly prevented TEGDMA-induced apoptosis in DMCs. Moreover, the autophagy activated by TEGDMA occurred via the AMPK/mTOR pathway, which could be abrogated by NAC pretreatment. More importantly, the tooth slice organ culture model provided further evidence of autophagy involvement in TEGDMA-triggered dental mesenchymal tissue toxicity and as a therapeutic target of NAC ex vivo. Our findings provide novel insights into the mechanisms of resin monomer-mediated toxicity and highlight autophagy as a promising therapeutic target of NAC for improving dental restorative biomaterials that enable dental tissue protection.}, }
@article {pmid32261862, year = {2014}, author = {Ray, C and Dutta, S and Sarkar, S and Sahoo, R and Roy, A and Pal, T}, title = {Intrinsic peroxidase-like activity of mesoporous nickel oxide for selective cysteine sensing.}, journal = {Journal of materials chemistry. B}, volume = {2}, number = {36}, pages = {6097-6105}, doi = {10.1039/c4tb00968a}, pmid = {32261862}, issn = {2050-7518}, abstract = {Mesoporous nickel oxide nanoflowers (NiO NFs) can be easily synthesized by a two-step synthetic procedure based on modified hydrothermal (MHT) treatment of nickel acetate and ethanol amine in water followed by thermal decomposition at 350 °C for 4 h. After thermal treatment, the porosity is increased by 18% with retention of parental nickel hydroxide size. In this study, for the first time, a new catalytic application of NiO NFs has been revealed in terms of peroxidase-like activity where colorless 3,3',5,5' tetramethylbenzidine (TMB) is oxidized to blue color product in the presence of H2O2 at room temperature. Comparative study confirms that mesoporous NiO NFs exhibit superior catalytic activity to the parent analogues, i.e. Ni(OH)2 or bulk NiO. This intrinsic peroxidase-like activity from an easily synthesized inorganic nanomaterial provides an alternative to horseradish peroxidase (HRP) enzyme. The lower Michaelis constant (Km) value indicates that the catalyst NiO NFs bind efficiently to the test substrate, i.e. TMB. Interestingly, the NiO NFs-catalyzed TMB oxidation, i.e. blue color formation, has been found to be selectively and successively inhibited by a variable amount of cysteine among a set of 21 congeners. Thus our adopted simple, low-cost and novel colorimetric assay stands to be a highly efficient approach for selective detection of cysteine with a limit of detection (LOD) value of ∼1.1 μM using a simple UV-vis spectrophotometer. The proposed method also exhibits outstanding selectivity and accuracy for N-acetyl cysteine (an analogue of cysteine) estimation in real pharmaceutical samples.}, }
@article {pmid32288656, year = {2006}, author = {Tesfaigzi, Y and Meek, P and Lareau, S}, title = {Exacerbations of chronic obstructive pulmonary disease and chronic mucus hypersecretion.}, journal = {Clinical and applied immunology reviews}, volume = {6}, number = {1}, pages = {21-36}, pmid = {32288656}, issn = {1529-1049}, support = {R01 ES009237/ES/NIEHS NIH HHS/United States ; R01 HL068111/HL/NHLBI NIH HHS/United States ; R56 HL068111/HL/NHLBI NIH HHS/United States ; }, abstract = {Chronic obstructive pulmonary disease (COPD) exacerbations are an important cause of the considerable morbidity and mortality found in COPD. COPD exacerbations increase with increasing severity of COPD, and some patients are prone to frequent exacerbations leading to hospital admission and readmission. These frequent exacerbations may have considerable impact on quality of life and activities of daily living. Factors that increase the risk for COPD exacerbations are associated with increased airway inflammation caused by common pollutants and bacterial and/or viral infections. These inflammatory responses cause mucus hypersecretion and, thereby, airway obstruction and associated exacerbations. While chronic mucus hypersecretion is a significant risk factor for frequent and severe exacerbations, patients with chronic mucus hypersecretion have a lower rate of relapse after initial treatment for acute exacerbation. The benefit of antibiotics for treatment of COPD exacerbations is small but significant. While the mechanisms of actions are not clear, mucolytic agents reduce the number of days of disability in subjects with exacerbations. Reducing mucous cell numbers in small airways could be a useful way to reduce chronic mucus hypersecretion. Our studies suggest that programmed cell death is crucial in the resolution of metaplastic mucous cells, and understanding these mechanisms may provide novel therapies to reduce the risk of COPD exacerbations.}, }
@article {pmid32688959, year = {2004}, author = {Desikan, R and Cheung, MK and Clarke, A and Golding, S and Sagi, M and Fluhr, R and Rock, C and Hancock, J and Neill, S}, title = {Hydrogen peroxide is a common signal for darkness- and ABA-induced stomatal closure in Pisum sativum.}, journal = {Functional plant biology : FPB}, volume = {31}, number = {9}, pages = {913-920}, doi = {10.1071/FP04035}, pmid = {32688959}, issn = {1445-4416}, abstract = {The requirement for hydrogen peroxide (H2O2) generation and action during stomatal closure induced by darkness and abscisic acid (ABA) was investigated in pea (Pisum sativum L.). Stomatal closure induced by darkness or ABA was inhibited by the H2O2-scavenging enzyme catalase or the antioxidant N-acetyl cysteine (NAC), or by diphenylene iodonium (DPI), an inhibitor of the H2O2-generating enzyme NADPH oxidase. Exogenous H2O2 induced stomatal closure in a dose- and time-dependent manner, and H2O2 was also required for ABA-inhibition of stomatal opening in the light. H2O2 accumulation in guard cells was increased by darkness or ABA, as assessed with the fluorescent dye dichlorodihydrofluorescein diacetate (H2-DCFDA) and confocal microscopy. Such increases were inhibited by catalase, NAC or DPI, consistent with the effects of these compounds on stomatal apertures. Employing polymerase chain reaction (PCR) with degenerate oligonucleotide primers, several NADPH oxidase homologues were identified from pea genomic DNA that had substantial identity to the Arabidopsis thaliana (L.) Heynh. rboh (respiratory burst oxidase homologue) genes. Furthermore, an antibody raised against the tomato rboh identified immunoreactive proteins in epidermal, mesophyll and guard cells.}, }
@article {pmid31293646, year = {2019}, author = {Zhou, Z and Xu, J and Bao, X and Shi, J and Liu, B and Chen, Y and Li, J}, title = {Nuclear Nrf2 Activity in Laryngeal Carcinoma is Regulated by SENP3 After Cisplatin-Induced Reactive Oxygen Species Stress.}, journal = {Journal of Cancer}, volume = {10}, number = {15}, pages = {3427-3434}, pmid = {31293646}, issn = {1837-9664}, abstract = {Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor that is activated by reactive oxygen species (ROS). Recent studies reported that hyperactivation of the Nrf2 pathway creates an environment that favors the survival of normal as well as malignant cells, protecting them against oxidative stress, chemotherapeutic agents, and radiotherapy. SUMO1/sentrin/SMT3 specific peptidase 3 (SENP3) reverses sumoylation of small ubiquitin-like modifier (SUMO)-conjugates. We demonstrated that Nrf2 was detected in the nuclei of laryngeal carcinoma cells, but not in cells of tissues surrounding the cancer, which correlated with the appearance of SENP3 in the nuclei. Silencing of Nrf2 in laryngeal carcinoma cell line Hep-2 significantly reduced cell viability and enhanced apoptosis rates under cisplatin, 5-fluorouracil (5-FU) and phenethyl isothiocyanate (PEITC) exposure. Cisplatin exposure induced ROS stress in Hep-2 cells in a time-dependent manner and was accompanied by increased Nrf2 and SENP3 protein accumulations, an effect reversed by the addition of the antioxidant N-acetyl-cysteine (NAC). Silencing of SENP3 led to reduced Nrf2 protein levels, whereas overexpression of SENP3 led to concomitant enhanced transcription of the Nrf2 target genes HO-1, NQO1, GCLC and GSTM1. Immunoprecipitation showed that overexpressed Nrf2 and SENP3 could be precipitated together, indicating that they were intracellular bound to each other. Our data identified intranuclear activation of Nrf2 is triggered by cisplatin-induced ROS development through the activity of SENP3. These findings provide novel insights into the Nrf2 reduced cancer cell response to the chemotherapy of laryngeal carcinoma.}, }
@article {pmid31289608, year = {2019}, author = {Zhang, Q and Jiang, L and Yu, J and Tian, L and Guo, T and Di, B and Quan, J and Feng, J and Liu, J}, title = {Palmitate up-regulates laminin expression via ROS/integrin αvβ3 pathway in HLSECs.}, journal = {Oncotarget}, volume = {10}, number = {41}, pages = {4083-4090}, pmid = {31289608}, issn = {1949-2553}, abstract = {AIMS/INTRODUCTION: To investigate the roles of reactive oxygen species (ROS) and integrin αvβ3 in palmitate-induced laminin expression of human liver sinusoidal endothelial cells (HLSECs).<br><br>RESULTS: The protein expression of integrin &#x3b1;v, integrin &#x3b2;3 and laminin are increased by palmitate in HLSECs in a time- and dose-dependent manner. NAC, the ROS inhibitor, significantly inhibited the up-regulation of protein expression of integrin &#x3b1;v, integrin &#x3b2;3 and laminin by palmitate (P < 0.05). Palmitate markedly enhanced ROS formation (P < 0.05), which was not inhibited by LM609, the antibody of integrin &#x3b1;v&#x3b2;3. Palmitate significantly increased laminin synthesis (P < 0.05), which was attenuated by LM609 and NAC (P < 0.05).<br><br>MATERIALS AND METHODS: HLSECs were treated with palmitate in the presence or absence of LM609 (10 &#x3bc;g/ml) or N-acetylcysteine (NAC) (2 mM). Expression of integrin &#x3b1;v, integrin &#x3b2;3 and laminin were measured by RT-PCR and Western blot. Immunocytochemistry were used for examining laminin expression. The generation of ROS was measured using the fluorescent signal 2',7' dichloro-fluorescein diacetate (DCFH-DA).<br><br>CONCLUSIONS: The results suggested that palmitate increases laminin expression through ROS/integrin &#x3b1;v/&#x3b2;3 pathway.}, }
@article {pmid31288199, year = {2019}, author = {Mlejnek, P and Dolezel, P and Maier, V and Kikalova, K and Skoupa, N}, title = {N-acetylcysteine dual and antagonistic effect on cadmium cytotoxicity in human leukemia cells.}, journal = {Environmental toxicology and pharmacology}, volume = {71}, number = {}, pages = {103213}, doi = {10.1016/j.etap.2019.103213}, pmid = {31288199}, issn = {1872-7077}, mesh = {Acetylcysteine/*pharmacology ; Cadmium/*toxicity ; Cell Survival/drug effects ; Chelating Agents/*pharmacology ; Dose-Response Relationship, Drug ; Environmental Pollutants/*toxicity ; Humans ; K562 Cells ; Reactive Oxygen Species/metabolism ; U937 Cells ; }, abstract = {Although cadmium (Cd[2+]) is unable to form reactive oxygen species (ROS) directly, many of its adverse effects are connected to increased ROS generation resulting in cell death. In support of this supposition, a large number of studies have shown protective effects of antioxidants such as N-acetylcysteine (NAC) against cadmium induced cytotoxicity. Here, we describe the cytotoxic effects of Cd[2+] on human leukemia U937 and K562 cells that were not mediated by oxidative stress. Surprisingly, we observed that addition of low concentrations of NAC can drastically potentiate cadmium cytotoxicity solely via ROS production. However, all adverse effects of the metal were prevented by NAC at high concentrations. Detailed analysis indicated that the protective effect of NAC was mediated by its ability to form stable complex with cadmium [Cd(NAC)2]. In conclusion, NAC exhibits dual and antagonistic effects on Cd[2+] cytotoxicity in human leukemia cells.}, }
@article {pmid31288160, year = {2019}, author = {Nakamura, T and Murata, Y and Nakamura, Y}, title = {Characterization of benzyl isothiocyanate extracted from mashed green papaya by distillation.}, journal = {Food chemistry}, volume = {299}, number = {}, pages = {125118}, doi = {10.1016/j.foodchem.2019.125118}, pmid = {31288160}, issn = {1873-7072}, mesh = {Acetylcysteine/chemistry ; Carica/*chemistry ; Cysteine/*chemistry ; Distillation ; Drug Stability ; Drug Storage ; Excipients/chemistry ; Freezing ; Glutathione/chemistry ; Isothiocyanates/chemistry/*isolation &amp; purification ; Plant Extracts/chemistry/*isolation &amp; purification ; Reproducibility of Results ; }, abstract = {The aim of this study was to extract benzyl isothiocyanate (BITC) from green papaya by distillation apparatus without using organic solvents, and to improve the stability of BITC in aqueous solution. The distillation of mashed green papaya successfully yielded BITC as a water solution with more than 80% purity with good reproducibility. The amount of BITC in the distilled water gradually decreased during its storage at 4 °C, whereas it was not significantly changed at -20 °C for a few months. Moreover, the addition of l-cysteine ameliorated the BITC decomposition by the 4 °C-storage, but not affected by N-acetyl-cysteine and glutathione. These results suggested that the combination of BITC extraction by distillation and cysteine supplementation as well as frozen storage might be a useful method for the preparation and storage of the safer grade of BITC-containing extract.}, }
@article {pmid31285782, year = {2019}, author = {Kim, JS and Jeong, K and Murphy, JM and Rodriguez, YAR and Lim, SS}, title = {A Quantitative Method to Measure Low Levels of ROS in Nonphagocytic Cells by Using a Chemiluminescent Imaging System.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {1754593}, pmid = {31285782}, issn = {1942-0994}, support = {R01 HL136432/HL/NHLBI NIH HHS/United States ; S10 RR027535/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Boron Compounds/pharmacology ; Focal Adhesion Kinase 1/metabolism ; HT29 Cells ; Humans ; Immunoblotting ; Iodobenzenes/pharmacology ; Onium Compounds/pharmacology ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Chemiluminescence (CL) is one of the most useful methods for detecting reactive oxygen species (ROS). Although fluorescence dyes or genetically encoded biosensors have been developed, CL is still used due to its high sensitivity, ease of use, and low cost. While initially established and used to measure high levels of ROS in phagocytic cells, CL assays are not ideal for measuring low levels of ROS. Here, we developed a newly modified CL assay using a chemiluminescent imaging system for measuring low concentrations of ROS in nonphagocytic cells. We found that dissolving luminol in NaOH, rather than DMSO, increased the H2O2-induced CL signal and that the addition of 4-iodophenylboronic acid (4IPBA) further increased CL intensity. Our new system also increased the rate and intensity of the CL signal in phorbol 12-myristate 13-acetate- (PMA-) treated HT-29 colon cancer cells compared to those in luminol only. We were able to quantify ROS levels from both cells and media in parallel using an H2O2 standard. A significant benefit to our system is that we can easily measure stimulus-induced ROS formation in a real-time manner and also investigate intracellular signaling pathways from a single sample simultaneously. We found that PMA induced tyrosine phosphorylation of protein tyrosine kinases (PTKs), such as focal adhesion kinase (FAK), protein tyrosine kinase 2 (Pyk2), and Src, and increased actin stress fiber formation in a ROS-dependent manner. Interestingly, treatment with either N-acetyl-L-cysteine (NAC) or diphenyleneiodonium (DPI) reduced the PMA-stimulated phosphorylation of these PTKs, implicating a potential role in cellular ROS signaling. Thus, our newly optimized CL assay using 4IPBA and a chemiluminescent imaging method provides a simple, real-time, and low-cost method for the quantification of low levels of ROS.}, }
@article {pmid31284671, year = {2019}, author = {Borowczyk, K and Olejarz, P and Kamińska, A and Głowacki, R and Chwatko, G}, title = {Application of Butylamine as a Conjugative Reagent to On-Column Derivatization for the Determination of Antioxidant Amino Acids in Brain Tissue, Plasma, and Urine Samples.}, journal = {International journal of molecular sciences}, volume = {20}, number = {13}, pages = {}, pmid = {31284671}, issn = {1422-0067}, support = {2016/23/N/NZ9/00071//Narodowe Centrum Nauki/ ; B1811100000234.01//Uniwersytet &#x141;&#xf3;dzki/ ; B1811100000234.01//Uniwersytet &#x141;&#xf3;dzki/ ; }, mesh = {Acetylcysteine/urine ; Adult ; Amino Acids/*blood/*urine ; Animals ; Antioxidants/*analysis ; Brain/*metabolism ; Butylamines/*chemistry ; Calibration ; Disulfides/chemistry ; Glutathione/analysis ; Humans ; Indicators and Reagents ; Limit of Detection ; Middle Aged ; Reproducibility of Results ; Swine ; o-Phthalaldehyde/chemistry ; }, abstract = {(1) Antioxidants are involved in body protection mechanisms against reactive oxygen species. Amino acids such as glutathione (GSH) and N-acetylcysteine (NAC) are known to be involved in providing protection against oxidative lethality. A quick and simple method for the determination of NAC and GSH in various biological matrices such as urine, plasma, and homogenates of brain tissues has been developed and described in this work. (2) The assay is based on reversed phase high performance liquid chromatography with spectrofluorimetric detection and on-column derivatization. Butylamine and o-phthaldialdehyde have been used as derivatization reagents. Since o-phthaldialdehyde constitutes a part of the mobile phase, the derivatization reaction and chromatographic separation occur simultaneously. (3) Linearity in the detector response for NAC in human urine was observed in the range of 5-200 nmol mL[-1], and NAC and GSH in the brain tissue homogenates were observed in the range of 0.5-5 nmol mL[-1] and 0.5-15 nmol mL[-1], respectively. Human plasma linearity ranges covered 0.25-5.00 nmol mL[-1] and 0.5-15 nmol mL[-1] for NAC and GSH, respectively. The LODs for NAC and GSH were 0.01 and 0.02 nmol mL[-1] while the LOQs were 0.02 and 0.05 nmol mL[-1], respectively. The usefulness of the proposed method was proven through its application to real samples.}, }
@article {pmid31283822, year = {2019}, author = {Mullier, E and Roine, T and Griffa, A and Xin, L and Baumann, PS and Klauser, P and Cleusix, M and Jenni, R and Alemàn-Gómez, Y and Gruetter, R and Conus, P and Do, KQ and Hagmann, P}, title = {N-Acetyl-Cysteine Supplementation Improves Functional Connectivity Within the Cingulate Cortex in Early Psychosis: A Pilot Study.}, journal = {The international journal of neuropsychopharmacology}, volume = {22}, number = {8}, pages = {478-487}, pmid = {31283822}, issn = {1469-5111}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Antioxidants/adverse effects/*therapeutic use ; Brain Mapping/methods ; *Dietary Supplements/adverse effects ; Double-Blind Method ; Europe ; Female ; Glutathione/metabolism ; Gyrus Cinguli/diagnostic imaging/*drug effects/metabolism/physiopathology ; Humans ; Magnetic Resonance Imaging ; Male ; Oxidative Stress/*drug effects ; Pilot Projects ; Psychotic Disorders/diagnosis/*drug therapy/metabolism/psychology ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: There is increasing evidence that redox dysregulation, which can lead to oxidative stress and eventually to impairment of oligodendrocytes and parvalbumin interneurons, may underlie brain connectivity alterations in schizophrenia. Accordingly, we previously reported that levels of brain antioxidant glutathione in the medial prefrontal cortex were positively correlated with increased functional connectivity along the cingulum bundle in healthy controls but not in early psychosis patients. In a recent randomized controlled trial, we observed that 6-month supplementation with a glutathione precursor, N-acetyl-cysteine, increased brain glutathione levels and improved symptomatic expression and processing speed.<br><br>METHODS: We investigated the effect of N-acetyl-cysteine supplementation on the functional connectivity between regions of the cingulate cortex, which have been linked to positive symptoms and processing speed decline. In this pilot study, we compared structural connectivity and resting-state functional connectivity between early psychosis patients treated with 6-month N-acetyl-cysteine (n&#x2009;=&#x2009;9) or placebo (n&#x2009;=&#x2009;11) supplementation with sex- and age-matched healthy control subjects (n&#x2009;=&#x2009;74).<br><br>RESULTS: We observed that 6-month N-acetyl-cysteine supplementation increases functional connectivity along the cingulum and more precisely between the caudal anterior part and the isthmus of the cingulate cortex. These functional changes can be partially explained by an increase of centrality of these regions in the functional brain network.<br><br>CONCLUSIONS: N-acetyl-cysteine supplementation has a positive effect on functional connectivity within the cingulate cortex in early psychosis patients. To our knowledge, this is the first study suggesting that increased brain glutathione levels via N-acetyl-cysteine supplementation may improve brain functional connectivity.}, }
@article {pmid31282090, year = {2020}, author = {Garcia-Keller, C and Smiley, C and Monforton, C and Melton, S and Kalivas, PW and Gass, J}, title = {N-Acetylcysteine treatment during acute stress prevents stress-induced augmentation of addictive drug use and relapse.}, journal = {Addiction biology}, volume = {25}, number = {5}, pages = {e12798}, pmid = {31282090}, issn = {1369-1600}, support = {I01 BX004727/BX/BLRD VA/United States ; K99 DA047426/DA/NIDA NIH HHS/United States ; R00 DA047426/DA/NIDA NIH HHS/United States ; R01 AA024526/AA/NIAAA NIH HHS/United States ; U01 DA045300/DA/NIDA NIH HHS/United States ; P50 DA046373/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Alcohol-Related Disorders/*complications/*psychology ; Animals ; Cocaine/administration &amp; dosage ; Cocaine-Related Disorders/*complications/*psychology ; Cues ; Disease Models, Animal ; Drug-Seeking Behavior/drug effects ; Ethanol/administration &amp; dosage ; Free Radical Scavengers/pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Recurrence ; Self Administration ; Stress, Psychological/*complications/psychology ; }, abstract = {Converging epidemiological studies show that a life-threatening event increases the incidence of posttraumatic stress disorder (PTSD), which carries 30% to 50% comorbidity with substance use disorders (SUDs). Such comorbidity results in greater drug use and poorer treatment outcomes. There is overlap between the enduring synaptic neuroadaptations produced in nucleus accumbens core (NAcore) by acute restraint stress and cocaine self-administration. Because of these coincident neuroadaptations, we hypothesized that an odor paired with acute restraint stress would reinstate drug seeking and chose two mechanistically distinct drugs of abuse to test this hypothesis: alcohol and cocaine. Rats were trained to self-administer either drug beginning 3 weeks after odor pairing with acute stress or sham, and acute restraint stress increased alcohol consumption. Following context extinction training, the stress-paired odor reinstated both alcohol and cocaine seeking, while an unpaired odor had no effect. N-Acetylcysteine (NAC) restores drug and stress-induced reductions in glial glutamate transporter-1 and has proven effective at reducing cue-induced reinstatement of drug seeking. We administered NAC for 5 days prior to reinstatement testing and abolished the capacity of the stress-paired odor to increase alcohol and cocaine seeking. Importantly, daily NAC given during or just following experiencing acute restraint stress also prevented the capacity of stress-paired odors to reinstate alcohol and cocaine seeking and prevented stress-induced deficits in behavioral flexibility. These data support using daily NAC treatment during or immediately after experiencing a strong acute stress to prevent subsequent conditioned stress responding, in particular relapse and cognitive deficits induced by stress-conditioned stimuli.}, }
@article {pmid31281581, year = {2019}, author = {Shen, M and Hu, Y and Yang, Y and Wang, L and Yang, X and Wang, B and Huang, M}, title = {Betulinic Acid Induces ROS-Dependent Apoptosis and S-Phase Arrest by Inhibiting the NF-κB Pathway in Human Multiple Myeloma.}, journal = {Oxidative medicine and cellular longevity}, volume = {2019}, number = {}, pages = {5083158}, pmid = {31281581}, issn = {1942-0994}, mesh = {Animals ; Apoptosis ; Cell Cycle Checkpoints ; Humans ; Mice ; Mice, Nude ; Multiple Myeloma/*drug therapy/genetics/pathology ; NF-kappa B/*metabolism ; Pentacyclic Triterpenes ; Reactive Oxygen Species ; Triterpenes/pharmacology/*therapeutic use ; Xenograft Model Antitumor Assays ; Betulinic Acid ; }, abstract = {Betulinic acid (BA), as a prospective natural compound, shows outstanding antitumor bioactivities against many solid malignancies. However, its mechanism against multiple myeloma (MM) remains elusive. Herein, for the first time, we studied the antitumor activity of BA against MM both in vivo and in vitro. We showed that BA mediated cytotoxicity in MM cells through apoptosis, S-phase arrest, mitochondrial membrane potential (MMP) collapse, and overwhelming reactive oxygen species (ROS) accumulation. Moreover, when the ROS scavenger N-acetyl cysteine (NAC) effectively abated elevated ROS, the BA-induced apoptosis was partially reversed. Our results revealed that BA-mediated ROS overproduction played a pivotal role in anticancer activity. Molecularly, we found that BA resulted in marked inhibition of the aberrantly activated NF-κB pathway in MM. As demonstrated by using the NF-κB pathway-specific activator TNF-α and the inhibitor BAY 11-7082, BA-mediated inhibition of the NF-κB pathway directly promoted the overproduction of ROS and, ultimately, cell death. Furthermore, BA also exerted enormous tumor-inhibitory effects via repressing proliferation and inhibiting the NF-κB pathway in our xenograft model. Overall, by blocking the NF-κB pathway that breaks redox homeostasis, BA, as a potent NF-κB inhibitor, is a promising therapeutic alternative for MM.}, }
@article {pmid31279279, year = {2019}, author = {Tu, HC and Lin, MY and Lin, CY and Hsiao, TH and Wen, ZH and Chen, BH and Fu, TF}, title = {Supplementation with 5-formyltetrahydrofolate alleviates ultraviolet B-inflicted oxidative damage in folate-deficient zebrafish.}, journal = {Ecotoxicology and environmental safety}, volume = {182}, number = {}, pages = {109380}, doi = {10.1016/j.ecoenv.2019.109380}, pmid = {31279279}, issn = {1090-2414}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Dietary Supplements ; Folic Acid Deficiency/metabolism/*prevention &amp; control ; Larva/drug effects/metabolism ; Leucovorin/*pharmacology ; Oxidative Stress/*drug effects/radiation effects ; Reactive Oxygen Species/metabolism ; Ultraviolet Rays/*adverse effects ; Vitamin B Complex/*pharmacology ; Zebrafish/*metabolism ; }, abstract = {Ultraviolet (UV) is an omnipresent environmental carcinogen transmitted by sunlight. Excessive UV irradiation has been correlated to an increased risk of skin cancers. UVB, the most mutagenic component among the three UV constituents, causes damage mainly through inducing DNA damage and oxidative stress. Therefore, strategies or nutrients that strengthen an individual's resistance to UV-inflicted harmful effects shall be beneficial. Folate is a water-soluble B vitamin essential for nucleotides biosynthesis, and also a strong biological antioxidant, hence a micronutrient with potential of modulating individual's vulnerability to UV exposure. In this study, we investigated the impact of folate status on UV sensitivity and the protective activity of folate supplementation using a zebrafish model. Elevated reactive oxygen species (ROS) level and morphological injury were observed in the larvae exposed to UVB, which were readily rescued by supplementing with folic acid, 5-formyltetrahydrofolate (5-CHO-THF) and N-acetyl-L-cysteine (NAC). The UVB-inflicted abnormalities and mortality were worsened in Tg(hsp:EGFP-γGH) larvae displaying folate deficiency. Intriguingly, only supplementation with 5-CHO-THF, as opposed to folic acid, offered significant and consistent protection against UVB-inflicted oxidative damage in the folate-deficient larvae. We concluded that the intrinsic folate status correlates with the vulnerability to UVB-induced damage in zebrafish larvae. In addition, 5-CHO-THF surpassed both folic acid and NAC in preventing UVB-inflicted oxidative stress and injury in our current experimental zebrafish model.}, }
@article {pmid31278946, year = {2019}, author = {Fatfat, M and Fakhoury, I and Habli, Z and Mismar, R and Gali-Muhtasib, H}, title = {Thymoquinone enhances the anticancer activity of doxorubicin against adult T-cell leukemia in vitro and in vivo through ROS-dependent mechanisms.}, journal = {Life sciences}, volume = {232}, number = {}, pages = {116628}, doi = {10.1016/j.lfs.2019.116628}, pmid = {31278946}, issn = {1879-0631}, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/drug effects ; Benzoquinones/metabolism/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Doxorubicin/pharmacology ; Human T-lymphotropic virus 1 ; Humans ; Leukemia-Lymphoma, Adult T-Cell/*drug therapy/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {AIMS: Adult T-cell leukemia (ATL) is a mature T-cell neoplasm associated with human T-cell lymphotropic virus (HTLV-1) infection. Major limitations in Doxorubicin (Dox) chemotherapy are tumor resistance and severe drug complications. Here, we combined Thymoquinone (TQ) with low concentrations of Dox and determined anticancer effects against ATL in cell culture and animal model.<br><br>MAIN METHODS: HTLV-1 positive (HuT-102) and HTLV-1 negative (Jurkat) CD4+ malignant T-cell lines were treated with TQ, Dox and combinations. Viability and cell cycle effects were determined by MTT assay and flow cytometry analysis, respectively. Combination effects on mitochondrial membrane potential and generation of reactive oxygen species (ROS) were assessed. Expression levels of key cell death proteins were investigated by western blotting. A mouse xenograft model of ATL in NOD/SCID was used for testing drug effects and tumor tissues were stained for Ki67 and TUNEL.<br><br>KEY FINDINGS: TQ and Dox caused greater inhibition of cell viability and increased sub-G1 cells in both cell lines compared to Dox or TQ alone. The combination induced apoptosis by increasing ROS and causing disruption of mitochondrial membrane potential. Pretreatment with N-acetyl cysteine (NAC) or pan caspase inhibitor significantly inhibited the apoptotic response suggesting that cell death is ROS- and caspase-dependent. TQ and Dox combination reduced tumor volume in NOD/SCID mice more significantly than single treatments through enhanced apoptosis without affecting the survival of mice.<br><br>SIGNIFICANCE: Our combination model offers the possibility to use up to twofold lower doses of Dox against ATL while exhibiting the same cancer inhibitory effects.}, }
@article {pmid31278820, year = {2019}, author = {de Sousa, JKT and Haddad, JPA and de Oliveira, AC and Vieira, CD and Dos Santos, SG}, title = {In vitro activity of antimicrobial-impregnated catheters against biofilms formed by KPC-producing Klebsiella pneumoniae.}, journal = {Journal of applied microbiology}, volume = {127}, number = {4}, pages = {1018-1027}, doi = {10.1111/jam.14372}, pmid = {31278820}, issn = {1365-2672}, support = {//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de Minas Gerais/ ; //Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; }, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects/growth &amp; development ; Catheters/*microbiology ; Chlorhexidine/pharmacology ; Drug Resistance, Bacterial ; Klebsiella pneumoniae/*drug effects/physiology ; Levofloxacin/pharmacology ; Silver Sulfadiazine/pharmacology ; Time Factors ; }, abstract = {AIM: To evaluate the activity and effectiveness of impregnated central venous catheters (CVC) against Klebsiella pneumoniae biofilms.<br><br>METHODS AND RESULTS: The antimicrobial activity and durability of impregnated-CVCs were evaluated over time and the size of zones of inhibition (ZI) was measured. Biofilm formation was observed by quantitative culture and also by scanning electron microscopy. The catheters impregnated with chlorhexidine/silver sulfadiazine (CHX/SS) reduced bacteria counts by 0&#xb7;3 log and were most effective (P&#xa0;<&#xa0;0&#xb7;01) against Klebsiella pneumoniae biofilms N-acetylcysteine/levofloxacin (NAC/LEV) catheters. It was observed that the catheter impregnated with NAC/LEV had initially the largest average ZI size being statistically significant (P&#xa0;<&#xa0;0&#xb7;01). The NAC/LEV combination remained active until day 30, whereas the combination of CHX/SS was completely inactivated from day 15 on.<br><br>CONCLUSIONS: The NAC/LEV combination showed greater durability on the catheters, but it was the CHX/SS combination that had the greater initial efficacy in bacterial inhibition. It was also observed that NAC/LEV-impregnated catheters do not prevent the emergence of resistant subpopulations inside the inhibition halos during antimicrobial susceptibility tests.<br><br>Our results highlighted that the in vitro efficacy of antimicrobial-impregnated CVCs is limited by time and that their colonization occurred earlier than expected. Our data also demonstrated that NAC/LEV remained active until day 30 of evaluation and CHX/SS combination was completely inactivated from day 15 on. Our findings suggested that implantable devices should be carefully used by medical community.}, }
@article {pmid31275528, year = {2019}, author = {Al-Kamel, A and Baraniya, D and Al-Hajj, WA and Halboub, E and Abdulrab, S and Chen, T and Al-Hebshi, NN}, title = {Subgingival microbiome of experimental gingivitis: shifts associated with the use of chlorhexidine and N-acetyl cysteine mouthwashes.}, journal = {Journal of oral microbiology}, volume = {11}, number = {1}, pages = {1608141}, pmid = {31275528}, issn = {2000-2297}, abstract = {This study aimed to demonstrate subgingival microbial changes associated with development, prevention, and treatment of experimental gingivitis using chlorhexidine (CHX) and N-acetylcysteine (NAC) mouthwashes. This randomized clinical trial comprised two parts: a 3-week prevention sub-study in which 30 study subjects were equally assigned to either mouthwash or placebo while developing experimental gingivitis; followed by a 2-week treatment sub-study in which 20 subjects with experimental gingivitis were assigned to either mouthwash. Subgingival samples were collected at the beginning and end of each sub-study for microbial profiling with 16S rRNA gene sequencing. As expected, CHX was effective in both preventing and reversing experimental gingivitis; NAC had a modest effect. Gingivitis was associated with enrichment of TM7 HOT-346/349, Tannerella HOT-286, Cardiobacterium valvarum, Campylobacter gracilis, Porphyromonas catoniae, Leptotrichia HOT-219, and Selen o monas spp. At the phylum/genus level, TM7 showed the strongest association. Gingival health was associated with increased abundance of Haemophilus parainfluenzae, Lautropia mirabilis, Rothia spp., Streptococcus spp., and Kingella oralis. CHX demonstrated largely indiscriminate antimicrobial action, resulting in significant drop in biomass and diversity. Our results substantiate the role of specific oral bacterial species in the development of gingivitis. They also indicate that NAC is not a promising mouthwash at the concentration tested.}, }
@article {pmid31273057, year = {2019}, author = {Huang, H and Chen, M and Liu, F and Wu, H and Wang, J and Chen, J and Liu, M and Li, X}, title = {N-acetylcysteine tiherapeutically protects against pulmonary fibrosis in a mouse model of silicosis.}, journal = {Bioscience reports}, volume = {39}, number = {7}, pages = {}, pmid = {31273057}, issn = {1573-4935}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Crystallization ; Disease Models, Animal ; Female ; Gene Expression Regulation/drug effects ; Glutathione Peroxidase/genetics/metabolism ; Interleukin-1beta/genetics/metabolism ; Interleukin-4/genetics/metabolism ; Interleukin-6/genetics/metabolism ; Lung/drug effects/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; NADPH Oxidase 2/genetics/metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; Oxidative Stress/drug effects ; Pulmonary Fibrosis/chemically induced/genetics/pathology/*prevention &amp; control ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Silicon Dioxide/administration &amp; dosage ; Silicosis/etiology/genetics/pathology/*prevention &amp; control ; Superoxide Dismutase/genetics/metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism ; Xanthine Oxidase/genetics/metabolism ; }, abstract = {Silicosis is a lethal pneumoconiosis disease characterized by chronic lung inflammation and fibrosis. The present study was to explore the effect of against crystalline silica (CS)-induced pulmonary fibrosis. A total of 138 wild-type C57BL/6J mice were divided into control and experimental groups, and killed on month 0, 1, 2, 3, 4, and 5. Different doses of N-acetylcysteine (NAC) were gavaged to the mice after CS instillation to observe the effect of NAC on CS induced pulmonary fibrosis and inflammation. The pulmonary injury was evaluated with Hematoxylin and eosin/Masson staining. Reactive oxygen species level was analyzed by DCFH-DA labeling. Commercial ELISA kits were used to determine antioxidant activity (T-AOC, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) and cytokines (TNF-α, IL-1β, IL-4, and IL-6). The expression of oxidising enzymes (NOX2, iNOS, SOD2, and XO) were detected by real time PCR. Immunohistochemistry (IHC) staining was performed to examine epithelial-mesenchymal transition-related markers. The mice treated with NAC presented markedly reduced CS-induced pulmonary injury and ameliorated CS-induced pulmonary fibrosis and inflammation. The level of malondialdehyde was reduced, while the activities of GSH-PX, SOD, and T-AOC were markedly enhanced by NAC. We also found the down-regulation of oxidising enzymes (NOX2, iNOS, SOD2, and XO) after NAC treatment. Moreover, E-cadherin expression was increased while vimentin and Cytochrome C expressions were decreased by NAC. These encouraging findings suggest that NAC exerts pulmonary protective effects in CS-induced pulmonary fibrosis and might be considered as a promising agent for the treatment of silicosis.}, }
@article {pmid31271289, year = {2019}, author = {Wang, YK and Yang, XN and Zhu, X and Xiao, XR and Yang, XW and Qin, HB and Gonzalez, FJ and Li, F}, title = {Role of Metabolic Activation in Elemicin-Induced Cellular Toxicity.}, journal = {Journal of agricultural and food chemistry}, volume = {67}, number = {29}, pages = {8243-8252}, pmid = {31271289}, issn = {1520-5118}, support = {ZIA BC005708/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Activation, Metabolic ; Biotransformation ; Cell Survival/drug effects ; Cytochrome P-450 Enzyme System/metabolism ; Hep G2 Cells ; Humans ; Hydroxylation ; Molecular Structure ; Pyrogallol/*analogs &amp; derivatives/chemistry/metabolism/toxicity ; }, abstract = {Elemicin, an alkenylbenzene constituent of natural oils of several plant species, is widely distributed in food, dietary supplements, and medicinal plants. 1'-Hydroxylation is known to cause metabolic activation of alkenylbenzenes leading to their potential toxicity. The aim of this study was to explore the relationship between elemicin metabolism and its toxicity through comparing the metabolic maps between elemicin and 1'-hydroxyelemicin. Elemicin was transformed into a reactive metabolite of 1'-hydroxyelemicin, which was subsequently conjugated with cysteine (Cys) and N-acetylcysteine (NAC). Administration of NAC could significantly ameliorate the elemicin- and 1'-hydroxyelemicin-induced cytotoxicity of HepG2 cells, while depletion of Cys with diethyl maleate (DEM) increased cytotoxicity. Recombinant human CYP screening and CYP inhibition experiments revealed that multiple CYPs, notably CYP1A1, CYP1A2, and CYP3A4, were responsible for the metabolic activation of elemicin. This study revealed that metabolic activation plays a critical role in elemicin cytotoxicity.}, }
@article {pmid31266772, year = {2019}, author = {Das, B and Pal, B and Bhuyan, R and Li, H and Sarma, A and Gayan, S and Talukdar, J and Sandhya, S and Bhuyan, S and Gogoi, G and Gouw, AM and Baishya, D and Gotlib, JR and Kataki, AC and Felsher, DW}, title = {MYC Regulates the HIF2α Stemness Pathway via Nanog and Sox2 to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells.}, journal = {Cancer research}, volume = {79}, number = {16}, pages = {4015-4025}, pmid = {31266772}, issn = {1538-7445}, support = {U56 CA112973/CA/NCI NIH HHS/United States ; R01 CA170378/CA/NCI NIH HHS/United States ; U01 CA188383/CA/NCI NIH HHS/United States ; R01 CA089305/CA/NCI NIH HHS/United States ; T32 CA196585/CA/NCI NIH HHS/United States ; R01 CA105102/CA/NCI NIH HHS/United States ; }, mesh = {ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/metabolism ; Animals ; Antigens, Ly/genetics/metabolism ; Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Membrane Proteins/genetics/metabolism ; Mice, SCID ; Mice, Transgenic ; Nanog Homeobox Protein/genetics/*metabolism ; Neoplasm Proteins/genetics/metabolism ; Neoplastic Stem Cells/metabolism/*pathology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/metabolism/*pathology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-myc/*genetics/metabolism ; Reactive Oxygen Species/metabolism ; SOXB1 Transcription Factors/genetics/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T-cell leukemia, MYC, maintains self-renewal in Sca1[+] CSCs versus Sca-1[-] non-CSCs. MYC preferentially bound to the promoter and activated hypoxia-inducible factor-2α (HIF2α) in Sca-1[+] cells only. Furthermore, the reprogramming factors, Nanog and Sox2, facilitated MYC regulation of HIF2α in Sca-1[+] versus Sca-1[-] cells. Reduced expression of HIF2α inhibited the self-renewal of Sca-1[+] cells; this effect was blocked through suppression of ROS by N-acetyl cysteine or the knockdown of p53, Nanog, or Sox2. Similar results were seen in ABCG2[+] CSCs versus ABCG2[-] non-CSCs from primary human T-cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the HIF2α stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications. SIGNIFICANCE: These findings show that the HIF2α stemness pathway maintains leukemic stem cells downstream of MYC in human and mouse T-cell leukemias. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4015/F1.large.jpg.}, }
@article {pmid31266188, year = {2019}, author = {Li, P and Li, L and Zhang, C and Cheng, X and Zhang, Y and Guo, Y and Long, M and Yang, S and He, J}, title = {Palmitic Acid and β-Hydroxybutyrate Induce Inflammatory Responses in Bovine Endometrial Cells by Activating Oxidative Stress-Mediated NF-κB Signaling.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {13}, pages = {}, pmid = {31266188}, issn = {1420-3049}, mesh = {3-Hydroxybutyric Acid/*toxicity ; Animals ; Cattle ; Cell Line ; Endometrium/*pathology/physiology ; Female ; Inflammation/chemically induced/metabolism/pathology ; NF-kappa B/*metabolism ; Oxidative Stress/*drug effects ; Palmitic Acid/*toxicity ; Signal Transduction/*drug effects ; }, abstract = {Ketosis is a nutritional metabolic disease in dairy cows, and researches indicated that ketonic cows always accompany reproductive problems. When ketosis occurs, the levels of non-esterified fatty acids (NEFAs) and β-hydroxybutyrate (BHBA) in the blood increase significantly. Palmitic acid (PA) is a main component of saturated fatty acids composing NEFA. The aim of this study was to investigate whether high levels of PA and BHBA induce inflammatory responses and regulatory mechanisms in bovine endometrial cells (BEND). Using an enzyme-linked immunosorbent assay, quantitative real-time PCR, and western blotting, we evaluated oxidative stress, pro-inflammatory factors, and the nuclear factor (NF)-κB pathway in cultured BEND cells treated with different concentrations of PA, BHBA, pyrrolidinedithiocarbamate (PDTC, an NF-κB pathway inhibitor), and N-acetylcysteine (NAC, an antioxidant). The content of malondialdehyde was significantly higher, the content of glutathione was lower, and antioxidant activity-glutathione peroxidase, superoxide dismutase, catalase, and total antioxidant capacity-was lower in treated cells compared with control cells. PA- and BHBA-induced oxidative stress activated the NF-κB signaling pathway and upregulated the release of pro-inflammatory factors. Moreover, PA- and BHBA-induced activation of NF-κB-mediated inflammatory responses was inhibited by PDTC and NAC. High concentrations of PA and BHBA induce inflammatory responses in BEND cells by activating oxidative stress-mediated NF-κB signaling.}, }
@article {pmid31258714, year = {2019}, author = {Feng, F and Zhang, J and Wang, Z and Wu, Q and Zhou, X}, title = {Efficacy and safety of N-acetylcysteine therapy for idiopathic pulmonary fibrosis: An updated systematic review and meta-analysis.}, journal = {Experimental and therapeutic medicine}, volume = {18}, number = {1}, pages = {802-816}, pmid = {31258714}, issn = {1792-0981}, abstract = {Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease with poor prognosis and limited treatment options. N-acetylcysteine (NAC), an anti-oxidant drug, has promising potential in the treatment of IPF. In the present systematic review and meta-analysis, the efficacy and safety of NAC for IPF were investigated. The following databases were comprehensively searched for relevant studies published until August 2018: Pubmed, Embase, Cochrane library, Chinese National Knowledge Infrastructure, Wangfang Database, VIP and the Chinese Biology Medical Database. A total of 21 controlled trials assessing the efficacy and safety of NAC therapy for IPF were identified and primary outcomes [forced vital capacity (FVC), adverse side effects] and secondary outcomes [diffusing capacity for carbon monoxide (DLCO) and its percentage predicted value (DLCO%), vital capacity (VC), partial arterial oxygen pressure (PaO2), 6-min walking distance test and mortality] were extracted for the meta-analysis. The risk ratio and mean difference or standardized mean difference with 95% confidence interval were calculated using RevMan 5.3 software. Analysis of the pooled data revealed that, compared with control treatments (routine treatment or drugs other than anti-oxidants), NAC therapy reduced the decline in lung function, as indicated by the FVC and DLCO, and slowed the progression of the disease, as indicated by the PaO2, while complications and mortality were similar. These results suggest good efficacy, tolerability and safety of the treatment. Furthermore, subgroup analysis revealed that combined therapy including NAC for IPF might be more effective than NAC monotherapy, while oral administration of NAC was safer than inhalation. In conclusion, the results of the present review and meta-analysis provide important information that may serve as a guide regarding NAC therapy for IPF in clinical practice.}, }
@article {pmid31256398, year = {2019}, author = {Sohail, N and Hira, K and Tariq, A and Sultana, V and Ehteshamul-Haque, S}, title = {Marine macro-algae attenuates nephrotoxicity and hepatotoxicity induced by cisplatin and acetaminophen in rats.}, journal = {Environmental science and pollution research international}, volume = {26}, number = {24}, pages = {25301-25311}, pmid = {31256398}, issn = {1614-7499}, support = {4505//Higher Education Commission, Pakistan (PK)/ ; }, mesh = {Acetaminophen/*toxicity ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Antineoplastic Agents/*toxicity ; Chemical and Drug Induced Liver Injury/metabolism ; Cisplatin/*toxicity ; Creatinine ; Kidney/drug effects ; Liver/drug effects ; Male ; Rats ; Seaweed/*chemistry ; }, abstract = {Cisplatin is considered one of the best anticancer medications often used for the treatment of various cancers even with its adverse effects. Acetaminophen (paracetamol) is a widely used analgesic-antipyretic drug that causes hepatotoxicity at higher than the effective doses. The present study assesses the nephroprotective and hepatoprotective effects of two seaweeds against cisplatin and acetaminophen toxicity in rats. Damage to the liver and kidney was induced by administering a single intraperitoneal dose of acetaminophen (600 mg/kg) or cisplatin (7 mg/kg) to groups of rats. The damage to the liver and kidney was assessed by the elevated liver (ALT, AST, ALP, LDH, electrolytes) and kidney (urea, creatinine) biomarkers. The ethanol extract of brown seaweed reversed the elevated levels of kidney and liver biomarkers along with triglycerides, cholesterol, and glucose. Among the two seaweeds, Sargassum ilicifolium showed better nephroprotective and hepatoprotective effects than the standard drug N-Acetyl-cysteine, Halymenia porphyroides showed only limited protection. Findings of this study provide evidence of nephroprotective and hepatoprotective effects of S. ilicifolium. Seaweed could be a beneficial dietary supplement to attenuate nephrotoxicity and hepatotoxicity.}, }
@article {pmid31254666, year = {2019}, author = {Dludla, PV and Mazibuko-Mbeje, SE and Nyambuya, TM and Mxinwa, V and Tiano, L and Marcheggiani, F and Cirilli, I and Louw, J and Nkambule, BB}, title = {The beneficial effects of N-acetyl cysteine (NAC) against obesity associated complications: A systematic review of pre-clinical studies.}, journal = {Pharmacological research}, volume = {146}, number = {}, pages = {104332}, doi = {10.1016/j.phrs.2019.104332}, pmid = {31254666}, issn = {1096-1186}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Animals ; Humans ; Inflammation/metabolism ; Obesity/*drug therapy/metabolism ; Oxidative Stress/drug effects ; Transcription Factors/metabolism ; }, abstract = {Excessive adiposity in an obese state is known to drive the onset of metabolic dysregulations, mostly involving chronic immune activation and oxidative stress. Prolonged inflammation and oxidative stress have been linked to impaired adipose tissue function and the development of the metabolic syndrome. Currently available therapies offer minimal prophylactic effects, while substantial experimental evidence supports the ameliorative effects of N-acetylcysteine (NAC) against various metabolic complications associated with obesity. The current review provides a comprehensive synthesis of studies published in major search engines such as PubMed, Cochrane library, Embase, and Google Scholar assessing the therapeutic effect of NAC against obesity associated complications. Overwhelming literature included in this review supports the ameliorative effects of NAC against such complications in both in vitro and in vivo models of obesity. In addition to attenuating an abnormal pro-inflammatory response and limiting oxidative damage, NAC could inhibit lipid accumulation by targeting adipogenic transcription factors such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein beta (C/EBPβ), and improve insulin sensitivity through augmenting phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Although necessary evidence informing on its optimal dose and its comparative effect with other well-studied pharmacological compounds is demonstrated, it is clear that future investigations are required to confirm the therapeutic effect of NAC in obese human subjects.}, }
@article {pmid31254584, year = {2019}, author = {Cortese, K and Marconi, S and D'Alesio, C and Calzia, D and Panfoli, I and Tavella, S and Aiello, C and Pedrelli, F and Bisio, A and Castagnola, P}, title = {The novel diterpene 7β-acetoxy-20-hydroxy-19,20-epoxyroyleanone from Salvia corrugata shows complex cytotoxic activities against human breast epithelial cells.}, journal = {Life sciences}, volume = {232}, number = {}, pages = {116610}, doi = {10.1016/j.lfs.2019.116610}, pmid = {31254584}, issn = {1879-0631}, mesh = {Apoptosis/drug effects ; Breast/cytology/*drug effects/metabolism ; Camphanes ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Diterpenes/isolation &amp; purification/*pharmacology ; Drugs, Chinese Herbal/*pharmacology ; Epithelial Cells/*drug effects/metabolism ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Panax notoginseng ; Reactive Oxygen Species/metabolism ; Resting Phase, Cell Cycle/drug effects ; Salvia miltiorrhiza ; }, abstract = {AIMS: The aim of this study was the characterization of the in vitro cytotoxic properties of a recently isolated diterpene compound, 7β-acetoxy-20-hydroxy-19,20-epoxyroyleanone (compound 1), extracted from Salvia corrugata, versus human cell lines.<br><br>MAIN METHODS: We used as model study immortalized breast epithelial cells MCF10A and two ERBB2[+] breast cancer (BCa) cell lines, SKBR-3 and BT474. Compound 1 was isolated by methanolic extraction from regenerated shoots of Salvia corrugata Vahl, and purified by high pressure liquid chromatography (HPLC). Flow cytometry (FCM) was employed for cell cycle, apoptosis and reactive oxygen species (ROS) analysis. Cell morphology was assessed by immunofluorescence and transmission electron microscopy (TEM).<br><br>KEY FINDINGS: Compound 1 inhibited cell survival of all breast cell lines. In particular, compound 1 promoted cell cycle arrest in the G0/G1 phase and apoptosis along with impairment of the mitochondrial function, which was reflected in a gross alteration of the mitochondrial network structure. Furthermore, we also detected a potent activation of the ERK1/2 kinase, which suggested the induction of reactive oxygen species (ROS). Partial rescue of survival obtained with n-acetylcysteine (NAC) when coadminstered with compound 1 further supported a contribution of ROS mediated mechanisms to the growth-arrest and proapoptotic activity of compound 1 in both BCa cell lines. ROS production was indeed confirmed in SKBR-3.<br><br>SIGNIFICANCE: Our findings show that compound 1 has a cytotoxic activity against both human normal and cancer cell lines derived from breast epithelia, which is mediated by ROS generation and mitochondrial damage.}, }
@article {pmid31253835, year = {2019}, author = {Badisa, RB and Wiley, C and Randell, K and Darling-Reed, SF and Latinwo, LM and Agharahimi, M and Soliman, KFA and Goodman, CB}, title = {Identification of cytotoxic markers in methamphetamine treated rat C6 astroglia-like cells.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {9412}, pmid = {31253835}, issn = {2045-2322}, support = {G12 MD007582/MD/NIMHD NIH HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; R25 GM107777/GM/NIGMS NIH HHS/United States ; U54 MD007582/MD/NIMHD NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Astrocytes/*drug effects/*metabolism ; Biomarkers ; Cell Line ; Cell Survival/drug effects ; Central Nervous System Stimulants/*pharmacology/toxicity ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Methamphetamine/*pharmacology/toxicity ; Rats ; Reactive Oxygen Species/metabolism ; Resting Phase, Cell Cycle/drug effects ; Time Factors ; }, abstract = {Methamphetamine (METH) is a powerfully addictive psychostimulant that has a pronounced effect on the central nervous system (CNS). The present study aimed to assess METH toxicity in differentiated C6 astroglia-like cells through biochemical and toxicity markers with acute (1 h) and chronic (48 h) treatments. In the absence of external stimulants, cellular differentiation of neuronal morphology was achieved through reduced serum (2.5%) in the medium. The cells displayed branched neurite-like processes with extensive intercellular connections. Results indicated that acute METH treatment neither altered the cell morphology nor killed the cells, which echoed with lack of consequence on reactive oxygen species (ROS), nitric oxide (NO) or inhibition of any cell cycle phases except induction of cytoplasmic vacuoles. On the other hand, chronic treatment at 1 mM or above destroyed the neurite-like processors and decreased the cell viability that paralleled with increased levels of ROS, lipid peroxidation and lactate, depletion in glutathione (GSH) level and inhibition at G0/G1 phase of cell cycle, leading to apoptosis. Pre-treatment of cells with N-acetyl cysteine (NAC, 2.5 mM for 1 h) followed by METH co-treatment for 48 h rescued the cells completely from toxicity by decreasing ROS through increased GSH. Our results provide evidence that increased ROS and GSH depletion underlie the cytotoxic effects of METH in the cells. Since loss in neurite connections and intracellular changes can lead to psychiatric illnesses in drug users, the evidence that we show in our study suggests that these are also contributing factors for psychiatric-illnesses in METH addicts.}, }
@article {pmid31248223, year = {2019}, author = {Song, IS and Jeong, YJ and Kim, JE and Shin, J and Jang, SW}, title = {Frugoside Induces Mitochondria-Mediated Apoptotic Cell Death through Inhibition of Sulfiredoxin Expression in Melanoma Cells.}, journal = {Cancers}, volume = {11}, number = {6}, pages = {}, pmid = {31248223}, issn = {2072-6694}, support = {NRF-2016K1A1A8A01938718//Procurement and development of foreign biological resources" funded by the Ministry of Science, ICT, and Future Planning of the government of South Korea/ ; }, abstract = {Malignant melanoma is the most life-threatening neoplasm of the skin. Despite the increase in incidence, melanoma is becoming more resistant to current therapeutic agents. The bioactive compound frugoside has been recently reported to inhibit growth when used in various cancer cells. However, this effect has not been demonstrated in melanoma. Here, we found that frugoside inhibited the rate of reduction of hyperoxidized peroxiredoxins (Prxs) by downregulating sulfiredoxin (Srx) expression. Furthermore, frugoside increased the accumulation of sulfinic Prxs and reactive oxygen species (ROS) and stimulated p-p38 activation, resulting in the mitochondria-mediated death of M14 and A375 human melanoma cells. The mitochondria-mediated cell death induced by frugoside was inhibited by the overexpression of Srx and antioxidants, such as N-acetyl cysteine and diphenyleneiodonium. In addition, we observed that frugoside inhibited tumor growth without toxicity through a M14 xenograft animal model. Taken together, our findings reveal that frugoside exhibits a novel antitumor effect based on a ROS-mediated cell death in melanoma cells, which may have therapeutic implications.}, }
@article {pmid31245853, year = {2020}, author = {Wang, X and Dawod, A and Nachliely, M and Harrison, JS and Danilenko, M and Studzinski, GP}, title = {Differentiation agents increase the potential AraC therapy of AML by reactivating cell death pathways without enhancing ROS generation.}, journal = {Journal of cellular physiology}, volume = {235}, number = {1}, pages = {573-586}, doi = {10.1002/jcp.28996}, pmid = {31245853}, issn = {1097-4652}, mesh = {Abietanes/pharmacology ; Antimetabolites, Antineoplastic/*pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cytarabine/*pharmacology ; Ergocalciferols/pharmacology ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/*drug therapy ; RNA Interference ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Receptors, Calcitriol/*metabolism ; U937 Cells ; Vitamin D/therapeutic use ; }, abstract = {Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D-based cell differentiation agents (doxercalciferol/carnosic acid [D2/CA]) added following the cytotoxic drug arabinocytosine (AraC) increases AML cell death (CD), a model for improved therapy of this disease. Because AraC-induced CD is known to involve reactive oxygen species (ROS) generation, here we investigated if the modulation of cellular REDOX status plays a role in the enhancement of cell death (ECD) by D2/CA. Using thiol antioxidants, such as N-acetyl cysteine (NAC), we found a significant inhibition of ECD, yet this occurred in the absence of any detectable change in cellular ROS levels. In contrast, NAC reduced the vitamin D receptor (VDR) abundance and its signaling of ECD. Importantly, VDR knockdown and NAC similarly inhibited ECD without producing an additive effect. Thus, the proposed post-AraC therapy may be compromised by agents that reduce VDR levels in AML blasts.}, }
@article {pmid31244408, year = {2019}, author = {Satpute, RM and Bhutia, YD and Lomash, V and Bhattacharya, R}, title = {Efficacy assessment of co-treated alpha-ketoglutarate and N-acetyl cysteine against the subchronic toxicity of cyanide in rats.}, journal = {Toxicology and industrial health}, volume = {35}, number = {6}, pages = {410-423}, doi = {10.1177/0748233719851902}, pmid = {31244408}, issn = {1477-0393}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/drug effects/pathology ; Cyanides/*metabolism ; Ketoglutaric Acids ; Kidney/drug effects/pathology ; Liver/drug effects/pathology ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Cyanide is an important industrial pollutant, major occupational hazard, and a potential chemical warfare agent. Its intentional or accidental exposure to humans is a big clinical problem because of its rapid mode of action. Certain plant origin foods also contain substantial amount of cyanide and cause chronic toxicity. This study explores the protective efficacy of co-treatment of alpha-ketoglutarate (AKG) and an antioxidant N-acetyl cysteine (NAC) against toxicity of subchronically exposed cyanide in rats. We explore the effect of AKG + NAC co-treatment on oxidative stress, inflammation, and histological changes induced due to long-term sublethal cyanide exposure. Cyanide induces oxidative stress by inhibiting metalloenzymes (catalase and superoxide dismutase) causing increase in lipid peroxidation (malondialdehyde) and decrease in reduced glutathione (GSH). It also increases the activity of cyclo-oxygenase enzymes causing oxidative stress-mediated inflammation in the brain. Cyanide exposure also causes degenerative changes in the brain as shown in histology. It also causes pathology in liver and kidney. AKG is known to form cyanohydrins with cyanide reducing the free cyanide levels, and its combination with NAC showed overall improvement in by reducing the oxidative stress and subsequent neuroinflammation. Their combination was also found to improve the histological outcome of vital tissues. AKG, an over-the-counter sport medicine, and the antioxidant NAC per se did not show any detrimental effects in any tested parameter. Hence, oral treatment with AKG and NAC can be beneficial for the treatment of chronic cyanide poisoning.}, }
@article {pmid31238866, year = {2019}, author = {Bozhokina, ES and Tsaplina, OA and Khaitlina, SY}, title = {The Opposite Effects of ROCK and Src Kinase Inhibitors on Susceptibility of Eukaryotic Cells to Invasion by Bacteria Serratia grimesii.}, journal = {Biochemistry. Biokhimiia}, volume = {84}, number = {6}, pages = {663-671}, doi = {10.1134/S0006297919060099}, pmid = {31238866}, issn = {1608-3040}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Humans ; Protein Kinase Inhibitors/*pharmacology ; Serratia/*drug effects ; rho-Associated Kinases/*antagonists &amp; inhibitors ; src-Family Kinases/*antagonists &amp; inhibitors ; }, abstract = {Bacterial internalization into eukaryotic cells is ensured by a sophisticated interplay of bacterial and host cell factors. Being a part of cell environment, opportunistic intracellular bacteria have developed various mechanisms providing their interaction with cell surface receptors (E-cadherin, integrins, epidermal growth factor receptor), activation of components of eukaryotic signaling pathways, and facilitation of bacterial uptake, survival, and intracellular replication. Our previous studies on the mechanisms underlying penetration of the opportunistic bacteria Serratia grimesii into cultured eukaryotic cells have shown that pretreatment of the cells with N-acetylcysteine (NAC) promotes S. grimesii invasion, and this effect correlates with the upregulation of E-cadherin expression. Since NAC has been shown to regulate expression of both Src kinase and ROCK, the aim of this work was to reveal the role of these kinases in S. grimesii invasion. We demonstrated that Y-27632, a specific inhibitor of ROCK, significantly promoted invasion of cultured eukaryotic cells by S. grimesii. On the other hand, invasion of the same cells by S. grimesii was inhibited with the Src kinase inhibitor Src-I1 and siRNA directed against RhoA. The effects of the inhibitors correlated with the corresponding changes in the E-cadherin gene expression, upregulation by the ROCK inhibition and downregulation by the Src kinase inhibition. These results prove the participation of ROCK and Src protein kinases in the invasion of eukaryotic cells by the opportunistic pathogen S. grimesii, as well as suggest that other signaling pathways might be involved in S. grimesii uptake, that are promoted by the ROCK inhibition with Y-27632.}, }
@article {pmid31234669, year = {2019}, author = {Gu, Q and Cuevas, E and Ali, SF and Paule, MG and Krauthamer, V and Jones, Y and Zhang, Y}, title = {An Alternative In Vitro Method for Examining Nanoparticle-Induced Cytotoxicity.}, journal = {International journal of toxicology}, volume = {38}, number = {5}, pages = {385-394}, doi = {10.1177/1091581819859267}, pmid = {31234669}, issn = {1092-874X}, mesh = {Animals ; Biological Assay ; Cell Survival/drug effects ; Cells, Cultured ; Endothelial Cells/drug effects ; *Fluoresceins ; *Fluorescent Dyes ; Gold/*toxicity ; Humans ; Male ; Metal Nanoparticles/*toxicity ; Mice ; Microvessels/cytology ; Neural Stem Cells/drug effects ; Rats, Sprague-Dawley ; Silver/*toxicity ; Toxicity Tests/methods ; }, abstract = {Conventional in vitro assays are often used as initial screens to identify potential toxic effects of nanoparticles (NPs). However, many NPs have shown interference with conventional in vitro assays, resulting in either false-positive or -negative outcomes. Here, we report an alternative method for the in vitro assessment of NP-induced cytotoxicity utilizing Fluoro-Jade C (FJ-C). To provide proof of concept and initial validation data, Ag-NPs and Au-NPs were tested in 3 different cell cultures including rat brain microvessel endothelial cells, mouse neural stem cells, and the human SH-SY5Y cell line. Conventional 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and lactate dehydrogenase (LDH) assays were run in parallel with the new method and served as references. The results demonstrate for the first time that FJ-C labeling can be a useful tool for assessing NP-induced cytotoxicity in vitro. Using these approaches, it was also demonstrated that removal of Ag-NPs-while keeping the Ag-ions that were released from the Ag-NPs in culture media-abolished the measured cytotoxicity, indicating that Ag-NPs rather than Ag-ions in solution contributed to the observed cytotoxic effects. Further, co-treatment of Ag-NPs with N-acetyl cysteine (NAC) prevented the observed cytotoxicity, suggesting a protective role of NAC in Ag-NP-induced cytotoxicity. Thus, this alternative in vitro assay is well suited for identify potential cytotoxicity associated with exposure to NPs.}, }
@article {pmid31233063, year = {2019}, author = {Wang, H and Cheng, X and Zhang, L and Xu, S and Zhang, Q and Lu, R}, title = {A surface-layer protein from Lactobacillus acidophilus NCFM induces autophagic death in HCT116 cells requiring ROS-mediated modulation of mTOR and JNK signaling pathways.}, journal = {Food &amp; function}, volume = {10}, number = {7}, pages = {4102-4112}, doi = {10.1039/c9fo00109c}, pmid = {31233063}, issn = {2042-650X}, mesh = {Anthracenes/pharmacology ; Apoptosis/drug effects ; Autophagic Cell Death/*drug effects ; Autophagy/drug effects ; Beclin-1/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; HCT116 Cells/*drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lactobacillus acidophilus/*metabolism ; MAP Kinase Signaling System/*drug effects ; Membrane Proteins/*pharmacology ; Microtubule-Associated Proteins/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {A surface-layer protein (Slp) derived from Lactobacillus acidophilus NCFM has been reported to possess multiple biological properties, including anti-inflammatory, inhibition of apoptosis in pathogen-invaded HT-29 cells and oxidative stress relief. However, its anti-tumor ability and underlying molecular mechanism are unknown. Here, we report that Slp suppresses cell proliferation and induces autophagic cell death in HCT116 cells. Accumulation of Beclin-1 and microtubule-associated protein 1 light chain 3 from II (LC3-II), and the degradation of p62 were observed when cells were treated with various concentrations of Slp (25, 50, 100 μg mL-1) for 24 h. We also found that the mammalian targets of rapamycin (mTOR) and c-Jun N-terminal kinase (JNK) signaling pathways were crucial mediators regulating Slp-induced autophagic cell death. Additionally, treatment with Slp resulted in the obvious formation of reactive oxygen species (ROS). SP600125, a JNK inhibitor, and N-acetylcysteine (NAC), a ROS inhibitor, attenuated Slp-induced autophagic cell death in HCT116 cells. Furthermore, NAC was found to prevent Slp-induced p70 and JNK phosphorylation. Taken together, our results suggest a novel mechanism of action of Slp induced autophagy, acting simultaneously through the ROS-mediated mTOR and JNK signaling pathways in HCT116 colon cancer cells.}, }
@article {pmid31232748, year = {2019}, author = {Kiliç, F and Keleş, S}, title = {Repetitive Behaviors Treated With N-Acetylcysteine: Case Series.}, journal = {Clinical neuropharmacology}, volume = {42}, number = {4}, pages = {139-141}, doi = {10.1097/WNF.0000000000000352}, pmid = {31232748}, issn = {1537-162X}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Female ; Humans ; Male ; Obsessive-Compulsive Disorder/*drug therapy ; Stereotypic Movement Disorder/*drug therapy ; Trichotillomania/*drug therapy ; Young Adult ; }, abstract = {OBJECTIVES: Skin-picking disorders, trichotillomania, and nail biting are all characterized by repetitive behaviors resulting in functional deterioration and remarkable changes in physical appearance with repeated attempts to stop or decrease the behavior. While standard pharmacotherapy for obsessive-compulsive disorder and related disorders consists of serotonergic reuptake inhibitors, their moderate efficacy pushed researchers to find alternative treatment approaches. Some of these alternatives are glutamate-modulating agents. The most widely studied of these glutamate modulator agents is N-acetylcysteine (NAC), which is a derivative of the amino acid cysteine.<br><br>METHODS: This report describes a case series of 3 patients in whom skin-picking disorders, trichotillomania, and nail biting were diagnosed at a center in Turkey.<br><br>RESULTS: First case was a 42-year-old female patient who had been picking her skin from her arm area, especially in stressful times. Second case was a 31-year-old female patient who has a habit of pulling her hair for the last 20 years. The third case was 24-year-old male patient with a habit of eating his own nails that he has had for as long as he could remember. We successfully treated 3 of our patients who suffer from previously mentioned disorders with NAC.<br><br>CONCLUSIONS: Outcome of our cases demonstrates the efficacy of NAC, which is effective and well tolerated on the treatment of obsessive-compulsive disorder-related disorders.}, }
@article {pmid31229567, year = {2019}, author = {Chen, X and Zhang, Y and Jiang, S and Huang, S}, title = {Maduramicin induces apoptosis through ROS-PP5-JNK pathway in skeletal myoblast cells and muscle tissue.}, journal = {Toxicology}, volume = {424}, number = {}, pages = {152239}, pmid = {31229567}, issn = {1879-3185}, support = {R01 CA115414/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line ; Coccidiostats/*toxicity ; Glycoproteins/*drug effects ; Lactones/*toxicity ; MAP Kinase Signaling System/*drug effects ; Male ; Mice ; Mice, Inbred ICR ; Muscle, Skeletal/*drug effects ; Myoblasts, Skeletal/*drug effects ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {Our previous work has shown that maduramicin, an effective coccidiostat used in the poultry production, executed its toxicity by inducing apoptosis of skeletal myoblasts. However, the underlying mechanism is not well understood. Here we show that maduramicin induced apoptosis of skeletal muscle cells by activating c-Jun N-terminal kinase (JNK) pathway in murine C2C12 and L6 myoblasts as well as skeletal muscle tissue. This is supported by the findings that inhibition of JNK with SP600125 or ectopic expression of dominant negative c-Jun attenuated maduramicin-induced apoptosis in C2C12 cells. Furthermore, we found that treatment with maduramicin reduced the cellular protein level of protein phosphatase 5 (PP5). Overexpression of PP5 substantially mitigated maduramicin-activated JNK and apoptosis. Moreover, we noticed that treatment with maduramicin elevated intracellular reactive oxygen species (ROS) level. Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, suppressed maduramicin-induced inhibition of PP5 and activation of JNK as well as apoptosis. The results indicate that maduramicin induction of ROS inhibits PP5, which results in activation of JNK cascade, leading to apoptosis of skeletal muscle cells. Our finding suggests that manipulation of ROS-PP5-JNK pathway may be a potential approach to prevent maduramicin-induced apoptotic cell death in skeletal muscle.}, }
@article {pmid31228512, year = {2019}, author = {Lee, C and Do, HTT and Her, J and Kim, Y and Seo, D and Rhee, I}, title = {Inflammasome as a promising therapeutic target for cancer.}, journal = {Life sciences}, volume = {231}, number = {}, pages = {116593}, doi = {10.1016/j.lfs.2019.116593}, pmid = {31228512}, issn = {1879-0631}, mesh = {Alarmins/metabolism ; Animals ; Apoptosis/physiology ; Autoimmune Diseases/immunology ; Carrier Proteins/metabolism ; Caspase 1/metabolism ; Caspases/metabolism ; Humans ; Immunity, Innate/immunology ; Inflammasomes/*metabolism/*physiology ; Inflammation/immunology ; Interleukin-18/metabolism ; Interleukin-1beta/metabolism ; NLR Proteins/physiology ; Neoplasms/*therapy ; Pathogen-Associated Molecular Pattern Molecules/metabolism ; Signal Transduction ; }, abstract = {Inflammasomes are the major mechanistic complexes that include members of the NOD-like receptor (NLRs) or AIM2-like receptors (ALRs) families, which are affiliated with the innate immune system. Once NLRs or ALRs are activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), the caspase-1 or -11 is activated by binding with NLRs or ALRs via its own unique cytosolic domains. As a result, caspase-1 or -11 enhances the production of IL-1β and IL-18, which results in inflammation via the recruitment of immune cells, such as macrophages, and the promotion of programmed cell death mechanisms such as pyroptosis. In addition, the consistent cascades of inflammasomes would precede both minor and severe autoimmune diseases and cancers. The clinical relevance of inflammasomes in multiple forms of cancer highlights their therapeutic promise as molecular targets. To closely analyze the physiological roles of inflammasomes in cancers, here, we describe the fundamental knowledge regarding the current issues of inflammasomes in relevant cancers, and discuss possible therapeutic values in targeting these inflammasomes for the prevention and treatment of cancer.}, }
@article {pmid31228442, year = {2019}, author = {Luo, Z and Shivakumar, P and Mourya, R and Gutta, S and Bezerra, JA}, title = {Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents.}, journal = {Gastroenterology}, volume = {157}, number = {4}, pages = {1138-1152.e14}, pmid = {31228442}, issn = {1528-0012}, support = {U01 DK062481/DK/NIDDK NIH HHS/United States ; U01 DK062470/DK/NIDDK NIH HHS/United States ; UL1 TR000150/TR/NCATS NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; U01 DK062436/DK/NIDDK NIH HHS/United States ; UL1 TR001108/TR/NCATS NIH HHS/United States ; U01 DK062452/DK/NIDDK NIH HHS/United States ; U01 DK062466/DK/NIDDK NIH HHS/United States ; U01 DK084575/DK/NIDDK NIH HHS/United States ; U01 DK062456/DK/NIDDK NIH HHS/United States ; U01 DK062445/DK/NIDDK NIH HHS/United States ; UL1 TR000130/TR/NCATS NIH HHS/United States ; U01 DK103140/DK/NIDDK NIH HHS/United States ; UL1 TR001878/TR/NCATS NIH HHS/United States ; U01 DK084538/DK/NIDDK NIH HHS/United States ; U01 DK062453/DK/NIDDK NIH HHS/United States ; U01 DK062503/DK/NIDDK NIH HHS/United States ; UL1 TR002535/TR/NCATS NIH HHS/United States ; P30 DK078392/DK/NIDDK NIH HHS/United States ; U01 DK103135/DK/NIDDK NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; U01 DK084536/DK/NIDDK NIH HHS/United States ; UL1 TR001425/TR/NCATS NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; UL1 TR001855/TR/NCATS NIH HHS/United States ; R01 DK055710/DK/NIDDK NIH HHS/United States ; R01 DK064008/DK/NIDDK NIH HHS/United States ; UL1 TR000077/TR/NCATS NIH HHS/United States ; U01 DK103149/DK/NIDDK NIH HHS/United States ; R01 DK083781/DK/NIDDK NIH HHS/United States ; U24 DK062456/DK/NIDDK NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; U01 DK062500/DK/NIDDK NIH HHS/United States ; U01 DK062497/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Age Factors ; Animals ; Biliary Atresia/diagnosis/*genetics/mortality/*therapy ; Case-Control Studies ; Child, Preschool ; Disease Models, Animal ; Female ; Gene Expression Profiling/*methods ; Gene Regulatory Networks ; Genetic Markers ; Genetic Predisposition to Disease ; Humans ; Infant ; Liver Transplantation ; Male ; Mice, Inbred BALB C ; Phenotype ; Predictive Value of Tests ; Progression-Free Survival ; RNA, Messenger/*genetics ; Risk Assessment ; Risk Factors ; Time Factors ; *Transcriptome ; Treatment Outcome ; }, abstract = {BACKGROUND &amp; AIMS: Little is known about the factors that affect outcomes of patients with biliary atresia and there are no medical therapies that increase biliary drainage.<br><br>METHODS: Liver biopsies and clinical data were obtained from infants with cholestasis and from children without liver disease (controls); messenger RNA (mRNA) was isolated, randomly assigned to discovery (n&#xa0;= 121) and validation sets (n&#xa0;= 50), and analyzed by RNA sequencing. Using the Superpc R package followed by Cox regression analysis, we sought to identify gene expression profiles that correlated with survival without liver transplantation at 24 months of age. We also searched for combinations of gene expression patterns, clinical factors, and laboratory results obtained at diagnosis and at 1 and 3 months after surgery that associated with transplant-free survival for 24 months of age. We induced biliary atresia in BALB/c mice by intraperitoneal administration of Rhesus rotavirus type A. Mice were given injections of the antioxidants N-acetyl-cysteine (NAC) or manganese (III) tetrakis-(4-benzoic acid)porphyrin. Blood and liver tissues were collected and analyzed by histology and immunohistochemistry.<br><br>RESULTS: We identified a gene expression pattern of 14 mRNAs associated with shorter vs longer survival times in the discovery and validation sets (P < .001). This gene expression signature, combined with level of bilirubin 3 months after hepatoportoenterostomy, identified children who survived for 24 months with an area under the curve value of 0.948 in the discovery set and 0.813 in the validation set (P < .001). Computer models correlated a cirrhosis-associated transcriptome with decreased times of transplant-free survival; this transcriptome included activation of genes that regulate the extracellular matrix and numbers of activated stellate cells and portal fibroblasts. Many mRNAs expressed at high levels in liver tissues from patients with 2-year transplant-free survival had enriched scores for glutathione metabolism. Among mice with biliary atresia given injections of antioxidants, only NAC reduced histologic features of liver damage and serum levels of aminotransferase, gamma-glutamyl transferase, and bilirubin. NAC also reduced bile duct obstruction and liver fibrosis and increased survival times.<br><br>CONCLUSIONS: In studies of liver tissues from infants with cholestasis, we identified a 14-gene expression pattern that associated with transplant-free survival for 2 years. mRNAs encoding proteins that regulate fibrosis genes were increased in liver tissues from infants who did not survive for 2 years, whereas mRNAs that encoded proteins that regulate glutathione metabolism were increased in infants who survived for 2 years. NAC reduced liver injury and fibrosis in mice with biliary atresia, and increased survival times. Agents such as NAC that promote glutathione metabolism might be developed for treatment of biliary atresia.}, }
@article {pmid31223283, year = {2019}, author = {Chen, Z and Gong, L and Zhang, P and Li, Y and Liu, B and Zhang, L and Zhuang, J and Xiao, D}, title = {Epigenetic Down-Regulation of Sirt 1 via DNA Methylation and Oxidative Stress Signaling Contributes to the Gestational Diabetes Mellitus-Induced Fetal Programming of Heart Ischemia-Sensitive Phenotype in Late Life.}, journal = {International journal of biological sciences}, volume = {15}, number = {6}, pages = {1240-1251}, pmid = {31223283}, issn = {1449-2288}, support = {R01 HL135623/HL/NHLBI NIH HHS/United States ; P01 HD083132/HD/NICHD NIH HHS/United States ; R01 HD088039/HD/NICHD NIH HHS/United States ; R01 HL118861/HL/NHLBI NIH HHS/United States ; R03 DA041492/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; *DNA Methylation ; Diabetes Mellitus, Experimental ; *Diabetes, Gestational ; Down-Regulation ; Epigenomics ; Female ; Fetal Development/*genetics ; Genetic Predisposition to Disease ; Myocardial Ischemia/*genetics ; Oxidative Stress ; Pregnancy ; Prenatal Exposure Delayed Effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Signal Transduction ; Sirtuin 1/*genetics ; }, abstract = {Rationale: The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. However, whether and how GDM exposure induces fetal programming of adult cardiac dysfunctional phenotype, especially the underlying epigenetic molecular mechanisms and theranostics remain unclear. To address this problem, we developed a late GDM rat model. Methods: Pregnant rats were made diabetic on day 12 of gestation by streptozotocin (STZ). Experiments were conducted in 6 weeks old offspring. Results: There were significant increases in ischemia-induced cardiac infarction and gender-dependent left ventricular (LV) dysfunction in male offspring in GDM group as compared to controls. Exposure to GDM enhanced ROS level and caused a global DNA methylation in offspring cardiomyocytes. GDM attenuated cardiac Sirt 1 protein and p-Akt/Akt levels, but enhanced autophagy-related proteins expression (Atg 5 and LC3 II/LC3 I) as compared to controls. Ex-vivo treatment of DNA methylation inhibitor, 5-Aza directly inhibited Dnmt3A and enhanced Sirt 1 protein expression in fetal hearts. Furthermore, treatment with antioxidant, N-acetyl-cysteine (NAC) in offspring reversed GDM-mediated DNA hypermethylation, Sirt1 repression and autophagy-related gene protein overexpression in the hearts, and rescued GDM-induced deterioration in heart ischemic injury and LV dysfunction. Conclusion: Our data indicated that exposure to GDM induced offspring cardiac oxidative stress and DNA hypermethylation, resulting in an epigenetic down-regulation of Sirt1 gene and aberrant development of heart ischemia-sensitive phenotype, which suggests that Sirt 1-mediated signaling is the potential therapeutic target for the heart ischemic disease in offspring.}, }
@article {pmid31223022, year = {2019}, author = {Gunturk, EE and Yucel, B and Gunturk, I and Yazici, C and Yay, A and Kose, K}, title = {The effects of N-acetylcysteine on cisplatin induced cardiotoxicity.}, journal = {Bratislavske lekarske listy}, volume = {120}, number = {6}, pages = {423-428}, doi = {10.4149/BLL_2019_068}, pmid = {31223022}, issn = {0006-9248}, mesh = {*Acetylcysteine/pharmacology ; Animals ; *Antineoplastic Agents/toxicity ; *Antioxidants/pharmacology ; Cardiotoxicity ; *Cisplatin/toxicity ; Oxidative Stress ; Rats ; }, abstract = {OBJECTIVES: Recent studies reported that oxidative stress is an important mechanism that contributes to cisplatin induced cardiotoxicity. In the present study, the effects of N-acetylcysteine (NAC), which is an antioxidant, on cisplatin induced cardiotoxicity were investigated in a rat model.<br><br>METHODS: Thirty two rats were separated into 4 equal groups: Control, NAC-250, CP (cisplatin), CP+NAC. Rats in the experimental groups were treated with a single dose of cisplatin intraperitoneally (ip) (10 mg/kg) and NAC (ip, 250 mg/kg) for 3 consecutive days. At the end of the experiment, cardiotoxicity was determined from plasma CK-MB, LDH, cTnI and cardiac myosin light chain-1 (CMLC-1) levels. In the tissue samples, total oxidant capacity (TOC), total antioxidant capacity (TAC), lipid hydroperoxide (ROOH) and thiol levels were measured. The hearts were also analyzed histopathologically.<br><br>RESULTS: It was determined that cisplatin increased the tissue TOC, ROOH levels and decreased TAC and thiol levels. NAC administration after cisplatin treatment was observed to have ameliorated histological and functional changes in heart.<br><br>CONCLUSIONS: In conclusion, the results of this experimental study suggested that oxidative stress had a serious effect on cisplatin cardiotoxicity, and NAC could be used as a therapeutic agent in addition to standard cisplatin treatment protocols (Tab. 3, Fig. 1, Ref. 35).}, }
@article {pmid31221193, year = {2019}, author = {Gouveia, MJ and Brindley, PJ and Azevedo, C and Gärtner, F and da Costa, JMC and Vale, N}, title = {The antioxidants resveratrol and N-acetylcysteine enhance anthelmintic activity of praziquantel and artesunate against Schistosoma mansoni.}, journal = {Parasites &amp; vectors}, volume = {12}, number = {1}, pages = {309}, pmid = {31221193}, issn = {1756-3305}, support = {R01 CA164719/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Antiprotozoal Agents/*pharmacology ; Artesunate/*pharmacology ; Biomphalaria/drug effects ; Drug Synergism ; Female ; Larva/drug effects ; Male ; Plant Extracts/pharmacology ; Praziquantel/*pharmacology ; Resveratrol/*pharmacology ; Schistosoma mansoni/*drug effects ; Schistosomiasis/drug therapy ; }, abstract = {BACKGROUND: Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. Despite its celebrated performance for treatment and control of schistosomiasis and other platyhelminth infections, praziquantel has some shortcomings and the inability of this drug to counteract disease sequelae prompts the need for novel therapeutic strategies.<br><br>METHODS: Using a host-parasite model involving Biomphalaria glabrata and Schistosoma mansoni we established mechanical transformation of S. mansoni cercariae into newly transformed schistosomula (NTS) and characterized optimal culture conditions. Thereafter, we investigated the antischistosomal activity and ability of the antioxidants N-acetylcysteine (NAC) and resveratrol (RESV) to augment the performance of praziquantel and/or artesunate (AS) against larval stages of the parasite. Drug effects were evaluated by using an automated microscopical system to study live and fixed parasites and by transmission electron microscopy (TEM).<br><br>RESULTS: Transformation rates of cercariae to schistosomula reached ~&#x2009;70% when the manipulation process was optimized. Several culture media were tested, with M199 supplemented with HEPES found to be suitable for S. mansoni NTS. Among the antioxidants studied, RESV alone or combined with anthelminthic drugs achieved better results rather N-acetylcysteine (NAC). TEM observations demonstrated that the combination of AS&#x2009;+&#x2009;RESV induced severe, extensive alterations to the tegument and subtegument of NTS when compared to the constituent compounds alone. Two anthelmintic-antioxidant combinations, praziquantel-resveratrol [combination index (CI)&#x2009;=&#x2009;0.74] and artesunate-resveratrol (CI&#x2009;=&#x2009;0.34) displayed moderate and strong synergy, respectively.<br><br>CONCLUSIONS: The use of viability markers including staining with propidium iodide increased the accuracy of drug screening assays against S. mansoni NTS. The synergies observed might be the consequence of increased action by RESV on targets of AS and PZQ and/or they may act through concomitantly on discrete targets to enhance overall antischistosomal action. Combinations of active agents, preferably with discrete modes of action including activity against developmental stages and/or the potential to ameliorate infection-associated pathology, might be pursued in order to identify novel therapeutic interventions.}, }
@article {pmid31216504, year = {2019}, author = {Gour, R and Ahmad, F and Prajapati, SK and Giri, SK and Lal Karna, SK and Kartha, KPR and Pokharel, YR}, title = {Synthesis of novel S-linked dihydroartemisinin derivatives and evaluation of their anticancer activity.}, journal = {European journal of medicinal chemistry}, volume = {178}, number = {}, pages = {552-570}, doi = {10.1016/j.ejmech.2019.06.018}, pmid = {31216504}, issn = {1768-3254}, mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Artemisinins/chemical synthesis/chemistry/*pharmacology ; Cell Cycle/drug effects ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Molecular Docking Simulation ; Molecular Structure ; PC-3 Cells ; Reactive Oxygen Species/analysis ; Structure-Activity Relationship ; Wound Healing/drug effects ; }, abstract = {We report herein the synthesis and anticancer activity of a set of novel S-linked artemisinins bearing an aliphatic/aromatic/heterocyclic nucleus as a substituent on the sulfur. The compounds were prepared from artemisinin via its lactol-form by an acid-catalyzed condensation of the desired thiol with the lactol. Both the C-10-α- and β-configured thiol ethers were synthesized with a view to making them available for the anticancer activity evaluation using a variety of cell lines. The results show that many of the synthetic derivatives studied possessed good potential as anticancer agents. In order to draw more information on the origin of the anticancer activity, one of the compounds (9a), that showed a broad-spectrum activity in terms of reducing the viability of most of the cell lines studied, in particular proven to be most effective against Prostate (PC-3) cells, was studied in detail to find the underlying mechanism of its action by MTT assay, immunoblotting, flow cytometry and microscopy. Pretreatment of the PC-3 cells with N-acetyl cysteine affected the efficacy of 9a, suggesting the role of reactive oxygen species in reducing their viability. Cell cycle analysis showed increase in G1 phase that was indicative of G1 cell cycle arrest. Wound healing assay revealed anti-migratory effect of 9a Quantitative PCR and western blot analysis showed changes in the gene expression of PCNA, E2F1, Pin1, cyclinD1, phospho-c-jun, c-Myc, eIF4E and other genes involved in proliferation and maintaining the transformed phenotype of prostate cancer cells. Here we report the anti-proliferative property of 9a with a vital and potent target(s) in prostate cancer cells with one of such targets being Pin1 belonging to the parvulin family of PPIases. The results suggest that 9a could be a promising agent in combating prostate cancer.}, }
@article {pmid31213808, year = {2019}, author = {El-Shorbagy, HM and Eissa, SM and Sabet, S and El-Ghor, AA}, title = {Apoptosis and oxidative stress as relevant mechanisms of antitumor activity and genotoxicity of ZnO-NPs alone and in combination with N-acetyl cysteine in tumor-bearing mice.}, journal = {International journal of nanomedicine}, volume = {14}, number = {}, pages = {3911-3928}, pmid = {31213808}, issn = {1178-2013}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Apoptosis/drug effects/genetics ; Caspase 3/metabolism ; DNA Damage/drug effects ; Gene Expression Regulation/drug effects ; Humans ; Mice, Inbred C57BL ; Nanoparticles/*toxicity/ultrastructure ; Neoplasms/*pathology ; Organ Specificity/drug effects ; *Oxidative Stress/drug effects ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Tissue Distribution/drug effects ; Tumor Suppressor Protein p53/metabolism ; Zinc Oxide/*toxicity ; }, abstract = {Background: Several in vitro studies have revealed that zinc oxide nanoparticles (ZnO-NPs) were able to target cancerous cells selectively with minimal damage to healthy cells. Purpose: In the current study, we aimed to evaluate the antitumor activity of ZnO-NPs in Ehrlich solid carcinoma (ESC) bearing mice by measuring their effect on the expression levels of P53, Bax and Bcl2 genes as indicators of apoptotic induction in tumor tissues. Also, we assessed the potential ameliorative or potentiation effect of 100 mg/kg N-acetyl cysteine (NAC) in combination with ZnO-NPs. Materials and methods: ESC bearing mice were gavaged with three different doses of ZnO-NPs (50, 300 and 500 mg/kg body weight) alone or in combination with NAC for seven consecutive days. In addition to measuring the tumor size, pathological changes, zinc content, oxidative stress biomarkers and DNA damage in ESC, normal muscle, liver and kidney tissues were assessed. Results: Data revealed a significant reduction in tumor size with a significant increase in p53 and Bax and decrease in Bcl2 expression levels in the tissues of ZnO-NPs treated ESC bearing mice. Moreover, a significant elevation of MDA accompanied with a significant reduction of CAT and GST. Also, a marked increase in all comet assay parameters was detected in ZnO-NPs treated groups. On the other hand, the combined treatment with ZnO-NPs and NAC significantly reduced reactive oxygen species production and DNA damage in liver and kidney tissues in all ZnO-NPs treated groups. Conclusion: ZnO-NPs exhibited a promising anticancer efficacy in ESC, this could serve as a foundation for developing new cancer therapeutics. Meanwhile, the combined treatment with ZnO-NPs and NAC could act as a protective method for the healthy normal tissue against ZnO-NPs toxicity, without affecting its antitumor activity.}, }
@article {pmid31212064, year = {2019}, author = {García-Arroyo, FE and Gonzaga, G and Muñoz-Jiménez, I and Osorio-Alonso, H and Iroz, A and Vecchio, M and Tapia, E and Roncal-Jiménez, CA and Johnson, RJ and Sánchez-Lozada, LG}, title = {Antioxidant supplements as a novel mean for blocking recurrent heat stress-induced kidney damage following rehydration with fructose-containing beverages.}, journal = {Free radical biology &amp; medicine}, volume = {141}, number = {}, pages = {182-191}, doi = {10.1016/j.freeradbiomed.2019.06.016}, pmid = {31212064}, issn = {1873-4596}, mesh = {Active Transport, Cell Nucleus ; Aldehyde Reductase/metabolism ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; *Beverages ; Blood Pressure ; Cell Nucleus/metabolism ; Dehydration ; Fluid Therapy ; Fructokinases/metabolism ; Fructose/*adverse effects ; Glutathione/metabolism ; *Heat-Shock Response ; Kidney Diseases/*metabolism ; Male ; Nitric Oxide Synthase Type III/metabolism ; Polymers/metabolism ; Protein Transport ; Rats ; Rats, Wistar ; }, abstract = {Recently repeated heat stress and dehydration have been reported to cause oxidative stress and kidney damage that is enhanced by rehydrating with fructose solutions. We hypothesized that antioxidants might provide a novel way to prevent kidney damage. To test this hypothesis, mild heat stress was induced by exposing rats to 37 °C during 1 h in a closed chamber. The supplementation with water-soluble antioxidants (Antiox), ascorbic acid 1% plus N-acetyl cysteine 600 mg/L was done either in the 10% fructose 2 h rehydration fluid immediately after heat stress (Fructose 10% + Antiox), and/or in the tap water (Water + Antiox) for the remainder of the day, or in both fluids. After 4 weeks, control rats exposed to heat with fructose rehydration developed impaired renal function, tubular injury, intrarenal oxidative stress, a reduction in Nrf2-Keap1 antioxidant pathway, stimulation of vasopressin and the intrarenal polyol-fructokinase pathway. In contrast, dosing the antioxidants in the tap water (i.e., before the heat exposure and rehydration with fructose) preserved renal function, prevented renal tubule dysfunction and avoided the increase in systemic blood pressure. These effects were likely due to the amplification of the antioxidant defenses through increased Nrf2 nuclear translocation stimulated by the antioxidants and by the prevention of polyol fructokinase pathway overactivation. More studies to understand the mechanisms implicated in this pathology are warranted as there is recent evidence that they may be operating in humans as well.}, }
@article {pmid31211651, year = {2020}, author = {Shen, Y and Li, P and Chen, X and Zou, Y and Li, H and Yuan, G and Hu, H}, title = {Activity of Sodium Lauryl Sulfate, Rhamnolipids, and N-Acetylcysteine Against Biofilms of Five Common Pathogens.}, journal = {Microbial drug resistance (Larchmont, N.Y.)}, volume = {26}, number = {3}, pages = {290-299}, doi = {10.1089/mdr.2018.0385}, pmid = {31211651}, issn = {1931-8448}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/pharmacology ; Biofilms/*drug effects/growth &amp; development ; Culture Media/chemistry/pharmacology ; Escherichia coli/drug effects/growth &amp; development ; Glycolipids/*pharmacology ; Helicobacter pylori/*drug effects/growth &amp; development ; Microbial Sensitivity Tests ; Plankton/drug effects/growth &amp; development ; Pseudomonas aeruginosa/drug effects/growth &amp; development ; Sodium Dodecyl Sulfate/*pharmacology ; Staphylococcus aureus/*drug effects/growth &amp; development ; Streptococcus mutans/drug effects/growth &amp; development ; }, abstract = {Bacteria in biofilms are more resistant to antibacterial agents than bacteria in planktonic form. Hence, antibacterial agents should be able to eradicate biofilms to ensure the best outcomes. Little is known about how well many antibacterial agents can disrupt biofilms. In this study, we compared sodium lauryl sulfate (SDS), rhamnolipids (RHL), and N-acetylcysteine (NAC) for their ability to eradicate mature biofilms and inhibit new biofilm formation against Helicobacter pylori, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus mutans. SDS and RHL effectively inhibited formation of five bacterial biofilms in a dose-dependent manner, even at concentrations below the minimal inhibitory concentrations (MICs), suggesting that their antibiofilm activities are unrelated to their antibacterial activities. In contrast, NAC at certain concentrations promoted biofilm formation by all bacteria except P. aeruginosa, whereas at supra-MIC concentrations, it inhibited biofilm formation against the four bacteria, suggesting that its antibiofilm activity depends on its antibacterial activity. NAC was ineffective at eradicating mature H. pylori biofilms, and it actually promoted their formation at concentrations >10 mg/mL. Our results suggest that RHL is superior at eradicating biofilms of H. pylori, E. coli, and S. mutans; SDS is more effective against S. aureus biofilms; and NAC is more effective against P. aeruginosa biofilms. Our results may help determine which antibiofilm agents are effective against certain bacterial strains and develop agents effective against specific bacterial threats.}, }
@article {pmid31207966, year = {2019}, author = {Riegger, J and Leucht, F and Palm, HG and Ignatius, A and Brenner, RE}, title = {Initial Harm Reduction by N-Acetylcysteine Alleviates Cartilage Degeneration after Blunt Single-Impact Cartilage Trauma in Vivo.}, journal = {International journal of molecular sciences}, volume = {20}, number = {12}, pages = {}, pmid = {31207966}, issn = {1422-0067}, support = {E/U2A/CD524/DF560//German Mistry of Defense/ ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Bone Morphogenetic Protein 7/pharmacology/therapeutic use ; Cartilage/drug effects/injuries/*metabolism/physiology ; Collagen Type II/metabolism ; Female ; Matrix Metalloproteinase 13/metabolism ; Osteoarthritis/*drug therapy/etiology ; Rabbits ; *Regeneration ; Wounds, Nonpenetrating/*complications/drug therapy ; }, abstract = {Joint injuries are highly associated with the development of post-traumatic osteoarthritis. Previous studies revealed cell- and matrix-protective effects of N-acetylcysteine (NAC) after ex vivo cartilage trauma, while chondroanabolic stimulation with bone morphogenetic protein 7 (BMP7) enhanced type II collagen (COL2) expression. Here, as a next step, we investigated the combined and individual efficacy of intra-articular antioxidative and chondroanabolic treatment in a rabbit in vivo cartilage trauma model. Animals were randomly divided into group A (right joint: trauma (T); left joint: T+BMP7) and group B (right joint: T+NAC; left joint: T+BMP7+NAC). Condyles were impacted with the use of a spring-loaded impact device to ensure defined, single trauma administration. After 12 weeks, histopathological analysis was performed and the presence of matrix metalloproteinase 13 (MMP-13) and COL2 was assessed. Trauma-induced hypocellularity, MMP-13 expression, and cell cluster formation were reduced in NAC-treated animals. In contrast, BMP7 further increased cluster formation. Moreover, synovial concentrations of COL2 carboxy propeptide (CPII) and proteoglycan staining intensities were enhanced in NAC- and NAC+BMP7-treated joints. For the first time, the efficacy of NAC regarding early harm reduction after blunt cartilage trauma was demonstrated in vivo. However, parallel administration of BMP7 was not significantly superior compared to NAC alone.}, }
@article {pmid31207191, year = {2019}, author = {Echtermeyer, F and Eberhardt, M and Risser, L and Herzog, C and Gueler, F and Khalil, M and Engel, M and Vondran, F and Leffler, A}, title = {Acetaminophen-induced liver injury is mediated by the ion channel TRPV4.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {33}, number = {9}, pages = {10257-10268}, doi = {10.1096/fj.201802233R}, pmid = {31207191}, issn = {1530-6860}, mesh = {Acetaminophen/*toxicity ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/etiology/metabolism/*pathology ; Hepatocytes/drug effects/metabolism/*pathology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Necrosis ; TRPV Cation Channels/antagonists &amp; inhibitors/*physiology ; }, abstract = {Overdosing of the analgesic acetaminophen (APAP) is one of the most common causes for acute liver failure in modern countries. Although the exact molecular mechanisms mediating hepatocellular necrosis are still elusive, it is preceded by oxidative stress triggered by excessive levels of the metabolite N-acetyl-para-benzoquinone imine (NAPQI). Here, we describe the role of the redox-sensitive transient receptor potential (TRP) ion channel TRP vanilloid 4 (TRPV4) for APAP-induced hepatoxicity. Both pharmacological inhibition and genetic deletion of TRPV4 ameliorate APAP-induced necrosis in mouse and human hepatocytes in vitro. Liver injury caused by a systemic overdose of APAP is reduced in TRPV4-deficient mice and in wild-type mice treated with a TRPV4 inhibitor. The reduction of hepatotoxicity accomplished by systemic TRPV4 inhibition is comparable to the protective effects of the antioxidant N-acetyl-cysteine. Although TRPV4 does not modulate intrahepatic levels of glutathione, both its inhibition and genetic deletion attenuate APAP-induced oxidative and nitrosative stress as well as mitochondrial membrane depolarization. NAPQI evokes a calcium influx by activating heterologously expressed TRPV4 channels and endogenous TRPV4 channels in hepatoma cells but not in primary mouse hepatocytes. Taken together, our data suggest that TRPV4 mediates APAP-induced hepatotoxicity and thus may be a suitable target for treatment of this critical side effect.-Echtermeyer, F., Eberhardt, M., Risser, L., Herzog, C., Gueler, F., Khalil, M., Engel, M., Vondran, F., Leffler, A. Acetaminophen-induced liver injury is mediated by the ion channel TRPV4.}, }
@article {pmid31206613, year = {2019}, author = {Monti, DA and Zabrecky, G and Kremens, D and Liang, TW and Wintering, NA and Bazzan, AJ and Zhong, L and Bowens, BK and Chervoneva, I and Intenzo, C and Newberg, AB}, title = {N-Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson's Disease.}, journal = {Clinical pharmacology and therapeutics}, volume = {106}, number = {4}, pages = {884-890}, doi = {10.1002/cpt.1548}, pmid = {31206613}, issn = {1532-6535}, mesh = {*Acetylcysteine/administration &amp; dosage/pharmacokinetics ; Administration, Oral ; Aged ; Antioxidants/administration &amp; dosage/pharmacokinetics ; Dopamine Plasma Membrane Transport Proteins/*metabolism ; Drug Monitoring/methods ; Female ; Functional Neuroimaging/methods ; Humans ; Infusions, Intravenous ; Male ; *Parkinson Disease/diagnosis/drug therapy ; *Putamen/diagnostic imaging/metabolism ; Symptom Assessment/methods ; Treatment Outcome ; }, abstract = {This study assessed the biological and clinical effects in patients with Parkinson's disease (PD) of N-acetyl-cysteine (NAC), the prodrug to l-cysteine, a precursor to the natural biological antioxidant glutathione. Forty-two patients with PD were randomized to either weekly intravenous infusions of NAC (50 mg/kg) plus oral doses (500 mg twice per day) for 3 months or standard of care only. Participants received prebrain and postbrain imaging with ioflupane (DaTscan) to measure dopamine transporter (DAT) binding. In the NAC group, significantly increased DAT binding was found in the caudate and putamen (mean increase from 3.4% to 8.3%) compared with controls (P < 0.05), along with significantly improved PD symptoms (P < 0.0001). The results suggest NAC may positively affect the dopaminergic system in patients with PD, with corresponding positive clinical effects. Larger scale studies are warranted.}, }
@article {pmid31206177, year = {2019}, author = {Zhang, Y and Zhao, W and Xu, H and Hu, M and Guo, X and Jia, W and Liu, G and Li, J and Cui, P and Lager, S and Sferruzzi-Perri, AN and Li, W and Wu, XK and Han, Y and Brännström, M and Shao, LR and Billig, H}, title = {Hyperandrogenism and insulin resistance-induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome.}, journal = {The Journal of physiology}, volume = {597}, number = {15}, pages = {3927-3950}, doi = {10.1113/JP277879}, pmid = {31206177}, issn = {1469-7793}, support = {MR/R022690/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Abortion, Spontaneous/etiology/*metabolism/physiopathology ; Animals ; Dihydrotestosterone/toxicity ; Female ; Glycogen/metabolism ; Hyperandrogenism/*complications ; Insulin Resistance ; Kelch-Like ECH-Associated Protein 1/metabolism ; Mitochondria/*metabolism/pathology ; NF-E2-Related Factor 2/metabolism ; Polycystic Ovary Syndrome/*metabolism/physiopathology ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase-1/metabolism ; Trophoblasts/*metabolism/pathology ; }, abstract = {KEY POINTS: Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown. Herein, pregnant rats chronically treated with 5α-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients. Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS) and impaired formation of the placenta. Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin. Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant rats. Our results provide insight into the fetal loss associated with hyperandrogenism and insulin resistance in women and suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.<br><br>ABSTRACT: Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5&#x3b1;-dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin-treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed superoxide dismutase 1 (SOD1) and Keap1/Nrf2 antioxidant responses constitute important contributors to fetal loss in DHT+insulin-treated pregnant rats. Many of the molecular pathways leading to placental abnormalities and fetal loss in DHT+insulin treatment were also seen in pregnant rats treated with DHT alone, whereas pregnant rats treated with insulin alone often exerted distinct effects on placental gene expression compared to insulin treatment in combination with DHT. We also found that treatment with the antioxidant N-acetylcysteine (NAC) improved fetal survival in DHT+insulin-treated pregnant rats, an effect related to changes in Keap1/Nrf2 and nuclear factor-&#x3ba;B signalling. However, NAC administration resulted in fetal loss in normal pregnant rats, most likely due to PCOS-like endocrine abnormality induced by the treatment. Our results suggest that the deleterious effects of hyperandrogenism and insulin resistance on fetal survival are related to a constellation of mitochondria-ROS-SOD1/Nrf2 changes in the placenta. Our findings also suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.}, }
@article {pmid31202080, year = {2019}, author = {Rastogi, A and Clark, CW and Conlin, SM and Brown, SE and Timme-Laragy, AR}, title = {Mapping glutathione utilization in the developing zebrafish (Danio rerio) embryo.}, journal = {Redox biology}, volume = {26}, number = {}, pages = {101235}, pmid = {31202080}, issn = {2213-2317}, support = {R01 ES025748/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Alkanesulfonic Acids/toxicity ; Animals ; Brain/drug effects/growth &amp; development/*metabolism ; Diethylhexyl Phthalate/analogs &amp; derivatives/toxicity ; Embryo, Nonmammalian ; Ethacrynic Acid/pharmacology ; Fluorescent Dyes/*chemistry ; Fluorocarbons/toxicity ; Glutathione/*metabolism ; Glutathione Transferase/antagonists &amp; inhibitors/metabolism ; Heart/drug effects/growth &amp; development ; Organogenesis/drug effects/physiology ; Pyrazoles/*chemistry ; Staining and Labeling/*methods ; Toxicity Tests, Chronic ; Zebrafish/embryology/growth &amp; development/*metabolism ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {Glutathione (GSH), the most abundant vertebrate endogenous redox buffer, plays key roles in organogenesis and embryonic development, however, organ-specific GSH utilization during development remains understudied. Monochlorobimane (MCB), a dye conjugated with GSH by glutathione-s-transferase (GST) to form a fluorescent adduct, was used to visualize organ-specific GSH utilization in live developing zebrafish (Danio rerio) embryos. Embryos were incubated in 20 μM MCB for 1 h and imaged on an epifluorescence microscope. GSH conjugation with MCB was high during early organogenesis, decreasing as embryos aged. The heart had fluorescence 21-fold above autofluorescence at 24 hpf, dropping to 8.5-fold by 48 hpf; this increased again by 72 hpf to 23.5-fold, and stayed high till 96 hpf (18-fold). The brain had lower fluorescence (10-fold) at 24 and 48 hpf, steadily increasing to 30-fold by 96 hpf. The sensitivity and specificity of MCB staining was then tested with known GSH modulators. A 10-min treatment at 48 hpf with 750 μM tert-butylhydroperoxide, caused organ-specific reductions in staining, with the heart losing 30% fluorescence, and, the brain ventricle losing 47% fluorescence. A 24 h treatment from 24-48 hpf with 100 μM of N-Acetylcysteine (NAC) resulted in significantly increased fluorescence, with the brain ventricle and heart showing 312% and 240% increases respectively, these were abolished upon co-treatment with 5 μM BSO, an inhibitor of the enzyme that utilizes NAC to synthesize GSH. A 60 min 100 μM treatment with ethacrynic acid, a specific GST inhibitor, caused 30% reduction in fluorescence across all measured structures. MCB staining was then applied to test for GSH disruptions caused by the toxicants perfluorooctanesulfonic acid and mono-(2-ethyl-hexyl)phthalate; MCB fluorescence responded in a dose, structure and age-dependent manner. MCB staining is a robust, sensitive method to detect spatiotemporal changes in GSH utilization, and, can be applied to identify sensitive target tissues of toxicants.}, }
@article {pmid31200101, year = {2019}, author = {Virel, A and Dudka, I and Laterveer, R and Af Bjerkén, S}, title = {[1]H NMR profiling of the 6-OHDA parkinsonian rat brain reveals metabolic alterations and signs of recovery after N-acetylcysteine treatment.}, journal = {Molecular and cellular neurosciences}, volume = {98}, number = {}, pages = {131-139}, doi = {10.1016/j.mcn.2019.06.003}, pmid = {31200101}, issn = {1095-9327}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antiparkinson Agents/*pharmacology ; Brain/drug effects/*metabolism ; Female ; *Metabolome ; Oxidative Stress ; Oxidopamine/toxicity ; Parkinson Disease/etiology/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disease caused by degeneration of dopamine neurons in the substantia nigra. The origin and causes of dopamine neurodegeneration in Parkinson's disease are not well understood but oxidative stress may play an important role in its onset. Much effort has been dedicated to find biomarkers indicative of oxidative stress and neurodegenerative processes in parkinsonian brains. By using proton nuclear magnetic resonance ([1]H NMR) to identify and quantify key metabolites, it is now possible to elucidate the metabolic pathways affected by pathological conditions like neurodegeneration. The metabolic disturbances in the 6-hydroxydopamine (6-OHDA) hemiparkinsonian rat model were monitored and the nature and size of these metabolic alterations were analyzed. The results indicate that a unilateral injection of 6-OHDA into the striatum causes metabolic changes that not only affect the injected hemisphere but also the contralateral, non-lesioned side. We could clearly identify specific metabolic pathways that were affected, which were mostly related with oxidative stress and neurotransmission. In addition, a partial metabolic recovery by carrying out an antioxidant treatment with N-acetylcysteine (NAC) was observable.}, }
@article {pmid31199953, year = {2019}, author = {Christiansen, D and Eibye, KH and Hostrup, M and Bangsbo, J}, title = {Blood flow-restricted training enhances thigh glucose uptake during exercise and muscle antioxidant function in humans.}, journal = {Metabolism: clinical and experimental}, volume = {98}, number = {}, pages = {1-15}, doi = {10.1016/j.metabol.2019.06.003}, pmid = {31199953}, issn = {1532-8600}, mesh = {Adult ; Antioxidants/*metabolism ; Diet ; Exercise Test ; Femoral Artery/physiology ; Glucose/*metabolism ; Glucose Transporter Type 4/metabolism ; Humans ; Male ; Muscle, Skeletal/*metabolism/*physiology ; Nitric Oxide/metabolism ; *Physical Education and Training ; Regional Blood Flow/physiology ; Rest/physiology ; Thigh/blood supply/*physiology ; Young Adult ; }, abstract = {This study examined the effects of blood-flow-restricted (BFR)-training on thigh glucose uptake at rest and during exercise in humans and the muscular mechanisms involved. Ten active men (~25 y; VO2max ~50 mL/kg/min) completed six weeks of training, where one leg trained with BFR (cuff pressure: ~180 mmHg) and the other leg without BFR. Before and after training, thigh glucose uptake was determined at rest and during exercise at 25% and 90% of leg incremental peak power output by sampling of femoral arterial and venous blood and measurement of femoral arterial blood flow. Furthermore, resting muscle samples were collected. After training, thigh glucose uptake during exercise was higher than before training only in the BFR-trained leg (p < 0.05) due to increased glucose extraction (p < 0.05). Further, BFR-training substantially improved time to exhaustion during exhaustive exercise (11 ± 5% vs. CON-leg; p = 0.001). After but not before training, NAC infusion attenuated (~50-100%) leg net glucose uptake and extraction during exercise only in the BFR-trained leg, which coincided with an increased muscle abundance of Cu/Zn-SOD (39%), GPX-1 (29%), GLUT4 (28%), and nNOS (18%) (p < 0.05). Training did not affect Mn-SOD, catalase, and VEGF abundance in either leg (p > 0.05), although Mn-SOD was higher in BFR-leg vs. CON-leg after training (p < 0.05). The ratios of p-AMPK-Thr[172]/AMPK and p-ACC-Ser[79]/ACC, and p-ACC-Ser[79], remained unchanged in both legs (p > 0.05), despite a higher p-AMPK-Thr[172] in BFR-leg after training (38%; p < 0.05). In conclusion, BFR-training enhances glucose uptake by exercising muscles in humans probably due to an increase in antioxidant function, GLUT4 abundance, and/or NO availability.}, }
@article {pmid31199053, year = {2019}, author = {Wu, MS and Chien, CC and Chang, J and Chen, YC}, title = {Pro-apoptotic effect of haem oxygenase-1 in human colorectal carcinoma cells via endoplasmic reticular stress.}, journal = {Journal of cellular and molecular medicine}, volume = {23}, number = {8}, pages = {5692-5704}, pmid = {31199053}, issn = {1582-4934}, mesh = {*Apoptosis/drug effects ; Caspase Inhibitors/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Colorectal Neoplasms/*enzymology/*pathology ; Endoplasmic Reticulum Chaperone BiP ; *Endoplasmic Reticulum Stress/drug effects ; Enzyme Activation/drug effects ; Heat-Shock Proteins/metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Protoporphyrins/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Several biological effects of haem oxygenase (HO)-1, including anti-inflammatory, antiapoptotic and antioxidative properties were reported; however, the role of HO-1 in apoptosis is still unclear. In the presence of stimulation by cobalt protoporphyrin (CoPP), an HO-1 inducer, apoptotic characteristics were observed, including DNA laddering, hypodiploid cells, and cleavages of caspase (Casp)-3 and poly(ADP) ribose polymerase (PARP) proteins in human colon carcinoma COLO205, HCT-15, LOVO and HT-29 cells in serum-free (SF) conditions with increased HO-1, but not heat shock protein 70 (HSP70) or HSP90. The addition of 10% foetal bovine serum (FBS) or 1% bovine serum albumin accordingly inhibited CoPP-induced apoptosis and HO-1 protein expression in human colon cancer cells. CoPP-induced apoptosis of colon cancer cells was prevented by the addition of the pan-caspase inhibitor, Z-VAD-FMK (VAD), and the Casp-3 inhibitor, Z-DEVD-FMK (DEVD). N-Acetyl cysteine inhibited reactive oxygen species-generated H2 O2 -induced cell death with reduced intracellular peroxide production, but did not affect CoPP-induced apoptosis in human colorectal carcinoma (CRC) cells. Two CoPP analogs, ferric protoporphyrin and tin protoporphyrin, did not affect the viability of human CRC cells or HO-1 expression by those cells, and knockdown of HO-1 protein expression by HO-1 small interfering (si)RNA reversed the cytotoxic effect elicited by CoPP. Furthermore, the carbon monoxide (CO) donor, CORM, but not FeSO4 or biliverdin, induced DNA ladders, and cleavage of Casp-3 and PARP proteins in human CRC cells. Increased phosphorylated levels of the endoplasmic reticular (ER) stress proteins, protein kinase R-like ER kinase (PERK), and eukaryotic initiation factor 2α (eIF2α) by CORM and CoPP were identified, and the addition of the PERK inhibitor, GSK2606414, inhibited CORM- and CoPP-induced apoptosis. Increased GRP78 level and formation of the HO-1/GRP78 complex were detected in CORM- and CoPP-treated human CRC cells. A pro-apoptotic role of HO-1 against the viability of human CRC cells via induction of CO and ER stress was firstly demonstrated herein.}, }
@article {pmid31196186, year = {2019}, author = {Tataranni, T and Mazzoccoli, C and Agriesti, F and De Luca, L and Laurenzana, I and Simeon, V and Ruggieri, V and Pacelli, C and Della Sala, G and Musto, P and Capitanio, N and Piccoli, C}, title = {Deferasirox drives ROS-mediated differentiation and induces interferon-stimulated gene expression in human healthy haematopoietic stem/progenitor cells and in leukemia cells.}, journal = {Stem cell research &amp; therapy}, volume = {10}, number = {1}, pages = {171}, pmid = {31196186}, issn = {1757-6512}, mesh = {Blotting, Western ; Cell Differentiation/drug effects ; Cell Line ; Deferasirox/*pharmacology ; Gene Expression/drug effects ; HL-60 Cells ; Hematopoietic Stem Cells/*drug effects/*metabolism ; Humans ; Interferons/*pharmacology ; Leukemia/metabolism ; Mitochondria/*drug effects/*metabolism ; Phosphorylation/drug effects/genetics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; STAT1 Transcription Factor/genetics/metabolism ; Signal Transduction/drug effects/genetics ; }, abstract = {BACKGROUND: Administration of the iron chelator deferasirox (DFX) in transfusion-dependent patients occasionally results in haematopoiesis recovery by a mechanism remaining elusive. This study aimed to investigate at a molecular level a general mechanism underlying DFX beneficial effects on haematopoiesis, both in healthy and pathological conditions.<br><br>METHODS: Human healthy haematopoietic stem/progenitor cells (HS/PCs) and three leukemia cell lines were treated with DFX. N-Acetyl cysteine (NAC) and fludarabine were added as antioxidant and STAT1 inhibitor, respectively. In vitro colony-forming assays were assessed both in healthy and in leukemia cells. Intracellular and mitochondrial reactive oxygen species (ROS) as well as mitochondrial content were assessed by cytofluorimetric and confocal microscopy analysis; mtDNA was assessed by qRT-PCR. Differentiation markers were monitored by cytofluorimetric analysis. Gene expression analysis (GEA) was performed on healthy HS/PCs, and differently expressed genes were validated in healthy and leukemia cells by qRT-PCR. STAT1 expression and phosphorylation were assessed by Western blotting. Data were compared by an unpaired Student t test or one-way ANOVA.<br><br>RESULTS: DFX, at clinically relevant concentrations, increased the clonogenic capacity of healthy human CD34[+] HS/PCs to form erythroid colonies. Extension of this analysis to human-derived leukemia cell lines Kasumi-1, K562 and HL60 confirmed DFX capacity to upregulate the expression of specific markers of haematopoietic commitment. Notably, the abovementioned DFX-induced effects are all prevented by the antioxidant NAC and accompanied with overproduction of mitochondria-generated reactive oxygen species (ROS) and increase of mitochondrial content and mtDNA copy number. GEA unveiled upregulation of genes linked to interferon (IFN) signalling and tracked back to hyper-phosphorylation of STAT1. Treatment of leukemic cell lines with NAC prevented the DFX-mediated phosphorylation of STAT1 as well as the expression of the IFN-stimulated genes. However, STAT1 inhibition by fludarabine was not sufficient to affect differentiation processes in leukemic cell lines.<br><br>CONCLUSIONS: These findings suggest a significant involvement of redox signalling as a major regulator of multiple DFX-orchestrated events promoting differentiation in healthy and tumour cells. The understanding of molecular mechanisms underlying the haematological response by DFX would enable to predict patient's ability to respond to the drug, to extend treatment to other patients or to anticipate the treatment, regardless of the iron overload.}, }
@article {pmid31195971, year = {2019}, author = {Rodriguez, LR and Bui, SN and Beuschel, RT and Ellis, E and Liberti, EM and Chhina, MK and Cannon, B and Lemma, M and Nathan, SD and Grant, GM}, title = {Curcumin induced oxidative stress attenuation by N-acetylcysteine co-treatment: a fibroblast and epithelial cell in-vitro study in idiopathic pulmonary fibrosis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {25}, number = {1}, pages = {27}, pmid = {31195971}, issn = {1528-3658}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Curcumin/*pharmacology ; Epithelial Cells/*drug effects/*metabolism ; Fibroblasts/*drug effects/*metabolism ; Humans ; Idiopathic Pulmonary Fibrosis/*metabolism ; Oxidative Stress/*drug effects ; Polymerase Chain Reaction ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease of unknown etiology with only two federally approved drug options. Given the complex molecular pathogenesis of IPF involving multiple cell types and multiple pathways, we explore the effects of a potential antifibrotic and antioxidant drug combination. Curcumin is a polyphenolic compound derived from turmeric with significant biological activity including a potential antifibrotic capacity. N-acetylcysteine (NAC) is a precursor to the antioxidant glutathione. To advance our understanding of these molecules, and to identify a clinical application, we present a small number of focused experiments that interrogates the effect of curcumin and NAC on pathways relevant to IPF in both fibroblasts and epithelial cells.<br><br>METHODS: Primary epithelial cell and fibroblasts isolated from patients with IPF were challenged with a combination treatment of NAC and curcumin. Evaluation of the antifibrotic potential and effect on oxidative stress was performed through QPCR gene expression analysis and functional assays including scratch tests, viability assays, and measurement of induced reactive oxygen species.<br><br>RESULTS: We demonstrate that curcumin alone does have antifibrotic potential, but that effect is accompanied by proapoptotic increases in oxidative stress. Coupled with this, we find that NAC alone can reduce oxidative stress, but that epithelial cell viability is decreased through this treatment. However, co-administration of these two molecules decreases oxidative stress and maintains high cell viability in both cell types. In addition, this co-treatment maintains an antifibrotic potential.<br><br>CONCLUSIONS: These findings suggest a novel application for these molecules in IPF and encourage further exploration of this potential therapeutic approach.}, }
@article {pmid31193715, year = {2019}, author = {Tessier, MEM and Shneider, BL and Brandt, ML and Cerminara, DN and Harpavat, S}, title = {A phase 2 trial of N-Acetylcysteine in Biliary atresia after Kasai portoenterostomy.}, journal = {Contemporary clinical trials communications}, volume = {15}, number = {}, pages = {100370}, pmid = {31193715}, issn = {2451-8654}, support = {K23 DK109207/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Biliary atresia (BA) is a life-threatening liver disease of infancy, characterized by extrahepatic biliary obstruction, bile retention, and progressive liver injury. The Kasai portoenterostomy (KP) is BA's only nontransplant treatment. Its success is variable and depends on restoration of hepatic bile flow. Many adjunctive therapeutics have been studied to improve outcomes after the KP, but none demonstrate effectiveness. This study tests if N-acetylcysteine (NAC), a precursor to the choleretic glutathione, improves bile flow after KP.<br><br>METHODS: This report describes the design of an open-label, single center, Phase 2 study to determine the effect of NAC following KP on markers of bile flow and outcomes in BA. The intervention is intravenous NAC (150&#x202f;mg/kg/day) administered continuously for seven days starting 0-24&#x202f;h after KP. The primary outcome is normalization of total serum bile acid (TSBA) concentrations within 24 weeks of KP. The secondary objectives are to describe NAC therapy's effect on other clinical parameters followed in BA for 24 months and to report adverse events occurring with therapy. This study follows the "minimax" clinical trial design.<br><br>DISCUSSION: This is the first clinical trial to test NAC's effectiveness in improving bile flow after KP in BA. It introduces three important concepts for future BA therapeutic trials: (1) the "minimax" study design, a pertinent design for rare diseases because it detects potential effects quickly with small subject size; (2) the more sensitive bile flow marker, TSBAs, which may correlate with positive long-term outcomes better than traditional bile flow markers such as serum bilirubin; and (3) liver enzyme changes immediately after KP, which can be a guideline for potential drug-induced liver injury in other BA peri-operative adjunctive therapeutic trials.}, }
@article {pmid31186685, year = {2019}, author = {Zhang, X and Zhang, HM}, title = {Alantolactone induces gastric cancer BGC-823 cell apoptosis by regulating reactive oxygen species generation and the AKT signaling pathway.}, journal = {Oncology letters}, volume = {17}, number = {6}, pages = {4795-4802}, pmid = {31186685}, issn = {1792-1074}, abstract = {Alantolactone (ALT), a natural sesquiterpene lactone, has been suggested to exert anti-cancer activities in various cancer cell lines. However, the effects and mechanisms of action of ALT in human gastric cancer remains to be elucidated. In the present study, the effects of ALT on BGC-823 cells were examined and the underlying molecular mechanisms associated with these effects were investigated. Cell viability was detected by using an MTT assay. Cell cycle, cell apoptosis and the level of reactive oxygen species (ROS) were assessed by flow cytometry, and the expression levels of proteins of interest were analyzed by western blot assay. The results demonstrated that ALT triggered apoptosis and induced G0/G1 phase arrest in a dose-dependent manner. Furthermore, the expression level of the anti-apoptosis protein Bcl-2 was downregulated, and expression of the pro-apoptosis proteins Bax and cleaved PARP were significantly upregulated. The cell cycle-associated proteins cyclin-dependent kinase inhibitor 1 and cyclin-dependent kinase inhibitor 1B were also increased, while cyclin D1 was deceased. In addition, ALT induced apoptosis via the inhibition of RAC-alpha serine/threonine-protein kinase (AKT) signaling and ROS generation, which was effectively inhibited by the ROS scavenger, N-acetyl cysteine. Therefore, the results from the present study indicated that the ROS-mediated inhibition of the AKT signaling pathway serves an important role in ALT-induced apoptosis in BGC-823 cells. In conclusion, the results demonstrated that ALT exerted significant anti-cancer effects against gastric cancer cells in vitro.}, }
@article {pmid31185751, year = {2019}, author = {Jia, C and Zhang, J and Zhuge, Y and Xu, K and Liu, J and Wang, J and Li, L and Chu, M}, title = {Synergistic effects of geldanamycin with fluconazole are associated with reactive oxygen species in Candida tropicalis resistant to azoles and amphotericin B.}, journal = {Free radical research}, volume = {53}, number = {6}, pages = {618-628}, doi = {10.1080/10715762.2019.1610563}, pmid = {31185751}, issn = {1029-2470}, mesh = {Amphotericin B/pharmacology ; Antifungal Agents/chemistry/*pharmacology ; Azoles/pharmacology ; Benzoquinones/*pharmacology ; Candida tropicalis/*drug effects/growth &amp; development/metabolism ; Drug Resistance, Fungal/*drug effects ; Fluconazole/*pharmacology ; Lactams, Macrocyclic/*pharmacology ; Microbial Sensitivity Tests ; Mitochondria/drug effects/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {With a significant increase in the incidence of system invasive fungal infections, the limited antifungal drugs and increased frequency of cross-resistance make it necessary to explore new and effective therapeutic strategies. Combination drug therapy has become one widely used choice to alleviate this problem. Geldanamycin (GdA), as an inhibitor of Hsp90, displayed broad antifungal activity when combined with fluconazole. However, due to its cytotoxicity, the dose and duration of GdA is limited. In this study, we observed the effect of fluconazole plus GdA on Candida tropicalis resistant to azoles and amphotericin B. The results showed that this synergism led to a decrease in growth and survival rate. In addition, fluconazole combined with GdA caused mitochondrial depolarisation, disruption of plasma membrane integrity and multinucleated morphology. However, the supplement of a reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), rescued the above phenotypes. This study indicated that the oxidative stress mediated by fluconazole plus GdA played an important role in the antifungal activity, and targeting oxidative stress might extend target choices to treat fungal infections.}, }
@article {pmid31181621, year = {2019}, author = {Crinelli, R and Zara, C and Smietana, M and Retini, M and Magnani, M and Fraternale, A}, title = {Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and β-mercaptoethylamine.}, journal = {Nutrients}, volume = {11}, number = {6}, pages = {}, pmid = {31181621}, issn = {2072-6643}, support = {PRIN [Research Projects of National Interest] 2010-2011-prot. 2010PHT9NF_004//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; Antiviral Agents/metabolism/pharmacology ; Cysteamine/*metabolism ; Glutathione/deficiency/*metabolism ; Humans ; Immunologic Factors/metabolism/pharmacology ; Prodrugs/metabolism/*pharmacology ; Retroviridae/drug effects ; Sulfhydryl Compounds/metabolism ; Virus Diseases/metabolism ; }, abstract = {Glutathione (GSH) has poor pharmacokinetic properties; thus, several derivatives and biosynthetic precursors have been proposed as GSH-boosting drugs. I-152 is a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-β-mercaptoethylamine (SMEA) designed to release the parent drugs (i.e., NAC and β-mercaptoethylamine or cysteamine, MEA). NAC is a precursor of L-cysteine, while MEA is an aminothiol able to increase GSH content; thus, I-152 represents the very first attempt to combine two pro-GSH molecules. In this review, the in-vitro and in-vivo metabolism, pro-GSH activity and antiviral and immunomodulatory properties of I-152 are discussed. Under physiological GSH conditions, low I-152 doses increase cellular GSH content; by contrast, high doses cause GSH depletion but yield a high content of NAC, MEA and I-152, which can be used to resynthesize GSH. Preliminary in-vivo studies suggest that the molecule reaches mouse organs, including the brain, where its metabolites, NAC and MEA, are detected. In cell cultures, I-152 replenishes experimentally depleted GSH levels. Moreover, administration of I-152 to C57BL/6 mice infected with the retroviral complex LP-BM5 is effective in contrasting virus-induced GSH depletion, exerting at the same time antiviral and immunomodulatory functions. I-152 acts as a pro-GSH agent; however, GSH derivatives and NAC cannot completely replicate its effects. The co-delivery of different thiol species may lead to unpredictable outcomes, which warrant further investigation.}, }
@article {pmid31181229, year = {2019}, author = {Romão, CM and Pereira, RC and Shimizu, MHM and Furukawa, LNS}, title = {N-acetyl-l-cysteine exacerbates kidney dysfunction caused by a chronic high-sodium diet in renal ischemia and reperfusion rats.}, journal = {Life sciences}, volume = {231}, number = {}, pages = {116544}, doi = {10.1016/j.lfs.2019.116544}, pmid = {31181229}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/prevention &amp; control ; Animals ; Blood Pressure/drug effects ; Brain Ischemia/metabolism/*physiopathology ; Free Radical Scavengers/pharmacology ; Ischemia/etiology/metabolism/pathology/physiopathology ; Kidney/*blood supply/drug effects/metabolism ; Male ; Rats ; Rats, Wistar ; Reperfusion/methods ; Reperfusion Injury/metabolism/*physiopathology ; Sodium Chloride, Dietary/administration &amp; dosage/*adverse effects ; }, abstract = {AIMS: To investigate the effect of long-term N-acetyl-l-cysteine (NAC) treatment in Wistar rats subjected to renal ischemia and reperfusion (IR) and a chronic high‑sodium diet (HSD).<br><br>MAIN METHODS: Adult male Wistar rats received an HSD (8.0% NaCl) or a normal&#x2011;sodium diet (NSD; 1.3% NaCl) and NAC (600&#x202f;mg/L) or normal drinking water starting at 8&#x202f;weeks of age. At 11&#x202f;weeks of age, the rats from both diet and NAC or water treatment groups underwent renal IR or Sham surgery and were followed for 10&#x202f;weeks. The study consisted of six animal groups: NSD&#x202f;+&#x202f;Sham&#x202f;+&#x202f;water; NSD&#x202f;+&#x202f;IR&#x202f;+&#x202f;water; NSD&#x202f;+&#x202f;IR&#x202f;+&#x202f;NAC; HSD&#x202f;+&#x202f;Sham&#x202f;+&#x202f;water; HSD&#x202f;+&#x202f;IR&#x202f;+&#x202f;water; and HSD&#x202f;+&#x202f;IR&#x202f;+&#x202f;NAC.<br><br>KEY FINDINGS: Tail blood pressure (tBP) increased with IR and NAC treatment in the NSD group but not in the HSD group. The serum creatinine level was higher after NAC treatment in both diet groups, and creatinine clearance was decreased in only the HSD&#x202f;+&#x202f;IR&#x202f;+&#x202f;NAC group. Albuminuria increased in the HSD&#x202f;+&#x202f;IR&#x202f;+&#x202f;water group and decreased in the HSD&#x202f;+&#x202f;IR&#x202f;+&#x202f;NAC group. Kidney mass was increased in the HSD&#x202f;+&#x202f;IR group and decreased with NAC treatment. Renal fibrosis was prevented with NAC treatment and cardiac fibrosis was decreased with NAC treatment in the HSD&#x202f;+&#x202f;IR group.<br><br>SIGNIFICANCE: NAC treatment promoted structural improvements, such as decreased albuminuria and fibrosis, in the kidney and heart. However, NAC could not recover kidney function or blood pressure from the effects of IR associated with an HSD. Therefore, in general, long-term NAC treatment is not effective and is deleterious to recovery of function after kidney injury.}, }
@article {pmid31180592, year = {2019}, author = {Silveira, JS and Antunes, GL and Kaiber, DB and da Costa, MS and Marques, EP and Ferreira, FS and Gassen, RB and Breda, RV and Wyse, ATS and Pitrez, P and da Cunha, AA}, title = {Reactive oxygen species are involved in eosinophil extracellular traps release and in airway inflammation in asthma.}, journal = {Journal of cellular physiology}, volume = {234}, number = {12}, pages = {23633-23646}, doi = {10.1002/jcp.28931}, pmid = {31180592}, issn = {1097-4652}, mesh = {Acetylcysteine/pharmacology ; Animals ; Asthma/*pathology ; Cytokines/metabolism ; Energy Metabolism/physiology ; Eosinophil Peroxidase/metabolism ; Eosinophils/*metabolism ; Extracellular Traps/*metabolism ; Female ; Goblet Cells/pathology ; Lung/*pathology ; Mice ; Mice, Inbred BALB C ; Mitochondria/metabolism ; Onium Compounds/pharmacology ; Ovalbumin/toxicity ; Oxidative Stress/physiology ; Reactive Oxygen Species/*metabolism ; Transcription Factor RelA/metabolism ; }, abstract = {In asthma, there are high levels of inflammatory mediators, reactive oxygen species (ROS), and eosinophil extracellular traps (EETs) formation in airway. Here, we attempted to investigate the ROS involvement in EETs release and airway inflammation in OVA-challenged mice. Before the intranasal challenge with ovalbumin (OVA), animals were treated with two ROS inhibitors, N-acetylcysteine (NAC) or diphenyleneiodonium (DPI). We showed that NAC treatment reduced inflammatory cells in lung. DPI and NAC treatments reduced eosinophil peroxidase (EPO), goblet cells hyperplasia, proinflammatory cytokines, NFκB p65 immunocontent, and oxidative stress in lung. However, only the NAC treatment improved mitochondrial energy metabolism. Moreover, the treatments with DPI and NAC reduced EETs release in airway. This is the first study to show that ROS are needed for EETs formation in asthma. Based on our results, NAC and DPI treatments can be an interesting alternative for reducing airway inflammation, mitochondrial damage, and EETs release in asthma.}, }
@article {pmid31178664, year = {2019}, author = {Wang, P and Chen, F and Wang, W and Zhang, XD}, title = {Hydrogen Sulfide Attenuates High Glucose-Induced Human Retinal Pigment Epithelial Cell Inflammation by Inhibiting ROS Formation and NLRP3 Inflammasome Activation.}, journal = {Mediators of inflammation}, volume = {2019}, number = {}, pages = {8908960}, pmid = {31178664}, issn = {1466-1861}, mesh = {Cell Line ; Cell Survival/drug effects ; Enzyme-Linked Immunosorbent Assay ; Epithelial Cells/cytology/*drug effects ; Glucose/*pharmacology ; Humans ; Hydrogen Sulfide/*pharmacology ; Inflammasomes/drug effects/*metabolism ; Inflammation/*metabolism ; Interleukin-18/metabolism ; Interleukin-1beta/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Reactive Oxygen Species/metabolism ; Retina/*cytology ; Signal Transduction/drug effects ; }, abstract = {Hydrogen sulfide (H2S) has been shown to protect against oxidative stress injury and inflammation in various high glucose-induced insult models. However, it remains unknown whether H2S protects human retinal pigment epithelial cells (RPE cells) from high glucose-induced damage. In the current study, cell viability, proinflammatory cytokines, ROS, and inflammasome markers were compared in a low glucose- and high glucose-induced cell culture system. The antioxidant N-acetylcysteine (NAC), NLRP3 siRNA, and NaHS were used to test RPE cell responses. The results demonstrate that compared with the low-glucose culture, high glucose triggered higher cell death and increased IL-18 and IL-1β mRNA expression and protein production. Furthermore, high glucose increased the mRNA expression levels of NLRP3, ACS, and caspase-1. Notably, NAC, a ROS scavenger, could attenuate high glucose-induced ROS formation and IL-18 and IL-1β mRNA and protein expression and block inflammasome activation. Silencing the NLRP3 gene expression also abolished IL-18 and IL-1β mRNA and protein expression. Intrudingly, H2S could ameliorate high glucose-induced ROS formation, IL-18 and IL-1β expression, and inflammasome activation. Taken together, the findings of the present study have demonstrated that H2S protects cultured RPE cells from high glucose-induced damage through inhibiting ROS formation and NLRP3 inflammasome activation. It might suggest that H2S represents a potential therapeutic target for the treatment of diabetic retinopathy.}, }
@article {pmid31178194, year = {2019}, author = {Yang, F and Zhang, S and Shang, X and Wang, X and Wang, L and Sun, Y}, title = {Short communication: N-Acetylcysteine-mediated augmentation of β-lactam antibacterial activity against methicillin-resistant Staphylococcus aureus isolated from bovine mastitis cases.}, journal = {Journal of dairy science}, volume = {102}, number = {8}, pages = {6920-6922}, doi = {10.3168/jds.2019-16389}, pmid = {31178194}, issn = {1525-3198}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Ampicillin/pharmacology ; Animals ; Anti-Bacterial Agents/*pharmacology ; Cattle ; Cefoxitin/pharmacology ; Female ; Mastitis, Bovine/*microbiology ; Methicillin-Resistant Staphylococcus aureus/*drug effects/*isolation &amp; purification ; Microbial Sensitivity Tests ; Oxacillin/pharmacology ; Penicillin G/pharmacology ; beta-Lactams/*pharmacology ; }, abstract = {The present study investigated the effects of N-acetylcysteine (NAC) on β-lactam antibacterial activity against 20 methicillin-resistant Staphylococcus aureus (MRSA) isolates from bovine mastitis. Minimum inhibitory concentrations (MIC) were determined by the E-test method. The presence of 10 mM NAC reduced the MIC of penicillin, ampicillin, oxacillin, cefoxitin, ceftazidime, and cefotaxime to MRSA. Importantly, the MIC of cefoxitin in MRSA in the presence of NAC was lower than the susceptible breakpoint of cefoxitin. The results provide a new way to use current β-lactam antibiotics combined with NAC against MRSA.}, }
@article {pmid31176737, year = {2019}, author = {Zhang, T and Zheng, P and Shen, X and Shao, R and Wang, B and Shen, H and Zhang, J and Xia, Y and Zou, P}, title = {Curcuminoid WZ26, a TrxR1 inhibitor, effectively inhibits colon cancer cell growth and enhances cisplatin-induced cell death through the induction of ROS.}, journal = {Free radical biology &amp; medicine}, volume = {141}, number = {}, pages = {93-102}, doi = {10.1016/j.freeradbiomed.2019.06.005}, pmid = {31176737}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cell Survival ; Cisplatin/administration &amp; dosage/*pharmacology ; Colonic Neoplasms/*drug therapy ; Curcumin/administration &amp; dosage/*analogs &amp; derivatives/*pharmacology ; DNA Damage ; *Drug Synergism ; HCT116 Cells ; Humans ; MAP Kinase Kinase 4/metabolism ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Piperazines/administration &amp; dosage ; Reactive Oxygen Species/*metabolism ; Surface Plasmon Resonance ; Thioredoxin Reductase 1/*antagonists &amp; inhibitors ; Xenograft Model Antitumor Assays ; }, abstract = {Colon cancer is one of the leading causes of cancer-related deaths. Chemotherapy has improved survival in patients with colon cancer, but has a narrow therapeutic window due to its toxicity. Therefore, novel therapies for colon cancer are urgently needed. We previously developed a curcumin analog WZ26 as an anti-cancer agent in pre-clinical evaluation. In the present study, we further explored the mechanism and target of WZ26 in colon cancer cells. Our results show that WZ26 targets thioredoxin reductase 1 (TrxR1) and increases cellular reactive oxygen species (ROS) levels, which results in the activation of JNK signaling pathway in human colon cancer cells. Furthermore, we found that WZ26 significantly enhances cisplatin-induced cell growth inhibition in colon cancer cells. WZ26 combined with cisplatin markedly increases the accumulation of ROS, and thereby induces DNA damage and activation of JNK signaling pathway. Pretreatment with antioxidant N-acetyl-l-cysteine (NAC) significantly abrogates the combined treatment-induced ROS generation, DNA damage and cell death. In addition, the activation of JNK signaling pathway prompted by WZ26 and cisplatin was also reversed by NAC pretreatment. In vivo, WZ26 combined with cisplatin significantly inhibits tumor growth in a colon cancer xenograft model. Remarkably, WZ26 attenuates the body weight loss evoked by cisplatin treatment. This study discloses a previously unrecognized mechanism underlying the biological activity of WZ26, and reveals that WZ26 and cisplatin combinational treatment might potentially become a more effective regimen in colon cancer therapy.}, }
@article {pmid31173817, year = {2019}, author = {Shen, T and Miao, Y and Ding, C and Fan, W and Liu, S and Lv, Y and Gao, X and De Boevre, M and Yan, L and Okoth, S and De Saeger, S and Song, S}, title = {Activation of the p38/MAPK pathway regulates autophagy in response to the CYPOR-dependent oxidative stress induced by zearalenone in porcine intestinal epithelial cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {131}, number = {}, pages = {110527}, doi = {10.1016/j.fct.2019.05.035}, pmid = {31173817}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Animals ; Autophagy/*drug effects ; Epithelial Cells/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Intestines/drug effects ; MAP Kinase Kinase 4/metabolism ; MAP Kinase Signaling System/*drug effects ; NADPH-Ferrihemoprotein Reductase/*metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Swine ; Zearalenone/*toxicity ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Zearalenone (ZEA) can widely contaminate crops and agricultural products. The ingestion of ZEA-contaminated food or feed affects the integrity and functions of the intestines. In this study, we aimed to find the potential protective mechanism against ZEA ingestion. We found that ZEA induced cell death in IPEC-J2 cells. Meanwhile, the cytoprotective autophagy was activated in ZEA-treated cells. Further studies demonstrated that a p38/MAPK inhibitor down-regulated autophagy and increased cell death compared to those of the controls. Furthermore, ZEA could induce the accumulation of ROS, and eliminating ROS with NAC resulted in a decline in cell death, p38/MAPK phosphorylation, and the expression of LC3-II compared to those of ZEA-group. In addition, cytochrome P450 reductase (CYPOR) was significantly increased in ZEA-treated cells compared to that in the controls, and an inhibitor of CYPOR decreased ROS levels and mitigated cell death compared to those of the ZEA-group. More importantly, we found that blocking both p38/MAPK signalling and autophagy could enhance CYPOR expression and elevate ROS levels. Overall, our study indicated that the p38/MAPK pathway could activate protective autophagy in response to the CYPOR-dependent oxidative stress that was induced by ZEA in IPEC-J2 cells.}, }
@article {pmid31173782, year = {2019}, author = {Alam, RT and Imam, TS and Abo-Elmaaty, AMA and Arisha, AH}, title = {Amelioration of fenitrothion induced oxidative DNA damage and inactivation of caspase-3 in the brain and spleen tissues of male rats by N-acetylcysteine.}, journal = {Life sciences}, volume = {231}, number = {}, pages = {116534}, doi = {10.1016/j.lfs.2019.06.009}, pmid = {31173782}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Brain/*drug effects/metabolism ; Caspase 3/metabolism ; *DNA Damage ; Drug Interactions ; Fenitrothion/administration &amp; dosage/*toxicity ; Insecticides/administration &amp; dosage/*toxicity ; Lipid Peroxidation/drug effects ; Male ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Protective Agents/pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spleen/*drug effects/metabolism ; }, abstract = {N-acetylcysteine (NAC) has largely been used as an effective chemo- protective agent owing to their beneficial effect in restoring several physiological parameters and relieving oxidative stress. Interestingly, it has been suggested that NAC mechanisms of action extend beyond being a precursor to the antioxidant glutathione and that they may involve several neurotropic and inflammatory pathways. Exposure to fenitrothion, an organophosphorus insecticide, promotes oxidative stress and induces several deleterious changes in the immune response and various tissues including cerebrum and spleen. The main objective of our study was to investigate ameliorative efficacy of N-acetylcysteine for immunological and neurological alterations and oxidative DNA damage induced by fenitrothion toxicity in cerebrum and spleen tissues of male rats. Our results revealed that oral exposure to fenitrothion for 30 days caused a reduction in the erythrocyte count in addition to leukocytosis, lymphocytosis, and neutrophilia. Also, this route of administration increased the serum levels of LDH, TNF-α, and IL-2 with reduction in serum immunoglobulins (IgG &amp; IgM) concentrations. Furthermore, a significant downregulation in the antioxidant markers (GSH &amp; SOD) with an elevation of free radical (MDA) levels were noticed. Regarding the brain, fenitrothion administration inhibited AchE activity and increased brain GABA, serotonin and dopamine levels. Moreover, it induced an elevation in oxidative DNA damage indicated by 8-hydroxy 2-deoxyguanosine (8OH2dG) and mRNA expression of pro-apoptotic genes, including Bax, and p53, but Bcl-2 expression was reduced. N-acetylcysteine co-treatment restored the normal physiological tone in most of these parameters. Immunostaining for GFAP and Caspase-3 markers in the brain and spleen tissues were increased respectively. In conclusion, N-acetylcysteine supplementation has an ameliorative effect against immunotoxic, neurotoxic and oxidative DNA damage induced by fenitrothion exposure.}, }
@article {pmid31172724, year = {2019}, author = {Kim, HJ and Lee, SH and Jeong, S and Hong, SJ}, title = {Protease-Activated Receptors 2-Antagonist Suppresses Asthma by Inhibiting Reactive Oxygen Species-Thymic Stromal Lymphopoietin Inflammation and Epithelial Tight Junction Degradation.}, journal = {Allergy, asthma &amp; immunology research}, volume = {11}, number = {4}, pages = {560-571}, pmid = {31172724}, issn = {2092-7355}, support = {HI13C1674/MHW/Ministry of Health and Welfare/Korea ; }, abstract = {PURPOSE: Protease-activated receptor 2 (PAR2) reportedly triggers the immune response in allergic asthma. We aimed to investigate the mechanism on allergic inflammation mediated by PAR2.<br><br>METHODS: Human lung epithelial cells (A549 cells) were used for in vitro, and the German cockroach extract (GCE)-induced mouse model was developed for in vivo studies.<br><br>RESULTS: In A549 cells, the levels of reactive oxygen species (ROS) and thymic stromal lymphopoietin (TSLP) were significantly increased by GCE treatment, but were suppressed by PAR2-antagonist (PAR2-ant) or N-acetylcysteine (NAC) treatment. Claudin-1 was degraded by GCE, and was restored by PAR2-ant or NAC in the cells. In the mouse model, the clinical appearance including bronchial hyperresponsiveness, bronchoalveolar lavage fluid analysis and total immunoglobulin E were significantly suppressed by PAR2-ant or NAC. Moreover, TSLP levels in the lung were suppressed by the same treatments in the lung. Claudin-1 was also degraded by GCE, and was restored by PAR2-ant or NAC.<br><br>CONCLUSIONS: ROS generation and epidermal tight junction degradation are triggered by protease, followed by the induction of TSLP in allergic asthma. Our findings could suggest that PAR2-ant or anti-oxidants could be considered for allergic diseases as preventive alternatives.}, }
@article {pmid31170649, year = {2019}, author = {Colak, N and Torun, H and Gruz, J and Strnad, M and Ayaz, FA}, title = {Exogenous N-Acetylcysteine alleviates heavy metal stress by promoting phenolic acids to support antioxidant defence systems in wheat roots.}, journal = {Ecotoxicology and environmental safety}, volume = {181}, number = {}, pages = {49-59}, doi = {10.1016/j.ecoenv.2019.05.052}, pmid = {31170649}, issn = {1090-2414}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Hydrogen Peroxide/metabolism ; Hydroxybenzoates/metabolism ; Metals, Heavy/*toxicity ; Oxidative Stress/*drug effects ; Seedlings/drug effects/enzymology/growth &amp; development ; Soil Pollutants/*toxicity ; Thiobarbituric Acid Reactive Substances/metabolism ; Triticum/*drug effects/enzymology/growth &amp; development ; }, abstract = {N-acetylcysteine (N-Acetyl L-cysteine, NAC) is a thiol compound derived from the addition of the acetyl group to cysteine amino acid. NAC has been used as an antioxidant, free radical scavenger, and chelating agent for reducing the deleterious effects on plants of biotic and abiotic environmental stresses. It can also relieve heavy metal (HM) toxicity, although its alleviating mechanism remains unknown. In this study, we compared HM-stressed (Cu, Hg, Cd and Pb, 100 μM each) wheat seedlings without NAC treatment and in combination with NAC (1 mM). In comparison to HMs alone, NAC treatment in combination with HMs (Cu, Cd, Hg and Pb, respectively) stimulated root growth (1.1-, 1.5-, 10.5- and 1.9-fold), and significantly increased fresh (1.3-, 1.5-, 4.3- and 1.4-fold) and dry (1.2-, 1.5-, 2.5- and 1.2-fold) mass. Combination treatment also led to significant reductions in HM concentrations (1.3-, 1.4-, 4- and 1.1-fold, respectively). GSH (1.1 - 1.8-fold), TBARS (1.4 - 2.7-fold) and H2O2 (1.6 - 1.8-fold) contents in treatment with HMs alone were significantly mitigated by the NAC combination. Some of the antioxidant enzyme activities increased or reduced by some HM treatments alone were stimulated by a combination of NAC with HMs, or remained unchanged or changed only insignificantly, supported by the phenolic pool of the plant. Ferulic, p-comaric and syringic acids were the major phenolic acids (PAs) in the roots in free, ester, glycoside and ester-bound forms, and their concentrations were increased by HM treatments alone, in comparison to the control seedlings, while PAs concentrations were relatively reduced by NAC in combination with HMs. These results indicate that NAC can alleviate HM toxicity and improve the growth of HM-stressed wheat seedlings by coordinated induction of the phenolic pool and the antioxidant defence system.}, }
@article {pmid31164169, year = {2019}, author = {McKetin, R and Dean, OM and Turner, A and Kelly, PJ and Quinn, B and Lubman, DI and Dietze, P and Carter, G and Higgs, P and Baker, AL and Sinclair, B and Reid, D and Manning, V and Te Pas, N and Liang, W and Thomas, T and Bathish, R and Kent, M and Raftery, D and Arunogiri, S and Cordaro, F and Hill, H and Berk, M}, title = {A study protocol for the N-ICE trial: A randomised double-blind placebo-controlled study of the safety and efficacy of N-acetyl-cysteine (NAC) as a pharmacotherapy for methamphetamine ("ice") dependence.}, journal = {Trials}, volume = {20}, number = {1}, pages = {325}, pmid = {31164169}, issn = {1745-6215}, support = {1128147//Australian National Health and Medical Research Council/ ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Amphetamine-Related Disorders/diagnosis/*drug therapy/physiopathology/psychology ; Australia ; *Central Nervous System Stimulants ; Clinical Trials, Phase II as Topic ; Craving/*drug effects ; Double-Blind Method ; Female ; Humans ; Male ; *Methamphetamine ; Middle Aged ; Multicenter Studies as Topic ; Randomized Controlled Trials as Topic ; Substance Abuse, Intravenous/diagnosis/*drug therapy/physiopathology/psychology ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: There are currently no approved pharmacotherapies for managing methamphetamine dependence. N-acetylcysteine (NAC) has been found to reduce the craving for methamphetamine and other drugs, but its effect on methamphetamine use and other clinically related endpoints are uncertain. The N-ICE trial is evaluating the safety and efficacy of NAC as a take-home pharmacotherapy for methamphetamine dependence.<br><br>METHODS/DESIGN: This is a two-arm parallel double-blind placebo-controlled three-site randomised trial (ratio 1:1) using permuted block randomisation, with variable block sizes. It is stratified by site, sex and whether the methamphetamine is injected or not. Participants (N&#x2009;=&#x2009;180; 60 per site) need to be dependent on methamphetamine, interested in reducing their methamphetamine use and not currently receiving treatment for substance use disorders. The trial is being conducted in outpatient settings in Melbourne, Geelong and Wollongong, Australia. Participants will receive either 2400&#x2009;mg oral NAC or a matched placebo, delivered as a take-home medication for 12&#x2009;weeks. Two 600&#x2009;mg capsules are self-administered in the morning and two more in the evening. Adherence is being monitored using eCAP&#x2122; medication bottle lids, which record the date and time of each occasion the bottle is opened. The primary outcome is methamphetamine use during the 12-week trial medication period, measured as (a) days of use, assessed using the timeline followback, and (b) methamphetamine-positive saliva tests, taken weekly. Secondary measures include weekly assessment of methamphetamine craving, severity of methamphetamine dependence, methamphetamine withdrawal symptoms and psychiatric symptoms (depression, suicidality, psychotic symptoms and hostility). Adverse events are monitored at each weekly assessment. Tolerability is assessed using the Treatment Satisfaction Questionnaire for Medication.<br><br>DISCUSSION: The N-ICE trial is the first clinical trial to assess whether NAC can reduce methamphetamine use. This trial will improve our understanding of the potential utility of NAC in managing methamphetamine dependence and clinically related outcomes. If found to be effective, take-home NAC could be a potentially scalable and affordable pharmacotherapy option for treating methamphetamine dependence.<br><br>TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12618000366257 . Registered on 29 May 2018.}, }
@article {pmid31162913, year = {2019}, author = {Akhter, N and Madhoun, A and Arefanian, H and Wilson, A and Kochumon, S and Thomas, R and Shenouda, S and Al-Mulla, F and Ahmad, R and Sindhu, S}, title = {Oxidative Stress Induces Expression of the Toll-Like Receptors (TLRs) 2 and 4 in the Human Peripheral Blood Mononuclear Cells: Implications for Metabolic Inflammation.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {53}, number = {1}, pages = {1-18}, doi = {10.33594/000000117}, pmid = {31162913}, issn = {1421-9778}, support = {RA 2015-027, RA AM-2016-007//Kuwait Foundation for the Advancement of Sciences (KFAS)/Kuwait ; }, mesh = {Cells, Cultured ; Humans ; Inflammation/*genetics/metabolism ; Interferon Regulatory Factor-3/genetics ; Interferon Regulatory Factors/genetics ; Leukocytes, Mononuclear/metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 2/*genetics ; Toll-Like Receptor 4/*genetics ; *Up-Regulation ; }, abstract = {BACKGROUND/AIMS: Innate immune toll-like receptors (TLRs) are emerging as nutrient sensors. Oxidative stress in the adipose tissue in obesity acts as a critical early trigger of altered pathophysiology. TLR2/TLR4 adipose upregulation has been associated with insulin resistance in humans; however, it remains unclear whether oxidative stress can modulate expression of TLR2/4 and related immune-metabolic regulators (IRF3/5) in immune cells. We, therefore, assessed their expression along with proinflammatory cytokines in the human PBMC following induction of oxidative stress.<br><br>METHODS: PBMC were isolated from blood of healthy donors using Ficoll-Paque method and cells were treated with H2O2 to induce oxidative stress. ROS was measured by DCFH-DA assay. Target gene and protein expression was determined using real-time RT-PCR and flow cytometry/confocal microscopy, respectively. TLR2/4 expression by H2O2 in presence of ROS-inhibitors or leptin/LPS/fatty acids was also assessed. Expression of phosphorylated/total ERK1/2, c-Jun, p38, and NF-&#x3ba;B was determined by western blotting. The data (mean&#xb1;SEM) were compared using unpaired student's t-test or ANOVA; all P-values <0.05 were considered significant.<br><br>RESULTS: TLR2/4 mRNA/protein expression was elevated by oxidative stress in PBMC compared to controls (P<0.001). This induction was abrogated by apocynin/N-acetyl cysteine treatments (P<0.01). H2O2-induced TLR2/4 gene expression was further enhanced by leptin, LPS, oleate, or palmitate (P<0.05). Oxidative stress also promoted expression of IRF3/5 and proinflammatory cytokines including IFN-&#x3b3;, IL-1&#x3b2;, IL-6, TNF-&#x3b1;, and MCP-1/CCL2. This oxidative stress in PBMC involved MAPK/NF-&#x3ba;B dependent signaling.<br><br>CONCLUSION: Taken together, oxidative stress upregulates expression of TLR2/4, IRF3/5 and signature proinflammatory cytokines in PBMC, involving MAPK/NF-&#x3ba;B dependent signaling, all of which may have implications for metabolic inflammation.}, }
@article {pmid31160972, year = {2019}, author = {Tripathi, A and Pandey, V and Sahu, AN and Singh, A and Dubey, PK}, title = {Di-(2-ethylhexyl) phthalate (DEHP) inhibits steroidogenesis and induces mitochondria-ROS mediated apoptosis in rat ovarian granulosa cells.}, journal = {Toxicology research}, volume = {8}, number = {3}, pages = {381-394}, pmid = {31160972}, issn = {2045-452X}, abstract = {Increased oxidative stress (OS) due to ubiquitous exposure to di-(2-ethylhexyl) phthalate (DEHP) can affect the quality of oocytes by inducing apoptosis and hampering granulosa cell mediated steroidogenesis. This study was carried out to investigate whether DEHP induced OS affects steroidogenesis and induces apoptosis in rat ovarian granulosa cells. OS was induced by exposing granulosa cells to various concentrations of DEHP (0.0, 100, 200, 400 and 800 μM) for 72 h in vitro. Intracellular reactive oxygen species (ROS), oxidative stress (OS), mitochondrial membrane potential, cellular senescence, apoptosis, steroid hormones (estradiol &amp; progesterone) and gene expression were analyzed. The results showed that an effective dose of DEHP (400 μg) significantly increased OS by elevating the ROS level, mitochondrial membrane potential, and β-galactosidase activity with higher mRNA expression levels of apoptotic genes (Bax, cytochrome-c and caspase3) and a lower level of an anti-apoptotic gene (Bcl2) as compared to the control. Further, DEHP significantly (P > 0.05) decreased the level of steroid hormones (estradiol and progesterone) in a conditioned medium and this effect was reciprocated with a lower expression (P > 0.05) of steroidogenic responsive genes (Cyp11a1, Cyp19A1, Star, ERβ1) in treated granulosa cells. Furthermore, co-treatment with N-Acetyl-Cysteine (NAC) rescues the effects of DEHP on OS, ROS, β-galactosidase levels and gene expression activities. Altogether, these results suggest that DEHP induces oxidative stress via ROS generation and inhibits steroid synthesis via modulating steroidogenic responsive genes, which leads to the induction of apoptosis through the activation of Bax/Bcl-2-cytochrome-c and the caspase-3-mediated mitochondrial apoptotic pathway in rat granulosa cells.}, }
@article {pmid31160542, year = {2019}, author = {Chunchai, T and Keawtep, P and Arinno, A and Saiyasit, N and Prus, D and Apaijai, N and Pratchayasakul, W and Chattipakorn, N and Chattipakorn, SC}, title = {N-acetyl cysteine, inulin and the two as a combined therapy ameliorate cognitive decline in testosterone-deprived rats.}, journal = {Aging}, volume = {11}, number = {11}, pages = {3445-3462}, pmid = {31160542}, issn = {1945-4589}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Apoptosis/drug effects ; Astrocytes/drug effects/metabolism ; Blood-Brain Barrier/drug effects/metabolism ; Brain/*drug effects/metabolism ; Castration ; Cognition/drug effects ; Cognitive Dysfunction/*drug therapy/metabolism ; Disease Models, Animal ; Drug Therapy, Combination ; Dysbiosis/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Inflammation/drug therapy/metabolism ; Inulin/pharmacology/*therapeutic use ; Male ; Malondialdehyde/metabolism ; Microglia/drug effects/metabolism ; Motor Activity/drug effects ; Oxidative Stress/*drug effects/physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Testosterone/*deficiency ; }, abstract = {Our previous studies reported that testosterone-deprived rats developed cognitive decline as a result of increased brain oxidative stress, microglia hyperactivity, and hippocampal dysplasticity. In addition, gut dysbiosis occurred in these rats. Previous studies demonstrated that n-acetyl cysteine (NAC) and a prebiotic (inulin) improved cognition in several pathological conditions. However, its effects on cognition in the testosterone-deprived condition have never been investigated. This study hypothesized that the administration of NAC, inulin, and a combined therapy improved cognition in castrated rats. Here we report that metabolic disturbance was not observed in the ORX rats, but gut dysbiosis was found in these rats. ORX rats developed blood-brain-barrier (BBB) breakdown, and increased brain oxidative stress as indicated by increased hippocampal production of reactive oxygen species (ROS) and an increase in brain malondialdehyde level. ORX rats also demonstrated glia hyperactivation, resulting in hippocampal apoptosis, hippocampal dysplasticity, and cognitive decline. All treatments equally ameliorated cognitive decline by improving gut dysbiosis, alleviating BBB dysfunction, decreasing hippocampal ROS production, decreasing hippocampal apoptosis, and reducing microglia and astrocyte activity. These findings suggest that NAC, inulin, and the combined therapy ameliorated the deleterious effects on the brain in castrated male rats similar to those treated with testosterone.}, }
@article {pmid31158660, year = {2019}, author = {Sharma, K and Lee, HH and Gong, DS and Park, SH and Yi, E and Schini-Kerth, V and Oak, MH}, title = {Fine air pollution particles induce endothelial senescence via redox-sensitive activation of local angiotensin system.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {252}, number = {Pt A}, pages = {317-329}, doi = {10.1016/j.envpol.2019.05.066}, pmid = {31158660}, issn = {1873-6424}, mesh = {Acetylcysteine/pharmacology ; Air Pollution/*adverse effects ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Angiotensins/*metabolism ; Animals ; Antioxidants/metabolism ; Blood Platelets/cytology ; Cell Cycle Checkpoints/drug effects ; Cell Division/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Cellular Senescence/*drug effects ; Coronary Vessels/cytology ; Endothelium, Vascular/cytology ; Human Umbilical Vein Endothelial Cells/metabolism/*physiology ; Humans ; Losartan/pharmacology ; Nitric Oxide Synthase Type III/biosynthesis ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Particulate Matter/*pharmacology ; Receptor, Angiotensin, Type 1/*metabolism ; Swine ; beta-Galactosidase/antagonists &amp; inhibitors/metabolism ; }, abstract = {Fine dust (FD) is a form of air pollution and is responsible for a wide range of diseases. Specially, FD is associated with several cardiovascular diseases (CVDs); long-term exposure to FD was shown to decrease endothelial function, but the underlying mechanism remains unclear. We investigated whether exposure to FD causes premature senescence-associated endothelial dysfunction in endothelial cells (ECs) isolated from porcine coronary arteries. The cells were treated with different concentrations of FD and senescence associated-beta galactosidase (SA-β-gal) activity, cell cycle progression, expression of endothelial nitric oxide synthase (eNOS), oxidative stress level, and vascular function were evaluated. We found that FD increased SA-β-gal activity, caused cell cycle arrest, and increased oxidative stress, suggesting the premature induction of senescence; on the other hand, eNOS expression was downregulated and platelet aggregation was enhanced. FD exposure impaired vasorelaxation in response to bradykinin and activated the local angiotensin system (LAS), which was inhibited by treatment with the antioxidant N-acetyl cysteine (NAC) and angiotensin II receptor type 1 (AT1) antagonist losartan (LOS). NAC and LOS also suppressed FD-induced SA-β-gal activity, increased EC proliferation and eNOS expression, and improved endothelial function. These results demonstrate that FD induces premature senescence of ECs and is associated with increased oxidative stress and activation of LAS. This study can serve as a pharmacological target for prevention and/or treatment of air pollution-associated CVD.}, }
@article {pmid31153952, year = {2019}, author = {Okazaki, Y and Tanaka, H and Hori, M and Toyokuni, S}, title = {l-Dehydroascorbic acid recycled by thiols efficiently scavenges non-thermal plasma-induced hydroxyl radicals.}, journal = {Archives of biochemistry and biophysics}, volume = {669}, number = {}, pages = {87-95}, doi = {10.1016/j.abb.2019.05.019}, pmid = {31153952}, issn = {1096-0384}, mesh = {Acetylcysteine/chemistry ; Ascorbic Acid/chemistry ; Cyclic N-Oxides/chemistry ; Dehydroascorbic Acid/*chemistry ; Dithiothreitol/chemistry ; Electron Spin Resonance Spectroscopy ; Free Radical Scavengers/*chemistry ; Glutathione/chemistry ; Hydroxyl Radical/analysis/*chemistry ; Plasma Gases/*chemistry ; Spin Labels ; }, abstract = {Recent development in electronics has enabled the use of non-thermal plasma (NTP) to strictly direct oxidative stress in a defined location at near-physiological temperature. In preclinical studies or human clinical trials, NTP promotes blood coagulation, wound healing with disinfection, and selective killing of cancer cells. Although these biological effects of NTP have been widely explored, the stoichiometric quantitation of free radicals in liquid phase has not been performed in the presence of biocompatible reducing agents, which may modify the final biological effects of NTP. Here we quantitated hydroxyl radicals, a major reactive oxygen species generated after NTP exposure, by electron paramagnetic resonance (EPR) spectroscopy using two distinct spin-trapping probes, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO), in the presence of thiols or antioxidants. l-Ascorbic acid (AsA) at 25-50 μM concentrations (physiological concentration in the serum) significantly scavenged these hydroxyl radicals, whereas dithiothreitol (DTT), reduced glutathione (GSH), and N-acetyl-cysteine (NAC) as thiols were required in millimolar concentrations to perform scavenging activities. l-Dehydroascorbic acid (DHA), an oxidized form of AsA, necessitated the presence of 25-50 μM DTT or sub-millimolar concentrations of GSH and NAC for the scavenging of hydroxyl radicals and failed to scavenge hydroxyl radicals by itself. These results suggest that the redox cycling of AsA/DHA via thiols and cellular AsA metabolism are important processes to be considered while applying NTP to cells and tissues. Further studies are warranted to elucidate the interaction between other reactive species generated by NTP and biomolecules to promote biological and medical applications of NTP.}, }
@article {pmid31153046, year = {2019}, author = {Lee, CW and Chi, MC and Hsu, LF and Yang, CM and Hsu, TH and Chuang, CC and Lin, WN and Chu, PM and Lee, IT}, title = {Carbon monoxide releasing molecule-2 protects against particulate matter-induced lung inflammation by inhibiting TLR2 and 4/ROS/NLRP3 inflammasome activation.}, journal = {Molecular immunology}, volume = {112}, number = {}, pages = {163-174}, doi = {10.1016/j.molimm.2019.05.005}, pmid = {31153046}, issn = {1872-9142}, mesh = {Animals ; Bronchoalveolar Lavage Fluid ; Carbon Monoxide/adverse effects ; Caspase 1/metabolism ; Humans ; Inflammasomes/*drug effects/metabolism ; Interleukin-1beta/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mitochondria/drug effects/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Organometallic Compounds/*pharmacology ; Particulate Matter/adverse effects ; Pneumonia/chemically induced/*drug therapy/metabolism ; Protective Agents/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 2/*metabolism ; Toll-Like Receptor 4/*immunology ; }, abstract = {Exposure to airborne particulate matter (PM) not only causes lung inflammation and chronic respiratory diseases, but also increases the incidence and mortality of cardiopulmonary diseases. The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation has been shown to play a critical role in the formation of many chronic disorders. On the other hand, carbon monoxide (CO) has been shown to possess anti-inflammatory and antioxidant effects in many tissues and organs. Here, we investigated the effects and mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on PM-induced inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that PM induced C-reactive protein (CRP) expression, NLRP3 inflammasome activation, IL-1β secretion, and caspase-1 activation, which were inhibited by pretreatment with CORM-2. In addition, transfection with siRNA of Toll-like receptor 2 (TLR2) or TLR4 and pretreatment with an antioxidant (N-acetyl-cysteine, NAC), the inhibitor of NADPH oxidase (diphenyleneiodonium, DPI), or a mitochondria-specific superoxide scavenger (MitoTEMPO) reduced PM-induced inflammatory responses. CORM-2 also inhibited PM-induced NADPH oxidase activity and NADPH oxidase- and mitochondria-derived ROS generation. However, pretreatment with inactivate CORM-2 (iCORM-2) had no effects on PM-induced inflammatory responses. Finally, we showed that CORM-2 inhibited PM-induced CRP, NLRP3 inflammasome, and ASC protein expression in the lung tissues of mice and IL-1β levels in the serum of mice. PM-enhanced leukocyte count in bronchoalveolar lavage fluid in mice was reduced by CORM-2. The results of this study suggested a protective role of CORM-2 in PM-induced lung inflammation by inhibiting the TLR2 and TLR4/ROS-NLRP3 inflammasome-CRP axial.}, }
@article {pmid31150806, year = {2019}, author = {Song, Y and Zhou, T and Zong, Y and Gu, B and Tan, X and Yang, L}, title = {Arsenic inhibited cholesterol efflux of THP-1 macrophages via ROS-mediated ABCA1 hypermethylation.}, journal = {Toxicology}, volume = {424}, number = {}, pages = {152225}, doi = {10.1016/j.tox.2019.05.012}, pmid = {31150806}, issn = {1879-3185}, mesh = {ATP Binding Cassette Transporter 1/*drug effects/*metabolism ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Arsenic/*pharmacology ; Cell Line ; Cholesterol/*metabolism ; DNA (Cytosine-5-)-Methyltransferase 1/antagonists &amp; inhibitors/metabolism ; DNA Methylation/drug effects ; Humans ; Macrophages/drug effects/*metabolism ; Methylation/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; S-Adenosylmethionine/pharmacology ; }, abstract = {Growing evidences indicate that epigenetic modification involves in the mechanisms of atherosclerosis, which intersects with oxidative stress pathway. Arsenic is an important environmental contaminant and has been linked to atherosclerosis. However, the exact mechanism is not well understood. In the present study, we analyzed the effect of arsenic on oxidative stress, ABCA1 promoter methylation and cholesterol efflux of THP-1 macrophages. Results showed that arsenic could induce ROS-mediated DNA methyltransferase 1 (DNMT1) transcription and activity up-regulation, causing ABCA1 promoter to be hypermethylated with repressed expression. In addition, arsenic depleted the methyl donor S-adenosylmethionine (SAM) and induced global DNA hypomethylation. Arsenic inhibited cholesterol efflux of THP-1 macrophages, which could be attenuated after pretreatment with NAC or DNMT inhibitor 5-Aza-2'-deoxycytidine, but not with SAM. All of the findings suggest that arsenic inhibit cholesterol efflux of THP-1 macrophages via ROS-mediated ABCA1 hypermethylation.}, }
@article {pmid31148586, year = {2019}, author = {Ryu, CM and Shin, JH and Yu, HY and Ju, H and Kim, S and Lim, J and Heo, J and Lee, S and Shin, DM and Choo, MS}, title = {N-acetylcysteine prevents bladder tissue fibrosis in a lipopolysaccharide-induced cystitis rat model.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {8134}, pmid = {31148586}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Animals ; CARD Signaling Adaptor Proteins/genetics ; Chemokine CXCL10/genetics ; Cystitis/chemically induced/*drug therapy/*prevention &amp; control ; Disease Models, Animal ; Female ; Fibrosis/drug therapy/prevention &amp; control ; Gene Expression Profiling ; Inflammation ; Lipopolysaccharides ; Protamines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Smad2 Protein/genetics ; Smad3 Protein/genetics ; Transforming Growth Factor beta2/genetics ; Transforming Growth Factor beta3/genetics ; Urinary Bladder/*drug effects/pathology ; }, abstract = {Therapeutic options for non-Hunner type interstitial cystitis (IC), which is histologically characterized by fibrosis and mast cell infiltration, are limited. We developed a rat model that replicates chronic inflammation and fibrosis and evaluated the therapeutic effect of N-acetylcysteine (NAC), a well-known anti-fibrotic agent, on the model. Intravesical instillation of lipopolysaccharide (LPS, 750 μg) after protamine sulfate (10 mg) was conducted twice per week for five consecutive weeks. One week after final instillation, 200 mg/kg NAC (n = 10, IC + NAC group) or phosphate-buffered saline (n = 10, IC group) was daily injected intraperitoneally once daily for 5 days. LPS instillation induced bladder fibrosis, mast cell infiltration, and apoptotic tissue damage. Functionally, LPS insult led to irregular micturition, decreased inter-contraction intervals, and decreased micturition volume. NAC significantly improved most of the voiding parameters and reversed histological damages including fibrosis. NAC inhibited the induction and nuclear localization of phospho-Smad2 protein in bladder tissues and the upregulation of genes related to fibrosis, such as Tgfb2, Tgfb3, Smad2, Smad3, Cxcl10, and Card10. This is the first study to demonstrate the beneficial effects on NAC in restoring voiding function, relieving tissue fibrosis and related bladder injuries, in the LPS-induced cystitis rat model.}, }
@article {pmid31147858, year = {2019}, author = {Bonilla-Porras, AR and Jimenez-Del-Rio, M and Velez-Pardo, C}, title = {N-acetyl-cysteine blunts 6-hydroxydopamine- and L-buthionine-sulfoximine-induced apoptosis in human mesenchymal stromal cells.}, journal = {Molecular biology reports}, volume = {46}, number = {4}, pages = {4423-4435}, pmid = {31147858}, issn = {1573-4978}, support = {1115-545-40590//Colciencias/ ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Buthionine Sulfoximine/metabolism ; Cell Death/drug effects ; Glutathione/metabolism ; Glutathione Peroxidase ; Humans ; Hydrogen Peroxide/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mesenchymal Stem Cells/*drug effects ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Oxidopamine/metabolism ; Reactive Oxygen Species/metabolism ; Glutathione Peroxidase GPX1 ; }, abstract = {Parkinson disease (PD) is characterized by the loss of dopaminergic (DAergic) neurons linked to environmental toxicants that cause oxidative stress (OS). The aim of this investigation was to establish the molecular response of human mesenchymal stroma cells (MSCs) depleted of glutathione (GSH) by the specific inhibitor L-buthionine-sulfoximine (BSO) to 6-hydroxydopamine (6-OHDA) and/or N-acetylcysteine (NAC) co-treatment. We found that treatment with BSO (10 mM) plus 6-OHDA (200 μM) induced apoptosis in MSCs through an oxidative stress (OS) mechanism involving H2O2, reflected by the detection of dichlorofluorescein-positive (DCF+) cells and oxidation of DJ-1 Cys106-SH into DJ-1 Cys106-SO3; an almost complete reduction in glutathione peroxidase 1 (GPX1) expression; activation of the transcription factor c-JUN, the pro-apoptotic protein BAX and BH-3-only protein PUMA; loss of mitochondrial membrane potential (∆Ψm); activation of the protease caspase-3 (CASP3) and apoptosis-inducing factor (AIF); chromatin condensation; and DNA fragmentation. Strikingly, co-treatment of MSCs with NAC (5 mM) and BSO + 6-OHDA significantly reduced the expression of OS and cell death markers but were unable to restore the expression of GPX1 compared to the expression in untreated or treated cells with NAC only. These findings highlighted the importance of the maintenance of the GSH-dependent (e.g., GPX1, GSH synthesis) and -independent (e.g., ROS scavenger molecules and thiol reducing activity) antioxidant systems (e.g., NAC) in the protection of MSCs from detrimental stress stimuli, thereby increasing the survival of stromal cells.}, }
@article {pmid31147037, year = {2019}, author = {Ghanbari, K and Roushani, M and Soheyli, E and Sahraei, R}, title = {An electrochemical tyrosinamide aptasensor using a glassy carbon electrode modified by N-acetyl-l-cysteine-capped Ag-In-S QDs.}, journal = {Materials science &amp; engineering. C, Materials for biological applications}, volume = {102}, number = {}, pages = {653-660}, doi = {10.1016/j.msec.2019.04.093}, pmid = {31147037}, issn = {1873-0191}, mesh = {Acetylcysteine/*chemistry ; Aptamers, Nucleotide/*chemistry ; Biosensing Techniques/*methods ; Carbon/*chemistry ; Dielectric Spectroscopy ; Electrochemical Techniques/*methods ; Electrodes ; Glass/*chemistry ; Humans ; Indium/chemistry ; Quantum Dots/*chemistry/ultrastructure ; Reproducibility of Results ; Silver/chemistry ; Sulfur/chemistry ; Time Factors ; Tyrosine/*analogs &amp; derivatives/blood ; }, abstract = {This paper reports an aptamer-based green approach for the electrochemical evaluation of tyrosinamide (Tyr-NH2). In this regard, at the first step, an aqueous synthetic strategy for preparing N-acetyl-l-cysteine (NAC)-capped Ag-In-S (AIS) quantum dots (QDs) with bright yellow/orange emission was developed. The conjugation of AIS QDs to NAC-biomolecules provides opportunities for using them as luminescent contrast agents for living cell tracking and labeling or sensing studies. In the next step, the design stage of the aptasensor, the glassy carbon electrode (GCE) was modified with the AIS QDs and then the Tyr-NH2 special aptamer, which has an amine group at its end, interacts with silver and indium ions at the surface of the AIS QDs and through the formation of covalent bonding of AgN and InN, attaches to the GCE surface modified with the AIS QDs. In this approach, for the first time, NAC-capped AIS QDs have been used to modify the electrode surface in the aptamer-based electrochemical sensor. The response changes of the [Fe(CN)6][4-/3-] as redox probe, during the modification of GCE surface, the fabrication and assessment of proposed aptasensing, using the cyclic voltammetry, differential pulse voltammetry and electrochemical impedance spectroscopy were recorded. The designed aptasensor for the Tyr-NH2 evaluation showed good linearity from 0.01 to 2.81 nM and 2.81-10.81 nM, and low detection limit of 3.34 pM. The obtained results of the stability, reproducibility and selectivity investigations implying that the reported aptasensor as the first aptamer-based electrochemical assay for Tyr-NH2, can be reliable for the determination of Tyr-NH2 in serum samples.}, }
@article {pmid31142898, year = {2019}, author = {Narasimha, VL and Shukla, L and S Shyam, RP and Kandasamy, A and Benegal, V}, title = {Relative effectiveness of N-acetylcysteine and baclofen as anticraving agents in cannabis dependence - A retrospective study with telephonic follow-up.}, journal = {Indian journal of psychiatry}, volume = {61}, number = {3}, pages = {228-231}, pmid = {31142898}, issn = {0019-5545}, abstract = {BACKGROUND: Cannabis dependence is associated with psychiatric, social, and legal consequences. Currently, there is no approved pharmacological treatment for cannabis dependence. Recent studies have reported the utility of N-acetylcysteine (NAC) and baclofen (BAC) in the long-term treatment of cannabis dependence, primarily as anticraving agents.<br><br>MATERIALS AND METHODS: We reviewed the records of all patients who received inpatient treatment during 2015-2017 for cannabis dependence syndrome. We included cases only if cannabis dependence was noted as the primary focus for seeking inpatient care. Data are collected up to 6 months following discharge and analyzed using Kaplan-Meier survival analysis. The time to the first use of cannabis (in days) following discharge is compared between three groups - psychosocial intervention (PSI) only, BAC in addition to PSI, and NAC in addition to PSI.<br><br>RESULTS: During the study period, 238 inpatients were diagnosed with cannabis dependence syndrome. However, cannabis dependence was the primary focus of treatment in only 72 patients. Among these patients, 29 (40.2%) received PSI only while 25 (34.8%) received BAC (mean dose = 55 mg per day, standard deviation [SD] = 2.5 mg) and 18 (25%) received NAC (mean dose = 1800 mg per day, SD = 500 mg) in addition to PSI. While 47 (62.5%) of the patients had comorbid psychiatric disorders, it was comparably distributed in the three groups. A survival analysis shows that the probability of cannabis-free survival is significantly higher in the NAC group as compared to the BAC group which is in turn higher than the PSI group (&#x3c7;[2] = 12.1, P = 0.002).<br><br>CONCLUSION: The use of anticraving medications, namely BAC and NAC, may be a useful option along with PSIs in patients with cannabis dependence and requires further exploration.}, }
@article {pmid31142771, year = {2019}, author = {Fozzatti, L and Alamino, VA and Park, S and Giusiano, L and Volpini, X and Zhao, L and Stempin, CC and Donadio, AC and Cheng, SY and Pellizas, CG}, title = {Interplay of fibroblasts with anaplastic tumor cells promotes follicular thyroid cancer progression.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {8028}, pmid = {31142771}, issn = {2045-2322}, mesh = {Adenocarcinoma, Follicular/*pathology ; Cancer-Associated Fibroblasts/*metabolism ; Carcinogenesis/pathology ; Cell Communication ; Cell Culture Techniques ; Cell Dedifferentiation ; Cell Line, Tumor ; Cell Proliferation ; Coculture Techniques ; Culture Media, Conditioned/metabolism ; Disease Progression ; Humans ; Neoplasm Invasiveness/pathology ; Paracrine Communication ; Stromal Cells/*pathology ; Thyroid Carcinoma, Anaplastic/*pathology ; Thyroid Gland/cytology/pathology ; Thyroid Neoplasms/*pathology ; Tumor Microenvironment ; }, abstract = {Thyroid cancer is the most common endocrine malignancy. Anaplastic thyroid cancer is one of the most aggressive thyroid tumors. It is known that activation of oncogenes and/or inactivation of tumor suppressor genes in tumor cells promotes tumorigenesis. The microenvironment of the tumor also plays a key role on cancer development and progression in a variety of tumors. However, the mechanisms by which tumor-stroma crosstalk in thyroid cancer remains poorly characterized. In this study we aimed to understand how interactions between fibroblasts and anaplastic thyroid cancer cells contribute to thyroid carcinogenesis. We first characterized the phenotypic changes of human fibroblasts in vitro through co-cultures by using transwells as well as by using anaplastic thyroid cancer cells-derived conditioned media. We found that fibroblasts acquired an activated phenotype or also known as cancer-associated fibroblast phenotype after being in contact with soluble factors secreted from anaplastic thyroid cancer cells, compared to the fibroblasts in mono-cultures. All the changes were partly mediated through Src/Akt activation. Treatment with the antioxidant N-acetyl-cysteine reversed in part the metabolic phenotype of activated fibroblasts. Remarkably, conditioned media obtained from these activated fibroblasts promoted cell proliferation and invasion of follicular thyroid cancer cell line, FTC-133 cells. Thus, a reciprocal and dynamic interaction exists between tumor and stromal cells, which results in the promotion of thyroid tumorigenesis. The present studies have advanced the understanding of the molecular basis of tumor-stroma communications, enabling identification and targeting of tumor-supportive mechanisms for novel treatment modalities.}, }
@article {pmid31141608, year = {2019}, author = {Miller, WP and Toro, AL and Barber, AJ and Dennis, MD}, title = {REDD1 Activates a ROS-Generating Feedback Loop in the Retina of Diabetic Mice.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {60}, number = {6}, pages = {2369-2379}, pmid = {31141608}, issn = {1552-5783}, mesh = {Acetylcysteine/pharmacology ; Animals ; Diabetes Mellitus, Experimental/*metabolism ; Feedback, Physiological/physiology ; Membrane Potential, Mitochondrial/physiology ; Mice ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/*metabolism ; Transcription Factors/metabolism/*physiology ; }, abstract = {PURPOSE: The present study was designed to evaluate the role of the stress response protein REDD1 in diabetes-induced oxidative stress and retinal pathology.<br><br>METHODS: Wild-type and REDD1-deficient mice were administered streptozotocin to induce diabetes. Some mice received the antioxidant N-acetyl-l-cysteine (NAC). Visual function was assessed by virtual optometry. Retinas were analyzed by Western blotting. Reactive oxygen species (ROS) were assessed by 2,7-dichlorofluoroscein. Similar analyses were performed on R28 retinal cells in culture exposed to hyperglycemic conditions, NAC, and/or the exogenous ROS source hydrogen peroxide.<br><br>RESULTS: In the retina of diabetic mice, REDD1 expression and ROS were increased. In cells in culture, hyperglycemic conditions enhanced REDD1 expression, ROS levels, and the mitochondrial membrane potential. However, similar effects were not observed in the retina of diabetic mice or cells lacking REDD1. In the retina of diabetic mice and cells exposed to hyperglycemic conditions, NAC normalized ROS and prevented an increase in REDD1 expression. Diabetic mice receiving NAC also exhibited improved contrast sensitivity as compared to diabetic controls. Hydrogen peroxide addition to culture medium increased REDD1 expression and attenuated Akt/GSK3 phosphorylation in a REDD1-dependent manner. In REDD1-deficient cells exposed to hyperglycemic conditions, expression of a dominant negative Akt or constitutively active GSK3 increased the mitochondrial membrane potential and promoted ROS.<br><br>CONCLUSIONS: The findings provide new insight into the mechanism whereby diabetes-induced hyperglycemia causes oxidative stress and visual dysfunction. Specifically, hyperglycemia-induced REDD1 activates a ROS-generating feedback loop that includes Akt/GSK3. Thus, therapeutic approaches targeting REDD1 expression and ROS may be beneficial for preventing diabetes-induced visual dysfunction.}, }
@article {pmid31139638, year = {2019}, author = {Joy, T and Rao, MS and Madhyastha, S and Pai, K}, title = {Effect of N-Acetyl Cysteine on Intracerebroventricular Colchicine Induced Cognitive Deficits, Beta Amyloid Pathology, and Glial Cells.}, journal = {Neuroscience journal}, volume = {2019}, number = {}, pages = {7547382}, pmid = {31139638}, issn = {2314-4262}, abstract = {Among the many factors responsible for the cognitive decline in Alzheimer's disease, beta amyloid protein and plaque formation is crucial. This amyloid pathology is associated with activation of glial cells and oxidative stress but whether oxidative stress activates beta amyloid protein in the neurons is not clear. Further the expression of microglia is also known to vary during pathogenesis of beta amyloid plaques. The aim of the present study is to evaluate the antioxidant effect of NAC on amyloid pathology and cognition and also to investigate the link between amyloid pathology and glial cells activation. Intracerebroventricular colchicine in rats known mimics human AD in many aspects including memory loss, oxidative stress, and hyper phosphorylation of tau protein. The animal groups consisted of age matched control, sham operated, AD, and NAC treated in AD models of rats. Cognitive function was evaluated in active avoidance test; beta amyloid protein, beta amyloid plaques, astrocytes, and microglia cells were quantified using immunohistochemistry in hippocampal and prefrontal cortices. Colchicine has resulted in significant cognitive loss, increased intraneuronal beta amyloid protein expression, increased reactive astrocytes, and activated microglia in all the regions of the hippocampus and prefrontal cortices. The antioxidant NAC has reversed the cognitive deficits and inhibited microglia activation but failed to inhibit BAP expression and astrocytosis. Intraneuronal BAP accumulation is deleterious and known to adversely affect cognition, but in this study in spite of intraneuronal BAP accumulation, the cognition is restored. It can be postulated that NAC might have reversed the effect of intraneuronal beta amyloid protein by acting on some downstream compensatory mechanisms which needs to be explored.}, }
@article {pmid31137980, year = {2019}, author = {Yokoyama, S and Hiramoto, K and Yamate, Y}, title = {Impaired skin barrier function caused by reactive oxygen species in mice with colonic tumours.}, journal = {Cutaneous and ocular toxicology}, volume = {38}, number = {4}, pages = {349-355}, doi = {10.1080/15569527.2019.1622559}, pmid = {31137980}, issn = {1556-9535}, mesh = {Acetylcysteine/pharmacology ; Animals ; Azoxymethane ; Colonic Neoplasms/blood/*metabolism ; Cytokines/blood ; Dextran Sulfate ; Mice, Inbred C57BL ; Mice, Knockout ; Reactive Oxygen Species/*metabolism ; Receptors, Immunologic/genetics ; Skin/metabolism ; }, abstract = {Purpose: We have previously reported that skin barrier function is disrupted in mice with colonic tumours induced by azoxymethane (AOM) and dextran sodium sulphate (DSS). We postulated that the impaired skin barrier function was associated with reactive oxygen species derived from gp91phox. In this study, we investigated the mechanisms underlying the impaired skin barrier function using gp91phox-/- mice. Materials and methods: We induced colonic tumorigenesis in C57BL/6j mice by AOM + DSS administration and evaluated the influence of reactive oxygen species on skin barrier function by using the hydroxyl radical scavenger N-acetyl-l-cysteine (NAC) or gp91phox-/- mice. Damage to the colon and skin following treatment with AOM + DSS was monitored using protein analysis methods and by detection of inflammatory mediators in the plasma. Results: NAC could not prevent the increase in transepidermal water loss (TEWL) and decrease in skin hydration level caused by AOM + DSS in gp91phox+/+ mice. However, gp91phox-/- mice showed no change in TEWL and skin hydration level. The dermal expression levels of nucleotide-binding domain, leucine-rich containing family, pyrin-domain containing 3 (NLRP3), and caspase-1 were reduced in gp91phox-/- mice. Moreover, the plasma concentrations of interleukin-18 and thymic stromal lymphopoietin (TSLP) were lower in gp91phox-/- mice than those in gp91phox+/+ mice. Inhibition of hydrogen peroxide production from superoxide anions in the gp91phox-/- status prevented the increased TEWL and decreased skin hydration level noted with degradation of NLRP3 and caspase-1. Conclusions: Superoxide anions may play an important role in the onset of the impaired skin barrier function in mice with colonic tumours.}, }
@article {pmid31133835, year = {2019}, author = {Prados-Pardo, &#xc1; and Martín-González, E and Mora, S and Merchán, A and Flores, P and Moreno, M}, title = {Increased Fear Memory and Glutamatergic Modulation in Compulsive Drinker Rats Selected by Schedule-Induced Polydipsia.}, journal = {Frontiers in behavioral neuroscience}, volume = {13}, number = {}, pages = {100}, pmid = {31133835}, issn = {1662-5153}, abstract = {Compulsive behavior is observed in several neuropsychiatric disorders such as obsessive-compulsive disorder (OCD), anxiety, depression, phobia, and schizophrenia. Thus, compulsivity has been proposed as a transdiagnostic symptom with a highly variable pharmacological treatment. Recent evidence shows that glutamate pharmacotherapy may be of benefit in impaired inhibitory control. The purpose of the present study was: first, to test the comorbidity between compulsivity and other neuropsychiatric symptoms on different preclinical behavioral models; second, to assess the therapeutic potential of different glutamate modulators in a preclinical model of compulsivity. Long Evans rats were selected as either high (HD) or low (LD) drinkers corresponding with their water intake in schedule-induced polydipsia (SIP). We assessed compulsivity in LD and HD rats by marble burying test (MBT), depression by forced swimming test (FST), anxiety by elevated plus maze (EPM) and fear behavior by fear conditioning (FC) test. After that, we measured the effects of acute administration (i.p.) of glutamatergic drugs: N-Acetylcysteine (NAC; 25, 50, 100 and 200 mg/kg), memantine (3.1 and 6.2 mg/kg) and lamotrigine (15 and 30 mg/kg) on compulsive drinking on SIP. The results obtained showed a relation between high compulsive drinking on SIP and a higher number of marbles partially buried in MBT, as well as a higher percentage of freezing on the retrieval day of FC test. We did not detect any significant differences between LD and HD rats in FST, nor in EPM. The psychopharmacological study of glutamatergic drugs revealed that memantine and lamotrigine, at all doses tested, decreased compulsive water consumption in HD rats compared to LD rats on SIP. NAC did not produce any significant effect on SIP. These results indicate that the symptom clusters of different forms of compulsivity and phobia might be found in the compulsive phenotype of HD rats selected by SIP. The effects of memantine and lamotrigine in HD rats point towards a dysregulation in the glutamatergic signaling as a possible underlying mechanism in the vulnerability to compulsive behavior on SIP. Further studies on SIP, could help to elucidate the therapeutic role of glutamatergic drugs as a pharmacological strategy on compulsive spectrum disorders.}, }
@article {pmid31133026, year = {2019}, author = {Rogliani, P and Matera, MG and Page, C and Puxeddu, E and Cazzola, M and Calzetta, L}, title = {Efficacy and safety profile of mucolytic/antioxidant agents in chronic obstructive pulmonary disease: a comparative analysis across erdosteine, carbocysteine, and N-acetylcysteine.}, journal = {Respiratory research}, volume = {20}, number = {1}, pages = {104}, pmid = {31133026}, issn = {1465-993X}, support = {NA//Edmond Pharma Srl/ ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Antioxidants/adverse effects/*therapeutic use ; Carbocysteine/adverse effects/*therapeutic use ; Expectorants/adverse effects/*therapeutic use ; Humans ; Pulmonary Disease, Chronic Obstructive/diagnosis/*drug therapy/epidemiology ; Randomized Controlled Trials as Topic/methods ; Thioglycolates/adverse effects/*therapeutic use ; Thiophenes/adverse effects/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: To date there are no head-to-head studies comparing different mucolytic/antioxidant agents. Considering the inconsistent evidence resulting from the pivotal studies on mucolytic/antioxidant agents tested in chronic obstructive pulmonary disease (COPD), and the recent publication of Reducing Exacerbations and Symptoms by Treatment with ORal Erdosteine in COPD (RESTORE) study, we have performed a meta-analysis to compare the efficacy and safety of erdosteine 600 mg/day, carbocysteine 1500 mg/day, and N-acetylcysteine (NAC) 1200 mg/day in COPD.<br><br>METHODS: A pairwise and network meta-analyses were performed to assess the efficacy of erdosteine, carbocysteine, and NAC on acute exacerbation of COPD (AECOPD), duration of AECOPD, and hospitalization. The frequency of adverse events (AEs) was also investigated.<br><br>RESULTS: Data obtained from 2753 COPD patients were extracted from 7 RCTs published between 2004 and 2017. In the pairwise meta-analysis mucolytic/antioxidant agents significantly reduced the risk of AECOPD (RR 0.74 95%CI 0.68-0.80). The network meta-analysis provided the following rank of effectiveness: erdosteine>carbocysteine>NAC. Only erdosteine reduced the risk of experiencing at least one AECOPD (P&#x2009;<&#x2009;0.01) and the risk of hospitalization due to AECOPD (P&#x2009;<&#x2009;0.05). Erdosteine and NAC both significantly reduced the duration of AECOPD (P&#x2009;<&#x2009;0.01). The AEs induced by erdosteine, carbocysteine, and NAC were mild in severity and generally well tolerated. The quality of evidence of this quantitative synthesis is moderate.<br><br>CONCLUSIONS: The overall efficacy/safety profile of erdosteine is superior to that of both carbocysteine and NAC. Future head-to-head studies performed on the same COPD populations are needed to definitely confirm the results of this meta-analysis.<br><br>TRIAL REGISTRATION: CRD42016053762 .}, }
@article {pmid31132808, year = {2020}, author = {Moro, F and Giannotti, G and Caffino, L and Marzo, CM and Di Clemente, A and Fumagalli, F and Cervo, L}, title = {Lasting reduction of nicotine-seeking behavior by chronic N-acetylcysteine during experimental cue-exposure therapy.}, journal = {Addiction biology}, volume = {25}, number = {4}, pages = {e12771}, doi = {10.1111/adb.12771}, pmid = {31132808}, issn = {1369-1600}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Behavior, Animal ; *Cues ; Drug-Seeking Behavior/*drug effects ; Extinction, Psychological ; Free Radical Scavengers/*pharmacology ; Glutamic Acid/*metabolism ; Implosive Therapy ; Male ; Nicotine/*administration &amp; dosage ; Nicotinic Agonists/*administration &amp; dosage ; Nucleus Accumbens/drug effects/metabolism ; Rats ; Receptors, AMPA/drug effects/metabolism ; Recurrence ; *Tobacco Use Disorder ; }, abstract = {Nicotine-associated cues can trigger reinstatement in humans as well as in animal models of drug addiction. To date, no behavioral intervention or pharmacological treatment has been effective in preventing relapse in the long term. A large body of evidence indicates that N-acetylcysteine (N-AC) blunts the activation of glutamatergic (GLUergic) neurons in the nucleus accumbens (Nacc) associated with reinstatement. We evaluated the effect of an experimental cue exposure therapy (eCET) alone or in combination with N-AC to verify whether restoring GLU homeostasis enhances extinction of nicotine-associated cues. Rats were trained to associate discriminative stimuli with intravenous nicotine or saline self-administration. Reinforced response was followed by cue signals. After rats met the self-administration criteria, the lasting anti-relapse activity of i.p. N-AC or vehicle was assessed in three different experimental conditions after 14 days of treatment: treatment + eCET; treatment + lever-presses extinction (LP-EXT); and treatment + abstinence. N-AC 100 mg/kg, but not 60 mg/kg, induced anti-relapse activity that persisted 50 days after treatment only when paired with either LP-EXT or eCET with the greater activity found in the latter condition. To identify potential mechanisms for behavioral results, separate groups of rats that received either N-AC or vehicle + eCET were killed at different time points for Nacc Western-blot analysis. Seven days after treatment, chronic N-AC restored the expression of proteins crucial for GLU homeostasis, while at 50 days, it increased the expression of type II metabotropic GLU receptors. These results suggest that N-AC treatment in combination with eCET may offer a novel strategy to prevent relapse in nicotine addiction.}, }
@article {pmid31127990, year = {2019}, author = {Zhao, Y and Xia, S and Cao, C and Du, X}, title = {Effect of TGF-β1 on Apoptosis of Colon Cancer Cells Via the ERK Signaling Pathway.}, journal = {Journal of B.U.ON. : official journal of the Balkan Union of Oncology}, volume = {24}, number = {2}, pages = {449-455}, pmid = {31127990}, issn = {2241-6293}, mesh = {Apoptosis/drug effects/*genetics ; Cell Proliferation/drug effects/genetics ; Colon/metabolism/pathology ; Colonic Neoplasms/drug therapy/*genetics/pathology ; Cyclooxygenase 2/*genetics ; Etoposide/pharmacology ; Fluorouracil/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; HT29 Cells ; Humans ; MAP Kinase Signaling System/genetics ; Mitogen-Activated Protein Kinase 1/*genetics ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/*genetics ; }, abstract = {PURPOSE: To study the effect of transforming growth factor (TGF)-β1 on apoptosis of colon cancer cells via the ERK signaling pathway.<br><br>METHODS: Human chemosensitive colon cancer cell line HT- 29 was used in this study. VEGF mRNA and protein level were detected using PCR and western blot. Enzyme-linked immunosorbent assay (ELISA) was used for prostaglandin (PG) detection. Cell proliferation was determined via MTT assay.<br><br>RESULTS: TGF-&#x3b2;1 had a significant effect on blocking the cancer cell growth (p<0.05). TGF-&#x3b2;1 significantly reduced the VEGF mRNA level (p<0.05) and eliminated the COX-2 expression in a dose-dependent manner, while p53 expression was increased (p<0.05). TGF-&#x3b2;1-induced inhibitory effect on COX-2 was significantly eliminated by the ERK inhibitor Compound C (p<0.05). The basal PGE2 production was eliminated in cells treated with TGF-&#x3b2;1 (p<0.05). N-acetylcysteine (NAC) treatment almost completely eliminated the reactive oxygen species (ROS) produced by TGF-&#x3b2;1 and ERK activation. Compared with administration of 5-FU or etoposide alone, TGF-&#x392;1 combined with 5-FU or etoposide significantly administration the viability of colon cancer HT-29 cells.<br><br>CONCLUSION: ERK is a newly-identified cancer target molecule, which can significantly control COX-2 in colon cancer cells treated with TGF-&#x3b2;1.}, }
@article {pmid31125706, year = {2019}, author = {Demecsová, L and Bočová, B and Zelinová, V and Tamás, L}, title = {Enhanced nitric oxide generation mitigates cadmium toxicity via superoxide scavenging leading to the formation of peroxynitrite in barley root tip.}, journal = {Journal of plant physiology}, volume = {238}, number = {}, pages = {20-28}, doi = {10.1016/j.jplph.2019.05.003}, pmid = {31125706}, issn = {1618-1328}, mesh = {Cadmium/*toxicity ; Cell Death/drug effects ; Dose-Response Relationship, Drug ; Hordeum/*drug effects/metabolism ; Hydrogen Peroxide/metabolism ; Lipid Peroxidation/drug effects ; Meristem/*drug effects/metabolism ; Nitric Oxide/*metabolism ; Peroxynitrous Acid/*metabolism ; Reactive Oxygen Species/metabolism ; Superoxides/*metabolism ; }, abstract = {The aim of this study was to observe the possible function of increased superoxide and NO production in the response of barley root tip to the harmful level of Cd. While superoxide generation was detected only in the transition zone, the formation of NO was observed in the apical elongation zones of the control root tips. However, the root region with the superoxide generation was also associated with peroxynitrite specific fluorescence signal. Superoxide, H2O2 and peroxynitrite generation increased with Cd treatment in a dose-dependent manner. In turn, NO level increased at low 10-20 μM but decreased at high 50-60 μM Cd concentrations in comparison with the control. While co-treatment of roots with rotenone markedly attenuated the Cd-induced superoxide generation and lipid peroxidation, it increased the level of NO in the root tips. Although rotenone did not influence the Cd-induced increase of GPX activity at 10-30 μM Cd concentrations, it markedly reversed the high 40-60 μM Cd concentrations-induced decline of GPX activity. Cd-induced cell death was associated with robust superoxide generation, but not with a high level of peroxynitrite. The Cd-evoked inhibition of root growth was significantly reversed by a strong antioxidant N-acetyl cysteine but not by a peroxynitrite scavenger uric acid, suggesting that similarly to Cd-induced cell death, an imbalance in the ROS homeostasis and not an enhanced level of peroxynitrite is responsible for the Cd-induced root growth inhibition. Based on these findings, it can be assumed that NO acts mainly in the regulation of superoxide level in the tips of root. Under Cd stress, the enhanced NO level is involved in the scavenging of highly toxic superoxide through the formation of peroxynitrite, thus reducing the superoxide-mediated cell death in barley root.}, }
@article {pmid31123658, year = {2019}, author = {Willborn, RJ and Hall, CP and Fuller, MA}, title = {Recycling N-acetylcysteine: A review of evidence for adjunctive therapy in schizophrenia.}, journal = {The mental health clinician}, volume = {9}, number = {3}, pages = {116-123}, pmid = {31123658}, issn = {2168-9709}, abstract = {INTRODUCTION: All symptoms in schizophrenia may impact functioning. Although Food and Drug Administration-approved medications typically benefit positive symptoms, negative symptoms are generally refractory to medication interventions. N-acetylcysteine's (NAC) influence on glutamatergic neurotransmission has been established. An emerging body of research has attempted to correlate this action with reduction in symptom severity, evaluating response in positive, negative, and cognitive symptom domains.<br><br>METHODS: A literature review was performed to analyze available data on NAC intervention and improvement in the positive, negative, and cognitive symptom domains in patients with schizophrenia. Quality of evidence was systematically assessed to determine level of certainty in results.<br><br>RESULTS: Three randomized controlled trials were identified. Across studies, negative symptoms decreased more with NAC compared to placebo; ranging between 11.9% and 24.1%. The assessment determined a low level of certainty regarding benefit of NAC on negative and cognitive symptoms and moderate certainty for NAC regarding findings of side effects and lack of benefit on positive symptoms.<br><br>DISCUSSION: Consistent reporting of benefit in negative symptoms is found across studies of NAC intervention. These improvements are notable for symptoms that have generally remained refractory to medication intervention. Inconsistent benefit was reported in positive and cognitive symptoms. GRADE (grading of recommendations assessment, development and evaluation) assessment of current evidence indicates a low certainty of benefit for negative symptoms with standard use of NAC in patients with schizophrenia. However, a trial of this low-risk intervention may be warranted in patients with resistant negative symptoms and subsequent impaired functioning despite appropriate antipsychotic therapy as they may experience additional benefit in this symptom domain.}, }
@article {pmid31120230, year = {2019}, author = {Naji, S and Issa, K and Eid, A and Iratni, R and Eid, AH}, title = {Cadmium Induces Migration of Colon Cancer Cells: Roles of Reactive Oxygen Species, P38 and Cyclooxygenase-2.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {52}, number = {6}, pages = {1517-1534}, doi = {10.33594/000000106}, pmid = {31120230}, issn = {1421-9778}, support = {MPP# 320133//American University of Beirut/Lebanon ; }, mesh = {Adenocarcinoma/*chemically induced/genetics/metabolism/pathology ; Cadmium/*toxicity ; Cell Movement/drug effects ; Colonic Neoplasms/*chemically induced/genetics/metabolism/pathology ; Cyclooxygenase 2/genetics/*metabolism ; Enzyme Activation/drug effects ; HT29 Cells ; Humans ; Reactive Oxygen Species/*metabolism ; Transcriptional Activation/drug effects ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {BACKGROUND/AIMS: Cadmium (Cd) is a heavy metal contaminant whose toxicity is associated with colorectal cancer (CRC). However, the underlying molecular mechanisms of Cd-induced CRC malignancy remain obscure.<br><br>METHODS: A monolayer scratch assay was employed to assess the migration of HT-29 human adenocarcinoma cells. Luciferase&#xa0;reporter&#xa0;assay was used to determine cyclooxygenase-2 (COX-2) transcriptional activity, and Western blotting was used to detect p38 Mitogen Activated Protein Kinase (MAPK) and Akt phosphorylation as well as COX-2 expression. Prostaglandin E2 (PGE2) levels were measured using Enzyme Linked Immunosorbent Assay (ELISA) and reactive oxygen species (ROS) formation was assessed using dihydroethidium (DHE) stain.<br><br>RESULTS: Here, we show that Cd potentiates the migratory capacity of HT-29 CRC cells. Cd caused a time-dependent increase in COX-2 expression. Celecoxib, a COX-2 selective inhibitor, significantly reduced Cd-induced migration. Cd also increased levels of ROS and phosphorylated p38. Importantly, Cd-induced COX-2 expression and migration were significantly abolished by N-Acetyl-Cysteine (NAC), a ROS scavenger, or SB202190, a specific p38 inhibitor. Furthermore, Cd-induced p38 phosphorylation was inhibited by NAC. Cd (100 nM) also increased PGE2 levels, which was abrogated by NAC, SB202190, or celecoxib. Exogenous PGE2 significantly potentiated cell migration. Cd caused a significant increase in Akt phosphorylation in a ROS-mediated pathway. Moreover, Cd-induced migration was significantly attenuated by LY294 002, a phosphatidylinositol-3-kinase inhibitor.<br><br>CONCLUSION: Taken together, our results suggest that exposure to low levels of Cd promotes a more migratory cancer phenotype in a ROS-p38-COX-2-PGE2 pathway as well as ROS-Akt pathway. Therefore, COX-2, PGE2 receptors or Akt represent potential targets in the treatment of CRC, particularly in patients exposed to Cd.}, }
@article {pmid31118506, year = {2019}, author = {Kang, JS and Lee, SJ and Lee, JH and Kim, JH and Son, SS and Cha, SK and Lee, ES and Chung, CH and Lee, EY}, title = {Angiotensin II-mediated MYH9 downregulation causes structural and functional podocyte injury in diabetic kidney disease.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {7679}, pmid = {31118506}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Actin Cytoskeleton/drug effects/ultrastructure ; Angiotensin II/pharmacology/*physiology ; Animals ; Calcium/metabolism ; Cell Adhesion ; Cell Line, Transformed ; Diabetes Mellitus, Experimental/metabolism/pathology ; Diabetic Nephropathies/metabolism/*pathology ; Down-Regulation ; Humans ; Losartan/pharmacology ; Mice ; Mice, Inbred C57BL ; Microfilament Proteins/metabolism ; Molecular Motor Proteins/biosynthesis/genetics/*physiology ; Myosin Heavy Chains/biosynthesis/genetics/*physiology ; NADPH Oxidase 4/biosynthesis/genetics ; Podocytes/drug effects/*metabolism/ultrastructure ; RNA Interference ; Rats ; Rats, Inbred Strains ; Reactive Oxygen Species/metabolism ; Receptors, Leptin/deficiency ; TRPC6 Cation Channel/physiology ; }, abstract = {MYH9, a widely expressed gene encoding nonmuscle myosin heavy chain, is also expressed in podocytes and is associated with glomerular pathophysiology. However, the mechanisms underlying MYH9-related glomerular diseases associated with proteinuria are poorly understood. Therefore, we investigated the role and mechanism of MYH9 in diabetic kidney injury. MYH9 expression was decreased in glomeruli from diabetic patients and animals and in podocytes treated with Ang II in vitro. Ang II treatment and siRNA-mediated MYH9 knockdown in podocytes resulted in actin cytoskeleton reorganization, reduced cell adhesion, actin-associated protein downregulation, and increased albumin permeability. Ang II treatment increased NOX4 expression and ROS generation. The Ang II receptor blocker losartan and the ROS scavenger NAC restored MYH9 expression in Ang II-treated podocytes, attenuated disrupted actin cytoskeleton and decreased albumin permeability. Furthermore, MYH9 overexpression in podocytes restored the effects of Ang II on the actin cytoskeleton and actin-associated proteins. Ang II-mediated TRPC6 activation reduced MYH9 expression. These results suggest that Ang II-mediated MYH9 depletion in diabetic nephropathy may increase filtration barrier permeability by inducing structural and functional podocyte injury through TRPC6-mediated Ca[2+] influx by NOX4-mediated ROS generation. These findings reveal a novel MYH9 function in maintaining urinary filtration barrier integrity. MYH9 may be a potential target for treating diabetic nephropathy.}, }
@article {pmid31115735, year = {2019}, author = {Niraula, P and Kim, MS}, title = {N-Acetylcysteine extends lifespan of Drosophila via modulating ROS scavenger gene expression.}, journal = {Biogerontology}, volume = {20}, number = {4}, pages = {533-543}, doi = {10.1007/s10522-019-09815-4}, pmid = {31115735}, issn = {1573-6768}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase/metabolism ; Drosophila ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; *Longevity/drug effects/physiology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Stress, Physiological/*drug effects ; }, abstract = {N-Acetylcysteine (NAc) has been shown to play a diversity of favorable health-related roles (e.g., antioxidant, paracetamol antidote, mucolytics, neuroprotective agent). Having said that, here in this study, we evaluate the health-promoting properties of NAc, particularly its ability to modulate organismal longevity. We note that 1 mg/ml NAc prolonged the lifespan of Drosophila. Furthermore, it was observed that NAc increased the capability of these flies to resist environmental stresses measured by starvation and paraquat stress assays. In an effort to reveal cellular mechanisms behind this interesting phenomenon, qPCR was performed, uncovering that transcript levels of catalase and phospholipid hydroperoxide glutathione peroxidase-key enzymes to fend off reactive oxygen species (ROS) assaults, were up-regulated. Correspondingly, enzyme activities of catalase and glutathione peroxidase were increased as well. Combined, we hope our research helps broaden the spectrum of clinical application for NAc so that one may eventually determine if NAc is a potentially useful anti-aging agent by encouraging others to scrutinize the hidden health benefits of NAc.}, }
@article {pmid31111056, year = {2019}, author = {Huang, S and You, J and Wang, K and Li, Y and Zhang, Y and Wei, H and Liang, X and Liu, Y}, title = {N-Acetylcysteine Attenuates Cisplatin-Induced Acute Kidney Injury by Inhibiting the C5a Receptor.}, journal = {BioMed research international}, volume = {2019}, number = {}, pages = {4805853}, pmid = {31111056}, issn = {2314-6141}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/*drug therapy ; Animals ; Apoptosis/drug effects ; Cisplatin/*adverse effects ; Complement C5a/metabolism ; Disease Models, Animal ; Inflammation ; Kidney/drug effects/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Neutrophils ; Oxidative Stress/drug effects ; Receptor, Anaphylatoxin C5a/*antagonists &amp; inhibitors/metabolism ; }, abstract = {N-acetylcysteine has been widely used as a nutritional supplement and drug in humans for its antioxidant properties. The complement activation fragment C5a is a strong proinflammatory molecule that mediates cell adhesion, chemotaxis, and the complex biological functions. However, the effect of NAC on the C5a, and the relationship of those two with cisplatin-induced acute kidney injury are unknown. In cisplatin induced AKI mouse model, mice with NAC administration had a marked improvement in renal function (BUN and Cr), decreased pathological damage, reduced inflammation, and alleviated renal oxidative stress. Furthermore, C5a and C5aR expression in the cisplatin-treated group was notably increased compared with the control group, and this increase could be significantly inhibited by NAC. In addition, neutrophils coexpressed distinctly with C5aR, and the number of infiltrating neutrophils (MPO[+]ly6G[+]) and inflammatory factors decreased with NAC treatment in the cisplatin-treated group. Overall, these data demonstrate that NAC could ameliorate cisplatin-induced nephrotoxicity in mice and the protective effects may be conducted by inhibiting the activation of kidney inflammation and the complement system.}, }
@article {pmid31105565, year = {2019}, author = {Lee, ES and Kim, JS and Lee, H and Ryu, JY and Lee, HJ and Sonn, JK and Lim, YB}, title = {Auranofin, an Anti-rheumatic Gold Drug, Aggravates the Radiation-Induced Acute Intestinal Injury in Mice.}, journal = {Frontiers in pharmacology}, volume = {10}, number = {}, pages = {417}, pmid = {31105565}, issn = {1663-9812}, abstract = {Pelvic and abdominal radiotherapy plays an important role in eradication of malignant cells; however, it also results in slight intestinal injury. The apoptosis of cells in the intestinal epithelium is a primary pathological factor that initiates radiation-induced intestinal injury. Auranofin, a gold-containing triethylphosphine, was approved for the treatment of rheumatoid arthritis, and its therapeutic application has been expanded to a number of other diseases, such as parasitic infections, neurodegenerative disorders, AIDS, and bacterial infections. Recently, a treatment strategy combining the use of auranofin and ionizing radiation aimed at increasing the radiosensitivity of cancer cells was proposed for improving the control of local cancers. In this study, we evaluated the effect of auranofin on the radiosensitivity of intestinal epithelial cells. The treatment with a combination of 1 μM auranofin and 5 Gy ionizing radiation showed clear additive effects on caspase 3 cleavage and apoptotic DNA fragmentation in IEC-6 cells, and auranofin administration significantly aggravated the radiation-induced intestinal injury in mice. Auranofin treatment also resulted in the activation of the unfolded protein response and in the inhibition of thioredoxin reductase, which is a key component of the cellular antioxidant system. Pre-treatment with N-acetyl cysteine, a well-known scavenger of reactive oxygen species, but not with a chemical chaperone, which inhibits endoplasmic reticulum stress and the ensuing unfolded protein response, significantly reduced the radiosensitizing effects of auranofin in the IEC-6 cells. In addition, transfection of IEC-6 cells with a small interfering RNA targeted against thioredoxin reductase significantly enhanced the radiosensitivity of these cells. These results suggest that auranofin-induced radiosensitization of intestinal epithelial cells is mediated through oxidative stress caused by the deregulation of thioredoxin redox system, and auranofin treatment can be an independent risk factor for the development of acute pelvic radiation disease.}, }
@article {pmid31104238, year = {2019}, author = {Mahmoud, SM and Abdel Moneim, AE and Qayed, MM and El-Yamany, NA}, title = {Potential role of N-acetylcysteine on chlorpyrifos-induced neurotoxicity in rats.}, journal = {Environmental science and pollution research international}, volume = {26}, number = {20}, pages = {20731-20741}, pmid = {31104238}, issn = {1614-7499}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Brain/drug effects/metabolism/pathology ; Chlorpyrifos/*toxicity ; Insecticides/*toxicity ; Male ; Neurotoxicity Syndromes/metabolism/pathology/*prevention &amp; control ; Oxidative Stress/drug effects ; Rats, Wistar ; }, abstract = {Chlorpyrifos (CPF) is a widely used organophosphate insecticide with several harmful effects. N-acetylcysteine (NAC) represents an ideal antixenobiotic; it can directly enter endogenous biochemical processes and is used as adjunctive treatment for psychiatric disorders. We aimed to evaluate the neuroprotective effect of NAC as an antioxidant drug against CPF-induced neurotoxicity in adult male albino rat brains. Twenty-eight male Wister rats were allocated into four groups (n = 7) and were administered the following for 28 days: group I (control group), physiological saline (0.9% NaCl); group II (CPF group), 10 mg/kg body weight (BW) CPF; group III (NAC group), 100 mg/kg BW NAC; and group VI (CPF+NAC group), NAC 1 h before CPF. CPF intoxication resulted in acetylcholinesterase inhibition, reduced glutathione content, and elevated levels of malondialdehyde and nitric oxide, which are oxidative stress biomarkers. CPF also depleted the activity of antioxidant enzymes, superoxide dismutase and catalase, and levels of inflammatory mediators, tumor necrosis factor-α, interleukin (IL)-6, and IL-1β. Levels of vascular endothelial growth factor, Bax, and the proapoptotic caspases-3 also increased, while brain-derived neurotrophic factor level decreased. Additionally, CPF significantly diminished Bcl-2 (an antiapoptotic protein) in rat brain cortical tissue. NAC treatment was found to protect brain tissue by reversing the CPF-induced neurotoxicity. Our results show the antioxidant, antiinflammatory, and antiapoptotic effects of NAC on CPF-induced neurotoxicity in rat brain tissue.}, }
@article {pmid31100592, year = {2019}, author = {Liu, J and Zhang, J and Ren, L and Wei, J and Zhu, Y and Duan, J and Jing, L and Sun, Z and Zhou, X}, title = {Fine particulate matters induce apoptosis via the ATM/P53/CDK2 and mitochondria apoptosis pathway triggered by oxidative stress in rat and GC-2spd cell.}, journal = {Ecotoxicology and environmental safety}, volume = {180}, number = {}, pages = {280-287}, doi = {10.1016/j.ecoenv.2019.05.013}, pmid = {31100592}, issn = {1090-2414}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Line ; Cyclin-Dependent Kinase 2/metabolism ; *DNA Damage ; Male ; Mice ; Mitochondria/*drug effects/metabolism ; Oxidative Stress/drug effects ; Particulate Matter/*toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Spermatocytes/*drug effects/metabolism/ultrastructure ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Fine particulate matters (PM2.5) have been associated with male reproductive toxicity because it can penetrate into the lung's gas-exchange region, and spread to the whole body via circulatory system. Previous studies have shown that PM2.5 could induce DNA damage and apoptosis by reactive oxygen species (ROS). The aim of the present study is to determine the exact mechanism and role of apoptosis induced by PM2.5 in spermatocyte cells. Male Sprague-Dawley (SD) rats were treated with normal saline (control group) or PM2.5 with the doses of 1.8, 5.4 and 16.2 mg/kg bw. via intratracheal instillation every 3 days for 30 days. Mouse spermatocyte-derived cells (GC-2spd cells) were treated with various concentrations (0, 50, 100, 200 μg/mL) of PM2.5 for 24 h. The results showed that exposure to PM2.5 resulted in injury of testicular tissue and impaired mitochondria integrity in GC-2spd cells. Moreover, PM2.5 induced DNA damage and apoptosis in GC-2spad cells via ROS generation, and the ATM/P53/CDK2 and mitochondria apoptosis pathway autophagy signal pathway were activated. N-Acetyl-L-cysteine (NAC), a well-known antioxidant, ameliorated DNA damage, and inhibited apoptosis. These findings demonstrated PM2.5 might induce apoptosis via the mitochondrial apoptosis pathway through causing DNA damage resulting from oxidative stress, and finally caused spermatogenesis disorder.}, }
@article {pmid31100478, year = {2019}, author = {Miller, DR and Ingersoll, MA and Chatterjee, A and Baker, B and Shrishrimal, S and Kosmacek, EA and Zhu, Y and Cheng, PW and Oberley-Deegan, RE and Lin, MF}, title = {p66Shc protein through a redox mechanism enhances the progression of prostate cancer cells towards castration-resistance.}, journal = {Free radical biology &amp; medicine}, volume = {139}, number = {}, pages = {24-34}, pmid = {31100478}, issn = {1873-4596}, support = {R03 CA230950/CA/NCI NIH HHS/United States ; R01 CA088184/CA/NCI NIH HHS/United States ; P30 GM127200/GM/NIGMS NIH HHS/United States ; R01 CA178888/CA/NCI NIH HHS/United States ; P30 CA036727/CA/NCI NIH HHS/United States ; T32 CA009476/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Disease Progression ; Drug Resistance, Neoplasm/*genetics ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Heterografts ; Humans ; Hydrogen Peroxide/pharmacology ; Kallikreins/genetics/metabolism ; Lymphatic Metastasis ; Male ; Mice ; Mice, Nude ; Prostate/drug effects/metabolism/pathology ; Prostate-Specific Antigen/genetics/metabolism ; Prostatic Neoplasms, Castration-Resistant/drug therapy/*genetics/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Receptors, Androgen/genetics/metabolism ; Src Homology 2 Domain-Containing, Transforming Protein 1/*genetics/metabolism ; }, abstract = {Prostate cancer (PCa) remains the second leading cause of cancer-related deaths in U.S. men due to the development of the castration-resistant (CR) PCa phenotype. A useful cell model for analysis of the molecular mechanism of PCa progression is required for developing targeted therapies toward CR PCa. In this study, we established a PCa cell progressive model in three separate cell lines, of which androgen-independent (AI) cells were derived from respective androgen-sensitive (AS) cells. Those AI PCa cells obtain the biochemical properties of the clinical CR phenotype, including AR and PSA expression as well as enhanced proliferation and tumorigenicity under androgen-deprived conditions. Thus, those AI cells recapitulate CR PCa and exhibit increased oxidant species levels as well as enhanced signaling of proliferation and survival pathways. H2O2 treatment directly enhanced AS cell growth and migration, which was counteracted by antioxidant N-acetyl cysteine (NAC). We further identified p66Shc protein enhances the production of oxidant species which contributes to phenotypic and cell signaling alterations from AS to AI PCa cells. H2O2-treated LNCaP-AS cells had a similar signaling profile to that of LNCaP-AI or p66Shc subclone cells. Conversely, the oxidant species-driven alterations of LNCaP-AI and p66Shc subclone cell signaling is mitigated by p66Shc knockdown. Moreover, LNCaP-AI cells and p66Shc subclones, but not LNCaP-AS cells, develop xenograft tumors with metastatic nodules, correlating with p66Shc protein levels. Together, the data shows that p66Shc enhances oxidant species production that plays a role in promoting PCa progression to the CR stage.}, }
@article {pmid31099374, year = {2019}, author = {Qi, F and Sun, Y and Lv, M and Qin, F and Cao, W and Bi, L}, title = {Effects of palmatine hydrochloride mediated photodynamic therapy on oral squamous cell carcinoma.}, journal = {Photochemical &amp; photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology}, volume = {18}, number = {6}, pages = {1596-1605}, doi = {10.1039/c9pp00040b}, pmid = {31099374}, issn = {1474-9092}, mesh = {Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/drug effects ; Berberine Alkaloids/chemistry/*pharmacology ; Carcinoma, Squamous Cell/*drug therapy/metabolism/pathology ; Cell Cycle Checkpoints/drug effects ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Female ; Humans ; Lasers ; Mice ; Mice, Inbred BALB C ; Molecular Structure ; Mouth Neoplasms/*drug therapy/metabolism/pathology ; Neoplasms, Experimental/*drug therapy/metabolism/pathology ; *Photochemotherapy ; Photosensitizing Agents/chemistry/*pharmacology ; Reactive Oxygen Species/analysis/metabolism ; Structure-Activity Relationship ; Tumor Cells, Cultured ; }, abstract = {Oral squamous cell carcinoma (OSCC) is a common malignant tumor, accounting for about 7% of all malignant tumors. Palmatine hydrochloride (PaH) is the alkaloid constituent of Fibraurea tinctoria Lour. The present study aims to investigate the antitumor effect of photodynamic therapy (PDT) with PaH (PaH-PDT) on human OSCC cell lines both in vitro and in vivo. The results indicate that PaH-PDT exhibited a potent phototoxic effect in cell proliferation and produced cell apoptosis. PaH-PDT increased the percentage of cells in the G0/G1 phase and decreased the CDK2 and Cyclin E1 protein level. In addition, PaH-PDT markedly increased the generation of intracellular ROS, which can be suppressed using the ROS scavenger N-acetylcysteine (NAC). Furthermore, PaH-PDT increased the expression of p53 protein in vitro and in vivo. In vivo experiments revealed that the PaH-PDT resulted in an effective inhibition of tumor growth and prolonged the survival time of tumor-bearing mice. Moreover, no obvious signs of side effects or a drop in body weight was observed. These results suggested that PaH was a promising sensitizer that can be combined with light to produce significant anti-tumor effects in oral squamous cell carcinoma via enhanced ROS production and up-regulated expression of p53.}, }
@article {pmid31097446, year = {2019}, author = {Liao, GY and Lee, MT and Fan, JJ and Hsiao, PW and Lee, CS and Su, SY and Hwang, JJ and Ke, FC}, title = {Blockage of glutamine-dependent anaplerosis affects mTORC1/2 activity and ultimately leads to cellular senescence-like response.}, journal = {Biology open}, volume = {8}, number = {5}, pages = {}, pmid = {31097446}, issn = {2046-6390}, abstract = {The purpose of study was to explore the role of glutamine-dependent anaplerosis in cell fate determination (proliferation and senescence) and the potential associated mechanism by employing a pharmacological inhibitor of glutamine-dependent anaplerosis, amino-oxyacetate (AOA). Using the WI38 normal human embryonic fibroblast cell line, we found that exposure to AOA induced mTORC1 inactivation-mTORC2 activation (within day 1), cell cycle arrest (day 2-6) and cellular senescence (day 4-6). These AOA effects were blocked by concomitantly providing anaplerotic factors [α-ketoglutarate (αKG), pyruvate or oxaloacetate], and not affected by ROS scavenger N-acetyl-cysteine (NAC). Moreover, AOA-induced cellular senescence in WI38 cells is associated with elevated protein levels of p53, p21[CIP1] and p16[INK4A] and decreased Rb protein level, which was blocked by αKG supplementation. In p16[INK4A]-deficient U2OS human osteosarcoma cells and p16[INK4A]-knockdown WI38 cells, AOA exposure also induced similar effects on cell proliferation, and protein level of P-Rb-S807/811 and Rb. Interestingly, no AOA induction of cellular senescence was observed in U2OS cells, yet was still seen in p16[INK4A]-knockdown WI38 cells accompanied by the presence of p16 antibody-reactive p12. In summary, we disclose that glutamine-dependent anaplerosis is essential to cell growth and closely associated with mTORC1 activation and mTORC2 inactivation, and impedes cellular senescence particularly associated with p16[INK4A].}, }
@article {pmid31094028, year = {2019}, author = {Xing, JJ and Hou, JG and Ma, ZN and Wang, Z and Ren, S and Wang, YP and Liu, WC and Chen, C and Li, W}, title = {Ginsenoside Rb3 provides protective effects against cisplatin-induced nephrotoxicity via regulation of AMPK-/mTOR-mediated autophagy and inhibition of apoptosis in vitro and in vivo.}, journal = {Cell proliferation}, volume = {52}, number = {4}, pages = {e12627}, pmid = {31094028}, issn = {1365-2184}, support = {2016-2018//Program for the Young Top-notch and Innovative Talents of Jilin Agricultural University/ ; 31770378//National Natural Science Foundation of China/ ; //Scientific Research Foundation for the Returned Overseas Chinese Scholars/ ; 20160209008YY//Jilin Science &amp; Technology Development Plan/ ; 20180201083YY//Jilin Science &amp; Technology Development Plan/ ; 20191102051YY//Jilin Science &amp; Technology Development Plan/ ; 20190103092JH//Jilin Science &amp; Technology Development Plan/ ; 20190304003YY//Jilin Science &amp; Technology Development Plan/ ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Blood Urea Nitrogen ; Cell Line ; Cisplatin/*pharmacology ; Creatinine/metabolism ; Ginsenosides/*pharmacology ; Glutathione/metabolism ; HEK293 Cells ; Humans ; Inflammation/metabolism ; Kidney/drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred ICR ; Oxidative Stress/drug effects ; Protective Agents/*pharmacology ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {OBJECTIVES: Based on previous reports that ginsenosides have been shown to exert better preventive effects on cisplatin-induced kidney injury, the present work aims to evaluate the protective effects of ginsenoside Rb3 (G-Rb3) on cisplatin-induced renal damage and underlying mechanisms in vivo and in vitro.<br><br>MATERIALS AND METHODS: The protective effect of G-Rb3 on cisplatin-induced acute renal failure in ICR mouse model and HEK293 cell model was investigated, and the underlying possible mechanisms were also explored. For animal experiment, renal function, kidney histology, inflammation, oxidative stress, relative protein molecules involved in apoptosis and autophagy signalling pathways were assessed. In addition, rapamycin (a specific inhibitor of mTOR), compound C (a specific inhibitor of AMPK) and acetylcysteine (NAC, a specific ROS scavenger) were employed to testify the effects of AMPK/mTOR signal pathway on the protective effects of G-Rb3 in HEK293 cells.<br><br>RESULTS: Pre-treatment with G-Rb3 at doses of 10 and 20&#xa0;mg/kg for ten days significantly reversed the increases in serum creatinine (CRE), blood urea nitrogen (BUN) and malondialdehyde (MDA), and decrease in glutathione (GSH) content and superoxide dismutase (SOD) activity. Histopathological examination further revealed that G-Rb3 inhibited cisplatin-induced nephrotoxicity. G-Rb3 diminished cisplatin-induced increase in protein expression levels of p62, Atg3, Atg5 and Atg7, and decrease in protein expression level of p-mTOR and the ratio of LC3-I/LC3-II, indicating that G-Rb3 suppressed cisplatin-induced activation of autophagy. Inhibition of autophagy induced inactivation of apoptosis, which suggested that autophagy played an adverse effect on cisplatin-evoked renal damage. Further, we found that G-Rb3 might potentially modulate the expressions of AMPK-related signal pathways.<br><br>CONCLUSIONS: These findings clearly suggested that G-Rb3-mediated alleviation of cisplatin-induced nephrotoxicity was in part due to regulation of AMPK-/mTOR-mediated autophagy and inhibition of apoptosis in vitro and in vivo.}, }
@article {pmid31093026, year = {2019}, author = {Savva, DA and Crist, M and Lardieri, A}, title = {N-Acetylcysteine for Gastric Lactobezoars in a 1-Month-Old.}, journal = {The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG}, volume = {24}, number = {3}, pages = {247-250}, pmid = {31093026}, issn = {1551-6776}, abstract = {Gastric lactobezoars are a result of the inability to digest milk and mucous. Formulas that contain high casein concentrations, medium triglyceride oils, or high caloric density can increase the risk of bezoar formation by decreasing gastric secretion or delaying gastric emptying. N-acetylcysteine (NAC) is used to clear thick mucus secretions and is hypothesized to be effective in the treatment of gastric lactobezoars due to the cleavage of disulfide bonds in mucoproteins. We describe the use of NAC in a 1-month-old full term male (4.5 kg) who was diagnosed with a gastric lactobezoar following an upper gastrointestinal series that showed a large persistent filling defect in the distal body, which was suggestive of a gastric lactobezoar. A dose of 45 mg (10 mg/kg) of 10% NAC was diluted in 50 mL of normal saline and given every 6 hours via a nasogastric (NG) tube. Administration was followed by clamping of the NG tube for 2 hours and aspiration of the stomach contents. NAC was discontinued when aspirates were a clear mucus consistency. The patient's gastric lactobezoar was successfully treated with a 10 mg/kg/dose of NAC that was given every 6 hours for a total of 4 doses.}, }
@article {pmid31086404, year = {2019}, author = {AnandBabu, K and Sen, P and Angayarkanni, N}, title = {Oxidized LDL, homocysteine, homocysteine thiolactone and advanced glycation end products act as pro-oxidant metabolites inducing cytokine release, macrophage infiltration and pro-angiogenic effect in ARPE-19 cells.}, journal = {PloS one}, volume = {14}, number = {5}, pages = {e0216899}, pmid = {31086404}, issn = {1932-6203}, mesh = {Cells, Cultured ; Cytokines/metabolism ; Glycation End Products, Advanced/*metabolism ; Homocysteine/*analogs &amp; derivatives/metabolism ; Humans ; Lipoproteins, LDL/*metabolism ; Macrophages/metabolism/pathology ; Macular Degeneration/metabolism/pathology ; Neovascularization, Pathologic/*metabolism/pathology ; Oxidative Stress ; Retinal Pigment Epithelium/*metabolism/pathology ; }, abstract = {Age-related Macular Degeneration (AMD) is one of the major vision-threatening diseases of the eye. Oxidative stress is one of the key factors in the onset and progression of AMD. In this study, metabolites associated with AMD pathology more so at the systemic level namely, oxidized LDL (oxLDL), homocysteine (Hcy), homocysteine thiolactone (HCTL), advanced glycation end product (AGE) were evaluated for their pro-oxidant nature in a localized ocular environment based on in vitro studies in human retinal pigment epithelial cells (ARPE-19 cells). Human ARPE-19 cells were treated with pro-oxidants 50 μg/mL oxLDL, 500 μM Hcy, 500 nM HCTL, 100 μg/mL AGE, 200 μM H2O2 and 200 μM H2O2 with and without pre-treatment of 5 mM N-acetyl cysteine (NAC). The cytokines IL-6, IL-8 and vascular endothelial growth factor (VEGF) secreted from ARPE-19 cells exposed to pro-oxidants were estimated by ELISA. In vitro angiogenesis assay was performed with conditioned media of the pro-oxidant treated ARPE-19 cells in Geltrex-Matrigel coated 96-well plate. The human acute monocytic leukemia cell line (THP-1) was differentiated into macrophages and its migration in response to conditioned media of ARPE-19 cells insulted with the pro-oxidants was studied by transwell migration assay. Western blot was performed to detect the protein expression of Bax, Bcl-2 and NF-κB to assess apoptotic changes. The compounds involved in the study showed a significant increase in reactive oxygen species (ROS) generation in ARPE-19 cells (oxLDL; Hcy; AGE: p < 0.001 and HCTL: p < 0.05). NAC pre-treatment significantly lowered the oxidative stress brought about by pro-oxidants as seen by lowered ROS and MDA levels in the cells. Treatment with pro-oxidants significantly increased the secretion of IL-6 (oxLDL: p < 0.05; Hcy, HCTL and AGE: p < 0.01) and IL-8 cytokines (oxLDL: p < 0.05; HCTL: p <. 001 and AGE: p < 0.01) in ARPE-19 cells. Serum samples of AMD patients (n = 23) revealed significantly higher IL-6 and IL-8 levels compared to control subjects (n = 23) (IL6: p < 0.01 and IL8: p < 0.05). The pro-oxidants also promoted VEGF secretion by ARPE-19 cells compared to untreated control (oxLDL: p < 0.001; Hcy: p < 0.01; HCTL and AGE: p < 0.05). In vitro angiogenesis assay showed that the conditioned media significantly increased the tube formation in RF/6A endothelial cells. Transwell migration assay revealed significant infiltration of macrophages in response to pro-oxidants. We further demonstrated that the pro-oxidants increased the Bax/Bcl-2 ratio and increased the NF-κB activation resulting in pro-apoptotic changes in ARPE-19 cells. Thus, oxLDL, Hcy, HCTL and AGE act as pro-oxidant metabolites in RPE that promote AMD through oxidative stress, inflammation, chemotaxis and neovascularization.}, }
@article {pmid31085771, year = {2019}, author = {Sivasinprasasn, S and Palee, S and Chattipakorn, K and Jaiwongkum, T and Apaijai, N and Pratchayasakul, W and Chattipakorn, SC and Chattipakorn, N}, title = {N-acetylcysteine with low-dose estrogen reduces cardiac ischemia-reperfusion injury.}, journal = {The Journal of endocrinology}, volume = {242}, number = {2}, pages = {37-50}, doi = {10.1530/JOE-19-0108}, pmid = {31085771}, issn = {1479-6805}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cardiotonic Agents/pharmacology ; Dose-Response Relationship, Drug ; Estradiol/pharmacology ; Estrogens/*pharmacology ; Female ; Heart Rate/drug effects/physiology ; Humans ; Mitochondria, Heart/drug effects/metabolism ; Myocardial Ischemia/metabolism/physiopathology/*prevention &amp; control ; Myocardial Reperfusion Injury/metabolism/physiopathology/*prevention &amp; control ; Myocardium/metabolism ; Myocytes, Cardiac/drug effects/metabolism ; Ovariectomy ; Rats, Wistar ; }, abstract = {Myocardial damage and mitochondrial dysfunction caused by cardiac ischemia-reperfusion (I/R) injury are intensified by endogenous estrogen deprivation. Although N-acetylcysteine (NAC) exerted cardioprotective effects, its benefits when used in combination with hormone therapy are unknown. We tested the hypothesis that a combination of NAC with low-dose estrogen improves cardiometabolic function and protects cardiac mitochondria against I/R injury, to a similar extent to regular-dose estrogen treatment, in estrogen-deprived rats. Female Wistar rats had a bilateral ovariectomy (OVX) or sham operation. Twelve weeks after the operation, OVX rats were treated with regular-dose estrogen (E; 50 µg/kg/day), low-dose estrogen (e; 25 µg/kg/day), NAC (N; 100 mg/kg/day) or combined low-dose estradiol with NAC (eN) for 4 weeks (n = 6/group). Metabolic parameters, echocardiography, heart rate variability and then cardiac I/R protocol involving 30-min coronary artery ligation, followed by 120-min reperfusion, were performed. OVX rats had increased body weight, visceral fat, fasting plasma glucose, HOMA-IR index, triglycerides, cholesterol and LDL levels (P < 0.05 vs sham). Only OVX-E and OVX-eN had a similarly improved HOMA-IR index. LVEF was increased in all treatment groups, but HRV was restored only by OVX-E and OVX-eN. After I/R, myocardial infarct size was decreased in both OVX-E and OVX-eN groups. OVX-E and OVX-eN rats similarly had a reduced mitochondrial ROS level and increased mitochondrial membrane potential in the ischemic myocardium. In conclusion, combined NAC with low-dose estrogen and regular-dose estrogen therapy similarly improve cardiometabolic function, prevent cardiac mitochondrial dysfunction and reduces the infarct size in estrogen-deprived rats with cardiac I/R injury.}, }
@article {pmid31085604, year = {2019}, author = {Lehmann, ML and Weigel, TK and Poffenberger, CN and Herkenham, M}, title = {The Behavioral Sequelae of Social Defeat Require Microglia and Are Driven by Oxidative Stress in Mice.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {39}, number = {28}, pages = {5594-5605}, pmid = {31085604}, issn = {1529-2401}, support = {ZIA MH001090/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/drug effects/*metabolism ; Organic Chemicals/toxicity ; *Oxidative Stress ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists &amp; inhibitors ; *Social Behavior ; Stress, Psychological/*metabolism ; }, abstract = {Chronic social defeat (CSD) in male mice can produce anxiety and aberrant socialization. Animals susceptible to CSD show activation of microglia, which have elevated levels of oxidative stress markers. We hypothesized that microglia and reactive oxygen species (ROS) production contribute to the CSD stress-induced changes in affective behavior. First, we selectively depleted microglia (99%) by administering the CSF1R (colony-stimulating factor 1 receptor) antagonist PLX5622 before and during the 14 d CSD procedure. Microglia-depleted mice in contrast to nondepleted mice were protected from the stress effects measured by light/dark and social interaction tests. ROS production, measured histochemically following dihydroethidium administration, was elevated by CSD, and the production was reduced to basal levels in mice lacking microglia. The deleterious stress effects were also blocked in nondepleted mice by continuous intracerebral administration of N-acetylcysteine (NAC), a ROS inhibitor. In a second experiment, at the end of the CSD period, PLX5622 was discontinued to allow microglial repopulation. After 14 d, the brain had a full complement of newly generated microglia. At this time, the mice that had previously been protected now showed behavioral deficits, and their brain ROS production was elevated, both in all brain cells and in repopulated microglia. NAC administration during repopulation prevented the behavioral decline in the repopulated mice, and it supported behavioral recovery in nondepleted stressed mice. The data suggest that microglia drive elevated ROS production during and after stress exposure. This elevated ROS activity generates a central state supporting dysregulated affect, and it hinders the restoration of behavioral and neurochemical homeostasis after stress cessation.SIGNIFICANCE STATEMENT Chronic psychosocial stress is associated with psychiatric disorders such as depression and anxiety. Understanding the details of CNS cellular contributions to stress effects could lead to the development of intervention strategies. Inflammation and oxidative stress are positively linked to depression severity, but the cellular nature of these processes is not clear. The chronic social defeat (CSD) paradigm in mice produces mood alterations and microglial activation characterized by elevated reactive oxygen species (ROS) production. The depletion of microglia or ROS inhibition prevented adverse stress effects. Microglial repopulation of the brain post-CSD reintroduced adverse stress effects, and ROS inhibition in this phase protected against the effects. The results suggest that stress-induced microglial ROS production drives a central state that supports dysregulated affective behavior.}, }
@article {pmid31084929, year = {2019}, author = {Bai, L and Qi, Y and Chen, S and Wang, J and Tang, C and Du, J and Jin, H and Huang, Y}, title = {Angiotensin II downregulates vascular endothelial cell hydrogen sulfide production by enhancing cystathionine γ-lyase degradation through ROS-activated ubiquitination pathway.}, journal = {Biochemical and biophysical research communications}, volume = {514}, number = {3}, pages = {907-912}, doi = {10.1016/j.bbrc.2019.05.021}, pmid = {31084929}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/*pharmacology ; Cystathionine gamma-Lyase/*genetics/metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation ; Human Umbilical Vein Endothelial Cells/cytology/*drug effects/metabolism ; Humans ; Hydrogen Sulfide/*antagonists &amp; inhibitors/metabolism ; Leupeptins/pharmacology ; Mutation ; Proteolysis/drug effects ; Signal Transduction ; Superoxides/metabolism ; Time Factors ; Ubiquitin/genetics/metabolism ; Ubiquitination/*drug effects ; }, abstract = {The interactions between vasoactive peptides and gasotransmitters have attracted considerable attention from scientists. However, the impact of angiotensin II (AngII) on the endogenous hydrogen sulfide/cystathionine γ-lyase (H2S/CSE) pathway in vascular endothelial cells remains unclear. In this study, we found, for the first time, that AngII downregulated the endogenous H2S/CSE pathway in a time-dependent manner. Mechanistically, AngII accelerated the degradation of the CSE protein and shortened its half-life in endothelial cells. AngII significantly induced Lys48 (K48)-linked CSE ubiquitination and subsequent CSE degradation but did not affect Lys63 (K63)-linked CSE ubiquitination in vascular endothelial cells. Treatment with the proteasome inhibitor MG132 and mutation of Lys48 to Arg in ubiquitin successfully blunted the inhibitory effects of AngII on the endogenous H2S/CSE pathway in vascular endothelial cells. Furthermore, we found that superoxide anion levels were significantly increased in AngII-treated endothelial cells compared with controls and that the ROS scavenger N-acetyl-l-cysteine (NAC) significantly abolished CSE ubiquitination. Taken together, our data suggested that AngII inhibited endogenous H2S generation through ubiquitination-mediated CSE degradation via the ROS pathway in vascular endothelial cells.}, }
@article {pmid31078888, year = {2019}, author = {Hamdi, H and Abid-Essefi, S and Eyer, J}, title = {Cytotoxic and genotoxic effects of epoxiconazole on F98 glioma cells.}, journal = {Chemosphere}, volume = {229}, number = {}, pages = {314-323}, doi = {10.1016/j.chemosphere.2019.05.018}, pmid = {31078888}, issn = {1879-1298}, mesh = {Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Damage ; Dose-Response Relationship, Drug ; Environmental Pollutants/*toxicity ; Epoxy Compounds/*toxicity ; Glioma/*pathology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; Triazoles/*toxicity ; }, abstract = {Epoxiconazole (EPX) is a very effective fungicide of the triazole family. Given its wide spectrum of use, the increased application of this pesticide may represent a serious risk on human health. Previous studies have found that EPX is cytotoxic to cells, although the exact mechanism remains elusive. In particular, the effect on the nervous system is poorly elucidated. Here we evaluated the implication of oxidative stress in the neurotoxicity and studied its apoptotic mechanism of action. We demonstrated that the treatment by EPX reduces the viability of cells in a dose dependent manner with an IC50 of 50 μM. It also provokes the reduction of cell proliferation. EPX could trigger arrest in G1/S phase of cell cycle with low doses, however with IC50, it induced an accumulation of F98 cells in G2/M phase. Moreover, EPX induced cytoskeleton disruption as evidenced by immunocytochemical analysis. It provoked also DNA fragmentation in a concentration dependent manner. The EPX induced apoptosis, which was observed by morphological changes and by positive Annexin V FITC-PI staining concurrent with a depolarization of mitochondria. Furthermore, the cell mortality provoked by EPX was significantly reduced by pretreatment with Z-VAD-FMK, a caspase inhibitor. Moreover, N-acetylcysteine (NAC) strongly restores cell viability that has been inhibited by EPX. The results of these findings highlight the implication of ROS generation in the neurotoxicity induced by EPX, indicating that the production of ROS is the main cause of the induction of apoptosis probably via the mitochondrial pathway.}, }
@article {pmid31077038, year = {2020}, author = {Sueck, F and Specht, J and Cramer, B and Humpf, HU}, title = {Identification of ochratoxin-N-acetyl-L-cysteine as a new ochratoxin A metabolite and potential biomarker in human urine.}, journal = {Mycotoxin research}, volume = {36}, number = {1}, pages = {1-10}, pmid = {31077038}, issn = {1867-1632}, support = {HU 730/10-2//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Acetylcysteine/*urine ; Biomarkers/*urine ; Chromatography, High Pressure Liquid/methods ; Food Contamination/analysis ; Glutathione/*urine ; Humans ; Mycotoxins/*urine ; Ochratoxins/analysis/*urine ; }, abstract = {Ochratoxin A (OTA) is a nephrotoxic mycotoxin with nephrocarcinogenic potential found in a broad spectrum of food commodities. The mode of action of this compound, as well as its metabolism, is still not fully understood. To determine whether the conjugation of OTA with glutathione plays an important role in human OTA metabolism, an ochratoxin-glutathione conjugate (OTB-GSH), as well as the corresponding urinary metabolite ochratoxin-N-acetyl-L-cysteine (OTB-NAC), were synthesized and their structures confirmed by NMR spectroscopy. By means of synthesized stable isotope-labeled d5-OTB-GSH and d5-OTB-NAC references, a sensitive HPLC-MS/MS method has been developed and applied for the screening of human urine samples. OTB-NAC could be detected in 11 of the analyzed 18 urine samples and was quantified in 5 urine samples in the range between 0.023 and 0.176 ng mg[-1] creatinine. OTB-GSH has not been detected in the urine samples. In OTB-NAC positive samples, this metabolite contributed to a comparable concentration range to the total OTA excretion as the parent compound. This is the first direct analysis of an OTA phase 2 metabolite in humans.}, }
@article {pmid31075539, year = {2019}, author = {Fuentes-Villalobos, F and Farkas, C and Riquelme-Barrios, S and Armijo, ME and Soto-Rifo, R and Pincheira, R and Castro, AF}, title = {DISC1 promotes translation maintenance during sodium arsenite-induced oxidative stress.}, journal = {Biochimica et biophysica acta. Gene regulatory mechanisms}, volume = {1862}, number = {6}, pages = {657-669}, doi = {10.1016/j.bbagrm.2019.05.001}, pmid = {31075539}, issn = {1876-4320}, mesh = {Animals ; Arsenites/*pharmacology ; Cell Survival/drug effects ; Cytoplasmic Granules/metabolism ; DNA Helicases/metabolism ; Eukaryotic Initiation Factor-3/metabolism ; Gene Expression Regulation ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Nerve Tissue Proteins/genetics/*metabolism ; Oncogene Protein v-akt ; Oxidative Stress/*drug effects ; Poly-ADP-Ribose Binding Proteins/metabolism ; RNA Helicases/metabolism ; RNA Recognition Motif Proteins/metabolism ; Sodium Compounds/*pharmacology ; Transcriptome ; Tuberous Sclerosis Complex 2 Protein/genetics ; }, abstract = {Variation in Disrupted-in-Schizophrenia 1 (DISC1) increases the risk for neurodegenerative diseases, schizophrenia, and other mental disorders. However, the functions of DISC1 associated with the development of these diseases remain unclear. DISC1 has been reported to inhibit Akt/mTORC1 signaling, a major regulator of translation, and recent studies indicate that DISC1 could exert a direct role in translational regulation. Here, we present evidence of a novel role of DISC1 in the maintenance of protein synthesis during oxidative stress. In order to investigate DISC1 function independently of Akt/mTORC1, we used Tsc2-/- cells, where mTORC1 activation is independent of Akt. DISC1 knockdown enhanced inhibition of protein synthesis in cells treated with sodium arsenite (SA), an oxidative agent used for studying stress granules (SGs) dynamics and translational control. N-acetyl-cysteine inhibited the effect of DISC1, suggesting that DISC1 affects translation in response to oxidative stress. DISC1 decreased SGs number in SA-treated cells, but resided outside SGs and maintained protein synthesis independently of a proper SG nucleation. DISC1-dependent stimulation of translation in SA-treated cells was supported by its interaction with eIF3h, a component of the canonical translation initiation machinery. Consistent with a role in the homeostatic maintenance of translation, DISC1 knockdown or overexpression decreased cell viability after SA exposure. Our data suggest that DISC1 is a relevant component of the cellular response to stress, maintaining certain levels of translation and preserving cell integrity. This novel function of DISC1 might be involved in its association with pathologies affecting tissues frequently exposed to oxidative stress.}, }
@article {pmid31073737, year = {2019}, author = {Siramolpiwat, S and Punjachaipornpon, T and Pornthisarn, B and Vilaichone, RK and Chonprasertsuk, S and Tangaroonsanti, A and Bhanthumkomol, P and Phumyen, A and Yasiri, A and Kaewmanee, M}, title = {N-Acetylcysteine Prevents Post-embolization Syndrome in Patients with Hepatocellular Carcinoma Following Transarterial Chemoembolization.}, journal = {Digestive diseases and sciences}, volume = {64}, number = {11}, pages = {3337-3345}, pmid = {31073737}, issn = {1573-2568}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Intravenous ; Aged ; Carcinoma, Hepatocellular/blood/diagnosis/*therapy ; Chemoembolization, Therapeutic/adverse effects/*trends ; Cohort Studies ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Inflammation Mediators/blood ; Liver Neoplasms/blood/diagnosis/*therapy ; Male ; Middle Aged ; Prospective Studies ; Syndrome ; Treatment Outcome ; }, abstract = {BACKGROUND: Post-embolization syndrome is a common complication after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). N-acetylcysteine (NAC) is known to ameliorate liver damage from several causes.<br><br>AIM: To determine the efficacy of intravenous NAC in the prevention of post-embolization syndrome in HCC patients following TACE.<br><br>METHODS: In this study, patients with HCC admitted for TACE were prospectively enrolled. All patients were randomized stratified by Child A or B to receive NAC or placebo. The NAC group received intravenous NAC 24&#xa0;h prior to TACE (150&#xa0;mg/kg/h for 1&#xa0;h followed by 12.5&#xa0;mg/kg/h for 4&#xa0;h, then continuous infusion 6.25&#xa0;mg/h for 48&#xa0;h after the procedure). The placebo group received an infusion of 5% glucose solution until 48&#xa0;h after procedure. The post-embolization syndrome was defined as: T&#x2009;&#x2265;&#x2009;38.5 c and serum ALT&#x2009;>&#x2009;3 times of pretreatment value.<br><br>RESULTS: In total, 111 HCC patients were enrolled; 57 were randomly assigned to NAC group and 54 to placebo group. The incidence of post-embolization syndrome was lower in NAC group (24.6%) compared to placebo group (48.2%); P&#x2009;=&#x2009;0.01. On multivariate analysis, receiving IV NAC (P&#x2009;=&#x2009;0.03) and HCC diameter (P&#x2009;<&#x2009;0.01) were associated with developing post-embolization syndrome. Post-TACE liver decompensation was documented in 26/111 (23.4%) patients. There was no difference in the incidence of post-TACE liver decompensation between NAC and placebo group.<br><br>CONCLUSIONS: In this study, intravenous NAC administration reduces the incidence of post-embolization syndrome after TACE in patients with HCC. However, it does not prevent post-TACE liver decompensation.<br><br>TRIAL REGISTRATION NUMBER: This study was registered with Thai Clinical Trial Registry (TCTR20150313002).}, }
@article {pmid31071510, year = {2019}, author = {Zhong, X and He, J and Zhang, X and Li, C and Tian, X and Xia, W and Gan, H and Xia, Y}, title = {UCP2 alleviates tubular epithelial cell apoptosis in lipopolysaccharide-induced acute kidney injury by decreasing ROS production.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {115}, number = {}, pages = {108914}, doi = {10.1016/j.biopha.2019.108914}, pmid = {31071510}, issn = {1950-6007}, mesh = {Acute Kidney Injury/chemically induced/metabolism/*pathology ; Animals ; Apoptosis/*drug effects ; Cell Line ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Epithelial Cells/*drug effects/metabolism/pathology ; Kidney Tubules/drug effects/*pathology ; Lipopolysaccharides/pharmacology ; Male ; Mice, Inbred C57BL ; Reactive Oxygen Species/*metabolism ; Uncoupling Protein 2/genetics/*metabolism ; Up-Regulation ; }, abstract = {Uncoupling protein 2 (UCP2), an anion transporter, modulates the production of mitochondrial reactive oxygen species (ROS) and plays an important role in protecting against cell apoptosis. However, the role of UCP2 in sepsis-associated AKI remains unclear. In the present study, we investigated the role of UCP2 in LPS-induced AKI in vitro and in vivo. UCP2 expression was increased in tubular epithelial cells (TECs) treated with LPS. Accordingly, UCP2 expression was distinctly upregulated in renal tissues from the animals with LPS-induced AKI. Furthermore, UCP2 silencing dramatically aggravated LPS-induced apoptosis, accompanied by increased ROS production in renal tubular epithelial cell. Additionally, the inhibition of UCP2 by genipin, a specific UCP2 inhibitor, exacerbated the kidney injury of animals with LPS-induced AKI. Moreover, NAC (N-acetylcysteine), a potent ROS scavenger, obviously suppressed apoptosis induced by UCP2 silencing, which suggests that the increased ROS levels were associated with tubular epithelial cell apoptosis induced by UCP2 silencing. Therefore, UCP2 exerts a protective effect on the LPS-induced apoptosis of tubular epithelial cells by reducing excess ROS production. In conclusion, our findings highlight the renoprotective actions of UCP2 on inhibiting the production of apoptotic factors and oxidative stress to improve tubular cell survival in the LPS-induced AKI model.}, }
@article {pmid31071081, year = {2019}, author = {Pereira, JEG and El Dib, R and Braz, LG and Escudero, J and Hayes, J and Johnston, BC}, title = {N-acetylcysteine use among patients undergoing cardiac surgery: A systematic review and meta-analysis of randomized trials.}, journal = {PloS one}, volume = {14}, number = {5}, pages = {e0213862}, pmid = {31071081}, issn = {1932-6203}, mesh = {Acetylcysteine/*blood ; Biomarkers ; Cardiac Surgical Procedures/adverse effects/methods ; Heart Diseases/*blood/diagnosis/*epidemiology/surgery ; Humans ; Mortality ; Odds Ratio ; Prognosis ; Publication Bias ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Workflow ; }, abstract = {BACKGROUND: Cardiac surgeries are complex procedures aiming to re-establish coronary flow and correct valvular defects. Oxidative stress, caused by inflammation and ischemia-reperfusion injury, is associated with these procedures, increasing the risk of adverse outcomes. N-acetylcysteine (NAC) acts as an antioxidant by replenishing the glutathione stores, and emerging evidence suggests that NAC may reduce the risk of adverse perioperative outcomes. We conducted a systematic review and meta-analysis to investigate the addition of NAC to a standard of care among adult patients undergoing cardiac surgery.<br><br>METHODS: We searched four databases (PubMed, EMBASE, CENTRAL, LILACS) from inception to October 2018 and the grey literaure for randomized controlled trials (RCTs) investigating the effect of NAC on pre-defined outcomes including mortality, acute renal insufficiency (ARI), acute cardiac insufficiency (ACI), hospital length of stay (HLoS), intensive care unit length of stay (ICULoS), arrhythmia and acute myocardial infarction (AMI). Reviewers independently screened potentially eligible articles, extracted data and assessed the risk of bias among eligible articles. We used the GRADE approach to rate the overall certainty of evidence for each outcome.<br><br>RESULTS: Twenty-nine RCTs including 2,486 participants proved eligible. Low to moderate certainty evidence demonstrated that the addition of NAC resulted in a non-statistically significant reduction in mortality (Risk Ratio (RR) 0.71; 95% Confidence Interval (CI) 0.40 to 1.25), ARI (RR 0.92; 95% CI 0.79 to 1.09), ACI (RR 0.77; 95% CI 0.44 to 1.38), HLoS (Mean Difference (MD) 0.21; 95% CI -0.64 to 0.23), ICULoS (MD -0.04; 95% CI -0.29 to 0.20), arrhythmia (RR 0.79; 95% CI 0.52 to 1.20), and AMI (RR 0.84; 95% CI 0.48 to 1.48).<br><br>LIMITATIONS: Among eligible trials, we observed heterogeneity in the population and interventions including patients with and without kidney dysfunction and interventions that differed in route of administration, dosage, and duration of treatment. This observed heterogeneity was not explained by our subgroup analyses.<br><br>CONCLUSIONS: The addition of NAC during cardiac surgery did not result in a statistically significant reduction in clinical outcomes. A large randomized placebo-controlled multi-centre trial is needed to determine whether NAC reduces mortality.<br><br>REGISTRATION: PROSPERO CRD42018091191.}, }
@article {pmid31070451, year = {2019}, author = {Balogh, E and Tóth, A and Méhes, G and Trencsényi, G and Paragh, G and Jeney, V}, title = {Hypoxia Triggers Osteochondrogenic Differentiation of Vascular Smooth Muscle Cells in an HIF-1 (Hypoxia-Inducible Factor 1)-Dependent and Reactive Oxygen Species-Dependent Manner.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {39}, number = {6}, pages = {1088-1099}, doi = {10.1161/ATVBAHA.119.312509}, pmid = {31070451}, issn = {1524-4636}, mesh = {Animals ; Cell Differentiation/drug effects ; Cells, Cultured ; Core Binding Factor Alpha 1 Subunit/*genetics ; Disease Models, Animal ; Disulfides/pharmacology ; Female ; Gene Expression Regulation ; Humans ; Hypoxia/*complications ; Hypoxia-Inducible Factor 1/*genetics ; Indole Alkaloids/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Smooth, Vascular/cytology ; Myocytes, Smooth Muscle/metabolism ; RNA, Messenger/genetics ; Random Allocation ; Reactive Oxygen Species/*metabolism ; Reference Values ; Signal Transduction/drug effects/genetics ; Vascular Calcification/*metabolism/physiopathology ; Vascular Endothelial Growth Factor A/*metabolism ; }, abstract = {Objective- Vascular calcification is associated with high risk of cardiovascular events and mortality. Osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) is the major cellular mechanism underlying vascular calcification. Because tissue hypoxia is a common denominator in vascular calcification, we investigated whether hypoxia per se triggers osteochondrogenic differentiation of VSMCs. Approach and Results- We studied osteochondrogenic differentiation of human aorta VSMCs cultured under normoxic (21% O2) and hypoxic (5% O2) conditions. Hypoxia increased protein expression of HIF (hypoxia-inducible factor)-1α and its target genes GLUT1 (glucose transporter 1) and VEGFA (vascular endothelial growth factor A) and induced mRNA and protein expressions of osteochondrogenic markers, that is, RUNX2 (runt-related transcription factor 2), SOX9 (Sry-related HMG box-9), OCN (osteocalcin) and ALP (alkaline phosphatase), and induced a time-dependent calcification of the extracellular matrix of VSMCs. HIF-1 inhibition by chetomin abrogated the effect of hypoxia on osteochondrogenic markers and abolished extracellular matrix calcification. Hypoxia triggered the production of reactive oxygen species, which was inhibited by chetomin. Scavenging reactive oxygen species by N-acetyl cysteine attenuated hypoxia-mediated upregulation of HIF-1α, RUNX2, and OCN protein expressions and inhibited extracellular matrix calcification, which effect was mimicked by a specific hydrogen peroxide scavenger sodium pyruvate and a mitochondrial reactive oxygen species inhibitor rotenone. Ex vivo culture of mice aorta under hypoxic conditions triggered calcification which was inhibited by chetomin and N-acetyl cysteine. In vivo hypoxia exposure (10% O2) increased RUNX2 mRNA levels in mice lung and the aorta. Conclusions- Hypoxia contributes to vascular calcification through the induction of osteochondrogenic differentiation of VSMCs in an HIF-1-dependent and mitochondria-derived reactive oxygen species-dependent manner.}, }
@article {pmid31069486, year = {2019}, author = {Lei, M and Wu, X and Huang, C and Qiu, Z and Wang, L and Zhang, R and Zhang, J}, title = {Trehalose induced by reactive oxygen species relieved the radial growth defects of Pleurotus ostreatus under heat stress.}, journal = {Applied microbiology and biotechnology}, volume = {103}, number = {13}, pages = {5379-5390}, doi = {10.1007/s00253-019-09834-8}, pmid = {31069486}, issn = {1432-0614}, support = {2014CB138303//National Basic Research Program of China (973 Program)/ ; CARS20//Agriculture Research System of China/ ; 1610132016048//Fundamental Research Funds for Central Non-profit Scientific Institution/ ; 31601803//National Natural Science Foundation of China/ ; }, mesh = {Ascorbic Acid/pharmacology ; Cysteine/pharmacology ; Glucosyltransferases/genetics ; *Heat-Shock Response ; Hot Temperature ; Malondialdehyde/analysis ; Mycelium/drug effects/growth &amp; development ; Oxidative Stress ; Pleurotus/*growth &amp; development/metabolism ; Reactive Oxygen Species/*metabolism ; Trehalase/genetics ; Trehalose/*biosynthesis ; }, abstract = {Trehalose is a nonreducing disaccharide, and it plays an intracellular protective role in organisms under various stress conditions. In this study, the trehalose synthesis and its protective role in Pleurotus ostreatus were investigated. As a signal in metabolic regulation, reactive oxygen species (ROS) accumulated in the mycelia of P. ostreatus under heat stress (HS). Furthermore, mycelial growth was significantly inhibited, and the malondialdehyde (MDA) level significantly increased under HS. First, exogenous addition of H2O2 inhibited mycelial growth and elevated the MDA level, while N-acetyl cysteine (NAC) and vitamin C (VC) reduced the MDA level and recovered mycelial growth under HS by scavenging ROS. These results indicated that the mycelial radial growth defect under HS might be partly caused by ROS accumulation. Second, adding NAC and VC to the media resulted in rescued trehalose accumulation, which indicated that ROS has an effect on inducing trehalose synthesis. Third, the mycelial growth was recovered by addition of trehalose to the media after HS, and the MDA level was reduced. This effect was further verified by the overexpression of genes for trehalose-6-phosphate synthase (TPS) and neutral trehalase (NTH), which led to increased and reduced trehalose content, respectively. In addition, adding validamycin A (NTH inhibitor) to the media promoted trehalose accumulation and the recovered mycelial growth after HS. In conclusion, trehalose production was partly induced by ROS accumulation in the mycelia under HS, and the accumulated trehalose could promote the recovery of growth after HS, partly by reducing the MDA level in the mycelia.}, }
@article {pmid31068539, year = {2019}, author = {Kim, DH and Kundu, J and Chae, IG and Lee, JK and Heo, JS and Chun, KS}, title = {Titanium dioxide nanoparticles induce COX-2 expression through ROS generation in human periodontal ligament cells.}, journal = {The Journal of toxicological sciences}, volume = {44}, number = {5}, pages = {335-345}, doi = {10.2131/jts.44.335}, pmid = {31068539}, issn = {1880-3989}, mesh = {Cell Survival/drug effects ; Cells, Cultured ; Cyclooxygenase 2/*metabolism ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Nanoparticles/*toxicity ; Periodontal Ligament/*cytology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Titanium/*toxicity ; }, abstract = {Titanium dioxide nanoparticles (TiO2-NPs) are used to improve the aesthetic of toothpaste. While TiO2-NPs have been used safely in toothpaste products for a long time, there haven't been studies to determine whether absorption of TiO2-NPs by the mucous membranes in the mouth induces pathogenic conditions. Here, we assessed whether TiO2-NPs induce cyclooxygenase-2 (COX-2) and investigated the molecular mechanisms underlying the pro-inflammatory effect of TiO2-NPs on human periodontal ligament (PDL) cells. Treatment of PDL cells with TiO2-NPs led to induction of both COX-2 mRNA and protein expression. TiO2-NPs stimulated the nuclear translocation of nuclear factor-kappaB (NF-κB) as well as its DNA binding by inducing phosphorylation and subsequent degradation of the inhibitory protein IκBα in PDL cells. TiO2-NPs treatment resulted in rapid activation of extracellular signal-regulated kinase (ERK)1/2 and Akt, which could be upstream of NF-κB. Treatment of PDL cells with both the MEK1/2 inhibitor U0126 and the PI3K inhibitor LY294002 strongly attenuated TiO2-NPs-induced activation of NF-κB, and also the expression of COX-2. PDL cells treated with TiO2-NPs exhibited increased accumulation of intracellular reactive oxygen species (ROS). Pretreatment of cells with ROS scavenger N-acetyl cysteine (NAC) abrogated the stimulatory effect of TiO2-NPs on p65, p50, and COX-2 expression. In conclusion, ROS, concomitantly overproduced by TiO2-NPs, induce COX-2 expression through activation of NF-κB signaling, which may contribute to the inflammatory effect of PDL cells.}, }
@article {pmid31066324, year = {2019}, author = {Livingston, MJ and Wang, J and Zhou, J and Wu, G and Ganley, IG and Hill, JA and Yin, XM and Dong, Z}, title = {Clearance of damaged mitochondria via mitophagy is important to the protective effect of ischemic preconditioning in kidneys.}, journal = {Autophagy}, volume = {15}, number = {12}, pages = {2142-2162}, pmid = {31066324}, issn = {1554-8635}, support = {R01 GM118915/GM/NIGMS NIH HHS/United States ; MC_UU_00018/2/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Apoptosis/drug effects/genetics ; Apoptosis Regulatory Proteins/metabolism ; Autophagosomes/drug effects/*metabolism ; Autophagy-Related Protein 7/genetics/*metabolism ; Beclin-1/genetics/metabolism/pharmacology ; Carbonyl Cyanide m-Chlorophenyl Hydrazone ; Cell Line ; *Ischemic Preconditioning ; Kidney/*blood supply/drug effects/metabolism/pathology ; Kidney Tubules, Proximal/drug effects/*metabolism/pathology ; Lysosomes/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/drug effects/*metabolism ; Mitochondrial Membranes/metabolism ; Mitophagy/drug effects/*genetics ; Protein Kinases/genetics/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/chemically induced/metabolism ; }, abstract = {Ischemic preconditioning (IPC) affords tissue protection in organs including kidneys; however, the underlying mechanism remains unclear. Here we demonstrate an important role of macroautophagy/autophagy (especially mitophagy) in the protective effect of IPC in kidneys. IPC induced autophagy in renal tubular cells in mice and suppressed subsequent renal ischemia-reperfusion injury (IRI). The protective effect of IPC was abolished by pharmacological inhibitors of autophagy and by the ablation of Atg7 from kidney proximal tubules. Pretreatment with BECN1/Beclin1 peptide induced autophagy and protected against IRI. These results suggest the dependence of IPC protection on renal autophagy. During IPC, the mitophagy regulator PINK1 (PTEN induced putative kinase 1) was activated. Both IPC and BECN1 peptide enhanced mitolysosome formation during renal IRI in mitophagy reporter mice, suggesting that IPC may protect kidneys by activating mitophagy. We further established an in vitro model of IPC by inducing 'chemical ischemia' in kidney proximal tubular cells with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Brief treatment with CCCP protected against subsequent injury in these cells and the protective effect was abrogated by autophagy inhibition. In vitro IPC increased mitophagosome formation, enhanced the delivery of mitophagosomes to lysosomes, and promoted the clearance of damaged mitochondria during subsequent CCCP treatment. IPC also suppressed mitochondrial depolarization, improved ATP production, and inhibited the generation of reactive oxygen species. Knockdown of Pink1 suppressed mitophagy and reduced the cytoprotective effect of IPC. Together, these results suggest that autophagy, especially mitophagy, plays an important role in the protective effect of IPC.Abbreviations: ACTB: actin, beta; ATG: autophagy related; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; BUN: blood urea nitrogen; CASP3: caspase 3; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; COX4I1: cytochrome c oxidase subunit 4I1; COX8: cytochrome c oxidase subunit 8; DAPI: 4',6-diamidino-2-phenylindole; DNM1L: dynamin 1 like; EGFP: enhanced green fluorescent protein; EM: electron microscopy; ER: endoplasmic reticulum; FC: floxed control; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; H-E: hematoxylin-eosin; HIF1A: hypoxia inducible factor 1 subunit alpha; HSPD1: heat shock protein family D (Hsp60) member 1; IMMT/MIC60: inner membrane mitochondrial protein; IPC: ischemic preconditioning; I-R: ischemia-reperfusion; IRI: ischemia-reperfusion injury; JC-1: 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mito-QC: mito-quality control; mRFP: monomeric red fluorescent protein; NAC: N-acetylcysteine; PINK1: PTEN induced putative kinase 1; PPIB: peptidylprolyl isomerase B; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; RPTC: rat proximal tubular cells; SD: standard deviation; sIPC: simulated IPC; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.}, }
@article {pmid31064816, year = {2019}, author = {Yang, L and Guan, G and Lei, L and Liu, J and Cao, L and Wang, X}, title = {Oxidative and endoplasmic reticulum stresses are involved in palmitic acid-induced H9c2 cell apoptosis.}, journal = {Bioscience reports}, volume = {39}, number = {5}, pages = {}, pmid = {31064816}, issn = {1573-4935}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line ; Endoplasmic Reticulum Stress/*drug effects ; Myocytes, Cardiac/*metabolism/pathology ; Oxidative Stress/*drug effects ; Palmitic Acid/*pharmacology ; Rats ; }, abstract = {Palmitic acid (PA) is the most common saturated long-chain fatty acid that causes damage to heart muscle cells. However, the molecular mechanism of PA toxicity in myocardial cells is not fully understood. In the present study, we explored the effects of PA on proliferation and apoptosis of H9c2 cardiomyocytes, and uncovered the signaling pathways involved in PA toxicity. Our study revealed induction of both oxidative and endoplasmic reticulum (ER) stresses and exacerbation of apoptosis in PA-treated H9c2 cells. Inhibition of oxidative stress by N-acetylcysteine (NAC) reduced apoptosis and decreased ER stress in PA-treated H9c2 cells. Moreover, inhibition of ER stress by 4-phenyl butyric acid decreased apoptosis and attenuated oxidative stress. In summary, the present study demonstrated that oxidative stress coordinates with ER stress to play important roles in PA-induced H9c2 cell apoptosis.}, }
@article {pmid31059810, year = {2019}, author = {Yang, L and Qiu, T and Yao, X and Jiang, L and Wei, S and Pei, P and Wang, Z and Bai, J and Liu, X and Yang, G and Liu, S and Sun, X}, title = {Taurine protects against arsenic trioxide-induced insulin resistance via ROS-Autophagy pathway in skeletal muscle.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {112}, number = {}, pages = {50-60}, doi = {10.1016/j.biocel.2019.05.001}, pmid = {31059810}, issn = {1878-5875}, mesh = {Animals ; Arsenic Trioxide/*adverse effects/pharmacology ; Autophagic Cell Death/*drug effects ; Cell Line ; *Insulin Resistance ; Male ; Mice ; Muscle, Skeletal/*metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Taurine/*pharmacology ; }, abstract = {Long-term and low-dose exposure to inorganic arsenic is associated with type 2 diabetes (T2D). In this study, C57BL/6 mice exposed to As2O3 showed impaired glucose tolerance, decrease in insulin sensitivity and insulin resistance were observed in the skeletal muscle and myotubes of mice that underwent As2O3 treatment. Decreased insulin-stimulated glucose uptake (ISGU) was also shown by the As2O3-treated myotubes. Moreover, the accumulation of ectopic fat in mice skeletal muscle and myotubes was observed after As2O3 treatment. The upregulated expression of autophagy-associated proteins and the increased number of acidic vesicular organelles (AVOs) indicated that autophagy was stimulated in the skeletal muscle and myotubes of mice after undergoing As2O3 treatment. TAU could prevent the effect of As2O3 on mice skeletal muscle and myotubes, as mentioned above. The impaired ISGU, decreased insulin-associated proteins expression, and increased TAG content caused by As2O3 were reversed by N-acetylcysteine (NAC) and 3-methyladenine (3-MA), and the As2O3-induced autophagy was inhibited by NAC, indicating involvement of ROS-autophagy pathway in the mechanism of As2O3-induced IR and lipid metabolism disorder. In summary, TAU protect against the As2O3-induced IR and ectopic fat accumulation in mice skeletal muscle and myotubes via ROS-autophagy pathway.}, }
@article {pmid31059712, year = {2019}, author = {Rajavel, T and Banu Priya, G and Suryanarayanan, V and Singh, SK and Pandima Devi, K}, title = {Daucosterol disturbs redox homeostasis and elicits oxidative-stress mediated apoptosis in A549 cells via targeting thioredoxin reductase by a p53 dependent mechanism.}, journal = {European journal of pharmacology}, volume = {855}, number = {}, pages = {112-123}, doi = {10.1016/j.ejphar.2019.04.051}, pmid = {31059712}, issn = {1879-0712}, mesh = {A549 Cells ; Apoptosis/*drug effects ; Down-Regulation/drug effects ; Homeostasis/*drug effects ; Humans ; Molecular Docking Simulation ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Protein Conformation ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sitosterols/metabolism/*pharmacology ; Thermodynamics ; Thioredoxin Reductase 1/chemistry/*metabolism ; Thioredoxin-Disulfide Reductase/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Daucosterol (DS) is a plant phytosterol which is shown to induce oxidative stress mediated apoptosis in various cancer cell lines. However, the molecular mechanism underlying its cellular action has not been documented against Non- Small Cell Lung Cancer (NSCLC). Therefore, we attempted to decipher the mechanisms responsible for DS-induced anti-proliferation on human NSCLC cells. The present study showed, DS strongly inhibits the growth of A549 cells after 72 h time point with an IC50 value of ∼20.9 μM. Further DS elicits increased reactive oxygen species level and promote intrinsic apoptotic cell death on A549 cells as evidenced by increased expression of caspase-3, caspase-9, Bax, PARP inactivation, cytochrome-c release, and diminished expression of bcl-2 protein. DS failed to display its apoptotic actions upon pretreatment with the reactive oxygen species inhibitor NAC (N-acetyl cysteine). Indeed, apoptotic signal which was enhanced through p53/p21 activation and knockdown of p53 expression also moderately affected the DS induced apoptosis. In addition, DS preferentially inhibited the cell growth of p53 wild-type NSCLC cell lines than the mutant p53 models. Further, we show that inhibition of Thioredoxin (TrxR) redox system is principally associated with DS induced oxidative stress mediated apoptotic cell death on A549 cells. Moreover, we also demonstrated that DS stably interacted with serine residues in TrxR active sites. The obtained results confirmed that the anti-proliferative mechanism and increased reactive oxygen species level of DS was associated with down-regulation of TrxR1 pathway which triggers the p53 mediated intrinsic apoptotic mode of cell death in NSCLC cells.}, }
@article {pmid31058639, year = {2019}, author = {Bhasin, P and Sharma, M and Bindal, D and Tomar, D and Sarin, A and Sharma, N}, title = {An In Vitro Evaluation of Antimicrobial Effects of Three Different Root Canal Irrigating Solutions against Enterococcus faecalis and Streptococcus mutans.}, journal = {The journal of contemporary dental practice}, volume = {20}, number = {2}, pages = {221-225}, pmid = {31058639}, issn = {1526-3711}, mesh = {*Anti-Infective Agents ; Dental Pulp Cavity ; *Enterococcus faecalis ; Female ; Male ; Root Canal Irrigants ; Sodium Hypochlorite ; Streptococcus mutans ; }, abstract = {AIM: The present study was conducted to evaluate and compare antimicrobial effect of 5.25% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX) and N-Acetylcysteine (NAC) irrigating solutions against Enterococcus faecalis (E. faecalis) and Streptococcus mutans (S.mutans).<br><br>MATERIALS AND METHODS: The present study was conducted on 40 freshly extracted noncarious permanent mandibular incisors teeth of both genders (males-12, females-14). In all teeth, root canal preparation was done up to size 40 K-file. Roots were sterilized and microbial suspension of mixed culture of the tested microorganisms was inoculated into canals and incubated for 48 h. Teeth were divided into four groups, group I (5.25% sodium hypochlorite), group II (2% chlorhexidine), group III (200 mg/mL N-Acetylcysteine NAC) and group IV (sterile distilled water). The antimicrobial effect in each group was compared.<br><br>RESULTS: Statistical evaluation was completed using statistical software Statistical Package for the Social Sciences (SPSS). Planktonic S. mutans bacterial count was lowest in group III followed by group I, group II and group IV.E. faecalis count was 6.14 &#xb1; 0.12 in group I, 5.76 &#xb1; 0.44 in group II, 3.88 &#xb1; 0.08 in group III and 11.98 &#xb1; 1.04 in group IV. The difference was significant (p < 0.05). The proportion of dead cell found to be 0.04&#xb1; 0.01, 0.72 &#xb1; 0.06, 0.01 &#xb1; 0.06 and 1.02 &#xb1; 0.11 in groups I, II, III and IV respectively. The difference was significant (p < 0.05).<br><br>CONCLUSION: NAC proved to be effective against E. faecalis and S. mutans. This solution can be considered alternative in root canal infections in addition with CHX and NaOCl.<br><br>CLINICAL SIGNIFICANCE: Effectiveness of three different irrigating solutions was compared and NAC found to be more efficient in decreasing bacterial count. Hence, NAC can be precisely used in irrigating root canals to achieve optimal clinical outcomes particularly regarding reoccurrences of infections. Furthermore, NAC could be proved as a promising innovation in future endodontic methodologies.}, }
@article {pmid31054874, year = {2019}, author = {Zhang, L and Xia, Q and Zhou, Y and Li, J}, title = {Endoplasmic reticulum stress and autophagy contribute to cadmium-induced cytotoxicity in retinal pigment epithelial cells.}, journal = {Toxicology letters}, volume = {311}, number = {}, pages = {105-113}, doi = {10.1016/j.toxlet.2019.05.001}, pmid = {31054874}, issn = {1879-3169}, mesh = {Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/*drug effects ; Autophagy-Related Proteins/metabolism ; Cadmium Chloride/*toxicity ; Cell Line ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/*drug effects ; Epithelial Cells/*drug effects/metabolism/pathology ; Humans ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/*drug effects/metabolism/pathology ; Signal Transduction/drug effects ; }, abstract = {Excessive accumulation of cadmium (Cd) in retina plays an important role in tobacco smoking-associated age-related macular degeneration (AMD). Plenty of evidence has revealed that the retinal pigment epithelium (RPE) is the primary site of pathology in AMD. Our current study demonstrated that Cd induced apoptosis in a human RPE cell line ARPE-19 cells, as it dose-dependently caused cell viability loss and activated caspase-3. The reactive oxygen species (ROS) were confirmed to be important mediators for Cd-triggered cell death in ARPE-19 cells. We found that endoplasmic reticulum (ER) stress was activated as its marker BiP was remarkably upregulated by Cd-exposure. Whereas the antioxidants N-acetylcysteine (NAC) and Tempol significantly suppressed the expression of BiP and CHOP, suggesting that ROS generation is an early trigger of Cd-activated ER stress. Furthermore, we found that Cd-induced oxidative stress significantly increased autophagic flux and p62 expression. A temporal impact of Cd exposure is possibly existed in p62 expression in ARPE-19 cells. Moreover, an ER stress inhibitor salubrinal diminished Cd-induced LC3BII expression and attenuated cytotoxicity, indicating that ER stress mediates autophagy and was implicated in apoptosis of Cd-exposed ARPE-19 cells. However, CHOP expression may not exert impact on the regulation of Cd-caused autophagy. Additionally, inhibition of autophagy with si-Beclin 1 and 3-Methyladenine significantly ameliorated Cd-induced CHOP expression and cytotoxicity, indicating that autophagy was detrimental in Cd-accumulated ARPE-19 cells, and a positive feedback regulation mechanism may exist between Cd-triggered ER stress and autophagy. Taken together, these results suggest that Cd-caused ER stress and autophagy are implicated in RPE cell death associated retinopathies especially related to smoking.}, }
@article {pmid31051153, year = {2019}, author = {John, JJ and Nagar, DP and Gujar, NL and Bhattacharya, R}, title = {Oxidative and histopathological alterations after sub-acute exposure of diisopropyl phosphorofluoridate in mice: Beneficial effect of N‑acetylcysteine.}, journal = {Life sciences}, volume = {228}, number = {}, pages = {98-111}, doi = {10.1016/j.lfs.2019.04.067}, pmid = {31051153}, issn = {1879-0631}, mesh = {Acetylcholinesterase/analysis ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain/*drug effects/pathology ; Butyrylcholinesterase/blood ; Catalase/analysis ; Cholinesterase Inhibitors/*toxicity ; Glutathione/analysis ; Glutathione Peroxidase/analysis ; Glutathione Reductase/analysis ; Isoflurophate/*toxicity ; Kidney/*drug effects/pathology ; Liver/*drug effects/pathology ; Male ; Malondialdehyde/analysis ; Mice ; Oxidative Stress/drug effects ; Superoxide Dismutase/analysis ; }, abstract = {AIMS: Protective efficacy of N‑acetylcysteine (NAC) was assessed against sub-acute diisopropyl phosphorofluoridate (DFP) poisoning in mice.<br><br>MAIN METHODS: Mice were allocated into nine groups of six each: vehicle control; DFP (0.125 LD50&#x202f;&#x2248;&#x202f;0.483&#x202f;mg/kg bwt, s.c.); DFP&#x202f;+&#x202f;Atropine (ATR, 10&#x202f;mg/kg bwt, i.p., 0&#x202f;min); DFP&#x202f;+&#x202f;Pralidoxime (2-PAM, 30&#x202f;mg/kg bwt, i.m., 0&#x202f;min); DFP&#x202f;+&#x202f;NAC (150&#x202f;mg/kg bwt, i.p., -60&#x202f;min); DFP&#x202f;+&#x202f;ATR&#x202f;+&#x202f;NAC; DFP&#x202f;+&#x202f;2-PAM&#x202f;+&#x202f;NAC; DFP&#x202f;+&#x202f;ATR&#x202f;+&#x202f;2-PAM; and DFP&#x202f;+&#x202f;ATR&#x202f;+&#x202f;2-PAM&#x202f;+&#x202f;NAC. Animals received various treatments for 21&#x202f;d daily. Plasma butyrylcholinesterase (BChE) was measured after 7, 14 and 21&#x202f;d of exposure. Brain acetylcholinesterase (AChE) and reduced glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and superoxide dismutase (SOD) were measured (brain, liver and kidney) after 21&#x202f;d of exposure. Histopathology, immunohistochemistry, and Western blot for inducible nitric oxide synthase (iNOS) and c-fos were also performed.<br><br>KEY FINDINGS: DFP significantly reduced BChE and AChE levels. Diminished GSH, CAT, SOD (brain and liver), GPx, GR, and elevated MDA (Brain) levels were also observed. DFP caused notable histopathology (brain, liver and kidney) and over expression of iNOS, and c-fos proteins (brain). NAC enhanced the protective efficacy of ATR and 2-PAM in most parameters, without any appreciable protection in iNOS and c-fos expression.<br><br>SIGNIFICANCE: NAC as an adjunct with ATR and 2-PAM, exhibited marked beneficial effects against sub-acute DFP poisoning, indicating its possible implications in the management of OP poisoning.}, }
@article {pmid31050281, year = {2019}, author = {Han, X and Kou, J and Zheng, Y and Liu, Z and Jiang, Y and Gao, Z and Cong, L and Yang, L}, title = {ROS Generated by Upconversion Nanoparticle-Mediated Photodynamic Therapy Induces Autophagy via PI3K/AKT/ mTOR Signaling Pathway in M1 Peritoneal Macrophage.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {52}, number = {6}, pages = {1325-1338}, doi = {10.33594/000000093}, pmid = {31050281}, issn = {1421-9778}, support = {KF201814//Foundation of Key Laboratories of Myocardial Ischemia Mechanism and Treatment/China ; WLD-QN1104//Wu Liande Youth Science Foundation of Harbin Medical University/China ; }, mesh = {Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Autophagy/*drug effects ; Beclin-1/metabolism ; Interleukin-12/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages, Peritoneal/cytology/drug effects/metabolism ; Metal Nanoparticles/*chemistry ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Photochemotherapy ; Porphyrins/chemistry/*pharmacology/therapeutic use ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; TOR Serine-Threonine Kinases/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND/AIMS: Atherosclerosis is a chronic inflammatory cardiovascular disease. Macrophages are major components of atherosclerotic plaques and play a key role in the development of atherosclerosis by secreting a variety of pro-inflammatory factors. Our previous studies have confirmed that upconversion nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) mediated photodynamic therapy (PDT) can promote cholesterol efflux and induce apoptosis in THP-1 macrophages. In this study, we investigated whether reactive oxygen species (ROS) generated by UCNPs-Ce6-mediated PDT can induce autophagy to inhibit the expression of pro-inflammatory factor in M1 peritoneal macrophages.<br><br>METHODS: Peritoneal macrophages were collected from C57/BL6 mice injected with 3% thioglycollate broth medium and induced by lipopolysaccharides and interferon-&#x3b3;. Intracellular ROS production was assessed by 2'-7'-dichloroflorescein diacetate and flow cytometry. Autophagy was assayed by western blot, transmission electron microscopy and immunofluorescence. Pro-inflammatory cytokines were detected by enzyme-linked immunosorbent assay and western blot.<br><br>RESULTS: Model M1 peritoneal macrophages were established after 24 h induction. Protein expression levels of LC3 II and Beclin1, and degradation of p62 increased and peaked at 2 h in the PDT group. Meanwhile, levels of inflammatory cytokines iNOS, IL-12, and TNF-&#x3b1; markedly decreased after PDT. The increase in autophagy levels and decrease in pro-inflammatory cytokines were significantly inhibited by 3-methyladenine. Furthermore, ROS generated by UCNPs- Ce6 mediated PDT activated autophagy. The expression of autophagy related-protein and inflammatory cytokines iNOS, IL-12, and TNF-&#x3b1; were inhibited by the ROS inhibitor N-acetyl cysteine.<br><br>CONCLUSION: ROS generated by UCNPs-Ce6-mediated PDT activated autophagy and inhibited the expression of pro-inflammatory factors of M1 peritoneal macrophage via the PI3K/AKT/mTOR signaling pathway.}, }
@article {pmid31047982, year = {2019}, author = {Chang, YW and Singh, KP}, title = {Nicotine-induced oxidative stress contributes to EMT and stemness during neoplastic transformation through epigenetic modifications in human kidney epithelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {374}, number = {}, pages = {65-76}, doi = {10.1016/j.taap.2019.04.023}, pmid = {31047982}, issn = {1096-0333}, mesh = {Cell Differentiation ; Cell Line ; Cell Transformation, Neoplastic/*drug effects ; Epigenesis, Genetic ; Epithelial Cells/*drug effects ; Epithelial-Mesenchymal Transition/*drug effects ; Humans ; Kidney/*cytology ; Nicotine/*toxicity ; Nicotinic Agonists/toxicity ; Oxidative Stress/*drug effects ; Reactive Oxygen Species ; }, abstract = {Nicotine is a component of cigarette smoke and mounting evidence suggests toxicity and carcinogenicity of tobacco smoke in kidney. Carcinogenicity of nicotine itself in kidney and the underlying molecular mechanisms are not well-understood. Hence, the objective of this study was to determine the carcinogenic effects of chronic nicotine exposure in Hk-2 human kidney epithelial cells. The effects of nicotine exposure on the expression of genes for cellular reprogramming, redox status, and growth signaling pathways were also evaluated to understand the molecular mechanisms. Results revealed that chronic exposure to nicotine induced growth and neoplastic transformation in HK-2 cells. Increased levels of intracellular reactive oxygen species (ROS), acquired stem cell-like sphere formation, and epithelial-mesenchymal-transition (EMT) changes were observed in nicotine exposed cells. Treatment with antioxidant N-acetyl cysteine (NAC) resulted in abrogation of EMT and stemness in HK-2 cells, indicating the role of nicotine-induced ROS in these morphological changes. The result also suggests that ROS controls the stemness through regulation of AKT pathway during early stages of carcinogenesis. Additionally, the expression of epigenetic regulatory genes was altered in nicotine-exposed cells and the changes were reversed by NAC. The epigenetic therapeutics 5-aza-2'-deoxycytidine and Trichostatin A also abrogated the stemness. This suggests the nicotine-induced oxidative stress caused epigenetic alterations contributing to stemness during neoplastic transformation. To our knowledge, this is the first report showing the ROS-mediated epigenetic modifications as the underlying mechanism for carcinogenicity of nicotine in human kidney epithelial cells. This study further suggests the potential of epigenetic therapeutics for pharmacological intervention in nicotine-induced kidney cancer.}, }
@article {pmid31046239, year = {2019}, author = {Li, R and Li, W and You, Y and Guo, X and Peng, Y and Zheng, J}, title = {Metabolic Activation and Cytotoxicity of Aloe-Emodin Mediated by Sulfotransferases.}, journal = {Chemical research in toxicology}, volume = {32}, number = {6}, pages = {1281-1288}, doi = {10.1021/acs.chemrestox.9b00081}, pmid = {31046239}, issn = {1520-5010}, mesh = {Activation, Metabolic/drug effects ; Animals ; Anthraquinones/chemistry/metabolism/*pharmacology ; Cell Survival/drug effects ; Cytosol/chemistry/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Hep G2 Cells ; Humans ; Liver/chemistry/metabolism ; Male ; Molecular Structure ; Pentachlorophenol/pharmacology ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Sulfotransferases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Aloe-emodin (AE) is a major anthraquinone ingredient of numerous traditional Chinese medicines with a variety of beneficial biological activities in vitro. Previous studies suggested that AE possessed cytotoxicity and genotoxicity. Nevertheless, the mechanisms of the toxic action of AE have not yet been fully clarified. The present study aimed at characterization of metabolic pathways of AE to better understand the mechanisms of AE-induced cytotoxicity. An AE-derived glutathione conjugate (AE-GSH) was observed in rat liver cytosol incubations containing AE and GSH, along with 3'-phosphoadenosine-5'-phosphosulfate (PAPS). Similar incubation fortified with N-acetylcysteine (NAC) in place of GSH offered an AE-NAC conjugate corresponding to the GSH conjugate. The formation of the two conjugates was found to require PAPS. The two conjugates were respectively detected in bile and urine of rats given AE. Sulfotransferase (SULT) inhibitor pentachlorophenol (PCP) suppressed the production of the observed AE-GSH/NAC conjugates in vivo, which suggested that SULTs participated in the process of the metabolic activation of AE. The presence of PCP attenuated cell susceptibility to AE-induced cytotoxicity. The present study illustrated potential association of sulfation-mediated bioactivation of AE with its cytotoxicity.}, }
@article {pmid31044749, year = {2019}, author = {Li, Y and Du, F and Fu, D}, title = {The effect of using simethicone with or without N-acetylcysteine before gastroscopy: A meta-analysis and systemic review.}, journal = {Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association}, volume = {25}, number = {4}, pages = {218-228}, pmid = {31044749}, issn = {1998-4049}, mesh = {Acetylcysteine/*pharmacology ; Antifoaming Agents/pharmacology ; Free Radical Scavengers/pharmacology ; Gastroscopy/*methods ; Humans ; Premedication/*methods ; Simethicone/*pharmacology ; }, abstract = {BACKGROUND/AIM: To assess the efficacy and safety of simethicone with or without N-acetylcysteine (NAC) as premedications before gastroscopy.<br><br>MATERIALS AND METHODS: We searched EMBASE, PubMed, Cochrane library and Web of Science database for randomized clinical controlled trials regarding simethicone &#xb1; NAC as oral drinking agents before gastroscopy. Statistical software RevMan5.3 was used for statistical analysis.<br><br>RESULTS: Ten randomized clinical trials that fulfilled the inclusion criteria were further pooled into a meta-analysis, which included 5,750 patients. The rate of positive findings in simethicone plus NAC group was higher than that in water group (risk ratio [RR] =1.31, 95%CI: 1.12-1.53, P = 0.0006) with high level of evidence. There was no significant difference on the rate of positive findings when comparing simethicone with simethicone plus NAC (RR = 1.02, 95%CI: 0.90-1.16, P = 0.71) and with water (RR = 1.13, 95%CI: 0.82-1.55, P = 0.46), respectively. Simethicone plus NAC showed better total mucosal visibility score than simethicone alone (MD = -0.14 (-0.25, -0.03), P = 0.01) without obvious heterogeneity. Both simethicone plus NAC and simethicone alone offer more benefit than water. The procedure time in simethicone group was shorter than that in water group (MD = -1.23 (-1.51, -0.96), P < 0.00001). Regarding adverse events, there was no significant difference in simethicone and water group (RR = 0.45, 95%CI: 0.2-1.0, P = 0.05, I[2] = 0%).<br><br>CONCLUSIONS: As premedication of gastroscopy, simethicone plus NAC offers more benefit on positive findings and total mucosal visibility score.}, }
@article {pmid31043768, year = {2019}, author = {Abdel-Wahab, WM and Moussa, FI}, title = {Neuroprotective effect of N-acetylcysteine against cisplatin-induced toxicity in rat brain by modulation of oxidative stress and inflammation.}, journal = {Drug design, development and therapy}, volume = {13}, number = {}, pages = {1155-1162}, pmid = {31043768}, issn = {1177-8881}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Brain/*drug effects ; Cisplatin/*antagonists &amp; inhibitors/*toxicity ; Inflammation/*drug therapy ; Male ; Neuroprotective Agents/chemistry/*pharmacology ; Oxidative Stress/*drug effects ; Rats ; }, abstract = {BACKGROUND: Neurotoxicity is a major obstacle to the effectiveness of cisplatin (CDDP) in cancer chemotherapy. Oxidative stress and inflammation are considered to be the major mechanisms involved in CDDP-induced neurotoxicity. The rationale of our study was to investigate the efficacy of N-acetylcysteine (NAC) at two different doses in the management of CDDP-induced toxicity in rat brain by monitoring its antioxidant and anti-inflammatory effects.<br><br>METHODS: Thirty-five male rats were divided into five groups (n=7) as follows: control group (0.5 mL saline), NAC100 group (100 mg/kg), CDDP group (8 mg/kg), NAC50-CDDP group (50 mg/kg NAC and 8 mg/kg CDDP), and NAC100-CDDP group (100 mg/kg NAC and 8 mg/kg CDDP). NAC was administered for 20 consecutive days, while CDDP was injected once on day 15 of the treatment protocol.<br><br>RESULTS: The neurotoxicity of CDDP was evidenced by a marked increase in acetylcholinesterase and monoamine oxidase activities. It also induced oxidative stress as indicated by increased levels of lipid peroxidation, nitric oxide, and protein carbonyl with a concomitant decline in reduced glutathione, glutathione peroxidase, glutathione S-transferase, superoxide dismutase, and catalase in the brain. Moreover, CDDP enhanced the synthesis of pro-inflammatory cytokines such as tumor necrosis factor-&#x3b1;, interleukin-1&#x3b2;, and interleukin-6. Treatment with NAC at the two selected doses significantly attenuated CDDP-induced changes in the brain cholinergic function, improved the brain oxidant/antioxidant status, and also reversed the overproduction of pro-inflammatory cytokines in brain and serum.<br><br>CONCLUSION: NAC could serve as an appropriate and safe complementary therapeutic agent to attenuate the toxicity of CDDP in the brain and therefore improve its outcomes in chemotherapy.}, }
@article {pmid31041622, year = {2019}, author = {Clements, CS and Bikkul, MU and Ofosu, W and Eskiw, C and Tree, D and Makarov, E and Kill, IR and Bridger, JM}, title = {Presence and distribution of progerin in HGPS cells is ameliorated by drugs that impact on the mevalonate and mTOR pathways.}, journal = {Biogerontology}, volume = {20}, number = {3}, pages = {337-358}, pmid = {31041622}, issn = {1573-6768}, mesh = {Cell Line ; Enzyme Inhibitors/pharmacology ; Humans ; Lamin Type A/*metabolism ; Mevalonic Acid/*metabolism ; Progeria/*metabolism/pathology ; }, abstract = {Hutchinson-Gilford progeria syndrome (HGPS) is a rare, premature ageing syndrome in children. HGPS is normally caused by a mutation in the LMNA gene, encoding nuclear lamin A. The classical mutation in HGPS leads to the production of a toxic truncated version of lamin A, progerin, which retains a farnesyl group. Farnesyltransferase inhibitors (FTI), pravastatin and zoledronic acid have been used in clinical trials to target the mevalonate pathway in HGPS patients to inhibit farnesylation of progerin, in order to reduce its toxicity. Some other compounds that have been suggested as treatments include rapamycin, IGF1 and N-acetyl cysteine (NAC). We have analysed the distribution of prelamin A, lamin A, lamin A/C, progerin, lamin B1 and B2 in nuclei of HGPS cells before and after treatments with these drugs, an FTI and a geranylgeranyltransferase inhibitor (GGTI) and FTI with pravastatin and zoledronic acid in combination. Confirming other studies prelamin A, lamin A, progerin and lamin B2 staining was different between control and HGPS fibroblasts. The drugs that reduced progerin staining were FTI, pravastatin, zoledronic acid and rapamycin. However, drugs affecting the mevalonate pathway increased prelamin A, with only FTI reducing internal prelamin A foci. The distribution of lamin A in HGPS cells was improved with treatments of FTI, pravastatin and FTI + GGTI. All treatments reduced the number of cells displaying internal speckles of lamin A/C and lamin B2. Drugs targeting the mevalonate pathway worked best for progerin reduction, with zoledronic acid removing internal progerin speckles. Rapamycin and NAC, which impact on the MTOR pathway, both reduced both pools of progerin without increasing prelamin A in HGPS cell nuclei.}, }
@article {pmid31035402, year = {2019}, author = {Šalamon, &#x160; and Kramar, B and Marolt, TP and Poljšak, B and Milisav, I}, title = {Medical and Dietary Uses of N-Acetylcysteine.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {8}, number = {5}, pages = {}, pmid = {31035402}, issn = {2076-3921}, support = {P3-0019 and P3-0388//Javna Agencija za Raziskovalno Dejavnost RS/ ; }, abstract = {N-acetylcysteine (NAC), a plant antioxidant naturally found in onion, is a precursor to glutathione. It has been used as a drug since the 1960s and is listed on the World Health Organization (WHO) Model List of Essential Medicines as an antidote in poisonings. There are numerous other uses or proposed uses in medicine that are still in preclinical and clinical investigations. NAC is also used in food supplements and cosmetics. Despite its abundant use, there are projections that the NAC global market will grow in the next five years; therefore, the purpose of this work is to provide a balanced view of further uses of NAC as a dietary supplement. Although NAC is considered a safe substance, the results among clinical trials are sometimes controversial or incomplete, like for many other antioxidants. More clinical trials are underway that will improve our understanding of NAC applicability.}, }
@article {pmid31030832, year = {2019}, author = {Xu, X and Xu, Y and Zhang, Q and Yang, F and Yin, Z and Wang, L and Li, Q}, title = {Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SAPK/JNK signalling pathways.}, journal = {Veterinary microbiology}, volume = {232}, number = {}, pages = {1-12}, pmid = {31030832}, issn = {1873-2542}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Benzothiazoles/pharmacology ; Chlorocebus aethiops ; *MAP Kinase Signaling System ; Porcine epidemic diarrhea virus/*physiology ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/*metabolism ; Thiocarbamates/pharmacology ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/*metabolism ; Vero Cells ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Porcine epidemic diarrhea virus (PEDV) is a member of Coronavirus, which causes severe watery diarrhea in piglets with high morbidity and mortality. ROS and p53 play key roles in regulating many kinds of cell process during viral infection, however, the exact function in PEDV-induced apoptosis remains unclear. In this study, the pro-apoptotic effect of PEDV was examined in Vero cells and we observed that PEDV infection increased MDM2 and CBP, promoted p53 phosphorylation at serine 20 and, promoted p53 nuclear translocation, leading to p53 activation in Vero cells. Treatment with the p53 inhibitor PFT-α could significantly inhibit PEDV-induced apoptosis. We also observed PEDV infection induced time-dependent ROS accumulation. Treatment with antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), significantly inhibited PEDV-induced apoptosis. Moreover, further inhibition tests were established to prove that p53 was regulated by ROS in PEDV-induced apoptosis. In addition, we also found that p38 MAPK and SAPK/JNK were activated in PEDV-infected Vero cells. However, treatment with the p38 MAPK inhibitor SB203580, and the SAPK/JNK inhibitor SP600125 reversed PEDV-induced apoptosis. Taken together, the results of this study demonstrate that activated p53 and accumulated ROS participated in PEDV-induced apoptosis and p53 could be regulated by ROS during PEDV infection. Activated p38 MAPK and SAPK/JNK exerted no influence on PEDV-induced apoptosis. These findings provide new insights into the function of p53 and ROS in the interaction of PEDV with Vero cells.}, }
@article {pmid31030296, year = {2019}, author = {Christensen, PM and Bangsbo, J}, title = {N-Acetyl cysteine does not improve repeated intense endurance cycling performance of well-trained cyclists.}, journal = {European journal of applied physiology}, volume = {119}, number = {6}, pages = {1419-1429}, pmid = {31030296}, issn = {1439-6327}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Bicycling/*physiology ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Humans ; Male ; Physical Endurance/*drug effects ; }, abstract = {PURPOSE: To evaluate the effect of antioxidant supplementation on intense endurance exercise performance and the physiologic exercise response acutely and in early recovery.<br><br>METHODS: Well-trained cyclists (n&#x2009;=&#x2009;11, peak VO2: 69&#x2009;&#xb1;&#x2009;7&#xa0;ml/min/kg) completed two identical standardized 20-min warm-up periods (WU-1 and WU-2) prior to two performance tests (PT) with a duration of ~&#x2009;4&#xa0;min representing a qualifying (PT-1) and final race (PT-2) on the same day separated by 90&#xa0;min. Subjects were supplemented orally with placebo (PLA) and N-acetyl cysteine (NAC; 20&#xa0;mg/kg) before exercise in a double-blinded crossover design.<br><br>RESULTS: Mean power during PT-1 did not differ (P&#x2009;=&#x2009;0.39) between PLA (400&#x2009;&#xb1;&#x2009;44&#xa0;W) and NAC (401&#x2009;&#xb1;&#x2009;44&#xa0;W) as was the case during PT-2 with similar performance (P&#x2009;=&#x2009;0.74) between PLA (401&#x2009;&#xb1;&#x2009;43&#xa0;W) and NAC (400&#x2009;&#xb1;&#x2009;42&#xa0;W). Subjective "readiness" was lowered by prior exhaustive exercise from PT-1 to PT-2 (P&#x2009;=&#x2009;0.012) in both PLA and NAC. Plasma total antioxidant capacity was not affected by supplementation and prior exhaustive exercise (respective main effects: P&#x2009;=&#x2009;0.83 and P&#x2009;=&#x2009;0.19) which also was observed for peak VO2 at ~&#x2009;5&#xa0;L/min (P&#x2009;=&#x2009;0.84 and P&#x2009;=&#x2009;0.30). In WU-1 and WU-2, both cycling economy at ~&#x2009;20% (P&#x2009;=&#x2009;0.10 and P&#x2009;=&#x2009;0.21) and plasma potassium at&#x2009;~&#x2009;5&#xa0;mmol/L (P&#x2009;=&#x2009;0.46 and P&#x2009;=&#x2009;0.26) were unaffected by supplementation and prior exercise.<br><br>CONCLUSIONS: Athletes executing maximal efforts of a ~&#x2009;4-min duration twice daily, as seen in track cycling, appear to gain no benefit from oral NAC supplementation on acute and subsequent performance following short-term recovery. Moreover, well-trained cyclists exhibit rapid recovery from a single bout of intense endurance cycling.}, }
@article {pmid31029906, year = {2019}, author = {Lee, CH and Huang, CW and Chang, PC and Shiau, JP and Lin, IP and Lin, MY and Lai, CC and Chen, CY}, title = {Reactive oxygen species mediate the chemopreventive effects of syringin in breast cancer cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {61}, number = {}, pages = {152844}, doi = {10.1016/j.phymed.2019.152844}, pmid = {31029906}, issn = {1618-095X}, mesh = {Animals ; Anticarcinogenic Agents/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/*drug therapy/metabolism/pathology/prevention &amp; control ; Caspases/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Female ; Glucosides/*pharmacology ; Humans ; MCF-7 Cells ; Mice, Inbred BALB C ; Oxidative Stress/drug effects ; Phenylpropionates/*pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND: Syringin (Syr), a phenylpropanoid glycoside extracted from Eleutherococcus senticosus, possesses various biological properties, including anticancer activities. However, the cytotoxicity effects of Syr on breast cancer have not yet been elucidated.<br><br>PURPOSE: In this study, we evaluated the anticancer potential of Syr on breast carcinoma and the mechanism involved.<br><br>STUDY DESIGN/METHODS: Non-tumorigenic (M10), tumorigenic (MCF7) and metastatic (MDA-MB-231) breast cancer cell lines as well as xenograft model were treated with Syr. Proliferation and cell cycle distribution were evaluated using the MTT, the colony formation assay and flow cytometry. The expression levels of cytotoxicity-related proteins were detected by Western blot.<br><br>RESULTS: Here, we found that colony formation inhibition, cell cycle arrest in the G2/M phase, down-regulation of X-linked inhibitor of apoptosis protein (XIAP), cleaved poly (ADP-ribose) polymerase (PARP) and caspase-3/9 activation were observed in MCF7 and MDA-MB-231 cells treated with Syr. Moreover, pretreatment with a pan-caspase inhibitor (Z-DEVD-FMK) inhibited Syr-induced apoptosis. In addition, treatment with Syr also increased the production of reactive oxygen species (ROS). However, the antioxidant N-acetyl-cysteine (NAC) reversed the ROS levels and rescued the apoptotic changes. Meanwhile, Syr inhibited the growth of breast cancer xenograft models and dramatically decreased tumor volume without any obvious body weight loss in vivo.<br><br>CONCLUSION: Our findings suggest that Syr induces oxidative stress to suppress the proliferation of breast cancer and thus might be an effective therapeutic agent to treat breast cancer.}, }
@article {pmid31026688, year = {2019}, author = {He, B and Wang, X and Zhu, J and Kong, B and Wei, L and Jin, Y and Fu, Z}, title = {Autophagy protects murine macrophages from β-cypermethrin-induced mitochondrial dysfunction and cytotoxicity via the reduction of oxidation stress.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {250}, number = {}, pages = {416-425}, doi = {10.1016/j.envpol.2019.04.044}, pmid = {31026688}, issn = {1873-6424}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Autophagy/drug effects ; Insecticides/*toxicity ; Macrophages/metabolism/physiology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/*drug effects/physiology ; Molecular Docking Simulation ; Oxidative Stress/physiology ; Pyrethrins/*toxicity ; Reactive Oxygen Species/metabolism ; Toxicity Tests ; }, abstract = {The immunotoxicity of synthetic pyrethroid (SPs) has garnered much attention, and our previous research demonstrated that β-CYP causes immunotoxicity and oxidative stress in macrophages. Nevertheless, the underlying mechanism remains largely unknown. In this study, the murine macrophage RAW 264.7 cells and murine peritoneal macrophages (PMs) were exposed to β-CYP. The results showed that β-CYP elevated intracellular ROS levels in both RAW 264.7 cells and PMs. Exposure to β-CYP also caused mitochondrial dysfunction with reduced mitochondrial membrane potential (MMP), intracellular ATP level and mitochondrial DNA (mtDNA) content in the two cell types. In addition, exposure of RAW 264.7 cells to β-CYP for 12 h and 24 h enhanced autophagy, with elevated Beclin1, Rab7, Lamp1 and LC3-II expression levels, while 48 h of exposure attenuated autophagy. In contrast, exposure of PMs to β-CYP for 12 h promoted autophagy, whereas exposure for 24 h and 48 h impaired autophagy. Cotreatment with an antioxidant, N-acetyl-L-cysteine (NAC), partially blocked the reduced MMP, intracellular ATP level and autophagy disturbance. Moreover, cotreatment with an autophagy agonist, rapamycin (RAPA), partially blocked mitochondrial dysfunction and oxidative stress in the two cell types, whereas cotreatment with an autophagy inhibitor, 3-methyladenine (3-MA), augmented the abovementioned toxic effects. Furthermore, mitochondrial ROS levels in both RAW 264.7 cells and PMs were elevated by exposure to β-CYP, and molecular docking showed that β-CYP docked with mouse respiratory chain complex I by binding to the ND2, ND4, and ND5 subunits of the protein complex. Taken together, the data obtained in the present study demonstrate that oxidative stress partially mediates mitochondrial dysfunction and autophagy disturbance upon exposure to β-CYP in macrophages, and autophagy plays a protective role against the toxic effects.}, }
@article {pmid31023645, year = {2019}, author = {Devi, TS and Yumnamcha, T and Yao, F and Somayajulu, M and Kowluru, RA and Singh, LP}, title = {TXNIP mediates high glucose-induced mitophagic flux and lysosome enlargement in human retinal pigment epithelial cells.}, journal = {Biology open}, volume = {8}, number = {4}, pages = {}, pmid = {31023645}, issn = {2046-6390}, support = {R01 EY014370/EY/NEI NIH HHS/United States ; R01 EY017313/EY/NEI NIH HHS/United States ; R01 EY022230/EY/NEI NIH HHS/United States ; P30 EY004068/EY/NEI NIH HHS/United States ; P30 DK020572/DK/NIDDK NIH HHS/United States ; R01 EY023992/EY/NEI NIH HHS/United States ; }, abstract = {Thioredoxin-interacting protein (TXNIP) plays a critical role in oxidative stress, inflammation, apoptosis and the pathogenesis of diabetic retinopathy (DR). However, the role of TXNIP in high glucose-induced retinal pigment epithelium (RPE) dysfunction is still unknown. Here, we show that high glucose (HG; 25 mM,) significantly increases TXNIP expression at both the mRNA and protein levels when compared to low glucose (LG; 5.5 mM) in a human RPE cell line (ARPE-19) and primary human RPE (HRPE) cells. TXNIP upregulation is associated with mitochondrial membrane depolarization, fragmentation and mitophagic flux to lysosomes. We used confocal live-cell imaging of RPE cells expressing mt-Keima, a coral protein that emits green light in mitochondria (alkaline or neutral pH) and red light in the acidic lysosome, to measure mitophagic flux. We observed an elongated mitochondrial network of green mt-Keima under LG, which is fragmented in HG. Red mt-Keima accumulates in lysosomes as small punctate aggregations under LG in both ARPE-19 and HRPE cells, whereas they are significantly enlarged (two- to threefold) under HG. Lysosomal enlargement under HG is further illustrated by lysosomal membrane protein LAMP1-mCherry expression in both ARPE-19 and HRPE cells. Furthermore, HG causes lysosomal cathepsin L inactivation and pro-inflammatory caspase-1 activation in ARPE-19 cells. TXNIP knockdown by shRNA prevents mitochondrial fragmentation, mitophagic flux and lysosome enlargement under HG. In addition, antioxidant N-acetylcysteine (NAC) and Amlexanox (Amlx), an inhibitor of protein kinase TBK1 and of the mitophagic adaptors Optineurin (Optn) and Sequestosome 1 (p62/SQSTM1), prevent mitophagic flux and lysosome enlargement. These results suggest that TXNIP mediates several deleterious effects of high glucose on RPE, which may be implicated in the development of DR.}, }
@article {pmid31023049, year = {2019}, author = {Tas, N and Altinbas, A and Noyan, T and Kokturk, S and Ayhan, S and Canakci, E}, title = {Acute acetaminophene-induced hepatotoxicity and nephrotoxicity; therapeutic effect of dexmedetomidine.}, journal = {Bratislavske lekarske listy}, volume = {120}, number = {4}, pages = {270-276}, doi = {10.4149/BLL_2019_047}, pmid = {31023049}, issn = {0006-9248}, mesh = {*Acetaminophen/adverse effects ; Acetylcysteine ; Animals ; *Antioxidants/pharmacology ; *Chemical and Drug Induced Liver Injury/drug therapy ; *Dexmedetomidine/pharmacology ; Glutathione/metabolism ; Liver/drug effects ; Oxidative Stress ; Rats ; }, abstract = {OBJECTIVE AND BACKGROUND: Acute acetaminophen (APAP) overdose has been shown to cause toxicity and the primary treatment medication is N-acetylcysteine (NAC). Dexmedetomidine (DEX) is a sedative drug with known antioxidant properties. We researched whether DEX has an injury-reducing effect on toxicity.<br><br>METHODS: Rats were divided into: Group I (control), Group II (APAP) Group III (NAC) Group IV (DEX) and Group V (NAC+DEX). Histopathologic investigations of tissues were performed and glutathione peroxidase (GSH-Px), catalase (CAT), malondialdehyde (MDA), myeloperoxidase (MPO) and beta trace protein (PGD2S) levels were studied in blood samples.<br><br>RESULTS: DEX administration for hepatotoxicity and nephrotoxicity induced with APAP, caused a significant reduction in oxidative injury markers like MDA and MPO, a significant increase in GSH-Px level and a significant degree of amelioration in liver histopathologic scores.<br><br>CONCLUSION: DEX administration for APAP toxicity causes a reduction in oxidative injury biomarkers, increased antioxidant biomarker levels and significant reduction in liver histopathologic scores. The beneficial effect of DEX use for detection of toxicity induced by acute APAP overdose, was shown in this study for the first time (Tab. 5, Fig. 2, Ref. 41).}, }
@article {pmid31022884, year = {2019}, author = {Kregiel, D and Rygala, A and Kolesinska, B and Nowacka, M and Herc, AS and Kowalewska, A}, title = {Antimicrobial and Antibiofilm N-acetyl-L-cysteine Grafted Siloxane Polymers with Potential for Use in Water Systems.}, journal = {International journal of molecular sciences}, volume = {20}, number = {8}, pages = {}, pmid = {31022884}, issn = {1422-0067}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Anti-Bacterial Agents/chemistry/*pharmacology ; Bacteria/*drug effects ; Bacterial Adhesion/drug effects ; Biofilms/*drug effects ; Drinking Water/*microbiology ; Siloxanes/chemistry/*pharmacology ; Water Purification ; }, abstract = {Antibiofilm strategies may be based on the prevention of initial bacterial adhesion, the inhibition of biofilm maturation or biofilm eradication. N-acetyl-L-cysteine (NAC), widely used in medical treatments, offers an interesting approach to biofilm destruction. However, many Eubacteria strains are able to enzymatically decompose the NAC molecule. This is the first report on the action of two hybrid materials, NAC-Si-1 and NAC-Si-2, against bacteria isolated from a water environment: Agrobacterium tumefaciens, Aeromonas hydrophila, Citrobacter freundii, Enterobacter soli, Janthinobacterium lividum and Stenotrophomonas maltophilia. The NAC was grafted onto functional siloxane polymers to reduce its availability to bacterial enzymes. The results confirm the bioactivity of NAC. However, the final effect of its action was environment- and strain-dependent. Moreover, all the tested bacterial strains showed the ability to degrade NAC by various metabolic routes. The NAC polymers were less effective bacterial inhibitors than NAC, but more effective at eradicating mature bacterial biofilms.}, }
@article {pmid31015207, year = {2019}, author = {Kong, Y and Wang, Y and Zhang, YY and Shi, MM and Mo, XD and Sun, YQ and Chang, YJ and Xu, LP and Zhang, XH and Liu, KY and Huang, XJ}, title = {Prophylactic oral NAC reduced poor hematopoietic reconstitution by improving endothelial cells after haploidentical transplantation.}, journal = {Blood advances}, volume = {3}, number = {8}, pages = {1303-1317}, pmid = {31015207}, issn = {2473-9537}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adolescent ; Adult ; Allografts ; Bone Marrow Cells/*metabolism/pathology ; Cellular Microenvironment/*drug effects ; Endothelial Cells/*metabolism/pathology ; Female ; Hematopoiesis/*drug effects ; *Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {Poor graft function (PGF) and prolonged isolated thrombocytopenia (PT) remain life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Endothelial cells (ECs) play a crucial role in regulating hematopoiesis in the bone marrow (BM) microenvironment. However, whether the impaired BM ECs are responsible for defective hematopoiesis in PGF and PT patients requires clarification, and clinical management is challenging. Two prospective clinical trials were included in the current study. In the first trial (N = 68), PGF and PT patients demonstrated defective BM ECs pre-HSCT and impaired BM EC dynamic reconstitution at early time points post-HSCT, which was positively correlated with reactive oxygen species (ROS) levels. Receiver operating characteristic curves showed that BM EC < 0.1% pre-HSCT could identify high-risk patients with PGF and PT. The second trial enrolled patients (N = 35) with EC < 0.1% who accepted oral N-acetyl-l-cysteine (NAC; 400 mg 3 times per day) from -14 days pre-HSCT to +2 months post-HSCT continuously, whereas the remaining EC ≥ 0.1% patients (N = 39) received allo-HSCT only. Prophylactic NAC intervention was safe and effective in preventing the occurrence of PGF and PT in EC < 0.1% patients by promoting the dynamic reconstitution of BM ECs and CD34[+] cells, along with reducing their ROS levels, which was further confirmed by in situ BM trephine biopsy analyses. These findings suggest that the impaired BM ECs pre-HSCT are responsible for the defective hematopoiesis in PGF and PT patients. Therefore, improvement of BM ECs through prophylactic NAC intervention may be a promising therapeutic approach to promote hematopoietic reconstitution post-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT03236220 and #NCT02978274.}, }
@article {pmid31014188, year = {2020}, author = {Cavalcanti da Silveira, CO and Gonçalves, ADS and Costa Franca, TC and Silva Filho, EA}, title = {Computational studies of mucin 2 and its interactions with thiolated chitosans: a new insight for mucus adhesion and drug retention.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {38}, number = {5}, pages = {1479-1487}, doi = {10.1080/07391102.2019.1610499}, pmid = {31014188}, issn = {1538-0254}, mesh = {*Chitosan ; Mucin-2 ; Mucus ; *Pharmaceutical Preparations ; Sulfhydryl Compounds ; }, abstract = {Chitosans have attracted the interest of the medicinal chemists as mucous adhesive excipients capable of increasing the residence period of drugs inside mucous membranes. Their interactions with the oligomeric mucus gel-forming glycoprotein mucin 2 throughout the intestine determine the level of mucus adhesion, which can be potentiated by the insertion of thiolated substituents on its structure. In this work, we studied the interactions between the mucin 2 and thiolated chitosans, ranking them based on the free energy of receptor-ligand interaction. Results show that when non-bonded interactions were considered, the chitosan-N-acetyl cysteine (AC-Chi) equaled itself in terms of free energy of bonding to the hexamer chitosan-thiobutylamidine (TBA-Chi). The unmodified chitosan (U-Chi) displayed the second greatest ΔG(binding), showing that the level of mucoadhesion of thiolated chitosans has assumed a diverse order, when considering only the non-binding interactions.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid31010676, year = {2019}, author = {Zhou, P and Chen, X and Li, M and Tan, J and Zhang, Y and Yuan, W and Zhou, J and Wang, G}, title = {2-D08 as a SUMOylation inhibitor induced ROS accumulation mediates apoptosis of acute myeloid leukemia cells possibly through the deSUMOylation of NOX2.}, journal = {Biochemical and biophysical research communications}, volume = {513}, number = {4}, pages = {1063-1069}, doi = {10.1016/j.bbrc.2019.04.079}, pmid = {31010676}, issn = {1090-2104}, mesh = {Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Flavones/*pharmacology ; Humans ; Leukemia, Myeloid, Acute/drug therapy/*pathology ; Mitochondria/physiology ; NADPH Oxidase 2/*metabolism ; Protein Processing, Post-Translational ; Reactive Oxygen Species/*metabolism ; Sumoylation/*drug effects ; }, abstract = {Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic malignancy with poor survival and frequent relapse. Recently, a posttranslational modification of proteins with small ubiquitin-like modifiers (SUMO) has been notably implicated in a wide spectrum of diseases, especially cancers. Ubc9, as the sole E2-conjugating enzyme in SUMOylation cascade, particularly has been associated with adverse clinical outcomes. 2-D08, a small molecular agent, functions by blocking the transfer of SUMO from the Ubc9 thioester to SUMO substrates without any effects on other individual steps in this process. However, both the effects and mechanisms of 2-D08 on AML cells are still unknown. In this study, we found that 2-D08 significantly suppressed cell viability and colony formation ability. Additionally, it induced mitochondrial-mediated apoptosis with dramatic accumulation of the reactive oxygen species (ROS), which could be almost completely rescued by the ROS scavenger N-acetylcysteine (NAC). Furthermore, we confirmed that the fatal accumulation of ROS was due to its aberrant generation instead of defective scavenging. In summary, our results suggest that 2-D08, as a specific SUMOylation inhibitor, induces ROS accumulation-mediated intrinsic apoptosis of AML cells possibly through deSUMOylation of NOX2. Therefore, 2-D08 might be a promising therapeutic agent for the treatment of AML in the future.}, }
@article {pmid31005714, year = {2019}, author = {Liang, QP and Xu, TQ and Liu, BL and Lei, XP and Hambrook, JR and Zhang, DM and Zhou, GX}, title = {Sasanquasaponin ΙΙΙ from Schima crenata Korth induces autophagy through Akt/mTOR/p70S6K pathway and promotes apoptosis in human melanoma A375 cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {58}, number = {}, pages = {152769}, doi = {10.1016/j.phymed.2018.11.029}, pmid = {31005714}, issn = {1618-095X}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Melanoma/*drug therapy ; Membrane Potential, Mitochondrial/drug effects ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/genetics/metabolism ; Saponins/chemistry/*pharmacology ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/genetics/metabolism ; Theaceae/*chemistry ; }, abstract = {BACKGROUND: Melanoma is a high fatality skin cancer which lacks effective drugs. Sasanquasaponin, an important sort of constituents in theaceae, has been demonstrated to have potent anti-tumor effect in breast cancer and hepatocellular carcinoma. As a sasanquasaponin, we speculate that Sasanquasaponin III (SQS III) isolated from Schima crenata Korth may also have anti-tumor activity.<br><br>PURPOSE: This study aims to investigate whether SQS III has anti-melanoma activity and examine the underlying mechanisms of SQS III against melanoma.<br><br>METHODS/STUDY DESIGNS: The anti-proliferative effect of SQS III was assessed by cells viability assay. Annexin V-FITC/PI double staining assay was utilized for detection of apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) production were detected using JC-1 and DCFH-DA assay, respectively. Autophagy was monitored using transmission electron microscopy (TEM) and GFP-LC3 transfection fluorescence analysis. Autophagosome-lysosome fusion and lysosomal degradation were determined using a GFP-LC3 &amp; LAMP1 co-localization assay and DQ-BSA staining. Proteins related to apoptosis and autophagy were analyzed by Western blotting.<br><br>RESULTS: Our results demonstrated that the SQS III exhibited potent anti-cancer activity in A375 cells by inducing both apoptosis and autophagy. In melanoma cells treated with SQS III, caspases were activated and PARP was cleaved, proving the occurrence of apoptosis. Mechanistic studies indicated that the pro-apoptosis activity of SQS III was mediated by death receptor pathway and mitochondrial dysfunction which was induced by ROS accumulation and reversed by the ROS inhibitor N-acetyl-cysteine (NAC). In addition to triggering apoptosis, SQS III may also cause autophagy in melanoma cells. Our results demonstrated that SQS III induced up-regulated expression of GFP-LC3, autophagosome-lysosomal fusion and lysosomal degradation. Additionally, the ROS accumulation was also involved in the activation of autophagy. Meanwhile, it was also found that after SQS III treatment, the expression of LC3-II was up-regulated and the AKT/mTOR signaling pathway was inhibited. The autophagy inhibitor 3-MA converted cytotoxicity and apoptosis of SQS III in A375 cells, which indicated that autophagy promoted the SQS III-induced apoptosis.<br><br>CONCLUSION: SQS III showed potent anti-cancer activity by inducing apoptosis and autophagy, which provides insights into its possible use as a therapy for melanoma.}, }
@article {pmid30999254, year = {2019}, author = {Lasek-Bal, A and Lukasik, M and Żak, A and Sulek, A and Bosak, M}, title = {Unverricht-Lundborg disease: Clinical course and seizure management based on the experience of polish centers.}, journal = {Seizure}, volume = {69}, number = {}, pages = {87-91}, doi = {10.1016/j.seizure.2019.04.008}, pmid = {30999254}, issn = {1532-2688}, mesh = {Adult ; Anticonvulsants/*therapeutic use ; Brain/drug effects ; Electroencephalography/methods ; Female ; Humans ; Magnetic Resonance Imaging/methods ; Male ; Middle Aged ; Myoclonus/drug therapy ; Poland ; Seizures/*drug therapy ; Unverricht-Lundborg Syndrome/*drug therapy ; Valproic Acid/*therapeutic use ; }, abstract = {UNLABELLED: The purpose of this paper was to present our experience following the longterm treatment of 11 patients with Unverricht-Lundborg disease (ULD) confirmed by molecular testing.<br><br>METHODS: We analyzed the clinical course, cognitive state, neuroimaging and neurophysiology results.<br><br>RESULTS: The data were collected from 9 unrelated families (F/M: 4/7) aged 25-49. The most frequent early manifestations of ULD include generalized tonic-clonic seizures (GTCS) accompanied by myoclonus 2 years later. Myoclonus was observed in all of the patients; its severity made it impossible for 91% to move independently. In two patients- mild atrophy of brain were observed in the MRI. More than half of the patients who underwent evoked potential presented no abnormalities. The dominant EEG-change was slow background activity in all of the patients. Seven patients had generalized seizure activity. The patients received antiepileptic therapy modifications depending on the severity of symptoms and stage of the disease. Five patients received N-acetyl-cysteine.<br><br>CONCLUSIONS: ULD patients require anti-epileptic polytherapy, mostly benefitting from managing GTCS and myoclonus with valproic acid and clonazepam treatment. Patients may benefit from add-on therapy with levetiracetam or topiramate. An increase in myoclonus, resulting from the progressive nature of the disease leads to significant disability in the majority of patients.}, }
@article {pmid30999090, year = {2019}, author = {Fusar-Poli, L and Surace, T and Vanella, A and Meo, V and Patania, F and Furnari, R and Signorelli, MS and Aguglia, E}, title = {The effect of adjunctive nutraceuticals in bipolar disorder: A systematic review of randomized placebo-controlled trials.}, journal = {Journal of affective disorders}, volume = {252}, number = {}, pages = {334-349}, doi = {10.1016/j.jad.2019.04.039}, pmid = {30999090}, issn = {1573-2517}, mesh = {Amino Acids/*therapeutic use ; Bipolar Disorder/psychology/*therapy ; *Dietary Supplements ; Fatty Acids/*therapeutic use ; Humans ; Micronutrients/*therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: Nutraceuticals are a group of compounds of growing interest for mental health professionals. Given the implication of certain nutrients in the onset of bipolar disorder, it has been hypothesized that nutraceuticals might be effective in improving symptoms of the condition (i.e. mania or depression). Our systematic review aimed to evaluate the effectiveness of adjunctive nutraceuticals compared to placebo.<br><br>METHODS: We searched the following databases from inception to February 2019: Web of Science, CINAHL, Embase, and PsycINFO. We included only original randomized controlled trials written in English, testing the efficacy of nutraceuticals in add-on to standard care, compared to placebo, in patients with bipolar disorder.<br><br>RESULTS: After identifying 6584 potentially relevant publications, we finally included 25 studies, among which six used fatty acids, seven micronutrients, seven amino acids. One study tested probiotics, while in four trials a combination of different types of nutraceuticals was used. Even if some compounds have shown promising results (i.e. fatty acids and N-acetyl cysteine for depression, amino acid drinks and folic acid for mania), the majority of nutraceuticals did not cause significant improvements in comparison to placebo.<br><br>LIMITATIONS: We could not perform a meta-analysis due to the high heterogeneity of trials, which were also affected by some methodological caveats.<br><br>CONCLUSIONS: Evidence regarding the efficacy of adjunctive nutraceuticals in bipolar disorder is inconsistent. Nevertheless, they appear generally free from relevant side effects. Well-designed trials are needed to further explore the potential role of nutraceuticals in different mood episodes.}, }
@article {pmid30998386, year = {2019}, author = {Xu, C and Xu, J and Ji, G and Liu, Q and Shao, W and Chen, Y and Gu, J and Weng, Z and Zhang, X and Wang, Y and Gu, A}, title = {Deficiency of X-ray repair cross-complementing group 1 in primordial germ cells contributes to male infertility.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {33}, number = {6}, pages = {7427-7436}, doi = {10.1096/fj.201801962RR}, pmid = {30998386}, issn = {1530-6860}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Female ; Germ Cells/drug effects/*metabolism ; Infertility, Male/*genetics ; Male ; Mice ; Mice, Knockout ; Mitochondria/drug effects/metabolism ; Oxidative Stress/drug effects ; Testis/cytology/metabolism ; X-ray Repair Cross Complementing Protein 1/*genetics ; }, abstract = {X-ray repair cross-complementing group 1 (Xrcc1), a key DNA repair gene, plays a vital role in maintaining genomic stability and is highly expressed in the early stages of spermatogenesis, but the exact functions remain elusive. Here we generated primordial germ cell-specific Xrcc1 knockout (cXrcc1[-/-]) mice to elucidate the effects of Xrcc1 on spermatogenesis. We demonstrated that Xrcc1 deficiency results in infertility in male mice due to impaired spermatogenesis. We found that cXrcc1[-/-] mice exhibited smaller size of testes as well as lower sperm concentration and motility than the wild-type mice. Mechanistically, we demonstrated that Xrcc1 deficiency in primordial germ cells induced elevated levels of reactive oxygen species, mitochondria dysfunction, apoptosis, and loss of stemness of spermatogonial stem cells (SSCs) in testes. In Xrcc1-deficienct SSCs, elevated oxidative stress and mitochondrial dysfunction could be partially reversed by treatment with the antioxidant N-acetylcysteine (NAC), whereas NAC treatment did not restore the fertility or ameliorate the apoptosis caused by loss of Xrcc1. Overall, our findings provided new insights into understanding the crucial role of Xrcc1 during spermatogenesis.-Xu, C., Xu, J., Ji, G., Liu, Q., Shao, W., Chen, Y., Gu, J., Weng, Z., Zhang, X., Wang, Y., Gu, A. Deficiency of X-ray repair cross-complementing group 1 in primordial germ cells contributes to male infertility.}, }
@article {pmid30996207, year = {2019}, author = {Sudo, K and VAN Dao, C and Miyamoto, A and Shiraishi, M}, title = {Comparative analysis of in vitro neurotoxicity of methylmercury, mercury, cadmium, and hydrogen peroxide on SH-SY5Y cells.}, journal = {The Journal of veterinary medical science}, volume = {81}, number = {6}, pages = {828-837}, pmid = {30996207}, issn = {1347-7439}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Cadmium/*toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; Heavy Metal Poisoning, Nervous System ; Humans ; Hydrogen Peroxide/toxicity ; L-Lactate Dehydrogenase/metabolism ; Mercury/*toxicity ; Metals, Heavy/toxicity ; Methylmercury Compounds/*toxicity ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Mercury (Hg) and cadmium (Cd) are the major toxic heavy metals and are known to induce neurotoxicity. Although many studies have shown that several heavy metals have neurotoxic effects, the cellular and molecular mechanisms thereof are still not clear. Oxidative stress is reported to be a common and important mechanism in cytotoxicity induced by heavy metals. However, the assays for identifying toxic mechanisms were not performed under the same experimental conditions, making it difficult to compare toxic properties of the heavy metals. In this study, we investigated the mechanisms underlying neurotoxicity induced by heavy metals and H2O2, focusing on cell death, cell proliferation, and oxidative stress under the same experimental condition. Our results showed that MeHg caused lactate dehydrogenase (LDH) release, caspase activation and cell-cycle alteration, and ROS generation in accordance with decreased cell viability. HgCl2 caused LDH release and cell-cycle alteration, but not caspase activation. CdCl2 had a remarkable effect on the cell cycle profiles without induction of LDH release, caspase activation, or ROS generation. Pretreatment with N-acetyl-l-cysteine (NAC) prevented the decrease in cell viability induced by MeHg and HgCl2, but not CdCl2. Our results demonstrate a clear difference in neurotoxic mechanisms induced by MeHg, HgCl2, CdCl2 or H2O2 in SH-SY5Y cells. Elucidating the characteristics and mechanisms of each heavy metal under the same experimental conditions will be helpful to understand the effect of heavy metals on health and to develop a more effective therapy for heavy metal poisoning.}, }
@article {pmid30993256, year = {2019}, author = {Argaev Frenkel, L and Rozenfeld, H and Rozenberg, K and Sampson, SR and Rosenzweig, T}, title = {N-Acetyl-l-Cysteine Supplement in Early Life or Adulthood Reduces Progression of Diabetes in Nonobese Diabetic Mice.}, journal = {Current developments in nutrition}, volume = {3}, number = {4}, pages = {nzy097}, pmid = {30993256}, issn = {2475-2991}, abstract = {BACKGROUND: Oxidative stress contributes to the pathologic process leading to the development, progression, and complications of type 1 diabetes (T1D).<br><br>OBJECTIVE: The aim of this study was to investigate the effect of the antioxidant N-acetyl-l-cysteine (NAC), supplemented during early life or adulthood on the development of T1D.<br><br>METHODS: NAC was administered to nonobese diabetic (NOD) female mice during pregnancy and lactation, and the development of diabetes was followed in offspring. In an additional set of experiments, offspring of untreated mice were given NAC during adulthood, and the development of T1D was followed. Morbidity rate, insulitis and serum cytokines were measured in the 2 sets of experiments. In addition, markers of oxidative stress, glutathione, lipid peroxidation, total antioxidant capacity and activity of antioxidant enzymes, were followed.<br><br>RESULTS: Morbidity rate was reduced in both treatment protocols. A decrease in interferon &#x3b3;, tumor necrosis factor &#x3b1;, interleukin 1&#x3b1;, and other type 1 diabetes-associated proinflammatory cytokines was found in mice supplemented with NAC in adulthood or during early life compared with control NOD mice. The severity of insulitis was higher in control NOD mice than in treated groups. NAC administration significantly reduced oxidative stress, as determined by reduced lipid peroxidation and increased total antioxidant capacity in serum and pancreas of mice treated in early life or in adulthood and increased pancreatic glutathione when administrated in adulthood. The activity of antioxidant enzymes was not affected in mice given NAC in adulthood, whereas an increase in the activity of superoxide dismutase and catalase was demonstrated in the pancreas of their offspring.<br><br>CONCLUSION: NAC decreased morbidity of NOD mice by attenuating the immune response, presumably by eliminating oxidative stress, and might be beneficial in reducing morbidity rates of T1D in high-risk individuals.}, }
@article {pmid30992317, year = {2019}, author = {Zheng, Y and Chen, Z and Gu, Z and Yang, X and Yu, M and Zhao, C and Lin, J and Xu, P and Zhu, L and Jacob, TJC and Peng, S and Chen, L and Wang, L}, title = {Starvation-induced autophagy is up-regulated via ROS-mediated ClC-3 chloride channel activation in the nasopharyngeal carcinoma cell line CNE-2Z.}, journal = {The Biochemical journal}, volume = {476}, number = {9}, pages = {1323-1333}, doi = {10.1042/BCJ20180979}, pmid = {30992317}, issn = {1470-8728}, mesh = {Acetylcysteine/pharmacology ; *Autophagic Cell Death ; Cell Line, Tumor ; Chloride Channels/*metabolism ; *Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Ion Transport/drug effects ; Microtubule-Associated Proteins/metabolism ; Nasopharyngeal Carcinoma/*metabolism/pathology ; Nasopharyngeal Neoplasms/*metabolism/pathology ; Neoplasm Proteins/*metabolism ; RNA-Binding Proteins/metabolism ; Reactive Oxygen Species/*metabolism ; *Up-Regulation ; }, abstract = {Nutrient deficiency develops frequently in nasopharyngeal carcinoma cell (CNE-2Z) due to the characteristics of aggregation and uncontrolled proliferation. Therefore, starvation can induce autophagy in these cells. Chloride channel 3 (ClC-3), a member of the chloride channel family, is involved in various biological processes. However, whether ClC-3 plays an important role in starvation-induced autophagy is unclear. In this study, Earle's balanced salt solution (EBSS) was used to induce autophagy in CNE-2Z cells. We found that autophagy and the chloride current induced by EBSS were inhibited by chloride channel blockers. ClC-3 knockdown inhibited the degradation of LC3-II and P62. Furthermore, when reactive oxygen species (ROS) generation was suppressed by antioxidant N-acetyl-l-cysteine (L-NAC) pretreatment, EBSS-induced autophagy was inhibited, and the chloride current was unable to be activated. Nevertheless, ClC-3 knockdown had little effect on ROS levels, indicating that ROS acted upstream of ClC-3 and that both ROS and ClC-3 participated in EBSS-induced autophagy regulation in CNE-2Z.}, }
@article {pmid30991248, year = {2019}, author = {Schulte, MHJ and Kaag, AM and Boendermaker, WJ and van den Brink, W and Goudriaan, AE and Wiers, RW}, title = {The effect of N-acetylcysteine and working memory training on neural mechanisms of working memory and cue reactivity in regular cocaine users.}, journal = {Psychiatry research. Neuroimaging}, volume = {287}, number = {}, pages = {56-59}, doi = {10.1016/j.pscychresns.2019.03.011}, pmid = {30991248}, issn = {1872-7506}, mesh = {Acetylcysteine/*pharmacology ; Brain/drug effects ; Cocaine/*adverse effects ; Cocaine-Related Disorders/*physiopathology/*psychology ; Cognition ; Cues ; Double-Blind Method ; Humans ; Male ; *Memory, Short-Term ; }, abstract = {The current study investigated the combined effects of N-acetylcysteine and working memory (WM) training on behavioral and neural mechanisms of cue reactivity and WM in cocaine users in a randomized, double-blind design. Twenty-four of 38 cocaine-using men completed a 25-day treatment with either 2400 mg/day NAC or placebo. Both groups performed WM-training. During pre- and post-test lab-visits, neural mechanisms of cue reactivity and WM, and cue-induced craving and WM performance were assessed. Additionally, exploratory whole brain analyses were performed. Overall, the hypotheses were not confirmed, possibly due to small sample size, low WM-training adherence and/or ongoing substance use.}, }
@article {pmid30991096, year = {2019}, author = {Ding, X and Wang, W and Chen, J and Zhao, Q and Lu, P and Lu, L}, title = {Salidroside protects inner ear hair cells and spiral ganglion neurons from manganese exposure by regulating ROS levels and inhibiting apoptosis.}, journal = {Toxicology letters}, volume = {310}, number = {}, pages = {51-60}, doi = {10.1016/j.toxlet.2019.04.016}, pmid = {30991096}, issn = {1879-3169}, mesh = {Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Chlorides/*toxicity ; Cytoprotection ; Dose-Response Relationship, Drug ; Glucosides/*pharmacology ; Hair Cells, Auditory, Inner/*drug effects/metabolism/pathology ; Manganese Compounds ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects ; Phenols/*pharmacology ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Spiral Ganglion/*drug effects/metabolism/pathology ; Tissue Culture Techniques ; }, abstract = {Manganese (Mn) is an essential cofactor for many enzymes and thus plays an important role in normal growth and development. However, persistent exposure to high Mn concentrations can result in deleterious effects on not only the central nervous system but also peripheral nerves, including nerves associated with the auditory system. Our initial research on cochlear organotypic cultures in vitro showed that N-acetylcysteine (NAC) clearly decreases Mn-induced losses in hair cells (HCs), auditory nerve fibers (ANFs) and spiral ganglion neurons (SGNs) in a concentration-dependent manner. Salidroside (SAL) (p-hydroxyphenethyl-b-d-glucoside; C14H20O7), which is extracted from Rhodiola rosea L, has many pharmacological actions and antioxidative, antiaging, neuroprotective and anticancer effects. We hypothesized that SAL could also protect HCs, ANFs and SGNs from Mn injury. Cochlear organotypic cultures were treated with 1 mM Mn alone or combined with SAL (1-1000 μM). The neurofilament staining results showed that HCs, ANFs and SGNs were seriously damaged at high concentrations (100-1000 μM) but less damaged at low concentrations (1-10 μM). SAL may protect against 1 mM Mn-induced HC loss and axonal degeneration, suggesting that SAL could be a promising drug for clinical applications.}, }
@article {pmid30991008, year = {2019}, author = {Khanal, T and Leung, YK and Jiang, W and Timchenko, N and Ho, SM and Kim, K}, title = {NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {33}, number = {7}, pages = {8335-8348}, pmid = {30991008}, issn = {1530-6860}, support = {P30 ES006096/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/adverse effects/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Chemical and Drug Induced Liver Injury/genetics/*metabolism/pathology ; Epigenesis, Genetic/drug effects ; Hep G2 Cells ; Humans ; Liver Failure, Acute/chemically induced/genetics/*metabolism/pathology ; Mice ; Mice, Knockout ; Orphan Nuclear Receptors/genetics/*metabolism ; RNA, Long Noncoding/*biosynthesis/genetics ; *Signal Transduction ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {Damage-induced long noncoding RNA (DINO) is a long noncoding RNA that directly interacts with p53 and thereby enhances p53 stability and activity in response to various cellular stresses. Here, we demonstrate that nuclear receptor subfamily 2 group E member 3 (NR2E3) plays a crucial role in maintaining active DINO epigenetic status for its proper induction and subsequent p53 activation. In acetaminophen (APAP)- or carbon tetrachloride-induced acute liver injuries, NR2E3 knockout (KO) mice exhibited far more severe liver injuries due to impaired DINO induction and p53 activation. Mechanistically, NR2E3 loss both in vivo and in vitro induced epigenetic DINO repression accompanied by reduced DINO chromatin accessibility. Furthermore, compared with the efficient reversal by a typical antidote N-acetylcysteine (NAC) treatment of APAP-induced liver injury in wild-type mice, the liver injury of NR2E3 KO mice was not effectively reversed, indicating that an intact NR2E3-DINO-p53-signaling axis is essential for NAC-mediated recovery against APAP-induced hepatotoxicity. These findings establish that NR2E3 is a critical component in p53 activation and a novel susceptibility factor to drug- or toxicant-induced acute liver injuries.-Khanal, T., Leung, Y.-K., Jiang, W., Timchenko, N., Ho, S.-M., Kim, K. NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries.}, }
@article {pmid30982784, year = {2019}, author = {Marshall, TM and Dardia, GP and Colvin, KL and Nevin, R and Macrellis, J}, title = {Neurotoxicity Associated with Traumatic Brain Injury, Blast, Chemical, Heavy Metal and Quinoline Drug Exposure.}, journal = {Alternative therapies in health and medicine}, volume = {25}, number = {1}, pages = {28-34}, pmid = {30982784}, issn = {1078-6791}, mesh = {Brain Injuries, Traumatic/*chemically induced ; Cadmium ; Environmental Exposure/*adverse effects ; Environmental Pollutants/*toxicity ; Humans ; Metals, Heavy/*toxicity ; Military Personnel/*psychology ; Neurodegenerative Diseases/*chemically induced ; Quinolines/*toxicity ; Zinc ; }, abstract = {Chronic, excessive exposure, and accumulation of neurotoxic agents such as heavy metals (lead, mercury, cadmium), mefloquine (Lariam), and food additives such as monosodium glutamate and aspartame cause neurotoxicity and brain damage. This chemical-induced brain damage closely resembles the pathophysiology of classical traumatic brain injury with decreased cognitive function, neurodegeneration, and increased psychiatric manifestations (depression, anxiety, sleep disturbances, and irritability). Current evidence supports a strong causal relationship between military-related exposure to specific neurotoxins, and the development of serious medical conditions and higher rates of suicide among service members. To address this current deficit in military health care, it is recommended that efficacious, nontoxic, neuroprotective, and neuroregenerative agents such as highly bioavailable magnesium, nutritional lithium, zinc, selenium, boron, ascorbate, tocopherols, heavy metal chelators, and glutathione precursors such as N-acetyl-cysteine be immediately used as a "protective shield" and to support critical healing processes in the brain and nervous system.}, }
@article {pmid30981873, year = {2019}, author = {Lupo, N and Jalil, A and Nazir, I and Gust, R and Bernkop-Schnürch, A}, title = {In vitro evaluation of intravesical mucoadhesive self-emulsifying drug delivery systems.}, journal = {International journal of pharmaceutics}, volume = {564}, number = {}, pages = {180-187}, doi = {10.1016/j.ijpharm.2019.04.035}, pmid = {30981873}, issn = {1873-3476}, mesh = {Adhesiveness ; Administration, Intravesical ; Animals ; Cell Survival/drug effects ; Chitosan/administration &amp; dosage/*chemistry ; *Drug Delivery Systems ; Emulsions ; Mucous Membrane/chemistry ; Mucus ; Niacinamide/administration &amp; dosage/*chemistry ; Sodium Dodecyl Sulfate/administration &amp; dosage/chemistry ; Swine ; Urinary Bladder/chemistry/drug effects ; }, abstract = {Intravesical mucoadhesive self-emulsifying drug delivery system (SEDDS) have been developed via synthesis and incorporation of S-protected chitosan CS-MNA into SEDDS. N-acetyl cysteine-6-mercaptonicotinamide (NAC-6-MNA) was synthetized via disulphide exchange reaction between N-acetyl cysteine and 6-mercaptonicotinamide dimer. NAC-6-MNA was attached to chitosan (CS) via carbodiimide mediated amide bond formation. The S-protected chitosan (CS-MNA) and chitosan (CS) were complexed with sodium dodecyl sulfate (CS-SDS and CS-MNA-SDS) and incorporated in SEDDS at a concentration of 1% (m/m). SEDDS, SEDDS-CS-SDS and SEDDS-CS-MNA-SDS were characterized regarding size and zeta potential. 6-MNA release from SEDDS-CS-MNA-SDS in presence of glutathione was evaluated. Mucoadhesive properties of these novel formulations were assessed via rheology measurements and residence time evaluation on porcine bladder. Cytotoxicity of formulations was determined on porcine bladder. S-protected chitosan displayed 465.42 ± 75.64 µmol of NAC-6-MNA per gram of polymer. SEDDS and SEDDS-CS-SDS and SEDDS-CS-MNA-SDS displayed a size of 22.5 ± 0.9, 37.4 ± 0.1 and 98.5 ± 5.7 nm at a concentration of 20% (m/v) in simulated urine pH 6.2, and a zeta potential of -5.1 ± 0.2, -1.6 ± 0.1 and -1.4 ± 0.2 mV at a concentration of 1% (m/v) in water at pH 6, respectively. 80% of MNA was released from SEDDS-CS-MNA-SDS in presence of glutathione. Viscosity of SEDDS-CS-SDS/mucus and SEDDS-CS-MNA-SDS/mucus was 6- and 18-fold higher than SEDDS/mucus after 90 min incubation. 2.6%, 5.8% and 14% of SEDDS, SEDDS-CS-SDS and SEDDS-CS-MNA-SDS remained on bladder mucosa within 120 min, respectively. No pronounced bladder cytotoxicity was observed in presence of 0.5% (m/v) formulations. According to these results, SEDDS-CS-MNA-SDS might be a promising carrier for intravesical drug administration.}, }
@article {pmid30979951, year = {2019}, author = {Zamora, R and Barclay, D and Yin, J and Alonso, EM and Leonis, MA and Mi, Q and Billiar, TR and Simmons, RL and Squires, RH and Vodovotz, Y}, title = {HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {5971}, pmid = {30979951}, issn = {2045-2322}, support = {U01 DK072146/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/*adverse effects ; Adolescent ; Analgesics, Non-Narcotic/*adverse effects ; Animals ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/*metabolism ; Child ; Child, Preschool ; Cohort Studies ; Drug Overdose/metabolism ; HMGB1 Protein/genetics/*metabolism ; Hepatocytes/drug effects/metabolism ; Humans ; Infant ; Inflammation/chemically induced/metabolism ; Liver Failure, Acute/*chemically induced/*metabolism ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Primary Cell Culture ; }, abstract = {Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1-2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2-3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.}, }
@article {pmid30978175, year = {2019}, author = {Wang, Y and Li, L and Fan, LH and Jing, Y and Li, J and Ouyang, YC and Wang, ZB and Hou, Y and Sun, QY}, title = {N-acetyl-L-cysteine (NAC) delays post-ovulatory oocyte aging in mouse.}, journal = {Aging}, volume = {11}, number = {7}, pages = {2020-2030}, pmid = {30978175}, issn = {1945-4589}, mesh = {Acetylcysteine/*pharmacology ; Aging/drug effects/metabolism/pathology ; Animals ; Antioxidants/*pharmacology ; Cellular Senescence/*drug effects/physiology ; Cytoplasmic Granules/drug effects/pathology ; Female ; Mice ; Mice, Inbred ICR ; Mitochondria/drug effects/metabolism ; Oocytes/*drug effects/metabolism/pathology ; Ovulation ; Reactive Oxygen Species/metabolism ; Spindle Apparatus/drug effects/pathology ; Time-Lapse Imaging ; }, abstract = {The quality of post-ovulatory oocytes decreases with aging. In this study, we aimed to investigate the effects of N-acetyl-L-cysteine (NAC), a broadly used antioxidant, on oocyte quality in mouse post-ovulatory oocyte aging in vitro. NAC at 0.6mM concentration was added to culture medium (M2), and the quality of oocytes was analyzed at 6h, 12h, 18h and 24h of culture. We found that the frequency of spindle defects decreased in NAC-treated oocytes compared to those without NAC treatment. NAC treatment significantly decreased abnormal distribution of cortical granules (CGs) in oocytes during aging for 18h and 24h. Decreased intracellular reactive oxygen species (ROS) was also observed. Increased intracellular ATP levels and decreased abnormal distribution of mitochondria could be observed with NAC supplementation during post-ovulatory oocyte aging in vitro. These results indicate that NAC will maintain the quality of oocytes, and delay post-ovulatory oocyte aging as studied in the mouse.}, }
@article {pmid30977273, year = {2019}, author = {Visacri, MB and Quintanilha, JCF and de Sousa, VM and Amaral, LS and de F L Ambrósio, R and Calonga, L and Curi, SFBB and de T Leme, MF and Chone, CT and Altemani, JMC and Mazzola, PG and Malaguti, C and Vercesi, AE and Lima, CSP and Moriel, P}, title = {Can acetylcysteine ameliorate cisplatin-induced toxicities and oxidative stress without decreasing antitumor efficacy? A randomized, double-blind, placebo-controlled trial involving patients with head and neck cancer.}, journal = {Cancer medicine}, volume = {8}, number = {5}, pages = {2020-2030}, pmid = {30977273}, issn = {2045-7634}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Administration, Oral ; Aged ; Chemoradiotherapy/adverse effects ; Cisplatin/*adverse effects/therapeutic use ; Double-Blind Method ; Drug Administration Schedule ; Drug-Related Side Effects and Adverse Reactions/*epidemiology/prevention &amp; control ; Female ; Head and Neck Neoplasms/*therapy ; Humans ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Treatment Outcome ; }, abstract = {The protective antioxidant activity of acetylcysteine (NAC) against toxicity due to cisplatin has been reported in experimental models; however, its efficacy in patients has not been elucidated. The aim of this study was to investigate the possible protective effect of NAC on cisplatin-induced toxicity and the effect of NAC on clinical response and oxidative stress in patients treated for head and neck cancer. This was a randomized, double-blind, placebo-controlled trial conducted in patients receiving high-dose cisplatin chemotherapy concomitant to radiotherapy. Patients were randomly assigned to groups and received: (a) 600 mg NAC syrup, orally once daily at night for 7 consecutive days or (b) placebo, administered similarly to NAC. Nephro-, oto-, hepato-, myelo-, and gastrointestinal toxicities, clinical responses, and plasma and cellular markers of oxidative stress were evaluated. Fifty-seven patients were included (n = 28, NAC arm; and n = 29, placebo arm). A high prevalence of most types of toxicities was observed after cisplatin chemotherapy; however, the parameters were similar between the two groups. There was a predominance of partial response to treatment. In the cellular and plasmatic oxidative stress analyses, minor differences were observed. Overall, there was no statistically significant difference between the groups for all outcomes. These findings show that low-dose oral NAC does not protect patients with head and neck cancer from cisplatin-induced toxicities and oxidative stress. The antitumor efficacy of cisplatin was apparently not impaired by NAC.}, }
@article {pmid30976815, year = {2019}, author = {Yang, Y and Yang, CL and Zhao, ZJ and Zuo, XX and Liang, TS and Yang, Y and Ma, SL and Yang, DK}, title = {Microwave hyperthermia enhances the sensitivity of lung cancer cells to gemcitabine through reactive oxygen species‑induced autophagic death.}, journal = {Oncology reports}, volume = {41}, number = {5}, pages = {3100-3110}, doi = {10.3892/or.2019.7085}, pmid = {30976815}, issn = {1791-2431}, mesh = {Adenine/analogs &amp; derivatives/pharmacology ; Autophagy/drug effects/*radiation effects ; Carcinoma, Non-Small-Cell Lung/pathology/*therapy ; Cell Line, Tumor ; Combined Modality Therapy/methods ; Deoxycytidine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Drug Resistance, Neoplasm/radiation effects ; Humans ; Hyperthermia, Induced/*methods ; Lung Neoplasms/pathology/*therapy ; Microwaves/therapeutic use ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/radiation effects ; TOR Serine-Threonine Kinases/metabolism ; Gemcitabine ; }, abstract = {The pleiotropic effects of hyperthermia on cancer cells have been well documented, and microwave hyperthermia (MWHT) has been widely applied for multifarious cancer treatment. However, the mechanisms underlying the anticancer effect of MWHT combined with gemcitabine (GEM) remain poorly understood. The aim of the present study was to investigate the role of autophagy in the thermo‑chemotherapy of human squamous cell lung carcinoma cells. It was observed that MWHT combined with GEM potently suppressed the viability of NCI‑H2170 and NCI‑H1703 cells, and induced G0/G1 cell cycle arrest. Notably, MWHT with GEM induced autophagy, as indicated by the formation of autophagic vacuoles, downregulation of p62 and upregulation of light chain 3‑II. It was further demonstrated that the autophagy was due to the production of reactive oxygen species (ROS), whereas N‑acetyl cysteine, an ROS scavenger, attenuated the level of autophagy. However, when the autophagy inhibitor 3‑methyladenine was used, there was no significant change in the production of ROS. Furthermore, it was observed that MWHT combined with GEM downregulated the protein expression levels of phosphoinositide 3‑kinase (PI3K), phosphorylated (p)‑PI3K, protein kinase B (AKT), p‑AKT, mammalian target of rapamycin (mTOR), p‑mTOR, phosphorylated S6 (pS6) and p70 S6 kinase, which are associated with autophagy. In addition, the results demonstrated that ROS served as an upstream mediator of PI3K/AKT/mTOR signaling. In light of these findings, the present study provides original insights into the molecular mechanisms underlying the cell death induced by MWHT combined with GEM, and this may be a promising approach for the treatment of human squamous cell lung carcinoma.}, }
@article {pmid30974967, year = {2019}, author = {Cui, BW and Bai, T and Yang, Y and Zhang, Y and Jiang, M and Yang, HX and Wu, M and Liu, J and Qiao, CY and Zhan, ZY and Wu, YL and Kang, DZ and Lian, LH and Nan, JX}, title = {Thymoquinone Attenuates Acetaminophen Overdose-Induced Acute Liver Injury and Inflammation Via Regulation of JNK and AMPK Signaling Pathway.}, journal = {The American journal of Chinese medicine}, volume = {47}, number = {3}, pages = {577-594}, doi = {10.1142/S0192415X19500307}, pmid = {30974967}, issn = {1793-6853}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Acetaminophen/*administration &amp; dosage/*adverse effects ; Animals ; Apoptosis/drug effects ; Benzoquinones/*pharmacology/*therapeutic use ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/*etiology/metabolism/*prevention &amp; control ; Disease Models, Animal ; Drug Overdose/*complications ; Hepatocytes/drug effects ; Humans ; Inflammation ; MAP Kinase Signaling System/*drug effects ; Male ; Mice ; *Phytotherapy ; Signal Transduction/*drug effects ; }, abstract = {Thymoquinone (TQ) is a main aromatic component of Nigella sativa L. seeds or Agastache rugosa (Fisch. &amp; C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by acetaminophen (APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or N-acetylcysteine (NAC) before a single APAP injection. Human Chang liver cells were incubated with TQ, SP600125 or AICAR in presence of APAP for 24 h. TQ pretreatment reduced levels of serum aminotransferases and increased hepatic glutathione and glutathione peroxidase activities via inhibiting CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R protein expression and IL-1 β release. APAP-enhanced JNK phosphorylation and APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ, SP600125 and AICAR. Our findings suggest that TQ may actively prevent APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways.}, }
@article {pmid30972452, year = {2019}, author = {Ghaderi, A and Bussu, A and Tsang, C and Jafarnejad, S}, title = {Retraction Note to: Effect of N-acetyl cysteine (NAC) supplementation on positive and negative syndrome scale in schizophrenia: a systematic review and meta-analysis of randomised controlled trials.}, journal = {European journal of clinical pharmacology}, volume = {75}, number = {5}, pages = {741}, doi = {10.1007/s00228-019-02676-3}, pmid = {30972452}, issn = {1432-1041}, abstract = {The authors have retracted this article [1] because there are fundamental errors in the data presented that undermine the conclusions drawn. All authors agree with this retraction. The authors are re-analysing their data and intend to submit a new manuscript for peer review in due course.}, }
@article {pmid30971653, year = {2019}, author = {Uchihara, Y and Tago, K and Funakoshi-Tago, M}, title = {[The mechanisms of taxodione-induced apoptosis in BCR-ABL-positive leukemia cells].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {153}, number = {4}, pages = {147-154}, doi = {10.1254/fpj.153.147}, pmid = {30971653}, issn = {0015-5691}, mesh = {*Apoptosis ; Cell Line, Tumor ; Diterpenes ; Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; }, abstract = {Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are caused by a fusion protein, BCR-ABL, which induces cellular transformation by activating the signaling molecules, STAT5 and Akt. The specific BCR-ABL inhibitors including imatinib, nilotinib, and dasatinib, are clinically utilized in the treatment with CML and ALL patients. Although these BCR-ABL inhibitors are initially successful in the treatment of leukemia, many patients develop drug resistance due to the appearance of the gatekeeper mutation of BCR-ABL, T315I. Recently, we found that taxodione, a quinone methide diterpene isolated from a conifer, Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which is positive for the bcr-abl gene. Taxodione reduced the activities of mitochondrial respiratory chain complex III, leading to the production of reactive oxygen species (ROS). An antioxidant agent, N-acetylcysteine (NAC), canceled taxodione-induced ROS production and apoptotic cell death, suggesting that taxodione induced apoptosis through ROS accumulation. Furthermore, in K562 cells treated with taxodione, BCR-ABL, STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation. Strikingly, NAC canceled these taxodione-caused inhibition of BCR-ABL, STAT5 and Akt. In addition, taxodione significantly induced apoptosis in transformed Ba/F3 cells by not only BCR-ABL but also T315I-mutated BCR-ABL through the generation of ROS, suggesting that taxodione has potential as anti-tumor drug with high efficacy to overcome BCR-ABL T315I mutation-mediated resistance in leukemia cells. It's also expected that these knowledge becomes an important clue in the development of anti-cancer drugs against the broad range of tumors.}, }
@article {pmid30968460, year = {2019}, author = {Li, Y and Chen, HS and Shaheen, M and Joo, DJ and Amiot, BP and Rinaldo, P and Nyberg, SL}, title = {Cold storage of porcine hepatocyte spheroids for spheroid bioartificial liver.}, journal = {Xenotransplantation}, volume = {26}, number = {4}, pages = {e12512}, pmid = {30968460}, issn = {1399-3089}, support = {R01 DK106667/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Albumins/metabolism ; Ammonia/metabolism ; Animals ; Cryopreservation/*methods ; Deferoxamine/pharmacology ; Glucose/pharmacology ; Hepatocytes/*cytology/drug effects/metabolism ; Iron Chelating Agents/pharmacology ; *Liver, Artificial ; Mannitol/pharmacology ; Metabolic Clearance Rate ; Organ Preservation Solutions/pharmacology ; Oxidation-Reduction ; Potassium Chloride/pharmacology ; Procaine/pharmacology ; Spheroids, Cellular/*cytology/drug effects/metabolism ; Swine ; Transplantation, Heterologous ; }, abstract = {BACKGROUND AND AIMS: Cell-based therapies for liver disease such as bioartificial liver rely on a large quantity and high quality of hepatocytes. Cold storage was previously shown to be a better way to preserve the viability and functionality of hepatocytes during transportation rather than freezing, but this was only proved at a lower density of rat hepatocytes spheroids. The purpose of this study was to optimize conditions for cold storage of high density of primary porcine hepatocyte spheroids.<br><br>METHODS: Porcine hepatocytes were isolated by a three-step perfusion method; hepatocyte spheroids were formed by a 24&#xa0;hours rocked culture technique. Hepatocyte cell density was 5&#xa0;&#xd7;&#xa0;10[6] /mL in 1000&#xa0;mL spheroid forming medium. Spheroids were then maintained in rocked culture at 37&#xb0;C (control condition) or cold stored at 4&#xb0;C for 24, 48 or 72&#xa0;hours in four different cold storage solutions: histidine-tryptophan-ketoglutarate (HTK) alone; HTK&#xa0;+&#xa0;1&#xa0;mM deferoxamine (DEF); HTK&#xa0;+&#xa0;5&#xa0;mM N-acetyl-L-cysteine (NAC); and HTK&#xa0;+&#xa0;1&#xa0;mM DEF&#xa0;+&#xa0;5&#xa0;mM NAC. The viability, ammonia clearance, albumin production, gene expression, and functional activity of cytochrome P450 enzymes were measured after recovery from the cold storage.<br><br>RESULTS: In this study, we observed that cold-induced injury was reduced by the addition of the iron chelator. Viability of HTK&#xa0;+&#xa0;DEF group hepatocyte spheroids was increased compared with other cold storage groups (P&#xa0;<&#xa0;0.05). Performance metrics of porcine hepatocyte spheroids cold stored for 24&#xa0;hours were similar to those in control conditions. The hepatocyte spheroids in control conditions started to lose their ability to clear ammonia while production of albumin was still active at 48 and 72&#xa0;hours (P&#xa0;<&#xa0;0.05). In contrast, the viability and functionality of hepatocyte spheroids including ammonia clearance and albumin secretion were preserved in HTK&#xa0;+&#xa0;DEF group at both 48- and 72-hour time points (P&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: The beneficial effects of HTK supplemented with DEF were more obvious after cold storage of high density of porcine hepatocyte spheroids for 72&#xa0;hours. The porcine hepatocyte spheroids were above the cutoff criteria for use in a spheroid-based bioartificial liver.}, }
@article {pmid30966512, year = {2018}, author = {Noi, I and Schlachet, I and Kumarasamy, M and Sosnik, A}, title = {Permeability of Novel Chitosan-g-Poly(Methyl Methacrylate) Amphiphilic Nanoparticles in a Model of Small Intestine In Vitro.}, journal = {Polymers}, volume = {10}, number = {5}, pages = {}, pmid = {30966512}, issn = {2073-4360}, support = {612765-MC-NANOTAR//European Commission/ ; }, abstract = {Engineering of drug nanocarriers combining fine-tuned mucoadhesive/mucopenetrating properties is currently being investigated to ensure more efficient mucosal drug delivery. Aiming to improve the transmucosal delivery of hydrophobic drugs, we designed a novel nanogel produced by the self-assembly of amphiphilic chitosan graft copolymers ionotropically crosslinked with sodium tripolyphosphate. In this work, we synthesized, for the first time, chitosan-g-poly(methyl methacrylate) nanoparticles thiolated by the conjugation of N-acetyl cysteine. First, we confirmed that both non-crosslinked and crosslinked nanoparticles in the 0.05[-]0.1% w/v concentration range display very good cell compatibility in two cell lines that are relevant to oral delivery, Caco-2 cells that mimic the intestinal epithelium and HT29-MTX cells that are a model of mucin-producing goblet cells. Then, we evaluated the effect of crosslinking, nanoparticle concentration, and thiolation on the permeability in vitro utilizing monolayers of (i) Caco-2 and (ii) Caco-2:HT29-MTX cells (9:1 cell number ratio). Results confirmed that the ability of the nanoparticles to cross Caco-2 monolayer was affected by the crosslinking. In addition, thiolated nanoparticles interact more strongly with mucin, resulting in a decrease of the apparent permeability coefficient (Papp) compared to the pristine nanoparticles. Moreover, for all the nanoparticles, higher concentration resulted in lower Papp, suggesting that the transport pathways can undergo saturation.}, }
@article {pmid30965648, year = {2019}, author = {Park, SY and Lee, SJ and Cho, HJ and Kim, JT and Yoon, HR and Lee, KH and Kim, BY and Lee, Y and Lee, HG}, title = {Epsilon-Globin HBE1 Enhances Radiotherapy Resistance by Down-Regulating BCL11A in Colorectal Cancer Cells.}, journal = {Cancers}, volume = {11}, number = {4}, pages = {}, pmid = {30965648}, issn = {2072-6694}, abstract = {Resistance to radiotherapy is considered an important obstacle in the treatment of colorectal cancer. However, the mechanisms that enable tumor cells to tolerate the effects of radiation remain unclear. Moreover, radiotherapy causes accumulated mutations in transcription factors, which can lead to changes in gene expression and radiosensitivity. This phenomenon reduces the effectiveness of radiation therapy towards cancer cells. In the present study, radiation-resistant (RR) cancer cells were established by sequential radiation exposure, and hemoglobin subunit epsilon 1 (HBE1) was identified as a candidate radiation resistance-associated protein based on RNA-sequencing analysis. Then, compared to radiosensitive (RS) cell lines, the overexpression of HBE1 in RR cell lines was used to measure various forms of radiation-induced cellular damage. Consequently, HBE1-overexpressing cell lines were found to exhibit decreased radiation-induced intracellular reactive oxygen species (ROS) production and cell mortality. Conversely, HBE1 deficiency in RR cell lines increased intracellular ROS production, G2/M arrest, and apoptosis, and decreased clonogenic survival rate. These effects were reversed by the ROS scavenger N-acetyl cysteine. Moreover, HBE1 overexpression was found to attenuate radiation-induced endoplasmic reticulum stress and apoptosis via an inositol-requiring enzyme 1(IRE1)-Jun amino-terminal kinase (JNK) signaling pathway. In addition, increased HBE1 expression induced by γ-irradiation in RS cells attenuated expression of the transcriptional regulator BCL11A, whereas its depletion in RR cells increased BCL11A expression. Collectively, these observations indicate that the expression of HBE1 during radiotherapy might potentiate the survival of radiation-exposed colorectal cancer cells.}, }
@article {pmid30959771, year = {2019}, author = {Armstrong, JA and Cash, NJ and Morton, JC and Tepikin, AV and Sutton, R and Criddle, DN}, title = {Mitochondrial Targeting of Antioxidants Alters Pancreatic Acinar Cell Bioenergetics and Determines Cell Fate.}, journal = {International journal of molecular sciences}, volume = {20}, number = {7}, pages = {}, pmid = {30959771}, issn = {1422-0067}, support = {EME/15/20/01/DH_/Department of Health/United Kingdom ; MR/N011384/1/MRC_/Medical Research Council/United Kingdom ; 102381/Z/13/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Acinar Cells/drug effects/*metabolism ; Adenosine Triphosphate/biosynthesis ; Animals ; Antioxidants/*metabolism ; Cell Death/drug effects ; *Cell Lineage/drug effects ; Cell Survival/drug effects ; *Energy Metabolism/drug effects ; Flavin-Adenine Dinucleotide/metabolism ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; NAD/metabolism ; Onium Compounds/pharmacology ; Organophosphorus Compounds/pharmacology ; Oxidation-Reduction ; Pancreas/*cytology ; Ubiquinone/analogs &amp; derivatives/pharmacology ; }, abstract = {Mitochondrial dysfunction is a core feature of acute pancreatitis, a severe disease in which oxidative stress is elevated. Mitochondrial targeting of antioxidants is a potential therapeutic strategy for this and other diseases, although thus far mixed results have been reported. We investigated the effects of mitochondrial targeting with the antioxidant MitoQ on pancreatic acinar cell bioenergetics, adenosine triphosphate (ATP) production and cell fate, in comparison with the non-antioxidant control decyltriphenylphosphonium bromide (DecylTPP) and general antioxidant N-acetylcysteine (NAC). MitoQ (µM range) and NAC (mM range) caused sustained elevations of basal respiration and the inhibition of spare respiratory capacity, which was attributable to an antioxidant action since these effects were minimal with DecylTPP. Although MitoQ but not DecylTPP decreased cellular NADH levels, mitochondrial ATP turnover capacity and cellular ATP concentrations were markedly reduced by both MitoQ and DecylTPP, indicating a non-specific effect of mitochondrial targeting. All three compounds were associated with a compensatory elevation of glycolysis and concentration-dependent increases in acinar cell apoptosis and necrosis. These data suggest that reactive oxygen species (ROS) contribute a significant negative feedback control of basal cellular metabolism. Mitochondrial targeting using positively charged molecules that insert into the inner mitochondrial member appears to be deleterious in pancreatic acinar cells, as does an antioxidant strategy for the treatment of acute pancreatitis.}, }
@article {pmid30959503, year = {2019}, author = {Sosinska-Zawierucha, P and Mackowiak, B and Breborowicz, A}, title = {N-Acetylcysteine and Sulodexide Reduce the Prothrombotic Effect of Uremic Serum on the Venous Endothelial Cells.}, journal = {Kidney &amp; blood pressure research}, volume = {44}, number = {2}, pages = {277-285}, doi = {10.1159/000499879}, pmid = {30959503}, issn = {1423-0143}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Anticoagulants ; Blood Specimen Collection ; Cells, Cultured ; Endothelial Cells/drug effects ; Endothelium, Vascular/*cytology/drug effects ; Female ; Free Radical Scavengers ; Glycosaminoglycans/*pharmacology/therapeutic use ; Humans ; Kidney Failure, Chronic/blood/complications/*drug therapy ; Male ; Thrombosis/*prevention &amp; control ; Uremia/*blood/drug therapy ; }, abstract = {BACKGROUND/AIMS: Thromboembolic episodes are a frequent problem in end stage renal failure patients. The pathomechanism of the disorder is complex, including bioincompatibility of renal replacement therapy, endothelial dysfunction, increased blood level of procoagulant factors and uremic toxins. We studied changes in the functional properties of venous endothelial cells (VEC) in the presence of uremic serum and evaluated their possible modulation by N-acetylcysteine (NAC) or sulodexide (SUL).<br><br>METHODS: Serum samples from 12 uremic patients treated with hemodialysis were studied ex vivo on in vitro cultured VEC. In separate experiments, NAC 1 mmol/L or SUL 0.5 LRU/mL were added to uremic serum samples. Both changes in the gene expression and secretory activity of VEC were studied.<br><br>RESULTS: Uremic serum increased the expression of the following genes: IL6 +97%, p < 0.002; VEGF +28%, p < 0.002; vWF +47%, p < 0.002; PECAM +76%, p < 0.002; ICAM-1 +275%, p < 0.002; t-PA +96%, p < 0.002. Changes in gene expression were reflected by the increased secretory activity of VEC treated with the uremic serum. Exposure of VEC to uremic serum supplemented with NAC or SUL resulted in weaker stimulation of the studied genes' expression. Also, secretion of the studied solutes, with the exception of ICAM-1, was reduced in the presence of NAC: IL6 -34%, p < 0.01; VEGF -40%, p < 0.005; vWF -25%, p < 0.001; t-PA -47%, p < 0.01, and MMP9 -37%, p < 0.001. SUL reduced the uremic serum-induced secretion of all solutes: IL6 -24%, p < 0.05; ICAM-1 -43%, p < 0.01; VEGF -38%, p < 0.01; vWF -23%, p < 0.01; t-PA -49%, p < 0.01, and MMP9 -25%, p < 0.05.<br><br>CONCLUSIONS: Uremic serum induces prothrombotic changes in VEC, which may cause a predisposition to thrombotic disorders in patients with renal failure. NAC and SUL reduce the effects of the uremic serum in VEC, which suggests their potential therapeutic application in uremic patients.}, }
@article {pmid30959453, year = {2019}, author = {Liu, X and Tang, J and Wang, L and Giesy, JP}, title = {Al2O3 nanoparticles promote secretion of antibiotics in Streptomyces coelicolor by regulating gene expression through the nano effect.}, journal = {Chemosphere}, volume = {226}, number = {}, pages = {687-695}, doi = {10.1016/j.chemosphere.2019.03.156}, pmid = {30959453}, issn = {1879-1298}, mesh = {Anti-Bacterial Agents/*metabolism ; Gene Expression/*genetics ; Nanoparticles/*chemistry ; Streptomyces coelicolor/*chemistry ; }, abstract = {Toxic effects of nanoparticles (NPs) on microorganisms have attracted substantial attention; however, there are few reports on whether NPs can affect the secondary metabolism of microbes. To investigate the toxic effects of Al2O3 NPs on cell growth and antibiotic secretion, Streptomyces coelicolor M145 was exposed to Al2O3 NPs with diameters of 30 and 80 nm and bulk Al2O3 at concentrations up to 1000 mg/L. The results indicated that differences in the toxicity of Al2O3 NPs were related to the particle size. In treatment with Al2O3 NPs, the maximum yields of undecylprodigiosin (RED) and actinorhodin (ACT) were 3.7- and 4.6-fold greater than that of the control, respectively, and the initial time of antibiotic production was much shorter. ROS quenching experiment by N-acetylcysteine (NAC) confirmed that ROS were responsible for the increased RED production. From 0 to 72 h, ROS had a significant impact on ACT production; however, after 72 h, the ROS content began to decrease until it disappeared. During ongoing exposure (0-144 h), ACT production continued to increase, indicating that in addition to ROS, nano effect of Al2O3 NPs also played roles in this process. Transcriptional analysis demonstrated that Al2O3 NPs could increase the expression levels of antibiotic biosynthetic genes and two-component systems (TCSs) and inhibit the expression levels of primary metabolic pathways. This study provides a new perspective for understanding the mechanisms of antibiotic production in nature and reveals important implications for exploring other uses of NPs in biomedical applications or regulation of antibiotics in nature.}, }
@article {pmid30957679, year = {2019}, author = {Morsch, ALBC and Wisniewski, E and Luciano, TF and Comin, VH and Silveira, GB and Marques, SO and Thirupathi, A and Silveira Lock, PC and De Souza, CT}, title = {Cigarette smoke exposure induces ROS-mediated autophagy by regulating sestrin, AMPK, and mTOR level in mice.}, journal = {Redox report : communications in free radical research}, volume = {24}, number = {1}, pages = {27-33}, pmid = {30957679}, issn = {1743-2928}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Autophagy/*drug effects ; Blotting, Western ; Cell Cycle Proteins/*metabolism ; Cigarette Smoking/*adverse effects ; Electrophoresis, Polyacrylamide Gel ; Male ; Mice ; Oxidative Stress/*drug effects ; Peroxidases/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Many pathological conditions linked to cigarette smoking are caused by the production of reactive oxygen species (ROS). The present study was conducted to analyze the effect of ROS on the lungs of Swiss mice exposed to cigarette smoking, focusing on autophagy-mediated mechanisms, and investigate the involvement of SESN2, AMPK, and mTOR signaling. Mice were exposed to cigarette smoke (CS) for 7, 15, 30, 45, and 60 days; the control group was not exposed to CS. Only mice exposed to CS for 45 days were selected for subsequent N-acetylcysteine (NAC) supplementation and smoke cessation analyses. Exposure to CS increased the production of ROS and induced molecular changes in the autophagy pathway, including an increase in phosphorylated AMPK and ULK1, reduction in phosphorylated mTOR, and increases in SESN2, ATG12, and LC3B levels. NAC supplementation reduced ROS levels and reversed all molecular changes observed upon CS treatment, suggesting the involvement of oxidative stress in inducing autophagy upon CS exposure. When exposure to CS was stopped, there were decreases in the levels of oxidative stress, AMPK and ULK1 phosphorylation, and autophagy-initiating molecules and increase in mTOR phosphorylation. In conclusion, these results suggest the involvement of ROS, SESN2, AMPK, and mTOR in the CS-induced autophagic process in the lung.}, }
@article {pmid30956824, year = {2019}, author = {Kiernan, EA and Fritzges, JA and Henry, KA and Katz, KD}, title = {A Case Report of Massive Acetaminophen Poisoning Treated with a Novel "Triple Therapy": N-Acetylcysteine, 4-Methylpyrazole, and Hemodialysis.}, journal = {Case reports in emergency medicine}, volume = {2019}, number = {}, pages = {9301432}, pmid = {30956824}, issn = {2090-648X}, abstract = {Massive acetaminophen (N-acetyl-p-aminophenol; APAP) ingestion is characterized by a rapid onset of mitochondrial dysfunction, including metabolic acidosis, lactemia, and altered mental status without hepatotoxicity which may not respond to the standard doses of N-acetylcysteine (NAC). A 64-year-old woman without medical history presented comatose after an ingestion of 208 tablets of Tylenol PM™ (APAP 500 mg and diphenhydramine 25 mg). The initial APAP concentration measured 1,017 µg/mL (therapeutic range 10-30 µg/mL), and elevated anion gap metabolic acidosis, lactemia, and 5-oxoprolinemia were detected. High-dose intravenous (IV) NAC, 4-methylpyrazole (4-MP), and hemodialysis (HD) were initiated. She was transferred to a liver transplant center and continued both NAC and HD therapies until complete resolution of metabolic acidosis and coma without developing hepatitis. She was discharged without sequelae. This is the fourth highest APAP concentration recorded in a surviving patient. Moreover, this is the first report of a novel "triple therapy" using NAC, 4-MP, and HD in the setting of massive APAP ingestion that presents with coma, elevated anion gap metabolic acidosis, and lactemia. Emergency physicians should recognize these critically ill patients and consider high-dose NAC, 4-MP, and HD to be initiated in the emergency department (ED).}, }
@article {pmid30956169, year = {2019}, author = {Zhang, Z and Dawson, PA and Piper, M and Simmons, DG}, title = {Postnatal N-acetylcysteine administration rescues impaired social behaviors and neurogenesis in Slc13a4 haploinsufficient mice.}, journal = {EBioMedicine}, volume = {43}, number = {}, pages = {435-446}, pmid = {30956169}, issn = {2352-3964}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Animals, Newborn ; *Behavior, Animal ; Brain/metabolism/physiopathology ; Disease Models, Animal ; Female ; Gene Expression ; Genotype ; *Haploinsufficiency ; Male ; Maze Learning ; Memory ; Mice ; Mice, Transgenic ; Neurogenesis/*drug effects/*genetics ; Phenotype ; *Social Behavior ; Sulfate Transporters/*genetics/metabolism ; Symporters/*genetics/metabolism ; }, abstract = {BACKGROUND: Sulfate availability is crucial for the sulfonation of brain extracellular matrix constituents, membrane phospholipids, neurosteroids, and neurotransmitters. Observations from humans and mouse models suggest dysregulated sulfate levels may be associated with neurodevelopmental disorders, such as autism. However, the cellular mechanisms governing sulfate homeostasis within the developing or adult brain are not fully understood.<br><br>METHODS: We utilized a mouse model with a conditional allele for the sulfate transporter Slc13a4, and a battery of behavioral tests, to assess the effects of disrupted sulfate transport on maternal behaviors, social interactions, memory, olfaction, exploratory behavior, anxiety, stress, and metabolism. Immunohistochemistry examined neurogenesis within the stem cells niches.<br><br>FINDINGS: The sulfate transporter Slc13a4 plays a critical role in postnatal brain development. Slc13a4 haploinsufficiency results in significant behavioral phenotypes in adult mice, notably impairments in social interaction and long-term memory, as well as increased neurogenesis in the subventricular stem cell niche. Conditional gene deletion shows these phenotypes have a developmental origin, and that full biallelic expression of Slc13a4 is required only in postnatal development. Furthermore, administration of N-acetylcysteine (NAC) within postnatal window P14-P30 prevents the onset of phenotypes in adult Slc13a4[+/-] mice.<br><br>INTERPRETATION: Slc13a4 haploinsufficient mice highlight a requirement for adequate sulfate supply in postnatal development for the maturation of important social interaction and memory pathways. With evidence suggesting dysregulated sulfate biology may be a feature of some neurodevelopmental disorders, the utility of sulfate levels as a biomarker of disease and NAC administration as an early preventative measure should be further explored.}, }
@article {pmid30956032, year = {2019}, author = {Lan, CE and Hung, YT and Fang, AH and Ching-Shuang, W}, title = {Effects of irradiance on UVA-induced skin aging.}, journal = {Journal of dermatological science}, volume = {94}, number = {1}, pages = {220-228}, doi = {10.1016/j.jdermsci.2019.03.005}, pmid = {30956032}, issn = {1873-569X}, mesh = {Animals ; Dose-Response Relationship, Radiation ; Elasticity/radiation effects ; Fibroblasts/metabolism/radiation effects ; Humans ; Matrix Metalloproteinase 1/metabolism ; Mice ; Mice, Hairless ; Models, Animal ; Reactive Oxygen Species/metabolism ; Skin/cytology/metabolism/*radiation effects ; Skin Aging/drug effects/*radiation effects ; Sunscreening Agents/administration &amp; dosage ; Time Factors ; Ultraviolet Rays/*adverse effects ; }, abstract = {BACKGROUND: Ultraviolet A (UVA) radiation is the most relevant component of solar radiation-induced skin aging. Sunscreens were used to minimize the harmful effects of UV radiation on our skin by reducing UV irradiance. We previously found that at equivalent fluence, UVB radiation at low irradiance (LI) has higher photocarcinogenic potential as compared to its high irradiance (HI) counterpart.<br><br>OBJECTIVES: To examine the effects of equivalent fluence of UVA radiation administered at different irradiance on photoaging.<br><br>METHODS: Both the hairless mice (SKH-1) and human dermal fibroblasts were irradiated with high irradiance UVA (HIUVA) or low irradiance UVA (LIUVA; 50% irradiance of HIUVA) at equivalent fluence. Parameters related to skin photoaging were evaluated.<br><br>RESULTS: For hairless mice receiving equivalent fluence of UVA radiation, LIUVA treated mice showed prominent skin aging as compared to its HIUVA treated counterpart. In addition, LIUVA radiation induced higher reactive oxygen species (ROS) production and c-Jun N-terminal kinases (JNK) phosphorylation as compared to their HIUVA treated counterparts. Pretreatment with N-acetylcysteine (NAC) abrogate the difference between HI and LIUVA radiation on fibroblasts in terms of intracellular ROS, JNK phosphorylation, MMP-1 expression and type I collagen expression.<br><br>CONCLUSION: UVA radiation administered at LI (a scenario similar to sunscreen use) led to more severe aging process as compared to its HI counterpart. Unexpected negative effect may be imposed on the skin if sunscreen use is accompanied by longer duration spent under the sun.}, }
@article {pmid30953354, year = {2019}, author = {Dong, Q and Li, S and Wang, W and Han, L and Xia, Z and Wu, Y and Tang, Y and Li, J and Cheng, X}, title = {FGF23 regulates atrial fibrosis in atrial fibrillation by mediating the STAT3 and SMAD3 pathways.}, journal = {Journal of cellular physiology}, volume = {234}, number = {11}, pages = {19502-19510}, doi = {10.1002/jcp.28548}, pmid = {30953354}, issn = {1097-4652}, mesh = {Actins/genetics ; Atrial Fibrillation/*genetics/physiopathology/surgery ; Collagen Type I/genetics ; Female ; Fibroblast Growth Factor-23 ; Fibroblast Growth Factors/*genetics ; Fibroblasts/metabolism/pathology ; Fibrosis/*genetics/physiopathology/surgery ; Gene Expression Regulation/genetics ; Heart Atria/metabolism/physiopathology/surgery ; Humans ; Male ; Reactive Oxygen Species/metabolism ; Rheumatic Heart Disease/genetics/physiopathology/surgery ; STAT3 Transcription Factor/*genetics ; Signal Transduction ; Smad3 Protein/*genetics ; }, abstract = {High fibroblast growth factor 23 (FGF23) concentrations are a strong predictor of atrial fibrillation (AF), but researchers have not clearly determined the mechanism by which FGF23 causes atrial fibrosis in patients with AF. This study aims to elucidate the mechanism by which FGF23 induces atrial fibrosis in patients with AF. Immunohistochemistry was used to study the expression of FGF23, FGFR4, and fibrotic factors in patients with a normal sinus rhythm (SR) and patients with AF. Cardiac fibroblasts (CFs) were cocultured with different concentrations of the recombinant FGF23 protein. Compared with the SR group, the levels of FGF23, FGFR4, α-smooth muscle actin (α-SMA), and collagen-1 were significantly increased in the AF group. Exposure to high concentrations of the recombinant FGF23 protein increased the accumulation of reactive oxygen species (ROS) and activated α-SMA, collagen-1, signal transducer and activator of transcription 3 (STAT3) and SMAD3 signaling in cultured CFs. The levels of fibrotic proteins in CFs stimulated with high concentrations of the recombinant FGF23 protein were reversed by N-acetylcysteine (NAC, a ROS inhibitor), ship information system 3 (a SMAD3 inhibitor), and Stattic (a STAT3 inhibitor). Furthermore, compared to untreated CFs, CFs treated with the recombinant FGF23 protein were characterized by an increased interaction between STAT3 and SMAD3. Based on these results, FGF23 induces atrial fibrosis in patients with AF by increasing ROS production and subsequently activating STAT3 and SMAD3 signaling.}, }
@article {pmid30951973, year = {2019}, author = {Delgobo, M and Agnes, JP and Gonçalves, RM and Dos Santos, VW and Parisotto, EB and Zamoner, A and Zanotto-Filho, A}, title = {N-acetylcysteine and alpha-lipoic acid improve antioxidant defenses and decrease oxidative stress, inflammation and serum lipid levels in ovariectomized rats via estrogen-independent mechanisms.}, journal = {The Journal of nutritional biochemistry}, volume = {67}, number = {}, pages = {190-200}, doi = {10.1016/j.jnutbio.2019.02.012}, pmid = {30951973}, issn = {1873-4847}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Cytokines/metabolism ; Dietary Supplements ; Estrogens/metabolism ; Female ; Glutathione/metabolism ; Inflammation/*drug therapy/metabolism ; Lipids/*blood ; NF-E2-Related Factor 2/metabolism ; Ovariectomy ; Oxidative Stress/*drug effects ; Rats, Wistar ; Thioctic Acid/*pharmacology ; }, abstract = {Sexual hormone deficiency has been associated with metabolic changes, oxidative stress and subclinical inflammation in postmenopausal women. Hormone replacement therapies are effective in many instances, even though some patients either do not respond or are not eligible. The aim of this study was to evaluate the impact of short- (15 days) versus long-term (60 days) sexual hormone depletion and whether antioxidant supplementation with N-acetylcysteine (NAC) and alpha-lipoic acid (LA) improves oxidative stress, metabolic, and inflammatory parameters in ovariectomized (OVX) rats. Short-term OVX rapidly depleted circulating estrogen, causing uterine atrophy and body weight gain without affecting oxidative damage, inflammatory and lipid metabolism markers. In contrast, long-term OVX augmented oxidative damage in serum and peripheral tissues as well as increased serum total cholesterol, TNF-α and IL6 levels. Triglycerides, glucose and HDL cholesterol were not altered. Long-term OVX-induced oxidative stress was associated with depletion of GSH and total non-enzymatic antioxidants as well as decreased activity of Glutathione Peroxidase (GPx) and Glutathione Reductase (GR), but not Superoxide Dismutase (SOD) and Catalase (CAT). NAC and LA supplementation prevented GSH and total non-enzymatic antioxidants depletion as well as restored GPx and GR activities, TNF-α, IL6 and cholesterol in OVX rats. NAC and LA effects appear to be independent on NRF2 activation and estrogen-like activity, since NAC/LA did not promote NRF2 activation and were not able to emulate estrogen effects in OVX rats and estrogen-receptor-positive cells. The herein presented data suggest that NAC and LA may improve some deleterious effects of sexual hormone depletion via estrogen-independent mechanisms.}, }
@article {pmid30951941, year = {2019}, author = {Zhang, Y and Wang, X and Chen, C and An, J and Shang, Y and Li, H and Xia, H and Yu, J and Wang, C and Liu, Y and Guo, S}, title = {Regulation of TBBPA-induced oxidative stress on mitochondrial apoptosis in L02 cells through the Nrf2 signaling pathway.}, journal = {Chemosphere}, volume = {226}, number = {}, pages = {463-471}, doi = {10.1016/j.chemosphere.2019.03.167}, pmid = {30951941}, issn = {1879-1298}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caspase 3/biosynthesis ; Caspase 9/biosynthesis ; Catalase/metabolism ; Cell Line ; Cytochromes c/metabolism ; Flame Retardants/*toxicity ; Glutathione/metabolism ; Heme Oxygenase-1/biosynthesis/genetics ; Hepatocytes/drug effects ; Humans ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*metabolism ; NAD(P)H Dehydrogenase (Quinone)/biosynthesis ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress/*drug effects ; Polybrominated Biphenyls/*toxicity ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Tetrabromobisphenol A (TBBPA) is a commonly used brominated flame retardant, which has a wide range of toxic effects on organisms. This study investigated the cytotoxic effects on human hepatocytes (L02 cells) after treated with 0, 5, 10, 20, and 40 μM of TBBPA. Results showed that TBBPA significantly increased intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and the ratio of oxidized/reduced glutathione (GSSG/GSH) dose-dependently. TBBPA also decreased the cell mitochondrial membrane potential (MMP), caused the release of cytochrome C (Cyt C) to cytoplasm and promoted the expression of caspase-9 and caspase-3, and finally increased the level of apoptosis. The ROS inhibitor N-acetyl-L-cysteine (NAC) relieved the oxidative stress responses, and prevented the decrease of MMP and increase of apoptosis. In addition, TBBPA promoted the expression of antioxidant genes related to Nrf2, such as quinone oxidoreductase 1 (NQO1), catalase (CAT), and heme oxygenase 1 (HO-1). Oxidative stress initiated by TBBPA, activated mitochondrial apoptosis and Nrf2 pathway, and increased the degree of apoptosis in L02 cells.}, }
@article {pmid30949204, year = {2019}, author = {Bisht, S and Nolting, J and Wenzel, J and Brossart, P and Feldmann, G}, title = {EF24 Suppresses Cholangiocellular Carcinoma Progression, Inhibits STAT3 Phosphorylation, and Induces Apoptosis via ROS-Mediated Oxidative Stress.}, journal = {Journal of oncology}, volume = {2019}, number = {}, pages = {8701824}, pmid = {30949204}, issn = {1687-8450}, abstract = {Therapeutic options for advanced stage cholangiocellular carcinoma (CCC) are very limited as of today and patients carry an exceptionally poor overall prognosis. In recent years, increasing evidence has been accumulated to suggest that malignant cells widely show increased intrinsic ROS levels and exhibit altered redox profiles as compared to normal counterparts, opening up potential avenues for therapeutic intervention. This study provides preclinical experimental evidence of therapeutic activity of the curcumin analog EF24 in cholangiocarcinoma models. In CCC cell lines, EF24 inhibited cell viability and induced apoptosis through excessive ROS generation. Moreover, administration of EF24 led to depletion of total intracellular GSH levels, induced mitochondrial depolarization, and abrogated STAT3 phosphorylation. Of interest, these effects were readily averted by treating the cells with exogenous antioxidants such as N-acetyl cysteine (NAC) or glutathione monoethyl ester (GEE). In vivo, EF24, solubilized using a cyclodextrin formulation, significantly suppressed the growth of tumor xenografts without exhibiting any toxic adverse effects. Immunohistochemical analysis of extracted tumor tissues demonstrated reduced nuclear staining for Ki-67 and downregulation of phospho-STAT3 as well as strong staining for oxidative stress biomarker 8-OHdG. Therefore, the data presented here suggest EF24 as potential therapeutic compound against CCC which might act at least to some extent through ROS-induced oxidative damage, subsequently inducing apoptosis. Further evaluation of this approach should be carried out in future follow-up studies.}, }
@article {pmid30948926, year = {2019}, author = {Zou, Z and Liu, B and Zeng, L and Yang, X and Huang, R and Wu, C and Zhu, H and Gao, Y and Yuan, D and Yu, J}, title = {Cx43 Inhibition Attenuates Sepsis-Induced Intestinal Injury via Downregulating ROS Transfer and the Activation of the JNK1/Sirt1/FoxO3a Signaling Pathway.}, journal = {Mediators of inflammation}, volume = {2019}, number = {}, pages = {7854389}, pmid = {30948926}, issn = {1466-1861}, mesh = {Animals ; Connexin 43/antagonists &amp; inhibitors/genetics/*metabolism ; Forkhead Box Protein O3/*metabolism ; Glycyrrhetinic Acid/analogs &amp; derivatives/pharmacology ; Intestinal Mucosa/drug effects/metabolism ; Intestines/*injuries ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Male ; Oleic Acids/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sepsis/*complications/drug therapy ; Sirtuin 1/*metabolism ; }, abstract = {Intestinal injury has long been considered to play a crucial role in the pathophysiology of sepsis and has even been characterized as the "motor" of it. Thus, we explored the effects of connexin43 (Cx43) on sepsis-induced intestinal injury in order to provide potential therapeutic strategies. Rat cecal ligation and puncture (CLP) models in vivo and cell models (IEC-6 cells) pretreated with LPS in vitro were used in the current study. Firstly, different methods, such as Cx43 inhibitors (18-α-GA and oleamide) or siRNA targeting Cx43 and N-acetyl cysteine (NAC) (a kind of ROS scavenger), were used to observe the effects of Cx43 channels mediating ROS transfer on intestinal injury. Secondly, the influence of ROS content on the activity of the JNK1/Sirt1/FoxO3a signaling pathway was explored through the application of NAC, sp600125 (a JNK1 inhibitor), and nicotinamide (a Sirt1 inhibitor). Finally, luciferase assays and ChIP were used to determine the direct regulation of FoxO3a on proapoptotic proteins, Bim and Puma. The results showed that sepsis-induced intestinal injury presented a dynamic change, coincident with the alternation of Cx43 expression. The inhibition of Cx43 attenuated CLP-induced intestinal injury in vivo and LPS-induced IEC-6 injury in vitro. The changes of Cx43 channel function regulated ROS transfer between the neighboring cells, which mediated the activation of the JNK1/Sirt1/FoxO3a signaling pathway. FoxO3a directly affected its downstream target genes, Bim and Puma, which are responsible for cell or tissue apoptosis. In summary, our results suggest that Cx43 inhibition suppresses ROS transfer and inactivates the JNK1/Sirt1/FoxO3a signaling pathway to protect against sepsis-induced intestinal injury.}, }
@article {pmid30946939, year = {2019}, author = {Mocelin, R and Marcon, M and da Rosa Araujo, AS and Herrmann, AP and Piato, A}, title = {Withdrawal effects following repeated ethanol exposure are prevented by N-acetylcysteine in zebrafish.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {93}, number = {}, pages = {161-170}, doi = {10.1016/j.pnpbp.2019.03.014}, pmid = {30946939}, issn = {1878-4216}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anxiety/chemically induced/prevention &amp; control ; Brain/drug effects/metabolism ; Catalase/metabolism ; Disease Models, Animal ; Ethanol/*adverse effects ; Female ; Lipid Peroxidation/drug effects ; Male ; Oxidative Stress/drug effects ; Substance Withdrawal Syndrome/*prevention &amp; control ; Superoxide Dismutase/metabolism ; Zebrafish ; }, abstract = {Alcohol abuse is a highly prevalent condition that substantially contributes to global morbidity and mortality. Most available pharmacological treatments offer little efficacy as relapse rates are high, due in part to the symptoms experienced during abstinence. The roles of oxidative stress and glutamatergic transmission in alcohol withdrawal have been demonstrated in several studies, suggesting that restoration of oxidative status and glutamatergic function may represent a new pharmacological target to prevent the behavioral and biochemical alterations observed during withdrawal. A well-known antioxidant and glutamatergic modulator, N-acetylcysteine (NAC), has shown promise in treating a variety of psychiatric conditions, including substance use disorders, and is a promising molecule in the management of alcohol withdrawal syndrome. Thus, the aim of this study was to investigate whether NAC is able to prevent the expression of behavioral and biochemical alterations induced by ethanol withdrawal in chronically exposed zebrafish. Animals were exposed to ethanol (1% v/v, 20 min) or control water, followed by treatment with NAC (1 mg/L, 10 min) or control water daily for 8 days; 24 h later, experimental animals were submitted to the novel tank test (NTT). Ethanol withdrawal decreased the distance traveled and increased the number of immobile episodes, indicating locomotor deficits; moreover, withdrawal decreased the number of entries and time spent in the top area, while increasing time spent in the bottom area, indicating anxiety-like behavior. Alcohol withdrawal also increased lipid peroxidation (TBARS) and decreased non-protein reduced sulfhydryl (NPSH) and superoxide dismutase (SOD) and catalase (CAT) activities. NAC attenuated these locomotor deficits and prevented the manifestation of anxiety-like behavior as well as the oxidative damage observed following ethanol withdrawal. Given its favorable safety profile, additional clinical and preclinical studies are warranted to unravel the long-term effects of NAC in the context of alcohol abuse and the exact mechanisms involved. Nevertheless, our study adds to the existing body of evidence supporting the clinical evaluation of NAC in substance abuse disorders.}, }
@article {pmid30930285, year = {2019}, author = {Boyman, L and Coleman, AK and Zhao, G and Wescott, AP and Joca, HC and Greiser, BM and Karbowski, M and Ward, CW and Lederer, WJ}, title = {Dynamics of the mitochondrial permeability transition pore: Transient and permanent opening events.}, journal = {Archives of biochemistry and biophysics}, volume = {666}, number = {}, pages = {31-39}, pmid = {30930285}, issn = {1096-0384}, support = {R01 HL105239/HL/NHLBI NIH HHS/United States ; T32 GM008181/GM/NIGMS NIH HHS/United States ; U01 HL116321/HL/NHLBI NIH HHS/United States ; R01 HL142290/HL/NHLBI NIH HHS/United States ; T32 AR007592/AR/NIAMS NIH HHS/United States ; R01 AR063631/AR/NIAMS NIH HHS/United States ; R01 AR071618/AR/NIAMS NIH HHS/United States ; R01 HL106059/HL/NHLBI NIH HHS/United States ; R01 AR071614/AR/NIAMS NIH HHS/United States ; T32 GM092237/GM/NIGMS NIH HHS/United States ; R01 MH106056/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Heart Ventricles/cytology/metabolism ; Membrane Potential, Mitochondrial ; Mitochondria, Heart/*metabolism ; Mitochondrial Membrane Transport Proteins/*physiology ; Mitochondrial Permeability Transition Pore ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {A gentle optical examination of the mitochondrial permeability transition pore (mPTP) opening events was carried out in isolated quiescent ventricular myocytes by tracking the inner membrane potential (ΔΨM) using TMRM (tetramethylrhodamine methyl ester). Zeiss Airyscan 880 ″super-resolution" or "high-resolution" imaging was done with very low levels of illumination (0.009% laser power). In cellular areas imaged every 9 s (ROI or regions of interest), transient depolarizations of variable amplitudes occurred at increasing rates for the first 30 min. The time to first depolarization events was 8.4 min (±1.1 SEM n = 21 cells). At longer times, essentially permanent and irreversible depolarizations occurred at an increasing fraction of all events. In other cellular areas surrounding the ROI, mitochondria were rarely illuminated (once per 5 min) and virtually no permanent depolarization events occurred for over 1 h of imaging. These findings suggest that photon stress due to the imaging itself plays an important role in the generation of both the transient mPTP opening events as well as the permanent mPTP opening events. Consistent with the evidence that photon "stress" in mitochondria loaded with virtually any photon absorbing substance, generates reactive oxygen species (ROS) [1-5], we show that cyclosporine-A (CsA, 10 μM) and the antioxidant n-acetyl cysteine (NAC, 10 mM), reduced the number of events by 80% and 93% respectively. Furthermore, CsA and NAC treatment led to the virtual disappearance of permanent depolarization events. Nevertheless, all transient depolarization events in any condition (control, CsA and NAC) appeared to repolarize with a similar half-time of 30 ± 6 s (n = 478) at 37 °C. Further experiments showed quantitatively similar results in cerebral vascular smooth muscle cells, using a different confocal system, and different photon absorbing reagent (TMRE; tetramethylrhodamine ethyl ester). In these experiments, using modest power (1% laser power) transient depolarization events were seen in only 8 out of 23 cells while with higher power (8%), all cells showed transient events, which align with the level of photon stress being the driver of the effect. Together, our findings suggest that photon-induced ROS is sufficient to cause depolarization events of individual mitochondria in quiescent cells; without electrical or mechanical activity to stimulates mitochondrial metabolism, and without raising the mitochondrial matrix Ca[2+]. In a broad context, these findings neither support nor deny the relevance or occurrence of ΔΨM depolarization events in specific putatively physiologic mitochondrial behaviors such as MitoFlashes [6,7] or MitoWinks [8]. Instead, our findings raise a caution with regards to the physiological and pathophysiological functions attributed to singular ΔΨM depolarization events when those functions are investigated using photon absorbing substances. Nevertheless, using photon stress as a tool ("Optical Stress-Probe"), we can extract information on the activation, reversibility, permanency and kinetics of mitochondrial depolarization. These data may provide new information on mPTP, help identify the mPTP protein complex, and establish the physiological function of the mPTP protein complex and their links to MitoFlashes and MitoWinks.}, }
@article {pmid30930024, year = {2019}, author = {Chandrasekharan, B and Saeedi, BJ and Alam, A and Houser, M and Srinivasan, S and Tansey, M and Jones, R and Nusrat, A and Neish, AS}, title = {Interactions Between Commensal Bacteria and Enteric Neurons, via FPR1 Induction of ROS, Increase Gastrointestinal Motility in Mice.}, journal = {Gastroenterology}, volume = {157}, number = {1}, pages = {179-192.e2}, pmid = {30930024}, issn = {1528-0012}, support = {R56 AI064462/AI/NIAID NIH HHS/United States ; R01 DK080684/DK/NIDDK NIH HHS/United States ; R56 DK089763/DK/NIDDK NIH HHS/United States ; I01 BX000136/BX/BLRD VA/United States ; R01 DK089763/DK/NIDDK NIH HHS/United States ; R01 AI064462/AI/NIAID NIH HHS/United States ; K01 DK114391/DK/NIDDK NIH HHS/United States ; T32 GM008169/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Choline O-Acetyltransferase/metabolism ; Enteric Nervous System/cytology/metabolism ; Gastrointestinal Motility/drug effects/*physiology ; Gastrointestinal Transit/drug effects/*physiology ; Germ-Free Life ; Ileum/drug effects/innervation/*metabolism ; In Situ Hybridization, Fluorescence ; Jejunum/drug effects/innervation/*metabolism ; *Lacticaseibacillus rhamnosus ; Mice ; Mice, Knockout ; Mitogen-Activated Protein Kinase 1/metabolism ; Muscle Contraction/drug effects ; Myenteric Plexus/cytology/*metabolism ; Neurons/drug effects/*metabolism ; Phosphorylation ; *Probiotics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Receptors, Formyl Peptide/genetics ; }, abstract = {BACKGROUND &amp; AIMS: Reduced gastrointestinal (GI) motility is a feature of disorders associated with intestinal dysbiosis and loss of beneficial microbes. It is not clear how consumption of beneficial commensal microbes, marketed as probiotics, affects the enteric nervous system (ENS). We studied the effects of the widely used probiotic and the commensal Lactobacillus rhamnosus GG (LGG) on ENS and GI motility in mice.<br><br>METHODS: Conventional and germ free C57B6 mice were gavaged with LGG and intestinal tissues were collected; changes in the enteric neuronal subtypes were assessed by real-time polymerase chain reaction, immunoblots, and immunostaining. Production of reactive oxygen species (ROS) in the jejunal myenteric plexi and phosphorylation (p) of mitogen-activated protein kinase 1 (MAPK1) in the enteric ganglia were assessed by immunoblots and immunostaining. Fluorescence in situ hybridization was performed on jejunal cryosections with probes to detect formyl peptide receptor 1 (FPR1). GI motility in conventional mice was assessed after daily gavage of LGG for 1 week.<br><br>RESULTS: Feeding of LGG to mice stimulated myenteric production of ROS, increased levels of phosphorylated MAPK1, and increased expression of choline acetyl transferase by neurons (P < .001). These effects were not observed in mice given N-acetyl cysteine (a ROS inhibitor) or LGG&#x3a9;SpaC (an adhesion-mutant strain of LGG) or FPR1-knockout mice. Gavage of mice with LGG for 1 week significantly increased stool frequency, reduced total GI transit time, and increased contractions of ileal circular muscle strips in ex&#xa0;vivo experiments (P < .05).<br><br>CONCLUSIONS: Using mouse models, we found that LGG-mediated signaling in the ENS requires bacterial adhesion, redox mechanisms, and FPR1. This pathway might be activated to increase GI motility in patients.}, }
@article {pmid30928439, year = {2019}, author = {Sreekanth, GP and Panaampon, J and Suttitheptumrong, A and Chuncharunee, A and Bootkunha, J and Yenchitsomanus, PT and Limjindaporn, T}, title = {Drug repurposing of N-acetyl cysteine as antiviral against dengue virus infection.}, journal = {Antiviral research}, volume = {166}, number = {}, pages = {42-55}, doi = {10.1016/j.antiviral.2019.03.011}, pmid = {30928439}, issn = {1872-9096}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antiviral Agents/pharmacology ; Dengue/*drug therapy ; Dengue Virus/*drug effects ; Disease Models, Animal ; Drug Repositioning ; Hep G2 Cells ; Hepatocytes/drug effects/pathology/virology ; Humans ; Interferons/drug effects/metabolism ; Liver/drug effects/pathology/virology ; Mice ; Oxidative Stress/drug effects ; Virus Replication/drug effects ; }, abstract = {Liver injury is one of the hallmark features of severe dengue virus (DENV) infection since DENV can replicate in the liver and induce hepatocytes to undergo apoptosis. N-acetyl cysteine (NAC), which is a clinically-used drug for treating acetaminophen toxicity, was found to benefit patients with DENV-induced liver injury; however, its mechanism of action remains unclear. Accordingly, our aim was to repurpose NAC in the preclinical studies to investigate its mechanism of action. Time of addition experiments in HepG2 cells elucidated effectiveness of NAC to reduce infectious virion at pre-, during- and post infection. In DENV-infected mice, NAC improved DENV-associated clinical manifestations, including leucopenia and thrombocytopenia, and reduced liver injury and hepatocyte apoptosis. Interestingly, we discovered that NAC significantly reduced DENV production in HepG2 cells and in liver of DENV-infected mice by induction of antiviral responses via interferon signaling. NAC treatment in DENV-infected mice helped to maintain antioxidant enzymes and redox balance in the liver. Therefore, NAC reduces DENV production and oxidative damage to ameliorate DENV-induced liver injury. Taken together, these findings suggest the novel therapeutic potential of NAC in DENV-induced liver injury and recommend evaluating its efficacy and safety in humans with DENV-induced liver injury.}, }
@article {pmid30926903, year = {2019}, author = {Im, DK and Cheong, H and Lee, JS and Oh, MK and Yang, KM}, title = {Protein kinase CK2-dependent aerobic glycolysis-induced lactate dehydrogenase A enhances the migration and invasion of cancer cells.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {5337}, pmid = {30926903}, issn = {2045-2322}, mesh = {Aerobiosis ; Animals ; Casein Kinase II/genetics/*metabolism ; Cell Cycle ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Citric Acid Cycle ; Glucose/*metabolism ; Glycolysis ; Humans ; Lactate Dehydrogenases/*metabolism ; Mice ; Neoplasms/*metabolism/pathology ; Pyruvic Acid/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {We investigated the intracellular metabolic fluxes of protein kinase CK2-activating (Cα OE) cells and role of lactate dehydrogenase A (LDHA) as a contributor of tumorigenesis after reprogrammed glucose metabolism. Facilitated aerobic glycolysis was confirmed via isotope tracer analysis, in which [13]C6-Glc or [13]C5-Gln was added to the media, following which metabolites converted from Cα OE cells were identified. We found a greater decrease in cell survival, colony-forming ability, migration, and Cα OE cell invasion under glucose (Glc)-depletion conditions than under glutamine (Gln)-depletion conditions. Cancer cell migration and invasion increased due to LDHA elevation of the altered metabolic axis driven by activated CK2. FX11 treatment and LDHA knockdown suppressed migration and invasion through ROS generation, but this was partially reversed by the antioxidant N-acetylcysteine (NAC). Moreover, LDHA inhibition decreased tumor growth in a mouse xenograft model transplanted with Cα OE cells. Finally, we concluded that LDHA is an excellent metabolic target for tumor therapy, based on CK2α derived aerobic glycolysis.}, }
@article {pmid30926546, year = {2019}, author = {Siemsen, BM and Reichel, CM and Leong, KC and Garcia-Keller, C and Gipson, CD and Spencer, S and McFaddin, JA and Hooker, KN and Kalivas, PW and Scofield, MD}, title = {Effects of Methamphetamine Self-Administration and Extinction on Astrocyte Structure and Function in the Nucleus Accumbens Core.}, journal = {Neuroscience}, volume = {406}, number = {}, pages = {528-541}, pmid = {30926546}, issn = {1873-7544}, support = {T32 DA007288/DA/NIDA NIH HHS/United States ; K99 DA047426/DA/NIDA NIH HHS/United States ; K99 DA041462/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; R01 DA033049/DA/NIDA NIH HHS/United States ; R00 DA036569/DA/NIDA NIH HHS/United States ; P50 DA046373/DA/NIDA NIH HHS/United States ; R01 DA012513/DA/NIDA NIH HHS/United States ; R21 DA044479/DA/NIDA NIH HHS/United States ; R01 DA010462/DA/NIDA NIH HHS/United States ; R00 DA040004/DA/NIDA NIH HHS/United States ; F32 DA029344/DA/NIDA NIH HHS/United States ; R37 DA003906/DA/NIDA NIH HHS/United States ; R03 DA045881/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Astrocytes/*drug effects/pathology/*physiology ; Dopamine Agents/administration &amp; dosage/toxicity ; Extinction, Psychological/*drug effects/*physiology ; Male ; Methamphetamine/*administration &amp; dosage/toxicity ; Nucleus Accumbens/*drug effects/pathology/*physiology ; Rats ; Rats, Sprague-Dawley ; Self Administration ; }, abstract = {Astrocytes provide support for neurons, regulate metabolic processes, and influence neuronal communication in a variety of ways, including through the homeostatic regulation of glutamate. Following 2-h cocaine or methamphetamine self-administration (SA) and extinction, rodents display decreased levels of basal glutamate in the nucleus accumbens core (NAcore), which transitions to elevated glutamate levels during drug seeking. We hypothesized that, like cocaine, this glutamate 'overflow' during methamphetamine seeking arises via decreased expression of the astroglial glutamate transporter GLT-1, and withdrawal of perisynaptic astroglial processes (PAPs) from synapses. As expected, methamphetamine self-administration and extinction decreased the level of contact made by PAPs in the NAcore, yet did not impact glutamate uptake, GLT-1 expression, or the general structural characteristics of astrocytes. Interestingly, systemic administration of N-acetylcysteine (NAC), a drug that both upregulates GLT-1 and promotes glial-glutamate release, reduced cued methamphetamine seeking. In order to test the impact of astrocyte activation and the induction of glial glutamate release within the NAcore, we employed astrocyte-specific expression of designer receptors exclusively activated by designer drugs (DREADDs). We show here that acute activation of Gq-coupled DREADDs in this region inhibited cued methamphetamine seeking. Taken together, these data indicate that cued methamphetamine seeking following two-hour SA is not mediated by deficient glutamate clearance in the NAcore, yet can be inhibited by engaging NAcore astrocytes.}, }
@article {pmid30925428, year = {2019}, author = {Pernar, M and Kokan, Z and Kralj, J and Glasovac, Z and Tumir, LM and Piantanida, I and Eljuga, D and Turel, I and Brozovic, A and Kirin, SI}, title = {Organometallic ruthenium(II)-arene complexes with triphenylphosphine amino acid bioconjugates: Synthesis, characterization and biological properties.}, journal = {Bioorganic chemistry}, volume = {87}, number = {}, pages = {432-446}, doi = {10.1016/j.bioorg.2019.03.048}, pmid = {30925428}, issn = {1090-2120}, mesh = {Amino Acids/chemistry/*pharmacology ; Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Density Functional Theory ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; HeLa Cells ; Humans ; Molecular Structure ; Organometallic Compounds/chemical synthesis/chemistry/*pharmacology ; Organophosphorus Compounds/chemistry/*pharmacology ; Ruthenium/chemistry/*pharmacology ; Structure-Activity Relationship ; }, abstract = {(p-Cymene)-ruthenium bioconjugates ML (1) and ML2 (2), bearing phosphane ligands substituted with chiral or non-chiral amino acid esters, L, were synthetized and characterized by instrumental methods (NMR, CD, MS) and DFT calculations (using the wB97xD functional). Cytotoxic activity of complexes 1 and 2 was investigated by using human cervical carcinoma cell line (HeLa) and MTT assay. Four (2pG, 2pA, 2mG and 2mA) out of ten synthesized ruthenium complexes showed significant toxicity, with IC50 values of 5-30 μM. Evaluation of the potential biomolecular targets of bioconjugates 2 by UV-Vis, fluorescence and CD spectroscopy revealed no measurable interaction with DNA, but micromolar affinity for proteins. The cytotoxicity of bioconjugates 2 is in correlation with their BSA binding constants, i. e. bioconjugates with lower IC50 values show higher binding affinities towards BSA. Compound 2mG with value of IC50 16 μM was selected for further biological characterization. The higher level of toxicity towards tumor compared to normal cell lines indicates its selective activity, important characteristic for potential medical use. It was detected 2mG caused increase of cells in the S phase of cell cycle and consequential decrease of cells in G0/G1 phase. Additionally, 2mG caused dose- and time-dependent increase of SubG0/G1 cell population, suggesting its ability to induce programmed cell death. Further investigation determined autophagy as the mode of cell death. The role of GSH in HeLa cells response to investigated organometallic ruthenium complexes was confirmed using specific regulators of GSH synthesis, buthionine sulfoximine and N-acetyl-cysteine. Pre-treatment of cells with ethacrynic acid and probenecid emphasized the role of GSH in detoxification of 2mG compound. The amount of total ruthenium accumulation in the cell did not correlate with toxicity of 2pG, 2pA, 2mG and 2mA, suggesting structure dependent differences in either cell uptake or kinetics of ruthenium complexes detoxification. We speculate that ruthenium complexes bind protein-based biomolecules further triggering cell death. Based on the gained knowledge, the synthesis and development of more tumor-specific ruthenium-based complexes as potential anticancer drugs can be expected.}, }
@article {pmid30919246, year = {2019}, author = {Al Omairi, NE and Al-Brakati, AY and Kassab, RB and Lokman, MS and Elmahallawy, EK and Amin, HK and Abdel Moneim, AE}, title = {Soursop fruit extract mitigates scopolamine-induced amnesia and oxidative stress via activating cholinergic and Nrf2/HO-1 pathways.}, journal = {Metabolic brain disease}, volume = {34}, number = {3}, pages = {853-864}, pmid = {30919246}, issn = {1573-7365}, mesh = {Acetylcholine/*pharmacology ; Amnesia/chemically induced/drug therapy ; Animals ; Antioxidants/pharmacology ; Heme Oxygenase-1/*drug effects/genetics ; Male ; Malondialdehyde/metabolism/pharmacology ; Nitric Oxide Synthase Type II/drug effects/metabolism ; Oxidative Stress/*drug effects ; Rats, Wistar ; Scopolamine/*pharmacology ; }, abstract = {Current therapeutic interventions for memory loss are inadequate and are associated with numerous adverse effects. There is an urgent need for new alternative agents for the treatment of memory loss and related disorders. Here, we investigated the potential neuroprotective role of soursop fruit extract (SSFE) in scopolamine (SCO)-induced amnesia and oxidative damage in the hippocampus of rats. Thirty-five rats were randomly allocated into 5 groups: control, SCO, SSFE, SCO, SSFE+SCO and N-acetylcysteine (NAC) + SCO. SCO-treatment increased acetylcholine esterase activity and decreased hippocampal levels of acetylcholine, serotonin, dopamine, norepinephrine, and histamine. The level of ATP increased. SCO-treated rats showed a disturbance in oxidative status, which was evident through the increase in malondialdehyde, and nitrites/nitrates and a decrease in cellular antioxidant molecules including glutathione, superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. A disturbance was also observed via downregulation of the nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 defense pathways. SCO-treatment enhances a neuroinflammatory state, as indicated by the release of tumor necrosis factor- α and interleukin-1β and increased inducible nitric oxide synthase and mRNA expression. SCO-treatment decreased the expression of the anti-apoptotic protein, B cell lymphoma 2 and increased the expression of the pro-apoptotic protein, Bcl-2 associated X protein, caspase-3 and cytochrome c in hippocampal neurons. SSFE pretreatment markedly ameliorated hippocampal changes. Our findings revealed that SSFE exerts its potential anti-amnestic effect mainly through the activation of the cholinergic system and Nrf2/HO-1 pathway.}, }
@article {pmid30917096, year = {2019}, author = {Buz, PT and Duman, FD and Erkisa, M and Demirci, G and Ari, F and Ulukaya, E and Acar, HY}, title = {Development of near-infrared region luminescent N-acetyl-L-cysteine-coated Ag2S quantum dots with differential therapeutic effect.}, journal = {Nanomedicine (London, England)}, volume = {14}, number = {8}, pages = {969-987}, doi = {10.2217/nnm-2018-0214}, pmid = {30917096}, issn = {1748-6963}, mesh = {Acetylcysteine/*chemistry ; Antineoplastic Agents/*chemistry ; Apoptosis/drug effects ; Biological Transport ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Damage/drug effects ; Free Radical Scavengers/*chemistry ; Humans ; Infrared Rays ; Luminescence ; Luminescent Agents/*chemistry ; Neoplasms/diagnostic imaging/therapy ; Oxidative Stress/drug effects ; Particle Size ; Quantum Dots/*chemistry ; Reactive Oxygen Species/metabolism ; Silver Compounds/*chemistry ; Surface Properties ; }, abstract = {AIM: N-acetyl-L-cysteine (NAC) is a free radical scavenger. We developed NAC-coated Ag2S (NAC-Ag2S) quantum dot (QD) as an optical imaging and therapeutic agent.<br><br>MATERIALS &amp; METHODS: QDs were synthesized in water. Their optical imaging potential and toxicity were studied in vitro.<br><br>RESULTS: NAC-Ag2S QDs have strong emission, that is tunable between 748 and 840&#xa0;nm, and are stable in biologically relevant media. QDs showed significant differences both in cell internalization and toxicity in vitro. QDs were quite toxic to breast and cervical cancer cells but not to lung derived cells despite the higher uptake. NAC-Ag2S reduces reactive oxygen species (ROS) but causes cell death via DNA damage and apoptosis.<br><br>CONCLUSION: NAC-Ag2S QDs are stable and strong signal-generating theranostic agents offering selective therapeutic effects.}, }
@article {pmid30916421, year = {2019}, author = {Zang, YQ and Feng, YY and Luo, YH and Zhai, YQ and Ju, XY and Feng, YC and Wang, JR and Yu, CQ and Jin, CH}, title = {Glycitein induces reactive oxygen species-dependent apoptosis and G0/G1 cell cycle arrest through the MAPK/STAT3/NF-κB pathway in human gastric cancer cells.}, journal = {Drug development research}, volume = {80}, number = {5}, pages = {573-584}, doi = {10.1002/ddr.21534}, pmid = {30916421}, issn = {1098-2299}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Humans ; Isoflavones/*pharmacology ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; NF-kappa B/metabolism ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/metabolism ; Stomach Neoplasms/drug therapy/*metabolism ; }, abstract = {Glycitein is an isoflavone that reportedly inhibits the proliferation of human breast cancer and prostate cancer cells. However, its anti-cancer molecular mechanisms in human gastric cancer remain to be defined. This study evaluated the antitumor effects of glycitein on human gastric cancer cells and investigated the underlying mechanisms. We used MTT assay, flow cytometry and western blotting to investigate its molecular mechanisms with focus on reactive oxygen species (ROS) production. Our results showed that glycitein had significant cytotoxic effects on human gastric cancer cells. Glycitein markedly decreased mitochondrial transmembrane potential (ΔΨm) and increased AGS cells mitochondrial-related apoptosis, and caused G0/G1 cell cycle arrest by regulating cycle-related protein. Mechanistically, accompanying ROS, glycitein can activate mitogen-activated protein kinase (MAPK) and inhibited the signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappaB (NF-κB) signaling pathways. Furthermore, the MAPK signaling pathway regulated the expression levels of STAT3 and NF-κB upon treatment with MAPK inhibitor and N-acetyl-L-cysteine (NAC). These findings suggested that glycitein induced AGS cell apoptosis and G0/G1 phase cell cycle arrest via ROS-related MAPK/STAT3/NF-κB signaling pathways. Thus, glycitein has the potential to a novel targeted therapeutic agent for human gastric cancer.}, }
@article {pmid30911553, year = {2019}, author = {Qiu, Z and He, Y and Ming, H and Lei, S and Leng, Y and Xia, ZY}, title = {Lipopolysaccharide (LPS) Aggravates High Glucose- and Hypoxia/Reoxygenation-Induced Injury through Activating ROS-Dependent NLRP3 Inflammasome-Mediated Pyroptosis in H9C2 Cardiomyocytes.}, journal = {Journal of diabetes research}, volume = {2019}, number = {}, pages = {8151836}, pmid = {30911553}, issn = {2314-6753}, mesh = {Animals ; Caspase 1/metabolism ; Cell Line ; Cell Survival/drug effects ; Glucose/*pharmacology ; Inflammasomes/drug effects/*metabolism ; Lipopolysaccharides/*pharmacology ; Myocardial Reperfusion Injury/*metabolism ; Myocytes, Cardiac/drug effects/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Pyroptosis/*drug effects ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {Diabetes aggravates myocardial ischemia-reperfusion (I/R) injury because of the combination effects of changes in glucose and lipid energy metabolism, oxidative stress, and systemic inflammatory response. Studies have indicated that myocardial I/R may coincide and interact with sepsis and inflammation. However, the role of LPS in hypoxia/reoxygenation (H/R) injury in cardiomyocytes under high glucose conditions is still unclear. Our objective was to examine whether lipopolysaccharide (LPS) could aggravate high glucose- (HG-) and hypoxia/reoxygenation- (H/R-) induced injury by upregulating ROS production to activate NLRP3 inflammasome-mediated pyroptosis in H9C2 cardiomyocytes. H9C2 cardiomyocytes were exposed to HG (30 mM) condition with or without LPS, along with caspase-1 inhibitor (Ac-YVAD-CMK), inflammasome inhibitor (BAY11-7082), ROS scavenger N-acetylcysteine (NAC), or not for 24 h, then subjected to 4 h of hypoxia followed by 2 h of reoxygenation (H/R). The cell viability, lactate dehydrogenase (LDH) release, caspase-1 activity, and intracellular ROS production were detected by using assay kits. The incidence of pyroptosis was detected by calcein-AM/propidium iodide (PI) double staining kit. The concentrations of IL-1β and IL-18 in the supernatants were assessed by ELISA. The mRNA levels of NLRP3, ASC, and caspase-1 were detected by qRT-PCR. The protein levels of NF-κB p65, NLRP3, ASC, cleaved caspase-1 (p10), IL-1β, and IL-18 were detected by western blot. The results indicated that pretreatment LPS with 1 μg/ml not 0.1 μg/ml could efficiently aggravate HG and H/R injury by activating NLRP3 inflammasome to mediate pyroptosis in H9C2 cells, as evidenced by increased LDH release and decreased cell viability in the cells, and increased expression of NLRP3, ASC, cleaved caspase-1 (p10), IL-1β, and IL-18. Meanwhile, Ac-YVAD-CMK, BAY11-7082, or NAC attenuated HG- and H/R-induced H9C2 cell injury with LPS stimulated by reversing the activation of NLRP3 inflammasome-mediated pyroptosis. In conclusion, LPS could increase the sensitivity of H9C2 cells to HG and H/R and aggravated HG- and H/R-induced H9C2 cell injury by promoting ROS production to induce NLRP3 inflammasome-mediated pyroptosis.}, }
@article {pmid30911326, year = {2019}, author = {Wang, Z and Yin, J and Li, M and Shen, J and Xiao, Z and Zhao, Y and Huang, C and Zhang, H and Zhang, Z and Cho, CH and Wu, X}, title = {Combination of shikonin with paclitaxel overcomes multidrug resistance in human ovarian carcinoma cells in a P-gp-independent manner through enhanced ROS generation.}, journal = {Chinese medicine}, volume = {14}, number = {}, pages = {7}, pmid = {30911326}, issn = {1749-8546}, abstract = {BACKGROUND: Shikonin (SKN), a naphthoquinone compound, is isolated from Chinese herbal medicine Lithospermum root and has been studied as an anticancer drug candidate in human tumor models. This study is designed to investigate whether SKN can sensitize the therapeutic effect of paclitaxel (PTX) in drug-resistant human ovarian carcinoma cells.<br><br>METHODS: Human ovarian carcinoma A2780 cell along with the paired PTX-resistant A2780/PTX cells were used. The effects of SKN, PTX or their combination on cell viability were conducted using Sulforhodamine B assay. P-glycoprotein (P-gp) expression was analyzed by flow cytometry after staining with P-gp-FITC anti-body. P-gp activity was determined by a fluorometric MDR assay kit or a rhodamine 123-based efflux assay, respectively. Apoptosis was evaluated by flow cytometry after Annexin V-FITC/PI co-staining. The effect of SKN, PTX or their combination on reactive oxygen species (ROS) generation and expression of pyruvate kinase M2 (PKM2) were investigated using flow cytometry or western blotting, respectively. PKM2 activity was detected by a Pyruvate Kinase Assay Kit.<br><br>RESULTS: SKN/PTX co-treatment led to synergistically enhanced cytotoxicity and apoptosis in PTX-resistant ovarian cancer cells, indicating the circumvention of multidrug resistance (MDR) of PTX by SKN. Further study indicated that the MDR reversal effect of SKN was independent of inhibiting activity of the efflux transporter P-gp. Notably, SKN/PTX significantly increased the generation of intracellular ROS in A2780/PTX cells, and scavenging intracellular ROS blocked the sensitizing effects of SKN in PTX-induced cytotoxicity and apoptosis in A2780/PTX cells, but not in A2780 cells. Furthermore, SKN/PTX-induced downregulation of PKM2 (a key enzyme in glycolysis) and the suppression of its activity were inhibited by a ROS scavenger N-acetyl cysteine (NAC), suggesting that the synergy of the SKN/PTX combination may be not rely on PKM2 suppression.<br><br>CONCLUSIONS: These results reveal a P-gp-independent mechanism through ROS generation for the SKN/PTX combination to overcome MDR in ovarian cancer.}, }
@article {pmid30906217, year = {2019}, author = {Wang, R and Xue, X and Wang, Y and Zhao, H and Zhang, Y and Wang, H and Miao, D}, title = {BMI1 Deficiency Results in Female Infertility by Activating p16/p19 Signaling and Increasing Oxidative Stress.}, journal = {International journal of biological sciences}, volume = {15}, number = {4}, pages = {870-881}, pmid = {30906217}, issn = {1449-2288}, mesh = {Animals ; Apoptosis/physiology ; Blotting, Western ; Cell Proliferation/physiology ; Cyclin-Dependent Kinase Inhibitor p19/metabolism ; Female ; Flow Cytometry ; Granulosa Cells/cytology/metabolism ; Immunohistochemistry ; Infertility, Female/*metabolism/*physiopathology ; Male ; Mice ; Microscopy, Electron ; Ovarian Follicle/cytology/metabolism ; Ovary/metabolism/physiology ; Oxidative Stress/physiology ; Polycomb Repressive Complex 1/genetics/metabolism ; Proto-Oncogene Proteins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {The polycomb repressor B lymphoma Mo-MLV insertion region 1 (BMI1) is a core composition of polycomb repressive complex 1 (PRC1) and contributes to diverse fundamental cellular processes including cell senescence, apoptosis and proliferation. To investigate the role and mechanism of BMI1 in maintaining normal female reproductive function, we compared the differences in reproductive phenotypes between Bmi1-deficient and wild-type female mice. The Bmi1-deficient female mice were then supplemented with N-acetylcysteine in their drinking water to explore whether antioxidant supplementation could improve reproductive dysfunction caused by BMI1 deficiency. The results revealed that Bmi1 deletion resulted in complete infertility in female mice, estrous cycle disorder, and follicular developmental disorders. The reactive oxygen species levels in the ovarian tissue were increased; the ability of antioxidant enzymes was downregulated; the expression levels of p19 and p53 proteins were significantly upregulated. We also found that oocytes derived from Bmi1-deficient mice could not develop into embryos by in vitro fertilization and in vitro culture of embryos. Furthermore, supplementation with the antioxidant NAC not only improved the reproductive defects caused by Bmi1 deletion, but also largely rescued the ability of Bmi1-deficient oocytes to develop into embryos in vitro. These results indicated that cells lacking Bmi1 resulted in female infertility by activating the p16/p19 signaling pathway, increasing oxidative stress and DNA damage, inhibiting granulosa cell proliferation, and inducing granulosa cell apoptosis. Thus, BMI1 may be a novel potential target for the clinical treatment of female infertility.}, }
@article {pmid30896878, year = {2019}, author = {Qin, X and Chen, Z}, title = {Metabolic dependence of cyclosporine A on cell proliferation of human non‑small cell lung cancer A549 cells and its implication in post‑transplant malignancy.}, journal = {Oncology reports}, volume = {41}, number = {5}, pages = {2997-3004}, doi = {10.3892/or.2019.7076}, pmid = {30896878}, issn = {1791-2431}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Carcinogenesis/drug effects/metabolism ; Carcinoma, Non-Small-Cell Lung/metabolism/*pathology/prevention &amp; control ; Cell Proliferation/*drug effects ; Cyclosporine/*adverse effects/metabolism ; Energy Metabolism ; Free Radical Scavengers/pharmacology ; Glucose/metabolism ; Graft Rejection/immunology/prevention &amp; control ; Humans ; Immunosuppressive Agents/*adverse effects/metabolism ; Lung Neoplasms/metabolism/*pathology/prevention &amp; control ; Organ Transplantation/adverse effects ; Palmitic Acid/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Cyclosporine A (CsA), a widely used immunosuppressant to prevent organ transplant rejection, is associated with an increased cancer risk following transplantation, particularly in the lung. However, the underlying mechanisms remain unclear. In the present study, using human non‑small cell lung cancer A549 cells, it was determined that CsA (0.1 or 1 µM) promoted cell proliferation with glucose alone as the energy source. CsA treatment increased the phosphorylation of protein kinase B (Akt) and consequently the expression of Cyclin D1. Inhibiting Akt signaling with the phosphatidylinositol 3‑kinase inhibitor wortmannin prevented this effect. Mechanistically, CsA treatment increased reactive oxygen species (ROS) generation, and the intracellular ROS scavenger N‑acetyl‑cysteine (NAC) attenuated CsA‑induced cell proliferation as well as the activation of Akt/Cyclin D1 signaling. However, notably, it was demonstrated that CsA treatment decreased cell proliferation and Akt phosphorylation under normal lipid loading. Further investigation indicated that palmitic acid induced excessive generation of ROS, while CsA treatment further stimulated this ROS production. Scavenging intracellular ROS with NAC attenuated the CsA‑mediated inhibition of cell proliferation. Collectively, the results indicated a pleiotropic effect of CsA in the regulation of A549 cell proliferation under different metabolic conditions. This indicated that CsA administration may contribute to increased post‑transplant cancer risk in organ recipients.}, }
@article {pmid30894323, year = {2019}, author = {Ingram, S and Mengozzi, M and Sacre, S and Mullen, L and Ghezzi, P}, title = {Differential induction of nuclear factor-like 2 signature genes with toll-like receptor stimulation.}, journal = {Free radical biology &amp; medicine}, volume = {135}, number = {}, pages = {245-250}, doi = {10.1016/j.freeradbiomed.2019.03.018}, pmid = {30894323}, issn = {1873-4596}, mesh = {Animals ; Gene Expression Regulation/drug effects ; Heme Oxygenase-1/genetics ; Inflammation/*genetics/metabolism/pathology ; Lipopolysaccharides/pharmacology ; Membrane Glycoproteins/genetics ; Membrane Proteins/genetics ; Mice ; NF-E2-Related Factor 2/*genetics ; Peroxiredoxins/*genetics ; Protein Kinase C/antagonists &amp; inhibitors/genetics ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; Staurosporine/pharmacology ; Thioredoxin Reductase 1/*genetics ; Toll-Like Receptor 2/genetics ; Toll-Like Receptor 3/genetics ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 7/genetics ; }, abstract = {Inflammation is associated with production of reactive oxygen species (ROS) and results in the induction of thioredoxin (TXN) and peroxiredoxins (PRDXs) and activation of nuclear factor-like 2 (Nrf2). In this study we have used the mouse RAW 264.7 macrophage and the human THP-1 monocyte cell line to investigate the pattern of expression of three Nrf2 target genes, PRDX1, TXN reductase (TXNRD1) and heme oxygenase (HMOX1), by activation of different Toll-like receptors (TLRs). We found that, while the TLR4 agonist lipopolysaccharide (LPS) induces all three genes, the pattern of induction with agonists for TLR1/2, TLR3, TLR2/6 and TLR7/8 differs depending on the gene and the cell line. In all cases, the extent of induction was HMOX1>TXNRD1>PRDX1. Since LPS was a good inducer of all genes in both cell lines, we studied the mechanisms mediating LPS induction of the three genes using mouse RAW 264.7 cells. To assess the role of ROS we used the antioxidant N-acetylcysteine (NAC). Only LPS induction of HMOX1 was inhibited by NAC while that of TXNRD1 and PRDX1 was unaffected. These three genes were also induced by phorbol myristate acetate (PMA), a ROS-inducer acting by activation of protein kinase C (PKC). The protein kinase inhibitor staurosporine inhibited the induction of all three genes by PMA but only that of HMOX1 by LPS. This indicates that activation of these genes by inflammatory agents is regulated by different mechanisms involving either ROS or protein kinases, or both.}, }
@article {pmid30892320, year = {2019}, author = {Palmieri, V and Dalchiele, EA and Perini, G and Motta, A and De Spirito, M and Zanoni, R and Marrani, AG and Papi, M}, title = {Biocompatible N-acetyl cysteine reduces graphene oxide and persists at the surface as a green radical scavenger.}, journal = {Chemical communications (Cambridge, England)}, volume = {55}, number = {29}, pages = {4186-4189}, doi = {10.1039/c9cc00429g}, pmid = {30892320}, issn = {1364-548X}, abstract = {We demonstrate that N-acetyl cysteine (NAC) reduces graphene oxide (GO) at room temperature. This represents a new green method to produce reduced GO (rGO). NAC adheres to the rGO surface as demonstrated by several spectroscopy techniques and avoids GO-mediated oxidation of glutathione. This method offers new opportunities for the production of green biocompatible rGO and NAC-based therapies.}, }
@article {pmid30890744, year = {2019}, author = {Poluektov, YM and Petrushanko, IY and Undrovinas, NA and Lakunina, VA and Khapchaev, AY and Kapelko, VI and Abramov, AA and Lakomkin, VL and Novikov, MS and Shirinsky, VP and Mitkevich, VA and Makarov, AA}, title = {Glutathione-related substances maintain cardiomyocyte contractile function in hypoxic conditions.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {4872}, pmid = {30890744}, issn = {2045-2322}, mesh = {Animals ; Arrhythmias, Cardiac/*drug therapy/pathology ; Calcium Signaling/drug effects ; Cell Hypoxia/*drug effects ; Electric Stimulation ; Glutathione/analogs &amp; derivatives/pharmacology ; Glutathione Disulfide/pharmacology ; Heart/drug effects/physiopathology ; Humans ; Muscle Contraction/drug effects ; Myocardial Contraction/*drug effects/physiology ; Myocytes, Cardiac/*drug effects ; Organ Culture Techniques ; Oxygen/metabolism ; Rats ; S-Nitrosoglutathione/pharmacology ; Sulfhydryl Compounds/pharmacology ; }, abstract = {Severe hypoxia leads to decline in cardiac contractility and induces arrhythmic events in part due to oxidative damage to cardiomyocyte proteins including ion transporters. This results in compromised handling of Ca[2+] ions that trigger heart contractile machinery. Here, we demonstrate that thiol-containing compounds such as N-acetylcysteine (NAC), glutathione ethyl ester (et-GSH), oxidized tetraethylglutathione (tet-GSSG), oxidized glutathione (GSSG) and S-nitrosoglutathione (GSNO) are capable of reducing negative effects of hypoxia on isolated rat cardiomyocytes. Preincubation of cardiomyocytes with 0.1 mM GSNO, 0.5 mM et-GSH, GSSG, tet-GSSG or with 10 mM NAC allows cells 5-times longer tolerate the hypoxic conditions and elicit regular Ca[2+] transients in response to electric pacing. The shape of Ca[2+] transients generated in the presence of GSNO, et-GSH and NAC was similar to that observed in normoxic control cardiomyocytes. The leader compound, GSNO, accelerated by 34% the recovery of normal contractile function of isolated rat heart subjected to ischemia-reperfusion. GSNO increased glutathionylation of Na,K-ATPase alpha-2 subunit, the principal ion-transporter of cardiac myocyte sarcolemma, which prevents irreversible oxidation of Na,K-ATPase and regulates its function to support normal Ca[2+] ion handling in hypoxic cardiomyocytes. Altogether, GSNO appears effective cardioprotector in hypoxic conditions worth further studies toward its cardiovascular application.}, }
@article {pmid30890312, year = {2019}, author = {Kazaz, IO and Demir, S and Yulug, E and Colak, F and Bodur, A and Yaman, SO and Karaguzel, E and Mentese, A}, title = {N-acetylcysteine protects testicular tissue against ischemia/reperfusion injury via inhibiting endoplasmic reticulum stress and apoptosis.}, journal = {Journal of pediatric urology}, volume = {15}, number = {3}, pages = {253.e1-253.e8}, doi = {10.1016/j.jpurol.2019.02.005}, pmid = {30890312}, issn = {1873-4898}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Animals ; Apoptosis/*drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*etiology/*prevention &amp; control ; Spermatic Cord Torsion/*complications ; Testis/*blood supply ; }, abstract = {BACKGROUND: In animal models, endoplasmic reticulum (ER) stress has been reported to play a vital role in mediating ischemia/reperfusion (I/R) injury in certain organs, such as brain, liver, and intestine. However, there are a limited number of studies examining the relationship between ER stress and torsion and detorsion (T/D)-induced testicular injury.<br><br>OBJECTIVE: To investigate the effects of N-acetylcysteine (NAC) on ER-stress and apoptosis in an experimental testicular I/R injury model.<br><br>DESIGN: A non-blinded experimental study with three arms. Rats were divided into three groups: control group, T/D group, and NAC group. In the pretreatment of the NAC group, 20&#xa0;mg/kg NAC was given intraperitoneally 30&#xa0;min before detorsion. Tissue 4-hydroxynonenal (4-HNE), 78-kDa glucose-regulated protein (GRP78), and activating transcription factor 6 (ATF6) levels were determined using enzyme-linked immunosorbent assay. The apoptosis levels were evaluated using terminal deoxynucleotide transferase-mediated dUTP nick-end label&#xa0;assay.<br><br>RESULTS: In T/D group, tissue 4-HNE, GRP78, ATF6, and apoptotic index levels were significantly higher than control group. These increases were significantly reversed with NAC pretreatment.<br><br>DISCUSSION: There are some potential drugs that have been shown to reduce ER stress in the experimental ischemia model, and it is questioned that these drug candidates can be used as a therapeutic agent in the treatment of ischemic diseases in the near future. This study was not without limitations. First, the authors applied NAC only 20&#xa0;mg/kg. In a future study, a dose-dependent assay should be performed to assess the likelihood of an additional testicular protective effect. One limitation of this research is also that in&#xa0;vivo studies cannot be extrapolated to possible effect in clinics. More experiments therefore need to be conducted to extrapolate the study findings to humans.<br><br>CONCLUSION: The study results showed that, after testicular torsion (TT), the ER stress-related apoptotic pathway plays a pivotal role in testicular injury. Further studies of other experimental models of TT may prove that NAC is a useful agent as an adjunctive treatment in surgical repair in human cases.}, }
@article {pmid30886864, year = {2019}, author = {Wang, W and Niu, S and Qiao, L and Wei, F and Yin, J and Wang, S and Ouyang, Y and Chen, D}, title = {Usnea Acid as Multidrug Resistance (MDR) Reversing Agent against Human Chronic Myelogenous Leukemia K562/ADR Cells via an ROS Dependent Apoptosis.}, journal = {BioMed research international}, volume = {2019}, number = {}, pages = {8727935}, pmid = {30886864}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Benzofurans/antagonists &amp; inhibitors/*pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Doxorubicin/pharmacology ; Drug Resistance, Multiple/drug effects ; Drug Resistance, Neoplasm/*drug effects ; Flow Cytometry ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; }, abstract = {PURPOSE: Multidrug resistance (MDR) is a major obstacle in chemotherapy of leukemia treatments. In this paper, we investigated Usnea Acid (UA) as MDR reversal agent on hematologic K562/ADR cells via ROS dependent apoptosis.<br><br>METHODS: CCK8 assay was used to measure cell viability rate of K562/ADR. Intracellular reactive oxygen species (ROS) generation, cell cycle distribution, cell apoptosis were measured with flow cytometry, respectively. Proteins related to apoptosis were measured by Western blot. Intracellular Adriamycin accumulation was observed by confocal microscopy and measured by flow cytometry.<br><br>RESULTS: In vitro study showed intracellular Adriamycin accumulation was remarkably increased by UA. Cell viability treated with Adr (4 &#x3bc;M) was decreased from 89.8%&#x2009;&#x2009;&#xb1; 4.7 to 32%&#x2009;&#x2009;&#xb1; 8.9 by combined with UA (4 &#x3bc;M). Adr-induced apoptosis and G1/G0 phase cell cycle arrest were remarkably increased by UA, as well as, intracellular ROS level. However, MDR reversing activity of UA was inhibited by N-acetyl cysteine (NAC), a ROS scavenger.<br><br>CONCLUSION: These data provide compelling evidence that UA is a promising agent against MDR in leukemia cell line and suggest a promising therapeutic approach for leukemia.}, }
@article {pmid30884334, year = {2019}, author = {Girgis, RR and Baker, S and Mao, X and Gil, R and Javitt, DC and Kantrowitz, JT and Gu, M and Spielman, DM and Ojeil, N and Xu, X and Abi-Dargham, A and Shungu, DC and Kegeles, LS}, title = {Effects of acute N-acetylcysteine challenge on cortical glutathione and glutamate in schizophrenia: A pilot in vivo proton magnetic resonance spectroscopy study.}, journal = {Psychiatry research}, volume = {275}, number = {}, pages = {78-85}, pmid = {30884334}, issn = {1872-7123}, support = {R01 MH100005/MH/NIMH NIH HHS/United States ; S10 OD021782/OD/NIH HHS/United States ; R01 MH110683/MH/NIMH NIH HHS/United States ; R21 MH099508/MH/NIMH NIH HHS/United States ; R01 MH110270/MH/NIMH NIH HHS/United States ; R01 MH075895/MH/NIMH NIH HHS/United States ; P41 EB015891/EB/NIBIB NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adolescent ; Adult ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glutamic Acid/*metabolism ; Glutathione/*metabolism ; Gyrus Cinguli/diagnostic imaging/*drug effects/metabolism ; Humans ; Male ; Middle Aged ; Prefrontal Cortex/diagnostic imaging/*drug effects/metabolism ; Proton Magnetic Resonance Spectroscopy ; Schizophrenia/*drug therapy/metabolism ; Young Adult ; }, abstract = {Findings from in vivo brain proton magnetic resonance spectroscopy ([1]H MRS) and preclinical studies have suggested region- and medication status-dependent increases in glutamate (Glu) levels and deficiencies in glutathione (GSH) levels in schizophrenia. N-acetylcysteine (NAC), a GSH synthesis precursor, has demonstrated modest clinical benefit in schizophrenia. The objective of this study was to examine the effects of acute administration of NAC on GSH and Glu levels measured with [1]H MRS in 19 patients with schizophrenia and 20 healthy control subjects. Levels of GSH were acquired in dorsal anterior cingulate cortex (dACC), and those of Glu in dACC and medial prefrontal cortex (mPFC), at baseline and 60 min following acute oral administration of 2400 mg of NAC. No differences in the levels of GSH or Glu were found at baseline or following NAC administration between patients with schizophrenia and control subjects in either of the targeted brain regions. Future studies measuring GSH levels in brain regions previously found to exhibit glutamatergic abnormalities or using genetic polymorphisms, while controlling for the age and medication status of the cohorts, are warranted to better identify groups of patients more likely to respond to NAC and its mode of action and mechanisms.}, }
@article {pmid30880122, year = {2019}, author = {Lebourgeois, S and González-Marín, MC and Antol, J and Naassila, M and Vilpoux, C}, title = {Evaluation of N-acetylcysteine on ethanol self-administration in ethanol-dependent rats.}, journal = {Neuropharmacology}, volume = {150}, number = {}, pages = {112-120}, doi = {10.1016/j.neuropharm.2019.03.010}, pmid = {30880122}, issn = {1873-7064}, mesh = {*Alcoholism ; Animals ; Cystine/*analogs &amp; derivatives/pharmacology ; Dose-Response Relationship, Drug ; Drug-Seeking Behavior/*drug effects ; Ethanol/*administration &amp; dosage ; Male ; Rats ; Rats, Wistar ; Self Administration ; }, abstract = {Many components of ethanol addiction such as reinforcement, withdrawal, extinction, and relapse are known to involve glutamate transmission. NAC could counteract glutamatergic dysregulation underlying ethanol addiction. We previously demonstrated the efficacy of N-acetylcysteine (NAC) treatment to reduce ethanol consumption, motivation, seeking, and relapse in rats displaying a binge drinking-like phenotype. The current study assessed whether acute NAC could reduce ethanol self-administration, ethanol-seeking behavior, motivation, and reacquisition of ethanol self-administration following abstinence in ethanol-dependent rats. Ethanol dependence was induced by chronic intermittent ethanol (CIE) vapor exposure for 10 weeks in male Wistar rats. Effects of NAC (0, 25, 50 or 100 mg/kg; i.p.) were evaluated during acute withdrawal, 8 h after inhalation chambers were turned off. We evaluated NAC effect on the expression of the xCT protein expression (the target of NAC) and glutamate transporters (GLT-1) in dependent rats. We showed that in dependent rats, the low dose of NAC (25 mg/kg) reduced ethanol self-administration and motivation to consume ethanol, evaluated in a progressive ratio paradigm. At 50 mg/kg, but not 25 mg/kg, NAC reduced extinction responding and reacquisition of self-administration after 1 month abstinence. The xCT protein expression was decreased in the nucleus accumbens in dependent compared with ethanol-naïve rats. Thus, NAC may be effective by decreasing glutamate transmission through presynaptic mechanisms (i.e. the stimulation of xc[--]mediated increase in extrasynaptic glutamate levels). Our results demonstrate that NAC decreased ethanol self-administration, extinction responding, and relapse in ethanol-dependent animals, and thus strongly support clinical development of NAC for alcohol use disorders.}, }
@article {pmid30877326, year = {2019}, author = {Kangas, BD and Doyle, RJ and Kohut, SJ and Bergman, J and Kaufman, MJ}, title = {Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates.}, journal = {Psychopharmacology}, volume = {236}, number = {7}, pages = {2143-2153}, pmid = {30877326}, issn = {1432-2072}, support = {K01 DA035974/DA/NIDA NIH HHS/United States ; R21 DA039301/DA/NIDA NIH HHS/United States ; R21-DA039301//National Institute on Drug Abuse/ ; K01-DA035974//National Institute on Drug Abuse/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cocaine/*administration &amp; dosage ; Cocaine-Related Disorders/drug therapy/psychology ; Cognition/*drug effects/physiology ; Conditioning, Operant/drug effects/physiology ; Discrimination Learning/*drug effects/physiology ; Dopamine Uptake Inhibitors/administration &amp; dosage ; Dose-Response Relationship, Drug ; Drug-Seeking Behavior/*drug effects/physiology ; Extinction, Psychological/drug effects/physiology ; Free Radical Scavengers/administration &amp; dosage ; Male ; Photic Stimulation/methods ; Primates ; *Reinforcement, Psychology ; Saimiri ; Self Administration ; }, abstract = {RATIONALE: Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N-acetylcysteine [NAC]) may attenuate CUD-related relapse behavior.<br><br>OBJECTIVES: The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior.<br><br>METHODS: First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03&#xa0;mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement.<br><br>RESULTS: Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups.<br><br>CONCLUSIONS: The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.}, }
@article {pmid30873870, year = {2019}, author = {Liu, Y and Kang, X and Niu, G and He, S and Zhang, T and Bai, Y and Li, Y and Hao, H and Chen, C and Shou, Z and Li, B}, title = {Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways.}, journal = {Artificial cells, nanomedicine, and biotechnology}, volume = {47}, number = {1}, pages = {626-635}, doi = {10.1080/21691401.2019.1575229}, pmid = {30873870}, issn = {2169-141X}, mesh = {Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; MAP Kinase Signaling System/*drug effects ; Melanoma/metabolism/*pathology ; Molecular Structure ; Naphthoquinones/chemistry/*pharmacology ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Shikonin, a botanical drug extracted from Lithospermum erythrorhizon, exhibits anti-cancer effects in various cancer cell lines. However, the mechanisms underlying these effects have not been completely elucidated yet. Here, we showed that Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation. Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1. Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2α, CHOP, and cleaved caspase-3. It also induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1. Upon suppression of autophagy by 3-methyladenine, Shikonin-induced apoptosis was enhanced in A375 cells. Moreover, after pretreatment with N-acetyl-cysteine, Shikonin increased the production of reactive oxygen species that are involved in regulating ER stress-mediated apoptosis and p38-activated autophagy, as evidenced by the reversion of cell viability and apoptosis and a decrease in p-eIF2α, CHOP, p-p38, LC3B-II, and Beclin 1 levels. Thus, we demonstrated that Shikonin induced apoptosis and autophagy in A375 cells via the activation of ROS-mediated ER stress and p38 pathways, indicating that Shikonin can serve as a potential agent for human melanoma therapy.}, }
@article {pmid30871975, year = {2019}, author = {Pan, T and Qi, J and You, T and Han, S and Yang, L and Miao, W and Wu, D and Ruan, C and Zhu, L and Han, Y}, title = {Circulating Heme Oxygenase-1 and Complement Activation in Transplant-Associated Thrombotic Microangiopathy.}, journal = {Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation}, volume = {25}, number = {8}, pages = {1486-1491}, doi = {10.1016/j.bbmt.2019.03.002}, pmid = {30871975}, issn = {1523-6536}, mesh = {Acetylcysteine/pharmacology ; Adolescent ; Adult ; Aged ; Allografts ; Child ; *Complement Activation ; Female ; Graft vs Host Disease/*blood/drug therapy ; *Hematopoietic Stem Cell Transplantation ; Heme Oxygenase-1/*blood ; Human Umbilical Vein Endothelial Cells/metabolism/pathology ; Humans ; Male ; Middle Aged ; Thrombotic Microangiopathies/*blood/drug therapy/etiology ; }, abstract = {Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication in patients after hematopoietic stem cell transplantation. The pathogenesis of TA-TMA is still unclear. Previous studies showed that complement activation plays an important role in the development of TA-TMA. However, no data showed which kind of complement component triggers this process. In this study we found that heme oxygenase-1, which could induce decay-accelerating factor (DAF) and inhibit the membrane-attack complex, was significantly decreased in patients with TA-TMA. DAF levels in the TA-TMA group were in line with the levels in the myocardial infarction group but were lower than levels in the healthy, noncomplication, infection, and graft-versus-host disease groups (P < .05). Human umbilical vein endothelial cells (HUVECs) incubated with TA-TMA plasma showed lower DAF levels compared with that incubated with normal human plasma. Notably, treatment with N-acetylcysteine (NAC), a drug against oxidation, increased the level of DAF. NAC could also inhibit complement activation in HUVECs incubated with TA-TMA plasma. Taken together, we propose that NAC represents a new potential therapy for patients facing TA-TMA.}, }
@article {pmid30868002, year = {2018}, author = {Ishtiaq, R and Imran, A and Raza, H and Anwar, Q and Ishtiaq, D and Jamil, A and Ali, QM and Khan, R}, title = {Acute Hepatitis in Infections Caused by Dengue Virus in Southern Punjab, Pakistan.}, journal = {Cureus}, volume = {10}, number = {12}, pages = {e3788}, pmid = {30868002}, issn = {2168-8184}, abstract = {Background Dengue is the most common vector-borne disease worldwide. It poses a significant health burden in tropical and subtropical countries. Common clinical presentations include retro-orbital pain, fever, headache, nausea, vomiting and aches and pains in the body. A severe form of dengue fever is known as dengue hemorrhagic fever (DHF) that includes signs of hemorrhage. Besides the typical signs and symptoms, atypical presentations of dengue include myositis, hepatitis and encephalitis. Hepatic involvement in dengue has varied presentations. This study aims to highlight the importance of acute hepatitis, an atypical presentation in dengue patients. Methods We conducted a descriptive, cross-sectional study in the Medical Unit-1 of Bahawal Victoria Hospital, Bahawalpur, a tertiary-care hospital serving the area of Southern Punjab, Pakistan. The relevant medical records of 63 patients admitted with dengue-associated hepatitis to the Medical Unit-1 of Bahawal Victoria Hospital, Bahawalpur, between January 1, 2015 and December 1, 2016, were reviewed. Informed consent was given. Information regarding demographic variables and disease course was collected and analyzed. Results This study included 55 men (87.3%) and eight (12.7%) women. Fifty (79.3%) patients were diagnosed with dengue fever (DF). Thirteen patients were managed on the lines of DHF. Out of the total 63 patients, only six were locals. The common clinical presentations in these patients included high fever, retro-orbital pain, severe headache, rash, dark-colored urine, bleeding problems and hepatomegaly. Higher levels of aspartate aminotransferase (AST) were noted in comparison to alanine transferase (ALT). Despite the complicated clinical course in some patients, all patients were managed successfully and discharged, except one. Conclusion The frequency of acute hepatitis in dengue patients is high, especially in young men. Early diagnosis and prompt treatment are necessary for better prognosis. Although no specific treatment guidelines are available, supportive treatment in a timely fashion can prevent complications. Transfusion with packed cell volume (PCV) and N-acetyl cysteine (NAC) has produced promising results.}, }
@article {pmid30867543, year = {2019}, author = {Jiang, QW and Kaili, D and Freeman, J and Lei, CY and Geng, BC and Tan, T and He, JF and Shi, Z and Ma, JJ and Luo, YH and Chandler, H and Zhu, H}, title = {Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling.}, journal = {Acta pharmacologica Sinica}, volume = {40}, number = {9}, pages = {1205-1211}, pmid = {30867543}, issn = {1745-7254}, mesh = {Animals ; Cell Movement/*physiology ; Cell Proliferation/physiology ; Cells, Cultured ; Cornea/cytology ; Diabetes Mellitus, Experimental/*physiopathology ; Epithelial Cells/*metabolism ; Humans ; Mice ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*physiology ; Tight Junctions/*metabolism ; Wound Healing/*physiology ; }, abstract = {Corneal wounds usually heal quickly; but diabetic patients have more fragile corneas and experience delayed and painful healing. In the present study, we compared the healing capacity of corneal epithelial cells (CECs) between normal and diabetic conditions and the potential mechanisms. Primary murine CEC derived from wild-type and diabetic (db/db) mice, as well as primary human CEC were prepared. Human CEC were exposed to high glucose (30 mM) to mimic diabetic conditions. Cell migration and proliferation were assessed using Scratch test and MTT assays, respectively. Reactive oxygen species (ROS) production in the cells was measured using dichlorofluorescein reagent. Western blot was used to evaluate the expression levels of Akt. Transepithelial electrical resistance (TEER) and zonula occludens-1 (ZO-1) expression were used to determine tight junction integrity. We found that the diabetic CEC displayed significantly slower cell proliferation and migration compared with the normal CEC from both mice and humans. Furthermore, ROS production was markedly increased in CEC grown under diabetic conditions. Treatment with an antioxidant N-acetyl cysteine (NAC, 100 μM) significantly decreased ROS production and increased wound healing in diabetic CEC. Barrier function was significantly reduced in both diabetic mouse and human CEC, while NAC treatment mitigated these effects. We further showed that Akt signaling was impaired in diabetic CEC, which was partially improved by NAC treatment. These results show that diabetic conditions lead to delayed wound-healing capacity of CEC and impaired tight junction formation in both mice and human. Increased ROS production and inhibited Akt signaling may contribute to this outcome, implicating these as potential targets for treating corneal wounds in diabetic patients.}, }
@article {pmid30866404, year = {2019}, author = {Siamwala, JH and Kumar, P and Veeriah, V and Muley, A and Rajendran, S and Konikkat, S and Majumder, S and Mani, KP and Chatterjee, S}, title = {Nitric Oxide Reverses the Position of the Heart during Embryonic Development.}, journal = {International journal of molecular sciences}, volume = {20}, number = {5}, pages = {}, pmid = {30866404}, issn = {1422-0067}, support = {UGC-FRP//University Grants Commission/ ; }, mesh = {Animals ; Bone Morphogenetic Protein 4/*genetics ; Cell Movement/drug effects ; Cells, Cultured ; Chick Embryo ; Embryonic Development ; Heart/drug effects/*physiology ; Heart Function Tests/drug effects ; Microscopy, Video ; Myocytes, Cardiac/*cytology/drug effects ; Nitric Oxide/*pharmacology ; Situs Inversus/*chemically induced/genetics ; Up-Regulation ; }, abstract = {Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) plays crucial roles in cardiac homeostasis. Adult cardiomyocyte specific overexpression of eNOS confers protection against myocardial-reperfusion injury. However, the global effects of NO overexpression in developing cardiovascular system is still unclear. We hypothesized that nitric oxide overexpression affects the early migration of cardiac progenitor cells, vasculogenesis and function in a chick embryo. Vehicle or nitric oxide donor DEAN (500 mM) were loaded exogenously through a small window on the broad side of freshly laid egg and embryonic development tracked by live video-microscopy. At Hamburg Hamilton (HH) stage 8, the cardiac progenitor cells (CPC) were isolated and cell migration analysed by Boyden Chamber. The vascular bed structure and heart beats were compared between vehicle and DEAN treated embryos. Finally, expression of developmental markers such as BMP4, Shh, Pitx2, Noggin were measured using reverse transcriptase PCR and in-situ hybridization. The results unexpectedly showed that exogenous addition of pharmacological NO between HH stage 7[-]8 resulted in embryos with situs inversus in 28 out of 100 embryos tested. Embryos treated with NO inhibitor cPTIO did not have situs inversus, however 10 embryos treated with L-arginine showed a situs inversus phenotype. N-acetyl cysteine addition in the presence of NO failed to rescue situs inversus phenotype. The heart beat is normal (120 beats/min) although the vascular bed pattern is altered. Migration of CPCs in DEAN treated embryos is reduced by 60% compared to vehicle. BMP4 protein expression increases on the left side of the embryo compared to vehicle control. The data suggests that the NO levels in the yolk are important in turning of the heart during embryonic development. High levels of NO may lead to situs inversus condition in avian embryo by impairing cardiac progenitor cell migration through the NO-BMP4-cGMP axis.}, }
@article {pmid30865562, year = {2019}, author = {Song, J and Wang, Y and Yuan, X and Ji, Q and Fan, C and Zhao, H and Hao, W and Ren, D}, title = {Stretching magnitude-dependent inactivation of AKT by ROS led to enhanced p53 mitochondrial translocation and myoblast apoptosis.}, journal = {Molecular biology of the cell}, volume = {30}, number = {10}, pages = {1182-1197}, pmid = {30865562}, issn = {1939-4586}, mesh = {Apoptosis/physiology ; Cell Line ; Humans ; Mechanoreceptors/metabolism ; Membrane Potential, Mitochondrial/physiology ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism ; Myoblasts/*metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Previously, we had shown that high magnitude stretch (HMS), rather than low magnitude stretch (LMS), induced significant apoptosis of skeletal muscle C2C12 myoblasts. However, the molecular mechanism remains obscure. In this study, we found that p53 protein accumulated in the nucleus of LMS-loaded cells, whereas it translocated into mitochondria of HMS-loaded cells. Knocking down endogenous p53 by shRNA abrogated HMS-induced apoptosis. Furthermore, we demonstrated that overaccumulation of reactive oxygen species (ROS) during HMS-inactivated AKT that was activated in LMS-treated cells, which accounted for the distinct p53 subcellular localizations under HMS and LMS. Blocking ROS generation by N-acetylcysteine (NAC) or overexpressing constitutively active AKT vector (CA-AKT) inhibited HMS-incurred p53 mitochondrial translocation and promoted its nuclear targeting. Moreover, both NAC and CA-AKT significantly attenuated HMS-induced C2C12 apoptosis. Finally, we found that Ser389 phosphorylation of p53 was a downstream event of ROS-inactivated AKT pathway, which was critical to p53 mitochondrial trafficking during HMS stimuli. Transfecting p53-shRNA C2C12s with the mutant p53 (S389A) that was unable to target p53 to mitochondria underwent significantly lower apoptosis than transfection with wild-type p53. Altogether, our study uncovered that mitochondrial localization of p53, resulting from p53 Ser389 phosphorylation through ROS-inactivated AKT pathway, prompted C2C12 myoblast apoptosis during HMS stimulation.}, }
@article {pmid30862482, year = {2019}, author = {Zhang, L and Lu, P and Yan, L and Yang, L and Wang, Y and Chen, J and Dai, J and Li, Y and Kang, Z and Bai, T and Xi, Y and Xu, J and Sun, G and Yang, T}, title = {MRPL35 Is Up-Regulated in Colorectal Cancer and Regulates Colorectal Cancer Cell Growth and Apoptosis.}, journal = {The American journal of pathology}, volume = {189}, number = {5}, pages = {1105-1120}, doi = {10.1016/j.ajpath.2019.02.003}, pmid = {30862482}, issn = {1525-2191}, mesh = {Animals ; *Apoptosis ; Biomarkers, Tumor/genetics/*metabolism ; Cell Cycle ; *Cell Proliferation ; Colorectal Neoplasms/genetics/metabolism/*pathology ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mice ; Mice, Nude ; Mitochondrial Proteins/genetics/*metabolism ; Prognosis ; Ribosomal Proteins/genetics/*metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {Mitochondrial ribosome proteins (MRPs), which are encoded by the nuclear genomic DNA, are important for mitochondrial-encoded protein synthesis and mitochondrial function. Emerging evidence suggests that several MRPs also exhibit important extra-mitochondrial functions, such as involvement in apoptosis, protein biosynthesis, and signal transduction. In this study, we demonstrate a significant role of MRP L35 (MRPL35) in colorectal cancer (CRC). The expression of MRPL35 was higher in CRC tissues than in matched cancer-adjacent tissues and higher in CRC cells than in normal mucosal epithelial cells. Higher MRPL35 expression in CRC tissue correlated with shorter overall survival for CRC patients. In vitro, down-regulation of MRPL35 led to increased production of reactive oxygen species (ROS) together with DNA damage, loss of cell proliferation, G2/M arrest, a decrease in mitochondrial membrane potential, apoptosis, and autophagy induction. MRPL35 knockdown inhibited tumor proliferation in a CRC xenograft nude mouse model. Furthermore, overexpression of MRPL35 or treatment of cells with the ROS scavenger, N-acetyl cysteine, abrogated ROS production, cell cycle arrest, and apoptosis in vitro. These findings suggest that MRPL35 plays an essential role in the development of CRC and may be a potential therapeutic target for CRC.}, }
@article {pmid30861304, year = {2019}, author = {Refsnes, M and Skuland, T and Lilleaas, E and Øvrevik, J and Låg, M}, title = {Concentration-dependent cytokine responses of silica nanoparticles and role of ROS in human lung epithelial cells.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {125}, number = {3}, pages = {304-314}, doi = {10.1111/bcpt.13221}, pmid = {30861304}, issn = {1742-7843}, mesh = {Bronchi/cytology/*drug effects/immunology ; Cell Line ; Dual Oxidases/genetics/metabolism ; Epithelial Cells/drug effects/immunology ; Gene Expression Regulation/drug effects/immunology ; Humans ; Interleukin-6/immunology/metabolism ; Interleukin-8/immunology/metabolism ; Mitogen-Activated Protein Kinase 14/metabolism ; Nanoparticles/*toxicity ; Particle Size ; Phosphorylation/drug effects/genetics ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/immunology/*metabolism ; Respiratory Mucosa/cytology/*drug effects/immunology ; Signal Transduction/drug effects/immunology ; Silicon Dioxide/*toxicity ; Transcription Factor RelA/metabolism ; }, abstract = {Reactive oxygen species (ROS) is regarded as a critical denominator in nanoparticle toxicology and inflammation. Previously, we have shown that silica nanoparticles sized 50 nm (Si50) induce release of CXCL8 and IL-6 from BEAS-2B cells, via mechanisms involving NFκB, p38 MAP kinase and TGF-α-activated EGF receptor. In the present study, the role of ROS-mediated mechanisms in the concentration-dependent Si50 induction of CXCL8 and IL-6 responses was examined. Si50 (200 µg/mL) induced a time-dependent ROS formation and a postponed increase in expression of haem oxygenase (HO-1) mRNA and protein. Pre-treatment with the ROS inhibitors N-acetyl cysteine (NAC) and diphenyleneiodonium (DPI) partially attenuated CXCL8 and IL-6 responses to 200 µg/mL, but not to 100 µg/mL Si50. The release of TGF-α induced by Si50 (200 µg/mL) was significantly reduced by NAC, but not by DPI nor siRNA against NADPH oxidase DUOX-1 (siDUOX-1). Furthermore, siDUOX-1 reduced Si50-induced CXCL8, but not IL-6. Both p38 and p65 phosphorylations were inhibited by siDUOX-1, but for NAC only p65 phosphorylation reached a significant reduction. Neither NAC nor DPI reduced Si50-induced CXCL8 and IL-6 gene expressions. In conclusion, Si50-induced CXCL8 and IL-6 involved both ROS-dependent and ROS-independent mechanisms. Notably, the role of ROS seemed restricted to effects of higher concentrations of Si50 and not mediated via the gene expression.}, }
@article {pmid30859735, year = {2020}, author = {Eshraghi, AA and Jung, HD and Mittal, R}, title = {Recent Advancements in Gene and Stem Cell-Based Treatment Modalities: Potential Implications in Noise-Induced Hearing Loss.}, journal = {Anatomical record (Hoboken, N.J. : 2007)}, volume = {303}, number = {3}, pages = {516-526}, doi = {10.1002/ar.24107}, pmid = {30859735}, issn = {1932-8494}, mesh = {Animals ; Evoked Potentials, Auditory, Brain Stem/physiology ; Genetic Therapy/*methods ; Hearing Loss, Noise-Induced/physiopathology/*therapy ; Humans ; Stem Cell Transplantation/*methods ; }, abstract = {Noise-induced hearing loss (NIHL) poses a significant burden on not only the economics of health care but also the quality of life of an individual, as we approach an unprecedented age of longevity. In this article, we will delineate the current landscape of management of NIHL. We discuss the most recent results from in vitro and in vivo studies that determine the effectiveness of established pharmacotherapy such as corticosteroid and potential emerging therapies like N-acetyl cysteine and neurotrophins (NTs), as well as highlight ongoing clinical trials for these therapeutic agents. We present an overview of how the recent advancements in the field of gene-based and stem cell-based therapies can help in developing effective therapeutic strategies for NIHL. Gene-based therapies have shown exciting results demonstrating cochlear cellular regeneration using Atoh1, NRF2 as well as NT gene therapy employing viral vectors. In addition, we will discuss the recent advancements in genome-editing technologies, such as CRISPR/Cas9, and its potential role in NIHL therapy. We will further discuss the current state of stem cell therapy as it pertains to treating neurodegenerative conditions including NIHL. Embryonic stem cells, adult-derived stem cells, and induced pluripotent stem cells all represent an enticing reservoir of replacing damaged cells as a result of NIHL. Finally, we will discuss the barriers that need to be overcome to translate these promising treatment modalities to the clinical practice in pursuit of improving quality of life of patients having NIHL. Anat Rec, 303:516-526, 2020. © 2019 American Association for Anatomy.}, }
@article {pmid30857628, year = {2019}, author = {Hu, B and Hu, S and Huang, H and Wei, Q and Ren, M and Huang, S and Tian, X and Su, J}, title = {Insecticides induce the co-expression of glutathione S-transferases through ROS/CncC pathway in Spodoptera exigua.}, journal = {Pesticide biochemistry and physiology}, volume = {155}, number = {}, pages = {58-71}, doi = {10.1016/j.pestbp.2019.01.008}, pmid = {30857628}, issn = {1095-9939}, mesh = {Animals ; Glutathione Transferase/genetics/*metabolism ; Insect Proteins/genetics ; Insecticide Resistance/genetics ; Insecticides/*pharmacology ; Reactive Oxygen Species/*metabolism ; Spodoptera/*drug effects/*metabolism ; }, abstract = {Glutathione S-transferases (GSTs) are a family of multifunctional enzymes that are involved in detoxification of electrophilic toxic compounds. Although the co-induced expression of GST genes by insecticides in insects has been documented in recent years, the underlying regulatory mechanisms are not understood. In this study, a total of thirty-one cytosolic S. exigua GSTs (SeGSTs) was cloned and identified. The bioinformatics and gene expression patterns were also analyzed. Out of them, SeGSTe9, SeGSTs6, SeGSTe1, SeGSTe6, SeGSTe8, SeGSTe14, and SeGSTd1 were significantly co-expressed following exposure to three insecticides (lambda-cyhalothrin, chlorpyrifos and chlorantraniliprole). The analysis of upstream sequences revealed that all of these seven SeGSTs harbored CncC/Maf binding site. The luciferase reporter assay showed that the pGL3-SeGST promoter construct exhibited a significant increase in luciferase activities after exposure to insecticides, and mutation of CncC/Maf binding site diminish the induction effect. These data indicate that CncC/Maf pathway regulates the co-expression of GST genes in response to different insecticides in S. exigua. Insecticides significantly enhanced the ROS content and treatment with the ROS inhibitor N-acetylcysteine (NAC) decreased the insecticide-induced luciferase activities of the PGL3-GSTe6 promoter construct, but not the CncC-mutated construct. These results indicate that ROS mediates GST gene expression after exposure to insecticides through CncC/Maf pathway. Overall, these data show that insecticides induce the co-expression of glutathione S-transferases through the ROS/CncC pathway in S. exigua.}, }
@article {pmid30851366, year = {2019}, author = {Dilshara, MG and Jayasooriya, RGPT and Choi, YH and Kim, GY}, title = {Camptothecin induces c-Myc- and Sp1-mediated hTERT expression in LNCaP cells: Involvement of reactive oxygen species and PI3K/Akt.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {127}, number = {}, pages = {53-60}, doi = {10.1016/j.fct.2019.03.001}, pmid = {30851366}, issn = {1873-6351}, mesh = {Camptothecin/*pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Enzyme Activation ; *Genes, myc ; Humans ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Sp1 Transcription Factor/*metabolism ; Telomerase/*metabolism ; Topoisomerase I Inhibitors/*pharmacology ; }, abstract = {Camptothecin (CPT), a quinoline alkaloid isolated from Camptotheca acuminate, targets topoisomerase I, which is continuously expressed in cancer cells. However, the molecular mechanisms responsible for CPT-induced telomerase inhibition remain unclear. Unexpectedly, we found that CPT upregulates hTERT expression and concomitantly increases telomerase activity. However, transfection of hTERT-targeting siRNA had no effect on CPT-induced G2/M phase arrest, suggesting that CPT-induced telomerase activation was not related to G2/M phase arrest. CPT simultaneously increased Nrf2 expression and the level of intracellular reactive oxygen species (ROS), whereas pretreatment with the antioxidants N-acetyl-cysteine (NAC) or glutathione (GSH) strongly attenuated ROS production, which was accompanied by hTERT downregulation. Additionally, transient Nrf2 knockdown enhanced CPT-induced ROS production and hTERT promoter activity. CPT also upregulated hTERT expression and telomerase activity by inducing c-Myc and Sp1 expression and activity. Moreover, c-Myc stimulated ROS production in response to CPT, leading to Sp1 activation, which promoted hTERT expression and telomerase activity. CPT treatment enhanced the phosphorylation of PI3K and Akt, which led to hTERT phosphorylation into the nucleus. These findings demonstrate that CPT positively regulates telomerase activity by upregulating hTERT expression and phosphorylation via the c-Myc/ROS/Sp1 and PI3K/Akt axis.}, }
@article {pmid30849338, year = {2019}, author = {Changchien, CY and Lin, YH and Cheng, YC and Chang, HH and Peng, YS and Chen, Y}, title = {Indoxyl sulfate induces myotube atrophy by ROS-ERK and JNK-MAFbx cascades.}, journal = {Chemico-biological interactions}, volume = {304}, number = {}, pages = {43-51}, doi = {10.1016/j.cbi.2019.02.023}, pmid = {30849338}, issn = {1872-7786}, mesh = {Animals ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Indican/*pharmacology ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mice ; Muscle Proteins/*antagonists &amp; inhibitors/metabolism ; Muscular Atrophy/*chemically induced/metabolism ; Reactive Oxygen Species/*metabolism ; SKP Cullin F-Box Protein Ligases/*antagonists &amp; inhibitors/metabolism ; Structure-Activity Relationship ; }, abstract = {Accumulations of uremic toxins has been widely recognized as the major trigger of skeletal muscle loss in chronic kidney disease (CKD), which is defined as uremic sarcopenia. Current study was aimed to examine the effects of representative uremic toxin, indoxyl sulfate (IS), on C2C12 myotubes. The incubation of IS (from 0.1 mM to 1.2 mM) exerted the reduction in myotube diameter without cell survival impairment. Elevated oxidative stress and mitogen-activated protein kinase (MAPKs) phosphorylation were observed after IS stimulation for 1 and 24 h. After N-acetylcysteine (NAC) treatment as antioxidants, the recovery in IS-induced decrease myotube diameter and ERK phosphorylation was observed. This findings were implicit the transduction of p-ERK in IS-induced ROS toxicity. Moreover, the increase of LC3β was found closely with IS treatment in C2C12 myotubes. The reverse effect of NAC on LC3β expression revealed the ROS-responsibility in autophagy regulation of CKD myopathy. The evaluation of IS-treated proteasome system showed increased phospho-myosin light chain, along with the upregulation of muscle atrophy F-box (MAFbx) mRNA and protein. This alteration in MAFbx was also identified in nephrectomy-induced CKD model. Besides, the inhibition of p-JNK was capable to attenuate IS-induced upward change in MAFbx protein expression. These findings indicated that IS-mediated myotube atrophy may manipulate through ROS-ERK axis and JNK-MAFbx regulation in C2C12 cells.}, }
@article {pmid30848314, year = {2019}, author = {Park, A and Koh, HC}, title = {NF-κB/mTOR-mediated autophagy can regulate diquat-induced apoptosis.}, journal = {Archives of toxicology}, volume = {93}, number = {5}, pages = {1239-1253}, doi = {10.1007/s00204-019-02424-7}, pmid = {30848314}, issn = {1432-0738}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Survival/drug effects ; Diquat/administration &amp; dosage/*toxicity ; Dose-Response Relationship, Drug ; Herbicides/*administration &amp; dosage/*toxicity ; NF-kappa B/metabolism ; Neurotoxicity Syndromes/*etiology/physiopathology/prevention &amp; control ; PC12 Cells ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Time Factors ; }, abstract = {Autophagy and apoptosis are the major types of cell death in pesticide-induced neurotoxicity, and autophagy is known to play a role in cell protection by inhibiting apoptosis. In this study, we characterized the relationship between autophagy and apoptosis in diquat (DQ)-induced cell death and explored a novel pharmacotherapeutic approach involving autophagy regulation to prevent DQ neurotoxicity. DQ was cytotoxic to PC12 cells in a concentration-dependent manner, as shown by decreased cell viability and decreased dopamine (DA) levels. DQ-induced apoptosis was found in PC12 cells, as demonstrated by activation of caspase-3 and -9 and by nuclear condensation. By monitoring expression of microtubule-associated protein 1A/1B light chain 3B (LC3-II) and p62, DQ was found to induce autophagy. Exposure of PC12 cells to DQ led to the production of reactive oxygen species (ROS), and N-acetyl-cysteine (NAC) antioxidant effectively blocked both apoptosis and autophagy. Interestingly, DQ in PC12 cells showed increased p53 and NF-κB in a time-dependent manner; furthermore, pifithrin-α (PFT-α), a p53 inhibitor, downregulates the cytotoxicity of DQ, as shown by decreased LC3-II and cleaved caspase-3. SN50, an NF-κB inhibitor, results in diminished LC3-II, cleaved caspase-3, and p53. DQ induces mitogen-activated protein kinase (MAPK) signaling including ERK, JNK, and p38, which inhibit regulated apoptosis and autophagic cell death by controlling mTOR signaling. In addition, modulation of DQ-induced apoptosis in response to autophagy regulation was investigated. Pretreatment with rapamycin, an autophagy inducer, significantly enhanced the viability of DQ-exposed cells by alleviating DQ-induced apoptosis. Conversely, cell pretreatment with 3-methyladenine (3MA), an autophagy inhibitor increased DQ toxicity. Our results suggest that DQ-induced cytotoxicity is modified by autophagy regulation. Pharmacologic induction of autophagy may be a useful treatment strategy in neurodegenerative disorders.}, }
@article {pmid30843602, year = {2019}, author = {Christiansen, D and Eibye, KH and Rasmussen, V and Voldbye, HM and Thomassen, M and Nyberg, M and Gunnarsson, TGP and Skovgaard, C and Lindskrog, MS and Bishop, DJ and Hostrup, M and Bangsbo, J}, title = {Cycling with blood flow restriction improves performance and muscle K[+] regulation and alters the effect of anti-oxidant infusion in humans.}, journal = {The Journal of physiology}, volume = {597}, number = {9}, pages = {2421-2444}, pmid = {30843602}, issn = {1469-7793}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Adult ; Antioxidants/administration &amp; dosage/pharmacology ; Glutathione/metabolism ; Humans ; Infusions, Intravenous ; Ischemic Preconditioning/*methods ; Male ; Muscle, Skeletal/blood supply/drug effects/metabolism/*physiology ; Physical Conditioning, Human/*methods ; Potassium/*metabolism ; Reactive Oxygen Species/metabolism ; Regional Blood Flow ; Sodium-Potassium-Exchanging ATPase/metabolism ; }, abstract = {KEY POINTS: Training with blood flow restriction (BFR) is a well-recognized strategy for promoting muscle hypertrophy and strength. However, its potential to enhance muscle function during sustained, intense exercise remains largely unexplored. In the present study, we report that interval training with BFR augments improvements in performance and reduces net K[+] release from contracting muscles during high-intensity exercise in active men. A better K[+] regulation after BFR-training is associated with an elevated blood flow to exercising muscles and altered muscle anti-oxidant function, as indicated by a higher reduced to oxidized glutathione (GSH:GSSG) ratio, compared to control, as well as an increased thigh net K[+] release during intense exercise with concomitant anti-oxidant infusion. Training with BFR also invoked fibre type-specific adaptations in the abundance of Na[+] ,K[+] -ATPase isoforms (α1 , β1 , phospholemman/FXYD1). Thus, BFR-training enhances performance and K[+] regulation during intense exercise, which may be a result of adaptations in anti-oxidant function, blood flow and Na[+] ,K[+] -ATPase-isoform abundance at the fibre-type level.<br><br>ABSTRACT: We examined whether blood flow restriction (BFR) augments training-induced improvements in K[+] regulation and performance during intense exercise in men, and also whether these adaptations are associated with an altered muscle anti-oxidant function, blood flow and/or with fibre type-dependent changes in Na[+] ,K[+] -ATPase-isoform abundance. Ten recreationally-active men (25&#xa0;&#xb1;&#xa0;4&#xa0;years, 49.7&#xa0;&#xb1;&#xa0;5.3&#xa0;mL&#xa0;kg[-1] &#xa0;min[-1]) performed 6 weeks of interval cycling, where one leg trained without BFR (control; CON-leg) and the other trained with BFR (BFR-leg, pressure: &#x223c;180&#xa0;mmHg). Before and after training, femoral arterial and venous K[+] concentrations and artery blood flow were measured during single-leg knee-extensor exercise at 25% (Ex1) and 90% of thigh incremental peak power (Ex2) with i.v. infusion of N-acetylcysteine (NAC) or placebo (saline) and a resting muscle biopsy was collected. After training, performance increased more in BFR-leg (23%) than in CON-leg (12%, P&#xa0;<&#xa0;0.05), whereas K[+] release during Ex2 was attenuated only from BFR-leg (P&#xa0;<&#xa0;0.05). The muscle GSH:GSSG ratio at rest and blood flow during exercise was higher in BFR-leg than in CON-leg after training (P&#xa0;<&#xa0;0.05). After training, NAC increased resting muscle GSH concentration and thigh net K[+] release during Ex2 only in BFR-leg (P&#xa0;<&#xa0;0.05), whereas the abundance of Na[+] ,K[+] -ATPase-isoform &#x3b1;1 in type II (51%), &#x3b2;1 in type I (33%), and FXYD1 in type I (108%) and type II (60%) fibres was higher in BFR-leg than in CON-leg (P&#xa0;<&#xa0;0.05). Thus, training with BFR elicited greater improvements in performance and reduced thigh K[+] release during intense exercise, which were associated with adaptations in muscle anti-oxidant function, blood flow and Na[+] ,K[+] -ATPase-isoform abundance at the fibre-type level.}, }
@article {pmid30841517, year = {2019}, author = {Kopincova, J and Kolomaznik, M and Mikolka, P and Kosutova, P and Topercerova, J and Matasova, K and Calkovska, A and Mokra, D}, title = {Recombinant Human Superoxide Dismutase and N-Acetylcysteine Addition to Exogenous Surfactant in the Treatment of Meconium Aspiration Syndrome.}, journal = {Molecules (Basel, Switzerland)}, volume = {24}, number = {5}, pages = {}, pmid = {30841517}, issn = {1420-3049}, support = {VEGA 1/0356/18//Vedeck&#xe1; Grantov&#xe1; Agent&#xfa;ra M&#x160;VVa&#x160; SR a SAV/ ; APVV-0435-11//Agent&#xfa;ra na Podporu V&#xfd;skumu a V&#xfd;voja/ ; APVV-15-0075//Agent&#xfa;ra na Podporu V&#xfd;skumu a V&#xfd;voja/ ; ITMS code: 26220120016//European Regional Development Fund/ ; ITMS code: 26220220187//European Social Fund/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Biomarkers ; Disease Models, Animal ; Humans ; Lung/drug effects/metabolism/physiopathology ; Lung Compliance/drug effects ; Meconium Aspiration Syndrome/drug therapy/etiology/metabolism/physiopathology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Rabbits ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/*pharmacology ; Respiratory Function Tests ; Superoxide Dismutase/*pharmacology ; Surface-Active Agents/*pharmacology ; }, abstract = {This study aimed to evaluate the molecular background of N-acetylcysteine (NAC) and recombinant human superoxide dismutase (rhSOD) antioxidant action when combined with exogenous surfactant in the treatment of meconium aspiration syndrome (MAS), considering redox signalling a principal part of cell response to meconium. Young New Zealand rabbits were instilled with meconium suspension (Mec) and treated by surfactant alone (Surf) or surfactant in combination with i.v. NAC (Surf + NAC) or i.t. rhSOD (Surf + SOD), and oxygen-ventilated for 5 h. Dynamic lung-thorax compliance, mean airway pressure, PaO2/FiO2 and ventilation efficiency index were evaluated every hour; post mortem, inflammatory and oxidative markers (advanced oxidation protein products, total antioxidant capacity, hydroxynonenal (HNE), p38 mitogen activated protein kinase, caspase 3, thromboxane, endothelin-1 and secretory phospholipase A2) were assessed in pulmonary tissue homogenates. rhSOD addition to surfactant improved significantly, but transiently, gas exchange and reduced levels of inflammatory and oxidative molecules with higher impact; Surf + NAC had stronger effect only on HNE formation, and duration of treatment efficacy in respiratory parameters. In both antioxidants, it seems that targeting reactive oxygen species may be strong supporting factor in surfactant treatment of MAS due to redox sensitivity of many intracellular pathways triggered by meconium.}, }
@article {pmid30838890, year = {2019}, author = {Wong, A and Nejad, C and Gantier, M and Choy, KW and Doery, J and Graudins, A}, title = {MicroRNA from a 12-h versus 20-h acetylcysteine infusion for paracetamol overdose.}, journal = {Human &amp; experimental toxicology}, volume = {38}, number = {6}, pages = {646-654}, doi = {10.1177/0960327119833740}, pmid = {30838890}, issn = {1477-0903}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Drug Overdose/*drug therapy/genetics ; Female ; Humans ; Infusions, Intravenous ; Male ; *MicroRNAs ; Young Adult ; }, abstract = {Paracetamol overdose is common and microRNA (miR)-122 expression is increased with liver injury. We aimed to measure miR-122 in the setting of an abbreviated paracetamol overdose treatment regimen. We compared miRNA expression in patients treated for paracetamol poisoning with an abbreviated 12-h intravenous acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) or a 20-h regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) (NACSTOP trial). miR-122 expression is increased (decreased cycle threshold (Ct) values) with paracetamol liver injury. We assessed miR-122 expression in patients receiving the two acetylcysteine regimens and in a separate group with acute liver injury (ALI). We examined 121 blood samples in 38 patients. After 20 h of acetylcysteine, median alanine transaminase (ALT) was 12 U/L (18, 14) versus 16 U/L (11, 21) (p = 0.17) and median miR-122 Ct was 30.1 (interquartile range (IQR): 28.9, 33.3) versus 31.4 (28.9, 33.9) (p = 0.7) in the NACSTOP abbreviated and control groups, respectively. Median normalized miR-122 Ct after 20 h of acetylcysteine was 2.2 (IQR 1.9, 6.4), 1.1 (0.7, 2.9), 63.9 (2.5, 168), 123.2 (40.9, 207.8) in the NACSTOP-abbreviated, NACSTOP-control, ALI and hepatotoxicity groups, respectively. There was no significant difference in ALT or miRNA between NACSTOP treatment groups and no signal of increased liver injury from an abbreviated 12-h acetylcysteine regimen. These findings suggest that an abbreviated acetylcysteine regimen in low-risk patients who have overdosed on paracetamol is safe. Further study is required to validate this finding utilizing miRNA as a comparative biomarker.}, }
@article {pmid30837634, year = {2019}, author = {Dong, L and Sun, W and Li, F and Shi, M and Meng, X and Wang, C and Meng, M and Tang, W and Liu, H and Wang, L and Song, L}, title = {The harmful effects of acute PM2.5 exposure to the heart and a novel preventive and therapeutic function of CEOs.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {3495}, pmid = {30837634}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium/metabolism ; Heart/*drug effects ; Interleukin-6/genetics/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Myocardium/metabolism/pathology ; Oils, Volatile/*pharmacology ; Oxidative Stress/drug effects ; Particulate Matter/*toxicity ; Reactive Oxygen Species/metabolism ; Ryanodine Receptor Calcium Release Channel/genetics/metabolism ; }, abstract = {Epidemiological researches have demonstrated the relationship between PM2.5 exposure and increased morbidity and mortality of cardiovascular injury. However, no effective therapeutic method was established. The purpose of this study is to investigate the effect of acute PM2.5 exposure on the mice heart tissue and explore the therapeutic effects of compound essential oils (CEOs) in this model. In this study, after mice were exposed to PM2.5 intratracheally, some obvious histopathological changes as well as some great alterations of proinflammatory cytokines were observed in the heart tissue. The imbalance of oxidative stress, the altered Ca[2+] channel related proteins and the increased intracellular free Ca[2+] were all involved in the heart impairment and would also be investigated in this model. The CEOs alleviated the heart impairment via its antioxidant effect rather than its anti-inflammatory function because our results revealed that oxidative stress related indicators were restored after CEOs administration. At the same time, increased concentration of intracellular free Ca[2+] and ROS induced by PM2.5 were reduced after NAC (N-Acetyl-L-cysteine) administration. These data suggested that the acute PM2.5 exposure would damage heart tissue by inducing the inflammatory response, oxidative stress and intracellular free Ca[2+] overload. PM2.5-induced oxidative stress probably increase intracellular free Ca[2+] via RYR2 and SERCA2a. CEOs have the potential to be a novel effective and convenient therapeutic method to prevent and treat the acute heart impairment induced by PM2.5 via its antioxidant function.}, }
@article {pmid30832310, year = {2019}, author = {Hsu, PS and Lin, CM and Chang, JF and Wu, CS and Sia, KC and Lee, IT and Huang, KY and Lin, WN}, title = {Participation of NADPH Oxidase-Related Reactive Oxygen Species in Leptin-Promoted Pulmonary Inflammation: Regulation of cPLA2α and COX-2 Expression.}, journal = {International journal of molecular sciences}, volume = {20}, number = {5}, pages = {}, pmid = {30832310}, issn = {1422-0067}, mesh = {Animals ; Cell Line, Tumor ; Cyclooxygenase 2/genetics/*metabolism ; Group IV Phospholipases A2/genetics/*metabolism ; Humans ; Leptin/*metabolism ; Lung/metabolism ; Male ; Mice ; Mice, Inbred ICR ; NADPH Oxidases/metabolism ; Oxidative Stress ; Pneumonia/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Leptin/metabolism ; }, abstract = {Obesity is a worldwide epidemic problem and correlates to varieties of acute or chronic lung diseases such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis. An increase of leptin, a kind of adipokine, in lean mice plasma has been found to impair immune responses and facilitate the infection of Klebsiella pneumoniae, resulting in increased pneumonia severity. Also, a higher leptin level is found in exhaled breath condensates of obese or asthmatic subjects, compared to healthy ones, suggesting that leptin is involved in the occurrence or exacerbation of lung injury. In previous studies, we showed that leptin stimulated cytosolic phospholipase A2-α (cPLA2α) gene expression in lung alveolar type II cells via mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB)-activated coactivator p300. Herein, we show that the in vivo application of leptin in the respiratory system upregulated the expression of inflammatory proteins cPLA2α and cyclooxygenase-2 (COX-2) together with leukocyte infiltration. Treatment with an ROS scavenger (N-acetylcysteine, NAC), an NADPH oxidase inhibitor (apocynin), or an activating protein (AP)-1 inhibitor (tanshinone IIA) attenuated leptin-mediated cPLA2α/COX-2 expression and leukocyte recruitment in the lung. Leptin increased intracellular oxidative stress in a leptin receptor (OB-R) and NADPH oxidase-dependent manner, leading to the phosphorylation of the AP-1 subunit c-Jun. In summation, leptin increased lung cPLA2α/COX-2 expression and leukocyte recruitment via the NADPH oxidase/ROS/AP-1 pathway. Understanding the inflammatory effects of leptin on the pulmonary system provides opportunities to develop strategies against lung injury related to metabolic syndrome or obesity.}, }
@article {pmid30829731, year = {2019}, author = {Bellos, I and Iliopoulos, DC and Perrea, DN}, title = {Allopurinol Administration for the Prevention of Contrast-Induced Nephropathy: A Network Meta-analysis With Trial Sequential Analysis.}, journal = {Journal of cardiovascular pharmacology}, volume = {73}, number = {5}, pages = {307-315}, doi = {10.1097/FJC.0000000000000663}, pmid = {30829731}, issn = {1533-4023}, mesh = {Acute Kidney Injury/chemically induced/epidemiology/physiopathology/*prevention &amp; control ; Allopurinol/adverse effects/*therapeutic use ; Contrast Media/*adverse effects ; Cytoprotection ; Fluid Therapy ; Gout Suppressants/adverse effects/*therapeutic use ; Humans ; Incidence ; Kidney/*drug effects/physiopathology ; Network Meta-Analysis ; Randomized Controlled Trials as Topic ; Risk Factors ; Treatment Outcome ; }, abstract = {Contrast-induced nephropathy represents a major source of morbidity in patients undergoing coronary angiography. Various preventive measures have been proposed, although the optimal one remains still unknown. The aim of the present meta-analysis is to accumulate current literature knowledge and evaluate the renoprotective effects of allopurinol administration before contrast medium exposure. To achieve this, MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov, and Google Scholar databases were searched from inception to November 8, 2018. Statistical meta-analysis was conducted with Review Manager 5.3, TSA 0.9.5.5 and R-3.4.3. Six studies were included with a total of 918 patients. Quantitative synthesis revealed that allopurinol leads to significantly reduced incidence of contrast-induced nephropathy compared with hydration alone [odds ratio: 0.29, 95% confidence interval: (0.09-0.90)]. Trial sequential analysis suggested that Z-curve crossed the O'Brien-Fleming significance boundaries, although required information size was not reached. Network meta-analysis indicated that allopurinol had the highest probability (81.2%) to rank as the most effective intervention compared with hydration and N-acetyl cysteine; however, significant overlap with the rest treatments was noted. In conclusion, the present meta-analysis suggests that allopurinol may represent a promising measure for the prevention of acute kidney injury after coronary angiography. Future large-scale randomized controlled trials should verify this finding, while combinations of allopurinol with other novel interventions should be evaluated to define the most effective strategy to be implemented in the clinical setting.}, }
@article {pmid30825206, year = {2019}, author = {Li, K and Deng, G and Deng, Y and Chen, S and Wu, H and Cheng, C and Zhang, X and Yu, B and Zhang, K}, title = {High cholesterol inhibits tendon-related gene expressions in tendon-derived stem cells through reactive oxygen species-activated nuclear factor-κB signaling.}, journal = {Journal of cellular physiology}, volume = {234}, number = {10}, pages = {18017-18028}, doi = {10.1002/jcp.28433}, pmid = {30825206}, issn = {1097-4652}, mesh = {Achilles Tendon/drug effects/*metabolism/pathology ; Animals ; Antioxidants/pharmacology ; Cells, Cultured ; Cholesterol/*metabolism ; Disease Models, Animal ; Female ; Gene Expression Regulation ; Hypercholesterolemia/drug therapy/genetics/*metabolism/pathology ; Male ; Mice, Knockout, ApoE ; NF-kappa B/*metabolism ; *Oxidative Stress/drug effects ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Stem Cells/drug effects/*metabolism/pathology ; Tendinopathy/genetics/*metabolism/pathology/prevention &amp; control ; }, abstract = {Clinical studies have indicated that increased serum cholesterol levels raised the risk of tendinopathy in hypercholesterolemia, but the effect of cholesterol on tendon-derived stem cells (TDSCs) and its underlying mechanism have not been studied. The purpose of this study is to investigate the association between cholesterol and tendinopathy in vitro and in vivo, and its underlying molecular mechanism as well. In TDSCs, the effect of cholesterol was assessed by quantitative polymerase chain reaction, western blot analysis, and immunofluorescence staining. Intracellular levels of reactive oxygen species (ROS) was detected, using flow cytometry. The link between nuclear factor (NF)-κB signaling and the effect of cholesterol was evaluated using a representative IκB kinase (IKK) inhibitor, BAY 11-7082. In addition, Achilles tendons from apolipoprotein E mice fed with a high-fat diet were histologically assessed using hematoxylin and eosin staining and immunohistochemistry. We found that high cholesterol apparently lowered the expression of tendon cell markers (collagen 1, scleraxis, tenomodulin), and elevated ROS levels via the NF-κB pathway both in vitro and in vivo. The ROS scavenger N-acetylcysteine (NAC) and BAY 11-7082 reversed the inhibiting effect of cholesterol on the tendon-related gene expressions of TDSCs. Moreover, NAC blocked cholesterol-induced phosphorylation of IκBα and p65. Significant histological alternation in vivo was shown in Achilles tendon in the hypercholesterolemic group. These results indicated that high cholesterol may inhibit the tendon-related gene expressions in TDSCs via ROS-activated NF-кB signaling, implying pathogenesis of tendinopathy in hypercholesterolemia and suggesting a new mechanism underlying hypercholesterolemia-induced tendinopathy.}, }
@article {pmid30822667, year = {2019}, author = {Liao, J and Yang, F and Tang, Z and Yu, W and Han, Q and Hu, L and Li, Y and Guo, J and Pan, J and Ma, F and Ma, X and Lin, Y}, title = {Inhibition of Caspase-1-dependent pyroptosis attenuates copper-induced apoptosis in chicken hepatocytes.}, journal = {Ecotoxicology and environmental safety}, volume = {174}, number = {}, pages = {110-119}, doi = {10.1016/j.ecoenv.2019.02.069}, pmid = {30822667}, issn = {1090-2414}, mesh = {Animals ; Apoptosis/*drug effects ; Caspase 1/*physiology ; Caspase 3/metabolism ; Cell Survival ; Chickens ; Copper/*toxicity ; Hepatocytes/*drug effects ; Interleukin-1beta/metabolism ; *Pyroptosis ; }, abstract = {The purpose of this study was to investigate the effects of copper (Cu) on hepatocyte pyroptosis and the relationship between pyroptosis and apoptosis in the mechanisms of Cu toxicity. Primary chicken hepatocytes were cultured in different concentrations of Cu sulfate (CuSO4) (0, 10, 50, and 100 μM), N-acetylcysteine (NAC) (1 mM), and Z-YVAD-fluoromethylketone (Z-YVAD-FMK) (10 μM) for 24 h, and the combination of Cu and NAC or Z-YVAD-FMK for 24 h. Cellular morphology and function, cell viability, mitochondria membrane potential (MMP), apoptosis rate, mRNA expression of pyroptosis-related and apoptosis-related genes, and Caspase-1, Caspase-3 proteins expression were determined. These results indicated that Cu markedly induced the mRNA expression of pyroptosis-related genes (Caspase-1, IL-1β, IL-18, and NLRP3) and Caspase-1 protein expression. Furthermore, contents of Caspase-1, IL-1β, and IL-18 in the supernatant fluid of culture hepatocytes were significantly increased in hepatocytes. NAC relieved excess Cu-caused the changes of above genes and proteins. Additionally, Z-YVAD-FMK, caspase-1 inhibitor, which attenuated Cu-induced the increased lactic dehydrogenase (LDH), aspartate amino transferase (AST), alanine aminotransferase (ALT) activities. Furthermore, treatment with Cu and Z-YVAD-FMK could down-regulate the mRNA levels of Caspase-3, Bak1, Bax, and CytC and Caspase-3 protein expression, up-regulate the mRNA expression of Bcl2, increase the MMP and reduce cell apoptosis compared to treatment with Cu in hepatocytes. Collectively, these finding evidenced that excess Cu induced pyroptosis by generating ROS in hepatocytes, and the inhibition of Caspase-1-dependent pyroptosis might attenuate Cu-induced apoptosis.}, }
@article {pmid30818202, year = {2019}, author = {Jin, L and Ni, J and Tao, Y and Weng, X and Zhu, Y and Yan, J and Hu, B}, title = {N-acetylcysteine attenuates PM2.5-induced apoptosis by ROS-mediated Nrf2 pathway in human embryonic stem cells.}, journal = {The Science of the total environment}, volume = {666}, number = {}, pages = {713-720}, doi = {10.1016/j.scitotenv.2019.02.307}, pmid = {30818202}, issn = {1879-1026}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Free Radical Scavengers/*pharmacology ; Human Embryonic Stem Cells/metabolism ; Humans ; NF-E2-Related Factor 2/*metabolism ; Particle Size ; Particulate Matter/*adverse effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {While the effects of fine particulate matter (PM2.5) on embryonic toxicity are widely accepted, its exact mechanisms have not yet been fully elucidated, which partially attribute to lack of ideal research model. Embryonic stem cells (ESCs) have the capacity to differentiate into all cell types of three germ layers. Thus, they are ideal resources for the reproductive toxicity assessment in vitro. In the present study, we investigated the effects of PM2.5 exposure on the oxidative stress and apoptosis of human ESCs (hESCs) and its possible mechanism. Our results showed that strong cytotoxicity high reactive oxygen species (ROS) level and fragmentation of nuclei were observed in the PM2.5-treated hESCs. Meanwhile, up-regulation of apoptosis as well as down-regulation of Nrf2 signaling pathway were also observed after PM2.5 treatment. However, we did not detect significant expression change or phosphorylation of Akt and Erk in PM2.5-treated hESCs. Interestingly, scavenging of PM2.5-induced ROS by N-acetylcysteine (NAC) could block cell apoptosis and rescue the activity of Nrf2 signaling pathway. In conclusion, we demonstrate that PM2.5 is toxic to hESCs by inhibition of ROS-mediated Nrf2 pathway activity. Our findings suggest activation of Nrf2 pathway will help develop new strategies for the prevention and treatment of PM2.5-associated disease.}, }
@article {pmid30816513, year = {2019}, author = {Kim, TH and Park, JH and Woo, JS}, title = {Resveratrol induces cell death through ROS‑dependent downregulation of Notch1/PTEN/Akt signaling in ovarian cancer cells.}, journal = {Molecular medicine reports}, volume = {19}, number = {4}, pages = {3353-3360}, doi = {10.3892/mmr.2019.9962}, pmid = {30816513}, issn = {1791-3004}, mesh = {Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Caspases/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Ovarian Neoplasms/*metabolism ; PTEN Phosphohydrolase/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptor, Notch1/genetics/*metabolism ; Resveratrol/*pharmacology ; Signal Transduction/*drug effects ; }, abstract = {Resveratrol, a natural polyphenol compound, has been reported to exert anticancer activity in various cancer cells. The present study investigated the effect and underlying mechanisms of resveratrol in the human ovarian cancer cell lines, A2780 and SKOV3. Treatment with resveratrol induced apoptotic cell death in dose‑ and time‑dependent manners, as well as a transient increase of reactive oxygen species (ROS) generation. Resveratrol‑induced cell death was attenuated by the antioxidant, N‑acetylcysteine (NAC), suggesting that ROS were involved in the observed cell death. Treatment with resveratrol resulted in a ROS‑dependent decrease of Notch1 signaling. When cells were transfected to overexpress Notch1 using EF.hlCN1.CMV.GFP, resveratrol‑induced cell death was blocked. Western blot analysis demonstrated that resveratrol also upregulated phospho‑phosphatase and tensin homolog (p‑PTEN) and downregulated phospho‑Akt (p‑Akt). Overexpression of p‑Akt by transfection with a constitutively active form (caAkt), and the p‑PTEN inhibitor SF1670 prevented resveratrol‑induced cell death. The caspase‑3 inhibitor z‑DEVD‑FMK significantly attenuated the resveratrol‑induced caspase‑3 cleavage. Taken together, the results of the present study suggest that resveratrol induces caspase‑dependent cell death through suppression of Notch1 and PTEN/Akt signaling and it is mediated by increased ROS generation in human ovarian cancer cells.}, }
@article {pmid30814814, year = {2019}, author = {Chandil, N and Pande, S and Sen, SS and Gupta, D}, title = {Comparison of Metformin and N Acetylcysteine on Clinical, Metabolic Parameter and Hormonal Profile in Women with Polycystic Ovarian Syndrome.}, journal = {Journal of obstetrics and gynaecology of India}, volume = {69}, number = {1}, pages = {77-81}, pmid = {30814814}, issn = {0971-9202}, abstract = {OBJECTIVE: Comparison of metformin and N acetylcysteine on clinical, metabolic parameter and hormonal profile in women with polycystic ovarian syndrome.<br><br>DESIGN: Prospective comparative study.<br><br>SETTING: Obstetrics and Gynecology department in Kamala Nehru Memorial Hospital Allahabad.<br><br>PATIENTS: On the basis of inclusion and exclusion criteria, 100 patients of PCOS were selected for study and assigned randomly in two groups to receive either metformin (1500&#xa0;mg/day) (group M) or N acetylcysteine (1800&#xa0;mg/day) (group N) for 24&#xa0;weeks.<br><br>INTERVENTIONS: Metabolic parameter and hormonal profile were determined before and after the treatment.<br><br>MAIN OUTCOME MEASURES: Metabolic parameters, fasting glucose, fasting insulin and testosterone changes.<br><br>RESULTS: Forty-five patients of both groups were ultimately evaluated. There was a significant improvement of body mass index, waist circumference and waist-hip ratio in group N, but there was no significant difference found in weight reduction among two groups. The biochemical marker of insulin resistance like fasting insulin, fasting glucose/insulin ratio improved significantly in group N. Greater reduction of total testosterone was observed in group N.<br><br>CONCLUSIONS: Better improvement of metabolic and hormonal profile was observed in N acetylcysteine group. Because of its less side effect comparing to metformin, NAC can be used as a substitute for insulin-sensitizing agent in treatment of PCOS.}, }
@article {pmid30811527, year = {2019}, author = {Will, JS and Snyder, CJ and Westerfield, KL}, title = {N-Acetylcysteine (NAC) for the Prevention of Liver Failure in Heat Injury-Mediated Ischemic Hepatitis.}, journal = {Military medicine}, volume = {184}, number = {9-10}, pages = {565-567}, doi = {10.1093/milmed/usz022}, pmid = {30811527}, issn = {1930-613X}, mesh = {Acetylcysteine/*standards/therapeutic use ; Acute Kidney Injury/etiology ; Adult ; Consciousness Disorders/etiology ; Free Radical Scavengers/standards/therapeutic use ; Heat Stress Disorders/*complications ; Hot Temperature/adverse effects ; Humans ; Liver Failure/*drug therapy/etiology/*prevention &amp; control ; Male ; Prospective Studies ; Rhabdomyolysis/etiology ; }, abstract = {Exertional Heat Illness with associated ischemic hepatitis (IH) is a common occurrence among military trainees; however, few specific therapies exist if unresponsive to appropriate supportive measures. A 27-year-old basic combat trainee presented with altered mental status, renal insufficiency, rhabdomyolysis, and a core temp of 107.9 °F after collapsing during a run, leading to the diagnosis of heat stroke. While the patient's azotemia and creatinine kinase levels rapidly improved with aggressive intravenous hydration, transaminases continued to increase to nearly 155 times the upper limit of normal. Further laboratory evaluation revealed coagulopathy and thrombocytopenia suggestive of acute liver failure (ALF). On hospital day three, the patient was started on N-acetylcysteine (NAC). Evaluation for infectious and autoimmune etiologies of ALF was unremarkable; thus, the patient's symptomatology was attributed to IH resulting from heat stroke. Liver function normalized on NAC. Heat Injury is common among US Army recruits and results in thousands of hospitalizations in recent years. IH is characterized by diffuse hepatocyte necrosis following an episode of hemodynamic instability, and is an established sequela of Heat Injury. The mortality of IH among critically ill patients has been estimated to be as high as 60%, with those demonstrating coagulopathy especially at risk. NAC is shown to improve the transplant-free survival rate in non-acetaminophen related ALF, consistent with its proposed mechanisms of improving hepatic blood flow and conjugating toxic metabolites. NAC therapy should be considered early in the course of heat injury-mediated IH to reduce reperfusion injury, improving transplant free outcomes.}, }
@article {pmid30808169, year = {2019}, author = {Li, D and Wang, S and Lei, Z and Sun, C and El-Toni, AM and Alhoshan, MS and Fan, Y and Zhang, F}, title = {Peroxynitrite Activatable NIR-II Fluorescent Molecular Probe for Drug-Induced Hepatotoxicity Monitoring.}, journal = {Analytical chemistry}, volume = {91}, number = {7}, pages = {4771-4779}, doi = {10.1021/acs.analchem.9b00317}, pmid = {30808169}, issn = {1520-6882}, mesh = {Acetaminophen ; Animals ; *Biosensing Techniques ; Cell Line, Tumor ; Cell Survival/drug effects ; Chemical and Drug Induced Liver Injury/*diagnosis ; Disease Models, Animal ; Female ; Fluorescence ; Fluorescent Dyes/chemical synthesis/chemistry/*metabolism ; Humans ; Infrared Rays ; Mice ; Mice, Nude ; Peroxynitrous Acid/chemistry/*metabolism ; }, abstract = {Drug-induced hepatotoxicity represents an important challenge for safety in drug development. The production of peroxynitrite (ONOO[-]) is proposed as an early sign in the progression of drug-induced hepatotoxicity. Currently, reported ONOO[-] probes mainly emit in the visible range or the first NIR window, which have limited in vivo biosensing application due to the autofluorescence and photon scattering. Herein, we developed a peroxynitrite activatable second near-infrared window (NIR-II) molecular probe for drug-induced hepatotoxicity monitoring, based on the fusion of an NIR-II fluorescence turn-on benzothiopyrylium cyanines skeleton and the phenyl borate. In the presence of ONOO[-], the probe IRBTP-B can turn on its NIR-II fluorescence by yielding its fluorophore IRBTP-O and display good linear response to ONOO[-]. Tissue phantom study confirmed reliable activated signals could be acquired at a penetration depth up to 5 mm. Using this probe, we disclose the upregulation of ONOO[-] in a preclinical drug-induced liver injury model and the remediation with N-acetyl cysteine (NAC) in vivo. We expect that this strategy will serve as a general method for the development of an activatable NIR-II probe based on the hydroxyl functionalized reactive sites by analyte-specific triggering.}, }
@article {pmid30805841, year = {2019}, author = {Turkmen, R and Birdane, YO and Demirel, HH and Yavuz, H and Kabu, M and Ince, S}, title = {Antioxidant and cytoprotective effects of N-acetylcysteine against subchronic oral glyphosate-based herbicide-induced oxidative stress in rats.}, journal = {Environmental science and pollution research international}, volume = {26}, number = {11}, pages = {11427-11437}, pmid = {30805841}, issn = {1614-7499}, support = {16.VF.11//Afyon Kocatepe University Scientific Research Projects Coordination Department/ ; }, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Cytoprotection ; Dose-Response Relationship, Drug ; Glycine/*analogs &amp; derivatives/toxicity ; Herbicides/*toxicity ; Kidney/drug effects/metabolism/pathology ; Liver/drug effects/metabolism/pathology ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Toxicity Tests, Subchronic ; Glyphosate ; }, abstract = {It is claimed that oxidative stress has a prominent role in the mechanism of toxic effects formed by glyphosate-based herbicide (GBH) in living systems. A strong thiol compound, N-acetylcysteine (NAC), has antioxidative and cytoprotective properties. The objective in this subchronic toxicity study was to identify the prophylactic effect of NAC over histopathological changes and oxidative stress induced by GBH in blood, renal, liver, cardiac, and brain tissues. A sum of 28 male Wistar rats were divided into four equal groups, each containing 7 rats. During the study, group I (control group) was supplied with normal rodent bait and tap water ad libitum. The applied agents were 160 mg/kg NAC to group II, 375 mg/kg as equivalent to 1/10 of lethal dose 50% (LD50) of GBH to group III, and 160 mg/kg of NAC and 375 mg/kg of GBH together once per day as oral gavage to group IV for 8 weeks. While GBH decreased the levels of GSH in blood, liver, kidney, and brain tissues, it considerably increased malondialdehyde levels. On the contrary, these parameters happened to improve in the group supplied with NAC. Besides, it was seen that NAC was observed to improve the histopathologic changes in rat tissues induced by GBH. It was concluded that NAC protects oxidative stress and tissue damage induced by GBH in blood and tissue and this prophylactic effect could be attributed to its antioxidant and free radical sweeper character.}, }
@article {pmid30802208, year = {2019}, author = {Ozkaya, H and Omma, T and Bag, YM and Uzunoglu, K and Isildak, M and Duymus, ME and Kismet, K and Senes, M and Fidanci, V and Celepli, P and Hucumenoglu, S and Aral, Y}, title = {Topical and Systemic Effects of N-acetyl Cysteine on Wound Healing in a Diabetic Rat Model.}, journal = {Wounds : a compendium of clinical research and practice}, volume = {31}, number = {4}, pages = {91-96}, pmid = {30802208}, issn = {1943-2704}, mesh = {*Acellular Dermis ; Conservative Treatment ; Debridement ; Graft Survival ; Humans ; Pilot Projects ; Skin Transplantation/*methods ; Transplantation, Autologous ; Treatment Outcome ; Varicose Ulcer/*pathology/physiopathology/*therapy ; Wound Healing ; }, abstract = {OBJECTIVE: This study evaluates the effects of topical and systemic N-acetyl cysteine (NAC) treatment on wound healing in a diabetic rat model.<br><br>MATERIALS AND METHODS: A total of 48 male Wistar Albino rats were randomly divided into 4 groups of 12. Diabetes was induced with an intraperitoneal injection of 60 mg/kg streptozotocin. A 2-cm x 1-cm full-thickness wound was created on the back of each animal. In group 1 (control) and group 3 (systemic NAC), the wounds were closed with 0.9% sodium chloride-treated sterile gauze. In group 2 (topical NAC) and group 4 (topical + systemic NAC), the wounds were closed with sterile gauze treated with 3 mL (300 mg) of NAC. The animals in groups 3 and 4 were administered 200 mg/kg of NAC once daily through an orogastric tube. On days 1 and 14, the wounded areas were measured. Tissue and blood samples were taken on day 14 for histopathological and biochemical examination.<br><br>RESULTS: On day 14, the wounded area in groups 2, 3, and 4 was found to be smaller than in group 1 (control). Histopathologically, epithelialization and fibrosis scores were significantly lower, whereas the inflammation score was higher in group 1 than in the other groups. Tissue oxidative stress parameters (malondialdehyde, fluorescent oxidation products, total oxidative stress) were higher in the control group than in the other groups. In groups 3 and 4 (which received systemic NAC), the oxidative stress parameters in serum samples were lower than those of the control group and group 2. Serum sulphydryl levels were the lowest in group 1.<br><br>CONCLUSIONS: The results of this study show that both topical and systemic administration of NAC improved wound healing in a diabetic rat model. This effect of NAC may be related to its antioxidant properties since a reduction in oxidative stress parameters in both tissue and serum were shown in the present study.}, }
@article {pmid30801904, year = {2019}, author = {Ucar, A and Özgeriş, FB and Yeltekin, A&#xc7; and Parlak, V and Alak, G and Keleş, MS and Atamanalp, M}, title = {The effect of N-acetylcysteine supplementation on the oxidative stress levels, apoptosis, DNA damage, and hematopoietic effect in pesticide-exposed fish blood.}, journal = {Journal of biochemical and molecular toxicology}, volume = {33}, number = {6}, pages = {e22311}, doi = {10.1002/jbt.22311}, pmid = {30801904}, issn = {1099-0461}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; *DNA Damage ; Fish Proteins/metabolism ; Hematopoiesis/*drug effects ; Oncorhynchus mykiss/*metabolism ; Oxidative Stress/*drug effects ; Oxidoreductases/metabolism ; Pesticides/*toxicity ; Pyrethrins/*toxicity ; }, abstract = {Cysteine is important for protein synthesis, detoxification, and diverse metabolic functions. However, cysteine metabolism has been poorly described in fish, and the role of the therapeutic effect in pesticide toxicology on aquatic organisms is unknown. The aim of this study was to determine the effects of regular cysteine treatment on the hematology, biochemistry, apoptosis, oxidative DNA damage, and antioxidant parameters in fish blood after chemical application. Therefore, fish were exposed to cypermethrin for 2 weeks. Then two different concentrations of N-acetylcysteine (NAC) were applied for a 4-day treatment period and compared with the group of the self-healing process. At the end of the treatment, the hematological index, blood biochemical parameters, paraoxonase (PON), arylesterase (ARE), and myeloperoxidase (MPO) activities in the fish blood samples were investigated. With regard to the hematological parameters, statistical differences were obtained except for mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) (P < 0.05). Enzyme activities (ARE, PON, and MPO), as well as some biochemical parameters (creatinin [Cre], alanine amino transferase, total glyceride, alkaline phosphatase, iron, calcium, low density lipoprotein-cholesterol [LDL-C], sodium, and potassium), were found to be importantly different among all groups at the P < 0.05 level, while 8-hydroxydeoxyguanosine and caspase-3 levels were determined to be high in the pesticide group but decreased significantly in NAC-treated groups (P < 0.05). According to the results of the study, acute cysteine treatment showed an ameliorative effect on the hematological index, biochemical parameters, PON, MPO, and ARE in the blood in the all the treatment group fish. The positive effect of NAC on protein synthesis, detoxification, and diverse metabolic functions against cypermethrin toxicity was more effective in 1.0 mM NAC. NAC has an important therapeutic effect on pesticide-induced hematoxicity for fish in terms of all the data.}, }
@article {pmid30799090, year = {2019}, author = {Yang, Y and Reichl, FX and Ilie, N and Shi, J and Dhein, J and Hickel, R and Högg, C}, title = {Antioxidants as a novel dental resin-composite component: Effect on elution and degree of conversion.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {35}, number = {4}, pages = {650-661}, doi = {10.1016/j.dental.2019.02.003}, pmid = {30799090}, issn = {1879-0097}, mesh = {*Antioxidants ; *Composite Resins ; Materials Testing ; Methacrylates ; Polymerization ; }, abstract = {OBJECTIVE: Ascorbic acid (Asc) and N-acetylcysteine (NAC) were reported to reduce genotoxicity induced by dental (co)monomers and their epoxy metabolites. The aim of the present study was to investigate Asc or NAC as novel components in light-curable methacrylate based dental composites regarding their effects on degree of conversion (DC) and elution of composite components. Additionally, the release of Asc or NAC was determined.<br><br>METHODS: Asc or NAC (1, 0.1, 0.01 or 0&#x2009;wt%) was experimentally incorporated into the composites Venus[&#xae;], Grandio[&#xae;] and Filtek[TM] Supreme XTE and polymerized according to the instruction of manufacturers. The samples were elussted in methanol and water. For each composite-antioxidant mixture and elution medium four samples (n&#x2009;=&#x2009;4) were prepared. The eluates were analyzed by gas chromatography/mass spectrometry (GC/MS), high-performance liquid chromatography/ultraviolett/diode array detection (HPLC/UV/DAD) and high-performance liquid chromatography/fluorescence detection (HPLC/FLD). DC of composite-antioxidant mixtures was measured in real-time with Fourier transform infrared spectroscopy (FTIR).<br><br>RESULTS: The highest concentrations of eluted Asc were 313.98&#x2009;&#x3bc;M (Venus[&#xae;]-1&#x2009;wt% Asc; 1 day; methanol) and 245.34&#x2009;&#x3bc;M (Filtek[TM] Supreme XTE-1&#x2009;wt% Asc; 5&#x2009;min; water). The highest concentrations of eluted NAC were 42.99&#x2009;&#x3bc;M (1 day; Filtek[&#x2122;] Supreme XTE-1&#x2009;wt% NAC; 1 day; methanol) and 108.11&#x2009;&#x3bc;M (Filtek[&#x2122;] Supreme XTE-1&#x2009;wt% NAC; 7 day; water). Triethylene glycol dimethacrylate (TEGDMA) elution was significantly increased in Venus[&#xae;]-1&#x2009;wt% Asc and Grandio[&#xae;]-1&#x2009;wt% Asc (1 day and 7 day methanol/water), compared to control. No significant difference was found for TEGDMA elution in Filtek[&#x2122;] Supreme XTE-1&#x2009;wt% Asc/NAC. DC was significantly decreased compared to control (=&#x2009;composite without antioxidant) in Grandio[&#xae;] and Filtek[&#x2122;] Supreme XTE after 1, 0.1 and 0.01&#x2009;wt% Asc incorporation and in Venus[&#xae;] after 1 and 0.1&#x2009;wt% Asc incorporation. For composite-NAC mixtures, only DC of Grandio[&#xae;]-1&#x2009;wt% NAC was significantly reduced.<br><br>SIGNIFICANCE: Incorporation of NAC (1&#x2009;wt%), as a novel composite component, into Filtek[&#x2122;] Supreme XTE, had no effect on DC and composite component elution, and supplies sufficient amount of antioxidant which may reduce toxicity. Therefore, it represents a beneficial mixture.}, }
@article {pmid30797898, year = {2019}, author = {Hong, Y and Fan, D}, title = {Ginsenoside Rk1 induces cell cycle arrest and apoptosis in MDA-MB-231 triple negative breast cancer cells.}, journal = {Toxicology}, volume = {418}, number = {}, pages = {22-31}, doi = {10.1016/j.tox.2019.02.010}, pmid = {30797898}, issn = {1879-3185}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Female ; Ginsenosides/*pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/drug effects/metabolism/pathology ; Phosphatidylinositol 3-Kinase/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Triple Negative Breast Neoplasms/*drug therapy/metabolism/pathology ; Xenograft Model Antitumor Assays ; }, abstract = {Ginsenoside Rk1 (Rk1) is a component found in processed ginseng that exhibits anti-insulin resistance, anti-inflammation and anti-cancer activities. However, there are few reports of Rk1 activity against triple negative breast cancer (TNBC). In this study, the anti-proliferation and potential mechanisms of Rk1 in MDA-MB-231 cells were investigated. Xenograft model exhibited that Rk1 significantly repressed tumor growth with low toxicity to major organs. Moreover, Rk1 dramatically inhibited cell proliferation, colony formation, promoted LDH release, and induced G0/G1 phase arrest. Rk1 also triggered intracellular reactive oxygen species (ROS) generation and mitochondrial membrane potential reduction. Western blot results revealed that Rk1 increased the expression of Bax, cytochrome C, cleaved caspase 3, 8 and 9 levels and decreased Bcl-2 level and blocked the PI3K/Akt pathway. Pretreatment with the pan-caspase inhibitor Z-VAD-FMK, PI3K/Akt pathway activator insulin or ROS scavenger N-acetylcysteine (NAC) further demonstrated that ROS/PI3K/Akt pathway was responsible for Rk1-induced apoptosis. Overall, this is the first study to illustrate the anti-triple negative breast cancer effects and mechanisms of Rk1 and ginsenoside Rk1 could be a new promising anti-tumor drug for TNBC.}, }
@article {pmid30797455, year = {2019}, author = {Godoy-Reyes, TM and Costero, AM and Gaviña, P and Martínez-Máñez, R and Sancenón, F}, title = {Colorimetric detection of normetanephrine, a pheochromocytoma biomarker, using bifunctionalised gold nanoparticles.}, journal = {Analytica chimica acta}, volume = {1056}, number = {}, pages = {146-152}, doi = {10.1016/j.aca.2019.01.003}, pmid = {30797455}, issn = {1873-4324}, mesh = {*Adrenal Gland Neoplasms ; Biomarkers, Tumor/*analysis ; Cell Line, Tumor ; Colorimetry/*methods ; Gold/*chemistry ; Humans ; Limit of Detection ; Metal Nanoparticles/*chemistry ; Normetanephrine/*analysis/urine ; *Pheochromocytoma ; }, abstract = {A simple and effective colorimetric method for the detection of normetanephrine (NMN), an O-methylated metabolite of norepinephrine, using functionalised gold nanoparticles is described. This metabolite is an important biomarker in the diagnosis of adrenal tumours such as pheocromocytoma or paraganglioma. The colorimetric probe consists of spherical gold nanoparticles (AuNPs) functionalised with two different ligands, which specifically recognize different functional groups in normetanephrine. Thus, a benzaldehyde-terminated ligand was used for the recognition of the amino alcohol moiety in NMN, by forming the corresponding oxazolidine. On the other hand, N-acetyl-cysteine was chosen for the recognition of the phenolic hydroxyl group through the formation of hydrogen bonds. The selective double molecular recognition between the probe and the hydroxyl and the amino-alcohol moieties of normetanephrine led to interparticle-crosslinking aggregation resulting in a change in the color of the solution, from red to blue, which could be observed by naked eye. The probe was highly selective towards normetanephrine and no color changes were observed in the presence of other neurotransmitter metabolites such as homovanillic acid (HVA) (dopamine metabolite), 5-hydroxyindoleacetic acid (5-HIAA) (serotonin metabolite), or other biomolecules present in urine such as glucose (Glc), uric acid (U.A), and urea. Finally, the probe was evaluated in synthetic urine with constituents that mimic human urine, where a limit of detection of 0.5 μM was achieved.}, }
@article {pmid30796177, year = {2019}, author = {Cui, J and Zhou, Z and Yang, H and Jiao, F and Li, N and Gao, Y and Wang, L and Chen, J and Quan, M}, title = {MST1 Suppresses Pancreatic Cancer Progression via ROS-Induced Pyroptosis.}, journal = {Molecular cancer research : MCR}, volume = {17}, number = {6}, pages = {1316-1325}, doi = {10.1158/1541-7786.MCR-18-0910}, pmid = {30796177}, issn = {1557-3125}, mesh = {Animals ; Apoptosis/physiology ; Carcinoma, Pancreatic Ductal/metabolism/pathology ; Cell Line, Tumor ; Cell Movement/physiology ; Cell Proliferation/physiology ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic/physiology ; Hepatocyte Growth Factor ; Humans ; Intracellular Signaling Peptides and Proteins ; Mice ; Mice, Nude ; Pancreas/metabolism/pathology ; Pancreatic Neoplasms/*metabolism/*pathology ; Prognosis ; Protein Serine-Threonine Kinases/*metabolism ; Proto-Oncogene Proteins ; Pyroptosis/*physiology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/physiology ; }, abstract = {Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, and its incidence is increasing annually. It is critical to reveal and delineate the molecular mechanism promoting PDAC development and progression. Mammalian STE20-like kinase 1 (MST1) is a proapoptotic cytoplasmic kinase and also one of the core components of the Hippo pathway. Here, we showed that MST1 expression was decreased in PDAC, and restored expression of MST1 promoted PDAC cell death and suppressed the proliferation, migration, invasion, and cell spheroid formation of PDAC via caspase-1-induced pyroptosis. Further studies demonstrated that pyroptosis induced by MST1 was independent of the Hippo pathway, but mediated by reactive oxygen species (ROS). And ROS scavenger N-acetyl-cysteine attenuated the activation of caspase-1 induced by MST1 and the effect of MST1 in PDAC cell death, proliferation, migration, and invasion. Collectively, our study demonstrated that MST1 suppressed the progression of PDAC cells at least partly through ROS-induced pyroptosis. IMPLICATIONS: In this study, we identified a new mechanism of MST1 in inhibiting PDAC development and progression and revealed that MST1 would be a potential prognostic and therapeutic target for PDAC.}, }
@article {pmid30789643, year = {2019}, author = {Luo, Z and Xu, X and Sho, T and Luo, W and Zhang, J and Xu, W and Yao, J and Xu, J}, title = {Effects of n-acetyl-cysteine supplementation in late gestational diet on maternal-placental redox status, placental NLRP3 inflammasome, and fecal microbiota in sows1.}, journal = {Journal of animal science}, volume = {97}, number = {4}, pages = {1757-1771}, pmid = {30789643}, issn = {1525-3163}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Diet/veterinary ; *Dietary Supplements ; Feces/microbiology ; Female ; Gastrointestinal Microbiome/*drug effects ; Glutathione Peroxidase/metabolism ; Inflammasomes/drug effects ; Malondialdehyde/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/drug effects ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Placenta/drug effects/metabolism ; Pregnancy ; Reproduction/*drug effects ; Superoxide Dismutase/metabolism ; Swine/*physiology ; }, abstract = {Although n-acetyl-cysteine (NAC) has been shown to efficiently alleviate oxidative stress, inflammatory response, and alter gut microbiota, little attention has been focused on their interactions with placental metabolic status of sows. The effects of NAC on the placental redox status, function, inflammasome, and fecal microbiota in sows were explored to clarify the correlation between the fecal microbiota and placenta. Sows were divided into either the control group or the NAC group which received dietary 0.5% NAC supplementation from day 85 of gestation to delivery. Plasma redox status, placental growth factors, nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, fecal microbial metabolites, and communities were evaluated. Compared with the control group, although NAC did not ameliorate reproductive performance of sows (P > 0.05), it significantly improved maternal-placental health, which was accompanied by increased activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), decreased level of malondialdehyde (MDA), and lowered expression of interleukin (IL)-1β and IL-18 through inhibiting NLRP3 inflammasome (P < 0.05). Additionally, NAC significantly increased placental insulin-like growth factors (IGFs) and E-cadherin contents (P < 0.05), elevated the expression of genes involved in angiogenesis and amino acids transporters (P < 0.05), and decreased the microtubule-associated protein light chain 3B (LC3B) and Beclin-1 protein expression (P < 0.05). Furthermore, NAC increased the relative abundances of fecal Prevotella, Clostridium cluster XIVa, and Roseburial/Eubacterium rectale (P < 0.05), which were negatively correlated with placental NLRP3 and positively with solute carrier family 7, member 8 (Slc7a8; P < 0.05). In conclusion, NAC supplementation during late gestation alleviated maternal-placental oxidative stress and inflammatory response, improved placental function, and altered fecal microbial communities.}, }
@article {pmid30786762, year = {2019}, author = {Mercantepe, F and Topcu, A and Rakici, S and Tumkaya, L and Yilmaz, A}, title = {The effects of N-acetylcysteine on radiotherapy-induced small intestinal damage in rats.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {244}, number = {5}, pages = {372-379}, pmid = {30786762}, issn = {1535-3699}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/*pharmacology ; Intestine, Small/*drug effects/*radiation effects ; Male ; Oxidative Stress/drug effects ; Radiation Injuries/*prevention &amp; control ; Radiotherapy/adverse effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Some six million cancer patients currently receive radiotherapy. Radiotherapy eliminates cancer cells by accelerating their death. However, radiotherapy is not selective, and it therefore harms healthy tissues around cancerous tissue. The latest studies have shown that the irradiation of biological materials causes a rapid increase in reactive oxygen species (ROS) in the tissue as a result of exposure of the target molecule to direct and indirect ionization. N-acetylcysteine (NAC) is an antioxidant that permits the elimination of free oxygen radicals and that contributes to glutathione synthesis. Our study, therefore, examined the effects of radiation resulting from radiotherapy on the small intestine at the molecular level, and prospectively considered the potential protective characteristics of NAC against gastrointestinal syndrome resulting from radiotherapy.}, }
@article {pmid30786124, year = {2019}, author = {Kwon, D and Lim, YM and Kwon, JT and Shim, I and Kim, E and Lee, DH and Yoon, BI and Kim, P and Kim, HM}, title = {Evaluation of pulmonary toxicity of benzalkonium chloride and triethylene glycol mixtures using in vitro and in vivo systems.}, journal = {Environmental toxicology}, volume = {34}, number = {5}, pages = {561-572}, pmid = {30786124}, issn = {1522-7278}, support = {NIER-RP2015-253//National Institute of Environmental Research/ ; NIER-RP2015-253//National Institute of Environmental Research (NIER), Republic of Korea/ ; }, mesh = {A549 Cells ; Animals ; Benzalkonium Compounds/administration &amp; dosage/metabolism/*toxicity ; Bronchoalveolar Lavage Fluid/chemistry ; Cell Culture Techniques ; Cell Survival/drug effects ; Cytokines/analysis ; Drug Synergism ; Humans ; Lung/*drug effects ; Lung Injury/*chemically induced/metabolism/pathology ; Male ; Oxidative Stress/*drug effects/immunology ; Pneumonia/*chemically induced/metabolism/pathology ; Polyethylene Glycols/administration &amp; dosage/metabolism/*toxicity ; Rats, Sprague-Dawley ; }, abstract = {Benzalkonium chloride (BAC) is a widely used disinfectant/preservative, and respiratory exposure to this compound has been reported to be highly toxic. Spray-form household products have been known to contain BAC together with triethylene glycol (TEG) in their solutions. The purpose of this study was to estimate the toxicity of BAC and TEG mixtures to pulmonary organs using in vitro and in vivo experiments. Human alveolar epithelial (A549) cells incubated with BAC (1-10 μg/mL) for 24 hours showed significant cytotoxicity, while TEG (up to 1000 μg/mL) did not affect cell viability. However, TEG in combination with BAC aggravated cell damage and inhibited colony formation as compared to BAC alone. TEG also exacerbated BAC-promoted production of reactive oxygen species (ROS) and reduction of glutathione (GSH) level in A549 cells. However, pretreatment of the cells with N-acetylcysteine (NAC) alleviated the cytotoxicity, indicating oxidative stress could be a mechanism of the toxicity. Quantification of intracellular BAC by LC/MS/MS showed that cellular distribution/absorption of BAC was enhanced in A549 cells when it was exposed together with TEG. Intratracheal instillation of BAC (400 μg/kg) in rats was toxic to the pulmonary tissues while that of TEG (up to 1000 μg/kg) did not show any harmful effect. A combination of nontoxic doses of BAC (200 μg/kg) and TEG (1000 μg/kg) promoted significant lung injury in rats, as shown by increased protein content and lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluids (BALF). Moreover, BAC/TEG mixture recruited inflammatory cells, polymorphonuclear leukocytes (PMNs), in terminal bronchioles and elevated cytokine levels, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) in BALF. These results suggest that TEG can potentiate BAC-induced pulmonary toxicity and inflammation, and thus respiratory exposure to the air mist from spray-form products containing this chemical combination is potentially harmful to humans.}, }
@article {pmid30784233, year = {2019}, author = {Schmidt, SJ and Hurlemann, R and Schultz, J and Wasserthal, S and Kloss, C and Maier, W and Meyer-Lindenberg, A and Hellmich, M and Muthesius-Digón, A and Pantel, T and Wiesner, PS and Klosterkötter, J and Ruhrmann, S and , }, title = {Multimodal prevention of first psychotic episode through N-acetyl-l-cysteine and integrated preventive psychological intervention in individuals clinically at high risk for psychosis: Protocol of a randomized, placebo-controlled, parallel-group trial.}, journal = {Early intervention in psychiatry}, volume = {13}, number = {6}, pages = {1404-1415}, doi = {10.1111/eip.12781}, pmid = {30784233}, issn = {1751-7893}, support = {01EE1407C//Bundesministerium f&#xfc;r Bildung und Forschung/International ; 01EE14071//Bundesministerium f&#xfc;r Bildung und Forschung/International ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Antipsychotic Agents/therapeutic use ; *Cognitive Behavioral Therapy ; Combined Modality Therapy/methods ; Double-Blind Method ; Female ; Humans ; Male ; Multicenter Studies as Topic ; Psychotic Disorders/*drug therapy/*prevention &amp; control/psychology/*therapy ; Randomized Controlled Trials as Topic/*methods ; Single-Blind Method ; Stress, Psychological/complications/drug therapy/therapy ; Young Adult ; }, abstract = {AIM: Meta-analyses indicate positive effects of both antipsychotic and cognitive-behavioural interventions in subjects clinically at high risk (CHR) for psychosis in terms of a delay or prevention of psychotic disorders. However, these effects have been limited regarding social functioning and the relative efficacy of both types of interventions remains unclear. Furthermore, neuroprotective substances seem to be a promising alternative agent in psychosis-prevention as they are associated with few and weak side-effects.<br><br>METHODS: In this multi-centre randomized controlled trial (RCT), we investigate the effects of two interventions on transition to psychosis and social functioning: (a) an integrated preventive psychological intervention (IPPI) including stress-/symptom-management and social-cognitive remediation; (b) N-acetyl-l-cysteine (NAC) as a pharmacological intervention with glutamatergic, neuroprotective and anti-inflammatory capabilities.<br><br>RESULTS: This is a double-blind, placebo-controlled RCT with regard to NAC and a single-blind RCT with regard to IPPI using a 2 &#xd7; 2-factorial design to investigate the individual and combined preventive effects of both interventions. To this aim, a total of 200 CHR subjects will be randomized stratified by site to one of four conditions: (a) IPPI and NAC; (b) IPPI and Placebo; (c) NAC and psychological stress management; (d) Placebo and psychological stress management. Interventions are delivered over 26&#x2009;weeks with a follow-up period of 12&#x2009;months.<br><br>CONCLUSION: This paper reports on the rationale and protocol of an indicated prevention trial to detect the most effective and tolerable interventions with regard to transition to psychosis as well as improvements in social functioning, and to evaluate the synergistic effects of these interventions.}, }
@article {pmid30777470, year = {2019}, author = {Hendrickson, RG}, title = {What is the most appropriate dose of N-acetylcysteine after massive acetaminophen overdose?.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {57}, number = {8}, pages = {686-691}, doi = {10.1080/15563650.2019.1579914}, pmid = {30777470}, issn = {1556-9519}, mesh = {Acetaminophen/*administration &amp; dosage/blood/toxicity ; Acetylcysteine/*administration &amp; dosage/blood/therapeutic use ; Analgesics, Non-Narcotic/*administration &amp; dosage/blood/toxicity ; Chemical and Drug Induced Liver Injury/blood/etiology/*prevention &amp; control ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Overdose/blood/*drug therapy/etiology ; Humans ; }, abstract = {While the traditional intravenous N-acetylcysteine (NAC) dosing regimen works well for the vast majority of acetaminophen overdoses, there may be cases of massive overdose where additional NAC may be necessary. Recent evidence suggests that patients with acetaminophen concentrations above the "300-line" develop hepatotoxicity at a higher rate than those below the 300-line, suggesting that an increase of dose may be beneficial at this cut-off. Additional clinical data suggest a further increase in doses at the 450-line and 600-lines. I propose a strategy for step-wise increases in NAC dosing in response to high acetaminophen concentrations at the 300-, 450-, and 600-lines after acute massive acetaminophen overdoses.}, }
@article {pmid30776665, year = {2019}, author = {Koola, MM}, title = {Antipsychotic-minocycline-acetylcysteine combination for positive, cognitive, and negative symptoms of schizophrenia.}, journal = {Asian journal of psychiatry}, volume = {40}, number = {}, pages = {100-102}, doi = {10.1016/j.ajp.2019.02.007}, pmid = {30776665}, issn = {1876-2026}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Bacterial Agents/*therapeutic use ; Antipsychotic Agents/*therapeutic use ; Drug Therapy, Combination ; Free Radical Scavengers/*therapeutic use ; Humans ; Minocycline/*therapeutic use ; Schizophrenia/*drug therapy/physiopathology ; }, abstract = {Preclinical evidence shows that the minocycline and N-acetylcysteine (NAC) combination synergistically improved cognition. Meta-analyses of randomized controlled trials (RCTs) with minocycline and NAC have shown some efficacy signal for positive, cognitive, and negative symptoms of schizophrenia. Hence, the combination may be more effective than either medication alone. The objective of this article is to highlight the potential role of the minocycline-NAC combination for the treatment of schizophrenia. The antipsychotic-minocycline-NAC combination is promising and has the potential to concurrently treat positive, cognitive, and primary negative symptoms. RCTs are warranted with the minocycline-NAC combination to address the unmet clinical need in schizophrenia.}, }
@article {pmid30774964, year = {2019}, author = {Sharp, AJ and Patel, N and Reeves, BC and Angelini, GD and Fiorentino, F}, title = {Pharmacological interventions for the prevention of contrast-induced acute kidney injury in high-risk adult patients undergoing coronary angiography: a systematic review and meta-analysis of randomised controlled trials.}, journal = {Open heart}, volume = {6}, number = {1}, pages = {e000864}, pmid = {30774964}, issn = {2053-3624}, support = {CH/1992027/7163/BHF_/British Heart Foundation/United Kingdom ; }, abstract = {OBJECTIVE: Quantify the efficacy of strategies to prevent contrast-induced acute kidney injury (CI-AKI) in high-risk patients undergoing coronary angiography (CAG) with or without percutaneous coronary intervention (PCI).<br><br>BACKGROUND: CI-AKI remains a common problem. The renoprotective efficacy of existing pharmacological agents remains uncertain in high-risk populations.<br><br>METHODS: Systematic review and meta-analysis of randomised controlled trials (RCTs) to compare different strategies versus hydration in patients with chronic kidney disease (CKD) undergoing CAG&#xb1;PCI. Primary outcome was incident CI-AKI. Fixed-effects meta-analyses estimated ORs, 95% CIs and heterogeneity.<br><br>RESULTS: Forty-eight RCTs were included. Seven pharmacological strategies were evaluated by multiple RCTs and 10 by one RCT each. These had varying risk of bias; >25% of trials were at high risk of performance bias. Five strategies significantly reduced the odds of CI-AKI: N-acetylcysteine (NAC) (27 trials, 5694 participants; OR=0.77, 95% CI 0.65 to 0.91, p=0.002, I[2]=36%), ascorbic acid (four trials, 759 participants; OR=0.59, 95% CI 0.39 to 0.89, p=0.01, I[2]=0%), statin (two trials, 3234 participants; OR=0.59, 95% CI 0.39 to 0.89, p=0.75, I[2]=0%), trimetazidine (two trials, 214 participants; OR=0.27, 95% CI 0.10 to 0.71, p=0.01, I[2]=0%) and nicorandil (two trials, 389 participants; OR=0.47, 95% CI 0.23 to 0.94, p=0.03, I[2]=52%). Theophylline had a similar, but non-significant, effect. A subgroup analysis found that the benefit of NAC was highest in patients requiring a high-contrast dose.<br><br>CONCLUSIONS: Several drugs are renoprotective in patients with CKD undergoing CAG&#xb1;PCI. The evidence is strongest for NAC. We recommend that NAC should be used when a high dose of contrast is anticipated.<br><br>TRIAL REGISTRATION NUMBER: PROSPERO registration CRD42014014704.Open Science Framework link: https://osf.io/vxg7d/?view_only=62bad0404b18405abd39ff2ead2575a8.}, }
@article {pmid30774957, year = {2019}, author = {Baetas, J and Rabaça, A and Gonçalves, A and Barros, A and Sousa, M and Sá, R}, title = {Protective role of N-acetylcysteine (NAC) on human sperm exposed to etoposide.}, journal = {Basic and clinical andrology}, volume = {29}, number = {}, pages = {3}, pmid = {30774957}, issn = {2051-4190}, abstract = {BACKGROUND: Although recent progress in cancer treatment has increased patient survival and improved quality of life, reproductive side effects are still for concern. One way to decrease gonadal impairment is to use cytoprotectors. In testicular cancer, etoposide is generally used in combination with other agents, but there are no in-vitro studies of sperm exposure to etoposide and cytoprotectors, namely N-acetylcysteine (NAC).<br><br>METHODS: Twenty semen samples were individually divided into five groups: control, incubation with NAC alone, incubation with etoposide alone, sequential exposure of NAC followed by etoposide (pre-treatment) and sequential exposure of etoposide followed by NAC (post-treatment). Sperm characteristics, chromatin condensation (aniline blue), DNA fragmentation (TUNEL), oxidative stress (OxyDNA labelling) and glutathione quantification were used to evaluate the capabilities of NAC as a prophylactic (pre-treatment) or ameliorator (post-treatment) agent over the effects caused in sperm during in-vitro exposure to etoposide.<br><br>RESULTS: No deleterious effects were observed on sperm motility or sperm membrane integrity. Results revealed that prophylactic use of NAC (pre-treatment) increased rates of immature sperm chromatin as compared to ameliorator use of NAC (post-treatment), and increased rates of sperm DNA fragmentation in relation to controls. Pre and post-treatment with NAC increased oxidative levels in comparison to controls, but also increased levels of cellular antioxidant glutathione.<br><br>CONCLUSIONS: The results indicate that NAC has the ability to counteract etoposide-induced toxicity rather than preventing the etoposide cytotoxic effects over sperm DNA, suggesting that the administration of NAC to cells formerly exposed to etoposide is preferable to its prophylactic use. As the results evidenced that NAC seems to be more efficient in attenuating sperm etoposide cytotoxic effects instead of being used as a chemoprophylactic agent, this reinforces the idea that there might be a new NAC mechanism over DNA.}, }
@article {pmid30774333, year = {2019}, author = {Zhu, Y and Song, F and Ju, Y and Huang, L and Zhang, L and Tang, C and Yang, H and Huang, C}, title = {NAC-loaded electrospun scaffolding system with dual compartments for the osteogenesis of rBMSCs in vitro.}, journal = {International journal of nanomedicine}, volume = {14}, number = {}, pages = {787-798}, pmid = {30774333}, issn = {1178-2013}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bone Marrow Cells/*cytology/drug effects ; Cell Adhesion/drug effects ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Cell Survival/drug effects ; Drug Liberation ; Elastic Modulus ; Hardness ; Kinetics ; Nanoparticles/chemistry/ultrastructure ; Osteogenesis/*drug effects ; Particle Size ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Porosity ; Rats, Sprague-Dawley ; Silicon Dioxide/chemistry ; Staining and Labeling ; Stromal Cells/cytology/drug effects ; Tissue Engineering/*methods ; Tissue Scaffolds/*chemistry ; Water/chemistry ; }, abstract = {PURPOSE: In this study, we aimed to develop a unique N-acetyl cysteine (NAC)-loaded polylactic-co-glycolic acid (PLGA) electrospun system with separate compartments for the promotion of osteogenesis.<br><br>MATERIALS AND METHODS: We first prepared solutions of NAC-loaded mesoporous silica nanoparticles (MSNs), PLGA, and NAC in N, N-dimethylformamide and tetrahydrofuran for the construction of the electrospun system. We then fed solutions to a specific injector for electrospinning. The physical and chemical properties of the scaffold were characterized through scanning electron microscopy, transmission electron microscopy, and Fourier transform infrared spectroscopy. The release of NAC and Si from different PLGA scaffolds was estimated. The cell viability, cell growth, and osteogenic potential of rat bone marrow-derived stroma cell (rBMSCs) on different PLGA scaffolds were evaluated through MTT assay, live/dead staining, phalloidin staining, and Alizarin red staining. The expression levels of osteogenic-related markers were analyzed through real-time PCR (qRT-PCR).<br><br>RESULTS: NAC was successfully loaded into MSNs. The addition of MSNs and NAC decreased the diameters of the electrospun fibers, increased the hydrophilicity and mechanical property of the PLGA scaffold. The release kinetic curve indicated that NAC was released from (PLGA + NAC)/(NAC@MSN) in a biphasic pattern, that featured an initial burst release stage and a later sustained release stage. This release pattern of NAC encapsulated on the (PLGA + NAC)/(NAC@MSN) scaffolds enabled to prolong the high concentrations of release of NAC, thus drastically affecting the osteogenic differentiation of rBMSCs.<br><br>CONCLUSION: A PLGA electrospun scaffold was developed, and MSNs were used as separate nanocarriers for recharging NAC concentration, demonstrating the promising use of (PLGA + NAC)/(NAC@MSN) for bone tissue engineering.}, }
@article {pmid30772714, year = {2019}, author = {Yuan, C and Wang, L and Zhu, L and Ran, B and Xue, X and Wang, Z}, title = {N-acetylcysteine alleviated bisphenol A-induced testicular DNA hypermethylation of rare minnow (Gobiocypris rarus) by increasing cysteine contents.}, journal = {Ecotoxicology and environmental safety}, volume = {173}, number = {}, pages = {243-250}, doi = {10.1016/j.ecoenv.2019.02.035}, pmid = {30772714}, issn = {1090-2414}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Benzhydryl Compounds/*toxicity ; Cyprinidae/*metabolism ; DNA Methylation/drug effects ; Male ; Phenols/*toxicity ; Sperm Motility/drug effects ; Testis/drug effects/metabolism ; }, abstract = {Ubiquitous BPA exposure resulted in DNA methylation errors and oxidative stress. Numerous studies have demonstrated that oxidative stress can lead to changes in DNA methylation levels and supplementation with antioxidants, including N-acetylcysteine (NAC), was able to restore these changes. Our previous study supposed that BPA-induced de novo synthesis of glutathione (GSH) promoted DNA methylation process in Gobiocypris rarus testes. To validate this conjecture and explore the protective effects of NAC on BPA toxicity, the present study was carried out. Adult male G. rarus was treated with 225 μg L[-1] BPA and/or NAC for 7 days. The sperm motility and DNA integrity of G. rarus were determined. Meanwhile, the levels of 5-methylcytosine (5mC), GSH, hydrogen peroxide (H2O2), DNA methyltransferase proteins (DNMTs), γ-glutamyl cysteine synthetase (GCS), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), homocysteine (HCY), nicotinamide adenine dinucleotide phosphate (NADPH) and cysteine in the testes were detected. Furthermore, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured. Results indicated that NAC addition resulted in increase of cysteine contents and partially inhibited the BPA-induced DNA hypermethylation of G. rarus testes. In addition, the changes in DNA methylation levels in the testes after BPA and/or NAC treatment might be controlled by DNA methylation process that mediated by DNMTs. Moreover, BPA exposure caused oxidative stress in the testes and the elimination of H2O2 might be mainly accomplished by CAT while it changed to mainly through GPx after NAC supplement. Finally, the positive response of testicular antioxidant enzyme system and the antioxidant activity of NAC itself protected sperm motility and DNA integrity from oxidative damage in each group.}, }
@article {pmid30772427, year = {2019}, author = {Fernandes, J and Gupta, GL}, title = {N-acetylcysteine attenuates neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat.}, journal = {Behavioural brain research}, volume = {364}, number = {}, pages = {356-365}, doi = {10.1016/j.bbr.2019.02.025}, pmid = {30772427}, issn = {1872-7549}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Antidepressive Agents/pharmacology ; Behavior, Animal/drug effects ; Cytokines/metabolism ; Depression/*drug therapy/metabolism ; Depressive Disorder/drug therapy/metabolism ; Disease Models, Animal ; Fluoxetine/pharmacology ; Hippocampus/metabolism ; Inflammation/drug therapy ; Male ; Neuroimmunomodulation/drug effects ; Rats ; Rats, Wistar ; Serotonin/metabolism ; Stress, Physiological ; Stress, Psychological ; }, abstract = {Depression is a heterogeneous disorder and associated with inflammatory responses. The influences of N-acetylcysteine (NAC) on neuroinflammation associated depression-like behavior have not been investigated yet, and associated biochemical changes are currently unclear. Therefore, we assessed the effects of NAC on neuroinflammation associated depression-like behavior induced through chronic unpredictable mild stress (CUMS) in rats. The antidepressant-like effect of NAC was depicted using the sucrose preference test and the forced swimming test (FST) while CUMS-induced alteration in the locomotor index was measured using the open field test (OFT) and actophotometer. Our results revealed that CUMS exposure markedly aggravated depression-like behavior, the levels of pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and reduced the serotonin levels. One-week consecutive NAC (50 and 100 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o., a selective serotonin reuptake inhibitor) treatment significantly increased sucrose preference index, reduced immobility time in the FST, and the increased the number of squares crossed, number of rearing in the OFT and locomotion in the actophotometer in the CUMS-exposed rats. Moreover, the levels of pro-inflammatory cytokines in the hippocampus as well as pre-frontal cortex were suppressed, and remarkably restored the serotonin levels by NAC (50 and 100 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.) administration. However, NAC (25 mg/kg, p.o.) exerted insignificant protection against CUMS-induced depressive-like behavior and associated neuro-inflammation. This study demonstrates that NAC exhibited the antidepressant-like effect in the CUMS-exposed rats, which might be mediated by anti-inflammatory potential and restoring serotonergic responses in the stressed rats.}, }
@article {pmid30771790, year = {2019}, author = {Jannatifar, R and Parivar, K and Roodbari, NH and Nasr-Esfahani, MH}, title = {Effects of N-acetyl-cysteine supplementation on sperm quality, chromatin integrity and level of oxidative stress in infertile men.}, journal = {Reproductive biology and endocrinology : RB&amp;E}, volume = {17}, number = {1}, pages = {24}, pmid = {30771790}, issn = {1477-7827}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Chromatin/*drug effects/genetics/metabolism ; DNA Damage ; *Dietary Supplements ; Free Radical Scavengers/administration &amp; dosage ; Humans ; Infertility, Male/*drug therapy/genetics/physiopathology ; Iran ; Male ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Semen Analysis ; Sperm Motility/drug effects ; Spermatozoa/*drug effects/metabolism/physiology ; }, abstract = {BACKGROUND: Infertile men have higher levels of semen reactive oxygen species (ROS) than fertile men. High levels of semen ROS can cause sperm dysfunction, sperm DNA damage and reduced male reproductive potential. This study investigated the effects of supplementation with N-acetyl-cysteine (NAC) on the sperm quality, chromatin integrity and levels of oxidative stress in infertile men.<br><br>METHODS: The study was carried out in the unit of ACECR Infertility Research Center, Qom, Iran. The patients consisted of 50 infertile men with asthenoteratozoospermia who received NAC (600&#x2009;mg/d) orally for 3&#x2009;months, after which they were compared with pre-treatment status. Semen was analyzed according to WHO (2010), followed by the assessment of protamine content [chromomycin A3 (CMA3)] and DNA integrity [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)]. Oxidative stress markers, i.e. total antioxidant capacity (TAC) and malondialdehyde (MDA), as well as hormonal profile (LH, FSH, Testosterone and Prolactin) were determined by ELISA kit.<br><br>RESULTS: After NAC treatment, patients' sperm count and motility increased significantly whereas abnormal morphology, DNA fragmentation and protamine deficiency showed significant decreases compared to pre-treatment levels (P&#x2009;<&#x2009;0.05). Hormonal profile improvement was associated with lowered FSH and LH levels and increased amount of testosterone (P&#x2009;<&#x2009;0.05). TAC significantly increased and MDA decreased with an inverse significant correlation between TAC and MDA (P&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: NAC oral supplementation may improve sperm parameters and oxidative/antioxidant status in infertile males.}, }
@article {pmid30770531, year = {2019}, author = {Ikonne, US and Vann, PH and Wong, JM and Forster, MJ and Sumien, N}, title = {Supplementation with N-Acetyl Cysteine Affects Motor and Cognitive Function in Young but Not Old Mice.}, journal = {The Journal of nutrition}, volume = {149}, number = {3}, pages = {463-470}, pmid = {30770531}, issn = {1541-6100}, mesh = {Acetylcysteine/*administration &amp; dosage ; *Aging ; Animal Feed ; Animals ; Cognition/*drug effects ; Diet/veterinary ; *Dietary Supplements ; Memory/drug effects ; Mice ; Motor Activity/*drug effects ; Spatial Learning/drug effects ; }, abstract = {BACKGROUND: N-acetyl cysteine (NAC) is a thiolic antioxidant that is thought to increase cellular glutathione (GSH) by augmenting the concentration of available cysteine, an essential precursor to GSH production. Manipulating redox status can affect brain function, and NAC intake has been associated with improving brain function in models of neurodegenerative diseases.<br><br>OBJECTIVES: The objective of the study was to determine if short-term dietary supplementation with NAC could ameliorate functional impairment associated with aging.<br><br>METHODS: C57BL/6J male mice aged 6, 12, or 24 mo were fed a control diet or the control diet supplemented with 0.3% NAC for a total of 12 wk. After 4 wk of dietary supplementation, mice began a series of behavioral tests to measure spontaneous activity (locomotor activity test), psychomotor performance (bridge-walking and coordinated running), and cognitive capacity (Morris water maze and discriminated active avoidance). The performance of the mice on these tests was analyzed through the use of analyses of variance with Age and Diet as factors.<br><br>RESULTS: Supplementation of NAC improved peak motor performance in a coordinated running task by 14% (P&#xa0;<&#xa0;0.05), and increased the time spent around the platform by 24% in a Morris water maze at age 6 mo. However, the supplementation had no to minimal effect on the motor and cognitive functions of 12- and 24-mo-old mice.<br><br>CONCLUSIONS: The findings of this preclinical study support the claim that NAC has nootropic properties in 6-mo-old mice, but suggest that it may not be useful for improving motor and cognitive impairments in older mice.}, }
@article {pmid30769050, year = {2019}, author = {Shieh, P and Jan, CR and Liang, WZ}, title = {The protective effects of the antioxidant N-acetylcysteine (NAC) against oxidative stress-associated apoptosis evoked by the organophosphorus insecticide malathion in normal human astrocytes.}, journal = {Toxicology}, volume = {417}, number = {}, pages = {1-14}, doi = {10.1016/j.tox.2019.02.004}, pmid = {30769050}, issn = {1879-3185}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Astrocytes/*drug effects/metabolism ; Cell Survival/drug effects/physiology ; Cytoprotection/drug effects/physiology ; Dose-Response Relationship, Drug ; Humans ; Insecticides/toxicity ; Malathion/*toxicity ; Organophosphorus Compounds/toxicity ; Oxidative Stress/*drug effects/physiology ; }, abstract = {Malathion is one of the most widely used organophosphorus insecticides in agriculture. However, malathion may be involved in the etiology of human brain dysfunction. Induction of ROS has been proposed as a mechanism of malathion-induced poisoning cases, but there are few data regarding the effects of malathion on oxidative stress-associated neurotoxicity in human glial cells. The aim was to explore the mechanism underlying effects of malathion on neurotoxicity in Gibco[®] Human Astrocytes (GHA cells) and evaluate the protective effects of the antioxidant (N-acetylcysteine, NAC). Cell viability was measured by the cell proliferation reagent (WST-1). Antioxidant enzymes (glutathione peroxidase and catalase) were measured by an ELISA reader. Cell cycle distribution and ROS productions were detected by flow cytometry. Cell cycle-related protein levels (cyclin E1, CDK2, cyclin A2, CDK1/CDC2, or cyclin B1) and apoptotic protein levels (Bcl-2, Bax, and cleaved caspase-9/caspase-3) were analyzed by Western blotting. In GHA cells, treatment with malathion (10-25 μM) for 24 h concentration-dependently induced cytotoxicity and cell cycle arrest. In terms of oxidative stresses, malathion elevated intracellular ROS levels, but reduced glutathion and antioxidant enzyme levels. Treatment with NAC (5 μM) reversed malathion-induced oxidative stress responses, and prevented malathion-evoked apoptosis by regulating apoptotic protein expressions. Together, in GHA cells, NAC mediated inhibition of malathion-activated mitochondrial apoptotic pathways that involved cell cycle arrest and ROS responses. These data provide further insights into the molecular mechanisms behind malathion poisoning, and might suggest that NAC with its protective effects may be a potential compound for prevention of malathion-induced brain injury.}, }
@article {pmid30761659, year = {2019}, author = {Soares, MPR and Silva, DP and Uehara, IA and Ramos, ES and Alabarse, PVG and Fukada, SY and da Luz, FC and Vieira, LQ and Oliveira, APL and Silva, MJB}, title = {The use of apocynin inhibits osteoclastogenesis.}, journal = {Cell biology international}, volume = {43}, number = {5}, pages = {466-475}, doi = {10.1002/cbin.11110}, pmid = {30761659}, issn = {1095-8355}, support = {//CAPES, Brazil/ ; 444744/2014-2//CNPq, Brazil/ ; //FAPEMIG, Brazil/ ; }, mesh = {Acetophenones/metabolism/*pharmacology ; Acetylcysteine/metabolism/pharmacology ; Animals ; Cell Differentiation/drug effects ; Female ; Macrophages/drug effects/metabolism ; Male ; Matrix Metalloproteinase 9 ; Membrane Proteins ; Mice ; Mice, Inbred C57BL ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; NFATC Transcription Factors ; Nerve Tissue Proteins ; Osteoclasts/*drug effects/metabolism ; Osteogenesis/*drug effects/physiology ; Reactive Oxygen Species ; Signal Transduction/drug effects ; Tartrate-Resistant Acid Phosphatase/metabolism ; }, abstract = {Reactive oxygen species (ROS) are produced by NADPH oxidase (NOX), an enzyme that reduces oxygen by using NADPH as a substrate. Apocynin (APO) is a catechol that is used as a NOX inhibitor, and N-acetyl-cysteine (NAC) can reduce intracellular ROS levels. In this work, the effect of APO and NAC on osteoclast formation were evaluated. APO and NAC significantly decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive cells and the osteoclast area. We analyzed bone-marrow derived monocyte-macrophages (BMMs) that differentiated into osteoclasts after RANKL stimulation. Stimulation was associated with either APO or NAC treatment and osteoclastogenesis marker expression, including NFATc1, MMP-9, and DC-STAMP, was evaluated. APO decreased the intracellular calcium concentration by calcium channels other than ITPR1 and TPC2. On the other hand, APO reduced Tnfrsf11a (RANK) expression and did not alter Fam102a (EEIG1) expression. Therefore, our results demonstrate that APO inhibits osteoclastogenesis by the RANK-RANKL-related signaling pathways, decreases osteoclast markers, and reduces intracellular calcium concentration.}, }
@article {pmid30761138, year = {2019}, author = {Alberts, BM and Bruce, C and Basnayake, K and Ghezzi, P and Davies, KA and Mullen, LM}, title = {Secretion of IL-1β From Monocytes in Gout Is Redox Independent.}, journal = {Frontiers in immunology}, volume = {10}, number = {}, pages = {70}, pmid = {30761138}, issn = {1664-3224}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/analysis ; Cell Survival/drug effects ; Furans/pharmacology ; Gene Expression ; Gout/*blood ; Heterocyclic Compounds, 4 or More Rings ; Humans ; Hyperuricemia ; Indenes ; Inflammasomes/metabolism ; Interleukin-1beta/chemistry/*genetics/*metabolism ; Lipopeptides/pharmacology ; Monocytes/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists &amp; inhibitors/genetics/metabolism ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Renal Insufficiency, Chronic/blood ; Sulfonamides/pharmacology ; Sulfones ; Superoxide Dismutase/genetics ; Thioredoxin Reductase 1/genetics ; Toll-Like Receptor 2/agonists/metabolism ; Uric Acid/blood/pharmacology ; }, abstract = {The pro-inflammatory cytokine interleukin-1β (IL-1β) plays important roles in immunity but is also implicated in autoimmune disease. The most well-established mechanism of IL-1β secretion is via activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome which requires an initial priming signal followed by an activating signal. However, the precise mechanism by which the inflammasome is activated remains unclear. The role of reactive oxygen species (ROS) in this process is contradictory, with some studies suggesting that ROS are crucial while others describe opposite effects. In this study, we evaluated the effects of oxidative stress on IL-1β secretion. Gout is a disease driven solely by IL-1β secretion in response to monosodium urate (MSU) crystals which form during periods of hyperuricemia and thus presents an opportunity to study factors contributing to IL-1β secretion. Sera and monocytes were isolated from patients with gout to determine whether differences in antioxidant status could explain the susceptibility of these individuals to gout attacks. In addition, sera and monocytes were collected from patients with chronic kidney disease (CKD) for comparison as this condition is associated with high levels of oxidative stress and disturbances in serum uric acid levels. There were differences in some aspects of antioxidant defenses in gout patients and these were mainly due to higher serum uric acid. Monocytes from gout patients were more responsive to priming, but not activation, of the NLRP3 inflammasome. However, expression of the components of the NLRP3 inflammasome were unaffected by priming or activation of the inflammasome, nor were these expression levels differentially regulated in gout patients. Inhibition of ROS by N-Acetyl Cysteine inhibited TLR2-induced priming of the NLRP3 inflammasome, but had no effect on MSU-induced activation. Together these findings demonstrate that oxidative stress only affects priming of the NLRP3 inflammasome but does not influence activation.}, }
@article {pmid30757995, year = {2019}, author = {Khan, SU and Khan, MU and Rahman, H and Khan, MS and Riaz, H and Novak, M and Opoku-Asare, I and Kaluski, E}, title = {A Bayesian network meta-analysis of preventive strategies for contrast-induced nephropathy after cardiac catheterization.}, journal = {Cardiovascular revascularization medicine : including molecular interventions}, volume = {20}, number = {1}, pages = {29-37}, doi = {10.1016/j.carrev.2018.06.005}, pmid = {30757995}, issn = {1878-0938}, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/chemically induced/diagnosis/mortality/*prevention &amp; control ; Aged ; Bayes Theorem ; Cardiac Catheterization/*adverse effects/mortality ; Contrast Media/administration &amp; dosage/*adverse effects ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Male ; Middle Aged ; Network Meta-Analysis ; Protective Factors ; Randomized Controlled Trials as Topic ; Renal Dialysis ; Risk Assessment ; Risk Factors ; Sodium Bicarbonate/therapeutic use ; }, abstract = {BACKGROUND: The optimal preventive strategy for contrast induced acute kidney injury (CIAKI) in patients undergoing cardiac catheterization remains uncertain.<br><br>OBJECTIVE: We conducted Bayesian network meta-analysis (NMA) to compare different preventive strategies for CIAKI in these cohorts.<br><br>METHODS: Forty-nine randomized controlled trials were extracted using MEDLINE, EMBASE and CENTRAL data bases (inception-1st December 2017). We calculated median of the odds ratio (OR) with the corresponding 95% credible interval (CrI). The ranking probability of each treatment was based on SUCRA (surface under the cumulative ranking curve).<br><br>RESULTS: In NMA of 28,063 patients [normal saline (NS: 9716 patients), sodium bicarbonate (NaHCO3: 4484 patients), statin (2542 patients), N-acetylcysteine (NAC: 3006 patients), NAC&#x202f;+&#x202f;NaHCO3 (774 patients), NS&#x202f;+&#x202f;NAC (3807 patients), NS&#x202f;+&#x202f;NaHCO3 (135 patients) and placebo (3599 patients)], statins reduced the relative risk of CIAKI compared with NS (OR: 0.50; 95% CrI, 0.25-0.99), and placebo (OR: 0.44; 95% CrI, 0.24-0.83). Subgroup analyses showed that in patients receiving low osmolar contrast, statins reduced the relative risk of CIAKI by 58% versus NS, and 51% versus placebo. There were no significant differences across all the treatments in terms of risk of hemodialysis or all-cause mortality. Statins had the highest probability for reducing the risk of CIAKI (SUCRA, 0.86), risk of hemodialysis (SUCRA, 0.88) and all-cause mortality (SUCRA, 0.81).<br><br>CONCLUSION: Statins were the superior preventive strategy for reducing the risk of CIAKI compared with NS alone and placebo.}, }
@article {pmid30756134, year = {2019}, author = {Rosenblat, JD}, title = {Targeting the immune system in the treatment of bipolar disorder.}, journal = {Psychopharmacology}, volume = {236}, number = {10}, pages = {2909-2921}, pmid = {30756134}, issn = {1432-2072}, mesh = {Anti-Inflammatory Agents/*administration &amp; dosage ; Antidepressive Agents/administration &amp; dosage ; Antimanic Agents/administration &amp; dosage ; Bipolar Disorder/*drug therapy/*immunology/psychology ; Clinical Trials as Topic/methods ; Drug Delivery Systems/*methods/trends ; Humans ; Immune System/drug effects/immunology ; Neuroimmunomodulation/*drug effects/*immunology ; Psychotropic Drugs/administration &amp; dosage ; }, abstract = {RATIONALE: Immune dysfunction has been strongly implicated in the pathophysiology of bipolar disorder (BD). As such, numerous clinical trials have investigated the effects of anti-inflammatory agents in the treatment of BD.<br><br>OBJECTIVES: Review clinical studies evaluating the effects of anti-inflammatory agents in the treatment of BD during all illness phases (e.g., depression, mania, and euthymia).<br><br>METHODS: Relevant databases were searched from inception to August 27, 2018 for clinical studies evaluating the effects of anti-inflammatory agents in BD.<br><br>RESULTS: The majority of identified clinical trials evaluated adjunctive anti-inflammatory agents in the acute treatment of bipolar depression, demonstrating antidepressant effects with N-acetylcysteine (NAC), pioglitazone, minocycline, and coenzyme Q10, along with mixed evidence for omega-3s, and non-steroidal anti-inflammatory drugs (NSAIDs). The anti-manic effects of adjunctive anti-inflammatory agents have been minimally studied, with some promising preliminary results supporting potential anti-manic effects of adjunctive celecoxib and NAC. Maintenance studies are also limited, with inadequate evidence to support mood stabilizing effects of anti-inflammatories while euthymic. Regardless of illness phase, early results suggest that anti-inflammatory agents are likely most beneficial in the subgroup of BD with immune dysregulation.<br><br>CONCLUSIONS: Several proof-of-concept clinical trials have shown promising results for anti-inflammatory agents in the treatment of bipolar depression with moderate effect sizes and good tolerability. The effects of anti-inflammatory agents during manic and euthymic periods remains uncertain. Future larger studies, using stratified samples, enriched for participants with immune dysfunction, are required to determine the role of immune modulating agents in the treatment of BD.}, }
@article {pmid30755039, year = {2019}, author = {Kim, RJ and Hah, YS and Gwark, JY and Park, HB}, title = {N-acetylcysteine reduces glutamate-induced cytotoxicity to fibroblasts of rat supraspinatus tendons.}, journal = {Connective tissue research}, volume = {60}, number = {5}, pages = {431-443}, doi = {10.1080/03008207.2019.1580702}, pmid = {30755039}, issn = {1607-8438}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Calcium/metabolism ; Caspase 3/metabolism ; Fibroblasts/drug effects/metabolism/*pathology ; Glutamic Acid/*toxicity ; Intracellular Space/metabolism ; Male ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Rotator Cuff/drug effects/*pathology ; }, abstract = {Purpose: Neuronal theory regarding rotator cuff degeneration has developed from the findings that glutamate, an amino acid and an excitatory neurotransmitter, is present in increased concentrations in tendon tissues with tendinopathy and that glutamate induces cell death in fibroblasts of origin in rat supraspinatus tendon. The purpose of the current study was to determine whether N-acetylcysteine (NAC) has cytoprotective effects against glutamate-induced fibroblast death. Materials and Methods: Primary cultured fibroblasts were obtained from rat supraspinatus tendons. Varying concentrations of glutamate (0.5, 1, 5, and 10 mM) and of NAC (0.5, 1, 2, and 5 mM) were used for evaluation of cytotoxicity. Cell viability, cell cycles, types of cell death, intracellular ROS production, expressions of caspase-3/7, and Ca[2+] influx were evaluated. Results: Glutamate significantly induced cell death, apoptosis, and Ca[2+] influx and significantly increased caspase-3/7 activity and intracellular ROS production (p < 0.001). NAC significantly reduced the glutamate-induced cell death, apoptosis, Ca[2+] influx, caspase-3/7 activity, and intracellular ROS production (p < 0.001). Conclusions: The glutamate-induced cytotoxic effects can be reduced by NAC, an antioxidant, through the reduction of intracellular oxidative stress and/or Ca[2+] influx.}, }
@article {pmid30746681, year = {2019}, author = {Fontes, LES and Martimbianco, ALC and Zanin, C and Riera, R}, title = {N-acetylcysteine as an adjuvant therapy for Helicobacter pylori eradication.}, journal = {The Cochrane database of systematic reviews}, volume = {2}, number = {2}, pages = {CD012357}, pmid = {30746681}, issn = {1469-493X}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Aged ; Anti-Bacterial Agents/*therapeutic use ; Chemotherapy, Adjuvant/adverse effects/methods ; Helicobacter Infections/*drug therapy ; *Helicobacter pylori ; Humans ; Middle Aged ; Randomized Controlled Trials as Topic ; Young Adult ; }, abstract = {BACKGROUND: Helicobacter pylori (H pylori) is one of the most common pathogens to establish and cause infection in human beings, affecting about 50% of the world's population. Prevalence may be as high as 83% in Latin American countries and as low as 17% in North America. Approximately 20% of infected people will manifest disease; people at high risk include those who live in low- and middle-income countries with poor sanitary conditions, since the mechanism of transmission seems to be oral-oral or faecal-oral (mostly during infancy). There are several antibiotic regimens to treat the infection, but antibiotic resistance is growing around the world. New adjuvant drugs - such as probiotics, statins, curcumin, and N-acetylcysteine (NAC) - are being tested to enhance eradication rates.N-acetylcysteine can destabilise the biofilm structure; it also has synergic action with antibiotics, and bactericidal effects. In addition, NAC has antioxidant properties, and has a primary mucolytic effect by reducing the thickness of the gastric mucus layer, both of which may exert beneficial adjuvant effects on H pylori eradication.<br><br>OBJECTIVES: To assess the efficacy and safety of N-acetylcysteine as an adjuvant therapy to antibiotics for Helicobacter pylori eradication.<br><br>SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to April 2018), Embase (1988 to April 2018), CINAHL (1982 to April 2018), LILACS (1982 to April 2018), grey literature databases and trials registries. We handsearched the reference lists of relevant studies. We screened 726 articles and assessed 18 for eligibility.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any antibiotic regimen plus NAC, in adults infected with H pylori. To be included, trials had to use a control consisting of the same antibiotic regimen with or without placebo. Outcomes of interest were eradication rates, and gastrointestinal, toxic, and allergic adverse events. Reporting of the primary outcomes listed here was not an inclusion criterion for the review.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and extracted data and completed the 'Risk of bias' assessments. A third review author independently confirmed the 'Risk of bias' assessments. We used Review Manager 5 software for data analysis. We contacted study authors if there was missing information.<br><br>MAIN RESULTS: We included eight RCTs (with a total of 559 participants) in this review. The studies recruited outpatients aged between 17 and 76 years who were referred to endoscopy centres in several different countries. The certainty of evidence was reduced for most outcomes due to the poor methodological quality of included studies; issues mainly related to the generation of allocation sequence, allocation concealment, and blinding (this last domain related specifically to adverse outcomes).We are uncertain whether the addition of NAC to antibiotics improves H pylori eradication rates, compared with the addition of placebo or no NAC (38.8% versus 49.1%, risk ratio (RR) 0.74, 95% confidence interval (CI) 0.51 to 1.08; participants = 559; studies = eight; very low-certainty evidence). A post-hoc sensitivity analysis, in which we removed studies that tested antibiotic regimens no longer recommended in clinical practice, showed that the addition of NAC may improve eradication rates compared to control (27.2% versus 37.6%, RR 0.71, 95% CI 0.53 to 0.94; participants = 397; published studies = five).We are uncertain whether NAC is associated with a higher risk of gastrointestinal adverse events compared to control (23.9% versus 18.9%, RR 1.25, 95% CI 0.85 to 1.85; participants = 336; studies = five; very low-certaintyevidence), or allergic adverse events (2% versus 0%, RR 2.98, 95% CI 0.32 to 27.74; participants = 336; studies = five; very low-certainty evidence). There were no reports of toxic adverse events amongst included studies.<br><br>AUTHORS' CONCLUSIONS: We are uncertain whether the addition of NAC to antibiotics improves H pylori eradication rates compared with the addition of placebo or no NAC. Due to the clinical, statistical and methodological heterogeneity found in included studies, and the uncertainty observed when analysing therapy subgroups, any possible beneficial effect of NAC should be regarded cautiously.We are uncertain whether NAC is associated with a higher risk of gastrointestinal or allergic adverse events compared with placebo or no NAC. There were no reports of toxic adverse events amongst the included studies.Further large, well-designed, randomised clinical studies should be conducted, with good reporting standards and appropriate collection of efficacy and safety outcomes, especially for current recommended antibiotic regimens.}, }
@article {pmid30746340, year = {2019}, author = {Xu, LN and Zhao, N and Chen, JY and Ye, PP and Nan, XW and Zhou, HH and Jiang, QW and Yang, Y and Huang, JR and Yuan, ML and Xing, ZH and Wei, MN and Li, Y and Shi, Z and Yan, XJ}, title = {Celastrol Inhibits the Growth of Ovarian Cancer Cells in vitro and in vivo.}, journal = {Frontiers in oncology}, volume = {9}, number = {}, pages = {2}, pmid = {30746340}, issn = {2234-943X}, abstract = {Celastrol is a natural triterpene isolated from the Chinese plant Thunder God Vine with potent antitumor activity. However, the effect of celastrol on the growth of ovarian cancer cells in vitro and in vivo is still unclear. In this study, we found that celastrol induced cell growth inhibition, cell cycle arrest in G2/M phase and apoptosis with the increased intracellular reactive oxygen species (ROS) accumulation in ovarian cancer cells. Pretreatment with ROS scavenger N-acetyl-cysteine totally blocked the apoptosis induced by celastrol. Additionally, celastrol inhibited the growth of ovarian cancer xenografts in nude mice. Altogether, these findings suggest celastrol is a potential therapeutic agent for treating ovarian cancer.}, }
@article {pmid30745108, year = {2019}, author = {Wang, Y and Wang, Y and Wu, J and Wang, W and Zhang, Y}, title = {Oxygen partial pressure plays a crucial role in B16 melanoma cell survival by regulating autophagy and mitochondrial functions.}, journal = {Biochemical and biophysical research communications}, volume = {510}, number = {4}, pages = {643-648}, doi = {10.1016/j.bbrc.2019.01.135}, pmid = {30745108}, issn = {1090-2104}, mesh = {Animals ; *Autophagy ; Cell Line, Tumor ; Cell Survival ; Melanoma, Experimental/*metabolism/pathology ; Mice ; Mitochondria/*metabolism/pathology ; Oxygen/*metabolism ; Partial Pressure ; Reactive Oxygen Species/metabolism ; Tumor Hypoxia ; }, abstract = {The oxygen partial pressure generally increases when cancerous cells become part of the blood vessels. The study was to investigate the influence of oxygen partial pressure on the apoptosis of B16 melanoma cells. Our results demonstrated that both short-term and long-term hypoxia/reoxygenation (H/R) treatment increased stress-induced intracellular reactive oxygen species (ROS). H/R treatment also increased apoptosis and autophagy in B16 cells. N-acetylcysteine (NAC), a ROS scavenger, can reduce ROS and aid survival. However, Bafilomycin A1, an autophagy inhibitor, can accelerate cell death. Thus, our work revealed that ROS and autophagy play critical roles in cellular H/R.}, }
@article {pmid30742845, year = {2019}, author = {Liu, Z and Hou, Y and Li, L and Yang, Y and Jia, J and Hong, Z and Li, T and Xu, Y and Fu, J and Sun, Y and Yamamoto, M and Wang, H and Pi, J}, title = {Nrf2 deficiency aggravates the increase in osteoclastogenesis and bone loss induced by inorganic arsenic.}, journal = {Toxicology and applied pharmacology}, volume = {367}, number = {}, pages = {62-70}, doi = {10.1016/j.taap.2019.02.003}, pmid = {30742845}, issn = {1096-0333}, mesh = {Animals ; Arsenites/*toxicity ; Bone Remodeling/*drug effects ; Female ; Femur/*drug effects/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-E2-Related Factor 2/*deficiency/genetics ; Osteoclasts/*drug effects/metabolism/pathology ; Osteogenesis/*drug effects ; Osteoporosis/*chemically induced/genetics/metabolism/pathology ; Oxidative Stress/drug effects ; RAW 264.7 Cells ; Signal Transduction/drug effects ; Sodium Compounds/*toxicity ; }, abstract = {Arsenic exposure increases the risk of various bone disorders. For instance, chronic exposure to low level arsenic can cause bone resorption by promoting osteoclast differentiation. Osteoclast precursor cells produce hydrogen peroxide after low level arsenic exposure and then undergo differentiation, producing cells which break down bone matrix. Nuclear factor E2-related factor 2 (Nrf2) regulates receptor activator of nuclear factor-κB dependent osteoclastogenesis by modulating intracellular reactive oxygen species (ROS) signaling via expression of cytoprotective enzymes. Here we tested the hypothesis that loss of Nrf2 will increase arsenic-induced bone loss. We treated 40 week-old Nrf2[+/+] and Nrf2[-/-] mice with 5 ppm arsenic in the drinking water, which produces a blood arsenic level similar to humans living in areas where arsenic exposure is endemic. After 4 months, Micro-CT and dual-energy x-ray analysis revealed a drastic overall decrease in the bone volume with arsenic treatment in mice lacking Nrf2. Deficiency of Nrf2 in RAW 264.7 cells or bone marrow-derived macrophages (BMMs) promoted arsenic-induced osteoclast differentiation. Lack of Nrf2 increases arsenic-induced ROS levels and phosphorylation of p38. N-Acetyl-cysteine and SB203580 pretreatment essentially abolished arsenic-induced phosphorylation of p38 and reversed arsenic-induced increased osteoclast differentiation in Nrf2 deficiency. Taken together, our data suggest that loss of Nrf2 causes increased oxidative stress and enhanced susceptibility to arsenic-induced bone loss.}, }
@article {pmid30737888, year = {2019}, author = {Hou, J and Chen, L and Liu, Z and Li, J and Yang, J and Zhong, A and Zhou, M and Sun, Y and Guo, L and Yang, Y and Sun, J and Wang, Z}, title = {Sustained release of N-acetylcysteine by sandwich structured polycaprolactone/collagen scaffolds for wound healing.}, journal = {Journal of biomedical materials research. Part A}, volume = {107}, number = {7}, pages = {1414-1424}, doi = {10.1002/jbm.a.36656}, pmid = {30737888}, issn = {1552-4965}, support = {No. 81501688, 81701922, 81601707, 81873941//National Natural Science Foundation of China/International ; No. 2017CFB263//National Science Foundation of Hubei Province/International ; No. 2016ZYCX034//Science Foundation of Wuhan Union Hospital/International ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biocompatible Materials/pharmacology ; Cell Movement/drug effects ; Collagen/*chemistry ; Delayed-Action Preparations ; Disease Models, Animal ; Mice ; NIH 3T3 Cells ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Polyesters/*chemistry ; Prosthesis Implantation ; Rats, Sprague-Dawley ; Tensile Strength ; Time Factors ; Tissue Scaffolds/*chemistry ; Wound Healing/*drug effects ; }, abstract = {PCL (poly-caprolactone) nanofibers have good biocompatibility and high porosity, which are usually utilized for application in wound dressings. However, wound healing could be hindered by the overproduction of reactive oxygen species (ROS) and different factors. Pure nanofibers cannot satisfy these requirements of wound healing. N-acetylcysteine (NAC), as an antioxidant, meets the requirements for wound healing by resisting the overproduction of ROS and by promoting angiogenesis and maturation of the epidermis. In this study, we prepared a sandwich structured PCL-Col/NAC scaffold using the molding method, which consisted of PCL nanofibers at the core and NAC-loaded collagen on both sides. The hydroscopicity and tensile modulus of PCL-Col/NAC scaffolds showed best performance of these properties among groups. Meanwhile, the drug release profiles of PCL-Col/NAC scaffolds were investigated using the HPLC method and the results suggested a sustained drug release of NAC for PCL-Col/NAC scaffolds. In addition, PCL-Col/NAC scaffolds presented better properties than the control groups in cell migration and proliferation. The in vivo wound healing therapy effect was studied using an oval (2 × 1 cm) full-thickness skin defect wound model for SD rats. After 21 days, gross view and histological analysis showed a favorable beneficial therapeutic effect as well as better epidermal maturation compared with the control groups. CD31 immunohistology results revealed relatively more new vessels in the PCL-Col/NAC group than the control groups. This study developed novel PCL-Col/NAC scaffolds with an excellent hydroscopicity, tensile modulus and the ability to promote epidermal maturation and angiogenesis, demonstrating its promising potential in wound healing treatment. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2019.}, }
@article {pmid30735975, year = {2019}, author = {Kao, CM and Ou, WJ and Lin, HD and Eva, AW and Wang, TL and Chen, SC}, title = {Toxicity of diuron in HepG2 cells and zebrafish embryos.}, journal = {Ecotoxicology and environmental safety}, volume = {172}, number = {}, pages = {432-438}, doi = {10.1016/j.ecoenv.2019.01.036}, pmid = {30735975}, issn = {1090-2414}, mesh = {Animals ; Catalase/metabolism ; Diuron/*toxicity ; Embryo, Nonmammalian/*drug effects ; Hep G2 Cells ; Herbicides/*toxicity ; Humans ; Oxidative Stress ; Proteomics ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Toxicity Tests ; Zebrafish ; }, abstract = {Diuron is an herbicide, which is used to control a wide variety of annual and perennial broadleaf, grassy weeds, and mosses. However, the toxicity of diuron in HepG2 cells and zebrafish embryos was unclear. In this study, HpeG2 cells and zebrafish embryos were exposed to different concentrations of diuron for 24 h and 48 h, respectively. Results reveal the diuron caused cytotoxicity and the generation of reactive oxygen species (ROS) in the treated HepG2 cells. The effects of diuron on the expression of catalase and superoxide dismutase (SOD1 and SOD2), an antioxidant enzyme, were investigated. Results showed that only SOD1 was significantly induced after treated diuron 48 h, but the expression of catalase and SOD2 was unaffected. Additionally, the cytotoxicity of diuron was not attenuated in cells pretreated with of N-acetyl-cysteine (NAC), a well-known antioxidant, indicating that oxidative stress could not contribute to cellular death in the treated HepG2 cells. In zebrafish embryos, results from proteomic analysis show that 332 differentially upregulated proteins and 199 down-regulated proteins were detected in the treated embryos (P < 0.05). In addition to the up-regulated antioxidant proteins (prdx3, cat, prdx4, txnrd1, prdx1, sod1, prdx2, and sod2), some decreased proteins were related to cytoskeleton formation, tight junction, and gap junction, which could be related to the malformation of the treated zebrafish embryos. In summary, diuron caused cytotoxicity in HepG2 cells, and the mechanisms of toxicity in zebrafish were addressed using the proteomic analysis.}, }
@article {pmid30734439, year = {2020}, author = {Goenaga, J and Powell, GL and Leyrer-Jackson, JM and Piña, J and Phan, S and Prakapenka, AV and Koebele, SV and Namba, MD and McClure, EA and Bimonte-Nelson, HA and Gipson, CD}, title = {N-acetylcysteine yields sex-specific efficacy for cue-induced reinstatement of nicotine seeking.}, journal = {Addiction biology}, volume = {25}, number = {1}, pages = {e12711}, pmid = {30734439}, issn = {1369-1600}, support = {R21 DA044479/DA/NIDA NIH HHS/United States ; R01 AG028084/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R00 DA036569/DA/NIDA NIH HHS/United States ; K99 DA036569/DA/NIDA NIH HHS/United States ; R03 DA045881/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Craving/drug effects ; *Cues ; Disease Models, Animal ; Drug-Seeking Behavior/*drug effects ; Estrous Cycle ; Extinction, Psychological ; Female ; Free Radical Scavengers/pharmacology ; Male ; Nicotine ; Rats ; Rats, Sprague-Dawley ; Sex Factors ; Substance Withdrawal Syndrome/physiopathology ; Tobacco Use Disorder/*drug therapy/physiopathology ; }, abstract = {Women report greater craving during certain phases of the menstrual cycle. As well, research indicates that pharmacotherapies for smoking may be less efficacious in women compared with men, which may be due to interactions with natural fluctuations in ovarian hormone levels. N-Acetylcysteine (NAC) is a glutamatergic compound that has shown some efficacy in treating substance use disorders and aids in the prevention of relapse. However, it is unclear whether NAC has sex-specific effectiveness for nicotine relapse treatment. Given that NAC has shown promise to reduce nicotine reinstatement in preclinical models using male rats, the exploration of potential sex differences in the efficacy of NAC is warranted. Using a rat model, we first investigated the ability of NAC treatment (100 mg/kg, ip) during nicotine withdrawal with extinction training to reduce cue-induced nicotine seeking in male and female rats. Next, we assessed whether NAC's effects were estrous cycle-dependent for female rats. Results show that following NAC treatment during extinction, reinstatement of nicotine seeking was significantly decreased in males but not females, indicating a sex-specific effect of NAC. Furthermore, for females, both vehicle- and NAC-treated groups significantly reinstated nicotine-seeking behavior compared with extinction, regardless of estrous cycle phase. These results suggest that NAC is inefficacious in reducing nicotine relapse in females regardless of estrous cycle phase at the dose evaluated here. These collective findings could have important clinical implications for use and efficacy of NAC as a pharmacotherapy for freely cycling women smokers.}, }
@article {pmid30733583, year = {2019}, author = {Kurokawa, H and Ito, H and Terasaki, M and Matsui, H}, title = {Hyperthermia enhances photodynamic therapy by regulation of HCP1 and ABCG2 expressions via high level ROS generation.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {1638}, pmid = {30733583}, issn = {2045-2322}, mesh = {ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cell Line, Tumor ; Doxorubicin/pharmacology ; Hyperthermia, Induced/*methods ; Mitochondria/metabolism/pathology ; Photochemotherapy/*methods ; Protein-Arginine N-Methyltransferases/metabolism ; Proton-Coupled Folate Transporter/*metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Stomach Neoplasms/metabolism/pathology/*therapy ; }, abstract = {Photodynamic therapy (PDT) is a cancer treatment that make use of the cancer-specific accumulation of porphyrins. We have reported that mitochondrial reactive oxygen species (mitROS) upregulate uptake transporter of porphyrins, heme carrier protein-1 (HCP-1). The accumulation of cancer-specific porphyrins was increased by mitROS production, thereby the cancer-specific PDT cytotoxicity was enhanced. Thus we investigated whether mitROS production by hyperthermia can enhanced the cytotoxicity of PDT or not. In this study, 1 h of hyperthermia at 42 °C increased the mitROS production, and both the accumulation of cancer-specific porphyrins and the PDT cytotoxicity increased. Moreover, the authors treated cells with N-acetyl-L-cysteine (NAC) to examine the effect of mitROS. NAC inhibited the increasing ROS production after hyperthermia to restrain the post-treatment increase of cancer-specific porphyrins accumulation. Moreover, the increase of ROS production in cancer cells after hyperthermia upregulated HCP-1 expression and downregulated ABCG2 expression. These regulation were inhibited by NAC. These results suggest that hyperthermia treatment increased mitROS production, which involved HpD accumulation and enhanced PDT effects in cancer cells. The mechanism of this phenomenon was most likely to be due to both the upregulation of HCP-1 and the downregulation of ABCG2 by mitROS.}, }
@article {pmid30731196, year = {2019}, author = {Leventhal, TM and Gottfried, M and Olson, JC and Subramanian, RM and Hameed, B and Lee, WM and , }, title = {Acetaminophen is Undetectable in Plasma From More Than Half of Patients Believed to Have Acute Liver Failure Due to Overdose.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {17}, number = {10}, pages = {2110-2116}, doi = {10.1016/j.cgh.2019.01.040}, pmid = {30731196}, issn = {1542-7714}, support = {U01 DK058369/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/blood/*poisoning ; Adult ; Analgesics, Non-Narcotic/blood/*poisoning ; Chemical and Drug Induced Liver Injury/blood/diagnosis/etiology ; Drug Overdose/blood ; Female ; Humans ; Liver Failure, Acute/blood/*chemically induced/diagnosis ; Male ; Middle Aged ; Plasma/chemistry ; Retrospective Studies ; }, abstract = {BACKGROUND &amp; AIMS: Evaluation of patients with acute liver injury (ALI) or acute liver failure (ALF) often includes measurement of plasma levels of acetaminophen, to determine exposure and/or toxicity. However, once liver injury has developed, acetaminophen might be undetectable in plasma. We investigated the association between level of acetaminophen measured and outcomes of patients designated as having ALF or ALI due to acetaminophen toxicity.<br><br>METHODS: We performed a retrospective analysis of data from 434 subjects in the Acute Liver Failure Study Group who met criteria for ALF (coagulopathy and hepatic encephalopathy within 26 weeks of the first symptoms, without pre-existing liver disease) or ALI (severe liver injury with coagulopathy but no encephalopathy) due to acetaminophen toxicity from January 1, 2010 through December 31, 2014. We collected data on patient demographics, biochemical features, reported acetaminophen use, N-acetylcysteine therapy, liver transplant, and outcomes. Descriptive statistics were used to assess patient demographics, clinical characteristics, and outcomes whereas differences in continuous variables between patients with vs without acetaminophen detection on admission were analyzed using the Wilcoxon rank-sum test. The primary aim was to determine the proportion of patients with detectable plasma levels of acetaminophen.<br><br>RESULTS: Acetaminophen was undetectable in serum samples from 227 patients (52%). There were no significant differences between groups of patients with detectable vs undetectable levels in demographic features, alcohol use, median levels of alanine aspartate, or use of N-acetylcysteine (given to 94.7% of patients with detectable acetaminophen vs 95.9% of those with undetectable acetaminophen; P=.63). We observed a significant difference in median dose taken between patients with detectable (29,500 mg; interquartile range, 15,000 mg-50,007 mg) vs no detectable parent compound (14,950 mg; interquartile range, 3960 mg-25,000) (P=.003). A lower proportion of patients with detectable plasma levels of acetaminophen (72.3%) survived without a liver transplant than of patients with undetectable levels (86.3%) in univariate analysis (P=.0006), although this was not significant in multivariable analysis (P=.12). Although most patients had unintentional overdoses, a higher proportion of patients with suicidal overdoses (43%) had detectable levels of acetaminophen than patients with accidental overdoses (29.3%; P=.01).<br><br>CONCLUSION: More than half of patients who present at the hospital with acetaminophen-induced ALI or ALF have undetectable levels of acetaminophen. Clinicians should not exclude acetaminophen toxicity because of undetectable levels or withhold N-acetylcysteine for patients with ALI or ALF when acetaminophen toxicity is suspected.}, }
@article {pmid30730250, year = {2019}, author = {Chang, CH and Lane, HY and Tseng, PT and Chen, SJ and Liu, CY and Lin, CH}, title = {Effect of N-methyl-D-aspartate-receptor-enhancing agents on cognition in patients with schizophrenia: A systematic review and meta-analysis of double-blind randomised controlled trials.}, journal = {Journal of psychopharmacology (Oxford, England)}, volume = {33}, number = {4}, pages = {436-448}, doi = {10.1177/0269881118822157}, pmid = {30730250}, issn = {1461-7285}, mesh = {Age Factors ; Cognition/*drug effects ; Excitatory Amino Acid Agonists/*pharmacology ; Humans ; Randomized Controlled Trials as Topic ; Receptors, N-Methyl-D-Aspartate/*agonists ; Schizophrenia/*drug therapy ; Sex Factors ; }, abstract = {BACKGROUND: Multiple N-methyl-d-aspartate (NMDA)-receptor-enhancing agents have demonstrated promising effects for cognition in schizophrenia. However, the results of studies have been conflicting. This updated meta-analysis explored the effect of NMDA-receptor-enhancing agents on cognitive function.<br><br>METHODS: We searched PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials and Cochrane Systematic Reviews for studies on the effect of NMDA-receptor-enhancing agents on cognitive function in patients with schizophrenia up to September 2018. Double-blind randomised placebo trials with cognition rating scales were included. We pooled studies by using a random-effect model for comparisons with add-on NMDA-receptor-enhancing agents. Cognitive function scores were compared between baseline and subsequent levels, and NMDA-receptor-positive modulators were assessed using the standardised mean difference (SMD) with 95% confidence intervals (CIs). We evaluated statistical heterogeneity through visual inspection of funnel plots and by using the I[2] statistic.<br><br>RESULTS: We identified 25 trials with 1951 participants meeting the inclusion criteria. NMDA-receptor-enhancing agents had a small but nonsignificant effect compared with the placebo on overall cognitive function (SMD&#x2009;=&#x2009;0.068, CI&#x2009;=&#x2009;-0.056 to 0.193, P&#x2009;=&#x2009;0.283). We identified trials enrolling patients aged between 30 and 39&#x2009;years old, which reported significant positive effects (SMD: 0.163, 95% CI: 0.016-0.310, P&#x2009;=&#x2009;0.030). Men were associated with a smaller effect of NMDA-receptor-positive modulators on overall cognitive function. Moreover, subgroup meta-analysis of cognitive domains revealed that N-acetyl cysteine (NAC) had a significant effect on working memory (P-value for interaction =&#x2009;0.038; SMD&#x2009;=&#x2009;0.679, CI&#x2009;=&#x2009;0.397-0.961, P&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Our meta-analysis revealed no significant effect of NMDA-enhancing agents on overall cognition. However, subgroup analysis suggested that NMDAR-enhancing agents may benefit young patients with schizophrenia, and NAC may have an effect on working memory. Additional trials with larger samples are suggested to evaluate these cognitive domains and ascertain the possible mechanisms.}, }
@article {pmid30726668, year = {2019}, author = {Bermejo-Velasco, D and Azémar, A and Oommen, OP and Hilborn, J and Varghese, OP}, title = {Modulating Thiol p Ka Promotes Disulfide Formation at Physiological pH: An Elegant Strategy To Design Disulfide Cross-Linked Hyaluronic Acid Hydrogels.}, journal = {Biomacromolecules}, volume = {20}, number = {3}, pages = {1412-1420}, doi = {10.1021/acs.biomac.8b01830}, pmid = {30726668}, issn = {1526-4602}, mesh = {Cross-Linking Reagents/*chemistry ; Disulfides/*chemistry ; Hyaluronic Acid/*chemistry ; Hydrogels/*chemistry ; *Hydrogen-Ion Concentration ; Oxidation-Reduction ; }, abstract = {The disulfide bond plays a crucial role in protein biology and has been exploited by scientists to develop antibody-drug conjugates, sensors, and for the immobilization other biomolecules to materials surfaces. In spite of its versatile use, the disulfide chemistry suffers from some inevitable limitations such as the need for basic conditions (pH > 8.5), strong oxidants, and long reaction times. We demonstrate here that thiol-substrates containing electron-withdrawing groups at the β-position influence the deprotonation of the thiol group, which is the key reaction intermediate in the formation of disulfide bonds. Evaluation of reaction kinetics using small molecule substrate such as l-cysteine indicated disulfide formation at a 2.8-fold higher (k1 = 5.04 × 10[-4] min[-1]) reaction rate as compared to the conventional thiol substrate, namely 3-mercaptopropionic acid (k1 = 1.80 × 10[-4] min[-1]) at physiological pH (pH 7.4). Interestingly, the same effect could not be observed when N-acetyl-l-cysteine substrate (k1 = 0.51 × 10[-4] min[-1]) was used. We further grafted such thiol-containing molecules (cysteine, N-acetyl-cysteine, and 3-mercaptopropionic acid) to a biopolymer namely hyaluronic acid (HA) and determined the p Ka value of different thiol groups by spectrophotometric analysis. The electron-withdrawing group at the β-position reduced the p Ka of the thiol group to 7.0 for HA-cysteine (HA-Cys); 7.4 for N-acetyl cysteine (HA-ActCys); and 8.1 for HA-thiol (HA-SH) derivatives, respectively. These experiments further confirmed that the concentration of thiolate (R-S[-]) ions could be increased with the presence of electron-withdrawing groups, which could facilitate disulfide cross-linked hydrogel formation at physiological pH. Indeed, HA grafted with cysteine or N-acetyl groups formed hydrogels within 3.5 min or 10 h, respectively, at pH 7.4. After completion of cross-linking reaction, both gels demonstrated a storage modulus G' ≈ 3300-3500 Pa, which indicated comparable levels of cross-linking. The HA-SH gel, on the other hand, did not form any gel at pH 7.4 even after 24 h. Finally, we demonstrated that the newly prepared hydrogels exhibited excellent hydrolytic stability but can be degraded by cell-directed processes (enzymatic and reductive degradation). We believe our study provides a valuable insight on the factors governing the disulfide formation and our results are useful to develop strategies that would facilitate generation of stable thiol functionalized biomolecules or promote fast thiol oxidation according to the biomedical needs.}, }
@article {pmid30724068, year = {2019}, author = {Han, PP and Shen, SG and Guo, RJ and Zhao, DX and Lin, YH and Jia, SR and Yan, RR and Wu, YK}, title = {ROS Is a Factor Regulating the Increased Polysaccharide Production by Light Quality in the Edible Cyanobacterium Nostoc flagelliforme.}, journal = {Journal of agricultural and food chemistry}, volume = {67}, number = {8}, pages = {2235-2244}, doi = {10.1021/acs.jafc.8b06176}, pmid = {30724068}, issn = {1520-5118}, mesh = {Bacterial Proteins/genetics/metabolism ; Culture Media/metabolism ; Hydrogen Peroxide/metabolism ; Light ; Nostoc/genetics/growth &amp; development/*metabolism/radiation effects ; Oxidation-Reduction ; Oxidative Stress/radiation effects ; Polysaccharides, Bacterial/*biosynthesis ; Reactive Oxygen Species/*metabolism ; }, abstract = {To explore the regulatory factor of light quality affecting exopolysaccharide (EPS) production, transcriptome analysis of Nostoc flagelliforme cells exposed to red light (R), blue light (B), and mixed light (B/R = 15:7) (BR) with white fluorescent light as control was performed. The differentially expressed genes mainly enriched in carbohydrate metabolism and energy metabolism. Significant enrichment in the oxidation-reduction process and energy metabolism indicated that intracellular redox homeostasis was disrupted. An assay of reactive oxygen species (ROS) and malondialdehyde contents demonstrated light quality induced oxidative stress. To illustrate the relationship between ROS level and EPS accumulation, the effects of the exogenous addition of ROS scavenger N-acetyl cysteine and inducer H2O2 on the oxidation-reduction level and EPS production were compared. The results revealed that light quality regulated EPS biosynthesis via the intracellular ROS level directly other than oxidative stress. Understanding such relationships might provide guidance for efficient EPS production to regulate the intracellular redox level.}, }
@article {pmid30721100, year = {2019}, author = {Liu, L and Zhao, Y and Lin, Y and Zhang, R and Luo, S and Ye, P and Luo, M}, title = {The antagonistic effect of tamoxifen against d-galactosamine/lipopolysaccharide-induced acute liver failure is associated with reactivation of hepatic nuclear factor-κB.}, journal = {Immunopharmacology and immunotoxicology}, volume = {41}, number = {2}, pages = {192-198}, doi = {10.1080/08923973.2019.1569044}, pmid = {30721100}, issn = {1532-2513}, mesh = {Animals ; Disease Models, Animal ; Galactosamine/*toxicity ; Lipopolysaccharides/*toxicity ; Liver/*metabolism/pathology ; *Liver Failure, Acute/chemically induced/drug therapy/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; NF-kappa B/*metabolism ; Tamoxifen/*pharmacology ; }, abstract = {Context: Tamoxifen (TAM) ameliorates D-galactosamine/lipopolysaccharide (Gal/LPS)-induced acute liver failure (ALF) through its antioxidative effect; thus, this study was designed to determine whether the effectiveness of TAM is related to nuclear factor-κB (NF-κB) reactivation. Materials and methods: Experimental mice were injected with TAM once daily for 3 consecutive days intraperitoneally (i.p). Twelve hours after pretreatment, Gal/LPS was given to mice (i.p) for ALF induction. In the positive control group, N-acetylcysteine (NAC) was administered immediately after ALF establishment. Except for survival observation, other animals were sacrificed 7 h after Gal/LPS treatment. Survival and hepatic failure were evaluated. For the oxidation assessment, the reduced/oxidized glutathione (GSH/GSSG) ratio and hepatic superoxide dismutase (SOD) activity were analyzed using both colorimetry and Western blotting. Lastly, hepatic NF-κB activation was measured through Western blot analysis of p65 and IκBα. Results: The results indicated that pretreatment with TAM dramatically attenuated Gal/LPS-induced ALF, as demonstrated by improved survival (70%), decreased transaminase levels, and reversed histopathological manifestation. In addition, the hepatic GSH/GSSG ratio and SOD activity were decreased in the ALF model. However, to some degree, TAM and NAC effectively prevented this undesirable phenomenon in contrast to the ALF model. Western blotting revealed that compared with mice in the ALF model group, mice treated with TAM or NAC showed reactivation of hepatic NF-κB. Conclusions: Taking the results together with those of other studies, we conclude that TAM may attenuate Gal/LPS-induced ALF by antagonizing oxidative stress through NF-κB reactivation.}, }
@article {pmid30719927, year = {2019}, author = {Singh, N and Siddarth, M and Ghosh, R and Tripathi, AK and Banerjee, BD}, title = {Heptachlor-induced epithelial to mesenchymal transition in HK-2 cells mediated via TGF-β1/Smad signalling.}, journal = {Human &amp; experimental toxicology}, volume = {38}, number = {5}, pages = {567-577}, doi = {10.1177/0960327119828136}, pmid = {30719927}, issn = {1477-0903}, mesh = {Cell Line ; Epithelial-Mesenchymal Transition/*drug effects ; Glutathione/metabolism ; Heptachlor/*toxicity ; Humans ; Insecticides/*toxicity ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Smad2 Protein/*genetics/metabolism ; Smad3 Protein/*genetics/metabolism ; Transforming Growth Factor beta1/*genetics ; }, abstract = {This study investigated the effect of heptachlor-induced oxidative stress (OS) on transforming growth factor (TGF)-β1-mediated epithelial to mesenchymal transition (EMT) in human renal proximal tubular epithelial (HK-2) cells. Following treatment of HK-2 cells with an increasing concentration of heptachlor (0.01-10 µM) for 24 h, the intracellular reactive oxygen species and malondialdehyde level increased, whereas the glutathione-s-hydroxylase (GSH) level declined significantly in a dose-dependent manner. Pretreatment with N-acetyl cysteine attenuates the heptachlor-induced OS. In this study, we have shown that heptachlor-induced OS regulates the mRNA expression of TGF-β1-mediated Smad signalling genes accompanied by increased nuclear localization of phosphorylated Smad-2 and phosphorylated Smad-3. Furthermore, the m-RNA and protein level of epithelial marker, that is, E-cadherin decreased while the mesenchymal marker, that is, α-smooth muscle actin increased in heptachlor exposed HK-2 cells. In conclusion, heptachlor-induced OS might be responsible for the activation of TGF-β1/Smad signalling which ultimately leads to renal damage by means of EMT.}, }
@article {pmid30712210, year = {2019}, author = {Li, S and Xu, Z and Xia, J and Qin, G and Sang, N}, title = {Sulfur dioxide induces apoptosis via reactive oxygen species generation in rat cardiomyocytes.}, journal = {Environmental science and pollution research international}, volume = {26}, number = {9}, pages = {8758-8767}, pmid = {30712210}, issn = {1614-7499}, support = {21777091//National Natural Science Foundation of China/ ; KF2016-17//State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences/ ; 015-006//Research Project Supported by Shanxi Scholarship Council of China/ ; 21377076//National Natural Science Foundation of China/ ; 91543203//National Natural Science Foundation of China/ ; 21222701//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Line ; Male ; Membrane Potential, Mitochondrial/drug effects ; Myocytes, Cardiac/*drug effects/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Sulfur Dioxide/*toxicity ; }, abstract = {Epidemiological evidence suggests that the incidence and mortality of cardiovascular diseases are closely related to sulfur dioxide (SO2). In the present study, H9C2 cells were incubated with 100 μM NaHSO3 with or without pretreatment of an antioxidant, N-acetyl-L-cysteine (NAC). The changes of apoptosis rate, mitochondrial membrane potential (MMP), ATP content, caspase-3 activity, and reactive oxygen species (ROS) were detected. Rats were inhaled 7 mg/m[3] SO2 and/or intraperitoneal injected with 50 mg/kg (bw) of NAC for 30 days. RT-PCR and Western blot were used to detect the mRNA and protein levels of apoptosis-related genes. We found that the apoptosis of H9C2 cells was induced by NaHSO3, which decreased the content of MMP and ATP, and induced the expression of caspase-3. NAC can inhibit the apoptosis induced by NaHSO3 treatment. SO2 and NaHSO3 decreased the expression of Bcl-2 and the ratio of Bcl-2/Bax, increased the expression of Bax and P53 accumulation and phosphorylation, and activated caspase-9 and caspase-3. Whereas NAC can reduce the changes of apoptosis-related proteins in rat heart. Our results suggest that SO2 induces ROS-mediated P53 and caspase-dependent mitochondrial signaling pathways in H9C2 cells and rat hearts. Antioxidant therapy can reduce the adverse reactions of SO2 and lead to a decline in the cardiovascular disease induced by SO2.}, }
@article {pmid30708342, year = {2019}, author = {King, B and Vance, J and Wall, GM and Shoup, R}, title = {Quantitation of free and total N-acetylcysteine amide and its metabolite N-acetylcysteine in human plasma using derivatization and electrospray LC-MS/MS.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1109}, number = {}, pages = {25-36}, doi = {10.1016/j.jchromb.2019.01.013}, pmid = {30708342}, issn = {1873-376X}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*blood/chemistry ; Chromatography, High Pressure Liquid/*methods ; Drug Stability ; Humans ; Limit of Detection ; Linear Models ; Reproducibility of Results ; Tandem Mass Spectrometry/*methods ; }, abstract = {Studies of N-acetylcysteine amide (NACA) in nonclinical models have demonstrated various antioxidant, anti-apoptotic, anti-inflammatory and neuroprotective effects, and it is currently being developed as a treatment for retinitis pigmentosa. Sensitive LC-MS/MS methods were developed and validated to quantitate reduced and total NACA and its major metabolite, N-acetylcysteine (NAC), in human plasma to support clinical studies involving NACA. To trap and stabilize reduced NACA and NAC at the time of collection, whole blood was immediately treated with 2-chloro-1-methylpyridinium iodide (CMPI) to convert free thiols to 1-methylpyridinyl thioether derivatives. Plasma was harvested and frozen until samples were assayed using protein precipitation and an LC-MS/MS separation based on hydrophilic-interaction chromatography (HILIC). To process NACA and NAC present as disulfides, an intermediate portion of the extract was further subjected to reduction with tris(2-carboxyethyl) phosphine; the released thiols were then reacted with CMPI, extracted, and analyzed as before, to measure total thiols. The method for NACA and NAC, whether free/reduced or total, covered a range from 50 ng/mL to 50 μg/mL in human plasma and required a single 25 μL plasma sample. Up to 180 samples could be assayed in a single session. The inter-run mean bias and precision (%CV) were within ±5% for the free thiol method and within ±8.5% for the total thiol method. Benchtop, freeze/thaw, and long-term stability were evaluated and acceptable. The NAC/NACA method applied to a clinical study demonstrated incurred sample reproducibility of 95.5% for NAC and 99.1% for NACA.}, }
@article {pmid30707992, year = {2019}, author = {Xu, D and Zhao, Y and Weng, X and Lu, Y and Li, W and Tang, K and Chen, W and Liu, Z and Qi, X and Zheng, J and Fassett, J and Zhang, Y and Xu, Y}, title = {Novel role of mitochondrial GTPases 1 in pathological cardiac hypertrophy.}, journal = {Journal of molecular and cellular cardiology}, volume = {128}, number = {}, pages = {105-116}, doi = {10.1016/j.yjmcc.2019.01.025}, pmid = {30707992}, issn = {1095-8584}, mesh = {Angiotensin II/genetics ; Animals ; Cardiomegaly/genetics/pathology ; Cardiomyopathy, Dilated/*genetics/pathology ; GTP Phosphohydrolases/*genetics ; Heart Failure/*genetics/pathology ; Humans ; MAP Kinase Kinase Kinases/*genetics ; Mice ; Mice, Knockout ; Mitochondria/genetics/metabolism ; Myocytes, Cardiac/metabolism/pathology ; Oxidative Stress/genetics ; }, abstract = {While most mitochondrial proteins are encoded in the nucleus and translated on cytosolic/endoplasmic reticulum ribosomes, proteins encoded by mitochondrial DNA are translated on mitochondrial ribosomes. Mitochondrial GTPases 1 (MTG1) regulates mitochondrial ribosome assembly and translation, but its impact on cardiac adaptation to stress is unknown. Here, we found that MTG1 is dramatically elevated in hearts of dilated cardiomyopathy patients and in mice exposed to left ventricular pressure overload (AB). To examine the role of MTG1 in cardiac hypertrophy and heart failure, MTG1 loss/gain of function studies were performed in cultured cardiomyocytes and mice exposed to hypertrophic stress. MTG1 shRNA and adenoviral overexpression studies indicated that MTG1 expression attenuates angiotensin II-induced hypertrophy in cultured cardiomyocytes, while MTG1 KO mice exhibited no observable cardiac phenotype under basal conditions. MTG1 deficiency significantly exacerbated AB-induced cardiac hypertrophy, expression of hypertrophic stress markers, fibrosis, and LV dysfunction in comparison to WT mice. Conversely, transgenic cardiac MTG1 expression attenuated AB-induced hypertrophy and LV dysfunction. Mechanistically, MTG1 preserved mitochondrial respiratory chain complex activity during pressure overload, which further attenuated ROS generation. Moreover, we demonstrated that TAK1, P38 and JNK1/2 activity is downregulated in the MTG1 overexpression group. Importantly, dampening oxidative stress with N-acetylcysteine (NAC) lowered hypertrophy in MTG1 KO to WT levels. Collectively, our data indicate that MTG1 protects against pressure overload-induced cardiac hypertrophy and dysfunction by preserving mitochondrial function and reducing oxidative stress and downstream TAK1 stress signaling.}, }
@article {pmid30704697, year = {2019}, author = {Papi, A and Zheng, J and Criner, GJ and Fabbri, LM and Calverley, PMA}, title = {Impact of smoking status and concomitant medications on the effect of high-dose N-acetylcysteine on chronic obstructive pulmonary disease exacerbations: A post-hoc analysis of the PANTHEON study.}, journal = {Respiratory medicine}, volume = {147}, number = {}, pages = {37-43}, doi = {10.1016/j.rmed.2018.12.014}, pmid = {30704697}, issn = {1532-3064}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Inhalation ; Administration, Oral ; Adrenal Cortex Hormones/administration &amp; dosage/therapeutic use ; Adrenergic beta-2 Receptor Agonists/administration &amp; dosage/therapeutic use ; Aged ; Bronchodilator Agents/therapeutic use ; China/epidemiology ; Disease Progression ; Expectorants/administration &amp; dosage/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Placebos/administration &amp; dosage ; Pulmonary Disease, Chronic Obstructive/*drug therapy/epidemiology/physiopathology ; Severity of Illness Index ; Smoking/*adverse effects ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) 600 mg twice daily is a well-tolerated oral antioxidant mucolytic that reduces the risk of moderate to severe chronic obstructive pulmonary disease (COPD) exacerbations. PANTHEON was one of the largest studies to evaluate NAC in COPD. It recruited current, ex- and never-smokers, concomitantly treated with other medications, and used a symptom-based definition of COPD exacerbations rather than the conventional healthcare resource utilisation (HCU) criteria.<br><br>METHODS: This manuscript reports post-hoc analyses of the PANTHEON dataset investigating whether smoking status or use of concomitant medications influenced the efficacy of NAC in terms of reducing exacerbations, defined according to HCU.<br><br>RESULTS: Compared with placebo (N&#x202f;=&#x202f;482), NAC (N&#x202f;=&#x202f;482) reduced the rate of HCU events by 20% (p&#x202f;=&#x202f;0.0027), with a larger effect in current/ex-smokers (23%; p&#x202f;<&#x202f;0.01). In patients receiving NAC and long-acting inhaled bronchodilator(s) but no ICS, there was a 60% reduction in the rate of exacerbations compared to those receiving placebo, long-acting bronchodilator(s) and ICS (p&#x202f;<&#x202f;0.0001).<br><br>CONCLUSIONS: Overall, these post-hoc hypothesis-generating analyses confirm that NAC reduces the rate of COPD exacerbations, particularly in patients with COPD who have a significant smoking history, and in those not treated with ICS. NAC may provide an alternative to ICS-containing combinations in these patient subgroups.<br><br>CLINICAL TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR-TRC-09000460.}, }
@article {pmid30704503, year = {2019}, author = {Wang, Z and Yin, F and Xu, J and Zhang, T and Wang, G and Mao, M and Wang, Z and Sun, W and Han, J and Yang, M and Jiang, Y and Hua, Y and Cai, Z}, title = {CYT997(Lexibulin) induces apoptosis and autophagy through the activation of mutually reinforced ER stress and ROS in osteosarcoma.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {38}, number = {1}, pages = {44}, pmid = {30704503}, issn = {1756-9966}, support = {81501584//Young Scientists Fund/ ; 81502604//Young Scientists Fund/ ; 81772859//National Natural Science Foundation of China/ ; 81702973//National Natural Science Foundation of China/ ; }, mesh = {Animals ; Apoptosis/*drug effects ; *Autophagy ; Bone Neoplasms/drug therapy/metabolism/*pathology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/drug effects/metabolism/pathology ; Osteosarcoma/drug therapy/metabolism/*pathology ; Pyridines/*pharmacology ; Pyrimidines/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND: Osteosarcoma (OS) is a common malignant cancer in children and adolescents and has a cure rate that has not improved in the last two decades. CYT997 (lexibulin) is a novel potent microtubule-targeting agent with various anticancer activities, such as proliferation inhibition, vascular disruption, and cell cycle arrest and apoptosis induction, in multiple cancers. However, the direct cytotoxic mechanisms of CYT997 have not yet been fully characterized.<br><br>METHODS: We evaluated apoptosis and autophagy in human osteosarcomas after treatment with CYT997 and investigated the underlying mechanisms. To explore relationships, we used the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), PERK inhibitor GSK2606414, ERO1 inhibitor EN460 and mitochondrial targeted protection peptide elamipretide. BALB/c-nu mice were inoculated with 143B tumor cells to investigate the in vivo effect of CYT997.<br><br>RESULTS: We explored the efficacy and mechanism of CYT997 in osteosarcoma (OS) in vitro and in vivo and demonstrated that CYT997 potently suppresses cell viability and induces apoptosis and autophagy. CYT997 triggered production of ROS and exerted lethal effects via endoplasmic reticulum (ER) stress in OS cells. NAC attenuated these effects. The PERK inhibitor GSK2606414, which can block the ER stress pathway, reduced ROS production and enhanced cell viability. Moreover, activation of ERO1 in the ER stress pathway was responsible for inducing ROS production. ROS produced by the mitochondrial pathway also aggravate ER stress. Protection of mitochondria can reduce apoptosis and autophagy. Finally, CYT997 prominently reduced tumor growth in vivo.<br><br>CONCLUSIONS: This study suggests that CYT997 induces apoptosis and autophagy in OS cells by triggering mutually enhanced ER stress and ROS and may thus be a promising agent against OS.}, }
@article {pmid30703484, year = {2019}, author = {Yun, JW and Zhao, Z and Yan, X and Vatamaniuk, MZ and Lei, XG}, title = {Glutathione peroxidase-1 inhibits transcription of regenerating islet-derived protein-2 in pancreatic islets.}, journal = {Free radical biology &amp; medicine}, volume = {134}, number = {}, pages = {385-393}, pmid = {30703484}, issn = {1873-4596}, support = {R01 DK053018/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology ; Cells, Cultured ; *Gene Expression Regulation ; Glutathione Peroxidase/genetics/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Islets of Langerhans/cytology/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oxidants/pharmacology ; Pancreatitis-Associated Proteins/*genetics/metabolism ; Promoter Regions, Genetic ; Transcription, Genetic ; Glutathione Peroxidase GPX1 ; }, abstract = {Our group previously demonstrated that overexpression of selenium-dependent glutathione peroxidase-1 (GPX1) in mice (OE) led to escalated glucose-stimulated insulin secretion and hyperinsulinemia. Because we found a strong correlation of this phenotype with a diminished expression of regenerating islet-derived protein 2 (REG2) in the OE pancreatic islets, the present study was to reveal underlying mechanisms for that down-regulation of REG2 by GPX1 as a major scavenger of reactive oxygen species. We first treated the OE and wild-type (WT) mice and their islets with ROS-generating diquat, streptozotocin, and H2O2 and ROS-scavenging ebselen and N-acetylcysteine (NAC). Their effects on pancreatic and islet REG2 protein and(or) secretion were opposite (P < 0.05). Thereafter, we identified 13 transcriptional factors with putative binding sites in the Reg2 proximate promoter, and found that only activator protein-1 (AP-1) and albumin D box-binding protein (DBP) mRNA and protein levels were affected (elevated) (P < 0.05) by the GPX1 overproduction in the OE pancreatic islets compared with the WT islets. Contrary to that of Reg2 expression, their mRNA abundances in the cultured islets were elevated (P < 0.05) by ebselen and NAC, but decreased (P < 0.05) by H2O2. Both AP-1 and DBP could bind to the Reg2 promoter at the location of -168 to 0 base pair (bp) in the OE islets. Deleting the AP-1 (-143/-137 and -60/-57 bp) and(or) DBP (-35/-29 bp) binding domains in the Reg2 promoter attenuated and(or) abolished the inhibition of Reg2 promoter activation by ebselen as the GPX1 mimic in βTC-3 cells. In conclusion, the down-regulation of Reg2 expression in the GPX1-overproducing pancreatic islets was mediated by a transcriptional inhibition of the gene through two ROS responsive transcription factors AP-1 and DBP. Our findings reveal GPX1 as a novel regulator of Reg2 expression, and linking these two previously-unrelated proteins will have broad biomedical implications.}, }
@article {pmid30701862, year = {2018}, author = {Kalyuzhin, OV}, title = {Effect of N-acetylcysteine on mucosal immunity of respiratory tract.}, journal = {Terapevticheskii arkhiv}, volume = {90}, number = {3}, pages = {89-95}, doi = {10.26442/terarkh201890389-95}, pmid = {30701862}, issn = {0040-3660}, mesh = {*Acetylcysteine/pharmacology ; *Expectorants/pharmacology ; Humans ; *Immunity, Mucosal/drug effects ; Mucociliary Clearance ; Mucus ; }, abstract = {The outcome of diseases accompanied or caused by mucostasis depends both on the restoration of drainage function of the airways and on the effectiveness of immune mechanisms against pathogens. N-acetylcysteine (NAC) is widely used as mucolytic and antioxidant remedy in clinical practice. In this regard, the data of the scientific literature on the direct and indirect effects of NAC on the mucosal immunity of the respiratory tract have been reviewed. NAC possesses pleiotropic immunomodulating properties, most of which contribute to the regression of clinical manifestations of acute and chronic inflammatory diseases of the respiratory tract. Biological and pharmacological effects of NAC include improvement in rheological properties of mucus, reduction of excess mucin production, restoration of mucociliary clearance and production of sIgA, suppression of excess production of IgE and IgG4, destruction of biofilms and inhibition of their formation, suppression of adhesion of pathogenic bacteria to epithelial cells, antioxidant activity, regulation of the production of pro-inflammatory and profibrotic cytokines. There was no convincing evidence that NAC is able to suppress any component of mucosal immunity. For final conclusions on this subject, further research are required.}, }
@article {pmid30700851, year = {2019}, author = {Zhang, NP and Liu, XJ and Xie, L and Shen, XZ and Wu, J}, title = {Impaired mitophagy triggers NLRP3 inflammasome activation during the progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {99}, number = {6}, pages = {749-763}, doi = {10.1038/s41374-018-0177-6}, pmid = {30700851}, issn = {1530-0307}, mesh = {Animals ; Diet, High-Fat/adverse effects ; Disease Progression ; Hepatocytes/physiology ; Inflammasomes/*metabolism ; Lipid Metabolism ; Male ; Mice, Inbred C57BL ; *Mitophagy ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Necroptosis ; Non-alcoholic Fatty Liver Disease/etiology/*metabolism ; Oxidative Stress ; Rats ; }, abstract = {Activation of inflammation is an important mechanism in the development of nonalcoholic steatohepatitis (NASH). This study aims to delineate how mitophagy affects NLRP3 inflammasome activation in hepatic lipotoxicity. Mice were fed a high fat/calorie diet (HFCD) for 24 weeks. Primary rat hepatocytes were treated with palmitic acid (PA) for various periods of time. Mitophagy was measured by protein levels of LC3II and P62. NLRP3, caspase-1, interleukin (IL)-18, and IL-1β at mRNA and protein levels were used as indicators of inflammasome activation. Along with steatotic progression in HFCD-fed mice, ratio of LC3II/β-actin was decreased concurrently with increased levels of liver P62, NLRP3, caspase-1, IL-1β, IL-18, and serum IL-1β levels in late-stage NASH. PA treatment resulted in mitochondrial oxidative stress and initiated mitophagy in primary hepatocytes. The addition of cyclosporine A did not change LC3II/Τοmm20 ratios; but P62 levels were increased after an extended duration of PA exposure, indicating a defect in autophagic activity. Along with impaired mitophagy, mRNA and protein levels of NLRP3, caspase-1, IL-18 and IL-1β were upregulated by PA treatment. Pretreatment with MCC950, N-acetyl cysteine or acetyl-L-carnitine reversed inflammasome activation and a pyroptotic cascade. Additionally, mitophagic flux was partially recovered as indicated by increases in LC3II/Tomm20 ratio, parkin, and PINK1 expression, and decreased P62 expression. The findings suggest that impaired mitophagy triggers hepatic NLRP3 inflammasome activation in a murine NASH model and primary hepatocytes. The new insights into inflammasome activation through mitophagy advance our understanding of how fatty acids elicit lipotoxicity through oxidant stress and autophagy in mitochondria.}, }
@article {pmid30700808, year = {2019}, author = {Lee, SI and Kang, KS}, title = {N-acetylcysteine modulates lipopolysaccharide-induced intestinal dysfunction.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {1004}, pmid = {30700808}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers/*metabolism ; Cell Line ; Dietary Supplements ; *Enteritis/immunology/metabolism ; Epithelial Cells/cytology/*metabolism ; Intestinal Mucosa/*metabolism/pathology ; Intestine, Small/metabolism/pathology ; Swine/metabolism ; Swine, Miniature/*metabolism ; }, abstract = {The gastrointestinal epithelium functions in nutrient absorption and pathogens barrier and its dysfunction directly affects livestock performance. N-Acetylcysteine (NAC) improves mucosal function, but its effects on intestinal functions at the molecular level remain unclear. Here, we performed gene expression profiling of the pig small intestine after dietary NAC treatment under LPS challenge and investigated the effects of NAC on intestinal epithelial cells in vitro. Dietary NAC supplementation under LPS challenge altered the small intestine expression of 959 genes related to immune response, inflammatory response, oxidation-reduction process, cytokine-cytokine receptor interaction, and the cytokine-mediated signalling, Toll-like receptor signalling pathway, Jak-STAT signalling pathway, and TNF signalling pathway. We then analysed the expression patterns of the top 10 altered genes, and found that NAC markedly stimulated HMGCS3 and LDHC expression in IPEC-J2 cells. In vitro, NAC pre-treatment significantly reduced TNF-α and NF-κB, TNF-α, IFN-γ, and IL-6 expression in LPS-induced IPEC-J2 cells. NAC treatment also significantly reduced oxidative stress in LPS-induced IPEC-J2 cells and alleviated intestinal barrier function and wound healing. Thus, NAC as a feed additive can enhance livestock intestinal health by modulating intestinal inflammation, permeability, and wound healing under LPS-induced dysfunction, improving our molecular understanding of the effects of NAC on the intestine.}, }
@article {pmid30699846, year = {2019}, author = {Ellegaard, PK and Licht, RW and Nielsen, RE and Dean, OM and Berk, M and Poulsen, HE and Mohebbi, M and Nielsen, CT}, title = {The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study.}, journal = {Journal of affective disorders}, volume = {245}, number = {}, pages = {1043-1051}, doi = {10.1016/j.jad.2018.10.083}, pmid = {30699846}, issn = {1573-2517}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antidepressive Agents/*therapeutic use ; Bipolar Disorder/*drug therapy/psychology ; Brief Psychiatric Rating Scale ; Depressive Disorder/drug therapy ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; }, abstract = {OBJECTIVE: To investigate the efficacy of adjunctive N-acetylcysteine (NAC) for the treatment of acute bipolar depression.<br><br>METHOD: A randomized, double-blind, multicentre, placebo-controlled trial including adult subjects diagnosed with bipolar disorder, currently experiencing a depressive episode. Participants were treated with 3&#x202f;g/day NAC or placebo as an adjunctive to standard treatment for 20 weeks, followed by a 4-week washout where the blinding was maintained. The primary outcome was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) score over the 20-week treatment phase. Linear Mixed Effects Repeated Measures (LMERM) was used for analysing the primary outcome.<br><br>RESULTS: A total of 80 subjects were included. The mean MADRS score at baseline was 30.1 and 28.8 in participants randomized to NAC and placebo, respectively. Regarding the primary outcome measure, the between-group difference (NAC vs. placebo) was 0.5, which was statistically non-significant (95% CI: -7.0-5.9;p&#x202f;=&#x202f;0.88). All findings regarding secondary outcomes were statistically or clinically insignificant.<br><br>LIMITATIONS: The study had a placebo response rate of 55.6% - high placebo response rates are associated with failure to separate from placebo.<br><br>CONCLUSIONS: Based on our primary outcome measure, we could not confirm previous studies showing a therapeutic effect of adjunctive NAC treatment on acute bipolar depression. Further studies with larger samples are needed to elucidate if specific subgroups could benefit from adjunctive NAC treatment.}, }
@article {pmid30698282, year = {2019}, author = {He, M and Ichinose, T and Yoshida, S and Nishikawa, M and Sun, G and Shibamoto, T}, title = {Role of iron and oxidative stress in the exacerbation of allergic inflammation in murine lungs caused by urban particulate matter &lt;2.5 μm and desert dust.}, journal = {Journal of applied toxicology : JAT}, volume = {39}, number = {6}, pages = {855-867}, doi = {10.1002/jat.3773}, pmid = {30698282}, issn = {1099-1263}, support = {81302403//National Nature Science Foundation of China/International ; //Environment Research and Technology Development fund (ERTDF 5-1457) of the Ministry of Environment, Government of Japan/International ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Asthma/*etiology ; Cytokines/analysis ; Deferoxamine/pharmacology ; *Dust/analysis ; Iron/*toxicity ; Lipopolysaccharides/toxicity ; Male ; Mice ; Mice, Inbred BALB C ; *Oxidative Stress ; Particulate Matter/analysis/*toxicity ; Trace Elements/toxicity ; }, abstract = {Simultaneous exposure of lipopolysaccharide (LPS) and urban particulate matter <2.5 μm (PM2.5) or desert dust exacerbated murine asthma. In the present study, the role of iron (Fe) contained in particles and oxidative stress was investigated using Fe chelator deferoxamine (DFO) and oxidative stress scavenger N-acetylcysteine (NAC) in a murine asthma model exacerbated by LPS + PM2.5 or LPS + Asian sand dust (ASD). When BALB/c mice were intratracheally challenged with ovalbumin (OVA) + LPS and either urban PM2.5 or ASD, LPS + PM2.5 and LPS + ASD caused exacerbation of OVA-induced lung eosinophilia along with T-helper 2 cytokine and eosinophil-relevant chemokine production in bronchoalveolar lavage fluid as well as the production of OVA-specific IgE in serum. LPS + PM2.5 with NAC tended to reduce the lung eosinophilia compared to the LPS + PM2.5 host, whereas LPS + PM2.5 with DFO did not reduce them. LPS + ASD with NAC moderately reduced the lung eosinophilia compared to the LPS + ASD host. LPS + ASD with DFO drastically reduced the lung eosinophilia compared to the LPS + ASD host. The concentration of Fe in urban PM2.5 and ASD were almost the same. However, the concentrations of trace metals Pb, Cu, As, Ni, Cr, Mo, Sb, Co, Se and Cd were greater in PM2.5 than in ASD. These results suggested that Fe and oxidative stress are at least partly involved in lung eosinophilia exacerbation caused by LPS + ASD. However, trace metals (except Fe) might also be involved in lung eosinophilia exacerbated by LPS + PM2.5.}, }
@article {pmid30692577, year = {2019}, author = {Costal-Oliveira, F and Stransky, S and Guerra-Duarte, C and Naves de Souza, DL and Vivas-Ruiz, DE and Yarlequé, A and Sanchez, EF and Chávez-Olórtegui, C and Braga, VMM}, title = {L-amino acid oxidase from Bothrops atrox snake venom triggers autophagy, apoptosis and necrosis in normal human keratinocytes.}, journal = {Scientific reports}, volume = {9}, number = {1}, pages = {781}, pmid = {30692577}, issn = {2045-2322}, support = {MR/M026310/1/MRC_/Medical Research Council/United Kingdom ; 201054/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Autophagy/drug effects ; Bothrops/*metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Disease Models, Animal ; Female ; Humans ; Keratinocytes/*cytology/drug effects/pathology ; L-Amino Acid Oxidase/*toxicity ; Mice ; Necrosis ; Oxidative Stress/drug effects ; Skin/drug effects/*pathology ; Snake Venoms/*enzymology ; }, abstract = {Snake venom L-amino acid oxidases (LAAOs) are flavoproteins, which perform diverse biological activities in the victim such as edema, myotoxicity and cytotoxicity, contributing to the development of clinical symptoms of envenomation. LAAO cytotoxicity has been described, but the temporal cascade of events leading to cell death has not been explored so far. This study evaluates the involvement of LAAO in dermonecrosis in mice and its cytotoxic effects in normal human keratinocytes, the major cell type in the epidermis, a tissue that undergoes extensive necrosis at the snakebite site. Pharmacological inhibition by the antioxidant NAC (N-acetyl cysteine) prevented B. atrox venom-induced necrosis. Consistent with the potential role of oxidative stress in wounding, treatment with purified LAAO decreased keratinocyte viability with an Effective Concentration (EC50) of 5.1 μg/mL. Cytotoxicity caused by LAAO was mediated by H2O2 and treated cells underwent autophagy, followed by apoptosis and necrosis. LAAO induced morphological alterations that precede cell death. Our results show the chronological events leading to cell death and the temporal resolution from autophagy, apoptosis and necrosis as distinct mechanisms triggered by LAAO. Fluorescently-labelled LAAO was efficiently and rapidly internalized by keratinocytes, suggesting that catalysis of intracellular substrates may contribute to LAAO toxicity. A better understanding of LAAO cytotoxicity and its mechanism of action will help to identify potential therapeutic strategies to ameliorate localized snake envenomation symptoms.}, }
@article {pmid30692515, year = {2019}, author = {Sano, H and Namekata, K and Kimura, A and Shitara, H and Guo, X and Harada, C and Mitamura, Y and Harada, T}, title = {Differential effects of N-acetylcysteine on retinal degeneration in two mouse models of normal tension glaucoma.}, journal = {Cell death &amp; disease}, volume = {10}, number = {2}, pages = {75}, pmid = {30692515}, issn = {2041-4889}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/*therapeutic use ; Glaucoma/*complications/*drug therapy ; Humans ; Mice ; Retinal Degeneration/*drug therapy ; }, abstract = {N-acetylcysteine (NAC) is widely used as a mucolytic agent and as an antidote to paracetamol overdose. NAC serves as a precursor of cysteine and stimulates the synthesis of glutathione in neural cells. Suppressing oxidative stress in the retina may be an effective therapeutic strategy for glaucoma, a chronic neurodegenerative disease of the retinal ganglion cells (RGCs) and optic nerves. Here we examined the therapeutic potential of NAC in two mouse models of normal tension glaucoma, in which excitatory amino-acid carrier 1 (EAAC1) or glutamate/aspartate transporter (GLAST) gene was deleted. EAAC1 is expressed in retinal neurons including RGCs, whereas GLAST is mainly expressed in Müller glial cells. Intraperitoneal administration of NAC prevented RGC degeneration and visual impairment in EAAC1-deficient (knockout; KO) mice, but not in GLAST KO mice. In EAAC1 KO mice, oxidative stress and autophagy were suppressed with increased glutathione levels by NAC treatment. Our findings suggest a possibility that systemic administration of NAC may be available for some types of glaucoma patients.}, }
@article {pmid30690121, year = {2019}, author = {Nerush, AS and Shсhukina, KM and Balalaeva, IV and Orlova, AG}, title = {Hydrogen peroxide in the reactions of cancer cells to cisplatin.}, journal = {Biochimica et biophysica acta. General subjects}, volume = {1863}, number = {4}, pages = {692-702}, doi = {10.1016/j.bbagen.2019.01.013}, pmid = {30690121}, issn = {1872-8006}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Cisplatin/*pharmacology ; Drug Screening Assays, Antitumor ; Female ; HeLa Cells ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors/*metabolism ; Uterine Cervical Neoplasms/*drug therapy/*metabolism/pathology ; }, abstract = {BACKGROUND: Hydrogen peroxide (H2O2) is thought to be one of the key components involved in the responses of tumor cells to chemotherapy. The aim of this study was to reveal the pathways and the phases of cisplatin-induced cell death that are characterized by changes of H2O2 level.<br><br>METHODS: The genetically encoded cytosolic fluorescent sensor HyPer2 was used for flow cytometric analysis of the cisplatin-induced changes in H2O2 level in HeLa Kyoto cells. Using a vital dye and the apoptotic markers PE Annexin V or TMRE the pathways and stages of cell death were investigated simultaneously with HyPer2 response. The H2O2 level was studied separately in viable and early apoptotic cells after 12, 18, 24&#x202f;h's incubation with cisplatin at several concentrations with or without the scavenger of reactive oxygen species NAC.<br><br>RESULTS: Cisplatin causes dose- and time-dependent increase of H2O2 level in TMRE-positive and PE Annexin V-negative cancer cells. The scavenging of ROS by NAC decreased the H2O2 level and restored cell viability.<br><br>CONCLUSION: &#x41d;2&#x41e;2 generation begins in cells that have already lost mitochondrial membrane potential but have not yet externalized phosphatidylserine. Prevention of apoptosis by NAC confirmed the role of H2O2 in apoptosis induction.<br><br>GENERAL SIGNIFICANCE: This is the first time that the sensor HyPer2 has been used in parallel with apoptotic markers and vital dye to demonstrate the role of H2O2 in different stages and types of tumor cell death under chemotherapeutic action.}, }
@article {pmid30689438, year = {2019}, author = {Mutsaers, A and Green, JP and Sivilotti, MLA and Yarema, MC and Tucker, D and Johnson, DW and Spyker, DA and Rumack, BH}, title = {Changing nomogram risk zone classification with serial testing after acute acetaminophen overdose: a retrospective database analysis.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {57}, number = {6}, pages = {380-386}, doi = {10.1080/15563650.2018.1529320}, pmid = {30689438}, issn = {1556-9519}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage ; Adolescent ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/administration &amp; dosage ; Canada/epidemiology ; Chemical and Drug Induced Liver Injury/*diagnosis/epidemiology/prevention &amp; control ; Clinical Decision-Making ; Databases, Factual ; *Decision Support Techniques ; Drug Overdose/*diagnosis/drug therapy/epidemiology ; Female ; Hospitalization ; Humans ; Male ; *Nomograms ; Patient Selection ; Predictive Value of Tests ; Prognosis ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Time Factors ; Time-to-Treatment ; Young Adult ; }, abstract = {CONTEXT: The Rumack-Matthew nomogram stratifies patients into discrete risk zones following acetaminophen (APAP) overdose. Treatment decisions have traditionally been based on the initial risk zone. "Line-crossing" between zones occurs and is poorly understood. The study objective was to characterize line-crossing behavior in acute APAP overdose patients, especially moving from below to above the nomogram treatment threshold.<br><br>METHODS AND MATERIALS: The study was a secondary analysis of the Canadian Acetaminophen Overdose Study (CAOS) database, a large medical record review of patients hospitalized in eight large Canadian cities (1980-2005) following APAP poisoning. Population consisted of acute APAP overdose patients with at least two serum concentrations performed during hospitalization. Using ordinal logistic regression, we studied the effects of patient demographics, ingestion size/timing, APAP concentrations, time to N-acetylcysteine (NAC), and co-ingestants on a three-level dependent variable: patients whose risk increased two or more zones, those remaining in the same or adjacent zone, and those whose risk fell by two or more zones.<br><br>RESULTS: Of the 3201 eligible hospitalizations with 7705 APAP concentrations, half (1679, 52.5%) crossed at least one zone (up or down) within 24&#x2009;h of acute ingestion, including 190 (5.9%), who crossed at least two lines into a higher risk zone, and 516 (16.1%) at least two lines into a lower risk zone. Of the 1251 patients initially below the nomogram treatment line of 150&#x2009;&#x3bc;g/mL, 131 (10.8%) patients crossed above this line. Being older, male, and co-ingesting opioids, antimuscarinics, or NSAIDs were independently associated with line-crossing.<br><br>CONCLUSIONS: Patients commonly crossed nomogram risk zones, including from below to above the current treatment threshold. These findings support recommendations for serial APAP testing until the individual risk of hepatic injury is clearly established.}, }
@article {pmid30684884, year = {2019}, author = {Dong, W and Wang, R and Gong, X and Liang, W and Dong, C}, title = {A far-red FRET fluorescent probe for ratiometric detection of l-cysteine based on carbon dots and N-acetyl-l-cysteine-capped gold nanoparticles.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {213}, number = {}, pages = {90-96}, doi = {10.1016/j.saa.2019.01.040}, pmid = {30684884}, issn = {1873-3557}, mesh = {Acetylcysteine/*chemistry ; Carbon/*chemistry ; Cysteine/*analysis/blood ; Fluorescence Resonance Energy Transfer/*methods ; Fluorescent Dyes/*chemistry ; Gold/*chemistry ; Humans ; Metal Nanoparticles/*chemistry/ultrastructure ; Particle Size ; Quantum Dots/*chemistry ; Spectrophotometry, Ultraviolet ; }, abstract = {A novel far-red fluorescence resonance energy transfer (FRET) fluorescent probe for ratiometric detection of l-cysteine (l-Cys) has been designed. The system was established a FRET assembly by positively charged carbon dots (CDs) and negatively charged N-acetyl-l-cysteine capped gold nanoparticles (NAC-AuNPs). The fluorescence of CDs at 539 nm could be effectively quenched in the presence of NAC-AuNPs owing to FRET process, while the emission of NAC-AuNPs at 630 nm was appeared. Subsequently, the interactions between l-Cys and NAC-AuNPs resulted in the decreased emission intensity of NAC-AuNPs, but the emission intensity of CDs kept almost constant due to the continuous FRET efficiency. The ratio of emission intensities at 539 and 630 nm (I539/I630) exhibited a linear correlation to the l-Cys concentration in the range of 1.0-110 μM with the detection limit of 0.16 μM. Moreover, this far-red ratiometric sensor also revealed excellent selectivity toward l-Cys over other amino acids, which showed very high potential in the practical application for diagnosing of cysteine-related disease.}, }
@article {pmid30684449, year = {2019}, author = {Perina, EA and Ivanov, VV and Pershina, AG and Perekucha, NA and Dzyuman, AN and Kaminskii, IP and Saltykova, IV and Sazonov, AE and Ogorodova, LM}, title = {Imbalance in the glutathione system in Opisthorchis felineus infected liver promotes hepatic fibrosis.}, journal = {Acta tropica}, volume = {192}, number = {}, pages = {41-48}, doi = {10.1016/j.actatropica.2019.01.017}, pmid = {30684449}, issn = {1873-6254}, mesh = {Animals ; Cricetinae ; Glutathione/metabolism ; Glutathione Peroxidase ; Glutathione Transferase/metabolism ; Lactoylglutathione Lyase/metabolism ; Liver Cirrhosis/*etiology/*parasitology ; Opisthorchiasis/*complications ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {Although data on oxidative stress during liver fluke infection have been previously presented, a comprehensive study of the glutathione system that plays a crucial role in scavenging of reactive oxygen species (ROS) and detoxification of primary and secondary oxidation products has not been addressed yet. In the present study, the hepatic glutathione system was investigated in a hamster model of experimental opisthorchiasis infection. It was shown that chronic oxidative stress in an Opisthorchis felineus infected liver, evidenced by abundant hydroperoxide accumulation, leads to strong imbalance in the hepatic glutathione system, namely the depletion of reduced form of glutathione (GSH), lowering of the GSH/GSSG ratio, and a decrease in the glutathione peroxidase and glyoxalase 1 activity. O. felineus infection provokes hepatocellular damage that results in the progression of liver fibrosis, accompanied by an increase in collagen deposition in the hepatic tissue. Modulation of hepatic GSH levels in the O. felineus infected liver through N-acetylcysteine (NAC) or l-buthionine-S, R-sulfoxinine (BSO) treatments lead to changes in expression and activity of glutathione S-transferase and glyoxalase I as well as markedly decreases or increases collagen content in the O. felineus infected liver and the severity of liver fibrosis, respectively. Thus, the glutathione system can be considered as a target for liver protection from O. felineus-induced injury.}, }
@article {pmid30680690, year = {2019}, author = {Islam, A and Kagawa, Y and Miyazaki, H and Shil, SK and Umaru, BA and Yasumoto, Y and Yamamoto, Y and Owada, Y}, title = {FABP7 Protects Astrocytes Against ROS Toxicity via Lipid Droplet Formation.}, journal = {Molecular neurobiology}, volume = {56}, number = {8}, pages = {5763-5779}, pmid = {30680690}, issn = {1559-1182}, support = {16H05116 and 18K19723//JSPS KAKENHI/ ; JP17dm0107071//Translational and Clinical Research Core Centers from AMED/ ; TBRF-RF 17-102//Tokyo Biochemical Research Foundation/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Astrocytes/drug effects/metabolism/*pathology ; Cell Survival/drug effects ; Cells, Cultured ; Down-Regulation/drug effects ; Fatty Acid-Binding Protein 7/*metabolism ; Humans ; Lipid Droplets/drug effects/*metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/drug effects/metabolism ; Models, Biological ; *Neuroprotection/drug effects ; Reactive Oxygen Species/*toxicity ; Signal Transduction/drug effects ; }, abstract = {Fatty acid-binding proteins (FABPs) bind and internalize long-chain fatty acids, controlling lipid dynamics. Recent studies have proposed the involvement of FABPs, particularly FABP7, in lipid droplet (LD) formation in glioma, but the physiological significance of LDs is poorly understood. In this study, we sought to examine the role of FABP7 in primary mouse astrocytes, focusing on its protective effect against reactive oxygen species (ROS) stress. In FABP7 knockout (KO) astrocytes, ROS induction significantly decreased LD accumulation, elevated ROS toxicity, and impaired thioredoxin (TRX) but not peroxiredoxin 1 (PRX1) signalling compared to ROS induction in wild-type astrocytes. Consequently, activation of apoptosis signalling molecules, including p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and increased expression of cleaved caspase 3 were observed in FABP7 KO astrocytes under ROS stress. N-acetyl L-cysteine (NAC) application successfully rescued the ROS toxicity in FABP7 KO astrocytes. Furthermore, FABP7 overexpression in U87 human glioma cell line revealed higher LD accumulation and higher antioxidant defence enzyme (TRX, TRX reductase 1 [TRXRD1]) expression than mock transfection and protected against apoptosis signalling (p38 MAPK, SAPK/JNK and cleaved caspase 3) activation. Taken together, these data suggest that FABP7 protects astrocytes from ROS toxicity through LD formation, providing new insights linking FABP7, lipid homeostasis, and neuropsychiatric/neurodegenerative disorders, including Alzheimer's disease and schizophrenia.}, }
@article {pmid30678686, year = {2019}, author = {Berk, M and Turner, A and Malhi, GS and Ng, CH and Cotton, SM and Dodd, S and Samuni, Y and Tanious, M and McAulay, C and Dowling, N and Sarris, J and Owen, L and Waterdrinker, A and Smith, D and Dean, OM}, title = {A randomised controlled trial of a mitochondrial therapeutic target for bipolar depression: mitochondrial agents, N-acetylcysteine, and placebo.}, journal = {BMC medicine}, volume = {17}, number = {1}, pages = {18}, pmid = {30678686}, issn = {1741-7015}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Bipolar Disorder/*drug therapy ; Combined Modality Therapy/*methods ; *Dietary Supplements ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Mitochondria/*drug effects ; Treatment Outcome ; }, abstract = {BACKGROUND: A phasic dysregulation of mitochondrial bioenergetics may operate in bipolar disorder, increased in mania and decreased in depression. We aimed to examine efficacy of two add-on treatments in bipolar depression: N-acetylcysteine (NAC) and NAC with a combination of nutraceutical agents that may increase mitochondrial biogenesis.<br><br>METHODS: A three-arm 16-week, double-blind, randomised, placebo-controlled trial, adjunctive to usual treatment, was conducted. Participants (n&#x2009;=&#x2009;181) with bipolar disorder and current depressive symptoms were randomised to 2000&#x2009;mg/day NAC (n&#x2009;=&#x2009;59), 2000&#x2009;mg/day NAC with the combination nutraceutical treatment (CT, n&#x2009;=&#x2009;61), or placebo (n&#x2009;=&#x2009;61). The primary outcome was change in Montgomery-&#xc5;sberg Depression Rating Scale (MADRS) total score from baseline to week 16. Young Mania Rating Scale, Clinical Global Impression (CGI)-Improvement and CGI-Severity scales, Patient Global Impression scale, Social and Occupational Functioning Assessment Scale (SOFAS), Longitudinal Interval Follow-Up Evaluation - Range of Impaired Functioning Tool (LIFE-RIFT), and Quality of Life Enjoyment, and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) were secondary outcomes.<br><br>RESULTS: One hundred forty-eight participants had post-randomisation data and were analysed (NAC&#x2009;=&#x2009;52, CT&#x2009;=&#x2009;47, Placebo&#x2009;=&#x2009;49). No between-group differences were found for the rate of change between baseline and 16&#x2009;weeks on any of the clinical and functioning variables. Improvements in MADRS, BDRS, SOFAS, and LIFE-RIFT scores from baseline to the week 20 post-discontinuation visit were significantly greater in the CT group compared to those in the placebo. At week 20, the CGI-I was significantly lower in the CT group versus placebo. Gastrointestinal symptoms were significantly greater in the NAC than in the placebo group.<br><br>CONCLUSIONS: These overall negative results, with no significant differences between groups detected at the primary outcome but some positive secondary signals, suggest either delayed benefit of the combination or an improvement of symptoms on withdrawal which warrants further exploration regarding the composition, mechanisms, and application of mitochondrial agents in illnesses characterised by mitochondrial dysfunction.<br><br>TRIAL REGISTRATION: ANZCTR (ACTRN12612000830897).}, }
@article {pmid30676497, year = {2019}, author = {Cui, J and Tang, L and Hong, Q and Lin, S and Sun, X and Cai, G and Bai, XY and Chen, X}, title = {N-Acetylcysteine Ameliorates Gentamicin-Induced Nephrotoxicity by Enhancing Autophagy and Reducing Oxidative Damage in Miniature Pigs.}, journal = {Shock (Augusta, Ga.)}, volume = {52}, number = {6}, pages = {622-630}, pmid = {30676497}, issn = {1540-0514}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Autophagy/*drug effects ; Gene Expression Regulation/*drug effects ; Gentamicins/*adverse effects/pharmacology ; Kidney/*metabolism/pathology ; *Kidney Diseases/chemically induced/drug therapy/metabolism/prevention &amp; control ; Oxidation-Reduction/drug effects ; Swine ; Swine, Miniature ; }, abstract = {The clinical use of gentamicin over prolonged periods is limited because of dose and time-dependent nephrotoxicity, in which intracellular oxidative stress and heightened inflammation have been implicated. Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. The aim of this study was to determine changes in autophagy in response to the antioxidant N-acetylcysteine (NAC), via its effects on oxidative stress, inflammation, apoptosis, and renal function, following treatment with gentamicin in mini pigs. Adult mini pigs were divided into isotonic saline solution, gentamicin, and gentamicin plus NAC combination treatment groups. Gentamicin-induced histopathological changes, including inflammatory cell infiltration and tubular necrosis, were attenuated by NAC. NAC ameliorated the gentamicin-induced decreases in the levels of autophagy-related proteins, such as LC3 (microtubule-associated protein 1 light chain 3), PINK1 (phosphatase and tensin homologue deleted on chromosome10-induced kinase 1), phospho-parkin, AMBRA1 (activatingmolecule in Beclin 1-regulated autophagy), p62/SQSTM1 (sequestosome protein 1), and polyubiquitinated protein aggregates. NAC also caused a significant reduction in oxidative damage markers, including 4-hydroxy-2-nonenal, protein carbonyls, γ-H2AX (gamma histone variant H2AX), and 8-hydroxy-2'-deoxyguanosine, in gentamicin-treated animals. These data show that the protective effects of NAC might be related, at least in part, to a reduced inflammatory response, as observed in animals treated with both gentamicin and NAC. These results suggest that autophagy could be a new therapeutic target for preventing gentamicin-induced kidney injury, and that NAC might ameliorate gentamicin-induced nephrotoxicity by autophagy.}, }
@article {pmid30676094, year = {2019}, author = {Li, Y and Ruan, X and Liebenthron, J and Montag, M and Zhou, Q and Kong, W and Du, J and Jin, F and Li, S and Cheng, J and Wang, H and Mueck, AO}, title = {Ovarian tissue cryopreservation for patients with premature ovary insufficiency caused by cancer treatment: optimal protocol.}, journal = {Climacteric : the journal of the International Menopause Society}, volume = {22}, number = {4}, pages = {383-389}, doi = {10.1080/13697137.2018.1554644}, pmid = {30676094}, issn = {1473-0804}, mesh = {Acetylcysteine/chemistry ; Adult ; Antioxidants/chemistry ; Clinical Protocols ; Cryopreservation ; Female ; Fertility Preservation ; Humans ; *Menopause, Premature ; Neoplasms/drug therapy ; *Ovarian Follicle ; *Primary Ovarian Insufficiency ; Prospective Studies ; *Survivors ; Treatment Outcome ; }, abstract = {Objective: Premature ovary insufficiency is frequent after chemotherapy/radiotherapy in cancer patients. Ovarian tissue (OT) cryopreservation and later retransplantation, the routine method in Europe, has recently been implemented at the first center in China. We investigated the protective effect of the antioxidant N-acetyl-l-cysteine (NAC) during the decisive freezing-thawing steps. Methods: Fifteen OT samples were obtained from each of 13 cancer patients prospectively and randomly assigned to a control group and four groups with different NAC concentrations (Group 1, 0 mM NAC; Group 2, 0.5 mM NAC; Group 3, 1 mM NAC; Group 4, 5 mM NAC; Group 5, 25 mM NAC). After thawing, the follicle viability, DNA fragmentation, levels of reactive oxygen species (ROS), and total antioxidant capacity (TAC) were evaluated. Results: OT cryopreserved and thawed with 25 mM NAC (Group 5) has the lowest proportion of apoptotic stroma cells, but the worst follicle viability. The other four groups show similar anti-apoptosis and good follicle viability. Group 4 presented the lowest ROS and highest TAC levels. Conclusions: OT cryopreserved and thawed in medium supplemented with 5 mM NAC shows the highest antioxidant and lowest ROS capability, good apoptotic parameters, and follicle viability. Our results need to be confirmed in larger patient cohorts prior to being accepted as a standard protocol.}, }
@article {pmid30673864, year = {2019}, author = {Al-Kamel, A and Al-Hajj, WA and Halboub, E and Abdulrab, S and Al-Tahami, K and Al-Hebshi, NN}, title = {N-acetyl cysteine versus chlorhexidine mouthwashes in prevention and treatment of experimental gingivitis: a randomized, triple-blind, placebo-controlled clinical trial.}, journal = {Clinical oral investigations}, volume = {23}, number = {10}, pages = {3833-3842}, pmid = {30673864}, issn = {1436-3771}, mesh = {Acetylcysteine/*therapeutic use ; Anti-Infective Agents, Local/*therapeutic use ; Chlorhexidine/*therapeutic use ; Dental Plaque Index ; Female ; Gingivitis/*drug therapy/prevention &amp; control ; Humans ; Male ; Mouthwashes/*therapeutic use ; Young Adult ; }, abstract = {OBJECTIVES: To compare the efficacy of N-acetyl cysteine (NAC) mouthwash with chlorhexidine (CHX) in prevention and treatment of experimental gingivitis MATERIALS AND METHODS: Sixty subjects were assigned randomly and blindly into one of three equal groups: NAC, CHX, or placebo group. The study was conducted in two stages: preventive and treatment substudies. Professional prophylaxis was performed ahead of starting the preventive substudy. Then, the subjects were instructed to stop oral hygiene practices and begin rinsing twice/day with 15 ml of the assigned mouthwash (1.25% NAC, 0.2% CHX, or inert base). Plaque index (PI), gingival index (GI), and papillary bleeding index (PBI) were measured at baseline, 7, 14, and 21 days. The treatment substudy started on day 21 in which the subjects in the placebo group (now with established experimental gingivitis) were assigned to NAC (n = 10) or CHX (n = 10); the abovementioned indices were measured at 28 and 35 days. Efficacy of these interventions was compared.<br><br>RESULTS: All groups accumulated plaque and developed some degree of gingivitis: full-blown in the placebo group and remarkably mild in the CHX group. NAC had slight preventive properties at days 14 and 21. In the treatment substudy, CHX was associated with remarkable reduction in plaque and gingivitis while NAC resulted in insignificant reductions.<br><br>CONCLUSIONS: 1.25% NAC is marginally effective in prevention and treatment of experimental gingivitis.<br><br>CLINICAL RELEVANCE: When compared with the placebo, NAC showed promising preventive and treatment effects of gingivitis that deserve further development and studies.<br><br>TRIAL REGISTRATION: ISRCTN31352091.}, }
@article {pmid30670922, year = {2019}, author = {Scaglione, F and Petrini, O}, title = {Mucoactive Agents in the Therapy of Upper Respiratory Airways Infections: Fair to Describe Them Just as Mucoactive?.}, journal = {Clinical medicine insights. Ear, nose and throat}, volume = {12}, number = {}, pages = {1179550618821930}, pmid = {30670922}, issn = {1179-5506}, abstract = {BACKGROUND: Upper and lower respiratory tract infections are common conditions for which medical advice is sought, and their management relies on the use of prescription and over-the-counter (OTC) medicines. Ambroxol, bromhexine, carbocysteine, erdosteine, N-acetyl cysteine (NAC), and sobrerol are mucoactive agents for which clinical trials have been conducted, have been awarded well-established status by regulatory authorities, and are available as OTC or prescription products.<br><br>OBJECTIVE: To briefly review the evidence-based efficacy and safety of these substances in the therapy of upper respiratory airways infections.<br><br>METHODS: We conducted searches in MEDLINE and other databases for clinical trials and reviews done on the efficacy and safety of ambroxol, bromhexine, carbocysteine, erdosteine, NAC, and sobrerol.<br><br>RESULTS: Clinical trials have shown that these mucolytics have an important place in the relief of cough symptoms by easing the elimination of mucus. All drugs have shown comparable efficacy in the symptomatic treatment of productive cough, with some shared characteristics and some specific features.<br><br>CONCLUSIONS AND RELEVANCE: All mucolytics reviewed have a good safety profile, although some precautions should be taken when using ambroxol and bromhexine, and the use of NAC and carbocysteine should be monitored in special patient groups. Overall, however, the available evidence from randomised, controlled, and observational trials, as well as pragmatic, real-life experience, suggests that these products are useful in the therapy of upper respiratory airways infections, including bronchitis, sinusitis, and rhinosinusitis.}, }
@article {pmid30668391, year = {2019}, author = {Li, X and Qu, Z and Jing, S and Li, X and Zhao, C and Man, S and Wang, Y and Gao, W}, title = {Dioscin-6'-O-acetate inhibits lung cancer cell proliferation via inducing cell cycle arrest and caspase-dependent apoptosis.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {53}, number = {}, pages = {124-133}, doi = {10.1016/j.phymed.2018.09.033}, pmid = {30668391}, issn = {1618-095X}, mesh = {Antineoplastic Agents, Phytogenic/chemistry/*pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Caspases/metabolism ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; NF-kappa B/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Saponins/chemistry/*pharmacology ; Signal Transduction/drug effects ; Spirostans/chemistry/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND: Lung cancer is the leading cause of global cancer-related mortality. Dioscin-6'-O-acetate (DA), a novel natural steroidal saponin, was firstly isolated from the rhizomes of Dioscorea althaeoides R. Knuth. Until now, there were no studies on its pharmacological activities.<br><br>PURPOSE: Here, we investigated the growth inhibitory effect and explored the underlying molecular mechanisms of DA against lung cancer cells.<br><br>METHODS/STUDY DESIGNS: NSCLC H460, H1299, H520 cells and SCLC H446 cells were treated with DA. To display the cytotoxic effects and possible mechanism of DA on these cells, MTT assay, flow cytometry and western blot analysis were carried out.<br><br>RESULTS: Our results showed that DA exerted strong anti-proliferative activity against lung cancer cells in a concentration- and time-dependent manner. Flow cytometry demonstrated DA induced the cell cycle arrest at S-phase (NCI-H460, NCI-H1299, NCI-H520) or G1-phase (NCI-H446), caused cellular apoptosis, generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Western blotting analysis showed DA treatment increased the levels of caspase 3, 8, 9, Bax, p21, p53, phosphorylated JNK and p38 MAPK and markedly decreased the expression of Bcl-2, p-ERK, p-PI3K, p-AKT and NF-&#x3ba;B. Blockade of caspases with Z-VAD-FMK converted apoptosis-related proteins. Suppression of p53 with pifithrin-&#x3b1; (PFT) attenuated cell cycle-related protein. Inhibition of ROS with N-acetyl-cysteine (NAC) adjusted apoptosis-related proteins and phosphorylated MAPK and PI3K, as well as NF-&#x3ba;B.<br><br>CONCLUSION: Overall, our study indicated that DA suppressed lung cancer cells proliferation via inducing cell-cycle arrest and enhancing caspase-dependent apoptosis, at least partly, through ROS-mediated PI3K/AKT, MAPK and NF-&#x3ba;B signaling pathways.}, }
@article {pmid30668358, year = {2019}, author = {Wu, YF and Ou, CC and Chien, PJ and Chang, HY and Ko, JL and Wang, BY}, title = {Chidamide-induced ROS accumulation and miR-129-3p-dependent cell cycle arrest in non-small lung cancer cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {56}, number = {}, pages = {94-102}, doi = {10.1016/j.phymed.2018.09.218}, pmid = {30668358}, issn = {1618-095X}, mesh = {A549 Cells ; Aminopyridines/*pharmacology ; Antineoplastic Agents/*pharmacology ; Benzamides/*pharmacology ; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics ; Cell Cycle Checkpoints/drug effects/genetics ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Lung Neoplasms/*drug therapy/genetics ; MicroRNAs/*genetics ; Reactive Oxygen Species/metabolism ; Telomerase/genetics ; }, abstract = {BACKGROUND: Epigenetic therapy is a promising popular treatment modality for various cancers. Histone modification and miRNA should not be underestimated in lung cancer. This study aimed to investigate whether chidamide, a histone deacetylase inhibitor (HDACi), which inhibits telomerase activity and induces cell cycle arrest, influences ROS and miRNA production in non-small cell lung cancer (NSCLC) cells.<br><br>METHODS: H1355 and A549 were treated with chidamide. The analysis of DNA content was measured by FACSCalibur equipped with a 488&#x202f;nm laser. H1355 cells were transfected with miR-129-3p mimic by Lipofectamine2000. Telomerase activity was performed on the telomeric repeat amplification protocol (TRAP) assay. Detection of thymidylate synthase (TS), p21, p53, pRB, and &#x3b2;-actin, were performed by western blot analysis.<br><br>RESULTS: Our data showed that expression of TS, p21, and pRB were altered in the presence of chidamide by PCR and western blot. Using BrdU-incorporation analysis, we found that chidamide induced G1 arrest through the regulation of the TS gene by miR-129-3p. Chidamide was shown to suppress telomerase activity in the TRAP assay and reduced the expression of human telomerase reverse transcriptase (hTERT) by PCR and q-PCR in H1355 and A549 cells. Chidamide increased the generation of reactive oxygen species (ROS) by flow cytometry. N-acetyl cysteine (NAC), a ROS scavenger, attenuated chidamide-induced telomerase activity inhibition.<br><br>CONCLUSION: Chidamide repressed telomerase activity through ROS accumulation and cell cycle arrest by miR-129-3p upregulation in both H1355 and A549 cells. This is the first study to demonstrate that chidamide induces miR-129-3p upregulation and ROS accumulation, leading to cell cycle arrest.}, }
@article {pmid30667049, year = {2019}, author = {Braun, TL and Patel, V and DeBord, LC and Rosen, T}, title = {A review of N-acetylcysteine in the treatment of grooming disorders.}, journal = {International journal of dermatology}, volume = {58}, number = {4}, pages = {502-510}, doi = {10.1111/ijd.14371}, pmid = {30667049}, issn = {1365-4632}, mesh = {Acetylcysteine/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Nail Biting/*therapy ; Obsessive-Compulsive Disorder/*drug therapy ; Trichotillomania/*drug therapy ; }, abstract = {BACKGROUND: Pathologic grooming disorders can lead to clinically significant distress and functional impairment. Studies on treatment of these disorders with selective serotonin reuptake inhibitors (SSRIs) and anticonvulsants have led to inconsistent findings. N-acetylcysteine (NAC) has shown promise in treatment of obsessive-compulsive and related disorders. The objective of this article is to perform an updated review of NAC in the treatment of grooming disorders.<br><br>METHODS: PubMed was searched from inception to October 2017 to identify literature on the use of NAC in the management of trichotillomania, onychophagia, and pathological skin picking. Case reports, case series, and randomized controlled trials were included. Data on study design, dosing regimens, comorbidities, concurrent treatment, and side effects were extracted from the included articles.<br><br>RESULTS: Fifteen articles were included in this review, which consisted of 10 case reports, one case series, and four randomized controlled trials. Dosing of oral NAC ranged from 450 to 2,400&#xa0;mg per day, and treatment periods lasted from 1 to 8&#xa0;months. Side effects were uncommon, mild, and usually gastrointestinal in nature, with severe aggression reported in one child.<br><br>CONCLUSIONS: While there are multiple reports of the safety and efficacy of NAC in the treatment of grooming disorders, there are currently few randomized controlled trials on this topic, and more research is needed to develop a formal treatment algorithm. While current data should be considered very preliminary, case reports have demonstrated mostly positive results and a lack of significant side effects. A trial of NAC may be a viable option for pathologic grooming disorders, especially in patients who have failed prior psychologic or pharmacologic treatment.}, }
@article {pmid30666999, year = {2019}, author = {Liu, J and Tang, Y and Yang, W and Tao, B and He, Y and Shen, X and Shen, T and Lin, C and Cai, K}, title = {Functionalization of titanium substrate with multifunctional peptide OGP-NAC for the regulation of osteoimmunology.}, journal = {Biomaterials science}, volume = {7}, number = {4}, pages = {1463-1476}, doi = {10.1039/c8bm01611a}, pmid = {30666999}, issn = {2047-4849}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Histones/chemistry/*pharmacology ; Immune System/*drug effects/immunology ; Intercellular Signaling Peptides and Proteins/chemistry/*pharmacology ; Mice ; Models, Molecular ; Molecular Structure ; Osteoclasts/*drug effects ; RAW 264.7 Cells ; Titanium/chemistry/*pharmacology ; }, abstract = {The immune response to an orthopedic implant is closely related to the nearby bone metabolism balance. To modify titanium (Ti) substrates and accordingly regulate the balance between osteoclast activation and osteoblast differentiation, a multifunctional peptide OGP-NAC was synthesized via conjugating an osteogenic growth peptide (OGP) with N-acetylcysteine (NAC). Then, the synthesized peptide was employed to functionalize Ti substrates and the response of both osteoblasts and osteoclasts was investigated in vitro. The results showed that OGP-NAC was successfully prepared and immobilized onto Ti substrate surfaces. Thereafter, studies on introducing RAW 264.7 cells (one kind of monocyte macrophage responsible for immune responses) to osteoclasts demonstrated that the peptide modified Ti surface could inhibit RAW 264.7 cells from secreting important inflammatory cytokines (TNF-α and IL-1β), and suppress the activation of MAPK, NF-κB and NFAT c1, which are important transcription factors for osteoclastogenesis. Meanwhile, the modified surface promoted osteoblast spreading, proliferation and differentiation. The study offers a feasible strategy to mediate the balance between osteoclast activation and osteoblast differentiation, having great potential for improving osseointegration of an orthopedic implant.}, }
@article {pmid30664687, year = {2019}, author = {Bagati, A and Moparthy, S and Fink, EE and Bianchi-Smiraglia, A and Yun, DH and Kolesnikova, M and Udartseva, OO and Wolff, DW and Roll, MV and Lipchick, BC and Han, Z and Kozlova, NI and Jowdy, P and Berman, AE and Box, NF and Rodriguez, C and Bshara, W and Kandel, ES and Soengas, MS and Paragh, G and Nikiforov, MA}, title = {KLF9-dependent ROS regulate melanoma progression in stage-specific manner.}, journal = {Oncogene}, volume = {38}, number = {19}, pages = {3585-3597}, pmid = {30664687}, issn = {1476-5594}, support = {P30 CA016056/CA/NCI NIH HHS/United States ; R01 CA224434/CA/NCI NIH HHS/United States ; CA220096//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/International ; R01 CA190533/CA/NCI NIH HHS/United States ; R21 CA220096/CA/NCI NIH HHS/United States ; R01 CA193981/CA/NCI NIH HHS/United States ; CA224434//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/International ; }, mesh = {Acetylcysteine/adverse effects ; Adult ; Aged ; Aged, 80 and over ; Animals ; Humans ; Kruppel-Like Transcription Factors/genetics/*metabolism ; Melanocytes/drug effects/metabolism/pathology ; Melanoma/genetics/metabolism/*pathology ; Melanoma, Experimental/chemically induced/metabolism/pathology ; Mice, Knockout ; Middle Aged ; Proto-Oncogene Proteins B-raf/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Skin Neoplasms/metabolism/*pathology ; }, abstract = {Although antioxidants promote melanoma metastasis, the role of reactive oxygen species (ROS) in other stages of melanoma progression is controversial. Moreover, genes regulating ROS have not been functionally characterized throughout the entire tumor progression in mouse models of cancer. To address this question, we crossed mice-bearing knock-out of Klf9, an ubiquitous transcriptional regulator of oxidative stress, with two conditional melanocytic mouse models: Braf[CA] mice, where Braf[V600E] causes premalignant melanocytic hyperplasia, and Braf[CA]/Pten[-/-] mice, where Braf[V600E] and loss of Pten induce primary melanomas and metastases. Klf9 deficiency inhibited premalignant melanocytic hyperplasia in Braf[CA] mice but did not affect formation and growth of Braf[CA]/Pten[-/-] primary melanomas. It also, as expected, promoted Braf[CA]/Pten[-/-] metastasis. Treatment with antioxidant N-acetyl cysteine phenocopied loss of Klf9 including suppression of melanocytic hyperplasia. We were interested in a different role of Klf9 in regulation of cell proliferation in Braf[CA] and Braf[CA]/Pten[-/-] melanocytic cells. Mechanistically, we demonstrated that BRAF[V600E] signaling transcriptionally upregulated KLF9 and that KLF9-dependent ROS were required for full-scale activation of ERK1/2 and induction of cell proliferation by BRAF[V600E]. PTEN depletion in BRAF[V600E]-melanocytes did not further activate ERK1/2 and cell proliferation, but rendered these phenotypes insensitive to KLF9 and ROS. Our data identified an essential role of KLF9-dependent ROS in BRAF[V600E] signaling in premalignant melanocytes, offered an explanation to variable role of ROS in premalignant and transformed melanocytic cells and suggested a novel mechanism for suppression of premalignant growth by topical antioxidants.}, }
@article {pmid30662622, year = {2018}, author = {Zhang, W and Hua, T and Li, J and Zheng, L and Wang, Y and Xu, M and Qi, G}, title = {CXCL16 is activated by p-JNK and is involved in H2O2-induced HK-2 cell injury via p-ERK signaling.}, journal = {American journal of translational research}, volume = {10}, number = {11}, pages = {3723-3732}, pmid = {30662622}, issn = {1943-8141}, abstract = {Acute kidney injury (AKI) leads to an abrupt deterioration of renal function. CXC chemokine ligand 16 (CXCL16) is a CXC-soluble chemokine and a cell surface scavenger receptor that is involved in tissue injury and inflammation. It is induced in AKI patients, but the molecular mechanism remains unclear. In this study, we have worked to determine the function of CXCL16 and to investigate the involvement of ERK and JNK signaling in AKI. We used H2O2 and recombinant human CXCL16 protein (rh CXCL16) to treat the human renal tubular epithelial cell line, HK-2, in vitro. The present results indicate that H2O2 inhibits proliferation, induces apoptosis, and up-regulates expression of CXCL16 and the CXCL16 receptor, CXCR6, in HK-2 cells. Furthermore, H2O2-induced proliferation inhibition, apoptosis, and inflammation in HK-2 cells were ameliorated by NAC (N-acetyl cysteine, the ROS scavenger) and SP600125 (the JNK inhibitor). The expression levels of CXCL16 and CXCR6 were also positively correlated with the phosphorylation level of JNK (p-JNK). Additionally, rh CXCL16 treatment led to effects like those of H2O2 treatment in HK-2 cells, with symptoms being effectively improved by CXCR6 siRNA and the ERK inhibitor (PD98059). In addition, rh CXCL16-induced HK-2 cell apoptosis, inflammation, and collagen deposition were lessened by CXCR6 siRNA and PD98059 treatment. In summary, the present results have indicated that CXCL16 is involved in H2O2-induced HK-2 cell injury, that CXCL16 is activated by p-JNK, and that the regulatory function of CXCL16 is involved in the phosphorylation of ERK.}, }
@article {pmid30660690, year = {2019}, author = {Li, E and Sun, Y and Lv, G and Li, Y and Zhang, Z and Hu, Z and Cao, W}, title = {Sinoporphyrin sodium based sonodynamic therapy induces anti-tumor effects in hepatocellular carcinoma and activates p53/caspase 3 axis.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {113}, number = {}, pages = {104-114}, doi = {10.1016/j.biocel.2019.01.009}, pmid = {30660690}, issn = {1878-5875}, mesh = {Animals ; Carcinoma, Hepatocellular/metabolism/pathology/*therapy ; Caspase 3/*metabolism ; Cell Line, Tumor ; Female ; Hep G2 Cells ; Humans ; Liver Neoplasms/metabolism/pathology/*therapy ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Porphyrins/*pharmacology ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/*metabolism ; *Ultrasonic Therapy ; Xenograft Model Antitumor Assays ; }, abstract = {Sonodynamic therapy (SDT) is a noninvasive therapeutic method via the activation of certain chemical sensitizers using low intensity ultrasound. In this work, we evaluated the antitumor effect of sinoporphyrin sodium (DVDMS) mediated SDT (DVDMS-SDT) on Hepatocellular carcinoma (HCC) cell lines both in vitro and in vivo. The results indicated that DVDMS-SDT was significantly more efficacious than PpIX-SDT in treating hepatocellular cell line Hep-G2. DVDMS-SDT also increased the ratio of cells in the G2/M phase and decreased the CDK1 and Cyclin B1 protein level. DVDMS-SDT markedly increased intracellular reactive oxygen species (ROS) in vitro. The increased ROS production up-regulated the expression of p53 and Bax, and down-regulated Bcl-2 expression, which led to the activation of caspase-3, ultimately initiated cell apoptosis. These effects could be partially reversed by the ROS scavenger N-acetylcysteine (NAC). In vivo experiments revealed that the DVDMS-SDT resulted in an effective inhibition of tumor growth and prolonged the survival time of tumor-bearing mice. More importantly, no obvious signs of side effects were observed. These results suggested that DVDMS-SDT is very effective in treating Hepatocellular carcinoma without side effects. The primary mechanism of SDT is due to the increased ROS activated the p53/Caspase 3 axis of apoptosis.}, }
@article {pmid30660392, year = {2019}, author = {Ma, Z and Song, G and Liu, D and Qian, D and Wang, Y and Zhou, J and Gong, J and Meng, H and Zhou, B and Yang, T and Song, Z}, title = {N-Acetylcysteine enhances the therapeutic efficacy of bone marrow-derived mesenchymal stem cell transplantation in rats with severe acute pancreatitis.}, journal = {Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]}, volume = {19}, number = {2}, pages = {258-265}, doi = {10.1016/j.pan.2019.01.004}, pmid = {30660392}, issn = {1424-3911}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Animals ; *Bone Marrow Cells ; Male ; *Mesenchymal Stem Cell Transplantation ; Oxidative Stress ; Pancreatitis/*chemically induced/*drug therapy ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Taurocholic Acid/toxicity ; }, abstract = {BACKGROUND: Severe acute pancreatitis (SAP) is a high mortality disease, for which there is a lack of effective therapies. Previous research has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs), which have immunomodulatory and antioxidant properties, have potential for the treatment of SAP. It remains unclear, however, whether the free radical scavenger N-acetylcysteine (NAC) can enhance the therapeutic efficacy of BMSC transplantation in SAP. In this study, we investigated the effect of combining treatment with NAC and BMSCs in a rat model of SAP.<br><br>METHODS: SAP was induced by injection of sodium taurocholate into the pancreatic duct and, after successful induction of SAP, the rats were treated with BMSCs and NAC, either singly or in combination.<br><br>RESULTS: After 3 days, serum levels of amylase, proinflammatory factors, malondialdehyde, and reactive oxygen species were significantly decreased in animals treated with BMSCs or NAC, compared with vehicle-treated animals. In contrast, total glutathione, superoxide dismutase and catalase were markedly increased after treatment with BMSCs or NAC. However, oxidative stress markers and inflammatory factors were significantly improved in the SAP&#xa0;+&#xa0;BMSCs&#xa0;+&#xa0;NAC group compared with those in the SAP&#xa0;+&#xa0;NAC group and the SAP&#xa0;+&#xa0;BMSCs group.<br><br>CONCLUSIONS: Combined NAC and BMSC therapy was found to alleviate oxidative stress damage to the pancreas and to inhibit the inflammatory response to a significantly greater extent than single therapy with either BMSCs or NAC. Because NAC enhances the therapeutic efficacy of BMSC transplantation in a rat model of SAP, combined therapy may provide a promising new approach for the treatment of SAP.}, }
@article {pmid30659606, year = {2019}, author = {Majumdar, S and Adiga, V and Raghavan, A and Rananaware, SR and Nandi, D}, title = {Comparative analysis of thymic subpopulations during different modes of atrophy identifies the reactive oxygen species scavenger, N-acetyl cysteine, to increase the survival of thymocytes during infection-induced and lipopolysaccharide-induced thymic atrophy.}, journal = {Immunology}, volume = {157}, number = {1}, pages = {21-36}, pmid = {30659606}, issn = {1365-2567}, mesh = {Acetylcysteine/*metabolism ; Animals ; Atrophy ; Cell Differentiation ; Cell Survival ; Disease Models, Animal ; Free Radical Scavengers/*metabolism ; Humans ; Lipopolysaccharides/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Reactive Oxygen Species/metabolism ; Salmonella Infections/*immunology ; Salmonella typhimurium/*physiology ; T-Lymphocytes/*physiology ; Thymocytes/*physiology ; Thymus Gland/*pathology ; }, abstract = {The development of immunocompetent T cells entails a complex pathway of differentiation in the thymus. Thymic atrophy occurs with ageing and during conditions such as malnutrition, infections and cancer chemotherapy. The comparative changes in thymic subsets under different modes of thymic atrophy and the mechanisms involved are not well characterized. These aspects were investigated, using mice infected with Salmonella Typhimurium, injection with lipopolysaccharide (LPS), an inflammatory but non-infectious stimulus, etoposide (Eto), a drug used to treat some cancers, and dexamethasone (Dex), a steroid used in some inflammatory diseases. The effects on the major subpopulations of thymocytes based on multicolour flow cytometry studies were, first, the CD4[-] CD8[-] double-negative (DN) cells, mainly DN2-4, were reduced with infection, LPS and Eto treatment, but not with Dex. Second, the CD8[+] CD3[lo] immature single-positive cells (ISPs) were highly sensitive to infection, LPS and Eto, but not Dex. Third, treatment with LPS, Eto and Dex reduced all three subpopulations of CD4[+] CD8[+] double-positive (DP) thymocytes, i.e. DP1, DP2 and DP3, but the DP3 subset was relatively more resistant during infection. Fourth, both CD4[+] and CD8[+] single-positive (SP) thymocytes were lowered by Eto and Dex, but not during infection. Notably, LPS lowered CD4[+] SP subsets, whereas the CD8[+] SP subsets were relatively more resistant. Interestingly, the reactive oxygen species quencher, N-acetyl cysteine, greatly improved the survival of thymocytes, especially DNs, ISPs and DPs, during infection and LPS treatment. The implications of these observations for the development of potential thymopoietic drugs are discussed.}, }
@article {pmid30655827, year = {2019}, author = {Qiu, M and Zhang, S and Ke, L and Tang, H and Zeng, X and Liu, J}, title = {JS-K enhances chemosensitivity of prostate cancer cells to Taxol via reactive oxygen species activation.}, journal = {Oncology letters}, volume = {17}, number = {1}, pages = {757-764}, pmid = {30655827}, issn = {1792-1074}, abstract = {The aim of the present study was to investigate the influence of the nitric oxide donor prodrug JS-K (C13H16N6O8) on Taxol-induced apoptosis in prostate cancer cells, and to investigate a potential reactive oxygen species (ROS)-associated mechanism. The effect of JS-K on the anticancer activity of Taxol was assessed in prostate cancer cells; cell viability, colony formation, apoptosis, ROS generation and expression levels of apoptosis-associated proteins were investigated. The function of ROS accumulation in the combined effects of JS-K and Taxol was determined using the antioxidant N-acetylcysteine (NAC) and the pro-oxidant oxidized glutathione (GSSG). The results of the present study demonstrated that JS-K was able to increase Taxol-induced suppression of prostate cancer cell proliferation, apoptosis, ROS accumulation and upregulation of apoptosis-associated proteins. Furthermore, NAC reversed the effect of JS-K on Taxol-induced apoptosis and conversely, the pro-oxidant GSSG exacerbated the effect of JS-K on Taxol-induced apoptosis in prostate cancer cells. In conclusion, JS-K enhances the chemosensitivity of prostate cancer cells to Taxol, via the upregulation of intracellular ROS.}, }
@article {pmid30654934, year = {2019}, author = {Higashi, T and Elmeligy, E and Mai, Y and Noya, Y and Terada, K and Mazaki, Y and Kuge, Y and Miwa, S}, title = {Glutathione and cysteines suppress cytotoxicity of gas phase of cigarette smoke by direct reacting with unsaturated carbonyl compounds in the gas phase.}, journal = {Biochemical and biophysical research communications}, volume = {509}, number = {4}, pages = {988-993}, doi = {10.1016/j.bbrc.2019.01.040}, pmid = {30654934}, issn = {1090-2104}, mesh = {Acrolein/toxicity ; Aldehydes/toxicity ; Antioxidants/pharmacology ; Chromatography, High Pressure Liquid ; Cysteine/analogs &amp; derivatives/*pharmacology ; Environmental Pollutants/toxicity ; Gases ; Glutathione/*pharmacology ; Ketones/toxicity ; Mass Spectrometry ; Protein Carbonylation/drug effects ; *Smoke ; Tobacco Products/*toxicity ; }, abstract = {Unsaturated carbonyl compounds, such as acrolein (ACR) and methyl vinyl ketone (MVK), are environmental pollutants, and are contained in smoke, automobile exhaust, and heated oil. We have previously reported that major cytotoxic factors in the gas phase of cigarette smoke are ACR and MVK. ACR and MVK induce cell damage by reactive oxygen species generation via protein kinase C and NADPH oxidases, and antioxidants, such as glutathione (GSH) and N-acetylcysteine (NAC), can effectively suppress their cytotoxic activities. In this study, we attempted to elucidate the molecular mechanism(s) for suppression of ACR- and MVK-induced cytotoxic activities by these antioxidants. GSH, NAC, L- and D-cysteines completely suppressed cell damage induced by gas phase extract of cigarette smoke. The results of HPLC and mass spectrometry showed that GSH and NAC directly reacted with ACR and MVK. Cysteines and cysteine derivatives suppressed ACR-induced GAPDH carbonylation, a representative protein for carbonylation. The current results suggest that GSH, NAC, and cysteines directly reacted with ACR and MVK, and suppressed these unsaturated carbonyl compounds-induced cell damage by inhibition of protein carbonylation.}, }
@article {pmid30654800, year = {2019}, author = {Matilla, E and Martín-Cano, FE and González-Fernández, L and Sánchez-Margallo, FM and Álvarez, IS and Macías-García, B}, title = {N-acetylcysteine addition after vitrification improves oocyte mitochondrial polarization status and the quality of embryos derived from vitrified murine oocytes.}, journal = {BMC veterinary research}, volume = {15}, number = {1}, pages = {31}, pmid = {30654800}, issn = {1746-6148}, support = {IB16159//Consejer&#xed;a de Educaci&#xf3;n y Empleo, Junta de Extremadura (ES)/ ; AGL2015-73249-JIN (AEI/FEDER/UE)//Ministerio de Econom&#xed;a y Competitividad/ ; AGL2017-84681-R (AEI/FEDER/UE)//Ministerio de Econom&#xed;a, Industria y Competitividad, Gobierno de Espa&#xf1;a/ ; }, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Blastocyst/metabolism ; Cryopreservation/methods/*veterinary ; Embryo, Mammalian/*metabolism ; Female ; Fertilization in Vitro/veterinary ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mitochondria/*drug effects ; Oocytes/*drug effects ; Reactive Oxygen Species/metabolism ; Vitrification/*drug effects ; }, abstract = {BACKGROUND: Vitrification is the safest method to cryopreserve oocytes, however the process alters mitochondrial function resulting from increased reactive oxygen species (ROS) production. Our aim was to alleviate ROS stress in vitrified mice oocytes using N-acetylcysteine (NAC at 1 mM), to improve the oocyte's developmental competence.<br><br>RESULTS: Hence, four experimental groups were compared: fresh oocytes (F-C), vitrified oocytes (V-C), NAC addition prior to oocyte vitrification (V-NAC-Pre) and NAC addition after vitrification (V-NAC-Post). V-NAC-Pre and V-NAC-Post exhibited higher levels of mitochondrial polarization compared to vitrified oocytes (36.5&#x2009;&#xb1;&#x2009;3.1, 37.7&#x2009;&#xb1;&#x2009;1.3 and 27.2&#x2009;&#xb1;&#x2009;2.4 measured as the spatial coefficient of variation/oocyte respectively, mean&#x2009;&#xb1;&#x2009;SEM; p&#x2009;<&#x2009;0.05). However, ROS production increased in vitrified oocytes added with NAC compared to the vitrified control (1124.7&#x2009;&#xb1;&#x2009;102.1 [V-NAC-Pre] and 1063.2&#x2009;&#xb1;&#x2009;82.1 [V-NAC-Post] vs. 794.6&#x2009;&#xb1;&#x2009;164.9 [V-C]; arbitrary fluorescence units/oocyte, mean&#x2009;&#xb1;&#x2009;SEM; p&#x2009;<&#x2009;0.05). ATP significantly decreased in V-NAC-Pre compared to V-NAC-Post oocytes (18.5&#x2009;&#xb1;&#x2009;6.9 vs. 54.2&#x2009;&#xb1;&#x2009;4.6 fmol/oocyte respectively, mean&#x2009;&#xb1;&#x2009;SEM; p&#x2009;<&#x2009;0.05), and no differences were observed between V-NAC-Post, F-C and V-C groups. Blastocyst rates derived from F-C oocytes was higher than those derived from V-NAC-Pre (90.7&#x2009;&#xb1;&#x2009;1.8 vs. 79.1&#x2009;&#xb1;&#x2009;1.8, respectively, mean %&#x2009;&#xb1;&#x2009;SEM,; p&#x2009;<&#x2009;0.05) but similar to those derived from V-NAC-Post (90.7&#x2009;&#xb1;&#x2009;1.8, mean %&#x2009;&#xb1;&#x2009;SEM, p&#x2009;>&#x2009;0.05). Total blastomere count of blastocysts derived from V-NAC-Post after in vitro fertilization (IVF) was higher than embryos produced from V-C.<br><br>CONCLUSIONS: The addition of NAC after vitrification improves the quality of vitrified mature murine oocytes while its addition prior to vitrification is advised against.}, }
@article {pmid30654434, year = {2019}, author = {Savion, N and Dahamshi, S and Morein, M and Kotev-Emeth, S}, title = {S-Allylmercapro-N-Acetylcysteine Attenuates the Oxidation-Induced Lens Opacification and Retinal Pigment Epithelial Cell Death In Vitro.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {8}, number = {1}, pages = {}, pmid = {30654434}, issn = {2076-3921}, support = {3511//Claire and Am&#xe9;d&#xe9;e Maratier Institute for the Study of Blindness and Visual Disorders, Tel Aviv University/ ; 3581//Aya Baharav fund for glaucoma research and prevention, Sackler Faculty of Medicine, Tel-Aviv University/ ; }, abstract = {The capacity of S-Allylmercapto-N-acetylcysteine (ASSNAC) to protect human retinal pigment epithelial (RPE) cells (line ARPE-19) and porcine lenses from oxidative stress was studied. Confluent ARPE-19 cultures were incubated with ASSNAC or N-acetyl-cysteine (NAC) followed by exposure to oxidants and glutathione level and cell survival were determined. Porcine lenses were incubated with ASSNAC and then exposed to H2O2 followed by lens opacity measurement and determination of glutathione (reduced (GSH) and oxidized (GSSG)) in isolated lens adhering epithelial cells (lens capsule) and fiber cells consisting the lens cortex and nucleus (lens core). In ARPE-19 cultures, ASSNAC (0.2 mM; 24 h) increased glutathione level by 2[-]2.5-fold with significantly higher increase in GSH compared to NAC treated cultures. Similarly, ex-vivo exposure of lenses to ASSNAC (1 mM) significantly reduced the GSSG level and prevented H2O2 (0.5 mM)-induced lens opacification. These results demonstrate that ASSNAC up-regulates glutathione level in RPE cells and protects them from oxidative stress-induced cell death as well as protects lenses from oxidative stress-induced opacity. Further validation of these results in animal models may suggest a potential use for ASSNAC as a protective therapy in retinal degenerative diseases as well as in attenuation of oxidative stress-induced lens opacity.}, }
@article {pmid30654433, year = {2019}, author = {Degroote, J and Van Noten, N and Wang, W and De Smet, S and Michiels, J}, title = {Effects of N-Acetyl-Cysteine Supplementation through Drinking Water on the Glutathione Redox Status during the Weaning Transition of Piglets.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {8}, number = {1}, pages = {}, pmid = {30654433}, issn = {2076-3921}, support = {IWT-LO 100856//Agentschap voor Innovatie door Wetenschap en Technologie/ ; }, abstract = {This study investigated the effect of N-acetyl-cysteine (NAC) supplementation through drinking water on animal performance and the glutathione (GSH) redox system in weaned piglets, particularly in relation to the immediate post-weaning feed intake. To this end, 168 piglets were weaned and either fed ad libitum or fasted the first two days, and either or not administered 200 mg/L NAC via the drinking water until d14 post-weaning. Next to animal performance until day 42 (d42), the GSH redox system was measured in erythrocytes, small intestinal mucosa, liver, lung, and kidney tissue at d0, d2, and d14 post-weaning. Animal performance and GSH levels were not affected by NAC, nor by fasting. Irrespective of treatment, a significant drop in GSH at d2 post-weaning was found as compared to d0, in particular in liver (-69%), distal jejunal mucosa (-72%), and lung tissue (-80%). Post-weaning changes of the GSH redox status were strongly tissue-dependent. To conclude, this research indicates that GSH redox homeostasis was largely affected in multiple organs during the weaning transition. NAC supplementation did not increase GSH levels in any tissue, not even in fasted animals, questioning the fact if cysteine is the first or only limiting factor determining the rate of GSH synthesis in the early post-weaning phase.}, }
@article {pmid30653950, year = {2019}, author = {Rudin, D and Lanzilotto, A and Bachmann, F and Housecroft, CE and Constable, EC and Drewe, J and Haschke, M and Krähenbühl, S}, title = {Non-immunological toxicological mechanisms of metamizole-associated neutropenia in HL60 cells.}, journal = {Biochemical pharmacology}, volume = {163}, number = {}, pages = {345-356}, doi = {10.1016/j.bcp.2019.01.011}, pmid = {30653950}, issn = {1873-2968}, mesh = {Aminopyrine/chemistry/metabolism/toxicity ; Anti-Inflammatory Agents, Non-Steroidal ; Apoptosis/drug effects ; Cell Membrane/drug effects ; Cell Survival/drug effects ; Dipyrone/chemistry/metabolism/*toxicity ; Granulocytes/drug effects/metabolism ; HL-60 Cells ; Hemin ; Hemoglobins ; Humans ; Hydrogen Peroxide ; Iron Compounds ; Lactoferrin/pharmacology ; Methemoglobin ; Molecular Structure ; Necrosis ; *Neutropenia ; Peroxidase/metabolism ; }, abstract = {Metamizole is an analgesic and antipyretic, but can cause neutropenia and agranulocytosis. We investigated the toxicity of the metabolites N-methyl-4-aminoantipyrine (MAA), 4-aminoantipyrine (AA), N-formyl-4-aminoantipyrine (FAA) and N-acetyl-4-aminoantipyrine (AAA) on neutrophil granulocytes and on HL60 cells (granulocyte precursor cell line). MAA, FAA, AA, and AAA (up to 100 µM) alone were not toxic for HL60 cells or granulocytes. In the presence of the myeloperoxidase substrate H2O2, MAA reduced cytotoxicity for HL60 cells at low concentrations (<50 µM), but increased cytotoxicity at 100 µM H2O2. Neutrophil granulocytes were resistant to H2O2 and MAA. Fe[2+] and Fe[3+] were not toxic to HL60 cells, irrespective of the presence of H2O2 and MAA. Similarly, MAA did not increase the toxicity of lactoferrin, hemoglobin or methemoglobin for HL60 cells. Hemin (hemoglobin degradation product containing a porphyrin ring and Fe[3+]) was toxic on HL60 cells and cytotoxicity was increased by MAA. EDTA, N-acetylcystein and glutathione prevented the toxicity of hemin and hemin/MAA. The absorption spectrum of hemin changed concentration-dependently after addition of MAA, suggesting an interaction between Fe[3+] and MAA. NMR revealed the formation of a stable MAA reaction product with a reaction pathway involving the formation of an electrophilic intermediate. In conclusion, MAA, the principle metabolite of metamizole, increased cytotoxicity of hemin by a reaction involving the formation of an electrophilic metabolite. Accordingly, cytotoxicity of MAA/hemin could be prevented by the iron chelator EDTA and by the electron donors NAC and glutathione. Situations with increased production of hemin may represent a risk factor for metamizole-associated granulocytopenia.}, }
@article {pmid30653365, year = {2019}, author = {Rosenhall, U and Skoog, B and Muhr, P}, title = {Treatment of military acoustic accidents with N-Acetyl-L-cysteine (NAC).}, journal = {International journal of audiology}, volume = {58}, number = {3}, pages = {151-157}, doi = {10.1080/14992027.2018.1543961}, pmid = {30653365}, issn = {1708-8186}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Female ; Free Radical Scavengers/*therapeutic use ; Hearing Loss, Noise-Induced/*drug therapy ; Humans ; Male ; Military Personnel ; Retrospective Studies ; Young Adult ; }, abstract = {OBJECTIVE: To study if the antioxidant (AO) N-Acetyl-L-cysteine (NAC) reduces the risk of hearing loss after acoustic accidents in humans.<br><br>DESIGN: A retrospective, observational study.<br><br>STUDY SAMPLE: Personnel of the Swedish Armed Forces (SAF) exposed to military acoustic accidents during a 5 year period. Included in the study were 221 cases (mean age: 22.9&#xa0;years). Most of the exposures, 84%, were weapon related. NAC (400&#x2009;mg) was given directly after the accident in 146 cases; 75 had not received NAC.<br><br>RESULTS: The prevalence of hearing thresholds &#x2265;25&#x2009;dB HL, and the incidence of threshold shifts &#x2265;10&#x2009;dB, was lower in the NAC group than in the non-NAC group directly after the noise exposure. The deterioration was temporary and not discernable a long time after the accident. The difference was most pronounced in the right ear. The risk reduction to get a temporary hearing loss (TTS), affecting one or both ears was 39% (significant) in the NAC group.<br><br>CONCLUSIONS: The study has demonstrated a significant reduction of the incidence of TTS by the use of NAC. Since cases of both permanent hearing loss (PTS) and noise-induced tinnitus are recruited from cases with TTS, the demonstrated risk reduction indicates a positive effect of NAC.}, }
@article {pmid30648648, year = {2019}, author = {Zhou, C and Zaman, N and Li, Y and Martinez-Arguelles, DB and Papadopoulos, V and Zirkin, B and Traore, K}, title = {Redox regulation of hormone sensitive lipase: Potential role in the mechanism of MEHP-induced stimulation of basal steroid synthesis in MA-10 Leydig cells.}, journal = {Reproductive toxicology (Elmsford, N.Y.)}, volume = {85}, number = {}, pages = {19-25}, doi = {10.1016/j.reprotox.2018.12.010}, pmid = {30648648}, issn = {1873-1708}, support = {R01 AG021092/AG/NIA NIH HHS/United States ; R15 ES032102/ES/NIEHS NIH HHS/United States ; SC2 GM099578/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line, Tumor ; Cholesterol/*metabolism ; Diethylhexyl Phthalate/*analogs &amp; derivatives/toxicity ; Endocrine Disruptors/*toxicity ; Leydig Cells/*drug effects/metabolism ; Male ; Mice ; Oxidation-Reduction ; Phosphoproteins/metabolism ; Plasticizers/*toxicity ; Progesterone/*metabolism ; Reactive Oxygen Species/metabolism ; Sterol Esterase/*metabolism ; }, abstract = {Mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a plasticizer with endocrine disruptor activity that has been shown to stimulate basal steroid biosynthesis in Leydig cells. The mechanism by which it does so is unknown. Using MA-10 mouse tumor Leydig cells, we assessed the effects of MEHP on reactive oxygen species (ROS) levels, and on the signal transduction pathways that mobilize cholesterol. Exposure to 0-300 μM MEHP stimulated basal progesterone production in a dose-dependent manner. Progesterone stimulation was correlated with increases in the phosphorylation of hormone-sensitive lipase (HSL; aka cholesteryl ester hydrolase), which is involved in the production of free cholesterol, and of steroidogenic acute regulatory (STAR) protein expression. Co-treating MA-10 cells with MEHP and the ROS scavenger N-acetyl cysteine (NAC) blocked the activation of HSL, blunted MEHP-induced STAR, and reduced basal progesterone formation. These observations suggest that ROS generation by MEHP leads to activation of HSL and increase in STAR which, together, result in increased free-cholesterol bioavailability and progesterone formation.}, }
@article {pmid30644245, year = {2019}, author = {Kheradmandi, R and Jorsaraei, SGA and Feizi, F and Moghadamnia, AA and Neamati, N}, title = {Protective Effect of N-Acetyl Cysteine on Chlorpyrifos-Induced Testicular Toxicity in Mice.}, journal = {International journal of fertility &amp; sterility}, volume = {13}, number = {1}, pages = {51-56}, pmid = {30644245}, issn = {2008-076X}, abstract = {BACKGROUND: Chlorpyrifos (CPF), an organophosphate pesticide, is widely used in farms in order to preserve crops and fruits. Previous studies have shown that CPF exposure might cause chronic toxicity in male genital system. The present study investigated the protective effect of N-Acetyl Cysteine (NAC), a potent antioxidant against testicular toxicity of CPF in male mice.<br><br>MATERIALS AND METHODS: In this experimental study, 42 adult male mice were divided into seven groups, CPF low (0.5 mg/kg.b.w) and high (5 mg/kg.b.w) doses groups, NAC group (35 mg/kg.b.w), NAC+CPF 0/5 mg/kg.b.w, NAC+CPF 5 mg/kg.b.w, dimethyl sulfoxide (DMSO, 0.75% solution mg/kg.b.w) and control group. All treatment were done intraperitoneally. Treatment was conducted for four consecutive weeks (five days each week). However NAC was injected to NAC+CPF groups five days before initiation of the treatment procedure. One week after the last injection, mice were sacrificed using anesthetic gas to evaluate alterations in testicular histology and sperm parameters.<br><br>RESULTS: Seminiferous tubules area and diameter were significantly diminished in the group treated with 5 mg/kg CPF (P<0.05). CPF also statistically reduced sperm parameters (count and motility) and damaged sperm morphology) at both doses (P<0.05). However, NAC significantly improved spermatogonia, spermatocytes, spermatid cell counts as well as sperm parameters in mice treated with both CPF concentrations (P<0.05).<br><br>CONCLUSION: According to our results, NAC may significantly ameliorate CPF-induced damages to spermatogonia, spermatocytes, spermatids cell counts and sperm parameters.}, }
@article {pmid30642937, year = {2019}, author = {Zeng, S and Soetaert, K and Ravon, F and Vandeput, M and Bald, D and Kauffmann, JM and Mathys, V and Wattiez, R and Fontaine, V}, title = {Isoniazid Bactericidal Activity Involves Electron Transport Chain Perturbation.}, journal = {Antimicrobial agents and chemotherapy}, volume = {63}, number = {3}, pages = {}, pmid = {30642937}, issn = {1098-6596}, mesh = {Adenosine Triphosphate/metabolism ; Antitubercular Agents/*pharmacology ; Cytochrome b Group/antagonists &amp; inhibitors ; Diarylquinolines/pharmacology ; Electron Transport/*drug effects ; Electron Transport Chain Complex Proteins/*antagonists &amp; inhibitors ; Electron Transport Complex IV/metabolism ; Imidazoles/pharmacology ; Isoniazid/*pharmacology ; Membrane Potentials/drug effects ; Mycobacterium bovis/*drug effects/metabolism ; Mycobacterium tuberculosis/*drug effects/metabolism ; Oxidation-Reduction/drug effects ; Oxygen Consumption/drug effects ; Piperidines/pharmacology ; Pyridines/pharmacology ; }, abstract = {Accumulating evidence suggests that the bactericidal activity of some antibiotics may not be directly initiated by target inhibition. The activity of isoniazid (INH), a key first-line bactericidal antituberculosis drug currently known to inhibit mycolic acid synthesis, becomes extremely poor under stress conditions, such as hypoxia and starvation. This suggests that the target inhibition may not fully explain the bactericidal activity of the drug. Here, we report that INH rapidly increased Mycobacterium bovis BCG cellular ATP levels and enhanced oxygen consumption. The INH-triggered ATP increase and bactericidal activity were strongly compromised by Q203 and bedaquiline, which inhibit mycobacterial cytochrome bc1 and FoF1 ATP synthase, respectively. Moreover, the antioxidant N-acetylcysteine (NAC) but not 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL) abrogated the INH-triggered ATP increase and killing. These results reveal a link between the energetic (ATP) perturbation and INH's killing. Furthermore, the INH-induced energetic perturbation and killing were also abrogated by chemical inhibition of NADH dehydrogenases (NDHs) and succinate dehydrogenases (SDHs), linking INH's bactericidal activity further to the electron transport chain (ETC) perturbation. This notion was also supported by the observation that INH dissipated mycobacterial membrane potential. Importantly, inhibition of cytochrome bd oxidase significantly reduced cell recovery during INH challenge in a culture settling model, suggesting that the respiratory reprogramming to the cytochrome bd oxidase contributes to the escape of INH killing. This study implicates mycobacterial ETC perturbation through NDHs, SDHs, cytochrome bc1, and FoF1 ATP synthase in INH's bactericidal activity and pinpoints the participation of the cytochrome bd oxidase in protection against this drug under stress conditions.}, }
@article {pmid30641872, year = {2019}, author = {Peerapanyasut, W and Kobroob, A and Palee, S and Chattipakorn, N and Wongmekiat, O}, title = {Activation of Sirtuin 3 and Maintenance of Mitochondrial Integrity by N-Acetylcysteine Protects Against Bisphenol A-Induced Kidney and Liver Toxicity in Rats.}, journal = {International journal of molecular sciences}, volume = {20}, number = {2}, pages = {}, pmid = {30641872}, issn = {1422-0067}, support = {114/2561 and 129/2561//Faculty of Medicine, Chiang Mai University/ ; 0154/2558//Royal Golden Jubilee PhD Program/ ; (N.C.)//National Science and Technology Development Agency/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Apoptosis/drug effects ; Benzhydryl Compounds/*toxicity ; Chemical and Drug Induced Liver Injury/metabolism/*prevention &amp; control ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Kidney Diseases/chemically induced/metabolism/*prevention &amp; control ; Male ; Mitochondria/drug effects/*metabolism ; Mitochondrial Dynamics/drug effects ; Oxidative Stress/drug effects ; Phenols/*toxicity ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; Sirtuins/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Mitochondrial impairment ensuing from oxidative imbalance is related to adverse consequences of bisphenol A (BPA), a globally utilized industrial chemical. Recent evidence reveals sirtuin 3 (SIRT3) as a key regulator of mitochondrial homeostasis; however, its role in BPA toxicity remains unidentified. This study explored the potential benefits of N-acetylcysteine (NAC), an effective antioxidant, against BPA toxicity in the kidney and liver, and examined whether SIRT3 was involved in this condition. Male Wistar rats were fed with vehicle, BPA (5, 50 mg/kg), BPA (50 mg/kg) plus NAC (100 mg/kg) and were evaluated after 5 weeks. NAC treatment significantly diminished BPA-induced kidney and liver functional disorders, histopathological alterations, oxidative stress, and apoptosis. The increased mitochondrial reactive oxygen species, the disrupted membrane potential, the swelling, and the impaired mitochondrial fission caused by BPA were also mitigated upon concurrent treatment with NAC. The benefits of NAC were associated with enhanced AMPK-PGC-1α-SIRT3 signaling protein expressions, which led to decreased acetylation of superoxide dismutase 2 (SOD2) and increased expression of mitochondrial antioxidant manganese superoxide dismutase (MnSOD). The findings demonstrate the efficacy of NAC in protecting BPA-induced kidney and liver injury, which, in part, is mediated by activating SIRT3 and improving mitochondrial function, dynamics, and oxidative imbalance.}, }
@article {pmid30639957, year = {2019}, author = {Galal, AAA and Ramadan, RA and Metwally, MMM and El-Sheikh, SMA}, title = {Protective effect of N-acetylcysteine on fenitrothion-induced toxicity: The antioxidant status and metabolizing enzymes expression in rats.}, journal = {Ecotoxicology and environmental safety}, volume = {171}, number = {}, pages = {502-510}, doi = {10.1016/j.ecoenv.2019.01.004}, pmid = {30639957}, issn = {1090-2414}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Animals ; Antioxidants/*metabolism ; Aspartate Aminotransferases/blood ; Biomarkers ; Brain/*drug effects/metabolism ; Creatinine/blood ; Cytochrome P-450 CYP1A1/genetics/metabolism ; Fenitrothion/*toxicity ; Gene Expression Regulation ; Glutathione Transferase/genetics/metabolism ; Kidney/*drug effects/metabolism ; Liver/*drug effects/metabolism ; Male ; Oxidative Stress/drug effects ; Rats ; }, abstract = {The existence of fenitrothion (FNT) in the soil, water, and food products has harmful effects on non-target organisms. Therefore, this study was conducted to evaluate the hepatotoxic, nephrotoxic and neurotoxic effects of FNT and the possible ameliorative effect of N-acetylcysteine (NAC), a precursor of intracellular GSH, on FNT-induced toxicity. For this purpose, thirty-two adult male albino rats were allocated into control group and groups treated with NAC (200 mg/kg), FNT (10 mg/kg) and FNT + NAC via gastric tube daily for 28 days. FNT intoxication significantly reduced food intake, water intake, body weight, and body weight gain and altered the expression of phase I and phase II xenobiotic-metabolizing enzymes-cytochrome P450 (CYP1A1) and glutathione S-transferase (GSTA4-4). In hepatic, renal and brain tissues, FNT induced oxidative stress, hepatopathy, nephropathy, and encephalopathy, and significantly increased pro-inflammatory cytokines. Furthermore, FNT exposure significantly elevated the level of hepatic and renal injury biomarkers and significantly inhibited the brain acetylcholinesterase activity. Co-administration of NAC with FNT modulated most of these altered biochemical, oxidative and inflammatory markers and restored the xenobiotic-metabolizing enzymes expression and histological structures. Our study indicated the involvement of oxidative damage, inflammation, and alteration of xenobiotic-metabolizing enzymes expression in FNT-induced toxicity and revealed that they were significantly improved by NAC co-treatment. These findings suggest that NAC administration might protect against FNT-induced toxicity in non-target organisms, including humans.}, }
@article {pmid30637807, year = {2019}, author = {Ahmadi, E and Shirazi, A and Shams-Esfandabadi, N and Nazari, H}, title = {Antioxidants and glycine can improve the developmental competence of vitrified/warmed ovine immature oocytes.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {54}, number = {3}, pages = {595-603}, doi = {10.1111/rda.13402}, pmid = {30637807}, issn = {1439-0531}, support = {//Shahrekord University/ ; }, mesh = {Animals ; Antioxidants/*pharmacology ; Blastocyst/drug effects ; Cell Nucleus/drug effects ; Cryopreservation/veterinary ; Female ; Glycine/*pharmacology ; In Vitro Oocyte Maturation Techniques/veterinary ; Oocytes/*drug effects ; Oxidative Stress/drug effects ; Sheep, Domestic ; Vitrification/*drug effects ; }, abstract = {Despite the numerous potential applications of oocyte cryopreservation, the poor success rate has limited its practical applications. In livestock, particularly in ovine, the oocytes have low developmental competence following vitrification/warming process. Considering the occurrence of osmotic and oxidative stresses during the vitrification/warming process, the application of antioxidants and osmolytes may improve the developmental competence of vitrified/warmed oocytes. In the present study, we aimed to evaluate the effects of the addition of ascorbic acid (AA) and N-acetyl cysteine (NAC) as antioxidants and glycine as an organic osmolyte either to the vitrification/warming solutions (VWS) or to the IVM medium on the developmental competence of vitrified/warmed ovine germinal vesicle stage oocytes. The survival rate in the vitrified groups was significantly lower than fresh ones. In vitrified/warmed oocytes, there was no significant difference in survival rate between supplemented and non-supplemented groups. The addition of AA and/or NAC to the VWS or IVM medium and adding glycine to the IVM medium reduced the proportion of apoptotic oocytes and fragmented embryos, which was reflected as an increase in the proportions of metaphase II stage oocytes and blastocyst production. The best result was achieved by supplementing the IVM medium with NAC. In our study condition, antioxidants and glycine could improve the developmental competence of vitrified/warmed ovine immature oocytes, especially when added during IVM.}, }
@article {pmid30636490, year = {2020}, author = {Peivandi Yazdi, A and Razavi, M and Sheikh, S and Boroumand, N and Salehi, M and Hashemy, SI}, title = {Clinical Trial Assessment of Intermittent and Continuous Infusion Dose of N-Acetylcysteine on Redox Status of the Body in Patients with Sepsis Admitted to the ICU.}, journal = {Journal of intensive care medicine}, volume = {35}, number = {12}, pages = {1383-1388}, doi = {10.1177/0885066618823152}, pmid = {30636490}, issn = {1525-1489}, mesh = {*Acetylcysteine/therapeutic use ; Humans ; Infusions, Intravenous ; Intensive Care Units ; Oxidation-Reduction/drug effects ; Prospective Studies ; *Sepsis/drug therapy/metabolism ; }, abstract = {PURPOSE: Conflicting results exist regarding the efficacy of N-acetyl cysteine (NAC) in sepsis treatment. A pivotal factor affecting the therapeutic potency of NAC in sepsis is timing and dosing of its infusion. We aimed to assess the effect of NAC on redox status of patients with sepsis and to compare its efficacy in intermittent and continuous infusion with the objective of developing the infusion regimen and optimizing the timing.<br><br>MATERIALS AND METHODS: A prospective, randomized clinical trial was designed to compare the antioxidative effect of NAC in intermittent infusion group (IV: 25 mg/kg bolus and then 25 mg/kg/8 hours 3 times) and continuous infusion group (IV: 25 mg/kg bolus and then 75 mg/kg over 24 hours) in 60 critically ill patients with sepsis (20 patients in each group). Blood samples were collected immediately before and after intervention for total antioxidant capacity (TAC) and malondialdehyde (MDA) assessment.<br><br>RESULTS: N-acetyl cysteine considerably increased TAC levels in both intermittent (0.68 &#xb1; 0.60; P value = .036) and continuous (0.69 &#xb1; 0.64; P value = .015) infusion groups when compared to placebo (0.61 &#xb1; 0.10); however, the difference in TAC levels between the intermittent and the continuous infusion did not reach statistical significance (P value = .942). Likewise, NAC treatment decreased MDA levels in both intermittent (19.45 &#xb1; 4.18; P value = 0.001) and continuous (22.47 &#xb1; 6.68; P value = .002) infusion groups when compared to placebo (31.76 &#xb1; 11.06), while the difference in MDA levels between the intermittent and the continuous infusion did not reach statistical significance (P value = .481).<br><br>CONCLUSION: Our data confirmed the antioxidative effect of NAC treatment in patients with sepsis, with no significant difference in intermittent and continuous infusion.}, }
@article {pmid30634146, year = {2019}, author = {Alak, G and Yeltekin, A&#xc7; and Özgeriş, FB and Parlak, V and Uçar, A and Sait Keleş, M and Atamanalp, M}, title = {Therapeutic effect of N- acetyl cysteine as an antioxidant on rainbow trout's brain in cypermethrin toxicity.}, journal = {Chemosphere}, volume = {221}, number = {}, pages = {30-36}, doi = {10.1016/j.chemosphere.2018.12.196}, pmid = {30634146}, issn = {1879-1298}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism/*therapeutic use ; Brain/drug effects/*metabolism ; Oncorhynchus mykiss/*metabolism ; Oxidative Stress/drug effects ; Pesticides/toxicity ; Pyrethrins/*toxicity ; }, abstract = {The aim of this study was to investigate the therapeutic effect of N-acetylcystein (NAC) against oxidative stress induced by Cypermethrin pesticide in rainbow trout (Oncorhynchus mykiss). The experiment was designed as 5 groups (A, B, C, D, and E). Group A was organized as control group and had no treatment. The other groups were treated with Cypermethrin for 14 days. At the end of this period, Groups B (1.0 mM NAC) and D (0.5 mM NAC) was performed with NAC for 96 h. Group C was not administered NAC, the recovery process was evaluated with this group. Group E was exposed to cypermethrin during 14 days and sampled. Acetylcholinesterase (AChE), malondialdehyde (MDA), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), paraoxonase (PON), arylesterase (AR), myeloperoxidase (MPO) activities, oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)), caspase-3 levels, and trace elements contents analyses were performed in all fish brains. According to the results, MDA, MPO, 8-OHdG and caspase-3 levels were significantly decreased compared to the other groups (pesticide and recovery) (p < 0.05), AChE, SOD, CAT, GPx, PON, and AR activities increased (p < 0.05). In brain tissue, no statistically significant difference was observed in trace element analysis of all application groups. According to the obtained data, the positive effect of N-acetylcysteine on protein synthesis, detoxification, and diverse metabolic functions against cypermethrin toxicity has been more effective in 1.0 mM NAC. NAC has important therapeutic effect on pesticide-induced neurotoxicity for fish in terms of all data. It was concluded that NAC has an antioxidant effect against pesticide-induced oxidative stress and the selected biochemical markers are useful for such studies.}, }
@article {pmid30633982, year = {2019}, author = {Hu, Y and Wang, Y and Yan, T and Feng, D and Ba, Y and Zhang, H and Zhu, J and Cheng, X and Cui, L and Huang, H}, title = {N-acetylcysteine alleviates fluoride-induced testicular apoptosis by modulating IRE1α/JNK signaling and nuclear Nrf2 activation.}, journal = {Reproductive toxicology (Elmsford, N.Y.)}, volume = {84}, number = {}, pages = {98-107}, doi = {10.1016/j.reprotox.2019.01.001}, pmid = {30633982}, issn = {1873-1708}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Endoribonucleases/genetics/metabolism ; Fluorides/*toxicity ; Gonadal Steroid Hormones/metabolism ; Heat-Shock Proteins/metabolism ; JNK Mitogen-Activated Protein Kinases/genetics/metabolism ; Male ; Multienzyme Complexes/genetics/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress/drug effects ; Protein Serine-Threonine Kinases/genetics/metabolism ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Testis/*drug effects/metabolism ; }, abstract = {We previously investigated excessive fluoride exposure elicited intracellular endoplasmic reticulum (ER) stress and led to Sertoli cells dysfunction in vitro. However, the mechanisms underlying fluoride-mediated male reproductive damage in vivo remain largely unknown. Considerable evidence has now revealed ER stress is closely linked with testicular oxidative damage. Hence, we aimed to explore whether ER stress signaling was involved in the testicular protective effects of antioxidant N-acetylcysteine (NAC) against testicular apoptosis induced by fluoride. Male SD rats were oral gavaged with sodium fluoride (NaF) for 7 weeks to induce fluorosis. The animals were pretreatment with or without NAC (150 mg/Bw•d). Our results demonstrated that sub-chronic NaF exposure triggered testicular apoptosis and sex hormonal disturbance in pituitary-testicular (PT) axis, promoted oxidative stress and the expression of ER stress mediators. Antioxidant NAC, however, prevented NaF-induced testicular apoptosis accompanied by activating Nrf2-mediated antioxidant potential. Simultaneously, NAC pretreatment downregulated XBP1 splicing, reduced JNK phosphorylation and further blocked cleavage of caspase-3, all these might contribute to the inhibition of testicular cell apoptosis. Collectively, the present results suggested that prolonged administration of NAC preserved testicular function and normalized sex hormonal disruption induced by NaF via the inhibition of Nrf2-associated oxidative damage and Ire1α-JNK-mediated apoptosis in rat testis.}, }
@article {pmid30633885, year = {2019}, author = {Wang, JN and Che, Y and Yuan, ZY and Lu, ZL and Li, Y and Zhang, ZR and Li, N and Li, RD and Wan, J and Sun, HD and Sun, N and Puno, PT and He, J}, title = {Acetyl-macrocalin B suppresses tumor growth in esophageal squamous cell carcinoma and exhibits synergistic anti-cancer effects with the Chk1/2 inhibitor AZD7762.}, journal = {Toxicology and applied pharmacology}, volume = {365}, number = {}, pages = {71-83}, doi = {10.1016/j.taap.2019.01.005}, pmid = {30633885}, issn = {1096-0333}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Checkpoint Kinase 1/*antagonists &amp; inhibitors/metabolism ; Checkpoint Kinase 2/*antagonists &amp; inhibitors/metabolism ; Diterpenes, Kaurane/*pharmacology ; Drug Synergism ; Esophageal Neoplasms/*drug therapy/enzymology/pathology ; Esophageal Squamous Cell Carcinoma/*drug therapy/enzymology/pathology ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; Phosphorylation ; Protein Kinase Inhibitors/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Thiophenes/*pharmacology ; Tumor Burden/drug effects ; Urea/*analogs &amp; derivatives/pharmacology ; Xenograft Model Antitumor Assays ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Natural products derived from herbal medicines have become a major focus of anti-cancer drug discovery studies. Acetyl-macrocalin B (A-macB) is an ent-diterpenoid isolated from Isodon silvatica. This study aimed to examine the effect and molecular action of A-macB in esophageal squamous cell carcinoma (ESCC) and explore possible drug synergistic modalities. A-macB induced cellular reactive oxygen species (ROS) generation, initiated the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and triggered the caspase-9-dependent apoptosis cascade in ESCC cells. The ROS scavenger N-acetylcysteine (NAC) and the specific p38 inhibitor SB203580 reversed the effects of A-macB on the p38 network and thus rescued ESCC cells from apoptosis. The cellular ROS increase was at least partially due to the suppression of glutathione-S-transferase P1 (GSTP1) by A-macB. A-macB also upregulated the Chk1/Chk2-Cdc25C/Cdc2/Cyclin B1 axis to induce G2/M phase arrest. The cell growth inhibition induced by A-macB was further enhanced by AZD7762, a specific Chk1/Chk2 inhibitor, with a combination index (CI) of <1. Moreover, A-macB efficiently suppressed xenograft growth without inducing significant toxicity, and AZD7762 potentiated the effects of A-macB in the suppression of tumor growth in vivo. Taken together, A-macB is a promising lead compound for ESCC and exerts synergistic anti-cancer effects with AZD7762.}, }
@article {pmid30633345, year = {2019}, author = {Zhao, J and Xu, SZ and Liu, J}, title = {Fibrinopeptide A induces C-reactive protein expression through the ROS-ERK1/2/p38-NF-κB signal pathway in the human umbilical vascular endothelial cells.}, journal = {Journal of cellular physiology}, volume = {234}, number = {8}, pages = {13481-13492}, doi = {10.1002/jcp.28027}, pmid = {30633345}, issn = {1097-4652}, mesh = {Active Transport, Cell Nucleus ; Animals ; Aorta/drug effects/metabolism ; C-Reactive Protein/*metabolism ; Fibrinopeptide A/metabolism/*pharmacology ; Human Umbilical Vein Endothelial Cells/*drug effects/*metabolism ; Humans ; Interleukin-1beta/genetics/metabolism ; Interleukin-6/genetics/metabolism ; MAP Kinase Signaling System/*drug effects ; Male ; Models, Animal ; NF-kappa B/metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Superoxides/metabolism ; Up-Regulation/drug effects ; }, abstract = {Atherosclerosis is a chronic inflammatory disease of the arterial wall. Inflammation causes endothelial injury and dysfunction, which is an initial step of atherosclerosis. Fibrinopeptide A (FPA) is a biomarker of the activation of the coagulation system, and a high concentration of FPA in the blood occurs in patients with ischemic cardiocerebrovascular diseases. The present research observed that FPA stimulated the generation of C-reactive protein (CRP), IL-1β, and IL-6 in human umbilical vascular endothelial cells (HUVECs); and anti-IL-1 β and anti-IL-6 neutralizing antibodies did not alter FPA-induced CRP expression in HUVECs. The subchronic administration of FPA into rats increased the plasma FPA and CRP levels. Further studies showed that FPA stimulated superoxide anion generation, activated ERK1/2 and p38, promoted nuclear factor κB (NF-κB) nuclear translocation, and raised the NF-κB level in the nuclei of HUVECs. Antioxidant N-acetylcysteine (NAC), complex II inhibitor thenoyltrifluoroacetone (TTFA), and NADPH oxidase inhibitor diphenyleneiodonium (DPI) inhibited FPA-stimulated generation of superoxide anion, and NAC reduced FPA-induced expressions of the phosphorylated ERK1/2 and p38. NAC, TTFA, DPI, inhibitors of ERK1/2, p38, and NF-κB all downregulated FPA-induced CRP expression. These results indicate that FPA induces CRP expression in HUVECs via the ROS-ERK1/2/p38-NF-κB signal pathway. Moreover, this is the first report that FPA produces a proinflammatory effect on the vascular endothelial cells.}, }
@article {pmid30632702, year = {2020}, author = {Goncalves, S and Goldstein, BJ}, title = {Acute N-Acetylcysteine Administration Ameliorates Loss of Olfactory Neurons Following Experimental Injury In Vivo.}, journal = {Anatomical record (Hoboken, N.J. : 2007)}, volume = {303}, number = {3}, pages = {626-633}, pmid = {30632702}, issn = {1932-8494}, support = {K08 DC013556/DC/NIDCD NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Cell Survival/drug effects ; Mice ; Nerve Degeneration/*drug therapy/pathology ; Neuroprotective Agents/pharmacology/*therapeutic use ; Olfactory Bulb/injuries ; Olfactory Mucosa/*drug effects/pathology ; Olfactory Receptor Neurons/*drug effects/pathology ; }, abstract = {The olfactory epithelium (OE) is the peripheral organ for the sense of smell, housing primary sensory neurons that project axons from the nose to the brain. Due to the presence of a basal stem cell niche, the adult mammalian OE is a dynamic tissue capable of replacing neurons following their loss. Nonetheless, certain conditions, such as blunt head trauma, can result in persistent olfactory loss, thought to be due to shearing of olfactory nerve filaments at the skull base, degeneration, and failures in proper regeneration/reinnervation. The identification of new treatment strategies aimed at preventing degeneration of olfactory neurons is, therefore, needed. In considering potential therapies, we have focused on N-acetylcysteine (NAC), a glutathione substrate shown to be neuroprotective, with a record of safe clinical use. Here, we have tested the use of NAC in an animal model of olfactory degeneration. Administered acutely, we found that NAC (100 mg/kg, twice daily) resulted in a reduction of olfactory neuronal loss from the OE of the nose following surgical ablation of the olfactory bulb. At 1 week postlesion, we identified 54 ± 8.1 mature neurons per 0.5 mm epithelium in NAC-treated animals vs. 28 ± 4.2 in vehicle-treated controls (P = 0.02). Furthermore, in an olfactory cell culture model, we have identified significant alterations in the expression of several genes involved in oxidative stress pathways following NAC exposure. Our results provide evidence supporting the potential therapeutic utility for NAC acutely following head trauma-induced olfactory loss. Anat Rec, 303:626-633, 2020. © 2019 American Association for Anatomy.}, }
@article {pmid30632301, year = {2019}, author = {Powell, GL and Leyrer-Jackson, JM and Goenaga, J and Namba, MD and Piña, J and Spencer, S and Stankeviciute, N and Schwartz, D and Allen, NP and Del Franco, AP and McClure, EA and Olive, MF and Gipson, CD}, title = {Chronic treatment with N-acetylcysteine decreases extinction responding and reduces cue-induced nicotine-seeking.}, journal = {Physiological reports}, volume = {7}, number = {1}, pages = {e13958}, pmid = {30632301}, issn = {2051-817X}, support = {DA036569-S1/NH/NIH HHS/United States ; DA036569/NH/NIH HHS/United States ; K99 DA036569/DA/NIDA NIH HHS/United States ; R03 DA045881/DA/NIDA NIH HHS/United States ; R00 DA036569/DA/NIDA NIH HHS/United States ; DA044479/NH/NIH HHS/United States ; R00 DA041462/DA/NIDA NIH HHS/United States ; DA045881/NH/NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cues ; Dendritic Spines/metabolism ; Drug-Seeking Behavior/*drug effects ; *Extinction, Psychological ; Glutamic Acid/metabolism ; Male ; Neuronal Plasticity ; Nicotine/administration &amp; dosage/*pharmacology ; Nucleus Accumbens/cytology/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Self Administration ; }, abstract = {N-acetylcysteine (NAC), a promising glutamatergic therapeutic agent, has shown some clinical efficacy in reducing nicotine use in humans and has been shown to reverse drug-induced changes in glutamatergic neurophysiology. In rats, nicotine-seeking behavior is associated with alterations in glutamatergic plasticity within the nucleus accumbens core (NAcore). Specifically, cue-induced nicotine-seeking is associated with rapid, transient synaptic plasticity (t-SP) in glutamatergic synapses on NAcore medium spiny neurons. The goal of the present study was to determine if NAC reduces nicotine-seeking behavior and reverses reinstatement-associated NAcore glutamatergic alterations. Rats were extinguished from nicotine self-administration, followed by subchronic NAC administration (0 or 100 mg/kg/d) for 4 days prior to cue-induced reinstatement. NAcore synaptic potentiation was measured via dendritic spine morphology and mRNA and protein of relevant glutamatergic genes were quantified. Nicotine-seeking behavior was not reduced by subchronic NAC treatment. Also, NAcore transcript and protein expression of multiple glutamatergic genes, as well as spine morphological measures, were unaffected by subchronic NAC. Finally, chronic NAC treatment (15 days total) during extinction and prior to reinstatement significantly decreased extinction responding and reduced reinstatement of nicotine-seeking compared to vehicle. Together, these results suggest that chronic NAC treatment is necessary for its therapeutic efficacy as a treatment strategy for nicotine addiction and relapse.}, }
@article {pmid30631353, year = {2018}, author = {Wang, L and Gagea, M and Martirosyan, K and Johansen, M and Madden, T and Norberg, L and Culotta, KS and Frank, SJ}, title = {Toxicity Evaluation of a Novel Magnetic Resonance Imaging Marker, CoCl2-N-Acetylcysteine, in Rats.}, journal = {Journal of toxicology}, volume = {2018}, number = {}, pages = {9173452}, pmid = {30631353}, issn = {1687-8191}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, abstract = {C4 (cobalt dichloride-N-acetylcysteine [1% CoCl2:2% NAC]) is a novel magnetic resonance imaging contrast marker that facilitates visualization of implanted radioactive seeds in cancer brachytherapy. We evaluated the toxicity of C4. Rats were assigned to control (0% CoCl2:NAC), low-dose (0.1% CoCl2:2% NAC), reference-dose (C4), and high-dose (10% CoCl2:2% NAC) groups. Agent was injected into the left quadriceps femoris muscle of the rats. Endpoints were organ and body weights, hematology, and serum chemistry and histopathologic changes of tissues at 48 hours and 28 and 63 days after dosing. Student's t tests were used. No abnormalities in clinical signs, terminal body and organ weights, or hematologic and serum chemistry were noted, and no gross or histopathologic lesions of systemic tissue toxicity were found in any treatment group at any time point studied. At the site of injection, concentration-dependent acute responses were observed in all treatment groups at 48 hours after dosing and were recovered by 28 days. No myofiber degeneration or necrosis was observed at 28 or 63 days in any group. In conclusion, a single intramuscular dose of C4 produced no acute or chronic systemic toxicity or inflammation in rats, suggesting that C4 may be toxicologically safe for clinical use in cancer brachytherapy.}, }
@article {pmid30631289, year = {2018}, author = {Yang, L and Zheng, L and Wan, Y and Chen, Z and Li, P and Wang, Y}, title = {Metoprolol, N-Acetylcysteine, and Escitalopram Prevents Chronic Unpredictable Mild Stress-Induced Depression by Inhibition of Endoplasmic Reticulum Stress.}, journal = {Frontiers in psychiatry}, volume = {9}, number = {}, pages = {696}, pmid = {30631289}, issn = {1664-0640}, abstract = {Background: Endoplasmic reticulum stress (ERS) has been recently suggested to be activated in the major depressive disorder (MDD). However, whether ERS is a potential therapeutic target for MDD is largely unknown. Here we attempted to assess the preventive effect of metoprolol (MET), N-acetylcysteine (NAC), and escitalopram (ESC) on chronic unpredictable mild stress (CUMS)-induced depression and investigate whether ERS mediates the antidepressant role of these drugs. Method: Forty-five sprague-dawley rats were randomly divided into five groups: control, CUMS, CUMS+ESC, CUMS+NAC, and CUMS+MET. Weight measurement, open field activity and sucrose preference were performed before and after stress. Hippocampal nerve cells and capillary ultrastructure were observed by transmission electron microscope, and hippocampal cells apoptosis were detected by flow cytometry. Furthermore, expression of ERS markers glucose-regulated protein 78 (GRP78), C/EBP-homologous protein (CHOP), and caspase-12 were measured by western blot and qRT-PCR. Results: The CUMS-induced rats showed significantly increased depressive-like behaviors including decreased open field activity and sucrose preference. Moreover, CUMS-exposed rats exhibited significantly increased hippocampal cell apoptosis, and showed damage in hippocampal nerve cells and capillary ultrastructure. Furthermore, ESC and NAC not only mitigated depressive-like behaviors, but also decreased apoptosis and pathologies, while MET fail to decrease apoptosis. Moreover, CUMS stimulation significantly elevated ERS by increasing the levels of GRP78, CHOP, and decreasing the level of caspase-12, while ESC, NAC, and MET significantly decreased the ERS. Conclusion: ESC, NAC, and MET might prevent the MDD partly through inactivating the ERS. These findings demonstrated ERS as a novel treatment target for depression.}, }
@article {pmid30626802, year = {2019}, author = {Chaudhary, N and Ueno-Shuto, K and Ono, T and Ohira, Y and Watanabe, K and Nasu, A and Fujikawa, H and Nakashima, R and Takahashi, N and Suico, MA and Kai, H and Shuto, T}, title = {Curcumin Down-Regulates Toll-Like Receptor-2 Gene Expression and Function in Human Cystic Fibrosis Bronchial Epithelial Cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {42}, number = {3}, pages = {489-495}, doi = {10.1248/bpb.b18-00928}, pmid = {30626802}, issn = {1347-5215}, mesh = {Bronchi/*cytology ; Cell Line ; Curcumin/*pharmacology ; Cystic Fibrosis ; Down-Regulation/drug effects ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/*drug effects ; Gene Expression Regulation/*drug effects ; Humans ; Oxidation-Reduction ; Proteasome Endopeptidase Complex ; Toll-Like Receptor 2/genetics/*metabolism ; }, abstract = {Cystic fibrosis (CF), the most common lethal inherited disorder caused by mutation in the gene encoding the CF transmembrane regulator (CFTR), is characterized by chronic inflammation that ultimately leads to death from respiratory failure. In CF patients, up-regulation of toll-like receptor-2 (TLR2), a pattern recognition receptor that senses CF-pathogenic bacteria Staphylococcus aureus peptidoglycan (PGN), in airway epithelial cells is observed, and enhanced proinflammatory responses towards PGN may result in detrimental effects in CF patients. Here, we showed that curcumin, a well known anti-inflammatory agent derived from the curry spice turmeric, inhibits TLR2 expression in CF bronchial epithelial cell line, CFBE41o- cells. Strong suppression of TLR2 gene and protein expression was observed at more than 40 µM of curcumin treatment in CFBE41o- cells. Consistent with decreased expression of TLR2, PGN-dependent interleukin-8 (IL-8) gene up-regulation was markedly reduced by 40 µM of curcumin treatment. Strong reductions of TLR2 gene expression and function were also observed in primary human CF bronchial epithelial cells, but not in human non-CF primary cells. Interestingly, curcumin treatment decreased nuclear expression of transcription factor specificity protein 1 (SP1), a factor that is critical for increased basal TLR2 expression in CF cell line and primary cells. Finally, curcumin-dependent SP1 reduction was diminished by anti-oxidant N-acetylcystein (NAC) and proteasomal inhibitor MG-132, suggesting the crucial roles of oxidative and proteasomal degradation pathways. Taken together, our study shows that curcumin down-regulates TLR2 gene expression and function in CF bronchial epithelial cells possibly by accelerating SP1 degradation via an oxidative process.}, }
@article {pmid30621764, year = {2019}, author = {,  and Dear, J}, title = {Randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with the 12-h regimen of N-acetylcysteine for paracetamol overdose-the PP100-01 for Overdose of Paracetamol (POP) trial: study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {20}, number = {1}, pages = {27}, pmid = {30621764}, issn = {1745-6215}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy ; Clinical Trials Data Monitoring Committees ; Clinical Trials, Phase I as Topic ; Data Interpretation, Statistical ; Drug Overdose ; Drug Therapy, Combination ; Edetic Acid/administration &amp; dosage/adverse effects/*analogs &amp; derivatives ; Female ; Humans ; Male ; Outcome Assessment, Health Care ; Pyridoxal Phosphate/administration &amp; dosage/adverse effects/*analogs &amp; derivatives ; Randomized Controlled Trials as Topic ; Research Design ; }, abstract = {BACKGROUND: Paracetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America. Current treatment involves the use of the antidote N-acetylcysteine (NAC) in patients deemed at risk of liver damage. This regimen was introduced in the 1970s and has remained largely unchanged even though the initial NAC infusion is frequently associated with adverse reactions, in particular nausea, vomiting, and anaphylactoid reactions. NAC has reduced efficacy for preventing liver injury in those patients who present later after overdose. We designed a randomised study investigating the safety and tolerability of a superoxide dismutase (SOD) mimetic, calmangafodipir (PP100-01), co-treatment with a 12-h NAC regimen compared with NAC treatment alone in patients with POD.<br><br>METHODS/DESIGN: We have designed an open-label, randomised, exploratory, rising dose design, NAC-controlled, phase 1 safety and tolerability study in patients treated with NAC for POD. A total of 24 patients will be assigned into one of three dosing cohorts of eight patients (n&#x2009;=&#x2009;6 for PP100-01 and NAC; n&#x2009;=&#x2009;2 for NAC alone). The doses of PP100-01 are 2, 5, and 10&#x2009;&#x3bc;mol/kg. The primary outcome is the safety and tolerability of PP100-01 when co-administered with a 12-h NAC regimen compared with NAC treatment alone. Furthermore, the study will explore if PP100-01 has potential efficacy for the treatment of paracetamol-induced liver injury by measurement of conventional clinical and exploratory biomarkers.<br><br>DISCUSSION: The aim of the study is to test the safety and tolerability of a SOD mimetic, PP100-01, in combination with a 12-h NAC regimen in patients presenting within 24&#x2009;h of POD. This study will provide valuable data regarding the incidence of adverse events caused by the 12-h NAC plus PP100-01 regimen and may provide evidence of PP100-01 efficacy in the treatment of paracetamol-induced liver injury.<br><br>TRIAL REGISTRATION: EudraCT, 2017-000246-21; ClinicalTrials.gov, NCT03177395 . Registered on 6 June 2017.}, }
@article {pmid30617744, year = {2019}, author = {Shin, SK and Cho, HW and Song, SE and Bae, JH and Im, SS and Hwang, I and Ha, H and Song, DK}, title = {Ablation of catalase promotes non-alcoholic fatty liver via oxidative stress and mitochondrial dysfunction in diet-induced obese mice.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {471}, number = {6}, pages = {829-843}, pmid = {30617744}, issn = {1432-2013}, mesh = {Animals ; Antioxidants ; Catalase/*metabolism ; Endoplasmic Reticulum Stress ; Hep G2 Cells ; Humans ; Hydrogen Peroxide/metabolism ; *Lipid Metabolism ; Liver/*metabolism/ultrastructure ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Liver/metabolism ; Non-alcoholic Fatty Liver Disease/*enzymology/etiology ; Obesity/*complications/enzymology ; Oxidative Stress ; }, abstract = {Hydrogen peroxide (H2O2) produced endogenously can cause mitochondrial dysfunction and metabolic complications in various cell types by inducing oxidative stress. In the liver, oxidative and endoplasmic reticulum (ER) stress affects the development of non-alcoholic fatty liver disease (NAFLD). Although a link between both stresses and fatty liver diseases has been suggested, few studies have investigated the involvement of catalase in fatty liver pathogenesis. We examined whether catalase is associated with NAFLD, using catalase knockout (CKO) mice and the catalase-deficient human hepatoma cell line HepG2. Hepatic morphology analysis revealed that the fat accumulation was more prominent in high-fat diet (HFD) CKO mice compared to that in age-matched wild-type (WT) mice, and lipid peroxidation and H2O2 release were significantly elevated in CKO mice. Transmission electron micrographs indicated that the liver mitochondria from CKO mice tended to be more severely damaged than those in WT mice. Likewise, mitochondrial DNA copy number and cellular ATP concentrations were significantly lower in CKO mice. In fatty acid-treated HepG2 cells, knockdown of catalase accelerated cellular lipid accumulation and depressed mitochondrial biogenesis, which was recovered by co-treatment with N-acetyl cysteine or melatonin. This effect of antioxidant was also true in HFD-fed CKO mice, suppressing fatty liver development and improving hepatic mitochondrial function. Expression of ER stress marker proteins and hepatic fat deposition also increased in normal-diet, aged CKO mice compared to WT mice. These findings suggest that H2O2 production may be an important event triggering NAFLD and that catalase may be an attractive therapeutic target for preventing NAFLD.}, }
@article {pmid30609081, year = {2019}, author = {Hosseini, E and Ghasemzadeh, M and Atashibarg, M and Haghshenas, M}, title = {ROS scavenger, N-acetyl-l-cysteine and NOX specific inhibitor, VAS2870 reduce platelets apoptosis while enhancing their viability during storage.}, journal = {Transfusion}, volume = {59}, number = {4}, pages = {1333-1343}, doi = {10.1111/trf.15114}, pmid = {30609081}, issn = {1537-2995}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Benzoxazoles/*pharmacology ; Blood Platelets/cytology/*metabolism ; *Blood Preservation ; Cell Survival/drug effects ; Free Radical Scavengers/*pharmacology ; Humans ; NADPH Oxidases/*antagonists &amp; inhibitors/metabolism ; Time Factors ; Triazoles/*pharmacology ; }, abstract = {BACKGROUND: Platelet storage is often complicated by deleterious changes that are started by reversible activation of the cells and can lead to procoagulant function and apoptosis during longer periods of storage. Given that increasing levels of reactive oxygen species (ROS) generation are associated with platelet activation and apoptosis, our study investigated whether ROS scavenging or the inhibition of ROS production can enhance the viability of stored platelets.<br><br>METHODS: For this study platelet-rich plasma platelet concentrates (PRP-PCs) were either treated with ROS-reducing agents (1 mM N-acetyl-L -cysteine [NAC] or 30 &#x3bc;M NADPH oxidase [NOX] inhibitor, VAS2870) or kept untreated during storage. P-selectin expression, phosphatidylserine (PS) exposure, levels of microparticle (MP) formation, and intraplatelet caspase activity of PCs were analyzed by flow cytometry during 7 days of storage while the platelet viability was also evaluated by MTT assay.<br><br>RESULTS: Both NAC- and VAS2870-treated platelets had significantly lower caspase activity, MP formation, and PS exposure during storage while they also showed improved viability. The platelet count and mean platelet volume (MPV) were also better preserved in the presence of NAC.<br><br>CONCLUSION: Our results confirmed that either the inhibition of ROS generation or the scavenging of these oxidant agents can attenuate platelet apoptosis while improving their viability during storage. In this study, the significant improvement of platelet viability obtained by NAC suggested that its supplementation with a designated safe concentration into PCs may better preserve the quality of these products, especially for longer storage.}, }
@article {pmid30606241, year = {2019}, author = {Deng, J and Liu, AD and Hou, GQ and Zhang, X and Ren, K and Chen, XZ and Li, SSC and Wu, YS and Cao, X}, title = {N-acetylcysteine decreases malignant characteristics of glioblastoma cells by inhibiting Notch2 signaling.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {38}, number = {1}, pages = {2}, pmid = {30606241}, issn = {1756-9966}, support = {Nos. 31571431//National Natural Science Foundation of China/ ; Nos. 31771541//National Natural Science Foundation of China/ ; No. 2016CFA053//Natural Science Foundation of Hubei Province of China/ ; No. 2018M642817//China Postdoctoral Science Foundation/ ; No.Z11//Hubei Postdoctoral Preferential Foundation/ ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antiviral Agents/pharmacology/*therapeutic use ; Disease Models, Animal ; Glioblastoma/*drug therapy/*genetics/pathology ; Humans ; Mice ; Receptor, Notch2/*genetics/*metabolism ; Signal Transduction ; Transfection ; }, abstract = {BACKGROUND: Glioblastomas multiforme (GBM) is the most devastating primary intracranial malignancy lacking effective clinical treatments. Notch2 has been established to be a prognostic marker and probably involved in GBM malignant progression. N-acetylcysteine (NAC), a precursor of intracellular glutathione (GSH), has been widely implicated in prevention and therapy of several cancers. However, the role of NAC in GBM remains unclear and the property of NAC independent of its antioxidation is largely unknown.<br><br>METHODS: The mRNA and protein levels of Notch family and other related factors were detected by RT-PCR and western blot, respectively. In addition, intracellular reactive oxygen species (ROS) was measured by flow cytometry-based DCFH-DA. Moreover, cell viability was assessed by CCK8 and cell cycle was analyzed by flow cytometry-based PI staining. The level of apoptosis was checked by flow cytometry-based Annexin V/PI. Cell migration and invasion were evaluated by wound healing and transwell invasion assays. At last, U87 Xenograft model was established to confirm whether NAC could restrain the growth of tumor.<br><br>RESULTS: Our data showed that NAC could decrease the protein level of Notch2. Meanwhile, NAC had a decreasing effect on the mRNA and protein levels of its downstream targets Hes1 and Hey1. These effects caused by NAC were independent of cellular GSH and ROS levels. The mechanism of NAC-mediated Notch2 reduction was elucidated by promoting Notch2 degradation through Itch-dependent lysosome pathway. Furthermore, NAC could prevent proliferation, migration, and invasion and might induce apoptosis in GBM cells via targeting Notch2. Significantly, NAC could suppress the growth of tumor in vivo.<br><br>CONCLUSIONS: NAC could facilitate Notch2 degradation through lysosomal pathway in an antioxidant-independent manner, thus attenuating Notch2 malignant signaling in GBM cells. The remarkable ability of NAC to inhibit cancer cell proliferation and tumor growth may implicate a novel application of NAC on GBM therapy.}, }
@article {pmid30605031, year = {2019}, author = {Boullhesen-Williams, T and Townsend, KL and Milovancev, M and White, NC and Harris, CG and Adiga, P}, title = {In vitro effect of 20% N-acetylcysteine on the viscosity of normal canine bile.}, journal = {American journal of veterinary research}, volume = {80}, number = {1}, pages = {74-78}, doi = {10.2460/ajvr.80.1.74}, pmid = {30605031}, issn = {1943-5681}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bile/*chemistry ; Dogs/*physiology ; Expectorants/*pharmacology ; Reference Values ; Viscosity/drug effects ; }, abstract = {OBJECTIVE To evaluate the in vitro effect of 20% N-acetylcysteine (NAC) on the viscosity of normal canine bile. ANIMALS Bile samples obtained from 10 adult dogs euthanized for reasons unrelated to biliary disease. PROCEDURES Each sample was centrifuged to remove particulates, then divided into 3 aliquots. One aliquot remained untreated (control). Each of the other aliquots was diluted 1:4 with 20% NAC or sterile water. The viscosity of all samples was measured with a rotational viscometer at 25°C. Viscosity of control samples was measured immediately after centrifugation and at 1 and 24 hours after treatment application to the diluted samples. Viscosity of diluted samples was measured at 1 and 24 hours after treatment application. RESULTS Mean viscosity differed significantly among the 3 groups at both 1 and 24 hours after treatment application. Relative to control samples, the addition of NAC and sterile water decreased the viscosity by approximately 3.35 mPa·s (95% confidence interval [CI], 1.58 to 5.12 mPa·s) and 2.74 mPa·s (95% CI, 1.33 to 4.14 mPa·s), respectively. Mean viscosity of the NAC-treated samples was approximately 0.61 mPa·s (95% CI, 0.21 to 1.01 mPa·s) less than that for the sterile water-treated samples. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that in vitro dilution of canine bile 1:4 with 20% NAC significantly decreased the viscosity of the resulting mixture. Further research is necessary to determine whether NAC is a safe and effective noninvasive treatment for dogs with persistent biliary sludge or gallbladder mucoceles.}, }
@article {pmid30604677, year = {2018}, author = {He, G and Li, Q and Li, W and Wang, L and Yang, J and Zeng, F}, title = {N-Acetylcysteine for Preventing of Acute Kidney Injury in Chronic Kidney Disease Patients Undergoing Cardiac Surgery: A Metaanalysis.}, journal = {The heart surgery forum}, volume = {21}, number = {6}, pages = {E513-E521}, doi = {10.1532/hsf.2193}, pmid = {30604677}, issn = {1522-6662}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/*prevention &amp; control ; Administration, Oral ; Anti-Inflammatory Agents/administration &amp; dosage/*therapeutic use ; Antioxidants/administration &amp; dosage/*therapeutic use ; Cardiac Surgical Procedures/*adverse effects ; Humans ; Infusions, Intravenous ; Intensive Care Units ; Length of Stay ; Postoperative Complications/prevention &amp; control ; Renal Insufficiency, Chronic/*complications/therapy ; Renal Replacement Therapy ; }, abstract = {OBJECTIVE: The aim of this study was to determine whether N-acetylcysteine (NAC) has an effect on acute kidney injury (AKI) in chronic kidney disease patients undergoing cardiac surgery.<br><br>METHODS: We reviewed literature through PubMed, Medline through PubMed and OVID, The Cochrane Library, Wan Fang Database, China Biology Medicine Database, Chinese Periodical Database, China Knowledge Resource Integrated Database, and Chinese Clinical Trial Registry (1980 to July 10, 2018). Two investigators independently collected the data and assessed the quality of each study. RevMan 5.3 was used for the present metaanalysis.<br><br>RESULTS: A total of 5 RCTs (N = 678 participants) were included in the primary analysis. Pooled analysis showed that intravenous infusion of NAC significantly reduced the incidence of AKI (RR = 0.77, 95% = 0.63 to 0.94, P < .01) and that NAC could decrease the adverse cardiac events (RR = 0.83, 95% = 0.70 to 0.97, P < .05), but that it may increase the length of stay in the ICU (mean difference [MD] = 2.1, 95% CI = 1.61 to 2.60, P < .01). There were no statistically significant differences between the 2 groups in the requirement for renal replacement therapy(RRT) (RR = 1.33, 95% = 0.63 to 2.81, P = .45) and all-cause mortality (RR = 0.51, 95% = 0.25 to 1.06, P = .07).<br><br>CONCLUSION: Our study shows that intravenous infusion of NAC could prevent postoperative AKI in preexisting-renal-failure patients undergoing cardiac surgery.}, }
@article {pmid30604234, year = {2019}, author = {Ozatik, FY and Teksen, Y and Kadioglu, E and Ozatik, O and Bayat, Z}, title = {Effects of hydrogen sulfide on acetaminophen-induced acute renal toxicity in rats.}, journal = {International urology and nephrology}, volume = {51}, number = {4}, pages = {745-754}, pmid = {30604234}, issn = {1573-2584}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*therapeutic use ; Acute Kidney Injury/chemically induced/*drug therapy/pathology ; Acute-Phase Proteins/metabolism ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Apoptosis/drug effects ; Cell Adhesion Molecules/metabolism ; Free Radical Scavengers/*therapeutic use ; Hydrogen Sulfide/*therapeutic use ; Kidney Tubules/pathology ; Lipocalin-2 ; Lipocalins/metabolism ; Male ; Oxidative Stress ; Proto-Oncogene Proteins/metabolism ; Rats ; Transforming Growth Factor beta/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {INTRODUCTION AND AIM: Hydrogen sulfide (H2S) is an endogenously produced gas-structure mediator. It is proposed to have antioxidant, anti-inflammatory and antiapoptotic effects. Acetaminophen (N-acetyl-P-aminophenol; APAP) is an antipyretic and analgesic medication known as paracetamol. When taken at therapeutic doses there are few side-effects, but at high doses APAP can cause clear liver and kidney damage in humans and experimental animals. In this study, the effects of the H2S donor of sodium hydrosulfide (NaHS) on acute renal toxicity induced by APAP in rats were researched in comparison with N-acetyl cysteine (NAC).<br><br>METHOD: Rats were divided into six groups (n&#x2009;=&#x2009;7) as control. APAP, APAP&#x2009;+&#x2009;NAC, APAP&#x2009;+&#x2009;NaHS 25&#xa0;&#xb5;mol/kg, NaHS 50&#xa0;&#xb5;mol/kg and NaHS 100&#xa0;&#xb5;mol/kg. After oral dose of 2&#xa0;g/kg APAP, NAC and NaHS were administered via the i.p. route for 7 days. In renal homogenates, KIM-1 (Kidney Injury Molecule-1), NGAL (neutrophil gelatinase-associated lipocalin), TNF-&#x3b1; and TGF&#x3b2; levels were measured with the ELISA method for tissue injury and inflammation. In renal tissue, oxidative stress levels were identified by spectrophotometric measurement of TAS and TOS. Histopathologic investigation of renal tissue used caspase 3 staining for apoptotic changes, Masson trichrome and H&amp;E staining for variations occurring in glomerular and tubular systems.<br><br>RESULTS: NaHS lowered KIM-1, NGAL, TNF-&#x3b1;, TGF-&#x3b2; and TOS levels elevated in renal tissue linked to APAP and increased TAS values. NaHS prevented apoptosis in the kidney and was identified to ensure histologic amelioration in glomerular and tubular structures. NaHS at 50&#xa0;&#xb5;mol/kg dose was more effective, with the effect reduced with 100&#xa0;&#xb5;mol/kg dose.<br><br>CONCLUSION: H2S shows protective effect against acute renal injury linked to APAP. This protective effect reduces with high doses of H2S. The anti-inflammatory and antioxidant activity of H2S may play a role in the renoprotective effect.}, }
@article {pmid30603674, year = {2018}, author = {Heil, J and Schultze, D and Schemmer, P and Bruns, H}, title = {N-acetylcysteine protects hepatocytes from hypoxia-related cell injury.}, journal = {Clinical and experimental hepatology}, volume = {4}, number = {4}, pages = {260-266}, pmid = {30603674}, issn = {2392-1099}, abstract = {AIM OF THE STUDY: Hepatocyte transplantation has been discussed as an alternative to liver transplantation in selected cases of acute and chronic liver failure and metabolic diseases. Immediately after infusion of hepatocytes, hypoxia-related cell injury is inevitable. N-acetylcysteine (NAC) has been suggested to attenuate hypoxic damage. This study's objective was to evaluate NAC's protective effect in a model of hypoxia-related hepatocyte injury.<br><br>MATERIAL AND METHODS: HepG2 cells were used as a model for hepatocytes and were cultured under standardized hypoxia or normoxia for 24 hours with or without NAC. Growth kinetics were monitored using trypan blue staining. The activation of apoptotic pathways was measured using quantitative real-time PCR for Bcl-2/Bax and p53. The proportions of vital, apoptotic and necrotic cells were verified by fluorescence activated cell sorting using annexin V-labelling. The expression of hypoxia inducible factor 1 (HIF-1) was measured indirectly using its downstream target vascular endothelial growth factor A (VEGF-A).<br><br>RESULTS: After NAC, cell proliferation increased under both hypoxia and normoxia by 528% and 320% (p < 0.05), while VEGF-A expression decreased under normoxia by 67% and 37% (p < 0.05). Compared to cells treated without NAC under hypoxia, the Bcl-2/Bax ratio increased significantly in cells treated with NAC. This finding was confirmed by an increased number of vital cells in FACS analysis.<br><br>CONCLUSIONS: NAC protects hepatocytes from hypoxic injury and ultimately activates anti-apoptotic pathways.}, }
@article {pmid30602106, year = {2018}, author = {Grant, JE and Chamberlain, SR}, title = {A Pilot Examination of Oxidative Stress in Trichotillomania.}, journal = {Psychiatry investigation}, volume = {15}, number = {12}, pages = {1130-1134}, pmid = {30602106}, issn = {1738-3684}, support = {/WT_/Wellcome Trust/United Kingdom ; }, abstract = {OBJECTIVE: Trichotillomania is a relatively common illness whose neurobiology is poorly understood. One treatment for adult trichotillomania, n-acetyl cysteine (NAC), has antioxidative properties, as well as effects on central glutamatergic transmission. Preclinical models suggest that excessive oxidative stress may be involved in its pathophysiology.<br><br>METHODS: Adults with trichotillomania provided a blood sample for analysis of compounds that may be influenced by oxidative stress [glutathione, angiotensin II, ferritin, iron, glucose, insulin and insulin growth factor 1 (IGF1), and hepcidin]. Participants were examined on symptom severity, disability, and impulsivity. The number of participants with out-of-reference range oxidative stress measures were compared against the null distribution. Correlations between oxidative stress markers and clinical measures were examined.<br><br>RESULTS: Of 14 participants (mean age 31.2 years; 92.9% female), 35.7% (n=5) had total glutathione levels below the reference range (p= 0.041). Other oxidative stress measures did not have significant proportions outside the reference ranges. Lower levels of glutathione correlated significantly with higher motor impulsiveness (Barratt Impulsiveness Scale sub-score) (r=0.97, p=0.001).<br><br>CONCLUSION: A third of patients with trichotillomania had low levels of glutathione, and lower levels of glutathione correlated significantly with higher motor impulsiveness. Because NAC is a precursor for cysteine, and cysteine is a rate limiting step for glutathione production, these results may shed light on the mechanisms through which NAC can have beneficial effects for impulsive symptoms. Confirmation of these results requires a suitable larger follow-up study, including an internal normative control group.}, }
@article {pmid30598724, year = {2018}, author = {Rawat, V and Bortolussi, G and Gazzin, S and Tiribelli, C and Muro, AF}, title = {Bilirubin-Induced Oxidative Stress Leads to DNA Damage in the Cerebellum of Hyperbilirubinemic Neonatal Mice and Activates DNA Double-Strand Break Repair Pathways in Human Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {1801243}, pmid = {30598724}, issn = {1942-0994}, mesh = {Animals ; Bilirubin/*metabolism ; Cerebellum/*physiopathology ; DNA Breaks, Double-Stranded/*drug effects ; DNA Damage/*genetics ; Humans ; Hyperbilirubinemia, Neonatal/*genetics ; Mice ; Oxidative Stress ; Transfection ; }, abstract = {Unconjugated bilirubin is considered a potent antioxidant when present at moderate levels. However, at high concentrations, it produces severe neurological damage and death associated with kernicterus due to oxidative stress and other mechanisms. While it is widely recognized that oxidative stress by different toxic insults results in severe damage to cellular macromolecules, especially to DNA, no data are available either on DNA damage in the brain triggered by hyperbilirubinemia during the neonatal period or on the activation of DNA repair mechanisms. Here, using a mouse model of neonatal hyperbilirubinemia, we demonstrated that DNA damage occurs in vivo in the cerebellum, the brain region most affected by bilirubin toxicity. We studied the mechanisms associated with potential toxic action of bilirubin on DNA in in vitro models, which showed significant increases in DNA damage when neuronal and nonneuronal cells were treated with 140 nM of free bilirubin (Bf), as determined by γH2AX Western blot and immunofluorescence analyses. Cotreatment of cells with N-acetyl-cysteine, a potent oxidative-stress inhibitor, prevented DNA damage by bilirubin, supporting the concept that DNA damage was caused by bilirubin-induced oxidative stress. Bilirubin treatment also activated the main DNA repair pathways through homologous recombination (HR) and nonhomologous end joining (NHEJ), which may be adaptive responses to repair bilirubin-induced DNA damage. Since DNA damage may be another important factor contributing to neuronal death and bilirubin encephalopathy, these results contribute to the understanding of the mechanisms associated with bilirubin toxicity and may be of relevance in neonates affected with severe hyperbilirubinemia.}, }
@article {pmid30597883, year = {2018}, author = {Kagota, S and Maruyama-Fumoto, K and Iwata, S and Shimari, M and Koyanagi, S and Shiokawa, Y and McGuire, JJ and Shinozuka, K}, title = {Perivascular Adipose Tissue-Enhanced Vasodilation in Metabolic Syndrome Rats by Apelin and N-Acetyl[-]l-Cysteine-Sensitive Factor(s).}, journal = {International journal of molecular sciences}, volume = {20}, number = {1}, pages = {}, pmid = {30597883}, issn = {1422-0067}, support = {JP16K08563//JSPS KAKENHI/ ; }, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/*pharmacology ; Adipose Tissue/drug effects/*metabolism ; Animals ; Apelin/*metabolism/pharmacology ; Biomarkers ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Mesenteric Arteries/drug effects/metabolism/physiopathology ; Metabolic Syndrome/etiology/*metabolism ; Nitric Oxide/metabolism ; RNA, Messenger/genetics ; Rats ; Receptor, Angiotensin, Type 1/genetics/metabolism ; Vasodilation/*drug effects ; }, abstract = {Perivascular adipose tissue (PVAT) can regulate vascular tone. In mesenteric arteries of SHRSP.Z-Lepr[fa]/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by PVAT-dependent mechanisms that disappear with increasing age. In this study, we investigated the mechanisms of the age-related changes and responsible factor(s) involved in the enhancing effects of mesenteric arterial PVAT in SHRSP.ZF. Acetylcholine- and sodium nitroprusside-induced relaxations of isolated arteries were greater with PVAT than without PVAT at 17 and 20 weeks of age (wks), and as expected, this enhancement by the presence of PVAT disappeared at 23 wks. PVAT mRNA levels of angiotensin II type 1 (AT1) receptor-associated protein was less and AT1 receptor was unchanged at 23 wks when compared to 20 wks. At 20 wks, the enhanced acetylcholine-induced relaxation by the presence of PVAT was inhibited by N-acetyl-l-cysteine (NAC). Acetylcholine-induced relaxation of arteries without PVAT was increased in the presence of exogenously added apelin. PVAT mRNA level of apelin was higher in SHRSP.ZF than in control Wistar-Kyoto rats, and the level was decreased with aging. These results suggest that AT1 receptor activation in PVAT, and changes in the regulation of apelin and a NAC-sensitive factor are related to the age-dependent deterioration of the vasodilation enhancing effects of mesenteric arterial PVAT in SHRSP.ZF.}, }
@article {pmid30595386, year = {2019}, author = {Chen, Y and Ji, Y and Jin, X and Sun, X and Zhang, X and Chen, Y and Shi, L and Cheng, H and Mao, Y and Li, X and Hou, Y and Zhang, D and Zhao, S and Ma, J and Huang, S}, title = {Mitochondrial abnormalities are involved in periodontal ligament fibroblast apoptosis induced by oxidative stress.}, journal = {Biochemical and biophysical research communications}, volume = {509}, number = {2}, pages = {483-490}, doi = {10.1016/j.bbrc.2018.12.143}, pmid = {30595386}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Adult ; Cell Survival/drug effects ; Cells, Cultured ; Fibroblasts/cytology/drug effects/metabolism/*pathology ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism/*pathology ; Mitochondrial Dynamics/drug effects ; *Oxidative Stress/drug effects ; Periodontal Ligament/cytology/drug effects/metabolism/*pathology ; Young Adult ; }, abstract = {Oxidative stress (OS)-induced apoptosis of periodontal ligament cells (PDLCs) has been suggested to be an important pathogenic factor of periodontitis. Mitochondrial abnormalities are closely linked to OS and act as the main players in apoptosis. Our aim was to investigate the potential mitochondrial abnormalities in PDLCs apoptosis induced by OS. In this study, significant reduction in viability and increased apoptosis were observed in H2O2-treated hPDLCs. H2O2 also induced mitochondrial dysfunction, judging by increased mitochondrial reactive oxygen species amounts, and decreased mitochondrial membrane potential as well as ATP levels. Furthermore, H2O2 significantly enhanced mitochondrial fission by decreasing the expression of Mfn1 and Mfn2, along with increasing the expression of Drp1, Fis1 and the cleavage of OPA1. Notably, NAC stabilized the balance of the mitochondrial dynamics, attenuated mitochondrial dysfunction, and inhibited apoptosis of hPDLCs in the presence of H2O2. In conclusion, the OS-induced apoptosis of hPDLCs may be mediated by mitochondria-dependent pathway.}, }
@article {pmid30593978, year = {2019}, author = {Stochelski, MA and Wilmanski, T and Walters, M and Burgess, JR}, title = {D3T acts as a pro-oxidant in a cell culture model of diabetes-induced peripheral neuropathy.}, journal = {Redox biology}, volume = {21}, number = {}, pages = {101078}, pmid = {30593978}, issn = {2213-2317}, mesh = {Antioxidants/*metabolism/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Dehydroepiandrosterone/pharmacology ; Diabetic Neuropathies/drug therapy/etiology/*metabolism ; Glutathione/metabolism ; Glutathione Transferase/metabolism ; Glycation End Products, Advanced/metabolism ; Humans ; Models, Biological ; Neurites/drug effects/metabolism ; Oxidative Stress/drug effects ; Thiones/*pharmacology ; Thiophenes/*pharmacology ; }, abstract = {Diabetes mellitus is one of the most common chronic diseases in the United States and peripheral neuropathy (PN) affects at least 50% of diabetic patients. Medications available for patients ameliorate symptoms (pain), but do not protect against cellular damage and come with severe side effects, leading to discontinued use. Our research group uses differentiated SH-SY5Y cells treated with advanced glycation end products (AGE) as a model to mimic diabetic conditions and to study the mechanisms of oxidative stress mediated cell damage and antioxidant protection. N-acetylcysteine (NAC), a common antioxidant supplement, was previously shown by our group to fully protect against AGE-induced damage. We have also shown that 3H-1,2-dithiole-3-thione (D3T), a cruciferous vegetable constituent and potent inducer of nuclear factor (erythroid-derived 2)- like 2 (Nrf2), can significantly increase cellular GSH concentrations and protect against oxidant species-induced cell death. Paradoxically, D3T conferred no protection against AGE-induced cell death or neurite degeneration. In the present study we establish a mechanism for this paradox by showing that D3T in combination with AGE increased oxidant species generation and depleted GSH via inhibition of glutathione reductase (GR) activity and increased expression of the NADPH generating enzyme glucose-6-phosphate dehydrogenase (G6PD). Blocking NADPH generation with the G6PD inhibitor dehydroepiandrosterone was found to protect against AGE-induced oxidant species generation, loss of viability, and neurite degeneration. It further reversed the D3T potentiation effect under AGE-treated conditions. Collectively, these results suggest that strategies aimed at combating oxidative stress that rely on upregulation of the endogenous antioxidant defense system via Nrf2 may backfire and promote further damage in diabetic PN.}, }
@article {pmid30593920, year = {2019}, author = {Giniatullin, A and Petrov, A and Giniatullin, R}, title = {Action of Hydrogen Peroxide on Synaptic Transmission at the Mouse Neuromuscular Junction.}, journal = {Neuroscience}, volume = {399}, number = {}, pages = {135-145}, doi = {10.1016/j.neuroscience.2018.12.027}, pmid = {30593920}, issn = {1873-7544}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Chloramines/metabolism ; Diaphragm/drug effects/innervation/metabolism ; Dose-Response Relationship, Drug ; Exocytosis/drug effects/physiology ; Female ; Glutathione/metabolism ; Hydrogen Peroxide/*pharmacology ; Male ; Membrane Lipids/metabolism ; Mice ; Neuromuscular Junction/*drug effects/physiology ; Oxidants/*pharmacology ; Phrenic Nerve/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Synaptic Transmission/*drug effects/physiology ; Synaptic Vesicles/drug effects/physiology ; Tissue Culture Techniques ; Tosyl Compounds/metabolism ; }, abstract = {Hydrogen peroxide (H2O2) is one of the reactive oxygen species (ROS), endogenously produced during metabolism, which acts as a second messenger. In skeletal muscles, hypoxia- or hyperthermia-induced increase in H2O2 might affect synaptic transmission by targeting the most redox-sensitive presynaptic compartment (Giniatullin et al., 2006). However, the effects of H2O2 as a signal molecule have not previously been studied in different patterns of the synaptic activity. Here, using optical and microelectrode recording of synaptic vesicle exocytosis, we studied the use-dependent action of low concentrations of H2O2 and other oxidants in the mouse neuromuscular junction. We found that: (i) H2O2 at low micromole concentrations inhibited both spontaneous and evoked transmitter releases from the motor nerve terminals in a use-dependent manner, (ii) the antioxidant N-acetylcysteine (NAC) eliminated these depressant effects, (iii) the influence of H2O2 was not associated with lipid oxidation suggesting a pure signaling action, (iv) the intracellular oxidant Chloramine-T or (v) the glutathione depletion produced similar to H2O2 depressant effects. Taken together, our data revealed the effective inhibition of neurotransmitter release by ROS, which was proportional to the intensity of synaptic activity at the neuromuscular junction. The combination of various oxidants suggested an intracellular location for redox-sensitive sites responsible for modulation of the synaptic transmission in the skeletal muscle.}, }
@article {pmid30590262, year = {2019}, author = {Vaughan, A and Stevanovic, S and Jafari, M and Rahman, M and Bowman, RV and Fong, KM and Ristovski, Z and Yang, IA}, title = {The effect of diesel emission exposure on primary human bronchial epithelial cells from a COPD cohort: N-acetylcysteine as a potential protective intervention.}, journal = {Environmental research}, volume = {170}, number = {}, pages = {194-202}, doi = {10.1016/j.envres.2018.12.035}, pmid = {30590262}, issn = {1096-0953}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Epithelial Cells ; Humans ; Particulate Matter ; *Pulmonary Disease, Chronic Obstructive ; Vehicle Emissions/*analysis ; }, abstract = {INTRODUCTION: Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death world-wide by 2020. Prolonged exposure to particulate matter is associated with COPD progression and mortality. Diesel emissions are a major contributor to particulate matter pollution. In this study we test a therapeutic antioxidant, N-acetylcysteine (NAC), for its ability to protect bronchial epithelial cells (pHBECs) from patients with COPD from adverse effects of diesel emission exposure.<br><br>METHODS: pHBECs from patients with or without COPD were cultured at air-liquid interface (ALI). Cells were exposed to diesel emissions for 30&#x202f;min with or without 3-h post-exposure treatment with 5&#x202f;mM N-acetylcysteine (NAC). Filtered laboratory air was tested as a negative control. Cell responses (cell viability, inflammation and oxidative stress) and gene expression profiles for intracellular and immune signaling were assessed.<br><br>RESULTS: Diesel emissions exposure increased IL-8 secretion and production, antioxidant production, and cytochrome P450 1a1 (CYP1a1) mRNA expression and suppressed superoxide dismutase-1 (SOD1) mRNA expression in bronchial epithelial cells from COPD patients. Treatment with N-acetyl cysteine attenuated the suppression of SOD1. Nanostring gene expression profiling of the filtered air controls showed COPD epithelial cells have increased expression of MHC class II and an interferon signaling profile.<br><br>CONCLUSIONS: This study indicates that bronchial epithelial cells from COPD patients may be vulnerable to diesel emission exposure due to reduced antioxidant capacity, and elevated CYP1a1 mRNA expression. NAC did not appear to offer protection. Future research will be needed to explore other means of recovering oxidant capacity in COPD airways.}, }
@article {pmid30587055, year = {2020}, author = {Geng, YD and Zhang, L and Wang, GY and Feng, XJ and Chen, ZL and Jiang, L and Shen, AZ}, title = {Xanthatin mediates G2/M cell cycle arrest, autophagy and apoptosis via ROS/XIAP signaling in human colon cancer cells.}, journal = {Natural product research}, volume = {34}, number = {18}, pages = {2616-2620}, doi = {10.1080/14786419.2018.1544976}, pmid = {30587055}, issn = {1478-6427}, mesh = {Antineoplastic Agents, Phytogenic/isolation &amp; purification/pharmacology ; Apoptosis/*drug effects ; Asteraceae/chemistry ; Autophagy/*drug effects ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Furans/isolation &amp; purification/pharmacology/*therapeutic use ; G2 Phase Cell Cycle Checkpoints ; Humans ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; Xanthium/chemistry ; }, abstract = {Xanthatin is a natural plant bicyclic sesquiterpene lactone extracted from Xanthium plants (Asteraceae). In the present study, we demonstrated for the first time that Xanthatin inhibited cell proliferation and mediated G2/M phase arrest in human colon cancer cells. Xanthatin also activated caspase and mediated apoptosis in these cells. Concomitantly, Xanthatin triggered cell autophagic response. We found down-regulation of X-linked inhibitor of apoptosis protein (XIAP) contribute to the induction of apoptosis and autophagy. Moreover, reactive oxygen species (ROS) production was triggered upon exposure to Xanthatin in colon cancer cells. ROS inhibitor N-acetylcysteine (NAC) significantly reversed Xanthatin-mediated XIAP down-regulation, G2/M phase arrest, apoptosis and autophagosome accumulation. In summary, our findings demonstrated that Xanthatin caused G2/M phase arrest and mediated apoptosis and autophagy through ROS/XIAP in human colon cancer cells. We provided molecular bases for developing Xanthatin as a promising antitumor candidate for colon cancer therapy. AbbreviationsROSreactive oxygen speciesDMSOdimethyl sulfoxide5-FU5-Fluorouracil3-MA3-MethyladenineDCFH-DA2'7'-dichlorfluorescein-diacetateNACN-acetylcysteineXIAPX-linked inhibitor of apoptosis protein.}, }
@article {pmid30586869, year = {2018}, author = {Granato, M and Gilardini Montani, MS and Angiolillo, C and D'Orazi, G and Faggioni, A and Cirone, M}, title = {Cytotoxic Drugs Activate KSHV Lytic Cycle in Latently Infected PEL Cells by Inducing a Moderate ROS Increase Controlled by HSF1, NRF2 and p62/SQSTM1.}, journal = {Viruses}, volume = {11}, number = {1}, pages = {}, pmid = {30586869}, issn = {1999-4915}, mesh = {Antineoplastic Agents/pharmacology ; Bortezomib/pharmacology ; Butyric Acid/pharmacology ; Cell Line, Tumor ; Down-Regulation ; Heat Shock Transcription Factors/*genetics ; Herpesvirus 8, Human/*drug effects/physiology ; Humans ; Metformin/pharmacology ; NF-E2-Related Factor 2/*genetics ; Quercetin/pharmacology ; RNA-Binding Proteins/*genetics ; Reactive Oxygen Species/*metabolism ; Sequestosome-1 Protein/*genetics ; Tetradecanoylphorbol Acetate/pharmacology ; Trans-Activators/genetics ; Transcriptional Activation ; Virus Activation/drug effects ; Virus Latency/*drug effects ; }, abstract = {Previous studies have indicated that cytotoxic treatments may induce or not activate viral lytic cycle activation in cancer cells latently infected by Kaposi's sarcoma-associated herpesvirus (KSHV). To investigate the molecular mechanisms responsible for such an effect, we compared two cytotoxic treatments able to induce the viral lytic cycle, named 12-O-tetradecanoylphorbol 13-acetate (TPA) (T) in combination with sodium butyrate (B) and bortezomib (BZ), with two cytotoxic treatments that did not activate this process, named metformin (MET) and quercetin (Q). Our results indicated that TB and bortezomib increased levels of oxygen reactive species (ROS) while metformin and quercetin reduced them. The finding that N-acetylcysteine (NAC), a reactive oxigen species (ROS) scavenger, counteracted K-bZIP expression induced by TB or bortezomib, confirmed that an ROS increase played a role in KSHV lytic cycle activation. Moreover, we found that TB and bortezomib up-regulated p62/Sequestosome1(p62/SQSTM1) protein, while metformin and quercetin down-regulated it. p62/SQSTM1 silencing or the inhibition of NF-E2-related factor 2 (NRF2) or Heat Shock Factor 1 (HSF1), that mediate p62/SQSTM1 transcription, also reduced KSHV lytic antigen expression induced by TB or bortezomib. Interestingly, such combination treatments further increased intracellular ROS and cytotoxicity induced by the single TB or bortezomib treatment, suggesting that NRF2, HSF1 and p62/SQSTM1 keep the ROS level under control, allowing primary effusion lymphoma (PEL) cells to continue to survive and KSHV to replicate.}, }
@article {pmid30584464, year = {2018}, author = {Luo, J and Xiang, Y and Xu, X and Fang, D and Li, D and Ni, F and Zhu, X and Chen, B and Zhou, M}, title = {High Glucose-Induced ROS Production Stimulates Proliferation of Pancreatic Cancer via Inactivating the JNK Pathway.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {6917206}, pmid = {30584464}, issn = {1942-0994}, mesh = {Acetylcysteine/metabolism ; Anthracenes/pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Glucose/*pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Oxidative Stress/drug effects ; Pancreatic Neoplasms/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Aberrant glucose metabolism of diabetes mellitus or hyperglycemia stimulates pancreatic tumorigenesis and progression. Hyperglycemic environment can increase the ROS level of tumors, but the role of upregulation of ROS levels in pancreatic cancer (PC) still remains controversial. Here, the same as other reports, we demonstrate that high glucose promoted pancreatic cancer cell growth and resulted in an increase in the level of ROS. However, it is interesting that the phosphorylation of JNK was reduced. When treating PC cells with N-acetyl-L-cysteine (NAC), the intracellular ROS generation is repressed, but the expression of phosphorylation of JNK and c-Jun increased. Moreover, the JNK inhibitor SP600125 significantly promoted cell proliferation and suppressed cell apoptosis of pancreatic cancer cells under high glucose conditions. Collectively, high levels of ROS induced by high glucose conditions stimulated the proliferation of pancreatic cancer cells, and it may be achieved by inactivating the JNK pathway.}, }
@article {pmid30575123, year = {2019}, author = {Yoon, DW and Kim, YS and Hwang, S and Khalmuratova, R and Lee, M and Kim, JH and Lee, GY and Koh, SJ and Park, JW and Shin, HW}, title = {Intermittent hypoxia promotes carcinogenesis in azoxymethane and dextran sodium sulfate-induced colon cancer model.}, journal = {Molecular carcinogenesis}, volume = {58}, number = {5}, pages = {654-665}, doi = {10.1002/mc.22957}, pmid = {30575123}, issn = {1098-2744}, support = {//the Korean Health Technology R&amp;D Project/International ; (HI15C2310)//Ministry of Health and Welfare, Republic of Korea/International ; (2017015015)//the National Research Foundation of Korea/International ; //National Research Foundation of Korea (NRF)/International ; (NRF-2018R1C1B6002290)//the Korea government (MSIT)/International ; }, mesh = {Animals ; Azoxymethane/*toxicity ; Carcinogenesis/chemically induced/metabolism/*pathology ; Carcinogens/toxicity ; Colitis/chemically induced/metabolism/*pathology ; Colonic Neoplasms/chemically induced/metabolism/*pathology ; Dextran Sulfate/*toxicity ; *Disease Models, Animal ; Hypoxia/*physiopathology ; Inflammation/chemically induced/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; }, abstract = {Intermittent hypoxia (IH), a characteristic of obstructive sleep apnea, is known to promote cancer progression and aggressiveness in mouse models. However, little is known regarding the effect of IH on cancer initiation. Here, the effect of IH on carcinogenesis was explored in azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced colon cancer models with three different protocols. In the first protocol, two other application time points (early or late initiation of IH) were applied. In the second protocol, mice were divided into only two groups, and then exposed to either N or IH conditions for 14 days. In the third protocol, a pharmacological inhibition study for anti-inflammation (5-aminosalicylate) or anti-oxidative stress (N-acetylcysteine [NAC]) was performed. The number of tumors was significantly higher in the IH-1 than in the N or IH-2 groups. 8-oxo-2'-deoxyguanosine (8-OHdG) levels were higher in tumors of the IH-1 group than in that of the N and IH-2 groups. Gene expression related to reactive oxygen species production was higher in the IH-1 group than in the N and IH-2 groups, and it showed a positive correlation with 8-OHdG levels. Prior to cancer development 8-OHdG levels were already elevated in colonic epithelial regions in the IH group, possibly due to an imbalance between oxidative stress and antioxidant systems. NAC treatment resulted in a significant reduction in the number of tumors in mice exposed to IH. In conclusion, IH promotes carcinogenesis in a chemically-induced colon cancer model where elevated 8-OHdG may contribute to the increased tumor induction.}, }
@article {pmid30574085, year = {2018}, author = {More, J and Galusso, N and Veloso, P and Montecinos, L and Finkelstein, JP and Sanchez, G and Bull, R and Valdés, JL and Hidalgo, C and Paula-Lima, A}, title = {N-Acetylcysteine Prevents the Spatial Memory Deficits and the Redox-Dependent RyR2 Decrease Displayed by an Alzheimer's Disease Rat Model.}, journal = {Frontiers in aging neuroscience}, volume = {10}, number = {}, pages = {399}, pmid = {30574085}, issn = {1663-4365}, abstract = {We have previously reported that primary hippocampal neurons exposed to synaptotoxic amyloid beta oligomers (AβOs), which are likely causative agents of Alzheimer's disease (AD), exhibit abnormal Ca[2+] signals, mitochondrial dysfunction and defective structural plasticity. Additionally, AβOs-exposed neurons exhibit a decrease in the protein content of type-2 ryanodine receptor (RyR2) Ca[2+] channels, which exert critical roles in hippocampal synaptic plasticity and spatial memory processes. The antioxidant N-acetylcysteine (NAC) prevents these deleterious effects of AβOs in vitro. The main contribution of the present work is to show that AβOs injections directly into the hippocampus, by engaging oxidation-mediated reversible pathways significantly decreased RyR2 protein content but increased single RyR2 channel activation by Ca[2+] and caused considerable spatial memory deficits. AβOs injections into the CA3 hippocampal region impaired rat performance in the Oasis maze spatial memory task, decreased hippocampal glutathione levels and overall content of plasticity-related proteins (c-Fos, Arc, and RyR2) and increased ERK1/2 phosphorylation. In contrast, in hippocampus-derived mitochondria-associated membranes (MAM) AβOs injections increased RyR2 levels. Rats fed with NAC for 3-weeks prior to AβOs injections displayed comparable redox potential, RyR2 and Arc protein contents, similar ERK1/2 phosphorylation and RyR2 single channel activation by Ca[2+] as saline-injected (control) rats. NAC-fed rats subsequently injected with AβOs displayed the same behavior in the spatial memory task as control rats. Based on the present in vivo results, we propose that redox-sensitive neuronal RyR2 channels partake in the mechanism underlying AβOs-induced memory disruption in rodents.}, }
@article {pmid30573364, year = {2019}, author = {Wen, H and Zhou, S and Song, J}, title = {Induction of apoptosis by magnolol via the mitochondrial pathway and cell cycle arrest in renal carcinoma cells.}, journal = {Biochemical and biophysical research communications}, volume = {508}, number = {4}, pages = {1271-1278}, doi = {10.1016/j.bbrc.2018.12.087}, pmid = {30573364}, issn = {1090-2104}, mesh = {Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Biphenyl Compounds/chemistry/*pharmacology ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Humans ; Inhibitory Concentration 50 ; Kidney Neoplasms/metabolism/*pathology ; Lignans/chemistry/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/*metabolism ; Neoplasm Metastasis ; Reactive Oxygen Species/metabolism ; }, abstract = {Magnolol (Mag), an effective natural compound isolated from the stem bark of Magnolia officinalis, was found to have the potential for antitumor activity by inducing apoptosis in tumor cells. However, the effect of Mag on renal carcinoma cells and its molecular mechanism are unexplored. Our study provided evidence that Mag induced apoptosis in 786-O and OS-RC-2 cell lines via the mitochondrial pathway and cell cycle arrest. In this work, we found that Mag induced morphological changes and inhibited the proliferation of 786-O and OS-RC-2 cells in a dose- and time-dependent manner but exerted no notable inhibitory effects on normal human renal proximal tubular (HK-2) cells. Treatment with Mag suppressed the migration and invasion ability of renal carcinoma cells. Moreover, Mag caused the openness of mPTP, the accumulation of intracellular ROS and decreased △Ψm, leading to mitochondrial dysfunction. However, pretreatment with the antioxidant N-acetyl cysteine (NAC) reversed the apoptosis induced by Mag and decreased the generation of ROS. In addition, the increased proportion of the G1/G0 phase indicated that Mag caused cell cycle arrest. Further analyses suggested that magnolol-induced apoptosis was related to the abnormal expression of p53, Bax, Bcl-2, cytochrome c and caspase activation. Together, the results above revealed that Mag had antitumor effects in renal carcinoma cells via ROS production as well as cell cycle arrest and the apoptotic mitochondrial pathway was suppressed in part by NAC.}, }
@article {pmid30573241, year = {2019}, author = {Cristallini, C and Barbani, N and Ventrelli, L and Summa, C and Filippi, S and Capelôa, T and Vitale, E and Albera, C and Messore, B and Giachino, C}, title = {Biodegradable microparticles designed to efficiently reach and act on cystic fibrosis mucus barrier.}, journal = {Materials science &amp; engineering. C, Materials for biological applications}, volume = {95}, number = {}, pages = {19-28}, doi = {10.1016/j.msec.2018.10.064}, pmid = {30573241}, issn = {1873-0191}, mesh = {A549 Cells ; Adult ; Biocompatible Materials/*metabolism ; Cell Proliferation ; Chromatography, High Pressure Liquid ; Cystic Fibrosis/*metabolism ; Drug Delivery Systems/methods ; Humans ; Mucus/*metabolism ; Polylactic Acid-Polyglycolic Acid Copolymer/metabolism ; Sputum/metabolism ; }, abstract = {Cystic fibrosis (CF) is a progressive genetic disease caused by mutations in the gene that produces the CF transmembrane conductance regulator (CFTR) protein. The malfunction of the CFTR protein causes a thick buildup of mucus in the lungs that clogs the airways and traps bacteria, thus leading to infections, extensive lung damage and respiratory failure. Micro-delivery systems are currently being investigated as an efficient way to cross the viscous and complex architecture of the CF mucus. In this study, we produced synthetic and natural microparticles (MPs) based on poly(dl‑lactide‑co‑glycolide) (PLGA) or gellan gum through tailored water/oil emulsion procedures. Morphological and physico-chemical characterizations were carried out on both classes of MPs showing particles having diameters within suitable ranges to reach the CF airways. In vitro biocompatibility tests were also performed on both MPs using a human lung cancer cell line (A549) demonstrating that treatment with MPs induces no cytotoxic effects. Both classes of MPs were loaded with a mucolytic agent (N‑acetyl cysteine, NAC) and their release kinetics evaluated using high performance liquid chromatography (HPLC). The analysis pointed out that the amount of NAC released from MPs resulted in a dose-dependent increment, with a rapid release kinetic to satisfy the requirement for inducing an early mucus degradation. Finally, mucolytic action of NAC-loaded MPs was evaluated in an artificial sputum model through its rheological analysis obtaining the lowest viscosity profile after the addition of drug-loaded MPs. Taken together, gained results allowed us to select suitable MPs as potential drug targeting platforms having a mucolytic action for CF treatment.}, }
@article {pmid30571738, year = {2018}, author = {Matsueda, Y and Arinuma, Y and Nagai, T and Hirohata, S}, title = {Synergistic enhancement of production of proinflammatory cytokines of human peripheral blood monocytes by anti-Sm and anti-RNP antibodies.}, journal = {PloS one}, volume = {13}, number = {12}, pages = {e0209282}, pmid = {30571738}, issn = {1932-6203}, mesh = {Antibodies, Monoclonal/administration &amp; dosage/blood/*immunology ; Autoantibodies/blood ; Cytochalasin D/pharmacology ; Cytokines/*biosynthesis ; Drug Synergism ; Humans ; In Vitro Techniques ; Inflammation Mediators/metabolism ; Interleukin-6/biosynthesis/genetics ; Lupus Erythematosus, Systemic/etiology/immunology ; Monocytes/drug effects/*immunology ; NF-kappa B/genetics ; RNA, Messenger/genetics/metabolism ; Receptors, Fc/antagonists &amp; inhibitors ; Ribonucleoproteins, Small Nuclear/immunology ; Tumor Necrosis Factor-alpha/genetics ; beta-Cyclodextrins/pharmacology ; snRNP Core Proteins/*immunology ; }, abstract = {The present study was performed to elucidate the roles of serum anti-Sm antibodies in the pathogenesis of systemic lupus erythematosus (SLE). Highly purified peripheral blood monocytes obtained from healthy donors were cultured in the presence of monoclonal anti-Sm antibody (anti-Sm mAb), monoclonal anti-U1-RNP antibody (anti-RNP mAb) or control murine IgG1 or IgG3. After various periods of incubation, levels of IL-6 and TNF-α in the culture supernatants were measured by ELISA and the expression of mRNA for various molecules in monocytes was determined using RT-PCR. Flow cytometry analysis confirmed the bindings of anti-Sm mAb and anti-RNP mAb on viable human monocytes. Both anti-Sm mAb and anti-RNP mAb significantly increased the production of IL-6 and TNF-α of human monocytes in a dose-dependent manner, although the latter was more potent than the former. Of note, anti-Sm mAb synergistically enhanced the production and mRNA expression of IL-6 and TNF-α of human monocytes in the presence of anti-RNP mAb. Notably, anti-RNP mAb, but not anti-Sm mAb, significantly enhanced the mRNA expression of RelA in human monocytes. Finally, anti-Sm mAb still up-regulated the IL-6 production of monocytes in the presence of anti-RNP mAb under the influence of N-acetyl cysteine or pyrrolidine dithiocarbamate that totally abrogated the IL-6 production provoked by anti-Sm mAb alone in the absence of anti-RNP mAb. These results demonstrate that anti-Sm and anti-RNP antibodies synergistically up-regulate the expression of IL-6 and TNF-α in human monocytes. The data also suggest that the effect of anti-Sm in the synergy with anti-RNP might not involve NFkB activation.}, }
@article {pmid30570876, year = {2018}, author = {Djikic, D and Markovic, D and Bogdanovic, A and Mitrovic-Ajtic, O and Suboticki, T and Diklic, M and Beleslin-Cokic, B and Bjelica, S and Kovacic, M and P Cokic, V}, title = {Oxidative and nitrosative stress in myeloproliferative neoplasms: the impact on the AKT / mTOR signaling pathway.}, journal = {Journal of B.U.ON. : official journal of the Balkan Union of Oncology}, volume = {23}, number = {5}, pages = {1481-1491}, pmid = {30570876}, issn = {1107-0625}, mesh = {Adult ; Aged ; Humans ; Middle Aged ; Myeloproliferative Disorders/genetics/*metabolism/pathology ; Nitrosative Stress/*physiology ; Oxidative Stress/*physiology ; Proto-Oncogene Proteins c-akt/*metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {PURPOSE: A common feature of malignancies is increased reactive oxygen species (ROS) and reactive nitrogen species (RNS). We analyzed the influence of oxidative and nitrosative stress on the activation of AKT/mTOR signaling pathway in myeloproliferative neoplasms (MPN).<br><br>METHODS: Oxidative stress-induced gene expression in circulatory CD34+ cells of MPN patients was studied by microarray analysis. Biomarkers of oxidative and nitrosative stress were determined using spectrophotometry in plasma and erythrocyte lysate. The levels of nitrotyrosine, inducible NO synthase (iNOS) and AKT/mTOR/p70S6K phosphorylation were determined by immunocytochemistry and immunoblotting in granulocytes of MPN patients.<br><br>RESULTS: Antioxidants superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1) gene expression were increased in circulatory CD34+ cells, while SOD1 and GPx enzymes were reduced in the erythrocytes of MPN. Plasma malonyl-dialdehyde and protein carbonyl levels were elevated in MPN. The total antioxidant capacity in plasma and erythrocyte catalase (CT) activities was the most prominent in primary myelofibrosis (PMF) with JAK2V617F heterozygosity. The total nitrite/nitrate (NOx) level was augmented in the plasma of PMF patients (p<0.001), while nitrotyrosine and iNOS were generally increased in the granulocytes of MPN patients. Activation of AKT/mTOR signaling was the most significant in PMF (p<0.01), but demonstrated JAK2V617F dependence and consequent p70S6K phosphorylation in the granulocytes of essential thrombocytemia (ET) and polycythemia vera (PV) patients. Hydrogen peroxide stimulated mTOR pathway, iNOS and nitrotyrosine quantities, the last one prevented by the antioxidant n-acetyl-cysteine (NAC) in the granulocytes of MPN.<br><br>CONCLUSION: Our study showed increased levels of oxidative and nitrosative stress parameters in MPN with JAK2V617F dependence. The ROS enhanced the constitutive activation of AKT/mTOR signaling and nitrosative parameters in MPN.}, }
@article {pmid30560188, year = {2019}, author = {Schlessinger, DI and Gray, J and Speiser, J and Lake, E}, title = {Ulcerated forehead nodule in an intravenous heroin user.}, journal = {JAAD case reports}, volume = {5}, number = {1}, pages = {63-65}, pmid = {30560188}, issn = {2352-5126}, }
@article {pmid30559650, year = {2018}, author = {Gil-Martínez, AL and Cuenca, L and Estrada, C and Sánchez-Rodrigo, C and Fernández-Villalba, E and Herrero, MT}, title = {Unexpected Exacerbation of Neuroinflammatory Response After a Combined Therapy in Old Parkinsonian Mice.}, journal = {Frontiers in cellular neuroscience}, volume = {12}, number = {}, pages = {451}, pmid = {30559650}, issn = {1662-5102}, abstract = {The design of therapeutic strategies that focus on the repositioning of anti-inflammatory and antioxidant drugs are a great bet to slow down the progression of neurodegenerative disorders. Despite the fact that Parkinson's disease (PD) is an age-related pathology, almost all experimental studies are carried out in young animals. Here, we evaluated the possible neuroprotective effect of the combination of the antioxidant N-acetylcysteine (NAC) and the anti-inflammatory HA-1077 in aged 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice (C57BL/6 mice, 20 months old), whose individual treatment has been shown to have neuroprotective effects in this Parkinsonism model. Interestingly, NAC+HA-1077-based treatment produced a significant increase in dopaminergic neuronal death accompanied by an increase in microglial and astroglial activation in the Substantia Nigra pars compacta (SNpc) and striatum of old-Parkinsonian mice compared to their control group. The astroglial response was also explored by co-immunostaining for GFAP and S100b together with p-JNK and it was found to be particularly exacerbated in the MPTP+NAC+HA-1077 group. The unexpected toxic effects found in the combined use of NAC and HA-1077 in old-Parkinsonian mice highlight the importance of taking into account that in elderly Parkinsonian patients the combination of some drugs (most of them used for other different age-related alterations) can have side effects that may result in the exacerbation of the neurodegenerative process.}, }
@article {pmid30555562, year = {2018}, author = {Sharma, A and Liaw, K and Sharma, R and Zhang, Z and Kannan, S and Kannan, RM}, title = {Targeting Mitochondrial Dysfunction and Oxidative Stress in Activated Microglia using Dendrimer-Based Therapeutics.}, journal = {Theranostics}, volume = {8}, number = {20}, pages = {5529-5547}, pmid = {30555562}, issn = {1838-7640}, support = {R01 EB018306/EB/NIBIB NIH HHS/United States ; }, mesh = {Chromatography, High Pressure Liquid ; Dendrimers/chemistry/*metabolism/*pharmacology ; Dynamic Light Scattering ; Immunohistochemistry ; Macrophages/drug effects/metabolism ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Microglia/drug effects/metabolism ; Mitochondria/*metabolism ; Oxidative Stress/drug effects ; }, abstract = {Mitochondrial oxidative stress is associated with many neurodegenerative diseases, such as traumatic brain injury (TBI). Targeted delivery of antioxidants to mitochondria has failed to translate into clinical success due to their nonspecific cellular localization, poor transport properties across multiple biological barriers, and associated side effects. These challenges, coupled with the complex function of the mitochondria, create the need for innovative delivery strategies. Methods: Neutral hydroxyl-terminated polyamidoamine (PAMAM) dendrimers have shown significant potential as nanocarriers in multiple brain injury models. N-acetyl cysteine (NAC) is a clinically used antioxidant and anti-inflammatory agent which has shown significant potency when delivered in a targeted manner. Here we present a mitochondrial targeting hydroxyl PAMAM dendrimer-drug construct (TPP-D-NAC) with triphenyl-phosphonium (TPP) for mitochondrial targeting and NAC for targeted delivery to mitochondria in injured glia. Co-localization and mitochondrial content of mitochondria-targeted and unmodified dendrimer were assessed in microglia and macrophages in vitro via immunohistochemistry and fluorescence quantification. Therapeutic improvements of TPP-D-NAC over dendrimer-NAC conjugate (D-NAC) and free NAC were evaluated in vitro in microglia under oxidative stress challenge. In vivo neuroinflammation targeting was confirmed in a rabbit model of TBI. Results: TPP-conjugated dendrimer co-localized significantly more with mitochondria than unmodified dendrimer without altering overall levels of cellular internalization. This targeting capability translated to significant improvements in the attenuation of oxidative stress by TPP-D-NAC compared to D-NAC and free NAC. Upon systemic administration in a rabbit TBI model, TPP-conjugated dendrimer co-localized specifically with mitochondria in activated microglia and macrophages in the white matter of the ipsilateral/injured hemisphere, confirming its BBB penetration and glial targeting capabilities. Conclusion: D-NAC has shown promising efficacy in many animal models of neurodegeneration, and this work provides evidence that modification for mitochondrial targeting can further enhance its therapeutic efficacy, particularly in diseases where oxidative stress-induced glial cell death plays a significant role in disease progression.}, }
@article {pmid30551603, year = {2018}, author = {Tardiolo, G and Bramanti, P and Mazzon, E}, title = {Overview on the Effects of N-Acetylcysteine in Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {23}, number = {12}, pages = {}, pmid = {30551603}, issn = {1420-3049}, support = {RF-2011-02352582//Ministero della Salute/ ; }, mesh = {Acetylcysteine/chemistry/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/chemistry/pharmacology/therapeutic use ; Antioxidants/chemistry/pharmacology/therapeutic use ; Clinical Trials as Topic ; Humans ; Neurodegenerative Diseases/*drug therapy ; Synaptic Transmission/drug effects ; }, abstract = {N-acetylcysteine (NAC), which is an acetylated cysteine compound, has aroused scientific interest for decades due to its important medical applications. It also represents a nutritional supplement in the human diet. NAC is a glutathione precursor and shows antioxidant and anti-inflammatory activities. In addition to the uses quoted in the literature, NAC may be considered helpful in therapies to counteract neurodegenerative and mental health diseases. Furthermore, this compound has been evaluated for its neuroprotective potential in the prevention of cognitive aging dementia. NAC is inexpensive, commercially available and no relevant side effects were observed after its administration. The purpose of this paper is to give an overview on the effects and applications of NAC in Parkinson's and Alzheimer's disorders and in neuropathic pain and stroke.}, }
@article {pmid30551454, year = {2019}, author = {Turkmen, R and Akosman, MS and Demirel, HH}, title = {Protective effect of N-acetylcysteine on MK-801-induced testicular oxidative stress in mice.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {109}, number = {}, pages = {1988-1993}, doi = {10.1016/j.biopha.2018.09.139}, pmid = {30551454}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Dizocilpine Maleate/*toxicity ; Free Radical Scavengers/*pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/*drug effects/physiology ; Testis/*drug effects/*metabolism ; }, abstract = {Experimental studies indicate that MK-801 causes organ injury in schizophrenic mice testes although it is molecular mechanism has not been clearly defined. In this study, we investigated the probable protective effect of N-Acetylcysteine (NAC) against MK-801- induced testicular toxicity in mice. In total, 24 Balb/C male mice were divided into 4 equal groups: the animals in the control group (vehicle treated) were intraperitoneally given 10 mL/kg/day saline solution, the animals in the experiment groups were intraperitoneally given 1 mg/kg/day MK-801 alone, 100 mg/kg/day NAC alone and MK-801 by 1 mg/kg/day for 14 days. The level of the testes' total oxidant status (TOS) in mice that were treated with MK-801 was significantly higher than those level in the other groups while the total antioxidant status (TAS) levels decreased. In comparison to the MK-801 group, the TOS levels were lower, and the TAS levels increased in the MK-801 + NAC group. In the morphometric analysis, the diameter and epithelial height of the seminiferous tubules of the testes showed no significant changes after MK-801 administration. Conversely, the weights of the testes decreased significantly. In the treatment with NAC, the weights of testes significantly increased in comparison to the MK-801 group. The histopathological examination revealed necrobiotic and degenerative changes in the epithelial cells, vacuole formation within the seminiferous tubules, a decrease in the number of the spermatozoid, and disorganization in the basement membrane of the seminiferous tubules in the MK-801 group in comparison to the control group. Administration of NAC alleviated several negative effects of MK-801 on the testicular damage in mice. In conclusion, our results showed that NAC protected the mice against the testicular toxicity of MK-801 when it was administrated intraperitoneally.}, }
@article {pmid30549998, year = {2018}, author = {Vural, G and Gumusyayla, S and Deniz, O and Neselioglu, S and Erel, O}, title = {Thiol-Disulfide Homeostasis in Cerebral Venous Sinus Thrombosis.}, journal = {Clinical laboratory}, volume = {64}, number = {11}, pages = {}, doi = {10.7754/Clin.Lab.2018.180707}, pmid = {30549998}, issn = {1433-6510}, mesh = {Adult ; Cavernous Sinus Thrombosis/diagnosis/*metabolism ; Disulfides/*metabolism ; Female ; *Homeostasis ; Humans ; Male ; Middle Aged ; Oxidative Stress ; Sulfhydryl Compounds/*metabolism ; Young Adult ; }, abstract = {BACKGROUND: The objective of this study is to examine thiol-disulfide homeostasis in patients with cerebral venous sinus thrombosis.<br><br>METHODS: Fifty-three patients diagnosed with cerebral venous sinus thrombosis and 80 healthy volunteers were included in the study. The native thiol and total thiol concentrations were measured with the newly developed automated method. In addition, their amount of disulfide bonds was calculated.<br><br>RESULTS: The total thiol and native thiol levels of the patients with cerebral venous sinus thrombosis were significantly lower than the healthy volunteers (p = 0.001, p = 0.001, respectively). In terms of dynamic disulfide bond formation, there was no statistically significant difference between the groups (p > 0.05). A significant negative correlation was determined between native thiol and total thiol levels and the number of sinuses that had thrombosis (r = -0.136, p = 0.033; r = -0.141, p = 0.015, respectively). There was no correlation between National Institutes of Health Stroke Scale score and thiol-disulfide homeostasis parameters.<br><br>CONCLUSIONS: This study is the first study to examine thiol-disulfide homeostasis in patients with cerebral venous sinus thrombosis. The thiol-disulfide balance is impaired under oxidative stress. This study revealed that this balance is disrupted in correlation with widespread thrombosis in patients with cerebral venous sinus thrombosis. Therefore, fortification of thiol deficiency with N-acetyl cysteine or alpha-lipoic acid can prevent the progress of thrombosis and can be beneficial in cerebral venous sinus thrombosis treatment.}, }
@article {pmid30549489, year = {2018}, author = {Bauer, IE and Green, C and Colpo, GD and Teixeira, AL and Selvaraj, S and Durkin, K and Zunta-Soares, GB and Soares, JC}, title = {A Double-Blind, Randomized, Placebo-Controlled Study of Aspirin and N-Acetylcysteine as Adjunctive Treatments for Bipolar Depression.}, journal = {The Journal of clinical psychiatry}, volume = {80}, number = {1}, pages = {}, doi = {10.4088/JCP.18m12200}, pmid = {30549489}, issn = {1555-2101}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics ; Adult ; Aged ; Analysis of Variance ; Anti-Inflammatory Agents, Non-Steroidal/*administration &amp; dosage/pharmacology ; Aspirin/*administration &amp; dosage/pharmacology ; Bayes Theorem ; Bipolar Disorder/complications/*drug therapy ; Chemotherapy, Adjuvant ; Depressive Disorder/complications/*drug therapy ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Treatment Outcome ; }, abstract = {OBJECTIVE: Neuroinflammation has been implicated in the pathophysiology of bipolar disorder. Some evidence shows that nonsteroidal anti-inflammatory drugs (NSAIDs) have promising antidepressant effects. The antioxidant N-acetylcysteine (NAC) may enhance the effects of NSAIDs. No study has, however, tested the adjunctive therapeutic benefits of an NSAID and NAC in bipolar disorder.<br><br>METHODS: The sample included 24 medicated patients diagnosed with DSM-IV-TR bipolar disorder who were aged 18-65 years and had a Montgomery-Asberg Depression Rating Scale (MADRS) score &#x2265; 20. Participants were randomly assigned to receive either aspirin (1,000 mg), NAC (1,000 mg), combined aspirin and NAC (1,000 mg each), or placebo. Data were collected between 2013 and 2017. The primary outcome was a &#x2265; 50% reduction in MADRS scores. Participants completed mood and global functioning questionnaires. They also underwent blood tests prior to and following 8 and 16 weeks of treatment. A Bayesian analytic method was adopted, and posterior probability distributions were calculated to determine the probability of treatment response.<br><br>RESULTS: Following the first 8-week treatment phase, individuals on treatment with placebo and NAC + aspirin had a similar probability for successful treatment response (about 70%). Following a 16-week treatment period, NAC + aspirin was associated with higher probability of treatment response (67%) compared to placebo (55%), NAC (57%), and aspirin (33%). There was no treatment effect on interleukin-6 and C-reactive protein levels at either 8 or 16 weeks.<br><br>CONCLUSIONS: The coadministration of NAC and aspirin during a period of 16 weeks was associated with a reduction in depressive symptoms. The adverse effects were minimal. These preliminary findings may serve as a starting point for future studies assessing the efficacy, tolerability, and safety of anti-inflammatory and antioxidant agents in the treatment of bipolar depression.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01797575.}, }
@article {pmid30549180, year = {2019}, author = {Hseu, YC and Yang, TY and Li, ML and Rajendran, P and Mathew, DC and Tsai, CH and Lin, RW and Lee, CC and Yang, HL}, title = {Chalcone flavokawain A attenuates TGF-β1-induced fibrotic pathology via inhibition of ROS/Smad3 signaling pathways and induction of Nrf2/ARE-mediated antioxidant genes in vascular smooth muscle cells.}, journal = {Journal of cellular and molecular medicine}, volume = {23}, number = {2}, pages = {775-788}, pmid = {30549180}, issn = {1582-4934}, mesh = {Actins/genetics/metabolism ; Animals ; Antioxidant Response Elements/drug effects ; Antioxidants/*pharmacology ; Aorta/cytology/metabolism ; Cell Line ; Cell Movement/drug effects ; Chalcone/*analogs &amp; derivatives/pharmacology ; Fibronectins/genetics/metabolism ; Fibrosis/prevention &amp; control ; Gene Expression Regulation ; Heme Oxygenase-1/genetics/metabolism ; Matrix Metalloproteinase 2/genetics/metabolism ; Matrix Metalloproteinase 9/genetics/metabolism ; Models, Biological ; Myocytes, Smooth Muscle/cytology/*drug effects/metabolism ; NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism ; NF-E2-Related Factor 2/antagonists &amp; inhibitors/*genetics/metabolism ; Rats ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Signal Transduction ; Smad3 Protein/antagonists &amp; inhibitors/*genetics/metabolism ; Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism ; Transforming Growth Factor beta1/pharmacology ; }, abstract = {TGF-β1 plays a crucial role in the pathogenesis of vascular fibrotic diseases. Chalcones are reportedly cancer chemo-preventive food components that are rich in fruits and vegetables. In this study, flavokawain A (FKA, 2-30 μM), a naturally occurring chalcone in kava extracts, was evaluated for its anti-fibrotic and antioxidant properties in TGF-β1-stimulated vascular smooth muscle (A7r5) cells, as well as its underlying molecular mechanism of action. Immunofluorescence data showed down-regulated F-actin expression with FKA treatment in TGF-β1-stimulated A7r5 cells. Western blotting demonstrated that FKA treatment suppressed the expression of α-SMA and fibronectin proteins under TGF-β1 stimulation. Findings from wound-healing and invasion experiments showed that FKA inhibits TGF-β1-mediated migration and invasion. Western blotting demonstrated that treatment with FKA down-regulated MMP-9 and MMP-2 and up-regulated TIMP-1 expression. Further evidence showed that FKA decreased TGF-β1-mediated phosphorylation and the transcriptional activity of Smad3. TGF-β1-induced excessive ROS production was remarkably reversed by FKA treatment in A7r5 cells, and inhibition by FKA or N-acetylcysteine (NAC) substantially diminished TGF-β1-induced p-Smad3 activation and wound-healing migration. Interestingly, FKA-mediated antioxidant properties were associated with increased nuclear translocation of Nrf2 and elevated antioxidant response element (ARE) luciferase activity. Activation of Nrf2/ARE signaling was accompanied by the induction of HO-1, NQO-1 and γ-GCLC genes in FKA-treated A7r5 cells. Notably, silencing of Nrf2 (siRNA transfection) significantly diminished the FKA-mediated antioxidant effects, indicating that FKA may inhibit TGF-β1-induced fibrosis through suppressing ROS generation in A7r5 cells. Our results suggested that anti-fibrotic and antioxidant activities of the chalcone flavokawain A may contribute to the development of food-based chemo-preventive drugs for fibrotic diseases.}, }
@article {pmid30548974, year = {2019}, author = {Puyo, CA and Earhart, A and Staten, N and Prince, OA and Haug, C and Kollef, M and Awad, M}, title = {Endotracheal intubation results in acute tracheal damage induced by mtDNA/TLR9/NF-κB activity.}, journal = {Journal of leukocyte biology}, volume = {105}, number = {3}, pages = {577-587}, pmid = {30548974}, issn = {1938-3673}, support = {//Department of Anesthesiology Division of Clinical and Translational Research/International ; }, mesh = {Acute Disease ; Animals ; Cell Movement ; Cytokines/metabolism ; DNA, Mitochondrial/*genetics ; Epithelium/metabolism ; HEK293 Cells ; Humans ; Inflammation Mediators/metabolism ; Interleukin-8/metabolism ; *Intubation, Intratracheal ; NF-kappa B/*metabolism ; Neutrophils/metabolism ; Pancreatic Elastase/metabolism ; Phenotype ; Reactive Oxygen Species/metabolism ; Swine ; Toll-Like Receptor 9/*metabolism ; Trachea/*metabolism/*pathology ; }, abstract = {Tracheitis secondary to placement of an endotracheal tube (ETT) is characterized by neutrophil accumulation in the tracheal lumen, which is generally associated with epithelial damage. Mitochondrial DNA (mtDNA), has been implicated in systemic inflammation and organ dysfunction following trauma; however, less is known about the effects of a foreign body on local trauma and tissue damage. We hypothesized that tracheal damage secondary to the ETT will result in local release of mtDNA at sufficient levels to induce TLR9 and NF-κB activation. In a swine model we compared the differences between uncoated, and chloroquine (CQ) and N-acetylcysteine (NAC) coated ETTs as measured by tracheal lavage fluids (TLF) over a period of 6 h. The swine model allowed us to recreate human conditions. ETT presence was characterized by neutrophil activation, necrosis, and release of proinflammatory cytokines mediated by TLR9/NF-κB induction. Amelioration of the tracheal damage was observed in the CQ and NAC coated ETT group as shown in tracheal tissue specimens and TLF. The role of TLR9/NF-κB dependent activity was confirmed by HEK-Blue hTLR9 reporter cell line analysis after coincubation with TLF specimens with predetermined concentrations of NAC or CQ alone or TLR9 inhibitory oligodeoxynucleotide (iODN). These findings indicate that therapeutic interventions aimed at preventing mtDNA/TLR9/NF-κB activity may have benefits in prevention of acute tracheal damage.}, }
@article {pmid30548715, year = {2019}, author = {Chan, WY and Khazandi, M and Hickey, EE and Page, SW and Trott, DJ and Hill, PB}, title = {In vitro antimicrobial activity of seven adjuvants against common pathogens associated with canine otitis externa.}, journal = {Veterinary dermatology}, volume = {30}, number = {2}, pages = {133-e38}, doi = {10.1111/vde.12712}, pmid = {30548715}, issn = {1365-3164}, support = {LP130100736//ARC Linkage Grant/ ; }, mesh = {Acetylcysteine/pharmacology ; Adjuvants, Pharmaceutic/*pharmacology ; Animals ; Anti-Infective Agents/*pharmacology ; Bacteria/*drug effects/pathogenicity ; Dogs ; Drug Resistance, Multiple, Bacterial ; Drug Synergism ; Edetic Acid/pharmacology ; Fungi/*drug effects/pathogenicity ; Laurates/pharmacology ; Malassezia/drug effects ; Microbial Sensitivity Tests ; Monoglycerides/pharmacology ; Otitis Externa/microbiology/*veterinary ; Pseudomonas aeruginosa/drug effects ; Staphylococcus/drug effects ; }, abstract = {BACKGROUND: An antibiotic adjuvant is a chemical substance used to modify or augment the effectiveness of primary antimicrobial agents against drug-resistant micro-organisms. Its use provides an alternative approach to address the global issue of antimicrobial resistance and enhance antimicrobial stewardship.<br><br>HYPOTHESIS/OBJECTIVES: To determine the antimicrobial activity of a panel of potential antimicrobial adjuvants against common pathogens associated with canine otitis externa (OE).<br><br>ANIMALS/ISOLATES: A number of type strains and clinical isolates (n&#xa0;=&#xa0;110) from canine OE were tested including Staphylococcus pseudintermedius, &#x3b2;-haemolytic Streptococcus spp., Pseudomonas aeruginosa, Proteus mirabilis and Malassezia pachydermatis.<br><br>METHODS AND MATERIALS: Antimicrobial activities of monolaurin, monocaprin, N-acetylcysteine (NAC), polymyxin B nonapeptide, Tris-EDTA, Tris-HCL and disodium EDTA were tested using microdilution methodology according to CLSI guidelines.<br><br>RESULTS: N-acetylcysteine, Tris-EDTA and disodium EDTA had antimicrobial activity against both type strains and otic pathogens. The other adjuvants tested had limited to no efficacy. NAC had a minimal inhibitory concentration (MIC) range of 2,500-10,000&#xa0;&#x3bc;g/mL for the various organisms. Pseudomonas aeruginosa isolates were eight times more susceptible to disodium EDTA in the presence of Tris-HCL in comparison to disodium EDTA alone. Malassezia pachydermatis isolates were most susceptible to Tris-EDTA (MIC90 &#xa0;=&#xa0;190/60&#xa0;&#x3bc;g/mL) and disodium EDTA (MIC90 &#xa0;=&#xa0;120&#xa0;&#x3bc;g/mL).<br><br>N-acetylcysteine, Tris-EDTA and disodium EDTA have intrinsic antimicrobial activity and represent promising adjuvants that could be used to enhance the efficacy of existing antibiotics against Gram-negative and multidrug-resistant bacterial infections. These agents could be combined with other antimicrobial agents in a multimodal approach for mixed ear infections in dogs.}, }
@article {pmid30547892, year = {2019}, author = {Waly, H and Ragab, SM and Hassanein, KM and Abou Khalil, NS and Ahmed, EA}, title = {Uranium exposure increases spermatocytes metaphase apoptosis in rats: inhibitory effect of thymoquinone and N-acetylcysteine.}, journal = {General physiology and biophysics}, volume = {38}, number = {2}, pages = {145-155}, doi = {10.4149/gpb_2018041}, pmid = {30547892}, issn = {0231-5882}, mesh = {*Acetylcysteine/pharmacology ; Animals ; Antioxidants ; *Apoptosis ; *Benzoquinones/pharmacology ; Male ; Metaphase ; Rats ; Rats, Wistar ; *Spermatocytes ; Superoxide Dismutase ; *Uranium/toxicity ; }, abstract = {Uranyl acetate (UA), a commercial stock from depleted uranium (DU), has a combined effect of chemical toxicity and mild radioactivity. Here, we investigated the potential antioxidant, antiapoptotic and cytoprotective effects of thymoquinone (TQ) and N-acetylcysteine (NAC) against UA-induced testicular damage in rats. UA reduced testicular superoxide dismutase (SOD) activity and nitric oxide (NO) and glutathione (GSH) levels relative to the control group. Interestingly, the testicular SOD activity and NO and GSH levels of UA/TQ- and UA/NAC-treated groups were also significantly lower relative to the control. A marked increase in spermatocytes metaphase apoptosis was found (stage XIII) in UA-treated rats, which is probably due to difficulties in segregation of homologous-chromosomes. This may clarify why UA exposure decreased round spermatids numbers and fertility in previous studies. To check the reason of partial metaphase arrest, the presence of DNA-damage-related γ-H2AX foci in late spermatocytes of all groups was checked, but only insignificant increase was found in UA-treated group. TQ or NAC supplementation reduced the apoptosis and improved the testicular histological alterations. Thus, TQ and NAC attenuate UA adverse effects on the testicular microenvironement through anti-apoptotic and cytoprotective but not antioxidant effects.}, }
@article {pmid30547092, year = {2018}, author = {Van Gennip, JLM and Boswell, CW and Ciruna, B}, title = {Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis.}, journal = {Science advances}, volume = {4}, number = {12}, pages = {eaav1781}, pmid = {30547092}, issn = {2375-2548}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Biomarkers ; Disease Models, Animal ; Disease Progression ; Immunologic Factors/immunology ; Immunomodulation ; Morphogenesis ; *Phenotype ; Receptor Protein-Tyrosine Kinases/metabolism ; Scoliosis/*etiology/*metabolism/pathology/therapy ; *Signal Transduction ; Spine/*metabolism/pathology ; Zebrafish ; Zebrafish Proteins/metabolism ; }, abstract = {The etiopathogenesis of idiopathic scoliosis (IS), a highly prevalent spinal deformity that occurs in the absence of obvious congenital or physiological abnormalities, is poorly understood. Although recent zebrafish genetic studies have linked cilia motility and cerebrospinal fluid (CSF) flow defects with scoliosis progression, underlying mechanisms were not identified. Here, we use next-generation sequencing and conditional genetic methodologies to define the spatial and biological origins of spinal curve formation in ptk7 mutant zebrafish, a faithful IS model. We demonstrate that focal activation of proinflammatory signals within the spinal cord is associated with, and sufficient for, induction of spinal curvatures. Furthermore, administration of acetylsalicylic acid (aspirin) or N-acetylcysteine (NAC) to juvenile ptk7 mutants significantly reduces the incidence and/or severity of scoliosis phenotypes. Together, our results implicate neuroinflammation, downstream of CSF defects, in spinal curve formation and provide intriguing evidence that simple immunomodulating therapies might prove effective in managing idiopathic-like spinal deformities.}, }
@article {pmid30541786, year = {2018}, author = {Niño, DF and Zhou, Q and Yamaguchi, Y and Martin, LY and Wang, S and Fulton, WB and Jia, H and Lu, P and Prindle, T and Zhang, F and Crawford, J and Hou, Z and Mori, S and Chen, LL and Guajardo, A and Fatemi, A and Pletnikov, M and Kannan, RM and Kannan, S and Sodhi, CP and Hackam, DJ}, title = {Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain.}, journal = {Science translational medicine}, volume = {10}, number = {471}, pages = {}, pmid = {30541786}, issn = {1946-6242}, support = {P50 MH094268/MH/NIMH NIH HHS/United States ; R01 NS097511/NS/NINDS NIH HHS/United States ; P50 HD103538/HD/NICHD NIH HHS/United States ; R01 DK083752/DK/NIDDK NIH HHS/United States ; R01 GM078238/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Administration, Oral ; Animals ; Animals, Newborn ; Antioxidants/administration &amp; dosage/pharmacology/therapeutic use ; Brain/*pathology/ultrastructure ; Cognitive Dysfunction/drug therapy/*etiology/pathology ; Dendrimers/chemistry ; Enterocolitis, Necrotizing/*complications ; HMGB1 Protein/metabolism ; Humans ; Intestinal Mucosa/metabolism ; Mice, Inbred C57BL ; Microglia/*pathology ; Myelin Sheath/drug effects/metabolism/ultrastructure ; Toll-Like Receptor 4/metabolism ; }, abstract = {Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.}, }
@article {pmid30539868, year = {2018}, author = {Liu, H and Xie, MR and Gao, H and Li, J}, title = {Influence of pharmorubicin on the left ventricular ejection fraction of patients with breast cancer: A mechanism study.}, journal = {Journal of cancer research and therapeutics}, volume = {14}, number = {Supplement}, pages = {S1183-S1187}, doi = {10.4103/0973-1482.202230}, pmid = {30539868}, issn = {1998-4138}, mesh = {Adult ; Aged ; Antibiotics, Antineoplastic/*adverse effects ; Breast Neoplasms/*drug therapy ; Echocardiography, Doppler ; Epirubicin/*adverse effects ; Female ; Humans ; Middle Aged ; Reactive Oxygen Species/*blood ; Stroke Volume/drug effects ; Ventricular Dysfunction, Left/*blood/chemically induced/diagnostic imaging ; Ventricular Function, Left/drug effects ; }, abstract = {AIMS: Breast cancer is a great public health problem. It remains unclear how pharmorubicin induces cardiac dysfunction in patients with breast cancer. Our study was aimed to explore the influence of pharmorubicin on the left ventricular ejection fraction (EF) of patients with breast cancer and its potential mechanism.<br><br>MATERIALS AND METHODS: Patients with breast cancer were enrolled at the same hospital. Group I consisted of 135 samples, who were under treatment of pharmorubicin (200 mg/m[2]). Group II consisted of 144 samples, who were under treatment the of pharmorubicin (360 mg/m[2]). Group III was used as control group, which consists of 120 samples without treatment of pharmorubicin. Color Doppler ultrasonic inspection and measurement were performed to examine EF. Flow cytometry was performed to assess oxygen free radical level in hemocytes. Further combination therapy (N-acetylcysteine [NAC] + pharmorubicin) was provided for patients, and the same examinations were performed for the assessment of cardiac function and oxygen free radical level.<br><br>RESULTS: The ultrasound results showed that pharmorubicin treatment significantly jeopardized cardiac function, verified by decrease of both EF and fractional shortening (FS) (P < 0. 05). Moreover, such effect was dose-dependent. Oxygen free radical level was remarkably increased after pharmorubicin treatment (P < 0. 05), verified by flow cytometry. Adjunctive therapy of NAC decreased oxygen free radical level and improved cardiac function of patients with breast cancer, suggesting NAC ameliorated side effect of pharmorubicin treatment.<br><br>CONCLUSIONS: Pharmorubicin treatment decreased EF and FS of patients with breast cancer through increasing oxygen free radical level in hemocytes. Adjunctive therapy of NAC could be a potential treatment to ameliorated side effect pharmorubicin treatment.}, }
@article {pmid30535793, year = {2019}, author = {Zhang, H and Li, Y and Chen, Y and Zhang, L and Wang, T}, title = {N-Acetylcysteine protects against intrauterine growth retardation-induced intestinal injury via restoring redox status and mitochondrial function in neonatal piglets.}, journal = {European journal of nutrition}, volume = {58}, number = {8}, pages = {3335-3347}, pmid = {30535793}, issn = {1436-6215}, support = {31772634//National Natural Science Foundation of China/ ; 31802094//National Natural Science Foundation of China/ ; 2018M632320//Postdoctoral Research Foundation of China (CN)/ ; klab201710//Open Project of Shanghai Key Laboratory of Veterinary Biotechnology/ ; BK20180531//Natural Science Foundation of Jiangsu Province/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; DNA, Mitochondrial/*drug effects/physiology ; Disease Models, Animal ; Fetal Growth Retardation/*physiopathology ; Intestinal Diseases/physiopathology/*prevention &amp; control ; Intestines/physiopathology ; Oxidation-Reduction ; Swine ; }, abstract = {PURPOSE: Intrauterine growth retardation (IUGR) is detrimental to the intestinal development of neonates, yet satisfactory treatment strategies remain limited. This study was, therefore, conducted using neonatal piglets as a model to investigate the potential of N-acetylcysteine (NAC) to alleviate intestinal damage caused by IUGR.<br><br>METHODS: Seven normal birth weight (NBW) and fourteen IUGR neonatal male piglets were selected and then fed a basal milk diet (NBW-CON and IUGR-CON groups) or a basal milk diet supplemented with 1.2&#xa0;g NAC per kg of diet (IUGR-NAC group) from 7 to 21&#xa0;days of age (n&#x2009;=&#x2009;7). Parameters associated with the severity of intestinal injury, villus morphology and ultrastructural structure, redox status, and mitochondrial function were analyzed.<br><br>RESULTS: Compared with the NBW-CON piglets, the IUGR-CON piglets exhibited decreased villus height and greater numbers of apoptotic cells in jejunum, along with the increases in malondialdehyde and protein carbonyl concentrations and a decreased adenosine triphosphate (ATP) content. Treatment with NAC significantly increased jejunal superoxide dismutase activity, reduced glutathione: oxidized glutathione ratio, and the mRNA abundance of nuclear respiratory factor 2, heme oxygenase 1, and superoxide dismutase 2 in the IUGR-NAC piglets compared with the IUGR-CON piglets. In addition, NAC improved the efficiency of mitochondrial oxidative metabolism and ATP generation, ameliorated mitochondrial swelling, and inhibited the overproduction of mitochondrial superoxide anion in the jejunal mucosa.<br><br>CONCLUSIONS: Dietary supplementation of NAC shows promise for attenuating the early intestinal injury of young piglets with IUGR, probably through its antioxidant action to restore redox status and mitochondrial function.}, }
@article {pmid30535451, year = {2019}, author = {Liang, Q and Zhang, Y and Huang, M and Xiao, Y and Xiao, F}, title = {Role of mitochondrial damage in Cr(VI)‑induced endoplasmic reticulum stress in L‑02 hepatocytes.}, journal = {Molecular medicine reports}, volume = {19}, number = {2}, pages = {1256-1265}, doi = {10.3892/mmr.2018.9704}, pmid = {30535451}, issn = {1791-3004}, mesh = {Apoptosis/drug effects ; Calcium/metabolism ; Cell Line ; Chromium/*adverse effects ; Electron Transport Complex I/metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Hepatocytes/drug effects/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Up-Regulation/drug effects ; }, abstract = {Although it is well reported that mitochondrial damage and endoplasmic reticulum (ER) stress (ERS) are involved in heavy metal‑induced cytotoxicity, the role of mitochondrial damage in hexavalent chromium [Cr(VI)]‑induced ERS and the correlation between the two have not been described and remain to be elucidated. The present study evaluated the ability of Cr(VI) to induce ERS in L‑02 hepatocytes, and subsequently examined the role of reactive oxygen species (ROS)‑mediated mitochondrial damage in Cr(VI)‑induced ERS. The findings demonstrated that Cr(VI) induced ERS, which was characterized by the upregulation of ERS‑associated genes and the substantial release of Ca2+ from the ER. The Cr(VI)‑induced mitochondrial production of ROS, by disturbing mitochondrial respiratory chain complexes I and II, may damage mitochondria directly by inducing mitochondrial permeability transition pore opening and mitochondrial membrane potential collapse. The results additionally demonstrated that Cr(VI) induced Ca2+ release from the ER through ROS/caveolin‑1/protein kinase B/inositol 1,4,5‑trisphosphate receptor signaling. The application of the ROS scavenger N‑acetyl‑cysteine confirmed the role of ROS in Cr(VI)‑mediated mitochondrial damage, ERS and apoptotic cell death. The data obtained demonstrated the role of mitochondrial damage in Cr(VI)‑induced ERS and provide novel insight into the elucidation of Cr(VI)‑induced cytotoxicity.}, }
@article {pmid30533390, year = {2018}, author = {Janatmakan, F and Javaherforoosh Zadeh, F and Alizadeh, M and Alizadeh, Z and Bahreini, A}, title = {The Comparison of the Effect of Mannitol and N Acetyl Cysteine on Liver Function in Partial Hepatectomy.}, journal = {Anesthesiology and pain medicine}, volume = {8}, number = {5}, pages = {e79677}, pmid = {30533390}, issn = {2228-7523}, abstract = {The alterations in liver function in patients after major liver resection are complex. Partial hepatectomy surgery is considered as a selective therapeutic approach in many benign and malignant liver tumors, secondary metastases, and liver trauma. According to surgical techniques most often based on vascular control and hepatic venous closure (Pringle maneuver), related complications such as ischemia and decreased venous return during and after surgery can be seen. In this study, the effects of Mannitol and N-acetylcysteine, on liver function, after hepatectomy surgery, were compared. This study was shown that infusion N-acetylcysteine next to mannitol, in partial hepatectomy surgeries, was not the significant difference to improve liver function, hemodynamic status, and laboratory tests.}, }
@article {pmid30528017, year = {2019}, author = {Sarker, NC and Rahman, S and Borhan, MS and Rajasekaran, P and Santra, S and Ozcan, A}, title = {Nanoparticles in mitigating gaseous emissions from liquid dairy manure stored under anaerobic condition.}, journal = {Journal of environmental sciences (China)}, volume = {76}, number = {}, pages = {26-36}, doi = {10.1016/j.jes.2018.03.014}, pmid = {30528017}, issn = {1001-0742}, mesh = {Anaerobiosis ; Animals ; *Dairying ; Greenhouse Gases/*chemistry/isolation &amp; purification ; Manure/*analysis/microbiology ; Nanoparticles/*chemistry ; }, abstract = {A number of mitigation techniques exist to reduce the emissions of pollutant gases and greenhouse gases (GHGs) from anaerobic storage of livestock manure. Nanoparticle (NP) application is a promising mitigating treatment option for pollutant gases, but limited research is available on the mode of NP application and their effectiveness in gaseous emission reduction. In this study, zinc silica nanogel (ZnSNL), copper silica nanogel (CuSNL), and N-acetyl cysteine (NACL) coated zinc oxide quantum dot (Qdot) NPs were compared to a control lacking NPs. All three NPs tested significantly reduced gas production and concentrations compared to non-treated manure. Overall, cumulative gas volumes were reduced by 92.73%-95.83%, and concentrations reduced by 48.98%-99.75% for H2S, and 20.24%-99.82% for GHGs. Thus, application of NPs is a potential treatment option for mitigating pollutant and GHG emissions from anaerobically stored manure.}, }
@article {pmid30520128, year = {2019}, author = {Zhao, C and Chen, J and Ling, Y and Wang, S}, title = {Quantitative proteomics using SILAC-MS identifies N-acetylcysteine-solution-triggered reversal response of renal cell carcinoma cell lines.}, journal = {Journal of cellular biochemistry}, volume = {120}, number = {6}, pages = {9506-9513}, doi = {10.1002/jcb.28226}, pmid = {30520128}, issn = {1097-4644}, mesh = {Acetylcysteine/*pharmacology ; Carcinoma, Renal Cell/*metabolism ; Cell Line, Tumor ; Humans ; *Isotope Labeling ; Kidney Neoplasms/*metabolism ; Molecular Sequence Annotation ; *Proteomics ; Reproducibility of Results ; Signal Transduction ; Solutions ; }, abstract = {N-acetylcysteine (NAC), a precursor for glutathione (GSH), causes permeable antioxidation protecting normal cells and disrupting cancer cells. In the present study, we found that a NAC-based medium can trigger a reversal response of human clear cell renal cell carcinoma (ccRCC). To further investigate the action of a NAC-based solution in ccRCC cell lines, 786-O and SN12C were incubated in a serum-free acid medium (low pH) in the presence of 2 mM NAC for 24 hours or in a serum-free medium (normal pH) as the control, and then a phenotypic and proteomic analyses were performed. To determine the reversal occurrence, we tested the phenotypic features associated with cancer cells. Under this premise, a systematic and in-depth analysis of NAC-solution-triggered protein alterations was carried out by quantitative proteomics in both cell lines. Among the paramount protein signature, we identified a large number of proteins associated with cancer features were downregulated, but other proteins in the KEGG pathways associated with recovery of the missing tumorigenicity, such as the p53 pathway and repair pathway, were significantly upregulated. Quantification of notable proteins was validated by messenger RNA (mRNA) and protein levels in the ccRCC cell line. Collectively, our data indicate that the NAC-based solution inhibits human ccRCC cell growth by decreasing cell proliferation and inducing apoptosis, limiting their migration by limiting cell motility and completely changing their metabolic mode. Thus, NAC-based solutions could be used for the prevention or treatment of ccRCC.}, }
@article {pmid30504711, year = {2018}, author = {Liang, Q and Xiao, Y and Liu, K and Zhong, C and Zeng, M and Xiao, F}, title = {Cr(VI)-Induced Autophagy Protects L-02 Hepatocytes from Apoptosis Through the ROS-AKT-mTOR Pathway.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {51}, number = {4}, pages = {1863-1878}, doi = {10.1159/000495713}, pmid = {30504711}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line ; Chromium/*adverse effects ; Cytoprotection/drug effects ; Free Radical Scavengers/pharmacology ; Hepatocytes/cytology/*drug effects/metabolism ; Humans ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {BACKGROUND/AIMS: Hexavalent chromium [Cr(VI)] pollution has become a global concern for both ecosystems and human health. Our previous study revealed Cr(VI) could induce both apoptosis and autophagy in L-02 hepatocytes. Here, we sought to explore the underlying mechanism of Cr(VI)-induced autophagy and its exact role in cell death.<br><br>METHODS: Autophagy ultrastructure was observed under transmission electron microscope (TEM), autophagy flux was measured with double-tagged mCherry-green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) assay, long-lived protein degradation assay, and LC3II expression assay in the presence of lysosomal inhibitor, bafilomycin A1 (BafA1). Reactive oxygen species (ROS) level was determined using fluorescent probe dichloro-dihydrofluorescein diacetate (DCFH-DA). The expression levels of Beclin-1, LC3, p62/ SQSTM1, and AKT-mammalian target of rapamycin (mTOR) pathway-related molecules including phosphorylation (p)-AKT, AKT, p-mTOR, and mTOR were examined using real-time polymerase chain reaction (RT-PCR) and western blotting. Apoptosis was determined using Annexin V- fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining.<br><br>RESULTS: Our results demonstrated Cr(VI) exposure activated autophagy in L-02 hepatocytes, as evidenced by the accumulation of autophagosomes, the increase of LC3-II and degradation of p62/ SQSTM1, and the enhanced overall degradation of proteins. We also confirmed Cr(VI)-induced LC3-II elevation mainly came from autophagy induction rather than lysosomal degradation impairment. ROS-AKT-mTOR pathway was associated with Cr(VI)-induced autophagy, and ROS scavenger N-acetylcysteine (NAC) pretreatment inhibited Cr(VI)-induced autophagy by alleviating the inhibition of the AKT-mTOR pathway. Autophagy inhibitors 3-methyladenine (3-MA) and chloroquine diphosphate (CDP) promoted Cr(VI)-induced apoptotic death.<br><br>CONCLUSION: These findings indicated Cr(VI)-induced autophagy protected L-02 hepatocytes from apoptosis through the ROS-AKT-mTOR pathway.}, }
@article {pmid30504355, year = {2018}, author = {Dane, K and Chaturvedi, S}, title = {Beyond plasma exchange: novel therapies for thrombotic thrombocytopenic purpura.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2018}, number = {1}, pages = {539-547}, pmid = {30504355}, issn = {1520-4383}, mesh = {ADAMTS13 Protein/antagonists &amp; inhibitors/blood ; Acute Disease ; Autoantibodies/blood ; Bortezomib/*therapeutic use ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Crotalid Venoms/*therapeutic use ; Disease-Free Survival ; Humans ; Lectins, C-Type/*therapeutic use ; Plasma Exchange ; Platelet Count ; Purpura, Thrombotic Thrombocytopenic/blood/*drug therapy/mortality/pathology ; Recurrence ; Rituximab/*therapeutic use ; Single-Domain Antibodies/*therapeutic use ; Survival Rate ; von Willebrand Factor/antagonists &amp; inhibitors/metabolism ; }, abstract = {The advent of plasma exchange has dramatically changed the prognosis of acute thrombotic thrombocytopenic purpura (TTP). Recent insights into TTP pathogenesis have led to the development of novel therapies targeting pathogenic anti-ADAMTS13 antibody production, von Willebrand factor (VWF)-platelet interactions, and ADAMTS13 replacement. Retrospective and prospective studies have established the efficacy of rituximab as an adjunct to plasma exchange for patients with acute TTP, either upfront or for refractory disease. Relapse prevention is a major concern for survivors of acute TTP, and emerging data support the prophylactic use of rituximab in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission. Capalcizumab, a nanobody directed against domain A1 of VWF that prevents the formation of VWF-platelet aggregates, recently completed phase 2 (TITAN) and 3 (HERCULES) trials with encouraging results. Compared with placebo, caplacizumab shortened the time to platelet recovery and may protect against microthrombotic tissue injury in the acute phase of TTP, though it does not modify the underlying immune response. Other promising therapies including plasma cell inhibitors (bortezomib), recombinant ADAMTS13, N-acetyl cysteine, and inhibitors of the VWF-glycoprotein Ib/IX interaction (anfibatide) are in development, and several of these agents are in prospective clinical studies to evaluate their efficacy and role in TTP. In the coming years, we are optimistic that novel therapies and international collaborative efforts will usher in even more effective, evidence-based approaches to address refractory acute TTP and relapse prevention.}, }
@article {pmid30515102, year = {2018}, author = {Gáll, T and Pethő, D and Nagy, A and Hendrik, Z and Méhes, G and Potor, L and Gram, M and Åkerström, B and Smith, A and Nagy, P and Balla, G and Balla, J}, title = {Heme Induces Endoplasmic Reticulum Stress (HIER Stress) in Human Aortic Smooth Muscle Cells.}, journal = {Frontiers in physiology}, volume = {9}, number = {}, pages = {1595}, pmid = {30515102}, issn = {1664-042X}, abstract = {Accumulation of damaged or misfolded proteins resulted from oxidative protein modification induces endoplasmic reticulum (ER) stress by activating the pathways of unfolded protein response. In pathologic hemolytic conditions, extracellular free hemoglobin is submitted to rapid oxidation causing heme release. Resident cells of atherosclerotic lesions, after intraplaque hemorrhage, are exposed to heme leading to oxidative injury. Therefore, we raised the question whether heme can also provoke ER stress. Smooth muscle cells are one of the key players of atherogenesis; thus, human aortic smooth muscle cells (HAoSMCs) were selected as a model cell to reveal the possible link between heme and ER stress. Using immunoblotting, quantitative polymerase chain reaction and immunocytochemistry, we quantitated the markers of ER stress. These were: phosphorylated eIF2α, Activating transcription factor-4 (ATF4), DNA-damage-inducible transcript 3 (also known as C/EBP homology protein, termed CHOP), X-box binding protein-1 (XBP1), Activating transcription factor-6 (ATF6), GRP78 (glucose-regulated protein, 78kDa) and heme responsive genes heme oxygenase-1 and ferritin. In addition, immunohistochemistry was performed on human carotid artery specimens from patients who had undergone carotid endarterectomy. We demonstrate that heme increases the phosphorylation of eiF2α in HAoSMCs and the expression of ATF4. Heme also enhances the splicing of XBP1 and the proteolytic cleavage of ATF6. Consequently, there is up-regulation of target genes increasing both mRNA and protein levels of CHOP and GRP78. However, TGFβ and collagen type I decreased. When the heme binding proteins, alpha-1-microglobulin (A1M) and hemopexin (Hpx) are present in cell media, the ER stress provoked by heme is inhibited. ER stress pathways are also retarded by the antioxidant N-acetyl cysteine (NAC) indicating that reactive oxygen species are involved in heme-induced ER stress. Consistent with these findings, elevated expression of the ER stress marker GRP78 and CHOP were observed in smooth muscle cells of complicated lesions with hemorrhage compared to either atheromas or healthy arteries. In conclusion, heme triggers ER stress in a time- and dose-dependent manner in HAoSMCs. A1M and Hpx as well as NAC effectively hamper heme-induced ER stress, supporting their use as a potential therapeutic approach to reverse such a deleterious effects of heme toxicity.}, }
@article {pmid30497009, year = {2019}, author = {Li, C and Zhang, H and Gong, X and Li, Q and Zhao, X}, title = {Synthesis, characterization, and cytotoxicity assessment of N-acetyl-l-cysteine capped ZnO nanoparticles as camptothecin delivery system.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {174}, number = {}, pages = {476-482}, doi = {10.1016/j.colsurfb.2018.11.043}, pmid = {30497009}, issn = {1873-4367}, mesh = {A549 Cells ; Acetylcysteine/*chemistry ; Antineoplastic Agents, Phytogenic/administration &amp; dosage/chemistry/pharmacology ; Camptothecin/administration &amp; dosage/chemistry/*pharmacology ; Cell Proliferation/*drug effects ; *Drug Delivery Systems ; Hemolysis/*drug effects ; Humans ; Metal Nanoparticles/*administration &amp; dosage/chemistry ; Zinc Oxide/*chemistry ; }, abstract = {The chemical stability, good biocompatibility and high drug loading capacity of zinc oxide nanoparticles (ZnO NPs) and their biomedical potentials make them a promising candidate for drug delivery. The aim of this study was to develop and assess a simple procedure for surface functionalization of ZnO NPs by N-acetyl-l-cysteine (NAC) for anticancer camptothecin (CPT) delivery. NAC capped ZnO NPs were successfully made using ZnCl2 and NaOH in the presence of NAC. CPT was covalently conjugated to the surface of as-synthesized ZnO-NAC NPs. To characterize the synthesized conjugate product (ZnO-NAC-CPT NPs), X-ray diffraction, Fourier Transform Infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, and dynamic light scattering method were used. Our results indicated that the ZnO-NAC-CPT NPs exhibit near-spherical morphology and uniform dispersion with an average diameter of ∼70 nm. The hemolysis assay showed that ZnO-NAC-CPT NPs has almost no hemolytic activity. In addition, MTT cytotoxicity assessment on A549 lung cancer cells revealed a drop of IC50 values from 1.17 μg/mL (free CPT) to 0.66 μg/mL (ZnO-NAC-CPT NPs). This result showed an augmented cancer-inhibitory effect of nanoconjugate complex. In conclusion, the novel ZnO-NAC-CPT NPs could be considered for new therapeutic endeavors.}, }
@article {pmid30496017, year = {2019}, author = {Düzenli, U and Altun, Z and Olgun, Y and Aktaş, S and Pamukoğlu, A and Çetinayak, HO and Bayrak, AF and Olgun, L}, title = {Role of N-acetyl cysteine and acetyl-l-carnitine combination treatment on DNA-damage-related genes induced by radiation in HEI-OC1 cells.}, journal = {International journal of radiation biology}, volume = {95}, number = {3}, pages = {298-306}, doi = {10.1080/09553002.2019.1547847}, pmid = {30496017}, issn = {1362-3095}, mesh = {Acetylcarnitine/*pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects/radiation effects ; Cell Survival/drug effects/radiation effects ; *DNA Damage ; DNA Repair/drug effects/radiation effects ; Drug Interactions ; Gene Expression Regulation/drug effects/radiation effects ; Mice ; Organ of Corti/cytology/*drug effects/metabolism/*radiation effects ; }, abstract = {PURPOSE: The aim of the present study was to evaluate the effect of acetyl-l-carnitine (ALC) and N-acetyl cysteine (NAC) on ionizing radiation (IR)-induced cytotoxicity and change in DNA damage-related genes in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells.<br><br>METHODS: HEI-OC1 cells were irradiated with 5&#x2009;Gy radiation and treated by eight combinations of NAC and/or ALC: control, NAC, ALC, IR, NAC&#x2009;+&#x2009;IR, ALC&#x2009;+&#x2009;NAC, ALC&#x2009;+&#x2009;IR, and ALC&#x2009;+&#x2009;NAC&#x2009;+&#x2009;IR. Cell viability, apoptotic cell death, and DNA damage were measured at the 72nd hour. Eighty-four IR-induced DNA-damage-related genes were determined by RT-PCR gene array and >10-fold changes were considered significant.<br><br>RESULTS: IR decreased cell viability by about 50% at 72&#x2009;hours of incubation. In particular, the ALC and/or NAC combination before IR protected the HEI-OC1 cells (p&#x2009;<&#x2009;.05). Single and combination treatment prior to IR led to lower apoptotic cell death (p&#x2009;<&#x2009;.05). There was a significant lower DNA damage in ALC&#x2009;+&#x2009;NAC&#x2009;+&#x2009;IR group compared to IR group (p&#x2009;<&#x2009;.05). Expressions of Brca2, Xpc, Mlh3, Rad51, Xrcc2, Hus1, Rad9a, Cdkn1a, Gadd45a which are the DNA-repair genes were found to be significantly higher in NAC&#x2009;+&#x2009;ALC&#x2009;+&#x2009;IR group than those in individual treatment of ALC or NAC.<br><br>CONCLUSIONS: ALC and/or NAC treatment prior to IR led to higher cell viability and lower apoptotic cell damage compared to the IR group. The results of the study show that the ALC&#x2009;+&#x2009;NAC combination treatment inhibits DNA damage and induces DNA-repair genes to repair radiation damage, and this combination treatment is more effective against radiation-induced DNA damage than NAC or ALC therapy individually.}, }
@article {pmid30487791, year = {2018}, author = {Liang, J and Jahraus, B and Balta, E and Ziegler, JD and Hübner, K and Blank, N and Niesler, B and Wabnitz, GH and Samstag, Y}, title = {Sulforaphane Inhibits Inflammatory Responses of Primary Human T-Cells by Increasing ROS and Depleting Glutathione.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {2584}, pmid = {30487791}, issn = {1664-3224}, mesh = {Anti-Inflammatory Agents/*pharmacology ; Arthritis, Rheumatoid/*drug therapy ; Brassicaceae/immunology ; Cells, Cultured ; Down-Regulation ; Glutathione/metabolism ; Humans ; Immunosuppression Therapy ; Inflammation/*drug therapy ; Interleukin-17/metabolism ; Interleukins/metabolism ; Isothiocyanates/*pharmacology ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics/metabolism ; Primary Cell Culture ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Sulfoxides ; T-Lymphocytes/drug effects/*immunology ; Interleukin-22 ; }, abstract = {The activity and function of T-cells are influenced by the intra- and extracellular redox milieu. Oxidative stress induces hypo responsiveness of untransformed T-cells. Vice versa increased glutathione (GSH) levels or decreased levels of reactive oxygen species (ROS) prime T-cell metabolism for inflammation, e.g., in rheumatoid arthritis. Therefore, balancing the T-cell redox milieu may represent a promising new option for therapeutic immune modulation. Here we show that sulforaphane (SFN), a compound derived from plants of the Brassicaceae family, e.g., broccoli, induces a pro-oxidative state in untransformed human T-cells of healthy donors or RA patients. This manifested as an increase of intracellular ROS and a marked decrease of GSH. Consistently, increased global cysteine sulfenylation was detected. Importantly, a major target for SFN-mediated protein oxidation was STAT3, a transcription factor involved in the regulation of TH17-related genes. Accordingly, SFN significantly inhibited the activation of untransformed human T-cells derived from healthy donors or RA patients, and downregulated the expression of the transcription factor RORγt, and the TH17-related cytokines IL-17A, IL-17F, and IL-22, which play a major role within the pathophysiology of many chronic inflammatory/autoimmune diseases. The inhibitory effects of SFN could be abolished by exogenously supplied GSH and by the GSH replenishing antioxidant N-acetylcysteine (NAC). Together, our study provides mechanistic insights into the mode of action of the natural substance SFN. It specifically exerts TH17 prone immunosuppressive effects on untransformed human T-cells by decreasing GSH and accumulation of ROS. Thus, SFN may offer novel clinical options for the treatment of TH17 related chronic inflammatory/autoimmune diseases such as rheumatoid arthritis.}, }
@article {pmid30486484, year = {2018}, author = {Subramanya, SB and Venkataraman, B and Meeran, MFN and Goyal, SN and Patil, CR and Ojha, S}, title = {Therapeutic Potential of Plants and Plant Derived Phytochemicals against Acetaminophen-Induced Liver Injury.}, journal = {International journal of molecular sciences}, volume = {19}, number = {12}, pages = {}, pmid = {30486484}, issn = {1422-0067}, support = {31M195//UNITED ARAB EMIRATES UNIVERSITY/ ; }, mesh = {Acetaminophen/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*drug therapy/*metabolism ; Glutathione/metabolism ; Humans ; Liver/*drug effects/*metabolism ; Oxidative Stress/drug effects ; Phytochemicals/*therapeutic use ; }, abstract = {Acetaminophen (APAP), which is also known as paracetamol or N-acetyl-p-aminophenol is a safe and potent drug for fever, pain and inflammation when used at its normal therapeutic doses. It is available as over-the-counter drug and used by all the age groups. The overdose results in acute liver failure that often requires liver transplantation. Current clinical therapy for APAP-induced liver toxicity is the administration of N-acetyl-cysteine (NAC), a sulphydryl compound an approved drug which acts by replenishing cellular glutathione (GSH) stores in the liver. Over the past five decades, several studies indicate that the safety and efficacy of herbal extracts or plant derived compounds that are used either as monotherapy or as an adjunct therapy along with conventional medicines for hepatotoxicity have shown favorable responses. Phytochemicals mitigate necrotic cell death and protect against APAP-induced liver toxicityby restoring cellular antioxidant defense system, limiting oxidative stress and subsequently protecting mitochondrial dysfunction and inflammation. Recent experimental evidences indicat that these phytochemicals also regulate differential gene expression to modulate various cellular pathways that are implicated in cellular protection. Therefore, in this review, we highlight the role of the phytochemicals, which are shown to be efficacious in clinically relevant APAP-induced hepatotoxicity experimental models. In this review, we have made comprehensive attempt to delineate the molecular mechanism and the cellular targets that are modulated by the phytochemicals to mediate the cytoprotective effect against APAP-induced hepatotoxicity. In this review, we have also defined the challenges and scope of phytochemicals to be developed as drugs to target APAP-induced hepatotoxicity.}, }
@article {pmid30481789, year = {2018}, author = {Vera, M and Torramade-Moix, S and Martin-Rodriguez, S and Cases, A and Cruzado, JM and Rivera, J and Escolar, G and Palomo, M and Diaz-Ricart, M}, title = {Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {51}, number = {3}, pages = {1287-1300}, doi = {10.1159/000495540}, pmid = {30481789}, issn = {1421-9778}, mesh = {Aged ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Atherosclerosis/etiology/metabolism/pathology/prevention &amp; control ; Cells, Cultured ; Endothelium, Vascular/*drug effects/metabolism/pathology ; Female ; Glutathione Peroxidase/*metabolism ; Humans ; Intercellular Adhesion Molecule-1/metabolism ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Renal Insufficiency, Chronic/complications/*drug therapy/metabolism/pathology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND/AIMS: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model.<br><br>METHODS: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques.<br><br>RESULTS: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia.<br><br>CONCLUSION: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population.}, }
@article {pmid30480814, year = {2019}, author = {Qiao, J and Chen, L and Huang, X and Guo, F}, title = {Effects of nebulized N--acetylcystein on the expression of HMGB1 and RAGE in rats with hyperoxia--induced lung injury.}, journal = {Journal of cellular physiology}, volume = {234}, number = {7}, pages = {10547-10553}, doi = {10.1002/jcp.27724}, pmid = {30480814}, issn = {1097-4652}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; HMGB1 Protein/*genetics ; Humans ; Hyperoxia/complications/*drug therapy/genetics/pathology ; Lung/drug effects/pathology ; Lung Injury/*drug therapy/etiology/genetics/pathology ; NF-kappa B/genetics ; Nebulizers and Vaporizers ; Rats ; Receptor for Advanced Glycation End Products/*drug effects ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/genetics ; }, abstract = {OBJECTIVE: To investigate the role of high mobility group box 1 (HMGB1) and receptor for advanced glycation end product (RAGE) in the lungs of hyperoxia-induced rats and the effect of N--acetlycystein (NAC).<br><br>METHODS: A model of hyperoxic lung injury was established, rats in the NAC intervention, and control, hyperoxia group were given nebulized NAC aerosol, nebulized same volume of saline once a day for 7 consecutive days, respectively. Wet/dry (W/ D) ratio of the lungs was determined to evaluate the edema of the lung tissues. Conventional hematoxylin-eosin (HE) staining was used to observe the pathological changes of lung tissues. Immunohistochemical staining was used to investigate the expression of HMGB1 and RAGE in the lung tissues. Quantitative reverse-transcription polymerase chain reaction and western blot analysis were used to measured the changes in the messenger RNA (mRNA) and protein expression of HMGB1 and RAGE, respectively.<br><br>RESULTS: Weight gain of the rats in the hyperoxia group was significantly slower than that in the control group and intervention group (p&#x2009;<&#x2009;0.05). HE staining results showed lung tissues in the hyperoxia group were severely damaged compared with control group. W/D ratio in hyperoxia group was significantly higher than that in control group and intervention group (p&#x2009;<&#x2009;0.05). Protein and mRNA expression of HMGB1 and RAGE in the hyperoxia group were significantly higher than control group and intervention group (p&#x2009;<&#x2009;0.05).<br><br>CONCLUSION: HMGB1 and RAGE were involved in the pathogenesis of hyperoxia-induced lung injury, inhalation of NAC might alleviate hyperoxia-induced lung injury by regulating the expression of HMGB1 and RAGE.}, }
@article {pmid30477535, year = {2018}, author = {Gil-Martínez, AL and Cuenca, L and Sánchez, C and Estrada, C and Fernández-Villalba, E and Herrero, MT}, title = {Effect of NAC treatment and physical activity on neuroinflammation in subchronic Parkinsonism; is physical activity essential?.}, journal = {Journal of neuroinflammation}, volume = {15}, number = {1}, pages = {328}, pmid = {30477535}, issn = {1742-2094}, support = {FIS PI13 01293//Ministerio de Educaci&#xf3;n, Cultura y Deporte/ ; 19540/PI/14//Fundaci&#xf3;n S&#xe9;neca/ ; 115009//FP7 Ideas: European Research Council/ ; }, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology ; Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Calcium-Binding Proteins/metabolism ; Disease Models, Animal ; Encephalitis/drug therapy/etiology/pathology/*rehabilitation ; Glial Fibrillary Acidic Protein/metabolism ; Imaging, Three-Dimensional ; Male ; Mice ; Mice, Inbred C57BL ; Microfilament Proteins/metabolism ; Microscopy, Confocal ; Neuroprostanes/*therapeutic use ; Parkinsonian Disorders/chemically induced/*complications ; Physical Conditioning, Animal/*methods/physiology ; S100 Calcium Binding Protein beta Subunit/metabolism ; Substantia Nigra/drug effects/pathology ; Time Factors ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {BACKGROUND: Neuroprotective strategies are becoming relevant to slow down dopaminergic cell death and inflammatory processes related to the progressive neurodegeneration in Parkinson's disease (PD). Interestingly, among others, physical activity (PA) or anti-oxidant agents (such as N-acetyl-L-cysteine, NAC) are common therapeutic strategies. Therefore, this study aims to analyze if there is a synergistic effect of physical activity along with NAC treatment on dopaminergic degeneration and neuroinflammatory response in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism model after subchronic intoxication.<br><br>METHODS: To ascertain this possibility, 48 8-week-old male mice (C57BL/6 strain) were used. Twenty four of them were placed individually in cages where voluntary physical activity was automatically monitored during 30&#xa0;days and were divided into groups: (i) control; (ii) NAC; (iii) MPTP, and (iv) MPTP+NAC. The other 24 mice were divided into the same four groups but without physical activity.<br><br>RESULTS: The data collected during the treatment period showed that there was an overall increase in the total running distance in all groups under physical activity, including Parkinsonian animals. However, the monitoring data per day showed that the activity routine by MPTP and MPTP+NAC groups was disrupted by alterations in the circardian rhythm because of MPTP intoxication. Results from post-mortem studies in the substantia nigra pars compacta (SNpc) showed significant decrease in the number of TH+ cells in all MPTP groups. Moreover, TH+ expression in the striatum was significantly decreased in all MPTP groups. Thus, PA&#x2009;+&#x2009;NAC treatment do not protect dopaminergic neurons against a subchronic intoxication of MPTP. Regarding glial response, the results obtained from microglial analysis do not show significant increase in the number of Iba-1+ cell in MPTP+NAC and MPTP+PA&#x2009;+&#x2009;NAC. In the striatum, a significant decrease is observed only in the MPTP+NAC group compared with that of the MPTP group. The microglial results are reinforced by those obtained from the analysis of astroglial response, in which a decrease in the expression of GFAP+ cells are observed in MPTP+NAC and MPTP+PA&#x2009;+&#x2009;NAC compared with MPTP groups both in the SNpc and in the striatum. Finally, from the study of the astroglial response by the co-localization of GFAP/S100b, we described some expression patterns observed based on the severity of the damage produced by the MPTP intoxication in the different treated groups.<br><br>CONCLUSIONS: These results suggest that the combination of physical activity with an anti-oxidant agent does not have a synergistic neuroprotective effect in the nigrostriatal pathway. Our results show a potential positive effect, only due to NAC treatment, on the neuroinflammatory response after subchronic MPTP intoxication. Thus, physical activity is not essential, under these conditions. However, we believe that physical activity, used for therapeutic purposes, has a beneficial long-term effect. In this line, these results open the door to design longer studies to demonstrate its promising effect as neuroprotective strategy.}, }
@article {pmid30477371, year = {2019}, author = {Mendonça, MCP and Ferreira, LB and Rizoli, C and Batista, &#xc2;G and Maróstica Júnior, MR and da Silva, EDN and Cadore, S and Durán, N and Cruz-Höfling, MAD and de Jesus, MB}, title = {N-Acetylcysteine reverses silver nanoparticle intoxication in rats.}, journal = {Nanotoxicology}, volume = {13}, number = {3}, pages = {326-338}, doi = {10.1080/17435390.2018.1544302}, pmid = {30477371}, issn = {1743-5404}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Humans ; Injections, Intraperitoneal ; Injections, Intravenous ; Liver/*drug effects ; Male ; Metal Nanoparticles/chemistry/*toxicity ; Rats ; Silver/chemistry/*toxicity ; }, abstract = {The increasing use of silver nanoparticles (AgNPs) in consumer products raises the risk of human toxicity. Currently, there are no therapeutic options or established treatment protocols in cases of AgNPs intoxication. We demonstrated previously that thiol antioxidants compounds can reverse the cytotoxicity induced by AgNPs in Huh-7 hepatocarcinoma cells. Here, we investigated the use of N-acetylcysteine (NAC) against the systemic toxic effects of AgNPs (79.3 nm) in rats. Biochemical, histopathological, hematological, and oxidative parameters showed that a single intravenous injection of AgNPs (5 mg/kg b.w.) induced deleterious effects such as hepatotoxicity, potentially as a result of AgNPs accumulation in the liver. Treatment with a single intraperitoneal injection of NAC (1 g/kg b.w.) one hour after AgNPs exposure significantly attenuated all toxic effects evaluated and altered the bioaccumulation and release patterns of AgNPs in rats. The findings show that NAC may be a promising candidate for clinical management of AgNPs intoxication.}, }
@article {pmid30471141, year = {2019}, author = {Pickering, G and Macian, N and Papet, I and Dualé, C and Coudert, C and Pereira, B}, title = {N-acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double-blind controlled trial in healthy subjects.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {33}, number = {3}, pages = {303-311}, doi = {10.1111/fcp.12437}, pmid = {30471141}, issn = {1472-8206}, support = {//University Hospital of Clermont-Ferrand/ ; }, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/*pharmacology ; Adult ; Analgesics, Non-Narcotic/*pharmacology ; Antidotes/pharmacology ; Chemical and Drug Induced Liver Injury/etiology ; Cross-Over Studies ; Double-Blind Method ; Drug Interactions ; Expectorants/pharmacology ; Glutathione/*metabolism ; Humans ; Male ; Pain/drug therapy ; Pain Measurement ; Young Adult ; }, abstract = {Paracetamol (APAP) may lead to hepatic changes even at therapeutic dosages. Glutathione (GSH) plays a pivotal role in APAP metabolism as it allows the detoxification of a toxic metabolite. N-Acetylcysteine (NAC) is APAP antidote, is also largely used as a mucoactive drug and is often associated with APAP. This study aims at evaluating if 1- NAC modifies APAP pain efficacy and 2- NAC prevents glutathione depletion with APAP at therapeutic doses. This double-blind randomized controlled study (NCT02206178) was carried out in 24 healthy volunteers. APAP was given for 4 days (1 g ×4 daily) with NAC or with placebo. Thermal pain tests, whole blood GSH, and hepatic enzymes (ASAT, ALAT) were measured before (D0) and after (D4) oral APAP-NAC or APAP-placebo intake. anova for repeated measures adapted to cross-overdesign was performed and a two-tailed type I error was fixed at 5%. The primary endpoint was the area under the curve (0-240 min) of pain intensity (Numerical Scale) after thermal pain stimulation using Pathway-Medoc[®] . APAP antinociceptive effect was similar in both groups. GSH was maintained to its baseline value in the APAP/NAC group but diminished in the APAP/placebo group (P = 0.033). This study shows for the first time that APAP antinociceptive effectiveness is not influenced by NAC. It also shows that the effect of APAP at therapeutic dosage on GSH may be counteracted by NAC. These issues are particularly important for patients as APAP is often prescribed for years as a first-line pain treatment and further trials in patients are now warranted.}, }
@article {pmid30468498, year = {2018}, author = {Wang, JY and Wang, X and Wang, XJ and Zheng, BZ and Wang, Y and Wang, X and Liang, B}, title = {Curcumin inhibits the growth via Wnt/β-catenin pathway in non-small-cell lung cancer cells.}, journal = {European review for medical and pharmacological sciences}, volume = {22}, number = {21}, pages = {7492-7499}, doi = {10.26355/eurrev_201811_16290}, pmid = {30468498}, issn = {2284-0729}, mesh = {A549 Cells ; Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Curcumin/*pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism ; Humans ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; Superoxide Dismutase/metabolism ; Wnt Signaling Pathway/*drug effects ; beta Catenin/*physiology ; }, abstract = {OBJECTIVE: In recent decades, the death rate from lung cancer appears to be an increasing yearly trend, particularly for non-small-cell lung cancer (NSCLC). Curcumin is a yellow pigment found in turmeric rhizomes, reported to exhibit various anti-inflammatory, anti-angiogenic, anti-proliferative, and antioxidant properties. Many reports have suggested that curcumin could induce apoptosis in malignant cells, and therefore, has great potential in tumor treatment. However, little is known about the effect of curcumin on NSCLC or its associated mode of action. Therefore, in this study, we explored curcumin's effect on NSCLC and investigated its associated mechanism.<br><br>MATERIALS AND METHODS: The non-small-cell lung cancer (NSCLC) cell line A549 was cultured and subjected to MTT and clonogenic survival assays to assess cell proliferation. Reactive oxygen species (ROS) levels were measured using a Fluostar Omega Spectrofluorimeter. Superoxide dismutase (SOD) and &#x3b3;-glutamyl cysteine synthetase (&#x3b3;-GCS) activity in A549 cells were both determined by a commercial determination kit. Expression levels of p-GSK3&#x3b2; (Ser9), c-Myc, cyclin D1, &#x3b2;-catenin &#x3b1;-tubulin, and proliferating cell nuclear antigen (PCNA) were analyzed by Western blot.<br><br>RESULTS: Results of the MTT and clonogenic survival assay indicated that curcumin reduced A549 proliferation. ROS levels and SOD and &#x3b3;-GCS activities were detected. Curcumin decreased intracellular ROS levels and increased SOD and &#x3b3;-GCS activity. Meanwhile, the ROS inhibitor N-Acetylcysteine (NAC) reversed the decrease in ROS levels and the increase in SOD and &#x3b3;-GCS activity. These results indicate that oxidative stress is involved in the curcumin-induced reduction of A549 viability. Curcumin also strongly inhibited &#x3b2;-catenin and p-GSK3&#x3b2; (Ser9) protein expression, as well as the expression of downstream cyclin D1 and c-Myc. Similarly, NAC reversed the inhibition of &#x3b2;-catenin and p-GSK3&#x3b2; (Ser9) protein expression, as well as the expression of downstream cyclin D1 and c-Myc.<br><br>CONCLUSIONS: We showed that curcumin inhibits NSCLC proliferation via the Wnt/&#x3b2;-catenin pathway.}, }
@article {pmid30466977, year = {2018}, author = {Pavithra, PS and Mehta, A and Verma, RS}, title = {Induction of apoptosis by essential oil from P. missionis in skin epidermoid cancer cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {50}, number = {}, pages = {184-195}, doi = {10.1016/j.phymed.2017.11.004}, pmid = {30466977}, issn = {1618-095X}, mesh = {Apoptosis/*drug effects ; Azulenes ; Carcinoma, Squamous Cell/drug therapy ; Caspases/metabolism ; Cell Cycle ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Oils, Volatile/*pharmacology ; Plant Oils/*pharmacology ; Polycyclic Sesquiterpenes ; Reactive Oxygen Species/metabolism ; Rutaceae/*chemistry ; Sesquiterpenes ; Signal Transduction/drug effects ; Spheroids, Cellular ; }, abstract = {BACKGROUND: The genus Pamburus (Rutaceae) comprises the only species, Pamburus missionis (Wight) Swingle. Pamburus missionis is traditionally used in the treatment of swellings, chronic rheumatism, paralysis and puerperal diseases.<br><br>PURPOSE: The present study investigates the cancer chemotherapeutic potential of essential oil (EO) from P. missionis.<br><br>METHODS: EO was isolated by steam distillation and chemical composition was determined by GC-MS. Cell viability was used to detect cytotoxic activity. Mechanism of cell death was studied using Annexin V-FITC/PI binding, cell cycle analysis, measurement of MMP and ROS generation by flow cytometry. Expression of apoptosis related proteins was investigated by western blot.<br><br>RESULTS: GC-MS analysis of the essential oil revealed the presence of 51 components. The major components were &#x3b2;-Caryophyllene, 4(14),11-Eudesmadiene, Aromadendrene oxide-(2) and Phytol. EO inhibited the growth and colony formation ability of A431 and HaCaT cells. EO treatment induced nuclear condensation and loss of membrane integrity, DNA fragmentation, increase in sub-G1 DNA content and increase in intracellular ROS level. Inhibition of intracellular ROS by ascorbic acid and N-acetyl cysteine treatment blocked EO induced apoptosis, revealing that apoptotic activity was by ROS accumulation. EO induced apoptosis was found to be due to the loss of mitochondrial membrane potential (&#x394;&#x3a8;m), increase in Bax/Bcl-2 ratio, release of cytochrome c and activation of caspases (cleaved form of caspase-3, caspase-8, caspase-9) and by PARP cleavage.<br><br>CONCLUSION: The present study revealed cancer chemotherapeutic potential of EO from P. missionis. EO induces cell death through intrinsic (mitochondrial) and extrinsic apoptotic pathway in A431 and HaCaT cells. These results suggest that EO could be used as a potential therapeutic agent for the treatment of skin epidermoid cancer.}, }
@article {pmid30466002, year = {2019}, author = {de Souza, GR and De-Oliveira, ACAX and Soares, V and Chagas, LF and Barbi, NS and Paumgartten, FJR and da Silva, AJR}, title = {Chemical profile, liver protective effects and analgesic properties of a Solanum paniculatum leaf extract.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {110}, number = {}, pages = {129-138}, doi = {10.1016/j.biopha.2018.11.036}, pmid = {30466002}, issn = {1950-6007}, mesh = {Acetaminophen/toxicity ; Analgesics/isolation &amp; purification/*pharmacology/therapeutic use ; Analgesics, Non-Narcotic/toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*metabolism/*prevention &amp; control ; Dose-Response Relationship, Drug ; Lipid Peroxidation/drug effects/physiology ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Pain Measurement/drug effects/methods ; Plant Extracts/isolation &amp; purification/*pharmacology/therapeutic use ; *Plant Leaves ; *Solanum ; }, abstract = {BACKGROUND/AIM: Solanum paniculatum L. (Solanaceae) is a plant native to South America where it is used in traditional medicine for different therapeutic indications. This study evaluated the chemical composition and the hepatoprotective and analgesic activities of S. paniculatum leaf extracts.<br><br>MATERIAL AND METHODS: The chemical profile of an ethyl acetate partition (SPOE) of a S. paniculatum leaf infusion (SPAE) was analysed by high performance liquid chromatography coupled to high-resolution electrospray mass spectrometry (HPLC-ESIMS). Liver protective effects of SPAE (600 and 1200&#x2009;mg/kg bw, po), or SPOE (300&#x2009;mg/kg bw, po) were evaluated in a C57BL/6 mouse model of acetaminophen (AP, 600&#x2009;mg/kg bw, ip) hepatotoxicity by measuring alanine (ALT) and aspartate (AST) aminotransferase activity in the serum, and reduced glutathione (GSH), and thiobarbituric acid reactive species (TBARs) levels in the hepatic tissue.<br><br>RESULTS: HPLC-ESIMS analysis of the SPOE fraction tentatively identified 35 flavonoids, esters of hydroxycinnamic acid and isomers of chlorogenic acid. SPAE (600 and 1200&#x2009;mg/kg bw) and SPOE (300&#x2009;mg/kg bw) antagonized the rise in ALT and AST, and the depletion of GSH, and elevation of TBARs levels in the liver caused by AP. The liver protective effects of SPOE (300&#x2009;mg/kg bw) against AP-induced liver toxicity mimicked those of N-acetyl-cysteine (NAC 300 or 600&#x2009;mg/kg bw ip). The mouse writhing assay showed that SPOE (300&#x2009;mg/kg bw po) has anti-nociceptive effects comparable to those of AP (180&#x2009;mg/kg bw po).<br><br>CONCLUSION: This study suggests that an extract of S. paniculatum leaves (SPOE), rich in phenolic compounds, is a promising herbal drug to prevent and treat AP poisoning and presents analgesic properties as well.}, }
@article {pmid30465824, year = {2019}, author = {Xu, MX and Ge, CX and Qin, YT and Gu, TT and Lou, DS and Li, Q and Hu, LF and Feng, J and Huang, P and Tan, J}, title = {Prolonged PM2.5 exposure elevates risk of oxidative stress-driven nonalcoholic fatty liver disease by triggering increase of dyslipidemia.}, journal = {Free radical biology &amp; medicine}, volume = {130}, number = {}, pages = {542-556}, doi = {10.1016/j.freeradbiomed.2018.11.016}, pmid = {30465824}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/toxicity ; Animals ; Dyslipidemias/*drug therapy/metabolism/pathology ; Hepatocytes/drug effects ; Humans ; Inflammation/*drug therapy/metabolism/pathology ; Insulin Resistance/genetics ; Lipid Metabolism/drug effects ; Liver/drug effects/metabolism ; Metabolic Syndrome/drug therapy/metabolism/pathology ; Mice ; Non-alcoholic Fatty Liver Disease/*drug therapy/metabolism/pathology ; Oxidative Stress/*drug effects ; Particulate Matter/chemistry/*toxicity ; Pyrrolidines/pharmacology ; Signal Transduction/drug effects ; Thiocarbamates/pharmacology ; }, abstract = {An increasing number of studies have shown that air pollution containing particulate matter (PM) ≤ 2.5 µm (PM2.5) plays a significant role in the development of metabolic disorder and other chronic diseases. Inflammation and oxidative stress caused by metabolic syndrome are widely determined to be critical factors in the development of nonalcoholic fatty liver disease (NAFLD) pathogenesis. However, there is no direct evidence of this, and the underlying molecular mechanism is still not fully understood. In this study, we investigated the role of inflammation and oxidative stress caused by prolonged PM2.5 exposure in dyslipidemia-associated chronic hepatic injury, and further determined whether an increase in hepatic inflammation and oxidative stress promoted lipid accumulation in the liver, ultimately increasing the risk of NAFLD. Therefore, we studied changes in indicators of metabolic disorder and in symbolic indices of NAFLD. We confirmed increases in insulin resistance, glucose tolerance, peripheral inflammation and dysarteriotony in PM2.5-induced mice. Oxidative stress and inflammatory response in the liver caused by PM2.5 inhalation contributed to abnormal hepatic function, further promoting lipid accumulation in the liver. Moreover, we observed inhibition of oxidative stress and inflammatory response by pyrrolidine dithiocarbamate (PDTC) and N-acetyl-L-cysteine (NAC) in vitro, suggesting that oxidative stress and inflammatory in liver cells aggravated by PM2.5 contributed to hepatic injury by altering normal lipid metabolism. These results indicate a new goal for preventing and treating air pollution-induced diseases: suppression of oxidative stress and inflammatory response.}, }
@article {pmid30465316, year = {2019}, author = {Marin, EH and Paek, H and Li, M and Ban, Y and Karaga, MK and Shashidharamurthy, R and Wang, X}, title = {Caffeic acid phenethyl ester exerts apoptotic and oxidative stress on human multiple myeloma cells.}, journal = {Investigational new drugs}, volume = {37}, number = {5}, pages = {837-848}, pmid = {30465316}, issn = {1573-0646}, mesh = {Antioxidants/metabolism ; Apoptosis/*drug effects ; Biomarkers, Tumor/*genetics ; Caffeic Acids/*pharmacology ; Cell Movement ; Cell Proliferation/drug effects ; Gene Expression Profiling ; Humans ; Multiple Myeloma/drug therapy/genetics/*pathology ; Oxidative Stress/*drug effects ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, abstract = {Caffeic acid phenethyl ester (CAPE) is a phenolic compound initially identified in bee glue. CAPE is reported to exhibit antitumor activity in many cancer models. However, the effect of CAPE on multiple myeloma (MM) is not well studied. We investigated the anti-myeloma effect of CAPE, and the data showed that CAPE inhibited the growth of human MM cells in a dose (1 ~ 30 μM) and time (24 ~72 h) dependent manner without altering the viability of normal human peripheral blood B cells. Stress and toxicity pathway analysis demonstrated that CAPE, in a dose- and time-related fashion, induced the expression of apoptotic and oxidative stress-response genes including growth arrest and DNA-damage inducible, alpha and gamma (GADD45A and GADD45G) and heme oxygenase-1. Apoptosis of MM cells by CAPE was further confirmed through flow cytometric analysis with up to 50% apoptotic cells induced by 50 μM CAPE within 24 h. Western blot analysis revealed the CAPE-induced activation of apoptosis executioner enzyme caspase-3, and corresponding cleavage of its downstream target poly(ADP-ribose)polymerase (PARP). The oxidative stress caused by CAPE cytotoxicity in MM cells was evaluated through measurement of reactive oxygen species (ROS) level, antioxidant intervention and glutathione depletion. The intracellular ROS level was not elevated by CAPE, but the pretreatment of antioxidant (N-acetyl cysteine) and glutathione synthesis inhibitor (buthionine sulfoximine) suggested that CAPE may cause oxidative stress by decrease of intracellular antioxidant level rather than over production of ROS. These data suggest that CAPE promotes apoptosis through oxidative stress in human multiple myeloma cells.}, }
@article {pmid30464456, year = {2018}, author = {Lee, D and Heo, DN and Nah, HR and Lee, SJ and Ko, WK and Lee, JS and Moon, HJ and Bang, JB and Hwang, YS and Reis, RL and Kwon, IK}, title = {Injectable hydrogel composite containing modified gold nanoparticles: implication in bone tissue regeneration.}, journal = {International journal of nanomedicine}, volume = {13}, number = {}, pages = {7019-7031}, pmid = {30464456}, issn = {1178-2013}, mesh = {Acetylcysteine/pharmacology ; Adipose Tissue/cytology ; Alkaline Phosphatase/metabolism ; Bone Regeneration/*drug effects ; Bone and Bones/drug effects/*physiology ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Gelatin/chemistry ; Gold/*chemistry ; Humans ; Hydrogels/*pharmacology ; *Injections ; Metal Nanoparticles/*chemistry ; Osteogenesis/drug effects ; Stem Cells/cytology/drug effects/metabolism ; }, abstract = {BACKGROUND: For effective bone regeneration, it is necessary to implant a biocompatible scaffold that is capable of inducing cell growth and continuous osteogenic stimulation at the defected site. Here, we suggest an injectable hydrogel system using enzymatic cross-linkable gelatin (Gel) and functionalized gold nanoparticles (GNPs).<br><br>METHODS: In this work, tyramine (Ty) was synthesized on the gelatin backbone (Gel-Ty) to enable a phenol crosslinking reaction with horseradish peroxidase (HRP). N-acetyl cysteine (NAC) was attached to the GNPs surface (G-NAC) for promoting osteodifferentiation.<br><br>RESULTS: The Gel-Ty hydrogels containing G-NAC (Gel-Ty/G-NAC) had suitable mechanical strength and biocompatibility to embed and support the growth of human adipose derived stem cells (hASCs) during a proliferation test for three days. In addition, G-NAC promoted osteodifferentiation both when it was included in Gel-Ty and when it was used directly in hASCs. The osteogenic effects were demonstrated by the alkaline phosphatase (ALP) activity test.<br><br>CONCLUSION: These findings indicate that the phenol crosslinking reaction is suitable for injectable hydrogels for tissue regeneration and G-NAC stimulate bone regeneration. Based on our results, we suggest that Gel-Ty/G-NAC hydrogels can serve both as a biodegradable graft material for bone defect treatment and as a good template for tissue engineering applications such as drug delivery, cell delivery, and various tissue regeneration uses.}, }
@article {pmid30458452, year = {2018}, author = {Liu, HJ and Wang, L and Kang, L and Du, J and Li, S and Cui, HX}, title = {Sulforaphane-N-Acetyl-Cysteine Induces Autophagy Through Activation of ERK1/2 in U87MG and U373MG Cells.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {51}, number = {2}, pages = {528-542}, doi = {10.1159/000495274}, pmid = {30458452}, issn = {1421-9778}, mesh = {Acetylcysteine/*analogs &amp; derivatives/metabolism/*pharmacology ; Anticarcinogenic Agents/*pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Databases, Factual ; Flavonoids/pharmacology ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Isothiocyanates/metabolism/*pharmacology ; MAP Kinase Signaling System/drug effects ; Microtubule-Associated Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3/*metabolism ; Proportional Hazards Models ; RNA Interference ; RNA, Small Interfering/metabolism ; Sulfoxides ; Tubulin/genetics/metabolism ; }, abstract = {BACKGROUND/AIMS: Sulforaphane-N-acetyl-cysteine (SFN-NAC) is a sulforaphane (SFN) metabolite with a longer half-life and better blood-brain barrier permeability than those of SFN. Previous studies have found that SFN-NAC can act via ERK to destroy microtubules and inhibit cell growth in lung cancer cells. However, the underlying mechanisms are unclear, and it is unknown whether SFN-NAC can inhibit the growth of glioma. Here, we have demonstrated for the first time that SFN-NAC activates autophagy-mediated downregulation of α-tubulin expression via the ERK pathway.<br><br>METHODS: U87MG and U373MG cells, two widely used glioma cell lines, were utilized in this study. Apoptosis assay, western blot analysis, co-immunoprecipitation, immunostaining, and electron microscopy were used to analyze the effect of SFN-NAC on &#x3b1;-tubulin and its interaction with microtube-associated protein 1 light-chain 3 (LC3).<br><br>RESULTS: SFN-NAC induced cell-cycle arrest in the G2/M phase and dose-dependently induced intracellular ERK activation, autophagy, and &#x3b1;-tubulin downregulation. These SFN-NAC-induced effects were reversed by inhibiting the ERK pathway with its inhibitor PD98059. U87MG and U373MG cells were transfected with LC3 small interfering RNA, and the subsequent inhibition of autophagy reversed the downregulation of &#x3b1;-tubulin by SFN-NAC. Furthermore, co-immunoprecipitation experiments and confocal microscopy confirmed that SFN-NAC promotes the binding of LC3 with &#x3b1;-tubulin in the cytoplasm. Cell viability experiments demonstrate that SFN-NAC inhibits the growth of U87MG and U373MG cell colonies.<br><br>CONCLUSION: These findings suggest that SFN-NAC is a novel potential anti-glioma agent.}, }
@article {pmid30458268, year = {2019}, author = {De, U and Son, JY and Jeon, Y and Ha, SY and Park, YJ and Yoon, S and Ha, KT and Choi, WS and Lee, BM and Kim, IS and Kwak, JH and Kim, HS}, title = {Plumbagin from a tropical pitcher plant (Nepenthes alata Blanco) induces apoptotic cell death via a p53-dependent pathway in MCF-7 human breast cancer cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {123}, number = {}, pages = {492-500}, doi = {10.1016/j.fct.2018.11.040}, pmid = {30458268}, issn = {1873-6351}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*administration &amp; dosage/chemistry/isolation &amp; purification ; Apoptosis/*drug effects ; Breast Neoplasms/*drug therapy/genetics/metabolism/physiopathology ; Caryophyllales/*chemistry ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Humans ; MCF-7 Cells ; Mice, Inbred BALB C ; Mice, Nude ; Naphthoquinones/*administration &amp; dosage/chemistry/isolation &amp; purification ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {Plumbagin (5-hydroxy-2-methyl-1,4-naphthaquinone) has displayed antitumor activity in vitro and in animal models; however, the underlying molecular mechanisms have not been fully explored. The aim of this study was to investigate the anticancer effects of plumbagin isolated from Nepenthes alata against MCF-7 breast cancer cells. We examined the cytotoxicity, cell cycle regulation, apoptotic cell death, and generation of intracellular reactive oxygen species (ROS) in MCF-7 cells. Plumbagin exhibited potent cytotoxicity in MCF-7 cells (wild-type p53) compared to that in SK-OV-3 (null-type) human epithelial ovarian cancer cells. Specifically, plumbagin upregulated the expression of p21[CIP1/WAF1] in MCF-7 cells, causing cell cycle arrest in the G2/M phase through inhibition of cyclin B1 levels. Plumbagin also significantly increased the ratio of Bax/Bcl-2 and release of cytochrome c, resulting in apoptotic cell death in MCF-7 cells. Furthermore, plumbagin dramatically increased the intracellular ROS level, whereas pretreatment with the ROS scavenger N-acetyl cysteine protected against plumbagin-induced cytotoxicity, suggesting that ROS formation plays a pivotal role in antitumor activity in MCF-7 cells. In mice bearing MCF-7 cell xenografts, plumbagin significantly reduced tumor growth and weight without apparent side effects. We therefore concluded that plumbagin exerts anticancer activity against MCF-7 cells through the generation of intracellular ROS, resulting in the induction of apoptosis via a p53-dependent pathway. This study thus identifies a new anticancer mechanism of plumbagin against p53-dependent breast cancer cells and suggests a novel strategy for overcoming of breast cancer therapy.}, }
@article {pmid30458253, year = {2019}, author = {Guo, L and Zhang, C and Chen, G and Wu, M and Liu, W and Ding, C and Dong, Q and Fan, E and Liu, Q}, title = {Reactive oxygen species inhibit biofilm formation of Listeria monocytogenes.}, journal = {Microbial pathogenesis}, volume = {127}, number = {}, pages = {183-189}, doi = {10.1016/j.micpath.2018.11.023}, pmid = {30458253}, issn = {1096-1208}, mesh = {Anti-Bacterial Agents/*pharmacology ; Biofilms/drug effects/*growth &amp; development ; Listeria monocytogenes/*drug effects/*growth &amp; development ; Oxidation-Reduction ; Reactive Oxygen Species/*pharmacology ; }, abstract = {Although the level of reactive oxygen species (ROS) is altered upon the formation of bacterial biofilm, the relationship between ROS alteration and biofilm formation is still unclear. The aim of the present study is to use Listeria monocytogenes (L. monocytogenes) as a model organism to examine whether ROS have an effect on the biofilm formation. After eliminating ROS by treatment with NAD(P)H oxidase inhibitor Diphenyleneiodonium chloride (DPI) or scavenging reagents N-acetylcysteine (NAC), the biofilm formation of L. monocytogenes was examined. Our data demonstrate that DPI and NAC induced-reduction of ROS enhances the biofilm formation in L. monocytogenes without affecting bacterial growth and activity. These data provide the evidence that ROS produced by L. monocytogenes inhibit the biofilm formation.}, }
@article {pmid30454901, year = {2018}, author = {Dawei, H and Honggang, D and Qian, W}, title = {AURKA contributes to the progression of oral squamous cell carcinoma (OSCC) through modulating epithelial-to-mesenchymal transition (EMT) and apoptosis via the regulation of ROS.}, journal = {Biochemical and biophysical research communications}, volume = {507}, number = {1-4}, pages = {83-90}, doi = {10.1016/j.bbrc.2018.10.170}, pmid = {30454901}, issn = {1090-2104}, mesh = {*Apoptosis ; Aurora Kinase A/*metabolism ; Carcinoma, Squamous Cell/*enzymology/*pathology ; Cell Line, Tumor ; Cell Proliferation/genetics ; *Disease Progression ; *Epithelial-Mesenchymal Transition ; Female ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Male ; Middle Aged ; Mouth Neoplasms/enzymology/*pathology ; Reactive Oxygen Species/*metabolism ; Up-Regulation/genetics ; }, abstract = {Oral squamous cell carcinoma (OSCC) is known as one of the most common cancer influencing the head and neck region. However, the molecular mechanisms revealing OSCC progression is largely unclear. Aurora kinase A (AURKA) is a serine-threonine kinase that functions in mitotic spindle formation and chromosome segregation, and is associated with the progression of human cancers. But its role in regulating OSCC development has not yet been investigated. In the study, we found that AURKA expression was up-regulated in OSCC cell lines and tumor specimens from patients. OSCC patients with high expression of AURKA exhibited a significant decreased overall survival rate. In vitro, AURKA knockdown markedly reduced the proliferation, migration and invasion of OSCC cells using cell counting kit-8 (CCK-8), EdU, colony formation and transwell analysis. EMT was suppressed by AURKA silence, as evidenced by the up-regulated expression of E-cadherin and down-regulated Vimentin in OSCC cells. In addition, apoptosis was markedly induced by AURKA inhibition through promoting the expression of cleaved Caspase-3 and poly (ADP)-ribose polymerase (PARP). Reactive oxygen species (ROS) production was also markedly enhanced in AURKA-knockdown OSCC cells. Importantly, we found that repressing ROS generation using its scavenger of n-acetylcysteine (NAC) significantly abolished AURKA silence-induced apoptosis, accompanied with restored proliferation and EMT. In vivo, AURKA knockdown notably inhibited tumor growth. Therefore, knockdown of AURKA suppressed cell proliferation, migration and invasion, and also induced apoptosis and ROS generation in OSCC possibly via the production of ROS, demonstrating that AURKA inhibition might represent a novel therapeutic target for the prevention of OSCC.}, }
@article {pmid30453788, year = {2019}, author = {Wong, A and Homer, N and Dear, JW and Choy, KW and Doery, J and Graudins, A}, title = {Paracetamol metabolite concentrations following low risk overdose treated with an abbreviated 12-h versus 20-h acetylcysteine infusion.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {57}, number = {5}, pages = {312-317}, doi = {10.1080/15563650.2018.1517881}, pmid = {30453788}, issn = {1556-9519}, mesh = {Acetaminophen/blood/pharmacokinetics/*poisoning ; Acetylcysteine/*administration &amp; dosage/adverse effects ; Adolescent ; Adult ; Analgesics, Non-Narcotic/blood/pharmacokinetics/*poisoning ; Antidotes/*administration &amp; dosage/adverse effects ; Biotransformation ; Chemical and Drug Induced Liver Injury/blood/diagnosis/*prevention &amp; control ; *Drug Overdose ; Female ; Humans ; Infusions, Intravenous ; Male ; Poisoning/blood/diagnosis/*drug therapy ; Treatment Outcome ; Victoria ; Young Adult ; }, abstract = {CONTEXT: To compare degree of liver injury and paracetamol metabolite concentrations after treatment with standard of care (20-h) vs. abbreviated (12-h) acetylcysteine regimens used in paracetamol overdose (NACSTOP trial).<br><br>METHODS: Timed blood samples from a cohort of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-h acetylcysteine regimen (200&#x2009;mg/kg over 4&#x2009;h, 50&#x2009;mg/kg over 8&#x2009;h) were assayed for paracetamol metabolites as a pilot study, using liquid chromatography/mass spectrometry. Control group subjects received a 20-h course of acetylcysteine (200&#x2009;mg/kg over 4&#x2009;h, 100&#x2009;mg/kg over 16&#x2009;h). The intervention group received a 12-h acetylcysteine regimen (stopped after at least 12&#x2009;h of treatment). Positive control groups not in the trial with acute liver injury (ALI) or hepatotoxicity were also studied.<br><br>RESULTS: One hundred and forty-one blood samples were collected from 40 patients receiving acetylcysteine after paracetamol overdose. Median ALT after 20&#x2009;h of acetylcysteine was 12&#x2009;U/L (IQR 8.14) in the abbreviated regimen group, compared to the control group 16&#x2009;U/L (IQR 11.21) (p&#x2009;=&#x2009;.46). There was no significant difference in median metabolite concentrations on presentation and after 20&#x2009;h of acetylcysteine between these two groups (p&#x2009;>&#x2009;.05). Presentation median sum CYP-metabolite/total metabolite percentages were 2.5 and 3.0 in the abbreviated and control NACSTOP groups, respectively.<br><br>CONCLUSIONS: An abbreviated 12-h acetylcysteine regimen for paracetamol overdose used in the NACSTOP trial had similar circulating metabolite concentrations compared to a 20-h regimen in selected subjects with low risk of hepatotoxicity. This suggests that further acetylcysteine may not be needed in the abbreviated group at time of cessation.}, }
@article {pmid30452899, year = {2019}, author = {Pei, X and Xiao, J and Wei, G and Zhang, Y and Lin, F and Xiong, Z and Lu, L and Wang, X and Pang, G and Jiang, Y and Jiang, L}, title = {Oenothein B inhibits human non-small cell lung cancer A549 cell proliferation by ROS-mediated PI3K/Akt/NF-κB signaling pathway.}, journal = {Chemico-biological interactions}, volume = {298}, number = {}, pages = {112-120}, doi = {10.1016/j.cbi.2018.09.021}, pmid = {30452899}, issn = {1872-7786}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/administration &amp; dosage/*pharmacology ; Apoptosis/drug effects/physiology ; Caspases/metabolism ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Hydrolyzable Tannins/administration &amp; dosage/*pharmacology ; I-kappa B Proteins/metabolism ; NF-kappa B/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Oenothein B has a wide range of biological activities. The present study probed into the underlying mechanism on how Oenothein B inhibits the proliferation of a lung cancer line A549. Our results showed that Oenothein B effectively inhibited the proliferation of A549 cells by inducing apoptosis and arresting cells at G1 stage. Furthermore, Oenothein B not only increased the level of intracellular reactive oxygen species (ROS), but also induced the upregulation of intracellular apoptotic triggers (cleavage caspase-3, PARP, cytochrome c level in the cytosol, Bax). Moreover, ROS inhibitor (N-acetyl-L-cystein, NAC) and PI3K agonist (Insulin-like growth factor 1, IGF-1) could resist cell proliferation inhibition induced by Oenothein B, respectively. ROS inhibitor significantly abrogated the activation of caspase 3/7 and 9 in the presence of Oenothein B. Additionally, suppression of p-PI3K and p-Akt, p-NF-κB by Oenothein B could be compensated by treatment with ROS inhibitor. To summarize, these results demonstrated that Oenothein B was able to prevent cell proliferation probably via ROS-mediated PI3K/Akt/NF-κB signaling pathway.}, }
@article {pmid30448838, year = {2018}, author = {Al-Nahdi, AMT and John, A and Raza, H}, title = {Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {51}, number = {1}, pages = {201-216}, doi = {10.1159/000495200}, pmid = {30448838}, issn = {1421-9778}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Electron Transport Complex IV/metabolism ; Glutamate Dehydrogenase/metabolism ; Glutathione/metabolism ; Hexokinase/metabolism ; Insulin Secretion/drug effects ; Insulin-Secreting Cells/cytology/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Oxidative Stress/*drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Protective Agents/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Streptozocin/pharmacology ; }, abstract = {BACKGROUND/AIMS: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic β-cells.<br><br>METHODS: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH-dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques.<br><br>RESULTS: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells.<br><br>CONCLUSION: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic &#x3b2;-cells against STZ-induced cytotoxicity.}, }
@article {pmid30447351, year = {2019}, author = {Li, C and Xie, N and Li, Y and Liu, C and Hou, FF and Wang, J}, title = {N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation.}, journal = {Free radical biology &amp; medicine}, volume = {130}, number = {}, pages = {512-527}, doi = {10.1016/j.freeradbiomed.2018.11.006}, pmid = {30447351}, issn = {1873-4596}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/chemically induced/drug therapy/metabolism/pathology ; Animals ; Antioxidants/pharmacology ; Cellular Senescence/drug effects ; Cisplatin/adverse effects ; Fibrosis/chemically induced/drug therapy/metabolism/pathology ; Humans ; Kidney/*metabolism/pathology ; Mice ; Oxidative Stress/drug effects ; Rats ; Renal Insufficiency, Chronic/chemically induced/*drug therapy/genetics/pathology ; Sirtuin 1/*genetics ; Tumor Suppressor Protein p53/*genetics ; }, abstract = {The mechanism underlying the development of chronic kidney disease (CKD) after acute kidney injury (AKI) remains unclear. Maladaptive repair has been considered an important mechanism of CKD post AKI. Renal tubular cells under maladaptive repair have characteristics of premature senescence. These premature senescent cells can generate profibrotic factors that promote organ fibrosis. The purpose of this study was to investigate whether cisplatin induces premature renal senescence and the role of premature renal senescence in the progression of CKD post AKI. As oxidative stress is a major cause of senescence, we further evaluated whether antioxidant therapy could protect renal tubular cells from cisplatin-induced premature senescence and retard the progression of CKD post AKI. The molecular mechanism of this protection was also investigated. We found that cisplatin induced premature renal senescence in vitro and in vivo. In a multiple-cisplatin-treatment murine model, renal interstitial fibrosis was accompanied by premature renal senescence. N-acetylcysteine (NAC), an antioxidant, attenuated premature senescence and decreased renal fibrosis, and its effects were dependent on sirtuin1 (SIRT1) activation and p53 deacetylation. These results indicate that cisplatin can induce premature renal senescence, which is associated with the development of CKD post cisplatin-induced AKI. SIRT1 activation and p53 deacetylation might be identified as potential targets for attenuating premature renal senescence and retarding the progression of CKD post AKI.}, }
@article {pmid30446769, year = {2019}, author = {Ghaderi, A and Bussu, A and Tsang, C and Jafarnejad, S}, title = {Effect of N-acetyl cysteine (NAC) supplementation on positive and negative syndrome scale in schizophrenia: a systematic review and meta-analysis of randomised controlled trials.}, journal = {European journal of clinical pharmacology}, volume = {75}, number = {3}, pages = {289-301}, pmid = {30446769}, issn = {1432-1041}, abstract = {OBJECTIVE: To conduct a systematic review and meta-analysis of published randomised controlled trials on the efficacy of NAC supplementation on positive and negative syndrome scale in schizophrenia.<br><br>METHODS: A meta-analysis was conducted, and studies were identified by a search of electronic databases from inception to May 2018. Combined and stratified analyses were used.<br><br>RESULTS: Seven trials were identified, and data from n&#x2009;=&#x2009;447 participants were included. Pooled analysis showed improvement of positive and negative syndrome scale following NAC treatment compared with placebo, for total (SMB&#x2009;=&#x2009;-&#x2009;0.96) [95% CI -&#x2009;1.69, -&#x2009;0.24; P&#x2009;=&#x2009;0.009], general (SMB&#x2009;=&#x2009;-&#x2009;1.04) [95% CI -&#x2009;1.80, -&#x2009;0.27; P&#x2009;=&#x2009;0.008] and negative (SMB&#x2009;=&#x2009;-&#x2009;0.73) [95% CI -&#x2009;1.29, -&#x2009;0.17; P&#x2009;=&#x2009;0.01] scores, respectively. Significant heterogeneity was found, and subgroup analysis showed significant reductions in studies with a treatment duration of &#x2264;&#x2009;24&#xa0;weeks, with a considerable effect size on total, general, and negative scores (Total SMD&#x2009;=&#x2009;-&#x2009;0.83; General SMD&#x2009;=&#x2009;-&#x2009;0.67; Negative SMD&#x2009;=&#x2009;-&#x2009;1.09) following NAC.<br><br>CONCLUSIONS: NAC improved all aspects of positive and negative syndrome scale in schizophrenic populations and may be more efficacious with treatment durations up to 24&#xa0;weeks.}, }
@article {pmid30446196, year = {2018}, author = {Jones, G and Keuthen, N and Greenberg, E}, title = {Assessment and treatment of trichotillomania (hair pulling disorder) and excoriation (skin picking) disorder.}, journal = {Clinics in dermatology}, volume = {36}, number = {6}, pages = {728-736}, doi = {10.1016/j.clindermatol.2018.08.008}, pmid = {30446196}, issn = {1879-1131}, mesh = {Acetylcysteine/therapeutic use ; Adolescent ; Antipsychotic Agents/therapeutic use ; Cognitive Behavioral Therapy ; Female ; Free Radical Scavengers/therapeutic use ; Humans ; Obsessive-Compulsive Disorder/*diagnosis/psychology/*therapy ; Self-Injurious Behavior/*diagnosis/psychology/*therapy ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Skin/injuries ; Trichotillomania/*diagnosis/*therapy ; Wounds and Injuries/etiology ; Young Adult ; }, abstract = {Recommendations are provided for the assessment and treatment of trichotillomania (hair pulling disorder, or HPD) and excoriation disorder (skin picking disorder, or SPD), two body-focused repetitive behavior (BFRB) disorders, based on their severity, comorbidities, and behavioral style. Habit reversal training (HRT) and stimulus control are first-line behavioral treatments that can be used in cases of all severity levels and may be particularly helpful when pulling or picking is performed with lowered awareness/intention. Acceptance and commitment therapy (ACT) and dialectical behavior therapy (DBT) are behavioral treatments that can be employed to augment HRT/stimulus control, especially when negative emotions trigger the pulling or picking. There are currently no FDA-approved pharmacologic treatments for HPD or SPD, though certain medications/supplements have shown varying degrees of efficacy in trials. N-acetylcysteine (NAC) should be considered for all severity levels and styles given its moderate gain/low side effect profile. Other pharmacologic interventions, including selective serotonin reuptake inhibitors (SSRIs), should be considered in cases with significant comorbidities or previous behavioral/NAC treatment failure.}, }
@article {pmid30443526, year = {2018}, author = {de Jesus Pires de Moraes, A and Andreato, LV and Branco, BHM and da Silva, EL and Gonçalves, MA and Dos Santos, RZ and Becker, AM and da Silveira Cavalcante, L and da Silva Casagrande, F and Benetti, M}, title = {Effects of N-acetylcysteine supplementation on cellular damage and oxidative stress indicators in volleyball athletes.}, journal = {Journal of exercise rehabilitation}, volume = {14}, number = {5}, pages = {802-809}, pmid = {30443526}, issn = {2288-176X}, abstract = {The purpose of this study was to evaluate the effects of N-acetylcysteine (NAC) supplementation on cellular damage and oxidative stress indicators in volleyball athletes. Twenty male volleyball athletes at national level performed a physical training session and were divided into 2 groups, which for 7 days took the placebo substance or NAC. After 7 days the athletes repeated the same training session. In both sessions, blood samples were collected 30 min before and immediately after the training session to measure cellular damage and oxidative stress markers. The main results show that, although higher concentrations of glutathione peroxidase and superoxide dismutase were observed in post-session 1 than those in postsession 2, the other markers showed an increase in antioxidant action after supplementation of NAC, once the effect of experimental conditions (P=0.030) were observed in: time effect (P<0.001) and interaction (P=0.019) for total glutathione; time effect (P<0.001) and interaction (P<0.001) for reduced glutathione; and time effect (P<0.001) for ferric-reducing antioxidant potential. The oxidant action indicated by the protein carbonyl was higher in the placebo group than in the NAC group (P=0.028), but a time effect (P<0.001) for the thiobarbituric acid reactive substances showed lower values in presession 1 than in presession 2. For the cellular damage markers, antagonistic results between markers were found. Based in the results, the supplementation of NAC during a short period was effective in reducing oxidant action and increasing antioxidant action. However, conclusive alterations in the responses of the cellular damage markers were not obtained.}, }
@article {pmid30442142, year = {2018}, author = {Hsieh Li, SM and Liu, ST and Chang, YL and Ho, CL and Huang, SM}, title = {Metformin causes cancer cell death through downregulation of p53-dependent differentiated embryo chondrocyte 1.}, journal = {Journal of biomedical science}, volume = {25}, number = {1}, pages = {81}, pmid = {30442142}, issn = {1423-0127}, support = {MAB-106-20//Ministry of National Defense-Medical Affairs Bureau/ ; MOST 105-2314-B-016-047//Ministry of Science and Technology, Taiwan/ ; A106-1017//Teh-Tzer Study Group for Human Medical Research Foundation/ ; }, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Basic Helix-Loop-Helix Transcription Factors/*genetics/metabolism ; Cell Line, Tumor ; Down-Regulation/*drug effects ; HeLa Cells ; Homeodomain Proteins/*genetics/metabolism ; Humans ; Hypoglycemic Agents/pharmacology ; Metformin/*pharmacology ; Mitochondria/physiology ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {BACKGROUND: Metformin is the most commonly used first-line medicine for type II diabetes mellitus. Acting via AMP-activated protein kinase, it has been used for more than 60 years and has an outstanding safety record. Metformin also offers protection against cancer, but its precise mechanisms remain unclear.<br><br>METHODS: We first examined the cytotoxic effects of metformin in the HeLa human cervical carcinoma and ZR-75-1 breast cancer cell lines using assays of cell viability, cleaved poly-ADP-ribose polymerase, and Annexin V-fluorescein isothiocyanate apoptosis, as well as flow cytometric analyses of the cell cycle profile and reactive oxygen species (ROS). We later clarified the effect of metformin on p53 protein stability using transient transfection and cycloheximide chase analyses.<br><br>RESULTS: We observed that metformin represses cell cycle progression, thereby inducing subG1 populations, and had induced apoptosis through downregulation of p53 protein and a target gene, differentiated embryo chondrocyte 1 (DEC1). In addition, metformin increased intracellular ROS levels, but N-acetyl cysteine, a ROS scavenger, failed to suppress metformin-induced apoptosis. Further results showed that metformin disrupted the electron transport chain and collapsed the mitochondrial membrane potential, which may be the cause of the elevated ROS levels. Examination of the mechanisms underlying metformin-induced HeLa cell death revealed that reduced stability of p53 in metformin-treated cells leads to decreases in DEC1 and induction of apoptosis.<br><br>CONCLUSION: The involvement of DEC1 provides new insight into the positive or negative functional roles of p53 in the metformin-induced cytotoxicity in tumor cells.}, }
@article {pmid30439416, year = {2019}, author = {Aparicio-Trejo, OE and Reyes-Fermín, LM and Briones-Herrera, A and Tapia, E and León-Contreras, JC and Hernández-Pando, R and Sánchez-Lozada, LG and Pedraza-Chaverri, J}, title = {Protective effects of N-acetyl-cysteine in mitochondria bioenergetics, oxidative stress, dynamics and S-glutathionylation alterations in acute kidney damage induced by folic acid.}, journal = {Free radical biology &amp; medicine}, volume = {130}, number = {}, pages = {379-396}, doi = {10.1016/j.freeradbiomed.2018.11.005}, pmid = {30439416}, issn = {1873-4596}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/chemically induced/*drug therapy/pathology ; Animals ; Disease Models, Animal ; Energy Metabolism/genetics ; Folic Acid/toxicity ; Glutathione/*metabolism ; Humans ; Mitochondria/*drug effects/metabolism/pathology ; Mitochondrial Dynamics/drug effects ; Oxidative Stress/drug effects ; Protein Processing, Post-Translational/drug effects ; Rats ; }, abstract = {Folic acid (FA)-induced acute kidney injury (AKI) is a widely used model for studies of the renal damage and its progression to chronic state. However, the molecular mechanisms by which FA induces AKI remain poorly understood. Since renal function depends on mitochondrial homeostasis, it has been suggested that mitochondrial alterations contribute to AKI development. Additionally, N-acetyl-cysteine (NAC) can be a protective agent to prevent mitochondrial and renal dysfunction in this model, given its ability to increase mitochondrial glutathione (GSH) and to control the S-glutathionylation levels, a reversible post-translational modification that has emerged as a mechanism able to link mitochondrial energy metabolism and redox homeostasis. However, this hypothesis has not been explored. The present study demonstrates for the first time that, at 24 h, FA induced mitochondrial bioenergetics, redox state, dynamics and mitophagy alterations, which are involved in the mechanisms responsible for the AKI development. On the other hand, NAC preadministration was able to prevent mitochondrial bioenergetics, redox state and dynamics alterations as well as renal damage. The protective effects of NAC on mitochondria and renal function could be related to its observed capacity to preserve the S-glutathionylation process and GSH levels in mitochondria. Taken together, our results support the idea that these mitochondrial processes can be targets for the prevention of the renal damage and its progression in FA-induced AKI model.}, }
@article {pmid30439361, year = {2019}, author = {Ali, T and Mushtaq, I and Maryam, S and Farhan, A and Saba, K and Jan, MI and Sultan, A and Anees, M and Duygu, B and Hamera, S and Tabassum, S and Javed, Q and da Costa Martins, PA and Murtaza, I}, title = {Interplay of N acetyl cysteine and melatonin in regulating oxidative stress-induced cardiac hypertrophic factors and microRNAs.}, journal = {Archives of biochemistry and biophysics}, volume = {661}, number = {}, pages = {56-65}, doi = {10.1016/j.abb.2018.11.007}, pmid = {30439361}, issn = {1096-0384}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cardiomegaly/*metabolism/pathology ; Cell Line ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation/drug effects ; Melatonin/*pharmacology ; MicroRNAs/*metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Early and specific diagnosis of oxidative stress linked diseases as cardiac heart diseases remains a major dilemma for researchers and clinicians. MicroRNAs may serve as a better tool for specific early diagnostics and propose their utilization in future molecular medicines. We aimed to measure the microRNAs expressions in oxidative stress linked cardiac hypertrophic condition induced through stimulants as Endothelin and Isoproterenol. Cardiac hypertrophic animal models were confirmed by BNP, GATA4 expression, histological assays, and increased cell surface area. High oxidative stress (ROS level) and decreased antioxidant activities were assessed in hypertrophied groups. Enhanced expression of miR-152, miR-212/132 while decreased miR-142-3p expression was observed in hypertrophic condition. Similar pattern of these microRNAs was detected in HL-1 cells treated with H2O2. Upon administration of antioxidants, the miRNAs expression pattern altered from that of the cardiac hypertrophied model. Present investigation suggests that oxidative stress generated during the cardiac pathology may directly or indirectly regulate anti-hypertrophy pathway elements through microRNAs including antioxidant enzymes, which need further investigation. The down-regulation of free radical scavengers make it easier for the oxidative stress to play a key role in disease progression.}, }
@article {pmid30429459, year = {2018}, author = {Wang, Y and Zhou, Y and Zheng, Z and Li, J and Yan, Y and Wu, W}, title = {Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption.}, journal = {Cell death &amp; disease}, volume = {9}, number = {11}, pages = {1134}, pmid = {30429459}, issn = {2041-4889}, mesh = {A549 Cells ; Aged ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects/genetics ; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism/pathology ; Cell Proliferation ; Drug Combinations ; Drug Resistance, Neoplasm/*drug effects/genetics ; Female ; *Gene Expression Regulation, Neoplastic ; HSP70 Heat-Shock Proteins ; Humans ; Isothiocyanates/metabolism/*pharmacology ; Lung Neoplasms/*drug therapy/genetics/metabolism/pathology ; Male ; Microtubules/drug effects/metabolism/ultrastructure ; Middle Aged ; Mitogen-Activated Protein Kinase 1 ; Mitogen-Activated Protein Kinase 3 ; Neoplasm Grading ; Paclitaxel/*pharmacology ; Proteasome Endopeptidase Complex ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; Sulfoxides ; Tubulin/genetics/metabolism ; }, abstract = {Long treatment with paclitaxel (PTX) might increase resistance and side-effects causing a failure in cancer chemotherapy. Here we uncovered that either sulforaphane-cysteine (SFN-Cys) or sulforaphane-N-acetyl-cysteine (SFN-NAC) induced apoptosis via phosphorylated ERK1/2-mediated upregulation of 26 S proteasome and Hsp70, and downregulation of βIII-tubulin, XIAP, Tau, Stathmin1 and α-tubulin causing microtubule disruption in human PTX-resistant non-small cell lung cancer (NSCLC) cells. Knockdown of either βIII-tubulin or α-tubulin via siRNA increased cell sensitivity to PTX, indicating that these two proteins help cells increase the resistance. Tissue microarray analysis showed that overexpression of βIII-tubulin correlated to NSCLC malignant grading. Immunofluorescence staining also showed that SFN metabolites induced a nest-like microtubule protein distribution with aggregation and disruption. Co-immunoprecipitation showed that SFN metabolites reduced the interaction between βIII-tubulin and Tau, and that between α-tubulin and XIAP. The combination of PTX with SFN metabolites decreased the resistance to PTX, and doses of both PTX and SFN metabolites, and enhanced apoptosis resulting from activated Caspase-3-caused microtubule degradation. Importantly, the effective dose of SFN metabolites combined with 20 nM PTX will be low to 4 μM. Thus, we might combine SFN metabolites with PTX for preclinical trial. Normally, more than 20 μM SFN metabolites only leading to apoptosis for SFN metabolites hindered their applications. These findings will help us develop a low-resistance and high-efficiency chemotherapy via PTX/SFN metabolites combination.}, }
@article {pmid30426142, year = {2019}, author = {Topcu, A and Mercantepe, F and Rakici, S and Tumkaya, L and Uydu, HA and Mercantepe, T}, title = {An investigation of the effects of N-acetylcysteine on radiotherapy-induced testicular injury in rats.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {392}, number = {2}, pages = {147-157}, pmid = {30426142}, issn = {1432-1912}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Glutathione/metabolism ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Radiation Injuries, Experimental/*drug therapy/metabolism/pathology ; Rats, Sprague-Dawley ; Testis/*drug effects/metabolism/pathology/radiation effects ; }, abstract = {According to data issued by the International Agency for Research on Cancer in 2012, the estimated number of new cases of all types of cancer worldwide was estimated to exceed 10 million, and 6 million of whom receive radiotherapy. Radiotherapy is the treatment of cancer using ionizing radiation. Our study investigated the effects of x-radiation resulting from radiotherapy (RT) on the testis at the molecular level, and prospectively considered the potential protective characteristics of antioxidants against testicular damage resulting from x-radiation. Forty male Sprague Dawley rats were allocated into five groups, control (group 1), abdominopelvic region 2-Gy-ionizing radiation (group 2), whole-body 6-Gy irradiation (group 3), 2 Gy abdominopelvic region irradiation and 300 mg/kg NAC treatment (group 4), and 6-Gy whole-body irradiation and 300 mg/kg NAC treatment (group 5). Disorganization and vacuolization were observed in the epithelial layer in atrophic seminiferous tubules in the only ionizing radiation (IR) groups. In addition, Johnsen's score decreased in the only IR groups, while testis tissue malondialdehyde (MDA) and glutathione (GSH) tissue levels increased. N-Acetylcysteine (NAC) treatment groups Johnsen's score and tissue GSH levels increased than only IR groups. On the other hand, tissue MDA levels decreased in the NAC treatment groups. The findings showed that ionizing radiation caused apoptosis in germinal epithelial cells led to the oxidative stress-mediated testicular injury. On the other hand, NAC may be useful in the prevention of testicular injury-suppressed ROS production.}, }
@article {pmid30423732, year = {2019}, author = {Guindani, C and Dozoretz, P and Araújo, PHH and Ferreira, SRS and de Oliveira, D}, title = {N-acetylcysteine side-chain functionalization of poly(globalide-co-ε-caprolactone) through thiol-ene reaction.}, journal = {Materials science &amp; engineering. C, Materials for biological applications}, volume = {94}, number = {}, pages = {477-483}, doi = {10.1016/j.msec.2018.09.060}, pmid = {30423732}, issn = {1873-0191}, mesh = {Acetylcysteine/chemical synthesis/*chemistry ; Antioxidants/pharmacology ; Benzothiazoles/chemistry ; Biphenyl Compounds/chemistry ; Picrates/chemistry ; Polyesters/chemical synthesis/*chemistry ; Proton Magnetic Resonance Spectroscopy ; Sulfhydryl Compounds/*chemistry ; Sulfonic Acids/chemistry ; Surface Properties ; }, abstract = {N-Acetylcysteine (NAC) is a drug well known for its antimucolytic action, antioxidant activity and ability to protect cells from oxidative stress. Conjugation of NAC with double bonds in the main polymer chain of poly(globalide-co-ε-caprolactone) (PGlCL) through thiol-ene reaction is reported. Different globalide (Gl) (an unsaturated macrolactone) to ε-caprolactone (CL) ratios were employed for PGlCL synthesis. The polymeric materials (PGlCL-NAC) were evaluated in terms of the number of functionalized double bonds, thermal properties, affinity for water and antioxidant potential. PGlCL-NAC containing more globalide repeating units presented higher degree of functionalization, due to the higher number of double bonds available to react through thiol-ene coupling. For high globalide contents (Gl/CL ratios above 50/50), NAC coupling in PGlCL chains resulted in completely amorphous copolymers with a more hydrophilic character, which should enhance bioresorption and cell adhesion characteristics. Functionalization also gave rise to a thioether linkage, conferring to PGlCL-NAC an antioxidant character, important for biomedical applications, where the material could combat cellular oxidative-stress.}, }
@article {pmid30421167, year = {2019}, author = {Rodrigues, FS and de Zorzi, VN and Funghetto, MP and Haupental, F and Cardoso, AS and Marchesan, S and Cardoso, AM and Schinger, MRC and Machado, AK and da Cruz, IBM and Duarte, MMMF and Xavier, LL and Furian, AF and Oliveira, MS and Santos, ARS and Royes, LFF and Fighera, MR}, title = {Involvement of the Cholinergic Parameters and Glial Cells in Learning Delay Induced by Glutaric Acid: Protection by N-Acetylcysteine.}, journal = {Molecular neurobiology}, volume = {56}, number = {7}, pages = {4945-4959}, pmid = {30421167}, issn = {1559-1182}, support = {11/2082-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 11/2082-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 11/2082-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 11/2082-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 11/2082-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Cholinergic Neurons/*drug effects/metabolism ; Glutarates/*toxicity ; Male ; Maze Learning/*drug effects/physiology ; Memory Disorders/chemically induced/metabolism/*prevention &amp; control ; Neuroglia/*drug effects/metabolism ; Rats ; Rats, Wistar ; }, abstract = {Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 μmol g body weight[-1], subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (α7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks.}, }
@article {pmid30417263, year = {2019}, author = {Boşgelmez, I&#x130; and Güvendik, G}, title = {Beneficial Effects of N-Acetyl-L-cysteine or Taurine Pre- or Post-treatments in the Heart, Spleen, Lung, and Testis of Hexavalent Chromium-Exposed Mice.}, journal = {Biological trace element research}, volume = {190}, number = {2}, pages = {437-445}, doi = {10.1007/s12011-018-1571-z}, pmid = {30417263}, issn = {1559-0720}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Chromium/administration &amp; dosage/*toxicity ; Heart/*drug effects ; Lipid Peroxidation/drug effects ; Lung/*drug effects/metabolism ; Male ; Mice ; Spleen/*drug effects/metabolism ; Sulfhydryl Compounds/antagonists &amp; inhibitors/metabolism ; Taurine/administration &amp; dosage/*pharmacology ; Testis/*drug effects/metabolism ; }, abstract = {Hexavalent chromium[Cr(VI)] compounds may induce toxic effects, possibly via reactive intermediates and radicals formed during Cr(VI) reduction. In this study, we probed the possible effects of N-acetyl-L-cysteine (NAC) and taurine pre- or post-treatments on Cr(VI)-induced changes in lipid peroxidation and nonprotein thiols (NPSH) in mice heart, lung, spleen, and testis tissues. The mice were randomly assigned to six groups, consisting of control, Cr(VI)-exposed (20 mg Cr/kg, intraperitoneal ,ip), NAC (200 mg/kg, ip) as pre-treatment and post-treatment, and taurine (1 g/kg, ip) pre-treatment and post-treatment groups. Lipid peroxidation and NPSH levels were determined and the results were compared with regard to tissue- and antioxidant-specific basis. Exposure to Cr(VI) significantly increased lipid peroxidation in all tissues as compared to the control (p < 0.05); and consistent with this data, NPSH levels were significantly decreased (p < 0.05). Notably, administration of NAC and taurine, either before or after Cr(VI) exposure, was able to ameliorate the lipid peroxidation (p < 0.05) in all tissues. In the case of NPSH content, while the decline could be alleviated by both NAC and taurine pre- and post-treatments in the spleen, diverging results were obtained in other tissues. The effects of Cr(VI) on the lung thiols were abolished by pre-treatment with NAC and taurine; however, post-treatments could not exert significant effect. While thiol depletion in the heart was totally replenished by NAC and taurine administrations, NAC pre-treatment was partially more effective than post-treatment. In contrast with lipid peroxidation data, NAC treatment could not provide a statistically significant beneficial effect on NPSH content of the testis, whereas the effect in this tissue by taurine was profound. Thus, these data highlight the importance of tissue-specific factors and the critical role of administration time. Overall, our data suggest that NAC and taurine may have potential in prevention of Cr(VI)-induced toxicity in the heart, lung, spleen, and testis tissues.}, }
@article {pmid30416532, year = {2018}, author = {Raffaele, M and Barbagallo, I and Licari, M and Carota, G and Sferrazzo, G and Spampinato, M and Sorrenti, V and Vanella, L}, title = {N-Acetylcysteine (NAC) Ameliorates Lipid-Related Metabolic Dysfunction in Bone Marrow Stromal Cells-Derived Adipocytes.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2018}, number = {}, pages = {5310961}, pmid = {30416532}, issn = {1741-427X}, abstract = {Recent experimental data suggest that fatty acids and lipotoxicity could play a role in the initiation and evolution of metabolic bone diseases such as osteoporosis. A functional bone marrow adipose tissue (BMAT) may provide support to surrounding cells and tissues or may serve as a lipid reservoir that protects skeletal osteoblasts from lipotoxicity. The present study examined the effect of N-acetylcysteine (NAC), a powerful antioxidant and precursor of glutathione, commonly used to treat chronic obstructive pulmonary disease, on triglycerides accumulation in bone marrow stromal cells-derived adipocytes. Quantification of Oil Red O stained cells showed that lipid droplets decreased following NAC treatment. Additionally, exposure of bone marrow stromal cells (HS-5) to NAC increased adiponectin, PPARγ, HO-1, and SIRT-1 and increased beta-oxidation markers such as PPARα and PPARδ mRNA levels. As there is now substantial interest in alternative medicine, the observed therapeutic value of NAC should be taken into consideration in diabetic patients.}, }
@article {pmid30415238, year = {2018}, author = {Choi, S and Lim, JW and Kim, H}, title = {Effect of thiol antioxidants on lipopolysaccharide-induced cyclooxygenase-2 expression in pulmonary epithelial cells.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {69}, number = {4}, pages = {}, doi = {10.26402/jpp.2018.4.04}, pmid = {30415238}, issn = {1899-1505}, mesh = {A549 Cells ; Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Cyclooxygenase 2/genetics/*metabolism ; Epithelial Cells/*drug effects/metabolism ; Glutathione/*pharmacology ; Humans ; Lipopolysaccharides ; Lung/cytology ; NF-kappa B/antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/antagonists &amp; inhibitors ; Transcription Factor AP-1/antagonists &amp; inhibitors ; }, abstract = {Cyclooxygenase-2 (COX-2) plays an important role in pulmonary inflammatory response, and its expression is regulated by several transcription factors including nuclear factor kappa-B (NF-κB), activator protein-1 (AP-1), and signal transducer and activator of transcription-3 (STAT-3), which are activated by oxidative stress. Glutathione (GSH) and N-acetyl cysteine (NAC) are thiol antioxidants that scavenge reactive oxygen species (ROS). The present study investigated whether lipopolysaccharide (LPS) induces COX-2 expression through ROS generation and the activation of oxidant-sensitive transcription factors such as NF-κB, AP-1, and STAT-3 in pulmonary epithelial A549 cells. The cells were pretreated with GSH or NAC for 1 hour prior to LPS stimulation. Intracellular ROS levels, DNA-binding activities of NF-κB, AP-1, and STAT-3, and mRNA and protein levels of COX-2 were determined. Our results showed that LPS increased ROS levels that peaked at 2 hours. LPS activated NF-κB, AP-1, and STAT-3 and induced the expression of COX-2 in A549 cells in a time-dependent manner. Pretreatment of thiol antioxidants GSH and NAC reduced ROS levels and attenuated the increase in ROS, the activation of NF-κB, AP-1, and STAT-3, and the expression of COX-2 in LPS-treated A549 cells. In conclusion, GSH and NAC suppress COX-2 expression by reducing ROS levels and inhibiting the activation of NF-κB, AP-1, and STAT-3 in pulmonary epithelial A549 cells exposed to LPS. Pretreatment with thiol antioxidants GSH and NAC may be beneficial for the treatment of pulmonary inflammation associated with oxidative stress.}, }
@article {pmid30415189, year = {2019}, author = {Wang, W and Mao, S and Yu, H and Wu, H and Shan, X and Zhang, X and Cui, G and Liu, X}, title = {Pinellia pedatisecta lectin exerts a proinflammatory activity correlated with ROS-MAPKs/NF-κB pathways and the NLRP3 inflammasome in RAW264.7 cells accompanied by cell pyroptosis.}, journal = {International immunopharmacology}, volume = {66}, number = {}, pages = {1-12}, doi = {10.1016/j.intimp.2018.11.002}, pmid = {30415189}, issn = {1878-1705}, mesh = {Animals ; Caspase 1/metabolism ; Humans ; Inflammasomes/metabolism ; Inflammation/*metabolism ; Interleukin-1beta/metabolism ; Macrophages/*immunology ; Membrane Potential, Mitochondrial/immunology ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pinellia/*immunology ; Plant Lectins/*immunology ; Pyroptosis/*immunology ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Pinellia pedatisecta, a widely used herb in Chinese medicine, has proinflammatory toxicity related to its Pinellia pedatisecta lectin (PPL), but the mechanism is still unknown. However, for safer use, it is necessary to clarify its proinflammatory mechanism. Herein, we studied the mechanism in RAW264.7 cells. PPL decreased the mitochondrial membrane potential (MMP) and increased the outflow of calcium, accompanied by the overproduction of reactive oxygen species (ROS), which resulted in the activation of the MAPK and NF-κB pathways and the release of IL-1β. The maturation of IL-1β relied on caspase-1 p20, the active caspase-1, as demonstrated by adding caspase-1 inhibitor. While caspase-1 was associated with the activation of the NLRP3 inflammasome, we further found that the stimulation of PPL also contributed to the activation. In addition, TXNIP was downregulated, whereas NLRP3/caspase-1 p20/ASC was upregulated, and there was binding of TXNIP with NLRP3. There was also binding of NLRP3 with ASC and caspase-1. Further, we found that N-acetylcysteine (NAC), an ROS scavenger, could inhibit the PPL-stimulated activation of these pathways and the release of IL-1β. Moreover, PPL led to cell pyroptosis with pyknotic nuclei and plasma membrane rupture, which could be inhibited by NAC. All of these findings demonstrated an important role of ROS in the inflammation caused by PPL. Taken together, our data provide new mechanistic insights into the possible endogenous signaling pathways involved in the inflammation of RAW264.7 cells, stimulated by PPL.}, }
@article {pmid30412806, year = {2019}, author = {Tiwari, SS and Chavan, BB and Kushwah, BS and Yerra, NV and Mukesh, S and Sangamwar, AT and Thaota, JR and Talluri, MVNK}, title = {In vitroand in vivo investigation of metabolic fate of riociguat by HPLC-Q-TOF/MS/MS and in silico evaluation of the metabolites by ADMET predictor[™].}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {164}, number = {}, pages = {326-336}, doi = {10.1016/j.jpba.2018.10.050}, pmid = {30412806}, issn = {1873-264X}, mesh = {Acetylcysteine/chemistry ; Administration, Oral ; Animals ; Antihypertensive Agents/administration &amp; dosage/*analysis/metabolism/toxicity ; Biotransformation ; Chromatography, High Pressure Liquid/instrumentation/methods ; Computer Simulation ; Data Mining ; Guanylate Cyclase/*antagonists &amp; inhibitors ; Humans ; Male ; Microsomes, Liver ; Pyrazoles/administration &amp; dosage/*analysis/metabolism/toxicity ; Pyrimidines/administration &amp; dosage/*analysis/metabolism/toxicity ; Rats ; Rats, Sprague-Dawley ; *Software ; Tandem Mass Spectrometry/instrumentation/methods ; }, abstract = {Riociguat, a guanyl cyclase inhibitor, is one of its kind drug regimen approved for management of pulmonary arterial hypertension and chronic thromboembolism pulmonary hypertension. Extensive literature review indicates lack of comprehensive reports on its metabolic fate. The present study reports the in vivo and in vitro identification and characterization of metabolites of riociguat, using high-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry. In vitro studies were conducted by incubating the drug in human and rat liver microsomes in presence of respective cofactors. In vivo studies were undertaken by oral administration of suspension of drug to male Sprague-Dawley rats followed by collection of urine, feces and blood at specific intervals. A total of 18 metabolites were observed in in vivo and in vitro matrices which includes hydroxyl, N-oxide, desmethyl, defluorinated hydroxyl, glucuronides and N-acetyl cysteine conjugates. Presence of N-acetyl cysteine conjugates strongly points towards the formation of a reactive metabolite intermediate trapped through N-acetyl cysteine and can be considered a matter of concern as the reactive metabolites have been known to manifest toxicities. Their presence was mimicked in in vitro samples as well. The toxicological properties of drug and metabolites were evaluated by using ADMET Predictor [™] software.}, }
@article {pmid30409442, year = {2019}, author = {Tarrant, BJ and Maitre, CL and Romero, L and Steward, R and Button, BM and Thompson, BR and Holland, AE}, title = {Mucoactive agents for adults with acute lung conditions: A systematic review.}, journal = {Heart &amp; lung : the journal of critical care}, volume = {48}, number = {2}, pages = {141-147}, doi = {10.1016/j.hrtlng.2018.09.010}, pmid = {30409442}, issn = {1527-3288}, mesh = {Acute Disease ; Administration, Inhalation ; Adult ; Ambroxol/administration &amp; dosage ; Deoxyribonuclease I/administration &amp; dosage ; Expectorants/*administration &amp; dosage ; Humans ; Lung Diseases/*drug therapy/metabolism ; Mannitol/administration &amp; dosage ; Mucociliary Clearance/*drug effects ; Recombinant Proteins/administration &amp; dosage ; }, abstract = {BACKGROUND AND OBJECTIVES: Inhaled mucoactive agents are used to enhance airway clearance, however efficacy and safety are unclear in adults with acute respiratory conditions.<br><br>METHODS: We systematically reviewed randomized controlled trials assessing respiratory function; safety; length of stay (LOS); mucus; radiology; and oxygenation.<br><br>RESULTS: No adverse events were reported for dornase alfa (n&#x202f;=&#x202f;63), N-acetylcysteine (NAC, n&#x202f;=&#x202f;50), ambroxol (n&#x202f;=&#x202f;140), hypertonic saline (n&#x202f;=&#x202f;33), heparin (n&#x202f;=&#x202f;384), mannitol (n&#x202f;=&#x202f;20) or isotonic saline. During invasive ventilation, NAC, dornase alfa and saline had no effect on mucus. Postoperatively, mucus characteristics improved with NAC (n&#x202f;=&#x202f;10). Ambroxol lowered LOS (mean difference 4 days) and halved complications following lung carcinoma resection (n&#x202f;=&#x202f;140). Heparin improved ventilator-free days (n&#x202f;=&#x202f;130, mean difference 3.9-4.6) and intensive care LOS (n&#x202f;=&#x202f;223, 3.2 days), but not ventilator-acquired pneumonia.<br><br>CONCLUSION: Dornase alfa, hypertonic saline and NAC were ineffective for atelectasis/mucus plugging while intubated. More data are required to support using NAC, ambroxol and heparin during acute illness.}, }
@article {pmid30408533, year = {2019}, author = {Lee, W and Woo, ER and Lee, DG}, title = {Effect of apigenin isolated from Aster yomena against Candida albicans: apigenin-triggered apoptotic pathway regulated by mitochondrial calcium signaling.}, journal = {Journal of ethnopharmacology}, volume = {231}, number = {}, pages = {19-28}, doi = {10.1016/j.jep.2018.11.005}, pmid = {30408533}, issn = {1872-7573}, mesh = {Antifungal Agents/*pharmacology ; Apigenin/*pharmacology ; Apoptosis/drug effects ; *Aster Plant ; Calcium Signaling/drug effects ; Candida albicans/*drug effects/physiology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/physiology ; Plant Components, Aerial ; Reactive Oxygen Species/metabolism ; }, abstract = {Aster yomena, a perennial herb that grows mainly in South Korea, has been employed in the traditional temple food for antibiotic efficacy. Recently, it was reported that apigenin isolated from A. yomena has a physical antifungal mechanism targeting membrane against Candida albicans.<br><br>AIM OF THE STUDY: Our study aimed to investigate the biochemical responses underlying the antifungal activity of apigenin isolated from A. yomena due to lack studies reporting the investigation of intracellular responses of apigenin in C. albicans.<br><br>MATERIALS AND METHODS: Apigenin was isolated from the aerial parts of A. yomena. To evaluate apigenin-induced inhibitory effects and membrane damages, the measurement of the cell viability assay and the flux of cytosolic components were performed with at various concentrations. Intracellular external potassium and calcium levels were assayed by an ion-selective electrode meter, Fura2-AM and Rhod2-AM, respectively. Mitochondrial dysfunctions were analyzed by using JC-1, Mitotracker Green FM, and MitoSOX Red dye. H2DCFDA, glutathione, and MDA assay were used to detect oxidative damage. Also, flow cytometry was carried out to detect apoptotic hallmarks using Annexin V-PI, TUNEL, and FITC-VAD-FMK staining. Tetraethylammoniumchloride (TEA), Ruthenium red (RR), and N-acetylcysteine (NAC) were used as a potassium channel blocker, mitochondrial calcium uptake inhibitor, and reactive oxygen species (ROS) scavenger, respectively.<br><br>RESULTS: We confirmed that there was no decrease of cell survival percentages in crude extracts of A. yomena treatment, however, only isolated apigenin has the antifungal effect in C. albicans. Apigenin triggered a dose-dependent mitochondrial calcium uptake followed by mitochondrial dysfunction, loss of the membrane potential and an increase in the mitochondrial mass and ROS. Apigenin also induced intracellular redox imbalance as indicated by the ROS accumulation, glutathione oxidation, and lipid peroxidation. Interestingly, NAC failed the restore the mitochondrial calcium levels and thus alleviate the mitochondrial damages, however, RR reduced the apigenin-induced redox imbalance. Furthermore, apigenin induced apoptosis activation marked by the phosphatidylserine exposure, DNA fragmentation, and caspase activation. The pro-apoptotic effect of apigenin was counteracted by RR and NAC pretreatment. In particular, RR significantly reduced the pro-apoptotic responses.<br><br>CONCLUSIONS: Apigenin isolated from A. yomena induced mitochondrial-mediated apoptotic pathway, and mitochondrial calcium signaling is main factor in its pathway in C. albicans.}, }
@article {pmid30408460, year = {2019}, author = {Gil, HN and Jung, E and Koh, D and Lim, Y and Lee, YH and Shin, SY}, title = {A synthetic chalcone derivative, 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139), triggers reactive oxygen species-induced apoptosis independently of p53 in A549 lung cancer cells.}, journal = {Chemico-biological interactions}, volume = {298}, number = {}, pages = {72-79}, doi = {10.1016/j.cbi.2018.11.003}, pmid = {30408460}, issn = {1872-7786}, mesh = {A549 Cells ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects/physiology ; Carcinoma, Non-Small-Cell Lung/drug therapy/pathology ; Caspases/metabolism ; Cell Line, Tumor ; Chalcones/*pharmacology ; DNA Damage/drug effects ; HCT116 Cells ; Histones/metabolism ; Humans ; Lung Neoplasms/drug therapy/pathology ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {2-Hydroxy-3',5,5'-trimethoxychalcone (named DK-139) is a synthetic chalcone derivative that has anti-inflammatory, anti-tumor, and endoplasmic reticulum-mediated apoptosis activities. However, the mode of action of DK-139 on reactive oxygen species (ROS)-induced apoptosis remains unknown. In this study, we found that DK-139 activated DNA damage responses, as was revealed by the accumulation of the tumor suppressor p53 and the phosphorylation of histone H2AX at Ser139 (called γ-H2AX), which are hallmarks of DNA damage responses. The occurrence of DK-139-induced DNA damage was confirmed through single-cell gel electrophoresis (comet tail assay). Interestingly, using p53-null HCT116 cells revealed that p53 was not involved in DK-139-induced apoptosis. Instead, we found that DK-139 increased the production of ROS, which led to the processing of caspase-2, BH3 interacting-domain death agonist (BID), caspase-9, and caspase-7. Pretreatment with the ROS scavenger N-acetyl cysteine reduced the frequency of DK-139-induced γ-H2AX formation, demonstrating that DK-139 triggered DNA damage through ROS production. In addition, NAC pretreatment prevented DK-139-induced processing of caspase-2, BID, caspase-9, caspase-7, and poly(ADP-ribose) polymerase. These results suggest that DK-139 triggers apoptosis through ROS-mediated DNA damage and activation of the caspase-2 cascade in A549 human lung cancer cells.}, }
@article {pmid30407312, year = {2018}, author = {Zhang, Q and Ju, Y and Ma, Y and Wang, T}, title = {N-acetylcysteine improves oxidative stress and inflammatory response in patients with community acquired pneumonia: A randomized controlled trial.}, journal = {Medicine}, volume = {97}, number = {45}, pages = {e13087}, pmid = {30407312}, issn = {1536-5964}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/*pharmacology ; Community-Acquired Infections/blood/drug therapy ; Female ; Humans ; Inflammation/drug therapy ; Male ; Malondialdehyde/blood ; Middle Aged ; Oxidative Stress/*drug effects ; Pneumonia/blood/*drug therapy ; Superoxide Dismutase/blood ; Treatment Outcome ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {Oxidative stress is considered to be part of the pathogenic mechanism for community-acquired pneumonia (CAP) and is closely linked to inflammation. Attenuation of oxidative stress would be expected to reduce pulmonary damage. Antioxidants have been found to be effective in alleviating lung injury and protecting against damage of other organs.The aim of the study was to compare the effect of adding N-acetylcysteine (NAC) to conventional treatment versus conventional treatment on oxidative stress, inflammatory factors, and radiological changes in CAP patients.Eligible CAP patients at Weihai Municipal Hospital were stratified and randomly assigned to either NAC group or non-NAC group between August 2016 and March 2017. The NAC group received conventional treatment for pneumonia and NAC (1200 mg/d). Thenon-NAC group received conventional therapy. malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant capacity (TAOC), tumor necrosis factor-α (TNF-α), and computed tomography (CT) images were evaluated at baseline and after treatment. The primary endpoint indicators were the changes in oxidative stress parameters (MDA, TAOC, SOD) and TNF-α after treatment in the NAC group compared with those in the non-NAC group. The secondary endpoint indicator was any difference in CT scores after treatment in the NAC group compared with the non-NAC group.Baseline levels of MDA, TAOC, SOD, and TNF-α were similar between the 2 groups before treatment. Plasma levels of MDA and TNF-α decreased more (P < .05 MDA:p 0.004, TNF-α:p <0.001) in the NAC group than the non-NAC group, and there was a reliable increase in TAOC content (p 0.005). There was no significant difference in increased plasma SOD activity between the groups (p 0.368), and the NAC group did not show a greater improvement from CT scores. No NAC-related adverse effects were observed.Addition of NAC therapy for CAP patients reduced MDA and TNF-α and increased TAOC. Treatment with NAC may help to reduce oxidative and inflammatory damage in pneumonia patients.}, }
@article {pmid30404736, year = {2018}, author = {Eid, BG and Abu-Sharib, AT and El-Bassossy, HM and Balamash, K and Smirnov, SV}, title = {Enhanced calcium entry via activation of NOX/PKC underlies increased vasoconstriction induced by methylglyoxal.}, journal = {Biochemical and biophysical research communications}, volume = {506}, number = {4}, pages = {1013-1018}, doi = {10.1016/j.bbrc.2018.10.171}, pmid = {30404736}, issn = {1090-2104}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Aorta/drug effects/metabolism ; Benzophenanthridines/pharmacology ; Calcium/*metabolism ; Endothelium, Vascular/drug effects/metabolism ; Enzyme Activation/drug effects ; Kidney/drug effects ; Male ; NADPH Oxidases/*metabolism ; Potassium Chloride/pharmacology ; Protein Kinase C/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Pyruvaldehyde/*pharmacology ; Rats, Wistar ; *Vasoconstriction/drug effects ; }, abstract = {Advanced glycation end-products (AGEs) play a pivotal role in macro- and micro-vascular diabetic complications. We investigated the mechanism by which methylglyoxal (an endogenous generator of AGEs) affects vascular contractility using the isolated artery technique. Contractile responses to vasoconstrictors phenylephrine (PE), angiotensin II (Ang II), vasopressin (VP) and KCl were measured in the isolated rat aorta following one-our exposure to methylglyoxal (50-200 μM). The perfused rat kidney was employed to confirm the effect of methylglyoxal on microvessels. Methylglyoxal-induced changes in cytosolic calcium were measured in the smooth muscle layer of the aorta with the calcium-sensing fluorophore Fluo-4 AM. Methylglyoxal significantly increased maximal contraction of the rat aorta to PE, Ang II and VP. Similar results were seen in response to the depolarizing vasoconstrictor KCl in macro and micro vessels. The methylglyoxal-induced increases in aortic contraction mediated by the agonist and KCl were endothelium independent. Methylglyoxal-induced increases in KCl-dependent aortic contraction were abolished after the removal of extracellular calcium or in the presence of the calcium channel blocker nifedipine. Incubation with the antioxidant N-acetyl-l-cysteine (NAC), apocynin (a nonselective NADPH oxidase (NOX) inhibitor) or chelerythrine (a protein kinase C (PKC) inhibitor) prior to methylglyoxal pre-treatment reversed the methylglyoxal-induced increases in the rat aortic contractility. In conclusion, the formation of AGEs increases vasoconstriction of both macro- and micro-vessels by increasing the voltage-activated calcium entry in vascular smooth muscles in a NOX and PKC dependent manner.}, }
@article {pmid30402957, year = {2019}, author = {Seidkhani-Nahal, A and Allameh, A and Soleimani, M}, title = {Antioxidant and reactive oxygen species scavenging properties of cellular albumin in HepG2 cells is mediated by the glutathione redox system.}, journal = {Biotechnology and applied biochemistry}, volume = {66}, number = {2}, pages = {163-171}, doi = {10.1002/bab.1708}, pmid = {30402957}, issn = {1470-8744}, mesh = {Free Radical Scavengers/*metabolism ; Glutathione/*metabolism ; Hep G2 Cells ; Humans ; Methionine/*analogs &amp; derivatives/pharmacology ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/*metabolism ; Serum Albumin, Human/*biosynthesis ; Sulfoxides/*pharmacology ; }, abstract = {This study was carried out to examine the role of intracellular albumin in the modulation of oxidative damage induced by glutathione modifiers in HepG2 cells. Also, the relationship of albumin synthesis with oxidative stress factors including antioxidants was studied. HepG2 cell culture was supplemented with glutathione modifiers; L-Buthionine-sulfoximine (BSO; 0.1 and 1.0 mM) or N-acetyl cysteine (NAC; 1 and 10 mM) and the cell viability and changes in reduced glutathione (GSH), oxidized glutathione (GSSG), reactive oxygen species (ROS), catalase, and superoxide dismutase were measured. Besides, albumin expression at protein and mRNA levels was determined in cells pretreated with BSO or NAC. Kinetic studies showed that albumin expression in HepG2 cells is correlated with GSH and GSSG levels. Changes in albumin expression at protein and mRNA levels reached their maximum (19% and 55%, respectively) in the cells 6 H after NAC treatments. A substantial decrease in intracellular albumin due to BSO (27%) was associated with a significant increase in the generation of cellular ROS (17%). In contrast, increased albumin synthesis (intracellular and secretory) was associated with inhibition in cellular ROS. Overall data may suggest that albumin expression in coordination with the glutathione redox system is part of the antioxidant defense mechanism in liver cells.}, }
@article {pmid30399561, year = {2019}, author = {Ahamed, M and Akhtar, MJ and Khan, MAM and Alrokayan, SA and Alhadlaq, HA}, title = {Oxidative stress mediated cytotoxicity and apoptosis response of bismuth oxide (Bi2O3) nanoparticles in human breast cancer (MCF-7) cells.}, journal = {Chemosphere}, volume = {216}, number = {}, pages = {823-831}, doi = {10.1016/j.chemosphere.2018.10.214}, pmid = {30399561}, issn = {1879-1298}, mesh = {Apoptosis ; Bismuth/*chemistry ; Breast Neoplasms/*genetics/metabolism ; Female ; Humans ; MCF-7 Cells ; Nanoparticles ; Oxidative Stress/drug effects ; }, abstract = {Bismuth oxide nanoparticles (Bi2O3 NPs) have shown great potential for several applications including cosmetics and biomedicine. However, there is paucity of research on toxicity of Bi2O3 NPs. In this study, we first examined dose-dependent cytotoxicity and apoptosis response of Bi2O3 NPs in human breast cancer (MCF-7) cells. We further explored the potential mechanisms of cytotoxicity of Bi2O3 NPs through oxidative stress. Physicochemical study demonstrated that Bi2O3 NPs have crystalline structure and spherical shape with mean size of 97 nm. Toxicity studies have shown that Bi2O3 NPs reduce cell viability and induce membrane damage dose-dependently in the concentration range of 50-300 μg/ml. Bi2O3 NPs also disturbed cell cycle of MCF-7 cells. Oxidative stress response of Bi2O3 NPs was evident by generation of reactive oxygen species (ROS), higher lipid peroxidation, reduction of glutathione (GSH) and low superoxide dismutase (SOD) enzyme activity. Interestingly, supplementation of external antioxidant N-acetyl-cysteine almost negated the effect of Bi2O3 NPs induced oxidative stress and cell death. We also found that exposure of Bi2O3 NPs induced apoptotic response in MCF-7 cells suggested by impaired regulation of Bcl-2, Bax and caspase-3 genes. Altogether, we found that Bi2O3 NPs induced cytotoxicity in MCF-7 cells through modulating the redox homeostasis via Bax/Bcl-2 pathway. This study warranted further research to delineate the underlying mechanism of Bi2O3 NPs induced toxicity at in vivo level.}, }
@article {pmid30396020, year = {2019}, author = {Bao, B and Yang, Z and Liu, Y and Xu, Y and Gu, B and Chen, J and Su, P and Tong, L and Wang, L}, title = {Two-photon semiconducting polymer nanoparticles as a new platform for imaging of intracellular pH variation.}, journal = {Biosensors &amp; bioelectronics}, volume = {126}, number = {}, pages = {129-135}, doi = {10.1016/j.bios.2018.10.027}, pmid = {30396020}, issn = {1873-4235}, mesh = {Biosensing Techniques/*methods ; HeLa Cells ; Humans ; Hydrogen-Ion Concentration ; Indoles/*chemistry ; Maleic Anhydrides/*chemistry ; Nanoparticles/*chemistry ; Photons ; Polymers/*chemistry ; Polystyrenes/*chemistry ; *Semiconductors ; }, abstract = {Intracellular pH (pHi) plays a crucial role in cell physiological and pathological processes. We herein report an efficient pH-sensitive sensor based on two-photon excitable semiconducting polymer nanoparticles (PFV/PSMA-DA NPs) for pHi sensing. PFV/PSMA NPs were functionalized with redox-active dopamine (DA) and the obtained PFV/PSMA-DA NPs showed sensitive and reversible pH response over the pH range of 5.0-9.0. Owning to the high biocompatibility and pH-responsive DA, PFV/PSMA-DA NPs show low cytotoxicity and the quantification and imaging of intracellular pH changes of HeLa cells were successfully realized. Moreover, the detection of intracellular pH fluctuation induced by redox species such as NAC (N-acetylcysteine) and H2O2 was also achieved by both one- and two-photon excitation of the PFV/PSMA-DA NPs probe. This work clearly shows that nanoprobe based on two-photon PFV/PSMA-DA NPs could serve as a promising platform for quantitatively monitoring the intracellular pH fluctuations.}, }
@article {pmid30389500, year = {2019}, author = {Yang, S and Sun, D and Wang, L and Wang, X and Shi, M and Jiang, X and Gao, X}, title = {The role of STAT3/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells.}, journal = {Cellular signalling}, volume = {53}, number = {}, pages = {327-338}, doi = {10.1016/j.cellsig.2018.10.021}, pmid = {30389500}, issn = {1873-3913}, mesh = {Angiotensin II/*metabolism ; *Autophagy ; Cell Line ; Cellular Senescence ; Humans ; Mesangial Cells/*cytology/metabolism ; STAT3 Transcription Factor/*metabolism ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {The kidney is one of the fastest-aging organs, and renal senescence has become a major disease affecting human health. Renal cellular senescence is regulated by the joint action of multiple signal transduction pathways. The previous study by our research group found that the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was involved in angiotensin II (Ang II)-induced senescence of human glomerular mesangial cells. However, the unique role of STAT3 activation in Ang II-induced senescence of human glomerular mesangial cells and the underlying mechanisms remain unclear. The present study revealed that Ang II induced premature senescence, promoted autophagy and activated oxidative stress responses in human glomerular mesangial cells. Autophagy mediates the senescence-inducing effect of Ang II on human glomerular mesangial cells. Inhibition of oxidative stress with N-acetylcysteine (NAC) or interference with STAT3/mechanistic target of rapamycin (mTOR) activity with S3I-201 or STAT3-siRNA suppressed autophagy to a certain extent, which was conducive to delaying the senescence of glomerular mesangial cells. The antioxidant probucol reduced autophagy in human glomerular mesangial cells and alleviated the aging process of these cells by regulating STAT3/mTOR. These findings identify a role of STAT3/mTOR-regulated autophagy in Ang II-induced senescence of human glomerular mesangial cells and may provide a theoretical basis for anti-senescence treatment in clinical practice.}, }
@article {pmid30388615, year = {2018}, author = {Zhang, Y and Zhang, R and Sun, H and Chen, Q and Yu, X and Zhang, T and Yi, M and Liu, JX}, title = {Copper inhibits hatching of fish embryos via inducing reactive oxygen species and down-regulating Wnt signaling.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {205}, number = {}, pages = {156-164}, doi = {10.1016/j.aquatox.2018.10.015}, pmid = {30388615}, issn = {1879-1514}, mesh = {Animals ; Copper/*toxicity ; Down-Regulation/*drug effects ; Embryo, Nonmammalian/*drug effects ; Reactive Oxygen Species/*metabolism ; Water Pollutants, Chemical/toxicity ; Wnt Signaling Pathway/*genetics ; Zebrafish/embryology/*physiology ; }, abstract = {The copper ion (Cu[2+]) has been reported to suppress the hatching of fish. However, little is known about the underlying mechanism. In this study, copper nanoparticles (CuNPs) and Cu[2+] were shown to significantly suppress hatching of zebrafish in a dosage-dependent manner, and reactive oxygen species (ROS) scavengers NAC (N-acetylcysteine) &amp; GSH (reduced glutathione) and Wnt signaling agonist BIO (6-bromoindirubin-3'-oxime) significantly alleviated the suppressing effects of Cu[2+] and CuNPs on egg hatching. Mechanistically, NAC, GSH, and BIO recovered the egg hatching in copper-treated group via increasing the embryonic motility rather than stimulating the expression and secretion of hatching enzymes before hatching. Additionally, no significant difference in egg hatching was observed between the control and Cu[2+]-treated group at 72 hpf (hours post fertilization) in cox17 mutant embryos, in which little ROS was producd after copper stimulation. This may be the first report that Cu[2+] and CuNPs suppress embryonic motility and the subsequent hatching via inducing ROS and at the same time down-regulating Wnt signaling in fish embryos.}, }
@article {pmid30387809, year = {2019}, author = {Liu, X and Wang, L and Cai, J and Liu, K and Liu, M and Wang, H and Zhang, H}, title = {N-acetylcysteine alleviates H2O2-induced damage via regulating the redox status of intracellular antioxidants in H9c2 cells.}, journal = {International journal of molecular medicine}, volume = {43}, number = {1}, pages = {199-208}, pmid = {30387809}, issn = {1791-244X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism ; Caspases/metabolism ; Enzyme Activation/drug effects ; Glutathione Reductase/metabolism ; Hydrogen Peroxide/*toxicity ; Intracellular Space/*metabolism ; MAP Kinase Kinase Kinase 5/metabolism ; Mitochondria/drug effects/metabolism ; Models, Biological ; Myocytes, Cardiac/drug effects/enzymology/*metabolism/*pathology ; Oxidation-Reduction ; PTEN Phosphohydrolase/metabolism ; Peroxiredoxins/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Thioredoxins/metabolism ; }, abstract = {N‑acetylcysteine (NAC) is a thiol‑containing antioxidant that modulates the intracellular redox state. NAC can scavenge reactive oxygen species (ROS) and maintain reduced glutathione (GSH) levels, in order to protect cardiomyocytes from oxidative stress. The present study aimed to determine whether NAC protects cardiomyocytes from oxidative damage by regulating the redox status of intracellular antioxidant proteins. The results revealed that NAC pretreatment increased cell viability and inhibited the activation of caspase‑3, ‑8 and ‑9 during hydrogen peroxide (H2O2)‑induced oxidative stress in H9c2 cells. Furthermore, decreased ROS levels, and increased total and reduced GSH levels were detected in response to NAC pretreatment. Non‑reducing redox western blotting was performed to detect the redox status of intracellular antioxidant proteins, including thioredoxin 1 (Trx1), peroxiredoxin 1 (Prx1), GSH reductase (GSR), and phosphatase and tensin homolog (PTEN). The results revealed that the reduced form of Trx1 was markedly increased, and the oxidized forms of Prx1, GSR and PTEN were decreased following NAC pretreatment. Furthermore, NAC pretreatment decreased H2O2‑induced phosphorylation of apoptosis signal‑regulating kinase 1, which depends on the redox state of Trx1, and increased H2O2‑induced phosphorylation of protein kinase B, which is essential to cell survival. To the best of our knowledge, the present study is the first to reveal that NAC pretreatment may alleviate oxidation of intracellular antioxidant proteins to inhibit oxidative stress‑induced cardiomyocyte apoptosis.}, }
@article {pmid30384368, year = {2018}, author = {Wang, X and Fu, YF and Liu, X and Feng, G and Xiong, D and Mu, GF and Chen, FP}, title = {ROS Promote Ox-LDL-Induced Platelet Activation by Up-Regulating Autophagy Through the Inhibition of the PI3K/AKT/mTOR Pathway.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {50}, number = {5}, pages = {1779-1793}, doi = {10.1159/000494795}, pmid = {30384368}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Autophagy/*drug effects ; Beclin-1/metabolism ; Blood Platelets/cytology/drug effects/metabolism ; Cell Adhesion/drug effects ; Humans ; Lipoproteins, LDL/*pharmacology ; Microtubule-Associated Proteins/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Platelet Activation/*drug effects ; Platelet Aggregation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; RNA-Binding Proteins/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND/AIMS: Oxidized low-density lipoprotein (oxLDL) promotes unregulated platelet activation in patients with dyslipidemic disorders. Although oxLDL stimulates activating signaling, researchers have not clearly determined how these events drive accelerated thrombosis. Here, we describe the mechanism by which ROS regulate autophagy during ox-LDL-induced platelet activation by modulating the PI3K/AKT/mTOR signaling pathway.<br><br>METHODS: For in vitro experiments, ox-LDL, the ROS scavenger N-acetylcysteine (NAC), the mTOR inhibitor rapamycin and the autophagy inhibitor 3-MA were used alone or in combination with other compounds to treat platelets. Then, platelet aggregation was evaluated on an aggregometer and platelet adhesion was measured under shear stress. The levels of a platelet activation marker (CD62p) were measured by flow cytometry, reactive oxygen species (ROS) levels were then quantified by measuring DCFH-DA fluorescence intensity via flow cytometry. Nitric oxide (NO) and superoxide (O2&#xb7;-) levels were determined by the nitric acid deoxidize enzyme method and lucigenin-enhanced chemiluminescence (CL), respectively. Transmission electron microscopy was used to observe the autophagosome formation, immunofluorescence staining was employed to detect LC3 expression and western blotting was used to measure the levels of PI3K/AKT/mTOR pathway- and autophagy-related proteins.<br><br>RESULTS: Ox-LDL-induced platelets showed a significant increase in platelet aggregation and adhesion, CD62p expression, ROS level and O2&#xb7;- content, with an elevated LC3II/LC3I ratio and Beclin1 expression, but a dramatic reduction in the levels of p62 and pathway-related proteins (all P < 0.05). However, platelet activation and autophagy were aggravated by the Rapamycin treatment, and decreased following treatment with NAC, 3-MA, or NAC and 3-MA, together with increased activity of the PI3K/AKT/mTOR pathway. Additionally, decreased platelet activation and autophagy were observed in platelets treated with NAC and Rapamycin or Rapamycin and 3-MA compared with platelets treated with Rapamycin alone, suggesting that both NAC and 3-MA reversed the effects of Rapamycin.<br><br>CONCLUSION: Inhibition of ROS production may reduce autophagy to suppress ox-LDL-induced platelet activation by activating PI3K/AKT/mTOR pathway.}, }
@article {pmid30383692, year = {2018}, author = {Guo, J and Li, B and Li, W and Pan, Y and Wang, Z and Wu, Y and Wang, F}, title = {Chinese herbal medicines compared with N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: Protocol for a systematic review.}, journal = {Medicine}, volume = {97}, number = {44}, pages = {e13077}, pmid = {30383692}, issn = {1536-5964}, mesh = {Acetylcysteine/*therapeutic use ; Drug Therapy, Combination ; Drugs, Chinese Herbal/*therapeutic use ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/physiopathology ; Quality of Life ; Randomized Controlled Trials as Topic ; Systematic Reviews as Topic ; Total Lung Capacity ; Treatment Outcome ; }, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a major public health problem worldwide. There is no curative treatment for IPF except lung transplantation. Chinese herbal medicines (CHMs) are widely used in the treatment of IPF in China. However, their effectiveness and safety are still obscure and deserve further investigation. The aim of the study was to assess the efficacy and safety of CHMs in treating IPF compared with N-acetylcysteine (NAC).<br><br>METHODS: This review summarizes and meta-analyzes randomized controlled trials (RCTs) of CHMs for the treatment of IPF. RCTs compare either CHMs alone or in combination with NAC or conventional medicine treatment (CMT) vs NAC alone or in combination with CMT have been included. The following electronic databases have been searched: PubMed, Cochrane Library, Embase, CNKI, CBM, VIP, and WANFANG DATA. The methodologic quality of RCTs has been assessed using the Cochrane risk assessment tool. All trials included are analyzed according to the criteria of the Cochrane Handbook. Review Manager 5.3, R-3.5.1 software, and GRADE pro GDT web solution are used for data synthesis and analysis.<br><br>RESULTS: This review evaluates the effects of CHMs on acute exacerbation, mortality, the quality of life, 6-minute walking test distance, lung function (total lung capacity, diffusing capacity of the lungs for carbon monoxide, and forced vital capacity), partial pressure of oxygen in blood (PaO2), and safety in patients with IPF.<br><br>CONCLUSION: This review provides clear evidence to assess the effectiveness and safety of CHMs for IPF.}, }
@article {pmid30381811, year = {2019}, author = {Ayaz, M and Yanardag, SB}, title = {SAH-Induced Electrophysiological Changes of Ventricular Myocytes and Role of N-acetylcysteine Protection.}, journal = {Journal of neurological surgery. Part A, Central European neurosurgery}, volume = {80}, number = {2}, pages = {72-80}, doi = {10.1055/s-0038-1655739}, pmid = {30381811}, issn = {2193-6323}, mesh = {Acetylcysteine/*therapeutic use ; Action Potentials/*drug effects ; Animals ; Calcium Channels/drug effects ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Heart Ventricles/*drug effects/pathology ; Male ; Myocytes, Cardiac/*drug effects ; Rabbits ; Sodium Channels/drug effects ; Subarachnoid Hemorrhage/*physiopathology ; }, abstract = {BACKGROUND: Electrocardiogram (ECG) changes in patients with subarachnoid hemorrhage (SAH) are frequent. ST- and/or T-wave changes in ECG seem to predominate.<br><br>STUDY AIMS: &#x2003;To investigate the ion channel mechanisms of SAH-induced ventricular excitation-contraction coupling changes and the possible protective effect of N-acetylcysteine (NAC).<br><br>METHODS: &#x2003;Three groups of rabbits were used for the experiments. In two groups, SAH was induced by replacing the cerebrospinal fluid (CSF) with fresh autologous blood. In the control group, CSF was replaced with isotonic saline. In one SAH group, NAC was administered daily beginning at SAH induction. On day 5, ventricular action potentials, ionic currents, contractions, and intracellular free ion concentrations were recorded from the myocytes.<br><br>RESULTS: &#x2003;In the SAH group, no change was found in the sodium currents, but the transient outward potassium currents were depressed, rapid repolarizing currents were increased, and t-type calcium currents were increased. Contractions and the intracellular free calcium concentration were depressed. NAC treatment, in contrast, not only restores these electrical remodeling changes but also the contractile abnormalities in the cardiac myocytes.<br><br>CONCLUSION: &#x2003;The changes in the action potential duration can be attributed to the measured ionic current changes. However, the exact mechanism, other than the oxidative stress, by which the NAC treatment protects the cardiac muscle needs additional investigations.}, }
@article {pmid30380633, year = {2018}, author = {Li, Y and Yu, J and Sun, T and Liu, C and Sun, Y and Wang, Y}, title = {Using the Marine Rotifer Brachionus plicatilis as an Endpoint to Evaluate Whether ROS-Dependent Hemolytic Toxicity Is Involved in the Allelopathy Induced by Karenia mikimotoi.}, journal = {Toxins}, volume = {10}, number = {11}, pages = {}, pmid = {30380633}, issn = {2072-6651}, mesh = {*Allelopathy ; Animals ; Dinoflagellida/*metabolism ; Harmful Algal Bloom ; *Hemolysis ; Reactive Oxygen Species/metabolism ; Reproduction ; Rotifera/*physiology ; }, abstract = {The toxic effects of the typically noxious bloom-forming dinoflagellate Karenia mikimotoi were studied using the allelopathic experimental system under controlled laboratory conditions. The potency of intact cell suspensions with whole cells, cell-free culture filtrate in different growth phases, and lysed cells with ultrasonication were compared, and the growth and reproduction of the marine rotifer Brachionus plicatilis were used as endpoints to evaluate toxic differences. The intact cell suspension resulted the most significant growth inhibition, including lethality, on the growth of B. plicatilis (p < 0.05). Lysed culture medium treated with ultrasonication and the cell-free culture filtrates at either the exponential or stationary phase exhibited limited negative impacts compared to the control according to changes in the population growth rate (r) and survival rate (p > 0.05). Reproduction presented a similar tendency to change, and the number of eggs produced per individual, as well as spawning period decreased in the whole cell and lysed cell suspensions. The key parameters in the lift table include the net reproductive rate (R0) and the intrinsic rate of increase (rm), which were more sensitive to treatment and were significantly suppressed compared to that of the control. The addition of the ROS inhibitor N-acetylcysteine (NAC) could not change the growth or reproduction patterns. Moreover, substantial hemolytic toxicity was found in the treatment of the intact cell suspension (p < 0.05), while limited toxicity was found in other treatments compared to that of the control. K. mikimotoi was speculated to secrete allelopathic substances onto the cell surface, and direct cell contact was necessary for allelopathic toxicity in B. plicatilis. Reactive oxygen species (ROS)-independent hemolytic toxicity was assumed to be the explanation for what was observed.}, }
@article {pmid30376582, year = {2018}, author = {Wang, H and Xing, X and Wang, J and Pang, B and Liu, M and Larios-Valencia, J and Liu, T and Liu, G and Xie, S and Hao, G and Liu, Z and Kan, B and Zhu, J}, title = {Hypermutation-induced in vivo oxidative stress resistance enhances Vibrio cholerae host adaptation.}, journal = {PLoS pathogens}, volume = {14}, number = {10}, pages = {e1007413}, pmid = {30376582}, issn = {1553-7374}, support = {R01 AI120489/AI/NIAID NIH HHS/United States ; }, mesh = {Adaptation, Physiological ; Animals ; Biofilms/*growth &amp; development ; Catalase/metabolism ; Cholera/genetics/*microbiology/pathology ; *Host-Pathogen Interactions ; Intestines/*microbiology ; Mice ; *Mutation ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Vibrio cholerae/*genetics ; Virulence ; }, abstract = {Bacterial pathogens are highly adaptable organisms, a quality that enables them to overcome changing hostile environments. For example, Vibrio cholerae, the causative agent of cholera, is able to colonize host small intestines and combat host-produced reactive oxygen species (ROS) during infection. To dissect the molecular mechanisms utilized by V. cholerae to overcome ROS in vivo, we performed a whole-genome transposon sequencing analysis (Tn-seq) by comparing gene requirements for colonization using adult mice with and without the treatment of the antioxidant, N-acetyl cysteine. We found that mutants of the methyl-directed mismatch repair (MMR) system, such as MutS, displayed significant colonization advantages in untreated, ROS-rich mice, but not in NAC-treated mice. Further analyses suggest that the accumulation of both catalase-overproducing mutants and rugose colony variants in NAC- mice was the leading cause of mutS mutant enrichment caused by oxidative stress during infection. We also found that rugose variants could revert back to smooth colonies upon aerobic, in vitro culture. Additionally, the mutation rate of wildtype colonized in NAC- mice was significantly higher than that in NAC+ mice. Taken together, these findings support a paradigm in which V. cholerae employs a temporal adaptive strategy to battle ROS during infection, resulting in enriched phenotypes. Moreover, ΔmutS passage and complementation can be used to model hypermuation in diverse pathogens to identify novel stress resistance mechanisms.}, }
@article {pmid30372895, year = {2018}, author = {Lakshmi, T and Sri Renukadevi, B and Senthilkumar, S and Haribalan, P and Parameshwari, R and Vijayaraghavan, R and Rajeshkumar, S}, title = {Seed and bark extracts of Acacia catechu protects liver from acetaminophen induced hepatotoxicity by modulating oxidative stress, antioxidant enzymes and liver function enzymes in Wistar rat model.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {108}, number = {}, pages = {838-844}, doi = {10.1016/j.biopha.2018.08.077}, pmid = {30372895}, issn = {1950-6007}, mesh = {Acacia/*chemistry ; Acetaminophen/*pharmacology ; Alanine Transaminase/metabolism ; Animals ; Antioxidants/pharmacology ; Aspartate Aminotransferases/metabolism ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism ; Female ; Hepatocytes/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism ; Oxidative Stress/drug effects ; Plant Bark/*chemistry ; Plant Extracts/*pharmacology ; Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; Seeds/*chemistry ; Superoxide Dismutase/metabolism ; }, abstract = {In this study we investigated the hepatoprotective effects and possible mechanism of Acacia catechu in acetaminophen (APAP) induced hepatotoxicity using female Wistar rat model. Hepatotoxicity was induced by oral administration of acetaminophen (750 mg/kg body weight) for 24 h. The seed (400 mg/kg body weight) and bark (400 mg/kg body weight) extract's treated groups exhibited hepatoprotective effects and was compared with well-known clinical anti-dote N-acetylcysteine (NAC). When groups treated with acetaminophen, significant increase of liver weight/body weight ratio, liver function enzymes such as alanine aminotransferase (ALT), alkaline phosphatase (ALP) and aspartate aminotransferase (AST) and decrease of antioxidant enzymes such as glutathione (GSH) and superoxide dismutase (SOD) were observed. The histopathology of APAP treated groups also showed moderate degree of sinusoidal congestion, centrilobular necrosis with polymorph nuclear cells infiltration, marked vacuolations and congestion. However, pretreatment with seed or bark extract groups decreased LPO accumulation, reduced the liver function enzymes and increased antioxidant defense enzymes. Moreover, histopathology of seed extract treated groups showed normal architecture whereas bark extract treated groups exhibited mild degree of vacuolations in the hepatocytes with minimal sinusoidal congestion. Taken together, our study concludes that A. catechu seed extract to be a more promising agent for protecting liver from APAP induced hepatotoxicity.}, }
@article {pmid30368897, year = {2019}, author = {Ansari, FA and Khan, AA and Mahmood, R}, title = {Ameliorative effect of carnosine and N-acetylcysteine against sodium nitrite induced nephrotoxicity in rats.}, journal = {Journal of cellular biochemistry}, volume = {120}, number = {5}, pages = {7032-7044}, doi = {10.1002/jcb.27971}, pmid = {30368897}, issn = {1097-4644}, support = {//DST-FIST/ ; //DST-PURSE/ ; //University Grants Commission, INDIA/ ; }, abstract = {The widespread use of sodium nitrite (NaNO2) for various industrial purposes has increased human exposure to alarmingly high levels of nitrate/nitrite. Because NaNO 2 is a strong oxidizing agent, induction of oxidative stress is one of the mechanisms by which it can exert toxicity in humans and animals. We have investigated the possible protection offered by carnosine (CAR) and N-acetylcysteine (NAC) against NaNO 2 -induced nephrotoxicity in rats. Animals orally received CAR at 100 mg/kg body weight/d for seven days or NAC at 100 mg/kg body weight/d for five days followed by a single oral dose of NaNO 2 at 60 mg/kg body weight. The rats were killed after 24 hours, and the kidneys were removed and processed for various analyses. NaNO 2 induced oxidative stress in kidneys, as shown by the decreased activities of antioxidant defense, brush border membrane, and metabolic enzymes. DNA-protein crosslinking and DNA fragmentation were also observed. CAR/NAC pretreatment significantly protected the kidney against these biochemical alterations. Histological studies supported these findings, showing kidney damage in NaNO 2 -treated animals and reduced tissue impairment in the combination groups. The protection offered by CAR and NAC against NaNO 2 -induced damage, and their nontoxic nature, makes them potential therapeutic agents against nitrite-induced nephrotoxicity.}, }
@article {pmid30362123, year = {2019}, author = {Moreno, NC and Garcia, CCM and Rocha, CRR and Munford, V and Menck, CFM}, title = {ATR/Chk1 Pathway is Activated by Oxidative Stress in Response to UVA Light in Human Xeroderma Pigmentosum Variant Cells.}, journal = {Photochemistry and photobiology}, volume = {95}, number = {1}, pages = {345-354}, doi = {10.1111/php.13041}, pmid = {30362123}, issn = {1751-1097}, support = {2012/16929-6//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2013/08028-1//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 2014/15982-6//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/International ; 150049/2018-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico (CNPq)/International ; //Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior (CAPES)/International ; }, mesh = {Ataxia Telangiectasia Mutated Proteins/*metabolism ; Cell Line, Tumor ; Checkpoint Kinase 1/*metabolism ; DNA-Directed DNA Polymerase/genetics ; Humans ; Metabolic Networks and Pathways/radiation effects ; *Oxidative Stress ; *Ultraviolet Rays ; Xeroderma Pigmentosum/genetics/*metabolism ; }, abstract = {The crucial role of DNA polymerase eta in protecting against sunlight-induced tumors is evidenced in Xeroderma Pigmentosum Variant (XP-V) patients, who carry mutations in this protein and present increased frequency of skin cancer. XP-V cellular phenotypes may be aggravated if proteins of DNA damage response (DDR) pathway are blocked, as widely demonstrated by experiments with UVC light and caffeine. However, little is known about the participation of DDR in XP-V cells exposed to UVA light, the wavelengths patients are mostly exposed. Here, we demonstrate the participation of ATR kinase in protecting XP-V cells after receiving low UVA doses using a specific inhibitor, with a remarkable increase in sensitivity and γH2AX signaling. Corroborating ATR participation in UVA-DDR, a significant increase in Chk1 protein phosphorylation, as well as S-phase cell cycle arrest, is also observed. Moreover, the participation of oxidative stress is supported by the antioxidant action of N-acetylcysteine (NAC), which significantly protects XP-V cells from UVA light, even in the presence of the ATR inhibitor. These findings indicate that the ATR/Chk1 pathway is activated to control UVA-induced oxidatively generated DNA damage and emphasizes the role of ATR kinase as a mediator of genomic stability in pol eta defective cells.}, }
@article {pmid30359634, year = {2019}, author = {Gonçalves, DF and Courtes, AA and Hartmann, DD and da Rosa, PC and Oliveira, DM and Soares, FAA and Dalla Corte, CL}, title = {6-Hydroxydopamine induces different mitochondrial bioenergetics response in brain regions of rat.}, journal = {Neurotoxicology}, volume = {70}, number = {}, pages = {1-11}, doi = {10.1016/j.neuro.2018.10.005}, pmid = {30359634}, issn = {1872-9711}, mesh = {Adrenergic Agents/toxicity ; Animals ; Brain/drug effects/*metabolism ; Energy Metabolism/drug effects/*physiology ; Male ; Mitochondria/drug effects/*metabolism ; Organ Culture Techniques ; Oxidative Stress/drug effects/physiology ; Oxidopamine/*toxicity ; Oxygen Consumption/drug effects/*physiology ; Rats ; Rats, Wistar ; }, abstract = {Mitochondrial dysfunction has been demonstrated to have a central role in Parkinson Disease (PD) pathophysiology. Some studies have indicated that PD causes an impairment in mitochondrial bioenergetics; however, the effects of PD on brain-region specific bioenergetics was never investigated before. This study aimed to evaluate mitochondrial bioenergetics in different rat brain structures in an in vitro model of PD using 6-OHDA. Rat brain slices of hippocampus, striatum, and cortex were exposed to 6-OHDA (100 μM) for 1 h and mitochondrial bioenergetic parameters, peroxide production, lactate dehydrogenase (LDH) and citrate synthase (CS) activities were analyzed. Hippocampus slices exposed to 6-OHDA presented increased peroxide production but, no mitochondrial adaptive response against 6-OHDA damage. Cortex slices exposed to 6-OHDA presented increased oxygen flux related to oxidative phosphorylation and energetic pathways exchange demonstrated by the increase in LDH activity, suggesting a mitochondrial compensatory response. Striatum slices exposed to 6-OHDA presented a decrease of oxidative phosphorylation and decrease of oxygen flux related to ATP-synthase indicating an impairment in the respiratory chain. The co-incubation of 6-OHDA with n-acetylcysteine (NAC) abolished the effects of 6-OHDA on mitochondrial function in all brain regions tested, indicating that the increased reactive oxygen species (ROS) production is responsible for the alterations observed in mitochondrial bioenergetics. The present results indicate a brain-region specific response against 6-OHDA, providing new insights into brain mitochondrial bioenergetic function in PD. These findings may contribute to the development of future therapies with a target on energy metabolism.}, }
@article {pmid30356434, year = {2018}, author = {Hassen, GW and Dhaliwal, A and Jenninigs, CA and Kalantari, H}, title = {The Role of Acetyl Cysteine in Cocaethylene (Non-Acetaminophen) Acute Liver Failure.}, journal = {Case reports in emergency medicine}, volume = {2018}, number = {}, pages = {4393064}, pmid = {30356434}, issn = {2090-648X}, abstract = {BACKGROUND: Acute liver failure can result from acetaminophen overdose, viral infection, toxins, and other disease conditions. Liver transplant is available in limited fashion and the criteria are strict as to who should get an available liver. N- Acetyl Cysteine (NAC) has been used in non-acetaminophen induced liver failure with success. Here we report a case of acute liver failure from cocaethylene that was reversed with NAC along with other medical therapy.<br><br>CASE PRESENTATION: A 50-year-old female patient presented to the Emergency Department (ED) with a two-day history of coffee ground vomiting and hematemesis. She reported occasional substance abuse and heavy alcoholism. She reported shortness of breath and chest pain from the recurrent forceful vomiting. The rest of the review of systems was unremarkable except a fall from intoxication. Physical examination revealed anicteric conjunctiva and nontender abdomen and her vital signs were within normal limits. Initial blood work revealed acute liver and renal failure. The patient was started with general medical management and liver transplant service rejected the case due to active substance abuse. She underwent brief hemodialysis and was started on NAC. Over the course of her hospital stay her liver function and kidney function improved significantly and patient was discharged to home.<br><br>CONCLUSION: In cases where liver transplant is not an option for various reasons including active substance abuse, a trial of N-Acetyl Cysteine may be beneficial and should be considered in the Emergency Department.}, }
@article {pmid30355916, year = {2018}, author = {Wang, X and Qian, H and Huang, X and Li, J and Zhang, J and Zhu, N and Chen, H and Zhu, C and Wang, J and Zhang, P and Jin, C and Ge, H}, title = {UCP2 Mitigates the Loss of Human Spermatozoa Motility by Promoting mROS Elimination.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {50}, number = {3}, pages = {952-962}, doi = {10.1159/000494479}, pmid = {30355916}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Iridoids/pharmacology ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*metabolism ; Reactive Oxygen Species/*metabolism ; Sperm Motility/drug effects/*physiology ; Spermatozoa/*metabolism ; Uncoupling Protein 2/antagonists &amp; inhibitors/*metabolism ; }, abstract = {BACKGROUND/AIMS: To demonstrate the function of uncoupling protein 2 (UCP2) in the regulation of human spermatozoa motility.<br><br>METHODS: Semen samples were collected from donors with either normal spermatozoa motility (normospermia [NS]) or poor spermatozoa motility (asthenospermia [AS]). UCP2 protein in spermatozoawas quantified by Western blotting. The level of mitochondrial reactive oxygen species (mROS) was evaluated by MitoSOX Red. The activity of mitochondrial membrane potential (MMP) in spermatozoa was evaluated by a JC-1 assay and the ATP level was monitored by a luciferin-luciferase assay.<br><br>RESULTS: UCP2 was expressed in both NS and AS groups, with the former exhibiting a higher level than the latter. Immunofluorescence analysis shows that UCP2 is mainly located at the mid-region of human spermatozoa. The inhibition of UCP2 by a highly selective inhibitor, Genipin, results in not only impaired spermatozoa mobility (P<.05) but also an elevated level of mROS (P<.05), suggesting that UCP2 is involved in the maintenance of the spermatozoa mobility, which probably is achieved by promoting mROS elimination. Furthermore, H2O2 treatment of spermatozoa increases the mROS level coupled with the loss of spermatozoa mobility. Unexpectedly, this treatment also has a positive impact on the expression of UCP2 within a certain range of supplemental H2O2, indicating the moderate mROS level possibly serves as a feedback signal to stimulate the expression of UCP2. Finally, the treatment of spermatozoa by an ROS scavenger, N-acetyl-l-cysteine (NAC),decreases the level of mROS and increases the curvilinear velocity (VCL) of spermatozoa, but the UCP2 level is not affected.<br><br>CONCLUSION: These results suggest an UCP2-mROS-motility regulatory system exists for maintaining spermatozoa mobility in humans. In such a system, UCP2 fulfills its function by promoting mROS elimination, and slightly over-produced mROS in turn serves as a signal to stimulates the expression of UCP2. This regulatory system represents a new potential target for the discovery of novel pharmaceuticals for the treatment of patients with low spermatozoa motility.}, }
@article {pmid30355847, year = {2018}, author = {Çakın, &#xd6; and Tazegul, G and Gümüş, A and Cengiz, M and Ramazanoğlu, A}, title = {Incidental Aluminum Phosphide Poisoning: Case Report and Current Management.}, journal = {Folia medica}, volume = {60}, number = {3}, pages = {464-467}, doi = {10.2478/folmed-2018-0001}, pmid = {30355847}, issn = {0204-8043}, mesh = {*Accidents ; Acetylcysteine/therapeutic use ; Adrenergic alpha-Agonists/*therapeutic use ; Adult ; Aluminum Compounds/*poisoning ; Crystalloid Solutions/therapeutic use ; *Fluid Therapy ; Free Radical Scavengers/*therapeutic use ; Glasgow Coma Scale ; Humans ; Hypotension/chemically induced/*therapy ; *Inhalation Exposure ; Male ; Norepinephrine/therapeutic use ; Pesticides/*poisoning ; Phosphines/*poisoning ; *Respiration, Artificial ; Tachycardia/chemically induced/*therapy ; }, abstract = {Aluminum phosphide (AlP) is a commonly used cheap rodenticide, insecticide, and fumigant. Most intoxications in the literature are suicidal ingestions, however, AlP may cause incidental inhalational toxicities as well. After ingestion or inhalation, nausea, vomiting, dyspnea and abdominal pain develops within minutes. Hallmark of toxicity is refractory hypotension, cardiac failure and severe metabolic acidosis developing within a matter of hours are the major cause of mortality. In Turkey, AlP tablets are widely accessible and are sold without any restrictions. However, there are few local case reports in the literature. Additionally, incidental AlP intoxications are rarely reported. Herein, we present a 25-year-old male patient incidentally poisoned with AlP. He was found unconscious in a grain storage unit protected by aluminum phosphide tablets. He had hypotension and tachycardia. Arterial blood gas analysis did not reveal metabolic acidosis. He was quickly intubated and admitted to Intensive Care Unit (ICU). Supportive care crystalloid solution, n-acetyl cysteine and norepinephrine infusion was administered. After 36 hours, he was extubated and discharged without any complications. There is no specific antidote or treatment for AlP toxicity. Literature is controversial regarding treatment approach. Inhalational toxicity may occur under extreme conditions, as presented in this case report. Preventive strategies should be considered to reduce incidents. Clinicians should also be aware that AlP is a widely available and highly toxic compound that has no specific antidote and toxicity needs to be urgently treated with best supportive care.}, }
@article {pmid30355525, year = {2018}, author = {Moniruzzaman, R and Rehman, MU and Zhao, QL and Jawaid, P and Mitsuhashi, Y and Imaue, S and Fujiwara, K and Ogawa, R and Tomihara, K and Saitoh, JI and Noguchi, K and Kondo, T and Noguchi, M}, title = {Roles of intracellular and extracellular ROS formation in apoptosis induced by cold atmospheric helium plasma and X-irradiation in the presence of sulfasalazine.}, journal = {Free radical biology &amp; medicine}, volume = {129}, number = {}, pages = {537-547}, doi = {10.1016/j.freeradbiomed.2018.10.434}, pmid = {30355525}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/radiation effects ; Calcium/metabolism ; Caspase 3/genetics/metabolism ; Caspase 8/genetics/metabolism ; Cations, Divalent ; Cell Line, Tumor ; Cell Survival/drug effects/radiation effects ; DNA Fragmentation/drug effects/radiation effects ; Gene Expression Regulation ; HCT116 Cells ; Helium/chemistry ; Humans ; Hydroxyl Radical/agonists/*metabolism ; Membrane Potential, Mitochondrial/drug effects/radiation effects ; Mitochondria/drug effects/metabolism/radiation effects ; Oxidants/*pharmacology ; Oxidative Stress ; Plasma Gases/*pharmacology ; Signal Transduction ; Sulfasalazine/antagonists &amp; inhibitors/*pharmacology ; T-Lymphocytes/drug effects/*metabolism/pathology/radiation effects ; X-Rays ; fas Receptor/genetics/metabolism ; }, abstract = {Sulfasalazine (SSZ) is a well-known anti-inflammatory drug and also an inhibitor of the cystine-glutamate antiporter that is known to reduce intracellular glutathione (GSH) level and increase cellular oxidative stress, indicating its anti-tumor potential. However, the combination of SSZ with other physical modalities remains unexplored. Here, the effects of SSZ on cold atmospheric helium plasma (He-CAP), which produces approximately 24 x higher concentration of hydroxyl radicals (. OH) compared to X-irradiation (IR) in aqueous solution, and on IR-induced apoptosis in human leukemia Molt-4 cells were studied to elucidate the mechanism of apoptosis enhancement. Both the Annexin V-FITC/PI and DNA fragmentation assay revealed that pre-treatment of cells with SSZ significantly enhanced He-CAP and IR-induced apoptosis. Similar enhancement was observed during the loss of mitochondrial membrane potential, intracellular Ca[2+] ions, and mitochondria- and endoplasmic reticulum-related proteins. The concentration of intracellular reactive oxygen species (ROS) was much higher in He-CAP treated cells than in X-irradiated cells. On the other hand, strong enhancement of Fas expression and caspase-8 and -3 activities were only observed in X-irradiated cells. It might be possible that the higher concentration of intracellular and extracellular ROS suppressed caspase activities and Fas expression in He-CAP-treated cells. Notably, pretreating the cells with an antioxidant N-acetyl-L-cysteine (NAC) dramatically decreased apoptosis in cells treated by He-CAP, but not by IR. These results suggest that IR-induced apoptosis is due to specific and effective ROS distribution since intracellular ROS formation is marginal and the high production of ROS inside and outside of cells plays unique roles in He-CAP induced apoptosis. We conclude that our data provides efficacy and mechanistic insights for SSZ, which might be helpful for establishing SSZ as a future sensitizer in He-CAP or IR therapy for cancer.}, }
@article {pmid30351107, year = {2018}, author = {Gangopadhyay, D and Das, M and Singh, KK and Sharma, P and Singh, RK and Tandon, P}, title = {Monitoring the in Vitro Thiazolidine Ring Formation of Antioxidant Drug N-Acetyl-l-cysteine at Basic pH and Detection of Reaction Intermediates: A Raman Spectroscopic and Ab Initio Study.}, journal = {The journal of physical chemistry. B}, volume = {122}, number = {45}, pages = {10306-10314}, doi = {10.1021/acs.jpcb.8b08512}, pmid = {30351107}, issn = {1520-5207}, mesh = {Acetylcysteine/*chemistry ; Antioxidants/*chemistry ; Cyclization ; Hydrogen-Ion Concentration ; Models, Chemical ; Spectrum Analysis, Raman ; Thiazolidines/*chemical synthesis ; }, abstract = {The important cyclization reaction of antioxidant drug N-acetyl-l-cysteine (NAC) has been monitored in vitro at basic pH with the help of time series Raman spectroscopy. The thiazoline ring formation of NAC at acidic pH is a well-known reaction and has been studied extensively. However, the formation of a thiazolidine ring from NAC at basic pH has not been investigated precisely till date. The effect of basicity of the medium on the rate of cyclization has been investigated by studying the reaction at five different basic pH values. Raman signatures of cyclization have been observed with the passage of time and are found to appear faster as the basicity of the medium increases. Ab initio calculations have been done to understand the plausible mechanism of the reaction at basic pH. It is observed that formation of a thiazolidine ring from NAC occurs primarily in four steps, which involve proton abstraction from the thiol (SH) group of NAC and subsequent formation of an S-C bond by a nucleophilic attack of the C-S group on the protonated C-O-H group in NAC. Correlation of the theoretically calculated results with experimental Raman spectral analysis has led to a detailed and proper understanding of this important biochemical reaction.}, }
@article {pmid30350914, year = {2019}, author = {Lee, AC and Aung, L}, title = {Treatment of hepatic veno-occlusive disease in children with N-acetylcysteine.}, journal = {Pediatric blood &amp; cancer}, volume = {66}, number = {2}, pages = {e27518}, doi = {10.1002/pbc.27518}, pmid = {30350914}, issn = {1545-5017}, mesh = {Acetylcysteine/*therapeutic use ; Antineoplastic Agents/adverse effects ; Child ; Child, Preschool ; Female ; Free Radical Scavengers/*therapeutic use ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hepatic Veno-Occlusive Disease/*drug therapy/etiology ; Humans ; Male ; Retrospective Studies ; }, abstract = {In our institution, hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) has been treated with N-acetylcysteine (NAC) since 2008-a loading dose of 150 mg/kg, followed by 12 doses of 70 mg/kg 6 hourly. Nine children were diagnosed with hepatic VOD/SOS. Hepatic VOD/SOS occurred in seven children after stem cell transplantation and two were receiving chemotherapy for Wilms tumor. Their clinical severity was classified as moderate in two and severe in seven by the European Society for Blood and Marrow Transplantation criteria. All children recovered and were discharged from 4 to 16 days after diagnosis. No side effects were observed. Intravenous NAC is an effective treatment for hepatic VOD/SOS.}, }
@article {pmid30350617, year = {2018}, author = {Balamurugan, TST and Huang, CH and Chang, PC and Huang, ST}, title = {Electrochemical Molecular Switch for the Selective Profiling of Cysteine in Live Cells and Whole Blood and for the Quantification of Aminoacylase-1.}, journal = {Analytical chemistry}, volume = {90}, number = {21}, pages = {12631-12638}, doi = {10.1021/acs.analchem.8b02799}, pmid = {30350617}, issn = {1520-6882}, mesh = {Acetylcysteine/chemistry ; Acrylates/*chemistry ; Amidohydrolases/*blood/chemistry ; Cysteine/*blood ; Electrochemical Techniques/*methods ; Enzyme Assays/*methods ; Escherichia coli/chemistry ; Humans ; Limit of Detection ; Metallocenes/*chemistry ; }, abstract = {A first-of-a-kind latent electrochemical redox probe, ferrocene carbamate phenyl acrylate (FCPA), was developed for the selective detection of cysteine (Cys) and aminoacylase (ACY-1). The electrochemical signal generated by this probe was shown to be highly specific to Cys and insensitive to other amino acids and biological redox reactants. The FCPA-incorporated electrochemical sensor exhibited a broad dynamic range of 0.25-100 μM toward Cys. This probe also proficiently monitored the ACY-1-catalyzed biochemical transformation of N-acetylcysteine (NAC) into Cys, and this proficiency was used to develop an electrochemical assay for quantifying active ACY-1, which it did so in a dynamic range of 10-200 pM (0.1-2 mU/cm[3]) with a detection limit of 1 pM (0.01 mU/cm[3]). Furthermore, the probe was utilized in real-time tracking and quantification of cellular Cys production, specifically in Escherichia coli W3110, along with a whole blood assay to determine levels of Cys and spiked ACY-1 in blood with a reliable analytical performance.}, }
@article {pmid30350305, year = {2019}, author = {Kumari, S and Mukherjee, A and Mukhopadhyay, CK}, title = {Dopamine promotes cathepsin B-mediated amyloid precursor protein degradation by reactive oxygen species-sensitive mechanism in neuronal cell.}, journal = {Molecular and cellular biochemistry}, volume = {454}, number = {1-2}, pages = {153-163}, pmid = {30350305}, issn = {1573-4919}, support = {BT/PR20394/MED/122/24/2016//Department of Biotechnology, Ministry of Science and Technology/ ; }, mesh = {Amyloid beta-Protein Precursor/*metabolism ; Animals ; Brain/enzymology/*metabolism ; Cathepsin B/genetics/*metabolism ; Cell Line, Tumor ; Dopamine/*metabolism ; Gene Expression Regulation ; Humans ; Lysosomes/enzymology ; Neurons/*metabolism ; PC12 Cells ; Proteolysis ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Recent literature suggested an important function of native amyloid precursor protein (APP) as amine oxidase implicating in protection of brain cells from catecholamine-induced toxicity. However, any role of catecholamines on regulation of native APP has not been explored. Here we report that dopamine (DA), one of the most prominent catecholamine neurotransmitters in brain, down-modulates native APP protein in several neuronal cell types. Using SH-SY5Y cells as model, we detected no alteration of transcript expression and unaffected translation suggested that DA might induce APP degradation. We actually found that DA treatment decreased the stability of APP. Lysosomal blockers inhibited DA-induced APP degradation, but specific proteasomal blocker failed to do so. We detected the role of cathepsin B in DA-induced APP degradation by using pharmacological inhibitor and specific siRNA. We also revealed that DA could increase cathepsin B expression at both transcript and protein levels. Using antioxidant N-acetyl cysteine, we detected increased level of reactive oxygen species generation that was found responsible for induced cathepsin B expression by DA and resultant APP degradation. Our study reveals the existence of reciprocal regulation of a catecholamine and an amine oxidase implicating in brain catecholamine homeostasis.}, }
@article {pmid30349987, year = {2019}, author = {Kitzler, TM and Gupta, IR and Osterman, B and Poulin, C and Trakadis, Y and Waters, PJ and Buhas, DC}, title = {Acute and Chronic Management in an Atypical Case of Ethylmalonic Encephalopathy.}, journal = {JIMD reports}, volume = {45}, number = {}, pages = {57-63}, pmid = {30349987}, issn = {2192-8304}, abstract = {Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene. ETHE1 is vital for the catabolism of hydrogen sulfide (H2S). Patients with pathogenic mutations in ETHE1 have markedly increased thiosulfate, which is a reliable index of H2S levels. Accumulation of H2S is thought to cause the characteristic metabolic derangement found in EE. Recently introduced treatment strategies in EE, such as combined use of metronidazole (MNZ) and N-acetylcysteine (NAC), are aimed at lowering chronic H2S load. Experience with treatment strategies directed against acute episodes of metabolic decompensation (e.g., hemodialysis) is limited. Here we present an unusually mild, molecularly confirmed, case of EE in a 19-year-old male on chronic treatment with MNZ and NAC. During an acute episode of metabolic decompensation, we employed continuous renal replacement therapy (CRRT) to regain metabolic control. On continuous treatment with NAC and MNZ during the months preceding the acute event, plasma thiosulfate levels ranged from 1.6 to 4 μg/mL (reference range up to 2 μg/mL) and had a mean value of 2.5 μg/mL. During the acute decompensation, thiosulfate levels were 6.7 μg/mL, with hyperlactatemia and perturbed organic acid, acylglycine, and acylcarnitine profiles. CRRT decreased thiosulfate within 24 h to 1.4 μg/mL. Following discontinuation of CRRT, mean thiosulfate levels were 3.2 μg/mL (range, 2.4-3.7 μg/mL) accompanied by clinical improvement with metabolic stabilization of blood gas, acylcarnitine, organic acid, and acylglycine profiles. In conclusion, CRRT may help to regain metabolic control in patients with EE who have an acute metabolic decompensation on chronic treatment with NAC and MNZ.}, }
@article {pmid30349052, year = {2018}, author = {Pan, JX and Tang, F and Xiong, F and Xiong, L and Zeng, P and Wang, B and Zhao, K and Guo, H and Shun, C and Xia, WF and Mei, L and Xiong, WC}, title = {APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress.}, journal = {Cell death &amp; disease}, volume = {9}, number = {11}, pages = {1077}, pmid = {30349052}, issn = {2041-4889}, support = {I01 BX000838/BX/BLRD VA/United States ; R01 AG045781/AG/NIA NIH HHS/United States ; R01 AG051773/AG/NIA NIH HHS/United States ; RF1 AG045781/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Alzheimer Disease/metabolism/physiopathology ; Amyloid beta-Peptides/*metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Antioxidants/metabolism ; Apoptosis/physiology ; Bone Resorption/metabolism/physiopathology ; Bone and Bones/metabolism/physiopathology ; Brain/metabolism/physiopathology ; Cells, Cultured ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/*metabolism/*physiology ; Osteoblasts/*metabolism/*physiology ; Osteogenesis/*physiology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Amyloid precursor protein (APP) is ubiquitously expressed in various types of cells including bone cells. Mutations in App gene result in early-onset Alzheimer's disease (AD). However, little is known about its physiological function in bone homeostasis. Here, we provide evidence for APP's role in promoting bone formation. Mice that knocked out App gene (APP[-/-]) exhibit osteoporotic-like deficit, including reduced trabecular and cortical bone mass. Such a deficit is likely due in large to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption was detected in the mutant mice. Further mechanical studies of APP[-/-] OBs showed an impairment in mitochondrial function, accompanied with increased reactive oxygen species (ROS) and apoptosis. Intriguingly, these deficits, resemble to those in Tg2576 animal model of AD that expresses Swedish mutant APP (APPswe), were diminished by treatment with an anti-oxidant NAC (n-acetyl-l-cysteine), uncovering ROS as a critical underlying mechanism. Taken together, these results identify an unrecognized physiological function of APP in promoting OB survival and bone formation, implicate APPswe acting as a dominant negative factor, and reveal a potential clinical value of NAC in treatment of AD-associated osteoporotic deficits.}, }
@article {pmid30348415, year = {2019}, author = {Farahani, KZ and Benvidi, A and Rezaeinasab, M and Abbasi, S and Abdollahi-Alibeik, M and Rezaeipoor-Anari, A and Zarchi, MAK and Abadi, SSADM}, title = {Potentiality of PARAFAC approaches for simultaneous determination of N-acetylcysteine and acetaminophen based on the second-order data obtained from differential pulse voltammetry.}, journal = {Talanta}, volume = {192}, number = {}, pages = {439-447}, doi = {10.1016/j.talanta.2018.08.092}, pmid = {30348415}, issn = {1873-3573}, mesh = {Acetaminophen/*blood ; Acetylcysteine/*blood ; Biphenyl Compounds/chemistry ; Boranes/chemistry ; Calibration ; Electrochemical Techniques/*methods ; Electrodes ; *Factor Analysis, Statistical ; Graphite/chemistry ; Kinetics ; Limit of Detection ; Nanoparticles/chemistry ; Oxidation-Reduction ; Silicon Dioxide/chemistry ; }, abstract = {N-acetylcysteine (N-AC) has widespread application such as pharmaceutical drug and nutritional supplement. Its adverse effects are rash, urticaria, and itchiness and large doses of N-AC could potentially cause damage to the heart and lungs. Therefore, in this work, a sensitive voltammetric sensor based on a carbon paste electrode modified with silica nano particles (i.e. Mobil Composition of Matter (No. 41) modified with Boron Trifluoride or BF3@MCM-41) with a combination of 4,4'-dihydroxybiphenyl (DHB) (BF3@MCM-41/DHB/CPE) was designed for determination of N-AC. The electrochemical oxidation of N-AC was examined using various techniques such as cyclic voltammetry (CV), chronoamperometry and differential pulse voltammetry (DPV). Under the optimum conditions, some parameters such as electron transfer coefficient (α) and heterogeneous rate constant (ks) were estimated for N-AC. Due to the use of N-AC for the treatment of acetaminophen (AC) overdose, the application of modified electrode was investigated for the simultaneous determination of N-AC and AC in blood serum and tablet samples. Since, the signals of these species overlap and due to the presence of interfering species in blood samples, the simultaneous determination of mentioned species is difficult or impossible. To overcome this challenge, parallel factor analysis (PARAFAC) was used for the analysis of the complex matrices to obtain the spectral profile of each component and interference. To achieve this goal, electrochemical second-order data were generated using a simple change in pulse height of differential pulse voltammetry. The results of the presently proposed strategy for the real samples analysis are similar to those obtained with HPLC. Thus, the proposed method has acceptable performance for simultaneous determination of the two species in real samples.}, }
@article {pmid30344285, year = {2018}, author = {Altintop, I and Tatli, M and Karakukcu, C and Soyer Sarica, Z and Hanım Yay, A and Balcioglu, E and Ozturk, A}, title = {Serum and Tissue HIF-2 Alpha Expression in CIN, N-Acetyl Cysteine, and Sildenafil-Treated Rat Models: An Experimental Study.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {54}, number = {4}, pages = {}, pmid = {30344285}, issn = {1648-9144}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Contrast Media/*adverse effects ; Disease Models, Animal ; Female ; Hypoxia-Inducible Factor 1, alpha Subunit/blood/genetics/*metabolism ; Kidney Diseases/chemically induced/*drug therapy/*metabolism ; Phosphodiesterase 5 Inhibitors/therapeutic use ; Rats ; Rats, Wistar ; Sildenafil Citrate/*therapeutic use ; }, abstract = {Background and Objectives: Contrast-induced nephropathy (CIN), is acute renal damage due to contrast agents. This study is conducted to evaluate serum and renal heterodimeric nuclear transcription factor (HIF)-2 alpha levels and its tissue expression in contrast-induced nephropathy, and in N-acetyl cysteine (NAC)-and Sildenafil-treated rat models. Materials/Methods: This randomized, controlled, interventional animal study was conducted on Wistar rats. Rats (n = 36) were randomly assigned to four groups: control (n = 9), CIN group (n = 9), CIN + NAC group (n = 9), and sildenafil (n = 9). The rat model was used to form iohexol-originated CIN. During the modeling, prophylactic treatment was performed at the 24th and 48th h. After 48 h of modeling, blood, urine, and tissue samples were obtained for biochemical analyses. HIF-2-α levels were measured in renal tissue, serum, and urine samples. Renal sections were also performed for histopathologic and immunohistochemical evaluations of renal injury and HIF-2-α expression. Results: In the CIN model, HIF-2α levels and other biochemical parameters were significantly increased (p < 0.01). Both sildenafil and NAC efficiently decreased renal damage due to contrast agents, as shown in histopathologic examinations (p < 0.05). Similarly, after treatment with sildenafil and NAC, HIF-2α levels were significantly decreased (p < 0.05). Conclusions: The current study shows that serum and tissue HIF-2α levels decrease in CIN. Besides, the levels and tissue expression of HIF-2α decrease with both NAC and sildenafil treatments. With further studies, HIF-2α can be investigated as a biomarker of CIN and can be used in the follow-up of patients with CIN.}, }
@article {pmid30342189, year = {2018}, author = {Martins, IL and Nunes, J and Charneira, C and Morello, J and Pereira, SA and Telo, JP and Marques, MM and Antunes, AMM}, title = {The first-line antiepileptic drug carbamazepine: Reaction with biologically relevant free radicals.}, journal = {Free radical biology &amp; medicine}, volume = {129}, number = {}, pages = {559-568}, doi = {10.1016/j.freeradbiomed.2018.10.408}, pmid = {30342189}, issn = {1873-4596}, mesh = {Acetylcysteine/*chemistry/metabolism ; Animals ; Anticonvulsants/*chemistry/metabolism ; Biotransformation ; Carbamazepine/*chemistry/metabolism ; Chromatography, Liquid ; Epilepsy/drug therapy/metabolism ; Glutathione/*chemistry/metabolism ; Humans ; Liver/*chemistry/metabolism ; Male ; Mass Spectrometry ; Oxygen/*chemistry/metabolism ; Rats ; Rats, Wistar ; }, abstract = {Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs by both adults and children. Despite its widespread use, CBZ is associated with central nervous system toxicity and severe hypersensitivity reactions, which raise concerns about its chronic use. While the precise mechanisms of CBZ-induced adverse events are still unclear, metabolic activation to the epoxide (CBZ-EP) has been thought to play a significant role. This work reports first-hand evidence that CBZ reacts readily with biologically relevant thiyl radicals with no need for bioactivation. Using liquid chromatography coupled with high resolution mass spectrometry, multiple products from direct reaction of CBZ with glutathione (GSH) and N-acetyl-L-cysteine (NAC) were unequivocally identified, including the same product obtained upon ring-opening of CBZ-EP. The product profile is complex and consistent with radical-mediated mechanisms. Importantly, side products and adducts compatible with this non-enzymatic pathway were identified in liver extracts from CBZ-treated Wistar rats. The reaction of CBZ with GSH and NAC is more extensive in the presence of oxygen. Taking into consideration that GSH conjugation is, in general, a detoxification pathway, these results suggest that under hyperoxia/oxidative stress conditions the bioavailability of the parent drug may be compromised. Additionally, this non-enzymatic process can be anticipated to play, at least in part, a role in the onset of CBZ-induced adverse reactions due to the concomitant generation of reactive oxygen species. Therefore, the search for causal relationships between the formation of non-enzymatically-driven CBZ products and the occurrence of CBZ-induced adverse events in human patients merits further research, aiming the translation of basic mechanistic findings into a clinical context that may ultimately lead to a safer CBZ prescription.}, }
@article {pmid30340029, year = {2018}, author = {Tang, S and Lu, C and Mo, L and Wang, X and Liang, Z and Qin, F and Liu, Y and Liu, Y and Huang, H and Huang, Y and Cai, H and Xiao, D and Guo, S and Ouyang, Y and Sun, B and Li, X}, title = {Hydrogen peroxide redistributes the localization of protein phosphatase methylesterase 1.}, journal = {Life sciences}, volume = {213}, number = {}, pages = {166-173}, doi = {10.1016/j.lfs.2018.10.029}, pmid = {30340029}, issn = {1879-0631}, mesh = {Active Transport, Cell Nucleus ; Carboxylic Ester Hydrolases/*metabolism ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Fibroblasts/drug effects/enzymology/metabolism ; HEK293 Cells ; Humans ; Hydrogen Peroxide/*pharmacology ; Intracellular Space/metabolism ; Male ; Methylation/drug effects ; Oxidative Stress/drug effects/physiology ; Phosphorylation/drug effects ; Primary Cell Culture ; Protein O-Methyltransferase ; Protein Phosphatase 2/metabolism ; }, abstract = {AIMS: Protein phosphatase methylesterase-1 (PME-1) is a serine hydrolase that catalyzes protein phosphatase 2A (PP2A) demethylation and negatively regulates its activity. PME-1 is compartmentalized within cells to precisely control the demethylation of PP2A. This study investigated the localization of PME-1 in human fibroblast cells (HDF) under oxidative stress.<br><br>MAIN METHODS: Alkaline demethylation and peptide competition assays were applied to detect the methylation sensitivity of anti-PP2Ac. The localization of PME-1, leucine carboxyl methyltransferase 1 (LCMT1), demethylated-phosphorylated-PP2Ac (dem-p-PP2Ac) and total PP2Ac was determined by immunofluorescence analysis, and protein expression was measured by Western blot. A HEK293 cell line stably expressing constructed PME-1-EGFP was used to dynamically monitor the nuclear export of PME-1 under oxidative stress.<br><br>KEY RESULTS: After hydrogen peroxide (H2O2) treatment, the protein expression of PME-1 remained unchanged, while PME-1 facilitated redistribution from the nucleus to the cytoplasm in HDF according to immunofluorescence analysis. In constructed HEK293 cells, the EGFP-tagged PME-1 was exported from the nucleus to the cytoplasm after H2O2 treatment, and nuclear export was eliminated after leptomycin B additions. Our observation of dem-p-PP2Ac species relocation from the nucleus to the cytoplasm under oxidative stress is consistent with the redistribution patterns of PME-1. Antioxidant N-acetyl cysteine can reverse the nuclear to cytoplasmic ratio of PME-1 proteins and dem-p-PP2Ac after H2O2 exposure.<br><br>SIGNIFICANCE: We found that PME-1 is exported from the nucleus to the cytoplasm upon H2O2 treatment and redistributes dem-p-PP2Ac in subcellular compartments. These findings offer new insight into the regulation of PME-1 localization and PP2A demethylation under oxidative stress.}, }
@article {pmid30339883, year = {2019}, author = {Chen, Q and Tang, L and Xin, G and Li, S and Ma, L and Xu, Y and Zhuang, M and Xiong, Q and Wei, Z and Xing, Z and Niu, H and Huang, W}, title = {Oxidative stress mediated by lipid metabolism contributes to high glucose-induced senescence in retinal pigment epithelium.}, journal = {Free radical biology &amp; medicine}, volume = {130}, number = {}, pages = {48-58}, doi = {10.1016/j.freeradbiomed.2018.10.419}, pmid = {30339883}, issn = {1873-4596}, mesh = {Autophagy ; Cell Cycle ; Cell Line ; Cellular Senescence ; Diabetic Retinopathy/*metabolism/pathology ; Glucose/*metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Lipid Droplets/metabolism ; Lipid Metabolism ; Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/*metabolism ; Signal Transduction ; }, abstract = {Retinal pigment epithelium (RPE) dysfunction is thought to increase the risk of the development and progression of diabetic retinopathy (DR), the leading cause of blindness. However, the molecular mechanism behind high glucose-induced RPE cell damage is still blurred. We reported that ARPE-19 exposed to 25 mM glucose for 48 h did not induce apoptosis, but senescence validated by SA-β-Gal staining, p21 expression and cell cycle distribution. High glucose also increased oxidant species that exerted a pivotal role in senescence, which could be relieved by the treatment with antioxidant N-acetylcysteine (NAC). The accumulation of lipid droplets and the increase of lipid oxidation were also observed in ARPE-19 treated with high glucose. And the supplementation of free fatty acids (FFAs) indicated that lipid metabolism was associated with the generation of hydrogen peroxide (H2O2) and subsequent senescence in ARPE-19. PI3K/Akt/mTOR signaling pathway was shown to be responsible for the accumulation of intracellular lipids by regulating fatty acid synthesis, which in turn controlled senescence. Furthermore, high glucose induced autophagy in ARPE-19 with the treatment of glucose for 48 h, and autophagy inhibitor hydroxychloroquine (HCQ) or bafilomycin further aggravated the senescence, accompanying by an increase in oxidant species. Whereas, prolonged high glucose exposure inhibited autophagy and increased apoptotic cells. Experiments above provide evidence that lipid metabolism plays an important role in oxidative stressed senescence of RPE.}, }
@article {pmid30338789, year = {2018}, author = {Jiang, HL and Cao, LQ and Chen, HY}, title = {Protective effects ROS up-regulation on premature ovarian failure by suppressing ROS-TERT signal pathway.}, journal = {European review for medical and pharmacological sciences}, volume = {22}, number = {19}, pages = {6198-6204}, doi = {10.26355/eurrev_201810_16025}, pmid = {30338789}, issn = {2284-0729}, mesh = {Animals ; Antioxidants/pharmacology ; Atrophy ; Disease Models, Animal ; Female ; Ovary/drug effects/*enzymology/pathology/physiopathology ; *Oxidative Stress/drug effects ; Primary Ovarian Insufficiency/*enzymology/pathology/physiopathology/prevention &amp; control ; RNA, Small Interfering/genetics/metabolism ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Telomerase/*metabolism ; }, abstract = {OBJECTIVE: Premature ovarian failure (POF) refers to the condition of pre-onset ovarian function failure, and is one commonly occurred disease in gynecology. Its pathogenic mechanism, however, is still unclear. Early study found decreased activity of telomerase reverse transcriptase (TERT). As an important factor to suppress TERT, oxidative stress has not been studied in POF. We, thus, investigated the role of reactive oxygen species (ROS)-TERT in POF.<br><br>MATERIALS AND METHODS: Rat POF model was induced by a single intraperitoneal injection of cyclophosphamide plus 12 mg/kg busulfan. Level of follicle stimulating hormone (FSH) and inhibin B was measured by enzyme-linked immunosorbent assay (ELISA), along with hematoxylin and eosin (HE) staining to confirm successful generation of models. Western blot was applied to measure TERT expression, and N-acetyl-cysteine (NAC) or TERT small interfere RNA (siRNA) was injected to suppress ROS or TERT level, followed by HE staining to observe POF condition.<br><br>RESULTS: In POF model, ovary tissues showed atrophy, less follicles, and more follicular atresia, plus mesenchymal hyperplasia. FSH and inhibin B level were significantly up-regulated and down-regulated, respectively (p<0.05). In POF rat, ROS level was elevated (p<0.05) whilst TERT level was decreased. NAC inhibited ROS level and enhanced TERT expression. In contrast, TERT siRNA further aggravated POF condition.<br><br>CONCLUSIONS: ROS up-regulation inhibits TERT expression, suppresses TERT activity and facilitates POF. The ROS-TERT pathway may work as the target for treating POF.}, }
@article {pmid30332851, year = {2018}, author = {Yu, CI and Chen, CY and Liu, W and Chang, PC and Huang, CW and Han, KF and Lin, IP and Lin, MY and Lee, CH}, title = {Sandensolide Induces Oxidative Stress-Mediated Apoptosis in Oral Cancer Cells and in Zebrafish Xenograft Model.}, journal = {Marine drugs}, volume = {16}, number = {10}, pages = {}, pmid = {30332851}, issn = {1660-3397}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Anthozoa ; Antineoplastic Agents/isolation &amp; purification/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*drug therapy ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Diterpenes/chemistry/isolation &amp; purification/*pharmacology/therapeutic use ; Humans ; Mouth Neoplasms/*drug therapy ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; Zebrafish ; }, abstract = {Presently, natural sources and herbs are being sought for the treatment of human oral squamous cell carcinoma (OSCC) in order to alleviate the side effects of chemotherapy. This study investigates the effect of sandensolide, a cembrane isolated from Sinularia flexibilis, to inhibit human OSCC cell growth with the aim of developing a new drug for the treatment of oral cancer. In vitro cultured human OSCC models (Ca9.22, SCC9 and HSC-3 cell lines) and oral normal cells (HGF-1), as well as a zebrafish xenograft model, were used to test the cytotoxicity of sandensolide (MTT assay), as well as to perform cell cycle analysis and Western blotting. Both the in vitro bioassay and the zebrafish xenograft model demonstrated the anti-oral cancer effect of sandensolide. Moreover, sandensolide was able to significantly suppress colony formation and induce apoptosis, as well as cell cycle arrest, in OSCC by regulating multiple key proteins. Induction of reactive oxygen species (ROS) was observed in sandensolide-treated oral cancer cells. However, these apoptotic changes were rescued by NAC pretreatment. These findings contribute to the knowledge of the model of action of sandensolide, which may induce oxidative stress-mediated cell death pathways as a potential agent in oral cancer therapeutics.}, }
@article {pmid30328963, year = {2019}, author = {Santos, P and Herrmann, AP and Elisabetsky, E and Piato, A}, title = {Anxiolytic properties of compounds that counteract oxidative stress, neuroinflammation, and glutamatergic dysfunction: a review.}, journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)}, volume = {41}, number = {2}, pages = {168-178}, pmid = {30328963}, issn = {1809-452X}, mesh = {Acetamides/*pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Anti-Anxiety Agents/*pharmacology ; Anxiety Disorders/*drug therapy ; Disease Models, Animal ; Fatty Acids, Omega-3/*pharmacology ; Glutamine/drug effects ; Humans ; Hypnotics and Sedatives/*pharmacology ; Neuroimmunomodulation/drug effects ; Oxidative Stress/drug effects ; }, abstract = {OBJECTIVE: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains.<br><br>METHODS: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders.<br><br>RESULTS: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects.<br><br>CONCLUSION: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.}, }
@article {pmid30326585, year = {2018}, author = {Otu, A and Langridge, P and Denning, DW}, title = {Nebulised N-Acetylcysteine for Unresponsive Bronchial Obstruction in Allergic Brochopulmonary Aspergillosis: A Case Series and Review of the Literature.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {4}, number = {4}, pages = {}, pmid = {30326585}, issn = {2309-608X}, abstract = {Many chronic lung diseases are characterized by the hypersecretion of mucus. In these conditions, the administration of mucoactive agents is often indicated as adjuvant therapy. N-acetylcysteine (NAC) is a typical example of a mucolytic agent. A retrospective review of patients with pulmonary aspergillosis treated at the National Aspergillosis Centre in Manchester, United Kingdom, with NAC between November 2015 and November 2017 was carried out. Six Caucasians with Aspergillus lung disease received NAC to facilitate clearance of their viscid bronchial mucus secretions. One patient developed immediate bronchospasm on the first dose and could not be treated. Of the remainder, two (33%) derived benefit, with increased expectoration and reduced symptoms. Continued response was sustained over 6[-]7 months, without any apparent toxicity. In addition, a systematic review of the literature is provided to analyze the utility of NAC in the management of respiratory conditions which have unresponsive bronchial obstruction as a feature.}, }
@article {pmid30324853, year = {2019}, author = {Gilardini Montani, MS and Santarelli, R and Granato, M and Gonnella, R and Torrisi, MR and Faggioni, A and Cirone, M}, title = {EBV reduces autophagy, intracellular ROS and mitochondria to impair monocyte survival and differentiation.}, journal = {Autophagy}, volume = {15}, number = {4}, pages = {652-667}, pmid = {30324853}, issn = {1554-8635}, mesh = {Apoptosis/genetics ; Autophagosomes/metabolism/*virology ; *Autophagy/genetics ; Autophagy-Related Protein 5/genetics/metabolism ; Cell Differentiation/genetics ; Cell Survival/genetics ; DNA-Binding Proteins/genetics/metabolism ; Dendritic Cells/metabolism/virology ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Herpesvirus 4, Human/*physiology ; Humans ; Interleukin-4/metabolism ; Kelch-Like ECH-Associated Protein 1/genetics/metabolism ; Mitochondria/*metabolism ; Mitochondrial Proteins/genetics/metabolism ; Monocytes/metabolism/*virology ; NF-E2-Related Factor 2/genetics/metabolism ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/genetics/metabolism ; Sequestosome-1 Protein/genetics/metabolism ; Signal Transduction/genetics ; Transcription Factors/genetics/metabolism ; rab GTP-Binding Proteins/genetics/metabolism ; rab7 GTP-Binding Proteins ; }, abstract = {EBV has been reported to impair monocyte in vitro differentiation into dendritic cells (DCs) and reduce cell survival. In this study, we added another layer of knowledge to this topic and showed that these effects correlated with macroautophagy/autophagy, ROS and mitochondrial biogenesis reduction. Of note, autophagy and ROS, although strongly interconnected, have been separately reported to be induced by CSF2/GM-CSF (colony stimulating factor 2) and required for CSF2-IL4-driven monocyte in vitro differentiation into DCs. We show that EBV infects monocytes and initiates a feedback loop in which, by inhibiting autophagy, reduces ROS and through ROS reduction negatively influences autophagy. Mechanistically, autophagy reduction correlated with the downregulation of RAB7 and ATG5 expression and STAT3 activation, leading to the accumulation of SQSTM1/p62. The latter activated the SQSTM1-KEAP1- NFE2L2 axis and upregulated the anti-oxidant response, reducing ROS and further inhibiting autophagy. ROS decrease correlated also with the reduction of mitochondria, the main source of intracellular ROS, achieved by the downregulation of NRF1 and TFAM, mitochondrial biogenesis transcription factors. Interestingly, mitochondria supply membranes and ATP required for autophagy execution, thus their reduction may further reduce autophagy in EBV-infected monocytes. In conclusion, this study shows for the first time that the interconnected reduction of autophagy, intracellular ROS and mitochondria mediated by EBV switches monocyte differentiation into apoptosis, giving new insights into the mechanisms through which this virus reduces immune surveillance. Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; BAF: bafilomycin A1; BECN1: beclin 1; CAT: catalase; CSF2: colony stimulating factor 2; CT: control; CYCS (cytochrome C: somatic); DCs: dendritic cells; EBV: Epstein-Barr virus; GSR: glutathione-disulfide reductase; KEAP1: kelch like ECH associated protein 1; IL4: interleukin 4; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MET: metformin; NAC: N-acetylcysteine; NFE2L2/NRF2 nuclear factor: erythroid 2 like 2; NRF1 (nuclear respiratory factor 1); clPARP1: cleaved poly(ADP-ribose) polymerase; Rapa: Rapamycin; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TFAM: (transcription factor A: mitochondrial); TUBA1A: tubulin alpha 1a.}, }
@article {pmid30318526, year = {2018}, author = {Tyagi, M and Maity, B and Saha, B and Bauri, AK and Subramanian, M and Chattopadhyay, S and Patro, BS}, title = {Spice-derived phenolic, malabaricone B induces mitochondrial damage in lung cancer cells via a p53-independent pathway.}, journal = {Food &amp; function}, volume = {9}, number = {11}, pages = {5715-5727}, doi = {10.1039/c8fo00624e}, pmid = {30318526}, issn = {2042-650X}, mesh = {A549 Cells ; Animals ; Apoptosis/drug effects ; Caspase 3/genetics/metabolism ; Caspase 9/genetics/metabolism ; Cell Line, Tumor ; Curcumin/pharmacology ; Cytochromes c/metabolism ; DNA Fragmentation ; HEK293 Cells ; Humans ; Inhibitory Concentration 50 ; Lung Neoplasms/*drug therapy ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, SCID ; Mitochondria/*drug effects ; Reactive Oxygen Species/metabolism ; Resorcinols/*pharmacology ; Tumor Suppressor Protein p53/genetics ; Xenograft Model Antitumor Assays ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {The spice-derived phenolic, malabaricone B (mal B) showed selective toxicity to human lung cancer (A549), malignant melanoma (A375) and T cell leukemia (Jurkat) cell lines, without showing toxicity to human normal intestinal (INT407), human kidney (HEK293) and lung fibroblast (WI-38) cells. Among the chosen cancer cell lines, mal B showed maximum cytotoxicity to the A549 cells (IC50 = 8.1 ± 1.0 μM), which was significantly better than that of curcumin (IC50 = 26.7 ± 3.1 μM). Further morphological studies by phase contrast microscopy and a clonogenic assay of the A549 cells revealed that mal B treatment increased the number of shrinking cells and also abolished the clonal proliferation of the cells. Mal B induced apoptotic cell death was confirmed by DNA laddering and quantified by cytoplasmic oligonucleosome formation and annexin V/PI assays. The mal B-induced apoptosis was mediated by an increase in the intracellular reactive oxygen species (ROS), because the cell-permeable antioxidants, N-acetylcysteine (NAC) and PEG-SOD, strongly inhibited its cytotoxicity to the A549 cells. Mal B increased the BAX level while simultaneously decreasing the BCL-2 and BCL-XL levels in the A549 cells, triggering the mitochondrial apoptotic pathway as revealed from the release of cytochrome c, and the activation of caspase-9 and caspase-3. Pre-treatment of cells with caspase-9, caspase-3 and pan-caspase inhibitors made them more resistant to mal B treatment. This effect of mal B was strongly associated with the concomitant decrease in anti-apoptotic (IAP1, IAP2 and survivin), angiogenic (growth factors) and cancer invasiveness (matrix metalloproteinase-9, COX-2) modulating proteins. Mal B induced cytotoxicity was unaffected by the shRNA-mediated depletion of p53 in A549 cells. Most importantly, mal B sensitized a wide range of human carcinoma cells regardless of their p53 status. Finally, mal B (100 mg kg-1) also inhibited lung tumor (xenograft) growth in SCID mice.}, }
@article {pmid30317657, year = {2019}, author = {Ung, TT and Nguyen, TT and Lian, S and Li, S and Xia, Y and Kim, NH and Jung, YD}, title = {Nicotine stimulates IL-6 expression by activating the AP-1 and STAT-3 pathways in human endothelial EA.hy926 cells.}, journal = {Journal of cellular biochemistry}, volume = {120}, number = {4}, pages = {5531-5541}, doi = {10.1002/jcb.27837}, pmid = {30317657}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cigarette Smoking/*mortality/pathology ; Endothelial Cells/*metabolism/pathology ; Humans ; Interleukin-6/*biosynthesis ; MAP Kinase Signaling System/*drug effects ; Nicotine/*pharmacology ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/*metabolism ; Transcription Factor AP-1/*metabolism ; Up-Regulation/*drug effects ; }, abstract = {Interleukin-6 (IL-6), a pleiotropic cytokine, plays a key role in endothelial injury and atherosclerosis. In this study, we investigated the effects of nicotine, a major psychoactive compound in cigarette smoke, on IL-6 expression and EA.hy926 endothelial cell invasion. Nicotine stimulated IL-6 expression via the activator protein 1 (AP-1) transcription factor. Pharmacological inhibition and mutagenesis studies indicated that p38 mitogen-activated protein kinase (MAPK) mediated the IL-6-induced upregulation of nicotine in EA.hy926 cells. Furthermore, the antioxidant compound N-acetyl-cysteine eliminated the nicotine-activated production of reactive oxygen species (ROS) and inhibited signal transducer and activator of transcription 3 (STAT-3) phosphorylation; these two mechanisms mediated the upregulation of IL-6 expression by nicotine. In addition, the EA.hy926 cells treated with nicotine displayed markedly enhanced invasiveness due to IL-6 upregulation. Our data demonstrate that nicotine induced IL-6 expression, which, in turn, enhanced the invasiveness of endothelial EA.hy926 cells, via activation of the p38 MAPK/AP-1 and ROS/STAT-3 signaling pathways.}, }
@article {pmid30316780, year = {2018}, author = {Ramírez-Camacho, I and Correa, F and El Hafidi, M and Silva-Palacios, A and Ostolga-Chavarría, M and Esparza-Perusquía, M and Olvera-Sánchez, S and Flores-Herrera, O and Zazueta, C}, title = {Cardioprotective strategies preserve the stability of respiratory chain supercomplexes and reduce oxidative stress in reperfused ischemic hearts.}, journal = {Free radical biology &amp; medicine}, volume = {129}, number = {}, pages = {407-417}, doi = {10.1016/j.freeradbiomed.2018.09.047}, pmid = {30316780}, issn = {1873-4596}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cardiotonic Agents/*pharmacology ; Electron Transport/drug effects ; Electron Transport Complex I/genetics/metabolism ; Electron Transport Complex III/genetics/metabolism ; Electron Transport Complex IV/genetics/metabolism ; Gene Expression Regulation ; Ischemic Postconditioning/methods ; Mitochondria, Heart/*drug effects/enzymology ; Mitochondrial Membranes/drug effects/enzymology ; Myocardial Reperfusion Injury/enzymology/genetics/pathology/*prevention &amp; control ; Myocardium/enzymology/pathology ; Oxidative Phosphorylation/drug effects ; Oxidative Stress/drug effects ; Oxygen Consumption/drug effects ; Rats ; Rats, Wistar ; }, abstract = {Electron leakage from dysfunctional respiratory chain and consequent superoxide formation leads to mitochondrial and cell injury during ischemia and reperfusion (IR). In this work we evaluate if the supramolecular assembly of the respiratory complexes into supercomplexes (SCs) is associated with preserved energy efficiency and diminished oxidative stress in post-ischemic hearts treated with the antioxidant N-acetylcysteine (NAC) and the cardioprotective maneuver of Postconditioning (PostC). Hemodynamic variables, infarct size, oxidative stress markers, oxygen consumption and the activity/stability of SCs were compared between groups. We found that mitochondrial oxygen consumption and the activity of respiratory complexes are preserved in mitochondria from reperfused hearts treated with both NAC and PostC. Both treatments contribute to recover the activity of individual complexes. NAC reduced oxidative stress and maintained SCs assemblies containing Complex I, Complex III, Complex IV and the adapter protein SCAFI more effectively than PostC. On the other hand, the activities of CI, CIII and CIV associated to SCs assemblies were preserved by this maneuver, suggesting that the activation of other cardioprotective mechanisms besides oxidative stress contention might participate in maintaining the activity of the mitochondrial respiratory complexes in such superstructures. We conclude that both the monomeric and the SCs assembly of the respiratory chain contribute to the in vivo functionality of the mitochondria. However, although the ROS-induced damage and the consequent increased production of ROS affect the assembly of SCs, other levels of regulation as those induced by PostC, might participate in maintaining the activity of the respiratory complexes in such superstructures.}, }
@article {pmid30315841, year = {2019}, author = {Wang, G and Ma, H and Wang, J and Khan, MF}, title = {Contribution of poly(ADP-ribose)polymerase-1 activation and apoptosis in trichloroethene-mediated autoimmunity.}, journal = {Toxicology and applied pharmacology}, volume = {362}, number = {}, pages = {28-34}, pmid = {30315841}, issn = {1096-0333}, support = {R01 ES016302/ES/NIEHS NIH HHS/United States ; R01 ES026887/ES/NIEHS NIH HHS/United States ; }, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Animals ; Antibodies, Antinuclear/blood ; Apoptosis/drug effects ; Autoimmunity/*drug effects ; DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Female ; Liver/drug effects/metabolism ; Mice, Knockout ; Poly (ADP-Ribose) Polymerase-1/*physiology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Solvents/*toxicity ; Trichloroethylene/*toxicity ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Trichloroethene (TCE), a common environmental toxicant and widely used industrial solvent, has been implicated in the development of various autoimmune diseases (ADs). Although oxidative stress has been involved in TCE-mediated autoimmunity, the molecular mechanisms remain to be fully elucidated. These studies were, therefore, aimed to further explore the contribution of oxidative stress to TCE-mediated autoimmune response by specifically assessing the role of oxidative DNA damage, its repair enzyme poly(ADP-ribose)polymerase-1 (PARP-1) and apoptosis. To achieve this, groups of female MRL +/+ mice were treated with TCE, TCE plus N-acetylcysteine (NAC) or NAC alone (TCE, 10 mmol/kg, i.p., every 4th day; NAC, 250 mg/kg/day in drinking water) for 6 weeks. TCE treatment led to significantly higher levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the livers compared to controls, suggesting increased oxidative DNA damage. TCE-induced DNA damage was associated with significant activation of PARP-1 and increases in caspase-3, cleaved caspase-8 and -9, and alterations in Bcl-2 and Bax in the livers. Moreover, the TCE-mediated alterations corresponded with remarkable increases in the serum anti-ssDNA antibodies. Interestingly, NAC supplementation not only attenuated elevated 8-OHdG, PARP-1, caspase-3, cleaved caspase-9, and Bax, but also the TCE-mediated autoimmune response supported by significantly reduced serum anti-ssDNA antibodies. These results suggest that TCE-induced activation of PARP-1 followed by increased apoptosis presents a novel mechanism in TCE-associated autoimmune response and could potentially lead to development of targeted preventive and/or therapeutic strategies.}, }
@article {pmid30315150, year = {2018}, author = {Klauser, P and Xin, L and Fournier, M and Griffa, A and Cleusix, M and Jenni, R and Cuenod, M and Gruetter, R and Hagmann, P and Conus, P and Baumann, PS and Do, KQ}, title = {N-acetylcysteine add-on treatment leads to an improvement of fornix white matter integrity in early psychosis: a double-blind randomized placebo-controlled trial.}, journal = {Translational psychiatry}, volume = {8}, number = {1}, pages = {220}, pmid = {30315150}, issn = {2158-3188}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/therapeutic use ; Antipsychotic Agents/therapeutic use ; Double-Blind Method ; Female ; Fornix, Brain/diagnostic imaging/*drug effects/pathology ; Humans ; Male ; Neuroprotective Agents/*therapeutic use ; Psychotic Disorders/diagnostic imaging/*drug therapy/*pathology ; Treatment Outcome ; White Matter/diagnostic imaging/*drug effects/pathology ; Young Adult ; }, abstract = {Mechanism-based treatments for schizophrenia are needed, and increasing evidence suggests that oxidative stress may be a target. Previous research has shown that N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor almost devoid of side effects, improved negative symptoms, decreased the side effects of antipsychotics, and improved mismatch negativity and local neural synchronization in chronic schizophrenia. In a recent double-blind randomized placebo-controlled trial by Conus et al., early psychosis patients received NAC add-on therapy (2700 mg/day) for 6 months. Compared with placebo-treated controls, NAC patients showed significant improvements in neurocognition (processing speed) and a reduction of positive symptoms among patients with high peripheral oxidative status. NAC also led to a 23% increase in GSH levels in the medial prefrontal cortex (GSHmPFC) as measured by [1]H magnetic resonance spectroscopy. A subgroup of the patients in this study were also scanned with multimodal MR imaging (spectroscopy, diffusion, and structural) at baseline (prior to NAC/placebo) and after 6 months of add-on treatment. Based on prior translational research, we hypothesized that NAC would protect white matter integrity in the fornix. A group × time interaction indicated a difference in the 6-month evolution of white matter integrity (as measured by generalized fractional anisotropy, gFA) in favor of the NAC group, which showed an 11% increase. The increase in gFA correlated with an increase in GSHmPFC over the same 6-month period. In this secondary study, we suggest that NAC add-on treatment may be a safe and effective way to protect white matter integrity in early psychosis patients.}, }
@article {pmid30314380, year = {2018}, author = {Joy, T and Rao, MS and Madhyastha, S}, title = {N-Acetyl Cysteine Supplement Minimize Tau Expression and Neuronal Loss in Animal Model of Alzheimer's Disease.}, journal = {Brain sciences}, volume = {8}, number = {10}, pages = {}, pmid = {30314380}, issn = {2076-3425}, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of neurofibrillary tangles (NFT), deposition of beta amyloid plaques, and consequent neuronal loss in the brain tissue. Oxidative stress to the neurons is often attributed to AD, but its link to NFT and β-amyloid protein (BAP) still remains unclear. In an animal model of AD, we boosted the oxidative defense by N-Acetyl cysteine (NAC), a precursor of glutathione, a powerful antioxidant and free radical scavenger, to understand the link between oxidative stress and NFT. In mimicking AD, intracerebroventricular (ICV) colchicine, a microtubule disrupting agent also known to cause oxidative stress was administered to the rats. The animal groups consisted of an age-matched control, sham operated, AD, and NAC treated in AD models of rats. Cognitive function was evaluated in a passive avoidance test; neuronal degeneration was quantified using Nissl staining. NFT in the form of abnormal tau expression in different regions of the brain were evaluated through immunohistochemistry using rabbit anti-tau antibody. ICV has resulted in significant cognitive and neuronal loss in medial prefrontal cortex (MFC) and all the regions of the hippocampus. It has also resulted in increased accumulation of intraneuronal tau in the hippocampus and MFC. NAC treatment in AD model rats has reversed the cognitive loss and neuronal degeneration. The intraneuronal tau expression also minimized with NAC treatment in AD model rats. Thus, our findings suggest that an antioxidant supplement during the progression of AD is likely to prevent neuronal degeneration by minimizing the neurofibrillary degeneration in the form of tau accumulation.}, }
@article {pmid30312797, year = {2018}, author = {Dong, B and Liu, C and Xue, R and Wang, Y and Sun, Y and Liang, Z and Fan, W and Jiang, J and Zhao, J and Su, Q and Dai, G and Dong, Y and Huang, H}, title = {Fisetin inhibits cardiac hypertrophy by suppressing oxidative stress.}, journal = {The Journal of nutritional biochemistry}, volume = {62}, number = {}, pages = {221-229}, doi = {10.1016/j.jnutbio.2018.08.010}, pmid = {30312797}, issn = {1873-4847}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cardiomegaly/*drug therapy/etiology ; Drug Synergism ; Enzymes/genetics/metabolism ; Flavonoids/*pharmacology ; Flavonols ; Gene Expression Regulation/drug effects ; MAP Kinase Signaling System/drug effects ; Male ; Mice, Inbred C57BL ; Myocytes, Cardiac/drug effects/pathology ; Oxidative Stress/*drug effects ; Phenylephrine/adverse effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Cardiac hypertrophy is a pathophysiological response to various pathological stresses and ultimately leads to heart failure. Oxidative stress is one of the critical processes involved in hypertrophy development. Fisetin, a small molecular flavonoid, has been shown to have anti-oxidative, anti-proliferative and anti-inflammatory properties. However, the effect of fisetin on cardiac hypertrophy remains unknown. In our present study, we showed that fisetin inhibited pressure overload-induced cardiac hypertrophy, improved cardiac function in vivo and suppressed phenylephrine (PE)-induced cardiomyocyte hypertrophy in vitro. Reactive oxygen species (ROS) levels were markedly decreased by fisetin treatment in both hypertrophic hearts and cardiomyocytes. Moreover, fisetin significantly up-regulated the expression of antioxidative genes, including catalase (CAT), superoxide dismutase 1 (SOD1) and heme oxygenase 1 (HO-1). Furthermore, co-treatment with N-acetylcysteine (NAC; ROS scavenger) and fisetin did not have synergistic inhibitory effects on PE-induced cardiomyocyte hypertrophy, indicating that the anti-hypertrophic effects of fisetin are mainly associated with the blockade of oxidative stress. Finally, the pro-hypertrophic signaling pathways, mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) kinase, were found to be suppressed by fisetin after pressure overload and PE treatment. In conclusion, our study revealed that fisetin protects against cardiac hypertrophy and that oxidative stress inhibition may be one of the pivotal mechanisms involved.}, }
@article {pmid30309503, year = {2018}, author = {Habas, K and Shang, L}, title = {Alterations in intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in human endothelial cells.}, journal = {Tissue &amp; cell}, volume = {54}, number = {}, pages = {139-143}, doi = {10.1016/j.tice.2018.09.002}, pmid = {30309503}, issn = {1532-3072}, mesh = {Atherosclerosis/*metabolism/physiopathology ; Cells, Cultured ; Cullin Proteins/*biosynthesis ; Human Umbilical Vein Endothelial Cells/drug effects/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Intercellular Adhesion Molecule-1/*biosynthesis ; Oxidative Stress/drug effects/physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Alterations of Endothelial cells (ECs) play a critical role in different pathogenesis of many serious human diseases, and dysfunction of the vascular endothelium is an indicator for human disorders. Endothelial dysfunction is considered to be an early indicator for atherosclerosis, which is characterised by overexpression of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Hydrogen peroxide (H2O2) released via neutrophils is an important mediator of endothelial cell function. Ambient production of superoxide anion (O2[-]) and subsequently H2O2 at low levels is critical for regulating endothelial cell functions and proliferation. In this study, we investigated the effects of H2O2 on the expression of adhesion molecules VCAM-1 and ICAM-1 in cultured human umbilical vein endothelial cells (HUVECs). Intracellular superoxide anion production was detected by using p-Nitro Blue Tetrazolium (NBT) assay. Our results showed that administration of 100μM of H2O2 on HUVECs for 2, 6, 12 and 24 h induced a time-dependent increase in ICAM-1 and VCAM-1 mRNA and protein expression levels with a significant increase observed from 6 h. HUVECs exposed to H2O2 exhibit increased O2[-], suggesting that H2O2 induced oxidative stress may be a reasonable for atherosclerosis. This increase can be reduced by the flavonoid, N-acetyl cysteine (NAC). The modulation of endothelial cell function through this mechanism may underlie the contribution of H2O2 to the development of vascular disease.}, }
@article {pmid30304829, year = {2018}, author = {Wang, J and Li, M and Zhang, W and Gu, A and Dong, J and Li, J and Shan, A}, title = {Protective Effect of N-Acetylcysteine against Oxidative Stress Induced by Zearalenone via Mitochondrial Apoptosis Pathway in SIEC02 Cells.}, journal = {Toxins}, volume = {10}, number = {10}, pages = {}, pmid = {30304829}, issn = {2072-6651}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cell Line ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/physiology ; Oxidative Stress/drug effects ; Protective Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; Swine ; Zearalenone/*toxicity ; }, abstract = {Zearalenone (ZEN), a nonsteroidal estrogen mycotoxin, is widely found in feed and foodstuffs. Intestinal cells may become the primary target of toxin attack after ingesting food containing ZEN. Porcine small intestinal epithelial (SIEC02) cells were selected to assess the effect of ZEN exposure on the intestine. Cells were exposed to ZEN (20 µg/mL) or pretreated with (81, 162, and 324 µg/mL) N-acetylcysteine (NAC) prior to ZEN treatment. Results indicated that the activities of glutathione peroxidase (Gpx) and glutathione reductase (GR) were reduced by ZEN, which induced reactive oxygen species (ROS) and malondialdehyde (MDA) production. Moreover, these activities increased apoptosis and mitochondrial membrane potential (ΔΨm), and regulated the messenger RNA (mRNA) expression of Bax, Bcl-2, caspase-3, caspase-9, and cytochrome c (cyto c). Additionally, NAC pretreatment reduced the oxidative damage and inhibited the apoptosis induced by ZEN. It can be concluded that ZEN-induced oxidative stress and damage may further induce mitochondrial apoptosis, and pretreatment of NAC can degrade this damage to some extent.}, }
@article {pmid30302628, year = {2018}, author = {Marchetti, DP and Steffens, L and Jacques, CE and Guerreiro, GB and Mescka, CP and Deon, M and de Coelho, DM and Moura, DJ and Viario, AG and Poletto, F and Coitinho, AS and Jardim, LB and Vargas, CR}, title = {Oxidative Imbalance, Nitrative Stress, and Inflammation in C6 Glial Cells Exposed to Hexacosanoic Acid: Protective Effect of N-acetyl-L-cysteine, Trolox, and Rosuvastatin.}, journal = {Cellular and molecular neurobiology}, volume = {38}, number = {8}, pages = {1505-1516}, pmid = {30302628}, issn = {1573-6830}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Catalase/metabolism ; Cell Survival/drug effects ; Chromans/*pharmacology ; Cytoplasmic Vesicles/metabolism ; DNA Damage ; Fatty Acids/*pharmacology ; Inflammation/*pathology ; Interleukin-1beta/metabolism ; Isoprostanes/metabolism ; Neuroglia/metabolism/*pathology ; Neuroprotective Agents/pharmacology ; Nitrates/metabolism ; Nitrites/metabolism ; *Nitrosative Stress/drug effects ; *Oxidative Stress/drug effects ; Rats ; Rosuvastatin Calcium/*pharmacology ; }, abstract = {X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very long-chain fatty acids from the cytosol into the peroxisome, to undergo β-oxidation. The mainly accumulated saturated fatty acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in tissues and body fluids. This peroxisomal disorder occurs in at least 1 out of 20,000 births. Considering that pathophysiology of this disease is not well characterized yet, and glial cells are widely used in studies of protective mechanisms against neuronal oxidative stress, we investigated oxidative damages and inflammatory effects of vesicles containing lecithin and C26:0, as well as the protection conferred by N-acetyl-L-cysteine (NAC), trolox (TRO), and rosuvastatin (RSV) was assessed. It was verified that glial cells exposed to C26:0 presented oxidative DNA damage (measured by comet assay and endonuclease III repair enzyme), enzymatic oxidative imbalance (high catalase activity), nitrative stress [increased nitric oxide (NO) levels], inflammation [high Interleukin-1beta (IL-1β) levels], and induced lipid peroxidation (increased isoprostane levels) compared to native glial cells without C26:0 exposure. Furthermore, NAC, TRO, and RSV were capable to mitigate some damages caused by the C26:0 in glial cells. The present work yields experimental evidence that inflammation, oxidative, and nitrative stress may be induced by hexacosanoic acid, the main accumulated metabolite in X-ALD, and that antioxidants might be considered as an adjuvant therapy for this severe neurometabolic disease.}, }
@article {pmid30301388, year = {2018}, author = {Lanza-Jacoby, S and Cheng, G}, title = {3,3'-Diindolylmethane enhances apoptosis in docetaxel-treated breast cancer cells by generation of reactive oxygen species.}, journal = {Pharmaceutical biology}, volume = {56}, number = {1}, pages = {407-414}, pmid = {30301388}, issn = {1744-5116}, mesh = {Antineoplastic Agents/*administration &amp; dosage ; Apoptosis/*drug effects/physiology ; Breast Neoplasms/drug therapy/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Docetaxel/*administration &amp; dosage ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Humans ; Indoles/*administration &amp; dosage ; Reactive Oxygen Species/agonists/*metabolism ; }, abstract = {CONTEXT: A major problem in the treatment of cancer is the development of toxic side effects and resistance to chemotherapy. The use of plant compounds to overcome resistance and prevent toxicity is a potential strategy for treatment.<br><br>OBJECTIVE: We evaluated whether 3,3'-diindolylmethane (DIM) enhanced the sensitivity of breast cancer cells to docetaxel (DOC).<br><br>MATERIALS AND METHODS: MDA-MB231 and Sk-BR-3 cells were treated with and without 25 or 50&#x2009;&#xb5;M of DIM and 1&#x2009;nM of DOC for 48 and 72&#x2009;h, respectively. MTT assay was used to measure cell survival. Apoptosis and intracellular reactive oxygen species (ROS) were determined by flow cytometry. The expression of proteins regulating ROS production and apoptosis was evaluated by immunoblotting technique.<br><br>RESULTS: Combining 25&#x2009;&#xb5;M of DIM with 1&#x2009;nM DOC decreased cell survival by 42% in MDA-MB231 cells and 59% in Sk-BR-3 cells compared to control, DIM, or DOC (p&#x2009;&#x2264;&#x2009;0.05). The combination treatment increased apoptosis over 20% (p&#x2009;&#x2264;&#x2009;0.01) in both cell lines, which was associated with decreased Bcl-2, increased Bax, cleaved PARP and activated JNK (p&#x2009;&#x2264;&#x2009;0.01). ROS production increased by 46.5% in the MDA-MB231 and 29.3% in Sk-BR-3 cells with the combination compared to DIM or DOC alone. Pretreating cells with N-acetyl-cysteine or Tiron abrogated the anti-survival effect of the combination. The increase in ROS was associated with a 54% decrease in MnSOD and 47% increase in NOX2 protein compared to the other groups.<br><br>CONCLUSIONS: Our findings indicated that DIM enhances the sensitivity of breast cancer cells to DOC treatment by increasing ROS, which led to decreased cell survival and apoptosis.}, }
@article {pmid30299418, year = {2019}, author = {Kinoshita, H and Orita, S and Inage, K and Yamauchi, K and Abe, K and Inoue, M and Norimoto, M and Umimura, T and Eguchi, Y and Fujimoto, K and Shiga, Y and Kanamoto, H and Aoki, Y and Furuya, T and Suzuki, M and Akazawa, T and Takahashi, K and Ohtori, S}, title = {Skeletal Muscle Cell Oxidative Stress as a Possible Therapeutic Target in a Denervation-Induced Experimental Sarcopenic Model.}, journal = {Spine}, volume = {44}, number = {8}, pages = {E446-E455}, doi = {10.1097/BRS.0000000000002891}, pmid = {30299418}, issn = {1528-1159}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Cell Line ; Denervation ; Disease Models, Animal ; Hydrogen Peroxide/pharmacology ; Male ; Mitogen-Activated Protein Kinases/metabolism ; Muscle Fibers, Skeletal ; Muscle, Skeletal/pathology ; Muscular Atrophy/*prevention &amp; control ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Sarcopenia/*drug therapy/physiopathology ; Sciatic Nerve/surgery ; }, abstract = {STUDY DESIGN: A basic study using a rodent model of sarcopenia.<br><br>OBJECTIVE: To elucidate the contribution of oxidative stress to muscle degeneration and the efficacy of antioxidant treatment for sarcopenia using an animal model of neurogenic sarcopenia.<br><br>SUMMARY OF BACKGROUND DATA: Oxidative stress has been reported to be involved in a number of pathologies, including musculoskeletal disorders. Its relationship with sarcopenia, one of the potential origins of lower back pain, however, is not yet fully understood.<br><br>METHODS: Myoblast cell lines (C2C12) were treated with H2O2, an oxidative stress inducer, and N-acetyl-L-cysteine (NAC), an antioxidant. Apoptotic effects induced by oxidative stress and the antioxidant effects of NAC were assessed by western blotting, immunocytochemistry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assays. An animal model of sarcopenia was produced via axotomy of the sciatic nerves to induce muscle atrophy. Twenty-four male Sprague-Dawley rats were divided into sham, sham+NAC, axotomy, and axotomy+NAC groups. Rats were provided water only or water containing NAC (1&#x200a;g/L) for 4 weeks. The gastrocnemius muscle was isolated and stained with hematoxylin and eosin (H&amp;E) 2 weeks after axotomy, from which muscle cells were harvested and protein extracted for evaluation.<br><br>RESULTS: Mitogen-activated protein kinases (MAPKs) were significantly activated by H2O2 treatment in C2C12 cells, which was ameliorated by NAC pretreatment. Furthermore, H2O2 induced apoptosis and death of C2C12 cells, which was prevented by NAC pretreatment. The weight of the gastrocnemius muscle was reduced in the axotomy group, which was prevented by NAC administration. Lastly, although muscle specimens from the axotomy group showed greater reductions in muscle fiber, the oral administration of NAC significantly inhibited amyotrophy via antioxidant effects.<br><br>CONCLUSION: The current in vitro and in vivo study demonstrated the possible involvement of oxidative stress in sarcopenic pathology. NAC represents a potential anti-sarcopenic drug candidate, preventing amyotrophy and fatty degeneration.<br><br>LEVEL OF EVIDENCE: 4.}, }
@article {pmid30296554, year = {2019}, author = {O'Gorman Tuura, R and Warnock, G and Ametamey, S and Treyer, V and Noeske, R and Buck, A and Sommerauer, M}, title = {Imaging glutamate redistribution after acute N-acetylcysteine administration: A simultaneous PET/MR study.}, journal = {NeuroImage}, volume = {184}, number = {}, pages = {826-833}, doi = {10.1016/j.neuroimage.2018.10.017}, pmid = {30296554}, issn = {1095-9572}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Basal Ganglia/drug effects/*metabolism ; Glutamic Acid/*metabolism ; Glutamine/metabolism ; Humans ; Magnetic Resonance Spectroscopy ; Male ; Positron-Emission Tomography ; Prefrontal Cortex/drug effects/*metabolism ; Young Adult ; }, abstract = {Glutamate is the most abundant excitatory neurotransmitter in the human brain, but in vivo imaging of acute fluctuations in glutamatergic levels has not been well established. The purpose of this study was to examine acute changes in glutamate after stimulation with N-acetylcysteine (NAC) using a simultaneous positron emission tomography/magnetic resonance spectroscopy (PET/MRS) approach. Ten healthy adult males were examined in two scanning sessions, and 5g NAC was administered 1 h prior to one of the scan sessions. Simultaneous PET/MR data were acquired using an integrated 3T PET/MR scanner. Glutamate (Glu), glutamine (Gln), and glutamate + glutamine (Glx) levels were assessed from MRS data collected from the basal ganglia with PRESS and from the left prefrontal cortex with PRESS and MEGAPRESS, and mGluR5 binding (BPND) was assessed from PET data collected with [[18]F]PSS232. NAC administration was associated with a significant reduction in Glx and Gln in the basal ganglia spectra, and in Glx in the frontal MEGAPRESS spectra (p < 0.05); no differences in [[18]F]PSS232 BPND were observed with NAC, although a correlation between pre-/post-treatment Glx and baseline BPnd was found. The MRS-visible Glx signal is sensitive to acute fluctuations in glutamate. The change in Glx was mostly driven by a change in Gln, lending weight to the notion that Gln can provide a proxy marker for neurotransmitter/synaptic glutamate. [[18]F]PSS232 binding is not sensitive to acute glutamate shifts independently, but was associated with the extent of glutamate liberation upon NAC stimulation.}, }
@article {pmid30296076, year = {2018}, author = {Kamiya, T and Watanabe, M and Hara, H and Mitsugi, Y and Yamaguchi, E and Itoh, A and Adachi, T}, title = {Induction of Human-Lung-Cancer-A549-Cell Apoptosis by 4-Hydroperoxy-2-decenoic Acid Ethyl Ester through Intracellular ROS Accumulation and the Induction of Proapoptotic CHOP Expression.}, journal = {Journal of agricultural and food chemistry}, volume = {66}, number = {41}, pages = {10741-10747}, doi = {10.1021/acs.jafc.8b04424}, pmid = {30296076}, issn = {1520-5118}, mesh = {A549 Cells ; Antineoplastic Agents/*chemistry/therapeutic use ; Apoptosis/drug effects ; Cell Death/drug effects ; Endoplasmic Reticulum Stress/drug effects ; Esters/chemistry/therapeutic use ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fatty Acids, Unsaturated/*chemistry/therapeutic use ; Humans ; Lung Neoplasms ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Transcription Factor CHOP/*drug effects/genetics ; }, abstract = {Royal jelly, a natural product secreted by honeybees, contains several fatty acids, such as 10-hydroxy-2-decenoic acid (DE), and shows anti- and pro-apoptotic properties. 4-Hydroperoxy-2-decenoic acid ethyl ester (HPO-DAEE), a DE derivative, exhibits potent antioxidative activity; however, it currently remains unclear whether HPO-DAEE induces cancer-cell death. In the present study, treatment with HPO-DAEE induced human-lung-cancer-A549-cell death (52.7 ± 10.2%) that was accompanied by DNA fragmentation. Moreover, the accumulation of intracellular reactive oxygen species (ROS, 2.38 ± 0.1-fold) and the induction of proapoptotic CCAAT-enhancer-binding-protein-homologous-protein (CHOP) expression (18.4 ± 4.0-fold) were observed in HPO-DAEE-treated cells. HPO-DAEE-elicited CHOP expression and cell death were markedly suppressed by pretreatment with N-acetylcysteine (NAC), an antioxidant, by 2.40 ± 1.57-fold and 5.7 ± 1.6%, respectively. Pretreatment with 4-phenylbutyric acid (PBA), an inhibitor of endoplasmic reticulum stress, also suppressed A549-cell death (38.4 ± 1.1%). Furthermore, we demonstrated the involvement of extracellular-signal-regulated protein kinase (ERK) and p38-related signaling in HPO-DAEE-elicited cell-death events. Overall, we concluded that HPO-DAEE induces A549-cell apoptosis through the ROS-ERK-p38 pathway and, at least in part, the CHOP pathway.}, }
@article {pmid30294906, year = {2018}, author = {Karuppagounder, SS and Alin, L and Chen, Y and Brand, D and Bourassa, MW and Dietrich, K and Wilkinson, CM and Nadeau, CA and Kumar, A and Perry, S and Pinto, JT and Darley-Usmar, V and Sanchez, S and Milne, GL and Pratico, D and Holman, TR and Carmichael, ST and Coppola, G and Colbourne, F and Ratan, RR}, title = {N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice.}, journal = {Annals of neurology}, volume = {84}, number = {6}, pages = {854-872}, pmid = {30294906}, issn = {1531-8249}, support = {P01 AG014930/AG/NIA NIH HHS/United States ; P01 NIA AG014930/NH/NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Arachidonate 5-Lipoxygenase/genetics/*metabolism ; Cation Transport Proteins/genetics/*metabolism ; Cell Nucleus/metabolism/pathology ; Cells, Cultured ; Cerebral Hemorrhage/chemically induced/complications ; Collagenases/toxicity ; Cytoplasm/metabolism ; Dinoprostone/*metabolism ; Disease Models, Animal ; Eicosanoids/metabolism ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Glutathione/metabolism ; Hemin/toxicity ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons/drug effects/metabolism ; Stroke/*drug therapy/etiology ; Treatment Outcome ; }, abstract = {OBJECTIVES: N-acetylcysteine (NAC) is a clinically approved thiol-containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an "antioxidant," poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke.<br><br>METHODS: Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons. Striatal infusion of collagenase was used to model intracerebral hemorrhage (ICH) in mice and rats. Chemical biology, targeted lipidomics, arachidonate 5-lipoxygenase (ALOX5) knockout mice, and viral-gene transfer were used to gain insight into the pharmacological targets and mechanism of action of NAC.<br><br>RESULTS: NAC prevented hemin-induced ferroptosis by neutralizing toxic lipids generated by arachidonate-dependent ALOX5 activity. NAC efficacy required increases in glutathione and is correlated with suppression of reactive lipids by glutathione-dependent enzymes such as glutathione S-transferase. Accordingly, its protective effects were mimicked by chemical or molecular lipid peroxidation inhibitors. NAC delivered postinjury reduced neuronal death and improved functional recovery at least 7 days following ICH in mice and can synergize with clinically approved prostaglandin E2 (PGE2).<br><br>INTERPRETATION: NAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE2 in vitro and in vivo. The findings provide novel insight into a target for NAC, beyond the generic characterization as an antioxidant, resulting in neuroprotection and offer a feasible combinatorial strategy to optimize efficacy and safety in dosing of NAC for treatment of neurological disorders involving ferroptosis such as ICH. Ann Neurol 2018;84:854-872.}, }
@article {pmid30290348, year = {2019}, author = {Abdel-Daim, MM and Dessouki, AA and Abdel-Rahman, HG and Eltaysh, R and Alkahtani, S}, title = {Hepatorenal protective effects of taurine and N-acetylcysteine against fipronil-induced injuries: The antioxidant status and apoptotic markers expression in rats.}, journal = {The Science of the total environment}, volume = {650}, number = {Pt 2}, pages = {2063-2073}, doi = {10.1016/j.scitotenv.2018.09.313}, pmid = {30290348}, issn = {1879-1026}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Gene Expression/drug effects ; Genetic Markers ; Insecticides/*toxicity ; Kidney/drug effects/metabolism ; Liver/drug effects/enzymology ; Male ; Protective Agents/*pharmacology ; Pyrazoles/*toxicity ; Rats ; Rats, Wistar ; Taurine/*pharmacology ; }, abstract = {Fipronil (FPN), a commonly used phenylpyrazole pesticide can induce oxidative tissue damage following hazard usage. Due to the extensive household and commercial usage of FPN, its toxic effects on mammals received considerable attention. Finding the proper antioxidant that can overcome FPN-induced damage is essential. Therefore, the present study aimed to assess the hepatorenal ameliorative outcomes of N-acetyl cysteine (NAC) and taurine (TAU) against hepatorenal damage induced by FPN in male Wistar rats. Compared to control rats, oral FPN (at a dose of 19.4 mg kg[-1] BW for five successive days) significantly increased serum activities (p ≤ 0.05) of alkaline phosphatase, lactate dehydrogenase and transaminases, in addition to total cholesterol, urea and creatinine levels. Moreover, FPN provoked oxidative damage indicated by increased malondialdehyde and nitric oxide formation and decreased glutathione concentration and activities of enzymatic antioxidants (superoxide dismutase, glutathione peroxidase and catalase) in the hepatic and renal tissues. Furthermore, FPN administration induced overexpression of the proapoptotic (Bax), while it downregulated the expression of the anti-apoptotic (Bcl-2) protein. Interestingly, oral administration of TAU (50 mg Kg[-1] BW) and NAC (50 mg Kg[-1] BW), alone or in combination, five days prior to and five days along with FPN administration, significantly ameliorated (p ≤ 0.05) and normalized the harmful effects of FPN on serum biomarkers of hepatorenal injury, lipid peroxidation and tissue antioxidants. In conclusion, TAU and NAC, alone or in combination, provided significant hepatorenal protection against oxidative stress and apoptosis induced by FPN.}, }
@article {pmid30290302, year = {2019}, author = {Solovieva, ME and Shatalin, YV and Solovyev, VV and Sazonov, AV and Kutyshenko, VP and Akatov, VS}, title = {Hydroxycobalamin catalyzes the oxidation of diethyldithiocarbamate and increases its cytotoxicity independently of copper ions.}, journal = {Redox biology}, volume = {20}, number = {}, pages = {28-37}, pmid = {30290302}, issn = {2213-2317}, mesh = {Cell Line ; Cell Survival/drug effects ; Copper/*metabolism ; Ditiocarb/chemistry/*metabolism/pharmacology ; Humans ; Hydrogen Peroxide/chemistry/metabolism/pharmacology ; Hydroxocobalamin/chemistry/*metabolism/pharmacology ; Ions/*metabolism ; *Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Spectrum Analysis ; }, abstract = {It is known that some metals (Cu, Zn, Cd, Au) markedly increase the toxic effect of thiocarbamates. It was shown in the present study that hydroxycobalamin (a form of vitamin B12, HOCbl), which incorporates cobalt, significantly enhances the cytotoxicity of diethyldithiocarbamate (DDC), decreasing its IC50 value in tumor cells three to five times. The addition of HOCbl to aqueous DDC solutions accelerated the reduction of oxygen. No hydrogen peroxide accumulation was observed in DDC + HOCbl solutions; however, catalase slowed down the oxygen reduction rate. Catalase as well as the antioxidants N-acetylcysteine (NAC) and glutathione (GSH) partially inhibited the cytotoxic effect of DDC + HOCbl, whereas ascorbate, pyruvate, and tiron, a scavenger of superoxide anion, had no cytoprotective effect. The administration of HOCbl into DDC solutions (> 1 mM) resulted in the formation of a crystalline precipitate, which was inhibited in the presence of GSH. The data of UV and NMR spectroscopy and HPLC and Mass Spectrometry (LC/MS) indicated that the main products of the reaction of DDC with HOCbl are disulfiram (DSF) and its oxidized forms, sulfones and sulfoxides. The increase in the cytotoxicity of DDC combined with HOCbl occurred both in the presence of Cu[2+] in culture medium and in nominally Cu-free solutions, as well as in growth medium containing the copper chelator bathocuproine disulfonate (BCS). The results indicate that HOCbl accelerates the oxidation of DDC with the formation of DSF and its oxidized forms. Presumably, the main cause of the synergistic increase in the toxic effect of DDC + HOCbl is the formation of sulfones and sulfoxides of DSF.}, }
@article {pmid30290020, year = {2018}, author = {Chang, SP and Huang, HM and Shen, SC and Lee, WR and Chen, YC}, title = {Nilotinib induction of melanogenesis via reactive oxygen species-dependent JNK activation in B16F0 mouse melanoma cells.}, journal = {Experimental dermatology}, volume = {27}, number = {12}, pages = {1388-1394}, doi = {10.1111/exd.13797}, pmid = {30290020}, issn = {1600-0625}, mesh = {Animals ; Anthracenes/pharmacology ; Antioxidants/metabolism ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival ; Enzyme Activation ; Imatinib Mesylate/pharmacology ; MAP Kinase Kinase 4/*metabolism ; Melanins/*biosynthesis ; Melanocytes/cytology ; Melanoma, Experimental/*metabolism ; Mice ; Mitochondria/metabolism ; Protein-Tyrosine Kinases/metabolism ; Pyrimidines/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Nilotinib (AMN), a second-generation tyrosine kinase inhibitor, induces apoptosis in various cancer cells, and our recent study showed that AMN effectively reduced the viability of human ovarian cancer cells via mitochondrion-dependent apoptosis. The effect of AMN in the melanogenesis of melanoma cells is still unclear. In the present study, we found that the addition of AMN but not imatinib (STI) significantly increased the darkness of B16F0 melanoma cells, and the absorptive value increased with the concentration of AMN. A decrease in the viability of B16F0 cells by AMN was detected in a concentration-dependent manner, accompanied by increased DNA ladders, hypodiploid cells and cleavage of the caspase-3 protein. An in vitro tyrosinase (TYR) activity assay showed that increased TYR activity by AMN was detected in a concentration-dependent manner; however, induction of TYR activity by STI at a concentration of 40 μmol/L was observed. Increased intracellular peroxide by AMN was detected in B16F0 cells, and application of the antioxidant, N-acetylcysteine (NAC), significantly reduced AMN-induced peroxide production which also reduced the darkness of B16F0 cells. Additionally, AMN induced c-Jun N-terminal kinase (JNK) protein phosphorylation in B16F0 cells, which was inhibited by the addition of NAC. AMN-induced melanogenesis of B16F0 cells was significantly inhibited by the addition of NAC and the JNK inhibitor, SP600125 (SP). Data of Western blotting showed that increased protein levels of melanogenesis-related enzymes of tyrosinase-related protein-1 (TRP1), TRP2 and TYR were observed in AMN-treated B16F0 cells which were inhibited by the addition of NAC and SP. Evidence is provided supporting AMN effectively inducing the melanogenesis of B16F0 melanoma cells via reactive oxygen species-dependent JNK activation.}, }
@article {pmid30289994, year = {2019}, author = {Zhang, R and Wang, Y and Pan, L and Tian, H}, title = {N-Acetylcysteine potentiates the haemodynamic-improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the p38 MAPK pathway.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {46}, number = {2}, pages = {163-172}, doi = {10.1111/1440-1681.13039}, pmid = {30289994}, issn = {1440-1681}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Animals ; Apoptosis/drug effects ; Cell Count ; Chemokine CCL2/metabolism ; Disease Models, Animal ; Drug Synergism ; Endothelial Cells/drug effects/pathology ; Hemodynamics/*drug effects ; Lipid Peroxidation/drug effects ; Lung/drug effects/metabolism/pathology/physiopathology ; MAP Kinase Signaling System/*drug effects ; Male ; Matrix Metalloproteinase 9/metabolism ; Neutrophils/cytology/drug effects ; Nitric Oxide/metabolism ; Oxidative Stress/drug effects ; Pulmonary Embolism/drug therapy/metabolism/*pathology/*physiopathology ; Rabbits ; Sildenafil Citrate/*pharmacology/therapeutic use ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {The current study aimed to investigate the effects of sildenafil and N-acetylcysteine (NAC) on the haemodynamics in a rabbit model of acute pulmonary thromboembolism (APT). We developed an APT model using healthy male China big-ear rabbits (2.7 ± 0.4 kg). The rabbits were divided into five groups subjected to various interventions. We recorded the haemodynamic parameters and assessed the oxidative stress and lipid peroxidation response in the groups. Additionally, we detected apoptosis-associated molecules, FoxO1, Bad and Bcl-2, in the lung tissue. Gelatine zymography was used to detect matrix metalloproteinase (MMP) activity in bronchoalveolar lavage (BLA). Pulmonary artery endothelial cells were isolated, and their apoptosis rates and MMP activity were assayed. N-acetylcysteine potentiated the haemodynamic-improving effect of sildenafil and significantly inhibited the oxidative stress response. N-acetylcysteine combined with sildenafil decreased MMP-2 and MMP-9 activity and NO consumption and inhibited apoptosis of pulmonary arterial endothelial cells. Moreover, NAC combined with sildenafil inhibited the expression of MCP-1 and p-p38 MAPK. Thus, NAC potentiates the haemodynamic-improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the MCP-1 and p38 MAPK signalling pathway. This study may provide a promising treatment method for APT.}, }
@article {pmid30283523, year = {2018}, author = {Bahrami, R and Akbari, E and Rasras, S and Jazayeri, N and Khodayar, MJ and Foruozandeh, H and Zeinali, M and Kartalaei, MM and Ardeshiri, M and Baiatinia, F and Ghanavatian, M}, title = {Effect of Local N-acetyl-cysteine in the Prevention of Epidural Fibrosis in Rat Laminectomy Model.}, journal = {Asian journal of neurosurgery}, volume = {13}, number = {3}, pages = {664-668}, pmid = {30283523}, issn = {1793-5482}, abstract = {BACKGROUND: Epidural fibrosis is a major contributing factor to the onset of failed back syndrome. Many studies have attempted to prevent this physiological response. Interestingly, N-acetyl-cysteine (NAC) has been effective in some cases in the treatment of pulmonary fibrosis.<br><br>OBJECTIVE: The objective of this study was to determine whether local NAC is an effective way to prevent epidural fibrosis after laminectomy in rats.<br><br>MATERIALS AND METHODS: Twenty Wistar rats were used in this study. Animals were divided into two groups: NAC group and a control group. We performed two-level laminectomy (L4-L5) in these rats. Rats in the control group just had laminectomy, and in the other group, L4 and L5 laminectomy followed by local treatment with NAC. Four weeks later, the rats were killed, and the laminectomy level was subjected to histopathological examination to evaluate epidural fibrosis and fibroblast density.<br><br>RESULTS: Histopathological examination showed that after 4 weeks of surgery the NAC group had significantly less epidural fibrosis and fibroblasts compared with control group.<br><br>CONCLUSION: Our findings indicate that NAC decreased spinal epidural fibrosis after laminectomy in rats.}, }
@article {pmid30282005, year = {2019}, author = {Saide, K and Sherwood, V and Wheeler, GN}, title = {Paracetamol-induced liver injury modelled in Xenopus laevis embryos.}, journal = {Toxicology letters}, volume = {302}, number = {}, pages = {83-91}, doi = {10.1016/j.toxlet.2018.09.016}, pmid = {30282005}, issn = {1879-3169}, support = {NC/L001659/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, mesh = {Acetaminophen/*toxicity ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Antioxidants/pharmacology ; Biomarkers/metabolism ; Chemical and Drug Induced Liver Injury/embryology/*etiology/metabolism/pathology ; Dose-Response Relationship, Drug ; Embryo, Nonmammalian/*drug effects/metabolism/pathology ; Glutathione/metabolism ; Liver/*drug effects/embryology/metabolism/pathology ; MicroRNAs/genetics/metabolism ; Oxidative Stress/drug effects ; Xenopus laevis/*embryology ; }, abstract = {INTRODUCTION: Failure to predict drug-induced liver injury (DILI) remains a major contributing factor to lead compound drop-out during drug development. Xenopus embryos are amenable for early stage medium throughput small molecule screens and so have the potential to be used in pre-clinical screens. To begin to assess the usefulness and limitations of Xenopus embryos for safety assessment in the early phases of drug development, paracetamol was used as a model hepatotoxin. Paracetamol overdose is associated with acute liver injury. In mammals, the main mechanism of paracetamol-induced acute liver injury is an increased amount of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) combined with a reduction of free glutathione (GSH). Humans that have taken an overdose of paracetamol are often treated with N-acetyl cysteine (NAC).<br><br>METHOD: Xenopus laevis embryos were treated with up to 5&#x2009;mM paracetamol from stage 38 to stage 45 during development, when the liver is functional. The presence of paracetamol-induced liver injury was assessed by: (1) microRNA-122 (miR-122) expression (a hepatic marker), (2) free GSH concentration (a marker of oxidative stress) and (3) NAC antioxidant intervention.<br><br>RESULTS: The amount of free GSH decreased significantly in embryos exposed to increasing paracetamol concentration. In embryos exposed to 5&#x2009;mM paracetamol, 22.57&#x2009;&#xb1;&#x2009;4.25&#x2009;nmol/mg GSH was detected compared to 47.11&#x2009;&#xb1;&#x2009;7.31&#x2009;nmol/mg untreated embryos (mean&#x2009;&#xb1;&#x2009;SEM). In tail tissue, miRNA-122 expression increased 6.3-fold with 3&#x2009;mM paracetamol concentration treatment compared to untreated embryos. NAC treatment altered the free GSH decline for embryos treated with up to 5&#x2009;mM. Embryos exposed to 1&#x2009;mM paracetamol and then exposed to 0.5&#x2009;mM NAC 24&#x2009;h prior to harvest, had a significantly higher amount of GSH compared to embryos that were only exposed to 1&#x2009;mM paracetamol (mean&#x2009;&#xb1;&#x2009;SEM; 97.1&#x2009;&#xb1;&#x2009;9.6&#x2009;nmol/mg and 54.5&#x2009;&#xb1;&#x2009;6.6&#x2009;nmol/mg respectively).<br><br>CONCLUSION: Xenopus laevis embryos exhibit similar characteristics of paracetamol-induced liver injury observed in mammalian models. These data indicate that the Xenopus embryo could be a useful in vivo model to assess DILI and aid lead compound prioritisation during the early phase of drug development, in combination with pre-clinical in vitro studies. Consequently, the Xenopus embryo could contribute to the reduction principle as defined by the National Centre for the Replacement, Refinement and Reduction of Animals in Research.}, }
@article {pmid30281301, year = {2018}, author = {Shpaizer, A and Nussinovich, A and Kanner, J and Tirosh, O}, title = {S-Nitroso-N-acetylcysteine Generates Less Carcinogenic N-Nitrosamines in Meat Products than Nitrite.}, journal = {Journal of agricultural and food chemistry}, volume = {66}, number = {43}, pages = {11459-11467}, doi = {10.1021/acs.jafc.8b04549}, pmid = {30281301}, issn = {1520-5118}, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemistry ; Color ; Food Analysis ; Meat Products/*analysis ; Nitrites/*chemistry ; Nitrosamines/*chemistry ; Oxygen/chemistry ; Reactive Nitrogen Species/chemistry ; }, abstract = {Nitrite reacts with secondary amines to form N-nitrosamines (N-NA), which lead to gastrointestinal cancers. The aim of this study was to compare nitrite with S-nitrosocysteine (Cys-SNO) and S-nitroso-N-acetylcysteine (NAC-SNO) with respect to N-NA formation, which was evaluated by determining the conversion of N-methylaniline to N-nitrosomethylaniline. Under neutral and acidic pH conditions, N-NA formation rate was nitrite > Cys-SNO > NAC-SNO. In the presence of copper or nucleophiles, NAC-SNO generated much less N-NA than Cys-SNO. Nitrite and Cys-SNO produced higher amounts of N-NA in the presence of oxygen, whereas NAC-SNO was almost oxygen insensitive. In meat in the stomach medium, NAC-SNO produced much lower amounts of N-NA than other additives. In heated meat, Cys-SNO and NAC-SNO generated the nitrosyl-hemochrome pink pigment, better than nitrite. In conclusion, NAC-SNO was much less reactive for N-NA formation than nitrite and Cys-SNO in conditions relevant to meat production and stomach digestion.}, }
@article {pmid30279737, year = {2018}, author = {Huang, MW and Lin, YJ and Chang, CW and Lei, FJ and Ho, EP and Liu, RS and Shyu, WC and Hsieh, CH}, title = {RGS4 deficit in prefrontal cortex contributes to the behaviors related to schizophrenia via system xc[-]-mediated glutamatergic dysfunction in mice.}, journal = {Theranostics}, volume = {8}, number = {17}, pages = {4781-4794}, pmid = {30279737}, issn = {1838-7640}, mesh = {Acetylcysteine/administration &amp; dosage ; Amino Acid Transport System y+/*biosynthesis ; Animals ; Behavior, Animal/drug effects ; Disease Models, Animal ; *Gene Expression Regulation ; Gene Knockdown Techniques ; Mice ; Organ Culture Techniques ; Prefrontal Cortex/*physiopathology ; RGS Proteins/genetics/*metabolism ; Schizophrenia/*physiopathology ; }, abstract = {Rationale: Although molecular investigations of regulator of G-protein signaling 4 (RGS4) alterations in schizophrenia patients yielded partially inconsistent findings, the previous studies suggested that RGS4 is both a positional and functional candidate gene for schizophrenia and is significantly decreased in the prefrontal cortex. However, the exact role of RGS4 in the pathophysiology of schizophrenia is unclear. Moreover, a whole genome transcription profile study showed the possibility of RGS4-regulated expression of SLC7A11(xCT), a component of cysteine/glutamate transporter or system xc[-]. We hypothesized that system xc[-] is a therapeutic target of RGS4 deficit-mediated schizophrenia. Methods: Pharmacological and genetic manipulation of RGS4 in organotypic brain slice cultures were used as an ex vivo model to investigate its role in system xc[-] and glutamatergic function. Lentiviral-based mouse models with RGS4 deficit in the prefrontal cortex and treatment with system xc[-] activator, N-acetyl cysteine (NAC), were utilized to observe their impacts on glutamatergic function and schizophrenic behaviors. Results: Genetic and pharmacological inhibition of RGS4 resulted in a significant decrease in SLC7A11 (xCT) expression and hypofunction of system xc[-] and reduced glutamatergic function in organotypic brain slice cultures. However, NAC restored the dysregulation of RGS4-mediated functional deficits of glutamate. Moreover, knockdown of RGS4 specifically in the prefrontal cortex caused mice to exhibit behaviors related to schizophrenia such as increased stereotypy, impaired prepulse inhibition, deficits in social interactions, working memory, and nesting behavior, while enhancing sensitivity to the locomotor stimulatory effect of MK-801. These mice displayed glutamatergic dysfunction in the prefrontal cortex, which may have contributed to the behavioral deficits. RGS4 knockdown mice that received NAC treatment had improved glutamatergic dysfunction and schizophrenia behaviors. Conclusion: Our results suggest that RGS4 deficit induces dysregulation and dysfunction of system xc[-], which further results in functional deficits of the glutamatergic system and subsequently to schizophrenia-related behavioral phenotypes. Activation of system xc[-] offers a promising strategy to treat RGS4 deficit-mediated schizophrenia.}, }
@article {pmid30279524, year = {2018}, author = {Jeong, AJ and Kim, YJ and Lim, MH and Lee, H and Noh, K and Kim, BH and Chung, JW and Cho, CH and Kim, S and Ye, SK}, title = {Microgravity induces autophagy via mitochondrial dysfunction in human Hodgkin's lymphoma cells.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {14646}, pmid = {30279524}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Autophagy/drug effects/*physiology ; Cell Line, Tumor ; Cell Proliferation/drug effects/physiology ; Gene Expression Regulation, Neoplastic ; Hodgkin Disease/pathology/*therapy ; Humans ; Mitochondria/drug effects/*metabolism ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; Stress, Physiological/drug effects ; *Weightlessness Simulation ; }, abstract = {Gravitational forces can impose physical stresses on the human body as it functions to maintain homeostasis. It has been reported that astronauts exposed to microgravity experience altered biological functions and many subsequent studies on the effects of microgravity have therefore been conducted. However, the anticancer mechanisms of simulated microgravity remain unclear. We previously showed that the proliferation of human Hodgkin's lymphoma (HL) cells was inhibited when these cells were cultured in time-averaged simulated microgravity (taSMG). In the present study, we investigated whether taSMG produced an anticancer effect. Exposure of human HL cells to taSMG for 2 days increased their reactive oxygen species (ROS) production and NADPH oxidase family gene expression, while mitochondrial mass, ATPase, ATP synthase, and intracellular ATP levels were decreased. Furthermore, human HL cells exposed to taSMG underwent autophagy via AMPK/Akt/mTOR and MAPK pathway modulation; such autophagy was inhibited by the ROS scavenger N-acetylcysteine (NAC). These results suggest an innovative therapeutic approach to HL that is markedly different from conventional chemotherapy and radiotherapy.}, }
@article {pmid30278102, year = {2019}, author = {Che, R and Ding, S and Zhang, Q and Yang, W and Yan, J and Lin, X}, title = {Haemolysin Sph2 of Leptospira interrogans induces cell apoptosis via intracellular reactive oxygen species elevation and mitochondrial membrane injury.}, journal = {Cellular microbiology}, volume = {21}, number = {1}, pages = {e12959}, doi = {10.1111/cmi.12959}, pmid = {30278102}, issn = {1462-5822}, mesh = {Apoptosis/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Endocytosis ; Hemolysin Proteins/*metabolism ; Humans ; Leptospira interrogans/growth &amp; development/*pathogenicity ; Mitochondrial Membranes/*drug effects ; Protein Transport ; Reactive Oxygen Species/*metabolism ; Virulence Factors/*metabolism ; }, abstract = {Leptospira interrogans causes widespread leptospirosis in humans and animals, with major symptoms of jaundice and haemorrhage. Sph2, a member of the sphingomyelinase haemolysins, is an important virulence factor for leptospire. In this study, the function and mechanism of Sph2 in the pathogenesis of leptospirosis were investigated to further understand the pathogenesis of leptospire. Real-time PCR analysis of expression levels during cell invasion showed that sph2 gene expression was transiently induced in human umbilical vein endothelial cells (HUVECs), human embryo liver cells (L02), and human epithelial lung cells (L132), with expression levels reaching a peak after 45 min of infection. Further functional analysis of recombinant Sph2 (rSph2) by LDH assays and confocal microscopy showed that rSph2 can be internalised by cells both by causing cell membrane damage and by a damage-independent clathrin-mediated endocytosis pathway. Subsequently, rSph2 is able to translocate to mitochondria, which led to an increase in the levels of reactive oxygen species (ROS) and a decrease of the mitochondrial membrane potential (ΔΨm). Further flowcytometry analyses after rSph2 exposure showed that 28.7%, 31%, and 27.3% of the HUVEC, L02, and L132 cells, respectively, became apoptotic. Because apoptosis could be decreased with the ROS inhibitor N-acetyl cysteine, these experiments suggested that rSph2 triggers apoptosis through mitochondrial membrane damage and ROS elevation. The ability of leptospiral haemolysin rSph2 to cause apoptosis likely contributes to the pathogenesis of leptospirosis.}, }
@article {pmid30274809, year = {2018}, author = {Saputro, I and Riestiano, B and Hoekstra, LT and Zarasade, L}, title = {The effect of oral N-acetylcystein on prevention of extensive tissue destruction in electrical burn injury.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {44}, number = {8}, pages = {2059-2063}, doi = {10.1016/j.burns.2018.08.025}, pmid = {30274809}, issn = {1879-1409}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Burns, Electric/metabolism/*pathology ; Creatine Kinase/*drug effects/metabolism ; Disease Models, Animal ; Male ; Necrosis ; Oxidative Stress ; Random Allocation ; Rats ; Rats, Wistar ; Rhabdomyolysis/metabolism/*pathology ; Skin/*drug effects/metabolism/pathology ; Wound Healing ; }, abstract = {BACKGROUND: Electric burn patients usually suffer permanent injury and sequelae. Salvage of the zone of stasis is an important topic in the treatment of burn patients. N-Acetylcysteine (NAC), as an antioxidant, has effect on the saving zone of stasis and extensive rhabdomyolisis. The aim of this study was therefore to evaluate the effect of oral NAC on tissue destruction indicators in an electric burn rat model.<br><br>MATERIAL AND METHODS: An experimental study was conducted with thirty six male Wistar albino rats divided into 2 groups. Group A (n=18) and group B (n=18) were electrical burn injury groups without and with NAC therapy, respectively. The extent of burn wounds were evaluated by planimetry using a digital wound measuring device. Blood samples were obtained to analyze creatine kinase (CK) levels as a marker of extensive rhabdomiolysis on the first hour after electric injury (baseline) and on the 7th day to see the antioxidant effect of NAC.<br><br>RESULTS: A significant decrease in tissue destruction was seen by the necrotic area on day 7 in the NAC therapy group compared to the control group (mean 2.26&#xb1;1.05cm[2] versus mean 7.12&#xb1;3.30cm[2] respectively; p=0.001), which was confirmed by the level of serum CK (day 7: group A, mean 140&#xb1;51U/L versus Group B, mean 102&#xb1;6U/L; p=0.007).<br><br>CONCLUSION: A decrease in electric burn necrotic area and tissue damage in the group using NAC treatment was demonstrated. NAC might have a beneficial effect in the treatment of electrical burns. Further experimental and clinical studies with NAC treatment are necessary to confirm these results.}, }
@article {pmid30274302, year = {2018}, author = {Castanares-Zapatero, D and Dinant, V and Ruggiano, I and Willem, H and Laterre, PF and Hantson, P}, title = {Pattern of Paracetamol Poisoning: Influence on Outcome and Complications.}, journal = {Toxics}, volume = {6}, number = {4}, pages = {}, pmid = {30274302}, issn = {2305-6304}, abstract = {Acute paracetamol poisoning due to a single overdose may be effectively treated by the early administration of N-acetylcysteine (NAC) as an antidote. The prognosis may be different in the case of intoxication due to multiple ingestions or when the antidote is started with delay. The aim of this work was to investigate the outcome of paracetamol poisoning according to the pattern of ingestion and determine the factors associated with the outcome. We performed a retrospective analysis over the period 2007[-]2017 of the patients who were referred to a tertiary hospital for paracetamol-related hepatotoxicity. Inclusion criteria were: accidental or voluntary ingestion of paracetamol, delay for NAC therapy of 12 h or more, liver enzymes (ALT) >1000 IU/L on admission. Ninety patients were considered. Poisoned patients following multiple ingestion were significantly older (45 ± 12 vs. 33 ± 14) (p = 0.001), with a higher incidence of liver steatosis (p = 0.016) or chronic ethanol abuse (p = 0.04). In comparison with the subgroup of favorable outcome, the patients with poor outcome were older, had higher values for ALT, bilirubin, lactate, and lower values for factor V and arterial pH. In multivariate analysis, the arterial lactate value was associated with a bad prognosis (p < 0.02) (adjusted odds ratio 1.74 and CI 95:1.09[-]2.77). The risk of poor outcome was greater in the subgroup with staggered overdose (p = 0.02), which had a higher mortality rate (p = 0.01). This retrospective analysis illustrates the different population patterns of patients who were admitted for a single ingestion of a paracetamol overdose versus multiple ingestions. This last subgroup was mainly represented by older patients with additional risk factors for hepatotoxicity; arterial lactate was a good predictor of severity.}, }
@article {pmid30273693, year = {2019}, author = {Moody, TW and Lee, L and Iordanskaia, T and Ramos-Alvarez, I and Moreno, P and Boudreau, HE and Leto, TL and Jensen, RT}, title = {PAC1 regulates receptor tyrosine kinase transactivation in a reactive oxygen species-dependent manner.}, journal = {Peptides}, volume = {120}, number = {}, pages = {170017}, pmid = {30273693}, issn = {1873-5169}, support = {Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; Z99 DK999999/ImNIH/Intramural NIH HHS/United States ; ZIA DK053200-26/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Carcinoma, Non-Small-Cell Lung/genetics/*metabolism/pathology ; Cell Line, Tumor ; Dual Specificity Phosphatase 2/genetics/*metabolism ; *Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics/*metabolism/pathology ; Neoplasm Proteins/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; *Transcriptional Activation ; }, abstract = {Pituitary adenylate cyclase activating polypeptide (PACAP) is a growth factor for lung cancer cells. PACAP-27 or PACAP-38 binds with high affinity to non-small cell lung cancer (NSCLC) cells, causing elevated cytosolic Ca[2+], increased proliferation and increased phosphorylation of extracellular regulated kinase (ERK) and the epidermal growth factor receptor (EGFR). The role of reactive oxygen species (ROS) was investigated in these processes. Addition of PACAP-38 to NCI-H838 or A549 cells increased the tyrosine phosphorylation of the EGFR, HER2 and ERK significantly by 4-, 3-, and 2-fold, respectively. The transactivation of the EGFR and HER2 was inhibited by gefitinib or lapatinib (tyrosine kinase inhibitors), PACAP (6-38) (PAC1 antagonist), N-acetylcysteine (NAC is an anti-oxidant) or dipheyleneiodonium (DPI is an inhibitor of Nox and Duox enzymes). PACAP-38 addition to NSCLC cells increased ROS which was inhibited by PACAP (6-38), NAC or DPI. Nox1, Nox2, Nox3, Nox4, Nox5, Duox1 and Duox2 mRNA was present in many NSCLC cell lines. PACAP-38 stimulated the growth of NSCLC cells whereas PACAP (6-38), gefitinib or DPI inhibited proliferation. The results show that ROS are essential for PAC1 to regulate EGFR and HER2 transactivation as well as proliferation of NSCLC cells.}, }
@article {pmid30273348, year = {2018}, author = {Pollini, S and Di Pilato, V and Landini, G and Di Maggio, T and Cannatelli, A and Sottotetti, S and Cariani, L and Aliberti, S and Blasi, F and Sergio, F and Rossolini, GM and Pallecchi, L}, title = {In vitro activity of N-acetylcysteine against Stenotrophomonas maltophilia and Burkholderia cepacia complex grown in planktonic phase and biofilm.}, journal = {PloS one}, volume = {13}, number = {10}, pages = {e0203941}, pmid = {30273348}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Biofilms/*drug effects ; Burkholderia cepacia complex/drug effects/*growth &amp; development/isolation &amp; purification ; Cystic Fibrosis/microbiology ; Dose-Response Relationship, Drug ; Drug Resistance, Bacterial/drug effects ; Humans ; In Vitro Techniques ; Microbial Sensitivity Tests ; Plankton/*drug effects ; Stenotrophomonas maltophilia/drug effects/*growth &amp; development/isolation &amp; purification ; Time Factors ; }, abstract = {Stenotrophomonas maltophilia and Burkholderia cepacia complex (Bcc) have been increasingly recognized as relevant pathogens in hospitalized, immunocompromised and cystic fibrosis (CF) patients. As a result of complex mechanisms, including biofilm formation and multidrug resistance phenotype, S. maltophilia and Bcc respiratory infections are often refractory to therapy, and have been associated with a worse outcome in CF patients. Here we demonstrate for the first time that N-acetylcysteine (NAC), a mucolytic agent with antioxidant and anti-inflammatory properties, may exhibit antimicrobial and antibiofilm activity against these pathogens. The antimicrobial and antibiofilm activity of high NAC concentrations, potentially achievable by topical administration, was tested against a collection of S. maltophilia (n = 19) and Bcc (n = 19) strains, including strains from CF patients with acquired resistance traits. Minimum Inhibitory Concentrations (MICs) and Minimum Bactericidal Concentrations (MBCs) ranged from 16 to 32 mg/ml and from 32 to >32 mg/ml, respectively. Sub-MIC concentrations (i.e., 0.25 × MIC) slowed down the growth kinetics of most strains. In time-kill assays, 2-day-old biofilms were more affected than planktonic cultures, suggesting a specific antibiofilm activity of NAC against these pathogens. Indeed, a dose- and time-dependent antibiofilm activity of NAC against most of the S. maltophilia and Bcc strains tested was observed, with a sizable antibiofilm activity observed also at 0.5 and 1 × MIC NAC concentrations. Furthermore, at those concentrations, NAC was also shown to significantly inhibit biofilm formation with the great majority of tested strains.}, }
@article {pmid30272303, year = {2018}, author = {Wei, S and Sun, T and Du, J and Zhang, B and Xiang, D and Li, W}, title = {Xanthohumol, a prenylated flavonoid from Hops, exerts anticancer effects against gastric cancer in vitro.}, journal = {Oncology reports}, volume = {40}, number = {6}, pages = {3213-3222}, pmid = {30272303}, issn = {1791-2431}, mesh = {Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Flavonoids/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Propiophenones/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Stomach Neoplasms/drug therapy/*metabolism ; bcl-2-Associated X Protein/*metabolism ; }, abstract = {Xanthohumol (Xn), a prenylated flavonoid isolated from Hops (Humulus lupulus L.), has demonstrated potent anticancer activity in multiple types of cancer. However, the effect of Xn on gastric cancer (GC) remains unknown. The aim of the present study was to investigate the effect of Xn on GC cell proliferation, apoptosis and metastasis. It was observed that Xn decreased the viability of GC cells, with very low or no toxicity to normal gastric epithelial cells GES‑1 at a concentration of 1‑100 µM. The proliferation of AGS cells was inhibited by Xn, as indicated by the decreased number of EdU‑positive cells. Xn treatment increased the number of apoptotic cells, downregulated the expression of Bcl‑2 and upregulated the expression of Bax, suggesting induction of apoptosis. The results from the wound healing and Transwell assays indicated that Xn suppressed AGS cell metastasis. Moreover, Xn induced reactive oxygen species (ROS) overproduction and inhibited nuclear factor (NF)‑κB signaling in AGS cells, which was reversed by the ROS inhibitor N‑acetylcysteine (NAC). NAC suppressed the effect of Xn on the proliferation, apoptosis and metastasis of AGS cells. Taken together, these results suggest that Xn exerts anticancer effects against GC via induction of ROS production and subsequent inhibition of NF‑κB signaling. Therefore, Xn may be a promising candidate treatment against GC progression.}, }
@article {pmid30266667, year = {2018}, author = {Roos, C and Dahlgren, D and Sjögren, E and Sjöblom, M and Hedeland, M and Lennernäs, H}, title = {Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {132}, number = {}, pages = {222-230}, doi = {10.1016/j.ejpb.2018.09.022}, pmid = {30266667}, issn = {1873-3441}, mesh = {Acetylcysteine/pharmacology ; Administration, Oral ; Animals ; Aprepitant/*administration &amp; dosage/pharmacokinetics ; Biological Availability ; Chemistry, Pharmaceutical/methods ; *Intestinal Absorption ; Intestinal Mucosa/metabolism ; Jejunum/*metabolism ; Male ; Mucus/metabolism ; *Nanoparticles ; Particle Size ; Rats ; Rats, Wistar ; Solubility ; Suspensions ; }, abstract = {The number of highly lipophilic active pharmaceutical ingredients (APIs) in pharmaceutical development has been constantly increasing over recent decades. These APIs often have inherent issues with solubility and dissolution, limiting their oral bioavailability. Traditionally, a reduction in particle size to the micrometer range has been used to improve dissolution. More recently, size reduction to the nanometer range has been introduced, which further increases the dissolution rate, but may also involve other mechanisms for increasing bioavailability. The effect of particle size on the absorption of aprepitant was investigated using the single-pass intestinal perfusion (SPIP) model in the rat jejunum. Phosphate buffer, fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) were used as perfusion media to increase understanding of the processes involved and the effects of colloidal structures. The role of mucus on intestinal absorption was investigated by adding the mucolytic agent N-acetyl-cysteine (NAC). The absorption of aprepitant from the nanosuspensions was similar with all perfusion media (buffer = FaSSIF = FeSSIF), whereas food had a pronounced effect on absorption from the microsuspensions (FeSSIF > FaSSIF > buffer). The colloidal structures hence contributed to absorption from the microsuspensions. Partitioning of aprepitant from the nanosuspension into the colloidal structures decreased the amount of nanoparticles available, which offset the effect of food. The appearance flux of aprepitant in blood was non-significantly decreased for nanosuspensions of aprepitant with NAC versus without NAC in buffer (ratio of 2:1), indicating that particle deposition in the mucus may have been decreased as the layer thinned, with subsequently reduced intestinal absorption. The study also showed that the SPIP model is suitable for investigating detailed absorption mechanisms using complex perfusion media, which increase the biorelevance of the model.}, }
@article {pmid30263131, year = {2018}, author = {Huang, JW and Clarkin, OJ and McCudden, C and Akbari, A and Chow, BJW and Shabana, W and Kanji, S and Davis, A and Hiremath, S}, title = {The Effect of N-Acetylcysteine on Creatinine Measurement: Protocol for a Systematic Review.}, journal = {Canadian journal of kidney health and disease}, volume = {5}, number = {}, pages = {2054358118801017}, pmid = {30263131}, issn = {2054-3581}, abstract = {BACKGROUND: N-acetylcysteine (NAC) is an antioxidant which can regenerate glutathione and is primarily used for acetaminophen overdose. It is also a potential therapy to prevent iatrogenic acute kidney injury or slow the progression of chronic kidney disease. It has been considered in this context by many studies with mixed results. Notably, a biological-mechanism rationale for a protective effect of NAC has never been adequately reported. Among conflicting reports, there appears to be evidence that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, a systematic review of the literature will be conducted to determine whether there is an effect of NAC on kidney function measured with serum creatinine.<br><br>OBJECTIVE: To determine the effect of NAC on kidney function.<br><br>DESIGN: A systematic review and meta-analysis.<br><br>SETTINGS: Prospective studies, with administration of NAC, in the absence of any other change in kidney function (such as contrast administration or surgery).<br><br>PATIENTS: Adult humans aged 18 years old or more, either healthy volunteers or with chronic kidney disease, were administered with NAC. Populations having little to no kidney function such as in end-stage kidney disease will be excluded.<br><br>MEASUREMENTS: Serum creatinine and/or cystatin C measurements before and after NAC administration.<br><br>METHODS: An information specialist will assist in searching MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify all study types including randomized controlled trials, and prospective cohort studies reporting change in serum creatinine after NAC administration. Two reviewers will independently screen the titles and abstracts of the studies obtained from the search using predefined inclusion criteria and will then extract data from the full texts of selected studies. The weighted mean difference will be calculated for change in creatinine with NAC, using random-effects analysis. Quality assessment will be done with the Cochrane Risk of Bias tool for randomized trials and the Newcastle-Ottawa Scale for observational studies.<br><br>RESULTS: The outcome of interest is kidney function as reported by either change in serum creatinine and/or serum cystatin C measurement for randomized trials or comparing baseline (pre-NAC dose) values and those following the NAC dose.<br><br>LIMITATIONS: Possible heterogeneity and publication bias and lack of mechanistic data.<br><br>CONCLUSIONS: This systematic review will provide a synthesis of current evidence on the effect of NAC on serum creatinine measurement. These findings will provide clinicians with guidelines and serve as a strong research base for future studies in this field.<br><br>This review is registered with PROSPERO, CRD42017055984.}, }
@article {pmid30261511, year = {2018}, author = {Zhang, P and Zhong, S and Wang, G and Zhang, SY and Chu, C and Zeng, S and Yan, Y and Cheng, X and Bao, Y and Hocher, B and Yang, X}, title = {N-Acetylcysteine Suppresses LPS-Induced Pathological Angiogenesis.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {49}, number = {6}, pages = {2483-2495}, doi = {10.1159/000493874}, pmid = {30261511}, issn = {1421-9778}, mesh = {Acetylcysteine/*pharmacology ; Angiotensins/genetics/metabolism ; Animals ; Antioxidants/*pharmacology ; Aorta, Thoracic/drug effects/physiology ; Chick Embryo ; Chickens ; Chorioallantoic Membrane/drug effects/metabolism ; Claudins/genetics/metabolism ; Lipopolysaccharides/*pharmacology ; NF-E2-Related Factor 2/genetics/metabolism ; Neovascularization, Physiologic/*drug effects ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {BACKGROUND/AIMS: Angiogenesis is a key feature during embryo development but is also part of the pathogenesis of cancer in adult life. Angiogenesis might be modulated by inflammation.<br><br>METHODS: We established an angiogenesis model in chick chorioallantoic membrane (CAM) induced by the exposure of lipopolysaccharide (LPS), and analyzed the effects of the antioxidant N-acetylcysteine (NAC) on angiogenesis in this model as well as on the expression of key genes known to involved in the regulation of angiogenesis.<br><br>RESULTS: Treatment with NAC was able to normalize LPS induced angiogenesis and restore the LPS-induced damage of vascular epithelium in chick CAM. Using quantitative PCR, we showed that NAC administration normalized the LPS induced expression of Keap1-Nrf2 signaling and oxidative stress key enzyme gene expressions (SOD, GPx and YAP1).<br><br>CONCLUSION: We established a LPS-induced angiogenesis model in chick CAM. NAC administration could effectively inhibit LPS-induced angiogenesis and restore the integrity of endothelium on chick CAM. LPS exposure caused an increased expression of genes involved in oxidative stress in chick CAM. NAC administration could abolish this effect.}, }
@article {pmid30259539, year = {2019}, author = {Henkel, R and Sandhu, IS and Agarwal, A}, title = {The excessive use of antioxidant therapy: A possible cause of male infertility?.}, journal = {Andrologia}, volume = {51}, number = {1}, pages = {e13162}, doi = {10.1111/and.13162}, pmid = {30259539}, issn = {1439-0272}, mesh = {Antioxidants/*adverse effects ; Humans ; Infertility, Male/*chemically induced/metabolism ; Male ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Reactive oxygen species and oxidative stress are closely associated with various pathologies such as neurodegenerative diseases, ageing and male infertility. Hence, antioxidants such as vitamin C, vitamin E, N-acetyl cysteine, L-carnitine and folic acid are regularly used in various treatment regimens to protect cells from the damage induced by free radicals. However, given their over-the-counter availability at unnaturally high concentrations and also the fact that they are commonly added to various food products, patients may run a risk of consuming excessive dosages of these compounds, which may then be toxic. The few studies that have assessed antioxidant overuse and the associated adverse effects found that large doses of dietary antioxidant supplements have varying-if any-therapeutic effects even though free radicals clearly damage cells-a phenomenon that has been termed the "antioxidant paradox." Furthermore, overuse of antioxidants such as vitamin C, vitamin E, N-acetyl cysteine may lead to reductive stress, which is reported to be as dangerous to cells as oxidative stress and can be the cause of diseases such as cancer or cardiomyopathy. Therefore, we feel that there is a need for more elaborate research to establish the clear benefits and risks involved in antioxidant therapy for male infertility.}, }
@article {pmid30258592, year = {2018}, author = {Chen, GW and Wu, M and Liu, WK and Xie, MM and Zhang, WS and Fan, EG and Liu, Q}, title = {Reactive oxygen species inhibits Listeria monocytogenes invasion into HepG2 epithelial cells.}, journal = {Food science &amp; nutrition}, volume = {6}, number = {6}, pages = {1501-1507}, pmid = {30258592}, issn = {2048-7177}, abstract = {Listeria monocytogenes (Lm) can colonize human gastrointestinal tract and subsequently cross the intestinal barrier. Reactive oxygen species (ROS) are produced by NADPH oxidase. However, the role of ROS in bacterial invasion remains to be less understood. Herein, we investigated the impact of ROS on Lm invasion to HepG2 using NADPH oxidase inhibitor, diphenyleneiodonium chloride (DPI), as well as the ROS scavenger, N-acetyl cysteine (NAC). Our results showed that inhibiting ROS increased the invasive capability of Lm. Moreover, after Lm infection, inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin 1beta (IL-1β) in HepG2 were significantly upregulated. However, after inhibiting ROS, the expression levels of TNF-α and IL-1β were downregulated, indicating a failure of host cells to activate the immune mechanism. Taken together, ROS in Lm might be as a signal for host cells to sense Lm invasion and then stimulate cells to activate the immune mechanism.}, }
@article {pmid30258443, year = {2018}, author = {Teskey, G and Cao, R and Islamoglu, H and Medina, A and Prasad, C and Prasad, R and Sathananthan, A and Fraix, M and Subbian, S and Zhong, L and Venketaraman, V}, title = {The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {2069}, pmid = {30258443}, issn = {1664-3224}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Anti-Bacterial Agents/*administration &amp; dosage ; Female ; *Granuloma, Respiratory Tract/drug therapy/immunology/pathology ; Humans ; Male ; Middle Aged ; Mycobacterium tuberculosis/*immunology ; *Tuberculosis, Multidrug-Resistant/drug therapy/immunology/pathology ; *Tuberculosis, Pulmonary/drug therapy/immunology/pathology ; }, abstract = {Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.}, }
@article {pmid30257359, year = {2018}, author = {Shang, XY and Chen, JJ and Song, XY and Wang, W and Chen, Y and Yao, GD and Song, SJ}, title = {Daphnegiravone D from Daphne giraldii Nitsche induces p38-dependent apoptosis via oxidative and nitrosative stress in hepatocellular carcinoma cells.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {107}, number = {}, pages = {1426-1433}, doi = {10.1016/j.biopha.2018.08.141}, pmid = {30257359}, issn = {1950-6007}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/enzymology/*pathology ; Daphne/*chemistry ; Flavonoids/chemistry/isolation &amp; purification/*pharmacology ; Hep G2 Cells ; Humans ; Liver Neoplasms/enzymology/*pathology ; Nitrosative Stress/drug effects ; Oxidative Stress/drug effects ; Protein Prenylation ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Daphnegiravone D (DGD), a prenylated flavonoid from Daphne giraldii Nitsche, significantly inhibited cell growth of several cancer cell lines without cytotoxicity on human normal cells. Our previous study showed that DGD could induce apoptosis in hepatocellular carcinoma Hep3B and HepG2 cells, but the detailed mechanism was still unclear. The present study provides that DGD-induced oxidative and nitrosative stress contribute to apoptotic cell death in Hep3B and HepG2 cells. Furthermore, there is a positive loop between oxidative stress and p38 activation, similar result is observed between nitrosative stress and p38. N-Acetylcysteine (NAC), a reactive oxygen species scavenger, could relieve DGD-induced oxidative stress, but exerts little effect on nitrosative stress. In addition, carboxy-PTIO (PTIO, a well-known scavenger of reactive nitrogen species) down-regulates the induction of nitrosative stress without obvious effect on oxidative stress in DGD-treated cells. In conclusion, the induction of oxidative and nitrosative stress could enhance p38-mediated apoptosis in DGD-treated Hep3B and HepG2 cells. Moreover, we speculated that OS and NS could not ultimately affect each other in DGD-treated HCC cells. This study gives a new insight on the mechanism of DGD-induced apoptotic cell death via oxidative and nitrosative stress in HCC cells.}, }
@article {pmid30257333, year = {2018}, author = {Nadeem, A and Al-Harbi, NO and Alfardan, AS and Ahmad, SF and AlAsmari, AF and Al-Harbi, MM}, title = {IL-17A-induced neutrophilic airway inflammation is mediated by oxidant-antioxidant imbalance and inflammatory cytokines in mice.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {107}, number = {}, pages = {1196-1204}, doi = {10.1016/j.biopha.2018.08.123}, pmid = {30257333}, issn = {1950-6007}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*metabolism ; Chemokine CCL2/metabolism ; Chemokine CXCL2/metabolism ; Chemokines/metabolism ; Cytokines/metabolism ; Inflammation/*pathology ; Interleukin-17/*administration &amp; dosage/metabolism ; Interleukin-6/metabolism ; Lung/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Neutrophils/metabolism ; Oxidants/metabolism ; Oxidative Stress/drug effects ; Pneumonia/*pathology ; }, abstract = {IL-17 A is produced by several innate and adaptive immune cells which include Th17, and innate lymphoid 3 cells in the lung. IL-17 A can activate airway epithelial cells (AECs), through IL-17 receptor (IL-17R) leading to production of chemokines/cytokines. Inflammatory nature of IL-17 A and its signaling has been assessed by several studies using IL-17 A/IL-17R knockout mice which show attenuated inflammation in different disease models. IL-17 A/IL-17R signaling also plays an important role in pulmonary inflammation through recruitment of neutrophils. However, effect of IL-17 A on oxidant-antioxidant balance in the lung and its association with pulmonary inflammation has not been evaluated earlier. Our study evaluated the effect of intranasal administration of IL-17 A on oxidant-antioxidant balance [inducible nitric oxide synthase (iNOS), nitrotyrosine, lipid peroxides, glutathione peroxidase, and total glutathione levels] and chemokines/cytokines expression (IL-6, MCP-1, and MIP-2) in the lung/AECs and their modulation by an antioxidant, N-acetyl cysteine (NAC). Our study shows that IL-17 A administration leads to increased neutrophilic inflammation along with concomitant increase in iNOS and nitrotyrosine/lipid peroxides. On the other hand, there was a reduction in GPx activity and total thiol levels after IL-17 A administration. IL-17 A administration also led to increased IL-6/MCP-1/MIP-2. IL-17A-induced oxidative stress/IL-6 expression and neutrophilic inflammation was attenuated by NAC treatment, whereas there was no effect on chemokines. This suggests that antioxidant NAC attenuates IL-17A-induced pulmonary inflammation by restoring oxidant-antioxidant balance and attenuation of IL-6 in the lung. Further, our study suggests that inflammatory pulmonary disorders which involve increase in IL-17 A may be ameliorated by NAC treatment.}, }
@article {pmid30256516, year = {2018}, author = {Zhou, M and Sun, G and Zhang, L and Zhang, G and Yang, Q and Yin, H and Li, H and Liu, W and Bai, X and Li, J and Wang, H}, title = {STK33 alleviates gentamicin-induced ototoxicity in cochlear hair cells and House Ear Institute-Organ of Corti 1 cells.}, journal = {Journal of cellular and molecular medicine}, volume = {22}, number = {11}, pages = {5286-5299}, pmid = {30256516}, issn = {1582-4934}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Apoptosis/drug effects ; Butadienes/administration &amp; dosage ; Caspase 3/genetics ; Cell Survival/drug effects ; Cochlea/*drug effects/pathology ; Gene Expression Regulation/drug effects ; Gentamicins/toxicity ; Hair Cells, Auditory/*drug effects/metabolism ; Humans ; Mice ; Mitochondria/drug effects/*genetics ; Nitriles/administration &amp; dosage ; Organ of Corti/drug effects/metabolism ; Protein Serine-Threonine Kinases/*genetics ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/genetics ; }, abstract = {Serine/threonine kinase 33 (STK33), a member of the calcium/calmodulin-dependent kinase (CAMK), plays vital roles in a wide spectrum of cell processes. The present study was designed to investigate whether STK33 expressed in the mammalian cochlea and, if so, what effect STK33 exerted on aminoglycoside-induced ototoxicity in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. Immunofluorescence staining and western blotting were performed to investigate STK33 expression in cochlear hair cells (HCs) and HEI-OC1 cells with or without gentamicin treatment. CCK8, flow cytometry, immunofluorescence staining and western blotting were employed to detect the effects of STK33 knockdown, and/or U0126, and/or N-acetyl-L-cysteine (NAC) on the sensitivity to gentamicin-induced ototoxicity in HEI-OC1 cells. We found that STK33 was expressed in both mice cochlear HCs and HEI-OC1 cells, and the expression of STK33 was significantly decreased in cochlear HCs and HEI-OC1 cells after gentamicin exposure. STK33 knockdown resulted in an increase in the cleaved caspase-3 and Bax expressions as well as cell apoptosis after gentamicin damage in HEI-OC1 cells. Mechanistic studies revealed that knockdown of STK33 led to activated mitochondrial apoptosis pathway as well as augmented reactive oxygen species (ROS) accumulation after gentamicin damage. Moreover, STK33 was involved in extracellular signal-regulated kinase 1/2 pathway in primary culture of HCs and HEI-OC1 cells in response to gentamicin insult. The findings from this work indicate that STK33 decreases the sensitivity to the apoptosis dependent on mitochondrial apoptotic pathway by regulating ROS generation after gentamicin treatment, which provides a new potential target for protection from the aminoglycoside-induced ototoxicity.}, }
@article {pmid30255760, year = {2019}, author = {Hashemi, G and Mirjalili, M and Basiri, Z and Tahamoli-Roudsari, A and Kheiripour, N and Shahdoust, M and Ranjbar, A and Mehrpooya, M and Ataei, S}, title = {A Pilot Study to Evaluate the Effects of Oral N-Acetyl Cysteine on Inflammatory and Oxidative Stress Biomarkers in Rheumatoid Arthritis.}, journal = {Current rheumatology reviews}, volume = {15}, number = {3}, pages = {246-253}, doi = {10.2174/1573403X14666180926100811}, pmid = {30255760}, issn = {1875-6360}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Adult ; Aged ; Anti-Inflammatory Agents/*therapeutic use ; Antioxidants/*therapeutic use ; Antirheumatic Agents/administration &amp; dosage ; Arthritis, Rheumatoid/blood/*drug therapy ; Biomarkers/blood ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Inflammation/blood/drug therapy ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Pilot Projects ; }, abstract = {BACKGROUND: Rheumatoid Arthritis (RA) is a common inflammatory disease of the joints. Due to the importance of inflammation and oxidative stress in the pathogenesis of RA, drugs that have anti-oxidant and anti-inflammatory properties, such as N-acetyl Cysteine (NAC), can be used as adjunctive therapy in patients with RA.<br><br>AIMS: The aim of this study was to evaluate the effects of oral NAC on inflammatory cytokines and oxidative stress in patients with RA.<br><br>METHODS: Adjunct to standard treatment, the NAC group (23 patients) received 600 mg of NAC twice daily and the placebo group (19 patients) received identical placebo twice daily for 12 weeks. Serum levels of Total Oxidant Status (TOS), Total Antioxidant Capacity (TAC), nitric oxide (NO), Total Thiol Groups (TTG), Malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-&#x3b1;), interleukin- 6 (IL-6), C-reactive Protein (CRP), and Erythrocyte Sedimentation Rate (ESR) were measured at baseline and at the end of the study.<br><br>RESULTS: Results showed that in the NAC group, the serum levels of MDA, NO, IL-6, TNF-&#x3b1;, ESR and CRP were significantly lower than the baseline. Also, the serum level of TAC and TTG, as antioxidant parameters, increased significantly. However, only NO, MDA and TTG showed a significant difference in the NAC group as compared to the placebo group at the end of study.<br><br>CONCLUSION: According to the results of this study, oral NAC can significantly reduce the several oxidative stress factors and inflammatory cytokines. These results need to be confirmed in larger studies while considering clinical outcomes of RA patients.}, }
@article {pmid30255182, year = {2018}, author = {Williams, MRM and Bertrand, B and Hughes, DL and Waller, ZAE and Schmidt, C and Ott, I and O'Connell, M and Searcey, M and Bochmann, M}, title = {Cyclometallated Au(iii) dithiocarbamate complexes: synthesis, anticancer evaluation and mechanistic studies.}, journal = {Metallomics : integrated biometal science}, volume = {10}, number = {11}, pages = {1655-1666}, doi = {10.1039/c8mt00225h}, pmid = {30255182}, issn = {1756-591X}, mesh = {Antineoplastic Agents/*chemical synthesis/*pharmacology ; Cell Proliferation/*drug effects ; Coordination Complexes/*chemistry ; Drug Screening Assays, Antitumor ; Gold/*chemistry ; Gold Compounds/chemistry/*pharmacology ; Humans ; Thiocarbamates/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {A series of cationic mixed cyclometallated (C^N)Au(iii) dithiocarbamate complexes has been synthesized in good yields [HC^N = 2-(p-t-butylphenyl)pyridine]. The crystal structure of [(C^N)AuS2CNEt2]PF6 (3) has been determined. The cytotoxic properties of the new complexes have been evaluated in vitro against a panel of human cancer cell lines and healthy cells and compared with a neutral mixed (C^C)Au(iii) dithiocarbamate complex (C^C = 4,4'-di-t-butylbiphenyl-2,2'-diyl). The complexes appeared to be susceptible to reduction by glutathione but were stable in the presence of N-acetyl cysteine. The potential mechanism of action of this class of compounds has been investigated by measuring the intracellular uptake of some selected complexes, by determining their interactions with higher order DNA structures, and by assessing the ability to inhibit thioredoxin reductase. The complexes proved unable to induce the formation of reactive oxygen species. The investigations add to the picture of the possible mode of action of this class of complexes.}, }
@article {pmid30253185, year = {2018}, author = {Perrone, M and Lopalco, A and Lopedota, A and Cutrignelli, A and Laquintana, V and Franco, M and Bernkop-Schnürch, A and Denora, N}, title = {S-preactivated thiolated glycol chitosan useful to combine mucoadhesion and drug delivery.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {132}, number = {}, pages = {103-111}, doi = {10.1016/j.ejpb.2018.09.015}, pmid = {30253185}, issn = {1873-3441}, mesh = {Acetylcysteine/chemistry ; Adhesiveness ; Caco-2 Cells ; Cell Survival/drug effects ; Chemistry, Pharmaceutical/methods ; Chitosan/chemistry ; Drug Carriers/chemistry ; Drug Compounding/methods ; *Drug Delivery Systems ; Drug Liberation ; Excipients/*chemistry ; Glutathione/chemistry ; Humans ; Naproxen/*administration &amp; dosage ; Nicotinic Acids/chemistry ; Polymers/*chemistry ; Sulfhydryl Compounds/chemistry ; Tablets ; }, abstract = {This work describes S-preactivated N-acetylcysteine (NAC)- and glutathione (GSH)-glycol chitosan (GC) polymer conjugates engineered as potential mucoadhesive platform. Preactivated thiomers (GC-NAC-MNA, GC-GSH-MNA) were synthesized by bond formation between GC-NAC or GC-GSH and 2-mercaptonicotinic acid (MNA) used as ligand. The presence of protected thiol moieties on this new class of thiolated GC made them not subject to oxidation. The structural modifications of the resulting derivatives were confirmed by proton Nuclear Magnetic Resonance ([1]H NMR) and Size Exclusion Chromatography (SEC). The conjugates displayed 91.2% and 90.1% of S-preactivation for GC-NAC-MNA and GC-GSH-MNA, respectively. The polymers were tested in ex-vivo and in vitro for their mucoadhesive properties and toxicity. The results showed that the preactivation of GC-NAC and GC-GSH increased their mucoadhesive abilities compared to their thiolated precursors by 1.4-, 4.4-fold in time of adhesion evaluated using rotating cylinder method, 1.6-, 1.5-fold in total work of adhesion (TWA) and 2.0-, 1.3-fold in maximum detachment force (MDA) determined using tensile studies, respectively. Moreover, water-uptake studies showed an improved in weight indicating water-uptake strongly dependent on derivations, before erosion occurred, whereas disintegration took place for the thiolated polymers within the first hour. The S-preactivated modification did not affect the cell viability of Caco2 cells exposed to the polymers. The release of the model drug sodium naproxen from tablets prepared with a lyophilized mixture of drug and polymer was studied via dissolution apparatus revealing that the preactivation on GC-GSH and GC-NAC involves a slowdown in the drug release rate. The results shown that the novel preactivated thiolated GC-derivatives can be considered promising excipients for the development of mucoadhesive drug delivery systems.}, }
@article {pmid30252537, year = {2019}, author = {Ibie, CO and Knott, RM and Thompson, CJ}, title = {Complexation of novel thiomers and insulin to protect against in vitro enzymatic degradation - towards oral insulin delivery.}, journal = {Drug development and industrial pharmacy}, volume = {45}, number = {1}, pages = {67-75}, doi = {10.1080/03639045.2018.1517776}, pmid = {30252537}, issn = {1520-5762}, mesh = {Administration, Oral ; Drug Delivery Systems/*methods ; Insulin/*administration &amp; dosage/*chemistry/metabolism ; Pepsin A/metabolism ; Peptide Hydrolases/metabolism ; Polymers/*administration &amp; dosage/*chemistry/metabolism ; Trypsin/metabolism ; }, abstract = {A significant barrier to oral insulin delivery is its enzymatic degradation in the gut. Nano-sized polymer-insulin polyelectrolyte complexes (PECS) have been developed to protect insulin against enzymatic degradation. Poly(allylamine) (Paa) was trimethylated to yield QPaa. Thiolation of Paa and QPaa was achieved by attaching either N-acetylcysteine (NAC) or thiobutylamidine (TBA) ligands (Paa-NAC/QPaa-NAC and Paa-TBA/QPaa-TBA thiomers). PEC formulations were prepared in Tris buffer (pH 7.4) at various polymer: insulin mass ratios (0.2:1-2:1). PECS were characterized by %transmittance of light and photon correlation spectroscopy. Insulin complexation efficiency and enzyme-protective effect of these complexes were determined by HPLC. Complexation with insulin was found to be optimal at mass ratios of 0.4-1:1 for all polymers. PECS in this mass range were positively-charged (20-40 mV), nanoparticles (50-200 nm), with high insulin complexation efficiency (>90%). Complexation with TBA polymers appeared to result in disulfide bridge formation between the polymers and insulin. In vitro enzymatic degradation assays of QPaa, Paa-NAC, and QPaa-NAC PECS showed that they all offered some protection against insulin degradation by trypsin and α-chymotrypsin, but not from pepsin. QPaa-NAC complexes with insulin are the most promising formulation for future work, given their ability to offer protection against intestinal enzymes. This work highlights the importance of optimizing polymer structure in the delivery of proteins.}, }
@article {pmid30245889, year = {2018}, author = {Saleem, TH and Abo El-Maali, N and Hassan, MH and Mohamed, NA and Mostafa, NAM and Abdel-Kahaar, E and Tammam, AS}, title = {Comparative Protective Effects of N-Acetylcysteine, N-Acetyl Methionine, and N-Acetyl Glucosamine against Paracetamol and Phenacetin Therapeutic Doses-Induced Hepatotoxicity in Rats.}, journal = {International journal of hepatology}, volume = {2018}, number = {}, pages = {7603437}, pmid = {30245889}, issn = {2090-3448}, abstract = {BACKGROUND AND AIMS: Both paracetamol (PA) and phenacetin (PH) are analgesic and antipyretic agents. Part of phenacetin therapeutic activity is attributed to its metabolism into paracetamol. Paracetamol causes direct hepatic oxidative stress damage. The present study aimed to investigate the possible damaging effects of both PA and PH, when used in therapeutic doses, on rat liver and to compare the antioxidant and hepatoprotective effects of N-acetylcysteine (NAC), N-acetyl-methionine (NAM), and N-acetylglucosamine (NAG) against PA- or PH-induced hepatic damage.<br><br>METHODS: 90 male Wistar albino rats (120-140 gm) were undertaken, categorized randomly into 9 groups of 10 rats each, and administered by gavage for 2 weeks with DMSO 1% (controls), PA, PA+NAC, PA+NAM, PA+NAG, PH, PH+NAC, PH+NAM, and PH+NAG. Biochemical assays of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), total thiols, and alpha-fetoprotein (AFP) in liver homogenates and serum assays of ALT, AST, 8-hydroxy guanine (8-OH-Gua), and AFP were done. Also histopathological examinations of liver tissues in various groups were done.<br><br>RESULTS: PA and PH cause significant increase in hepatic levels of MDA, NO, and AFP and serum ALT, AST, and 8-OH-Gua levels, with significant decrease in hepatic GSH and total thiols. NAG and NAC significantly improve the PA- and PH-induced hepatic and blood, biochemical, and histopathological disturbances, respectively.<br><br>CONCLUSIONS: Both PA and PH induce oxidative stress in rat liver within their therapeutic doses. NAG and NAC in pharmacological doses can antagonize the oxidative damaging effect of both PA and PH.}, }
@article {pmid30245604, year = {2018}, author = {Alhusaini, A and Faddaa, L and Ali, HM and Hassan, I and El Orabi, NF and Bassiouni, Y}, title = {Amelioration of the Protein Expression of Cox2, NFκB, and STAT-3 by Some Antioxidants in the Liver of Sodium Fluoride-Intoxicated Rats.}, journal = {Dose-response : a publication of International Hormesis Society}, volume = {16}, number = {3}, pages = {1559325818800153}, pmid = {30245604}, issn = {1559-3258}, abstract = {The present study aimed to explore the efficiency of N-acetyl cysteine (NACC) or thymoquinone (TMQ) alone or in combination in the downregulation of inflammatory molecule expression and decreasing hepatic injury in response to sodium fluoride (SF). Sodium fluoride upregulated serum alanine and aspartate transferases activities, tumor necrosis factor α and hepatic malondialdehyde and nitric oxide levels, and the expression of cyclooxygenase 2, nuclear factor κB cell, and signal transducer and activator of transcription 3. In contrast, hepatic glutathione level, superoxide dismutase activity, and nuclear factor erythroid 2-related factor 2 expression were decreased. However, the concurrent treatment with antioxidants, alone or in combination, modulated the levels of these parameters. Histopathological examination revealed that SF treatment resulted in focal areas of massive hepatic degeneration and many degenerated hepatocytes, whereas the treatment with TMQ or NACC exhibited moderate improvement in cellular degeneration of the liver with many abnormal cells. Rats receiving a combination of TMQ and NACC showed marked improvement in cellular degeneration of liver with apparently normal hepatic architecture with very few degenerated hepatocytes. The results also revealed that the combination of TMQ and NACC is the most effective regimen in ameliorating SF toxicity, suggesting their efficacy against the toxicity of fluoride compounds. Their activities might be mediated via multiple molecular pathways.}, }
@article {pmid30243219, year = {2018}, author = {Jin, X and Asghar, S and Zhang, M and Chen, Z and Huang, L and Ping, Q and Xiao, Y}, title = {N-acetylcysteine modified hyaluronic acid-paclitaxel conjugate for efficient oral chemotherapy through mucosal bioadhesion ability.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {172}, number = {}, pages = {655-664}, doi = {10.1016/j.colsurfb.2018.09.025}, pmid = {30243219}, issn = {1873-4367}, mesh = {Acetylcysteine/administration &amp; dosage/chemical synthesis/pharmacology/*therapeutic use ; Adhesiveness ; Administration, Oral ; Animals ; Drug Liberation ; Gastrointestinal Tract/drug effects ; Humans ; Hyaluronic Acid/chemical synthesis/*chemistry ; MCF-7 Cells ; Male ; Micelles ; Mucins/chemistry ; Mucous Membrane/*drug effects ; Oxidation-Reduction ; Paclitaxel/pharmacokinetics/pharmacology/*therapeutic use ; Particle Size ; Rats, Sprague-Dawley ; Static Electricity ; Sulfhydryl Compounds/chemistry ; Tissue Distribution/drug effects ; }, abstract = {N-acetylcysteine modified hyaluronic acid-paclitaxel (NAC-HA-PTX) conjugate was designed to improve the water solubility and oral bioavailability of PTX through mucosal bioadhesion ability. The average size of spherical NAC-HA-PTX micelles was 187 nm with a zeta potential of -25.38 mV. Mucin adhesion study showed that the amount of mucin adhered to NAC-HA-PTX micelles was 1.98-fold greater than that of hyaluronic acid-paclitaxel (HA-PTX) micelles. The fluorescence micrographs showed that the biodistribution sequence of coumarin 6-loaded micelles in the gastrointestinal tract was duodenum > jejunum > ileum, and NAC-modified micelles significantly exhibited better mucoadhesive properties than the corresponding unmodified ones. The pharmacokinetic study showed that the area under the curve (AUC0-24h) of NAC-HA-PTX micelles was 2.32-fold and 2.56-fold higher compared to that of HA-PTX micelles and PTX solution (Taxol) after oral administration, respectively. NAC-HA-PTX micelles appear to be a promising drug delivery system to improve the bioavailability of insoluble drugs for efficient tumor therapy via oral administration.}, }
@article {pmid30243020, year = {2018}, author = {Shaposhnikov, MV and Zemskaya, NV and Koval, LA and Schegoleva, EV and Zhavoronkov, A and Moskalev, AA}, title = {Effects of N-acetyl-L-cysteine on lifespan, locomotor activity and stress-resistance of 3 Drosophila species with different lifespans.}, journal = {Aging}, volume = {10}, number = {9}, pages = {2428-2458}, pmid = {30243020}, issn = {1945-4589}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Dose-Response Relationship, Drug ; Drosophila/*physiology ; Female ; Locomotion/*drug effects ; Longevity/*drug effects ; Male ; Sex Characteristics ; Stress, Physiological/*drug effects ; }, abstract = {N-acetyl-L-cysteine (NAC) is a derivative of the sulphur-containing amino acid L-cysteine with potential anti-aging properties. We studied 3 Drosophila species with contrast longevity differences (D. virilis is longest-lived, D. kikkawai is shortest-lived and D. melanogaster has moderate lifespan) to test the effects of NAC at 8 different concentrations (from 10 nM to 100 mM) on the lifespan, stress-resistance and locomotor activity. Except the adverse effects of highest (10 mM and 100 mM) concentrations NAC demonstrated sexually opposite and male-biased effects on Drosophila lifespan, stress-resistance and locomotor activity and not satisfied the criteria of a geroprotector in terms of the reproducibility of lifespan extending effects in different model organisms. The concentration- and sex-dependent changes in the relative expression levels of the antioxidant genes (Cat/CG6871 and Sod1/CG11793) and genes involved in hydrogen sulfide biosynthesis (Cbs/CG1753, Eip55E/CG5345 and Nfs1/CG12264) suggest the involvement of hormetic mechanisms in the geroprotective effects of NAC.}, }
@article {pmid30241048, year = {2018}, author = {Lee, CY and Su, CH and Tsai, PK and Yang, ML and Ho, YC and Lee, SS and Chen, CH and Chen, WY and Lin, ML and Chen, CJ and Chian, CY and Huang-Liu, R and Chang, YL and Kuan, YH}, title = {Cadmium nitrate-induced neuronal apoptosis is protected by N-acetyl-l-cysteine via reducing reactive oxygen species generation and mitochondria dysfunction.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {108}, number = {}, pages = {448-456}, doi = {10.1016/j.biopha.2018.09.054}, pmid = {30241048}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cadmium Compounds/*pharmacology ; Caspases/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/metabolism ; Necrosis/chemically induced/drug therapy/metabolism ; Neurons/*drug effects/metabolism ; Nitrates/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Cigarette smoking is a well-established risk factor for various diseases, such as cardiovascular diseases, neurodegeneration, and cancer. Cadmium nitrate (Cd(NO3)2) is one of the major products from the cigarette smoke. Up to now, no supporting evidence on Cd(NO3)2-induced apoptosis and its related working mechanism in neurons has been found. In present study, the mode of cell death, caspase activities, reactive oxygen species (ROS) generation, and mitochondrial dysfunction in N2a cells, which are neuron-like cells, were assessed by Annexin V-FITC and PI assays, caspase fluorometric assay, DCFH-DA fluorescence assay, and JC-1 fluorescence assay respectively. The results showed that not only Cd(NO3)2 induced apoptosis and necrosis but also the activities of caspase-3 and -9 expressed in a concentration-dependent manner. In addition, Cd(NO3)2 also induced both mitochondrial dysfunction and ROS generation in a concentration-dependent manner. All these indicated that in N2a cells parallel trends could be observed in apoptosis, caspase-3 and -9 activities, mitochondrial dysfunction, and ROS generation when induced by Cd(NO3)2. Furthermore, Cd(NO3)2-induced apoptosis, caspases activities, mitochondrial dysfunction, and ROS generation were reduced by N-acetyl-l-cysteine (NAC). These results indicated that Cd(NO3)2-induced neuronal apoptosis was reduced by NAC via intrinsic apoptotic caspase cascade activities and their up-stream factors, including mitochondrial dysfunction and ROS generation.}, }
@article {pmid30240709, year = {2019}, author = {An, J and Zhou, Q and Wu, M and Wang, L and Zhong, Y and Feng, J and Shang, Y and Chen, Y}, title = {Interactions between oxidative stress, autophagy and apoptosis in A549 cells treated with aged black carbon.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {54}, number = {}, pages = {67-74}, doi = {10.1016/j.tiv.2018.09.008}, pmid = {30240709}, issn = {1879-3177}, mesh = {A549 Cells ; Apoptosis/drug effects ; Autophagy/drug effects ; Carbon/*toxicity ; Humans ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {After emitted from incomplete combustion of fossil fuels and biomass, ambient black carbon (BC) was then undergone photochemical oxidization processes in the air to form aged BC particles, also called oxidized BC (OBC). This study aimed to investigate the interactions between oxidative stress, autophagy and apoptosis induced by OBC in A549 cells and to explore associated molecular mechanisms. First, OBC could stimulate oxidative stress, autophagy and apoptosis dose-dependently, as evidenced by increased intercellular reactive oxygen species (ROS) levels, up-regulated autophagosome markers (light chain 3, LC3), and elevated apoptosis rate. Inhibitors of oxidative stress (N-acetylcysteine, NAC), autophagy (bafilomycin A1, Baf) and apoptosis (Z-DEVD-FMK) were used to investigate their interactions. NAC pretreatment could significantly reduce autophagy and apoptosis. Additionally, pretreatment with Baf or Z-DEVD-FMK could also significantly suppress the other two biological effects. Furthermore, OBC up regulated the expressions of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), phosphorylated protein kinase B (Akt) and mammalian target of rapamycin (mTOR). The Akt inhibitor (MK-2206) significantly reduced both autophagy and apoptosis. Taken together, dual-direction regulation existed between each two of oxidative stress, autophagy, and apoptosis in A549 cells exposed to OBC. In addition, the autophagy process is modulated by the PI3K/Akt pathway regardless of mTOR activity.}, }
@article {pmid30239089, year = {2019}, author = {Tan, SI and Brewster, DJ and Horrigan, D and Sarode, V}, title = {Pharmacological and non-surgical renal protective strategies for cardiac surgery patients undergoing cardiopulmonary bypass: a systematic review.}, journal = {ANZ journal of surgery}, volume = {89}, number = {4}, pages = {296-302}, doi = {10.1111/ans.14800}, pmid = {30239089}, issn = {1445-2197}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Acute Kidney Injury/*drug therapy/*etiology/physiopathology/prevention &amp; control ; Anesthetics/administration &amp; dosage/therapeutic use ; Cardiac Surgical Procedures/*adverse effects ; Cardiopulmonary Bypass/*adverse effects ; Coronary Artery Bypass/adverse effects ; Female ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Humans ; Ischemic Preconditioning/methods ; Male ; Postoperative Complications/epidemiology ; Protective Agents/administration &amp; dosage/therapeutic use ; Randomized Controlled Trials as Topic ; Renal Replacement Therapy/methods/mortality ; Risk Factors ; Volatilization ; }, abstract = {BACKGROUND: Post-operative acute kidney injury after cardiopulmonary bypass (AKI-CPB) for cardiac surgery is a frequent complication. It may require renal replacement therapy (RRT), which is associated with an increased morbidity and mortality. This review explores the efficacy of proposed pharmacological and non-surgical renal protective strategies.<br><br>METHODS: A comprehensive literature search was done using Ovid MEDLINE, Embase and Scopus databases. Keywords included were cardiopulmonary bypass, cardiac surgery, coronary artery bypass, renal protection and renal preservation. Eligible articles consisted of all studies on patients who had undergone cardiac surgery via CPB with an outcome of AKI and/or RRT reported. All studies underwent a quality check via the risk of bias tool. The three most researched interventions (based on number of randomized controlled trials and total patients analysed) and their renal outcomes were then analysed with Review Manager Software.<br><br>RESULTS: Eighty-eight articles were extracted. A total of 26 management strategies for renal protection following CPB were identified. N-acetylcysteine (NAC), remote ischaemic preconditioning (RIPC) and the use of volatile anaesthetic agents (VAAs) were further analysed. NAC, RIPC and VAA had no statistically significant benefit in reducing either AKI-CPB or the need for RRT following CPB.<br><br>CONCLUSION: NAC, RIPC and VAA were found to have no statistical significant benefit in reducing either AKI-CPB or the need for RRT following CPB. There remains clinical uncertainty with all currently proposed pharmacological and non-surgical renal protective strategies for CPB. Future research in this area should analyse the effects of combined interventions or specifically focus on 'at-risk' patients.}, }
@article {pmid30237126, year = {2018}, author = {Jia, Y and Wang, F and Guo, Q and Li, M and Wang, L and Zhang, Z and Jiang, S and Jin, H and Chen, A and Tan, S and Zhang, F and Shao, J and Zheng, S}, title = {Curcumol induces RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling in hepatic stellate cells.}, journal = {Redox biology}, volume = {19}, number = {}, pages = {375-387}, pmid = {30237126}, issn = {2213-2317}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carbon Tetrachloride/toxicity ; Cell Proliferation/drug effects ; Cells, Cultured ; Hepatic Stellate Cells/*metabolism ; Liver Cirrhosis/chemically induced/*drug therapy/pathology ; Male ; Mice ; Mice, Inbred ICR ; Mitochondria/drug effects/metabolism ; Mitogen-Activated Protein Kinase 8/antagonists &amp; inhibitors/*metabolism ; Mitogen-Activated Protein Kinase 9/antagonists &amp; inhibitors/*metabolism ; Necrosis/*pathology ; Phosphorylation/drug effects ; RNA Interference ; RNA, Small Interfering/genetics ; Random Allocation ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/*metabolism ; Sesquiterpenes/*pharmacology ; }, abstract = {It is generally recognized that hepatic fibrogenesis is an end result of increased extracellular matrix (ECM) production from the activation and proliferation of hepatic stellate cells (HSCs). An in-depth understanding of the mechanisms of HSC necroptosis might provide a new therapeutic strategy for prevention and treatment of hepatic fibrosis. In this study, we attempted to investigate the effect of curcumol on necroptosis in HSCs, and further to explore the molecular mechanisms. We found that curcumol ameliorated the carbon tetrachloride (CCl4)-induced mice liver fibrosis and suppressed HSC proliferation and activation, which was associated with regulating HSC necroptosis through increasing the phosphorylation of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3). Moreover, curcumol promoted the migration of RIPK1 and RIPK3 into necrosome in HSCs. RIPK3 depletion impaired the anti-fibrotic effect of curcumol. Importantly, we showed that curcumol-induced RIPK3 up-regulation significantly increased mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization. ROS scavenger, N-acetyl-L-cysteine (NAC) impaired RIPK3-mediated necroptosis. In addition, our study also identified that the activation of c-Jun N-terminal kinase1/2 (JNK1/2) was regulated by RIPK3, which mediated curcumol-induced ROS production. Down-regulation of RIPK3 expression, using siRIPK3, markedly abrogated JNK1/2 expression. The use of specific JNK1/2 inhibitor (SP600125) resulted in the suppression of curcumol-induced ROS production and mitochondrial depolarization, which in turn, contributed to the inhibition of curcumol-triggered necroptosis. In summary, our study results reveal the molecular mechanism of curcumol-induced HSC necroptosis, and suggest a potential clinical use of curcumol-targeted RIPK1/RIPK3 complex-dependent necroptosis via JNK1/2-ROS signaling for the treatment of hepatic fibrosis.}, }
@article {pmid30237006, year = {2018}, author = {Safi, R and Kallas, R and Bardawil, T and Mehanna, CJ and Abbas, O and Hamam, R and Uthman, I and Kibbi, AG and Nassar, D}, title = {Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behçet's disease.}, journal = {Journal of dermatological science}, volume = {92}, number = {2}, pages = {143-150}, doi = {10.1016/j.jdermsci.2018.08.010}, pmid = {30237006}, issn = {1873-569X}, mesh = {Adult ; Apoptosis/*immunology ; Behcet Syndrome/blood/*immunology/pathology ; Biopsy ; Case-Control Studies ; Cells, Cultured ; Coculture Techniques ; Endothelial Cells ; Extracellular Traps/*immunology/metabolism ; Female ; Healthy Volunteers ; Humans ; Male ; Middle Aged ; Neutrophils/immunology/*metabolism ; Skin/blood supply/cytology/immunology/pathology ; }, abstract = {BACKGROUND AND OBJECTIVES: Behçet's disease (BD) is a multi-system inflammatory disorder that can cause vasculitis. Here we questioned whether Neutrophils in BD cause vasculitis via releasing Neutrophil Extracellular Traps (NETs), a process called NETosis.<br><br>METHODS: Circulating neutrophils were isolated from a cohort of Middle Eastern BD patients with an active disease and healthy volunteers. The percentage of NETs release was monitored in neutrophils stimulated or not with BD serum, and treated or not with Colchicine, Dexamethasone, Cl-amidine or N-Acetyl Cysteine (NAC). The mRNA expression levels of PAD4 (a key enzyme in NETosis) was also assessed. The effect of NETs on the proliferation and cell death of endothelial cells was investigated using an in vitro co-culture model. The presence of NETs in skin tissues of BD patients was examined using immunolabeling of NETs associated proteins.<br><br>RESULTS: Circulating Neutrophils from BD patients were more prone to release NETs in vitro and expressed higher levels of PAD4 compared to healthy volunteers. Spontaneous NETs formation in BD neutrophils was inhibited by Colchicine and Dexamethasone, two drugs used to treat BD. NETs formation was also inhibited by Cl-amidine, a specific PAD4 inhibitor, and by NAC, a ROS inhibitor. Interestingly, serum from BD patients stimulated circulating neutrophils from healthy volunteers to release more NETs and increased their mRNA PAD4 expression. Moreover, endothelial cells cultured in the presence of NETs from BD patients showed a decrease in proliferation and an increase in apoptosis and cell death. Finally, NETosis was predominantly identified around affected blood vessels in biopsies of vasculitis from BD patients.<br><br>CONCLUSION: Our results provide evidence on the implication of NETosis in the pathophysiology of BD especially in inducing vasculitis.}, }
@article {pmid30232291, year = {2018}, author = {Pilipow, K and Scamardella, E and Puccio, S and Gautam, S and De Paoli, F and Mazza, EM and De Simone, G and Polletti, S and Buccilli, M and Zanon, V and Di Lucia, P and Iannacone, M and Gattinoni, L and Lugli, E}, title = {Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity.}, journal = {JCI insight}, volume = {3}, number = {18}, pages = {}, pmid = {30232291}, issn = {2379-3708}, mesh = {Animals ; Antigens, CD19 ; Antineoplastic Agents/*immunology ; Antioxidants/*metabolism/*pharmacology ; CD8-Positive T-Lymphocytes/*drug effects ; Cell Differentiation/drug effects ; Female ; Gene Expression Profiling ; Humans ; Immunity, Cellular ; Immunologic Memory ; Immunotherapy, Adoptive ; Male ; Mice ; Mice, Inbred NOD ; Stem Cells/*drug effects ; }, abstract = {Adoptive T cell transfer (ACT) immunotherapy benefits from early differentiated stem cell memory T (Tscm) cells capable of persisting in the long term and generating potent antitumor effectors. Due to their paucity ex vivo, Tscm cells can be derived from naive precursors, but the molecular signals at the basis of Tscm cell generation are ill-defined. We found that less differentiated human circulating CD8+ T cells display substantial antioxidant capacity ex vivo compared with more differentiated central and effector memory T cells. Limiting ROS metabolism with antioxidants during naive T cell activation hindered terminal differentiation, while allowing expansion and generation of Tscm cells. N-acetylcysteine (NAC), the most effective molecule in this regard, induced transcriptional and metabolic programs characteristic of self-renewing memory T cells. Upon ACT, NAC-generated Tscm cells established long-term memory in vivo and exerted more potent antitumor immunity in a xenogeneic model when redirected with CD19-specific CAR, highlighting the translational relevance of NAC as a simple and inexpensive method to improve ACT.}, }
@article {pmid30223245, year = {2018}, author = {Nowacka, M and Rygała, A and Kręgiel, D and Kowalewska, A}, title = {Poly(silsesquioxanes) and poly(siloxanes) grafted with N-acetylcysteine for eradicating mature bacterial biofilms in water environment.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {172}, number = {}, pages = {627-634}, doi = {10.1016/j.colsurfb.2018.09.017}, pmid = {30223245}, issn = {1873-4367}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/pharmacology ; Bacteria/*drug effects ; Biofilms/*drug effects ; Hydrodynamics ; Light ; Microbial Sensitivity Tests ; Organosilicon Compounds/chemical synthesis/*chemistry ; Siloxanes/chemical synthesis/*chemistry ; Temperature ; *Water Microbiology ; Wettability ; }, abstract = {Bacteria adapt to their living environment forming organised biofilms. The survival strategy makes them more resistant to disinfectants, which results in acute biofilm-caused infections, secondary water pollution by biofilm metabolites and bio-corrosion. New, efficient and environmentally friendly strategies must be developed to solve this problem. Water soluble N-acetyl derivative of L-cysteine (NAC) is a non-toxic compound of mucolytic and bacteriostatic properties that can interfere with the formation of biofilms. However, it can also be a source of C and N for undesired microorganisms, as well as a reason for some adverse human health effects. Consequently, novel procedures are required, that would decrease the take-up of NAC but not reduce its antibacterial properties. We have grafted N-acetyl-l-cysteine onto linear poly(vinylsilsesquioxanes) and poly(methylvinylsiloxanes) via thiol-ene addition. Antibacterial activity of the obtained hybrid materials (respectively, NAC-Si-1 and NAC-Si-2) was determined against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus strains. Native NAC inhibited growth of planktonic cells for the tested bacteria at concentration 0.25% w/v. Inhibition with equivalent solutions of the polymer derivatives was less effective due to the lack of SH groups. However, the tested polymers proved to be quite effective in eradication of mature biofilms. Treatment with 1% w/v emulsions of the hybrid polymers resulted in a significant reduction of viable cells in biofilm matrix despite the absence of thiol moieties. The effect was most pronounced for mature biofilms of S. aureus eradicated with NAC-Si-2.}, }
@article {pmid30222967, year = {2018}, author = {Zulato, E and Ciccarese, F and Agnusdei, V and Pinazza, M and Nardo, G and Iorio, E and Curtarello, M and Silic-Benussi, M and Rossi, E and Venturoli, C and Panieri, E and Santoro, MM and Di Paolo, V and Quintieri, L and Ciminale, V and Indraccolo, S}, title = {LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and γ-irradiation.}, journal = {Biochemical pharmacology}, volume = {156}, number = {}, pages = {479-490}, doi = {10.1016/j.bcp.2018.09.019}, pmid = {30222967}, issn = {1873-2968}, mesh = {AMP-Activated Protein Kinase Kinases ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects/radiation effects ; Cisplatin/*pharmacology ; *Gamma Rays ; Gene Expression Regulation, Neoplastic/drug effects/radiation effects ; Glutathione/*metabolism ; Humans ; Hydrogen Peroxide/*pharmacology ; Magnetic Resonance Spectroscopy ; Oxidative Stress/*drug effects ; Protein Serine-Threonine Kinases/genetics/*metabolism ; }, abstract = {The liver kinase B1 (LKB1) gene is a tumor suppressor associated with the hereditary Peutz-Jeghers syndrome and frequently mutated in non-small cell lung cancer and in cervical cancer. Previous studies showed that the LKB1/AMPK axis is involved in regulation of cell death and survival under metabolic stress. By using isogenic pairs of cancer cell lines, we report here that the genetic loss of LKB1 was associated with increased intracellular levels of total choline containing metabolites and, under oxidative stress, it impaired maintenance of glutathione (GSH) levels. This resulted in markedly increased intracellular reactive oxygen species (ROS) levels and sensitivity to ROS-induced cell death. These effects were rescued by re-expression of LKB1 or pre-treatment with the anti-oxidant and GSH replenisher N-acetyl cysteine. This role of LKB1 in response to ROS-inducing agents was largely AMPK-dependent. Finally, we observed that LKB1 defective cells are highly sensitive to cisplatin and γ-irradiation in vitro, suggesting that LKB1 mutated tumors could be targeted by oxidative stress-inducing therapies.}, }
@article {pmid30221369, year = {2019}, author = {Fujita, M and Yamamoto, Y and Watanabe, S and Sugawara, T and Wakabayashi, K and Tahara, Y and Horie, N and Fujimoto, K and Kusakari, K and Kurokawa, Y and Kawakami, T and Kojima, K and Kojima, H and Ono, A and Katsuoka, Y and Tanabe, H and Yokoyama, H and Kasahara, T}, title = {Cause of and countermeasures for oxidation of the cysteine-derived reagent used in the amino acid derivative reactivity assay.}, journal = {Journal of applied toxicology : JAT}, volume = {39}, number = {2}, pages = {191-208}, doi = {10.1002/jat.3707}, pmid = {30221369}, issn = {1099-1263}, mesh = {Acetylcysteine/*chemistry ; Allergens/administration &amp; dosage/chemistry/toxicity ; Animal Testing Alternatives/*methods ; Animals ; Biological Assay/*methods ; Copper/chemistry ; Edetic Acid/*chemistry ; Ferric Compounds/chemistry ; Models, Chemical ; Oxidation-Reduction ; Skin/drug effects/metabolism ; }, abstract = {The amino acid derivative reactivity assay (ADRA) is an in chemico alternative to animal testing for skin sensitization that solves certain problems found in the use of the direct peptide reactivity assay (DPRA). During a recent validation study conducted at multiple laboratories as part of the process to include ADRA in an existing OECD test guideline, one of the nucleophilic reagents used in ADRA-N-(2-(1-naphthyl)acetyl)-l-cysteine (NAC)-was found to be susceptible to oxidation in much the same manner that the cysteine peptide used in DPRA was. Owing to this, we undertook a study to clarify the cause of the promotion of NAC oxidation. In general, cysteine and other chemicals that have thiol groups are known to oxidize in the presence of even minute quantities of metal ions. When metal ions were added to the ADRA reaction solution, Cu[2+] promoted NAC oxidation significantly. When 0.25 μm of EDTA was added in the presence of Cu[2+] , NAC oxidation was suppressed. Based on this, we predicted that the addition of EDTA to the NAC stock solution would suppress NAC oxidation. Next, we tested 82 chemicals used in developing ADRA to determine whether EDTA affects ADRA's ability to predict sensitization. The results showed that the addition of EDTA has virtually no effect on the reactivity of NAC with a test chemical, yielding an accuracy of 87% for predictions of skin sensitization, which was roughly the same as ADRA.}, }
@article {pmid30218457, year = {2019}, author = {Zhang, T and Zhao, G and Zhu, X and Jiang, K and Wu, H and Deng, G and Qiu, C}, title = {Sodium selenite induces apoptosis via ROS-mediated NF-κB signaling and activation of the Bax-caspase-9-caspase-3 axis in 4T1 cells.}, journal = {Journal of cellular physiology}, volume = {234}, number = {3}, pages = {2511-2522}, doi = {10.1002/jcp.26783}, pmid = {30218457}, issn = {1097-4652}, mesh = {Animals ; Apoptosis/genetics ; Breast Neoplasms/*drug therapy/genetics/pathology ; Caspase 3/genetics ; Caspase 9/genetics ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mammary Neoplasms, Animal/*drug therapy/genetics/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; NF-kappa B/genetics ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sodium Selenite/*pharmacology ; Transcription Factor RelA/genetics ; bcl-2-Associated X Protein/genetics ; }, abstract = {Sodium selenite (SSE), a source of inorganic selenium, has been widely used as a clinical cancer treatment, but the precise molecular mechanisms of SSE remain to be elucidated. Our in vitro experiments have confirmed that SSE treatment causes a transient increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling and p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha phosphorylation levels in 4T1 cells. The inhibition of NF-κB subsequently increased the expression of the apoptosis gene B-cell lymphoma-2-associated X (Bax) and downregulated the transcription of antiapoptosis genes, such as B-cell lymphoma-2, cellular inhibitor of apoptosis 1, and X-linked inhibitor of apoptosis. Additionally, the accumulation of ROS caused mitochondrial dysfunction, leading to the activation of caspase-9 and -3, thereby resulting in apoptosis. However, modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed these events. Similarly, in vitro murine syngeneic breast tumor models showed that SSE inhibits tumor growth by promoting apoptosis. These results indicate that SSE induces apoptosis via ROS-mediated inhibition of NF-κB signaling and activation of the Bax-caspase-9-caspase-3 axis.}, }
@article {pmid30217947, year = {2018}, author = {Hou, Q and Hu, K and Liu, X and Quan, J and Liu, Z}, title = {HADC regulates the diabetic vascular endothelial dysfunction by targetting MnSOD.}, journal = {Bioscience reports}, volume = {38}, number = {5}, pages = {}, pmid = {30217947}, issn = {1573-4935}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/genetics ; Caspase 3/genetics ; Diabetic Angiopathies/*genetics/pathology ; Endothelial Cells/drug effects/*metabolism/pathology ; Gene Expression Regulation/drug effects ; Gene Knockdown Techniques ; Glucose/metabolism ; Histone Deacetylase 2/antagonists &amp; inhibitors/*genetics ; Humans ; Metalloporphyrins/pharmacology ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*genetics ; bcl-2-Associated X Protein/genetics ; }, abstract = {Vascular dysfunction is a common result of diabetes in humans. However, the mechanism underlying diabetic vascular dysfunction is not fully understood. Here in the present study, we showed that the histone deacetylase 2 (HDAC2) promoted the endothelial dysfunction induced by diabetes. The expression and activity of HDAC2 were up-regulated in vascular endothelial cells (ECs) from diabetic patients and mice. The expression of HDAC2 was also increased by high glucose stress in isolated human ECs. HDAC2 knockdown repressed the proliferation rate and promoted high glucose-induced apoptosis of ECs, which was associated with the activation of apoptotic pathways (Bcl-2, Caspase 3, and Bax). By contrast, HDAC2 overexpression led to opposing results. Significantly, we observed that HDAC2 regulated the accumulation of reactive oxygen species (ROS) induced by high glucose in ECs, which accounted for the effects of HDAC2 on proliferation and apoptosis because antioxidants, N-acetyl-l-cysteine (NAC) or MnTBAP treatment blocked the effects of HDAC2 on apoptosis of ECs under high glucose condition. Mechanism study revealed that HDAC2 bound to the promoter of MnSOD and repressed the expression of MnSOD by regulating the level of acetylated H3K9 and H3K27, which led to the promotion of oxidative stress and contributed to the function of HDAC2 in ECs under high glucose condition. Altogether, our evidence demonstrated that HDAC2-MnSOD signaling was critical in oxidative stress and proliferation as well as the survival of ECs under high glucose condition.}, }
@article {pmid30217943, year = {2018}, author = {Li, X and Wei, X and Chen, C and Zhang, Z and Liu, D and Hei, Z and Yao, W}, title = {N-Acetylcysteine inhalation improves pulmonary function in patients received liver transplantation.}, journal = {Bioscience reports}, volume = {38}, number = {5}, pages = {}, pmid = {30217943}, issn = {1573-4935}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Breath Tests ; Exhalation/genetics ; Female ; Humans ; Intercellular Adhesion Molecule-1/blood ; Interleukin-8/blood ; Liver Transplantation/*adverse effects ; Lung/metabolism/pathology ; Lung Diseases/blood/*drug therapy/etiology/pathology ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Postoperative Complications/blood/*drug therapy/physiopathology ; Tumor Necrosis Factor-alpha/blood ; Uteroglobin/blood ; }, abstract = {Postoperative pulmonary complications (PPCs) following orthotopic liver transplantation (OLT) are associated with high morbidity and mortality rates. The effect of N-acetylcysteine (NAC) inhalation on the incidence of PPCs and the outcomes of patients undergoing OLT is unknown. This prospective randomized controlled clinical trial was conducted to investigate the effect of NAC inhalation during OLT on PPCs. Sixty patients were randomly assigned to the NAC group (n = 30) or the control group (n = 30) to receive inhaled NAC or sterilized water, respectively, for 30 min before surgery and 3 h after reperfusion. The incidence of early PPCs and outcomes including survival rate were assessed. Biomarkers including tumor necrosis factor (TNF)-α, interleukin (IL)-8, Clara cell secretory protein (CC16), intercellular adhesion molecule (ICAM)-1, and superoxide dismutase (SOD) were measured in exhaled breath condensate (EBC) at T1 (before surgery) and T2 (at the end of operation) as well as in serum at T1, T2, T3 (12 h after operation), and T4 (24 h after operation). A total of 42 patients (20 in the NAC group and 22 in the control group) were enrolled in the final analysis. Atomization inhaled NAC significantly reduced the incidence of PPCs after OLT. The levels of TNF-α, IL-8, CC16, and ICAM-1 in EBC were significantly lower, and SOD activity was higher, at T2 in the NAC group; similar data were found in serum at T2, T3, and T4. In summary, perioperative NAC inhalation may reduce the incidence of PPCs and improve patient outcomes after OLT.}, }
@article {pmid30216807, year = {2018}, author = {Watanabe, J and Yamada, M and Niibe, K and Zhang, M and Kondo, T and Ishibashi, M and Egusa, H}, title = {Preconditioning of bone marrow-derived mesenchymal stem cells with N-acetyl-L-cysteine enhances bone regeneration via reinforced resistance to oxidative stress.}, journal = {Biomaterials}, volume = {185}, number = {}, pages = {25-38}, doi = {10.1016/j.biomaterials.2018.08.055}, pmid = {30216807}, issn = {1878-5905}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Bone Regeneration/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Glutathione/metabolism ; Male ; *Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cells/cytology/*drug effects ; Oxidative Stress/drug effects ; Rats, Sprague-Dawley ; }, abstract = {Oxidative stress on transplanted bone marrow-derived mesenchymal stem cells (BMSCs) during acute inflammation is a critical issue in cell therapies. N-acetyl-L cysteine (NAC) promotes the production of a cellular antioxidant molecule, glutathione (GSH). The aim of this study was to investigate the effects of pre-treatment with NAC on the apoptosis resistance and bone regeneration capability of BMSCs. Rat femur-derived BMSCs were treated in growth medium with or without 5 mM NAC for 6 h, followed by exposure to 100 μM H2O2 for 24 h to induce oxidative stress. Pre-treatment with NAC significantly increased intracellular GSH levels by up to two fold and prevented H2O2-induced intracellular redox imbalance, apoptosis and senescence. When critical-sized rat femur defects were filled with a collagen sponge containing fluorescent-labeled autologous BMSCs with or without NAC treatment, the number of apoptotic and surviving cells in the transplanted site after 3 days was significantly lower and higher in the NAC pre-treated group, respectively. By the 5th week, significantly enhanced new bone formation was observed in the NAC pre-treated group. These data suggest that pre-treatment of BMSCs with NAC before local transplantation enhances bone regeneration via reinforced resistance to oxidative stress-induced apoptosis at the transplanted site.}, }
@article {pmid30214307, year = {2018}, author = {Li, X and Hong, X and Gao, X and Gu, X and Xiong, W and Zhao, J and Yu, H and Cui, M and Xie, M and Bai, Y and Sun, S}, title = {Methyl jasmonate enhances the radiation sensitivity of esophageal carcinoma cells by inhibiting the 11-ketoprostaglandin reductase activity of AKR1C3.}, journal = {Cancer management and research}, volume = {10}, number = {}, pages = {3149-3158}, pmid = {30214307}, issn = {1179-1322}, abstract = {PURPOSE: In our previous study, we found that AKR1C3 was a radioresistance gene in KY170R cells. Downregulating the expression of AKR1C3 could enhance the radiosensitivity of esophageal carcinoma cells. In this study, we investigated whether methyl jasmonate (MeJ), an inhibitor of Aldo-keto reductase family1 member C3 (AKR1C3), could overcome radiation resistance in AKR1C3 highly expressed cells.<br><br>PATIENTS AND METHODS: We used clone formation assays to detect radiosensitivity effects. Flow cytometry assays were used to detect reactive oxygen species (ROS) accumulation and apoptosis. Enzyme linked immunosorbent assays (ELISAs) were used to detect the concentrations of prostaglandin F2 (PGF2) and prostaglandin D2 (PGD2) in the cells after incubation with MeJ. Western blotting was used to detect AKR1C3 and peroxisome proliferator-activated receptor gamma (PPAR&#x3b3;) expression.<br><br>RESULTS: We found that AKR1C3 was highly expressed in radioresistant esophageal carcinoma cells. MeJ inhibited the expression of AKR1C3 and enhanced the radiation sensitivity of esophageal carcinoma cells expressing high levels of AKR1C3 (P<0.05). MeJ could inhibit the 11-ketoprostaglandin reductase activity of AKR1C3 in a dose-dependent manner in KY170R cells. Incubation of KY170R cells with 200 &#xb5;mol/L of MeJ for 24 h reduced the expression of PGF2 by roughly 30% (P<0.05). The PPAR pathway inhibitor GW9662 prevented the radiation sensitivity enhancement imparted by MeJ. After adding GW9662, there were no significant differences between the radiation sensitivities of MeJ-treated and -untreated KY170R cells (P>0.05). The radiation sensitivity effect of MeJ also depended upon the generation of ROS in KY170R cells; 48 h after irradiation, ROS levels in the MeJ group was twofold higher than in the untreated KY170R cells (P<0.05). The ROS scavenger, N-acetyl cysteine, could reverse the radiosensitivity effects of MeJ (P>0.05).<br><br>CONCLUSION: Our results indicate that MeJ can increase the radiation sensitivity of AKR1C3-overexpressing KY170R cells by inhibiting the 11-ketoprostaglandin reductase activity of AKR1C3 and increasing cellular ROS levels.}, }
@article {pmid30212240, year = {2019}, author = {Ehre, C and Rushton, ZL and Wang, B and Hothem, LN and Morrison, CB and Fontana, NC and Markovetz, MR and Delion, MF and Kato, T and Villalon, D and Thelin, WR and Esther, CR and Hill, DB and Grubb, BR and Livraghi-Butrico, A and Donaldson, SH and Boucher, RC}, title = {An Improved Inhaled Mucolytic to Treat Airway Muco-obstructive Diseases.}, journal = {American journal of respiratory and critical care medicine}, volume = {199}, number = {2}, pages = {171-180}, pmid = {30212240}, issn = {1535-4970}, support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; UH3 HL123645/HL/NHLBI NIH HHS/United States ; P30 DK065988/DK/NIDDK NIH HHS/United States ; P01 HL108808/HL/NHLBI NIH HHS/United States ; R43 HL112436/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Asthma/*drug therapy/physiopathology ; Cystic Fibrosis/*drug therapy/physiopathology ; Disease Models, Animal ; Dithiothreitol/therapeutic use ; Expectorants/*therapeutic use ; Humans ; In Vitro Techniques ; Male ; Mice ; Mucociliary Clearance/*drug effects ; Mucus/*drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology ; }, abstract = {RATIONALE: Airways obstruction with thick, adherent mucus is a pathophysiologic and clinical feature of muco-obstructive respiratory diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis (CF). Mucins, the dominant biopolymer in mucus, organize into complex polymeric networks via the formation of covalent disulfide bonds, which govern the viscoelastic properties of the mucus gel. For decades, inhaled N-acetylcysteine (NAC) has been used as a mucolytic to reduce mucin disulfide bonds with little, if any, therapeutic effects. Improvement of mucolytic therapy requires the identification of NAC deficiencies and the development of compounds that overcome them.<br><br>OBJECTIVES: Elucidate the pharmacological limitations of NAC and test a novel mucin-reducing agent, P3001, in preclinical settings.<br><br>METHODS: The study used biochemical (e.g., Western blotting, mass spectrometry) and biophysical assays (e.g., microrheology/macrorheology, spinnability, mucus velocity measurements) to test compound efficacy and toxicity in in vitro and in vivo models and patient sputa.<br><br>MEASUREMENTS AND MAIN RESULTS: Dithiothreitol and P3001 were directly compared with NAC in vitro and both exhibited superior reducing activities. In vivo, P3001 significantly decreased lung mucus burden in &#x3b2;ENaC-overexpressing mice, whereas NAC did not (n&#x2009;=&#x2009;6-24 mice per group). In NAC-treated CF subjects (n&#x2009;=&#x2009;5), aerosolized NAC was rapidly cleared from the lungs and did not alter sputum biophysical properties. In contrast, P3001 acted faster and at lower concentrations than did NAC, and it was more effective than DNase in CF sputum ex vivo.<br><br>CONCLUSIONS: These results suggest that reducing the viscoelasticity of airway mucus is an achievable therapeutic goal with P3001 class mucolytic agents.}, }
@article {pmid30210840, year = {2018}, author = {Hamid, ZA and Tan, HY and Chow, PW and Harto, KAW and Chan, CY and Mohamed, J}, title = {The Role of N-Acetylcysteine Supplementation on the Oxidative Stress Levels, Genotoxicity and Lineage Commitment Potential of Ex Vivo Murine Haematopoietic Stem/Progenitor Cells.}, journal = {Sultan Qaboos University medical journal}, volume = {18}, number = {2}, pages = {e130-e136}, pmid = {30210840}, issn = {2075-0528}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Lineage ; Cell Proliferation ; Cell Survival/drug effects ; Cells, Cultured ; Colony-Forming Units Assay ; Free Radical Scavengers/*pharmacology ; Hematopoietic Stem Cells/cytology/*drug effects/metabolism ; Malaysia ; Male ; Mice ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism/toxicity ; }, abstract = {OBJECTIVES: The ex vivo maintenance of haematopoietic stem/progenitor cells (HSPCs) is crucial to ensure a sufficient supply of functional cells for research or therapeutic applications. However, when exposed to reactive oxygen species (ROS) in a normoxic microenvironment, HSPCs exhibit genomic instability which may diminish their quantity and quality. This study aimed to investigate the role of N-acetylcysteine (NAC) supplementation on the oxidative stress levels, genotoxicity and lineage commitment potential of murine haematopoietic stem/progenitor cells (HSPCs).<br><br>METHODS: This study was carried out at the Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia, between June 2016 and July 2017. Bone marrow cells were isolated from nine mice and cultured in a growth medium. Various concentrations of NAC between 0.125-2 &#x3bc;M were added to the culture for 48 hours; these cells were then compared to non-supplemented cells harvested from the remaining three mice as the control group. A trypan blue exclusion test was performed to determine cell viability, while intracellular ROS levels and genotoxicity were determined by hydroethidine staining and comet assay, respectively. The lineage commitment potential of erythroid, myeloid and pre-B-lymphoid progenitor cells was evaluated via colony-forming cell assay.<br><br>RESULTS: NAC supplementation at 0.25, 0.5 and 2 &#x3bc;M significantly increased cell viability (P <0.050), while intracellular ROS levels significantly decreased at 0.25 and 0.5 &#x3bc;M (P <0.050). Moreover, DNA damage was significantly reduced at all NAC concentrations (P <0.050). Finally, the potential lineage commitment of the cells was not significantly affected by NAC supplementation (P >0.050).<br><br>CONCLUSION: The findings of this study indicate that NAC supplementation may potentially overcome the therapeutic limitations of ex vivo-maintained HSPCs.}, }
@article {pmid30206579, year = {2018}, author = {Cecchin, D and Farina, AP and Bedran-Russo, AK}, title = {Efficacy of Natural Collagen Crosslinkers on the Compromised Adhesive Bond Strength to NaOCl-treated Pulp Chamber Dentin.}, journal = {The journal of adhesive dentistry}, volume = {20}, number = {4}, pages = {365-369}, doi = {10.3290/j.jad.a40984}, pmid = {30206579}, issn = {1461-5185}, mesh = {*Collagen ; Dental Bonding ; Dental Cements ; *Dental Pulp Cavity ; Dentin ; *Dentin-Bonding Agents ; Humans ; Materials Testing ; Resin Cements ; Root Canal Irrigants ; Tensile Strength ; }, abstract = {PURPOSE: To evaluate the efficacy of natural collagen crosslinkers on compromised adhesive bond strength to NaOCl-treated pulp chamber dentin.<br><br>MATERIALS AND METHODS: Mesial surfaces of the pulp chamber dentin of 120 extracted human molars were obtained. The dentin fragments were divided into six groups according to the protocols used: no treatment (negative control), sodium hypochlorite (NaOCl) for 30 min and final irrigation with 17% EDTA for 3 min (positive control). After treatment with NaOCl and EDTA, the dentin surfaces of the experimental groups were treated for 5 min with one of the following: grape seed extract (GSE), tannic acid (TA), green tea (GT), or n-acetyl cysteine (NAC). Half of the samples of each group were bonded with an etch-and-rinse (Single Bond; 3M Oral Care) and the other half using a self-etch (Scotchbond Universal; 3M Oral Care) adhesive. The restoration was completed with composite. The bonded specimens were sectioned to produce sticks and subjected to the microtensile bond strength test. Data were analyzed by two-way ANOVA and Tukey's HSD test (p < 0.05).<br><br>RESULTS: Both adhesives had similar bond strengths (p > 0.05). The NaOCl-treated group had significantly lower bond strength than the negative control (p < 0.05). The application of NAC did not recover compromised bonding (p > 0.05). On the other hand, GSE, TA and GT had significant reversal effects of the bond strengths to NaOCl-treated dentin (p < 0.05).<br><br>CONCLUSION: Compromised bonding of adhesives to NaOCl-treated dentin can be reversed by the application of either GSE, TA or GT.}, }
@article {pmid30205620, year = {2018}, author = {Chang, JF and Liang, SS and Thanasekaran, P and Chang, HW and Wen, LL and Chen, CH and Liou, JC and Yeh, JC and Liu, SH and Dai, HM and Lin, WN}, title = {Translational Medicine in Pulmonary-Renal Crosstalk: Therapeutic Targeting of p-Cresyl Sulfate Triggered Nonspecific ROS and Chemoattractants in Dyspneic Patients with Uremic Lung Injury.}, journal = {Journal of clinical medicine}, volume = {7}, number = {9}, pages = {}, pmid = {30205620}, issn = {2077-0383}, support = {410031034022 and A0103017//Fu Jen Catholic University Research Foundation/ ; 106-2221-E-151-051-//Ministry of Science and Technology/ ; ECKH10505//En Chu Kong Hospital/ ; }, abstract = {Molecular mechanisms and pathological features of p-Cresyl sulfate (PCS)-induced uremic lung injury (ULI) in chronic kidney disease (CKD) remain unclear. We analyzed pleural effusions (PE) from CKD and non-CKD patients for uremic toxins, reactive oxygen species (ROS), and chemotactic cytokines. Correlations between PE biomarkers and serum creatinine were also studied. Cell viability and inflammatory signaling pathways were investigated in PCS-treated human alveolar cell model. To mimic human diseases, CKD-ULI mouse model was developed with quantitative comparison of immunostaining and morphometric approach. PE from CKD patients enhance expressions of uremic toxins, hydroxyl radicals, and IL-5/IL-6/IL-8/IL-10/IL-13/ENA-78/GRO α/MDC/thrombopoietin/VEGF. PE concentrations of ENA-78/VEGF/IL-8/MDC/PCS/indoxyl sulphate correlate with serum creatinine concentrations. In vitro, PCS promotes alveolar cell death, cPLA2/COX-2/aquaporin-4 expression, and NADPH oxidase/mitochondria activation-related ROS. Intracellular ROS is abrogated by non-specific ROS scavenger N-acetyl cysteine (NAC), inhibitors of NADPH oxidase and mitochondria-targeted superoxide scavenger. However, only NAC protects against PCS-induced cell death. In vivo, expressions of cPLA2/COX2/8-OHdG, resident alveolar macrophages, recruited leukocytes, alveolar space, interstitial edema and capillary leakage increase in lung tissues of CKD-ULI mice, and NAC pretreatment ameliorates alveolar[-]capillary injury. PCS causes alveolar[-]capillary injury through triggering intracellular ROS, downstream prostaglandin pathways, cell death, and activating leukocytes to release multiplex chemoattractants and extracellular ROS. Thus PCS and nonspecific ROS serve as potential therapeutic targets.}, }
@article {pmid30203030, year = {2019}, author = {Arumugam, P and Shankaran, D and Bothra, A and Gandotra, S and Rao, V}, title = {The MmpS6-MmpL6 Operon Is an Oxidative Stress Response System Providing Selective Advantage to Mycobacterium tuberculosis in Stress.}, journal = {The Journal of infectious diseases}, volume = {219}, number = {3}, pages = {459-469}, doi = {10.1093/infdis/jiy526}, pmid = {30203030}, issn = {1537-6613}, mesh = {Bacterial Proteins/*genetics/*metabolism ; Gene Expression Regulation, Bacterial/drug effects ; Humans ; Macrophages/microbiology ; Mycobacterium tuberculosis/drug effects/*genetics/growth &amp; development/*metabolism ; Naphthoquinones/pharmacology ; Operon/*genetics ; Oxidation-Reduction/drug effects ; *Oxidative Stress/drug effects ; Reactive Oxygen Species ; THP-1 Cells ; Triclosan/pharmacology ; }, abstract = {BACKGROUND: The stress response adaptability of Mycobacterium tuberculosis (Mtb) is still unresolved. In this study, we ascribe an important function to the MmpS6-MmpL6 (M6) operon in Mtb stress management.<br><br>METHODS: By using a novel promoter probe in a high-throughput unbiased screen, we identified several quinones as potent inducers of the M6 operon in addition to triclosan.<br><br>RESULTS: Triclosan and plumbagin effectively altered the intracellular redox potential in Mtb suggestive of oxidative stress in bacteria. Presence of the functional M6 operon correlated with an enhanced ability of clinical strains to survive in the presence of triclosan.<br><br>CONCLUSIONS: Similar to the addition of a powerful reactive oxygen species-quenching agent such as N-acetyl cysteine in the medium, introduction of the complete M6 operon was sufficient to increase tolerance of the M6- strains to triclosan and plumbagin by effectively ablating the change in intracellular redox potential of Mtb, signifying the importance of this operon in oxidative stress survival in mycobacteria.}, }
@article {pmid30197667, year = {2018}, author = {Moon, SC and Choi, HJ and Chung, TW and Lee, JH and Lee, SO and Jung, MH and Kim, BJ and Choi, JY and Ha, KT}, title = {Sorbus commixta water extract induces apoptotic cell death via a ROS-dependent pathway.}, journal = {Oncology letters}, volume = {16}, number = {4}, pages = {4193-4200}, pmid = {30197667}, issn = {1792-1074}, abstract = {The stembark of Sorbus commixta Hedl. has been used for treating asthma, bronchitis, gastritis and edema. However, the anticancer and proapoptotic effects of the water extract of the stembark of S. commixta (SCE) remain unknown. In the present study, it was shown that SCE inhibited the cell viability of the hepatocellular carcinoma cell lines Hep3B and HepG2, and of the colon carcinoma cell line HCT116. DNA content analysis indicated that SCE increased the sub-G1 population of HCT116 cells. In addition, degradation of nuclear DNA and levels of proapoptotic cascade components, including caspase-9, caspase-3 and poly ADP-ribose polymerase, were augmented by SCE treatment. Mitochondrial membrane potential and the ratio of B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) were also reduced. Furthermore, SCE increased the expression of proapoptotic proteins, including p21, p27 and p53. Mouse double minute 2 homology, a negative regulator of p53, was cleaved by SCE treatment. Intracellular reactive oxygen species (ROS) production was also increased by SCE treatment. However, the SCE-induced cytotoxic effects and the increased expression of proapoptotic proteins, including p53 and p21, and reduced Bcl-2/Bax ratio, could be attenuated by N-acetyl cysteine, an ROS inhibitor. Taken together, these results indicate that SCE is a potent proapoptotic herbal medicine, which exerts its effects via the ROS-mediated mitochondrial pathway.}, }
@article {pmid30196390, year = {2018}, author = {Wardi, J and Ernst, O and Lilja, A and Aeed, H and Katz, S and Ben-Nachum, I and Ben-Dror, I and Katz, D and Bernadsky, O and Kandhikonda, R and Avni, Y and Fraser, IDC and Weinstain, R and Biro, A and Zor, T}, title = {3-Aminobenzamide Prevents Concanavalin A-Induced Acute Hepatitis by an Anti-inflammatory and Anti-oxidative Mechanism.}, journal = {Digestive diseases and sciences}, volume = {63}, number = {12}, pages = {3382-3397}, pmid = {30196390}, issn = {1573-2568}, mesh = {Acute Disease ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Benzamides/*pharmacology ; Cells, Cultured ; Concanavalin A/pharmacology ; Disease Models, Animal ; *Hepatitis/metabolism/prevention &amp; control ; *Macrophages/drug effects/physiology ; Mice ; Mitogens/pharmacology ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Treatment Outcome ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND AND AIMS: Concanavalin A is known to activate T cells and to cause liver injury and hepatitis, mediated in part by secretion of TNFα from macrophages. Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been shown to prevent tissue damage in various animal models of inflammation. The objectives of this study were to evaluate the efficacy and mechanism of the PARP-1 inhibitor 3-aminobenzamide (3-AB) in preventing concanavalin A-induced liver damage.<br><br>METHODS: We tested the in vivo effects of 3-AB on concanavalin A-treated mice, its effects on lipopolysaccharide (LPS)-stimulated macrophages in culture, and its ability to act as a scavenger in in vitro assays.<br><br>RESULTS: 3-AB markedly reduced inflammation, oxidative stress, and liver tissue damage in concanavalin A-treated mice. In LPS-stimulated RAW264.7 macrophages, 3-AB inhibited NF&#x3ba;B transcriptional activity and subsequent expression of TNF&#x3b1; and iNOS and blocked NO production. In vitro, 3-AB acted as a hydrogen peroxide scavenger. The ROS scavenger N-acetylcysteine (NAC) and the ROS formation inhibitor diphenyleneiodonium (DPI) also inhibited TNF&#x3b1; expression in stimulated macrophages, but unlike 3-AB, NAC and DPI were unable to abolish NF&#x3ba;B activity. PARP-1 knockout failed to affect NF&#x3ba;B and TNF&#x3b1; suppression by 3-AB in stimulated macrophages.<br><br>CONCLUSIONS: Our results suggest that 3-AB has a therapeutic effect on concanavalin A-induced liver injury by inhibiting expression of the key pro-inflammatory cytokine TNF&#x3b1;, via PARP-1-independent NF&#x3ba;B suppression and via an NF&#x3ba;B-independent anti-oxidative mechanism.}, }
@article {pmid30195043, year = {2019}, author = {Gaydos, J and McNally, A and Burnham, EL}, title = {The impact of alcohol use disorders on pulmonary immune cell inflammatory responses to Streptococcus pneumoniae.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {80}, number = {}, pages = {119-130}, pmid = {30195043}, issn = {1873-6823}, support = {R24 AA019661/AA/NIAAA NIH HHS/United States ; UL1 TR002535/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Alcoholism/*complications/immunology ; Bronchoalveolar Lavage Fluid/cytology/immunology ; Case-Control Studies ; Cells, Cultured ; Chemokines/metabolism ; Cytokines/metabolism ; Female ; Humans ; Immunity, Cellular/drug effects/immunology ; Lung/drug effects/*immunology/microbiology ; Macrophages, Alveolar/drug effects/immunology ; Male ; Pneumonia, Pneumococcal/chemically induced/*immunology ; Streptococcus pneumoniae/*immunology ; }, abstract = {Community-acquired pneumonia due to Streptococcus pneumoniae occurs commonly in alcohol use disorders (AUDs). Pneumonia in the AUD patient is associated with poorer outcomes, and specific therapies to mitigate disease severity in these patients do not exist. Numerous investigations have attributed increased severity of pneumonia in AUDs to aberrant function of the alveolar macrophage (AM), a lung immune cell critical in host defense initiation. No studies have examined the response of human AMs to S. pneumoniae in AUDs. We hypothesized that the inflammatory mediators released by AMs after S. pneumoniae stimulation would differ quantitatively in individuals with AUDs compared to non-AUD participants. We further postulated that AM inflammatory mediators would be diminished after exposure to the antioxidant, N-acetylcysteine (NAC). For comparison, responses of peripheral blood mononuclear cells (PBMCs) to pneumococcal protein were also examined. Otherwise healthy participants with AUDs and smoking-matched controls underwent bronchoalveolar lavage and peripheral blood sampling to obtain AMs and PBMCs, respectively. Freshly collected cells were cultured with increasing doses of heat-killed S. pneumoniae protein, with and without exposure to N-acetylcysteine. Cell culture supernatants were collected, and inflammatory mediators were measured, including interferon (IFN)-γ, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. IFN-γ and IL-6 were significantly higher in unstimulated AM cell culture supernatants from subjects with AUDs. After stimulation with pneumococcal protein, a dose-response and time-dependent increase in pro-inflammatory cytokine production by both AMs and PBMCs was also observed; differences were not observed between AUD and non-AUD subjects. Addition of NAC to pneumococcal-stimulated AMs and PBMCs was generally associated with diminished cytokine production, with the exception of IL-1β that was elevated in AM culture supernatants from subjects with AUDs. Our observations suggest that AUDs contribute to basal alterations in AM pro-inflammatory cytokine elaboration, but did not support consistent differences in pneumococcal-stimulated AM or PBMC inflammatory mediator secretion that were referable to AUDs.}, }
@article {pmid30194941, year = {2018}, author = {Li, B and Sun, Y and Wang, JP and Chi, RF and Wang, K and Yang, ZJ and Qin, FZ and Fan, B}, title = {Antioxidant N-acetylcysteine inhibits maladaptive myocyte autophagy in pressure overload induced cardiac remodeling in rats.}, journal = {European journal of pharmacology}, volume = {839}, number = {}, pages = {47-56}, doi = {10.1016/j.ejphar.2018.08.034}, pmid = {30194941}, issn = {1879-0712}, mesh = {Acetylcysteine/*pharmacology ; Adaptation, Physiological/*drug effects ; Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Antioxidants/pharmacology ; Autophagy/*drug effects ; *Blood Pressure/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibrosis ; Male ; Myocytes, Cardiac/*cytology/*drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Rats ; Rats, Sprague-Dawley ; Ventricular Remodeling/*drug effects ; }, abstract = {Increased oxidative stress and myocyte autophagy co-exist in cardiac remodeling. However, it is unclear whether oxidative stress mediates maladaptive myocyte autophagy in pathological ventricular remodeling. In this study, we tested the hypothesis that antioxidants prevent maladaptive myocyte autophagy in pressure overload-induced left ventricular (LV) remodeling. Sprague-Dawley rats underwent abdominal aortic constriction (AAC) or sham operation. The animals were randomized to receive an antioxidant N-acetylcysteine (NAC), an autophagy inhibitor 3-methyladenine (3-MA) or placebo treatment for 2 weeks. We measured LV structure and function by echocardiography and hemodynamics, myocyte autophagy and oxidative stress assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG). AAC rats exhibited increased LV hypertrophy assessed by LV wall thickness and myocyte cross-sectional area. NAC prevented LV hypertrophy in AAC rats. There were no significant differences in LV fractional shortening, end-diastolic dimension and the maximal rate of LV pressure rise among the groups. AAC rats showed an increase in myocardial 8-OHdG that was prevented by NAC. The expression of LC3 II protein, a marker of autophagy, was increased at 2 weeks after AAC. Immunohistochemical scores further confirmed the increase in LC3 expression in AAC rats. The expression of autophagic proteins Beclin1 and Atg12 and ERK activity were also increased in AAC rats. NAC prevented the increases in LC3 II protein, LC3 scores, Beclin1, Atg12 and ERK activity in AAC rats. Inhibition of autophagy by 3-MA prevented LV hypertrophy after pressure overload. These findings suggest that antioxidants may be of value to prevent pressure overload-induced cardiac remodeling through inhibition of maladaptive myocyte autophagy.}, }
@article {pmid30194156, year = {2018}, author = {Jurkowska, H and Wróbel, M}, title = {Inhibition of Human Neuroblastoma Cell Proliferation by N-acetyl-L-cysteine as a Result of Increased Sulfane Sulfur Level.}, journal = {Anticancer research}, volume = {38}, number = {9}, pages = {5109-5113}, doi = {10.21873/anticanres.12831}, pmid = {30194156}, issn = {1791-7530}, mesh = {Acetylcysteine/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Neuroblastoma/drug therapy/*metabolism ; Sulfur Compounds/*metabolism ; Sulfurtransferases/metabolism ; Up-Regulation ; }, abstract = {BACKGROUND/AIM: In various cancer cells, the level of sulfane sulfur-containing compounds is decreased compared to normal cells. In the present study the effect of N-acetyl-L-cysteine (NAC), which acts as a precursor of H2S synthesis, on the human neuroblastoma SH-SY5Y cell proliferation, the activity of 3-mercaptopyruvate sulfurtransferase (MPST), and the level of sulfane sulfur were investigated.<br><br>MATERIALS AND METHODS: SH-SY5Y cells were treated with NAC, while untreated cells were used as the control. The toxicity of NAC on the cells was studied by the LDH cytotoxicity assay; cell proliferation was examined by the MTT method. MPST activity and sulfane sulfur level were also analyzed in the NAC-treated cells.<br><br>RESULTS: The addition of NAC to the medium, in non-cytotoxic concentrations, resulted in inhibition of the SH-SY5Y cell proliferation after 48 h of culture. The MPST activity and the level of sulfane sulfur-containing compounds were also elevated under the same culture conditions.<br><br>CONCLUSION: The antiproliferative activity of NAC in the SH-SY5Y cells was associated with an increase in the MPST activity and consequently with an increase in the intracellular level of sulfane sulfur in these cells.}, }
@article {pmid30190676, year = {2018}, author = {Grienke, U and Radić Brkanac, S and Vujčić, V and Urban, E and Ivanković, S and Stojković, R and Rollinger, JM and Kralj, J and Brozovic, A and Radić Stojković, M}, title = {Biological Activity of Flavonoids and Rare Sesquiterpene Lactones Isolated From Centaurea ragusina L.}, journal = {Frontiers in pharmacology}, volume = {9}, number = {}, pages = {972}, pmid = {30190676}, issn = {1663-9812}, abstract = {The endemic Croatian species Centaurea ragusina L., like other species from the genus Centaurea, has been traditionally used in Croatia as an antibacterial agent and for the treatment of gastrointestinal and urogenital disorders. In several chromatographic steps, three flavonoids and three sesquiterpene lactones (STLs) were isolated and identified from the most active fractions of the ethanol extract. Two STLs, one for which we created the trivial name ragusinin, and hemistepsin A are here reported for the first time as constituents of the genus Centaurea. All six compounds were screened for their effect on several tumor and one normal cell lines. Among them, ragusinin showed the best bioactivity and high specificity to affect tumor murine SCCVII, human HeLa and Caco-2 cell lines, but not the viability of normal V79 fibroblasts. Due to these characteristics the action of ragusinin was investigated in more detail. Since DNA is the primary target for many drugs with antibacterial and anticancer activity, we studied its interaction with ragusinin. Rather moderate binding affinity to DNA excluded it as the primary target of ragusinin. Due to the possibility of STL interaction with glutathione (GSH), the ubiquitous peptide that traps reactive compounds and other xenobiotics to prevent damage to vital proteins and nucleic acids, its role in deactivation of ragusinin was evaluated. Addition of the GSH precursor N-acetyl-cysteine potentiated the viability of HeLa cells, while the addition of GSH inhibitor L-buthionine sulfoximine decreased it. Moreover, pre-treatment of HeLa cells with the inhibitor of glutathione-S-transferase decreased their viability indicating the detoxifying role of GSH in ragusinin treated cells. Cell death, derived by an accumulation of cells in a G2 phase of the cell cylce, was shown to be independent of poly (ADP-ribose) polymerase and caspase-3 cleavage pointing toward an alternative cell death pathway.}, }
@article {pmid30187952, year = {2019}, author = {Deng, F and Xu, Q and Long, J and Xie, H}, title = {Suppressing ROS-TFE3-dependent autophagy enhances ivermectin-induced apoptosis in human melanoma cells.}, journal = {Journal of cellular biochemistry}, volume = {120}, number = {2}, pages = {1702-1715}, doi = {10.1002/jcb.27490}, pmid = {30187952}, issn = {1097-4644}, support = {C2018345//Medical Scientific Research Project of the Hunan province of China/ ; }, abstract = {Melanoma is an aggressive skin malignancy with a high mortality rate; however, successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to its observed antitumor effects. However, the molecular mechanisms of ivermectin remain poorly understood. In the current study, we tested the involvement of autophagy in the ivermectin mechanism of action in human melanoma cells. We exposed SK-MEL-28 cells to different concentrations of ivermectin (2.5, 5, and 10 μM) for 24 hours. Here, ivermectin-induced apoptosis, as evidenced by the upregulation of cleaved poly (ADP-ribose) polymerase, BAX expression, and caspase-3 activity and downregulation of BCL-2 expression. In line with the apoptosis response, ivermectin triggered autophagy. Pharmacological or genetic inhibition of autophagy further sensitized SK-MEL-28 cells to ivermectin-induced apoptosis. Mechanistically, ivermectin-induced TFE3[(Ser321)] dephosphorylation, activated TFE3 nuclear translocation and increased TFE3 reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes, and subsequently, initiated autophagy in SK-MEL-28 cells. Moreover, N-acetyl-cysteine, an reactive oxygen species (ROS) scavenger, abrogated the effects of ivermectin on TFE3-dependent autophagy. Taken together, we demonstrated that ivermectin increases TFE3-dependent autophagy through ROS signaling pathways in human melanoma cells and that inhibiting autophagy enhances ivermectin-induced apoptosis in human melanoma cells.}, }
@article {pmid30187827, year = {2018}, author = {Mehrbani Azar, Y and Green, R and Niesler, CU and van de Vyver, M}, title = {Antioxidant Preconditioning Improves the Paracrine Responsiveness of Mouse Bone Marrow Mesenchymal Stem Cells to Diabetic Wound Fluid.}, journal = {Stem cells and development}, volume = {27}, number = {23}, pages = {1646-1657}, doi = {10.1089/scd.2018.0145}, pmid = {30187827}, issn = {1557-8534}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/analogs &amp; derivatives/pharmacology ; Bone Marrow Cells/*drug effects/metabolism ; Cytokines/genetics/metabolism ; Diabetic Angiopathies/metabolism/*therapy ; Mesenchymal Stem Cell Transplantation/methods ; Mesenchymal Stem Cells/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; *Paracrine Communication ; Transcriptome ; }, abstract = {Mesenchymal stem cells (MSCs) are a promising therapeutic tool for the treatment of nonhealing diabetic wounds. The pathological nature of the niche microenvironment limits the use of autologous cell therapy in diabetic patients. Prolonged exposure of endogenous MSCs to a pathological microenvironment in vivo reduces their ability to respond to environmental cues. This study investigated the effectiveness of ex vivo antioxidant treatment [N-acetylcysteine (7.5 mM NAC) and Ascorbic acid 2-phosphate (0.6 mM AAP)] to restore the paracrine function of diabetic MSCs. Healthy control [bone marrow stem cells derived from wild-type mice (SC[WT])] (source: wild-type C57BL/6J mice) (n = 12) and impaired/dysfunctional [bone marrow stem cells derived from ob/ob mice (SC[ob])] (source: obese diabetic, B6.Cg-Lep[ob]/J mice) (n = 12) MSCs were isolated. Ex vivo treatment groups (SC[WT] vs. SC[ob]) were as follows: (1) no treatment (baseline phenotype), (2) stimulated with diabetic wound fluid (DWF) (baseline response), (3) antioxidant preconditioning (preconditioned phenotype), and (4) antioxidant preconditioned with subsequent stimulation with DWF (preconditioned response). The paracrine responsiveness on both the molecular (mRNA expression of 80 cytokines and receptors, quantitative polymerase chain reaction microarray) and protein (23-plex bead-array Luminex assay) level was assessed. At baseline, 31 genes were overexpressed (> × 2-fold) and 39 genes were underexpressed (> × 2-fold) in SC[ob] versus SC[WT]. In conditioned media, significant differences (P < 0.05) were detected at baseline for two proinflammatory cytokines [tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ)], four chemokines [keratinocyte chemoattractant (KC), granulocyte colony-stimulating factor (GCSF), Eotaxin, and macrophage chemoattractant protein (MCP1)], and one anti-inflammatory cytokine [interleukin 10 (IL10)]. Following stimulation with DWF, significant differences (P < 0.05) were detected in the secretion of two chemokines [granulocyte macrophage colony-stimulating factor (GMCSF) and Eotaxin], three proinflammatory cytokines (TNFα, IFNγ, and IL9), and four anti-inflammatory cytokines (IL10, IL4, IL13, and IL3). Antioxidant preconditioning significantly dampened the excessive TNFα response observed in SC[ob] and improved the secretion of IL10. Taken together these data suggest that the combined ex vivo treatment of autologous stem cells with NAC and AAP could potentially be an effective strategy to restore the paracrine function of impaired diabetic MSCs before transplantation.}, }
@article {pmid30187808, year = {2019}, author = {Kuttikrishnan, S and Siveen, KS and Prabhu, KS and Khan, AQ and Akhtar, S and Mateo, JM and Merhi, M and Taha, R and Omri, HE and Mraiche, F and Dermime, S and Uddin, S}, title = {Sanguinarine suppresses growth and induces apoptosis in childhood acute lymphoblastic leukemia.}, journal = {Leukemia &amp; lymphoma}, volume = {60}, number = {3}, pages = {782-794}, doi = {10.1080/10428194.2018.1494270}, pmid = {30187808}, issn = {1029-2403}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Benzophenanthridines/*pharmacology ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Humans ; Isoquinolines/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Sanguinarine (Sang), a plant-derived compound isolated from the roots of Sanguinaria canadensis was evaluated for its potential pro-apoptotic effects in precursor B acute lymphoblastic leukemia (Pre-ALL) cell lines. Treatment of 697, REH, RS4;11, and SupB15 cell lines with Sang exhibited significant inhibition of cell viability via induction of apoptotic cell death. Sang-mediated apoptosis was found to be associated with the increased expression of proapoptotic bax with concomitant decrease of Bcl-2 expression leading to depolarization of mitochondria membrane resulting in loss of mitochondrial membrane potential (MMP). The reduced MMP caused the leakage in mitochondrial membrane and release of cytochrome c into the cytosol. The cytochrome c then mediates the activation of caspase-cascade and subsequently PARP cleavage. Furthermore, pretreatment with z-VAD-FMK, a pan-caspase inhibitor, abrogated Sang-induced inhibition of cell viability, induction of apoptosis. Sang treatment also reduced the phosphorylation of AKT and suppressed the expression of a number of anti-apoptotic genes such as cIAP1, cIAP2, and XIAP. Sang mediates its anti-cancer activity by generation of reactive oxygen species (ROS) due to depletion of glutathione level in leukemic cell lines. Pretreatment of these cells with N-acetyl cysteine (NAC) prevented Sang-induced depletion of glutathione level and mitochondrial-caspase-induced apoptosis. Finally, Sang treatment of Pre-ALL cell suppressed colony formation ability of these cells suggesting Sang has an anti-leukemic potential. Altogether, our data suggest that Sang is an efficient inducer of intrinsic apoptotic cell death via generation of ROS and exhibition of anti-leukemic effect in Pre-ALL cells raises the possibility to develop Sang as a therapeutic modality for the treatment and management of Pre-ALL.}, }
@article {pmid30178848, year = {2018}, author = {Chen, X and Fang, M}, title = {Oxidative stress mediated mitochondrial damage plays roles in pathogenesis of diabetic nephropathy rat.}, journal = {European review for medical and pharmacological sciences}, volume = {22}, number = {16}, pages = {5248-5254}, doi = {10.26355/eurrev_201808_15723}, pmid = {30178848}, issn = {2284-0729}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood Glucose/drug effects/metabolism ; Diabetes Mellitus, Experimental/chemically induced/*metabolism/pathology ; Diabetic Nephropathies/*metabolism/pathology ; Female ; Kidney Glomerulus/drug effects/metabolism ; Mitochondria/drug effects/*metabolism/pathology ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Streptozocin/toxicity ; }, abstract = {OBJECTIVE: Diabetic nephropathy (DN) is considered as a complication of diabetes and accounts for about 40%. Reactive oxygen species (ROS) level continues to increase in DN. However, whether specific ROS levels can alleviate renal damage by improving mitochondrial function has not been investigated.<br><br>MATERIALS AND METHODS: DN model was established by intraperitoneal injection of streptozotocin (STZ). The rats were divided into normal group, STZ model group, and N-acetylcysteine (NAC) group. Fasting blood glucose was tested to assess the modeling. The renal injury was evaluated by using hematoxylin-eosin (HE) staining and periodate-Schiff staining. Serum creatinine and 24 h urinary protein levels were determined by renal function detection kit. The levels of ROS and malondialdehyde (MDA) were assessed by the kit to evaluate the effects of oxidative stress and NAC in rats. The mitochondrial damage marker Cyto C level was detected by Western blot.<br><br>RESULTS: Blood glucose, serum creatinine, and urinary protein levels were significantly increased in model group compared with the normal group (p<0.05). Blood glucose levels, serum creatinine, and urinary protein levels were markedly improved after the ROS and MDA levels reduced by NAC. Meanwhile, glomerular hypertrophy, mesangial matrix accumulation, and severe renal injury were observed in the model group. NAC administration markedly improved glomerular morphology and mesangial matrix aggregation. Cyto C expression in the model group increased significantly compared with normal control group (p<0.05), while NAC effectively inhibited Cyto C levels.<br><br>CONCLUSIONS: Oxidative stress-mediated mitochondrial damage is an important part of the pathogenesis of DN. Inhibition of ROS production can be a potential target for DN treatment.}, }
@article {pmid30176959, year = {2018}, author = {Sodhi, CP and Fulton, WB and Good, M and Vurma, M and Das, T and Lai, CS and Jia, H and Yamaguchi, Y and Lu, P and Prindle, T and Ozolek, JA and Hackam, DJ}, title = {Fat composition in infant formula contributes to the severity of necrotising enterocolitis.}, journal = {The British journal of nutrition}, volume = {120}, number = {6}, pages = {665-680}, pmid = {30176959}, issn = {1475-2662}, support = {R01 DK117186/DK/NIDDK NIH HHS/United States ; R01 DK083752/DK/NIDDK NIH HHS/United States ; R03 DK111473/DK/NIDDK NIH HHS/United States ; R01 GM078238/GM/NIGMS NIH HHS/United States ; R01 DK118568/DK/NIDDK NIH HHS/United States ; K08 DK101608/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; *Diet ; Dietary Fats/metabolism/*pharmacology ; *Digestion ; Enterocolitis, Necrotizing/etiology/*metabolism ; Enterocytes/drug effects/metabolism/pathology ; Fatty Acids, Unsaturated/metabolism ; Food, Formulated ; Humans ; Ileum/drug effects/metabolism ; Infant Formula/*chemistry ; Infant Nutritional Physiological Phenomena ; Infant, Newborn ; Inflammation/etiology/metabolism ; Intestinal Mucosa/*drug effects/metabolism/pathology ; Lipase/metabolism ; Mice ; Oxidative Stress ; Severity of Illness Index ; Triglycerides/metabolism/*pharmacology ; }, abstract = {Necrotising enterocolitis (NEC) is a devastating disease that typically affects formula-fed premature infants, suggesting that dietary components may influence disease pathogenesis. TAG are the major fat components of infant formula, and their digestion requires pancreatic lipases, which may be naturally deficient in premature neonates. We hypothesise that NEC develops partly from the accumulation of incompletely digested long-chain TAG-containing unsaturated fatty acids within the intestinal epithelial cells, leading to oxidative stress and enterocyte damage. We further hypothesise that the administration of a formula that contains reduced TAG ('pre-digested fat') that do not require lipase action may reduce NEC severity. To test these hypotheses, we induced NEC in neonatal mice using three different fat formulations, namely 'standard fat', 'pre-digested fat' or 'very low fat', and determined that mice fed 'standard fat' developed severe NEC, which was significantly reduced in mice fed 'pre-digested fat' or 'very low fat'. The expression level of the critical fat-digesting enzyme carboxyl ester lipase was significantly lower in the newborn compared with older pups, leading to impaired fat digestion. The accumulation of mal-digested fat resulted in the significant accumulation of fat droplets within the intestinal epithelium of the distal ileum, resulting in the generation of reactive oxygen species and intestinal inflammation. Strikingly, these changes were prevented in pups fed 'pre-digested fat' or 'very low fat' formulas. These findings suggest that nutritional formula containing a pre-digested fat system may overcome the natural lipase deficiency of the premature gut, and serve as a novel approach to prevent NEC.}, }
@article {pmid30176835, year = {2018}, author = {Yang, C and Bosker, FJ and Li, J and Schoevers, RA}, title = {N-acetylcysteine as add-on to antidepressant medication in therapy refractory major depressive disorder patients with increased inflammatory activity: study protocol of a double-blind randomized placebo-controlled trial.}, journal = {BMC psychiatry}, volume = {18}, number = {1}, pages = {279}, pmid = {30176835}, issn = {1471-244X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Antidepressive Agents/*administration &amp; dosage ; Depressive Disorder, Major/diagnostic imaging/*drug therapy/metabolism ; Depressive Disorder, Treatment-Resistant/diagnostic imaging/*drug therapy/metabolism ; Diffusion Tensor Imaging/methods ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Free Radical Scavengers/administration &amp; dosage ; Humans ; Inflammation/diagnostic imaging/drug therapy/metabolism ; Inflammation Mediators/*antagonists &amp; inhibitors/metabolism ; Male ; Oxidative Stress/drug effects/physiology ; Psychotherapy/methods ; Treatment Outcome ; }, abstract = {BACKGROUND: A subgroup of depressed patients with increased inflammatory activity was shown to be more susceptible to develop Treatment Resistant Depression (TRD). Earlier studies with anti-inflammatory drugs have shown benefits in the treatment of major depressive disorder (MDD), but the effects are expected to be higher in patients with increased inflammatory activity. Supplementation of N-acetylcysteine (NAC) to ongoing antidepressant therapy may positively influence outcome of depression treatment in these patients. Therefore, this study aims to investigate the efficacy of NAC supplementation in patients with insufficient response to standard antidepressant treatment, and to explore potential roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD.<br><br>METHODS/DESIGN: A double-blind randomized placebo-controlled study comparing NAC versus placebo as add-on medication to antidepressant treatment with 12-week treatment and 8-week follow up in patients with TRD and increased inflammatory activity. Apart from clinical efficacy defined as the change in Hamilton Depression Rating Scale (HAMD)-17 score, secondary outcomes include changes in pathophysiological mechanisms related to depression as well as changes in local brain activity (functional Magnetic Resonance Imaging, fMRI) and white matter integrity (Diffusion Tensor Imaging, DTI). Importantly, sole patients with CRP levels with values between 0.85 and 10&#xa0;mg/L will be included.<br><br>DISCUSSION: This is the first clinical trial taking both TRD and increased inflammatory activity as inclusion criteria. This study will provide reliable evidence for the efficacy of NAC in patients with TRD displaying increased inflammatory activity. And this study also will help explore further the roles of inflammation and oxidative stress involved in the alleged pathophysiological processes of TRD.<br><br>TRIAL REGISTRATION: The trial protocol has been registered on "ClinicalTrials.gov"with protocol ID "NAC-2015-TJAH" and ClinicalTrials.gov ID " NCT02972398 ".}, }
@article {pmid30175773, year = {2018}, author = {Jin, CY and Molagoda, IMN and Park, C and Kwon, TK and Yun, SJ and Kim, WJ and Kim, GY and Choi, YH}, title = {Piceatannol-Induced Apoptosis Is Reversed by N-Acetyl-L-cysteine through Restoration of XIAP Expression.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {41}, number = {9}, pages = {1372-1378}, doi = {10.1248/bpb.b18-00157}, pmid = {30175773}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Down-Regulation ; Humans ; Leukemia/drug therapy/genetics ; Stilbenes/*pharmacology ; X-Linked Inhibitor of Apoptosis Protein/*genetics ; }, abstract = {Piceatannol, a naturally occurring stilbene derivative mainly found in grapes, possesses apoptotic activity in various cancer cell lines, in addition to potent antioxidant activity. In the current study, we showed that piceatannol exhibits potent cytotoxic effects in all tested leukemia cell lines (THP-1, HL-60, U937, and K562). These effects were accompanied by induction of DNA damage, an increase in the proportion of cells in the sub-G1 phase of the cell cycle, and inhibition of reactive oxygen species (ROS) generation. However, N-acetyl-L-cysteine (NAC), a strong ROS scavenger, significantly inhibited piceatannol-induced apoptosis, suggesting that piceatannol-induced apoptosis does not occur via inhibition of ROS generation. Piceatannol also resulted in a significant increase in mitochondrial depolarization, along with a decline in Bcl-2 expression, which was not restored by NAC. Conversely, ectopic Bcl-2 overexpression moderately inhibited piceatannol-induced apoptosis. Furthermore, piceatannol strongly inhibited X-linked inhibitor of apoptosis protein (XIAP) expression, which was restored by NAC. A transient knockdown of XIAP significantly increased piceatannol-induced apoptosis in the presence of NAC, suggesting that XIAP downregulation increases piceatannol-induced apoptosis, and that NAC could reverse this effect by increasing XIAP expression. Taken together, these results suggest that piceatannol induces apoptosis in human leukemia cell lines by downregulating XIAP expression, regardless of antioxidant activity.}, }
@article {pmid30175269, year = {2018}, author = {Yang, J and Zheng, X and Mahdi, A and Zhou, Z and Tratsiakovich, Y and Jiao, T and Kiss, A and Kövamees, O and Alvarsson, M and Catrina, SB and Lundberg, JO and Brismar, K and Pernow, J}, title = {Red Blood Cells in Type 2 Diabetes Impair Cardiac Post-Ischemic Recovery Through an Arginase-Dependent Modulation of Nitric Oxide Synthase and Reactive Oxygen Species.}, journal = {JACC. Basic to translational science}, volume = {3}, number = {4}, pages = {450-463}, pmid = {30175269}, issn = {2452-302X}, abstract = {This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.}, }
@article {pmid30174507, year = {2018}, author = {Zhang, C and Yu, G and Shen, Y}, title = {The naturally occurring xanthone α-mangostin induces ROS-mediated cytotoxicity in non-small scale lung cancer cells.}, journal = {Saudi journal of biological sciences}, volume = {25}, number = {6}, pages = {1090-1095}, pmid = {30174507}, issn = {1319-562X}, abstract = {Small cell lung cancer (NSCLC) accounts for 85% of total deaths globally, and recent studies indicate the increasing risks of NSCLC in China and South Asian countries. Hence, development of new therapeutics against NSCLC has been a major concern. α-Mangostin, a naturally occurring xanthone, found abundantly in pericarps of mangosteen fruit is well known for its medicinal importance. The anticancer properties of α-mangostin against several types of cancer are also well documented. But the mechanism of action of α-mangostin against lung cancer is not well understood and requires further investigation. Therefore in the present study, we explored the therapeutic potential of α-mangostin against A549 cells. Treatment of A549 cells with α-mangostin resulted in a dose-dependent loss of cell viability, while the non-malignant cells such as hPBMC and WI-38 remained unaffected. Further we observed that the ROS plays an important role in α-mangostin -induced apoptosis in A549 cells, and administration of N-acetyl cysteine significantly abrogates α-mangostin -mediated cytotoxicity in lung cancer cells. Overall, α-mangostin induces ROS-mediated cytotoxicity in NSCLC cells.}, }
@article {pmid30172667, year = {2018}, author = {Lejay, A and Paradis, S and Lambert, A and Charles, AL and Talha, S and Enache, I and Thaveau, F and Chakfe, N and Geny, B}, title = {N-Acetyl Cysteine Restores Limb Function, Improves Mitochondrial Respiration, and Reduces Oxidative Stress in a Murine Model of Critical Limb Ischaemia.}, journal = {European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery}, volume = {56}, number = {5}, pages = {730-738}, doi = {10.1016/j.ejvs.2018.07.025}, pmid = {30172667}, issn = {1532-2165}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Calcium/metabolism ; Ischemia/*drug therapy/metabolism ; Male ; Mice ; Mitochondria/*drug effects ; Muscle, Skeletal/blood supply ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE/BACKGROUND: The aim of this study was to investigate whether antioxidant therapy might decrease oxidative stress related deleterious effects in the setting of critical limb ischaemia (CLI).<br><br>METHODS: Twenty Swiss mice were submitted to sequential right femoral and iliac ligatures; the left limb served as control. The mice were assigned to two groups: in the first group (no-treatment group, n&#xa0;=&#xa0;10) no treatment was administered; in the second group (N-acetyl cysteine [NAC] group, n&#xa0;=&#xa0;10) NAC was administered by dissolution in drinking water for 4 weeks, starting on day 7, when CLI was effective. Clinical and functional scores were assessed by two blinded investigators. Mice were killed on day 40 and mitochondrial respiratory chain complex activities, calcium retention capacity, oxidative stress, and histological analysis were analysed.<br><br>RESULTS: Ischaemic muscles in the no-treatment group showed significantly impaired mitochondrial respiration and calcium retention capacity, with increased production of reactive oxygen species; but no statistical difference was noticed when comparing ischaemic muscles in the NAC group (n&#xa0;=&#xa0;10) to contralateral muscles (n&#xa0;=&#xa0;10) and to control muscles in the no-treatment group (n&#xa0;=&#xa0;10). Ischaemic muscles in the no-treatment group exhibited myopathic features such as wider range in fibre size, rounded shape, centrally located nuclei, and smaller cross sectional areas, but none of these features were observed in contralateral muscles or in NAC-group muscles (ischaemic or controls).<br><br>CONCLUSION: Targeting inhibition of oxidative stress may be a potential therapeutic strategy for muscle protection in CLI and might be considered as potential adjunctive therapy to revascularisation procedures.}, }
@article {pmid30168649, year = {2018}, author = {Huy, H and Song, HY and Kim, MJ and Kim, WS and Kim, DO and Byun, JE and Lee, J and Park, YJ and Kim, TD and Yoon, SR and Choi, EJ and Lee, CH and Noh, JY and Jung, H and Choi, I}, title = {TXNIP regulates AKT-mediated cellular senescence by direct interaction under glucose-mediated metabolic stress.}, journal = {Aging cell}, volume = {17}, number = {6}, pages = {e12836}, pmid = {30168649}, issn = {1474-9726}, support = {CRC-15-02-KRIBB//National Research Council of Science &amp; Technology (NST)/International ; }, mesh = {Animals ; Carrier Proteins/*metabolism ; *Cellular Senescence/drug effects ; Diabetes Mellitus, Type 1/metabolism/pathology ; Energy Metabolism/drug effects ; Enzyme Activation/drug effects ; Fibroblasts/drug effects/metabolism ; Glucose/*toxicity ; Kidney/pathology ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; *Stress, Physiological/drug effects ; Thioredoxins/*metabolism ; }, abstract = {Aging is associated with an inevitable and universal loss of cell homeostasis and restricts an organism's lifespan by an increased susceptibility to diseases and tissue degeneration. The glucose uptake associated with producing energy for cell survival is one of the major causes of ROS production under physiological conditions. However, the overall mechanisms by which glucose uptake results in cellular senescence remain mysterious. In this study, we found that TXNIP deficiency accelerated the senescent phenotypes of MEF cells under high glucose condition. TXNIP[-/-] MEF cells showed greater induced glucose uptake and ROS levels than wild-type cells, and N-acetylcysteine (NAC) treatment rescued the cellular senescence of TXNIP[-/-] MEF cells. Interestingly, TXNIP[-/-] MEF cells showed continuous activation of AKT during long-term subculture, and AKT signaling inhibition completely blocked the cellular senescence of TXNIP[-/-] MEF cells. In addition, we found that TXNIP interacted with AKT via the PH domain of AKT, and their interaction was increased by high glucose or H2 O2 treatment. The inhibition of AKT activity by TXNIP was confirmed using western blotting and an in vitro kinase assay. TXNIP deficiency in type 1 diabetes mice (Akita) efficiently decreased the blood glucose levels and finally increased mouse survival. However, in normal mice, TXNIP deficiency induced metabolic aging of mice and cellular senescence of kidney cells by inducing AKT activity and aging-associated gene expression. Altogether, these results suggest that TXNIP regulates cellular senescence by inhibiting AKT pathways via a direct interaction under conditions of glucose-derived metabolic stress.}, }
@article {pmid30166100, year = {2018}, author = {Tovilovic-Kovacevic, G and Krstic-Milosevic, D and Vinterhalter, B and Toljic, M and Perovic, V and Trajkovic, V and Harhaji-Trajkovic, L and Zogovic, N}, title = {Xanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {47}, number = {}, pages = {151-160}, doi = {10.1016/j.phymed.2018.03.052}, pmid = {30166100}, issn = {1618-095X}, mesh = {Autophagy/*drug effects ; Brain Neoplasms/pathology ; Cell Cycle Checkpoints ; Cell Differentiation/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gentiana/*chemistry ; Glioblastoma/pathology ; Humans ; Oxidative Stress ; Plant Extracts/pharmacology ; Plant Roots/chemistry ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Xanthones/*pharmacology ; }, abstract = {BACKGROUND: Glioblastoma multiforme (GMB) is the most malignant of all brain tumors with poor prognosis. Anticancer potential of xanthones, bioactive compounds found in Gentiana dinarica, is well-documented. Transformation of G. dinarica roots with Agrobacterium rhizogenes provides higher xanthones accumulation, which enables better exploitation of these anticancer compounds.<br><br>HYPOTHESIS/PURPOSE: The aim of this study was to investigate antiglioma effect of three different G. dinarica extracts: E1-derived from untransformed roots, E2-derived from roots transformed using A. rhizogenes strain A4M70GUS, and E3-derived from roots transformed using A. rhizogenes strain 15834/PI. Further, mechanisms involved in anticancer potential of the most potent extract were examined in detail, and its active component was determined.<br><br>METHODS: The cell viability was assessed using MTT and crystal violet test. Cell cycle analysis, the expression of differentiation markers, the levels of autophagy, and oxidative stress were analyzed by flow cytometry. Autophagy and related signaling pathways were assessed by immunoblotting.<br><br>RESULTS: E3, in contrast to E1 and E2, strongly reduced growth of U251 human glioblastoma cells, triggered cell cycle arrest in G2/M phase, changed cellular morphology, and increased expression of markers of differentiated astrocytes (glial fibrillary acidic protein) and neurons (&#x3b2;-tubulin). E3 stimulated autophagy, as demonstrated by enhanced intracellular acidification, increased microtubule-associated light chain 3B (LC3-I) conversion to autophagosome associated LC3-II, and decreased level of selective autophagy target p62. Induction of autophagy was associated with Akt-dependent inhibition of main autophagy suppressor mammalian target of rapamycin (mTOR). Both genetic and pharmacological inhibition of autophagy suppressed the expression of differentiation markers, but had no effect on cell cycle arrest in E3-treated cells. E3 stimulated oxidative stress, and antioxidants vitamin E and N-acetyl cysteine inhibited autophagy and differentiation of E3-treated U251 cells. The most prevalent compound of E3, xanthone aglycone norswertianin, also arrested glioblastoma cell proliferation in G2/M phase and induced glioblastoma cell differentiation through induction of autophagy and oxidative stress.<br><br>CONCLUSION: These results indicate that E3 and its main active component norswertianin may serve as a potential candidate for differentiation therapy of glioblastoma.}, }
@article {pmid30166097, year = {2018}, author = {Pavithra, PS and Mehta, A and Verma, RS}, title = {Synergistic interaction of β-caryophyllene with aromadendrene oxide 2 and phytol induces apoptosis on skin epidermoid cancer cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {47}, number = {}, pages = {121-134}, doi = {10.1016/j.phymed.2018.05.001}, pmid = {30166097}, issn = {1618-095X}, mesh = {Apoptosis/*drug effects ; Azulenes/*pharmacology ; Carcinoma, Squamous Cell ; Caspases/metabolism ; Cell Cycle Checkpoints ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Humans ; Keratinocytes/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Oils, Volatile/pharmacology ; Phytol/*pharmacology ; Polycyclic Sesquiterpenes ; Reactive Oxygen Species/metabolism ; Rutaceae/chemistry ; Sesquiterpenes/*pharmacology ; }, abstract = {BACKGROUND: Pamburus missionis (Wight) Swingle (Rutaceae) is traditionally used in the treatment of swellings, chronic rheumatism, paralysis and puerperal diseases. In a previous study the authors demonstrated apoptotic activity of Pamburus missionis essential oil (EO) on A431 and HaCaT cells. The major components of EO were β-caryophyllene (25.40%), 4(14),11- eudesmadiene (7.17%), aromadendrene oxide 2 (14.01%) (AO-(2) and phytol (6.88%).<br><br>PURPOSE OF STUDY: To investigate the role as well as the interactions among EO components inducing apoptosis in A431 and HaCaT cells.<br><br>METHODS: Isobolographic analysis and combination index methods were used to detect the type of interactions among the essential oil (EO) components. Cell viability was used to detect cytotoxic activity. Mechanism of cell death was studied using Annexin V-FITC/PI binding assay, cell cycle analysis, measurement of MMP and ROS generation by flow cytometry. Expression of apoptosis associated proteins was investigated by western blot.<br><br>RESULTS: Combination of P. missionis EO components: &#x3b2;-caryophyllene/ aromadendrene oxide 2 (&#x3b2;-C/AO-(2)), &#x3b2;-caryophyllene/phytol (&#x3b2;-C/P) and aromadendrene oxide 2 /phytol (AO-(2)/P) inhibited growth and colony formation ability of skin epidermoid A431 and precancerous HaCaT cells. Synergistic interaction was observed between &#x3b2;-C/AO-(2) and &#x3b2;-C/P combination while AO-(2)/P exhibited an additive effect. Combination of components induced chromatin condensation, phosphatidylserine externalisation, increase in sub-G1 DNA content, cell cycle arrest at G0/G1 phase and intracellular ROS accumulation. Inhibition of intracellular ROS by N-acetyl cysteine treatment blocked apoptosis induced by the combinations. The combinations induced apoptosis in A431 and HaCaT cells mediated by loss of mitochondrial membrane potential (&#x394;&#x3a8;m), increase in Bax/Bcl-2 ratio, release of cytosolic cytochrome c and activation of caspases (cleaved form of caspase-3, caspase-8, caspase-9) and by PARP cleavage.<br><br>CONCLUSION: The present study demonstrates interactions among &#x3b2;-C, AO-(2) and P in the induction of apoptosis on A431 and HaCaT cells. These data suggest the combination of &#x3b2;-caryophyllene with aromadendrene oxide 2 and phytol could be potential therapeutics for the treatment of skin epidermoid cancer and precancerous cells.}, }
@article {pmid30161099, year = {2018}, author = {Lei, Q and Yi, T and Chen, C}, title = {NF-κB-Gasdermin D (GSDMD) Axis Couples Oxidative Stress and NACHT, LRR and PYD Domains-Containing Protein 3 (NLRP3) Inflammasome-Mediated Cardiomyocyte Pyroptosis Following Myocardial Infarction.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {24}, number = {}, pages = {6044-6052}, pmid = {30161099}, issn = {1643-3750}, mesh = {Animals ; Cell Line ; Disease Models, Animal ; Inflammasomes/*metabolism ; Intracellular Signaling Peptides and Proteins ; Myocardial Infarction/complications ; Myocytes, Cardiac/metabolism ; NF-kappa B/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Neoplasm Proteins/*metabolism ; Oxidative Stress/*physiology ; Phosphate-Binding Proteins ; Pyroptosis/drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {BACKGROUND Pyroptosis and oxidative stress play pivotal roles in cardiomyocyte loss after myocardial infarction. NF-κB is associated with oxidative stress and gasdermin D (GSDMD), the effector molecule of pyroptosis. However, the exact relationship between oxidative stress and cardiomyocyte pyroptosis remains unknown. MATERIAL AND METHODS We measured inflammasome-mediated cardiomyocyte pyroptosis in vivo via membrane pore formation, lactate dehydrogenase (LDH) release, and expression of caspase-1, cleaved caspase-1, NACHT, LRR and PYD domains-containing protein 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC). Furthermore, we induced pyroptosis in vitro by oxygen-glucose deprivation (OGD) in H9C2 cells. NLRP3 inflammasome-mediated pyroptosis was confirmed by LDH assay kit and Western blot. Oxidative stress was evaluated by reactive oxygen species (ROS) and superoxide dismutase (SOD) activity. We suppressed oxidative stress with N-acetyl-cysteine (NAC) and measured subsequent changes to the NF-κB-GSDMD axis and pyroptosis by LDH assay kit and Western blot. Then, we inhibited NF-κB activation with pyrrolidine dithiocarbamate (PDTC) and measured changes to GSDMD activity and pyroptosis by qRT-PCR, Western blot, and LDH assay kit. RESULTS Suppression of oxidative stress by NAC reduced NF-κB and GSDMD activation and increased pyroptosis, characterized by LDH release and NLRP3 inflammasome activation in H9C2 cells under OGD. Moreover, inhibition of NF-κB activation reduced GSDMD transcription and activation and NLRP3 inflammasome-mediated pyroptosis of H9C2 cells under OGD. CONCLUSIONS We demonstrated that the NF-κB-GSDMD axis functioned as a bridge between oxidative stress and NLRP3 inflammasome-mediated cardiomyocyte pyroptosis. Our findings provide important insight into the mechanism of myocardial infarction-related ventricular remodeling.}, }
@article {pmid30158441, year = {2018}, author = {Yang, JP and Shin, JH and Seo, SH and Kim, SG and Lee, SH and Shin, EH}, title = {Effects of Antioxidants in Reducing Accumulation of Fat in Hepatocyte.}, journal = {International journal of molecular sciences}, volume = {19}, number = {9}, pages = {}, pmid = {30158441}, issn = {1422-0067}, support = {0564-20160008//foundation of Sunchang-gun health and longevity research institute/ ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Ascorbic Acid/pharmacology ; Cell Survival/drug effects ; Endoplasmic Reticulum/drug effects/metabolism ; Hep G2 Cells ; Hepatocytes/*drug effects/*metabolism ; Humans ; Oleic Acid/pharmacology ; Reactive Oxygen Species/metabolism ; Triglycerides/metabolism ; Xanthophylls/pharmacology ; }, abstract = {The progress of the hepatic steatosis (HS), a clinicopathological status, is influenced by cellular oxidative stress, lipogenesis, fatty acid (FA) oxidation, and inflammatory responses. Because antioxidants are gaining attention as potent preventive agents for HS, we aimed to investigate anti-lipogenic effects of the antioxidants vitamin C (VC), N-acetylcysteine (NAC), and astaxanthin (ATX) using hepatocytes. For this, we established an in vitro model using 1 mM oleic acid (OA) and human liver hepatocellular carcinoma (HepG2) cells; 10 μM antioxidants were evaluated for their ability to reduce fat accumulation in hepatocytes. Our results showed that all three antioxidants were effective to reduce fat accumulation for the molecular targets such as reduction in lipid droplets, triglyceride (TG) concentration, reactive oxygen species (ROS) production, and cell apoptosis, as well as in gene expressions of endoplasmic reticulum (ER) stress-related effectors, lipogenesis, and inflammatory cytokines. There were simultaneous increases in diphenyl-1-picrylhydrazyl (DPPH) radical scavenging effect, cell survival, AMPK phosphorylation, NRF2-related gene expression for cellular defense, and FA β-oxidation. However, among these, ATX more effectively inhibited ER stress and lipogenesis at the intracellular level than VC or NAC. Consequently, ATX was also more effective in inhibiting cell death, lipotoxicity, and inflammation. Our result emphasizes that ATX achieved greater lipotoxicity reduction than VC and NAC.}, }
@article {pmid30157294, year = {2018}, author = {Tamborindeguy, MT and Matte, BF and Ramos, GO and Alves, AM and Bernardi, L and Lamers, ML}, title = {NADPH-oxidase-derived ROS alters cell migration by modulating adhesions dynamics.}, journal = {Biology of the cell}, volume = {110}, number = {10}, pages = {225-236}, doi = {10.1111/boc.201800011}, pmid = {30157294}, issn = {1768-322X}, support = {#443649/2014-3//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; //Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior/ ; }, mesh = {Animals ; Biphenyl Compounds ; CHO Cells ; *Cell Adhesion/drug effects ; *Cell Movement/drug effects ; Cricetulus ; NADPH Oxidases/*metabolism ; Onium Compounds ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND INFORMATION: Cell migration requires the coordinated activation of structural and signalling molecules, such as the RhoGTPase Rac1. It is known that the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex assembly, which generates reactive oxygen species (ROS) at the cell membrane, also relies on Rac1 activation, indicating a possible effect of ROS during cell migration. In this study, we evaluated the effect of NADPH-oxidase-derived ROS on the migration process.<br><br>RESULTS: Using time-lapse videos of CHO.K1 cells plated on fibronectin (2&#xa0;&#x3bc;g/ml) or collagen (5&#xa0;&#x3bc;g/cm[2]), we observed that depletion of ROS by N-acetyl-cysteine (NAC, 10&#xa0;mM), an unspecific antioxidant, or diphenyliodonium (DPI, 10&#xa0;&#x3bc;M), a NADPH-oxidase inhibitor, induced a &#x223c;50% decrease in migration speed and severely impacted migration directionality. Then, we analysed the effects of NADPH oxidase on three migratory events: protrusion rate, adhesion process and signalling pathways related to cell migration. DPI induced an increase of &#x223c;3 protrusion/cell, which were 2&#xd7; faster but had a &#x223c;50% retraction when compared with control. By pull-down assay, we observed no changes on Rac1 activation, indicating that ROS-mediated effects were related to downstream molecules, such as adhesion-related molecules. A reduction of the adhesion marker FAK-Y397 levels in cells treated with NAC and DPI was observed. In order to analyse adhesion dynamics, CHO.K1 cells transfected with paxillin-GFP analysed with total internal reflectance fluorescence (TIRF) indicated that DPI (5&#xa0;&#x3bc;M) induced larger adhesions when compared with control.<br><br>CONCLUSION: These results indicate that the local generation of NADPH-oxidase-derived ROS can modulate cell migration due to changes on adhesion dynamics and signalling.<br><br>SIGNIFICANCE: This study highlights the physiological requirement of ROS for cell migration and the potential use of these molecules as targets to modulate the cell migration process at different diseases.}, }
@article {pmid30148067, year = {2018}, author = {Tungjai, M and Sukantamala, S and Malasaem, P and Dechsupa, N and Kothan, S}, title = {An evaluation of the antioxidant properties of iodinated radiographic contrast media: An in vitro study.}, journal = {Toxicology reports}, volume = {5}, number = {}, pages = {840-845}, pmid = {30148067}, issn = {2214-7500}, abstract = {This study reveals the antioxidant properties of iodinated radiographic contrast media to be used in diagnostic radiology. Di(phenyl)-(2,4,6-trinitrophenyl) iminoazanium (DPPH), ferric reducing ability of plasma (FRAP), and 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) assays were used for determining in vitro the antioxidant properties of five iodinated radiographic contrast media such as iobitridol (xenetix), iodixanol (visipaque), iohexol (omnipaque), ioxaglate (hexabrix), and isovue (iopamiro). An ascorbic acid and Trolox solution served as a positive control. The absorbance intensity of the colored product was recorded using a spectrophotometer. For DPPH and ABTS assay, the absorbance intensity at 533 and 752 nm, respectively was decreased when compared to control; it indicated an increase in antioxidant activity. For FRAP assay, the absorbance intensity at 593 nm was increased when compared to control; it indicated an increase in antioxidant activity. The results showed that five iodinated radiographic contrast media did not differ in DPPH[•] radical-scavenging activity when compared to a corresponding control. The ferric reducing ability of all of these iodinated radiographic contrast media also did not differ when compared to a corresponding control, except for iobitridol at 200 mgI/mL and ioxaglate at 50-200 mgI/mL. All iodinated radiographic contrast media showed ABTS[•+] radical-scavenging activity. This finding suggested that iobitridol, iodixanol, iohexol, ioxaglate, and isovue exhibited weak in vitro antioxidant properties. The antioxidant ability depended on the type of free radical production and the concentration of iodinated radiographic contrast media.}, }
@article {pmid30146791, year = {2019}, author = {Yang, HL and Lin, RW and Rajendran, P and Mathew, DC and Thigarajan, V and Lee, CC and Hsu, CJ and Hseu, YC}, title = {Antrodia salmonea-induced oxidative stress abrogates HER-2 signaling cascade and enhanced apoptosis in ovarian carcinoma cells.}, journal = {Journal of cellular physiology}, volume = {234}, number = {3}, pages = {3029-3042}, doi = {10.1002/jcp.27123}, pmid = {30146791}, issn = {1097-4652}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/metabolism ; Antrodia/*chemistry ; Apoptosis/genetics ; Carcinoma/*drug therapy/genetics/pathology ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Medicine, Chinese Traditional ; Mitochondria/drug effects/genetics ; Ovarian Neoplasms/*drug therapy/genetics/pathology ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-akt/genetics ; Reactive Oxygen Species/metabolism ; Receptor, ErbB-2/*genetics ; Signal Transduction/genetics ; }, abstract = {Antrodia salmonea is well known in Taiwan as a traditional Chinese medicinal fungus and has demonstrated antioxidant, anti-inflammatory, and anticancer effects. However, the anticancer activity of A. salmonea against human ovarian cancer is still elusive. Therefore, we investigated the antiovarian tumor activity of a fermented culture broth of A. salmonea and exhibits its underlying molecular mechanism. A. salmonea shows a significant effect on cell viability in human ovarian carcinoma (SKOV-3 or A2780) cell lines with an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Increased terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells and annexin V-propidium iodide stained cells indicate that A. salmonea induces late apoptosis in SKOV-3 cells. Notably, treatment with A. salmonea induced the following events: Apoptosis; caspase-3, -8, -9 and poly(ADP-ribose) polymerase activation; first apoptosis signal (Fas) and Fas ligand activation; Bid cleavage; and Bax2-B-cell lymphoma 2 dysregulation. The results show that A. salmonea-induced apoptosis was mediated by both mitochondrial and death receptor pathways. An increase in intracellular reactive oxygen species (ROS) was also observed in A. salmonea-treated cells, whereas the antioxidant N-acetylcysteine (NAC) prevented A. salmonea-induced cell death and DNA fragmentation, indicating that A. salmonea-induced apoptosis was mediated by ROS generation. Interestingly, A. salmonea-induced apoptosis is associated with the suppression of human epidermal growth factor receptor-2 (HER-2/neu) and phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) expression in HER-2/neu overexpressing SKOV-3 cells. NAC significantly prevented A. salmonea-induced HER-2/neu depletion and PI3K/AKT inactivation, indicating that A. salmonea-triggered apoptosis is mediated by ROS-inhibited HER-2/neu signaling cascades. To our knowledge, this is the first report describing the anticancer activity of this potentially beneficial mushroom against human ovarian carcinoma.}, }
@article {pmid30145925, year = {2019}, author = {Zhang, L and Qiang, P and Yu, J and Miao, Y and Chen, Z and Qu, J and Zhao, Q and Chen, Z and Liu, Y and Yao, X and Liu, B and Cui, L and Jing, H and Sun, G}, title = {Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer.}, journal = {Autophagy}, volume = {15}, number = {3}, pages = {391-406}, pmid = {30145925}, issn = {1554-8635}, mesh = {A549 Cells ; Animals ; Antineoplastic Agents/chemistry/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Autophagosomes/drug effects/metabolism ; Autophagy/*drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism ; Cathepsin D/metabolism ; Cytoskeletal Proteins/metabolism ; Endothelial Cells/metabolism/ultrastructure ; HEK293 Cells ; HeLa Cells ; Human Umbilical Vein Endothelial Cells/drug effects ; Humans ; Lung Neoplasms/*drug therapy/metabolism ; Lysosomes/drug effects/metabolism ; Membrane Transport Proteins/metabolism ; Mice, Inbred BALB C ; Mice, Nude ; Piperidines/chemistry/*pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {Currently, particular focus is placed on the implication of autophagy in a variety of human diseases, including cancer. Discovery of small-molecule modulators of autophagy as well as their potential use as anti-cancer therapeutic agents would be of great significance. To this end, a series of curcumin analogs previously synthesized in our laboratory were screened. Among these compounds, (3E,5E)-3-(3,4-dimethoxybenzylidene)-5-[(1H-indol-3-yl)methylene]-1-methylpiperidin-4-one (CA-5f) was identified as a potent late-stage macroautophagy/autophagy inhibitor via inhibiting autophagosome-lysosome fusion. We found that CA-5f neither impaired the hydrolytic function nor the quantity of lysosomes. Use of an isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic screen in combination with bioinformatics analysis suggested that treatment of human umbilical vein endothelial cells (HUVECs) with CA-5f for 1 h suppressed the levels of cytoskeletal proteins and membrane traffic proteins. Subsequent studies showed that CA-5f exhibited strong cytotoxicity against A549 non-small cell lung cancer (NSCLC) cells, but low cytotoxicity to normal human umbilical vein endothelial cells (HUVECs), by increasing mitochondrial-derived reactive oxygen species (ROS) production. Moreover, CA-5f effectively suppressed the growth of A549 lung cancer xenograft as a single agent with an excellent tolerance in vivo. Results from western blot, immunofluorescence, and TdT-mediated dUTP nick end labeling (TUNEL) assays showed that CA-5f inhibited autophagic flux, induced apoptosis, and did not affect the level of CTSB (cathepsin B) and CTSD (cathepsin D) in vivo, which were consistent with the in vitro data. Collectively, these results demonstrated that CA-5f is a novel late-stage autophagy inhibitor with potential clinical application for NSCLC therapy. Abbreviations: 3-MA, 3-methyladenine; ANXA5, annexin A5; ATG, autophagy related; CA-5f, (3E,5E)-3-(3,4-dimethoxybenzylidene)-5-[(1H-indol-3-yl)methylene]-1-methylpiperidin-4-one; CQ, chloroquine; CTSB, cathepsin B; CTSD, cathepsin D; DMSO, dimethyl sulfoxide; DNM2, dynamin 2; EBSS, Earle's balanced salt solution; GFP, green fluorescent protein; HCQ, hydroxyl CQ; HEK293, human embryonic kidney 293; HUVEC, human umbilical vein endothelial cells; LAMP1, lysosomal associated membrane protein 1; LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry; LDH, lactic acid dehydrogenase; LMO7, LIM domain 7; MAP1LC3B/LC3B, microtubule associated protein 1 light chain 3 beta; NAC, N-acetyl cysteine; MYO1E, myosin IE; NSCLC, non-small cell lung cancer; PARP1, poly(ADP-ribose) polymerase 1; PI, propidium iodide; RFP, red fluorescent protein; ROS, reactive oxygen species; SQSTM1, sequestosome 1; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.}, }
@article {pmid30145358, year = {2018}, author = {Zhang, M and Xia, H and Yu, M and Zhu, L and Ju, L and Chen, J and Zhao, J and Xiao, Y and Chen, K}, title = {N-acetylcysteine prevents cytotoxic effects induced by man-made mineral fibers in a human bronchial epithelial cell line.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {53}, number = {}, pages = {200-207}, doi = {10.1016/j.tiv.2018.08.012}, pmid = {30145358}, issn = {1879-3177}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Bronchi/cytology ; Caspases/metabolism ; Cell Line ; Epithelial Cells/*drug effects/metabolism ; Free Radical Scavengers/*pharmacology ; Humans ; Mineral Fibers/*toxicity ; fas Receptor/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Man-made mineral fibres (MMMFs) such as glass wool (GW), rock wool (RW) and refractory ceramic fibres (RCFs) are widely used as substitutes of asbestos. The present study aimed to investigate the cytotoxic effects on human bronchial epithelial cells (BEAS-2B) exposed to GW1, RW1 and RCF2, considering their properties similar to that of asbestos. We assessed cell viability; cell morphological changes; apoptotic rate; DNA damage; reactive oxygen species (ROS) generation; activities of caspase-3, caspase-8 and caspase-9; and expression levels of FasL, phosphorylated p38, and total p38 MAPK proteins. N-acetyl-l-cysteine (NAC) was used as an ROS scavenger. We observed that MMMFs, especially RCF2, evidently changed cellular morphology, promoted DNA damage, and induced apoptosis. In addition, the cytotoxicities of MMMFs were dependent on ROS generation, and NAC could decrease their toxicity. Furthermore, our results showed that apoptosis induced by MMMFs was mediated by the mitochondrial apoptotic pathway and Fas death receptor pathway. Moreover, the p38 MAPK signalling pathway was also involved in the cytotoxicities of MMMFs. NAC exerts a protective effect against apoptosis and DNA damage induced by GW1, RW1 and RCF2. This study provides important implications for understanding the potential toxic effects of GW1, RW1 and RCF2 exposure; it also indicates that NAC may prevent respiratory diseases induced by exposure to MMMFs.}, }
@article {pmid30141099, year = {2019}, author = {Mischoulon, D and Rapaport, MH}, title = {Current Role of Herbal and Natural Preparations.}, journal = {Handbook of experimental pharmacology}, volume = {250}, number = {}, pages = {225-252}, doi = {10.1007/164_2018_152}, pmid = {30141099}, issn = {0171-2004}, mesh = {Antidepressive Agents/*pharmacology ; Depression/*psychology ; Humans ; *Hypericum ; }, abstract = {Depression remains difficult to manage, despite the many registered treatments available. For many depressed individuals, particularly those who have not responded to and/or had adverse effects from standard therapies, herbal and natural medications represent a potentially valuable alternative. This chapter will review several natural remedies used in the treatment of depression. Specific remedies covered include St. John's wort (SJW), S-adenosyl-L-methionine (SAMe), omega-3 fatty acids, rhodiola, and others. We will begin by providing some historical and social context about these remedies. Then we will review efficacy and safety data, as well as biological mechanisms of action of these therapies. Finally, we will discuss the limitations of the current state of knowledge and provide suggestions for a productive research agenda focused on natural remedies. While many questions about these treatments remain unanswered and much work needs to be done before we determine their place in the psychiatric armamentarium, we believe that this chapter will give psychiatrists a good perspective on the pros and cons of herbal and natural antidepressants as part of the pharmacological armamentarium and sensible guidelines on how and when they should be used.}, }
@article {pmid30141055, year = {2018}, author = {McQueen, G and Lally, J and Collier, T and Zelaya, F and Lythgoe, DJ and Barker, GJ and Stone, JM and McGuire, P and MacCabe, JH and Egerton, A}, title = {Effects of N-acetylcysteine on brain glutamate levels and resting perfusion in schizophrenia.}, journal = {Psychopharmacology}, volume = {235}, number = {10}, pages = {3045-3054}, pmid = {30141055}, issn = {1432-2072}, support = {MR/L003988/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Brain/blood supply/metabolism ; Caudate Nucleus/drug effects/*metabolism ; Cerebrovascular Circulation/*drug effects ; Creatine/metabolism ; Cross-Over Studies ; Double-Blind Method ; Female ; Glutamic Acid/*metabolism ; Gyrus Cinguli/drug effects/*metabolism ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Proton Magnetic Resonance Spectroscopy ; Regional Blood Flow/drug effects ; Rest ; Schizophrenia/*drug therapy/metabolism/physiopathology ; }, abstract = {RATIONALE: N-Acetylcysteine (NAC) is currently under investigation as an adjunctive treatment for schizophrenia. The therapeutic potential of NAC may involve modulation of brain glutamate function, but its effects on brain glutamate levels in schizophrenia have not been evaluated.<br><br>OBJECTIVES: The aim of this study was to examine whether a single dose of NAC can alter brain glutamate levels. A secondary aim was to characterise its effects on regional brain perfusion.<br><br>METHODS: In a double-blind placebo-controlled crossover study, 19 patients with a diagnosis of schizophrenia underwent two MRI scans, following oral administration of 2400&#xa0;mg NAC or matching placebo. Proton magnetic resonance spectroscopy was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling was used to assess the effects of NAC on resting cerebral blood flow (rCBF) in the same regions.<br><br>RESULTS: Relative to the placebo condition, the NAC condition was associated with lower levels of Glx/Cr, in the ACC (P&#x2009;<&#x2009;0.05), but not in the caudate nucleus. There were no significant differences in CBF in the NAC compared to placebo condition.<br><br>CONCLUSIONS: These data provide preliminary evidence that NAC can modulate ACC glutamate in patients with schizophrenia. In contrast, physiological effects of NAC on the brain were not detectable as between session changes in rCBF. Future studies assessing the effects of a course of treatment with NAC on glutamate metabolites in schizophrenia are indicated.}, }
@article {pmid30140368, year = {2018}, author = {Chen, T and Li, M and Fan, X and Cheng, J and Wang, L}, title = {Sodium Tanshinone IIA Sulfonate Prevents Angiotensin II-Induced Differentiation of Human Atrial Fibroblasts into Myofibroblasts.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {6712585}, pmid = {30140368}, issn = {1942-0994}, mesh = {Angiotensin II/*metabolism ; Atrial Fibrillation/*physiopathology ; Cell Differentiation ; Fibroblasts ; Humans ; Myofibroblasts/*metabolism ; Phenanthrenes/*metabolism ; Signal Transduction ; }, abstract = {Differentiation of atrial fibroblasts into myofibroblasts plays a critical role in atrial fibrosis. Sodium tanshinone IIA sulfonate (DS-201), a water-soluble derivative of tanshinone IIA, has been shown to have potent antifibrotic properties. However, the protective effects of DS-201 on angiotensin II- (Ang II-) induced differentiation of atrial fibroblasts into myofibroblasts remain to be elucidated. In this study, human atrial fibroblasts were stimulated with Ang II in the presence or absence of DS-201. Then, α-smooth muscle actin (α-SMA), collagen I, and collagen III expression and reactive oxygen species (ROS) generation were measured. The expression of transforming growth factor-β1 (TGF-β1) and the downstream signaling of TGF-β1, such as phosphorylation of Smad2/3, were also determined. The results demonstrated that DS-201 significantly prevented Ang II-induced human atrial fibroblast migration and decreased Ang II-induced α-SMA, collagen I, and collagen III expression. Furthermore, increased production of ROS and expression of TGF-β1 stimulated by Ang II were also significantly inhibited by DS-201. Consistent with these results, DS-201 significantly inhibited Ang II-evoked Smad2/3 phosphorylation and periostin expression. These results and the experiments involving N-acetyl cysteine (antioxidant) and an anti-TGF-β1 antibody suggest that DS-201 prevent Ang II-induced differentiation of atrial fibroblasts to myofibroblasts, at least in part, through suppressing oxidative stress and inhibiting the activation of TGF-β1 signaling pathway. All of these data indicate the potential utility of DS-201 for the treatment of cardiac fibrosis.}, }
@article {pmid30140363, year = {2018}, author = {Marrone, M and La Rovere, RML and Guarnieri, S and Di Filippo, ES and Monaco, G and Pietrangelo, T and Bultynck, G and Fulle, S and Mancinelli, R}, title = {Superoxide Anion Production and Bioenergetic Profile in Young and Elderly Human Primary Myoblasts.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {2615372}, pmid = {30140363}, issn = {1942-0994}, mesh = {Adult ; Aged ; Biopsy/*methods ; Cell Differentiation ; Cells, Cultured ; Female ; Humans ; Male ; Muscle Fibers, Skeletal/*metabolism ; Muscle, Skeletal/*metabolism ; Myoblasts/*metabolism/pathology ; Superoxides/*metabolism ; }, abstract = {Sarcopenia is the age-related loss of skeletal muscle mass, strength, and function. It is associated with regenerative difficulties by satellite cells, adult muscle stem cells, and alteration of oxidative management, mainly the increase in superoxide anions (O2[•-]). We aimed to investigate the relation between regenerative deficit in elderly and increase in O2[•-] production along with mitochondrial alterations. Myoblasts and myotubes from skeletal muscle of young and elderly healthy subjects (27.8 ± 6 and 72.4 ± 6.5 years old) were measured: (1) superoxide dismutase activity and protein content, (2) mitochondrial O2[•-] production levels, (3) O2[•-] production variability, and (4) mitochondrial bioenergetic profile. Compared to young myoblasts, elderly myoblasts displayed decreased SOD2 protein expression, elevated mitochondrial O2[•-] baseline levels, and decreased oxidative phosphorylation and glycolysis. Additionally, elderly versus young myotubes showed elevated mitochondrial O2[•-] levels when stressed with N-acetyl cysteine or high glucose and higher glycolysis despite showing comparable oxidative phosphorylation levels. Altogether, the elderly may have less metabolic plasticity due to the impaired mitochondrial function caused by O2[•-]. However, the increased energy demand related to the differentiation process appears to activate compensatory mechanisms for the partial mitochondrial dysfunction.}, }
@article {pmid30126957, year = {2018}, author = {Cao, R and Teskey, G and Islamoglu, H and Abrahem, R and Munjal, S and Gyurjian, K and Zhong, L and Venketaraman, V}, title = {Characterizing the Effects of Glutathione as an Immunoadjuvant in the Treatment of Tuberculosis.}, journal = {Antimicrobial agents and chemotherapy}, volume = {62}, number = {11}, pages = {}, pmid = {30126957}, issn = {1098-6596}, mesh = {Adjuvants, Immunologic/pharmacology ; Anti-Bacterial Agents/pharmacology ; Antitubercular Agents/pharmacology ; Cell Line ; Drug Therapy, Combination/methods ; Ethambutol/pharmacology ; Glutathione/*pharmacology ; Humans ; Isoniazid/pharmacology ; Microbial Sensitivity Tests/methods ; Mycobacterium tuberculosis/drug effects ; Pyrazinamide/pharmacology ; Rifampin/pharmacology ; THP-1 Cells/drug effects ; Tuberculosis/*drug therapy ; Tuberculosis, Multidrug-Resistant/drug therapy ; }, abstract = {Mycobacterium tuberculosis is the etiological agent that is responsible for causing tuberculosis (TB), which continues to affect millions of people worldwide, and the rate of resistance of M. tuberculosis to antibiotics is ever increasing. We tested the synergistic effects of N-acetyl cysteine (NAC; the precursor molecule for the synthesis of glutathione [GSH]) and individual first-line antibiotics typically given for the treatment of TB, such as isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA), to improve the ability of macrophages to control intracellular M. tuberculosis infection. GSH, a pleiotropic antioxidant molecule, has previously been shown to display both antimycobacterial and immune-enhancing effects. Our results indicate that there was not only an increase in beneficial immunomodulatory effects but also a greater reduction in the intracellular viability of M. tuberculosis when macrophages were treated with the combination of antibiotics (INH, RIF, EMB, or PZA) and NAC.}, }
@article {pmid30125844, year = {2018}, author = {Ma, J and Li, X}, title = {Insight into the negative impact of ionic liquid: A cytotoxicity mechanism of 1-methyl-3-octylimidazolium bromide.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {242}, number = {Pt B}, pages = {1337-1345}, doi = {10.1016/j.envpol.2018.08.003}, pmid = {30125844}, issn = {1873-6424}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cytochromes c/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Heme Oxygenase-1/metabolism ; Hep G2 Cells ; Humans ; Imidazoles/*toxicity ; Ionic Liquids/*toxicity ; Mitochondria/drug effects/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Ionic liquids (ILs) as a green replacement for volatile organic solvents are increasingly used in large-scale commercial applications. A good understanding of the toxic mechanisms and environmental impact of ILs is neede to reduce the risk for human health and the environment. For this purpose, we aimed to evaluate the possible impacts of 1-methyl-3-octylimidazolium bromide ([C8mim]Br) exposure on human hepatocellular carcinoma (HepG2) cells as to elucidate the cytotoxic mechanism of [C8mim]Br. Biochemical assays revealed that [C8mim]Br exposure altered the protein levels of heat shock protein 70 (HSP70) and HSP90, generally inhibiting total antioxidative capacity (T-AOC), depleting heme oxygenase-1 (HO-1) and increasing transcription and activity of inducible nitric oxide synthase (iNOS) in HepG2 cells. These results indicated that [C8mim]Br may induce biochemical disturbances and cause oxidative stress in HepG2 cells. Moreover, increased phosphorylation of p53, mitochondrial membrane disruption, cyclooxygenase-2 activation, Bcl-2 family protein modulation, cytochrome c and Smac/DIABLO release, and inhibition of apoptosis inhibitory protein-2 (c-IAP2) and survivin were also observed in [C8mim]Br-treated cells, suggesting that [C8mim]Br-induced apoptosis might be mediated by the mitochondrial pathway. Further research showed that [C8mim]Br exposure increased tumour necrosis factor α (TNF-α) transcription and content and promoted the expression of Fas and FasL, indicating that TNF-α and Fas/FasL are involved in the apoptosis induced by [C8mim]Br. Additionally, [C8mim]Br cytotoxicity was partly inhibited by N-acetyl-cysteine (NAC), and NAC reversed [C8mim]Br-mediated mitochondrial dysfunction and blocked apoptotic events by inhibiting the generation of reactive oxygen species (ROS). This work first demonstrated that the ROS-mediated mitochondrial and death receptor-initiated apoptotic pathway is involved in [C8mim]Br-induced HepG2 cell apoptosis.}, }
@article {pmid30124146, year = {2018}, author = {Kabra, A and Sharma, R and Kabra, R and Baghel, US}, title = {Emerging and Alternative Therapies For Parkinson Disease: An Updated Review.}, journal = {Current pharmaceutical design}, volume = {24}, number = {22}, pages = {2573-2582}, doi = {10.2174/1381612824666180820150150}, pmid = {30124146}, issn = {1873-4286}, mesh = {Antiparkinson Agents/chemistry/*therapeutic use ; Complementary Therapies/*methods ; Humans ; *Neurosurgical Procedures ; Parkinson Disease/*therapy ; }, abstract = {Parkinson's disease (PD) is standout amongst the most common neurodegenerative malady with unpredictable dynamic pathology. At present, accessible traditional choices for PD have certain impediments of their own, and subsequently persistent consistence and fulfillment are low. Current contemporary treatment options just give symptomatic alleviation constrained control to anticipate malady progression, bringing about poor patient consistence and fulfilment. Numerous rising pharmacotherapies for PD are in various phases of medical improvement. Treatments incorporate adenosine A2A receptor antagonists, anti-apoptotic agents, monoamine oxidase inhibitors, glutamate receptor antagonists, and antioxidants for example, N-acetyl cysteine, edaravone, and coenzyme Q10. Other rising nonpharmacotherapies incorporate microRNAs, viral vector gene therapy, stem cells transglutaminases, RTP801, and glial derived neurotrophic factor (GDNF). Furthermore, surgeries including profound pallidotomy, deep brain stimulation, thalamotomy and gamma knife surgery have developed as elective mediations for cutting edge PD patients who have totally used common medications and still suffer from unrelenting motor symptoms. Complementary and Alternative medicine (CAM) modalities, such as Yoga, acupuncture, Tai Chi, Music therapies are highly practiced in several countries, offer some of the safer and effective treatment modalities for PD. While a few of these treatments hold much assurance in postponing the beginning of ailment and moderating its progression, more pharmacotherapies and careful mediations should be examined in various phases of PD. Therefore, the main objective of our review is to fill the gap between the researches and provide updated and productive information about the research reported in the last couple of years and can fulfil the most reassuring plausibility for encourage treatment of Parkinson Disease.}, }
@article {pmid30119245, year = {2018}, author = {Demiroren, K and Basunlu, MT and Erten, R and Cokluk, E}, title = {A comparison of the effects of thymoquinone, silymarin and N-acetylcysteine in an experimental hepatotoxicity.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {106}, number = {}, pages = {1705-1712}, doi = {10.1016/j.biopha.2018.07.125}, pmid = {30119245}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology ; Actins/metabolism ; Alanine Transaminase/blood ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Becaplermin/blood ; Benzoquinones/*pharmacology ; Biomarkers/blood ; Carbon Tetrachloride ; Chemical and Drug Induced Liver Injury/blood/etiology/pathology/*prevention &amp; control ; Cytoprotection ; Disease Models, Animal ; Glutathione/metabolism ; Hepatic Stellate Cells/drug effects/metabolism/pathology ; Interleukin-6/blood ; Liver/*drug effects/metabolism/pathology ; Male ; Oxidative Stress/*drug effects ; Rats, Wistar ; Silymarin/*pharmacology ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {This study investigated the effects of thymoquinone, silymarin, and N-acetylcysteine in a rat model with carbon tetrachloride (CCl4)-induced hepatotoxicity. Although numerous similar studies are available, we aimed to compare the efficacy of these agents by considering N-acetylcysteine as a reference compound. A total of 50 male Wistar albino rats were randomly designated as 5 groups: Group I, CCl4; group II, thymoquinone and CCl4; group III, silymarin and CCl4; group IV, N-acetylcysteine and CCl4; group V, control group. CCl4 was administered intraperitoneally at a dose of 1.5 mL/kg (a mixture of CCl4: olive oil, 1:2) twice a week. Thymoquinone was administered at a dose of 10 mg/kg, silymarin was administered at a dose of 100 mg/kg, and N-acetylcysteine was administered at a dose of 100 mg/kg by daily intraperitoneal injection. At the end of four weeks, blood and liver tests were analyzed. The results were evaluated statistically via the one-way ANOVA test. A p-value <0.05 was considered statistically significant. Thymoquinone, silymarin, and N-acetylcysteine improved the levels of alanine aminotransferase, tumor necrosis factor-α, platelet-derived growth factor-BB, and interleukin-6, which were increased by CCl4. Thymoquinone and silymarin showed the positive increase in liver glutathione levels. Thymoquinone, silymarin, and N-acetylcysteine improved blood total oxidant status. In the histological examinations of liver tissue, thymoquinone decreased necrosis, and inflammation. The most positive decrease in the α-smooth muscle actin-stained hepatic stellate cell count was only observed with thymoquinone. These findings suggest that thymoquinone, silymarin, and N-acetylcysteine have potential for the treatment of diseases causing liver injury. Among these agents, thymoquinone showed the best results on most of the parameters. Since TQ appears to be at least as effective as SM and NAC in our in-vitro study, we propose that it is time for clinical studies with thymoquinone on hepatotoxicity.}, }
@article {pmid30118760, year = {2018}, author = {Hu, Z and Wang, F and Wu, Z and Gu, H and Dong, N and Jiang, X and Xu, J and Wu, Z and Wechsler, DS and Zheng, D}, title = {FOXO3a-dependent up-regulation of Mxi1-0 promotes hypoxia-induced apoptosis in endothelial cells.}, journal = {Cellular signalling}, volume = {51}, number = {}, pages = {233-242}, doi = {10.1016/j.cellsig.2018.08.009}, pmid = {30118760}, issn = {1873-3913}, mesh = {Acetylcysteine/metabolism ; *Apoptosis ; Basic Helix-Loop-Helix Transcription Factors/genetics/*metabolism ; Caspase 8/metabolism ; Cell Hypoxia ; Cells, Cultured ; Forkhead Box Protein O3/genetics/*metabolism ; Gene Expression Regulation/genetics ; Human Umbilical Vein Endothelial Cells/*metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Tumor Suppressor Proteins/genetics/*metabolism ; Up-Regulation ; }, abstract = {Endothelial cell apoptosis induced by hypoxia is implicated in the pathogenesis of vascular diseases. However, the underlying mechanism is not clearly elucidated. In this study, we found that hypoxia increased Mxi1-0 expression, and the Mxi1-0 siRNA could inhibit caspase-8 activation and apoptosis in HUVECs induced by hypoxia. In addition, hypoxia induced FOXO3 activation, while Mxi1-0 expression and apoptosis were inhibited by transfection with FOXO3 siRNA. Using ChIP assay, we confirmed that FOXO3a binds to the Mxi1-0 promoter region. Furthermore, hypoxia treatment leads to remarkable production of reactive oxygen species (ROS), while ROS scavenger N-acetyl-L-cysteine (NAC) inhibits hypoxia-induced ROS production, apoptosis and FOXO3a-mediated Mxi1-0 up-regulation. Finally, we found that the HIF-1α siRNA inhibited hypoxia-induced HIF-1α expression and ROS production, as well as FOXO3a/Mxi1-0 activation and apoptosis in HUVECs. Taken together, this study identifies a HIF-1α/FOXO3a/Mxi1-0/caspase-8 signaling pathway in hypoxia-induced endothelial cell apoptosis. These data also indicate that HIF-1α-dependent ROS production is required for FOXO3a-mediated Mxi1-0 up-regulation and apoptosis in hypoxic endothelial cells.}, }
@article {pmid30116486, year = {2018}, author = {Zheng, X and Jia, B and Tian, XT and Song, X and Wu, ML and Kong, QY and Li, H and Liu, J}, title = {Correlation of Reactive Oxygen Species Levels with Resveratrol Sensitivities of Anaplastic Thyroid Cancer Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {6235417}, pmid = {30116486}, issn = {1942-0994}, mesh = {Antioxidants/pharmacology/*therapeutic use ; Humans ; Reactive Oxygen Species/*metabolism ; Resveratrol/pharmacology/*therapeutic use ; Thyroid Carcinoma, Anaplastic/*diagnosis ; }, abstract = {Anaplastic thyroid carcinoma (ATC) is the most lethal thyroid malignancy without a reliable therapeutic agent. Resveratrol possesses cancer-suppressive effects, while its effect(s) on ATC cells remains unknown. Because oxidative damage caused by increased reactive oxygen species (ROS) is one of the therapeutic effects of anticancer drugs and oxidative stress-caused mitochondria swelling is observed in resveratrol-treated cancer cells, the oxidative statuses and their relevance with resveratrol sensitivities are elucidated using THJ-16T and THJ-11T ATC cells established from two human anaplastic thyroid carcinoma cases. The results revealed that resveratrol-treated THJ-16T rather than THJ-11T cells showed remarkable growth arrest and extensive apoptosis accompanied with the elevated ROS generation and the attenuated superoxide dismutase 2 (SOD2) and catalase (CAT) levels. Mitochondrial impairment and the enhanced caspase-9/caspase-3 activation are found only in resveratrol-sensitive THJ-16T cells. Treatment with the antioxidant N-acetylcysteine (NAC) partly attenuated resveratrol-induced ROS generation and apoptosis of THJ-16T cells. The levels of resveratrol metabolic enzymes (SULT1A1 and SULT1C2) in THJ-16T cells were lower than those in THJ-11T cells and therefore reversely related with resveratrol sensitivities of ATC cells. Our findings demonstrate the ability of resveratrol to increase ROS generation and oxidative-related cellular lesions in resveratrol-sensitive THJ-16T cells presumably through activating the ROS-mitochondrial signal pathway. The levels of SULTs and ROS may reflect the response manners of ATC cells to resveratrol.}, }
@article {pmid30116167, year = {2018}, author = {Elbaky, NAA and El-Orabi, NF and Fadda, LM and Abd-Elkader, OH and Ali, HM}, title = {Role of N-Acetylcysteine and Coenzyme Q10 in the Amelioration of Myocardial Energy Expenditure and Oxidative Stress, Induced by Carbon Tetrachloride Intoxication in Rats.}, journal = {Dose-response : a publication of International Hormesis Society}, volume = {16}, number = {3}, pages = {1559325818790158}, pmid = {30116167}, issn = {1559-3258}, abstract = {This study is designed to evaluate the potential impact of N-acetyl cysteine (NAC) and coenzyme Q10 (CoQ10) each alone or in combination against carbon tetrachloride (CCl4)-induced cardiac damage in rats. Animals were treated with CCl4 in single intraperitoneal dose of 1 mL/Kg body weight; CCl4-intoxicated animals were pretreated with 20 mg/kg/d NAC or pretreated with 200 mg/kg/d CoQ10 or NAC and CoQ10 with the same previously mentioned doses. Carbon tetrachloride-intoxicated rats showed a significant elevation in nitric oxide and lipid peroxides and downregulation in reduced glutathione level and calcium adenosine triphosphatase. Cardiac glycolytic enzymes levels such as lactate dehydrogenase, phosphofructokinase, and hexokinase were declined coupled with a reduction in glucose content after CCl4 treatment. Moreover, myocardial hydroxyproline level was significantly increased after CCl4-treatment indicating accumulation of interstitial collagen. N-acetyl cysteine and/or CoQ10 effectively alleviated the disturbances in myocardial oxidative stress and antioxidant markers. These antioxidants effectively upregulated the reduction in cardiac energetic biomarkers due to CCl4 treatment. N-acetyl cysteine and/or CoQ10 significantly decreased hydroxyproline level compared to that of CCl4-treated rats. The current data showed that the aforementioned antioxidants have a remarkable cardioprotective effect, suggesting that they may be useful as prophylactic agents against the detrimental effects of cardiotoxins.}, }
@article {pmid30114478, year = {2018}, author = {Giustarini, D and Galvagni, F and Dalle Donne, I and Milzani, A and Severi, FM and Santucci, A and Rossi, R}, title = {N-acetylcysteine ethyl ester as GSH enhancer in human primary endothelial cells: A comparative study with other drugs.}, journal = {Free radical biology &amp; medicine}, volume = {126}, number = {}, pages = {202-209}, doi = {10.1016/j.freeradbiomed.2018.08.013}, pmid = {30114478}, issn = {1873-4596}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Cell Proliferation/*drug effects ; Culture Media/chemistry/pharmacology ; Cysteine/chemistry ; Endothelial Cells/drug effects ; Ethyl Ethers/chemistry/*pharmacology ; Glutathione/analogs &amp; derivatives/chemistry/*metabolism/pharmacology ; Human Umbilical Vein Endothelial Cells/drug effects ; Humans ; Pyrrolidonecarboxylic Acid/chemistry/pharmacology ; Thiazolidines/chemistry/pharmacology ; }, abstract = {Several drugs are currently in use as glutathione (GSH) enhancers in clinical, pre-clinical and experimental research. Here we compare the ability of N-acetylcysteine (NAC), 2-oxothiazolidine-4-carboxylic acid (OTC), glutathione ethyl ester (GSH-EE) and N-acetylcysteine ethyl ester (NACET) to increase the intracellular concentration of GSH using primary human umbilical vein endothelial cells (HUVEC) as in vitro model. Our experiments highlighted that NACET is largely the most efficient molecule in increasing the intracellular levels of GSH, cysteine, and γ-glutamylcysteine. This is because NACET is lipophilic and can freely cross plasma membrane but, inside the cell, it is de-esterified to the more hydrophilic NAC, which, in turn, is trapped into the cell and slowly transformed into cysteine. The higher availability of cysteine is matched by an increase in GSH synthesis, cysteine availability being the rate limiting step for this reaction. Surprisingly, the increase in GSH concentration was not linear but peaked at 0.5 mM NACET and gradually decreased when cells were treated with higher concentrations of NACET. We demonstrated that this puzzling ceiling effect was due to the fact that NAC released from NACET turned out to be a competitive inhibitor of the enzyme glutamate-cysteine ligase, with a Ki value of 3.2 mM. By using a cell culture medium lacking of cysteine and methionine, we could demonstrate that the slight increase in intracellular levels of cysteine and GSH induced by NAC in HUVEC grown in standard medium was due to the reduction of the cystine present in the medium itself there rather than to the action of NAC as Cys pro-drug. This fact may explain why NAC works well as GSH enhancer at very high concentrations in pre-clinical and in vitro studies, whereas it failed in most clinical trials.}, }
@article {pmid30112986, year = {2019}, author = {Song, W and Liu, M and Wu, J and Zhai, H and Chen, Y and Peng, Z}, title = {Preclinical Pharmacokinetics of Triptolide: A Potential Antitumor Drug.}, journal = {Current drug metabolism}, volume = {20}, number = {2}, pages = {147-154}, doi = {10.2174/1389200219666180816141506}, pmid = {30112986}, issn = {1875-5453}, mesh = {Animals ; Antineoplastic Agents/*pharmacokinetics/toxicity ; Diterpenes/*pharmacokinetics/toxicity ; Drug Interactions ; Epoxy Compounds/pharmacokinetics/toxicity ; Humans ; Phenanthrenes/*pharmacokinetics/toxicity ; }, abstract = {BACKGROUND: Triptolide, a bioactive component in Tripterygium wilfordii extracts, possess strong antiproliferative activity on all 60-National Cancer Institute (NCI) cancer cell lines. However, the widespread use of triptolide in the clinical practice is greatly limited for its multi-organ toxicity and narrow therapeutic window. All the toxic characteristics of triptolide are associated with the pharmacokinetics especially its distribution and accumulation in the target organ.<br><br>METHODS: The literature review was done using PubMed search, SciFinder and Google Scholar databases with specific keywords such as triptolide, pharmacokinetics, drug-drug interaction, transporters, metabolism, modification to collect the related full-length articles and abstracts from 2000 to 2018.<br><br>RESULTS: Oral triptolide is rapidly and highly absorbed. Grapefruit juice affects oral absorption, increasing the area under the concentration-time curve (AUC) by 153 % and the maximum concentration (Cmax) by 141 %. The AUC and the Cmax are not dose proportional. Triptolide distributes into the liver, heart, spleen, lung and kidney. Biotransformation of triptolide in rats includes hydroxylation, sulfate, glucuronide, N-acetylcysteine (NAC) and Glutathione (GSH) conjugation and combinations of these pathways. Less than 4 % of triptolide was recovered from the feces, bile and urine within 24 h. After repeating dosage, triptolide was eliminated quickly without accumulation in vivo. As a substrate of P-glycoprotein (P-gp) and CYP3A4, triptolide could have clinically significant pharmacokinetic interactions with those proteins substrates/inhibitors.<br><br>CONCLUSION: The findings of this review confirm the importance of pharmacokinetic character for understanding the pharmacology and toxicology of triptolide.}, }
@article {pmid30111318, year = {2018}, author = {Park, HJ and Lee, DG and Seong, JB and Lee, HS and Kwon, OS and Kang, BS and Park, JW and Lee, SR and Lee, DS}, title = {Peroxiredoxin I maintains luteal function by regulating unfolded protein response.}, journal = {Reproductive biology and endocrinology : RB&amp;E}, volume = {16}, number = {1}, pages = {79}, pmid = {30111318}, issn = {1477-7827}, support = {NRF-2017R1A2B4008176//National Research Foundation of Korea (KR)/ ; NRF-2015R1A4A1042271//National Research Foundation of Korea (KR)/ ; KGM4611821//Korea Research Institute of Bioscience and Biotechnology/ ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/genetics ; Cholagogues and Choleretics/pharmacology ; Corpus Luteum/drug effects/*metabolism ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress ; Female ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Mice, Inbred C57BL ; Mice, Knockout ; Peroxiredoxins/genetics/*metabolism ; Progesterone/blood ; *Signal Transduction ; Taurochenodeoxycholic Acid/pharmacology ; *Unfolded Protein Response ; }, abstract = {BACKGROUND: Mounting evidence shows that ROS regulation by various antioxidants is essential for the expression of enzymes involved in steroidogenesis and maintenance of progesterone production by the corpus luteum (CL). However, the underlying mechanisms of peroxiredoxin 1 (PRDX1), an antioxidant enzyme, in luteal function for progesterone production in mice have not been reported. The aim of this study was to evaluate the functional link between PRDX1 and progesterone production in the CL of Prdx1 knockout (K/O) mice in the functional stage of CL.<br><br>METHODS: The expression pattern of the unfolded protein response (UPR) signaling pathways, endoplasmic reticulum (ER) stress-induced apoptosis related genes and peroxiredoxins 1 (PRDX1) were investigated by western blotting analysis in CL tissue of 10&#xa0;weeks mice during functional stage of CL. The protein levels of these genes after ER-stress inducer tunicamycin (Tm), ER-stress inhibitor tauroursodeoxycholic acid (TUDCA) and ROS scavenger, N-acetylcysteine (NAC) stimulation by intraperitoneal (i.p) injection were also investigated in CL tissue of wild type (WT) mice. Finally, we examined progesterone production and UPR signaling related gene expression in CL tissue of Prdx1 K/O mice.<br><br>RESULTS: We demonstrated that PRDX1 deficiency in the functional stage activates the UPR signaling pathways in response to ER stress-induced apoptosis. Interestingly, CL number, serum progesterone levels, and steroidogenic enzyme expression in Prdx1 K/O mice decreased significantly, compared to those in wild type mice. Levels of UPR signaling pathway markers (GRP78/BIP, P50ATF6, and phosphorylated (p)-eIF2) and ER-stress associated apoptotic factors (CHOP, p-JNK, and cleaved caspase-3) were dramatically increased in the CL tissue of Prdx1 K/O mice. In addition, administration of the NAC, reduced progesterone production and activated ER-stress-induced UPR signaling in the CL tissue obtained from the ovary of Prdx1 K/O mice. Taken together, these results indicated that reduction in serum progesterone levels and activation of ER-stress-induced UPR signaling are restored by NAC injection in the CL of Prdx1 K/O mice.<br><br>CONCLUSION: These observations provide the first evidence regarding the basic mechanisms connecting PRDX1 and progesterone production in the functional stage of CL.}, }
@article {pmid30108739, year = {2017}, author = {Liu, S and Zhao, Y and He, R and Kong, L and Xi, J and Sun, J and Shao, Y and Pan, X and Zhang, J and Zhuang, R}, title = {Identification of novel N-acetylcysteine derivatives for the treatment of hepatocellular injury.}, journal = {MedChemComm}, volume = {8}, number = {12}, pages = {2238-2247}, pmid = {30108739}, issn = {2040-2503}, abstract = {New anti-hepatocellular injury drugs with better curative effects and fewer side effects are urgently needed at present. In this study, a series of novel N-acetylcysteine (NAC) derivatives were designed, synthesized and biologically evaluated for their anti-hepatocellular injury activities against two different cell models. In the biological evaluation against hydrogen peroxide (H2O2)-induced LO2 hepatocytes, half of the target compounds exhibited moderate to potent activities in improving the model cell viability, and two compounds (6a and 6b) displayed more potent activities in decreasing malondialdehyde (MDA) levels than the positive control NAC. In further 4-acetamidophenol (APAP)-induced LO2 cell experiment, compounds 6a and 6b could not only improve the cell viability but also significantly reduce the secretion of MDA. Additionally, compound 6a displayed excellent Caco-2 permeability and oral bioavailability in rats. All these experimental results suggested that compounds 6a and 6b could serve as potential lead molecules for further development of anti-hepatocellular injury drugs.}, }
@article {pmid30107137, year = {2018}, author = {Garg, G and Singh, S and Singh, AK and Rizvi, SI}, title = {N-acetyl-l-cysteine attenuates oxidative damage and neurodegeneration in rat brain during aging.}, journal = {Canadian journal of physiology and pharmacology}, volume = {96}, number = {12}, pages = {1189-1196}, doi = {10.1139/cjpp-2018-0209}, pmid = {30107137}, issn = {1205-7541}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/*pharmacology ; Aging/*drug effects/metabolism ; Animals ; Antioxidants/pharmacology ; Biomarkers/metabolism ; Brain/*drug effects/metabolism ; Disease Models, Animal ; Down-Regulation/drug effects ; Inflammation/metabolism ; Male ; Neurodegenerative Diseases/*drug therapy/metabolism ; Nitric Oxide/metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Sodium-Potassium-Exchanging ATPase/metabolism ; Up-Regulation/drug effects ; }, abstract = {N-acetyl-l-cysteine (NAC) is a precursor of cysteine, which is known to increase the level of glutathione (GSH) in the brain. Several neurodegenerative changes linked to oxidative stress take place in the aging brain. This study aimed to assess the neuroprotective effect of NAC supplementation on age-dependent neurodegeneration in the rat brain. Young (4 months) and old (24 months) Wistar rats (n = 6 rats/group) were supplemented with NAC (100 mg/kg b.w. orally) for 14 days. Enzymatic and nonenzymatic antioxidants such as superoxide dismutase and catalase, and GSH and total thiol respectively, prooxidants such as protein carbonyl, advanced oxidation protein products, reactive oxygen species, and malondialdehyde were assessed in the brain homogenates. Furthermore, nitric oxide level, acetylcholinesterase activity, and Na[+]/K[+]-ATPase activity were measured and gene expression studies were also performed. The results indicated that NAC augmented the level of enzymatic and nonenzymatic antioxidants with a significant reduction in prooxidant levels in old rats. NAC supplementation also downregulated the expression of inflammatory markers (TNF-α, IL-1β, IL-6) and upregulated the expression of marker genes associated with aging (sirtuin-1) and neurodegeneration (neuron-specific enolase, neuroglobin, synapsin-I, myelin basic protein 2) in old rats. The present findings support a neuroprotective role of NAC which has therapeutic implication in controlling age-related neurological disorders.}, }
@article {pmid30106438, year = {2018}, author = {Dong, X and Ni, B and Fu, J and Yin, X and You, L and Leng, X and Liang, X and Ni, J}, title = {Emodin induces apoptosis in human hepatocellular carcinoma HepaRG cells via the mitochondrial caspase‑dependent pathway.}, journal = {Oncology reports}, volume = {40}, number = {4}, pages = {1985-1993}, pmid = {30106438}, issn = {1791-2431}, mesh = {Apoptosis/*drug effects ; Carcinoma, Hepatocellular/drug therapy/metabolism/*pathology ; Caspases/*metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Emodin/*pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Liver Neoplasms/drug therapy/metabolism/*pathology ; Membrane Potential, Mitochondrial/*drug effects ; Mitochondria/drug effects/enzymology/*pathology ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, abstract = {Emodin‑induced hepatotoxicity in vivo and in vitro has been gaining increasing attention. However, the exact molecular pathways underlying these effects remain poorly clarified. The aim of the present study was to evaluate the cytotoxic effect of emodin on HepaRG cells and to define the underlying mechanism. The results demonstrated that emodin evidently inhibited HepaRG cell growth in a dose‑ and time‑dependent manner by blocking cell cycle progression in the S and G2/M phase and by inducing apoptosis. Emodin treatment also resulted in generation of reactive oxygen species (ROS), which abrogated mitochondrial membrane potential (MMP). The above effects were all suppressed by antioxidants, such as N‑acetylcysteine (NAC). Further studies by western blot analysis howed that emodin upregulated p53, p21, Bax, cyclin E, cleaved caspase‑3, 8 and 9, and cleaved poly(ADP‑ribose)polymerase (PARP). However, the protein expression of Bcl‑2, cyclin A and CDK2 was downregulated. Taken together, our results suggest that emodin induces apoptosis via the mitochondrial apoptosis pathway through cell cycle arrest and ROS generation in HepaRG cells.}, }
@article {pmid30106373, year = {2018}, author = {L'honoré, A and Commère, PH and Negroni, E and Pallafacchina, G and Friguet, B and Drouin, J and Buckingham, M and Montarras, D}, title = {The role of Pitx2 and Pitx3 in muscle stem cells gives new insights into P38α MAP kinase and redox regulation of muscle regeneration.}, journal = {eLife}, volume = {7}, number = {}, pages = {}, pmid = {30106373}, issn = {2050-084X}, support = {Marie Curie IRG 248496//Seventh Framework Programme/International ; Postdoc Fellowship//Fondation pour la Recherche M&#xe9;dicale/International ; REGSAT//Agence Nationale de la Recherche/International ; ANR-10-LABX-73//Agence Nationale de la Recherche/International ; OptiStem 223098//Seventh Framework Programme/International ; Postdoc Fellowship//AFM-T&#xe9;l&#xe9;thon/International ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Cell Differentiation/genetics ; Cellular Senescence/genetics ; Homeodomain Proteins/*genetics ; Mice ; Mitogen-Activated Protein Kinase 14/*genetics ; Muscle, Skeletal/cytology ; Mutation ; Oxidation-Reduction ; Reactive Oxygen Species ; Regeneration/*genetics ; Satellite Cells, Skeletal Muscle ; Stem Cells/cytology ; Transcription Factors/*genetics ; Homeobox Protein PITX2 ; }, abstract = {Skeletal muscle regeneration depends on satellite cells. After injury these muscle stem cells exit quiescence, proliferate and differentiate to regenerate damaged fibres. We show that this progression is accompanied by metabolic changes leading to increased production of reactive oxygen species (ROS). Using Pitx2/3 single and double mutant mice that provide genetic models of deregulated redox states, we demonstrate that moderate overproduction of ROS results in premature differentiation of satellite cells while high levels lead to their senescence and regenerative failure. Using the ROS scavenger, N-Acetyl-Cysteine (NAC), in primary cultures we show that a physiological increase in ROS is required for satellite cells to exit the cell cycle and initiate differentiation through the redox activation of p38α MAP kinase. Subjecting cultured satellite cells to transient inhibition of P38α MAP kinase in conjunction with NAC treatment leads to their rapid expansion, with striking improvement of their regenerative potential in grafting experiments.}, }
@article {pmid30104262, year = {2018}, author = {Scott, A and Lugg, ST and Aldridge, K and Lewis, KE and Bowden, A and Mahida, RY and Grudzinska, FS and Dosanjh, D and Parekh, D and Foronjy, R and Sapey, E and Naidu, B and Thickett, DR}, title = {Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages.}, journal = {Thorax}, volume = {73}, number = {12}, pages = {1161-1169}, pmid = {30104262}, issn = {1468-3296}, support = {G1100196/MRC_/Medical Research Council/United Kingdom ; MR/N021185/1//Medical Research Council/United Kingdom ; MR/J011266/1/MRC_/Medical Research Council/United Kingdom ; MR/L008335/1/MRC_/Medical Research Council/United Kingdom ; MR/L002736/1//Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Survival/drug effects ; Chemokine CCL2/metabolism ; Complex Mixtures/*adverse effects ; *Electronic Nicotine Delivery Systems ; Gases/*adverse effects ; Humans ; Inflammation/etiology/metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Macrophages, Alveolar/*pathology/*physiology ; Matrix Metalloproteinase 9/metabolism ; Necrosis/etiology ; Nicotine/adverse effects ; Phagocytosis/drug effects ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/metabolism ; THP-1 Cells ; Tumor Necrosis Factor-alpha/metabolism ; Vaping/adverse effects ; }, abstract = {OBJECTIVE: Vaping may increase the cytotoxic effects of e-cigarette liquid (ECL). We compared the effect of unvaped ECL to e-cigarette vapour condensate (ECVC) on alveolar macrophage (AM) function.<br><br>METHODS: AMs were treated with ECVC and nicotine-free ECVC (nfECVC). AM viability, apoptosis, necrosis, cytokine, chemokine and protease release, reactive oxygen species (ROS) release and bacterial phagocytosis were assessed.<br><br>RESULTS: Macrophage culture with ECL or ECVC resulted in a dose-dependent reduction in cell viability. ECVC was cytotoxic at lower concentrations than ECL and resulted in increased apoptosis and necrosis. nfECVC resulted in less cytotoxicity and apoptosis. Exposure of AMs to a sub-lethal 0.5% ECVC/nfECVC increased ROS production approximately 50-fold and significantly inhibited phagocytosis. Pan and class one isoform phosphoinositide 3 kinase inhibitors partially inhibited the effects of ECVC/nfECVC on macrophage viability and apoptosis. Secretion of interleukin 6, tumour necrosis factor &#x3b1;, CXCL-8, monocyte chemoattractant protein 1 and matrix metalloproteinase 9 was significantly increased following ECVC challenge. Treatment with the anti-oxidant N-acetyl-cysteine (NAC) ameliorated the cytotoxic effects of ECVC/nfECVC&#x2009;to levels not significantly different from baseline and restored phagocytic function.<br><br>CONCLUSIONS: ECVC is significantly more toxic to AMs than non-vaped ECL. Excessive production of ROS, inflammatory cytokines and chemokines induced by e-cigarette vapour may induce an inflammatory state in AMs within the lung that is partly dependent on nicotine. Inhibition of phagocytosis also suggests users may suffer from impaired bacterial clearance. While further research is needed to fully understand the effects of e-cigarette exposure in humans in vivo, we caution against the widely held opinion that e-cigarettes are safe.}, }
@article {pmid30103798, year = {2018}, author = {Tsay, TB and Yang, MC and Chang, WH and Chen, PH and Chen, LW}, title = {Lactobacillus salivarius reverse antibiotic-induced lung defense impairment in a ventilator model.}, journal = {Journal of translational medicine}, volume = {16}, number = {1}, pages = {225}, pmid = {30103798}, issn = {1479-5876}, support = {NSC101-2314-B-010-005-MY3//National Science Council/International ; VGHKS100-055//Kaohsiung Veterans General Hospital/International ; ZBH 106-12//Zuoying Armed Forces General Hospital/International ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Bacterial Agents/*adverse effects ; DNA/metabolism ; Hormones, Ectopic/metabolism ; Intercellular Signaling Peptides and Proteins ; Intestinal Mucosa/drug effects/pathology ; Ligilactobacillus salivarius/*physiology ; Lung/*immunology/microbiology/pathology ; Macrophages, Alveolar/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Myeloid Differentiation Factor 88/metabolism ; NF-kappa B/metabolism ; Neutrophil Infiltration/drug effects ; Pancreatitis-Associated Proteins/metabolism ; Peroxynitrous Acid/metabolism ; Phagocytosis/drug effects ; Pneumonia/complications ; Protein Binding/drug effects ; Pseudomonas aeruginosa/drug effects ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 4/metabolism ; *Ventilators, Mechanical ; }, abstract = {BACKGROUND: Widespread use of antibiotics in the intensive care unit is a potential cause of the emergence of hospital-acquired pneumonia. This study determined whether Lactobacillus salivarius feeding could reverse antibiotic-induced lung defense impairment in a ventilator model.<br><br>METHODS: C57BL/6 wild-type (WT) mice received mechanical ventilation for 3&#xa0;h after intramuscular antibiotic treatment for 6&#xa0;days. Treatment with dead Lactobacillus salivarius and fructo-oligosaccharides (FOS) feeding were used to stimulate antibacterial protein expression in the intestine. Reactive oxygen species (ROS) in the intestinal mucosa was detected using 2'7'-dichlorofluorescein diacetate. The peroxynitrite production of alveolar macrophages (AMs) was measured using dihydrorhodamine 123 oxidation assay. N-acetylcysteine (NAC), an ROS scavenger, was orally administered to mice receiving antibiotics with FOS feeding.<br><br>RESULTS: Antibiotic treatment decreased Pseudomonas aeruginosa (PA) phagocytic activity and activity of AMs and protein expression of regenerating islet-derived protein 3&#x3b2; (Reg3&#x3b2;) as well as Toll-like receptor 4 (TLR4) in the intestinal mucosa in the ventilator model. Antibiotic treatment also decreased ROS production in the intestinal mucosa, peroxynitrite production of AMs, and RELM&#x3b2; expression as well as NF-&#x3ba;B DNA binding activity of the intestinal mucosa in WT mice but not in MyD88[-/-] mice. Treatment with dead L. salivarius or FOS feeding increased ROS production, bacterial killing activity, and protein expression of Reg3&#x3b2; as well as TLR4 in the intestinal mucosa and reversed the inhibitory effects of antibiotics on PA phagocytic activity of AMs.<br><br>CONCLUSION: Taken together with the finding that ablation of FOS-induced intestinal ROS using NAC decreased peroxynitrite production as well as PA phagocytic activity of AMs and protein expression of CRP-ductin, IL-17, Reg3&#x3b2;, and RELM&#x3b2; in the intestinal mucosa, we conclude that commensal microflora plays a key role in stimulating lung immunity. Intestinal ROS plays a role as a predictive indicator and modulator of pulmonary defense mechanisms. Antibiotic treatment reduces lung defense against PA infection through the decrease in intestinal Reg3&#x3b2; and TLR4 expression. Treatment with dead L. salivarius or FOS feeding reverses the antibiotic-induced lung defense impairment through the intestinal ROS/MyD88 pathways.}, }
@article {pmid30092096, year = {2018}, author = {Buranasin, P and Mizutani, K and Iwasaki, K and Pawaputanon Na Mahasarakham, C and Kido, D and Takeda, K and Izumi, Y}, title = {High glucose-induced oxidative stress impairs proliferation and migration of human gingival fibroblasts.}, journal = {PloS one}, volume = {13}, number = {8}, pages = {e0201855}, pmid = {30092096}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Adult ; Aged ; Antioxidants/pharmacology ; Cell Movement/drug effects/*physiology ; Cell Proliferation/drug effects/*physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Female ; Fibroblasts/drug effects/*metabolism/pathology ; Gingiva/drug effects/injuries/*metabolism/pathology ; Glucose/*adverse effects/metabolism ; Heme Oxygenase-1/metabolism ; Humans ; Male ; Middle Aged ; Oxidative Stress/drug effects/*physiology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase-1/metabolism ; Wound Healing/drug effects/physiology ; }, abstract = {Delayed gingival wound healing is widely observed in periodontal patients with diabetes. However, the molecular mechanisms of the impaired function of gingival fibroblasts in diabetes remain unclear. The purpose of this study was to investigate changes in the properties of human gingival fibroblasts (HGFs) under high-glucose conditions. Primary HGFs were isolated from healthy gingiva and cultured with 5.5, 25, 50, and 75 mM glucose for 72 h. In vitro wound healing, 5-ethynyl-2'-deoxyuridine (EdU), and water-soluble tetrazolium salt (WST-8) assays were performed to examine cell migration and proliferation. Lactase dehydrogenase (LDH) levels were measured to determine cytotoxicity. The mRNA expression levels of oxidative stress markers were quantified by real-time PCR. Intracellular reactive oxygen species (ROS) were also measured in live cells. The antioxidant N-acetyl-l-cysteine (NAC, 1 mM) was added to evaluate the involvement of ROS in the glucose effect on HGFs. As a result, the in vitro wound healing assay showed that high glucose levels significantly reduced fibroblast migration and proliferation at 6, 12, 24, 36, and 48 h. The numbers of cells positive for EdU staining were decreased, as was cell viability, at 50 and 75 mM glucose. A significant increase in LDH was proportional to the glucose concentration. The mRNA levels of heme oxygenase-1 and superoxide dismutase-1 and ROS levels were significantly increased in HGFs after 72 h of exposure to 50 mM glucose concentration. The addition of NAC diminished the inhibitory effect of high glucose in the in vitro wound healing assay. The results of the present study show that high glucose impairs the proliferation and migration of HGFs. Fibroblast dysfunction may therefore be caused by high glucose-induced oxidative stress and may explain the delayed gingival wound healing in diabetic patients.}, }
@article {pmid30090654, year = {2018}, author = {Marie, A and Meunier, J and Brun, E and Malmstrom, S and Baudoux, V and Flaszka, E and Naert, G and Roman, F and Cosnier-Pucheu, S and Gonzalez-Gonzalez, S}, title = {N-acetylcysteine Treatment Reduces Age-related Hearing Loss and Memory Impairment in the Senescence-Accelerated Prone 8 (SAMP8) Mouse Model.}, journal = {Aging and disease}, volume = {9}, number = {4}, pages = {664-673}, pmid = {30090654}, issn = {2152-5250}, abstract = {Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly population. SAMP8 mouse model presents accelerated senescence and has been identified as a model of gerontological research. SAMP8 displays a progressive age-related decline in brain function associated with a progressive hearing loss mimicking human aging memory deficits and ARHL. The molecular mechanisms associated with SAMP8 senescence process involve oxidative stress leading to chronic inflammation and apoptosis. Here, we studied the effect of N-acetylcysteine (NAC), an antioxidant, on SAMP8 hearing loss and memory to determine the potential interest of this model in the study of new antioxidant therapies. We observed a strong decrease of auditory brainstem response thresholds from 45 to 75 days of age and an increase of distortion product amplitudes from 60 to 75 days in NAC treated group compared to vehicle. Moreover, NAC treated group presented also an increase of memory performance at 60 and 105 days of age. These results confirm that NAC delays the senescence process by slowing the age-related hearing loss, protecting the cochlear hair cells and improving memory, suggesting that antioxidants could be a pharmacological target for age-related hearing and memory loss.}, }
@article {pmid30089506, year = {2018}, author = {Dalugama, C and Gawarammana, IB}, title = {Lessons learnt from managing a case of dengue hemorrhagic fever complicated with acute liver failure and acute kidney injury: a case report.}, journal = {Journal of medical case reports}, volume = {12}, number = {1}, pages = {215}, pmid = {30089506}, issn = {1752-1947}, mesh = {Acetylcysteine/therapeutic use ; Acidosis, Lactic/etiology/therapy ; Acute Kidney Injury/diagnosis/*etiology/therapy ; Adult ; Antioxidants/therapeutic use ; Diabetes Mellitus, Type 2/complications/therapy ; Erythrocyte Transfusion ; Female ; Fluid Therapy ; Humans ; Liver Failure, Acute/diagnosis/*etiology/therapy ; Renal Replacement Therapy ; Severe Dengue/*complications/diagnosis/therapy ; }, abstract = {BACKGROUND: Dengue is a common arboviral infection with a diverse spectrum of clinical manifestations. Dengue hemorrhagic fever is a more severe form of infection characterized by plasma leak and hemoconcentration. Although hepatic dysfunction is common in dengue illness, massive liver necrosis is rarely reported. Lactic acidosis is a poor prognostic marker in liver failure related to dengue. Management of acute renal injury in dengue hemorrhagic fever due to prolonged shock is challenging as the fluid reabsorption during the recovery phase expands the intravascular volume and precipitates heart failure and pulmonary edema.<br><br>CASE PRESENTATION: We report the case of a 43-year-old Sri Lankan Sinhalese woman with serologically confirmed dengue fever presenting with evidence of plasma leakage developing acute liver failure evidenced by deranged liver functions, coagulopathy, and altered sensorium and acute kidney injury with anuria. She had elevated serum lactate levels. In addition to the "standard care," she was managed with intravenously administered N-acetyl cysteine and blood transfusions, even in the absence of bleeding or dropping packed cell volume, targeting a higher packed cell volume anticipating a better oxygenation at tissue level. Continuous veno-venous hemodialysis was employed and continued for 138&#xa0;hours removing the fluids reabsorbed during the recovery phase to prevent her from developing heart failure and pulmonary edema. She made full recovery with no sequelae.<br><br>CONCLUSIONS: N-acetyl cysteine and packed cell transfusion aiming at a higher packed cell volume to maintain adequate tissue perfusion during shock may be beneficial in acute liver failure due to dengue virus. The use of a continuous form of renal replacement such as continuous veno-venous hemodialysis is of paramount importance in managing fluid states in the recovery phase of dengue hemorrhagic fever in those with renal impairment. Interesting observations made in the fluid dynamics during the reabsorption phase need further studies preferably with an animal model.}, }
@article {pmid30088830, year = {2018}, author = {Cho, RL and Yang, CC and Tseng, HC and Hsiao, LD and Lin, CC and Yang, CM}, title = {Haem oxygenase-1 up-regulation by rosiglitazone via ROS-dependent Nrf2-antioxidant response elements axis or PPARγ attenuates LPS-mediated lung inflammation.}, journal = {British journal of pharmacology}, volume = {175}, number = {20}, pages = {3928-3946}, pmid = {30088830}, issn = {1476-5381}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology ; Cell Line ; Epithelial Cells/drug effects/metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Hypoglycemic Agents/*pharmacology ; Lipopolysaccharides/pharmacology ; Lung/cytology ; Lung Diseases/*metabolism ; Male ; Mice, Inbred ICR ; NF-E2-Related Factor 2/metabolism ; PPAR gamma/agonists/*metabolism ; Reactive Oxygen Species/metabolism ; Rosiglitazone/*pharmacology ; Up-Regulation ; }, abstract = {BACKGROUND AND PURPOSE: Haem oxygenase-1 (HO-1) is induced by thiazolidinediones including rosiglitazone and exerts anti-inflammatory effects in various models. However, the molecular mechanisms underlying rosiglitazone-induced HO-1 expression remain largely unknown in human pulmonary alveolar epithelial cells (HPAEpiCs).<br><br>EXPERIMENTAL APPROACH: HO-1 expression was determined by real time-PCR, Western blotting and promoter reporter analyses. Signalling pathways were investigated using pharmacological inhibitors or specific siRNAs. Interactions between nuclear factor erythroid-2-related factor (Nrf2) and antioxidant response elements (ARE) binding site of the HO-1 promoter were investigated with chromatin immunoprecipitation assays.<br><br>KEY RESULTS: Up-regulation of HO-1 in HPAEpiCs or in mice by rosiglitazone blunted ICAM-1 expression and monocyte adhesion to HPAEpiCs challenged with LPS. Rosiglitazone-induced HO-1 expression was significantly attenuated by NADPH oxidase (NOX) inhibitors (apocynin and diphenyleneiodonium) or ROS scavenger (N-acetyl cysteine). The involvement of NOX activity and ROS generation in rosiglitazone-induced HO-1 expression was confirmed by transfection with p47[phox] or NOX2 siRNA. Moreover, pretreatment with the inhibitors of c-Src (c-Srci II), proline-rich tyrosine kinase 2 (Pyk2) (PF431396), Akt (Akti VIII) or PPAR&#x3b3; (GW9662) and transfection with siRNA of c-Src, Pyk2, Akt or PPAR&#x3b3; abolished the rosiglitazone-induced HO-1 expression in HPAEpiCs. Subsequently, Nrf2 was activated by phosphorylation of c-Src, Pyk2 and Akt, which turned on transcription of HO-1 gene by binding to AREs binding site and enhancing ARE promoter activity.<br><br>CONCLUSIONS AND IMPLICATIONS: Rosiglitazone induces HO-1 expression via either NOX/ROS/c-Src/Pyk2/Akt-dependent Nrf2 activation or PPAR&#x3b3; in HPAEpiCs and suppresses LPS-mediated inflammatory responses, suggesting that PPAR&#x3b3; agonists may be useful for protection against pulmonary inflammation.}, }
@article {pmid30087615, year = {2018}, author = {Krause, BJ and Casanello, P and Dias, AC and Arias, P and Velarde, V and Arenas, GA and Preite, MD and Iturriaga, R}, title = {Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition.}, journal = {Frontiers in physiology}, volume = {9}, number = {}, pages = {901}, pmid = {30087615}, issn = {1664-042X}, abstract = {Chronic intermittent hypoxia (CIH), the main attribute of obstructive sleep apnea (OSA), produces oxidative stress, endothelial dysfunction, and hypertension. Nitric oxide (NO) plays a critical role in controlling the vasomotor tone. The NO level depends on the L-arginine level, which can be reduced by arginase enzymatic activity, and its reaction with the superoxide radical to produce peroxynitrite. Accordingly, we hypothesized whether a combination of an arginase inhibitor and an antioxidant may restore the endothelial function and reduced arterial blood pressure (BP) in CIH-induced hypertensive rats. Male Sprague-Dawley rats 200 g were exposed either to CIH (5% O2, 12 times/h 8 h/day) or sham condition for 35 days. BP was continuously measured by radio-telemetry in conscious animals. After 14 days, rats were treated with 2(S)-amino-6-boronohexanoic acid (ABH 400 μg/kg day, osmotic pump), N-acetylcysteine (NAC 100 mg/kg day, drinking water), or the combination of both drugs until day 35. At the end of the experiments, external carotid and femoral arteries were isolated to determine vasoactive contractile responses induced by KCL and acetylcholine (ACh) with wire-myography. CIH-induced hypertension (~8 mmHg) was reverted by ABH, NAC, and ABH/NAC administration. Carotid arteries from CIH-treated rats showed higher contraction induced by KCl (3.4 ± 0.4 vs. 2.4 ± 0.2 N/m[2]) and diminished vasorelaxation elicits by ACh compared to sham rats (12.8 ± 1.5 vs. 30.5 ± 4.6%). ABH reverted the increased contraction (2.5 ± 0.2 N/m[2]) and the reduced vasorelaxation induced by ACh in carotid arteries from CIH-rats (38.1 ± 4.9%). However, NAC failed to revert the enhanced vasocontraction (3.9 ± 0.6 N/m[2]) induced by KCl and the diminished ACh-induced vasorelaxation in carotid arteries (10.7 ± 0.8%). Femoral arteries from CIH rats showed an increased contractile response, an effect partially reverted by ABH, but completely reverted by NAC and ABH/NAC. The impaired endothelial-dependent relaxation in femoral arteries from CIH rats was reverted by ABH and ABH/NAC. In addition, ABH/NAC at high doses had no effect on liver and kidney gross morphology and biochemical parameters. Thus, although ABH, and NAC alone and the combination of ABH/NAC were able to normalize the elevated BP, only the combined treatment of ABH/NAC normalized the vascular reactivity and the systemic oxidative stress in CIH-treated rats.}, }
@article {pmid30086646, year = {2018}, author = {Dator, R and von Weymarn, LB and Villalta, PW and Hooyman, CJ and Maertens, LA and Upadhyaya, P and Murphy, SE and Balbo, S}, title = {In Vivo Stable-Isotope Labeling and Mass-Spectrometry-Based Metabolic Profiling of a Potent Tobacco-Specific Carcinogen in Rats.}, journal = {Analytical chemistry}, volume = {90}, number = {20}, pages = {11863-11872}, pmid = {30086646}, issn = {1520-6882}, support = {P01 CA138338/CA/NCI NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; R50 CA211256/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Carcinogens/administration &amp; dosage/*analysis/*metabolism ; Chromatography, Liquid ; Injections, Intraperitoneal ; Isotope Labeling ; Mass Spectrometry ; *Metabolomics ; Molecular Structure ; Nitrosamines/administration &amp; dosage/metabolism/urine ; Rats ; Rats, Inbred F344 ; }, abstract = {The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent lung carcinogen that exerts its carcinogenic effects upon metabolic activation. The identification and quantitation of NNK metabolites could identify potential biomarkers of bioactivation and detoxification of this potent carcinogen and may be used to predict lung cancer susceptibility among smokers. Here, we used in vivo isotope-labeling and high-resolution-mass-spectrometry-based methods for the comprehensive profiling of all known and unknown NNK metabolites. The sample-enrichment, LC-MS, and data-analysis workflow, including a custom script for automated d0- d4- m/ z-pair-peak detection, enabled unbiased identification of numerous NNK metabolites. The structures of the metabolites were confirmed using targeted LC-MS[2] with retention-time (tR) and MS[2]-fragmentation comparisons to those of standards when possible. Eleven known metabolites and unchanged NNK were identified simultaneously. More importantly, our workflow revealed novel NNK metabolites, including 1,3-Diol (13), α-OH-methyl-NNAL-Gluc (14), nitro-NK- N-oxide (15), nitro-NAL- N-oxide (16), γ-OH NNAL (17), and three N-acetylcysteine (NAC) metabolites (18a-c). We measured the differences in the relative distributions of a panel of nitroso-containing NNK-specific metabolites in rats before and after phenobarbital (PB) treatment, and this served as a demonstration of a general strategy for the detection of metabolic differences in animal and cell systems. Lastly, we generated a d4-labeled NNK-metabolite mixture to be used as internal standards (d4-rat urine) for the relative quantitation of NNK metabolites in humans, and this new strategy will be used to assess carcinogen exposure and ultimately to evaluate lung-cancer risk and susceptibility in smokers.}, }
@article {pmid30082742, year = {2018}, author = {Gallo, A and Menezo, Y and Dale, B and Coppola, G and Dattilo, M and Tosti, E and Boni, R}, title = {Metabolic enhancers supporting 1-carbon cycle affect sperm functionality: an in vitro comparative study.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {11769}, pmid = {30082742}, issn = {2045-2322}, mesh = {Animals ; Carbon/*metabolism ; Cattle ; Humans ; Hydrogen-Ion Concentration ; Lipid Peroxidation/physiology ; Male ; Membrane Potential, Mitochondrial/physiology ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Sperm Motility/*physiology ; Spermatozoa/*metabolism/*physiology ; Urochordata ; }, abstract = {The sperm plasma membrane is a sensitive target to oxidative stress. The most representative reactive oxygen species (ROS) scavengers in the genital tract, hypotaurine and glutathione, require, for their synthesis, cysteine whose availability is associated with the 1-carbon cycle (1-CC). Human, bovine and ascidian spermatozoa were incubated with compounds supporting the 1-CC (Vitamin B6, Methylcobalamin, 5 Methyl Tetrahydrofolate, Zinc Bisglycinate and N-acetyl-cysteine) (TRT) and compared to the effects induced solely by N-acetyl-cysteine (NAC). In control groups (CNTRL), spermatozoa were incubated with medium alone. After 90 and 180 minutes of incubation, the mitochondrial membrane potential (ΔΨM) in TRT and NAC was significantly (P < 0.01) higher than in CNTRL. At H2DCFDA evaluation, ROS production differed between species whereas, at 2-OH Ethidium, it significantly decreased in bovine TRT group. Intracellular pH (pHi) did not significantly vary in relation to treatment. In ascidian spermatozoa, the NAC supplementation decreased external pH, which in turn brought to a pHi lowering. Buffering seawater with NaHCO3 reversed the beneficial effects of N-acetyl-cysteine supplementation. In conclusion, both fully supporting the 1-CC and treatment with N-acetyl-cysteine alone improved kinetics, ΔΨM and ROS production in mammalian sperm demonstrating for the first time the direct in vitro effects of these compounds on sperm functionality.}, }
@article {pmid30081847, year = {2018}, author = {Zhang, W and Song, J and Zhang, Y and Ma, Y and Yang, J and He, G and Chen, S}, title = {Intermittent high glucose-induced oxidative stress modulates retinal pigmented epithelial cell autophagy and promotes cell survival via increased HMGB1.}, journal = {BMC ophthalmology}, volume = {18}, number = {1}, pages = {192}, pmid = {30081847}, issn = {1471-2415}, support = {14JCYBJC27400//Tianjin Science and Technology Project of China/ ; 81700846//National Natural Science Foundation of China/ ; }, mesh = {*Autophagy ; Blotting, Western ; Cell Line ; Cell Survival ; Glucose/*metabolism ; HMGB1 Protein/*metabolism ; Humans ; Immunohistochemistry ; Microscopy, Electron ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Retinal Diseases/metabolism/*pathology ; Retinal Pigment Epithelium/metabolism/*ultrastructure ; }, abstract = {BACKGROUND: In this study, we evaluated the effects of intermittent high glucose on oxidative stress production in retinal pigmented epithelial (RPE) cells and explored whether the mechanisms of autophagy and apoptosis in oxidative stress are associated with high-mobility group box 1 (HMGB1) protein.<br><br>METHODS: Cultured human RPE cell line ARPE-19 cells were exposed to intermittent high glucose-induced oxidative stress. Reactive oxygen species (ROS) was determined by 2', 7'-dichlorofluorescin diacetate (DCFH-DA); and malonyldialdehyde (MDA), superoxide dismutase (SOD) by commercial kits. Transmission electron microscopy was used to observe the generation of autophagosome. And MTT assay was used to examine the effect of autophagy on cell viability. For the inhibition experiments, cells were pre-incubated with lysosomal inhibitors NH4Cl or N-acetyl cysteine (NAC).Western blot was used to measure the expression patterns of autophagic markers, including LC3 and p62. The expression of HMGB1 was detected by immunohistochemistry.Cells were pre-incubated with HMGB1 inhibitor ethyl pyruvate (EP) ,then detected the expression pattern of autophagic markers and level of cellular ROS.<br><br>RESULTS: We found that intermittent high glucose significantly increased oxidative stress levels (as indicated by ROS, MDA, SOD), increased in the generation of autophagosome, decreased the level of p62, induced conversion of LC3 I to LC3 II. We further demonstrated that the NH4Cl/NAC inhibited intermittent high glucose-induced autophage by altered level of LC3 and p62. Intermittent high glucose-induced autophagy is independent of HMGB1 signaling, inhibition of HMGB1 release by EP decreased expression pattern of autophagic markers and level of cellular viability.<br><br>CONCLUSIONS: Under intermittent high glucose condition, autophagy may be required for preventing oxidative stress-induced injury in RPE. HMGB1 plays important roles in signaling for both autophagy and oxidative stress.}, }
@article {pmid30079136, year = {2018}, author = {Bhilare, NV and Dhaneshwar, SS and Mahadik, KR}, title = {Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation.}, journal = {World journal of hepatology}, volume = {10}, number = {7}, pages = {496-508}, pmid = {30079136}, issn = {1948-5182}, abstract = {AIM: To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid (INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.<br><br>METHODS: INH was conjugated with N-acetyl cysteine (NAC) and N-(2)-mercaptopropionyl glycine using the Schotten-Baumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.<br><br>RESULTS: Prodrugs were found to be stable in acidic (pH 1.2) and basic (pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly (59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially.<br><br>CONCLUSION: The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.}, }
@article {pmid30078345, year = {2018}, author = {Parousis, A and Carter, HN and Tran, C and Erlich, AT and Mesbah Moosavi, ZS and Pauly, M and Hood, DA}, title = {Contractile activity attenuates autophagy suppression and reverses mitochondrial defects in skeletal muscle cells.}, journal = {Autophagy}, volume = {14}, number = {11}, pages = {1886-1897}, pmid = {30078345}, issn = {1554-8635}, mesh = {Animals ; Autophagy/*physiology ; Cells, Cultured ; Down-Regulation ; Exercise Therapy ; Gene Expression Regulation ; Mice ; Mitochondria, Muscle/*pathology/physiology ; Mitochondrial Diseases/metabolism/pathology/physiopathology/*prevention &amp; control ; Mitophagy/physiology ; Muscle Contraction/*physiology ; Muscle Fibers, Skeletal/physiology ; *Muscle, Skeletal/metabolism/pathology/physiopathology/ultrastructure ; Oxygen Consumption/physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {UNLABELLED: Macroautophagy/autophagy is a survival mechanism that facilitates protein turnover in post-mitotic cells in a lysosomal-dependent process. Mitophagy is a selective form of autophagy, which arbitrates the selective recognition and targeting of aberrant mitochondria for degradation. Mitochondrial content in cells is the net balance of mitochondrial catabolism via mitophagy, and organelle biogenesis. Although the latter process has been well described, mitophagy in skeletal muscle is less understood, and it is currently unknown how these two opposing mechanisms converge during contractile activity. Here we show that chronic contractile activity (CCA) in muscle cells induced mitochondrial biogenesis and coordinately enhanced the expression of TFEB (transcription factor EB) and PPARGC1A/PGC-1α, master regulators of lysosome and mitochondrial biogenesis, respectively. CCA also enhanced the expression of PINK1 and the lysosomal protease CTSD (cathepsin D). Autophagy blockade with bafilomycin A1 (BafA) reduced mitochondrial state 3 and 4 respiration, increased ROS production and enhanced the accumulation of MAP1LC3B-II/LC3-II and SQSTM1/p62. CCA ameliorated this mitochondrial dysfunction during defective autophagy, increased PPARGC1A, normalized LC3-II levels and reversed mitochondrially-localized SQSTM1 toward control levels. NAC emulated the LC3-II reductions induced by contractile activity, signifying that a decrease in oxidative stress could represent a mechanism of autophagy normalization brought about by CCA. CCA enhances mitochondrial biogenesis and lysosomal activity, and normalizes autophagy flux during autophagy suppression, partly via ROS-dependent mechanisms. Thus, contractile activity represents a potential therapeutic intervention for diseases in which autophagy is inhibited, such as vacuolar myopathies in skeletal muscle, by establishing a healthy equilibrium of anabolic and catabolic pathways.<br><br>ABBREVIATIONS: AMPK: AMP-activated protein kinase; BafA: bafilomycin A1; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCA: chronic contractile activity; COX4I1: cytochrome c oxidase subunit 4I1; DMEM: Dulbecco's modified Eagle's medium; GFP: green fluorescent protein; LSD: lysosomal storage diseases; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; PPARGC1A: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SOD2: superoxide dismutase 2, mitochondrial; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.}, }
@article {pmid30078025, year = {2018}, author = {Poh, WY and Omar, MS and Tan, HP}, title = {Predictive factors for contrast-induced acute kidney injury in high-risk patients given N-acetylcysteine prophylaxis.}, journal = {Annals of Saudi medicine}, volume = {38}, number = {4}, pages = {269-276}, pmid = {30078025}, issn = {0975-4466}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/chemically induced/epidemiology/*prevention &amp; control ; Aged ; Contrast Media/*adverse effects ; Cross-Sectional Studies ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Incidence ; *Inpatients ; Malaysia/epidemiology ; Male ; Middle Aged ; Prognosis ; Prospective Studies ; *Risk Assessment ; Risk Factors ; }, abstract = {BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is rec.ognized as a common complication of radiographic contrast-enhanced procedures. N-acetylcysteine (NAC) is commonly prescribed, but CI-AKI can still develop despite NAC administration as prophylaxis.<br><br>OBJECTIVE: Identify the predictive factors for development of CI-AKI in patients prescribed NAC.<br><br>DESIGN: Prospective, cross-sectional.<br><br>SETTING: A tertiary hospital in Malaysia.<br><br>PATIENTS AND METHODS: All adult patients who were prescribed NAC for prevention of CI-AKI were identified through an NAC drug us.age monitoring card maintained by the inpatient pharmacy. The study was conducted from March to July 2017.<br><br>MAIN OUTCOME MEASURES: Statistically significant predictive fac.tors for development of CI-AKI despite NAC administration.<br><br>SAMPLE SIZE: 152 RESULTS: The most commonly recognized risk factors for CI-AKI present in the study population were renal impairment (n=131, 86.2%), anemia (n=107, 70.4%), and diabetes mellitus (n=90, 59.2%). Hydration therapy was initiated in 128 patients (84.2%) prior to the contrast-enhanced procedure. Sixty-one (40.1%) were treated with nephrotoxic medications concomitantly with NAC. Fifteen (9.9%) patients developed AKI. Hypotension (OR: 6.02; 95% CI 1.25-28.97) and use of high contrast volume (OR: 6.56; 95% CI: 1.41-30.64) significantly increased the odds for AKI. Prior hydration therapy (OR: 0.13; 95% CI 0.03-0.59) showed protective effects.<br><br>CONCLUSION: The risk predictors identified for CI-AKI were hypotension, high contrast volume and prior hydration therapy.<br><br>LIMITATION: May not have identified other confounding factors for development of CI-AKI.<br><br>CONFLICT OF INTEREST: None.}, }
@article {pmid30077909, year = {2018}, author = {Dong, S and Massalha, N and Plewa, MJ and Nguyen, TH}, title = {The impact of disinfection Ct values on cytotoxicity of agricultural wastewaters: Ozonation vs. chlorination.}, journal = {Water research}, volume = {144}, number = {}, pages = {482-490}, doi = {10.1016/j.watres.2018.07.065}, pmid = {30077909}, issn = {1879-2448}, mesh = {Acetylcysteine/chemistry ; Agriculture ; Animals ; CHO Cells ; *Chlorine ; Cricetulus ; Disinfectants/*toxicity ; Disinfection/methods ; Halogenation ; *Ozone ; Time Factors ; Toxicity Tests, Chronic ; Waste Disposal, Fluid/*methods ; Wastewater/chemistry/*toxicity ; Water Pollutants, Chemical/analysis/toxicity ; }, abstract = {Toxicity arising from toxic disinfection byproducts is an unintended result of disinfection during water reclamation. To ensure safe water reclamation treatment, it is important to develop a disinfection strategy with minimal formation of overall toxicity in the reclaimed water. The cumulative disinfectant concentration over time (Ct) is a useful concept for pathogen control during reuse water disinfection. We evaluated the toxicity impact of Ct values and different methods to achieve identical Ct values by ozonation or chlorination of wastewaters from four agricultural sources on mammalian cells. N-acetylcysteine (NAC) reactivity of the wastewater organic extracts was determined to reveal their impact on the thiol-specific biological detoxification mechanism. The results demonstrated that for two sources and for both ozonation and chlorination, higher Ct values enhanced cytotoxicity. The ozonated waters were at least 10% less toxic and as much as 22.4 times less toxic than either the non-disinfected controls or the chlorinated waters. Chlorination consistently induced higher cytotoxicity than ozonation by between 2.2 and 22.4 fold, respectively, and induced similar or higher cytotoxicity than the non-disinfected controls, by at most 4.4 fold. Given the same Ct values, the combination of high disinfectant concentration and short contact time produced finished wastewaters with higher toxicity, than the combination of low disinfectant concentration and long contact time. NAC thiol reactivity was positively and significantly correlated with mammalian cell cytotoxicity, and agreed with 80% of the cytotoxicity rank order. This suggests that the induction of cytotoxicity involved reactions with agents that acted as thiol pool quenchers. The overall results indicate that the cytotoxicity of wastewaters may increase when higher Ct values are applied to inactivate recalcitrant pathogens. To counteract the potential increase in cytotoxicity at high Ct values, for both ozonation and chlorination, lower disinfectant dose and longer contact time may be adopted.}, }
@article {pmid30071509, year = {2018}, author = {Han, X and Zhong, Z and Kou, J and Zheng, Y and Liu, Z and Jiang, Y and Zhang, Z and Gao, Z and Cong, L and Tian, Y and Yang, L}, title = {ROS Generated by Upconversion Nanoparticle-Mediated Photodynamic Therapy Induces Autophagy Via PI3K/AKT/ mTOR Signaling Pathway in M1 Peritoneal Macrophage.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {48}, number = {4}, pages = {1616-1627}, doi = {10.1159/000492283}, pmid = {30071509}, issn = {1421-9778}, mesh = {Animals ; Autophagy/*drug effects ; Cell Survival/drug effects ; Enzyme Inhibitors/pharmacology ; Interleukin-12/metabolism ; Macrophages, Peritoneal/cytology/drug effects/metabolism ; Magnetite Nanoparticles/chemistry/*toxicity ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Photochemotherapy ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, IgG/metabolism ; Signal Transduction/*drug effects ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factor TFIIH ; Transcription Factors/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND/AIMS: Atherosclerosis is a chronic inflammatory cardiovascular disease. Macrophages are major components of atherosclerotic plaques and play a key role in the development of atherosclerosis by secreting a variety of pro-inflammatory factors. Our previous studies have confirmed that upconversion nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) mediated photodynamic therapy (PDT) can promote cholesterol efflux and induce apoptosis in THP-1 macrophages. In this study, we investigated whether reactive oxygen species (ROS) generated by UCNPs-Ce6-mediated PDT can induce autophagy to inhibit the expression of pro-inflammatory factor in M1 peritoneal macrophages.<br><br>METHODS: Peritoneal macrophages were collected from C57/BL6 mice injected with 3% thioglycollate broth medium and induced by lipopolysaccharides and interferon-&#x3b3;. Intracellular ROS production was assessed by 2'-7'-dichloroforescein diacetate and flow cytometry. Autophagy was assayed by western blot, transmission electron microscopy and immunofluorescence. Pro-inflammatory cytokines were detected by enzyme-linked immunosorbent assay and western blot.<br><br>RESULTS: Model M1 peritoneal macrophages were established after 24 h induction. Protein expression levels of LC3 II and Beclin1, and degradation of p62 increased and peaked at 2 h in the PDT group. Meanwhile, levels of inflammatory cytokines iNOS, IL-12, and TNF-&#x3b1; markedly decreased after PDT. The increase in autophagy levels and decrease in pro-inflammatory cytokines were significantly inhibited by 3-methyladenine. Furthermore, ROS generated by UCNPs-Ce6 mediated PDT activated autophagy. The expression of autophagy related-protein and inflammatory cytokines iNOS, IL-12, and TNF-&#x3b1; were inhibited by the ROS inhibitor N-acetyl cysteine.<br><br>CONCLUSIONS: ROS generated by UCNPs-Ce6-mediated PDT activated autophagy and inhibited the expression of pro-inflammatory factors of M1 peritoneal macrophage via the PI3K/AKT/mTOR signaling pathway.}, }
@article {pmid30069915, year = {2018}, author = {Turk, BR and Nemeth, CL and Marx, JS and Tiffany, C and Jones, R and Theisen, B and Kambhampati, S and Ramireddy, R and Singh, S and Rosen, M and Kaufman, ML and Murray, CF and Watkins, PA and Kannan, S and Kannan, R and Fatemi, A}, title = {Dendrimer-N-acetyl-L-cysteine modulates monophagocytic response in adrenoleukodystrophy.}, journal = {Annals of neurology}, volume = {84}, number = {3}, pages = {452-462}, pmid = {30069915}, issn = {1531-8249}, support = {R01 NS097511/NS/NINDS NIH HHS/United States ; R01 EB018306/EB/NIBIB NIH HHS/United States ; R01EB018306/EB/NIBIB NIH HHS/United States ; R01NS097511/NS/NINDS NIH HHS/United States ; R01 HD069562/HD/NICHD NIH HHS/United States ; R01HD069562/HD/NICHD NIH HHS/United States ; }, mesh = {ATP Binding Cassette Transporter, Subfamily D, Member 1/*genetics ; ATP-Binding Cassette Transporters/genetics ; Acetylcysteine/metabolism ; Adrenoleukodystrophy/*genetics/*metabolism ; Adult ; Aged ; Antioxidants/metabolism ; Brain/metabolism ; Child ; Dendrimers/*metabolism ; Female ; Humans ; Male ; Microglia/metabolism ; Middle Aged ; Phenotype ; Young Adult ; }, abstract = {OBJECTIVE: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder due to mutations in the peroxisomal very long-chain fatty acyl-CoA transporter, ABCD1, with limited therapeutic options. ALD may manifest in a slowly progressive adrenomyeloneuropathy (AMN) phenotype, or switch to rapid inflammatory demyelinating cerebral disease (cALD), in which microglia have been shown to play a pathophysiological role. The aim of this study was to determine the role of patient phenotype in the immune response of ex vivo monophagocytic cells to stimulation, and to evaluate the efficacy of polyamidoamine dendrimer conjugated to the antioxidant precursor N-acetyl-cysteine (NAC) in modulating this immune response.<br><br>METHODS: Human monophagocytic cells were derived from fresh whole blood, from healthy (n = 4), heterozygote carrier (n = 4), AMN (n = 7), and cALD (n = 4) patients. Cells were exposed to very long-chain fatty acids (VLCFAs; C24:0 and C26:0) and treated with dendrimer-NAC (D-NAC).<br><br>RESULTS: Ex vivo exposure to VLCFAs significantly increased tumor necrosis factor &#x3b1; (TNF&#x3b1;) and glutamate secretion from cALD patient macrophages. Additionally, a significant reduction in total intracellular glutathione was observed in cALD patient cells. D-NAC treatment dose-dependently reduced TNF&#x3b1; and glutamate secretion and replenished total intracellular glutathione levels in cALD patient macrophages, more efficiently than NAC. Similarly, D-NAC treatment decreased glutamate secretion in AMN patient cells.<br><br>INTERPRETATION: ALD phenotypes display unique inflammatory profiles in response to VLCFA stimulation, and therefore ex vivo monophagocytic cells may provide a novel test bed for therapeutic agents. Based on our findings, D-NAC may be a viable therapeutic strategy for the treatment of cALD. Ann Neurol 2018;84:452-462.}, }
@article {pmid30069898, year = {2018}, author = {Malmir, M and Soleimani Mehranjani, M and Naderi Noreini, S and Faraji, T}, title = {Protective antioxidant effects of N-acetylcysteine against impairment of spermatogenesis caused by paranonylphenol.}, journal = {Andrologia}, volume = {50}, number = {10}, pages = {e13114}, doi = {10.1111/and.13114}, pmid = {30069898}, issn = {1439-0272}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Disease Models, Animal ; Endocrine Disruptors/*toxicity ; Environmental Pollutants/*toxicity ; Male ; Malondialdehyde/blood/metabolism ; Mice ; Oxidative Stress/drug effects ; Phenols/*toxicity ; Seminiferous Tubules/drug effects/metabolism ; Sperm Count ; Sperm Motility/drug effects ; Spermatogenesis/*drug effects ; Testosterone/blood/metabolism ; }, abstract = {Paranonylphenol (p-NP) is an environmental pollutant that causes oxidative stress. The purpose of this study was to evaluate the protective effect of N-acetylcysteine (NAC) as an antioxidant on sperm parameters and testis in mice after treatment with p-NP. Adult mice were randomly divided into four groups (n = 6, each group) including 1-control, 2- p-NP (250 mg kg[-1] day[-1]), 3- NAC (150 mg kg[-1] day[-1]) and 4- p-NP + NAC. After 35 days of oral treatment, the mean of spermatogenic index (p < 0.02), sperm count (p < 0.01), daily sperm production (p < 0.01), sperm tail length (p < 0.02), progressive movement (p < 0.04), normal morphology (p < 0.04) and viability (p < 0.01) of spermatozoa and also serum testosterone level (p < 0.04) were significantly reduced in p-NP group when compared to other groups. While the count of the positive TUNEL cells in the seminiferous tubules (p < 0.01) and level of the malondialdehyde (MDA) in testis (p < 0.02) and serum (p < 0.01) significantly increased. In the histopathologic assay in the p-NP group, apoptosis, atrophy, oedema, reduction in sperm density in lumens and vacuoles were observed. The findings of this study indicate that NAC as a potent antioxidant be able to compensate the adverse effects of p-NP in spermatogenesis, testis and levels of testosterone and MDA in the p-NP + NAC group significantly compared to the p-NP group.}, }
@article {pmid30068034, year = {2018}, author = {Li, DD and Luo, Z and Ling, SC and Wu, K and Chen, GH and Cheng, J}, title = {Mitochondrial apoptotic pathway mediated the Zn-induced lipolysis in yellow catfish Peteobagrus fulvidraco.}, journal = {Chemosphere}, volume = {208}, number = {}, pages = {907-915}, doi = {10.1016/j.chemosphere.2018.05.200}, pmid = {30068034}, issn = {1879-1298}, mesh = {Animals ; Apoptosis/*drug effects ; Catfishes/*physiology ; Lipid Metabolism/drug effects ; Lipolysis/*drug effects ; Liver/drug effects/metabolism/*pathology ; Mitochondria/drug effects/metabolism/*pathology ; Zinc/*pharmacology ; }, abstract = {In the study, effects of waterborne zinc (Zn) exposure on apoptosis were investigated, and the potential mechanism of apoptosis participating in the Zn-induced variations of lipid metabolism was explored in a low vertebrate, yellow catfish Pelteobagrus fulvidraco. We found that Zn induced occurrence of apoptosis of livers and hepatocytes in yellow catfish. Waterborne Zn also increased hepatic transcriptional levels of p53, cytochrome c (Cycs), caspase 3a (Casp3a) and caspase 3b (Casp3b) of yellow catfish. Zn increased caspase 3 activity and reduced the mitochondrial permeability transition (MTP) in yellow catfish hepatocytes. Z-VAD-fmk (caspase inhibitor) and CsA pretreatment (MTP inhibitor) attenuated the Zn-induced apoptosis and reduction in MTP. Z-VAD-fmk pretreatments attenuated the Zn-induced increase in transcriptional levels of p53, Cycs and Casp3b although the differences were not statistically significant between the Zn group and Zn + Z-VAD-fmk group. In contrast, Zn and N-acetylcysteine (NAC) did not significantly influence the reactive oxygen species (ROS) production. Zn significantly reduced triglyceride (TG) content, increased the activities of carnitine palmitoyltransferase 1 (CPT I), hormone-sensitive lipase (HSL) and adipose TAG lipase (ATGL), and the transcriptional levels of p53, Cycs and caspase 3b of the hepatocytes; these Zn-induced effects on TG contents, activities of CPT I, HSL and ATGL, and mRNA levels of p53, Cycs and caspase 3b could partly be reversed by Z-VAD-fmk, suggesting that Zn induced the mitochondrial-mediated apoptosis and reduced lipid accumulation. Taken together, our study demonstrated the importance of mitochondria-mediated apoptosis in Zn-induced lipolysis, which suggested a new mechanism for elucidating metal element influencing lipid metabolism.}, }
@article {pmid30066041, year = {2019}, author = {Sharma, M and Naura, AS and Singla, SK}, title = {Modulatory effect of 4-phenyl butyric acid on hyperoxaluria-induced renal injury and inflammation.}, journal = {Molecular and cellular biochemistry}, volume = {451}, number = {1-2}, pages = {185-196}, pmid = {30066041}, issn = {1573-4919}, support = {EMR/2016/001583//Science and Engineering Research Board/ ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Biomarkers/analysis ; Hyperoxaluria/*complications ; Inflammation/*drug therapy/etiology/metabolism/pathology ; Kidney Diseases/*drug therapy/etiology/metabolism/pathology ; Male ; Oxidative Stress/*drug effects ; Phenylbutyrates/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Hyperoxaluria-associated deposition of calcium oxalate crystals results from oxalate-induced renal injury and inflammation. The present study was designed to evaluate the effect of 4-Phenyl butyric acid (4-PBA), a chemical chaperone, in ethylene glycol-induced hyperoxaluria and compare its effect with antioxidant, N-acetyl cysteine (NAC). Male Sprague-Dawley rats were given ethylene glycol in drinking water for 28 days to induce hyperoxaluria. 4-PBA and NAC were given by oral gavage. Effect of 4-PBA was analyzed in both prophylactic and curative regimens. After every 7 days, 24-h urine samples were analyzed for kidney injury and inflammation markers. Increased amounts of kidney injury markers like Kidney injury molecule-1, Lactate dehydrogenase, and N-acetyl-β-glucoseaminidase were found in the urine of hyperoxaluric rats which were significantly reduced by 4-PBA treatment in both prophylactic and curative regimens. Inflammatory markers IL-1β, IL-6, and MCP-1 were also raised in the urine of hyperoxaluric rats which were significantly decreased by 4-PBA treatment. Hyperoxaluria was accompanied with renal oxidative stress as reflected by decreased glutathione redox status and increased reactive oxygen species which was significantly reduced by 4-PBA treatment. Histological study with H&amp;E and Pizzolato staining showed numerous calcium oxalate crystal deposits in the renal tissues of hyperoxaluric rats. However, no significant crystal deposits were seen in the 4-PBA-treated hyperoxaluric rats. N-acetyl cysteine treatment effectively decreased renal oxidative stress but did not alter the production of inflammatory markers. Collectively, the present study suggested the potential protective effect of 4-PBA in hyperoxaluria-induced renal injury and inflammation.}, }
@article {pmid30065965, year = {2018}, author = {Sharma, R and Sharma, A and Kambhampati, SP and Reddy, RR and Zhang, Z and Cleland, JL and Kannan, S and Kannan, RM}, title = {Scalable synthesis and validation of PAMAM dendrimer-N-acetyl cysteine conjugate for potential translation.}, journal = {Bioengineering &amp; translational medicine}, volume = {3}, number = {2}, pages = {87-101}, pmid = {30065965}, issn = {2380-6761}, support = {R01 HD076901/HD/NICHD NIH HHS/United States ; }, abstract = {Dendrimer-N-acetyl cysteine (D-NAC) conjugate has shown significant promise in multiple preclinical models of brain injury and is undergoing clinical translation. D-NAC is a generation-4 hydroxyl-polyamidoamine dendrimer conjugate where N-acetyl cysteine (NAC) is covalently bound through disulfide linkages on the surface of the dendrimer. It has shown remarkable potential to selectively target and deliver NAC to activated microglia and astrocytes at the site of brain injury in several animal models, producing remarkable improvements in neurological outcomes at a fraction of the free drug dose. Here we present a highly efficient, scalable, greener, well-defined route to the synthesis of D-NAC, and validate the structure, stability and activity to define the benchmarks for this compound. This newly developed synthetic route has significantly reduced the synthesis time from three weeks to one week, uses industry-friendly solvents/reagents, and involves simple purification procedures, potentially enabling efficient scale up.}, }
@article {pmid30061828, year = {2018}, author = {Prabhu, KS and Siveen, KS and Kuttikrishnan, S and Iskandarani, AN and Khan, AQ and Merhi, M and Omri, HE and Dermime, S and El-Elimat, T and Oberlies, NH and Alali, FQ and Uddin, S}, title = {Greensporone C, a Freshwater Fungal Secondary Metabolite Induces Mitochondrial-Mediated Apoptotic Cell Death in Leukemic Cell Lines.}, journal = {Frontiers in pharmacology}, volume = {9}, number = {}, pages = {720}, pmid = {30061828}, issn = {1663-9812}, abstract = {Therapeutic agents used in the treatment of cancer are known to develop resistance against cancer cells. Hence, there is a continuing need to investigate novel agents for the treatment and management of cancer. Antitumor activity of greensporone C (GC), a new resorcylic acid lactone isolated from an organic extract of a culture of a Halenospora sp. freshwater fungus, was subjected for screening against a panel of leukemic cell lines (K562, U937, and AR320). In all the three cell lines, cell proliferation was inhibited in dose-dependent fashion. GC further arrested the cells in SubG0 phase in dose-dependent manner. Annexin V/PI dual staining data confirmed apoptotic death of treated K562 and U937 leukemic cells. Treatment with GC suppressed constitutively phosphorylated AKT and downregulated expression of inhibitor of apoptotic proteins XIAP, cIAP-1, and cIAP-2. In summation to this, GC-treated leukemic cells upregulated protein expression of pro-apoptotic proteins, Bax with concomitant decrease in expression of anti-apoptotic proteins including Bcl-2 and Bcl-xL. Upregulation of Bax was associated with cytochrome c release which was confirmed from the collapse of mitochondrial membrane. Released cytochrome c further activated caspase cascade which in turn initiated apoptosis process. Anticancer activity of this isolated fungal compound GC was potentiated via stimulating production of reactive oxygen species (ROS) along with depletion of reduced glutathione (GSH) levels in K562 and U937 leukemic cells. Pretreatment of these cells with N-acetyl cysteine prevented GC-induced depletion of reduced GSH level and mitochondrial-caspase-induced apoptosis. Altogether, our data show that GC modulates the apoptotic response of human leukemic cells and raises the possibility of its use as a novel therapeutic strategy for hematological malignancies.}, }
@article {pmid30059877, year = {2018}, author = {Zhang, D and Li, Y and Zhang, T and Liu, J and Jahejo, AR and Yang, L and Chen, P and Ning, G and Huo, N and Ma, H and Yan, F and Tian, W}, title = {Protective effects of zinc and N-acetyl-L-cysteine supplementation against cadmium induced erythrocyte cytotoxicity in Arbor Acres broiler chickens (Gallus gallus domesticus).}, journal = {Ecotoxicology and environmental safety}, volume = {163}, number = {}, pages = {331-339}, doi = {10.1016/j.ecoenv.2018.07.069}, pmid = {30059877}, issn = {1090-2414}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cadmium/*toxicity ; Chickens ; Erythrocytes/*drug effects ; Oxidative Stress/drug effects ; Zinc/*pharmacology ; }, abstract = {Cadmium (Cd) is one of the most toxic metals released into the environment. Here, we investigated the protective role of Zn[2+] and/or N-acetyl-L-cysteine (NAC) against Cd cytotoxicity in the erythrocytes of Arbor Acres (AA) broiler chickens. Four hundred one-day-old AA chickens were divided into 12 groups for in vitro and in vivo studies. Zn[2+] and/or NAC was given to the Cd exposed AA chickens to assess their protective roles. This was accomplished by investigating nuclear morphological abnormalities, oxidative stress (SOD, CAT, GPx, GSH and T-AOC), cell apoptosis, ROS accumulation and mitochondrial membrane potential (MMP). Results showed that Cd led to dose- and time-dependent cytotoxicity in the erythrocytes of AA chickens characterized by morphological abnormalities, nucleus damage, increased apoptosis rate and antioxidants depletion. Zn[2+] or NAC significantly decreased the erythrocyte apoptosis, ROS production and mitochondrial membrane depolarization caused by Cd. SOD, CAT, GPx, GSH and T-AOC activities significantly decreased both in serum and erythrocytes of Cd exposed AA chickens. The supplementation with Zn[2+] or NAC alleviated Cd induced oxidative stress through promoting SOD or GPx/GSH activities respectively. NAC presented a better role in reducing apoptosis, improving antioxidant activities more than Zn[2+] in vitro. The combined use of Zn[2+] and NAC enhanced cytoprotection in Cd exposed erythrocytes of AA chickens compared to Zn[2+] or NAC alone. In conclusion, Zn[2+] and NAC exerted remarkable protective roles in Cd exposed erythrocytes of AA chickens by inhibiting cell apoptosis and oxidative stress, and this provides a promising approach to antagonize Cd poisoning in poultry.}, }
@article {pmid30055241, year = {2018}, author = {Zhao, X and Jin, Y and Yang, L and Hou, Z and Liu, Y and Sun, T and Pei, J and Li, J and Yao, C and Wang, X and Chen, G}, title = {Promotion of SIRT1 protein degradation and lower SIRT1 gene expression via reactive oxygen species is involved in Sb-induced apoptosis in BEAS-2b cells.}, journal = {Toxicology letters}, volume = {296}, number = {}, pages = {73-81}, doi = {10.1016/j.toxlet.2018.07.047}, pmid = {30055241}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimony/*toxicity ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line ; Gene Expression/drug effects ; MAP Kinase Signaling System/drug effects ; Plasmids ; Rats ; Reactive Oxygen Species/*metabolism ; Sincalide/metabolism ; Sirtuin 1/*biosynthesis/genetics/*metabolism ; }, abstract = {Antimony (Sb) has been reported to lead to pulmonary damage, but the underlying mechanism remains unclear. Accumulating evidence indicates that silent mating type information regulation 2 homolog 1 (SIRT1), an NAD[+]-dependent deacetylase, mediates stimuli-induced cellular apoptosis. Here, we investigated whether SIRT1 plays a role in Sb-triggered apoptosis in human bronchial epithelial cells (BEAS-2b). First, we showed that Sb initiated apoptosis. Furthermore, the expression of SIRT1 was markedly downregulated by Sb treatment, while overexpression of SIRT1 through resveratrol treatment or transfection with SIRT1-Flag plasmid attenuated the Sb-induced apoptosis. Accelerated degradation of SIRT1 protein and lower SIRT1 gene expression contributed to low expression of SIRT1. In addition, Sb activated the ERK and JNK pathways; however, inhibition of ERK rather than JNK rescued SIRT1 suppression. Subsequent analyses demonstrated that antioxidant N-acetylcysteine (NAC) attenuated SIRT1 repression, increased SIRT1 mRNA levels and decreased SIRT1 protein degradation in Sb-treated cells. In addition, NAC also inhibited JNK and ERK activation by Sb exposure. These data suggest that reactive oxygen species-dependent SIRT1 suppression mediates Sb-stimulated cell apoptosis in BEAS-2b cells via lower SIRT1 gene expression and protein stability.}, }
@article {pmid30052510, year = {2019}, author = {Kavčič, N and Pegan, K and Vandenabeele, P and Turk, B}, title = {Comparative study of the differential cell death protecting effect of various ROS scavengers.}, journal = {Biological chemistry}, volume = {400}, number = {2}, pages = {149-160}, doi = {10.1515/hsz-2017-0317}, pmid = {30052510}, issn = {1437-4315}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Cell Death/*drug effects ; Cells, Cultured ; Cyclic N-Oxides/pharmacology ; Free Radical Scavengers/*pharmacology ; Mice ; Models, Biological ; Oxidative Stress ; Porphyrins/pharmacology ; Reactive Oxygen Species/*metabolism ; Spin Labels ; Tumor Necrosis Factor-alpha/metabolism ; alpha-Tocopherol/pharmacology ; }, abstract = {Oxidative stress has for a long time been associated with cell death, especially classical necrosis, however, its role in other cell death pathways is less clear. Here, we evaluated in a comparative way, the effect of four different reactive oxygen species (ROS) scavengers, N-acetyl-L-cysteine (NAC), α-tocopherol and two superoxide dismutase mimetics, n(III)tetrakis(4-benzoic acid)porphyrin chloride, and 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol), in four different cell death models, including menadione-triggered necrosis, staurosporine-induced apoptosis and tumor necrosis factor (TNF)-induced apoptosis and necroptosis. While menadione-triggered necrosis was completely prevented by the classical ROS scavenger NAC and to a substantial amount by the other scavengers, ROS targeting was found to have a marginal effect on the other cell death modalities investigated. Despite its side-effects at higher concentrations, Tempol was able to substantially prevent TNF-induced apoptosis and to a somewhat lesser extent TNF-induced necroptosis. However, this seems to be separated from its ROS-scavenging function.}, }
@article {pmid30050936, year = {2018}, author = {Alhusaini, AM and Faddah, LM and El Orabi, NF and Hasan, IH}, title = {Role of Some Natural Antioxidants in the Modulation of Some Proteins Expressions against Sodium Fluoride-Induced Renal Injury.}, journal = {BioMed research international}, volume = {2018}, number = {}, pages = {5614803}, pmid = {30050936}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Acute Kidney Injury/drug therapy/*metabolism ; Animals ; Antioxidants/*pharmacology ; Benzoquinones/pharmacology ; Glutathione ; Kidney ; Male ; *Oxidative Stress ; Rats ; Rats, Wistar ; Sodium Fluoride/*toxicity ; }, abstract = {BACKGROUND: The aim of the present work is to find the effects of N-acetylcysteine (NAC) and/or thymoquinone (THQ) in the protection against acute renal injury induced by sodium fluoride (NaF).<br><br>METHOD: Rats were distributed into five groups: G1 was normal (control), G2 was intoxicated with 10mg/kg NaF i.p., G3 was treated with 10mg THQ /kg, G4 was treated with 20mg NAC /kg, and G5 was treated with a combination of THQ and NAC. The previous treatments were given daily along with NaF for four weeks orally.<br><br>RESULT: Rats intoxicated with NaF showed a significant increase in serum urea, creatinine, uric acid, renal lipid peroxidation, nitric oxide, and TNF-&#x3b1; levels, whereas the activity of superoxide dismutase (SOD) and glutathione (GSH) level was reduced. The expressions of Toll-like receptor-4 (TLR4), Lipocalin, vascular adhesion molecule-1(VCAM-1), and BAX proteins were upregulated, whereas Bcl-2 and NF-E2-related factor 2 (Nrf2) proteins expressions were downregulated. DNA fragmentation was also amplified. Histological analysis revealed that NaF caused a destructive renal cortex in the form of the glomerular corpuscle, the obliterated proximal and distal convoluted tubules, vacuolization in tubular cells focal necrosis, and cell infiltration. THQ and NAC supplementation counteracted NaF-induced nephrotoxicity as reflected by the increase in renal GSH and SOD. THQ and NAC ameliorated all the altered proteins expressions, improved renal architecture, and declined DNA fragmentation.<br><br>CONCLUSION: The role of oxidative stress in the enhancement of NaF toxicity suggested the renoprotective effects of NAC and THQ against the toxicity of fluoride via multiple mechanisms.}, }
@article {pmid30050888, year = {2018}, author = {Mostajeran, F and Tehrani, HG and Rahbary, B}, title = {N-Acetylcysteine as an Adjuvant to Letrozole for Induction of Ovulation in Infertile Patients with Polycystic Ovary Syndrome.}, journal = {Advanced biomedical research}, volume = {7}, number = {}, pages = {100}, pmid = {30050888}, issn = {2277-9175}, abstract = {BACKGROUND: This study was aimed to evaluate the influence of oral N-acetylcysteine (NAC) application as an adjuvant to letrozole on induced ovulation outcomes in patients with polycystic ovary syndrome (PCOS).<br><br>MATERIALS AND METHODS: This was a placebo-controlled double-blind randomized clinical trial with 130 PCOS patients who were infertile. First, patients were randomly divided into two groups. Patients in Group 1 were administered letrozole 5 mg/d plus NAC 1.2 g/d and patients in Group 2 were administered letrozole plus placebo for 5 days starting at the 3[rd] day of the menstruation period. On the 12[th] day of the cycle, ultrasound evaluation was performed, and in whom at least one follicle with an 18-20 mm diameter was found, 10,000 unit human chorionic gonadotropin (hCG) was prescribed, and 36 h after hCG injection, timed intercourse was advised. On the 16[th] day, after hCG injection, serum &#x3b2;-hCG level was evaluated.<br><br>RESULTS: The number of follicles >18 mm was significantly higher in the letrozole + NAC group (P = 0.007). The ovulation and pregnancy rates were also significantly higher in the letrozole + NAC group (P = 0.045). No adverse side effects and no cases of ovarian hyperstimulation syndrome were observed in NAC group.<br><br>CONCLUSION: NAC is demonstrated to be a safe and well-tolerated adjuvant to letrozole and can increase the pregnancy rates in PCOS patients.}, }
@article {pmid30050663, year = {2018}, author = {Li, H and Luo, YF and Wang, YS and Yang, Q and Xiao, YL and Cai, HR and Xie, CM}, title = {Using ROS as a Second Messenger, NADPH Oxidase 2 Mediates Macrophage Senescence via Interaction with NF-κB during Pseudomonas aeruginosa Infection.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {9741838}, pmid = {30050663}, issn = {1942-0994}, mesh = {Acetylcysteine/metabolism ; Animals ; Cellular Senescence/physiology ; Humans ; Interleukin-6/metabolism ; Macrophages/*cytology/*metabolism ; NADPH Oxidase 2/*metabolism ; NF-kappa B/*metabolism ; Pseudomonas Infections/*metabolism ; Pseudomonas aeruginosa/pathogenicity ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Pseudomonas aeruginosa (PA) is one of the most prevalent pathogens that cause nosocomial infection in critical patients. However, the mechanisms underlying macrophage growth status and functional changes during PA infection are yet unknown. In the present study, NADPH oxidase, gp91[phox] (NOX2) mediated macrophage to senescence in a PAO1 colony-dependent manner. gp91[phox] might regulate the senescence process through mutual interaction with the NF-κB pathway. During infection, the overexpression or downregulation of gp91[phox] in macrophage could affect the nuclear activity of NF-κB p65, while the downregulation of NF-κB p65 led to a suppressed expression of gp91[phox]. Reactive oxygen species (ROS) served as the second messenger between both molecules as the ROS inhibitor, N-acetylcysteine (NAC), could partially restore these changes. Consequently, the level of ROS and inflammatory cytokines, including IL-6 and TNFα, elevated during PAO1 infection, and their production altered as a result of the genetic manipulation of gp91[phox] and NF-κB p65, as well as NAC treatment. Also, the senescent phenotypes, SA-β-gal staining and p16[ink4a], changed after genetic manipulation with gp91[phox] and NF-κB p65 and NAC treatment. The capacity of phagocytosis in macrophages was decreased during senescence. In conclusion, PA directs the macrophage towards senescence, and senescent macrophages exhibit a decreased ability of phagocytosis. This process of senescence was regulated by the interactions between NADPH oxidase gp91[phox] and NF-κB p65 via ROS as a second messenger.}, }
@article {pmid30045259, year = {2018}, author = {Shafiei, E and Bahtoei, M and Raj, P and Ostovar, A and Iranpour, D and Akbarzadeh, S and Shahryari, H and Anvaripour, A and Tahmasebi, R and Netticadan, T and Movahed, A}, title = {Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting: A randomized, open-labeled, placebo-controlled trial.}, journal = {Medicine}, volume = {97}, number = {30}, pages = {e11383}, pmid = {30045259}, issn = {1536-5964}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Antioxidants/administration &amp; dosage ; Cardiotonic Agents/administration &amp; dosage ; Coronary Artery Bypass/*adverse effects/methods ; *Coronary Disease/metabolism/surgery ; Drug Monitoring ; Female ; Humans ; Male ; Melatonin/*administration &amp; dosage ; Middle Aged ; *Myocardial Reperfusion Injury/drug therapy/etiology/metabolism ; Oxidative Stress/*drug effects ; Treatment Outcome ; }, abstract = {OBJECTIVES: This study assessed the efficacy of oral consumption of N-acetyl cysteine (NAC) and melatonin (ML) in reducing early reperfusion injury and acute oxidative stress in patients undergoing coronary artery bypass grafting (CABG) with respect to the measurements of cardiac troponin I, lactate, malondealdehyde (MDA), and tumor necrosis factor-α (TNF-α) levels in the blood.<br><br>METHODS: This study was a randomized, open-label, placebo-controlled trial. Eighty eight patients, aged between 39 to 76 years and eligible for CABG, were recruited and randomly assigned into 3 intervention groups through a simple randomization method and underwent CABG surgery. Blood samples were withdrawn from arterial line, before the induction of anesthesia (before the start of surgery), after incision (before aortic cross-clamping), during global ischemia (during aortic cross-clamping), after aortic cross-clamping (on set of reperfusion), 15 minutes after reperfusion, and after recovery at the intense care unit. The blood samples were analyzed for troponin I, lactate, MDA and TNF-&#x3b1; levels.<br><br>RESULTS: There was no significant difference in influencing variables among the groups at the baseline. Overall mean troponin I, lactate, and TNF- &#x3b1; levels were significantly different between the intervention groups (all P&#x200a;<&#x200a;.001) at the recovery phase. Post-hoc pairwise comparisons showed that the differences of mean serum levels between ML and control groups were statistically significant for MDA, TNF- &#x3b1;, lactate, and troponin I (P&#x200a;<&#x200a;.001, P&#x200a;=&#x200a;.001, and P&#x200a;=&#x200a;.001, respectively). The differences between NAC and control groups and between ML and NAC groups were only significant for mean lactate level (P&#x200a;<&#x200a;.001).<br><br>CONCLUSION: The current study revealed that ML and NAC are potent antioxidants with similar efficacy in terms of reducing CABG related cardiac injury and oxidative stress with the dosage employed for the intervention.}, }
@article {pmid30042177, year = {2018}, author = {Shimura, T and Sasatani, M and Kawai, H and Kamiya, K and Kobayashi, J and Komatsu, K and Kunugita, N}, title = {Radiation-Induced Myofibroblasts Promote Tumor Growth via Mitochondrial ROS-Activated TGFβ Signaling.}, journal = {Molecular cancer research : MCR}, volume = {16}, number = {11}, pages = {1676-1686}, doi = {10.1158/1541-7786.MCR-18-0321}, pmid = {30042177}, issn = {1557-3125}, mesh = {Animals ; Cell Differentiation/radiation effects ; HeLa Cells ; Humans ; Lung/*metabolism/pathology/*radiation effects ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/metabolism/pathology/radiation effects ; Myofibroblasts/*metabolism/pathology/*radiation effects ; Neoplasms/*metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Transforming Growth Factor beta/*metabolism ; Tumor Microenvironment ; }, abstract = {Fibroblasts are a key stromal cell in the tumor microenvironment (TME) and promote tumor growth via release of various growth factors. Stromal fibroblasts in cancer, called cancer-associated fibroblasts (CAF), are related to myofibroblasts, an activated form of fibroblast. While investigating the role of stroma fibroblasts on radiation-related carcinogenesis, it was observed following long-term fractionated radiation (FR) that the morphology of human diploid fibroblasts changed from smaller spindle shapes to larger flat shapes. These cells expressed smooth muscle actin (α-SMA) and platelet-derived growth factor receptors, markers of myofibroblasts and CAFs, respectively. Long-term FR induces progressive damage to the fibroblast nucleus and mitochondria via increases in mitochondrial reactive oxygen species (ROS) levels. Here, it is demonstrated that long-term FR-induced α-SMA-positive cells have decreased mitochondrial membrane potential and activated oxidative stress responses. Antioxidant N-acetyl cysteine suppressed radiation-induced mitochondrial damage and generation of myofibroblasts. These results indicate that mitochondrial ROS are associated with the acquisition of myofibroblasts after long-term FR. Mechanistically, mitochondrial ROS activated TGFβ signaling which in turn mediated the expression of α-SMA in radiation-induced myofibroblasts. Finally, in vivo tumor growth analysis in a human tumor xenograft model system revealed that long-term FR-induced myofibroblasts promote tumor growth by enhancing angiogenesis.Implications: Radiation affects malignant cancer cells directly and indirectly via molecular alterations in stromal fibroblasts such as activation of TGFβ and angiogenic signaling pathways. Mol Cancer Res; 16(11); 1676-86. ©2018 AACR.}, }
@article {pmid30041247, year = {2018}, author = {Wu, H and Chen, Z and Chen, JZ and Pei, LG and Xie, J and Wei, ZH and Kang, LN and Wang, L and Xu, B}, title = {High Mobility Group B-1 (HMGB-1) Promotes Apoptosis of Macrophage-Derived Foam Cells by Inducing Endoplasmic Reticulum Stress.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {48}, number = {3}, pages = {1019-1029}, doi = {10.1159/000491970}, pmid = {30041247}, issn = {1421-9778}, mesh = {Animals ; Apoptosis/*drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Foam Cells/cytology/metabolism ; HMGB1 Protein/metabolism/*pharmacology ; Heat-Shock Proteins/metabolism ; Lipoproteins, LDL/pharmacology ; Macrophages/cytology/drug effects/metabolism ; Mice ; Oxidative Stress/drug effects ; RAW 264.7 Cells ; Signal Transduction/drug effects ; Transcription Factor CHOP/metabolism ; }, abstract = {BACKGROUND/AIMS: High mobility group B-1 (HMGB-1)-induced endoplasmic reticulum stress (ERS) has been implicated in inflammation and dendritic cell maturation. C/EBP-homologous protein (CHOP) is a vital component of ERS and apoptosis and plays a critical role in atherosclerosis. However, only a little information is available about the role of HMGB-1 in foam cell formation. Thus, the role of HMGB-1-induced ERS/CHOP pathway in apoptosis and formation of macrophage-derived foam cells is investigated.<br><br>METHODS: RAW264.7 cells were treated with oxidized low-density lipoprotein (oxLDL) in the absence and/or presence of HMGB-1, N-acetylcysteine (NAC, an antioxidant), glycyrrhizin (Gly, an HMGB-1 inhibitor), tunicamycin (TM, an ERS inducer), and 4-phenylbutyrate (4-PBA, an ERS inhibitor). Reactive oxygen species (ROS) production was examined by dihydroethidium (DHE) staining. Oil Red O staining, intracellular total cholesterol assay, and Dil-oxLDL uptake assay evaluated the accumulation of lipids in macrophages. Cell apoptosis was measured by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Western blot detected the expression of HMGB-1/ERS/CHOP pathway.<br><br>RESULTS: oxLDL induced HMGB-1 translocation and secretion in a dose- and time-dependent manner, which was inhibited by NAC. oxLDL-induced lipid accumulation in macrophages was promoted synergistically by HMGB-1 that was attenuated by Gly. Moreover, TM synergized with oxLDL induced lipid accumulation and apoptosis of macrophages; however, 4-PBA alleviated the oxLDL-induced apoptotic foam cells. Additionally, the inhibition of ERS with 4-PBA suppressed the expression of HMGB-1-induced CHOP.<br><br>CONCLUSIONS: OxLDL triggered HMGB-1 secretion in macrophages via oxidative stress. Furthermore, HMGB-1 promoted the formation and apoptosis of macrophage-derived foam cells via activation of ERS/CHOP pathway.}, }
@article {pmid30037745, year = {2018}, author = {Kong, P and Chen, L and Shi, X and Pan, H and Yu, M and Ge, H and Zhu, J and Ma, G and Li, L and Ding, Q and Zhou, W and Wang, S}, title = {Microwave ablation combined with doxorubicin enhances cell death via promoting reactive oxygen species generation in breast cancer cells.}, journal = {Diagnostic and interventional imaging}, volume = {99}, number = {12}, pages = {783-791}, doi = {10.1016/j.diii.2018.06.004}, pmid = {30037745}, issn = {2211-5684}, mesh = {*Ablation Techniques ; Animals ; Antibiotics, Antineoplastic/*therapeutic use ; Breast Neoplasms/*pathology/*therapy ; *Cell Death ; Combined Modality Therapy ; Doxorubicin/*therapeutic use ; Mice ; Microwaves/*therapeutic use ; Random Allocation ; *Reactive Oxygen Species ; Tumor Cells, Cultured ; }, abstract = {PURPOSE: To evaluate the mechanism for enhancing cell death induced by microwave ablation (MWA) combined with doxorubicin treatment in breast cancer cells.<br><br>MATERIALS AND METHODS: Different temperatures of heat treatment were used to mimic the tumor affected by sublethal heat during MWA in vitro. Breast cancer cells were treated at 43&#xb0;C and 45&#xb0;C, with or without doxorubicin. Cell viability, apoptosis, and intracellular reactive oxygen species (ROS) were evaluated in MDA-MB-231 and SUM-1315 cells. Nude mice breast cancer models were randomly divided into control, MWA, doxorubicin, and combined treatment groups. Tumor apoptosis and DNA damage were evaluated in these groups.<br><br>RESULTS: The combined group had lower cell viability than the heat or doxorubicin group (all P<0.05), and enhanced apoptosis rate was observed in the combined group compared to others (all P<0.01) in MDA-MB-231 and SUM-1315. Increased capase3 (all P<0.01) and decreased Bcl-Xl (all P<0.01) were detected after combined therapy compared to single treated group in vitro. The raisedCaspase3 and DNA damage marker histone H2A.X induced by combined treatment were also approved in the nude mice models. Combined treatment promoted ROS generation compared to doxorubicin or MWA treatment (all P < 0.01). NF-&#x3ba;B expression in the combined group was higher than that of the single treatment group (all P<0.05). N-acetylcysteine (NAC), a ROS scavenger, partly restrained the combined treatment induced cell proliferation inhibition, Caspase3 and NF-&#x3ba;B compared to doxorubicin treatment (all P<0.05).<br><br>CONCLUSION: MWA combined with doxorubicin promote cell death via ROS induced cell apoptosis and DNA damage. Increasing ROS has potential for improving the efficiency of combined treatment.}, }
@article {pmid30037311, year = {2018}, author = {Mohammadi-Sardoo, M and Mandegary, A and Nabiuni, M and Nematollahi-Mahani, SN and Amirheidari, B}, title = {Mancozeb induces testicular dysfunction through oxidative stress and apoptosis: Protective role of N-acetylcysteine antioxidant.}, journal = {Toxicology and industrial health}, volume = {34}, number = {11}, pages = {798-811}, doi = {10.1177/0748233718778397}, pmid = {30037311}, issn = {1477-0393}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Male ; Maneb/*toxicity ; Mice ; Oxidative Stress/*drug effects ; Spermatogenesis/drug effects ; Testis/*drug effects/pathology/physiopathology ; Zineb/*toxicity ; }, abstract = {Mancozeb (MZB) is one of the fungicides used in pest control programs that might affect human health including reproductive system. The aim of this study was to demonstrate the mechanisms through which MZB induces testicular tissue damage and the probable protective effect of N-acetylcysteine (NAC), a modified amino acid, with antioxidant property, against MZB toxicity in an animal model. Male albino mice (n = 8) were exposed to different doses of MZB (250 and 500 mg/kg/day) by oral gavage without or with NAC (200 mg/kg, twice/week) for 40 days. Sub-chronic MZB dose-dependently decreased sperm motility and count. Exposure to MZB increased lipid peroxidation and protein carbonyl, while it reduced antioxidant enzymes activities, total antioxidant capacity, and glutathione content. The histopathological examination clearly showed deleterious changes in the testicular structure. At the molecular levels, the results of quantitative real time-poly chain reaction (qRT-PCR) showed that MZB upregulated oxidative stress markers inducible nitric oxide synthase (iNOS) and NADPH oxidase 4 (NOX4) and downregulated expression of the glutathione peroxidase 1 (Gpx1) gene as one of the most important antioxidant enzymes. MZB also induced apoptosis dose-dependently in the testes as determined by the terminal dUTP nick-end labeling assay and immunoblotting. NAC administration decreased the mRNA levels of both iNOS and NOX4 with a concomitant increase in Gpx1 expression. It also significantly decreased MZB-induced oxidative stress and apoptosis. Collectively, the present study showed MZB-induced oxidative damage in testes leading to apoptosis. It revealed that antioxidants such as NAC can mitigate oxidant injury induced by the dithiocarbamate pesticides in the reproductive system.}, }
@article {pmid30035805, year = {2018}, author = {Quintanilla, ME and Morales, P and Ezquer, F and Ezquer, M and Herrera-Marschitz, M and Israel, Y}, title = {Commonality of Ethanol and Nicotine Reinforcement and Relapse in Wistar-Derived UChB Rats: Inhibition by N-Acetylcysteine.}, journal = {Alcoholism, clinical and experimental research}, volume = {42}, number = {10}, pages = {1988-1999}, doi = {10.1111/acer.13842}, pmid = {30035805}, issn = {1530-0277}, support = {1180042//FONDECYT/International ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Alcohol Drinking/*drug therapy/genetics/*psychology ; Animals ; Ethanol/*administration &amp; dosage ; Female ; Nicotine/*administration &amp; dosage ; Rats ; Rats, Transgenic ; Rats, Wistar ; Recurrence ; *Reinforcement, Psychology ; Self Administration ; }, abstract = {BACKGROUND: Life expectancy is greatly reduced in individuals presenting alcohol use disorders and chronic smoking. Literature studies suggest that common mechanisms may apply to the chronic use and relapse of both alcohol and nicotine. It is hypothesized that an increased brain oxidative stress and neuroinflammation are involved in perpetuating these conditions and that a common treatment may be considered for both.<br><br>METHODS: Rats bred as high ethanol (EtOH) drinkers (UChB) were allowed chronic access to EtOH solutions and water and were thereafter deprived of EtOH for a prolonged period, subsequently allowing reaccess to EtOH, which leads to marked relapse binge-like drinking. Separately, EtOH-na&#xef;ve animals were chronically administered nicotine intraperitoneally and tested under either a conditioned place preference (CPP) reinstatement condition or allowed a free-choice drinking of nicotine solutions and water. Oral N-acetylcysteine (NAC) (100&#xa0;mg/kg) was administered daily to the animals to determine its effect on both chronic voluntary EtOH and nicotine intake, on EtOH relapse and nicotine-CPP reinstatement. Oxidative stress was evaluated in hippocampus as the oxidized/reduced glutathione ratio (GSSG/GSH), and neuroinflammation by glial fibrillary acidic protein (GFAP) immunohistochemistry.<br><br>RESULTS: Marked increases in hippocampal oxidative stress (GSSG/GSH) and neuroinflammation (astrocyte reactivity, GFAP) were observed after both chronic EtOH and chronic nicotine treatment. Oral NAC administration (i) fully abolished the increased oxidative stress and the neuroinflammation induced by both drugs, (ii) greatly inhibited EtOH intake (70%) and EtOH relapse binge-like drinking (76%), and (iii) markedly inhibited (90%) voluntary nicotine intake and fully suppressed nicotine-CPP reinstatement.<br><br>CONCLUSIONS: Data indicate that (i) oxidative stress and neuroinflammation are tightly associated with chronic EtOH and nicotine intake and drug relapse and (ii) NAC inhibits the relapse for both drugs, suggesting that the oral chronic administration of NAC may be of value in the concomitant treatment of alcohol and nicotine use disorders.}, }
@article {pmid30035652, year = {2018}, author = {Ceylan, B and Ozansoy, M and Kılıç, &#xdc; and Yozgat, Y and Ercan, &#xc7; and Yıldız, P and Aslan, T}, title = {N-acetylcysteine suppresses colistimethate sodium-induced nephrotoxicity via activation of SOD2, eNOS, and MMP3 protein expressions.}, journal = {Renal failure}, volume = {40}, number = {1}, pages = {423-434}, pmid = {30035652}, issn = {1525-6049}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Acetylglucosaminidase/blood ; Acute Kidney Injury/blood/chemically induced/*drug therapy/pathology ; Animals ; Colistin/analogs &amp; derivatives/toxicity ; Creatinine/blood ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology/therapeutic use ; Humans ; Kidney/drug effects/pathology ; Male ; Matrix Metalloproteinase 3/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: To investigate the molecular mechanisms of colistimethate sodium-induced nephrotoxicity and the protective effect of N-acetylcysteine (NAC) against nephrotoxicity.<br><br>METHODS: Twenty-eight Wistar rats were divided into four groups comprised of control, colistin, NAC, and colistin-NAC co-treatment, respectively. Serum creatinine and urine N-acetyl-&#x3b2;-d-glucosaminidase (NAG) levels were measured at different time intervals. Histological changes, apoptosis, total oxidant and antioxidant status, and the expression levels of endothelial nitric oxide synthase (eNOS), superoxide dismutase 2 (SOD2), and matrix metalloproteinase 3 (MMP3) were evaluated in renal tissue.<br><br>RESULTS: In the colistin group, post-treatment creatinine levels were higher than pretreatment levels (p&#x2009;=&#x2009;.001). There was a significant increase in urine NAG level following colistin treatment on day 10, compared to the baseline value and the first day of treatment (p&#x2009;=&#x2009;.001 and .0001, respectively). Urine NAG levels were higher in the colistin group on the 10th day of treatment than in the other groups (p&#x2009;<&#x2009;.01). Colistin treatment increased the apoptosis index and renal histological damage score (RHDS) significantly and these changes were reversed in NAC co-treatment (RHSD and apoptosis index were 45 and 0 for sterile saline group, 29 and 2 for NAC group, 122 and 7 for colistin group, and 66 and 2 for colistin&#x2009;+&#x2009;NAC group). We observed no difference between groups regarding total antioxidant and total oxidant status in the kidneys. The expression levels of eNOS, SOD2, and MMP3 decreased significantly in the kidneys of colistin-treated rats; these changes were reversed in the kidneys of NAC co-treated rats.<br><br>CONCLUSIONS: N-acetylcysteine prevented colistin-induced nephrotoxicity through activation of expression levels of SOD2, eNOS, and MMP3.}, }
@article {pmid30034421, year = {2018}, author = {Yesil, Y and Ozdemir, AA}, title = {Evaluation of the children with acute acetaminophen overdose and intravenous N-acetylcysteine treatment.}, journal = {Pakistan journal of medical sciences}, volume = {34}, number = {3}, pages = {590-594}, pmid = {30034421}, issn = {1682-024X}, abstract = {OBJECTIVE: To evaluate the demographic and clinical features associated with acetaminophen overdose and to identify the clinical use of IV (intravenous) N- Acetylcysteine (NAC) treatment in children.<br><br>METHODS: This prospective study was conducted in Kanuni Sultan Suleyman Training and Research Hospital between August 2016 and August 2017. A total of 59 patients with overdose acetaminophen ingestion were included in this study. The toxic dose for acute acetaminophen intake was defined as greater than 150 mg/kg. Rumack-Matthew nomogram was used to evaluate the risk of acute intoxication and to determine the decision of using antidote.<br><br>RESULTS: The mean age of the patients was 8.5&#xb1;6.4 y and 34 of them (58%) were female. The mean time from ingestion to admission was 4.3&#xb1;4.7 h. The mean ingested acetaminophen dose was 142.1&#xb1;80 mg/kg. Twenty four patients (41%) received NAC and there were significant differences in terms of acetaminophen dose, creatinine and INR between antidote and decontamination therapy groups at admission time (p= 0.00, p= 0.03, p= 0.02, respectively). The complication due to antidote therapy was observed in only 1 patient.<br><br>CONCLUSIONS: This study confirms that the side effects due to IV NAC therapy are uncommon and it is generally well tolerated in children.}, }
@article {pmid30025127, year = {2018}, author = {Li, X and Kang, B and Woo, IH and Eom, Y and Lee, HK and Kim, HM and Song, JS}, title = {Effects of Topical Mucolytic Agents on the Tears and Ocular Surface: A Plausible Animal Model of Mucin-Deficient Dry Eye.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {59}, number = {7}, pages = {3104-3114}, doi = {10.1167/iovs.18-23860}, pmid = {30025127}, issn = {1552-5783}, mesh = {Acetylcysteine/administration &amp; dosage/*adverse effects ; Administration, Ophthalmic ; Animals ; Cell Count ; Conjunctiva/*drug effects/metabolism ; Cornea/drug effects/metabolism ; *Disease Models, Animal ; Dry Eye Syndromes/*chemically induced/metabolism/pathology ; Enzyme-Linked Immunosorbent Assay ; Expectorants/administration &amp; dosage/*adverse effects ; Goblet Cells/pathology ; Male ; Microscopy, Electron, Scanning ; Mucin 5AC/*deficiency ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Tears/*metabolism ; }, abstract = {PURPOSE: A topical mucolytic agent, N-acetylcysteine (NAC), has been used to create an animal model without the intestinal mucus layer. In this study, we investigated the effects of topical NAC on the tears and ocular surface.<br><br>METHODS: NAC-treated models were established by topically administering 10% NAC four times daily for 5 days in male Sprague-Dawley rats. Clinical parameters and the expression of mucin proteins and genes were evaluated. Alterations in the conjunctival epithelium and goblet cells were observed.<br><br>RESULTS: The NAC group showed significant decreases in tear secretion, corneal wetting ability, tear MUC5AC concentration, and conjunctival goblet cell numbers as compared with the control group (all P < 0.01). In addition, significant increases in corneal fluorescein score and rose bengal scores were observed in the NAC group versus in the control group (P < 0.05 and P < 0.01, respectively). Hematoxylin and eosin (H&amp;E) staining and scanning electron microscopy clearly showed damage in the epithelial cell layer and microvilli of the NAC group. Although there was no significant difference in MUC16 gene expression, the MUC16 concentration of the tear film and ocular surface tissue was significantly increased in the NAC group versus in the control group (P < 0.01 and P < 0.05, respectively). Five-day treatment with 3% diquafosol had minimal therapeutic effect in NAC-treated rat eyes.<br><br>CONCLUSIONS: Topical administration of 10% NAC induced ocular surface damage and tear film instability by prompting MUC16 disruption and release from the ocular surface. This animal model could be used to study dry eye disease, especially the mucin-deficiency subtype.}, }
@article {pmid30024038, year = {2018}, author = {Yan, M and Ye, L and Yin, S and Lu, X and Liu, X and Lu, S and Cui, J and Fan, L and Kaplowitz, N and Hu, H}, title = {Glycycoumarin protects mice against acetaminophen-induced liver injury predominantly via activating sustained autophagy.}, journal = {British journal of pharmacology}, volume = {175}, number = {19}, pages = {3747-3757}, pmid = {30024038}, issn = {1476-5381}, support = {R01 DK067215/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/*antagonists &amp; inhibitors ; Animals ; Autophagy/*drug effects ; Chemical and Drug Induced Liver Injury/*drug therapy/pathology ; Coumarins/administration &amp; dosage/*pharmacology ; Dose-Response Relationship, Drug ; Injections, Intraperitoneal ; Male ; Mice ; Mice, Inbred C57BL ; Protective Agents/administration &amp; dosage/*pharmacology ; Structure-Activity Relationship ; }, abstract = {BACKGROUND AND PURPOSE: Acetaminophen-induced acute liver injury (AILI) is the most frequent cause of acute liver failure in developed countries. Given the significant limitations associated with N-acetyl cysteine, the only antidote used to treat AILI, the development of novel therapeutic approaches that can offer a wide range of therapeutic time-windows is clearly needed. Glycycoumarin (GCM), a natural coumarin purified from liquorice, has been previously demonstrated to possess potent hepatoprotective effects. In the present study, we aimed to investigate the therapeutic potential of GCM against AILI.<br><br>EXPERIMENTAL APPROACH: Acetaminophen (300&#xa0;mg&#xb7;kg[-1]) was administered to male C57BL/6 mice, with and without GCM. Serum transaminases, haematoxylin and eosin staining and Western blot were used to assess hepatic damage.<br><br>KEY RESULTS: GCM (50&#xa0;mg&#xb7;kg[-1]) was highly effective against acetaminophen-induced hepatotoxicity. Moreover, GCM was superior to N-acetyl cysteine, in terms of the dosage and the therapeutic time-windows. Further mechanistic investigations revealed that the therapeutic action of GCM was not a result of inhibition of acetaminophen metabolic activation or associated with Nrf2. Instead, the protective effect of GCM appeared to be predominantly dependent on sustained activation of autophagy, which attenuated acetaminophen-induced mitochondrial oxidative stress and JNK activation.<br><br>CONCLUSIONS AND IMPLICATIONS: Collectively, our results indicate that GCM alleviated acetaminophen-induced oxidative stress through activating autophagy, thereby protecting against AILI. Our findings suggest that GCM has potential as a novel therapeutic agent for treating AILI.}, }
@article {pmid30023950, year = {2018}, author = {Prakash, S and Hazari, PP and Meena, VK and Mishra, AK}, title = {Radiolabeling and Preclinical Evaluation of a New S-Alkylated Cysteine Derivative Conjugated to C-Substituted Macrocycle for Positron Emission Tomography.}, journal = {ACS omega}, volume = {3}, number = {6}, pages = {6497-6505}, pmid = {30023950}, issn = {2470-1343}, abstract = {A new S-alkylated cysteine-derivatized tumor targeting agent, 2,2'-(12-(2-((2-acetamido-2-carboxyethyl)thio)acetamido)-11,13-dioxo-1,4,7,10-tetraazacyclotridecane-4,7-diyl)diacetic acid was developed for positron emission tomography (PET) imaging. N-Acetyl cysteine (NAC) was conjugated to ATRIDAT as a specific targeting agent toward L-type and ASC amino acid transporter systems in the oncogenic cells. NAC was attached via S-alkylation to prevent its incorporation at undesired recognition sites affecting the signal-to-noise ratio. NAC-ATRIDAT was subjected to gallium-68 complexation with >75% radiolabeling yield. The radiocomplex was purified through the tc18 cartridge to obtain 99.89% radiochemical yield. IC-50 of the NAC-ATRIDAT conjugate was 0.8 mM in A549 cells as evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide assay. Binding affinity experiments on A549 cells showed noteworthy binding with KD in the nanomolar range. A time course study showed a Km value of 0.19 μM and Vmax value of 0.49 pmol/μg protein/min showing reasonable tumor kinetics. Efflux studies showed that the synthesized radioligand is transported majorly by LAT followed by the ASC system. Clearance was found to be renal with 7.67 ± 1.48% ID/g uptake at 30 min which substantially declined to 0.52 ± 0.% ID/g at 4 h. A significant uptake of 10.06 ± 1.056% ID/g was observed at the tumor site in mice at 1 h. μPET images revealed a high contrast with a tumor-to-kidney ratio of 4.8 and a tumor-to-liver ratio of 35.85 at 1 h after injection. These preclinical in vitro and in vivo evaluation supports its potential on the way of becoming a successful [68]Ga-radiolabeled amino acid-based PET imaging agent.}, }
@article {pmid30023335, year = {2018}, author = {Nikravesh, H and Khodayar, MJ and Mahdavinia, M and Mansouri, E and Zeidooni, L and Dehbashi, F}, title = {Protective Effect of Gemfibrozil on Hepatotoxicity Induced by Acetaminophen in Mice: the Importance of Oxidative Stress Suppression.}, journal = {Advanced pharmaceutical bulletin}, volume = {8}, number = {2}, pages = {331-339}, pmid = {30023335}, issn = {2228-5881}, abstract = {Purpose: Gemfibrozil (GEM) apart from agonist activity at peroxisome proliferator-activated receptor-alpha (PPAR-α) has antioxidant and anti-inflammatory properties. Accordingly, the present study was designed to investigate the protective effect of GEM on acute liver toxicity induced by acetaminophen (APAP) in mice. Methods: In this study, mice divided in seven groups include, control group, APAP group, GEM group, three APAP groups pretreated with GEM at the doses of 25, 50 and 100 mg/kg respectively and APAP group pretreated with N-Acetyl cysteine. GEM, NAC or vehicle were administered for 10 days. In last day, GEM and NAC were gavaged 1 h before and 1 h after APAP injection. Twenty four hours after APAP, mice were sacrificed. Serum parameters include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver tissue markers including catalase enzyme activity, reactive oxygen species (ROS), malondialdehyde and reduced glutathione (GSH) levels determined and histopathological parameters measured. Results: GEM led to significant decrease in serum ALT and AST activities and increase in catalase activity and hepatic GSH level and reduces malondialdehyde and ROS levels in the liver tissue. In confirmation, histopathological findings revealed that GEM decrease degeneration, vacuolation and necrosis of hepatocytes and infiltration of inflammatory cells. Conclusion: Present data demonstrated that GEM has antioxidant properties and can protect the liver from APAP toxicity, just in the same pathway that toxicity occurs by toxic ROS and that GEM may be an alternative therapeutic agent to NAC in APAP toxicity.}, }
@article {pmid30021379, year = {2018}, author = {Yan, J and Li, M and Wang, XD and Lu, ZY and Ni, XL}, title = {Peperomin E (PepE) protects against high fat diet-induced atherosclerosis in Apolipoprotein E deficient (ApoE[-/-]) mice through reducing inflammation via the suppression of NLRP3 signaling pathway.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {105}, number = {}, pages = {862-869}, doi = {10.1016/j.biopha.2018.04.140}, pmid = {30021379}, issn = {1950-6007}, mesh = {Animals ; Apolipoproteins E/*deficiency ; Atherosclerosis/metabolism/*prevention &amp; control ; Benzodioxoles/pharmacology/*therapeutic use ; Cell Survival/drug effects/physiology ; Diet, High-Fat/*adverse effects ; Inflammation/drug therapy/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein/*antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Signal Transduction/*drug effects/physiology ; }, abstract = {Peperomin E (PepE) is a type of secolignan, a major component of the plant Peperomia dindygulensis. It has been shown to exert anti-inflammatory effects; however, the effects of PepE on human atherosclerosis remain unexplored. In the study, we investigated the role of PepE in high fat diet (HFD) induced atherosclerosis using apolipoprotein E defcient (ApoE[-/-]) mice. Elevated serum homocyteine, cholesterol, and triglyceride levels, accelerated progression of atherosclerosis and exacerbated macrophage infiltration into atherosclerotic lesions were observed in HFD-fed ApoE[-/-] mice, which were attenuated by PepE treatment. ApoE[-/-] mice fed with HFD exhibited significantly high levels of inflammation-associated regulators in artery tissues, accompanied with an increased expression of p-inhibitor of κBα (IκBα) and p-nuclear factor-kappa B (NF-κB), and the process was blocked by PepE administration. Further, we found NOD-like receptor pyrin 3 (NLRP3) inflammasome activation in artery tissues of HFD-fed ApoE[-/-] mice. In vitro, silencing NLRP3 using small interfering RNA efficiently inhibited oxidized-low-density lipoprotein (oxLDL)-induced ASC and Caspase-1 expressions, interleukin (IL)-1β and IL-18 production in human aortic endothelial cells (HAECs). Further experiments indicated that NLRP3-ASC pathway was activated by reactive oxygen species (ROS), since ROS scavenger of N-acetyl-cysteine (NAC) prevented, which was further reduced by PepE addition. However, the anti-inflammatory effects of PepE on oxLDL-incubated HAECs were abolished by over-expression NLRP3. Together, our study revealed that PepE inhibited atherosclerosis development in HFD-fed ApoE[-/-] mice by suppressing NLRP3 inflammatory signaling pathway, and suggested that PepE might be a potential therapeutic strategy in the prevention of atherosclerosis.}, }
@article {pmid30020504, year = {2019}, author = {Moitra, S}, title = {N-acetylcysteine (NAC) in COPD: benefits often lost in trials.}, journal = {QJM : monthly journal of the Association of Physicians}, volume = {112}, number = {5}, pages = {387-388}, doi = {10.1093/qjmed/hcy166}, pmid = {30020504}, issn = {1460-2393}, mesh = {Acetylcysteine/*therapeutic use ; Clinical Trials as Topic ; Humans ; Oxidative Stress/drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy ; }, }
@article {pmid30020312, year = {2018}, author = {Ozturk, O and Eroglu, HA and Ustebay, S and Kuzucu, M and Adali, Y}, title = {An experimental study on the preventive effects of N-acetyl cysteine and ozone treatment against contrast-induced nephropathy.}, journal = {Acta cirurgica brasileira}, volume = {33}, number = {6}, pages = {508-517}, doi = {10.1590/s0102-865020180060000005}, pmid = {30020312}, issn = {1678-2674}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Contrast Media/*adverse effects ; Creatinine/blood ; Ioxaglic Acid/adverse effects ; Kidney/drug effects/pathology ; Kidney Diseases/*chemically induced/pathology/*prevention &amp; control ; Lipocalin-2/blood ; Male ; Oxidative Stress/drug effects ; Ozone/*pharmacology ; Protein Carbonylation ; Random Allocation ; Rats, Wistar ; Reference Values ; Reproducibility of Results ; Spectrophotometry/methods ; Treatment Outcome ; Urea/blood ; }, abstract = {PURPOSE: To compare the preventive effects of N-acetyl cysteine (NAC), ozone preconditioning and ozone treatment against contrast-induced nephropathy (CIN) in an experimental rat model.<br><br>METHODS: Thirty adult male Wistar rats were randomly distributed into five groups (n=6 for each group). Group I served as control and Group II had only contrast agent, while Group III received NAC and Group IV received intraperitoneal ozone 6 hours before and 6 hours after introduction of contrast agent. Ozone treatment was applied for 5 days after the contrast agent was introduced in Group V. After induction of CIN, groups were compared in terms of serum levels of urea, creatinine, neutrophil gelatinase associated lipocalin, protein carbonyl, total antioxidant capacity (TAC) as well as degree of renal injury at histopathologic level.<br><br>RESULTS: Groups II-V displayed more obvious histopathological alterations such as hemorrhage and renal tubular injury compared with Group I. TAC (p=0.043) and creatinine (p=0.046) levels increased significantly in Group II after the intervention. In Group III, protein carbonyl level diminished remarkably (p=0.046), while creatinine level was increased (p=0.046) following the intervention. TAC level was higher in Group IV (p=0.028) and Group V (p=0.026) following the procedure.<br><br>CONCLUSION: The N-acetyl cysteine and ozone treatment may alleviate the biochemical and histopathological deleterious effects of contrast-induced nephropathy via enhancement of total antioxidant capacity and decreasing oxidative stress.}, }
@article {pmid30019966, year = {2018}, author = {Morley, KC and Baillie, A and Van Den Brink, W and Chitty, KE and Brady, K and Back, SE and Seth, D and Sutherland, G and Leggio, L and Haber, PS}, title = {N-acetyl cysteine in the treatment of alcohol use disorder in patients with liver disease: Rationale for further research.}, journal = {Expert opinion on investigational drugs}, volume = {27}, number = {8}, pages = {667-675}, doi = {10.1080/13543784.2018.1501471}, pmid = {30019966}, issn = {1744-7658}, mesh = {Acetylcysteine/adverse effects/pharmacology/*therapeutic use ; Alcohol Drinking/adverse effects/prevention &amp; control ; Alcoholism/complications/*drug therapy/physiopathology ; Animals ; Antioxidants/adverse effects/pharmacology/*therapeutic use ; Humans ; Liver Diseases, Alcoholic/drug therapy/physiopathology ; Oxidative Stress/drug effects ; }, abstract = {INTRODUCTION: Alcoholic liver disease (ALD) is the leading cause of alcohol-related death and one of the most common forms of liver disease. Abstinence from alcohol is crucial to reducing morbidity and mortality associated with the disease. However, there are few pharmacotherapies for alcohol use disorder suitable for those with significant liver disease.<br><br>AREAS COVERED: This paper presents a rationale for investigating the use of N-acetyl cysteine (NAC) to promote abstinence or reduce heavy alcohol consumption for patients with an alcohol use disorder, particularly in the presence of liver disease. NAC is an antioxidant with glutamatergic modulating and anti-inflammatory properties. Evidence is emerging that oxidative stress, neuro-inflammation and dysregulation of glutamatergic neurotransmission play a key role in alcohol use disorder. Similarly, oxidative stress is known to contribute to ALD. We outline the studies that have investigated NAC to reduce alcohol consumption including preclinical and clinical studies. We also review the evidence for NAC in other addictions as well as psychiatric and physical comorbidities associated with alcohol use disorders.<br><br>EXPERT OPINION: NAC is low cost, well-tolerated and could have promise for the treatment of alcohol use disorder in the presence of liver disease. Clinical trials directly examining efficacy in this population are required.}, }
@article {pmid30012208, year = {2018}, author = {Huang, C and Lu, H and Xu, J and Yu, H and Wang, X and Zhang, X}, title = {Protective roles of autophagy in retinal pigment epithelium under high glucose condition via regulating PINK1/Parkin pathway and BNIP3L.}, journal = {Biological research}, volume = {51}, number = {1}, pages = {22}, pmid = {30012208}, issn = {0717-6287}, mesh = {Autophagy/*drug effects/physiology ; Cell Line ; Flow Cytometry ; Glucose/*pharmacology ; Humans ; Membrane Proteins/*drug effects/metabolism ; Microscopy, Electron, Transmission ; Protein Kinases/*drug effects/metabolism ; Proto-Oncogene Proteins/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/cytology/*drug effects ; Signal Transduction/physiology ; Tumor Suppressor Proteins/*drug effects/metabolism ; Ubiquitin-Protein Ligases/*drug effects/metabolism ; }, abstract = {BACKGROUND: Our study aimed to investigate the roles of autophagy against high glucose induced response in retinal pigment epithelium (ARPE-19 cells).<br><br>METHODS: The morphological changes and reactive oxygen species (ROS) generation in ARPE-19 cells under high glucose treatment were respectively detected using the transmission electron microscopy and flow cytometry. The expression levels of Parkin, PINK1, BNIP3L, LC3-I and LC3-II in ARPE-19 cells received high glucose treatment were measured by western blot after pretreatment of carbonyl cyanide m-chlorophenylhydrazone (CCCP), 3-methyladenine (3-MA), N-acetyl cysteine (NAC) or cyclosporin A (CsA) followed by high glucose treatment.<br><br>RESULTS: ARPE-19 cells subjected to high glucose stress showed an obvious reduction in the LC3-I expression and significant increase in the number of autophagosomes, in the intracellular ROS level, and in the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p&#x2009;<&#x2009;0.05). Pretreatment with CCCP significantly reduced the LC3-I expression and increased the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p&#x2009;<&#x2009;0.05). ARPE-19 cells pretreated with CsA under high glucose stress showed markedly down-regulated expressions of Parkin, PINK1 and BNIP3L compared with the cells treated with high glucose (p&#x2009;<&#x2009;0.05). Pretreatment of ARPE-19 cells with NAC or 3-MA under high glucose stress resulted in a marked reduction in the expression levels of PINK1, BNIP3L and LC3-II (p&#x2009;<&#x2009;0.05). Meanwhile, the expression level of Parkin in the ARPE-19 cells pretreated with NAC under high glucose stress was comparable with that in the control cells.<br><br>CONCLUSION: Autophagy might have protective roles against high glucose induced injury in ARPE19 cells via regulating PINK1/Parkin pathway and BNIP3L.}, }
@article {pmid30011378, year = {2018}, author = {Hegab, II and Abd-Ellatif, RN and Sadek, MT}, title = {The gastroprotective effect of N-acetylcysteine and genistein in indomethacin-induced gastric injury in rats.}, journal = {Canadian journal of physiology and pharmacology}, volume = {96}, number = {11}, pages = {1161-1170}, doi = {10.1139/cjpp-2017-0730}, pmid = {30011378}, issn = {1205-7541}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*adverse effects ; Anti-Ulcer Agents/*pharmacology/therapeutic use ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Drug Therapy, Combination ; Gastric Mucosa/drug effects/pathology ; Genistein/*pharmacology/therapeutic use ; Humans ; Indomethacin/*adverse effects ; Male ; Matrix Metalloproteinase 9/metabolism ; Rats ; Rats, Wistar ; Stomach Ulcer/chemically induced/pathology/*prevention &amp; control ; }, abstract = {The protective effect of N-acetylcysteine (NAC) and genistein (GEN) on an experimental model of indomethacin (IND)-induced gastric injury was investigated. A total of 50 male rats were divided into 5 groups: (1) control, (2) IND, (3) NAC pretreated, (4) GEN pretreated, and (5) NAC+GEN pretreated. Rats in groups 3-5 were orally administered NAC (500 mg/kg), GEN (10 mg/kg), or both, respectively, once daily for 7 days before the induction of gastric injury by IND (50 mg/kg). The stomach was removed for biochemical analysis and histopathological examination. Pretreatment with NAC, GEN, or both significantly improved ulcer indices and increased nitric oxide level and superoxide dismutase activity. They also significantly decreased malondialdehyde, tumour necrosis factor α levels, and myeloperoxidase activity, and downregulated matrix metalloproteinase 9 (MMP-9) gene expression compared to the IND group. NAC alone ameliorated IND-induced apoptosis, whereas GEN only significantly increased prostaglandin E2 level. Further, coadministration of both resulted in a significantly better gastroprotective effect versus solo administration. Coadministration of NAC and GEN has an additive gastroprotective effect in IND-induced gastric injury, which may be through interaction of their potential cytoprotective, antioxidant, anti-inflammatory, and antiapoptotic mechanisms together with regulation of MMP-9 expression.}, }
@article {pmid30010817, year = {2019}, author = {Canesi, F and Mateo, V and Couchie, D and Karabina, S and Nègre-Salvayre, A and Rouis, M and El Hadri, K}, title = {A thioredoxin-mimetic peptide exerts potent anti-inflammatory, antioxidant, and atheroprotective effects in ApoE2.Ki mice fed high fat diet.}, journal = {Cardiovascular research}, volume = {115}, number = {2}, pages = {292-301}, doi = {10.1093/cvr/cvy183}, pmid = {30010817}, issn = {1755-3245}, mesh = {Animals ; Anti-Inflammatory Agents/chemical synthesis/*pharmacology ; Antioxidants/chemical synthesis/*pharmacology ; Aorta/drug effects/metabolism/pathology ; Aortic Diseases/genetics/metabolism/pathology/*prevention &amp; control ; Atherosclerosis/genetics/metabolism/pathology/*prevention &amp; control ; Cells, Cultured ; *Diet, High-Fat ; Disease Models, Animal ; Female ; Inflammation Mediators/*metabolism ; Macrophages, Peritoneal/drug effects/metabolism ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; *Molecular Mimicry ; Oligopeptides/chemical synthesis/*pharmacology ; Oxidative Stress/*drug effects ; *Plaque, Atherosclerotic ; Signal Transduction ; Sulfhydryl Compounds/chemical synthesis/*pharmacology ; Thioredoxins/metabolism ; }, abstract = {AIMS: Oxidative stress and inflammation play a pathogenic role in atherosclerosis. Thioredoxin-1 (Trx-1) is an anti-oxidative, anti-inflammatory protein with atheroprotective effects. However, in vivo cleavage of Trx-1 generates a truncated pro-inflammatory protein, Trx-80, which compromises the therapeutic use of Trx-1. Here we analysed whether the thioredoxin-mimetic peptide (TxMP), CB3 might exert anti-oxidative, anti-inflammatory, and atheroprotective effects in ApoE2.Ki mice.<br><br>METHODS AND RESULTS: We synthesized a small TxMP, Ac-Cys-Pro-Cys-amide, CB3 and characterized its antioxidant and anti-inflammatory effects on cultured peritoneal murine macrophages. CB3 significantly and dose-dependently reduced the level of reactive oxygen species in lipopolysaccharides (LPS)-activated macrophages. In addition, it efficiently lowered LPS-induced inflammatory process through NF-&#x3ba;B inhibition, as evidenced by the reduced secretion of monocyte chemoattractant protein-1, interleukin (IL)-1&#x3b2;, IL-6, and tumor necrosis factor (TNF)-&#x3b1; by macrophages. Nevertheless, CB3 did not affect cholesterol accumulation in macrophages. A daily-administered dose of 10&#x2009;&#xb5;g/g body weight CB3 to ApoE2.Ki mice on high fat diet did not affect plasma of total cholesterol and triglycerides levels but significantly reduced the plasma levels of pro-inflammatory cytokines (IL-33 and TNF-&#x3b1;) and oxidative markers. In contrast, it significantly induced the plasma levels of anti-inflammatory proteins (adiponectin, IL-10). In addition, CB3 reduced the number of pro-inflammatory M1 macrophages in spleen and decreased the ratio of M1/M2 macrophages in atherosclerotic lesion areas. Finally, CB3 significantly reduced the surface area of aortic lesions.<br><br>CONCLUSIONS: Our results clearly showed that similar to the full length Trx-1, CB3 exerts protective effects, by reducing inflammation and oxidative stress in macrophages and in ApoE2.Ki mice. The atheroprotective effect of CB3 opens promising therapeutic approaches for treatment of atherosclerosis.}, }
@article {pmid30008280, year = {2018}, author = {Panizzutti, B and Bortolasci, C and Hasebe, K and Kidnapillai, S and Gray, L and Walder, K and Berk, M and Mohebbi, M and Dodd, S and Gama, C and Magalhães, PV and Cotton, SM and Kapczinski, F and Bush, AI and Malhi, GS and Dean, OM}, title = {Mediator effects of parameters of inflammation and neurogenesis from a N-acetyl cysteine clinical-trial for bipolar depression.}, journal = {Acta neuropsychiatrica}, volume = {30}, number = {6}, pages = {334-341}, doi = {10.1017/neu.2018.13}, pmid = {30008280}, issn = {1601-5215}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Bipolar Disorder/*blood/complications/*drug therapy ; Brain-Derived Neurotrophic Factor/blood ; C-Reactive Protein/metabolism ; Encephalitis/*blood/complications ; Female ; Humans ; Interleukins/blood ; Male ; Middle Aged ; *Neurogenesis ; Treatment Outcome ; Tumor Necrosis Factor-alpha/blood ; Young Adult ; }, abstract = {OBJECTIVE: This study aimed to explore effects of adjunctive treatment with N-acetyl cysteine (NAC) on markers of inflammation and neurogenesis in bipolar depression.<br><br>METHODS: This is a secondary analysis of a placebo-controlled randomised trial. Serum samples were collected at baseline, week 8, and week 32 of the open-label and maintenance phases of the clinical trial to determine changes in interleukin (IL)-6, IL-8, IL-10, tumour necrosis factor-&#x3b1; (TNF-&#x3b1;), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following adjunctive NAC treatment, and to explore mediation and moderator effects of the listed markers.<br><br>RESULTS: Levels of brain-derived neurotrophic factor (BDNF), tumour necrosis factor-&#x3b1; (TNF-&#x3b1;), C-reactive protein (CRP), interleukins (IL) -6, 8, or 10 were not significantly changed during the course of the trial or specifically in the open-label and maintenance phases. There were no mediation or moderation effects of the biological factors on the clinical parameters.<br><br>CONCLUSION: The results suggest that these particular biological parameters may not be directly involved in the therapeutic mechanism of action of adjunctive NAC in bipolar depression.}, }
@article {pmid30007250, year = {2018}, author = {Lete, I and Mendoza, N and de la Viuda, E and Carmona, F}, title = {Effectiveness of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain in the treatment of endometriosis-associated pelvic pain: LEAP study.}, journal = {European journal of obstetrics, gynecology, and reproductive biology}, volume = {228}, number = {}, pages = {221-224}, doi = {10.1016/j.ejogrb.2018.07.002}, pmid = {30007250}, issn = {1872-7654}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Bromelains/*therapeutic use ; Drug Combinations ; Endometriosis/*complications ; Female ; Humans ; Pelvic Pain/*drug therapy/etiology ; Pregnancy ; Thioctic Acid/*therapeutic use ; }, abstract = {OBJECTIVE: To assess the impact of an antioxidant preparation with N-acetyl cysteine, alpha lipoic acid and bromelain on endometriosis-associated pelvic pain.<br><br>STUDY DESIGN: Multicenter, open-label, non-comparative clinical trial in a representative sample of women with endometriosis-associated pelvic pain.<br><br>RESULTS: In total, 398 patients with a mean age of 34.6&#x202f;&#xb1;&#x202f;7.2 years were treated with a combination of N-acetyl cysteine, alpha lipoic acid and bromelain for 6 months. At baseline, 92.7% of the patients had pain intensity > 4 on the visual analogue scale (VAS); at 3 months of treatment, this percentage decreased to 87.2% (p&#x202f;=&#x202f;0.074) and at 6 months the percentage was 82.7% (p&#x202f;<&#x202f;0.05).<br><br>CONCLUSIONS: Women with endometriosis who wish to become pregnant and are treated with a preparation containing N-acetyl cysteine, alpha lipoic acid and bromelain experienced a significant improvement in endometriosis-associated pelvic pain and required lower intake of rescue analgesics.}, }
@article {pmid30005897, year = {2018}, author = {Gabe, Y and Miyaji, A and Kohno, M and Hachiya, A and Moriwaki, S and Baba, T}, title = {Substantial evidence for the rhododendrol-induced generation of hydroxyl radicals that causes melanocyte cytotoxicity and induces chemical leukoderma.}, journal = {Journal of dermatological science}, volume = {91}, number = {3}, pages = {311-316}, doi = {10.1016/j.jdermsci.2018.06.007}, pmid = {30005897}, issn = {1873-569X}, mesh = {Antioxidants/pharmacology ; Butanols/*toxicity ; Cell Line ; Cell Survival/drug effects ; Humans ; Hydroxyl Radical/*metabolism ; Hypopigmentation/*chemically induced/metabolism/pathology ; Melanocytes/*drug effects/metabolism/pathology ; Monophenol Monooxygenase/metabolism ; Oxidative Stress/*drug effects ; Skin/*drug effects/metabolism/pathology ; Skin Lightening Preparations/*toxicity ; Skin Pigmentation/*drug effects ; }, abstract = {BACKGROUND: Rhododendrol (4-(4-hydroxyphenyl)-2-butanol) has been used as a lightening/whitening cosmetic but was recently reported to induce leukoderma. Although rhododendrol has been shown to be transformed by tyrosinase to hydroxyl-rhododendrol, which is cytotoxic to melanocytes, its detailed mechanism of action including the involvement of reactive oxygen species is not clearly understood.<br><br>OBJECTIVE: To confirm the relationship of hydroxyl radical generation to melanocyte cytotoxicity induced by rhododendrol, this study was performed.<br><br>METHODS: An electron spin resonance method with a highly sensitive detection system was utilized to monitor hydroxyl radicals generated from two distinct normal human epidermal melanocyte lines with different levels of tyrosinase activity after the addition of various amounts of rhododendrol. Cytotoxicity of rhododendrol was analyzed by AlamarBlue assay under the same condition.<br><br>RESULTS: Hydroxyl radicals were generated depending on the amounts of rhododendrol and/or tyrosinase. After the correlation between hydroxyl radical generation with melanocyte viability was confirmed, an inhibitor of oxidative stress, N-acetyl cysteine, was shown to dramatically diminish rhododendrol-induced generation of hydroxyl radicals and melanocyte cytotoxicity by increasing glutathione levels. In contrast, buthionine sulfoximine, which depletes glutathione, augmented both of those parameters.<br><br>CONCLUSION: Suppressing oxidative stress would prevent and/or mitigate some phenol derivative-induced leukoderma by avoiding hydroxyl radical-initiated melanocyte cytotoxicity.}, }
@article {pmid29996215, year = {2018}, author = {Xiao, M and Yang, R and Guan, MJ and Zhao, N and Xie, KQ and Zeng, T}, title = {[Protective effects of N-acetyl-L-cysteine against binge drinking-induced fatty liver in mice].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {36}, number = {3}, pages = {169-173}, doi = {10.3760/cma.j.issn.1001-9391.2018.03.003}, pmid = {29996215}, issn = {1001-9391}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; *Binge Drinking ; Fatty Liver, Alcoholic/*drug therapy ; Liver/drug effects/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Random Allocation ; Sterol Regulatory Element Binding Protein 1/genetics/metabolism ; }, abstract = {Objective: To investigate the roles of N-acetyl-L-cysteine (NAC) against binge drinking-induced fatty liver in mice. Methods: SPF male C57BL/6 mice were randomly divided into 3 groups, i.e. control group, model group, and NAC/ethanol group (n=10). Mice in model and NAC/ethanol groups were exposed to 3 doses of ethanol (6 g/kg bw) to induced fatty liver, while mice in control group received equal volume and equal energy of maltodextrin solution. NAC was administered to mice at 1 h before ethanol exposure (100 mg/kg bw, i.p.). The mice were sacrificed at 6 h after the last ethanol exposure. The liver and epididymal adipose tissues were collected. Histopathological examination and biochemical assay kit were used to evaluate the fat accumulation, while Western-blot was performed to detect the protein levels of some key factors involved in fat metabolism in liver and adipose tissues. Results: Compored with control group mice, the liver index and liver weight were significantly increased compared with model group, the liver index and TG level in NAC/ethanol group mice were all significantly decreased (P<0.05). Histological examination showed NAC effectively suppressed binge drinking-induced fat accumulation in mice liver. In addition, NAC had no significant effects on the protein levels of peroxisome proliferator-activated receptor-α (PPAR-α), Acy-CoA oxidase (ACOX), sterol regulatory element binding protein 1 c (SREBP-1c) and fatty acid synthase (FAS). Furthermore, the protein levels of hormone sensitive lipase (HSL) did not significantly differ among 3 groups, whereas NAC prevented binge drinking-induced increase of HSL phosphorylation at ser563 and ser660. Conclusion: NAC could effectively attenuate binge drinking-induced fatty liver, which might be associated with the inhibition of lipid mobilization by suppressing the phosphorylation of HSL.}, }
@article {pmid29990298, year = {2018}, author = {Ahmadi, J and Joukar, S and Anani, H and Karami-Mohajeri, S}, title = {Dihydroxyacetone as a definitive treatment for aluminium phosphide poisoning in rats.}, journal = {Arhiv za higijenu rada i toksikologiju}, volume = {69}, number = {2}, pages = {169-177}, doi = {10.2478/aiht-2018-69-3106}, pmid = {29990298}, issn = {1848-6312}, mesh = {Aluminum Compounds/*toxicity ; Animals ; Dihydroxyacetone/*therapeutic use ; Male ; Pesticides/*toxicity ; Phosphines/*toxicity ; Poisoning/*drug therapy ; Rats ; Shock, Cardiogenic/*chemically induced/*drug therapy ; }, abstract = {Aluminium phosphide (AlP), a very toxic pesticide also known as the rice tablet, releases phosphine gas upon contact with water, moisture, or gastric acid. Its mortality rate in humans is 70-100 % due to cardiogenic shock and refractory hypotension. Dihydroxyacetone (DHA) is a simple ketonic carbohydrate, mainly used for sunless skin tanning. It also plays a beneficial role in the treatment of hypotension and cardiogenic shock by restoring blood volume and cellular respiration. The aim of this study was to investigate the its effect on the haemodynamics and electrocardiogram (ECG) in male rats poisoned with AlP. The animals were divided into the following groups: control (received 1 mL corn oil, orally), AlP (received 15 mg kg-1 AlP solved in corn oil, orally), AlP plus DHA (treated with 50 mg kg-1 of DHA 30 min after receiving AlP), and AlP plus N-acetyl cysteine (NAC) (treated with 200 mg kg-1 of NAC 30 min after receiving AlP). The animals were then anaesthetised and ECG, blood pressure, and heart rate were recorded for 120 min. Treatment with AlP alone and in combination with NAC was associated with progressive hypotension, tachycardia, and ECG disturbances in rats, resulting in 100 % mortality 3 h after poisoning. However, DHA achieved 100 % survival in the poisoned rats and prevented AlP-induced ECG and haemodynamic abnormalities. The main mechanism of DHA in the treatment of AlP poisoning is unclear, but the findings suggest the promising therapeutic potential of DHA against AlP poisoning.}, }
@article {pmid29986212, year = {2018}, author = {Pinto, S and Sato, VN and De-Souza, EA and Ferraz, RC and Camara, H and Pinca, APF and Mazzotti, DR and Lovci, MT and Tonon, G and Lopes-Ramos, CM and Parmigiani, RB and Wurtele, M and Massirer, KB and Mori, MA}, title = {Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis.}, journal = {Redox biology}, volume = {18}, number = {}, pages = {84-92}, pmid = {29986212}, issn = {2213-2317}, support = {P40 OD010440/OD/NIH HHS/United States ; }, mesh = {Animals ; Caenorhabditis elegans/*drug effects/physiology ; Cytochrome P-450 CYP1A2 Inhibitors/pharmacology ; Enoxacin/*pharmacology ; Gene Expression Regulation/*drug effects ; Longevity/*drug effects ; MicroRNAs/*genetics ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Topoisomerase II Inhibitors/pharmacology ; }, abstract = {Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidative stress conditions. Enoxacin-induced longevity required the transcription factor SKN-1/Nrf2 and was blunted by the antioxidant N-acetyl-cysteine, suggesting a prooxidant-mediated mitohormetic response. The longevity effects of enoxacin were also dependent on the miRNA pathway, consistent with changes in miRNA expression elicited by the drug. Among these differentially expressed miRNAs, the widely conserved miR-34-5p was found to play an important role in enoxacin-mediated longevity. Enoxacin treatment down-regulated miR-34-5p and did not further extend lifespan of long-lived mir-34 mutants. Moreover, N-acetyl-cysteine abrogated mir-34(gk437)-induced longevity. Evidence also points to double-stranded RNA-specific adenosine deaminases (ADARs) as new targets of enoxacin since ADAR loss-of-function abrogates enoxacin-induced lifespan extension. Thus, enoxacin increases lifespan by reducing miR-34-5p levels, interfering with the redox balance and promoting healthspan.}, }
@article {pmid29985958, year = {2018}, author = {Cavallin, LE and Ma, Q and Naipauer, J and Gupta, S and Kurian, M and Locatelli, P and Romanelli, P and Nadji, M and Goldschmidt-Clermont, PJ and Mesri, EA}, title = {KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis.}, journal = {PLoS pathogens}, volume = {14}, number = {7}, pages = {e1007175}, pmid = {29985958}, issn = {1553-7374}, support = {R01 CA136387/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Carcinogenesis/*metabolism ; Herpesvirus 8, Human/*pathogenicity ; Humans ; Mice ; Mice, Nude ; Platelet-Derived Growth Factor/metabolism ; Proto-Oncogene Proteins c-sis/metabolism ; Receptor, Platelet-Derived Growth Factor alpha/*metabolism ; Sarcoma, Kaposi/metabolism/*virology ; Signal Transduction ; }, abstract = {Kaposi's sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth.}, }
@article {pmid29985056, year = {2020}, author = {Calvo, R and Espinosa, M and Figueroa, D and Pozo, LM and Conget, P}, title = {Assessment of Cell Viability of Fresh Osteochondral Allografts in N-Acetylcysteine-Enriched Medium.}, journal = {Cartilage}, volume = {11}, number = {1}, pages = {117-121}, pmid = {29985056}, issn = {1947-6043}, mesh = {Acetylcysteine/*pharmacology ; Allografts/*drug effects ; Cell Survival/*drug effects ; Chondrocytes/*drug effects ; Culture Media ; Femur/cytology ; Humans ; Tissue Preservation/*methods ; }, abstract = {OBJECTIVE: The purpose of this study was to evaluate the effect of N-acetylcysteine (NAC)-enriched storage medium on fresh osteochondral viability at 4°C. Our hypothesis was that the cell viability of chondrocytes obtained from human osteochondral tissue and stored at 4°C significantly improves in the presence of NAC.<br><br>DESIGN: Controlled laboratory study. For this study, 8 samples of femoral condyle osteochondral tissue were obtained from patients undergoing total knee replacement. The samples were stored at either 4&#xb0;C in phosphate-buffered saline (PBS) or at 3 different concentrations of NAC (NAC 1, 2, and 5 mM). Cell viability was analyzed at time 0 and 4 weeks by flow cytometry. The results of cell viability (median) were analyzed statistically using analysis of variance and Tukey's post hoc test. P values <0.05 were considered statistically significant.<br><br>RESULTS: The viability at time 0 was 95.5% &#xb1; 3.7%. At 4 weeks, the cell viability was 56.8% &#xb1; 20.1% in the control group (PBS), 83.8% &#xb1; 11.9% in the group stored with NAC 1 mM, 73.4% &#xb1; 13.6% in the group stored with NAC 2 mM, and 66.4% &#xb1; 27.7% in the group stored with NAC 5 mM. A statistically significant difference from the baseline viability (time 0) was observed in the PBS control group (P = 0.0018) but not in the other groups. A statistically significant difference was observed in the NAC 1 mM group compared with the PBS group (P = 0.0255).<br><br>CONCLUSION: The use of NAC at 1 mM concentration improves cell viability after 4 weeks of storage in chondrocytes obtained from human osteochondral tissue.}, }
@article {pmid29985009, year = {2018}, author = {Allen, EM and Hughes, EF and Anderson, CJ and Woehrle, NS}, title = {N-acetylcysteine blocks serotonin 1B agonist-induced OCD-related behavior in mice.}, journal = {Behavioral neuroscience}, volume = {132}, number = {4}, pages = {258-268}, doi = {10.1037/bne0000251}, pmid = {29985009}, issn = {1939-0084}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Disease Models, Animal ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Humans ; Male ; Mice ; Obsessive-Compulsive Disorder/*drug therapy/metabolism ; Receptor, Serotonin, 5-HT1B/*metabolism ; *Task Performance and Analysis ; }, abstract = {Glutamate-modulating agents are of increasing interest in obsessive-compulsive disorder (OCD). Current pharmacotherapies for OCD target the serotonin and dopamine systems, and are limited in efficacy. N-acetylcysteine (NAC) is an over-the-counter amino acid supplement that inhibits glutamate neurotransmission and has been shown in preliminary studies to reduce symptoms in OCD and related compulsive disorders. Despite growing interest in NAC as a novel psychiatric medication, no studies currently exist examining the effects of NAC in animal models of compulsive disorders. Here, we investigate NAC in a well-validated mouse model of OCD that is predictive of treatment efficacy as well as the time course for therapeutic onset of OCD medications. NAC (60 mg/kg/day or 120 mg/kg/day) was administered via the drinking water of mice for 3 weeks prior to behavioral testing. Mice were tested in the delayed alternation task (DAT) and open field test following acute serotonin 1B receptor (5-HT1B) agonist challenge to induce OCD-related behavior. We found that both doses of NAC blocked 5-HT1B agonist-induced deficits on the DAT. In a separate study, we administered NAC (60 mg/kg/day) for 1 week or 3 weeks in the drinking water of mice prior to examining OCD-related behavior. We found that blockade of 5-HT1B agonist-induced OCD-like behavior is present at 3 weeks, but not 1 week, of NAC treatment. Together, our findings suggest that NAC is a novel OCD treatment with potential utility as monotherapy and therapeutic effects that emerge on a time-course similar to established medications. (PsycINFO Database Record}, }
@article {pmid29982513, year = {2018}, author = {Rodriguez, BM and Khouzami, L and Decostre, V and Varnous, S and Pekovic-Vaughan, V and Hutchison, CJ and Pecker, F and Bonne, G and Muchir, A}, title = {N-acetyl cysteine alleviates oxidative stress and protects mice from dilated cardiomyopathy caused by mutations in nuclear A-type lamins gene.}, journal = {Human molecular genetics}, volume = {27}, number = {19}, pages = {3353-3360}, doi = {10.1093/hmg/ddy243}, pmid = {29982513}, issn = {1460-2083}, support = {MR/P003311/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*administration &amp; dosage/metabolism ; Animals ; Antioxidants/administration &amp; dosage/metabolism ; Cardiomyopathy, Dilated/drug therapy/*genetics/metabolism/physiopathology ; Disease Models, Animal ; Glutathione/metabolism ; Heart/drug effects/physiopathology ; Heart Failure/drug therapy/*genetics/metabolism/pathology ; Heart Ventricles/drug effects/physiopathology ; Humans ; Lamin Type A/*genetics ; Mice ; Mutation ; Myocardium/pathology ; Oxidative Stress/drug effects ; }, abstract = {Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscular and electrical dysfunction of the heart, often leading to heart failure-related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. We showed here an increase in oxidative stress levels in the hearts of mice carrying LMNA mutation, associated with a decrease of the key cellular antioxidant glutathione (GHS). Oral administration of N-acetyl cysteine, a GHS precursor, led to a marked improvement of GHS content, a decrease in oxidative stress markers including protein carbonyls and an improvement of left ventricular structure and function in a model of LMNA cardiomyopathy. Collectively, our novel results provide therapeutic insights into LMNA cardiomyopathy.}, }
@article {pmid29980037, year = {2018}, author = {Hong, H and Wu, H and Chen, J and Wu, B and Yu, H and Yan, B and Liang, Y}, title = {Cytotoxicity induced by iodinated haloacetamides via ROS accumulation and apoptosis in HepG-2 cells.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {242}, number = {Pt A}, pages = {191-197}, doi = {10.1016/j.envpol.2018.06.090}, pmid = {29980037}, issn = {1873-6424}, mesh = {Acetamides/*toxicity ; Acetylcysteine/metabolism ; Apoptosis/drug effects ; Disinfectants/*toxicity ; Disinfection ; Halogenation ; Hep G2 Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Reactive Oxygen Species/*metabolism ; Toxicity Tests ; }, abstract = {Iodinated haloacetamides (I-HAcAms) are emerging disinfection by-products and have received great concern due to their extremely high health risk. Previous studies have demonstrated the cytotoxicity of I-HAcAms, but the biological mechanism remained unclear. In this study, cytotoxicity mechanisms of 4 I-HAcAms species were preliminarily examined using HepG-2 cells. The results showed that the cytotoxicity could be ranked as follows: diiodoacetamide (DIAcAm)> iodoacetamide (IAcAm)> bromoiodoacetamide (BIAcAm)> chloroiodoacetamide (CIAcAm). Reactive oxygen species (ROS) and apoptosis played an important role in the cytotoxicity for all I-HAcAms species. Moreover, the ROS and cytotoxicity could be completely reversed by the addition of an antioxidant (N-acetylcysteine (NAC)), but the apoptosis could not. Specifically, the apoptosis induced by DIAcAm and IAcAm was partially reversed by NAC, suggesting that in addition to ROS, other pathways were also possible; While For BIAcAm and CIAcAm, the apoptosis was not reversed by NAC at all, which is potentially due to ROS-independent pathways. The apoptosis mechanisms were further analyzed via Bax and Bcl-2 gene expression and the corresponding protein expression in HepG-2 cells, that mitochondrial pathway was important in the apoptosis of HepG-2 cells induced by all I-HAcAms species. Overall, the mitochondrial pathway provided a potential explanation for BIAcAm and CIAcAm-induced apoptosis, while both ROS and mitochondrial pathways explained DIAcAm and IAcAm-induced apoptosis.}, }
@article {pmid29978533, year = {2018}, author = {Gao, HJ and Sun, YL and Song, GZ and Su, B and Zhang, MM and Ren, CJ and Wang, YW}, title = {Preventive effects of N-acetyl-l-cysteine against imidacloprid intoxication on Bombyx mori larvae.}, journal = {Archives of insect biochemistry and physiology}, volume = {99}, number = {2}, pages = {e21497}, doi = {10.1002/arch.21497}, pmid = {29978533}, issn = {1520-6327}, support = {SDAIT-18-05//Modern Agricultural Technology System of Shandong Province/ ; 2017GNC13102//Key Research Program of Shandong Province/ ; ZR2017BC046//Natural Science Foundation of Shandong Province/ ; SYL2017XTTD03//Shandong "Double Tops" Program/ ; }, mesh = {Acetylcysteine/administration &amp; dosage/*metabolism ; Animals ; Antioxidants/administration &amp; dosage/*metabolism ; Bombyx/*drug effects/growth &amp; development/metabolism ; Energy Metabolism/drug effects ; Insecticides/*toxicity ; Larva/drug effects/growth &amp; development/metabolism ; Longevity/drug effects ; Malondialdehyde/metabolism ; Neonicotinoids/*toxicity ; Nitro Compounds/*toxicity ; Plant Leaves ; Pupa/drug effects/growth &amp; development ; }, abstract = {Imidacloprid, a widely used neonicotinoid insecticide, is toxic to silkworm (Bombyx mori). To explore whether N-acetyl-l-cysteine (NAC) has an effect on preventing silkworm (B. mori) from toxification caused by imidacloprid, we fed the fifth-instar larvae with mulberry leaves dipped in 200 mg/L NAC solution before exposing in imidacloprid, and investigated the silkworm growth, survival rate, feed efficiency, cocoon quality, and the activities of antioxidant enzymes in midgut. The results showed that addition of NAC could significantly increase body weight, survival rate, and feed efficiency of imidacloprid poisoned silkworm larvae (P < 0.05), as well as cocoon mass, cocoon shell mass, and the ratio of cocoon shell (P < 0.05). Furthermore, it could significantly promote the activities of the antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxide in the midgut of fifth-instar larvae under imidacloprid exposure at the late stage of treatment. In addition, it also could downregulate the malondialdehyde content. The results of our findings proved that the added NAC may have some beneficial effects on protection or restoration of antioxidant balance in imidacloprid exposed larvae.}, }
@article {pmid29976081, year = {2018}, author = {Hsiao, YT and Kuo, CL and Chueh, FS and Liu, KC and Bau, DT and Chung, JG}, title = {Curcuminoids Induce Reactive Oxygen Species and Autophagy to Enhance Apoptosis in Human Oral Cancer Cells.}, journal = {The American journal of Chinese medicine}, volume = {46}, number = {5}, pages = {1145-1168}, doi = {10.1142/S0192415X1850060X}, pmid = {29976081}, issn = {1793-6853}, mesh = {Antineoplastic Agents, Phytogenic/chemistry/*pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Curcumin/chemistry/*pharmacology ; Humans ; Mitochondria/drug effects/metabolism ; Mouth Neoplasms/drug therapy/metabolism/*physiopathology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Numerous studies support the use of herbal medicine or natural products for chemotherapy in human cancers. Reports have associated curcumin (CUR), dimethoxy curcumin (DMC) and bisdemethoxycurcumin (BDMC) with numerous biological activities including anticancer activities, but no available information have shown that these induced apoptotic cell death and autophagy in human oral cancer cells. In the present study, we investigated the effect of CUR, DMC and BDMC on the cell viability, apoptotic cell death, reactive oxygen species (ROS), Ca[Formula: see text], mitochondria membrane potential (MMP) and caspase activities using flow cytometry assay and autophagy by monodansylcadaverine (MDC) and acridine orange (AO) staining in human oral cancer SAS cells. Results indicated that CUR, DMC and BDMC decreased total viable cell number through the induction of cell autophagy and apoptosis in SAS cells. Cells were pretreated with N-acetyl-cysteine (NAC), 3-methyladenine (3MA), rapamycin and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoro-methylketone (Z-VAD-fmk) and then were treated with CUR, DMC and BDMC that led to increased total viable cell number when compared to CUR, DMC and BDMC treatments only. Results indicated induced apoptotic cell death through ROS, mitochondria-dependent pathway and induction of cell autophagy. Based on those observations, we suggest that CUR, DMC and BDMC could be used as a potential anticancer agent in human oral cancer.}, }
@article {pmid29972340, year = {2018}, author = {Calzetta, L and Matera, MG and Rogliani, P and Cazzola, M}, title = {Multifaceted activity of N-acetyl-l-cysteine in chronic obstructive pulmonary disease.}, journal = {Expert review of respiratory medicine}, volume = {12}, number = {8}, pages = {693-708}, doi = {10.1080/17476348.2018.1495562}, pmid = {29972340}, issn = {1747-6356}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/*therapeutic use ; Bronchi/*metabolism ; Expectorants/*therapeutic use ; Glutathione/metabolism ; Humans ; Pulmonary Disease, Chronic Obstructive/*drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {N-acetyl-l-cysteine (NAC), a derivative of the naturally occurring amino acid l-cysteine, is a mucolytic agent that may also act as an antioxidant by providing cysteine intracellularly for increased production of glutathione. It is also used for the treatment of acetaminophen overdose. Areas covered: The recent international recommendations for the treatment of chronic obstructive pulmonary disease (COPD) report that NAC, because of its mucolytic activity, reduces acute exacerbation of COPD (AECOPD) with a modest improvement in health status. However, NAC is a pleiotropic drug with heterogeneous pharmacologic characteristics that certainly include mucolytic activity, but also has anti-infective properties and specific antioxidant and anti-inflammatory effects in the airways. Thus, the mechanisms leading to the protective role of this agent against AECOPD need to be adequately addressed. Expert commentary: The protective effect of NAC against AECOPD seems to be related not only to its well-documented mucolytic activity but also to activation of antioxidant pathways, inhibition of pro-oxidant and inflammatory pathways, and modulation of human bronchial tone. Thus, the dogma that NAC acts prevalently as a mucolytic agent is outdated, and the hypothesis that its anti-inflammatory effect is secondary to the antioxidant activity has been rejected.}, }
@article {pmid29968701, year = {2018}, author = {Wang, H and Wang, Y and Xia, T and Liu, Y and Liu, T and Shi, X and Li, Y}, title = {Pathogenesis of Abnormal Hepatic Lipid Metabolism Induced by Chronic Intermittent Hypoxia in Rats and the Therapeutic Effect of N-Acetylcysteine.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {24}, number = {}, pages = {4583-4591}, pmid = {29968701}, issn = {1643-3750}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Body Weight ; Cytokines/metabolism ; Hypoxia/*drug therapy/metabolism/physiopathology ; Inflammation/pathology ; Lipid Metabolism/physiology ; Liver/metabolism/*pathology ; Male ; Oxidative Stress/physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND The pathogenesis of chronic intermittent hypoxia (CIH)-induced abnormal hepatic lipid metabolism in rats remains unclear. Here, we investigated the therapeutic effect of N-acetylcysteine (NAC) on abnormal hepatic lipid metabolism. MATERIAL AND METHODS Rats were subjected to hypoxia and NAC treatment, and evaluated in terms of hepatic lipid metabolism, hepatocyte ultrastructure, oxidative stress in hepatocytes, expression of nuclear factor-kappa B (NF-κB) and inflammatory cytokines (IL-1β, IL-6, and TNFα), serum lipoprotein lipase (LPL) levels, and blood lipids (triglycerides and cholesterol). RESULTS Compared to the normoxic control group, animals in the hypoxic model group showed significant body weight gain; abnormal hepatic lipid metabolism; lipid vacuolization; accumulation of lipid droplets; abundant autophagosomes and lysosomes; significant increases in oxidative stress, inflammation level, and blood lipid levels; and significantly reduced LPL levels. Compared to control animals, rats in the treatment group exhibited normal body weight gain, improved lipid metabolism, fewer lipid droplets, alleviated ultrastructural injuries, decreased oxidative stress and inflammation level, as well as elevated LPL and reduced blood lipid levels. CONCLUSIONS The harmful effects of CIH on rat liver are possibly associated with the reactive oxygen species (ROS)/NF-κB signaling pathway. NAC is capable of attenuating lipid metabolism alterations and abnormal body weight gain in the CIH rat model, via a possible mechanism related to inhibition of ROS/NF-κB signaling.}, }
@article {pmid29963003, year = {2018}, author = {Avezov, K and Aizenbud, D and Lavie, L}, title = {Intermittent Hypoxia Induced Formation of "Endothelial Cell-Colony Forming Units (EC-CFUs)" Is Affected by ROS and Oxidative Stress.}, journal = {Frontiers in neurology}, volume = {9}, number = {}, pages = {447}, pmid = {29963003}, issn = {1664-2295}, abstract = {Intermittent hypoxia (IH)-the hallmark of obstructive sleep apnea (OSA)-increases leukocyte activation, production of NADPH-oxidase dependent reactive oxygen species (ROS) and oxidative stress, affecting endothelial function. However, IH and oxidative stress can also stimulate adaptive-protective mechanisms by inducing the development of Endothelial Cell-Colony Forming Units (EC-CFUs), which are considered as a good surrogate marker for endothelial progenitor cells (EPCs), and likely reflect a reparatory response to vascular damage or tissue ischemia by leukocytes. Blood samples were obtained from 15 healthy consenting volunteers to evaluate the effects of IH and sustained hypoxia (SH) in vitro on EC-CFUs development and functions. The variables measured included: their numbers, the area, the proliferative capacity and ROS production. Additionally, NADPH-oxidase, VEGF and nuclear factor-erythroid 2 related factor 2 (Nrf2) expression, as well as their paracrine effects on endothelial tube formation were determined. The involvement of ROS was probed using the anti-oxidant N-acetylcysteine (NAC) and NADPH-oxidase inhibitors apocynin and diphenyl-iodide. Compared to normoxia, IH-dependent increases in EC-CFUs numbers were observed, showing an individual donor-dependent trait. Also, the expression of VEGF and gp91phox, a subunit of NADPH-oxidase, were significantly increased. ROS production and oxidative stress markers were also significantly increased, but Nrf2 expression and colony size were unaffected by IH. Additionally, conditioned media harvested from IH- and SH-treated mature EC-CFUs, significantly increased endothelial tube formation. These effects were markedly attenuated or diminished by the ROS and NADPH-oxidase inhibitors employed. In conclusion, we show here for the first time that IH-associated oxidative stress promotes EC-CFUs' vascular and paracrine capacities through ROS. However, the large inter-individual variability expressed in EC-CFUs numbers and functions to a given IH stimulus, may represent an individual trait with a potential clinical significance.}, }
@article {pmid29962570, year = {2018}, author = {Tharoor, H and Mara, S and Gopal, S}, title = {Role of Novel Dietary Supplement N-acetyl Cysteine in Treating Negative Symptoms in Schizophrenia: A 6-Month Follow-up Study.}, journal = {Indian journal of psychological medicine}, volume = {40}, number = {2}, pages = {139-142}, pmid = {29962570}, issn = {0253-7176}, abstract = {BACKGROUND: Abnormal metabolism of dopamine and glutamate in schizophrenia induces oxidative stress that is exacerbated by brain glutathione (GSH) deficiency. N-acetyl cysteine (NAC) increases brain GSH levels and is being used as an adjunctive agent in patients with schizophrenia. This open-label exploratory study in a naturalistic setting was conceived to examine the efficacy of NAC augmentation in treating negative syndrome in schizophrenia.<br><br>AIMS: To examine the efficacy of add-on NAC (1200 mg) in treating negative symptoms measured using Scale for the Assessment of Negative Symptoms (SANS) and clinical global impression (CGI) at baseline and 24 weeks.<br><br>SUBJECTS AND METHODS: In a 24-week feasibility study with open-label design, thirty patients with the International Classification of Diseases-Tenth Edition diagnosis of schizophrenia were recruited. Eligible patients were required to have been treated with stable dose of clozapine or amisulpride for negative symptoms for a minimum period of 8 weeks were selected for the study. The subjects were assigned to receive NAC (1.2 g/day) as an add-on treatment. Severity of negative symptoms was measured using SANS and CGI-severity at baseline and improvement with NAC measured using CGI-improvement at 24 weeks. Serum interleukin-6 was assessed before NAC initiation at baseline.<br><br>RESULTS: NAC augmentation showed a significantly greater improvement in negative symptoms on total SANS and CGI scores at 24 weeks.<br><br>CONCLUSIONS: NAC may be effective as an adjunct for the treatment of negative symptoms in schizophrenia.}, }
@article {pmid29960031, year = {2018}, author = {Fang, XY and Zhang, H and Zhao, L and Tan, S and Ren, QC and Wang, L and Shen, XF}, title = {A new xanthatin analogue 1β-hydroxyl-5α-chloro-8-epi-xanthatin induces apoptosis through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition in human hepatocellular carcinoma.}, journal = {Biochimie}, volume = {152}, number = {}, pages = {43-52}, doi = {10.1016/j.biochi.2018.06.018}, pmid = {29960031}, issn = {1638-6183}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/enzymology/etiology/metabolism/*pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Furans/*pharmacology/therapeutic use ; Glutathione/metabolism ; Humans ; Janus Kinase 2/*antagonists &amp; inhibitors ; Liver Neoplasms/enzymology/etiology/metabolism/*pathology ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {1β-hydroxyl-5α-chloro-8-epi-xanthatin (XTT), a sesquiterpene lactone isolated from Xanthium sibiricum, possessed potent cytotoxicity on cancer cells in vitro. The objective of this study was to investigate the anti-tumor effect and underlying mechanisms of XTT on human hepatocellular carcinoma (HCC). Firstly, XTT inhibited the cell growth and induced apoptosis in human HCC cells, which was associated with the induction of Bax and cleaved-caspase-3, inhibition of Bcl-2 and survivin expression. Importantly, XTT induced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), and depletion of glutathione (GSH) in HCC cells through covalently modification of GSH. Furthermore, XTT caused obvious activation of extracellular regulated protein kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) and inactivation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) in HCC cells. ROS scavenger N-acetyl cysteine abrogated the effects of XTT on ERK/p38 MAPK activation and JAK2/STAT3 inhibition, and rescued HCC cells from XTT-induced apoptosis. Additionally, inhibitors of ERK/p38 MAPKs or activator of JAK2/STAT3 partially abolished XTT-mediated effect. In summary, XTT inhibited cell growth and induced apoptosis in HCC cells through ROS-mediated ERK/p38 MAPK activation and JAK2/STAT3 inhibition by GSH depletion. These findings also show the therapeutic potential of XTT in HCC.}, }
@article {pmid29958412, year = {2018}, author = {Bernhardt, LK and Bairy, KL and Madhyastha, S}, title = {Neuroprotective Role of N-acetylcysteine against Learning Deficits and Altered Brain Neurotransmitters in Rat Pups Subjected to Prenatal Stress.}, journal = {Brain sciences}, volume = {8}, number = {7}, pages = {}, pmid = {29958412}, issn = {2076-3425}, abstract = {Prenatal adversaries like stress are known to harm the progeny and oxidative stress, which is known to be one of the causative factors. N-acetyl cysteine (NAC), which is a potent antioxidant, has been shown to play a neuroprotective role in humans and experimental animals. This study examines the benefits of NAC on the prenatal stress-induced learning and memory deficits and alteration in brain neurotransmitter in rat pups. Pregnant dams were restrained (45 min; 3 times/day) during the early or late gestational period. Other groups received early or late gestational restrain stress combined with NAC treatment throughout the gestational period. At postnatal day (PND) 28, offspring were tested in a shuttle box for assessing learning and memory, which was followed by a brain neurotransmitter (dopamine, norepinephrine, and serotonin) estimation on PND 36. Late gestational stress resulted in learning deficits, the inability to retain the memory, and reduced brain dopamine content while not affecting norepinephrine and serotonin. NAC treatment in prenatally stressed rats reversed learning and memory deficits as well as brain dopamine content in offspring. These findings suggest that NAC protect the progeny from an undesirable cognitive sequel associated with prenatal stress.}, }
@article {pmid29958141, year = {2018}, author = {Zheng, W and Zhou, CY and Zhu, XQ and Wang, XJ and Li, ZY and Chen, XC and Chen, F and Che, XY and Xie, X}, title = {Oridonin enhances the cytotoxicity of 5-FU in renal carcinoma cells by inducting necroptotic death.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {106}, number = {}, pages = {175-182}, doi = {10.1016/j.biopha.2018.06.111}, pmid = {29958141}, issn = {1950-6007}, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Renal Cell/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Diterpenes, Kaurane/*pharmacology ; Dose-Response Relationship, Drug ; Fluorouracil/*pharmacology ; Glutathione/metabolism ; HMGB1 Protein/metabolism ; Humans ; Kidney Neoplasms/*drug therapy/metabolism/pathology ; L-Lactate Dehydrogenase/metabolism ; Mice, Nude ; Mitogen-Activated Protein Kinases/metabolism ; Necrosis ; Oxidative Stress/drug effects ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Signal Transduction/drug effects ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND: 5-fluorouracil (5-FU) is widely used for the treatment of renal carcinoma. However, drug resistance remains the reason for failure of chemotherapy. Oridonin, extracted from Chinese herb medicine, displays anti-tumor effect in several types of cancer. Whether oridonin could enhance the effect of 5-FU in renal carcinoma has not been studied.<br><br>METHODS: 786-O cells were used in the current study. Cell death was measured by MTT assay or live- and dead-cell staining assay. Glutathione (GSH) level was examined by ELISA. Necroptosis was identified by protein levels of receptors interaction protein-1 (RIP-1) and RIP-3, lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1) release, and poly [ADP-ribose] polymerase-1 (Parp-1) activity. Using a xenograft assay in nude mice, we tested the anti-tumor effects of the oridonin combined with 5-FU.<br><br>RESULTS: 5-FU only induced apoptosis in 786-O cells. Oridonin activated both apoptosis and necroptosis in 786-O cells. Oridonin-induced necroptosis was reversed by addition of GSH or its precursorN-acetylcysteine (NAC). Oridonin-induced necroptosis was associated by activated JNK, p38, and ERK in 786-O cells, which were abolished by GSH or NAC treatment. However, JNK, p38, and ERK inhibitors showed no effect on oridonin induced-cell death. GSH or NAC treatment partly abolished the synergistic effects of oridonin and 5-FU on cell death. Oridonin enhanced the cytotoxicity of 5-FU both in vitro and in vivo.<br><br>CONCLUSION: Oridonin enhances the cytotoxicity of 5-FU in renal cancer cells partially through inducing necroptosis, providing evidence of using necroptosis inducers in combination with chemotherapeutic agents for cancer treatment.}, }
@article {pmid29958049, year = {2019}, author = {Rhodes, KM and Baker, DF and Smith, BT and Braakhuis, AJ}, title = {Acute Effect of Oral N-Acetylcysteine on Muscle Soreness and Exercise Performance in Semi-Elite Rugby Players.}, journal = {Journal of dietary supplements}, volume = {16}, number = {4}, pages = {443-453}, doi = {10.1080/19390211.2018.1470129}, pmid = {29958049}, issn = {1939-022X}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; *Athletes ; Dietary Supplements ; Double-Blind Method ; Exercise Test ; *Football ; Humans ; Male ; Myalgia/*drug therapy ; New Zealand ; *Physical Functional Performance ; Placebos ; Surveys and Questionnaires ; }, abstract = {N-acetylcysteine (NAC) supplementation may enhance performance and reduce soreness from acute, repeated-sprint, high-intensity exercise. Our aim was to investigate whether semi-elite rugby union athletes may benefit. In a randomized block design, 17 semi-elite male rugby players were assigned to receive either 1 g oral NAC (n = 8) or placebo (n = 9) for six days. The mean percentage effect of NAC on exercise performance was assessed through completion of a broken bronco exercise test on days 5 and 6 of supplementation. Players self-reported muscle soreness and tolerability to supplements using a modified Muscle Pain and Treatment Satisfaction Questionnaire throughout the supplement duration. NAC produced a likely beneficial performance effect on maximum shuttle sprint time (2.4%; 90% confidence limit ± 4.8%) but was unclear on total time during back-to-back broken bronco tests compared to placebo. NAC had a likely protective effect on subjective muscle soreness during days 1-4 of supplementation (-19% ± 27%) but a very likely harmful effect on days 5 and 6 of supplementation (71% ± 59%). Daily supplementation with 1 g of oral NAC for six days produced no adverse side effects, reduced muscle soreness after one bout of damaging exercise, but increased soreness following the second bout. The performance effects were generally unclear apart from maximal sprint time.}, }
@article {pmid29957018, year = {2018}, author = {Yu, W and Xiang, Y and Luo, G and Zhao, X and Xiao, B and Cheng, Y and Feng, C and Duan, C and Xia, X and Wong, VKW and Dai, R}, title = {Salubrinal Enhances Doxorubicin Sensitivity in Human Cholangiocarcinoma Cells Through Promoting DNA Damage.}, journal = {Cancer biotherapy &amp; radiopharmaceuticals}, volume = {33}, number = {6}, pages = {258-265}, doi = {10.1089/cbr.2018.2447}, pmid = {29957018}, issn = {1557-8852}, mesh = {Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Bile Duct Neoplasms/*drug therapy/genetics/pathology ; Bile Ducts, Intrahepatic/pathology ; Cell Line, Tumor ; Cholangiocarcinoma/*drug therapy/genetics/pathology ; Cinnamates/*pharmacology/therapeutic use ; DNA Damage/*drug effects ; Doxorubicin/pharmacology/therapeutic use ; Drug Resistance, Neoplasm/drug effects/genetics ; Drug Synergism ; Eukaryotic Initiation Factor-2/antagonists &amp; inhibitors ; Humans ; Reactive Oxygen Species/metabolism ; Thiourea/*analogs &amp; derivatives/pharmacology/therapeutic use ; }, abstract = {Cholangiocarcinoma (CCA) is a highly malignant and aggressive tumor of the bile duct that arises from epithelial cells. Chemotherapy is an important treatment strategy for CCA patients, but its efficacy remains limited due to drug resistance. Salubrinal, an inhibitor of eukaryotic translation initiation factor 2 alpha (eIF2α), has been reported to affect antitumor activities in cancer chemotherapy. In this study, the authors investigated the effect of salubrinal on the chemosensitivity of doxorubicin in CCA cells. They showed that doxorubicin induces CCA cell death in a dose- and time-dependent manner. Doxorubicin triggers reactive oxygen species (ROS) generation and induces DNA damage in CCA cells. In addition, ROS inhibitor N-acetylcysteine (NAC) pretreatment inhibits doxorubicin-induced CCA cell death. Importantly, these data demonstrate a synergistic death induction effect contributed by the combination of salubrinal and doxorubicin in CCA cells. It is notable that salubrinal promotes doxorubicin-induced ROS production and DNA damage in CCA cells. Taken together, these data suggest that salubrinal enhances the sensitivity of doxorubicin in CCA cells through promoting ROS-mediated DNA damage.}, }
@article {pmid29950999, year = {2018}, author = {Li, X and Qiu, Z and Jin, Q and Chen, G and Guo, M}, title = {Cell Cycle Arrest and Apoptosis in HT-29 Cells Induced by Dichloromethane Fraction From Toddalia asiatica (L.) Lam.}, journal = {Frontiers in pharmacology}, volume = {9}, number = {}, pages = {629}, pmid = {29950999}, issn = {1663-9812}, abstract = {The roots of Toddalia asiatica (L.) Lam. (TA) has been often used in Chinese folk medicine to treat different diseases, including but not limited to arthritis, injuries, stomachache, and even tumors. However, the anti-cancer effects and the action mechanisms of TA remain elusive. Therefore, we firstly evaluated the effects of different extracts of TA on the growth of human colon cancer cells, and then tried to further elucidate their underlying molecular mechanisms. As a result, the dichloromethane fraction (DF) was found to possess the highest anti-proliferative activity with IC50 value at 18 μg/mL among all of the four extracts from TA, and strongly inhibited HT-29 cell growth and halted cell cycle progression in G2/M phase. DF also induced phosphatidylserine externalization and activated caspases -8, -9, and -3, suggesting DF induced apoptosis through intrinsic and extrinsic pathways. Furthermore, we found that HT-29 cell cycle arrest induced by DF could be the result of reactive oxygen species (ROS), as the ROS scavenger N-acetyl cysteine (NAC) attenuating it. Taken together, these results indicated that DF induced cell cycle arrest at G2/M phase and apoptosis in HT-29 cells, and could be a promising source for developing natural therapeutics for colon cancer.}, }
@article {pmid29946187, year = {2018}, author = {Sodhi, K and Nichols, A and Mallick, A and Klug, RL and Liu, J and Wang, X and Srikanthan, K and Goguet-Rubio, P and Nawab, A and Pratt, R and Lilly, MN and Sanabria, JR and Xie, Z and Abraham, NG and Shapiro, JI}, title = {The Na/K-ATPase Oxidant Amplification Loop Regulates Aging.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {9721}, pmid = {29946187}, issn = {2045-2322}, support = {P01 HL034300/HL/NHLBI NIH HHS/United States ; R01 HL105649/HL/NHLBI NIH HHS/United States ; U01 HL071556/HL/NHLBI NIH HHS/United States ; R01 HL109015/HL/NHLBI NIH HHS/United States ; R15 DK106666/DK/NIDDK NIH HHS/United States ; }, mesh = {Adipose Tissue/drug effects/metabolism/radiation effects ; Aging/genetics/*metabolism ; Animals ; Apoptosis/drug effects/physiology/radiation effects ; Blotting, Western ; Caspase 9/metabolism ; Cell Proliferation/drug effects/radiation effects ; Cell Survival/drug effects/radiation effects ; DNA Damage/drug effects/radiation effects ; Echocardiography ; In Situ Nick-End Labeling ; L-Lactate Dehydrogenase/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Ouabain/pharmacology ; Oxidative Stress/drug effects/genetics/radiation effects ; Protein Carbonylation/drug effects/radiation effects ; Real-Time Polymerase Chain Reaction ; Signal Transduction/physiology/radiation effects ; Sodium-Potassium-Exchanging ATPase/*metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Ultraviolet Rays ; Vitamin E/pharmacology ; Water/metabolism ; }, abstract = {As aging involves oxidant injury, we examined the role of the recently described Na/K-ATPase oxidant amplification loop (NKAL). First, C57Bl6 old mice were given a western diet to stimulate oxidant injury or pNaKtide to antagonize the NKAL. The western diet accelerated functional and morphological evidence for aging whereas pNaKtide attenuated these changes. Next, human dermal fibroblasts (HDFs) were exposed to different types of oxidant stress in vitro each of which increased expression of senescence markers, cell-injury, and apoptosis as well as stimulated the NKAL. Further stimulation of the NKAL with ouabain augmented cellular senescence whereas treatment with pNaKtide attenuated it. Although N-Acetyl Cysteine and Vitamin E also ameliorated overall oxidant stress to a similar degree as pNaKtide, the pNaKtide produced protection against senescence that was substantially greater than that seen with either antioxidant. In particular, pNaKtide appeared to specifically ameliorate nuclear oxidant stress to a greater degree. These data demonstrate that the NKAL is intimately involved in the aging process and may serve as a target for anti-aging interventions.}, }
@article {pmid29945211, year = {2018}, author = {He, B and Wang, X and Wei, L and Kong, B and Jin, Y and Xie, X and Fu, Z}, title = {β-Cypermethrin and its metabolite 3-phenoxybenzoic acid induce cytotoxicity and block granulocytic cell differentiation in HL-60 cells.}, journal = {Acta biochimica et biophysica Sinica}, volume = {50}, number = {8}, pages = {740-747}, doi = {10.1093/abbs/gmy068}, pmid = {29945211}, issn = {1745-7270}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects/genetics ; Benzoates/*pharmacology ; Cell Differentiation/*drug effects/genetics ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression Regulation, Leukemic/drug effects ; HL-60 Cells ; Humans ; Leukemia, Promyelocytic, Acute/genetics/metabolism/pathology ; Pyrethrins/metabolism/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {The most widely used type II pyrethroid is β-cypermethrin (β-CYP), and 3-phenoxybenzoic acid (3-PBA) is one of its primary metabolites. Although CYP has been shown to pose toxic effects in some immune cells, as of now the immunotoxicity of CYP on immune progenitor cells has not been well studied. In this study, we evaluated the immunotoxicity of β-CYP and 3-PBA on the human promyelocytic leukemia cell line, HL-60. Both β-CYP and 3-PBA reduced cell viability. In addition, both β-CYP and 3-PBA stimulated the intrinsic apoptotic pathway in a dose- and time-dependent manner, while only β-CYP induced cell cycle arrest in G1 stage. Moreover, exposure to β-CYP and 3-PBA at 100 μM inhibited all-trans retinoic acid (ATRA)-induced mRNA expressions of the granulocytic differentiation-related genes, CD11b and CSF-3R. Furthermore, exposure to β-CYP and 3-PBA resulted in a downregulation of the granulocytic differentiation promoting transcriptional factors, PU.1 and C/EBPε. Furthermore, we found that β-CYP and 3-PBA exposure led to elevated levels of cellular reactive oxygen species (ROS), and that pretreatment with N-acetylcysteine (NAC) blocked the toxic effects caused by β-CYP and 3-PBA. The results obtained in the present study provide evidence showing the immunotoxic effects of β-CYP and 3-PBA on promyelocytic cells as well as its possible underlying mechanism.}, }
@article {pmid29943637, year = {2018}, author = {Miller, EJ and Gemensky-Metzler, AJ and Wilkie, DA and Wynne, RM and Curto, EM and Chandler, HL}, title = {Effects of grape seed extract, lutein, and fish oil on responses of canine lens epithelial cells in vitro.}, journal = {American journal of veterinary research}, volume = {79}, number = {7}, pages = {770-778}, doi = {10.2460/ajvr.79.7.770}, pmid = {29943637}, issn = {1943-5681}, mesh = {Animals ; Antioxidants/*pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dogs ; Epithelial Cells/*drug effects ; Fish Oils/*pharmacology ; Grape Seed Extract/*pharmacology ; Lens, Crystalline/*cytology/drug effects ; Lutein/*pharmacology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE To determine the effects of grape seed extract (GSE), lutein, and fish oil containing omega-3 fatty acids on oxidative stress, migration, proliferation, and viability of lens epithelial cells (LECs). SAMPLE Lens capsules or cultured LECs obtained from canine cadavers. PROCEDURES An antioxidant reductive capacity assay was used to determine reducing capability of each substance. The LECs were cultured and incubated with various substances, including N-acetyl cysteine (NAC), when appropriate, and dimethyl sulfoxide (DMSO) as positive and vehicle control substances, respectively. A dichlorofluorescein assay was used to evaluate reactive oxygen species (ROS) production, and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine cell viability. Ex vivo posterior capsule opacification (PCO) was used to evaluate LEC migration and proliferation. RESULTS Antioxidant reductive effects of GSE surpassed those of NAC, lutein, and fish oil containing omega-3 fatty acids. The GSE reduced ROS production in LECs, compared with the DMSO vehicle control, whereas lutein was pro-oxidative. All test substances reduced cell viability. Ex vivo PCO was not altered by GSE, was decreased by lutein, and was increased by fish oil containing omega-3 fatty acids, compared with results for the DMSO vehicle control. CONCLUSIONS AND CLINICAL RELEVANCE Only GSE had significant antioxidant capabilities and reduced ROS production; however, no effect on ex vivo PCO was detected. Fish oil containing omega-3 fatty acids increased ex vivo PCO. No conclusions could be made regarding antioxidant effects of these substances on LECs. These findings suggested that the substances will not decrease PCO.}, }
@article {pmid29942446, year = {2018}, author = {Danduga, RCSR and Reddy, DS and Seshadri, SM and Has, KSS and Kumar, KP}, title = {Effect of combination therapy with pramipexole and n-acetylcysteine on global cerebral ischemic reperfusion injury in rats.}, journal = {Iranian journal of basic medical sciences}, volume = {21}, number = {6}, pages = {569-576}, pmid = {29942446}, issn = {2008-3866}, abstract = {OBJECTIVES: The study was intended to investigate the combined influence of two neuroprotective agents pramipexole and n-acetylcysteine on global cerebral ischemic reperfusion injury (GCIRI) model in rats.<br><br>MATERIALS AND METHODS: GCIRI was induced by bilateral common carotid artery ligation (BCCA) in rats. Animals were divided into six groups. Groups I, II, and III received saline intraperitoneally (IP) (5 ml/kg/day, 0.9 % saline). The remaining groups IV, V, and VI were treated with n-acetylcysteine (NAC-150 mg/kg/day, IP), pramipexole (PPX-0.23 mg/kg/day, IP) alone and in combination, respectively. BCCA was done in all groups except in groups I (control) and II (sham control) of animals. The treatment was given for one week before the surgery and continued for two days after surgery. Subsequently, behavioral performances, biochemical estimations, proinflammatory cytokines, and histopathological evaluations were done.<br><br>RESULTS: NAC, PPX, and combination treatment groups showed significant ameliorative effects on behavioral, biochemical, proinflammatory cytokines, and histopathological studies as compared with the BCCA group. Whereas, the combination group showed a significant difference in ameliorating the pathological changes of biochemical parameters and histopathological changes in comparison with the PPX alone treated group but not with the NAC alone group.<br><br>CONCLUSION: The study concluded that in the combination treatment group the histopathological parameter improved and the oxidative stress parameters were mitigated significantly compared with the PPX alone treatment group but not with the NAC alone treatment group.}, }
@article {pmid29941169, year = {2018}, author = {Jin, J and Richardson, L and Sheller-Miller, S and Zhong, N and Menon, R}, title = {Oxidative stress induces p38MAPK-dependent senescence in the feto-maternal interface cells.}, journal = {Placenta}, volume = {67}, number = {}, pages = {15-23}, pmid = {29941169}, issn = {1532-3102}, support = {R01 HD084532/HD/NICHD NIH HHS/United States ; R03 HD086354/HD/NICHD NIH HHS/United States ; T32 ES007254/ES/NIEHS NIH HHS/United States ; }, mesh = {Amnion/*cytology/metabolism ; Cells, Cultured ; *Cellular Senescence ; Decidua/*cytology/metabolism ; Epithelial Cells/metabolism/*physiology ; Female ; Humans ; Maternal-Fetal Relations ; Oxidative Stress/drug effects/*physiology ; Placenta/*cytology/metabolism ; Pregnancy ; Reactive Oxygen Species/metabolism ; Smoke/adverse effects ; Stromal Cells/cytology/physiology ; Nicotiana ; Up-Regulation ; p38 Mitogen-Activated Protein Kinases/metabolism/*physiology ; }, abstract = {OBJECTIVE: This study tested the mechanism of the oxidative stress (OS)-induced senescence pathway at the feto-maternal interface cells.<br><br>METHODS: Primary amnion mesenchymal cells (AMCs), chorion and decidual cells isolated from the placental membranes of women at normal term (not in labor) were exposed to OS-inducing cigarette smoke extract (CSE) for 48&#x202f;h. Reactive oxygen species (ROS) was measured using 2'7'-dichlorodihydrofluorescein. Western blot analysis determined phosphorylated (P) p38MAPK and p53 expression. Senescence-associated &#x3b2;-Galactosidase (SA-&#x3b2;-Gal) and matrix metallopeptidase 9 (MMP9) histochemistry were used to measure senescence and inflammation respectively. Cotreatment of cells with the antioxidant, N-acetyl cysteine (NAC), or the p38MAPK inhibitor, SB203580 (SB), verified the activation specificity.<br><br>RESULTS: CSE increased ROS production from AMCs, chorion cells, and decidual cells (P&#x202f;<&#x202f;0.05) compared to controls. Western blot analysis determined that CSE induced p38MAPK activation (P&#x202f;<&#x202f;0.05) and cotreatment with NAC inhibited ROS production and p38MAPK activation (P&#x202f;<&#x202f;0.05) in all cell types. CSE did not increase p53 phosphorylation in any of the cells; however, AMCs showed constitutive P-p53 expression. CSE increased senescence in AMCs and chorion cells compared to controls (P&#x202f;=&#x202f;0.01 and P&#x202f;=&#x202f;0.003, respectively); however, senescence was not observed in decidual cells. Senescence was significantly reduced following cotreatment with SB and NAC (AMCs; P&#x202f;=&#x202f;0.01 and chorion; P&#x202f;=&#x202f;0.009). CSE increased MMP9 in all cells that was reduced by NAC.<br><br>CONCLUSION: OS induced p38MAPK activation and inflammation in all cell types that was associated with senescence in fetal cells but not in maternal cells.}, }
@article {pmid29940243, year = {2018}, author = {Tang, B and Ma, J and Ha, X and Zhang, Y and Xing, Y}, title = {Tumor necrosis factor-alpha upregulated PHLPP1 through activating nuclear factor-kappa B during myocardial ischemia/reperfusion.}, journal = {Life sciences}, volume = {207}, number = {}, pages = {355-363}, doi = {10.1016/j.lfs.2018.06.023}, pmid = {29940243}, issn = {1879-0631}, mesh = {Animals ; Animals, Newborn ; Disease Models, Animal ; Gene Expression Regulation ; Heart Ventricles/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Cells/cytology/metabolism ; Myocardial Ischemia/*metabolism ; NF-kappa B/*metabolism ; NF-kappa B p50 Subunit/*metabolism ; Nuclear Proteins/*metabolism ; Phosphoprotein Phosphatases/*metabolism ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*metabolism ; Serine/chemistry ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {AIMS: The pleckstrin homology domain leucine-rich repeat protein phosphatase 1 (PHLPP1) specifically regulates phospho-Ser473 of protein kinase B (PKB, Akt) opposing cell survival during myocardial ischemia/reperfusion (I/R). Previous studies demonstrated PHLPP1 expression level was controlled by several mechanisms. However, the regulation mechanism of cardiac PHLPP1 expression following myocardial I/R remains unknown.<br><br>MAIN METHODS: The current study utilized the mouse model of myocardial I/R injury in vivo and the neonatal rat ventricular myocytes (NRVMs) of hypoxia/reoxygenation (H/R) injury in vitro. Expression of PHLPP1, nuclear factor-kappa B (NF-&#x3ba;B) and pNF-&#x3ba;B were determined by western blot. The expression of PHLPP1 and translocation of NF-&#x3ba;B was assessed by immunofluorescence. Chromatin immunoprecipitation (ChIP) assay was used to detect the binding of NF-&#x3ba;B to the promoter region of phlpp1 gene.<br><br>KEY FINDINGS: Myocardial I/R had no effect on cardiac PHLPP1 expression following I/R (30&#x202f;min/2&#x202f;h) but decreased after 4&#x202f;h reperfusion. In vitro, H/R (4&#x202f;h/1&#x202f;h) and tumor necrosis factor-alpha (TNF-&#x3b1;)-stimulation resulted in upregulation of PHLPP1 in NRVMs, which was blocked with etanercept. Yet, H2O2-induced oxidative stress had no obvious effect on PHLPP1 expression of NRVMs at early stage but N-acetylcysteine (NAC) pretreatment increased PHLPP1 levels after 4&#x202f;h H2O2 stimulation. TNF-&#x3b1; and H/R led to both expression and transcriptional activity of NF-&#x3ba;B, accompany with higher expression of PHLPP1. Pyrrolidine dithiocarbamate (PDTC), a NF-&#x3ba;B inhibitor, prevented the response not only in TNF-&#x3b1;-treated cardiomyocytes but also in H/R-treated group.<br><br>SIGNIFICANCE: These results implicated that TNF-&#x3b1; involved in cardiac PHLPP1 upregulation during reoxygenation, which was mediated by NF-&#x3ba;B transcriptional activity.}, }
@article {pmid29940171, year = {2018}, author = {Niino, T and Tago, K and Yasuda, D and Takahashi, K and Mashino, T and Tamura, H and Funakoshi-Tago, M}, title = {A 5-hydroxyoxindole derivative attenuates LPS-induced inflammatory responses by activating the p38-Nrf2 signaling axis.}, journal = {Biochemical pharmacology}, volume = {155}, number = {}, pages = {182-197}, doi = {10.1016/j.bcp.2018.06.021}, pmid = {29940171}, issn = {1873-2968}, mesh = {Animals ; HEK293 Cells ; Humans ; Inflammation Mediators/*antagonists &amp; inhibitors/*metabolism ; Lipopolysaccharides/*toxicity ; Male ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/*metabolism ; Oxindoles/*pharmacology ; RAW 264.7 Cells ; Signal Transduction/drug effects/physiology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {5-Hydroxyoxindole is a urinary metabolite of indole that exhibits antioxidant activity. In the present study, we found that a 5-hydroxyoxindole derivative (5-HI) significantly inhibited LPS-induced inflammatory effects in the murine macrophage cell line, RAW264.7. 5-HI induced the expression of the transcription factor, Nrf2, which is typically ubiquitinated by Keap1, an adaptor component of the ubiquitin E3 ligase complex, resulting in its proteasomal degradation. By utilizing Keap1-/- MEFs reconstituted with Keap1 mutants harboring substitutions in their major cysteine residues, we clarified the importance of Cys151 in Keap1 as a sensor for 5-HI in the induction of Nrf2 expression. Furthermore, 5-HI induced the activation of the MKK3/6-p38 pathway, which is required for the transcriptional activation of Nrf2. The knockdown of Nrf2 enhanced the LPS-induced expression of inflammatory mediators, including iNOS, NO, and CCL2, and effectively repressed the inhibitory effects of 5-HI on their expression. Although 5-HI and antioxidant N-acetyl cysteine (NAC) both reduced LPS-induced ROS generation, the treatment with NAC did not affect the LPS-induced expression of inflammatory mediators, suggesting that the anti-inflammatory activity of 5-HI mediated by Nrf2 is independent of redox control. Furthermore, when injected into mice with 5-HI, the expression of Nrf2 was significantly increased, and the LPS-induced mRNA expression of CXCL1, CCL2, TNFα, and IL-6 were remarkably inhibited in the kidneys, liver, and lungs, and the production of these cytokines in serum was effectively reduced. Collectively, these results suggest that 5-HI has potential in the treatment of inflammatory diseases through the activation of Nrf2.}, }
@article {pmid29936684, year = {2019}, author = {Kostić, S and Mićovic, &#x17d; and Andrejević, L and Cvetković, S and Stamenković, A and Stanković, S and Obrenović, R and Labudović-Borović, M and Hrnčić, D and Jakovljević, V and Djurić, D}, title = {The effects of L-cysteine and N-acetyl-L-cysteine on homocysteine metabolism and haemostatic markers, and on cardiac and aortic histology in subchronically methionine-treated Wistar male rats.}, journal = {Molecular and cellular biochemistry}, volume = {451}, number = {1-2}, pages = {43-54}, pmid = {29936684}, issn = {1573-4919}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta/*cytology/drug effects/metabolism ; Biomarkers/*metabolism ; Cysteine/*pharmacology ; Heart/drug effects/*physiology ; Hemostatics ; Homocysteine/*metabolism ; Male ; Methionine/*administration &amp; dosage ; Rats ; Rats, Wistar ; }, abstract = {Methionine is the precursor of homocysteine, a sulfur amino acid intermediate in the methylation and transsulfuration pathways; methionine-rich diets were used to induce hyperhomocysteinemia, and cardiovascular pathology was often observed. Other sulfur amino acids interfere with this metabolism, i.e., L-cysteine (Cys) and N-aceyl-L-cysteine (NAC), and probably also affect cardiovascular system. Their effects are controversial due to their ability to act both as anti- or pro-oxidant. Thus, this study aimed to elucidate their influence on levels of homocysteine, folate and vitamin B12, levels of different haemostatic parameters (fibrinogen, D-dimer, vWF Ag, vWF Ac) in rat serum or plasma as well as their effects on cardiac and aortic tissue histology in subchronically methionine-treated rats. Wistar albino rats were divided into 4 experimental groups: (a) control group (0.9% sodium chloride 0.1-0.2 mL/day) (n = 10) (K); (b) DL-methionine (0.8 mmol/kg/bw/day) (n = 10) (M); (c) DL-methionine (0.8 mmol/kg/bw/day) + L-cysteine (7 mg/kg/bw/day) (n = 8) (C); (d) DL-methionine (0.8 mmol/ kg/bw/day) + N-acetyl-L-cysteine (50 mg/kg/bw/day) (n = 8) (N). All substances were applied i.p., treatment duration 3 weeks. Lower levels of vitamin B12 in all the groups were found. Folate was reduced only in N group. Decreased fibrinogen was noted in C and N groups and increased D-dimer only in C. VWF activity was reduced in M and C groups. Deleterious effects in heart were observed, especially after Cys and NAC application. Aortic tissue remained unchanged. In conclusion, it could be said that sulfur amino acids have the significant impact on cardiovascular system in subchronically methionine-treated rats. This study points out the relevance of their complex interactions and deleterious effects mediated by either direct influence or procoagulant properties.}, }
@article {pmid29935984, year = {2018}, author = {Wu, CY and Tsai, YL and Hsieh, CP and Wang, TC and Chan, MH and Chen, HH}, title = {Attenuation of toluene-induced brain stimulation reward enhancement and behavioral disturbances by N-acetylcysteine in mice.}, journal = {Toxicology}, volume = {408}, number = {}, pages = {39-45}, doi = {10.1016/j.tox.2018.06.011}, pmid = {29935984}, issn = {1879-3185}, mesh = {Acetylcysteine/*pharmacology ; Amino Acid Transport System y+/agonists/metabolism ; Animals ; Behavior, Animal/*drug effects ; Brain/*drug effects/metabolism/physiopathology ; Excitatory Amino Acid Agonists/*pharmacology ; Exploratory Behavior/drug effects ; Interpersonal Relations ; Male ; Mice, Inbred C57BL ; Motor Activity/drug effects ; Neuroprotective Agents/*pharmacology ; Receptors, Metabotropic Glutamate/agonists/metabolism ; Recognition, Psychology/drug effects ; *Reward ; Solvents/*toxicity ; Toluene/*toxicity ; }, abstract = {Toluene, a commonly used organic solvent, produces a variety of behavioral disturbances in both humans and animals comparable to noncompetitive N-methyl-D-aspartate receptor (NMDARs) antagonists, such as phencyclidine (PCP). N-acetylcysteine (NAC) is capable of reversing the psychotomimetic effects of PCP via activation of cystine-glutamate antiporters (xCT). The present study examined whether NAC is capable of attenuating the toluene-induced brain stimulation reward enhancement and behavioral manifestations. Male mice received various doses of NAC prior to toluene exposure for assessment of intracranial self-stimulation (ICSS) thresholds, rotarod test, novel object recognition task and social interaction test. NAC ameliorated the lowering of ICSS thresholds, motor incoordination, object recognition memory impairments and social withdrawal induced by toluene. Furthermore, the capacity of NAC to ameliorate acute toluene-induced deficits in object recognition and social interaction was blocked by the xCT inhibitor (S)-4-carboxyphenylglycine and the mGluR2/3 antagonist LY341495. These results indicate that NAC could prevent toluene-induced reward facilitation and behavioral disturbances and its beneficial effects, at least for cognitive function and social interaction, are associated with activation of the xCT and mGluR2/3. These findings show the potential promise for NAC to treat toluene dependence and to prevent toluene intoxication caused by unintentional or deliberate inhalation.}, }
@article {pmid29935072, year = {2018}, author = {Elnagar, AMB and Ibrahim, A and Soliman, AM}, title = {Histopathological Effects of Titanium Dioxide Nanoparticles and The Possible Protective Role of N-Acetylcysteine on The Testes of Male Albino Rats.}, journal = {International journal of fertility &amp; sterility}, volume = {12}, number = {3}, pages = {249-256}, pmid = {29935072}, issn = {2008-076X}, abstract = {BACKGROUND: Titanium dioxide (TiO2) is a white pigment which is used in paints, plastics, etc. It is reported that TiO2 induces oxidative stress and DNA damage. N-acetylcysteine (NAC) has been used to fight oxidative stress-induced damage in different tissues. The objective of this study was to evaluate the toxic effects of orally administered TiO2 nanoparticles and the possible protective effect of NAC on the testes of adult male albino rats.<br><br>MATERIALS AND METHODS: In this experimental study, 50 adult male albino rats were classified into five groups. Group I was the negative control, group II was treated with gum acacia solution , group III was treated with NAC, group IV was treated with TiO2 nanoparticles, and group V was treated with 100 mg/kg of NAC and 1200 mg/kg TiO2 nanoparticles. Total testosterone, glutathione (GSH), and serum malondialdehyde (MDA) levels were estimated. The testes were subjected to histopathological, electron microscopic examinations, and immunohistochemical detection for tumor necrosis factor (TNF)-&#x3b1;. Cells from the left testis were examined to detect the degree of DNA impairment by using the comet assay.<br><br>RESULTS: TiO2 nanoparticles induced histopathological and ultrastructure changes in the testes as well as positive TNF-&#x3b1; immunoreaction in the testicular tissue. Moreover, there was an increase in serum MDA while a decrease in testosterone and GSH levels in TiO2 nanoparticles-treated group. TiO2 resulted in DNA damage. Administration of NAC to TiO2- treated rats led to improvement of the previous parameters with modest protective effects against DNA damage.<br><br>CONCLUSION: TiO2-induced damage to the testes was mediated by oxidative stress. Notably, administration of NAC protected against TiO2's damaging effects.}, }
@article {pmid29934599, year = {2018}, author = {Han, H and Chou, CC and Li, R and Liu, J and Zhang, L and Zhu, W and Hu, J and Yang, B and Tian, J}, title = {Chalcomoracin is a potent anticancer agent acting through triggering Oxidative stress via a mitophagy- and paraptosis-dependent mechanism.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {9566}, pmid = {29934599}, issn = {2045-2322}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Benzofurans/*pharmacology ; Calcium/metabolism ; Calpain/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cytoplasm/drug effects/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Homeostasis/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinases/metabolism ; Mitophagy/*drug effects ; Oxidative Stress/*drug effects ; PC-3 Cells ; Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Chalocomoracin (CMR), one of the major secondary metabolites found in fungus-infected mulberry leaves, is a potent anticancer agent. However, its anticancer mechanism remains elusive. Here, we demonstrated the potent anti-tumor activity and molecular mechanism of CMR both in vitro and in vivo. We showed for the first time that CMR treatment markedly promoted paraptosis along with extensive cytoplasmic vacuolation derived from the endoplasmic reticulum, rather than apoptosis, in PC-3 and MDA-MB-231cell lines. Additional studies revealed that ectopic expression of Myc-PINK1 (PTEN-induced kinase 1), a key regulator of mitophagy, rendered LNCap cells susceptible to CMR-induced paraptosis, suggesting that the mitophagy-dependent pathway plays a crucial role in inducing paraptosis by activating PINK1. CMR treatment directly upregulated PINK1 and downregulated Alix genes in MDA-MB-231 and PC-3 cell lines. Furthermore, mitophagy signaling and paraptosis with cytoplasmic vacuolation could be blocked by antioxidant N-acetylcysteine (NAC), indicating the novel pathway was triggered by reactive oxygen species (ROS) production. An in vivo MDA-MB-231 xenograft tumor model revealed that CMR suppressed tumor growth by inducing vacuolation production through the same signal changes as those observed in vitro. These data suggest that CMR is a potential therapeutic entity for cancer treatment through a non-apoptotic pathway.}, }
@article {pmid29929056, year = {2018}, author = {Guo, L and Zhang, H and Li, W and Zhan, D and Wang, M}, title = {N-acetyl cysteine inhibits lipopolysaccharide-mediated induction of interleukin-6 synthesis in MC3T3-E1 cells through the NF-kB signaling pathway.}, journal = {Archives of oral biology}, volume = {93}, number = {}, pages = {149-154}, doi = {10.1016/j.archoralbio.2018.06.007}, pmid = {29929056}, issn = {1879-1506}, mesh = {Acetylcysteine/*pharmacology ; Blotting, Western ; Cell Line ; Cell Proliferation ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Interleukin-6/*metabolism ; Lipopolysaccharides/*pharmacology ; NF-kappa B/*metabolism ; Osteoblasts/*metabolism ; Polymerase Chain Reaction ; RNA, Messenger/metabolism ; Signal Transduction ; }, abstract = {BACKGROUND: Interleukin-6 (IL-6) is a potent stimulator of osteoclastic activity. Lipopolysaccharide (LPS) has been shown to regulate the expression of potent inflammatory factors, including TNF-α and IL-6. Currently, effective therapeutic treatments for bacteria-caused bone destruction are limited. N-acetyl cysteine (NAC) is an antioxidant small molecule that possibly modulates osteoblastic differentiation. However, whether NAC can affect the LPS-mediated reduction of IL-6 synthesis in MC3T3-E1 cells is still unknown.<br><br>AIMS: The aim of this study was to investigate the role of NAC in the LPS -mediated reduction of IL-6 synthesis by MC3T3-E1 cells and to explore the underlying molecular mechanisms. In addition, we aimed to determine the involvement of the NF-kB pathway in any changes in IL-6 expression observed in response to LPS and NAC.<br><br>METHODS: MC3T3-E1 cells (ATCC, CRL-2593) were cultured in &#x3b1;-minimum essential medium. Cells were stimulated using NAC or LPS at various concentrations. Cell proliferation was observed at multiple time points using a cell counting kit 8 (CCK-8). IL-6 mRNA expression and protein synthesis were determined using quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay analyses. NF-kB mRNA expression and protein synthesis was determined using qPCR and Western blots analyses.<br><br>RESULTS: The results demonstrate that LPS induced IL-6 and NF-kB mRNA expression and protein synthesis in the cultured MC3T3-E1 cells. However, these effects were abolished following pre-treatment with NAC. Pretreatment with NAC (1&#x202f;mmol/l) or BAY11-7082 (10&#x202f;&#x3bc;mol/l) both significantly inhibited the NF-kB activity induced by LPS.<br><br>CONCLUSION: NAC inhibits the LPS-mediated induction of IL-6 synthesis in MC3T3-E1 cells through the NF-kB pathway.}, }
@article {pmid29929000, year = {2018}, author = {Rasheduzzaman, M and Moon, JH and Lee, JH and Nazim, UM and Park, SY}, title = {Telmisartan generates ROS-dependent upregulation of death receptor 5 to sensitize TRAIL in lung cancer via inhibition of autophagy flux.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {102}, number = {}, pages = {20-30}, doi = {10.1016/j.biocel.2018.06.006}, pmid = {29929000}, issn = {1878-5875}, mesh = {A549 Cells ; AMP-Activated Protein Kinases/metabolism ; Apoptosis/drug effects ; Autophagy/*drug effects ; Humans ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Molecular Targeted Therapy ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Telmisartan/*pharmacology/therapeutic use ; Up-Regulation/*drug effects ; }, abstract = {Telmisartan broadly used for the treatment of hypertension that is also known for its anticancer properties. TRAIL has the potential to kill tumor cells with minimal toxicity in normal cells by binding to death receptors, DR4 and DR5. Unfortunately, these TRAIL-death receptors have failed as most human cancers are resistant to TRAIL-mediated apoptosis. In this study, we evaluated telmisartan as a novel TRAIL-DR5-targeting agent with the aim of rendering TRAIL-based cancer therapies more active. Herein, we demonstrated that telmisartan could sensitize TRAIL and enhance NSCLC tumor cell death. The molecular mechanism includes the blocking of AMPK phosphorylation causes inhibition of autophagy flux by telmisartan resulting in ROS generation leading to death receptor (DR5) upregulation and subsequent activation of the caspase cascade by TRAIL treatment. Furthermore, using chloroquine and siATG5 significantly enhances ROS production and application of the ROS scavenger N-acetyl-cysteine (NAC) rescues the cells undergoing apoptosis by abrogating the expression of DR5 and finally the caspase cascade. Additionally, NAC treatment also maintains autophagy flux and makes the cells unresponsive to TRAIL. In summary, telmisartan in combination with TRAIL exhibits enhanced cytotoxic capacity toward lung cancer cells, thereby providing the potential for effective and novel therapeutic approaches to treat lung cancer.}, }
@article {pmid29925172, year = {2018}, author = {Yao, B and Liu, DW and Chai, WZ and Wang, XT and Zhang, HM}, title = {[Effect of N-acetyl-L-cysteine on vascular heterogeneity of microcirculation in endotoxemia rabbits and its mechanism].}, journal = {Zhonghua yi xue za zhi}, volume = {98}, number = {23}, pages = {1869-1872}, doi = {10.3760/cma.j.issn.0376-2491.2018.23.013}, pmid = {29925172}, issn = {0376-2491}, mesh = {Acetylcysteine ; Animals ; Cardiac Output ; *Endotoxemia ; Lipopolysaccharides ; Microcirculation ; Rabbits ; }, abstract = {Objective: To study the effect of N-acetyl-L-cysteine (NAC) on vascular heterogeneity in microcirculation dysfunction caused by endotoxemia and its mechanism. Methods: Eighteen Japanese big ear rabbits were divided into three groups: Control group, Lipopolysaccharides (LPS) group and LPS+ NAC group.A dose of 2 mg/kg LPS was injected to set up endotoxemia rabbit models.Rabbits in the LPS+ NAC group were infused with NAC at a dose of 350 mg/kg, and the same amount of normal saline were infected intravenously to the rabbits in the Control and LPS group.Macrocirculation parameters (central venous pressure, mean arterial pressure and cardiac output) and microcirculation parameters (microvascular flow index and flow heterogeneity index) in all the groups were recorded at 0 and 2 h. Artery and vein S-nitrosohemoglobin were detected at 2 h. Variables were compared by one-way analysis of variance.Dunnett-t3 was used for comparisons between two groups. Results: Microvascular flow index in Control group and LPS+ NAC group at 2 h were much higher than that in LPS group (2.82±0.09 vs 1.11±0.16, P<0.001; 1.60±0.17 vs 1.11±0.16, P<0.001), and flow heterogeneity index in Control group and LPS+ NAC group at 2 h were significantly lower than that in LPS group (0.16±0.06 vs 1.16±0.33, P<0.001; 0.80±0.12 vs 1.16±0.33, P=0.035). The arterial-venous difference of S-nitrosohemoglobin content in Control group and LPS+ NAC group were higher than LPS group [(41±6) vs (27±5) nmol/L, P=0.002; (36±5) vs (27±5) nmol/L, P=0.010]. Conclusions: In endotoxemia rabbits, NAC can improve the microcirculation dysfunction, especially vascular heterogeneity. It indicated that NAC could improve the ability of S-nitrosohemoglobin-mediated nitric oxide release from red blood cells.}, }
@article {pmid29923368, year = {2018}, author = {Wang, YC and Lee, AS and Lu, LS and Ke, LY and Chen, WY and Dong, JW and Lu, J and Chen, Z and Chu, CS and Chan, HC and Kuzan, TY and Tsai, MH and Hsu, WL and Dixon, RAF and Sawamura, T and Chang, KC and Chen, CH}, title = {Human electronegative LDL induces mitochondrial dysfunction and premature senescence of vascular cells in vivo.}, journal = {Aging cell}, volume = {17}, number = {4}, pages = {e12792}, pmid = {29923368}, issn = {1474-9726}, support = {1-04-RA-13//American Diabetes Association/International ; HL-63364/NH/NIH HHS/United States ; MOST 105-2320-B-037-004-MY3//Ministry of Science and Technology in Taiwan/International ; MOST-104-2320-B-715-009-MY3//Ministry of Science and Technology in Taiwan/International ; NSC 101-2314-B-039-039//Ministry of Science and Technology in Taiwan/International ; NSC 102-2314-B-039-019//Ministry of Science and Technology in Taiwan/International ; MOST 103-2314-B-715-008//Ministry of Science and Technology in Taiwan/International ; DMR-100-008//China Medical University Hospital in Taiwan/International ; DMR-101-007//China Medical University Hospital in Taiwan/International ; DMR-102-007//China Medical University Hospital in Taiwan/International ; DMR-102-108//China Medical University Hospital in Taiwan/International ; DMR-106-008//China Medical University Hospital in Taiwan/International ; RD-1020082//Mackay Medical College in Taiwan/International ; RD-1030085//Mackay Medical College in Taiwan/International ; USTP-NTUT-TMU-105-06//University System of Taipei Joint Research Program and Taipei Medical University/International ; USTP-NTUT-TMU-106-01//University System of Taipei Joint Research Program and Taipei Medical University/International ; TMU104-AE1-B27//University System of Taipei Joint Research Program and Taipei Medical University/International ; NHRI-EX103-10305SI//National Health Research Institutes of Taiwan/International ; NHRI-EX104-10305SI//National Health Research Institutes of Taiwan/International ; BM104010092//Academia Sinica in Taiwan/International ; //China Medical University under the "Aim for the Top University Plan" of the Ministry of Education, Taiwan/International ; MOHW104-TDU-B-212-113002//Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence/International ; //Mao-Kuei Lin Research Fund of Chicony Electronics/International ; KMU-DK106001//Kaohsiung Medical University/International ; KMU-TP105D00//Kaohsiung Medical University/International ; }, mesh = {Animals ; Cells, Cultured ; Cellular Senescence/*drug effects ; Endothelium, Vascular/*drug effects/metabolism ; Humans ; Injections, Intravenous ; Lipoproteins, LDL/administration &amp; dosage/blood/*pharmacology ; Mesocricetus ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/*drug effects/metabolism ; }, abstract = {Dysregulation of plasma lipids is associated with age-related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low-density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg[-1] day[-1]) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence-associated β-galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5-treated but not L1-treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high-fat diet, nuclear γH2AX deposition and senescence-associated β-galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N-acetyl-cysteine (free-radical scavenger) or caffeine (ATM blocker), as well as in lectin-like oxidized LDL receptor-1 (LOX-1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free-radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5-induced endothelial senescence. In conclusion, L5 may promote mitochondrial free-radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5-induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease.}, }
@article {pmid29923297, year = {2018}, author = {Liu, H and Wang, L and Zeng, Q and Zhao, L and Cui, Y and Hou, C and Zhang, B and Zhang, Z and Zhang, S and Chen, X and Wang, A}, title = {Oxidative stress-mediated autophagic cell death participates in the neurotoxic effect on SH-SY5Y cells induced by excessive iodide.}, journal = {Environmental toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1002/tox.22571}, pmid = {29923297}, issn = {1522-7278}, abstract = {Excessive iodide could induce intellectual damage in children, which has attracted broad attention. To investigate the neurotoxic effect of iodide and its mechanism, a human dopaminergic neuroblastoma cell line (SH-SY5Y) was treated with different concentrations of potassium iodide (KI). The results showed that excessive iodide could decrease cell viability, reduce glutathione (GSH) and superoxide dismutase (SOD), and increase the degree of autophagy (by changing the cellular ultrastructure and raising the autophagy-related mRNA and protein expression of LC3, Beclin1, and p62), which were correlated with the immunofluorescence labeling. Furthermore, treatment with the autophagy inhibitor 3-methyladenine (3MA), antioxidant N-acetylcysteine (NAC) and 30 mM KI for 24 h was conducted in the following research. 3MA significantly decreased autophagy-related mRNA and protein expression and improved cell viability, indicating that excess iodide induced autophagic cell death. In addition, oxidative stress regulated autophagy, reflected by the results that NAC decreased the mRNA and protein expression of LC3, Beclin1, and p62. In summary, autophagic cell death mediated by oxidative stress may participate in excessive iodide-induced SH-SY5Y cell death.}, }
@article {pmid29914195, year = {2018}, author = {Chen, YC and Lu, MC and El-Shazly, M and Lai, KH and Wu, TY and Hsu, YM and Lee, YL and Liu, YC}, title = {Breaking down Leukemia Walls: Heteronemin, a Sesterterpene Derivative, Induces Apoptosis in Leukemia Molt4 Cells through Oxidative Stress, Mitochondrial Dysfunction and Induction of Talin Expression.}, journal = {Marine drugs}, volume = {16}, number = {6}, pages = {}, pmid = {29914195}, issn = {1660-3397}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/chemistry/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Cell Line, Tumor ; HEK293 Cells ; Humans ; Leukemia/*drug therapy ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/drug effects/metabolism ; Oxidative Stress/drug effects ; Porifera/*metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Sesterterpenes/chemistry/pharmacology ; Talin/genetics/*metabolism ; Terpenes/chemistry/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {Heteronemin, the most abundant secondary metabolite in the sponge Hippospongia sp., exhibited potent cytotoxic activity against several cancer cell lines. It increased the percentage of apoptotic cells and reactive oxygen species (ROS) in Molt4 cells. The use of ROS scavenger, N-acetyl cysteine (NAC), suppressed both the production of ROS from mitochondria and cell apoptosis that were induced by heteronemin treatment. Heteronemin upregulated talin and phosphorylated talin expression in Molt4 cells but it only upregulated the expression of phosphorylated talin in HEK293 cells. However, pretreatment with NAC reversed these effects. Talin siRNA reversed the activation of pro-apoptotic cleaved caspases 3 and 9. On the other hand, the downstream proteins including FAK and NF-&amp;kappa;B (p65) were not affected. In addition, we confirmed that heteronemin directly modulated phosphorylated talin expression through ROS generation resulting in cell apoptosis, but it did not affect talin/FAK complex. Furthermore, heteronemin interfered with actin microfilament and caused morphology changes. Taken together, these findings suggest that the cytotoxic effect of heteronemin is associated with oxidative stress and induction of phosphorylated talin expression. Our results suggest that heteronemin represents an interesting candidate which can be further developed as a drug lead against leukemia.}, }
@article {pmid29910612, year = {2018}, author = {Martínez-Torres, AC and Zarate-Triviño, DG and Lorenzo-Anota, HY and Ávila-Ávila, A and Rodríguez-Abrego, C and Rodríguez-Padilla, C}, title = {Chitosan gold nanoparticles induce cell death in HeLa and MCF-7 cells through reactive oxygen species production.}, journal = {International journal of nanomedicine}, volume = {13}, number = {}, pages = {3235-3250}, pmid = {29910612}, issn = {1178-2013}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Caspases/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Death/drug effects ; Cell Survival/drug effects ; Chitosan/*chemistry/pharmacology ; Dose-Response Relationship, Drug ; Female ; Gold/chemistry/*pharmacology ; HeLa Cells ; Humans ; Leukocytes, Mononuclear/drug effects/metabolism ; MCF-7 Cells ; Metal Nanoparticles/*administration &amp; dosage/chemistry ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Nanotechnology has gained important interest, especially in the development of new therapies; the application of gold nanoparticles (AuNPs) in the treatment and detection of diseases is a growing trend in this field. As cancer represents a serious health problem around the world, AuNPs are studied as potential drugs or drug carriers for anticancer agents. Recent studies show that AuNPs stabilized with chitosan (CH) possess interesting biological activities, including potential antitumor effects that could be selective to cancer cells.<br><br>MATERIALS AND METHODS: In this study, we synthesized sodium citrate-AuNPs and CH-capped AuNPs of 3-10 nm, and analyzed their cytotoxicity in cervical (HeLa) and breast (MCF-7) cancer cells, and in peripheral blood mononuclear cells (PBMCs). Then, we evaluated the clonogenic potential, cell cycle, nuclear alterations, caspase dependence, and reactive oxygen species (ROS) production in HeLa and MCF-7 cells after chitosan gold nanoparticles (CH-AuNPs) exposure.<br><br>RESULTS: Our data showed that CH-AuNPs are cytotoxic in a dose-dependent manner in the cancer cell lines tested, while they induce low cytotoxicity in PBMCs. Sodium citrate gold nanoparticles did not show cytotoxic effects. In both HeLa and MCF-7 cell lines, CH-AuNPs inhibit clonogenic potential without inducing cell cycle arrest or nuclear alterations. The cell death mechanism is specific for the type of cancer cell line tested, as it depends on caspase activation in HeLa cells, whereas it is caspase independent in MCF-7 cells. In all cases, ROS production is mandatory for cell death induction by CH-AuNPs, as ROS inhibition with N-acetyl cysteine inhibits cell death.<br><br>CONCLUSION: Our results show that CH-AuNPs are selective for HeLa and MCF-7 cancer cells, rather than normal PBMCs, and that ROS production seems to be a conserved feature of the cell death mechanism induced by CH-AuNPs. These results improve the knowledge of CH-AuNPs and open the way to the design of new pharmacological strategies using these agents against cancer.}, }
@article {pmid29908912, year = {2018}, author = {Couto, JP and Moreira, R}, title = {Oral N-acetylcysteine in the treatment of obsessive-compulsive disorder: A systematic review of the clinical evidence.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {86}, number = {}, pages = {245-254}, doi = {10.1016/j.pnpbp.2018.06.005}, pmid = {29908912}, issn = {1878-4216}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Humans ; Obsessive-Compulsive Disorder/*drug therapy ; Psychotropic Drugs/*therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {Obsessive-compulsive disorder (OCD) is characterized by the presence of obsessions and/or compulsions. It is a leading cause of morbidity worldwide, as it can interfere with all aspects of life. Despite the adequate treatment trials, half of patients preserve residual or impairing symptoms and selective serotonin reuptake inhibitors (SSRIs) are not free from adverse side effects. This work aims to systematically review the current evidence available concerning the efficacy of N-acetylcysteine (NAC) in the treatment of OCD. Five randomized placebo-controlled trials (RCTs), 3 case reports and 2 case series were included. The studies developed so far are somehow contradictory. However, our pooled result from the 4 observational studies (n = 13) showed a mean reduction in Y-BOCS score after NAC treatment of -11 points (p = .01). Pooled mean difference from 4 of the 5 RCTs included was 3.35, with a95% confidence interval of -0.21-6.91 and a p-value barely below statistical significance (p = .07). This result trends to favour the use of NAC over placebo in OCD patients. NAC has an optimal tolerability profile, even in higher doses, and the most frequently reported adverse events were gastrointestinal. Despite the degree of evidence being D, in our opinion the potential of NAC is underestimated. Considering its exceptional tolerability profile, the use as an add-on agent should be contemplated, on an ad hoc basis.}, }
@article {pmid29908644, year = {2018}, author = {Hu, J and Wang, H and Hu, YF and Xu, XF and Chen, YH and Xia, MZ and Zhang, C and Xu, DX}, title = {Cadmium induces inflammatory cytokines through activating Akt signaling in mouse placenta and human trophoblast cells.}, journal = {Placenta}, volume = {65}, number = {}, pages = {7-14}, doi = {10.1016/j.placenta.2018.03.008}, pmid = {29908644}, issn = {1532-3102}, mesh = {Animals ; Cadmium/*pharmacology ; Cells, Cultured ; Cytokines/*genetics/metabolism ; Female ; Humans ; Inflammation/genetics/metabolism ; Inflammation Mediators/*metabolism ; Male ; Mice ; Placenta/*drug effects/metabolism ; Pregnancy ; Proto-Oncogene Proteins c-akt/*metabolism ; Signal Transduction/drug effects ; Trophoblasts/*drug effects/metabolism ; Up-Regulation/drug effects ; }, abstract = {INTRODUCTION: Several reports demonstrated that cadmium (Cd) had proinflammatory activities. The present study aimed to investigate whether Cd induces inflammatory cytokines in mouse placenta and human trophoblast cells.<br><br>METHODS: Human JEG-3&#x202f;cells were treated with different concentration of CdCl2 (0-50&#x202f;&#x3bc;M) or CdCl2 (25&#x202f;&#x3bc;M) for different times. The pregnant mice were administered with CdCl2 (3.0&#x202f;mg/kg, i.p.) on GD15.<br><br>RESULTS: TNF-&#x3b1;, IL-8 and IL-6 mRNAs were elevated in CdCl2-treated JEG-3&#x202f;cells. Several inflammatory cytokines were up-regulated in Cd-treated placenta of mice. Moreover, keratinocyte chemokine (KC), a functional analogue of human IL-8, was increased in maternal serum and amniotic fluid from CdCl2-exposed mice. Additional experiment showed that gestational Cd exposure activated Akt signaling in mouse placenta. Co-culture with CdCl2 elevated pAkt level in JEG-3&#x202f;cells in concentration- and time-dependent manners. LY294002, a specific inhibitor of PI3K, blocked CdCl2-evoked Akt phosphorylation in JEG-3&#x202f;cells. Concomitantly, LY294002 inhibited CdCl2-induced IL-8 in JEG-3&#x202f;cells. N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, blocked CdCl2-evoked Akt phosphorylation in mouse placenta and human trophoblast cells. Additionally, NAC attenuated Cd-induced up-regulation of KC in amniotic fluid.<br><br>DISCUSSION: Cd induces inflammatory cytokines partially through activating Akt signaling in mouse placenta and human trophoblast cells. NAC may be exploited for prevention of Cd-induced placental inflammation.}, }
@article {pmid29908097, year = {2018}, author = {Nilsson, JL&#xc5; and Blomgren, A and Nilsson, UJ and Högestätt, ED and Grundemar, L}, title = {N,N'-Bis(2-mercaptoethyl)isophthalamide Binds Electrophilic Paracetamol Metabolites and Prevents Paracetamol-Induced Liver Toxicity.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {123}, number = {5}, pages = {589-593}, doi = {10.1111/bcpt.13058}, pmid = {29908097}, issn = {1742-7843}, support = {//Medical Faculty of Lund University (ALF)/ ; //AFA Insurance/ ; //EmeraMed Ltd/ ; }, mesh = {Acetaminophen/*adverse effects/pharmacokinetics ; Acetylcysteine/pharmacology ; Administration, Oral ; Analgesics, Non-Narcotic/*adverse effects/pharmacology ; Animals ; Antidotes/pharmacology ; Benzene Derivatives/metabolism/*therapeutic use ; Benzoquinones/*pharmacokinetics ; Chelating Agents/metabolism/*therapeutic use ; Chemical and Drug Induced Liver Injury/etiology/metabolism/*prevention &amp; control ; Disease Models, Animal ; Imines/*pharmacokinetics ; Mice ; Sulfhydryl Compounds/metabolism/*therapeutic use ; }, abstract = {Paracetamol overdosing may cause liver injury including fulminant liver failure due to generation of the toxic metabolites, N-acetyl-p-benzoquinone imine (NAPQI) and p-benzoquinone (p-BQ). Herein, the chelating agent, N,N'-Bis(2-mercaptoethyl)isophthalamide (NBMI), was examined for its potential ability to entrap NAPQI and p-BQ and to prevent paracetamol-induced liver injury. Both NBMI and the conventional paracetamol antidote N-acetylcysteine (NAC) were investigated with regard to their abilities to scavenge the NAPQI and p-BQ in a Transient Receptor Potential Ankyrin 1-dependent screening assay. Stoichiometric evaluations indicated that NBMI was able to entrap these metabolites more efficiently than NAC. Furthermore, oral administration of either NBMI (680 mg/kg) or NAC (680 mg/kg) prevented the development of the characteristic liver necrosis and elevation of serum alanine aminotransferase in a mouse model for paracetamol-induced liver injury. In summary, these results show that NBMI is able to entrap the toxic metabolites NAPQI and p-BQ and to prevent paracetamol-induced liver injury in mice.}, }
@article {pmid29907918, year = {2018}, author = {Bikkul, MU and Clements, CS and Godwin, LS and Goldberg, MW and Kill, IR and Bridger, JM}, title = {Farnesyltransferase inhibitor and rapamycin correct aberrant genome organisation and decrease DNA damage respectively, in Hutchinson-Gilford progeria syndrome fibroblasts.}, journal = {Biogerontology}, volume = {19}, number = {6}, pages = {579-602}, pmid = {29907918}, issn = {1573-6768}, mesh = {Cell Line ; Comet Assay ; DNA Damage/*drug effects ; Diphosphonates/pharmacology/*therapeutic use ; Drug Therapy, Combination ; Farnesyltranstransferase/*antagonists &amp; inhibitors ; Female ; Fibroblasts/drug effects ; Genome, Human/*drug effects ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology/*therapeutic use ; Insulin-Like Growth Factor I/pharmacology ; Lamin Type A/genetics ; Lamins/genetics ; Membrane Proteins/genetics ; Metalloendopeptidases/genetics ; Mutation ; Progeria/*drug therapy/genetics/metabolism ; Protein Processing, Post-Translational ; Sirolimus/pharmacology/*therapeutic use ; }, abstract = {Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal premature ageing disease in children. HGPS is one of several progeroid syndromes caused by mutations in the LMNA gene encoding the nuclear structural proteins lamins A and C. In classic HGPS the mutation G608G leads to the formation of a toxic lamin A protein called progerin. During post-translational processing progerin remains farnesylated owing to the mutation interfering with a step whereby the farnesyl moiety is removed by the enzyme ZMPSTE24. Permanent farnesylation of progerin is thought to be responsible for the proteins toxicity. Farnesyl is generated through the mevalonate pathway and three drugs that interfere with this pathway and hence the farnesylation of proteins have been administered to HGPS children in clinical trials. These are a farnesyltransferase inhibitor (FTI), statin and a bisphosphonate. Further experimental studies have revealed that other drugs such as N-acetyl cysteine, rapamycin and IGF-1 may be of use in treating HGPS through other pathways. We have shown previously that FTIs restore chromosome positioning in interphase HGPS nuclei. Mis-localisation of chromosomes could affect the cells ability to regulate proper genome function. Using nine different drug treatments representing drug regimes in the clinic we have shown that combinatorial treatments containing FTIs are most effective in restoring specific chromosome positioning towards the nuclear periphery and in tethering telomeres to the nucleoskeleton. On the other hand, rapamycin was found to be detrimental to telomere tethering, it was, nonetheless, the most effective at inducing DNA damage repair, as revealed by COMET analyses.}, }
@article {pmid29905752, year = {2018}, author = {Fan, RF and Cao, CY and Chen, MH and Shi, QX and Xu, SW}, title = {Gga-let-7f-3p promotes apoptosis in selenium deficiency-induced skeletal muscle by targeting selenoprotein K.}, journal = {Metallomics : integrated biometal science}, volume = {10}, number = {7}, pages = {941-952}, doi = {10.1039/c8mt00083b}, pmid = {29905752}, issn = {1756-591X}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Chickens ; *Endoplasmic Reticulum Stress ; Free Radical Scavengers/pharmacology ; Hydrogen Peroxide/pharmacology ; Male ; MicroRNAs/*genetics ; Muscle, Skeletal/drug effects/metabolism/*pathology ; Oxidants/pharmacology ; *Oxidative Stress ; Selenium/*deficiency ; Selenoproteins/genetics/*metabolism ; }, abstract = {Selenoprotein K (SELENOK) is primarily observed in the endoplasmic reticulum, and serves to maintain the normal physiological functions of skeletal muscle. Skeletal muscle development and regeneration are associated with significant changes in the expression of specific microRNAs (miRNAs). Downregulated SELENOK expression is observed in chicken muscles deficient of Se. However, the mechanisms of miRNA regulation of SELENOK expression remain elusive. Here, deep sequencing was used to detect the miRNA profiles of muscle in Se deficient (-Se group) and normal (C group) chickens. A dual-luciferase reporter assay was adopted to verify the relationship between SELENOK and gga-let-7f-3p. In addition, gga-let-7f-3p was either overexpressed or knocked-down in chicken myoblasts. Furthermore, the cells were treated with N-acetyl-l-cysteine (NAC) or hydrogen peroxide (H2O2) in order to probe the factors involved in oxidative stress, endoplasmic reticulum stress (ERS) and apoptosis, respectively. Relative to the C group, there were 132 differentially expressed miRNAs (including 57 upregulated and 75 downregulated) in the muscles of the -Se group. The dual-luciferase reporter assay showed that SELENOK was a primary target of gga-let-7f-3p. It was also observed that the overexpression or knock-down of gga-let-7f-3p significantly influenced the SELENOK expression. Moreover, NAC blocked mimics of ga-let-7f-3p, thus inducing oxidative stress, ERS and apoptosis. Simultaneously, gga-let-7f-3p inhibitors blocked the stimulant effects caused by H2O2 in chicken myoblasts. Furthermore, Se deficiency downregulated the SELENOK protein expression and induced oxidative stress, ERS and apoptosis in chicken muscles. In conclusion, the gga-let-7f-3p-SELENOK pathway played a pivotal role in Se deficiency mediated muscle injuries through the induction of oxidative stress and ERS, ultimately promoting apoptosis.}, }
@article {pmid29904431, year = {2018}, author = {Yu, W and Song, X and Lin, C and Ji, W}, title = {Interventions and mechanisms of N-acetylcysteine on monocrotaline-induced pulmonary arterial hypertension.}, journal = {Experimental and therapeutic medicine}, volume = {15}, number = {6}, pages = {5503-5509}, pmid = {29904431}, issn = {1792-0981}, abstract = {The aim of the present study was to investigate the impact of N-acetylcysteine (NAC) on the expression of activin receptor-like kinase-1 (ALK-1) and mothers against decapentaplegic homolog 1 (Smad1) in the pulmonary artery of rats with pulmonary arterial hypertension (PAH), and to explore the possible mechanisms underlying its effects on pulmonary vascular remodeling (PVR). In total, 32 Wistar rats were randomly divided into four groups: Control, model, low-dose (100 mg/kg/day) NAC and high-dose (500 mg/kg/day) NAC. Monocrotaline (MCT) was intraperitoneally injected to prepare the model, and the right ventricular hypertrophy index (RVHI) and hemodynamic parameters were detected 6 weeks later. Hematoxylin and eosin staining was used to observe the pulmonary arterial structural changes and evaluate the peri-pulmonary artery inflammation score. Additionally, western blot analysis was used to detect the protein expression of ALK-1 and Smad1 in the pulmonary artery. The results demonstrated that treatment with NAC reduced RVHI and mean pulmonary artery pressure. In addition, NAC reduced the MCT-induced PVR, pulmonary inflammation score and upregulation of ALK-1 and Smad1. These results indicate that ALK-1 and Smad1 participate in the formation of PAH and the process of PVR, and suggest that NAC may inhibit PAH by inhibiting the expression of ALK-1 and Smad1 in the pulmonary artery.}, }
@article {pmid29901107, year = {2018}, author = {Liu, Y and Wang, N and Zhang, S and Liang, Q}, title = {Autophagy protects bone marrow mesenchymal stem cells from palmitate‑induced apoptosis through the ROS‑JNK/p38 MAPK signaling pathways.}, journal = {Molecular medicine reports}, volume = {18}, number = {2}, pages = {1485-1494}, pmid = {29901107}, issn = {1791-3004}, mesh = {Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Bone Marrow Cells/cytology/drug effects/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Gene Expression Regulation ; JNK Mitogen-Activated Protein Kinases/*genetics/metabolism ; Mesenchymal Stem Cells/cytology/*drug effects/metabolism ; Microtubule-Associated Proteins/genetics/metabolism ; Palmitates/*pharmacology ; Protein Isoforms/genetics/metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sequestosome-1 Protein/genetics/metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/*genetics/metabolism ; }, abstract = {In recent years, the association between saturated fatty acids (FA) and bone cells has received a high level of attention. Previous studies have shown that palmitate (PA), a common saturated FA, can cause apoptosis in bone marrow mesenchymal stem cells (BMSCs). However, whether PA can induce autophagy, an important intracellular protection mechanism that is closely associated with apoptosis, in BMSCs is still unknown; the association between autophagy and apoptosis is also unclear. The aim of the present study was to determine whether PA can induce autophagy in BMSCs. When BMSCs were treated with PA for >18 h, p62 began to accumulate, indicating that autophagic flux was impaired by prolonged exposure to PA. In addition, the proportion of apoptotic cells was increased when autophagy was inhibited by the autophagy inhibitor 3‑methyladenine. Furthermore, inducing autophagy by pretreating cells with rapamycin, a known inducer of autophagy, markedly reduced PA‑induced apoptosis, suggesting that autophagy may serve a protective role in PA‑induced apoptosis in BMSCs. PA also increased intracellular reactive oxygen species (ROS) production, which was decreased by the antioxidant N‑Acetyl‑cysteine, and promoted the activation of c‑Jun N‑terminal kinases (JNKs) and p38 mitogen‑activated protein kinase (MAPK). The addition of JNK and p38 MAPK inhibitors substantially reduced autophagy. Therefore, the results indicated that PA can induce autophagy in BMSCs and protect cells from PA‑induced apoptosis through the ROS‑JNK/p38 MAPK signaling pathways. These results may improve the general understanding of the mechanisms through which BMSCs adapt to PA‑induced apoptosis. The present study also provides a novel approach for the prevention and treatment of PA‑induced lipotoxicity.}, }
@article {pmid29898141, year = {2018}, author = {Amini, S and Robabi, HN and Tashnizi, MA and Vakili, V}, title = {Selenium, Vitamin C and N-Acetylcysteine do not Reduce the Risk of Acute Kidney Injury after Off-Pump CABG: a Randomized Clinical Trial.}, journal = {Brazilian journal of cardiovascular surgery}, volume = {33}, number = {2}, pages = {129-134}, pmid = {29898141}, issn = {1678-9741}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*etiology/mortality/*prevention &amp; control ; Adult ; Aged ; Aged, 80 and over ; Antioxidants/*therapeutic use ; Ascorbic Acid/*therapeutic use ; Coronary Artery Bypass, Off-Pump/*adverse effects/mortality ; Creatinine/blood ; Female ; Glomerular Filtration Rate ; Hospital Mortality ; Humans ; Length of Stay ; Male ; Middle Aged ; Renal Replacement Therapy ; Respiration, Artificial ; Risk Assessment ; Selenium/*therapeutic use ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {OBJECTIVE: The aim of this study was to investigate the impact of perioperative administration of N-acetylcysteine, selenium and vitamin C on the incidence and outcomes of acute kidney injury after off-pump coronary bypass graft surgery.<br><br>METHODS: 291 patients requiring elective off-pump coronary bypass graft surgery were randomized to receive either N-acetylcysteine, vitamin C and selenium 600 mg, 1500 mg, 0.5 mg, and nothing orally twice a day, respectively, from the day before to 2 days after surgery. They were assessed for the development of acute kidney injury using Acute Kidney Injury Network criteria, time of onset, its severity and duration, duration of mechanical ventilation, intensive care unit and hospital length of stay, and in-hospital mortality.<br><br>RESULTS: 272 patients completed the study. The total incidence of acute kidney injury was 22.1% (n=60) with 14 (20.9%), 15 (22.1%), 21 (31.8%), and 10 (14.1%) patients in the vitamin C, NAC, selenium, and control groups, respectively (P=0.096). We did not register significant differences in the incidence, the time of occurrence, the severity and the duration of acute kidney injury, as well as the duration of mechanical ventilation, the intensive care unit and hospital length of stay, and the in-hospital mortality among the four groups.<br><br>CONCLUSION: We found that perioperative administration of N-acetylcysteine, vitamin C and selenium were not effective in preventing acute kidney injury and associated morbidity and mortality after off-pump coronary bypass graft surgery.}, }
@article {pmid29895403, year = {2018}, author = {Singer, AJ and Towery, H and McClain, SA}, title = {Effect of tadalafil on reduction of necrosis in the ischemic zone in a rat comb burn model.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {44}, number = {6}, pages = {1427-1432}, doi = {10.1016/j.burns.2018.05.013}, pmid = {29895403}, issn = {1879-1409}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Burns/*pathology ; Disease Models, Animal ; Disease Progression ; Free Radical Scavengers/pharmacology ; Ischemia/*pathology ; Naproxen/pharmacology ; Necrosis ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Skin/blood supply/*drug effects/pathology ; Tadalafil/*pharmacology ; Vasodilator Agents/*pharmacology ; }, abstract = {OBJECTIVES: A major goal of burn management is to reduce the progression of necrosis in the zone of ischemia surrounding the central zone of necrosis. A rat comb burn model is often used to assess the progression of necrosis in the zone of ischemia. We compared various combinations of naproxen [NPX], N-acetyl cysteine [NAC], and tadalafil [TD] (a phosphodiesterase-5 inhibitor used as a vasodilator to treat erectile dysfunction) in a rat comb burn model to determine their effects on injury progression.<br><br>METHODS: We created two comb burns on the backs of 40 anesthetized Sprague-Dawley rats using a brass comb with four rectangular prongs preheated in boiling water and applied for 30s, resulting in four rectangular 10&#xd7;20mm full-thickness burns separated by three 5&#xd7;20mm unburned interspaces, representing the ischemic zones. We randomized five animals each to daily oral gavage with TD (1mg/kg), NPX (10mg/kg), NAC (500mg/kg), NAC+NPX, TD+NPX, TD+NAC, TD+NPX+NAC, or normal saline [NS]. Wounds were observed daily for gross evidence of necrosis in the unburned interspaces and full-thickness biopsies from the interspaces were evaluated with Hematoxylin &amp; Eosin seven days after injury for histological evidence of necrosis.<br><br>RESULTS: The percentages of interspaces with histological evidence of necrosis at day seven were TD-40%, NPX-93%, NAC-97%, NS-87%, TD+NPX-50%, TD+NAC-40%, TD+NPX+NAC-33%, and NPX+NAC-60% (P<0.001). Repeated measures ANOVA demonstrated reduced gross percentage of interspace area undergoing necrosis in all groups that included TD, compared with all groups not including TD (P<0.001). There were no differences among the various treatments within the groups that did or did not include TD.<br><br>CONCLUSIONS: Daily oral therapy with tadalafil reduces necrosis in the unburned interspaces compared with naproxen, NAC, or their combination in a rat comb burn model. Addition of naproxen or NAC to tadalafil does not further reduce injury progression.}, }
@article {pmid29894800, year = {2018}, author = {Kundu, J and Kim, DH and Chae, IG and Lee, JK and Lee, S and Jeong, CH and Chun, KS}, title = {Silicon dioxide nanoparticles induce COX-2 expression through activation of STAT3 signaling pathway in HaCaT cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {52}, number = {}, pages = {235-242}, doi = {10.1016/j.tiv.2018.06.008}, pmid = {29894800}, issn = {1879-3177}, mesh = {Cell Line ; Cyclooxygenase 2/genetics/metabolism ; Humans ; Janus Kinase 2/metabolism ; Nanoparticles/*toxicity ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/genetics/metabolism ; Signal Transduction/drug effects ; Silicon Dioxide/*toxicity ; src-Family Kinases/metabolism ; }, abstract = {Silicon dioxide nanoparticles (SiO2-NPs) are widely used in biomedicines and consumer products, such as sunscreens and cosmetics. However, SiO2-NPs can cause adverse effects on human health, depending on the size and concentration of nanoparticles. The present study was aimed at investigating the molecular mechanism underlying SiO2-NPs-induced inflammation in human keratinocyte (HaCaT) cells. Incubation of HaCaT cells with SiO2-NPs induced the expression of cyclooxygenase-2 (COX-2) mRNA and protein. Treatment of cells with SiO2-NPs also induced the phosphorylation, DNA binding and the reporter gene activity of signal transducer and activator of transcription 3 (STAT3). Transfection of cells with STAT3 siRNA abrogated SiO2-NPs-induced COX-2 expression. Moreover, SiO2-NPs enhanced the phosphorylation of Janus kinase2 (JAK2), Src and Akt. Pharmacological inhibition of either JAK2, Src or Akt abrogated SiO2-NPs-induced STAT3 transcriptional activity and the expression of COX-2. Treatment with LY294002 also attenuated SiO2-NPs-induced Src phosphorylation, while, JAK2 phosphorylation was not changed. In addition, SiO2-NPs generated reactive oxygen species (ROS) and treatment of N-acetyl cysteine (NAC) attenuated the phosphorylation of JAK2, Src, Akt and STAT3, as well as the expression of COX-2 in SiO2-NPs-treated HaCaT cells. Taken together, our study provides the first report that SiO2-NPs induce COX-2 expression in HaCaT cells by activating the STAT3 signaling through ROS-mediated phosphorylation of upstream kinases, Akt/Src and JAK2.}, }
@article {pmid29892141, year = {2018}, author = {Etemad, L and Moshiri, M and Balali-Mood, M}, title = {Delayed Complications and Long-Term Management of Sulfur Mustard Poisoning: A Narrative Review of Recent Advances by Iranian Researchers Part ІІ: Clinical Management and Therapy.}, journal = {Iranian journal of medical sciences}, volume = {43}, number = {3}, pages = {235-247}, pmid = {29892141}, issn = {0253-0716}, abstract = {The present study aimed to review and discuss the recommended and recently suggested protocols by Iranian researchers for a long-term treatment of delayed complications of sulfur mustard (DCSM) in veterans. As indicated clinically, patients who suffer from delayed ocular complications of sulfur mustard (DOCS) benefit from treatments for dry eyes, therapeutic contact lenses, amniotic membrane transplantation; blepharorrhaphy, tarsorrhaphy, limbal stem cell transplantation; corneal transplantation, topical steroids, and immunosuppressive. In spite of penetrating keratoplasty, lamellar keratoplasty and keratolimbal allograft had a good long-term survival. Delayed respiratory complications (DRCS) are the most common effects and life-threatening in Iranian veterans. The recommended treatment protocols include regular clinical evaluations, respiratory physiotherapy and rehabilitation, N-acetyl cysteine; warm humidified air, long-acting b2-agonists, and inhaled corticosteroids. Azithromycin has also been effective in improving clinical conditions, pulmonary function tests, inflammatory indexes, and life quality of the veterans. Interferon gamma (IFN-γ) and helium: oxygen combination were also used in severe DRCS with good results. Some of the delayed cutaneous complications (DCCS) such as itching affects the quality of life of victims. Regular but not frequent showering and bathing, applying sunscreen compounds, topical corticosteroids, and systemic antihistamines reduce the problems of DCCS patients. Several compounds such as capsaicin cream, pimecrolimus, IFN-γ, phenol-menthol; Aloe vera/olive oil cream, cetirizine, doxepine, and hydroxyzine were evaluated in DCCS patients with some benefits. The physicians in charge of veterans emphasize the importance of a healthy lifestyle, appropriate financial/social/cultural supports, and a degree of reassurance and supportive care on the clinical improvement of patients.}, }
@article {pmid29890337, year = {2018}, author = {Lee, J and Song, K and Huh, E and Oh, MS and Kim, YS}, title = {Neuroprotection against 6-OHDA toxicity in PC12 cells and mice through the Nrf2 pathway by a sesquiterpenoid from Tussilago farfara.}, journal = {Redox biology}, volume = {18}, number = {}, pages = {6-15}, pmid = {29890337}, issn = {2213-2317}, mesh = {Animals ; Hydrogen Peroxide/adverse effects ; Male ; Mice ; Mice, Inbred ICR ; NF-E2-Related Factor 2/*metabolism ; Neuroprotection/*drug effects ; Neuroprotective Agents/chemistry/*pharmacology ; Oxidopamine/*adverse effects ; PC12 Cells ; Rats ; Sesquiterpenes/chemistry/*pharmacology ; Signal Transduction/*drug effects ; Tussilago/*chemistry ; }, abstract = {Oxidative stress plays a key role in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Therefore, the nuclear factor-E2-related factor 2 (Nrf2), a key regulator of the antioxidative response, is considered to be important as a therapeutic target for neurodegenerative diseases. We investigated the underlying mechanism of Nrf2-mediated neuroprotective effects against oxidative stress in the PC12 cell line by 7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), one of the sesquiterpenoids in Farfarae Flos. Pretreatment of PC12 cells with ECN had a protective effect against hydrogen peroxide (H2O2)- or 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. ECN upregulated the ARE-luciferase activity and induced the mRNA expression of Nrf2 and antioxidant enzyme heme oxygenase-1 (HO-1). Knockdown of Nrf2 by small, interfering RNA (siRNA) abrogated the upregulation of HO-1, indicating that ECN had induced HO-1 via the Nrf2 pathway. Pretreatment with the thiol reducing agents, N-acetylcysteine (NAC) or dithiothreitol (DTT), attenuated Nrf2 activation and HO-1 expression. However, the non-thiol reducing antioxidant, Trolox, failed to inhibit HO-1 induction by ECN. These results suggest that ECN may directly interact with Kelch-like ECH-associated protein 1 (Keap1) and modify critical cysteine thiols present in the proteins responsible for Nrf2-mediated upregulation of HO-1. In a 6-OHDA-induced mouse model of PD, administration of ECN ameliorated motor impairments and dopaminergic neuronal damage. Taken together, ECN exerts neuroprotective effects by activating the Nrf2/HO-1 signaling pathway in both PC12 cells and mice. Thus, ECN, as an Nrf2 activator, could be an attractive therapeutic candidate for the neuroprotection or treatment of neurodegenerative diseases.}, }
@article {pmid29890257, year = {2018}, author = {Robinson, B and Dumas, M and Gu, Q and Kanungo, J}, title = {N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish.}, journal = {Neuroscience letters}, volume = {682}, number = {}, pages = {56-61}, pmid = {29890257}, issn = {1872-7972}, support = {FD999999//Intramural FDA HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Anesthetics, Dissociative/toxicity ; Animals ; Biogenic Monoamines/*antagonists &amp; inhibitors/physiology ; Dose-Response Relationship, Drug ; Embryo, Nonmammalian/*drug effects/physiology ; Embryonic Development/drug effects/physiology ; Free Radical Scavengers/pharmacology ; Heart Rate/*drug effects/physiology ; Ketamine/*toxicity ; Neurons/*drug effects/physiology ; Zebrafish ; }, abstract = {N-acetylcysteine, a precursor molecule of glutathione, is an antioxidant. Ketamine, a pediatric anesthetic, has been implicated in cardiotoxicity and neurotoxicity including modulation of monoaminergic systems in mammals and zebrafish. Here, we show that N-acetylcysteine prevents ketamine's adverse effects on development and monoaminergic neurons in zebrafish embryos. The effects of ketamine and N-acetylcysteine alone or in combination were measured on the heart rate, body length, brain serotonergic neurons and tyrosine hydroxylase-immunoreactive (TH-IR) neurons. In the absence of N-acetylcysteine, a concentration of ketamine that produces an internal embryo exposure level comparable to human anesthetic plasma concentrations significantly reduced heart rate and body length and those effects were prevented by N-acetylcysteine co-treatment. Ketamine also reduced the areas occupied by serotonergic neurons in the brain, whereas N-acetylcysteine co-exposure counteracted this effect. TH-IR neurons in the embryo brain and TH-IR cells in the trunk were significantly reduced with ketamine treatment, but not in the presence of N-acetylcysteine. In our continued search for compounds that can prevent ketamine toxicity, this study using specific endpoints of developmental toxicity, cardiotoxicity and neurotoxicity, demonstrates protective effects of N-acetylcysteine against ketamine's adverse effects. This is the first study that shows the protective effects of N-acetylcysteine on ketamine-induced developmental defects of monoaminergic neurons as observed in a whole organism.}, }
@article {pmid29885452, year = {2018}, author = {Sangobowale, M and Nikulina, E and Bergold, PJ}, title = {Minocycline plus N-acetylcysteine protect oligodendrocytes when first dosed 12 hours after closed head injury in mice.}, journal = {Neuroscience letters}, volume = {682}, number = {}, pages = {16-20}, pmid = {29885452}, issn = {1872-7972}, support = {R01 NS076693/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Corpus Callosum/drug effects/pathology ; Drug Therapy, Combination ; Free Radical Scavengers/administration &amp; dosage ; Head Injuries, Closed/*drug therapy/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Minocycline/*administration &amp; dosage ; Neuroprotection/*drug effects/physiology ; Oligodendroglia/*drug effects/pathology ; Time Factors ; }, abstract = {The mouse closed head injury (CHI) model of traumatic brain injury (TBI) produces widespread demyelination. Myelin content is restored by minocycline (MINO) plus n-acetylcysteine (NAC) or MINO alone when first dosed at 12 h after CHI. In a rat controlled cortical impact model of TBl, a first dose of MINO plus NAC one h after injury protects resident oligodendrocytes that induce remyelination. In contrast, MINO less effectively protects oligodendrocytes and remyelination is mediated by oligodendrocyte precursor cell proliferation and differentiation. MINO plus NAC or MINO alone is hypothesized to work similarly in the CHI model as in the controlled cortical impact model even when first dosed at 12-h post-CHI. We tested this hypothesis by examining the time course of the changes in the oligodendrocyte antigenic markers CC1, 2',3'-Cyclic-nucleotide 3'-phosphodiesterase and phospholipid protein between 2 and 14 days post-CHI in mice treated with saline, NAC, MINO or MINO plus NAC. CHI produced a long-lasting loss of these markers that was not altered by NAC treatment. In contrast, oligodendrocyte marker expression was maintained by MINO plus NAC between 2 and 14 days post-injury. MINO alone did not prevent the early loss of oligodendrocyte markers, but marker expression significantly increased by 14-days post-injury. These data suggest that MINO plus NAC or MINO alone when first dosed 12 h after CHI increase myelin content using similar mechanisms seen when first dosed 1 h after closed head injury. These data also suggest that drugs protect oligodendrocytes with a clinically useful therapeutic time window.}, }
@article {pmid29882920, year = {2018}, author = {Zhao, Z and Yang, Y and Liu, W and Li, Z}, title = {T59, a New Compound Reconstructed from Curcumin, Induces Cell Apoptosis through Reactive Oxygen Species Activation in Human Lung Cancer Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {23}, number = {6}, pages = {}, pmid = {29882920}, issn = {1420-3049}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Curcumin/*analogs &amp; derivatives ; Humans ; Lung Neoplasms/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Membrane Potentials/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Curcumin is acknowledged for its antioxidant, anti-inflammatory, anti-cancer, and wound-healing properties. However, the biological activity and the molecular mechanisms of T59, which is a new derivative of curcumin, are not fully understood. The present study was aimed to determine the cytoxicity role of T59 in human lung cancer and the molecular mechanisms. Cytotoxicity and cell apoptosis effects induced by T59 were determined by MTT, AO staining, Annexin V, and JC-1. Compared with curcumin, T59 exerted more effective cytotoxicity and cell apoptosis effects in A549 and H1975. With the decreasing level of the mitochondrion membrane potential, the generation of reactive oxygen species (ROS) was increased and induced by T59. Furthermore, the expressions of cleaved-caspase-3 and Bax were increased, which were reversed by NAC mainly through the PI3K/AKT signaling pathway. Our results suggested that T59 has the potential for further investigation and study to act as an anti-cancer therapeutic against human lung cancer.}, }
@article {pmid29876880, year = {2019}, author = {Mocelin, R and Marcon, M and D'ambros, S and Mattos, J and Sachett, A and Siebel, AM and Herrmann, AP and Piato, A}, title = {N-Acetylcysteine Reverses Anxiety and Oxidative Damage Induced by Unpredictable Chronic Stress in Zebrafish.}, journal = {Molecular neurobiology}, volume = {56}, number = {2}, pages = {1188-1195}, pmid = {29876880}, issn = {1559-1182}, support = {401162/2016-8; 302800/2017-4//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; 17/2551-0000974-6//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado do Rio Grande do Sul/ ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Anxiety/*drug therapy/metabolism ; Behavior, Animal/*drug effects ; Brain/*drug effects/metabolism ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Stress, Psychological/*drug therapy/metabolism ; Superoxide Dismutase/metabolism ; Zebrafish ; }, abstract = {There is accumulating evidence on the use of N-acetylcysteine (NAC) in the treatment of patients with neuropsychiatric disorders. As a multi-target drug and a glutathione precursor, NAC is a promising molecule in the management of stress-related disorders, for which there is an expanding field of research investigating novel therapies targeting oxidative pathways. The deleterious effects of chronic stress in the central nervous system are a result of glutamatergic hyperactivation, glutathione (GSH) depletion, oxidative stress, and increased inflammatory response, among others. The aim of this study was to investigate the effects of NAC in zebrafish submitted to unpredictable chronic stress (UCS). Animals were initially stressed or not for 7 days, followed by treatment with NAC (1 mg/L, 10 min) or vehicle for 7 days. UCS decreased the number of entries and time spent in the top area in the novel tank test, which indicate increased anxiety levels. It also increased reactive oxygen species (ROS) levels and lipid peroxidation (TBARS) while decreased non-protein thiols (NPSH) and superoxide dismutase (SOD) activity. NAC reversed the anxiety-like behavior and oxidative damage observed in stressed animals. Additional studies are needed to investigate the effects of this agent on glutamatergic modulation and inflammatory markers related to stress. Nevertheless, our study adds to the existing body of evidence supporting the clinical evaluation of NAC in mood disorders, anxiety, post-traumatic stress disorder, and other conditions associated with stress.}, }
@article {pmid29875964, year = {2018}, author = {Benlamkaddem, S and Iken, I and Houari, N and Elbouazzaoui, A and Boukatta, B and Sbai, H and Achour, S and Kanjaa, N}, title = {Paracetamol self-poisoning: when oral N-acetylcysteine saves life? a case report.}, journal = {The Pan African medical journal}, volume = {29}, number = {}, pages = {83}, pmid = {29875964}, issn = {1937-8688}, mesh = {Acetaminophen/pharmacokinetics/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Antidotes/*administration &amp; dosage ; Drug Overdose ; Female ; Humans ; Suicide, Attempted ; Tablets ; Treatment Outcome ; Young Adult ; }, abstract = {Paracetamol is the most widely drug involved in accidental paediatric exposures and deliberate self-poisoning cases because of its availability. N-acetyl cystein is the main treatment for this poisoning. We report a case of a 24-year-old Arab female who has deliberately ingested 100 tablets of 500 mg paracetamol each (50g). Her first examination was normal. She has received oral N-acetyl cystein (NAC) 6 hours after the ingestion. Serum paracetamol level done 18 hours post ingestion was 900 mg/l. On review the next days, she did not develop any symptoms of liver failure. However, due to the massive paracetamol ingestion associated with high serum paracetamol levels, oral NAC was continued for 3 days. The patient was discharged well on the fifth day of hospitalization. Our patient has ingested one of the highest paracetamol overdose (50g) with the highest paracetamol blood levels ever reported in medical literature. She was treated, six hours after ingestion, with oral NAC for 3 days without any side effects.}, }
@article {pmid29872728, year = {2018}, author = {Glady, A and Tanaka, M and Moniaga, CS and Yasui, M and Hara-Chikuma, M}, title = {Involvement of NADPH oxidase 1 in UVB-induced cell signaling and cytotoxicity in human keratinocytes.}, journal = {Biochemistry and biophysics reports}, volume = {14}, number = {}, pages = {7-15}, pmid = {29872728}, issn = {2405-5808}, abstract = {Members of NADPH oxidase (Nox) enzyme family are important sources of reactive oxygen species (ROS) and are known to be involved in several physiological functions in response to various stimuli including UV irradiation. UVB-induced ROS have been associated with inflammation, cytotoxicity, cell death, or DNA damage in human keratinocytes. However, the source and the role of UVB-induced ROS remain undefined. Here, we show that Nox1 is involved in UVB-induced p38/MAPK activation and cytotoxicity via ROS generation in keratinocytes. Nox1 knockdown or inhibitor decreased UVB-induced ROS production in human keratinocytes. Nox1 knockdown impaired UVB-induced p38 activation, accompanied by reduced IL-6 levels and attenuated cell toxicity. Treatment of cells with N-acetyl-L-cysteine (NAC), a potent ROS scavenger, suppressed p38 activation as well as consequent IL-6 production and cytotoxicity in response to UVB exposure. p38 inhibitor also suppressed UVB-induced IL-6 production and cytotoxicity. Furthermore, the blockade of IL-6 production by IL-6 neutralizing antibody reduced UVB-induced cell toxicity. In vivo assay using wild-type mice, the intradermal injection of lysates from UVB-irradiated control cells, but not from UVB-irradiated Nox1 knockdown cells, induced inflammatory swelling and IL-6 production in the skin of ears. Moreover, administration of Nox1 inhibitor suppressed UVB-induced increase in IL-6 mRNA expression in mice skin. Collectively, these data suggest that Nox1-mediated ROS production is required for UVB-induced cytotoxicity and inflammation through p38 activation and inflammatory cytokine production, such as IL-6. Thus, our findings suggest Nox1 as a therapeutic target for cytotoxicity and inflammation in response to UVB exposure.}, }
@article {pmid29868300, year = {2018}, author = {Benvenutti, R and Marcon, M and Reis, CG and Nery, LR and Miguel, C and Herrmann, AP and Vianna, MRM and Piato, A}, title = {N-acetylcysteine protects against motor, optomotor and morphological deficits induced by 6-OHDA in zebrafish larvae.}, journal = {PeerJ}, volume = {6}, number = {}, pages = {e4957}, pmid = {29868300}, issn = {2167-8359}, abstract = {BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. In addition to its highly debilitating motor symptoms, non-motor symptoms may precede their motor counterparts by many years, which may characterize a prodromal phase of PD. A potential pharmacological strategy is to introduce neuroprotective agents at an earlier stage in order to prevent further neuronal death. N-acetylcysteine (NAC) has been used against paracetamol overdose hepatotoxicity by restoring hepatic concentrations of glutathione (GSH), and as a mucolytic in chronic obstructive pulmonary disease by reducing disulfide bonds in mucoproteins. It has been shown to be safe for humans at high doses. More recently, several studies have evidenced that NAC has a multifaceted mechanism of action, presenting indirect antioxidant effect by acting as a GSH precursor, besides its anti-inflammatory and neurotrophic effects. Moreover, NAC modulates glutamate release through activation of the cystine-glutamate antiporter in extra-synaptic astrocytes. Its therapeutic benefits have been demonstrated in clinical trials for several neuropsychiatric conditions but has not been tested in PD models yet.<br><br>METHODS: In this study, we evaluated the potential of NAC to prevent the damage induced by 6-hydroxydopamine (6-OHDA) on motor, optomotor and morphological parameters in a PD model in larval zebrafish.<br><br>RESULTS: NAC was able to prevent the motor deficits (total distance, mean speed, maximum acceleration, absolute turn angle and immobility time), optomotor response impairment and morphological alterations (total length and head length) caused by exposure to 6-OHDA, which reinforce and broaden the relevance of its neuroprotective effects.<br><br>DISCUSSION: NAC acts in different targets relevant to PD pathophysiology. Further studies and clinical trials are needed to assess this agent as a candidate for prevention and adjunctive treatment of PD.}, }
@article {pmid29867560, year = {2018}, author = {Vereshchaka, IV and Bulgakova, NV and Maznychenko, AV and Gonchar, OO and Prylutskyy, YI and Ritter, U and Moska, W and Tomiak, T and Nozdrenko, DM and Mishchenko, IV and Kostyukov, AI}, title = {C60 Fullerenes Diminish Muscle Fatigue in Rats Comparable to N-acetylcysteine or β-Alanine.}, journal = {Frontiers in physiology}, volume = {9}, number = {}, pages = {517}, pmid = {29867560}, issn = {1664-042X}, abstract = {The aim of this study is to detect the effects of C60 fullerenes, which possess pronounced antioxidant properties, in comparison with the actions of the known exogenous antioxidants N-acetylcysteine (NAC) and β-Alanine in terms of exercise tolerance and contractile property changes of the m. triceps surae (TS) during development of the muscle fatigue in rats. The electrical stimulation of the TS muscle during four 30 min series in control rats led to total reduction of the muscle contraction force. Furthermore, the effects of prior intraperitoneal (i.p.) or oral C60FAS application and preliminary i.p. injection of NAC or β-Alanine on muscle contraction force under fatigue development conditions is studied. In contrast to control rats, animals with C60FAS, NAC, or β-Alanine administration could maintain a constant level of muscle effort over five stimulation series. The accumulation of secondary products and changes in antioxidant levels in the muscle tissues were also determined after the fatigue tests. The increased levels of lactic acid, thiobarbituric acid reactive substances and H2O2 after stimulation were statistically significant with respect to intact muscles. In the working muscle, there was a significant (p < 0.05) increase in the activity of endogenous antioxidants: reduced glutathione, catalase, glutathione peroxidase, and superoxide dismutase. Treated animal groups showed a decrease in endogenous antioxidant activity relative to the fatigue-induced animals (P < 0.05). Oral C60FAS administration clearly demonstrated an action on skeletal muscle fatigue development similar to the effects of i.p. injections of the exogenous antioxidants NAC or β-Alanine. This creates opportunities to oral use of C60FAS as a potential therapeutic agent. Due to the membranotropic activity of C60 fullerenes, non-toxic C60FAS has a more pronounced effect on the prooxidant-antioxidant homeostasis of muscle tissues in rats.}, }
@article {pmid29866754, year = {2018}, author = {Uemura, T and Watanabe, K and Ko, K and Higashi, K and Kogure, N and Kitajima, M and Takayama, H and Takao, K and Sugita, Y and Sakamoto, A and Terui, Y and Toida, T and Kashiwagi, K and Igarashi, K}, title = {Protective Effects of Brain Infarction by N-Acetylcysteine Derivatives.}, journal = {Stroke}, volume = {49}, number = {7}, pages = {1727-1733}, doi = {10.1161/STROKEAHA.118.021755}, pmid = {29866754}, issn = {1524-4628}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Acrolein/metabolism ; Animals ; Brain/*drug effects/metabolism ; Brain Infarction/*drug therapy/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Glutathione/metabolism ; Mice ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: We recently found that acrolein (CH2=CH-CHO) is more strongly involved in brain infarction compared with reactive oxygen species. In this study, we looked for acrolein scavengers with less side effects.<br><br>METHODS: Photochemically induced thrombosis model mice were prepared by injection of Rose Bengal. Effects of N-acetylcysteine (NAC) derivatives on brain infarction were evaluated using the public domain National Institutes of Health image program.<br><br>RESULTS: NAC, NAC ethyl ester, and NAC benzyl ester (150 mg/kg) were administered intraperitoneally at the time of induction of ischemia, or these NAC derivatives (50 mg/kg) were administered 3&#xd7; at 24-h intervals before induction of ischemia and 1 more administration at the time of induction of ischemia. The size of brain infarction decreased in the order NAC benzyl ester>NAC ethyl ester>NAC in both experimental conditions. Detoxification of acrolein occurred through conjugation of acrolein with glutathione, which was catalyzed by glutathione S-transferases, rather than direct conjugation between acrolein and NAC derivatives. The level of glutathione S-transferases at the locus of brain infarction was in the order of administration of NAC benzyl ester>NAC ethyl ester>NAC>no NAC derivatives, suggesting that NAC derivatives stabilize glutathione S-transferases.<br><br>CONCLUSIONS: The results indicate that detoxification of acrolein by NAC derivatives is caused through glutathione conjugation with acrolein catalyzed by glutathione S-transferases, which can be stabilized by NAC derivatives. This is a new concept of acrolein detoxification by NAC derivatives.}, }
@article {pmid29864961, year = {2018}, author = {Wang, ZH and Zhan-Sheng, H}, title = {Catalpol inhibits migration and induces apoptosis in gastric cancer cells and in athymic nude mice.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {103}, number = {}, pages = {1708-1719}, doi = {10.1016/j.biopha.2018.03.094}, pmid = {29864961}, issn = {1950-6007}, mesh = {Animals ; Antineoplastic Agents/pharmacology/therapeutic use ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Movement/*drug effects ; Cell Proliferation/drug effects ; Cisplatin/pharmacology/therapeutic use ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Iridoid Glucosides/chemistry/*pharmacology/therapeutic use ; Male ; Mice, Nude ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Stomach Neoplasms/genetics/*pathology ; }, abstract = {Gastric cancer is one of the leading factors, causing tumor-associated death worldwide. However, due to the limited therapeutic strategies in inhibition of gastric cancer, further studies are still required to develop effective treatments. In the present study, we attempted to explore the effects of catalpol, extracted from a traditional Chinese herb Rehmannia glutinosa, on gastric cancer progression in cells and in xenograft nude mice. The results indicated that catalpol dose-dependently reduced the proliferation of cancer cells. The migrated cells were also decreased with catalpol treatment, as evidenced by the down-regulated expressions of matrix metalloproteinase-2 (MMP-2), alpha-smooth muscle actin (α-SMA), Ras homolog gene family, member A (RhoA), Rho kinase 1 (ROCK1) and N-cadherin. Further, catalpol induced apoptosis in gastric cancer cells. Apoptosis-related markers including cleaved Caspase-3 and PARP were highly expressed in catalpol-treated cells. However, the cells with pre-treatment of caspases inhibitor reversed catalpol-induced apoptosis. Further, catalpol also enhanced reactive oxygen species (ROS) generation in gastric cancer cells, which was eliminated by N-acetylcystein (NAC) pre-incubation, an important ROS scavenger. Of note, catalpol potentiated the anti-cancer effects of cisplatin (DDP) in suppressing gastric cancer cells. In vivo, catalpol prevented the tumor growth in xenograft nude mice, while no significant difference was observed in body weight. The immunohistochemical analysis showed that catalpol increased the number of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive cells, whereas decreased the number of KI-67-positive cells. Together, the results above indicated that catalpol has a potential value in treating gastric cancer.}, }
@article {pmid29862216, year = {2018}, author = {Mazraati, P and Minaiyan, M}, title = {Hepatoprotective Effect of Metadoxine on Acetaminophen-induced Liver Toxicity in Mice.}, journal = {Advanced biomedical research}, volume = {7}, number = {}, pages = {67}, pmid = {29862216}, issn = {2277-9175}, abstract = {BACKGROUND: Metadoxine (pyridoxine pyrrolidone carboxylate) is considered to be a beneficial agent for the treatment of experimental hepatotoxicity due to alcohol, CCl4, and bile duct ligation. Hence, the therapeutic effect of metadoxine and N-acetylcysteine (NAC) as reference drug was investigated in mice exposed to acute hepatotoxicity induced by a single oral toxic dose of acetaminophen (650 mg/kg).<br><br>MATERIALS AND METHODS: Metadoxine (200 and 400 mg/kg) and NAC (300 mg/kg) were given orally (p. o.), 2 h after acetaminophen administration. Serum aminotransferases, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, hepatic glutathione (GSH), and malondialdehyde (MDA) levels were determined for evaluating the extent of hepatotoxicity due to acetaminophen and its protection by metadoxine.<br><br>RESULTS: Findings indicated that metadoxine significantly reduced the level of serum ALT, AST, and ALP but not total bilirubin which increased by acetaminophen intoxication. Administration of metadoxine also attenuated oxidative stress by suppressing lipid peroxidation (MDA) and prevented the depletion of reduced GSH level which caused by acetaminophen toxicity. Besides, metadoxine ameliorated histopathological hepatic tissue injury induced by acetaminophen.<br><br>CONCLUSION: In most parameters examined, the effect of metadoxine was comparable to NAC. Hence, metadoxine could be considered as a beneficial therapeutic candidate to protect against acute acetaminophen hepatotoxicity.}, }
@article {pmid29859988, year = {2018}, author = {Uchihara, Y and Tago, K and Taguchi, H and Narukawa, Y and Kiuchi, F and Tamura, H and Funakoshi-Tago, M}, title = {Taxodione induces apoptosis in BCR-ABL-positive cells through ROS generation.}, journal = {Biochemical pharmacology}, volume = {154}, number = {}, pages = {357-372}, doi = {10.1016/j.bcp.2018.05.018}, pmid = {29859988}, issn = {1873-2968}, mesh = {Apoptosis/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Diterpenes/isolation &amp; purification/*pharmacology ; Dose-Response Relationship, Drug ; Fusion Proteins, bcr-abl/*metabolism ; Humans ; K562 Cells ; Plant Extracts/isolation &amp; purification/*pharmacology ; Reactive Oxygen Species/*metabolism ; *Taxodium ; }, abstract = {Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are hematopoietic malignancies caused by the constitutive activation of BCR-ABL tyrosine kinase. Although direct BCR-ABL inhibitors, such as imatinib, were initially successful in the treatment of leukemia, many patients developed drug resistance over time due to the gatekeeper mutation of BCR-ABL T315I. In the present study, we found that taxodione, a quinone methide diterpene isolated from Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which were transformed by BCR-ABL. Taxodione reduced the activities of mitochondrial respiratory chain (MRC) complexes III and V, which appeared to induce the production of reactive oxygen species (ROS). N-acetylcysteine (NAC), an antioxidant agent, canceled taxodione-induced ROS production, reductions in MRC activities, particularly complex V, and apoptotic cell death. Furthermore, in K562 cells treated with taxodione, BCR-ABL and its major signaling molecules, such as STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation, suggesting that these actions seem to be a mechanism how taxodione functions as an anti-tumor drug. Strikingly, NAC canceled these taxodione-caused anti-cancer effects. Taxodione induced apoptosis in transformed Ba/F3 cells induced not only by BCR-ABL, but also T315I-mutated BCR-ABL through the generation of ROS. Collectively, the present results suggest that in the treatment of leukemia, taxodione has potential as a compound with high efficacy to overcome BCR-ABL T315I mutation-mediated resistance in leukemia cells.}, }
@article {pmid29859004, year = {2018}, author = {Colle, D and Farina, M and Ceccatelli, S and Raciti, M}, title = {Paraquat and Maneb Exposure Alters Rat Neural Stem Cell Proliferation by Inducing Oxidative Stress: New Insights on Pesticide-Induced Neurodevelopmental Toxicity.}, journal = {Neurotoxicity research}, volume = {34}, number = {4}, pages = {820-833}, pmid = {29859004}, issn = {1476-3524}, mesh = {Animals ; Cell Death/drug effects/physiology ; Cell Proliferation/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cerebral Cortex/drug effects/metabolism/pathology ; Dose-Response Relationship, Drug ; Herbicides/toxicity ; Maneb/*toxicity ; Neural Stem Cells/*drug effects/metabolism/pathology ; Neurotoxicity Syndromes/metabolism/pathology ; Oxidative Stress/*drug effects/physiology ; Paraquat/*toxicity ; Pesticides/*toxicity ; Rats, Sprague-Dawley ; }, abstract = {Pesticide exposure has been linked to the pathogenesis of neurodevelopmental and neurodegenerative disorders including autism spectrum disorders, attention deficit/hyperactivity, and Parkinson's disease (PD). Developmental exposure to pesticides, even at low concentrations not harmful for the adult brain, can lead to neuronal loss and functional deficits. It has been shown that prenatal or early postnatal exposure to the herbicide paraquat (PQ) and the fungicide maneb (MB), alone or in combination, causes permanent toxicity in the nigrostriatal dopamine system, supporting the idea that early exposure to these pesticides may contribute to the pathophysiology of PD. However, the mechanisms mediating PQ and MB developmental neurotoxicity are not yet understood. Therefore, we investigated the neurotoxic effect of low concentrations of PQ and MB in primary cultures of rat embryonic neural stem cells (NSCs), with particular focus on cell proliferation and oxidative stress. Exposure to PQ alone or in combination with MB (PQ + MB) led to a significant decrease in cell proliferation, while the cell death rate was not affected. Consistently, PQ + MB exposure altered the expression of major genes regulating the cell cycle, namely cyclin D1, cyclin D2, Rb1, and p19. Moreover, PQ and PQ + MB exposures increased the reactive oxygen species (ROS) production that could be neutralized upon N-acetylcysteine (NAC) treatment. Notably, in the presence of NAC, Rb1 expression was normalized and a normal cell proliferation pattern could be restored. These findings suggest that exposure to PQ + MB impairs NSCs proliferation by mechanisms involving alterations in the redox state.}, }
@article {pmid29854076, year = {2018}, author = {Xie, C and Yi, J and Lu, J and Nie, M and Huang, M and Rong, J and Zhu, Z and Chen, J and Zhou, X and Li, B and Chen, H and Lu, N and Shu, X}, title = {N-Acetylcysteine Reduces ROS-Mediated Oxidative DNA Damage and PI3K/Akt Pathway Activation Induced by Helicobacter pylori Infection.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {1874985}, pmid = {29854076}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; DNA Damage/*physiology ; Helicobacter Infections/*drug therapy ; Helicobacter pylori/*drug effects ; Humans ; Male ; Mice ; Phosphatidylinositol 3-Kinases/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: H. pylori infection induces reactive oxygen species- (ROS-) related DNA damage and activates the PI3K/Akt pathway in gastric epithelial cells. N-Acetylcysteine (NAC) is known as an inhibitor of ROS; the role of NAC in H. pylori-related diseases is unclear.<br><br>AIM: The aim of this study was to evaluate the role of ROS and the protective role of NAC in the pathogenesis of H. pylori-related diseases.<br><br>METHOD: An in vitro coculture system and an in vivo Balb/c mouse model of H. pylori-infected gastric epithelial cells were established. The effects of H. pylori infection on DNA damage and ROS were assessed by the comet assay and fluorescent dichlorofluorescein assay. The level of PI3K/Akt pathway-related proteins was evaluated by Western blotting. The protective role of N-acetylcysteine (NAC) was also evaluated with in vitro and in vivo H. pylori infection models.<br><br>RESULTS: The results revealed that, in vitro and in vivo, H. pylori infection increased the ROS level and induced DNA damage in gastric epithelial cells. NAC treatment effectively reduced the ROS level and inhibited DNA damage in GES-1 cells and the gastric mucosa of Balb/c mice. H. pylori infection induced ROS-mediated PI3K/Akt pathway activation, and NAC treatment inhibited this effect. However, the gastric mucosa pathological score of the NAC-treated group was not significantly different from that of the untreated group. Furthermore, chronic H. pylori infection decreased APE-1 expression in the gastric mucosa of Balb/c mice.<br><br>CONCLUSIONS: An increased ROS level is a critical mechanism in H. pylori pathogenesis, and NAC may be beneficial for the treatment of H. pylori-related gastric diseases linked to oxidative DNA damage.}, }
@article {pmid29850372, year = {2018}, author = {Deng, Y and Fu, Y and Xu, S and Wang, P and Yang, N and Li, C and Yu, Q}, title = {Detection and Structural Characterization of Nucleophiles Trapped Reactive Metabolites of Limonin Using Liquid Chromatography-Mass Spectrometry.}, journal = {Journal of analytical methods in chemistry}, volume = {2018}, number = {}, pages = {3797389}, pmid = {29850372}, issn = {2090-8865}, abstract = {Limonin (LIM), a furan-containing limonoid, is one of the most abundant components of Dictamnus dasycarpus Turcz. Recent studies demonstrated that LIM has great potential for inhibiting the activity of drug-metabolizing enzymes. However, the mechanisms of LIM-induced enzyme inactivation processes remain unexplored. The main objective of this study was to identify the reactive metabolites of LIM using liquid chromatography-mass spectrometry. Three nucleophiles, glutathione (GSH), N-acetyl cysteine (NAC), and N-acetyl lysine (NAL), were used to trap the reactive metabolites of LIM in in vitro and in vivo models. Two different types of mass spectrometry, a hybrid quadrupole time-of-flight (Q-TOF) mass spectrometry and a LTQ velos Pro ion trap mass spectrometry, were employed to acquire structural information of nucleophile adducts of LIM. In total, six nucleophile adducts of LIM (M1-M6) with their isomers were identified; among them, M1 was a GSH and NAL conjugate of LIM, M2-M4 were glutathione adducts of LIM, M5 was a NAC and NAL conjugate of LIM, and M6 was a NAC adduct of LIM. Additionally, CYP3A4 was found to be the key enzyme responsible for the bioactivation of limonin. This metabolism study largely facilitates the understanding of mechanisms of limonin-induced enzyme inactivation processes.}, }
@article {pmid29849877, year = {2018}, author = {Pei, Y and Liu, H and Yang, Y and Yang, Y and Jiao, Y and Tay, FR and Chen, J}, title = {Biological Activities and Potential Oral Applications of N-Acetylcysteine: Progress and Prospects.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {2835787}, pmid = {29849877}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Administration, Oral ; Glutathione/pharmacology/*therapeutic use ; Humans ; Inflammation/*drug therapy ; }, abstract = {N-Acetylcysteine (NAC), a cysteine prodrug and glutathione (GSH) precursor, has been used for several decades in clinical therapeutic practices as a mucolytic agent and for the treatment of disorders associated with GSH deficiency. Other therapeutic activities of NAC include inhibition of inflammation/NF-κB signaling and expression of proinflammatory cytokines. N-Acetylcysteine is also a nonantibiotic compound possessing antimicrobial property and exerts anticarcinogenic and antimutagenic effects against certain types of cancer. Recently, studies describing potentially important biological and pharmacological activities of NAC have stimulated interests in using NAC-based therapeutics for oral health care. The present review focused on the biological activities of NAC and its potential oral applications. The potential side effects of NAC and formulations for drug delivery were also discussed, with the intent of advancing NAC-associated treatment modalities in oral medicine.}, }
@article {pmid29849372, year = {2017}, author = {Thoppil, J and Berman, A and Kessler, B and Sud, P and Nogar, J}, title = {Hand Compartment Syndrome Due to N-acetylcysteine Extravasation.}, journal = {Clinical practice and cases in emergency medicine}, volume = {1}, number = {4}, pages = {377-379}, pmid = {29849372}, issn = {2474-252X}, abstract = {N-acetylcysteine (NAC) is the antidote for acetaminophen (APAP)-induced hepatotoxicity. Both intravenous (IV) and oral (PO) NAC formulations are available with equal efficacy. Adverse events from either preparation are rare. We describe a hand compartment syndrome after extravasation of NAC requiring emergent fasciotomy during phase three of treatment for suspected APAP toxicity. Extravasation injuries leading to compartment syndrome are rare. It is unclear whether IV NAC induced a direct tissue-toxic insult, or functioned as a space-occupying lesion to cause a compartment syndrome. Compartment syndrome from extravasation of NAC is possible. In cases where IV access is difficult, PO NAC is an alternative.}, }
@article {pmid29847303, year = {2020}, author = {Yolland, COB and Phillipou, A and Castle, DJ and Neill, E and Hughes, ME and Galletly, C and Smith, ZM and Francis, PS and Dean, OM and Sarris, J and Siskind, D and Harris, AWF and Rossell, SL}, title = {Improvement of cognitive function in schizophrenia with N-acetylcysteine: A theoretical review.}, journal = {Nutritional neuroscience}, volume = {23}, number = {2}, pages = {139-148}, doi = {10.1080/1028415X.2018.1478766}, pmid = {29847303}, issn = {1476-8305}, mesh = {Acetylcysteine/*therapeutic use ; Cognition/*drug effects/physiology ; Cognitive Dysfunction/drug therapy/physiopathology ; Glutathione/physiology ; Humans ; Neuroprotective Agents ; Oxidative Stress/drug effects/physiology ; Receptors, N-Methyl-D-Aspartate/drug effects/physiology ; Schizophrenia/*drug therapy/*physiopathology ; }, abstract = {Objectives: Schizophrenia is a debilitating psychiatric illness associated with positive and negative symptoms as well as significant impairments in cognition. Current antipsychotic medications do not alleviate these cognitive deficits, and more effective therapeutic options are required. Increased oxidative stress and altered antioxidant levels, including glutathione (GSH) have been observed both in individuals with cognitive impairment and in people with schizophrenia. A GSH precursor, the antioxidant N-acetylcysteine (NAC) has been investigated as a novel treatment for the cognitive symptoms of schizophrenia, and recent research suggests that NAC may be a promising adjunctive treatment option. However, the current literature lacks integration as to why NAC may effectively improve cognition in schizophrenia. The present theoretical synthesis aimed to address this gap by examining the processes by which NAC may improve cognitive function in schizophrenia. Methods: The schizophrenia literature was reviewed in three key domains: cognitive impairment, the relationship between oxidative stress and cognition, and the efficacy of NAC as a novel treatment. This led to a theoretical analysis of the neurobiological processes by which NAC may improve cognition in schizophrenia. Results: This theoretical review concluded that improved cognition may result from a combination of factors, including decreased oxidative stress, neuroprotection of cognitive networks and an increase in glutamatergic modulation of the N-methyl-d-aspartate receptor system. Whilst a number of mechanisms by which NAC may improve cognition and symptoms in schizophrenia have been proposed, there is still limited understanding of the specific metabolic pathways involved and how they interrelate and modify specific symptomology. Discussion: Exploration of how NAC treatment may act to improve cognitive function could guide clinical trials by investigation of the specific neurotransmitter systems and processes involved, allowing for targeted neurological outcome measures. Future research would benefit from the investigation of both in vivo cortical GSH concentration and peripheral plasma GSH in a population of individuals with chronic schizophrenia.}, }
@article {pmid29845722, year = {2019}, author = {Zheng, J and Yuan, X and Zhang, C and Jia, P and Jiao, S and Zhao, X and Yin, H and Du, Y and Liu, H}, title = {N-Acetylcysteine alleviates gut dysbiosis and glucose metabolic disorder in high-fat diet-fed mice.}, journal = {Journal of diabetes}, volume = {11}, number = {1}, pages = {32-45}, doi = {10.1111/1753-0407.12795}, pmid = {29845722}, issn = {1753-0407}, support = {31570801//National Natural Science Foundation of China/ ; 31500747//National Natural Science Foundation of China/ ; 31672077//National Natural Science Foundation of China/ ; 2015144//CAS Youth Innovation Promotion Association/ ; 2014AA093604//National Programs for High Technology Research and Development/ ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Bacteria/classification/drug effects/genetics ; Blood Glucose/analysis ; Diet, High-Fat/*adverse effects ; Dysbiosis/metabolism/microbiology/*prevention &amp; control ; Feces/microbiology ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Gastrointestinal Microbiome/*drug effects/genetics ; Glucose Intolerance/blood/prevention &amp; control ; Glucose Metabolism Disorders/etiology/microbiology/*prevention &amp; control ; Hyperglycemia/blood/prevention &amp; control ; Lipopolysaccharides/blood ; Mice, Inbred C57BL ; RNA, Ribosomal, 16S/genetics ; Sequence Analysis, DNA ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC), an antioxidative reagent for clinical diseases, shows potential in the treatment of diabetes and other metabolic diseases. However, it is unknown how NAC modulates the gut microbiota of mice with metabolic syndrome. The aim of the present study was to demonstrate the preventive effect of NAC on intestinal dysbiosis and glucose metabolic disorder.<br><br>METHODS: Mice (C57BL/6J strain) were fed either a normal chow diet (NCD), NCD plus NAC, a high-fat diet (HFD), or HFD plus NAC for 5&#x2009;months, after which glucose levels, circulating endotoxins and key metabolism-related proteins were determined. Fecal samples were analyzed by 16S rRNA sequencing. A novel analysis was performed to predict functional changes in gut microbiota. In addition, Spearman's correlation analysis was performed between metabolic biomarkers and bacterial abundance.<br><br>RESULTS: Treatment with NAC significantly reversed the glucose intolerance, fasting glucose concentrations, and gains in body weight and plasma endotoxin in HFD-fed mice. Further, NAC upregulated occludin and mucin glycoprotein levels in the proximal colon of HFD-treated mice. Noticeably, NAC promoted the growth of beneficial bacteria (i.e. Akkermansia, Bifidobacterium, Lactobacillus and Allobaculum) and decreased populations of diabetes-related genera, including Desulfovibrio and Blautia. In addition, NAC may affect the metabolic pathways of intestinal bacteria, including lipopolysaccharide biosynthesis, oxidative stress, and bacterial motility. Finally, the modified gut microbiota was closely associated with the metabolic changes in NAC-treated HFD-fed mice.<br><br>CONCLUSIONS: N-Acetylcysteine may be a potential drug to prevent glucose metabolic disturbances by reshaping the structure of the gut microbiota.}, }
@article {pmid29844459, year = {2018}, author = {El-Serafi, I and Remberger, M and El-Serafi, A and Benkessou, F and Zheng, W and Martell, E and Ljungman, P and Mattsson, J and Hassan, M}, title = {The effect of N-acetyl-l-cysteine (NAC) on liver toxicity and clinical outcome after hematopoietic stem cell transplantation.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {8293}, pmid = {29844459}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents, Alkylating/adverse effects/*therapeutic use ; Bilirubin/blood ; Busulfan/adverse effects/*therapeutic use ; *Hematopoietic Stem Cell Transplantation ; Humans ; Liver/*drug effects ; Liver Function Tests ; Transplantation Conditioning/*adverse effects ; Treatment Outcome ; }, abstract = {UNLABELLED: Busulphan (Bu) is a myeloablative drug used for conditioning prior to hematopoietic stem cell transplantation. Bu is predominantly metabolized through glutathione conjugation, a reaction that consumes the hepatic glutathione. N-acetyl-l-cysteine (NAC) is a glutathione precursor used in the treatment of acetaminophen hepatotoxicity. NAC does not interfere with the busulphan myeloablative effect. We investigated the effect of NAC concomitant treatment during busulphan conditioning on the liver enzymes as well as the clinical outcome. Prophylactic NAC treatment was given to 54 patients upon the start of busulphan conditioning. These patients were compared with 54 historical matched controls who did not receive NAC treatment. In patients treated with NAC, aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were significantly (P < 0.05) decreased after conditioning compared to their start values. Within the NAC-group, liver enzymes were normalized in those patients (30%) who had significantly high start values. No significant decrease in enzyme levels was observed in the control group. Furthermore, NAC affected neither Bu kinetics nor clinical outcome (sinusoidal obstruction syndrome incidence, graft-versus-host disease and/or graft failure).<br><br>IN CONCLUSION: NAC is a potential prophylactic treatment for hepatotoxicity during busulphan conditioning. NAC therapy did not alter busulphan kinetics or affect clinical outcome.}, }
@article {pmid29807795, year = {2018}, author = {Kim, YH and Yoon, YJ and Lee, YJ and Kim, CH and Lee, S and Choung, DH and Han, DC and Kwon, BM}, title = {Piperlongumine derivative, CG-06, inhibits STAT3 activity by direct binding to STAT3 and regulating the reactive oxygen species in DU145 prostate carcinoma cells.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {28}, number = {14}, pages = {2566-2572}, doi = {10.1016/j.bmcl.2018.05.025}, pmid = {29807795}, issn = {1464-3405}, mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Binding Sites/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dioxolanes/chemistry/*pharmacology ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Interleukin-6/antagonists &amp; inhibitors/metabolism ; Male ; Molecular Structure ; Phosphorylation/drug effects ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/metabolism ; Structure-Activity Relationship ; }, abstract = {Piperlongumine (PL), isolated from Piper longum L., is receiving intense interest due to its selectively ability to kill cancer cells but not normal cells. We synthesized a number of analogues by replacing the cyclic amide of PL with aliphatic amides to explore structural diversity. Compound CG-06 had the strongest cytotoxic profile of this series, showing potent effects in human prostate cancer DU-145 cells, in which signal transducer and activator of transcription 3 (STAT3) is constitutively active. CG-06 inhibited STAT3 phosphorylation at tyrosine 705 in a dose- and time dependent manner in DU-145 cells and suppressed IL-6-induced STAT3 phosphorylation at Tyr-705 in DU-145 and LNCaP cell lines. CG-06 decreased the expression levels of STAT3 target genes, such as cyclin A, Bcl-2, and survivin. Notably, we used drug affinity responsive target stability (DARTS) to show that CG-06 binds directly to STAT3, and the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) rescued the CG-06-induced suppression p-STAT3. Our results suggest that CG-06 is a novel inhibitor of STAT3 and may be a useful lead molecule for the development of a therapeutic STAT3 inhibitor.}, }
@article {pmid29807114, year = {2018}, author = {Hu, Y and Zhou, Y and Yang, G and Wang, Y and Zheng, Z and Li, J and Yan, Y and Wu, W}, title = {Sulforaphane-N-Acetyl-Cysteine inhibited autophagy leading to apoptosis via Hsp70-mediated microtubule disruption.}, journal = {Cancer letters}, volume = {431}, number = {}, pages = {85-95}, doi = {10.1016/j.canlet.2018.05.035}, pmid = {29807114}, issn = {1872-7980}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Anticarcinogenic Agents/pharmacology ; *Apoptosis ; *Autophagy ; Carcinoma, Non-Small-Cell Lung/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Female ; HSP70 Heat-Shock Proteins/*metabolism ; Humans ; Isothiocyanates/*pharmacology ; Lung Neoplasms/metabolism ; Macrolides/chemistry ; Male ; Microtubules/*metabolism ; Middle Aged ; Phenotype ; Stathmin/metabolism ; Sulfoxides ; Tissue Array Analysis ; Tubulin/chemistry ; }, abstract = {Sulforaphane-N-acetyl-cysteine (SFN-NAC) is a potential drug to inhibit human non-small cell lung cancer (NSCLC), but the underlying mechanisms are elusive. Here, we uncovered that SFN-NAC induced apoptosis via flow cytometer assay and transmission electron microscopy. Further, SFN-NAC increased LC3 II/LC3 I and the number of LC3 punctas, but Western blot showed that SFN-NAC inhibited cell autophagy in response to a co-treatment of Bafilomycin A1 and SFN-NAC. Furthermore, immunofluorescence staining and Western blot showed that SFN-NAC triggered microtubule disruption causing apoptosis via downregulating α-tubulin and phosphorylated ERK1/2-mediated Stathmin-1. Besides, SFN-NAC upregulated Hsp70 via phosphorylating ERK1/2. Confocal microscopy and immunoprecipitation assay showed that SFN-NAC promoted the colocalization and interaction of Hsp70 and α-tubulin; knockdown of Hsp70 enhanced SFN-NAC-induced microtubule disruption, lowered LC3 II/LC3 I and promoted apoptosis. Interestingly, tissue microarray analysis showed that the increased expression of either α-tubulin or Hsp70 correlated to NSCLC malignant grading, indicating that microtubule and Hsp70 are two key targets for SFN-NAC. These results will give us a new insight into SFN-NAC-induced apoptosis so that we develop more efficient therapeutics to treat NSCLC.}, }
@article {pmid29806036, year = {2017}, author = {Doherty, E and Perl, A}, title = {Measurement of Mitochondrial Mass by Flow Cytometry during Oxidative Stress.}, journal = {Reactive oxygen species (Apex, N.C.)}, volume = {4}, number = {10}, pages = {275-283}, pmid = {29806036}, issn = {2380-2367}, support = {R01 DK078922/DK/NIDDK NIH HHS/United States ; R01 DK049221/DK/NIDDK NIH HHS/United States ; R01 AI122176/AI/NIAID NIH HHS/United States ; R01 AI048079/AI/NIAID NIH HHS/United States ; R21 AI061066/AI/NIAID NIH HHS/United States ; R01 AI072648/AI/NIAID NIH HHS/United States ; }, abstract = {Properly assessing mitochondrial health is crucial to understand their role in disease. MitoTracker green (MTG) and nonylacridine orange (NAO) are fluorescent probes which have been commonly used to assess mitochondrial mass. This is based on the assumption that both MTG and NAO accumulate in mitochondria regardless of the mitochondrial transmembrane potential (ΔΨm). Here, we utilized flow cytometry to evaluate the performance of these probes for assessment of mitochondrial mass relative to forward (FSC) and side scatter (SSC) in human peripheral blood lymphocytes (PBL). In isolated mitochondria, two subpopulations were identified by FSC and SSC measurements which were matched to subpopulations stained by MTG and NAO. The performance of these dyes was examined under oxidative and nitrosative stress induced by rotenone and NOC-18 while N-acetylcysteine (NAC) was employed as an antioxidant. Production of reactive oxygen species (ROS) and ΔΨm were monitored in parallel. With respect to representation of mitochondrial mass, neither MTG nor NAO was affected by ΔΨm. However, MTG showed significant correlation with cytosolic and mitochondrial ROS production and nitrosative stress. Our data suggest that NAO may be more suitable than MTG for assessment of mitochondrial mass by flow cytometry during oxidative stress.}, }
@article {pmid29803870, year = {2018}, author = {Tomko, RL and Gilmore, AK and Gray, KM}, title = {The role of depressive symptoms in treatment of adolescent cannabis use disorder with N-Acetylcysteine.}, journal = {Addictive behaviors}, volume = {85}, number = {}, pages = {26-30}, pmid = {29803870}, issn = {1873-6327}, support = {R01 DA026777/DA/NIDA NIH HHS/United States ; K23 DA042935/DA/NIDA NIH HHS/United States ; R01 DA042114/DA/NIDA NIH HHS/United States ; U01 DA031779/DA/NIDA NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Depression/*psychology ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Marijuana Abuse/*drug therapy/psychology ; Young Adult ; }, abstract = {Relative to adults, adolescents are at greater risk of developing a cannabis use disorder (CUD) and risk may be exacerbated by co-occurring depressive symptoms. N-Acetylcysteine (NAC), an over-the-counter antioxidant, is thought to normalize glutamate transmission. Oxidative stress and glutamate transmission are disrupted in both depression and CUD. Thus, NAC may be particularly effective at promoting cannabis abstinence among adolescents with elevated depressive symptoms. Secondary analyses were conducted using a sub-sample of adolescents with CUD (N = 74) who participated in an 8-week randomized placebo-controlled clinical trial examining the efficacy of NAC for cannabis cessation. It was hypothesized that NAC would reduce severity of depressive symptoms, and that decreases depressive symptom severity would mediate decreases in positive weekly urine cannabinoid tests (11-nor-9-carboxy-Δ9-tetrahydrocannabinol). Additionally, it was expected that adolescents with greater severity of baseline depressive symptoms would be more likely to become abstinent when assigned NAC relative to placebo. Results from linear mixed models and generalized estimating equations did not suggest that NAC reduced severity of depressive symptoms, and the hypothesis that NAC's effect on cannabis cessation would be mediated by reduced depressive symptoms was not supported. However, an interaction between treatment condition and baseline severity of depressive symptoms as a predictor of weekly urine cannabinoid tests was significant, suggesting that NAC was more effective at promoting abstinence among adolescents with heightened baseline depressive symptoms. These secondary findings, though preliminary, suggest a need for further examination of the role of depressive symptoms in treatment of adolescent CUD with NAC.}, }
@article {pmid29802900, year = {2018}, author = {Behroozi, F and Abdkhodaie, MJ and Abandansari, HS and Satarian, L and Ashtiani, MK and Jaafari, MR and Baharvand, H}, title = {Smart liposomal drug delivery for treatment of oxidative stress model in human embryonic stem cell-derived retinal pigment epithelial cells.}, journal = {International journal of pharmaceutics}, volume = {548}, number = {1}, pages = {62-72}, doi = {10.1016/j.ijpharm.2018.05.056}, pmid = {29802900}, issn = {1873-3476}, mesh = {Acetylcysteine/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Cell Survival/drug effects ; Cells, Cultured ; Drug Liberation ; Epithelial Cells/*drug effects/metabolism ; Human Embryonic Stem Cells/cytology ; Humans ; Liposomes ; Oxidative Stress ; Phospholipids/administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/cytology ; Selenium/*administration &amp; dosage ; }, abstract = {Oxidative stress has been implicated in the progression of age-related macular degeneration (AMD). Treatment with antioxidants seems to delay progression of AMD. In this study, we suggested an antioxidant delivery system based on redox-sensitive liposome composed of phospholipids and a diselenide centered alkyl chain. Dynamic light scattering assessment indicated that the liposomes had an average size of 140 nm with a polydispersity index below 0.2. The percentage of encapsulation efficiency of the liposomes was calculated by high-performance liquid chromatography. The carriers were loaded with N-acetyl cysteine as a model antioxidant drug. We demonstrated responsiveness of the nanocarrier and its efficiency in drug delivery in an oxidative stress model of human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells. The modeled cells treated with diselenide containing liposomes loaded with 10 mM NAC, showed a better therapeutic effect with a cell metabolic activity of 90%, which was significantly higher compared to insensitive liposomes or NAC treated groups (P < 0.05). In addition, the expression of oxidative-sensitive gene markers in diselenide containing liposomes groups were improved. Our results demonstrated fabricated smart liposomes opens new opportunity for targeted treatment of retinal degeneration.}, }
@article {pmid29799741, year = {2018}, author = {Hou, L and Zhou, X and Gan, F and Liu, Z and Zhou, Y and Qian, G and Huang, K}, title = {Combination of Selenomethionine and N-Acetylcysteine Alleviates the Joint Toxicities of Aflatoxin B1 and Ochratoxin A by ERK MAPK Signal Pathway in Porcine Alveolar Macrophages.}, journal = {Journal of agricultural and food chemistry}, volume = {66}, number = {23}, pages = {5913-5923}, doi = {10.1021/acs.jafc.8b01858}, pmid = {29799741}, issn = {1520-5118}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aflatoxin B1/administration &amp; dosage/*toxicity ; Animals ; Cell Line ; Drug Interactions ; Immunotoxins/toxicity ; MAP Kinase Signaling System/*drug effects/physiology ; Macrophages, Alveolar/drug effects/immunology/*metabolism ; Ochratoxins/administration &amp; dosage/*toxicity ; Selenomethionine/*administration &amp; dosage ; Swine ; }, abstract = {Our previous studies showed that aflatoxin B1 (AFB1) and ochratoxin A (OTA) could trigger joint immune toxicity. Little is known about the combined effects of selenomethionine (SeMet) and N-acetylcysteine (NAC) on the joint toxicities of the two toxins. In this study, results showed that SeMet or NAC alone or in combination significantly alleviated the downswing of cell viability, glutathione production, and phagorytosis induced by AFB1 and OTA in porcine alveolar macrophages. The uptrend of lactate dehydrogenase activities, apoptosis, reactive oxygen species levels, and the relative mRNA of inflammatory cytokines triggered by the two toxins was decreased. Combination of them was more effective than single application. Knockdown of p38, c-JUN N-terminal kinase (JNK), or extracellular signal-regulated kinase (ERK) via use of the corresponding specific siRNA could alleviate the joint toxicities of AFB1 and OTA. However, the ERK but not p38 or JNK pathway was involved in the protection of SeMet and NAC against the immunotoxicity. In conclusion, combination of SeMet and NAC might be a new therapeutic orientation for preventing the joint toxicities induced by AFB1 and OTA.}, }
@article {pmid29796316, year = {2018}, author = {Kaga, AK and Barbanera, PO and do Carmo, NOL and Rosa, LRO and Fernandes, AAH}, title = {Effect of N-Acetylcysteine on Dyslipidemia and Carbohydrate Metabolism in STZ-Induced Diabetic Rats.}, journal = {International journal of vascular medicine}, volume = {2018}, number = {}, pages = {6428630}, pmid = {29796316}, issn = {2090-2824}, abstract = {BACKGROUND: Type 1 diabetes mellitus (T1DM) is characterized by insulin-deficient production leading to hyperglycemia, which is associated with diabetic complications such as cardiovascular diseases. Antioxidants have been proving a good alternative to diabetic complications, with N-acetylcysteine (NAC) having antioxidant characteristics. The aim of this study was to assess the effect of NAC on the lipid profile and the atherogenic index (AI) in streptozotocin- (STZ-) induced diabetic rats.<br><br>METHOD: 32 male Wistar rats (60 days of age) weighting &#xb1;250&#x2009;g were randomly distributed into four groups (n = 8): CTRL: control rats; CTRL+NAC: control rats treated with NAC; DM: diabetic rats; DM+NAC: diabetic rats treated with NAC. T1DM was induced using STZ (60&#x2009;mg/kg, ip; single dose), and NAC (25&#x2009;mg/kg/day) was administrated by gavage, for 37 days. The animals received chow and water ad libitum. After the experimental period, blood and cardiac tissue samples were collected to analyze energetic metabolism, lipid profile, and AI.<br><br>RESULTS: NAC decreased (p < 0.01) glycemia, energy intake, carbohydrate, and protein consumption in diabetic rats (DM+NAC), when compared with DM, while the alimentary efficiency was improved (p < 0.01) in treated diabetic rats (DM+NAC). Diabetic rats treated with NAC decreased (p < 0.01) lipid profile and AI in diabetic rats (DM+NAC) when compared to DM.<br><br>CONCLUSION: NAC improves lipid profile and decreases AI in STZ-induced diabetic rats.}, }
@article {pmid29792860, year = {2018}, author = {Sharma, M and Sharma, KB and Chauhan, S and Bhattacharyya, S and Vrati, S and Kalia, M}, title = {Diphenyleneiodonium enhances oxidative stress and inhibits Japanese encephalitis virus induced autophagy and ER stress pathways.}, journal = {Biochemical and biophysical research communications}, volume = {502}, number = {2}, pages = {232-237}, doi = {10.1016/j.bbrc.2018.05.149}, pmid = {29792860}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Autophagy/drug effects ; Cells, Cultured ; Encephalitis Virus, Japanese/*drug effects/pathogenicity/physiology ; Endoplasmic Reticulum Stress/drug effects ; HeLa Cells ; Humans ; Mice ; Onium Compounds/*pharmacology ; Oxidative Stress/drug effects ; Swine ; Virus Replication/drug effects ; }, abstract = {Diphenyleneiodonium (DPI) and N-acetyl-l-cysteine (NAC), two widely used anti-oxidants, were employed to evaluate the role of oxidative stress in Japanese encephalitis virus (JEV) induced autophagy, stress responses and replication. DPI and NAC exerted opposite effects on ROS levels in JEV infected mouse neuronal cells (Neuro2a), mouse embryonic fibroblasts (MEFs) and human epithelial cells (HeLa). While NAC effectively quenched ROS, DPI enhanced ROS levels, suggesting that DPI induces oxidative stress in JEV infected cells. DPI treatment of JEV infected Neuro2a cells further blocked autophagy induction and activation of all three arms of the ER stress pathway, and, inhibited virus particle release. Autophagy induction in JEV infection has been previously shown to be linked to the activation of XBP1 and ATF6 ER stress sensors. Our data suggests that DPI mediated block of autophagy is a result of inhibition of ER stress responses and is not associated with an anti-oxidative effect. Since DPI has a wide inhibitory potential for all Flavin dependent enzymes, it is likely that the signalling pathways for ER stress and autophagy during JEV infection are modulated by DPI sensitive enzymes.}, }
@article {pmid29792347, year = {2018}, author = {Schmidt, LE and Rasmussen, DN and Petersen, TS and Macias-Perez, IM and Pavliv, L and Kaelin, B and Dart, RC and Dalhoff, K}, title = {Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to traditional three-bag regimen in paracetamol overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {56}, number = {11}, pages = {1128-1134}, doi = {10.1080/15563650.2018.1475672}, pmid = {29792347}, issn = {1556-9519}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Administration, Intravenous/*standards ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antidotes/*therapeutic use ; Child ; Child, Preschool ; Denmark ; Dose-Response Relationship, Drug ; Drug Overdose/*drug therapy ; Female ; Humans ; Infant ; Male ; Middle Aged ; *Practice Guidelines as Topic ; Young Adult ; }, abstract = {Context: The intravenous (IV) N-acetylcysteine (NAC) regimen used worldwide in paracetamol overdose is complex with three separate weight-based doses and is associated with a high incidence of adverse events including non-allergic anaphylactoid reactions (NAARs). In 2012, Denmark adopted the two-bag IV NAC regimen which combined the first two infusions of the three-bag regimen and kept the third infusion unchanged. We compared the safety and efficacy of the two-bag IV NAC regimen with the traditional Danish three-bag regimen. Methods: A medical chart review was conducted in three Danish medical centers from January 2012 through December 2014. Safety and efficacy data were compared for patients who received the traditional infusion protocol in Denmark or the 20-h two-bag IV regimen. Results: Four hundred and ninety-three cases received the two-bag regimen and 274 received the three-bag regimen. The overall incidence of NAARs was 9% with all being mild to moderate in intensity. Fewer subjects in the two-bag group (4%) developed NAARs compared to 17% in the three-bag group (p < .001). Overall, 31 patients (4%) developed hepatotoxicity. There was no apparent difference in hepatotoxicity rates between the groups and no deaths or liver transplants. Patients receiving the two-bag regimen had fewer interruptions or delays (5%) compared to the three-bag regimen cohort (12%). Overall, there were very few medication errors reported (1%). Conclusions: The incidence of NAARs was lower in patients receiving acetylcysteine in a two-bag regimen compared to the traditional Danish three-bag regimen without an apparent reduction in efficacy.}, }
@article {pmid29789603, year = {2018}, author = {Jing, B and Jin, J and Xiang, R and Liu, M and Yang, L and Tong, Y and Xiao, X and Lei, H and Liu, W and Xu, H and Deng, J and Zhou, L and Wu, Y}, title = {Vorinostat and quinacrine have synergistic effects in T-cell acute lymphoblastic leukemia through reactive oxygen species increase and mitophagy inhibition.}, journal = {Cell death &amp; disease}, volume = {9}, number = {6}, pages = {589}, pmid = {29789603}, issn = {2041-4889}, mesh = {Animals ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Synergism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred NOD ; Mice, SCID ; Mitochondria/drug effects/metabolism/ultrastructure ; Mitophagy/*drug effects ; Models, Biological ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*pathology ; Quinacrine/*pharmacology ; Reactive Oxygen Species/*metabolism ; Vorinostat/*pharmacology ; }, abstract = {Despite recent progress in the treatment, the outcome of adult acute T-cell lymphoblastic leukemia (T-ALL) is poor. Development of novel approach to combat this disease is urgently required. Vorinostat, a pan-histone deacetylase (HDAC) inhibitor, exerts promising anticancer activity in a variety of solid and hematologic malignancies. However, the efficacy of vorinostat monotherapy is unsatisfactory. Here, we show that quinacrine (QC), an anti-malaria drug with potent autophagy inhibitory activity, could synergistically enhance vorinostat-induced cell death at a non-toxic concentration. Compared to the single treatment, QC plus vorinostat significantly induced apoptosis, disrupted the mitochondrial transmembrane potential, and decreased Mcl-1 and Bcl-2/Bax ratio. Interestingly, the application of QC plus vorinostat resulted in mitophagy blockade, as reflected by the increase in the K63-linked ubiquitination of mitochondria protein and the formation of mitochondrial aggresomes. QC plus vorinostat markedly increased the reactive oxygen species (ROS) level in cells. Moreover, the ROS scavenger N-acetylcysteine (NAC) abrogated QC plus vorinostat-induced ROS, decreased the ubiquitination of mitochondria proteins, and cell death. Finally, using a xenograft mouse model, we demonstrated that QC plus vorinostat significantly reduced cell proliferation and induced cell death in vivo. Taken together, our results showed that the combination of QC with vorinostat may represent a novel regimen for the treatment of T-cell acute lymphoblastic leukemia, which deserves clinical evaluation in the future.}, }
@article {pmid29785182, year = {2018}, author = {Wang, L and Lin, E and Johansen, MJ and Madden, T and Felix, E and Martirosyan, KS and Frank, SJ}, title = {Reactive Oxygen Species Generation in Human Cells by a Novel Magnetic Resonance Imaging Contrast Agent.}, journal = {Journal of toxicology}, volume = {2018}, number = {}, pages = {6362426}, pmid = {29785182}, issn = {1687-8191}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, abstract = {The novel positive-contrast magnetic resonance imaging (MRI) marker C4 consists of an aqueous solution of cobalt chloride (CoCl2) complexed with the chelator N-acetylcysteine (NAC). We evaluated whether the presence of C4 or its components would produce reactive oxygen species (ROS, including hydroxyl, peroxyl, or other reactive oxygen species) in cultured cells. Human cancer or normal cells were incubated with 1% (w/v) CoCl2·6H2O or 2% NAC or a combination of both (1% CoCl2·6H2O : 2% NAC in an aqueous solution, abbreviated as Co : NAC) in the presence or absence of H2O2. Intracellular ROS levels were measured and quantified by change in relative fluorescence units. Student's t-tests were used. In all cell lines exposed to 1000 μM H2O2, the Co : NAC led to ≥94.7% suppression of ROS at 5 minutes and completely suppressed ROS at 60 and 90 minutes; NAC suppressed ROS by ≥76.6% at 5 minutes and by ≥94.5% at 90 minutes; and CoCl2·6H2O suppressed ROS by ≥37.2% at 30 minutes and by ≥48.6% at 90 minutes. These results demonstrate that neither Co : NAC nor its components generated ROS; rather, they suppressed ROS production in cultured cells, suggesting that C4 would not enhance ROS production in clinical use.}, }
@article {pmid29784845, year = {2018}, author = {Mossine, VV and Chance, DL and Waters, JK and Mawhinney, TP}, title = {Interaction of Bacterial Phenazines with Colistimethate in Bronchial Epithelial Cells.}, journal = {Antimicrobial agents and chemotherapy}, volume = {62}, number = {8}, pages = {}, pmid = {29784845}, issn = {1098-6596}, mesh = {Anti-Bacterial Agents/*pharmacology ; Cell Line ; Colistin/*analogs &amp; derivatives/pharmacology ; Drug Resistance, Multiple, Bacterial ; Epithelial Cells/*microbiology ; Humans ; Phenazines/*pharmacology ; Polymyxins/pharmacology ; Pseudomonas aeruginosa ; Pyocyanine/pharmacology ; }, abstract = {Multidrug-resistant bacterial infections are being increasingly treated in clinics with polymyxins, a class of antibiotics associated with adverse effects on the kidney, nervous system, or airways of a significant proportion of human and animal patients. Although many of the resistant pathogens display enhanced virulence, the hazard of cytotoxic interactions between polymyxin antibiotics and bacterial virulence factors (VFs) has not been assessed, to date. We report here the testing of paired combinations of four Pseudomonas aeruginosa VF phenazine toxins, pyocyanin (PYO), 1-hydroxyphenazine (1-HP), phenazine-1-carboxylic acid (PCA), and phenazine-1-carboxamide (PCN), and two commonly prescribed polymyxin drugs, colistin-colistimethate sodium (CMS) and polymyxin B, in three human airway cell lines, BEAS-2B, HBE-1, and CFT-1. Cytotoxicities of individual antibiotics, individual toxins, and their combinations were evaluated by the simultaneous measurement of mitochondrial metabolic, total transcriptional/translational, and Nrf2 stress response regulator activities in treated cells. Two phenazines, PYO and 1-HP, were cytotoxic at clinically relevant concentrations (100 to 150 μM) and prompted a significant increase in oxidative stress-induced transcriptional activity in surviving cells. The polymyxin antibiotics arrested cell proliferation at clinically achievable (<1 mM) concentrations as well, with CMS displaying surprisingly high cytotoxicity (50% effective dose [ED50] = 180 μM) in BEAS-2B cells. The dose-response curves were probed by a median-effect analysis, which established a synergistically enhanced cytotoxicity of the PYO-CMS combination in all three airway cell lines; a particularly strong effect on BEAS-2B cells was observed, with a combination index (CI) of 0.27 at the ED50 PCA, PCN, and 1-HP potentiated CMS cytotoxicity to a smaller extent. The cytotoxicity of CMS could be reduced with 10 mM N-acetyl-cysteine. Iron chelators, while ineffective against the polymyxins, could rescue all three bronchial epithelial cell lines treated with lethal PYO or CMS-PYO doses. These findings suggest that further evaluations of CMS safety are needed, along with a search for means to moderate potentially cytotoxic interactions.}, }
@article {pmid29784372, year = {2018}, author = {Correa, AL and Gonçalves, JM and Rossini, PO and Bernardes, JS and Neves, CA and Araki, K and Angnes, L}, title = {Fast and reliable BIA/amperometric quantification of acetylcysteine using a nanostructured double hydroxide sensor.}, journal = {Talanta}, volume = {186}, number = {}, pages = {354-361}, doi = {10.1016/j.talanta.2018.04.053}, pmid = {29784372}, issn = {1873-3573}, mesh = {Acetylcysteine/*analysis ; *Electrochemical Techniques/instrumentation ; Electrodes ; *Flow Injection Analysis/instrumentation ; Hydroxides/*chemistry ; Nanostructures/*chemistry ; }, abstract = {This study reports the preparation and characterization of nickel/lead hydroxide nanoparticles used to construct electrochemical sensors, which were investigated for amperometric quantification of N-acetylcysteine (NAC). The newly synthesised material presents good uniformity, with the lead (II) ions homogenously incorporated into the alpha nickel hydroxide crystal structure, confirmed by X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy analyses. Films of nanoparticles (3 nm in size) were prepared on conductive fluorine-doped tin oxide-coated glass slides and used connected to a specially built batch injection analysis (BIA) cell with a capacity of only 4 mL and the electrode positioned in the bottom. To attain optimal analytical performance, the main parameters for BIA measurements (volume injected, different velocities of injection and best distance of the pipette from the electrode) were evaluated, as was the working potential, to determine the optimal conditions. Linear responses were obtained for the concentration range from 20 to 220 μmol L[-1], and the limits of detection (3σ/slope) and quantification (10σ/slope) were calculated as 0.23 μmol L[-1] and 0.70 μmol L[-1], respectively. The new NAC sensor does not exhibit a memory effect and has enormous potential utility in the quantitative determination of N-acetylcysteine in drugs. The results of the analysis of NAC obtained using BIA presented good concordance with those obtained by chromatography. The analytical frequency attained using BIA (120 analysis h[-1]) compares very favourably with the one obtained using chromatography (6 analysis h[-1]).}, }
@article {pmid29783176, year = {2018}, author = {Réus, GZ and Maciel, AL and Abelaira, HM and de Moura, AB and de Souza, TG and Dos Santos, TR and Darabas, AC and Parzianello, M and Matos, D and Abatti, M and Vieira, AC and Fucillini, V and Michels, M and Dal-Pizzol, F and Quevedo, J}, title = {ω-3 and folic acid act against depressive-like behavior and oxidative damage in the brain of rats subjected to early- or late-life stress.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {53}, number = {}, pages = {120-133}, doi = {10.1016/j.nut.2018.03.006}, pmid = {29783176}, issn = {1873-1244}, mesh = {Animals ; Antidepressive Agents/pharmacology ; Antioxidants/pharmacology ; Behavior, Animal/*drug effects ; Brain/*drug effects ; Depressive Disorder/*prevention &amp; control ; Disease Models, Animal ; Fatty Acids, Omega-3/*pharmacology ; Folic Acid/*pharmacology ; Lipid Peroxidation/drug effects ; Maternal Deprivation ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Stress, Psychological/complications ; }, abstract = {OBJECTIVES: To investigate the antidepressant and antioxidant effects of omega-3, folic acid and n-acetylcysteine (NAC) in rats which were subjected to early or late life stress.<br><br>METHODS: Early stress was induced through maternal deprivation (MD), while late life stress was induced using the chronic mild stress (CMS) protocol. Young rats which were subjected to MD and the adult rats which were subjected to CMS were treated with omega-3 fatty acids (0.72&#x2009;g/kg), NAC (20&#x2009;mg/kg) or folic acid (50&#x2009;mg/kg) once/day, for a period of 20 days. Then, the animals' immobility times were evaluated using the forced swimming test. Oxidative stress parameters were evaluated in the brain.<br><br>RESULTS: Depressive-like behavior induced by CMS was prevented by NAC and folic acid, and depressive-like behavior induced by MD was prevented by NAC, folic acid and omega-3. NAC, folic acid and omega-3 were able to exert antioxidant effects in the brain of rats subjected to CMS or MD. These preventive treatments decreased the levels of protein carbonylation and lipid peroxidation, and also decreased the concentrations of nitrite/nitrate and reduced the activity of myeloperoxidase activity in the rat brain which was induced by CMS or MD. NAC, folic acid and omega-3 increased superoxide dismutase and catalase activities in the rat brain subjected to early or late life stress.<br><br>CONCLUSIONS: NAC, omega-3 and folic acid may present interesting lines of treatment based on their antioxidant properties, which cause an inhibition of behavioral and brain changes that occur from stressful life events.}, }
@article {pmid29781282, year = {2018}, author = {Jiao, X and Xiao, Y and Li, Y and Liang, M and Xie, X and Wang, X and Tang, B}, title = {Evaluating Drug-Induced Liver Injury and Its Remission via Discrimination and Imaging of HClO and H2S with a Two-Photon Fluorescent Probe.}, journal = {Analytical chemistry}, volume = {90}, number = {12}, pages = {7510-7516}, doi = {10.1021/acs.analchem.8b01106}, pmid = {29781282}, issn = {1520-6882}, mesh = {Antidepressive Agents/*adverse effects ; Chemical and Drug Induced Liver Injury/*diagnostic imaging/pathology ; Duloxetine Hydrochloride/adverse effects ; Fluorescent Dyes/*chemistry ; Fluoxetine/adverse effects ; Humans ; Hydrogen Sulfide/*analysis ; Hypochlorous Acid/*analysis ; Molecular Structure ; *Optical Imaging ; *Protons ; }, abstract = {Drug-induced liver injury (DILI) has aroused wide concern. Finding new markers or indicators as well as detoxification molecules for DILI is of great significance and good application prospect, which can help develop effective preclinical screening methodology and corresponding treatment protocols. Herein, in this article, DILI caused by antidepressant drugs of duloxetine and fluoxetine and its remission were evaluated by a two-photon fluorescent probe, RPC-1, through discriminating and imaging HClO and H2S simultaneously. By being applied both in vitro and in vivo, RPC-1 revealed slight up-regulation of HClO and negligible liver damage after administration of either of the two drugs. In contrast, an apparent up-regulation of HClO and obvious liver damage was observed after combined administration of the drugs. Meanwhile, the pretreatment of N-acetyl cysteine (NAC) resulted in the increasing of endogenous H2S level, which contributed to the remission of DILI. The histological analysis and serological test both gave good consistency with the imaging results. These findings demonstrate that HClO may be an appropriate indicator of DILI, and H2S plays an important role in the antidotal effect of NAC. We envision that RPC-1 can be used as a powerful tool to predict clinical DILI and study the effect of antidote, as well as explore the molecular mechanisms involved.}, }
@article {pmid29780252, year = {2018}, author = {Wu, S and Yang, Y and Li, F and Huang, L and Han, Z and Wang, G and Yu, H and Li, H}, title = {Chelerythrine induced cell death through ROS-dependent ER stress in human prostate cancer cells.}, journal = {OncoTargets and therapy}, volume = {11}, number = {}, pages = {2593-2601}, pmid = {29780252}, issn = {1178-6930}, abstract = {INTRODUCTION: Prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer-related mortality worldwide and the third in USA in 2017. Chelerythrine (CHE), a naturalbenzo[c]phenanthridine alkaloid, formerly identified as a protein kinase C inhibitor, has also shown anticancer effect through a number of mechanisms. Herein, effect and mechanism of the CHE-induced apoptosis via reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress in prostate cancer cells were studied for the first time.<br><br>METHODS: In our present study, we investigated whether CHE induced cell viability decrease, colony formation inhibition, and apoptosis in a dose-dependent manner in PC-3 cells. In addition, we showed that CHE increases intracellular ROS and leads to ROS-dependent ER stress and cell apoptosis.<br><br>RESULTS: Pre-treatment with N-acetyl cysteine, an ROS scavenger, totally reversed the CHE-induced cancer cell apoptosis as well as ER stress activation, suggesting that the ROS generation was responsible for the anticancer effects of CHE.<br><br>CONCLUSION: Taken together, our findings support one of the anticancer mechanisms by which CHE increased ROS accumulation in prostate cancer cells, thereby leading to ER stress and caused intrinsic apoptotic signaling. The study reveals that CHE could be a potential candidate for application in the treatment of prostate cancer.}, }
@article {pmid29778909, year = {2018}, author = {Nogueira, GB and Punaro, GR and Oliveira, CS and Maciel, FR and Fernandes, TO and Lima, DY and Rodrigues, AM and Mouro, MG and Araujo, SRR and Higa, EMS}, title = {N-acetylcysteine protects against diabetic nephropathy through control of oxidative and nitrosative stress by recovery of nitric oxide in rats.}, journal = {Nitric oxide : biology and chemistry}, volume = {78}, number = {}, pages = {22-31}, doi = {10.1016/j.niox.2018.05.003}, pmid = {29778909}, issn = {1089-8611}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Catalase/metabolism ; Diabetes Mellitus, Experimental/chemically induced/complications ; Diabetic Nephropathies/etiology/*prevention &amp; control ; Glutathione/metabolism ; Kidney/pathology ; Male ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Nitrosative Stress/*drug effects ; Oxidative Stress/*drug effects ; Protective Agents/*therapeutic use ; Rats, Wistar ; Streptozocin ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The diabetes mellitus (DM) induces several changes, with substantial increase of reactive oxygen species (ROS). The ROS cause damage to systemic and renal microvasculature, which could be one of the mechanisms involved in the development of diabetic nephropathy (DN). The ROS modulate other substances like the nitric oxide (NO), a vasodilator with important role in the renal function. N-acetylcysteine (NAC) is an antioxidant that acts replenishing intracellular cysteine levels, which is essential for glutathione formation. The aim of this study was to evaluate the effect of early or late NAC treatment on oxidative/nitrosative stress in DN progression. All rats were submitted to unilateral nephrectomy and diabetes was induced with streptozotocin. The animals were allocated into six groups: controls that received water (CTL) or NAC (CTL + NAC); diabetic groups that received early or late, water (DM-E; DM-L) or NAC (DM + NAC-E; DM + NAC-L), started on 5th day (early) or 4th week (late) after diabetes induction, during 8 weeks. After NAC treatment, the rats were placed in individual metabolic cages to obtain urine and blood samples for analysis of metabolic profile, renal function, thiobarbituric acid reactive substances (TBARS) and NO. At the end of the protocol, the renal cortex was removed for TBARS, NOS evaluation, antioxidants markers and histology. The DM-E group compared to CTL showed a significant increase in glycemia and proteinuria and impaired renal function; there was a significant increase of TBARS in plasma, urine and renal tissue, and also a significant decrease in plasma NO, which were reverted after early NAC treatment. The eNOS was decreased and iNOS was increased in DM-E vs. CTL, p < 0.05. The early NAC treatment in DM rats reduced proteinuria, creatinine, urea, TBARS and iNOS and, increased creatinine clearance, NO and eNOS, increasing significantly the antioxidant defenses, promoting elevated catalase and glutathione compared to DM-E group, all p < 0.05. The late NAC treatment in diabetic rats vs.DM-E showed reduced proteinuria and TBARS excretion and higher values of creatinine clearance and NO, all statistically significant. Histological analysis of the animals in DM-E or DM-L showed significant tubular changes with degeneration and vacuolization in tubular cells, dilated tubular lumen, intense glycosidic degeneration, and discreet mesangial expansion with interstitial fibrosis area. The DM + NAC-E group showed moderate glycosidic degeneration, however, did not present tubular degeneration or fibrosis. The DM + NAC-L group showed severe glycosidic degeneration, moderate tubular cell degeneration, light and focal dilatation of the tubules, with no fibrosis. Our study showed that NAC protected the diabetic rats against renal injury, probably due to the control of oxidative stress via recovery of the NO bioavailability, showing that early NAC was more effective than late treatment. All these data suggest that NAC may be useful in the adjuvant treatment in a safe way, in the early phase of the disease. Eventually, prolonged treatment, even if it is started later, could change the natural history of the disease, delaying the complications of diabetes in renal tissue.}, }
@article {pmid29778019, year = {2018}, author = {Salem, GA and Shaban, A and Diab, HA and Elsaghayer, WA and Mjedib, MD and Hnesh, AM and Sahu, RP}, title = {Phoenix dactylifera protects against oxidative stress and hepatic injury induced by paracetamol intoxication in rats.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {104}, number = {}, pages = {366-374}, doi = {10.1016/j.biopha.2018.05.049}, pmid = {29778019}, issn = {1950-6007}, mesh = {Acetaminophen/*pharmacology ; Animals ; Antioxidants/metabolism ; Chemical and Drug Induced Liver Injury/*drug therapy ; Liver/*drug effects ; Liver Function Tests/methods ; Male ; Oxidative Stress/*drug effects ; Phoeniceae/*chemistry ; Plant Extracts/*pharmacology ; Plant Leaves/chemistry ; Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The current studies were sought to determine effects of antioxidant potential of aqueous and methanolic extracts of Phoenix dactylifera leaves (PLAE and PLME) against the widely-used analgesic paracetamol (PCM) induced hepatotoxicity. Groups of rats were treated with or without PCM (1500 mg/kg), PLAE and PLME (300 mg/kg) and n-acetylcysteine (NAC, 50 mg/kg) followed by assessments of liver function tests, oxidative stress, antioxidant defenses, and hepatotoxicity. We observed that PCM significantly elevated serum liver markers, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and bilirubin compared to control (untreated) group. These PCM-induced effects were associated with oxidative stress as demonstrated by increased levels of malondialdehyde (MDA) and reduced levels of hepatic antioxidant enzymes, glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Pretreatment of PLME decreased ALT and AST by 78.2% and tissue MDA by 54.1%, and increased hepatic GPx (3.5 folds), CAT (7 folds) and SOD (2.5 folds) compared to PCM group. These PLME-mediated effects were comparable to NAC pretreatment. Histological analysis demonstrates that PLME conserved hepatic tissues against lesions such as inflammation, centrilobular necrosis, and hemorrhages induced by PCM. In contrast, PLAE-mediated effects were less effective in reducing levels of liver function enzymes, oxidative stress, and liver histopathological profiles, and restoring antioxidant defenses against PCM-induced intoxication. These findings indicate that PLME exerts protective effects against PCM-induced hepatotoxicity via scavenging free radicals and restoring hepatic antioxidant enzymes. Thus, PLME and its bioactive components could further be evaluated for their pharmacological properties against drug-induced deleterious effects.}, }
@article {pmid29775111, year = {2018}, author = {Gong, X and Cao, P and Liu, L and Lin, Y and Yang, Q and Zhou, L and Wu, T and Luo, M}, title = {Tamoxifen Prevents D-galactosamine/Lipopolysaccharide-Induced Murine Acute Hepatic Failure through Inhibition of Oxidative Stress and Mmd-2 Upregulation.}, journal = {Immunological investigations}, volume = {47}, number = {6}, pages = {547-557}, doi = {10.1080/08820139.2018.1464024}, pmid = {29775111}, issn = {1532-4311}, mesh = {Acetylcysteine/administration &amp; dosage ; Alanine Transaminase/blood ; Animals ; Antigens, Differentiation/*biosynthesis ; Antioxidants/*therapeutic use ; Aspartate Aminotransferases/blood ; Catalase/metabolism ; Galactosamine/toxicity ; Glutathione Peroxidase/metabolism ; Lipopolysaccharides/toxicity ; Liver Failure, Acute/chemically induced/*prevention &amp; control ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/*drug effects ; Superoxide Dismutase/metabolism ; Tamoxifen/*therapeutic use ; Up-Regulation ; }, abstract = {Oxidative stress is considered one of the major mechanisms underlying lipopolysaccharide (LPS)-induced acute liver failure (ALF). Tamoxifen has been reported to ameliorate LPS-induced ALF via the induction of monocyte to macrophage differentiation-associated 2 (Mmd-2). Whether antioxidant effects are involved remains unknown. Mice were given tamoxifen (TAM) once a day for 3 days. Twelve hours later, d-galactosamine (GaIN) and LPS were injected intraperitoneally to induce ALF. N-Acetylcysteine (NAC) was administered immediately after ALF induction as a positive control. The results showed that serum transaminases increased and hepatic antioxidants decreased significantly in the model group. ALF was alleviated markedly by TAM or NAC treatment. This demonstrated that ALF may be associated with excessive oxidative stress caused by decreased expression of antioxidant enzymes. Both TAM and NAC increased the levels and activity of these antioxidant enzymes significantly (p < 0.05). Hepatic Mmd-2 expression was downregulated in the control group while remaining stable or exhibiting elevated levels in the TAM or NAC groups. The results indicate that TAM may protect mice from GaIN/LPS-induced ALF through increased activity of antioxidant enzymes and upregulation of Mmd-2 expression.}, }
@article {pmid29773887, year = {2019}, author = {Zhou, J and Li, WL and Wang, ZX and Chen, NY and Tang, Y and Hu, XX and Deng, JH and Lu, Y and Lu, GD}, title = {Varacin-1, a novel analog of varacin C, induces p53-independent apoptosis in cancer cells through ROS-mediated reduction of XIAP.}, journal = {Acta pharmacologica Sinica}, volume = {40}, number = {2}, pages = {222-230}, pmid = {29773887}, issn = {1745-7254}, mesh = {Antineoplastic Agents/chemical synthesis/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cyclic S-Oxides/chemical synthesis/*pharmacology ; Ethylamines/chemical synthesis/*pharmacology ; Humans ; Reactive Oxygen Species/metabolism ; Sulfides/chemical synthesis/*pharmacology ; X-Linked Inhibitor of Apoptosis Protein/*metabolism ; }, abstract = {Varacin C is a promising anticancer agent and possesses acid-promoted and photo-induced DNA-damaging activities. In this study, we synthesized an analog varacin-1 (VCA-1) and examined its anticancer potentials. The results demonstrated that VCA-1 caused dose-dependent apoptotic cell death in cancer cells. Note that this action is independent of p53 status, because VCA-1 induced similar levels of apoptosis in two different panels of cell lines (HCT116 p53- wild-type vs. HCT116 p53-knockout colon cancer cells, and p53-expressing U2OS vs. p53-deficient saos2 osteosarcoma cancer cells). VCA-1-induced apoptosis was found to be mainly via the extrinsic apoptosis pathway involving caspase-8 activation and XIAP reduction. Forced over-expression of XIAP markedly prevented apoptosis, indicating its essential role in VCA-1 induced apoptosis. On the other hand, VCA-1 treatment enhanced intracellular ROS (reactive oxygen species) generation also in a p53-independent manner, and consequently promoted caspase activation. Pretreatment of N-acetyl cysteine (an antioxidant), rather than z-VAD (specific caspase inhibitor), markedly prevented XIAP reduction, suggesting that XIAP reduction may be resulted from oxidative stress. In conclusion, data from this study reveal the essential roles of ROS generation and XIAP reduction in VCA-1-induced apoptosis in cancer cells. VCA-1 may be a novel cancer therapeutic agent, especially in p53-mutant human cancers.}, }
@article {pmid29773091, year = {2018}, author = {Qian, M and Tan, HM and Yu, N and Wang, T and Zhang, Q}, title = {Inactivated Sendai Virus Induces ROS-dependent Apoptosis and Autophagy in Human Prostate Cancer Cells.}, journal = {Biomedical and environmental sciences : BES}, volume = {31}, number = {4}, pages = {280-289}, doi = {10.3967/bes2018.036}, pmid = {29773091}, issn = {0895-3988}, mesh = {Apoptosis/*physiology ; Autophagy/*physiology ; Cell Line, Tumor ; Cell Survival ; Humans ; Male ; Oncolytic Virotherapy ; Prostatic Neoplasms/*metabolism ; Reactive Oxygen Species/*metabolism ; Sendai virus/*immunology/physiology ; *Virus Inactivation ; }, abstract = {OBJECTIVE: The current study aims to investigate the effect of Hemagglutinating virus of Japan envelope (HVJ-E) on induction of apoptosis and autophagy in human prostate cancer PC3 cells, and the underlying mechanisms.<br><br>METHODS: PC3 cells were treated with HVJ-E at various multiplicity of infection (MOI), and the generated reactive oxygen species (ROS), cell viability, apoptosis, and autophagy were detected, respectively. Next, the role of ROS played in the regulation of HVJ-E-induced apoptosis and autuphagy in PC3 cells were analysed. In the end, the relationship between HVJ-E-induced apoptosis and autuophagy was investigated by using rapamycin and chloroquine.<br><br>RESULTS: Flow cytometry assay revealed that HVJ-E treatment induced dose-dependent apoptosis and that the JNK and p38 MAPK signaling pathways were involved in HVJ-E-induced apoptosis in PC3 cells. In addition, HVJ-E was able to induce autophagy in PC3 cells via the class III PI3K/beclin-1 pathway. The data also implyed that HVJ-E-triggered autophagy and apoptosis were ROS dependent. When ROS was blocked with N-acetylcysteine (NAC), HVJ-E-induced LC3-II conversion and apoptosis were reversed. Interestingly, HVJ-E-induced apoptosis was significantly increased by an inducer of autophagy, rapamycin pretreatment, both in vitro and in vivo.<br><br>CONCLUSION: HVJ-E exerts anticancer effects via autophagic cell death in prostate cancer cells.}, }
@article {pmid29770192, year = {2018}, author = {Sharafkhah, M and Abdolrazaghnejad, A and Zarinfar, N and Mohammadbeigi, A and Massoudifar, A and Abaszadeh, S}, title = {Safety and efficacy of N-acetyl-cysteine for prophylaxis of ventilator-associated pneumonia: a randomized, double blind, placebo-controlled clinical trial.}, journal = {Medical gas research}, volume = {8}, number = {1}, pages = {19-23}, pmid = {29770192}, issn = {2045-9912}, abstract = {Ventilator-associated-pneumonia (VAP) is characterized by morbidity, mortality, and prolonged length of stay in intensive care unit (ICU). The present study aimed to examine the effect of N-acetyl-cysteine (NAC) in preventing VAP in patients hospitalized in ICU. We performed a prospective, randomized, double-blind, placebo-controlled trial of 60 mechanically ventilated patients at high risk of developing VAP. NAC (600 mg/twice daily) and placebo (twice daily) were administered to NAC group (n = 30) and control group (n = 30), respectively, through the nasogastric tube in addition to routine care. The clinical response was considered as primary (incidence of VAP) and secondary outcomes. Twenty-two (36.6%) patients developed VAP. Patients treated with NAC were significantly less likely to develop clinically confirmed VAP compared with patients treated with placebo (26.6% vs. 46.6%; P = 0.032). Patients treated with NAC had significantly less ICU length of stay (14.36 ± 4.69 days vs. 17.81 ± 6.37 days, P = 0.028) and less hospital stay (19.23 ± 5.54 days vs. 24.61 ± 6.81 days; P = 0.03) than patients treated with placebo. Time to VAP was significantly longer in the NAC group (9.42 ± 1.9 days vs. 6.46 ± 2.53 days; P = 0.002). The incidence of complete recovery was significantly higher in the NAC group (56.6% vs. 30%; P = 0.006). No adverse events related to NAC were identified. NAC is safe and effective to prevent and delay VAP, and improve its complete recovery rate in a selected, high-risk ICU population.}, }
@article {pmid29769783, year = {2018}, author = {Issac, TG and Telang, AV and Chandra, SR}, title = {Trichotillomania Ranging from "Ritual to Illness" and as a Rare Clinical Manifestation of Frontotemporal Dementia: Review of Literature and Case Report.}, journal = {International journal of trichology}, volume = {10}, number = {2}, pages = {84-88}, pmid = {29769783}, issn = {0974-7753}, abstract = {Frontotemporal dementia (FTD) is the most common form of dementia in the younger age group and often exists with comorbid obsessions and compulsions in up to 80% of the patients. Trichotillomania or compulsive "hair-pulling" disorder is a rare manifestation of FTD and is a poorly evaluated symptom in this condition. The release of "grooming functions" due to frontal disinhibition is often attributed to the evolutionary perspective; however, recent findings also implicate the role of neurotransmitter dysfunction. Trichotillomania is currently classified under obsessive and compulsive behavioral spectrum disorders and is often encountered in the younger population with research evidence of response to selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and newer drugs such as N-acetyl cysteine. The role of behavioral therapy also has robust evidence in trichotillomania. We herewith report the case of a middle-aged male patient who presented with features of personality change and behavioral problems in terms of anger, agitation, and disinhibitory behavior who on detailed clinical evaluation and radiological assessment had features consistent with behavioral variant of FTD along with compulsive "hair plucking" behavior which responded minimally with SSRIs. FTD can have features of trichotillomania which is an often overlooked and relatively uncommon manifestation of dementias. Treatment options such as N-acetyl cysteine and behavioral therapy could have potential utility in this degenerative condition hitherto at an earlier stage.}, }
@article {pmid29754474, year = {2018}, author = {Gu, LL and Shen, ZL and Li, YL and Bao, YQ and Lu, H}, title = {Oxymatrine Causes Hepatotoxicity by Promoting the Phosphorylation of JNK and Induction of Endoplasmic Reticulum Stress Mediated by ROS in LO2 Cells.}, journal = {Molecules and cells}, volume = {41}, number = {5}, pages = {401-412}, pmid = {29754474}, issn = {0219-1032}, mesh = {Acetylcysteine/pharmacology ; Alkaloids/pharmacology/*toxicity ; Amino Acid Chloromethyl Ketones/pharmacology ; Anthracenes/pharmacology ; Antioxidants/pharmacology ; Antiviral Agents/pharmacology/*toxicity ; Apoptosis/drug effects ; Butylamines/pharmacology ; Cell Line ; Chemical and Drug Induced Liver Injury/etiology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Hepatocytes/*drug effects/enzymology ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Phosphorylation/drug effects ; Protein Processing, Post-Translational/*drug effects ; Quinolizines/pharmacology/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Oxymatrine (OMT) often used in treatment for chronic hepatitis B virus infection in clinic. However, OMT-induced liver injury has been reported. In this study, we aim to investigate the possible mechanism of OMT-induced hepatotoxicity in human normal liver cells (L02). Exposed cells to OMT, the cell viability was decreased and apoptosis rate increased, the intracellular markers of oxidative stress were changed. Simultaneously, OMT altered apoptotic related proteins levels, including Bcl-2, Bax and pro-caspase-8/-9/-3. In addition, OMT enhanced the protein levels of endoplasmic reticulum (ER) stress makers (GRP78/Bip, CHOP, and cleaved-Caspase-4) and phosphorylation of c-Jun N-terminal kinase (p-JNK), as well as the mRNA levels of GRP78/Bip, CHOP, caspase-4, and ER stress sensors (IREI, ATF6, and PERK). Pre-treatment with Z-VAD-fmk, JNK inhibitor SP600125 and N-acetyl-l-cysteine (NAC), a ROS scavenger, partly improved the survival rates and restored OMT-induced cellular damage, and reduced caspase-3 cleavage. SP600125 or NAC reduced OMT-induced p-JNK and NAC significantly lowered caspase-4. Furthermore, 4-PBA, the ER stress inhibitor, weakened inhibitory effect of OMT on cells, on the contrary, TM worsen. 4-PBA also reduced the levels of p-JNK and cleaved-caspase-3 proteins. Therefore, OMT-induced injury in L02 cells was related to ROS mediated p-JNK and ER stress induction. Antioxidant, by inhibition of p-JNK or ER stress, may be a feasible method to alleviate OMT-induced liver injury.}, }
@article {pmid29753208, year = {2018}, author = {Yan, M and Huo, Y and Yin, S and Hu, H}, title = {Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions.}, journal = {Redox biology}, volume = {17}, number = {}, pages = {274-283}, pmid = {29753208}, issn = {2213-2317}, mesh = {Acetaminophen/*adverse effects/therapeutic use ; Acetylcysteine/*therapeutic use ; Autophagy/genetics ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology/prevention &amp; control ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Metabolic Detoxication, Phase I/genetics ; Metabolic Detoxication, Phase II/genetics ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in many developed countries. Mitochondrial oxidative stress is considered to be the predominant cellular event in APAP-induced liver injury. Accordingly, N-acetyl cysteine, a known scavenger of reactive oxygen species (ROS), is recommended as an effective clinical antidote against APAP-induced acute liver injury (AILI) when it is given at an early phase; however, the narrow therapeutic window limits its use. Hence, the development of novel therapeutic approaches that can offer broadly protective effects against AILI is clearly needed. To this end, it is necessary to better understand the mechanisms of APAP hepatotoxicity. Up to now, in addition to mitochondrial oxidative stress, many other cellular processes, including phase I/phase II metabolism, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and liver regeneration, have been identified to be involved in the pathogenesis of AILI, providing new targets for developing more effective therapeutic interventions against APAP-induced liver injury. In this review, we summarize intracellular and extracellular events involved in APAP hepatotoxicity, along with emphatic discussions on the possible therapeutic approaches targeting these different cellular events.}, }
@article {pmid29752770, year = {2018}, author = {Mohammadi, P and Hassani-Bafrani, H and Tavalaee, M and Dattilo, M and Nasr-Esfahani, MH}, title = {One-carbon cycle support rescues sperm damage in experimentally induced varicocoele in rats.}, journal = {BJU international}, volume = {122}, number = {3}, pages = {480-489}, doi = {10.1111/bju.14385}, pmid = {29752770}, issn = {1464-410X}, mesh = {Animals ; Antioxidants/pharmacology ; Carbon Cycle/*drug effects/physiology ; Dietary Supplements ; Infertility, Male/etiology/*therapy ; Lipid Peroxidation/drug effects ; Male ; Micronutrients/*pharmacology ; Rats ; Rats, Wistar ; Semen Analysis/methods ; Spermatozoa/*drug effects/physiology ; Testis/physiopathology ; Varicocele/*complications/therapy ; }, abstract = {OBJECTIVES: To investigate whether micronutrients in support of the one-carbon cycle and glutathione synthesis are effective in improving sperm damage after surgical varicocoele induction in rats and whether any effect is achieved without a rebound reductive stress as seen with oral antioxidants.<br><br>MATERIALS AND METHODS: Surgical varicocoele was induced in adult male Wistar rats and resulted in significant damage to the testis and sperm cells measured at 2 and 4 months after surgery. At 2 months after surgery, rats received a 2-month oral supplementation in support of the one-carbon cycle containing B vitamins (B2, B3, B6, folic acid and B12), N-acetyl-cysteine, zinc, small amounts of vitamin E, and a natural source of betalains and quercetine (Condensyl[&#xae;] ; Parthenogen SAGL, Lugano, Switzerland and Nurilia SARL, Lyon, France).<br><br>RESULTS: One-carbon cycle supplementation, compared to untreated controls, significantly improved the morphometric characteristics of testis (P < 0.05), sperm concentration, motility and abnormal morphology (P < 0.001), sperm chromatin condensation (aniline blue staining, P < 0.05), sperm DNA damage (acridine orange staining, P < 0.05) and sperm lipid peroxidation (BODIPY C11, P < 0.001). The improvement in both nuclear condensation and DNA damage and the lack of excessive inhibition of lipid peroxidation confirmed that no reductive stress had occurred.<br><br>CONCLUSIONS: Micronutrients in support of the one-carbon cycle are effective in the treatment of surgically induced varicocoele in rats, probably by activating natural antioxidant defences and epigenetics. These results support the idea that essential micronutrients including B vitamins may also have a positive influence in clinical varicocoele, which should be tested in prospective clinical trials.}, }
@article {pmid29752433, year = {2018}, author = {He, Y and Zhou, L and Fan, Z and Liu, S and Fang, W}, title = {Palmitic acid, but not high-glucose, induced myocardial apoptosis is alleviated by N‑acetylcysteine due to attenuated mitochondrial-derived ROS accumulation-induced endoplasmic reticulum stress.}, journal = {Cell death &amp; disease}, volume = {9}, number = {5}, pages = {568}, pmid = {29752433}, issn = {2041-4889}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Diabetes Mellitus, Experimental/metabolism/pathology ; Endoplasmic Reticulum Stress/*drug effects ; Glucose/*pharmacology ; Male ; Mitochondria, Heart/*metabolism/pathology ; Myocardium/*metabolism/pathology ; Myocytes, Cardiac/metabolism/pathology ; Palmitic Acid/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {Pharmacological inhibition of reactive oxygen species (ROS) is a potential strategy to prevent diabetes-induced cardiac dysfunction. This study was designed to investigate precise effects of antioxidant N‑acetylcysteine (NAC) in alleviating diabetic cardiomyopathy (DCM). Echocardiography and histologic studies were performed 12 weeks after streptozocin injection. Protein levels involved in endoplasmic reticulum stress (ERS) and apoptosis were analyzed by western blotting in diabetic hearts or high-glucose (HG, 30 mM)- and palmitic acid (PA, 300 μM)-cultured neonatal rat cardiomyocytes (NRCMs). ROS generation and structural alterations of mitochondria were also assessed. We report that NAC alleviated diabetes-induced cardiac abnormality, including restored ejection fraction (EF %), fraction shortening (FS %), peak E to peak A ratio (E/A) and reduced cardiac hypertrophy and fibrosis. These effects were concomitant with blocked ERS and apoptosis, as evidenced by inactivation of phosphorylated inositol-requiring enzyme-1α (IRE1α)/spliced X-box binding protein 1 (XBP1), phosphorylated protein kinase-like kinase (PERK)/phosphorylated eukaryotic initiation factor 2α (eIF2α) and glucose-regulated protein 78 (GRP78)/activating transcription factor 6 (ATF6α)/C/EBP homologous protein (CHOP) pathways, as well as suppressed Bcl-2-associated X protein (BAX)/B-cell lymphoma-2 (Bcl-2) and cleaved caspase 3 expressions. Mechanistically, PA mediated excessive mitochondrial ROS generation and oxidative stress, which were antagonized by NAC and Mito-TEMPO, a mitochondrial ROS inhibitor. No effects were noted by addition of apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, and NADPH oxidase 4 (NOX 4) and NOX 2 expressions were not altered, indicating that PA-induced ROS generation is independent of NADPH oxidases. Most intriguingly, HG failed to promote ROS production despite its ability to promote ERS and apoptosis in NRCMs. Collectively, these findings indicate that NAC primarily abrogates PA-mediated mitochondrial ROS through ERS and therefore alleviates myocardial apoptosis but has little effect on HG-induced cardiac injury. This uncovers a potential role for NAC in formulating novel cardioprotective strategies in DCM patients.}, }
@article {pmid29746502, year = {2018}, author = {Sun, X and Guo, S and Wang, W and Cao, Z and Dan, J and Cheng, J and Cao, W and Tian, F and Cao, W and Tian, Y}, title = {Potential involvement of the 18 kDa translocator protein and reactive oxygen species in apoptosis of THP-1 macrophages induced by sonodynamic therapy.}, journal = {PloS one}, volume = {13}, number = {5}, pages = {e0196541}, pmid = {29746502}, issn = {1932-6203}, mesh = {Aminolevulinic Acid/pharmacology ; Apoptosis/drug effects/*physiology ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Humans ; Macrophages/metabolism/physiology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Protoporphyrins ; Reactive Oxygen Species/metabolism ; Receptors, GABA/*metabolism/physiology ; THP-1 Cells/physiology ; Ultrasonic Therapy/*methods ; }, abstract = {Sonodynamic therapy (SDT) with exogenous protoporphyrin IX (PpIX) or endogenous PpIX derived from 5-aminolevulinic acid (ALA) has been carried out to produce apoptotic effects on macrophages, indicating a potential treatment methodology for atherosclerosis. Our previous studies have found that mitochondria damage by reactive oxygen species (ROS) plays a major role in the SDT-induced apoptosis. This study aimed at investigating the potential involvement of the mitochondrial 18 kDa translocator protein (TSPO) and ROS in the pro-apoptotic effects of SDT on THP-1 macrophages. THP-1 macrophages were divided into control and SDT groups, and went through pretreatment of the specific TSPO ligand PK11195 and ROS scavengers N-Acetyl Cysteine (NAC), then compared with groups without pretreatment. Application of PK11195 reduced intracellular accumulation of endogenous PpIX. PK11195 and NAC reduced the generation of intracellular ROS and oxidation of cardiolipin induced by SDT, respectively. PK11195 and NAC also reduced SDT-induced mitochondrial membrane potential (ΔΨm) loss, the translocation of cytochrome c and cell apoptosis. PpIX accumulation, ROS generation and cell apoptosis were also attenuated by siTSPO. Our findings indicate the pivotal role of TSPO and ROS in SDT-induced cardiolipin oxidation, ΔΨm collapse, cytochrome c translocation and apoptosis in THP-1 macrophages.}, }
@article {pmid29745443, year = {2018}, author = {Ghassemi-Rad, J and Maleki, M and Knickle, AF and Hoskin, DW}, title = {Myricetin-induced oxidative stress suppresses murine T lymphocyte activation.}, journal = {Cell biology international}, volume = {42}, number = {8}, pages = {1069-1075}, doi = {10.1002/cbin.10977}, pmid = {29745443}, issn = {1095-8355}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; Dendritic Cells/cytology/drug effects/metabolism ; Female ; Flavonoids/chemistry/*pharmacology ; Hydrogen Peroxide/chemistry/pharmacology ; Interferon-gamma/analysis ; Interleukin-2/analysis ; Lymphocyte Activation/*drug effects ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/cytology/immunology/metabolism ; }, abstract = {A number of polyphenolic compounds present in fruits and vegetables have the capacity to modulate immune responses; however, the impact of the common plant-derived flavonoid myricetin on T lymphocyte function has not been investigated. We show that myricetin inhibited mouse T lymphocyte activation by bead-immobilized anti-CD3 and anti-CD28 monoclonal antibodies, as indicated by a dose-dependent reduction in cell proliferation and decreased synthesis of interferon-γ, interleukin (IL)-2, IL-4, and IL-17 associated with different T helper cell subsets. This effect was attributed to myricetin-induced reactive oxygen species (ROS) since myricetin caused hydrogen peroxide (H2 O2) to accumulate in cell-free culture medium and H2 O2 inhibited T cell proliferation and cytokine synthesis. In addition, the antioxidant N-acetyl cysteine restored the ability of myricetin-treated T lymphocytes to proliferate in response to a mitogenic stimulus. The presence of dendritic cells or bone marrow-derived macrophages negated the inhibitory effect of myricetin on T cell activation, and H2 O2 in T cell cultures that were treated with exogenous H2 O2 was reduced when antigen-presenting cells were also present. These findings suggest that antioxidant molecules produced by dendritic cells and macrophages protected T cells from myricetin-induced oxidative stress, and underscore the importance of considering immune cell interactions when evaluating the immunomodulatory activity of ROS-generating phytochemicals.}, }
@article {pmid29743905, year = {2018}, author = {Biernacka-Fiałkowska, B and Szuksztul, M and Suślik, W and Dzierwa, K and Tekieli, &#x141; and Kostkiewicz, M and Podolec, P and Pieniążek, P}, title = {Intravenous N-acetylcysteine for the PRevention Of Contrast-induced nephropathy - a prospective, single-center, randomized, placebo-controlled trial. The INPROC trial.}, journal = {Postepy w kardiologii interwencyjnej = Advances in interventional cardiology}, volume = {14}, number = {1}, pages = {59-66}, pmid = {29743905}, issn = {1734-9338}, abstract = {INTRODUCTION: Contrast-induced nephropathy (CIN) is a common clinical problem that is growing in importance as an increasing number of tests and procedures which utilize contrast media (CM) are performed.<br><br>AIM: To evaluate the efficacy of intravenous N-acetylcysteine (NAC) for prevention of CIN after diagnostic and/or interventional procedures requiring CM administration.<br><br>MATERIAL AND METHODS: In a prospective, single-center, randomized, placebo-controlled trial the preventive effects of N-acetylcysteine were evaluated in 222 patients undergoing elective angiography and/or angioplasty. Patients were randomly assigned to receive either NAC or placebo. All patients received intravenous hydration with normal saline before and after catheterization. Serum creatinine (SCr) and estimated glomerular filtration rate were assessed at baseline, at 48-72 h and 10-15 days after CM administration. Contrast-induced nephropathy was defined as an increase in SCr of at least 44 &#xb5;mol/l (0.5 mg/dl) or an increase of &#x2265; 25% of the baseline value 48-72 h after CM administration.<br><br>RESULTS: Contrast-induced nephropathy occurred in 30 of 222 patients (13.5%): 9 of 108 patients in NAC (8.3%) and 21 of 114 patients in the control group (18.4%; p = 0.0281). The multivariate Cox analysis revealed that elevated SCr at 10-15 days (HR = 2.69; p = 0.018) and baseline SCr level (HR = 1.009; p = 0.015) were independent prognostic variables for adverse events during follow-up.<br><br>CONCLUSIONS: Our findings suggest that intravenous NAC along with intravenous hydration may help prevent declining renal function after CM exposure. Elevated SCr level 10-15 days after CM administration was associated with increased risk of adverse events in long-term observation, while elevated SCr within 72 h was not. Measuring SCr at least 10 days after exposure to CM may provide a better outcome measure.}, }
@article {pmid29742938, year = {2018}, author = {Aldini, G and Altomare, A and Baron, G and Vistoli, G and Carini, M and Borsani, L and Sergio, F}, title = {N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why.}, journal = {Free radical research}, volume = {52}, number = {7}, pages = {751-762}, doi = {10.1080/10715762.2018.1468564}, pmid = {29742938}, issn = {1029-2470}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Disulfides/*metabolism ; Free Radical Scavengers/*pharmacology ; Glutathione/*metabolism ; Humans ; }, abstract = {The main molecular mechanisms explaining the well-established antioxidant and reducing activity of N-acetylcysteine (NAC), the N-acetyl derivative of the natural amino acid l-cysteine, are summarised and critically reviewed. The antioxidant effect is due to the ability of NAC to act as a reduced glutathione (GSH) precursor; GSH is a well-known direct antioxidant and a substrate of several antioxidant enzymes. Moreover, in some conditions where a significant depletion of endogenous Cys and GSH occurs, NAC can act as a direct antioxidant for some oxidant species such as NO2 and HOX. The antioxidant activity of NAC could also be due to its effect in breaking thiolated proteins, thus releasing free thiols as well as reduced proteins, which in some cases, such as for mercaptoalbumin, have important direct antioxidant activity. As well as being involved in the antioxidant mechanism, the disulphide breaking activity of NAC also explains its mucolytic activity which is due to its effect in reducing heavily cross-linked mucus glycoproteins. Chemical features explaining the efficient disulphide breaking activity of NAC are also explained.}, }
@article {pmid29742703, year = {2018}, author = {Ashraf, U and Bajantri, B and Roa-Gomez, G and Venkatram, S and Cantin, A and Diaz-Fuentes, G}, title = {Nebulized heparin and N-acetylcysteine for smoke inhalational injury: A case report.}, journal = {Medicine}, volume = {97}, number = {19}, pages = {e0638}, pmid = {29742703}, issn = {1536-5964}, mesh = {Acetylcysteine/*administration &amp; dosage ; Anticoagulants/*administration &amp; dosage ; Bronchial Diseases/drug therapy/etiology ; Combined Modality Therapy ; Edema/drug therapy/etiology ; Expectorants/*administration &amp; dosage ; Heparin/*administration &amp; dosage ; Humans ; Male ; Middle Aged ; Nebulizers and Vaporizers ; Smoke Inhalation Injury/complications/*drug therapy ; Tracheal Diseases/drug therapy/etiology ; }, abstract = {RATIONALE: Every year, ∼40,000 people suffer burn-related injuries in the United States. Despite recent advances, the odds of dying from exposure to fire, flames, or smoke are one in ∼1500. Smoke inhalation causes injury to the airways via a complex physiological process, and the treatment is mainly supportive. Many recent interventions aim to decrease the formation of fibrin casts, the main cause of airway damage in these patients. Among these, treatment with a combination of nebulized heparin and N-acetylcysteine (NAC) has shown benefit.<br><br>PATIENT CONCERNS: We describe the case of a 58-year-old man who presented after smoke inhalation during a fire. Soot was found in the nostrils when he was admitted to our hospital, and after he began coughing up carbonaceous material, he was electively intubated and placed on volume assist control ventilation.<br><br>DIAGNOSIS: Bronchoscopy on the first day of intensive care confirmed the injury from smoke inhalation and revealed mucosal edema and soot involving the tracheobronchial tree.<br><br>INTERVENTIONS AND OUTCOMES: Inhaled unfractionated heparin of 10,000&#x200a;IU in 3&#x200a;mL of 0.9% normal saline alternating every 2&#x200a;hours with 3&#x200a;mL of 20% NAC was started 48&#x200a;hours after admission and continued for 7 days. Bronchoscopy on the fifth day of intensive care showed significant improvement in airway edema and a resolution of soot.<br><br>LESSONS: On the basis of our experience with this case and limited literature, we posit that nebulized heparin and NAC may be of benefit in patients with inhalational smoke-induced lung injury and mild-to-severe lung injury scores.}, }
@article {pmid29742465, year = {2018}, author = {Knickle, A and Fernando, W and Greenshields, AL and Rupasinghe, HPV and Hoskin, DW}, title = {Myricetin-induced apoptosis of triple-negative breast cancer cells is mediated by the iron-dependent generation of reactive oxygen species from hydrogen peroxide.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {118}, number = {}, pages = {154-167}, doi = {10.1016/j.fct.2018.05.005}, pmid = {29742465}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Catalase/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage ; Female ; Flavonoids/*pharmacology ; Humans ; Hydrogen Peroxide/*pharmacology ; Iron/*metabolism ; Mitochondria/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; Triple Negative Breast Neoplasms/enzymology/metabolism/*pathology ; }, abstract = {Myricetin is a dietary phytochemical with anticancer activity; however, the effect of myricetin on breast cancer cells remains unclear. Here, we show that myricetin inhibited the growth of triple-negative breast cancer (TNBC) cells but was less inhibitory for normal cells. The effect of myricetin was comparable to epigallocatechin gallate and doxorubicin, and greater than resveratrol and cisplatin. Myricetin-treated TNBC cells showed evidence of early and late apoptosis/necrosis, which was associated with intracellular reactive oxygen species (ROS) accumulation, extracellular regulated kinase 1/2 and p38 mitogen-activated protein kinase activation, mitochondrial membrane destabilization and cytochrome c release, and double-strand DNA breaks. The antioxidant N-acetyl-cysteine protected myricetin-treated TNBC cells from cytotoxicity due to DNA damage. Myricetin also induced hydrogen peroxide (H2O2) production in cell-free culture medium, as well as in the presence of TNBC cells and normal cells. In addition, deferiprone-mediated inhibition of intracellular ROS generation via the iron-dependent Fenton reaction and inhibition of extracellular ROS accumulation with superoxide dismutase plus catalase prevented myricetin-induced cytotoxicity in TNBC cell cultures. We conclude that the cytotoxic effect of myricetin on TNBC cells was due to oxidative stress initiated by extracellular H2O2 formed by autoxidation of myricetin, leading to intracellular ROS production via the Fenton reaction.}, }
@article {pmid29741731, year = {2018}, author = {Yang, Y and Cheng, L and Deng, X and Yu, H and Chao, L}, title = {Expression of GRIM-19 in unexplained recurrent spontaneous abortion and possible pathogenesis.}, journal = {Molecular human reproduction}, volume = {24}, number = {7}, pages = {366-374}, doi = {10.1093/molehr/gay020}, pmid = {29741731}, issn = {1460-2407}, mesh = {Abortion, Habitual/*genetics/*immunology/pathology ; Adult ; Apoptosis Regulatory Proteins/*genetics/metabolism ; Case-Control Studies ; Cell Differentiation/genetics/immunology ; Cells, Cultured ; Female ; Genetic Predisposition to Disease ; Humans ; Immune Tolerance/genetics/immunology ; Jurkat Cells ; Lymphocyte Count ; NADH, NADPH Oxidoreductases/*genetics/metabolism ; Parity/physiology ; Pregnancy ; T-Lymphocytes, Regulatory/pathology/physiology ; TOR Serine-Threonine Kinases/metabolism ; Th17 Cells/pathology/physiology ; Young Adult ; }, abstract = {STUDY QUESTION: Is aberrant expression of gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) associated with unexplained recurrent spontaneous abortion (URSA)?<br><br>SUMMARY ANSWER: GRIM-19 deficiency may regulate regulatory T cell/T helper 17 cell (Treg/Th17) balance partly through reactive oxygen species (ROS)-mammalian target of rapamycin (mTOR) signaling axis in URSA.<br><br>WHAT IS KNOWN ALREADY: Immunological disorders may cause impaired maternal immune tolerance to the fetus and result in fetal rejection. The differentiation of Treg and Th17 cells is controlled by phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway. GRIM-19 participates in the immune response, but its role in URSA is largely unknown.<br><br>STUDY DESIGN, SIZE, DURATION: The current study included 28 URSA patients and 30 non-pregnant healthy women.<br><br>The proportion of Treg and Th17 cells in peripheral blood of URSA patients and control subjects were assessed with flow cytometry. The expression of GRIM-19 in peripheral blood lymphocytes (PBLs) was measured with quantitative real-time PCR and western blot analysis. Furthermore, the ROS level in the PBLs of URSA patients and control subjects were assessed by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Then, Akt/mTOR expression in the PBLs was measured. Downregulation of GRIM-19 in Jurkat cells was performed by specific siRNA. Then, intracellular ROS production and the expression of p-mTOR, which is known to enhance Th17 differentiation and decrease Treg cell differentiation, were detected. Finally, N-acetylcysteine (NAC) was used to decrease the intracellular ROS level, and the expression of p-mTOR was measured.<br><br>The proportion of Treg cells was reduced in URSA patients, whereas the proportion of Th17 cells was increased. The expression of GRIM-19 was significantly lower in PBLs of URSA patients. Furthermore, there is a considerable increase in intracellular ROS production and a high level of p-Akt and p-mTOR expression in the PBLs of URSA patients compared with the control subjects. In parallel to this, downregulation of GRIM-19 in the Jurkat cells by siRNA results in an increased ROS production and an increased expression of p-mTOR. Importantly, the upregulation of p-mTOR resulting from GRIM-19 loss was significantly reversed in the cells treatment with ROS inhibitor N-acetyl-l-cysteine (NAC), indicating that ROS was indeed required for GRIM-19 depletion induced p-mTOR expression.<br><br>LARGE SCALE DATA: None.<br><br>A large number of researches have confirmed that the differentiation of Treg and Th17 cells is controlled by PI3K/Akt/mTOR signaling pathway. We have not shown the regulatory role of ROS and PI3K/Akt/mTOR in Treg and Th17 differentiation in this study.<br><br>Our study has demonstrated that GRIM-19 deficiency may play a role in regulating Treg/Th17 balance partly through ROS-mTOR signaling axis in URSA. The present study offers a new perspective to the roles of GRIM-19 in immunoregulation.<br><br>This work was supported by the National Natural Science Foundation of China (Grant numbers 81571511, 81701528, 81370711 and 30901603), the Shandong Provincial Natural Science Foundation (Grant numbers ZR2017PH052 and ZR2013HM090) and the Science Foundation of Qilu Hospital of Shandong University, Fundamental Research Funds of Shandong University (Grant numbers 2015QLQN50 and 2015QLMS24). The authors declare that there is no conflict of interest that could prejudice the impartiality of the present research.}, }
@article {pmid29738966, year = {2018}, author = {Shen, F and Wen, HM and Shan, CX and Kang, A and Dong, B and Chai, C and Zhang, JY and Zhang, Q and Li, W}, title = {Sulfotransferase-catalyzed biotransformation of liguzinediol and comparison of its metabolism in different species using UFLC-QTOF-MS.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1089}, number = {}, pages = {1-7}, doi = {10.1016/j.jchromb.2018.04.048}, pmid = {29738966}, issn = {1873-376X}, mesh = {Acetylcysteine/chemistry ; Animals ; Biotransformation ; Catalysis ; Cell Culture Techniques/methods ; Chromatography, High Pressure Liquid/methods ; Dogs ; Haplorhini ; Humans ; Liver/cytology/metabolism ; Metabolome ; Metabolomics/methods ; Molecular Structure ; Pyrazines/chemistry/*metabolism ; Rats ; Signal Transduction ; Sulfotransferases/*metabolism ; Tandem Mass Spectrometry/*methods ; }, abstract = {Liguzinediol (2,5-dihydroxymethyl-3,6-dimethylpyrazine, LZDO) is a potential agent for the low-risk treatment of heart failure. 2-N-acetylcysteine-LZDO (2-NAC-LZDO) and 2-cysteine-LZDO (2-Cys-LZDO) are major LZDO metabolites found in the pharmacokinetic studies of rats and beagle dogs. To elucidate the biotransformation pathway and related enzymes, an incubation system with 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as a cofactor and N-acetylcysteine (NAC) as a trapping agent was established using liver cytosol. An ultra-flow liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UFLC-QTOF-MS) method was used to identify the major metabolites. 2-NAC-LZDO could be detected among four species (humans, monkeys, dogs, and rats) and is the dominant metabolite in human liver cytosol (HLC). The sulfotransferase (SULT) inhibitors 2,6-dichloro-4-nitrophenol (DCNP) and quercetin at a concentration of 1 μM, suppressed 2-NAC-LZDO formation in HLC by 87 and 46%, respectively. This result suggested that sulfotransferase was involved in 2-NAC-LZDO formation. The metabolism of LZDO in different species indicated that SULT activity in dogs, rats, and monkeys was higher than that in humans. Further SULT phenotyping revealed that SULT1A1 is the predominant enzyme involved in the sulfation of LZDO. The underlying mechanism for the biotransformation of LZDO was demonstrated. The potential pathway is via the sulfation of LZDO to form sulfate, and the spontaneous cleavage of the sulfate group to generate highly reactive electrophilic cations, which can bind to NAC to form the major metabolites.}, }
@article {pmid29738273, year = {2018}, author = {Mirrasekhian, E and Nilsson, JL&#xc5; and Shionoya, K and Blomgren, A and Zygmunt, PM and Engblom, D and Högestätt, ED and Blomqvist, A}, title = {The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1-mediated hypothermia and is associated with prostaglandin inhibition in the brain.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {32}, number = {10}, pages = {5751-5759}, doi = {10.1096/fj.201800272R}, pmid = {29738273}, issn = {1530-6860}, mesh = {Acetaminophen/*adverse effects/pharmacology ; Animals ; Antipyretics/*adverse effects/pharmacology ; Brain/*metabolism/pathology ; Dinoprostone/*biosynthesis ; Hypothermia/chemically induced/*metabolism/pathology ; Mice ; Mice, Knockout ; TRPA1 Cation Channel/*biosynthesis ; }, abstract = {The mode of action of paracetamol (acetaminophen), which is widely used for treating pain and fever, has remained obscure, but may involve several distinct mechanisms, including cyclooxygenase inhibition and transient receptor potential ankyrin 1 (TRPA1) channel activation, the latter being recently associated with paracetamol's propensity to elicit hypothermia at higher doses. Here, we examined whether the antipyretic effect of paracetamol was due to TRPA1 activation or cyclooxygenase inhibition. Treatment of wild-type and TRPA1 knockout mice rendered febrile by immune challenge with LPS with a dose of paracetamol that did not produce hypothermia (150 mg/kg) but is known to be analgetic, abolished fever in both genotypes. Paracetamol completely suppressed the LPS-induced elevation of prostaglandin E2 in the brain and also reduced the levels of several other prostanoids. The hypothermia induced by paracetamol was abolished in mice treated with the electrophile-scavenger N-acetyl cysteine. We conclude that paracetamol's antipyretic effect in mice is dependent on inhibition of cyclooxygenase activity, including the formation of pyrogenic prostaglandin E2, whereas paracetamol-induced hypothermia likely is mediated by the activation of TRPA1 by electrophilic metabolites of paracetamol, similar to its analgesic effect in some experimental paradigms.-Mirrasekhian, E., Nilsson, J. L. Å., Shionoya, K., Blomgren, A., Zygmunt, P. M., Engblom, D., Högestätt, E. D., Blomqvist, A. The antipyretic effect of paracetamol occurs independent of transient receptor potential ankyrin 1-mediated hypothermia and is associated with prostaglandin inhibition in the brain.}, }
@article {pmid29736011, year = {2018}, author = {Musicki, B and Bhunia, AK and Karakus, S and Burnett, AL}, title = {S-nitrosylation of NOS pathway mediators in the penis contributes to cavernous nerve injury-induced erectile dysfunction.}, journal = {International journal of impotence research}, volume = {30}, number = {3}, pages = {108-116}, pmid = {29736011}, issn = {1476-5489}, support = {R01 DK067223/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cyclic GMP/metabolism ; Erectile Dysfunction/*etiology ; Male ; Nerve Crush ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/*metabolism ; Penile Erection/drug effects/physiology ; Penis/*innervation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/*physiology ; }, abstract = {cGMP-independent nitric oxide (NO) signaling occurs via S-nitrosylation. We evaluated whether aberrant S-nitrosylation operates in the penis under conditions of cavernous nerve injury and targets proteins involved in regulating erectile function. Adult male Sprague-Dawley rats underwent bilateral cavernous nerve crush injury (BCNI) or sham surgery. Rats were given a denitrosylation agent N-acetylcysteine (NAC, 300 mg/kg/day) or vehicle in drinking water starting 2 days before BCNI and continuing for 2 weeks following surgery. After assessment of erectile function (intracavernous pressure), penes were collected for measurements of S-nitrosylation by Saville-Griess and TMT-switch assays and PKG-I function by immunoblotting of phospho (P)-VASP-Ser-239. Erectile function was decreased (P < 0.05) after BCNI, and it was preserved (P < 0.05) by NAC treatment. Total S-nitrosothiols and total S-nitrosylated proteins were increased (P < 0.05) after BCNI, and these were partially prevented by NAC treatment. S-nitrosylation of sGC was increased (P < 0.05) after BCNI, and it was prevented (P < 0.05) by NAC treatment. S-nitrosylation of eNOS was increased (P < 0.05) after BCNI, and showed a trend towards decrease by NAC treatment. Protein expression of P-VASP-Ser-239 was decreased (P < 0.05) after BCNI, and showed a trend towards increase by NAC treatment. In conclusion, erectile dysfunction following BCNI is mediated in part by S-nitrosylation of eNOS and its downstream signaling mediator GC, while denitrosylation protects erectile function by preserving the NO/cGMP signaling pathway.}, }
@article {pmid29733744, year = {2019}, author = {Berger, M and Wraith, K and Woodward, C and Aburima, A and Raslan, Z and Hindle, MS and Moellmann, J and Febbraio, M and Naseem, KM}, title = {Dyslipidemia-associated atherogenic oxidized lipids induce platelet hyperactivity through phospholipase Cγ2-dependent reactive oxygen species generation.}, journal = {Platelets}, volume = {30}, number = {4}, pages = {467-472}, pmid = {29733744}, issn = {1369-1635}, support = {PG/11/37/28884/BHF_/British Heart Foundation/United Kingdom ; PG/12/49/29441/BHF_/British Heart Foundation/United Kingdom ; PG/13/90/30578/BHF_/British Heart Foundation/United Kingdom ; RG/16/5/32250/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Animals ; Dyslipidemias/*diagnosis/*genetics/pathology ; Humans ; Lipoproteins, LDL/*metabolism ; Mice ; Phospholipase C gamma/*metabolism ; Platelet Activation/*genetics ; Reactive Oxygen Species ; }, abstract = {Oxidized low-density lipoprotein (oxLDL) and associated oxidized phosphocholine-headgroup phospholipids (oxPCs) activate blood platelets through ligation of the scavenger receptor CD36. Previously, we found that oxLDL stimulated phosphorylation of phospholipase Cγ2 (PLCγ2). However, the functional relevance of PLCγ2 phosphorylation in oxLDL-mediated platelet hyperactivity remained elusive. Here, we set out to explore the functional importance of PLCγ2 in oxLDL-mediated platelet activation using human and genetically modified murine platelets. The CD36-specific oxidized phospholipid (oxPCCD36) triggered the generation of reactive oxygen species (ROS) in platelets under static and arterial flow conditions. The ROS generation in response to oxPCCD36 was sustained for up to 3 h but ablated in CD36- and PLCγ2-deficient platelets. The functional importance of ROS generation in response to atherogenic lipid stress was examined through measurement of P-selectin expression. OxPCCD36 induced P-selectin expression, but required up to 60 min incubation, consistent with the timeline for ROS generation. P-selectin expression was not observed in CD36- and PLCγ2-deficient mice. The ability of oxPCCD36 and oxLDL to stimulate P-selectin expression was prevented by incubation of platelets with the ROS scavenger N-acetyl-cysteine (NAC) and the NOX-2 inhibitor gp91ds-tat, but not with the NOX-1 inhibitor ML171. In summary, we provide evidence that prolonged exposure to oxLDL-associated oxidized phospholipids induces platelet activation via NOX-2-mediated ROS production in a CD36- and PLCγ2-dependent manner.}, }
@article {pmid29731195, year = {2018}, author = {Jin, SP and Li, Z and Choi, EK and Lee, S and Kim, YK and Seo, EY and Chung, JH and Cho, S}, title = {Urban particulate matter in air pollution penetrates into the barrier-disrupted skin and produces ROS-dependent cutaneous inflammatory response in vivo.}, journal = {Journal of dermatological science}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jdermsci.2018.04.015}, pmid = {29731195}, issn = {1873-569X}, abstract = {BACKGROUND: Particulate matter (PM) is an integral part of air pollution, which is a mixture of particles suspended in the air. Recently, it has been reported that PM is associated with increased risks of skin diseases, especially atopic dermatitis in children. However, it is unclear if PM directly goes into the skin and what mechanisms are involved in response to PM.<br><br>OBJECTIVE: To see whether PM could penetrate into the barrier-disrupted skin, produce reactive oxygen species (ROS), and elicit an inflammatory response.<br><br>METHODS: We collected PMs during a winter in Seoul and used cultured keratinocytes for in vitro study and tape-stripped BALB/c mice for in vivo study.<br><br>RESULTS: Keratinocyte cytotoxicity increased in a dose-dependent manner by PM treatment. IL-8 and MMP-1 mRNA expression and protein levels were significantly increased compared to control by qPCR and ELISA, respectively. Cellular ROS production was increased by PM treatment, and antioxidant N-acetyl cysteine pretreatment prevented induction of inflammatory cytokines IL-8 and MMP-1. In PM-treated keratinocytes, electron-dense subcellular particles were observed by transmission electron microscopy. PM was observed inside hair follicles in both intact and barrier-disrupted skin in vivo. Additionally, intercellular penetration of PM was seen in the barrier-disrupted skin. Repeated PM application induced epidermal thickening and dermal inflammation with neutrophil infiltration. Finally, N-acetyl cysteine could ameliorate skin inflammation induced by PM application.<br><br>CONCLUSION: PM penetrates into the barrier-disrupted skin, causing inflammation, demonstrating detrimental effects in the skin.}, }
@article {pmid29728968, year = {2018}, author = {Ansari, FA and Khan, AA and Mahmood, R}, title = {Protective effect of carnosine and N-acetylcysteine against sodium nitrite-induced oxidative stress and DNA damage in rat intestine.}, journal = {Environmental science and pollution research international}, volume = {25}, number = {20}, pages = {19380-19392}, pmid = {29728968}, issn = {1614-7499}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Carnosine/*pharmacology ; DNA Damage/*drug effects ; Intestines/drug effects/pathology ; Male ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Rats ; Sodium Nitrite/*toxicity ; }, abstract = {The widespread use of sodium nitrite (NaNO2) as food preservative, rampant use of nitrogenous fertilizers for agricultural practices, and improper disposal of nitrogenous wastes have drastically increased human exposure to high nitrite levels causing various health disorders and death. In the present study, the protective effect of carnosine and N-acetylcysteine (NAC) against NaNO2-induced intestinal toxicity in rats was investigated. Animals were given a single acute oral dose of NaNO2 at 60 mg/kg body weight with or without prior administration of either carnosine at 100 mg/kg body weight/day for 7 days or NAC at 100 mg/kg body weight/day for 5 days. Rats were killed after 24 h, and intestinal preparations were used for the evaluation of biochemical alterations and histological abrasions. Administration of NaNO2 alone decreased the activities of intestinal brush border membrane and metabolic enzymes and significantly weakened the anti-oxidant defense system. DNA damage was also evident as observed by increased DNA-protein crosslinking and fragmentation. However, prior administration of carnosine or NAC significantly ameliorated NaNO2-induced damage in intestinal cells. Histological studies support these biochemical results, showing intestinal damage in NaNO2-treated animals and reduced tissue injury in the combination groups. The intrinsic anti-oxidant properties of carnosine and NAC must have contributed to the observed mitigation of nitrite-induced metabolic alterations and oxidative damage. Based on further validation from clinical trials, carnosine and NAC can potentially be used as chemo-preventive agents against NaNO2 toxicity.}, }
@article {pmid29728112, year = {2018}, author = {Gu, Y and Huang, F and Wang, Y and Chen, C and Wu, S and Zhou, S and Hei, Z and Yuan, D}, title = {Connexin32 plays a crucial role in ROS-mediated endoplasmic reticulum stress apoptosis signaling pathway in ischemia reperfusion-induced acute kidney injury.}, journal = {Journal of translational medicine}, volume = {16}, number = {1}, pages = {117}, pmid = {29728112}, issn = {1479-5876}, support = {2013B051000035//Science and Technology Project of Guangdong Province/International ; 81571926//National Natural Science Foundation of China/International ; 81401628//National Natural Science Foundation of China/International ; 81372090//National Natural Science Foundation of China/International ; 81772127//National Natural Science Foundation of China/International ; 81500493//National Natural Science Foundation of China/International ; 201508030003//Guangzhou Science and Technology Plan/International ; 201607010233//Guangzhou Science and Technology Plan/International ; 17ykpy55//Outstanding Young Teacher Training Program of Sun Yat-sen University/International ; 2015A030313098//Natural Science Foundation of Guangdong Province/International ; }, mesh = {Acetylcysteine/pharmacology ; Acute Kidney Injury/*etiology/*metabolism ; Animals ; *Apoptosis/drug effects ; Connexins/*metabolism ; Endoplasmic Reticulum Chaperone BiP ; *Endoplasmic Reticulum Stress/drug effects ; Epithelial Cells/drug effects/pathology ; Gene Deletion ; Gene Knockout Techniques ; Kidney/pathology ; Male ; Mice, Inbred C57BL ; Phenylbutyrates/pharmacology ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/*complications ; *Signal Transduction/drug effects ; Taurochenodeoxycholic Acid/pharmacology ; Gap Junction beta-1 Protein ; }, abstract = {BACKGROUND: Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) not only prolongs the length of hospital stay, but also seriously affects the patient's survival rate. Although our previous investigation has verified that reactive oxygen species (ROS) transferred through gap junction composed of connexin32 (Cx32) contributed to AKI, its underlying mechanisms were not fully understood and viable preventive or therapeutic regimens were still lacking. Among various mechanisms involved in organs I/R-induced injuries, endoplasmic reticulum stress (ERS)-related apoptosis is currently considered to be an important participant. Thus, in present study, we focused on the underlying mechanisms of I/R-induced AKI, and postulated that Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI.<br><br>METHODS: We established renal I/R models with Cx32[+/+] and Cx32[-/-] mice, which underwent double kidneys clamping and recanalization. ROS scavenger (N-acetylcysteine, NAC) and ERS inhibitors (4-phenyl butyric acid, 4-PBA, and tauroursodeoxycholic acid, TUDCA) were used to decrease the content of ROS and attenuate ERS activation, respectively.<br><br>RESULTS: Renal damage was progressively exacerbated in a time-dependent manner at the reperfusion stage, that was consistent with the alternation of ERS activation, including glucose regulated protein 78 (BiP/GRP78), X box-binding protein1, and C/EBP homologous protein expression. TUDCA or 4-PBA application attenuated I/R-induced ERS activation and protected against renal tubular epithelial cells apoptosis and renal damage. Cx32 deficiency decreased ROS generation and distribution between the neighboring cells, which attenuated I/R-induced ERS activation, and improved cell apoptosis and renal damage.<br><br>CONCLUSION: Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI. Cx32 deficiency, ROS elimination, and ERS inhibition all could protect against I/R-induced AKI.}, }
@article {pmid29726290, year = {2018}, author = {Di Tucci, C and Di Feliciantonio, M and Vena, F and Capone, C and Schiavi, MC and Pietrangeli, D and Muzii, L and Benedetti Panici, P}, title = {Alpha lipoic acid in obstetrics and gynecology.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {34}, number = {9}, pages = {729-733}, doi = {10.1080/09513590.2018.1462320}, pmid = {29726290}, issn = {1473-0766}, mesh = {Abortion, Threatened/prevention &amp; control ; Antioxidants/*pharmacology ; Dietary Supplements ; Female ; Gynecology ; Humans ; Obstetrics ; Oxidative Stress/*drug effects ; Polycystic Ovary Syndrome/metabolism ; Pregnancy ; Thioctic Acid/*pharmacology ; }, abstract = {Alpha-Lipoic acid (ALA) is a natural antioxidant synthetized by plants and animals, identified as a catalytic agent for oxidative decarboxylation of pyruvate and α-ketoglutarate. In this review, we analyzed the action of ALA in gynecology and obstetrics focusing in particular on neuropathic pain and antioxidant and anti-inflammatory action. A comprehensive literature search was performed in PubMed and Cochrane Library for retrieving articles in English language on the antioxidant and anti-inflammatory effects of ALA in gynecological and obstetrical conditions. ALA reduces oxidative stress and insulin resistance in women with polycystic ovary syndrome (PCOS). The association of N-acetyl cysteine (NAC), alpha-lipoic acid (ALA), and bromelain (Br) is used for prevention and treatment of endometriosis. In association with omega-3 polyunsaturated fatty acids (n-3 PUFAs) with amitriptyline is used for treatment of vestibulodynia/painful bladder syndrome (VBD/PBS). A promising area of research is ALA supplementation in patients with threatened miscarriage to improve the subchorionic hematoma resorption. Furthermore, ALA could be used in prevention of diabetic embryopathy and premature rupture of fetal membranes induced by inflamation. In conclusion, ALA can be safely used for treatment of neuropatic pain and as a dietary support during pregnancy.}, }
@article {pmid29715519, year = {2018}, author = {Guo, TZ and Wei, T and Huang, TT and Kingery, WS and Clark, JD}, title = {Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome.}, journal = {The journal of pain}, volume = {19}, number = {10}, pages = {1147-1156}, pmid = {29715519}, issn = {1528-8447}, support = {I01 RX001475/RX/RRD VA/United States ; R01 NS072143/NS/NINDS NIH HHS/United States ; R01 NS072168/NS/NINDS NIH HHS/United States ; R01 NS094438/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology ; Casts, Surgical ; Complex Regional Pain Syndromes/etiology/*physiopathology ; Disease Models, Animal ; Immobilization/adverse effects/methods ; Inflammation/etiology/*physiopathology ; Male ; Oxidative Stress/drug effects/*physiology ; Pain/etiology/*physiopathology ; Rats ; Rats, Sprague-Dawley ; Tibial Fractures/complications/*physiopathology ; }, abstract = {UNLABELLED: Clinical evidence suggests that vitamin C (Vit C) may protect against the development of complex regional pain syndrome (CRPS) after fracture or surgery. Tibia fracture followed by 4 weeks of cast immobilization (fracture/cast) in rats results in nociceptive, vascular, and bone changes resembling clinical CRPS. In this study, fracture/cast rats were treated with the oxidative stress inhibitors Vit C, N-acetyl cysteine, or 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl to examine their effects on CRPS-related nociceptive and vascular changes. Administration of these agents significantly reduced fracture/cast-induced cutaneous allodynia by 64 to 78%, muscle hyperalgesia by 34 to 40%, and hind limb unweighting by 48 to 89%. Treatments with Vit C and N-acetyl cysteine reduced the oxidative stress markers malondialdehyde in the skin, muscle, and sciatic nerve, and lactate in the gastrocnemius muscle of the fracture/cast limb. Furthermore, Vit C treatment inhibited the post-fracture upregulation of substance P and calcitonin gene-related peptide in the sciatic nerve and the increased expression of the pain-related inflammatory mediators, including interleukin (IL)-6, and nerve growth factor in the skin and IL-1β, and IL-6 in the muscle of the post-fracture/cast limb. These data suggest that oxidative stress may contribute to the nociceptive features of the rat CRPS model.<br><br>PERSPECTIVE: Vit C reduced the CRPS-like signs, oxidative stress, and the upregulation of neuropeptide production and inflammatory mediators observed after tibia fracture and casting in rats. Limiting oxidative stress by use of Vit C or alternative strategies could reduce the risk of developing CRPS after surgery or other forms of trauma.}, }
@article {pmid29713994, year = {2018}, author = {Zarbato, GF and de Souza Goldim, MP and Giustina, AD and Danielski, LG and Mathias, K and Florentino, D and de Oliveira Junior, AN and da Rosa, N and Laurentino, AO and Trombetta, T and Gomes, ML and Steckert, AV and Moreira, AP and Schuck, PF and Fortunato, JJ and Barichello, T and Petronilho, F}, title = {Dimethyl Fumarate Limits Neuroinflammation and Oxidative Stress and Improves Cognitive Impairment After Polymicrobial Sepsis.}, journal = {Neurotoxicity research}, volume = {34}, number = {3}, pages = {418-430}, pmid = {29713994}, issn = {1476-3524}, mesh = {Animals ; Catalase/metabolism ; *Cognition Disorders/complications/etiology/therapy ; Cytokines/metabolism ; Dimethyl Fumarate/*therapeutic use ; Disease Models, Animal ; Exploratory Behavior/drug effects ; Glutathione Peroxidase/metabolism ; Immunosuppressive Agents/*therapeutic use ; Inflammation/*drug therapy/*etiology ; Lipid Peroxidation/drug effects ; Male ; Neutrophil Infiltration/drug effects ; Nitrates/metabolism ; Nitrites/metabolism ; Oxidative Stress/*drug effects ; Protein Carbonylation/drug effects ; Rats ; Rats, Wistar ; Recognition, Psychology/drug effects ; Sepsis/*complications ; Superoxide Dismutase/metabolism ; }, abstract = {Sepsis is caused by a dysregulated host response to infection, often associated with acute central nervous system (CNS) dysfunction, which results in long-term cognitive impairment. Dimethyl fumarate (DMF) is an important agent against inflammatory response and reactive species in CNS disorders. Evaluate the effect of DMF on acute and long-term brain dysfunction after experimental sepsis in rats. Male Wistar rats were submitted to the cecal ligation and puncture (CLP) model. The groups were divided into sham (control) + vehicle, sham + NAC, sham + DMF, CLP + vehicle, CLP + NAC, and CLP + DMF. The animals were treated with DMF (15 mg/kg at 0 and 12 h after CLP, per gavage) and the administration of n-acetylcysteine (NAC) (20 mg/kg; 3, 6, and 12 h after CLP, subcutaneously) was used as positive control. Twenty-four hours after CLP, cytokines, myeloperoxidase (MPO), nitrite/nitrate (N/N), oxidative damage to lipids and proteins, and antioxidant enzymes were evaluated in the hippocampus, total cortex, and prefrontal cortex. At 10 days after sepsis induction, behavioral tests were performed to assess cognitive damage. We observed an increase in cytokine levels, MPO activity, N/N concentration, and oxidative damage, a reduction in SOD and GPx activity in the brain structures, and cognitive damage in CLP rats. DMF treatment was effective in reversing these parameters. DMF reduces sepsis-induced neuroinflammation, oxidative stress, and cognitive impairment in rats subjected to the CLP model.}, }
@article {pmid29713542, year = {2018}, author = {Majzoub, A and Agarwal, A}, title = {Systematic review of antioxidant types and doses in male infertility: Benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate.}, journal = {Arab journal of urology}, volume = {16}, number = {1}, pages = {113-124}, pmid = {29713542}, issn = {2090-598X}, abstract = {OBJECTIVE: To explore the current evidence concerning the effect of oral antioxidant supplementation on various male fertility outcomes, as antioxidants are widely available compounds that are commonly used for the treatment of male infertility.<br><br>MATERIALS AND METHODS: PubMed, Medline and Cochrane electronic databases were searched according to a modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines looking for studies investigating the effect of antioxidant therapy on infertile men. The studies were explored looking for antioxidants: (i) types and doses; (ii) mechanism of action and rationale for use; and (iii) effect on the different outcome measures reported.<br><br>RESULTS: In all, 26 studies reported a significant positive effect of antioxidant therapy on basic semen parameters, advanced sperm function, outcomes of assisted reproductive therapy, and live-birth rate. Vitamin E, vitamin C, carnitines, N-acetyl cysteine, co-enzyme Q10, zinc, selenium, folic acid and lycopene were most commonly used. The vitamins' mechanism of action and reported doses is presented in Table 1, Table 2.<br><br>CONCLUSION: Antioxidants generally have a favourable effect on male fertility. Further studies are needed to identify the optimal antioxidant regimen that can be used safely and efficiently in clinical practice.}, }
@article {pmid29709909, year = {2018}, author = {Kim, MY and Bo, HH and Choi, EO and Kwon, DH and Kim, HJ and Ahn, KI and Ji, SY and Jeong, JW and Park, SH and Hong, SH and Kim, GY and Park, C and Kim, HS and Moon, SK and Yun, SJ and Kim, WJ and Choi, YH}, title = {Induction of Apoptosis by Citrus unshiu Peel in Human Breast Cancer MCF-7 Cells: Involvement of ROS-Dependent Activation of AMPK.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {41}, number = {5}, pages = {713-721}, doi = {10.1248/bpb.b17-00898}, pmid = {29709909}, issn = {1347-5215}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/*metabolism ; Caspases/metabolism ; Cell Survival/drug effects ; *Citrus ; Fruit ; Humans ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Plant Extracts/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {The fruit of Citrus unshiu MARKOVICH used for various purposes in traditional medicine has various pharmacological properties including antioxidant, anti-inflammatory, and antibacterial effects. Recently, the possibility of anti-cancer activity of the extracts or components of this fruit has been reported; however, the exact mechanism has not yet been fully understood. In this study, we evaluated the anti-proliferative effect of water extract of C. unshiu peel (WECU) on human breast cancer MCF-7 cells and investigated the underlying mechanism. Our results showed that reduction of MCF-7 cell survival by WECU was associated with the induction of apoptosis. WECU-induced apoptotic cell death was related to the activation of caspase-8 and -9, representative initiate caspases of extrinsic and intrinsic apoptosis pathways, respectively, and increase in the Bax : Bcl-2 ratio accompanied by cleavage of poly(ADP-ribose) polymerase (PARP). WECU also increased the mitochondrial dysfunction and cytosolic release of cytochrome c. In addition, AMP-activated protein kinase (AMPK) and its downstream target molecule, acetyl-CoA carboxylase, were activated in a concentration-dependent manner in WECU-treated cells. In contrast, compound C, an AMPK inhibitor, significantly inhibited WECU-induced apoptosis, while inhibiting increased expression of Bax and decreased expression of Bcl-2 by WECU and inhibition of WECU-induced PARP degradation. Furthermore, WECU provoked the production of reactive oxygen species (ROS); however, the activation of AMKP and apoptosis by WECU were prevented, when the ROS production was blocked by antioxidant N-acetyl cysteine. Therefore, our data indicate that WECU suppresses MCF-7 cell proliferation by activating the intrinsic and extrinsic apoptosis pathways through ROS-dependent AMPK pathway activation.}, }
@article {pmid29708299, year = {2018}, author = {Park, WH and Han, BR and Park, HK and Kim, SZ}, title = {Arsenic trioxide induces growth inhibition and death in human pulmonary artery smooth muscle cells accompanied by mitochondrial O2•- increase and GSH depletion.}, journal = {Environmental toxicology}, volume = {}, number = {}, pages = {}, doi = {10.1002/tox.22569}, pmid = {29708299}, issn = {1522-7278}, abstract = {Arsenic trioxide (ATO; As2 O3) induces cell death in various cells via oxidative stress. Expose to chronic arsenic is involved in the development of vascular diseases. However, little is known about the cytotoxic effects of ATO on human normal vascular smooth muscle cells (VSMCs). Thus, in this study, we investigated the effects of ATO on cell growth and death in human pulmonary artery smooth muscle (HPASM) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. ATO treatment decreased the growth of HPASM cells with an IC50 of ∼30-50 μM at 24 h, and ATO induced HPASM cell death via apoptosis or necrosis dependent on the doses of it at this time. Treatment with 50 μM ATO did not increase ROS levels at the early time points, but it significantly increased mitochondrial O2•- levels at 24 h. ATO also induced GSH depletion in HPASM cells. N-acetyl cysteine (NAC; a well-known antioxidant) did not significantly affect apoptotic cell death, ROS levels, or GSH depletion in ATO-treated HPASM cells. However, l-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) intensified mitochondrial O2•- levels in ATO-treated HPASM cells, and significantly increased cell death and GSH depletion in these cells as well. In summary, we provided the first evidence that ATO inhibited the growth of HPASM cells, and induced apoptotic and/or necrotic cell death in these cells, accompanied by increases in mitochondrial O2•- level and GSH depletion.}, }
@article {pmid29705635, year = {2018}, author = {Shukla, A and Trivedi, SP}, title = {An in vitro analysis of the rat C6 glioma cells to elucidate the linear alkylbenzene sulfonate induced oxidative stress and consequent G2/M phase cell cycle arrest and cellular apoptosis.}, journal = {Chemosphere}, volume = {205}, number = {}, pages = {443-451}, doi = {10.1016/j.chemosphere.2018.04.127}, pmid = {29705635}, issn = {1879-1298}, mesh = {Acetylcysteine/pharmacology ; Alkanesulfonic Acids/*adverse effects ; Animals ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Glioma/*pathology ; Humans ; M Phase Cell Cycle Checkpoints/*drug effects ; Oxidative Stress/*drug effects ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Linear alkylbenzene Sulphonate (LAS) is the anionic surfactant component of globally consumed detergents. Exposure of sub-inhibitory fractions viz., 1/10th (T1), 1/5th (T2), and 1/2.5th (T3) of IC50 for 48 h, of LAS (5 μM, 10 μM, and 20 μM, respectively) to viable C6 glioma cells of rat, besides imparting morphological alterations leads to gross cytotoxicity. Expression of the damaged DNA coupled with cleaved PARP (p < 0.05; p < 0.01 and p < 0.001) were recorded for T1, T2 and T3, respectively. Subsequently, the cell cycle at G2/M check point was significantly arrested (p < 0.05 for T1 and T2; p < 0.01 for T3). The flow cytometric analysis reveals the initiation of apoptosis in C6 cells as is evident by a significant increase (p < 0.01 for T1, p < 0.001 for T2, and T3) in the intake of annexin-V, the calcium dependent apoptotic phospholipid binding protein. Moreover, significantly increased reactive oxygen species (ROS) (p < 0.05; p < 0.01 and p < 0.001) after 6 h of exposure for all the three sets, registered a declining trend (P < 0.001) when T3 cells were co-treated with N-acetyl cysteine (NAC). Furthermore, the significant attenuation (p < 0.01) of expression of the cleaved PARP and a consequent decrease (p < 0.05) in the cell cycle arrest at G2/M phase after scavenging ROS induced oxidative stress by treating C6 cells with NAC clearly evinces that LAS induced apoptosis is mediated by intracellular ROS. Thus, these findings provide a tangible basis for further investigations including in vivo studies, to unravel the molecular mechanism involved in ROS mediated and LAS induced cytotoxic manifestations.}, }
@article {pmid29704993, year = {2018}, author = {Kocyigit, A and Guler, EM and Karatas, E and Caglar, H and Bulut, H}, title = {Dose-dependent proliferative and cytotoxic effects of melatonin on human epidermoid carcinoma and normal skin fibroblast cells.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {829-830}, number = {}, pages = {50-60}, doi = {10.1016/j.mrgentox.2018.04.002}, pmid = {29704993}, issn = {1879-3592}, mesh = {Acetylcysteine/pharmacology ; Carcinoma, Squamous Cell/drug therapy/*metabolism ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; *DNA Damage ; Dose-Response Relationship, Drug ; Fibroblasts/cytology/drug effects/metabolism ; Humans ; Melatonin/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mutagenicity Tests ; Reactive Oxygen Species/metabolism ; Single-Cell Analysis/*methods ; Skin/*cytology/drug effects/metabolism ; }, abstract = {New in vitro studies have demonstrated that N-acetyl-5-methoxytryptamine (Melatonin) has cytotoxic and apoptotic effects on various cell types although most of the previous investigations document that it is a potent antioxidant. However, the precise molecular mechanism(s) of its effects are not fully elucidated. In this study, we examined dose-dependent cytotoxic, genotoxic, apoptotic and reactive oxygen species (ROS) generating effects of melatonin in human epidermoid carcinoma cells (A-431) and human normal skin fibroblastic cells (CCD-1079Sk). The cells were incubated with different doses of melatonin (0.031-5 mM) for 24 h. Cell viability was assessed based on luminometric ATP cell viability assay. Intracellular ROS was detected using 2,7-dichlorodihydrofluorescein-diacetate (H2DCF-DA) fluorescent probes. Genotoxicity was evaluated by alkaline single cell gel electrophoresis assay (Comet Assay). Apoptosis was evaluated by western blotting, DAPI staining, acridine orange/ethidium bromide and Annexin V-FITC/propidium iodide double staining methods Mitochondrial membrane potentials were measured by flow cytometry. Although lower doses of melatonin (0.031-0.06 mM) increased cell proliferation and decreased ROS generation, higher doses (0.125-5 mM) markedly inhibited the cell viability, induced DNA damage, apoptosis and ROS generation. Cytotoxic, genotoxic, apoptotic and ROS generating effects were significantly higher in cancer cells than those observed in normal cells. Melatonin-induced cell death, and ROS generating activity were effectively inhibited by N-acetyl-l-cysteine (NAC) In conclusion, at low doses, melatonin has proliferative effects on both cancer and normal cells, whereas high concentrations have cytotoxic effects. Cytotoxic, genotoxic and apoptotic effects at higher doses of melatonin may be due to its ROS production capacity.}, }
@article {pmid29704590, year = {2018}, author = {Yawalkar, R and Changotra, H and Gupta, GL}, title = {Protective influences of N-acetylcysteine against alcohol abstinence-induced depression by regulating biochemical and GRIN2A, GRIN2B gene expression of NMDA receptor signaling pathway in rats.}, journal = {Neurochemistry international}, volume = {118}, number = {}, pages = {73-81}, doi = {10.1016/j.neuint.2018.04.011}, pmid = {29704590}, issn = {1872-9754}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alcohol Abstinence/*psychology ; Animals ; Brain/drug effects/metabolism ; Depression/drug therapy/genetics/*metabolism/*psychology ; Dose-Response Relationship, Drug ; Gene Expression ; Male ; Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/*biosynthesis/genetics ; Signal Transduction/drug effects/physiology ; }, abstract = {Evidences have indicated a high degree of comorbidity of alcoholism and depression. N-acetylcysteine (NAC) has shown its clinical efficiency in the treatment of several psychiatric disorders and is identified as a multi-target acting drug. The ability of NAC to prevent alcohol abstinence-induced depression-like effects and underlying mechanism(s) have not been adequately addressed. This study was aimed to investigate the beneficial effects of NAC in the alcohol abstinence-induced depression developed following long-term voluntary alcohol intake. For evaluation of the effects of NAC, Sprague-Dawley rats were enabled to voluntary drinking of 4.5%, 7.5% and 9% v/v alcohol for fifteen days. NAC (25, 50, and 100 mg/kg) and fluoxetine (5 mg/kg) were injected intraperitoneally for three consecutive days during the alcohol abstinence period on the days 16, 17, 18. The behavioral studies were conducted employing forced swim test (FST), and tail suspension test (TST) on day 18 to determine the effects of N-acetylcysteine and fluoxetine in the ethanol withdrawal induced-depression. Blood alcohol concentration, alcohol biomarkers like SGPT, SGOT, ALP, GGT, and MCV were estimated by using commercially available kits. Serotonin concentrations were measured in the plasma, hippocampus and pre-frontal cortex using the rat ELISA kit. The expression of GRIN1, GRIN2A, GRIN2B genes for the N-methyl d-aspartate receptors (NMDAR) subunits in the hippocampus and the prefrontal cortex were also examined by reverse-transcription quantitative polymerase chain reaction. The results revealed that alcohol abstinence group depicted increased immobility time in FST and TST. Further, NAC exerted significant protective effect at the doses 50 mg/kg and 100 mg/kg, but 25 mg/kg showed insignificant protection against alcohol abstinence-induced depression. The increased level of biochemical parameters following ethanol abstinence were also reversed by NAC at the dose of 100 mg/kg. The significant reversal effect of NAC on the serotonin level following alcohol abstinence was greater in the hippocampus as compared to the third-day alcohol withdrawal group. The increased expression levels of GRIN2A and GRIN2B following ethanol abstinence were reversed with a higher dose of NAC (100 mg/kg) treatment. In conclusion, the results of the study reveal that NAC has remarkable protective effects in the alcohol abstinence-induced depression by modulating alcohol markers, serotonin levels and GRIN2A, GRIN2B gene expression of NMDAR signaling pathway in rats.}, }
@article {pmid29698568, year = {2018}, author = {Duryee, MJ and Dusad, A and Hunter, CD and Kharbanda, KK and Bruenjes, JD and Easterling, KC and Siebler, JC and Thiele, GM and Chakkalakal, DA}, title = {N-Acetyl Cysteine Treatment Restores Early Phase Fracture Healing in Ethanol-Fed Rats.}, journal = {Alcoholism, clinical and experimental research}, volume = {42}, number = {7}, pages = {1206-1216}, pmid = {29698568}, issn = {1530-0277}, support = {I21 RX000353/RX/RRD VA/United States ; R01 AA026723/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dose-Response Relationship, Drug ; Ethanol/administration &amp; dosage/*toxicity ; Femur/*drug effects/*injuries/metabolism ; Fracture Healing/*drug effects/physiology ; Inflammation Mediators/antagonists &amp; inhibitors/metabolism ; Male ; Rats ; Rats, Wistar ; Treatment Outcome ; }, abstract = {BACKGROUND: Fracture healing in alcoholics is delayed and often associated with infections resulting in prolonged rehabilitation. It has been reported that binge drinking of alcohol increases oxidative stress and delays fracture healing in rats, which is prevented by treatment with the antioxidant n-acetyl cysteine (NAC). Oxidative stress is a significant factor in pathologies of various organs resulting from chronic alcoholism. Therefore, we hypothesize that treatment with NAC reduces oxidative stress and restores fracture healing in chronic alcoholics.<br><br>METHODS: Rats (10&#xa0;months old) were pair-fed the Lieber-DeCarli ethanol (EtOH) diet or control diet for 16&#xa0;weeks. A closed fracture was performed and rats allowed to recover for 72&#xa0;hours. Rats were divided into 4 groups-control, control&#xa0;+&#xa0;NAC, EtOH, and EtOH&#xa0;+&#xa0;NAC-and injected intraperitoneally with 200&#xa0;mg/kg of NAC daily for 3&#xa0;days. Serum and bone fracture callus homogenates were collected and assayed for traditional markers of inflammation, oxidative stress, and bone regeneration.<br><br>RESULTS: The oxidative stress marker malondialdehyde (MDA) was increased in both serum and bone tissue in EtOH-fed animals compared to controls. NAC treatment significantly (p&#xa0;<&#xa0;0.01) reduced MDA to near normal levels and dramatically increased the index of antioxidant efficacy (catalase/MDA ratio) (p&#xa0;<&#xa0;0.01). Inflammatory markers tumor necrosis factor-&#x3b1;, interferon-&#x3b3;, and interleukin-6 were significantly decreased in serum and callus following NAC treatment. NAC treatment reduced EtOH-induced bone resorption as evidenced by significant decreases in C-telopeptide of type-I-collagen levels (p&#xa0;<&#xa0;0.05) and band-5 tartrate-resistant acid phosphatase levels in the tissue (p&#xa0;<&#xa0;0.001).<br><br>CONCLUSIONS: Oxidative stress and excessive inflammation are involved in the inhibition of fracture healing by EtOH. In this study, early short-term treatment of EtOH-fed animals with the antioxidant NAC reduced oxidative stress and normalized the innate immune response to fracture in the early phase of fracture healing, thereby restoring the normal onset of bone regeneration.}, }
@article {pmid29697170, year = {2018}, author = {Powell, CR and Dillon, KM and Wang, Y and Carrazzone, RJ and Matson, JB}, title = {A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {57}, number = {21}, pages = {6324-6328}, pmid = {29697170}, issn = {1521-3773}, support = {R01 GM123508/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Cell Survival/drug effects ; Hydrogen Peroxide/pharmacology ; Molecular Structure ; Myocytes, Cardiac/drug effects/metabolism ; Oxidation-Reduction ; Rats ; Reactive Oxygen Species/chemistry/*metabolism ; Sulfides/chemistry/*metabolism/pharmacology ; }, abstract = {Persulfides (RSSH) have been hypothesized as critical components in sulfur-mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H2 S). Hindering the study of persulfides is a lack of persulfide-donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS-responsive (ROS=reactive oxygen species), self-immolative persulfide donor. The donor, termed BDP-NAC, showed selectivity towards H2 O2 over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N-acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H2 O2 revealed that BDP-NAC mitigated the effects of a highly oxidative environment in a dose-dependent manner over relevant controls and to a greater degree than common H2 S donors sodium sulfide (Na2 S) and GYY4137. BDP-NAC also rescued cells more effectively than a non-persulfide-releasing control compound in concert with common H2 S donors and thiols.}, }
@article {pmid29693189, year = {2018}, author = {Sánchez-Carranza, JN and Díaz, JF and Redondo-Horcajo, M and Barasoain, I and Alvarez, L and Lastres, P and Romero-Estrada, A and Aller, P and González-Maya, L}, title = {Gallic acid sensitizes paclitaxel-resistant human ovarian carcinoma cells through an increase in reactive oxygen species and subsequent downregulation of ERK activation.}, journal = {Oncology reports}, volume = {39}, number = {6}, pages = {3007-3014}, doi = {10.3892/or.2018.6382}, pmid = {29693189}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; *Down-Regulation ; Drug Resistance, Neoplasm/*drug effects ; Drug Synergism ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; G2 Phase Cell Cycle Checkpoints ; Gallic Acid/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Ovarian Neoplasms/drug therapy/*metabolism ; Paclitaxel/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Paclitaxel (PTX) is currently used as a front-line chemotherapeutic agent for several types of cancer, including ovarian carcinoma; however, PTX-resistance frequently arises through multiple mechanisms. The development of new strategies using natural compounds and PTX in combination has been the aim of several prior studies, in order to enhance the efficacy of chemotherapy. In this study, we found the following: (i) gallic acid (GA), a phenolic compound, potentiated the capacity of PTX to decrease proliferation and to cause G2/M cycle arrest in the PTX-resistant A2780AD ovarian cancer cell line; (ii) GA exerted a pro-oxidant action by increasing the production of reactive oxygen species (ROS), and co-treatment with the antioxidant agent N‑acetyl-L‑cysteine (NAC) prevented GA+PTX-induced cell proliferation inhibition and G2/M phase arrest; (iii) PTX stimulated ERK phosphorylation/activation, and co-treatment with the MEK/ERK inhibitor PD98049 potentiated the proliferation inhibition and G2/M phase arrest; (iv) and finally, GA abrogated the PTX-induced stimulation of ERK phosphorylation, a response that was prevented by co-treatment with NAC. Taken together, these results indicate that GA sensitizes PTX-resistant ovarian carcinoma cells via the ROS‑mediated inactivation of ERK, and suggest that GA could represent a useful co-adjuvant to PTX in ovarian carcinoma treatment.}, }
@article {pmid29692782, year = {2018}, author = {Luan, J and Zhang, X and Wang, S and Li, Y and Fan, J and Chen, W and Zai, W and Wang, S and Wang, Y and Chen, M and Meng, G and Ju, D}, title = {NOD-Like Receptor Protein 3 Inflammasome-Dependent IL-1β Accelerated ConA-Induced Hepatitis.}, journal = {Frontiers in immunology}, volume = {9}, number = {}, pages = {758}, pmid = {29692782}, issn = {1664-3224}, mesh = {Animals ; Concanavalin A/toxicity ; Hepatitis, Autoimmune/*immunology/metabolism/pathology ; Inflammasomes/*immunology/metabolism ; Interleukin-1beta/*immunology/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein/*immunology/metabolism ; }, abstract = {Autoimmune hepatitis (AIH) is a progressive inflammatory disorders of unknown etiology, characterized by immune-mediated destruction of hepatocytes and massive production of cytokines. Interleukin-1β is a pleiotropic proinflammatory cytokine and well known to be critical in a variety of autoimmune diseases. However, the role of interleukin-1β (IL-1β) in AIH is still indistinct. Here, we first investigated the significance of NOD-like receptor protein 3 (NLRP3) inflammasome-dependent IL-1β in the pathogenesis of AIH with a murine model of immune-mediated hepatitis induced by Concanavalin A (ConA). In ConA-treated mice, pathogenic elevated NLRP3, Cleaved caspase-1 and IL-1β levels, as well as an inflammatory cell death known as pyroptosis predominantly occurred in the livers. Strikingly, NLRP3[-/-] and caspase-1[-/-] mice were broadly protected from hepatitis as determined by decreased histological liver injury, serum aminotransferase (ALT)/aspartate transaminase levels, and pyroptosis. In vivo intervention with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) strongly suppressed ConA-induced hepatitis by decreasing tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) secretion, and inflammatory cell infiltration into livers. Additionally, rhIL-1Ra-pretreated mice developed significantly reduced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation. Scavenging of ROS by N-acetyl-cysteine also attenuated NLRP3 inflammasome activation and liver inflammation, indicating that the essential role of ROS in mediating NLRP3 inflammasome activation in ConA-induced hepatitis. In conclusion, our results demonstrated that NLRP3 inflammasome-dependent IL-1β production was crucial in the pathogenesis of ConA-induced hepatitis, which shed light on the development of promising therapeutic strategies for AIH by blocking NLRP3 inflammasome and IL-1β.}, }
@article {pmid29691026, year = {2018}, author = {Wu, SW and Liu, X and Miller, AL and Cheng, YS and Yeh, ML and Lu, L}, title = {Strengthening injectable thermo-sensitive NIPAAm-g-chitosan hydrogels using chemical cross-linking of disulfide bonds as scaffolds for tissue engineering.}, journal = {Carbohydrate polymers}, volume = {192}, number = {}, pages = {308-316}, pmid = {29691026}, issn = {1879-1344}, support = {R01 AR056212/AR/NIAMS NIH HHS/United States ; }, mesh = {Acrylic Resins/*chemistry ; Animals ; Biocompatible Materials/*chemistry/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chitosan/*chemistry ; Disulfides/*chemistry ; Hydrogels/*chemistry ; Injections ; Mice ; NIH 3T3 Cells ; Temperature ; *Tissue Engineering ; Tissue Scaffolds/*chemistry ; }, abstract = {In the present study, we fabricated non-toxic, injectable, and thermo-sensitive NIPAAm-g-chitosan (NC) hydrogels with thiol modification for introduction of disulfide cross-linking strategy. Previously, NIPAAm and chitosan copolymer has been proven to have excellent biocompatibility, biodegradability and rapid phase transition after injection, suitable to serve as cell carriers or implanted scaffolds. However, weak mechanical properties significantly limit their potential for biomedical fields. In order to overcome this issue, we incorporated thiol side chains into chitosan by covalently conjugating N-acetyl-cysteine (NAC) with carbodiimide chemistry to strengthen mechanical properties. After oxidation of thiols into disulfide bonds, modified NC hydrogels did improve the compressive modulus over 9 folds (11.4 kPa). Oscillatory frequency sweep showed a positive correlation between storage modulus and cross-liking density as well. Additionally, there was no cytotoxicity observed to mesenchymal stem cells, fibroblasts and osteoblasts. We suggested that the thiol-modified thermo-sensitive polysaccharide hydrogels are promising to be a cell-laden biomaterial for tissue regeneration.}, }
@article {pmid29688786, year = {2018}, author = {Kimmitt, BA and Moore, GE and Stiles, J}, title = {Comparison of the efficacy of various concentrations and combinations of serum, ethylenediaminetetraacetic acid, tetracycline, doxycycline, minocycline, and N-acetylcysteine for inhibition of collagenase activity in an in vitro corneal degradation model.}, journal = {American journal of veterinary research}, volume = {79}, number = {5}, pages = {555-561}, doi = {10.2460/ajvr.79.5.555}, pmid = {29688786}, issn = {1943-5681}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Anti-Bacterial Agents/*administration &amp; dosage ; Collagenases/chemistry ; Cornea/*drug effects ; Corneal Diseases/*prevention &amp; control ; Disease Models, Animal ; Dogs ; Doxycycline/*administration &amp; dosage ; Edetic Acid/*administration &amp; dosage ; Horses ; Matrix Metalloproteinase Inhibitors/*administration &amp; dosage ; Minocycline/*administration &amp; dosage ; Serum/*chemistry ; Tetracycline/*administration &amp; dosage ; }, abstract = {OBJECTIVE To compare the efficacy of various concentrations and combinations of serum, EDTA, 3 tetracyclines, and N-acetylcysteine (NAC) for collagenase inhibition in an in vitro corneal degradation model. SAMPLE Grossly normal corneas from recently euthanized dogs and horses and fresh serum from healthy dogs and horses. PROCEDURES Serum was pooled by species for in vitro use. For each species, sections of cornea were dried, weighed, and incubated with clostridial collagenase (800 U/mL) in 5 mL of a 5mM calcium chloride-saline (0.9% NaCl) incubation solution and 500 μL of 1 of 19 treatments (homologous serum; 0.3%, 1.0%, or 2% EDTA; 0.1%, 0.5%, or 1.0% tetracycline, doxycycline, or minocycline; 0.5%, 1.0%, or 5.0% NAC; serum with 0.5% tetracycline; serum with 1.0% EDTA; or 1.0% EDTA with 0.5% tetracycline). Positive and negative control specimens were incubated with 5 mL of incubation solution with and without collagenase, respectively. Each control and treatment was replicated 4 times for each species. Following incubation, corneal specimens were dried and reweighed. The percentage corneal degradation was calculated and compared among treatments within each species. RESULTS Treatments with tetracyclines at concentrations ≥ 0.5%, with EDTA at concentrations ≥ 0.3%, and with NAC at concentrations ≥ 0.5% were more effective at preventing corneal degradation than serum in both species. The efficacy of each combination treatment was equal to or less than that of its components. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested EDTA, tetracyclines, and NAC may be beneficial for topical treatment of keratomalacia, but in vivo studies are required.}, }
@article {pmid29687671, year = {2018}, author = {Muñoz Romo, R and M Borobia Pérez, A and A Muñoz, M and Carballo Cardona, C and Cobo Mora, J and Carcas Sansuán, AJ}, title = {Efficient diagnosis and treatment of acute paracetamol poisoning: cost-effectiveness analysis of approaches based on a hospital toxicovigilance program.}, journal = {Emergencias : revista de la Sociedad Espanola de Medicina de Emergencias}, volume = {30}, number = {3}, pages = {169-176}, pmid = {29687671}, issn = {2386-5857}, mesh = {Acetaminophen/*poisoning ; Acute Disease ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Non-Narcotic/*poisoning ; *Cost-Benefit Analysis ; Decision Trees ; Emergency Service, Hospital/economics ; Female ; Hospitals, University/economics ; Humans ; Male ; Middle Aged ; Nomograms ; Pharmacovigilance ; Poisoning/*diagnosis/economics/*therapy ; Sensitivity and Specificity ; Spain ; Tertiary Care Centers/economics ; }, abstract = {OBJECTIVES: To evaluate 5 diagnostic-therapeutic strategies for suspected acute paracetamol poisoning in terms of cost-effectiveness in a tertiary university hospital with an active, validated poisoning surveillance program (SAT-HULP).<br><br>MATERIAL AND METHODS: Cost-effectiveness analysis of the 5 diagnostic-therapeutic alternatives considered when attending patients with suspected paracetamol poisoning. The alternatives were chosen by means of a decision tree. We studied patients detected by the SAT-HULP program between April 1, 2011, and January 31, 2015. The diagnostic-therapeutic alternatives were as follows: 1) systematic treatment of all patients with N-acetylcysteine (NAC), 2) NAC treatment according to the reported dose; 3) NAC treatment according to a R&#xfc;mack-Matthew nomogram; 4) NAC treatment according to urine test results confirmed by a blood test, and 5) treatment according to elimination half-life calculation. Probability data were obtained from the SAT-HULP program and validation studies corresponding to the diagnostic tests. Deterministic and probabilistic sensitivity analyses were performed.<br><br>RESULTS: The approaches that were most cost-effective were those guided by reported doses and nomograms. The incremental cost-effectiveness of treatment according to reported dose was &#x20ac;5985.37. The sensitivity analysis showed that the model was highly dependent on variations in the main variables; the probabilistic sensitivity analysis indicated an incremental cost-effectiveness of &#x20ac;25 111.06 (SD, &#x20ac;1 534 420.16; range, &#x20ac;42 136.03-&#x20ac;92 358.75) between the first approach (treat all cases) and last (calculate elimination half-life); half-life calculation was the more efficient.<br><br>CONCLUSION: Treating according to nomogram was the most efficient diagnostic-therapeutic approach to treating paracetamol poisoning in our hospital. However, when the prevalence of paracetamol poisoning is higher and uncertainty is greater, it would be more efficient to treat based on calculating the half-life.}, }
@article {pmid29686303, year = {2018}, author = {Puyo, CA and Earhart, A and Staten, N and Huang, Y and Desai, A and Lai, H and Venkatesh, R}, title = {Mitochondrial DNA induces Foley catheter related bladder inflammation via Toll-like receptor 9 activation.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {6377}, pmid = {29686303}, issn = {2045-2322}, mesh = {Animals ; Catheters/*adverse effects ; Cells, Cultured ; Cystitis/*etiology/metabolism/pathology ; Cytokines/genetics/metabolism ; DNA, Mitochondrial/genetics/*metabolism ; Female ; Inflammation/*etiology/metabolism/pathology ; NF-kappa B/genetics/metabolism ; Neutrophil Activation ; Neutrophils/*immunology/metabolism/pathology ; Signal Transduction ; Swine ; Toll-Like Receptor 9/genetics/*metabolism ; Urinary Bladder/*immunology/injuries/pathology ; }, abstract = {Bladder instrumentation engages the innate immune system via neutrophil activation, promoting inflammation and pain. Elevated levels of mitochondrial DNA (mtDNA) have been associated with tissue damage and organ dysfunction. We hypothesized that local bladder trauma induced by a Foley catheter (FC) will result in mtDNA release, migration of neutrophils into the bladder lumen, and activation of the Toll-like receptor 9 (TLR9) and nuclear factor kappa B (NF-κB) pathway leading to bladder tissue damage. We randomized 10 swine into two groups receiving uncoated, or chloroquine/N-Acetylcysteine (CQ/NAC)-coated FCs. Urine samples were analyzed for mtDNA activation of TLR9/NF-κB as demonstrated by indicators of neutrophil adhesion, migration, and activation. We found that uncoated FCs resulted in a unique active neutrophil phenotype that correlated with bladder epithelial injury, neutrophilia, necrosis, mtDNA release, TLR9/NF-κB activation, transcription and secretion of pro-inflammatory cytokines, and enhanced respiratory burst. In our study we observed that the high levels of mtDNA and elevated TLR9/NF-κB activity were ameliorated in the CQ/NAC-coated FC group. These findings suggest that post-migrated bladder luminal neutrophils are involved in local tissue damage and amelioration of the mtDNA/TLR9/NF-κB inflammatory axis may represent a therapeutic target to prevent inflammation, and bladder tissue injury.}, }
@article {pmid29684906, year = {2018}, author = {Douša, M}, title = {The determination of pharmaceutically active thiols using hydrophilic interaction chromatography followed postcolumn derivatization with o-phthaldialdehyde and fluorescence detection.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {156}, number = {}, pages = {1-7}, doi = {10.1016/j.jpba.2018.04.007}, pmid = {29684906}, issn = {1873-264X}, mesh = {Acetonitriles/chemistry ; Acetylcysteine/analysis ; Captopril/analysis ; Chromatography, High Pressure Liquid/methods ; Cysteine/analysis ; Hydrophobic and Hydrophilic Interactions ; Propylamines ; Spectrometry, Fluorescence ; Sulfhydryl Compounds/*analysis/chemistry ; Temperature ; o-Phthalaldehyde/*chemistry ; }, abstract = {A rapid, precise and specific hydrophilic interaction chromatography (HILIC) combined with postcolumn derivatization using o-phthaldialdehyde and fluorescence detection was developed and validated for the determination of selected pharmaceutically active thiols. The analysis was carried out on a Diol HILIC column using a mobile phase consisting of acetonitrile and solution of 10 mmol/L citric acid adjusted with 1-propylamine to pH 5.5 in ratio 75:25 (v/v) for separation of cysteine and homocysteine and in ratio 85:15 (v/v) for separation of N-acetyl-l-cysteine and captopril. The postcolumn derivatization reaction was performed at room temperature using reagent (5 mmol/L OPA in 0.05 mol/L 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid at pH 7) delivered at the flow rate of 0.3 mL/min. Fluorescence detection was carried out at excitation and emission wavelength of 345 nm and 450 nm, respectively. The effect of chromatographic conditions including acetonitrile content, salt concentration in the mobile phase and mobile phase pH on the retention of tested thiols was investigated. The postcolumn reaction conditions such as reaction temperature, derivatization reagent flow rate, o-phthaldialdehyde concentration and derivatization reagent pH were deeply studied. The developed method was validated in terms of linearity, accuracy, precision and selectivity according to the International Conference on Harmonisation guidelines. The HILIC method was successfully applied for the analysis of commercially available samples of pharmaceutically active thiols such as captopril, N-acetyl-l-cysteine (NAC) and cysteine.}, }
@article {pmid29684820, year = {2018}, author = {Hou, D and Liu, Z and Xu, X and Liu, Q and Zhang, X and Kong, B and Wei, JJ and Gong, Y and Shao, C}, title = {Increased oxidative stress mediates the antitumor effect of PARP inhibition in ovarian cancer.}, journal = {Redox biology}, volume = {17}, number = {}, pages = {99-111}, pmid = {29684820}, issn = {2213-2317}, mesh = {Animals ; Cell Line, Tumor ; DNA Damage/drug effects ; DNA Repair/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice ; NADPH Oxidase 1/antagonists &amp; inhibitors/*genetics ; NADPH Oxidase 4/antagonists &amp; inhibitors/*genetics ; Ovarian Neoplasms/*drug therapy/genetics/pathology ; Oxidative Stress/drug effects ; Poly (ADP-Ribose) Polymerase-1/antagonists &amp; inhibitors/*genetics ; Poly(ADP-ribose) Polymerase Inhibitors/administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Tissue Array Analysis ; Xenograft Model Antitumor Assays ; }, abstract = {PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS). Importantly, antioxidant N-acetylcysteine (NAC) significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells.}, }
@article {pmid29683755, year = {2018}, author = {Modarresi, A and Nafar, M and Sahraei, Z and Salamzadeh, J and Chaibakhsh, S and Ziaie, S and Parvin, M and Panahi, Y and Einollahi, B}, title = {N-acetylcysteine decreases urinary level of neutrophil gelatinase-associated lipocalin in deceased-donor renal transplant recipients: a randomized clinical trial.}, journal = {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals}, volume = {23}, number = {6}, pages = {589-596}, doi = {10.1080/1354750X.2018.1468823}, pmid = {29683755}, issn = {1366-5804}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/diagnosis/etiology/urine ; Adult ; Biomarkers/*urine ; Delayed Graft Function/physiopathology/prevention &amp; control ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Humans ; Kidney Transplantation/adverse effects/*methods ; Lipocalin-2/*urine ; Male ; Middle Aged ; Tissue Donors ; }, abstract = {CONTEXT: Acute kidney injury (AKI) is a common complication after kidney transplantation (KT), especially in recipients from deceased donors. Urinary neutrophil gelatinase-associated lipocalin (u-NGAL) is an early and sensitive marker of AKI after transplantation.<br><br>OBJECTIVES: We assessed the renoprotective effect of N-acetylcysteine (NAC) on u-NGAL levels as an early prognostic marker of graft function immediately after transplantation.<br><br>MATERIALS AND METHODS: A double-blind, randomized, placebo-controlled trial was conducted on 70 deceased-donor KT recipients (www.irct.ir , trial registration number: IRCT2014090214693N4). Patients received 600&#x2009;mg oral NAC or placebo twice daily from day 0 to 5 and urine samples were taken before, and on the first and fifth days after transplantation. U-NGAL and early graft function were compared between the two groups.<br><br>RESULTS: NAC significantly reduced u-NGAL levels compared to placebo (p value&#x2009;=&#x2009;0.02), while improvement in early graft function with NAC did not reach statistical significance.<br><br>CONCLUSIONS: This study showed that NAC administration in deceased-donor KT recipients can reduce tubular kidney injury, evidenced by u-NGAL measurements. Improvement in early graft function needs a larger sample size to reach a statistical conclusion.}, }
@article {pmid29682727, year = {2018}, author = {Kim, WH and Hur, M and Park, SK and Jung, DE and Kang, P and Yoo, S and Bahk, JH}, title = {Pharmacological interventions for protecting renal function after cardiac surgery: a Bayesian network meta-analysis of comparative effectiveness.}, journal = {Anaesthesia}, volume = {73}, number = {8}, pages = {1019-1031}, doi = {10.1111/anae.14227}, pmid = {29682727}, issn = {1365-2044}, mesh = {Acute Kidney Injury/*etiology/*prevention &amp; control ; Bayes Theorem ; Cardiac Surgical Procedures/*adverse effects ; Humans ; Network Meta-Analysis ; Postoperative Complications/*prevention &amp; control ; }, abstract = {Many drugs have been investigated as potentially protective of renal function after cardiac surgery. However, their comparative effectiveness has not been established. We performed an arm-based hierarchical Bayesian network meta-analysis including 95 randomised controlled trials with 28,833 participants, which allowed us to compare some agents not previously compared directly. Renal outcomes, including: the incidence of postoperative renal dysfunction and haemodialysis; serum creatinine level at 24 hours postoperatively; all-cause mortality; and length of hospital and ICU stay, were compared. Exploratory meta-regression was conducted for potential effect modifiers. A random effects model was selected according to the evaluation of model fit by deviance information criteria. Atrial natriuretic peptide (odds ratio (95%CrI) 0.28 (0.17-0.48); moderate-quality evidence), B-type natriuretic peptide, dexmedetomidine, levosimendan and N-acetyl cysteine significantly decreased the rate of postoperative renal dysfunction compared with placebo. Atrial natriuretic peptide (OR (95%CrI) 0.24 (0.10-0.58); low-quality evidence), B-type natriuretic peptide, and dexamethasone significantly decreased the need for haemodialysis. Levosimendan significantly decreased mortality, OR (95%CrI) 0.49 (0.27-0.91); low-quality evidence). The benefit of atrial natriuretic peptide was still apparent when baseline renal function was normal. None of the potential effect modifiers were significantly correlated with our renal outcomes. Atrial natriuretic peptide was ranked best regarding renal dysfunction, haemodialysis and length of hospital stay. Levosimendan was ranked best regarding mortality and ICU stay. However, our results should be interpreted cautiously given the assumptions made about transitivity and consistency.}, }
@article {pmid29682647, year = {2018}, author = {Xiao, K and Liu, Q and Al Awwad, N and Zhang, H and Lai, L and Luo, Y and Lee, JS and Li, Y and Lam, KS}, title = {Reversibly disulfide cross-linked micelles improve the pharmacokinetics and facilitate the targeted, on-demand delivery of doxorubicin in the treatment of B-cell lymphoma.}, journal = {Nanoscale}, volume = {10}, number = {17}, pages = {8207-8216}, pmid = {29682647}, issn = {2040-3372}, support = {R01 CA115483/CA/NCI NIH HHS/United States ; P30 CA093373/CA/NCI NIH HHS/United States ; R01 EB012569/EB/NIBIB NIH HHS/United States ; R01 HD086195/HD/NICHD NIH HHS/United States ; R01 CA199668/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antibiotics, Antineoplastic/*pharmacokinetics ; Cell Line, Tumor ; Disulfides/chemistry ; Doxorubicin/*pharmacokinetics ; *Drug Delivery Systems ; Female ; Humans ; Lymphoma, B-Cell/*drug therapy ; Mice, Inbred BALB C ; Mice, Nude ; *Micelles ; Nanoparticles ; Tissue Distribution ; Xenograft Model Antitumor Assays ; }, abstract = {Doxorubicin (DOX) is commonly used to treat human malignancies, and its efficacy can be maximized by limiting the cardiac toxicity when combined with nanoparticles. Here, we reported a unique type of reversibly disulfide cross-linked micellar formulation of DOX (DOX-DCMs) for the targeted therapy of B-cell lymphoma. DOX-DCMs exhibited high drug loading capacity, optimal particle sizes (15-20 nm), outstanding stability in human plasma, and stimuli-responsive drug release profile under reductive conditions. DOX-DCMs significantly improved the pharmacokinetics of DOX, and its elimination half-life (t1/2) and area under curve (AUC) were 5.5 and 12.4 times of that of free DOX, respectively. Biodistribution studies showed that DOX-DCMs were able to preferentially accumulate in the tumor site and significantly reduce the cardiac uptake of DOX. In a xenograft model of human B-cell lymphoma, compared with the equivalent dose of free DOX and non-crosslinked counterpart, DOX-DCMs not only significantly inhibited the tumor growth and prolonged the survival rate, but also remarkably reduced DOX-associated cardiotoxicity. Furthermore, the exogenous administration of N-acetylcysteine (NAC) at 24 h further improved the therapeutic efficacy of DOX-DCMs, which provides a "proof-of-concept" for precise drug delivery on-demand, and may have great translational potential as future cancer nano-therapeutics.}, }
@article {pmid29680280, year = {2018}, author = {Yellepeddi, VK and Mohammadpour, R and Kambhampati, SP and Sayre, C and Mishra, MK and Kannan, RM and Ghandehari, H}, title = {Pediatric oral formulation of dendrimer-N-acetyl-l-cysteine conjugates for the treatment of neuroinflammation.}, journal = {International journal of pharmaceutics}, volume = {545}, number = {1-2}, pages = {113-116}, pmid = {29680280}, issn = {1873-3476}, support = {R01 HD076901/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/chemistry/pharmacokinetics ; Administration, Oral ; Age Factors ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage/chemistry/pharmacology ; Area Under Curve ; Caco-2 Cells ; Caprylates/chemistry ; Dendrimers/*chemistry ; *Drug Carriers ; Drug Compounding ; Drug Stability ; Glycerides/chemistry ; Humans ; Intestinal Absorption ; Intestinal Mucosa/metabolism ; Male ; Permeability ; Rats, Sprague-Dawley ; Technology, Pharmaceutical/methods ; }, abstract = {N-Acetyl-l-cysteine (NAC) commonly used as an antidote in acetaminophen poisoning has shown promise in the treatment of neurological disorders such as cerebral palsy (CP). However, NAC suffers from drawbacks such as poor oral bioavailability and suboptimal blood-brain-barrier (BBB) permeability limiting its clinical success. It was previously demonstrated that intravenous administration of dendrimer-NAC (D-NAC) conjugates have shown significant promise in the targeted treatment of neuroinflammation, in multiple preclinical models. Development of an oral formulation of D-NAC may open new administrative routes for this compound. Here, we report the gastrointestinal stability, in vitro transepithelial permeability, and in vivo oral absorption and pharmacokinetics in rats of a pediatric formulation of D-NAC containing Capmul MCM (glycerol monocaprylate) as a penetration enhancer. D-NAC was stable for 6 h in all five simulated gastrointestinal fluids with no signs of chemical degradation. The apparent permeability (Papp) of D-NAC increased 9-fold in the formulation containing Capmul. The area under the curve [AUC]0-∞ of D-NAC with Capmul increased by 47% when compared to D-NAC alone. These results indicate that an oral pediatric formulation containing D-NAC and Capmul can be an effective option for the treatment of neuroinflammation.}, }
@article {pmid29679867, year = {2018}, author = {Zhao, S and Liu, Y and Wang, F and Xu, D and Xie, P}, title = {N-acetylcysteine protects against microcystin-LR-induced endoplasmic reticulum stress and germ cell apoptosis in zebrafish testes.}, journal = {Chemosphere}, volume = {204}, number = {}, pages = {463-473}, doi = {10.1016/j.chemosphere.2018.04.020}, pmid = {29679867}, issn = {1879-1298}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Enzyme Inhibitors/toxicity ; Germ Cells/*drug effects/pathology ; Male ; Marine Toxins ; Microcystins/*toxicity ; Oxidative Stress/drug effects ; Protective Agents/pharmacology ; Testis/*drug effects/pathology ; Zebrafish/*growth &amp; development/metabolism ; }, abstract = {Previous studies have shown that microcystin-LR (MCLR) is a reproductive toxicant that induces germ cell apoptosis in the testes, but the underlying mechanisms have not been well understood. In this study, we investigated that MCLR induces germ cell apoptosis is through activation of endoplasmic reticulum (ER) stress and N-acetylcysteine (NAC), an antioxidant could protect against germ cell apoptosis by inhibiting the ER stress. Healthy male zebrafish were intraperitoneally injected with NAC (500 nM), beginning at 2 h before different doses of MCLR (0, 50, 100, 200 μg/kg). As expected, acute MCLR exposure resulted in oxidative stress and germ cell apoptosis in zebrafish testes. Further analysis showed that NAC significantly alleviated MCLR-induced testicular germ cell apoptosis and inhibited the caspase-dependent apoptotic proteins. Meanwhile H&amp;E staining showed that NAC could rescue testicular damage induced by MCLR. Moreover, MCLR induced activation of ER stress which consequently triggered apoptosis in zebrafish testes. Interestingly, NAC was effective in improving the total antioxidant capacity (T-AOC) level and activity of antioxidant enzymes in NAC pretreated groups. NAC significantly attenuated MCLR-induced upregulation of GRP78 in testes. In addition, NAC significantly attenuated MCLR-triggered testicular eIF2s1 and MAPK8 activation, indicating that NAC counteracts MCLR-induced unfolded protein response (UPR) in testes. Taken together, the results observed in this study suggested that ER stress plays a critical role in germ cell apoptosis exposed to MCLR and NAC could protect against apoptosis via inhibiting ER stress in zebrafish testes.}, }
@article {pmid29679669, year = {2018}, author = {Kim, TW and Moon, JW and Yu, HG}, title = {N-acetylcysteine protects against chorioretinal damage induced by photodynamic therapy for experimental choroidal neovascularization in a rat model.}, journal = {Photodiagnosis and photodynamic therapy}, volume = {23}, number = {}, pages = {12-17}, doi = {10.1016/j.pdpdt.2018.04.006}, pmid = {29679669}, issn = {1873-1597}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Choroidal Neovascularization/chemically induced/*prevention &amp; control ; Disease Models, Animal ; Fluorescein Angiography ; Lasers, Semiconductor ; Photochemotherapy/*methods ; Photosensitizing Agents/*adverse effects ; Rats ; Rats, Inbred BN ; Verteporfin/*adverse effects ; }, abstract = {PURPOSE: We explored the protective effects of N-acetylcysteine (NAC) on chorioretinal damage induced by photodynamic therapy (PDT) in an experimental rat model of choroidal neovascularization (CNV).<br><br>METHODS: Experimental CNV was induced by an argon laser in 24 Brown Norway rats 7 days prior to PDT. Commencing 1 day after CNV induction, 0.5&#x202f;mL of NAC was orally administered daily to the NAC&#x202f;+&#x202f;group (12 rats), and 0.5&#x202f;mL of normal saline to the NAC- group (12 rats). Diode laser treatment was delivered for 42&#x202f;s (total energy, 25&#x202f;J/cm2) to the left eye prior to verteporfin infusion (PDT-) and to the right eye 15-20&#x202f;min after such infusion (PDT+). Fluorescein angiography was performed just prior to PDT and enucleation to evaluate fluorescein leakage and CNV closure. We compared the CNV thickness, PDT-induced apoptosis [evaluated via terminal dUTP nick-end labeling (TUNEL)], fluorescein angiographic data, and extents of immunohistofluorescent staining for cleaved caspase-3 and superoxide dismutase (SOD) between the two groups.<br><br>RESULTS: Fourteen days after diode laser treatment, the CNV closure rate was significantly higher in the PDT-treated than the control group. However, the CNV closure rates did not differ significantly between the NAC- and NAC&#x202f;+&#x202f;groups. The TUNEL activity (a measure of PDT-induced apoptosis) of retinal cells was higher in the NAC-/PDT&#x202f;+&#x202f;than the NAC+/PDT&#x202f;+&#x202f;group at 1, 3, 7, and 14 days. The cleaved caspase-3 and SOD levels were higher in the NAC-/PDT&#x202f;+&#x202f;than the NAC+/PDT&#x202f;+&#x202f;group at 3 and 7 days.<br><br>CONCLUSIONS: PDT triggers oxygen radical-induced injury to, and apoptosis in, the retina. NAC may reduce PDT-induced damage to the retina without compromising the therapeutic efficacy of CNV.}, }
@article {pmid29679655, year = {2018}, author = {Sancho-Martínez, SM and Prieto-García, L and Prieto, M and Fuentes-Calvo, I and López-Novoa, JM and Morales, AI and Martínez-Salgado, C and López-Hernández, FJ}, title = {N-acetylcysteine transforms necrosis into apoptosis and affords tailored protection from cisplatin cytotoxicity.}, journal = {Toxicology and applied pharmacology}, volume = {349}, number = {}, pages = {83-93}, doi = {10.1016/j.taap.2018.04.010}, pmid = {29679655}, issn = {1096-0333}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents/*toxicity ; Apoptosis/*drug effects ; Caspases/analysis/metabolism ; Cell Line ; Cell Survival/drug effects ; Cisplatin/*toxicity ; Free Radical Scavengers/*pharmacology ; Humans ; Jurkat Cells ; Kidney Diseases/chemically induced/pathology ; Lipid Peroxidation/drug effects ; Male ; Necrosis/*chemically induced ; Rats ; Rats, Wistar ; }, abstract = {Nephrotoxicity is the main limitation to the dosage and anticancer efficacy of cisplatin. Cisplatin produces tubular epithelial cell apoptosis and necrosis depending on the concentration of the drug. Protection from cisplatin nephrotoxicity must therefore tackle both cell death modes. For its ability to reduce cisplatin reactivity, in addition to its antioxidant effect, we tested and found that N-acetylcysteine (NAC) was most effective at inhibiting cisplatin cytotoxicity. NAC has no significant effect on cell death induced by either cycloheximide or Fas activation, indicating a rather selective action. Pt-DNA-binding experiments suggest that the differential effectiveness of NAC is due to its capacity to quench cisplatin reactivity inside the cell. NAC abolishes cisplatin-induced apoptosis, and transforms the necrosis induced by high concentrations of cisplatin into apoptosis. In fact, NAC allows the anti-apoptotic molecule Bcl-2 to reduce the cell death caused by pro-necrotic concentrations of cisplatin, to a significantly greater extent than in the absence of NAC. In rats, a dosage of NAC that significantly ameliorates cisplatin nephrotoxicity, has little effect on gentamicin nephrotoxicity. These characteristics provide NAC with a rationale as a potential nephroprotectant specifically tailored to and especially effective for therapeutic courses with platinated antineoplastics, which prompts to deepening into further preclinical knowledge, and to initiate clinical studies with NAC and mixed therapies composed of NAC and antiapoptotic drugs.}, }
@article {pmid29677486, year = {2018}, author = {Cerda, MM and Pluth, MD}, title = {S Marks the Spot: Linking the Antioxidant Activity of N-Acetyl Cysteine to H2S and Sulfane Sulfur Species.}, journal = {Cell chemical biology}, volume = {25}, number = {4}, pages = {353-355}, doi = {10.1016/j.chembiol.2018.04.001}, pmid = {29677486}, issn = {2451-9448}, mesh = {*Acetylcysteine ; *Antioxidants ; Cysteine ; Sulfur ; }, abstract = {N-Acetyl cysteine (NAC) is commonly used as an antioxidant and cytoprotectant, yet a broadly applicable mechanism of these activities has remained elusive. In this issue of Cell Chemical Biology, Ezeriņa et al. (2018) report an alternative mechanism for NAC cytoprotection and antioxidant activity by demonstrating that NAC treatment increases sulfane sulfur production via intermediate H2S generation.}, }
@article {pmid29673449, year = {2018}, author = {Yu, CH and Jiang, L and Wang, Y and Cui, NX and Zhao, X and Yi, ZC}, title = {Inhibition of Erythroid Differentiation of Human Leukemia K562 Cells by N-acetylcysteine and Ascorbic Acid through Downregulation of ROS.}, journal = {Biomedical and environmental sciences : BES}, volume = {31}, number = {3}, pages = {247-251}, doi = {10.3967/bes2018.032}, pmid = {29673449}, issn = {0895-3988}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cell Differentiation/*drug effects ; Down-Regulation ; Erythroid Cells/*drug effects ; Hemin/pharmacology ; Humans ; K562 Cells ; Reactive Oxygen Species/*metabolism ; }, abstract = {This study investigated the effects of N-acetylcysteine (NAC) and ascorbic acid (AA) on hemin-induced K562 cell erythroid differentiation and the role of reactive oxygen species (ROS) in this process. Hemin increased ROS levels in a concentration-dependent manner, whereas NAC and AA had opposite effects. Both NAC and AA eliminated transient increased ROS levels after hemin treatment, inhibited hemin-induced hemoglobin synthesis, and decreased mRNA expression levels of β-globin, γ-globin, and GATA-1 genes significantly. Pretreatment with 5,000 μmol/L AA for 2 h resulted in a considerably lower inhibition ratio of hemoglobin synthesis than that when pretreated for 24 h, whereas the ROS levels were the lowest when treated with 5,000 μmol/L AA for 2 h. These results show that NAC and AA might inhibit hemin-induced K562 cell erythroid differentiation by downregulating ROS levels.}, }
@article {pmid29672839, year = {2019}, author = {Zhou, SN and Lu, JX and Wang, XQ and Shan, MR and Miao, Z and Pan, GP and Jian, X and Li, P and Ping, S and Pang, XY and Bai, YP and Liu, C and Wang, SX}, title = {S-Nitrosylation of Prostacyclin Synthase Instigates Nitrate Cross-Tolerance In Vivo.}, journal = {Clinical pharmacology and therapeutics}, volume = {105}, number = {1}, pages = {201-209}, doi = {10.1002/cpt.1094}, pmid = {29672839}, issn = {1532-6535}, mesh = {Aged ; Aged, 80 and over ; Amino Acid Sequence ; Animals ; Cattle ; Cricetinae ; Cytochrome P-450 Enzyme System/genetics/*metabolism ; Dose-Response Relationship, Drug ; Drug Tolerance/*physiology ; Female ; Human Umbilical Vein Endothelial Cells ; Humans ; Intramolecular Oxidoreductases/genetics/*metabolism ; Male ; Mice ; Mice, Knockout ; Middle Aged ; Nitrates/*metabolism ; Nitric Oxide/*metabolism ; Nitroglycerin/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Vasodilator Agents/pharmacology ; }, abstract = {Development of nitrate tolerance is a major drawback to nitrate therapy. Prostacyclin (PGI2) is a powerful vasodilator produced from prostaglandin (PGH2) by prostacyclin synthase (PGIS) in endothelial cells. This study aimed to determine the role of PGIS S-nitrosylation in nitrate tolerance induced by nitroglycerin (GTN). In endothelial cells, GTN increased PGIS S-nitrosylation and disturbed PGH2 metabolism, which were normalized by mutants of PGIS cysteine 231/441 to alanine (C231/441A). Clearance of nitric oxide by carboxy-PTIO or inhibition of S-nitrosylation by N-acetyl-cysteine decreased GTN-induced PGIS S-nitrosylation. Enforced expression of mutated PGIS with C231/441A markedly abolished GTN-induced PGIS S-nitrosylation and nitrate cross-tolerance in Apoe[-/-] mice. Inhibition of cyclooxygenase 1 by aspirin, supplementation of PGI2 by beraprost, and inhibition of PGIS S-nitrosylation by N-acetyl-cysteine improved GTN-induced nitrate cross-tolerance in rats. In patients, increased PGIS S-nitrosylation was associated with nitrate tolerance. In conclusion, GTN induces nitrate cross-tolerance through PGIS S-nitrosylation at cysteine 231/441.}, }
@article {pmid29671417, year = {2018}, author = {Thummayot, S and Tocharus, C and Jumnongprakhon, P and Suksamrarn, A and Tocharus, J}, title = {Cyanidin attenuates Aβ25-35-induced neuroinflammation by suppressing NF-κB activity downstream of TLR4/NOX4 in human neuroblastoma cells.}, journal = {Acta pharmacologica Sinica}, volume = {39}, number = {9}, pages = {1439-1452}, pmid = {29671417}, issn = {1745-7254}, mesh = {Acetylcysteine/pharmacology ; Amyloid beta-Peptides ; Anthocyanins/*pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Cell Line, Tumor ; Humans ; Inflammation/chemically induced/*metabolism ; NADPH Oxidase 4/antagonists &amp; inhibitors/metabolism ; NF-kappa B/*metabolism ; Neuroblastoma/*metabolism ; Neuroprotective Agents/*pharmacology ; Peptide Fragments ; Signal Transduction/*drug effects ; Toll-Like Receptor 4/antagonists &amp; inhibitors/metabolism ; }, abstract = {Cyanidin is polyphenolic pigment found in plants. We have previously demonstrated that cyanidin protects nerve cells against Aβ25-35-induced toxicity by decreasing oxidative stress and attenuating apoptosis mediated by both the mitochondrial apoptotic pathway and the ER stress pathway. To further elucidate the molecular mechanisms underlying the neuroprotective effects of cyanidin, we investigated the effects of cyanidin on neuroinflammation mediated by the TLR4/NOX4 pathway in Aβ25-35-treated human neuroblastoma cell line (SK-N-SH). SK-N-SH cells were exposed to Aβ25-35 (10 μmol/L) for 24 h. Pretreatment with cyanidin (20 μmol/L) or NAC (20 μmol/L) strongly inhibited the NF-κB signaling pathway in the cells evidenced by suppressing the degradation of IκBα, translocation of the p65 subunit of NF-κB from the cytoplasm to the nucleus, and thereby reducing the expression of iNOS protein and the production of NO. Furthermore, pretreatment with cyanidin greatly promoted the translocation of the Nrf2 protein from the cytoplasm to the nucleus; upregulating cytoprotective enzymes, including HO-1, NQO-1 and GCLC; and increased the activity of SOD enzymes. Pretreatment with cyanidin also decreased the expression of TLR4, directly improved intracellular ROS levels and regulated the activity of inflammation-related downstream pathways including NO production and SOD activity through TLR4/NOX4 signaling. These results demonstrate that TLR4 is a primary receptor in SK-N-SH cells, by which Aβ25-35 triggers neuroinflammation, and cyanidin attenuates Aβ-induced inflammation and ROS production mediated by the TLR4/NOX4 pathway, suggesting that inhibition of TLR4 by cyanidin could be beneficial in preventing neuronal cell death in the process of Alzheimer's disease.}, }
@article {pmid29670681, year = {2018}, author = {O'Leary, AJ and Drummond, SE and Edge, D and O'Halloran, KD}, title = {Diaphragm Muscle Weakness Following Acute Sustained Hypoxic Stress in the Mouse Is Prevented by Pretreatment with N-Acetyl Cysteine.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {4805493}, pmid = {29670681}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Atrophy ; Autophagy/drug effects/genetics ; Biomechanical Phenomena ; Carbon Dioxide/metabolism ; Chymotrypsin/metabolism ; Diaphragm/drug effects/*pathology/physiopathology ; Forkhead Box Protein O3/metabolism ; Gene Expression Regulation/drug effects ; Hypoxia/*complications/genetics/physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; MAP Kinase Signaling System/drug effects ; Male ; Mice, Inbred C57BL ; Muscle Fibers, Skeletal/drug effects/pathology ; Muscle Weakness/*drug therapy/etiology/genetics/*prevention &amp; control ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Proteasome Endopeptidase Complex/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Pulmonary Ventilation/drug effects ; Respiration ; *Stress, Physiological/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Oxygen deficit (hypoxia) is a major feature of cardiorespiratory diseases characterized by diaphragm dysfunction, yet the putative role of hypoxic stress as a driver of diaphragm dysfunction is understudied. We explored the cellular and functional consequences of sustained hypoxic stress in a mouse model. Adult male mice were exposed to 8 hours of normoxia, or hypoxia (FiO2 = 0.10) with or without antioxidant pretreatment (N-acetyl cysteine, 200 mg/kg i.p.). Ventilation and metabolism were measured. Diaphragm muscle contractile function, myofibre size and distribution, gene expression, protein signalling cascades, and oxidative stress (TBARS) were determined. Hypoxia caused pronounced diaphragm muscle weakness, unrelated to increased respiratory muscle work. Hypoxia increased diaphragm HIF-1α protein content and activated MAPK, mTOR, Akt, and FoxO3a signalling pathways, largely favouring protein synthesis. Hypoxia increased diaphragm lipid peroxidation, indicative of oxidative stress. FoxO3 and MuRF-1 gene expression were increased. Diaphragm 20S proteasome activity and muscle fibre size and distribution were unaffected by acute hypoxia. Pretreatment with N-acetyl cysteine substantially enhanced cell survival signalling, prevented hypoxia-induced diaphragm oxidative stress, and prevented hypoxia-induced diaphragm dysfunction. Hypoxia is a potent driver of diaphragm weakness, causing myofibre dysfunction without attendant atrophy. N-acetyl cysteine protects the hypoxic diaphragm and may have application as a potential adjunctive therapy.}, }
@article {pmid29670103, year = {2018}, author = {Weyemi, U and Paul, BD and Snowman, AM and Jailwala, P and Nussenzweig, A and Bonner, WM and Snyder, SH}, title = {Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis.}, journal = {Nature communications}, volume = {9}, number = {1}, pages = {1526}, pmid = {29670103}, issn = {2041-1723}, support = {P50 DA000266/DA/NIDA NIH HHS/United States ; R01 MH018501/MH/NIMH NIH HHS/United States ; R37 MH018501/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Animals ; Antioxidants/chemistry ; *Behavior, Animal ; Corpus Striatum/metabolism ; DNA Damage ; Fibroblasts/metabolism ; HEK293 Cells ; Heterozygote ; Histones/*deficiency/physiology ; Humans ; Mice ; Mice, Knockout ; Microscopy, Confocal ; Models, Neurological ; Motor Skills ; NF-E2-Related Factor 2/*metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Phenotype ; Phosphorylation ; Reactive Oxygen Species/metabolism ; }, abstract = {ATM drives DNA repair by phosphorylating the histone variant H2AX. While ATM mutations elicit prominent neurobehavioral phenotypes, neural roles for H2AX have been elusive. We report impaired motor learning and balance in H2AX-deficient mice. Mitigation of reactive oxygen species (ROS) with N-acetylcysteine (NAC) reverses the behavioral deficits. Mouse embryonic fibroblasts deficient for H2AX exhibit increased ROS production and failure to activate the antioxidant response pathway controlled by the transcription factor NRF2. The NRF2 targets GCLC and NQO1 are depleted in the striatum of H2AX knockouts, one of the regions most vulnerable to ROS-mediated damage. These findings establish a role for ROS in the behavioral deficits of H2AX knockout mice and reveal a physiologic function of H2AX in mediating influences of oxidative stress on NRF2-transcriptional targets and behavior.}, }
@article {pmid29667811, year = {2018}, author = {Qin, X and Peng, Y and Zheng, J}, title = {In Vitro and in Vivo Studies of the Electrophilicity of Physcion and its Oxidative Metabolites.}, journal = {Chemical research in toxicology}, volume = {31}, number = {5}, pages = {340-349}, doi = {10.1021/acs.chemrestox.8b00026}, pmid = {29667811}, issn = {1520-5010}, mesh = {Animals ; Cytochrome P-450 Enzyme System/chemistry/metabolism ; Emodin/*analogs &amp; derivatives/chemical synthesis/chemistry/metabolism ; Humans ; Hydroxylation ; Male ; Molecular Structure ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/chemistry/metabolism ; }, abstract = {Physcion (1,8-dihydroxy-3-methoxy-6-methyl-9,10-anthracenedione) is a bioactive component found in Polygoni Multiflori Radix (PMR), which has been widely used as traditional Chinese medicine. Unfortunately, studies showed hepatotoxicity of PMR during its clinical use. The mechanisms of its toxic action remain unknown. The major objectives of this study were to characterize oxidative metabolites of physcion in vitro and in vivo and to determine the electrophilicity of the parent compound and its oxidative metabolites. Five oxidative metabolites (M1-M5) were detected in rat liver microsomal incubations after exposure to physcion, and the formation of the metabolites was NADPH dependent. M1-M4 were monohydroxylation metabolites, and M5 was O-demethylation metabolite. A total of three N-acetylcysteine (NAC) conjugates (M6-M8) were observed in rat liver microsomes fortified with NAC as a trapping agent. M6 was derived from M4 conjugated with a molecule of NAC; M7 and M8 originated from parent compound physcion adducted with a molecule of NAC, respectively. M1-M8 were also observed in urine of rats given physcion. HLM incubations produced four oxidative metabolites and two NAC conjugates. The structures of M3, M7, and M8 were characterized by LC-Q-TOF MS and NMR. Recombinant P450 enzyme incubations demonstrated that CYPs2C19, 1A2, 2B6, and 3A4 were mainly involved in hydroxylation of physcion. The metabolism study assisted us to better understand the mechanisms of physcion-induced hepatotoxicity.}, }
@article {pmid29665402, year = {2018}, author = {Costa-Silva, DGD and Leandro, LP and Vieira, PB and de Carvalho, NR and Lopes, AR and Schimith, LE and Nunes, MEM and de Mello, RS and Martins, IK and de Paula, AA and Cañedo, AD and Moreira, JCF and Posser, T and Franco, JL}, title = {N-acetylcysteine inhibits Mancozeb-induced impairments to the normal development of zebrafish embryos.}, journal = {Neurotoxicology and teratology}, volume = {68}, number = {}, pages = {1-12}, doi = {10.1016/j.ntt.2018.04.003}, pmid = {29665402}, issn = {1872-9738}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Behavior, Animal/drug effects ; Cell Death/drug effects ; Comet Assay ; DNA Damage/drug effects ; Embryo, Nonmammalian/*drug effects ; Embryonic Development/*drug effects ; Fungicides, Industrial/antagonists &amp; inhibitors/toxicity ; Maneb/antagonists &amp; inhibitors/*toxicity ; Reactive Oxygen Species/metabolism ; *Zebrafish ; Zineb/antagonists &amp; inhibitors/*toxicity ; }, abstract = {Mancozeb (MZ), a manganese/zinc-containing ethylene-bis-dithiocarbamate (EBCD) fungicide has been claimed to present low acute toxicity and short environmental persistence, however, its effects on embryogenesis in non-target organisms is unclear. Here, we used zebrafish embryos (5 hpf) to assess the potential embryotoxic effects induced by MZ (up to 72 hpf) as well as the role of reactive oxygen species (ROS) in this process by pre-treatment with a classical antioxidant (N-acetylcysteine, NAC). Markers of reactive oxygen species production (ROS), glutathione (GSH) levels and glutathione S-transferase (GST) activity were measured along with genotoxicity (comet assay), cell death (Acridine Orange) and behavioral parameters (spontaneous movement, touch stimulation and swimming response), in order to determine potential mechanisms of embryotoxicity. According to results, MZ was able to induce morphological abnormalities such as body axis distortion, DNA damage, cell death, increased ROS generation and changes in behavioral endpoints during zebrafish development. All these toxic effects were inhibited by the pre-treatment with NAC indicating a key role of redox unbalance during MZ-induced embryotoxicity. At least in our knowledge, this is the first report on the deleterious effect of MZ to the normal embryogenesis of zebrafish. In addition, the importance of ROS generation during this pathophysiological condition was highlighted.}, }
@article {pmid29664420, year = {2018}, author = {Cacciotti, I and Chronopoulou, L and Palocci, C and Amalfitano, A and Cantiani, M and Cordaro, M and Lajolo, C and Callà, C and Boninsegna, A and Lucchetti, D and Gallenzi, P and Sgambato, A and Nocca, G and Arcovito, A}, title = {Controlled release of 18-β-glycyrrhetic acid by nanodelivery systems increases cytotoxicity on oral carcinoma cell line.}, journal = {Nanotechnology}, volume = {29}, number = {28}, pages = {285101}, doi = {10.1088/1361-6528/aabecc}, pmid = {29664420}, issn = {1361-6528}, mesh = {Cell Death/drug effects ; Cell Line, Tumor ; Chitosan/chemistry ; Delayed-Action Preparations/pharmacology/therapeutic use ; *Drug Delivery Systems ; Drug Liberation ; Dynamic Light Scattering ; Fibroblasts/cytology/drug effects ; Gingiva/cytology ; Glycyrrhetinic Acid/*administration &amp; dosage/pharmacology/*therapeutic use ; Humans ; Kinetics ; Mouth Neoplasms/*drug therapy/pathology ; Nanofibers/chemistry/ultrastructure ; Nanoparticles/*chemistry/ultrastructure ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {The topical treatment for oral mucosal diseases is often based on products optimized for dermatologic applications; consequently, a lower therapeutic effect may be present. 18-β-glycyrrhetic acid (GA) is extracted from Glycirrhiza glabra. The first aim of this study was to test the cytotoxicity of GA on PE/CA-PJ15 cells. The second aim was to propose and test two different delivery systems, i.e. nanoparticles and fibers, to guarantee a controlled release of GA in vitro. We used chitosan and poly(lactic-co-glycolic) acid based nanoparticles and polylactic acid fibers. We tested both delivery systems in vitro on PE/CA-PJ15 cells and on normal human gingival fibroblasts (HGFs). The morphology of GA-loaded nanoparticles (GA-NPs) and fibers (GA-FBs) was investigated by electron microscopy and dynamic light scattering; GA release kinetics was studied spectrophotometrically. MTT test was used to assess GA cytotoxicity on both cancer and normal cells. Cells were exposed to different concentrations of GA (20-500 μmol l[-1]) administered as free GA (GA-f), and to GA-NPs or GA-FBs. ROS production was evaluated using dichlorodihydrofluorescein as a fluorescent probe. Regarding the cytotoxic effect of GA on PE/CA-PJ15 cells, the lowest TC50 value was 200 μmol l[-1] when GA was added as GA-NPs. No cytotoxic effects were observed when GA was administered to HGFs. N-acetyl Cysteine reduced mortality induced by GA-f in PE/CA-PJ15 cells. The specific effect of GA on PE/CA-PJ15 cells is mainly due to the different sensitivity of cancer cells to ROS over-production; GA-NPs and GA-FBs formulations increase, in vitro, this toxic effect on oral cancer cells.}, }
@article {pmid29663874, year = {2018}, author = {di Michele, F and Siracusano, A and Talamo, A and Niolu, C}, title = {N-Acetyl Cysteine and Vitamin D Supplementation in Treatment Resistant Obsessive-compulsive Disorder Patients: A General Review.}, journal = {Current pharmaceutical design}, volume = {24}, number = {17}, pages = {1832-1838}, doi = {10.2174/1381612824666180417124919}, pmid = {29663874}, issn = {1873-4286}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Dietary Supplements ; Humans ; Inflammation/drug therapy ; Neuroprotective Agents/*therapeutic use ; Obsessive-Compulsive Disorder/*drug therapy ; Vitamin D/administration &amp; dosage/*therapeutic use ; }, abstract = {OBJECTIVE: Obsessive-compulsive Disorder (OCD) is a disabling mental illness for which pharmacological and psychosocial interventions are all too often inadequate. This demonstrates the need for more targeted therapeutics. Recent preclinical and clinical studies have implicated the dysfunction of glutamatergic neurotransmission in the pathophysiology of OCD. Moreover, there are studies suggesting that neuroimmune abnormalities may play an important role in the pathogenesis of OCD. N-acetyl cysteine (NAC) is a safe and readily available agent that would modify the synaptic release of glutamate in subcortical brain regions via modulation of the cysteine-glutamate antiporter. The modulation of inflammatory pathways may also play a role in the benefits seen following NAC treatment. Therefore NAC can be considered a neuroprotective agent.<br><br>METHODS: This paper explores the role of NAC in the treatment of OCD conditions refractory to first-line pharmacological interventions, reviewing the clinical studies published in the last decade.<br><br>RESULTS: The possible benefit mechanisms of NAC for this disorder will be discussed, as well as the role of vitamin D supplementation, given its specific property of stimulating the formation of glutathione in the brain.<br><br>CONCLUSION: Nutraceutical supplementation in treatment resistance OCD may be important not only for improving obsessive-compulsive symptomatology, but also from a psychological perspective, given its better acceptance by the patients compared to pharmacological treatment.}, }
@article {pmid29662624, year = {2018}, author = {Lin, LT and Liu, SY and Leu, JD and Chang, CY and Chiou, SH and Lee, TC and Lee, YJ}, title = {Arsenic trioxide-mediated suppression of miR-182-5p is associated with potent anti-oxidant effects through up-regulation of SESN2.}, journal = {Oncotarget}, volume = {9}, number = {22}, pages = {16028-16042}, pmid = {29662624}, issn = {1949-2553}, abstract = {Arsenic trioxide (ATO) is a traditional Chinese medicine that can induce oxidative stress for treatment of cancer cells. However, ATO may generate anti-oxidative responses to compromise the cytotoxic effect, but the underlying mechanisms remain unclear. Here we found that ATO could inhibit miR-182-5p expression in patient-derived primary S1 glioblastoma (GBM) cells accompanied by up-regulation of Sestrin-2 (SESN2) mRNA, a known anti-oxidant molecule. This phenomenon was also detected in a U87MG glioma cell line, human lung adenocarcinoma H1299 cell line and A549 cell line. Pretreatment with a free radical scavenger N-acetylcysteine (NAC) reduced the oxidative stress induced by ATO. Concomitantly, ATO mediated suppression of miR-182-5p and enhancement of SESN2 expression were also compromised. The MTT assay further showed that ATO induced cytotoxicity was enhanced by transfection of miR-182-5p mimics. Overexpression of miR-182-5p mimics significantly suppressed the expression of SENS2 and a firefly luciferase reporter gene fused to 3'- untranslated region (UTR) of SESN2 mRNA. Use of ribonucleoprotein immunoprecipitation (RNP-IP), ATO mediated suppression of miR-182-5p led to the stabilization of SESN2 mRNA as a result of Argonaute-2 (AGO2) dependent gene silencing. Furthermore, high expression of miR-182-5p and low expression of SESN2 mRNA tend to be associated with longer survival of glioma or lung cancer patients using public available gene expression datasets and online tools for prediction of clinical outcomes. Taken together, current data suggest that the miR-182-5p/SENS2 pathway is involved in ATO induced anti-oxidant responses, which may be important for the design of novel strategy for cancer treatment.}, }
@article {pmid29662002, year = {2018}, author = {Gong, X and Smith, JR and Swanson, HM and Rubin, LP}, title = {Carotenoid Lutein Selectively Inhibits Breast Cancer Cell Growth and Potentiates the Effect of Chemotherapeutic Agents through ROS-Mediated Mechanisms.}, journal = {Molecules (Basel, Switzerland)}, volume = {23}, number = {4}, pages = {}, pmid = {29662002}, issn = {1420-3049}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Bridged-Ring Compounds/pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Synergism ; Epithelial Cells/drug effects/metabolism/pathology ; Female ; Humans ; Lutein/*pharmacology ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Taxoids/pharmacology ; Triple Negative Breast Neoplasms/*metabolism/*pathology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Increasing evidence suggests that dietary carotenoids may reduce the risk of breast cancer. However, anti-breast cancer effects of carotenoids have been controversial, albeit understudied. Here, we investigated the effects of specific carotenoids on a wide range of breast cancer cell lines, and found that among several carotenoids (including β-carotene, lutein, and astaxanthin), lutein significantly inhibits breast cancer cell growth by inducing cell-cycle arrest and caspase-independent cell death, but it has little effect on the growth of primary mammary epithelial cells (PmECs). Moreover, lutein-mediated growth inhibition of breast cancer cells is quantitatively similar to that induced by chemotherapeutic taxanes, paclitaxel and docetaxel, and exposure to lutein plus taxanes additively inhibits breast cancer cell growth. Analysis of mechanisms showed that lutein treatment significantly increases the intracellular reactive oxygen species (ROS) production in triple-negative breast cancer (TNBC) cells, but not in normal PmECs. Lutein-induced growth inhibition is also attenuated by the radical oxygen scavenger N-acetyl cysteine, suggesting a role for ROS generation in the growth inhibitory effect of lutein on TNBC cells. Additionally, we found that the p53 signaling pathway is activated and HSP60 levels are increased by lutein treatment, which may contribute partly to the induction of growth inhibition in TNBC cells. Our findings show that lutein promotes growth inhibition of breast cancer cells through increased cell type-specific ROS generation and alternation of several signaling pathways. Dietary lutein supplementation may be a promising alternative and/or adjunct therapeutic candidate against breast cancer.}, }
@article {pmid29661657, year = {2018}, author = {Schulte, MHJ and Wiers, RW and Boendermaker, WJ and Goudriaan, AE and van den Brink, W and van Deursen, DS and Friese, M and Brede, E and Waters, AJ}, title = {Reprint of The effect of N-acetylcysteine and working memory training on cocaine use, craving and inhibition in regular cocaine users: correspondence of lab assessments and Ecological Momentary Assessment.}, journal = {Addictive behaviors}, volume = {83}, number = {}, pages = {79-86}, doi = {10.1016/j.addbeh.2018.03.023}, pmid = {29661657}, issn = {1873-6327}, abstract = {INTRODUCTION: Effective treatment for cocaine use disorder should dampen hypersensitive cue-induced motivational processes and/or strengthen executive control. Using a randomized, double-blind, placebo-controlled intervention, the primary aim of this study was to investigate the effect of N-Acetylcysteine (NAC) and working memory (WM)-training to reduce cocaine use and craving and to improve inhibition assessed in the laboratory and during Ecological Momentary Assessment (EMA). The second aim was to examine correspondence between laboratory and EMA data.<br><br>METHODS: Twenty-four of 38 cocaine-using men completed a 25-day intervention with 2400mg/day NAC or placebo and WM-training as well as two lab-visits assessing cocaine use, craving and inhibition (Stop Signal task). Additionally, cocaine use, craving and cognition (Stroop task) were assessed using EMA during treatment, with 26 participants completing 819 assessments.<br><br>RESULTS: Cocaine problems according to the Drug Use Disorder Identification Test (DUDIT) decreased more after NAC than after placebo, and the proportion of cocaine-positive urines at lab-visit 2 was lower in the NAC group. No NAC effects were found on craving. For cocaine use and craving, results from the lab data were generally similar to EMA results. NAC also showed some effects on cognitive control: improved inhibition assessed with the Stop Signal task in the lab, and decreased classic Stroop performance during EMA. There were no significant effects of number of completed WM-training sessions.<br><br>CONCLUSIONS: Overall this study revealed mixed findings regarding the treatment of cocaine use disorders with NAC and WM-training. The effect of NAC on inhibition should be further investigated.}, }
@article {pmid29660332, year = {2018}, author = {Lin, B and Xu, J and Feng, DG and Wang, F and Wang, JX and Zhao, H}, title = {DUSP14 knockout accelerates cardiac ischemia reperfusion (IR) injury through activating NF-κB and MAPKs signaling pathways modulated by ROS generation.}, journal = {Biochemical and biophysical research communications}, volume = {501}, number = {1}, pages = {24-32}, doi = {10.1016/j.bbrc.2018.04.101}, pmid = {29660332}, issn = {1090-2104}, mesh = {Animals ; Disease Models, Animal ; Dual-Specificity Phosphatases/*deficiency/genetics/metabolism ; *MAP Kinase Signaling System ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocardial Reperfusion Injury/*etiology/*metabolism/pathology ; Myocytes, Cardiac/metabolism/pathology ; NF-kappa B/*metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Inflammation and oxidative stress are significantly involved in the progression of a variety of diseases, including myocardial ischemia/reperfusion (IR). In the present study, we hypothesized a protective role of dual-specificity phosphatase 14 (DUSP14) in myocardial IR, as well as the underlying molecular mechanism. The results indicated that DUSP14 was down-regulated following cardiac IR injury. Subsequently, the wild type (WT) and DUSP14-knockout (KO) mice were included to further reveal the potential role of DUSP14 in cardiac IR injury progression. DUSP14-KO mice exhibited increased infarction area and elevated apoptosis, as evidenced by the increased TUNEL-positive cells in ischemia heart following reperfusion compared to WT mice. Further, DUSP14-KO significantly aggregated cardiac dysfunction of mice after IR injury. Cardiac IR injury to DUSP14-KO mice led to markedly increased expression of pro-inflammatory cytokines and activated nuclear factor-κB (NF-κB) pathway in the heart in comparison to WT mice. Meanwhile, mitogen-activated protein kinases (MAPKs), including p38, ERK1/2 and JNK, were significantly activated by DUSO14-KO in mice after IR injury. Compared to WT mice, DUSP14-KO mice showed markedly increased oxidative stress markers in cardiac tissues, including malondialdehyde (MDA), NADPH oxidase-4 (NOX4) and p47, while decreased activities or expressions of anti-oxidants, such as glutathione (GSH), glutathione peroxidase (GPx), glutathion reductases (GR), superoxide dismutase (SOD) and hemeoxygenase-1 (HO-1). DUSP14-knockdown (KD) in primary cardiomyocytes using its specific siRNA sequence elevated hypoxia and reoxygenation (HR)-induced activation of NF-κB and MAPKs signaling pathways, and reactive oxygen species (ROS) generation. Intriguingly, pre-treatment of ROS scavenger, N-acetylcysteine (NAC), markedly abolished DUSP14-KD-augmented NF-κB and MAPKs activation in HR-stimulated primary cardiomyocytes. Together, the results above indicated that DUSP14 might be served as a positive regulator to attenuate cardiac IR injury. Suppressing DUSP14 exacerbated cardiac injury through activating NF-κB and MAPKs signaling pathways regulated by ROS production. Thus, DUSP14 could be a valuable target for developing treatments for myocardial IR injury.}, }
@article {pmid29657376, year = {2018}, author = {Gupta, K and Mehrotra, M and Kumar, P and Gogia, AR and Prasad, A and Fisher, JA}, title = {Smoke Inhalation Injury: Etiopathogenesis, Diagnosis, and Management.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {22}, number = {3}, pages = {180-188}, pmid = {29657376}, issn = {0972-5229}, abstract = {Smoke inhalation injury is a major determinant of morbidity and mortality in fire victims. It is a complex multifaceted injury affecting initially the airway; however, in short time, it can become a complex life-threatening systemic disease affecting every organ in the body. In this review, we provide a summary of the underlying pathophysiology of organ dysfunction and provide an up-to-date survey of the various critical care modalities that have been found beneficial in caring for these patients. Major pathophysiological change is development of edema in the respiratory tract. The tracheobronchial tree is injured by steam and toxic chemicals, leading to bronchoconstriction. Lung parenchyma is damaged by the release of proteolytic elastases, leading to release of inflammatory mediators, increase in transvascular flux of fluids, and development of pulmonary edema and atelectasis. Decreased levels of surfactant and immunomodulators such as interleukins and tumor-necrosis-factor-α accentuate the injury. A primary survey is conducted at the site of fire, to ensure adequate airway, breathing, and circulation. A good intravenous access is obtained for the administration of resuscitation fluids. Early intubation, preferably with fiberoptic bronchoscope, is prudent before development of airway edema. Bronchial hygiene is maintained, which involves therapeutic coughing, chest physiotherapy, deep breathing exercises, and early ambulation. Pharmacological agents such as beta-2 agonists, racemic epinephrine, N-acetyl cysteine, and aerosolized heparin are used for improving oxygenation of lungs. Newer agents being tested are perfluorohexane, porcine pulmonary surfactant, and ClearMate. Early diagnosis and treatment of smoke inhalation injury are the keys for better outcome.}, }
@article {pmid29656983, year = {2018}, author = {Nawathe, A and David, AL}, title = {Prophylaxis and treatment of foetal growth restriction.}, journal = {Best practice &amp; research. Clinical obstetrics &amp; gynaecology}, volume = {49}, number = {}, pages = {66-78}, doi = {10.1016/j.bpobgyn.2018.02.007}, pmid = {29656983}, issn = {1532-1932}, mesh = {Anticoagulants/administration &amp; dosage ; Aspirin/administration &amp; dosage ; Clinical Trials as Topic ; Cyclooxygenase Inhibitors/administration &amp; dosage ; Diet, Healthy ; Female ; Fetal Growth Retardation/*prevention &amp; control/therapy ; *Gestational Age ; Heparin/administration &amp; dosage ; Humans ; Placenta/physiopathology ; Pregnancy ; Pregnancy Outcome ; Risk Factors ; Uterus/blood supply ; }, abstract = {Foetal growth restriction (FGR) and associated placental pathologies such as pre-eclampsia and stillbirth arise in early pregnancy when inadequate remodelling of maternal spiral arteries leads to persistent high-resistance low-flow uteroplacental circulation. Current interventions concentrate on targeting the placental ischaemia-reperfusion injury and oxidative stress associated with an imbalance in angiogenic/anti-angiogenic factors. Recent meta-analyses confirm that aspirin modestly reduces the risk for small-for-gestational-age pregnancy in high-risk women. A dose of ≥100 mg starting by 16 weeks of gestation is recommended. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent FGR; further research is needed to confirm efficacy. Once FGR is diagnosed, no treatment will improve foetal growth. Potential FGR therapies such as phosphodiesterase type-5 inhibitors or maternal VEGF gene therapy aim to improve poor placentation and/or uterine blood flow. Melatonin, creatine and N-acetyl cysteine have potential as novel neuroprotective and cardioprotective agents in FGR.}, }
@article {pmid29655793, year = {2018}, author = {Yanling, Q and Xiaoning, C and Fei, B and Liyun, F and Huizhong, H and Daqing, S}, title = {Inhibition of NLRP9b attenuates acute lung injury through suppressing inflammation, apoptosis and oxidative stress in murine and cell models.}, journal = {Biochemical and biophysical research communications}, volume = {503}, number = {2}, pages = {436-443}, doi = {10.1016/j.bbrc.2018.04.079}, pmid = {29655793}, issn = {1090-2104}, mesh = {Acute Lung Injury/genetics/*immunology/pathology ; Animals ; *Apoptosis ; Cell Line ; Cytokines/immunology ; Lung/immunology/pathology ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidative Stress ; Pneumonia/genetics/*immunology/pathology ; Reactive Oxygen Species/immunology ; Receptors, G-Protein-Coupled/genetics/*immunology ; }, abstract = {Acute lung injury (ALI), known a severe disease along with high morbidity and mortality, is lacking of specific therapies. Inflammation, apoptosis and oxidative stress are critical pathologies that contribute to ALI. Recently, there is study indicated that NLRP9b, a NOD-like receptor (NLR) member, is critical in modulation of inflammatory response. However, the effects of NLRP9b on sepsis-associated ALI, and the underlying molecular mechanism have not been understood. In the present study, the wild type (WT) and NLRP9b-knockout (NLRP9b[-/-]) mice with C57B/L6 background were subjected to a cecal ligation and puncture (CLP) for ALI murine model establishment. The findings indicated that NLRP9b[-/-] improved the survival rate of CLP-induced ALI mice, and inhibited pulmonary histopathological alterations, inflammation, and apoptosis. NLRP9b[-/-] reduced the activation of inhibitor of κBα/nuclear factor kappa B (IκBα/NF-κB), apoptosis-associated speck-like protein containing a Caspase-recruitment domain (ASC)/Casapse-1 and Caspase-3/poly (ADP-ribose) polymerase (PARP) signaling pathways in CLP-challenged mice with ALI. In vitro, mouse epithelial cells (MLE-12) were incubated with lipopolysaccharide (LPS) or recombinant NLRP9b caused a significant increased of pro-inflammatory cytokines or chemokine, and reactive oxygen species (ROS) generation; however, these changes were markedly alleviated by NLRP9-knockdown using its specific siRNA sequence. Pre-treatment of MLE-12 cells with ROS scavenger of N-acetylcysteine (NAC) remarkably decreased lipopolysaccharide (LPS)- and rMuNLRP9-induced production of ROS, and the secretion of inflammatory cytokines or chemokine, as well as the activity of IκBα/NF-κB, ASC/Casapse-1 and Caspase-3/PARP signaling pathways. Together, the findings here suggested that NLRP9b played an essential role in lung inflammation, apoptosis and oxidative stress of sepsis-induced ALI animal model or in LPS-induced MLE-12 cells, providing that NLRP9b inhibition might be a potential therapeutic option for ALI.}, }
@article {pmid29649567, year = {2018}, author = {Walker, A and Singh, A and Tully, E and Woo, J and Le, A and Nguyen, T and Biswal, S and Sharma, D and Gabrielson, E}, title = {Nrf2 signaling and autophagy are complementary in protecting breast cancer cells during glucose deprivation.}, journal = {Free radical biology &amp; medicine}, volume = {120}, number = {}, pages = {407-413}, pmid = {29649567}, issn = {1873-4596}, support = {R01 CA193895/CA/NCI NIH HHS/United States ; }, mesh = {Adaptation, Physiological/physiology ; Antioxidants/metabolism ; Autophagy/*physiology ; Breast Neoplasms/*metabolism/pathology ; Cell Line, Tumor ; Female ; Glucose/*deficiency ; Humans ; NF-E2-Related Factor 2/*metabolism ; Signal Transduction/*physiology ; }, abstract = {Autophagy can serve as a mechanism for survival of cells during nutrient deprivation by recycling cellular macromolecules and organelles transiently to provide essential metabolic substrates. However, autophagy itself causes metabolic stress to cells, and other cellular protective mechanisms likely cooperate with autophagy to promote cell survival during nutrient deprivation. In this study, we explored protective mechanisms in breast cancer cells in the setting of glucose deprivation. While breast cancer cells (MCF7 and T47D) survive in glucose-free medium for three days or more, autophagy is induced in this setting. Blocking autophagy pharmacologically with chloroquine or by knock-out of an essential autophagy gene, such as Beclin 1 or ATG7, markedly reduces the ability of cells to survive during glucose deprivation. Autophagy previously was shown to degrade p62, a protein that sequesters KEAP1, and KEAP1 in turn sequesters Nrf2, a master regulator of the antioxidant response. Hence, we investigated how the Nrf2 signaling pathway might be affected by glucose deprivation and autophagy. We found that while glucose deprivation does cause decreased cellular levels of p62, Nrf2 protein levels and activity unexpectedly increase in this setting. Moreover, this increase in Nrf2 activity provides important protection to breast cancer cells during glucose deprivation, since siRNA knockdown of Nrf2 markedly impairs survival during glucose deprivation. Antioxidants, N-acetyl cysteine and glutathione also protect these cells during glucose deprivation, leading us to conclude that Nrf2 signaling via its antioxidant activity has a critical and previously undescribed role of protecting cells during glucose deprivation-induced autophagy.}, }
@article {pmid29649125, year = {2018}, author = {Wang, S and Wang, M and Wang, M and Tian, Y and Sun, X and Sun, G and Sun, X}, title = {Bavachinin Induces Oxidative Damage in HepaRG Cells through p38/JNK MAPK Pathways.}, journal = {Toxins}, volume = {10}, number = {4}, pages = {}, pmid = {29649125}, issn = {2072-6651}, mesh = {Apoptosis/drug effects ; Cell Line, Tumor ; Flavonoids/*toxicity ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; MAP Kinase Signaling System/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Drug-induced liver injury is one of the main causes of drug non-approval and drug withdrawal by the Food and Drug Administration (FDA). Bavachinin (BVC) is a natural product derived from the fruit of the traditional Chinese herb Fructus Psoraleae (FP). There have been reports of acute liver injury following the administration of FP and its related proprietary medicines. To explore BVC hepatotoxicity and its mechanisms, we used the HepaRG cell line. In our recent research, we showed that BVC induces HepaRG cell death, mainly via BVC-induced oxidative damage. The formation of ROS is closely related to the activation of the stress-activated kinases, JNK and p38, while SP600125 (SP, JNK inhibitor) and SB203580 (SB, p38 inhibitor) pretreatment inhibited the generation of ROS. On the other hand, N-acetylcysteine (NAC) pretreatment prevented the phosphorylation of p38 but not that of JNK. Taken together, these data reveal that BVC induces HepaRG cell death via ROS and the JNK/p38 signaling pathways.}, }
@article {pmid29642488, year = {2018}, author = {Huang, HW and Tang, JY and Ou-Yang, F and Wang, HR and Guan, PY and Huang, CY and Chen, CY and Hou, MF and Sheu, JH and Chang, HW}, title = {Sinularin Selectively Kills Breast Cancer Cells Showing G2/M Arrest, Apoptosis, and Oxidative DNA Damage.}, journal = {Molecules (Basel, Switzerland)}, volume = {23}, number = {4}, pages = {}, pmid = {29642488}, issn = {1420-3049}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis ; Breast Neoplasms/drug therapy/*genetics/metabolism ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; *DNA Damage ; Diterpenes/*pharmacology ; Dose-Response Relationship, Drug ; Female ; G2 Phase Cell Cycle Checkpoints/*drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Heterocyclic Compounds, 3-Ring/*pharmacology ; Humans ; Poly(ADP-ribose) Polymerases/metabolism ; }, abstract = {The natural compound sinularin, isolated from marine soft corals, is antiproliferative against several cancers, but its possible selective killing effect has rarely been investigated. This study investigates the selective killing potential and mechanisms of sinularin-treated breast cancer cells. In 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium, inner salt (MTS) assay, sinularin dose-responsively decreased the cell viability of two breast cancer (SKBR3 and MDA-MB-231) cells, but showed less effect on breast normal (M10) cells after a 24 h treatment. According to 7-aminoactinomycin D (7AAD) flow cytometry, sinularin dose-responsively induced the G2/M cycle arrest of SKBR3 cells. Sinularin dose-responsively induced apoptosis on SKBR3 cells in terms of a flow cytometry-based annexin V/7AAD assay and pancaspase activity, as well as Western blotting for cleaved forms of poly(ADP-ribose) polymerase (PARP), caspases 3, 8, and 9. These caspases and PARP activations were suppressed by N-acetylcysteine (NAC) pretreatment. Moreover, sinularin dose-responsively induced oxidative stress and DNA damage according to flow cytometry analyses of reactive oxygen species (ROS), mitochondrial membrane potential (MitoMP), mitochondrial superoxide, and 8-oxo-2'-deoxyguanosine (8-oxodG)). In conclusion, sinularin induces selective killing, G2/M arrest, apoptosis, and oxidative DNA damage of breast cancer cells.}, }
@article {pmid29641241, year = {2018}, author = {Moore, K}, title = {N-Acetyl Cysteine and Curcumin in Pediatric Acute-Onset Neuropsychiatric Syndrome.}, journal = {Journal of child and adolescent psychopharmacology}, volume = {28}, number = {4}, pages = {293-294}, doi = {10.1089/cap.2017.0165}, pmid = {29641241}, issn = {1557-8992}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Disease ; Child, Preschool ; Curcumin/*administration &amp; dosage ; Female ; Humans ; Neurodevelopmental Disorders/diagnosis/*drug therapy ; Obsessive-Compulsive Disorder/diagnosis/*drug therapy ; Syndrome ; Treatment Outcome ; }, }
@article {pmid29636851, year = {2018}, author = {Żukowski, P and Maciejczyk, M and Matczuk, J and Kurek, K and Waszkiel, D and Żendzian-Piotrowska, M and Zalewska, A}, title = {Effect of N-Acetylcysteine on Antioxidant Defense, Oxidative Modification, and Salivary Gland Function in a Rat Model of Insulin Resistance.}, journal = {Oxidative medicine and cellular longevity}, volume = {2018}, number = {}, pages = {6581970}, pmid = {29636851}, issn = {1942-0994}, mesh = {Acetylcysteine/*metabolism ; Animals ; Antioxidants/*metabolism ; Disease Models, Animal ; Insulin Resistance/*physiology ; Male ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Rats ; Rats, Wistar ; Salivary Glands/*abnormalities ; }, abstract = {Oxidative stress plays a crucial role in the salivary gland dysfunction in insulin resistance (IR). It is not surprising that new substances are constantly being sought that will protect against the harmful effects of IR in the oral cavity environment. The purpose of this study was to evaluate the effect of N-acetylcysteine (NAC) on oxidative stress and secretory function of salivary glands in a rat model of insulin resistance. Rats were divided into 4 groups: C-normal diet, C + NAC-normal diet + NAC, HFD-high-fat diet, and HFD + NAC. We have demonstrated that NAC elevated enzymatic (superoxide dismutase, catalase, and peroxidase) and nonenzymatic antioxidants (reduced glutathione (GSH) and total antioxidant capacity (TAS)) in the parotid glands of HFD + NAC rats, while in the submandibular glands increased only GSH and TAS levels. NAC protects against oxidative damage only in the parotid glands and increased stimulated salivary secretion; however, it does not increase the protein secretion in the both salivary glands. Summarizing, NAC supplementation prevents the decrease of stimulated saliva secretion, seen in the HFD rats affected. NAC improves the antioxidative capacity of the both glands and protects against oxidative damage to the parotid glands of IR rats.}, }
@article {pmid29636531, year = {2018}, author = {Huang, CF and Yang, CY and Tsai, JR and Wu, CT and Liu, SH and Lan, KC}, title = {Low-dose tributyltin exposure induces an oxidative stress-triggered JNK-related pancreatic β-cell apoptosis and a reversible hypoinsulinemic hyperglycemia in mice.}, journal = {Scientific reports}, volume = {8}, number = {1}, pages = {5734}, pmid = {29636531}, issn = {2045-2322}, mesh = {Animals ; Apoptosis/*drug effects ; Biomarkers ; Cell Line ; Glucose/metabolism ; Hyperglycemia/blood/*metabolism ; Insulin-Secreting Cells/*metabolism ; Insulins/*blood ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Lipid Peroxidation/drug effects ; MAP Kinase Signaling System/drug effects ; Mice ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Trialkyltin Compounds/*pharmacology ; }, abstract = {Tributyltin (TBT), an endocrine disrupting chemical, can be found in food (particular in fish and seafood) and drinking water by contamination. Here, we elucidated the effects and possible mechanisms of low-dose TBT on the growth and function of pancreatic β-cells and glucose metabolism in mice. Submicromolar-concentration of TBT significantly induced β-cell cytotoxicity and apoptosis, which were accompanied by poly (ADP-ribose) polymerase cleavage and mitogen-activated protein kinases-JNK and ERK1/2 phosphorylation. TBT could also suppress the glucose-stimulated insulin secretion in β-cells and isolated mouse islets. TBT increased reactive oxygen species production. TBT-induced β-cell cytotoxicity and apoptosis were significantly prevented by antioxidant N-acetylcysteine (NAC) and JNK inhibitor SP600125, but not ERK1/2 inhibitor PD98059 and p38 inhibitor SB203580. Both NAC and SP600125 inhibited JNK phosphorylation and reduced cell viability in TBT-treated β-cells. Four-week exposure of TBT (0.25 mg/kg) to mice revealed the decreased plasma insulin, increased blood glucose and plasma malondialdehyde, suppressed islet insulin secretion, and increased islet caspase-3 activity, which could be reversed by NAC treatment. After removing the TBT exposure for 2 weeks, the TBT-induced glucose metabolism alteration was significantly reversed. These results suggest that low-dose TBT can induce β-cell apoptosis and interfere with glucose homeostasis via an oxidative stress-related pathway.}, }
@article {pmid29635121, year = {2018}, author = {Calzetta, L and Rogliani, P and Facciolo, F and Rinaldi, B and Cazzola, M and Matera, MG}, title = {N-Acetylcysteine protects human bronchi by modulating the release of neurokinin A in an ex vivo model of COPD exacerbation.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {103}, number = {}, pages = {1-8}, doi = {10.1016/j.biopha.2018.04.011}, pmid = {29635121}, issn = {1950-6007}, mesh = {Acetylcysteine/blood/*therapeutic use ; Biological Availability ; Bronchi/*pathology ; *Disease Progression ; Female ; Humans ; Inflammation/pathology ; Lipopolysaccharides ; Male ; Middle Aged ; *Models, Biological ; Neurokinin A/*metabolism ; Oxidative Stress/drug effects ; Protective Agents/*therapeutic use ; Pulmonary Disease, Chronic Obstructive/blood/*drug therapy/pathology ; Regression Analysis ; }, abstract = {AIMS: N-Acetylcysteine (NAC) reduces the risk of exacerbation of chronic obstructive pulmonary disease (COPD). Although NAC also has anti-inflammatory activity, the detailed mechanism leading to its protective role remains to be elucidated. We tested the impact of NAC against the effects of lipopolysaccharide (LPS) in an ex vivo model of COPD exacerbation, and investigated the role of neurokinin A (NKA) in this context.<br><br>MAIN METHODS: Isolated airways from COPD patients were incubated overnight with LPS (100&#x202f;ng/ml). NAC was tested at concentrations resembling the plasma levels elicited by oral administration of NAC at 200&#x202f;mg/day (very low dose), 600&#x202f;mg/day (low dose) and 1.200&#x202f;mg/day (high dose).<br><br>KEY FINDINGS: NAC at high concentrations normalized the peroxidase activity, H2O2, malondialdehyde (MDA), nitric oxide, glutathione (GSH), total antioxidant capacity (TAC), and interleukin 6 (IL-6) (overall change 34.32%&#x202f;&#xb1;&#x202f;4.22%, P&#x202f;<&#x202f;0.05 vs. LPS-treated). NAC at low concentrations modulated peroxidase activity, H2O2, MDA, GSH, TAC, and IL-6 (overall change 34.88%&#x202f;&#xb1;&#x202f;7.39%, P&#x202f;<&#x202f;0.05 vs. LPS-treated). NAC at very-low concentrations was effective on peroxidase activity, H2O2, GSH, and IL-6 (overall change 35.05&#x202f;&#xb1;&#x202f;7.71%, P&#x202f;<&#x202f;0.05 vs. LPS-treated). Binary logistic regression analysis indicated that the modulatory effect of NAC on NKA levels was associated with a reduction of pro-oxidant factors and IL-6, and selectively blocking the NK2 receptor abolished such an association.<br><br>SIGNIFICANCE: This study demonstrates that, along with its well-known antioxidant activity, the protective effect of NAC against the detrimental effect of LPS is due to the modulation of NKA and IL-6 levels.}, }
@article {pmid29633091, year = {2018}, author = {Xu, Y and Zheng, X and Liang, B and Gao, J and Gu, Z}, title = {Vitamins for Prevention of Contrast-induced Acute Kidney Injury: A Systematic Review and Trial Sequential Analysis.}, journal = {American journal of cardiovascular drugs : drugs, devices, and other interventions}, volume = {18}, number = {5}, pages = {373-386}, doi = {10.1007/s40256-018-0274-3}, pmid = {29633091}, issn = {1179-187X}, support = {No. 2015YW24//Sanya Medical and Health Science and Technology Innovation Project of China/ ; }, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/chemically induced/epidemiology/*prevention &amp; control ; Ascorbic Acid/*administration &amp; dosage ; Contrast Media/*adverse effects ; Humans ; Incidence ; Sodium Chloride/therapeutic use ; Vitamin E/*administration &amp; dosage ; }, abstract = {BACKGROUND: To date, universally accepted preventive measures for contrast-induced acute kidney injury (CI-AKI) do not exist, and they warrant further research.<br><br>OBJECTIVE: The purpose of this study was to evaluate the efficacy of vitamins, including vitamin C and E, for prevention of CI-AKI.<br><br>METHODS: We electronically searched the MEDLINE, EMBASE, and Cochrane databases. The outcome of interest was the incidence of CI-AKI.<br><br>RESULTS: A total of 19 studies were included in this meta-analysis. Pooled analysis showed that vitamin C plus saline [relative risk (RR)&#x2009;=&#x2009;0.63, 95% confidence interval (CI) 0.49-0.82, p&#x2009;=&#x2009;0.0005] and vitamin E plus saline (RR&#x2009;=&#x2009;0.39, 95% CI 0.24-0.62, p&#x2009;<&#x2009;0.0001) significantly reduced the incidence of CI-AKI compared to saline alone. The effect of vitamin C plus saline was further confirmed by trial sequential analysis (TSA). However, TSA indicated that more trials are required to confirm the efficacy of vitamin E plus saline. There was no significant difference in preventing CI-AKI between vitamin C and N-acetylcysteine (NAC) (RR&#x2009;=&#x2009;0.90, 95% CI 0.47-1.71, p&#x2009;=&#x2009;0.75), between vitamin C plus NAC and saline (RR&#x2009;=&#x2009;0.62, 95% CI 0.30-1.30, p&#x2009;=&#x2009;&#xa0;0.20), as well as between vitamin C plus NAC and NAC (RR&#x2009;=&#x2009;0.97, 95% CI 0.49-1.92, p&#x2009;=&#x2009;0.93).<br><br>CONCLUSIONS: Vitamin C plus saline administration is effective at reducing the risk of CI-AKI. Evidence for the use of vitamin E plus saline in this context is encouraging, but more trials are required. Furthermore, this meta-analysis and TSA indicated insufficient power to draw a definitive conclusion on the effect of vitamin C plus NAC, versus saline or NAC alone, which needs to be explored further.}, }
@article {pmid29630780, year = {2018}, author = {Goto, N and Tsujimoto, M and Nagai, H and Masaki, T and Ito, S and Wakamatsu, K and Nishigori, C}, title = {4-(4-Hydroxyphenyl)-2-butanol (rhododendrol)-induced melanocyte cytotoxicity is enhanced by UVB exposure through generation of oxidative stress.}, journal = {Experimental dermatology}, volume = {27}, number = {7}, pages = {754-762}, doi = {10.1111/exd.13555}, pmid = {29630780}, issn = {1600-0625}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/radiation effects ; Butanols/metabolism/*toxicity ; Caspase Inhibitors/pharmacology ; Cell Survival/drug effects/radiation effects ; Cells, Cultured ; Endoplasmic Reticulum Stress/drug effects/radiation effects ; Humans ; Hypopigmentation/etiology ; Melanins/metabolism ; Melanocytes/*drug effects/metabolism/radiation effects ; Oxidative Stress/drug effects/radiation effects ; Reactive Oxygen Species/metabolism ; Skin Lightening Preparations/metabolism/*toxicity ; Ultraviolet Rays/adverse effects ; }, abstract = {4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD), a skin-whitening agent, was reported to cause skin depigmentation in some users, which is attributed to its cytotoxicity to melanocyte. It was reported that cytotoxicity to melanocyte is possibly mediated by oxidative stress in a tyrosinase activity-dependent manner. We examined the effect of UV radiation (UVR) on RD-induced melanocyte cytotoxicity as an additional aggravating factor. UVR enhanced RD-induced cytotoxicity in normal human epidermal melanocytes (NHEMs) via the induction of endoplasmic reticulum (ER) stress. Increased generation of intracellular reactive oxygen species (ROS) was detected. Pretreatment with N-acetyl cysteine (NAC), antioxidant and precursor of glutathione significantly attenuated ER stress-induced cytotoxicity in NHEMs treated with RD and UVR. Increase in cysteinyl-RD-catechol and RD-pheomelanin in NHEMs treated with RD and UVR suggested that, after UVR excitation, RD or RD metabolites are potent ROS-generating substances and that the tendency to produce RD-pheomelanin during melanogenesis amplifies ROS generation in melanocytes. Our results help to elucidate the development mechanisms of RD-induced leukoderma and provide information for innovation of safe skin-whitening compounds.}, }
@article {pmid29629029, year = {2018}, author = {Kim, MY and Choi, EO and HwangBo, H and Kwon, DH and Ahn, KI and Kim, HJ and Ji, SY and Hong, SH and Jeong, JW and Kim, GY and Park, C and Choi, YH}, title = {Reactive oxygen species-dependent apoptosis induction by water extract of Citrus unshiu peel in MDA-MB-231 human breast carcinoma cells.}, journal = {Nutrition research and practice}, volume = {12}, number = {2}, pages = {129-134}, pmid = {29629029}, issn = {1976-1457}, abstract = {BACKGROUND/OBJECTIVES: Although several recent studies have reported the anti-cancer effects of extracts or components of Citrus unshiu peel, which has been used for various purposes in traditional medicine, the molecular mechanisms for their effects remain unclear. In the present study, the anti-cancer activity of a water-soluble extract of C. unshiu peel (WECU) in MDA-MB-231 human breast carcinoma cells at the level of apoptosis induction was investigated.<br><br>MATERIALS/METHODS: Cytotoxicity was evaluated using the MTT assay. Apoptosis was detected using DAPI staining and flow cytometry analyses. Mitochondrial membrane potential, reactive oxygen species (ROS) assay, caspase activity and Western blotting were used to confirm the basis of apoptosis.<br><br>RESULTS: The results indicated that WECU-induced apoptosis was related to the activation of caspase-8, and -9, representative initiator caspases of extrinsic and intrinsic apoptosis pathways, respectively, and caspase-3 accompanied by proteolytic degradation of poly(ADP-ribose) polymerase and down-regulation of the inhibitors of apoptosis protein family members. WECU also increased the pro-apoptotic BAX to anti-apoptotic BCL-2 ratio, loss of mitochondrial membrane potential and cytochrome c release from mitochondria to cytoplasm. Furthermore, WECU provoked the generation of ROS, but the reduction of cell viability and induction of apoptosis by WECU were prevented when ROS production was blocked by antioxidant N-acetyl cysteine.<br><br>CONCLUSIONS: These results suggest that WECU suppressed proliferation of MDA-MB-231 cells by activating extrinsic and intrinsic apoptosis pathways in a ROS-dependent manner.}, }
@article {pmid29627502, year = {2018}, author = {Wang, P and Gao, C and Wang, W and Yao, LP and Zhang, J and Zhang, SD and Li, J and Fang, SH and Fu, YJ}, title = {Juglone induces apoptosis and autophagy via modulation of mitogen-activated protein kinase pathways in human hepatocellular carcinoma cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {116}, number = {Pt B}, pages = {40-50}, doi = {10.1016/j.fct.2018.04.004}, pmid = {29627502}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Androstadienes/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Carcinoma, Hepatocellular/*drug therapy/enzymology/pathology ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Enzyme Activation ; Hep G2 Cells ; Humans ; Liver Neoplasms/*drug therapy/enzymology/pathology ; MAP Kinase Kinase 4/*metabolism ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Naphthoquinones/*pharmacology/therapeutic use ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Wortmannin ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Juglone (JG), a naturally-occurring naphthoquinone of Manchurian walnut (Juglans mandshurica) was shown to inhibit proliferation in various tumor types. However, the molecular mechanisms of JG on the induction of apoptosis and autophagy in HepG2 cells have not been examined. Herein, we investigated that JG could inhibit cell proliferation by induction of G2/M phase arrest. Also, occurrence of apoptosis was closely related with loss of mitochondrial membrane potential, the changes of apoptosis-related proteins after treatment with JG. In addition, we found that JG caused autophagy, as evidenced by increased expressions of LC3-II and Beclin-1. Interestingly, inhibition of JG-induced autophagy by 3-methyladenine (3-MA) and wortmannin (WT) significantly decreased apoptosis, whereas the apoptosis inhibitor z-VAD-fmk slightly enhanced autophagy. Furthermore, the induction of autophagy and apoptosis was associated with activation of MAPK family members (p38 and JNK) and production of reactive oxygen species (ROS). Both JNK inhibitor (SP600125) and ROS scavenger (N-acetylcysteine, NAC) could attenuate JG-induced autophagy and apoptosis. However, the p38-specific inhibitor SB203580 enhanced autophagic and apoptotic death. Moreover, the ROS scavenger NAC prevented phosphorylation of both p38 and JNK. Collectively, our data revealed that JG induced G2/M phase arrest, apoptosis, and autophagy through the ROS-dependent signaling pathway.}, }
@article {pmid29627441, year = {2018}, author = {Wahyudi, LD and Jeong, J and Yang, H and Kim, JH}, title = {Amentoflavone-induced oxidative stress activates NF-E2-related factor 2 via the p38 MAP kinase-AKT pathway in human keratinocytes.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {99}, number = {}, pages = {100-108}, doi = {10.1016/j.biocel.2018.04.006}, pmid = {29627441}, issn = {1878-5875}, mesh = {Biflavonoids/*pharmacology ; Cells, Cultured ; Cytochrome P-450 CYP2C9 Inhibitors/pharmacology ; Gene Expression Regulation/*drug effects ; Humans ; Keratinocytes/drug effects/metabolism/*pathology ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidative Stress/*drug effects ; Phosphorylation ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Reactive Oxygen Species ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that responds to oxidative stress and xenobiotics. Multiple lines of evidence suggest that Nrf2 activation protects against aging, inflammation, and many diseases, including cancer. Nrf2 activators derived from natural sources have been widely studied. In this study, we investigated the effect of amentoflavone (AFN), a biflavonoid found in many plants, on Nrf2 signaling in human keratinocytes (HaCaT cells). AFN significantly increased ARE luciferase activity by Nrf2 accumulation in the nucleus. Subsequently, the levels of a Nrf2 target protein, NQO-1, were significantly increased by AFN in a dose- and time-dependent manner. To verify the mechanism of AFN-induced activation of Nrf2 signaling, we measured generation of reactive oxygen species (ROS). Interestingly AFN triggered mild ROS production. Additionally, AFN-induced Nrf2 activation was inhibited by N-acetyl cysteine. Therefore, we studied the effect of ROS-related signaling on Nrf2 by measuring the activation of AKT and members of the mitogen-activated protein kinase family, such as extracellular signal-regulated kinase (ERK1/2) and p38. The results showed that the pharmacological inhibitor of PI3K/AKT (LY294002) or p38 (SB 203580), but not ERK1/2 (U0126), abrogated AFN-induced Nrf2 activation. Subsequently, we found that silencing or inhibition of p38 resulted in decrease of AKT phosphorylation as well as inhibition of Nrf2 accumulation. Furthermore, we found that AFN stabilized Nrf2 by inhibiting its ubiquitination. Taken together, our results suggest that AFN contributes to Nrf2 activation through ROS-mediated activation of the p38-AKT pathway in HaCaT cells.}, }
@article {pmid29624820, year = {2018}, author = {Ercan, UK and Sen, B and Brooks, AD and Joshi, SG}, title = {Escherichia coli cellular responses to exposure to atmospheric-pressure dielectric barrier discharge plasma-treated N-acetylcysteine solution.}, journal = {Journal of applied microbiology}, volume = {125}, number = {2}, pages = {383-397}, doi = {10.1111/jam.13777}, pmid = {29624820}, issn = {1365-2672}, mesh = {Acetylcysteine/*pharmacology ; DNA Damage/drug effects ; Escherichia coli/*drug effects/genetics ; Gene Expression/drug effects ; Humans ; Nitrosative Stress/*drug effects ; Oxidative Stress/*drug effects ; Peroxynitrous Acid/metabolism ; *Plasma ; }, abstract = {AIM: To understand the underlying cellular mechanisms during inactivation of Escherichia coli in response to antimicrobial solution of nonthermal plasma-activated N-acetylcysteine (NAC).<br><br>METHODS AND RESULTS: The recommended techniques were used to demonstrate E.&#xa0;coli cellular and transcriptomic changes caused associated with peroxynitrite and compared with plasma-treated NAC solution. The findings demonstrate that E.&#xa0;coli cells respond to plasma-treated NAC and undergo severe oxidative and nitrosative stress, and leading to stress-induced damages to different components of bacterial cells, which includes loss of membrane potential, formation of oxidized glutathione (GSSG), formation of nitrotyrosine (a known marker of nitrosative stress), DNA damage, and generated a prominent pool of peroxynitrite. Reverse-transcriptase (RT)-polymerase chain reaction analysis of reactive nitrogen species (RNS) responsive genes indicated their differential expressions.<br><br>CONCLUSION: For the first time, we report that the plasma-treated NAC solution activates predominantly nitrosative stress-responsive genes in E.&#xa0;coli and is responsible for cell death.<br><br>The reactive species generated in solutions by nonthermal plasma treatment depends on the type of solution or solvent used. The plasma-treated NAC solution rapidly inactivates E.&#xa0;coli, mostly involving highly RNS generated in NAC solution, and has high potential as disinfectant.}, }
@article {pmid29623672, year = {2018}, author = {Dludla, PV and Dias, SC and Obonye, N and Johnson, R and Louw, J and Nkambule, BB}, title = {A Systematic Review on the Protective Effect of N-Acetyl Cysteine Against Diabetes-Associated Cardiovascular Complications.}, journal = {American journal of cardiovascular drugs : drugs, devices, and other interventions}, volume = {18}, number = {4}, pages = {283-298}, doi = {10.1007/s40256-018-0275-2}, pmid = {29623672}, issn = {1179-187X}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/therapeutic use ; Cardiovascular Diseases/*drug therapy/*etiology ; Diabetes Complications/*drug therapy ; Diabetes Mellitus, Type 2/*complications ; Humans ; Protective Agents/*therapeutic use ; }, abstract = {INTRODUCTION: Heart failure is the leading cause of death in patients with diabetes. No treatment currently exists to specifically protect these patients at risk of developing cardiovascular complications. Accelerated oxidative stress-induced tissue damage due to persistent hyperglycemia is one of the major factors implicated in deteriorated cardiac function within a diabetic state. N-acetyl cysteine (NAC), through its enhanced capacity to endogenously synthesize glutathione, a potent antioxidant, has displayed abundant health-promoting properties and has a favorable safety profile.<br><br>OBJECTIVE: An increasing number of experimental studies have reported on the strong ameliorative properties of NAC. We systematically reviewed the data on the cardioprotective potential of this compound to provide an informative summary.<br><br>METHODS: Two independent reviewers systematically searched major databases, including PubMed, Cochrane Library, Google scholar, and Embase for available studies reporting on the ameliorative effects of NAC as a monotherapy or in combination with other therapies against diabetes-associated cardiovascular complications. We used the ARRIVE and JBI appraisal guidelines to assess the quality of individual studies included in the review. A meta-analysis could not be performed because the included studies were heterogeneous and data from randomized clinical trials were unavailable.<br><br>RESULTS: Most studies support the ameliorative potential of NAC against a number of diabetes-associated complications, including oxidative stress. We discuss future prospects, such as identification of additional molecular mechanisms implicated in diabetes-induced cardiac damage, and highlight limitations, such as insufficient studies reporting on the comparative effect of NAC with common glucose-lowering therapies. Information on the comparative analysis of NAC, in terms of dose selection, administration mode, and its effect on different cardiovascular-related markers is important for translation into clinical studies.<br><br>CONCLUSIONS: NAC exhibits strong potential for the protection of the diabetic heart at risk of myocardial infarction through inhibition of oxidative stress. The effect of NAC in preventing both ischemia and non-ischemic-associated cardiac damage is also of interest. Consistency in dose selection in most studies reported remains important in dose translation for clinical relevance.}, }
@article {pmid29619634, year = {2018}, author = {Ellegaard, PK and Licht, RW and Poulsen, HE and Nielsen, RE and Berk, M and Dean, OM and Mohebbi, M and Nielsen, CT}, title = {Add-on treatment with N-acetylcysteine for bipolar depression: a 24-week randomized double-blind parallel group placebo-controlled multicentre trial (NACOS-study protocol).}, journal = {International journal of bipolar disorders}, volume = {6}, number = {1}, pages = {11}, pmid = {29619634}, issn = {2194-7511}, abstract = {BACKGROUND: Oxidative stress and inflammation may be involved in the development and progression of mood disorders, including bipolar disorder. Currently, there is a scarcity of useful treatment options for bipolar depressive episodes, especially compared with the efficacy of treatment for acute mania. N-Acetylcysteine (NAC) has been explored for psychiatric disorders for some time given its antioxidant and anti-inflammatory properties. The current trial aims at testing the clinical effects of adjunctive NAC treatment (compared to placebo) for bipolar depression. We will also explore the biological effects of NAC in this context. We hypothesize that adjunctive NAC treatment will reduce symptoms of depression, which will be reflected by changes in selected markers of oxidative stress.<br><br>METHODS AND ANALYSIS: In the study, we will include adults diagnosed with bipolar disorder, in a currently depressive episode. Participants will undertake a 20-week, adjunctive, randomized, double-blinded, parallel group placebo-controlled trial comparing 3 grams of adjunctive NAC daily with placebo. The primary outcome is the mean change over time from baseline to end of study on the Montgomery-Asberg Depression Rating Scale (MADRS). Among the secondary outcomes are mean changes from baseline to end of study on the Bech-Rafaelsen Melancholia Scale (MES), the Young Mania Rating Scale (YMRS), the WHO-Five Well-being Index (WHO-5), the Global Assessment of Functioning scale (GAF-F), the Global Assessment of Symptoms scale (GAF-S) and the Clinical Global Impression-Severity scale (CGI-S). The potential effects on oxidative stress by NAC treatment will be measured through urine and blood samples. DNA will be examined for potential polymorphisms related to oxidative defences.<br><br>TRIAL REGISTRATION: Registered at The European Clinical Trials Database, ClinicalTrials.gov: NCT02294591 and The Danish Data Protection Agency: 2008-58-0035.}, }
@article {pmid29617550, year = {2018}, author = {Lucyk, S}, title = {Calculated decisions: Acetaminophen Overdose and N-Acetylcysteine (NAC) Dosing.}, journal = {Emergency medicine practice}, volume = {20}, number = {4 Suppl}, pages = {S3-S5}, pmid = {29617550}, issn = {1559-3908}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*therapeutic use ; Decision Making ; Drug Overdose/*drug therapy ; Humans ; Time Factors ; }, }
@article {pmid29610575, year = {2018}, author = {Sun, Y and Wang, C and Wang, L and Dai, Z and Yang, K}, title = {Arsenic trioxide induces apoptosis and the formation of reactive oxygen species in rat glioma cells.}, journal = {Cellular &amp; molecular biology letters}, volume = {23}, number = {}, pages = {13}, pmid = {29610575}, issn = {1689-1392}, mesh = {Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology/therapeutic use ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Glioma/*drug therapy/pathology ; Humans ; Oxides/*pharmacology/therapeutic use ; Primary Cell Culture ; Rats ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {BACKGROUND: Arsenic trioxide (As2O3) has a dramatic therapeutic effect on acute promyelocytic leukemia (APL) patients. It can also cause apoptosis in various tumor cells. This study investigated whether As2O3 has an antitumor effect on glioma and explored the underlying mechanism.<br><br>RESULTS: MTT and trypan blue assays showed that As2O3 remarkably inhibited growth of C6 and 9&#xa0;L glioma cells. Cell viability decreased in glioma cells to a greater extent than in normal glia cells. The annexin V-FITC/PI and Hoechest/PI staining assays revealed a significant increase in apoptosis that correlated with the duration of As2O3 treatment and occurred in glioma cells to a greater extent than in normal glial cells. As2O3 treatment induced reactive oxygen species (ROS) production in C6 and 9&#xa0;L cells in a time-dependent manner. Cells pretreated with the antioxidant N-acetylcysteine (NAC) showed significantly lower As2O3-induced ROS generation. As2O3 significantly inhibited the expression of the anti-apoptotic gene Bcl-2, and upregulated the proapoptotic gene Bax in both C6 and 9&#xa0;L glioma cells in a time-dependent manner.<br><br>CONCLUSIONS: As2O3 can significantly inhibit the growth of glioma cells and it can induce cell apoptosis in a time- and concentration-dependent manner. ROS were found to be responsible for apoptosis in glioma cells induced by As2O3. These results suggest As2O3 is a promising agent for the treatment of glioma.}, }
@article {pmid29609096, year = {2018}, author = {Lam, CF and Yeung, HT and Lam, YM and Ng, RK}, title = {Reactive oxygen species activate differentiation gene transcription of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway.}, journal = {Leukemia research}, volume = {68}, number = {}, pages = {112-119}, doi = {10.1016/j.leukres.2018.03.012}, pmid = {29609096}, issn = {1873-5835}, mesh = {Acetylcysteine/pharmacology ; Cell Differentiation/*genetics ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Leukemia, Myeloid, Acute/metabolism/*pathology ; *MAP Kinase Signaling System ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-jun/*metabolism ; Reactive Oxygen Species/*metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Transcription, Genetic/*genetics ; }, abstract = {Reactive oxygen species (ROS) and altered cellular redox status are associated with many malignancies. Acute myeloid leukemia (AML) cells are maintained at immature state by differentiation blockade, which involves deregulation of transcription factors in myeloid differentiation. AML cells can be induced to differentiate by phorbol-12-myristate-13-acetate (PMA), which possesses pro-oxidative activity. However, the signaling events mediated by ROS in the activation of transcriptional program during AML differentiation has not been fully elucidated. Here, we investigated AML cell differentiation by treatment with PMA and ROS scavenger N-acetyl-l-cysteine (NAC). We observed elevation of intracellular ROS level in the PMA-treated AML cells, which correlated with differentiated cell morphology and increased CD11b[+] mature cell population. The effect of PMA can be abolished by NAC co-treatment, supporting the involvement of ROS in the process. Moreover, we demonstrated that short ROS elevation mediated cell cycle arrest, but failed to activate myeloid gene transcription; whereas prolonged ROS elevation activated JNK/c-JUN signaling pathway. Inhibition of JNK suppressed the expression of key myeloid transcriptional regulators c-JUN, SPI-1 and MAFB, and prevented AML cells from undergoing terminal differentiation. These findings provide new insights into the crucial role of JNK/c-Jun signaling pathway in the activation of transcriptional program during ROS-mediated AML differentiation.}, }
@article {pmid29605633, year = {2018}, author = {Kim, JH and Park, SJ and Chae, U and Seong, J and Lee, HS and Lee, SR and Lee, S and Lee, DS}, title = {Peroxiredoxin 2 mediates insulin sensitivity of skeletal muscles through regulation of protein tyrosine phosphatase oxidation.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {99}, number = {}, pages = {80-90}, doi = {10.1016/j.biocel.2018.03.019}, pmid = {29605633}, issn = {1878-5875}, mesh = {Animals ; Cells, Cultured ; Embryo, Mammalian/cytology/drug effects/metabolism ; Fibroblasts/cytology/drug effects/metabolism ; Gene Expression Regulation/*drug effects ; Glucose/metabolism ; Glucose Tolerance Test ; Homeodomain Proteins/*physiology ; Hypoglycemic Agents/pharmacology ; Insulin/*pharmacology ; *Insulin Resistance ; Male ; Mice ; Mice, Knockout ; Muscle, Skeletal/cytology/*drug effects/metabolism ; Oxidation-Reduction ; Phosphorylation ; Protein Tyrosine Phosphatases/*chemistry/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Insulin signaling is essential for regulating glucose homeostasis. Numerous studies have demonstrated that reactive oxygen species (ROS) affect insulin signaling, and low ROS levels can act as a signal to regulate cellular function. Peroxiredoxins (Prxs) are highly abundant and widely expressed antioxidant enzymes. However, it is unclear whether antioxidant enzymes, such as Prx2, mediate insulin signaling. The aim of our study was to investigate the influence of Prx2 deficiency on insulin signaling. Our western blot results showed that Prx2 deficiency enhanced insulin signaling and increased oxidation of protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homologue (PTEN) in mouse embryonic fibroblasts (MEFs) treated with insulin. In addition, we assessed ROS levels with a Cytosol-HyPer H2O2 sensor. As a result, increased ROS levels and Akt activation were decreased by N-acetyl-cysteine (Nac), which acted as an antioxidant in Prx2-deficient MEFs. Body weight measurements and glucose tolerance test (GTT) revealed significant body weight reduction and increase in glucose clearance in Prx2[-/-] mice fed a high-fat diet. Interestingly, glucose transporter type 4 (GLUT4) was significantly higher in Prx2[-/-] mice than in wild-type mice according to western blotting results. Western blotting also revealed that Akt phosphorylation was higher in Prx2[-/-] MEFs and muscle tissue than in wild-type. Together, our findings indicate that increased ROS due to Prx2 deficiency promotes insulin sensitivity and glucose clearance in skeletal muscles by increasing protein tyrosine phosphatase (PTPs) oxidation. These results provide novel insights into the fundamental mechanisms of insulin signaling induced by Prx2 deficiency and suggest that ROS-based therapeutic strategies can be used to suppress insulin resistance.}, }
@article {pmid29605103, year = {2018}, author = {Porcu, M and Urbano, MR and Verri, WA and Barbosa, DS and Baracat, M and Vargas, HO and Machado, RCBR and Pescim, RR and Nunes, SOV}, title = {Effects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein.}, journal = {Psychiatry research}, volume = {263}, number = {}, pages = {268-274}, doi = {10.1016/j.psychres.2018.02.056}, pmid = {29605103}, issn = {1872-7123}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Biomarkers/blood ; C-Reactive Protein/*metabolism ; Depression/*blood/*drug therapy/psychology ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Quality of Life/psychology ; Treatment Outcome ; }, abstract = {UNLABELLED: Outcomes in a RCTs of 12 weeks of theclinical efficacy of N-acetylcysteine (NAC) as an adjunctive treatment on depression and anxiety symptoms and its effects on high-sensitivity C-reactive protein (hs-CRP) levels. A wide array of measures were made. The 17-item version of the Hamilton Depression Rating Scale (HDRS17); the Hamilton Anxiety Rating Scale (HAM-A); Sheehan Disability Scale; Quality of Life; Clinical Global Impression (CGI); anthropometrics measures; and vital signs and biochemical laboratory. There were no significant differences among the groups regarding demographic, clinical features, use of medication, metabolic syndrome and comorbidities. From baseline to week 12, individuals receiving NAC, versus placebo, had a statistically significant reduction in depressive symptoms on HDRS17 (p < 0.01) and anxiety symptoms on HAM-A (p = 0.04), but only for individuals with levels of hs-CRP > 3 mg/L at baseline. Individuals receiving NAC with baseline levels of hs-CRP > 3 mg/L, had more significant reduction in uric acid levels compared to individuals with baseline levels of hs-CRP ≤ 3 mg/L on week 12. Participants receiving placebogained significantly more weight during the 12 weeks for baseline levels of hs-CRP ≤ 3 mg/L and hs-CRP > 3 mg/L, and individuals receiving NAC in both groups did not have significant weight change during the 12 weeks. No individuals were withdrawn from the study because of adverse event. NAC group exhibited significantly greater reduction on hs-CRP levels than placebo group from baseline to week 12.<br><br>TRIAL REGISTRATION: clinicaltrials.gov Identifier; NCT02252341.}, }
@article {pmid29604597, year = {2018}, author = {Shi, L and Qin, H and Jin, X and Yang, X and Lu, X and Wang, H and Wang, R and Yu, D and Feng, B}, title = {The natural phenolic peperobtusin A induces apoptosis of lymphoma U937 cells via the Caspase dependent and p38 MAPK signaling pathways.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {102}, number = {}, pages = {772-781}, doi = {10.1016/j.biopha.2018.03.141}, pmid = {29604597}, issn = {1950-6007}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis/*drug effects ; Caspases/*metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chromans/chemistry/*pharmacology ; Humans ; Imidazoles/pharmacology ; Lymphoma/*enzymology/*pathology ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Phenols/chemistry/*pharmacology ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; U937 Cells ; bcl-2-Associated X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Our previous research found the ethyl acetate extract of Peperomia tetraphylla (EAEPT) inhibited the growth of U937 cells by blocking the cell cycle and prompted apoptosis via the reactive oxygen species (ROS)-medicated mitochondria pathway. While the compounds in EAEPT which possessed the anti-tumor activity were unclear. Peperobtusin A is a phenolic compound, which was isolated from the whole plant of Peperomia tetraphylla. In this work, we found that peperobtusin A had the anti-proliferative effects against human lymphoma U937 cells and induced apoptosis in a dose dependent manner. Peperobtusin A significantly enhanced the formation of intracellular ROS and induced the loss of mitochondrial membrane potential (Δψm). And peperobtusin A could increase the ratio of Bax/Bcl-2, induce the cleavage of Bid, Caspase-3, Caspase-8 and Caspase-9 and enhance the level of P-P38. Moreover, peperobtusin A induced the accumulation of cells at S phase. Through using of inhibitors such as antioxidant NAC, pan-caspase inhibitor Z-VAD-FMK, p38 MAPK specific inhibitor SB203580, we found that intracellular ROS generation, activation of Caspases and p38 MAPK played very important roles in the apoptosis induced by peperobtusin A in U937 cells. Our results indicated that intracellular ROS generation, the Caspase-dependent and p38 MAPK signaling pathways involved in apoptosis induced by peperobtusin A in U937 cells.}, }
@article {pmid29604498, year = {2018}, author = {Pan, YX and Luo, Z and Zhuo, MQ and Wei, CC and Chen, GH and Song, YF}, title = {Oxidative stress and mitochondrial dysfunction mediated Cd-induced hepatic lipid accumulation in zebrafish Danio rerio.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {199}, number = {}, pages = {12-20}, doi = {10.1016/j.aquatox.2018.03.017}, pmid = {29604498}, issn = {1879-1514}, mesh = {Acetylcysteine/chemistry/pharmacology ; Animals ; Cadmium Chloride/metabolism/*toxicity ; Fatty Acid Synthases/genetics/metabolism ; Glucosephosphate Dehydrogenase/genetics/metabolism ; Lipid Metabolism/drug effects/genetics ; Liver/*drug effects/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Oxidative Stress/*drug effects ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/metabolism ; Triglycerides/metabolism ; Up-Regulation/drug effects ; Water Pollutants, Chemical/*toxicity ; Zebrafish/growth &amp; development/*metabolism ; Zebrafish Proteins/genetics/metabolism ; }, abstract = {The present study was performed to determine the effect of waterborne CdCl2 exposure influencing lipid deposition and metabolism, oxidative stress and mitochondrial dysfunction, and explore the underlying molecular mechanism of cadmium (Cd)-induced disorder of hepatic lipid metabolism in fish. To this end, adult zebrafish were exposed to three waterborne CdCl2 concentrations (0(control), 5 and 25 μg Cd/l, respectively) for 30 days. Lipid accumulation, the activities of enzymes related to lipid metabolism and oxidative stress, as well as the expression level of genes involved in lipid metabolism and mitophagy were determined in the liver of zebrafish. Waterborne CdCl2 exposure increased hepatic triglyceride (TG) and Cd accumulation, the activities of fatty acid synthase (FAS), 6-phosphogluconate dehydrogenase (6PGD), glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME), and the mRNA level of fatty acid synthase (fas), acetyl-CoA carboxylase alpha (acaca), glucose 6-phosphate dehydrogenase (g6pd) and malic enzyme (me), but reduced the mRNA level of carnitine palmitoyl transferase 1 (cpt1), hormone-sensitive lipase alpha (hsla), and adipose triacylglyceride lipase (atgl). The activities of superoxide dismutase (SOD), glutathoinine peroxidase (GPx) and cytochrome c oxidase (COX) and the ATP level were significantly reduced after CdCl2 exposure. CdCl2 exposure significantly increased the mRNA level of genes (microtubule-associated protein light chain 3 alpha (lc3a), PTEN-induced putative kinase 1 (pink1), NIP3-like protein X (nix) and PARKIN (parkin)) related to mitophagy. To elucidate the mechanism, reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA) were used to verify the role of ROS and mitochondrial dysfunction in Cd-induced disorder of lipid metabolism. NAC pretreatment reversed the Cd-induced up-regulation of TG accumulation and activities of lipogenic enzymes, and the Cd-induced down-regulation of mRNA levels of lipolytic genes. Meanwhile, NAC pretreatment also blocked the mitochondrial membrane potential (MMP) collapse and decreased the ATP level, suggesting that ROS played a crucial role in regulating the Cd-induced mitochondrial dysfunction. Taken together, our findings, for the first time, highlight the importance of the oxidative stress and mitochondrial dysfunction in Cd-induced disorder of hepatic lipid metabolism, which proposed a novel mechanism for elucidating metal element exposure inducing the disorder of lipid metabolism in vertebrates.}, }
@article {pmid29604375, year = {2018}, author = {Thrimawithana, TR and Rupenthal, ID and Räsch, SS and Lim, JC and Morton, JD and Bunt, CR}, title = {Drug delivery to the lens for the management of cataracts.}, journal = {Advanced drug delivery reviews}, volume = {126}, number = {}, pages = {185-194}, doi = {10.1016/j.addr.2018.03.009}, pmid = {29604375}, issn = {1872-8294}, mesh = {Cataract/*drug therapy ; *Drug Delivery Systems ; Humans ; }, abstract = {Cataracts are one of the most prevalent diseases of the lens, affecting its transparency and are the leading cause of reversible blindness in the world. The clarity of the lens is essential for its normal physiological function of refracting light onto the retina. Currently there is no pharmaceutical treatment for prevention or cure of cataracts and surgery to replace the affected lens remains the gold standard in the management of cataracts. Pharmacological treatment for prevention of cataracts is hindered by many physiological barriers that must be overcome by a therapeutic agent to reach the avascular lens. Various therapeutic agents and formulation strategies are currently being investigated to prevent cataract formation as access to surgery is limited. This review provides a summary of recent research in the field of drug delivery to the lens for the management of cataracts including models used to study cataract treatments and discusses the future perspectives in the field.}, }
@article {pmid29604266, year = {2018}, author = {Yang, G and Bai, Y and Wu, X and Sun, X and Sun, M and Liu, X and Yao, X and Zhang, C and Chu, Q and Jiang, L and Wang, S}, title = {Patulin induced ROS-dependent autophagic cell death in Human Hepatoma G2 cells.}, journal = {Chemico-biological interactions}, volume = {288}, number = {}, pages = {24-31}, doi = {10.1016/j.cbi.2018.03.018}, pmid = {29604266}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Down-Regulation/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Microtubule-Associated Proteins/genetics/metabolism ; Patulin/chemistry/*pharmacology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/genetics/metabolism ; Up-Regulation/drug effects ; }, abstract = {Patulin (PAT) is a secondary metabolite produced by certain species of Penicillium, Byssochlamys and Aspergillus. It has been shown to induce liver toxicity, but the possible molecular mechanisms are not completely elucidated. In our study, we treated Human Hepatoma G2 (HepG2) cells by 3-methyladenine (3-MA), an autophagosome formation inhibitor, and rapamycin, an autophagosome formation stimulator. The results showed that 3-MA protected the HepG2 cells against PAT cytotoxicity, while rapamycin decreased the cell viability. Thus, autophagy may play an important role in PAT-induced toxicity. To uncover the mechanism by which cells decrease proliferation and activation of autophagy, we found that collapses of mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) level were increased under treatment with PAT. Further, we elucidated that the expression of p-Akt1 and p-MTOR was inhibited during this process. N-acetyl-l-cysteine (NAC), a ROS inhibitor, protected against PAT-induced cytotoxicity, decreased the protein expression of LC3-II, and up-regulated the level of p-Akt1 and p-MTOR. These findings suggested that PAT-induced autophagic cell death was ROS-dependent in HepG2 cells. In conclusion, it is possible that PAT elicited autophagy through ROS-Akt1-MTOR pathway in the HepG2 cells.}, }
@article {pmid29600051, year = {2018}, author = {Feng, J and Liu, B and Xu, J and Wang, Q and Huang, L and Ou, W and Gu, J and Wu, J and Li, S and Zhuo, C and Zhou, Y}, title = {In vitro effects of N-acetylcysteine alone and combined with tigecycline on planktonic cells and biofilms of Acinetobacter baumannii.}, journal = {Journal of thoracic disease}, volume = {10}, number = {1}, pages = {212-218}, pmid = {29600051}, issn = {2072-1439}, abstract = {BACKGROUND: Acinetobacter baumannii (A. baumannii), as a common opportunistic pathogen, has strong ability to form biofilms, which has led to drug resistance and chronic infections. The combination of N-acetylcysteine (NAC) and tigecycline (TGC) was demonstrated to synergistically inhibit biofilm-associated bacterial infections, including methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. The purpose of this study is to investigate the effect of NAC and TGC on planktonic cells and biofilms of A. baumannii.<br><br>METHODS: Minimum inhibitory concentrations (MICs) of NAC were determined by broth microdilution method. Biofilm susceptibility was assessed by crystal violet stain. Interactive effects of NAC and TGC on planktonic cells were determined by checkerboard MIC assay. Viable cell count was used to evaluate the combined effect of NAC and TGC on biofilm-embedded bacteria.<br><br>RESULTS: MICs of NAC against 25 A. baumannii isolates ranged from 16 to 128 mg/mL. NAC alone (0.5-128 mg/mL) significantly inhibited biofilm formation and disrupted preformed biofilms. The combination of NAC and TGC induced a partial synergistic effect (60%) and additive effect (28%) on planktonic bacteria. For biofilm-embedded bacteria, treatment with 16 mg/mL NAC alone or 2 &#xb5;g/mL TGC alone resulted in significant bactericidal effects (P<0.01 and P<0.05, respectively); synergistic bactericidal effect was found at 4 mg/mL NAC combined with 0.5 &#xb5;g/mL TGC (P<0.01).<br><br>CONCLUSIONS: NAC alone significantly inhibited biofilm formation of A. baumannii. The combination of NAC and TGC induced partial synergistic effect against planktonic cells and synergistic effect against biofilm-embedded A. baumannii, which might be a therapeutic option for biofilm-related infections of A. baumannii.}, }
@article {pmid29599711, year = {2018}, author = {Berry, A and Bellisario, V and Panetta, P and Raggi, C and Magnifico, MC and Arese, M and Cirulli, F}, title = {Administration of the Antioxidant N-Acetyl-Cysteine in Pregnant Mice Has Long-Term Positive Effects on Metabolic and Behavioral Endpoints of Male and Female Offspring Prenatally Exposed to a High-Fat Diet.}, journal = {Frontiers in behavioral neuroscience}, volume = {12}, number = {}, pages = {48}, pmid = {29599711}, issn = {1662-5153}, abstract = {A growing body of evidence suggests the consumption of high-fat diet (HFD) during pregnancy to model maternal obesity and the associated increase in oxidative stress (OS), might act as powerful prenatal stressors, leading to adult stress-related metabolic or behavioral disorders. We hypothesized that administration of antioxidants throughout gestation might counteract the negative effects of prenatal exposure to metabolic challenges (maternal HFD feeding during pregnancy) on the developing fetus. In this study, female C57BL/6J mice were fed HFD for 13 weeks (from 5-weeks of age until delivery) and were exposed to the N-acetyl-cysteine (NAC) antioxidant from 10-weeks of age until right before delivery. Body weight of the offspring was assessed following birth, up to weaning and at adulthood. The metabolic, neuroendocrine and emotional profile of the adult offspring was tested at 3-months of age. Prenatal HFD increased mother's body weight and offspring's weight at the time of weaning, when administered in conjunction with NAC. In females, NAC administration reduced high levels of leptin resulting from prenatal HFD. Prenatal NAC administration also resulted in greater glucose tolerance and insulin sensitivity while increasing adiponectin levels, as well as increasing exploratory behavior, an effect accompanied by reduced plasma corticosterone levels in response to restraint stress. Analysis of glutathione levels in the hypothalamus and in brown adipose tissue indicates that, while HFD administration to pregnant dams led to reduced levels of glutathione in the offspring, as in the male hypothalamus, NAC was able to revert this effect and to increase glutathione levels both in the periphery (Brown Adipose Tissue, both males and females) and in the central nervous system (males). Overall, results from this study indicate that the body redox milieu should be tightly regulated during fetal life and that buffering OS during pregnancy can have important long-term consequences on metabolic and behavioral endpoints.}, }
@article {pmid29590661, year = {2018}, author = {Lin, CL and Lee, CH and Chen, CM and Cheng, CW and Chen, PN and Ying, TH and Hsieh, YH}, title = {Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {46}, number = {1}, pages = {322-334}, doi = {10.1159/000488433}, pmid = {29590661}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Diosgenin/*analogs &amp; derivatives/chemistry/pharmacology ; Down-Regulation/drug effects ; Drugs, Chinese Herbal/pharmacology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Female ; HeLa Cells ; Heat-Shock Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; RNA Interference ; Reactive Oxygen Species/*metabolism ; Saponins/chemistry/*pharmacology ; Transcription Factor CHOP/antagonists &amp; inhibitors/genetics/metabolism ; Up-Regulation/drug effects ; Uterine Cervical Neoplasms/metabolism/pathology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {BACKGROUND/AIMS: Protodioscin (PD) is a steroidal saponin with anti-cancer effects on a number of cancer cells, but the anti-tumor effects and mechanism of action of PD on human cervical cancer cells is unclear.<br><br>METHODS: We determined cell viability using the MTT assay. Cell death, mitochondrial membrane potential (MMP), intracellular reactive oxygen species (ROS) generation, and endoplasmic reticulum (ER) stress were measured on a flow cytometry. Caspase activation, ER stress, and MMP-dependent apoptosis proteins in cervical cancer cells in response to PD were determined by Western blot analysis. The ability of ATF4 binding to ChIP promoter was measured using the ChIP assay.<br><br>RESULTS: We demonstrated that PD inhibits cell viability, causes a loss of mitochondrial function, and induces apoptosis, as evidenced by up-regulation of caspase-8, -3, -9, -PARP, and Bax activation, and down-regulation of Bcl-2 expression. PD was shown to induce ROS and the ER stress pathway, including GRP78, p-eIF-2&#x3b1;, ATF4, and CHOP. Pre-treatment with NAC, a ROS production inhibitor, significantly reduced ER stress and apoptosis-related proteins induced by PD. Transfection of GRP78/CHOP-siRNA effectively inhibited PD-induced ER stress-dependent apoptosis. Moreover, treatment with PD significantly increased p38 and JNK activation. Co-administration of a JNK inhibitor (SP600125) or p38 inhibitor (SB203580) abolished cell death and ER stress effects during PD treatment. In addition, PD induced the expression of nuclear ATF4 and CHOP, as well as the binding ability of ATF4 to the CHOP promoter.<br><br>CONCLUSION: Our results suggest that PD is a promising therapeutic agent for the treatment of human cervical cancer.}, }
@article {pmid29589623, year = {2018}, author = {Khanehzar, A and Fraire, JC and Xi, M and Feizpour, A and Xu, F and Wu, L and Coronado, EA and Reinhard, BM}, title = {Nanoparticle-cell interactions induced apoptosis: a case study with nanoconjugated epidermal growth factor.}, journal = {Nanoscale}, volume = {10}, number = {14}, pages = {6712-6723}, pmid = {29589623}, issn = {2040-3372}, support = {R01 CA138509/CA/NCI NIH HHS/United States ; }, mesh = {*Apoptosis ; Cell Line, Tumor ; Epidermal Growth Factor/*metabolism ; ErbB Receptors/metabolism ; Humans ; *Nanoparticles ; Reactive Oxygen Species/metabolism ; }, abstract = {In addition to the intrinsic toxicity associated with the chemical composition of nanoparticles (NP) and their ligands, biofunctionalized NP can perturb specific cellular processes through NP-cell interactions and induce programmed cell death (apoptosis). In the case of the epidermal growth factor (EGF), nanoconjugation has been shown to enhance the apoptotic efficacy of the ligand, but the critical aspects of the underlying mechanism and its dependence on the NP morphology remain unclear. In this manuscript we characterize the apoptotic efficacy of nanoconjugated EGF as a function of NP size (with sphere diameters in the range 20-80 nm), aspect ratio (A.R., in the range of 4.5 to 8.6), and EGF surface loading in EGFR overexpressing MDA-MB-468 cells. We demonstrate a significant size and morphology dependence in this relatively narrow parameter space with spherical NP with a diameter of approx. 80 nm being much more efficient in inducing apoptosis than smaller spherical NP or rod-shaped NP with comparable EGF loading. The nanoconjugated EGF is found to trigger an EGFR-dependent increase in cytoplasmic reactive oxygen species (ROS) levels but no indications of increased mitochondrial ROS levels or mitochondrial membrane damage are detected at early time points of the apoptosis induction. The increase in cytoplasmic ROS is accompanied by a perturbation of the intracellular glutathione homeostasis, which represents an important check-point for NP-EGF mediated apoptosis. Abrogation of the oxidative stress through the inhibition of EGFR signaling by the EGFR inhibitor AG1478 or addition of antioxidants N-acetyl cysteine (NAC) or tempol, but not trolox, successfully suppressed the apoptotic effect of nanoconjugated EGF. A model to account for the observed morphology dependence of EGF nanoconjugation enhanced apoptosis and the underlying NP-cell interactions is discussed.}, }
@article {pmid29588126, year = {2018}, author = {Breier, A and Liffick, E and Hummer, TA and Vohs, JL and Yang, Z and Mehdiyoun, NF and Visco, AC and Metzler, E and Zhang, Y and Francis, MM}, title = {Effects of 12-month, double-blind N-acetyl cysteine on symptoms, cognition and brain morphology in early phase schizophrenia spectrum disorders.}, journal = {Schizophrenia research}, volume = {199}, number = {}, pages = {395-402}, doi = {10.1016/j.schres.2018.03.012}, pmid = {29588126}, issn = {1573-2509}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Antipsychotic Agents/adverse effects/*therapeutic use ; Brain/diagnostic imaging/*drug effects ; Cognition/*drug effects ; Double-Blind Method ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Schizophrenia/diagnostic imaging/*drug therapy ; Schizophrenic Psychology ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Currently approved medications for schizophrenia are relatively ineffective for negative symptoms and cognitive impairment. N-Acetyl Cysteine (NAC) is a neuroprotective agent that improved general symptoms, cognitive impairment and negative symptoms in some but not all studies, but failed to improve positive symptoms in patients with schizophrenia. Progressive brain mass loss (PBML) has been consistently observed in early phase schizophrenia. NAC mitigates the deleterious effects oxidative stress, inflammation and glutamatergic excitotoxicity and these three pathological processes are hypothesized to contribute to PBML.<br><br>METHODS: In this study, we assessed the effects NAC (3600mg/day) in a 52-week, double-blind, placebo controlled trial on symptoms, and cognition in early phase schizophrenia spectrum disorders (N=60). In the context of the clinical trial, we explored the effects of NAC on brain morphology.<br><br>RESULTS: NAC significantly improved (time&#xd7;group) PANSS total (F=14.7, p<0.001), negative (F=5.1, p=0.024) and disorganized thought (F=13.7, p<0.001) symptom scores. NAC failed to improve PANSS positive symptoms and BACS cognitive scores. In preliminary analyses, baseline right (r=-0.48, p=0.041) and left (r=-0.45, p=0.018) total cortical thickness, and thickness in other cortical regions, were associated with NAC related improvement in PANSS total scores, but NAC, as compared to placebo, did not significantly impact brain morphology over the study treatment period.<br><br>CONCLUSIONS: These results replicate some but not all previous findings of NAC efficacy. Preliminary results suggest that NAC's symptom effects may be related to structural integrity, but NAC failed to demonstrate treatment effects on longitudinal measures of brain morphology. ClinicalTrials.gov Identifier: NCT01339858.}, }
@article {pmid29587772, year = {2018}, author = {Aizawa, H and Koarai, A and Shishikura, Y and Yanagisawa, S and Yamaya, M and Sugiura, H and Numakura, T and Yamada, M and Ichikawa, T and Fujino, N and Noda, M and Okada, Y and Ichinose, M}, title = {Oxidative stress enhances the expression of IL-33 in human airway epithelial cells.}, journal = {Respiratory research}, volume = {19}, number = {1}, pages = {52}, pmid = {29587772}, issn = {1465-993X}, mesh = {Aged ; Antiviral Agents/toxicity ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Female ; Gene Expression ; Humans ; Hydrogen Peroxide/toxicity ; Interleukin-33/*biosynthesis/genetics ; MAP Kinase Signaling System/drug effects/physiology ; Male ; Middle Aged ; Oxidative Stress/drug effects/*physiology ; Poly I-C/toxicity ; Respiratory Mucosa/drug effects/*metabolism/virology ; Rhinovirus/drug effects/physiology ; }, abstract = {BACKGROUND: Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, and its possible involvement in the pathophysiology of COPD and viral-induced exacerbations has been demonstrated. IL-33 has been shown to be increased in the airway epithelial cells from COPD patients, but the regulating mechanism of IL-33 expression in airway epithelial cells remains largely unknown. In the current study, we examined whether oxidative stress, which participates in the pathogenesis of COPD, affects the expression of IL-33 in airway epithelial cells and also evaluated the effect during viral infection.<br><br>METHODS: The involvement of oxidative stress in the expression of IL-33, and its signal pathway was examined after stimulation with hydrogen peroxide (H2O2), with or without stimulation by polyinosinic-polycytidylic acid [poly (I:C)], a synthetic analogue of dsRNA that mimics viral infection, or rhinovirus infection in NCI-H292 cells and primary human bronchial epithelial cells (HBECs). In addition, the effect of antioxidant, N-acetylcysteine (NAC) in the expression of IL-33 was compared between HBECs from healthy subjects and those from COPD patients.<br><br>RESULTS: Treatment with H2O2 significantly potentiated IL-33 expression in NCI-H292 cells, and the potentiation was reversed by NAC treatment. Mitogen-activated protein kinase (MAPK) inhibitors, but not nuclear factor-kappa B inhibitors, also significantly decreased the H2O2-potentiated IL-33 expression. In addition, H2O2 significantly potentiated the poly (I:C)- or rhinovirus-stimulated IL-33 expression. In HBECs from healthy subjects, H2O2-potentiated IL-33 expression and its reversal by NAC was also confirmed. Under the condition without H2O2-stimulation, treatment with NAC significantly decreased the expression of IL-33 in HBECs from COPD patients, but not in those from healthy subjects.<br><br>CONCLUSIONS: These results demonstrate that oxidative stress involves in the expression of IL-33 in airway epithelial cells via MAPK signal pathway and it augments IL-33 expression during viral infection. This mechanism may participate in the regulation of IL-33 expression in airway epithelial cells in COPD and the viral-induced exacerbations. Modulation of this pathway could become a therapeutic target for viral-induced exacerbations of COPD.}, }
@article {pmid29582407, year = {2019}, author = {Kuruoglu, T and Onger, ME and Turan, DB and Kuruoglu, E}, title = {In Vitro Activity of Linezolid, Daptomycin and N-acetylcysteine Agents on Staphylococcus Aureus Biofilms in the Ventriculoperitoneal Shunt Model.}, journal = {Turkish neurosurgery}, volume = {29}, number = {1}, pages = {66-71}, doi = {10.5137/1019-5149.JTN.22470-18.1}, pmid = {29582407}, issn = {2651-5032}, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects ; Catheter-Related Infections/microbiology ; Catheters, Indwelling/microbiology ; Daptomycin/*pharmacology ; In Vitro Techniques ; Linezolid/*pharmacology ; Methicillin-Resistant Staphylococcus aureus/drug effects ; Microbial Sensitivity Tests ; Prosthesis-Related Infections/microbiology ; Staphylococcal Infections/*microbiology ; Staphylococcus aureus/*physiology ; Ventriculoperitoneal Shunt/adverse effects ; }, abstract = {AIM: To examine the effects of N-acetylcysteine (NAC) alone and in combination with linezolid (LIN) and daptomycin (DAPT) on methicillin-sensitive Staphylococcus aureus (MSSA) biofilm formation.<br><br>MATERIAL AND METHODS: Twelve groups (each containing six molds) of standard ventriculoperitoneal shunts were infected with MSSA. By using microbiological and electron microscopic evaluation methods, NAC was evaluated, alone and in combination with DAPT and LIN, in terms of preventing and eliminating biofilm capacity. The effect of NAC alone and in combination with DAPT and LIN were shown by microbial counts and electron microscopic observation.<br><br>RESULTS: There was no significant difference in biofilm formation in shunts after different antibiotic treatments. However, the combination of NAC and DAPT had the highest bactericidal effects of all the groups.<br><br>CONCLUSION: The resistance of bacteria and the dose-dependent effects of antibiotics can be considered.}, }
@article {pmid29582092, year = {2018}, author = {Piao, MJ and Ahn, MJ and Kang, KA and Ryu, YS and Hyun, YJ and Shilnikova, K and Zhen, AX and Jeong, JW and Choi, YH and Kang, HK and Koh, YS and Hyun, JW}, title = {Particulate matter 2.5 damages skin cells by inducing oxidative stress, subcellular organelle dysfunction, and apoptosis.}, journal = {Archives of toxicology}, volume = {92}, number = {6}, pages = {2077-2091}, pmid = {29582092}, issn = {1432-0738}, mesh = {Air Pollution/adverse effects ; Animals ; Apoptosis/*drug effects ; Autophagy/drug effects ; Cell Line ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Keratinocytes/*drug effects/metabolism/pathology ; Mice ; Mitochondrial Swelling/*drug effects ; Oxidative Stress/*drug effects ; Particle Size ; Particulate Matter/metabolism/*toxicity ; Reactive Oxygen Species/metabolism ; Skin/*drug effects/metabolism/pathology ; }, abstract = {The skin is the largest organ of the human body and the one mostly exposed to outdoor contaminants. To evaluate the biological mechanisms underlying skin damage caused by fine particulate matter (PM2.5), we analyzed the effects of PM2.5 on cultured human keratinocytes and the skin of experimental animals. PM2.5 was applied to human HaCaT keratinocytes at 50 µg/mL for 24 h and to mouse skin at 100 µg/mL for 7 days. The results indicate that PM2.5 induced oxidative stress by generating reactive oxygen species both in vitro and in vivo, which led to DNA damage, lipid peroxidation, and protein carbonylation. As a result, PM2.5 induced endoplasmic reticulum stress, mitochondrial swelling, and autophagy, and caused apoptosis in HaCaT cells and mouse skin tissue. The PM2.5-induced cell damage was attenuated by antioxidant N-acetyl cysteine, confirming that PM2.5 cellular toxicity was due to oxidative stress. These findings contribute to understanding of the pathophysiological mechanisms triggered in the skin by PM2.5, among which oxidative stress may play a major role.}, }
@article {pmid29581375, year = {2018}, author = {Pasupathy, S and Tavella, R and Beltrame, JF}, title = {Response by Pasupathy et al to Letters Regarding Article, "Early Use of N-acetylcysteine (NAC) With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Reduces Myocardial Infarct Size (The NACIAM Trial [N-Acetylcysteine in Acute Myocardial Infarction])".}, journal = {Circulation}, volume = {137}, number = {13}, pages = {1424-1425}, doi = {10.1161/CIRCULATIONAHA.117.032512}, pmid = {29581375}, issn = {1524-4539}, mesh = {Acetylcysteine ; Humans ; *Myocardial Infarction ; Nitrates ; *Percutaneous Coronary Intervention ; *ST Elevation Myocardial Infarction ; }, }
@article {pmid29581372, year = {2018}, author = {Khan, AA and Boyle, AJ}, title = {Letter by Khan and Boyle Regarding Article, "Early Use of N-Acetylcysteine (NAC) With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction Reduces Myocardial Infarct Size (The NACIAM Trial [N-Acetylcysteine in Acute Myocardial Infarction])".}, journal = {Circulation}, volume = {137}, number = {13}, pages = {1418-1419}, doi = {10.1161/CIRCULATIONAHA.117.032281}, pmid = {29581372}, issn = {1524-4539}, mesh = {Acetylcysteine ; Humans ; *Myocardial Infarction ; Nitrates ; *Percutaneous Coronary Intervention ; *ST Elevation Myocardial Infarction ; }, }
@article {pmid29580986, year = {2018}, author = {Gao, X and Zheng, Y and Peng, L and Ruan, X and Ji, H and Qiu, Y and Liu, X and Teng, P and Guo, D and Jiang, S}, title = {Maduramicin induces apoptosis in chicken myocardial cells via intrinsic and extrinsic pathways.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {50}, number = {}, pages = {190-200}, doi = {10.1016/j.tiv.2018.03.008}, pmid = {29580986}, issn = {1879-3177}, mesh = {Animals ; Anti-Bacterial Agents/*toxicity ; Apoptosis/drug effects ; Calcium/metabolism ; Caspases/genetics ; Cell Survival/drug effects ; Cells, Cultured ; Chickens ; Cytochromes c/genetics ; Glutathione/metabolism ; Lactones/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; Myocytes, Cardiac/*drug effects/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics ; Reactive Oxygen Species/metabolism ; }, abstract = {Maduramicin is one of the most extensively used anticoccidial drugs for the treatment of Eimeria spp. infections. However, overdosage, misuse and drug interactions have resulted in the development of ionophore toxic syndrome. Heart and skeletal muscles have been identified as the main target organs of toxicity. In the present study, primary chicken myocardial cells were isolated to investigate the toxicity and underlying mechanisms of maduramicin. Our results showed that maduramicin causes morphological changes and a decrease in the viability of chicken myocardial cells. Annexin V-FITC/PI and 4',6-diamidino-2-phenylindole (DAPI) staining showed a significant increase in the number of apoptotic cells. Furthermore, caspases-3/8/9 were activated at the gene and protein levels and this was accompanied by the upregulation of apoptosis-related genes, including bcl-2, bax, and cytochrome C. Treatment with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (O-Me) fluoromethyl ketone (z-VAD-fmk) ameliorated the apoptosis and cytotoxicity. Furthermore, intracellular Ca[2+] and reactive oxygen species (ROS) were elevated, whereas mitochondrial membrane potential (MMP) and intracellular glutathione (GSH) decreased with exposure to maduramicin. The antioxidant N-acetyl-cysteine (NAC) had no significant effect on maduramicin-induced cytotoxicity and apoptosis. Taken together, our findings demonstrate that maduramicin is cytotoxic to primary chicken myocardial cells via caspase dependent and independent apoptotic pathways.}, }
@article {pmid29580927, year = {2018}, author = {Erdemli, ME and Arif Aladag, M and Altinoz, E and Demirtas, S and Turkoz, Y and Yigitcan, B and Bag, HG}, title = {Acrylamide applied during pregnancy causes the neurotoxic effect by lowering BDNF levels in the fetal brain.}, journal = {Neurotoxicology and teratology}, volume = {67}, number = {}, pages = {37-43}, doi = {10.1016/j.ntt.2018.03.005}, pmid = {29580927}, issn = {1872-9738}, mesh = {Acetylcysteine/pharmacology ; Acrylamide/antagonists &amp; inhibitors/*toxicity ; Animals ; Brain/*metabolism/pathology ; Brain-Derived Neurotrophic Factor/*metabolism ; Female ; Intracranial Hemorrhages/chemically induced ; Male ; Necrosis/chemically induced/pathology ; Oxidative Stress/drug effects ; Pregnancy ; Rats ; }, abstract = {OBJECTIVES: The aim of this study is to elucidate the possible mechanism of neurotoxic effect of acrylamide (AA) applied during pregnancy on fetal brain development and to show the effect of N-acetylcysteine (NAC) on AA toxicity.<br><br>MATERIALS AND METHODS: Four groups were formed with 9 pregnant rats each as control (C), acrylamide (AA), N-acetylcysteine (NAC), acrylamide plus N-acetylcysteine (AA plus NAC) groups. Caesarian section was implemented on the 20th day of pregnancy. Malondialdehyde (MDA), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and Brain-derived neurotrophic factor (BDNF) levels were analyzed and histopathologic examinations were performed in brain tissues of the fetuses.<br><br>RESULTS: Our data indicated that AA caused necrotic death and hemorrhagic damages in fetal brain tissue with decreasing BNDF levels and increasing oxidative stress. N-acetylcysteine prevented the toxic effects of its on fetal brain (p&#x202f;<&#x202f;0.05).<br><br>CONCLUSION: Our study indicated that acrylamide has toxic effects in the fetal brain and N-acetylcysteine prevents its toxic effect.}, }
@article {pmid29579890, year = {2018}, author = {Lopez-Lopez, V and Ros, J and Ferreras, D and Sanmartin, J and Martinez, M and Pons Miñano, JA and Sanchez-Bueno, F and Robles-Campos, R and Ramirez-Romero, P and Parrilla-Paricio, P}, title = {Molecular Adsorbent Recirculating System Treatment Can Reduce Blood Levels of N-Acetylcysteine in Patients With Acetaminophen Overdose: Case Reports.}, journal = {Transplantation proceedings}, volume = {50}, number = {2}, pages = {687-689}, doi = {10.1016/j.transproceed.2017.09.053}, pmid = {29579890}, issn = {1873-2623}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/blood/*therapeutic use ; Adolescent ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Drug Overdose/*therapy ; Female ; Free Radical Scavengers/blood/therapeutic use ; Humans ; Male ; Sorption Detoxification/adverse effects/*methods ; }, abstract = {BACKGROUND: Acetaminophen poisoning continues to be a major cause of liver failure that can lead to liver transplantation. N-acetylcysteine (NAC) is the cornerstone of treatment. Some authors use a Molecular Adsorbent Recirculating System (MARS) system in acetaminophen poisoning. It is reported that the MARS system eliminates acetaminophen more efficiently than conventional dialysis. It is theoretically possible that treatment with MARS administered after NAC will increase the effectiveness of treatment.<br><br>CASE REPORTS: The first patient, a woman of 14 years old, presented blood levels of 112 mg/dL 12 hours after ingestion of 15 g of acetaminophen. Treatment with NAC was initiated. At 17 and 23 hours after ingestion, blood levels were 23.5 &#x3bc;g/mL and 5.9 &#x3bc;g/mL, respectively. The second patient, a woman of 28 years old, presented blood levels of 115 mg/dL 4 hours after ingestion of 40 g of acetaminophen. Treatment with NAC was initiated. At 14 and 23 hours after ingestion, blood levels were 15.8 &#x3bc;g/mL and&#xa0;<2 &#x3bc;g/mL, respectively. In both patients, we performed MARS after completing treatment with NAC, and after the first session, blood levels were below the lower limit of detection (&#x2264;2 &#x3bc;g/mL).<br><br>DISCUSSION: The correct timing of MARS to avoid interactions with the administered dose of NAC in acetaminophen overdose is essential so as to not impair the effectiveness of this treatment. These considerations in the management of this entity help in the resolution of liver failure, thus avoiding the need for a liver transplant.}, }
@article {pmid29577492, year = {2018}, author = {Triquell, MF and Díaz-Luján, C and Romanini, MC and Ramirez, JC and Paglini-Oliva, P and Schijman, AG and Fretes, RE}, title = {Nitric oxide synthase and oxidative-nitrosative stress play a key role in placental infection by Trypanosoma cruzi.}, journal = {American journal of reproductive immunology (New York, N.Y. : 1989)}, volume = {80}, number = {1}, pages = {e12852}, doi = {10.1111/aji.12852}, pmid = {29577492}, issn = {1600-0897}, mesh = {Animals ; Chagas Disease/*metabolism/*parasitology ; Chorionic Gonadotropin/metabolism ; Female ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type III/*metabolism ; Nitrosative Stress/*physiology ; Oxidative Stress/*physiology ; Placenta/*metabolism/*parasitology ; Pregnancy ; Reactive Oxygen Species/metabolism ; Trophoblasts/metabolism ; Trypanosoma cruzi/*pathogenicity ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {PROBLEM: The innate immune response of the placenta may participate in the congenital transmission of Chagas disease through releasing reactive oxygen and nitrogen intermediates.<br><br>METHOD OF STUDY: Placental explants were cultured with 1&#xa0;&#xd7;&#xa0;10[6] and 1&#xa0;&#xd7;&#xa0;10[5] trypomastigotes of Tulahuen and Lucky strains and controls without parasites, and with the addition of nitric oxide synthase inhibitor N&#x3c9;-Nitro-l-arginine methyl ester (l-NAME) and N-acetyl cysteine (NAC) as the reactive oxygen species (ROS) scavenger. Detachment of the syncytiotrophoblast (STB) was examined by histological analysis, and the nitric oxide synthase, endothelial (eNOS), and nitrotyrosine expressions were analyzed by immunohistochemistry, as well as the human chorionic gonadotrophin (hCG) levels in the culture supernatant through ELISA assays. Parasite load with qPCR using Taqman primers was quantified.<br><br>RESULTS: The higher number of T. cruzi (10[6]) increased placental infection, eNOS expression, nitrosative stress, and STB detachment, with the placental barrier being injured by oxidative stress.<br><br>CONCLUSION: The higher number of parasites caused deleterious consequences to the placental barrier, and the inhibitors (l-NAME and NAC) prevented the damage caused by trypomastigotes in placental villi but not that of the infection. Moreover, trophoblast eNOS played a key role in placental infection with the highest inoculum of Lucky, demonstrating the importance of the enzyme and nitrosative-oxidative stress in Chagas congenital transmission.}, }
@article {pmid29574134, year = {2018}, author = {Rendell, R and Fairhall, S and Graham, S and Rutter, S and Auton, P and Smith, A and Perrott, R and Jugg, B}, title = {Assessment of N-acetylcysteine as a therapy for phosgene-induced acute lung injury.}, journal = {Toxicology letters}, volume = {290}, number = {}, pages = {145-152}, doi = {10.1016/j.toxlet.2018.03.025}, pmid = {29574134}, issn = {1879-3169}, mesh = {Acetylcysteine/*therapeutic use ; Acute Lung Injury/chemically induced/*drug therapy ; Animals ; Female ; Glutathione/metabolism ; Lung/pathology ; Phosgene/*toxicity ; Pulmonary Edema/chemically induced ; Respiratory Rate/drug effects ; Swine ; }, abstract = {The toxic industrial chemical (TIC[1]) phosgene remains an important chemical intermediate in many industrial processes. Inhalation of phosgene can cause an acute lung injury (ALI) which, in severe cases may result in death. There are currently no effective pharmacological therapies or evidence-based treatment guidelines for managing exposed individuals. N-acetylcysteine (NAC) is a commercially available drug licensed in the UK and elsewhere for the treatment of paracetamol (acetaminophen) overdose. It has a number of mechanisms of action which may provide therapeutic benefit for the treatment of phosgene-induced ALI. It has previously been shown to provide therapeutic efficacy against the lung damaging effects of sulfur mustard vapour exposure, when given by the inhaled route, in the pig (Jugg et al., 2013). Our research objective was to determine whether inhaled NAC might also be therapeutic for other chemicals, in this case, phosgene. This study has demonstrated that multiple nebulised doses, administered from 30 min after exposure of terminally anaesthetised pigs to phosgene, is not an effective therapy when administered at the times and doses employed in this study. There remains no pharmacological treatment for phosgene-induced lung injury.}, }
@article {pmid29574133, year = {2018}, author = {Tsai, MS and Wang, YH and Lai, YY and Tsou, HK and Liou, GG and Ko, JL and Wang, SH}, title = {Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice.}, journal = {Toxicology letters}, volume = {290}, number = {}, pages = {97-109}, doi = {10.1016/j.toxlet.2018.03.024}, pmid = {29574133}, issn = {1879-3169}, mesh = {Acetaminophen/*analogs &amp; derivatives/toxicity ; Acetylcysteine/pharmacology ; Acute Lung Injury/chemically induced/*prevention &amp; control ; Animals ; Apoptosis/*drug effects ; Cytochrome P-450 CYP2E1/*metabolism ; DNA Damage ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors ; Glucuronosyltransferase/*metabolism ; Inflammation/*prevention &amp; control ; Kaempferols/*pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; NF-E2-Related Factor 2/physiology ; Oxidative Stress/*drug effects ; Superoxide Dismutase/metabolism ; }, abstract = {Acetaminophen (APAP) overdose can induce acute liver injury (ALI) with significant morbidity and mortality. Propacetamol is an APAP prodrug, which is clinically bioequivalent to APAP. Kaempferol, a dietary flavonoid, has antioxidant, anti-inflammatory, and anti-apoptotic effects. In this study, we investigated the protective effect of kaempferol on propacetamol-induced ALI and its underlying mechanism in mice. Kaempferol pretreatment (125 mg/kg) before propacetamol injection significantly decreased propacetamol-induced serum ALT and AST activities, and DNA fragmentation. Kaempferol administration also reduced propacetamol-induced oxidative stress by inhibiting thiobarbituric acid reactive substances (TBARS) and 3-nitrotyrosine (3-NT) formation partly through downregulation of cytochrome P450 2E1 (CYP2E1) expression, upregulation of UDP glucuronosyltransferase family 1 member A1 (UGT1A1) expression, restoration of the activities of antioxidant enzymes including SOD, GPx and catalase toward normal, recovery of propacetamol-suppressed Nrf2 and GCLC expressions, and maintenance of normal glutathione level. Furthermore, kaempferol markedly attenuated APAP-induced serum TNF-α and IL-6 productions, downregulated APAP-induced phosphorylations of JNK and ERK, and decreased early hepatic apoptosis via decreasing Bax/Bcl-2 ratio and caspase 3 activation. Furthermore, administration of N-acetylcysteine (NAC) and kaempferol significantly rescued more mice than a low dose of NAC only did when a lethal dose of propacetamol injected and therapized at a delayed time point. These data suggested that kaempferol protects the liver against propacetamol-induced injury through anti-oxidative, anti-inflammatory and anti-apoptotic activities.}, }
@article {pmid29573703, year = {2018}, author = {Valdivieso, &#xc1;G and Dugour, AV and Sotomayor, V and Clauzure, M and Figueroa, JM and Santa-Coloma, TA}, title = {N-acetyl cysteine reverts the proinflammatory state induced by cigarette smoke extract in lung Calu-3 cells.}, journal = {Redox biology}, volume = {16}, number = {}, pages = {294-302}, pmid = {29573703}, issn = {2213-2317}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants ; Cigarette Smoking/adverse effects ; Cystic Fibrosis Transmembrane Conductance Regulator/*genetics ; Epithelial Cells ; Humans ; Lung/*drug effects/pathology ; Mitochondria/drug effects/genetics/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Nicotiana/chemistry/*toxicity ; }, abstract = {Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are lethal pulmonary diseases. Cigarette consumption is the main cause for development of COPD, while CF is produced by mutations in the CFTR gene. Although these diseases have a different etiology, both share a CFTR activity impairment and proinflammatory state even under sterile conditions. The aim of this work was to study the extent of the protective effect of the antioxidant N-acetylcysteine (NAC) over the proinflammatory state (IL-6 and IL-8), oxidative stress (reactive oxygen species, ROS), and CFTR levels, caused by Cigarette Smoke Extract (CSE) in Calu-3 airway epithelial cells. CSE treatment (100 µg/ml during 24 h) decreased CFTR mRNA expression and activity, and increased the release of IL-6 and IL-8. The effect on these cytokines was inhibited by N-acetyl cysteine (NAC, 5 mM) or the NF-kB inhibitor, IKK-2 (10 µM). CSE treatment also increased cellular and mitochondrial ROS levels. The cellular ROS levels were normalized to control values by NAC treatment, although significant effects on mitochondrial ROS levels were observed only at short times (5´) and effects on CFTR levels were not observed. In addition, CSE reduced the mitochondrial NADH-cytochrome c oxidoreductase (mCx I-III) activity, an effect that was not reverted by NAC. The reduced CFTR expression and the mitochondrial damage induced by CSE could not be normalized by NAC treatment, evidencing the need for a more specific reagent. In conclusion, CSE causes a sterile proinflammatory state and mitochondrial damage in Calu-3 cells that was partially recovered by NAC treatment.}, }
@article {pmid29567110, year = {2018}, author = {Han, A and Zou, L and Gan, X and Li, Y and Liu, F and Chang, X and Zhang, X and Tian, M and Li, S and Su, L and Sun, Y}, title = {ROS generation and MAPKs activation contribute to the Ni-induced testosterone synthesis disturbance in rat Leydig cells.}, journal = {Toxicology letters}, volume = {290}, number = {}, pages = {36-45}, doi = {10.1016/j.toxlet.2018.03.016}, pmid = {29567110}, issn = {1879-3169}, mesh = {Animals ; Cells, Cultured ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/physiology ; JNK Mitogen-Activated Protein Kinases/physiology ; Leydig Cells/*drug effects/metabolism ; MAP Kinase Signaling System/*physiology ; Male ; Nickel/*toxicity ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Testosterone/*biosynthesis ; p38 Mitogen-Activated Protein Kinases/physiology ; }, abstract = {Nickel (Ni) can disorder testosterone synthesis in rat Leydig cells, whereas the mechanisms remain unclear. The aim of this study was to investigate the role of reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) in Ni-induced disturbance of testosterone synthesis in rat Leydig cells. The testosterone production and ROS levels were detected in Leydig cells. The mRNA and protein levels of testosterone synthetase, including StAR, CYP11A1, 3β-HSD, CYP17A1 and 17β-HSD, were determined. Effects of Ni on the ERK1/2, p38 and JNK MAPKs were also investigated. The results showed that Ni triggered ROS generation, consequently resulted in the decrease of testosterone synthetase expression and testosterone production in Leydig cells, which were then attenuated by ROS scavengers of N-acetylcysteine (NAC) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), indicating that ROS are involved in the Ni-induced testosterone biosynthesis disturbance. Meanwhile Ni activated the ERK1/2, p38 and JNK MAPKs. Furthermore, Ni-inhibited testosterone synthetase expression levels and testosterone secretion were all alleviated by co-treatment with MAPK specific inhibitors (U0126 and SB203580, respectively), implying that Ni inhibited testosterone synthesis through activating ERK1/2 and p38 MAPK signal pathways in Leydig cells. In conclusion, these findings suggest that Ni causes testosterone synthesis disorder, partly, via ROS and MAPK signal pathways.}, }
@article {pmid29565458, year = {2018}, author = {Si, L and Yan, X and Hao, W and Ma, X and Ren, H and Ren, B and Li, D and Dong, Z and Zheng, Q}, title = {Licochalcone D induces apoptosis and inhibits migration and invasion in human melanoma A375 cells.}, journal = {Oncology reports}, volume = {39}, number = {5}, pages = {2160-2170}, pmid = {29565458}, issn = {1791-2431}, mesh = {Animals ; Antineoplastic Agents/*administration &amp; dosage/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chalcones/*administration &amp; dosage/pharmacology ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Matrix Metalloproteinase 2/*metabolism ; Matrix Metalloproteinase 9/*metabolism ; Melanoma/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred C57BL ; Neoplasm Invasiveness ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {The aim of the present study was to determine the effects of Licochalcone D (LD) on the apoptosis and migration and invasion in human melanoma A375 cells. Cell proliferation was determined by sulforhodamine B assay. Apoptosis was assessed by Hoechst 33258 and Annexin V‑FITC/PI staining and JC‑1 assay. Total intracellular reactive oxygen species (ROS) was examined by DCFH‑DA. Wound healing and Transwell assays were used to detect migration and invasion of the cells. The activities of matrix metalloproteinase (MMP‑2 and MMP‑9) were assessed via gelatin zymography. Tumor growth in vivo was evaluated in C57BL/6 mice. RT‑PCR, qPCR, ELISA and western blot analysis were utilized to measure the mRNA and protein levels. Our results showed that LD inhibited the proliferation of A375 and SK‑MEL‑5 cells in a concentration‑dependent manner. After treatment with LD, A375 cells displayed obvious apoptotic characteristics, and the number of apoptotic cells was significantly increased. Pro‑apoptotic protein Bax, caspase‑9 and caspase‑3 were upregulated, while anti‑apoptotic protein Bcl‑2 was downregulated in the LD‑treated cells. Meanwhile, LD induced the loss of mitochondrial membrane potential (ΔΨm) and increased the level of ROS. ROS production was inhibited by the co‑treatment of LD and free radical scavenger N‑acetyl‑cysteine (NAC). Furthermore, LD also blocked A375 cell migration and invasion in vitro which was associated with the downregulation of MMP‑9 and MMP‑2. Finally, intragastric administration of LD suppressed tumor growth in the mouse xenograft model of murine melanoma B16F0 cells. These results suggest that LD may be a potential drug for human melanoma treatment by inhibiting proliferation, inducing apoptosis via the mitochondrial pathway and blocking cell migration and invasion.}, }
@article {pmid29561067, year = {2018}, author = {Firth, J and Rosenbaum, S and Ward, PB and Curtis, J and Teasdale, SB and Yung, AR and Sarris, J}, title = {Adjunctive nutrients in first-episode psychosis: A systematic review of efficacy, tolerability and neurobiological mechanisms.}, journal = {Early intervention in psychiatry}, volume = {12}, number = {5}, pages = {774-783}, pmid = {29561067}, issn = {1751-7893}, support = {P117413F07//Medical Research Council/United Kingdom ; }, mesh = {Dietary Supplements/*adverse effects ; Drug Therapy, Combination/methods ; Humans ; Nutrients/*adverse effects/*therapeutic use ; Psychotic Disorders/*diet therapy/drug therapy ; }, abstract = {AIM: The effects of nutrient-based treatments, including adjunctive vitamin or antioxidant supplementation, have been explored extensively in long-term schizophrenia. However, no systematic evaluation of trials in "first-episode psychosis" (FEP) has been conducted, despite the potential benefits of using these treatments during the early stages of illness. Therefore, we aimed to review all studies examining efficacy, tolerability and the biological mechanisms of action, of nutrient supplementation in FEP.<br><br>METHODS: A systematic review of electronic databases was conducted from inception to July 2017. All information on feasibility, clinical outcomes and mechanistic findings from nutrient supplementation clinical trials was extracted and systematically synthesized.<br><br>RESULTS: Eleven studies with a total of 451 patients with FEP (from 8 independent randomized controlled trials) were eligible for inclusion. Six studies examined omega-3 fatty acids, with inconsistent effects on psychiatric symptoms. However, mechanistic studies found significant improvements in hippocampal neuronal health and brain glutathione. Antioxidants "n-acetyl cysteine" (n = 1) and vitamin C (n = 2) also improved oxidative status in FEP, which was associated with reduced psychiatric symptoms. No benefits were found for vitamin E (n = 1). Finally, one study trialling the amino acid taurine, showed significant improvements in positive symptoms and psychosocial functioning.<br><br>CONCLUSION: There is preliminary evidence that taurine improves outcomes in FEP, whereas effects of omega-3 and antioxidant vitamins/amino-acids are inconsistent; perhaps mainly benefitting patients with high levels of oxidative stress. Future studies should evaluate multifaceted dietary and supplementation interventions in FEP; targeting-specific nutritional deficits and the range of aberrant biological processes implicated in the disorder.}, }
@article {pmid29552311, year = {2018}, author = {Liu, H and Cheng, XH}, title = {MiR-29b reverses oxaliplatin-resistance in colorectal cancer by targeting SIRT1.}, journal = {Oncotarget}, volume = {9}, number = {15}, pages = {12304-12315}, pmid = {29552311}, issn = {1949-2553}, abstract = {Oxaliplatin is a commonly used chemotherapeutic drug for the treatment of advanced colorectal cancer. However, acquired drug resistance against oxaliplatin remains a major obstacle for efficient use of it, and mechanisms underlying oxaliplatin resistance are still required to be explored. In the present study, we exposed colorectal cancer cell line SW480 to oxaliplatin for a long time to obtain oxaliplatin-resistant colorectal cancer cell model (OR-SW480). We found that intracellular expression of miR-29b was decreased when the SW480 cells became oxaliplatin-resistant. More importantly, overexpression of miR-29b resensitized OR-SW480 cells to oxaliplatin treatment. Mechanically, gene of SIRT1 was identified to be the target of miR-29b. Overexpression of miR-29b in oxaliplatin-treated OR-SW480 decreased the expression of SIRT1 to enhance the ROS production and JNK phosphorylation, and thus promoting apoptosis via activation of caspase 9, 7 and 3. On the other hand, expression plasmid of SIRT1, N-acetyl cysteine or SP600125 (JNK specific inhibitor) abolished the effect of miR-29b on oxaliplatin-treated OR-SW480. We therefore demonstrated that miR-29b reverses oxaliplatin-resistance in colorectal cancer by targeting SIRT1/ROS/JNK pathway.}, }
@article {pmid29552072, year = {2017}, author = {Modarresi, A and Ziaie, S and Salamzadeh, J and Sahraei, Z and Nafar, M and Panahi, Y and Parvin, M and Einollahi, B}, title = {Study of The Effects of N-Acetylcysteine on Oxidative Stress Status of Patients on Maintenance-Hemodialysis Undergoing Cadaveric Kidney Transplantation.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {16}, number = {4}, pages = {1631-1638}, pmid = {29552072}, issn = {1735-0328}, abstract = {N-acetylcysteine (NAC) is a potent antioxidant that acts through regenerating glutathione stores and scavenging oxygen-free radicals. This study assesses the short-term effects of NAC in cadaveric kidney transplant (KT) recipients. A double blind, randomized, placebo controlled trial was designed and patients were randomly assigned to receive either NAC or placebo. Glutathione peroxidase (GPX) activity in erythrocytes and serum malondialdehyde (MDA) levels were measured and serum creatinine levels and estimated glomerular filtration rate (eGFR) determined in the early phase after transplantation, were also compared between two study groups. Thirty-seven males and 20 females, with mean ± SD age of 44.6 ± 12.4 years completed the study. Significant difference (P = 0.02) was seen between GPX activity reduction in the placebo group, and that of the NAC group and on the levels of MDA there was no significant difference between two study groups (P = 0.53). Significant improvement in immediate graft function (IGF), (68% versus 40%, P = 0.05) and the first week eGFR were observed in the NAC group compared to the placebo group (52.46 ± 2.77 versus 38.75 ± 19.67 mL/min/1.73 m[2], P = 0.02). It seems that the protective mechanisms of NAC, other than its antioxidant properties, can be favorable in KT patients.}, }
@article {pmid29549478, year = {2018}, author = {Wang, X and Li, R and Zhao, X and Yu, X and Sun, Q}, title = {Metformin Promotes HaCaT Cell Apoptosis through Generation of Reactive Oxygen Species via Raf-1-ERK1/2-Nrf2 Inactivation.}, journal = {Inflammation}, volume = {41}, number = {3}, pages = {948-958}, pmid = {29549478}, issn = {1573-2576}, support = {2014QLKY34//Shandong University basic research business funded projects/ ; }, mesh = {Apoptosis/*drug effects ; Cell Line ; Humans ; Keratinocytes/*pathology ; MAP Kinase Signaling System ; Metformin/*pharmacology ; NF-E2-Related Factor 2/metabolism ; Proto-Oncogene Proteins c-raf/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Although metformin (MET) may be useful for the treatment of psoriasis, the mechanisms underlying its method of action have yet to be fully elucidated. Here, the relationship between MET function and reactive oxygen species (ROS) levels and the underlying mechanism were explored in human immortalized keratinocyte cell line (HaCaT). HaCaT cells were incubated with MET at 0, 10, 20, 40, and 60 mM for 24 h. The cell viability was evaluated by the CCK-8 assay. The cell apoptosis rate and intracellular ROS levels were examined using flow cytometry. The protein expression and the phosphorylation levels of nuclear factor erythroid-derived 2 related factor 2 (Nrf2), Raf-1, and ERK1/2 were assessed by Western blot. The specific ROS scavenger N-acetyl-cysteine (NAC) and the specific Nrf2 agonist Oltipraz (OPZ) were used to analyze the effect of MET. MET decreased HaCaT cell proliferation and induced HaCaT cell apoptosis in a dose-dependent manner. MET was found to elevate intracellular ROS levels in a dose-dependent manner, while pretreatment with NAC attenuated these effects. MET inhibits the protein expression and the phosphorylation levels of Nrf2. The combination of OPZ and MET can significantly increase the cell viability, decrease the rate of apoptosis, and attenuate the intracellular ROS levels relative to MET alone. MET inhibits the protein expression and the phosphorylation levels of Raf-1 and ERK1/2. MET was found to attenuate Raf-1-ERK1/2 signaling in HaCaT cells to suppress the expression and phosphorylation levels of Nrf2, which contributed to the intracellular generation of ROS and the pro-apoptotic effects of MET.}, }
@article {pmid29546526, year = {2018}, author = {Grisanti, S and Cosentini, D and Tovazzi, V and Bianchi, S and Lazzari, B and Consoli, F and Roca, E and Berruti, A and Ferrari, VD}, title = {Hepatoprotective effect of N-acetylcysteine in trabectedin-induced liver toxicity in patients with advanced soft tissue sarcoma.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {26}, number = {8}, pages = {2929-2935}, pmid = {29546526}, issn = {1433-7339}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Antineoplastic Agents, Alkylating/*toxicity ; Disease-Free Survival ; Female ; Humans ; Liver/*pathology ; Male ; Middle Aged ; Retrospective Studies ; Sarcoma/*complications/drug therapy/pathology ; Trabectedin/*toxicity ; }, abstract = {PURPOSE: Trabectedin is one of the few active agents in soft tissue sarcoma (STS) but hepatotoxicity is frequent and represents a dose-limiting factor. Protective strategies aiming at counteracting this important side effect have a crucial clinical impact. Due to its antioxidant properties, N-acetylcysteine (NAC) has a recognized hepatoprotective effect and this provides the rationale for testing NAC in the management of trabectedin-induced hepatotoxicity.<br><br>METHODS: Patients with recurrent or metastatic soft tissue sarcoma, consecutively observed at our institution, who were considered eligible to trabectedin, received concomitant NAC if they had impaired hepatic or renal function at baseline or developed hepatotoxicity during treatment. The study aim was to retrospectively explore trabectedin administration in terms of number of cycles, mean dose, and dose intensity (DI) in patients who received NAC as compared with those who did not. Secondary end points were progression-free survival (PFS) and overall survival (OS).<br><br>RESULTS: A total number of 18 patients were enrolled in this study. Nine received NAC and nine did not. The median number of administered trabectedin cycles, mean trabectedin dose/cycles, and median DI was comparable in the two groups (p&#x2009;=&#x2009;0.450, p&#x2009;=&#x2009;0.534, and p&#x2009;=&#x2009;0.450, respectively). The PFS and OS curves overlapped.<br><br>CONCLUSION: This explorative study suggests that NAC can have a hepatoprotective activity in patients receiving trabectedin allowing to maintain an adequate dose intensity and continuative administration in patients with impaired liver and renal function or developing treatment-induced hepatotoxicity. A prospective randomized trial is warranted.}, }
@article {pmid29544934, year = {2018}, author = {Chakouri, N and Reboul, C and Boulghobra, D and Kleindienst, A and Nottin, S and Gayrard, S and Roubille, F and Matecki, S and Lacampagne, A and Cazorla, O}, title = {Stress-induced protein S-glutathionylation and phosphorylation crosstalk in cardiac sarcomeric proteins - Impact on heart function.}, journal = {International journal of cardiology}, volume = {258}, number = {}, pages = {207-216}, doi = {10.1016/j.ijcard.2017.12.004}, pmid = {29544934}, issn = {1874-1754}, mesh = {Animals ; Carrier Proteins/*metabolism ; Cytoskeletal Proteins ; Glutathione/*metabolism ; Heart/physiology ; Male ; Myocardial Contraction/*physiology ; Oxidative Stress/*physiology ; Phosphorylation/physiology ; Protein S/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Ventricular Function, Left/*physiology ; }, abstract = {BACKGROUND: The interplay between oxidative stress and other signaling pathways in the contractile machinery regulation during cardiac stress and its consequences on cardiac function remains poorly understood. We evaluated the effect of the crosstalk between β-adrenergic and redox signaling on post-translational modifications of sarcomeric regulatory proteins, Myosin Binding Protein-C (MyBP-C) and Troponin I (TnI).<br><br>METHODS AND RESULTS: We mimicked in vitro high level of physiological cardiac stress by forcing rat hearts to produce high levels of oxidized glutathione. This led to MyBP-C S-glutathionylation associated with lower protein kinase A (PKA) dependent phosphorylations of MyBP-C and TnI, increased myofilament Ca[2+] sensitivity, and decreased systolic and diastolic properties of the isolated perfused heart. Moderate physiological cardiac stress achieved in vivo with a single 35 min exercise (Low stress induced by exercise, LSE) increased TnI and cMyBP-C phosphorylations and improved cardiac function in vivo (echocardiography) and ex-vivo (isolated perfused heart). High stress induced by exercise (HSE) altered strongly oxidative stress markers and phosphorylations were unchanged despite increased PKA activity. HSE led to in vivo intrinsic cardiac dysfunction associated with myofilament Ca[2+] sensitivity defects. To limit protein S-glutathionylation after HSE, we treated rats with N-acetylcysteine (NAC). NAC restored the ability of PKA to modulate myofilament Ca[2+] sensitivity and prevented cardiac dysfunction observed in HSE animals.<br><br>CONCLUSION: Under cardiac stress, adrenergic and oxidative signaling pathways work in concert to alter myofilament properties and are key regulators of cardiac function.}, }
@article {pmid29544732, year = {2018}, author = {Hung, JH and Wee, SK and Omar, HA and Su, CH and Chen, HY and Chen, PS and Chiu, CC and Wu, MS and Teng, YN}, title = {Nuclear factor erythroid-2-related factor regulates LRWD1 expression and cellular adaptation to oxidative stress in human embryonal carcinoma cells.}, journal = {Biochimie}, volume = {148}, number = {}, pages = {99-106}, doi = {10.1016/j.biochi.2018.03.001}, pmid = {29544732}, issn = {1638-6183}, mesh = {Base Sequence ; Carcinoma, Embryonal/*pathology ; Cell Death ; Cell Line, Tumor ; *Gene Expression Regulation, Neoplastic ; Gene Silencing ; Humans ; Microtubule Proteins/*genetics ; NF-E2-Related Factor 2/deficiency/genetics/*metabolism ; *Oxidative Stress ; Oxygen/metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Leucine-rich repeats and WD repeat domain-containing protein 1 (LRWD1) is implicated in the regulation of signal transduction, transcription, RNA processing and tumor development. However, LRWD1 transcriptional regulation is not fully understood. This study aimed to investigate the relationship between LRWD1 expression and reactive oxygen species (ROS) level in human embryonal carcinoma cell line, NT2/D1 cells, which will help in understanding the transcriptional regulatory role of ROS in cells. Results showed that the exposure of NT2/D1 cells to various concentrations of hydrogen peroxide (H2O2) and the nitric oxide (NO) donor sodium nitroprusside (SNP) caused a significant increase in the mRNA and protein expression of LRWD1. In addition, LRWD1 promoter luciferase reporter assay, and Chromatin Immunoprecipitation assay (CHIP assay) showed that nuclear factor erythroid-2-related factor (Nrf2) was involved in the regulation of LRWD1 expression in response to oxidative stress. The involvement of Nrf2 was confirmed by shRNA-mediated knockdown of Nrf2 in NT2/D1 cells, which caused a significant decrease in LRWD1 expression in response to oxidative stress. Similarly, LRWD1 knockdown resulted in the accumulation of H2O2 and superoxide anion radical (O2-). Blocking ROS production by N-acetyl cysteine (NAC) protected NT2/D1 shLRWD1cells from H2O2-induced cell death. Collectively, oxidative stress increased LRWD1 expression through a Nrf2-dependent mechanism, which plays an important role in cellular adaptation to oxidative stress. These results highlight an evidence, on the molecular level, about LRWD1 transcriptional regulation under oxidative stress.}, }
@article {pmid29540445, year = {2018}, author = {Marian, AJ and Tan, Y and Li, L and Chang, J and Syrris, P and Hessabi, M and Rahbar, MH and Willerson, JT and Cheong, BY and Liu, CY and Kleiman, NS and Bluemke, DA and Nagueh, SF}, title = {Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM): A Randomized, Placebo-Controlled, Double-Blind Pilot Study.}, journal = {Circulation research}, volume = {122}, number = {8}, pages = {1109-1118}, pmid = {29540445}, issn = {1524-4571}, support = {R01 HL088498/HL/NHLBI NIH HHS/United States ; R01 HL132401/HL/NHLBI NIH HHS/United States ; R34 HL105563/HL/NHLBI NIH HHS/United States ; UL1 TR000371/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Aged ; Antioxidants/pharmacology/*therapeutic use ; Cardiomyopathy, Hypertrophic/*drug therapy/genetics/metabolism/pathology ; Connectin/genetics ; Double-Blind Method ; Echocardiography, Doppler ; Exome ; Female ; Fibrosis ; Heart/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Myocardium/pathology ; Pilot Projects ; Polymorphism, Single Nucleotide ; }, abstract = {RATIONALE: Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with antioxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM.<br><br>OBJECTIVE: To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM.<br><br>METHODS AND RESULTS: HALT-HCM (Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy) is a double-blind, randomized, sex-matched, placebo-controlled single-center pilot study in patients with HCM. Patients with HCM, who had a left ventricular wall thickness of &#x2265;15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated &#x2264;2.4 g per day. Clinical evaluation, blood chemistry, and 6-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging, the latter whenever not contraindicated, before and after 12 months of treatment. Eighty-five of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographic, echocardiographic, and cardiac magnetic resonance imaging phenotypes at the baseline between the 2 groups were similar. WSE in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC group and 11 in the placebo group completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and cardiac magnetic resonance imaging indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement-a surrogate for fibrosis-were small.<br><br>CONCLUSIONS: Treatment with NAC for 12 months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM.<br><br>CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01537926.}, }
@article {pmid29538624, year = {2018}, author = {Cieslik, KA and Sekhar, RV and Granillo, A and Reddy, A and Medrano, G and Heredia, CP and Entman, ML and Hamilton, DJ and Li, S and Reineke, E and Gupte, AA and Zhang, A and Taffet, GE}, title = {Improved Cardiovascular Function in Old Mice After N-Acetyl Cysteine and Glycine Supplemented Diet: Inflammation and Mitochondrial Factors.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {73}, number = {9}, pages = {1167-1177}, pmid = {29538624}, issn = {1758-535X}, support = {R01 HL089792/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*metabolism ; Aging/*physiology ; Animals ; Antioxidants/metabolism ; Cardiovascular Physiological Phenomena/*drug effects ; Cellular Senescence/physiology ; Diet Therapy/*methods ; *Dietary Supplements ; Glutathione/metabolism ; Glycine/*metabolism ; Inflammation/metabolism ; Mice ; Mitochondria/metabolism ; Oxidative Stress ; }, abstract = {Metabolic, inflammatory, and functional changes occur in cardiovascular aging which may stem from oxidative stress and be remediable with antioxidants. Glutathione, an intracellular antioxidant, declines with aging, and supplementation with glutathione precursors, N-acetyl cysteine (NAC) and glycine (Gly), increases tissue glutathione. Thirty-month old mice were fed diets supplemented with NAC or NAC+Gly and, after 7 weeks, cardiac function and molecular studies were performed. The NAC+Gly supplementation improved diastolic function, increasing peak early filling velocity, and reducing relaxation time, left atrial volume, and left ventricle end diastolic pressure. By contrast, cardiac function did not improve with NAC alone. Both diet supplementations decreased cardiac levels of inflammatory mediators; only NAC+Gly reduced leukocyte infiltration. Several mitochondrial genes reduced with aging were upregulated in hearts by NAC+Gly diet supplementation. These Krebs cycle and oxidative phosphorylation enzymes, suggesting improved mitochondrial function, and permeabilized cardiac fibers from NAC+Gly-fed mice produced ATP from carbohydrate and fatty acid sources, whereas fibers from control old mice were less able to utilize fatty acids. Our data indicate that NAC+Gly supplementation can improve diastolic function in the old mouse and may have potential to prevent important morbidities for older people.}, }
@article {pmid29536746, year = {2018}, author = {Yasar, M and Erdi, I and Kaya, B}, title = {The preventive effects of atorvastatin and N-acetyl cysteine in experimentally induced ischemia-reperfusion injury in rats.}, journal = {Bratislavske lekarske listy}, volume = {119}, number = {3}, pages = {167-174}, doi = {10.4149/BLL_2017_105}, pmid = {29536746}, issn = {0006-9248}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Atorvastatin/*pharmacology ; Catalase/drug effects/metabolism ; Cecal Diseases/*metabolism/pathology ; Cecum/*drug effects/metabolism/pathology ; Disease Models, Animal ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione Peroxidase/drug effects/metabolism ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; Intestinal Volvulus/*metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Rats ; Rats, Wistar ; Reperfusion Injury/*metabolism/pathology ; Superoxide Dismutase/drug effects/metabolism ; }, abstract = {AIM: We investigated the effects of atorvastatin and N-acetyl cysteine in decreasing ischemia-reperfusion damage after detorsion of a volvulus of the cecum and ascending colon.<br><br>METHODS: Wistar albino rats (250-300 g) were divided into four groups. A cecal-ascending colon volvulus was created by the intestinal clockwise 720&#xb0; rotation. At the end of one hour, the bowel was detorsioned. Group I (n = 7) was the sham (laparotomy) group, Group II (n = 7) the control (no treatment, volvulus or detorsion), Group III (n = 7) (N-acetyl cysteine administered) , and Group IV (n = 7) (atorvastatin administered) group. Blood samples were collected from each group via peripheral veins and centrifuged one hour after detorsion. The parameters of ischemia including malondialdehyde, glutathione peroxidase, catalase, and superoxide dismutase were then observed in the serous fluid.<br><br>RESULTS: Malondialdehyde and superoxide dismutase increased in the control group, whereas they were reduced in the Group III and Group IV (p = 0.005; p = 0.008, respectively). The glutathione peroxidase levels revealed no significant differences (p > 0.05), whereas the catalase levels of the group III was higher than in each of the other three groups (p < 0.001). Histopathological evaluation detected reduced lesioning of the organ in the groups which were given atorvastatin and N-acetyl cysteine.<br><br>CONCLUSION: Atorvastatin and of N-acetyl cysteine have a similar preventive effect in experimental ischemia-reperfusion injury (Tab. 8, Fig. 6, Ref. 24).}, }
@article {pmid29526616, year = {2018}, author = {Polyak, E and Ostrovsky, J and Peng, M and Dingley, SD and Tsukikawa, M and Kwon, YJ and McCormack, SE and Bennett, M and Xiao, R and Seiler, C and Zhang, Z and Falk, MJ}, title = {N-acetylcysteine and vitamin E rescue animal longevity and cellular oxidative stress in pre-clinical models of mitochondrial complex I disease.}, journal = {Molecular genetics and metabolism}, volume = {123}, number = {4}, pages = {449-462}, pmid = {29526616}, issn = {1096-7206}, support = {K12 DK094723/DK/NIDDK NIH HHS/United States ; R01 HD065858/HD/NICHD NIH HHS/United States ; R01 GM120762/GM/NIGMS NIH HHS/United States ; K23 DK102659/DK/NIDDK NIH HHS/United States ; U54 HD086984/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Genetically Modified ; Antioxidants/pharmacology ; Caenorhabditis elegans ; Cells, Cultured ; *Drug Evaluation, Preclinical ; Electron Transport Complex I/genetics/*metabolism ; Fibroblasts/drug effects/metabolism/pathology ; Free Radical Scavengers/pharmacology ; Humans ; *Longevity ; Mitochondria/drug effects/metabolism/pathology ; Mitochondrial Diseases/*drug therapy/genetics/metabolism/pathology ; Mutant Proteins/genetics/metabolism ; Mutation ; Oxidative Stress/*drug effects ; Vitamin E/*pharmacology ; }, abstract = {Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.}, }
@article {pmid29526615, year = {2018}, author = {Boyer, M and Sowa, M and Di Meo, I and Eftekharian, S and Steenari, MR and Tiranti, V and Abdenur, JE}, title = {Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy.}, journal = {Molecular genetics and metabolism}, volume = {124}, number = {1}, pages = {57-63}, doi = {10.1016/j.ymgme.2018.02.008}, pmid = {29526615}, issn = {1096-7206}, mesh = {Acetylcysteine/therapeutic use ; Amino Acids/*administration &amp; dosage/chemistry ; Biomarkers ; Brain Diseases, Metabolic, Inborn/diagnosis/*diet therapy/*drug therapy ; Cysteine ; Diet/methods ; Female ; Humans ; Infant ; Infant, Newborn ; Lactic Acid/analysis ; Male ; Malonates/analysis ; Methionine ; Metronidazole/therapeutic use ; Mitochondrial Proteins/genetics ; Mutation ; *Neonatal Screening ; Nucleocytoplasmic Transport Proteins/genetics ; Purpura/diagnosis/*diet therapy/*drug therapy ; Sulfur ; }, abstract = {Ethylmalonic encephalopathy (EE) is a devastating neurodegenerative disease caused by mutations in the ETHE1 gene critical for hydrogen sulfide (H2S) detoxification. Patients present in infancy with hypotonia, developmental delay, diarrhea, orthostatic acrocyanosis and petechiae. Biochemical findings include elevated C4, C5 acylcarnitines and lactic and ethylmalonic acid (EMA) in body fluids. Current treatment modalities include metronidazole and N-acetylcysteine (NAC) to lower the production and promote detoxification of toxic H2S. Patients are typically identified after the onset of clinical symptoms and there is limited information about long term response to treatment. We report the findings of two unrelated patients with EE, identified through newborn screening, who were managed with conventional treatment (NAC, metronidazole alternated with neomycin) and in patient 2, a novel dietary treatment restricting sulfur containing amino acids. Pathogenic mutations were confirmed in the ETHE1 gene (homozygous splice site mutation in patient 1, c.505 + 1G > A; compound heterozygous mutations in patient 2, c.131_132delAG + c.566delG). Both patients were started on metronidazole and NAC by 10 weeks of age and treated for 23 months. Patient 1 did not accept the metabolic formula due to palatability and parental refusal for gastrostomy tube placement. She demonstrated improved biomarkers (EMA, lactic acid and thiosulfate) and an attenuated clinical course. Patient 2 was started on a low methionine and cysteine diet at 8 months of age utilizing SOD Anamix® Early Years, (Nutricia). Baseline EMA levels were (642 mg/g Cr; n = 2) and decreased with medical treatment by 38% to a mean of 399 (n = 4, SD = 71, p 0.0013). With dietary treatment EMA levels were further reduced by 42% to a mean of 233 (n = 8, SD = 52, p 0.0030). Lactic acid, thiosulfates and clinical outcomes were also improved. Our long-term follow-up confirms previous reports of clinical improvement with NAC and metronidazole treatment. Additionally, our studies suggest that a diet restricted in sulfur-containing amino acids results in further improvement in clinical outcomes and biochemical markers.}, }
@article {pmid29524842, year = {2018}, author = {Hernández, H and Parra, A and Tobar, N and Molina, J and Kallens, V and Hidalgo, M and Varela, D and Martínez, J and Porras, O}, title = {Insights into the HyPer biosensor as molecular tool for monitoring cellular antioxidant capacity.}, journal = {Redox biology}, volume = {16}, number = {}, pages = {199-208}, pmid = {29524842}, issn = {2213-2317}, mesh = {Antioxidants/*isolation &amp; purification/metabolism ; *Biosensing Techniques ; Endoplasmic Reticulum/metabolism ; Humans ; Hydrogen Peroxide/*chemistry ; Mitochondria/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; }, abstract = {Aerobic metabolism brings inexorably the production of reactive oxygen species (ROS), which are counterbalanced by intrinsic antioxidant defenses avoiding deleterious intracellular effects. Redox balance is the resultant of metabolic functioning under environmental inputs (i.e. diet, pollution) and the activity of intrinsic antioxidant machinery. Monitoring of intracellular hydrogen peroxide has been successfully achieved by redox biosensor advent; however, to track the intrinsic disulfide bond reduction capacity represents a fundamental piece to understand better how redox homeostasis is maintained in living cells. In the present work, we compared the informative value of steady-state measurements and the kinetics of HyPer, a H2O2-sensitive fluorescent biosensor, targeted at the cytosol, mitochondrion and endoplasmic reticulum. From this set of data, biosensor signal recovery from an oxidized state raised as a suitable parameter to discriminate reducing capacity of a close environment. Biosensor recovery was pH-independent, condition demonstrated by experiments on pH-clamped cells, and sensitive to pharmacological perturbations of enzymatic disulfide reduction. Also, ten human cell lines were characterized according their H2O2-pulse responses, including their capacity to reduce disulfide bonds evaluated in terms of their migratory capacity. Finally, cellular migration experiments were conducted to study whether migratory efficiency was associated with the disulfide reduction activity. The migration efficiency of each cell type correlates with the rate of signal recovery measured from the oxidized biosensor. In addition, HyPer-expressing cells treated with N-acetyl-cysteine had accelerated recovery rates and major migratory capacities, both reversible effects upon treatment removal. Our data demonstrate that the HyPer signal recovery offers a novel methodological tool to track the cellular impact of redox active biomolecules.}, }
@article {pmid29522769, year = {2018}, author = {Villagarcía, HG and Castro, MC and Arbelaez, LG and Schinella, G and Massa, ML and Spinedi, E and Francini, F}, title = {N-Acetyl-l-Cysteine treatment efficiently prevented pre-diabetes and inflamed-dysmetabolic liver development in hypothalamic obese rats.}, journal = {Life sciences}, volume = {199}, number = {}, pages = {88-95}, doi = {10.1016/j.lfs.2018.03.008}, pmid = {29522769}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/therapeutic use ; Blood Glucose/drug effects/metabolism ; Hypothalamus/*drug effects/metabolism ; Insulin Resistance/physiology ; Liver/*drug effects/*metabolism ; Male ; Obesity/blood/*drug therapy ; Oxidative Stress/drug effects/physiology ; Prediabetic State/blood/*prevention &amp; control ; Rats ; Rats, Wistar ; Treatment Outcome ; }, abstract = {AIM: Hypothalamic obese rats are characterized by pre-diabetes, dyslipidemia, hyperadiposity, inflammation and, liver dysmetabolism with oxidative stress (OS), among others. We studied endocrine-metabolic dysfunctions and, liver OS and inflammation in both monosodium l-glutamate (MSG)-neonatally damaged and control litter-mate (C) adult male rats, either chronically treated with N-Acetyl-l-Cysteine since weaned (C-NAC and MSG-NAC) or not.<br><br>METHODOLOGY: We evaluated circulating TBARS, glucose, insulin, triglycerides, uric acid (UA) and, aspartate and alanine amino-transferase; insulin sensitivity markers (HOMA indexes, Liver Index of Insulin Sensitivity -LISI-) were calculated and liver steps of the insulin-signaling pathway were investigated. Additionally, we monitored liver OS (protein carbonyl groups, GSH and iNOS level) and inflammation-related markers (COX-2 and TNF&#x3b1; protein content; gene expression level of Il1b, Tnf&#x3b1; and Pai-1); and carbohydrate and lipid metabolic functions (glucokinase/fructokinase activities and, mRNA levels of Srebp1c, Fas and Gpat).<br><br>KEY FINDINGS: Chronic NAC treatment in MSG rats efficiently decreased the high circulating levels of triglycerides, UA, transaminases and TBARS, as well as peripheral (high insulinemia and HOMA indexes) and liver (LISI and the P-AKT:AKT and P-eNOS:eNOS protein ratio values) insulin-resistance. Moreover, NAC therapy in MSG rats prevented liver dysmetabolism by decreasing local levels of OS and inflammation markers. Finally, NAC-treated MSG rats retained normal liver glucokinase and fructokinase activities, and Srebp1c, Fas and Gpat (lipogenic genes) expression levels.<br><br>SIGNIFICANCE: Our study strongly supports that chronic oral antioxidant therapy (NAC administration) prevented the development of pre-diabetes, dyslipidemia, and inflamed-dysmetabolic liver in hypothalamic obese rats by efficiently decreasing high endogenous OS.}, }
@article {pmid29521616, year = {2018}, author = {Kókai, D and Mosolygó, T and Virók, DP and Endrész, V and Burián, K}, title = {N-acetyl-cysteine increases the replication of Chlamydia pneumoniae and prolongs the clearance of the pathogen from mice.}, journal = {Journal of medical microbiology}, volume = {67}, number = {5}, pages = {702-708}, doi = {10.1099/jmm.0.000716}, pmid = {29521616}, issn = {1473-5644}, abstract = {Purpose. Within the community, 10 % of acquired pneumonia is caused by Chlamydia pneumoniae. N-acetyl-cysteine (NAC) is one of the most commonly used mucolytics in respiratory diseases, but its effect on C. pneumoniae infection has not yet been investigated. In this study, our aim was to investigate whether NAC influences the replication of C. pneumoniae. After determining that NAC does have an effect on C. pneumoniae replication, the effect of an alternative drug called Ambroxol (Ax) was investigated.Methodology. The in vitro effect of NAC and Ax was studied on C. pneumoniae-infected A549 and McCoy cells. Furthermore, the influence of NAC and Ax was examined in mice infected intranasally with C. pneumoniae.Results. NAC treatment resulted in approximately sixfold more efficient C. pneumoniae growth in tissue culture compared to the untreated control cells, and this effect was shown to be based on the increased binding of the bacterium to the host cells. The C. pneumoniae-infected mice to which NAC was given had prolonged and more severe infections than the control mice. Ax decreased C. pneumoniae replication in vitro, which was partially associated with the increased expression of indolamine 2,3-dioxygenase. In animals, using the adapted usual human dose, Ax did not alter the number of recoverable C. pneumoniae.Conclusion. Based on our results, it might be recommended that a mucolytic agent other than NAC, such as Ax, be used in respiratory diseases suspected to be caused by C. pneumoniae.}, }
@article {pmid29521247, year = {2018}, author = {Batooei, M and Tahamoli-Roudsari, A and Basiri, Z and Yasrebifar, F and Shahdoust, M and Eshraghi, A and Mehrpooya, M and Ataei, S}, title = {Evaluating the Effect of Oral N-acetylcysteine as an Adjuvant Treatment on Clinical Outcomes of Patients with Rheumatoid Arthritis: A Randomized, Double Blind Clinical Trial.}, journal = {Reviews on recent clinical trials}, volume = {13}, number = {2}, pages = {132-138}, doi = {10.2174/1574887113666180307151937}, pmid = {29521247}, issn = {1876-1038}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Adult ; Aged ; Antirheumatic Agents/therapeutic use ; Arthritis, Rheumatoid/*drug therapy ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Treatment Outcome ; }, abstract = {OBJECTIVE: Oxidative stress and Overproduction of pro-inflammatory cytokines are contributed in Rheumatoid Arthritis (RA) pathogenesis. N-acetylcysteine (NAC) is an antioxidant and antiinflammatory agent which demonstrated analgesic effects in some studies. This study is designed to assess the effects of oral NAC as an adjuvant therapy on the clinical outcomes of patients with active RA.<br><br>METHODS: In this randomized clinical trial, 51 RA patients with active RA were studied in 2 groups: NAC group (27 patients) received standard treatment of RA and 600 mg NAC twice a day for 12 weeks, and placebo group (24 patients) received the standard treatment of RA and placebo. Disease activity score (DAS28) was used to assess the activity of RA, Visual Analog Scale (VAS) for the severity of pain, Health Assessment Questionnaire (HAQ) for the patients' physical performance, and Global Health (GH) parameter for the patients' assessment of their disease activity. The number of tender and swollen joints and Erythrocyte Sedimentation Rate (ESR) were also determined for each patient. Data were analyzed using SPSS version 16.0 (Chicago, IL, USA).<br><br>RESULTS: After 12 weeks of intervention, there were no significant differences between two groups in DAS28 score and ESR (P values were 0.4 and 0.6, respectively). However, GH, VAS, and HAQ scores were improved significantly in the NAC group compared to the placebo group.<br><br>CONCLUSION: Our findings indicate that oral administration of NAC may be associated with improving health status in RA patients and considered as an adjuvant therapy in these patients. Further studies with larger sample size, longer study duration and higher doses of NAC are needed to confirm the effects of oral NAC in RA patients.}, }
@article {pmid29519317, year = {2018}, author = {Huang, RZ and Huang, XC and Zhang, B and Jia, HY and Liao, ZX and Wang, HS}, title = {16-O-caffeoyl-16-hydroxylhexadecanoic acid, a medicinal plant-derived phenylpropanoid, induces apoptosis in human hepatocarcinoma cells through ROS-dependent endoplasmic reticulum stress.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {41}, number = {}, pages = {33-44}, doi = {10.1016/j.phymed.2018.01.024}, pmid = {29519317}, issn = {1618-095X}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Caffeic Acids/*pharmacology ; Calcium/metabolism ; Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Heat-Shock Proteins/metabolism ; Humans ; Liver Neoplasms/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Plants, Medicinal/chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer death, and novel chemotherapeutic drugs for treating HCC are urgently needed. 16-O-caffeoyl-16-hydroxylhexadecanoic acid (CHHA) is a new phenylpropanoid isolated by our group from Euphorbia nematocypha which is commonly used to treat solid tumors. However, the underlying mechanisms responsible for the CHHA-induced apoptosis in cancer cells, particularly in HCC, remain unknown.<br><br>PURPOSE: In the present work, we evaluated the growth inhibitory effect of CHHA on HCC cells and explored the underlying molecular mechanisms.<br><br>METHODS/STUDY DESIGNS: The anti-proliferative activity of CHHA was evaluated by MTT assay. Cell cycle, apoptosis, reactive oxygen species and mitochondrial membrane potential were determined by flow cytometry. ER localization was performed by ER-tracker red staining. The effect of CHHA on the expression of mRNA in HCC cells was detected by RT-PCR. The potential mechanisms for proteins level in ER pathway and apoptosis were analyzed by Western blot.<br><br>RESULTS: Our results showed that CHHA exerted strong anti-proliferative activity against both HepG2 and Bel-7402 cells in a concentration- and time-dependent manner. Mechanistic studies demonstrated that CHHA induced apoptosis through mitochondrial apoptotic pathway, and arrested the cell cycle at G1 phase. CHHA was also found to induce endoplasmic reticulum (ER) stress, accompanied by ROS production, increase of intracellular calcium and up-regulation of GRP78, CHOP, caspase-12 and p-PERK. Inhibition of endoplasmic reticulum stress by salubrinal pretreatment could suppress both apoptosis and ER stress, indicating that ER stress induction contributes to apoptosis and is required for the latter. Besides, the ROS scavenger N-acetyl cysteine (NAC) significantly attenuated apoptosis induced by CHHA and reversed CHHA-stimulated the expression of ER markers.<br><br>CONCLUSION: In conclusion, CHHA inhibited HCC cell growth and induced apoptosis through mitochondria-mediated pathway and ROS-mediated endoplasmic reticulum stress. This provides molecular bases for developing CHHA into a drug candidate for the treatment of HCC.}, }
@article {pmid29518632, year = {2018}, author = {Wang, YL and Zhu, QF and Cheng, LM and Wang, ST and Qin, SS and Zheng, SJ and Xiao, HM and Li, JJ and Liu, SM and Yuan, BF and Feng, YQ}, title = {Stable isotope labeling - dispersive solid phase extraction - liquid chromatography - tandem mass spectrometry for quantitative analysis of transsulfuration pathway thiols in human serum.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1083}, number = {}, pages = {12-19}, doi = {10.1016/j.jchromb.2018.02.036}, pmid = {29518632}, issn = {1873-376X}, mesh = {Breast Neoplasms/metabolism ; Chromatography, Liquid/*methods ; Diabetes Mellitus, Type 2/metabolism ; Female ; Humans ; Isotope Labeling/*methods ; Least-Squares Analysis ; Limit of Detection ; Linear Models ; ROC Curve ; Reproducibility of Results ; Solid Phase Extraction/*methods ; Sulfhydryl Compounds/*blood ; Tandem Mass Spectrometry/*methods ; }, abstract = {Low-molecular-weight thiols play important roles in a variety of pathological processes and are closely associated with a wide range of diseases. In this study, a selective and sensitive method was developed for the simultaneous determination of all the 7 thiols occurring in the transsulfuration pathway (Cysteine (Cys), homocysteine (Hcys), glutathione (GSH), N-acetylcysteine (Nac), cysteinylglycine (CysGly), glutamylcysteine (GluCys) and cysteamine (CA)) in human serum by in-vitro stable isotope labeling - dispersive solid phase extraction - liquid chromatography - tandem mass spectrometry analysis (IL-DSPE-LC-MS/MS). In the proposed method, a pair of stable isotope-labeling reagents, BQB (ω-bromoacetonylquinolinium bromide) and BQB-D7, were utilized to label thiols in human serum samples and thiol standards, respectively. The BQB labeled thiols which carry a positive charge were extracted and purified with C8-SO3H-based DSPE followed by LC-MS/MS analysis. Good linearities for 7 thiols occurring in the transsulfuration pathway were obtained with the coefficient of determination (R[2]) >0.9901. The limits of detection (LODs) were in the range of 0.7-6.0 nmol/L. The method was further applied to investigate the contents change of 7 thiols in human serum samples of type 2 diabetes mellitus (T2DM) patients and breast cancer (BC) patients. The results showed that the contents of these thiols occurring in the transsulfuration pathway significantly changed and were highly diseases-related. In addition, partial least squares discriminant analysis (PLS-DA) suggested excellent classification performance between patients and healthy controls. The findings indicated that these significantly changed thiols occurring in the transsulfuration pathway in T2DM patients and BC patients might serve as the indicator for the diagnosis of T2DM and BC. Taken together, the developed IL-DSPE-LC-MS/MS method provides a promising tool for the sensitive analysis of thiols from complex biological samples, which may promote the in-depth investigation of the functions of thiols.}, }
@article {pmid29513056, year = {2018}, author = {Tillinger, JA and Gupta, C and Ila, K and Ahmed, J and Mittal, J and Van De Water, TR and Eshraghi, AA}, title = {l-N-acetylcysteine protects outer hair cells against TNFα initiated ototoxicity in vitro.}, journal = {Acta oto-laryngologica}, volume = {138}, number = {8}, pages = {676-684}, doi = {10.1080/00016489.2018.1440086}, pmid = {29513056}, issn = {1651-2251}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Aldehydes ; Animals ; Drug Evaluation, Preclinical ; Free Radical Scavengers/pharmacology/*therapeutic use ; Glutathione/metabolism ; Glutathione Synthase/metabolism ; Hair Cells, Auditory, Outer/*drug effects ; Hearing Loss/metabolism/*prevention &amp; control ; In Vitro Techniques ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha ; }, abstract = {OBJECTIVE: The present study is aimed at determining the efficacy and exploring the mechanisms by which l-N-acetylcysteine (l-NAC) provides protection against tumor necrosis factor-alpha (TNFα)-induced oxidative stress damage and hair cell loss in 3-day-old rat organ of Corti (OC) explants. Previous work has demonstrated a high level of oxidative stress in TNFα-challenged OC explants. TNFα can potentially play a significant role in hair cell loss following an insult to the inner ear. l-NAC has shown to provide effective protection against noise-induced hearing loss in laboratory animals but mechanisms of this otoprotective effect are not well-defined.<br><br>DESIGN: Rat OC explants were exposed to either: (1) saline control (N&#x2009;=&#x2009;12); (2) TNF&#x3b1; (2&#x2009;&#x3bc;g/ml, N&#x2009;=&#x2009;12); (3) TNF&#x3b1;+l-NAC (5&#x2009;mM, N&#x2009;=&#x2009;12); (4) TNF&#x3b1;+l-NAC (10&#x2009;mM, N&#x2009;=&#x2009;12); or (5) l-NAC (10&#x2009;mM, N&#x2009;=&#x2009;12). Outer hair cell (OHC) density, levels of reactive oxygen species (ROS), lipid peroxidation of cell membranes, gluthathione activity, and mitochondrial viability were assayed.<br><br>RESULTS: l-NAC (5 and 10&#x2009;mM) provided protection for OHCs from ototoxic level of TNF&#x3b1; in OC explants. Groups treated with TNF&#x3b1;+l-NAC (5&#x2009;mM) showed a highly significant reduction of both ROS (p&#x2009;<&#x2009;0.01) and 4-hydroxy-2-nonenal immunostaining (p&#x2009;<&#x2009;0.001) compared to TNF&#x3b1;-challenged explants. Total glutathione levels were low in TNF&#x3b1;-challenged explants compared to control and TNF&#x3b1;+l-NAC (5&#x2009;mM) treated explants (p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: l-NAC is a promising treatment for protecting auditory HCs from TNF&#x3b1;-induced oxidative stress and subsequent loss via programmed cell death.}, }
@article {pmid29512790, year = {2018}, author = {Wu, W and Liu, BH and Xie, CL and Xia, XD and Zhang, YM}, title = {Neuroprotective effects of N-acetyl cysteine on primary hippocampus neurons against hydrogen peroxide-induced injury are mediated via inhibition of mitogen-activated protein kinases signal transduction and antioxidative action.}, journal = {Molecular medicine reports}, volume = {17}, number = {5}, pages = {6647-6654}, doi = {10.3892/mmr.2018.8699}, pmid = {29512790}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain Injuries/chemically induced/*drug therapy/enzymology/pathology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Hippocampus/enzymology/*injuries/pathology ; Hydrogen Peroxide/*adverse effects/pharmacology ; MAP Kinase Signaling System/*drug effects ; Neurons/*enzymology/pathology ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {N-acetyl cysteine (NAC) has been extensively reported to exert neuroprotective effects on the central nervous system. Oxidative stress may contribute to the underlying mechanisms causing Alzheimer's disease (AD). The effect of NAC against oxidative stress injury was investigated in a cellular model of AD in the present study and the underlying mechanisms were revealed. The neuroprotective action of NAC (1, 10, 100 and 1,000 µmol/l) on a cellular model of AD [hydrogen peroxide (H2O2)‑induced (3, 30 and 300 µmol/l) toxicity in primary rat hippocampus neurons] demonstrated the underlying mechanisms. Cytotoxicity was measured using the MTT assay, and light microscopy and the dichloro-dihydro-fluorescein diacetate method were used to detect the reactive oxygen species (ROS) levels. Furthermore, the levels of mitogen-activated protein kinases (MAPKs) signal transduction and tau protein phosphorylation were measured via western blotting. NAC (100 µmol/l) protected hippocampus neurons against H2O2‑mediated toxicity, as evidenced by enhanced cell viability. Using MTT assay and light microscopy for the observation of cell death, NAC ameliorated cell viability, which was induced by H2O2 injury (P<0.05). NAC was found to mitigate the excessive production of ROS (P<0.05). Another mechanism involved in the neuroprotective action of NAC may be its ability to inhibit MAPK signal transduction following H2O2 exposure. In addition, NAC may protect cells against H2O2‑induced toxicity by attenuating increased tau phosphorylation. Thus, the protective ability of NAC is hypothesized to result from inhibition of oxidative stress and downregulation of MAPK signal transduction and tau phosphorylation.}, }
@article {pmid29506454, year = {2018}, author = {Sun, S and Zhang, C and Gao, J and Qin, Q and Zhang, Y and Zhu, H and Yang, X and Yang, D and Yan, H}, title = {Benzoquinone induces ROS-dependent mitochondria-mediated apoptosis in HL-60 cells.}, journal = {Toxicology and industrial health}, volume = {34}, number = {4}, pages = {270-281}, doi = {10.1177/0748233717750983}, pmid = {29506454}, issn = {1477-0393}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology ; Caspases/metabolism ; Dose-Response Relationship, Drug ; HL-60 Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Benzene exposure affects the hematopoietic system and leads to the occurrence of various types of leukemia and hematotoxicity. It has been confirmed that active metabolites of benzene, including 1,4-benzoquinone (1,4-BQ), can induce reactive oxygen species (ROS) and apoptosis in the bone marrow, and recent studies have also suggested that benzene exposure can affect mitochondrial function in both experimental animals and cell lines. However, the potential relationship among ROS production, mitochondrial damages, and subsequent apoptosis following benzene exposure has not been well studied in detail. In the present study, we utilized HL-60 cells, a well-characterized human myeloid cell line, as an in vitro model and examined the effects of 1,4-BQ on intracellular ROS formation, mitochondria damage, and the occurrence of apoptotic events with or without using the ROS scavenger N-acetyl-l-cysteine (NAC). The results demonstrated that 1,4-BQ could dose-dependently induce production of ROS and mitochondrial damage as characterized by mitochondrial membrane potential disruption, mitochondrial ultrastructure alteration, and induced apoptosis and activated caspase-3 and caspase-9. Preincubation of HL-60 cells with NAC prior to 1,4-BQ treatment could block 1,4-BQ-induced production of ROS and the occurrence of apoptosis. These results demonstrated that 1,4-BQ induced apoptosis in HL-60 cells through a ROS-dependent mitochondrial-mediated pathway.}, }
@article {pmid29502477, year = {2018}, author = {Shen, FC and Weng, SW and Tsao, CF and Lin, HY and Chang, CS and Lin, CY and Lian, WS and Chuang, JH and Lin, TK and Liou, CW and Wang, PW}, title = {Early intervention of N-acetylcysteine better improves insulin resistance in diet-induced obesity mice.}, journal = {Free radical research}, volume = {52}, number = {11-12}, pages = {1296-1310}, doi = {10.1080/10715762.2018.1447670}, pmid = {29502477}, issn = {1029-2470}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/*therapeutic use ; Animals ; Diet/*adverse effects ; *Insulin Resistance ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/metabolism ; Obesity/*drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Secondary Prevention ; }, abstract = {Reactive oxygen species (ROS) plays a crucial role in pathogenesis of insulin resistance (IR) and type 2 diabetes. In the United Kingdom, Prospective Diabetes Study and its 10-year post-trial monitoring, a beneficial effect of early optimisation of blood glucose control is clearly demonstrated. In this study, we investigated whether ROS scavenger N-acetylcysteine (NAC) and the time point of intervention can affect IR in a diet-induced obesity mouse model. Male C57B/L6 mice were fed chow diet (CD), high-fat high-sucrose diet (HFD), CD + NAC[1-6] (NAC intervention 1st to 6th month), HFD + NAC[1-6], and HFD + NAC[3-6] (NAC intervention 3rd to 6th month) for a 6-month treatment course. HFD group showed significantly increased body weight (BW) and body fat, decreased motor activity (MA), impaired intraperitoneal glucose tolerance test (IPGTT), and insulin tolerance test (IPITT) throughout the study. HFD + NAC[1-6], as compared with HFD group, had increased MA, improved IPGTT and IPITT since first month, followed by decreased BW and body fat. HFD + NAC[3-6] group, although showed improved IPGTT and IPITT than HFD group, still had higher BW, decreased MA, and impaired IPGTT and IPITT as compared with HFD + NAC[1-6] at the end of the study. NAC significantly increased MA, and ameliorated the HFD-induced mitochondrial and intracellular ROS expression, DNA and protein oxidative damage, and adipose tissue inflammation. We concluded that ROS scavenger can improve IR and chronic inflammation in diet-induced obesity mice. This action is likely better expressed through early intervention. The mechanism is probably through a virtuous circle of suppressed oxidative stress, and increased motor activity, which helps to reduce body fat.}, }
@article {pmid29502200, year = {2018}, author = {Luna, E and Decker, SC and Riddle, DM and Caputo, A and Zhang, B and Cole, T and Caswell, C and Xie, SX and Lee, VMY and Luk, KC}, title = {Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity.}, journal = {Acta neuropathologica}, volume = {135}, number = {6}, pages = {855-875}, pmid = {29502200}, issn = {1432-0533}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; R01 NS088322/NS/NINDS NIH HHS/United States ; T32 AG000255/AG/NIA NIH HHS/United States ; P50 NS053488/NS/NINDS NIH HHS/United States ; T32-AG000255/AG/NIA NIH HHS/United States ; NS053488/NS/NINDS NIH HHS/United States ; NS088322/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Death/physiology ; Cells, Cultured ; Female ; Gene Knockdown Techniques ; Hippocampus/*metabolism/pathology ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Knockout ; Nerve Tissue Proteins/metabolism ; Neurons/*metabolism/pathology ; Primary Cell Culture ; Protein Aggregation, Pathological/*metabolism/pathology ; Proteostasis Deficiencies/metabolism/pathology ; alpha-Synuclein/genetics/*metabolism ; }, abstract = {The accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulations are poorly understood. We show here that Math2-expressing neurons in the hippocampal Cornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate gyrus neurons, which are relatively spared. Math2[+] neurons also exhibited more rapid and severe cell loss in both in vitro and in vivo models of synucleinopathy. Toxicity resulting from PFF exposure was dependent on endogenous aSyn and could be attenuated by N-acetyl-cysteine through a glutathione-dependent process. Moreover, aSyn expression levels strongly correlate with relative vulnerability among hippocampal neuron subtypes of which Math2[+] neurons contained the highest amount. Consistent with this, antisense oligonucleotide (ASO)-mediated knockdown of aSyn reduced the neuronal pathology in a time-dependent manner. However, significant neuroprotection was observed only with early ASO intervention and a substantial reduction of aSyn pathology, indicating toxicity occurs after a critical threshold of pathological burden is exceeded in vulnerable neurons. Together, our findings reveal considerable heterogeneity in endogenous aSyn levels among hippocampal neurons and suggest that this may contribute to the selective vulnerability observed in the context of synucleinopathies.}, }
@article {pmid29500146, year = {2018}, author = {Aydın, AF and Kondakçı, G and Hatipoğlu, S and Doğru-Abbasoğlu, S and Uysal, M}, title = {N-Acetylcysteine supplementation decreased brain lipid and protein oxidations produced by experimental homocysteine thiolactone exposure: Relevance to neurodegeneration.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {25}, number = {2}, pages = {125-129}, doi = {10.1016/j.pathophys.2018.02.004}, pmid = {29500146}, issn = {0928-4680}, abstract = {High levels of homocysteine (Hcy) have neurotoxic effects. Homocysteine thiolactone (HcyT), a thioester of Hcy, plays a role in Hcy-induced toxicity. In this study, effects of HcyT treatment (500 mg/kg body weight/day in drinking water) for 6 weeks on serum Hcy levels and brain prooxidant-antioxidant balance were investigated in rats. The effect of N-acetylcysteine (NAC) treatment (1 g/kg body weight/day in chow) for 6 weeks on HcyT-induced neurotoxicity was evaluated. Reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), diene conjugate (DC), protein carbonyl (PC) and advanced oxidation protein products (AOPP) were determined in the brain tissue. Ferric reducing antioxidant power (FRAP) and non-protein sulfydryl groups (NPSH) levels as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were also measured to evaluate the antioxidant potential of brain the tissue. HcyT elevated serum Hcy levels and brain ROS, TBARS, DC, PC and AOPP levels. However, HcyT did not affect FRAP levels and SOD, and GSH-Px activities. NAC treatment decreased serum Hcy and brain ROS, TBARS, DC, PC and AOPP levels in HCyT-treated rats. Our results indicate that NAC supplementation may be effective in decreasing serum Hcy levels and HcyT-induced oxidative stress in brain of rats.}, }
@article {pmid29498634, year = {2018}, author = {Hossain, MK and Saha, SK and Abdal Dayem, A and Kim, JH and Kim, K and Yang, GM and Choi, HY and Cho, SG}, title = {Bax Inhibitor-1 Acts as an Anti-Influenza Factor by Inhibiting ROS Mediated Cell Death and Augmenting Heme-Oxygenase 1 Expression in Influenza Virus Infected Cells.}, journal = {International journal of molecular sciences}, volume = {19}, number = {3}, pages = {}, pmid = {29498634}, issn = {1422-0067}, mesh = {Animals ; Apoptosis Regulatory Proteins/genetics/*metabolism ; Cell Death/genetics ; Cell Line ; Cells, Cultured ; Cytopathogenic Effect, Viral/genetics ; Dogs ; Gene Expression Regulation ; Gene Expression Regulation, Viral ; Gene Order ; Genetic Vectors/genetics ; Heme Oxygenase-1/*genetics/metabolism ; *Host-Pathogen Interactions ; Humans ; Influenza A virus/*physiology ; Influenza, Human/genetics/metabolism/virology ; Madin Darby Canine Kidney Cells ; Membrane Proteins/genetics/*metabolism ; Models, Biological ; Reactive Oxygen Species/*metabolism ; Virus Replication ; }, abstract = {Influenza virus remains a major health concern worldwide, and there have been continuous efforts to develop effective antivirals despite the use of annual vaccination programs. The purpose of this study was to determine the anti-influenza activity of Bax inhibitor-1 (BI-1). Madin-Darby Canine Kidney (MDCK) cells expressing wild type BI-1 and a non-functional BI-1 mutant, BI-1 ∆C (with the C-terminal 14 amino acids deleted) were prepared and infected with A/PR/8/34 influenza virus. BI-1 overexpression led to the suppression of virus-induced cell death and virus production compared to control Mock or BI-1 ∆C overexpression. In contrast to BI-1 ∆C-overexpressing cells, BI-1-overexpressing cells exhibited markedly reduced virus-induced expression of several viral genes, accompanied by a substantial decrease in ROS production. We found that treatment with a ROS scavenging agent, N-acetyl cysteine (NAC), led to a dramatic decrease in virus production and viral gene expression in control MDCK and BI-1 ∆C-overexpressing cells. In contrast, NAC treatment resulted in the slight additional suppression of virus production and viral gene expression in BI-1-overexpressing cells but was statistically significant. Moreover, the expression of heme oxygenase-1 (HO-1) was also significantly increased following virus infection in BI-1-overexpressing cells compared to control cells. Taken together, our data suggest that BI-1 may act as an anti-influenza protein through the suppression of ROS mediated cell death and upregulation of HO-1 expression in influenza virus infected MDCK cells.}, }
@article {pmid29491325, year = {2018}, author = {Tanno, S and Yamamoto, K and Kurata, Y and Adachi, M and Inoue, Y and Otani, N and Mishima, M and Yamamoto, Y and Kuwabara, M and Ogino, K and Miake, J and Ninomiya, H and Shirayoshi, Y and Okada, F and Yamamoto, K and Hisatome, I}, title = {Protective Effects of Topiroxostat on an Ischemia-Reperfusion Model of Rat Hearts.}, journal = {Circulation journal : official journal of the Japanese Circulation Society}, volume = {82}, number = {4}, pages = {1101-1111}, doi = {10.1253/circj.CJ-17-1049}, pmid = {29491325}, issn = {1347-4820}, mesh = {Allopurinol/pharmacology/therapeutic use ; Animals ; Arrhythmias, Cardiac/drug therapy ; Myocardial Reperfusion Injury/*drug therapy ; Nitriles/pharmacology/*therapeutic use ; Protective Agents/pharmacology/therapeutic use ; Pyridines/pharmacology/*therapeutic use ; Rats ; Reactive Oxygen Species/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Ventricular Dysfunction, Left/prevention &amp; control ; Xanthine Dehydrogenase/antagonists &amp; inhibitors ; }, abstract = {BACKGROUND: Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, inhibition of XO is expected to suppress ROS-induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated.Methods and Results:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion.<br><br>CONCLUSIONS: Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation.}, }
@article {pmid29483230, year = {2018}, author = {Zhu, W and Wang, H and Wei, J and Sartor, GC and Bao, MM and Pierce, CT and Wahlestedt, CR and Dykxhoorn, DM and Dong, C}, title = {Cocaine Exposure Increases Blood Pressure and Aortic Stiffness via the miR-30c-5p-Malic Enzyme 1-Reactive Oxygen Species Pathway.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {71}, number = {4}, pages = {752-760}, pmid = {29483230}, issn = {1524-4563}, support = {K99 DA040744/DA/NIDA NIH HHS/United States ; R00 DA040744/DA/NIDA NIH HHS/United States ; R01 AG041754/AG/NIA NIH HHS/United States ; R21 AI116346/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Blood Pressure/drug effects ; Cardiovascular Diseases/chemically induced/metabolism ; Cocaine/*pharmacology ; *Cocaine-Related Disorders/complications/metabolism/physiopathology ; Disease Models, Animal ; Down-Regulation ; Injections ; Malate Dehydrogenase/*metabolism ; Mice ; MicroRNAs/*metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/physiology ; Vascular Stiffness/drug effects ; Vasoconstrictor Agents/pharmacology ; }, abstract = {Cocaine abuse increases the risk of cardiovascular mortality and morbidity; however, the underlying molecular mechanisms remain elusive. By using a mouse model for cocaine abuse/use, we found that repeated cocaine injection led to increased blood pressure and aortic stiffness in mice associated with elevated levels of reactive oxygen species (ROS) in the aortas, a phenomenon similar to that observed in hypertensive humans. This ROS elevation was correlated with downregulation of Me1 (malic enzyme 1), an important redox molecule that counteracts ROS generation, and upregulation of microRNA (miR)-30c-5p that targets Me1 expression by directly binding to its 3'UTR (untranslated region). Remarkably, lentivirus-mediated overexpression of miR-30c-5p in aortic smooth muscle cells recapitulated the effect of cocaine on Me1 suppression, which in turn led to ROS elevation. Moreover, in vivo silencing of miR-30c-5p in smooth muscle cells resulted in Me1 upregulation, ROS reduction, and significantly suppressed cocaine-induced increases in blood pressure and aortic stiffness-a similar effect to that produced by treatment with the antioxidant N-acetyl cysteine. Discovery of this novel cocaine-↑miR-30c-5p-↓Me1-↑ROS pathway provides a potential new therapeutic avenue for treatment of cocaine abuse-related cardiovascular disease.}, }
@article {pmid29483228, year = {2018}, author = {Neves, KB and Rios, FJ and van der Mey, L and Alves-Lopes, R and Cameron, AC and Volpe, M and Montezano, AC and Savoia, C and Touyz, RM}, title = {VEGFR (Vascular Endothelial Growth Factor Receptor) Inhibition Induces Cardiovascular Damage via Redox-Sensitive Processes.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {71}, number = {4}, pages = {638-647}, doi = {10.1161/HYPERTENSIONAHA.117.10490}, pmid = {29483228}, issn = {1524-4563}, support = {R01 HL133864/HL/NHLBI NIH HHS/United States ; RG/13/7/30099/BHF_/British Heart Foundation/United Kingdom ; RE/13/5/30177/BHF_/British Heart Foundation/United Kingdom ; CH/12/429762/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology ; Animals ; Antioxidants/metabolism ; Endothelium, Vascular/*metabolism ; Gefitinib/*pharmacology ; Humans ; Mice ; NADPH Oxidases/metabolism ; Oxidation-Reduction/*drug effects ; Oxidative Stress/drug effects ; Phthalazines/*pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyridines/*pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Signal Transduction/drug effects ; *Vascular Endothelial Growth Factors/antagonists &amp; inhibitors/metabolism ; *Vasoconstriction/drug effects/physiology ; Vasoconstrictor Agents/pharmacology ; *Vasodilation/drug effects/physiology ; }, abstract = {Although VEGF (vascular endothelial growth factor) inhibitors (VEGFIs), are effective anticancer therapies, they cause hypertension through unknown mechanisms. We questioned whether changes in vascular redox state may be important, because VEGF signaling involves nitric oxide (NO) and reactive oxygen species. Molecular mechanisms, including NOS, NADPH oxidase (Nox)-derived reactive oxygen species, antioxidant systems, and vasoconstrictor signaling pathways, were probed in human endothelial cells and vascular smooth muscle exposed to vatalanib, a VEGFI. Vascular functional effects of VEGFI were assessed ex vivo in mouse arteries. Cardiovascular and renal in vivo effects were studied in vatalanib- or gefitinib (EGFI [epidermal growth factor inhibitor])-treated mice. In endothelial cells, vatalanib decreased eNOS (Ser[1177]) phosphorylation and reduced NO and H2O2 production, responses associated with increased Nox-derived O2[-] and ONOO[-] formation. Inhibition of Nox1/4 (GKT137831) or Nox1 (NoxA1ds), prevented vatalanib-induced effects. Nrf-2 (nuclear factor erythroid 2-related factor 2) nuclear translocation and expression of Nrf-2-regulated antioxidant enzymes were variably downregulated by vatalanib. In human vascular smooth muscles, VEGFI increased Nox activity and stimulated Ca[2+] influx and MLC20 phosphorylation. Acetylcholine-induced vasodilatation was impaired and U46619-induced vasoconstriction was enhanced by vatalanib, effects normalized by N-acetyl-cysteine and worsened by L-NAME. In vatalanib-, but not gefitinib-treated mice vasorelaxation was reduced and media:lumen ratio of mesenteric arteries was increased with associated increased cardiovascular and renal oxidative stress, decreased Nrf-2 activity and downregulation of antioxidant genes. We demonstrate that inhibition of VEGF signaling induces vascular dysfunction through redox-sensitive processes. Our findings identify Noxs and antioxidant enzymes as novel targets underling VEGFI-induced vascular dysfunction. These molecular processes may contribute to vascular toxicity and hypertension in VEGFI-treated patients.}, }
@article {pmid29482444, year = {2018}, author = {Abd-Ellah, HF and Abou-Zeid, NRA and Nasr, NM}, title = {The possible protective effect of N-acetyl-L-cysteine and folic acid in combination against aspartame-induced cerebral cortex neurotoxicity in adult male rats: a light and transmission electron microscopic study.}, journal = {Ultrastructural pathology}, volume = {42}, number = {3}, pages = {228-245}, doi = {10.1080/01913123.2018.1440270}, pmid = {29482444}, issn = {1521-0758}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Aspartame/*toxicity ; Cerebral Cortex/*drug effects/pathology/ultrastructure ; Folic Acid/*pharmacology ; Male ; Microscopy, Electron, Transmission ; Neuroprotective Agents/pharmacology ; Rats ; Rats, Wistar ; Sweetening Agents/*toxicity ; }, abstract = {The purpose of this study is to investigate structural and ultrastructural alterations in the rat's brain cerebral cortex after aspartame (ASP) treatment and to evaluate the possible ameliorating role of N-acetyl-L-cysteine (NAC) and folic acid (FA). Forty adult rats were divided into four equal groups: Group I, received appropriate vehicle only and served as control. Group II, received oral doses of both NAC (600 mg/kg body weight (b.w.)) and FA (12 mg/kg b.w.) daily for 42 days. Group III, received oral doses of ASP (500 mg/kg b.w.) daily for 42 days. Group IV, received both NAC and FA, concurrently with ASP at the same doses, route and period of administration of the previous groups. Histological examination of the cerebral cortex of ASP-treated rats showed severe degenerative changes, especially in the nerve cells. Some of these cells appeared shrunken, irregular in shape, while the others appeared swollen and were surrounded by pericellular halos. Immunohistochemical and morphometric study of ASP-treated group revealed a weak B-cell lymphoma-2 (Bcl-2) immunoexpression in the cytoplasm of many cells, while intense positive immunoreaction for glial fibrillary acidic protein (GFAP) was observed in the cytoplasm and processes of astrocytes compared to control group with statistically significant difference (p < 0.001). Light microscopic results were confirmed by ultrastructural findings. However, NAC and FA in combination had an obvious protective effect against ASP-induced injury in the rat's cerebral cortex. In conclusion, these results suggested that NAC combined with FA can ameliorate the toxic effect of ASP on the rat's cerebral cortex.}, }
@article {pmid29474366, year = {2018}, author = {Piao, S and Lee, JW and Nagar, H and Jung, SB and Choi, S and Kim, S and Lee, I and Kim, SM and Shin, N and Lee, YR and Lee, SD and Park, JB and Irani, K and Won, M and Hur, GM and Jeon, BH and Kim, DW and Kim, CS}, title = {CR6 interacting factor 1 deficiency promotes endothelial inflammation by SIRT1 downregulation.}, journal = {PloS one}, volume = {13}, number = {2}, pages = {e0192693}, pmid = {29474366}, issn = {1932-6203}, mesh = {Animals ; Cell Cycle Proteins/genetics/*physiology ; *Down-Regulation ; Enzyme-Linked Immunosorbent Assay ; Human Umbilical Vein Endothelial Cells ; Humans ; Mice ; Nuclear Proteins/genetics/*physiology ; Oxidative Phosphorylation ; Signal Transduction ; Sirtuin 1/*genetics ; }, abstract = {AIMS: CR6 interacting factor 1 (CRIF1) deficiency impairs mitochondrial oxidative phosphorylation complexes, contributing to increased mitochondrial and cellular reactive oxygen species (ROS) production. CRIF1 downregulation has also been revealed to decrease sirtuin 1 (SIRT1) expression and impair vascular function. Inhibition of SIRT1 disturbs oxidative energy metabolism and stimulates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-induced inflammation. Therefore, we hypothesized that both CRIF1 deficiency-induced mitochondrial ROS production and SIRT1 reduction play stimulatory roles in vascular inflammation.<br><br>METHODS AND RESULTS: Plasma levels and mRNA expression of proinflammatory cytokines (tumor necrosis factor (TNF)-&#x3b1;, interleukin (IL)-1&#x3b2;, and IL-6) were markedly elevated in endothelium-specific CRIF1-knockout mice and CRIF1-silenced endothelial cells, respectively. Moreover, CRIF1 deficiency-induced vascular adhesion molecule-1 (VCAM-1) expression was consistently attenuated by the antioxidant N-acetyl-cysteine and NF-&#x3ba;B inhibitor (BAY11). We next showed that siRNA-mediated CRIF1 downregulation markedly activated NF-&#x3ba;B. SIRT1 overexpression not only rescued CRIF1 deficiency-induced NF-&#x3ba;B activation but also decreased inflammatory cytokines (TNF-&#x3b1;, IL-1&#x3b2;, and IL-6) and VCAM-1 expression levels in endothelial cells.<br><br>CONCLUSIONS: These results strongly suggest that CRIF1 deficiency promotes endothelial cell inflammation by increasing VCAM-1 expression, elevating inflammatory cytokines levels, and activating the transcription factor NF-&#x3ba;B, all of which were inhibited by SIRT1 overexpression.}, }
@article {pmid29471107, year = {2018}, author = {Qian, M and Lou, Y and Wang, Y and Zhang, M and Jiang, Q and Mo, Y and Han, K and Jin, S and Dai, Q and Yu, Y and Wang, Z and Wang, J}, title = {PICK1 deficiency exacerbates sepsis-associated acute lung injury and impairs glutathione synthesis via reduction of xCT.}, journal = {Free radical biology &amp; medicine}, volume = {118}, number = {}, pages = {23-34}, doi = {10.1016/j.freeradbiomed.2018.02.028}, pmid = {29471107}, issn = {1873-4596}, mesh = {Acute Lung Injury/etiology/*metabolism ; Adult ; Aged ; Amino Acid Transport System y+/*metabolism ; Animals ; Carrier Proteins/*metabolism ; Cell Cycle Proteins ; Female ; Glutathione/*biosynthesis ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Nuclear Proteins/deficiency/*metabolism ; Oxidative Stress/physiology ; Sepsis/complications/*metabolism ; }, abstract = {The role of oxidative stress has been well documented in the development of sepsis-induced acute lung injury (ALI). Protein interaction with C-kinase 1 (PICK1) participates in oxidative stress-related neuronal diseases. However, its function in lung infections and inflammatory diseases is not known. We therefore sought to investigate whether PICK1 is involved in sepsis-induced ALI. Cecal ligation and puncture (CLP) was performed in anesthetized wild type (WT) and PICK1 knock out (KO, PICK1[-/-]) mice with C57BL/6 background. At the time of CLP, mice were given fluid resuscitation. Mouse lungs were harvested at 24 and 72 h for Western blot analysis, qRT-PCR, BALF analysis, Hematoxylin and Eosin staining, TUNEL staining, maleimide staining, flow cytometry analysis, GCL, GSH, GSSG and cysteine levels measurement. A marked elevation of PICK1 mRNA and protein level were demonstrated in lung tissue, which was accompanied by increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and consumption of glutathione (GSH). N-acetylcysteine (NAC), buthionine sulfoximine (BSO) and GSH-monoethyl ester (GSH-MEE) were injected into mice via caudal vein to regulate glutathione (GSH) level in lung. Alterations of lung GSH content induced PICK1 level change after CLP challenge. In PICK1[-/-] underwent with CLP, lung injury and survival were significantly aggravated compared with wild-type mice underwent with CLP. Concomitantly, CLP-induced lung cell apoptosis was exacerbated in PICK1[-/-] mice. The level of xCT, other than PKCα, in lung tissue was significantly lowered in PICK1[-/-] but not in wild type that underwent CLP surgery. Meanwhile, Nrf2 activation, which dominating xCT expression, was inhibited in PICK1-/- but not in wild type mice that underwent CLP surgery, as well. Moreover, higher level of PICK1 was detected in PBMCs of septic patients than healthy controls. Taken together, PICK1 plays a pivotal role in sepsis-induced ALI by regulating GSH synthesis via affecting the substrate-specific subunit of lung cystine/glutamate transporter, xCT.}, }
@article {pmid29467937, year = {2018}, author = {Hsu, SPC and Kuo, JS and Chiang, HC and Wang, HE and Wang, YS and Huang, CC and Huang, YC and Chi, MS and Mehta, MP and Chi, KH}, title = {Temozolomide, sirolimus and chloroquine is a new therapeutic combination that synergizes to disrupt lysosomal function and cholesterol homeostasis in GBM cells.}, journal = {Oncotarget}, volume = {9}, number = {6}, pages = {6883-6896}, pmid = {29467937}, issn = {1949-2553}, abstract = {Glioblastoma (GBM) cells are characterized by high phagocytosis, lipogenesis, exocytosis activities, low autophagy capacity and high lysosomal demand are necessary for survival and invasion. The lysosome stands at the cross roads of lipid biosynthesis, transporting, sorting between exogenous and endogenous cholesterol. We hypothesized that three already approved drugs, the autophagy inducer, sirolimus (rapamycin, Rapa), the autophagy inhibitor, chloroquine (CQ), and DNA alkylating chemotherapy, temozolomide (TMZ) could synergize against GBM. This repurposed triple therapy combination induced GBM apoptosis in vitro and inhibited GBM xenograft growth in vivo. Cytotoxicity is caused by induction of lysosomal membrane permeabilization and release of hydrolases, and may be rescued by cholesterol supplementation. Triple treatment inhibits lysosomal function, prevents cholesterol extraction from low density lipoprotein (LDL), and causes clumping of lysosome associated membrane protein-1 (LAMP-1) and lipid droplets (LD) accumulation. Co-treatment of the cell lines with inhibitor of caspases and cathepsin B only partially reverse of cytotoxicities, while N-acetyl cysteine (NAC) can be more effective. A combination of reactive oxygen species (ROS) generation from cholesterol depletion are the early event of underling mechanism. Cholesterol repletion abolished the ROS production and reversed the cytotoxicity from QRT treatment. The shortage of free cholesterol destabilizes lysosomal membranes converting aborted autophagy to apoptosis through either direct mitochondria damage or cathepsin B release. This promising anti-GBM triple therapy combination severely decreases mitochondrial function, induces lysosome-dependent apoptotic cell death, and is now poised for further clinical testing and validation.}, }
@article {pmid29462817, year = {2018}, author = {Yin, S and Jiang, B and Huang, G and Zhang, Y and You, B and Chen, Y and Gong, Y and Chen, J and Yuan, Z and Zhao, Y and Li, M and Hu, F and Yang, Z and Peng, Y}, title = {The Interaction of N-Acetylcysteine and Serum Transferrin Promotes Bacterial Biofilm Formation.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {45}, number = {4}, pages = {1399-1409}, doi = {10.1159/000487566}, pmid = {29462817}, issn = {1421-9778}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Bacterial Infections/drug therapy/pathology/veterinary ; Bacterial Proteins/genetics/metabolism ; Biofilms/*drug effects ; Disease Models, Animal ; Extracellular Matrix/metabolism ; Humans ; Male ; Microscopy, Confocal ; Pseudomonas aeruginosa/metabolism ; Rats ; Rats, Sprague-Dawley ; Staphylococcus aureus/*physiology ; Transcription Factors/genetics/metabolism ; Transferrins/*pharmacology ; }, abstract = {BACKGROUND/AIMS: N-acetylcysteine (NAC) is a novel and promising agent with activity against bacterial biofilms. Human serum also inhibits biofilm formation by some bacteria. We tested whether the combination of NAC and human serum offers greater anti-biofilm activity than either agent alone.<br><br>METHODS: Microtiter plate assays and confocal laser scanning microscopy were used to evaluate bacterial biofilm formation in the presence of NAC and human serum. qPCR was used to examine expression of selected biofilm-associated genes. Extracellular matrix (ECM) was observed by transmission electron microscopy. The antioxidants GSH or ascorbic acid were used to replace NAC, and human transferrin, lactoferrin, or bovine serum albumin were used to replace serum proteins in biofilm formation assays. A rat central venous catheter model was developed to evaluate the effect of NAC on biofilm formation in vivo.<br><br>RESULTS: NAC and serum together increased biofilm formation by seven different bacterial strains. In Staphylococcus aureus, expression of genes for some global regulators and for genes in the ica-dependent pathway increased markedly. In Pseudomonas aeruginosa, transcription of las, the PQS quorum sensing (QS) systems, and the two-component system GacS/GacA increased significantly. ECM production by S. aureus and P. aeruginosa was also enhanced. The potentiation of biofilm formation is due mainly to interaction between NAC and transferrin. Intravenous administration of NAC increased colonization by S. aureus and P. aeruginosa on implanted catheters.<br><br>CONCLUSIONS: NAC used intravenously or in the presence of blood increases bacterial biofilm formation rather than inhibits it.}, }
@article {pmid29462796, year = {2018}, author = {Zhang, P and Yang, M and Zeng, L and Liu, C}, title = {P38/TRHr-Dependent Regulation of TPO in Thyroid Cells Contributes to the Hypothyroidism of Triclosan-Treated Rats.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {45}, number = {4}, pages = {1303-1315}, doi = {10.1159/000487558}, pmid = {29462796}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cell Survival/drug effects ; Hypothyroidism/chemically induced/metabolism/*pathology ; Imidazoles/pharmacology ; Iodide Peroxidase/*metabolism ; Liver/enzymology ; Male ; Oxidative Stress/drug effects ; Pyridines/pharmacology ; RNA Interference ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Receptors, Thyrotropin-Releasing Hormone/antagonists &amp; inhibitors/genetics/*metabolism ; Signal Transduction/drug effects ; Thyroid Gland/*metabolism ; Thyroid Hormones/blood ; Thyroxine/blood ; Triclosan/toxicity ; Triiodothyronine/blood ; Up-Regulation/drug effects ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {BACKGROUND/AIMS: Triclosan, as an antimicrobial agent and a potential endocrine disruptor, has been used extensively in diverse products, resulting in widespread human exposure. In recent years, studies suggest that triclosan could disturb thyroid functions and decline thyroid hormones (THs).<br><br>METHODS: To verify our hypothesis that the MAPK pathway may function significantly in triclosan-induced hypothyroidism, Sprague-Dawley rats were gavaged with triclosan for 31 consecutive days; Nthy-ori 3-1 cells were treated with triclosan in the presence/absence of NAC, inhibitors (SB203580 and SB202474), or TRHr siRNA. Tissues and/or cells were analyzed by several techniques including transmission electron microscopy, confocal laser scanning microscopy, gene silencing, western blot, and real-time PCR.<br><br>RESULTS: Triclosan led to histopathologic changes in the thyroid and decreases in triiodothyronine (T3) and thyroxine (T4). Triclosan stimulated ROS production and oxidative stress occurrence, thereby activating the p38 pathway in vivo and in vitro. Thyrotropin releasing hormone receptor (TRHr) was induced when the p38 pathway was activated, and was suppressed when that pathway was inhibited. Moreover, thyroid peroxidase (TPO) was restrained and modulated by the p38/TRHr pathway after triclosan treatment. Furthermore, deiodinase 3 (D3) and hepatic enzymes (Ugt2b1, CYP1a1, CYP1a2, CYP2b1, CYP3a1, and Sult1e1) were also induced by triclosan.<br><br>CONCLUSION: Taken together, p38/TRHr-dependent regulation of TPO in thyroid cells contributes to the hypothyroidism of triclosan-treated rats.}, }
@article {pmid29462716, year = {2018}, author = {Le Moal, E and Juban, G and Bernard, AS and Varga, T and Policar, C and Chazaud, B and Mounier, R}, title = {Macrophage-derived superoxide production and antioxidant response following skeletal muscle injury.}, journal = {Free radical biology &amp; medicine}, volume = {120}, number = {}, pages = {33-40}, doi = {10.1016/j.freeradbiomed.2018.02.024}, pmid = {29462716}, issn = {1873-4596}, mesh = {Animals ; Antioxidants/*metabolism ; Inflammation/metabolism ; Macrophages/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/*injuries/*physiology ; Reactive Oxygen Species/metabolism ; Regeneration/*physiology ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; }, abstract = {Macrophages are key players of immunity that display different functions according to their activation states. In a regenerative context, pro-inflammatory macrophages (Ly6C[pos]) are involved in the mounting of the inflammatory response whereas anti-inflammatory macrophages (Ly6C[neg]) dampen the inflammation and promote tissue repair. Reactive oxygen species (ROS) production is a hallmark of tissue injury and of subsequent inflammation as described in a bacterial challenge context. However, whether macrophages produce ROS following a sterile tissue injury is uncertain. In this study, we used complementary in vitro, ex vivo and in vivo experiments in mouse to show that macrophages do not release ROS following a sterile injury in skeletal muscle. Furthermore, expression profiles of genes involved in the response to oxidative stress in Ly6C[pos] and Ly6C[neg] macrophage subsets did not indicate any antioxidant response in this context. Finally, in vivo, pharmacological antioxidant supplementation with N-Acetyl-cysteine (NAC) following skeletal muscle injury did not alter macrophage phenotype during skeletal muscle regeneration. Overall, these results indicate that following a sterile injury, macrophage-derived ROS release is not involved in the regulation of the inflammatory response in the regenerating skeletal muscle.}, }
@article {pmid29462456, year = {2018}, author = {Conus, P and Seidman, LJ and Fournier, M and Xin, L and Cleusix, M and Baumann, PS and Ferrari, C and Cousins, A and Alameda, L and Gholam-Rezaee, M and Golay, P and Jenni, R and Woo, TW and Keshavan, MS and Eap, CB and Wojcik, J and Cuenod, M and Buclin, T and Gruetter, R and Do, KQ}, title = {N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis.}, journal = {Schizophrenia bulletin}, volume = {44}, number = {2}, pages = {317-327}, pmid = {29462456}, issn = {1745-1701}, support = {UL1 TR000170/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adolescent ; Adult ; Antioxidants/administration &amp; dosage/*pharmacology ; *Biomarkers ; Cognitive Dysfunction/*drug therapy/etiology/metabolism/physiopathology ; Double-Blind Method ; Female ; Glutathione/*drug effects ; Glutathione Peroxidase ; Humans ; Magnetic Resonance Spectroscopy ; Male ; *Outcome Assessment, Health Care ; Oxidation-Reduction ; Prefrontal Cortex/*drug effects/metabolism ; Psychotic Disorders/complications/*drug therapy/metabolism/physiopathology ; Schizophrenia/complications/*drug therapy/metabolism/physiopathology ; Young Adult ; }, abstract = {Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.}, }
@article {pmid29459829, year = {2018}, author = {Gu, SH and Li, G and Hsieh, HY and Lin, PL and Li, S}, title = {Stimulation of JNK Phosphorylation by the PTTH in Prothoracic Glands of the Silkworm, Bombyx mori.}, journal = {Frontiers in physiology}, volume = {9}, number = {}, pages = {43}, pmid = {29459829}, issn = {1664-042X}, abstract = {In this study, phosphorylation of c-Jun N-terminal kinase (JNK) by the prothoracicotropic hormone (PTTH) was investigated in prothoracic glands (PGs) of the silkworm, Bombyx mori. Results showed that JNK phosphorylation was stimulated by the PTTH in time- and dose-dependent manners. In vitro activation of JNK phosphorylation in PGs by the PTTH was also confirmed in an in vivo experiment, in which a PTTH injection greatly increased JNK phosphorylation in PGs of day-6 last instar larvae. JNK phosphorylation caused by PTTH stimulation was greatly inhibited by U73122, a potent and specific inhibitor of phospholipase C (PLC) and an increase in JNK phosphorylation was also detected when PGs were treated with agents (either A23187 or thapsigargin) that directly elevated the intracellular Ca[2+] concentration, thereby indicating involvement of PLC and Ca[2+]. Pretreatment with an inhibitor (U0126) of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) and an inhibitor (LY294002) of phosphoinositide 3-kinase (PI3K) failed to significantly inhibit PTTH-stimulated JNK phosphorylation, indicating that ERK and PI3K were not related to JNK. We further investigated the effect of modulation of the redox state on JNK phosphorylation. In the presence of either an antioxidant (N-acetylcysteine, NAC) or diphenylene iodonium (DPI), PTTH-stimulated JNK phosphorylation was blocked. The JNK kinase inhibitor, SP600125, markedly inhibited PTTH-stimulated JNK phosphorylation and ecdysteroid synthesis. The kinase assay of JNK in PGs confirmed its stimulation by PTTH and inhibition by SP600125. Moreover, PTTH treatment did not affect JNK or Jun mRNA expressions. Based on these findings, we concluded that PTTH stimulates JNK phosphorylation in Ca[2+]- and PLC-dependent manners and that the redox-regulated JNK signaling pathway is involved in PTTH-stimulated ecdysteroid synthesis in B. mori PGs.}, }
@article {pmid29458843, year = {2018}, author = {Wang, Q and Du, X and Ma, K and Shi, P and Liu, W and Sun, J and Peng, M and Huang, Z}, title = {A critical role for very long-chain fatty acid elongases in oleic acid-mediated Saccharomyces cerevisiae cytotoxicity.}, journal = {Microbiological research}, volume = {207}, number = {}, pages = {1-7}, doi = {10.1016/j.micres.2017.11.001}, pmid = {29458843}, issn = {1618-0623}, mesh = {Acetylcysteine/pharmacology ; Acetyltransferases/*genetics ; Ascorbic Acid/pharmacology ; Catalase/metabolism ; Cell Membrane/*metabolism ; Fatty Acid Elongases ; Glutathione/metabolism ; Membrane Proteins/*genetics ; Oleic Acid/*toxicity ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*genetics ; Superoxide Dismutase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Elongases FEN1/ELO2 and SUR4/ELO3 are important enzymes involved in the elongation of long-chain fatty acids (LCFAs) to very long-chain fatty acids (VLCFAs) in Saccharomyces cerevisiae. The molecular mechanism of the involvement of these elongases in lipotoxicity is unclear. In the present study, we investigated the role of VLCFA elongases in oleic acid-mediated yeast cytotoxicity. The spot test showed that yeast strains with the deletion of ELO2 or ELO3 were strikingly sensitive to oleic acid, while there was no change on the growth of strain with deleted ELO1 which was involved in the elongation of C14 fatty acid (FA) to C16 FA. By using GC-MS, the unsaturation index was increased in elo2△ and elo3△ mutants after treatment with oleic acid (OLA). However, the proportion of VLCFAs was increased in response to OLA in the wild-type strain. The growth inhibition of elo2△ and elo3△ could be partially rescued by two commonly used antioxidant agents N-acetyl cysteine (NAC) and Ascorbic acid (VC). The further study showed that exposure to excess OLA led to an increase in the levels of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS), and a decline in the quantity of reduced glutathione (GSH) in both the wild type and mutant strains. However, the antioxidant enzyme activities of superoxide dismutase (SOD) and catalase (CAT) were increased in the wild type and elo1△ strains, while they were significantly decreased in the mutants of elo2△ and elo3△ after treated with excess OLA. Thus, oxidative damage mainly contributed to the cell death induced by OLA in ole2△ and ole3△. Taken together, although disruption of ELO2 or ELO3 did not affect the cellular lipid unsaturation, they altered the distribution and propotion of cellular VLCFAs, leading to the cell membrane impairment, which augmented the ability of OLA to permeabilize the plasma membrane. The data suggest that the very long-chain fatty acids elongases ELO2 and ELO3 play important roles in lipotoxic cell death induced by OLA through maintaining a balanced FA composition in plasma membrane.}, }
@article {pmid29457669, year = {2018}, author = {Bhardwaj, JK and Saraf, P and Kumari, P and Mittal, M and Kumar, V}, title = {N-Acetyl-cysteine mediated inhibition of spermatogonial cells apoptosis against malathion exposure in testicular tissue.}, journal = {Journal of biochemical and molecular toxicology}, volume = {32}, number = {4}, pages = {e22046}, doi = {10.1002/jbt.22046}, pmid = {29457669}, issn = {1099-0461}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Goats ; Malathion/*toxicity ; Male ; Spermatogonia/*metabolism/pathology ; Testis/*metabolism/pathology ; }, abstract = {Toxicological studies so far suggest that excessive use of malathion, an organophosphate insecticide, causes serious ill-effects in mammalian reproductive physiology. The present study aims at assessing malathion-induced toxicity in a dose- and time-dependent manner with mitigating effects of N-acetyl-l-cysteine. The testicular germ cell viability was monitored using MTT assay, where NAC, being an antioxidant significantly reduced malathion-induced toxicity by enhancing the frequency of cell viability. The histomorphological analysis showed that NAC successfully diminished several apoptotic features in testicular cells, induced by malathion. The differential EB/AO staining revealed a significant decline in the percentage of apoptosis after NAC supplementation. NAC also diminished the malathion-induced DNA fragmentation along with significantly reduction in oxidative stress parameters causing decrease in lipid peroxidation and enhancement of ferric reducing antioxidant power within testicular germ cells. Thus, NAC mitigated the malathion-induced toxicity, proving its potential in infertility treatment.}, }
@article {pmid29457216, year = {2018}, author = {Zheng, W and Zhang, QE and Cai, DB and Yang, XH and Qiu, Y and Ungvari, GS and Ng, CH and Berk, M and Ning, YP and Xiang, YT}, title = {N-acetylcysteine for major mental disorders: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Acta psychiatrica Scandinavica}, volume = {137}, number = {5}, pages = {391-400}, doi = {10.1111/acps.12862}, pmid = {29457216}, issn = {1600-0447}, mesh = {Acetylcysteine/adverse effects/*pharmacology ; Antioxidants/adverse effects/*pharmacology ; Bipolar Disorder/*drug therapy ; Depressive Disorder, Major/*drug therapy ; Humans ; *Randomized Controlled Trials as Topic ; Schizophrenia/*drug therapy ; }, abstract = {OBJECTIVE: This systematic review and meta-analysis of randomized controlled trials (RCTs) examined the efficacy and safety of adjunctive N-acetylcysteine (NAC), an antioxidant drug, in treating major depressive disorder (MDD), bipolar disorder, and schizophrenia.<br><br>METHODS: The PubMed, Cochrane Library, PsycINFO, CNKI, CBM, and WanFang databases were independently searched and screened by two researchers. Standardized mean differences (SMDs), risk ratios, and their 95% confidence intervals (CIs) were computed.<br><br>RESULTS: Six RCTs (n = 701) of NAC for schizophrenia (three RCTs, n = 307), bipolar disorder (two RCTs, n = 125), and MDD (one RCT, n = 269) were identified and analyzed as separate groups. Adjunctive NAC significantly improved total psychopathology (SMD = -0.74, 95% CI: -1.43, -0.06; I[2] = 84%, P = 0.03) in schizophrenia, but it had no significant effect on depressive and manic symptoms as assessed by the Young Mania Rating Scale in bipolar disorder and only a small effect on major depressive symptoms. Adverse drug reactions to NAC and discontinuation rates between the NAC and control groups were similar across the three disorders.<br><br>CONCLUSIONS: Adjunctive NAC appears to be a safe treatment that has efficacy for schizophrenia, but not for bipolar disorder or MDD. Further higher quality RCTs are warranted to determine the role of adjunctive NAC in the treatment of major psychiatric disorders.}, }
@article {pmid29450735, year = {2018}, author = {Martacic, J and Filipovic, MK and Borozan, S and Cvetkovic, Z and Popovic, T and Arsic, A and Takic, M and Vucic, V and Glibetic, M}, title = {N-acetyl-L-cysteine protects dental tissue stem cells against oxidative stress in vitro.}, journal = {Clinical oral investigations}, volume = {22}, number = {8}, pages = {2897-2903}, pmid = {29450735}, issn = {1436-3771}, support = {III41030//Ministry od Education, Science and Technological development Republic of Serbia/ ; OI175061//Ministry of Education, Science and technological development Republic of Serbia/ ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/metabolism ; Cells, Cultured ; Child ; Dental Pulp/*cytology ; Fatty Acids/metabolism ; Humans ; In Vitro Techniques ; Lipid Peroxidation ; Oxidative Stress/*drug effects ; Stem Cells/*drug effects ; }, abstract = {OBJECTIVES: The aim of our study was to investigate whether N-acetyl-L-cysteine (NAC) could protect stem cells from exfoliated deciduous teeth (SHED) against oxidative damage, during in vitro cultivation, to preserve regenerative potential of these cells. Accordingly, we examined the potential of cell culture supplementation with NAC in prevention of lipid peroxidation, unfavorable changes of total lipids fatty acid composition, and the effects on the activity of antioxidant enzymes.<br><br>MATERIAL AND METHODS: We analyzed the extent of oxidative damage in SHED after 48&#xa0;h treatment with different NAC concentrations. Cellular lipid peroxidation was determined upon reaction with thiobarbituric acid. All enzyme activities were measured spectrophotometrically, based on published methods. Fatty acid methyl esters were analyzed by gas-liquid chromatography.<br><br>RESULTS: Concentration of 0.1&#xa0;mM NAC showed the most profound effects on SHED, significantly decreasing levels of lipid peroxidation in comparison to control. This dose also diminished the activities of antioxidant enzymes. Furthermore, NAC treatment significantly changed fatty acid composition of cells, reducing levels of oleic acid and monounsaturated fatty acids and increasing linoleic acid, n-6, and total polyunsaturated fatty acid (PUFA) proportions.<br><br>CONCLUSION: Low dose of NAC significantly decreased lipid peroxidation and altered fatty acid composition towards increasing PUFA. The reduced oxidative damage of cellular lipids could be strongly related to improved SHED survival in vitro.<br><br>CLINICAL RELEVANCE: Low doses of antioxidants, applied during stem cells culturing and maintenance, could improve cellular characteristics in vitro. This is prerequisite for successful use of stem cells in various clinical applications.}, }
@article {pmid29442452, year = {2017}, author = {Olakowska, E and Marcol, W and Właszczuk, A and Woszczycka-Korczyńska, I and Lewin-Kowalik, J}, title = {The neuroprotective effect of N-acetylcysteine in spinal cord-injured rats.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {26}, number = {9}, pages = {1329-1334}, doi = {10.17219/acem/65478}, pmid = {29442452}, issn = {1899-5276}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Male ; Nerve Regeneration ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Wistar ; Spinal Cord Injuries/*drug therapy ; }, abstract = {BACKGROUND: Spinal cord injury (SCI) is an important cause of impairment of sensory and motor nerve function. It has been shown that free-radical species play an important role in the pathogenesis of acute tissue trauma after SCI. There are no proven pharmacological therapies that provide neuroprotection and stimulate axonal growth after trauma.<br><br>OBJECTIVES: The aim of this study was to investigate the neuroprotective effect of N-acetylcysteine (NAC) on the regeneration of spinal cord injuries in rats.<br><br>MATERIAL AND METHODS: A total of 20 male Wistar C rats were subjected to SCI and divided into control and experimental groups. In the control group (n = 10) trepanation and SCI by means of a pressure impactor was performed without any therapy. In the study group (n = 10), 1 dose of NAC was applied intraperitoneally (150 mg/kg b.w.) immediately after SCI, and another one after 24 h. The functional outcome on the Basso-Beattie-Bresnahan (BBB) scale and sciatic functional index (SFI) and morphological features of regeneration were analyzed during a 12-week follow-up. The spinal cords and brains were collected 12 weeks after SCI for histopathological and immunohistochemical analyses.<br><br>RESULTS: The rats treated with NAC presented some improvement in locomotor activity and spinal cord morphology when compared to the control group. Namely, the hind paw angle of rotation was significantly lower in the NAC group than in the control group. No differences were observed between the control and study groups in terms of interlimb coordination. The area of the main lesion was only slightly decreased in the NAC group as compared to the control group. The length of lesions in the injured spinal cord in the NAC group was diminished in comparison to the control group. The number of FG-positive cells was higher in the NAC group than in the control group.<br><br>CONCLUSIONS: The study showed that the neuroprotective activity of NAC had limited positive influence on the regeneration of the isolated SCI in rats.}, }
@article {pmid29440631, year = {2018}, author = {Leung, ELH and Luo, LX and Liu, ZQ and Wong, VKW and Lu, LL and Xie, Y and Zhang, N and Qu, YQ and Fan, XX and Li, Y and Huang, M and Xiao, DK and Huang, J and Zhou, YL and He, JX and Ding, J and Yao, XJ and Ward, DC and Liu, L}, title = {Inhibition of KRAS-dependent lung cancer cell growth by deltarasin: blockage of autophagy increases its cytotoxicity.}, journal = {Cell death &amp; disease}, volume = {9}, number = {2}, pages = {216}, pmid = {29440631}, issn = {2041-4889}, mesh = {A549 Cells ; Animals ; Autophagy/drug effects ; Benzimidazoles/*pharmacology ; Cell Line, Tumor ; Female ; Humans ; Lung Neoplasms/*drug therapy/genetics/metabolism/pathology ; Mice ; Mice, Nude ; Proto-Oncogene Proteins p21(ras)/antagonists &amp; inhibitors/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Deltarasin is a recently identified small molecule that can inhibit KRAS-PDEδ interactions by binding to a hydrophobic pocket on PDEδ, resulting in the impairment of cell growth, KRAS activity, and RAS/RAF signaling in human pancreatic ductal adenocarcinoma cell lines. Since KRAS mutations are the most common oncogene mutations in lung adenocarcinomas, implicated in over 30% of all lung cancer cases, we examined the ability of deltarasin to inhibit KRAS-dependent lung cancer cell growth. Here, for the first time, we document that deltarasin produces both apoptosis and autophagy in KRAS-dependent lung cancer cells in vitro and inhibits lung tumor growth in vivo. Deltarasin induces apoptosis by inhibiting the interaction of with PDEδ and its downstream signaling pathways, while it induces autophagy through the AMPK-mTOR signaling pathway. Importantly, the autophagy inhibitor, 3-methyl adenine (3-MA) markedly enhances deltarasin-induced apoptosis via elevation of reactive oxygen species (ROS). In contrast, inhibition of ROS by N-acetylcysteine (NAC) significantly attenuated deltarasin-induced cell death. Collectively, these observations suggest that the anti-cancer cell activity of deltarasin can be enhanced by simultaneously blocking "tumor protective" autophagy, but inhibited if combined with an anti-oxidant.}, }
@article {pmid29437942, year = {2018}, author = {Miyashita, L and Suri, R and Dearing, E and Mudway, I and Dove, RE and Neill, DR and Van Zyl-Smit, R and Kadioglu, A and Grigg, J}, title = {E-cigarette vapour enhances pneumococcal adherence to airway epithelial cells.}, journal = {The European respiratory journal}, volume = {51}, number = {2}, pages = {}, pmid = {29437942}, issn = {1399-3003}, support = {MR/P011284/1/MRC_/Medical Research Council/United Kingdom ; MR/L009242/1/MRC_/Medical Research Council/United Kingdom ; G1000758/MRC_/Medical Research Council/United Kingdom ; 204457/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; 204457/WT_/Wellcome Trust/United Kingdom ; MR/PO11284/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Adult ; Animals ; Bacterial Adhesion ; Cell Line ; Electronic Nicotine Delivery Systems ; Epithelial Cells/metabolism/*microbiology ; Female ; Humans ; Male ; Mice ; Oxidative Stress ; Platelet Membrane Glycoproteins/*metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Respiratory System/metabolism/microbiology ; Streptococcus pneumoniae/metabolism/*physiology ; Vaping/*adverse effects ; }, abstract = {E-cigarette vapour contains free radicals with the potential to induce oxidative stress. Since oxidative stress in airway cells increases platelet-activating factor receptor (PAFR) expression, and PAFR is co-opted by pneumococci to adhere to host cells, we hypothesised that E-cigarette vapour increases pneumococcal adhesion to airway cells.Nasal epithelial PAFR was assessed in non-vaping controls, and in adults before and after 5 min of vaping. We determined the effect of vapour on oxidative stress-induced, PAFR-dependent pneumococcal adhesion to airway epithelial cells in vitro, and on pneumococcal colonisation in the mouse nasopharynx. Elemental analysis of vapour was done by mass spectrometry, and oxidative potential of vapour assessed by antioxidant depletion in vitroThere was no difference in baseline nasal epithelial PAFR expression between vapers (n=11) and controls (n=6). Vaping increased nasal PAFR expression. Nicotine-containing and nicotine-free E-cigarette vapour increased pneumococcal adhesion to airway cells in vitro Vapour-stimulated adhesion in vitro was attenuated by the PAFR blocker CV3988. Nicotine-containing E-cigarette vapour increased mouse nasal PAFR expression, and nasopharyngeal pneumococcal colonisation. Vapour contained redox-active metals, had considerable oxidative activity, and adhesion was attenuated by the antioxidant N-acetyl cysteine.This study suggests that E-cigarette vapour has the potential to increase susceptibility to pneumococcal infection.}, }
@article {pmid29437147, year = {2018}, author = {Coleman, MC and Goetz, JE and Brouillette, MJ and Seol, D and Willey, MC and Petersen, EB and Anderson, HD and Hendrickson, NR and Compton, J and Khorsand, B and Morris, AS and Salem, AK and Fredericks, DC and McKinley, TO and Martin, JA}, title = {Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis.}, journal = {Science translational medicine}, volume = {10}, number = {427}, pages = {}, pmid = {29437147}, issn = {1946-6242}, support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; P50 AR055533/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Chondrocytes/cytology/metabolism ; Female ; Intra-Articular Fractures/*metabolism/*prevention &amp; control ; Male ; Mitochondria/*metabolism ; Osteoarthritis/metabolism/prevention &amp; control ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Swine ; }, abstract = {We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA.}, }
@article {pmid29436588, year = {2018}, author = {Li, K and Li, Y and Mi, J and Mao, L and Han, X and Zhao, J}, title = {Resveratrol protects against sodium nitroprusside induced nucleus pulposus cell apoptosis by scavenging ROS.}, journal = {International journal of molecular medicine}, volume = {41}, number = {5}, pages = {2485-2492}, pmid = {29436588}, issn = {1791-244X}, mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cells, Cultured ; Nitric Oxide Donors/*adverse effects ; Nitroprusside/*adverse effects ; Nucleus Pulposus/cytology/*drug effects ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Resveratrol ; Stilbenes/*pharmacology ; }, abstract = {Oxidative stress induced disc cell apoptosis plays an important role in intervertebral disc (IVD) degeneration. The present study aims to investigate effects of resveratrol (RV), a natural polyphenol compound, on sodium nitroprusside (SNP) induced nucleus pulposus (NP) cell apoptosis and related mechanism. Rat NP cells were pretreated with RV, N-acetyl cysteine (NAC) and carboxy-PTIO (PTIO) before SNP treatment. Cell Counting Kit-8 assay was carried out for cell viability evaluation. Annexin V/propidium iodide (PI), Hoechst 33258 and Actin‑Tracker Green and Tubulin-Tracker Red staining were conducted to detect NP cell apoptosis and apoptotic structural changes. Mitochondrial membrane potential (ΔΨm) was analyzed with tetramethylrhodamine methyl ester staining. DCFH-DA and DAF-FM DA staining was used to determine intracellular reactive oxygen species (ROS) and nitric oxide (NO) levels. An ex vivo experiment was also carried out followed by TUNEL assay of sections of discs. SNP induced NP cell apoptosis, excessive production of intracellular ROS and NO, reduction of ΔΨm as well as disruption of cytoskeletal and morphological structure. Meanwhile, organ culture results showed that SNP induced NP cell apoptosis ex vivo. RV and NAC siginificantly inhibited SNP induced NP cell apoptosis, production of intracellular ROS, deline of ΔΨm as well as disruption of cytoskeletal and morphological structure, while RV did not suppress NO production. RV and NAC could also suppress SNP induced NP cell apoptosis ex vivo. However, PTIO did not prevent SNP induced NP cell apoptosis, though it scavenged NO significantly. In conclusion, RV protects against SNP induced NP cell apoptosis by scavenging ROS but not NO, suggesting a promising prospect of RV in IVD degeneration retardation.}, }
@article {pmid29435131, year = {2018}, author = {Tung, JN and Lin, PL and Wang, YC and Wu, DW and Chen, CY and Lee, H}, title = {PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in non-small cell lung cancer via upregulation of YAP1 expression.}, journal = {Oncotarget}, volume = {9}, number = {4}, pages = {4637-4646}, pmid = {29435131}, issn = {1949-2553}, abstract = {Programmed death ligand (PD-L1) expression was associated with tumor immune escape and subsequent poor prognosis in non-small cell lung cancer (NSCLC). This expression was higher in patients with EGFR-mutated NSCLC tumors than in those with EGFR-wild-type (WT) NSCLC tumors. We therefore hypothesized that poor prognosis mediated by higher PD-L1 may be partially through conferring resistance to tyrosine kinase inhibitor (TKI) in NSCLC regardless of EGFR mutation. The change in PD-L1 expression following gene manipulation corresponded with changes in expression of HIF-1α and YAP1. The expression of HIF-1α and YAP1 was concomitantly decreased by PD-L1 silencing or by ROS scavenger treatment (N-acetylcysteine, NAC); however, a ROS inducer treatment (pyocyanin) completely reversed the decreased expression of both genes in EGFR-mutated and -wild-type (WT) NSCLC cells. The MTT assay indicated that the inhibitory concentration of gefitinib yielding 50% cell viability (IC50) depended on PD-L1-mediated YAP1 expression. Mechanistic studies indicated that upregulation of YAP1 by PD-L1 might be responsible for EGFR mutation-independent TKI resistance via the ROS/HIF-1α axis. An unfavorable TKI response was more common in patient tumors with high PD-L1 or YAP1 mRNA expression than in patient tumors with low mRNA expression of these genes. In conclusion, PD-L1 might confer EGFR mutation-independent TKI resistance in NSCLC cells via upregulation of YAP1 expression.}, }
@article {pmid29434769, year = {2018}, author = {Cai, Z and Shi, T and Zhuang, R and Fang, H and Jiang, X and Shao, Y and Zhou, H}, title = {Protective effect of N-acetylcysteine activated carbon release microcapsule on myocardial ischemia-reperfusion injury in rats.}, journal = {Experimental and therapeutic medicine}, volume = {15}, number = {2}, pages = {1809-1818}, pmid = {29434769}, issn = {1792-0981}, abstract = {With the development of science and technology, and development of artery bypass, methods such as cardiopulmonary cerebral resuscitation have been practiced in recent years. Despite this, some methods fail to promote or recover the function of tissues and organs, and in some cases, may aggravate dysfunction and structural damage to tissues. The latter is typical of ischemia-reperfusion (IR) injury. Lipid peroxidation mediated by free radicals is an important process of myocardial IR injury. Myocardial IR has been demonstrated to induce the formation of large numbers of free radicals in rats, which promotes the peroxidation of lipids within unsaturated fatty acids in the myocardial cell membrane. Markers of lipid peroxidation include malondialdehyde, superoxide dismutase and lactic dehydrogenase. Recent studies have demonstrated that N-acetylcysteine (NAC) is able to dilate blood vessels, prevent oxidative damage, improve immunity, inhibit apoptosis and the inflammatory response and promote glutathione synthesis in cells. NAC also improves the systolic function of myocardial cells and cardiac function, prevents myocardial apoptosis, protects ventricular remodeling and vascular remodeling, reduces opiomelanocortin levels in the serum and increases the content of nitric oxide in the serum, thus improving vascular endothelial function. Therefore, NAC has potent pharmacological activity; however, the relatively fast metabolism of NAC, along with its large clinical dose and low bioavailability, limit its applications. The present study combined NAC with medicinal activated carbons, and prepared N-acetylcysteine activated carbon sustained-release microcapsules (ACNACs) to overcome the limitations of NAC. It was demonstrated that ACNACs exerted greater effective protective effects than NAC alone on myocardial IR injury in rats.}, }
@article {pmid29432840, year = {2018}, author = {Zhang, X and Wang, Y and Velkov, T and Tang, S and Dai, C}, title = {T-2 toxin-induced toxicity in neuroblastoma-2a cells involves the generation of reactive oxygen, mitochondrial dysfunction and inhibition of Nrf2/HO-1 pathway.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {114}, number = {}, pages = {88-97}, doi = {10.1016/j.fct.2018.02.010}, pmid = {29432840}, issn = {1873-6351}, mesh = {Animals ; Apoptosis/drug effects ; Cell Line, Tumor ; Heme Oxygenase-1/genetics/*metabolism ; Humans ; Mice ; Mitochondria/*drug effects/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Neuroblastoma/etiology/genetics/*metabolism/physiopathology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; T-2 Toxin/*toxicity ; }, abstract = {The molecular mechanisms of T-2 mycotoxin induced neurotoxicity remains enigmatic. In the present study we show that T-2 toxin induced neurotoxicity in mouse neuroblastoma2a (N2a) cells is both dose- and time-dependent and is associated with oxidative stress, mitochondrial dysfunction and apoptosis. T-2 toxin treatment of N2a cells at 10, 20, 40 and 80 ng/mL for 24 h significantly up-regulated the mRNA expression of p53, Bax, and caspase-8 and down-regulated the expression of Nrf2 and HO-1 mRNA and protein expression. Activation of caspases-8, -9 and -3 was also evident in a concentration-dependent manner. Pre-treatment of the cells with the antioxidant N-acetyl-cysteine markedly suppressed T-2 toxin-induced neurotoxicity and caspase activation. Conversely, pre-treatment of the cells with the Nrf2 inhibitor brusatol or the HO-1 inhibitor zinc protoporphyrin IX, enhanced T-2 toxin induced neurotoxicity and increased the activation of caspase-9 and -3. Taken together, these novel findings suggest that T-2 toxin-induced neurotoxicity in N2a cells involves oxidative stress, mitochondrial dysfunction and apoptosis via the inhibition of the Nrf2/HO-1 and activation of p53 pathway. The present study highlights the potential of developing much needed pharmacological interventions to prevent T-2 toxin neurotoxicity.}, }
@article {pmid29431641, year = {2018}, author = {Zhou, Y and Yang, G and Tian, H and Hu, Y and Wu, S and Geng, Y and Lin, K and Wu, W}, title = {Sulforaphane metabolites cause apoptosis via microtubule disruption in cancer.}, journal = {Endocrine-related cancer}, volume = {25}, number = {3}, pages = {255-268}, doi = {10.1530/ERC-17-0483}, pmid = {29431641}, issn = {1479-6821}, mesh = {Anticarcinogenic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Humans ; Isothiocyanates/*pharmacology ; MAP Kinase Signaling System ; Male ; Microscopy, Electron, Transmission ; Microtubules/*drug effects/ultrastructure ; Prostatic Neoplasms/*metabolism/ultrastructure ; Sulfoxides ; Tubulin/metabolism ; }, abstract = {Sulforaphane (SFN) inhibited growth in many cancers, but its half-life is 2 h in circulation. However, its metabolites, sulforaphane-cysteine (SFN-Cys) and sulforaphane-N-acetyl-cysteine (SFN-NAC) had longer half-lives and decreased the cell viability in both dose- and time-dependent manners in human prostate cancer. Flow cytometry assay revealed that these two SFN metabolites induced apoptosis with the features such as vacuolization, disappeared nuclear envelope, nuclear agglutination and fragmentation via transmission electron microscopy observation. Western blot showed that the sustained phosphorylation of ERK1/2 mediated by SFN metabolites caused activation and upregulation of cleaved Caspase 3 and downregulation of α-tubulin. High expression of α-tubulin was demonstrated to be positively correlated with cancer pathological grading. Both co-immunoprecipitation and immunofluorescence staining implicated the interaction between SFN metabolite-induced phosphorylated ERK1/2 and α-tubulin, and Caspase 3 cleavage assay showed that α-tubulin might be the substrate for cleaved Caspase 3. More, the SFN metabolite-mediated reduction of α-tubulin increased the depolymerization and instability of microtubules by microtubule polymerization assay. Reversely, microtubule-associated protein Stathmin-1 phosphorylation was increased via phosphorylated ERK1/2 and total Stathmin-1 was reduced, which might promote over-stability of microtubules. Immunofluorescence staining also showed that SFN metabolites induced the 'nest-like' structures of microtubule distribution resulting from the disrupted and aggregated microtubules, and abnormal nuclear division, suggesting that the disturbance of spindle formation and mitosis turned up. Thus, SFN-Cys and SFN-NAC triggered the dynamic imbalance of microtubules, microtubule disruption leading to cell apoptosis. These findings provided a novel insight into the chemotherapy of human prostate cancer.}, }
@article {pmid29431536, year = {2018}, author = {Crum, EM and Barnes, MJ and Stannard, SR}, title = {Multiday Pomegranate Extract Supplementation Decreases Oxygen Uptake During Submaximal Cycling Exercise, but Cosupplementation With N-acetylcysteine Negates the Effect.}, journal = {International journal of sport nutrition and exercise metabolism}, volume = {28}, number = {6}, pages = {586-592}, doi = {10.1123/ijsnem.2017-0407}, pmid = {29431536}, issn = {1543-2742}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Athletic Performance ; Bicycling/*physiology ; Cross-Over Studies ; Dietary Supplements ; Double-Blind Method ; Female ; Humans ; Lythraceae/*chemistry ; Male ; Middle Aged ; Nitric Oxide/blood ; *Oxygen Consumption ; Performance-Enhancing Substances/*administration &amp; dosage ; *Sports Nutritional Physiological Phenomena ; Young Adult ; }, abstract = {Pomegranate extract (POMx) has been suggested as an ergogenic aid due to its rich concentration of polyphenols, which are proposed to enhance nitric oxide bioavailability, thereby improving the efficiency of oxygen usage and, consequently, endurance exercise performance. Although acute POMx supplementation improves aerobic exercise performance in untrained individuals, trained athletes appear to require chronic supplementation for a similar effect. Furthermore, the combination of POMx with a thiol antioxidant may prove more effective than POMx alone, due to the protective effects of thiols on nitric oxide. Thus, this study hypothesized that multiday POMx supplementation would decrease the oxygen uptake (VO2) required by trained cyclists to perform submaximal exercise and increase performance during a time trial, and that thiol (N-acetylcysteine [NAC]) cosupplementation would enhance these effects. Eight cyclists completed four 8-day supplementation periods: POMx only, NAC only, POMx + NAC (BOTH), and placebo. Following supplementation, they performed submaximal cycling and a 5-min time trial, with VO2 and muscle oxygen saturation (SmO2) being recorded. A three-way (POMx × NAC × Intensity) repeated-measures analysis of variance with a Fisher's least significant difference post hoc assessment was performed for dependent variables (p ≤ .05). VO2 during submaximal exercise was reduced with POMx versus placebo (-2.6 ml·min[-1]·kg[-1], p = .009) and BOTH (-2.5 ml·min[-1]·kg[-1], p < .05) and increased with NAC (+1.9 ml·min[-1]·kg[-1], p < .03), despite no main effect of treatment on SmO2 or performance. It appears that POMx's high polyphenol content reduced the VO2 required during submaximal exercise. However, NAC cosupplementation annulled this effect; thus, NAC may interact with nitric oxide to reduce its bioavailability.}, }
@article {pmid29429900, year = {2018}, author = {Ezeriņa, D and Takano, Y and Hanaoka, K and Urano, Y and Dick, TP}, title = {N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production.}, journal = {Cell chemical biology}, volume = {25}, number = {4}, pages = {447-459.e4}, pmid = {29429900}, issn = {2451-9448}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antioxidants/metabolism/*pharmacology ; Cell Line ; Cysteine/metabolism ; Humans ; Hydrogen Sulfide/*metabolism ; Mitochondria/*drug effects/metabolism ; Sulfur/*metabolism ; Sulfurtransferases/metabolism ; }, abstract = {The cysteine prodrug N-acetyl cysteine (NAC) is widely used as a pharmacological antioxidant and cytoprotectant. It has been reported to lower endogenous oxidant levels and to protect cells against a wide range of pro-oxidative insults. As NAC itself is a poor scavenger of oxidants, the molecular mechanisms behind the antioxidative effects of NAC have remained uncertain. Here we show that NAC-derived cysteine is desulfurated to generate hydrogen sulfide, which in turn is oxidized to sulfane sulfur species, predominantly within mitochondria. We provide evidence suggesting the possibility that sulfane sulfur species produced by 3-mercaptopyruvate sulfurtransferase and sulfide:quinone oxidoreductase are the actual mediators of the immediate antioxidative and cytoprotective effects provided by NAC.}, }
@article {pmid29426002, year = {2018}, author = {Pan, X and Wu, X and Yan, D and Peng, C and Rao, C and Yan, H}, title = {Acrylamide-induced oxidative stress and inflammatory response are alleviated by N-acetylcysteine in PC12 cells: Involvement of the crosstalk between Nrf2 and NF-κB pathways regulated by MAPKs.}, journal = {Toxicology letters}, volume = {288}, number = {}, pages = {55-64}, doi = {10.1016/j.toxlet.2018.02.002}, pmid = {29426002}, issn = {1879-3169}, mesh = {Acetylcysteine/*pharmacology ; Acrylamide/antagonists &amp; inhibitors/*toxicity ; Animals ; Cytokines/biosynthesis ; Free Radical Scavengers/*pharmacology ; Inflammation/*chemically induced/pathology ; Lipid Peroxidation/drug effects ; Mitogen-Activated Protein Kinases/drug effects/metabolism ; NF-E2-Related Factor 2/*drug effects ; NF-kappa B/*drug effects ; Oxidative Stress/*drug effects ; PC12 Cells ; Rats ; Reactive Oxygen Species/metabolism ; Receptor Cross-Talk/drug effects ; Signal Transduction/drug effects ; }, abstract = {Acrylamide (ACR) is a classic neurotoxin in animals and humans. However, the mechanism underlying ACR neurotoxicity remains controversial, and effective prevention and treatment measures against this condition are scarce. This study focused on clarifying the crosstalk between the involved signaling pathways in ACR-induced oxidative stress and inflammatory response and investigating the protective effect of antioxidant N-acetylcysteine (NAC) against ACR in PC12 cells. Results revealed that ACR exposure led to oxidative stress characterized by significant increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels and glutathione (GSH) consumption. Inflammatory response was observed based on the dose-dependently increased levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). NAC attenuated ACR-induced enhancement of MDA and ROS levels and TNF-α generation. In addition, ACR activated nuclear transcription factor E2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) signaling pathways. Knockdown of Nrf2 by siRNA significantly blocked the increased NF-κB p65 protein expression in ACR-treated PC12 cells. Down-regulation of NF-κB by specific inhibitor BAY11-7082 similarly reduced ACR-induced increase in Nrf2 protein expression. NAC treatment increased Nrf2 expression and suppressed NF-κB p65 expression to ameliorate oxidative stress and inflammatory response caused by ACR. Further results showed that mitogen-activated protein kinases (MAPKs) pathway was activated prior to the activation of Nrf2 and NF-κB pathways. Inhibition of MAPKs blocked Nrf2 and NF-κB pathways. Collectively, ACR activated Nrf2 and NF-κB pathways which were regulated by MAPKs. A crosstalk between Nrf2 and NF-κB pathways existed in ACR-induced cell damage. NAC protected against oxidative damage and inflammatory response induced by ACR by activating Nrf2 and inhibiting NF-κB pathways in PC12 cells.}, }
@article {pmid29426000, year = {2018}, author = {Xu, Y and Li, Y and Ma, L and Xin, G and Wei, Z and Zeng, Z and Xing, Z and Li, S and Niu, H and Huang, W}, title = {d-galactose induces premature senescence of lens epithelial cells by disturbing autophagy flux and mitochondrial functions.}, journal = {Toxicology letters}, volume = {289}, number = {}, pages = {99-106}, doi = {10.1016/j.toxlet.2018.02.001}, pmid = {29426000}, issn = {1879-3169}, mesh = {Adenosine Triphosphate/metabolism ; Antioxidants/pharmacology/therapeutic use ; *Autophagy/drug effects ; Calcium Signaling/drug effects ; Cataract/metabolism/pathology/prevention &amp; control ; Cell Line ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Eye Proteins/genetics/metabolism ; Galactose/*adverse effects ; *Gene Expression Regulation/drug effects ; Humans ; Hypoglycemic Agents/pharmacology/therapeutic use ; Lens, Crystalline/cytology/drug effects/*metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Metformin/pharmacology/therapeutic use ; Mitochondria/drug effects/*metabolism ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/agonists/metabolism ; }, abstract = {Cataract is the leading cause of blindness with an estimated 16 million people affected worldwide. d-galactose (d-gal) is a reducing sugar that widely distributed in foodstuffs, and studies show that d-gal could promote cataract formation by damaging nature lens epithelial cells (LECs). However, the underlying mechanism is unclear. In our present study, d-gal resulted in premature senescence of LECs, which was confirmed by determining the β-galactosidase activity, cell proliferative potential and cell cycle distribution, though apoptosis of LECs was not observed. We also verified that d-gal induced the impairment of autophagy flux by measuring the expression of LC3II and P62. Meanwhile, we found that d-gal induced mitochondrial dysfunctions of LECs through increasing reactive oxygen species (ROS), reducing ATP synthesis and mitochondrial potential (MMP), enhancing the concentration of cytoplasm Ca[2+] and permeability transition pore (mPTP) opening. Metformin, as a potential anti-aging agent, suppressed the senescence of LECs by restoring autophagy flux and mitochondria functions. Nevertheless, the antioxidant N-acetylcysteine (NAC) scavenged ROS significantly but was not efficient in preventing LECs from premature senescence. Our data suggests that restoring autophagy activity and improving mitochondrial functions may be a potential strategy for the prevention of LECs senescence-related cataract.}, }
@article {pmid29425586, year = {2018}, author = {Luo, WW and Zhao, WW and Lu, JJ and Wang, YT and Chen, XP}, title = {Cucurbitacin B suppresses metastasis mediated by reactive oxygen species (ROS) via focal adhesion kinase (FAK) in breast cancer MDA-MB-231 cells.}, journal = {Chinese journal of natural medicines}, volume = {16}, number = {1}, pages = {10-19}, doi = {10.1016/S1875-5364(18)30025-6}, pmid = {29425586}, issn = {1875-5364}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Breast Neoplasms/enzymology/*metabolism/pathology/physiopathology ; Cell Adhesion/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Collagen Type I/metabolism ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Female ; Fibronectins/metabolism ; Focal Adhesion Kinase 1/*metabolism ; Humans ; Neoplasm Invasiveness/pathology ; Neoplasm Metastasis/*pathology ; Paxillin/metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Triterpenes/antagonists &amp; inhibitors/chemistry/*pharmacology ; }, abstract = {Metastasis is responsible for the majority of cancer-related deaths and prevention of metastasis remains a big challenge for cancer therapy. Cucurbitacin B (Cuc B) is a natural triterpenoid with potent anticancer activities while its effect on metastasis remains unclear. In the present study, the inhibitory effect and mechanisms of Cuc B on metastasis were investigated in MDA-MB-231 breast cancer cells. The cells were treated with or without Cuc B, and the cytotoxicity was determined by MTT assay. The effect of Cuc B on metastasis was evaluated with wound healing, transwell, and adhesion assays. Furthermore, the adhesion of cancer cells to endothelial cells was determined. The protein expression was determined by Western blotting. Cuc B (< 100 nmol·L[-1]) showed no obvious cytotoxicity to MDA-MB-231 cells, but significantly inhibited migration, invasion, and adhesion to Matrigel, fibronectin, type I collagen, and endothelial cells. Cuc B dramatically inhibited the phosphorylation of focal adhesion kinase (FAK) and paxillin in dose- and time-dependent manners. Furthermore, Cuc B induced intracellular reactive oxygen species (ROS) generation, which could be reduced by N-acetyl-l-cysteine (NAC). In addition, NAC pretreatment could reverse Cuc B-induced suppression of migration and adhesion, expression of FAK, but showed no effect on paxillin expression. In summary, Cuc B suppressed ROS-dependent metastasis through FAK pathway in breast cancer MDA-MB-231 cells, demonstrating novel mechanisms for the anticancer effects of Cuc B.}, }
@article {pmid29425508, year = {2018}, author = {Kitase, Y and Vallejo, JA and Gutheil, W and Vemula, H and Jähn, K and Yi, J and Zhou, J and Brotto, M and Bonewald, LF}, title = {β-aminoisobutyric Acid, l-BAIBA, Is a Muscle-Derived Osteocyte Survival Factor.}, journal = {Cell reports}, volume = {22}, number = {6}, pages = {1531-1544}, pmid = {29425508}, issn = {2211-1247}, support = {P01 AG039355/AG/NIA NIH HHS/United States ; P01 AR046798/AR/NIAMS NIH HHS/United States ; R01 AR057404/AR/NIAMS NIH HHS/United States ; UL1 TR001108/TR/NCATS NIH HHS/United States ; }, mesh = {Aging/*metabolism ; Aminoisobutyric Acids/*metabolism ; Animals ; Female ; Hindlimb Suspension ; Male ; Mice ; Muscle, Skeletal/*metabolism ; Osteocytes/*metabolism ; Oxidative Stress ; }, abstract = {Exercise has beneficial effects on metabolism and on tissues. The exercise-induced muscle factor β-aminoisobutyric acid (BAIBA) plays a critical role in the browning of white fat and in insulin resistance. Here we show another function for BAIBA, that of a bone-protective factor that prevents osteocyte cell death induced by reactive oxygen species (ROS). l-BAIBA was as or more protective than estrogen or N-acetyl cysteine, signaling through the Mas-Related G Protein-Coupled Receptor Type D (MRGPRD) to prevent the breakdown of mitochondria due to ROS. BAIBA supplied in drinking water prevented bone loss and loss of muscle function in the murine hindlimb unloading model, a model of osteocyte apoptosis. The protective effect of BAIBA was lost with age, not due to loss of the muscle capacity to produce BAIBA but likely to reduced Mrgprd expression with aging. This has implications for understanding the attenuated effect of exercise on bone with aging.}, }
@article {pmid29424917, year = {2018}, author = {Zheng, BZ and Liu, TD and Chen, G and Zhang, JX and Kang, X}, title = {The effect of curcumin on cell adhesion of human esophageal cancer cell.}, journal = {European review for medical and pharmacological sciences}, volume = {22}, number = {2}, pages = {551-560}, doi = {10.26355/eurrev_201801_14209}, pmid = {29424917}, issn = {2284-0729}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Cell Adhesion/*drug effects ; Cell Line, Tumor ; Curcumin/*pharmacology ; Esophageal Neoplasms/metabolism/pathology ; Fulvestrant/pharmacology ; Glutathione/metabolism ; Humans ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: Esophageal cancer is the 8th most common cancers worldwide and the 6th most common cause of death among cancers. Curcumin has been reported to have the function of anti-inflammatory, antioxidant, anti-rheumatoid, and anti-atherosclerosis role. It can also reduce lipid, eliminate free radicals and inhibit the growth of the tumor. Many reports had suggested that curcumin has shown great potential in the treatment of tumors by inducing apoptosis. Little is known about the effects of curcumin on cell adhesion of tumor cancer. Therefore, in this study, we attempted to look for a new approach to target resistant cells and improve efficacy without toxicity.<br><br>MATERIALS AND METHODS: Human esophageal cancer cell line (Eca-109 cells) was cultured. Cell adhesion was detected under a microplate reader. Reactive oxygen species were measured using Fluostar Omega Spectrofluorimeter. SOD activity and GSH content in cells were detected by commercial determination kit. The expression of p-JAK, p-STAT3 and STAT3 were measured by Western blot and RT-PCR.<br><br>RESULTS: Cell adhesion assay showed curcumin enhances cell-cell adhesion and cell-matrix adhesion in Eca-109 cells. ROS levels, SOD activity and total GSH content were detected and the results showed curcumin decreases intracellular ROS levels but increases SOD activity and total GSH content. Then, NAC (ROS inhibitor) and ICI (ER inhibitor) were pre-treated. Results showed ICI reversed the decreasing of intracellular ROS levels and the increasing of SOD activity and total GSH content affected by curcumin, but NAC had no such impact. Taken together, ER rather than ROS involves in cell adhesion affected by curcumin. Meanwhile, the downregulating of p-JAK, p-SATA3 and total STAT3 were caused by curcumin but NAC had no such influence. They were reversed by ICI, but NAC had no such influence.<br><br>CONCLUSIONS: Curcumin could increase cell adhesion through inhibiting JAK/STAT3 mediated by ER in Eca-109.}, }
@article {pmid29424349, year = {2018}, author = {Otrubová, O and Turecký, L and Uličná, O and Janega, P and Luha, J and Muchová, J}, title = {Therapeutic effects of N-acetyl-L-cysteine on liver damage induced by long-term CCl4 administration.}, journal = {General physiology and biophysics}, volume = {37}, number = {1}, pages = {23-31}, doi = {10.4149/gpb_2017016}, pmid = {29424349}, issn = {0231-5882}, mesh = {Acetylcysteine/*administration &amp; dosage/*adverse effects ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; *Carbon Tetrachloride ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/*pathology ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Interactions ; Liver/*drug effects/metabolism/*pathology ; Male ; Rats ; Rats, Wistar ; Treatment Outcome ; }, abstract = {N-acetyl-L-cysteine (NAC) is a drug routinely used in several health problems, e.g. liver damage. There is some information emerged on its negative effects in certain situations. The aim of our study was to examine its ability to influence liver damage induced by long-term burden. We induced liver damage by CCl4 (10 weeks) and monitored the impact of parallel NAC administration (daily 150 mg/kg of b.w.) on liver morphology and some biochemical parameters (triacylglycerols, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, proteins, albumins and cholinesterase). NAC significantly decreased levels of bile acids and bilirubin in plasma and triacylglycerols in liver, all of them elevated by impairment with CCl4. Reduction of cholesterol induced by CCl4 was completely recovered in the presence of NAC as indicated by its elevation to control levels. NAC administration did not improve the histological parameters. Together with protective effects of NAC, we found also its deleterious properties: parallel administration of CCl4 and NAC increased triacylglycerols, ALT and AST activity and significantly increased plasma cholinesterase activity. We have observed nonsignificantly increased percentage of liver tissue fibrosis. Our results have shown that NAC administered simultaneously with liver damaging agent CCl4, exhibits not only protective, but also deleterious effects as indicated by several biochemical parameters.}, }
@article {pmid29423816, year = {2018}, author = {Yarema, M and Chopra, P and Sivilotti, MLA and Johnson, D and Nettel-Aguirre, A and Bailey, B and Victorino, C and Gosselin, S and Purssell, R and Thompson, M and Spyker, D and Rumack, B}, title = {Anaphylactoid Reactions to Intravenous N-Acetylcysteine during Treatment for Acetaminophen Poisoning.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {14}, number = {2}, pages = {120-127}, pmid = {29423816}, issn = {1937-6995}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*adverse effects/therapeutic use ; Adolescent ; Adult ; Aged ; Analgesics, Non-Narcotic/blood/*poisoning ; Anaphylaxis/*epidemiology/etiology ; Antidotes/*adverse effects/therapeutic use ; Canada/epidemiology ; Cohort Studies ; Drug Overdose/drug therapy ; Female ; Histamine Antagonists/therapeutic use ; Humans ; Incidence ; Male ; Middle Aged ; Retrospective Studies ; Sex Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Anaphylactoid reactions to intravenous (IV) N-acetylcysteine (NAC) are well-recognized adverse events during treatment for acetaminophen (APAP) poisoning. Uncertainty exists regarding their incidence, severity, risk factors, and management. We sought to determine the incidence, risk factors, and treatment of anaphylactoid reactions to IV NAC in a large, national cohort of patients admitted to hospital for acetaminophen overdose.<br><br>METHODS: This retrospective medical record review included all patients initiated on the 21-h IV NAC protocol for acetaminophen poisoning in 34 Canadian hospitals between February 1980 and November 2005. The primary outcome was any anaphylactoid reaction, defined as cutaneous (urticaria, pruritus, angioedema) or systemic (hypotension, respiratory symptoms). We examined the incidence, severity and timing of these reactions, and their association with patient and overdose characteristics using multivariable analysis.<br><br>RESULTS: An anaphylactoid reaction was documented in 528 (8.2%) of 6455 treatment courses, of which 398 (75.4%) were cutaneous. Five hundred four (95.4%) reactions occurred during the first 5 h. Of 403 patients administered any medication for these reactions, 371 (92%) received an antihistamine. Being female (adjusted OR 1.24 [95%CI 1.08, 1.42]) and having taken a single, acute overdose (1.24 [95%CI 1.10, 1.39]) were each associated with more severe reactions, whereas higher serum APAP concentrations were associated with fewer reactions (0.79 [95%CI 0.68, 0.92]).<br><br>CONCLUSION: Anaphylactoid reactions to the 21-h IV NAC protocol were uncommon and involved primarily cutaneous symptoms. While the protective effects of higher APAP concentrations are of interest in understanding the pathophysiology, none of the associations identified are strong enough to substantially alter the threshold for NAC initiation.}, }
@article {pmid29423685, year = {2018}, author = {Stojanović, M and Todorović, D and Šćepanović, L and Mitrović, D and Borozan, S and Dragutinović, V and Labudović-Borović, M and Krstić, D and Čolović, M and Djuric, D}, title = {Subchronic methionine load induces oxidative stress and provokes biochemical and histological changes in the rat liver tissue.}, journal = {Molecular and cellular biochemistry}, volume = {448}, number = {1-2}, pages = {43-50}, pmid = {29423685}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Animals ; Glutathione/metabolism ; Hepatocytes/metabolism/pathology ; Liver/*metabolism/pathology ; Macrophages/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Methionine/*adverse effects/pharmacology ; Necrosis ; Oxidative Stress/*drug effects ; Oxidoreductases/metabolism ; Rats ; Rats, Wistar ; }, abstract = {The aim of this study was to assess the effects of L-cysteine (Cys) (7 mg/kg) and N-acetyl-L-cysteine (NAC) (50 mg/kg) in the rat liver caused by subchronic i.p. application of methionine (Met) (0.8 mmol/kg) during 21 days. Malondialdehyde (MDA) concentration, glutathione content (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and acetylcholinesterase (AchE) activities were determined in the liver tissue and activities of liver enzymes (AST, ALT, ALP, and GGT) and concentrations of total proteins and albumin were determinated in plasma/serum. Catalase, superoxide dismutase, and acetylcholinesterase activities were increased by Cys and NAC. Met caused periportal mononuclear infiltration and rare focal necrosis of hepatocytes. In Cys- and NAC-supplemented groups, intracellular edema and microvesicular fatty changes without necrosis were noticed. We observed decrease of AST, ALT, and ALP activity in the methionine-treated group. Our results indicate that Cys and NAC application can increase activity of antioxidative enzymes and prevent intensive histological changes in liver in condition of subchronic methionine exposure.}, }
@article {pmid29422061, year = {2018}, author = {Oldham, JM and Witt, LJ and Adegunsoye, A and Chung, JH and Lee, C and Hsu, S and Chen, LW and Husain, A and Montner, S and Vij, R and Strek, ME and Noth, I}, title = {N-acetylcysteine exposure is associated with improved survival in anti-nuclear antibody seropositive patients with usual interstitial pneumonia.}, journal = {BMC pulmonary medicine}, volume = {18}, number = {1}, pages = {30}, pmid = {29422061}, issn = {1471-2466}, support = {K23 HL138190/HL/NHLBI NIH HHS/United States ; T32 HL007605/HL/NHLBI NIH HHS/United States ; K23HL138190//National Heart, Lung, and Blood Institute (US)/ ; }, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Antibodies, Antinuclear/immunology ; Cohort Studies ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/immunology/mortality ; Kaplan-Meier Estimate ; Lung Transplantation/statistics &amp; numerical data ; Male ; Middle Aged ; Multivariate Analysis ; Proportional Hazards Models ; Retrospective Studies ; Survival Rate ; }, abstract = {BACKGROUND: Mortality is similarly high among individuals with usual interstitial pneumonia (UIP) due to idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF). Circulating anti-nuclear antibodies (ANA) are commonly found in this patient population, suggesting possible aberrant immune activation. Because an environment of oxidative stress can result from immunologic activation, we hypothesized that ANA positive patients with UIP would have improved outcome when exposed to the antioxidant N-acetylcysteine (NAC) compared to ANA negative patients.<br><br>METHODS: A single center, retrospective cohort analysis was performed. Patients with UIP due to IPF and IPAF were stratified according to ANA status to and NAC exposure. Transplant-free survival (TFS) was assessed using the Kaplan-Meier estimator and multivariable Cox regression adjusted for diagnosis, gender/age/physiology score, immunosuppressant exposure and anti-fibrotic exposure.<br><br>RESULTS: Of 293 individuals with UIP due to IPF (74%) or IPAF (26%), NAC exposure was documented in 58 (19.8%). Among NAC exposed individuals, 33 (56.9%) were ANA seropositive and 25 (43.1%) were seronegative. NAC exposure was associated with improved TFS survival among ANA seropositive individuals in unadjusted analysis (plogrank&#x2009;=&#x2009;0.02) and after multi-variable adjustment (HR 0.51, 95% CI 0.30-0.87; p&#x2009;=&#x2009;0.01). There was no association between NAC exposure and TFS in ANA seronegative individuals (HR 1.26, 95% CI 0.69-2.32; p&#x2009;=&#x2009;0.45). Formal interaction testing confirmed NAC*ANA interaction (p&#x2009;=&#x2009;0.04) and sensitivity analysis demonstrated an increasing effect size associated with NAC therapy as ANA titer increased. Among patients with available genetic data, a marginally higher proportion of ANA positive patients (p&#x2009;=&#x2009;0.08) carried the rs3750920 (TOLLIP) genotype previously shown to predict favorable outcome in NAC exposed patients.<br><br>CONCLUSION: NAC exposure is associated with improved transplant-free survival ANA positive patients with UIP. These findings support the prospective collection of ANA data in in future NAC clinical trials performed in patients with UIP.}, }
@article {pmid29417439, year = {2018}, author = {Gomes, LM and Scaini, G and Carvalho-Silva, M and Gomes, ML and Malgarin, F and Kist, LW and Bogo, MR and Rico, EP and Zugno, AI and Deroza, PFP and Réus, GZ and de Moura, AB and Quevedo, J and Ferreira, GC and Schuck, PF and Streck, EL}, title = {Antioxidants Reverse the Changes in the Cholinergic System Caused by L-Tyrosine Administration in Rats.}, journal = {Neurotoxicity research}, volume = {34}, number = {4}, pages = {769-780}, pmid = {29417439}, issn = {1476-3524}, mesh = {Acetylcholinesterase/*metabolism ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Avoidance Learning/drug effects/physiology ; Brain/*drug effects/*enzymology ; Choline O-Acetyltransferase/*metabolism ; Deferoxamine/pharmacology ; Male ; Memory/drug effects/physiology ; Neuroprotective Agents/pharmacology ; Rats, Wistar ; Tyrosine/*toxicity ; }, abstract = {Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in the activity of the enzyme tyrosine aminotransferase, leading to tyrosine accumulation in the body. Although the mechanisms involved are still poorly understood, several studies have showed that higher levels of tyrosine are related to oxidative stress and therefore may affect the cholinergic system. Thus, the aim of this study was to investigate the effects of chronic administration of L-tyrosine on choline acetyltransferase activity (ChAT) and acetylcholinesterase (AChE) in the brain of rats. Moreover, we also examined the effects of one antioxidant treatment (N-acetylcysteine (NAC) + deferoxamine (DFX)) on cholinergic system. Our results showed that the chronic administration of L-tyrosine decreases the ChAT activity in the cerebral cortex, while the AChE activity was increased in the hippocampus, striatum, and cerebral cortex. Moreover, we found that the antioxidant treatment was able to prevent the decrease in the ChAT activity in the cerebral cortex. However, the increase in AChE activity induced by L-tyrosine was partially prevented the in the hippocampus and striatum, but not in the cerebral cortex. Our results also showed no differences in the aversive and spatial memory after chronic administration of L-tyrosine. In conclusion, the results of this study demonstrated an increase in AChE activity in the hippocampus, striatum, and cerebral cortex and an increase of ChAT in the cerebral cortex, without cognitive impairment. Furthermore, the alterations in the cholinergic system were partially prevented by the co-administration of NAC and DFX. Thus, the restored central cholinergic system by antioxidant treatment further supports the view that oxidative stress may be involved in the pathophysiology of tyrosinemia type II.}, }
@article {pmid29416235, year = {2017}, author = {Sayed, E and Gaballah, K and Younis, E and Yassen, K and El-Einen, AK}, title = {The effect of intravenous infusion of N-acetyl cysteine in cirrhotic patients undergoing liver resection: A randomized controlled trial.}, journal = {Journal of anaesthesiology, clinical pharmacology}, volume = {33}, number = {4}, pages = {450-456}, pmid = {29416235}, issn = {0970-9185}, abstract = {BACKGROUND AND AIMS: Liver resection can lead to hepatocellular dysfunction. The aim was to evaluate the effect of N-acetyl cysteine (NAC) on liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), international normalized ratio (INR), C-reactive protein (CRP), and intercellular adhesion molecule 1 (ICAM 1) in cirrhotic patients undergoing liver resection.<br><br>MATERIAL AND METHODS: A randomized controlled trial (RCT), Pan African Clinical Trial registry (PACTR201508001251260). 60 Child A patients were studied. NAC group (n = 30) received intravenous infusion of NAC 10 g/24 h in 250 ml of 5% dextrose during surgery and for 2 days. Controls (C) (n = 30) received a similar volume of 5% dextrose. All above parameter were measured during and after surgery.<br><br>RESULTS: ALT and AST were significantly elevated after surgery, but to a less extent with NAC versus C (day 3; 118.3 &#xb1; 18.6 vs. 145.4 &#xb1; 14.0 U/L. P < 0.01) and (121.5 &#xb1; 19.5 vs. 146.6 &#xb1; 15.1 U/L, P = 0.00), respectively. Lower serum CRP and ICAM 1 with NAC versus C on day 3 (44.2 &#xb1; 13.4 vs. 68.7 &#xb1; 48.2 mg/l, P = 0.003), (308.8 &#xb1; 38.2 vs. 352.8 &#xb1; 59.4 ng/ml, P = 0.002), respectively. Hospital stay was shorter with NAC versus C (6.1 &#xb1; 0.8 vs. 6.9 &#xb1; 1.2 days, P = 0.006). Duration of surgery, INR, and hemodynamics were comparable.<br><br>CONCLUSION: Prophylactic NAC in hepatic patients undergoing liver surgery attenuated postoperative increase in transaminases, ICAM 1, and CRP blood levels. The impact of these findings and the cost benefit of reduced hospital stay on enhanced recovery after surgery needs to be evaluated.}, }
@article {pmid29416034, year = {2018}, author = {Wu, X and Zhang, H and Qi, W and Zhang, Y and Li, J and Li, Z and Lin, Y and Bai, X and Liu, X and Chen, X and Yang, H and Xu, C and Zhang, Y and Yang, B}, title = {Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis.}, journal = {Cell death &amp; disease}, volume = {9}, number = {2}, pages = {171}, pmid = {29416034}, issn = {2041-4889}, mesh = {Animals ; Aorta/drug effects/pathology ; Apolipoproteins E/deficiency/metabolism ; Atherosclerosis/metabolism/*pathology ; CARD Signaling Adaptor Proteins/metabolism ; Caspase 1/metabolism ; Caspase Inhibitors/pharmacology ; Endothelial Cells/drug effects/*metabolism/*pathology ; Humans ; Inflammasomes/metabolism ; Interleukin-18/metabolism ; Interleukin-1beta/metabolism ; Mice ; Models, Biological ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Nicotine/*toxicity ; Pyroptosis/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cigarette smoking is a major risk factor for atherosclerosis and other cardiovascular diseases. Increasing evidence has demonstrated that nicotine impairs the cardiovascular system by targeting vascular endothelial cells, but the underlying mechanisms remain obscure. It is known that cell death and inflammation are crucial processes leading to atherosclerosis. We proposed that pyroptosis may be implicated in nicotine-induced atherosclerosis and therefore conducted the present study. We found that nicotine resulted in larger atherosclerotic plaques and secretion of inflammatory cytokines in ApoE[-/-] mice fed with a high-fat diet (HFD). Treatment of human aortic endothelial cells (HAECs) with nicotine resulted in NLRP3-ASC inflammasome activation and pyroptosis, as evidenced by cleavage of caspase-1, production of downstream interleukin (IL)-1β and IL-18, and elevation of LDH activity and increase of propidium iodide (PI) positive cells, which were all inhibited by caspase-1 inhibitor. Moreover, silencing NLRP3 or ASC by small interfering RNA efficiently suppressed nicotine-induced caspase-1 cleavage, IL-18 and IL-1β production, and pyroptosis in HAECs. Further experiments revealed that the nicotine-NLRP3-ASC-pyroptosis pathway was activated by reactive oxygen species (ROS), since ROS scavenger (N-acetyl-cysteine, NAC) prevented endothelial cell pyroptosis. We conclude that pyroptosis is likely a cellular mechanism for the pro-atherosclerotic property of nicotine and stimulation of ROS to activate NLRP3 inflammasome is a signaling mechanism for nicotine-induced pyroptosis.}, }
@article {pmid29415988, year = {2018}, author = {Wang, J and Feng, Y and Han, P and Wang, F and Luo, X and Liang, J and Sun, X and Ye, J and Lu, Y and Sun, X}, title = {Photosensitization of A2E triggers telomere dysfunction and accelerates retinal pigment epithelium senescence.}, journal = {Cell death &amp; disease}, volume = {9}, number = {2}, pages = {178}, pmid = {29415988}, issn = {2041-4889}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cellular Senescence/drug effects/radiation effects ; DNA Damage ; HEK293 Cells ; Humans ; Photosensitivity Disorders ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/*drug effects/*metabolism ; Retinoids/*pharmacology/*radiation effects ; Telomere/drug effects/*metabolism ; }, abstract = {Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in elderly people. AMD is classified as early, intermediate, advanced non-neovascular, and advanced neovascular forms depending on the clinical features. However, the exact pathogenesis remains unclear. Retinal pigment epithelium (RPE) cells degeneration is a hallmark of AMD. With aging, lipofuscin accumulates in RPE cells. N-retinylidene-N-retinylethanolamine (named A2E), a well-known fluorophore of lipofuscin, may contribute to RPE cells degeneration. In this study, we showed that photosensitization of A2E increased DNA damage, including telomere deprotection and deletion, and triggered cellular senescence. In addition, we found that the antioxidant N-acetyl-cysteine (NAC) partially alleviated this DNA damage. Telomerase overexpression rescued A2E-mediated RPE cell senescence, indicating that telomere dysfunction plays an important role in A2E-based senescence. We further showed that the senescence induced by A2E photosensitization may affect the microenvironment of the retina by expressing several factors of the secretory phenotype (SASP) including IL1B, IL13RA2, and CXCR4 through the NF-κB pathway. We propose that expression of these factors create a pro-inflammatory environment that drives retina degeneration. Moreover, our findings suggest that protecting telomeres is a valuable strategy for treating retinal degeneration diseases, such as AMD.}, }
@article {pmid29413434, year = {2018}, author = {Squeglia, LM and Tomko, RL and Baker, NL and McClure, EA and Book, GA and Gray, KM}, title = {The effect of N-acetylcysteine on alcohol use during a cannabis cessation trial.}, journal = {Drug and alcohol dependence}, volume = {185}, number = {}, pages = {17-22}, pmid = {29413434}, issn = {1879-0046}, support = {K01 DA036739/DA/NIDA NIH HHS/United States ; K23 AA025399/AA/NIAAA NIH HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; UG1 DA013727/DA/NIDA NIH HHS/United States ; R01 DA042114/DA/NIDA NIH HHS/United States ; U01 DA031779/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Alcohol Drinking/*drug therapy ; Alcoholism/*drug therapy ; *Cannabis ; Double-Blind Method ; Female ; Humans ; Male ; Marijuana Abuse/*drug therapy ; Middle Aged ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Individuals with alcohol use disorder (AUD) do not always respond to currently available treatments, and evaluation of new candidate pharmacotherapies is indicated. N-acetylcysteine (NAC), an over-the-counter supplement, has shown promise in treating a variety of substance use disorders, but little research has evaluated its merits as a treatment for AUD. This secondary analysis from the National Drug Abuse Treatment Clinical Trials Network examined the effects of NAC versus placebo on alcohol use among participants with cannabis use disorder (CUD) enrolled in a 12-week, multi-site cannabis cessation trial.<br><br>METHODS: Participants (N&#x202f;=&#x202f;302, ages 18-50) were randomized to double-blind NAC (1200&#x202f;mg, twice daily) or placebo. Neither alcohol use nor desire for alcohol cessation were requirements for participation. Participants that returned for at least one treatment visit and had recorded alcohol use data (i.e., total drinks per week, drinking days per week, and binge drinking days per week) were included in the analysis (n&#x202f;=&#x202f;277).<br><br>RESULTS: Compared to the placebo group, participants in the NAC group had increased odds of between-visit alcohol abstinence [OR&#x202f;=&#x202f;1.37; 95% CI&#x202f;=&#x202f;1.06-1.78; p&#x202f;=&#x202f;0.019], fewer drinks per week [RR&#x202f;=&#x202f;0.67; 95% CI&#x202f;=&#x202f;0.48-0.99; p&#x202f;=&#x202f;0.045], and fewer drinking days per week [RR&#x202f;=&#x202f;0.69; 95% CI&#x202f;=&#x202f;0.51-0.92; p&#x202f;=&#x202f;0.014]. Changes in concurrent cannabis use amounts were not correlated to any of the alcohol use variables.<br><br>DISCUSSION: These findings indicate that NAC may be effective at reducing consumption of alcohol by &#x223c;30% among treatment-seeking adults with CUD, suggesting a need for further trials focused on the effects of NAC on alcohol consumption among individuals seeking treatment for AUD.}, }
@article {pmid29410962, year = {2017}, author = {Quan, JH and Kang, BH and Yang, JB and Rhee, YE and Noh, HT and Choi, IW and Cha, GH and Yuk, JM and Lee, YH}, title = {Trichomonas vaginalis Induces SiHa Cell Apoptosis by NF-κB Inactivation via Reactive Oxygen Species.}, journal = {BioMed research international}, volume = {2017}, number = {}, pages = {3904870}, pmid = {29410962}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis/drug effects ; Cell Line, Tumor ; Humans ; Mitochondria/drug effects/metabolism ; Models, Biological ; NF-kappa B/*metabolism ; Parasites/drug effects/physiology ; Reactive Oxygen Species/*metabolism ; Trichomonas vaginalis/drug effects/*physiology ; }, abstract = {Trichomonas vaginalis induces apoptosis in host cells through various mechanisms; however, little is known about the relationship between apoptosis, reactive oxygen species (ROS), and NF-κB signaling pathways in the cervical mucosal epithelium. Here, we evaluated apoptotic events, ROS production, and NF-κB activity in T. vaginalis-treated cervical mucosal epithelial SiHa cells, with or without specific inhibitors, using fluorescence microscopy, DNA fragmentation assays, subcellular fractionation, western blotting, and luciferase reporter assay. SiHa cells treated with live T. vaginalis at a multiplicity of infection of 5 (MOI 5) for 4 h produced intracellular and mitochondrial ROS in a parasite-load-dependent manner. Incubation with T. vaginalis caused DNA fragmentation, cleavage of caspase 3 and PARP, and release of cytochrome c into the cytoplasm. T. vaginalis-treated SiHa cells showed transient early NF-κB p65 nuclear translocation, which dramatically dropped at 4 h after treatment. Suppression of NF-κB activity was dependent on parasite burden. However, treatment with the ROS scavenger, N-acetyl-C-cysteine (NAC), reversed the effect of T. vaginalis on apoptosis and NF-κB inactivation in SiHa cells. Taken together, T. vaginalis induces apoptosis in human cervical mucosal epithelial cells by parasite-dose-dependent ROS production through an NF-κB-regulated, mitochondria-mediated pathway.}, }
@article {pmid29409946, year = {2018}, author = {Gong, Y and Yu, Z and Gao, Y and Deng, L and Wang, M and Chen, Y and Li, J and Cheng, B}, title = {FABP4 inhibitors suppress inflammation and oxidative stress in murine and cell models of acute lung injury.}, journal = {Biochemical and biophysical research communications}, volume = {496}, number = {4}, pages = {1115-1121}, doi = {10.1016/j.bbrc.2018.01.150}, pmid = {29409946}, issn = {1090-2104}, mesh = {A549 Cells ; Acute Lung Injury/*drug therapy/*immunology/pathology ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage ; Biphenyl Compounds/administration &amp; dosage ; Cytokines/immunology ; Fatty Acid-Binding Proteins/*antagonists &amp; inhibitors/*immunology ; Humans ; Inflammation Mediators/immunology ; Lipopolysaccharides ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects/*immunology ; Pyrazoles/administration &amp; dosage ; Reactive Oxygen Species/immunology ; Survival Rate ; Treatment Outcome ; }, abstract = {Acute lung injury (ALI) is a severe disease with high morbidity and mortality, and is characterized by devastating inflammation of the lung and increased production of reactive oxygen species (ROS). Recent studies have indicated that fatty acid binding protein (FABP4) is important in the regulation of inflammation. However, the role of FABP4 in sepsis-related ALI, and the specific mechanism of action have not been examined. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) and recombinant FABP4 (hrFABP4) resulted in the production of pro-inflammatory cytokines, inflammatory cytokines, and ROS, while these changes were ameliorated by pretreatment with the FABP4 inhibitor BMS309403 and FABP4 siRNA. Sequentially, treatment of A549 cells with N-acetylcysteine (NAC) significantly attenuated LPS and hrFABP4-induced the generation of ROS and the release of inflammatory cytokines. In vivo, a cecal ligation and puncture (CLP)-induced ALI murine model was successfully established. Then, the mice were treated with FABP4 inhibitor BMS309403. The results showed treatment with BMS309403 improved the survival rate of CLP-induced ALI mice, and prevented lung inflammation, histopathological changes, and increase of FABP4 induced by CLP. These data indicate that FABP4 plays an important role in lung inflammation of sepsis-induced ALI. Blockade of FABP4 signaling exhibits a protective effect in a CLP-induced ALI mouse model, and in A549 cell LPS specifically induces enhanced expression of FABP4, which then causes inflammatory cytokine production by elevating the ROS level.}, }
@article {pmid29408318, year = {2018}, author = {Adebambo, OA and Shea, D and Fry, RC}, title = {Cadmium disrupts signaling of the hypoxia-inducible (HIF) and transforming growth factor (TGF-β) pathways in placental JEG-3 trophoblast cells via reactive oxygen species.}, journal = {Toxicology and applied pharmacology}, volume = {342}, number = {}, pages = {108-115}, doi = {10.1016/j.taap.2018.01.010}, pmid = {29408318}, issn = {1096-0333}, support = {P42 ES005948/ES/NIEHS NIH HHS/United States ; R01 ES019315/ES/NIEHS NIH HHS/United States ; }, mesh = {Cadmium/*toxicity ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Female ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists &amp; inhibitors/*metabolism ; Placenta/cytology/drug effects/*metabolism ; Pregnancy ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/physiology ; Transforming Growth Factor beta/antagonists &amp; inhibitors/*metabolism ; Trophoblasts/drug effects/*metabolism ; }, abstract = {Epidemiologic studies indicate an association between exposure to cadmium (Cd) and placental-related pregnancy disorders. While a precise mechanism is unknown, oxidative imbalance and dysregulation of the hypoxia inducible factor (HIF) and transforming growth factor beta (TGF-β) pathways have been implicated in placental disease pathogenesis. Here we investigated key oxidative and placentation pathways in JEG-3 placental trophoblast cells treated with Cd alone, environmental water samples predominated by Cd with low concentrations of other metals (e.g. inorganic arsenic (iAs)) collected from a waste-site, and a matched mixture of Cd and iAs prepared in the laboratory. The induction of cytosolic reactive oxygen species (ROS), expression of metallothionein (MT) isoforms, HIF1α and downstream targets, and expression of TGFβ pathway-associated genes and proteins were assessed. Additionally, the effect of pre-treatment with the antioxidant N-acetyl cysteine (NAC) on ROS generation and effects on HIF, MT and TGF-β signaling pathways was examined. Cd and Cd-mixture treated cells displayed higher levels of ROSs with accompanying disruption of HIF and TGFβ pathway signaling versus controls, with the Cd-mixture eliciting a greater effect. Conversely, pretreatment with NAC reduced Cd-induced ROS production and disruption of HIF, MT and TGFβ pathway signaling. The results indicate that treatment of placental trophoblast cells with Cd results in increased production of ROSs that disrupt placentation pathways involved in disease pathogenesis. Also, co-occurrence of Cd with other toxic metals, particularly arsenic, may induce detrimental health effects that are currently underestimated when analyzed as single metals.}, }
@article {pmid29407546, year = {2018}, author = {Pavithra, PS and Mehta, A and Verma, RS}, title = {Aromadendrene oxide 2, induces apoptosis in skin epidermoid cancer cells through ROS mediated mitochondrial pathway.}, journal = {Life sciences}, volume = {197}, number = {}, pages = {19-29}, doi = {10.1016/j.lfs.2018.01.029}, pmid = {29407546}, issn = {1879-0631}, mesh = {Apoptosis/*drug effects ; Carcinoma, Squamous Cell/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Mitochondria/*metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; Sesquiterpenes, Guaiane ; Skin Neoplasms/*drug therapy/metabolism/pathology ; }, abstract = {AIMS: Aromadendrene oxide 2 (AO-(2)) is an oxygenated sesquiterpene naturally found as a chemical component of essential oils. In the present study anticancer activity of AO-(2) has been investigated on A431 human epidermoid cancer and precancerous HaCaT cells.<br><br>MATERIAL AND METHODS: Cell viability was used to detect cytotoxic activity. Mechanism of cell death induced by AO-(2) treatments was studied using Annexin V-FITC/PI binding, cell cycle analysis, measurement of MMP and ROS generation by flow cytometry. Expression of apoptosis related proteins was investigated by western blot.<br><br>KEY FINDINGS: AO-(2) inhibited the growth and colony formation ability of A431 and HaCaT cells in concentration dependent manner. It induced cell cycle arrest at G0/G1 phase and apoptosis through intracellular ROS accumulation. Inhibition of intracellular ROS by ascorbic acid and N-acetyl cysteine treatment completely blocked apoptotic effect. N-acetyl cysteine treatment significantly reversed G0/G1 arrest induced by AO-(2). AO-(2) treatment caused loss of mitochondrial membrane potential (&#x394;&#x3a8;m), increase in Bax/Bcl-2 ratios, cytochrome c release, activation of caspases (cleaved caspase-3 and caspase-9) and PARP cleavage. AO-(2) also significantly inhibited the growth of multicellular tumor spheroids of A431 and HaCaT cells.<br><br>SIGNIFICANCE: The results of the present study reveals that AO-(2) a chemical component of essential oils induces apoptosis in A431 and HaCaT cells.}, }
@article {pmid29406268, year = {2019}, author = {Sharabi, H and Khatib, N and Ginsberg, Y and Weiner, Z and Ross, MG and Tamar, BK and Efrat, S and Mordechai, H and Beloosesky, R}, title = {Therapeutic N-Acetyl-Cysteine (Nac) Following Initiation of Maternal Inflammation Attenuates Long-Term Offspring Cerebral Injury, as Evident in Magnetic Resonance Imaging (MRI).}, journal = {Neuroscience}, volume = {403}, number = {}, pages = {118-124}, doi = {10.1016/j.neuroscience.2018.01.013}, pmid = {29406268}, issn = {1873-7544}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/diagnostic imaging/*drug effects/growth &amp; development ; Brain Injuries/diagnostic imaging/*drug therapy/etiology/physiopathology ; Disease Models, Animal ; Escherichia coli ; Female ; *Inflammation/physiopathology ; Lipopolysaccharides ; Male ; Neuroprotective Agents/*pharmacology ; Pregnancy ; *Pregnancy Complications/physiopathology ; Prenatal Exposure Delayed Effects ; Random Allocation ; Rats, Sprague-Dawley ; }, abstract = {Maternal infection/inflammation may induce fetal inflammatory responses, which have been associated with long-term offspring cerebral injury. We previously demonstrated that prophylactic N-Acetyl-Cysteine (NAC), administered prior to and following maternal lipopolysaccharide (LPS), reduced offspring cerebral injury as evident on MRI. In the present study, we used MRI to examine the effect of therapeutic NAC following maternal LPS-induced inflammation on neonatal brain injury. Pregnant Sprague-Dawley dams (n = 6) at day 18 of gestation received either intraperitoneal injection of LPS or saline (Control) at time 0. Animals were randomized to receive intravenous injection (tail vein) of NAC or saline at time +30 min. Pups were delivered spontaneously and allowed to mature until postnatal day 25. Male offspring (6-8 per group) were examined by MRI and analyzed using voxel-based analysis. Diffusion Tensor Imaging (DTI), an advanced MRI technique, was performed and quantitative parameters extracted (mean and radial diffusivity) and used to assess white and gray matter brain injury. Offspring of LPS-treated dams exhibited significantly increased mean, axial and radial diffusivity (RD) levels in white and gray matter consistent with cerebral injury. In contrast, offspring of NAC-treated LPS PS dams demonstrated reduced mean, axial and RD levels in most regions; similar to the saline group. Maternal NAC treatment following maternal inflammation significantly influenced brain micro-structure integrity as demonstrated by MRI-DTI scans. These findings suggest that maternal NAC therapy may be effective in human pregnancies associated with maternal/fetal inflammation, such as preterm rupture of membranes and chorioamnionitis.}, }
@article {pmid29404930, year = {2018}, author = {Ma, WQ and Zhao, Y and Wang, Y and Han, XQ and Zhu, Y and Liu, NF}, title = {Comparative efficacy of pharmacological interventions for contrast-induced nephropathy prevention after coronary angiography: a network meta-analysis from randomized trials.}, journal = {International urology and nephrology}, volume = {50}, number = {6}, pages = {1085-1095}, pmid = {29404930}, issn = {1573-2584}, support = {81770451//National Natural Science Foundation of China/ ; }, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*drug therapy/*etiology/prevention &amp; control ; Contrast Media/*adverse effects ; Coronary Angiography ; Drug Therapy, Combination ; Free Radical Scavengers/*therapeutic use ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Natriuretic Peptide, Brain/analogs &amp; derivatives/*therapeutic use ; Network Meta-Analysis ; Prostaglandins/therapeutic use ; Randomized Controlled Trials as Topic ; Sodium Bicarbonate/therapeutic use ; Vitamins/therapeutic use ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) is the major complication related to contrast media administration in patients after coronary angiography (CAG). However, inconsistent results have been published in the literature regarding the effects of pharmacological drugs on CIN prevention. We conducted a network meta-analysis to evaluate the relative efficacy of pharmacological interventions for the prevention of CIN.<br><br>METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to July 2017. We included any randomized controlled trials of eleven pharmacological interventions that reported the prevention of CIN.<br><br>RESULTS: We identified 3850 records through database searches, of which 107 studies comprising 21,450 participants were finally identified. Compared with intravenous saline, intravenous saline plus pharmacological drugs including statin [relative risk (RR) 0.57; 95% credibility interval (CrI) 0.39 to 0.83], N-acetylcysteine (NAC) (RR 0.84; 95% CrI, 0.71 to 0.98), vitamin and its analogues (RR 0.66; 95% CrI 0.45 to 0.97), brain natriuretic peptide (BNP) and its analogues (RR 0.46; 95% CrI 0.30 to 0.70), prostaglandin analogues (RR 0.37; 95% CrI 0.18 to 0.76), NAC plus sodium bicarbonate (SB) (RR 0.60; 95% CrI 0.39 to 0.90), and statin plus NAC (RR 0.39; 95% CrI 0.21 to 0.70), have helped to reduce the incidence of CIN in patients after CAG. The top four ranked treatments were statin plus NAC, BNP and its analogues, statin, and vitamin and its analogues, respectively. NAC plus intravenous saline was associated with lower incidence of short-term all-cause mortality than intravenous saline alone (RR 0.62; 95% CI, 0.40 to 0.96; P&#xa0;=&#xa0;0.03). However, no evidence indicated that any of the pharmacological drugs were associated with a reduced requirement for dialysis and major adverse cardiac and cerebrovascular events (MACCE).<br><br>CONCLUSIONS: Statin plus NAC plus intravenous saline seems to be the most effective treatment for the prevention of CIN in patients after CAG. NAC plus intravenous saline may have a protective role against short-term all-cause mortality. However, none of these drugs has effectively decreased the requirement for dialysis and MACCE.}, }
@article {pmid29404664, year = {2018}, author = {Flórez, MR and Costas-Rodríguez, M and Grootaert, C and Van Camp, J and Vanhaecke, F}, title = {Cu isotope fractionation response to oxidative stress in a hepatic cell line studied using multi-collector ICP-mass spectrometry.}, journal = {Analytical and bioanalytical chemistry}, volume = {410}, number = {9}, pages = {2385-2394}, doi = {10.1007/s00216-018-0909-x}, pmid = {29404664}, issn = {1618-2650}, mesh = {Cell Survival ; Copper/analysis/*metabolism ; Hep G2 Cells ; Hepatocytes/chemistry/cytology/*metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Isotopes/analysis/metabolism ; Mass Spectrometry/methods ; *Oxidative Stress ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Reactive oxygen species (ROS) are generated in biological processes involving electron transfer reactions and can act in a beneficial or deleterious way. When intracellular ROS levels exceed the cell's anti-oxidant capacity, oxidative stress occurs. In this work, Cu isotope fractionation was evaluated in HepG2 cells under oxidative stress conditions attained in various ways. HepG2 is a well-characterised human hepatoblastoma cell line adapted to grow under high oxidative stress conditions. During a pre-incubation stage, cells were exposed to a non-toxic concentration of Cu for 24 h. Subsequently, the medium was replaced and cells were exposed to one of three different external stressors: H2O2, tumour necrosis factor α (TNFα) or UV radiation. The isotopic composition of the intracellular Cu was determined by multi-collector ICP-mass spectrometry to evaluate the isotope fractionation accompanying Cu fluxes between cells and culture medium. For half of these setups, the pre-incubation solution also contained N-acetyl-cysteine (NAC) as an anti-oxidant to evaluate its protective effect against oxidative stress via its influence on the extent of Cu isotope fractionation. Oxidative stress caused the intracellular Cu isotopic composition to be heavier compared to that in untreated control cells. The H2O2 and TNFα exposures rendered similar results, comparable to those obtained after mild UV exposure. The heaviest Cu isotopic composition was observed under the strongest oxidative conditions tested, i.e., when the cell surfaces were directly exposed to UV radiation without apical medium and in absence of NAC. NAC mitigated the extent of isotope fractionation in all cases.}, }
@article {pmid29397791, year = {2018}, author = {Li, B and Chen, M and Lu, M and Xin-Xiang, J and Meng-Xiong, P and Jun-Wu, M}, title = {Glutaredoxin 3 promotes migration and invasion via the Notch signalling pathway in oral squamous cell carcinoma.}, journal = {Free radical research}, volume = {52}, number = {4}, pages = {390-401}, doi = {10.1080/10715762.2018.1435871}, pmid = {29397791}, issn = {1029-2470}, mesh = {Carcinoma, Squamous Cell/*metabolism/*pathology ; Carrier Proteins/*metabolism ; *Cell Movement ; Female ; Humans ; Male ; Middle Aged ; Mouth Neoplasms/*metabolism/*pathology ; Receptors, Notch/*metabolism ; *Signal Transduction ; }, abstract = {Substantial evidence indicates that the alteration of the cellular redox status is a critical factor involved in cell growth and death and results in tumourigenesis. Cancer cells have an efficient antioxidant system to counteract the increased generation of ROS. However, whether this ability to survive high levels of ROS has an important role in the growth and metastasis of tumours is not well understood. Glutaredoxin 3 (GLRX3), also known as TXNL2, Grx3 and PICOT, maintains a low level of ROS, thus contributing to the survival and metastasis of several types of cancer. However, little is known about the role of GLRX3 and the underlying mechanisms that suppress oral squamous cell carcinoma (OSCC) progression. Here, by using immunohistochemical staining, we demonstrated that GLRX3 was overexpressed in human OSCC, and enhanced GLRX3 expression correlated with metastasis and with decreased overall patient survival. Knockdown of GLRX3 in human OSCC cell lines reduced Notch activity by reversing the epithelial-mesenchymal transition (EMT), resulting in the inhibition of in vitro migration and invasion. Importantly, knockdown of GLRX3 triggered the generation of ROS. Furthermore, N-acetyl cysteine (NAC), an ROS scavenger, enhanced the effects of GLRX3 knockdown on Notch-dependent EMT. Collectively, these findings suggested the vital roles of GLRX3 in OSCC progression through its relationship with EMT progression, and these data also suggest that a strategy of blocking ROS to enhance the activity of GLRX3 knockdown warrants further attention in the treatment of OSCC.}, }
@article {pmid29396859, year = {2018}, author = {Kong, Y and Shi, MM and Zhang, YY and Cao, XN and Wang, Y and Zhang, XH and Xu, LP and Huang, XJ}, title = {N-acetyl-L-cysteine improves bone marrow endothelial progenitor cells in prolonged isolated thrombocytopenia patients post allogeneic hematopoietic stem cell transplantation.}, journal = {American journal of hematology}, volume = {93}, number = {7}, pages = {931-942}, doi = {10.1002/ajh.25056}, pmid = {29396859}, issn = {1096-8652}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adolescent ; Adult ; Bone Marrow/*pathology ; Case-Control Studies ; Cells, Cultured ; Endothelial Progenitor Cells/*drug effects/pathology ; Female ; Hematopoietic Stem Cell Transplantation ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Middle Aged ; Reactive Oxygen Species/metabolism ; Thrombocytopenia/pathology/*therapy ; Thrombopoiesis/drug effects ; Transplantation, Homologous ; Young Adult ; }, abstract = {Prolonged isolated thrombocytopenia (PT) is a serious complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to murine studies, endothelial progenitor cells (EPCs) play a crucial role in the regulation of hematopoiesis and thrombopoiesis in the bone marrow (BM) microenvironment. We previously showed that the reduced frequency of BM EPCs was an independent risk factor for the occurrence of PT following allo-HSCT. However, the functional role of BM EPCs and methods to improve the impaired BM EPCs in PT patients are unknown. In the current case-control study, we investigated whether the BM EPCs in PT patients differed from those in good graft function patients. Moreover, we evaluated whether N-acetyl-L-cysteine (NAC, a reactive oxygen species [ROS] scavenger) could enhance BM EPCs from PT patients in vitro and in vivo. The PT patients exhibited dysfunctional BM EPCs characterized by high levels of ROS and apoptosis and decreased migration and angiogenesis capabilities. In vitro treatment with NAC improved the quantity and function of the BM EPCs cultivated from the PT patients by downregulating the p38 MAPK pathway and rescued the impaired BM EPCs to support megakaryocytopoiesis. Furthermore, according to the results of a preliminary clinical study, NAC is safe and effective in PT patients. In summary, these results suggested that the reduced and dysfunctional BM EPCs are involved in the occurrence of PT. The defective BM EPCs in the PT patients can be quantitatively and functionally improved by NAC, indicating that NAC is a promising therapeutic approach for PT patients following allo-HSCT.}, }
@article {pmid29396710, year = {2018}, author = {Scheffel, MJ and Scurti, G and Wyatt, MM and Garrett-Mayer, E and Paulos, CM and Nishimura, MI and Voelkel-Johnson, C}, title = {N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner.}, journal = {Cancer immunology, immunotherapy : CII}, volume = {67}, number = {4}, pages = {691-702}, pmid = {29396710}, issn = {1432-0851}, support = {P01 CA154778/CA/NCI NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P01 CA154778/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cells, Cultured ; Forkhead Box Protein O1/*metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; *Immunotherapy, Adoptive ; Lymphocyte Activation ; Melanoma/*drug therapy/immunology/metabolism ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Signal Transduction ; T-Lymphocytes, Cytotoxic/*immunology ; }, abstract = {Therapeutic outcomes for adoptive cell transfer (ACT) therapy are constrained by the quality of the infused T cells. The rapid expansion necessary to obtain large numbers of cells results in a more terminally differentiated phenotype with decreased durability and functionality. N-acetyl cysteine (NAC) protects against activation-induced cell death (AICD) and improves anti-tumor efficacy of Pmel-1 T cells in vivo. Here, we show that these benefits of NAC can be extended to engineered T cells and significantly increases T-cell survival within the tumor microenvironment. The addition of NAC to the expansion protocol of human TIL13838I TCR-transduced T cells that are under evaluation in a Phase I clinical trial, demonstrated that findings in murine cells extend to human cells. Expansion of TIL13838I TCR-transduced T cells in NAC also increased their ability to kill target cells in vitro. Interestingly, NAC did not affect memory subsets, but diminished up-regulation of senescence (CD57) and exhaustion (PD-1) markers and significantly decreased expression of the transcription factors EOMES and Foxo1. Pharmacological inhibition of the PI3K/Akt pathway ablates the decrease in Foxo1 induced by NAC treatment of activated T cells. This suggests a model in which NAC through PI3K/Akt activation suppresses Foxo1 expression, thereby impacting its transcriptional targets EOMES, PD-1, and granzyme B. Taken together, our results indicate that NAC exerts pleiotropic effects that impact the quality of TCR-transduced T cells and suggest that the addition of NAC to current clinical protocols should be considered.}, }
@article {pmid29395036, year = {2018}, author = {Peyron, I and Dimitrov, JD and Delignat, S and Gangadharan, B and Srivastava, A and Kaveri, SV and Lacroix-Desmazes, S}, title = {Oxidation of factor VIII increases its immunogenicity in mice with severe hemophilia A.}, journal = {Cellular immunology}, volume = {325}, number = {}, pages = {64-68}, doi = {10.1016/j.cellimm.2018.01.008}, pmid = {29395036}, issn = {1090-2163}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies/immunology ; Antigen-Presenting Cells/immunology/metabolism ; Disease Models, Animal ; Factor VIII/*immunology/metabolism/pharmacology ; Hemophilia A/drug therapy/*immunology/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oxidation-Reduction ; Oxidative Stress/immunology ; }, abstract = {The development of antibodies against therapeutic factor VIII (FVIII) represents the major complication of replacement therapy in patients with severe hemophilia A. Amongst the environmental risk factors that influence the anti-FVIII immune response, the presence of active bleeding or hemarthrosis has been evoked. Endothelium damage is typically associated with the release of oxidative compounds. Here, we addressed whether oxidation contributes to FVIII immunogenicity. The control with N-acetyl cysteine of the oxidative status in FVIII-deficient mice, a model of severe hemophilia A, reduced the immune response to exogenous FVIII. Ex vivo exposure of therapeutic FVIII to HOCl induced a mild oxidation of the molecule as evidenced by the loss of free amines and resulted in increased FVIII immunogenicity in vivo when compared to native FVIII. The increased immunogenicity of oxidized FVIII was not reverted by treatment of mice with N-acetyl cysteine, and did not implicate an increased maturation of professional antigen-presenting cells. Our data document that oxidation influences the immunogenicity of therapeutic FVIII.}, }
@article {pmid29393399, year = {2018}, author = {Chen, J and Lou, Q and He, L and Wen, C and Lin, M and Zhu, Z and Wang, F and Huang, L and Lan, W and Iwamoto, A and Yang, X and Liu, H}, title = {Reduced-gliotoxin induces ROS-mediated anoikis in human colorectal cancer cells.}, journal = {International journal of oncology}, volume = {52}, number = {3}, pages = {1023-1032}, doi = {10.3892/ijo.2018.4264}, pmid = {29393399}, issn = {1791-2423}, mesh = {Acetylcysteine/pharmacology ; Anoikis/*drug effects ; Antineoplastic Agents/chemistry/*pharmacology/therapeutic use ; Colorectal Neoplasms/*drug therapy/pathology ; Gliotoxin/chemistry/*pharmacology/therapeutic use ; HCT116 Cells ; HT29 Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/physiology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Reduced-gliotoxin is a small molecule derived from the secondary metabolites of marine fungi; compared to other gliotoxin analogues, it exhibits potent anticancer effects. However, the molecular basis of the death of colorectal cancer (CRC) cells induced by reduced-gliotoxin is unclear. Thus, the aim of this study was to investigate the potency of reduced-gliotoxin against CRC cells and to elucidate the underlying mechanisms. Cell morphology, flow cytometric analysis and western bolt analysis were performed to examine the functions and mechanisms of cell death induced by reduced-gliotoxin. Our findings demonstrated that reduced-gliotoxin triggered rapid cell detachment and induced anoikis in CRC cells. Mechanistically, our data indicated that the anoikis induced by reduced-gliotoxin was associated with the disruption of integrin-associated cell detachment and multiple signaling pathways. Furthermore, reduced-gliotoxin induced the excessive production of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP), resulting in the activation of both endogenous and exogenous apoptotic pathways and eventually, in the apoptosis of CRC cells. The blockage of ROS generation with N-acetylcysteine (NAC) attenuated the anoikis induced by reduced-gliotoxin. Taken together, these results suggest that reduced-gliotoxin may prove to be a potential candidate in the treatment of CRC.}, }
@article {pmid29392783, year = {2018}, author = {Sánchez-Santos, A and Martínez-Hernández, MG and Contreras-Ramos, A and Ortega-Camarillo, C and Baiza-Gutman, LA}, title = {Hyperglycemia-induced mouse trophoblast spreading is mediated by reactive oxygen species.}, journal = {Molecular reproduction and development}, volume = {85}, number = {4}, pages = {303-315}, doi = {10.1002/mrd.22965}, pmid = {29392783}, issn = {1098-2795}, mesh = {Animals ; Diabetes, Gestational/*metabolism/pathology ; Female ; Hyperglycemia/*metabolism/pathology ; Mice ; *Oxidative Stress ; Pregnancy ; Pregnancy Proteins/*metabolism ; Reactive Oxygen Species/*metabolism ; Trophoblasts/*metabolism/pathology ; }, abstract = {During embryo implantation, the outer layer of the blastocyst interacts with the endometrium giving rise to the development of the trophoblast cell lineage. The cells in this lineage participate in the penetration of endometrium due to their motility and invasive properties. The mechanisms that regulate the differentiation and invasive ability of these cells are essential for the establishment and maintenance of an efficient exchange between maternal and fetal tissues during pregnancy. In this context, hyperglycemia can induce oxidative stress causing alterations in the placenta. This study evaluated the role of reactive oxygen species (ROS) in the actions of high glucose concentration (HG) on trophoblast spreading and the expression of extracellular proteases in cultured mouse conceptuses. Blastocysts from gestational day 4 (GD4) were cultured until GD7 in HAM-F10 medium and further treated for 48 hr with HG (25 mM glucose) from GD7 to GD9. This treatment induced larger trophoblast outgrowths and increased ROS concentration, which was associated with increased expression levels of urokinase-type plasminogen activator (PLAU), plasminogen activator inhibitor 1 (PAI-1), and matrix metalloproteinase 9 (MMP-9). These effects were prevented by treatment with the non-specific antioxidant N-acetylcysteine (NAC) or apocynin, an inhibitor of NADPH oxidase. Our data suggest that the HG-induced trophoblast spreading and the expression of PLAU, PAI-1, and MMP-9 were mediated by the production of ROS via NADPH oxidase activity. Our results shed light on placental alterations in gestational diabetes mellitus.}, }
@article {pmid29392716, year = {2018}, author = {Kong, Y and Song, Y and Tang, FF and Zhao, HY and Chen, YH and Han, W and Yan, CH and Wang, Y and Zhang, XH and Xu, LP and Huang, XJ}, title = {N-acetyl-L-cysteine improves mesenchymal stem cell function in prolonged isolated thrombocytopenia post-allotransplant.}, journal = {British journal of haematology}, volume = {180}, number = {6}, pages = {863-878}, doi = {10.1111/bjh.15119}, pmid = {29392716}, issn = {1365-2141}, mesh = {Acetylcysteine/*administration &amp; dosage ; Bone Marrow Cells/*metabolism/pathology ; Case-Control Studies ; Female ; *Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute/metabolism/pathology/*therapy ; Male ; Mesenchymal Stem Cells/*metabolism/pathology ; Pilot Projects ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology/*therapy ; Prospective Studies ; Thrombocytopenia/*drug therapy/etiology/metabolism/pathology ; }, abstract = {Prolonged isolated thrombocytopenia (PT) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). Murine studies and in vitro experiments suggest that mesenchymal stem cells (MSCs) can, not only to support haematopoiesis, but also preferentially support megakaryocytopoiesis in bone marrow (BM). However, little is known about the quantity and function of BM MSCs in PT patients. In a case-control study, we found that BM MSCs from PT patients exhibited significantly reduced proliferative capacities, increased reactive oxygen species and senescence. Antioxidant (N-acetyl-L-cysteine, NAC) treatment in vitro not only quantitatively and functionally improved BM MSCs derived from PT patients through down-regulation of the p38 (also termed MAPK14) and p53 (also termed TP53) pathways but also partially rescued the impaired ability of BM MSCs to support megakaryocytopoiesis. Subsequently, a pilot study showed that the overall response of NAC treatment was obtained in 7 of the enrolled PT patients (N = 10) without significant side effects. Taken together, the results indicated that dysfunctional BM MSCs played a role in the pathogenesis of PT and the impaired BM MSCs could be improved by NAC in vitro. Although requiring further validation, our data indicate that NAC might be a potential therapeutic approach for PT patients after allo-HSCT.}, }
@article {pmid29392418, year = {2018}, author = {Burini, RC and Borges-Santos, MD and Moreto, F and Yu, YM}, title = {Comparative effects of acute-methionine loading on the plasma sulfur-amino acids in NAC-supplemented HIV+ patients and healthy controls.}, journal = {Amino acids}, volume = {50}, number = {5}, pages = {569-576}, pmid = {29392418}, issn = {1438-2199}, support = {99/01716-0//Funda&#xe7;&#xe3;o de Amparo &#xe0; Pesquisa do Estado de S&#xe3;o Paulo/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Antiretroviral Therapy, Highly Active ; Cysteine/*blood ; *Dietary Supplements ; Female ; Glutathione/*blood ; *HIV Infections/blood/therapy ; *HIV-1 ; Humans ; Male ; Methionine/*blood ; Middle Aged ; }, abstract = {In this study, an acute overloading of methionine (MetLo) was used to investigate the trassulfuration pathway response comparing healthy controls and HIV+ patients under their usual diet and dietary N-acetyl-L-cysteine (NAC) supplementation. MetLo (0.1 g Met/kg mass weight) was given after overnight fasting to 20 non-HIV+ control subjects (Co) and 12 HIV+ HAART-treated patients. Blood samples were taken before and after the MetLo in two different 7-day dietary situations, with NAC (1 g/day) or with their usual diet (UD). The amino acids (Met, Hcy, Cys, Tau, Ser, Glu and Gln) and GSH were determined by HPLC and their inflow rate into circulation (plasma) was estimated by the area under the curve (AUC). Under UD, the HIV+ had lower plasma GSH and amino acids (excepting Hcy) and higher oxidative stress (GSSG/GSH ratio), similar remethylation (RM: Me/Hcy + Ser ratio), transmethylation (TM; Hcy/Met ratio) and glutaminogenesis (Glu/Gln ratio), lower transsulfuration (TS: Cys/Hcy + Ser ratio) and Cys/Met ratio and, higher synthetic rates of glutathione (GG: GSH/Cys ratio) and Tau (TG: Tau/Cys ratio). NAC supplementation changed the HIV pattern by increasing RM above control, normalizing plasma Met and TS and, increasing plasma GSH and GG above controls. However, plasma Cys was kept always below controls probably, associatively to its higher consumption in GG (more GSSG than GSH) and TG. The failure of restoring normal Cys by MetLo, in addition to NAC, in HIV+ patients seems to be related to increased flux of Cys into GSH and Tau pathways, probably strengthening the cell-antioxidant capacity against the HIV progression (registered at http://www.clinicaltrials.gov , NCT00910442).}, }
@article {pmid29392100, year = {2017}, author = {Naveed, S and Amray, A and Waqas, A and Chaudhary, AM and Azeem, MW}, title = {Use of N-Acetylcysteine in Psychiatric Conditions among Children and Adolescents: A Scoping Review.}, journal = {Cureus}, volume = {9}, number = {11}, pages = {e1888}, pmid = {29392100}, issn = {2168-8184}, abstract = {N-acetylcysteine (NAC) is a well-known antidote for acetaminophen toxicity and is easily available over the counter. It has antioxidant and anti-inflammatory properties and an established tolerance and safety profile. Owing to its neuroprotective effects, its clinical use has recently expanded to include the treatment of different psychiatric and non-psychiatric disorders. Although a number of randomized controlled trials have documented the clinical evidence for NAC, there are no reviews that summarize the evidence. The present scoping review summarizes the study designs, the patient characteristics, the evidence and the limitations in randomized controlled trials designed to explore the efficacy of NAC for psychiatric conditions in the pediatric population.}, }
@article {pmid29391265, year = {2018}, author = {Singh, V and Keisham, A and Bhalla, A and Sharma, N and Agarwal, R and Sharma, R and Singh, A}, title = {Efficacy of Granulocyte Colony-Stimulating Factor and N-Acetylcysteine Therapies in Patients With Severe Alcoholic Hepatitis.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {16}, number = {10}, pages = {1650-1656.e2}, doi = {10.1016/j.cgh.2018.01.040}, pmid = {29391265}, issn = {1542-7714}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Aged ; Drug Therapy, Combination/methods ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Granulocyte Colony-Stimulating Factor/*administration &amp; dosage ; Hepatitis, Alcoholic/*drug therapy/pathology ; Humans ; Immunologic Factors/*administration &amp; dosage ; India ; Liver Function Tests ; Male ; Middle Aged ; Pentoxifylline/administration &amp; dosage ; Pilot Projects ; Prospective Studies ; Survival Analysis ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND &amp; AIMS: Patients with alcoholic hepatitis (AH) have high mortality, so new therapies are needed. Administration of granulocyte colony stimulating factor (G-CSF) increases survival times of patients with AH. It is not known whether addition of N-acetyl cysteine (NAC) to G-CSF could further increase survival time. We performed a randomized controlled pilot study to compare the efficacy of standard medical therapy with pentoxifylline to treatment with a combination of G-CSF and standard medical therapy as well as to the combination of NAC, G-CSF, and standard medical therapy in patients with severe AH.<br><br>METHODS: We performed an open-label, single-center study of 57 patients with severe AH admitted to a Liver Intensive Care unit in India from October 2014 through March 2017. Patients were randomly assigned to groups that received standard medical therapy (with pentoxifylline) plus G-CSF for 5 days (G-CSF group; n&#xa0;= 18), standard medical therapy plus G-CSF and intravenous NAC for 5 days (combination group; n&#xa0;= 19), or standard medical therapy alone&#xa0;(n&#xa0;= 20). Clinical data and blood samples were collected at baseline; on day 6; and 1, 2, and 3 months after the study began. CD34+ cells were measured in blood samples collected on days 0 and 6. The primary outcome was proportion of patients surviving for 90 days. Secondary outcomes were mobilization of CD34+ cells at day 6, as well as Child Turcotte Pugh, model for end-stage liver disease, and modified discriminant function scores until day&#xa0;90.<br><br>RESULTS: Significantly higher proportions of patients in the G-CSF group (16/18) and the combination group (13/19) survived for 90 days than in the standard medical therapy group (6/20) (P&#xa0;=&#xa0;.0001 for G-CSF group and P = .037 and combination group). The GGSF and combination groups each had increased numbers of CD34+ cells from baseline until day 6, compared with the standard medical therapy group. The G-CSF group (but not the combination group) had significantly larger median reductions in modified discriminant function scores at study months 1 (reduction of 60.36%), 2 (reduction of 75.36%), and 3 (reduction of 88.73%) vs the standard medical therapy group (P = .02; P = .05; and P = .00, respectively). The G-CSF group had a significantly larger median reduction in model for end-stage liver disease score at 3 months (reduction of 55.77%; P&#xa0;= .01), but not in Child Turcotte Pugh score, compared with the standard medical therapy group. All groups had similar numbers of complications.<br><br>CONCLUSION: In a pilot randomized controlled trial, we found administration of G-CSF to improve liver function and increase survival times in patients with severe AH, compared with standard therapy. We found no evidence for benefit of adding NAC to G-CSF. These findings require confirmation in larger trials. ClincialTrials.gov, number: NCT02971306.}, }
@article {pmid29387038, year = {2017}, author = {Bhatti, J and Nascimento, B and Akhtar, U and Rhind, SG and Tien, H and Nathens, A and da Luz, LT}, title = {Systematic Review of Human and Animal Studies Examining the Efficacy and Safety of N-Acetylcysteine (NAC) and N-Acetylcysteine Amide (NACA) in Traumatic Brain Injury: Impact on Neurofunctional Outcome and Biomarkers of Oxidative Stress and Inflammation.}, journal = {Frontiers in neurology}, volume = {8}, number = {}, pages = {744}, pmid = {29387038}, issn = {1664-2295}, abstract = {BACKGROUND: No new therapies for traumatic brain injury (TBI) have been officially translated into current practice. At the tissue and cellular level, both inflammatory and oxidative processes may be exacerbated post-injury and contribute to further brain damage. N-acetylcysteine (NAC) has the potential to downregulate both processes. This review focuses on the potential neuroprotective utility of NAC and N-acetylcysteine amide (NACA) post-TBI.<br><br>METHODS: Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to July 2017. Studies that examined clinical and laboratory effects of NAC and NACA post-TBI in human and animal studies were included. Risk of bias was assessed in human and animal studies according to the design of each study (randomized or not). The primary outcome assessed was the effect of NAC/NACA treatment on functional outcome, while secondary outcomes included the impact on biomarkers of inflammation and oxidation. Due to the clinical and methodological heterogeneity observed across studies, no meta-analyses were conducted.<br><br>RESULTS: Our analyses revealed only three human trials, including two randomized controlled trials (RCTs) and 20 animal studies conducted using standardized animal models of brain injury. The two RCTs reported improvement in the functional outcome post-NAC/NACA administration. Overall, the evidence from animal studies is more robust and demonstrated substantial improvement of cognition and psychomotor performance following NAC/NACA use. Animal studies also reported significantly more cortical sparing, reduced apoptosis, and lower levels of biomarkers of inflammation and oxidative stress. No safety concerns were reported in any of the studies included in this analysis.<br><br>CONCLUSION: Evidence from the animal literature demonstrates a robust association for the prophylactic application of NAC and NACA post-TBI with improved neurofunctional outcomes and downregulation of inflammatory and oxidative stress markers at the tissue level. While a growing body of scientific literature suggests putative beneficial effects of NAC/NACA treatment for TBI, the lack of well-designed and controlled clinical investigations, evaluating therapeutic outcomes, prognostic biomarkers, and safety profiles, limits definitive interpretation and recommendations for its application in humans at this time.}, }
@article {pmid29383185, year = {2017}, author = {Casaburi, I and Avena, P and De Luca, A and Sirianni, R and Rago, V and Chimento, A and Trotta, F and Campana, C and Rainey, WE and Pezzi, V}, title = {GPER-independent inhibition of adrenocortical cancer growth by G-1 involves ROS/Egr-1/BAX pathway.}, journal = {Oncotarget}, volume = {8}, number = {70}, pages = {115609-115619}, pmid = {29383185}, issn = {1949-2553}, abstract = {We previously demonstrated that treatment of the H295R adrenocortical cancer cell line with the non-steroidal, high-affinity GPER (G protein-coupled estrogen receptor 1) agonist G-1 reduced tumor growth in vitro and in vivo through a GPER independent action. Moreover, we observed that G-1 treatment induces cell-cycle arrest and apoptosis following a sustained ERK1/2 activation. However, the precise mechanisms causing these effects were not clarified. Starting from our preliminary published results, we performed a microarray study that clearly evidenced a strong and significative up-regulation of EGR-1 gene in H295R cells treated for 24h with micromolar concentration of G-1. The microarray findings were confirmed by RT-PCR and Western-blot analysis as well as by immunofluorescence that revealed a strong nuclear staining for EGR-1 after G-1 treatment. EGR-1 is a point of convergence of many intracellular signaling cascades that control tumor cell growth and proliferation as well as others that relate to cell death machinery. Here we found that the increased Egr-1 expression was a consequence of G-1-mediated ROS-dependent ERK activation that were promptly reversed by the presence of the antioxidant n-acetyl-cysteine. Finally, we observed that silencing EGR-1 gene expression reversed the main effects induced by G-1 in ACC cells, including upregulation of the negative regulator of cell cycle, p21[Waf1/Cip1] and the positive regulator of mitochondrial apoptotic pathway, BAX, as well as the cell growth inhibition. The identified ROS/MAPK/Egr-1/BAX pathway as a potential off-target effect of the G-1 could be useful in implementing the pharmacological approach for ACC therapy.}, }
@article {pmid29383104, year = {2017}, author = {Chen, MS and Wang, SF and Hsu, CY and Yin, PH and Yeh, TS and Lee, HC and Tseng, LM}, title = {CHAC1 degradation of glutathione enhances cystine-starvation-induced necroptosis and ferroptosis in human triple negative breast cancer cells via the GCN2-eIF2α-ATF4 pathway.}, journal = {Oncotarget}, volume = {8}, number = {70}, pages = {114588-114602}, pmid = {29383104}, issn = {1949-2553}, abstract = {Cancer cells exhibit an abnormal amino acid metabolism and a dependence on specific amino acids, which might provide potential targets for treating cancer patients. In this study, we demonstrated that human triple negative breast cancer (TNBC) cells were highly susceptible to cystine starvation. We found that necrostatin-1 (Nec-1, a RIP1 inhibitor), necrosulfonamide (an MLKL inhibitor), deferoxamine (an ion chelator), ferrostatin-1 (a ferroptosis inhibitor) and RIP1 knockdown can prevent cystine-starvation-induced cell death, suggesting that cystine starvation induces necroptosis and ferroptosis in TNBC cells. Moreover, cystine starvation induced mitochondrial fragmentation, dysfunction, and ROS production. A mitochondrial ROS scavenger, Necrox-5, can prevent cystine-starvation-induced cell death. In addition, cystine starvation was found to activate GCN2, but not PERK, to increase the phosphorylation of eIF2α at serine 51, the protein expression of ATF4, and the expression of ATF4 target genes such as CHAC1, which might be downstream of the RIP1/RIP3-MLKL pathway and contribute to cystine-starvation-induced cell death. Knockdown of CHAC1 rescued the cystine-starvation-induced reduction in glutathione (GSH) levels and cell death. Furthermore, N-acetyl-cysteine (NAC), Trolox, and Nec-1 significantly prevented the cystine-starvation-induced increase in intracellular ROS levels, mitochondrial fragmentation and cell death. In summary, these results suggest that CHAC1 degradation of GSH enhances cystine-starvation-induced necroptosis and ferroptosis through the activated GCN2-eIF2α-ATF4 pathway in TNBC cells. Our findings improve our understanding of the mechanism underlying cystine-starvation-induced TNBC cell death.}, }
@article {pmid29382173, year = {2018}, author = {Chao, TL and Wang, TY and Lee, CH and Yiin, SJ and Ho, CT and Wu, SH and You, HL and Chern, CL}, title = {Anti-Cancerous Effect of Inonotus taiwanensis Polysaccharide Extract on Human Acute Monocytic Leukemia Cells through ROS-Independent Intrinsic Mitochondrial Pathway.}, journal = {International journal of molecular sciences}, volume = {19}, number = {2}, pages = {}, pmid = {29382173}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; *Apoptosis ; Autophagy ; Basidiomycota/*chemistry ; Caspase Inhibitors/pharmacology ; Cell Line, Tumor ; DNA Fragmentation ; Endodeoxyribonucleases/metabolism ; Fungal Polysaccharides/*pharmacology ; Humans ; Leukemia, Myeloid/metabolism ; Membrane Potential, Mitochondrial ; Mitochondria/drug effects/*metabolism ; Monocytes/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Acute leukemia is one of the commonly diagnosed neoplasms and causes human death. However, the treatment for acute leukemia is not yet satisfactory. Studies have shown that mushroom-derived polysaccharides display low toxicity and have been used clinically for cancer therapy. Therefore, we set out to evaluate the anti-cancerous efficacy of a water-soluble polysaccharide extract from Inonotus taiwanensis (WSPIS) on human acute monocytic leukemia THP-1 and U937 cell lines in vitro. Under our experimental conditions, WSPIS elicited dose-dependent growth retardation and induced apoptotic cell death. Further analysis showed that WSPIS-induced apoptosis was associated with a mitochondrial apoptotic pathway, such as the disruption of mitochondrial membrane potential (MMP), followed by the activation of caspase-9, caspase-3, and PARP (poly(ADP-ribose) polymerase) cleavage. However, a broad caspase inhibitor, Z-VAD.fmk, could not prevent WSPIS-induced apoptosis. These data imply that mechanism(s) other than caspase might be involved. Thus, the involvement of endonuclease G (endoG), a mediator arbitrating caspase-independent oligonucleosomal DNA fragmentation, was examined. Western blotting demonstrated that WSPIS could elicit nuclear translocation of endoG. MMP disruption after WSPIS treatment was accompanied by intracellular reactive oxygen species (ROS) generation. However, pretreatment with N-acetyl-l-cysteine (NAC) could not attenuate WSPIS-induced apoptosis. In addition, our data also show that WSPIS could inhibit autophagy. Activation of autophagy by rapamycin decreased WSPIS-induced apoptosis and cell death. Taken together, our findings suggest that cell cycle arrest, endonuclease G-mediated apoptosis, and autophagy inhibition contribute to the anti-cancerous effect of WSPIS on human acute monocytic leukemia cells.}, }
@article {pmid29379435, year = {2017}, author = {Hira, S and Saleem, U and Anwar, F and Ahmad, B}, title = {Antioxidants Attenuate Isolation- and L-DOPA-Induced Aggression in Mice.}, journal = {Frontiers in pharmacology}, volume = {8}, number = {}, pages = {945}, pmid = {29379435}, issn = {1663-9812}, abstract = {Aggression is a major hallmark worldwide attributing negative traits in personality. Wide variety of antioxidants is used for the treatment of many ailments. The present study was conducted to evaluate the role of antioxidants such as ascorbic acid (15.42 and 30.84 mg/kg), beta carotene (1.02 and 2.05 mg/kg), vitamin E (2.5 and 5.0 mg/kg), and N-acetyl cysteine (102.85 and 205.70 mg/kg) in the treatment of aggression. Two aggression models (isolation induced aggression model and L-DOPA induced aggression model) were used in the study. Male albino mice (n = 330) were used in the study which were further subdivided into 11 groups (Group I-control, group II-diseased, group III-standard group, group IV-V treated with ascorbic, group VI-VII treated with beta carotene, group VIII-IX treated with vitamin E, group X-XI treated with N-acetyl cysteine for 14 consecutive days). Different biochemical markers (glutathione, superoxide dismutase, and catalase) were determined to evaluate the antioxidant potential in oxidative stress. High dose of vitamin E (5.0 mg/kg) was more effective to reduce the aggression in isolated animals while all other antioxidants produced dose-dependent anti-aggressive effect except N-acetyl cysteine which had marked anti-aggressive effect at low dose (102.75 mg/kg). Low doses of vitamin E (2.5 mg/kg) and N-acetyl cysteine (102.75 mg/kg) and high dose of beta carotene (2.05 mg/kg) were effective to prevent all aggression parameters in acute anti-aggressive activity against L-DOPA induced aggression. However, all test antioxidants were equally effective in chronic anti-aggressive studies against L-DOPA induced aggression. It may be concluded that selected antioxidants can reverse the aggression which is a key symptom of many neurological disorder.}, }
@article {pmid29378951, year = {2018}, author = {Song, E and Ramos, SV and Huang, X and Liu, Y and Botta, A and Sung, HK and Turnbull, PC and Wheeler, MB and Berger, T and Wilson, DJ and Perry, CGR and Mak, TW and Sweeney, G}, title = {Holo-lipocalin-2-derived siderophores increase mitochondrial ROS and impair oxidative phosphorylation in rat cardiomyocytes.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {115}, number = {7}, pages = {1576-1581}, pmid = {29378951}, issn = {1091-6490}, support = {FDN-143219//CIHR/Canada ; }, mesh = {Animals ; Gentisates/pharmacology ; Hydroxybenzoates/pharmacology ; Iron/metabolism ; Lipocalin-2/*physiology ; Male ; Mice ; Mice, Knockout ; Mitochondria/drug effects/metabolism/*pathology ; Myocytes, Cardiac/drug effects/metabolism/*pathology ; Oxidative Phosphorylation ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/drug therapy/metabolism/*pathology ; Siderophores/*metabolism ; }, abstract = {Lipocalin-2 (Lcn2), a critical component of the innate immune response which binds siderophores and limits bacterial iron acquisition, can elicit spillover adverse proinflammatory effects. Here we show that holo-Lcn2 (Lcn2-siderophore-iron, 1:3:1) increases mitochondrial reactive oxygen species (ROS) generation and attenuates mitochondrial oxidative phosphorylation in adult rat primary cardiomyocytes in a manner blocked by N-acetyl-cysteine or the mitochondria-specific antioxidant SkQ1. We further demonstrate using siderophores 2,3-DHBA (2,3-dihydroxybenzoic acid) and 2,5-DHBA that increased ROS and reduction in oxidative phosphorylation are direct effects of the siderophore component of holo-Lcn2 and not due to apo-Lcn2 alone. Extracellular apo-Lcn2 enhanced the potency of 2,3-DHBA and 2,5-DHBA to increase ROS production and decrease mitochondrial respiratory capacity, whereas intracellular apo-Lcn2 attenuated these effects. These actions of holo-Lcn2 required an intact plasma membrane and were decreased by inhibition of endocytosis. The hearts, but not serum, of Lcn2 knockout (LKO) mice contained lower levels of 2,5-DHBA compared with wild-type hearts. Furthermore, LKO mice were protected from ischemia/reperfusion-induced cardiac mitochondrial dysfunction. Our study identifies the siderophore moiety of holo-Lcn2 as a regulator of cardiomyocyte mitochondrial bioenergetics.}, }
@article {pmid29378152, year = {2018}, author = {Rosa, LRO and Kaga, AK and Barbanera, PO and Queiroz, PM and do Carmo, NOL and Fernandes, AAH}, title = {Beneficial effects of N-acetylcysteine on hepatic oxidative stress in streptozotocin-induced diabetic rats.}, journal = {Canadian journal of physiology and pharmacology}, volume = {96}, number = {4}, pages = {412-418}, doi = {10.1139/cjpp-2017-0559}, pmid = {29378152}, issn = {1205-7541}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism ; Biomarkers/metabolism ; Diabetes Mellitus, Experimental/blood/*drug therapy/pathology ; Fatty Acids/metabolism ; Hyperglycemia/complications/drug therapy ; Insulin/blood ; Liver/drug effects/enzymology/pathology ; Male ; *Oxidative Stress/drug effects ; Rats, Wistar ; Streptozocin ; Triglycerides/metabolism ; Urea/blood ; }, abstract = {Diabetes is one of the leading diseases worldwide and, thus, finding new therapeutic alternatives is essential. The development of non-alcoholic fatty liver disease is a notable diabetic complication. Therefore, antioxidant therapy became a leading topic in the world of diabetes research. The objective of this present study was to evaluate the effects of antioxidant N-acetylcysteine (NAC) administration on serum biochemical parameters and oxidative stress parameters in hepatic tissue of the diabetic rats. Thirty-two animals were divided in 4 groups (n = 8): G1, normal rats; G2, normal rats + NAC; G3, diabetic rats; and G4, diabetic rats + NAC. Diabetes was induced in diabetic groups through streptozotocin. NAC administration was effective in improving hyperglycemia and hypoinsulinemia, as well as reducing serum alanine-aminotransferase and urea, hepatic triglycerides accumulation, and oxidative stress biomarkers in the diabetic liver, as well as improving the activity of hepatic antioxidant enzymes. This effect was likely due to NAC's ability of restoring intracellular glutathione, an important compound for the antioxidant defense, as well as due to NAC's direct antioxidant properties. Thus, NAC administration was useful for reducing hepatic oxidative stress and decreased the deposit of triacylglycerols, minimizing diabetic hepatic damage, making it a promising therapeutic adjuvant in the future.}, }
@article {pmid29375391, year = {2017}, author = {Pai, WY and Lo, WY and Hsu, T and Peng, CT and Wang, HJ}, title = {Angiotensin-(1-7) Inhibits Thrombin-Induced Endothelial Phenotypic Changes and Reactive Oxygen Species Production via NADPH Oxidase 5 Downregulation.}, journal = {Frontiers in physiology}, volume = {8}, number = {}, pages = {994}, pmid = {29375391}, issn = {1664-042X}, abstract = {Background and Aims: The angiotensin-(1-7)/angiotensin-converting enzyme 2/Mas receptor axis counter-regulates the detrimental effects of angiotensin II. Beneficial effects of angiotensin-(1-7), including anti-inflammation, oxidative stress reduction, and anti-thrombosis, have been reported. Previous studies documented that ramipril decreased thrombin generation in human hypertension and that the anti-thrombotic effects of captopril and losartan were angiotensin-(1-7)-dependent, suggesting an interaction between thrombin and angiotensin-(1-7). However, it is not clear whether angiotensin-(1-7) can alleviate the endothelial phenotypic changes induced by thrombin. We have previously documented cytoskeleton remodeling, cell adhesion, and cell migration as dominant altered phenotypes in thrombin-stimulated human aortic endothelial cells (HAECs). In this study, we investigated whether angiotensin-(1-7) can modulate thrombin-induced phenotypic changes. Furthermore, we investigated whether NAPDH oxidase 5 (Nox5)-produced reactive oxygen species (ROS) play a significant role in angiotensin-(1-7)-mediated phenotypic changes. Methods: HAECs were pretreated with 100 nM angiotensin-(1-7) for 1 h, followed by stimulation with 2 units/mL thrombin for different times. Immunofluorescent assay, monocyte adhesion assay, wound-healing assay, ROS assay, real-time PCR, Western blotting, and Nox5 siRNA transfection were conducted. HAECs were pretreated with the ROS scavenger N-acetylcysteine (NAC) to determine whether thrombin-induced phenotypic changes depended on ROS production. Results: Angiotensin-(1-7) prevented thrombin-induced actin cytoskeleton derangements, monocyte adhesion, and migratory impairment. Nox5 siRNA transfection confirmed that thrombin-induced Nox5 expression stimulated ROS production and increased HO-1/NQO-1/ICAM-1/VCAM-1 gene expression, all of which were decreased by angiotensin-(1-7). Phenotypic changes induced by thrombin were prevented by NAC pretreatment. Conclusion: Angiotensin-(1-7) prevents actin cytoskeleton derangement, monocyte adhesion, and migration impairment induced by thrombin via downregulation of ROS production. In addition, thrombin-induced Nox5 expression is involved in the production of ROS, and angiotensin-(1-7) decreases ROS through its inhibitory effect on Nox5 expression.}, }
@article {pmid29373603, year = {2018}, author = {Guo, MY and Wang, H and Chen, YH and Xia, MZ and Zhang, C and Xu, DX}, title = {N-acetylcysteine alleviates cadmium-induced placental endoplasmic reticulum stress and fetal growth restriction in mice.}, journal = {PloS one}, volume = {13}, number = {1}, pages = {e0191667}, pmid = {29373603}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cadmium/*toxicity ; Down-Regulation/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Female ; Fetal Growth Retardation/*prevention &amp; control ; Mice ; Placenta/*drug effects ; Pregnancy ; Real-Time Polymerase Chain Reaction ; }, abstract = {Cadmium (Cd) is a developmental toxicant that induces fetal growth restriction (FGR). Placental endoplasmic reticulum (ER) stress is associated with FGR. This study investigated the effects of N-acetylcysteine (NAC) on Cd-induced placental ER stress and FGR. Pregnant mice were intraperitoneally injected with CdCl2 daily from gestational day (GD)13 to GD17. As expected, Cd reduced fetal weight and crown-rump length. Cd decreased the internal space of blood vessels in the placental labyrinth layer and inhibited placental cell proliferation. Several genes of growth factors, such as Vegf-a, placental growth factor, Igf1 and Igf1r, and several genes of nutrient transport pumps, such as Glut1, Fatp1 and Snat2, were down-regulated in placenta of Cd-treated mice. Moreover, Cd evoked placental ER stress. Of interest, NAC alleviated Cd-induced FGR. Additional experiment showed that NAC inhibited Cd-induced impairment of placental development and placental ER stress. Therefore, NAC may be exploited for prevention of Cd-induced placental insufficiency and FGR.}, }
@article {pmid29371534, year = {2017}, author = {Fernández-Rivero, ME and Del Pozo, JL and Valentín, A and de Diego, AM and Pemán, J and Cantón, E}, title = {Activity of Amphotericin B and Anidulafungin Combined with Rifampicin, Clarithromycin, Ethylenediaminetetraacetic Acid, N-Acetylcysteine, and Farnesol against Candida tropicalis Biofilms.}, journal = {Journal of fungi (Basel, Switzerland)}, volume = {3}, number = {1}, pages = {}, pmid = {29371534}, issn = {2309-608X}, abstract = {We evaluated the activity of (1) amphotericin-B (AMB), combined with rifampicin (RIF), clarithromycin (CLA), N-acetylcysteine (NAC), ethylenediaminetetraacetic acid (EDTA), and farnesol (FAR) (1000, 1000, 1000, 4000, and 30,000 mg/L, and 300 µM, respectively), against Candida tropicalis biofilms formed on polytetrafluoroethylene (PTFE) and (2) anidulafungin (ANF) combined with the same compounds at 8, 10, 5, 40, and 30 mg/L, and 30 µM, respectively, against biofilms formed on titanium. Biofilm growth kinetics were performed in a CDC Biofilm Reactor (CBR). PTFE or titanium disks were removed from the CBR at 24, 48, 72, and 96 h to determine the Log10CFU/cm[2]. Killing kinetics were performed by adding the drugs to 24-h-mature biofilms (time 0). Disks were removed after 24, 48, and 72 h of drug exposure to determine Log10CFU/cm[2]. Viable cells in biofilms were 4.73 and 4.29 Log10CFU/cm[2] on PTFE and titanium, respectively. Maximum Log10 decreases in CFU/cm[2] depend on the combination and were: 3.53 (AMB + EDTA), 2.65 (AMB + RIF), 3.07 (AMB + NAC), 2.52 (AMB + CLA), 1.49 (AMB + FAR), 2.26 (ANF + EDTA), 2.45 (ANF + RIF), 2.47 (ANF + NAC), 1.52 (ANF + CLA), and 0.44 (ANF + FAR). In conclusion, EDTA, NAC, RIF, and CLA improve the activity of AMB and ANF against biofilms developed on both surfaces, which could be an effective strategy against C. tropicalis biofilm-related infections.}, }
@article {pmid29367760, year = {2018}, author = {Tan, EHP and Sng, MK and How, ISB and Chan, JSK and Chen, J and Tan, CK and Wahli, W and Tan, NS}, title = {ROS release by PPARβ/δ-null fibroblasts reduces tumor load through epithelial antioxidant response.}, journal = {Oncogene}, volume = {37}, number = {15}, pages = {2067-2078}, pmid = {29367760}, issn = {1476-5594}, mesh = {Animals ; Antioxidants/*metabolism ; Cells, Cultured ; Epithelial Cells/drug effects/metabolism ; Fibroblasts/*metabolism ; Gene Knockdown Techniques ; HCT116 Cells ; HT29 Cells ; Humans ; Mice ; Mice, Knockout ; PPAR delta/*genetics ; PPAR-beta/*genetics ; Reactive Oxygen Species/*metabolism/*pharmacology ; Tumor Burden/*drug effects/genetics ; }, abstract = {Tumor stroma has an active role in the initiation, growth, and propagation of many tumor types by secreting growth factors and modulating redox status of the microenvironment. Although PPARβ/δ in fibroblasts was shown to modulate oxidative stress in the wound microenvironment, there has been no evidence of a similar effect in the tumor stroma. Here, we present evidence of oxidative stress modulation by intestinal stromal PPARβ/δ, using a FSPCre-Pparb/d[-/-] mouse model and validated it with immortalized cell lines. The FSPCre-Pparb/d[-/-] mice developed fewer intestinal polyps and survived longer when compared with Pparb/d[fl/fl] mice. The pre-treatment of FSPCre-Pparb/d[-/-] and Pparb/d[fl/fl] with antioxidant N-acetyl-cysteine prior DSS-induced tumorigenesis resulted in lower tumor load. Gene expression analyses implicated an altered oxidative stress processes. Indeed, the FSPCre-Pparb/d[-/-] intestinal tumors have reduced oxidative stress than Pparb/d[fl/fl] tumors. Similarly, the colorectal cancer cells and human colon epithelial cells also experienced lower oxidative stress when co-cultured with fibroblasts depleted of PPARβ/δ expression. Therefore, our results establish a role for fibroblast PPARβ/δ in epithelial-mesenchymal communication for ROS homeostasis.}, }
@article {pmid29364969, year = {2018}, author = {Rahali, S and Li, Y and Anand-Srivastava, MB}, title = {Contribution of oxidative stress and growth factor receptor transactivation in natriuretic peptide receptor C-mediated attenuation of hyperproliferation of vascular smooth muscle cells from SHR.}, journal = {PloS one}, volume = {13}, number = {1}, pages = {e0191743}, pmid = {29364969}, issn = {1932-6203}, mesh = {Animals ; Cells, Cultured ; Male ; Muscle, Smooth, Vascular/*pathology ; *Oxidative Stress ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Receptors, Atrial Natriuretic Factor/*physiology ; Receptors, Growth Factor/*genetics ; }, abstract = {Earlier studies have shown the implication of growth factor receptor activation in angiotensin II (Ang II)-induced hyperproliferation of aortic VSMC as well as in hyperproliferation of VSMC from spontaneously hypertensive rats (SHR). We previously showed that NPR-C specific agonist C-ANP4-23 attenuates the hyperproliferation of VSMC from SHR through the inhibition of MAP kinase, Giα protein signaling and overexpression of cell cycle proteins. The aim of the present study was to investigate if C-ANP4-23- mediated attenuation of hyperproliferation of VSMC from SHR also involves growth factor receptor activation and upstream signaling molecules. For this study, C-ANP 4-23 (10 nmole/kg body weight) was injected intraperitoneally into 2 week-old prehypertensive SHR and Wistar Kyoto (WKY) rats twice per week for 6 weeks. The blood pressure in SHR was significantly attenuated by C-ANP4-23 treatment. In addition, C-ANP4-23 treatment also attenuated the hyperproliferation of VSMC from SHR as well as the enhanced phosphorylation of EGF-R, PDGF-R, IGF-R and c-Src. Furthermore, the enhanced levels of superoxide anion, NADPH oxidase activity, and enhanced expression of Nox4,Nox1,Nox2 and P47phox in SHR compared to WKY rats was also significantly attenuated by C-ANP4-23 treatment. In addition, N-acetyl cysteine (NAC), a scavenger of O2-, inhibitors of growth factor receptors and of c-Src, all inhibited the overexpression of cell cycle proteins cyclin D1 and cdk4 in VSMC from SHR. These results suggest that in vivo treatment of SHR with C-ANP4-23 inhibits the enhanced oxidative stress, c-Src and EGF-R, PDGF-R, IGF-R activation which through the inhibition of overexpression of cell cycle proteins result in the attenuation of hyperproliferation of VSMC.}, }
@article {pmid29364751, year = {2018}, author = {Panahi, G and Pasalar, P and Zare, M and Rizzuto, R and Meshkani, R}, title = {High glucose induces inflammatory responses in HepG2 cells via the oxidative stress-mediated activation of NF-κB, and MAPK pathways in HepG2 cells.}, journal = {Archives of physiology and biochemistry}, volume = {124}, number = {5}, pages = {468-474}, doi = {10.1080/13813455.2018.1427764}, pmid = {29364751}, issn = {1744-4160}, mesh = {Acetylcysteine/pharmacology ; Free Radical Scavengers/pharmacology ; *Gene Expression Regulation/drug effects ; Glucose/adverse effects ; Hep G2 Cells ; Hepatocytes/drug effects/immunology/*metabolism/pathology ; Humans ; Hyperglycemia/immunology/*metabolism/pathology ; Interleukin-6/agonists/antagonists &amp; inhibitors/genetics/metabolism ; *MAP Kinase Signaling System/drug effects ; NF-kappa B/*agonists/metabolism ; Osmolar Concentration ; *Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Plasminogen Activator Inhibitor 1/agonists/chemistry/genetics/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Processing, Post-Translational/drug effects ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/metabolism ; Reproducibility of Results ; Tumor Necrosis Factor-alpha/*agonists/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {OBJECTIVE: The aim of this study was to investigate the effects of high glucose (HG) on inflammation in HepG2 cells.<br><br>METHODS: The molecular mechanisms linking HG to inflammation was assessed in HepG2 cells exposed to HG (33&#x2009;mM).<br><br>RESULTS: The results showed that HG significantly enhanced TNF-&#x3b1;, IL-6 and PAI-1 expression in HepG2 cells. Increased expression of cytokines was accompanied by enhanced phosphorylation of JNK, P38, ERK and IKK&#x3b1;/IKK&#x3b2;. In addition, JNK, ERK, P38 and NF-kB inhibitors could significantly attenuate HG-induced expression of TNF-&#x3b1;, IL-6 and PAI-1. Furthermore, HG could promote the generation of reactive oxygen species (ROS), while N-acetyl cysteine, a ROS scavenger, had an inhibitory effect on the expression of TNF-&#x3b1;, IL-6 and PAI-1 in HG-treated cells.<br><br>CONCLUSIONS: Our results indicated that HG-induced inflammation is mediated through the generation of ROS and activation of the MAPKs and NF-kB signalling pathways in HepG2 cells.}, }
@article {pmid29362765, year = {2018}, author = {Jiang, G and Zhang, L and Wang, H and Chen, Q and Wu, X and Yan, X and Chen, Y and Xie, M}, title = {Protective effects of a Ganoderma atrum polysaccharide against acrylamide induced oxidative damage via a mitochondria mediated intrinsic apoptotic pathway in IEC-6 cells.}, journal = {Food &amp; function}, volume = {9}, number = {2}, pages = {1133-1143}, doi = {10.1039/c7fo01619k}, pmid = {29362765}, issn = {2042-650X}, mesh = {Acrylamide/*toxicity ; Animals ; Apoptosis/*drug effects ; Cell Line ; Cytochromes c/metabolism ; Ganoderma/*chemistry ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; Mitochondria/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Plant Extracts/*pharmacology ; Polysaccharides/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxide Dismutase/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {The preventive role of a purified Ganoderma atrum polysaccharide PSG-1-F2 as a new dietary antioxidant against the intestinal toxicity of acrylamide (ACR) was investigated in vitro. Our results showed that ACR could induce oxidative stress in IEC-6 cells by the overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA), and as well as the reduction in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). In addition, the induction of a mitochondria-mediated intrinsic apoptotic pathway by ACR was evidenced by the events of loss of mitochondrial membrane potential, bax/bcl-2 dysregulation, cytochrome c release, and activation of caspase-3. Interestingly, PSG-1-F2 was able to suppress ACR toxicity by improving the redox status of IEC-6 cells and by attenuating mitochondria-mediated apoptosis. Its protective effect was even superior to the clinically used antioxidant N-acetylcysteine (NAC). This study uniquely introduces PSG-1-F2 as a potential inhibitor of ACR-induced stress and toxicities.}, }
@article {pmid29359643, year = {2018}, author = {Vural, G and Bektas, H and Gumusyayla, S and Deniz, O and Alışık, M and Erel, O}, title = {Impaired thiol-disulphide homeostasis in patients with axonal polyneuropathy.}, journal = {Neurological research}, volume = {40}, number = {3}, pages = {166-172}, doi = {10.1080/01616412.2018.1428522}, pmid = {29359643}, issn = {1743-1328}, mesh = {Aged ; Disulfides/*metabolism ; Female ; Homeostasis/*physiology ; Humans ; Male ; Middle Aged ; Neural Conduction/physiology ; Polyneuropathies/*metabolism/*physiopathology ; Prospective Studies ; Statistics, Nonparametric ; Sulfhydryl Compounds/*metabolism ; }, abstract = {OBJECTIVE: The objective of this study is to examine thiol-disulphide homeostasis in patients with polyneuropathy dominated by diabetic or non-diabetic axonal degeneration.<br><br>MATERIALS-METHODS: Fifty-four patients diagnosed with polyneuropathy dominated by axonal damage and 41 healthy subjects were included in the study. The patients were grouped into two groups according to whether or not they had diabetes. The native thiol and total thiol concentrations were measured with the newly developed automated method.<br><br>RESULTS: While there was no significant difference between the patients with diabetic and non-diabetic polyneuropathy in terms of native thiol and total thiol levels (p&#xa0;>&#xa0;0.05), the native thiol and total thiol levels of the groups with both diabetic polyneuropathy and non-diabetic polyneuropathy were significantly low compared to the control group (p&#xa0;<&#xa0;0.01). The level of disulphides in the patients with diabetic polyneuropathy was significantly higher than that of the patients with non-diabetic polyneuropathy and the healthy individuals (p&#xa0;<&#xa0;0.05). The loss in the sural nerve sensory neural action potential amplitude was positively correlated with the decrease in the levels of both native thiol and total thiol (p&#xa0;<&#xa0;0.05).<br><br>DISCUSSION: In our study, we observed that the thiol-disulphide balance was also impaired in patients with non-diabetic polyneuropathy similar to patients with diabetic polyneuropathy, and we therefore considered that impaired the thiol-disulphide homeostasis could be the last common path in patients with polyneuropathy with axonal damage, regardless of the aetiology. Therefore, fortification of thiol deficiency with N-acetyl cysteine or alpha-lipoic acid can fix the thiol-disulphide balance and help decelerate the axonal damage.}, }
@article {pmid29357409, year = {2018}, author = {Small, DM and Sanchez, WY and Roy, SF and Morais, C and Brooks, HL and Coombes, JS and Johnson, DW and Gobe, GC}, title = {N-acetyl-cysteine increases cellular dysfunction in progressive chronic kidney damage after acute kidney injury by dampening endogenous antioxidant responses.}, journal = {American journal of physiology. Renal physiology}, volume = {314}, number = {5}, pages = {F956-F968}, pmid = {29357409}, issn = {1522-1466}, support = {R01 HL131834/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*toxicity ; Acute Kidney Injury/*complications/metabolism/pathology/physiopathology ; Animals ; Antioxidants/*toxicity ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Disease Models, Animal ; Disease Progression ; Energy Metabolism/drug effects ; Kidney/*drug effects/metabolism/pathology/physiopathology ; Male ; Mice, Inbred C57BL ; Microscopy, Fluorescence, Multiphoton ; Mitochondria/drug effects/metabolism/pathology ; NAD/metabolism ; Oxidative Stress/*drug effects ; PPAR gamma/metabolism ; Phosphorylation ; Renal Insufficiency, Chronic/*chemically induced/metabolism/pathology/physiopathology ; Signal Transduction/drug effects ; Time Factors ; Transforming Growth Factor beta1/metabolism ; }, abstract = {Oxidative stress and mitochondrial dysfunction exacerbate acute kidney injury (AKI), but their role in any associated progress to chronic kidney disease (CKD) remains unclear. Antioxidant therapies often benefit AKI, but their benefits in CKD are controversial since clinical and preclinical investigations often conflict. Here we examined the influence of the antioxidant N-acetyl-cysteine (NAC) on oxidative stress and mitochondrial function during AKI (20-min bilateral renal ischemia plus reperfusion/IR) and progression to chronic kidney pathologies in mice. NAC (5% in diet) was given to mice 7 days prior and up to 21 days post-IR (21d-IR). NAC treatment resulted in the following: prevented proximal tubular epithelial cell apoptosis at early IR (40-min postischemia), yet enhanced interstitial cell proliferation at 21d-IR; increased transforming growth factor-β1 expression independent of IR time; and significantly dampened nuclear factor-like 2-initiated cytoprotective signaling at early IR. In the long term, NAC enhanced cellular metabolic impairment demonstrated by increased peroxisome proliferator activator-γ serine-112 phosphorylation at 21d-IR. Intravital multiphoton microscopy revealed increased endogenous fluorescence of nicotinamide adenine dinucleotide (NADH) in cortical tubular epithelial cells during ischemia, and at 21d-IR that was not attenuated with NAC. Fluorescence lifetime imaging microscopy demonstrated persistent metabolic impairment by increased free/bound NADH in the cortex at 21d-IR that was enhanced by NAC. Increased mitochondrial dysfunction in remnant tubular cells was demonstrated at 21d-IR by tetramethylrhodamine methyl ester fluorimetry. In summary, NAC enhanced progression to CKD following AKI not only by dampening endogenous cellular antioxidant responses at time of injury but also by enhancing persistent kidney mitochondrial and metabolic dysfunction.}, }
@article {pmid29348106, year = {2018}, author = {Mukhtiar, M and Jan, SU and Khan, MF and Ullah, N and Hussain, A and Rehman, S and Qureshi, MM}, title = {Report: Palladium glutathione, N-acetylcysteine, D-penicillamine conjugation chemistry.}, journal = {Pakistan journal of pharmaceutical sciences}, volume = {31}, number = {1}, pages = {213-219}, pmid = {29348106}, issn = {1011-601X}, mesh = {Acetylcysteine/*chemistry ; Glutathione/*chemistry ; Oxidation-Reduction ; Palladium/*chemistry/toxicity ; Penicillamine/*chemistry ; Solutions ; Vanadium/*chemistry/toxicity ; }, abstract = {The metalloelement Palladium has a number of potential Pharmaco-clinical advantages. Palladium compounds have antiviral, antibacterial, neuroprotective and antitumor properties. However studies have also indicated some mild to serious toxic effects of Palladium metalloelements. Biothiols are important antioxidants that provide protection against metals toxicity. The interaction of metalloelements with biothiols can provide valuable information about the level of toxicity of the metalloelements and about the protective role of biothiols thereof. In this piece of work the effect of salt and complexes of Palladium on the status of different thiols (GSH, NAC, and D-Pen) in aqueous medium, were examined, The thiol quantification was carried out using Elman's method through UV-visible spectrophotometry and [1]H- NMR. Results of the study performed in aqueous medium showed that level of different thiols depleted after the addition of the inorganic salts and organic complexes of Palladium. The mechanism of interaction of Palladium with thiols was examined using H-NMR. The results indicate that the depletion in the level of thiols may be due to 1:1 or 1:2 conjugation of Palladium with thiols. These conjugation reactions further suggest that the Palladium have xenobiotic nature causing oxidative stress and thiols play their role in detoxification and biotransformation of these metalloelements.}, }
@article {pmid29341047, year = {2018}, author = {Behr, J and Günther, A and Bonella, F and Geißler, K and Koschel, D and Kreuter, M and Prasse, A and Schönfeld, N and Sitter, H and Müller-Quernheim, J and Costabel, U}, title = {German Guideline for Idiopathic Pulmonary Fibrosis - Update on Pharmacological Therapies 2017.}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {72}, number = {2}, pages = {155-168}, doi = {10.1055/s-0043-123035}, pmid = {29341047}, issn = {1438-8790}, mesh = {Acetylcysteine/adverse effects/therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Antacids/adverse effects/therapeutic use ; Bosentan/adverse effects/therapeutic use ; Clinical Trials as Topic ; Evidence-Based Medicine ; Female ; Gastroesophageal Reflux/drug therapy ; *Guideline Adherence ; Humans ; Idiopathic Pulmonary Fibrosis/diagnosis/*drug therapy ; Imatinib Mesylate/adverse effects/therapeutic use ; Indoles/adverse effects/therapeutic use ; Male ; Middle Aged ; Phenylpropionates/therapeutic use ; Pyridazines/therapeutic use ; Pyridones/adverse effects/therapeutic use ; Pyrimidines/adverse effects/therapeutic use ; Sildenafil Citrate/adverse effects/therapeutic use ; Sulfonamides/adverse effects/therapeutic use ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease with a median survival of 2 - 4 years after diagnosis. Since the publication of the German IPF guideline in 2013 new treatment trials have been published, necessitating an update of the pharmacological therapy of IPF. Different from the previous guideline, the GRADE system was discarded and replaced by the Oxford evidence classification system which allows a more differentiated judgement. The following pharmacological therapies were rated not suitable for the treatment of IPF patients (recommendation A; evidence 1-b): triple therapy with prednisolone, azathioprine and acetyl-cysteine; imatinib; ambrisentan; bosentan; macitentan. A less clear but still negative recommendation (B, 1-b) was attributed to the treatment of IPF with the phosphodiesterase-5-inhibitor sildenafil and acetyl-cysteine monotherapy. In contrast to the international guideline antacid therapy as a general treatment for IPF was rated negative, based on conflicting results of recent analyses (recommendation C; evidence 4). An unanimous positive recommendation was granted for the antifibrotic drugs nintedanib and pirfenidone for the treatment of IPF (A, 1-a). For some open questions in the management of IPF patients for which firm evidence is lacking the guideline also offers recommendations based on expert consensus.}, }
@article {pmid29333010, year = {2017}, author = {Totadri, S and Trehan, A and Bansal, D and Jain, R}, title = {Sinusoidal Obstruction Syndrome during Treatment for Wilms' Tumor: A Life-threatening Complication.}, journal = {Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical &amp; Paediatric Oncology}, volume = {38}, number = {4}, pages = {447-451}, pmid = {29333010}, issn = {0971-5851}, abstract = {CONTEXT: Survival rates exceed 90% in Wilms' tumor (WT). Actinomycin-D (ACT-D) which is indispensable in the management of WT is associated with the development of sinusoidal obstruction syndrome (SOS), a potentially fatal complication.<br><br>AIMS: The aim is to study the presentation, management, and outcome of SOS complicating ACT-D administration in WT.<br><br>SETTINGS AND DESIGN: Retrospective file review conducted in a Pediatric Hematology-Oncology unit.<br><br>MATERIALS AND METHODS: Patients diagnosed and treated for WT from January 2012 to December 2015 were analyzed. SOS was diagnosed clinically, based on McDonalds criteria, requiring two of the following: jaundice, hepatomegaly and/or right upper quadrant pain, weight gain with or without ascites.<br><br>RESULTS: Of 104 patients treated, SOS occurred in 5 (4.8%). Age: 6 months to 5 years, 3 were girls. Tumor involved left kidney in 3, right in 1 and a horseshoe kidney in 1. Histopathology was consistent with WT in 4 and clear cell sarcoma kidney in 1. One had pulmonary metastases. Three developed SOS preoperatively and two during adjuvant chemotherapy. None received radiotherapy. Clinical manifestations comprised of jaundice, hepatomegaly, ascites/weight gain, respiratory distress, hypotension, and encephalopathy. Laboratory findings included thrombocytopenia, elevated serum transaminases, and coagulopathy. Treatment included fluid restriction, broad spectrum antibiotics, and transfusional support. Two children received N-acetyl cysteine infusion. Defibrotide was administered to two patients. Four recovered and one succumbed to multi-organ failure. Two patients were safely re-challenged with 50% doses of ACT-D.<br><br>CONCLUSIONS: SOS is a clinical diagnosis. Systematic supportive care can enable complete recovery. Under close monitoring, re-challenge of ACT-D can be performed in gradually escalating doses.}, }
@article {pmid29331654, year = {2018}, author = {Xu, Y and Mao, X and Qin, B and Peng, Y and Zheng, J}, title = {In vitro and in vivo metabolic activation of rhein and characterization of glutathione conjugates derived from rhein.}, journal = {Chemico-biological interactions}, volume = {283}, number = {}, pages = {1-9}, doi = {10.1016/j.cbi.2018.01.001}, pmid = {29331654}, issn = {1872-7786}, mesh = {Acetylcysteine/chemistry ; Animals ; Anthraquinones/chemistry/*metabolism/pharmacology/urine ; Bile/chemistry/drug effects/metabolism ; Chromatography, High Pressure Liquid ; Cytochrome P-450 Enzyme System/genetics/metabolism ; Glutathione/*chemistry ; Humans ; Male ; Microsomes, Liver/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/biosynthesis/genetics ; Tandem Mass Spectrometry ; }, abstract = {Rhein (RH), 4,5-dihydroxyanthrauinone-2-carboxylic acid, is found in rhubarb (Dahuang), a traditional herbal medicine. RH has reportedly demonstrated multiple pharmacologic properties. Previous studies have also shown that RH induced hepatotoxicity, but the mechanisms of the adverse effect remain unknown. The major objective of the present study was to study the metabolic pathways of RH in order to identify potential reactive metabolites. One mono-hydroxylation metabolite (M1) was detected in urine and bile of rats given RH. M1 was also observed in rat and human liver microsomal incubations after exposure to RH. A total of three (GSH) conjugates (M2, M3 and M5) were detected in bile of rats treated with RH. We concluded that M2-M3 were directly derived from parent compound RH through spontaneous reaction with GSH. M5 was derived from M1 by reaction with GSH, which required cytoslic GSTs. M5 was further metabolized to the corresponding NAC conjugate (mercapturic acid) and was excreted in urine. P450 2C9 was mainly involved in the oxidation of RH.}, }
@article {pmid29329583, year = {2018}, author = {Nance, E and Kambhampati, SP and Smith, ES and Zhang, Z and Zhang, F and Singh, S and Johnston, MV and Kannan, RM and Blue, ME and Kannan, S}, title = {Correction to: Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome.}, journal = {Journal of neuroinflammation}, volume = {15}, number = {1}, pages = {14}, pmid = {29329583}, issn = {1742-2094}, support = {U54 HD083091/HD/NICHD NIH HHS/United States ; }, abstract = {After publication of the article [1], it has been brought to our attention that an author's name has been formatted incorrectly.}, }
@article {pmid29329563, year = {2018}, author = {Liu, CW and Lee, TL and Chen, YC and Liang, CJ and Wang, SH and Lue, JH and Tsai, JS and Lee, SW and Chen, SH and Yang, YF and Chuang, TY and Chen, YL}, title = {PM2.5-induced oxidative stress increases intercellular adhesion molecule-1 expression in lung epithelial cells through the IL-6/AKT/STAT3/NF-κB-dependent pathway.}, journal = {Particle and fibre toxicology}, volume = {15}, number = {1}, pages = {4}, pmid = {29329563}, issn = {1743-8977}, mesh = {A549 Cells ; Air Pollutants/chemistry/*toxicity ; Animals ; Cell Survival/drug effects ; Humans ; Inhalation Exposure ; Intercellular Adhesion Molecule-1/blood/*genetics ; Interleukin-6/blood/metabolism ; Lung/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B/metabolism ; Oxidative Stress/*drug effects/genetics ; Particulate Matter/chemistry/*toxicity ; Proto-Oncogene Proteins c-akt/metabolism ; Pulmonary Disease, Chronic Obstructive/*blood ; STAT3 Transcription Factor/metabolism ; *Signal Transduction ; Solubility ; }, abstract = {BACKGROUND: Epidemiological studies have shown that ambient air pollution is closely associated with increased respiratory inflammation and decreased lung function. Particulate matters (PMs) are major components of air pollution that damages lung cells. However, the mechanisms remain to be elucidated. This study examines the effects of PMs on intercellular adhesion molecule-1 (ICAM-1) expression and the related mechanisms in vitro and in vivo.<br><br>RESULT: The cytotoxicity, reactive oxygen species (ROS) generation, and monocyte adherence to A549 cells were more severely affected by treatment with O-PMs (organic solvent-extractable fraction of SRM1649b) than with W-PMs (water-soluble fraction of SRM1649b). We observed a significant increase in ICAM-1 expression by O-PMs, but not W-PMs. O-PMs also induced the phosphorylation of AKT, p65, and STAT3. Pretreating A549 cells with N-acetyl cysteine (NAC), an antioxidant, attenuated O-PMs-induced ROS generation, the phosphorylation of the mentioned kinases, and the expression of ICAM-1. Furthermore, an AKT inhibitor (LY294002), NF-&#x3ba;B inhibitor (BAY11-7082), and STAT3 inhibitor (Stattic) significantly down-regulated O-PMs-induced ICAM-1 expression as well as the adhesion of U937 cells to epithelial cells. Interleukin-6 (IL-6) was the most significantly changed cytokine in O-PMs-treated A549 cells according to the analysis of the cytokine antibody array. The IL-6 receptor inhibitor tocilizumab (TCZ) and small interfering RNA for IL-6 significantly reduced ICAM-1 secretion and expression as well as the reduction of the AKT, p65, and STAT3 phosphorylation in O-PMs-treated A549 cells. In addition, the intratracheal instillation of PMs significantly increased the levels of the ICAM-1 and IL-6 in lung tissues and plasma in WT mice, but not in IL-6 knockout mice. Pre-administration of NAC attenuated those PMs-induced adverse effects in WT mice. Furthermore, patients with chronic obstructive pulmonary disease (COPD) had higher plasma levels of ICAM-1 and IL-6 compared to healthy subjects.<br><br>CONCLUSION: These results suggest that PMs increase ICAM-1 expression in pulmonary epithelial cells in vitro and in vivo through the IL-6/AKT/STAT3/NF-&#x3ba;B signaling pathway.}, }
@article {pmid29327458, year = {2018}, author = {Siddarth, M and Chawla, D and Raizada, A and Wadhwa, N and Banerjee, BD and Sikka, M}, title = {Lead-induced DNA damage and cell apoptosis in human renal proximal tubular epithelial cell: Attenuation via N-acetyl cysteine and tannic acid.}, journal = {Journal of biochemical and molecular toxicology}, volume = {32}, number = {3}, pages = {e22038}, doi = {10.1002/jbt.22038}, pmid = {29327458}, issn = {1099-0461}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; *DNA Damage ; Epithelial Cells/*metabolism/pathology ; Humans ; Kidney Tubules, Proximal/*metabolism/pathology ; Lead/*toxicity ; Tannins/*pharmacology ; }, abstract = {This study investigates the exposure of lead-induced reactive oxygen species (ROS) generation, DNA damage, and apoptosis and also evaluates the therapeutic intervention using antioxidants in human renal proximal tubular cells (HK-2 cells). Following treatment of HK-2 cells with an increasing concentration of lead nitrate (0-50 μM) for 24 h, the intracellular ROS level increased whereas the GSH level decreased significantly in a dose-dependent manner. Comet assay results revealed that lead nitrate showed the ability to increase the levels of DNA strand breaks in HK-2 cells. Lead exposure also induced apoptosis through caspase-3 activation at 30 μg/mL. Pretreatment with N-acetylcysteine (NAC) and tannic acid showed a significant ameliorating effect on lead-induced ROS, DNA damage, and apoptosis. In conclusion, lead induces ROS, which may exacerbate the DNA damage and apoptosis via caspase-3 activation. Additionally, supplementation of antioxidants such as NAC and tannic acid may be used as salvage therapy for lead-induced DNA damage and apoptosis in an exposed person.}, }
@article {pmid29327381, year = {2018}, author = {Wang, JP and Chi, RF and Wang, K and Ma, T and Guo, XF and Zhang, XL and Li, B and Qin, FZ and Han, XB and Fan, BA}, title = {Oxidative stress impairs myocyte autophagy, resulting in myocyte hypertrophy.}, journal = {Experimental physiology}, volume = {103}, number = {4}, pages = {461-472}, doi = {10.1113/EP086650}, pmid = {29327381}, issn = {1469-445X}, mesh = {Animals ; Antioxidants/metabolism ; Autophagy/*physiology ; Autophagy-Related Protein 5/metabolism ; Beclin-1/metabolism ; Cell Line ; Hypertrophy, Left Ventricular/metabolism/*pathology ; Male ; Microtubule-Associated Proteins/metabolism ; Muscle Cells/metabolism/*pathology ; Myocytes, Cardiac/metabolism/pathology ; Oxidative Stress/*physiology ; Phosphorylation/physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {NEW FINDINGS: What is the central question of this study? Does oxidative stress induce impairment of autophagy that results in myocyte hypertrophy early after pressure overload? What is the main finding and its importance? In cultured myocytes, hydrogen peroxide decreased autophagy and increased hypertrophy, and inhibition of autophagy enhanced myocyte hypertrophy. In rats with early myocardial hypertrophy after pressure overload, myocyte autophagy was progressively decreased. The antioxidant N-acetyl-cysteine or the superoxide dismutase mimic tempol prevented the decrease of myocyte autophagy and attenuated myocyte hypertrophy early after pressure overload. These findings suggest that oxidative stress impairs myocyte autophagy that results in myocyte hypertrophy.<br><br>ABSTRACT: Insufficient or excessive myocyte autophagy is associated with left ventricular (LV) hypertrophy. Reactive oxygen species mediate myocyte hypertrophy in vitro and pressure overload-induced LV hypertrophy in vivo. In the present study, we tested the hypothesis that oxidative stress induces an impairment of autophagy that results in myocyte hypertrophy. H9C2 cardiomyocytes pretreated with the autophagy inhibitor 3-methyladenine were exposed to 10 and 50&#xa0;&#x3bc;m hydrogen peroxide (H2 O2) for 48&#xa0;h. Male Sprague-Dawley rats underwent abdominal aortic constriction (AAC) or sham operation. The animals were killed 24, 48 or 72&#xa0;h after surgery. In a separate group, the AAC and sham-operated rats randomly received the antioxidant N-acetyl-cysteine or the superoxide dismutase mimic tempol for 72&#xa0;h. In H9C2 cardiomyocytes, H2 O2 decreased the ratio of microtubule-associated protein light chain 3 (LC3) II to LC3 I and increased P62 and phosphorylated ERK (p-ERK) proteins and myocyte surface area. 3-Methyladenine further increased H2 O2 -induced p-ERK expression. In rats after AAC, the heart to body weight ratio was progressively increased, the LC3 II/I ratio was progressively decreased, p62 and p-ERK expression was increased, and expression of Beclin1, Atg5 and Atg12 was decreased. N-Acetyl-cysteine or tempol prevented the decreases in the LC3 II/I ratio and Beclin1 and Atg5 expression and attenuated the increases in LV wall thickness, myocyte diameter and brain natriuretic peptide expression in AAC rats. In conclusion, oxidative stress decreases Beclin1 and Atg5 expression that results in impairment of autophagy, leading to myocyte hypertrophy. These findings suggest that antioxidants or restoration of autophagy might be of value in the prevention of early myocardial hypertrophy after pressure overload.}, }
@article {pmid29326556, year = {2017}, author = {Bi, C and Tham, DKL and Perronnet, C and Joshi, B and Nabi, IR and Moukhles, H}, title = {The Oxidative Stress-Induced Increase in the Membrane Expression of the Water-Permeable Channel Aquaporin-4 in Astrocytes Is Regulated by Caveolin-1 Phosphorylation.}, journal = {Frontiers in cellular neuroscience}, volume = {11}, number = {}, pages = {412}, pmid = {29326556}, issn = {1662-5102}, abstract = {The reperfusion of ischemic brain tissue following a cerebral stroke causes oxidative stress, and leads to the generation of reactive oxygen species (ROS). Apart from inflicting oxidative damage, the latter may also trigger the upregulation of aquaporin 4 (AQP4), a water-permeable channel expressed by astroglial cells of the blood-brain barrier (BBB), and contribute to edema formation, the severity of which is known to be the primary determinant of mortality and morbidity. The mechanism through which this occurs remains unknown. In the present study, we have attempted to address this question using primary astrocyte cultures treated with hydrogen peroxide (H2O2) as a model system. First, we showed that H2O2 induces a significant increase in AQP4 protein levels and that this is inhibited by the antioxidant N-acetylcysteine (NAC). Second, we demonstrated using cell surface biotinylation that H2O2 increases AQP4 cell-surface expression independently of it's increased synthesis. In parallel, we found that caveolin-1 (Cav1) is phosphorylated in response to H2O2 and that this is reversed by the Src kinase inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). PP2 also abrogated the H2O2-induced increase in AQP4 surface levels, suggesting that the phosphorylation of tyrosine-14 of Cav1 regulates this process. We further showed that dominant-negative Y14F and phosphomimetic Y14D mutants caused a decrease and increase in AQP4 membrane expression respectively, and that the knockdown of Cav1 inhibits the increase in AQP4 cell-surface, expression following H2O2 treatment. Together, these findings suggest that oxidative stress-induced Cav1 phosphorylation modulates AQP4 subcellular distribution and therefore may indirectly regulate AQP4-mediated water transport.}, }
@article {pmid29322434, year = {2018}, author = {Nozari, Y and Eshraghi, A and Talasaz, AH and Bahremand, M and Salamzadeh, J and Salarifar, M and Pourhosseini, H and Jalali, A and Mortazavi, SH}, title = {Protection from Reperfusion Injury with Intracoronary N-Acetylcysteine in Patients with STEMI Undergoing Primary Percutaneous Coronary Intervention in a Cardiac Tertiary Center.}, journal = {American journal of cardiovascular drugs : drugs, devices, and other interventions}, volume = {18}, number = {3}, pages = {213-221}, doi = {10.1007/s40256-017-0258-8}, pmid = {29322434}, issn = {1179-187X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Cardiotonic Agents/*administration &amp; dosage ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Infusions, Intravenous ; Injections, Intra-Arterial ; Iran/epidemiology ; Male ; Middle Aged ; Myocardial Reperfusion Injury/diagnostic imaging/*prevention &amp; control ; Percutaneous Coronary Intervention/*adverse effects/trends ; Prospective Studies ; ST Elevation Myocardial Infarction/diagnostic imaging/*therapy ; *Tertiary Care Centers/trends ; }, abstract = {BACKGROUND: Evidence suggests that oxidative stress plays a principal role in myocardial damage following ischemia/reperfusion events. Recent studies have shown that the antioxidant properties of N-acetylcysteine (NAC) may have cardioprotective effects in high doses, but-to the best of our knowledge-few studies have assessed this.<br><br>OBJECTIVES: Our objective was to investigate the impact of high-dose NAC on ischemia/reperfusion injury.<br><br>METHODS: We conducted a randomized double-blind placebo-controlled trial in which 100 consecutive patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) were randomly assigned to the case group (high-dose NAC 100&#xa0;mg/kg bolus followed by intracoronary NAC 480&#xa0;mg during PCI then intravenous NAC 10&#xa0;mg/kg for 12&#xa0;h) or the control group (5% dextrose). We measured differences in peak creatine kinase-myocardial band (CK-MB) concentration, highly sensitive troponin T (hs-TnT), thrombolysis in myocardial infarction (TIMI) flow, myocardial blush grade (MBG), and corrected thrombolysis in myocardial infarction frame count (cTFC).<br><br>RESULTS: The peak CK-MB level was comparable between the two groups (P&#xa0;=&#xa0;0.327), but patients receiving high-dose NAC demonstrated a significantly larger reduction in hs-TnT (P&#xa0;=&#xa0;0.02). In total, 94% of the NAC group achieved TIMI flow grade 3 versus 80% of the control group (P&#xa0;=&#xa0;0.03). No significant differences were observed between the two groups in terms of changes in the cTFC and MBG.<br><br>CONCLUSIONS: In this study, NAC improved myocardial reperfusion markers and coronary blood flow, as revealed by differences in peak hs-TnT and TIMI flow grade 3 levels, respectively. Further studies with large samples are warranted to elucidate the role of NAC in this population. ClinicalTrials.gov identifier: NCT01741207, and the Iranian Registry of Clinical Trials (IRCT; http://irct.ir) registration number: IRCT201301048698N8.}, }
@article {pmid29316860, year = {2018}, author = {Murakami, Y and Fujino, T and Hasegawa, T and Kurachi, R and Miura, A and Daikoh, T and Usui, T and Hayase, F and Watanabe, H}, title = {Receptor for advanced glycation end products (RAGE)-mediated cytotoxicity of 3-hydroxypyridinium derivatives.}, journal = {Bioscience, biotechnology, and biochemistry}, volume = {82}, number = {2}, pages = {312-319}, doi = {10.1080/09168451.2017.1422971}, pmid = {29316860}, issn = {1347-6947}, mesh = {Acetaldehyde/analogs &amp; derivatives/metabolism ; Animals ; Cytotoxins/*chemistry/*toxicity ; Glyceraldehyde/metabolism ; Humans ; Oxidative Stress/drug effects ; PC12 Cells ; Pyridines/*chemistry/*toxicity ; Rats ; Receptor for Advanced Glycation End Products/*metabolism ; }, abstract = {Advanced glycation end products (AGEs) formed from glyceraldehyde (Gcer) and glycolaldehyde (Gcol) are involved in the pathogenesis of diabetic complications, via interactions with a receptor for AGEs (RAGE). In this study, we aimed to elucidate the RAGE-binding structure in Gcer and Gcol-derived AGEs and identify the minimal moiety recognized by RAGE. Among Gcer and Gcol-derived AGEs, GLAP (glyceraldehyde-derived pyridinium) and GA-pyridine elicited toxicity in PC12 neuronal cells. The toxic effects of GLAP and GA-pyridine were suppressed in the presence of anti-RAGE antibody or the soluble form of RAGE protein. Furthermore, the cytotoxicity test using GLAP analog compounds indicated that the 3-hydroxypyridinium (3-HP) structure is sufficient for RAGE-dependent toxicity. Surface plasmon resonance analysis showed that 3-HP derivatives directly interact with RAGE. These results indicate that GLAP and GA-pyridine are RAGE-binding epitopes, and that 3-HP, a common moiety of GLAP and GA-pyridine, is essential for the interaction with RAGE.}, }
@article {pmid29315209, year = {2018}, author = {Kuo, LM and Chen, PJ and Sung, PJ and Chang, YC and Ho, CT and Wu, YH and Hwang, TL}, title = {The Bioactive Extract of Pinnigorgia sp. Induces Apoptosis of Hepatic Stellate Cells via ROS-ERK/JNK-Caspase-3 Signaling.}, journal = {Marine drugs}, volume = {16}, number = {1}, pages = {}, pmid = {29315209}, issn = {1660-3397}, mesh = {Animals ; Anthozoa/*metabolism ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line ; Cell Survival/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Hepatic Stellate Cells/*drug effects/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sterols/*pharmacology ; }, abstract = {The activation of hepatic stellate cells (HSCs) is a significant phenomenon during the pathogenesis of liver disorders, including liver cirrhosis and fibrosis. Here, we identified that the extract from a gorgonian coral Pinnigorgia sp. (Pin) induced apoptosis of HSC-T6 cells. Pin inhibited the viability of HSC-T6 cells and increased their subG1 population, DNA fragmentation, caspase-3 activation, and reactive oxygen species (ROS) production in a concentration-dependent manner. The Pin-induced ROS generation and apoptotic effects were significantly reversed by a thiol antioxidant, N-acetylcysteine (NAC). Additionally, Pin induced ERK/JNK phosphorylation and pharmacological inhibition of ERK/JNK rescued the Pin-induced cell death. Pin-activated ERK/JNK were significantly reduced after the administration of NAC; however, the inhibition of ERK/JNK failed to change the Pin-induced ROS production. Similarly, pinnigorgiol A, a pure compound isolated from Pin, elicited ROS production and apoptosis in HSC-T6 cells. The pinnigorgiol A-induced apoptosis was retrained by NAC. Together, it appears that Pin leads to apoptosis in HSC-T6 cells through ROS-mediated ERK/JNK signaling and caspase-3 activation. Pinnigorgiol A serves as a bioactive compound of Pin and may exhibit therapeutic potential by clearance of HSCs.}, }
@article {pmid29313384, year = {2018}, author = {Wang, H and Yu, X and Su, C and Shi, Y and Zhao, L}, title = {Chitosan nanoparticles triggered the induction of ROS-mediated cytoprotective autophagy in cancer cells.}, journal = {Artificial cells, nanomedicine, and biotechnology}, volume = {46}, number = {sup1}, pages = {293-301}, doi = {10.1080/21691401.2017.1423494}, pmid = {29313384}, issn = {2169-141X}, mesh = {Apoptosis/drug effects ; Autophagy/*drug effects ; Biological Transport ; Cell Line, Tumor ; Cell Survival/drug effects ; Chitosan/*chemistry/metabolism/*pharmacology ; Cytoprotection/*drug effects ; Humans ; Nanoparticles/*chemistry ; Reactive Oxygen Species/*metabolism ; }, abstract = {There is a close relationship between autophagy and apoptosis during cancer cell death. We used chitosan nanoparticles (CS NPs) to explore the effects of internalized NPs on the induction of autophagy and to confirm the role of autophagic responses elicited by nanomaterials on the tumour cell's fate. CS NPs at nontoxic concentrations ranging from 10-100 μg/mL triggered the induction of autophagy. With the addition of CS NPs, the aggregation of endogenous LC3 was significantly enhanced and acidic autophagic bodies had been accumulated. CS NPs significantly triggered the occurrence of autophagy by increasing the ratio of LC3 II to LC3 I and CS NPs-mediated autophagy was implicated in reactive oxygen species (ROS) generation and the ROS scavenger N-acetylcysteine (NAC) attenuated CS-induced autophagy. The addition of blank NPs produced a negative effect on cytotoxicity and cellular apoptosis of free Dox, and with the pre-treatment of chloroquine (CQ) as a known autophagy inhibitor, the inhibition rates of cells treated with the combination of Dox and blank CS NPs had been significantly increased. The findings demonstrated that CS NPs have the ability to induce protective autophagy via ROS generation and they were believed to inhibit tumour cell death.}, }
@article {pmid29313067, year = {2018}, author = {Rivera-Del Valle, N and Cheng, T and Irwin, ME and Donnella, H and Singh, MM and Chandra, J}, title = {Combinatorial effects of histone deacetylase inhibitors (HDACi), vorinostat and entinostat, and adaphostin are characterized by distinct redox alterations.}, journal = {Cancer chemotherapy and pharmacology}, volume = {81}, number = {3}, pages = {483-495}, pmid = {29313067}, issn = {1432-0843}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; P50 CA100632/CA/NCI NIH HHS/United States ; R01 CA115811/CA/NCI NIH HHS/United States ; }, mesh = {Adamantane/*analogs &amp; derivatives/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Benzamides/*pharmacology ; Cell Line, Tumor ; DNA Fragmentation/*drug effects ; Drug Therapy, Combination ; Gene Expression Profiling ; Histone Deacetylase Inhibitors/*pharmacology ; Histone Deacetylases/metabolism ; Humans ; Hydroquinones/*pharmacology ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy ; Pyridines/*pharmacology ; Vorinostat/*pharmacology ; }, abstract = {PURPOSE: Amongst the epigenetically targeted therapies, targeting of the histone deacetylases (HDACs) has yielded numerous drugs for clinical use in hematological malignancies, but none as yet for acute lymphocytic leukemia (ALL). Single agent activity of HDAC inhibitors (HDACi) has been elusive in ALL, and has prompted study of combinatorial strategies. Because several HDACi raise levels of intracellular oxidative stress, we evaluated combinations of two structurally distinct HDACi with the redox active compound adaphostin in ALL.<br><br>METHODS: The HDACi vorinostat and entinostat were tested in combination with adaphostin in human ALL cell lines. DNA fragmentation, caspase activation, mitochondrial disruption and levels of &#xa0;intracellular peroxides, superoxide and glutathione were measured in cells treated with the HDACi/adaphostin combinations. Antioxidant blockade of cell death induction and gene expression profiling of cells treated with vorinostat/adaphostin versus entinostat/adaphostin combinations were evaluated.<br><br>RESULTS: Both combinations synergistically induced apoptotic DNA fragmentation, which was preceded by an increase in superoxide levels, a reduction in mitochondrial membrane potential, and an increase in caspase-9 activation. The antioxidant N-acetylcysteine (NAC) blocked superoxide generation and prevented reduction of mitochondrial membrane potential. NAC decreased DNA fragmentation and caspase activity in cells treated with adaphostin and vorinostat, but not in those treated with adaphostin and entinostat. Gene expression arrays revealed differential regulation of several redox genes prior to cell death induction.<br><br>CONCLUSIONS: A redox modulatory agent, adaphostin, enhances efficacy of two HDACi, vorinostat or entinostat, but via different mechanisms indicating a point of divergence in the mechanisms of synergy between the two distinct HDACi and adaphostin.}, }
@article {pmid29311483, year = {2018}, author = {Sun, Y and Li, J and Zhang, Y and Tu, Y and Huang, C and Tao, J and Yang, M and Yang, L}, title = {The Polysaccharide Extracted from Umbilicaria esculenta Inhibits Proliferation of Melanoma Cells through ROS-Activated Mitochondrial Apoptosis Pathway.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {41}, number = {1}, pages = {57-64}, doi = {10.1248/bpb.b17-00562}, pmid = {29311483}, issn = {1347-5215}, mesh = {Antineoplastic Agents/isolation &amp; purification/*pharmacology ; Apoptosis/*drug effects ; Ascomycota/*chemistry ; Cell Culture Techniques ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Fungal Polysaccharides/isolation &amp; purification/*pharmacology ; Human Umbilical Vein Endothelial Cells ; Humans ; Melanoma/metabolism/*pathology ; Mitochondria/*drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Melanoma is one of the most aggressive skin cancers with an increasing rate of morbidity. Umbilicaria esculenta is an edible lichen and its main component of extracts-polysaccharide (PUE) has shown significant antitumor effects in a variety of cancer types such as stomach adenocarcinoma. However, whether it has an anti-melanoma effect and the underlying mechanism has not been revealed. In this article, we showed that PUE extracted from Umbilicaria esculenta could inhibit the growth of A875 and A375 melanoma cells but without obvious toxicity to normal vascular endothelial cells. The generation of reactive oxygen species (ROS) in A875 cells was significantly elevated when treated with PUE for 24h. In addition, the expression of caspase-3 and -9 also increased as compared to the controlled group which resulted in the apoptosis of A875 melanoma cells. In the meantime, when pre-treated with N-acetylcysteine (NAC), the ROS scavenger, PUE induced apoptosis and cell death could be reversed via suppression of elevated generation of ROS and ROS-mediated caspase-9 expression. In summary, our study demonstrated that PUE extracts from Umbilicaria esculenta have a potent anti-melanoma effect through the induction of ROS and caspases-3 and -9. It could provide a promising strategy of melanoma therapy with the components from the extracts of natural and edible plants such as lichen Umbilicaria esculenta.}, }
@article {pmid29307964, year = {2017}, author = {Bhalla, A and Jyothinath, P and Singh, S}, title = {Antioxidant Therapy in Patients with Severe Aluminum Phosphide Poisoning: A Pilot Study.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {21}, number = {12}, pages = {836-840}, pmid = {29307964}, issn = {0972-5229}, abstract = {BACKGROUND: N-acetyl cysteine (NAC) is a powerful antioxidant and has been used extensively in the treatment of paracetamol overdose with great success. Aluminum phosphide (ALP) ingestion results in significant oxidative stress. In this study, we evaluated the effects of NAC on mortality in patients with severe ALP poisoning.<br><br>SUBJECTS AND METHODS: This prospective intervention study was carried out in the emergency medical unit attached to the Nehru Hospital at PGIMER, Chandigarh, over a period of 1 year. All the patients presenting with severe ALP poisoning were randomized into two group. The treatment group received NAC in the dose of 150 mg/kg intravenous over 1 h, followed by 50 mg/kg over 4 h, followed by 100 mg/kg 16 h in 5% dextrose. The placebo group received 5% dextrose. The primary end point was mortality.<br><br>RESULTS: A total of 50 patients were recruited. The baseline parameters were comparable in both groups. The survivors in the treatment group received 19 g of NAC, but the nonsurvivors received only 12.15 g of NAC. The overall mortality in the study group was 88% with 87.5% mortality in the treatment group and 88.5% in the placebo group.<br><br>CONCLUSIONS: Antioxidant therapy in the form of NAC in severe ALP poisoning did not confer any survival benefit.}, }
@article {pmid29307815, year = {2018}, author = {Jia, Z and Wang, M and Wang, X and Wang, L and Qiu, L and Song, L}, title = {Transcriptome sequencing reveals the involvement of reactive oxygen species in the hematopoiesis from Chinese mitten crab Eriocheir sinensis.}, journal = {Developmental and comparative immunology}, volume = {82}, number = {}, pages = {94-103}, doi = {10.1016/j.dci.2017.12.030}, pmid = {29307815}, issn = {1879-0089}, mesh = {Acetylcysteine/pharmacology ; Animals ; Brachyura/*physiology ; Cell Differentiation ; Cells, Cultured ; Energy Metabolism ; Gene Expression Profiling ; Gene Ontology ; *Hematopoiesis ; Hematopoietic Stem Cells/*physiology ; Hemocytes/*physiology ; Mitochondria/*metabolism ; NADH Dehydrogenase/*genetics/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {Reactive oxygen species (ROS) produced in vivo during various electron transfer reactions are generally kept at a certain level since they are harmful to cells. However, it can sensitize hematopoietic progenitors to differentiation, and plays a signaling role in the regulation of hematopoietic cell fate. In the present study, the transcriptomes of crab HPT and hemocytes were sequenced using the Ion Torrent Proton sequencing platform. A total of 51,229,690 single end reads were obtained from six single-end libraries, which were assembled into 31346 unireads as reference. After mapping and transcript assembling, 362 differently expressed genes were identified and 301 of them were deemed to be more abundant in HPT. GO annotation revealed that they were mostly implicated in DNA, RNA and protein synthesis, cell division, mitochondria activities and energy metabolism. The expression level of mitochondrial complexes I (mitochondrial NADH-ubiquinone oxidoreductase) which was the main natural producers of mitochondrial ROS was found to be 8.6-fold (p < 0.01) higher in HPT than that in hemocytes. In hemocytes, the proteinase genes associated with proPO activation from the 61 up-regulated genes in hemocytes were the main up-regulated genes which might be the potential markers for mature hemocytes. ROS level in HPT cells was relatively higher which was confirmed with the high expression level of mitochondria related genes identified by transcriptome sequencing. After the ROS level was depressed by N-acetyl-l-cysteine (NAC), the production of hemocytes from HPT was inhibited, and the recovery of the total hemocytes counts was delayed. These results collectively indicated that the genes in redox system were more active in HPT, and ROS could function as an important modulator in the hematopoiesis of crab and promote the production of hemocytes from HPT.}, }
@article {pmid29307443, year = {2018}, author = {Karmacharya, MB and Hada, B and Park, SR and Choi, BH}, title = {Low-Intensity Ultrasound Reduces High Glucose-Induced Nitric Oxide Generation in Retinal Pigment Epithelial Cells.}, journal = {Ultrasound in medicine &amp; biology}, volume = {44}, number = {3}, pages = {647-656}, doi = {10.1016/j.ultrasmedbio.2017.12.004}, pmid = {29307443}, issn = {1879-291X}, mesh = {Blotting, Western ; Cells, Cultured ; Epithelial Cells/*metabolism ; Humans ; Nitric Oxide/*metabolism ; Retinal Pigments/*metabolism ; Ultrasonics/*methods ; }, abstract = {Diabetic retinopathy (DR) is a severe micro-vascular complication of diabetes. High glucose (HG)-evoked nitric oxide (NO) production mediated by increased oxidative stress is a key factor in DR pathogenesis. In this study, we examined whether low-intensity ultrasound (LIUS) stimulation can reduce HG-induced NO generation. We determined that LIUS stimulation decreased the HG-induced NO generation possibly via inhibition of reactive oxygen species (ROS) and subsequently diminished the associated pro-inflammatory pathway involving the induced expression of inducible nitric oxide synthase, cyclooxygenase-2 and vascular endothelial growth factor. In addition, we determined that LIUS stimulation reduced the quantity of NO produced by N-acetylcysteine, which was not mediated by ROS. These results indicate that LIUS can inhibit both ROS-dependent and -independent NO generation processes in ARPE-19 cells. We envision LIUS as a potential therapeutic alternative to treat DR. Further studies are required to understand the underlying mechanism of the LIUS-induced reduction of NO generation for DR therapy.}, }
@article {pmid29306259, year = {2017}, author = {Danehpoya, F and Karimipour, M and Zirak Javanmard, M and Pourheydar, B}, title = {Effects of n-acetylcysteine on ovarian tissue autografted intogranulation tissue compared to back muscle in rats.}, journal = {Turkish journal of medical sciences}, volume = {47}, number = {6}, pages = {1931-1939}, doi = {10.3906/sag-1704-170}, pmid = {29306259}, issn = {1300-0144}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Autografts/drug effects ; Back Muscles/diagnostic imaging/*surgery ; Female ; Models, Animal ; Ovary/diagnostic imaging/*drug effects/surgery/*transplantation ; Photomicrography ; Random Allocation ; Rats ; Transplantation, Autologous/*methods ; }, abstract = {Background/aim: Ovarian transplantation can preserve fertility in cancer patients. The aim of this study was to compare ovarian transplantation into granulation tissue (GT) versus back muscle (BM) sites and also to investigate the effects of N-acetylcysteine (NAC) as an antioxidant on ovarian survival in a rat autograft model.Materials and methods: Twenty-eight adult female rats were divided into four equal groups (n = 7 each) as follows: Group 1, ovarian tissue grafted into GT + saline (GT + saline); Group 2, ovarian tissue grafted into GT + NAC (GT + NAC); Group 3, ovarian tissue grafted into BM + saline (BM + saline); and Group 4, ovarian tissue grafted into BM + NAC (BM + NAC). After 28 days, serum concentrations of malondialdehyde (MDA), progesterone, and estradiol (E2) were measured. Ovarian follicle counts were performed from hematoxylin and eosin-stained slides. Furthermore, apoptosis was assessed by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL). Results: There were no significant differences found in levels of MDA, progesterone, and E2 among the groups. The percentage of apoptotic granulosa cells was significantly (P < 0.05) lower in the ovarian tissue autografted in the GT + NAC group compared to the GT + saline and BM + NAC groups. In addition, the number of blood vessels formed in the ovarian tissue in the GT + NAC group was significantly higher than in the GT + saline and BM + NAC groups (P < 0.05 and P < 0.001 respectively).Conclusion: The granulation tissue site is a suitable candidate for ovarian graft in rats. Furthermore, NAC could not restore autografted ovarian functions.}, }
@article {pmid29305260, year = {2018}, author = {Xu, Y and Gao, CC and Pan, ZG and Zhou, CW}, title = {Irigenin sensitizes TRAIL-induced apoptosis via enhancing pro-apoptotic molecules in gastric cancer cells.}, journal = {Biochemical and biophysical research communications}, volume = {496}, number = {3}, pages = {998-1005}, doi = {10.1016/j.bbrc.2018.01.003}, pmid = {29305260}, issn = {1090-2104}, mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage ; Antineoplastic Combined Chemotherapy Protocols/*administration &amp; dosage ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/*metabolism ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Synergism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Isoflavones/*administration &amp; dosage ; Male ; Mice ; Mice, Nude ; Stomach Neoplasms/*drug therapy/*metabolism/pathology ; TNF-Related Apoptosis-Inducing Ligand/*administration &amp; dosage ; Up-Regulation/drug effects ; }, abstract = {Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promising value for cancer therapy due to its capacity to induce apoptosis in cancer cells. Nevertheless, TRAIL therapy is greatly hampered by its resistance. Irigenin (Iri), isoflavonoids, can be isolated from the rhizome of Belamcanda chinensis, and has been shown anti-cancer properties. In this study, we explored if Iri could enhance TRAIL-regulated apoptosis in TRAIL resistant gastric cancer cells. Iri significantly potentiated TRAIL-triggered cytotoxicity. Iri alone and TRAIL alone showed no effective role in apoptosis induction, whereas combined treatment with Iri and TRAIL markedly induced apoptosis in cancer cells, as evidenced by the up-regulation of cleaved Caspase-8/-9/-3 and PARP. Additionally, the sensitization to TRAIL was along with the enhancement of pro-apoptotic proteins, including FAS-associated protein with death domain (FADD), death receptor 5 (DR5) and Bax. And suppressing FADD, DR5 and Bax by si RNA significantly reduced the apoptosis and enhanced the cell viability induced by the co-application of Iri and TRAIL. Moreover, the sensitization to TRAIL was accompanied by the decrease of Cellular-FLICE inhibitory protein (c-FLIP), Bcl-2 and Survivin. Additionally, Iri could sensitize TRAIL to produce reactive oxygen species (ROS). Pre-treatment of N-acetyl-cysteine (NAC), ROS scavenger, attenuated Iri plus TRAIL-induced apoptosis and improved cell viability. Finally, combination of Iri and TRAIL inhibited tumor growth in the xenograft model. Collectively, our present study gave new insights into the effects of Iri on potentiating TRAIL-sensitivity, and suggested that Iri could be a potential candidate for sensitizer of TRAIL-resistant cancer cell treatment.}, }
@article {pmid29304389, year = {2018}, author = {García-Alcántara, F and Murillo-Cuesta, S and Pulido, S and Bermúdez-Muñoz, JM and Martínez-Vega, R and Milo, M and Varela-Nieto, I and Rivera, T}, title = {The expression of oxidative stress response genes is modulated by a combination of resveratrol and N-acetylcysteine to ameliorate ototoxicity in the rat cochlea.}, journal = {Hearing research}, volume = {358}, number = {}, pages = {10-21}, doi = {10.1016/j.heares.2017.12.004}, pmid = {29304389}, issn = {1878-5891}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Auditory Fatigue/drug effects ; Brain Stem/*drug effects/physiopathology ; Cochlea/*drug effects/metabolism/pathology ; Cytoprotection ; Disease Models, Animal ; Drug Therapy, Combination ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Furosemide ; Gene Expression Regulation ; Hearing/*drug effects ; Hearing Loss/chemically induced/metabolism/physiopathology/*prevention &amp; control ; Inflammation Mediators/metabolism ; Kanamycin ; Male ; Oxidative Stress/*drug effects/genetics ; Rats, Wistar ; Reaction Time/drug effects ; Resveratrol/*pharmacology ; }, abstract = {Aminoglycoside antibiotics are used widely in medicine despite their ototoxic side-effects. Oxidative stress and inflammation are key mechanisms determining the extent and severity of the damage. Here we evaluate the protective effect of a treatment with resveratrol plus N-acetylcysteine on the ototoxic actions of kanamycin and furosemide in the rat. Resveratrol (10 mg/kg) and N-acetylcysteine (400 mg/kg) were administered together to Wistar rats on 5 consecutive days. The second day, a concentrated solution of kanamycin and furosemide was placed on the round window to induce ototoxicity. Hearing was assessed by recording auditory brainstem responses before and 5, 16 and 23 days after the beginning of the treatment. Cochlear samples were taken at day 5 (end of the treatment) and at day 23, and targeted PCR arrays or RT-qPCR were performed to analyze oxidative balance and inflammation related genes, respectively. In addition, the cytoarchitecture and the presence of apoptosis, oxidative stress and inflammation markers were evaluated in cochlear sections. Results indicate that administration of resveratrol plus N-acetylcysteine reduced the threshold shifts induced by ototoxic drugs at high frequencies (≈10 dB), although this protective effect fades after the cessation of the treatment. Gene expression analysis showed that the treatment modulated the expression of genes involved in the cellular oxidative (Gpx1, Sod1, Ccs and Noxa1) and inflammatory (Il1b, Il4, Mpo and Ncf) responses to injury. Thus, co-administration of resveratrol and NAC, routinely used individually in patients, could reduce the ototoxic secondary effects of aminoglycosides.}, }
@article {pmid29299971, year = {2018}, author = {Wang, M and Su, P}, title = {The role of the Fas/FasL signaling pathway in environmental toxicant-induced testicular cell apoptosis: An update.}, journal = {Systems biology in reproductive medicine}, volume = {64}, number = {2}, pages = {93-102}, doi = {10.1080/19396368.2017.1422046}, pmid = {29299971}, issn = {1939-6376}, mesh = {Animals ; Apoptosis/*drug effects ; Environmental Pollutants/*toxicity ; Fas Ligand Protein/*metabolism ; Fertility/drug effects ; Humans ; Infertility, Male/*chemically induced/metabolism/pathology/physiopathology ; Leydig Cells/drug effects/metabolism/pathology ; Male ; Risk Assessment ; Sertoli Cells/drug effects/metabolism/pathology ; Signal Transduction/*drug effects ; Spermatogenesis/drug effects ; Spermatozoa/drug effects/metabolism/pathology ; Testis/*drug effects/metabolism/pathology ; fas Receptor/*metabolism ; }, abstract = {UNLABELLED: The Fas/FasL signaling pathway is one of the major pathways that regulate apoptosis. Increasing studies have shown that the activation of the Fas/FasL signaling pathway is closely associated with testicular cell apoptosis. However, the mechanism involved is still unclear. We discuss recent findings regarding the molecular mechanisms by which environmental toxicants induce testicular pathology via Fas/FasL signaling. These findings suggest that Fas/FasL signaling is employed to impact the sensitivity (a response to external factors) of germ cells, disrupt steroidogenic hormone and cytokine metabolism mediated by Sertoli cells, and elicit the activation of NFAT (nuclear factor of activated T-cells) in Leydig cell apoptosis. Consequently, degeneration of testicular somatic (Sertoli and Leydig) and spermatogenic cells, leads to decreased numbers of mature sperm and subsequently translates into infertility issues. Collectively, these findings illustrate that it is beneficial to develop potential targets for a new generation of new pharmaceutical therapies that would alleviate testicular dysfunctions.<br><br>ABBREVIATIONS: BTB: blood-testis barrier; DD: death domains; DR3: death receptor 3; DR4: death receptor 4; DR5: death receptor 5; DED: death effector domain; DISC: death-inducing signaling complex; ER&#x3b1;: estrogen receptor alpha; FADD: Fas-associated death domain; FSH: follicle- stimulating hormone; IL-1&#x3b2;: interleukin 1 beta; LH: luteinizing hormone; LPS: lipopolysaccharide; mFas: membrane Fas; MMP2: matrix metalloproteinase-2; MTA1: metastasis-associated protein 1; NAC: N-acetylcysteine; NCCD: the Nomenclature Committee on Cell Death; NFAT: nuclear factor of activated T-cells; NF-kB: nuclear transcription factor-kappaB; NO: nitric oxide; NP: 4-nonylphenol; PCD: programmed cell death; PP1/PP2A: protein phosphatase 1 and 2A; ROS: reactive oxygen species; sFas: soluble Fas; T: testosterone; TGF-&#x3b2;: transforming growth factor-beta; THD: TNF homology domain; TIMP-2: tissue inhibitor of metalloproteinase-2; TNF: tumor necrosis factor; TNF-&#x3b1;: tumor necrosis factor-alpha; TNF-R1: Tumor necrosis factor receptor 1; TNFRSF1A: TNF receptor superfamily member 1A.}, }
@article {pmid29296199, year = {2017}, author = {Chen, J and Chen, B and Zou, Z and Li, W and Zhang, Y and Xie, J and Liu, C}, title = {Costunolide enhances doxorubicin-induced apoptosis in prostate cancer cells via activated mitogen-activated protein kinases and generation of reactive oxygen species.}, journal = {Oncotarget}, volume = {8}, number = {64}, pages = {107701-107715}, pmid = {29296199}, issn = {1949-2553}, abstract = {The management of castration-resistant prostate cancer (CRPC) is challenging, attributable to a lack of efficacious therapies. Chemotherapy is one of the most important treatments for CRPC. Doxorubicin has been extensively used in many different tumors and is often combined with other drugs to enhance effects and reduce toxicity. Costunolide is a natural sesquiterpene lactone with anti-cancer properties. In this study, we first demonstrated that the combination of costunolide and doxorubicin induced apoptosis significantly more than either drug alone in prostate cancer cell lines. Costunolide combined with doxorubicin induced mitochondria-mediated apoptosis through a loss of mitochondrial membrane potential and modulation of Bcl-2 family proteins. We found that this drug combination significantly increased the production of reactive oxygen species (ROS), as well as phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases, which play upstream roles in mitochondria-mediated apoptosis. Further studies showed that N-acetyl cysteine blocked JNK and p38 phosphorylation, suggesting that ROS were upstream activators of JNK and p38. However, a JNK inhibitor, but not a p38 inhibitor, blocked the increase in ROS observed in cells treated with a combination of costunolide and doxorubicin, suggesting that ROS and JNK could activate each other. In vivo, inhibition of tumor growth and induction of apoptosis were greater in mice treated with the costunolide and doxorubicin combination than in mice treated with either drug alone, without an increase in toxicity. Therefore, we suggested that costunolide in combination with doxorubicin was a new potential chemotherapeutic strategy for treating prostate cancer.}, }
@article {pmid29294389, year = {2018}, author = {Katikireddy, KR and White, TL and Miyajima, T and Vasanth, S and Raoof, D and Chen, Y and Price, MO and Price, FW and Jurkunas, UV}, title = {NQO1 downregulation potentiates menadione-induced endothelial-mesenchymal transition during rosette formation in Fuchs endothelial corneal dystrophy.}, journal = {Free radical biology &amp; medicine}, volume = {116}, number = {}, pages = {19-30}, pmid = {29294389}, issn = {1873-4596}, support = {P30 EY003790/EY/NEI NIH HHS/United States ; R01 EY020581/EY/NEI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Cell Differentiation ; Cell Line ; Cornea/*pathology ; DNA Damage ; Endothelial Cells/*physiology ; Fibronectins/metabolism ; Fuchs' Endothelial Dystrophy/*therapy ; Gene Expression Regulation ; Humans ; Mesenchymal Stem Cells/*physiology ; Middle Aged ; NAD(P)H Dehydrogenase (Quinone)/genetics/*metabolism ; Oxidative Stress ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Rosette Formation ; Snail Family Transcription Factors/metabolism ; Vitamin K 3/metabolism ; }, abstract = {Fuchs endothelial corneal dystrophy (FECD) is a genetic and oxidative stress disorder of post-mitotic human corneal endothelial cells (HCEnCs), which normally exhibit hexagonal shape and form a compact monolayer compatible with normal corneal functioning and clear vision. FECD is associated with increased DNA damage, which in turn leads to HCEnC loss, resulting in the formation rosettes and aberrant extracellular matrix (ECM) deposition in the form of pro-fibrotic guttae. Since the mechanism of ECM deposition in FECD is currently unknown, we aimed to investigate the role of endothelial-mesenchymal transition (EMT) in FECD using a previously established cellular in vitro model that recapitulates the characteristic rosette formation, by employing menadione (MN)-induced oxidative stress. We demonstrate that MN treatment alone, or a combination of MN and TGF-β1 induces reactive oxygen species (ROS), cell death, and EMT in HCEnCs during rosette formation, resulting in upregulation of EMT- and FECD-associated markers such as Snail1, N-cadherin, ZEB1, and transforming growth factor-beta-induced (TGFβI), respectively. Additionally, FECD ex vivo specimens displayed a loss of organized junctional staining of plasma membrane-bound N-cadherin, with corresponding increase in fibronectin and Snail1 compared to ex vivo controls. Addition of N-acetylcysteine (NAC) downregulated all EMT markers and abolished rosette formation. Loss of NQO1, a metabolizing enzyme of MN, led to greater increase in intracellular ROS levels as well as a significant upregulation of Snail1, fibronectin, and N-cadherin compared to normal cells, indicating that NQO1 regulates Snail1-mediated EMT. This study provides first line evidence that MN-induced oxidative stress leads to EMT in corneal endothelial cells, and the effect of which is further potentiated when redox cycling activity of MN is enhanced by the absence of NQO1. Given that NAC inhibits Snail-mediated EMT, this may be a potential therapeutic intervention for FECD.}, }
@article {pmid29292841, year = {2018}, author = {Lv, Y and Li, Y and Zhang, D and Zhang, A and Guo, W and Zhu, S}, title = {HMGB1-induced asthmatic airway inflammation through GRP75-mediated enhancement of ER-mitochondrial Ca[2+] transfer and ROS increased.}, journal = {Journal of cellular biochemistry}, volume = {119}, number = {5}, pages = {4205-4215}, doi = {10.1002/jcb.26653}, pmid = {29292841}, issn = {1097-4644}, mesh = {Animals ; Asthma/*immunology/pathology ; Calcium/*immunology ; Endoplasmic Reticulum/*immunology/pathology ; HMGB1 Protein/antagonists &amp; inhibitors/*immunology ; HSP70 Heat-Shock Proteins/*immunology ; Inflammation/immunology/pathology ; Male ; Membrane Proteins/*immunology ; Mice ; Mice, Inbred BALB C ; Mitochondria/*immunology/pathology ; Reactive Oxygen Species/*immunology ; }, abstract = {Imbalanced T-helper (TH)1/Th2 response contributes significantly to asthma pathogenesis. Our study indicated that HMGB1 play an important role in the release of Th2-associated cytokines of asthma. However, the specific mechanism about HMGB1-induced imbalanced TH1/Th2 response is not known. In vivo, an OVA-induced asthma mouse model was set up and mice treated with anti-HMGB1 IgG. The mice treated with the anti-HMGB1 IgG ameliorated airway hyper-reactivity, disruption of Th1/Th2 balance and the upregulation of GRP75 induced by OVA. In vitro, the exposure of normal human bronchial epithelial cells to HMGB1 resulted in the upregulation of GRP75, proinflammatory cytokine production, enhanced ER-Mitochondrial Ca[2+] transfer, and enhancement of reactive oxygen species (ROS). While HMGB1-induced these changes were attenuated by GRP75 siRNA treatment. Sequentially, pretreatment with 2-APB, SKF960365 (SKF) and Ru360 which inhibit ER-Mitochondrial Ca[2+] transfer significantly lowered HMGB1-induced the generation of ROS and the release of Th2 cytokines in 16HBE cells. Meanwhile, N-acetylcysteine (NAC) significantly attenuated the HMGB1-mediated pro-inflammatory cytokines release. Therefore, these results indicate that GRP75-mediated ER-Mitochondrial Ca[2+] transfer may be an important contributor in imbalanced of Th1/Th2 balance of asthma. Moreover, HMGB1 specifically induces the release of Th2 cytokines through GRP75-mediated enhancement of ER-Mitochondrial Ca[2+] transfer and ROS increased.}, }
@article {pmid29291983, year = {2018}, author = {Echeverri-Ruiz, N and Haynes, T and Landers, J and Woods, J and Gemma, MJ and Hughes, M and Del Rio-Tsonis, K}, title = {A biochemical basis for induction of retina regeneration by antioxidants.}, journal = {Developmental biology}, volume = {433}, number = {2}, pages = {394-403}, pmid = {29291983}, issn = {1095-564X}, support = {R01 EY026816/EY/NEI NIH HHS/United States ; R21 EY023925/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Differentiation/drug effects ; Chick Embryo ; Ciliary Body/cytology ; Disulfides/metabolism ; Fibroblast Growth Factor 2/pharmacology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; MAP Kinase Signaling System/drug effects ; Oxidation-Reduction ; Regeneration/*drug effects/physiology ; Retina/drug effects/*physiology ; Stem Cells/cytology/*drug effects ; Sulfhydryl Compounds/metabolism ; }, abstract = {The use of antioxidants in tissue regeneration has been studied, but their mechanism of action is not well understood. Here, we analyze the role of the antioxidant N-acetylcysteine (NAC) in retina regeneration. Embryonic chicks are able to regenerate their retina after its complete removal from retinal stem/progenitor cells present in the ciliary margin (CM) of the eye only if a source of exogenous factors, such as FGF2, is present. This study shows that NAC modifies the redox status of the CM, initiates self-renewal of the stem/progenitor cells, and induces regeneration in the absence of FGF2. NAC works as an antioxidant by scavenging free radicals either independently or through the synthesis of glutathione (GSH), and/or by reducing oxidized proteins through a thiol disulfide exchange activity. We dissected the mechanism used by NAC to induce regeneration through the use of inhibitors of GSH synthesis and the use of other antioxidants with different biochemical structures and modes of action, and found that NAC induces regeneration through its thiol disulfide exchange activity. Thus, our results provide, for the first time, a biochemical basis for induction of retina regeneration. Furthermore, NAC induction was independent of FGF receptor signaling, but dependent on the MAPK (pErk1/2) pathway.}, }
@article {pmid30931204, year = {2018}, author = {Salvi, R and Ding, D and Jiang, H and Chen, GD and Greco, A and Manohar, S and Sun, W and Ralli, M}, title = {Hidden Age-Related Hearing Loss and Hearing Disorders: Current Knowledge and Future Directions.}, journal = {Hearing, balance and communication}, volume = {16}, number = {2}, pages = {74-82}, pmid = {30931204}, issn = {2169-5717}, support = {R01 DC011808/DC/NIDCD NIH HHS/United States ; R01 DC014452/DC/NIDCD NIH HHS/United States ; R01 DC014693/DC/NIDCD NIH HHS/United States ; }, abstract = {Age-related hearing loss, which affects roughly 35% of those over the age of 70, is the second most common disorder among the elderly. The severity of age related hearing loss may actually be worse if assessments are made under more realistic conditions, such as communicating in noise. Emerging data from humans and animal models suggest that damage to the inner hair cells and/or type I neurons, that relay sound information to the brain may contribute to hearing deficits in a noisy background. Data obtained from carboplatin-treated chinchillas suggest that tone-in-noise thresholds are a sensitive and frequency dependent method of detecting damage to the IHC/type I system. Therefore, tone detection thresholds measured in broadband noise may provide an efficient method of detecting the deficits in specific frequency regions. Preliminary data obtained in elderly subject with normal thresholds in quiet compared to young subjects illustrate the importance of repeating these measurements in broadband noise because thresholds in noise were worse for our elderly subjects than young subjects, even though both groups had similar hearing thresholds in quiet. N-acetyl cysteine supplementation which protects against inner hair cell loss in animal models, may represent a viable therapy for protecting the inner hair cell/type I neurons.}, }
@article {pmid29289682, year = {2018}, author = {Osipyants, AI and Poloznikov, AA and Smirnova, NA and Hushpulian, DM and Khristichenko, AY and Chubar, TA and Zakhariants, AA and Ahuja, M and Gaisina, IN and Thomas, B and Brown, AM and Gazaryan, IG and Tishkov, VI}, title = {L-ascorbic acid: A true substrate for HIF prolyl hydroxylase?.}, journal = {Biochimie}, volume = {147}, number = {}, pages = {46-54}, pmid = {29289682}, issn = {1638-6183}, support = {R01 NS101967/NS/NINDS NIH HHS/United States ; }, mesh = {Ascorbic Acid/chemistry/*metabolism ; Cell Line, Tumor ; Humans ; Prolyl Hydroxylases/*metabolism/*pharmacology ; Prolyl-Hydroxylase Inhibitors/pharmacology ; Protein Binding ; Stereoisomerism ; }, abstract = {L-Ascorbate (L-Asc), but not D-isoascorbate (D-Asc) and N-acetylcysteine (NAC) suppress HIF1 ODD-luc reporter activation induced by various inhibitors of HIF prolyl hydroxylase (PHD). The efficiency of suppression by L-Asc was sensitive to the nature of HIF PHD inhibitor chosen for reporter activation. In particular, the inhibitors developed to compete with alpha-ketoglutarate (αKG), were less sensitive to suppression by the physiological range of L-Asc (40-100 μM) than those having a strong iron chelation motif. Challenging those HIF activators in the reporter system with D-Asc demonstrated that the D-isomer, despite exhibiting the same reducing potency with respect to ferric iron, had almost no effect compared to L-Asc. Similarly, no effect on reporter activation was observed with cell-permeable reducing agent NAC up to 1 mM. Docking of L-Asc and D-Asc acid into the HIF PHD2 crystal structure showed interference of Tyr310 with respect to D-Asc. This suggests that L-Asc is not merely a reducing agent preventing enzyme inactivation. Rather, the overall results identify L-Asc as a co-substrate of HIF PHD that may compete for the binding site of αKG in the enzyme active center. This conclusion is in agreement with the results obtained recently in cell-based systems for TET enzymes and jumonji histone demethylases, where L-Asc has been proposed to act as a co-substrate and not as a reducing agent preventing enzyme inactivation.}, }
@article {pmid29289511, year = {2018}, author = {DeHart, DN and Fang, D and Heslop, K and Li, L and Lemasters, JJ and Maldonado, EN}, title = {Opening of voltage dependent anion channels promotes reactive oxygen species generation, mitochondrial dysfunction and cell death in cancer cells.}, journal = {Biochemical pharmacology}, volume = {148}, number = {}, pages = {155-162}, pmid = {29289511}, issn = {1873-2968}, support = {P50 CA058187/CA/NCI NIH HHS/United States ; R01 AA021191/AA/NIAAA NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P20 GM103542/GM/NIGMS NIH HHS/United States ; T32 DK083262/DK/NIDDK NIH HHS/United States ; R56 DK037034/DK/NIDDK NIH HHS/United States ; R01 DK037034/DK/NIDDK NIH HHS/United States ; R01 DK073336/DK/NIDDK NIH HHS/United States ; R01 CA184456/CA/NCI NIH HHS/United States ; R37 DK037034/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Cell Death ; Hep G2 Cells ; Hepatocytes/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mitochondria/*drug effects/metabolism ; Molecular Structure ; Piperazines/pharmacology ; Pyridines/pharmacology ; Pyrimidines/chemistry/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Voltage-Dependent Anion Channels ; }, abstract = {Enhancement of aerobic glycolysis and suppression of mitochondrial metabolism characterize the pro-proliferative Warburg phenotype of cancer cells. High free tubulin in cancer cells closes voltage dependent anion channels (VDAC) to decrease mitochondrial membrane potential (ΔΨ), an effect antagonized by erastin, the canonical promotor of ferroptosis. Previously, we identified six compounds (X1-X6) that also block tubulin-dependent mitochondrial depolarization. Here, we hypothesized that VDAC opening after erastin and X1-X6 increases mitochondrial metabolism and reactive oxygen species (ROS) formation, leading to ROS-dependent mitochondrial dysfunction, bioenergetic failure and cell death. Accordingly, we characterized erastin and the two most potent structurally unrelated lead compounds, X1 and X4, on ROS formation, mitochondrial function and cell viability. Erastin, X1 and X4 increased ΔΨ followed closely by an increase in mitochondrial ROS generation within 30-60 min. Subsequently, mitochondria began to depolarize after an hour or longer indicative of mitochondrial dysfunction. N-acetylcysteine (NAC, glutathione precursor and ROS scavenger) and MitoQ (mitochondrially targeted antioxidant) blocked increased ROS formation after X1 and prevented mitochondrial dysfunction. Erastin, X1 and X4 selectively promoted cell killing in HepG2 and Huh7 human hepatocarcinoma cells compared to primary rat hepatocytes. X1 and X4-dependent cell death was blocked by NAC. These results suggest that ferroptosis induced by erastin and our erastin-like lead compounds was caused by VDAC opening, leading to increased ΔΨ, mitochondrial ROS generation and oxidative stress-induced cell death.}, }
@article {pmid29288670, year = {2018}, author = {Cui, YQ and Liu, YJ and Zhang, F}, title = {The suppressive effects of Britannin (Bri) on human liver cancer through inducing apoptosis and autophagy via AMPK activation regulated by ROS.}, journal = {Biochemical and biophysical research communications}, volume = {497}, number = {3}, pages = {916-923}, doi = {10.1016/j.bbrc.2017.12.144}, pmid = {29288670}, issn = {1090-2104}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Antineoplastic Agents, Phytogenic/chemistry/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Humans ; Inula/chemistry ; Lactones/chemistry/*pharmacology ; Liver Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Sesquiterpenes/chemistry/*pharmacology ; }, abstract = {Britannin (Bri), isolated from Inula aucheriana, is a sesquiterpene lactone (SL), a class of secondary metabolites. Previous studies have suggested the anti-cancer potential of Bri; however, the molecular mechanism remains elusive. The present study investigated the effects of Bri on liver cancer progression. Our findings indicated that Bri significantly suppressed the growth of liver cancer cell lines. Mechanistic researches revealed that Bri induced apoptosis through the extrinsic and intrinsic apoptotic pathways, as evidenced by the increase of Caspase-8, -9 and -3 cleavages. In addition, Bri-triggered autophagy in liver cancer cells, supported by the up-regulation of light chain 3 (LC3) II, p62, autophagy-related 5 (ATG5) and Beclin 1, as well as the occurrence of autophagic vacuoles. Importantly, Bri increased AMPK activation, while decreased the activity of its down-streaming signal, mTOR. Of note, suppression of AMP-activated protein kinase (AMPK) activation using its inhibitor, Compound C, could inhibit both apoptosis and autophagy induced by Bri. Furthermore, Bri was found to induce reactive oxygen species (ROS) generation in hepatic cancer cells. Notably, reducing ROS production by its scavenger, N-acetyl cysteine (NAC), could down-regulate p-AMPK levels, while up-regulate the phosphorylated mechanistic target of rapamycin (p-mTOR) expressions, accompanied with the restored cell viability, as well as the reduced apoptosis and autophagy in Bri-treated liver cancer cells. Finally, Bri inhibited the tumor growth in vivo without side effects. In conclusion, our study illustrated that Bri could induce apoptosis and autophagy by activating AMPK regulated by ROS in liver cancer cells, supplying molecular bases for developing Bri into an effective candidate against liver cancer.}, }
@article {pmid29281792, year = {2018}, author = {Stack, DE and Conrad, JA and Mahmud, B}, title = {Structural Identification and Kinetic Analysis of the in Vitro Products Formed by Reaction of Bisphenol A-3,4-quinone with N-Acetylcysteine and Glutathione.}, journal = {Chemical research in toxicology}, volume = {31}, number = {2}, pages = {81-87}, doi = {10.1021/acs.chemrestox.7b00239}, pmid = {29281792}, issn = {1520-5010}, mesh = {Acetylcysteine/*chemistry ; Benzhydryl Compounds/*chemistry ; Benzoquinones/*chemistry ; Glutathione/*chemistry ; Kinetics ; Molecular Structure ; Phenols/*chemistry ; }, abstract = {Bisphenol A (BPA) has received considerable attention as an endocrine disrupting chemical and a possible substrate for genotoxic metabolites. BPA metabolism leads to formation of electrophilic o-quinones cable of binding to DNA and other endogenous nucleophiles. We have structurally identified the products resulting from the reaction of bisphenol A-3,4-quinone (BPAQ) with N-acetylcysteine (NAC) and glutathione (GSH). The major and minor isomers are both the result of 1,6-conjugate addition and are produced almost instantly in high yield. Reactions using 1.3 equiv of GSH showed the presence of a bis-glutathionyl adduct which was not observed using higher GSH concentration relative to BPAQ. NAC reactions with BPAQ showed no bis-N-acetylcysteinyl adducts. Stopped-flow kinetic analysis reveals the 1,6-conjugate additions to be reversible with a forward free energy of activation of 9.2 and 7.8 kcal/mol for the NAC and GSH reactions, respectively. The bimolecular forward rate constant at 19.4 °C was approximately three time faster for GSH compared to NAC, 1547 vs 496 M[-1] s[-1]. The free energy of activation for the reverse reactions were similar, 11.7 and 11.2 kcal/mol for NAC and GSH, respectively. We plan to use this model system to further explore the mechanism of adduct formation between sulfur nucleophiles and o-quinones and the resulting chemical properties of both NAC and GSH adducts.}, }
@article {pmid29278702, year = {2018}, author = {Chen, C and Ma, X and Yang, C and Nie, W and Zhang, J and Li, H and Rong, P and Yi, S and Wang, W}, title = {Hypoxia potentiates LPS-induced inflammatory response and increases cell death by promoting NLRP3 inflammasome activation in pancreatic β cells.}, journal = {Biochemical and biophysical research communications}, volume = {495}, number = {4}, pages = {2512-2518}, doi = {10.1016/j.bbrc.2017.12.134}, pmid = {29278702}, issn = {1090-2104}, mesh = {Animals ; Apoptosis/drug effects/*immunology ; Carrier Proteins/*immunology ; Cell Hypoxia/drug effects/*immunology ; Cell Line ; Inflammasomes/drug effects/*immunology ; Insulin-Secreting Cells/drug effects/*immunology ; Lipopolysaccharides ; Mice ; NF-kappa B/immunology ; NLR Family, Pyrin Domain-Containing 3 Protein/*immunology ; Reactive Oxygen Species/*immunology ; Thioredoxins/*immunology ; }, abstract = {Hypoxia and islet inflammation are involved in β-cell failure in type 2 diabetes (T2D). Elevated plasma LPS levels have been verified in patients with T2D, and hypoxia occurs in islets of diabetic mice. Activation of inflammasomes in ischemic or hypoxic conditions was identified in various tissues. Here, we investigated whether hypoxia activates the inflammasome in β cells and the possible mechanisms involved. In mouse insulinoma cell line 6 (MIN6), hypoxia (1% O2) primes the NLRP3 inflammasome along with NF-κB signaling activation. Our results demonstrate that hypoxia can activate the NLRP3 inflammasome in LPS-primed MIN6 to result in initiating the β cell inflammatory response and cell death in vitro. Reactive oxygen species (ROS) and the thioredoxin-interacting protein (TXNIP) are up-regulated in response to hypoxia. Finally, the role of the ROS-TXNIP axis in mediating the activation of the NLRP3 inflammasome and cell death was characterized by pretreating with the ROS scavenger N-acetylcysteine (NAC) and performing TXNIP knockdown experiments in MIN6. Our data indicate for the first time that the inflammasome is involved in the inflammatory response and cell death in hypoxia-induced β cells through the ROS-TXNIP-NLRP3 axis in vitro. This provides new insight into the relationship between hypoxia and inflammation in T2D.}, }
@article {pmid29273567, year = {2018}, author = {Huang, AM and Lin, KW and Lin, WH and Wu, LH and Chang, HC and Ni, C and Wang, DL and Hsu, HY and Su, CL and Shih, C}, title = {1-Hydroxy-3-[(E)-4-(piperazine-diium)but-2-enyloxy]-9,10-anthraquinone ditrifluoroactate induced autophagic cell death in human PC3 cells.}, journal = {Chemico-biological interactions}, volume = {281}, number = {}, pages = {60-68}, doi = {10.1016/j.cbi.2017.12.010}, pmid = {29273567}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Anthraquinones/chemical synthesis/chemistry/*toxicity ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Macrolides/pharmacology ; Microscopy, Electron, Transmission ; Microtubule-Associated Proteins/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {The autophagy of human prostate cancer cells (PC3 cells) induced by a new anthraquinone derivative, 1-Hydroxy-3-[(E)-4-(piperazine-diium)but-2-enyloxy]-9,10-anthraquinone ditrifluoroactate (PA) was investigated, and the relationship between autophagy and reactive oxygen species (ROS) generation was studied. The results indicated that PA induced PC3 cell death in a time- and dose-dependent manner, could inhibit PC3 cell growth by G1 phase cell cycle arrest and corresponding decrease in the G2/M cell population and induced S-phase arrest accompanied by a significant decrease G2/M and G1 phase numbers after PC3 cells treated with PA for 48 h, and increased the accumulation of autophagolysosomes and microtubule-associated protein LC3-ll, a marker of autophagy. However, these phenomenon were not observed in the group pretreated with the autophagy inhibitor 3-MA or Bafilomycin A1 (BAF), suggesting that PA induced PC3 cell autophagy. In addition, we found that PA triggered ROS generation in cells, while the levels of ROS decreased in the N-acetylcysteine (NAC) co-treatment, indicating that PA-mediated autophagy was partly blocked by NAC. In summary, the autophagic cell death of human PC3 cells mediated by PA-triggered ROS generation.}, }
@article {pmid29268509, year = {2017}, author = {Wang, J and Huang, J and Wang, L and Chen, C and Yang, D and Jin, M and Bai, C and Song, Y}, title = {Urban particulate matter triggers lung inflammation via the ROS-MAPK-NF-κB signaling pathway.}, journal = {Journal of thoracic disease}, volume = {9}, number = {11}, pages = {4398-4412}, pmid = {29268509}, issn = {2072-1439}, abstract = {BACKGROUND: Particulate matter (PM) is a high risk factor for various respiratory diseases and triggers an inflammatory response in lung tissues. However, the molecular mechanism of the PM-induced inflammatory response is incompletely understood.<br><br>METHODS: Human bronchial epithelial cells (HBECs) were treated with the urban PM 1649b for assessment of the inflammatory response. The intracellular level of reactive oxygen species (ROS) was measured by flow cytometry. PM-activated signaling pathways were addressed with specific inhibitors. In vivo, the C57 mice model of PM-induced acute lung inflammation was established with intratracheal instillation of PM for 2 consecutive days. The oxidant stress in lung tissues was assessed with dihydroethidium (DHE) staining, and malondialdehyde (MDA) activity and hydrogen peroxide (H2O2) assays. The histopathologic changes in lung tissues and number of inflammatory cells in bronchoalveolar lavage fluid (BALF) were examined. Expression of pro-inflammatory cytokines in BALF was measured by ELISA.<br><br>RESULTS: PM increased the expression of interleukin (IL)-1&#x3b2;, IL-6, IL-8, matrix metalloproteinase (MMP)-9 and cyclooxygenase (COX)-2 in a dose-dependent manner. ROS generation and activation of MAPK (ERK, JNK, p38 MAPK) and NF-&#x3ba;B pathways were detected in PM-exposed HBECs. Pretreatment with N-acetylcysteine (NAC) led to the inflammatory response, ROS level and activation of the MAPK and NF-&#x3ba;B pathways to be attenuated. Blockade of ERK, JNK or p38 MAPK pathway with specific inhibitor prevented the release of pro-inflammatory cytokines and activation of the NF-&#x3ba;B pathway. Inhibition of the NF-&#x3ba;B pathway reduced the expression of pro-inflammatory cytokines. In vivo, PM exposure increased oxidant stress in lung tissues, infiltration of inflammatory cells around PM in lung tissues, the number of total cells and inflammatory cells in BALF, and the concentrations of IL-1&#x3b2;, IL-6, IL-8 and MMP-9 in BALF, all of which were reversed partially upon NAC treatment.<br><br>CONCLUSIONS: PM exposure enhanced the airway inflammatory response significantly through ROS-mediated activation of MAPK (ERK, JNK, p38 MAPK) and downstream NF-&#x3ba;B signaling pathways. Oxidative stress appeared to be the key regulator for PM-induced lung inflammation. These results suggested the molecular mechanism of lung inflammation caused by PM.}, }
@article {pmid29267216, year = {2017}, author = {Tsai, CY and Chen, CY and Chiou, YH and Shyu, HW and Lin, KH and Chou, MC and Huang, MH and Wang, YF}, title = {Epigallocatechin-3-Gallate Suppresses Human Herpesvirus 8 Replication and Induces ROS Leading to Apoptosis and Autophagy in Primary Effusion Lymphoma Cells.}, journal = {International journal of molecular sciences}, volume = {19}, number = {1}, pages = {}, pmid = {29267216}, issn = {1422-0067}, mesh = {Antineoplastic Agents/pharmacology ; Antiviral Agents/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Catechin/*analogs &amp; derivatives/pharmacology/therapeutic use ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; HEK293 Cells ; Herpesviridae Infections/complications/*drug therapy ; Herpesvirus 8, Human/*drug effects ; Humans ; Lymphoma, Primary Effusion/*drug therapy/virology ; Reactive Oxygen Species/*metabolism ; Virus Replication/*drug effects ; }, abstract = {Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to induce cell death in cancer cells. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by human herpesvirus 8 (HHV8). In this study, we examined the role of EGCG on PEL cells in cell death and HHV8 replication. We performed trypan blue exclusion assay to assess the cell viability of PEL cells, flow cytometry analysis to examine the cell cycle distribution and reactive oxygen species (ROS) generation, caspase-3 activity to assay apoptosis, acridine orange staining to determine autophagy, and immunoblotting to detect the protein levels involved in apoptosis and autophagy as well as mitogen activated protein kinases (MAPKs) activation upon EGCG treatment. The expression of the HHV8 lytic gene was determined by luciferase reporter assay and reverse transcription-PCR, and viral progeny production was determined by PCR. Results revealed that EGCG induced cell death and ROS generation in PEL cells in a dose-dependent manner. N-acetylcysteine (NAC) inhibited the EGCG-induced ROS and rescued the cell from EGCG-induced cell death. Even though EGCG induced ROS generation in PEL cells, it reduced the production of progeny virus from PEL cells without causing HHV8 reactivation. These results suggest that EGCG may represent a novel strategy for the treatment of HHV8 infection and HHV8-associated lymphomas.}, }
@article {pmid29262719, year = {2019}, author = {Marcondes-Alves, L and Fattori, V and Borghi, SM and Lourenco-Gonzalez, Y and Bussmann, AJC and Hirooka, EY and Casagrande, R and Verri, WA and Arakawa, NS}, title = {Kaurenoic acid extracted from Sphagneticola trilobata reduces acetaminophen-induced hepatotoxicity through inhibition of oxidative stress and pro-inflammatory cytokine production in mice.}, journal = {Natural product research}, volume = {33}, number = {6}, pages = {921-924}, doi = {10.1080/14786419.2017.1416372}, pmid = {29262719}, issn = {1478-6427}, mesh = {Acetaminophen/*toxicity ; Animals ; Antioxidants/metabolism ; Asteraceae/*chemistry ; Brazil ; Chemical and Drug Induced Liver Injury/*drug therapy ; Diterpenes/isolation &amp; purification/*pharmacology ; Interleukin-10/metabolism ; Interleukin-1beta/metabolism ; Interleukin-33/metabolism ; Liver/drug effects/metabolism ; Male ; Mice ; Oxidative Stress/*drug effects ; Phytochemicals/isolation &amp; purification/pharmacology ; Plant Roots/chemistry ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug that is safe at therapeutic doses. However, acetaminophen overdose can be fatal. Currently, the only treatment available is the N-acetyl cysteine. The diterpene kaurenoic acid (ent-kaur-16-en-19-oic acid, KA) is the major constituent of Sphagneticola trilobata (L.) Pruski. KA presents anti-inflammatory, anti-nociceptive and antioxidant properties. In this study, we evaluated the efficacy of KA in a model of acetaminophen-induced hepatotoxicity. KA increased, in a dose-dependent manner, the survival rate after acetaminophen overdose. KA reduced acetaminophen-induced hepatic necrosis and ALT and AST levels. KA decreased acetaminophen-induced neutrophil and macrophage recruitment, oxidative stress and the production of IL-33, TNF-α and IL-1β, alongside with normalisation of IL-10 levels in the liver. Therefore, KA showed preclinical efficacy in acetaminophen-induced hepatotoxicity and lethality.}, }
@article {pmid29262647, year = {2017}, author = {D'Sousa Costa, CO and Araujo Neto, JH and Baliza, IRS and Dias, RB and Valverde, LF and Vidal, MTA and Sales, CBS and Rocha, CAG and Moreira, DRM and Soares, MBP and Batista, AA and Bezerra, DP}, title = {Novel piplartine-containing ruthenium complexes: synthesis, cell growth inhibition, apoptosis induction and ROS production on HCT116 cells.}, journal = {Oncotarget}, volume = {8}, number = {61}, pages = {104367-104392}, pmid = {29262647}, issn = {1949-2553}, abstract = {Piplartine (piperlongumine) is a plant-derived molecule that has been receiving intense interest due to its anticancer characteristics that target the oxidative stress. In the present paper, two novel piplartine-containing ruthenium complexes [Ru(piplartine)(dppf)(bipy)](PF6)2 (1) and [Ru(piplartine)(dppb)(bipy)](PF6)2 (2) were synthesized and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes are more potent than metal-free piplartine in a panel of cancer cell lines on monolayer cultures, as well in 3D model of cancer multicellular spheroids formed from human colon carcinoma HCT116 cells. Mechanistic studies uncovered that the complexes reduced the cell growth and caused phosphatidylserine externalization, internucleosomal DNA fragmentation, caspase-3 activation and loss of the mitochondrial transmembrane potential on HCT116 cells. Moreover, the pre-treatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced the complexes-induced apoptosis, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. Treatment with the complexes also caused a marked increase in the production of reactive oxygen species (ROS), including hydrogen peroxide, superoxide anion and nitric oxide, and decreased reduced glutathione levels. Application of N-acetyl-cysteine, an antioxidant, reduced the ROS levels and apoptosis induced by the complexes, indicating activation of ROS-mediated apoptosis pathway. RNA transcripts of several genes, including gene related to the cell cycle, apoptosis and oxidative stress, were regulated under treatment. However, the complexes failed to induce DNA intercalation. In conclusion, the complexes are more potent than piplartine against different cancer cell lines and are able to induce caspase-dependent and mitochondrial intrinsic apoptosis on HCT116 cells by ROS-mediated pathway.}, }
@article {pmid29262627, year = {2017}, author = {Enríquez-Cortina, C and Bello-Monroy, O and Rosales-Cruz, P and Souza, V and Miranda, RU and Toledo-Pérez, R and Luna-López, A and Simoni-Nieves, A and Hernández-Pando, R and Gutiérrez-Ruiz, MC and Calvisi, DF and Marquardt, JU and Bucio, L and Gomez-Quiroz, LE}, title = {Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis.}, journal = {Oncotarget}, volume = {8}, number = {61}, pages = {104136-104148}, pmid = {29262627}, issn = {1949-2553}, abstract = {Primary liver cancers represent the second leading cause of cancer-related deaths worldwide. Diverse etiological factors include chronic viral hepatitis, aflatoxin and alcohol exposure as well as aberrant liver lipid overload. Cholesterol has been identified as a key inducer of metabolic impairment, oxidative stress and promoter of cellular dysfunction. The aim of this work was to address the oxidative stress-mediated DNA damage induced by cholesterol overload, and its role in the development of hepatocellular carcinoma. C57BL/6 male mice were fed with a high cholesterol diet, followed by a single dose of N-diethylnitrosamine (DEN, 10 μg/g, ip). Reactive oxygen species generation, DNA oxidation, antioxidant and DNA repair proteins were analyzed at different time points. Diet-induced cholesterol overload caused enhanced oxidative DNA damage in the liver and was associated with a decrease in key DNA repair genes as early as 7 days. Interestingly, we found a cell survival response, induced by cholesterol, judged by a decrement in Bax to Bcl2 ratio. Importantly, N-acetyl-cysteine supplementation significantly prevented DNA oxidation damage. Furthermore, at 8 months after DEN administration, tumor growth was significantly enhanced in mice under cholesterol diet in comparison to control animals. Together, these results suggest that cholesterol overload exerts an oxidative stress-mediated effects and promotes the development of liver cancer.}, }
@article {pmid29258545, year = {2017}, author = {Nance, E and Kambhampati, SP and Smith, ES and Zhang, Z and Zhang, F and Singh, S and Johnston, MV and Kannan, RM and Blue, ME and Kannan, S}, title = {Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome.}, journal = {Journal of neuroinflammation}, volume = {14}, number = {1}, pages = {252}, pmid = {29258545}, issn = {1742-2094}, support = {U54 HD079123/HD/NICHD NIH HHS/United States ; R21 NS100085/NS/NINDS NIH HHS/United States ; F32 NS010085/NS/NINDS NIH HHS/United States ; R01 EB018306/EB/NIBIB NIH HHS/United States ; S10 RR027445/RR/NCRR NIH HHS/United States ; R01 HD069562/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Brain/drug effects/*pathology ; Cytokines/genetics/metabolism ; Dendrimers/pharmacology/*therapeutic use ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/*therapeutic use ; Gene Expression Regulation/drug effects/genetics ; Glutamic Acid/metabolism ; Glutathione/metabolism ; Lipopolysaccharides/pharmacology ; Methyl-CpG-Binding Protein 2/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/*drug effects/metabolism ; Mutation/genetics ; Rett Syndrome/*drug therapy/genetics/pathology ; Tissue Distribution/drug effects/genetics ; }, abstract = {BACKGROUND: Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome.<br><br>METHODS: To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc[-]) is upregulated in Mecp2-null glia when compared to WT, the role of Xc[-] in the uptake of NAC and L-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan.<br><br>RESULTS: We demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc[-] was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc[-] for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival.<br><br>CONCLUSIONS: These results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT.}, }
@article {pmid29258061, year = {2017}, author = {Reyes, DRA and Gomes, MJ and Rosa, CM and Pagan, LU and Damatto, FC and Damatto, RL and Depra, I and Campos, DHS and Fernandez, AAH and Martinez, PF and Okoshi, K and Okoshi, MP}, title = {N-Acetylcysteine Influence on Oxidative Stress and Cardiac Remodeling in Rats During Transition from Compensated Left Ventricular Hypertrophy to Heart Failure.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {44}, number = {6}, pages = {2310-2321}, doi = {10.1159/000486115}, pmid = {29258061}, issn = {1421-9778}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Aortic Valve Stenosis/*drug therapy/metabolism/pathology ; Glutathione/metabolism ; Heart Failure/*drug therapy/metabolism/pathology ; Hypertrophy, Left Ventricular/*drug therapy/metabolism/pathology ; MAP Kinase Signaling System/drug effects ; Male ; Oxidative Stress/*drug effects ; Rats, Wistar ; }, abstract = {BACKGROUND/AIMS: To evaluate the effects of the antioxidant N-acetylcysteine (NAC) on cardiac structure and function in rats with long-term ascending aortic stenosis (AS).<br><br>METHODS: Four months after inducing AS, Wistar rats were assigned into the groups Sham, AS, and AS treated with NAC (AS-NAC) and followed for eight weeks. Cardiac structure and function were evaluated by echocardiogram. Myocardial antioxidant enzymes activity was measured by spectrophotometry and malondialdehyde serum concentration by HPLC. Gene expression of NADPH oxidase subunits NOX2, NOX4, p22 phox, and p47 phox was assessed by real time RT-PCR and protein expression of MAPK proteins by Western blot. Statistical analyzes were performed with Goodman and ANOVA or Mann-Whitney Results: NAC restored myocardial total glutathione (Sham 20.8&#xb1;3.00; AS 12.6&#xb1;2.92; AS-NAC 17.6&#xb1;2.45 nmol/g tissue; p<0.05 AS vs Sham and AS-NAC). Malondialdehyde serum concentration was lower in AS-NAC and myocardial lipid hydroperoxide was higher in AS (Sham 199&#xb1;48.1; AS 301&#xb1;36.0; AS-NAC 181&#xb1;41.3 nmol/g tissue). Glutathione peroxidase activity was lower in AS than Sham. Echocardiogram showed LV concentric hypertrophy with systolic and diastolic dysfunction before and after treatment; no differences were observed between AS-NAC and AS groups. NAC reduced p-ERK and p-JNK protein expression, attenuated myocardial fibrosis, and decreased the frequency of right ventricular hypertrophy.<br><br>CONCLUSION: N-acetylcysteine restores myocardial total glutathione, reduces systemic and myocardial oxidative stress, improves MAPK signaling, and attenuates myocardial fibrosis in aortic stenosis rats.}, }
@article {pmid29258000, year = {2018}, author = {Tran, PL and Tran, PT and Tran, HNK and Lee, S and Kim, O and Min, BS and Lee, JH}, title = {A prenylated flavonoid, 10-oxomornigrol F, exhibits anti-inflammatory effects by activating the Nrf2/heme oxygenase-1 pathway in macrophage cells.}, journal = {International immunopharmacology}, volume = {55}, number = {}, pages = {165-173}, doi = {10.1016/j.intimp.2017.12.015}, pmid = {29258000}, issn = {1878-1705}, mesh = {Animals ; Anti-Inflammatory Agents/*therapeutic use ; Flavonoids/*therapeutic use ; Heme Oxygenase-1/metabolism ; MAP Kinase Signaling System/*drug effects ; Macrophages/*drug effects/immunology ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Morus/immunology ; NF-E2-Related Factor 2/metabolism ; Prenylation ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; Sepsis/*drug therapy ; }, abstract = {Prenylated flavonoids are a unique class of naturally occurring flavonoids that have various pharmacological activities. In the present study, we investigated the anti-inflammatory effect in murine macrophages of a prenylated flavonoid, 10-oxomornigrol F (OMF), which was isolated from the twigs of Morus alba (Moraceae). OMF inhibited the lipopolysaccharide (LPS)-induced production of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 in RAW264.7 cells, as well as in mouse bone marrow-derived macrophages (BMMs). OMF also rescued LPS-induced septic mortality in ICR mice. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 was also significantly suppressed by OMF treatment in RAW264.7 cells. Treatment of RAW264.7 cells with OMF induced heme oxygenase (HO)-1 mRNA and protein expression and increased the nuclear translocation of the nuclear factor-E2-related factor 2 (Nrf2) as well as the expression of Nrf2 target genes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1). Treatment of RAW264.7 cells with OMF increased the intracellular level of reactive oxygen species (ROS) and the phosphorylation levels of p38 mitogen-activated protein kinase (MAPK); co-treatment with the antioxidant N-acetyl-cysteine (NAC) blocked this OMF-induced p38 MAPK phosphorylation. Moreover, NAC, or SB203580 (a p38 MAPK inhibitor), blocked the OMF-induced nuclear translocation of Nrf2 and HO-1 expression, suggesting that OMF induces HO-1 expression by activating Nrf2 through the p38 MAPK pathway. Consistent with the notion that the Nrf2/HO-1 pathway has anti-inflammatory properties, inhibiting HO-1 significantly abrogated the anti-inflammatory effects of OMF in LPS-stimulated RAW264.7 cells. Taken together, these findings suggest that OMF exerts its anti-inflammatory effect by activating the Nrf2/HO-1 pathway, and may be a potential Nrf2 activator to prevent or treat inflammatory diseases.}, }
@article {pmid29255249, year = {2017}, author = {Giam, B and Kuruppu, S and Chu, PY and Smith, AI and Marques, FZ and Fiedler, A and Horlock, D and Kiriazis, H and Du, XJ and Kaye, DM and Rajapakse, NW}, title = {N-Acetylcysteine Attenuates the Development of Renal Fibrosis in Transgenic Mice with Dilated Cardiomyopathy.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {17718}, pmid = {29255249}, issn = {2045-2322}, mesh = {Acetylcysteine/*metabolism/pharmacology ; Animals ; Cardio-Renal Syndrome/*physiopathology ; Cardiomyopathy, Dilated/genetics/physiopathology ; Disease Models, Animal ; Fibrosis/*prevention &amp; control ; Glomerular Filtration Rate ; Glutathione/metabolism ; Kidney/metabolism/physiopathology ; Kidney Diseases/pathology ; Kidney Glomerulus/pathology ; Male ; Mice ; Mice, Transgenic ; Myocardium/metabolism ; Nephritis/metabolism ; Oxidative Stress ; Urinary Tract/metabolism ; }, abstract = {Mechanisms underlying the renal pathology in cardiorenal syndrome (CRS) type 2 remain elusive. We hypothesised that renal glutathione deficiency is central to the development of CRS type 2. Glutathione precursor, N-acetylcysteine (NAC;40 mg/kg/day; 8 weeks) or saline were administered to transgenic mice with dilated cardiomyopathy (DCM) and wild-type (WT) controls. Cardiac structure, function and glutathione levels were assessed at the end of this protocol. Renal fibrosis, glutathione content, expression of inflammatory and fibrotic markers, and function were also evaluated. In both genotypes, NAC had minimal effect on cardiac glutathione, structure and function (P ≥ 0.20). In NAC treated DCM mice, loss of glomerular filtration rate (GFR), tubulointerstitial and glomerular fibrosis and renal oxidised glutathione levels were attenuated by 38%, 99%, 70% and 52% respectively, compared to saline treated DCM mice (P ≤ 0.01). Renal expression of PAI-1 was greater in saline treated DCM mice than in WT mice (P < 0.05). Renal PAI-1 expression was less in NAC treated DCM mice than in vehicle treated DCM mice (P = 0.03). Renal IL-10 expression was greater in the former cohort compared to the latter (P < 0.01). These data indicate that normalisation of renal oxidized glutathione levels attenuates PAI-1 expression and renal inflammation preventing loss of GFR in experimental DCM.}, }
@article {pmid29253822, year = {2018}, author = {Zhao, YL and Liu, WW and Liu, W and Lu, ZY and Xuan, DH and Zhang, X and Liu, XL and Hayashi, T and Yamato, M and Ogura, T and Fujisaki, H and Hattori, S and Tashiro, SI and Onodera, S and Ikejima, T}, title = {Phorbol ester (PMA)-treated U937 cells cultured on type I collagen-coated dish express a lower production of pro-inflammatory cytokines through lowered ROS levels in parallel with cell aggregate formation.}, journal = {International immunopharmacology}, volume = {55}, number = {}, pages = {158-164}, doi = {10.1016/j.intimp.2017.12.013}, pmid = {29253822}, issn = {1878-1705}, mesh = {Acetylcysteine/pharmacology ; Cell Aggregation ; Cell Differentiation ; Collagen Type I/*metabolism ; Cytokines/genetics/metabolism ; Gene Expression Regulation ; Humans ; Inflammation Mediators/metabolism ; Macrophages/*immunology ; Phagocytosis ; Phorbol Esters/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; U937 Cells ; }, abstract = {The present study is aimed to investigate the effect of collagen I on U937 cells, human monocyte-like histiocytic lymphoma cell line. Differentiation of U937 cells was induced by phorbol ester (PMA) treatment. The cells were cultured on the collagen I-coated plate. PMA-stimulated U937 cells formed multicellular aggregates on collagen I-coated surface, whereas PMA-unstimulated cells kept themselves away off each other. Moreover, the levels of reactive oxygen species (ROS) and productions of pro-inflammatory cytokines such as IL-1β, TNFα and PGE2, pro-inflammatory mediator, were down-regulated in differentiated U937 cells cultured on collagen I-coated dishes. However, collagen I did not influence the capacity of E. coli phagocytosis. Cell aggregation as well as the down-regulation of IL-1β, TNFα and PGE2 caused by the culture on collagen I-coated surface were suppressed by ROS donor, tert-butylhydroperoxide (tBHP). The sizes of cell aggregates became bigger in differentiated U937 cells by treatment with ROS scavengers such as N-acetylcysteine (NAC), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH). In conclusion, collagen I-coated culture induces the differentiated U937 cells to form cell aggregates and decreases the production of pro-inflammatory cytokines through down-regulating ROS generation.}, }
@article {pmid29251317, year = {2018}, author = {Li, Z and Tang, Y and Zhu, S and Li, D and Han, X and Gu, G and Xing, N and Ren, J and Guo, Z and Jiao, W and Yan, L and Xu, Z and Zhang, W}, title = {Ethanol extract of Patrinia scabiosaefolia induces the death of human renal cell carcinoma 786-O cells via SIRT-1 and mTOR signaling-mediated metabolic disruptions.}, journal = {Oncology reports}, volume = {39}, number = {2}, pages = {764-772}, doi = {10.3892/or.2017.6139}, pmid = {29251317}, issn = {1791-2431}, mesh = {Antineoplastic Agents/*pharmacology ; Calcium/metabolism ; Carcinoma, Renal Cell/drug therapy/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Ethanol/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Kidney Neoplasms/drug therapy/*metabolism ; Niacinamide/pharmacology ; Patrinia/*chemistry ; Phosphorylation/drug effects ; Plant Extracts/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sirtuin 1/*metabolism ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Recently, natural plant extracts have shown tremendous potential as novel antitumor drugs. Patrinia scabiosaefolia, a traditional prescription for inflammatory diseases, has been reported to effectively suppress various types of cancers. However, the mechanisms underlying its antitumor properties remain elusive. In the present study, we investigated the antitumor effects of an ethanol extract of Patrinia scabiosaefolia (EPS) on human renal cell carcinoma 786-O cells. After 24 h of incubation with EPS, the cell viability and colony number of 786-O cells were significantly decreased in a concentration-dependent manner as compared to the control group as determined by MTT and colony formation assays, respectively. The necrotic rate and apoptotic rate in the EPS exposure group were significantly higher than these rates noted in the control group as revealed by LDH release assay and Hoechst 33342/ PI double staining, respectively. At the concentration of 1.0 mg/ml, the necrotic and apoptotic rates reached 41.7±6.6 and 7.8±1.4%, respectively (P<0.01). However, the fluorescence intensity of intracellular calcium concentration ([Ca2+]i) was markedly elevated from 0.029±0.0007 to 0.060±0.003 (P<0.001) after the intervention of EPS. Moreover, the fluorescence intensity of intracellular ROS in the EPS exposure group was significantly higher (0.074±0.005) compared to that observed in the control group (0.033±0.001, P<0.001), which was partly attenuated by the specific antioxidant N-acetylcysteine (NAC). Furthermore, our results demonstrated that EPS significantly downregulated the expression of SIRT-1 and obviously induced the dephosphorylation of mTOR. Moreover, combined treatment with the SIRT-1 inhibitor nicotinamide and EPS was able to significantly enhance the induction of necrosis and reduction in cell viability of 786-O cells noted following treatment with EPS alone. In summary, we conclude that EPS induced the death of 786-O cells via SIRT-1 and mTOR signaling-mediated metabolic disruptions, which provide novel insight into the application of natural plant extracts for the treatment of cancers.}, }
@article {pmid29248592, year = {2018}, author = {Liu, L and Chang, X and Zhang, Y and Wu, C and Li, R and Tang, L and Zhou, Z}, title = {Fluorochloridone induces primary cultured Sertoli cells apoptosis: Involvement of ROS and intracellular calcium ions-mediated ERK1/2 activation.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {47}, number = {}, pages = {228-237}, doi = {10.1016/j.tiv.2017.12.006}, pmid = {29248592}, issn = {1879-3177}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Calcium Chelating Agents/pharmacology ; Calcium Signaling/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Endoplasmic Reticulum/drug effects/enzymology/metabolism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Herbicides/*toxicity ; Hormesis ; MAP Kinase Signaling System/*drug effects ; Male ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Processing, Post-Translational/drug effects ; Pyrrolidinones/*toxicity ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists &amp; inhibitors/metabolism ; Sertoli Cells/cytology/*drug effects ; }, abstract = {Fluorochloridone (FLC) is a widely used pyrrolidone selective herbicide and reported to induce testis injuries in male rats, but the underlying mechanism is largely unknown. In the present study, primary-cultured Sertoli cells were exposed to FLC at the concentration of 0-10.00μM to study the mechanism of FLC-induced apoptosis. The roles of ROS, intracellular calcium, endoplasmic reticulum (ER), and ERK1/2 were looked at with ROS scavenger N-acetyl-cysteine (NAC), intracellular calcium chelator BAPTA-AM, ER calcium depleting agent thapsigargin (TG), and ERK1/2 inhibitor U0126, respectively. FLC induced dose-dependent apoptosis increase as well as the elevation in levels of ROS, intracellular calcium, and ERK1/2 activation. FLC treatment led to constantly increasing apoptotic rates and ERK1/2 activation over time, while inversed-V shaped change tendencies of ROS and intracellular calcium levels were observed. FLC-induced ROS generation disrupted the intracellular calcium homeostasis by attacking the ER, and the elevated intracellular calcium levels resulted in ERK1/2 over-phosphorylation and consequently promoted Sertoli cell apoptosis. Taken together, ROS and intracellular calcium-mediated ERK1/2 activation led to FLC-induced Sertoli cell apoptosis.}, }
@article {pmid29248572, year = {2018}, author = {Xiao, C and He, P and Han, J and Tang, M and Wang, Z and Mi, Y and Liu, X}, title = {1,3-Dichloro-2-propanol evokes inflammation and apoptosis in BV-2 microglia via MAPKs and NF-κB signaling pathways mediated by reactive oxygen species.}, journal = {Toxicology letters}, volume = {284}, number = {}, pages = {103-112}, doi = {10.1016/j.toxlet.2017.12.011}, pmid = {29248572}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cell Line ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Food Contamination ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Microglia/*drug effects/immunology/pathology ; Mitogen-Activated Protein Kinases/*metabolism ; NF-kappa B/*metabolism ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; alpha-Chlorohydrin/*analogs &amp; derivatives/toxicity ; }, abstract = {1,3-dichloro-2-propanol (1,3-DCP) is a widely concerned food processing contaminant which has been investigated for decades. While the neurotoxicity of 1,3-DCP and related mechanisms are still elusive. Herein, the effect of 1,3-DCP on neurotoxicity was investigated using BV-2 microglia cells. 1,3-DCP significantly decreased cell viability from 78.6% to 59.2% at doses between 2 and 20 mM. AO/EB and JC-1 staining indicated that 1,3-DCP induced apoptosis by means of the decrease of mitochondrial membrane potential. Meanwhile, western blot showed that 1,3-DCP stimulated inflammation of BV-2 cells through phosphorylation of MAPKs and activation of NF-κB pathways mediated by reactive oxygen species (ROS). Furthermore, the degree of inflammation and apoptosis has eased through MAPKs and NF-κB pathways with cells pretreated by N-acetylcysteine (NAC). Overall, these results presented here suggested that 1,3-DCP has neurotoxic effect on BV-2 microglia mainly via MAPKs and NF-κB pathways mediated by ROS.}, }
@article {pmid29248134, year = {2017}, author = {Monti, D and Sotgia, F and Whitaker-Menezes, D and Tuluc, M and Birbe, R and Berger, A and Lazar, M and Cotzia, P and Draganova-Tacheva, R and Lin, Z and Domingo-Vidal, M and Newberg, A and Lisanti, MP and Martinez-Outschoorn, U}, title = {Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer.}, journal = {Seminars in oncology}, volume = {44}, number = {3}, pages = {226-232}, pmid = {29248134}, issn = {1532-8708}, support = {K08 CA175193/CA/NCI NIH HHS/United States ; P30 CA056036/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Apoptosis ; Breast Neoplasms/*drug therapy/metabolism/pathology ; Carcinoma, Ductal, Breast/*drug therapy/metabolism/pathology ; Carcinoma, Intraductal, Noninfiltrating/*drug therapy/metabolism/pathology ; Carcinoma, Papillary/drug therapy/metabolism/pathology ; Caveolin 1/metabolism ; Cell Proliferation ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Ki-67 Antigen/metabolism ; *Mastectomy ; Middle Aged ; Monocarboxylic Acid Transporters/metabolism ; Muscle Proteins/metabolism ; Neoadjuvant Therapy ; Neoplasm Staging ; Pilot Projects ; Stromal Cells/metabolism ; Treatment Outcome ; Tumor Microenvironment ; }, abstract = {BACKGROUND: High oxidative stress as defined by hydroxyl and peroxyl activity is often found in the stroma of human breast cancers. Oxidative stress induces stromal catabolism, which promotes cancer aggressiveness. Stromal cells exposed to oxidative stress release catabolites such as lactate, which are up-taken by cancer cells to support mitochondrial oxidative phosphorylation. The transfer of catabolites between stromal and cancer cells leads to metabolic heterogeneity between these cells and increased cancer cell proliferation and reduced apoptosis in preclinical models. N-Acetylcysteine (NAC) is an antioxidant that reduces oxidative stress and reverses stromal catabolism and stromal-carcinoma cell metabolic heterogeneity, resulting in reduced proliferation and increased apoptosis of cancer cells in experimental models of breast cancer. The purpose of this clinical trial was to determine if NAC could reduce markers of stromal-cancer metabolic heterogeneity and markers of cancer cell aggressiveness in human breast cancer.<br><br>METHODS: Subjects with newly diagnosed stage 0 and I breast cancer who were not going to receive neoadjuvant therapy prior to surgical resection were treated with NAC before definitive surgery to assess intra-tumoral metabolic markers. NAC was administered once a week intravenously at a dose of 150 mg/kg and 600 mg twice daily orally on the days not receiving intravenous NAC. Histochemistry for the stromal metabolic markers monocarboxylate transporter 4 (MCT4) and caveolin-1 (CAV1) and the Ki67 proliferation assay and TUNEL apoptosis assay in carcinoma cells were performed in pre- and post-NAC specimens.<br><br>RESULTS: The range of days on NAC was 14-27 and the mean was 19 days. Post-treatment biopsies showed significant decrease in stromal MCT4 and reduced Ki67 in carcinoma cells. NAC did not significantly change stromal CAV1 and carcinoma TUNEL staining. NAC was well tolerated.<br><br>CONCLUSIONS: NAC as a single agent reduces MCT4 stromal expression, which is a marker of glycolysis in breast cancer with reduced carcinoma cell proliferation. This study suggests that modulating metabolism in the tumor microenvironment has the potential to impact breast cancer proliferation.}, }
@article {pmid29247182, year = {2017}, author = {Ahamed, M and Khan, MAM and Akhtar, MJ and Alhadlaq, HA and Alshamsan, A}, title = {Ag-doping regulates the cytotoxicity of TiO2 nanoparticles via oxidative stress in human cancer cells.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {17662}, pmid = {29247182}, issn = {2045-2322}, mesh = {A549 Cells ; Animals ; Apoptosis/drug effects/radiation effects ; Hep G2 Cells ; Hepatocytes/drug effects/physiology/radiation effects ; Humans ; MCF-7 Cells ; Metal Nanoparticles/chemistry/*therapeutic use ; Neoplasms/*radiotherapy ; Oxidative Stress ; *Photochemotherapy ; Photosensitivity Disorders ; Rats ; Reactive Oxygen Species/metabolism ; Silver/chemistry/*therapeutic use ; Titanium/chemistry/*therapeutic use ; Ultraviolet Rays ; }, abstract = {We investigated the anticancer potential of Ag-doped (0.5-5%) anatase TiO2 NPs. Characterization study showed that dopant Ag was well-distributed on the surface of host TiO2 NPs. Size (15 nm to 9 nm) and band gap energy (3.32 eV to 3.15 eV) of TiO2 NPs were decreases with increasing the concentration of Ag dopant. Biological studies demonstrated that Ag-doped TiO2 NP-induced cytotoxicity and apoptosis in human liver cancer (HepG2) cells. The toxic intensity of TiO2 NPs was increases with increasing the amount of Ag-doping. The Ag-doped TiO2 NPs further found to provoke reactive oxygen species (ROS) generation and antioxidants depletion. Toxicity induced by Ag-doped TiO2 NPs in HepG2 cells was efficiently abrogated by antioxidant N-acetyl-cysteine (ROS scavenger). We also found that Ag-doped TiO2 NPs induced cytotoxicity and oxidative stress in human lung (A549) and breast (MCF-7) cancer cells. Interestingly, Ag-doped TiO2 NPs did not cause much toxicity to normal cells such as primary rat hepatocytes and human lung fibroblasts. Overall, we found that Ag-doped TiO2 NPs have potential to selectively kill cancer cells while sparing normal cells. This study warranted further research on anticancer potential of Ag-doped TiO2 NPs in various types of cancer cells and in vivo models.}, }
@article {pmid29243793, year = {2017}, author = {Vanella, L and Li Volti, G and Distefano, A and Raffaele, M and Zingales, V and Avola, R and Tibullo, D and Barbagallo, I}, title = {A new antioxidant formulation reduces the apoptotic and damaging effect of cigarette smoke extract on human bronchial epithelial cells.}, journal = {European review for medical and pharmacological sciences}, volume = {21}, number = {23}, pages = {5478-5484}, doi = {10.26355/eurrev_201712_13938}, pmid = {29243793}, issn = {2284-0729}, mesh = {Acetylcysteine/chemistry ; Antioxidants/chemistry/*pharmacology ; Apoptosis/*drug effects ; Bronchi/cytology ; Cell Line ; Curcumin/chemistry ; Cytokines/genetics/metabolism ; Drug Compounding ; Epithelial Cells/drug effects/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Humans ; NF-E2-Related Factor 2/metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; Oxidative Stress/drug effects ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Smoke/*analysis ; Nicotiana/chemistry ; }, abstract = {OBJECTIVE: In this study we evaluated the possible protective effect of an antioxidant formulation containing microfiltered milk derived polypeptides, Curcumin, Vitamin B2, Carnitine and N-Acetyl-cysteine (NAC) in an in vitro model of chronic obstructive pulmonary disease (COPD).<br><br>MATERIALS AND METHODS: Human bronchial epithelial cells (16HBE) were used in this study. Cells were treated for 24 h in the presence or absence of 10% of cigarette smoke extract (CSE) and in the presence or absence of antioxidant formulation. We evaluated cell viability by MTT assay, reactive oxygen species by flow cytometer and quantitative analysis of gene expression by Real-time PCR.<br><br>RESULTS: The data obtained showed a significant increase of cell viability in CSE-exposed cells and a significant reduction of reactive oxygen species (ROS) production compared to cells treated with only CSE. The antioxidant effects of formulation were confirmed by a decrease of inflammatory cytokines genes IL-1&#x3b2;, IL-6, TNF&#x3b1;, nitric oxide synthase gene (NOS2) and through an induction of antioxidant genes such as heme oxygenase 1 (HO-1), nuclear transcription factor erythroid 2 (NRF2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1&#x3b1;).<br><br>CONCLUSIONS: The results suggest that antioxidants combination plays a protective role on oxidative stress and inflammation, in an in vitro model of COPD, activating key genes in response to oxidative stress and decreasing the cytokines responsible for the inflammatory pathways.}, }
@article {pmid29241082, year = {2018}, author = {Schulte, MHJ and Wiers, RW and Boendermaker, WJ and Goudriaan, AE and van den Brink, W and van Deursen, DS and Friese, M and Brede, E and Waters, AJ}, title = {The effect of N-acetylcysteine and working memory training on cocaine use, craving and inhibition in regular cocaine users: correspondence of lab assessments and Ecological Momentary Assessment.}, journal = {Addictive behaviors}, volume = {79}, number = {}, pages = {24-31}, doi = {10.1016/j.addbeh.2017.11.044}, pmid = {29241082}, issn = {1873-6327}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Cocaine-Related Disorders/psychology/*rehabilitation ; *Craving ; Ecological Momentary Assessment ; Free Radical Scavengers/*therapeutic use ; Humans ; *Inhibition, Psychological ; *Learning ; Male ; *Memory, Short-Term ; Middle Aged ; Stroop Test ; }, abstract = {INTRODUCTION: Effective treatment for cocaine use disorder should dampen hypersensitive cue-induced motivational processes and/or strengthen executive control. Using a randomized, double-blind, placebo-controlled intervention, the primary aim of this study was to investigate the effect of N-Acetylcysteine (NAC) and working memory (WM)-training to reduce cocaine use and craving and to improve inhibition assessed in the laboratory and during Ecological Momentary Assessment (EMA). The second aim was to examine correspondence between laboratory and EMA data.<br><br>METHODS: Twenty-four of 38 cocaine-using men completed a 25-day intervention with 2400mg/day NAC or placebo and WM-training as well as two lab-visits assessing cocaine use, craving and inhibition (Stop Signal task). Additionally, cocaine use, craving and cognition (Stroop task) were assessed using EMA during treatment, with 26 participants completing 819 assessments.<br><br>RESULTS: Cocaine problems according to the Drug Use Disorder Identification Test (DUDIT) decreased more after NAC than after placebo, and the proportion of cocaine-positive urines at lab-visit 2 was lower in the NAC group. No NAC effects were found on craving. For cocaine use and craving, results from the lab data were generally similar to EMA results. NAC also showed some effects on cognitive control: improved inhibition assessed with the Stop Signal task in the lab, and decreased classic Stroop performance during EMA. There were no significant effects of number of completed WM-training sessions.<br><br>CONCLUSIONS: Overall this study revealed mixed findings regarding the treatment of cocaine use disorders with NAC and WM-training. The effect of NAC on inhibition should be further investigated.}, }
@article {pmid29237267, year = {2018}, author = {Huang, CH and Huang, CY and Huang, MH}, title = {Unsaturated Squalene Content in Emulsion Vaccine Adjuvants Plays a Crucial Role in ROS-Mediated Antigen Uptake and Cellular Immunity.}, journal = {Molecular pharmaceutics}, volume = {15}, number = {2}, pages = {420-429}, doi = {10.1021/acs.molpharmaceut.7b00800}, pmid = {29237267}, issn = {1543-8392}, mesh = {Adjuvants, Immunologic/chemistry/*pharmacology ; Animals ; Antigens/immunology/metabolism ; Cells, Cultured ; Dendritic Cells/drug effects/immunology ; Drug Design ; Emulsions ; Female ; Immunity, Cellular/*drug effects ; Immunogenicity, Vaccine ; Mice ; Mice, Inbred C57BL ; Primary Cell Culture ; Reactive Oxygen Species/immunology/*metabolism ; Squalene/chemistry/*pharmacology ; Vaccines/administration &amp; dosage/chemistry/*immunology ; }, abstract = {Emulsion-based adjuvants have been demonstrated to be an effective tool in increasing vaccine efficacy. Here, we aimed to launch a mechanistic study on how emulsion adjuvants interact with immune cells and to elucidate the roles of the core oil in vaccine immunogenicity. Our results showed that treatment of dendritic cells (DCs) and splenocytes with a squalene-based emulsion (referred as SqE) induced reactive oxidative species (ROS) production and resulted in an increase in apoptotic and necrotic cells in a concentration- and time-dependent manner. Furthermore, DCs cocultured with cellular debris of SqE-pretreated splenocytes resulted in a higher level of ovalbumin (OVA) antigen uptake by DCs than those cocultured with untreated splenocytes. Interestingly, the potency was rather attenuated when splenocytes were pretreated with N-acetyl-cysteine, an antioxidant. Notably, SqE possesses a high impact on eliciting ROS-mediated antigen uptake compared with a squalane-based emulsion (SqA). Concordantly, immunogenicity studies have shown that SqE is better able than SqA to activate antigen-presenting cells, and to enhance antigen-specific T-cell immunity. Taken together, our results show that unsaturated squalene oil cored within emulsions plays a crucial role in ROS-mediated antigen uptake and cellular immunity, providing a basis for the design and development of vaccine adjuvant.}, }
@article {pmid29236922, year = {2018}, author = {Herrmann, AP and Andrejew, R and Benvenutti, R and Gama, CS and Elisabetsky, E}, title = {Effects of N-acetylcysteine on amphetamine-induced sensitization in mice.}, journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)}, volume = {40}, number = {2}, pages = {169-173}, pmid = {29236922}, issn = {1809-452X}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Amphetamine/administration &amp; dosage/*pharmacology ; Animals ; Behavior, Animal/*drug effects ; Central Nervous System Stimulants/administration &amp; dosage/*pharmacology ; Disease Models, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity/*drug effects ; Schizophrenia/*drug therapy ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice.<br><br>METHODS: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed.<br><br>RESULTS: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption.<br><br>CONCLUSION: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification.}, }
@article {pmid29234086, year = {2017}, author = {Costa, F and Sousa, DM and Parreira, P and Lamghari, M and Gomes, P and Martins, MCL}, title = {N-acetylcysteine-functionalized coating avoids bacterial adhesion and biofilm formation.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {17374}, pmid = {29234086}, issn = {2045-2322}, mesh = {Acetylcysteine/*chemistry/pharmacology ; Bacterial Adhesion/*drug effects ; Biofilms/*drug effects ; Chitosan/chemistry ; *Coated Materials, Biocompatible ; Materials Testing ; Methicillin-Resistant Staphylococcus aureus/*drug effects/physiology ; Surface Properties ; }, abstract = {N-acetyl cysteine (NAC) is an FDA-approved drug clinically applied on a broad range of pathologies. Further research has been conducted with this drug to benefit from its antimicrobial activity potential. However, NAC has a very short half-life and therefore strategies that accomplish high local concentrations would be beneficial. In this study, covalent immobilization of NAC was performed, in order to obtain long-lasting high local concentration of the drug onto a chitosan(Ch)-derived implant-related coating. For the development of NAC-functionalized Ch films, water-based carbodiimide chemistry was applied to avoid the use of toxic organic solvents. Here we report the optimization steps performed to immobilize NAC onto the surface of pre-prepared Ch coatings, to ensure full exposure of NAC. Surface characterization using ellipsometry, water contact angle measurements and X-ray photoelectron spectroscopy (XPS), demonstrated the success of NAC immobilization at 4 mg/mL. Quartz crystal microbalance with dissipation (QCM-D) demonstrated that surface immobilized NAC decreases protein adsorption to Ch coatings. Biological studies confirmed that immobilized NAC4 avoids methicillin-resistant Staphylococcus aureus adhesion to Ch coating, impairing biofilm formation, without inducing cytotoxic effects. This is particularly interesting towards further developments as a prevention coating.}, }
@article {pmid29233792, year = {2018}, author = {Paschalis, V and Theodorou, AA and Margaritelis, NV and Kyparos, A and Nikolaidis, MG}, title = {N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione.}, journal = {Free radical biology &amp; medicine}, volume = {115}, number = {}, pages = {288-297}, doi = {10.1016/j.freeradbiomed.2017.12.007}, pmid = {29233792}, issn = {1873-4596}, mesh = {Acetylcysteine/administration &amp; dosage ; Adolescent ; Adult ; Dietary Supplements ; Double-Blind Method ; Erythrocytes/*physiology ; Exercise/*physiology ; F2-Isoprostanes/metabolism ; Glutathione/*metabolism ; Humans ; Male ; Oxidation-Reduction ; *Oxidative Stress ; *Physical Functional Performance ; Placebos ; Young Adult ; }, abstract = {Most of the evidence indicates that chronic antioxidant supplementation induces negative effects in healthy individuals. However, it is currently unknown whether specific redox deficiencies exist and whether targeted antioxidant interventions in deficient individuals can induce positive effects. We hypothesized that the effectiveness of antioxidant supplements to decrease oxidative stress and promote exercise performance depends on the redox status of the individuals that receive the antioxidant treatment. To this aim, we investigated whether N-acetylcysteine (NAC) supplementation would enhance exercise performance by increasing glutathione concentration and by reducing oxidative stress only in individuals with low resting levels of glutathione. We screened 100 individuals for glutathione levels and formed three groups with low, moderate and high levels (N = 36, 12 per group). After by-passing the regression to the mean artifact, by performing a second glutathione measurement, the individuals were supplemented with NAC (2 × 600mg, twice daily, for 30 days) or placebo using a double-blind cross-over design. We performed three whole-body performance tests (VO2max, time trial and Wingate), measured two systemic oxidative stress biomarkers (F2-isoprostanes and protein carbonyls) and assessed glutathione-dependent redox metabolism in erythrocytes (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase and NADPH). The low glutathione group improved after NAC supplementation in VO2max, time trial and Wingate by 13.6%, 15.4% and 11.4%, respectively. Thirty days of NAC supplementation were sufficient to restore baseline glutathione concentration, reduce systemic oxidative stress and improve erythrocyte glutathione metabolism in the low glutathione group. On the contrary, the 30-day supplementation period did not affect performance and redox state of the moderate and high glutathione groups, although few both beneficial and detrimental effects in performance were observed. In conclusion, individuals with low glutathione levels were linked with decreased physical performance, increased oxidative stress and impaired redox metabolism of erythrocytes. NAC supplementation restored both performance and redox homeostasis.}, }
@article {pmid29233052, year = {2019}, author = {McGinn, KA and Weigartz, K and Lintner, A and Scalese, MJ and Kahn, SA}, title = {Nebulized Heparin With N-Acetylcysteine and Albuterol Reduces Duration of Mechanical Ventilation in Patients With Inhalation Injury.}, journal = {Journal of pharmacy practice}, volume = {32}, number = {2}, pages = {163-166}, doi = {10.1177/0897190017747143}, pmid = {29233052}, issn = {1531-1937}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Adult ; Aged ; Albuterol/*administration &amp; dosage ; Anticoagulants ; Cohort Studies ; Female ; Heparin/*administration &amp; dosage ; Humans ; Intensive Care Units ; Male ; Middle Aged ; Nebulizers and Vaporizers ; Respiration, Artificial/*methods ; Retrospective Studies ; Smoke Inhalation Injury/drug therapy/*therapy ; }, abstract = {OBJECTIVE: Nebulized heparin has been proposed to improve pulmonary function in patients with inhalation injuries. The purpose of this study was to evaluate the impact of nebulized heparin with N-acetylcysteine (NAC) and albuterol on the duration of mechanical ventilation in burn patients.<br><br>METHODS: This is a retrospective study evaluating mechanically ventilated adult patients admitted to a regional burn center with inhalation injury. Outcomes were compared between patients who were prescribed a combination of nebulized heparin with NAC and albuterol versus similar patients who did not.<br><br>RESULTS: A total of 48 patients met inclusion criteria (heparin n = 22; nonheparin n = 26). Patients in the nonheparin group had higher percentage of total body surface area (TBSA) burned (29.00 [5.75-51.88] vs 5.25 [0.50-13.25] %TBSA; P = .009), longer duration of mechanical ventilation (6.50 [2.75-17.00] vs 3.00 [1.00-8.25] days; P = .022), and longer intensive care unit length of stay (LOS) (3.00 [3.00-28.75] vs 5.50 days [2.00-11.25]; P = .033). Upon regression, use of heparin was the only variable associated with reducing the duration of mechanical ventilation (P = .039).<br><br>CONCLUSION: Nebulized heparin in combination with NAC and albuterol was associated with a significant reduction in the duration of mechanical ventilation.}, }
@article {pmid29230270, year = {2017}, author = {Kong, X and Lu, AL and Yao, XM and Hua, Q and Li, XY and Qin, L and Zhang, HM and Meng, GX and Su, Q}, title = {Activation of NLRP3 Inflammasome by Advanced Glycation End Products Promotes Pancreatic Islet Damage.}, journal = {Oxidative medicine and cellular longevity}, volume = {2017}, number = {}, pages = {9692546}, pmid = {29230270}, issn = {1942-0994}, mesh = {Animals ; Cell Death/drug effects/physiology ; Glycation End Products, Advanced/*metabolism/pharmacology ; Humans ; Inflammasomes/*metabolism ; Islets of Langerhans/drug effects/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; }, abstract = {Accumulation of advanced glycation end products (AGEs) contributes to ageing and age-related diseases, especially type 2 diabetes. The NLRP3 inflammasome, as a vital component of the innate immune system, is implicated in the pathogenesis of type 2 diabetes. However, the role of the NLRP3 inflammasome in AGE-induced pancreatic islet damage remains largely unclear. Results showed that administration of AGEs (120 mg/kg for 6 weeks) in C57BL/6J mice induced an abnormal response to glucose (as measured by glucose tolerance and insulin release), pancreatic β-cell ultrastructural lesion, and cell death. These effects were associated with an excessive superoxide anion level, significant increased protein expression levels for NADPH oxidase 2 (NOX2), thioredoxin-interacting protein (TXNIP), NLRP3, and cleaved IL-1β, enhanced caspase-1 activity, and a significant increase in the levels of TXNIP-NLRP3 protein interaction. Ablation of the NLRP3 inflammasome or treatment with antioxidant N-acetyl-cysteine (NAC) clearly ameliorated these effects. In conclusion, our results reveal a possible mechanism for AGE-induced pancreatic islet damage upon NLRP3 inflammasome activation.}, }
@article {pmid29229551, year = {2018}, author = {Nuvoli, B and Camera, E and Mastrofrancesco, A and Briganti, S and Galati, R}, title = {Modulation of reactive oxygen species via ERK and STAT3 dependent signalling are involved in the response of mesothelioma cells to exemestane.}, journal = {Free radical biology &amp; medicine}, volume = {115}, number = {}, pages = {266-277}, doi = {10.1016/j.freeradbiomed.2017.12.008}, pmid = {29229551}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Androstadienes/*pharmacology ; Antineoplastic Agents/*pharmacology ; Aromatase Inhibitors/*pharmacology ; Asbestos/adverse effects ; Cell Death ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclic AMP/metabolism ; Environmental Exposure/adverse effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Mesothelioma/*drug therapy ; Oxidative Stress ; Pleural Neoplasms/*drug therapy ; Reactive Oxygen Species/metabolism ; Receptors, Estrogen ; Receptors, G-Protein-Coupled ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Treatment Outcome ; }, abstract = {Pleural mesothelioma is a deadly form of cancer. The prognosis is extremely poor due to the limited treatment modalities. Uptake of asbestos fibres, the leading cause of mesothelioma, lead to the accumulation of reactive-oxygen-species (ROS). Interestingly, increasing ROS production by using ROS-generating drugs may offer a strategy to selectively trigger cell death. Exemestane, an aromatase inhibitor, has previously shown anti-tumor properties in mesothelioma preclinical models suggesting a role of G protein-coupled receptor 30 (GPR30) in the drug response. As exemestane, in addition to blocking estrogen biosynthesis, generates ROS that are able to arrest the growth of breast cancer, we explored the role of ROS, antioxidant defense system, and ROS-induced signalling pathways in mesothelioma cells during exemestane response. Here we report that exemestane treatment reduced cell proliferation with an increase in ROS production and reduction of cyclic adenosine monophosphate (cAMP) levels in MSTO-H211, Ist-Mes1, Ist-Mes2 and MPP89 exemestane-sensitive mesothelioma cell lines, but not in NCI-H2452 exemestane-insensitive mesothelioma cells. Exemestane induced a significant antioxidant response in NCI-H2452 cells, as highlighted by an increase in γ-glutamylcysteine levels, catalase (Cat), superoxide-dismutase and (SOD) and glutathione-peroxidase (GSH-Px) activity and nuclear factor E2-related factor 2 (Nrf2) activation, responsible for drug insensitivity. Conversely, exemestane elevated ROS levels along with increased ERK phosphorylation and a reduction of p-STA3 in exemestane-sensitive mesothelioma cells. ROS generation was the crucial event of exemestane action because ROS inhibitor N-acetyl-L-cysteine (NAC) abrogated p-ERK and p-STAT3 modulation and cellular death. Exemestane also modulates ERK and STAT3 signalling via GPR30. Results indicate an essential role of ROS in the antiproliferative action of exemestane in mesothelioma cells. It is likely that the additional oxidative insults induced by exemestane results in the lethal effects of mesothelioma cells by increasing ROS production. As such, manipulating ROS levels with exemestane seems to be a feasible strategy to selectively kill mesothelioma cells with less toxicity to normal cells by regulating ERK and STAT3 activity.}, }
@article {pmid29229321, year = {2018}, author = {Groom, KM and David, AL}, title = {The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction.}, journal = {American journal of obstetrics and gynecology}, volume = {218}, number = {2S}, pages = {S829-S840}, doi = {10.1016/j.ajog.2017.11.565}, pmid = {29229321}, issn = {1097-6868}, mesh = {Anticoagulants/*therapeutic use ; Aspirin/*therapeutic use ; Female ; Fetal Growth Retardation/drug therapy/*prevention &amp; control ; Genetic Therapy ; Heparin/*therapeutic use ; Heparin, Low-Molecular-Weight/therapeutic use ; Humans ; Phosphodiesterase 5 Inhibitors/*therapeutic use ; Placental Insufficiency ; Placentation ; Platelet Aggregation Inhibitors/*therapeutic use ; Pregnancy ; Vascular Endothelial Growth Factor A/genetics ; }, abstract = {Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta-mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4-9.2); use of low-molecular-weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction consortium. Other targeting approaches include nanoparticles and microRNAs to deliver drugs locally to the uterine arterial endothelium or trophoblast. In vitro and in vivo studies and animal models have demonstrated effects of nitric oxide donors, dietary nitrate, hydrogen sulphide donors, statins, and proton pump inhibitors on maternal blood pressure, uteroplacental resistance indices, and angiogenic/antiangiogenic factors. Data from human pregnancies and, in particular, pregnancies with fetal growth restriction remain very limited. Early research into melatonin, creatine, and N-acetyl cysteine supplementation in pregnancy suggests they may have potential as neuro- and cardioprotective agents in fetal growth restriction.}, }
@article {pmid29228057, year = {2017}, author = {Gao, X and Lampraki, EM and Al-Khalidi, S and Qureshi, MA and Desai, R and Wilson, JB}, title = {N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation.}, journal = {PloS one}, volume = {12}, number = {12}, pages = {e0189167}, pmid = {29228057}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chronic Disease ; Herpesvirus 4, Human/*physiology ; Inflammation/*physiopathology ; Mice ; Mice, Transgenic ; Viral Matrix Proteins/*physiology ; }, abstract = {Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body's natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure therapies for chronic inflammation.}, }
@article {pmid29227181, year = {2018}, author = {Jaramillo, IC and Sturrock, A and Ghiassi, H and Woller, DJ and Deering-Rice, CE and Lighty, JS and Paine, R and Reilly, C and Kelly, KE}, title = {Effects of fuel components and combustion particle physicochemical properties on toxicological responses of lung cells.}, journal = {Journal of environmental science and health. Part A, Toxic/hazardous substances &amp; environmental engineering}, volume = {53}, number = {4}, pages = {295-309}, pmid = {29227181}, issn = {1532-4117}, support = {I01 BX001777/BX/BLRD VA/United States ; K25 ES027504/ES/NIEHS NIH HHS/United States ; R01 ES017431/ES/NIEHS NIH HHS/United States ; R01 ES027015/ES/NIEHS NIH HHS/United States ; }, mesh = {Air Pollutants/*toxicity ; Biofuels/*toxicity ; Cell Line ; Cell Survival/drug effects ; Cytochrome P-450 CYP1A1/biosynthesis ; Cytochrome P-450 CYP1B1/biosynthesis ; Humans ; Interleukin-8/metabolism ; Lung/*drug effects/immunology/metabolism ; Oxidative Stress/drug effects ; Particle Size ; Particulate Matter/*toxicity ; Polycyclic Aromatic Hydrocarbons/*toxicity ; TRPA1 Cation Channel/metabolism ; Vehicle Emissions/*toxicity ; }, abstract = {The physicochemical properties of combustion particles that promote lung toxicity are not fully understood, hindered by the fact that combustion particles vary based on the fuel and combustion conditions. Real-world combustion-particle properties also continually change as new fuels are implemented, engines age, and engine technologies evolve. This work used laboratory-generated particles produced under controlled combustion conditions in an effort to understand the relationship between different particle properties and the activation of established toxicological outcomes in human lung cells (H441 and THP-1). Particles were generated from controlled combustion of two simple biofuel/diesel surrogates (methyl decanoate and dodecane/biofuel-blended diesel (BD), and butanol and dodecane/alcohol-blended diesel (AD)) and compared to a widely studied reference diesel (RD) particle (NIST SRM2975/RD). BD, AD, and RD particles exhibited differences in size, surface area, extractable chemical mass, and the content of individual polycyclic aromatic hydrocarbons (PAHs). Some of these differences were directly associated with different effects on biological responses. BD particles had the greatest surface area, amount of extractable material, and oxidizing potential. These particles and extracts induced cytochrome P450 1A1 and 1B1 enzyme mRNA in lung cells. AD particles and extracts had the greatest total PAH content and also caused CYP1A1 and 1B1 mRNA induction. The RD extract contained the highest relative concentration of 2-ring PAHs and stimulated the greatest level of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNFα) cytokine secretion. Finally, AD and RD were more potent activators of TRPA1 than BD, and while neither the TRPA1 antagonist HC-030031 nor the antioxidant N-acetylcysteine (NAC) affected CYP1A1 or 1B1 mRNA induction, both inhibitors reduced IL-8 secretion and mRNA induction. These results highlight that differences in fuel and combustion conditions affect the physicochemical properties of particles, and these differences, in turn, affect commonly studied biological/toxicological responses.}, }
@article {pmid29225138, year = {2018}, author = {Jeong, M and Kim, HM and Ahn, JH and Lee, KT and Jang, DS and Choi, JH}, title = {9-Hydroxycanthin-6-one isolated from stem bark of Ailanthus altissima induces ovarian cancer cell apoptosis and inhibits the activation of tumor-associated macrophages.}, journal = {Chemico-biological interactions}, volume = {280}, number = {}, pages = {99-108}, doi = {10.1016/j.cbi.2017.12.011}, pmid = {29225138}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Ailanthus/*chemistry/metabolism ; Antineoplastic Agents, Phytogenic/chemistry/isolation &amp; purification/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase Inhibitors/pharmacology ; Caspases/chemistry/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Chemokines/genetics/metabolism ; Female ; Humans ; Indole Alkaloids/chemistry/isolation &amp; purification/*pharmacology ; Macrophages/cytology/drug effects/*metabolism ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Oligopeptides/pharmacology ; Ovarian Neoplasms/metabolism/pathology ; Plant Bark/chemistry/metabolism ; Reactive Oxygen Species/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {The stem bark of Ailanthus altissima is used in traditional medicine in Asia to treat a variety of diseases, including cancer. The aim of this study was to identify compounds with tumoricidal activity from A. altissima stem bark and to investigate their mechanisms of action. Among the 13 compounds isolated from the ethyl acetate fraction of A. altissima stem bark, the β-carboline alkaloid 9-hydroxycanthin-6-one had potent cytotoxicity in all three ovarian cancer cell types examined. 9-Hydroxycanthin-6-one induced apoptosis through the activation of caspases-3, -8, and -9. 9-Hydroxycanthin-6-one increased the intracellular levels of reactive oxygen species (ROS), and pre-treatment with the antioxidant N-acetyl-l-cysteine (NAC) attenuated the pro-apoptotic activity of 9-hydroxycanthin-6-one. Additionally, 9-hydroxycanthin-6-one was found to decrease the expressions of MCP-1 and RANTES, major determinants of macrophage recruitment at tumor sites, in ovarian cancer cells. Treatment with 9-hydroxycanthin-6-one inhibited the levels of M2 phenotype markers and some cancer-promoting factors, such as MMP-2, MMP-9, and VEGF, in macrophages educated in ovarian cancer conditioned medium. Taken together, these data suggest that 9-hydroxycanthin-6-one isolated from A. altissima stem bark induces apoptosis in human ovarian cancer cells through the caspase- and ROS-dependent pathways and inhibits the activation of tumor-associated macrophages.}, }
@article {pmid29223047, year = {2018}, author = {Upadhyaya, P and Zarth, AT and Fujioka, N and Fritz, VA and Hecht, SS}, title = {Identification and analysis of a mercapturic acid conjugate of indole-3-methyl isothiocyanate in the urine of humans who consumed cruciferous vegetables.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1072}, number = {}, pages = {341-346}, pmid = {29223047}, issn = {1873-376X}, support = {R01 CA081301/CA/NCI NIH HHS/United States ; R37 CA081301/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*urine ; Adolescent ; Adult ; *Brassica ; Female ; Glucosinolates ; Humans ; Indoles/chemistry/*urine ; Isocyanates/chemistry/*urine ; Male ; Middle Aged ; *Vegetables ; Young Adult ; }, abstract = {Glucobrassicin, a quantitatively significant constituent of Brassica vegetables, gives rise to indole-3-carbinol (I3C) and its dimer di-indolylmethane (DIM) when the vegetables are chewed. I3C and DIM have been extensively studied with respect to their anti-carcinogenic properties. However, the presumed intermediate isothiocyanate in their formation, indole-3-methyl isothiocyanate (IMITC), has to our knowledge never been observed, despite the fact that isothiocyanates derived from cruciferous vegetables are known to have anti-carcinogenic properties. Therefore, we investigated the formation and presence in human urine of IMITC by analyzing for its N-acetylcysteine conjugate, IMITC-NAC, in order to gain a more complete understanding of the biochemical pathways leading to formation of I3C and DIM upon consumption of vegetables rich in glucobrassicin. Standard IMITC-NAC was synthesized and its structure confirmed by NMR and MS. IMITC-NAC was identified in extracts of Brussels sprouts chopped in the presence of N-acetylcysteine. An LC-ESI-MS/MS-SRM method for analysis of IMITC-NAC, with [[13]C,[15]N]IMITC-NAC as internal standard, was developed and validated. Then, ten subjects (7 females) consumed a salad of Brussels sprouts and cabbage (containing 100-500μmol glucobrassicin) once daily for 3days. Urine was collected at intervals up to 24h after vegetable consumption. Levels of IMITC-NAC in the urine of these 10 subjects ranged from 0.2 to 30.2pmol/mL urine. These results provide the first evidence for the presumed intermediacy of IMITC in the formation of I3C and DIM in humans who consumed Brussels sprouts and cabbage as a source of glucobrassicin.}, }
@article {pmid29223039, year = {2018}, author = {Yang, L and Duan, Z and Liu, X and Yuan, Y}, title = {N-acetyl-l-cysteine ameliorates the PM2.5-induced oxidative stress by regulating SIRT-1 in rats.}, journal = {Environmental toxicology and pharmacology}, volume = {57}, number = {}, pages = {70-75}, doi = {10.1016/j.etap.2017.11.011}, pmid = {29223039}, issn = {1872-7077}, mesh = {Acetylcysteine/*pharmacology ; Air Pollutants/*toxicity ; Animals ; Antioxidants/*pharmacology ; Forkhead Box Protein O3/genetics ; Lung/drug effects/metabolism/pathology ; Male ; Oxidative Stress/drug effects ; Particulate Matter/*toxicity ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; Sirtuin 1/genetics ; Superoxide Dismutase/genetics ; }, abstract = {Silent information regulator 1 (SIRT1), a class III histone deacetylase, plays a major role in combating cellular oxidative stress injury. However, the role of SIRT1 in oxidative stress induced by particulate matter remains unclear. A total of 32 healthy male Sprague-Dawley rats were divided into PM2.5, PM2.5+NAC, filtered air (control), and filtered air+NAC (NAC control) groups. The expressions of MnSOD, SIRT1, and FOXO3a were examined at both transcriptional and protein levels. The expression levels of MnSOD, SIRT1, and FOXO3a reduced significantly (P<0.05) in the PM2.5 group as compared to the control group. However, their expression levels were increased after NAC intervention. These results suggested that SIRT1 exerted a protective effect against PM2.5-induced respiratory oxidative damage by regulating the expression of FOXO3a. NAC can activate SIRT1 and exert an anti-oxidative role in PM2.5-induced oxidative injury.}, }
@article {pmid29222055, year = {2018}, author = {Zhou, Q and Fu, X and Wang, X and Wu, Q and Lu, Y and Shi, J and Klaunig, JE and Zhou, S}, title = {Autophagy plays a protective role in Mn-induced toxicity in PC12 cells.}, journal = {Toxicology}, volume = {394}, number = {}, pages = {45-53}, doi = {10.1016/j.tox.2017.12.001}, pmid = {29222055}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Animals ; Autophagy/drug effects/physiology ; Cell Respiration/drug effects ; Chlorides/*toxicity ; Chloroquine/pharmacology ; Dopamine/metabolism ; Manganese Compounds ; Mitochondria/drug effects/metabolism ; Neurosecretory Systems/*drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; PC12 Cells ; Rats ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/pharmacology ; }, abstract = {Excessive environmental or occupational exposure to manganese (Mn) is associated with increased risk of neuron degenerative disorders. Oxidative stress and mitochondrial dysfunction are the main mechanisms of Mn mediated neurotoxicity. Selective removal of damaged mitochondria by autophagy has been proposed as a protective mechanism against neuronal toxicant-induced neurotoxicity. Whether autophagic flux plays a role in Mn-induced cytotoxicity remains to be fully elucidated. The present study was designed to investigate the effect of Mn exposure on autophagy, and how modulation of autophagic flux alters the sensitivities of cells to Mn-elicited cytotoxicity. Rat adrenal pheochromocytoma PC12 cells were treated with Mn for 24h to establish a cellular mode of Mn toxicity. Treatment of cells with Mn resulted in increased expression of autophagic marker LC3-II protein, as well as accumulation of p62, indicating an interference of autophagy flux caused by Mn. Pre-incubation of cells with antioxidant N-acetyl-l-cysteine (NAC) or resveratrol improved cell survival, accompanied by decreased LC3-II expression and increased expression level of p62, suggesting a down regulation of autophagy flux. To further determine the role of autophagy in Mn-induced cytotoxicity, the effect of chloroquine and rapamycin on cell viability was examined. Inhibition of autophagy flux by chloroquine exacerbated Mn-induced cytotoxicity, while induction of autophagy by rapamycin significantly reduced cell death caused by Mn. Furthermore, it was found that rapamycin, NAC and resveratrol improved cellular oxygen consumption accompanied by a decrease in cellular ROS generation and increase in GSH level, while chloroquine suppressed cellular respiration and deteriorated cellular oxidative stress. Collectively, these results demonstrate that autophagy plays a protective role in Mn-induced cell toxicity. Antioxidants NAC and resveratrol confer protective role in Mn toxicity mainly through maintaining mitochondrial dynamics and function, other than a modulation of autophagy flux.}, }
@article {pmid29219630, year = {2018}, author = {McNulty, R and Lim, JME and Chandru, P and Gunja, N}, title = {Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {56}, number = {7}, pages = {618-621}, doi = {10.1080/15563650.2017.1408812}, pmid = {29219630}, issn = {1556-9519}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects ; Adult ; Anaphylaxis/chemically induced ; Chemical and Drug Induced Liver Injury/prevention &amp; control ; Drug Overdose/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; }, abstract = {OBJECTIVE: Acetylcysteine (NAC), an effective antidote for paracetamol poisoning, is commonly associated with adverse reactions. This has been postulated to be related to the rapid initial infusion rate (150 mg/kg over 1 h) of the traditional three-bag protocol. We hypothesized that a slower rate would result in fewer adverse reactions. Our institution in Western Sydney moved to a modified two-bag protocol in February 2015 - first bag: 200 mg/kg over 4 h (50 mg/kg/h) and second bag: (100 mg/kg over 16 h).<br><br>METHODS: Data was extracted from our database on paracetamol overdoses treated with NAC from August 2010 to September 2016. We compared adverse reactions in patients receiving the modified two-bag protocol with a historical control (traditional three-bag regimen with initial bolus of 150&#x2009;mg/kg/h).<br><br>RESULTS: Over the study period 1011 paracetamol poisonings presented to our toxicology service, of which 476 required NAC (three-bag&#x2009;=&#x2009;313, two-bag&#x2009;=&#x2009;163). Demographic characteristics of the two groups were similar. Fewer anaphylactoid reactions (itch, rash, and swelling) occurred using the two-bag regimen (14% versus 5%, p&#x2009;=&#x2009;.002), a relative reduction of 66%. Similarly, there were fewer prescriptions of anti-allergy medications in the two-bag group (11% versus 4%, p&#x2009;=&#x2009;.01). There was no difference in incidence of hepatotoxicity.<br><br>CONCLUSIONS: Adverse reactions to NAC were less common with the two-bag regimen. These results add to the accumulating evidence that reducing the initial NAC infusion rate reduces the risk of adverse reactions.}, }
@article {pmid29216924, year = {2017}, author = {Dalugama, C and Gawarammana, IB}, title = {Dengue hemorrhagic fever complicated with acute liver failure: a case report.}, journal = {Journal of medical case reports}, volume = {11}, number = {1}, pages = {341}, pmid = {29216924}, issn = {1752-1947}, mesh = {Acetylcysteine/*therapeutic use ; Blood Transfusion/*methods ; Free Radical Scavengers/*therapeutic use ; Humans ; Liver Failure, Acute/etiology/*therapy ; Male ; Middle Aged ; Severe Dengue/complications/*therapy ; }, abstract = {BACKGROUND: Dengue is a common arboviral infection with a clinically diverse spectrum of presentations. Although hepatic dysfunction is commonly identified in patients will dengue illness, acute liver failure is rare. The etiopathogenesis of hepatic dysfunction is multifactorial and related to direct viral invasion of hepatocytes, immunological factors and hypoxia particularly in cases of shock in dengue hemorrhagic fever. Ideal management of dengue-related hepatic dysfunction and acute liver failure is still debated.<br><br>CASE PRESENTATION: We report a 53-year-old Sri Lankan Sinhalese male with serologically confirmed dengue fever presenting with evidence of plasma leakage developing acute liver failure evidenced by deranged liver functions, coagulopathy and altered sensorium. In addition to the 'standard care', the patient was managed with intravenous N-acetyl cysteine and blood transfusions even in the absence of bleeding or dropping packed cell volume (PCV), targeting a higher PCV in anticipation of better oxygenation at tissue level. He made a full recovery with no sequential infections.<br><br>CONCLUSION: N-acetyl cysteine and packed cell transfusion aiming at a higher PCV to maintain adequate tissue perfusion during shock may be beneficial in acute liver failure due to dengue virus. Large randomized trials should be carried out to establish the efficacy of these treatment strategies to support these observations and change the current practice.}, }
@article {pmid29208507, year = {2018}, author = {Britto, RM and Silva-Neto, JAD and Mesquita, TRR and Vasconcelos, CML and de Almeida, GKM and Jesus, ICG and Santos, PHD and Souza, DS and Miguel-Dos-Santos, R and de Sá, LA and Dos Santos, FSM and Pereira-Filho, RN and Albuquerque-Júnior, RLC and Quintans-Júnior, LJ and Guatimosim, S and Lauton-Santos, S}, title = {Myrtenol protects against myocardial ischemia-reperfusion injury through antioxidant and anti-apoptotic dependent mechanisms.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {111}, number = {}, pages = {557-566}, doi = {10.1016/j.fct.2017.12.003}, pmid = {29208507}, issn = {1873-6351}, mesh = {Animals ; Antioxidants/*metabolism ; Apoptosis/*drug effects ; Bicyclic Monoterpenes ; Catalase/metabolism ; Glutathione Peroxidase/metabolism ; Heart/drug effects/physiopathology ; Humans ; Male ; Monoterpenes/*administration &amp; dosage ; Myocardial Reperfusion Injury/metabolism/physiopathology/*prevention &amp; control ; Myocardium/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Myrtenol is a monoterpene with multiple pharmacological activities. However, although monoterpenes have been proposed to play beneficial roles in a variety of cardiac disorders, pharmacological actions of myrtenol in the heart are not yet reported. Hence, the aim of this study was to evaluate whether myrtenol promotes cardioprotection against myocardial ischemia-reperfusion (IR) injury, and the mechanisms involved in these effects. Male Wistar rats were orally treated for seven consecutive days with myrtenol (50 mg/kg) or N-acetyl cysteine (1.200 mg/kg, NAC). Afterward, hearts were subjected to myocardial IR injury. Here, we show that the severe impairment of contractile performance induced by IR was significantly prevented by myrtenol or NAC. Moreover, myrtenol abolished aberrant electrocardiographic waveform (ST-segment elevation), as well as reduced life-threatening arrhythmias and infarct size induced by IR injury. Importantly, myrtenol fully prevented the massive increase of cardiac reactive oxygen species generation and oxidative stress damage. Accordingly, myrtenol restored the impairment of endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and reductase) activities and balance of pro- and anti-apoptotic pathways (Bax and Bcl-2), associated with decreased apoptotic cells. Taken together, our data show that myrtenol promotes cardioprotection against IR injury through attenuation of oxidative stress and inhibition of pro-apoptotic pathway.}, }
@article {pmid29207893, year = {2018}, author = {Kumfu, S and Khamseekaew, J and Palee, S and Srichairatanakool, S and Fucharoen, S and Chattipakorn, SC and Chattipakorn, N}, title = {A combination of an iron chelator with an antioxidant exerts greater efficacy on cardioprotection than monotherapy in iron-overload thalassemic mice.}, journal = {Free radical research}, volume = {52}, number = {1}, pages = {70-79}, doi = {10.1080/10715762.2017.1414208}, pmid = {29207893}, issn = {1029-2470}, mesh = {Animals ; Antioxidants/*metabolism ; Disease Models, Animal ; Humans ; Iron Chelating Agents/pharmacology ; Iron Overload/*drug therapy ; Male ; Mice ; Oxidative Stress ; beta-Thalassemia/*drug therapy ; }, abstract = {Many recent studies have shown that antioxidant compounds decrease cardiac oxidative stress, decrease cardiac iron deposition, and improve cardiac dysfunction in iron-overload induced cardiomyopathy in animal models. Interestingly, a therapy including the combination of the iron chelator deferiprone (DFP) plus the antioxidant N-acetylcysteine (NAC) has been shown to significantly decrease oxidative stress and restore heart and brain function in iron-overloaded rats. However, the cardioprotective effects of this combined DFP and NAC treatment in thalassemic mice have not been investigated. We hypothesised that the combination of DFP and NAC exerts better cardioprotection than monotherapy via decreasing cardiac iron accumulation, oxidative stress, and apoptosis in thalassemic mice. The iron-overload condition was induced in heterozygous β[KO] HT and wild-type mice by instigating high iron diet consumption (FE) for three months. Then, iron chelator DFP (75 mg/kg/day twice a day), antioxidant NAC (100 mg/kg/day once a day), and combined DFP plus NAC were fed via oral gavage for one month with continuous iron feeding. Left ventricular (LV) function, heart rate variability (HRV), apoptosis, and cardiac iron accumulation were determined. Chronic iron-overload in mice led to increased cardiac iron deposition, oxidative stress, apoptosis, and impaired LV function and HRV. Although DFP and NAC showed similar cardioprotective efficacy, combined DFP plus NAC exerted greater efficacy in reducing both cardiac iron deposition and cellular apoptosis than monotherapy. In conclusion, combined iron chelator and NAC treatment exert the greatest cardioprotective efficacy when compared with either of the monotherapies in iron-overload thalassemic mice.}, }
@article {pmid29207099, year = {2018}, author = {Xia, Q and Liu, C and Zheng, X}, title = {N-acetylcysteine ameliorates contrast‑induced kidney injury in rats with unilateral hydronephrosis.}, journal = {Molecular medicine reports}, volume = {17}, number = {2}, pages = {2203-2210}, pmid = {29207099}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Biomarkers ; Contrast Media/*adverse effects ; Disease Models, Animal ; Hydronephrosis/drug therapy/*etiology/*pathology/physiopathology ; Kidney Function Tests ; Kidney Tubules/drug effects/metabolism/pathology ; Male ; Protective Agents/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Rats ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {The aim of the present study was to investigate the protective effects of N‑acetylcysteine (NAC) on contrast‑induced acute kidney injury in rats with unilateral hyronephrosis. Eighty‑two male Sprague Dawley rats were randomized to undergo sham operation (n=14) or unilateral ureteral obstruction (UUO) (n=68). After 3 weeks, the UUO animals were randomized to three groups: NAC gastric perfusion, UUO+iohexol+NAC (n=24); normal saline perfusion, UUO+iohexol (n=24); and controls, UUO (n=20). After 3 days, UUO+iohexol+NAC and UUO+iohexol rats were injected with iohexol. One day after contrast, half of the rats were sacrificed to assess the pathological changes to the kidneys, serum creatinine, serum neutrophil gelatinase‑associated lipocalin (NGAL), renal cell apoptosis rate and expression of apoptosis regulators Bcl‑2/Bax. The remaining rats underwent obstruction relief and were analyzed 3 weeks later. Compared with the controls, serum NGAL levels were high in UUO+iohexol rats 1 day following injection and 3 weeks after obstruction relief, but UUO+iohexol+NAC rats exhibited lower serum NGAL levels compared with UUO+iohexol rats (all P<0.05). Following modeling, UUO+iohexol rats exhibited a significantly higher apoptosis rate of renal tubular cells, higher expression of Bax mRNA, and lower ratio of Bcl‑2/Bax (all P<0.05). Three weeks after obstruction relief, UUO+iohexol+NAC rats exhibited a lower apoptosis rate, lower Bax mRNA expression, higher expression of Bcl‑2 mRNA and higher ratio of Bcl‑2/Bax (all P<0.05) compared with day 1 following drug administration. The prophylactic use of NAC reduced the apoptotic rate of renal tubular cells following contrast exposition, which was accompanied by changes in the expression of Bcl‑2/Bax mRNA.}, }
@article {pmid29206074, year = {2019}, author = {Abubaker, AA and Vara, D and Eggleston, I and Canobbio, I and Pula, G}, title = {A novel flow cytometry assay using dihydroethidium as redox-sensitive probe reveals NADPH oxidase-dependent generation of superoxide anion in human platelets exposed to amyloid peptide β.}, journal = {Platelets}, volume = {30}, number = {2}, pages = {181-189}, doi = {10.1080/09537104.2017.1392497}, pmid = {29206074}, issn = {1369-1635}, support = {PG/15/40/31522/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Amyloid beta-Peptides/*metabolism ; Blood Platelets ; Ethidium/*analogs &amp; derivatives/pharmacology/therapeutic use ; Flow Cytometry/*methods ; Humans ; NADPH Oxidases/*metabolism ; Reactive Oxygen Species ; Superoxides/*metabolism ; }, abstract = {Reactive oxygen species (ROS) generation is critical in the regulation of platelets, which has important implications in the modulation of hemostasis and thrombosis. Nonetheless, despite several assays have been described and successfully utilized in the past, the analysis of ROS generation in human platelets remains challenging. Here we show that dihydroethidium (DHE) allows the characterization of redox responses upon platelet activation by physiological and pathological stimuli. In particular, the flow cytometry assay that we describe here allowed us to confirm that thrombin, collagen-related peptide (CRP) and arachidonic acid but not adenosine diphosphate (ADP) stimulate superoxide anion formation in a concentration-dependent manner. 0.1unit/ml thrombin, 3 μg/ml CRP and 30 μM arachidonic acid are commonly used to stimulate platelets in vitro and here were shown to stimulate a significant increase in superoxide anion formation. The ROS scavenger N-acetylcysteine (NAC) abolished superoxide anion generation in response to all tested stimuli, but the pan-NADPH oxidase (NOX) inhibitor VAS2870 only inhibited superoxide anion formation in response to thrombin and CRP. The involvement of NOXs in thrombin and CRP-dependent responses was confirmed by the inhibition of platelet aggregation induced by these stimuli by VAS2870, while platelet aggregation in response to arachidonic acid was insensitive to this inhibitor. In addition, the pathological platelet stimulus amyloid β (Aβ) 1-42 peptide induced superoxide anion formation in a concentration-dependent manner. Aβ peptide stimulated superoxide anion formation in a NOX-dependent manner, as proved by the use of VAS2870. Aβ 1-42 peptide displayed only moderate activity as an aggregation stimulus, but was able to significantly potentiate platelet aggregation in response to submaximal agonists concentrations, such as 0.03 unit/ml thrombin and 10 μM arachidonic acid. The inhibition of NOXs by 10 μM VAS2870 abolished Aβ-dependent potentiation of platelet aggregation in response to 10 μM arachidonic acid, suggesting that the pro-thrombotic activity of Aβ peptides depends on NOX activity. Similar experiments could not be performed with thrombin or collagen, as NOXs are required for the signaling induced by these stimuli. These findings shed some new light on the pro-thrombotic activity of Aβ peptides. In summary, here we describe a novel and reliable assay for the detection of superoxide anion in human platelets. This is particularly important for the investigation of the pathophysiological role of redox stress in platelets, a field of research of increasing importance, but hindered by the absence of a reliable and easily accessible ROS detection methodology applicable to platelets.}, }
@article {pmid29202574, year = {2017}, author = {Palmieri, A and Avantaggiato, A and Cura, F and Papalia, R and Casale, M and Bressi, F and Scapoli, L}, title = {Effect of biostimulation on oral fibroblast: a pilot study.}, journal = {Journal of biological regulators and homeostatic agents}, volume = {31}, number = {4 Suppl 2}, pages = {139-145}, pmid = {29202574}, issn = {0393-974X}, mesh = {Acetylcysteine/*pharmacology ; Amino Acids/*pharmacology ; Cells, Cultured ; Dermis/cytology/drug effects/metabolism ; Extracellular Matrix/chemistry/drug effects/genetics/metabolism ; Fibroblasts/cytology/*drug effects/*metabolism ; Gene Expression Regulation/*drug effects ; Glucosamine/*pharmacology ; Humans ; Pilot Projects ; Polydeoxyribonucleotides/*pharmacology ; *Rejuvenation ; Wound Healing/drug effects ; }, abstract = {Bio-stimulation is a technique in aesthetic medicine in which different drugs such as nucleotides, antioxidants and glucosaminoglycans precursors are injected in the dermis to improving the anabolic function of dermal fibroblasts, i.e., protein synthesis, replication and production of extracellular matrix components. It can be achieved with multiple intra-dermal injections, using two protocols: 1) Polydeoxyribonucleotide (PDRN) plus glucosamine sulphate (Gluc); 2) N-acetylcysteine (NAC) and amino acids (Aa) (named Bio- NAC procedure). Since the role of drugs used in biostimulation on human dermal fibroblasts is not completely understood, the aim of this study is to evaluate the effect of these substances in primary cell cultures by using RT-PCR and a panel of specific genes (ELN, DSP, FN1, FBN1, ITGA1, ITGA2, ITGA5, ITGB1, COL1A1,COL3A1) to detect their effect on cell metabolism and extracellular matrix components. Both the treatments were responsible for Elastine and Desmoplakin genes activation. Only NAC plus Aa treatment enhance the expression of other genes related to tissue growth and elasticity like FBN1, ITGA1 and ITGB1. All the other genes investigated (FN1, ITGA5, ITGA2, COL1A1, COL3A1) were down-regulated by both treatments. Since the precise role of these proteins in tissue integrity and aging is not known, this study confirms the usefulness of biostimulation therapies in enhancing some of the genes responsible of cellular wellbeing. This study could be useful to consider the possibility of injective biostimulation in oral cavity, clinical applications in oral healing and in gingival atrophy as well.}, }
@article {pmid29201174, year = {2017}, author = {Zhou, H and Shi, T and Yan, J and Chen, X and Liao, L and Zhao, S and Fang, H and Zhuang, R}, title = {Effects of activated carbon N-acetylcysteine sustained-release microcapsule on dipeptidyl peptidase IV expression in young rats with non-alcoholic fatty liver disease.}, journal = {Experimental and therapeutic medicine}, volume = {14}, number = {5}, pages = {4737-4744}, pmid = {29201174}, issn = {1792-0981}, abstract = {Non-alcoholic fatty liver disease (NAFLD) in children has become the most common liver disease influencing adolescent health and one of the most influencing chronic liver diseases among children in Chinese wealthy families, particularly in coastal regions. However, the medicine available for the treatment of NAFLD is deficient. In order to solve this problem, our team studied the activated carbon N-acetylcysteine (NAC) sustained-release microcapsule, which improves the oxidation resistance, bioavailability and drug stability of acetylcysteine and reduces toxic and side effects. In addition, it accords with the characteristics of medication in infants and children. The present study mainly discusses whether the activated carbon NAC sustained-release microcapsule has effects on dipeptidyl peptidase IV (DPPIV) activity and protein in young rats with NAFLD, and whether it has the effect of an DPPIV inhibitor, hoping to provide new thoughts and methods with respect of basic studies on young rats with NAFLD/non-alcoholic steatohepatitis.}, }
@article {pmid29199610, year = {2017}, author = {Panahi, Y and Ghanei, M and Hashjin, MM and Rezaee, R and Sahebkar, A}, title = {Potential Utility of N-acetylcysteine for Treating Mustard Lung.}, journal = {Critical reviews in eukaryotic gene expression}, volume = {27}, number = {3}, pages = {247-266}, doi = {10.1615/CritRevEukaryotGeneExpr.2017019740}, pmid = {29199610}, issn = {1045-4403}, mesh = {Acetylcysteine/*therapeutic use ; Apoptosis/drug effects ; Chemical Warfare Agents/toxicity ; Humans ; Inflammation/chemically induced/*drug therapy/pathology ; Lung/drug effects/physiopathology ; Lung Diseases/chemically induced/*drug therapy/pathology ; Mustard Gas/*toxicity ; Oxidative Stress/drug effects ; }, abstract = {More than a century after the introduction of sulfur mustard (SM), as a chemical warfare agent, it has affected thousands of military and civilians on several occasions. The most notable toxic effects of this easily produced chemical, are lung damage ranges from necrotic, hemorrhagic, and infectious acute-lung injury to chronic conditions (i.e., mustard lung). While there is no definite treatment for individuals exposed to sulfur mustard, corticosteroids, mucolytics, bronchodilators, antibiotics, immunosuppressive medicines, and magnesium are being used to help victims. In the pathophysiology of SM-induced lung conditions, oxidative stress and inflammation play undeniable roles; thus, N-acetyl-L-cysteine (NAC) has been used as a treatment. In this narrative review article, we discuss the mechanisms involved in SM-induced lung damage along with the properties of NAC that can help patients recover from these deleterious effects.}, }
@article {pmid29196951, year = {2018}, author = {Mocelin, R and Marcon, M and D'ambros, S and Herrmann, AP and da Rosa Araujo, AS and Piato, A}, title = {Behavioral and Biochemical Effects of N-Acetylcysteine in Zebrafish Acutely Exposed to Ethanol.}, journal = {Neurochemical research}, volume = {43}, number = {2}, pages = {458-464}, pmid = {29196951}, issn = {1573-6903}, support = {401162/2016-8//Conselho Nacional de Desenvolvimento Cient&#xed;fico e Tecnol&#xf3;gico/ ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anxiety/prevention &amp; control ; Behavior, Animal/*drug effects ; Brain/drug effects/metabolism ; Disease Models, Animal ; Ethanol/administration &amp; dosage/*pharmacology ; Female ; Lipid Peroxidation/*drug effects ; Male ; Oxidative Stress/*drug effects ; Zebrafish ; }, abstract = {Alcohol hangover refers to unpleasant symptoms experienced as a direct consequence of a binge drinking episode. The effects observed in this condition are related to the increase in alcohol metabolites and imbalance in oxidative status. N-acetylcysteine (NAC) is a mucolytic agent and an antidote for paracetamol overdose. Preclinical and clinical studies have shown that NAC is a multi-target drug acting through neuroprotective, antioxidant and neurotrophic mechanisms as well as a glutamate modulator. The aim of this study was to investigate the effects of NAC in zebrafish acutely exposed to ethanol (EtOH). Animals pretreated or not with NAC (1 mg/L, 10 min) were exposed for 60 min to standard tank water (EtOH-) or to 1% EtOH (EtOH+) to evaluate anxiety-like behavior and locomotion in the novel tank test and oxidative damage in the brain. Zebrafish (Danio rerio) exposed to EtOH displayed a decrease in the distance traveled, crossings, entries and time spent in the top area in the novel tank test. Exposure to EtOH also caused oxidative damage, shown by increased lipid peroxidation, decreased non-protein thiols and increased production of reactive oxygen species (DCF assay). NAC prevented both the behavioral alterations and the oxidative stress observed in EtOH+ animals. Given the effects of NAC in preventing the acute behavioral and biochemical effects of EtOH, additional studies are warranted to further investigate the basis of its anecdotal use to prevent hangover.}, }
@article {pmid29196947, year = {2018}, author = {Fernandes, AMM and Vilela, PGF and Valera, MC and Bolay, C and Hiller, KA and Schweikl, H and Schmalz, G}, title = {Effect of bleaching agent extracts on murine macrophages.}, journal = {Clinical oral investigations}, volume = {22}, number = {4}, pages = {1771-1781}, pmid = {29196947}, issn = {1436-3771}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antigens, Surface/*drug effects/immunology ; Bleaching Agents/*toxicity ; Buthionine Sulfoximine/pharmacology ; Carbamide Peroxide ; Cell Survival/drug effects ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Hydrogen Peroxide/*toxicity ; Macrophages/drug effects ; Mice ; Peroxides/*toxicity ; Tooth Bleaching ; Tumor Necrosis Factor-alpha/immunology ; Urea/*analogs &amp; derivatives/toxicity ; }, abstract = {OBJECTIVES: The aim of this study was to evaluate the cytotoxicity and the influence of bleaching agents on immunologically cell surface antigens of murine macrophages in vitro.<br><br>MATERIALS AND METHODS: RAW 264.7 cells were exposed to bleaching gel extracts (40% hydrogen peroxide or 20% carbamide peroxide) and different H2O2 concentrations after 1 and 24-h exposure periods and 1-h exposure and 23-h recovery. Tests were performed with and without N-acetyl cysteine (NAC) and buthionine sulfoximine (BSO). Cell viability was determined by MTT assay. The expression of surface markers CD14, CD40, and CD54 with and without LPS stimulation was detected by flow cytometry, while the production of TNF-&#x3b1; was measured by ELISA. Statistical analysis was performed using the Mann-Whitney U test (&#x3b1;&#x2009;=&#x2009;0.05).<br><br>RESULTS: Extracts of bleaching agents were cytotoxic for cells after a 1-h exposure; cells could not recover after 24&#xa0;h. This effect can be mitigated by the antioxidant NAC and increased by BSO, an inhibitor of glutathione (GSH) synthesis. LPS stimulated expression of all surface markers and TNF-&#x3b1; production. Exposure to bleaching agent extracts and H2O2 leads to a reduction of TNF-&#x3b1;, CD14, and CD40 expression, while the expression of CD54 was upregulated at non-cytotoxic concentrations. Whereas NAC reduced this effect, it was increased in the presence of BSO.<br><br>CONCLUSIONS: Extracts of bleaching agents were irreversibly cytotoxic to macrophages after a 1-h exposure. Only the expression of CD54 was upregulated. The reactions are mediated by the non-enzymatic antioxidant GSH.<br><br>CLINICAL RELEVANCE: The addition of an antioxidant can downregulate unfavorable effects of dental bleaching.}, }
@article {pmid29193446, year = {2018}, author = {Dixon, CL and Richardson, L and Sheller-Miller, S and Saade, G and Menon, R}, title = {A distinct mechanism of senescence activation in amnion epithelial cells by infection, inflammation, and oxidative stress.}, journal = {American journal of reproductive immunology (New York, N.Y. : 1989)}, volume = {79}, number = {3}, pages = {}, pmid = {29193446}, issn = {1600-0897}, support = {R01 HD084532/HD/NICHD NIH HHS/United States ; R03 HD067446/HD/NICHD NIH HHS/United States ; R03 HD086354/HD/NICHD NIH HHS/United States ; T32 ES007254/ES/NIEHS NIH HHS/United States ; }, mesh = {Amnion/*pathology ; Cells, Cultured ; Cellular Senescence ; Epithelial Cells/*immunology ; Extraembryonic Membranes/*pathology ; Female ; Humans ; Imidazoles/pharmacology ; Infections/*immunology ; Inflammation/*immunology ; Interleukin-6/metabolism ; Lipopolysaccharides/immunology ; Oxidative Stress ; Pregnancy ; Premature Birth/*immunology ; Primary Cell Culture ; Pyridines/pharmacology ; Tumor Necrosis Factor-alpha/immunology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {PROBLEM: We investigated p38MAPK activation-induced fetal membrane cell senescence in response to inflammation (tumour necrosis factor-alpha [TNF-α]) and infection (lipopolysaccharide [LPS]), factors associated with spontaneous preterm birth.<br><br>METHOD OF STUDY: Primary amnion epithelial cells (AECs) were exposed to TNF-&#x3b1;, 50&#xa0;ng/mL and LPS, 100&#xa0;ng/mL. Cigarette smoke extract (CSE), a known OS inducer, was used as positive control. AECs were cotreated with the antioxidant N-acetyl cysteine (NAC) and p38MAPK inhibitor SB203580 to determine the effect of OS and p38MAPK. Western blot analysis was performed for active (Phospho-p38MAPK) and total p38MAPK. Senescence was determined by flow cytometry, and culture supernatants were tested for IL-6 using ELISA.<br><br>RESULTS: TNF-&#x3b1;, but not LPS, increased p38MAPK activation compared to untreated cells (P&#xa0;=&#xa0;.01). The number of senescent cells and senescence-associated IL-6 was higher in both TNF-&#x3b1; and LPS-treated cells compared to control (P&#xa0;=&#xa0;.001, P&#xa0;=&#xa0;.01, respectively). Antioxidant NAC inhibited p38MAPK activation by TNF-&#x3b1;. p38MAPK inhibitor SB203580 reduced the development of senescence and IL-6 by TNF-&#x3b1; and LPS. CSE treatment validated our current data.<br><br>CONCLUSION: TNF-&#x3b1; caused OS-mediated p38MAPK induction, senescence, and IL-6 increase from AECs. LPS also induced senescence and IL-6 increase. Inflammatory and infectious factors may cause premature fetal cell senescence contributing to preterm birth pathophysiology.}, }
@article {pmid29187671, year = {2018}, author = {Yang, Y and Tang, X and Hao, F and Ma, Z and Wang, Y and Wang, L and Gao, Y}, title = {Bavachin Induces Apoptosis through Mitochondrial Regulated ER Stress Pathway in HepG2 Cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {41}, number = {2}, pages = {198-207}, doi = {10.1248/bpb.b17-00672}, pmid = {29187671}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Anti-Bacterial Agents/*adverse effects/chemistry ; Apoptosis/*drug effects ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Flavonoids/*adverse effects/antagonists &amp; inhibitors ; Free Radical Scavengers/pharmacology ; GTP Phosphohydrolases/antagonists &amp; inhibitors/chemistry/genetics/metabolism ; Hep G2 Cells ; Hepatocytes/cytology/*drug effects/metabolism ; Humans ; Mitochondria, Liver/*drug effects/enzymology/metabolism ; Osmolar Concentration ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Protective Agents/pharmacology ; Protein Processing, Post-Translational/drug effects ; Proto-Oncogene Proteins c-akt/agonists/metabolism ; RNA Interference ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/metabolism ; Taurochenodeoxycholic Acid/pharmacology ; }, abstract = {As a traditional herbal medicine, the fruits of Psoralea corylifolia L. (Fructus Psoraleae (FP)) have been widely used for the treatment of various skin diseases for hundred years. Recently, the emerging FP-induced toxic effects, especially hepatotoxicity, in clinic are getting the public's attention. However, its exact toxic components and mechanisms underlying remain unclear. Bavachin, one of flavonoids in FP, has been documented as a hepatotoxic substance, and the present study aimed to determine the toxicity caused by bavachin and the possible toxic mechanisms involved using human hepatocellular carcinoma (HepG2) cells. Our results showed that bavachin could significantly inhibited cell proliferation and trigger the endoplasmic reticulum (ER) stress in a dose dependent manner. Downregulating ER stress using tauroursodeoxycholic acid (TUDCA) obvious attenuated bavachin-triggerd cell apoptosis. Then, small interfering RNA (siRNA) knock-down of Mitofusion2 (Mfn2) resulted in a remarkable aggravation of ER stress through the inhibition of the phosphorylation of protein kinase B (Akt). Additionally, suppression of reactive oxygen species (ROS) by ROS Scavenger (N-acetyl-l-cystein (NAC)) also reduced bavachin-induced ER stress. Taken together, our study demonstrated that bavachin-induced ER stress caused cell apoptosis by Mfn2-Akt pathway, and that ROS may participate upstream in this mechanism. Here, we not only provide a new understanding of ROS/Mfn2/Akt pathway in bavachin-induced cytotoxicity via the ER stress, but also identify a new specific intervention to prevent FP-induced hepatotoxicity in the future.}, }
@article {pmid29187367, year = {2018}, author = {Kurosaki, Y and Imoto, A and Kawakami, F and Yokoba, M and Takenaka, T and Ichikawa, T and Katagiri, M and Ishii, N}, title = {Oxidative stress increases megalin expression in the renal proximal tubules during the normoalbuminuric stage of diabetes mellitus.}, journal = {American journal of physiology. Renal physiology}, volume = {314}, number = {3}, pages = {F462-F470}, doi = {10.1152/ajprenal.00108.2017}, pmid = {29187367}, issn = {1522-1466}, mesh = {Animals ; Antioxidants/pharmacology ; Cell Line ; Diabetes Mellitus, Experimental/chemically induced/*metabolism ; Dose-Response Relationship, Drug ; Glucose/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Kidney Tubules, Proximal/drug effects/*metabolism ; Low Density Lipoprotein Receptor-Related Protein-2/genetics/*metabolism ; Male ; Oxidants/pharmacology ; *Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Streptozocin ; Telmisartan/pharmacology ; Time Factors ; Up-Regulation ; }, abstract = {Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.}, }
@article {pmid29187031, year = {2018}, author = {Sangobowale, MA and Grin'kina, NM and Whitney, K and Nikulina, E and St Laurent-Ariot, K and Ho, JS and Bayzan, N and Bergold, PJ}, title = {Minocycline plus N-Acetylcysteine Reduce Behavioral Deficits and Improve Histology with a Clinically Useful Time Window.}, journal = {Journal of neurotrauma}, volume = {35}, number = {7}, pages = {907-917}, doi = {10.1089/neu.2017.5348}, pmid = {29187031}, issn = {1557-9042}, abstract = {There are no drugs to manage traumatic brain injury (TBI) presently. A major problem in developing therapeutics is that drugs to manage TBI lack sufficient potency when dosed within a clinically relevant time window. Previous studies have shown that minocycline (MINO, 45 mg/kg) plus N-acetylcysteine (NAC, 150 mg/kg) synergistically improved cognition and memory, modulated inflammation, and prevented loss of oligodendrocytes that remyelinated damaged white matter when first dosed 1 h after controlled cortical impact (CCI) in rats. We show that MINO (45 mg/kg) plus NAC (150 mg/kg) also prevent brain injury in a mouse closed head injury (CHI) TBI model. Using the CHI model, the concentrations of MINO and NAC were titrated to determine that MINO (22.5 mg/kg) plus NAC (75 mg/kg) was more potent than the original formulation. MINO (22.5 mg/kg) plus NAC (75 mg/kg) also limited injury in the rat CCI model. The therapeutic time window of MINO plus NAC was then tested in the CHI and CCI models. Mice and rats could acquire an active place avoidance task when MINO plus NAC was first dosed at 12 h post-injury. A first dose at 12 h also limited gray matter injury in the hippocampus and preserved myelin in multiple white matter tracts. Mice and rats acquired Barnes maze when MINO plus NAC was first dosed at 24 h post-injury. These data suggest that MINO (22.5 mg/kg) plus NAC (75 mg/kg) remain potent when dosed at clinically useful time windows. Both MINO and NAC are drugs approved by the Food and Drug Administration and have been administered safely to patients in clinical trials at the doses in the new formulation. This suggests that the drug combination of MINO plus NAC may be effective in treating patients with TBI.}, }
@article {pmid29182711, year = {2017}, author = {Hara, Y and McKeehan, N and Dacks, PA and Fillit, HM}, title = {Evaluation of the Neuroprotective Potential of N-Acetylcysteine for Prevention and Treatment of Cognitive Aging and Dementia.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {4}, number = {3}, pages = {201-206}, doi = {10.14283/jpad.2017.22}, pmid = {29182711}, issn = {2426-0266}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacokinetics/*therapeutic use ; *Cognitive Aging ; Dementia/*drug therapy ; Humans ; Neuroprotective Agents/pharmacokinetics/*therapeutic use ; Nootropic Agents/pharmacokinetics/therapeutic use ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disease for which there is no cure and only a few treatments providing little relief. Increased oxidative stress that is associated with aging is strongly implicated in the pathogenesis and progression of Alzheimer's disease. Studies have shown that levels of the endogenous antioxidant glutathione decline at an early stage of Alzheimer's disease with decreased levels correlating with worse cognitive functions. N-acetylcysteine, a drug also widely available as a dietary supplement, is a precursor of L-cysteine, which in turn is a component of glutathione. Because cysteine availability is a limiting factor for glutathione synthesis, treatment with N-acetylcysteine may increase glutathione levels and thereby counter oxidative stress, promote redox -regulated cell signaling, and improve immune responses. In this review, we evaluate the existing literature and the potential of N-acetylcysteine in promoting cognitive health and alleviating cognitive decline associated with dementia. Discussion will also include possible mechanisms of action of N-acetylcysteine, its effects on aging biology, and safety of long-term use. Based on the available literature, a nutraceutical formulation containing N-acetylcysteine among other compounds has shown some pro-cognitive benefits in Alzheimer's patients and older adults, but the evidence for N-acetylcysteine alone is less robust. Although N-acetylcysteine crosses the blood-brain-barrier, low bioavailability is an obstacle. One promising avenue of research may be to explore derivatives of N-acetylcysteine such as N-acetylcysteine amide, which has been reported in preclinical studies to have higher permeability through cellular and mitochondrial membranes with increased central nervous system bioavailability compared to N-acetylcysteine.}, }
@article {pmid29179951, year = {2018}, author = {Lv, W and Sui, L and Yan, X and Xie, H and Jiang, L and Geng, C and Li, Q and Yao, X and Kong, Y and Cao, J}, title = {ROS-dependent Atg4 upregulation mediated autophagy plays an important role in Cd-induced proliferation and invasion in A549 cells.}, journal = {Chemico-biological interactions}, volume = {279}, number = {}, pages = {136-144}, doi = {10.1016/j.cbi.2017.11.013}, pmid = {29179951}, issn = {1872-7786}, mesh = {Adenocarcinoma/*metabolism ; Autophagy/*drug effects ; Autophagy-Related Proteins/genetics/*metabolism ; Cadmium/*pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cysteine Endopeptidases/genetics/*metabolism ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Neoplasm Invasiveness ; Reactive Oxygen Species ; Up-Regulation/*drug effects ; }, abstract = {Cadmium (Cd) is a toxic heavy metal that is widely used in industry and agriculture. In this study the role of autophagy in Cd-induced proliferation, migration and invasion was investigated in A549 cells. Exposure to Cd (2 μM) significantly increased reactive oxygen species (ROS) production, induced autophagy and enhanced cell growth, migration and invasion in A549 cells. Western blot analysis showed that the expression of autophagy-related proteins, LC3-II, Beclin-1 and Atg4 and invasion-related protein MMP-9 were upregulated in Cd-treated cells. N-acetyl cysteine (NAC) markedly prevented Cd-induced proliferation of A549 cells and the increasing protein level of LC3-II and Atg4. Blocking Atg4 expression by siRNA strongly reduced Beclin-1 and LC3-II protein expression and the number of autophagosome positive cells induced by Cd. Furthermore, Atg4 siRNA increased the number of cells at G0/G1 phase, reduced the number of S and G2/M phase cells, and inhibited Cd-induced cell growth significantly compared with that of Cd-treated Control siRNA cells. 3-MA pretreatment increased the percentage of G0/G1 phase cells, decreased S phase and G2/M phase percentage, and inhibited Cd-induced cell growth remarkably compared with that of only Cd-treated cells. Knocking down Atg4 reduced the number of cells that migrated and invaded through the Matrigel matrix significantly and led to a significant decrease of MMP-9 expression. In addition, in lung tissues of Cd-treated BALB/c mice, the increased expression of LC3-II, Beclin-1 and Atg4 were observed. Taken together, our results demonstrated that ROS-dependent Atg4-mediated autophagy plays an important role in Cd-induced cell growth, migration and invasion in A549 cells.}, }
@article {pmid29178427, year = {2018}, author = {Schiavoni, I and Scagnolari, C and Horenstein, AL and Leone, P and Pierangeli, A and Malavasi, F and Ausiello, CM and Fedele, G}, title = {CD38 modulates respiratory syncytial virus-driven proinflammatory processes in human monocyte-derived dendritic cells.}, journal = {Immunology}, volume = {154}, number = {1}, pages = {122-131}, pmid = {29178427}, issn = {1365-2567}, mesh = {ADP-ribosyl Cyclase 1/antagonists &amp; inhibitors/genetics/immunology/*metabolism ; Antiviral Agents/therapeutic use ; Cells, Cultured ; Cyclic ADP-Ribose/metabolism ; Dendritic Cells/drug effects/*enzymology/immunology/*virology ; Enzyme Activation ; Enzyme Inhibitors/therapeutic use ; Host-Pathogen Interactions ; Humans ; Interferon Type I/metabolism ; Membrane Glycoproteins/antagonists &amp; inhibitors/genetics/immunology/*metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Respiratory Syncytial Virus Infections/drug therapy/*enzymology/immunology/*virology ; Respiratory Syncytial Virus, Human/*immunology ; Signal Transduction ; }, abstract = {Respiratory syncytial virus (RSV) is the most common cause of hospitalization due to bronchiolitis in infants. Although the mechanisms behind this association are not completely elucidated, they appear to involve an excessive immune response causing lung pathology. Understanding the host response to RSV infection may help in the identification of targets for therapeutic intervention. We infected in-vitro human monocyte-derived dendritic cells (DCs) with RSV and analysed various aspects of the cellular response. We found that RSV induces in DCs the expression of CD38, an ectoenzyme that catalyses the synthesis of cyclic ADPR (cADPR). Remarkably, CD38 was under the transcriptional control of RSV-induced type I interferon (IFN). CD38 and a set of IFN-stimulated genes (ISGs) were inhibited by the anti-oxidant N-acetyl cysteine. When CD38-generated cADPR was restrained by 8-Br-cADPR or kuromanin, a flavonoid known to inhibit CD38 enzymatic activity, RSV-induced type I/III IFNs and ISGs were markedly reduced. Taken together, these results suggest a key role of CD38 in the regulation of anti-viral responses. Inhibition of CD38 enzymatic activity may represent an encouraging approach to reduce RSV-induced hyperinflammation and a novel therapeutic option to treat bronchiolitis.}, }
@article {pmid29177809, year = {2018}, author = {Reffatto, V and Rasinger, JD and Carroll, TS and Ganay, T and Lundebye, AK and Sekler, I and Hershfinkel, M and Hogstrand, C}, title = {Parallel in vivo and in vitro transcriptomics analysis reveals calcium and zinc signalling in the brain as sensitive targets of HBCD neurotoxicity.}, journal = {Archives of toxicology}, volume = {92}, number = {3}, pages = {1189-1203}, pmid = {29177809}, issn = {1432-0738}, support = {016249-2//Sixth Framework Programme/ ; 186908/I30//Research Council of Norway/ ; 016249-2//Sixth Framework Programme (BE)/ ; }, mesh = {Animals ; Apoptosis/drug effects/physiology ; Brain/drug effects/metabolism ; Calcium Signaling/*drug effects/physiology ; Cell Line ; Cells, Cultured ; Female ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Hippocampus/cytology/drug effects/metabolism ; Hydrocarbons, Brominated/*toxicity ; Mice, Inbred Strains ; Neurotoxicity Syndromes/*genetics/*metabolism/pathology ; Signal Transduction/drug effects ; Zinc/*metabolism ; }, abstract = {Hexabromocyclododecane (HBCD) is a brominated flame retardant (BFR) that accumulates in humans and affects the nervous system. To elucidate the mechanisms of HBCD neurotoxicity, we used transcriptomic profiling in brains of female mice exposed through their diet to HBCD (199 mg/kg body weight per day) for 28 days and compared with those of neuronal N2A and NSC-19 cell lines exposed to 1 or 2 µM HBCD. Similar pathways and functions were affected both in vivo and in vitro, including Ca[2+] and Zn[2+] signalling, glutamatergic neuron activity, apoptosis, and oxidative stress. Release of cytosolic free Zn[2+] by HBCD was confirmed in N2A cells. This Zn[2+] release was partially quenched by the antioxidant N-acetyl cysteine indicating that, in accordance with transcriptomic analysis, free radical formation is involved in HBCD toxicity. To investigate the effects of HBCD in excitable cells, we isolated mouse hippocampal neurons and monitored Ca[2+] signalling triggered by extracellular glutamate or zinc, which are co-released pre-synaptically to trigger postsynaptic signalling. In control cells application of zinc or glutamate triggered a rapid rise of intracellular [Ca[2+]]. Treatment of the cultures with 1 µM of HBCD was sufficient to reduce the glutamate-dependent Ca[2+] signal by 50%. The effect of HBCD on zinc-dependent Ca[2+] signalling was even more pronounced, resulting in the reduction of the Ca[2+] signal with 86% inhibition at 1 µM HBCD. Our results show that low concentrations of HBCD affect neural signalling in mouse brain acting through dysregulation of Ca[2+] and Zn[2+] homeostasis.}, }
@article {pmid29175645, year = {2018}, author = {Chiesa, E and Dorati, R and Modena, T and Conti, B and Genta, I}, title = {Multivariate analysis for the optimization of microfluidics-assisted nanoprecipitation method intended for the loading of small hydrophilic drugs into PLGA nanoparticles.}, journal = {International journal of pharmaceutics}, volume = {536}, number = {1}, pages = {165-177}, doi = {10.1016/j.ijpharm.2017.11.044}, pmid = {29175645}, issn = {1873-3476}, mesh = {Drug Carriers/chemistry ; Hydrophobic and Hydrophilic Interactions ; Lactic Acid/*chemistry ; Microfluidics/methods ; Multivariate Analysis ; Nanoparticles/*chemistry ; Particle Size ; Pharmaceutical Preparations/*chemistry ; Polyglycolic Acid/*chemistry ; Polylactic Acid-Polyglycolic Acid Copolymer ; }, abstract = {Design of Experiment-assisted evaluation of critical process (total flow rate, TFR, flow rate ratio, FRR) and formulation (polymer concentration and structure, drug:polymer ratio) variables in a novel microfluidics-based device, a staggered herringbone micromixer (SHM), for poly(lactic-co-glycolic acid) copolymer (PLGA) nanoparticles (NPs) manufacturing was performed in order to systematically evaluate and mathematically describe their effects on NPs sizes and drug encapsulation; a small hydrophilic moiety, N-acetylcysteine, was chosen as challenging model drug. SHM-assisted nanoprecipitation method consistently yielded NPs with tailor made sizes (in the range of 100-900 nm) and polydispersity index range from 0.061 to 0.286. Significant effects on NPs sizes were highlighted for TFR and FRR: increasing TFR (from 5 to 15 mL/min) and decreasing FRR (from 1:1 to 1:5 v/v, acetonitrile: buffer) NPs with mean diameter <200 nm were obtained. SHM technique allowed for flexible, application-specific tuning of PLGA NPs size using organic solvents with relatively low toxicity (acetone, acetonitrile), varying aqueous phase composition (Tris buffer vs PVA aqueous solution) and PLGA characteristics (Mw ranging from 25-90 kDa, capped or un-capped PLGA, different lactide:glycolide molar ratio). A very satisfactory N-Ac encapsulation efficiency (more than 67%) and a prolonged release (by 168 h) were achieved.}, }
@article {pmid29173475, year = {2018}, author = {Lipko, M and Debski, B}, title = {Mechanism of insulin-like effect of chromium(III) ions on glucose uptake in C2C12 mouse myotubes involves ROS formation.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {45}, number = {}, pages = {171-175}, doi = {10.1016/j.jtemb.2017.10.012}, pmid = {29173475}, issn = {1878-3252}, mesh = {Animals ; Chromium/*metabolism ; Glucose/metabolism ; Insulin/metabolism ; Ions/metabolism ; Mice ; Muscle Fibers, Skeletal/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Chromium is considered a trace element which improves glucose tolerance, but mechanism accounting for this insulin-like action is not recognized. The main purpose of this study was to examine the role of reactive oxygen species (ROS) in chromium and insulin stimulated glucose transport using antioxidants. Effect of chromium ions on phosphatases, enzymes involved in inhibition of insulin signaling was also investigated. Experiments were performed in vitro on C2C12 mouse myotubes. ROS level was measured with the use of confocal microscope and 2',7' dichlorodihydrofluorescein diacetate (DCFH-DA). Glucose metabolism was assayed by the measurement of 2-[[3]H]-deoxyglucose uptake. Cr[3+] ions and insulin treatment caused significant increase of ROS formation and also stimulated glucose uptake in C2C12 cells in concentration dependent manner. Antioxidants (L-ascorbic acid and N-acetyl cysteine 100μM) and DPI (diphenyleneiodonium-NADPH oxidase inhibitor, 10μM) abolished insulin- and Cr-inducted glucose transport. Our results confirm the hypothesis that the ROS are integral part of insulin signaling pathway and that the insulin mimetic effect of Cr[3+] ions depends on the antioxidant status of the cells. Surprisingly, chromium treatment resulted in increased activity of membrane phosphatases.}, }
@article {pmid29167125, year = {2018}, author = {Bernard, O and Jeny, F and Uzunhan, Y and Dondi, E and Terfous, R and Label, R and Sutton, A and Larghero, J and Vanneaux, V and Nunes, H and Boncoeur, E and Planès, C and Dard, N}, title = {Mesenchymal stem cells reduce hypoxia-induced apoptosis in alveolar epithelial cells by modulating HIF and ROS hypoxic signaling.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {314}, number = {3}, pages = {L360-L371}, doi = {10.1152/ajplung.00153.2017}, pmid = {29167125}, issn = {1522-1504}, mesh = {Alveolar Epithelial Cells/*cytology/physiology ; Animals ; *Apoptosis ; Cells, Cultured ; Humans ; Hypoxia/*physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Male ; Mesenchymal Stem Cells/*cytology/physiology ; Pulmonary Alveoli/*cytology/physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Distal lung diseases, such as pulmonary fibrosis or acute lung injury, are commonly associated with local alveolar hypoxia that may be deleterious through the stimulation of alveolar epithelial cell (AEC) apoptosis. In various murine models of alveolar injury, administration of allogenic human mesenchymal stem cells (hMSCs) exerts an overall protective paracrine effect, limiting lung inflammation and fibrosis. However, the precise mechanisms on lung cells themselves remain poorly understood. Here, we investigated whether hMSC-conditioned medium (hMSC-CM) would protect AECs from hypoxia-induced apoptosis and explored the mechanisms involved in this cytoprotective effect. Exposure of rat primary AECs to hypoxia (1.5% O2 for 24 h) resulted in hypoxia-inducible factor (HIF)-1α protein stabilization, partly dependent on reactive oxygen species (ROS) accumulation, and in a twofold increase in AEC apoptosis that was prevented by the HIF inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl-indazole and the antioxidant drug N-acetyl cysteine. Incubation of AECs with hMSC-CM significantly reduced hypoxia-induced apoptosis. hMSC-CM decreased HIF-1α protein expression, as well as ROS accumulation through an increase in antioxidant enzyme activities. Expression of Bnip3 and CHOP, two proapoptotic targets of HIF-1α and ROS pathways, respectively, was suppressed by hMSC-CM, while Bcl-2 expression was restored. The paracrine protective effect of hMSC was partly dependent on keratinocyte growth factor and hepatocyte growth factor secretion, preventing ROS and HIF-1α accumulation.}, }
@article {pmid29166940, year = {2017}, author = {Vignal, C and Pichavant, M and Alleman, LY and Djouina, M and Dingreville, F and Perdrix, E and Waxin, C and Ouali Alami, A and Gower-Rousseau, C and Desreumaux, P and Body-Malapel, M}, title = {Effects of urban coarse particles inhalation on oxidative and inflammatory parameters in the mouse lung and colon.}, journal = {Particle and fibre toxicology}, volume = {14}, number = {1}, pages = {46}, pmid = {29166940}, issn = {1743-8977}, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/chemistry/*toxicity ; Animals ; Antioxidants/pharmacology ; Colon/*drug effects/immunology/metabolism ; Cytokines/immunology/*metabolism ; Inflammation Mediators/immunology/*metabolism ; Inhalation Exposure/*adverse effects ; Lung/*drug effects/immunology/metabolism ; Male ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; Particle Size ; Particulate Matter/chemistry/*toxicity ; Solubility ; Solvents/chemistry ; Water/chemistry ; }, abstract = {BACKGROUND: Air pollution is a recognized aggravating factor for pulmonary diseases and has notably deleterious effects on asthma, bronchitis and pneumonia. Recent studies suggest that air pollution may also cause adverse effects in the gastrointestinal tract. Accumulating experimental evidence shows that immune responses in the pulmonary and intestinal mucosae are closely interrelated, and that gut-lung crosstalk controls pathophysiological processes such as responses to cigarette smoke and influenza virus infection. Our first aim was to collect urban coarse particulate matter (PM) and to characterize them for elemental content, gastric bioaccessibility, and oxidative potential; our second aim was to determine the short-term effects of urban coarse PM inhalation on pulmonary and colonic mucosae in mice, and to test the hypothesis that the well-known antioxidant N-acetyl-L-cysteine (NAC) reverses the effects of PM inhalation.<br><br>RESULTS: The collected PM had classical features of urban particles and possessed oxidative potential partly attributable to their metal fraction. Bioaccessibility study confirmed the high&#xa0;solubility of some metals at the gastric level. Male mice were exposed to urban coarse PM in a ventilated inhalation chamber for 15&#xa0;days at a concentration relevant to episodic elevation peak of air pollution. Coarse PM inhalation induced systemic oxidative stress, recruited immune cells to the lung, and increased cytokine levels in the lung and colon. Concomitant oral administration of NAC reversed all the observed effects relative to the inhalation of coarse PM.<br><br>CONCLUSIONS: Coarse PM-induced low-grade inflammation in the lung and colon is mediated by oxidative stress and deserves more investigation as potentiating factor for inflammatory diseases.}, }
@article {pmid29165875, year = {2018}, author = {Tang, JY and Huang, HW and Wang, HR and Chan, YC and Haung, JW and Shu, CW and Wu, YC and Chang, HW}, title = {4β-Hydroxywithanolide E selectively induces oxidative DNA damage for selective killing of oral cancer cells.}, journal = {Environmental toxicology}, volume = {33}, number = {3}, pages = {295-304}, doi = {10.1002/tox.22516}, pmid = {29165875}, issn = {1522-7278}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Breaks, Double-Stranded/drug effects ; DNA Damage/*drug effects ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Free Radical Scavengers/pharmacology ; Gingival Neoplasms ; Humans ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Plant Extracts/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Reactive oxygen species (ROS) induction had been previously reported in 4β-hydroxywithanolide (4βHWE)-induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8-oxo-2'deoxyguanosine [8-oxodG]) were detected in 4βHWE-treated oral cancer (Ca9-22) and/or normal (HGF-1) cells. 4βHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N-acetylcysteine (NAC). For immunofluorescence, 4βHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4βHWE-treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine-DNA glycolyase (Fpg)-based comet assay and 8-oxodG-based flow cytometry, the 8-oxodG expressions were higher in 4βHWE-treated oral cancer cells than in oral normal cells. All the 4βHWE-induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4βHWE selectively induced DSB and oxidative DNA damage for the ROS-mediated selective killing of oral cancer cells.}, }
@article {pmid29157011, year = {2018}, author = {Lee, W and Lee, DG}, title = {Reactive oxygen species modulate itraconazole-induced apoptosis via mitochondrial disruption in Candida albicans.}, journal = {Free radical research}, volume = {52}, number = {1}, pages = {39-50}, doi = {10.1080/10715762.2017.1407412}, pmid = {29157011}, issn = {1029-2470}, mesh = {Apoptosis/*drug effects ; Candida albicans/*growth &amp; development ; Humans ; Itraconazole/*adverse effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Itraconazole (ITC), a well-known fungistatic agent, has potent fungicidal activity against Candida albicans. However, its mechanism of fungicidal activity has not been elucidated yet, and we aimed to identify the mechanism of ITC against C. albicans. ITC caused cell shrinkage via potassium leakage through the ion channel. Since shrunken cells could indicate apoptosis, we investigated apoptotic features. Annexin V-FITC and TUNEL assays indicated that fungicidal activity of ITC was involved in apoptosis. Subsequently, we confirmed an intracellular factor that could cause apoptosis. ITC treatment caused reactive oxygen species (ROS) accumulation. To confirm whether ROS is related with ITC-triggered cell death, cell viability was examined using the ROS scavenger N-acetylcysteine (NAC). NAC pretreatment recovered ITC-induced cell death, indicating that antifungal activity of ITC is associated with ROS, which is also confirmed by impaired glutathione-related antioxidant system and oxidized intracellular lipids. Moreover, ITC-induced mitochondrial dysfunction, in turn, triggered cytochrome c release and metacaspase activation, leading to apoptosis. Unlike the only ITC-treatment group, cells with NAC pretreatment did not show significant damage to mitochondria, and attenuated apoptotic features. Therefore, our results suggest that ITC induces apoptosis as fungicidal mechanism, and intracellular ROS is major factor to trigger the apoptosis by ITC in C. albicans.}, }
@article {pmid29154739, year = {2017}, author = {Bae, H and Jeong, CH and Cheng, WN and Hong, K and Seo, HG and Han, SG}, title = {Oxidative stress-induced inflammatory responses and effects of N-acetylcysteine in bovine mammary alveolar cells.}, journal = {The Journal of dairy research}, volume = {84}, number = {4}, pages = {418-425}, doi = {10.1017/S002202991700067X}, pmid = {29154739}, issn = {1469-7629}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cattle ; Cells, Cultured ; Cyclooxygenase 2/analysis ; Epithelial Cells/drug effects/physiology ; Female ; Humans ; Inflammation/etiology ; MAP Kinase Signaling System/drug effects/physiology ; Mammary Glands, Animal/*cytology ; Mastitis, Bovine/*etiology/*prevention &amp; control ; NF-kappa B/antagonists &amp; inhibitors/physiology ; Oxidative Stress/*physiology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/physiology ; Reactive Oxygen Species/pharmacology ; Vitamin K 3/pharmacology ; }, abstract = {Bovine mastitis, an inflammation of the udder, results in reduced milk production and poor milk quality. Mastitis is usually, but not always, a response to pathogen infection. High milk yield can produce oxidative stress in the mammary tissue. High milk yield is also known to be associated with bovine mastitis. Thus, in the current study, we hypothesised that oxidative stress increases inflammatory responses in bovine mammary cells. To examine the hypothesis, we produced cellular oxidative stress and investigated resulting inflammatory responses in bovine mammary alveolar cells (MAC-T). To produce oxidative stress, cells were treated with the reactive oxygen species (ROS; e.g., superoxide anion)-producing agent, menadione (MD; 0-10 µm; 6 h). To ensure the ROS-induced responses, cells were pretreated with an antioxidant NAC (0-10 mm; 1 h). Results showed that MD elevated intracellular ROS levels and protein expression of cyclooxygenase-2 (COX-2), a biomarker of inflammation. Pretreatment of cells with NAC attenuated MD-induced COX-2 expression by scavenging intracellular ROS and enhancing intracellular glutathione levels. MD-induced COX-2 expression was mediated by activation of extracellular signal receptor-activated kinase 1/2 (ERK1/2), Akt, and nuclear factor-kappa B (NF-κB). NAC attenuated activation of these intracellular signalling molecules. Treatment of cells with pharmacological inhibitors for ERK1/2, Akt, and NF-κB confirmed the association of these signalling pathways in MD-induced COX-2 expression. These results support our hypothesis that oxidative stress, which is found in high-yielding dairy cows, can produce cellular inflammation in bovine mammary alveolar cells and prevention of oxidative stress can attenuate such pathological responses. This may be relevant for cases of clinical mastitis for which no pathogen can be isolated.}, }
@article {pmid29152699, year = {2018}, author = {El-Maddawy, ZK and El-Sayed, YS}, title = {Comparative analysis of the protective effects of curcumin and N-acetyl cysteine against paracetamol-induced hepatic, renal, and testicular toxicity in Wistar rats.}, journal = {Environmental science and pollution research international}, volume = {25}, number = {4}, pages = {3468-3479}, doi = {10.1007/s11356-017-0750-3}, pmid = {29152699}, issn = {1614-7499}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism/*pharmacology ; Curcumin/*pharmacology ; Kidney/*drug effects/enzymology ; Lipid Peroxidation/drug effects ; Liver/*drug effects/enzymology ; Male ; Oxidative Stress/*drug effects ; Rats, Wistar ; Sperm Count ; Sperm Motility/drug effects ; Testis/*drug effects/enzymology ; }, abstract = {This study aimed to investigate the possible protective role of curcumin (CUR) vs. N-acetyl cysteine (NAC) against paracetamol (PCM)-induced oxidative damage and impairment of liver, kidney, and testicular functions, as well as hematotoxicity, in albino rats. A large single dose of PCM induced lipid peroxidation along with a significant decline in glutathione content and catalase activity in the liver, kidneys, and testicles. The apparent oxidative damage was associated with evident hepatic, renal, and testicular dysfunction, which was confirmed in histopathological lesions, and increased serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activities. PCM decreased serum total protein, albumin, and globulin contents; increased bilirubin, urea, and creatinine contents; and induced hematotoxicity. PCM also reduced the sperm cell count, sperm motility, and alive sperm rate and increased the sperm abnormality rate. Pretreatment of PCM-intoxicated animals with CUR or NAC substantially alleviated the increase in malondialdehyde and maintained the antioxidants at control levels. These pretreatments also minimized liver, kidney, and testicular histopathological changes and normalized their functions. CUR similarly mitigated the PCM hemato- and hepatotoxicity compared with NAC. However, it exhibited a pronounced nephroprotection, rather than reproductive protection as did NAC. Our findings demonstrate that a large single dose of PCM is not only associated with hepatotoxicity but also nephrotoxicity and reproductive toxicity. Both CUR and NAC administration provided substantial organ protection with pronounced efficacy against PCM nephrotoxicity with CUR and reproductive toxicity with NAC, which was possibly mediated through their antioxidant activities, as well as their specific characteristics.}, }
@article {pmid29148959, year = {2017}, author = {Kinikini, M}, title = {Effect of Measuring γ-Glutamyl Transpeptidase and Using Smoflipid in a Parenteral Nutrition Infusion in a Patient With Severe Malabsorption and Overlapping Primary Sclerosing Cholangitis and Ulcerative Colitis.}, journal = {JPEN. Journal of parenteral and enteral nutrition}, volume = {41}, number = {1_suppl}, pages = {24S-27S}, doi = {10.1177/0148607117742632}, pmid = {29148959}, issn = {1941-2444}, mesh = {Aged ; Biomarkers/blood ; Cholangitis, Sclerosing/complications/*therapy ; Colectomy ; Colitis, Ulcerative/complications/*therapy ; Fat Emulsions, Intravenous/*adverse effects/chemistry/therapeutic use ; Fatty Acids/administration &amp; dosage ; Fatty Acids, Omega-6/administration &amp; dosage/adverse effects ; Humans ; Liver Diseases/etiology/prevention &amp; control ; Malabsorption Syndromes/complications/*therapy ; Male ; Oxidative Stress ; Parenteral Nutrition, Total/*adverse effects/methods ; Treatment Outcome ; gamma-Glutamyltransferase/*blood ; }, abstract = {Studies discussing inflammation and oxidative stress state that these conditions are known contributors in the pathogenesis of cholestatic diseases and ulcerative colitis, and studies examining patients with liver disease have found decreased antioxidant status and significant elevation of lipid peroxides as compared with healthy subjects. One hypothesis in liver disease is that deficient antioxidant defense mechanisms may lead to excess oxygen free radical formation, which promotes deleterious processes in the liver. The role of oxidant agents in cells is complex and depends on the balance between oxidant and antioxidant particles, but there is 1 potential marker of oxidative stress that can be readily utilized for our patients who are receiving nutrition support: γ-glutamyl transpeptidase (GGT). GGT is thought to induce oxidative stress in the artery wall in the presence of free iron and is likely an indicator of a depleted supply of glutathione, especially in the liver, which can lead to a cascade of problems related to increased oxidative stress. One could consider giving these patients liposomal glutathione or the components that make up glutathione, such as glycine, glutamine, and N-acetyl-cysteine, but unfortunately total parenteral nutrition (TPN) in the United States contains no cysteine or glutamine. Another possible way would be to give additional antioxidants, such as selenium and zinc, as well as vitamins A, C, and E. In this case report, I demonstrate the potential effect that switching from a straight ω-6 fatty acid solution to a blended fatty acid solution had on liver function tests, specifically GGT, for a 66-year-old patient dependent on TPN for the prior 16 months.}, }
@article {pmid29139022, year = {2018}, author = {Sato, Y and Yamada, S and Takeda, S and Hattori, N and Nakamura, K and Tanaka, H and Mizuno, M and Hori, M and Kodera, Y}, title = {Effect of Plasma-Activated Lactated Ringer's Solution on Pancreatic Cancer Cells In Vitro and In Vivo.}, journal = {Annals of surgical oncology}, volume = {25}, number = {1}, pages = {299-307}, doi = {10.1245/s10434-017-6239-y}, pmid = {29139022}, issn = {1534-4681}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Adhesion/drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Humans ; Injections, Intraperitoneal ; Male ; Mice ; Mice, Inbred BALB C ; Pancreatic Neoplasms/*drug therapy ; Peritoneal Neoplasms/*drug therapy ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: The medical applications of nonequilibrium atmospheric pressure plasma in cancer therapy have attracted attention. We previously reported on the antitumor effect of plasma-activated medium. However, this approach requires plasma-activated liquids that are administrable to the human body. In this study, we produced plasma-activated lactated Ringer's solution (PAL) and evaluated its antitumor effect and mechanism. Furthermore, we evaluated the effect of the intraperitoneal administration of PAL using a peritoneal dissemination mouse tumor model.<br><br>METHODS: The antitumor effect of PAL on pancreatic cancer cell lines was evaluated using proliferation and apoptosis assays. In addition, cellular reactive oxygen species (ROS) generation was examined. The role of ROS was assessed using a proliferation assay with N-acetyl cysteine (NAC). An adhesion assay was performed to evaluate the effect of PAL on cell adhesion. Finally, pancreatic cancer cells stably expressing luciferase (AsPC-1/CMV-Luc) were injected intraperitoneally into mice, followed by intraperitoneal injection of PAL. Peritoneal dissemination was monitored using in vivo bioluminescent imaging.<br><br>RESULTS: The antitumor effect of PAL was shown in all cell lines in vitro. The TUNEL assay showed that PAL induced apoptosis. ROS uptake was observed in PAL-treated cells, and the antitumor effect was inhibited by NAC. Cell adhesion also was suppressed by PAL. The intraperitoneal administration of PAL suppressed the formation of peritoneal nodules in vivo.<br><br>CONCLUSIONS: Our study demonstrated the antitumor effects of PAL in vitro and in vivo. Intraperitoneal administration of PAL may be a novel therapeutic option for peritoneal metastases.}, }
@article {pmid29137811, year = {2018}, author = {Gailer, J}, title = {Improving the safety of metal-based drugs by tuning their metabolism with chemoprotective agents.}, journal = {Journal of inorganic biochemistry}, volume = {179}, number = {}, pages = {154-157}, doi = {10.1016/j.jinorgbio.2017.11.008}, pmid = {29137811}, issn = {1873-3344}, support = {96114//CIHR/Canada ; }, mesh = {Acetylcysteine/chemistry/pharmacology ; Animals ; Antineoplastic Agents/blood/*pharmacology/toxicity ; Cisplatin/blood/*pharmacology/toxicity ; Glutathione/chemistry/pharmacology ; Humans ; Methionine/chemistry/pharmacology ; Protective Agents/chemistry/*pharmacology ; Sulfur Compounds/chemistry/*pharmacology ; Thiosulfates/chemistry/pharmacology ; }, abstract = {Metal-based drugs remain a tiny minority of all drugs that are on the market. The success story of the quintessential metal-based drug cisplatin (CP), which is intravenously administered to 70% of all cancer patients, however, demonstrates the inherent potential of metal-based drugs. A distinct disadvantage of CP is the dose-limiting severe toxic-side effects that it exerts in patients. To better understand the biomolecular basis for its toxicity, we employed a metallomics method to observe all platinum metabolites that are formed in blood plasma. These investigations revealed that a highly toxic CP-derived hydrolysis product - the highly toxic monoaqua hydrolysis complex (MHC) - is formed within 5min. More importantly, the application of this research tool has unraveled the mechanisms by which the chemoprotective agents sodium thiosulfate, d-methionine, N-acetyl-cysteine and l-glutathione modulate the metabolism of CP in plasma, namely by rapidly reacting with the MHC to form platinum‑sulfur complexes. Since CP remained in plasma for a considerable time, the possibility of 'tuning' its metabolism with chemoprotective agents in a desirable way has emerged. These observations are highly relevant because these chemoprotective agents were previously shown to significantly reduce the toxicity of CP in animal models, often without appreciably affecting its anticancer efficiency. Collectively, these results suggest that the toxicity of other metal-based drugs may be overcome if their metabolism in the bloodstream is adequately tuned with a suitable chemoprotective agent. This principle strategy has considerable potential in terms of harnessing the full potential of bringing more metal-based drugs to the market.}, }
@article {pmid29137484, year = {2018}, author = {Wang, JP and Chi, RF and Liu, J and Deng, YZ and Han, XB and Qin, FZ and Li, B}, title = {The role of endogenous reactive oxygen species in cardiac myocyte autophagy.}, journal = {Physiological research}, volume = {67}, number = {1}, pages = {31-40}, doi = {10.33549/physiolres.933653}, pmid = {29137484}, issn = {1802-9973}, mesh = {Animals ; Antioxidants/*pharmacology ; Autophagy/drug effects/*physiology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Hydrogen Peroxide/toxicity ; Male ; Myocytes, Cardiac/drug effects/*metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {Autophagy is implicated in the maintenance of cardiac homeostasis. Autophagy is activated in heart failure, in which reactive oxygen species (ROS) are increased. Exogenous ROS have been shown to induce cardiomyocyte autophagy alterations. However, little is known about the influences of physiological levels of endogenous ROS on cardiomyocyte autophagy. In the present study, we tested the hypothesis that endogenous ROS in cardiomyocytes play an important role in inducing autophagy. Cultured H9C2 cardiomyocytes or Sprague-Dawley rats were treated with the antioxidant N-acetyl-cysteine (NAC) or the superoxide dismutase mimic tempol under the basal or nutrient deprivation conditions. The autophagic flux was assessed by the lysosomal inhibitor chloroquine. In H9C2 cardiomyocytes, under a basal condition, NAC or tempol increased the ratio of LC3 II/I proteins and reduced LC3 II autophagic flux. Under nutrient deprivation, NAC increased the LC3 II/I ratio and reduced LC3 II autophagic flux. In vivo studies in rats, NAC treatment increased the LC3 II/I ratio and p-Akt protein expression in myocardium. We concluded that the antioxidants reduced autophagic flux in cardiomyocytes under the basal or nutrient deprivation conditions, suggesting that endogenous ROS promote autophagy flux under physiological conditions, and this effect is mediated, at least in part, through Akt inhibition.}, }
@article {pmid29132195, year = {2018}, author = {Kemp, R and Mole, J and Gomez, D and , }, title = {Current evidence for the use of N-acetylcysteine following liver resection.}, journal = {ANZ journal of surgery}, volume = {88}, number = {6}, pages = {E486-E490}, doi = {10.1111/ans.14295}, pmid = {29132195}, issn = {1445-2197}, mesh = {Acetylcysteine/*therapeutic use ; Evidence-Based Medicine ; Female ; Hepatectomy/adverse effects/*methods/mortality ; Humans ; Infusions, Intravenous ; Liver Failure/mortality/*surgery ; Male ; Multivariate Analysis ; Postoperative Care/methods ; Prognosis ; Randomized Controlled Trials as Topic ; Risk Assessment ; Survival Rate ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) has many uses in medicine; notable in the management of paracetamol toxicity, acute liver failure and liver surgery. The aim of this review was to critically appraise the published literature for the routine use of NAC in liver resection surgery.<br><br>METHODS: An electronic search was performed of EBSCOhost (Medline and CINAHL database), PubMed and the Cochrane Library for the period 1990-2016. MeSH headings: 'acetyl-cysteine', 'liver resection' and 'hepatectomy' were used to identify all relevant articles published in English.<br><br>RESULTS: Following the search criteria used, three articles were included. Two of these studies were randomized controlled trials. All the studies collated data on morbidity and mortality. All three studies did not show a significant difference in overall complications rates in patients that underwent hepatic resection that had NAC infusion compared with patients that did not. In one study, NAC administration was associated with a higher frequency of grade A post-hepatectomy liver failure. In another study, a significantly higher incidence of delirium was observed in the NAC group, which led to the trial to be terminated early.<br><br>CONCLUSION: The current published data do not support the routine use of NAC following liver resection.}, }
@article {pmid29126981, year = {2018}, author = {Sepehrmanesh, Z and Heidary, M and Akasheh, N and Akbari, H and Heidary, M}, title = {Therapeutic effect of adjunctive N-acetyl cysteine (NAC) on symptoms of chronic schizophrenia: A double-blind, randomized clinical trial.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {82}, number = {}, pages = {289-296}, doi = {10.1016/j.pnpbp.2017.11.001}, pmid = {29126981}, issn = {1878-4216}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Antipsychotic Agents/adverse effects/*therapeutic use ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Male ; Psychiatric Status Rating Scales ; Schizophrenia/*drug therapy ; Schizophrenic Psychology ; Treatment Outcome ; }, abstract = {BACKGROUND: Schizophrenia is one of the most disabling psychiatric syndromes with the prevalence of 1% in the general population. Despite availability of various antipsychotics, negative symptoms and cognitive impairment are difficult to treat. In addition antipsychotic monotherapy is not effective in most of these patients. Current evidence indicates the roles of glutamatergic system in this disorder. N-acetyl cysteine (NAC) also increases extracellular glutamate. This study was conducted to evaluate the clinical effects of oral NAC as an add-on to maintenance medication for the treatment of chronic schizophrenia.<br><br>MATERIALS AND METHODS: This 12-week, double-blind, randomized, placebo-controlled, clinical trial was performed to determine the effectiveness of 1200mg N-acetyl cysteine as an adjunctive treatment with conventional antipsychotic medications in 84 patients with chronic schizophrenia. The subjects were evaluated with the Positive and Negative Syndrome Scale (PANSS), Mini-Mental State Examination (MMSE), and a standard neuropsychological screening test. Data were analyzed with SPSS-16 software.<br><br>RESULTS: NAC-treated patients showed significantly improvement in the positive (F=5.47, P=0.02) and negative (F=0.20, df=1) PANSS subscale. Also the general and total PANSS score of NAC group declined over times whilst it was increased for placebo group. Regarding cognitive functions, improvement was observed in some explored areas, such as attention, short-term and working memory, executive functioning and speed of processing. There was no significant difference between the 2 groups in the frequency of adverse effects.<br><br>CONCLUSION: The present study detected improvement in positive, negative, general and total psychopathology symptoms as well as cognitive performance with NAC treatment. It is also well-tolerated, safe and easy-to-use agent as an effective therapeutic strategy to improve outcome in schizophrenia treatment.}, }
@article {pmid29125808, year = {2017}, author = {Li, M and Zhang, X and Yu, J and Wu, X and Sun, L}, title = {Monocyte-Derived Procoagulant Microvesicles Induced by High Glucose Can Be Attenuated by the Antioxidant N-Acetyl-L-Cysteine, Partly Through the P38/MAPK Pathway.}, journal = {Metabolic syndrome and related disorders}, volume = {15}, number = {10}, pages = {521-526}, doi = {10.1089/met.2017.0089}, pmid = {29125808}, issn = {1557-8518}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Blood Coagulation/*drug effects ; Cell Line ; Cytoplasmic Vesicles/*drug effects ; Diabetes Mellitus/metabolism ; Glucose/*antagonists &amp; inhibitors/*pharmacology ; Humans ; MAP Kinase Signaling System/*drug effects ; Monocytes/*drug effects ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/*drug effects ; }, abstract = {BACKGROUND: Microvesicles (MVs) are small membrane vesicles that are derived from many different cell types by a process of exocytic budding of the plasma membrane. MVs may be associated with a higher incidence of vascular disease in diabetic patients, but the mechanism of this association is unclear. Diabetic patients also show hypercoagulability and platelet hyperaggregability. In this study, we investigated the generation and activity of high glucose (HG)-induced MVs from monocytes to elucidate the potential mechanism of such MVs in diabetes.<br><br>METHODS: HG-induced MV generation from THP-1 monocytes before and after N-acetyl-L-cysteine (NAC) treatment was examined by enzyme-linked immunosorbent assay. MV activity was measured by spectrophotometry. Apoptosis and generation of reactive oxidative species (ROS) from THP-1 cells were detected by flow cytometry. Extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and P38/MAPK pathway components were also analyzed in treated monocytes.<br><br>RESULTS: MVs were generated from THP-1 cells after 20&#x2009;hr of exposure to HG (4.6-fold higher than untreated control cells), which was concomitant with a 3.3-fold increase in apoptosis (P&#x2009;<&#x2009;0.01). The procoagulant activity (PCA) of the generated MVs was increased significantly by 4.1-fold (P&#x2009;<&#x2009;0.01) relative to untreated cells. ROS levels peaked 2&#x2009;hr after HG exposure. The frequency of MVs was greatly decreased after NAC treatment (P&#x2009;<&#x2009;0.01). Both the ERK/MAPK and P38/MAPK pathway were activated after HG stimulation, whereas treatment with a P38 inhibitor decreased MV generation by 66% compared to untreated control.<br><br>CONCLUSIONS: The generation of monocyte-derived MVs induced by HG was associated with PCA, concomitant with apoptosis and ROS generation. The P38/MAPK pathway was partly involved in this process as evidenced by the reduction in MV generation following treatment with a P38 inhibitor. Our results could provide insights into novel mechanisms of thrombogenicity in an HG state.}, }
@article {pmid29123322, year = {2017}, author = {Azimi, I and Petersen, RM and Thompson, EW and Roberts-Thomson, SJ and Monteith, GR}, title = {Hypoxia-induced reactive oxygen species mediate N-cadherin and SERPINE1 expression, EGFR signalling and motility in MDA-MB-468 breast cancer cells.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {15140}, pmid = {29123322}, issn = {2045-2322}, mesh = {Breast Neoplasms/*pathology ; Cadherins/*metabolism ; Cell Line, Tumor ; *Cell Movement ; ErbB Receptors/metabolism ; Gene Expression ; Gene Expression Regulation ; Gene Regulatory Networks ; Humans ; *Hypoxia ; Plasminogen Activator Inhibitor 1/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {One of the hallmarks of the tumour microenvironment is hypoxia resulting from increased oxygen consumption by proliferative cancer cells and altered vasculature. Hypoxic tension initiates various cellular signals and can drive epithelial to mesenchymal transition (EMT), a process important in cancer progression. In this study, using the antioxidant N-acetylcysteine (NAC), we show that hypoxia-induced reactive oxygen species (ROS) in MDA-MB-468 breast cancer cells, selectively regulate hypoxia-induced increases in N-cadherin and SERPINE1, two proteins involved in cell adhesion. Treatment of cells with NAC also attenuated hypoxia-mediated activation of EGFR, but did not have any effect on hypoxia-mediated induction of HIF1α. Exogenous hydrogen peroxide phenocopied the effects of hypoxia on N-cadherin and SERPINE1 expression and EGFR activation, suggesting its possible involvement in these hypoxia-mediated events. Reflective of their effect on cell adhesion proteins and EGFR (associated with migratory phenotypes), NAC also reduced cell migration under hypoxic conditions, a crucial event in metastasis. Our findings suggest a selective role for redox signalling in the regulation of specific components of the responses to hypoxia and induction of EMT in breast cancer cells. This study provides new evidence supporting the potential of targeting ROS as a therapeutic strategy for the control of breast cancer metastasis.}, }
@article {pmid29122013, year = {2017}, author = {David, J and Nandakumar, A and Muniroh, M and Akiba, S and Yamamoto, M and Koriyama, C}, title = {Suppression of methylmercury-induced MIP-2 expression by N-acetyl-L-cysteine in murine RAW264.7 macrophage cell line.}, journal = {European journal of medical research}, volume = {22}, number = {1}, pages = {45}, pmid = {29122013}, issn = {2047-783X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chemokine CXCL2/*biosynthesis ; Cytokines/biosynthesis ; Macrophages/*drug effects/immunology ; Methylmercury Compounds/*toxicity ; Mice ; RAW 264.7 Cells ; }, abstract = {BACKGROUND: The aim of this study is to examine the inflammatory-cytokine expressions in the presence of non-cytotoxic dose of methylmercury (MeHg) in murine macrophages, which is suspected to play an important role in brain damage caused by MeHg exposure. We focused on murine macrophage inflammatory protein-2 (MIP-2), keratinocyte chemoattractant (KC), and monocyte chemoattractant protein-5 (MCP-5). MIP-2 and KC are murine functional homologues of human IL-8 and MCP-5 for human MCP-1. Furthermore, we examined the suppressive effect of N-acetyl-L-cysteine (NAC) on the MeHg-induced inflammatory cytokines.<br><br>METHODS: In a murine RAW264.7 macrophage cell line, MeHg-induced cytokine expressions were measured using real-time PCR. The suppressive effect of NAC was examined by putting it into the culture medium together with MeHg (co-treatment). In addition, pre- and post-treatment experiments were conducted, in which the cells were treated with NAC before and after MeHg exposure, respectively.<br><br>RESULTS: Exposure to a non-cytotoxic dose of MeHg up-regulated the mRNA expression of MIP-2 and MCP-5. On the other hand, KC expression was not induced in the presence of MeHg. Effect of MeHg on MIP-2 expressions was suppressed by pre-, co-, and post-treatment with NAC. However, the suppressive effect of pre-treatment was less than the post-treatment, which was as effective as co-treatment.<br><br>CONCLUSION: In functional homologues of human IL-8, only MIP-2 expression, not KC, was activated in the presence of non-cytotoxic dose of MeHg in murine RAW264.7 macrophage cell line. The more evident inhibitory effect of NAC observed in post-treatment experiments suggests a possible involvement of intracellular activities such as antioxidant effects.}, }
@article {pmid29120799, year = {2018}, author = {Wang, LL and Yu, QL and Han, L and Ma, XL and Song, RD and Zhao, SN and Zhang, WH}, title = {Study on the effect of reactive oxygen species-mediated oxidative stress on the activation of mitochondrial apoptosis and the tenderness of yak meat.}, journal = {Food chemistry}, volume = {244}, number = {}, pages = {394-402}, doi = {10.1016/j.foodchem.2017.10.034}, pmid = {29120799}, issn = {1873-7072}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Calcium/metabolism ; Catalase/metabolism ; Cattle ; Cytochromes c/metabolism ; Food Quality ; Glutathione Peroxidase/metabolism ; Hydrogen Peroxide/pharmacology ; Male ; *Meat ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Muscle/drug effects/*metabolism/pathology ; *Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {This study investigated the effect of reactive oxygen species-mediated oxidative stress on activation of mitochondrial apoptosis and tenderness of yak meat during postmortem ageing. Oxidative stress degree, Ca[2+] levels, membrane permeability transition pore opening, mitochondrial membrane potential, apoptotic factors and the shear force were examined. Results showed that the ROS generated by H2O2 significantly increased mitochondrial oxidative stress by decreasing the activities of superoxide dismutase, catalase and glutathione peroxidase, and increasing lipid peroxidation. Furthermore, oxidative stress enhanced Ca[2+] production and cytochrome c release, changed the levels of Bcl-2 family proteins and activated caspase-9 and -3 activities. Ultimately, oxidative stress increased the apoptosis rate and tenderness of yak meat. These observations confirmed that ROS-mediated oxidative stress participates in the activation of the apoptotic cascade reaction involving Ca[2+] and Bcl-2 family proteins. The results further suggested that ROS-mediated oxidative stress plays a significant role in meat tenderization through the mitochondrial apoptotic pathway.}, }
@article {pmid29117515, year = {2018}, author = {Rogalska, A and Bukowska, B and Marczak, A}, title = {Metformin and epothilone A treatment up regulate pro-apoptotic PARP-1, Casp-3 and H2AX genes and decrease of AKT kinase level to control cell death of human hepatocellular carcinoma and ovary adenocarcinoma cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {47}, number = {}, pages = {48-62}, doi = {10.1016/j.tiv.2017.11.001}, pmid = {29117515}, issn = {1879-3177}, mesh = {Adenocarcinoma/drug therapy/metabolism ; Antineoplastic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/drug therapy/metabolism ; Caspase 3/chemistry/genetics/metabolism ; Cell Line, Tumor ; DNA Damage ; Drug Resistance, Neoplasm ; Epothilones/*pharmacology ; Female ; Gene Expression Regulation, Neoplastic/*drug effects ; Histones/agonists/genetics/metabolism ; Humans ; Hypoglycemic Agents/pharmacology ; Liver Neoplasms/*drug therapy/metabolism/pathology ; Metformin/*pharmacology ; Neoplasm Proteins/agonists/antagonists &amp; inhibitors/genetics/metabolism ; Ovarian Neoplasms/*drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; Poly (ADP-Ribose) Polymerase-1/chemistry/genetics/metabolism ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/metabolism ; }, abstract = {High mortality rates in ovarian and liver cancer are largely a result of resistance to currently used chemotherapy. Here, we investigated genotoxic and pro-oxidant effects of metformin (MET) and epothilone A (A) in combination with respect to apoptosis in HepG2 and SKOV-3 cancer cells. Reactive oxygen species (ROS) was studied using 2',7'-dichlorodihydrofluoresein diacetate, and samples were analyzed for the presence and absence of the N-acetylcysteine (NAC). Expression of genes involved in programmed cell death, oxidative and alkylating DNA damage was measured. Probes were analyzed in the presence of Akt or nuclear factor-κB inhibitor. Compared to either drug alone, combination of epothilone A and metformin was more potent; decreased Akt level; and elevated percentage of apoptotic cells, induced cell cycle arrest at G1 phase and elevated the sub-G1 cell population by increasing the mRNA level of caspase-3, poly (ADP-ribose) polymerase-1 and H2AX. The anticancer effect of the drug combination was partially reversed by NAC supplementation, suggesting that ROS generation is required to induce apoptosis. The present study demonstrates that novel combination such as epothilone A and MET show promise in expanding ovarian and liver cancer therapy.}, }
@article {pmid29116368, year = {2018}, author = {Swanepoel, T and Möller, M and Harvey, BH}, title = {N-acetyl cysteine reverses bio-behavioural changes induced by prenatal inflammation, adolescent methamphetamine exposure and combined challenges.}, journal = {Psychopharmacology}, volume = {235}, number = {1}, pages = {351-368}, pmid = {29116368}, issn = {1432-2072}, support = {77323//South African National Research Foundation/International ; }, mesh = {3,4-Dihydroxyphenylacetic Acid ; Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Antioxidants/*pharmacology ; Behavior, Animal/*drug effects ; Biogenic Monoamines/metabolism ; Corpus Striatum/drug effects ; Cytokines/metabolism ; Dopamine/metabolism ; Female ; Form Perception/drug effects ; Free Radical Scavengers/*pharmacology ; Inflammation/complications ; Lipid Peroxidation/drug effects ; Lipopolysaccharides/toxicity ; Male ; Memory/drug effects ; Methamphetamine/administration &amp; dosage/*toxicity ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced ; Prepulse Inhibition/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Recognition, Psychology/drug effects ; Reflex, Startle/drug effects ; Schizophrenia/chemically induced/*drug therapy/metabolism ; Serotonin ; Social Behavior ; }, abstract = {RATIONALE: Schizophrenia is associated with prenatal inflammation and/or postnatal stressors such as drug abuse, resulting in immune-redox dysfunction. Antioxidants may offer therapeutic benefits.<br><br>OBJECTIVES: The objective of this study is to investigate N-acetyl cysteine (NAC) as a therapeutic antioxidant to reverse schizophrenia-like bio-behavioural changes in rats exposed to maternal immune activation (MIA), adolescent methamphetamine (MA) or a combination thereof.<br><br>METHODS: Sprague-Dawley offspring prenatally exposed to saline/lipopolysaccharide (LPS) received saline or MA (0.2-6&#xa0;mg&#xa0;kg[-1] twice daily&#xa0;&#xd7;&#xa0;16&#xa0;days) during adolescence and divided into LPS, MA and LPS + MA groups. Vehicle/NAC (150&#xa0;mg&#xa0;kg[-1]&#xa0;&#xd7;&#xa0;14&#xa0;days) was administered following MA/saline exposure on postnatal day 51-64. Social interaction, novel object recognition and prepulse inhibition (PPI) of startle, as well as regional brain monoamines, lipid peroxidation, plasma reactive oxygen species (ROS) and pro- and anti-inflammatory cytokines (TNF-&#x3b1;; IL-10), were assessed.<br><br>RESULTS: NAC reversed LPS, MA and LPS + MA-induced anxiety-like social withdrawal behaviours, as well as MA and LPS + MA-induced deficits in recognition memory. PPI deficits were evident in MA, LPS and LPS + MA models, with NAC reversing that following LPS + MA. NAC reversed LPS, MA and LPS + MA-induced frontal cortical dopamine (DA) and noradrenaline (NA) elevations, LPS and LPS + MA-induced frontal cortical 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and striatal NA deficits as well as LPS + MA-induced frontal cortical 5-HT turnover. Decreased IL-10 in the LPS, MA and LPS + MA animals, and increased TNF-&#x3b1; in the LPS and MA animals, was reversed with NAC. NAC also reversed elevated lipid peroxidation and ROS in the LPS and LPS + MA animals.<br><br>CONCLUSIONS: Prenatal LPS, LPS + postnatal MA challenge during adolescence, and to a lesser extent MA alone, promotes schizophrenia-like bio-behavioural changes later in life that are reversed by NAC, emphasizing therapeutic potential for schizophrenia and MA-associated psychosis. The nature and timing of the dual-hit are critical.}, }
@article {pmid30090499, year = {2017}, author = {Mao, Y and Zhang, M and Yang, J and Sun, H and Wang, D and Zhang, X and Yu, F and Li, J}, title = {The UCP2-related mitochondrial pathway participates in rhein-induced apoptosis in HK-2 cells.}, journal = {Toxicology research}, volume = {6}, number = {3}, pages = {297-304}, pmid = {30090499}, issn = {2045-452X}, abstract = {Rhein is one of the main active compounds in total rhubarb anthraquinones (TRAs) that were reported to cause nephrotoxicity. This paper explored the mechanism of how rhein induced apoptosis in human renal proximal tubular epithelial cells (HK-2 cells). In this study, rhein was found to induce apoptosis in HK-2 cells according to the results of annexin V/PI staining assay. The underlying mechanisms were investigated, and the mitochondria-mediated pathway was found to be critical. A series of related biological events were explored, including the disruption of mitochondrial membrane potential (MMP), the decrease of the ATP level, the release of cytochrome c (Cyt-c) from the mitochondrion to the cytosol, and down-regulation of Bcl-2 and up-regulation of Bax. Furthermore, rhein significantly increased the levels of ROS and inhibited the expression of mitochondrial uncoupling protein 2 (UCP2). UCP2 inhibition dramatically boosted oxidative stress and exacerbated rhein-induced apoptosis, whereas co-incubation with an ROS scavenger N-acetylcysteine (NAC) could decrease rhein-induced apoptosis. In conclusion, our results have demonstrated that rhein induced apoptosis in HK-2 cells via the UCP2-related mitochondrial pathway and rhein might be a weak inhibitor of UCP2. Our findings provide new evidence that UCP2 plays an important role in the mitochondrial apoptotic pathway.}, }
@article {pmid30460002, year = {2016}, author = {Manjunath, KS and Udnur, H}, title = {HRCT diagnosis of combined pulmonary fibrosis and emphysema in a patient of chronic obstructive pulmonary disease with pulmonary hypertension and clinical or radiograph suspicion of pulmonary fibrosis.}, journal = {BJR case reports}, volume = {2}, number = {4}, pages = {20150070}, pmid = {30460002}, issn = {2055-7159}, abstract = {Combined pulmonary fibrosis and emphysema (CPFE) is a unique pulmonary condition characterized by simultaneous coexistence of both upper lobe emphysema and lower lobe fibrosis. Pulmonologists should be aware of the entity while evaluating patients with chronic obstructive pulmonary disease (COPD) or pulmonary fibrosis. Airflow and lung volume are relatively preserved but oxygenation is disproportionately impaired in patients with CPFE. We describe a case of an 83-year-old male patient with past history of heavy smoking, in whom the search for the cause of pulmonary arterial hypertension and exercise-induced arterial oxygen desaturation disproportionate to be explained by COPD resulted in a diagnosis of CPFE. He complained of dyspnoea on exertion and non-productive cough. Physical examination revealed basal Velcro rales and clubbing. Chest radiography showed prominent vascular markings, preserved lung volume and subtle fibrosis of the bases. Definitive diagnosis was made on CT scan of the chest, which revealed upper lobe emphysema and lower lobe fibrosis and honeycombing. The patient was managed by long-term oxygen therapy, inhaled corticosteroid, long-acting bronchodilator and antimuscarinic agents, diuretic, pirfenidone (antifibrotic agent), proton pump inhibitor and N-acetyl cysteine (antioxidant). We emphasize the importance of the diagnosis of CPFE in early stages through CT in a case of COPD with clinical, laboratory and chest radiographic evidence of fibrosis and the fact that CPFE is associated with pulmonary hypertension, a poor prognostic indicator.}, }
@article {pmid30090463, year = {2016}, author = {Tian, X and Xiao, BB and Wu, A and Yu, L and Zhou, J and Wang, Y and Wang, N and Guan, H and Shang, ZF}, title = {Hydroxylated-graphene quantum dots induce cells senescence in both p53-dependent and -independent manner.}, journal = {Toxicology research}, volume = {5}, number = {6}, pages = {1639-1648}, pmid = {30090463}, issn = {2045-452X}, abstract = {The numerous particular chemical/physical properties make graphene quantum dots (GQDs) attractive for various biomedical applications such as drug delivery, bioimaging and tumor photodynamic therapy (PDT). In the present study, the critical roles of hydroxyl-modified GQDs (OH-GQDs) on lung carcinoma A549 (wild type p53) and H1299 (p53-null) cells were investigated. Our data showed that a medium concentration (50 μg mL[-1]) of OH-GQDs significantly decreased the viability of A549 and H1299 cells. OH-GQDs treatment enhanced intracellular reactive oxygen species (ROS) generation. Furthermore, we found that treatment with ROS scavenger N-acetylcysteine (NAC) at least partially abolished the cytotoxic effect of OH-GQDs on A549 and H1299 cells. Hydroxylated GQDs lead to G0-G1 arrest and cells senescence. Signal pathway analysis revealed that OH-GQDs activated the expression of p21 in both a p53-dependent and -independent manner. Consistent with this, OH-GQDs could also inhibit the phosphorylation of Rb in both A549 and H1299 cells. These findings provide valuable information for the consideration of biomedical application of GQDs in the future.}, }
@article {pmid30123617, year = {2016}, author = {Wang, W and Sun, H and Che, Y and Jiang, X}, title = {Rasfonin promotes autophagy and apoptosis via upregulation of reactive oxygen species (ROS)/JNK pathway.}, journal = {Mycology}, volume = {7}, number = {2}, pages = {64-73}, pmid = {30123617}, issn = {2150-1203}, abstract = {Rasfonin is a fungal secondary metabolite demonstrating with antitumour effects. Reactive oxygen species (ROS) are formed as a natural by-product of the normal metabolism of oxygen and have important roles in cell signalling and homeostasis. Studies reported that many fungal secondary metabolites activated either autophagy or apoptosis through ROS generation. In former study, we revealed that rasfonin induced both autophagy and apoptosis, however, whether it promoted aforementioned processes via upregulation of ROS generation remains explored. In the current work, we demonstrated that rasfonin induced autophagy and apoptosis concomitant with a dramatically ROS production. N-Acetylcysteine (NAC), an often used ROS inhibitor, decreased both autophagic flux and caspase-dependent apoptosis by rasfonin. Flow cytometry analysis revealed NAC was able to reduce rasfonin-dependent apoptosis and necrosis. In methanethiosulfonate (MTS) assay, we observed that NAC significantly blocked rasfonin-induced cell viability loss. In addition, we found that rasfonin increased the phosphorylation of c-Jun NH2-terminal kinase (JNK), which was inhibited by NAC. SP600125, an inhibitor of JNK, reduced rasfonin-dependent autophagic flux and apoptosis. Moreover, we demonstrated that rasfonin inhibited the phosphorylation of both 4E-binding protein 1 (4E-BP1) and S6 kinase 1 (S6K1), two main substrates of mammalian target of rapamycin (mTOR). Collectively, rasfonin activated autophagy and apoptosis through upregulation of ROS/JNK signalling.}, }
@article {pmid29756048, year = {2016}, author = {Lu, Y and Cederbaum, AI}, title = {Alcohol Upregulation of CYP2A5: Role of Reactive Oxygen Species.}, journal = {Reactive oxygen species (Apex, N.C.)}, volume = {1}, number = {2}, pages = {117-130}, pmid = {29756048}, issn = {2380-2367}, support = {R01 AA018790/AA/NIAAA NIH HHS/United States ; R21 AA020877/AA/NIAAA NIH HHS/United States ; R21 AA021362/AA/NIAAA NIH HHS/United States ; }, abstract = {Hepatic cytochrome P450 (CYP) 2E1 and CYP2A5 activate many important drugs and hepatotoxins. CYP2E1 is induced by alcohol, but whether CYP2A5 is upregulated by alcohol is not known. This article reviews recent studies on the induction of CYP2A5 by alcohol and the mechanism and role of reactive oxygen species (ROS) in this upregulation. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity and protein and mRNA levels. This induction was blunted in CYP2E1 knockout mice and by a CYP2E1 inhibitor, but was restored in CYP2E1 knockin mice, suggesting a role for CYP2E1 in the induction of CYP2A5 by alcohol. Since CYP2E1 actively generates ROS, the possible role of ROS in the induction of CYP2A5 by alcohol was determined. ROS production was elevated by ethanol treatment. The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol-induced elevation of ROS and blunted the alcohol-mediated induction of CYP2A5. These results suggest that ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. Alcohol treatment activated nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), a transcription factor which up-regulates expression of CYP2A5. The antioxidants blocked the activation of Nrf2. The alcohol-induced elevation of CYP2A5, but not CYP2E1, was lower in Nrf2 knockout mice. We propose that increased generation of ROS from the alcohol-induced CYP2E1 activates Nrf2, which subsequently up-regulates the expression of CYP2A5. Thus, a novel consequence of the alcohol-mediated induction of CYP2E1 and increase in ROS is the activation of redox-sensitive transcription factors, such as Nrf2, and expression of CYP2A5. Further perspectives on this alcohol-CYP2E1-ROS-Nrf2-CYP2A5 pathway are presented.}, }
@article {pmid29629310, year = {2015}, author = {Pritchard, NL and Keane, JL}, title = {Wound haematoma: The first sign in a case of late postpartum HELLP syndrome.}, journal = {Case reports in women's health}, volume = {8}, number = {}, pages = {1-3}, pmid = {29629310}, issn = {2214-9112}, abstract = {HELLP syndrome, a severe manifestation of preeclampsia characterised by haemolysis, elevated liver enzymes, and thrombocytopaenia, occurs in 0.5-0.9% of pregnancies and is associated with significant maternal and fetal morbidity and mortality. We present the case of a 30 year old primigravida (RL) who developed a wound haematoma nearly 72 h after an emergency caesarean section for failure to progress, with no prior hypertension or proteinuria documented. Although RL remained completely asymptomatic, investigations for delayed bleeding revealed severe class I HELLP syndrome with a platelet count of < 50,000 μL, significant haemolysis (haptoglobin < 0.06, LDH 1585), acute renal failure (eGFR 64, creatinine 103), fulminant hepatic failure (AST 2539, ALT 3200) and significant autoanticoagulation (INR 3.2, activated prothrombin time 46, fibrinogen 3.0). Paracetamol had been administered for post-operative analgesia and a paracetamol level was in the toxic level. Multidisciplinary input was sought from anaesthetics, intensive care, toxicology, general medicine, haematology and gastroenterology, with care subsequently coordinated in an intensive care unit. Blood pressure was strictly controlled with a sodium nitroprusside infusion. In addition to supportive care, vitamin K, a N-acetyl cysteine infusion, lactulose and mechanical thromboprophylaxis were administered. Eight weeks postpartum there were no residual biochemical abnormalities, the patient was well, and had a normal blood pressure. Our case reinforces the importance of a high level of clinical suspicion for the HELLP syndrome in women, irrespective of blood pressure in the first 48 h postpartum.}, }
@article {pmid29805908, year = {2014}, author = {Tsoy, A and Umbayev, B and Shalakhmetova, T and Askarova, S}, title = {Role of ROS in Aβ42 Mediated Activation of Cerebral Endothelial Cells.}, journal = {Central Asian journal of global health}, volume = {3}, number = {Suppl}, pages = {179}, doi = {10.5195/cajgh.2014.179}, pmid = {29805908}, issn = {2166-7403}, abstract = {INTRODUCTION: There is substantial evidence that the deposition of aggregated amyloid-beta peptide (Aβ) in brain parenchyma and brain vessels is the main cause of neuronal dysfunction and death in Alzheimer's disease (AD). Aβ exhibits multiple cytotoxic effects on neurons and glial cells and causes dysfunction of the blood brain barrier (BBB). In AD brains, an increased deposition of Aβ in the cerebral vasculature has been found to be correlated with increased transmigration of blood-borne inflammatory cells and neurovascular inflammation. However, regulatory mediators of these processes remain to be elucidated. In this study, we examined the role of ROS in actin polymerization and expression of adhesion molecules (P-selectin) on the surface of the cerebral endothelial cells (CECs) that are activated by Aβ42.<br><br>MATERIALS AND METHODS: Mouse BEnd3 line (ATCC) was used in this research. BEnd3 cells respond to A&#x3b2; treatment similarly to human primary CECs and are a common model to investigate CECs' function. We used immortalized bEnd3 cells as the following: controls; cells incubated with A&#x3b2;42 for 10, 30, and 60 minutes; cells incubated with 30 mM of antioxidant N-acetylcysteine (NAC) for 1 hr; and, cells pre-treated with NAC followed by A&#x3b2;42 exposure. We measured DHE fluorescence to investigate intracellular ROS production. Immunofluorescent microscopy of anti-P-selectin and oregon green phalloidin was used to quantify the surface P-selectin expression and actin polymerization, and Western blot analysis was used to analyze total P-selectin expression.<br><br>RESULTS: The results of this study have demonstrated a significant time-dependent ROS accumulation after 10 minutes, 30 minutes, and 60 minutes of A&#x3b2;42 treatment, while A&#x3b2;42 stimulated ROS production in CECs was attenuated by pre-treatment with the NAC antioxidant. We also found that A&#x3b2;42 increased P-selectin fluorescence at the surface of bEnd3 cells in a time dependent manner in parallel to ROS elevation. However, total expression levels of P-selectin were not changed following exposure to A&#x3b2;42. Pretreatment with NAC attenuated A&#x3b2;42 induced P-selectin localization, while NAC alone did not significantly affect P selectin localization. As a positive control, H2O2 also increased P-selectin expression on the cell surface, which peaked after 30 minutes of H2O2 treatment. Exposure of CECs with A&#x3b2;42 promoted actin polymerization, which peaked after 10 minutes of A&#x3b2;42 treatment, while no significant increase of F-actin intensity was observed when cells were pre-treated with NAC. H2O2 was able to mimic A&#x3b2;42 induced oxidative stress, causing increased actin polymerization with similar timing.<br><br>CONCLUSIONS: The results of our study have indicated that A&#x3b2;42 induced accumulation of P-selectin on the surface of bEnd3 cells and promoted actin polymerization, and all these events were correlated with ROS generation. The rapid post-translational cell signaling response mediated by ROS may well represent an important physiological trigger of the microvascular inflammatory responses in AD and requires further investigations.}, }
@article {pmid30625885, year = {2009}, author = {Park, JH and Kim, TK and Kim, HK and Baik, SW}, title = {Apoptosis of the GABAergic interneuron in the dorsal horn of the chronic post-ischemic pain model.}, journal = {Korean journal of anesthesiology}, volume = {57}, number = {3}, pages = {350-357}, doi = {10.4097/kjae.2009.57.3.350}, pmid = {30625885}, issn = {2005-7563}, abstract = {BACKGROUND: It is well known that the GABAergic inhibitory interneuronal system plays an important role in modulation of the noxious stimulation transmitted from the primary afferent input. Some studies have revealed the role that the GABA inhibitory interneuronal system plays in the modulation of pain transmission and the changes in the GABAergic interneurons that occur during the neuropathic pain. This study was conducted to evaluate the apoptosis of the GABAergic interneuron, which is assumed to contribute to neuropathic pain.<br><br>METHODS: Male Sprague-Dawley rats weighing 290-310 g were used to create a CPIP (chronic post-ischemic pain) model, which was made by placing a tourniquet on the left hindpaw of the rats. The tourniquet was maintained for 3 hours, after which it was released to allow reperfusion. Thirty minutes prior to reperfusion, N-acetyl-L-cysteine (NAC group) or normal saline (control group) was injected. After reperfusion, mechanical allodynia and cold allodynia were measured. In addition, the release of cytochrome c into the cytosol was evaluated through western blot or immunohistochemistry of the spinal cord.<br><br>RESULTS: Mechanical and cold allodynia developed and the number of GABA interneurons was reduced in the control group. Additionally, The cytochrome c from the GABA interneuron was released into the cytosol in the control group, but the amount released was reduced in response to treatment with NAC.<br><br>CONCLUSIONS: The results of this study showed that the GABA interneuron in the Rexed laminae I, II released cytochrome c into the cytosol in CPIP neuropathic pain model, which is known to lead to apoptosis. However, treatment with N-acetyl-L-cysteine prevented this process.}, }
@article {pmid29115506, year = {2018}, author = {Wang, C and Zhang, C and Zhou, F and Gao, L and Wang, Y and Wang, C and Zhang, Y}, title = {Angiotensin II induces monocyte chemoattractant protein‑1 expression by increasing reactive oxygen species‑mediated activation of the nuclear factor‑κB signaling pathway in osteoblasts.}, journal = {Molecular medicine reports}, volume = {17}, number = {1}, pages = {1166-1172}, doi = {10.3892/mmr.2017.7971}, pmid = {29115506}, issn = {1791-3004}, mesh = {Angiotensin II/*metabolism/pharmacology ; Animals ; Cell Line ; Chemokine CCL2/*genetics/metabolism ; Enzyme Activation ; *Gene Expression ; Mice ; NF-kappa B/*metabolism ; Osteoblasts/drug effects/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptor, Angiotensin, Type 1/genetics/metabolism ; *Signal Transduction/drug effects ; }, abstract = {The present study investigated the effect of angiotensin II (Ang II) on monocyte chemoattractant protein‑1 (MCP‑1) expression and the underlying mechanism in osteoblasts. MCP‑1 expression levels were analyzed by ELISA and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Ang II type 1 receptor (AT1R) expression levels was examined by RT‑qPCR, western blotting and immunostaining. In addition, the nuclear factor (NF)‑κB signaling pathway was investigated via western blot analysis. Reactive oxygen species (ROS) were also detected by flow cytometry and fluorescent microscopy. The results of the present study ndicated that Ang II upregulated MCP‑1 expression in osteoblasts, which was mitigated by agonists of the AT1R, including olmesartan, a ROS scavenger N‑acetylcysteine (NAC), ammonium pyrrolidinethiocarbamate (PDTC) and nuclear factor (NF)‑κB, but not by the Ang II type 2 receptor antagonist, PD123319. Furthermore, Ang II increased the generation of ROS and activated the NF‑κB signaling pathway. These effects of Ang II were blocked by olmesartan, NAC and PDTC, but not by PD1123319 in osteoblasts. In conclusion, these data indicated that Ang II enhanced ROS production and activated NF‑κB signaling via AT1R, thus upregulating MCP‑1 expression in osteoblasts.}, }
@article {pmid29114910, year = {2018}, author = {Zhang, L and Xu, S and Huang, Q and Xu, H}, title = {N-acetylcysteine attenuates the cuprizone-induced behavioral changes and oligodendrocyte loss in male C57BL/7 mice via its anti-inflammation actions.}, journal = {Journal of neuroscience research}, volume = {96}, number = {5}, pages = {803-816}, doi = {10.1002/jnr.24189}, pmid = {29114910}, issn = {1097-4547}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Behavior, Animal/*drug effects ; Brain/drug effects/metabolism/pathology ; Chelating Agents/pharmacology ; Cuprizone/*pharmacology ; Drug Interactions ; Glutathione Peroxidase/metabolism ; Interleukin-1beta/metabolism ; Male ; Malondialdehyde/metabolism ; Memory, Short-Term/drug effects ; Mice, Inbred C57BL ; Microglia/drug effects/metabolism/pathology ; Oligodendroglia/*drug effects/metabolism/pathology ; Random Allocation ; Recognition, Psychology/drug effects ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Previous animal studies have linked white matter damage to certain schizophrenia-like behaviors in cuprizone (CPZ)-exposed mouse. Mitochondrial dysfunction, oxidative stress, neuroinflammation, and oligodendrocyte loss coexist in the brain of such mice. The aim of this study was to examine effects of the antioxidant N-acetylcysteine (NAC) on CPZ-induced behavioral changes and concurrent oligodendrocyte loss, oxidative stress, and neuroinflammation in these animals. Male C57BL/6 mice were given intraperitoneal saline or NAC at doses of 100, 200, and 400 mg/kg/day for 2 weeks; animals were fed a CPZ-containing diet (0.2%, w/w) during days 5-14. During days 15-17, the mice were examined in open-field, social recognition, and Y-maze tests (1 test per day). Six mice in each group were then used for biochemical and enzyme-linked immunosorbent assay analyses, while the remaining animals were used for immunohistochemical and immunofluorescence staining. The mice exposed to CPZ for 10 days showed significantly lower spontaneous alternation in the Y-maze, lower activity of total superoxide dismutase, and glutathione peroxidase, but higher levels of malondialdehyde in the cerebral cortex and hippocampus, elevated concentrations of interleukin-1β and tumor necrosis factor-α in the brain regions mentioned above and caudate putamen, and a decreased number of mature oligodendrocytes, but increased number of microglia in all the brain regions examined. These changes, however, were not seen or effectively alleviated in NAC-treated mice at all three doses. These results demonstrate that NAC protected mature oligodendrocytes against the toxic effects of CPZ, likely via its antioxidant and anti-inflammatory actions.}, }
@article {pmid29111231, year = {2017}, author = {Ding, R and Zhang, C and Zhu, X and Cheng, H and Zhu, F and Xu, Y and Liu, Y and Wen, L and Cao, J}, title = {ROS-AKT-mTOR axis mediates autophagy of human umbilical vein endothelial cells induced by cooking oil fumes-derived fine particulate matters in vitro.}, journal = {Free radical biology &amp; medicine}, volume = {113}, number = {}, pages = {452-460}, doi = {10.1016/j.freeradbiomed.2017.10.386}, pmid = {29111231}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Autophagosomes/drug effects/metabolism ; Autophagy/drug effects/*genetics ; Beclin-1/genetics/metabolism ; Cooking ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation ; Human Umbilical Vein Endothelial Cells ; Humans ; Microtubule-Associated Proteins/genetics/metabolism ; Particulate Matter/*pharmacology ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/*genetics/metabolism ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/*metabolism ; Signal Transduction ; Smoke/adverse effects ; TOR Serine-Threonine Kinases/*genetics/metabolism ; }, abstract = {Cooking oil fumes-derived PM2.5 (COFs-derived PM2.5) exposure can induce oxidative stress and cytotoxic effects. Here we investigated the role of ROS-AKT-mTOR axis in COFs-derived PM2.5-induced autophagy in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with different concentrations of COFs-derived PM2.5, together with or without N-acetyl-L-cysteine (NAC, a radical scavenger) or 3-methyladenine (3-MA, an autophagy inhibitor). Cell viability was assessed with MTT assay, and ROS level was measured with DCFH-DA assay after the treatment. Transmission electron microscopy (TEM) was used to evaluate the formation of autophagosomes, while immunofluorescent assay and western blot were used to assess the expression of LC3-I/II and beclin 1. Proteins involved in the PI3K-AKT-mTOR signaling pathway were measured with western blot. The results showed that the treatment of COFs-derived PM2.5 dose-dependently reduced the viability of HUVECs and increased the ROS levels in the cells. Both immunofluorescent assay and western blot showed that treatment with COFs-derived PM2.5 significantly increased LC3-II and beclin 1 levels, as well as the ratio of LC3-II/LC3-I, which could be rescued by the co-incubation with NAC or 3-MA. TEM also confirmed the increased formation of autophagosomes in the cells treated with COFs-derived PM2.5, while co-treatment with NAC evidently decreased autophagosomes formation. In addition, western blot also showed that the phosphorylation of PI3K, AKT, and mTOR all decreased by the treatment of COFs-derived PM2.5, which was effectively rescued by the co-treatment with NAC. These findings demonstrate ROS-AKT-mTOR axis plays a critical role in HUVECs autophagy induced by COFs-derived PM2.5.}, }
@article {pmid29109043, year = {2018}, author = {Zhang, W and Zhang, S and Zhang, M and Yang, L and Cheng, B and Li, J and Shan, A}, title = {Individual and combined effects of Fusarium toxins on apoptosis in PK15 cells and the protective role of N-acetylcysteine.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {111}, number = {}, pages = {27-43}, doi = {10.1016/j.fct.2017.10.057}, pmid = {29109043}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Fusarium/*chemistry ; Gene Expression Regulation/drug effects ; Lipid Peroxidation ; Mycotoxins/administration &amp; dosage/*toxicity ; Oxidative Stress ; Reactive Oxygen Species ; Superoxide Dismutase ; Swine ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Deoxynivalenol (DON), zearalenone (ZEN) and fumonisin B1 (FB1) are among the most toxicologically important Fusarium toxins commonly found in nature that lead to nephrotoxicity in animals. The present study investigated that the individual and combined effects of subcytotoxic DON (0.25 μM), ZEN (20 μM) and FB1 (10 μM) on oxidative stress and apoptosis in porcine kidney cells (PK15). In addition, the protective effect of N-acetylcysteine (NAC) against the toxicity of Fusarium toxins was also evaluated. Our results showed that the activities of glutathione reductase (GR) and total superoxide dismutase (SOD) were affected by DON, ZEN and FB1, and this change in activity induced reactive oxygen species (ROS) and malondialdehyde (MDA) production, increased apoptosis and regulated the mRNA expression of Bax, Bcl-2, caspase-3, caspase-9, cytochrome c (cyto c) and P53. This study demonstrated the complexity of combined mycotoxin infection since the combination of toxins exhibited more profound defects in the oxidative stress responses and apoptosis. Moreover, NAC reduced the oxidative damage and inhibited the apoptosis induced by Fusarium toxins. It was concluded that oxidative damage and apoptosis through the mitochondria-dependent channel were the mechanisms of Fusarium toxin mediated toxicity, and NAC reversed these damages to some extent.}, }
@article {pmid29107181, year = {2017}, author = {Zhao, X and Xing, F and Cong, Y and Zhuang, Y and Han, M and Wu, Z and Yu, S and Wei, H and Wang, X and Chen, G}, title = {Antimony trichloride induces a loss of cell viability via reactive oxygen species-dependent autophagy in A549 cells.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {93}, number = {}, pages = {32-40}, doi = {10.1016/j.biocel.2017.10.007}, pmid = {29107181}, issn = {1878-5875}, mesh = {A549 Cells ; Antimony/*pharmacology ; Autophagy/*drug effects ; Cell Survival/drug effects ; Chlorides/*pharmacology ; Dose-Response Relationship, Drug ; Humans ; Reactive Oxygen Species/*metabolism ; }, abstract = {Antimony (Sb) is one of the most prevalent heavy metals and frequently leads to biological toxicity. Although autophagy is believed to be involved in metal-associated cytotoxicity, there is no evidence of its involvement following exposure. Moreover, the underlying mechanism of autophagy remains unclear. In this study, treatment with antimony trichloride caused autophagy in a dose- and time-dependent manner in A549 cells but did not affect the level of Atg5 or Atg7 mRNA expression. Furthermore, Sb enhanced autophagic flux while upregulating p62 gene and protein levels. The classic mechanistic target of rapamycin (mTOR) pathway is not involved in Sb-induced autophagy. However, Sb-induced autophagy and the upregulation of p62 were inhibited by treatment with the antioxidant N-acetylcysteine (NAC). Subsequent analyses demonstrated that the inhibition of autophagy protected A549 cells from a loss of cell viability, while the activation of autophagy by rapamycin had the opposite effect. These data suggest that reactive oxygen species-dependent autophagy mediates Sb-stimulated cell viability loss in A549 cells.}, }
@article {pmid29105806, year = {2018}, author = {Martino, T and Kudrolli, TA and Kumar, B and Salviano, I and Mencalha, A and Coelho, MGP and Justo, G and Costa, PRR and Sabino, KCC and Lupold, SE}, title = {The orally active pterocarpanquinone LQB-118 exhibits cytotoxicity in prostate cancer cell and tumor models through cellular redox stress.}, journal = {The Prostate}, volume = {78}, number = {2}, pages = {140-151}, pmid = {29105806}, issn = {1097-0045}, support = {P30 CA006973/CA/NCI NIH HHS/United States ; P50 CA058236/CA/NCI NIH HHS/United States ; R01 CA143299/CA/NCI NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Nude ; Naphthoquinones/*pharmacology ; *Prostate/drug effects/metabolism/pathology ; *Prostatic Neoplasms/drug therapy/metabolism/pathology ; Pterocarpans/*pharmacology ; Reactive Oxygen Species/analysis ; Treatment Outcome ; }, abstract = {BACKGROUND: The targeted induction of reactive oxygen species (ROS) is a developing mechanism for cancer therapy. LQB-118 is a pterocarpanquinone and ROS-inducing agent with proven antineoplastic activity. Here, LQB-118 efficacy and mechanism of activity, were examined in Prostate Cancer (PCa) cell and tumor models.<br><br>METHODS: PC3, LNCaP, and LAPC4 PCa cells were applied. Dicoumarol treatment was used to inhibit quinone reductase activity. N-acetylcysteine (NAC) was applied as a ROS scavenger. ROS production was quantified by H2 DCFDA flow cytometry. LQB-118 treated cells were evaluated for changes in lipid peroxidation, viability, and apoptosis. Treatment-induced gene expression was measured by RT-qPCR and Western Blot. SOD1 knockdown was achieved with siRNA or miRNA mimic transfection. MicroRNA specificity was determined by 3'UTR reporter assay. Oral LQB-118 treatment (10&#x2009;mg/kg/day) efficacy was determined in athymic male nude mice bearing subcutaneous PC3 xenograft tumors.<br><br>RESULTS: LQB-118 treatment triggered PCa cell death and apoptosis. Therapeutic activity was at least partially dependent upon quinone reduction and ROS generation. LQB-118 treatment caused an increase in cellular ROS and lipid peroxidation. Treated cells exhibited elevated levels of NQO1, Nrf2, and SOD1. The miRNAs miR-206, miR-1, and miR-101 targeted and reduced SOD1 expression. The knockdown of SOD1, by siRNA or miRNA, enhanced LQB-118 cytotoxicity. Orally administered LQB-118 treatment significantly reduced the growth of established PCa xenograft tumors.<br><br>CONCLUSION: LQB-118 is a developing and orally active pterocarpanquinone agent that effectively kills PCa cells through quinone reduction and ROS generation. The inhibition SOD1 expression enhances LQB-118 activity, presumably by impairing the cellular antioxidant response.}, }
@article {pmid29101900, year = {2018}, author = {Kanaan, GN and Ichim, B and Gharibeh, L and Maharsy, W and Patten, DA and Xuan, JY and Reunov, A and Marshall, P and Veinot, J and Menzies, K and Nemer, M and Harper, ME}, title = {Glutaredoxin-2 controls cardiac mitochondrial dynamics and energetics in mice, and protects against human cardiac pathologies.}, journal = {Redox biology}, volume = {14}, number = {}, pages = {509-521}, pmid = {29101900}, issn = {2213-2317}, support = {FDN 143278//CIHR/Canada ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Cardiomegaly/genetics/metabolism/pathology/prevention &amp; control ; Cells, Cultured ; *Energy Metabolism ; Glutaredoxins/genetics/*metabolism ; Heart Diseases/genetics/*metabolism/pathology/prevention &amp; control ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism/pathology ; *Mitochondrial Dynamics ; Oxidation-Reduction ; Oxidative Stress ; Protective Factors ; }, abstract = {Glutaredoxin 2 (GRX2), a mitochondrial glutathione-dependent oxidoreductase, is central to glutathione homeostasis and mitochondrial redox, which is crucial in highly metabolic tissues like the heart. Previous research showed that absence of Grx2, leads to impaired mitochondrial complex I function, hypertension and cardiac hypertrophy in mice but the impact on mitochondrial structure and function in intact cardiomyocytes and in humans has not been explored. We hypothesized that Grx2 controls cardiac mitochondrial dynamics and function in cellular and mouse models, and that low expression is associated with human cardiac dysfunction. Here we show that Grx2 absence impairs mitochondrial fusion, ultrastructure and energetics in primary cardiomyocytes and cardiac tissue. Moreover, provision of the glutathione precursor, N-acetylcysteine (NAC) to Grx2-/- mice did not restore glutathione redox or prevent impairments. Using genetic and histopathological data from the human Genotype-Tissue Expression consortium we demonstrate that low GRX2 is associated with fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, GRX2 is important in the control of cardiac mitochondrial structure and function, and protects against human cardiac pathologies.}, }
@article {pmid29101755, year = {2018}, author = {Duan, X and Peng, D and Zhang, Y and Huang, Y and Liu, X and Li, R and Zhou, X and Liu, J}, title = {Sub-cytotoxic concentrations of ionic silver promote the proliferation of human keratinocytes by inducing the production of reactive oxygen species.}, journal = {Frontiers of medicine}, volume = {12}, number = {3}, pages = {289-300}, pmid = {29101755}, issn = {2095-0225}, mesh = {Apoptosis/drug effects ; Cell Line ; Cell Proliferation/*drug effects ; Fluorescent Antibody Technique ; Humans ; Keratinocytes/cytology/*drug effects ; Proliferating Cell Nuclear Antigen/metabolism ; Reactive Oxygen Species/*metabolism ; Silver/*pharmacology ; }, abstract = {Silver-containing preparations are widely used in the management of skin wounds, but the effects of silver ions on skin wound healing remain poorly understood. This study investigated the effects of silver ions (Ag[+]) on the proliferation of human skin keratinocytes (HaCaT) and the production of intracellular reactive oxygen species (ROS). After treating HaCaT cells with Ag[+] and/or the active oxygen scavenger N-acetyl cysteine (NAC), cell proliferation and intracellular ROS generation were assessed using CCK-8 reagent and DCFH-DA fluorescent probe, respectively. In addition, 5-bromo-2-deoxyUridine (BrdU) incorporation assays, cell cycle flow cytometry, and proliferating cell nuclear antigen (PCNA) immunocytochemistry were conducted to further evaluate the effects of sub-cytotoxic Ag[+] concentrations on HaCaT cells. The proliferation of HaCaT cells was promoted in the presence of 10[-6] and 10[-5] mol/L Ag[+] at 24, 48, and 72 h. Intracellular ROS generation also significantly increased for 5-60 min after exposure to Ag[+]. The number of BrdU-positive cells and the presence of PCNA in HaCaT cells increased 48 h after the addition of 10[-6] and 10[-5] mol/L Ag[+], with 10[-5] mol/L Ag[+] markedly increasing the cell proliferation index. These effects of sub-cytotoxic Ag[+] concentrations were repressed by 5 mmol/L NAC. Our results suggest that sub-cytotoxic Ag[+] concentrations promote the proliferation of human keratinocytes and might be associated with a moderate increase in intracellular ROS levels. This study provides important experimental evidence for developing novel silver-based wound agents or dressings with few or no cytotoxicity.}, }
@article {pmid29101699, year = {2018}, author = {Zhang, Y and Yang, Z and Chen, Y and Li, R and Geng, H and Dong, W and Cai, Z and Dong, C}, title = {Fine chalk dust induces inflammatory response via p38 and ERK MAPK pathway in rat lung.}, journal = {Environmental science and pollution research international}, volume = {25}, number = {2}, pages = {1742-1751}, pmid = {29101699}, issn = {1614-7499}, support = {21575084//the National Natural Science Foundation of China/ ; 21405099//the National Natural Science Foundation of China/ ; 91543202//the key Program of National Natural Science of China/ ; 201601D202087//Nature Science Foundation of Shanxi Province in China/ ; 2014110//Foundation of Educational Committee of Shanxi Province in China/ ; }, mesh = {Acetylcysteine/therapeutic use ; Air Pollutants/*toxicity ; Animals ; Calcium Carbonate/*toxicity ; Dietary Supplements ; Dust ; Inflammation/chemically induced/*genetics ; Lung/*drug effects/metabolism/pathology ; MAP Kinase Signaling System/*drug effects ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Up-Regulation/drug effects ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Chalk teaching is widely used in the world due to low cost, especially in some developing countries. During teaching with chalks, a large amount of fine chalk dust is produced. Although exposure to chalk dust is associated with respiratory diseases, the mechanism underlying the correlation between chalk dust exposure and adverse effects has not fully been elucidated. In this study, inflammation and its signal pathway in rat lungs exposed to fine chalk dust were examined through histopathology analyses; pro-inflammatory gene transcription; and protein levels measured by HE staining, RT-PCR, and western blot analysis. The results demonstrated that fine chalk dust increased neutrophils and up-regulated inflammatory gene mRNA levels (TNF-α, IL-6, TGF-β1, iNOS, and ICAM-1), and oxidative stress marker (HO-1) level, leading to the increase of inflammatory cell infiltration and inflammatory injury on the lungs. These inflammation responses were mediated, at least in part, via p38 and extracellular regulated proteinase (ERK) mitogen-activated protein kinase (MAPK) signaling mechanisms. In contrast, N-acetyl-L-cysteine (NAC) supplement significantly ameliorated these changes in inflammatory responses. Our results support the hypothesis that fine chalk dust can damage rat lungs and the NAC supplement may attenuate fine chalk dust-associated lung inflammation.}, }
@article {pmid29100878, year = {2018}, author = {Isaev, NK and Avilkina, S and Golyshev, SA and Genrikhs, EE and Alexandrova, OP and Kapkaeva, MR and Stelmashook, EV}, title = {N-acetyl-l-cysteine and Mn[2+] attenuate Cd[2+]-induced disturbance of the intracellular free calcium homeostasis in cultured cerebellar granule neurons.}, journal = {Toxicology}, volume = {393}, number = {}, pages = {1-8}, doi = {10.1016/j.tox.2017.10.017}, pmid = {29100878}, issn = {1879-3185}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cadmium Chloride/*toxicity ; Calcium/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cerebellum/cytology ; Homeostasis/drug effects ; Manganese/*pharmacology ; Microscopy, Electron, Transmission ; Mitochondria/*drug effects/pathology/ultrastructure ; Neurons/*drug effects/metabolism/pathology/ultrastructure ; Rats, Wistar ; }, abstract = {Cadmium is a highly toxic heavy metal that is capable of accumulating in the body via direct exposure or through the alimentary and respiratory tract, leading to neurodegeneration. In this article, we show that the application of CdCl2 (0.001-0.005mM) for 48h induced high dose-dependent death rate of cultured cerebellar granule neurons (CGNs). Unlike Trolox or vitamin E, antioxidant N-acetyl-l-cysteine (NAC, 1mM) and Mn[2+] (0.0025-0.005mM) significantly protected CGNs from this toxic effect. Using Fluo-4 AM, measurements of intracellular calcium ions demonstrated that 24h-exposure to Cd[2+] induced intensive increase of Fluo-4 fluorescence in neurons accompanied by mitochondria swelling. These data imply that the cadmium-induced Ca[2+] increase is an important element in the death of neurons due to toxic effect of cadmium and the mechanism of protective action of manganese and NAC is mediated by the prevention of increase in calcium levels.}, }
@article {pmid29100379, year = {2017}, author = {Pan, H and Jansson, KH and Beshiri, ML and Yin, J and Fang, L and Agarwal, S and Nguyen, H and Corey, E and Zhang, Y and Liu, J and Fan, H and Lin, H and Kelly, K}, title = {Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer.}, journal = {Oncotarget}, volume = {8}, number = {44}, pages = {77181-77194}, pmid = {29100379}, issn = {1949-2553}, support = {P01 CA163227/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; }, abstract = {Advanced prostate cancer (PrCa) is treated with androgen deprivation therapy, and although there is usually a significant initial response, recurrence arises as castrate resistant prostate cancer (CRPC). New approaches are needed to treat this genetically heterogeneous, phenotypically plastic disease. CRPC with combined homozygous alterations to PTEN and TP53 comprise about 30% of clinical samples. We screened eleven traditional Chinese medicines against a panel of androgen-independent Pten/Tp53 null PrCa-derived cell lines and identified gambogic acid (GA) as a highly potent growth inhibitor. Mechanistic analyses revealed that GA disrupted cellular redox homeostasis, observed as elevated reactive oxygen species (ROS), leading to apoptotic and ferroptotic death. Consistent with this, we determined that GA inhibited thioredoxin, a necessary component of cellular anti-oxidative, protein-reducing activity. In other clinically relevant models, GA displayed submicromolar, growth inhibitory activity against a number of genomically-representative, CRPC patient derived xenograft organoid cultures. Inhibition of ROS with N-acetyl-cysteine partially reversed growth inhibition in CRPC organoids, demonstrating ROS imbalance and implying that GA may have additional mechanisms of action. These data suggest that redox imbalances initiated by GA may be useful, especially in combination therapies, for treating the heterogeneity and plasticity that contributes to the therapeutic resistance of CRPC.}, }
@article {pmid29097487, year = {2018}, author = {Vural, A and Koçyiğit, &#x130; and Şan, F and Eroğlu, E and Ketenci, &#x130; and Ünal, A and Tokgöz, B and Ünlü, Y}, title = {Long-Term Protective Effect of N-Acetylcysteine against Amikacin-Induced Ototoxicity in End-Stage Renal Disease: A Randomized Trial.}, journal = {Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis}, volume = {38}, number = {1}, pages = {57-62}, doi = {10.3747/pdi.2017.00133}, pmid = {29097487}, issn = {1718-4304}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Amikacin/*adverse effects ; Audiometry, Pure-Tone/methods ; Ear Diseases/chemically induced/*prevention &amp; control ; Free Radical Scavengers/*therapeutic use ; Humans ; Interleukin-6/blood ; Kidney Failure, Chronic/therapy ; Middle Aged ; Peritoneal Dialysis, Continuous Ambulatory/adverse effects ; Peritonitis/*drug therapy/etiology ; Prospective Studies ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: The aim of the study is to evaluate the long-term protective effect of N-acetylcysteine (NAC), an antioxidant agent, against aminoglycoside (AG)-induced ototoxicity.<br><br>METHODS: A total of 40 patients receiving continuous ambulatory peritoneal dialysis (CAPD) and having their first peritonitis attacks and planned to be treated with AGs were enrolled in the study. They were randomized into 2 groups: 1 group received additional NAC and the other did not. All patients underwent hearing tests with pure tone audiometry (PTA) after the diagnosis, at 1 month and 12 months and at the same time the tumor necrosis factor (TNF)-&#x3b1; and interleukin (IL)-6 levels were measured.<br><br>RESULTS: Patients taking NAC had better hearing test results in both ears at 1 month except 2,000 Hz for the left ear, which wasn't significantly different between the 2 groups. Although patients taking NAC had generally better PTA results at 12 months, differences between the 2 groups were not statistically significant. Baseline IL-6 level was significantly higher in the NAC group than the control group. Both TNF-&#x3b1; and IL-6 levels at 1 month were significantly lower in the NAC group than in the control group. On the other hand, there was no significant difference between the 2 groups in terms of TNF-&#x3b1; and IL-6 levels at 12 months.<br><br>CONCLUSIONS: The results of the current study showed that NAC, a potent anti-inflamatory drug, may be otoprotective, but that the effect is not long-lasting.}, }
@article {pmid29095935, year = {2017}, author = {Smith, RL and Tan, JME and Jonker, MJ and Jongejan, A and Buissink, T and Veldhuijzen, S and van Kampen, AHC and Brul, S and van der Spek, H}, title = {Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity.}, journal = {PloS one}, volume = {12}, number = {11}, pages = {e0187424}, pmid = {29095935}, issn = {1932-6203}, mesh = {Animals ; Anti-HIV Agents/*pharmacology ; Caenorhabditis elegans/drug effects ; DNA-Directed DNA Polymerase/*metabolism ; Humans ; Mitochondria/*drug effects ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Inhibitors/*poisoning ; }, abstract = {Use of some HIV-1 nucleoside reverse transcriptase inhibitors (NRTI) is associated with severe adverse events. However, the exact mechanisms behind their toxicity has not been fully understood. Mitochondrial dysfunction after chronic exposure to specific NRTIs has predominantly been assigned to mitochondrial polymerase-γ inhibition by NRTIs. However, an increasing amount of data suggests that this is not the sole mechanism. Many NRTI induced adverse events have been linked to the incurrence of oxidative stress, although the causality of events leading to reactive oxygen species (ROS) production and their role in toxicity is unclear. In this study we show that short-term effects of first generation NRTIs, which are rarely discussed in the literature, include inhibition of oxygen consumption, decreased ATP levels and increased ROS production. Collectively these events affect fitness and longevity of C. elegans through mitohormetic signalling events. Furthermore, we demonstrate that these effects can be normalized by addition of the anti-oxidant N-acetylcysteine (NAC), which suggests that ROS likely influence the onset and severity of adverse events upon drug exposure.}, }
@article {pmid29093283, year = {2017}, author = {Alkadasi, B and Abdulrab, S and Gaafer, S and Kalakonda, B and Hosny, M and Shaker, O and Hosny, M}, title = {Effect of adjunctive use of systemic antioxidant therapy (N-acetylcysteine) on soluble receptor activator nuclear factor κB ligand levels in gingival crevicular fluid following surgical periodontal treatment for chronic periodontitis.}, journal = {Journal of oral science}, volume = {59}, number = {4}, pages = {519-526}, doi = {10.2334/josnusd.16-0701}, pmid = {29093283}, issn = {1880-4926}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Case-Control Studies ; Chronic Periodontitis/*drug therapy/metabolism/surgery ; Combined Modality Therapy ; Dental Plaque Index ; Enzyme-Linked Immunosorbent Assay ; Female ; Gingival Crevicular Fluid/*metabolism ; Humans ; Male ; Middle Aged ; Periodontal Pocket ; RANK Ligand/*metabolism ; Severity of Illness Index ; }, abstract = {N-acetylcysteine (NAC) is an anti-oxidant drug that has been used as a mucolytic agent and a paracetamol antidote for many years. This study was designed to determine the efficacy of the adjunctive use of NAC for periodontal treatment. Thirty subjects with moderate-to-severe chronic periodontitis were randomized to surgery with NAC (600 mg; S-NAC), surgery only (S-nonNAC), and healthy control groups. Gingival crevicular fluid (GCF) samples were obtained from all patients and sRANKL levels were determined by enzyme-linked immunosorbent assay at baseline, and 1, 3, and 7 months post-surgery. Plaque and gingival indices, probing depths, and clinical attachment levels were recorded at the same time. There was a significant reduction in probing depth at 3 months in the S-NAC group when compared to the S-nonNAC group (P < 0.05). However, no statistically significant differences in plaque and gingival indices, probing depths, clinical attachment levels, and sRANKL levels in GCF were noted between the surgical treatment groups at the end of 7 months. Hence, the use of adjunctive NAC resulted in a significant reduction in probing depths in the S-NAC group when compared to the S-nonNAC group at 3 months, but no statistically significant differences in GCF sRANKL levels were observed in the sites that underwent surgical treatment with or without NAC at different time intervals.}, }
@article {pmid29089150, year = {2017}, author = {Park, EJ and Kim, YM and Chang, KC}, title = {Hemin Reduces HMGB1 Release by UVB in an AMPK/HO-1-dependent Pathway in Human Keratinocytes HaCaT Cells.}, journal = {Archives of medical research}, volume = {48}, number = {5}, pages = {423-431}, doi = {10.1016/j.arcmed.2017.10.007}, pmid = {29089150}, issn = {1873-5487}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Antigens, CD ; Cadherins/metabolism ; Cell Line ; Cytokines/metabolism ; Enzyme Induction ; HMGB1 Protein/*metabolism ; Heme Oxygenase-1/*biosynthesis ; Hemin/*pharmacology ; Humans ; Keratinocytes/*drug effects/metabolism/*radiation effects ; Protoporphyrins/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Ultraviolet Rays/*adverse effects ; }, abstract = {BACKGROUND AND AIMS: High mobility group box 1 (HMGB1) plays an important role as a pro-inflammatory cytokine that regulates inflammation in various diseases. We hypothesized that hemin might reduce HMGB1 release through the induction of HO-1 in UVB-induced HaCaTs.<br><br>METHODS: The effects of hemin on the release of HMGB1 in UVB exposure were evaluated. The mechanisms were investigated using various signal inhibitors and small interfering RNA techniques.<br><br>RESULTS: Treatment with hemin inhibited reactive oxygen species (ROS) in UVB-induced HaCaTs in a dose-dependent manner. HMGB1 release by UVB was significantly reduced by hemin, N-acetyl-cysteine and DPI (NADPH oxidase inhibitor). Hemin increased HO-1 induction followed by phosphorylation of AMPK in a time- and dose-dependent manner. Additionally, hemin significantly increased the NAD[+]/NADH ratio in HaCaTs. The inhibitory effects of UVB-induced HMGB1 release by hemin were significantly reversed not only with pharmacological inhibitors of AMPK (compound c) or HO-1 (ZnPPIX) but also through transfection of small interfering RNAs (siRNAs) for AMPK or HO-1. Interestingly, hemin decreased phosphor-AMPK expression by HO-1 siRNA transfection, but it failed to induce HO-1 in AMPK siRNA-transfected cells, which suggested that HO-1 was involved in AMPK activation by hemin in HaCaT. Moreover, recombinant HMGB1 induced Snail and inhibited E-Cadherin in HaCaTs, whereas hemin reversed those effects through rHMGB1.<br><br>CONCLUSIONS: It is concluded that the increased activity of HO-1/AMPK and scavenging ROS are, at least in part, responsible for the inhibition of UVB-induced HMGB1 release in keratinocyte HaCaTs. Therefore, hemin may be a useful agent for preventing UVB-induced skin cancer.}, }
@article {pmid29088066, year = {2017}, author = {Skoupa, N and Dolezel, P and Ruzickova, E and Mlejnek, P}, title = {Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells.}, journal = {International journal of molecular sciences}, volume = {18}, number = {11}, pages = {}, pmid = {29088066}, issn = {1422-0067}, mesh = {ATP Binding Cassette Transporter, Subfamily B/genetics/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics/*metabolism ; Acetylcysteine/metabolism ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Benzylidene Compounds/*pharmacology ; Cell Line, Tumor ; Glutathione/metabolism ; Humans ; Leukemia/metabolism ; Neoplasm Proteins/genetics/*metabolism ; *Oxidative Stress ; Piperidones/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {The synthetic curcumin analogue, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24), suppresses NF-κB activity and exhibits antiproliferative effects against a variety of cancer cells in vitro. Recently, it was reported that EF-24-induced apoptosis was mediated by a redox-dependent mechanism. Here, we studied the effects of N-acetylcysteine (NAC) on EF-24-induced cell death. We also addressed the question of whether the main drug transporters, ABCB1 and ABCG2, affect the cytotoxic of EF-24. We observed that EF-24 induced cell death with apoptotic hallmarks in human leukemia K562 cells. Importantly, the loss of cell viability was preceded by production of reactive oxygen species (ROS), and by a decrease of reduced glutathione (GSH). However, neither ROS production nor the decrease in GSH predominantly contributed to the EF-24-induced cell death. We found that EF-24 formed an adduct with GSH, which is likely the mechanism contributing to the decrease of GSH. Although NAC abrogated ROS production, decreased GSH and prevented cell death, its protective effect was mainly due to a rapid conversion of intra- and extra-cellular EF-24 into the EF-24-NAC adduct without cytotoxic effects. Furthermore, we found that neither overexpression of ABCB1 nor ABCG2 reduced the antiproliferative effects of EF-24. In conclusion, a redox-dependent-mediated mechanism only marginally contributes to the EF-24-induced apoptosis in K562 cells. The main mechanism of NAC protection against EF-24-induced apoptosis is conversion of cytotoxic EF-24 into the noncytotoxic EF-24-NAC adduct. Neither ABCB1 nor ABCG2 mediated resistance to EF-24.}, }
@article {pmid29085973, year = {2018}, author = {Liow, KY and Chow, SC}, title = {The cathepsin B inhibitor z-FA-CMK induces cell death in leukemic T cells via oxidative stress.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {391}, number = {1}, pages = {71-82}, pmid = {29085973}, issn = {1432-1912}, mesh = {Cathepsin B/*antagonists &amp; inhibitors/*metabolism ; Cell Death/drug effects/physiology ; Cysteine Proteinase Inhibitors/*toxicity ; Dose-Response Relationship, Drug ; Humans ; Jurkat Cells ; Leukemia, T-Cell/*metabolism ; Oxidative Stress/*drug effects/physiology ; Reactive Oxygen Species ; }, abstract = {The cathepsin B inhibitor benzyloxycarbonyl-phenylalanine-alanine-chloromethyl ketone (z-FA-CMK) was recently found to induce apoptosis at low concentrations in Jurkat T cells, while at higher concentrations, the cells die of necrosis. In the present study, we showed that z-FA-CMK readily depletes intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) generation. The toxicity of z-FA-CMK in Jurkat T cells was completely abrogated by N-acetylcysteine (NAC), suggesting that the toxicity mediated by z-FA-CMK is due to oxidative stress. We found that L-buthionine sulfoximine (BSO) which depletes intracellular GSH through the inhibition of GSH biosynthesis in Jurkat T cells did not promote ROS increase or induce cell death. However, NAC was still able to block z-FA-CMK toxicity in Jurkat T cells in the presence of BSO, indicating that the protective effect of NAC does not involve GSH biosynthesis. This is further corroborated by the protective effect of the non-metabolically active D-cysteine on z-FA-CMK toxicity. Furthermore, in BSO-treated cells, z-FA-CMK-induced ROS increased which remains unchanged, suggesting that the depletion of GSH and increase in ROS generation mediated by z-FA-CMK may be two separate events. Collectively, our results demonstrated that z-FA-CMK toxicity is mediated by oxidative stress through the increase in ROS generation.}, }
@article {pmid29081093, year = {2017}, author = {Yang, LM and Zhao, J and Wang, HT and Xu, XX and JIiao, YM and Ding, RG}, title = {[The protective effect of N-acetylcysteine on acute lung injury induced by PFIB inhalation].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {35}, number = {7}, pages = {481-486}, doi = {10.3760/cma.j.issn.1001-9391.2017.07.001}, pmid = {29081093}, issn = {1001-9391}, mesh = {Acetylcysteine/*therapeutic use ; Acute Lung Injury/chemically induced/*drug therapy ; Administration, Inhalation ; Animals ; Lung/*physiopathology ; Male ; Mice ; Mice, Inbred ICR ; Protective Factors ; Random Allocation ; Rats ; Rats, Wistar ; }, abstract = {Objective: To study the protective effect of N-acetylcysteine on acute lung injury induced by PFIB inhalation and its mechanism. Methods: Survival experiment: 48 male ICR (CD-1) mice were randomly divided into 4 groups, i. e., PFIB control group, NAC prevention group, NAC treatment group, and NAC prevention + treatment group, each group contains 12 animals. The mice of PFIB C group were exposed to PFIB without any treatment. The mice of NAC P group were exposed to PFIB 30min after NAC administration. The mice of NAC T group were exposed to PFIB 1h before NAC administration, The mice of NAC P+T group were administrated with NAC twice (30 min before and 1h after PFIB inhalation) . 150 mg/kg NAC was given by each time. The 7 days survival rate of mice after lethal dose PFIB exposure was observed. 18 male Wistar rats were randomly divided into 3 groups i.e., normal control group (N-C) , PFIB control group (PFIB-C) and NAC prevention group (NAC-P) , with each group contains 6 animals in the second experiment. The rats of N-C group received no treatment. The rats of NAC-P group and PFIB-C group were exposed to PFIB 30min after treatment of NAC (420 mg/Kg, i.p.) and saline, respectively. The respiratory functions of animals were tested before and 24 h after PFIB inhalation. The arterial blood gas was analyzed after rats were anesthetized 24 hours post sublethal dose PFIB exposure. Then samples of BALF, plasma and lung tissue were collected. Wet lung/body weight ratio, protein and phospholipid content in BALF, and T-SOD, GSH, GSH-Px in plasma and lung tissue were measured. The expression of Peroxiredoxin 2 was detected by Westernblot assay. Results: NAC prevention can significantly improve the survival of mice exposed to a lethal dose PFIB while NAC treatment is ineffective. Severe lung edema was observed in rats 24 h after PFIB exposure. Compared to N-C group, the wet lung/body weight ratio, protein and phospholipid content in BALF, and respiratory rate of PFIB control group all increased significantly (P<0.01) . The arterial oxygen partial pressure (PaO(2)) reduced significantly (P<0.05) . The GSH-Px activity in lung tissue reduced significantly (P<0.01) while the expression of Peroxiredoxin 2 increased significantly (P<0.01) . NAC prophylaxis significantly reduced the wet lung/body weight ratio, protein and phospholipid content in BALF, respiratory rate of rats exposed to PFIB (P<0.01) . Compared with PFIB-C group, the PaO(2) (P<0.05) and the activity of GSH-Px (P<0.01) and the expression of Peroxiredoxin 2 in lung tissue (P<0.01) were increased significantly. Conclusion: Acute lung injury induced by PFIB inhalation is related to oxidative stress caused by the stimulation to lung. induced and pulmonary subjected to stimulate the generation of exposure, NAC prevention can regulation of the redox system in lung tissue and protect target organ of the treated animals effectively.}, }
@article {pmid29079703, year = {2018}, author = {Zhou, C and Routh, VH}, title = {Thioredoxin-1 Overexpression in the Ventromedial Nucleus of the Hypothalamus Preserves the Counterregulatory Response to Hypoglycemia During Type 1 Diabetes in Male Rats.}, journal = {Diabetes}, volume = {67}, number = {1}, pages = {120-130}, pmid = {29079703}, issn = {1939-327X}, support = {R01 DK081538/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Blood Glucose/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Type 1/genetics/*metabolism ; Glucose/pharmacology ; Hypoglycemia/*metabolism ; Hypothalamus/*metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Thioredoxins/genetics/*metabolism ; Ventromedial Hypothalamic Nucleus/drug effects/*metabolism ; }, abstract = {We previously showed that the glutathione precursor, N-acetylcysteine (NAC), prevented hypoglycemia-associated autonomic failure (HAAF) and impaired activation of ventromedial hypothalamus (VMH) glucose-inhibited (GI) neurons by low glucose after recurrent hypoglycemia (RH) in nondiabetic rats. However, NAC does not normalize glucose sensing by VMH GI neurons when RH occurs during diabetes. We hypothesized that recruiting the thioredoxin (Trx) antioxidant defense system would prevent HAAF and normalize glucose sensing after RH in diabetes. To test this hypothesis, we overexpressed Trx-1 (cytosolic form of Trx) in the VMH of rats with streptozotocin (STZ)-induced type 1 diabetes. The counterregulatory response (CRR) to hypoglycemia in vivo and the activation of VMH GI neurons in low glucose using membrane potential sensitive dye in vitro was measured before and after RH. VMH Trx-1 overexpression normalized both the CRR and glucose sensing by VMH GI neurons in STZ rats. VMH Trx-1 overexpression also lowered the insulin requirement to prevent severe hyperglycemia in STZ rats. However, like NAC, VMH Trx-1 overexpression did not prevent HAAF or normalize activation of VMH GI neurons by low glucose in STZ rats after RH. We conclude that preventing HAAF in type 1 diabetes may require the recruitment of both antioxidant systems.}, }
@article {pmid29079519, year = {2018}, author = {de Medeiros, WA and da Silva, LA and Dall'Igna, DM and Michels, M and Manfredini, A and Dos Santos Cardoso, J and Constantino, L and Scaini, G and Vuolo, F and Streck, EL and Ritter, C and Dal-Pizzol, F}, title = {N-acetylcysteine effects on a murine model of chronic critical limb ischemia.}, journal = {Biochimica et biophysica acta. Molecular basis of disease}, volume = {1864}, number = {2}, pages = {454-463}, doi = {10.1016/j.bbadis.2017.10.027}, pmid = {29079519}, issn = {0925-4439}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Hindlimb/*pathology ; Hypoxia/pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Inflammation ; Interleukin-6/metabolism ; Ischemia/*drug therapy/metabolism ; Lactic Acid/metabolism ; Male ; Muscle, Skeletal/metabolism ; Nitrates/metabolism ; Nitrites/metabolism ; Oxidative Stress ; Oxygen/chemistry/metabolism ; Oxygen Consumption ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {During chronic limb ischemia, oxidative damage and inflammation are described. Besides oxidative damage, the decrease of tissue oxygen levels is followed by several adaptive responses. The purpose of this study was to determine whether supplementation with N-acetylcysteine (NAC) is effective in an animal model of chronic limb ischemia. Chronic limb ischemia was induced and animals were treated once a day for 30 consecutive days with NAC (30mg/kg). After this time clinical scores were recorded and soleus muscle was isolated and lactate levels, oxidative damage and inflammatory parameters were determined. In addition, several mechanisms associated with hypoxia adaptation were measured (vascular endothelial growth factor - VEGF and hypoxia inducible factor - HIF levels, ex vivo oxygen consumption, markers of autophagy/mitophagy, and mitochondrial biogenesis). The adaptation to chronic ischemia in this model included an increase in muscle VEGF and HIF levels, and NAC was able to decrease VEGF, but not HIF levels. In addition, ex vivo oxygen consumption under hypoxia was increased in muscle from ischemic animals, and NAC was able to decrease this parameter. This effect was not mediated by a direct effect of NAC on oxygen consumption. Ischemia was followed by a significant increase in muscle myeloperoxidase activity, as well as interleukin-6 and thiobarbituric acid reactive substances species levels. Supplementation with NAC was able to attenuate inflammatory and oxidative damage parameters, and improve clinical scores. In conclusion, NAC treatment decreases oxidative damage and inflammation, and modulates oxygen consumption under hypoxic conditions in a model of chronic limb ischemia.}, }
@article {pmid29073716, year = {2018}, author = {Conde-Rioll, M and Gajate, C and Fernández, JJ and Villa-Pulgarin, JA and Napolitano, JG and Norte, M and Mollinedo, F}, title = {Antitumor activity of Lepidium latifolium and identification of the epithionitrile 1-cyano-2,3-epithiopropane as its major active component.}, journal = {Molecular carcinogenesis}, volume = {57}, number = {3}, pages = {347-360}, doi = {10.1002/mc.22759}, pmid = {29073716}, issn = {1098-2744}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*chemistry/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Female ; Humans ; Lepidium/*chemistry ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, SCID ; Neoplasms/*drug therapy/metabolism/pathology ; Nitriles/*chemistry/*pharmacology/therapeutic use ; Propane/*analogs &amp; derivatives/chemistry/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sulfhydryl Compounds/*chemistry/*pharmacology/therapeutic use ; }, abstract = {Consumption of Brassica (Cruciferae) vegetables is associated with a reduced risk of cancer, but identification of the active components and insights into the underlying molecular events are scarce. Here we found that an extract of Lepidium latifolium, a cruciferous plant native to southern Europe, Mediterranean countries and Asia, showed in vitro cytotoxic activity, inducing caspase-dependent apoptosis, in a variety of human tumor cells, and the plant juice showed in vivo antitumor activity in a HT-29 human colon cancer xenograft mouse model. The epithionitrile 1-cyano-2,3-epithiopropane (CETP) was identified as the major active cancer cell-killing principle of L. latifolium. Synthetic and plant-derived CETP displayed similar proapoptotic activities as assessed by biochemical and morphological analyses. Analysis of the antiproliferative capacity of CETP on a wide number of cancer cell lines from the NCI-60 cell line panel followed by COMPARE analysis, showed an activity profile different from known anticancer agents. Flow cytometry and biochemical analyses revealed that CETP-induced apoptosis involved mitochondria, as assessed by loss of mitochondrial transmembrane potential and generation of reactive oxygen species, while overexpression of Bcl-XL and Bcl-2 prevented CETP-induced apoptosis. Inhibition of reactive oxygen species by glutathione and N-acetyl cysteine reduced the apoptotic response induced by CETP. FADD dominant negative form, blocking Fas/CD95 signaling, and a specific caspase-8 inhibitor also inhibited CETP-induced killing. Taken together, our data suggest that the cancer cell-killing action of CETP, involving both intrinsic and extrinsic apoptotic signaling pathways, underlies the antitumor activity of L. latifolium plant, which could be of potential interest in cancer treatment.}, }
@article {pmid29071218, year = {2017}, author = {Adikwu, E and Bokolo, B}, title = {Melatonin and N- Acetylcysteine as Remedies for Tramadol-Induced Hepatotoxicity in Albino Rats.}, journal = {Advanced pharmaceutical bulletin}, volume = {7}, number = {3}, pages = {367-374}, pmid = {29071218}, issn = {2228-5881}, abstract = {Purpose: The therapeutic benefit derived from the clinical use of tramadol (TD) has been characterized by hepatotoxicity due to misuse and abuse. The implications of drug-induced hepatotoxicity include socio-economic burden which makes the search for remedy highly imperative. The present study investigated the protective effects of melatonin (MT) and n-acetylcysteine (NAC) on TD-induced hepatotoxicity in albino rats. Methods: Forty five adult rats used for this study were divided into nine groups of five rats each. The rats were pretreated with 10mg/kg/day of NAC, 10mg/kg/day of MT and combined doses of NAC and MT prior to the administration of 15 mg/kg/day of TD intraperitoneally for 7 days respectively. At the termination of drug administration, rats were weighed, sacrificed, and serum was extracted and evaluated for liver function parameters. The liver was harvested, weighed and evaluated for oxidative stress indices and liver enzymes. Results: Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, conjugated bilirubin, and malondialdehyde levels were significantly (P<0.05) increased in rats administered with TD when compared to control. Furthermore, glutathione, superoxide dismutase and catalase levels were decreased significantly (P<0.05) in rats administered with TD when compared to control. The Liver of TD-treated rats showed necrosis of hepatocytes. However, the observed biochemical and liver histological alterations in TD-treated rats were attenuated in NAC and MT pretreated rats. Interestingly, pretreatment with combined doses of NAC and MT produced significant (P<0.05) effects on all evaluated parameters in comparison to their individual doses. Conclusion: Based on the findings in this study, melatonin and n- acetylcysteine could be used clinically as remedies for tramadol associated hepatotoxity.}, }
@article {pmid29070760, year = {2017}, author = {Ahn, KI and Choi, EO and Kwon, DH and HwangBo, H and Kim, MY and Kim, HJ and Ji, SY and Hong, SH and Jeong, JW and Park, C and Kim, ND and Kim, WJ and Choi, YH}, title = {Induction of apoptosis by ethanol extract of Citrus unshiu Markovich peel in human bladder cancer T24 cells through ROS-mediated inactivation of the PI3K/Akt pathway.}, journal = {Bioscience trends}, volume = {11}, number = {5}, pages = {565-573}, doi = {10.5582/bst.2017.01218}, pmid = {29070760}, issn = {1881-7823}, mesh = {Antineoplastic Agents, Phytogenic/isolation &amp; purification/*pharmacology ; Apoptosis/*drug effects ; Cell Culture Techniques ; Cell Line, Tumor ; Cell Survival/drug effects ; Citrus/*chemistry ; Elafin/*metabolism ; Ethanol/chemistry ; Humans ; Plant Extracts/isolation &amp; purification/*pharmacology ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Urinary Bladder Neoplasms/metabolism/pathology ; }, abstract = {Citrus unshiu peel has been used to prevent and treat various diseases in traditional East-Asian medicine including in Korea. Extracts of C. unshiu peel are known to have various pharmacological effects including antioxidant, anti-inflammatory, and antibacterial properties. Although the possibility of their anti-cancer activity has recently been reported, the exact mechanisms in human cancer cells have not been sufficiently studied. In this study, the inhibitory effect of ethanol extract of C. unshiu peel (EECU) on the growth of human bladder cancer T24 cells was evaluated and the underlying mechanism was investigated. The present study demonstrated that the suppression of T24 cell viability by EECU is associated with apoptosis induction. EECU-induced apoptosis was found to correlate with an activation of caspase-8, -9, and -3 in concomitance with a decrease in the expression of the inhibitor of apoptosis family of proteins and an increase in the Bax:Bcl-2 ratio accompanied by the proteolytic degradation of poly(ADP-ribose) polymerase. EECU also increased the generation of reactive oxygen species (ROS), collapse of mitochondrial membrane potential, and cytochrome c release to the cytosol, along with a truncation of Bid. In addition, EECU inactivated phosphatidylinositol 3-kinase (PI3K) as well as Akt, a downstream molecular target of PI3K, and LY294002, a specific PI3K inhibitor significantly enhanced EECU-induced apoptosis and cell viability reduction. However, N-acetyl cysteine, a general ROS scavenger, completely reversed the EECU-induced dephosphorylation of PI3K and Akt, as well as cell apoptosis. Taken together, these findings suggest that EECU inhibits T24 cell proliferation by activating intrinsic and extrinsic apoptosis pathways through a ROS-mediated inactivation of the PI3K/Akt pathway.}, }
@article {pmid29069230, year = {2017}, author = {Horst, A and de Souza, JA and Santos, MCQ and Riffel, APK and Kolberg, C and Partata, WA}, title = {Effects of N-acetylcysteine on spinal cord oxidative stress biomarkers in rats with neuropathic pain.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {50}, number = {12}, pages = {e6533}, pmid = {29069230}, issn = {1414-431X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants ; Ascorbic Acid/analysis ; Biomarkers/analysis ; Constriction ; Free Radical Scavengers/*pharmacology ; Lipid Peroxides/analysis ; Male ; Neuralgia/*drug therapy/*metabolism ; Oxidative Stress/*drug effects ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Reproducibility of Results ; Sciatic Neuropathy ; Spinal Cord/*drug effects/*metabolism ; Time Factors ; Treatment Outcome ; }, abstract = {N-acetylcysteine (NAC) inhibits nociceptive transmission. This effect has been associated partly with its antioxidant properties. However, the effect of NAC on the levels of lipid hydroperoxides (a pro-oxidant marker), content of ascorbic acid (a key antioxidant molecule of nervous tissue) and total antioxidant capacity (TAC) is unknown. Thus, our study assessed these parameters in the lumbosacral spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve, one of the most commonly employed animal models of neuropathic pain. Thirty-six male Wistar rats weighing 200-300 g were equally divided into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve). All rats received intraperitoneal injections of NAC (150 mg·kg-1·day-1) or saline for 1, 3, or 7 days. Rats were killed 1, 3, and 7 days after surgery. NAC treatment prevented the CCI-induced increase in lipid hydroperoxide levels only at day 1, although the amount was higher than that found in naive rats. NAC treatment also prevented the CCI-induced increase in ascorbic acid content, which occurred at days 1, 3, and 7. No significant change was found in TAC with NAC treatment. The changes observed here may be related to the antinociceptive effect of NAC because modulation of oxidative-stress parameters seemed to help normalize the spinal cord oxidative status altered by pain.}, }
@article {pmid29069221, year = {2017}, author = {Shen, JC and Zhang, YC and Zhao, MF}, title = {Protective effects of deferasirox and N-acetyl-L-cysteine on iron overload-injured bone marrow.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {50}, number = {12}, pages = {e6087}, pmid = {29069221}, issn = {1414-431X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Benzoates/*pharmacology ; Colony-Forming Units Assay ; Deferasirox ; Disease Models, Animal ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; Hematopoiesis/drug effects ; Hematopoietic Stem Cells/*drug effects ; Iron Chelating Agents/*pharmacology ; Iron Overload/*prevention &amp; control ; Male ; Mice, Inbred C57BL ; Protective Agents/*pharmacology ; Reactive Oxygen Species/analysis ; Reference Values ; Reproducibility of Results ; Time Factors ; Treatment Outcome ; Triazoles/*pharmacology ; }, abstract = {Using an iron overload mouse model, we explored the protective effect of deferasirox (DFX) and N-acetyl-L-cysteine (NAC) on injured bone marrow hematopoietic stem/progenitor cells (HSPC) induced by iron overload. Mice were intraperitoneally injected with 25 mg iron dextran every 3 days for 4 weeks to establish an iron overload (Fe) model. DFX or NAC were co-administered with iron dextran in two groups of mice (Fe+DFX and Fe+NAC), and the function of HSPCs was then examined. Iron overload markedly decreased the number of murine HSPCs in bone marrow. Subsequent colony-forming cell assays showed that iron overload also decreased the colony forming capacity of HSPCs, the effect of which could be reversed by DFX and NAC. The bone marrow hematopoiesis damage caused by iron overload could be alleviated by DFX and NAC.}, }
@article {pmid29068588, year = {2017}, author = {Ada, S and Hanci, D and Ulusoy, S and Vejselova, D and Burukoglu, D and Muluk, NB and Cingi, C}, title = {Potential protective effect of N-acetyl cysteine in acoustic trauma: An experimental study using scanning electron microscopy.}, journal = {Advances in clinical and experimental medicine : official organ Wroclaw Medical University}, volume = {26}, number = {6}, pages = {893-897}, doi = {10.17219/acem/64332}, pmid = {29068588}, issn = {1899-5276}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cochlea/*drug effects/metabolism/ultrastructure ; Disease Models, Animal ; Epithelial Cells/drug effects/metabolism/ultrastructure ; Hair Cells, Auditory/drug effects/metabolism/ultrastructure ; Hearing Loss, Noise-Induced/etiology/metabolism/pathology/*prevention &amp; control ; *Microscopy, Electrochemical, Scanning ; Noise/*adverse effects ; Oxidative Stress/*drug effects ; Rats, Wistar ; Stereocilia/drug effects/ultrastructure ; }, abstract = {BACKGROUND: Oxidative stress has been associated with pathological processes involved in acoustic trauma.<br><br>OBJECTIVES: In this prospective experimental study, we investigated the potential preventive effect of N-acetyl cysteine (NAC) in rats exposed to acoustic trauma (AT). Light microscopic and scanning electron microscopic (SEM) evaluations were performed.<br><br>MATERIAL AND METHODS: Healthy Wistar albino rats (n = 18) were divided into 3 groups: group 1 (control group, n = 6), group 2 (acoustic trauma group, n = 6), and group 3 (AT+NAC group, n = 6). The rats in group 2 were exposed to AT. The rats in group 3 received NAC at a dose of 100 mg/kg/day by gavage for 7 days, and then 10 min after the 7th-day dose, they were exposed to AT.<br><br>RESULTS: From light and scanning electron microscopy evaluations in the control group, the cochlear structure and epithelium were normal. In group 2 (AT group), extensive hair cell loss was observed in the cochlea by light microscopy evaluation. In the SEM evaluation, various epithelial damage and loss of stereocilia were also observed. In group 3 (AT+NAC group), decreased damage with preserved cochlear structures was seen by light microscopy. In the SEM evaluation, although stereocilia loss was also seen, nearly normal cell structures and vertical and symmetrical alignment of stereocilia structures were observed compared to the AT group.<br><br>CONCLUSIONS: NAC reduced cochlear damage due to acoustic trauma. Because NAC has antioxidant capacity, AT mat have caused an increase in free radicals and death of outer hair cells. NAC is an antioxidant agent and it prevented cochlear damage due to AT in rats.}, }
@article {pmid29064553, year = {2018}, author = {Zaki, SM and Mohamed, EA and Motawie, AG and Abdel Fattah, S}, title = {N-acetylcysteine versus progesterone on the cisplatin-induced peripheral neurotoxicity.}, journal = {Folia morphologica}, volume = {77}, number = {2}, pages = {234-245}, doi = {10.5603/FM.a2017.0090}, pmid = {29064553}, issn = {0015-5659}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cisplatin/*adverse effects/pharmacology ; Inflammation Mediators/metabolism ; Male ; *Neurotoxicity Syndromes/metabolism/pathology/prevention &amp; control ; Progesterone/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Cisplatin-induced peripheral nerve neurotoxicity (CIPN) is the main obstacle in cisplatin treatment. The aim of this study was to compare the modulatory effects of N-acetylcysteine (NAC) and progesterone on CIPN, because there are scarce literature data on the protective effect of the proge-sterone on the CIPN.<br><br>MATERIALS AND METHODS: Twenty-four rats were divided into four groups: control, cisplatin-treated, concomitant cisplatin-treated and NAC-treated, and concomitant cisplatin-treated and progesterone-treated. Electron microscopic, immunohistochemical, real time polymerase chain reaction and histomorphome-tric analysis; oxidative/antioxidative markers (MDA/GSH and SOD), neurotoxic/ neuroprotective markers (iNOS/nNOS), inflammatory mediators (TNF-a and NF-kB) and BAX were done.<br><br>RESULTS: The myelin sheath in the cisplatin-treated group elucidated infolding. The myelin was disfigured, degenerated, and extensively split with areas of focal loss. The axoplasm was atrophic. Ballooning and vacuolations of the mitochon-dria with alterations of Remak bundles structures were observed. Fewer of these changes were noted in the NAC and progesterone-treated groups. Decrease of the antioxidant SOD and GSH (81% and 64%) and increase of the oxidant MDA (9 folds), increment of the neurotoxic iNOS (1.9 folds) and decrement of the neuroprotective nNOS (64%) and elevation of the inflammatory mediators' TNF-a and NF-kB (8.3 and 11 folds) in the cisplatin-treated group. Increase of the antioxidant SOD (1.3 and 2.5 folds) and GSH (120% and 79%) and decrease of the oxidant MDA (69% and 88%), decrement of the neurotoxic iNOS (56% and 68%) and increment of the neuroprotective nNOS (1.6 and one folds) and elevation of the inflammatory mediators' TNF-a and NF-kB were observed in the NAC and progesterone-treated groups, respectively.<br><br>CONCLUSIONS: The toxic effect of CIPN might be attributed to either oxidative or severe inflammatory stress. Progesterone is efficient in ameliorating these effects; however, NAC is better. (Folia Morphol 2018; 77, 2: 234-245).}, }
@article {pmid29062551, year = {2017}, author = {Mohammadi, H and Jalilian, J and Karimi, MY and Shetab-Boushehri, SV}, title = {In Vitro Cysteine Reactivates Organophosphate Insecticide Dichlorvos-Inhibited Human Cholinesterases.}, journal = {Sultan Qaboos University medical journal}, volume = {17}, number = {3}, pages = {e293-e300}, pmid = {29062551}, issn = {2075-0528}, mesh = {Acetylcysteine/*therapeutic use ; Antidotes ; *Cholinesterase Inhibitors ; Cholinesterase Reactivators/*therapeutic use ; Cholinesterases/*blood/drug effects ; Cysteine/*pharmacology ; Dichlorvos ; *Enzyme Activation ; Erythrocytes/enzymology ; Feasibility Studies ; Humans ; In Vitro Techniques ; Insecticides ; Iran ; Organophosphate Poisoning/*drug therapy/enzymology ; Pralidoxime Compounds/therapeutic use ; }, abstract = {OBJECTIVES: Organophosphate (OP) pesticides inhibit both red blood cell (RBC) and plasma cholinesterases (ChEs). Oximes, especially pralidoxime (2-PAM), are widely used as antidotes to treat OP poisoning. In addition, N-acetylcysteine (NAC) is sometimes used as an adjuvant antidote. The current study aimed to assess the feasibility of using NAC as a single therapeutic agent for OP poisoning in comparison to in vitro 2-PAM.<br><br>METHODS: This study was carried out at the Razi Drug Research Center of Iran University of Medical Sciences, Tehran, Iran, between April and September 2014. A total of 22 healthy human subjects were recruited and 8 mL citrated blood samples were drawn from each subject. Dichlorvos-inhibited blood samples were separately exposed to low and high doses (final concentrations of 300 and 600 &#x3bc;mol.L[-1], respectively) of 2-PAM, NAC and cysteine. Plasma and RBCs were then separated by centrifugation and their ChE activity was measured using spectrophotometry.<br><br>RESULTS: Although cysteine-and not NAC-increased the ChE activity of both plasma and RBCs over those of dichlorvos, it did not increase them over those of a high dose of 2-PAM.<br><br>CONCLUSION: These results suggest that the direct reactions of 2-PAM and cysteine with dichlorvos and the reactivation of phosphorylated ChEs occurr via an associative stepwise addition-elimination process. High therapeutic blood concentrations of cysteine are needed for the elevation of ChE activity in plasma and RBCs; however, both this agent and NAC may still be effective in the reactivation of plasma and RBC ChEs.}, }
@article {pmid29062463, year = {2017}, author = {Michelucci, A and De Marco, A and Guarnier, FA and Protasi, F and Boncompagni, S}, title = {Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1[Y522S/WT] Mice.}, journal = {Oxidative medicine and cellular longevity}, volume = {2017}, number = {}, pages = {6792694}, pmid = {29062463}, issn = {1942-0994}, support = {R01 AR053349/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*metabolism ; Humans ; Mice ; Muscle, Skeletal/*physiology ; Myopathy, Central Core/*genetics/pathology ; Ryanodine Receptor Calcium Release Channel/*metabolism ; }, abstract = {Central core disease (CCD) is a congenital myopathy linked to mutations in the ryanodine receptor type 1 (RYR1), the sarcoplasmic reticulum Ca[2+] release channel of skeletal muscle. CCD is characterized by formation of amorphous cores within muscle fibers, lacking mitochondrial activity. In skeletal muscle of RYR1[Y522S/WT] knock-in mice, carrying a human mutation in RYR1 linked to malignant hyperthermia (MH) with cores, oxidative stress is elevated and fibers present severe mitochondrial damage and cores. We treated RYR1[Y522S/WT] mice with N-acetylcysteine (NAC), an antioxidant provided ad libitum in drinking water for either 2 or 6 months. Our results show that 2 months of NAC treatment starting at 2 months of age, when mitochondrial and fiber damage was still minimal, (i) reduce formation of unstructured and contracture cores, (ii) improve muscle function, and (iii) decrease mitochondrial damage. The beneficial effect of NAC treatment is also evident following 6 months of treatment starting at 4 months of age, when structural damage was at an advanced stage. NAC exerts its protective effect likely by lowering oxidative stress, as supported by the reduction of 3-NT and SOD2 levels. This work suggests that NAC administration is beneficial to prevent mitochondrial damage and formation of cores and improve muscle function in RYR1[Y522S/WT] mice.}, }
@article {pmid29061063, year = {2017}, author = {Mao, LQ and Li, XB}, title = {Effects of N-acetyl cysteine to improve acute lung injury in rats.}, journal = {Bratislavske lekarske listy}, volume = {118}, number = {9}, pages = {552-556}, doi = {10.4149/BLL_2017_106}, pmid = {29061063}, issn = {0006-9248}, mesh = {Acetylcysteine/*pharmacology ; Acute Lung Injury/chemically induced/metabolism/*pathology ; Animals ; Bronchoalveolar Lavage Fluid ; Dexamethasone/pharmacology ; Free Radical Scavengers/*pharmacology ; Glucocorticoids/pharmacology ; Lipopolysaccharides/toxicity ; Lung/*drug effects/metabolism/pathology ; Male ; NF-kappa B/*drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Toll-Like Receptor 4/*drug effects/metabolism ; Transforming Growth Factor beta1/*drug effects/metabolism ; }, abstract = {AIM: To study the mechanism of NAC to improve LPS induced acutelung lung injury.<br><br>METHODS: The 40 rats were divided into 4 groups included NC group, Model group, NAC group and DXM group. The rats of Model, NAC and DXM groups were injected LPS, NAC group and DXM group were resepectively injected NAC (200 mg/kg) or DXM (70 mg/kg). Collecting the bronchoalveolar lavage fluid (BALF) from lung, and measuring the TGF-&#x3b2;1 concentration of BALF and lung tissue in 4 groups; After executing the rats, taken the lung tissue to observant lung pathological morphology and evaluated TGF-&#x3b2;1 expression of difference groups. Measuring the TLR-4 and NF-&#x3ba;b in 4 groups by WB assay.<br><br>RESULTS: Compared with Model group, The NAC and DXM groups were improved in H (et) E staining, the TGF-&#x3b2;1 concentration of NAC and DXM groups were significantly reduced in BALF and lung tissue (p < 0.05, respectively). TLR-4 and NF-&#x3ba;b proteins of NAC and DXM groups were lower than that of Model group in IHC and WB assays (p < 0.05, respectively).<br><br>CONCLUSION: NAC had effects to protect LPS induced lung injury via TLR-4/NF-&#x3ba;b signaling pathway (Fig. 5, Ref. 19).}, }
@article {pmid29058042, year = {2018}, author = {Shen, X and Sun, Y and Wang, M and Shu, H and Zhu, LJ and Yan, PY and Zhang, JF and Jin, X}, title = {Chronic N-acetylcysteine treatment alleviates acute lipopolysaccharide-induced working memory deficit through upregulating caveolin-1 and synaptophysin in mice.}, journal = {Psychopharmacology}, volume = {235}, number = {1}, pages = {179-191}, pmid = {29058042}, issn = {1432-2072}, support = {81371224, 81671145//National Natural Science Foundation of China/International ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Caveolin 1/*metabolism ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Hippocampus/drug effects/metabolism ; Lipopolysaccharides/*pharmacology ; Male ; Memory Disorders/metabolism ; Memory, Short-Term/*drug effects ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Prefrontal Cortex/drug effects/metabolism ; Synaptophysin/*metabolism ; Up-Regulation/*drug effects ; }, abstract = {RATIONALE: Working memory (WM) is a dynamic encoding process and an active representation of information over a short time. The ability to guide forthcoming behavior would be disrupted if WM was impaired by various factors including inflammation, stress, free radicals, and disease states such as schizophrenia. However, the mechanism underlying acute working memory impairment remains to be defined.<br><br>OBJECTIVES: In this study, we tested the hypothesis that decreased caveolin-1 (Cav-1) and synaptophysin (SYP) accounted for the WM impairment challenged with acute intraperitoneally lipopolysaccharide (LPS), which mimicked neuroinflammation. Delayed alternation T-maze task (DAT) was used to assess working memory of adult male C57BL/6 mice, and western blot and immunostaining were used to detect protein expression and distribution in medial prefrontal cortex (mPFC) and hippocampus.<br><br>RESULTS: Our results showed that LPS dose-dependently induced working memory deficit accompanied by the decrease of Cav-1 and SYP in mPFC but not hippocampus. In addition, LPS significantly decreased protein level of Cav-1 and SYP in neurons by activating microglia cells. More important, 2-week N-acetylcysteine (NAC) treatment dose-dependently inhibited LPS-induced working memory deficit by improving the ability to use Lose-shift but not Win-shift strategy and significantly inhibited LPS-induced downregulation of Cav-1 and SYP in mPFC.<br><br>CONCLUSIONS: Taken together, our findings demonstrate that chronic NAC treatment alleviates acute LPS-induced working memory deficit through upregulating Cav-1 and SYP in mice.}, }
@article {pmid29057033, year = {2017}, author = {Pang, N and Chen, T and Deng, X and Chen, N and Li, R and Ren, M and Li, Y and Luo, M and Hao, H and Wu, J and Wang, L}, title = {Polydatin Prevents Methylglyoxal-Induced Apoptosis through Reducing Oxidative Stress and Improving Mitochondrial Function in Human Umbilical Vein Endothelial Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2017}, number = {}, pages = {7180943}, pmid = {29057033}, issn = {1942-0994}, mesh = {Apoptosis/*drug effects ; Drugs, Chinese Herbal/pharmacology/*therapeutic use ; Endothelial Cells/*metabolism ; Glucosides/pharmacology/*therapeutic use ; Human Umbilical Vein Endothelial Cells/*drug effects ; Humans ; Mitochondria/*metabolism ; Oxidative Stress ; Stilbenes/pharmacology/*therapeutic use ; }, abstract = {Methylglyoxal (MGO), an active metabolite of glucose, has been reported to induce vascular cell apoptosis in diabetic complication. Polydatin (PD), a small natural compound from Polygonum cuspidatum, has a number of biological functions, such as antioxidative, anti-inflammatory, and nephroprotective properties. However, the protective effects of PD on MGO-induced apoptosis in endothelial cells remain to be elucidated. In this study, human umbilical vein endothelial cells (HUVECs) were used to explore the effects of PD on MGO-induced cell apoptosis and the possible mechanism involved. HUVECs were pretreated with PD for 2 h, followed by stimulation with MGO. Then cell apoptosis, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) impairment, mitochondrial morphology alterations, and Akt phosphorylation were assessed. The results demonstrated that PD significantly prevented MGO-induced HUVEC apoptosis. PD pretreatment also significantly inhibited MGO-induced ROS production, MMP impairment, mitochondrial morphology changes, and Akt dephosphorylation. These results and the experiments involving N-acetyl cysteine (antioxidant), Cyclosporin A (mitochondrial protector), and LY294002 (Akt inhibitor) suggest that PD prevents MGO-induced HUVEC apoptosis, at least in part, through inhibiting oxidative stress, maintaining mitochondrial function, and activating Akt pathway. All of these data indicate the potential application of PD for the treatment of diabetic vascular complication.}, }
@article {pmid29055102, year = {2018}, author = {Gadalla, MA and Huang, S and Wang, R and Norman, RJ and Abdullah, SA and El Saman, AM and Ismail, AM and van Wely, M and Mol, BWJ}, title = {Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis.}, journal = {Ultrasound in obstetrics &amp; gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology}, volume = {51}, number = {1}, pages = {64-76}, doi = {10.1002/uog.18933}, pmid = {29055102}, issn = {1469-0705}, mesh = {Anovulation/*drug therapy ; *Birth Rate ; Clomiphene/*therapeutic use ; Endometrium/*drug effects/pathology ; Estrogen Antagonists/*therapeutic use ; Female ; Fertility Agents, Female ; Humans ; Infant, Newborn ; *Live Birth ; Ovulation Induction ; Pregnancy ; Pregnancy Outcome ; Pregnancy Rate ; Randomized Controlled Trials as Topic ; Tamoxifen/*therapeutic use ; }, abstract = {OBJECTIVES: To compare the impact of clomiphene citrate (CC) vs other drug regimens on mid-cycle endometrial thickness (EMT), ovulation, pregnancy and live birth rates in women with World Health Organization (WHO) group II ovulatory disorders.<br><br>METHODS: We searched MEDLINE, EMBASE, Scopus, Web of Science, The Cochrane Central Register of Clinical Trials (CENTRAL) and the non-MEDLINE subset of PubMed from inception to December 2016 and cross-checked references of relevant articles. We included only randomized controlled trials (RCTs) comparing CC used alone vs other drug regimens for ovulation induction in women with WHO group II anovulation. Outcomes were mid-cycle EMT, ovulation, pregnancy and live birth rates. We pooled weighted mean differences (WMD) with 95% confidence intervals (CI) for continuous variables (EMT) and risk ratios (RR) with 95% CI for binary variables (ovulation, pregnancy and live birth rates).<br><br>RESULTS: We retrieved 1718 articles of which 33 RCTs (4349 women, 7210 ovulation induction cycles) were included. In 15 RCTs that compared CC with letrozole, EMT was lower in the CC group (1957 women, 3892&#x2009;cycles; WMD, -1.39; 95% CI, -2.27 to -0.51; I[2] &#x2009;=&#x2009;100%), ovulation rates after CC and letrozole were comparable (1710 women, 3217&#x2009;cycles; RR, 0.97; 95% CI, 0.90-1.04; I[2] &#x2009;=&#x2009;47%), while CC led to a lower pregnancy rate (1957 women, 3892&#x2009;cycles; RR, 0.78; 95% CI, 0.63-0.95; I[2] &#x2009;=&#x2009;43%) and a lower live birth rate (RR, 0.70; 95% CI, 0.49-0.98; I[2] &#x2009;=&#x2009;35%). In two RCTs that compared CC with CC plus metformin, EMT, ovulation and pregnancy rates were comparable (101 women, 140&#x2009;cycles; WMD, -0.23; 95% CI, -0.92 to 0.45; I[2] &#x2009;=&#x2009;78%; RR, 0.84; 95% CI, 0.67-1.06; I[2] &#x2009;=&#x2009;0%; and RR, 0.79; 95% CI, 0.33-1.87; I[2] &#x2009;=&#x2009;0%). In three studies that compared CC with CC plus N-acetyl cysteine (NAC), EMT was lower in the CC group (340 women, 300&#x2009;cycles; WMD, -1.51; 95% CI, -1.98 to -1.04; I[2] &#x2009;=&#x2009;45%). In two studies that compared CC with CC&#x2009;+&#x2009;nitric oxide (NO) donor, EMT was lower in the CC group (120 women, 304&#x2009;cycles; WMD, -1.75; 95% CI, -2.08 to -1.41; I[2] &#x2009;=&#x2009;0%). Compared with CC plus NO donor or NAC, CC showed statistically significant lower ovulation and pregnancy rates. Compared with tamoxifen in three studies, CC showed a tendency towards lower EMT (571 women, 844&#x2009;cycles; WMD, -1.34; 95% CI, -2.70 to 0.01; I[2] &#x2009;=&#x2009;96%) with comparable ovulation and pregnancy rates.<br><br>CONCLUSIONS: In women with WHO group II ovulatory disorders, ovulation induction with CC might result in lower EMT than other ovulation induction regimens. Whether the lower EMT caused the lower pregnancy and live birth rates remains to be elucidated. Letrozole seems to be beneficial for these women. However, our findings should be interpreted with caution as the quality of evidence was very low. Copyright &#xa9; 2017 ISUOG. Published by John Wiley &amp; Sons Ltd.}, }
@article {pmid29053023, year = {2018}, author = {Cullen, KR and Klimes-Dougan, B and Westlund Schreiner, M and Carstedt, P and Marka, N and Nelson, K and Miller, MJ and Reigstad, K and Westervelt, A and Gunlicks-Stoessel, M and Eberly, LE}, title = {N-Acetylcysteine for Nonsuicidal Self-Injurious Behavior in Adolescents: An Open-Label Pilot Study.}, journal = {Journal of child and adolescent psychopharmacology}, volume = {28}, number = {2}, pages = {136-144}, pmid = {29053023}, issn = {1557-8992}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Administration, Oral ; Adolescent ; Depression/*drug therapy/epidemiology ; Dose-Response Relationship, Drug ; Female ; Free Radical Scavengers/administration &amp; dosage/adverse effects ; Humans ; Impulsive Behavior/*drug effects ; Pilot Projects ; Psychiatric Status Rating Scales ; Self-Injurious Behavior/*drug therapy ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Nonsuicidal self-injury (NSSI) is common in adolescents and young adults, and few evidence-based treatments are available for this significant problem. N-acetylcysteine (NAC) is a widely available nutritional supplement that has been studied in some psychiatric disorders relevant to NSSI including mood and addictive disorders. This pilot study tested the use of NAC as a potential treatment for NSSI in youth.<br><br>METHODS: Thirty-five female adolescents and young adults with NSSI aged 13-21 years were enrolled in this study that had an open-label, single-arm study design. All participants were given oral NAC as follows: 600&#x2009;mg twice daily (weeks 1-2), 1200&#x2009;mg twice daily (weeks 3-4), and 1800&#x2009;mg twice daily (weeks 5-8). Patients were seen every 2 weeks throughout the trial, at which time youth reported the frequency of NSSI episodes. Levels of depression, impulsivity, and global psychopathology were measured at baseline and at the end of the trial using the Beck Depression Inventory-II (BDI-II), Barratt Impulsivity Scale, and Symptoms Checklist-90 (SCL-90).<br><br>RESULTS: About two-thirds of the enrolled female youth completed the trial (24/35). NAC was generally well tolerated in this sample. NAC treatment was associated with a significant decrease in NSSI frequency at visit 6 and visit 8 compared to baseline. We also found that depression scores and global psychopathology scores (but not impulsivity scores) decreased after NAC treatment. Decrease in NSSI was not correlated with decrease in BDI-II or SCL-90 scores, suggesting these might be independent effects.<br><br>CONCLUSION: We provide preliminary evidence that NAC may have promise as a potential treatment option for adolescents with NSSI. The current results require follow-up with a randomized, placebo-controlled trial to confirm efficacy.}, }
@article {pmid29052278, year = {2018}, author = {Ansari, FA and Mahmood, R}, title = {Carnosine and N-acetyl cysteine protect against sodium nitrite-induced oxidative stress in rat blood.}, journal = {Cell biology international}, volume = {42}, number = {3}, pages = {281-293}, doi = {10.1002/cbin.10893}, pmid = {29052278}, issn = {1095-8355}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Carnosine/*pharmacology ; Cytochrome-B(5) Reductase/blood ; Drug Interactions ; Erythrocytes/drug effects/metabolism ; Male ; Methemoglobin/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Protective Agents/pharmacology ; Rats ; Rats, Wistar ; Sodium Nitrite/antagonists &amp; inhibitors/blood/*toxicity ; }, abstract = {Sodium nitrite (NaNO2) is widely used in the food industry as a preservative and colorant in meat and fish products. Industrialization and improper agricultural practices have greatly increased human exposure to high nitrite levels, mainly through contaminated drinking water, causing various health disorders. We have investigated the protective effect of carnosine (CAR) and N-acetyl cysteine (NAC) on NaNO2 -induced toxicity in rat blood. CAR is a bioactive dipeptide found in mammalian muscle while NAC is a synthetic sulfhydryl amino acid and an important precursor of glutathione. Animals were given a single acute oral dose of NaNO2 at 60 mg/kg body weight with or without prior administration of either CAR or NAC. Rats were sacrificed after 24 h, blood was withdrawn and plasma and erythrocytes were isolated. Administration of NaNO2 alone increased methemoglobin levels and methemoglobin reductase activity, decreased the activities of antioxidant defense and metabolic enzymes and significantly weakened the total antioxidant capacity of rat erythrocytes. Similar effects were seen in plasma of NaNO2 -treated rats. In contrast, administration of CAR or NAC, prior to NaNO2 treatment, markedly attenuated the NaNO2 -elicited deleterious effects. Thus, CAR and NAC can mitigate nitrite-induced metabolic alterations and oxidative damage probably due to their intrinsic biochemical antioxidant properties. This study suggests that CAR and NAC can be potentially used as therapeutic/protective agents against NaNO2 toxicity.}, }
@article {pmid29050275, year = {2017}, author = {Zhao, Y and Li, ETS and Wang, M}, title = {Alisol B 23-acetate induces autophagic-dependent apoptosis in human colon cancer cells via ROS generation and JNK activation.}, journal = {Oncotarget}, volume = {8}, number = {41}, pages = {70239-70249}, pmid = {29050275}, issn = {1949-2553}, abstract = {Alisol B 23-acetate (AB23A), a natural triterpenoid from the rhizome of Alisma orientale, a Chinese medicinal herb, has multiple physiological activities including anticancer. However, its effect on human colon cancer and the underlying mechanism are not clear. Here, we reported for the first time that AB23A induced cell cycle G1 phase arrest and apoptotic cell death in colon cancer cells. Autophagy also occurred in AB23A-treated HCT116 cells as evidenced by the accumulation of microtubule-associated protein 1 light chain 3 form II (LC3-II) and degradation of SQSTM1/p62. An autophagy inhibitor, 3-methyladenine (3-MA) was found to attenuate AB23A-mediated autophagy, apoptosis, and cell death, indicating that AB23A-induced apoptotic response was dependent on the induction of autophagy. In addition, the treatment of HCT116 cells with AB23A resulted in the generation of reactive oxygen species (ROS) and phosphorylation of c-Jun N-terminal kinase (JNK). A ROS scavenger, N-acetylcysteine (NAC) and a JNK-specific inhibitor, SP600125 attenuated AB23A-induced autophagy and apoptotic cell death. Moreover, NAC was able to eliminate AB23A-induced JNK phosphorylation. This finding provides a novel mechanism of action of AB23A in colon cancer HCT116 cells that AB23A induces autophagic-dependent apoptotic cell death in colon cancer cells, at least in part, though the accumulation of intracellular ROS and subsequent activation of JNK.}, }
@article {pmid29049376, year = {2017}, author = {Murphy-Marshman, H and Quensel, K and Shi-Wen, X and Barnfield, R and Kelly, J and Peidl, A and Stratton, RJ and Leask, A}, title = {Antioxidants and NOX1/NOX4 inhibition blocks TGFβ1-induced CCN2 and α-SMA expression in dermal and gingival fibroblasts.}, journal = {PloS one}, volume = {12}, number = {10}, pages = {e0186740}, pmid = {29049376}, issn = {1932-6203}, mesh = {Actins/*metabolism ; Antioxidants/*pharmacology ; Cells, Cultured ; Connective Tissue Growth Factor/*metabolism ; Fibroblasts/metabolism ; Gingiva/cytology/*metabolism ; Humans ; NADPH Oxidase 1/*antagonists &amp; inhibitors ; NADPH Oxidase 4/*antagonists &amp; inhibitors ; Skin/cytology/*metabolism ; Transforming Growth Factor beta1/*antagonists &amp; inhibitors/physiology ; }, abstract = {TGFbeta induces fibrogenic responses in fibroblasts. Reactive oxygen species (ROS)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) may contribute to fibrogenic responses. Here, we examine if the antioxidant N-acetylcysteine (NAC), the NOX inhibitor diphenyleneiodonium (DPI) and the selective NOX1/NOX4 inhibitor GKT-137831 impairs the ability of TGFbeta to induce profibrotic gene expression in human gingival (HGF) and dermal (HDF) fibroblasts. We also assess if GKT-137831 can block the persistent fibrotic phenotype of lesional scleroderma (SSc) fibroblasts. We use real-time polymerase chain reaction and Western blot analysis to evaluate whether NAC and DPI impair the ability of TGFbeta1 to induce expression of fibrogenic genes in fibroblasts. The effects of GKT-137831 on TGFbeta-induced protein expression and the persistent fibrotic phenotype of lesional scleroderma (SSc) fibroblasts were tested using Western blot and collagen gel contraction analyses. In HDF and HGF, TGFbeta1 induces CCN2, CCN1, endothelin-1 and alpha-smooth muscle actin (SMA) in a fashion sensitive to NAC. Induction of COL1A1 mRNA was unaffected. Similar results were seen with DPI. NAC and DPI impaired the ability of TGFbeta1 to induce protein expression of CCN2 and alpha-SMA in HDF and HGF. GKT-137831 impaired TGFbeta-induced CCN2 and alpha-SMA protein expression in HGF and HDF. In lesional SSc dermal fibroblasts, GKT-137831 reduced alpha-SMA and CCN2 protein overexpression and collagen gel contraction. These results are consistent with the hypothesis that antioxidants or NOX1/4 inhibition may be useful in blocking profibrotic effects of TGFbeta on dermal and gingival fibroblasts and warrant consideration for further development as potential antifibrotic agents.}, }
@article {pmid29048101, year = {2017}, author = {Park, WH}, title = {Gallic acid inhibits the growth of calf pulmonary arterial endothelial cells through cell death and glutathione depletion.}, journal = {Molecular medicine reports}, volume = {}, number = {}, pages = {}, doi = {10.3892/mmr.2017.7585}, pmid = {29048101}, issn = {1791-3004}, abstract = {Gallic acid (GA) exhibits a number of cellular effects, including apoptosis, which is associated with oxidative stress. The present study investigated the effects of GA on calf pulmonary arterial endothelial cell (CPAEC) growth and death, along with the levels of reactive oxygen species (ROS) and glutathione (GSH). GA treatment inhibited the growth of CPAECs at 24 h, and the half‑maximal inhibitory concentration (IC50) value of GA was ~30 µM. GA treatment also induced cell death, which was accompanied by a loss of mitochondrial membrane potential (ΔѰm). GA treatment in CPAECs resulted in decreased ROS levels, including O2•‑, whereas the number of GSH‑depleted cells increased. Neither a pan‑caspase inhibitor (benzyloxycarbonyl‑Val‑Ala‑Asp‑fluoromethylketone) nor buthionine sulfoximine treatment affected GA‑induced cell growth inhibition, cell death, ROS and GSH levels in CPAECs, whereas co‑treatment with N‑acetyl‑cysteine (NAC) resulted in enhanced cell growth inhibition, cell death and ΔѰm loss in these cells. Although NAC treatment did not significantly influence ROS levels in GA‑treated CPAECs, it significantly enhanced GSH depletion in these cells. In conclusion, GA inhibited the growth of CPAECs via cell death, which was associated with GSH depletion rather than alterations to ROS levels.}, }
@article {pmid29046125, year = {2017}, author = {Onoda, A and Takeda, K and Umezawa, M}, title = {Pretreatment with N-acetyl cysteine suppresses chronic reactive astrogliosis following maternal nanoparticle exposure during gestational period.}, journal = {Nanotoxicology}, volume = {11}, number = {8}, pages = {1012-1025}, doi = {10.1080/17435390.2017.1388864}, pmid = {29046125}, issn = {1743-5404}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Intranasal ; Animals ; Animals, Newborn ; Antioxidants/*therapeutic use ; Aquaporin 4/metabolism ; Astrocytes/*drug effects/metabolism ; Brain/*drug effects/growth &amp; development/metabolism ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Maternal Exposure/*adverse effects ; Mice ; Mice, Inbred ICR ; Nanoparticles/*toxicity ; Oxidative Stress/drug effects ; Pregnancy ; Prenatal Exposure Delayed Effects/etiology/*prevention &amp; control ; Soot/*toxicity ; }, abstract = {Early pregnant employees are potentially and unintendedly exposed to industrial chemicals including nanoparticles. Developmental toxicity of nanoparticle exposure has been concerned because exposure to fine particle including carbon black nanoparticle (CB-NP) during the brain developmental stage enhances the risk of brain disorders. Maternal CB-NP exposure dose-dependently induces astrogliosis, which is an abnormal increase in the reactive astrocytes with glial fibrillary acidic protein (GFAP) and aquaporin-4 overexpression due to the destruction of nearby neurons and blood vessels. The present study aimed to investigate protective effects of antioxidants on the histopathological denaturation with astrogliosis following maternal CB-NP exposure in offspring mice, thereby to evaluate the role of oxidative stress on the developmental toxicity. Pregnant ICR mice were treated with CB-NP by intranasal instillation on gestational days 5 and 9. N-acetyl cysteine (NAC) or ascorbic acid was intraperitoneally administered to the pregnant mice 1 h prior to CB-NP instillation. The brains were collected from 6- to 12-week-old offspring mice and analyzed using western blotting and immunohistochemistry. NAC suppressed GFAP overexpression in 6- and 12-week-old offspring mice following maternal CB-NP exposure. However, NAC did not suppress aquaporin-4 overexpression following maternal CB-NP exposure. Ascorbic acid did not suppress, but rather slightly and significantly enhanced the expression of GFAP and aquaporin-4. These results indicate that astrogliosis by maternal CB-NP exposure is partially prevented by NAC pretreatment. Oxidative stress is a possible key factor of developmental neurotoxicity of maternal NP exposure. This study will contribute to elucidating the mechanisms underlying the effects of developmental neurotoxicity of NPs.}, }
@article {pmid29045497, year = {2017}, author = {Krzyżanowska, W and Pomierny, B and Bystrowska, B and Pomierny-Chamioło, L and Filip, M and Budziszewska, B and Pera, J}, title = {Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia.}, journal = {PloS one}, volume = {12}, number = {10}, pages = {e0186243}, pmid = {29045497}, issn = {1932-6203}, mesh = {Acetylcysteine/administration &amp; dosage ; Amino Acid Transport Systems, Acidic/*genetics ; Animals ; Astrocytes/drug effects/metabolism ; Brain Ischemia/*drug therapy/genetics/pathology ; Ceftriaxone/administration &amp; dosage ; Excitatory Amino Acid Transporter 2/*genetics ; Frontal Lobe/drug effects/metabolism ; Gene Expression Regulation/drug effects ; Glutamic Acid/*metabolism ; Hippocampus/drug effects/metabolism ; Humans ; Infarction, Middle Cerebral Artery ; Rats ; Synaptic Transmission/drug effects ; }, abstract = {One of the major players in the pathophysiology of cerebral ischemia is disrupted homeostasis of glutamatergic neurotransmission, resulting in elevated extracellular glutamate (Glu) concentrations and excitotoxicity-related cell death. In the brain, Glu concentrations are regulated by Glu transporters, including Glu transporter-1 (GLT-1) and cystine/Glu antiporter (system xc-). Modulation of these transporters by administration of ceftriaxone (CEF, 200 mg/kg, i.p.) or N-acetylcysteine (NAC, 150 mg/kg, i.p.) for 5 days before focal cerebral ischemia may induce brain tolerance to ischemia by significantly limiting stroke-related damage and normalizing Glu concentrations. In the present study, focal cerebral ischemia was induced by 90-minute middle cerebral artery occlusion (MCAO). We compared the effects of CEF and NAC pretreatment on Glu concentrations in extracellular fluid and cellular-specific expression of GLT-1 and xCT with the effects of two reference preconditioning methods, namely, ischemic preconditioning and chemical preconditioning in rats. Both CEF and NAC significantly reduced Glu levels in the frontal cortex and hippocampus during focal cerebral ischemia, and this decrease was comparable with the Glu level achieved with the reference preconditioning strategies. The results of immunofluorescence staining of GLT-1 and xCT on astrocytes, neurons and microglia accounted for the observed changes in extracellular Glu levels to a certain extent. Briefly, after MCAO, the expression of GLT-1 on astrocytes decreased, but pretreatment with CEF seemed to prevent this downregulation. In addition, every intervention used in this study seemed to reduce xCT expression on astrocytes and neurons. The results of this study indicate that modulation of Glu transporter expression may restore Glu homeostasis. Moreover, our results suggest that CEF and NAC may induce brain tolerance to ischemia by influencing GLT-1 and system xc- expression levels. These transporters are presumably good targets for the development of novel therapies for brain ischemia.}, }
@article {pmid29045036, year = {2018}, author = {Wang, HF and Wang, ZQ and Ding, Y and Piao, MH and Feng, CS and Chi, GF and Luo, YN and Ge, PF}, title = {Endoplasmic reticulum stress regulates oxygen-glucose deprivation-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {24}, number = {1}, pages = {29-38}, pmid = {29045036}, issn = {1755-5949}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects/*physiology ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/drug effects/*physiology ; Free Radical Scavengers/pharmacology ; Glucose/*deficiency ; Glutathione/metabolism ; Humans ; Hypoxia/*metabolism ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Neuroblastoma/pathology ; Phenylbutyrates/pharmacology ; RNA, Small Interfering/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Time Factors ; Transfection ; }, abstract = {AIMS: Endoplasmic reticulum (ER) stress has been demonstrated to regulate neuronal death caused by ischemic insults via activation of apoptosis, but it still remains unclear whether ER stress participates in regulation of parthanatos, a new type of programmed cell death characterized by PARP-1 overactivation and intracellular accumulation of PAR polymer.<br><br>METHODS: we used oxygen-glucose deprivation (OGD) and human SH-SY5Y cells to simulate neuronal damage caused by ischemia.<br><br>RESULTS: Oxygen-glucose deprivation induced time-dependent death in SH-SY5Y cells, which was accompanied with upregulation of PARP-1, accumulation of PAR polymer, decline of mitochondrial membrane potentials and nuclear translocation of AIF. Pharmacological inhibition of PARP-1 with its specific inhibitor 3AB rescued OGD-induced cell death, as well as prevented PAR polymer accumulation, mitochondrial depolarization, and AIF translocation into nucleus. Similar results could be found when PARP-1 was genetically knocked down with SiRNA. These indicated that OGD triggered parthanatos in SH-SY5Y cells. Then, we found inhibition of overproduction of ROS with antioxidant NAC attenuated obviously OGD-induced parthanatos in SH-SY5Y cells, suggesting ROS regulated OGD-induced parthanatos. Additionally, OGD also induced upregulation of ER stress-related proteins. Mitigation of ER stress with chemical chaperone 4-PBA or trehalose suppressed significantly OGD-induced overproduction of ROS, PARP-1 upregulation, PAR polymer accumulation, and nuclear accumulation of AIF, and cell death in SH-SY5Y cells.<br><br>CONCLUSION: Endoplasmic reticulum stress regulates OGD-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS.}, }
@article {pmid29043702, year = {2018}, author = {Cheraghi, E and Soleimani Mehranjani, M and Shariatzadeh, SMA and Nasr Esfahani, MH and Alani, B}, title = {N-Acetylcysteine Compared to Metformin, Improves The Expression Profile of Growth Differentiation Factor-9 and Receptor Tyrosine Kinase c-Kit in The Oocytes of Patients with Polycystic Ovarian Syndrome.}, journal = {International journal of fertility &amp; sterility}, volume = {11}, number = {4}, pages = {270-278}, pmid = {29043702}, issn = {2008-076X}, abstract = {BACKGROUND: Paracrine disruption of growth factors in women with polycystic ovarian syndrome (PCOS) results in production of low quality oocyte, especially following ovulation induction. The aim of this study was to investigate the effects of metformin (MET), N-acetylcysteine (NAC) and their combination on the hormonal levels and expression profile of GDF-9, BMP-15 and c-kit, as hallmarks of oocyte quality, in PCOS patients.<br><br>MATERIALS AND METHODS: This prospective randomized, double-blind, placebo controlled trial aims to study the effects of MET, NAC and their combination (MET+NAC) on expression of GDF-9, BMP-15 and c-kit mRNA in oocytes [10 at the germinal vesicle (GV) stage, 10 at the MI stage, and 10 at the MII stage from per group] derived following ovulation induction in PCOS. Treatment was carried out for six weeks, starting on the third day of previous cycle until oocyte aspiration. The expression of GDF9, BMP15 and c-kit were determined by quantitative real time polymerase chain reaction (RT-qPCR) and western blot analysis. Data were analyzed with one-way ANOVA.<br><br>RESULTS: The follicular fluid (FF) level of c-kit protein significantly decreased in the NAC group compared to the other groups. Significant correlations were observed between the FF soluble c-kit protein with FF volume, androstenedione and estradiol. The GDF-9 expression in unfertilized mature oocytes were significantly higher in the NAC group compared to the other groups (P<0.001). Similar difference was not observed between the MET, NAC+MET and control groups. The c-kit expression in unfertilized mature oocytes were significantly lower in the NAC group compared to the other groups (P<0.001). Similar difference was not observed between the MET, NAC+MET and control groups (Registration number: IRCT201204159476N1).<br><br>CONCLUSION: We concluded that NAC can improve the quality of oocytes in PCOS.}, }
@article {pmid29039609, year = {2017}, author = {Zhang, Y and Guo, Y and Wang, M and Dong, H and Zhang, J and Zhang, L}, title = {Quercetrin from Toona sinensis leaves induces cell cycle arrest and apoptosis via enhancement of oxidative stress in human colorectal cancer SW620 cells.}, journal = {Oncology reports}, volume = {38}, number = {6}, pages = {3319-3326}, pmid = {29039609}, issn = {1791-2431}, mesh = {Apoptosis/drug effects ; Apoptotic Protease-Activating Factor 1/genetics ; Caspase 3/genetics ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Colorectal Neoplasms/*drug therapy/genetics/pathology ; Gene Expression Regulation, Neoplastic/drug effects ; Glutathione Peroxidase/genetics ; Humans ; Meliaceae/chemistry ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Plant Extracts/*administration &amp; dosage/chemistry ; Quercetin/administration &amp; dosage/*analogs &amp; derivatives/chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {Finding effective strategies against colorectal cancer (CRC) is still an emergent health problem. In the present study, we investigated the anticancer activity of quercetrin from Toona sinensis leaves (QTL) and explored the underlying mechanism in human CRC cell line SW620. The cells were treated with various concentrations of QTL and the cytotoxic effects of QTL were determined using the MTT assay. Apoptosis and cell cycle status were detected by flow cytometry. Reactive oxygen species (ROS) levels and mitochondrial membrane potential (∆Ψm) were assessed using DCF-DA and JC-1 fluorescence spectrophotometry, respectively. Western blot analysis was used to quantify the expression of apoptosis‑related proteins. RT-PCR was applied to determine the mRNA levels of glutathione peroxidase (GPx) and catalase (CAT). QTL exhibited growth inhibitory effects and caused cell cycle arrest in the G2/M phase, which was accompanied by increased expression of p53 and p21 proteins. QTL promoted apoptosis which was consistent with the upregulated expression of Bax, cytochrome c, caspase-9, Apaf-1 and caspase-3. In addition, QTL induced the loss of mitochondrial membrane potential and triggered ROS generation, as revealed by the downregulated mRNA expression and enzymatic activity of GPx and CAT. Furthermore, both N‑acetyl cysteine (NAC) and GSH attenuated the QTL-induced growth inhibition observed in SW620 cells along with the increase of ROS levels. These findings revealed that QTL inhibited the growth of CRC cells and facilitated apoptosis by enhancing oxidative stress. QTL may therefore have potential for use in CRC chemotherapy.}, }
@article {pmid29039537, year = {2017}, author = {Liu, X and Chen, Y and Zhang, Y and Du, J and Lv, Y and Mo, S and Liu, Y and Ding, F and Wu, J and Li, J}, title = {Juglone potentiates TRAIL‑induced apoptosis in human melanoma cells via activating the ROS‑p38‑p53 pathway.}, journal = {Molecular medicine reports}, volume = {16}, number = {6}, pages = {9645-9651}, doi = {10.3892/mmr.2017.7806}, pmid = {29039537}, issn = {1791-3004}, mesh = {Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Melanoma/*metabolism ; Naphthoquinones/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; Tumor Suppressor Protein p53/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL)‑based cancer therapy offers promise as TRAIL can kill cancer cells without apparent toxicity towards normal cells. However, intrinsic or acquired resistance to TRAIL inseveral types of cancer cell has become a major challenge in TRAIL‑based cancer therapy. Juglone is a natural compound isolated from walnut trees. In the present study, it was demonstrated that juglone sensitized melanoma cells to TRAIL‑induced cytotoxicity by MTT and crystal violet assays. Flow cytometry analysis indicated that juglone potentiated TRAIL‑induced cell death. Western blot assay demonstrated that the expressions of cleaved poly(ADP‑ribose) polymerase (PARP) and cleaved caspase 3 were markedly increased in the juglone combined with TRAIL group. Exposure to TRAIL alone did not induce the production of reactive oxygen species (ROS), activation of p38 orincrease of p53 in the TRAIL‑resistant melanoma cells, as determined by flow cytometry and western blot analysis. However, exposure to TRAIL in combination with juglone markedly increased the production of ROS, activated p38 and increased p53, compared with the cells treated with either juglone or TRAIL alone. Pretreatment with N‑acetyl cysteine, a ROS scavenger, significantly reduced the cytotoxicity of juglone in combination with TRAIL, which further supported that ROS was involved in the juglone‑induced sensitization of TRAIL. In conclusion, juglone potentiated TRAIL‑induced apoptosis in melanoma cells, and these effects were partially mediated through the ROS‑p38‑p53 pathway. These findings suggested that juglone may be a potential sensitizer for TRAIL therapy in the treatment of melanoma.}, }
@article {pmid29037773, year = {2018}, author = {Monrroy, H and Vargas, JI and Glasinovic, E and Candia, R and Azúa, E and Gálvez, C and Rojas, C and Cabrera, N and Vidaurre, J and Álvarez, N and González, J and Espino, A and González, R and Parra-Blanco, A}, title = {Use of N-acetylcysteine plus simethicone to improve mucosal visibility during upper GI endoscopy: a double-blind, randomized controlled trial.}, journal = {Gastrointestinal endoscopy}, volume = {87}, number = {4}, pages = {986-993}, doi = {10.1016/j.gie.2017.10.005}, pmid = {29037773}, issn = {1097-6779}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Aged, 80 and over ; Antifoaming Agents/*administration &amp; dosage ; Double-Blind Method ; Endoscopy, Gastrointestinal/*methods ; Expectorants/*administration &amp; dosage ; Female ; Gastric Mucosa/*diagnostic imaging ; Humans ; Male ; Middle Aged ; Simethicone/*administration &amp; dosage ; Stomach Diseases/diagnostic imaging ; Water/administration &amp; dosage ; }, abstract = {BACKGROUND AND AIM: Upper GI endoscopy (UGE) is essential for the diagnosis of gastrointestinal diseases. Mucus and bubbles may decrease mucosal visibility. The use of mucolytics could improve visualization. Our aim was to determine whether premedication with simethicone or simethicone plus N-acetylcysteine is effective in improving visibility during UGE.<br><br>METHODS: This was a randomized, double-blinded, placebo-controlled trial with 2 control groups: no intervention and water 100 mL (W); and 3 intervention groups: simethicone 200 mg (S); S&#xa0;+ N-acetylcysteine (NAC) 500 mg (S+NAC500); and S&#xa0;+ NAC 1000 mg (S+NAC1000). The solution was ingested 20 minutes before UGE. Gastric visibility was evaluated in 4 segments with a previously described scale. A score of less than 7 points was defined as adequate visibility (AV). Water volume was used to improve visibility, and adverse reactions were evaluated as a secondary outcome. Multiple group comparison was performed using non-parametric one-way analysis of variance (ANOVA).<br><br>RESULTS: Two hundred thirty patients were included in the study, 68% female, mean age 49 years. The most common indication for UGE was epigastric pain/dyspepsia (33%). AV was more frequent in the S+NAC500 and S+NAC1000 groups (65% and 67%) compared with no intervention (44%, P&#xa0;= .044) and water (41%, P&#xa0;= .022). The gastric total visibility scale (TVS) was significantly better in the S+NAC500 and S+NAC1000 groups compared with water (P&#xa0;= .03 and P&#xa0;= .008). Simethicone was not different from no intervention and water. S+NAC1000 required less water volume to improve visibility. No adverse reactions from the study drugs were observed.<br><br>CONCLUSIONS: Premedication with S+NAC500 and S+NAC1000 improves visibility during UGE. The use of simethicone did not show improvements in gastric visibility. TVS was worse in patients using water alone. (Clinical trial registration number: NCT 01653171.).}, }
@article {pmid29037138, year = {2017}, author = {Stelmashook, EV and Genrikhs, EE and Kapkaeva, MR and Zelenova, EA and Isaev, NK}, title = {N-Acetyl-L-cysteine in the Presence of Cu[2+] Induces Oxidative Stress and Death of Granule Neurons in Dissociated Cultures of Rat Cerebellum.}, journal = {Biochemistry. Biokhimiia}, volume = {82}, number = {10}, pages = {1176-1182}, doi = {10.1134/S0006297917100108}, pmid = {29037138}, issn = {1608-3040}, mesh = {Acetylcysteine/*toxicity ; Animals ; Apoptosis/*drug effects ; Cells, Cultured ; Cerebellum/cytology/drug effects/metabolism ; Chelating Agents/pharmacology ; Copper/chemistry/*toxicity ; Ethylenediamines/pharmacology ; Microscopy, Fluorescence ; Neurons/cytology/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Polycyclic Compounds/chemistry ; Rats ; Rats, Wistar ; Zinc/pharmacology ; }, abstract = {Addition into the culture medium of the antioxidant N-acetylcysteine (NAC, 1 mM) in the presence of Cu2+ (0.0005-0.001 mM) induced intensive death of cultured rat cerebellar granule neurons, which was significantly decreased by the zinc ion chelator TPEN (N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine). However, the combined action of NAC and Zn2+ did not induce destruction of the neurons. Measurement of the relative intracellular concentration of Zn2+ with the fluorescent probe FluoZin-3 AM or of free radical production using a CellROX Green showed that incubation of the culture for 4 h with Cu2+ and NAC induced an intensive increase in the fluorescence of CellROX Green but not of FluoZin-3. Probably, the protective effect of TPEN in this case could be mediated by its ability to chelate Cu2+. Incubation of cultures in a balanced salt solution in the presence of 0.01 mM Cu2+ caused neuronal death already after 1 h if the NAC concentration in the solution was within 0.005-0.05 mM. NAC at higher concentrations (0.1-1 mM) together with 0.01 mM Cu2+ did not cause the death of neurons. These data imply that the antioxidant NAC can be potentially harmful to neurons even in the presence of nanomolar concentrations of variable valence metals.}, }
@article {pmid29032182, year = {2018}, author = {Wang, L and Xue, GB}, title = {Catalpol suppresses osteosarcoma cell proliferation through blocking epithelial-mesenchymal transition (EMT) and inducing apoptosis.}, journal = {Biochemical and biophysical research communications}, volume = {495}, number = {1}, pages = {27-34}, doi = {10.1016/j.bbrc.2017.10.054}, pmid = {29032182}, issn = {1090-2104}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Bone Neoplasms/*drug therapy/metabolism/*pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drugs, Chinese Herbal/pharmacology ; Epithelial-Mesenchymal Transition/drug effects ; Humans ; Iridoid Glucosides/*pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Osteosarcoma/*drug therapy/metabolism/*pathology ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {Catalpol, an iridoid glucoside compound, is reported to possess diverse pharmacological actions. However, its effects on osteosarcoma are little to be known. In the present study, we showed that catalpol could strongly suppress osteosarcoma progression. Catalpol dose-dependently reduced the cancer cell viability. The migration of osteosarcoma cells was also consistently suppressed by catalpol treatment using the wound healing and transwell migration analysis. Catalpol reduced the expressions of Kras, receptor for activated C-kinase 1(RACK1) and matrix metalloproteinase (MMP)-2 in a dose-dependent manner, revealing the blockage of migration. Moreover, both intrinsic and extrinsic apoptosis were triggered by catalpol, as evidenced by improved cleaved Caspase-8/-9/-3 and Poly-(ADP-ribose) polymerase (PARP). Release of Cyto-c in cytoplasm and Bax up-regulation in total cells were observed in catalpol-treated cells, while mitochondrial Cyto-c and cellular Bcl-2 were down-regulated by catalpol. Reactive oxygen species (ROS) production was also involved in catalpol-induced cell death. Further, ROS scavenger, N-acetylcysteine (NAC), impeded catalpol-caused apoptosis. And suppression of signal transducer and activator of transcription 3/Janus kinase 2 gene/Src (STAT3/JAK2/Src) was involved in catalpol-induced cell death. In vivo, catalpol showed effective ability to reduce the tumor growth. Our results illustrated that catalpol might be considered as a promising pharmacological agent to suppress osteosarcoma.}, }
@article {pmid29031221, year = {2017}, author = {Hu, Y and Wang, LS and Li, Y and Li, QH and Li, CL and Chen, JM and Weng, D and Li, HP}, title = {Effects of particulate matter from straw burning on lung fibrosis in mice.}, journal = {Environmental toxicology and pharmacology}, volume = {56}, number = {}, pages = {249-258}, doi = {10.1016/j.etap.2017.10.001}, pmid = {29031221}, issn = {1872-7077}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Bleomycin/*adverse effects ; Bronchoalveolar Lavage Fluid/immunology ; Disease Models, Animal ; Fires ; Interleukin-6/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Particle Size ; Particulate Matter/*adverse effects/analysis ; Pulmonary Fibrosis/chemically induced/*drug therapy/immunology ; Random Allocation ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVE: To investigate the impacts of particulate matter 2.5 (PM2.5) from straw burning on the acute exacerbation of lung fibrosis in mice and the preventive effects of N-acetylcysteine (NAC).<br><br>METHODS: The composition, particle size, and 30-min concentration change in an exposure system of the PM2.5 from straw-burning were determined. Forty C57BL male mice were equally randomized to two groups: bleomycin (BLM)-induced lung fibrosis with an exposure to air (BLM+air) and BLM+PM2.5 groups. On day 7 after receiving intratracheal injection of BLM, mice were exposed to air or PM2.5 in an exposure system for 30min twice daily and then sacrificed after one-week or four-week exposure (10 mice/group). Mouse survival, lung histopathology, macrophage accumulation in the lung, and pro-inflammatory cytokine levels in alveolar lavage fluid (ALF) were determined.<br><br>RESULTS: PM2.5 from straw burning were mainly composed of organic matter (74.1%); 10.92% of the inorganic matter of the PM2.5 were chloride ion; 4.64% were potassium ion; other components were sulfate, nitrate, and nitrite. Particle size was 10nm-2&#x3bc;m. Histopathology revealed a greater extent of inflammatory cell infiltration in the lung, widened alveolar septum, and lung fibrosis in the BLM+PM2.5 group than in the BLM+air group and a greater extent of those adverse effects after four-week than after one-week exposure to PM2.5. The BLM+PM2.5 group also showed macrophages containing particular matter and increased pulmonary collagen deposition as the exposure to PM2.5 increased. Interleukin (IL)-6 and TNF-&#x3b1; levels in ALF were significantly higher in the BLM+PM2.5 group than in the BLM+air group (P<0.05) and significantly higher after four-week exposure than after one-week exposure to PM2.5 (P<0.05). TGF-&#x3b2; levels in ALF after four-week exposure were significantly higher in the BLM+PM2.5 group than in the BLM+air group (P<0.05). The levels of IL-6, TNF-&#x3b1;, and TGF-&#x3b2; in peripheral serum were not significantly different in the BLM+PM2.5 and BLM+air groups. Lung hydroxyproline contents increased as the exposure to PM2.5 increased and were significantly higher after four-week than after one-week exposure (P=0.019). Exposure to PM2.5 did not affect the survival of normal mice (100%) but reduced the survival of mice with BLM-induced IPF (30%), whereas NAC extended the survival (70%, vs. BLM+PM2.5, P=0.032).<br><br>CONCLUSION: Exposure of mice with BLM-induced IPF to PM2.5 from straw burning exacerbated lung inflammation and fibrosis and increased mortality; NAC increased the mouse survival, indicating protective effects.}, }
@article {pmid29031197, year = {2017}, author = {Wang, Q and Du, X and Zhou, B and Li, J and Lu, W and Chen, Q and Gao, J}, title = {Mitochondrial dysfunction is responsible for fatty acid synthase inhibition-induced apoptosis in breast cancer cells by PdpaMn.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {96}, number = {}, pages = {396-403}, doi = {10.1016/j.biopha.2017.10.008}, pmid = {29031197}, issn = {1950-6007}, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Breast Neoplasms/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Fatty Acid Synthases/*antagonists &amp; inhibitors/*metabolism ; Female ; Humans ; MCF-7 Cells ; Manganese/chemistry/*pharmacology ; Mice ; Mice, Inbred BALB C ; Mitochondria/drug effects/*metabolism ; }, abstract = {Targeting cellular metabolism is becoming a hallmark to overcome drug resistance in breast cancer treatment. Activation of fatty acid synthase (FASN) has been shown to promote breast cancer cell growth. However, there is no concrete report underlying the mechanism associated with mitochondrial dysfunction in relation to fatty acid synthase inhibition-induced apoptosis in breast cancer cells. The current study is aimed at exploring the effect of the novel manganese (Mn) complex, labeled as PdpaMn, on lipid metabolism and mitochondrial function in breast cancer cells. Herein, we observed that PdpaMn displayed strong cytotoxicity on breast cancer cell lines and selectively targeted the tumor without affecting the normal organs or cells in vivo. We also observed that PdpaMn could bind to TE domain of FASN and decrease the activity and the level of expression of FASN, which is an indication that FASN could serve as a target of PdpaMn. In addition, we demonstrated that PdpaMn increased intrinsic apoptosis in breast cancer cells relayed by a suppressed the level of expression of FASN, followed by the release of mitochondrial cytochrome c and the activation of caspases-9. Instigated by the above observations, we hypothesized that PdpaMn-induced apoptosis events are dependent on mitochondrial dysfunction. Indeed, we found that mitochondrial membrane potential (MMP) collapse, mitochondrial oxygen consumption reduction and adenosine triphosphate (ATP) release were deeply repressed. Furthermore, our results showed that PdpaMn significantly increased the reactive oxygen species (ROS) production, and the protection conferred by the free radical scavenger N-acetyl-cysteine (NAC) indicates that PdpaMn-induced apoptosis through an oxidative stress-associated mechanism. More so, the above results have demonstrated that mitochondrial dysfunction participated in FASN inhibition-induce apoptosis in breast cancer cells by PdpaMn. Therefore, PdpaMn may be considered as a good candidate for anti-breast cancer therapeutic option.}, }
@article {pmid29030305, year = {2017}, author = {Lupo, N and Fodor, B and Muhammad, I and Yaqoob, M and Matuszczak, B and Bernkop-Schnürch, A}, title = {Entirely S-protected chitosan: A promising mucoadhesive excipient for metronidazole vaginal tablets.}, journal = {Acta biomaterialia}, volume = {64}, number = {}, pages = {106-115}, doi = {10.1016/j.actbio.2017.10.014}, pmid = {29030305}, issn = {1878-7568}, mesh = {Animals ; *Chitosan/chemical synthesis/chemistry/pharmacokinetics/pharmacology ; Female ; *Metronidazole/chemistry/pharmacokinetics/pharmacology ; Swine ; Vagina/metabolism ; Vaginal Creams, Foams, and Jellies ; }, abstract = {AIM: Synthesis and evaluation of an entirely S-protected chitosan as mucoadhesive excipient for vaginal drug delivery.<br><br>METHODS: N-acetyl-cysteine was linked to 6-mercaptonicotinamide via disulphide exchange reaction. The obtained ligand, NAC-6-MNA, was subsequently attached to chitosan by carbodiimide mediated amide bond formation in two concentrations. The synthesized S-protected chitosan was chemically characterized and mucoadhesive properties and stability against oxidation were investigated. Moreover, metronidazole tablets comprising the S-protected chitosan were evaluated regarding water uptake capacity, disintegration behaviour, residence time on vaginal mucosa, release of the encapsulated drug and antimicrobial activity.<br><br>RESULTS: S-protected chitosan displayed 160&#xb1;19 (CS-MNA-160) and 320&#xb1;38 (CS-MNA-320)&#xb5;mol of ligand per gram of polymer. At pH 4.2, CS-MNA-160 and CS-MNA-320 showed 5.2-fold and 6.2-fold increase in mucus viscosity in comparison to unmodified chitosan (One-way ANOVA, p<.001), whereas, 9.9-fold (CS-MNA-160) and 15.6-fold (CS-MNA-320) (One-way ANOVA, p<.001) increase in viscosity was measured at pH 6. The S-protected chitosan remained stable against oxidation in presence of 0.5%v/v hydrogen peroxide. Metronidazole tablets consisting in S-protected chitosan showed prolonged residence time on vaginal mucosa and improved water uptake capacity and disintegration time in comparison to tablets consisting of unmodified chitosan. Moreover, CS-MNA-320 metronidazole tablets displayed prolonged drug release and antimicrobial activity.<br><br>CONCLUSIONS: On the basis of the achieved results, entirely S-protected chitosan represents a promising excipient for the development of metronidazole vaginal tablets.<br><br>STATEMENT OF SIGNIFICANCE: S-protected thiomers are polymers modified with thiol groups protected by aromatic ligands and characterized by strong mucoadhesive properties and high stability against oxidation. Up to date, the entirely S-protection of thiol groups was achieved via the synthesis of the ligand 2-((2-amino-2-carboxyethyl)disulfanyl)nicotinic acid) which can be directly bound to the backbone of polymers bearing carboxylic moieties as pectin. However, this ligand is not suitable for positively charged polymers due to the negative charge. In this paper, the synthesis of a suitable ligand for the entirely S-protection of positively charged polymers is presented. The first entirely S-protected chitosan was synthesized, characterized and its mucoadhesive properties were assessed. Moreover, metronidazole tablets comprising the entirely S-protected chitosan were developed and evaluated as vaginal drug delivery system.}, }
@article {pmid29030088, year = {2017}, author = {Jannig, PR and Alves, CRR and Voltarelli, VA and Bozi, LHM and Vieira, JS and Brum, PC and Bechara, LRG}, title = {Effects of N-acetylcysteine on isolated skeletal muscle contractile properties after an acute bout of aerobic exercise.}, journal = {Life sciences}, volume = {191}, number = {}, pages = {46-51}, doi = {10.1016/j.lfs.2017.10.012}, pmid = {29030088}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Male ; Muscle Contraction/*drug effects ; Muscle Fatigue/*drug effects ; Muscle, Skeletal/*drug effects/*physiology ; Physical Conditioning, Animal/adverse effects ; Rats, Wistar ; }, abstract = {AIMS: The current study tested the hypotheses that 1) an acute bout of aerobic exercise impairs isolated skeletal muscle contractile properties and 2) N-acetylcysteine (a thiol antioxidant; NAC) administration can restore the impaired muscle contractility after exercise.<br><br>MAIN METHODS: At rest or immediately after an acute bout of aerobic exercise, extensor digitorum longus (EDL) and soleus muscles from male Wistar rats were harvested for ex vivo skeletal muscle contraction experiments. Muscles from exercised animals were incubated in Krebs Ringer's buffer in absence or presence of 20mM of NAC. Force capacity and fatigue properties were evaluated.<br><br>KEY FINDINGS: Exercised EDL and soleus displayed lower force production across various stimulation frequencies (p<0.001), indicating that skeletal muscle force production was impaired after an acute bout of exercise. However, NAC treatment restored the loss of force production in both EDL and soleus after fatiguing exercise (p<0.05). Additionally, NAC treatment increased relative force production at different time points during a fatigue-induced protocol, suggesting that NAC treatment mitigates fatigue induced by successive contractions.<br><br>SIGNIFICANCE: NAC treatment improves force capacity and fatigue properties in ex vivo skeletal muscle from rats submitted to an acute bout of aerobic exercise.}, }
@article {pmid29027761, year = {2018}, author = {Ruiz, M and Bégou, M and Launay, N and Ranea-Robles, P and Bianchi, P and López-Erauskin, J and Morató, L and Guilera, C and Petit, B and Vaurs-Barriere, C and Guéret-Gonthier, C and Bonnet-Dupeyron, MN and Fourcade, S and Auwerx, J and Boespflug-Tanguy, O and Pujol, A}, title = {Oxidative stress and mitochondrial dynamics malfunction are linked in Pelizaeus-Merzbacher disease.}, journal = {Brain pathology (Zurich, Switzerland)}, volume = {28}, number = {5}, pages = {611-630}, pmid = {29027761}, issn = {1750-3639}, support = {FP7-241622//European Commission/International ; PI14/00410//Spanish Institute for Health Carlos III/International ; CP11/00080//Spanish Institute for Health Carlos III/International ; CPII16/00016//Spanish Institute for Health Carlos III/International ; //Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa/International ; 2014SGR1430//Autonomous Government of Catalonia/International ; 2012 BE1 00710//Autonomous Government of Catalonia/International ; //Center for Biomedical Research on Rare Diseases/International ; BFI07.126//Department of Education, Universities and Research of the Basque Country Government/International ; AP2008-03728//Spanish Ministry of Education/International ; //Neurodis Foundation/International ; //Regional Council of Auvergne/International ; FP7-241622//European Regional Development Fund/International ; //Les amis de Ianis association/International ; //Paris Diderot University and Auvergne University/International ; }, mesh = {Animals ; Cells, Cultured ; Child ; Child, Preschool ; DNA, Mitochondrial ; Fibroblasts/metabolism/pathology ; Glutamic Acid/metabolism ; Humans ; Infant ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/metabolism/pathology ; *Mitochondrial Dynamics ; Mitochondrial Proteins/metabolism ; Myelin Proteolipid Protein/genetics/metabolism ; *Oxidative Stress ; Pelizaeus-Merzbacher Disease/*metabolism/pathology ; RNA, Messenger/metabolism ; Spinal Cord/metabolism/pathology ; }, abstract = {Pelizaeus-Merzbacher disease (PMD) is a fatal hypomyelinating disorder characterized by early impairment of motor development, nystagmus, choreoathetotic movements, ataxia and progressive spasticity. PMD is caused by variations in the proteolipid protein gene PLP1, which encodes the two major myelin proteins of the central nervous system, PLP and its spliced isoform DM20, in oligodendrocytes. Large duplications including the entire PLP1 gene are the most frequent causative mutation leading to the classical form of PMD. The Plp1 overexpressing mouse model (PLP-tg[66/66]) develops a phenotype very similar to human PMD, with early and severe motor dysfunction and a dramatic decrease in lifespan. The sequence of cellular events that cause neurodegeneration and ultimately death is poorly understood. In this work, we analyzed patient-derived fibroblasts and spinal cords of the PLP-tg[66/66] mouse model, and identified redox imbalance, with altered antioxidant defense and oxidative damage to several enzymes involved in ATP production, such as glycolytic enzymes, creatine kinase and mitochondrial proteins from the Krebs cycle and oxidative phosphorylation. We also evidenced malfunction of the mitochondria compartment with increased ROS production and depolarization in PMD patient's fibroblasts, which was prevented by the antioxidant N-acetyl-cysteine. Finally, we uncovered an impairment of mitochondrial dynamics in patient's fibroblasts which may help explain the ultrastructural abnormalities of mitochondria morphology detected in spinal cords from PLP-tg[66/66] mice. Altogether, these results underscore the link between redox and metabolic homeostasis in myelin diseases, provide insight into the pathophysiology of PMD, and may bear implications for tailored pharmacological intervention.}, }
@article {pmid29024807, year = {2017}, author = {Barquissau, V and Capel, F and Dardevet, D and Feillet-Coudray, C and Gallinier, A and Chauvin, MA and Rieusset, J and Morio, B}, title = {Reactive oxygen species enhance mitochondrial function, insulin sensitivity and glucose uptake in skeletal muscle of senescence accelerated prone mice SAMP8.}, journal = {Free radical biology &amp; medicine}, volume = {113}, number = {}, pages = {267-279}, doi = {10.1016/j.freeradbiomed.2017.10.012}, pmid = {29024807}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Biological Transport ; Electron Transport Complex I/genetics/*metabolism ; Electron Transport Complex II/genetics/*metabolism ; Electron Transport Complex IV/genetics/*metabolism ; Female ; Gene Expression Regulation ; Glucose/metabolism ; Insulin/metabolism/pharmacology ; Insulin Resistance ; Mice ; Mice, Transgenic ; Mitochondria, Muscle/drug effects/metabolism ; Muscle, Skeletal/drug effects/*metabolism ; Oxidative Stress ; Phosphorylation ; Progeria/drug therapy/genetics/*metabolism ; Protein Carbonylation ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Xanthine Oxidase/genetics/metabolism ; }, abstract = {Whereas reactive oxygen species (ROS) can have opposite impacts on insulin signaling, they have mainly been associated with mitochondrial dysfunction in skeletal muscle. We analyzed the relationship between these three features in skeletal muscle of senescence accelerated mice (SAM) prone (P8), which are characterized by enhanced oxidative stress compared to SAM resistant (R1). Oxidative stress, ROS production, antioxidant system, mitochondrial content and functioning, as well as in vitro and in vivo insulin signaling were investigated in gastrocnemius and quadriceps muscles. In SAMP8 compared to SAMR1, muscle content in carbonylated proteins was two-fold (p < 0.01) and ROS production by xanthine oxidase 70% (p < 0.05) higher. Furthermore, insulin-induced Akt phosphorylation measured in vivo and ex vivo as well as muscle glucose uptake measured ex vivo were significantly higher (p < 0.05). Mitochondrial respiration evidenced uncoupling and higher respiration rates with substrates of complexes II and IV, in agreement with higher maximal activity of complexes II and IV (+ 18% and 62%, respectively, p < 0.05). By contrast, maximal activity of complex I was 22% lower (p < 0.05). All strain differences were corrected after 6 months of N-acetylcysteine (NAC) treatment, thus supporting the involvement of high ROS production in these differences. In conclusion in muscle of SAMP8 compared to SAMR1, high ROS production is associated to higher insulin sensitivity and glucose uptake but to lower mitochondrial complex I activity. These conflicting adaptations, with regards to the resulting imbalance between NADH production and use, were associated with intrinsic adjustments in the mitochondrial respiration chain (mitochondrial uncoupling, enhanced complexes II and IV activity). We propose that these bioenergetics adaptations may help at preserving muscle metabolic flexibility of SAMP8.}, }
@article {pmid29019035, year = {2017}, author = {Jang, S and Yayeh, T and Leem, YH and Park, EM and Ito, Y and Oh, S}, title = {Concanavalin A Induces Cortical Neuron Apoptosis by Causing ROS Accumulation and Tyrosine Kinase Activation.}, journal = {Neurochemical research}, volume = {42}, number = {12}, pages = {3504-3514}, pmid = {29019035}, issn = {1573-6903}, mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Astrocytes/metabolism ; Cell Death/drug effects ; Cells, Cultured ; Concanavalin A/*pharmacology ; Male ; Microglia/metabolism ; NADPH Oxidases/metabolism ; Neurons/*drug effects/metabolism ; Onium Compounds/pharmacology ; Phosphorylation ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {The lectin, concanavalin A (Con A), is the most extensively investigated member of the lectin family of plant proteins, but its effects on cortical neurons and astrocytes are poorly understood. In cultured cortical neurons and astrocytes, Con A exhibited dose-dependent neurotoxicity, but this was not observed in astrocytes. Similarly, in the cortical areas of rat brains, intracranial administration of Con A caused neuronal but no astrocyte damage. Methyl-α-D-mannopyranoside, a competitor of Con A, blocked Con A-induced cell death, whereas AMPA/KA receptor antagonists showed partial blocking effects. Furthermore, the mRNA levels of TNF-α, IL-1β, and IL-6 were elevated in astrocytes and cortical neurons treated with Con A. Intracellular reactive oxygen species (ROS) levels were increased in Con A-treated cortical neurons, and N-acetyl-cysteine (NAC, an antioxidant) and diphenyleneiodonium (DPI, a NADPH oxidase inhibitor) reduced intracellular ROS accumulation. Likewise, AG556 (a TNF-α inhibitor) and AG82 (a tyrosine kinase inhibitor) both reduced Con A-induced intracellular ROS accumulation. Furthermore, Con A-induced tyrosine phosphorylation was decreased by NAC and by AG556. Taken together, Con A-induced apoptosis in cortical neurons occurred as a sequel to Con A binding to neuronal glycoproteins and intracellular ROS accumulation. Interestingly, Con A-induced cellular damage was observed in cortical neurons but not in astrocytes or microglia.}, }
@article {pmid29018354, year = {2017}, author = {da Silva, KS and Pinto, PR and Fabre, NT and Gomes, DJ and Thieme, K and Okuda, LS and Iborra, RT and Freitas, VG and Shimizu, MHM and Teodoro, WR and Marie, SKN and Woods, T and Brimble, MA and Pickford, R and Rye, KA and Okamoto, M and Catanozi, S and Correa-Giannela, ML and Machado, UF and Passarelli, M}, title = {N-acetylcysteine Counteracts Adipose Tissue Macrophage Infiltration and Insulin Resistance Elicited by Advanced Glycated Albumin in Healthy Rats.}, journal = {Frontiers in physiology}, volume = {8}, number = {}, pages = {723}, pmid = {29018354}, issn = {1664-042X}, abstract = {Background: Advanced glycation endproducts elicit inflammation. However, their role in adipocyte macrophage infiltration and in the development of insulin resistance, especially in the absence of the deleterious biochemical pathways that coexist in diabetes mellitus, remains unknown. We investigated the effect of chronic administration of advanced glycated albumin (AGE-albumin) in healthy rats, associated or not with N-acetylcysteine (NAC) treatment, on insulin sensitivity, adipose tissue transcriptome and macrophage infiltration and polarization. Methods: Male Wistar rats were intraperitoneally injected with control (C) or AGE-albumin alone, or, together with NAC in the drinking water. Biochemical parameters, lipid peroxidation, gene expression and protein contents were, respectively, determined by enzymatic techniques, reactive thiobarbituric acid substances, RT-qPCR and immunohistochemistry or immunoblot. Carboxymethyllysine (CML) and pyrraline (PYR) were determined by LC/mass spectrometry (LC-MS/MS) and ELISA. Results: CML and PYR were higher in AGE-albumin as compared to C. Food consumption, body weight, systolic blood pressure, plasma lipids, glucose, hepatic and renal function, adipose tissue relative weight and adipocyte number were similar among groups. In AGE-treated animals, insulin resistance, adipose macrophage infiltration and Col12a1 mRNA were increased with no changes in M1 and M2 phenotypes as compared to C-albumin-treated rats. Total GLUT4 content was reduced by AGE-albumin as compared to C-albumin. NAC improved insulin sensitivity, reduced urine TBARS, adipose macrophage number and Itgam and Mrc mRNA and increased Slc2a4 and Ppara. CD11b, CD206, Ager, Ddost, Cd36, Nfkb1, Il6, Tnf, Adipoq, Retn, Arg, and Il12 expressions were similar among groups. Conclusions: AGE-albumin sensitizes adipose tissue to inflammation due to macrophage infiltration and reduces GLUT4, contributing to insulin resistance in healthy rats. NAC antagonizes AGE-albumin and prevents insulin resistance. Therefore, it may be a useful tool in the prevention of AGE action on insulin resistance and long-term complications of DM.}, }
@article {pmid28990065, year = {2017}, author = {Jia, G and Leng, B and Wang, H and Dai, H}, title = {Inhibition of cardiotrophin‑1 overexpression is involved in the anti‑fibrotic effect of Astrogaloside IV.}, journal = {Molecular medicine reports}, volume = {16}, number = {6}, pages = {8365-8370}, doi = {10.3892/mmr.2017.7676}, pmid = {28990065}, issn = {1791-3004}, mesh = {Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; Collagen Type I/metabolism ; Cytokines/*genetics ; Fibrosis ; Gene Expression Regulation/*drug effects ; Gene Knockdown Techniques ; Male ; Myocardium/metabolism/pathology ; Myofibroblasts/drug effects/metabolism ; RNA Interference ; Rats ; Reactive Oxygen Species/metabolism ; Saponins/*pharmacology ; Triterpenes/*pharmacology ; }, abstract = {Astragaloside IV (AsIV), one of the major active ingredients in Astragalus membranaceus, has demonstrated remarkable antifibrotic effects via its antioxidative activity. Cardiac fibrosis is an important pathological mechanism during cardiac remodelling associated with heart failure. In the present study, the mechanism underlying the antifibrotic effect of AsIV upon isoprenaline (ISO) stimulation was investigated. AsIV significantly improved cardiac fibrosis in vivo and dose‑dependently inhibited ISO‑induced CF proliferation in vitro. The ISO‑triggered elevation in reactive oxygen species (ROS) levels was remarkably inhibited by AsIV, as well as ROS scavenger N‑acetylcysteine (NAC), and not affected by cardiotrophin‑1 (CT‑1) knockdown. In addition, AsIV effectively reversed ISO‑induced upregulation of CT‑1 expression, which was blunted by pretreatment with NAC. Cardiac fibroblast (CF) proliferation and collagen Ι overexpression induced by ISO stimulation were effectively abrogated by AsIV, NAC, and CT‑1 small interfering RNA transfection. Taken together, these results demonstrated that AsIV was able to effectively inhibit ISO‑induced CF proliferation and collagen production through negative regulation of ROS‑mediated CT‑1 upregulation.}, }
@article {pmid28987348, year = {2017}, author = {Karimi-Maleh, H and Salehi, M and Faghani, F}, title = {Application of novel Ni(II) complex and ZrO2 nanoparticle as mediators for electrocatalytic determination of N-acetylcysteine in drug samples.}, journal = {Journal of food and drug analysis}, volume = {25}, number = {4}, pages = {1000-1007}, pmid = {28987348}, issn = {2224-6614}, mesh = {Acetylcysteine/*analysis/urine ; Catalysis ; Electrochemical Techniques/instrumentation/*methods ; Humans ; Nanoparticles/*chemistry ; Nickel/*chemistry ; Zirconium/*chemistry ; }, abstract = {The electrooxidation of N-acetylcysteine (N-AC) was studied by a novel Ni(II) complex modified ZrO2 nanoparticle carbon paste electrode [Ni(II)/ZrO2/NPs/CPE] using voltammetric methods. The results showed that Ni(II)/ZrO2/NPs/CPE had high electrocatalytic activity for the electrooxidation of N-AC in aqueous buffer solution (pH = 7.0). The electrocatalytic oxidation peak currents increase linearly with N-AC concentrations over the concentration ranges of 0.05-600μM using square wave voltammetric methods. The detection limit for N-AC was equal to 0.009μM. The catalytic reaction rate constant, kh, was calculated (7.01 × 10[2] M[-1] s[-1]) using the chronoamperometry method. Finally, Ni(II)/ZrO2/NPs/CPE was also examined as an ultrasensitive electrochemical sensor for the determination of N-AC in real samples such as tablet and urine.}, }
@article {pmid28987048, year = {2017}, author = {Hołyńska-Iwan, I and Wróblewski, M and Olszewska-Słonina, D and Tyrakowski, T}, title = {[The application of N-acetylcysteine in optimization of specific pharmacological therapies].}, journal = {Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego}, volume = {43}, number = {255}, pages = {140-144}, pmid = {28987048}, issn = {1426-9686}, mesh = {Acetylcysteine/adverse effects/metabolism/pharmacology/*therapeutic use ; Antioxidants/adverse effects/metabolism/pharmacology/therapeutic use ; Expectorants/adverse effects/metabolism/pharmacology/therapeutic use ; Free Radicals/metabolism ; Glutathione/metabolism ; Humans ; Superoxide Dismutase/metabolism ; }, abstract = {Based on the analysis of data from clinical trials it could be postulated that N-acetylcysteine has a positive impact on the treatment of various diseases. However, less is known about specific molecular and physiological mechanisms underlying the reported therapeutic effects. N-acetylcysteine (NAC, N-acetyl-L-cysteine) is an amino acid derivative containing a thiol group. It is a precursor of L-cysteine and glutathione. NAC is well absorbed and safe for the body at doses up to 300 mg per kg of body weight. Side effects are relatively rare. NAC is used as an mucolytic agent in adjunctive therapy of respiratory diseases causing the retention of secretions, as well as an antidote in the treatment of paracetamol poisoning. Moreover, NAC protects against the toxic effects of reactive oxygen species and their active metabolites. NAC is involved in free radical scavenging processes via several independent mechanisms, including a direct reduction of free radicals, providing substrates for oxidation-reduction reactions and activation of antioxidant enzymes. In the blood, NAC decreases the level of low density lipoprotein peroxidation. In various tissues, NAC may increase the levels of glutathione and cysteine and stimulate the superoxide dismutase action. NAC is used as a supplement in the treatment of various diseases associated with impaired exterior and intracellular oxidative balance. NAC increases the concentrations of amino acids and their derivatives, including cysteine, cystine, and glutathione. It also stabilizes the antioxidant status of the cells and the intercellular spaces. NAC changes the levels of transcription factors, modifying the transcription of selected genes and acting on the protein translation. It works on the activation of several enzymes in the cells and outside the cells. Based on the analysis of data from clinical trials it can be concluded, that an administration of NAC may be beneficial for these groups of patients, in whom the reversible accumulation and the negative action of free radicals was observed.}, }
@article {pmid28986287, year = {2018}, author = {Zafar, A and Singh, S and Satija, YK and Saluja, D and Naseem, I}, title = {Deciphering the molecular mechanism underlying anticancer activity of coumestrol in triple-negative breast cancer cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {46}, number = {}, pages = {19-28}, doi = {10.1016/j.tiv.2017.10.007}, pmid = {28986287}, issn = {1879-3177}, mesh = {Cell Line, Tumor ; Coumestrol/*therapeutic use ; DNA Damage/drug effects ; Female ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Electron, Scanning ; Models, Molecular ; Phytoestrogens/*therapeutic use ; Protein Binding ; Protein Conformation ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species ; Triple Negative Breast Neoplasms/*drug therapy/ultrastructure ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Triple-negative breast cancer (TNBC) represents the highly aggressive subgroup of breast cancers with poor prognosis due to absence of estrogen receptor (ER). Therefore, alternative targeted therapies are required against ER-negative breast cancers. Coumestrol, a phytoestrogen inhibits cell growth of ER-negative breast cancer MDA-MB-231 cells; the exact mechanism has not yet been reported. Unlike normal cells, cancer cells contain elevated copper which play an integral role in angiogenesis. The current focus of the work was to identify any possible role of copper in coumestrol cytotoxic action against breast cancer MDA-MB-231 cells. Results demonstrated that coumestrol inhibited cell viability, induced ROS generation, DNA damage, G1/S cell cycle arrest, up-regulation of Bax and apoptosis induction via caspase-dependent mitochondrial mediated pathway in MDA-MB-231 cells. Further, addition of copper chelator, neocuproine and ROS scavenger, N-acetyl cysteine were ineffective in abrogating coumestrol-mediated apoptosis. This suggests non-involvement of copper and ROS in coumestrol-induced apoptosis. To account for coumestrol-mediated up-regulation of Bax and apoptosis induction, direct binding potential between coumestrol and Bax/Bcl-2 was studied using in silico molecular docking studies. We propose that coumestrol directly enters cells and combines with Bax/Bcl-2 to alter their structures, thereby causing Bax binding to the outer mitochondrial membrane and Bcl-2 release from the mitochondria to initiate apoptosis. Thus, non-copper targeted ROS independent DNA damage is the central mechanism of coumestrol in ER-negative MDA-MB-231 cells. These findings will be useful in better understanding of anticancer mechanisms of coumestrol and establishing it as a lead molecule for TNBC treatment.}, }
@article {pmid28986255, year = {2017}, author = {Olson, DH and Burrill, JS and Kuzmicic, J and Hahn, WS and Park, JM and Kim, DH and Bernlohr, DA}, title = {Down regulation of Peroxiredoxin-3 in 3T3-L1 adipocytes leads to oxidation of Rictor in the mammalian-target of rapamycin complex 2 (mTORC2).}, journal = {Biochemical and biophysical research communications}, volume = {493}, number = {3}, pages = {1311-1317}, doi = {10.1016/j.bbrc.2017.09.171}, pmid = {28986255}, issn = {1090-2104}, support = {R01 DK084669/DK/NIDDK NIH HHS/United States ; P30 DK050456/DK/NIDDK NIH HHS/United States ; T32 HL007741/HL/NHLBI NIH HHS/United States ; }, mesh = {3T3-L1 Cells ; Acetylcysteine/pharmacology ; Adipocytes/metabolism ; Animals ; Biological Transport/drug effects ; Carrier Proteins/*metabolism ; Down-Regulation ; Glucose/metabolism ; Insulin/pharmacology ; Insulin Resistance ; Mechanistic Target of Rapamycin Complex 2 ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Multiprotein Complexes/*metabolism ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Peroxiredoxin III/genetics/*metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Rapamycin-Insensitive Companion of mTOR Protein ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Mitochondrially-derived oxidative stress has been implicated in the development of obesity-induced insulin resistance and is correlated with down regulation of Peroxiredoxin-3 (Prdx3). Prdx3 knockout mice exhibit whole-body insulin resistance, while Prdx3 transgenic animals remain insulin sensitive when placed on a high fat diet. To define the molecular events linking mitochondrial oxidative stress to insulin action, Prdx3 was silenced in 3T3-L1 adipocytes (Prdx3 KD) and the resultant cells evaluated for mitochondrial function, endoplasmic reticulum stress (ER stress), mitochondrial unfolded protein response (mtUPR) and insulin signaling. Prdx3 KD cells exhibit a two-fold increase in H2O2, reduced insulin-stimulated glucose transport and attenuated S[473] phosphorylation of the mTORC2 substrate, Akt. Importantly, the decrease in glucose uptake can be rescued by pre-treatment with the antioxidant N-acetyl-cysteine (NAC). The changes in insulin sensitivity occur independently from activation of the ER stress or mtUPR pathways. Analysis of mTORC2, the complex responsible for phosphorylating Akt at S[473], reveals increased cysteine oxidation of Rictor in Prdx3 KD cells that can be rescued with NAC. Taken together, these data suggest mitochondrial dysfunction in adipocytes may attenuate insulin signaling via oxidation of the mammalian-target of rapamycin complex 2 (mTORC2).}, }
@article {pmid28986085, year = {2018}, author = {Yu, CY and Jerry Teng, CL and Hung, PS and Cheng, CC and Hsu, SL and Hwang, GY and Tzeng, YM}, title = {Ovatodiolide isolated from Anisomeles indica induces cell cycle G2/M arrest and apoptosis via a ROS-dependent ATM/ATR signaling pathways.}, journal = {European journal of pharmacology}, volume = {819}, number = {}, pages = {16-29}, doi = {10.1016/j.ejphar.2017.09.050}, pmid = {28986085}, issn = {1879-0712}, mesh = {Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; DNA Damage ; Diterpenes/*pharmacology ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Lamiaceae/*chemistry ; M Phase Cell Cycle Checkpoints/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Ovatodiolide was isolated from the traditional Chinese medicinal herb Anisomeles indica, possesses anti-bacterial and anti-inflammatory properties; however, the anti-cancer activity and its mechanisms have been limitedly reported. This study aimed to examine the effect and molecular action of ovatodiolide in lung cancer cells. Cell cycle distribution and reactive oxygen species (ROS) generation were measured by flow cytometry. Apoptosis was detected by propidium iodide/annexin V staining and TUNEL assay. DNA damage was investigated by comet assay and γ-H2AX staining. Caspase activity was determined using caspase fluorometric kits. Moreover, protein levels were examined by western blot. Ovatodiolide provoked reactive oxygen species generation and DNA damage, as well as inhibited cell growth and induced apoptosis in human lung cancer A549 and H1299 cell lines. DNA damage-related molecules, ATM/ATR and CHK1/CHK2 were activated by ovatodiolide. Moreover, ovatodiolide-mediated G2/M arrest was associated with the decrease of Cyclin B1 and CDC25C levels, and increase of p21[WAF1/CIP1] expression. Additionally, ovatodiolide-triggered apoptosis was through both intrinsic and extrinsic pathways characterized by the elevating PUMA, Bax, and DR5 proteins, decreasing Bcl-2 and Mcl-1, and activating caspase-8, caspase-9 and caspase-3. Caffeine, an ATM/ATR inhibitor, rescued ovatodiolide-mediated cell cycle arrest and apoptosis, but not reactive oxygen species generation. Nevertheless, antioxidant N-acetyl-cysteine completely blocked ovatodiolide-mediated molecular events, G2/M arrest, and apoptosis. These observations suggest that ovatodiolide stimulates reactive oxygen species generation, causes oxidative stress and DNA damage; subsequently, provokes DNA damage signaling pathways, eventually leads to block cell cycle at G2/M phase and trigger apoptosis in lung cancer A549 and H1299 cells.}, }
@article {pmid28985871, year = {2017}, author = {Yamada, Y and Iskender, I and Arni, S and Hillinger, S and Cosgun, T and Yu, K and Jungraithmayr, W and Cesarovic, N and Weder, W and Inci, I}, title = {Ex vivo treatment with inhaled N-acetylcysteine in porcine lung transplantation.}, journal = {The Journal of surgical research}, volume = {218}, number = {}, pages = {341-347}, doi = {10.1016/j.jss.2017.06.061}, pmid = {28985871}, issn = {1095-8673}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Drug Evaluation, Preclinical ; Female ; Free Radical Scavengers/*administration &amp; dosage ; *Lung Transplantation ; Primary Graft Dysfunction/*prevention &amp; control ; Swine ; }, abstract = {BACKGROUND: We have shown the beneficial effects of N-acetylcysteine (NAC) on posttransplant lung function, when both donor and recipient were pretreated intravenously. However, systemic treatment of multiorgan donors may not be clinically relevant. Thus, we hypothesized that ex vivo treatment of donors with nebulized NAC would be adequate to prevent from ischemia-reperfusion injury after lung transplantation.<br><br>METHODS: Lungs were retrieved from domestic pigs and stored at 4&#xb0;C for 24 h followed by 2 h of ex&#xa0;vivo lung perfusion (EVLP) to administer 50&#xa0;mg/kg of NAC via nebulization in the NAC group (n&#xa0;=&#xa0;6). The control group received nebulized saline (n&#xa0;=&#xa0;5). Left lungs were transplanted and isolated at 1 h of reperfusion by occluding the right main bronchus and pulmonary artery, followed by 5 h of observation. Physiological data during EVLP and after reperfusion were recorded. Inflammatory response, markers of oxidative stress, and microscopic lung injury were analyzed.<br><br>RESULTS: There was a trend toward better oxygenation throughout reperfusion period in the treatment group, which was accompanied by inhibited inflammatory response related to reduction in myeloperoxidase activity during EVLP and nuclear factor-&#x3ba;B activation at the end of reperfusion.<br><br>CONCLUSIONS: Ex&#xa0;vivo treatment of donor lungs with inhaled NAC reduced inflammatory response via its antioxidant activity in experimental porcine lung transplantation.}, }
@article {pmid28983599, year = {2017}, author = {Zhang, L and Wang, X and Wang, R and Zheng, X and Li, N and Li, H and Cao, X and Zhou, B and Lin, Y and Yang, L}, title = {Baicalin potentiates TRAIL‑induced apoptosis through p38 MAPK activation and intracellular reactive oxygen species production.}, journal = {Molecular medicine reports}, volume = {16}, number = {6}, pages = {8549-8555}, doi = {10.3892/mmr.2017.7633}, pmid = {28983599}, issn = {1791-3004}, mesh = {Apoptosis/*drug effects ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Flavonoids/*pharmacology ; Humans ; Intracellular Space/*metabolism ; Reactive Oxygen Species/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {The combination of tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) with other agents has been recognized as a promising strategy to overcome TRAIL resistance in cancer cells. Baicalin (5, 6‑dihydroxy‑7‑o‑glucuronide flavone) is a flavonoid from the root of the medicinal herb Scutellaria baicalensis Georgi, which has been reported to exert antioxidant, anti‑inflammatory, antiviral and anticancer activities in vitro. However, the effect of baicalin on TRAIL‑induced cytotoxicity has not been previously reported. In the present study, the effect of combining TRAIL and baicalin was investigated in non‑small cell lung cancer cell lines. The results revealed that baicalin was able to sensitize A549 and H2009 cells to TRAIL‑induced apoptosis. This was detected by the potentiation of poly‑adenosine‑5'‑diphosphate‑ribose polymerase cleavage and Annexin V‑fluorescein isothiocyanate staining of cells co‑treated with baicalin and TRAIL. In addition, p38 mitogen‑activated protein kinase was activated in baicalin and TRAIL co‑treated cancer cells, whereas the p38 inhibitor SB203580 effectively suppressed cell death within the co‑treated cells. Butylated hydroxyanisole and N‑acetyl‑cysteine, known reactive oxygen species (ROS) scavengers, significantly suppressed the potentiated cytotoxicity induced by baicalin and TRAIL co‑treatment. The present study is the first, to the best of our knowledge, to demonstrate that baicalin enhances the anticancer activity of TRAIL via p38 activation and ROS accumulation, and may be exploited for anticancer therapy.}, }
@article {pmid28983589, year = {2017}, author = {Zhang, J and Liu, Q and Shi, L and Qin, P and Wang, Q}, title = {Honokiol triggers receptor‑interacting protein kinase 3‑mediated cell death of neuroblastoma cells by upregulating reactive oxygen species.}, journal = {Molecular medicine reports}, volume = {16}, number = {6}, pages = {8525-8529}, doi = {10.3892/mmr.2017.7628}, pmid = {28983589}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Biphenyl Compounds/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gene Silencing/drug effects ; Humans ; Lignans/*pharmacology ; Neuroblastoma/*metabolism/*pathology ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism ; Time Factors ; Up-Regulation/*drug effects ; }, abstract = {Neuroblastoma is the most common form of childhood extracranial tumor and almost half of neuroblastoma cases occur in infants under two years old. Neuroblastoma accounts for ~6‑10% of childhood cancers and 15% of cancer‑associated childhood mortality. However, an effective treatment remains to be developed. Honokiol exhibits long‑lasting central muscle relaxation, anti‑inflammatory, antibacterial, antimicrobial, antiulcer, antioxidation, antiaging and antitumor effects. Honokiol has been previously demonstrated to kill neuroblastoma cells, however, the underlying mechanism of action remains unclear. The present study reports that honokiol inhibits the growth of neuroblastoma cells via upregulation of reactive oxygen species (ROS). MTT assays demonstrated that treatment of Neuro‑2a neuroblastoma cells with honokiol resulted in time‑ and dose‑dependent inhibition of cell proliferation, which was associated with upregulation of the protein expression of receptor‑interacting protein kinase 3 (RIP3), as demonstrated by western blot analysis. Furthermore, knockdown of RIP3 by small interfering RNA, or pharmacological inhibition of RIP3 by the RIP3 specific inhibitor necrosulfonamide, reversed honokiol‑induced loss of cell viability in Neuro‑2a cells. Importantly, honokiol significantly increased the intracellular ROS levels as determined by a 2',7'‑dichlorofluorescin diacetate assay, while ROS scavenger N‑acetyl cysteine significantly prevented the induction of ROS and RIP3 by honokiol. The results of the present study indicate that honokiol may suppress the growth of neuroblastoma Neuro‑2a cells, at least partially, through ROS‑mediated upregulation of RIP3.}, }
@article {pmid28981107, year = {2017}, author = {Habermann, KJ and Grünewald, L and van Wijk, S and Fulda, S}, title = {Targeting redox homeostasis in rhabdomyosarcoma cells: GSH-depleting agents enhance auranofin-induced cell death.}, journal = {Cell death &amp; disease}, volume = {8}, number = {10}, pages = {e3067}, pmid = {28981107}, issn = {2041-4889}, mesh = {Antioxidants/metabolism ; Apoptosis/drug effects ; Auranofin/*administration &amp; dosage ; Buthionine Sulfoximine/administration &amp; dosage ; Cell Line, Tumor ; Glutathione/antagonists &amp; inhibitors/*metabolism ; Humans ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects/genetics ; Piperazines/administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Rhabdomyosarcoma/*drug therapy/metabolism/pathology ; Thioredoxin-Disulfide Reductase/antagonists &amp; inhibitors/metabolism ; Thioredoxins/antagonists &amp; inhibitors/*metabolism ; gamma-Glutamylcyclotransferase/antagonists &amp; inhibitors ; }, abstract = {Rhabdomyosarcoma (RMS) cells have recently been reported to be sensitive to oxidative stress. Therefore, we investigated whether concomitant inhibition of the two main antioxidant defense pathways, that is, the thioredoxin (TRX) and the glutathione (GSH) systems, presents a new strategy to trigger cell death in RMS. In this study, we discover that GSH-depleting agents, i.e. γ-glutamylcysteine synthetase inhibitor, buthionine sulfoximine (BSO) or the cystine/glutamate antiporter inhibitor erastin (ERA), synergize with thioredoxin reductase (TrxR) inhibitor auranofin (AUR) to induce cell death in RMS cells. Interestingly, AUR causes accumulation of ubiquitinated proteins when combined with BSO or ERA, in line with recent reports showing that AUR inhibits the proteasome besides TrxR. Consistently, AUR/BSO or AUR/ERA cotreatment increases ubiquitination and expression of the short-lived proteins NOXA and MCL-1, accompanied by increased binding of NOXA to MCL-1. Notably, NOXA knockdown significantly rescues RMS cells from AUR/BSO- or AUR/ERA-induced cell death. In addition, AUR acts together with BSO or ERA to stimulate BAX/BAK and caspase activation. Of note, BSO or ERA abolish the AUR-stimulated increase in GSH levels, leading to reduced GSH levels upon cotreatment. Although AUR/BSO or AUR/ERA cotreatment enhances reactive oxygen species (ROS) production, only thiol-containing antioxidants (i.e., N-acetylcysteine (NAC), GSH), but not the non-thiol-containing ROS scavenger α-Tocopherol consistently suppress AUR/BSO- and AUR/ERA-stimulated cell death in both cell lines. Importantly, re-supply of GSH or its precursor NAC completely prevents AUR/ERA- and AUR/BSO-induced accumulation of ubiquitinated proteins, NOXA upregulation and cell death, indicating that GSH depletion rather than ROS production is critical for AUR/BSO- or AUR/ERA-mediated cell death. Thus, by demonstrating that GSH-depleting agents enhance the antitumor activity of AUR, we highlight new treatment options for RMS by targeting the redox homeostasis.}, }
@article {pmid28981086, year = {2017}, author = {Alvarez-Sola, G and Uriarte, I and Latasa, MU and Jimenez, M and Barcena-Varela, M and Santamaría, E and Urtasun, R and Rodriguez-Ortigosa, C and Prieto, J and Corrales, FJ and Baulies, A and García-Ruiz, C and Fernandez-Checa, JC and Berraondo, P and Fernandez-Barrena, MG and Berasain, C and Avila, MA}, title = {Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice.}, journal = {Cell death &amp; disease}, volume = {8}, number = {10}, pages = {e3083}, pmid = {28981086}, issn = {2041-4889}, support = {P50 AA011999/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetaminophen/adverse effects ; Animals ; Apolipoprotein A-I/chemistry/*genetics ; Chemical and Drug Induced Liver Injury/*genetics/pathology ; Fibroblast Growth Factors/chemistry/*genetics ; Gene Expression Regulation ; Genetic Engineering ; Humans ; Lipid Metabolism/genetics ; Liver Regeneration/*genetics ; Mice ; }, abstract = {The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the pro-regenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP) poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAP-intoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective. Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the stimulation of liver regeneration.}, }
@article {pmid28980294, year = {2018}, author = {Soleimani, A and Habibi, MR and Hasanzadeh Kiabi, F and Alipour, A and Habibi, V and Azizi, S and Emami Zeydi, A and Sohrabi, FB}, title = {The effect of intravenous N-acetylcysteine on prevention of atrial fibrillation after coronary artery bypass graft surgery: a double-blind, randomised, placebo-controlled trial.}, journal = {Kardiologia polska}, volume = {76}, number = {1}, pages = {99-106}, doi = {10.5603/KP.a2017.0183}, pmid = {28980294}, issn = {1897-4279}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Administration, Intravenous ; Adult ; Aged ; Atrial Fibrillation/etiology/*prevention &amp; control ; Coronary Artery Bypass/*adverse effects ; Double-Blind Method ; Electrocardiography ; Female ; Humans ; Inflammation/blood/prevention &amp; control ; Male ; Middle Aged ; Monitoring, Physiologic ; Postoperative Complications/*prevention &amp; control ; Receptors, Immunologic/blood ; Treatment Outcome ; }, abstract = {BACKGROUND: Atrial fibrillation (AF) is one of the most frequently occurring dysrhythmias after coronary artery bypass graft (CABG) surgery.<br><br>AIM: The aim of this study was to evaluate the effect of intravenous N-acetylcysteine (NAC) on the prevention of AF after CABG surgery.<br><br>METHODS: In a double-blind, randomised controlled trial, a total of 150 patients who were scheduled for on-pump CABG surgery were randomly assigned into two groups. In group A, patients received an intravenous NAC infusion (50 mg/kg) after induction of anaesthesia. These patients additionally received two intravenous doses of NAC on postoperative days 1 and 2. Patients in group B received normal saline (as a placebo) with the same volume, during the same time interval. During the first three days after surgery, postoperative AF (POAF) was assessed by continuous electrocardiogram monitoring; serum high-sensitivity C-reactive protein (hsCRP) level was also assessed before and three days after surgery.<br><br>RESULTS: During follow-up, 17 patients (17/141, 12.1%) developed POAF. POAF occurred in four (5.6%) patients in the NAC group and 13 (18.8%) patients in the placebo group (OR 0.23; 95% CI 0.08-0.82; p = 0.02). In the multivariable logistic regression analysis, the only predictor of AF after CABG surgery was the use of NAC (OR 0.21; 95% CI 0.06-0.73; p = 0.01). Also, the hsCRP level trend in the NAC group was different from the trend in the control group (group time interaction or interaction effect) (p < 0.001).<br><br>CONCLUSIONS: It seems that perioperative intravenous NAC therapy can be effectively used to reduce inflammation and the incidence of POAF after CABG surgery. The clinical trial registration number: IRCT2015040921669N1.}, }
@article {pmid28979696, year = {2017}, author = {Dang, Y and Zhao, Q and Luo, B and Pan, L and Wei, Q and Zhang, R and Fan, Q and Chen, J and Chang, R and Zhang, J and Li, Z}, title = {Effects of acrylonitrile-induced oxidative stress on testicular apoptosis through activation of NF-κB signaling pathway in male sprague dawley rats.}, journal = {American journal of translational research}, volume = {9}, number = {9}, pages = {4227-4235}, pmid = {28979696}, issn = {1943-8141}, abstract = {Acrylonitrile (ACN) treatment can induce testicular toxicity in Sprague-Dawley (SD) rats, with the toxicity potentially related to apoptosis, mediated by nuclear factor-κB (NF-κB). The present study investigated the potential role of NF-κB in the induction of apoptosis and testicular toxicity in ACN-treated rats. Adult male SD rats were randomly divided into 3 treatment groups: a control group (corn oil), an ACN group (50 mg/kg) in which ACN was administered by gavage, and an ACN and N-acetylcysteine (ACN+NAC) group. The rats were given NAC (300 mg/kg) 30 min prior to the administration of ACN, and ACN was administered by gavage for 90 days. The ACN treatment markedly increased malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity in the testis. Glutathione (GSH) was significantly depleted in the ACN groups, and the effects of ACN were blocked by the anti-oxidant NAC. The ACN treatment also increased the expression of NF-κB (p65) and phosphorylated-IκB kinase (IKK)-α/β and decreased the expression of an inhibitor of NF-κB (IκB-α). The pretreatment with NAC significantly inhibited the activation of NF-κB. In addition, the expression of Bax increased after the ACN treatment, and the induction of Bax was abolished by NAC. Taken together, the data suggested that ACN-induced oxidative stress activated the NF-κB signaling pathway, which modulated the expression of Bax and contributed to testicular apoptosis.}, }
@article {pmid28978056, year = {2017}, author = {Tao, S and Yuan, Q and Mao, L and Chen, FL and Ji, F and Cui, ZH}, title = {Vitamin D deficiency causes insulin resistance by provoking oxidative stress in hepatocytes.}, journal = {Oncotarget}, volume = {8}, number = {40}, pages = {67605-67613}, pmid = {28978056}, issn = {1949-2553}, abstract = {Vitamin D deficiency could cause insulin resistance. However, the underlying mechanisms are unclear. The 1α-Hydroxylase ["1α(OH)ase"] is a key enzyme for activate vitamin D3 synthesis. Here, we show that 1α(OH)ase stable knockdown by targeted shRNA led to vitamin D3 depletion in L02 hepatocytes. 1α(OH)ase silence also inhibited insulin-induced downstream signaling (IRS-1, ERK and AKT) transduction and glucose transporter 4 expression. Further, 1α(OH)ase shRNA in L02 hepatocytes led to significant reactive oxygen species production, p53-p21 activation and DNA damages. Such effects were almost completely reversed with co-treatment of n-acetylcysteine, which is an established anti-oxidant. Remarkably, insulin-induced downstream signaling transduction and glucose transporter 4 expression were recovered with n-acetylcysteine co-treatment in 1α(OH)ase-silenced L02 hepatocytes. Together, our results suggest that vitamin D deficiency-induced insulin resistance is possibly caused by oxidative stress in hepatocytes.}, }
@article {pmid28974245, year = {2017}, author = {Dósa, E and Heltai, K and Radovits, T and Molnár, G and Kapocsi, J and Merkely, B and Fu, R and Doolittle, ND and Tóth, GB and Urdang, Z and Neuwelt, EA}, title = {Dose escalation study of intravenous and intra-arterial N-acetylcysteine for the prevention of oto- and nephrotoxicity of cisplatin with a contrast-induced nephropathy model in patients with renal insufficiency.}, journal = {Fluids and barriers of the CNS}, volume = {14}, number = {1}, pages = {26}, pmid = {28974245}, issn = {2045-8118}, support = {R01 CA137488/CA/NCI NIH HHS/United States ; R01 CA199111/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects/pharmacokinetics ; Aged ; Antineoplastic Agents/*adverse effects ; Cisplatin/*adverse effects ; Dose-Response Relationship, Drug ; Female ; Free Radical Scavengers/*administration &amp; dosage/adverse effects/pharmacokinetics ; Humans ; Infusions, Intravenous ; Injections, Intra-Arterial ; Male ; *Maximum Tolerated Dose ; Middle Aged ; Renal Insufficiency ; }, abstract = {BACKGROUND: Cisplatin neuro-, oto-, and nephrotoxicity are major problems in children with malignant tumors, including medulloblastoma, negatively impacting educational achievement, socioemotional development, and overall quality of life. The blood-labyrinth barrier is somewhat permeable to cisplatin, and sensory hair cells and cochlear supporting cells are highly sensitive to this toxic drug. Several chemoprotective agents such as N-acetylcysteine (NAC) were utilized experimentally to avoid these potentially serious and life-long side effects, although no clinical phase I trial was performed before. The purpose of this study was to establish the maximum tolerated dose (MTD) and pharmacokinetics of both intravenous (IV) and intra-arterial (IA) NAC in adults with chronic kidney disease to be used in further trials on oto- and nephroprotection in pediatric patients receiving platinum therapy.<br><br>METHODS: Due to ethical considerations in pediatric tumor patients, we used a clinical population of adults with non-neoplastic disease. Subjects with stage three or worse renal failure who had any endovascular procedure were enrolled in a prospective, non-randomized, single center trial to determine the MTD for NAC. We initially aimed to evaluate three patients each at 150, 300, 600, 900, and 1200&#xa0;mg/kg&#xa0;NAC. The MTD was defined as one dose level below the dose producing grade 3 or 4 toxicity. Serum NAC levels were assessed before, 5 and 15&#xa0;min post NAC. Twenty-eight subjects (15 men; mean age 72.2&#xa0;&#xb1;&#xa0;6.8&#xa0;years) received NAC IV (N&#xa0;=&#xa0;13) or IA (N&#xa0;=&#xa0;15).<br><br>RESULTS: The first participant to experience grade 4 toxicity was at the 600&#xa0;mg/kg IV dose, at which time the protocol was modified to add an additional dose level of 450&#xa0;mg/kg NAC. Subsequently, no severe NAC-related toxicity arose and 450&#xa0;mg/kg NAC was found to be the MTD in both IV and IA groups. Blood levels of NAC showed a linear dose response (p&#xa0;<&#xa0;0.01). Five min after either IV or IA NAC MTD dose administration, serum NAC levels reached the 2-3&#xa0;mM concentration which seemed to be nephroprotective in previous preclinical studies.<br><br>CONCLUSIONS: In adults with kidney impairment, NAC can be safely given both IV and IA at a dose of 450&#xa0;mg/kg. Additional studies are needed to confirm oto- and nephroprotective properties in the setting of cisplatin treatment. Clinical Trial Registration URL: https://eudract.ema.europa.eu . Unique identifier: 2011-000887-92.}, }
@article {pmid28968988, year = {2017}, author = {Cui, ZH and Yuan, Q and Mao, L and Chen, FL and Ji, F and Tao, S}, title = {Insulin resistance in vitamin D-deficient mice is alleviated by n-acetylcysteine.}, journal = {Oncotarget}, volume = {8}, number = {38}, pages = {63281-63289}, pmid = {28968988}, issn = {1949-2553}, abstract = {Vitamin D deficiency will lead to insulin resistance. In the current study, vitamin D3 1α-Hydroxylase ["1α(OH)ase"] knockout mice were generated to mimic vitamin D deficiency in vivo. As compared to the wild-type mice, the liver tissues of the knockout mice showed impaired insulin signaling, decreased glucose transporter 4 expression and increased reactive oxygen species production. Meanwhile, p53-p21 activation, apoptosis intensity and pro-inflammatory cytokines (IL-6, IL-1 and MIP-1α) level were significantly increased in the knockout mice livers. Significantly, such effects in the knockout mice were largely attenuated by supplement with anti-oxidant n-acetylcysteine (NAC). Remarkably, insulin resistance and metabolic abnormalities in the knockout mice were largely alleviated after treatment of NAC. Therefore, inhibition of oxidative stress by NAC alleviated insulin resistance in vitamin D-deficient mice. Oxidative stress could be the primary cause of insulin resistance by vitamin D deficiency.}, }
@article {pmid28968439, year = {2017}, author = {Kim, JH and Park, SJ and Kim, B and Choe, YG and Lee, DS}, title = {Insulin-stimulated lipid accumulation is inhibited by ROS-scavenging chemicals, but not by the Drp1 inhibitor Mdivi-1.}, journal = {PloS one}, volume = {12}, number = {10}, pages = {e0185764}, pmid = {28968439}, issn = {1932-6203}, mesh = {3T3-L1 Cells ; Adipocytes/cytology/metabolism ; Animals ; Antioxidants/metabolism ; Dynamins/*antagonists &amp; inhibitors ; Free Radicals/*metabolism ; Insulin/*pharmacology ; *Lipid Metabolism ; Mice ; Quinazolinones/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Adipocyte differentiation is regulated by intracellular reactive oxygen species (ROS) generation and mitochondrial fission and fusion processes. However, the correlation between intracellular ROS generation and mitochondrial remodeling during adipocyte differentiation is still unknown. Here, we investigated the effect on adipocyte differentiation of 3T3-L1 cells of intracellular ROS inhibition using N-acetyl cysteine (Nac) and Mito-TEMPO and of mitochondrial fission inhibition using Mdivi-1. Differentiated 3T3-L1 adipocytes displayed an increase in mitochondrial fission, ROS generation, and the expression of adipogenic and mitochondrial dynamics-related proteins. ROS scavenger (Nac or Mito-TEMPO) treatment inhibited ROS production, lipid accumulation, the expression of adipogenic and mitochondrial dynamics-related proteins, and mitochondrial fission during adipogenesis of 3T3-L1 cells. On the other hand, treatment with the mitochondrial fission inhibitor Mdivi-1 inhibited mitochondrial fission but did not inhibit ROS production, lipid accumulation, or the expression of adipogenic and mitochondrial dynamics-related proteins, with the exception of phosphorylated Drp1 (Ser616), in differentiated 3T3-L1 adipocytes. The inhibition of mitochondrial fission did not affect adipocyte differentiation, while intracellular ROS production decreased in parallel with inhibition of adipocyte differentiation. Therefore, our results indicated that ROS are an essential regulator of adipocyte differentiation in 3T3-L1 cells.}, }
@article {pmid28966297, year = {2017}, author = {Ge, G and Yan, Y and Cai, H}, title = {Ginsenoside Rh2 Inhibited Proliferation by Inducing ROS Mediated ER Stress Dependent Apoptosis in Lung Cancer Cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {40}, number = {12}, pages = {2117-2124}, doi = {10.1248/bpb.b17-00463}, pmid = {28966297}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 4/metabolism ; Apoptosis/*drug effects ; Caspases, Initiator/metabolism ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/*drug effects ; Ginsenosides/*pharmacology/therapeutic use ; Humans ; Lung Neoplasms/*drug therapy ; Phenylbutyrates/pharmacology ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/metabolism ; Up-Regulation ; }, abstract = {Ginsenoside Rh2 (G-Rh2), a component extracted from roots of ginseng, exhibited anti-cancer pharmacological activities by inhibiting proliferation and inducing apoptosis in lung cancer cells. However, the mechanisms of G-Rh2 suppressing lung cancer development remained elusive. This study tried to investigate the possible mechanism involved in anti-proliferative effect of G-Rh2 in lung cancer cells. As results, G-Rh2 inhibited the proliferation of H1299 cells in a dose-dependent manner by inducing cell apoptosis. Activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein homologous protein (CHOP), and caspase-4 were involved in G-Rh2-induced apoptosis of H1299 cells. It was also found that G-Rh2 could up-regulate expressions of ATF4, CHOP and caspase-4 in H1299 cells in a dose-dependent manner. In addition, NAC (N-acetylcysteine, a reactive oxygen species (ROS) scavenger) treatment dramatically decreased ROS generation in H1299 cells; both of NAC and 4-PBA (4-phenylbutyrate, a specific endoplasmic reticulum (ER) stress inhibitor) administration impaired apoptosis and expression levels of ATF4, CHOP and caspase-4 in G-Rh2 incubated H1299 cells. In vivo assays extended the significance of these results, showing that G-Rh2 inhibited lung cancer growth and the inhibition effects of G-Rh2 in tumor growth were significantly reduced by inhibition of ER stress. In conclusion, G-Rh2 inhibited proliferation of H1299 cells by inducing ROS mediated ER stress dependent cell apoptosis.}, }
@article {pmid28962577, year = {2017}, author = {Akhtar, F and Rouse, CA and Catano, G and Montalvo, M and Ullevig, SL and Asmis, R and Kharbanda, K and Maffi, SK}, title = {Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress.}, journal = {Journal of neuroinflammation}, volume = {14}, number = {1}, pages = {195}, pmid = {28962577}, issn = {1742-2094}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antimetabolites/administration &amp; dosage ; Brain/*drug effects/metabolism ; Buthionine Sulfoximine/administration &amp; dosage ; Cytokines/genetics/metabolism ; Enzyme-Linked Immunosorbent Assay ; Ethanol/*toxicity ; Female ; Fetus/*drug effects/pathology ; Free Radical Scavengers/administration &amp; dosage ; Glutathione/metabolism ; Inflammation/*chemically induced ; Male ; Mice ; Oxidative Stress/*drug effects ; Pregnancy ; *Prenatal Exposure Delayed Effects/chemically induced/pathology/physiopathology ; RNA, Messenger/metabolism ; }, abstract = {BACKGROUND: Maternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive.<br><br>METHODS: Ethanol (EtOH) (2.5&#xa0;g/kg) was administered to pregnant mice at gestational days 16-17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1&#x3b2;, IFN &#x3b3;, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-&#x3b2;, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes.<br><br>RESULTS: We show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1&#x3b2;, IFN-&#x3b3;) in fetal brain tissue observed at 6-24&#xa0;h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1&#x3b2;, IFN-&#x3b3;, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-&#x3b2;, CXCL10, CCL22, Chi, Arg, and CCR2).<br><br>CONCLUSIONS: Taken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors.}, }
@article {pmid28961512, year = {2018}, author = {Wang, B and Yee Aw, T and Stokes, KY}, title = {N-acetylcysteine attenuates systemic platelet activation and cerebral vessel thrombosis in diabetes.}, journal = {Redox biology}, volume = {14}, number = {}, pages = {218-228}, pmid = {28961512}, issn = {2213-2317}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Blood Platelets/drug effects ; Brain/*blood supply/drug effects/metabolism ; Diabetes Mellitus, Type 1/blood/chemically induced/*complications/metabolism ; Male ; Mice, Inbred C57BL ; Platelet Activation/*drug effects ; Platelet Aggregation Inhibitors/*therapeutic use ; Pyruvaldehyde/metabolism ; Streptozocin ; Thrombosis/blood/*drug therapy/*etiology/metabolism ; }, abstract = {OBJECTIVE: We previously demonstrated that diabetes exacerbates stroke-induced brain injury, and that this correlates with brain methylglyoxal (MG)-to-glutathione (GSH) status. Cerebral injury was reversed by N-acetylcysteine (NAC). Here we tested if the pro-thrombotic phenotype seen in the systemic circulation and brain during diabetes was associated with increased MG-glycation of proteins, and if NAC could reverse this.<br><br>METHODS: The streptozotocin (STZ)-induced mouse model of type 1 diabetes was used. Thrombus formation in venules and arterioles (pial circulation) was determined by intravital videomicroscopy using the light-dye method. Circulating blood platelet-leukocyte aggregates (PLAs) were analyzed by flow cytometry 1 wk before other measurements. GSH and MG levels in platelets were measured by HPLC. MG-modified proteins, glutathione peroxidase-1 (GPx-1), and superoxide dismutase-1 (SOD1) levels were detected in platelets by western blot at 20 weeks. Proteins involved in coagulation were quantified by ELISA. NAC (2mM) was given in drinking water for 3 weeks before the terminal experiment.<br><br>RESULTS: Thrombus development was accelerated by diabetes in a time-dependent manner. % PLAs were significantly elevated by diabetes. Plasma activated plasminogen activator inhibitor type 1 levels were progressively increased with diabetes duration, with tail bleeding time reduced by 20 wks diabetes. Diabetes lowered platelet GSH levels, GPx-1 and SOD-1 expression. This was associated with higher MG levels, and increased MG-adduct formation in platelets. NAC treatment partly or completely reversed the effects of diabetes.<br><br>CONCLUSION: Collectively, these results show that the diabetic blood and brain become progressively more susceptible to platelet activation and thrombosis. NAC, given after the establishment of diabetes, may offer protection against the risk for stroke by altering both systemic and vascular prothrombotic responses via enhancing platelet GSH, and GSH-dependent MG elimination, as well as correcting levels of antioxidants such as SOD1 and GPx-1.}, }
@article {pmid28959647, year = {2017}, author = {Killilea, DW and Chow, D and Xiao, SQ and Li, C and Stoller, ML}, title = {Flame retardant tris(1,3-dichloro-2-propyl)phosphate (TDCPP) toxicity is attenuated by N-acetylcysteine in human kidney cells.}, journal = {Toxicology reports}, volume = {4}, number = {}, pages = {260-264}, pmid = {28959647}, issn = {2214-7500}, abstract = {Prolonged exposure to the flame retardants found in many household products and building materials is associated with adverse developmental, reproductive, and carcinogenic consequences. While these compounds have been studied in numerous epidemiological and animal models, less is known about the effects of flame retardant exposure on cell function. This study evaluated the toxicity of the commonly used fire retardant tris(1,3-dichloro-2-propyl)phosphate (TDCPP) in cell line derived from the kidney, a major tissue target of organohalogen toxicity. TDCPP inhibited cell growth at lower concentrations (IC50 27 μM), while cell viability and toxicity were affected at higher concentrations (IC50 171 μM and 168 μM, respectively). TDCPP inhibited protein synthesis and caused cell cycle arrest, but only at higher concentrations. Additionally, the antioxidant N-acetylcysteine (NAC) reduced cell toxicity in cells treated with TDCPP, suggesting that exposure to TDCPP increased oxidative stress in the cells. In summary, these data show that low concentrations of TDCPP result in cytostasis in a kidney cell line, whereas higher concentrations induce cell toxicity. Furthermore, TDCPP toxicity can be attenuated by NAC, suggesting that antioxidants may be effective countermeasures to some organohalogen exposures.}, }
@article {pmid28949027, year = {2018}, author = {Nakagawa, Y and Suzuki, T and Inomata, A}, title = {Preventive effects of fructose and N-acetyl-L-cysteine against cytotoxicity induced by the psychoactive compounds N-methyl-5-(2-aminopropyl)benzofuran and 3,4-methylenedioxy-N-methamphetamine in isolated rat hepatocytes.}, journal = {Journal of applied toxicology : JAT}, volume = {38}, number = {2}, pages = {284-291}, doi = {10.1002/jat.3523}, pmid = {28949027}, issn = {1099-1263}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Benzofurans/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Energy Metabolism/drug effects ; Fructose/*pharmacology ; Hepatocytes/*drug effects/metabolism/pathology ; Male ; Membrane Potential, Mitochondrial/drug effects ; N-Methyl-3,4-methylenedioxyamphetamine/*toxicity ; Oxidative Stress/drug effects ; Propylamines/*toxicity ; Psychotropic Drugs/*toxicity ; Rats, Inbred F344 ; }, abstract = {Psychoactive compounds, N-methyl-5-(2-aminopropyl)benzofuran (5-MAPB) and 3,4-methylenedioxy-N-methamphetamine (MDMA), are known to be hepatotoxic in humans and/or experimental animals. As previous studies suggested that these compounds elicited cytotoxicity via mitochondrial dysfunction and/or oxidative stress in rat hepatocytes, the protective effects of fructose and N-acetyl-l-cysteine (NAC) on 5-MAPB- and MDMA-induced toxicity were studied in rat hepatocytes. These drugs caused not only concentration-dependent (0-4 mm) and time-dependent (0-3 hours) cell death accompanied by the depletion of cellular levels of adenosine triphosphate (ATP) and glutathione (reduced form; GSH) but also an increase in the oxidized form of GSH. The toxic effects of 5-MAPB were greater than those of MDMA. Pretreatment of hepatocytes with either fructose at a concentration of 10 mm or NAC at a concentration of 2.5 mm prevented 5-MAPB-/MDMA-induced cytotoxicity. In addition, the exposure of hepatocytes to 5-MAPB/MDMA caused the loss of mitochondrial membrane potential, although the preventive effect of fructose was weaker than that of NAC. These results suggest that: (1) 5-MAPB-/MDMA-induced cytotoxicity is linked to mitochondrial failure and depletion of cellular GSH; (2) insufficient cellular ATP levels derived from mitochondrial dysfunction were ameliorated, at least in part, by the addition of fructose; and (3) GSH loss via oxidative stress was prevented by NAC. Taken collectively, these results indicate that the onset of toxic effects caused by 5-MAPB/MDMA may be partially attributable to cellular energy stress as well as oxidative stress.}, }
@article {pmid28946922, year = {2017}, author = {Calvo, PL and Tandoi, F and Haak, TB and Brunati, A and Pinon, M and Olio, DD and Romagnoli, R and Spada, M}, title = {NBAS mutations cause acute liver failure: when acetaminophen is not a culprit.}, journal = {Italian journal of pediatrics}, volume = {43}, number = {1}, pages = {88}, pmid = {28946922}, issn = {1824-7288}, mesh = {Acetaminophen/*adverse effects/*therapeutic use ; Diagnosis, Differential ; Disease Progression ; Fever/drug therapy ; Genetic Predisposition to Disease ; Graft Survival ; Humans ; Infant ; Liver Failure, Acute/chemically induced/diagnosis/*genetics ; Liver Transplantation/*methods ; Male ; Mutation ; Neoplasm Proteins/*genetics ; Prognosis ; Risk Assessment ; Treatment Outcome ; }, abstract = {BACKGROUND: Pediatric acute-liver-failure due to acetaminophen (APAP) administration at therapeutic dosage is rare, while viral infections and metabolic defects are the prevalent causes. Yet, as acetaminophen is routinely used in febrile illnesses, it may be mistakenly held responsible for the acute liver damage.<br><br>CASE PRESENTATION: An 11&#xa0;month old boy had been on acetaminophen for 10&#xa0;days (total dose 720&#xa0;mg&#xa0;=&#xa0;72&#xa0;mg/kg) when he developed acute-liver-failure with encephalopathy. As he rapidly improved on N-acetylcysteine (NAC) infusion, it was concluded that chronic acetaminophen administration in an infant had lead to acute-liver-failure even at therapeutic doses, that N-acetylcysteine infusion had been life-saving and should be immediately started in similar circumstances. The child, however, had two further episodes of acute liver damage over a 34-month period, without having been given acetaminophen, as the parents carefully avoided using it. His clinical, laboratory and radiological findings between the acute episodes were unremarkable. His features and skeletal surveys were not suggestive of a syndromic condition. He then went on to suffer another episode of acute-liver-failure with multi-organ failure, necessitating an urgent liver transplant. All efforts to come to a diagnosis for the causes of his recurrent episodes of liver failure had been unsuccessful, until a biallelic mutation in the NBAS gene was reported to be associated with recurrent acute-liver-failure in children. The boy's DNA analysis revealed compound heterozygous pathogenic mutations in the NBAS gene. Liver failure episodes in these patients are triggered and worsened by fever, most likely due to thermal susceptibility of hepatocytes, hence APAP, rather than being a culprit, is part of the supportive treatment.<br><br>CONCLUSIONS: We suggest that, in acute-liver-failure with a history of acetaminophen exposure at therapeutic dosage, clinicians should not be contented with administering NAC, but should consider an alternative etiology, above all if the episodes are recurrent, and actively start supportive and antipyretic treatment while seeking the advice of a specialist unit.}, }
@article {pmid28942748, year = {2017}, author = {Marx, W and Moseley, G and Berk, M and Jacka, F}, title = {Nutritional psychiatry: the present state of the evidence.}, journal = {The Proceedings of the Nutrition Society}, volume = {76}, number = {4}, pages = {427-436}, doi = {10.1017/S0029665117002026}, pmid = {28942748}, issn = {1475-2719}, mesh = {Biological Psychiatry/*methods ; Diet/*adverse effects/psychology ; Humans ; Mental Disorders/*etiology ; Nutritional Sciences/*methods ; Nutritional Status ; Risk Factors ; }, abstract = {Mental illness, including depression, anxiety and bipolar disorder, accounts for a significant proportion of global disability and poses a substantial social, economic and heath burden. Treatment is presently dominated by pharmacotherapy, such as antidepressants, and psychotherapy, such as cognitive behavioural therapy; however, such treatments avert less than half of the disease burden, suggesting that additional strategies are needed to prevent and treat mental disorders. There are now consistent mechanistic, observational and interventional data to suggest diet quality may be a modifiable risk factor for mental illness. This review provides an overview of the nutritional psychiatry field. It includes a discussion of the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research. Potential biological pathways related to mental disorders include inflammation, oxidative stress, the gut microbiome, epigenetic modifications and neuroplasticity. Consistent epidemiological evidence, particularly for depression, suggests an association between measures of diet quality and mental health, across multiple populations and age groups; these do not appear to be explained by other demographic, lifestyle factors or reverse causality. Our recently published intervention trial provides preliminary clinical evidence that dietary interventions in clinically diagnosed populations are feasible and can provide significant clinical benefit. Furthermore, nutraceuticals including n-3 fatty acids, folate, S-adenosylmethionine, N-acetyl cysteine and probiotics, among others, are promising avenues for future research. Continued research is now required to investigate the efficacy of intervention studies in large cohorts and within clinically relevant populations, particularly in patients with schizophrenia, bipolar and anxiety disorders.}, }
@article {pmid28942246, year = {2017}, author = {Long, Z and Cao, M and Su, S and Wu, G and Meng, F and Wu, H and Liu, J and Yu, W and Atabai, K and Wang, X}, title = {Inhibition of hepatocyte nuclear factor 1b induces hepatic steatosis through DPP4/NOX1-mediated regulation of superoxide.}, journal = {Free radical biology &amp; medicine}, volume = {113}, number = {}, pages = {71-83}, pmid = {28942246}, issn = {1873-4596}, support = {R01 DK110098/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Diabetes Mellitus, Experimental/metabolism ; Diet, High-Fat ; Dipeptidyl Peptidase 4/*metabolism ; Disease Models, Animal ; Endoplasmic Reticulum Stress ; Hepatocyte Nuclear Factor 1-beta/*metabolism ; Insulin Resistance ; Liver/enzymology/*metabolism ; Male ; Mice ; NADPH Oxidase 1/*metabolism ; Non-alcoholic Fatty Liver Disease/enzymology/etiology/*metabolism ; Obesity/metabolism ; Superoxides/*metabolism ; }, abstract = {Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder that is closely associated with insulin resistance and type 2 diabetes. Previous studies have suggested that hepatocyte nuclear factor 1b (HNF1b) ameliorates insulin resistance. However, the role of HNF1b in the regulation of lipid metabolism and hepatic steatosis remains poorly understood. We found that HNF1b expression was decreased in steatotic livers. We injected mice with lentivirus (LV) expressing HNF1b shRNA to generate mice with hepatic knockdown of HNF1b. We also injected high fat (HF) diet-induced obese and db/db diabetic mice with LV expressing HNF1b to overexpress HNF1b. Knockdown of HNF1b increased hepatic lipid contents and induced insulin resistance in mice and in hepatocytes. Knockdown of HNF1b worsened HF diet-induced increases in hepatic lipid contents, liver injury and insulin resistance in mice and PA-induced lipid accumulation and impaired insulin signaling in hepatocytes. Moreover, overexpression of HNF1b alleviated HF diet-induced increases in hepatic lipid content and insulin resistance in mice. Knockdown of HNF1b increased expression of genes associated with lipogenensis and endoplasmic reticulum (ER) stress. DPP4 and NOX1 expression was increased by knockdown of HNF1b and HNF1b directly bound with the promoters of DPP4 and NOX1. Overexpression of DPP4 or NOX1 was associated with an increase in lipid droplets in hepatocytes and decreased expression of DPP4 or NOX1 suppressed the effects of knockdown of HNF1b knockdown on triglyceride (TG) formation and insulin signaling. Knockdown of HNF1b increased superoxide level and decreased glutathione content, which was inhibited by downregulation of DPP4 and NOX1. N-acetylcysteine (NAC) suppressed HNF1b knockdown-induced ER stress, TG formation and insulin resistance. Palmitic acid (PA) decreased HNF1b expression which was inhibited by NAC. Taken together, these studies demonstrate that HNF1b plays an essential role in controlling hepatic TG homeostasis and insulin sensitivity by regulating DPP4/NOX1mediated generation of superoxide.}, }
@article {pmid28941500, year = {2017}, author = {Mantel, A and McDonald, JT and Goldsborough, K and Harvey, VM and Chan, J}, title = {Prostaglandin D2 Uses Components of ROS Signaling to Enhance Testosterone Production in Keratinocytes.}, journal = {The journal of investigative dermatology. Symposium proceedings}, volume = {18}, number = {2}, pages = {S81-S84}, doi = {10.1016/j.jisp.2017.01.003}, pmid = {28941500}, issn = {1529-1774}, support = {R33 AI102223/AI/NIAID NIH HHS/United States ; T34 GM105550/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aldehydes/metabolism ; Alopecia ; Androstenedione/*metabolism ; Cells, Cultured ; Free Radical Scavengers/pharmacology ; Humans ; Keratinocytes/*metabolism ; Prostaglandin D2/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Testosterone/*biosynthesis ; }, abstract = {Elevated levels of prostaglandin D2 (PGD2) have been shown to be present in the bald scalp of androgenic alopecia (AGA) patients and to functionally inhibit hair growth. However, its precise mechanism in AGA has yet to be clearly defined. Although testosterone plays a critical role in the initiation and progression of AGA, the existence of a possible link between PGD2 and testosterone in skin has not been investigated. Here we show that human keratinocytes treated with PGD2 show enhanced capacity to convert the weak androgen, androstenedione, to testosterone. At the same time, treatment with PGD2 induced reactive oxygen species as indicated by generation of the lipid peroxidation product, 4-hydroxynonenal. To determine whether these two events are linked, we used the reactive oxygen species scavenger N-acetyl-cysteine, which blocked the enhanced testosterone production from PGD2-treated keratinocytes. Our study suggests the existence of a possible crosstalk between the PGD2-reactive oxygen species axis and testosterone metabolism in keratinocytes. Thus, we propose that AGA patients might benefit from the use of N-acetyl-cysteine or other antioxidants as a supplement to currently available or emerging AGA therapies such as finasteride, minoxidil, and PGD2 receptor blockers.}, }
@article {pmid28940353, year = {2018}, author = {Coles, LD and Tuite, PJ and Öz, G and Mishra, UR and Kartha, RV and Sullivan, KM and Cloyd, JC and Terpstra, M}, title = {Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress.}, journal = {Journal of clinical pharmacology}, volume = {58}, number = {2}, pages = {158-167}, pmid = {28940353}, issn = {1552-4604}, support = {P30 NS076408/NS/NINDS NIH HHS/United States ; P41 EB015894/EB/NIBIB NIH HHS/United States ; R01 AG039396/AG/NIA NIH HHS/United States ; UL1 TR000114/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Aged ; Aged, 80 and over ; Antioxidants/*pharmacology ; Brain/*drug effects/metabolism ; Catalase/blood ; Female ; Glutathione/*metabolism ; Humans ; Male ; Middle Aged ; Models, Biological ; Oxidative Stress/drug effects ; Parkinson Disease/*metabolism ; }, abstract = {Parkinson's disease (PD) is associated with oxidative stress and decreased nigral glutathione (GSH), suggesting that therapies that boost GSH may have a disease-modifying effect. Intravenous administration of a high dose of N-acetylcysteine (NAC), a well-known antioxidant and GSH precursor, increases blood and brain GSH in individuals with PD and with Gaucher disease and in healthy controls. To characterize the pharmacokinetics of repeated high oral doses of NAC and their effect on brain and blood oxidative stress measures, we conducted a 4-week open-label prospective study of oral NAC in individuals with PD (n = 5) and in healthy controls (n = 3). Brain GSH was measured in the occipital cortex using [1] H-MRS at 3 and 7 tesla before and after 28 days of 6000 mg NAC/day. Blood was collected prior to dosing and at predetermined collection times before and after the last dose to assess NAC, cysteine, GSH, catalase, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations and the reduced-to-oxidized GSH ratio (GSH/ glutathione disulfide [GSSG]). Symptomatic adverse events were reported by 3 of the 5 subjects with PD. NAC plasma concentration-time profiles were described by a first-order absorption, 1-compartment pharmacokinetic model. Although peripheral antioxidant measures (catalase and GSH/GSSG) increased significantly relative to baseline, indicators of oxidative damage, that is, measures of lipid peroxidation (4-HNE and MDA) were unchanged. There were no significant increases in brain GSH, which may be related to low oral NAC bioavailability and small fractional GSH/GSSG blood responses. Additional studies are needed to further characterize side effects and explore the differential effects of NAC on measures of antioxidant defense and oxidative damage.}, }
@article {pmid28939293, year = {2017}, author = {Escribano, BM and Luque, E and Aguilar-Luque, M and Feijóo, M and Caballero-Villarraso, J and Torres, LA and Ramirez, V and García-Maceira, FI and Agüera, E and Santamaria, A and Túnez, I}, title = {Dose-dependent S-allyl cysteine ameliorates multiple sclerosis disease-related pathology by reducing oxidative stress and biomarkers of dysbiosis in experimental autoimmune encephalomyelitis.}, journal = {European journal of pharmacology}, volume = {815}, number = {}, pages = {266-273}, doi = {10.1016/j.ejphar.2017.09.025}, pmid = {28939293}, issn = {1879-0712}, mesh = {Acute-Phase Proteins/metabolism ; Animals ; Biomarkers/metabolism ; Carrier Proteins/metabolism ; Cysteine/*analogs &amp; derivatives/pharmacology ; Dose-Response Relationship, Drug ; Dysbiosis/*complications/*metabolism ; Encephalomyelitis, Autoimmune, Experimental/*complications ; Intestinal Mucosa/metabolism ; Intestines/drug effects/microbiology ; Lipopolysaccharides/metabolism ; Male ; Membrane Glycoproteins/metabolism ; Multiple Sclerosis/*complications ; Oxidative Stress/*drug effects ; Rats ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Garlic is a component of the Mediterranean diet. S-allyl cysteine (SAC), the most common organosulphur present in garlic, possesses neuroprotective properties. This investigation was performed to evaluate the dose-dependent protective action of SAC on oxidative damage, inflammation and gut microbiota alterations biomarkers. Experimental autoimmune encephalomyelitis (EAE) as a model of multiple sclerosis (MS) was induced by the myelin oligodendrocyte glycoprotein (MOG), whose effects were quantified by examining the changes in: clinical score, lipid peroxidation products, carbonylated proteins, glutathione system, tumor necrosis factor alpha (TNFα), and lipopolysaccharide membrane bacteria (LPS). Our results reveal that MOG induces paralysis, oxidative damage and increases in LPS binding protein (LBP) and LPS levels. In this work, two doses of SAC were compared with two dose of N-acetyl cysteine (NAC). SAC was more effective than NAC and it prevented the harmful effects induced by MOG more effectively at the dose of 50mg/kg than that of 18mg/kg. Surprisingly, NAC increases LBP levels while SAC had not such negative effect. In conclusion the data show the ability of SAC to modify EAE evolution.}, }
@article {pmid28938845, year = {2018}, author = {Turnu, L and Porro, B and Alfieri, V and Di Minno, A and Russo, E and Barbieri, S and Bonomi, A and Dello Russo, A and Tondo, C and D'Alessandra, Y and Cavalca, V and Tremoli, E and Colombo, GI and Casella, M}, title = {Does Fluoroscopy Induce DNA Oxidative Damage in Patients Undergoing Catheter Ablation?.}, journal = {Antioxidants &amp; redox signaling}, volume = {28}, number = {12}, pages = {1137-1143}, doi = {10.1089/ars.2017.7334}, pmid = {28938845}, issn = {1557-7716}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/administration &amp; dosage ; Aged ; Catheter Ablation/*adverse effects ; DNA/*metabolism ; DNA Damage/*physiology ; Deoxyguanosine/administration &amp; dosage/analogs &amp; derivatives ; Female ; Fluoroscopy/*adverse effects ; Humans ; Male ; Middle Aged ; Oxidation-Reduction ; Oxidative Stress/*physiology ; }, abstract = {As no studies before now have thoroughly investigated the risk associated with the exposure to low-dose ionizing radiations in patients undergoing catheter ablation (CA), we aimed to evaluate the oxidative and DNA damage in 59 CA patients (10 of whom received N-acetylcysteine (NAC) before the procedure). A burst of oxidized/reduced glutathione ratio was observed 3 hours after procedure that was diminished by NAC administration. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) concentrations, index of oxidative DNA damage, showed a peak 24 hours after CA. A positive correlation between 8-OHdG peak and fluoroscopy time and a negative correlation among 8-OHdG decrease (from the peak to 48 hours after CA) and all procedure parameters were found. Furthermore, DNA tail percentages (which reflect the extent and the number of DNA strand breaks) positively correlated with 8-OHdG concentrations. This study evaluates for the first time the kinetic of oxidative damage in patients undergoing CA procedure. Our findings raise the question of whether 8-OHdG can be used as a circulating biomarker of DNA oxidative damage induced by low-dose ionizing radiations in different clinical settings. Antioxid. Redox Signal. 28, 1137-1143.}, }
@article {pmid28936177, year = {2017}, author = {Chang, HW and Li, RN and Wang, HR and Liu, JR and Tang, JY and Huang, HW and Chan, YH and Yen, CY}, title = {Withaferin A Induces Oxidative Stress-Mediated Apoptosis and DNA Damage in Oral Cancer Cells.}, journal = {Frontiers in physiology}, volume = {8}, number = {}, pages = {634}, pmid = {28936177}, issn = {1664-042X}, abstract = {Withaferin A (WFA) is one of the most active steroidal lactones with reactive oxygen species (ROS) modulating effects against several types of cancer. ROS regulation involves selective killing. However, the anticancer and selective killing effects of WFA against oral cancer cells remain unclear. We evaluated whether the killing ability of WFA is selective, and we explored its mechanism against oral cancer cells. An MTS tetrazolium cell proliferation assay confirmed that WFA selectively killed two oral cancer cells (Ca9-22 and CAL 27) rather than normal oral cells (HGF-1). WFA also induced apoptosis of Ca9-22 cells, which was measured by flow cytometry for subG1 percentage, annexin V expression, and pan-caspase activity, as well as western blotting for caspases 1, 8, and 9 activations. Flow cytometry analysis shows that WFA-treated Ca9-22 oral cancer cells induced G2/M cell cycle arrest, ROS production, mitochondrial membrane depolarization, and phosphorylated histone H2A.X (γH2AX)-based DNA damage. Moreover, pretreating Ca9-22 cells with N-acetylcysteine (NAC) rescued WFA-induced selective killing, apoptosis, G2/M arrest, oxidative stress, and DNA damage. We conclude that WFA induced oxidative stress-mediated selective killing of oral cancer cells.}, }
@article {pmid28934876, year = {2017}, author = {Ozcamdalli, M and Misir, A and Kizkapan, TB and Uzun, E and Duygulu, F and Yazici, C and Kafadar, IH}, title = {Comparison of Intra-articular Injection of Hyaluronic Acid and N-Acetyl Cysteine in the Treatment of Knee Osteoarthritis: A Pilot Study.}, journal = {Cartilage}, volume = {8}, number = {4}, pages = {384-390}, pmid = {28934876}, issn = {1947-6043}, abstract = {Objective To compare the relative effectiveness of intra-articular N-acetyl cysteine (NAC) and hyaluronic acid (HA) on pain, function and cartilage degradation markers in patients with mild to moderate knee osteoarthritis (OA). Design We prospectively conducted a clinical trial with 20 patients having a diagnosis of Kellgren-Lawrence grade 2-3 knee OA, and randomly allocated to the HA or NAC groups. Groups were matched on age, sex, and body mass index. Injections of 3-mL HA (Hylan G-F 20) or 3-mL NAC (Asist ampoule) were administered as a single shot. Functional status and pain were evaluated before and after injection, using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the visual analogue scale (VAS) scores. Pre- and posttreatment concentrations of serum C-reactive protein (CRP), synovial fluid chondroitin-6-sulfate (C-6S), matrix metalloproteinase-3 (MMP-3), cross-linked C-terminal telopeptide of type 2 collagen (CTX-II), total oxidant status (TOS), and total antioxidant concentration (TAC) were obtained. Results WOMAC, VAS scores, and CRP levels were comparable between groups prior to treatment. Both HA and NAC produced comparable reductions in TOS and MMP-3. NAC was more effective in reducing C-6S and CTX-II (P < 0.05). No effects on TAC were noted. Conclusions NAC is effective in lowering some cartilage degradation markers, with comparable outcomes to HA for pain and function. NAC could provide a cheaper alternative to HA for intra-articular injection treatment of mild to moderate knee OA. Future placebo controlled trials are warranted to evaluate effectiveness in a larger patient population with a wider range of age and OA severity.}, }
@article {pmid28934030, year = {2017}, author = {Wan, C and Xue, R and Zhan, Y and Wu, Y and Li, X and Pei, F}, title = {Metabolomic Analysis of N-acetylcysteine Protection of Injury from Gadolinium-DTPA Contrast Agent in Rats with Chronic Renal Failure.}, journal = {Omics : a journal of integrative biology}, volume = {21}, number = {9}, pages = {540-549}, doi = {10.1089/omi.2017.0114}, pmid = {28934030}, issn = {1557-8100}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Contrast Media/*toxicity ; Gadolinium DTPA/*toxicity ; Kidney Failure, Chronic/chemically induced/*drug therapy ; Male ; Metabolomics/*methods ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Gadolinium-based contrast agents (GBCAs) are frequently used to enhance the diagnostic efficacy of magnetic resonance imaging. On the other hand, the association between GBCA administration in patients with advanced renal disease and nephrogenic systemic fibrosis (NSF) was also noted. NSF is a systemic disorder characterized by widespread tissue fibrosis that may lead to death. N-acetylcysteine (NAC) protects rats from injury induced by gadolinium-based contrast agents, but the underlying mechanisms remain unclear. In this study, a nuclear magnetic resonance-based metabolomic approach was used to systematically investigate the protective effects of NAC on Gd-DTPA-induced injury. Thirty-two male Sprague-Dawley rats were given adenine (200 mg·kg[-1] body weight) by oral gavage once a day for 3 weeks to induce chronic renal failure (CRF). NAC (600 mg/L in drinking water for 9 days) pretreatment was initiated 2 days before Gd-DTPA injection (a single tail vein injection, 2 mmol/kg body weight). Serum and liver samples were collected on day 7 after Gd-DTPA injection. By study design, the serum and hepatic metabolic changes of rats were measured in four groups of eight each: CRF, CRF-Gd, CRF-Gd-NAC, and CRF-NAC. Gd-DTPA administration to rats with CRF resulted in disturbances of several metabolic pathways, including glucose, lipid, glutamate, choline, gut microbiota, one-carbon, and purine metabolism. NAC pretreatment reversed the abundance changes of high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein, glutamate, glutamine, oxidized glutathione, choline, phosphocholine, glycerophosphocholine, trimethylamine, and trimethylamine-N-oxide induced by Gd-DTPA. It is noteworthy, however, that the ameliorating effects of NAC on the disturbance of glutamate, choline, and gut microbiota metabolism may be specific to Gd-DTPA. In all, these findings could be potentially useful to decipher the underlying mechanisms of NAC protective effects from the injury induced by gadolinium-based contrast agents.}, }
@article {pmid28931831, year = {2017}, author = {Mohamed, R and Sharma, I and Ibrahim, AS and Saleh, H and Elsherbiny, NM and Fulzele, S and Elmasry, K and Smith, SB and Al-Shabrawey, M and Tawfik, A}, title = {Hyperhomocysteinemia Alters Retinal Endothelial Cells Barrier Function and Angiogenic Potential via Activation of Oxidative Stress.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {11952}, pmid = {28931831}, issn = {2045-2322}, support = {R01 EY012830/EY/NEI NIH HHS/United States ; R01 EY023315/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Disease Models, Animal ; Endothelial Cells/*pathology ; Humans ; Hyperhomocysteinemia/*complications/*pathology ; Mice, Inbred C57BL ; Neovascularization, Pathologic/*pathology ; *Oxidative Stress ; Permeability ; Retina/*pathology ; Retinal Diseases/*pathology ; }, abstract = {Hyperhomocysteinemia (HHcy) is associated with several human visual disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Breakdown of the blood-retinal barrier (BRB) is linked to vision loss in DR and AMD. Our previous work revealed that HHcy altered BRB in retinal endothelial cells in vivo. Here we hypothesize that homocysteine (Hcy) alters retinal endothelial cell barrier function and angiogenic potential via activation of oxidative stress. Human retinal endothelial cells (HRECs) treated with and without different concentrations of Hcy showed a reduction of tight junction protein expression, increased FITC dextran leakage, decreased transcellular electrical resistance and increased angiogenic potential. In addition, HRECs treated with Hcy showed increased production of reactive oxygen species (ROS). The anti-oxidant N-acetyl-cysteine (NAC) reduced ROS formation and decreased FITC-dextran leakage in Hcy treated HRECs. A mouse model of HHcy, in which cystathionine-β-synthase is deficient (cbs [-/-]), was evaluated for oxidative stress by dichlolorofluorescein (DCF), dihydroethidium (DHE) staining. There was a marked increase in ROS production and augmented GSH reductase and antioxidant regulator NRF2 activity, but decreased antioxidant gene expression in retinas of hyperhomocysteinemic mice. Our results suggest activation of oxidative stress as a possible mechanism of HHcy induced retinal endothelial cell dysfunction.}, }
@article {pmid28928799, year = {2017}, author = {Zhang, Y and Ding, S and Li, C and Wang, Y and Chen, Z and Wang, Z}, title = {Effects of N-acetylcysteine treatment in acute respiratory distress syndrome: A meta-analysis.}, journal = {Experimental and therapeutic medicine}, volume = {14}, number = {4}, pages = {2863-2868}, pmid = {28928799}, issn = {1792-0981}, abstract = {Acute respiratory distress syndrome (ARDS) is a serious complication of acute lung injury. Severe systemic inflammation is the main cause of multiple organ dysfunction and high mortality. Removal of reactive oxygen species by anti-oxidants has been applied in clinical practice. N-acetylcysteine (NAC) is the most commonly used anti-oxidant. However, the benefit of anti-oxidant therapy was not consistently demonstrated by previous studies. In the present study, a meta-analysis was performed to evaluate the effects of NAC for adult patients with ARDS. The PubMed, Cochrane and EMBASE databases were searched to retrieve all of the available randomized controlled trials (RCTs) published until October 2015. Quality evaluation of included studies was performed according to the modified Jadad scale score. The Cochrane Collaboration Review Manager 5.3 software was used to perform the meta-analysis. Five RCTs comprising 183 patients were found to be eligible for inclusion in the meta-analysis. Pooled analysis showed that NAC did not contribute to reduce short-term mortality [risk ratio (RR)=0.73; 95% confidence interval (CI): 0.50-1.07; P=0.10] or 30-day mortality (RR=0.72; 95% CI: 0.44-1.19; P=0.20) when compared with those in the control group. However, duration of intensive care unit (ICU) stay in the NAC group was shortened [weighted mean difference (WMD), -4.56; 95% CI: (-7.32 to -1.80); P=0.001]. There was no significant difference in the ratio of partial arterial oxygen pressure to the fraction of inspired oxygen between the two groups [WMD, 54.34; 95% CI: (-30.50 to 139.17); P=0.21]. No severe adverse reactions were observed in the patients included. Although the duration of ICU stay was shortened, the clinical benefits of NAC were limited for ARDS based on the present meta-analysis. As the number of included trials and patients was small, additional trials are required to provide sufficient evidence for the efficacy of NAC in ARDS.}, }
@article {pmid28926928, year = {2017}, author = {Liao, W and Xiang, W and Wang, FF and Wang, R and Ding, Y}, title = {Curcumin inhibited growth of human melanoma A375 cells via inciting oxidative stress.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {95}, number = {}, pages = {1177-1186}, doi = {10.1016/j.biopha.2017.09.026}, pmid = {28926928}, issn = {1950-6007}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Curcumin/*pharmacology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Melanoma/metabolism/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Time Factors ; Up-Regulation/drug effects ; }, abstract = {Curcumin, a polyphenol compound, possesses potent pharmacological properties in preventing cancers, which make it as a potential anti-cancer mediator. However, it is still unknown that whether Curcumin induced melanoma A375 cell was associated with oxidative stress. Here, we firstly found a fascinating result that Curcumin could reduce the proliferation and induced apoptosis of human melanoma A375 cells. Meanwhile, IC50 of Curcumin on A375 cells is 80μM at 48h. In addition, Curcumin caused oxidative stress through inducing further ROS burst, decreasing GSH, and wrecking mitochondria membrane potential (MMP), which were reversed by ROS inhibitor N-acetylcysteine (NAC). Moreover, MMP disruption led to the release of Cytochrome c from mitochondria and subsequently led to intracellular apoptosis. Furthermore, we found that ROS-dependent HIF-1α and its downstream proteins also play an important role on Curcumin induced apoptosis. In conclusion, our results shed new lights on the therapy of melanoma that Curcumin may be a promising candidate.}, }
@article {pmid28923094, year = {2017}, author = {Li, P and Hou, G and Zhang, R and Gan, Y and Xu, Y and Song, L and Zhou, Q}, title = {High-magnitude compression accelerates the premature senescence of nucleus pulposus cells via the p38 MAPK-ROS pathway.}, journal = {Arthritis research &amp; therapy}, volume = {19}, number = {1}, pages = {209}, pmid = {28923094}, issn = {1478-6362}, mesh = {Animals ; Cellular Senescence/*physiology ; Intervertebral Disc Degeneration/*metabolism ; MAP Kinase Signaling System/*physiology ; Male ; Nucleus Pulposus/*metabolism/*pathology ; Pressure/adverse effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Mechanical overloading can lead to disc degeneration. Nucleus pulposus (NP) cell senescence is aggravated within the degenerated disc. This study was designed to investigate the effects of high compression on NP cell senescence and the underlying molecular mechanism of this process.<br><br>METHODS: Rat NP cells seeded in decalcified bone matrix were subjected to non-compression (control) or compression (2% or 20% deformation, 1.0&#xa0;Hz, 6&#xa0;hours/day). The reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the p38 MAPK inhibitor SB203580 were used to investigate the roles of the ROS and p38 MAPK pathway under high-magnitude compression. Additionally, we studied the effects of compression (0.1 or 1.3&#xa0;MPa, 1.0&#xa0;Hz, 6&#xa0;hours/day) in a rat disc organ culture.<br><br>RESULTS: Both in scaffold and organ cultures, high-magnitude compression (20% deformation or 1.3&#xa0;MPa) increased senescence-associated &#x3b2;-galactosidase (SA-&#x3b2;-Gal) activity, senescence marker (p16 and p53) expression, G1 cell cycle arrest, and ROS generation, and decreased cell proliferation, telomerase activity and matrix (aggrecan and collagen II) synthesis. Further analysis of the 20% deformation group showed that NAC inhibited NP cell senescence but had no obvious effect on phospho-p38 MAPK expression and that SB203580 significantly attenuated ROS generation and NP cell senescence.<br><br>CONCLUSIONS: High-magnitude compression can accelerate NP cell senescence through the p38 MAPK-ROS pathway.}, }
@article {pmid28916389, year = {2018}, author = {Choi, YS and Kim, C and Moon, JH and Lee, JY}, title = {Removal and killing of multispecies endodontic biofilms by N-acetylcysteine.}, journal = {Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]}, volume = {49}, number = {1}, pages = {184-188}, pmid = {28916389}, issn = {1678-4405}, mesh = {Acetylcysteine/*pharmacology ; Actinomyces/*drug effects/physiology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects ; Calcium Hydroxide/pharmacology ; Chlorhexidine/pharmacology ; Dental Pulp Cavity/microbiology ; Dental Pulp Diseases/*microbiology ; Enterococcus faecalis/*drug effects/physiology ; Humans ; Ligilactobacillus salivarius/*drug effects/physiology ; Microbial Viability/drug effects ; Streptococcus mutans/*drug effects/physiology ; }, abstract = {Removal of bacterial biofilm from the root canal system is essential for the management of endodontic disease. Here we evaluated the antibacterial effect of N-acetylcysteine (NAC), a potent antioxidant and mucolytic agent, against mature multispecies endodontic biofilms consisting of Actinomyces naeslundii, Lactobacillus salivarius, Streptococcus mutans and Enterococcus faecalis on sterile human dentin blocks. The biofilms were exposed to NAC (25, 50 and 100mg/mL), saturated calcium hydroxide or 2% chlorhexidine solution for 7 days, then examined by scanning electron microscopy. The biofilm viability was measured by viable cell counts and ATP-bioluminescence assay. NAC showed greater efficacy in biofilm cell removal and killing than the other root canal medicaments. Furthermore, 100mg/mL NAC disrupted the mature multispecies endodontic biofilms completely. These results demonstrate the potential use of NAC in root canal treatment.}, }
@article {pmid28915583, year = {2017}, author = {Wimana, Z and Gebhart, G and Guiot, T and Vanderlinden, B and Larsimont, D and Doumont, G and Van Simaeys, G and Goldman, S and Flamen, P and Ghanem, G}, title = {N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by [89]Zr-Trastuzumab and [18]F-FDG PET imaging.}, journal = {Oncotarget}, volume = {8}, number = {34}, pages = {56185-56198}, pmid = {28915583}, issn = {1949-2553}, abstract = {Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab ([89]Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity ([89]Zr-Trastuzumab HER2-immunoPET) and glucose metabolism ([18]F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.}, }
@article {pmid28911605, year = {2016}, author = {He, X and Ma, L and Xia, Q and Fu, PP}, title = {7-N-Acetylcysteine-pyrrole conjugate-A potent DNA reactive metabolite of pyrrolizidine alkaloids.}, journal = {Journal of food and drug analysis}, volume = {24}, number = {4}, pages = {682-694}, pmid = {28911605}, issn = {2224-6614}, mesh = {Acetylcysteine ; Animals ; DNA/*chemistry ; Humans ; Pyrroles ; Pyrrolizidine Alkaloids ; Rats ; Rats, Inbred F344 ; }, abstract = {Plants containing pyrrolizidine alkaloids (PAs) are widespread throughout the world and are the most common poisonous plants affecting livestock, wildlife, and humans. PAs require metabolic activation to form reactive dehydropyrrolizidine alkaloids (dehydro-PAs) that are capable of alkylating cellular DNA and proteins, form (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-DNA and DHP-protein adducts, and lead to cytotoxicity, genotoxicity, and tumorigenicity. In this study, we determined that the metabolism of riddelliine and monocrotaline by human and rat liver microsomes in the presence of N-acetylcysteine both produced 7-N-acetylcysteine-DHP (7-NAC-DHP) and DHP. Reactions of 7-NAC-DHP with 2'-deoxyguanosine (dG), 2'-deoxyadenosine (dA), and calf thymus DNA in aqueous solution followed by enzymatic hydrolysis yielded DHP-dG and/or DHP-dA adducts. These results indicate that 7-NAC-DHP is a reactive metabolite that can lead to DNA adduct formation.}, }
@article {pmid28905938, year = {2018}, author = {Wang, Y and Guo, SH and Shang, XJ and Yu, LS and Zhu, JW and Zhao, A and Zhou, YF and An, GH and Zhang, Q and Ma, B}, title = {Triptolide induces Sertoli cell apoptosis in mice via ROS/JNK-dependent activation of the mitochondrial pathway and inhibition of Nrf2-mediated antioxidant response.}, journal = {Acta pharmacologica Sinica}, volume = {39}, number = {2}, pages = {311-327}, pmid = {28905938}, issn = {1745-7254}, mesh = {Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cytochromes c/metabolism ; Diterpenes/*adverse effects ; Epoxy Compounds/adverse effects ; JNK Mitogen-Activated Protein Kinases/metabolism ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred ICR ; NF-E2-Related Factor 2/metabolism ; Phenanthrenes/*adverse effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Sertoli Cells/*drug effects/pathology ; Signal Transduction/drug effects ; Testis/*drug effects/pathology ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Triptolide (TP), an oxygenated diterpene, has a variety of beneficial pharmacodynamic activities but its clinical applications are restricted due to severe testicular injury. This study aimed to delineate the molecular mechanisms of TP-induced testicular injury in vitro and in vivo. TP (5-50000 nmol/L) dose-dependently decreased the viability of TM4 Sertoli cells with an IC50 value of 669.5-269.45 nmol/L at 24 h. TP (125, 250, and 500 nmol/L) dose-dependently increased the accumulation of ROS, the phosphorylation of JNK, mitochondrial dysfunction and activation of the intrinsic apoptosis pathway in TM4 cells. These processes were attenuated by co-treatment with the antioxidant N-acetyl cysteine (NAC, 1 mmol/L). Furthermore, TP treatment inhibited the translocation of Nrf2 from cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), catalase (CAT) and hemeoxygenase 1 (HO-1), thus abrogating Nrf2-mediated defense mechanisms against oxidative stress. Moreover, siRNA knockdown of Nrf2 significantly potentiated TP-induced apoptosis of TM4 cells. The above results from in vitro experiments were further validated in male mice after oral administration of TP (30, 60, and 120 mg·kg[-1]·d[-1], for 14 d), as evidenced by the detected indexes, including dose-dependently decreased SDH activity, increased MDA concentration, altered testicle histomorphology, elevated caspase-3 activation, apoptosis induction, increased phosphorylation of JNK, and decreased gene expression of NQO1, CAT and HO-1 as well as nuclear protein expression of Nrf2 in testicular tissue. Our results demonstrate that TP activates apoptosis of Sertoli cells and injury of the testis via the ROS/JNK-mediated mitochondrial-dependent apoptosis pathway and down-regulates Nrf2 activation.}, }
@article {pmid28904489, year = {2017}, author = {Nakhaee, S and Mehrpour, O and Balali-Mood, M}, title = {Does N-acetyl Cysteine Have Protective Effects in Acute Aluminum Phosphide Poisoning?.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {21}, number = {8}, pages = {539-540}, pmid = {28904489}, issn = {0972-5229}, }
@article {pmid28904004, year = {2017}, author = {Hall, SR and Toulany, J and Bennett, LG and Martinez-Farina, CF and Robertson, AW and Jakeman, DL and Goralski, KB}, title = {Jadomycins Inhibit Type II Topoisomerases and Promote DNA Damage and Apoptosis in Multidrug-Resistant Triple-Negative Breast Cancer Cells.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {363}, number = {2}, pages = {196-210}, doi = {10.1124/jpet.117.241125}, pmid = {28904004}, issn = {1521-0103}, support = {//CIHR/Canada ; }, mesh = {Apoptosis/*drug effects/physiology ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; DNA Damage/*drug effects/physiology ; DNA Topoisomerases, Type II/*metabolism ; Dose-Response Relationship, Drug ; Drug Resistance, Multiple/drug effects/physiology ; Drug Resistance, Neoplasm/drug effects/physiology ; Humans ; Isoquinolines/*pharmacology/therapeutic use ; Protein Kinase Inhibitors/*pharmacology ; Triple Negative Breast Neoplasms/drug therapy/*metabolism/pathology ; }, abstract = {Jadomycins are natural products that kill drug-sensitive and multidrug-resistant (MDR) breast cancer cells. To date, the cytotoxic activity of jadomycins has never been tested in MDR breast cancer cells that are also triple negative. Additionally, there is only a rudimentary understanding of how jadomycins cause cancer cell death, which includes the induction of intracellular reactive oxygen species (ROS). We first created a paclitaxel-resistant, triple-negative breast cancer cell line [paclitaxel-resistant MDA-MB-231 breast cancer cells (231-TXL)] from drug-sensitive control MDA-MB-231 cells (231-CON). Using thiazolyl blue methyltetrazolium bromide cell viability-measuring assays, jadomycins B, S, and F were found to be equipotent in drug-sensitive 231-CON and MDR 231-TXL cells; and using ROS-detecting assays, these jadomycins were determined to increase ROS activity in both cell lines by up to 7.3-fold. Jadomycins caused DNA double-strand breaks in 231-CON and 231-TXL cells as measured by γH2AX Western blotting. Coincubation with the antioxidant N-acetyl cysteine or pro-oxidant auranofin did not affect jadomycin-mediated DNA damage. Jadomycins induced apoptosis in 231-CON and 231-TXL cells as measured by annexin V affinity assays, a process that was retained when ROS were inhibited. This indicated that jadomycins are capable of inducing MDA-MB-231 apoptotic cell death independently of ROS activity. Using quantitative polymerase chain reaction, Western blotting, and direct topoisomerase inhibition assays, it was determined that jadomycins inhibit type II topoisomerases and that jadomycins B and F selectively poison topoisomerase IIβ We therefore propose novel mechanisms through which jadomycins induce breast cancer cell death independently of ROS activity, through inhibition or poisoning of type II topoisomerases and the induction of DNA damage and apoptosis.}, }
@article {pmid28902442, year = {2017}, author = {Wu, Q and Wan, J and He, Z and Liu, R}, title = {Spectroscopic investigations on the conformational changes of lysozyme effected by different sizes of N-acetyl-l-cysteine-capped CdTe quantum dots.}, journal = {Journal of biochemical and molecular toxicology}, volume = {31}, number = {12}, pages = {}, doi = {10.1002/jbt.21982}, pmid = {28902442}, issn = {1099-0461}, mesh = {Acetylcysteine/chemistry ; Cadmium Compounds/chemistry ; Catalytic Domain ; Enzyme Inhibitors/*chemistry ; Muramidase/antagonists &amp; inhibitors/*chemistry ; Particle Size ; Protein Binding ; Protein Structure, Secondary ; Quantum Dots/*chemistry ; Tellurium/chemistry ; Thermodynamics ; }, abstract = {The effect of N-acetyl-l-cysteine-capped CdTe quantum dots (NAC-CdTe QDs) with different sizes on lysozyme was investigated by isothermal titration calorimetry (ITC), enzyme activity assays, and multi-spectroscopic methods. ITC results proved that NAC-CdTe QDs can spontaneously bind with lysozyme and hydrophobic force plays a major role in stabilizing QDs-lysozyme complex. Multi-spectroscopic measurements revealed that NAC-CdTe QDs caused strong quenching of the lysozyme's fluorescence in a size-dependent quenching manner. Moreover, the changes of secondary structure and microenvironment in lysozyme caused by the NAC-CdTe QDs were higher with a bigger size. The results of enzyme activity assays showed that the interaction between lysozyme and NAC-CdTe QDs inhibited the activity of lysozyme and the inhibiting effect was in a size-dependent manner. Based on these results, we conclude that NAC-CdTe QDs with larger particle size had a larger impact on the structure and function of lysozyme.}, }
@article {pmid28901751, year = {2017}, author = {Yun, Y and Gao, R and Yue, H and Guo, L and Li, G and Sang, N}, title = {Sulfate Aerosols Promote Lung Cancer Metastasis by Epigenetically Regulating the Epithelial-to-Mesenchymal Transition (EMT).}, journal = {Environmental science &amp; technology}, volume = {51}, number = {19}, pages = {11401-11411}, doi = {10.1021/acs.est.7b02857}, pmid = {28901751}, issn = {1520-5851}, mesh = {Aerosols/*toxicity ; Cadherins ; Cell Line, Tumor ; China ; Epithelial-Mesenchymal Transition/*drug effects ; Humans ; Lung Neoplasms/*pathology ; *Neoplasm Metastasis ; Sulfates/*toxicity ; }, abstract = {Secondary inorganic aerosols (SIA), particularly sulfate aerosols, are central particulate matter (PM) constituents of severe haze formation in China and exert profound impacts on human health; however, our understanding of the mechanisms by which sulfate aerosols cause malignancy in lung carcinogenesis remains incomplete. Here, we show that exposure to secondary inorganic aerosols induced the invasion and migration of lung epithelial cells, and that (NH4)2SO4 exerted the most serious effects in vitro and promoted lung tumor metastasis in vivo. This action was associated with alterations of phenotype markers in the epithelial-to-mesenchymal transition (EMT), such as the up-regulation of fibronectin (Fn1) and the down-regulation of E-cadherin (E-cad). Hypoxia-inducible factor 1α (HIF-1α)-Snail signaling, regulated by the generation of reactive oxygen species (ROS), was involved in the (NH4)2SO4-induced EMT, and the potent antioxidant N-acetylcysteine (NAC) inhibited the activation of HIF-1α-Snail and blocked the EMT, cell invasion, and migration in response to (NH4)2SO4. Additionally, CpG hypermethylation in the E-cad promoter regions partly contributed to the (NH4)2SO4-regulated E-cad repression, and the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-Aza) restored the (NH4)2SO4-induced down-regulation of E-cad. Our findings reveal a potential mechanistic basis for exploring the association between sulfate aerosol exposure and increased malignancy during lung carcinogenesis, and suggest new approaches for the treatment, improvement, and prevention of lung cancer resulting from sulfate aerosol exposure in severe haze-fog.}, }
@article {pmid28901511, year = {2017}, author = {Liu, Y and Liu, K and Wang, N and Zhang, H}, title = {N‑acetylcysteine induces apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells.}, journal = {Molecular medicine reports}, volume = {16}, number = {5}, pages = {6626-6633}, pmid = {28901511}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Cell Line ; Cytochromes c/metabolism ; Endoplasmic Reticulum/*drug effects/metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Glutathione/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Oxidation-Reduction/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Transcription Factor CHOP/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {N‑acetylcysteine (NAC), a precursor of glutathione, is a widely used thiol‑containing antioxidant and modulator of the intracellular redox state. Our previous study demonstrated that excess reduced glutathione (GSH) from NAC treatment paradoxically led to a reduction in glutathione redox potential, increased mitochondrial oxidation and caused cytotoxicity at lower reactive oxygen species levels in H9c2 cells. However, no detailed data are available on the molecular mechanisms of NAC‑induced cytotoxicity on H9c2 cells. In the present study, it was demonstrated that NAC‑induced cytotoxicity towards H9c2 cells was associated with apoptosis. The activation of caspase‑9 and ‑3, and cleavage of procaspase‑9 and ‑3, but not of caspase‑8, were involved in NAC‑induced apoptosis. The dissipation of mitochondrial transmembrane potential, release of cytochrome c, translocation of B cell lymphoma‑2 (Bcl‑2)‑associated X protein (Bax) to the mitochondria, and the increased ratio of Bax/Bcl‑2 mRNA indicated that NAC treatment‑induced apoptosis occurred mainly through the mitochondria‑dependent pathway. Redox western blot analysis demonstrated that NAC did not disrupt the highly oxidized environment of the endoplasmic reticulum, which was indicated by maintenance of the oxidized form of protein disulfide isomerase, an essential chaperone in the formation of disulfide bond formation in the endoplasmic reticulum. In addition, no significant changes in the expression of binding immunoglobulin protein or C/EBP homologous protein were apparent in the process of NAC‑induced apoptosis. Taken together, the present study demonstrated for the first time, to the best of our knowledge, that NAC induced apoptosis via the mitochondria‑dependent pathway but not via endoplasmic reticulum stress in H9c2 cells, and the exogenous GSH from NAC did not alter the oxidized milieu of the endoplasmic reticulum.}, }
@article {pmid28901448, year = {2017}, author = {Kim, KC and Ruwan Kumara, MHS and Kang, KA and Piao, MJ and Oh, MC and Ryu, YS and Jo, JO and Mok, YS and Shin, JH and Park, Y and Kim, SB and Yoo, SJ and Hyun, JW}, title = {Exposure of keratinocytes to non‑thermal dielectric barrier discharge plasma increases the level of 8‑oxoguanine via inhibition of its repair enzyme.}, journal = {Molecular medicine reports}, volume = {16}, number = {5}, pages = {6870-6875}, doi = {10.3892/mmr.2017.7454}, pmid = {28901448}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; DNA/isolation &amp; purification/metabolism ; DNA Damage/*drug effects ; DNA Glycosylases/genetics/*metabolism ; Down-Regulation/*drug effects ; Enzyme-Linked Immunosorbent Assay ; Guanine/*analogs &amp; derivatives/analysis/metabolism ; Humans ; Keratinocytes/cytology/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Plasma Gases/*toxicity ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Up-Regulation/*drug effects ; }, abstract = {Oxidative stress enhances cellular DNA oxidation and may cause mutations in DNA bases, including 8‑oxoguanine (8‑oxoG). Our recent study reported that exposure of cells to non‑thermal dielectric barrier discharge (DBD) plasma generates reactive oxygen species and damages DNA. The present study investigated the effect of non‑thermal DBD plasma exposure on the formation of 8‑oxoG in HaCaT human keratinocytes. Cells exposed to DBD plasma exhibited increased level of 8‑oxoG. In addition, mRNA and protein expression levels of 8‑oxoguanine glycosylase 1 (OGG1), an 8‑oxoG repair enzyme, were reduced in plasma‑exposed cells. Furthermore, the expression level of nuclear factor erythroid 2‑related factor 2 (Nrf2), a transcription factor that regulates OGG1 gene expression, was reduced following exposure to DBD plasma. Pretreatment of cells with an antioxidant, N‑acetyl cysteine (NAC), prior to plasma exposure suppressed the formation of 8‑oxoG and restored the expression levels of OGG1 and Nrf2. In addition, phosphorylation of protein kinase B (Akt), which regulates the activation of Nrf2, was reduced following plasma exposure. However, phosphorylation was restored by pretreatment with NAC. These findings suggested that non‑thermal DBD plasma exposure generates 8‑oxoG via inhibition of the Akt‑Nrf2‑OGG1 signaling pathway in HaCaT cells.}, }
@article {pmid28898494, year = {2017}, author = {Duailibi, MS and Cordeiro, Q and Brietzke, E and Ribeiro, M and LaRowe, S and Berk, M and Trevizol, AP}, title = {N-acetylcysteine in the treatment of craving in substance use disorders: Systematic review and meta-analysis.}, journal = {The American journal on addictions}, volume = {26}, number = {7}, pages = {660-666}, doi = {10.1111/ajad.12620}, pmid = {28898494}, issn = {1521-0391}, mesh = {Acetylcysteine/*pharmacology ; Craving/*drug effects ; Humans ; Neurotransmitter Agents/pharmacology ; Substance-Related Disorders/*drug therapy/psychology ; Treatment Outcome ; }, abstract = {BACKGROUND AND OBJECTIVES: Recent neurobiological evidences along with clinical observations justify the use of N-acetylcysteine (NAC) as a medication for craving. The objective of our study was to assess the evidence of efficacy of NAC for craving in substance use disorders in randomized clinical trials (RCTs).<br><br>METHODS: Systematic review of the RCTs literature (PROSPERO number 56698) until February, 2017, using MEDLINE, Cochrane Library and clinicaltrials.gov. We included seven RCTs (n&#x2009;=&#x2009;245); most with small-to-moderate sample sizes. The main outcome was the Hedges' g for continuous scores in a random-effects model. Heterogeneity was evaluated with the I[2] and the &#x3c7;[2] test. Publication bias was evaluated using the Begg's funnel plot and the Egger's test. Meta-regression was performed using the random-effects model.<br><br>RESULTS: Comparing NAC versus placebo, NAC was significantly superior for craving symptoms (Hedges' g&#x2009;=&#x2009;0.94; 95%CI 0.55-1.33). The funnel plot showed the risk of publication bias was low and between-study heterogeneity was not significant (I[2] &#x2009;=&#x2009;44.4%, p&#x2009;=&#x2009;0.07 for the &#x3c7;[2] test). A subgroup analysis performed using meta-regression showed no particular influence.<br><br>DISCUSSION AND CONCLUSIONS: NAC was superior to placebo for craving reduction in SUDs. The relatively small number of trials and their heterogeneous methodology were possible limitations; however, these positive thrilling results stimulate further studies for clarifying the potential impact of NAC for craving symptoms in SUDs.<br><br>SCIENTIFIC SIGNIFICANCE: The safety profile of NAC and favorable tolerability, in addition to being an over-the-counter medication, presents with an interesting potential clinical use for craving in SUDs.<br><br>SCIENTIFIC SIGNIFICANCE: The safety profile of NAC and its favorable tolerability, in addition to being anover-the-counter medication, presents with an interesting potential clinical use for craving in SUDs. (Am J Addict 2017;26:660-666).}, }
@article {pmid28898446, year = {2018}, author = {Wang, B and Fu, J and Yu, T and Xu, A and Qin, W and Yang, Z and Chen, Y and Wang, H}, title = {Contradictory effects of mitochondria- and non-mitochondria-targeted antioxidants on hepatocarcinogenesis by altering DNA repair in mice.}, journal = {Hepatology (Baltimore, Md.)}, volume = {67}, number = {2}, pages = {623-635}, doi = {10.1002/hep.29518}, pmid = {28898446}, issn = {1527-3350}, support = {81522035//National Natural Science Foundation of China/International ; 81670568//National Natural Science Foundation of China/International ; 81521091//National Natural Science Foundation of China/International ; 81372206//National Natural Science Foundation of China/International ; 81472768//National Natural Science Foundation of China/International ; 91529306//National Natural Science Foundation of China/International ; 2015ZX09J15107//State Key Project for Infectious Diseases/International ; 15431901600//Shanghai Committee of Science and Technology/International ; 16QA1404900//Shanghai Committee of Science and Technology/International ; 14XD1400100//Shanghai Committee of Science and Technology/International ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ataxia Telangiectasia Mutated Proteins/physiology ; Chromans/pharmacology ; DNA Repair/*drug effects ; Diethylnitrosamine ; Liver Neoplasms, Experimental/*chemically induced/prevention &amp; control ; Male ; Mice ; Mitochondria/*drug effects ; Oligopeptides/pharmacology ; Organophosphorus Compounds/pharmacology ; Reactive Oxygen Species/metabolism ; Ubiquinone/analogs &amp; derivatives/pharmacology ; }, abstract = {Conflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancer patients. Despite recent studies about antioxidants accelerating the progression of lung cancer and melanoma, antioxidants may still play a role in cancer prevention. Both tumor and antioxidants types influence the actual efficacy. However, little is known about the impact of different types of antioxidants on primary hepatocellular carcinoma (HCC), including non-mitochondrial- and mitochondrial-targeted antioxidants. Utilizing mouse models of chemical hepatocarcinogenesis, we showed that administration of non-mitochondria-targeted antioxidants N-acetylcysteine (NAC) and the soluble vitamin E analog, Trolox, prevented tumorigenesis, whereas administration of mitochondria-targeted antioxidants SS-31 (the mitochondria-targeted peptide) and Mito-Q (a derivative of ubiquinone) facilitated tumorigenesis. RNA sequencing revealed that NAC and SS-31 caused very different changes in the oxidation-reduction state and DNA damage response. In diethylnitrosamine (DEN)-treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ataxia-telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) for DNA repair whereas SS-31 and Mito-Q aggravated damage by inactivating them. Interestingly, partial recovery of SS-31-scavengened mitochondrial reactive oxygen species (mtROS) could alleviate SS-31-aggravated DNA damage. Localization of ATM between mitochondria and nuclei was altered after NAC and SS-31 treatment. Furthermore, blockage of phospho-ATR (p-ATR) led to the recurrence of NAC-ameliorated DEN HCC. In contrast, reactivation of p-ATR blocked SS-31-promoted DEN HCC. Conclusion: These results demonstrate that the type of antioxidants plays a previously unappreciated role in hepatocarcinogenesis, and provide a mechanistic rationale for exploring the therapeutic use of antioxidants for liver cancer. (Hepatology 2018;67:623-635).}, }
@article {pmid28898308, year = {2016}, author = {Capece, J and Pavlovsky, F}, title = {[The treatment of cannabis dependence: Clinical work, psychotherapy and evidence].}, journal = {Vertex (Buenos Aires, Argentina)}, volume = {XXVII}, number = {130}, pages = {469-473}, pmid = {28898308}, issn = {0327-6139}, mesh = {Humans ; Marijuana Abuse/*therapy ; *Psychotherapy ; }, abstract = {Identifying compulsive consumption of marijuana in association with another mental disorder (attentional defcit disorder, bipolar disorder, depression or psychosis) presents the challenge of clarifying validated therapeutic strategies, especially within the teen population, in which it shows the highest prevalence. The ever-increasing prevalence and the need for regional treatments, demand that we approach this health matter as a public health issue. The ideological con?icts related to the necessary decriminalization of consumption and the current debate on the medical use of marijuana often confuse the urgent need to establish effective therapeutic strategies for the population affected by this mental disorder. Family therapy and community reinforcement are one of the most effcient interventions, other than the traditional individual and group therapies. Contingent, motivational and cognitive-behavioral tailored interventions appear to be most effcient and recommendable. Aerobic exercise and the use of mobile technology also show effectiveness. The administration of medications such as gabepentin, the aminoacid n-acetyl cysteine (NAC) and the cannabinoid cannabidiol (CBD) appear to be very promising. Usual medications, such as valproic acid, quetiapine and bupropion, increase craving, therefore intensifying the need for consumption and thus yielding overall negative results.}, }
@article {pmid28894829, year = {2017}, author = {Rivera, A and Raymond, M and Grobman, A and Abouyared, M and Angeli, SI}, title = {The effect of n-acetyl-cysteine on recovery of the facial nerve after crush injury.}, journal = {Laryngoscope investigative otolaryngology}, volume = {2}, number = {3}, pages = {109-112}, pmid = {28894829}, issn = {2378-8038}, abstract = {OBJECTIVE: Facial nerve dysfunction can vary in severity and recovery is dependent on the character of the injury. N-acetyl-cysteine prevents oxidative stress and cellular damage, and its use in the setting of nerve dysfunction from crush injury has not yet been established. In this study, rats with facial nerve crush injury will be treated with n-acetyl-cysteine or control and functional recovery and electrophysiologic outcome will be compared.<br><br>STUDY DESIGN: Prospective, randomized animal study.<br><br>METHODS: Twenty-four Wistar rats underwent unilateral facial nerve crush injury. Rats were implanted with a subcutaneous osmotic pump filled with saline (n&#x2009;=&#x2009;12) or n-acetyl-cysteine 50 mg/kg/day (n&#x2009;=&#x2009;12). Functional and electromyographic recovery was recorded at two and four weeks postoperatively.<br><br>RESULTS: When compared to untreated rats, n-acetyl-cysteine treated rats had a greater electromyography amplitude recovery at 2 weeks with regard to eye blink (p=0.006) but not vibrissae function. At four weeks, the electromyography amplitude recovery of the vibrissae function was greater in n-acetyl-cysteine treated rats (P=0.001), but the amplitude recovery difference in eye blink was only marginally significant between groups (p=0.07). The functional score was higher in n-acetyl-cysteine-treated rats than in untreated rats at all of the time points.<br><br>CONCLUSION: This study demonstrated that n-acetyl-cysteine facilitated facial nerve recovery with improved functional and electromyography outcomes in the setting of crush injury.<br><br>LEVEL OF EVIDENCE: NA.}, }
@article {pmid28893509, year = {2017}, author = {Li, W and Yu, KN and Ma, J and Shen, J and Cheng, C and Zhou, F and Cai, Z and Han, W}, title = {Non-thermal plasma induces mitochondria-mediated apoptotic signaling pathway via ROS generation in HeLa cells.}, journal = {Archives of biochemistry and biophysics}, volume = {633}, number = {}, pages = {68-77}, doi = {10.1016/j.abb.2017.09.005}, pmid = {28893509}, issn = {1096-0384}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects/genetics ; Caspase 3/genetics/metabolism ; Caspase 9/genetics/metabolism ; Cell Proliferation/drug effects ; Cytochromes c/metabolism ; *Gene Expression Regulation, Neoplastic ; HeLa Cells ; Humans ; Mitochondria/*drug effects/metabolism/pathology ; Plasma Gases/antagonists &amp; inhibitors/*pharmacology ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Protein Transport/drug effects ; Proto-Oncogene Proteins c-bcl-2/antagonists &amp; inhibitors/genetics/metabolism ; Reactive Oxygen Species/*agonists/metabolism ; Signal Transduction ; bcl-2-Associated X Protein/agonists/genetics/metabolism ; }, abstract = {Non-thermal plasma (NTP) has been proposed as a novel therapeutic method for anticancer treatment. Although increasing evidence suggests that NTP selectively induces apoptosis in some types of tumor cells, the molecular mechanisms underlying this phenomenon remain unclear. In this study, we further investigated possible molecular mechanisms for NTP-induced apoptosis of HeLa cells. The results showed that NTP exposure significantly inhibited the growth and viability of HeLa cells. Morphological observation and flow cytometry analysis demonstrated that NTP exposure induced HeLa cell apoptosis. NTP exposure also activated caspase-9 and caspase-3, which subsequently cleaved poly (ADP- ribose) polymerase. Furthermore, NTP exposure suppressed Bcl-2 expression, enhanced Bax expression and translocation to mitochondria, activated mitochondria-mediated apoptotic pathway, followed by the release of cytochrome c. Further studies showed that NTP treatment led to ROS generation, whereas blockade of ROS generation by N-acetyl-l-cysteine (NAC, ROS scavengers) significantly prevented NTP-induced mitochondrial alteration and subsequent apoptosis of HeLa cells via suppressing Bax translocation, cytochrome c and caspase-3 activation. Taken together, our results indicated that NTP exposure induced mitochondria-mediated intrinsic apoptosis of HeLa cells was activated by ROS generation. These findings provide insights to the therapeutic potential and clinical research of NTP as a novel tool in cervical cancer treatment.}, }
@article {pmid28892098, year = {2017}, author = {Capra, J and Eskelinen, S}, title = {Correlation between E-cadherin interactions, survivin expression, and apoptosis in MDCK and ts-Src MDCK cell culture models.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {97}, number = {12}, pages = {1453-1470}, pmid = {28892098}, issn = {1530-0307}, mesh = {Animals ; Apoptosis/*physiology ; Cadherins/*metabolism ; Cell Culture Techniques ; Dogs ; Down-Regulation ; Inhibitor of Apoptosis Proteins/*metabolism ; Madin Darby Canine Kidney Cells ; Up-Regulation ; }, abstract = {Survivin, a member of inhibitor of apoptosis (IAP) protein family, is a multifunctional protein expressed in most cancers. In addition to inhibition of apoptosis, it regulates proliferation and promotes migration. Its presence and function in cells is strongly regulated via transcription factors, intracellular localization, and degradation. We analyzed the presence of survivin at protein level in various culture environments and under activation of Src tyrosine kinase in epithelial canine kidney MDCK cells in order to elucidate factors controlling survivin 'lifespan'. We used untransformed and temperature sensitive ts-Src MDCK cells as a model and forced them to grow in suspension (1D), in 2D on hard and soft surfaces and in soft 3D Matrigel environment with or without EGTA. In addition, we tested the effect of stressful conditions by cultivating the cells in the presence of an anti-cancer drug and a generator of reactive oxygen species (ROS), piperlongumine (PL) with or without an antioxidant, N-acetylcysteine (NAC). We could confirm that inhibition of apoptosis and simultaneous downregulation of survivin in MDCK cells required both intact cell-cell junctions, trans-interactions of E-cadherin and soft 3D matrix environment. In ts-Src-transformed MDCK cells, survivin was upregulated as soon as the cell-cell junctions were disintegrated. ROS generation with PL-induced cell death of ts-Src MDCK cells concomitantly with survivin downregulation. NAC rescued the ts-Src MDCK cells from ROS-induced apoptosis without upregulation of survivin resulting in a situation resembling untransformed MDCK cells in 3D environment and E-cadherin delineating the lateral cell walls.}, }
@article {pmid28891980, year = {2017}, author = {Jiang, Y and Jiao, Y and Wang, Z and Li, T and Liu, Y and Li, Y and Zhao, X and Wang, D}, title = {Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study.}, journal = {International journal of molecular sciences}, volume = {18}, number = {9}, pages = {}, pmid = {28891980}, issn = {1422-0067}, mesh = {Animals ; Antineoplastic Agents/pharmacology/*therapeutic use ; Apoptosis/drug effects ; *Autophagy ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Brain Neoplasms/*drug therapy/metabolism ; Cell Line, Tumor ; Glioblastoma/*drug therapy/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lysosomes/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Microtubule-Associated Proteins/metabolism ; Morphinans/pharmacology/*therapeutic use ; Reactive Oxygen Species/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Glioblastoma is the most common malignant primary brain tumor, and it is one of the causes of cancer fatality in both adult and pediatric populations. Patients with glioblastoma require chemotherapy after surgical resection and radiotherapy. Therefore, chemotherapy constitutes a viable approach for the eradication of glioblastoma cells. In this study, the anti-tumor activity of sinomenine hydrochloride (SH) was evaluated in U87 and SF767 cells in vitro and in vivo. The results showed that SH potently inhibited U87 and SF767 cell viability and did not cause caspase-dependent cell death, as demonstrated by the absence of significant early apoptosis and caspase-3 cleavage. Instead, SH activated an autophagy-mediated cell death pathway, as indicated by the accumulated microtubule-associated protein light chain 3B (LC3B)-II, triggered autophagic flux and enhanced cell viability after pretreatment with autophagy inhibitors. SH-mediated autophagy in the two cell lines was implicated in reactive oxygen species (ROS) generation, protein kinase B (Akt)-mammalian target of rapamycin (mTOR) pathway suppression and c-Jun NH2-terminal kinase (JNK) pathway activation. The ROS antioxidant N-acetylcysteine (NAC), the Akt-specific activator insulin-like growth factor-1 (IGF-1) and the JNK-specific inhibitor SP600125 attenuated SH-induced autophagy. Moreover, ROS activated autophagy via the Akt-mTOR and JNK pathways. Additionally, SH treatment may promote lysosome biogenesis through activating transcription factor EB (TFEB). The in vivo study found that SH effectively suppressed glioblastoma growth without exhibiting significant toxicity. In conclusion, our findings reveal a novel mechanism of action of SH in cancer cells via the induction of autophagy through ROS generation and autophagy-lysosome pathway activation; these findings also supply a new potential therapeutic agent for the treatment of human glioblastoma.}, }
@article {pmid28887840, year = {2017}, author = {Pinniger, GJ and Terrill, JR and Assan, EB and Grounds, MD and Arthur, PG}, title = {Pre-clinical evaluation of N-acetylcysteine reveals side effects in the mdx mouse model of Duchenne muscular dystrophy.}, journal = {The Journal of physiology}, volume = {595}, number = {23}, pages = {7093-7107}, pmid = {28887840}, issn = {1469-7793}, mesh = {Acetylcysteine/administration &amp; dosage/*adverse effects/therapeutic use ; Animals ; Body Weight/drug effects ; Drug Evaluation, Preclinical ; Free Radical Scavengers/administration &amp; dosage/*adverse effects/therapeutic use ; Liver/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscle Strength ; Muscle, Skeletal/drug effects/metabolism/physiopathology ; Muscular Dystrophy, Duchenne/*drug therapy/genetics ; Oxidative Stress ; }, abstract = {KEY POINTS: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation and oxidative stress. The antioxidant N-acetylcysteine (NAC) has been proposed as a therapeutic intervention for DMD boys, but potential adverse effects of NAC have not been widely investigated. We used young (6 weeks old) growing mdx mice to investigate the capacity of NAC supplementation (2% in drinking water for 6 weeks) to improve dystrophic muscle function and to explore broader systemic effects of NAC treatment. NAC treatment improved normalised measures of muscle function, and decreased inflammation and oxidative stress, but significantly reduced body weight gain, muscle weight and liver weight. Unexpected significant adverse effects of NAC on body and muscle weights indicate that interpretation of muscle function based on normalised force measures should be made with caution and careful consideration is needed when proposing the use of NAC as a therapeutic treatment for young DMD boys.<br><br>ABSTRACT: Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle wasting disease characterised by severe muscle weakness, necrosis, inflammation and oxidative stress. The antioxidant N-acetylcysteine (NAC) has been proposed as a potential therapeutic intervention for DMD boys. We investigated the capacity of NAC to improve dystrophic muscle function in the mdx mouse model of DMD. Young (6&#xa0;weeks old) mdx and non-dystrophic C57 mice receiving 2% NAC in drinking water for 6&#xa0;weeks were compared with untreated mice. Grip strength and body weight were measured weekly, before the 12&#xa0;week old mice were anaesthetised and extensor digitorum longus (EDL) muscles were excised for functional analysis and tissues were sampled for biochemical analyses. Compared to untreated mice, the mean (SD) normalised grip strength was significantly greater in NAC-treated mdx [3.13 (0.58) vs 4.87 (0.78)&#xa0;g&#xa0;body weight (bw)[-1] ; P&#xa0;<&#xa0;0.001] and C57 mice [3.90 (0.32) vs 5.32 (0.60)&#xa0;g&#xa0;bw[-1] ; P&#xa0;<&#xa0;0.001]. Maximum specific force was significantly greater in NAC-treated mdx muscles [9.80 (2.27) vs 13.07 (3.37)&#xa0;N&#xa0;cm[-2] ; P&#xa0;=&#xa0;0.038]. Increased force in mdx mice was associated with reduced thiol oxidation and inflammation in fast muscles, and increased citrate synthase activity in slow muscle. Importantly, NAC significantly impaired body weight gain in both strains of young growing mice, and reduced liver weight in C57 mice and muscle weight in mdx mice. These potentially adverse effects of NAC emphasise the need for caution when interpreting improvements in muscle function based on normalised force measures, and that careful consideration be given to these effects when proposing NAC as a potential treatment for young DMD boys.}, }
@article {pmid28886718, year = {2017}, author = {Hoffer, BJ and Pick, CG and Hoffer, ME and Becker, RE and Chiang, YH and Greig, NH}, title = {Repositioning drugs for traumatic brain injury - N-acetyl cysteine and Phenserine.}, journal = {Journal of biomedical science}, volume = {24}, number = {1}, pages = {71}, pmid = {28886718}, issn = {1423-0127}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Brain Injuries, Traumatic/*drug therapy ; Cholinesterase Inhibitors/therapeutic use ; *Drug Repositioning ; Humans ; Mice ; Physostigmine/*analogs &amp; derivatives/therapeutic use ; Psychotropic Drugs/*therapeutic use ; Rats ; }, abstract = {Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults of less than 45 years of age and the elderly, and contributes to about 30% of all injury deaths in the United States of America. Whereas there has been a significant improvement in our understanding of the mechanism that underpin the primary and secondary stages of damage associated with a TBI incident, to date however, this knowledge has not translated into the development of effective new pharmacological TBI treatment strategies. Prior experimental and clinical studies of drugs working via a single mechanism only may have failed to address the full range of pathologies that lead to the neuronal loss and cognitive impairment evident in TBI and other disorders. The present review focuses on two drugs with the potential to benefit multiple pathways considered important in TBI. Notably, both agents have already been developed into human studies for other conditions, and thus have the potential to be rapidly repositioned as TBI therapies. The first is N-acetyl cysteine (NAC) that is currently used in over the counter medications for its anti-inflammatory properties. The second is (-)-phenserine ((-)-Phen) that was originally developed as an experimental Alzheimer's disease (AD) drug. We briefly review background information about TBI and subsequently review literature suggesting that NAC and (-)-Phen may be useful therapeutic approaches for TBI, for which there are no currently approved drugs.}, }
@article {pmid28884184, year = {2017}, author = {Liu, H and Li, RS and Zhou, J and Huang, CZ}, title = {Branched polyethylenimine-functionalized carbon dots as sensitive and selective fluorescent probes for N-acetylcysteine via an off-on mechanism.}, journal = {The Analyst}, volume = {142}, number = {22}, pages = {4221-4227}, doi = {10.1039/c7an01136a}, pmid = {28884184}, issn = {1364-5528}, abstract = {N-Acetylcysteine (NAC) plays an important role in optimizing the protective ability of cells as well as in the treatment of some chronic clinical conditions. Unfortunately, current methods for determining NAC based on fluorescence assay strategies remain poorly investigated. In this study, a new fluorescence method for highly sensitive and selective detection of NAC was developed. The detection method employed the fluorescence (FL) signal of branched polyethylenimine-functionalized carbon dots (PEI-CDs) via an off-on mechanism. The detection system was based on the formation of cupric amine complexes by the reaction of Cu[2+] ions with surface amino groups on PEI-CDs. The FL of PEI-CDs at 460.0 nm upon exciting at 360.0 nm was quenched as a result of electron transfer between the complexes and PEI-CDs. Upon addition of NAC to Cu[2+]-CD solution, electron transfer occurred from the mercapto group on NAC to Cu[2+], leading to the formation of Cu[+] species and the dissociation of cupric amine complexes. As a result, the FL signal of PEI-CDs was turned on since single excited electrons cannot be transferred from PEI-CDs to the cupric amine complexes. The detection limit of this method was 0.56 μM, while the linear response ranged from 5.56 μM to 277.8 μM.}, }
@article {pmid28881798, year = {2017}, author = {Kumar, V and Jagadish, N and Suri, A}, title = {Role of A-Kinase anchor protein (AKAP4) in growth and survival of ovarian cancer cells.}, journal = {Oncotarget}, volume = {8}, number = {32}, pages = {53124-53136}, pmid = {28881798}, issn = {1949-2553}, abstract = {Ovarian cancer represents one of the most common malignancies among women with very high mortality rate worldwide. A-kinase anchor protein 4 (AKAP4), a unique cancer testis (CT) antigen has been shown to be associated with various malignant properties of cancer cells. However, its involvement in various molecular pathways in ovarian cancer remains unknown. In present investigation, employing gene silencing approach, we examined the role of AKAP4 in cell cycle, apoptosis and epithelial-mesenchymal transition (EMT). Further, we also investigated the effect of ablation of AKAP4 on tumor growth in SCID mice ovarian cancer xenograft mouse model. Our results showed that ablation of AKAP4 resulted in increased reactive oxygen species (ROS) generation, DNA damage, cell cycle arrest and apoptosis in ovarian cancer cells. AKAP4 knockdown lead to degradation of protien kinase A (PKA) which was rescued by proteosome inhibitor MG-132. ROS quencher N-acetyl cysteine (NAC) treatment rescued cell cycle arrest and resumed cell division. Subsequently, increased expression of pro-apoptotic molecules and decreased expression of pro-survival/anti-apoptotic factors was observed. As a result of AKAP4 depletion, DNA damage response proteins p-γH2AX, p-ATM and p21 were upregulated. Also, knockdown of CREB resulted in similar findings. Further, PKA inhibitor (H89) and oxidative stress resulted in similar phenotype of ovarian cancer cells as observed in AKAP4 ablated cells. Collectively, for the first time our data showed the involvement of AKAP4 in PKA degradation and perturbed signaling through PKA-CREB axis in AKAP4 ablated ovarian cancer cells.}, }
@article {pmid28880234, year = {2017}, author = {Wang, W and Wu, H and Yu, H and Zhang, X and Cui, G and Wang, K and Mao, S and Pan, Y}, title = {Typhonium giganteum Lectin Exerts A Pro-Inflammatory Effect on RAW 264.7 via ROS and The NF-κB Signaling Pathway.}, journal = {Toxins}, volume = {9}, number = {9}, pages = {}, pmid = {28880234}, issn = {2072-6651}, mesh = {Animals ; *Araceae/chemistry ; Inflammation Mediators/*pharmacokinetics ; Lectins/*pharmacology ; Macrophages/drug effects/*metabolism ; Medicine, Chinese Traditional ; Mice ; NF-kappa B/*metabolism ; RAW 264.7 Cells ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Typhonii rhizoma, a widely used herb in traditional Chinese medicine, has acute irritating toxicity related to Typhonium giganteum lectin (TGL). TGL exhibits acute inflammatory effects, but the underlying molecular mechanisms are largely unknown. This paper is designed to assess the pro-inflammatory response of TGL on RAW 264.7 cells. RAW 264.7 treated with 6.25, 12.5, 25, and 50 µg/mL TGL showed elevated levels of inflammatory factors (TNF-α, IL-1β) and of p-IκB and p-p65, all dose-dependent, indicating that TGL had a substantial inflammatory effect and mobilized the nuclear factor-κB (NF-κB) pathway. All four TGL treatments also induced the up-regulation of reactive oxygen species (ROS) and cytosolic free Ca[2+] and down-regulation of mitochondrial membrane potential (MMP). The production of cytokines and p-IκB, p-p65 were reduced by N-acetylcysteine (NAC), an ROS scavenger, which somewhat abrogated ROS production. The results showed the TGL-activated inflammatory signaling pathway NF-κB to be associated with the overproduction of ROS. Moreover, 50 μg/mL treatment with TGL led to cell apoptosis after 1 h and increased necrosis over time. These results provided potential molecular mechanisms for the observed inflammatory response to TGL including up-regulation of ROS and cytosolic free Ca[2+], down-regulation of MMP, the mobilization of the NF-κB pathway, and the subsequent overproduction of pro-inflammatory factors resulting in apoptosis. Long-term stimulation with TGL resulted in strong toxic effects related to inflammation that induced necrosis in macrophages.}, }
@article {pmid28879668, year = {2018}, author = {Siegert, M and Kranawetvogl, A and Thiermann, H and John, H}, title = {N-Acetylcysteine as a chemical scavenger for sulfur mustard: New insights by mass spectrometry.}, journal = {Drug testing and analysis}, volume = {10}, number = {2}, pages = {243-253}, doi = {10.1002/dta.2299}, pmid = {28879668}, issn = {1942-7611}, mesh = {Acetylcysteine/chemistry/*metabolism ; Alkylation ; Antidotes/*chemistry ; Chromatography, Liquid ; Kinetics ; Mustard Gas/*chemistry ; Proteolysis ; Serum Albumin, Human/chemistry/*metabolism ; Tandem Mass Spectrometry ; }, abstract = {The vesicant sulfur mustard (SM) is a banned chemical warfare agent. Although, SM has been used in combat since WWI, there is no causal therapy currently available. Accordingly, development and investigation of antidotes and scavengers targeting SM are of high clinical relevance. N-acetylcysteine (NAC) was shown to mitigate symptoms of SM intoxications in vitro and in vivo. However, it is still unclear whether the beneficial effects of NAC are only due to physiological processes or also due to chemical scavenging of SM. Therefore, in this study, we examined the scavenging potential of NAC toward SM. Co-incubations of SM and different NAC concentrations in human serum were performed to monitor diverse adducts (covalent reaction products) of human serum albumin (HSA), NAC, and SM. After proteolytic cleavage of HSA with proteinase K the alkylated tripeptide hydroxyethylthioethyl-CysProPhe (HETE-CPF) and the disulfide bridged tripeptide NAC-CPF were detected. Samples were analyzed by microbore liquid chromatography-electrospray ionization-high-resolution tandem-mass spectrometry (μLC-ESI MS/HR MS). Furthermore, degradation kinetics of SM in phosphate buffered saline were measured in the presence and absence of NAC. Although NAC-CPF was identified and characterized for the first time by mass spectrometry and reaction products of NAC and SM were detected and identified by MS/HR MS, analyses clearly documented minor reactivity not significantly contributing to reduction of SM concentrations. Therefore, we conclude that chemical scavenging of SM by NAC does not play the key role in NAC therapy of SM poisoning.}, }
@article {pmid28875258, year = {2017}, author = {Abhishek, A and Benita, S and Kumari, M and Ganesan, D and Paul, E and Sasikumar, P and Mahesh, A and Yuvaraj, S and Ramprasath, T and Selvam, GS}, title = {Molecular analysis of oxalate-induced endoplasmic reticulum stress mediated apoptosis in the pathogenesis of kidney stone disease.}, journal = {Journal of physiology and biochemistry}, volume = {73}, number = {4}, pages = {561-573}, pmid = {28875258}, issn = {1877-8755}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line ; Endoplasmic Reticulum Stress/*drug effects ; Kidney Calculi/*pathology ; Oxalates/*toxicity ; Rats ; }, abstract = {Oxalate, a non-essential end product of metabolism, causes hyperoxaluria and eventually calcium oxalate (CaOx) stone disease. Kidney cells exposed to oxalate stress results in generation of reactive oxygen species (ROS) and progression of stone formation. Perturbations in endoplasmic reticulum (ER) result in accumulation of misfolded proteins and Ca[2+] ions homeostasis imbalance and serve as a common pathway for various diseases, including kidney disorders. ER stress induces up-regulation of pro-survival protein glucose-regulated protein 78 (GRP78) and pro-apoptotic signaling protein C/EBP homologous protein (CHOP). Since the association of oxalate toxicity and ER stress on renal cell damage is uncertain, the present study is an attempt to elucidate the interaction of GRP78 with oxalate by computational analysis and study the role of ER stress in oxalate-mediated apoptosis in vitro and in vivo. Molecular docking results showed that GRP78-oxalate/CaOx interaction takes place. Oxalate stress significantly up-regulated expression of ER stress markers GRP78 and CHOP both in vitro and in vivo. Exposure of oxalate increased ROS generation and altered antioxidant enzyme activities. N-Acetyl cysteine treatment significantly ameliorated oxalate-mediated oxidative stress and moderately attenuated ER stress marker expression. The result indicates oxalate toxicity initiated oxidative stress-induced ER stress and also activating ER stress mediated apoptosis directly. In addition, the up-regulation of transforming growth factor β-1 revealed oxalate may induce kidney fibrosis through ER stress-mediated mechanisms. The present study provide insights into the pathogenic role of oxidative and ER stress by oxalate exposure in the formation of calcium oxalate stone.}, }
@article {pmid28874629, year = {2017}, author = {Aslan, GI and Otgun, I and Acer, T and Tepeoglu, M and Hicsonmez, A}, title = {The effect of intraperitoneal n-acetylcysteine on postoperative adhesions in rat models.}, journal = {Annali italiani di chirurgia}, volume = {88}, number = {}, pages = {258-262}, pmid = {28874629}, issn = {2239-253X}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Apoptosis/drug effects ; Cecum/injuries/surgery ; Drug Evaluation, Preclinical ; Female ; Fibrosis ; Instillation, Drug ; Peritoneal Cavity ; Peritoneal Diseases/*prevention &amp; control ; Rats ; Rats, Wistar ; Single-Blind Method ; Tissue Adhesions/*prevention &amp; control ; }, abstract = {AIM: In this study, we researched the effect of local administration of N-acetylcysteine (NAC) on postoperative intraabdominal adhesion formation in the rat models.<br><br>METHODS: 20 female Wistar Albino rats which were 5-7 months old are used for the study. The rats were divided into two equal groups. Group one was administered saline solution (n=10) while group two was administered NAC (n=10) after caecal abrasion. They were dissected on postoperative tenth day and were examined macroscopically and microscopically for the adhesion formation. Intraperitoneal adhesion formation was scored blinded with Evans model. The most adherent bowel section was excised for histopathologic examination. Mann Whitney U test were used for statistical analysis.<br><br>RESULTS: In Group one, all rats have had adhesions. None of the rats in Group two had either severe inflammatory cell reaction or dense interstitial fibrosis. Macroscopic adhesion formation and microscopic inflammatory cell reaction and interstitial fibrosis formation after surgery were less at the group two (NAC applied) (p<0.05, p<0.05, p<0.05).<br><br>CONCLUSION: We believe that the intraperitoneal single dose usage of NAC may be promising for decreasing the postoperative intraabdominal adhesions.<br><br>KEY WORDS: N-acetylcysteine, Postoperative adhesion, Rat, Fibrosis.}, }
@article {pmid28872660, year = {2018}, author = {Murphy, NP and Lampe, KJ}, title = {Fabricating PLGA microparticles with high loads of the small molecule antioxidant N-acetylcysteine that rescue oligodendrocyte progenitor cells from oxidative stress.}, journal = {Biotechnology and bioengineering}, volume = {115}, number = {1}, pages = {246-256}, doi = {10.1002/bit.26443}, pmid = {28872660}, issn = {1097-0290}, mesh = {Acetylcysteine/chemical synthesis/*pharmacology ; Animals ; Antioxidants/chemical synthesis/*pharmacology ; Biocompatible Materials/*chemical synthesis ; Cell Survival/drug effects ; Cells, Cultured ; Drug Carriers/*chemical synthesis ; Lactic Acid/*chemical synthesis ; Mice ; Oligodendrocyte Precursor Cells/*drug effects/physiology ; *Oxidative Stress ; Polyglycolic Acid/*chemical synthesis ; Polylactic Acid-Polyglycolic Acid Copolymer ; }, abstract = {Reactive oxygen species (ROS), encompassing all oxygen radical or non-radical oxidizing agents, play key roles in disease progression. Controlled delivery of antioxidants is therapeutically relevant in such oxidant-stressed environments. Encapsulating small hydrophilic molecules into hydrophobic polymer microparticles via traditional emulsion methods has long been a challenge due to rapid mass transport of small molecules out of particle pores. We have developed a simple alteration to the existing water-in-oil-in-water (W/O/W) drug encapsulation method that dramatically improves loading efficiency: doping external water phases with drug to mitigate drug diffusion out of the particle during fabrication. PLGA microparticles with diameters ranging from 0.6 to 0.9 micrometers were fabricated, encapsulating high loads of 0.6-0.9 µm diameter PLGA microparticles were fabricated, encapsulating high loads of the antioxidant N-acetylcysteine (NAC), and released active, ROS-scavenging NAC for up to 5 weeks. Encapsulation efficiencies, normalized to the theoretical load of traditional encapsulation without doping, ranged from 96% to 400%, indicating that NAC-loaded external water phases not only prevented drug loss due to diffusion, but also doped the particles with additional drug. Antioxidant-doped particles positively affected the metabolism of oligodendrocyte progenitor cells (OPCs) under H2 O2 -mediated oxidative stress when administered both before (protection) or after (rescue) injury. Antioxidant doped particles improved outcomes of OPCs experiencing multiple doses of H2 O2 by increasing the intracellular glutathione content and preserving cellular viability relative to the injury control. Furthermore, antioxidant-doped particles preserve cell number, number of process extensions, cytoskeletal morphology, and nuclear size of H2 O2 -stressed OPCs relative to the injury control. These NAC-doped particles have the potential to provide temporally-controlled antioxidant therapy in neurodegenerative disorders such as multiple sclerosis (MS) that are characterized by continuous oxidative stress.}, }
@article {pmid28871946, year = {2017}, author = {Qin, Y and Wei, J and Zhang, Y and Kang, L and Kang, B and Shen, H and Zheng, X and Wang, Y and Jia, Z and Zhang, Y}, title = {[Mechanism for the inhibition of proliferation and promotion of apoptosis in Huh7.5 cells by iron overload].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {33}, number = {8}, pages = {1056-1061}, pmid = {28871946}, issn = {1007-8738}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Cation Transport Proteins/analysis ; Cell Line, Tumor ; Cell Proliferation ; Hepatitis C, Chronic/therapy ; Hepatocytes/metabolism/*pathology ; Humans ; Iron Overload/metabolism/*pathology ; Oxidative Stress ; Receptors, Transferrin/analysis ; }, abstract = {Objective To investigate the effect of iron overload on biological activity and apoptosis in Huh7.5 cells. Methods Huh7.5 cells were cultured in the medium supplemented with 50, 100, 200 μmol/L ferric ammonium citrate (FAC). Fluorescence microscopy was employed to determine cell iron load labeled by Phen Green FL; proliferation activity of Huh7.5 cells was evaluated by MTT assay; protein and mRNA levels of transferrin receptor (TfR1), TfR2, divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1) in Huh7.5 cells were detected by Western blotting and real-time PCR, respectively; cell reactive oxygen species (ROS) labeled by dichlorofluorescin diacetate (DCFH-DA) and cell apoptosis labeled by annexinV-FITC/PI were analyzed by flow cytometry. Results FAC treatment increased intracellular iron load in a dose-dependent manner. Compared with control group, mRNA and protein expressions of TfR1, TfR2 and DMT1 were down-regulated, while mRNA and protein expression of FPN1 was significantly up-regulated in FAC treated groups. With the increasing dose of FAC, intracellular ROS level increased significantly and cell proliferation activity decreased significantly. The cell apoptosis rate in FAC treated groups were remarkably higher than that in control group, but after antioxidant N-acetylcysteine (NAC) was added, the cell apoptosis in FAC treated group was inhibited obviously. Conclusion Iron overload can inhibit the proliferation and promote the apoptosis of Huh7.5 cells through oxidative stress.}, }
@article {pmid28871381, year = {2017}, author = {Kurashige, T and Shimamura, M and Nagayama, Y}, title = {N-Acetyl-L-cysteine protects thyroid cells against DNA damage induced by external and internal irradiation.}, journal = {Radiation and environmental biophysics}, volume = {56}, number = {4}, pages = {405-412}, pmid = {28871381}, issn = {1432-2099}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Differentiation/drug effects/radiation effects ; Cell Line ; DNA Breaks, Double-Stranded/drug effects/radiation effects ; *DNA Damage ; Dose-Response Relationship, Radiation ; Iodine Radioisotopes/adverse effects/metabolism ; Micronucleus Tests ; Radiation-Protective Agents/*pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Thyroid Gland/cytology/*drug effects/metabolism/*radiation effects ; }, abstract = {We evaluated the effect of the antioxidant N-acetyl-L-cysteine (NAC) on the levels of reactive oxygen species (ROS), DNA double strand breaks (DSB) and micronuclei (MN) induced by internal and external irradiation using a rat thyroid cell line PCCL3. In internal irradiation experiments, ROS and DSB levels increased immediately after [131]I addition and then gradually declined, resulting in very high levels of MN at 24 and 48 h. NAC administration both pre- and also post-[131]I addition suppressed ROS, DSB and MN. In external irradiation experiments with a low dose (0.5 Gy), ROS and DSB increased shortly and could be prevented by NAC administration pre-, but not post-irradiation. In contrast, external irradiation with a high dose (5 Gy) increased ROS and DSB in a bimodal way: ROS and DSB levels increased immediately after irradiation, quickly returned to the basal levels and gradually rose again after >24 h. The second phase was in parallel with an increase in 4-hydroxy-2-nonenal. The number of MN induced by the second wave of ROS/DSB elevations was much higher than that by the first peak. In this situation, NAC administered pre- and post-irradiation comparably suppressed MN induced by a delayed ROS elevation. In conclusion, a prolonged ROS increase during internal irradiation and a delayed ROS increase after external irradiation with a high dose caused serious DNA damage, which were efficiently prevented by NAC. Thus, NAC administration even both after internal or external irradiation prevents ROS increase and eventual DNA damage.}, }
@article {pmid28869924, year = {2017}, author = {Van Huizen, AV and Tseng, AS and Beane, WS}, title = {Methylisothiazolinone toxicity and inhibition of wound healing and regeneration in planaria.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {191}, number = {}, pages = {226-235}, doi = {10.1016/j.aquatox.2017.08.013}, pmid = {28869924}, issn = {1879-1514}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Glutathione/pharmacology ; Head/physiology ; Planarians/drug effects/*physiology ; Regeneration/*drug effects ; Tail/physiology ; Thiazoles/chemistry/*toxicity ; Water Pollutants, Chemical/chemistry/*toxicity ; Wound Healing/*drug effects ; }, abstract = {Methylisothiazolinone (MIT) is a common biocide used in cosmetic and industrial settings. Studies have demonstrated that MIT is a human sensitizer, to the extent that in 2013 MIT was named allergen of the year. Recently, we showed that MIT exposure in Xenopus laevis (the African clawed frog) inhibits wound healing and tail regeneration. However, it is unknown whether MIT affects these processes in other animals. Here, we investigated the effects of MIT exposure in planaria-non-parasitic freshwater flatworms able to regenerate all tissues after injury. Using a common research strain of Dugesia japonica, we determined that intact planarians exposed to 15μM MIT displayed both neuromuscular and epithelial-integrity defects. Furthermore, regenerating (head and tail) fragments exposed to 15μM MIT failed to close wounds or had significantly delayed wound healing. Planarian wounds normally close within 1h after injury. However, most MIT-exposed animals retained open wounds at 24h and subsequently died, and those few animals that were able to undergo delayed wound healing without dying exhibited abnormal regeneration. For instance, head regeneration was severely delayed or inhibited, with anterior structures such as eyes failing to form in newly produced tissues. These data suggest that MIT directly affects both wound healing and regeneration in planarians. Next, we investigated the ability of thiol-containing antioxidants to rescue planarian wound closure during MIT exposure. The data reveal both n-acetyl cysteine and glutathione were each able to fully rescue MIT inhibition of wound healing. Lastly, we established MIT toxicity levels by determining the LC50 of 5 different planarian species: D. japonica, Schmidtea mediterranea, Girardia tigrina, Girardia dorotocephala, and Phagocata gracilis. Our LC50 data revealed that concentrations as low as 39μM (4.5ppm) are lethal to planarians, with concentrations of just 5μM inhibiting wound healing, and suggest that phylogeny is predictive of species toxicity levels. Together these results indicate MIT may have broad wound healing effects on aquatic species in general and are not limited to X. laevis alone. Future studies should investigate the impact of MIT on wound healing in other organisms, including non-aquatic organisms and mammals.}, }
@article {pmid28867370, year = {2017}, author = {Li, J and Tan, G and Cheng, B and Liu, D and Pan, W}, title = {Transport mechanism of chitosan-N-acetylcysteine, chitosan oligosaccharides or carboxymethyl chitosan decorated coumarin-6 loaded nanostructured lipid carriers across the rabbit ocular.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {120}, number = {}, pages = {89-97}, doi = {10.1016/j.ejpb.2017.08.013}, pmid = {28867370}, issn = {1873-3441}, mesh = {Acetylcysteine/administration &amp; dosage/*chemistry ; Administration, Ophthalmic ; Animals ; Chitosan/administration &amp; dosage/*analogs &amp; derivatives/chemistry ; Cornea/*metabolism ; Coumarins/administration &amp; dosage ; Delayed-Action Preparations/administration &amp; dosage/chemistry ; Drug Carriers/*chemistry ; Drug Delivery Systems/methods ; Drug Liberation/drug effects ; Excipients/chemistry ; Lipids/*administration &amp; dosage ; Male ; Nanostructures/administration &amp; dosage/*chemistry ; Oligosaccharides/administration &amp; dosage/*chemistry ; Ophthalmic Solutions/administration &amp; dosage/chemistry ; Particle Size ; Permeability ; Rabbits ; Thiazoles/administration &amp; dosage ; }, abstract = {To facilitate the hydrophobic drugs modeled by coumarin-6 (Cou-6) acrossing the cornea to the anterior chamber of the rabbit eye, chitosan (CS) derivatives including chitosan-N-acetyl-l-cysteine (CS-NAC), chitosan oligosaccharides (COS) and carboxymethyl chitosan (CMCS) modified nanostructured lipid carriers (NLCs) were designed and characterized. We found that, with similar size distribution and positivecharges, different CS derivatives based on NLCs led to distinctive delivery performance. In vivo precorneal retention study on rabbits revealed that these CS derivatives coating exhibited a stronger resistant effect than Cou-6 eye drops and Cou-6-NLC (P<0.05), moreover, the AUC(0-∞), Cmax and MRT(0-∞) of them followed the sequence of CMCS-Cou-6-NLC<COS-Cou-6-NLC<CS-NAC-Cou-6-NLC. Confocal laser fluorescence microscopy (CLSM) for in vitro corneal penetration study showed that COS-, and CS-NAC-coated NLCs penetrated through the whole corneal epithelium barrier (about 40μm), while CMCS failed to significantly enhance the intraocular drug penetration as expected, displayed a negligible fluorescence at 30μm deep. In addition, penetration through the intact cornea was achieved and the penetration levels through the ocular tissues were increased thoroughly for the COS and CS-NAC coating ones compared with CMCS-NLC (P<0.05), and successfully reduced the conjunctival-to-corneal permeability ratio (ratio(C-S/C)) thus resulted in a higher bioavailability, which was confirmed by ex vivo fluorescence imaging on ocular tissues. In summary, CS-NAC-NLC and COS-NLC are promising ocular drug delivery systems to achieve prolonged precorneal retention, higher corneal permeability and enhanced ocular bioavailability. And comparatively speaking, CS-NAC-NLC possesses the highest potential for ocular drug delivery.}, }
@article {pmid28866821, year = {2017}, author = {Bromfield, JJ and Iacovides, SM}, title = {Evaluating lipopolysaccharide-induced oxidative stress in bovine granulosa cells.}, journal = {Journal of assisted reproduction and genetics}, volume = {34}, number = {12}, pages = {1619-1626}, pmid = {28866821}, issn = {1573-7330}, support = {R01 HD084316/HD/NICHD NIH HHS/United States ; R01HD084316//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; }, mesh = {Animals ; Antioxidants/pharmacology ; Cattle ; Cells, Cultured ; Female ; Granulosa Cells/drug effects/metabolism/*pathology ; Inflammation/chemically induced/metabolism/*pathology ; Leukocytes, Mononuclear/drug effects/metabolism/*pathology ; Lipopolysaccharides/*toxicity ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {PURPOSE: The purpose of this study was to evaluate the capacity of bovine granulosa cells to generate reactive oxygen intermediates in response to lipopolysaccharide. We hypothesized that granulosa cells increase reactive oxygen intermediates in response to Gram-negative lipopolysaccharide in a similar manner to immune cells.<br><br>METHODS: Bovine peripheral blood mononuclear cells and granulosa cells were cultured in the presence of lipopolysaccharide. Oxidative stress was evaluated using the fluorescent marker dye CellROX, and oxidative stress-related genes were measured using real-time RT-PCR.<br><br>RESULTS: As expected, peripheral blood mononuclear cells increased oxidative stress in response to lipopolysaccharide as measured by accumulation of the fluorescent marker dye CellROX. While granulosa cells demonstrate the capacity to increase accumulation of CellROX dye in response to a positive control menadione, lipopolysaccharide had no effect on accumulation of CellROX dye. The expression of GSR, SOD1, and SOD2 were variable in peripheral blood mononuclear cells treated with lipopolysaccharide but were consistently upregulated when co-incubated with the antioxidant, N-acetyl cysteine. The expression of oxidative stress-related genes was not altered in granulosa cells, with the exception of elevated SOD1 following lipopolysaccharide exposure in the absence of antioxidant.<br><br>CONCLUSIONS: Combined, these data suggest that while reactive stress is important in pathogen killing and inflammation in immune cells, granulosa cells do not increase oxidative stress in response to lipopolysaccharide.}, }
@article {pmid28866420, year = {2017}, author = {Khalifa, MMA and Bakr, AG and Osman, AT}, title = {Protective effects of phloridzin against methotrexate-induced liver toxicity in rats.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {95}, number = {}, pages = {529-535}, doi = {10.1016/j.biopha.2017.08.121}, pmid = {28866420}, issn = {1950-6007}, mesh = {Acetylcysteine/pharmacology ; Animals ; Biomarkers/metabolism ; Caspase 3/metabolism ; Inflammation/metabolism/pathology ; Liver/drug effects/metabolism/*pathology ; Male ; Methotrexate/*adverse effects ; Oxidative Stress/drug effects ; Phlorhizin/administration &amp; dosage/chemistry/*pharmacology ; Protective Agents/administration &amp; dosage/chemistry/*pharmacology ; Rats ; Survival Analysis ; }, abstract = {BACKGROUND: Liver is the largest internal organ concerning with metabolism, hormonal balance and clarifying of the toxins. One of the main complications of methotrexate (MTX) therapy was the hepatic injury.<br><br>OBJECTIVE: This study was conducted to elucidate the possible protective effects of phloridzin (PHL) against MTX-induced hepatotoxicity as compared to standard agent N-acetylcysteine (NAC).<br><br>MATERIALS AND METHODS: Rats were randomly divided into a normal control group, a respective group (PHL 40mg/kg/day orally (p.o.) for 10 consecutive days), a hepatotoxicity control group (MTX 20mg/kg, i.p., once), and three treated groups received NAC (150mg/kg/day; a reference standard), PHL (40mg/kg/day) and PHL (80mg/kg/day) p.o. for 10 consecutive days, at the end of the day 3 of the experiment rats were administered MTX. Assessed biomarkers included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) as liver function parameters, serum tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) and cyclooxygenase-II (COX-II), as inflammatory biomarkers, hepatic total antioxidant capacity (TAC), thiobarbituric acid reactive substances (TBARS), glutathione reduced (GSH), nitrite (NO2[-]), catalase (CAT), glutathione-S-transferase (GST) and superoxide dismutase (SOD) as oxidative stress biomarkers. Furthermore, hepatic caspase-3 expression was assessed. Biochemical and molecular estimations reinforced by histopathological findings.<br><br>RESULTS: Rats pre-treated with PHL significantly reduced hepatic injury, evidenced by significant reductions in ALT, AST and LDH, TNF-&#x3b1; and COX-II levels, significant reductions in hepatic NO2[-] and TBARS levels, and significant elevations in hepatic TAC, GSH, GST, CAT and SOD levels. Additionally, downregulation of hepatic caspase-3 expression. Finally, histopathological results consistent with our previous findings.<br><br>CONCLUSION: PHL protects against hepatic injury in rats mainly through mitigation of oxidative stress, inflammation and apoptosis in hepatic tissues and may be promising to alleviate and early treatment of MTX-induced hepatoxicity in man.}, }
@article {pmid28864499, year = {2017}, author = {Doody, EE and Groebner, JL and Walker, JR and Frizol, BM and Tuma, DJ and Fernandez, DJ and Tuma, PL}, title = {Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {313}, number = {6}, pages = {G558-G569}, pmid = {28864499}, issn = {1522-1547}, support = {R01 AA017626/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetaldehyde/metabolism ; Acetylation ; Alcohol Dehydrogenase/*metabolism ; Animals ; Antioxidants/pharmacology ; Biotransformation ; Cytochrome P-450 CYP2E1/*metabolism ; Cytochrome P-450 CYP2E1 Inhibitors/pharmacology ; Endocytosis ; Ethanol/*metabolism/toxicity ; Growth Hormone/genetics/*metabolism ; Hep G2 Cells ; Humans ; Janus Kinase 2/genetics/metabolism ; Liver/drug effects/*enzymology ; Microtubule Proteins/metabolism ; Oxidative Stress ; Protein Processing, Post-Translational ; Protein Transport ; Rats ; Reactive Oxygen Species/metabolism ; STAT5 Transcription Factor/genetics/metabolism ; Signal Transduction ; }, abstract = {The liver metabolizes alcohol using alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1). Both enzymes metabolize ethanol into acetaldehyde, but CYP2E1 activity also results in the production of reactive oxygen species (ROS) that promote oxidative stress. We have previously shown that microtubules are hyperacetylated in ethanol-treated polarized, hepatic WIF-B cells and livers from ethanol-fed rats. We have also shown that enhanced protein acetylation correlates with impaired clathrin-mediated endocytosis, constitutive secretion, and nuclear translocation and that the defects are likely mediated by acetaldehyde. However, the roles of CYP2E1-generated metabolites and ROS in microtubule acetylation and these alcohol-induced impairments have not been examined. To determine if CYP2E1-mediated alcohol metabolism is required for enhanced acetylation and the trafficking defects, we coincubated cells with ethanol and diallyl sulfide (DAS; a CYP2E1 inhibitor) or N-acetyl cysteine (NAC; an antioxidant). Both agents failed to prevent microtubule hyperacetylation in ethanol-treated cells and also failed to prevent impaired secretion or clathrin-mediated endocytosis. Somewhat surprisingly, both DAS and NAC prevented impaired STAT5B nuclear translocation. Further examination of microtubule-independent steps of the pathway revealed that Jak2/STAT5B activation by growth hormone was prevented by DAS and NAC. These results were confirmed in ethanol-exposed HepG2 cells expressing only ADH or CYP2E1. Using quantitative RT-PCR, we further determined that ethanol exposure led to blunted growth hormone-mediated gene expression. In conclusion, we determined that alcohol-induced microtubule acetylation and associated defects in microtubule-dependent trafficking are mediated by ADH metabolism whereas impaired microtubule-independent Jak2/STAT5B activation is mediated by CYP2E1 activity.NEW &amp; NOTEWORTHY Impaired growth hormone-mediated signaling is observed in ethanol-exposed hepatocytes and is explained by differential effects of alcohol dehydrogenase (ADH)- and cytochrome P450 2E1 (CYP2E1)-mediated ethanol metabolism on the Jak2/STAT5B pathway.}, }
@article {pmid28861643, year = {2018}, author = {Birnie-Gauvin, K and Larsen, MH and Aarestrup, K and Willmore, WG and Cooke, SJ}, title = {N-acetylcysteine manipulation fails to elicit an increase in glutathione in a teleost model.}, journal = {Fish physiology and biochemistry}, volume = {44}, number = {1}, pages = {137-142}, pmid = {28861643}, issn = {1573-5168}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Dose-Response Relationship, Drug ; Glutathione/*metabolism ; Oxidative Stress/drug effects ; Trout/*metabolism ; }, abstract = {Levels of oxidative stress can be affected by a range of compounds including toxins and pharmaceuticals. Antioxidants are important protective compounds which counteract the damaging effects of oxidative stress. Glutathione (GSH) is one of the main antioxidants for many organisms and can be synthesized from administered N-acetylcysteine (NAC). NAC has therefore often been used in a wide range of taxa to manipulate levels of GSH. Our objective was to validate this approach in a wild temperate teleost fish model, the brown trout (Salmo trutta). We used intracoelomic injections of NAC in saline and vegetable shortening, at two different concentrations (100 and 400 mg/kg), with the appropriate controls and shams, under controlled laboratory settings. We found that NAC failed to elicit an increase in GSH over three time periods and concluded that NAC is not an effective method to enhance GSH levels in teleost fish using the concentrations and vehicles tested here. We emphasize the importance of validation studies across all new species/taxa when possible and suggest that more investigation is required with regard to NAC manipulation in fish if this approach is to be used.}, }
@article {pmid28858636, year = {2017}, author = {Sheller-Miller, S and Urrabaz-Garza, R and Saade, G and Menon, R}, title = {Damage-Associated molecular pattern markers HMGB1 and cell-Free fetal telomere fragments in oxidative-Stressed amnion epithelial cell-Derived exosomes.}, journal = {Journal of reproductive immunology}, volume = {123}, number = {}, pages = {3-11}, pmid = {28858636}, issn = {1872-7603}, support = {R01 HD084532/HD/NICHD NIH HHS/United States ; T32 ES007254/ES/NIEHS NIH HHS/United States ; }, mesh = {Alarmins/*metabolism ; Amnion/*physiology ; Cells, Cultured ; Cellular Senescence ; Cigarette Smoking/adverse effects ; Culture Media, Conditioned/adverse effects ; Epithelial Cells/*pathology ; Exosomes/*metabolism/pathology ; Female ; HMGB1 Protein/*metabolism ; Humans ; Inflammation/genetics/*metabolism ; Labor, Obstetric ; Oxidative Stress ; Parturition ; Pregnancy ; Primary Cell Culture ; Telomere/*metabolism ; }, abstract = {Term labor in humans is associated with increased oxidative stress (OS) -induced senescence and damages to amnion epithelial cells (AECs). Senescent fetal cells release alarmin high-mobility group box 1 (HMGB1) and cell-free fetal telomere fragments (cffTF) which can be carried by exosomes to other uterine tissues to produce parturition-associated inflammatory changes. This study characterized AEC-derived exosomes under normal and OS conditions and their packaging of HMGB1 and cffTF. Primary AECs were treated with either standard media or oxidative stress-induced media (exposure to cigarette smoke extract for 48h). Senescence was determined, and exosomes were isolated and characterized. To colocalize HMGB1 and cffTF in amnion exosomes, immunofluorescent staining and in situ hybridization were performed, followed by confocal microscopy. Next generation sequencing (NGS) determined exosomal cffTF and other cell-free amnion cell DNA specificity. Regardless of condition, primary AECs produce exosomes with a classic size, shape, and markers. OS and senescence caused the translocation of HMGB1 and cffTF from AECs' nuclei to cytoplasm compared to untreated cells, which was inhibited by antioxidant N-acetyl cysteine (NAC). Linescans confirmed colocalization of HMGB1 and cffTF in exosomes were higher in the cytoplasm after CSE treatment compared to untreated AECs. NGS determined that besides cffTF, AEC exosomes also carry genomic and mitochondrial DNA, regardless of growth conditions. Sterile inflammatory markers HMGB1 and cffTF from senescent fetal cells are packaged inside exosomes. We postulate that this exosomal cargo can act as a fetal signal at term and can cause labor-associated changes in neighboring tissues.}, }
@article {pmid28852176, year = {2017}, author = {Zhang, S and Li, T and Zhang, L and Wang, X and Dong, H and Li, L and Fu, D and Li, Y and Zi, X and Liu, HM and Zhang, Y and Xu, H and Jin, CY}, title = {A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up-regulation in gastric cancer cells.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {9873}, pmid = {28852176}, issn = {2045-2322}, support = {R01 CA193967/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Biomarkers ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chalcone/analogs &amp; derivatives/chemistry/*pharmacology ; Disease Models, Animal ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism ; Signal Transduction/drug effects ; Stomach Neoplasms/genetics/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {A new series of etherification chalcone derivatives were designed and synthesized through Willimison etherification and Claisen-Schmidt condensation. Among them, compound 2-c which was given chemical name of S17, has been successfully screened out as the most potent one on gastric cancer cell line(MGC803) through the investigation for their effects against the growth of five cancer cell lines (EC109, HepG2, MCF7, MGC803, SKNSH). S17 exhibited strong anti-proliferative activity on other two gastric cancer cells (HGC27 and SGC7901), but less cytotoxicity to non-malignant gastric epithelial cells GES1. S17 potently killed gastric cancer cells with causing modulation of Bcl-2 family proteins and activation of caspase 9/3 cascade. S17 also up-regulated DR5 expression and DR5 knockdown partially reversed S17-induced apoptosis, caspase activation and MMP decrease. S17 robustly induced generation of ROS with Keap/Nrf2 pathway activated and the application of ROS scavenger N-acetyl cysteine (NAC) completely blocked these effects by S17 in MGC803 cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.}, }
@article {pmid28849708, year = {2018}, author = {Yeo, EH and Goh, WL and Chow, SC}, title = {The aminopeptidase inhibitor, z-L-CMK, is toxic and induces cell death in Jurkat T cells through oxidative stress.}, journal = {Toxicology mechanisms and methods}, volume = {28}, number = {3}, pages = {157-166}, doi = {10.1080/15376516.2017.1373882}, pmid = {28849708}, issn = {1537-6524}, mesh = {Amino Acid Chloromethyl Ketones/antagonists &amp; inhibitors/*toxicity ; Apoptosis/*drug effects ; Biomarkers/metabolism ; Caspase Inhibitors/pharmacology ; Caspases/chemistry/metabolism ; Cell Nucleus Shape/drug effects ; Cell Survival/drug effects ; Glutathione/antagonists &amp; inhibitors/metabolism ; Humans ; Jurkat Cells ; Leucyl Aminopeptidase/*antagonists &amp; inhibitors/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Necrosis/*chemically induced ; Nucleosomes/drug effects/immunology/metabolism ; Osmolar Concentration ; Oxidative Stress/*drug effects ; Peptide Fragments/metabolism ; Protease Inhibitors/chemistry/*toxicity ; Proteolysis/drug effects ; T-Lymphocytes/cytology/*drug effects/immunology/metabolism ; }, abstract = {The leucine aminopeptidase inhibitor, benzyloxycarbonyl-leucine-chloromethylketone (z-L-CMK), was found to be toxic and readily induce cell death in Jurkat T cells. Dose-response studies show that lower concentration of z-L-CMK induced apoptosis in Jurkat T cells whereas higher concentration causes necrosis. In z-L-CMK-induced apoptosis, both the initiator caspases (-8 and -9) and effector caspases (-3 and -6) were processed to their respective subunits. However, the caspases remained intact in z-L-CMK-induced necrosis. The caspase inhibitor, z-VAD-FMK inhibited z-L-CMK-mediated apoptosis and caspase processing but has no effect on z-L-CMK-induced necrosis in Jurkat T cells. The high mobility group protein B1 (HMGB1) protein was found to be released into the culture medium by the necrotic cells and not the apoptotic cells. These results indicate that the necrotic cell death mediated by z-L-CMK at high concentrations is via classical necrosis rather than secondary necrosis. We also demonstrated that cell death mediated by z-L-CMK was associated with oxidative stress via the depletion of intracellular glutathione (GSH) and increase in reactive oxygen species (ROS), which was blocked by N-acetyl cysteine. Taken together, the results demonstrated that z-L-CMK is toxic to Jurkat T cells and induces apoptosis at low concentrations, while at higher concentrations the cells die of necrosis. The toxic side effects in Jurkat T cells mediated by z-L-CMK are associated with oxidative stress via the depletion of GSH and accumulation of ROS.}, }
@article {pmid28849167, year = {2017}, author = {Yu, W and Ji, W and Mi, L and Lin, C}, title = {Mechanisms of N‑acetylcysteine in reducing monocrotaline‑induced pulmonary hypertension in rats: Inhibiting the expression of Nox1 in pulmonary vascular smooth muscle cells.}, journal = {Molecular medicine reports}, volume = {16}, number = {5}, pages = {6148-6155}, doi = {10.3892/mmr.2017.7326}, pmid = {28849167}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Hypertension, Pulmonary/*drug therapy ; Hypertrophy, Right Ventricular/metabolism ; Lung/drug effects/metabolism ; Male ; Monocrotaline/*pharmacology ; Muscle, Smooth, Vascular/*drug effects/metabolism ; Myocytes, Smooth Muscle/*drug effects/metabolism ; NADPH Oxidase 1/*metabolism ; Pulmonary Artery/drug effects/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Vascular Remodeling/drug effects ; }, abstract = {The aim of the present study was to investigate the impact of N‑acetylcysteine (NAC) on the expression of reduced nicotinamide adenine dinucleotide phosphate oxidase 1 (Nox1), and the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) in rats exhibiting monocrotaline (MCT)‑induced pulmonary hypertension, and to investigate the possible mechanisms and treatment roles of NAC in pulmonary vascular remodeling (PVR). A total of 18 Wistar rats were randomly divided into three groups: The control (C) group; the MCT (M) group; and the NAC (N) group. The right ventricular hypertrophy index (RVHI) and other indicators were recorded 6 weeks subsequently. Groups C and M were divided into two subgroups: Groups C1 and M1 (control); and group C2 and M2 group (treated with ML171). Group N was not sub‑divided. PASMCs were isolated, and the vascular remodeling and Nox1 positioning were observed. The expression of Nox mRNA in each group, and the proliferation, apoptosis, and superoxide dismutase (SOD) activity of PASMCs, prior to and following the ML171 treatment, were measured. NAC was able to decrease RVHI and other indicators (P<0.001). The mRNA expression of Nox1 and Nox4 in group M was significantly increased compared with group C (P<0.05), and NAC was able to significantly decrease the expression of these two factors in lung tissue (P<0.001). MCT‑PASMCs exhibited differences in Nox1 mRNA expression (P<0.001), and the total SOD activity was Nox1‑dependently increased (r=0.949; P<0.001). NAC was able to decrease Nox1‑derived reactive oxygen species in PASMCs, thereby improving PVR. Nox1 was able to increase SOD activity, thereby demonstrating its positive effect on the proliferation of MCT‑PASMCs.}, }
@article {pmid28848957, year = {2017}, author = {Zhou, S and Yeung, LWY and Forbes, MW and Mabury, S and Abbatt, JPD}, title = {Epoxide formation from heterogeneous oxidation of benzo[a]pyrene with gas-phase ozone and indoor air.}, journal = {Environmental science. Processes &amp; impacts}, volume = {19}, number = {10}, pages = {1292-1299}, doi = {10.1039/c7em00181a}, pmid = {28848957}, issn = {2050-7895}, mesh = {Air Pollution, Indoor/*analysis ; Animals ; Benzo(a)pyrene/*chemistry ; Chromatography, High Pressure Liquid ; DNA Adducts/analysis ; Epoxy Compounds/*analysis ; Humans ; *Models, Theoretical ; Molecular Structure ; Oxidation-Reduction ; Ozone/*chemistry ; Tandem Mass Spectrometry ; }, abstract = {The formation of two classes of epoxide products from the heterogeneous reaction of benzo[a]pyrene (BaP) with gas-phase ozone was demonstrated. BaP was coated on a Pyrex glass tube and oxidized with different concentrations of ozone. After oxidation, the epoxide products were derivatized by N-acetylcystein (NAC) and then analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results show that in addition to mono-epoxides, diol-epoxides were also formed. BaP exposed to genuine indoor air also produces mono- and diol-epoxides, having similar chromatograms to those produced by oxidation of BaP by low concentrations of ozone. Although it is well recognized that diol-epoxides are formed from BaP oxidation in the human body and that they exhibit carcinogenicity via formation of adducts with DNA, this is the first demonstration that such classes of compounds can be formed by abiotic heterogeneous oxidation.}, }
@article {pmid28840690, year = {2017}, author = {Mao, SH and Yu, HL and Wu, H and Wang, W and Li, XN}, title = {[Pro-inflammatory mechanism of lectin from Pinellia pedatisecta on macrophage].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {42}, number = {13}, pages = {2497-2502}, doi = {10.19540/j.cnki.cjcmm.20170516.001}, pmid = {28840690}, issn = {1001-5302}, mesh = {Animals ; Inflammasomes/*metabolism ; Interleukin-1beta/metabolism ; Lectins/*pharmacology ; Macrophages/*drug effects ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pinellia/*chemistry ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; }, abstract = {To investigate the mechanism of lectin from Pinellia pedatisecta(PPL) on macrophage-induced inflammation and its association with inflammatory corpuscles NLRP3. Lectin from P. pedatisecta was isolated and purified by gel chromatography, and its purity was analyzed by using SDS-PAGE gel electrophoresis. ELISA was used to investigate the effect of PPL on inflammatory cytokines released by macrophages, with IL-1β as indicators;and fluorescence probe DCFH-DA fluorometer was used to determine changes in active oxygen ROS of macrophages after application of lectin from P. pedatisecta.RAW264.7 cells were pre-treated with ROS inhibitor N-acetylcysteine (NAC) to investigate the effect on ROS and the release of inflammatory factor IL-1β from macrophages to research the relationship between them. The protein levels of NLRP3, Caspase-1 p20, ASC and TXNIP were determined by Western blot.The results showed that isolated and purified PPL could reach electrophoretic purity; PPL stimulated macrophages and induced the excessive release of ROS, leading to strong oxidative stress reaction, and the levels of intracellular inflammatory factorsIL-1β were significantly increased. NAC could inhibit PPL-induced ROS excessive production and significantly reduce the release of IL-1β. In addition, PPL could induce the increase in protein expression levels of Caspase-1 p20, NLRP3 and ASC, and significantly reduce TXNIP expression. The results showed that PPL could cause a strong oxidative stress response by stimulating macrophages, activate inflammatory corpuscles NLRP3, and result in large amount of IL-1β release. That is, PPL could lead to inflammatory cascade reaction by promoting the maturation and secretion of IL-1β through ROS-TXNIP-NLRP3-IL-1β signaling pathway.}, }
@article {pmid28840582, year = {2017}, author = {Goldstein, DS and Jinsmaa, Y and Sullivan, P and Sharabi, Y}, title = {N-Acetylcysteine Prevents the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells.}, journal = {Neurochemical research}, volume = {42}, number = {11}, pages = {3289-3295}, pmid = {28840582}, issn = {1573-6903}, support = {ZIA NS003033/ImNIH/Intramural NIH HHS/United States ; ZIA NS003125/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dopamine/*metabolism ; Dose-Response Relationship, Drug ; Monoamine Oxidase/*metabolism ; Monoamine Oxidase Inhibitors/*pharmacology ; Oxidation-Reduction/drug effects ; PC12 Cells ; Rats ; Selegiline/*pharmacology ; }, abstract = {The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease proposes that the deaminated dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is toxic to nigrostriatal dopaminergic neurons. Inhibiting monoamine oxidase (MAO) should therefore slow the disease progression; however, MAO inhibition increases spontaneous oxidation of dopamine, as indicated by increased 5-S-cysteinyl-dopamine (Cys-DA) levels, and the oxidation products may also be toxic. This study examined whether N-acetylcysteine (NAC), a precursor of the anti-oxidant glutathione, attenuates the increase in Cys-DA production during MAO inhibition. Rat pheochromocytoma PC12 cells were incubated with NAC, the MAO-B inhibitor selegiline, or both. Selegiline decreased DOPAL and increased Cys-DA levels (p < 0.0001 each). Co-incubation of NAC at pharmacologically relevant concentrations (1-10 µM) with selegiline (1 µM) attenuated or prevented the Cys-DA response to selegiline, without interfering with the selegiline-induced decrease in DOPAL production or inhibiting tyrosine hydroxylation. NAC therefore mitigates the increase in spontaneous oxidation of dopamine during MAO inhibition.}, }
@article {pmid28838338, year = {2017}, author = {Sarac, M and Bakal, U and Tartar, T and Kuloglu, T and Yardim, M and Artas, G and Aydin, S and Kazez, A}, title = {Ghrelin and NUCB2/Nesfatin-1 expression in unilateral testicular torsion-induced rats with and without N-acetylcysteine.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {63}, number = {7}, pages = {40-45}, doi = {10.14715/cmb/2017.63.7.7}, pmid = {28838338}, issn = {1165-158X}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism ; Calcium-Binding Proteins/*metabolism ; DNA-Binding Proteins/*metabolism ; Ghrelin/*metabolism ; Leydig Cells/drug effects/metabolism/pathology ; Lipids/blood ; Male ; Nerve Tissue Proteins/*metabolism ; Nucleobindins ; Oxidative Stress/drug effects ; Rats, Wistar ; Spermatic Cord Torsion/blood/*drug therapy/*metabolism/pathology ; }, abstract = {Testicular torsion (TT) is a common urological problem in the field of pediatric surgery. The degree and duration of torsion determines the degree of testicular damage; however, its effects on the expression of octanoylated ghrelin and nucleobindin 2 (NUCB2) /nesfatin-1 synthetized from testicular tissue remain unclear. We explored the effects of experimentally induced unilateral TT on serum and contralateral testicular tissue ghrelin and NUCB2/nesfatin-1 levels, and determined whether N-acetyl cysteine (NAS) treatment had any effects on their expression. A total of 42 Wistar Albino strain rats were divided into 7 groups: Group (G) I control, GII sham, GIII 12-hour torsion, GIV 12-hour torsion + detorsion + 100 mg/kg NAS, GV 24-hour torsion, GVI 24-hour torsion + detorsion + 100 mg/kg NAS, and GVII 100 mg/kg NAS. Octanoylated ghrelin and NUCB2/nesfatin-1 concentrations were evaluated in serum using the ELISA method and in testicular tissue with immunohistochemical methods. Immunoreactivity of octanoylated ghrelin significantly increased in GI compared to GIII, GV, and GVI (p<0.05). NUCB2/nesfatin-1 immunoreactivity increased in GV and GVIII relative to GI (p<0.05). In the 12-hour torsion group, a significant decrease in octanoylated ghrelin levels with NAS treatment was observed; however, in the 24-hour torsion group, a significant decrease was not observed. In the 12-hour torsion + NAS treatment group, a significant change was not observed in NUCB2/nesfatin-1 expression. Following 24-hour torsion, an increase in NUCB2/nesfatin-1 levels was observed, and NAS treatment did not reverse this increase. It was determined that increases in the expression of octanoylated ghrelin and NUCB2/nesfatin-1, the latter of which was a result of TT, reflect damage in this tissue. Importantly, NAS treatment could prevent this damage. Thus, there may be a clinical application for the combined use of NAS and octanoylated ghrelin in preventing TT-related infertility.}, }
@article {pmid28835936, year = {2017}, author = {Behrouzi Lak, T and Hajshafiha, M and Nanbakhsh, F and Oshnouei, S}, title = {N-acetyl cysteine in ovulation induction of PCOS women underwent intrauterine insemination: An RCT.}, journal = {International journal of reproductive biomedicine}, volume = {15}, number = {4}, pages = {203-208}, pmid = {28835936}, issn = {2476-4108}, abstract = {BACKGROUND: N-acetyl cysteine (NAC) was proposed as an adjuvant to clomiphene citrate for ovulation induction in patients with polycystic ovary syndrome (PCOS) without clomiphene citrate resistance.<br><br>OBJECTIVE: To evaluate the effect of NAC on pregnancy rate in PCOS patients who were candidates for intrauterine insemination.<br><br>MATERIALS AND METHODS: In this randomized clinical trial, 97 PCOS women aged 18-38 years were enrolled in two groups, randomly. For the case group (n=49), NAC (1.2 gr)+ clomiphene citrate (100 mg) + letrozole (5mg) were prescribed daily from the third day of menstruation cycle for five days. The control group (n=48) had the same drug regimen without NAC. In order to follicular development, recombinant human follicle stimulating hormone (r-hFSH; Gonal-F&#xae;) was injected on days of 7-11 menstrual cycles in all participants. When the follicle size was 18mm or more, 10000 IU human chorionic gonadotropin was injected intramuscular and the intrauterine insemination was performed after 34-36 hr.<br><br>RESULTS: There were not significant differences between study groups regarding mean endometrial thickness (p=0.14), the mean number of mature follicles (p=0.20), and the pregnancy rate (p=0.09).<br><br>CONCLUSION: NAC is ineffective in inducing or augmenting ovulation in PCOS patients who were candidates for intrauterine insemination and cannot be recommended as an adjuvant to CC in such patients.}, }
@article {pmid28834244, year = {2018}, author = {Riegger, J and Joos, H and Palm, HG and Friemert, B and Reichel, H and Ignatius, A and Brenner, RE}, title = {Striking a new path in reducing cartilage breakdown: combination of antioxidative therapy and chondroanabolic stimulation after blunt cartilage trauma.}, journal = {Journal of cellular and molecular medicine}, volume = {22}, number = {1}, pages = {77-88}, pmid = {28834244}, issn = {1582-4934}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Aged ; Aged, 80 and over ; Anabolic Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Biomarkers/metabolism ; Bone Morphogenetic Protein 7/pharmacology/therapeutic use ; Cartilage, Articular/*pathology ; Cell Survival/drug effects ; Chondrocytes/drug effects/metabolism/*pathology ; Collagen Type II/metabolism ; Cytoprotection/drug effects ; Extracellular Matrix/metabolism ; Fibroblast Growth Factors/pharmacology/therapeutic use ; Gene Expression Regulation/drug effects ; Humans ; Insulin-Like Growth Factor I/pharmacology/therapeutic use ; Middle Aged ; Wounds, Nonpenetrating/*drug therapy/pathology ; }, abstract = {Cartilage injury can trigger crucial pathomechanisms, including excessive cell death and expression of matrix-destructive enzymes, which contribute to the progression of a post-traumatic osteoarthritis (PTOA). With the intent to create a novel treatment strategy for alleviating trauma-induced cartilage damage, we complemented a promising antioxidative approach based on cell and chondroprotective N-acetyl cysteine (NAC) by chondroanabolic stimulation. Overall, three potential pro-anabolic growth factors - IGF-1, BMP7 and FGF18 - were tested comparatively with and without NAC in an ex vivo human cartilage trauma-model. For that purpose, full-thickness cartilage explants were subjected to a defined impact (0.59 J) and subsequently treated with the substances. Efficacy of the therapeutic approaches was evaluated by cell viability, as well as various catabolic and anabolic biomarkers, representing the present matrix turnover. Although monotherapy with NAC, FGF18 or BMP7 significantly prevented trauma-induced cell dead and breakdown of type II collagen, combination of NAC and one of the growth factors did not yield significant benefit as compared to NAC alone. IGF-1, which possessed only moderate cell protective and no chondroprotective qualities after cartilage trauma, even reduced NAC-mediated cell and chondroprotection. Despite significant promotion of type II collagen expression by IGF-1 and BMP7, addition of NAC completely suppressed this chondroanabolic effect. All in all, NAC and BMP7 emerged as best combination. As our findings indicate limited benefits of the simultaneous multidirectional therapy, a sequential application might circumvent adverse interferences, such as suppression of type II collagen biosynthesis, which was found to be reversed 7 days after NAC withdrawal.}, }
@article {pmid28833034, year = {2017}, author = {Tang, Y and Wang, B and Sun, X and Li, H and Ouyang, X and Wei, J and Dai, B and Zhang, Y and Li, X}, title = {Rheumatoid arthritis fibroblast-like synoviocytes co-cultured with PBMC increased peripheral CD4[+] CXCR5[+] ICOS[+] T cell numbers.}, journal = {Clinical and experimental immunology}, volume = {190}, number = {3}, pages = {384-393}, pmid = {28833034}, issn = {1365-2249}, mesh = {Acetylcysteine/pharmacology ; Adult ; Arthritis, Rheumatoid/*immunology/pathology ; CD4-Positive T-Lymphocytes/*immunology/pathology ; Coculture Techniques ; Female ; Fibroblasts/*immunology/pathology ; Humans ; Inducible T-Cell Co-Stimulator Protein/immunology ; Lymphocyte Count ; Male ; Middle Aged ; Reactive Oxygen Species/immunology ; Receptors, CXCR5/immunology ; Synovial Membrane/*immunology/pathology ; }, abstract = {'Circulating' T follicular helper cells (Tfh), characterized by their surface phenotypes CD4[+] chemokine receptor 5 (CXCR5)[+] inducible co-stimulatory molecule (ICOS)[+] , have been identified as the CD4[+] T cell subset specialized in supporting the activation, expansion and differentiation of B cells. Fibroblast-like synoviocytes (FLS) are critical in promoting inflammation and cartilage destruction in rheumatoid arthritis (RA), and the interaction between FLS and T cells is considered to facilitate FLS activation and T cell recruitment. However, it remains unknown whether RA-FLS co-cultured with activated peripheral blood mononuclear cells (PBMC) has immunoregulatory effects on peripheral Tfh. In the present study, we co-cultured RA-FLS with or without anti-CD3/CD28-stimulated PBMC. The results showed that RA-FLS co-cultured with stimulated PBMC could increase the numbers of CD4[+] CXCR5[+] ICOS[+] T cells of RA PBMC possibly via the production of interleukin (IL)-6, a critical cytokine involved in the differentiation of Tfh cells. We also observed increased reactive oxygen species (ROS) levels in the co-culture system of RA-FLS and PBMC. The percentage of CD4[+] CXCR5[+] ICOS[+] T cells was decreased when ROS production was inhibited by N-acetyl-L-cysteine (NAC), a specific inhibitor which can decrease ROS production. In addition, we showed that the higher levels of tumour necrosis factor (TNF)-α and IL-1β in the co-culture system and the blocking of TNF receptor 2 (TNF-R2) and IL-1β receptor (IL-1βR) both decreased the numbers of CD4[+] CXCR5[+] ICOS[+] T cells. Our study reveals a novel mechanistic insight into how the interaction of RA-FLS and PBMC participates in the RA pathogenesis, and also provides support for the biologicals application for RA.}, }
@article {pmid28831476, year = {2017}, author = {Huang, P and Zhang, YH and Zheng, XW and Liu, YJ and Zhang, H and Fang, L and Zhang, YW and Yang, C and Islam, K and Wang, C and Naranmandura, H}, title = {Phenylarsine oxide (PAO) induces apoptosis in HepG2 cells via ROS-mediated mitochondria and ER-stress dependent signaling pathways.}, journal = {Metallomics : integrated biometal science}, volume = {9}, number = {12}, pages = {1756-1764}, doi = {10.1039/c7mt00179g}, pmid = {28831476}, issn = {1756-591X}, mesh = {Apoptosis/drug effects ; Arsenicals/*pharmacology ; Carcinoma, Hepatocellular/drug therapy/metabolism/*pathology ; Endoplasmic Reticulum Stress/*drug effects ; Humans ; Liver Neoplasms/drug therapy/metabolism/*pathology ; Mitochondria/drug effects/metabolism/pathology ; Platelet Aggregation Inhibitors/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tumor Cells, Cultured ; }, abstract = {Arsenic trioxide (As2O3) is an old drug that has recently been reintroduced as a therapeutic agent for acute promyelocytic leukemia (APL). Although As2O3 is also applied to treat other types of cancer in vitro and in vivo, it has been reported that single agent As2O3 has poor efficacy against non-hematologic malignant cancers in clinical trials. Recently, a few reports have indicated that organic arsenic compounds can be a possible alternative for the treatment of As2O3-resistant cancers. In this study, we aimed to investigate whether the organic arsenic compound phenylarsine oxide (PAO) has potent cytotoxic effects against human hepatocellular carcinoma (HCC) HepG2 cells. Our results showed that PAO not only had a potent inhibitory effect on the proliferation of HepG2 cells but also activated apoptosis-related proteins (e.g., caspase-3 and -9 and poly-ADP ribose polymerase) in a dose- and time-dependent manner. Furthermore, intracellular ROS were specifically accumulated in the mitochondria and endoplasmic reticulum (ER) after exposure to PAO, implying that they are the target organelles for PAO-induced cytotoxicity. Additionally, when the cells were pretreated with antioxidant N-acetylcysteine (NAC), apoptosis and ER-stress were attenuated significantly, suggesting that induction of apoptosis and cell death probably occurs through the ROS-mediated mitochondria and ER-stress dependent signaling pathways.}, }
@article {pmid28830914, year = {2017}, author = {Gleixner, AM and Hutchison, DF and Sannino, S and Bhatia, TN and Leak, LC and Flaherty, PT and Wipf, P and Brodsky, JL and Leak, RK}, title = {N-Acetyl-l-Cysteine Protects Astrocytes against Proteotoxicity without Recourse to Glutathione.}, journal = {Molecular pharmacology}, volume = {92}, number = {5}, pages = {564-575}, pmid = {28830914}, issn = {1521-0111}, support = {P30 DK079307/DK/NIDDK NIH HHS/United States ; P50 GM067082/GM/NIGMS NIH HHS/United States ; R03 NS088395/NS/NINDS NIH HHS/United States ; R15 NS093539/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Astrocytes/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Cytoprotection/*drug effects/physiology ; Dose-Response Relationship, Drug ; Female ; *Glutathione ; HSP70 Heat-Shock Proteins/antagonists &amp; inhibitors/physiology ; Leupeptins/toxicity ; Male ; Protein Folding/*drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {N-acetyl-l-cysteine (NAC) exhibits protective properties in brain injury models and has undergone a number of clinical trials. Most studies of NAC have focused on neurons. However, neuroprotection may be complemented by the protection of astrocytes because healthier astrocytes can better support the viability of neurons. Here, we show that NAC can protect astrocytes against protein misfolding stress (proteotoxicity), the hallmark of neurodegenerative disorders. Although NAC is thought to be a glutathione precursor, NAC protected primary astrocytes from the toxicity of the proteasome inhibitor MG132 without eliciting any increase in glutathione. Furthermore, glutathione depletion failed to attenuate the protective effects of NAC. MG132 elicited a robust increase in the folding chaperone heat shock protein 70 (Hsp70), and NAC mitigated this effect. Nevertheless, three independent inhibitors of Hsp70 function ablated the protective effects of NAC, suggesting that NAC may help preserve Hsp70 chaperone activity and improve protein quality control without need for Hsp70 induction. Consistent with this view, NAC abolished an increase in ubiquitinated proteins in MG132-treated astrocytes. However, NAC did not affect the loss of proteasome activity in response to MG132, demonstrating that it boosted protein homeostasis and cell viability without directly interfering with the efficacy of this proteasome inhibitor. The thiol-containing molecules l-cysteine and d-cysteine both mimicked the protective effects of NAC, whereas the thiol-lacking molecule N-acetyl-S-methyl-l-cysteine failed to exert protection or blunt the rise in ubiquitinated proteins. Collectively, these findings suggest that the thiol group in NAC is required for its effects on glial viability and protein quality control.}, }
@article {pmid28828308, year = {2017}, author = {Mahakalkar, SM and Nagrale, D and Gaur, S and Urade, C and Murhar, B and Turankar, A}, title = {N-acetylcysteine as an add-on to Directly Observed Therapy Short-I therapy in fresh pulmonary tuberculosis patients: A randomized, placebo-controlled, double-blinded study.}, journal = {Perspectives in clinical research}, volume = {8}, number = {3}, pages = {132-136}, pmid = {28828308}, issn = {2229-3485}, abstract = {PURPOSE: Pulmonary tuberculosis is associated with increased oxidative stress, enhanced lipid peroxidation, and decreased glutathione (GSH) levels. N-acetylcysteine (NAC) effectively increases GSH levels, improves lipid peroxidation, and decreases reactive oxygen species levels as reported by earlier studies. Hence, we planned to clinically evaluate the effect of NAC as add-on to Directly Observed Therapy Short-I (DOTS-I) regimen on treatment outcome in PTB with the objectives to study the effect of NAC as an add-on to intensive phase of DOTS-I (2 months) on sputum conversion, radiological improvement, GSH peroxidase (GPx) level, and weight and immunological response compared to placebo add-on at the end of 2 and 6 months.<br><br>MATERIALS AND METHODS: This was a design-prospective, randomized, parallel group, add-on design, placebo-controlled, double-blinded, 24-week study. Parameters studied were sputum acid-fast bacillus examination, radiological improvements, GPx level, weight, and Mantoux response. NAC/placebo was added to DOTS Category I in intensive phase.<br><br>RESULTS: Totally 48 patients completed the study. In NAC group, 23 patients achieved sputum negativity in 3 weeks while 14 patients in PLACEBO group. There was a significant clearing of infiltration and reduction in cavity size in NAC group compared to placebo at 2 months. At 2 and 6 months, NAC significantly raised GPx level and body weight. In 2 months, the patients with Mix &#x2264;5 became Mx positive (100%) in NAC group while none in placebo group.<br><br>CONCLUSION: NAC addition to DOTS-I significantly brings about faster sputum negativity, improves radiological response, weight, raises serum GPx level, and rectifies the deregulated immune response. Thus, NAC may be a useful adjuvant to DOTS in PTB.}, }
@article {pmid28827139, year = {2017}, author = {Wei, Z and Caty, J and Whitson, J and Zhang, AD and Srinivasagan, R and Kavanagh, TJ and Yan, H and Fan, X}, title = {Reduced Glutathione Level Promotes Epithelial-Mesenchymal Transition in Lens Epithelial Cells via a Wnt/β-Catenin-Mediated Pathway: Relevance for Cataract Therapy.}, journal = {The American journal of pathology}, volume = {187}, number = {11}, pages = {2399-2412}, pmid = {28827139}, issn = {1525-2191}, support = {P30 EY011373/EY/NEI NIH HHS/United States ; R21 EY024553/EY/NEI NIH HHS/United States ; T32 EY024236/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Cataract/metabolism/*therapy ; Cell Proliferation/physiology ; Epithelial Cells/*metabolism ; Epithelial-Mesenchymal Transition/*physiology ; Glutathione/*metabolism ; Humans ; Lens, Crystalline/*metabolism ; Mice ; Oxidative Stress/*physiology ; Transforming Growth Factor beta/metabolism ; Wnt Signaling Pathway/physiology ; beta Catenin/metabolism ; }, abstract = {The epithelial-mesenchymal transition (EMT) process plays a pivotal role in the pathogenesis of posterior capsular opacification because of remnant lens epithelial cell proliferation, migration, and transformation after cataract surgery. The latter, we hypothesize, may result in posterior capsule wrinkling and opacification because of a profound change in the lens growth environment via a 1000-fold reduction of extracellular glutathione (GSH) levels. To test this hypothesis, we investigated the EMT process in cell culture and GSH biosynthesis deficiency mouse models. Our data indicate a dramatic increase of pro-EMT markers, such as type I collagen, α-smooth muscle actin, vimentin, and fibronectin, under conditions of lens GSH depletion. Further study suggests that decreased GSH triggers the Wnt/β-catenin signal transduction pathway, independent of transforming growth factor-β. Equally important, the antioxidants N-acetyl cysteine and GSH ethyl ester could significantly attenuate the EMT signaling stimulated by decreased GSH levels. These findings were further confirmed by mock cataract surgery in both gamma glutamyl-cysteine ligase, catalytic subunit, and gamma glutamyl-cysteine ligase, modifier subunit, knockout mouse models. Remarkably, increased EMT marker expression, β-catenin activation, and translocation into the nucleus were found in both knockout mice compared with the wild type, and such increased expression could be significantly attenuated by N-acetyl cysteine or GSH ethyl ester treatment. This study, for the first time we believe, links oxidative stress to lens fibrosis and posterior capsular opacification formation via EMT-mediated mechanisms.}, }
@article {pmid28826881, year = {2017}, author = {Chiesa, E and Monti, L and Paganini, C and Dorati, R and Conti, B and Modena, T and Rossi, A and Genta, I}, title = {Polyethylene Glycol-Poly-Lactide-co-Glycolide Block Copolymer-Based Nanoparticles as a Potential Tool for Off-Label Use of N-Acetylcysteine in the Treatment of Diastrophic Dysplasia.}, journal = {Journal of pharmaceutical sciences}, volume = {106}, number = {12}, pages = {3631-3641}, doi = {10.1016/j.xphs.2017.08.004}, pmid = {28826881}, issn = {1520-6017}, mesh = {Acetylcysteine/*chemistry/*pharmacology ; Animals ; Drug Carriers/chemistry ; Dwarfism/*drug therapy ; Mice ; Mice, Inbred C57BL ; Nanoparticles/administration &amp; dosage/*chemistry ; Off-Label Use ; Particle Size ; Polyesters/*chemistry ; Polyethylene Glycols/*chemistry ; Polymers/chemistry ; Tissue Distribution ; }, abstract = {Potential off-label therapeutic role of N-acetylcysteine (N-Ac) was recently demonstrated in the treatment of diastrophic dysplasia (DTD) using mutant mice; its main drawback is the rapid clearance from blood due to the liver metabolism. Our goal was to investigate the potential of polyethylene glycol polylactide-co-glycolide block copolymer (PLGA-PEG)-based nanoparticles (NPs) in order to improve in vivo biodistribution performances and N-Ac pharmacokinetic profile after subcutaneous administration in mice. Results suggest that N-Ac can be effectively loaded into NPs (about 99 μg/mg NPs) using a suitably optimized nanoprecipitation method. Thanks to the good physical characteristics (mean diameter <100 nm, zeta potential about -8 mV) NPs can reach skeletal tissue in particular femoral head and proximal tibia epiphysis at the sixth hour after injection, remaining in the tissues till 24 h. Furthermore, pharmacokinetic study revealed a sustained N-Ac concentration in plasma with a peak concentration of 2.48 ± 1.72 μM at the 24th hour after injection. Overall, results highlight the actual interest of N-Ac-loaded PLGA-PEG NPs as useful platform for N-Ac parenteral administration.}, }
@article {pmid28819717, year = {2018}, author = {Nour-Eldein, NH and Hassanin, EA and El-Sayed, WM}, title = {Mitigation of Acute Aluminum Toxicity by Sodium Selenite and N-Acetylcysteine in Adult Male Rats.}, journal = {Biological trace element research}, volume = {183}, number = {1}, pages = {128-137}, doi = {10.1007/s12011-017-1126-8}, pmid = {28819717}, issn = {1559-0720}, mesh = {Acetylcysteine/*pharmacology ; Aluminum/toxicity ; Aluminum Chloride ; Aluminum Compounds/*toxicity ; Animals ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism ; Chlorides/*toxicity ; *Kidney Diseases/chemically induced/drug therapy/metabolism ; Lipid Peroxidation/*drug effects ; Male ; Rats ; Rats, Wistar ; Sodium Selenite/*pharmacology ; }, abstract = {The objective of this study is to investigate the toxic effects of aluminum and the potential alleviation of selenite and N-acetylcysteine (NAC) on this toxicity. Acute aluminum toxicity was induced by intraperitoneal (i.p.) injection of AlCl3 (30 mg Al[3+]/kg) for four consecutive days. Al[3+] damaged the synthetic capability and regeneration power of liver cells and induced inflammation. It also damaged the kidney and disturbed the lipid profile enhancing the total cholesterol level and LDL-cholesterol level increasing the risks of atherosclerosis. Al[3+] reduced the cellular antioxidant milieu typified by the decrease in reduced glutathione, vitamin E, and four antioxidant enzymes and induced lipid peroxidation (LPO). Selenite at 1 mg Se/kg and NAC at 150 mg/kg injected either simultaneously with or after Al[3+] mitigated most of these damaging effects probably by the virtue of scavenging the free radicals, binding aluminum and stimulating its excretion and reducing its bioavailability, bolstering the endogenous antioxidant defense systems, stabilizing the cell membrane, and preventing LPO. The beneficial effects of selenite and NAC against aluminum toxicity were also confirmed by the light and electron histopathology study. There were no significant differences between the two regimens used (protection and therapeutic) in the current study probably due to the short time of exposure, and the abrogation of Al[3+] toxicity offered by selenite was better than that provided by NAC on the histopathology level.}, }
@article {pmid28819639, year = {2017}, author = {Phensy, A and Driskill, C and Lindquist, K and Guo, L and Jeevakumar, V and Fowler, B and Du, H and Kroener, S}, title = {Antioxidant Treatment in Male Mice Prevents Mitochondrial and Synaptic Changes in an NMDA Receptor Dysfunction Model of Schizophrenia.}, journal = {eNeuro}, volume = {4}, number = {4}, pages = {}, pmid = {28819639}, issn = {2373-2822}, support = {R01 AG053588/AG/NIA NIH HHS/United States ; R00 AG037716/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Antioxidants/*therapeutic use ; Disease Models, Animal ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Postsynaptic Potentials/drug effects/genetics ; Glutamate Decarboxylase/genetics/metabolism ; Glutathione/metabolism ; Green Fluorescent Proteins/genetics/metabolism ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Transgenic ; Mitochondria/*drug effects/metabolism ; Parvalbumins/metabolism ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Schizophrenia/*complications/genetics ; Superoxides/metabolism ; Synapses/*drug effects ; }, abstract = {Glutamate theories of schizophrenia suggest that the disease is associated with a loss of NMDA receptors, specifically on GABAergic parvalbumin-expressing interneurons (PVIs), leading to changes in the excitation-inhibition balance in the prefrontal cortex (PFC). Oxidative stress contributes to the loss of PVI and the development of schizophrenia. Here, we investigated whether the glutathione precursor N-acetyl cysteine (NAC) can prevent changes in synaptic transmission at pyramidal cells and PVIs that result from developmental NMDAR blockade and how these changes are related to mitochondrial dysfunction in the PFCs of mice. Perinatal treatment with ketamine induced persistent changes in the reduced glutathione/oxidized glutathione (glutathione disulfide) ratio in the medial PFC, indicating long-lasting increases in oxidative stress. Perinatal ketamine treatment also reduced parvalbumin expression, and it induced a decline in mitochondrial membrane potential, as well as elevations in mitochondrial superoxide levels. At the level of synaptic function ketamine reduced inhibition onto layer 2/3 pyramidal cells and increased excitatory drive onto PVI, indicating long-lasting disruptions in the excitation-inhibition balance. These changes were accompanied by layer-specific alterations in NMDAR function in PVIs. All of these changes were mitigated by coadministration of NAC. In addition, NAC given only during late adolescence was also able to restore normal mitochondria function and inhibition at pyramidal cells. These results show that ketamine-induced alterations in PFC physiology correlate with cell type-specific changes in mitochondria function. The ability of NAC to prevent or restore these changes supports the usefulness of antioxidant supplementation in the treatment of schizophrenia.}, }
@article {pmid28816938, year = {2017}, author = {Chen, H and Li, Y and Zhu, Y and Wu, L and Meng, J and Lin, N and Yang, D and Li, M and Ding, W and Tong, X and Su, Q}, title = {Advanced glycation end products promote ChREBP expression and cell proliferation in liver cancer cells by increasing reactive oxygen species.}, journal = {Medicine}, volume = {96}, number = {33}, pages = {e7456}, pmid = {28816938}, issn = {1536-5964}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/*biosynthesis ; Carcinoma, Hepatocellular/*metabolism ; Cell Proliferation ; Cell Survival ; Glycation End Products, Advanced/*pharmacokinetics ; Humans ; Liver Neoplasms/*metabolism ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Transcription Factors/metabolism ; Tumor Cells, Cultured ; }, abstract = {The aim of the study was to elucidate the mechanism by which advanced glycation end products (AGEs) promote cell proliferation in liver cancer cells.We treated liver cancer HepG2 cells with 200 mg/L AGEs or bovine serum albumin (BSA) and assayed for cell viability, cell cycle, and apoptosis. We performed real-time PCR and Western blot analysis for RNA and protein levels of carbohydrate responsive element-binding protein (ChREBP) in AGEs- or BSA-treated HepG2 cells. We analyzed the level of reactive oxygen species (ROS) in HepG2 cells treated with AGEs or BSA.We found that increased S-phase cell percentage and decreased apoptosis contributed to AGEs-induced liver cancer cell proliferation. Real-time PCR and Western blot analysis showed that AGEs stimulated RNA and protein levels of ChREBP, a transcription factor promoting glycolysis and maintaining cell proliferation in liver cancer cells. Intriguingly, the level of ROS was higher in AGEs-treated liver cancer cells. Treating liver cancer cells with antioxidant N-acetyl cystein (NAC) partly blocked AGEs-induced ChREBP expression and cell proliferation.Our results suggest that the AGEs-ROS-ChREBP pathway plays a critical role in promoting ChREBP expression and liver cancer cell proliferation.}, }
@article {pmid28815354, year = {2018}, author = {Guan, Y and Tan, Y and Liu, W and Yang, J and Wang, D and Pan, D and Sun, Y and Zheng, C}, title = {NF-E2-Related Factor 2 Suppresses Intestinal Fibrosis by Inhibiting Reactive Oxygen Species-Dependent TGF-β1/SMADs Pathway.}, journal = {Digestive diseases and sciences}, volume = {63}, number = {2}, pages = {366-380}, pmid = {28815354}, issn = {1573-2568}, support = {2013225303//Science and Technology Program of Liaoning Province/International ; }, mesh = {Animals ; Cell Line ; Colitis/chemically induced/drug therapy ; Female ; Fibroblasts ; Fibrosis/*metabolism/prevention &amp; control ; Gene Expression Regulation/drug effects/physiology ; Humans ; Hydroquinones/pharmacology ; Mice ; Mice, Inbred BALB C ; NF-E2-Related Factor 2/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Smad Proteins/genetics/*metabolism ; Transforming Growth Factor beta1/genetics/*metabolism ; Trinitrobenzenesulfonic Acid/toxicity ; }, abstract = {BACKGROUND AND AIMS: This study aimed to evaluate the antifibrotic effects of NF-E2-Related Factor 2 (Nrf2) on intestinal fibrosis. Intestinal fibrosis is a common complication of Crohn's disease; however, its mechanism of intestinal fibrosis is largely unclear.<br><br>METHODS: BALB/c mice received 2,4,6-trinitrobenzene sulfonic acid weekly via intrarectal injections to induce chronic fibrotic colitis. They also diet containing received 1% (w/w) tert-butylhydroquinone (tBHQ), which is an agonist of Nrf2. Human intestinal fibroblasts (CCD-18Co cells) were pretreated with tBHQ or si-Nrf2 followed by stimulation with transforming growth factor-&#x3b2;1 (TGF-&#x3b2;1), which transformed the cells into myofibroblasts. The main fibrosis markers such as &#x3b1;-smooth muscle actin, collagen I, tissue inhibitor of metalloproteinase-1, and TGF-&#x3b2;1/SMADs signaling pathway were detected by quantitative real-time RT-PCR, immunohistochemical analysis, and Western blot analysis. Levels of cellular reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate.<br><br>RESULTS: tBHQ suppressed the intestinal fibrosis through the TGF-&#x3b2;1/SMADs signaling pathway in TNBS-induced colitis and CCD-18Co cells. Moreover, Nrf2 knockdown enhanced the TGF-&#x3b2;1-induced differentiation of CCD-18Co cells. ROS significantly increased in TGF-&#x3b2;1-stimulated CCD-18Co cells. Pretreatment with H2O2, the primary component of ROS, was demonstrated to block the effect of tBHQ on reducing the expression of TGF-&#x3b2;1. Moreover, scavenging ROS by N-acetyl cysteine could inhibit the increasing expression of TGF-&#x3b2;1 promoted by Nrf2 knockdown.<br><br>CONCLUSIONS: The results suggested that Nrf2 suppressed intestinal fibrosis by inhibiting ROS/TGF-&#x3b2;1/SMADs pathway in vivo and in vitro.}, }
@article {pmid28814068, year = {2017}, author = {Uh, ST and Koo, SM and Kim, Y and Kim, K and Park, S and Jang, AS and Kim, D and Kim, YH and Park, CS}, title = {The activation of NLRP3-inflammsome by stimulation of diesel exhaust particles in lung tissues from emphysema model and RAW 264.7 cell line.}, journal = {The Korean journal of internal medicine}, volume = {32}, number = {5}, pages = {865-874}, pmid = {28814068}, issn = {2005-6648}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Caspase 1/metabolism ; Cigarette Smoking/adverse effects ; Disease Models, Animal ; Female ; Inflammasomes/drug effects/immunology/*metabolism ; Interleukin-1beta/metabolism ; Lung/drug effects/immunology/*metabolism ; Macrophages/drug effects/immunology/*metabolism ; Mice ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein/immunology/*metabolism ; Pancreatic Elastase ; *Particulate Matter ; Pulmonary Emphysema/chemically induced/immunology/*metabolism/prevention &amp; control ; RAW 264.7 Cells ; Signal Transduction ; Time Factors ; *Vehicle Emissions ; }, abstract = {BACKGROUND/AIMS: Diesel exhaust particles (DEPs) lead to elevation of reactive oxygen species, which can activate the nucleotide-binding oligomerization domain-like receptor (NLR) family members containing the pyrin domain 3 (NLRP3)-inf lammasome. In this study, we elucidated whether NLRP3 -inf lammasome is activated by DEPs and whether antioxidants (N-acetylcysteine [NAC]) could inhibit such activation.<br><br>METHODS: RAW 264.7 cells and ex vivo lung tissues explants obtained from elastase-induced emphysema animal models were stimulated with cigarette smoking extract (CSE), DEPs, and lipopolysaccharide, and levels of interleukin-1&#x3b2; (IL-1&#x3b2;), caspase-1 and nucleotide-binding oligomerization domain-like receptor (NLR) family members containing the pyrin domain (NLRP3)-inflammasome were assessed by Western blotting and immunohistochemistry.<br><br>RESULTS: NAC and caspase-1 inhibitor suppressed CSE- and DEP-induced secretion of IL-1&#x3b2; in RAW 264.7 cells. The expression levels of the NLRP3-inflammasome and caspase-1 were upregulated in RAW 264.7 cells by stimulation with CSE and DEPs and were inhibited by NAC. CSE and DEPs increased the secretion of IL-1&#x3b2; in lung tissues from both the normal and elastase-induced emphysema groups. The secretion of IL-1&#x3b2; by CSE and DEPs was increased in the elastin-induced emphysema group more than that in the normal group (CSE: 309 &#xb1; 19 pg/mL vs. 151 &#xb1; 13 pg/mL, respectively, p < 0.05; DEP: 350 &#xb1; 24 pg/mL vs. 281 &#xb1; 15 pg/mL, respectively, p < 0.05). NAC inhibited CSE- and DEP-induced IL-1&#x3b2; secretion in both the normal and elastase-induced emphysema groups. NLRP3-inflammasome expression as determined by immunohistochemistry was increased by CSE and DEPs in both the normal and elastin-induced emphysema groups, and was suppressed by NAC.<br><br>CONCLUSIONS: The NLRP3-inf lammasome is activated by DEPs in ex vivo tissue explants from elastase-induced emphysema animal model, and this activation is inhibited by NAC.}, }
@article {pmid28813624, year = {2017}, author = {Murley, JS and Miller, RC and Weichselbaum, RR and Grdina, DJ}, title = {TP53 Mutational Status and ROS Effect the Expression of the Survivin-Associated Radio-Adaptive Response.}, journal = {Radiation research}, volume = {188}, number = {5}, pages = {579-590}, pmid = {28813624}, issn = {1938-5404}, support = {R01 CA132998/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Dose-Response Relationship, Radiation ; Gene Expression Regulation/drug effects/*radiation effects ; Genomics ; HCT116 Cells ; Humans ; Inhibitor of Apoptosis Proteins/*metabolism ; Mutation ; Radiation Tolerance/drug effects/*genetics ; Reactive Oxygen Species/*metabolism ; Survivin ; Tumor Suppressor Protein p53/*genetics ; }, abstract = {A survivin-associated radio-adaptive response, characterized by increased radiation resistance or sensitization, was induced by exposure to 5 mGy of ionizing radiation and was correlated to the TP53 mutational status of exposed cells. Ten human cancer lines were investigated: colorectal carcinomas HCT116 and RKO [TP53 wild-type (WT)] and their respective TP53 null isogenic lines; breast adenocarcinomas MCF7 (TP53 WT) and MDA-MB-231 (TP53 Mut); lung carcinomas A549 (TP53 WT) and NCI-H1975 (TP53 Mut); and pancreatic carcinomas Hs766T (TP53 WT) and Panc-1 (TP53 Mut). Radiation induced (5 mGy) changes in the subsequent responses to 2 Gy in a multi-dose paradigm. Effects on radiation sensitivity were associated with changes in survivin's intracellular translocation to the cytoplasm (TP53 WT) or nucleus (TP53 Mut). Survival responses were determined using a colony forming assay. Intracellular localization of survivin was determined by ELISA and correlated with survival response. Two 2 Gy doses had minimal effects on the intracellular translocation of survivin. When preceded 15 min earlier by a 5 mGy exposure, survivin translocated to the cytoplasm in all of the TP53 WT cell lines, and to the nuclei in the TP53 null and Mut cells. All TP53 WT cells were protected (P < 0.001) by 5 mGy exposures, while Mut cells were sensitized (P < 0.001). HCT116 and RKO TP53 WT cells were admixed with their respective isogenic TP53 null counterparts in different proportions: 75% to 25%, 50% to 50% and 25% to 75%, respectively. All mixed confluent cultures expressed enhanced radio-sensitization (P ≤ 0.047) characteristic of TP53 Mut cells, which could be inhibited by their exposure to the antioxidant N-acetyl-l-cysteine (NAC) indicating a role for intercellular signaling by reactive oxygen species (ROS). ROS signaling in propagating the survivin-mediated response is involved in both intra- and intercellular communication processes.}, }
@article {pmid28812231, year = {2018}, author = {Palomares, T and Cordero, M and Bruzos-Cidon, C and Torrecilla, M and Ugedo, L and Alonso-Varona, A}, title = {The Neuroprotective Effect of Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cells is Impaired by N-acetyl Cysteine Supplementation.}, journal = {Molecular neurobiology}, volume = {55}, number = {1}, pages = {13-25}, pmid = {28812231}, issn = {1559-1182}, mesh = {Acetylcysteine/*toxicity ; Adipocytes/*drug effects/physiology ; Cell Differentiation/drug effects/physiology ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Coculture Techniques/methods ; Culture Media, Conditioned/*pharmacology ; Humans ; Mesenchymal Stem Cells/*drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects/physiology ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {Oxidative stress is a common feature in neurodegenerative diseases associated with neuroinflammation, and therefore, has been proposed as a key target for novel therapies for these diseases. Recently, adipose-derived stem cell (ASC)-based cell therapy has emerged as a novel strategy for neuroprotection. In this study, we evaluate the therapeutic role of ASC-conditioned medium (ASC-CM) against H2O2-induced neurotoxicity in a new in vitro model of ec23/brain-derived neurotrophic factor (BDNF)-differentiated human SH-SY5Y neuron-like cells (SH-SY5Yd). In the presence of ASC-CM, stressed SH-SY5Yd cells recover normal axonal morphology (with an almost complete absence of H2O2-induced axonal beading), electrophysiological features, and cell viability. This beneficial effect of ASC-CM was associated with its antioxidant capacity and the presence of growth factors, namely, BDNF, glial cell line-derived neurotrophic factor, and transforming growth factor β1. Moreover, the neuroprotective effect of ASC-CM was very similar to that obtained from treatment with BDNF, an essential factor for SH-SY5Yd cell survival. Importantly, we also found that the addition of the antioxidant agent N-acetyl cysteine to ASC-CM abolished its restorative effect; this was associated with a strong reduction in reactive oxygen species (ROS), in contrast to the moderate decrease in ROS produced by ASC-CM alone. These results suggest that neuronal restorative effect of ASC-CM is associated with not only the release of essential neurotrophic factors, but also the maintenance of an appropriate redox state to preserve neuronal function.}, }
@article {pmid28812210, year = {2018}, author = {Wang, B and Tang, Y and Sun, X and Ouyang, X and Li, H and Wei, J and Zhang, Y and Li, X}, title = {Increased IL-6 expression on THP-1 by IL-34 stimulation up-regulated rheumatoid arthritis Th17 cells.}, journal = {Clinical rheumatology}, volume = {37}, number = {1}, pages = {127-137}, pmid = {28812210}, issn = {1434-9949}, support = {81373214//National Natural Science Foundation of China/ ; 81671606//National Natural Science Foundation of China/ ; 2015010//Special Grant for Translational Medicine/ ; }, mesh = {Acetylcysteine/pharmacology ; Arthritis, Rheumatoid/*metabolism ; Cell Line ; Coculture Techniques ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Interleukin-6/*metabolism ; Interleukins/*pharmacology ; Leukocytes, Mononuclear/drug effects/metabolism ; Male ; Middle Aged ; Monocytes/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Th17 Cells/drug effects/*metabolism ; Up-Regulation/drug effects ; }, abstract = {IL-34 is a pleiotropic cytokine, which is a key regulator of monocytes/macrophages and might participate in the pathogenesis of RA. In this study, we aimed to explore the effect of IL-34 on the monocyte-like cell line THP-1 and the quantitative variation of Th17 cells in THP-1 and RA CD4[+]T cells coculture system. CD4[+]T cells were purified from RA PBMC using immunomagnetic beads. THP-1 were cultured with RA CD4[+]T cells. The frequency of Th17 cells was determined by FACS. Fluorscence indensity and expression of ROS were detected by FACS and cell staining, respectively. The expression of IL-6, IL-23, IL-21, TNF-α and IL-1β in the coculture supernatants were detected by ELISA. We found that CSF-1R was constitutively expressed on peripheral monocytes as well as THP-1, but not on the T/B cells. IL-34-CSF-1R binding could activate THP-1 to secret IL-6. IL-34 could up-regulate the numbers of Th17 cells in coculture system, which was possibly via the production of IL-6. We further observed ROS levels were increased in the coculture system. The percentage of Th17 cells was reduced when ROS production was inhibited by NAC, a specific inhibitor of ROS production. In addition, TNFRII antagonist but not IL-1βR antagonist could restrict the production of ROS, expression of IL-6 and generation of Th17 cells. In conclusion, IL-34-stimulated THP-1 can produce higher levels of ROS, which promoted IL-6 secretion and up-regulated Th17 cells. Our study suggests a novel mechanistic insight into how the interaction of IL-34-stimulated monocytes and CD4[+]T cells participates in the RA pathogenesis.}, }
@article {pmid28811603, year = {2017}, author = {Liao, HY and Kao, CM and Yao, CL and Chiu, PW and Yao, CC and Chen, SC}, title = {2,4,6-Trinitrotoluene Induces Apoptosis via ROS-Regulated Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in HepG2 and Hep3B Cells.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {8148}, pmid = {28811603}, issn = {2045-2322}, mesh = {Apoptosis/*drug effects/genetics ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Damage ; *Endoplasmic Reticulum Stress/genetics ; Gene Expression Profiling ; Humans ; Mitochondria/*drug effects/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Transcription Factor CHOP/genetics/metabolism ; Transcriptome ; Trinitrotoluene/*pharmacology ; }, abstract = {2,4,6-trinitrotoluene (TNT) has been reported to cause numerous adverse effects. However, the detailed molecular mechanisms underlying TNT-induced liver toxicity need to be elucidated. In this study, we used HepG2 (p53wt) and Hep3B (p53null) cell lines to investigate the cytotoxic effects of TNT. At first, we found that TNT significantly decreased cell viability and induced DNA damage. Thereafter, through transcriptomic analysis, we observed that the diverse biological functions affected included mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Mitochondrial dysfunction was evidenced by the loss of mitochondrial membrane potential, increased expression of cleaved-caspase-9&amp;-3 and increased caspase-3/7 activity, indicating that apoptosis had occurred. In addition, the expressions of some ER stress-related proteins had increased. Next, we investigated the role of reactive oxygen species (ROS) in TNT-induced cellular toxicity. The levels of DNA damage, mitochondrial dysfunction, ER stress and apoptosis were alleviated when the cells were pretreated with N-acetyl-cysteine (NAC). These results indicated that TNT caused the ROS dependent apoptosis via ER stress and mitochondrial dysfunction. Finally, the cells transfected with CHOP siRNA significantly reversed the TNT-induced apoptosis, which indicated that ER stress led to apoptosis. Overall, we examined TNT-induced apoptosis via ROS dependent mitochondrial dysfunction and ER stress in HepG2 and Hep3B cells.}, }
@article {pmid28810622, year = {2017}, author = {Li, JX and Jin, EZ and Yu, LH and Li, Y and Liu, NN and Dong, YM and Li, X and Li, XQ}, title = {Oral N-acetylcysteine for prophylaxis of contrast-induced nephropathy in patients following coronary angioplasty: A meta-analysis.}, journal = {Experimental and therapeutic medicine}, volume = {14}, number = {2}, pages = {1568-1576}, pmid = {28810622}, issn = {1792-0981}, abstract = {It is acknowledged that contrast-induced nephropathy (CIN) is a common cause of acute renal insufficiency after cardiac catheterization and affects mortality and morbidity. To date, it is unknown whether oral N-acetylcysteine (NAC) is able to prevent contrast-induced nephropathy (CIN) in patients undergoing coronary angioplasty. A meta-analysis of randomized controlled trials was performed to assess the effects of NAC in the prevention of CIN in patients following coronary angioplasty. A total of 19 studies published prior to January 2015 that investigated the efficacy of oral NAC for the prevention of CIN were collected from Medline, Cochrane and Embase databases and conference proceedings from cardiology and nephrology meetings. The primary point of investigation was CIN, and the secondary points were renal failure requiring dialysis, mortality and length of hospitalization. The meta-analysis was performed using fixed- or random-effect models according to heterogeneity. Up to January 2015, 19 randomized placebo-controlled clinical trials met the inclusion criteria for the meta-analysis, including 4,514 patients. The pooled data showed that oral NAC did not reduce the CIN incidence [relative risk 0.84, 95% confidence interval (CI) 0.65-1.10; P=0.20], without heterogeneity among trials (I[2]=29%). Thus, the present meta-analysis suggests that oral NAC therapy is not effective as an alternative treatment to prevent CIN in patients following angioplasty. Further high quality randomized clinical controlled trials are required to confirm the usage and availability of this treatment.}, }
@article {pmid28810523, year = {2017}, author = {Zuo, J and Dou, DY and Wang, HF and Zhu, YH and Li, Y and Luan, JJ}, title = {Reactive oxygen species mediated NF-κB/p38 feedback loop implicated in proliferation inhibition of HFLS-RA cells induced by 1,7-dihydroxy-3,4-dimethoxyxanthone.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {94}, number = {}, pages = {1002-1009}, doi = {10.1016/j.biopha.2017.07.164}, pmid = {28810523}, issn = {1950-6007}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Cell Proliferation/*drug effects ; Cells, Cultured ; Fibroblasts/drug effects/metabolism ; Humans ; NF-kappa B/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Synovial Membrane/drug effects/metabolism ; Up-Regulation/drug effects ; Xanthones/*pharmacology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {1,7-Dihydroxy-3,4-dimethoxyxanthone (XAN) is a bioactive compound isolated from Securidaca inappendiculata Hassk. and exerts the inhibitory effects on fibroblast-like synoviocytes by targeting NF-κB and p38. This study was designed to elucidate mechanisms underlying the divergent regulation on the two pathways in HFLS-RA cells by XAN. Expressions of hallmark proteins and transcription of GADD45α mRNA were determined by Western-blot and RT-qPCR methods, respectively. Fluorescence staining was employed to evaluate intracellular oxidative stress. Effects of XAN and N-acetyl-l-cysteine (NAC) on the proliferation of cells were investigated by MTT assay, and pro-apoptotic effects of XAN were assessed by Annexin V-FITC/PI method. It was found XAN blocked NF-κB signaling in HFLS-RA cells shortly after treatment. Moreover, it up-regulated both transcription and expression of GADD45α, and subsequently activated p38 pathway. As time went on, XAN significantly promoted the generation of reactive oxygen species (ROS), which accompanied with sustained up-regulation of p-p38 and increased apoptosis. 48H later, dual-effects of XAN on NF-κB and p38 were reversed. As activation of p38 and increased apoptosis induced by XAN were antagonized by NAC, they were deemed as ROS mediated effects. Furthermore, the accumulated ROS should also account for the activation of NF-κB in the late stage of treatments via interfering in p38/MSK1/NF-κB feedback. Altogether, these findings suggested XAN-induced ROS contributed great importance to the proliferation inhibition of HFLS-RA cells by mediating NF-κB/p38 feedback loop and apoptosis, which provided us a panoramic view of potential target in the therapy of RA by XAN.}, }
@article {pmid28807058, year = {2017}, author = {Kurauchi, K and Nishikawa, T and Miyahara, E and Okamoto, Y and Kawano, Y}, title = {Role of metabolites of cyclophosphamide in cardiotoxicity.}, journal = {BMC research notes}, volume = {10}, number = {1}, pages = {406}, pmid = {28807058}, issn = {1756-0500}, mesh = {Acetylcysteine/pharmacology ; Acrolein/metabolism/pharmacology/toxicity ; Aldehyde Dehydrogenase/metabolism ; Animals ; Apoptosis/*drug effects ; Cardiotoxicity/metabolism/prevention &amp; control ; Cardiotoxins/*pharmacology/toxicity ; Cell Line ; Cell Survival/drug effects ; Cyclophosphamide/analogs &amp; derivatives/metabolism/*pharmacology/toxicity ; Free Radical Scavengers/pharmacology ; Immunosuppressive Agents/metabolism/pharmacology/toxicity ; Myocytes, Cardiac/*drug effects ; Phosphoramide Mustards/metabolism/pharmacology/toxicity ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: The dose-limiting toxic effect of cyclophosphamide (CY) is cardiotoxicity. The pathogenesis of myocardial damage is poorly understood, and there is no established means of prevention. In previous studies, we suggested that for CY-induced cardiotoxicity, whereas acrolein is the key toxic metabolite, carboxyethylphosphoramide mustard (CEPM) is protective. We sought to verify that acrolein is the main cause of cardiotoxicity and to investigate whether aldehyde dehydrogenase (ALDH), which is associated with greater CEPM production, is involved in the protective effect for cardiotoxicity. We also evaluated the protective effect of N-acetylcysteine (NAC), an amino acid with antioxidant activity and a known acrolein scavenger.<br><br>METHODS: H9c2 cells were exposed to CY metabolites HCY (4-hydroxy-cyclophosphamide), acrolein or CEPM. The degree of cytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, and the production of reactive oxygen species (ROS). We also investigated how the myocardial cellular protective effects of CY metabolites were modified by NAC. To quantify acrolein levels, we measured the culture supernatants using high performance liquid chromatography. We measured ALDH activity after exposure to HCY or acrolein and the same with pre-treatment with NAC.<br><br>RESULTS: Exposure of H9c2 cells to CEPM did not cause cytotoxicity. Increased ROS levels and myocardial cytotoxicity, however, were induced by HCY and acrolein. In cell cultures, HCY was metabolized to acrolein. Less ALDH activity was observed after exposure to HCY or acrolein. Treatment with NAC reduced acrolein concentrations.<br><br>CONCLUSIONS: Increased ROS generation and decreased ALDH activity confirmed that CY metabolites HCY and acrolein are strongly implicated in cardiotoxicity. By inhibiting ROS generation, increasing ALDH activity and decreasing the presence of acrolein, NAC has the potential to prevent CY-induced cardiotoxicity.}, }
@article {pmid28804952, year = {2017}, author = {Hsu, SS and Jan, CR and Liang, WZ}, title = {Evaluation of cytotoxicity of propofol and its related mechanism in glioblastoma cells and astrocytes.}, journal = {Environmental toxicology}, volume = {32}, number = {12}, pages = {2440-2454}, doi = {10.1002/tox.22458}, pmid = {28804952}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Astrocytes/cytology/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Caspase Inhibitors/pharmacology ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Glioblastoma ; Humans ; Propofol/*pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Propofol (2,6-diisopropylphenol), one of the extensively and commonly used anesthetic agents, has been shown to affect the biological behavior of various models. Previous researches have shown that propofol-induced cytotoxicity might cause anticancer effect in different cells. However, the mechanisms underlying the effect of propofol on cytotoxicity is still elusive in human glioblastoma cells. The aims of this study were to evaluate effects of propofol on cytotoxicity, cell cycle distribution and ROS production, and establish the relationship between oxidative stress and cytotoxicity in GBM 8401 human glioblastoma cells and DI TNC1 rat astrocytes. Propofol (20-30 μM) concentration-dependently induced cytotoxicity, cell cycle arrest, and increased ROS production in GBM 8401 cells but not in DI TNC1 cells. In GBM 8401 cells, propofol induced G2/M phase cell arrest, which affected the CDK1, cyclin B1, p53, and p21 protein expression levels. Furthermore, propofol induced oxygen stresses by increasing O2- and H2 O2 levels but treatment with the antioxidant N-acetylcysteine (NAC) partially reversed propofol-regulated antioxidative enzyme levels (superoxide dismutase, catalase, and glutathione peroxidase). Most significantly, propofol induced apoptotic effects by decreasing Bcl-2 but increasing Bax, cleaved caspase-9/caspase-3 levels, which were partially reversed by NAC. Moreover, the pancaspase inhibitor Z-VAD-FMK also partially prevented propofol-induced apoptosis. Together, in GBM 8401 cells but not in DI TNC1 cells, propofol activated ROS-associated apoptosis that involved cell cycle arrest and caspase activation. These findings indicate that propofol not only can be an anesthetic agent which reduces pain but also has the potential to be used for the treatment of human glioblastoma.}, }
@article {pmid28801613, year = {2017}, author = {Liu, Y and Tan, S and Zhang, H and Kong, X and Ding, L and Shen, J and Lan, Y and Cheng, C and Zhu, T and Xia, W}, title = {Selective effects of non-thermal atmospheric plasma on triple-negative breast normal and carcinoma cells through different cell signaling pathways.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {7980}, pmid = {28801613}, issn = {2045-2322}, mesh = {Apoptosis/drug effects ; Carcinoma/*metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cells, Cultured ; Humans ; Plasma Gases/*pharmacology ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor ; *Signal Transduction ; Triple Negative Breast Neoplasms/*metabolism ; }, abstract = {Non-thermal atmospheric plasma (NTP) has shown its selective anticancer effects in many types of tumors in vitro and one of the main mechanisms is that the different increase of intracellular ROS in cancer and homologous normal cells. In this study, we report that NTP treatment reduces the proliferation in triple negative breast cancer (TNBC) and normal cell lines. Simultaneously, STAT3 pathway is inhibited by NTP effects. However, it is observed that normal cells MCF10A are more sensitive to ROS toxicity induced by NTP than cancer cells MDA-MB-231. When 5 mM of ROS inhibitor N-acetyl cysteine (NAC) is employed in NTP treatments, the proliferation of normal breast cells MCF10A recovers. Meanwhile, NTP effects remain significant inhibition of MDA-MB-231 cells. Our results further reveal that NTP can induce apoptosis in MDA-MB-231 cells through inhibiting interleukin-6 receptor (IL-6R) pathway. Moreover, the mechanism of NTP anti-cancer selectivity relates to constantly HER2/Akt activation induced by NTP especially in MCF10A cells but not in MDA-MB-231 cells. Therefore, these two different cell signaling pathways induced by NTP treatments in TNBC and homologous normal cells make NTP becoming a potential tool in future therapy.}, }
@article {pmid28801140, year = {2017}, author = {Che, Y and Wang, J and Yuan, Z and Li, Y and Lu, Z and Zhang, Z and Zhang, J and Wan, J and Sun, H and Chen, Z and Pu, J and He, J}, title = {The therapeutic effects of Longikaurin A, a natural ent-kauranoid, in esophageal squamous cell carcinoma depend on ROS accumulation and JNK/p38 MAPK activation.}, journal = {Toxicology letters}, volume = {280}, number = {}, pages = {106-115}, doi = {10.1016/j.toxlet.2017.08.005}, pmid = {28801140}, issn = {1879-3169}, mesh = {Antineoplastic Agents, Phytogenic/pharmacology ; Carcinoma, Squamous Cell/genetics/*metabolism ; Diterpenes, Kaurane/*pharmacology ; Enzyme Activation/drug effects ; Esophageal Neoplasms/genetics/*metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Effective treatments for esophageal squamous cell carcinoma (ESCC), one of the most common cancers in China, are lacking. Longikaurin A (LK-A), an ent-kauranoid diterpenoid isolated from Isodon ternifolius, has been shown to have potent cytotoxic effects on ESCC cells both in vivo and in vitro, mainly by inducing apoptosis. In this study, LK-A inhibited ESCC cells viability and induced G2/M cell cycle arrest. Moreover, LK-A was also highly effective in a KYSE-30 xenograft nude mouse model. Treatment with Z-VAD(OMe)-FMK partially attenuated LK-A-induced apoptosis. LK-A significantly induced reactive oxygen species (ROS) production in ESCC cells, and LK-A-induced apoptosis was attenuated by the ROS scavenger N-acetyl cysteine (NAC). Furthermore, we found that treatment with LK-A activated both the JNK and p38 MAPK signaling pathways, resulting in increases in ROS levels and apoptosis induction. Taken together, these findings indicate that LK-A exerts novel anti-tumor effects in ESCC cells by activating the JNK and p38 MAPK pathways and inducing increases in ROS production, which suggest that the compound may have potential as a clinical therapeutic agent.}, }
@article {pmid28798231, year = {2017}, author = {Khalafalla, MG and Woods, LT and Camden, JM and Khan, AA and Limesand, KH and Petris, MJ and Erb, L and Weisman, GA}, title = {P2X7 receptor antagonism prevents IL-1β release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy.}, journal = {The Journal of biological chemistry}, volume = {292}, number = {40}, pages = {16626-16637}, pmid = {28798231}, issn = {1083-351X}, support = {R01 DE023342/DE/NIDCR NIH HHS/United States ; }, mesh = {Animals ; CD28 Antigens/genetics/metabolism ; Disease Models, Animal ; Epithelial Cells/*metabolism/pathology ; Inflammasomes ; Interferon-gamma/genetics/metabolism ; Interleukin-18/genetics/metabolism ; Interleukin-1beta/*metabolism ; Ion Transport/drug effects/genetics ; Mice ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; Potassium/metabolism ; Purinergic P2X Receptor Antagonists/*pharmacology ; Pyridines/*pharmacology ; Receptors, Purinergic P2X7/genetics/*metabolism ; Sjogren's Syndrome/genetics/*metabolism/pathology ; Sodium/metabolism ; Submandibular Gland/*metabolism/pathology ; Tetrazoles/*pharmacology ; }, abstract = {Salivary gland inflammation is a hallmark of Sjögren's syndrome (SS), a common autoimmune disease characterized by lymphocytic infiltration of the salivary gland and loss of saliva secretion, predominantly in women. The P2X7 receptor (P2X7R) is an ATP-gated nonselective cation channel that induces inflammatory responses in cells and tissues, including salivary gland epithelium. In immune cells, P2X7R activation induces the production of proinflammatory cytokines, including IL-1β and IL-18, by inducing the oligomerization of the multiprotein complex NLRP3-type inflammasome. Here, our results show that in primary mouse submandibular gland (SMG) epithelial cells, P2X7R activation also induces the assembly of the NLRP3 inflammasome and the maturation and release of IL-1β, a response that is absent in SMG cells isolated from mice deficient in P2X7Rs (P2X7R[-/-]). P2X7R-mediated IL-1β release in SMG epithelial cells is dependent on transmembrane Na[+] and/or K[+] flux and the activation of heat shock protein 90 (HSP90), a protein required for the activation and stabilization of the NLRP3 inflammasome. Also, using the reactive oxygen species (ROS) scavengers N-acetyl cysteine and Mito-TEMPO, we determined that mitochondrial reactive oxygen species are required for P2X7R-mediated IL-1β release. Lastly, in vivo administration of the P2X7R antagonist A438079 in the CD28[-/-], IFNγ[-/-], NOD.H-2[h4] mouse model of salivary gland exocrinopathy ameliorated salivary gland inflammation and enhanced carbachol-induced saliva secretion. These findings demonstrate that P2X7R antagonism in vivo represents a promising therapeutic strategy to limit salivary gland inflammation and improve secretory function.}, }
@article {pmid28797292, year = {2017}, author = {Lee, HY and Lee, JS and Kim, HG and Kim, WY and Lee, SB and Choi, YH and Son, CG}, title = {The ethanol extract of Aquilariae Lignum ameliorates hippocampal oxidative stress in a repeated restraint stress mouse model.}, journal = {BMC complementary and alternative medicine}, volume = {17}, number = {1}, pages = {397}, pmid = {28797292}, issn = {1472-6882}, mesh = {Animals ; Antioxidants/metabolism/*pharmacology ; Astrocytes/drug effects ; Corticosterone/blood ; Cytokines/metabolism ; Disease Models, Animal ; Epinephrine/blood ; Hippocampus/*drug effects/metabolism ; Inflammation/chemically induced/metabolism ; Male ; Malondialdehyde/metabolism ; Mice, Inbred BALB C ; Microglia/drug effects/metabolism ; NF-kappa B/metabolism ; Neuroprotective Agents/*pharmacology ; Nitric Oxide/metabolism ; Oxidative Stress/*drug effects ; Plant Extracts/*pharmacology ; Reactive Oxygen Species/metabolism ; Restraint, Physical/psychology ; Stress, Psychological/*metabolism ; *Thymelaeaceae ; }, abstract = {BACKGROUND: Chronic stress contributes to the development of brain disorders, such as neurodegenerative and psychiatric diseases. Oxidative damage is well known as a causative factor for pathogenic process in brain tissues. The aim of this study is to evaluate the neuroprotective effect of a 30% ethanol extract of Aquilariae Lignum (ALE) in repeated stress-induced hippocampal oxidative injury.<br><br>METHODS: Fifty BALB/c male mice (12&#xa0;weeks old) were randomly divided into five groups (n&#xa0;=&#xa0;10). For 11 consecutive days, each group was orally administered with distilled water, ALE (20 or 80&#xa0;mg/kg) or N-acetylcysteine (NAC; 100&#xa0;mg/kg), and then all mice (except unstressed group) were subjected to restraint stress for 6&#xa0;h. On the final day, brain tissues and sera were isolated, and stress hormones and hippocampal oxidative alterations were examined. We also treated lipopolysaccharide (LPS, 1&#xa0;&#x3bc;g/mL)-stimulated BV2 microglial cells with ALE (1 and 5&#xa0;&#x3bc;g/mL) or NAC (10&#xa0;&#x3bc;M) to investigate the pharmacological mechanism.<br><br>RESULTS: Restraint stress considerably increased the serum levels of corticosterone and adrenaline and the hippocampal levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). ALE administration significantly attenuated the above abnormalities. ALE also significantly normalized the stress-induced activation of astrocytes and microglial cells in the hippocampus as well as the elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-&#x3b1;) and interleukin-1 beta (IL-1&#x3b2;). The in vitro assay outcome supplemented ALE could dramatically block NF-&#x3ba;B activation in microglia. The anti-oxidative stress effects of ALE were supported by the results of antioxidant components, 4-hydroxynonenal (4-HNE), NADPH oxidase 2 (NOX2), inducible nitric oxide synthase (iNOS) and NFE2L2 (Nrf2) in the hippocampal tissues.<br><br>CONCLUSIONS: We firstly demonstrated the neuroprotective potentials of A. Lignum against hippocampal oxidative injury in repeated restraint stress. The corresponding mechanisms might involve modulations in the release of ROS, pro-inflammatory cytokines and stress hormones.}, }
@article {pmid28782507, year = {2017}, author = {So, KY and Kim, SH and Jung, KT and Lee, HY and Oh, SH}, title = {MAPK/JNK1 activation protects cells against cadmium-induced autophagic cell death via differential regulation of catalase and heme oxygenase-1 in oral cancer cells.}, journal = {Toxicology and applied pharmacology}, volume = {332}, number = {}, pages = {81-91}, doi = {10.1016/j.taap.2017.07.022}, pmid = {28782507}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Autophagy/*drug effects ; Cadmium/*toxicity ; Caspase 3/genetics/metabolism ; Catalase/genetics/*metabolism ; Cell Line, Tumor ; Heme Oxygenase-1/genetics/*metabolism ; Humans ; Mitogen-Activated Protein Kinase 8/genetics/*metabolism ; Mouth Neoplasms/chemically induced/drug therapy ; Oxidative Stress/drug effects ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Up-Regulation ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Antioxidant enzymes are related to oral diseases. We investigated the roles of heme oxygenase-1 (HO-1) and catalase in cadmium (Cd)-induced oxidative stress and the underlying molecular mechanism in oral cancer cells. Exposing YD8 cells to Cd reduced the expression levels of catalase and superoxide dismutase 1/2 and induced the expression of HO-1 as well as autophagy and apoptosis, which were reversed by N-acetyl-l-cysteine (NAC). Cd-exposed YD10B cells exhibited milder effects than YD8 cells, indicating that Cd sensitivity is associated with antioxidant enzymes and autophagy. Autophagy inhibition via pharmacologic and genetic modulations enhanced Cd-induced HO-1 expression, caspase-3 cleavage, and the production of reactive oxygen species (ROS). Ho-1 knockdown increased autophagy and apoptosis. Hemin treatment partially suppressed Cd-induced ROS production and apoptosis, but enhanced autophagy and CHOP expression, indicating that autophagy induction is associated with cellular stress. Catalase inhibition by pharmacological and genetic modulations increased Cd-induced ROS production, autophagy, and apoptosis, but suppressed HO-1, indicating that catalase is required for HO-1 induction. p38 inhibition upregulated Cd-induced phospho-JNK and catalase, but suppressed HO-1, autophagy, apoptosis. JNK suppression exhibited contrary results, enhancing the expression of phospho-p38. Co-suppression of p38 and JNK1 failed to upregulate catalase and procaspase-3, which were upregulated by JNK1 overexpression. Overall, the balance between the responses of p38 and JNK activation to Cd appears to have an important role in maintaining cellular homeostasis via the regulation of antioxidant enzymes and autophagy induction. In addition, the upregulation of catalase by JNK1 activation can play a critical role in cell protection against Cd-induced oxidative stress.}, }
@article {pmid28782153, year = {2018}, author = {Borlak, J and van Bömmel, F and Berg, T}, title = {N-acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury.}, journal = {Liver international : official journal of the International Association for the Study of the Liver}, volume = {38}, number = {2}, pages = {365-376}, doi = {10.1111/liv.13538}, pmid = {28782153}, issn = {1478-3231}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Aminopyridines/*adverse effects ; Analgesics/*adverse effects ; Antidotes/*administration &amp; dosage ; Biomarkers/blood ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/blood/diagnosis/*drug therapy ; Disease Progression ; Drug Therapy, Combination ; Female ; Glucocorticoids/*administration &amp; dosage ; Glutathione/metabolism ; Hepatocytes/drug effects/metabolism ; Humans ; Infusions, Intravenous ; Liver/*drug effects/metabolism/pathology ; Liver Transplantation ; Male ; Middle Aged ; Prednisolone/*administration &amp; dosage ; Recovery of Function ; Retrospective Studies ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {BACKGROUND &amp; AIMS: The analgesic flupirtine has been linked to cases of severe idiosyncratic drug-induced liver injury (sFILI). We therefore examined whether N-acetylcysteine (NAC) and glucocorticoid therapy is effective in the management of sFILI.<br><br>METHODS: In a retrospective cohort study efficacy of NAC-infusion and oral prednisolone treatments on liver-function-tests (LFTs) and clinical outcome of 21 sFILI cases was evaluated by comparing it to an external cohort of 30 sFILI cases not receiving the antidote. LFTs were also assayed in human hepatocyte cultures treated with flupirtine for 96&#xa0;hours. Additionally, modulation of glutathione stores in cultures of human hepatocytes treated with 80 drugs was investigated.<br><br>RESULTS: Upon admission, patients presented Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin elevations of up to 90-, 35- and 30-fold of upper limits of normal (ULN) respectively. The average INR was 2.2, and 50% of patients had a high Model for end-stage liver disease (MELD) score of &#x2265;25 and included 5 cases of 28-32. The combined NAC/prednisolone treatment was well tolerated and led to significant ALT, AST and INR improvements within 2&#xa0;weeks. However, the hyperbilirubinaemia resolved slowly. Two patients with late start of NAC/prednisolone treatment developed hepatic encephalopathy and required liver transplantation; the remaining patients recovered without long-term sequela. Based on serum biochemistries sFILI cases resolved more rapidly (P&#xa0;<&#xa0;.01) when compared to untreated sFILI patients and included a case with fatal outcome. Additionally, in vitro studies revealed glutathione depletion as a common culprit for drugs with liver liabilities.<br><br>CONCLUSIONS: Based on these initial findings a prospective randomized clinical trial (RCT) is needed to confirm safety and efficacy of NAC/prednisolone treatment in sFILI.}, }
@article {pmid28780989, year = {2017}, author = {Boerner, EB and Costabel, U and Wessendorf, TE and Theegarten, D and Bonella, F}, title = {Idiopathic pleuroparenchymal fibroelastosis (PPFE) - A case study of a rare entity.}, journal = {Revista portuguesa de pneumologia}, volume = {23}, number = {6}, pages = {352-355}, doi = {10.1016/j.rppnen.2017.06.006}, pmid = {28780989}, issn = {2173-5115}, mesh = {Female ; Fibrosis ; Humans ; Middle Aged ; Pleura/*pathology ; Pleural Diseases/complications/*diagnosis ; Pulmonary Fibrosis/complications/*diagnosis ; }, abstract = {Idiopathic pleuroparenchymal fibroelastosis (IPPFE) was recognized as a rare new entity. We report the case of a 63 years old female suffering from progressive dyspnea and dry cough for three years. Two years before admission to our hospital, idiopathic pulmonary fibrosis (IPF) was diagnosed in another hospital and treatment with prednisolone and N-acetylcysteine (NAC) was commenced. At admission HRCT showed upper lobe dominant fibrosis and associated pleural thickening. Surgical biopsies were re-evaluated and revealed fibroelastosis with pleural thickening and a probable UIP pattern, consistent with idiopathic PPFE. Treatment with pirfenidone was initiated due to progression under prednisolone and NAC. Upper lobe predominant pleural thickening with associated subpleural fibrotic changes should raise suspicion of PPFE.}, }
@article {pmid28780423, year = {2017}, author = {Amano, R and Yamashita, A and Kasai, H and Hori, T and Miyasato, S and Saito, S and Yokoe, H and Takahashi, K and Tanaka, T and Otoguro, T and Maekawa, S and Enomoto, N and Tsubuki, M and Moriishi, K}, title = {Cinnamic acid derivatives inhibit hepatitis C virus replication via the induction of oxidative stress.}, journal = {Antiviral research}, volume = {145}, number = {}, pages = {123-130}, doi = {10.1016/j.antiviral.2017.07.018}, pmid = {28780423}, issn = {1872-9096}, mesh = {Antiviral Agents/chemical synthesis/*pharmacology ; Cell Line ; Cinnamates/chemical synthesis/chemistry/*pharmacology ; DNA Replication/drug effects ; Hepacivirus/*drug effects/physiology ; Hepatitis C/virology ; High-Throughput Screening Assays ; Humans ; *Oxidative Stress ; RNA, Viral ; Reactive Oxygen Species/metabolism ; Replicon/drug effects ; STAT3 Transcription Factor/metabolism ; Virus Replication/*drug effects ; }, abstract = {Several cinnamic acid derivatives have been reported to exhibit antiviral activity. In this study, we prepared 17 synthetic cinnamic acid derivatives and screened them to identify an effective antiviral compound against hepatitis C virus (HCV). Compound 6, one of two hit compounds, suppressed the viral replications of genotypes 1b, 2a, 3a, and 4a with EC50 values of 1.5-8.1 μM and SI values of 16.2-94.2. The effect of compound 6 on the phosphorylation of Tyr[705] in signal transducer and activator of transcription 3 (STAT3) was investigated because a cinnamic acid derivative AG490 was reported to suppress HCV replication and the activity of Janus kinase (JAK) 2. Compound 6 potently suppressed HCV replication, but it did not inhibit the JAK1/2-dependent phosphorylation of STAT3 Tyr[705] at the same concentration. Furthermore, a pan-JAK inhibitor tofacitinib potently impaired phosphorylation of STAT3 Tyr [705], but it did not inhibit HCV replication in the replicon cells and HCV-infected cells at the same concentration, supporting the notion that the phosphorylated state of STAT3 Tyr[705] is not necessarily correlated with HCV replication. The production of reactive oxygen species (ROS) was induced by treatment with compound 6, whereas N-acetyl-cysteine restored HCV replication and impaired ROS production in the replicon cells treated with compound 6. These data suggest that compound 6 inhibits HCV replication via the induction of oxidative stress.}, }
@article {pmid28778520, year = {2017}, author = {Wang, W and Li, D and Ding, X and Zhao, Q and Chen, J and Tian, K and Qiu, Y and Lu, L}, title = {N-Acetylcysteine protects inner ear hair cells and spiral ganglion neurons from manganese exposure by regulating ROS levels.}, journal = {Toxicology letters}, volume = {279}, number = {}, pages = {77-86}, doi = {10.1016/j.toxlet.2017.07.903}, pmid = {28778520}, issn = {1879-3169}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Chlorides/*toxicity ; Cytoprotection ; Dose-Response Relationship, Drug ; Hair Cells, Auditory, Inner/*drug effects/metabolism/pathology ; Manganese Compounds ; Neuroprotective Agents/*pharmacology ; Organ Culture Techniques ; Oxidative Stress/*drug effects ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Spiral Ganglion/*drug effects/metabolism ; Time Factors ; }, abstract = {Manganese (Mn) is an indispensable cofactor for many enzymes and a basic factor for many reproductive and metabolic pathways. However, exposure to high concentrations of Mn can result in deleterious effects on the central nervous system and peripheral nerves, including nerves associated with the auditory system. Based on our studies of cochlear organotypic cultures, Mn exposure induces a significant loss of hair cells (HCs), auditory nerve fibers (ANFs) and spiral ganglion neurons (SGNs) in a concentration-dependent manner. Additionally, N-acetylcysteine (NAC), a glutathione (GSH) provider and a direct scavenger of reactive oxygen species (ROS), clearly decreases Mn-induced ROS accumulation, caspase-3 activation and TUNEL staining, which indicate increased cell survival. Based on these results, Mn exposure exerts ototoxic and neurotoxic effects on the auditory system. Furthermore, 20mM NAC may prevent 1mM Mn-induced hair cell loss and axonal degeneration, indicating that NAC could be a promising drug for clinical applications.}, }
@article {pmid28778482, year = {2017}, author = {Chan, PC and Wang, YC and Chen, YL and Hsu, WN and Tian, YF and Hsieh, PS}, title = {Importance of NADPH oxidase-mediated redox signaling in the detrimental effect of CRP on pancreatic insulin secretion.}, journal = {Free radical biology &amp; medicine}, volume = {112}, number = {}, pages = {200-211}, doi = {10.1016/j.freeradbiomed.2017.07.032}, pmid = {28778482}, issn = {1873-4596}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; C-Reactive Protein/*pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Etanercept/pharmacology ; Gene Expression Regulation ; Guanidines/pharmacology ; Humans ; Insulin/*metabolism ; Insulin Secretion ; Insulin-Secreting Cells/cytology/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; NADPH Oxidases/antagonists &amp; inhibitors/*genetics/metabolism ; NF-kappa B/antagonists &amp; inhibitors/genetics/metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors/genetics/metabolism ; Oxidation-Reduction ; Proline/analogs &amp; derivatives/pharmacology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/genetics/metabolism ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Elevations in C-reactive protein (CRP) levels are positively correlated with the progress of type 2 diabetes mellitus. However, the effect of CRP on pancreatic insulin secretion is unknown. Here, we showed that purified human CRP impaired insulin secretion in isolated mouse islets and NIT-1 insulin-secreting cells in dose- and time-dependent manners. CRP increased NADPH oxidase-mediated ROS (reactive oxygen species) production, which simultaneously promoted the production of nitrotyrosine (an indicator of RNS, reactive nitrogen species) and TNFα, to diminish cell viability, insulin secretion in islets and insulin-secreting cells. These CRP-mediated detrimental effects on cell viability and insulin secretion were significantly reversed by adding NAC (a potent antioxidant), apocynin (a selective NADPH oxidase inhibitor), L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor), aminoguanidine (a selective iNOS inhibitor), PDTC (a selective NFκB inhibitor) or Enbrel (an anti-TNFα fusion protein). However, CRP-induced ROS production failed to change after adding L-NAME, aminoguanidine or PDTC. In isolated islets and NIT-1 cells, the elevated nitrotyrosine contents by CRP pretreatment were significantly suppressed by adding L-NAME but not PDTC. Conversely, CRP-induced increases in TNF-α production were significantly reversed by administration of PDTC but not L-NAME. In addition, wild-type mice treated with purified human CRP showed significant decreases in the insulin secretion index (HOMA-β cells) and the insulin stimulation index in isolated islets that were reversed by the addition of L-NAME, aminoguanidine or NAC. It is suggested that CRP-activated NADPH-oxidase redox signaling triggers iNOS-mediated RNS and NFκB-mediated proinflammatory cytokine production to cause β cell damage in state of inflammation.}, }
@article {pmid28772167, year = {2017}, author = {Tu, C and Xu, R and Koleti, M and Zoldan, J}, title = {Glycogen synthase kinase-3 inhibition sensitizes human induced pluripotent stem cells to thiol-containing antioxidants induced apoptosis.}, journal = {Stem cell research}, volume = {23}, number = {}, pages = {182-187}, doi = {10.1016/j.scr.2017.07.019}, pmid = {28772167}, issn = {1876-7753}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Line ; Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors/metabolism ; Humans ; Induced Pluripotent Stem Cells/*cytology/drug effects/*enzymology ; Protein Kinase Inhibitors/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Pyridines ; Pyrimidines ; Sirolimus/pharmacology ; Sulfhydryl Compounds/*pharmacology ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Inhibition of glycogen synthase kinase 3 (GSK3) is an extensively used strategy to activate Wnt pathway for pluripotent stem cell (PSC) differentiation. However, the effects of such inhibition on PSCs, besides upregulating the Wnt pathway, have rarely been investigated despite that GSK3 is broadly involved in other cellular activities such as insulin signaling and cell growth/survival regulation. Here we describe a previously unknown synergistic effect between GSK3 inhibition (e.g., Chir99021 and LY2090314) and various normally non-toxic thiol-containing antioxidants (e.g., N-acetylcysteine, NAC) on the induction of apoptosis in human induced pluripotent stem cells (iPSCs). Neither Chir99021 nor the antioxidants individually induced significant apoptosis, whereas their combined treatment resulted in rapid and extensive apoptosis, with substantial caspase 3 activity observed within 3h and over 90% decrease in cell viability after 24h. We confirmed the generality of this phenomenon with multiple independent iPSCs lines, various thiol-based antioxidants and distinct GSK3 inhibitors. Mechanistically, we demonstrated that rapamycin treatment could substantially reduce cell death, suggesting the critical role of mammalian target of rapamycin (mTOR). Akt dysregulation was also found to partially contribute to cell apoptosis but was not the primary cause. Further, this coordinated proapoptotic effect was not detected in mouse ESCs but was present in another human cells line: a breast cancer cell line (MDA-MB-231). Given the wide use of GSK3 inhibition in biomedical research: from iPSC differentiation to cancer intervention and the treatment of neuronal diseases, researchers can potentially take advantage of or avoid this synergistic effect for improved experimental or clinical outcome.}, }
@article {pmid28771932, year = {2018}, author = {Tujios, SR and Lee, WM}, title = {Acute liver failure induced by idiosyncratic reaction to drugs: Challenges in diagnosis and therapy.}, journal = {Liver international : official journal of the International Association for the Study of the Liver}, volume = {38}, number = {1}, pages = {6-14}, pmid = {28771932}, issn = {1478-3231}, support = {R01 DK058369/DK/NIDDK NIH HHS/United States ; U01 DK058369/DK/NIDDK NIH HHS/United States ; U01 DK083023/DK/NIDDK NIH HHS/United States ; }, mesh = {Chemical and Drug Induced Liver Injury/diagnosis/*etiology/mortality/therapy ; Humans ; Liver Failure, Acute/*chemically induced/diagnosis/mortality/therapy ; Predictive Value of Tests ; Prognosis ; Risk Factors ; Severity of Illness Index ; }, abstract = {Acute liver failure (ALF) requires urgent attention to identify etiology and determine prognosis, in order to assess likelihood of survival or need for transplantation. Identifying idiosyncratic drug-induced liver injury (iDILI) may be particularly difficult, but the illness generally follows a subacute course, allowing time to assess outcome and find a liver graft if needed. Not all drugs that cause iDILI lead to ALF; the most common are antibiotics including anti-tuberculous medications, non-steroidal anti-inflammatory agents and herbal and dietary supplements (HDS). Determining causality remains challenging particularly if altered mentation is present; identifying the causative agent depends in part on knowing the propensity of the drugs that have been taken in the proper time interval, plus excluding other causes. In general, iDILI that reaches the threshold of ALF will more often than not require transplantation, since survival without transplant is around 25%. Treatment consists of withdrawal of the presumed offending medication, consideration of N-acetylcysteine (NAC), as well as intensive care. Corticosteroids have not proven useful except perhaps in instances of apparent autoimmune hepatitis caused by a limited number of agents. Recently developed prognostic scoring systems may also aid in predicting outcome in this setting.}, }
@article {pmid28771210, year = {2017}, author = {Song, YC and Wu, BJ and Chiu, CC and Chen, CL and Zhou, JQ and Liang, SR and Duh, CY and Sung, PJ and Wen, ZH and Wu, CY}, title = {Coral-Derived Natural Marine Compound GB9 Impairs Vascular Development in Zebrafish.}, journal = {International journal of molecular sciences}, volume = {18}, number = {8}, pages = {}, pmid = {28771210}, issn = {1422-0067}, mesh = {Animals ; Animals, Genetically Modified/embryology/genetics ; Anthozoa/*chemistry ; Neovascularization, Physiologic/*drug effects ; Sesquiterpenes/chemistry/*pharmacology ; Zebrafish/*embryology/genetics ; }, abstract = {Blood vessels in vertebrates are established and genetically controlled in an evolutionarily-conserved manner during embryogenesis. Disruption of vascular growth by chemical compounds or environmental hormones may cause developmental defects. This study analyzed the vascular impacts of marine compound GB9 in zebrafish. GB9 was isolated from the marine soft coral Capnella imbricata and had shown anti-neuroinflammatory and anti-nociceptive activities. However, the role of GB9 on vascular development has not been reported. We first tested the survival rate of embryos under exogenous 5, 7.5, 10, and 15 μM GB9 added to the medium and determined a sub-lethal dosage of 10 μM GB9 for further assay. Using transgenic Tg(fli:eGFP) fish to examine vascular development, we found that GB9 treatment impaired intersegmental vessel (ISV) growth and caudal vein plexus (CVP) patterning at 25 hours post-fertilization (hpf) and 30 hpf. GB9 exposure caused pericardial edema and impaired circulation at 48-52 hpf, which are common secondary effects of vascular defects and suggest the effects of GB9 on vascular development. Apoptic cell death analysis showed that vascular defects were not caused by cell death, but were likely due to the inhibition of migration and/or proliferation by examining ISV cell numbers. To test the molecular mechanisms of vascular defects in GB9-treated embryos, we examined the expression of vascular markers and found the decreased expression of vascular specific markers ephrinb2, flk, mrc1, and stabilin. In addition, we examined whether GB9 treatment impairs vascular growth due to an imbalance of redox homeostasis. We found an enhanced effect of vascular defects during GB9 and H2O2 co-treatment. Moreover, exogenous N-acetyl-cysteine (NAC) treatment rescued the vascular defects in GB9 treated embryos. Our results showed that GB9 exposure causes vascular defects likely mediated by the imbalance of redox homeostasis.}, }
@article {pmid28770700, year = {2018}, author = {Haga, S and Kanno, A and Ozawa, T and Morita, N and Asano, M and Ozaki, M}, title = {Detection of Necroptosis in Ligand-Mediated and Hypoxia-Induced Injury of Hepatocytes Using a Novel Optic Probe-Detecting Receptor-Interacting Protein (RIP)1/RIP3 Binding.}, journal = {Oncology research}, volume = {26}, number = {3}, pages = {503-513}, pmid = {28770700}, issn = {1555-3906}, mesh = {Animals ; *Apoptosis ; Caspases/metabolism ; Cells, Cultured ; GTPase-Activating Proteins/*metabolism ; Hepatocytes/metabolism/*pathology ; Hypoxia/*physiopathology ; Ligands ; Luminescent Measurements ; Mice ; *Necrosis ; *Optical Phenomena ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism ; }, abstract = {Liver injury is often observed in various pathological conditions including posthepatectomy state and cancer chemotherapy. It occurs mainly as a consequence of the combined necrotic and apoptotic types of cell death. In order to study liver/hepatocyte injury by the necrotic type of cell death, we studied signal-regulated necrosis (necroptosis) by developing a new optic probe for detecting receptor-interacting protein kinase 1 (RIP)/RIP3 binding, an essential process for necroptosis induction. In the mouse hepatocyte cell line, TIB-73 cells, TNF-α/cycloheximide (T/C) induced RIP1/3 binding only when caspase activity was suppressed by the caspase-specific inhibitor z-VAD-fmk (zVAD). T/C/zVAD-induced RIP1/3 binding was inhibited by necrostatin-1 (Nec-1), an allosteric inhibitor of RIP1. The reduced cell survival by T/C/zVAD was improved by Nec-1. These facts indicate that T/C induces necroptosis of hepatocytes when the apoptotic pathway is inhibited/unavailable. FasL also induced cell death, which was only partially inhibited by zVAD, indicating the possible involvement of necroptosis rather than apoptosis. FasL activated caspase 3 and, similarly, induced RIP1/3 binding when the caspases were inactivated. Interestingly, FasL-induced RIP1/3 binding was significantly suppressed by the antioxidants Trolox and N-acetyl cysteine (NAC), suggesting the involvement of reactive oxygen species (ROS) in FasL-induced necroptotic cellular processes. H2O2, by itself, induced RIP1/3 binding that was suppressed by Nec-1, but not by zVAD. Hypoxia induced RIP1/3 binding after reoxygenation, which was suppressed by Nec-1 or by the antioxidants. Cell death induced by hypoxia/reoxygenation (H/R) was also improved by Nec-1. Similar to H2O2, H/R did not require caspase inhibition for RIP1/3 binding, suggesting the involvement of a caspase-independent mechanism for non-ligand-induced and/or redox-mediated necroptosis. These data indicate that ROS can induce necroptosis and mediate the FasL- and hypoxia-induced necroptosis via a molecular mechanism that differs from a conventional caspase-dependent pathway. In conclusion, necroptosis is potentially involved in liver/hepatocyte injury induced by oxidative stress and FasL in the absence of apoptosis.}, }
@article {pmid28770235, year = {2017}, author = {O'Halloran, KD and Lewis, P}, title = {Respiratory muscle dysfunction in animal models of hypoxic disease: antioxidant therapy goes from strength to strength.}, journal = {Hypoxia (Auckland, N.Z.)}, volume = {5}, number = {}, pages = {75-84}, pmid = {28770235}, issn = {2324-1128}, abstract = {The striated muscles of breathing play a critical role in respiratory homeostasis governing blood oxygenation and pH regulation. Upper airway dilator and thoracic pump muscles retain a remarkable capacity for plasticity throughout life, both in health and disease states. Hypoxia, whatever the cause, is a potent driver of respiratory muscle remodeling with evidence of adaptive and maladaptive outcomes for system performance. The pattern, duration, and intensity of hypoxia are key determinants of respiratory muscle structural-, metabolic-, and functional responses and adaptation. Age and sex also influence respiratory muscle tolerance of hypoxia. Redox stress emerges as the principal protagonist driving respiratory muscle malady in rodent models of hypoxic disease. There is a growing body of evidence demonstrating that antioxidant intervention alleviates hypoxia-induced respiratory muscle dysfunction, and that N-acetyl cysteine, approved for use in humans, is highly effective in preventing hypoxia-induced respiratory muscle weakness and fatigue. We posit that oxygen homeostasis is a key driver of respiratory muscle form and function. Hypoxic stress is likely a major contributor to respiratory muscle malaise in diseases of the lungs and respiratory control network. Animal studies provide an evidence base in strong support of the need to explore adjunctive antioxidant therapies for muscle dysfunction in human respiratory disease.}, }
@article {pmid28769003, year = {2017}, author = {Nakamura, M and Kuse, Y and Tsuruma, K and Shimazawa, M and Hara, H}, title = {The Involvement of the Oxidative Stress in Murine Blue LED Light-Induced Retinal Damage Model.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {40}, number = {8}, pages = {1219-1225}, doi = {10.1248/bpb.b16-01008}, pmid = {28769003}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; *Disease Models, Animal ; Electroretinography ; Light/*adverse effects ; Male ; Mice ; Opsins/metabolism ; Oxidative Stress ; Retina/metabolism/pathology/physiology/*radiation effects ; Retinal Degeneration/*etiology/metabolism/pathology/physiopathology ; }, abstract = {The aim of study was to establish a mouse model of blue light emitting diode (LED) light-induced retinal damage and to evaluate the effects of the antioxidant N-acetylcysteine (NAC). Mice were exposed to 400 or 800 lx blue LED light for 2 h, and were evaluated for retinal damage 5 d later by electroretinogram amplitude and outer nuclear layer (ONL) thickness. Additionally, we investigated the effect of blue LED light exposure on shorts-wave-sensitive opsin (S-opsin), and rhodopsin expression by immunohistochemistry. Blue LED light induced light intensity dependent retinal damage and led to collapse of S-opsin and altered rhodopsin localization from inner and outer segments to ONL. Conversely, NAC administered at 100 or 250 mg/kg intraperitoneally twice a day, before dark adaptation and before light exposure. NAC protected the blue LED light-induced retinal damage in a dose-dependent manner. Further, blue LED light-induced decreasing of S-opsin levels and altered rhodopsin localization, which were suppressed by NAC. We established a mouse model of blue LED light-induced retinal damage and these findings indicated that oxidative stress was partially involved in blue LED light-induced retinal damage.}, }
@article {pmid28762308, year = {2018}, author = {Rababa’h, AM and Hijjawi, TB and Alzoubi, KH and Al Demour, S and Ababneh, MA}, title = {The Nephroprotective Effect of N-Acetyl-L-Cysteine and Atorvastatin against Imipenem induced Nephrotoxicity.}, journal = {Current molecular pharmacology}, volume = {11}, number = {2}, pages = {155-161}, doi = {10.2174/1874467210666170731115928}, pmid = {28762308}, issn = {1874-4702}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism ; Atorvastatin/pharmacology/*therapeutic use ; Blood Urea Nitrogen ; Creatinine/blood/urine ; Glomerular Filtration Rate ; Glycosuria/complications/urine ; Imipenem/*adverse effects ; Kidney/drug effects/enzymology/*pathology/physiopathology ; Kidney Diseases/blood/*chemically induced/*drug therapy/physiopathology ; Male ; Protective Agents/pharmacology/*therapeutic use ; Proteinuria/complications/urine ; Rats, Sprague-Dawley ; Thiobarbituric Acid Reactive Substances/metabolism ; Urea/urine ; }, abstract = {BACKGROUND AND OBJECTIVE: Imipenem has played an important role in the treatment of broad-spectrum bacterial infection. However, nephrotoxicity due to imipenem remains an important clinical challenge. The aim of this study is to test the hypothesis stating that N-acetyl-L-cysteine (NAC) and atorvastatin possess a nephroprotective effect against imipenem-induced nephrotoxicity.<br><br>METHODS: Adult Sprague Dawley rats were randomly assigned into six groups (n=8-10 rats/group; total n=55). The groups were (control, imipenem only, NAC only, atorvastatin only, NAC with imipenem, and atorvastatin with imipenem). Rats were treated with NAC or atorvastatin for six weeks. Serum and urinary creatinine and blood urea nitrogen (BUN) levels were measured. Additionally, urinary protein, urinary glucose and kidney levels of oxidants/antioxidants biomarkers were measured.<br><br>RESULTS: The administration of 300mg/kg/d imipenem induced nephrotoxicity as indicated by the significant reduction of serum creatinine, serum BUN and calculated GFR in the imipenem only-treated group compared to the control. These effects of imipenem were normalized by either NAC or atorvastatin. Moreover, the levels of catalase, superoxide dismutase and glutathione peroxidase were significantly reduced in the imipenem group. However, pre-administration of NAC and atorvastatin neutralized the levels of these enzymes and protected against imipenem-induced nephrotoxicity.<br><br>CONCLUSION: We concluded that the pre-administration of either NAC or atorvastatin protects the kidneys from imipenem-induced nephrotoxicity, through their antioxidant effects.}, }
@article {pmid28761349, year = {2017}, author = {Lochner, C and Roos, A and Stein, DJ}, title = {Excoriation (skin-picking) disorder: a systematic review of treatment options.}, journal = {Neuropsychiatric disease and treatment}, volume = {13}, number = {}, pages = {1867-1872}, pmid = {28761349}, issn = {1176-6328}, abstract = {Although pathological skin-picking has been documented in the medical literature since the 19th century, it has only recently been included as a distinct entity in psychiatric classification systems. In the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition and the proposed International Classification of Diseases, Eleventh Revision, excoriation (skin-picking) disorder (ED), also known as neurotic excoriation, psychogenic excoriation, or dermatillomania), is described as recurrent picking of skin, leading to skin lesions and significant distress or functional impairment. ED is listed as one of the obsessive-compulsive and related disorders, given its overlap with conditions such as trichotillomania (hair-pulling disorder). Arguably, its inclusion and delineation in the diagnostic nomenclature will lead to increased awareness of the condition, more research, and ultimately in treatment advances. This systematic review aims to provide readers with an up-to-date view of current treatment options for ED. A MEDLINE search of the ED treatment literature was conducted to collate relevant articles published between 1996 and 2017. The findings indicate that a number of randomized controlled trails on ED have now been published, and that current management options include behavioral therapy (habit reversal or acceptance-enhanced behavior therapy), and medication (selective serotonin reuptake inhibitors or N-acetyl cysteine).}, }
@article {pmid28758971, year = {2017}, author = {Chien, MH and Chow, JM and Lee, WJ and Chen, HY and Tan, P and Wen, YC and Lin, YW and Hsiao, PC and Yang, SF}, title = {Tricetin Induces Apoptosis of Human Leukemic HL-60 Cells through a Reactive Oxygen Species-Mediated c-Jun N-Terminal Kinase Activation Pathway.}, journal = {International journal of molecular sciences}, volume = {18}, number = {8}, pages = {}, pmid = {28758971}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Caspases/metabolism ; Chromones/*pharmacology ; Enzyme Activation/drug effects ; HL-60 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; MAP Kinase Signaling System/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Tricetin is a dietary flavonoid with cytostatic properties and antimetastatic activities in various solid tumors. The anticancer effect of tricetin in nonsolid tumors remains unclear. Herein, the molecular mechanisms by which tricetin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. Results showed that tricetin inhibited cell viability in various types of AML cell lines. Tricetin induced morphological features of apoptosis such as chromatin condensation and phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Of note, tricetin-induced cell growth inhibition was dramatically reversed by a pan caspase and caspase-8- and -9-specific inhibitors, suggesting that this compound mainly acts through a caspase-dependent pathway. Moreover, treatment of HL-60 cells with tricetin induced sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), and inhibition of ERK and JNK by their specific inhibitors respectively promoted and abolished tricetin-induced cell apoptosis. Dichlorofluorescein (DCF) staining showed that intracellular reactive oxygen species (ROS) levels were higher in tricetin-treated HL-60 cells compared to the control group. Moreover, an ROS scavenger, N-acetylcysteine (NAC), reversed tricetin-induced JNK activation and subsequent cell apoptosis. In conclusion, our results indicated that tricetin induced cell death of leukemic HL-60 cells through induction of intracellular oxidative stress following activation of a JNK-mediated apoptosis pathway. A combination of tricetin and an ERK inhibitor may be a better strategy to enhance the anticancer activities of tricetin in AML.}, }
@article {pmid28755860, year = {2017}, author = {Brillant, N and Elmasry, M and Burton, NC and Rodriguez, JM and Sharkey, JW and Fenwick, S and Poptani, H and Kitteringham, NR and Goldring, CE and Kipar, A and Park, BK and Antoine, DJ}, title = {Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by integrated photoacoustic imaging and mechanistic biomarkers in vivo.}, journal = {Toxicology and applied pharmacology}, volume = {332}, number = {}, pages = {64-74}, doi = {10.1016/j.taap.2017.07.019}, pmid = {28755860}, issn = {1096-0333}, support = {MR/K026739/1/MRC_/Medical Research Council/United Kingdom ; MR/L012707/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/administration &amp; dosage ; Alanine Transaminase/blood ; Animals ; Bilirubin/blood ; Biomarkers/blood ; Cell Survival/drug effects ; Chemical and Drug Induced Liver Injury/*diagnostic imaging ; Glutathione/blood ; HMGB1 Protein/blood ; Liver/diagnostic imaging/*drug effects ; Male ; Mice ; Mice, Inbred C57BL ; MicroRNAs/blood ; *Photoacoustic Techniques ; }, abstract = {The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration.}, }
@article {pmid28753257, year = {2017}, author = {Toma, L and Sanda, GM and Niculescu, LS and Deleanu, M and Stancu, CS and Sima, AV}, title = {Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE-receptor, oxidative, and endoplasmic reticulum stress.}, journal = {BioFactors (Oxford, England)}, volume = {43}, number = {5}, pages = {685-697}, doi = {10.1002/biof.1373}, pmid = {28753257}, issn = {1872-8081}, mesh = {Antioxidants/*pharmacology ; C-Reactive Protein/genetics ; Caffeic Acids/*pharmacology ; Diabetes Mellitus, Type 2/*drug therapy/pathology ; Endoplasmic Reticulum Stress/drug effects ; Endothelial Cells/drug effects/metabolism ; Gene Expression Regulation/drug effects ; Glycation End Products, Advanced/genetics ; Humans ; Inflammation/*drug therapy/metabolism/pathology ; Lipoproteins, LDL/pharmacology ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Receptor for Advanced Glycation End Products/genetics ; Receptors, CCR2/genetics ; Vascular Cell Adhesion Molecule-1/genetics ; }, abstract = {Type 2 diabetes mellitus is a worldwide epidemic and its atherosclerotic complications determine the high morbidity and mortality of diabetic patients. Caffeic acid (CAF), a phenolic acid present in normal diets, is known for its antioxidant properties. The aim of this study was to investigate CAF's anti-inflammatory properties and its mechanism of action, using cultured human endothelial cells (HEC) incubated with glycated low-density lipoproteins (gLDL). Levels of the receptor for advanced glycation end-products (RAGE), inflammatory stress markers (C reactive protein, CRP; vascular cell adhesion molecule-1, VCAM-1; monocyte chemoattractant protein-1, MCP-1), and oxidative stress and endoplasmic reticulum stress (ERS) markers were evaluated in gLDL-exposed HEC, in the presence/absence of CAF. RAGE silencing or blocking, specific inhibitors for oxidative stress (apocynin, N-acetyl-cysteine), and ERS (salubrinal) were used. The results showed that: (i) gLDL induced CRP synthesis and secretion through mechanisms involving NADPH oxidase-dependent oxidative stress and ERS in HEC; (ii) gLDL-RAGE interaction, oxidative stress, and ERS stimulated the secretion of VCAM-1 and MCP-1 in HEC; and (iii) CAF reduced the secretion of CRP, VCAM-1, and MCP-1 in gLDL-exposed HEC by inhibiting RAGE expression, oxidative stress, and ERS. In conclusion, CAF might be a promising alternative to ameliorate a wide spectrum of disorders due to its complex mechanisms of action resulting in anti-inflammatory and antioxidative properties. © 2017 BioFactors, 43(5):685-697, 2017.}, }
@article {pmid28752910, year = {2017}, author = {Showell, MG and Mackenzie-Proctor, R and Jordan, V and Hart, RJ}, title = {Antioxidants for female subfertility.}, journal = {The Cochrane database of systematic reviews}, volume = {7}, number = {7}, pages = {CD007807}, pmid = {28752910}, issn = {1469-493X}, mesh = {Abortion, Spontaneous/epidemiology ; Administration, Oral ; Antioxidants/*administration &amp; dosage/adverse effects ; Female ; Humans ; Infertility, Female/*drug therapy ; Live Birth/epidemiology ; Oxidative Stress ; Pentoxifylline/adverse effects/therapeutic use ; Pregnancy ; Pregnancy Rate ; Pregnancy, Multiple ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility.<br><br>OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women.<br><br>SEARCH METHODS: We searched the following databases (from their inception to September 2016) with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, the Cochrane Central Register of Studies (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of appropriate studies and searched for ongoing trials in the clinical trials registers.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We pooled studies using a fixed-effect model, and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. We assessed the overall quality of the evidence by applying GRADE criteria.<br><br>MAIN RESULTS: We included 50 trials involving 6510 women. Investigators compared oral antioxidants, including combinations of antioxidants, N-acetyl-cysteine, melatonin, L-arginine, myo-inositol, D-chiro-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, pentoxifylline and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant.Very low-quality evidence suggests that antioxidants may be associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 2.13, 95% CI 1.45 to 3.12, P > 0.001, 8 RCTs, 651 women, I[2] = 47%). This suggests that among subfertile women with an expected live birth rate of 20%, the rate among women using antioxidants would be between 26% and 43%.Very low-quality evidence suggests that antioxidants may be associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.52, 95% CI 1.31 to 1.76, P < 0.001, 26 RCTs, 4271 women, I[2] = 66%). This suggests that among subfertile women with an expected clinical pregnancy rate of 22%, the rate among women using antioxidants would be between 27% and 33%. Heterogeneity was moderately high.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 0.79, 95% CI 0.58 to 1.08, P = 0.14, 18 RCTs, 2834 women, I[2] = 23%, very low quality evidence). This suggests that, among subfertile women with an expected miscarriage rate of 7%, use of antioxidants would be expected to result in a miscarriage rate of between 4% and 7%. There was also insufficient evidence to determine whether there was a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.73 to 1.38, P = 0.98, 8 RCTs, 2163 women, I[2] = 4%, very low quality evidence). This suggests that among subfertile women with an expected multiple pregnancy rate of 8%, use of antioxidants would be expected to result in a multiple pregnancy rate between 6% and 11%. Likewise, there was insufficient evidence to determine whether there was a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10, P = 0.47, 3 RCTs, 343 women, I[2] = 0%, very low quality evidence). This suggests that among subfertile women with an expected gastrointestinal disturbance rate of 2%, use of antioxidants would be expected to result in a rate between 1% and 11%. Overall adverse events were reported by 35 trials in the meta-analysis, but there was insufficient evidence to draw any conclusions.Only one trial reported on live birth, clinical pregnancy or adverse effects in the antioxidant versus antioxidant comparison, and no conclusions could be drawn.Very low-quality evidence suggests that pentoxifylline may be associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.07, 95% CI 1.20 to 3.56, P = 0.009, 3 RCTs, 276 women, I[2] = 0%). This suggests that among subfertile women with an expected clinical pregnancy rate of 25%, the rate among women using pentoxifylline would be between 28% and 53%.There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 1.34, 95% CI 0.46 to 3.90, P = 0.58, 3 RCTs, 276 women, I[2] = 0%) or multiple pregnancy (OR 0.78, 95% CI 0.20 to 3.09, one RCT, 112 women, very low quality evidence). This suggests that among subfertile women with an expected miscarriage rate of 4%, the rate among women using pentoxifylline would be between 2% and 15%. For multiple pregnancy, the data suggest that among subfertile women with an expected multiple pregnancy rate of 9%, the rate among women using pentoxifylline would be between 2% and 23%.The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.<br><br>AUTHORS' CONCLUSIONS: In this review, there was very low-quality evidence to show that taking an antioxidant may provide benefit for subfertile women, but insufficient evidence to draw any conclusions about adverse events. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.}, }
@article {pmid28751209, year = {2017}, author = {Gozal, E and Metz, CJ and Dematteis, M and Sachleben, LR and Schurr, A and Rane, MJ}, title = {PKA activity exacerbates hypoxia-induced ROS formation and hypoxic injury in PC-12 cells.}, journal = {Toxicology letters}, volume = {279}, number = {}, pages = {107-114}, pmid = {28751209}, issn = {1879-3169}, support = {P30 GM103507/GM/NIGMS NIH HHS/United States ; R01 HL074296/HL/NHLBI NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Adrenal Gland Neoplasms/*enzymology/genetics/pathology ; Animals ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics/*metabolism ; Electron Transport Complex IV/metabolism ; Energy Metabolism ; Neurons/drug effects/*enzymology/pathology ; *Oxidative Stress/drug effects ; PC12 Cells ; Pheochromocytoma/*enzymology/genetics/pathology ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Time Factors ; Transfection ; *Tumor Hypoxia ; Vitamin K 3/pharmacology ; }, abstract = {Hypoxia is a primary factor in many pathological conditions. Hypoxic cell death is commonly attributed to metabolic failure and oxidative injury. cAMP-dependent protein kinase A (PKA) is activated in hypoxia and regulates multiple enzymes of the mitochondrial electron transport chain, thus may be implicated in cellular energy depletion and hypoxia-induced cell death. Wild type (WT) PC-12 cells and PKA activity-deficient 123.7 PC-12 cells were exposed to 3, 6, 12 and 24h hypoxia (0.1% or 5% O2). Hypoxia, at 24h 0.1% O2, induced cell death and increased reactive oxygen species (ROS) in WT PC-12 cells. Despite lower ATP levels in normoxic 123.7 cells than in WT cells, hypoxia only decreased ATP levels in WT cells. However, menadione-induced oxidative stress similarly affected both cell types. While mitochondrial COX IV expression remained consistently higher in 123.7 cells, hypoxia decreased COX IV expression in both cell types. N-acetyl cysteine antioxidant treatment blocked hypoxia-induced WT cell death without preventing ATP depletion. Transient PKA catα expression in 123.7 cells partially restored hypoxia-induced ROS but did not alter ATP levels or COX IV expression. We conclude that PKA signaling contributes to hypoxic injury, by regulating oxidative stress rather than by depleting ATP levels. Therapeutic strategies targeting PKA signaling may improve cellular adaptation and recovery in hypoxic pathologies.}, }
@article {pmid28750364, year = {2017}, author = {Zou, J and Zhang, Y and Sun, J and Wang, X and Tu, H and Geng, S and Liu, R and Chen, Y and Bi, Z}, title = {Deoxyelephantopin Induces Reactive Oxygen Species-Mediated Apoptosis and Autophagy in Human Osteosarcoma Cells.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {42}, number = {5}, pages = {1812-1821}, doi = {10.1159/000479537}, pmid = {28750364}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Antineoplastic Agents, Phytogenic/chemistry/pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/*drug effects ; Bone Neoplasms/metabolism/pathology ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Lactones/chemistry/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Osteosarcoma/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/chemistry/*pharmacology ; }, abstract = {BACKGROUND/AIMS: Osteosarcoma is the predominant form of primary bone malignancy. Although the combinational application of neoadjuvant chemotherapy and surgical resection significantly increases the survival rate, the therapeutic outcome remains unsatisfactory. Deoxyelephantopin (DET), an active ingredient of Elephantopus scaber, has been reported to have an anti-tumor effect in recent publications. This study aimed to investigate whether DET has antineoplastic effects on osteosarcoma cells and its underlying mechanism.<br><br>METHODS: Cell viability and morphological changes were assessed by MTT and Live/dead assays. Cell apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential were detected utilizing Annexin V-FITC/PI double staining, DCFH-DA and JC-1 probes, respectively. Autophagy was detected by mRFP-GFP-LC3 adenovirus transfection and western blot.<br><br>RESULTS: DET dose-dependently reduced the viability of osteosarcoma cells following the increase in intracellular ROS levels. Pretreatment with N-acetylcysteine (NAC) reversed this effect. Furthermore, DET induced mitochondrial apoptosis. Depolarized cells were increased, and apoptosis-related proteins, such as Bax, Bcl-2, cleaved caspase-9, cleaved caspase-3 and cleaved ploy ADP-ribose polymerase, were activated. Additionally, we found that DET could induce autophagy in osteosarcoma cells, but autophagy inhibition did not affect the decrease in cell viability.<br><br>CONCLUSION: DET induced apoptosis in osteosarcoma cells through ROS generation, mitochondrial dysfunction and caspase activation; in addition, autophagy was involved in the effects of DET on osteosarcoma cells.}, }
@article {pmid28747595, year = {2017}, author = {Styllou, P and Styllou, M and Hickel, R and Högg, C and Reichl, FX and Scherthan, H}, title = {NAC ameliorates dental composite-induced DNA double-strand breaks and chromatin condensation.}, journal = {Dental materials journal}, volume = {36}, number = {5}, pages = {638-646}, doi = {10.4012/dmj.2016-316}, pmid = {28747595}, issn = {1881-1361}, mesh = {*Acetylcysteine ; Bisphenol A-Glycidyl Methacrylate ; *Chromatin ; Composite Resins ; DNA ; *DNA Damage ; Humans ; Methacrylates ; Polyethylene Glycols ; Polymethacrylic Acids ; }, abstract = {Released (co)monomers from dental composite components can induce DNA damage of which DNA double-strand breaks (DSBs) threaten genome integrity. Here, we tested whether the administration of the antioxidant N-acetylcysteine (NAC) is able to reduce the dental composite-induced DSBs in primary human gingiva fibroblasts. The dental composites Bis-GMA (bisphenol-A-glycerolate dimethacrylate), GMA (glycidyl methacrylate), HEMA (2-hydroxyethyl methacrylate) and TEGDMA (triethyleneglycol dimethacrylate) were found to induce co-localizing microscopic nuclear foci numbers of the DSB markers γ-H2AX and 53BP1 per cell in the order: GMA>Bis-GMA>TEGDMA>HEMA. Supplementation of (co)monomer-containing culture medium with NAC led to a significant reduction of resin-induced DSBs as well as to an amelioration of dental monomer-induced nuclear chromatin condensation in gingival fibroblasts. Thus, antioxidant treatment can reduce radical-induced chromatin and DNA damage and open avenues to mitigate genotoxic effects of dental composite compounds.}, }
@article {pmid28743626, year = {2017}, author = {Ko, EY and Cho, SH and Kwon, SH and Eom, CY and Jeong, MS and Lee, W and Kim, SY and Heo, SJ and Ahn, G and Lee, KP and Jeon, YJ and Kim, KN}, title = {The roles of NF-κB and ROS in regulation of pro-inflammatory mediators of inflammation induction in LPS-stimulated zebrafish embryos.}, journal = {Fish &amp; shellfish immunology}, volume = {68}, number = {}, pages = {525-529}, doi = {10.1016/j.fsi.2017.07.041}, pmid = {28743626}, issn = {1095-9947}, mesh = {Acetylcysteine/metabolism ; Animals ; Embryo, Nonmammalian ; Fish Diseases/*immunology ; Fish Proteins/*metabolism ; Gene Expression Regulation ; Inflammation/immunology/*veterinary ; Inflammation Mediators/*metabolism ; Lipopolysaccharides/administration &amp; dosage ; NF-kappa B/*metabolism ; Pyrrolidines/metabolism ; Reactive Oxygen Species/*metabolism ; Thiocarbamates/metabolism ; *Zebrafish ; }, abstract = {In this study, the roles of reactive oxygen species (ROS) and NF-κB on inflammation induction in lipopolysaccharide (LPS)-stimulated zebrafish embryos were evaluated using N-acetyl-l-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), specific inhibitors of ROS and NF-κB, respectively. LPS-stimulated zebrafish embryos showed increasing production of NO and ROS and expression of iNOS and COX-2 protein, compared to a control group without LPS. However, NAC significantly inhibited production of NO and ROS and markedly suppressed expression of iNOS and COX-2 protein in LPS-stimulated zebrafish embryos. The mRNA expressions of NF-κB such as p65NF-κB and IκB-A were significantly increased after LPS stimulation, whereas PDTC attenuated mRNA expression of NF-κB. PDTC also inhibited production of NO and reduced expression of iNOS and COX-2 protein in LPS-stimulated zebrafish embryos. Taken together, these results indicated that LPS increases pro-inflammatory mediators in zebrafish embryos through ROS and NF-κB regulation.}, }
@article {pmid28740404, year = {2017}, author = {Chang, YT and Huang, CY and Tang, JY and Liaw, CC and Li, RN and Liu, JR and Sheu, JH and Chang, HW}, title = {Reactive oxygen species mediate soft corals-derived sinuleptolide-induced antiproliferation and DNA damage in oral cancer cells.}, journal = {OncoTargets and therapy}, volume = {10}, number = {}, pages = {3289-3297}, pmid = {28740404}, issn = {1178-6930}, abstract = {We previously reported that the soft coral-derived bioactive substance, sinuleptolide, can inhibit the proliferation of oral cancer cells in association with oxidative stress. The functional role of oxidative stress in the cell-killing effect of sinuleptolide on oral cancer cells was not investigated as yet. To address this question, we introduced the reactive oxygen species (ROS) scavenger (N-acetylcysteine [NAC]) in a pretreatment to evaluate the sinuleptolide-induced changes to cell viability, morphology, intracellular ROS, mitochondrial superoxide, apoptosis, and DNA damage of oral cancer cells (Ca9-22). After sinuleptolide treatment, antiproliferation, apoptosis-like morphology, ROS/mitochondrial superoxide generation, annexin V-based apoptosis, and γH2AX-based DNA damage were induced. All these changes were blocked by NAC pretreatment at 4 mM for 1 h. This showed that the cell-killing mechanism of oral cancer cells of sinuleptolide is ROS dependent.}, }
@article {pmid28739487, year = {2017}, author = {Liu, J and Liu, Y and Chen, J and Hu, C and Teng, M and Jiao, K and Shen, Z and Zhu, D and Yue, J and Li, Z and Li, Y}, title = {The ROS-mediated activation of IL-6/STAT3 signaling pathway is involved in the 27-hydroxycholesterol-induced cellular senescence in nerve cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {45}, number = {Pt 1}, pages = {10-18}, doi = {10.1016/j.tiv.2017.07.013}, pmid = {28739487}, issn = {1879-3177}, mesh = {Animals ; Cell Line ; Cell Survival/*drug effects/physiology ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation/drug effects ; Humans ; Hydroxycholesterols/administration &amp; dosage/*toxicity ; Interleukin-6/*metabolism ; Mice ; *Microglia ; Pheochromocytoma ; Rats ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*metabolism ; }, abstract = {The oxysterol 27-hydroxycholesterol (27HC) is a selective estrogen receptor modulator (SERMs), which like endogenous estrogen 17β-estradiol (E2) induces the proliferation of ER-positive breast cancer cells in vitro. Interestingly, the observation that 27HC induces adverse effects in neural system, distinguishing it from E2. It has been suggested that high levels of circulating cholesterol increase the entry of 27HC into the brain, which may induce learning and memory impairment. Based on this evidence, 27HC may be associated with neurodegenerative processes and interrupted cholesterol homeostasis in the brain. However, the biological events that participate in this process remain largely elusive. In the present study, we demonstrated that 27HC induced apparent cellular senescence in nerve cells. Senescence-associated β-galactosidase (SA-β-Gal) assay revealed that 27HC induced senescence in both BV2 cells and PC12 cells. Furthermore, we demonstrated that 27HC promoted the accumulation of cellular reactive oxygen species (ROS) in nerve cells and subsequently activation of IL-6/STAT3 signaling pathway. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) markedly blocked 27HC-induced ROS production and activation of IL-6/STAT3 signaling pathway. Either blocking the generation of ROS or inhibition of IL-6/STAT3 both attenuated 27HC-induced cellular senescence. In sum, these findings not only suggested a mechanism whereby 27HC induced cellular senescence in nerve cells, but also helped to recognize the 27HC as a novel harmful factor in neurodegenerative diseases.}, }
@article {pmid28737762, year = {2017}, author = {Zhang, ZM and Ma, KW and Gao, L and Hu, Z and Schwizer, S and Ma, W and Song, J}, title = {Mechanism of host substrate acetylation by a YopJ family effector.}, journal = {Nature plants}, volume = {3}, number = {}, pages = {17115}, pmid = {28737762}, issn = {2055-0278}, support = {R35 GM119721/GM/NIGMS NIH HHS/United States ; S10 OD021832/OD/NIH HHS/United States ; }, mesh = {Acetyl Coenzyme A/chemistry ; Acetylation ; Bacterial Proteins/*chemistry/metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Models, Molecular ; Phytic Acid/chemistry ; Protein Conformation ; Ralstonia solanacearum/metabolism ; Type III Secretion Systems ; Yersinia/*metabolism ; }, abstract = {The Yersinia outer protein J (YopJ) family of bacterial effectors depends on a novel acetyltransferase domain to acetylate signalling proteins from plant and animal hosts. However, the underlying mechanism is unclear. Here, we report the crystal structures of PopP2, a YopJ effector produced by the plant pathogen Ralstonia solanacearum, in complex with inositol hexaphosphate (InsP6), acetyl-coenzyme A (AcCoA) and/or substrate Resistance to Ralstonia solanacearum 1 (RRS1-R)WRKY. PopP2 recognizes the WRKYGQK motif of RRS1-RWRKY to position a targeted lysine in the active site for acetylation. Importantly, the PopP2-RRS1-RWRKY association is allosterically regulated by InsP6 binding, suggesting a previously unidentified role of the eukaryote-specific cofactor in substrate interaction. Furthermore, we provide evidence for the reaction intermediate of PopP2-mediated acetylation, an acetyl-cysteine covalent adduct, lending direct support to the 'ping-pong'-like catalytic mechanism proposed for YopJ effectors. Our study provides critical mechanistic insights into the virulence activity of YopJ class of acetyltransferases.}, }
@article {pmid28735473, year = {2018}, author = {Lei, B and Sun, S and Xu, J and Feng, C and Yu, Y and Xu, G and Wu, M and Peng, W}, title = {Low-concentration BPAF- and BPF-induced cell biological effects are mediated by ROS in MCF-7 breast cancer cells.}, journal = {Environmental science and pollution research international}, volume = {25}, number = {4}, pages = {3200-3208}, doi = {10.1007/s11356-017-9709-7}, pmid = {28735473}, issn = {1614-7499}, support = {21507078//the National Natural Science Foundation of China/ ; 41430644//the National Natural Science Foundation of China/ ; 41373098//the National Natural Science Foundation of China/ ; OGL-201410//the Open Fund of State Key Laboratory of Organic Geochemistry/ ; IRT13078//the Program for Changjiang Scholars and Innovative Research Team in University/ ; }, mesh = {Benzhydryl Compounds/*toxicity ; Breast Neoplasms/pathology ; Cell Proliferation ; Cell Survival/drug effects/physiology ; DNA Damage/drug effects/physiology ; Female ; Humans ; MCF-7 Cells ; Oxidation-Reduction/drug effects ; Phenols/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Reactive oxygen species (ROS) induced by bisphenol A (BPA) have been implicated in cellular oxidative damage and carcinogenesis. It is not known whether the potential alternatives of BPA, bisphenol AF (BPAF), and bisphenol F (BPF) can also induce ROS involved in mediating biological responses. This study evaluated the toxicity of BPAF and BPF on cell proliferation, DNA damage, intracellular calcium homeostasis, and ROS generation in MCF-7 human breast cancer cells. The results showed that BPAF at 0.001-1 μM and BPF at 0.01-1 μM significantly increased cell viability and at 25 and 50 μM, both compounds decreased cell viability. At 0.01-10 μM, both BPAF and BPF increased DNA damage and significantly elevated ROS and intracellular Ca[2+] levels in MCF-7 cells. These biological effects were attenuated by the ROS scavenger N-acetylcysteine (NAC), indicating that ROS played a key role in the observed biological effects of BPAF and BPF on MCF-7 cells. These findings can deepen our understanding on the toxicity of BPAF and BPF, and provide basis data to further evaluate the potential health harm and establish environmental standard of BPAF and BPF.}, }
@article {pmid28730106, year = {2017}, author = {Zhang, YH and Li, J and Yang, WZ and Xian, ZH and Feng, QT and Ruan, XC}, title = {Mitochondrial expression and activity of P-glycoprotein under oxidative stress in outer blood-retinal barrier.}, journal = {International journal of ophthalmology}, volume = {10}, number = {7}, pages = {1055-1063}, pmid = {28730106}, issn = {2222-3959}, abstract = {AIM: To investigate the role of oxidative stress in regulating the functional expression of P-glycoprotein (P-gp) in mitochondria of D407 cells.<br><br>METHODS: D407 cells were exposed to different ranges of concentrations of H2O2. The mitochondrial location of P-gp in the cells subjected to oxidative stress was detected by confocal analysis. Expression of P-gp in isolated mitochondria was assessed by Western blot. The pump activity of P-gp was evaluated by performing the efflux study on isolated mitochondria with Rhodamine 123 (Rho-123) alone and in the presence of P-gp inhibitor (Tariquidar) using flow cytometry analysis. The cells were pretreated with 10 mmol/L N-acetylcysteine (NAC) for 30min before exposing to H2O2, and analyzed the mitochondrial extracts by Western blot and flow cytometry.<br><br>RESULTS: P-gp was co-localized in the mitochondria by confocal laser scanning microscopy, and it was also detected in the mitochondria of D407 cells using Western blot. Exposure to increasing concentrations of H2O2 led to gradually increased expression and location of P-gp in the mitochondria of cells. Rho-123 efflux assay showed higher uptake of Rho-123 on isolated mitochondria in the presence of Tariquidar both in normal and oxidative stress state. H2O2 up-regulated P-gp in D407 cells, which could be reversed by NAC treatment.<br><br>CONCLUSION: H2O2 could up-regulate the functional expression of P-gp in mitochondria of D407 cells, while antioxidants might suppress oxidative-stress-induced over-expression of functional P-gp. It is indicative that limiting the mitochondrial P-gp transport in retinal pigment epithelium cells would be to improve the effect of mitochondria-targeted antioxidant therapy in age-related macular degeneration-like retinopathy.}, }
@article {pmid28729056, year = {2017}, author = {Zhou, M and Wang, M and Zhong, RF and Liao, XM and Deng, LL and Xu, GB and He, X and Li, J and Li, YJ and Liu, T and Wang, YL and Liao, SG}, title = {Discovery and structure-activity relationship of auriculatone: A potent hepatoprotective agent against acetaminophen-induced liver injury.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {27}, number = {16}, pages = {3636-3642}, doi = {10.1016/j.bmcl.2017.07.028}, pmid = {28729056}, issn = {1464-3405}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/pharmacology ; Binding Sites ; Cell Line ; Cell Survival/drug effects ; Cytochrome P-450 CYP3A/chemistry/metabolism ; Glutathione/metabolism ; Humans ; Liver/*drug effects/metabolism ; Molecular Docking Simulation ; Oleanolic Acid/*analogs &amp; derivatives/pharmacology ; Protective Agents/chemistry/*pharmacology ; Protein Structure, Tertiary ; Structure-Activity Relationship ; }, abstract = {Acetaminophen (APAP, paracetamol) overdose has been the most frequent cause of drug-induced liver failure. APAP-induced liver toxicity can be fatal in many cases even with treatment of the clinically used N-acetylcysteine (NAC), and the need for novel therapeutic agents is apparent. Through evaluating the hepatoprotective effects of the co-occurring substances present in oleanolic acid tablets which have been used in China for decades as an adjuvant therapy for acute and chronic hepatitis, auriculatone was found to protect HL-7702 cells from APAP-induced liver injury comparable to NAC at the concentration of 10μM. Structure activity relationship on auriculatone and its analogs showed that absence of the C17 carboxyl group of auriculatone was essential to achieve good hepatoprotective activity, and that the C3-OH, C16 carbonyl and C12-C13 olefinic group were critical for retaining the exceptional activity of auriculatone. Any modifications in the current investigation were all detrimental to the hepatoprotective activity. Docking and drug-metabolizing activity studies demonstrated that CYP3A4 was likely the main target of auriculatone, and that auriculatone elicited the hepatoprotective effect possibly through inhibiting CYP3A4's metabolism of APAP to the toxic metabolite NAPQI. The work may pave the way for the use of auriculatone in the treatment of APAP-induced liver injury.}, }
@article {pmid28720395, year = {2017}, author = {Sharma, S and Gralla, J and Ordonez, JG and Hurtado, ME and Swenson, ER and Schoene, RB and Kelly, JP and Callacondo, D and Rivard, C and Roncal-Jimenez, C and Sirota, J and Fuquay, R and Jackson, BP and Swenson, KE and Johnson, RJ and Hurtado, A and Escudero, E}, title = {Acetazolamide and N-acetylcysteine in the treatment of chronic mountain sickness (Monge's disease).}, journal = {Respiratory physiology &amp; neurobiology}, volume = {246}, number = {}, pages = {1-8}, doi = {10.1016/j.resp.2017.07.005}, pmid = {28720395}, issn = {1878-1519}, mesh = {Acetazolamide/*therapeutic use ; Acetylcysteine/*therapeutic use ; Adult ; Altitude Sickness/blood/*drug therapy/urine ; Analysis of Variance ; Blood Gas Analysis ; Carbonic Anhydrase Inhibitors/*therapeutic use ; Chi-Square Distribution ; Chronic Disease ; Cobalt/blood/urine ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*therapeutic use ; Hematocrit/methods ; Humans ; Male ; Middle Aged ; Peru ; Prospective Studies ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {Patients suffering from chronic mountain sickness (CMS) have excessive erythrocytosis. Low -level cobalt toxicity as a likely contributor has been demonstrated in some subjects. We performed a randomized, placebo controlled clinical trial in Cerro de Pasco, Peru (4380m), where 84 participants with a hematocrit (HCT) ≥65% and CMS score>6, were assigned to four treatment groups of placebo, acetazolamide (ACZ, which stimulates respiration), N-acetylcysteine (NAC, an antioxidant that chelates cobalt) and combination of ACZ and NAC for 6 weeks. The primary outcome was change in hematocrit and secondary outcomes were changes in PaO2, PaCO2, CMS score, and serum and urine cobalt concentrations. The mean (±SD) hematocrit, CMS score and serum cobalt concentrations were 69±4%, 9.8±2.4 and 0.24±0.15μg/l, respectively for the 66 participants. The ACZ arm had a relative reduction in HCT of 6.6% vs. 2.7% (p=0.048) and the CMS score fell by 34.9% vs. 14.8% (p=0.014) compared to placebo, while the reduction in PaCO2 was 10.5% vs. an increase of 0.6% (p=0.003), with a relative increase in PaO2 of 13.6% vs. 3.0%. NAC reduced CMS score compared to placebo (relative reduction of 34.0% vs. 14.8%, p=0.017), while changes in other parameters failed to reach statistical significance. The combination of ACZ and NAC was no better than ACZ alone. No changes in serum and urine cobalt concentrations were seen within any treatment arms. ACZ reduced polycythemia and CMS score, while NAC improved CMS score without significantly lowering hematocrit. Only a small proportion of subjects had cobalt toxicity, which may relate to the closing of contaminated water sources and several other environmental protection measures.}, }
@article {pmid28720375, year = {2017}, author = {Khoshaman, K and Yousefi, R and Moosavi-Movahedi, AA}, title = {Protective role of antioxidant compounds against peroxynitrite-mediated modification of R54C mutant αA-crystallin.}, journal = {Archives of biochemistry and biophysics}, volume = {629}, number = {}, pages = {43-53}, doi = {10.1016/j.abb.2017.07.007}, pmid = {28720375}, issn = {1096-0384}, mesh = {Antioxidants/*pharmacology ; Humans ; *Mutation ; Peroxynitrous Acid/*pharmacology ; Protein Conformation/drug effects ; Protein Stability/drug effects ; alpha-Crystallins/chemistry/*genetics/*metabolism ; }, abstract = {As a highly potent reactive oxygen and nitrogen species, peroxynitrite (PON) has endogenous production in the eye ball and contributes to a variety of ocular disorders. In the current study the structural characteristics, chaperone-like activity and conformational stability of R54C mutant αA-crystallin (αA-Cry) were studied upon modification with PON and in the presence of three antioxidant compounds such as ascorbic acid (ASA), glutathione (GSH) and N-acetylcysteine (NAC) using gel electrophoresis and different spectroscopy methods. The results of both fluorescence analysis and gel electrophoresis suggested that PON modification leads to dityrosine-mediated intermolecular cross-linking of this cataractogenic mutant protein. Also, the propensity of R54C mutant αA-Cry for disulfide cross-linking was increased upon PON modification. In addition, the PON-modified protein indicated structural alteration, reduced chemical stability and different pattern of proteolysis. Upon modification with PON, mutant αA-Cry displayed a significant increase in the chaperone-like activity against aggregation of γ-crystallin and insulin. In addition, different antioxidant compounds indicated a prominent role in neutralizing the PON damaging effects on structural integrity and stability of this protein. The results of this study may highlight the importance of antioxidant-rich foods or potent antioxidant supplements in protection of lens crystallins against PON-mediated structural damages and cataract development.}, }
@article {pmid28715732, year = {2017}, author = {Park, S and Park, JA and Yoo, H and Park, HB and Lee, Y}, title = {Proteasome inhibitor-induced cleavage of HSP90 is mediated by ROS generation and caspase 10-activation in human leukemic cells.}, journal = {Redox biology}, volume = {13}, number = {}, pages = {470-476}, pmid = {28715732}, issn = {2213-2317}, mesh = {Acetylcysteine/pharmacology ; Carrier Proteins/genetics/metabolism ; Caspase 10/genetics/*metabolism ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; HCT116 Cells ; HSP90 Heat-Shock Proteins/genetics/*metabolism ; HT29 Cells ; Humans ; Leukemia/*metabolism ; Leupeptins/pharmacology ; MCF-7 Cells ; Protease Inhibitors/*pharmacology ; Proteolysis/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Heat shock protein 90 (HSP90) is a molecular chaperone that supports the stability of client proteins. The proteasome is one of the targets for cancer therapy, and studies are underway to use proteasome inhibitors as anti-cancer drugs. In this study, we found that HSP90 was cleaved to a 55kDa protein after treatment with proteasome inhibitors including MG132 in leukemia cells but was not cleaved in other tissue-derived cells. HSP90 has two major isoforms (HSP90α and HSP90β), and both were cleaved by MG132 treatment. MG132 treatment also induced a decrease in HSP90 client proteins. MG132 treatment generated ROS, and the cleavage of HSP90 was blocked by a ROS scavenger, N-acetylcysteine (NAC). MG132 activated several caspases, and the activation was reduced by pretreatment with NAC. Based on an inhibitor study, the cleavage of HSP90 induced by MG132 was dependent on caspase 10 activation. Furthermore, active recombinant caspase 10 induced HSP90 cleavage in vitro. MG132 upregulated VDUP-1 expression and reduced the GSH levels implying that the regulation of redox-related proteins is involved. Taken all together, our results suggest that the cleavage of HSP90 by MG132 treatment is mediated by ROS generation and caspase 10 activation. HSP90 cleavage may provide an additional mechanism involved in the anti-cancer effects of proteasome inhibitors.}, }
@article {pmid28714083, year = {2018}, author = {Jaiswal, P and Attar, BM and Yap, JE and Devani, K and Jaiswal, R and Wang, Y and Szynkarek, R and Patel, D and Demetria, M}, title = {Acute liver failure with amiodarone infusion: A case report and systematic review.}, journal = {Journal of clinical pharmacy and therapeutics}, volume = {43}, number = {1}, pages = {129-133}, doi = {10.1111/jcpt.12594}, pmid = {28714083}, issn = {1365-2710}, mesh = {Aged ; Female ; Humans ; *Amiodarone/adverse effects ; *Anti-Arrhythmia Agents/adverse effects ; Hospitalization ; Infusions, Intravenous/methods ; *Liver Failure, Acute/chemically induced ; }, abstract = {WHAT IS KNOWN AND OBJECTIVE: Amiodarone, a commonly used class III antiarrhythmic agent notable for a relatively long half-life of up to 6 months and its pronounced adverse effect profile, is used for both acute and chronic management of cardiac arrhythmias. Chronic use of amiodarone has been associated with asymptomatic hepatotoxicity; however, acute toxicity is thought to be uncommon. There are only six reported cases of acute liver failure (ALF) secondary to amiodarone. In all these cases the outcome of death during the same hospitalization resulted. We aimed to report the only case of acute liver failure secondary to amiodarone infusion in the existing literature where the patient survived.<br><br>CASE SUMMARY: A 79-year-old woman admitted with atrial flutter was being treated with intravenous (IV) amiodarone when she abruptly developed coagulopathy, altered mental status and liver enzyme derangement. She was diagnosed with acute liver failure (ALF) secondary to an amiodarone adverse drug reaction, with a calculated score of seven on the Naranjo adverse drug reaction probability scale. Amiodarone was immediately withheld, and N-acetylcysteine (NAC) was initiated. Clinical improvement was seen within 48&#xa0;hours of holding the drug and within 24&#xa0;hours of initiating NAC. On post-hospital follow-up visit she was reported to have complete recovery.<br><br>WHAT IS NEW AND CONCLUSION: This report emphasizes the importance of monitoring liver enzymes and mental status while a patient is being administered IV amiodarone. N-acetylcysteine administration may have possibly contributed to the early and successful recovery from ALF in our patient. To date, she is the only patient in the existing literature who has been reported to survive ALF secondary to amiodarone administration.}, }
@article {pmid28711476, year = {2018}, author = {Retsa, C and Knebel, JF and Geiser, E and Ferrari, C and Jenni, R and Fournier, M and Alameda, L and Baumann, PS and Clarke, S and Conus, P and Do, KQ and Murray, MM}, title = {Treatment in early psychosis with N-acetyl-cysteine for 6months improves low-level auditory processing: Pilot study.}, journal = {Schizophrenia research}, volume = {191}, number = {}, pages = {80-86}, doi = {10.1016/j.schres.2017.07.008}, pmid = {28711476}, issn = {1573-2509}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Acoustic Stimulation ; Adult ; Antipsychotic Agents/pharmacology/*therapeutic use ; Contingent Negative Variation/*drug effects ; Double-Blind Method ; Electroencephalography ; Evoked Potentials, Auditory/*drug effects ; Female ; Follow-Up Studies ; Humans ; Male ; Pilot Projects ; Psychotic Disorders/*drug therapy ; Young Adult ; }, abstract = {Sensory impairments constitute core dysfunctions in schizophrenia. In the auditory modality, impaired mismatch negativity (MMN) has been observed in chronic schizophrenia and may reflect N-methyl-d-aspartate (NMDA) hypo-function, consistent with models of schizophrenia based on oxidative stress. Moreover, a recent study demonstrated deficits in the N100 component of the auditory evoked potential (AEP) in early psychosis patients. Previous work has shown that add-on administration of the glutathione precursor N-acetyl-cysteine (NAC) improves the MMN and clinical symptoms in chronic schizophrenia. To date, it remains unknown whether NAC also improves general low-level auditory processing and if its efficacy would extend to early-phase psychosis. We addressed these issues with a randomized, double-blind study of a small sample (N=15) of early psychosis (EP) patients and 18 healthy controls from whom AEPs were recorded during an active, auditory oddball task. Patients were recorded twice: once prior to NAC/placebo administration and once after six months of treatment. The N100 component was significantly smaller in patients before NAC administration versus controls. Critically, NAC administration improved this AEP deficit. Source estimations revealed increased activity in the left temporo-parietal lobe in patients after NAC administration. Overall, the data from this pilot study, which call for replication in a larger sample, indicate that NAC improves low-level auditory processing in early psychosis.}, }
@article {pmid28706398, year = {2017}, author = {Syed, MH and Khandelwal, PN and Thawani, VR and Katare, SS}, title = {Efficacy of Atorvastatin in Prevention of Contrast-induced Nephropathy in High-risk Patients Undergoing Angiography: A Double-blind Randomized Controlled Trial.}, journal = {Journal of pharmacology &amp; pharmacotherapeutics}, volume = {8}, number = {2}, pages = {50-53}, pmid = {28706398}, issn = {0976-500X}, abstract = {OBJECTIVE: To evaluate the efficacy and safety of atorvastatin (ATN) 80 mg in the prevention of contrast medium- induced nephropathy (CIN) in high risk patients undergoing angiograph.<br><br>MATERIALS AND METHODS: This was a prospective, double-blind, two-arm, parallel group RCT. A total of 216 patients undergoing coronary angiography were screened, and 188 eligible patients were randomized to two treatment arms. Patients in Group A received tablet N-acetylcysteine (NAC) 1200 mg once daily, and patients in Group B received tablet atorvastatin 80 mg + NAC 1200 mg once daily, for 3 days before, and 2 days after angiography.<br><br>RESULTS: A total of 160 patients completed the trial. Postprocedure, nine and two CIN cases were found in Group A and B, respectively. The mean change in serum creatinine was 0.086 &#xb1; 0.168 in Group A and 0.021 &#xb1; 0.083 in Group B, which was statistically significant (P = 0.0289). Postprocedure, the estimated glomerular filteration rate was reduced by 19.52 in Group A and 13.55 in Group B (P = 0.003).<br><br>CONCLUSION: This trial indicates the positive role of statins in preventive strategy against CIN along with NAC.}, }
@article {pmid28705614, year = {2017}, author = {Vukosavljevic, B and Murgia, X and Schwarzkopf, K and Schaefer, UF and Lehr, CM and Windbergs, M}, title = {Tracing molecular and structural changes upon mucolysis with N-acetyl cysteine in human airway mucus.}, journal = {International journal of pharmaceutics}, volume = {533}, number = {2}, pages = {373-376}, doi = {10.1016/j.ijpharm.2017.07.022}, pmid = {28705614}, issn = {1873-3476}, mesh = {Acetylcysteine/*chemistry ; Freeze Drying ; Humans ; Microscopy, Electron, Scanning ; Mucus/*chemistry ; Respiratory Mucosa ; Rheology ; Spectrum Analysis, Raman ; }, abstract = {The conducting airways of the human lungs are lined by mucus, which lubricates the lung epithelium and provides a first-line protection against airborne threats. As a novel approach for visualization of the human mucus microstructure, we applied confocal Raman microscopy as a label-free and chemically selective technique. We were successfully able to chemically resolve the pulmonary surfactant from the mucus matrix and show its spatial distribution, as well as to visualize the structural changes within the freeze-dried mucus mesh upon chemical mucolysis. Subsequently, we performed rheological measurements before and after mucolysis and correlated morphology and chemical structure of the mucus with its rheological characteristics. These results do not only enrich the knowledge about the mucus microstructure, but can also, significantly contribute to rational development of future lung therapeutics.}, }
@article {pmid28704996, year = {2017}, author = {Sun, Q and Qi, W and Xiao, X and Yang, SH and Kim, D and Yoon, KS and Clark, JM and Park, Y}, title = {Imidacloprid Promotes High Fat Diet-Induced Adiposity in Female C57BL/6J Mice and Enhances Adipogenesis in 3T3-L1 Adipocytes via the AMPKα-Mediated Pathway.}, journal = {Journal of agricultural and food chemistry}, volume = {65}, number = {31}, pages = {6572-6581}, pmid = {28704996}, issn = {1520-5118}, support = {R21 ES023128/ES/NIEHS NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases/genetics/*metabolism ; Adipocytes/cytology/*drug effects/metabolism ; Adipogenesis/*drug effects ; Adiposity/*drug effects ; Animals ; Diet, High-Fat/adverse effects ; Female ; Humans ; Imidazoles/*adverse effects ; Insecticides/*adverse effects ; Male ; Mice ; Mice, Inbred C57BL ; Neonicotinoids ; Nitro Compounds/*adverse effects ; Obesity/etiology/*metabolism ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Signal Transduction/drug effects ; }, abstract = {Imidacloprid, a neonicotinoid insecticide, was previously reported to enhance adipogenesis and resulted in insulin resistance in cell culture models. It was also reported to promote high fat diet-induced obesity and insulin resistance in male C57BL/6J mice. Thus, the goal of the present study was to determine the effects of imidacloprid and dietary fat interaction on the development of adiposity and insulin resistance in female C57BL/6J mice. Mice were fed with a low (4% w/w) or high fat (20% w/w) diet containing imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) for 12 weeks. Mice fed with imidacloprid (0.6 mg/kg bw/day) significantly enhanced high fat diet-induced weight gain and adiposity. Treatment with imidacloprid significantly increased serum insulin levels with high fat diet without effects on other markers of glucose homeostasis. AMPKα activation was significantly inhibited by 0.6 and 6 mg imidacloprid/kg bw/day in white adipose tissue. Moreover, AMPKα activation with 5-aminoimidazole-4-carboxamide ribonucleotide abolished the effects of imidacloprid (10 μM) on enhanced adipogenesis in 3T3-L1 adipocytes. N-Acetyl cysteine also partially reversed the effects of imidacloprid on reduced phosphorylation of protein kinase B (AKT) in C2C12 myotubes. These results indicate that imidacloprid may potentiate high fat diet-induced adiposity in female C57BL/6J mice and enhance adipogenesis in 3T3-L1 adipocytes via the AMPKα-mediated pathway. Imidacloprid might also influence glucose homeostasis partially by inducing cellular oxidative stress in C2C12 myotubes.}, }
@article {pmid28703421, year = {2018}, author = {Gaykwad, C and Garkhal, J and Chethan, GE and Nandi, S and De, UK}, title = {Amelioration of oxidative stress using N-acetylcysteine in canine parvoviral enteritis.}, journal = {Journal of veterinary pharmacology and therapeutics}, volume = {41}, number = {1}, pages = {68-75}, pmid = {28703421}, issn = {1365-2885}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Dogs ; Enteritis/drug therapy/*veterinary/virology ; Erythrocyte Count/veterinary ; Hemoglobins/analysis ; Oxidative Stress/*drug effects ; Parvoviridae Infections/drug therapy/*veterinary ; *Parvovirus, Canine ; Polymerase Chain Reaction/veterinary ; }, abstract = {Previously, antioxidants have not been evaluated for treatment of parvoviral diarrhea in dogs. In this study, antioxidant potential of N-acetylcysteine (NAC) in dogs infected with canine parvovirus with a nonblinded randomized clinical trial has been carried out. A total 18 parvo-infected dogs were randomly divided into two groups: nine parvo-infected dogs were treated with supportive treatment and nine parvo-infected dogs were treated with NAC along with supportive treatment. Simultaneously, nine healthy dogs were kept as healthy control. In parvo-infected dogs, marked hemoconcentration, leucopenia, neutropenia and oxidative stress were noticed compared to healthy dogs. The NAC treatment progressively improved the leukocyte, neutrophil, monocyte, and eosinophil counts over the time in parvovirus-infected dogs compared to dogs that received only supportive treatment. In addition, NAC treatment significantly improved glutathione S-transferase (GST) activity and decreased nitrite plus nitrate (NOx) and malondialdehyde (MDA) concentrations on day 3 and 5 compared to supportive treatment in parvo-infected dogs. However, supportive treatment alone failed to ameliorate oxidative stress in the infected dogs till day 5. The results of this study suggest that NAC represents a potential additional treatment option that could be considered to improve the health condition and minimize the duration of hospitalization in case of canine parvoviral diarrhea.}, }
@article {pmid28701253, year = {2017}, author = {Spence, J and Chintapenta, M and Kwon, HI and Blaszczyk, AT}, title = {A Brief Review of Three Common Supplements Used in Alzheimer's Disease.}, journal = {The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists}, volume = {32}, number = {7}, pages = {412-414}, doi = {10.4140/TCP.n.2017.412}, pmid = {28701253}, issn = {0888-5109}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aequorin/*administration &amp; dosage ; Alzheimer Disease/*drug therapy ; Apoproteins/*administration &amp; dosage ; Dietary Supplements ; Fatty Acids, Omega-3/*administration &amp; dosage/adverse effects ; Humans ; Recombinant Proteins/administration &amp; dosage ; }, abstract = {Individuals with Alzheimer's disease (AD) and their caregivers are using supplements in an effort to halt the progression of the disease. Individuals at risk for or fearing Alzheimer's may use these supplements to try to prevent the disease. Senior care pharmacists are accessible and uniquely qualified to answer questions, make recommendations, and attempt to make drug therapy safe and effective for these individuals. With this in mind, it is important to know the data supporting (or not supporting) common supplements marketed toward those with AD. A review of efficacy and safety data, drug interactions, as well as the mechanism of action believed to benefit those with AD of three common supplements (Prevagen, Cerefolin NAC, and the omega-3 polyunsaturated fatty acid DHA), are highlighted.}, }
@article {pmid28700660, year = {2017}, author = {Grellet, S and Tzelepi, K and Roskamp, M and Williams, P and Sharif, A and Slade-Carter, R and Goldie, P and Whilde, N and Śmiałek, MA and Mason, NJ and Golding, JP}, title = {Cancer-selective, single agent chemoradiosensitising gold nanoparticles.}, journal = {PloS one}, volume = {12}, number = {7}, pages = {e0181103}, pmid = {28700660}, issn = {1932-6203}, mesh = {Apoptosis/drug effects ; Caspase Inhibitors/*chemistry/*pharmacology ; Cell Line ; Cell Line, Tumor ; Gold/*chemistry ; Humans ; Magnetic Resonance Spectroscopy ; Metal Nanoparticles/*chemistry ; Microscopy, Electron, Transmission ; }, abstract = {Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics.}, }
@article {pmid28698075, year = {2017}, author = {Nemati, M and Nemati, S and Taheri, AM and Heidari, B}, title = {Comparison of metformin and N-acetyl cysteine, as an adjuvant to clomiphene citrate, in clomiphene-resistant women with polycystic ovary syndrome.}, journal = {Journal of gynecology obstetrics and human reproduction}, volume = {46}, number = {7}, pages = {579-585}, doi = {10.1016/j.jogoh.2017.07.004}, pmid = {28698075}, issn = {2468-7847}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adjuvants, Pharmaceutic/administration &amp; dosage ; Adult ; Clomiphene/*administration &amp; dosage ; Drug Administration Schedule ; Drug Resistance/drug effects ; Drug Synergism ; Drug Therapy, Combination ; Female ; Fertility Agents, Female/*therapeutic use ; Follow-Up Studies ; Humans ; Infertility, Female/*drug therapy/etiology ; Metformin/*administration &amp; dosage ; Ovulation Induction/*methods ; Polycystic Ovary Syndrome/complications/*drug therapy ; Pregnancy ; Pregnancy Rate ; }, abstract = {OBJECTIVE: To evaluate the effects of short- and long-term treatment with metformin and NAC, in an adjuvant to clomiphene citrate (CC), on the improvement of hormonal profile (SHBG, total testosterone, FBS, and fasting insulin) and fertility status in CC-resistant women with PCOS.<br><br>MATERIALS AND METHODS: One hundred and eight CC-resistant PCOS patients participated in the study and received either metformin (1500mg/day) or NAC (1800mg/day) with 100mg/day of CC for 8 and 12 weeks. Mean BMI, hirsutism score, LH/FSH ratio, endometrial thickness, mature follicle number, and serum concentrations of LH, FSH, E2, fasting insulin, total testosterone and FBS were evaluated before and after short- and long-term treatment. Furthermore, ovulation and pregnancy rates in the first and second cycles were also determined in treated patients.<br><br>RESULTS: There was no significant difference in all variables before and 8 weeks after treatment with metformin and NAC. The BMI- and insulin-lowering effects of metformin were significantly higher than NAC after long-term treatment. However, the reducing-effect of NAC on hirsutism score and FBS levels was significantly more than metformin after 12 weeks. Treatment with metformin and NAC significantly increased ovulation and pregnancy rates in CC-resistant PCOS patients. In the first and second cycles, ovulation and pregnancy rates in patients treated with NAC were slightly higher than those received metformin.<br><br>CONCLUSIONS: Compared with metformin, administration of NAC in an adjuvant to CC is recommended for improving of hormonal profile and treatment of anovulatory infertility in hyperinsulinemic patients especially women with PCOS who are CC-resistant.}, }
@article {pmid28696987, year = {2017}, author = {Trojian, TH and Wang, DH and Leddy, JJ}, title = {Nutritional Supplements for the Treatment and Prevention of Sports-Related Concussion-Evidence Still Lacking.}, journal = {Current sports medicine reports}, volume = {16}, number = {4}, pages = {247-255}, doi = {10.1249/JSR.0000000000000387}, pmid = {28696987}, issn = {1537-8918}, mesh = {Acetylcysteine/administration &amp; dosage ; Athletes ; Athletic Injuries/prevention &amp; control/*therapy ; Brain Concussion/prevention &amp; control/*therapy ; Caffeine/adverse effects ; *Dietary Supplements ; Fatty Acids, Omega-3/administration &amp; dosage ; Humans ; *Sports Nutritional Physiological Phenomena ; Vitamins/administration &amp; dosage ; }, abstract = {Concussions are common neurologic events that affect many athletes. Very little has been studied on the treatment of concussions with supplements and medications. The U.S. Food and Drug Administration (FDA) reminds us that no supplement has been proven to treat concussions. Many animal studies show that supplements have potential for improving the effects of a brain injury but none have been shown to be of consistent benefit in human studies. Animal studies on severe traumatic brain injury (TBI) may not therefore be applicable transfer to sports-related concussions (SRC).Of the many supplements reviewed in this article, omega-3 fatty acids (Ω-3 FA) have potential for SRC treatment but in the one human trial those taking higher dosages preinjury had more concussions. In animal studies, postinjury administration was as effective as pretreatment. N-acetyl-cysteine has demonstrated a positive short-term effect on blast injuries in soldiers if administered within 24 h, but there are no studies in SRC. Caffeine, conversely, may be detrimental if taken after SRC. Lower serum levels of vitamins D, C, or E preinjury have worse outcomes in animal studies. Preinjury correction of deficiencies may be of benefit. Current human trials for nicotinamide ribose, melatonin, and branched chain amino acids (BCAA) may soon provide more evidence for the use of these supplements to reduce the impact of SRC in athletes.}, }
@article {pmid28695002, year = {2017}, author = {Fischak, C and Klaus, R and Werkmeister, RM and Hohenadl, C and Prinz, M and Schmetterer, L and Garhöfer, G}, title = {Effect of Topically Administered Chitosan-N-acetylcysteine on Corneal Wound Healing in a Rabbit Model.}, journal = {Journal of ophthalmology}, volume = {2017}, number = {}, pages = {5192924}, pmid = {28695002}, issn = {2090-004X}, abstract = {PURPOSE: The present study was performed to investigate the effect of topically administered chitosan-N-acetylcysteine (C-NAC) on corneal wound healing in a rabbit model.<br><br>METHODS: A total of 20 New Zealand White rabbits were included in the randomized, masked, placebo-controlled experiment. A monocular epithelial debridement was induced by manual scraping under general anesthesia. Animals were randomized to receive either C-NAC two times daily or placebo. Monitoring of corneal wound healing was performed with ultra-high-resolution optical coherence tomography (OCT) and epithelial fluorescein staining. Measurements were done immediately after and up to 72 hours after wound induction.<br><br>RESULTS: No difference in wound size was found immediately after surgical debridement between the C-NAC group and the placebo group. Wound healing was significantly faster in the C-NAC group compared to the placebo group (p < 0.01 for both methods). A good correlation was found between the OCT technique and the epithelial fluorescein staining in terms of wound size (r = 0.94).<br><br>CONCLUSIONS: Administration of C-NAC containing eye drops twice daily leads to a faster corneal wound healing in a rabbit model of corneal debridement as compared to placebo. Ultra-high-resolution OCT is considered a noninvasive, dye-free alternative to conventional fluorescein staining in assessing corneal wound healing also in humans.}, }
@article {pmid28691804, year = {2017}, author = {Dong, S and Masalha, N and Plewa, MJ and Nguyen, TH}, title = {Toxicity of Wastewater with Elevated Bromide and Iodide after Chlorination, Chloramination, or Ozonation Disinfection.}, journal = {Environmental science &amp; technology}, volume = {51}, number = {16}, pages = {9297-9304}, doi = {10.1021/acs.est.7b02345}, pmid = {28691804}, issn = {1520-5851}, mesh = {Animals ; *Bromides ; CHO Cells ; Chlorine ; Cricetinae ; Cricetulus ; Disinfectants ; *Disinfection ; Halogenation ; *Iodides ; Ozone ; *Wastewater ; Water Pollutants, Chemical/*toxicity ; *Water Purification ; }, abstract = {Water reuse is receiving unprecedented attention as many areas around the globe attempt to better-manage their fresh water resources. Wastewaters in coastal regions may contain elevated levels of bromide (Br[-]) and iodide (I[-]) from seawater intrusion or high mineral content in the source waters. Disinfection of such wastewater is essential to prevent the spread of pathogens; however, little is known about the toxicity of the treated wastewater. In this study, we evaluated the genotoxicity to Chinese hamster ovary (CHO) cells induced by municipal secondary wastewater effluent amended with elevated Br[-] and I[-] after disinfection by chlorine, chloramines, or ozone. We calibrated and applied an N-acetylcysteine (NAC) thiol reactivity assay as a surrogate for thiol reactivity with biological proteins (glutathione) of wastewater samples. Chlorination of wastewaters produced CHO cell genotoxicity comparable to chloramination, 3.9 times more genotoxic than the nondisinfected controls. Ozonated wastewater was at least 3 times less genotoxic than the samples treated with chlorine-based disinfectants and was not significantly different compared with the nondisinfected controls. Positive and significant correlations were observed among genotoxicity, cytotoxicity, and NAC thiol reactivity for all disinfected samples. These results indicate that the ozonation of wastewater with high Br[-] and I[-] levels may yield organics with lower genotoxicity to CHO cells than chlorine-based disinfection. NAC thiol reactivity, although excluding the possible effect of bromate from ozonation in this work, could be used as a rapid in chemico screen for potential genotoxicity and cytotoxicity in mammalian cells exposed to disinfected wastewaters.}, }
@article {pmid28690887, year = {2017}, author = {Changizi, V and Bahrami, M and Esfahani, M and Shetab-Boushehri, SV}, title = {Prevention of γ-Radiation-Induced DNA Damage in Human Lymphocytes Using a Serine-Magnesium Sulfate Mixture.}, journal = {Sultan Qaboos University medical journal}, volume = {17}, number = {2}, pages = {e162-e167}, pmid = {28690887}, issn = {2075-0528}, mesh = {Acetylcysteine/pharmacology ; Cell Survival/drug effects/radiation effects ; Comet Assay ; Cysteine/pharmacology ; DNA Damage/*drug effects ; Drug Combinations ; Gamma Rays/*adverse effects ; Humans ; Iran ; Lymphocytes/*radiation effects ; Magnesium Sulfate/*pharmacology ; Radiation Injuries/prevention &amp; control ; Radiation-Protective Agents/*pharmacology ; Serine/*pharmacology ; }, abstract = {OBJECTIVES: Ionising radiation has deleterious effects on human cells. N-acetylcysteine (NAC) and cysteine, the active metabolite of NAC, are well-known radioprotective agents. Recently, a serine-magnesium sulfate combination was proposed as an antidote for organophosphate toxicity. This study aimed to investigate the use of a serine-magnesium sulfate mixture in the prevention of γ-radiation-induced DNA damage in human lymphocytes as compared to NAC and cysteine.<br><br>METHODS: This study was carried out at the Iran University of Medical Sciences, Tehran, Iran, between April and September 2016. Citrated blood samples of 7 mL each were taken from 22 healthy subjects. Each sample was divided into 1 mL aliquots, with the first aliquot acting as the control while the second was exposed to 2 Gy of &#x3b3;-radiation at a dose rate of 102.7 cGy/minute. The remaining aliquots were separately incubated with 600 &#x3bc;M concentrations each of serine, magnesium sulfate, serine-magnesium sulfate, NAC and cysteine before being exposed to 2 Gy of &#x3b3;-radiation. Lymphocytes were isolated using a separation medium and methyl-thiazole-tetrazolium and comet assays were used to evaluate cell viability and DNA damage, respectively.<br><br>RESULTS: The serine-magnesium sulfate mixture significantly increased lymphocyte viability and reduced DNA damage in comparison to serine, magnesium sulfate, NAC or cysteine alone (P <0.01 each).<br><br>CONCLUSION: The findings of the present study support the use of a serine-magnesium sulfate mixture as a new, non-toxic, potent and efficient radioprotective agent.}, }
@article {pmid28690196, year = {2017}, author = {Wu, CL and Huang, LY and Chang, CL}, title = {Linking arsenite- and cadmium-generated oxidative stress to microsatellite instability in vitro and in vivo.}, journal = {Free radical biology &amp; medicine}, volume = {112}, number = {}, pages = {12-23}, doi = {10.1016/j.freeradbiomed.2017.07.006}, pmid = {28690196}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Arsenites/antagonists &amp; inhibitors/*toxicity ; Cadmium Chloride/antagonists &amp; inhibitors/*toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA/*genetics/metabolism ; DNA Damage ; DNA Mismatch Repair/*drug effects ; DNA-Binding Proteins/genetics/metabolism ; Gene Expression Regulation ; Genes, Reporter ; HCT116 Cells ; Humans ; Microsatellite Instability/*drug effects ; Microsatellite Repeats/drug effects ; MutL Protein Homolog 1/genetics/metabolism ; MutS Homolog 2 Protein/genetics/metabolism ; Oxidative Stress ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Sodium Compounds/antagonists &amp; inhibitors/*toxicity ; Zebrafish ; }, abstract = {Mismatch repair (MMR) corrects replicative errors and minimizes DNA damage that occurs frequently in microsatellites. MMR deficiency is manifested as microsatellite instability (MSI), which contributes to hypermutability and cancer pathogenesis. Genomic instability, including MSI and chromosomal instability, appears to be responsible for the carcinogenesis of arsenic and cadmium, common contaminants in our environment. However, few studies have addressed arsenic- or cadmium-induced MSI, especially its potential link with arsenic- or cadmium-generated oxidative stress, due to the lack of quantifiable MSI assays and cost-effective animal models. Here, using a dual-fluorescent reporter, we demonstrate that sub-lethal doses of cadmium or arsenite, but not arsenate, increased the MSI frequency in human colorectal cancer cells. Arsenite- and cadmium-induced MSI occurred concomitantly with increased levels of reactive species and oxidative DNA damage, and with decreased levels of MMR proteins. However, N-acetyl-l-cysteine (NAC) suppressed arsenite- and cadmium-induced MSI and oxidative stress while restoring the levels of MMR proteins in the cells. Similarly, MSI was induced separately by arsenite and cadmium, and suppressed by NAC, in zebrafish in a fluorescinated PCR-based assay with newly-developed microsatellite markers and inter-segmental comparisons. Of five selected antioxidants examined, differential effects were exerted on the MSI induction and cytotoxicity of both arsenite and cadmium. Compared to MMR-proficient cells, MMR-deficient cells were more resistant to arsenic-mediated and cadmium-mediated cytotoxicity. Our findings demonstrate a novel linkage between arsenite-generated and cadmium-generated oxidative stress and MSI induction. Our findings also caution that antioxidants must be individually validated before being used for preventing arsenite- and cadmium-induced MSI that is associated with cancer development.}, }
@article {pmid28686657, year = {2017}, author = {Clark, RSB and Empey, PE and Bayır, H and Rosario, BL and Poloyac, SM and Kochanek, PM and Nolin, TD and Au, AK and Horvat, CM and Wisniewski, SR and Bell, MJ}, title = {Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children.}, journal = {PloS one}, volume = {12}, number = {7}, pages = {e0180280}, pmid = {28686657}, issn = {1932-6203}, support = {KL2 TR000146/TR/NCATS NIH HHS/United States ; R01 NS069247/NS/NINDS NIH HHS/United States ; T32 HD040686/HD/NICHD NIH HHS/United States ; U01 NS081041/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/blood/cerebrospinal fluid/*pharmacokinetics/pharmacology ; Adjuvants, Pharmaceutic/*pharmacokinetics/pharmacology ; Adolescent ; Antioxidants/*pharmacokinetics/pharmacology ; Biomarkers/blood ; Body Temperature ; Brain Injuries, Traumatic/blood/cerebrospinal fluid/*drug therapy/mortality ; Child ; Child, Preschool ; Double-Blind Method ; Drug Administration Schedule ; Female ; Glasgow Coma Scale ; Glasgow Outcome Scale ; Humans ; Intracranial Pressure/drug effects ; Intubation, Gastrointestinal ; Male ; Probenecid/blood/cerebrospinal fluid/*pharmacokinetics/pharmacology ; Survival Analysis ; }, abstract = {BACKGROUND: There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children.<br><br>METHODS: IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score &#x2264;8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h&#xd7;11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h&#xd7;17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1-96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months.<br><br>RESULTS: There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3&#xb1;2,212.3 to 16,786.1&#xb1;3,285.3 in serum and from 269.3&#xb1;113.0 to 467.9&#xb1;262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3&#xb1;10.0 to 52.9&#xb1;25.8 in serum and 5.4&#xb1;1.0 to 4.6&#xb1;2.1 &#x3bc;g/mL in CSF, at 24 to 72 h post-bolus, respectively (mean&#xb1;SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups.<br><br>CONCLUSIONS: Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT01322009.}, }
@article {pmid28686023, year = {2017}, author = {Grigoryan, A and Eisenberg, AS and Juszczak, LJ}, title = {PHOXI: A High Quantum Yield, Solvent-Sensitive Blue Fluorescent 5-Hydroxytryptophan Derivative Synthesized within Ten Minutes under Aqueous, Ambient Conditions.}, journal = {The journal of physical chemistry. B}, volume = {121}, number = {30}, pages = {7256-7266}, pmid = {28686023}, issn = {1520-5207}, support = {P41 GM103311/GM/NIGMS NIH HHS/United States ; SC3 GM105562/GM/NIGMS NIH HHS/United States ; }, mesh = {5-Hydroxytryptophan/chemical synthesis/*chemistry ; Amyloid beta-Peptides/chemistry ; Circular Dichroism ; Fluorescent Dyes/*chemical synthesis/chemistry ; Indoles/*chemical synthesis/chemistry ; Oxazoles/*chemical synthesis/chemistry ; Peptide Fragments/chemistry ; Quantum Theory ; Solvents/*chemistry ; Spectrometry, Fluorescence ; Water/chemistry ; }, abstract = {Multiple tryptophan (Trp) proteins are not amenable to fluorescence study because individual residue emission is not resolvable. Biosynthetic incorporation of an indole analogue such as 5-hydroxyindole has not provided sufficient spectroscopic resolution because of low quantum yield and small emission shift. Here, 5-hydroxyindole is used as the starting framework for building a blue emitting fluorophore of high quantum yield, 2-phenyl-6H-oxazolo[4,5-e]indole (PHOXI). This is a three reagent reaction completed in 10 min under ambient conditions in borate buffer at pH 8. Reaction conditions have been optimized using 5-hydroxyindole. Derivatization is demonstrated on tryptophanyl 5-hydroxytryptophan (5-HTP) and a stable β-hairpin "zipper" peptide with four tryptophan residues, TrpZip2, where Trp 4 has been replaced with 5-HTP, W4 → 5-HTP. Reaction optimization yields a PHOXI fluorophore that is essentially free of byproducts. Reaction specificity is demonstrated by the lack of reaction with N-acetyl-cysteine and amyloid β-40, a peptide containing all amino acids except tryptophan, proline, and cysteine and lacking 5-HTP. Fluorescence study of PHOXI-derivatized 5-hydroxyindole in different solvents reveals the sensitivity of PHOXI to solvent polarity with a remarkable 87 nm red-shift in water relative to cyclohexane while maintaining high quantum yield. Thus, PHOXI joins the ranks of solvatochromic fluorophores such as PRODAN. Surprisingly, DFT calculations reveal coplanarity of the oxazolo/indole extended ring system and the phenyl substituent for both the HOMO and LUMO orbitals. Despite the crowded environment of three additional Trps in TrpZip2, CD spectroscopy shows that the TrpZip2 β-hairpin structure is partially retained upon PHOXI incorporation. In an environment of smaller residues, PHOXI incorporation can be less disruptive of protein secondary structure, especially at molecular interfaces and other environments where there is typically less steric hindrance.}, }
@article {pmid28685618, year = {2018}, author = {Haber, M and James, J and Kim, J and Sangobowale, M and Irizarry, R and Ho, J and Nikulina, E and Grin'kina, NM and Ramadani, A and Hartman, I and Bergold, PJ}, title = {Minocycline plus N-acteylcysteine induces remyelination, synergistically protects oligodendrocytes and modifies neuroinflammation in a rat model of mild traumatic brain injury.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {38}, number = {8}, pages = {1312-1326}, pmid = {28685618}, issn = {1559-7016}, support = {R01 NS076693/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Antioxidants/*therapeutic use ; Brain Injuries, Traumatic/complications/*drug therapy/pathology ; Disease Models, Animal ; Drug Synergism ; Inflammation/complications/drug therapy/pathology ; Male ; Minocycline/*therapeutic use ; Oligodendroglia/*drug effects/pathology ; Rats ; Rats, Sprague-Dawley ; Remyelination/*drug effects ; }, abstract = {Mild traumatic brain injury afflicts over 2 million people annually and little can be done for the underlying injury. The Food and Drug Administration-approved drugs Minocycline plus N-acetylcysteine (MINO plus NAC) synergistically improved cognition and memory in a rat mild controlled cortical impact (mCCI) model of traumatic brain injury.[3] The underlying cellular and molecular mechanisms of the drug combination are unknown. This study addressed the effect of the drug combination on white matter damage and neuroinflammation after mCCI. Brain tissue from mCCI rats given either sham-injury, saline, MINO alone, NAC alone, or MINO plus NAC was investigated via histology and qPCR at four time points (2, 4, 7, and 14 days post-injury) for markers of white matter damage and neuroinflammation. MINO plus NAC synergistically protected resident oligodendrocytes and decreased the number of oligodendrocyte precursor cells. Activation of microglia/macrophages (MP/MG) was synergistically increased in white matter two days post-injury after MINO plus NAC treatment. Patterns of M1 and M2 MP/MG were also altered after treatment. The modulation of neuroinflammation is a potential mechanism to promote remyelination and improve cognition and memory. These data also provide new and important insights into how drug treatments can induce repair after traumatic brain injury.}, }
@article {pmid28684849, year = {2017}, author = {Kundukad, B and Schussman, M and Yang, K and Seviour, T and Yang, L and Rice, SA and Kjelleberg, S and Doyle, PS}, title = {Mechanistic action of weak acid drugs on biofilms.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {4783}, pmid = {28684849}, issn = {2045-2322}, mesh = {Acetic Acid/*pharmacology ; Acetylcysteine/*pharmacology ; Biofilms/*drug effects ; Extracellular Matrix/drug effects ; Hydrogen-Ion Concentration ; Polysaccharides, Bacterial ; Pseudomonas aeruginosa/*drug effects ; }, abstract = {Selective permeability of a biofilm matrix to some drugs has resulted in the development of drug tolerant bacteria. Here we studied the efficacy of a weak organic acid drug, N-acetyl-L-cysteine (NAC), on the eradication of biofilms formed by the mucoid strain of Pseudomonas aeruginosa and investigated the commonality of this drug with that of acetic acid. We showed that NAC and acetic acid at pH < pKa can penetrate the matrix and eventually kill 100% of the bacteria embedded in the biofilm. Once the bacteria are killed, the microcolonies swell in size and passively shed bacteria, suggesting that the bacteria act as crosslinkers within the extracellular matrix. Despite shedding of the bacteria, the remnant matrix remains intact and behaves as a pH-responsive hydrogel. These studies not only have implications for drug design but also offer a route to generate robust soft matter materials.}, }
@article {pmid28684792, year = {2017}, author = {Shrestha, R and Shrestha, R and Qin, XY and Kuo, TF and Oshima, Y and Iwatani, S and Teraoka, R and Fujii, K and Hara, M and Li, M and Takahashi-Nakaguchi, A and Chibana, H and Lu, J and Cai, M and Kajiwara, S and Kojima, S}, title = {Fungus-derived hydroxyl radicals kill hepatic cells by enhancing nuclear transglutaminase.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {4746}, pmid = {28684792}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Candida albicans/drug effects/enzymology/genetics/*pathogenicity ; Candida glabrata/drug effects/enzymology/genetics/*pathogenicity ; Candidiasis/drug therapy/enzymology/genetics/microbiology ; Cell Death/drug effects ; Cell Line ; Cell Nucleus/drug effects/*enzymology/microbiology ; Free Radical Scavengers/*pharmacology ; Fungal Proteins/genetics/metabolism ; GTP-Binding Proteins/deficiency/genetics/immunology ; Gene Deletion ; Gene Expression Regulation ; Hepatocytes/drug effects/*enzymology/microbiology ; Host-Pathogen Interactions ; Humans ; Hydroxyl Radical ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidases/deficiency/genetics ; Peptides/*pharmacology ; Primary Cell Culture ; Protein Glutamine gamma Glutamyltransferase 2 ; Saccharomyces cerevisiae/physiology ; Signal Transduction ; Transglutaminases/deficiency/genetics/immunology ; }, abstract = {We previously reported the importance of induced nuclear transglutaminase (TG) 2 activity, which results in hepatic cell death, in ethanol-induced liver injury. Here, we show that co-incubation of either human hepatic cells or mouse primary hepatocytes derived from wild-type but not TG2[-/-] mice with pathogenic fungi Candida albicans and C. glabrata, but not baker's yeast Saccharomyces cerevisiae, induced cell death in host cells by enhancing cellular, particularly nuclear, TG activity. Further pharmacological and genetic approaches demonstrated that this phenomenon was mediated partly by the production of reactive oxygen species (ROS) such as hydroxyl radicals, as detected by a fluorescent probe and electron spin resonance. A ROS scavenger, N-acetyl cysteine, blocked enhanced TG activity primarily in the nuclei and inhibited cell death. In contrast, deletion of C. glabrata nox-1, which encodes a ROS-generating enzyme, resulted in a strain that failed to induce the same phenomena. A similar induction of hepatic ROS and TG activities was observed in C. albicans-infected mice. An antioxidant corn peptide fraction inhibited these phenomena in hepatic cells. These results address the impact of ROS-generating pathogens in inducing nuclear TG2-related liver injuries, which provides novel therapeutic targets for preventing and curing alcoholic liver disease.}, }
@article {pmid28684297, year = {2018}, author = {Wang, J and Li, XM and Bai, Z and Chi, BX and Wei, Y and Chen, X}, title = {Curcumol induces cell cycle arrest in colon cancer cells via reactive oxygen species and Akt/ GSK3β/cyclin D1 pathway.}, journal = {Journal of ethnopharmacology}, volume = {210}, number = {}, pages = {1-9}, doi = {10.1016/j.jep.2017.06.037}, pmid = {28684297}, issn = {1872-7573}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/administration &amp; dosage/isolation &amp; purification/*pharmacology ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Colonic Neoplasms/*drug therapy/pathology ; Curcuma/chemistry ; Cyclin D1/metabolism ; Dose-Response Relationship, Drug ; Flow Cytometry ; Glycogen Synthase Kinase 3 beta/metabolism ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Sesquiterpenes/administration &amp; dosage/isolation &amp; purification/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {Curcuma kwangsiensis S. G. Lee &amp; C. F. Liang (Guangxi ezhu, in Chinese) belongs to the Zingiberaceae family, has been used as a traditionally Chinese medicine nearly 2000 year. Curcumol is one of the guaiane-type sesquiterpenoid hemiketal isolated from medicine plant Curcuma kwangsiensis S. G. Lee &amp; C. F. Liang, which has been reported possesses anti-cancer effects. Our previous study found that the most contribution to inhibit nasopharyngeal carcinoma cell growth was curcumol.<br><br>AIM OF THE STUDY: To assess the effect of curcumol on cell cycle arrest against human colon cancer cells (CRC) cells (LoVo and SW480) and explore its mechanism in vitro and in vivo.<br><br>MATERIALS AND METHODS: Curcumol was dissolved in absolute ethyl alcohol. The concentration of absolute ethyl alcohol in the control group or in experimental samples was always 1/500 (v/v) of the final medium volume. LoVo and SW480 cells were treated with different concentrations of curcumol (0, 53, 106, 212 and 424&#x3bc;M). And then the cell cycle of each group was examined by flow cytometry. The protein levels of PI3K, p-Akt, cyclin D1, cyclin E, CDK2, CDK4 and GSK3&#x3b2; were determined by Western blot. The mRNA expression of PI3K, Akt, cyclin D1, CDK4, P27, p21, and P16 in the treated cells were analyzed by real-time RT-PCR. In addition, the antitumor activity of curcumol was evaluated in nude mice bearing orthotopic tumor implants.<br><br>RESULTS: Curcumol induced cell cycle arrest in G1/S phase. RT-qPCR and Western blot data showed that curcumol enhanced the expression of GSK3&#x3b2;, P27, p21 and P16, and decreased the levels of PI3K, phosphorylated Akt (p-Akt), cyclin D1, CDK4, cyclin E and CDK2. Furthermore, curcumol induced reactive oxygen species (ROS) generation in LoVo cells, and ROS scavenger N-acetylcysteine (NAC) significantly reversed curcumol-induced cell growth inhibition. Besides, curcumol also prevented the growth of human colon cancer cells xenografts in nude mouse, accompanied by the reduction of PI3K, Akt, cyclin D1, CDK4, cycln E and significant increase of GSK3&#x3b2;.<br><br>CONCLUSIONS: Curcumol caused cell cycle arrest at the G0/G1 phase by ROS production and Akt/ GSK3&#x3b2;/cyclin D1 pathways inactivation, indicating the potential of curcumol in the prevention of colon cancer carcinogenesis.}, }
@article {pmid28682321, year = {2017}, author = {Lim, GB}, title = {Pharmacotherapy: NAC plus nitrate therapy in PCI.}, journal = {Nature reviews. Cardiology}, volume = {14}, number = {8}, pages = {444}, pmid = {28682321}, issn = {1759-5010}, mesh = {Acetylcysteine/*therapeutic use ; Drug Therapy, Combination ; Humans ; Myocardial Infarction/*therapy ; Nitroglycerin/*therapeutic use ; *Percutaneous Coronary Intervention ; Postoperative Complications/*prevention &amp; control ; Preoperative Care/*methods ; Vasodilator Agents/therapeutic use ; }, }
@article {pmid28681938, year = {2018}, author = {Ahn, J and Chung, YW and Park, JB and Yang, KM}, title = {ω-hydroxyundec-9-enoic acid induces apoptosis by ROS mediated JNK and p38 phosphorylation in breast cancer cell lines.}, journal = {Journal of cellular biochemistry}, volume = {119}, number = {1}, pages = {998-1007}, doi = {10.1002/jcb.26267}, pmid = {28681938}, issn = {1097-4644}, mesh = {Animals ; Antineoplastic Agents/*administration &amp; dosage/pharmacology ; Breast Neoplasms/*drug therapy/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Female ; Humans ; MAP Kinase Kinase 4/*metabolism ; Mice ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Undecylenic Acids/*administration &amp; dosage/pharmacology ; Xenograft Model Antitumor Assays ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {ω-Hydroxyundec-9-enoic acid (ω-HUA), a plant secondary metabolite, exhibits anti-fungal activity. However, its effect on breast cancer cells is unknown. Here, we investigated the anti- breast cancer activity of ω-HUA and its underlying mechanism. Treatment of human breast cancer cell lines, MDA-MB-231 and MDA-MB-435, with ω-HUA induced apoptotic cell death with increased cleaved caspase-3 and poly (ADP-ribose) polymerase (PARP) levels, and p38 and JNK phosphorylation. Inhibition of these mitogen-activated protein kinase (MAPK) pathways using specific inhibitors or siRNA, for p38 and JNK, respectively, blocked the ω-HUA-induced apoptosis in a dose-dependent manner. Moreover, pretreatment of the cells with antioxidant N-acetyl cysteine (NAC) inhibited ω-HUA-induced increased reactive oxygen species (ROS) levels, cleaved caspase-3 and cleaved PARP, and phosphorylated JNK, phosphorylated p38, and increased cell viability and colony-forming ability. MDA-MB-231 xenograft model showed that the ω-HUA-treated group exhibited greater tumor regression and significantly reduced tumor weight compared to that exhibited by the vehicle-administered group. Collectively, ω-HUA-induced intracellular ROS generation induced breast cancer cell apoptosis through JNK and p38 signaling pathway activation, resulting in tumor regression. The results suggested that ω-HUA is an effective supplement for inhibiting human breast cancer growth.}, }
@article {pmid28681934, year = {2018}, author = {Tomiyama, R and Takakura, K and Takatou, S and Le, TM and Nishiuchi, T and Nakamura, Y and Konishi, T and Matsugo, S and Hori, O}, title = {3,4-dihydroxybenzalacetone and caffeic acid phenethyl ester induce preconditioning ER stress and autophagy in SH-SY5Y cells.}, journal = {Journal of cellular physiology}, volume = {233}, number = {2}, pages = {1671-1684}, doi = {10.1002/jcp.26080}, pmid = {28681934}, issn = {1097-4652}, mesh = {Autophagy/*drug effects ; Caffeic Acids/*pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Gene Expression Regulation/drug effects ; Humans ; Microtubule-Associated Proteins/genetics/metabolism ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Oxidopamine/toxicity ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; Signal Transduction/drug effects ; Time Factors ; Unfolded Protein Response/drug effects ; }, abstract = {3,4-dihydroxybenzalacetone (DBL) and Caffeic acid phenethyl ester (CAPE) are both catechol-containing phenylpropanoid derivatives with diverse bioactivities. In the present study, we analyzed the ability of these compounds to activate the unfolded protein response (UPR) and the oxidative stress response. When human SH-SY5Y neuroblastoma cells were treated with DBL or CAPE, the expression of endoplasmic reticulum (ER) stress-related genes such as HSPA5, HYOU1, DDIT3, and SEC61b increased to a larger extent in response to CAPE treatment, while that of antioxidant genes such as HMOX1, GCLM, and NQO1 increased to a larger extent in response to DBL treatment. DNA microarray analysis confirmed the strong link of these compounds to ER stress. Regarding the mechanism, activation of the UPR by these compounds was associated with enhanced levels of oxidized proteins in the ER, and N-acetyl cysteine (NAC), which provides anti-oxidative effects, suppressed the induction of the UPR-target genes. Furthermore, both compounds enhanced the expression of LC3-II, a marker of autophagy, and 4-Phenylbutyric acid (4-PBA), a chemical chaperone that reduces ER stress, suppressed it. Finally, pretreatment of cells with DBL, CAPE or low doses of ER stressors protected cells against a neurotoxin 6-hydroxydopamine (6-OHDA) in an autophagy-dependent manner. These results suggest that DBL and CAPE induce oxidized protein-mediated ER stress and autophagy that may have a preconditioning effect in SH-SY5Y cells.}, }
@article {pmid28680151, year = {2017}, author = {Rainey, NE and Saric, A and Leberre, A and Dewailly, E and Slomianny, C and Vial, G and Zeliger, HI and Petit, PX}, title = {Synergistic cellular effects including mitochondrial destabilization, autophagy and apoptosis following low-level exposure to a mixture of lipophilic persistent organic pollutants.}, journal = {Scientific reports}, volume = {7}, number = {1}, pages = {4728}, pmid = {28680151}, issn = {2045-2322}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Apoptosis ; Autophagy ; Caco-2 Cells ; Calcium/metabolism ; Cell Survival/drug effects ; Drug Synergism ; Endoplasmic Reticulum/drug effects ; Endosulfan/*toxicity ; Environmental Pollutants/*toxicity ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects ; Oxidative Stress ; Polychlorinated Dibenzodioxins/*toxicity ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; Toxicity Tests, Subchronic ; }, abstract = {Humans are exposed to multiple exogenous environmental pollutants. Many of these compounds are parts of mixtures that can exacerbate harmful effects of the individual mixture components. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is primarily produced via industrial processes including incineration and the manufacture of herbicides. Both endosulfan and TCDD are persistent organic pollutants which elicit cytotoxic effects by inducing reactive oxygen species generation. Sublethal concentrations of mixtures of TCDD and endosulfan increase oxidative stress, as well as mitochondrial homeostasis disruption, which is preceded by a calcium rise and, in fine, induce cell death. TCDD+Endosulfan elicit a complex signaling sequence involving reticulum endoplasmic destalilization which leads to Ca[2+] rise, superoxide anion production, ATP drop and late NADP(H) depletion associated with a mitochondrial induced apoptosis concomitant early autophagic processes. The ROS scavenger, N-acetyl-cysteine, blocks both the mixture-induced autophagy and death. Calcium chelators act similarly and mitochondrially targeted anti-oxidants also abrogate these effects. Inhibition of the autophagic fluxes with 3-methyladenine, increases mixture-induced cell death. These findings show that subchronic doses of pollutants may act synergistically. They also reveal that the onset of autophagy might serve as a protective mechanism against ROS-triggered cytotoxic effects of a cocktail of pollutants in Caco-2 cells and increase their tumorigenicity.}, }
@article {pmid28679317, year = {2018}, author = {Wu, JP and Kang, NX and Zhang, MY and Gao, HW and Li, XR and Liu, YL and Xu, QM and Yang, SL}, title = {Oleiferoside W from the roots of Camellia oleifera C. Abel, inducing cell cycle arrest and apoptosis in A549 cells.}, journal = {Journal of Asian natural products research}, volume = {20}, number = {8}, pages = {793-806}, doi = {10.1080/10286020.2017.1347640}, pmid = {28679317}, issn = {1477-2213}, mesh = {A549 Cells ; Antineoplastic Agents, Phytogenic/administration &amp; dosage/chemistry/*pharmacology ; Apoptosis/*drug effects ; Camellia/*chemistry ; Cell Cycle Checkpoints/*drug effects ; Dose-Response Relationship, Drug ; Humans ; Molecular Structure ; Plant Roots/*chemistry ; Reactive Oxygen Species ; Saponins/administration &amp; dosage/chemistry/*pharmacology ; Triterpenes/administration &amp; dosage/chemistry/*pharmacology ; }, abstract = {Camellia oleifera C. Abel has been widely cultivated in China, and a group of bioactive constituents such as triterpeniod saponin have been isolated from C. oleifera C. Abel. In the current study, a new triterpeniod saponin was isolated from the EtOH extract of the roots of C. oleifera C. Abel, named as oleiferoside W, and the cytotoxic properties of oleiferoside W were evaluated in non-small cell lung cancer A549 cells. At the same time the inducing apoptosis, the depolarization of mitochondrial membrane potential (Δψ), the up-regulation of related pro-apoptotic proteins, such as cleaved-PARP, cleaved-caspase-3, and the down-regulation of anti-apoptotic marker Bcl-2/Bax were measured on oleiferoside W. Furthermore, the function, inducing the generation of reactive oxygen species (ROS) and apoptosis, of oleiferoside W could be reversed by N-acetylcysteine (NAC). In conclusion, our findings showed that oleiferoside W induced apoptosis involving mitochondrial pathway and increasing intracellular ROS production in the A549 cells, suggesting that oleiferoside W may have the possibility to be a useful anticancer agent for therapy in lung cancer.}, }
@article {pmid28678861, year = {2017}, author = {de Bragança, AC and Moreau, RLM and de Brito, T and Shimizu, MHM and Canale, D and de Jesus, DA and Silva, AMG and Gois, PH and Seguro, AC and Magaldi, AJ}, title = {Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and Allopurinol in oxidative stress and muscle fiber damage.}, journal = {PloS one}, volume = {12}, number = {7}, pages = {e0179199}, pmid = {28678861}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Animals ; Aquaporin 2/metabolism ; Blotting, Western ; Epithelial Sodium Channels/metabolism ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Hallucinogens/toxicity ; Kidney/*drug effects/metabolism ; Kidney Tubules, Collecting/drug effects/metabolism ; Male ; Muscle Fibers, Skeletal/*drug effects/metabolism/pathology ; N-Methyl-3,4-methylenedioxyamphetamine/*toxicity ; Oxidative Stress/*drug effects ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Rhabdomyolysis/*chemically induced/prevention &amp; control ; Solute Carrier Family 12, Member 1/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Water/metabolism ; }, abstract = {BACKGROUND: Ecstasy (Ec) use produces hyperthermia, excessive sweating, intense thirst, an inappropriate antidiuretic hormone secretion (SIADH) and a multisystemic toxicity due to oxidative stress (OS). Intense thirst induces high intake of pure water, which associated with SIADH, usually develops into acute hyponatremia (Hn). As Hn is induced rapidly, experiments to check if Ec acted directly on the Inner Medullary Collecting Ducts (IMCD) of rats were conducted. Rhabdomyolysis and OS were also studied because Ec is known to induce Reactive Oxygen Species (ROS) and tissue damage. To decrease OS, the antioxidant inhibitors N-acetylcysteine (NAC) and Allopurinol (Allo) were used.<br><br>METHODS: Rats were maintained on a lithium (Li) diet to block the Vasopressin action before Ec innoculation. AQP2 (Aquaporin 2), ENaC (Epitheliun Sodium Channel) and NKCC2 (Sodium, Potassium, 2 Chloride) expression were determined by Western Blot in isolated IMCDs. The TBARS (thiobarbituric acid reactive substances) and GSH (reduced form of Glutathione) were determined in the Ec group (6 rats injected with Ec-10mg/kg), in Ec+NAC groups (NAC 100mg/Kg/bw i.p.) and in Allo+Ec groups (Allo 50mg/Kg/i.p.).<br><br>RESULTS: Enhanced AQP2 expression revealed that Ec increased water transporter expression, decreased by Li diet, but the expression of the tubular transporters did not change. The Ec, Ec+NAC and Allo+Ec results showed that Ec increased TBARS and decreased GSH, showing evidence of ROS occurrence, which was protected by NAC and Allo. Rhabdomyolysis was only protected by Allo.<br><br>CONCLUSION: Results showed that Ec induced an increase in AQP2 expression, evidencing another mechanism that might contribute to cause rapid hyponatremia. In addition, they showed that NAC and Allo protected against OS, but only Allo decreased rhabdomyolysis and hyperthermia.}, }
@article {pmid28678840, year = {2017}, author = {Mahavadi, S and Sriwai, W and Manion, O and Grider, JR and Murthy, KS}, title = {Diabetes-induced oxidative stress mediates upregulation of RhoA/Rho kinase pathway and hypercontractility of gastric smooth muscle.}, journal = {PloS one}, volume = {12}, number = {7}, pages = {e0178574}, pmid = {28678840}, issn = {1932-6203}, support = {R01 DK028300/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Blotting, Western ; Cells, Cultured ; Diabetes Mellitus/genetics/metabolism/physiopathology ; Free Radical Scavengers/pharmacology ; Gastric Mucosa/metabolism ; Gene Expression/drug effects ; Glucose/pharmacology ; Hyperglycemia/genetics/metabolism/physiopathology ; Mice, Inbred C57BL ; Mice, Obese ; MicroRNAs/genetics ; Muscle Contraction/*physiology ; Muscle, Smooth/metabolism/*physiology ; *Oxidative Stress ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics ; Stomach/physiology ; Up-Regulation ; rho-Associated Kinases/genetics/*metabolism ; rhoA GTP-Binding Protein/genetics/*metabolism ; }, abstract = {The pathogenesis of diabetes-associated motility disorders are multifactorial and attributed to abnormalities in extrinsic and intrinsic innervation, and a decrease in the number of interstitial cells of Cajal, and nNOS expression and activity. Here we studied the effect of hyperglycemia on smooth muscle function. Using smooth muscles from the fundus of ob/ob mice and of wild type (WT) mice treated with 30 mM glucose (HG), we identified the molecular mechanism by which hyperglycemia upregulates RhoA/Rho kinase pathway and muscle contraction. RhoA expression, Rho kinase activity and muscle contraction were increased, while miR-133a expression was decreased in smooth muscle of ob/ob mice and in smooth muscle treated with HG. Intraperitoneal injections of pre-miR-133a decreased RhoA expression in WT mice and reversed the increase in RhoA expression in ob/ob mice. Intraperitoneal injections of antagomiR-133a increased RhoA expression in WT mice and augmented the increase in RhoA expression in ob/ob mice. The effect of pre-miR-133a or antagomiR-133a in vitro in smooth muscle treated with HG was similar to that obtained in vivo, suggesting that the expression of RhoA is negatively regulated by miR-133a and a decrease in miR-133a expression in diabetes causes an increase in RhoA expression. Oxidative stress (levels of reactive oxygen species and hydrogen peroxide, and expression of superoxide dismutase 1 and NADPH oxidase 4) was increased in smooth muscle of ob/ob mice and in HG-treated smooth muscle. Treatment of ob/ob mice with N-acetylcysteine (NAC) in vivo or addition of NAC in vitro to HG-treated smooth muscle reversed the effect of glucose on the expression of miR-133a and RhoA, Rho kinase activity and muscle contraction. NAC treatment also reversed the decrease in gastric emptying in ob/ob mice. We conclude that oxidative stress in diabetes causes a decrease in miR-133a expression leading to an increase in RhoA/Rho kinase pathway and muscle contraction.}, }
@article {pmid28676007, year = {2017}, author = {Nikbakht, M and Ahmadi, F and Vaseghi, G and Talasaz, AH and Eshraghi, A and Naderi, J and Daneshmehr, MA}, title = {The Role of N-Acetylcysteine in Platelet Aggregation and Reperfusion Injury in Recent Years.}, journal = {Current clinical pharmacology}, volume = {12}, number = {2}, pages = {83-91}, doi = {10.2174/1574884712666170704145842}, pmid = {28676007}, issn = {2212-3938}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Disease Models, Animal ; Humans ; Platelet Aggregation/*drug effects ; Platelet Aggregation Inhibitors/pharmacology ; Reperfusion Injury/*drug therapy ; Species Specificity ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is an amino acid that contains a cysteine group and is currently used widely in various fields of medical research especially in cardiology. In this review, potential benefits of NAC in the aggregation of platelet and reperfusion injury are evaluated.<br><br>METHODS: The available evidence was collected by searching Scopus, Pub-Med, Medline, Cochrane central register of controlled trials, and Cochrane database systematic reviews. Our searching was performed without time limitation and only English language articles were included in this review. Key words used as search terms included "N-acetylcysteine", "platelet aggregation", "reperfusion injury".<br><br>RESULTS: Over the past decade, several investigations were carried out to ascertain reperfusion injury and antiplatelet properties of NAC, and in this article the results of investigations in both models (human and animal) were addressed in detail. The results revealed that NAC has an important antiplatelet property in animal models while this effect is not very significant in human models and needs more investigations. However, its reperfusion injury in both models is worth noticing.<br><br>CONCLUSION: Due to the limited data about effectiveness of NAC in both human and animal as antiplatelet agent, more investigation is needed to evaluate NAC efficacy in platelet aggregation and reperfusion injury especially in human studies in the future.}, }
@article {pmid28669854, year = {2017}, author = {Nemeth, CL and Drummond, GT and Mishra, MK and Zhang, F and Carr, P and Garcia, MS and Doman, S and Fatemi, A and Johnston, MV and Kannan, RM and Kannan, S and Wilson, MA}, title = {Uptake of dendrimer-drug by different cell types in the hippocampus after hypoxic-ischemic insult in neonatal mice: Effects of injury, microglial activation and hypothermia.}, journal = {Nanomedicine : nanotechnology, biology, and medicine}, volume = {13}, number = {7}, pages = {2359-2369}, pmid = {28669854}, issn = {1549-9642}, support = {U54 HD079123/HD/NICHD NIH HHS/United States ; R01 NS097511/NS/NINDS NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; T32 HD007414/HD/NICHD NIH HHS/United States ; R01 HD076901/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics/therapeutic use ; Animals ; Animals, Newborn ; Antioxidants/*administration &amp; dosage/pharmacokinetics/therapeutic use ; Cerebral Palsy/drug therapy/pathology ; Dendrimers/*chemistry ; Disease Models, Animal ; Drug Carriers/*chemistry ; *Drug Delivery Systems ; Female ; Hippocampus/drug effects/pathology ; Hypothermia, Induced ; Hypoxia-Ischemia, Brain/*drug therapy/pathology/therapy ; Mice ; Microglia/drug effects/pathology ; Tissue Distribution ; }, abstract = {Perinatal hypoxic-ischemic encephalopathy (HIE) can result in neurodevelopmental disability, including cerebral palsy. The only treatment, hypothermia, provides incomplete neuroprotection. Hydroxyl polyamidoamine (PAMAM) dendrimers are being explored for targeted delivery of therapy for HIE. Understanding the biodistribution of dendrimer-conjugated drugs into microglia, neurons and astrocytes after brain injury is essential for optimizing drug delivery. We conjugated N-acetyl-L-cysteine to Cy5-labeled PAMAM dendrimer (Cy5-D-NAC) and used a mouse model of perinatal HIE to study effects of timing of administration, hypothermia, brain injury, and microglial activation on uptake. Dendrimer conjugation delivered therapy most effectively to activated microglia but also targeted some astrocytes and injured neurons. Cy5-D-NAC uptake was correlated with brain injury in all cell types and with activated morphology in microglia. Uptake was not inhibited by hypothermia, except in CD68+ microglia. Thus, dendrimer-conjugated drug delivery can target microglia, astrocytes and neurons and can be used in combination with hypothermia for treatment of HIE.}, }
@article {pmid28667779, year = {2017}, author = {You, BR and Park, WH}, title = {Suberoylanilide hydroxamic acid induces thioredoxin1-mediated apoptosis in lung cancer cells via up-regulation of miR-129-5p.}, journal = {Molecular carcinogenesis}, volume = {56}, number = {12}, pages = {2566-2577}, doi = {10.1002/mc.22701}, pmid = {28667779}, issn = {1098-2744}, mesh = {3' Untranslated Regions/genetics ; A549 Cells ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Knockdown Techniques ; Glutathione/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Hydroxamic Acids/*pharmacology ; Lung Neoplasms/genetics/metabolism/pathology ; MAP Kinase Kinase Kinase 5/metabolism ; MAP Kinase Signaling System/drug effects ; MicroRNAs/*genetics ; Reactive Oxygen Species/metabolism ; Thioredoxins/*genetics/metabolism ; Up-Regulation/*drug effects ; Vorinostat ; }, abstract = {Histone deacetylase (HDAC) inhibitors, especially suberoylanilide hydroxamic acid (SAHA) induce apoptosis in various cancer cells. Here, we investigated the effect of SAHA on apoptosis in lung cancer cells and addressed the role of reactive oxygen species (ROS), glutathione (GSH), and thioredoxin1 (Trx1) levels in this process. We also identified the miRNAs that down-regulate Trx1 expression at RNA level and thereby influence apoptotic cell death of SAHA increased intracellular ROS levels and promoted apoptotic cell death in cancerous cells but not in non-cancerous normal lung cells. Likewise, SAHA induced GSH depletion specifically in cancerous cells. While N-acetyl cysteine (NAC) reduced ROS level and reversed the effect of SAHA on cell death, L-buthionine sulfoximine (BSO) further enhanced GSH depletion, and promoted cell death. SAHA decreased the mRNA and protein levels of Trx1 in lung cancer cells. Knockdown/suppression of Trx1 intensified apoptosis in SAHA-treated lung cancer cells whereas overexpression of Trx1 prevented the cell death in these cells. SAHA up-regulated the level of miR-129-5p, which binds to 3' untranslated region (3'UTR) of Trx1 and down-regulates Trx1 expression. Down-regulation of Trx1 led to activation of apoptosis-signal regulating kinase (ASK), which induced apoptotic cell death by triggering ASK-JNK or ASK-p38 kinase pathway. In conclusion, changes in ROS and GSH levels in SAHA-treated lung cancer cells partially co-related with cell death. SAHA induced apoptosis via the down-regulation of Trx1, which was regulated by miR-129-5p.}, }
@article {pmid28664726, year = {2017}, author = {Liu, D and Li, J and Cheng, B and Wu, Q and Pan, H}, title = {Ex Vivo and in Vivo Evaluation of the Effect of Coating a Coumarin-6-Labeled Nanostructured Lipid Carrier with Chitosan-N-acetylcysteine on Rabbit Ocular Distribution.}, journal = {Molecular pharmaceutics}, volume = {14}, number = {8}, pages = {2639-2648}, doi = {10.1021/acs.molpharmaceut.7b00069}, pmid = {28664726}, issn = {1543-8392}, mesh = {Acetylcysteine/*chemistry ; Animals ; Chitosan/analogs &amp; derivatives/*chemistry ; Cornea/metabolism ; Coumarins/*chemistry ; Drug Carriers/*chemistry ; Eye/*metabolism ; *Lipids ; Nanoparticles/*chemistry ; Nanostructures/*chemistry ; Rabbits ; Thiazoles/*chemistry ; }, abstract = {This study is focused on further understanding the characteristics of chitosan-N-acetylcysteine surface-modified nanostructured lipid carriers (CS-NAC-NLCs) in their interaction with ocular mucosa. Coumarin-6 (C6)-labeled NLCs, including uncoated NLCs, chitosan hydrochloride (CH)-, and CS-NAC-coated NLCs, were developed using a melt-emulsification technique and subsequently decorated with different types or portions of chitosan derivatives. Mucoadhesion was evaluated ex vivo using a flow-through process with fluorescence detection. The results demonstrated that the presence of CS-NAC on the C6-NLC surface provided the most obvious enhancement in adhesion due to the formation of both noncovalent (ionic) and covalent (disulfide bridges) interactions with mucus chains. Meanwhile, the concentration of CS-NAC in the formulation positively influenced the viscosity of the nanoparticles and hence prolonged their retention in the ocular tissue. Transcorneal penetration studies revealed that CS-NAC-NLC particles were able to penetrate through the entire corneal epithelium primarily via a transcellular route. The transport depth and velocity strongly relied on the modification material and the particle size. Ex vivo fluorescence imaging and in vivo ocular distribution investigations showed that C6 was broadly distributed in rabbit eye tissues and absorbed by aqueous humor after CS-NAC-NLC instillation. In relation to C6 eye drops, CS-NAC-NLCs achieved considerably higher Cmax (4.01-fold), MRT0-∞ (1.87-fold), and AUC0-∞ (16.29-fold) in the aqueous humor. Moreover, the increase in drug absorption was greater in the cornea than in the conjunctiva. Thereby, it is possible to draw a conclusion that CS-NAC-NLCs presented great potential for drug application to the front portion of the eye.}, }
@article {pmid28663055, year = {2017}, author = {Wang, XY and Li, YL and Wang, HY and Zhu, M and Guo, D and Wang, GL and Gao, YT and Yang, Z and Li, T and Yang, CY and Chen, YM}, title = {Propofol inhibits invasion and proliferation of C6 glioma cells by regulating the Ca[2+] permeable AMPA receptor-system xc[-] pathway.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {44}, number = {}, pages = {57-65}, doi = {10.1016/j.tiv.2017.06.026}, pmid = {28663055}, issn = {1879-3177}, mesh = {Anesthetics, Intravenous/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Calcium/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Glioma/*metabolism/pathology ; Glutamic Acid/metabolism ; Glutathione/metabolism ; Propofol/*pharmacology ; Rats ; Receptors, AMPA/*metabolism ; }, abstract = {Anesthetics are documented to affect tumors; therefore, we studied the antiglioma effect of propofol on proliferation and invasiveness of glioma cells and explored the underlying mechanism. C6 glioma cells were cultured and treated with propofol, and cell viability, invasiveness, and migration were measured. Glutamate release was measured using an enzyme-catalyzed kinetic reaction. xCT protein and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor GluR2 subunit protein expression was assessed with Western blot analysis and immunofluorescent staining. We observed that propofol significantly inhibited C6 glioma cell viability, invasiveness, and migration and decreased glutamate release. An agonist of the cystine/glutamate antiporter system (system xc[-]), N-acetylcysteine (NAC), reversed propofol's effects, and propofol could inhibit C6 glioma cell proliferation by adding excess exogenous glutamate (100μM). Finally, propofol increased the surface expression of GluR2, but decreased surface expression of xCT. The effects of propofol on surface expression of GluR2 and xCT could be rescued by (R, S)-AMPA, an agonist of Ca[2+] permeable AMPA receptor (CPAR). Thus, propofol can inhibit cell viability, invasiveness, and migration of C6 glioma cells, and the CPAR-system xc[-] pathway contributes to these events.}, }
@article {pmid28659986, year = {2017}, author = {Ghanizadeh, A and Mohammadi, MR and Bahraini, S and Keshavarzi, Z and Firoozabadi, A and Alavi Shoshtari, A}, title = {Efficacy of N-Acetylcysteine Augmentation on Obsessive Compulsive Disorder: A Multicenter Randomized Double Blind Placebo Controlled Clinical Trial.}, journal = {Iranian journal of psychiatry}, volume = {12}, number = {2}, pages = {134-141}, pmid = {28659986}, issn = {1735-4587}, abstract = {Objective: Glutamate is considered a target for treating obsessive-compulsive disorder (OCD). The efficacy and safety of the nutritional supplement of N-Acetylcysteine (NAC) as an adjuvant to serotonin reuptake inhibitor (SSRI) for treating children and adolescents with OCD has never been examined. Method: This was a 10-week randomized double-blind placebo-controlled clinical trial with 34 OCD outpatients. The patients received citalopram plus NAC or placebo. Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Pediatric Quality of Life Inventory (PedsQL™) were used. Adverse effects were monitored. Results: YBOCS score was not different between the two groups at baseline, but the score was different between the two groups at the end of this trial (P<0.02). The YBOCS score of NAC group significantly decreased from 21.0(8.2) to 11.3(5.7) during this study. However, no statistically significant decrease of YBOCS was found in the placebo group. The Cohen's d effect size was 0.83. The mean change of score of resistance/control to obsessions in the NAC and placebo groups was 1.8(2.3) and 0.8(2.1), respectively (P = 0.2). However, the mean score of change for resistance/control to compulsion in the NAC and placebo groups was 2.3(1.8) and 0.9(2.3), respectively. Cohen's d effect size was 0.42. The score of three domains of quality of life significantly decreased in N-Acetylcysteine group during this trial. However, no statistically significant decrease was detected in the placebo group. No serious adverse effect was found in the two groups. Conclusion: This trial suggests that NAC adds to the effect of citalopram in improving resistance/control to compulsions in OCD children and adolescents. In addition, it is well tolerated.}, }
@article {pmid28655635, year = {2017}, author = {Liu, N and Jiang, L and Sun, X and Yao, X and Zhai, X and Liu, X and Wu, X and Bai, Y and Wang, S and Yang, G}, title = {Mono-(2-ethylhexyl) phthalate induced ROS-dependent autophagic cell death in human vascular endothelial cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {44}, number = {}, pages = {49-56}, doi = {10.1016/j.tiv.2017.06.024}, pmid = {28655635}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Autophagy/drug effects ; Cell Line ; Cell Survival/drug effects ; Diethylhexyl Phthalate/*analogs &amp; derivatives/toxicity ; Endothelial Cells/*drug effects/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Microtubule-Associated Proteins/metabolism ; Proto-Oncogene Proteins c-akt/*genetics ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Sirolimus/pharmacology ; }, abstract = {Mono-(2-ethylhexyl) phthalate (MEHP) is an active metabolite of di-(2-ethylhexyl) phthalate (DEHP). MEHP has toxic effects on cardiovascular system, but the possible molecular mechanisms are not completely elucidated. In our study, 3-methyladenine (3-MA), an autophagosome formation inhibitor, protected the EA.hy926 cells against MEHP cytotoxicity, and rapamycin, an autophagosome formation stimulator, further decreased the cell viability in the MEHP-treated EA.hy926 cells. Thus, autophagy may play an important role in MEHP-induced toxicity. MEHP increased the autophagosome number in EA.hy926 cells detected under transmission electron microscope. Collapses of ΔΨm and reactive oxygen species (ROS) level were increased in a dose-dependent manner under treatment with 0-200μM MEHP for 24h. N-acetyl-l-cysteine (NAC), a ROS inhibitor, protected against MEHP-induced cytotoxicity and decreased the protein expression of LC3-II. These findings suggested that MEHP-induced autophagic cell death was ROS-dependent in EA.hy926 cells. Knockdown of Akt1 with Akt1 siRNA aggravated MEHP-induced cell death, and insulin, an Akt1 activator, alleviated MEHP-induced cell death. These results were consistent with the expression of LC3-II using western blot. The phospho-Akt1[(Ser473)] (p-Akt1) level was enhanced after pretreatment with NAC. In conclusion, it is possible that ROS elicited autophagy through Akt1 pathway in the MEHP-treated EA.hy926 cells.}, }
@article {pmid28653879, year = {2017}, author = {Lee, YS and Choi, YJ and Lee, J and Shim, DM and Park, WY and Seo, SW}, title = {TP53 alteration determines the combinational cytotoxic effect of doxorubicin and an antioxidant NAC.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {39}, number = {6}, pages = {1010428317700159}, doi = {10.1177/1010428317700159}, pmid = {28653879}, issn = {1423-0380}, mesh = {A549 Cells ; Acetylcysteine/*administration &amp; dosage ; Antioxidants/administration &amp; dosage ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Doxorubicin/administration &amp; dosage/adverse effects ; *Drug Synergism ; Heart Failure/chemically induced/*drug therapy/pathology ; Humans ; MCF-7 Cells ; Neoplasms/*drug therapy/pathology ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/*genetics ; }, abstract = {The anticancer effect of doxorubicin is closely related to the generation of reactive oxygen species. On the contrary, doxorubicin-induced reactive oxygen species induces heart failure, a critical side effect of doxorubicin. Antioxidant supplementation has been proposed to reduce the side effects. However, the use of antioxidants may hamper the anticancer effect of doxorubicin. In this study, doxorubicin-induced reactive oxygen species was shown to differentially affect cancer cells based on their TP53 genetic status; doxorubicin-induced apoptosis was attenuated by an antioxidant, N-acetylcysteine, in TP53 wild cells; however, N-acetylcysteine caused a synergistic increase in the apoptosis rate in TP53-altered cells. N-acetylcysteine prevented phosphorylation of P53 protein that had been induced by doxorubicin. However, N-acetylcysteine increased the cleavage of poly (ADP-ribose) polymerase in the presence of doxorubicin. Synergy score of 26 patient-derived cells were evaluated after the combination treatment of doxorubicin and N-acetylcysteine. The synergy score was significantly higher in TP53-altered group compared with those in TP53 wild group. In conclusion, TP53 genetic alteration is a critical factor that determines the use of antioxidant supplements during doxorubicin treatment.}, }
@article {pmid28644070, year = {2017}, author = {Wang, T and Shimizu, Y and Wu, X and Kelly, GT and Xu, X and Wang, L and Qian, Z and Chen, Y and Garcia, JGN}, title = {Particulate matter disrupts human lung endothelial cell barrier integrity via Rho-dependent pathways.}, journal = {Pulmonary circulation}, volume = {7}, number = {3}, pages = {617-623}, pmid = {28644070}, issn = {2045-8932}, support = {R01 HL091889/HL/NHLBI NIH HHS/United States ; }, abstract = {Increased exposure to ambient particulate matter (PM) is associated with elevated morbidity and mortality in patients with cardiopulmonary diseases and cancer. We and others have shown that PM induces lung microvascular barrier dysfunction which potentially enhances the systemic toxicity of PM. However, the mechanisms by which PM disrupts vascular endothelial integrity remain incompletely explored. We hypothesize that PM induces endothelial cell (EC) cytoskeleton rearrangement via Rho GTPase-dependent pathways to facilitate vascular hyperpermeability. Fine PM induced time-dependent activation of cytoskeletal machinery with increases in myosin light chain (MLC) phosphorylation and EC barrier disruption measured by transendothelial electrical resistance (TER), events attenuated by the Rho-dependent kinase (ROCK) inhibitor Y-27632 or the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC). Both Y-27632 and NAC prevented PM-induced stress fiber formation and phospho-MLC accumulation in human lung ECs. PM promotes rapid accumulation of Rho-GTP. This event is attenuated by NAC or knockdown of RhoA (siRNA). Consistent with ROCK activation, PM induced phosphorylation of myosin light chain phosphatase (MYPT) at Thr850, a post-translational modification known to inhibit phosphatase activity. Furthermore, PM activates the guanine nucleotide exchange factor (GEF) for Rho, p115, with p115 translocation to the cell periphery, in a ROS-dependent manner. Together these results demonstrate that fine PM induces EC cytoskeleton rearrangement via Rho-dependent pathways that are dependent upon the generation of oxidative stress. As the disruption of vascular integrity further contributes to cardiopulmonary physiologic derangements, these findings provide pharmacologic targets for prevention of PM-induced cardiopulmonary toxicity.}, }
@article {pmid28644049, year = {2018}, author = {Salmonson, H and Sjöberg, G and Brogren, J}, title = {The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {56}, number = {1}, pages = {63-68}, doi = {10.1080/15563650.2017.1339887}, pmid = {28644049}, issn = {1556-9519}, mesh = {Acetaminophen/administration &amp; dosage/pharmacokinetics/*poisoning ; Alanine Transaminase/blood ; Drug Compounding ; Drug Overdose/therapy ; Female ; Humans ; Male ; Retrospective Studies ; }, abstract = {OBJECTIVE: The use of the standard procedure for managing overdoses with immediate release (IR) paracetamol is questionable when applied to overdoses with modified release (MR) formulations. This study describes the pharmacokinetics of paracetamol and the clinical outcomes following overdoses with a MR formulation.<br><br>METHODS: Medical records including laboratory analyses concerning overdoses of MR paracetamol from 2009 to 2015 were collected retrospectively. Inclusion criteria were ingestion of a toxic dose, known time of intake and documented measurements of serum paracetamol and liver function tests. Graphical analysis, descriptive statistics and population pharmacokinetic modelling were used to describe data.<br><br>RESULTS: Fifty-three cases were identified. Median age was 26 years (range 13-68), median dose was 20&#x2009;g (range 10-166) and 74% were females. The pharmacokinetic analysis showed a complex, dose dependent serum versus time profile with prolonged absorption and delayed serum peak concentrations with increasing dose. Ten patients had persistently high serum levels for 24&#x2009;h or more, six of them had a second peak 8-19&#x2009;h after ingestion. Seven of 34 patients receiving N-acetylcysteine (NAC) within 8&#x2009;h had alanine aminotransferase (ALT) above reference range. Three of them developed hepatotoxicity (ALT >1000&#x2009;IU/l).<br><br>DISCUSSION AND CONCLUSIONS: The pharmacokinetic and clinical analysis showed that the standard treatment protocol, including risk assessment and NAC regimen, used for IR paracetamol poisoning not appear suitable for MR formulation. Individual and tailored treatment may be valuable but further studies are warranted to determine optimal regimen of overdoses with MR formulation.}, }
@article {pmid28641207, year = {2017}, author = {Zhang, X and Tang, X and Wang, M and Zhang, W and Zhou, B and Wang, Y}, title = {ROS and calcium signaling mediated pathways involved in stress responses of the marine microalgae Dunaliella salina to enhanced UV-B radiation.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {173}, number = {}, pages = {360-367}, doi = {10.1016/j.jphotobiol.2017.05.038}, pmid = {28641207}, issn = {1873-2682}, mesh = {Acetylcysteine/metabolism ; Antioxidants/metabolism ; Biological Transport/radiation effects ; Calcium Signaling/*radiation effects ; Calcium-Transporting ATPases/metabolism ; Glutathione/biosynthesis ; Microalgae/cytology/metabolism/*radiation effects ; Oxidative Stress/*radiation effects ; Reactive Oxygen Species/*metabolism ; Ultraviolet Rays/*adverse effects ; Volvocida/cytology/metabolism/*radiation effects ; }, abstract = {UV-B ray has been addressed to trigger common metabolic responses on marine microalgae, however, the upstream events responsible for these changes in marine microalgae are poorly understood. In the present study, a species of marine green microalgae Dunaliella salina was exposed to a series of enhanced UV-B radiation ranging from 0.25 to 1.00 KJ·m[-2] per day. The role of ROS and calcium signaling in the D. salina responses to UV-B was discussed. Results showed that enhanced UV-B radiation markedly decreased the cell density in a dose-dependent manner, but the contents of protein and glycerol that were essential for cell growth increased. It suggested that it was cell division instead of cell growth that UV-B exerted negative effects on. The subcellular damages on nuclei and plasmalemma further evidenced the hypothesis. The nutrient absorption was affected with UV-B exposure, and the inhibition on PO4[3-] uptake was more serious compared to NO3[-] uptake. UV-B radiation promoted reactive oxygen species (ROS) formation and thiobarbituric acid reactive substances (TBARS) contents, decreased the redox status and altered the antioxidant enzyme activities. The addition of the ROS scavenger and the glutathione biosynthesis precursor N-acetyl-l-cysteine (NAC) alleviated the stress degree, implying ROS-mediated pathway was involved in the stress response to UV-B radiation. Transient increase in Ca[2+]-ATPase was triggered simultaneously with UV-B exposure. Meanwhile, the addition of an intracellular free calcium chelator aggravated the damage of cell division, but exogenous calcium and ion channel blocker applications did not, inferring that endogenously initiated calcium signaling played roles in response to UV-B. Cross-talk analysis showed a relatively clear relationship between ROS inhibition and Ca[2+]-ATPase suppression, and a relation between Ca[2+] inhibition and GPx activity change was also observed. It was thus presumed that ROS-coupled calcium signaling via the glutathione cycle was involved in the response of marine microalgae to UV-B stimuli.}, }
@article {pmid28637361, year = {2018}, author = {Ganesan, D and Al-Sayed, E and Albert, A and Paul, E and Singab, ANB and Govindan Sadasivam, S and Saso, L}, title = {Antioxidant activity of phenolic compounds from extracts of Eucalyptus globulus and Melaleuca styphelioides and their protective role on D-glucose-induced hyperglycemic stress and oxalate stress in NRK-49Fcells.}, journal = {Natural product research}, volume = {32}, number = {11}, pages = {1274-1280}, doi = {10.1080/14786419.2017.1343324}, pmid = {28637361}, issn = {1478-6427}, mesh = {Animals ; Antioxidants/*chemistry/*pharmacology ; Cell Line ; Enzymes/metabolism ; Eucalyptus/*chemistry ; Gallic Acid/analogs &amp; derivatives/pharmacology ; Glucose/pharmacology ; Glucosides/pharmacology ; Glycosides/pharmacology ; Humans ; Hydrolyzable Tannins/pharmacology ; Hyperglycemia/drug therapy ; Lipid Peroxidation/drug effects ; Melaleuca/*chemistry ; Oxalates ; Phenols/pharmacology ; Plant Extracts/chemistry/pharmacology ; Protective Agents/chemistry/pharmacology ; }, abstract = {Phytochemicals serve as potential therapeutic agents for the prevention and treatment of diseases. In this study, we elucidate the renoprotective activity of compounds isolated from Eucalyptus globulus and Melaleuca styphelioides extracts in glucose- and oxalate-challenged NRK-49F cell model. The antioxidant potential of isolated compounds was evaluated based on their effect on antioxidant enzyme activities and lipid peroxidation levels. The results demonstrated that exposure of NRK-49F cells to glucose and oxalate stress augmented cell damage and attenuated antioxidant enzyme activities. The phytochemicals 2,2,8-trimethyl-6-formyl-chrom-3-ene-7-O-β-D-glucopyranoside, Cornusiin B and tellimagrandin I treatment restored antioxidant enzyme activity, significantly lowered lipid peroxidation levels and effectively protected cells from glucose and oxalate stress equivalent to the known antioxidant, N-acetyl cysteine. Pterocarinin A significantly reversed cellular damage owing to glucose stress. In conclusion, the compounds isolated from E. globulus and M. styphelioides showed potential cytoprotective and anti-oxidative property against glucose- and oxalate-induced oxidative stress in NRK-49F cells.}, }
@article {pmid28634445, year = {2017}, author = {Phensy, A and Duzdabanian, HE and Brewer, S and Panjabi, A and Driskill, C and Berz, A and Peng, G and Kroener, S}, title = {Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment.}, journal = {Frontiers in behavioral neuroscience}, volume = {11}, number = {}, pages = {106}, pmid = {28634445}, issn = {1662-5153}, abstract = {Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70-120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.}, }
@article {pmid28634219, year = {2017}, author = {Pasupathy, S and Tavella, R and Grover, S and Raman, B and Procter, NEK and Du, YT and Mahadavan, G and Stafford, I and Heresztyn, T and Holmes, A and Zeitz, C and Arstall, M and Selvanayagam, J and Horowitz, JD and Beltrame, JF}, title = {Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]).}, journal = {Circulation}, volume = {136}, number = {10}, pages = {894-903}, doi = {10.1161/CIRCULATIONAHA.117.027575}, pmid = {28634219}, issn = {1524-4539}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Nitrates/administration &amp; dosage/*therapeutic use ; Percutaneous Coronary Intervention/*methods ; ST Elevation Myocardial Infarction/*surgery/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Contemporary ST-segment-elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention.<br><br>METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging-assessed infarct size. Secondary end points included cardiac magnetic resonance-determined myocardial salvage and creatine kinase kinetics.<br><br>RESULTS: Of 112 randomized patients with ST-segment-elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance-assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37-79) compared with placebo (27%; interquartile range, 14-42; P<0.01) and median creatine kinase areas under the curve were 22&#x2009;000 and 38&#x2009;000 IU&#xb7;h in the NAC and placebo groups, respectively (P=0.08).<br><br>CONCLUSIONS: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes.<br><br>CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000.}, }
@article {pmid28633804, year = {2017}, author = {Liao, CY and Chung, CH and Wu, CC and Lin, FH and Tsao, CH and Wang, CC and Chien, WC}, title = {Protective effect of N-acetylcysteine on progression to end-stage renal disease: Necessity for prospective clinical trial.}, journal = {European journal of internal medicine}, volume = {44}, number = {}, pages = {67-73}, doi = {10.1016/j.ejim.2017.06.011}, pmid = {28633804}, issn = {1879-0828}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Comorbidity ; *Disease Progression ; Female ; Follow-Up Studies ; Humans ; Kidney Failure, Chronic/*physiopathology ; Male ; Middle Aged ; Multivariate Analysis ; Propensity Score ; Renal Dialysis ; Renal Insufficiency, Chronic/*complications/*therapy ; Retrospective Studies ; Risk Factors ; Risk Reduction Behavior ; Survival Analysis ; Taiwan ; Young Adult ; }, abstract = {BACKGROUND: We aimed to evaluate the potential benefits of N-acetylcysteine (NAC) on the risk of chronic kidney disease (CKD) progression to dialysis-requiring end-stage renal disease (ESRDd).<br><br>METHODS: In a population-based cohort study of 145,062 individuals, 123,608 CKD patients who were followed up for 10years were included, and CKD patients treated with NAC (ICD-9-CM) were compared with those who were not treated. Using propensity score matching, we analyzed the predictors of CKD progression to ESRDd by Cox proportional hazards regression with adjustments for sex, age, and comorbidities, and evaluated the effect of NAC using cumulative defined daily dose (cDDD).<br><br>RESULTS: NAC use was associated with a reduced risk for progression to ESRDd [hazard ratio (HR), 0.819; 95% confidence interval (CI), 0.781-0.965; P=0.017]. Risk reduction was proportional to cDDD in NAC users compared with that in NAC non users (HR, 0.835, 0.811, and 0.799 for cDDD 91-180, 181-360, and >360, respectively; P for trend=0.018). Risk reduction was apparent in women (P=0.001) and in younger-aged patients of 18-29years (P=0.021) and 30-39years (P=0.033), in the presence of hypertension (P=0.003), and in the absence of diabetes mellitus (P=0.042) and congestive heart failure (P=0.036).<br><br>CONCLUSION: NAC use was associated with a reduced risk for progression to ESRDd. These results, obtained from retrospective data, indicate that a prospective study is warranted.}, }
@article {pmid28633061, year = {2017}, author = {Gatti, R and Morigi, R}, title = {1,4-Anthraquinone: A new useful pre-column reagent for the determination of N-acetylcysteine and captopril in pharmaceuticals by high performance liquid chromatography.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {143}, number = {}, pages = {299-304}, doi = {10.1016/j.jpba.2017.06.011}, pmid = {28633061}, issn = {1873-264X}, mesh = {Acetylcysteine ; Anthraquinones ; Captopril ; *Chromatography, High Pressure Liquid ; Indicators and Reagents ; Reproducibility of Results ; }, abstract = {1,4-Anthraquinone (ANQ) is proposed as a novel pre-column reagent for high performance liquid chromatography (HPLC) determination of N-acetylcysteine (NAC) and captopril (CAP) in pharmaceutical formulations. The derivatization reactions were carried out at room temperature: NAC at pH 8 for 1min, while CAP at pH 7.5 for 20min. Both reactions reached completeness at a reagent to thiol molar ratio of about 2.5. The synthesised derivatives were characterized by [1]H NMR and IR. The chromatographic separations were performed on a C18 Phenomenex Synergi Fusion 4μm (250mm×4.6mm I.D.) stainless steel column with detection at λ=300nm. The mobile phase consisted of methanol/triethylammonium (TEA) phosphate buffer (pH 3; 0.05mol/L) 75:25 (v/v) at a flow-rate of 0.4mL/min for NAC and 88:12 (v/v), at a flow-rate of 0.6mL/min for CAP. The validation parameters (linearity, sensitivity, accuracy, precision, specificity and stability) were highly satisfactory. Linear response was observed (determination coefficient ≥0.9996). Detection limits were about 8 and 18ng/mL for NAC and CAP, respectively. Intra-day precision (relative standard deviation, R.S.D.) was ≤1.58%, for thiol to internal standard (IS) peak area ratio and ≤0.33%, for thiol and IS retention times (tR), without significant differences between intra- and inter-day data. Thiol recovery studies were satisfactory (99.50%) with R.S.D. ≤0.56%. The results highlight the high sensitivity of the method and the remarkable reactivity and selectivity of the reagent towards the thiol function. The developed method is suitable for the quality control of both thiols in commercial products. The method can be applied in any analytical laboratory not requiring a sophisticated instrumentation.}, }
@article {pmid28632169, year = {2017}, author = {Kitahara, A and Takahashi, K and Morita, N and Murashima, T and Onuma, H and Sumitani, Y and Tanaka, T and Kondo, T and Hosaka, T and Ishida, H}, title = {The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 β-Cells.}, journal = {Marine drugs}, volume = {15}, number = {6}, pages = {}, pmid = {28632169}, issn = {1660-3397}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line, Tumor ; Chemokine CCL2/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; MAP Kinase Signaling System/drug effects ; Mice ; Oxidative Stress/*drug effects ; Palmitates/antagonists &amp; inhibitors/*pharmacology ; Vascular Endothelial Growth Factor A/metabolism ; Xanthophylls/pharmacology ; }, abstract = {Astaxanthin, an antioxidant agent, can protect pancreatic β-cells of db/db mice from glucotoxicity and resolve chronic inflammation in adipose tissue. Nonetheless, the effects of astaxanthin on free-fatty-acid-induced inflammation and cellular stress in β-cells remain to be demonstrated. Meanwhile, palmitate enhances the secretion of pro-inflammatory adipokines monocyte chemoattractant protein-1 (MCP-1) and VEGF120 (vascular endothelial growth factor). We therefore investigated the influence of astaxanthin on palmitate-stimulated MCP-1 and VEGF120 secretion in mouse insulinoma (MIN6) pancreatic β-cells. Furthermore, whether astaxanthin prevents cellular stress in MIN6 cells was also assessed. Pre-treatment with astaxanthin or with N-acetyl-cysteine (NAC) which is an antioxidant drug, significantly attenuated the palmitate-induced MCP-1 release through downregulation of phosphorylated c-Jun NH2-terminal protein kinase (JNK) pathways, and suppressed VEGF120 through the PI3K/Akt pathways relative to the cells stimulated with palmitate alone. In addition, palmitate significantly upregulated homologous protein (CHOP) and anti-glucose-regulated protein (GRP78), which are endoplasmic reticulum (ER) stress markers, in MIN6 cells. On the other hand, astaxanthin attenuated the increased CHOP content, but further up-regulated palmitate-stimulated GRP78 protein expression. By contrast, NAC had no effects on either CHOP or GRP78 enhancement induced by palmitate in MIN6 cells. In conclusion, astaxanthin diminishes the palmitate-stimulated increase in MCP-1 secretion via the downregulation of JNK pathways in MIN6 cells, and affects VEGF120 secretion through PI3K/Akt pathways. Moreover, astaxanthin can prevent not only oxidative stress caused endogenously by palmitate but also ER stress, which NAC fails to attenuate, via upregulation of GRP78, an ER chaperon.}, }
@article {pmid28628905, year = {2017}, author = {Chen, H and Tang, X and Zhou, B and Zhou, Z and Xu, N and Wang, Y}, title = {A ROS-mediated mitochondrial pathway and Nrf2 pathway activation are involved in BDE-47 induced apoptosis in Neuro-2a cells.}, journal = {Chemosphere}, volume = {184}, number = {}, pages = {679-686}, doi = {10.1016/j.chemosphere.2017.06.006}, pmid = {28628905}, issn = {1879-1298}, mesh = {Acetylcysteine/metabolism ; Antioxidants/metabolism ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Glutamate-Cysteine Ligase/metabolism ; Halogenated Diphenyl Ethers/*toxicity ; Heme Oxygenase-1/genetics ; Humans ; Mitochondria/*metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Our previous study showed that 2,2'-,4,4'-tetrabromodiphenyl ether (BDE-47) is cytotoxic and induces apoptosis in Neuro-2a cells. In the present study, we aimed to investigate whether nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an antioxidant transcriptional regulator of oxidative stress and apoptosis, is involved in this process. The results of toxicological experiments showed that BDE-47 decreased the cellular mitochondrial membrane potential (MMP) and increased cytochrome c release to the cytoplasm, followed by an increase in intracellular caspase-9 and caspase-3 activity, suggesting that a mitochondrial pathway was involved in the apoptotic process. Intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) contents as well as the oxidized/reduced glutathione (GSSG/GSH) ratio were elevated simultaneously in a concentration-dependent manner, indicating that BDE-47 induced oxidative stress. The ROS scavenger N-acetyl-l-cysteine (NAC) not only alleviated the oxidative stress but also blocked apoptosis and the decrease in MMP induced by BDE-47, indicating that the overproduction of ROS participates in a mitochondria-mediated apoptotic pathway. Moreover, BDE-47 stimulated the transcriptional induction of the Nrf-2 gene and induced mRNA expression of the main antioxidant response genes in the Nrf-2 pathway, including heme oxygenase 1 (HO-1), NAD(P)H/quinone oxidoreductase-1 (NQO1), glutamate-cysteine ligase modifier (GCLM) and glutathione peroxidase (GPX). Additionally, NAC and the p38 mitogen activated protein kinase (MAPK) signaling pathway inhibitor SB 203580 greatly reduced Nrf2 and HO-1 induction. We hypothesized that the ROS mediated mitochondrial pathway is involved in the BDE-47-induced apoptosis in Neuro-2a cells and that the Nrf2 pathway helps protect Neuro-2a cells from BDE-47-induced apoptosis.}, }
@article {pmid28627665, year = {2017}, author = {Zhang, Y and Cui, W and Zhai, Q and Zhang, T and Wen, X}, title = {N-acetylcysteine ameliorates repetitive/stereotypic behavior due to its antioxidant properties without activation of the canonical Wnt pathway in a valproic acid-induced rat model of autism.}, journal = {Molecular medicine reports}, volume = {16}, number = {2}, pages = {2233-2240}, doi = {10.3892/mmr.2017.6787}, pmid = {28627665}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Autistic Disorder/chemically induced/drug therapy/*pathology ; Behavior, Animal/drug effects ; Brain/metabolism/pathology ; Glutathione/metabolism ; Glycogen Synthase Kinase 3 beta ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Rats ; Rats, Sprague-Dawley ; Valproic Acid/*toxicity ; Wnt Signaling Pathway/*drug effects ; beta Catenin/metabolism ; }, abstract = {N-acetylcysteine (NAC) is widely used as an antioxidant, and previous studies have suggested that it may have potential as an alternative therapeutic strategy for the treatment of patients with autism. However, the exact effects of NAC administration on the development of autism, as well as the molecular mechanisms underlying its actions, have yet to be fully elucidated. The present study aimed to investigate the effects of NAC on the oxidative status of rats in a valproic acid (VPA)‑induced model of autism, and to examine the involvement of the canonical Wnt signaling pathway in the actions of NAC. Rats exposed to VPA were monitored for behavioral changes, and oxidative stress indicators and key molecules of the canonical Wnt pathway were investigated using colorimetric and western blot analysis, respectively. The present results demonstrated that NAC ameliorated repetitive and stereotypic activity in autism model rats. Furthermore, NAC was revealed to relieve oxidative stress, as demonstrated by the increased glutathione and reduced malondialdehyde levels compared with VPA‑treated rats. However, NAC did not appear to affect the activity of the canonical Wnt signaling pathway. The present findings suggested that the beneficial effects of NAC in autism may be associated with its antioxidative properties, and may not be mediated by the canonical Wnt pathway. However, it may be hypothesized that the canonical Wnt pathway can be indirectly regulated by NAC through the activation of other signaling pathways or upstream factors. Taken together, the present study has contributed to the elucidation of the molecular mechanisms that underlie the actions of NAC in autism, suggesting its potential for the development of novel therapeutic strategies for the treatment of patients with autism.}, }
@article {pmid28624886, year = {2017}, author = {Wong, A and Landersdorfer, C and Graudins, A}, title = {Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning.}, journal = {European journal of clinical pharmacology}, volume = {73}, number = {9}, pages = {1103-1110}, pmid = {28624886}, issn = {1432-1041}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/blood/*pharmacokinetics/therapeutic use ; Chemical and Drug Induced Liver Injury/blood/*drug therapy/metabolism ; Computer Simulation ; Drug Overdose/blood/*drug therapy/metabolism ; Humans ; Infusions, Intravenous ; *Models, Biological ; }, abstract = {PURPOSE: Paracetamol overdose is common and is treated with acetylcysteine to prevent the development of hepatotoxicity. N-acetyl-p-benzoquinone imine (NAPQI) is the toxic metabolite of paracetamol overdose. We aimed to assess the expected acetylcysteine concentration time profiles following delivery of modified acetylcysteine regimens proposed for those at high and low risk of hepatotoxicity. In addition, we will determine acetylcysteine concentrations post-cessation of abbreviated infusions.<br><br>METHOD: We performed pharmacokinetic simulations using Berkeley Madonna (version 8.3.23.0) comparing the time course of acetylcysteine concentration during and after the cessation of an abbreviated 12-h regimen (250&#xa0;mg/kg) using a two-bag infusion and compared this to the standard 21-h three-bag (300&#xa0;mg/kg) regimen. We also simulated extended duration acetylcysteine regimens and other increased dosing strategies that have been recommended in specific paracetamol poisoning scenarios.<br><br>RESULTS: A more sustained serum concentration is achieved when the acetylcysteine loading dose is delivered over 4&#xa0;h using the two-bag compared to the 1-h loading dose of the three-bag regimen. When administering an abbreviated 12-h acetylcysteine regimen, circulating acetylcysteine is detectable for 8&#xa0;h after cessation of the infusion. This may provide a continued hepatoprotective effect if NAPQI is still being generated after the infusion is ceased.<br><br>CONCLUSION: This pharmacokinetic simulation study is an important step in determining plasma acetylcysteine concentrations that are likely to be achieved using various modified treatment regimens. Importantly, for patients at low risk of liver injury after acute overdose, acetylcysteine is likely to be detectable many hours post-cessation of a 12-h regimen. This should provide a safety factor against development of hepatotoxicity for any ongoing paracetamol metabolism after cessation of the acetylcysteine infusion.}, }
@article {pmid28623823, year = {2017}, author = {Gray, KM and Sonne, SC and McClure, EA and Ghitza, UE and Matthews, AG and McRae-Clark, AL and Carroll, KM and Potter, JS and Wiest, K and Mooney, LJ and Hasson, A and Walsh, SL and Lofwall, MR and Babalonis, S and Lindblad, RW and Sparenborg, S and Wahle, A and King, JS and Baker, NL and Tomko, RL and Haynes, LF and Vandrey, RG and Levin, FR}, title = {A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults.}, journal = {Drug and alcohol dependence}, volume = {177}, number = {}, pages = {249-257}, pmid = {28623823}, issn = {1879-0046}, support = {UG1 DA020024/DA/NIDA NIH HHS/United States ; K01 DA036739/DA/NIDA NIH HHS/United States ; R01 DA026777/DA/NIDA NIH HHS/United States ; UG1 DA013727/DA/NIDA NIH HHS/United States ; UG1 DA015831/DA/NIDA NIH HHS/United States ; R01 DA042114/DA/NIDA NIH HHS/United States ; U10 DA013732/DA/NIDA NIH HHS/United States ; U10 DA013045/DA/NIDA NIH HHS/United States ; UG1 DA013732/DA/NIDA NIH HHS/United States ; K24 DA029647/DA/NIDA NIH HHS/United States ; HHSN271201200017C/DA/NIDA NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; UG3 DA043231/DA/NIDA NIH HHS/United States ; UG1 DA013714/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Cannabis ; Double-Blind Method ; Female ; Free Radical Scavengers/therapeutic use ; Humans ; Male ; Marijuana Abuse/*diagnosis/*drug therapy/psychology ; Marijuana Smoking/drug therapy/psychology ; Medication Adherence/psychology ; Sulpiride ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults.<br><br>METHODS: In a 12-week double-blind randomized placebo-controlled trial, treatment-seeking adults ages 18-50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200mg (n=153) or placebo (n=149) twice daily. All participants received contingency management (CM) and medical management. The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment, compared between NAC and placebo participants.<br><br>RESULTS: There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence (odds ratio=1.00, 95% confidence interval 0.63-1.59, p=0.984). Overall, 22.3% of urine cannabinoid tests in the NAC group were negative, compared with 22.4% in the placebo group. Many participants were medication non-adherent; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group.<br><br>CONCLUSIONS: In contrast with prior findings in adolescents, there is no evidence that NAC 1200mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM. This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development, cannabis use profiles, responses to embedded behavioral treatment, medication adherence, and other factors.}, }
@article {pmid28623559, year = {2017}, author = {Meyer, A and Laverny, G and Allenbach, Y and Grelet, E and Ueberschlag, V and Echaniz-Laguna, A and Lannes, B and Alsaleh, G and Charles, AL and Singh, F and Zoll, J and Lonsdorfer, E and Maurier, F and Boyer, O and Gottenberg, JE and Nicot, AS and Laporte, J and Benveniste, O and Metzger, D and Sibilia, J and Geny, B}, title = {IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis.}, journal = {Acta neuropathologica}, volume = {134}, number = {4}, pages = {655-666}, doi = {10.1007/s00401-017-1731-9}, pmid = {28623559}, issn = {1432-0533}, support = {ANR-10-INBS-0009//Agence Nationale de la Recherche/ ; ANR-10-LABX-0030-//Agence Nationale de la Recherche/ ; ANR-10-IDEX-0002-02//Agence Nationale de la Recherche/ ; }, mesh = {Acetylcysteine/pharmacology ; Adult ; Aged ; Animals ; Cell Line ; Cytokines/blood ; Dermatomyositis/drug therapy/*metabolism/pathology ; Female ; Free Radical Scavengers/pharmacology ; Freund's Adjuvant ; Humans ; Inflammation/drug therapy/*metabolism/pathology ; Interferon-beta/*metabolism ; Male ; Mice, Inbred BALB C ; Middle Aged ; Mitochondria/drug effects/*metabolism/pathology ; Muscle Weakness/drug therapy/metabolism/pathology ; Muscle, Skeletal/drug effects/*metabolism/pathology ; Nervous System Autoimmune Disease, Experimental/drug therapy/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Transcriptome ; }, abstract = {Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down-regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-β induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-β induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN-inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM.}, }
@article {pmid28621211, year = {2018}, author = {Ahmad, J and Siddiqui, MA and Akhtar, MJ and Alhadlaq, HA and Alshamsan, A and Khan, ST and Wahab, R and Al-Khedhairy, AA and Al-Salim, A and Musarrat, J and Saquib, Q and Fareed, M and Ahamed, M}, title = {Copper doping enhanced the oxidative stress-mediated cytotoxicity of TiO2 nanoparticles in A549 cells.}, journal = {Human &amp; experimental toxicology}, volume = {37}, number = {5}, pages = {496-507}, doi = {10.1177/0960327117714040}, pmid = {28621211}, issn = {1477-0903}, mesh = {A549 Cells ; Caspase 3/metabolism ; Cell Survival/drug effects ; Copper/*toxicity ; Glutathione/metabolism ; Humans ; Microscopy, Electron, Transmission ; Nanoparticles/*toxicity/ultrastructure ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Titanium/*toxicity ; }, abstract = {Physicochemical properties of titanium dioxide nanoparticles (TiO2 NPs) can be tuned by doping with metals or nonmetals. Copper (Cu) doping improved the photocatalytic behavior of TiO2 NPs that can be applied in various fields such as environmental remediation and nanomedicine. However, interaction of Cu-doped TiO2 NPs with human cells is scarce. This study was designed to explore the role of Cu doping in cytotoxic response of TiO2 NPs in human lung epithelial (A549) cells. Characterization data demonstrated the presence of both TiO2 and Cu in Cu-doped TiO2 NPs with high-quality lattice fringes without any distortion. The size of Cu-doped TiO2 NPs (24 nm) was lower than pure TiO2 NPs (30 nm). Biological results showed that both pure and Cu-doped TiO2 NPs induced cytotoxicity and oxidative stress in a dose-dependent manner. Low mitochondrial membrane potential and higher caspase-3 enzyme (apoptotic markers) activity were also observed in A549 cells exposed to pure and Cu-doped TiO2 NPs. We further observed that cytotoxicity caused by Cu-doped TiO2 NPs was higher than pure TiO2 NPs. Moreover, antioxidant N-acetyl cysteine effectively prevented the reactive oxygen species generation, glutathione depletion, and cell viability reduction caused by Cu-doped TiO2 NPs. This is the first report showing that Cu-doped TiO2 NPs induced cytotoxicity and oxidative stress in A549 cells. This study warranted further research to explore the role of Cu doping in toxicity mechanisms of TiO2 NPs.}, }
@article {pmid28617566, year = {2017}, author = {Costa, DLC and Diniz, JB and Requena, G and Joaquim, MA and Pittenger, C and Bloch, MH and Miguel, EC and Shavitt, RG}, title = {Randomized, Double-Blind, Placebo-Controlled Trial of N-Acetylcysteine Augmentation for Treatment-Resistant Obsessive-Compulsive Disorder.}, journal = {The Journal of clinical psychiatry}, volume = {78}, number = {7}, pages = {e766-e773}, doi = {10.4088/JCP.16m11101}, pmid = {28617566}, issn = {1555-2101}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Aged ; Anxiety Disorders/diagnosis/drug therapy/psychology ; Comorbidity ; Depressive Disorder/diagnosis/drug therapy/psychology ; Double-Blind Method ; Drug Resistance ; Drug Therapy, Combination ; Female ; Humans ; Male ; Middle Aged ; Obsessive-Compulsive Disorder/diagnosis/*drug therapy/psychology ; Psychiatric Status Rating Scales/statistics &amp; numerical data ; Psychometrics ; Selective Serotonin Reuptake Inhibitors/adverse effects/*therapeutic use ; Young Adult ; }, abstract = {OBJECTIVE: To evaluate the efficacy of serotonin reuptake inhibitor (SRI) augmentation with N-acetylcysteine (NAC), a glutamate modulator and antioxidant medication, for treatment-resistant obsessive-compulsive disorder (OCD).<br><br>METHODS: We conducted a randomized, double-blind, placebo-controlled, 16-week trial of NAC (3,000 mg daily) in adults (aged 18-65 years) with treatment-resistant OCD, established according to DSM-IV criteria. Forty subjects were recruited at an OCD-specialized outpatient clinic at a tertiary hospital (May 2012-October 2014). The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores. To evaluate the variables group, time, and interaction effects for Y-BOCS scores at all time points, we used nonparametric analysis of variance with repeated measures. Secondary outcomes were the severity scores for anxiety, depression, specific OCD symptom dimensions, and insight.<br><br>RESULTS: Both groups showed a significant reduction of baseline Y-BOCS scores at week 16: the NAC group had a reduction of 4.3 points (25.6 to 21.3), compared with 3.0 points (24.8 to 21.8) for the placebo group. However, there were no significant differences between groups (P = .92). Adding NAC was superior to placebo in reducing anxiety symptoms (P = .02), but not depression severity or specific OCD symptom dimensions. In general, NAC was well tolerated, despite abdominal pain being more frequently reported in the NAC group (n [%]: NAC = 9 [60.0], placebo = 2 [13.3]; P < .01).<br><br>CONCLUSIONS: Our trial did not demonstrate a significant benefit of NAC in reducing OCD severity in treatment-resistant OCD adults. Secondary analysis suggested that NAC might have some benefit in reducing anxiety symptoms in treatment-resistant OCD patients.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01555970.}, }
@article {pmid28614987, year = {2018}, author = {Garg, BD and Kabra, NS}, title = {Role of amino acid supplementation in the prevention of necrotizing enterocolitis in preterm neonates - a review of current evidences.}, journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians}, volume = {31}, number = {17}, pages = {2349-2366}, doi = {10.1080/14767058.2017.1342797}, pmid = {28614987}, issn = {1476-4954}, mesh = {Amino Acids/*administration &amp; dosage ; Dietary Supplements ; Enteral Nutrition ; Enterocolitis, Necrotizing/diet therapy/*prevention &amp; control ; Female ; Humans ; *Infant, Extremely Low Birth Weight/growth &amp; development ; Infant, Newborn ; *Infant, Premature/growth &amp; development/physiology ; Infant, Premature, Diseases/diet therapy/*prevention &amp; control ; Pregnancy ; }, abstract = {BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most common acute and fatal gastrointestinal emergency in very low birth weight (VLBW) preterm neonates with mortality range from 15 to 30%. NEC is likely due to multifactorial process such as oxidative injury, ischemic necrosis, and over-reactive inflammatory response to intestinal microbes.<br><br>AIMS: To evaluate the role of amino acid supplementation for reduction of neonatal NEC in preterm neonates.<br><br>METHOD: The literature search was done for various randomized control trial (RCT) by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, Scopus, Index Copernicus, African Index Medicus (AIM), Thomson Reuters (ESCI), Chemical Abstracts Service (CAS) and other database.<br><br>RESULTS: This review included 15 RCTs that fulfilled inclusion criteria. The total neonates enrolled in these different RCT are 3424 (amino acid group 1711 and control 1713). Almost all participating neonates were of VLBW or extremely low birth weight (ELBW). In two trials, birth weight was between 1500-2000 grams. The intervention was started within first few days after birth and continued up to 30th day of postnatal age in most of the trials. In two trials, intervention was continued up to 120th day of postnatal age. Arginine, glutamine and N-acetyl cysteine (NAC) were used at the dose of 1.5&#x2009;mol/kg/day (261&#x2009;mg/kg/day), 0.3 grams/kg/day and 16-32&#x2009;mg/kg/day, respectively.<br><br>CONCLUSION: Role of amino acid in the prevention of neonatal NEC is not exclusively supported by the current evidence. Only three studies were able to show reduction in the incidence of NEC with amino acid supplementation (arginine, glutamine), and the remaining studies did not report any positive effect. Amino acid supplementation was not associated with significant reduction in mortality due to any causes. However, arginine supplementation was associated with significant reduction in mortality due to NEC. Two studies on glutamine were reported significant reduction in the incidence of invasive infection. Only one study reported significant positive effects on growth parameters and less time to reach full enteral feeds. None of the studies showed any effect on the duration of hospital stay.}, }
@article {pmid28611340, year = {2017}, author = {Nabi, T and Nabi, S and Rafiq, N and Shah, A}, title = {Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study.}, journal = {Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association}, volume = {23}, number = {3}, pages = {169-175}, pmid = {28611340}, issn = {1998-4049}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Case-Control Studies ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Hepatic Encephalopathy/*complications/drug therapy ; Humans ; Incidence ; Infusions, Intravenous ; Length of Stay/statistics &amp; numerical data ; Liver Failure, Acute/diagnosis/*drug therapy/epidemiology/etiology ; Liver Transplantation/methods ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND/AIMS: Acute liver failure (ALF) is a rare but severe medical emergency. To date, there is no established treatment for non-acetaminophen-induced acute liver failure (NAI-ALF) other than liver transplantation, and little is known about the use of N-acetylcysteine (NAC) in NAI-ALF. A randomized case control study was conducted with the aim to determine the effect of NAC on the mortality of NAI-ALF patients, as well as to evaluate the safety and efficacy of NAC use.<br><br>PATIENTS AND METHODS: A total of 80 patients diagnosed with NAI-ALF were included in the study. Forty patients received NAC infusion for 72 h whereas the control group received placebo. The variables evaluated were demographic characteristics, signs and symptoms, biochemical parameters, and clinical course during hospitalization.<br><br>RESULTS: The two groups (NAC and control) were comparable for various baseline characteristics (such as etiology of ALF, INR, alanine aminotransferase, creatinine, albumin, and grade of encephalopathy), except for age. Although majority of patients had undetermined etiology (32.5% in NAC group and 42.5% in control group), the second main cause was acute hepatitis E and drug or toxin-induced ALF. The mortality decreased to 28% with the use of NAC versus 53% in the control group (P = 0.023). The use of NAC was associated with shorter length of hospital stay in survived patients (P = 0.002). Moreover, the survival of patients was improved by NAC (P = 0.025). Also, drug-induced ALF showed improved outcome compared to other etiologies.<br><br>CONCLUSION: The findings of the study recommend the use of NAC along with conventional treatments in patients with NAI-ALF in non-transplant centers while awaiting referrals and conclude the use of NAC as safe.}, }
@article {pmid28609563, year = {2017}, author = {Desrochers, J and Wojciechowski, J and Klein-Schwartz, W and Gobburu, JVS and Gopalakrishnan, M}, title = {Bayesian Forecasting Tool to Predict the Need for Antidote in Acute Acetaminophen Overdose.}, journal = {Pharmacotherapy}, volume = {37}, number = {8}, pages = {916-926}, doi = {10.1002/phar.1972}, pmid = {28609563}, issn = {1875-9114}, mesh = {Acetaminophen/blood/pharmacokinetics/*poisoning ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Non-Narcotic/blood/pharmacokinetics/*poisoning ; Antidotes/*administration &amp; dosage ; Bayes Theorem ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Cohort Studies ; Drug Administration Schedule ; Drug Overdose/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; Young Adult ; }, abstract = {STUDY OBJECTIVE: Acetaminophen (APAP) overdose is the leading cause of acute liver injury in the United States. Patients with elevated plasma acetaminophen concentrations (PACs) require hepatoprotective treatment with N-acetylcysteine (NAC). These patients have been primarily risk-stratified using the Rumack-Matthew nomogram. Previous studies of acute APAP overdoses found that the nomogram failed to accurately predict the need for the antidote. The objectives of this study were to develop a population pharmacokinetic (PK) model for APAP following acute overdose and evaluate the utility of population PK model-based Bayesian forecasting in NAC administration decisions.<br><br>Limited APAP concentrations from a retrospective cohort of acute overdosed subjects from the Maryland Poison Center were used to develop the population PK model and to investigate the effect of type of APAP products and other prognostic factors. The externally validated population PK model was used a prior for Bayesian forecasting to predict the individual PK profile when one or two observed PACs were available. The utility of Bayesian forecasted APAP concentration-time profiles inferred from one (first) or two (first and second) PAC observations were also tested in their ability to predict the observed NAC decisions.<br><br>MAIN RESULTS: A one-compartment model with first-order absorption and elimination adequately described the data with single activated charcoal and APAP products as significant covariates on absorption and bioavailability. The Bayesian forecasted individual concentration-time profiles had acceptable bias (6.2% and 9.8%) and accuracy (40.5% and 41.9%) when either one or two PACs were considered, respectively. The sensitivity and negative predictive value of the Bayesian forecasted NAC decisions using one PAC were 84% and 92.6%, respectively.<br><br>CONCLUSION: The population PK analysis provided a platform for acceptably predicting an individual's concentration-time profile following acute APAP overdose with at least one PAC, and the individual's covariate profile, and can potentially be used for making early NAC administration decisions.}, }
@article {pmid28607932, year = {2017}, author = {Gao, W and Liang, JX and Ma, C and Dong, JY and Yan, Q}, title = {The Protective Effect of N-Acetylcysteine on Ionizing Radiation Induced Ovarian Failure and Loss of Ovarian Reserve in Female Mouse.}, journal = {BioMed research international}, volume = {2017}, number = {}, pages = {4176170}, pmid = {28607932}, issn = {2314-6141}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Apoptosis/drug effects/radiation effects ; Cell Proliferation/drug effects/radiation effects ; Disease Models, Animal ; Embryo Implantation/drug effects/radiation effects ; Endometrium/drug effects/radiation effects ; Female ; Humans ; Mice ; Ovarian Follicle/drug effects/*physiopathology/radiation effects ; Ovarian Reserve/drug effects/radiation effects ; Primary Ovarian Insufficiency/*drug therapy/physiopathology ; Radiation, Ionizing ; Radiation-Protective Agents/*administration &amp; dosage ; }, abstract = {Ionizing radiation may cause irreversible ovarian failure, which, therefore, calls for an effective radioprotective reagent. The aim of the present study was to evaluate the potential radioprotective effect of N-acetylcysteine (NAC) on ionizing radiation induced ovarian failure and loss of ovarian reserve in mice. Kun-Ming mice were either exposed to X-irradiation (4 Gy), once, and/or treated with NAC (300 mg/kg), once daily for 7 days before X-irradiation. We examined the serum circulating hormone levels and the development of ovarian follicles as well as apoptosis, cell proliferation, and oxidative stress 24 hours after X-irradiation. In addition, morphological observations on the endometrial luminal epithelium and the fertility assessment were performed. We found that NAC successfully restored the ovarian and uterine function, enhanced the embryo implantation, improved the follicle development, and altered the abnormal hormone levels through reducing the oxidative stress and apoptosis level in granulosa cells while promoting the proliferation of granulosa cells. In conclusion, the radioprotective effect of NAC on mice ovary from X-irradiation was assessed, and our results suggested that NAC can be a potential radioprotector which is capable of preventing the ovarian failure occurrence and restoring the ovarian reserve.}, }
@article {pmid28607630, year = {2017}, author = {Prevatto, JP and Torres, RC and Diaz, BL and Silva, PMRE and Martins, MA and Carvalho, VF}, title = {Antioxidant Treatment Induces Hyperactivation of the HPA Axis by Upregulating ACTH Receptor in the Adrenal and Downregulating Glucocorticoid Receptors in the Pituitary.}, journal = {Oxidative medicine and cellular longevity}, volume = {2017}, number = {}, pages = {4156361}, pmid = {28607630}, issn = {1942-0994}, mesh = {Animals ; Antioxidants/metabolism/*therapeutic use ; Down-Regulation ; Glucocorticoids/*metabolism ; Hypothalamo-Hypophyseal System/*metabolism ; Male ; Pituitary-Adrenal System/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; Receptors, Corticotropin/*metabolism ; Up-Regulation ; }, abstract = {Glucocorticoid (GC) production is physiologically regulated through a negative feedback loop mediated by the GC, which appear disrupted in several pathological conditions. The inability to perform negative feedback of the hypothalamus-pituitary-adrenal (HPA) axis in several diseases is associated with an overproduction of reactive oxygen species (ROS); however, nothing is known about the effects of ROS on the functionality of the HPA axis during homeostasis. This study analyzed the putative impact of antioxidants on the HPA axis activity and GC-mediated negative feedback upon the HPA cascade. Male Wistar rats were orally treated with N-acetylcysteine (NAC) or vitamin E for 18 consecutive days. NAC-treated rats were then subjected to a daily treatment with dexamethasone, which covered the last 5 days of the antioxidant therapy. We found that NAC and vitamin E induced an increase in plasma corticosterone levels. NAC intensified MC2R and StAR expressions in the adrenal and reduced GR and MR expressions in the pituitary. NAC also prevented the dexamethasone-induced reduction in plasma corticosterone levels. Furthermore, NAC decreased HO-1 and Nrf2 expression in the pituitary. These findings show that antioxidants induce hyperactivity of the HPA axis via upregulation of MC2R expression in the adrenal and downregulation of GR and MR in the pituitary.}, }
@article {pmid28605780, year = {2017}, author = {Martinez Cantarin, MP and Whitaker-Menezes, D and Lin, Z and Falkner, B}, title = {Uremia induces adipose tissue inflammation and muscle mitochondrial dysfunction.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {32}, number = {6}, pages = {943-951}, doi = {10.1093/ndt/gfx050}, pmid = {28605780}, issn = {1460-2385}, mesh = {Adiponectin/metabolism ; Adult ; Animals ; Case-Control Studies ; Cell Line ; Female ; Humans ; Inflammation/immunology/metabolism ; Interleukin-6/metabolism ; Intra-Abdominal Fat/*immunology/metabolism ; Kidney Failure, Chronic/*immunology/pathology ; Macrophages/immunology/metabolism ; Male ; Mice ; Middle Aged ; Mitochondria, Muscle/*metabolism ; Muscle, Skeletal/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Uremia/*immunology/metabolism ; }, abstract = {BACKGROUND.: End-stage renal disease (ESRD) is associated with inflammation and increased reactive oxygen species (ROS). Inflammation and oxidative stress are associated with several complications of ESRD. The aim of this study was to determine histological characteristics of adipose tissue and muscle mitochondrial function in uremia and its relationship with inflammation.<br><br>METHODS.: ESRD patients (n &#x2009;=&#x2009;18) and controls (n &#x2009;=&#x2009;6) were enrolled for studies of adipose and muscle tissue by immunohistochemistry and western blot. In a uremic muscle cell model, C2C12 cells were exposed to uremic serum and inflammatory cytokines. Mitochondrial function was studied by MitoTracker Orange, translocase of the mitochondrial outer membrane 20 (TOMM20) and mitochondrial oxidative phosphorylation complex subunit expression.<br><br>RESULTS.: ESRD patients had increased macrophage infiltration in subcutaneous and visceral adipose tissue compared with controls, even in nonobese ESRD patients (P&#x2009;<&#x2009;0.05). Compared with controls, TOMM20 expression in muscle tissue was lower in ESRD, consistent with reduced mitochondrial function (P&#x2009;<&#x2009;0.05). C2C12 exposed to uremia had decreased mitotracker intensity (P&#x2009;<&#x2009;0.05) and the reduced mitochondrial function was rescued by N-acetyl cysteine (P&#x2009;<&#x2009;0.01). Similarly, C2C12 cells exposed to tumor necrosis factor &#x3b1; (TNF-&#x3b1;)/interleukin-6 (IL-6) have decreased mitotracker intensity (P&#x2009;<&#x2009;0.01) that was rescued with adiponectin (P&#x2009;<&#x2009;0.05). C2C12 exposed to TNF-&#x3b1;, IL-6 and buthionine sulfoximine had decreased TOMM20 expression and cells exposed to TNF-&#x3b1; showed a decrease in subunits of mitochondrial complexes I and III.<br><br>CONCLUSION.: Our data indicate that uremia is associated with increased adipose tissue macrophage infiltration and concurrent muscle tissue mitochondrial dysfunction induced by inflammation/ROS. Adipose tissue is a potential source of inflammation in ESRD that is not due to increased adiposity and may contribute to mitochondrial dysfunction in uremia.}, }
@article {pmid28602912, year = {2017}, author = {Park, JM and Han, YM and Jeong, M and Chung, MH and Kwon, CI and Ko, KH and Hahm, KB}, title = {Synthetic 8-hydroxydeoxyguanosine inhibited metastasis of pancreatic cancer through concerted inhibitions of ERM and Rho-GTPase.}, journal = {Free radical biology &amp; medicine}, volume = {110}, number = {}, pages = {151-161}, doi = {10.1016/j.freeradbiomed.2017.06.003}, pmid = {28602912}, issn = {1873-4596}, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs &amp; derivatives/pharmacology ; 8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Claudin-1/agonists/genetics/metabolism ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Deoxyguanosine/*analogs &amp; derivatives/pharmacology ; Epithelial-Mesenchymal Transition/*drug effects/genetics ; Focal Adhesion Kinase 1/genetics/metabolism ; GTPase-Activating Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; *Gene Expression Regulation, Neoplastic ; Humans ; Hyaluronan Receptors/genetics/metabolism ; Imidazoles/pharmacology ; Lung Neoplasms/*drug therapy/genetics/metabolism/secondary ; Matrix Metalloproteinases/genetics/metabolism ; Mice ; Mice, Nude ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/metabolism ; Pancreatic Neoplasms/*drug therapy/genetics/metabolism/pathology ; Pyrroles/pharmacology ; Signal Transduction ; Transcription Factors/antagonists &amp; inhibitors/genetics/metabolism ; Vimentin/antagonists &amp; inhibitors/genetics/metabolism ; Xenograft Model Antitumor Assays ; Zonula Occludens-1 Protein/agonists/genetics/metabolism ; rho-Associated Kinases/genetics/metabolism ; }, abstract = {8-hydroxydeoxyguanosine (8-OHdG) is generated consequent to oxidative stress, but its paradoxical anti-oxidative, anti-inflammatory, and anti-mutagenic effects via Rho-GTPase inhibition were noted in various models of inflammation and cancer. Metastasis occurs through cell detachment, epithelial-mesenchymal transition (EMT), and cell migration; during these processes, changes in cell morphology are initiated through Rho-GTPase-dependent actin cytoskeleton polymerization. In this study, we explored the anti-metastatic mechanisms of 8-OHdG in Panc-1 pancreatic cancer cells. 8-OHdG inhibits cell migration by inactivating ERM and Rho-GTPase proteins, and inhibiting focal adhesion kinase (FAK) and matrix metalloproteinases (MMPs). At 15min, 8-OHdG significantly inactivated ERM (p < 0.05) and led to a significant retardation of wound healing; siERM and H1152 (ROCK inhibitor) had similar effects (p < 0.05). However, FAK inhibitor 14, DPI (NOX inhibitor), and NAC (antioxidant) significantly delayed wound healing without inhibiting ERM or CD44 (p < 0.05). In the experiments on cell migration, siERM, siCD44, DPI, and 8-OHdG significantly inhibited MMPs. 8-OHdG significantly decreased DCF-DA activation in Panc-1 pancreatic cancer cells and down-regulated NOXs (nox-1, nox-2, and nox-3). Finally, all of these anti-migration actions of 8-OHdG resulted in significant inhibition of EMT, as evidenced by the up-regulation of ZO-1 and claudin-1 and down-regulation of vimentin. We found significant inhibition of lung metastasis of Panc-1 cells by 8-OHdG. In conclusion, exogenous 8-OHdG had potent anti-metastasis effects mediated by either ERM or Rho GTPase inhibition in metastasis-prone pancreatic cancer cells.}, }
@article {pmid28600879, year = {2018}, author = {Andreeva, ER and Udartseva, OO and Zhidkova, OV and Buravkov, SV and Ezdakova, MI and Buravkova, LB}, title = {IFN-gamma priming of adipose-derived stromal cells at "physiological" hypoxia.}, journal = {Journal of cellular physiology}, volume = {233}, number = {2}, pages = {1535-1547}, doi = {10.1002/jcp.26046}, pmid = {28600879}, issn = {1097-4652}, mesh = {Adipose Tissue/cytology/*drug effects/metabolism ; Animals ; Cell Hypoxia ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Coculture Techniques ; Coturnix ; Culture Media, Conditioned/metabolism ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Interferon-gamma/*pharmacology ; Mesenchymal Stem Cells/*drug effects/metabolism ; Neovascularization, Physiologic ; Osteogenesis/drug effects ; Oxidative Stress/drug effects ; Paracrine Communication/drug effects ; Phenotype ; Reactive Oxygen Species/metabolism ; Time Factors ; }, abstract = {Multipotent mesenchymal stromal cells (MSCs) are considered cue regulators of tissue remodeling. Their activity is strongly governed by local milieu, where O2 level is most important. The elevation of inflammatory mediators and acute O2 lowering may additionally modulate MSC activity. In present paper the priming effects of IFN-gamma on adipose tissue-derived MSCs (ASCs) at tissue-related O2 level (5%) and acute hypoxic stress (0.1% O2) were assessed as alterations of ASCs' CFU-F, proliferation, migration, osteo-commitment. IFN-gamma priming provoked ROS elevation, cell growth slowdown, attenuation of both spontaneous and induced osteodifferentiation of tissue O2 -adapted ASCs. The prominent changes in ASC cytoskeleton-related gene transcription was detected. IFN-gamma exposure shifted the ASC paracrine profile, suppressing the production of VEGF and IL-8, while MCP-1 and IL-6 were stimulated. Conditioned medium of IFN-gamma-primed ASCs did not activate vessel growth in the CAM assay, but induced endothelial cell migration in "wound closure." Short-term hypoxia suppressed CFU-F number, IFN-gamma-induced elevation of IL-6 and endothelial cell migration, while it abolished IFN-gamma-provoked VEGF inhibition. After N-acetyl cysteine treatment ROS level was partly abolished providing additional enhancement of IL-6 and suppression of IL-8 and VEGF production. These findings demonstrated that paracrine activity of ASCs in part may be governed by ROS level. Thus, this study first demonstrated that IFN-gamma priming itself and in combination with acute O2 deprivation could supply dual effects on ASC functions providing both stimulatory and hampering effects. The equilibrium of these factors is a substantial requirement for the execution of MSC remodeling functions.}, }
@article {pmid28600122, year = {2017}, author = {Pant, K and Saraya, A and Venugopal, SK}, title = {Oxidative stress plays a key role in butyrate-mediated autophagy via Akt/mTOR pathway in hepatoma cells.}, journal = {Chemico-biological interactions}, volume = {273}, number = {}, pages = {99-106}, doi = {10.1016/j.cbi.2017.06.001}, pmid = {28600122}, issn = {1872-7786}, mesh = {Autophagy/*drug effects ; Butyrates/*pharmacology ; Carcinoma, Hepatocellular/*metabolism/*pathology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Humans ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Structure-Activity Relationship ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Hepatocellular Carcinoma (HCC) is one of the most aggressive forms of cancer, responsible for a number of deaths in humans. Butyrate, one of the short chain fatty acids produced by the gut microbiota during anaerobic fermentation, was shown to be beneficial for inhibiting cancer growth. In this study, we showed that sodium butyrate induced autophagy via reactive oxygen species (ROS) in hepatoma cells. Butyrate (0-6 mM) incubation significantly increased intracellular ROS levels (45.2% compared to control), which in turn inhibited phosphorylation of akt and mTOR, leading to the upregulation of autophagic proteins, such as beclin 1, ATG 5, LC3-II, followed by the increased autophagosome formation (34.4% compared to control cells). Addition of a known antioxidant, N-acetyl cysteine (NAC), reversed these butyrate-induced ROS and autophagy. It was also found that butyrate-induced ROS enhanced MAPK activation, which was inhibited by NAC. In conclusion, our data showed that butyrate induced ROS, which in turn induced autophagy via inhibition of akt/mTOR pathway. Hence, butyrate could be considered as a potential candidate for HCC treatment.}, }
@article {pmid28599922, year = {2017}, author = {Lowe, DW and Fraser, JL and Rollins, LG and Bentzley, J and Nie, X and Martin, R and Singh, I and Jenkins, D}, title = {Vitamin D improves functional outcomes in neonatal hypoxic ischemic male rats treated with N-acetylcysteine and hypothermia.}, journal = {Neuropharmacology}, volume = {123}, number = {}, pages = {186-200}, doi = {10.1016/j.neuropharm.2017.06.004}, pmid = {28599922}, issn = {1873-7064}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Calcitriol/*pharmacology ; Disease Models, Animal ; Female ; Hippocampus/drug effects/metabolism/pathology ; *Hypothermia, Induced ; Hypoxia-Ischemia, Brain/pathology/physiopathology/psychology/*therapy ; Male ; Maze Learning/drug effects ; Memory/drug effects ; Motor Skills/drug effects ; Neuroprotective Agents/*pharmacology ; Random Allocation ; Rats, Sprague-Dawley ; Sex Characteristics ; Vitamin D/blood ; Vitamin D3 24-Hydroxylase/metabolism ; }, abstract = {Hypothermia treatment neuroprotects approximately 50% of neonates who present with moderate to severe hypoxic ischemic encephalopathy (HIE). N-acetylcysteine (NAC), a potent antioxidant, is neuroprotective in combination with hypothermia in neonatal hypoxia-ischemia (HI) female rats, but less protective in males. Vitamin D is a neurosteroid, which may provide immunomodulation and improve outcomes for both sexes. We investigated the efficacy of this combination of drugs with hypothermia after severe HI, as well as potential mechanisms of vitamin D effects in the transition to chronic inflammation. DOL 7 rats were randomized to sham, or HI and hypothermia treated with either saline (HYPO), NAC (50 mg/kg/d, HNAC), or HNAC plus 1,25-dihydroxy-vitamin D3 (0.1 μg/kg/d, HNAC + VitD) daily for 2 weeks. A second set of animals were randomized and treated for 11 days to investigate vitamin D metabolism and inflammatory mediators. Rats treated with HNAC + VitD performed significantly better on tests of strength and use of affected limb, adaptive sensorimotor skills, motor sequence learning, and working memory than either HYPO or HNAC, particularly benefiting male rats. Significantly fewer rats in the HNAC + VitD group had severe hemispheric volume loss. HI injury decreased serum vitamin D at 11 days and induced the enzyme that deactivates vitamin D in the hippocampus, particularly in males. Persistent vitamin D dysregulation was seen in both hippocampi in males, which was not reversed by hypothermia. Vitamin D in combination with hypothermia and NAC supports functional recovery in both sexes of neonatal rats significantly better than hypothermia alone or hypothermia and NAC in this severe HI model.}, }
@article {pmid28595554, year = {2018}, author = {Colovic, MB and Vasic, VM and Djuric, DM and Krstic, DZ}, title = {Sulphur-containing Amino Acids: Protective Role Against Free Radicals and Heavy Metals.}, journal = {Current medicinal chemistry}, volume = {25}, number = {3}, pages = {324-335}, doi = {10.2174/0929867324666170609075434}, pmid = {28595554}, issn = {1875-533X}, mesh = {Amino Acids/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Free Radicals/*antagonists &amp; inhibitors ; Humans ; Metals, Heavy/*antagonists &amp; inhibitors ; Sulfur/*pharmacology ; }, abstract = {BACKGROUND: Sulphur is an abundant element in biological systems, which plays an important role in processes essential for life as a constituent of proteins, vitamins and other crucial biomolecules. The major source of sulphur for humans is plants being able to use inorganic sulphur in the purpose of sulphur-containing amino acids synthesis. Sulphur-containing amino acids include methionine, cysteine, homocysteine, and taurine. Methionine and cysteine are classified as proteinogenic, canonic amino acids incorporated in protein structure. Sulphur amino acids are involved in the synthesis of intracellular antioxidants such as glutathione and N-acetyl cysteine. Moreover, naturally occurring sulphur-containing ligands are effective and safe detoxifying agents, often used in order to prevent toxic metal ions effects and their accumulation in human body.<br><br>METHODS: Literature search for peer-reviewed articles was performed using PubMed and Scopus databases, and utilizing appropriate keywords.<br><br>RESULTS: This review is focused on sulphur-containing amino acids - methionine, cysteine, taurine, and their derivatives - glutathione and N-acetylcysteine, and their defense effects as antioxidant agents against free radicals. Additionally, the protective effects of sulphur-containing ligands against the toxic effects of heavy and transition metal ions, and their reactivation role towards the enzyme inhibition are described.<br><br>CONCLUSION: Sulphur-containing amino acids represent a powerful part of cell antioxidant system. Thus, they are essential in the maintenance of normal cellular functions and health. In addition to their worthy antioxidant action, sulphur-containing amino acids may offer a chelating site for heavy metals. Accordingly, they may be supplemented during chelating therapy, providing beneficial effects in eliminating toxic metals.}, }
@article {pmid28595547, year = {2018}, author = {Bartekova, M and Barancik, M and Ferenczyova, K and Dhalla, NS}, title = {Beneficial Effects of N-acetylcysteine and N-mercaptopropionylglycine on Ischemia Reperfusion Injury in the Heart.}, journal = {Current medicinal chemistry}, volume = {25}, number = {3}, pages = {355-366}, doi = {10.2174/0929867324666170608111917}, pmid = {28595547}, issn = {1875-533X}, mesh = {Acetylcysteine/chemistry/*pharmacology/*therapeutic use ; Animals ; Antioxidants/chemistry/*pharmacology/*therapeutic use ; Heart/*drug effects/physiopathology ; Humans ; Myocardial Reperfusion Injury/*drug therapy/physiopathology ; Oxidative Stress/drug effects ; Tiopronin/chemistry/*therapeutic use ; }, abstract = {BACKGROUND: Ischemia-reperfusion (I/R) injury of the heart as a consequence of myocardial infarction or cardiac surgery represents a serious clinical problem. One of the most prominent mechanisms of I/R injury is the development of oxidative stress in the heart. In this regard, I/R has been shown to enhance the production of reactive oxygen/nitrogen species in the heart which lead to the imbalance between the pro-oxidants and antioxidant capacities of the endogenous radical-scavenging systems.<br><br>OBJECTIVES: Increasing the antioxidant capacity of the heart by the administration of exogenous antioxidants is considered beneficial for the heart exposed to I/R. N-acetylcysteine (NAC) and Nmercaptopropionylglycine (MPG) are two sulphur containing amino acid substances, which belong to the broad category of exogenous antioxidants that have been tested for their protective potential in cardiac I/R injury.<br><br>OBSERVATIONS: Pretreatment of hearts with both NAC and MPG has demonstrated that these agents attenuate the I/R-induced alterations in sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils in addition to improving cardiac function. While experimental studies have revealed promising data suggesting beneficial effects of NAC and MPG in cardiac I/R injury, the results of clinical trials are not conclusive because both positive and no effects of these substances have been reported on the post-ischemic recovery of heart following cardiac surgery or myocardial infarction.<br><br>CONCLUSION: It is concluded that both NAC and MPG exert beneficial effects in preventing the I/Rinduced injury; however, further studies are needed to establish their effectiveness in reversing the I/R-induced abnormalities in the heart.}, }
@article {pmid28594401, year = {2017}, author = {Han, XB and Li, HX and Jiang, YQ and Wang, H and Li, XS and Kou, JY and Zheng, YH and Liu, ZN and Li, H and Li, J and Dou, D and Wang, Y and Tian, Y and Yang, LM}, title = {Upconversion nanoparticle-mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage-derived foam cells via ROS generation.}, journal = {Cell death &amp; disease}, volume = {8}, number = {6}, pages = {e2864}, pmid = {28594401}, issn = {2041-4889}, mesh = {Animals ; *Atherosclerosis/drug therapy/metabolism/pathology ; Autophagy/*drug effects ; Cholesterol/*metabolism ; Foam Cells/*metabolism/pathology ; Humans ; Macrophages, Peritoneal/*metabolism/pathology ; Mice ; Nanoparticles/*chemistry ; Photochemotherapy/*methods ; Reactive Oxygen Species/*metabolism ; THP-1 Cells ; }, abstract = {Macrophage-derived foam cells are a major component of atherosclerotic plaques and have an important role in the progression of atherosclerotic plaques, thus posing a great threat to human health. Photodynamic therapy (PDT) has emerged as a therapeutic strategy for atherosclerosis. Here, we investigated the effect of PDT mediated by upconversion fluorescent nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) on the cholesterol efflux of THP-1 macrophage-derived foam cells and explored the possible mechanism of this effect. First, we found that PDT notably enhanced the cholesterol efflux and the induction of autophagy in both THP-1 and peritoneal macrophage-derived foam cells. The autophagy inhibitor 3-methyladenine and an ATG5 siRNA significantly attenuated PDT-induced autophagy, which subsequently suppressed the ABCA1-mediated cholesterol efflux. Furthermore, the reactive oxygen species (ROS) produced by PDT were responsible for the induction of autophagy, which could be blocked by the ROS inhibitor N-acetyl cysteine (NAC). NAC also reversed the PDT-induced suppression of p-mTOR and p-Akt. Therefore, our findings demonstrate that PDT promotes cholesterol efflux by inducing autophagy, and the autophagy was mediated in part through the ROS/PI3K/Akt/mTOR signaling pathway in THP-1 and peritoneal macrophage-derived foam cells.}, }
@article {pmid28592194, year = {2017}, author = {Long, Y and Huang, C and Wu, J and Cheng, JN and Liang, GN and Jiang, CX and Wan, Q}, title = {2,3',4,4',5-Pentachlorobiphenyl impairs insulin-induced NO production partly through excessive ROS production in endothelial cells.}, journal = {Toxicology mechanisms and methods}, volume = {27}, number = {8}, pages = {592-597}, doi = {10.1080/15376516.2017.1337259}, pmid = {28592194}, issn = {1537-6524}, mesh = {Acetylcysteine/pharmacology ; Endothelium, Vascular/*drug effects/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Insulin/*pharmacology ; Nitric Oxide/*biosynthesis ; Polychlorinated Biphenyls/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Polychlorinated biphenyls (PCBs) have been reported to be associated with increased risk to hypertension, atherosclerosis, cardiovascular disease, etc. 2,3',4,4',5-Pentachlorobiphenyl, known as PCB-118, is a member of coplanar PCBs which renders their structure similar to polychlorinated dibenzo-p-dioxins (PCDDs) and has dioxin-like activity. In our current study, we investigated the effect of PCB-118 exposure on nitric oxide (NO) production and the underlying mechanisms in vitro. Exposure of PCB-118 impaired insulin-induced NO production and endothelial nitric oxide synthase (eNOS) activity in human umbilical vein endothelial cells (HUVECs) with no significant effect on cell viability. Furthermore, PCB-118 treatment induced oxidative stress. In addition, scavenging of reactive oxygen species (ROS) by 10 μM N-acetyl-l-cysteine (NAC) partly rescued impaired insulin-induced eNOS activities and NO productions induced by PCB-118 in HUVECs. Taken together, these results indicate that PCB-118 mediates lower eNOS activity and impairs insulin-induced NO production partly through excessive ROS production in endothelial cells.}, }
@article {pmid28591670, year = {2017}, author = {Saini, V and Manral, A and Arora, R and Meena, P and Gusain, S and Saluja, D and Tiwari, M}, title = {Novel synthetic analogs of diallyl disulfide triggers cell cycle arrest and apoptosis via ROS generation in MIA PaCa-2 cells.}, journal = {Pharmacological reports : PR}, volume = {69}, number = {4}, pages = {813-821}, doi = {10.1016/j.pharep.2017.03.006}, pmid = {28591670}, issn = {2299-5684}, mesh = {Allyl Compounds/*chemistry ; Antineoplastic Agents/*chemical synthesis/*pharmacology ; Apoptosis/*drug effects ; Biomarkers ; Cell Cycle Checkpoints/*drug effects ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; Cell Survival/*drug effects ; DNA Fragmentation ; Disulfides/*chemistry ; Gene Expression Regulation/drug effects ; Humans ; Molecular Structure ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Diallyl disulfide (DADS), a principal organosulfur component of garlic, is known for its medicinal properties including anti-cancer activity. Prior studies have demonstrated that the compounds containing Diallyl disulfide moieties exhibited diverse therapeutic potential with promising biological activities. In the present study, we have investigated the in vitro anticancer activity of Diallyl disulfide derivatives (5a-5l and 7e-7m) against human cancer cell lines.<br><br>METHODS: The effect of DADS analogs on different cancer cell lines was measured through MTT assay. Cell cycle progression, apoptosis, DNA fragmentation and levels of ROS were analyzed through FACS and confocal imaging.<br><br>RESULTS: Bis[3-(3-fluorophenyl)prop-2-ene]disulfide (compound 5b) was the most potent compound among the tested DADS derivatives. FACS analysis revealed that increase in ROS generation by compound 5b was accompanied by cell cycle arrest in the G2/M phase and apoptosis in MIA PaCa-2 cells. Further, the apoptosis was confirmed by TUNEL assay. Western blot analysis showed that compound 5b induces G2/M phase arrest via ROS mediated DNA-damage, which in turn, induces phosphorylation of Chk1/Cdc25c/Cdc2 pathway. Furthermore, altered levels of ROS triggers intrinsic apoptotic cascade, as evidenced by dissipated mitochondrial membrane potential (&#x3c8;), decrease in Bcl-2/Bax ratio, cytochrome c release and cleavage of procaspase-3. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the compound 5b induced augmented intracellular ROS levels and cell death.<br><br>CONCLUSION: Taken together, the anti-proliferative effects of compound 5b were attributed to intracellular ROS accumulation, which in turn, triggers apoptosis by mediating DNA damage-induced G2/M phase arrest and evoking mitochondrial apoptotic pathway in MIA PaCa-2 cells.}, }
@article {pmid28590115, year = {2017}, author = {McCormick, J and Grunfeld, AM and Ertas, YN and Biswas, AN and Marsh, KL and Wagner, S and Glöggler, S and Bouchard, LS}, title = {Aqueous Ligand-Stabilized Palladium Nanoparticle Catalysts for Parahydrogen-Induced [13]C Hyperpolarization.}, journal = {Analytical chemistry}, volume = {89}, number = {13}, pages = {7190-7194}, doi = {10.1021/acs.analchem.7b01363}, pmid = {28590115}, issn = {1520-6882}, abstract = {Parahydrogen-induced polarization (PHIP) is a method for enhancing NMR sensitivity. The pairwise addition of parahydrogen in aqueous media by heterogeneous catalysts can lead to applications in chemical and biological systems. Polarization enhancement can be transferred from [1]H to [13]C for longer lifetimes by using zero field cycling. In this work, water-dispersible N-acetylcysteine- and l-cysteine-stabilized palladium nanoparticles are introduced, and carbon polarizations up to 2 orders of magnitude higher than in previous aqueous heterogeneous PHIP systems are presented. P[13]C values of 1.2 and 0.2% are achieved for the formation of hydroxyethyl propionate from hydroxyethyl acrylate and ethyl acetate from vinyl acetate, respectively. Both nanoparticle systems are easily synthesized in open air, and TEM indicates an average size of 2.4 ± 0.6 nm for NAC@Pd and 2.5 ± 0.8 nm for LCys@Pd nanoparticles with 40 and 25% ligand coverage determined by thermogravimetric analysis, respectively. As a step toward biological relevance, results are presented for the unprotected amino acid allylglycine upon aqueous hydrogenation of propargylglycine.}, }
@article {pmid28588678, year = {2017}, author = {Shi, H and Gu, Y and Xie, Z and Zhou, Q and Mao, G and Lin, X and Liu, K and Liu, Y and Zou, B and Zhao, J}, title = {Mechanism of N-acetyl-cysteine inhibition on the cytotoxicity induced by titanium dioxide nanoparticles in JB6 cells transfected with activator protein-1.}, journal = {Experimental and therapeutic medicine}, volume = {13}, number = {6}, pages = {3549-3554}, pmid = {28588678}, issn = {1792-0981}, abstract = {The present study investigated the mechanism of N-acetyl-cysteine (NAC) inhibition on the cytotoxicity induced by titanium dioxide (TiO2) nanoparticles (NPs) using murine epidermal JB6 cells transfected with activator protein-1 (AP-1), JB6-AP-1 cells. Confocal microscopy was performed to localize TiO2 NPs in cultured cells. The level of reactive oxygen species (ROS) present in cells was evaluated by staining with 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium. AP-1 gene expression levels in the cells were detected using the luciferase assay. Confocal microscopy indicated that TiO2 NPs passed through the cell membrane into the cytoplasm; however, they did not penetrate the nuclear membrane. The present findings indicated that NAC markedly inhibited ROS generation and significantly inhibited cytotoxicity (P<0.05) induced by TiO2 NPs. Furthermore, alternative studies have demonstrated that AP-1 luciferase activity induced by TiO2 NPs may be significantly inhibited by NAC. In conclusion, the ability for NAC to inhibit the cytotoxicity induced by TiO2 NPs may primarily occur by blocking ROS generation in the cultured cells.}, }
@article {pmid28580603, year = {2017}, author = {Onphachanh, X and Lee, HJ and Lim, JR and Jung, YH and Kim, JS and Chae, CW and Lee, SJ and Gabr, AA and Han, HJ}, title = {Enhancement of high glucose-induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2 /Akt/NF-κB pathway.}, journal = {Journal of pineal research}, volume = {63}, number = {2}, pages = {}, doi = {10.1111/jpi.12427}, pmid = {28580603}, issn = {1600-079X}, mesh = {Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Regulation, Enzymologic/*drug effects ; Glucose/*pharmacology ; Humans ; Melatonin/*pharmacology ; NF-kappa B/*metabolism ; Neurons/cytology/*metabolism ; Protein Kinases/*biosynthesis ; Proto-Oncogene Proteins c-akt/*metabolism ; Receptor, Melatonin, MT2/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Hyperglycemia is a representative hallmark and risk factor for diabetes mellitus (DM) and is closely linked to DM-associated neuronal cell death. Previous investigators reported on a genome-wide association study and showed relationships between DM and melatonin receptor (MT), highlighting the role of MT signaling by assessing melatonin in DM. However, the role of MT signaling in DM pathogenesis is unclear. Therefore, we investigated the role of mitophagy regulators in high glucose-induced neuronal cell death and the effect of melatonin against high glucose-induced mitophagy regulators in neuronal cells. In our results, high glucose significantly increased PTEN-induced putative kinase 1 (PINK1) and LC-3B expressions; as well it decreased cytochrome c oxidase subunit 4 expression and Mitotracker™ fluorescence intensity. Silencing of PINK1 induced mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial membrane potential impairment, increased expressions of cleaved caspases, and increased the number of annexin V-positive cells. In addition, high glucose-stimulated melatonin receptor 1B (MTNR1B) mRNA and PINK1 expressions were reversed by ROS scavenger N-acetyl cysteine pretreatment. Upregulation of PINK1 expression in neuronal cells is suppressed by pretreatment with MT2 receptor-specific inhibitor 4-P-PDOT. We further showed melatonin stimulated Akt phosphorylation, which was followed by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation. Silencing of PINK1 expression abolished melatonin-regulated mitochondrial ROS production, cleaved caspase-3 and caspase-9 expressions, and the number of annexin V-positive cells. In conclusion, we have demonstrated the melatonin stimulates PINK1 expression via an MT2 /Akt/NF-κB pathway, and such stimulation is important for the prevention of neuronal cell apoptosis under high glucose conditions.}, }
@article {pmid28580117, year = {2017}, author = {Li, Y and Xie, X and Yang, X and Li, M and Jiao, X and Sun, Y and Wang, X and Tang, B}, title = {Two-photon fluorescent probe for revealing drug-induced hepatotoxicity via mapping fluctuation of peroxynitrite.}, journal = {Chemical science}, volume = {8}, number = {5}, pages = {4006-4011}, pmid = {28580117}, issn = {2041-6520}, abstract = {Drug-induced injury has attracted increasing attention in public health issues. Among them, hepatotoxicity has been regarded as the leading clinical problem caused by drug toxicity. However, owing to the complexity of the involved pathophysiological mechanisms and the lack of noninvasive, straightforward, and real-time tools, drug-induced hepatotoxicity has rarely been predicted satisfactorily. In this paper, by utilizing the reactive species peroxynitrite (ONOO[-]) as a biomarker, we present a two-photon fluorescent probe, TP-KA, holding rapid response, high specificity and sensitivity towards ONOO[-], to investigate drug (acetaminophen and tolcapone)-related liver injury and the remediate effect of N-acetyl cysteine (NAC). With the support of TP-KA, we obtained direct and visual evidence of the upregulation of ONOO[-] during drug challenge both in live cells and mice, which was accompanied by liver tissue injury and tyrosine nitration. These findings demonstrate that ONOO[-] is a good and appropriate biomarker of hepatotoxicity, and nitrosative stress may be necessary for acetaminophen and tolcapone to exert their toxicity. Moreover, TP-KA can be employed as a powerful tool to pre-detect drug-induced organism injury and study the effect of antidotes.}, }
@article {pmid28577939, year = {2017}, author = {Zhang, L and Li, J and Hu, J and Li, D and Wang, X and Zhang, R and Zhang, H and Shi, M and Chen, H}, title = {Cigarette smoke extract induces EGFR-TKI resistance via promoting EGFR signaling pathway and ROS generation in NSCLC cell lines.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {109}, number = {}, pages = {109-116}, doi = {10.1016/j.lungcan.2017.05.011}, pmid = {28577939}, issn = {1872-8332}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Antineoplastic Agents/*therapeutic use ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/*drug therapy ; Cigarette Smoking/adverse effects ; Drug Resistance, Neoplasm ; ErbB Receptors/antagonists &amp; inhibitors/genetics/*metabolism ; Free Radical Scavengers/pharmacology ; Gefitinib ; Humans ; Lung Neoplasms/*drug therapy ; Protein Kinase Inhibitors/pharmacology/*therapeutic use ; Quinazolines/pharmacology/*therapeutic use ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {OBJECTIVES: Epithelial growth factor receptor (EGFR) somatic-mutated non-small cell lung cancer (NSCLC) patients with smoking history always show a poor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The aim of the study is to explore the molecular mechanism of EGFR-TKI resistance induced by cigarette smoke extract and investigate the novel anti-resistance strategies.<br><br>METHODS: The effect of cigarette smoke extract (CSE) on gefitinib sensitivity, EGFR signaling, apoptosis and reactive oxygen species (ROS) levels were detected in vitro by MTT assays, western blot, flow cytometry and laser scanning confocal microscope, respectively.<br><br>RESULTS: MTT assays presented that CSE claimed antagonistic effect on gefitinib sensitivity via the up-regulated half maximal inhibitory concentration (IC50) values, western blot showed that CSE instigated EGFR, AKT phosphorylation, while N-Acetyl-l-Cysteine (NAC) could alleviate gefitinib resistance and abort the aberrant phosphorylation in both PC-9 and A549 cells. Confocal microscope and flow cytometry displayed that ROS generation increased after CSE exposure in NSCLC cells and this change could be inhibited by NAC.<br><br>CONCLUSION: Cigarette smoke extract induces EGFR-TKI resistance via promoting EGFR signaling and ROS generation in NSCLC cell lines which could be suppressed by NAC. Alternatively, combined NAC with EGFR-TKIs to treat EGFR mutated NSCLC patients with smoking history may be a potential choice in clinical setting.}, }
@article {pmid28577450, year = {2017}, author = {Vezir, &#xd6; and Çömelekoğlu, &#xdc; and Sucu, N and Yalın, AE and Yılmaz, &#x15e;N and Yalın, S and Söğüt, F and Yaman, S and Kibar, K and Akkapulu, M and Koç, M&#x130; and Seçer, D}, title = {N-Acetylcysteine-induced vasodilatation is modulated by KATP channels, Na[+]/K[+]-ATPase activity and intracellular calcium concentration: An in vitro study.}, journal = {Pharmacological reports : PR}, volume = {69}, number = {4}, pages = {738-745}, doi = {10.1016/j.pharep.2017.03.019}, pmid = {28577450}, issn = {2299-5684}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta/*drug effects ; Calcium/chemistry/*metabolism ; Gene Expression Regulation/drug effects ; KATP Channels/genetics/*metabolism ; Male ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Wistar ; Sodium-Potassium-Exchanging ATPase/*metabolism ; Vasodilation/*drug effects ; }, abstract = {BACKGROUND: In this study, we aimed to investigate the role of ATP-sensitive potassium (KATP) channel, Na[+]/K[+]-ATPase activity, and intracellular calcium levels on the vasodilatory effect of N-acetylcysteine (NAC) in thoracic aorta by using electrophysiological and molecular techniques.<br><br>METHODS: Rat thoracic aorta ring preparations and cultured thoracic aorta cells were divided into four groups as control, 2mM NAC, 5mM NAC, and 10mM NAC. Thoracic aorta rings were isolated from rats for measurements of relaxation responses and Na[+]/K[+]-ATPase activity. In the cultured thoracic aorta cells, we measured the currents of KATP channel, the concentration of intracellular calcium and mRNA expression level of KATP channel subunits (KCNJ8, KCNJ11, ABCC8 and ABCC9).<br><br>RESULTS: The relaxation rate significantly increased in all NAC groups compared to control. Similarly, Na[+]/K[+]- ATPase activity also significantly decreased in NAC groups. Outward KATP channel current significantly increased in all NAC groups compared to the control group. Intracellular calcium concentration decreased significantly in all groups with compared control. mRNA expression level of ABCC8 subunit significantly increased in all NAC groups compared to the control group. Pearson correlation analysis showed that relaxation rate was significantly associated with KATP current, intracellular calcium concentration, Na[+]/K[+]-ATPase activity and mRNA expression level of ABCC8 subunit.<br><br>CONCLUSION: Our findings suggest that NAC relaxes vascular smooth muscle cells through a direct effect on KATP channels, by increasing outward K+ flux, partly by increasing mRNA expression of KATP subunit ABCC8, by decreasing in intracellular calcium and by decreasing in Na[+]/K[+]-ATPase activity.}, }
@article {pmid28577134, year = {2017}, author = {Arimilli, S and Schmidt, E and Damratoski, BE and Prasad, GL}, title = {Role of Oxidative Stress in the Suppression of Immune Responses in Peripheral Blood Mononuclear Cells Exposed to Combustible Tobacco Product Preparation.}, journal = {Inflammation}, volume = {40}, number = {5}, pages = {1622-1630}, pmid = {28577134}, issn = {1573-2576}, support = {100300-660969//RAI Services Company/ ; }, mesh = {Acetylcysteine/pharmacology ; Cells, Cultured ; Cytokines/metabolism ; Humans ; Immunity/*drug effects ; Leukocytes, Mononuclear/cytology/*immunology ; Oxidative Stress/*immunology ; T-Lymphocytes, Cytotoxic/drug effects ; Tobacco Products/*adverse effects ; }, abstract = {Cigarette smoking is a major risk factor for several human diseases. Chronic inflammation, resulting from increased oxidative stress, has been suggested as a mechanism that contributes to the increased susceptibility of smokers to cancer and microbial infections. We have previously shown that whole-smoke conditioned medium (WS-CM) and total particulate matter (TPM) prepared from Kentucky 3R4F reference cigarettes [collectively called as combustible tobacco product preparations (TPPs)] potently suppressed agonist-stimulated cytokine secretion and target cell killing in peripheral blood mononuclear cells (PBMCs). Here we have investigated the role of oxidative stress from TPPs, which alters inflammatory responses in vitro. Particularly, we investigated the mechanisms of WS-CM-induced suppression of select cytokine secretions in Toll-like receptor (TLR) agonist-stimulated cells and target cell killing by effector cells in PBMCs. Pretreatment with N-acetyl cysteine (NAC), a precursor of reduced glutathione and an established anti-oxidant, protected against DNA damage and cytotoxicity caused by exposure to WS-CM. Similarly, secretion of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 in response to TLR-4 stimulation was restored by pretreatment with NAC. Target cell killing, a functional measure of cytolytic cells in PBMCs, is suppressed by WS-CM. Pretreatment with NAC restored the target cell killing in WS-CM treated PBMCs. This was accompanied by higher perforin levels in the effector cell populations. Collectively, these data suggest that reducing oxidative stress caused by cigarette smoke components restores select immune responses in this ex vivo model.}, }
@article {pmid28576491, year = {2017}, author = {Gong, Y and Lan, H and Yu, Z and Wang, M and Wang, S and Chen, Y and Rao, H and Li, J and Sheng, Z and Shao, J}, title = {Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells.}, journal = {Biochemical and biophysical research communications}, volume = {491}, number = {2}, pages = {522-529}, doi = {10.1016/j.bbrc.2017.05.173}, pmid = {28576491}, issn = {1090-2104}, mesh = {A549 Cells ; Acute Lung Injury/*drug therapy/genetics/mortality/pathology ; Alveolar Epithelial Cells/drug effects/metabolism/pathology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Apoptosis/drug effects ; Disease Models, Animal ; Gene Expression ; Glycolysis/*drug effects ; Humans ; Lactic Acid/pharmacology ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Phosphofructokinase-2/antagonists &amp; inhibitors/*genetics/metabolism ; Pneumonia/*drug therapy/genetics/mortality/pathology ; Pyridines/*pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Sepsis/*drug therapy/genetics/mortality/pathology ; Survival Analysis ; }, abstract = {Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP. The mice treated with the 3PO ameliorated the survival rate, histopathological changes, lung inflammation, lactate increased and lung apoptosis of mice with CLP-induced sepsis. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) resulted in cell apoptosis, inflammatory cytokine production, enhanced glycolytic flux and reactive oxygen species (ROS) increased. While these changes were attenuated by 3PO treatment. Sequentially, treatment of A549 cells with lactate caused cell apoptosis and enhancement of ROS. Pretreatment with N-acetylcysteine (NAC) significantly lowered LPS and lactate-induced the generation of ROS and cell apoptosis in A549 cells. Therefore, these results indicate that anaerobic glycolysis may be an important contributor in cell apoptosis of sepsis-related ALI. Moreover, LPS specifically induces apoptotic insults to A549 cell through lactate-mediated enhancement of ROS.}, }
@article {pmid28560439, year = {2017}, author = {Kim, DH and Park, JE and Chae, IG and Park, G and Lee, S and Chun, KS}, title = {Isoliquiritigenin inhibits the proliferation of human renal carcinoma Caki cells through the ROS-mediated regulation of the Jak2/STAT3 pathway.}, journal = {Oncology reports}, volume = {38}, number = {1}, pages = {575-583}, doi = {10.3892/or.2017.5677}, pmid = {28560439}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Carcinoma, Renal Cell/*drug therapy ; Caspase 3/metabolism ; Caspase 7/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Chalcones/*pharmacology/therapeutic use ; Cyclin D1/metabolism ; Cyclin D2/metabolism ; Down-Regulation ; Humans ; Janus Kinase 2/metabolism ; Kidney Neoplasms/*drug therapy ; NADPH Oxidases/antagonists &amp; inhibitors ; Onium Compounds/pharmacology ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-mdm2/metabolism ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/*drug effects ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Isoliquiritigenin (ISL) is a flavonoid with chalcone structure that has been noted in licorice and shallot, which are generally used in traditional Chinese medicine. ISL has demonstrated various pharmacological effects including antioxidant, anti-inflammatory and antitumor activity. However, the molecular mechanisms underlying the anticancer effects of ISL remain poorly understood. The present study revealed that ISL significantly decreased viability and induced apoptosis in human renal carcinoma Caki cells. The ISL-induced apoptosis was associated with the cleavage of caspase-9, -7 and -3, and that of PARP. Moreover, ISL increased the expression of pro-apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2, and Bcl-xl, thereby increasing cytochrome c release. Treatment of cells with ISL also induced the expression of p53 through downregulation of murine double minute 2 (Mdm2). Furthermore, ISL generated reactive oxygen species (ROS), and pretreatment with ROS scavenger N-acetyl cysteine (NAC) and NADPH oxidase inhibitor diphenyleneiodonium abrogated the ISL-induced apoptosis. One of the key oncogenic signaling pathways is mediated through signal transducer and activator of transcription 3 (STAT3), which promotes abnormal cell proliferation. Incubation of cells with ISL markedly diminished phosphorylation and DNA binding activity of STAT3, and reduced expression of STAT3 responsive gene products, such as cyclin D1 and D2. ISL also attenuated constitutive phosphorylation of upstream kinase, Janus-activated kinase 2 (Jak2). Pretreatment with NAC abrogated the inhibitory effect of ISL on activation of STAT3 and blocked the cleavage of caspase-9, -7 and -3, and that of PARP in Caki cells. Taken together, the present study provides the first report that ISL induces apoptosis in Caki cells via generation of ROS, which causes induction of p53 and inhibition of the STAT3 signaling pathway.}, }
@article {pmid28558396, year = {2017}, author = {Behr, J and Günther, A and Bonella, F and Geißler, K and Koschel, D and Kreuter, M and Prasse, A and Schönfeld, N and Sitter, H and Müller-Quernheim, J and Costabel, U}, title = {[German Guideline for Idiopathic Pulmonary Fibrosis - Update on Pharmacological Therapies 2017].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {71}, number = {7}, pages = {460-474}, doi = {10.1055/s-0043-106160}, pmid = {28558396}, issn = {1438-8790}, mesh = {Adult ; Aged ; Aged, 80 and over ; Clinical Trials as Topic ; Consensus ; Drug Therapy, Combination ; Evidence-Based Medicine ; Germany ; *Guideline Adherence ; Humans ; Idiopathic Pulmonary Fibrosis/diagnosis/*drug therapy ; Lung Volume Measurements ; Middle Aged ; Patient Care Team ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease with a median survival of 2 - 4 years after diagnosis. Since the publication of the German IPF guideline in 2013 new treatment trials have been published, necessitating an update of the pharmacological therapy of IPF. Different from the previous guideline, the GRADE system was discarded and replaced by the Oxford evidence classification system which allows a more differentiated judgement. The following pharmacological therapies were rated not suitable for the treatment of IPF patients (recommendation A; evidence 1-b): triple therapy with prednisolone, azathioprine and acetyl-cysteine; imatinib; ambrisentan; bosentan; macitentan. A less clear but still negative recommendation (B, 1-b) was attributed to the treatment of IPF with the phosphodiesterase-5-inhibitor sildenafil and acetyl-cysteine monotherapy. In contrast to the international guideline antacid therapy as a general treatment for IPF was rated negative, based on conflicting results of recent analyses (recommendation C; evidence 4). An unanimous positive recommendation was granted for the antifibrotic drugs nintedanib and pirfenidone for the treatment of IPF (A, 1-a). For some open questions in the management of IPF patients for which firm evidence is lacking the guideline also offers recommendations based on expert consensus.}, }
@article {pmid28557352, year = {2018}, author = {Lebourgeois, S and González-Marín, MC and Jeanblanc, J and Naassila, M and Vilpoux, C}, title = {Effect of N-acetylcysteine on motivation, seeking and relapse to ethanol self-administration.}, journal = {Addiction biology}, volume = {23}, number = {2}, pages = {643-652}, doi = {10.1111/adb.12521}, pmid = {28557352}, issn = {1369-1600}, mesh = {Acetylcysteine/*pharmacology ; Alcohol Abstinence ; Alcoholism ; Animals ; Behavior, Animal/*drug effects ; Central Nervous System Depressants/*administration &amp; dosage ; Conditioning, Operant ; Drug-Seeking Behavior/*drug effects ; Ethanol/*administration &amp; dosage ; Extinction, Psychological ; Male ; Motivation/*drug effects ; Rats ; Rats, Long-Evans ; Reinforcement, Psychology ; Self Administration ; }, abstract = {Alcohol use disorder is a chronic and highly relapsing disorder, characterized by a loss of control over alcohol consumption and craving. Several studies suggest a key role of glutamate in this disorder. In recent years, the modulation of cystine/glutamate exchange via the xc[-] system has emerged as a new therapeutic alternative for reducing the excitatory glutamatergic transmission observed after ethanol self-administration in both rats and humans. The objective of this study was to determine whether a treatment with N-acetylcysteine (NAC), a cystine prodrug, could reduce ethanol self-administration, ethanol-seeking behavior and reacquisition of ethanol self-administration. Male Long Evans rats were trained to self-administer 20 percent ethanol in operant cages for several weeks. Once the consumption surpassed 1 g of ethanol/kg body weight/15 minutes, the effect of an acute intraperitoneal injection of NAC (0, 25, 50 or 100 mg/kg) 1 hour before the beginning of each test was evaluated on different aspects of the operant self-administration behavior. We demonstrated antimotivational properties of NAC (100 mg/kg), as ethanol-reinforced responding was reduced in a fixed ratio (-35 percent) and in a progressive ratio schedule (-81 percent). NAC also reduced ethanol-seeking behavior (-77 percent) evaluated as extinction responding in a single extinction session. NAC was able to reduce reacquisition in rats that were abstinent for 17 days, while NAC had no effect on ethanol relapse in rats previously exposed to six extinction sessions. Overall, our results demonstrate that NAC limits motivation, seeking behavior and reacquisition in rats, making it a potential new treatment for the maintenance of abstinence.}, }
@article {pmid28555929, year = {2017}, author = {He, M and Ichinose, T and Yoshida, S and Ito, T and He, C and Yoshida, Y and Arashidani, K and Takano, H and Sun, G and Shibamoto, T}, title = {PM2.5-induced lung inflammation in mice: Differences of inflammatory response in macrophages and type II alveolar cells.}, journal = {Journal of applied toxicology : JAT}, volume = {37}, number = {10}, pages = {1203-1218}, doi = {10.1002/jat.3482}, pmid = {28555929}, issn = {1099-1263}, mesh = {Acetylcysteine/pharmacology ; Alveolar Epithelial Cells/cytology/*drug effects ; Animals ; Biomarkers/*metabolism ; Bronchoalveolar Lavage Fluid ; Chemokine CCL2/genetics/metabolism ; Cyclooxygenase 2/genetics/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Interleukin-6/genetics/metabolism ; Lipopolysaccharides/toxicity ; Lung/cytology/drug effects/metabolism ; Macrophages/cytology/*drug effects ; Male ; Membrane Proteins/genetics/metabolism ; Mice ; Mice, Inbred BALB C ; Myeloid Differentiation Factor 88/genetics/metabolism ; NF-kappa B/genetics/metabolism ; Particle Size ; Particulate Matter/*toxicity ; Pneumonia/blood/chemically induced/*drug therapy ; Polycyclic Aromatic Hydrocarbons/analysis ; Polymyxin B/pharmacology ; RAW 264.7 Cells ; Tumor Necrosis Factor-alpha/genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Particulate matter 2.5 (<PM2.5 μm) leads to chronic obstructive pulmonary disease. In this study, biomarkers related to inflammation and oxidative stress in vitro and in vivo experiments were investigated to clarify the PM2.5-induced lung inflammation mechanisms. In an in vitro study using RAW264.7 cells, PM2.5 caused phosphorylation of nuclear factor-κB, p38 mitogen-activated protein kinase and extracellular response kinases, an increase of proinflammatory gene and protein expressions (e.g. monocyte chemotactic protein-1, tumor necrosis factor-α). These biomarkers were substantially attenuated by polymyxin B (PMB). PM2.5 induced heme oxygenase-1 (HO-1) gene, which was attenuated by N-acetylcysteine (NAC). However, the suppressive effects of NAC on inflammatory biomarkers were very weak. In bone marrow-derived macrophages (BMDMs) of wild-type BALB/c mice, the effects of PMB and NAC on PM2.5-induced inflammatory responses were similar to RAW264.7 cells. In BMDMs of MyD88[-/-] mice, PM2.5-induced proinflammatory mediators were substantially more attenuated. PM2.5 caused an increase of proinflammatory gene expressions (interleukin-6, cyclooxygenase 2) and HO-1 gene in MLE-12 cells (mouse alveolar cell line). These biomarkers were substantially attenuated by NAC, but not by PMB. When BALB/c mice were exposed intratracheally to 0.2 mg PM2.5, PM2.5 caused severe lung inflammation, an increase of neutrophils along with proinflammatory mediators in bronchoalveolar lavage fluid. The inflammation was attenuated by NAC, particularly by NAC + PMB, but not by PMB alone. These results indicate that macrophages may act sensitively to lipopolysaccharide (LPS) present in PM2.5 and release proinflammatory mediators via the LPS/MyD88 pathway. However, type II alveolar cells may react sensitively to oxidative stress induced by PM2.5 and cause inflammatory response. Therefore, overall, PM2.5 may cause predominantly oxidative stress-dependent inflammation rather than LPS/MyD88-dependent inflammation in type II alveolar cell-rich lungs. Copyright © 2017 John Wiley &amp; Sons, Ltd.}, }
@article {pmid28554049, year = {2017}, author = {Cha, H and Lee, S and Hwan Kim, S and Kim, H and Lee, DS and Lee, HS and Lee, JH and Park, JW}, title = {Increased susceptibility of IDH2-deficient mice to dextran sodium sulfate-induced colitis.}, journal = {Redox biology}, volume = {13}, number = {}, pages = {32-38}, pmid = {28554049}, issn = {2213-2317}, mesh = {Animals ; *Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Colitis, Ulcerative/etiology/genetics/*metabolism/pathology ; Dextran Sulfate/toxicity ; Histone Deacetylases/metabolism ; Isocitrate Dehydrogenase/deficiency/*genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Proteins/metabolism ; }, abstract = {Inflammatory bowel disease (IBD) is a group of chronic, relapsing, immunological, inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease (CD). It has been reported that UC, which is studied using a dextran sodium sulfate (DSS)-induced colitis model, is associated with the production of reactive oxygen species (ROS) and the apoptosis of intestine epithelial cells (IEC). Mitochondrial NADP[+]-dependent isocitrate dehydrogenase (IDH2) has been reported as an essential enzyme in the mitochondrial antioxidant system via generation of NADPH. Therefore, we evaluated the role of IDH2 in DSS-induced colitis using IDH2-deficient (IDH2[-/-]) mice. We observed that DSS-induced colitis in IDH2[-/-] mice was more severe than that in wild-type IDH2[+/+] mice. Our results also suggest that IDH2 deficiency exacerbates PUMA-mediated apoptosis, resulting from NF-κB activation regulated by histone deacetylase (HDAC) activity. In addition, DSS-induced colitis is ameliorated by an antioxidant N-acetylcysteine (NAC) through attenuation of oxidative stress, resulting from deficiency of the IDH2 gene. In conclusion, deficiency of IDH2 leads to increased mitochondrial ROS levels, which inhibits HDAC activity, and the activation of NF-κB via acetylation is enhanced by attenuated HDAC activity, which causes PUMA-mediated apoptosis of IEC in DSS-induced colitis. The present study supported the rationale for targeting IDH2 as an important cancer chemoprevention strategy, particularly in the prevention of colorectal cancer.}, }
@article {pmid28548367, year = {2017}, author = {Chang, YT and Wu, CY and Tang, JY and Huang, CY and Liaw, CC and Wu, SH and Sheu, JH and Chang, HW}, title = {Sinularin induces oxidative stress-mediated G2/M arrest and apoptosis in oral cancer cells.}, journal = {Environmental toxicology}, volume = {32}, number = {9}, pages = {2124-2132}, doi = {10.1002/tox.22425}, pmid = {28548367}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology/toxicity ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Caspases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Diterpenes/*pharmacology/toxicity ; G2 Phase Cell Cycle Checkpoints/drug effects ; Heterocyclic Compounds, 3-Ring/*pharmacology/toxicity ; Humans ; Mouth Neoplasms/*drug therapy ; Oxidative Stress/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Soft corals-derived natural product, sinularin, was antiproliferative against some cancers but its effect and detailed mechanism on oral cancer cells remain unclear. The subject of this study is to examine the antioral cancer effects and underlying detailed mechanisms in terms of cell viability, oxidative stress, cell cycle analysis, and apoptosis analyses. In MTS assay, sinularin dose-responsively decreased cell viability of three oral cancer cells (Ca9-22, HSC-3, and CAL 27) but only little damage to oral normal cells (HGF-1). This cell killing effect was rescued by the antioxidant N-acetylcysteine (NAC) pretreatment. Abnormal cell morphology and induction of reactive oxygen species (ROS) were found in sinularin-treated oral cancer Ca9-22 cells, however, NAC pretreatment also recovered these changes. Sinularin arrested the Ca9-22 cells at G2/M phase and dysregulated the G2/M regulatory proteins such as cdc2 and cyclin B1. Sinularin dose-responsively induced apoptosis on Ca9-22 cells in terms of flow cytometry (annexin V and pancaspase analyses) and western blotting (caspases 3, 8, 9) and poly (ADP-ribose) polymerase (PARP). These apoptotic changes of sinularin-treated Ca9-22 cells were rescued by NAC pretreatment. Taken together, sinularin induces oxidative stress-mediated antiproliferation, G2/M arrest, and apoptosis against oral cancer cells and may be a potential marine drug for antioral cancer therapy.}, }
@article {pmid28546450, year = {2017}, author = {Hertzel, AV and Xu, H and Downey, M and Kvalheim, N and Bernlohr, DA}, title = {Fatty acid binding protein 4/aP2-dependent BLT1R expression and signaling.}, journal = {Journal of lipid research}, volume = {58}, number = {7}, pages = {1354-1361}, pmid = {28546450}, issn = {1539-7262}, support = {P30 DK050456/DK/NIDDK NIH HHS/United States ; R01 DK053189/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Fatty Acid-Binding Proteins/*metabolism ; Gene Expression Regulation ; Gene Knockout Techniques ; Lipopolysaccharides/pharmacology ; Mice ; RAW 264.7 Cells ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Leukotriene B4/*genetics ; *Signal Transduction ; Uncoupling Protein 2/metabolism ; }, abstract = {Previous studies have shown that reduced levels of the adipocyte fatty acid binding protein (FABP)4 (AFABP/aP2), result in metabolic improvement including potentiated insulin sensitivity and attenuated atherosclerosis. Mechanistically, pharmacologic or genetic inhibition of FABP4 in macrophages upregulates UCP2, attenuates reactive oxygen species (ROS) production, polarizes cells toward the anti-inflammatory M2 state, and reduces leukotriene (LT) secretion. At the protein level, FABP4 stabilizes LTA4 toward chemical hydrolysis, thereby potentiating inflammatory LTC4 synthesis. Herein, we extend the FABP4-LT axis and demonstrate that genetic knockout of FABP4 reduces expression of the major macrophage LT receptor, LTB4 receptor 1 (BLT1R), via a ROS-dependent mechanism. Consistent with inflammation driving BLT1R expression, M1 polarized macrophages express increased levels of BLT1R relative to M2 polarized macrophages and treatment with proinflammatory lipopolysaccharide increased BLT1R mRNA and protein expression. In FABP4 knockout macrophages, silencing of UCP2, increased ROS levels and led to increased expression of BLT1R mRNA. Similarly, addition of exogenous H2O2 upregulated BLT1R expression, whereas the addition of a ROS scavenger, N-acetyl cysteine, decreased BLT1R levels. As compared with WT macrophages, LTB4-BLT1R-dependent JAK2-phosphorylation was reduced in FABP4 knockout macrophages. In summary, these results indicate that FABP4 regulates the expression of BLT1R and its downstream signaling via control of oxidative stress in macrophages.}, }
@article {pmid28545464, year = {2017}, author = {Salcher, S and Hermann, M and Kiechl-Kohlendorfer, U and Ausserlechner, MJ and Obexer, P}, title = {C10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy.}, journal = {Molecular cancer}, volume = {16}, number = {1}, pages = {95}, pmid = {28545464}, issn = {1476-4598}, mesh = {Apoptosis/genetics ; Autophagy/*genetics ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival/genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Doxorubicin/pharmacology ; Etoposide/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Forkhead Box Protein O3/*genetics/metabolism ; Gene Expression ; Gene Silencing ; Humans ; Intracellular Signaling Peptides and Proteins ; Models, Biological ; Neuroblastoma/genetics/metabolism/pathology ; Phosphorylation ; Proteins/*metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Stress, Physiological ; }, abstract = {BACKGROUND: Neuroblastoma is the most common solid tumor in childhood and develops from undifferentiated progenitor cells of the sympathetic nervous system. In neuronal tumor cells DNA-damaging chemotherapeutic agents activate the transcription factor FOXO3 which regulates the formation of reactive oxygen species (ROS) and cell death as well as a longevity program associated with therapy resistance. We demonstrated before that C10ORF10/DEPP, a transcriptional target of FOXO3, localizes to peroxisomes and mitochondria and impairs cellular ROS detoxification. In the present study, we investigated the impact of FOXO3 and DEPP on the regulation of autophagy. Autophagy serves to reduce oxidative damage as it triggers a self-degradative process for the removal of aggregated or misfolded proteins and damaged organelles.<br><br>METHODS: The effect of FOXO3 and DEPP on autophagy induction was analyzed using live cell fluorescence microscopy and immunoblot analyses of SH-EP cells transfected with a plasmid for EYFP-LC3 and with siRNAs specific for LC3, respectively. ROS steady-state levels were measured with reduced MitoTrackerRed CM-H2XROS. Cellular apoptosis was analyzed by flow cytometry and the caspase 3/7 assay.<br><br>RESULTS: We report for the first time that DEPP induces ROS accumulation and thereby mediates the formation of autophagosomes as inhibition of ROS formation by N-acetyl-cysteine completely blocks autophagy. We further demonstrate that H2O2-treatment triggers autophagy-induction by FOXO3-mediated DEPP expression. Importantly, knockdown of DEPP was sufficient to efficiently inhibit autophagy-induction under different stress conditions such as serum starvation and genotoxic stress, suggesting that DEPP expression is critical for the initiation of autophagy in neuroblastoma. FOXO3-triggered autophagy partially protects neuroblastoma cells from cell death. Consistent with this concept, we demonstrate that inhibition of autophagy by LC3-knockdown significantly increased etoposide- and doxorubicin-induced apoptosis. These results were also confirmed by the use of the autophagy-inhibitor chloroquine that significantly enhanced the chemotherapeutic effect of etoposide and doxorubicin in neuronal tumor cells.<br><br>CONCLUSION: Targeting FOXO3/DEPP-triggered autophagy is a promising strategy to sensitize neuroblastoma cells to chemotherapy.}, }
@article {pmid28543759, year = {2017}, author = {Sinha, N and Panda, PK and Naik, PP and Das, DN and Mukhopadhyay, S and Maiti, TK and Shanmugam, MK and Chinnathambi, A and Zayed, ME and Alharbi, SA and Sethi, G and Agarwal, R and Bhutia, SK}, title = {Abrus agglutinin promotes irreparable DNA damage by triggering ROS generation followed by ATM-p73 mediated apoptosis in oral squamous cell carcinoma.}, journal = {Molecular carcinogenesis}, volume = {56}, number = {11}, pages = {2400-2413}, doi = {10.1002/mc.22679}, pmid = {28543759}, issn = {1098-2744}, mesh = {Abrus/chemistry ; Animals ; Antineoplastic Agents, Phytogenic/chemistry/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Carcinoma, Squamous Cell/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/*drug effects ; Humans ; Mice ; Mice, Nude ; Mitochondria/drug effects/metabolism/pathology ; Models, Molecular ; Mouth/drug effects/metabolism/pathology ; Mouth Neoplasms/*drug therapy/metabolism/pathology ; Plant Lectins/chemistry/pharmacology/*therapeutic use ; Reactive Oxygen Species/metabolism ; Tumor Protein p73/*metabolism ; }, abstract = {Oral cancer, a type of head and neck cancer, is ranked as one of the top most malignancies in India. Herein, we evaluated the anticancer efficacy of Abrus agglutinin (AGG), a plant lectin, in oral squamous cell carcinoma. AGG selectively inhibited cell growth, and caused cell cycle arrest and mitochondrial apoptosis through a reactive oxygen species (ROS)-mediated ATM-p73 dependent pathway in FaDu cells. AGG-induced ROS accumulation was identified as the major mechanism regulating apoptosis, DNA damage and DNA-damage response, which were significantly reversed by ROS scavenger N-acetylcysteine (NAC). Moreover, AGG was found to interact with mitochondrial manganese-dependent superoxide dismutase that might inhibit its activity and increase ROS in FaDu cells. In oral cancer p53 is mutated, thus we focused on p73; AGG resulted in p73 upregulation and knock down of p73 caused a decrease in AGG-induced apoptosis. Interestingly, AGG-dependent p73 expression was found to be regulated by ROS, which was reversed by NAC treatment. A reduction in the level of p73 in AGG-treated shATM cells was found to be associated with a decreased apoptosis. Moreover, administration of AGG (50 μg/kg body weight) significantly inhibited the growth of FaDu xenografts in athymic nude mice. In immunohistochemical analysis, the xenografts from AGG-treated mice displayed a decrease in PCNA expression and an increase in caspase-3 activation as compared to the controls. In conclusion, we established a connection among ROS, ATM and p73 in AGG-induced apoptosis, which might be useful in enhancing the therapeutic targeting of p53 deficient oral squamous cell carcinoma.}, }
@article {pmid28543603, year = {2017}, author = {Hamed, S and Emara, M and Shawky, RM and El-Domany, RA and Youssef, T}, title = {Silver nanoparticles: Antimicrobial activity, cytotoxicity, and synergism with N-acetyl cysteine.}, journal = {Journal of basic microbiology}, volume = {57}, number = {8}, pages = {659-668}, doi = {10.1002/jobm.201700087}, pmid = {28543603}, issn = {1521-4028}, mesh = {Acetylcysteine/*pharmacology ; Anti-Infective Agents/*pharmacology ; Candida albicans/drug effects/ultrastructure ; Cell Line ; Drug Resistance, Bacterial ; Drug Resistance, Fungal ; Drug Synergism ; Escherichia coli/drug effects/ultrastructure ; Humans ; *Metal Nanoparticles/chemistry/toxicity ; Microbial Sensitivity Tests ; Muramic Acids/metabolism ; Oxidoreductases/metabolism ; Pseudomonas aeruginosa/drug effects/ultrastructure ; Silver/metabolism/*pharmacology/toxicity ; Staphylococcus aureus/drug effects/ultrastructure ; }, abstract = {The fast progression of nanotechnology has led to novel therapeutic interventions. Antimicrobial activities of silver nanoparticles (Ag NPs) were tested against standard ATCC strains of Staphylococcus aureus (ATCC 9144), Escherichia coli (O157:H7), Pseudomonas aeruginosa (ATCC 27853), and Candida albicans (ATCC 90028) in addition to 60 clinical isolates collected from cancer patients. Antimicrobial activity was tested by disk diffusion method and MIC values for Ag NPs alone and in combination with N-acetylcysteine (NAC) against tested pathogens were determined by broth microdilution method. Ag NPs showed a robust antimicrobial activity against all tested pathogens and NAC substantially enhanced the antimicrobial activity of Ag NPs against all tested pathogens. Synergism between Ag NPs and NAC has been confirmed by checkerboard assay. The effect of Ag NPs on tested pathogens was further scrutinized by Transmission Electron Microscope (TEM) which showed disruption of cell wall in both bacteria and fungi. Ag NPs abrogated the activity of respiratory chain dehydrogenase of all tested pathogens and released muramic acid content from S. aureus in culture. The cytotoxic effect of Ag NPs alone and in combination with NAC was examined using human HepG2 cells and this revealed no cytotoxicity at MIC values of Ag NPs and interestingly, NAC reduced the cytotoxic effect of Ag NPs at concentrations higher than their MIC values. Taken together, Ag NPs have robust antimicrobial activity and NAC substantially enhances their antimicrobial activities against MDR pathogens which would provide a novel safe, effective, and inexpensive therapeutic approach to control the prevalence of MDR pathogens.}, }
@article {pmid28543404, year = {2017}, author = {Bidovec, K and Božič, J and Dolenc, I and Turk, B and Turk, V and Stoka, V}, title = {Tumor Necrosis Factor-α Induced Apoptosis in U937 Cells Promotes Cathepsin D-Independent Stefin B Degradation.}, journal = {Journal of cellular biochemistry}, volume = {118}, number = {12}, pages = {4813-4820}, doi = {10.1002/jcb.26152}, pmid = {28543404}, issn = {1097-4644}, mesh = {Apoptosis/*drug effects ; Cathepsin D/*metabolism ; Cystatin B/*metabolism ; Humans ; Proteolysis/*drug effects ; Tumor Necrosis Factor-alpha/*pharmacology ; U937 Cells ; }, abstract = {Lysosomal cathepsins were previously found to be involved in tumor necrosis factor-α (TNFα)-induced apoptosis. However, there are opposing views regarding their role as either initiators or amplifiers of the signaling cascade as well as the order of molecular events during this process. In this study, we investigated the role of cathepsin D (catD) in TNFα/cycloheximide-induced apoptosis in U937 human monocytic cells. TNFα-induced apoptosis proceeds through caspase-8 activation, processing of the pro-apoptotic molecule Bid, mitochondrial membrane permeabilization, and caspase-3 activation. The translocation of lysosomal catD into the cytosol was a late event, suggesting that lysosomal membrane permeabilization and the release of cathepsins are not required for the induction of apoptosis, but rather amplifies the process through the generation of reactive oxygen species. For the first time, we show that apoptosis is accompanied by degradation of the cysteine cathepsin inhibitor stefin B (StfB). CatD did not exhibit a crucial role in this step. However, this degradation was partially prevented through pre-incubation with the antioxidant N-acetyl cysteine, although it did not prevent apoptosis and its progression. These results suggest that the degradation of StfB, as a response to TNFα, could induce a cell death amplification effect as a result of progressive damage to lysosomes during TNFα treatment. J. Cell. Biochem. 118: 4813-4820, 2017. © 2017 Wiley Periodicals, Inc.}, }
@article {pmid28542135, year = {2017}, author = {Jiang, Y and Wang, X and Hu, D}, title = {Furanodienone induces G0/G1 arrest and causes apoptosis via the ROS/MAPKs-mediated caspase-dependent pathway in human colorectal cancer cells: a study in vitro and in vivo.}, journal = {Cell death &amp; disease}, volume = {8}, number = {5}, pages = {e2815}, pmid = {28542135}, issn = {2041-4889}, mesh = {Animals ; Apoptosis/*drug effects ; Carcinogenesis/drug effects/metabolism/pathology ; Caspases/*metabolism ; Cell Cycle Checkpoints/*drug effects ; Cell Proliferation/drug effects ; Colorectal Neoplasms/*enzymology/*pathology ; Disease Models, Animal ; Furans/chemistry/*pharmacology ; HT29 Cells ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/metabolism ; Models, Biological ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/chemistry/*pharmacology ; Signal Transduction/drug effects ; Tumor Stem Cell Assay ; Xenograft Model Antitumor Assays ; }, abstract = {Furanodienone, a major bioactive constituents of sesquiterpene derived from Rhizoma Curcumae, has been proven to possess the potent anticancer efficacy on human breast cancer cells. Here, we investigated the cytotoxicity of furanodienone on human colorectal carcinoma cell lines in vitro and in vivo, as well as its underlying molecular mechanisms in the induction of apoptosis. In this study, we found that furanodienone significantly inhibited proliferation of RKO and HT-29 cells, induced mitochondrial dysfunction characterized by collapse of mitochondrial transmembrane potential and reduction of ATP level, and promoted the production of reactive oxygen species (ROS) that functions upstream of caspase-dependent apoptosis. The antioxidant N-acetyl cysteine, a ROS scavenger, abolished this apoptosis induced by furanodienone. In addition, furanodienone elevated the expression of p-p38, p-JNK, but decreased p-ERK, as a result of the produced ROS. The specific inhibitors U0126, SP600125 and SB202190 attenuated the expression of MAPKs, and regulated the expression of cleaved caspase-8, -9 and -3. Furthermore, the potential inhibitory effect of furanodienone on CRC cells was also corroborated in mouse xenograft model. In conclusion, the results demonstrated that furanodienone-triggered ROS plays a pivotal role in apoptosis as an upstream molecule-modulating activity of caspases in mitochondrial pathway via stimulating MAPKs signaling pathway. Our finding may provide a novel candidate for development of antitumor drugs targeting on colorectal cancer.}, }
@article {pmid28535741, year = {2017}, author = {Nouri, A and Heidarian, E and Nikoukar, M}, title = {Effects of N-acetyl cysteine on oxidative stress and TNF-α gene expression in diclofenac-induced hepatotoxicity in rats.}, journal = {Toxicology mechanisms and methods}, volume = {27}, number = {8}, pages = {561-567}, doi = {10.1080/15376516.2017.1334732}, pmid = {28535741}, issn = {1537-6524}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*toxicity ; Ascorbic Acid/metabolism ; Catalase/metabolism ; Chemical and Drug Induced Liver Injury/etiology/pathology/physiopathology/*prevention &amp; control ; Diclofenac/*toxicity ; Gene Expression/*drug effects ; Lipids/blood ; Liver/drug effects/enzymology/metabolism ; Liver Function Tests ; Male ; Malondialdehyde/blood ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Silymarin/administration &amp; dosage ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/*genetics ; }, abstract = {The consumption of non-steroidal anti-inflammatory drug, such as diclofenac, can lead to hepatotoxicity. In the present study, protective effect of N-acetyl cysteine (NAC) on diclofenac-induced hepatotoxicity was investigated. Thirty-two male rats were divided into four groups. Group 1 (control group) was treated with normal saline (1 ml/kg, i.p.) for 4 d. Group 2 (test without treatment) received diclofenac only (50 mg/kg, i.p.) for 4 d. Groups 3 and 4 received diclofenac (50 mg/kg, i.p.) plus NAC (150 mg/kg, p.o) and silymarin (100 mg/kg, p.o) for 4 d, respectively. At the end of experiment, serum glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), alkaline phosphatase (ALP), lipid profile, uric acid, protein carbonyl content, MDA, liver TNF-α, ferric-reducing antioxidant power, liver catalase, superoxide dismutase, vitamin C, and histopathological examination were done. In group 2, diclofenac caused a significant increase (p < .05) in the levels of serum ALP, GOT, GPT, TNF-α, uric acid, protein carbonyl content, MDA, and liver TNF-α gene expression as opposed to group 1. In treated groups with NAC and silymarin, a significant reduction (p < .05) was seen in all above mentioned parameters as well as improved liver histopathological changes compared with group 2. This study confirmed the protective effect of NAC on diclofenac-induced hepatotoxicity in rats due to not only reduces liver inflammatory cells, TNF-α, serum MDA, and PC but also through increases liver vitamin C, catalase, and superoxide dismutase activities.}, }
@article {pmid28532657, year = {2018}, author = {Robinson, RK and Birrell, MA and Adcock, JJ and Wortley, MA and Dubuis, ED and Chen, S and McGilvery, CM and Hu, S and Shaffer, MSP and Bonvini, SJ and Maher, SA and Mudway, IS and Porter, AE and Carlsten, C and Tetley, TD and Belvisi, MG}, title = {Mechanistic link between diesel exhaust particles and respiratory reflexes.}, journal = {The Journal of allergy and clinical immunology}, volume = {141}, number = {3}, pages = {1074-1084.e9}, pmid = {28532657}, issn = {1097-6825}, support = {G1000758/MRC_/Medical Research Council/United Kingdom ; MR/K020293/1/MRC_/Medical Research Council/United Kingdom ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; }, mesh = {Aged ; Air Pollutants/*toxicity ; Animals ; *Asthma/chemically induced/metabolism/pathology/physiopathology ; *Bronchial Spasm/chemically induced/metabolism/pathology/physiopathology ; Female ; Gene Expression Regulation/*drug effects ; Guinea Pigs ; Humans ; Male ; Mice ; Middle Aged ; Particulate Matter/*toxicity ; Reflex/*drug effects ; *Vehicle Emissions ; }, abstract = {BACKGROUND: Diesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves, which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms, such as cough and bronchospasm.<br><br>OBJECTIVE: We sought to identify the mechanisms involved in activation of airway sensory afferents by DEPs.<br><br>METHODS: In this study we use in&#xa0;vitro and in&#xa0;vivo electrophysiologic techniques, including a unique model that assesses depolarization (a marker of sensory nerve activation) of human vagus.<br><br>RESULTS: We demonstrate a direct interaction between DEP and airway C-fiber afferents. In anesthetized guinea pigs intratracheal administration of DEPs activated airway C-fibers. The organic extract (DEP-OE) and not the cleaned particles evoked depolarization of guinea pig and human vagus, and this was inhibited by a transient receptor potential ankyrin-1 antagonist and the antioxidant N-acetyl cysteine. Polycyclic aromatic hydrocarbons, major constituents of DEPs, were implicated in this process through activation of the aryl hydrocarbon receptor and subsequent mitochondrial reactive oxygen species production, which is known to activate transient receptor potential ankyrin-1 on nociceptive C-fibers.<br><br>CONCLUSIONS: This study provides the first mechanistic insights into how exposure to urban air pollution leads to activation of guinea pig and human sensory nerves, which are responsible for respiratory symptoms. Mechanistic information will enable the development of appropriate therapeutic interventions and mitigation strategies for those susceptible subjects who are most at risk.}, }
@article {pmid28532282, year = {2017}, author = {Jong, K and Ju, B and Zhang, S}, title = {Synthesis of pH-responsive N-acetyl-cysteine modified starch derivatives for oral delivery.}, journal = {Journal of biomaterials science. Polymer edition}, volume = {28}, number = {14}, pages = {1525-1537}, doi = {10.1080/09205063.2017.1333698}, pmid = {28532282}, issn = {1568-5624}, mesh = {Acetylcysteine/*chemical synthesis/*chemistry ; Administration, Oral ; Chemistry Techniques, Synthetic ; Doxorubicin/administration &amp; dosage/chemistry ; Drug Carriers/*chemical synthesis/*chemistry ; Drug Liberation ; Hydrogen-Ion Concentration ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Molecular Conformation ; Starch/*chemistry ; }, abstract = {In this study, a novel type of pH-responsive polymer PyHES-NAC (2-hydroxy-3-(2-propynyloxy) propyl hydroxyethyl starch (PyHES)) - (N-acetyl-cysteine (NAC)) was synthesized. First, PyHES was prepared via hydrophobic modification of hydroxyl groups in hydroxyethyl starch (HES) with propynylglycidyl ether (PGE), and then pH-responsive carboxylic acid group was connected to propynyl group via thiol-yne click reaction with NAC. Aqueous PyHES-NAC solutions exhibited a good transference between hydrophobic (or self-assembly) and hydrophilic static along with the change of pH value and protective properties of drugs under acidic conditions. 10.0% DOX was released under artificial gastric fluid after 2 h, whereas an immediate release (above 80%) was observed under artificial intestinal fluid. Drug loading capacity of PyHES-NAC was increased by the increase of degree of substitution (DS) of hydrophobic propynyl groups in PyHES, and 41 wt% DOX Loading capacity was the highest value in our study area.}, }
@article {pmid28531807, year = {2017}, author = {Williams, L and Charron, MJ and Sellers, RS}, title = {High post-natal mortality associated with defects in lung maturation and reduced adiposity in mice with gestational exposure to high fat and N-acetylcysteine.}, journal = {Research in veterinary science}, volume = {114}, number = {}, pages = {262-265}, doi = {10.1016/j.rvsc.2017.05.020}, pmid = {28531807}, issn = {1532-2661}, mesh = {Acetylcysteine/*adverse effects ; *Adiposity/drug effects ; Animals ; Diet, High-Fat/*adverse effects ; Female ; Lung/*abnormalities/drug effects/growth &amp; development ; Mice ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced/*pathology/*physiopathology ; }, abstract = {Studies have demonstrated that maternal consumption of a high fat diet (HFD) increases offspring susceptibility to metabolic disease. This study was initiated to identify the mechanistic contribution of oxidative stress on this phenomenon. Two weeks prior to mating, dams were fed either HFD or Control diet with or without supplementation with the anti-oxidant N-acetylcysteine (NAC). Pups born to HFD dams had reduced crown rump length (CRL) at birth and higher neonatal mortality compared to pups from Control dams. Supplementation with NAC normalized CRL in pups from HFD dams, but notably increased mortality. Histological examination of the lungs postnatally and prenatally, revealed normal branching morphogenesis but delayed alveolarization in pups from dams fed HFD+NAC. Discontinuation of NAC at ED17.5 with re-introduction at PD3 improved offspring survival and lung maturation. Additionally, interscapular brown adipose tissue (BAT) was reduced in ED18.5 embryos from HFD dams. These findings suggest that increased mortality in offspring from dams fed HFD+NAC during pregnancy may in part be the result of delayed pulmonary alveolarization and decreased BAT.}, }
@article {pmid28529629, year = {2017}, author = {Zhou, J and Jin, B and Jin, Y and Liu, Y and Pan, J}, title = {The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo.}, journal = {Theranostics}, volume = {7}, number = {6}, pages = {1447-1462}, pmid = {28529629}, issn = {1838-7640}, mesh = {Animals ; Antineoplastic Agents/*administration &amp; dosage/pharmacology ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; *Drug Repositioning ; Heterografts ; Humans ; Melanoma/*drug therapy/pathology ; Mice ; Niclosamide/*administration &amp; dosage/pharmacology ; Treatment Outcome ; Uveal Neoplasms/*drug therapy/pathology ; }, abstract = {Uveal melanoma (UM) is a lethal intraocular malignancy with an average survival of only 2~8 months in patients with hepatic metastasis. Currently, there is no effective therapy for metastatic UM. Here, we reported that niclosamide, an effective repellence of tapeworm that has been approved for use in patients for approximately 50 years, exhibited strong antitumor activity in UM cells in vitro and in vivo. We showed that niclosamide potently inhibited UM cell proliferation, induced apoptosis and reduced migration and invasion. p-Niclosamide, a water-soluble niclosamide, exerted potent in vivo antitumor activity in a UM xenograft mouse model. Mechanistically, niclosamide abrogated the activation of the NF-κB pathway induced by tumor necrosis factor α (TNFα) in UM cells, while niclosamide elevated the levels of intracellullar and mitochondrial reactive oxygen species (ROS) in UM cells. Quenching ROS by N-acetylcysteine (NAC) weakened the ability of niclosamide-mediated apoptosis. Matrix metalloproteinase 9 (MMP-9) knockdown by shRNA potentiated, while ectopic expression of MMP-9 rescued, the niclosamide-attenuated invasion, implying that MMP-9 is pivotal for invasion blockage by niclosamide in UM cells. Furthermore, our results showed that niclosamide eliminated cancer stem-like cells (CSCs) as reflected by a decrease in the Aldefluor[+] percentage and serial re-plating melanosphere formation, and these phenotypes were associated with the suppressed Wnt/β-catenin pathway by niclosamide in UM. Niclosamide caused a dose- and time-dependent reduction of β-catenin and the key components [e.g., DVLs, phospho-GSK3β (S9), c-Myc and Cyclin D1] in the canonical Wnt/β-catenin pathway. Additionally, niclosamide treatment in UM cells reduced ATP and cAMP contents, and decreased PKA-dependent phosphorylation of β-catenin at S552 and S675 which determine the stability of β-catenin protein, suggesting that niclosamide may work as a mitochondrial un-coupler. Taken together, our results shed light on the mechanism of antitumor action of niclosamide and warrant clinical trial for treatment of UM patients.}, }
@article {pmid28529596, year = {2017}, author = {Lim, SC and Jeon, HJ and Kee, KH and Lee, MJ and Hong, R and Han, SI}, title = {Andrographolide induces apoptotic and non-apoptotic death and enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in gastric cancer cells.}, journal = {Oncology letters}, volume = {13}, number = {5}, pages = {3837-3844}, pmid = {28529596}, issn = {1792-1074}, abstract = {Andrographolide, a natural compound isolated from Andrographis paniculata, has been reported to possess antitumor activity. In the present study, the effect of andrographolide in human gastric cancer (GC) cells was investigated. Andrographolide induced cell death with apoptotic and non-apoptotic features. At a low concentration, andrographolide potentiated apoptosis and reduction of clonogenicity triggered by recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL). Exposure of GC cells to andrographolide altered the expression level of several growth-inhibiting and apoptosis-regulating proteins, including death receptors. It was demonstrated that activity of the TRAIL-R2 (DR5) pathway was critical in the development of andrographolide-mediated rhTRAIL sensitization, since its inhibition significantly reduced the extent of apoptosis induced by the combination of rhTRAIL and andrographolide. In addition, andrographolide increased reactive oxygen species (ROS) generation in a dose-dependent manner. N-acetyl cysteine prevented andrographolide-mediated DR5 induction and the apoptotic effect induced by the combination of rhTRAIL and andrographolide. Collectively, the present study demonstrated that andrographolide enhances TRAIL-induced apoptosis through induction of DR5 expression. This effect appears to involve ROS generation in GCs.}, }
@article {pmid28527359, year = {2017}, author = {Ahamed, M and Akhtar, MJ and Khan, MAM and Alhadlaq, HA and Aldalbahi, A}, title = {Nanocubes of indium oxide induce cytotoxicity and apoptosis through oxidative stress in human lung epithelial cells.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {156}, number = {}, pages = {157-164}, doi = {10.1016/j.colsurfb.2017.05.020}, pmid = {28527359}, issn = {1873-4367}, mesh = {A549 Cells ; Epithelial Cells/drug effects/metabolism ; Glutathione/metabolism ; Humans ; Indium/chemistry/*pharmacology ; Lung/cytology/*drug effects/metabolism ; *Nanostructures ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {The demand for semiconductor indium oxide (In2O3) nanocrystals is increasing because of their diverse applications, including in biomedicine. However, there is a scarcity of studies on the biological interaction of indium oxide nanocrystals. Here, we explored the underlying mechanisms of toxicity induced by indium oxide nanocubes in human lung epithelial (A549) cells. Prepared indium oxide nanocubes were crystalline with an average size of 21nm. Biointeraction studies have shown that indium oxide nanocubes induce cell viability reduction and cell membrane damage in a dose- and time-dependent manner. Indium oxide nanocubes were also found to induce reactive oxygen species (ROS) generation, glutathione depletion and lower activity of superoxide oxide dismutase. Further, indium oxide nanocubes induced a mitochondrial membrane potential loss and altered the mRNA expression levels of apoptotic genes (p53, bax, bcl-2, CASP3 &amp; CASP9). The activities of apoptotic enzymes (caspase-3 and -9) were also higher in indium oxide nanocube-treated cells. Finally, we observed that the cytotoxicity and apoptosis induction of indium oxide nanocubes were efficiently prevented by N-acetyl-cysteine. We believe that this is the first report suggesting that indium oxide nanocubes induce toxicity in lung cells via ROS generation and oxidative stress. This study warrants future research on the toxicity mechanisms of indium oxide nanoparticles in animal models.}, }
@article {pmid28527032, year = {2017}, author = {Valente, MJ and Amaral, C and Correia-da-Silva, G and Duarte, JA and Bastos, ML and Carvalho, F and Guedes de Pinho, P and Carvalho, M}, title = {Methylone and MDPV activate autophagy in human dopaminergic SH-SY5Y cells: a new insight into the context of β-keto amphetamines-related neurotoxicity.}, journal = {Archives of toxicology}, volume = {91}, number = {11}, pages = {3663-3676}, doi = {10.1007/s00204-017-1984-z}, pmid = {28527032}, issn = {1432-0738}, support = {SFRH/BD/89879/2012//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; SFRH/BPD/98304/2013//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; PT2020 UID/MULTI/04378/2013//Funda&#xe7;&#xe3;o para a Ci&#xea;ncia e a Tecnologia/ ; NORTE-01-0145-FEDER-000024//Norte Portugal Regional Operational Programme/ ; }, mesh = {Acetylcysteine/pharmacology ; Amphetamines/toxicity ; Apoptosis/drug effects ; Autophagy/*drug effects ; Benzodioxoles/administration &amp; dosage/*toxicity ; Cell Line ; Central Nervous System Stimulants/toxicity ; Dopamine Uptake Inhibitors/toxicity ; Dopaminergic Neurons/*drug effects/metabolism/pathology ; Dose-Response Relationship, Drug ; Humans ; Methamphetamine/administration &amp; dosage/*analogs &amp; derivatives/toxicity ; Microtubule-Associated Proteins/metabolism ; Neurotoxicity Syndromes/etiology ; Oxidative Stress/drug effects ; Pyrrolidines/administration &amp; dosage/*toxicity ; Synthetic Cathinone ; }, abstract = {Autophagy has an essential role in neuronal homeostasis and its dysregulation has been recently linked to neurotoxic effects of a growing list of psychoactive drugs, including amphetamines. However, the role of autophagy in β-keto amphetamine (β-KA) designer drugs-induced neurotoxicity has hitherto not been investigated. In the present study, we show that two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV), elicit morphological changes consistent with autophagy and neurodegeneration, including formation of autophagic vacuoles and neurite retraction in dopaminergic SH-SY5Y cells. Methylone and MDPV prompted the formation of acidic vesicular organelles (AVOs) and lead to increased expression of the autophagy-associated protein LC3-II in a concentration- and time-dependent manner. Electron microscopy confirmed the presence of autophagosomes with typical double membranes and autolysosomes in cells exposed to both β-KA. The autophagic flux was further confirmed using bafilomycin A1, a known inhibitor of the late phase of autophagy. Moreover, we showed that autophagy markers were activated before the triggering of cell death and caspase 3 activation, suggesting that β-KA-induced autophagy precedes apoptotic cell death. To address the role of oxidative stress in autophagy induction, we also investigated the effects of antioxidant treatment with N-acetyl-L-cysteine (NAC) on autophagy and apoptotic markers altered by these drugs. NAC significantly attenuated methylone- and MDPV-induced cell death by completely inhibiting the generation of reactive oxygen and nitrogen species, and hampering both apoptotic and autophagic activity, suggesting that oxidative stress plays an important role in mediating autophagy and apoptosis elicited by these drugs.}, }
@article {pmid28522564, year = {2017}, author = {Yanagisawa, S and Baker, JR and Vuppusetty, C and Fenwick, P and Donnelly, LE and Ito, K and Barnes, PJ}, title = {Decreased phosphatase PTEN amplifies PI3K signaling and enhances proinflammatory cytokine release in COPD.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {313}, number = {2}, pages = {L230-L239}, pmid = {28522564}, issn = {1522-1504}, support = {093080/Z/10/Z//Wellcome Trust/United Kingdom ; }, mesh = {Aged ; Cell Line ; Cytokines/*metabolism ; Epithelial Cells/metabolism ; Female ; Humans ; Inflammation/*metabolism ; Lung/metabolism ; Male ; Oxidative Stress/physiology ; PTEN Phosphohydrolase/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation/physiology ; Proto-Oncogene Proteins c-akt/metabolism ; Pulmonary Disease, Chronic Obstructive/*metabolism ; Signal Transduction/physiology ; Smoke/adverse effects ; Smoking/adverse effects ; }, abstract = {The phosphatidylinositol 3-kinase (PI3K) pathway is activated in chronic obstructive pulmonary disease (COPD), but the regulatory mechanisms for this pathway are yet to be elucidated. The aim of this study was to determine the expression and role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of the PI3K pathway, in COPD. PTEN protein expression was measured in the peripheral lung of COPD patients compared with smoking and nonsmoking controls. The direct influence of cigarette smoke extract (CSE) on PTEN expression was assessed using primary lung epithelial cells and a cell line (BEAS-2B) in the presence or absence of l-buthionine-sulfoximine (BSO) to deplete intracellular glutathione. The impact of PTEN knockdown by RNA interference on cytokine production was also examined. In peripheral lung, PTEN protein was significantly decreased in patients with COPD compared with the subjects without COPD (P < 0.001) and positively correlated with the severity of airflow obstruction (forced expiratory volume in 1-s percent predicted; r = 0.50; P = 0.0012). Conversely, phosphorylated Akt, as a marker of PI3K activation, showed a negative correlation with PTEN protein levels (r = -0.41; P = 0.0042). In both primary bronchial epithelial cells and BEAS-2B cells, CSE decreased PTEN protein, which was reversed by N-acetyl cysteine treatment. PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory cytokines, such as IL-6, CXCL8, CCL2, and CCL5. In conclusion, oxidative stress reduces PTEN protein levels, which may result in increased PI3K signaling and amplification of inflammation in COPD.}, }
@article {pmid28517024, year = {2017}, author = {Lanthier, N and Stärkel, P}, title = {Treatment of severe alcoholic hepatitis: past, present and future.}, journal = {European journal of clinical investigation}, volume = {47}, number = {7}, pages = {531-539}, doi = {10.1111/eci.12767}, pmid = {28517024}, issn = {1365-2362}, mesh = {Adrenal Cortex Hormones/therapeutic use ; Alcohol Abstinence/trends ; Antioxidants/therapeutic use ; Apoptosis/physiology ; Bile Acids and Salts/administration &amp; dosage ; Dietary Supplements ; Gastrointestinal Microbiome/physiology ; Granulocyte Colony-Stimulating Factor/therapeutic use ; Hepatitis, Alcoholic/*therapy ; Humans ; Liver Regeneration/physiology ; Liver Transplantation/trends ; Metabolic Syndrome/complications ; Nutritional Support/trends ; Opportunistic Infections/complications/therapy ; Organ Sparing Treatments/trends ; Oxidative Stress/physiology ; Stem Cell Transplantation/trends ; Thiamine/administration &amp; dosage ; Vitamin B Complex/therapeutic use ; }, abstract = {Alcoholic hepatitis (AH) manifests as a clinical syndrome characterized by recent jaundice and liver function deterioration in an actively drinking patient. The principal cause of AH is alcoholic steatohepatitis (ASH) defined histologically by the coexistence of steatosis, hepatocyte ballooning and satellitosis. While nonsevere AH usually responds to alcohol abstinence, severe AH, identified by Maddrey scoring ≥ 32, has a bad prognosis and is traditionally treated by a 28-day course of prednisone therapy. A recent trial, which showed no improvement of long-term survival but significant reduced mortality after 28 days of corticoid therapy compared to placebo, opens a debate on its efficacy. N-acetyl-cysteine supplementation combined with steroid therapy is also able to reduce the 28-day mortality compared to steroid alone. While guidelines recommend high-calorie intake and protein supplementation in decompensated liver diseases, intensive enteral nutrition together with corticoid treatment does not reduce mortality compared to corticoid alone in a recent study with ASH patients. Stimulation of liver regeneration through interleukin-22, granulocyte colony-stimulating factor or farnesoid X receptor agonists, inhibition of apoptosis, early liver transplantation and modulation of gut microbiota through antibiotic or faecal transplantation approaches constitute new therapeutic perspectives that are investigated in current clinical trials. Inhibition of oxidative stress, modulation of gut fungal populations and stimulation of progenitor cell proliferation and pro-regenerative inflammatory pathways constitute prospects for future human trials. For long-term survival, strategies for persistent alcohol abstinence remain the key of success, opening another large research field.}, }
@article {pmid28512265, year = {2017}, author = {Vo, MC and Nguyen-Pham, TN and Lee, HJ and Jung, SH and Choi, NR and Hoang, MD and Kim, HJ and Lee, JJ}, title = {Chaetocin enhances dendritic cell function via the induction of heat shock protein and cancer testis antigens in myeloma cells.}, journal = {Oncotarget}, volume = {8}, number = {28}, pages = {46047-46056}, pmid = {28512265}, issn = {1949-2553}, mesh = {Antigens, Neoplasm/metabolism ; Apoptosis ; B-Lymphocytes/*drug effects/physiology ; Cancer Vaccines/*immunology ; Cell Line, Tumor ; Cross-Priming ; Dendritic Cells/*immunology/transplantation ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Immunotherapy, Adoptive/*methods ; Interleukin-10/metabolism ; Lymphocyte Activation ; Multiple Myeloma/immunology/*therapy ; Neoplasm Proteins/metabolism ; Piperazines/pharmacology ; T-Lymphocytes, Cytotoxic/*immunology ; Ultraviolet Rays ; Up-Regulation ; }, abstract = {Dendritic cells (DC)-based vaccines are considered useful in cancer immuno-therapy, and the interactions of DC and dying tumor cells are important and promising for cancer immunotherapy. We investigated whether chaetocin could be used to induce death of myeloma cells, for loading onto DCs can affect DCs function. In this study, we show that the dying myeloma cells treated with chaetocin resulted in the induction of heat shock protein (HSP) 90, which was inhibited by antioxidant N-acetyl cysteine, and showed an increase in the expression of MAGE-A3 and MAGE-C1/CT7. DCs loaded with chaetocin-treated dying myeloma cells produced low levels of IL-10 and enhanced the cross presentation of DCs. Additionally, these DCs most potently inhibited regulatory T cells, induced Th1 polarization and activated myeloma-specific cytotoxic T lymphocytes compared with DCs loaded with UVB-irradiated dying myeloma cells. These results suggest that the pretreatment of myeloma cells with chaetocin can enhance DC function through the up-regulation of HSP90 and cancer testis antigens in dying myeloma cells and can potently induce the Th1 polarization of DCs and myeloma-specific cytotoxic T lymphocytes.}, }
@article {pmid28509526, year = {2019}, author = {Schiattarella, M and Caiazzo, G and Di Caprio, R and Lembo, S and Raimondo, A and Ayala, F and Balato, N and Monfrecola, G and Fortunato, G and Balato, A}, title = {Paraoxonases and psoriasis: negative imbalance of antioxidant endogenous mechanisms.}, journal = {Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia}, volume = {154}, number = {2}, pages = {192-196}, doi = {10.23736/S0392-0488.17.05537-7}, pmid = {28509526}, issn = {1827-1820}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants/*metabolism ; Aryldialkylphosphatase/*genetics ; Case-Control Studies ; Female ; Gene Expression Regulation ; Humans ; Hydrogen Peroxide/administration &amp; dosage ; Male ; Middle Aged ; Oxidative Stress/*genetics ; Psoriasis/enzymology/genetics/*pathology ; Severity of Illness Index ; }, abstract = {BACKGROUND: Numerous reports have shown that psoriasis patients are more exposed to lipoprotein peroxidation and to a decrease in the activity of paraoxonase (PON)1, an antioxidant and anti-inflammatory enzyme. Thus, it has been suggested that malfunction of the antioxidant system and an increased production of reactive oxygen species drive immune inflammatory events, that result in progressive skin cell damage in patients with psoriasis. The PON protein family, including PON1, PON2 and PON3, is one of the most important endogenous defense mechanisms against oxidative stress. In the present study, we investigated PON gene expression in psoriasis and in cutaneous oxidative stress.<br><br>METHODS: The study population included 10 patients affected by moderate-to-severe plaque psoriasis and 15 healthy donors who have undergone to plastic surgery, were used as control. Skin punch biopsies of lesional and non lesional psoriatic skin were performed for analysis of PON2 and PON3 gene expression. In addition, oxidation assays in ex vivo full-thickness healthy skin organ cultures were performed.<br><br>RESULTS: No significant differences were observed between PON2 and PON3 gene expression in psoriatic lesional and non lesional skin compared with healthy controls. H2O2 treatment induced a signi&#xfb01;cant decrease of PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures; conversely the pretreatment of samples with the antioxidant reagent N-acetyl-L-cysteine (NAC) induced a significant increase. Interestingly, no significant alterations were reported for PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures stimulated with IL-17.<br><br>CONCLUSIONS: Taken together our findings have revealed that a strong pro-oxidative activity is not effectively countered by antioxidant endogenous mechanisms both in psoriatic skin and in ex vivo experimental model.}, }
@article {pmid28504001, year = {2018}, author = {Al-Attrache, H and Chamieh, H and Hamzé, M and Morel, I and Taha, S and Abdel-Razzak, Z}, title = {N-acetylcysteine potentiates diclofenac toxicity in Saccharomyces cerevisiae: stronger potentiation in ABC transporter mutant strains.}, journal = {Drug and chemical toxicology}, volume = {41}, number = {1}, pages = {89-94}, doi = {10.1080/01480545.2017.1320404}, pmid = {28504001}, issn = {1525-6014}, mesh = {ATP-Binding Cassette Transporters/genetics/*metabolism ; Acetylcysteine/*toxicity ; Anti-Inflammatory Agents, Non-Steroidal/metabolism/*toxicity ; Antioxidants/*toxicity ; Diclofenac/metabolism/*toxicity ; Disulfides/metabolism ; Dose-Response Relationship, Drug ; Drug Synergism ; Genotype ; Mutation ; Oxidative Stress/drug effects ; Phenotype ; Saccharomyces cerevisiae/*drug effects/genetics/growth &amp; development/metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Time Factors ; Transcription Factors/genetics/metabolism ; }, abstract = {Diclofenac (DCF) adverse reactions involve diverse mechanisms in different models. We recently demonstrated that DCF-induced toxicity in HepaRG decreases as they express DCF-metabolizing enzymes. DCF metabolism promotes toxicity in Saccharomyces cerevisiae expressing heterologous cytochromes-P450. N-Acetylcysteine (NAC) is used to treat diverse medical conditions due to its multiple properties (antioxidant, metal chelator, thiol-disulfide disruption). The latter property accounts for its mucolytic effects and broadens its potential molecular targets to signal transduction proteins, ABC transporters and others. Interaction of NAC with DCF effects depends on the experimental model. This study aims to investigate NAC/DCF interaction and the involvement of ABC transporters in wild type and mutant Saccharomyces cerevisiae. DCF inhibited yeast growth in a dose- and time-dependent manner and the cells started adapting to DCF 24-h post-treatment. NAC potentiated DCF-induced toxicity if added prior or parallel to DCF. Pretreatment with NAC increased its potentiation effect and compromised cells adaption to DCF. Post-treatment with NAC potentiated DCF toxicity without compromising adaptation. Moreover, mutant strains in ABC transporters Pdr5, Yor1, Bpt1 or Pdr15, were more sensitive to DCF; while mutant strains in Pdr5, Vmr1 or Pdr12 were more sensitive to NAC/DCF interaction. DCF ± NAC elicited on the mutant strain in Yap1, an oxidative stress-related protein, the same effects as on the wild type. Therefore, oxidative stress does not seem to be key actor in DCF toxicity in our model. Our hypothesis is that NAC potentiation effect is at least due to its ability to disrupt disulfide bridge in proteins required to overcome DCF toxicity in yeast.}, }
@article {pmid28503420, year = {2017}, author = {Chen, XD and Su, MY and Chen, TT and Hong, HY and Han, AD and Li, WS}, title = {Oxidative stress affects retinal pigment epithelial cell survival through epidermal growth factor receptor/AKT signaling pathway.}, journal = {International journal of ophthalmology}, volume = {10}, number = {4}, pages = {507-514}, pmid = {28503420}, issn = {2222-3959}, abstract = {AIM: To investigate the cross-talk between oxidative stress and the epidermal growth factor receptor (EGFR)/AKT signaling pathway in retinal pigment epithelial (RPE) cells.<br><br>METHODS: Human RPE cell lines (ARPE-19 cell) were treated with different doses of epidermal growth factor (EGF) and hydrogen peroxide (H2O2). Cell viability was determined by a methyl thiazolyl tetrazolium assay. Cell proliferation was examined by a bromodeoxyuridine (BrdU) incorporation assay. EGFR/AKT signaling was detected by Western blot. EGFR localization was also detected by immunofluorescence. In addition, EGFR/AKT signaling was intervened upon by EGFR inhibitor (erlotinib), PI3K inhibitor (A66) and AKT inhibitor (MK-2206), respectively. H2O2-induced oxidative stress was blocked by antioxidant N-acetylcysteine (NAC).<br><br>RESULTS: EGF treatment increased ARPE-19 cell viability and proliferation through inducing phosphorylation of EGFR and AKT. H2O2 inhibited ARPE-19 cell viability and proliferation and also suppressed EGF-stimulated increase of RPE cell viability and proliferation by affecting the EGFR/AKT signaling pathway. EGFR inhibitor erlotinib blocked EGF-induced phosphorylation of EGFR and AKT, while A66 and MK-2206 only blocked EGF-induced phosphorylation of AKT. EGF-induced phosphorylation and endocytosis of EGFR were also affected by H2O2 treatment. In addition, antioxidant NAC attenuated H2O2-induced inhibition of ARPE-19 cell viability through alleviating reduction of EGFR, and phosphorylated and total AKT proteins.<br><br>CONCLUSION: Oxidative stress affects RPE cell viability and proliferation through interfering with the EGFR/AKT signaling pathway. The EGFR/AKT signaling pathway may be an important target in oxidative stress-induced RPE cell dysfunction.}, }
@article {pmid28499986, year = {2017}, author = {da Costa, M and Bernardi, J and Costa, L and Fiuza, T and Brandão, R and Ribeiro, MF and Amaral, JD and Rodrigues, CMP and Pereira, ME}, title = {N-acetylcysteine treatment attenuates the cognitive impairment and synaptic plasticity loss induced by streptozotocin.}, journal = {Chemico-biological interactions}, volume = {272}, number = {}, pages = {37-46}, doi = {10.1016/j.cbi.2017.05.008}, pmid = {28499986}, issn = {1872-7786}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/*pharmacology/*therapeutic use ; Animals ; Cerebral Cortex/drug effects/metabolism ; Cognitive Dysfunction/*chemically induced/*drug therapy/prevention &amp; control ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Immunohistochemistry ; Male ; Maze Learning/drug effects ; Mice ; Motor Activity/drug effects ; Neuronal Plasticity/*drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Physostigmine/pharmacology ; Receptor, trkB/metabolism ; Streptozocin/toxicity ; Superoxide Dismutase/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by severe neuronal and glial structural changes and progressive cognitive decline. N-acetylcysteine (NAC) is a well-known pharmacological agent with pro-neurogenic properties and neuroprotective effects. In this study, we evaluated NAC protective effects on cognitive impairment and associated pathological markers in a streptozotocin (STZ)-induced sporadic dementia of AD type mice model. Animals were divided into six groups: I) Sham, II) NAC, III) physostigmine (PHY), IV) STZ, V) NAC + STZ and VI) PHY + NAC. NAC (5 mg/kg) and PHY (0.25 mg/kg) were administrated orally for 30 consecutive days and STZ (2.5 mg/kg) intracerebroventricularly at the first and third days. Novel object recognition (NOR, days 26-27) and Morris water maze (MWM, days 26-30) tasks were assessed to evaluate learning and memory. On the thirty-first day animals were euthanized and brains collected for biochemical analysis. Interestingly, our results showed that STZ treatment induced cognitive impairment in mice in the NOR and MWM tasks. Both NAC and PHY treatments prevented from this impairment. The increase in AChE activity and decrease in pTrkB and MnSOD levels caused by STZ in the cerebral cortex and hippocampus, were prevented by the NAC and PHY treatments. The decrease in SYN, MAP2 and GFAP expressions were also prevented by NAC and PHY treatments. In conclusion, NAC treatment prevented the cognitive impairment induced by STZ, normalizing the AChE activity and rescuing the synaptic plasticity loss. Our results suggest that NAC is a promising therapeutic strategy for the treatment of AD.}, }
@article {pmid28499416, year = {2017}, author = {Dludla, PV and Nkambule, BB and Dias, SC and Johnson, R}, title = {Cardioprotective potential of N-acetyl cysteine against hyperglycaemia-induced oxidative damage: a protocol for a systematic review.}, journal = {Systematic reviews}, volume = {6}, number = {1}, pages = {96}, pmid = {28499416}, issn = {2046-4053}, mesh = {Acetylcysteine/*therapeutic use ; Cardiotonic Agents/*therapeutic use ; Diabetic Cardiomyopathies/*prevention &amp; control ; Humans ; Hyperglycemia/*complications/drug therapy/physiopathology ; Oxidative Stress/*drug effects ; *Research Design ; *Review Literature as Topic ; Systematic Reviews as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: Hyperglycaemia-induced oxidative damage is a well-established factor implicated in the development of diabetic cardiomyopathy (DCM) in diabetic individuals. Some of the well-known characteristics of DCM include increased myocardial left ventricular wall thickness and remodelling that result in reduced cardiac efficiency. To prevent this, an increasing number of pharmacological compounds such as N-acetyl cysteine (NAC) are explored for their antioxidant properties. A few studies have shown that NAC can ameliorate hyperglycaemia-induced oxidative damage within the heart. Hence, the objective of this review is to synthesise the available evidence pertaining to the cardioprotective role of NAC against hyperglycaemia-induced oxidative damage and thus prevent DCM.<br><br>METHODS: This systematic review protocol will be reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement. We will perform a comprehensive search on major databases such as EMBASE, Cochrane Library, PubMed and Google scholar for original research articles published from January 1960 to March 2017. We will only report on literature that is available in English. Two authors will independently screen for eligible studies using pre-defined criteria, and data extraction will be done in duplicate. All discrepancies will be resolved by consensus or consultation of a third reviewer. The quality of studies will be checked using Cochrane Risk of Bias Assessment Tool and The Joanna Briggs Institute (JBI) Critical Appraisal tools for non-randomised experimental studies. Heterogeneity across studies will be assessed using the Cochrane Q statistic and the inconsistency index (I [2]). We will use the random effects model to calculate a pooled estimate.<br><br>DISCUSSION: Although several studies have shown that NAC can ameliorate hyperglycaemia-induced oxidative damage within the heart, this systematic review will be the first pre-registered synthesis of data to identify the cardioprotective potential of NAC against hyperglycaemia-induced oxidative damage. This result will help guide future research evaluating the cardioprotective role of NAC against DCM and better identify possible mechanisms of action for NAC to prevent oxidative damage with a diabetic heart.<br><br>SYSTEMIC REVIEW REGISTRATION: PROSPERO CRD42017055851 .}, }
@article {pmid28499252, year = {2017}, author = {Youn, GS and Cho, H and Kim, D and Choi, SY and Park, J}, title = {Crosstalk between HDAC6 and Nox2-based NADPH oxidase mediates HIV-1 Tat-induced pro-inflammatory responses in astrocytes.}, journal = {Redox biology}, volume = {12}, number = {}, pages = {978-986}, pmid = {28499252}, issn = {2213-2317}, mesh = {Animals ; Astrocytes/cytology/drug effects/*immunology/virology ; Cell Line ; Chemokines/genetics/metabolism ; Gene Knockdown Techniques ; HIV-1/immunology/*metabolism ; Histone Deacetylase 6/genetics/*metabolism ; Humans ; Hydroxamic Acids/pharmacology ; Indoles/pharmacology ; Mice ; NADPH Oxidase 2/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; tat Gene Products, Human Immunodeficiency Virus/*immunology ; }, abstract = {Histone deacetylase 6 (HDAC6) likely is important in inflammatory diseases. However, how HDAC6 exerts its effect on inflammatory processes remains unclear. HIV-1 transactivator of transcription (Tat) activates NADPH oxidase resulting in generation of reactive oxygen species (ROS), leading to extensive neuro-inflammation in the central nervous system. We investigated the correlation of HDAC6 and NADPH oxidase in HIV-1 Tat-stimulated astrocytes. HDAC6 knockdown attenuated HIV-1 Tat-induced ROS generation and NADPH oxidase activation. HDAC6 knockdown suppressed HIV-1 Tat-induced expression of NADPH oxidase subunits, such as Nox2, p47phox, and p22phox. Specific inhibition of HDAC6 using tubastatin A suppressed HIV-1 Tat-induced ROS generation and activation of NADPH oxidase. N-acetyl cysteine, diphenyl iodonium, and apocynin suppressed HIV-1 Tat-induced expression of HDAC6 and the pro-inflammatory chemokines CCL2, CXCL8, and CXCL10. Nox2 knockdown attenuated HIV-1 Tat-induced HDAC6 expression and subsequent expression of chemokines. The collective results point to the potential crosstalk between HDAC6 and NADPH oxidase, which could be a combined therapeutic target for relief of HIV-1 Tat-mediated neuro-inflammation.}, }
@article {pmid28497199, year = {2018}, author = {Lin, CC and Yang, CC and Chen, YW and Hsiao, LD and Yang, CM}, title = {Arachidonic Acid Induces ARE/Nrf2-Dependent Heme Oxygenase-1 Transcription in Rat Brain Astrocytes.}, journal = {Molecular neurobiology}, volume = {55}, number = {4}, pages = {3328-3343}, pmid = {28497199}, issn = {1559-1182}, support = {MOST104-2320-B-182A-003-MY3//Ministry of Science and Technology, Taiwan/ ; MOST104-2320-B-182-010//Ministry of Science and Technology, Taiwan/ ; MOST105-2320-B-182-005-MY3//Ministry of Science and Technology, Taiwan/ ; EMRPD1G0171//Ministry of Education/ ; EMRPD1G0281//Ministry of Education/ ; CMRPD1F0022//Chang Gung Medical Research Foundation/ ; CMRPG3E2232//Chang Gung Medical Research Foundation/ ; CMRPG3F1531//Chang Gung Medical Research Foundation/ ; CMRPG5F0201//Chang Gung Medical Research Foundation/ ; CMRPD1F0511//Chang Gung Medical Research Foundation/ ; }, mesh = {Animals ; Antioxidant Response Elements/*genetics ; Arachidonic Acid/*pharmacology ; Astrocytes/drug effects/*metabolism ; Brain/*cytology ; Focal Adhesion Kinase 2/metabolism ; Heme Oxygenase-1/*genetics/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Models, Biological ; NADPH Oxidases/metabolism ; NF-E2-Related Factor 2/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Receptors, Platelet-Derived Growth Factor/metabolism ; Transcription, Genetic/*drug effects ; Up-Regulation/drug effects ; src-Family Kinases/metabolism ; }, abstract = {Arachidonic acid (AA) is a major product of phospholipid hydrolysis catalyzed by phospholipase A2 during neurodegenerative diseases. AA exerts as a second messenger to regulate various signaling components which may be involved in different pathophysiological processes. Astrocytes are the main types of CNS resident cells which maintain and support the physiological function of brain. AA has been shown to induce ROS generation through activation of NADPH oxidases (Noxs) which may play a key role in the expression of heme oxygenase-1 (HO-1). Therefore, this study was designed to investigate the mechanisms underlying AA-induced HO-1 expression in rat brain astrocytes (RBA-1). We found that AA induced HO-1 protein and mRNA expression and promoter activity in RBA-1, which was mediated through the synthesis of 15-deoxy-Δ12,14-prostaglandin D2-activated peroxisome proliferator-activated receptor-γ (PPARγ) receptors. This note was confirmed by transfection with PPARγ small interfering RNAs (siRNA) which attenuated the AA-mediated responses. AA-induced HO-1 expression was mediated through Nox/ROS generation, which was inhibited by Nox inhibitors (diphenyleneiodonium and apocynin) and ROS scavengers (N-acetyl cysteine). Moreover, AA-induced HO-1 expression was mediated through phosphorylation of Src, Pyk2, platelet-derived growth factor, PI3K/Akt, and ERK1/2 which were inhibited by the pharmacological inhibitors including PP1, PF431396, AG1296, LY294002, and U0126 or by transfection with respective siRNAs. AA-enhanced Nrf2 expression and HO-1 promoter activity was inhibited by transfection with Nrf2 siRNA or by these pharmacological inhibitors. Furthermore, chromatin immunoprecipitation assay confirmed that Nrf2 and PPARγ were associated with the proximal antioxidant response element (ARE)-binding site on HO-1 promoter, suggesting that Nrf2/PPARγ are key transcription factors modulating HO-1 expression. AA-induced ARE promoter activity was also reduced by these pharmacological inhibitors. These findings suggested that AA increases formation of Nrf2 and PPARγ complex and binding with ARE1 binding site through Src, Pyk2, PI3K/Akt, and ERK1/2, which further induced HO-1 expression in RBA-1 cells.}, }
@article {pmid28496415, year = {2017}, author = {Lin, AH and Liu, MH and Ko, HB and Perng, DW and Lee, TS and Kou, YR}, title = {Inflammatory Effects of Menthol vs. Non-menthol Cigarette Smoke Extract on Human Lung Epithelial Cells: A Double-Hit on TRPM8 by Reactive Oxygen Species and Menthol.}, journal = {Frontiers in physiology}, volume = {8}, number = {}, pages = {263}, pmid = {28496415}, issn = {1664-042X}, abstract = {Clinical studies suggest that smokers with chronic obstructive pulmonary disease who use menthol cigarettes may display more severe lung inflammation than those who smoke non-menthol cigarette. However, the mechanisms for this difference remain unclear. Menthol is a ligand of transient receptor potential melastatin-8 (TRPM8), a Ca[2+]-permeant channel sensitive to reactive oxygen species (ROS). We previously reported that exposure of human bronchial epithelial cells (HBECs) to non-menthol cigarette smoke extract (Non-M-CSE) triggers a cascade of inflammatory signaling leading to IL-8 induction. In this study, we used this in vitro model to compare the inflammatory effects of menthol cigarette smoke extract (M-CSE) and Non-M-CSE and delineate the mechanisms underlying the differences in their impacts. Compared with Non-M-CSE, M-CSE initially increased a similar level of extracellular ROS, suggesting the equivalent oxidant potency. However, M-CSE subsequently produced more remarkable elevations in intracellular Ca[2+], activation of the mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling, and IL-8 induction. The extracellular ROS responses to both CSE types were totally inhibited by N-acetyl-cysteine (NAC; a ROS scavenger). The intracellular Ca[2+] responses to both CSE types were also totally prevented by NAC, AMTB (a TRPM8 antagonist), or EGTA (an extracellular Ca[2+] chelator). The activation of the MAPK/NF-κB signaling and induction of IL-8 to both CSE types were suppressed to similar levels by NAC, AMTB, or EGTA. These results suggest that, in addition to ROS generated by both CSE types, the menthol in M-CSE may act as another stimulus to further activate TRPM8 and induce the observed responses. We also found that menthol combined with Non-M-CSE induced greater responses of intracellular Ca[2+] and IL-8 compared with Non-M-CSE alone. Moreover, we confirmed the essential role of TRPM8 in these responses to Non-M-CSE or M-CSE and the difference in these responses between the both CSE types using HBECs with TRPM8 knockdown and TRPM8 knockout, and using HEK293 cells transfected with hTRPM8. Thus, compared with exposure to Non-M-CSE, exposure to M-CSE induced greater TRPM8-mediated inflammatory responses in HBECs. These augmented effects may be due to a double-hit on lung epithelial TRPM8 by ROS generated from CSE and the menthol in M-CSE.}, }
@article {pmid28495448, year = {2017}, author = {Jeayeng, S and Wongkajornsilp, A and Slominski, AT and Jirawatnotai, S and Sampattavanich, S and Panich, U}, title = {Nrf2 in keratinocytes modulates UVB-induced DNA damage and apoptosis in melanocytes through MAPK signaling.}, journal = {Free radical biology &amp; medicine}, volume = {108}, number = {}, pages = {918-928}, pmid = {28495448}, issn = {1873-4596}, support = {R01 AR056666/AR/NIAMS NIH HHS/United States ; }, mesh = {Apoptosis ; Cells, Cultured ; Coculture Techniques ; DNA Damage ; Humans ; Keratinocytes/*physiology ; MAP Kinase Signaling System ; Melanocytes/*physiology ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidative Stress ; Paracrine Communication ; Primary Cell Culture ; Pyrimidine Dimers/metabolism ; RNA, Small Interfering/genetics ; Signal Transduction ; Ultraviolet Rays ; alpha-MSH/metabolism ; }, abstract = {Responses of melanocytes (MC) to ultraviolet (UV) irradiation can be influenced by their neighbouring keratinocytes (KC). We investigated the role of Nrf2 in regulating paracrine effects of KC on UVB-induced MC responses through phosphorylation of MAPKs in association with oxidative stress in primary human MC cocultured with primary human KC using a transwell co-culture system and small-interfering RNA-mediated silencing of Nrf2 (siNrf2). The mechanisms by which Nrf2 modulated paracrine factors including α-melanocyte-stimulating hormone (α-MSH) and paracrine effects of KC on UVB-mediated apoptosis were also assessed. Our findings showed that co-culture of MC with siNrf2-transfected KC enhanced UVB-mediated cyclobutane pyrimidine dimer (CPD) formation, apoptosis and oxidant formation, together with phosphorylation of ERK, JNK and p38 in MC. Treatment of MC with conditioned medium (CM) from Nrf2-depleted KC also increased UVB-mediated MC damage, suggesting that KC modulated UVB-mediated MC responses via paracrine effects. Additionally, depletion of Nrf2 in KC suppressed UVB-induced α-MSH levels as early as 30min post-irradiation, although pretreatment with N-acetylcysteine (NAC) elevated its levels in CM from siNrf2-transfected KC. Furthermore, NAC reversed the effect of CM from Nrf2-depleted KC on UVB-induced apoptosis and inflammatory response in MC. Our study demonstrates for the first time that KC provided a rescue effect on UVB-mediated MC damage, although depletion of Nrf2 in KC reversed its protective effects on MC in a paracrine fashion in association with elevation of ROS levels and activation of MAPK pathways in MC. Nrf2 may indirectly regulate the paracrine effects of KC probably by affecting levels of the paracrine factor α-MSH via a ROS-dependent mechanism.}, }
@article {pmid28495234, year = {2017}, author = {Posadino, AM and Phu, HT and Cossu, A and Giordo, R and Fois, M and Thuan, DTB and Piga, A and Sotgia, S and Zinellu, A and Carru, C and Pintus, G}, title = {Oxidative stress-induced Akt downregulation mediates green tea toxicity towards prostate cancer cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {42}, number = {}, pages = {255-262}, doi = {10.1016/j.tiv.2017.05.005}, pmid = {28495234}, issn = {1879-3177}, mesh = {Catechin/*analogs &amp; derivatives/toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA/metabolism ; Down-Regulation ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Oxidants/*toxicity ; Oxidative Stress/drug effects ; Prostatic Neoplasms/drug therapy/metabolism ; Protein Carbonylation/drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/metabolism ; Tea/*toxicity ; }, abstract = {Green tea consumption has been shown to possess cancer chemopreventive activity. Polyphenol E (PE) is a widely used standardized green tea extract formulation. This study was designed to investigate the impact of PE on prostate cancer cells (PC3), analyze the potential signals involved and elucidate whether anti- or pro-oxidant effects may be implicated. Treatment of PC3 cells with 30 and 100μg/ml PE significantly decreased cell viability and proliferation. At the tested concentrations, PE did not exert any antioxidant activity, eliciting instead a pro-oxidant effect at concentrations 30 and 100μg/ml, which was consistent with the observed PE cytotoxicity. PE-induced cell death was associated with mitochondrial dysfunction and downregulation of Akt activation, thus suggesting their implication in the PE-elicited cell dysfunction. Cell exposure to the ROS scavenger N-Acetyl Cysteine prevented PE-induced ROS increase, pAkt impairment, and cell death, clearly indicating the causative role of ROS in the observed phenomena. Failure of PE to induce PC3 damage in cells overexpressing Akt further confirms its implication in the PE-elicited cell death. Our findings showed an association between the antiproliferative and the pro-oxidant effect elicited by PE on PC3 cells and delineates a molecular signaling pattern potentially implicated in the toxicity of PE towards prostate cancer cells.}, }
@article {pmid28492308, year = {2017}, author = {Yang, L and Chen, Y and Pan, W and Wang, H and Li, N and Tang, B}, title = {Visualizing the Conversion Process of Alcohol-Induced Fatty Liver to Steatohepatitis in Vivo with a Fluorescent Nanoprobe.}, journal = {Analytical chemistry}, volume = {89}, number = {11}, pages = {6196-6201}, doi = {10.1021/acs.analchem.7b01144}, pmid = {28492308}, issn = {1520-6882}, mesh = {Animals ; Fatty Liver/*diagnostic imaging ; Fatty Liver, Alcoholic/*diagnostic imaging ; Fluorescent Dyes/administration &amp; dosage/*chemistry/metabolism ; Humans ; Injections, Intravenous ; Mice ; Nanoparticles/administration &amp; dosage/*chemistry/metabolism ; *Optical Imaging ; }, abstract = {Excess alcohol consumption and the associated development of alcoholic liver disease (ALD) are major public health challenges worldwide. Since patients with the severe stages of ALD no longer benefit from clinical therapies, early warning of ALD holds significant promise for increasing the cure rate of ALD. Herein, we develop a bicolor fluorescent nanoprobe for dynamically monitoring the conversion process of alcohol-induced fatty liver to steatohepatitis in vivo through simultaneous imaging of microRNA 155 and osteopontin mRNA, which are related to fatty liver and steatohepatitis, respectively. The fluorescence imaging results indicate that the nanoprobe can effectively differentiate alcohol-induced fatty liver and steatohepatitis. Moreover, the nanoprobe can monitor the transmutation process of alcohol-induced fatty liver to steatohepatitis and assess the remission effects of N-acetyl cysteine for alcohol-induced liver injury. We anticipate the developed nanoprobe and imaging method can provide new ways for early warning, treatments, and prognosis of ALD.}, }
@article {pmid28488455, year = {2017}, author = {Liu, C and Huang, Y and Zhang, Y and Chen, X and Kong, X and Dong, Y}, title = {Intracellular methylglyoxal induces oxidative damage to pancreatic beta cell line INS-1 cell through Ire1α-JNK and mitochondrial apoptotic pathway.}, journal = {Free radical research}, volume = {51}, number = {4}, pages = {337-350}, doi = {10.1080/10715762.2017.1289376}, pmid = {28488455}, issn = {1029-2470}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Endoplasmic Reticulum/drug effects/metabolism ; Endoribonucleases/*metabolism ; Glucose/administration &amp; dosage/metabolism/pharmacology ; Insulin-Secreting Cells/*drug effects/metabolism/pathology ; Intracellular Space/*metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mitochondria/*drug effects/pathology ; Multienzyme Complexes/*metabolism ; Oxidative Stress/*drug effects ; Protein Serine-Threonine Kinases/*metabolism ; Pyruvaldehyde/administration &amp; dosage/*pharmacology ; Rats ; }, abstract = {An increased intracellular methylglyoxal (MGO) under hyperglycemia led to pancreatic beta cell death. However, its mechanism in which way with MGO induced beta cell death remains unknown. We investigated both high glucose and MGO treatment significantly inclined intracellular MGO concentration and inhibited cell viability in vitro. MGO treatment also triggered intracellular advanced glycation end products (AGEs) formation, declined mitochondrial membrane potential (MMP), increased oxidative stress and the expression of ER stress mediators Grp78/Bip and p-PERK; activated mitochondrial apoptotic pathway, which could mimic by Glo1 knockdown. Aminoguanidine (AG), a MGO scavenger, however, prevented AGEs formation and MGO-induced cell death by inhibiting oxidative stress and ER stress. Furthermore, both antioxidant N-acetylcysteine (NAC) and ER stress inhibitor 4-phenylbutyrate (4-PBA) could attenuate MGO-induced cell death through ameliorating ER stress. MGO treatment down-regulated Ire1α, a key ER stress mediator, increased JNK phosphorylation and activated mitochondrial apoptosis; down-regulated Bcl-2 expression which could be attenuated by the JNK inhibitor SP600125 and further inhibited cytochrome c leakage from mitochondria and blocked the conversion of pro caspase 3 into cleaved caspase 3, all these might contribute to the inhibition of INS-1 cell apoptosis. Ire1α down-regulation by Ire1α siRNAs mimicked MGO-induced cytotoxicity by activating the JNK phosphorylation and mitochondrial apoptotic pathway. In summary, we demonstrated that increased intracellular MGO induced cytotoxicity in INS-1 cells primarily by activating oxidative stress and further triggering mitochondrial apoptotic pathway, and ER stress-mediated Ire1α-JNK pathway. These findings may have implication on new mechanism of glucotoxicity-mediated pancreatic beta-cell dysfunction.}, }
@article {pmid28487945, year = {2017}, author = {Yao, M and Gao, F and Wang, X and Shi, Y and Liu, S and Duan, H}, title = {Nox4 is involved in high glucose-induced apoptosis in renal tubular epithelial cells via Notch pathway.}, journal = {Molecular medicine reports}, volume = {15}, number = {6}, pages = {4319-4325}, doi = {10.3892/mmr.2017.6516}, pmid = {28487945}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Amyloid Precursor Protein Secretases/metabolism ; Annexin A5/metabolism ; Apoptosis/drug effects/*physiology ; Apoptosis Regulatory Proteins/metabolism ; Caspase 3/metabolism ; Cell Line ; Down-Regulation/drug effects ; Epithelial Cells/drug effects/*metabolism ; Fluoresceins/pharmacology ; Glucose/*metabolism ; Humans ; Kidney Tubules/drug effects/*metabolism ; NADPH Oxidase 4/*metabolism ; NADPH Oxidases/metabolism ; Onium Compounds/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Notch/drug effects/*metabolism ; Signal Transduction/physiology ; Up-Regulation/drug effects ; bcl-2-Associated X Protein/metabolism ; rac1 GTP-Binding Protein ; }, abstract = {It has previously been demonstrated that nicotinamide adenine dinucleotide phosphate‑oxidase (NADPH) oxidase 4 (Nox4), is important in the pathogenesis of diabetic nephropathy (DN), however the exact mechanisms remain to be elucidated. The present study aimed to examine the effect of Nox4 on the alteration of the Notch pathway and cell apoptosis in the renal tubular epithelial cell line, HKC, under conditions of high glucose (HG; 30 mmol/l glucose). Nox4 and the Notch pathway were inhibited by N‑acetylcysteine (NAC), diphenylene iodonium (DPI) or γ‑secretase inhibitor (DAPT). The protein levels of Nox4, Notch1, Notch intracellular domain 1 (NICD1), phosphorylated (p) Ras‑related C3 botulinum toxin substrate 1 (Rac1), Rac1, B‑cell lymphoma 2 apoptosis regulator (Bcl‑2), Bcl‑2 associated protein X apoptosis regulator (Bax) and cleaved caspase‑3 were determined by western blotting. The Nox4 and Notch1 mRNA levels were detected by reverse transcription‑quantitative polymerase chain reaction. Intracellular reactive oxygen species (ROS) levels were detected via chloromethyl‑2',7'‑dichlorodihydrofluorescein diacetate. Apoptotic cells were determined using an Annexin V/propidium iodide apoptosis detection kit. HG upregulated Nox4, Notch1, NICD1, p‑Rac1, Bax and cleaved caspase‑3 expression levels and downregulated Bcl‑2 expression in cultured HKC cells, compared with cells cultured in normal glucose levels. Inhibition of the Notch pathway via DAPT increased Bcl‑2 expression, decreased Bax and cleaved caspase‑3 levels and prevented HKC cell apoptosis. Inhibition of Nox4 by NAC and DPI inhibited the Notch signaling pathway and ROS generation, which prevented HKC cell apoptosis. These findings indicated that Nox4 potentially mediates HG‑induced HKC cell apoptosis via the Notch pathway, and may be involved in renal tubular epithelial cell injury in DN.}, }
@article {pmid28487634, year = {2017}, author = {SanMartín, CD and Veloso, P and Adasme, T and Lobos, P and Bruna, B and Galaz, J and García, A and Hartel, S and Hidalgo, C and Paula-Lima, AC}, title = {RyR2-Mediated Ca[2+] Release and Mitochondrial ROS Generation Partake in the Synaptic Dysfunction Caused by Amyloid β Peptide Oligomers.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {115}, pmid = {28487634}, issn = {1662-5099}, abstract = {Amyloid β peptide oligomers (AβOs), toxic aggregates with pivotal roles in Alzheimer's disease, trigger persistent and low magnitude Ca[2+] signals in neurons. We reported previously that these Ca[2+] signals, which arise from Ca[2+] entry and subsequent amplification by Ca[2+] release through ryanodine receptor (RyR) channels, promote mitochondrial network fragmentation and reduce RyR2 expression. Here, we examined if AβOs, by inducing redox sensitive RyR-mediated Ca[2+] release, stimulate mitochondrial Ca[2+]-uptake, ROS generation and mitochondrial fragmentation, and also investigated the effects of the antioxidant N-acetyl cysteine (NAC) and the mitochondrial antioxidant EUK-134 on AβOs-induced mitochondrial dysfunction. In addition, we studied the contribution of the RyR2 isoform to AβOs-induced Ca[2+] release, mitochondrial Ca[2+] uptake and fragmentation. We show here that inhibition of NADPH oxidase type-2 prevented the emergence of RyR-mediated cytoplasmic Ca[2+] signals induced by AβOs in primary hippocampal neurons. Treatment with AβOs promoted mitochondrial Ca[2+] uptake and increased mitochondrial superoxide and hydrogen peroxide levels; ryanodine, at concentrations that suppress RyR activity, prevented these responses. The antioxidants NAC and EUK-134 impeded the mitochondrial ROS increase induced by AβOs. Additionally, EUK-134 prevented the mitochondrial fragmentation induced by AβOs, as previously reported for NAC and ryanodine. These findings show that both antioxidants, NAC and EUK-134, prevented the Ca[2+]-mediated noxious effects of AβOs on mitochondrial function. Our results also indicate that Ca[2+] release mediated by the RyR2 isoform causes the deleterious effects of AβOs on mitochondrial function. Knockdown of RyR2 with antisense oligonucleotides reduced by about 50% RyR2 mRNA and protein levels in primary hippocampal neurons, decreased by 40% Ca[2+] release induced by the RyR agonist 4-chloro-m-cresol, and significantly reduced the cytoplasmic and mitochondrial Ca[2+] signals and the mitochondrial fragmentation induced by AβOs. Based on our results, we propose that AβOs-induced Ca[2+] entry and ROS generation jointly stimulate RyR2 activity, causing mitochondrial Ca[2+] overload and fragmentation in a feed forward injurious cycle. The present novel findings highlight the specific participation of RyR2-mediated Ca[2+] release on AβOs-induced mitochondrial malfunction.}, }
@article {pmid28487393, year = {2017}, author = {Martinez de Lizarrondo, S and Gakuba, C and Herbig, BA and Repessé, Y and Ali, C and Denis, CV and Lenting, PJ and Touzé, E and Diamond, SL and Vivien, D and Gauberti, M}, title = {Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi.}, journal = {Circulation}, volume = {136}, number = {7}, pages = {646-660}, pmid = {28487393}, issn = {1524-4539}, support = {R01 HL056621/HL/NHLBI NIH HHS/United States ; R01 HL103419/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Blood Platelets/cytology/metabolism ; Chlorides/toxicity ; Disease Models, Animal ; Ferric Compounds/toxicity ; Fibrinolytic Agents/pharmacology/*therapeutic use ; Infarction, Middle Cerebral Artery/*drug therapy/etiology ; Male ; Mice ; Platelet Aggregation/drug effects ; Ristocetin/pharmacology ; Thromboembolism/chemically induced/*drug therapy ; Thrombosis/prevention &amp; control ; Tissue Plasminogen Activator/therapeutic use ; von Willebrand Factor/chemistry/metabolism ; }, abstract = {BACKGROUND: Platelet cross-linking during arterial thrombosis involves von Willebrand Factor (VWF) multimers. Therefore, proteolysis of VWF appears promising to disaggregate platelet-rich thrombi and restore vessel patency in acute thrombotic disorders such as ischemic stroke, acute coronary syndrome, or acute limb ischemia. N-Acetylcysteine (NAC, a clinically approved mucolytic drug) can reduce intrachain disulfide bonds in large polymeric proteins. In the present study, we postulated that NAC might cleave the VWF multimers inside occlusive thrombi, thereby leading to their dissolution and arterial recanalization.<br><br>METHODS: Experimental models of thrombotic stroke induced by either intra-arterial thrombin injection or ferric chloride application followed by measurement of cerebral blood flow using a combination of laser Doppler flowmetry and MRI were performed to uncover the effects of NAC on arterial thrombi. To investigate the effect of NAC on larger vessels, we also performed ferric chloride-induced carotid artery thrombosis. In vitro experiments were performed to study the molecular bases of NAC thrombolytic effect, including platelet aggregometry, platelet-rich thrombi lysis assays, thromboelastography (ROTEM), and high-shear VWF string formation using microfluidic devices. We also investigated the putative prohemorrhagic effect of NAC in a mouse model of intracranial hemorrhage induced by in situ collagenase type VII injection.<br><br>RESULTS: We demonstrated that intravenous NAC administration promotes lysis of arterial thrombi that are resistant to conventional approaches such as recombinant tissue-type plasminogen activator, direct thrombin inhibitors, and antiplatelet treatments. Through in vitro and in vivo experiments, we provide evidence that the molecular target underlying the thrombolytic effects of NAC is principally the VWF that cross-link platelets in arterial thrombi. Coadministration of NAC and a nonpeptidic GpIIb/IIIa inhibitor further improved its thrombolytic efficacy, essentially by accelerating thrombus dissolution and preventing rethrombosis. Thus, in a new large-vessel thromboembolic stroke model in mice, this cotreatment significantly improved ischemic lesion size and neurological outcome. It is important to note that NAC did not worsen hemorrhagic stroke outcome, suggesting that it exerts thrombolytic effects without significantly impairing normal hemostasis.<br><br>CONCLUSIONS: We provide evidence that NAC is an effective and safe alternative to currently available antithrombotic agents to restore vessel patency after arterial occlusion.}, }
@article {pmid28487354, year = {2017}, author = {Giacoppo, D and Gargiulo, G and Buccheri, S and Aruta, P and Byrne, RA and Cassese, S and Dangas, G and Kastrati, A and Mehran, R and Tamburino, C and Capodanno, D}, title = {Preventive Strategies for Contrast-Induced Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Procedures: Evidence From a Hierarchical Bayesian Network Meta-Analysis of 124 Trials and 28 240 Patients.}, journal = {Circulation. Cardiovascular interventions}, volume = {10}, number = {5}, pages = {}, doi = {10.1161/CIRCINTERVENTIONS.116.004383}, pmid = {28487354}, issn = {1941-7632}, mesh = {Acute Kidney Injury/chemically induced/diagnosis/*prevention &amp; control ; Bayes Theorem ; Cardiac Catheterization/*adverse effects ; Contrast Media/administration &amp; dosage/*adverse effects ; Coronary Angiography/*adverse effects ; *Fluid Therapy/adverse effects ; Humans ; Markov Chains ; Monte Carlo Method ; Odds Ratio ; Percutaneous Coronary Intervention/*adverse effects ; Protective Agents/adverse effects/*therapeutic use ; Protective Factors ; Radiography, Interventional/*adverse effects ; Randomized Controlled Trials as Topic ; Risk Assessment ; Risk Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: The effectiveness of currently available effective preventive strategies for contrast-induced acute kidney injury (CIAKI) is a matter of debate.<br><br>METHODS AND RESULTS: We performed a Bayesian random-effects network meta-analysis of 124 trials (28&#x2009;240 patients) comparing a total of 10 strategies: saline, statin, N-acetylcysteine (NAC), sodium bicarbonate (NaHCO3), NAC+NaHCO3, ascorbic acid, xanthine, dopaminergic agent, peripheral ischemic preconditioning, and natriuretic peptide. Compared with saline, the risk of CIAKI was reduced by using statin (odds ratio [OR], 0.42; 95% credible interval [CrI], 0.26-0.67), xanthine (OR, 0.32; 95% CrI, 0.17-0.57), ischemic preconditioning (OR, 0.48; 95% CrI, 0.26-0.87), NAC+NaHCO3 (OR, 0.50; 95% CrI, 0.33-0.76), NAC (OR, 0.68; 95% CrI, 0.55-0.84), and NaHCO3 (OR, 0.66; 95% CrI, 0.47-0.90). The benefit of statin therapy was consistent across multiple sensitivity analyses, whereas the efficacy of all the other strategies was questioned by restricting the analysis to high-quality trials. Overall, high heterogeneity was observed for comparisons involving xanthine and ischemic preconditioning, although the impact of NAC and xanthine was probably influenced by publication bias/small-study effect. Hydration alone was the least effective preventive strategy for CIAKI. Meta-regressions did not reveal significant associations with baseline creatinine and contrast volume. In patients with diabetes mellitus, no strategy was found to reduce the incidence of CIAKI.<br><br>CONCLUSIONS: In patients undergoing percutaneous coronary procedures, statin administration is associated with a marked and consistent reduction in the risk of CIAKI compared with saline. Although xanthine, NAC, NaHCO3, NAC+NaHCO3, ischemic preconditioning, and natriuretic peptide may have nephroprotective effects, these results were not consistent across multiple sensitivity analyses.}, }
@article {pmid28485782, year = {2017}, author = {Yao, H and Cai, ZY and Sheng, ZX}, title = {NAC attenuates adriamycin-induced nephrotic syndrome in rats through regulating TLR4 signaling pathway.}, journal = {European review for medical and pharmacological sciences}, volume = {21}, number = {8}, pages = {1938-1943}, pmid = {28485782}, issn = {2284-0729}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cytokines/analysis ; Doxorubicin/*toxicity ; Male ; NF-kappa B/analysis ; Nephrotic Syndrome/chemically induced/*drug therapy/immunology ; Proteinuria/drug therapy ; Rats ; Rats, Wistar ; Signal Transduction/*drug effects ; Toll-Like Receptor 4/*physiology ; }, abstract = {OBJECTIVE: Nephrotic syndrome (NS) is a detrimental renal disease that affects a large population. It is suggested that Toll-like Receptor 4 (TLR4) signaling pathway plays an important role in NS. The aim of this study was to evaluate the immunosuppressive effect of N-acetylcysteine (NAC) in the treatment of NS elucidate its interaction with TLR4 pathway in a rat model.<br><br>MATERIALS AND METHODS: Rat NS model was constructed using the Bertain method by injecting adriamycin (4.5 mg/kg) intravenously at day 1, and injecting 2 mg/kg adriamycin (ADR) at day 7. NS rats were treatment with NAC of 150 mg/kg daily through gavage. Control rats received equivalent amounts of saline daily. Quantitative Real-time PCR was used to evaluate TLR4 expression in kidney tissues after treatments. Western blot analysis was used to evaluate NF-&#x3ba;Bp65 expression. ELISA was used to evaluate the expression of immunological factors, including TNF-&#x3b1;, IL-6, and IL-1&#x3b2;.<br><br>RESULTS: Rat NS models demonstrated higher protein levels in urine, accompanied by an increased in the TLR4 level. After NAC treatment, TLR4 level was reduced. NAC treatment also attenuated the NF-&#x3ba;Bp65 overexpression in NS rats. Concomitantly, TNF-&#x3b1;, IL-6, and IL-1&#x3b2; levels, which are indicators of immunological and informatory responses, were also decreased after NAC treatment.<br><br>CONCLUSIONS: NAC treatment ameliorated nephrotic syndrome in NS rat models by suppressing TLR4 signaling, as well as immunological and inflammatory responses.}, }
@article {pmid28482716, year = {2017}, author = {Zhou, DZ and Sun, HY and Yue, JQ and Peng, Y and Chen, YM and Zhong, ZJ}, title = {Dihydromyricetin induces apoptosis and cytoprotective autophagy through ROS-NF-κB signalling in human melanoma cells.}, journal = {Free radical research}, volume = {51}, number = {5}, pages = {517-528}, doi = {10.1080/10715762.2017.1328552}, pmid = {28482716}, issn = {1029-2470}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Autophagy ; Cell Line, Tumor ; Cytoprotection ; Drug Screening Assays, Antitumor ; Flavonols/*pharmacology ; Humans ; Melanoma/*drug therapy ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Skin Neoplasms/*drug therapy ; }, abstract = {Dihydromyricetin (DHM), a Rattan tea extract, has recently been shown to have anti-cancer activity in mammalian cells. In this study, we investigated the effect of DHM on human melanoma cells. Apart from induction of apoptosis, we demonstrated that DHM induced an autophagic response. Moreover, pharmacological inhibition or genetic blockade of autophagy enhanced DHM-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in DHM-treated human melanoma cells. Further study suggested that the nuclear factor kappa B (NF-κB) signalling pathway was involved in DHM-induced autophagy. Moreover, N-acetyl-cysteine (NAC), an ROS scavenger, abrogated the effects of DHM on NF-κB-dependent autophagy. Taken together, this evidence demonstrates that a strategy of blocking ROS-NF-κB-dependent autophagy to enhance the activity of DHM warrants further attention for the treatment of human melanoma.}, }
@article {pmid28475371, year = {2018}, author = {Kiyekbayeva, L and Mohamed, NM and Yerkebulan, O and Mohamed, EI and Ubaidilla, D and Nursulu, A and Assem, M and Srivedavyasasri, R and Ross, SA}, title = {Phytochemical constituents and antioxidant activity of Echinops albicaulis.}, journal = {Natural product research}, volume = {32}, number = {10}, pages = {1203-1207}, doi = {10.1080/14786419.2017.1323213}, pmid = {28475371}, issn = {1478-6427}, mesh = {Alkaloids/analysis ; Antioxidants/chemistry/isolation &amp; purification/*pharmacology ; Antiprotozoal Agents/chemistry/*pharmacology ; Apigenin/analysis ; Drug Evaluation, Preclinical/methods ; Echinops Plant/*chemistry ; Flavonoids/analysis/chemistry/isolation &amp; purification ; Humans ; Leukocytes, Mononuclear/drug effects/metabolism ; Molecular Structure ; Phytochemicals/*analysis/chemistry ; Plant Extracts/chemistry ; Reactive Oxygen Species/metabolism ; Sitosterols/analysis ; Thiophenes/chemistry/isolation &amp; purification ; Trypanosoma brucei brucei/drug effects ; }, abstract = {Two thiophenes; 5-(3-buten-1-ynyl)-2,2'-bithiophene (2) and α-tertthienyl (9), two alkaloids; echinopsine (10) and echinorine (11), three flavonoids; genkwanin (5), apigenin (6), and rutin (7), two triterpenoids; lupeol acetate (1) and lupeol linoleate (4), together with 2,6,10-trimethyldodeca-2,6,10-triene (4) and β-sitosterol glucoside (8) were isolated from the aerial parts of Echinops albicaulis. Antioxidant, antimicrobial and antiprotozoal activities were evaluated. E. albicaulis aqueous methanolic extract (50, 10, and 1 mg/mL) showed significant antioxidant activity comparable to the potent antioxidant, N-acetyl cysteine, moreover, the aqueous methanolic extract (1 mg/mL) significantly reduced intracellular reactive oxygen species in active cell cultures of human peripheral blood mononuclear cells under oxidative stress more than the reference antioxidant N-acetyl cysteine. None of the isolated compounds showed antimicrobial or antiprotozoal activities at concentration up to 20 μg/mL.}, }
@article {pmid28468627, year = {2017}, author = {Yin, Y and Sui, C and Meng, F and Ma, P and Jiang, Y}, title = {The omega-3 polyunsaturated fatty acid docosahexaenoic acid inhibits proliferation and progression of non-small cell lung cancer cells through the reactive oxygen species-mediated inactivation of the PI3K /Akt pathway.}, journal = {Lipids in health and disease}, volume = {16}, number = {1}, pages = {87}, pmid = {28468627}, issn = {1476-511X}, mesh = {A549 Cells ; Adaptor Proteins, Signal Transducing/antagonists &amp; inhibitors/genetics/metabolism ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Caspase 3/genetics/metabolism ; Catalase/antagonists &amp; inhibitors/genetics/metabolism ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Docosahexaenoic Acids/*pharmacology ; *Gene Expression Regulation, Neoplastic ; Humans ; Inhibitor of Apoptosis Proteins/genetics/metabolism ; Matrix Metalloproteinase 9/genetics/metabolism ; Phosphatidylinositol 3-Kinases/*genetics/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphoproteins/antagonists &amp; inhibitors/genetics/metabolism ; Phosphorylation/drug effects ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/*agonists/metabolism ; Signal Transduction ; Survivin ; Vascular Endothelial Growth Factor A/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {BACKGROUND: Docosahexaenoic acid(DHA) inhibits tumor growth and progression in various cancers, including lung cancer. However, the mechanisms involved remain unclear. The aim of this study was to identify the mechanism of DHA in inhibiting progression of non-small cell lung cancer (NSCLC) in vitro.<br><br>METHODS: The proliferation of A549 was tested by MTT, and cell apoptosis was analysed using flow cytometer. The migration and invasion were examined respectively by wound healing assay and Transwell invasion assay. The level of ROS (reactive oxygen species, ROS) was checked by DCF (dichlorodihydrofluorescein, DCF) production in cells. The apoptosis associated protein (caspase-3, PARP,Bax,Bcl-2 and survivin) and metastases associated proteins including HEF1, MMP9 and VEGF were detected by Western blot, and the same method was used in the expression of PI3K and Akt.<br><br>RESULTS: DHA inhibited proliferation and induced apoptosis of A549 cells. Moreover, it suppressed the invasion and metastasis of A549 cells, while downregulating the levels of metastasis-associated proteins, including HEF1, matrix metallopeptidase (MMP9), and vascular endothelial growth factor (VEGF), in a dose -dependent manner. In addition, DHA inactivated Akt phosphorylation. All of these responses were associated with the accumulation of intracellular ROS. DHA downregulated the level of antioxidant enzymes such as catalase, while the antioxidant N-acetyl-cysteine (NAC) reversed the effect of DHA, which further validated our findings.<br><br>CONCLUSIONS: The present study demonstrates that DHA inhibits the development of non-small lung tumors through an ROS-mediated inactivation of the PI3K/Akt signaling pathway.}, }
@article {pmid28467758, year = {2017}, author = {Khatib, N and Weiner, Z and Ginsberg, Y and Awad, N and Beloosesky, R}, title = {Protective Effect of N-Acetyl-Cysteine (NAC) in Lipopolysaccharide (LPS)-Associated Inflammatory Response in Rat Neonates.}, journal = {Rambam Maimonides medical journal}, volume = {8}, number = {2}, pages = {}, pmid = {28467758}, issn = {2076-9172}, abstract = {OBJECTIVE: Increased inflammatory response may be associated with adverse clinical outcomes, especially in the neonatal period. The aims of this study were to determine whether N-acetyl-cysteine (NAC), an anti-inflammatory agent, attenuates the inflammatory response in young rats and to determine the most effective route of administration.<br><br>METHODS: Four groups of Sprague-Dawley rats (in each group four rats) were studied at 30 days of age. One hour following intraperitoneal (IP) injection of lipopolysaccharide 50 &#x3bc;g/kg, the rats were randomized to subcutaneous (SC), per os (PO), or intraperitoneal (IP) injection of NAC 300 mg/kg, or saline. The control group received saline injection (IP). Three hours following the N-acetyl-cysteine injection the rats were sacrificed, then serum tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) and IL-6 levels were determined by ELISA.<br><br>RESULTS: Lipopolysaccharide significantly increased the neonatal serum IL-6 and TNF-&#x3b1; (2051.0&#xb1;349 and 147.0&#xb1;25.8 pg/mL, respectively; P<0.01) levels compared to 10 pg/mL in the controls. N-acetyl-cysteine administered one hour following lipopolysaccharide injection significantly attenuated the inflammatory response. Intraperitoneal administration of NAC decreased IL-6 and TNF-&#x3b1; concentration to 294.6 and 17.1 pg/mL, respectively, and was more effective than SC or PO administration.<br><br>CONCLUSIONS: N-acetyl-cysteine attenuated the inflammatory response in the neonatal rats, and IP was the most effective administration route.}, }
@article {pmid28467607, year = {2018}, author = {Yin, S and Miao, X and Zhang, X and Chen, X and Wen, H}, title = {Environmental temperature affects physiology and survival of nanosecond pulsed electric field-treated cells.}, journal = {Journal of cellular physiology}, volume = {233}, number = {2}, pages = {1179-1190}, doi = {10.1002/jcp.25984}, pmid = {28467607}, issn = {1097-4652}, mesh = {Ablation Techniques/*methods ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Separation/methods ; Cell Survival/drug effects ; Centrifugation ; Electric Stimulation/*methods ; Flow Cytometry ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/metabolism/pathology ; Neoplasms/metabolism/pathology/*therapy ; Reactive Oxygen Species/metabolism ; Sucrose/pharmacology ; *Temperature ; Time Factors ; }, abstract = {Nanosecond pulsed electric field (nsPEF) is a novel non-thermal tumor ablation technique. However, how nsPEF affect cell physiology at different environmental temperature is still kept unknown. But this issue is of critical clinical practice relevance. This work aim to investigate how nsPEF treated cancer cells react to different environmental temperatures (0, 4, 25, and 37°C). Their cell viability, apoptosis, mitochondrial membrane potential, and reactive oxygen species (ROS) were examined. Lower temperature resulted in higher apoptosis rate, decreased mitochondria membrane potential, and increased ROS levels. Sucrose and N-acetylcysteine (NAC) pre-incubation inhibit ROS generation and increase cell survival, protecting nsPEF-treated cells from low temperature-caused cell death. This work provides an experimental basis for hypothermia and fluid transfusion during nsPEF ablation with anesthesia.}, }
@article {pmid28467574, year = {2017}, author = {Atayoğlu, K and Gürleyik, G and Demirel, G and Özkara, S}, title = {Effect of N-acetylcysteine on neutrophil functions during experimental acute pancreatitis.}, journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma &amp; emergency surgery : TJTES}, volume = {23}, number = {2}, pages = {100-106}, doi = {10.5505/tjtes.2016.59844}, pmid = {28467574}, issn = {1307-7945}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Animals ; *Neutrophils/drug effects/metabolism ; Pancreatitis/*metabolism ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Systemic inflammatory responses and extrapancreatic vital organ impairment are mediated by activated neutrophil functions and products, such as oxygen-derived free radicals, in patients with acute pancreatitis (AP). The present study is an examination of effects of an antioxidant, N-acetylcysteine (NAC), on local and systemic histopathological changes and neutrophil functions during AP.<br><br>METHODS: This experimental study was performed on 24 Wistar albino rats equally divided into 3 groups: Group 1 comprised sham laparotomy, Group 2 had AP induced with taurocholate infusion, and Group 3 consisted of AP with NAC treatment. Histopathological features in pancreas, kidney, and lung tissues were examined for local and systemic changes during AP. Neutrophil functions were evaluated using flow cytometry.<br><br>RESULTS: Serum levels of pancreatic enzymes were elevated, and histopathological parameters showed acinar cell damage and pancreatic tissue necrosis in the 2 groups with AP. Severe histopathological changes were found in pulmonary and renal tissues, and flow cytometry results indicated defective neutrophil functions in the group with AP alone. NAC treatment significantly ameliorated phagocytosis, chemotaxis, and opsonization of neutrophils (p<0.05). NAC treatment also ameliorated systemic changes in pulmonary and renal tissue damage in all microscopic parameters (p<0.05).<br><br>CONCLUSION: Uncontrolled and defective neutrophil functions could provoke severe systemic inflammatory responses. In addition to local inflammation and necrosis, severe systemic responses and histopathological changes in extrapancreatic vital organs occur during AP. Treatment with antioxidant NAC significantly reverses detrimental systemic responses in extrapancreatic vital organs by significantly ameliorating neutrophil functions despite ongoing AP.}, }
@article {pmid28465675, year = {2017}, author = {McLeay, Y and Stannard, S and Houltham, S and Starck, C}, title = {Dietary thiols in exercise: oxidative stress defence, exercise performance, and adaptation.}, journal = {Journal of the International Society of Sports Nutrition}, volume = {14}, number = {}, pages = {12}, pmid = {28465675}, issn = {1550-2783}, mesh = {Adaptation, Physiological/*drug effects ; Antioxidants/administration &amp; dosage/metabolism ; Athletes ; *Athletic Performance ; *Diet ; Exercise/*physiology ; Humans ; *Oxidative Stress ; Performance-Enhancing Substances/administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/*administration &amp; dosage ; }, abstract = {Endurance athletes are susceptible to cellular damage initiated by excessive levels of aerobic exercise-produced reactive oxygen species (ROS). Whilst ROS can contribute to the onset of fatigue, there is increasing evidence that they play a crucial role in exercise adaptations. The use of antioxidant supplements such as vitamin C and E in athletes is common; however, their ability to enhance performance and facilitate recovery is controversial, with many studies suggesting a blunting of training adaptations with supplementation. The up-regulation of endogenous antioxidant systems brought about by exercise training allows for greater tolerance to subsequent ROS, thus, athletes may benefit from increasing these systems through dietary thiol donors. Recent work has shown supplementation with a cysteine donor (N-acetylcysteine; NAC) improves antioxidant capacity by augmenting glutathione levels and reducing markers of oxidative stress, as well as ergogenic potential through association with delayed fatigue in numerous experimental models. However, the use of this, and other thiol donors may have adverse physiological effects. A recent discovery for the use of a thiol donor food source, keratin, to potentially enhance endogenous antioxidants may have important implications for endurance athletes hoping to enhance performance and recovery without blunting training adaptations.}, }
@article {pmid28465088, year = {2017}, author = {Ding, H and Wang, X and Wang, H and Zhu, L and Wang, Q and Jia, Y and Wei, W and Zhou, C and Wu, H and Ding, K}, title = {Nrf2-ARE signaling provides neuroprotection in traumatic brain injury via modulation of the ubiquitin proteasome system.}, journal = {Neurochemistry international}, volume = {111}, number = {}, pages = {32-44}, doi = {10.1016/j.neuint.2017.04.016}, pmid = {28465088}, issn = {1872-9754}, mesh = {Animals ; Antioxidant Response Elements/*physiology ; Apoptosis/drug effects ; Brain/metabolism ; Brain Injuries, Traumatic/drug therapy/*metabolism ; Male ; Mice ; Mice, Knockout ; NF-E2-Related Factor 2/genetics/*metabolism ; Neuroprotection/physiology ; Oxidative Stress/drug effects ; Ubiquitin/*metabolism ; }, abstract = {The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway exhibits protective effects in a variety of neurological diseases. However, the role of this pathway in traumatic brain injury (TBI) is not fully understood. This study investigates whether the Nrf2-ARE pathway provides neuroprotection following TBI via regulation of the ubiquitin proteasome system (UPS), and examines the involvement of this pathway in redox homeostasis. We found that activation the Nrf2-ARE pathway can mitigate secondary brain injury induced by TBI. Furthermore, we found that inhibiting the Nrf2-ARE pathway weakened the UPS following TBI. Treatment of TBI with the proteasome inhibitor, MG132, increased neuronal apoptosis, and evidence of brain water content was found. These data suggest that the Nrf2-ARE pathway provides neuroprotection following TBI via modulation of the UPS. In addition, the results indicated that the content of glutathione (GSH) was significantly increased after activation of Nrf2, and the level of ROS decreased; however, this effect contradictory in the Nrf2 knockout mice. Further studies found that treatment with the ROS agonist, ferric ammonium citrate (FAC), resulted in additional damage exerted by the ubiquitin proteasome pathways, and a significant increase in the amount of ubiquitinated proteins. In contrast, the activity of the ubiquitin proteasome pathways was vastly enhanced, and the level of ubiquitination proteins was significantly decreased following treatment with the inhibitor, N-acetylcysteine (NAC). The above mentioned results were also verified in in vitro experiments. In conclusion, the activation the Nrf2-ARE pathway improves neurological impairment caused by TBI via modulation of the UPS, and the redox homeostasis is one of the vital regulatory mechanisms.}, }
@article {pmid28459216, year = {2017}, author = {Sinha, N and Panda, PK and Naik, PP and Maiti, TK and Bhutia, SK}, title = {Abrus agglutinin targets cancer stem-like cells by eliminating self-renewal capacity accompanied with apoptosis in oral squamous cell carcinoma.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {39}, number = {5}, pages = {1010428317701634}, doi = {10.1177/1010428317701634}, pmid = {28459216}, issn = {1423-0380}, mesh = {Animals ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*drug therapy/genetics/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Self Renewal/*drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Glycogen Synthase Kinase 3 beta/antagonists &amp; inhibitors/genetics ; Humans ; Hyaluronan Receptors/genetics ; Lithium Chloride/administration &amp; dosage ; Mice ; Mouth Neoplasms/*drug therapy/genetics/pathology ; Neoplastic Stem Cells/drug effects ; Plant Lectins/*administration &amp; dosage/chemistry ; Reactive Oxygen Species/metabolism ; Wnt Signaling Pathway/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {The accumulating evidences show that Abrus agglutinin, a plant lectin, displays a broad range of anticancer activity including cancer-specific induction of apoptosis; however, the underlying molecular mechanism of Abrus agglutinin-induced oral cancer stem cell elimination remains elusive. Our data documented that Abrus agglutinin effectively downregulated the CD44[+] expression with the increased CD44[-] population in different oral cancer cells. After 24-h Abrus agglutinin treatment, FaDu cells were quantified for orosphere formation in ultra-low attachment plates and data showed that Abrus agglutinin inhibited the number and size of orosphere in a dose-dependent manner in FaDu cells. Furthermore, Abrus agglutinin hindered the plasticity of FaDu orospheres as supported by reduced sphere formation and downregulated the self-renewal property via inhibition of Wnt-β-catenin signaling pathway. Introduction of LiCl, a glycogen synthase kinase 3β inhibitor, rescued the Abrus agglutinin-stimulated inhibition of β-catenin and phosphorylated glycogen synthase kinase 3β in FaDu cell-derived orospheres confirming importance of Wnt signaling in Abrus agglutinin-mediated inhibition of stemness. In this connection, our data showed that Abrus agglutinin restrained proliferation and induced apoptosis in FaDu-derived cancer stem cells in dose-dependent manner. Moreover, western blot data demonstrated that Abrus agglutinin increased the Bax/Bcl-2 ratio with activation of poly(adenosine diphosphate-ribose) polymerase and caspase-3 favoring apoptosis induction in orospheres. Abrus agglutinin induced reactive oxygen species accumulation in orospheres and pretreatment of N-acetyl cysteine, and a reactive oxygen species scavenger inhibited Abrus agglutinin-mediated caspase-3 activity and β-catenin expression indicating reactive oxygen species as a principal regulator of Wnt signaling and apoptosis. In conclusion, Abrus agglutinin has a potential role as an integrative therapeutic approach for combating oral cancer through targeting self-renewability of orospheres via reactive oxygen species-mediated apoptosis.}, }
@article {pmid28455747, year = {2017}, author = {Wang, LP and Fan, SJ and Li, SM and Wang, XJ and Gao, JL and Yang, XH}, title = {Oxidative stress promotes myocardial fibrosis by upregulating KCa3.1 channel expression in AGT-REN double transgenic hypertensive mice.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {469}, number = {9}, pages = {1061-1071}, pmid = {28455747}, issn = {1432-2013}, support = {H2015209153//Natural Science Foundation of Hebei Province/International ; 81600316//National Natural Science Foundation of China/International ; 81372029//National Natural Science Foundation of China/International ; }, mesh = {Angiotensinogen/*metabolism ; Animals ; Cell Cycle Proteins ; Disease Models, Animal ; Female ; Fibrosis/*metabolism/pathology ; Humans ; Hypertension/*metabolism/pathology ; Intermediate-Conductance Calcium-Activated Potassium Channels/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic/*metabolism ; Myocardium/*metabolism/pathology ; Nerve Tissue Proteins/*metabolism ; Oxidative Stress/*physiology ; Transferases ; Up-Regulation/physiology ; }, abstract = {The intermediate-conductance Ca[2+]-activated K[+] (KCa3.1) channels play a pivotal role in the cardiac fibroblast proliferation and inflammatory reaction during the progression of myocardial fibrosis. However, the relationship between KCa3.1 expression and oxidative stress, the important factor of promoting fibrosis, has not been clearly established. This study was designed to investigate whether the role of oxidative stress in promoting myocardial fibrosis is related to KCa3.1 channel by using biochemical approaches. It was found that mean blood pressure, plasma Ang II level, and myocardium malondialdehyde (MDA) content of angiotensinogen-renin (AGT-REN) double transgenic hypertension (dTH) mice were higher than those in wild-type (WT) mice of the same age (4, 8 and 12 months) and were significantly increased with age. However, plasma Ang (1-7) level and myocardium superoxide dismutase (SOD) activity showed a downward trend and were lower than those of the same-aged WT mice (4, 8 and 12 months). In addition, protein expression of myocardium KCa3.1 channel in 4-, 8-, and 12-month-old dTH mice were significantly higher than that of the same-aged WT mice and gradually increased with age. TRAM-34, a blocker of KCa3.1 channel, and losartan mitigated the myocardial structural and functional damage by inhibiting collagen deposition and decreasing the expression of β-MHC. After intervention of ROS scavenger N-acetyl cysteine (NAC) and NADPH inhibitor apocynin (Apo) in 6-month-old dTH mice for 4 weeks, myocardial oxidative stress level was reduced and KCa3.1 channel protein expression was decreased. Meanwhile, Apo inhibited the myocardium p-ERK1/2/T-ERK protein expression in dTH mice, and after blockage of ERK1/2 pathway with PD98059, the KCa3.1 protein expression was reduced. These results demonstrate for the first time that KCa3.1 channel is likely to be a critical target on the oxidative stress for its promoting role in myocardial fibrosis, and the ERK1/2 pathway may be involved in the regulation of oxidative stress to KCa3.1.}, }
@article {pmid28455589, year = {2017}, author = {Jang, S and Bak, EJ and Cha, JH}, title = {N-acetylcysteine prevents the development of gastritis induced by Helicobacter pylori infection.}, journal = {Journal of microbiology (Seoul, Korea)}, volume = {55}, number = {5}, pages = {396-402}, pmid = {28455589}, issn = {1976-3794}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/therapeutic use ; Animals ; Asymptomatic Infections ; Bacterial Load/drug effects ; Culture Media/chemistry ; Diet ; Disease Models, Animal ; Gastritis/*microbiology/*prevention &amp; control ; Gerbillinae ; Helicobacter Infections/*drug therapy/microbiology/pathology ; Helicobacter pylori/*drug effects/growth &amp; development ; Humans ; Stomach/microbiology/pathology ; }, abstract = {Helicobacter pylori (H. pylori) is a human gastric pathogen, causing various gastric diseases ranging from gastritis to gastric adenocarcinoma. It has been reported that combining N-acetylcysteine (NAC) with conventional antibiotic therapy increases the success rate of H. pylori eradication. We evaluated the effect of NAC itself on the growth and colonization of H. pylori, and development of gastritis, using in vitro liquid culture system and in vivo animal models. H. pylori growth was evaluated in broth culture containing NAC. The H. pylori load and histopathological scores of stomachs were measured in Mongolian gerbils infected with H. pylori strain 7.13, and fed with NAC-containing diet. In liquid culture, NAC inhibited H. pylori growth in a concentration-dependent manner. In the animal model, 3-day administration of NAC after 1 week from infection reduced the H. pylori load; 6-week administration of NAC after 1 week from infection prevented the development of gastritis and reduced H. pylori colonization. However, no reduction in the bacterial load or degree of gastritis was observed with a 6-week administration of NAC following 6-week infection period. Our results indicate that NAC may exert a beneficial effect on reduction of bacterial colonization, and prevents the development of severe inflammation, in people with initial asymptomatic or mild H. pylori infection.}, }
@article {pmid28455206, year = {2017}, author = {Palazzo, C and Trapani, G and Ponchel, G and Trapani, A and Vauthier, C}, title = {Mucoadhesive properties of low molecular weight chitosan- or glycol chitosan- and corresponding thiomer-coated poly(isobutylcyanoacrylate) core-shell nanoparticles.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {117}, number = {}, pages = {315-323}, doi = {10.1016/j.ejpb.2017.04.020}, pmid = {28455206}, issn = {1873-3441}, mesh = {Animals ; Chitosan/chemistry/*metabolism ; Cyanoacrylates/chemistry/*metabolism ; Drug Carriers/chemistry/*metabolism ; Enbucrilate ; Intestinal Mucosa/*metabolism ; Jejunum/metabolism ; Male ; Molecular Weight ; Nanoparticles/chemistry/*metabolism ; Organ Culture Techniques ; Rats ; Rats, Wistar ; }, abstract = {The aim of the present work was to evaluate the mucoadhesive properties of poly(isobutyl cyanoacrylate) (PIBCA) nanoparticles (NPs) coated with Low Molecular Weight (LMW) chitosan (CS)- and glycol chitosan (GCS)-based thiomers as well as with the corresponding LMW unmodified polysaccharides. For this purpose, all the CS- and GCS-based thiomers were prepared under simple and mild conditions starting from the LMW unmodified polymers CS and GCS. The resulting NPs were of spherical shape with diameters ranging from 400 to 600nm and 187 to 309nm, for CS- and GCS-based NPs, respectively. The mucoadhesive characteristics of these core shell NPs were studied in Ussing chambers measuring the percentage of NPs stuck on the mucosal of fresh intestinal tissue after 2h of incubation. Moreover, incubation of nanoparticle formulations with the intestinal tissue induced changes in transmucosal electrical resistance which were measured to gain information into the opening of tight junctions and to control the integrity of the mucosa. Thus, it was found that PIBCA NPs coated with the GCS-Glutathione conjugate (GCGPIBCA NPs) possessed the most favorable mucoadhesive performances. Moreover, both GCGPIBCA- and GCS-N-acetyl-cysteine (GCNPIBCA)-core-shell NPs might induced an enlargement of the epithelial cell tight junctions. In conclusion, coating of PIBCA NPs with GCS-based thiomers may be useful for improving the mucoadhesive and permeation properties of these nanocarriers.}, }
@article {pmid28452187, year = {2018}, author = {Feng, Y and Huang, X and Li, L and Chen, Z}, title = {N-acetylcysteine versus ascorbic acid or N-acetylcysteine plus ascorbic acid in preventing contrast-induced nephropathy: A meta-analysis.}, journal = {Nephrology (Carlton, Vic.)}, volume = {23}, number = {6}, pages = {530-538}, doi = {10.1111/nep.13068}, pmid = {28452187}, issn = {1440-1797}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Antioxidants/adverse effects/*therapeutic use ; Ascorbic Acid/adverse effects/*therapeutic use ; Biomarkers/blood ; Chi-Square Distribution ; Contrast Media/administration &amp; dosage/*adverse effects ; Creatinine/blood ; Drug Therapy, Combination ; Humans ; Kidney Diseases/blood/chemically induced/diagnosis/*prevention &amp; control ; Odds Ratio ; Protective Factors ; Randomized Controlled Trials as Topic ; Risk Factors ; Treatment Outcome ; }, abstract = {AIM: The purpose of the present study was to evaluate the efficacy of N-acetylcysteine (NAC) versus ascorbic acid (VC) or NAC plus (+) VC on the prevention of contrast-induced nephropathy (CIN) in patients undergoing contrast administration.<br><br>METHODS: We searched databases including Medline, Embase and Cochrane Library up to Feb 22 (th), 2017. Pooled risk ratios (RRs) or weighted mean difference (WMD) with their 95% confidence intervals (CIs) were calculated using fixed-effects model or random-effects model when appropriate. All analyses were performed using the Review Manager 5.2.<br><br>RESULTS: A totalof six randomized controlled trials including 919 patients (478 cases received NAC administration and 441 cases received VC or NAC&#xa0;+&#xa0;VC administration) were considered in the meta-analysis. Results showed that there was no significant difference in preventing CIN between NAC and NAC&#xa0;+&#xa0;VC administration as well as between NAC and VC administration. In addition, significant difference was found in serum creatinine level between NAC and VC or NAC&#xa0;+&#xa0;VC administration (WMD&#xa0;=&#xa0;-0.31, 95% CI: -0.48 to -0.14, P&#xa0;=&#xa0;0.0003) as well as NAC and VC administration (WMD&#xa0;=&#xa0;-0.05, 95% CI: -0.08 to -0.02, P&#xa0;=&#xa0;0.002). Besides, NAC and NAC&#xa0;+&#xa0;VC administration also has significant difference (WMD&#xa0;=&#xa0;-0.72, 95% CI: -1.33 to -0.11, P&#xa0;=&#xa0;0.02).<br><br>CONCLUSION: In conclusion, the prevention effect of NAC administration and VC or NAC&#xa0;+&#xa0;VC administration on CIN was similar in patients undergoing contrast administration. But NAC administration was associated with a significantly lower serum creatinine levels compared to VC and NAC&#xa0;+&#xa0;VC administration.}, }
@article {pmid28451559, year = {2017}, author = {Fallahzadeh-Abarghooei, L and Samadaei-Ghadikolaie, M and Saadat, I and Saadat, M}, title = {Effect of Sodium Arsenite on the Expression of Antioxidant Genes (SOD2 and CAT) in MCF-7 and Jurkat Cell Lines.}, journal = {Iranian journal of public health}, volume = {46}, number = {2}, pages = {229-234}, pmid = {28451559}, issn = {2251-6085}, abstract = {BACKGROUND: Sodium arsenite (NaAsO2) has potent cytotoxic activity in human cancer cells. Oxidative stress has been suggested as a mechanism for arsenic-induced carcinogenesis. The purpose of the present study was to evaluate the alteration of mRNA levels of catalase (CAT) and superoxide dismutase 2 (SOD2) in MCF-7 and Jurkat cells after exposure to NaAsO2.<br><br>METHODS: Methylthiazol tetrazolium (MTT) viability assay was performed to evaluate cytotoxicity of NaAsO2 in MCF-7 and Jurkat cells. For evaluating the expression levels of the CAT and SOD2, we used two concentrations of NaAsO2 (5 and 15 &#x3bc;M), lower than the concentrations at which 50% of cell viability were lost. The cells were treated with co-treatment of NaAsO2 (15 &#x3bc;M) and N-acetyl-cysteine (NAC; 5 &#x3bc;M) in the media for 24 h. The control cells were maintained in sodium arsenite free growth medium. The experiments were done triplicate. Using quantitative real-time PCR, the expression levels of CAT and SOD2 were quantified. One sample student's t test was performed for comparisons of mRNA levels between treatment groups and their corresponding untreated control cells.<br><br>RESULTS: CAT mRNA level decreased significantly in both cell lines following exposure to NaAsO2 (P<0.05). Expression levels of SOD2 decreased in Jurkat cells and increased in MCF-7 cells after treatment with NaAsO2 (P<0.05).<br><br>CONCLUSION: After cells exposure to NaAsO2, CAT mRNA level decreased in both examined cell lines but the alterations of SOD2 mRNA level is cell specific. The NAC modulated the NaAsO2 associated alterations of CAT and SOD2 mRNA levels, therefore, the NaAsO2 might act through inducing reactive oxygen species.}, }
@article {pmid28450161, year = {2017}, author = {Chen, TC and Yu, J and Nouri Nigjeh, E and Wang, W and Myint, PT and Zandi, E and Hofman, FM and Schönthal, AH}, title = {A perillyl alcohol-conjugated analog of 3-bromopyruvate without cellular uptake dependency on monocarboxylate transporter 1 and with activity in 3-BP-resistant tumor cells.}, journal = {Cancer letters}, volume = {400}, number = {}, pages = {161-174}, doi = {10.1016/j.canlet.2017.04.015}, pmid = {28450161}, issn = {1872-7980}, mesh = {Adenosine Triphosphate/metabolism ; Alkylation ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Dose-Response Relationship, Drug ; *Drug Resistance, Neoplasm ; Glyceraldehyde-3-Phosphate Dehydrogenases ; Glycolysis/drug effects ; HCT116 Cells ; Humans ; MCF-7 Cells ; Monocarboxylic Acid Transporters/genetics/*metabolism ; Monoterpenes/*pharmacology ; Necrosis ; Neoplasms/*drug therapy/genetics/metabolism/pathology ; Pyruvates/*pharmacology ; RNA Interference ; Signal Transduction/drug effects ; Symporters/genetics/*metabolism ; Transfection ; }, abstract = {The anticancer agent 3-bromopyruvate (3-BP) is viewed as a glycolytic inhibitor that preferentially kills glycolytic cancer cells through energy depletion. However, its cytotoxic activity is dependent on cellular drug import through transmembrane monocarboxylate transporter 1 (MCT-1), which restricts its anticancer potential to MCT-1-positive tumor cells. We created and characterized an MCT-1-independent analog of 3-BP, called NEO218. NEO218 was synthesized by covalently conjugating 3-BP to perillyl alcohol (POH), a natural monoterpene. The responses of various tumor cell lines to treatment with either compound were characterized in the presence or absence of supplemental pyruvate or antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH). Drug effects on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) enzyme activity were investigated by mass spectrometric analysis. The development of 3-BP resistance was investigated in MCT-1-positive HCT116 colon carcinoma cells in vitro. Our results show that NEO218: (i) pyruvylated GAPDH on all 4 of its cysteine residues and shut down enzymatic activity; (ii) severely lowered cellular ATP content below life-sustaining levels, and (iii) triggered rapid necrosis. Intriguingly, supplemental antioxidants effectively prevented cytotoxic activity of NEO218 as well as 3-BP, but supplemental pyruvate powerfully protected cells only from 3-BP, not from NEO218. Unlike 3-BP, NEO218 exerted its potent cytotoxic activity irrespective of cellular MCT-1 status. Treatment of HCT116 cells with 3-BP resulted in prompt development of resistance, based on the emergence of MCT-1-negative cells. This was not the case with NEO218, and highly 3-BP-resistant cells remained exquisitely sensitive to NEO218. Thus, our study identifies a mechanism by which tumor cells develop rapid resistance to 3-BP, and presents NEO218 as a superior agent not subject to this cellular defense. Furthermore, our results offer alternative interpretations of previously published models on the role of supplemental antioxidants: Rather than quenching reactive oxygen species (ROS), supplemental NAC or GSH directly interact with 3-BP, thereby neutralizing the drug's cytotoxic potential before it can trigger ROS production. Altogether, our study introduces new aspects of the cytotoxic mechanism of 3-BP, and characterizes NEO218 as an analog able to overcome a key cellular defense mechanism towards this drug.}, }
@article {pmid28445976, year = {2017}, author = {Yang, H and Xie, Y and Yang, D and Ren, D}, title = {Oxidative stress-induced apoptosis in granulosa cells involves JNK, p53 and Puma.}, journal = {Oncotarget}, volume = {8}, number = {15}, pages = {25310-25322}, pmid = {28445976}, issn = {1949-2553}, mesh = {Animals ; Apoptosis/drug effects/physiology ; Apoptosis Regulatory Proteins/*metabolism ; Cell Line ; Female ; Granulosa Cells/cytology/drug effects/*metabolism ; HEK293 Cells ; Humans ; Hydrogen Peroxide/metabolism/pharmacology ; MAP Kinase Kinase 4/*metabolism ; MAP Kinase Signaling System ; Mice ; Oxidative Stress/drug effects/*physiology ; Proto-Oncogene Proteins/*metabolism ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/*metabolism ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {Reactive oxygen species (ROS) play important roles in follicular development and survival. Granulosa cell death is associated with increased ROS, but the mechanism of granulosa cell death induced by ROS is not clear. In order to define the molecular link between ROS and granulosa cell death, COV434, human granulosa tumor cells, were treated with H2O2. Compared to control cells, H2O2 induced granulosa cell death in a dose- and time-dependent manner. H2O2 induced an increase in Bax, Bak and Puma, and a decrease in anti-apoptotic molecules such as Bcl-2, Bcl-xL and Mcl-1. Both knockdown of Puma and overexpression of Bcl-xL could inhibit H2O2-induced granulosa cell death. These results suggest that suppression of Puma and overexpression of anti-apoptotic Bcl-2 family members could improve granulosa cell survival. To explore the mechanisms responsible for these findings, ROS in granulosa cells treatment with H2O2 were measured. The results showed that ROS was increased in a H2O2 dose- and time-dependent manner at the earlier time point. In addition, H2O2 induced an increase in Nrf2 and phosphorylation of JNK and p53. SP600125, an inhibitor of JNK, inhibits H2O2-induced phosphorylation of JNK and p53, and granulosa cell death. Antioxidant N-acetylcysteine (NAC) dose-dependently prevents H2O2-induced granulosa cell death. Furthermore, NAC also prevents phosphorylation of JNK and p53 induced by H2O2. Taken together, these data suggest that H2O2 regulates cell death in granulosa cells via the ROS-JNK-p53 pathway. These findings provide an improved understanding of the mechanisms underlying granulosa cell apoptosis, which could potentially be useful for future clinical applications.}, }
@article {pmid28444875, year = {2017}, author = {Jang, JH and Kim, EA and Park, HJ and Sung, EG and Song, IH and Kim, JY and Woo, CH and Doh, KO and Kim, KH and Lee, TJ}, title = {Methylglyoxal-induced apoptosis is dependent on the suppression of c-FLIPL expression via down-regulation of p65 in endothelial cells.}, journal = {Journal of cellular and molecular medicine}, volume = {21}, number = {11}, pages = {2720-2731}, pmid = {28444875}, issn = {1582-4934}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Aorta/drug effects/metabolism ; Apoptosis/*drug effects ; CASP8 and FADD-Like Apoptosis Regulating Protein/*genetics/metabolism ; Caspase Inhibitors/pharmacology ; Caspases/genetics/metabolism ; Dose-Response Relationship, Drug ; Gene Expression Regulation ; Glycation End Products, Advanced/chemistry/metabolism ; Human Umbilical Vein Endothelial Cells/cytology/*drug effects/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Pyruvaldehyde/*pharmacology ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/metabolism ; Signal Transduction ; Tissue Culture Techniques ; Transcription Factor RelA/antagonists &amp; inhibitors/*genetics/metabolism ; }, abstract = {Methylglyoxal (MGO) is a reactive dicarbonyl metabolite of glucose, and its plasma levels are elevated in patients with diabetes. Studies have shown that MGO combines with the amino and sulphhydryl groups of proteins to form stable advanced glycation end products (AGEs), which are associated with vascular endothelial cell (EC) injury and may contribute to the progression of atherosclerosis. In this study, MGO induced apoptosis in a dose-dependent manner in HUVECs, which was attenuated by pre-treatment with z-VAD, a pan caspase inhibitor. Treatment with MGO increased ROS levels, followed by dose-dependent down-regulation of c-FLIPL . In addition, pre-treatment with the ROS scavenger NAC prevented the MGO-induced down-regulation of p65 and c-FLIPL , and the forced expression of c-FLIPL attenuated MGO-mediated apoptosis. Furthermore, MGO-induced apoptotic cell death in endothelium isolated from mouse aortas. Finally, MGO was found to induce apoptosis by down-regulating p65 expression at both the transcriptional and posttranslational levels, and thus, to inhibit c-FLIPL mRNA expression by suppressing NF-κB transcriptional activity. Collectively, this study showed that MGO-induced apoptosis is dependent on c-FLIPL down-regulation via ROS-mediated down-regulation of p65 expression in endothelial cells.}, }
@article {pmid28444395, year = {2017}, author = {Volgers, C and Benedikter, BJ and Grauls, GE and Hellebrand, PHM and Savelkoul, PHM and Stassen, FRM}, title = {Effects of N-acetyl-L-cysteine on the membrane vesicle release and growth of respiratory pathogens.}, journal = {FEMS microbiology letters}, volume = {364}, number = {9}, pages = {}, doi = {10.1093/femsle/fnx087}, pmid = {28444395}, issn = {1574-6968}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Bacteria/*drug effects/*growth &amp; development/pathogenicity ; Cytoplasmic Vesicles/*drug effects ; Expectorants/pharmacology ; Haemophilus influenzae/drug effects/growth &amp; development ; Humans ; Macrophages/drug effects/microbiology ; Moraxella catarrhalis/drug effects/growth &amp; development ; Pseudomonas aeruginosa/drug effects/growth &amp; development ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Respiratory Tract Infections/drug therapy/microbiology ; Streptococcus pneumoniae/drug effects/growth &amp; development ; }, abstract = {Bacterial infections contribute to the disease progression of chronic obstructive pulmonary disease by stimulating mucus production in the airways. This increased mucus production and other symptoms are often alleviated when patients are treated with mucolytics such as N-acetyl-L-cysteine (NAC). Moreover, NAC has been suggested to inhibit bacterial growth. Bacteria can release membrane vesicles (MVs) in response to stress, and recent studies report a role for these proinflammatory MVs in the pathogenesis of airways disease. Yet, until now it is not clear whether NAC also affects the release of these MVs. This study set out to determine whether NAC, at concentrations reached during high-dose nebulization, affects bacterial growth and MV release of the respiratory pathogens non-typeable Haemophilus influenzae (NTHi), Moraxella catarrhalis (Mrc), Streptococcus pneumoniae (Spn) and Pseudomonas aeruginosa (Psa). We observed that NAC exerted a strong bacteriostatic effect, but also induced the release of proinflammatory MVs by NTHi, Mrc and Psa, but not by Spn. Interestingly, NAC also markedly blunted the release of TNF-α by naive macrophages in response to MVs. This suggests that the application of NAC by nebulization at a high dosage may be beneficial for patients with airway conditions associated with bacterial infections.}, }
@article {pmid28441068, year = {2017}, author = {Schmidl, D and Werkmeister, R and Kaya, S and Unterhuber, A and Witkowska, KJ and Baumgartner, R and Höller, S and O'Rourke, M and Peterson, W and Wolter, A and Prinz, M and Schmetterer, L and Garhöfer, G}, title = {A Controlled, Randomized Double-Blind Study to Evaluate the Safety and Efficacy of Chitosan-N-Acetylcysteine for the Treatment of Dry Eye Syndrome.}, journal = {Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics}, volume = {33}, number = {5}, pages = {375-382}, doi = {10.1089/jop.2016.0123}, pmid = {28441068}, issn = {1557-7732}, mesh = {Acetylcysteine/administration &amp; dosage/*adverse effects/*therapeutic use ; Adult ; Chitosan/administration &amp; dosage/adverse effects/*analogs &amp; derivatives/therapeutic use ; Cohort Studies ; Double-Blind Method ; Dry Eye Syndromes/*drug therapy ; Female ; Humans ; Male ; Tears/chemistry/metabolism ; Tomography, Optical Coherence ; }, abstract = {PURPOSE: This study was designed to evaluate the effect of chitosan-N-acetylcysteine (C-NAC) eye drops on tear film thickness (TFT) in patients with dry eye syndrome (DES).<br><br>METHODS: This was a controlled, randomized, double-blind clinical investigation with patients assigned to 2 cohorts. In Cohort I, 21 patients were randomized to receive 1 instillation of C-NAC eye drops in 1 eye and placebo (normal saline solution) in the contralateral eye. In Cohort II, 17 patients were randomized to receive C-NAC eye drops once (QD) or twice (BID) daily for 5 days. TFT was assessed with a custom-built ultrahigh-resolution optical coherence tomography system.<br><br>RESULTS: In Cohort I, mean TFT increased from 3.9&#x2009;&#xb1;&#x2009;0.5&#x2009;&#x3bc;m predose to 4.8&#x2009;&#xb1;&#x2009;1.1&#x2009;&#x3bc;m 10&#x2009;min postdose after treatment with C-NAC. The increase was significantly different from placebo over time (P&#x2009;<&#x2009;0.0001) and remained stable until 24&#x2009;h postdose. In Cohort II, TFT increased with QD and BID instillation, with no significant difference between regimens. In both groups, Ocular Surface Disease Index scores improved, fewer patients presented with corneal damage, and symptoms of ocular discomfort/conjunctival redness were reduced.<br><br>CONCLUSIONS: A single instillation of C-NAC significantly increased mean TFT in patients with DES as early as 10&#x2009;min after instillation and lasted for 24&#x2009;h. The magnitude of the increase in TFT following a single instillation was comparable with that after instillation twice daily over 5 days. Corneal damage improved in >60% of patients. C-NAC could be a viable treatment option for DES.}, }
@article {pmid28439707, year = {2018}, author = {Zaki, SM and Abdalla, IL and Sadik, AOE and Mohamed, EA and Kaooh, S}, title = {Protective Role of N-Acetylcysteine on Isoprenaline-Induced Myocardial Injury: Histological, Immunohistochemical and Morphometric Study.}, journal = {Cardiovascular toxicology}, volume = {18}, number = {1}, pages = {9-23}, doi = {10.1007/s12012-017-9407-1}, pmid = {28439707}, issn = {1559-0259}, mesh = {Acetylcysteine/*pharmacology ; Actins/metabolism ; Animals ; Collagen/metabolism ; Cytoprotection ; Disease Models, Animal ; *Immunohistochemistry ; *Isoproterenol ; Male ; Myocardial Infarction/chemically induced/metabolism/pathology/*prevention &amp; control ; Myocytes, Cardiac/*drug effects/metabolism/ultrastructure ; Proliferating Cell Nuclear Antigen/metabolism ; Rats, Wistar ; Time Factors ; }, abstract = {Several researchers studied the protective effect of the N-acetylcysteine (NAC) when it was given before the induction of myocardial infarction (MI). Other researchers studied such protective effect when it was before done and after done of the MI. The missing data are the comparison between the protective effect of NAC before myocardial injury with its protective effect both before and after myocardial injury. The aim of the study was to compare the cardioprotective effect of NAC on the isoprenaline-induced myocardial injury before the isoprenaline (ISP) injection with its protective effect both before and after the ISP injection. This study was applied over both short and long time periods. A total of 90 male adult Wistar albino rats were used in the study. The rats were divided into four groups: control group, ISP-treated group, NAC-pretreated group and NAC-pre-&amp; posttreated group. Based on the duration of the experiment, the second and third groups were further subdivided into a and b groups. Histological, immunohistochemical and histomorphometric analysis were used. The myocytes in the ISP-treated groups were fragmented, disrupted with karyolysis. The blood vessels were dilated, congested and associated with blood extravasation, interstitial edema and cellular inflammatory infiltration. Much improvement was observed in the NAC-pretreated group. Focal degeneration was detected in the muscle fibers. The capillaries were normal. Minimal blood extravasation and cellular infiltration were seen. The cardiac muscle fibers in the NAC-pre-&amp; posttreated group were regularly arranged. The mean collagen fiber area percent of the ISP-treated groups was significantly higher by 8.3-folds and 10.1-folds as compared with that of the control group and was also higher by 5.5-folds and 6.8-folds as compared with that of the NAC-pre-&amp;posttreated groups. The α-SMA area percent in the ISP-treated groups was significantly higher by 12.2-folds and 23.9-folds as compared with that of the control group and was higher by 7.5-folds and 15-folds as compared with that of the NAC-pre-&amp; posttreated groups. The mean PCNA area percent of the ISP-treated groups was significantly higher by 126.2 and 164.8% as compared with that of the control group and was higher by 106.3 and 141.5% as compared with that of NAC-pre-&amp; posttreated groups. ISP had deleterious effects on the heart. Administration of NAC before ISP injection could largely reduce the ISP-induced short- and long-term alterations. The protection was maximum with the use of NAC before the ISP injection and continued after the injection for 12 days.}, }
@article {pmid28439512, year = {2016}, author = {Tunç, S and Kesiktas, E and Yilmaz, Y and Açikalin, A and Oran, G and Yavuz, M and Gencel, E and Eser, C}, title = {Assessing the effects of melatonin and N-acetylcysteine on the McFarlane flap using a rat model.}, journal = {Plastic surgery (Oakville, Ont.)}, volume = {24}, number = {3}, pages = {204-208}, pmid = {28439512}, issn = {2292-5503}, abstract = {OBJECTIVE: To determine the effects of N-acetylcysteine (NAC) and melatonin, alone and in combination, on McFarlane flap viability in a rat model.<br><br>METHODS: Forty Wistar rats were divided into four groups and received daily intraperitoneal injections for one week before surgery: control (sham [n=10]); melatonin (n=10); NAC (n=10); and NAC+melatonin (n=10). One week after surgery, the experiment was terminated and photographs were taken for topographic studies. A transillumination study was performed to observe vascularization in the flaps and biopsies were obtained for histopathological studies.<br><br>RESULTS: Flap viability was significantly greater in the antioxidant- (ie, NAC and melatonin) treated groups compared with the control group; however, there were no significant differences among the groups that received antioxidants.<br><br>CONCLUSIONS: Melatonin and NAC are important antioxidants that can be used alone or in combination to increase flap viability and prevent distal necrosis in rats.}, }
@article {pmid28438658, year = {2017}, author = {Du, X and West, MB and Cai, Q and Cheng, W and Ewert, DL and Li, W and Floyd, RA and Kopke, RD}, title = {Antioxidants reduce neurodegeneration and accumulation of pathologic Tau proteins in the auditory system after blast exposure.}, journal = {Free radical biology &amp; medicine}, volume = {108}, number = {}, pages = {627-643}, doi = {10.1016/j.freeradbiomed.2017.04.343}, pmid = {28438658}, issn = {1873-4596}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Auditory Cortex/pathology ; Benzenesulfonates/*therapeutic use ; Blast Injuries/*drug therapy ; Cell Death ; Cells, Cultured ; Hair Cells, Auditory/*physiology ; Male ; Neurodegenerative Diseases/*drug therapy ; Neurons/*physiology ; Rats ; Rats, Inbred Strains ; Spiral Ganglion/pathology ; Unfolded Protein Response ; Vestibulocochlear Nerve Diseases/*drug therapy ; tau Proteins/metabolism ; }, abstract = {Cochlear neurodegeneration commonly accompanies hair cell loss resulting from aging, ototoxicity, or exposures to intense noise or blast overpressures. However, the precise pathophysiological mechanisms that drive this degenerative response have not been fully elucidated. Our laboratory previously demonstrated that non-transgenic rats exposed to blast overpressures exhibited marked somatic accumulation of neurotoxic variants of the microtubule-associated protein, Tau, in the hippocampus. In the present study, we extended these analyses to examine neurodegeneration and pathologic Tau accumulation in the auditory system in response to blast exposure and evaluated the potential therapeutic efficacy of antioxidants on short-circuiting this pathological process. Blast injury induced ribbon synapse loss and retrograde neurodegeneration in the cochlea in untreated animals. An accompanying perikaryal accumulation of neurofilament light chain and pathologic Tau oligomers were observed in neurons from both the peripheral and central auditory system, spanning from the spiral ganglion to the auditory cortex. Due to its coincident accumulation pattern and well-documented neurotoxicity, our results suggest that the accumulation of pathologic Tau oligomers may actively contribute to blast-induced cochlear neurodegeneration. Therapeutic intervention with a combinatorial regimen of 2,4-disulfonyl α-phenyl tertiary butyl nitrone (HPN-07) and N-acetylcysteine (NAC) significantly reduced both pathologic Tau accumulation and indications of ongoing neurodegeneration in the cochlea and the auditory cortex. These results demonstrate that a combination of HPN-07 and NAC administrated shortly after a blast exposure can serve as a potential therapeutic strategy for preserving auditory function among military personnel or civilians with blast-induced traumatic brain injuries.}, }
@article {pmid28438466, year = {2017}, author = {Skvarc, DR and Dean, OM and Byrne, LK and Gray, L and Lane, S and Lewis, M and Fernandes, BS and Berk, M and Marriott, A}, title = {The effect of N-acetylcysteine (NAC) on human cognition - A systematic review.}, journal = {Neuroscience and biobehavioral reviews}, volume = {78}, number = {}, pages = {44-56}, doi = {10.1016/j.neubiorev.2017.04.013}, pmid = {28438466}, issn = {1873-7528}, mesh = {Acetylcysteine ; Antioxidants ; *Cognition ; Glutathione ; Humans ; Oxidative Stress ; }, abstract = {Oxidative stress, neuroinflammation and neurogenesis are commonly implicated as cognitive modulators across a range of disorders. N-acetylcysteine (NAC) is a glutathione precursor with potent antioxidant, pro-neurogenesis and anti-inflammatory properties and a favourable safety profile. A systematic review of the literature specifically examining the effect of NAC administration on human cognition revealed twelve suitable articles for inclusion: four examining Alzheimer's disease; three examining healthy participants; two examining physical trauma; one examining bipolar disorder, one examining schizophrenia, and one examining ketamine-induced psychosis. Heterogeneity of studies, insufficiently powered studies, infrequency of cognition as a primary outcome, heterogeneous methodologies, formulations, co-administered treatments, administration regimes, and assessment confounded the drawing of firm conclusions. The available data suggested statistically significant cognitive improvements following NAC treatment, though the paucity of NAC-specific research makes it difficult to determine if this effect is meaningful. While NAC may have a positive cognitive effect in a variety of contexts; larger, targeted studies are warranted, specifically evaluating its role in other clinical disorders with cognitive sequelae resulting from oxidative stress and neuroinflammation.}, }
@article {pmid28435431, year = {2017}, author = {Zhou, Q and Song, W and Xiao, W}, title = {Dioscin induces demethylation of DAPK-1 and RASSF-1alpha genes via the antioxidant capacity, resulting in apoptosis of bladder cancer T24 cells.}, journal = {EXCLI journal}, volume = {16}, number = {}, pages = {101-112}, pmid = {28435431}, issn = {1611-2156}, abstract = {DNA methylation at CpG rich regions often occurs at tumor suppressor gene promoters, resulting in reduced gene expression and final carcinogenesis. Hypermethylation of tumor suppressor genes, including DAPK-1 and RASSF-1α genes, have been found in patients with bladder carcinoma (BC) in some western countries. Reactive oxygen species (ROS) was reported to play a causative role in gene hypermethylation. In this study, we detected the methylation status and expression of DAPK1 and RASSF-1α genes in tissue samples from Chinese BC patients, using methylation-specific PCR, reverse transcription PCR and western blotting. Further, we examined the ability of dioscin, a natural antioxidant, to regulate methylation status and expression of DAPK-1 and RASSF-1α genes in BC cell lines. In our results, DAPK-1 and RASSF-1α genes showed higher methylation level and lower express level in BC tissues than matched normal tissues. Treatment with dioscin decreased viability of BC 5637 and T24 cells, but not non-cancer bladder epithelial cell, SV-HUC-1. Dioscin triggered demethylation of DAPK1 and RASSF-1α genes in T24 cells and increased the gene and protein expression in 5637 and T24 cells. Both dioscin and substituted antioxidants (N-acetyl cysteine and Vitamin E) decreased intracellular ROS, but the effect of dioscin was abolished by adding H2O2. Similar to dioscin, the substituted antioxidants also induced the gene demethylation and T24 cell apoptosis. Co-treatment with dioscin and H2O2 had no such effects. Collectively, dioscin induces demethylation of DAPK-1 and RASSF-1α genes via the antioxidant capacity, resulting in apoptosis of bladder cancer T24 cells or inhibitory cell viability.}, }
@article {pmid28432944, year = {2017}, author = {Chiarante, N and García Vior, MC and Awruch, J and Marino, J and Roguin, LP}, title = {Phototoxic action of a zinc(II) phthalocyanine encapsulated into poloxamine polymeric micelles in 2D and 3D colon carcinoma cell cultures.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {170}, number = {}, pages = {140-151}, doi = {10.1016/j.jphotobiol.2017.04.009}, pmid = {28432944}, issn = {1873-2682}, mesh = {Antioxidants/chemistry/metabolism ; Apoptosis/*drug effects/radiation effects ; Caspase 3/metabolism ; Cell Culture Techniques ; Cell Line, Tumor ; Cell Survival/drug effects ; Colonic Neoplasms/metabolism/pathology ; Drug Carriers/*chemistry ; Endoplasmic Reticulum/metabolism ; Humans ; Indoles/*chemistry/*toxicity ; Isoindoles ; Light ; Lysosomes/metabolism ; *Micelles ; Organometallic Compounds/chemistry/*toxicity ; Photosensitizing Agents/chemistry/pharmacology/*toxicity ; Reactive Oxygen Species/metabolism ; Zinc Compounds ; }, abstract = {Photodynamic therapy is emerging as a hopeful method for the treatment of oncological diseases. In the search of novel therapeutic strategies for colorectal cancer, in this work we reported the photocytotoxic activity of a lipophilic zinc(II) phthalocyanine on a murine colon adenocarcinoma cell line (CT26 cells). The 2,9(10),16(17),23(24) tetrakis[(2-dimethylamino)ethylsulfanyl]phthalocyaninatozinc(II), named Pc9, was encapsulated into Tetronic® 1107 polymeric poloxamine micelles (T1107) and assayed in 2D and 3D cell cultures. We showed that the formulation Pc9-T1107 was efficient to reduce cell viability after photodynamic treatment both in 2D cultures (IC50 10±2nM) as well as in CT26 spheroids (IC50 370±11nM). Cellular uptake of Pc9-T1107 was a time- and concentration-dependent process, being the phthalocyanine formulation mainly incorporated into lysosomal vesicles and endoplasmic reticulum cisterns, but not in mitochondria. Pc9-T1107 also induced the formation of reactive oxygen species immediately after cell irradiation. We also found that the phototoxic action of Pc9-T1107 was partially reversed in the presence of antioxidants, such as TROLOX and N-acetyl-cysteine. In addition, we showed that Pc9-T1107 treatment triggered an apoptotic cell death, as suggested by the detection of pyknotic nuclei, the reduction in the expression levels of procaspase-3 and the increase in caspase-3 enzymatic activity.}, }
@article {pmid28432429, year = {2017}, author = {Camire, J and Kim, D and Kwon, S}, title = {Enhanced production of recombinant proteins by a small molecule protein synthesis enhancer in combination with an antioxidant in recombinant Chinese hamster ovary cells.}, journal = {Bioprocess and biosystems engineering}, volume = {40}, number = {7}, pages = {1049-1056}, doi = {10.1007/s00449-017-1767-1}, pmid = {28432429}, issn = {1615-7605}, mesh = {Acetylcysteine ; Animals ; Antioxidants ; CHO Cells ; Cricetinae ; Cricetulus ; Recombinant Proteins/*metabolism ; }, abstract = {The improvement in the production of recombinant proteins has been linked in a number of small molecules such as carboxylic acids to the inhibition of histone deacetylase, leading to increased transcription of genes. However, carboxylic acids such as pentanoic acid and butanoic acid have been shown to promote an apoptotic response in Chinese hamster ovary (CHO) cell culture. Supplementation of cultures with antioxidants has shown the ability to reduce the apoptotic response of carboxylic acid supplementation, leading to increased therapeutic protein production. In this study, we showed that pentanoic acid reduced the number of cells entering early apoptosis relative to butanoic acid by 15.4%. Additionally, supplementation of butanoic acid- and pentanoic acid-treated cultures with N-acetyl cysteine (NAC) reduced the population of cells entering early apoptosis by 5.3 and 10.0%, respectively, while increasing productivity by 19.5% in the presence of pentanoic acid and NAC. Conversely, a decrease of 5.7% in production was observed in response to combined butanoic acid and N-acetyl cysteine treatment. The results presented herein provide evidence that a culture supplementation method is critical for optimization of biopharmaceutical manufacturing processes.}, }
@article {pmid28432072, year = {2017}, author = {Tang, K and Zhao, Y and Li, H and Zhu, M and Li, W and Liu, W and Zhu, G and Xu, D and Peng, W and Xu, YW}, title = {Translocase of Inner Membrane 50 Functions as a Novel Protective Regulator of Pathological Cardiac Hypertrophy.}, journal = {Journal of the American Heart Association}, volume = {6}, number = {4}, pages = {}, pmid = {28432072}, issn = {2047-9980}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cardiomegaly/*genetics/metabolism ; Cardiomyopathy, Dilated/*genetics/metabolism ; Case-Control Studies ; Catalase/metabolism ; Down-Regulation ; Electron Transport Complex I/metabolism ; Electron Transport Complex II/metabolism ; Electron Transport Complex IV/metabolism ; Fibrosis ; Humans ; MAP Kinase Kinase 4/genetics ; MAP Kinase Kinase Kinase 5/genetics ; Membrane Transport Proteins/*genetics/metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Mitochondrial Precursor Protein Import Complex Proteins ; Myocardium/*pathology ; Myocytes, Cardiac ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxide Dismutase/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics ; }, abstract = {BACKGROUND: Translocase of inner membrane 50 (TIM50) is a member of the translocase of inner membrane (TIM) complex in the mitochondria. Previous research has demonstrated the role of TIM50 in the regulation of oxidative stress and cardiac morphology. However, the role of TIM50 in pathological cardiac hypertrophy remains unknown.<br><br>METHODS AND RESULTS: In the present study we found that the expression of TIM50 was downregulated in hypertrophic hearts. Using genetic loss-of-function animal models, we demonstrated that TIM50 deficiency increased heart and cardiomyocyte size with more severe cardiac fibrosis compared with wild-type littermates. Moreover, we generated cardiomyocyte-specific TIM50 transgenic mice in which the hypertrophic and fibrotic phenotypes were all alleviated. Next, we tested reactive oxygen species generation and the activities of the antioxidant enzymes superoxide dismutase and catalase, and also respiratory chain complexes I, II, and IV, finding that all the activities were regulated by TIM50. Meanwhile, expression of the ASK1-JNK/P38 axis was increased in TIM50-deficient mice, and TIM50 overexpression decreased the activity of the ASK1-JNK/P38 axis. Finally, we treated mice with the antioxidant N-acetyl cysteine to reduce oxidative stress. After N-acetyl cysteine treatment, the deteriorative hypertrophic and fibrotic phenotypes caused by TIM50 deficiency were all remarkably reversed.<br><br>CONCLUSIONS: These data indicated that TIM50 could attenuate pathological cardiac hypertrophy primarily by reducing oxidative stress. TIM50 could be a promising target for the prevention and therapy of cardiac hypertrophy and heart failure.}, }
@article {pmid28430291, year = {2017}, author = {Bernhardt, LK and Madhyastha, S and Bairy, L and Kishore, A}, title = {Status of the brain antioxidant system at different growing periods after prenatal stress and N -acetyl cysteine administration.}, journal = {Folia neuropathologica}, volume = {55}, number = {1}, pages = {38-48}, doi = {10.5114/fn.2017.66712}, pmid = {28430291}, issn = {1509-572X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain/*drug effects/embryology ; Female ; Male ; Oxidative Stress/*drug effects ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Rats ; Rats, Wistar ; Restraint, Physical ; Stress, Psychological ; }, abstract = {Prenatal stress-induced neurobehavioral deficits observed in offspring are multifactorial, including oxidative stress in the developing brain. The time by which the developing brain acquires self-defense against oxidative stress is not clear. Hence in the present study we aimed to evaluate the brain antioxidant status during different developing periods. Further the study also evaluates the role of the glutathione precursor, N-acetyl cysteine (NAC) on the brain antioxidant status. Pregnant rats were subjected to restraint stress during an early or late gestational period. Another set of rats received NAC during the entire gestational period along with early or late gestational stress. The study parameters included several antioxidant studies directly from rat brain homogenate on postnatal day 24 or 48. Early or late gestational stress has caused severe oxidative stress in the developing brain on postnatal day 24 in all the parameters studied. However, brain reduced glutathione (GSH), superoxide dismutase (SOD) and total antioxidant activity (TAO) were not affected by either early or late gestational stress on postnatal day 48, but the brain malondialdehyde (MDA) level remained high and brain glutathione reductase (GSS-Rd) level remained low on postnatal day 48. Prenatal NAC treatment has reversed the oxidative damage in all the parameters on postnatal day 24 and also the brain MDA level and GSS-Rd level on postnatal day 48. This study confirms that the growing brain acquires antioxidant capacity over time but during early postnatal development it is vulnerable to oxidative stress and related neurological consequences. N-acetyl cysteine treatment during the prenatal period as an antioxidant supplement exerted a beneficiary effect in this study. Hence glutathione supplement in the nutritional source would be an idealistic approach to prenatal stress-induced neurological comorbidities in children..}, }
@article {pmid28427645, year = {2017}, author = {Guss, KL and Pavanni, S and Prati, B and Dazzi, L and de Oliveira, JP and Nogueira, BV and Pereira, TMC and Fronza, M and Endringer, DC and Scherer, R}, title = {Ultrasound-assisted extraction of Achyrocline satureioides prevents contrast-induced nephropathy in mice.}, journal = {Ultrasonics sonochemistry}, volume = {37}, number = {}, pages = {368-374}, doi = {10.1016/j.ultsonch.2017.01.035}, pmid = {28427645}, issn = {1873-2828}, mesh = {Achyrocline/*chemistry ; Animals ; Antioxidants/chemistry/isolation &amp; purification/pharmacology ; Biphenyl Compounds/chemistry ; Contrast Media/*adverse effects ; Creatinine/blood ; Flavonoids/analysis ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Mice ; Nitric Oxide/biosynthesis ; Phenols/analysis ; Picrates/chemistry ; Plant Extracts/chemistry/*isolation &amp; purification/*pharmacology ; Quercetin/analysis ; *Ultrasonic Waves ; Urea/blood ; }, abstract = {Achyrocline satureioides or Macela, has been largely used in traditional folk medicine in Brazil as an anti-inflammatory agent and to treat various digestive disorders. The aim of the present study was to evaluate the preventive action of the extracts of A. satureioides obtained by maceration and ultrasound-assisted extraction, quercetin and N-acetylcysteine against contrast-induced nephropathy in mice. The antioxidant activity, cytotoxicity and inhibition of nitric oxide (NO) production in macrophages were evaluated. Also, chemical analyses of phenolic compounds, total flavonoids, and quercetin by LC-MS/MS present in various extracts of A. satureioides were performed. Thirty six mice were divided into six groups: control group (C), Contrast-Induced Nephropathy group (CIN), Group N-acetylcysteine 200mg/kg (NAC); Group quercetin 10mg/kg (Q), Group Macela 10mg/kg (M10), and Group Macela 50mg/kg (M50). The serum levels of urea and creatinine, advanced oxidation protein products (AOPP) and renal ultrastructure were evaluated by electron microscopy scanning. Ultrasound-assisted extraction improved the quality of extract (with 100% ethanol), since did not show toxicity to fibroblasts, and showed potent antioxidant activity and a high content of phenolic compounds, flavonoids, and quercetin, in addition to being able to reduce the production of NO in dose-dependent effect in macrophages. Results showed that animals treated with Macela extracts maintained normal levels of urea, creatinine, and AOPP, while preserving ultrastructure of the renal cells. The obtained results were more promising than NAC and Q groups in protecting against renal failure caused by CIN, showing that the plant can be a promising drug for preventing this disease.}, }
@article {pmid28427237, year = {2017}, author = {Chen, F and Wang, X and Jin, X and Zhao, J and Gou, S}, title = {Oxidative DNA double strand breaks and autophagy in the antitumor effect of sterically hindered platinum(II) complexes in NSCLCs.}, journal = {Oncotarget}, volume = {8}, number = {19}, pages = {30933-30955}, pmid = {28427237}, issn = {1949-2553}, mesh = {Animals ; Antineoplastic Agents/chemical synthesis/*chemistry/*pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Carcinoma, Non-Small-Cell Lung/genetics/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects/genetics ; DNA Breaks, Double-Stranded/*drug effects ; DNA Repair/drug effects ; Disease Models, Animal ; Humans ; Hydrogen Peroxide/pharmacology ; Lung Neoplasms/genetics/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Molecular Structure ; Organoplatinum Compounds/chemical synthesis/*chemistry/*pharmacology ; Oxidation-Reduction ; Oxidative Stress/*genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {A series of novel platinum(II) complexes with (1R,2R)-N1,N2-diisobutyl-1,2-diaminocyclohexane as a carrier ligand, while N1,N2-diisobutyl moiety serving as steric hindrance were designed, synthesized and characterized. The in vitro biological assays demonstrated that complex 3 had increased cytotoxicity against lung cancer cells, especially non-small-cell lung cancer (NSCLC) compared to its mono-substituted complex 3a, indicating that the sterically hindered alkyl moieties have significant influences on its antitumor property. However, the mechanism still remains unclear. The further studies revealed that complex 3 could induce ROS overproduction, severe DNA double strands breaks and inhibit the activation of DNA damage repair proteins within nucleus, leading to cell-cycle arrest and cell death. Moreover, complex 3 could induce autophagy via the accumulation of autophagic vacuoles and alterations of autophagic protein expression. Interestingly, the ROS scavengers, N-acetyl-cysteine (NAC) could reverse complex 3-induced DNA double strands breaks and autophagic responses more significantly compared to complex 3a. The results demonstrated that the ROS generation plays an important role in the DNA double strands breaks and autophagic responses in the antitumor effect of complex 3 with N1,N2-diisobutyl moiety. Our study offered a novel therapeutic strategy and put new insights into the anticancer research of the complexes with N1,N2-diisobutyl moiety served as steric hindrance.}, }
@article {pmid28427227, year = {2017}, author = {Noguera, NI and Pelosi, E and Angelini, DF and Piredda, ML and Guerrera, G and Piras, E and Battistini, L and Massai, L and Berardi, A and Catalano, G and Cicconi, L and Castelli, G and D'Angiò, A and Pasquini, L and Graziani, G and Fioritoni, G and Voso, MT and Mastrangelo, D and Testa, U and Lo-Coco, F}, title = {High-dose ascorbate and arsenic trioxide selectively kill acute myeloid leukemia and acute promyelocytic leukemia blasts in vitro.}, journal = {Oncotarget}, volume = {8}, number = {20}, pages = {32550-32565}, pmid = {28427227}, issn = {1949-2553}, mesh = {Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use ; Arsenic Trioxide ; Arsenicals/pharmacology/*therapeutic use ; Ascorbic Acid/pharmacology/*therapeutic use ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/mortality/pathology ; Leukemia, Promyelocytic, Acute/*drug therapy/mortality/pathology ; Oxides/pharmacology/*therapeutic use ; Reactive Oxygen Species ; Survival Analysis ; Tumor Cells, Cultured ; }, abstract = {The use of high-dose ascorbate (ASC) for the treatment of human cancer has been attempted several decades ago and has been recently revived by several in vitro and in vivo studies in solid tumors. We tested the cytotoxic effects of ASC, alone or in combination with arsenic trioxide (ATO) in acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL). Leukemic cell lines and primary blasts from AML and APL patients were treated with graded concentrations of ASC, alone or in association with standard concentration (1 μM) of ATO. The ASC/ATO combination killed myeloid blasts, including leukemic CD34+ cells, while sparing CD34+ progenitors obtained from normal cord blood and bone marrow. Actually, approximately one-third (11/36) of primary AML cases were highly sensitive to the ASC/ATO combination. The mechanism of cell killing appeared to be related to increased oxidative stress and overproduction of ROS in a non-quantitative fashion, which resulted in induction of apoptosis. These effects were reverted by the addition of the antioxidant N-Acetyl-Cysteine (NAC). In the APL NB4 model, ASC induced direct degradation of the PML and PML/RARA proteins via caspase activation, while the transcriptional repressor DAXX was recruited in re-constituted PML nuclear bodies. Our findings encourage the design of pilot studies to explore the potential clinical benefit of ASC alone or in combination with ATO in advanced AML and APL.}, }
@article {pmid28426681, year = {2017}, author = {Vieira, GLT and Lossie, AC and Lay, DC and Radcliffe, JS and Garner, JP}, title = {Preventing, treating, and predicting barbering: A fundamental role for biomarkers of oxidative stress in a mouse model of Trichotillomania.}, journal = {PloS one}, volume = {12}, number = {4}, pages = {e0175222}, pmid = {28426681}, issn = {1932-6203}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/therapeutic use ; Animals ; Biomarkers/*metabolism ; Deoxyguanosine/analogs &amp; derivatives/metabolism/urine ; *Disease Models, Animal ; *Grooming ; Mice ; Mice, Inbred C57BL ; *Oxidative Stress ; Trichotillomania/drug therapy/*metabolism ; }, abstract = {Barbering, where a "barber" mouse plucks hair from its cagemates or itself, is both a spontaneously occurring abnormal behavior in mice and a well validated model of Trichotillomania (TTM). N-Acetylcysteine, (NAC) a cysteine derived food additive, is remarkably effective in treating TTM patients, but its mechanism of action is unknown. Reactive Oxygen Species (ROS), also known as free radicals, form as a natural byproduct of the normal metabolism of oxygen. Under normal circumstances, cells are able to defend themselves against ROS damage with antioxidant pathways. NAC is the precursor to the main antioxidant produced to defend the brain. Therefore, we hypothesized that barbering is a disease of oxidative stress, whereby ROS and/or a failure of antioxidant defenses leads to neuronal damage that induces barbering in susceptible animals. We tested this hypothesis in 32 female C57BL/6J mice by treating half with 1g/kg BW/day of NAC in their diet, and testing for protection against developing barbering behavior and curing of barbering behavior, and simultaneously testing for a panel of biomarkers of oxidative stress. NAC reduced the chance that mice would be barbers, and this effect did not differ between healthy (i.e. prevention) and affected animals (i.e. cure). Barbering animals had elevated urinary antioxidant capacity, indicative of oxidative stress, at all timepoints. Additionally, after treatment the risk of barbering increased with decreasing hydroxy-2'-deoxyguanosine (8-OHdG) levels, and with increasing glutathione (GSH) and oxidized glutathione (GSSG) levels, further indicating that barbering mice were under oxidative stress regardless of treatment with NAC. We did not find compelling evidence that urinary total antioxidant capacity, or urinary 8-OHdG, could predict response to NAC treatment. We conclude that NAC is effective in preventing and/or curing barbering at least in part by promoting GSH synthesis, thereby preventing oxidative damage.}, }
@article {pmid28423628, year = {2017}, author = {Lin, JF and Tsai, TF and Yang, SC and Lin, YC and Chen, HE and Chou, KY and Hwang, TI}, title = {Benzyl isothiocyanate induces reactive oxygen species-initiated autophagy and apoptosis in human prostate cancer cells.}, journal = {Oncotarget}, volume = {8}, number = {12}, pages = {20220-20234}, pmid = {28423628}, issn = {1949-2553}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Blotting, Western ; Cell Line, Tumor ; Cell Survival/drug effects ; Flow Cytometry ; Humans ; Isothiocyanates/*pharmacology ; Male ; Membrane Potential, Mitochondrial/drug effects ; Prostatic Neoplasms/*pathology ; Reactive Oxygen Species ; }, abstract = {Benzyl isothiocyanate (BITC) in cruciferous plants, which are part of the human diet, has been shown to induce apoptosis in various types of cancer. In this study, we show that BITC effectively suppresses the growth of cultured human prostate cancer cells (CRW-22Rv1 and PC3) by causing mitochondrial membrane potential loss, caspase 3/7 activation and DNA fragmentation. Furthermore, BITC induces ROS generation in these cells. The induction of apoptosis by BITC was significantly attenuated in the presence of N-acetylcysteine (NAC) and catalase (CAT), well-studied ROS scavengers. The induction of autophagy in BITC-treated cells were also diminished by the application of NAC or CAT. In addition, BITC-induced apoptosis and autophagy were both enhanced by the pretreatment of catalase inhibitor, 3-Amino-1,2,4-triazole (3-AT). Pretreatment with specific inhibitors of autophagy (3-methyladenine or bafilomycin A1) or apoptosis (Z-VAD-FMK) reduced BITC-induced autophagy and apoptosis, respectively, but did not abolish BITC-induced ROS generation. In conclusion, the present study provides evidences that BITC caused prostate cancer cell death was dependent on the ROS status, and clarified the mechanism underlying BITC-induced cell death, which involves the induction of ROS production, autophagy and apoptosis, and the relationship between these three important processes.}, }
@article {pmid28421844, year = {2017}, author = {Wong, A and Sivilotti, MLA and Graudins, A}, title = {Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {55}, number = {5}, pages = {346-351}, doi = {10.1080/15563650.2017.1290253}, pmid = {28421844}, issn = {1556-9519}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/therapeutic use ; Adolescent ; Adult ; Aged ; Alanine Transaminase/*blood ; Analgesics, Non-Narcotic/blood/*poisoning ; Chemical and Drug Induced Liver Injury/blood/*diagnosis/drug therapy ; Drug Overdose/*blood/diagnosis/drug therapy ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Sensitivity and Specificity ; Young Adult ; }, abstract = {CONTEXT: The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses.<br><br>OBJECTIVE: The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose.<br><br>METHODS: We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase &#x2265;1000&#x2009;IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50&#x2009;IU/L.<br><br>RESULTS: Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000&#x2009;mg/L&#x2009;&#xd7;&#x2009;IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500&#x2009;mg/L&#x2009;&#xd7;&#x2009;IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity.<br><br>CONCLUSIONS: In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000&#x2009;mg/L&#x2009;&#xd7;&#x2009;IU/L, it was very strongly associated with the development of acute liver injury and hepatotoxicity, especially when calculated more than eight hours post-ingestion. When below 1500&#x2009;mg/L&#x2009;&#xd7;&#x2009;IU/L the likelihood of developing hepatotoxicity was very low. Persistently high serial multiplication product calculations were associated with the greatest risk of hepatotoxicity.}, }
@article {pmid28420969, year = {2017}, author = {Israel, Y and Karahanian, E and Ezquer, F and Morales, P and Ezquer, M and Rivera-Meza, M and Herrera-Marschitz, M and Quintanilla, ME}, title = {Acquisition, Maintenance and Relapse-Like Alcohol Drinking: Lessons from the UChB Rat Line.}, journal = {Frontiers in behavioral neuroscience}, volume = {11}, number = {}, pages = {57}, pmid = {28420969}, issn = {1662-5153}, abstract = {This review article addresses the biological factors that influence: (i) the acquisition of alcohol intake; (ii) the maintenance of chronic alcohol intake; and (iii) alcohol relapse-like drinking behavior in animals bred for their high-ethanol intake. Data from several rat strains/lines strongly suggest that catalase-mediated brain oxidation of ethanol into acetaldehyde is an absolute requirement (up 80%-95%) for rats to display ethanol's reinforcing effects and to initiate chronic ethanol intake. Acetaldehyde binds non-enzymatically to dopamine forming salsolinol, a compound that is self-administered. In UChB rats, salsolinol: (a) generates marked sensitization to the motivational effects of ethanol; and (b) strongly promotes binge-like drinking. The specificity of salsolinol actions is shown by the finding that only the R-salsolinol enantiomer but not S-salsolinol accounted for the latter effects. Inhibition of brain acetaldehyde synthesis does not influence the maintenance of chronic ethanol intake. However, a prolonged ethanol withdrawal partly returns the requirement for acetaldehyde synthesis/levels both on chronic ethanol intake and on alcohol relapse-like drinking. Chronic ethanol intake, involving the action of lipopolysaccharide diffusing from the gut, and likely oxygen radical generated upon catechol/salsolinol oxidation, leads to oxidative stress and neuro-inflammation, known to potentiate each other. Data show that the administration of N-acetyl cysteine (NAC) a strong antioxidant inhibits chronic ethanol maintenance by 60%-70%, without inhibiting its initial intake. Intra-cerebroventricular administration of mesenchymal stem cells (MSCs), known to release anti-inflammatory cytokines, to elevate superoxide dismutase levels and to reverse ethanol-induced hippocampal injury and cognitive deficits, also inhibited chronic ethanol maintenance; further, relapse-like ethanol drinking was inhibited up to 85% for 40 days following intracerebral stem cell administration. Thus: (i) ethanol must be metabolized intracerebrally into acetaldehyde, and further into salsolinol, which appear responsible for promoting the acquisition of the early reinforcing effects of ethanol; (ii) acetaldehyde is not responsible for the maintenance of chronic ethanol intake, while other mechanisms are indicated; (iii) the systemic administration of NAC, a strong antioxidant markedly inhibits the maintenance of chronic ethanol intake; and (iv) the intra-cerebroventricular administration of anti-inflammatory and antioxidant MSCs inhibit both the maintenance of chronic ethanol intake and relapse-like drinking.}, }
@article {pmid28419535, year = {2017}, author = {Ahmaditabar, P and Momtazi-Borojeni, AA and Rezayan, AH and Mahmoodi, M and Sahebkar, A and Mellat, M}, title = {Enhanced Entrapment and Improved in Vitro Controlled Release of N-Acetyl Cysteine in Hybrid PLGA/Lecithin Nanoparticles Prepared Using a Nanoprecipitation/Self-Assembly Method.}, journal = {Journal of cellular biochemistry}, volume = {118}, number = {12}, pages = {4203-4209}, doi = {10.1002/jcb.26070}, pmid = {28419535}, issn = {1097-4644}, mesh = {Acetylcysteine/administration &amp; dosage/*chemistry/pharmacology ; Alveolar Epithelial Cells/*drug effects ; Animals ; Cell Line ; Delayed-Action Preparations ; Lecithins/chemistry ; Mice ; Nanoparticles/*chemistry ; Polyglactin 910/chemistry ; }, abstract = {To enhance the in vitro controlled release of N-acetyl cysteine (NAC), hybrid nanoparticles (NPs) consisting of a poly(lactide-co-glycolide) (PLGA) hydrophobic core and a soybean lecithin mono-layer coat were prepared. Hybrid NPs were synthesized using a nanoprecipitation combined with self-assembly method. To characterize prepared NPs, zeta potential, diameter size, surface morphology, disparity, and lipid coating of hybrid NPs were detrmined using dynamic light scattering, scanning electron microscope and Fourier transform infrared spectroscopy techniques. High-performance liquid chromatography was employed to evaluate drug loading yield and encapsulation efficiency and in vitro drug release of prepared NPs. The cytotoxicity of hybrid NPs was assayed on normal L929 alveolar epithelial cells using MTT method. Prepared NPs were found to disperse as individual NPs with a well-defined spherical shape. The hydrodynamic diameter and surface charge of NAC-loaded hybrid NPs were 81.8 ± 1.3 nm and -33.1 ± 2.1 mV, respectively. Drug loading yield and encapsulation efficiency of NAC-loaded hybrid NPs were found to be 38 ± 2.1% and 67 ± 5.7%, respectively. Prepared hybrid NPs showed no significant cytotoxicity against normal alveolar cells. Our data suggest that the hybrid PLGA-lecithin NPs may be An efficient controlled release drug delivery system for NAC. J. Cell. Biochem. 118: 4203-4209, 2017. © 2017 Wiley Periodicals, Inc.}, }
@article {pmid28419143, year = {2017}, author = {Han, X and Han, Y and Zheng, Y and Sun, Q and Ma, T and Zhang, J and Xu, L}, title = {Chaetocin induces apoptosis in human melanoma cells through the generation of reactive oxygen species and the intrinsic mitochondrial pathway, and exerts its anti-tumor activity in vivo.}, journal = {PloS one}, volume = {12}, number = {4}, pages = {e0175950}, pmid = {28419143}, issn = {1932-6203}, mesh = {Animals ; Antineoplastic Agents/chemistry/pharmacology/*therapeutic use ; Apoptosis/*drug effects ; Cell Line, Tumor ; Chaetomium/chemistry ; Female ; Humans ; Melanoma/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice, Nude ; Mitochondria/drug effects/metabolism/pathology ; Piperazines/chemistry/pharmacology/therapeutic use ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Skin/*drug effects/metabolism/pathology ; Skin Neoplasms/*drug therapy/metabolism/pathology ; }, abstract = {Chaetocin is a small-molecule natural product produced by Chaetomium species fungi, and it has a potent anti-proliferative pharmacological activity on various cancer cells. However, the effect of chaetocin on anti-melanoma pharmacological role has not been investigated. Therefore, in this study, we explored the effect of chaetocin on cell proliferation in the human melanoma Sk-Mel-28 and A375 cells and the growth of tumor xenografts in nude mice. The results indicated that chaetocin treatment significantly suppressed cell proliferation and induced apoptosis in the Sk-Mel-28 and A375 cells in a dose- and time-dependent manner. Furthermore, chaetocin treatment resulted in an increased level of cellular reactive oxygen species (ROS), and pre-incubation of cells with N-acetylcysteine (NAC) significantly abrogated chaetocin-induced apoptosis in the melanoma cells. A significant reduction of mitochondrial membrane potential and the release of cytochrome c were observed after chaetocin treatment. Additionally, chaetocin treatment significantly up-regulated the protein levels of Bax, cleaved caspase-9/-3, simultaneously down-regulated the protein levels of Bcl-2, procaspase-9/-3, and activated caspase-9/-3 activity in the melanoma cells. The in vivo data demonstrated that chaetocin treatment significantly inhibited the growth of melanoma tumor xenografts in nude mice, which was closely associated with apoptosis induction, a reduced level of PCNA (proliferating cell nuclear antigen) expression, and activation of capase-9/-3 in tumor xenografts. These are the first data to demonstrate that chaetocin exerts a proapoptotic activity on human melanoma cells through ROS generation and the intrinsic mitochondrial pathway. Therefore, chaetocin might represent an effective candidate for melanoma chemotherapy.}, }
@article {pmid28418588, year = {2017}, author = {Lee, EY and Bae, HC and Lee, H and Jang, Y and Park, YH and Kim, JH and Ryu, WI and Choi, BH and Kim, JH and Jeong, SH and Son, SW}, title = {Intracellular ROS levels determine the apoptotic potential of keratinocyte by Quantum Dot via blockade of AKT Phosphorylation.}, journal = {Experimental dermatology}, volume = {26}, number = {11}, pages = {1046-1052}, doi = {10.1111/exd.13365}, pmid = {28418588}, issn = {1600-0625}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; Carboxylic Acids ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Survival ; Cells, Cultured ; Epidermis/*metabolism ; Humans ; Keratinocytes/metabolism ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Quantum Dots/chemistry/*toxicity ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Quantum dots (QDs) have shown great potential for biomedical use in a broad range including diagnostic agents. However, the regulatory mechanism of dermal toxicity is poorly understood. In this study, we investigated how QDs-induced apoptosis is regulated in human keratinocytes. We also examined the effect of carboxylic acid-coated QDs (QD 565 and QD 655) on reactive oxygen species (ROS) production and apoptosis-related cellular signalling. The viability of keratinocyte was inhibited by two types of QDs in a concentration-dependent manner. QDs induce ROS production and blockade of AKT phosphorylation. Moreover, the cleavage of AKT-dependent pro-apoptotic proteins such as poly (ADP-ribose) polymerase, caspases-3 and caspases-9 was significantly increased. We also found that a decrease in cellular ROS level by ROS scavenger, N-acetylcysteine (NAC), resulting in the abolishment of QDs-induced AKT de-phosphorylation and cellular apoptosis. Interestingly, QD 655 had a more cytotoxic effect including oxidative stress and AKT-dependent apoptosis than QD 565. In addition, QD 655 had the cytotoxic potential in the human skin equivalent model (HSEM). These data show that QD-induced intracellular ROS levels may be an important parameter in QD-induced apoptosis. These findings from this study indicate that intracellular ROS levels might determine the apoptotic potential of keratinocyte by QD via blockade of AKT phosphorylation.}, }
@article {pmid28418078, year = {2017}, author = {Roy, A and Ahir, M and Bhattacharya, S and Parida, PK and Adhikary, A and Jana, K and Ray, M}, title = {Induction of mitochondrial apoptotic pathway in triple negative breast carcinoma cells by methylglyoxal via generation of reactive oxygen species.}, journal = {Molecular carcinogenesis}, volume = {56}, number = {9}, pages = {2086-2103}, doi = {10.1002/mc.22665}, pmid = {28418078}, issn = {1098-2744}, mesh = {Animals ; Antineoplastic Agents/*therapeutic use ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Drug Screening Assays, Antitumor ; Humans ; Mice ; Mice, Inbred BALB C ; Mitochondria/*drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Pyruvaldehyde/*therapeutic use ; Reactive Oxygen Species/*metabolism ; Transcription Factor RelA/metabolism ; Triple Negative Breast Neoplasms/*drug therapy/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Triple negative breast cancer (TNBC) tends to form aggressive tumors associated with high mortality and morbidity which urge the need for development of new therapeutic strategies. Recently, the normal metabolite Methylglyoxal (MG) has been documented for its anti-proliferative activity against human breast cancer. However, the mode of action of MG against TNBC remains open to question. In our study, we investigated the anticancer activity of MG in MDA MB 231 and 4T1 TNBC cell lines and elucidated the underlying mechanisms. MG dose-dependently caused cell death, induced apoptosis, and generated ROS in both the TNBC cell lines. Furthermore, such effects were attenuated in presence of ROS scavenger N-Acetyl cysteine. MG triggered mitochondrial cytochrome c release in the cytosol and up-regulated Bax while down-regulated anti-apoptotic protein Bcl-2. Additionally, MG treatment down-regulated phospho-akt and inhibited the nuclear translocation of the p65 subunit of NF-κB. MG exhibited a tumor suppressive effect in BALB/c mouse 4T1 breast tumor model as well. The cytotoxic effect was studied using MTT assay. Apoptosis, ROS generation, and mitochondrial dysfunction was evaluated by flow cytometry as well as fluorescence microscopy. Western blot assay was performed to analyze proteins responsible for apoptosis. This study demonstrated MG as a potent anticancer agent against TNBC both in vitro and in vivo. The findings will furnish fresh insights into the treatment of this subgroup of breast cancer.}, }
@article {pmid28415723, year = {2017}, author = {Wang, H and Bouzakoura, S and de Mey, S and Jiang, H and Law, K and Dufait, I and Corbet, C and Verovski, V and Gevaert, T and Feron, O and Van den Berge, D and Storme, G and De Ridder, M}, title = {Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species.}, journal = {Oncotarget}, volume = {8}, number = {22}, pages = {35728-35742}, pmid = {28415723}, issn = {1949-2553}, mesh = {Animals ; Apoptosis/drug effects ; Auranofin/*pharmacology ; Cell Line, Tumor ; DNA Damage/drug effects ; Disease Models, Animal ; Glutathione/metabolism ; Hypoxia/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Oxygen Consumption/drug effects ; Radiation Tolerance/*drug effects ; Radiation-Sensitizing Agents/*pharmacology ; Reactive Oxygen Species/*metabolism ; Thioredoxin-Disulfide Reductase/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Auranofin (AF) is an anti-arthritic drug considered for combined chemotherapy due to its ability to impair the redox homeostasis in tumor cells. In this study, we asked whether AF may in addition radiosensitize tumor cells by targeting thioredoxin reductase (TrxR), a critical enzyme in the antioxidant defense system operating through the reductive protein thioredoxin. Our principal findings in murine 4T1 and EMT6 tumor cells are that AF at 3-10 μM is a potent radiosensitizer in vitro, and that at least two mechanisms are involved in TrxR-mediated radiosensitization. The first one is linked to an oxidative stress, as scavenging of reactive oxygen species (ROS) by N-acetyl cysteine counteracted radiosensitization. We also observed a decrease in mitochondrial oxygen consumption with spared oxygen acting as a radiosensitizer under hypoxic conditions. Overall, radiosensitization was accompanied by ROS overproduction, mitochondrial dysfunction, DNA damage and apoptosis, a common mechanism underlying both cytotoxic and antitumor effects of AF. In tumor-bearing mice, a simultaneous disruption of the thioredoxin and glutathione systems by the combination of AF and buthionine sulfoximine was shown to significantly improve tumor radioresponse. In conclusion, our findings illuminate TrxR in cancer cells as an exploitable radiobiological target and warrant further validation of AF in combination with radiotherapy.}, }
@article {pmid28411131, year = {2017}, author = {Shahidi, S and Zargooshnia, S and Asl, SS and Komaki, A and Sarihi, A}, title = {Influence of N-acetyl cysteine on beta-amyloid-induced Alzheimer's disease in a rat model: A behavioral and electrophysiological study.}, journal = {Brain research bulletin}, volume = {131}, number = {}, pages = {142-149}, doi = {10.1016/j.brainresbull.2017.04.001}, pmid = {28411131}, issn = {1873-2747}, mesh = {Acetylcysteine/metabolism/*pharmacology/*therapeutic use ; Alzheimer Disease/metabolism/physiopathology ; Amyloid beta-Peptides/drug effects/*metabolism ; Animals ; Avoidance Learning/drug effects ; Disease Models, Animal ; Excitatory Postsynaptic Potentials/drug effects ; Hippocampus/drug effects ; Long-Term Potentiation/drug effects ; Male ; Maze Learning/drug effects ; Memory/drug effects ; Neurons/drug effects ; Rats ; Rats, Wistar ; }, abstract = {Alzheimer's disease is an age-related neurodegenerative disorder characterized by a progressive decline in cognitive function due to the extracellular accumulation and deposition of beta-amyloid peptide (Aβ). The purpose of this study was to evaluate the protective effect of N-acetyl cysteine (NAC) on learning and memory in an Aβ-induced Alzheimer's disease model in adult male rats, using behavioral and electrophysiological methods Thirty-five rats were divided into five groups: control, sham-operated, Aβ, Aβ+NAC (1-14days), and Aβ+NAC (14-28days). Learning and memory were evaluated behaviorally using the passive avoidance test and electrophysiologically by assessing hippocampal long-term potentiation, a cellular mechanism of learning and memory. Intrahippocampal Aβ injections reduced step-through latency in the passive avoidance test, and decreased both the amplitude of hippocampal neuron population spikes and the slope of excitatory postsynaptic potentials, compared to the sham and control groups. Administration of NAC in rats receiving Aβ alleviated the Aβ-induced deficits in comparison to the Aβ-only group. The results of this study suggest that NAC shows potential for treatment of Alzheimer's disease.}, }
@article {pmid28410397, year = {2017}, author = {Visagie, MH and van den Bout, I and Joubert, AM}, title = {A bis-sulphamoylated estradiol derivative induces ROS-dependent cell cycle abnormalities and subsequent apoptosis.}, journal = {PloS one}, volume = {12}, number = {4}, pages = {e0176006}, pmid = {28410397}, issn = {1932-6203}, mesh = {2-Methoxyestradiol ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Autophagy/drug effects ; Cell Line, Tumor ; DNA Breaks, Double-Stranded/drug effects ; Estradiol/*analogs &amp; derivatives/*toxicity ; G2 Phase Cell Cycle Checkpoints/drug effects ; Histones/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; M Phase Cell Cycle Checkpoints/drug effects ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Clinical trials have revealed that the potential anticancer agent, 2-methoxyestradiol (2ME2) has limitations due to its low bioavailability. Subsequently, 2ME2 derivatives including (8R,13S,14S,17S)-2-ethyl-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrane-3,17-diyl bis(sulphamate) (EMBS) have shown improved efficacies in inducing apoptosis. However, no conclusive data exist to explain the mode of action exerted by these drugs. This study investigated the mode of action used by EMBS as a representative of the sulphamoylated 2ME2 derivatives. Hydrogen peroxide and superoxide production was quantified using dichlorofluorescein diacetate and hydroethidine. Cell proliferation and mitochondrial metabolism were investigated using crystal violet and Alamar Blue. Apoptosis was assessed using Annexin V-FITC while mitochondrial integrity was assessed using Mitocapture. Autophagy was visualised using LC3B II antibodies. The effects of EMBS on H2A phosphorylation and nuclei were visualised using phospho H2A antibody and 4',6-diamidino-2-phenylindole, dihydrochloride. Data showed that EMBS exposure leads to increased reactive oxygen species (ROS) production which is correlated with loss of cell proliferation, mitochondrial membrane damage, decreased metabolic activity, G2/M arrest, endoreduplication, DNA double stranded breaks, micronuclei and apoptosis induction. Treatment of EMBS-exposed cells with the ROS scavenger, N-acetyl cysteine, abrogated ROS production, cell cycle arrest and apoptosis implying an essential role for ROS production in EMBS signaling. The inhibition of c-Jun N-terminal kinase (JNK) activity also inhibited EMBS-induced apoptosis suggesting that EMBS triggers apoptosis via the JNK pathway. Lastly, evaluation of LC3IIB protein levels indicated that autophagy is not activated in EMBS-exposed cells. Our data shows that EMBS targets a pathway that leads to increased ROS production as an early event that culminates in G2/M arrest and apoptosis by means of JNK-signaling in cancer cells. This study suggests a novel oxidative stress-dependent mode of action for sulphamoylated derivatives.}, }
@article {pmid28409295, year = {2017}, author = {Rojas-Valencia, L and Velez-Pardo, C and Jimenez-Del-Rio, M}, title = {Metal chelator TPEN selectively induces apoptosis in K562 cells through reactive oxygen species signaling mechanism: implications for chronic myeloid leukemia.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {30}, number = {3}, pages = {405-421}, doi = {10.1007/s10534-017-0015-0}, pmid = {28409295}, issn = {1572-8773}, mesh = {Adult ; Antineoplastic Agents/administration &amp; dosage/chemistry/*pharmacology ; Apoptosis/*drug effects ; Cells, Cultured ; Chelating Agents/administration &amp; dosage/chemistry/*pharmacology ; Drug Screening Assays, Antitumor ; Ethylenediamines/administration &amp; dosage/chemistry/*pharmacology ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/metabolism/pathology ; Male ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Young Adult ; Zinc/chemistry/pharmacology ; }, abstract = {Chronic myeloid leukemia (CML) is a hematologic disorder characterized by the constitutive expression of BCR-ABL tyrosine kinase. Although successful implementation of tyrosine kinase inhibitors for the treatment of CML remain a traditional choice for molecularly targeted therapy, some patients present primary or secondary resistance to such therapy. Therefore, alternative therapeutic strategies are required to treat resistant CML cells. Accordingly, new anti-proliferative and/or pro-apoptotic compounds would be needed for clinical treatment. In the present investigation, we demonstrate that TPEN (e.g. 3 μM), a lipid-soluble metal chelator, induces apoptosis in K562 cells via a molecular cascade involving H2O2 ≫ JNK, NF-κB > c-JUN, P73 > PUMA, BAX > loss of ΔΨm > CASPASE-3 > nuclei/DNA fragmentation. Fragmentation of the nuclei and DNA are indicative of cell death by apoptosis. Remarkably, the antioxidant N-acetyl-cysteine, and inhibitors of the transcription factors CASPASE 3 and (JNK) kinase, decreased oxidative stress (OS) and cell death in these cells. This is evidenced by fluorescence microscopy, flow cytometry and immunocytochemistry for OS markers (e.g. generation of H2O2 and DJ 1 oxidation) and nuclear expression of apoptotic markers (e.g. activated caspase 3 and JNK kinase). In addition, TPEN causes no detectable damage in human peripheral blood lymphocyte cells (hPBLCs). We conclude that TPEN selectively induces apoptosis in K562 cells via an OS-mechanism. Our findings may provide insight into more effective CML anticancer therapies.}, }
@article {pmid28403598, year = {2017}, author = {Palleschi, G and Carbone, A and Zanello, PP and Mele, R and Leto, A and Fuschi, A and Al Salhi, Y and Velotti, G and Al Rawashdah, S and Coppola, G and Maurizi, A and Maruccia, S and Pastore, AL}, title = {Prospective study to compare antibiosis versus the association of N-acetylcysteine, D-mannose and Morinda citrifolia fruit extract in preventing urinary tract infections in patients submitted to urodynamic investigation.}, journal = {Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica}, volume = {89}, number = {1}, pages = {45-50}, doi = {10.4081/aiua.2017.1.45}, pmid = {28403598}, issn = {1124-3562}, mesh = {Acetylcysteine/administration &amp; dosage ; Aged ; Anti-Bacterial Agents/*administration &amp; dosage ; Antibiosis/drug effects ; Antibiotic Prophylaxis/methods ; Bacterial Adhesion/physiology ; Dioxolanes/*administration &amp; dosage ; Female ; Fluoroquinolones/*administration &amp; dosage ; Fruit ; Humans ; Incidence ; Male ; Mannose/administration &amp; dosage ; Middle Aged ; Morinda/*chemistry ; Piperazines/*administration &amp; dosage ; Plant Extracts/administration &amp; dosage ; Prospective Studies ; Urinary Tract Infections/*prevention &amp; control ; Urodynamics ; }, abstract = {BACKGROUND: The abuse of antimicrobical drugs has increased the resistance of microorganisms to treatments, thus to make urinary tract infections (UTIs) more difficult to eradicate. Among natural substances used to prevent UTI, literature has provided preliminary data of the beneficial effects of D-mannose, N-acetylcysteine, and Morinda citrifolia fruit extract, due to their complementary mechanism of action which contributes respectively to limit bacteria adhesion to the urothelium, to destroy bacterial pathogenic biofilm, and to the anti-inflammatory and analgesic activity. The purpose of this study was to compare the administration of an association of D-mannose, N-acetylcysteine (NAC) and Morinda citrifolia extract versus antibiotic therapy in the prophylaxis of UTIs potentially associated with urological mini-invasive diagnostics procedures, in clinical model of the urodynamic investigation.<br><br>METHODS: 80 patients eligible for urodynamic examination, 42 men and 38 women, have been prospectively enrolled in the study and randomised in two groups (A and B) of 40 individuals. Patients of group A followed antibiotic therapy with Prulifloxacine, by mouth 400 mg/day for 5 days, while patients of the group B followed the association of mannose and NAC therapy, two vials/day for 7 days. Ten days after the urodynamic study, the patients were submitted to urine examination and urine culture.<br><br>RESULTS: The follow up assessment didn't show statistical significant difference between the two groups regarding the incidence of UTI.<br><br>CONCLUSIONS: The association of mannose and NAC therapy resulted similar to the antibiotic therapy in preventing UTIs in patients submitted to urodynamic examination. This result leads to consider the possible use of these nutraceutical agents as a good alternative in the prophylaxis of the UTI afterwards urological procedures in urodynamics.}, }
@article {pmid28400474, year = {2017}, author = {Fu, G and Xu, Q and Qiu, Y and Jin, X and Xu, T and Dong, S and Wang, J and Ke, Y and Hu, H and Cao, X and Wang, D and Cantor, H and Gao, X and Lu, L}, title = {Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1.}, journal = {The Journal of experimental medicine}, volume = {214}, number = {5}, pages = {1453-1469}, pmid = {28400474}, issn = {1540-9538}, mesh = {Animals ; Cell Differentiation/physiology ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/physiopathology ; Male ; Mice ; Mice, Knockout ; Protein Serine-Threonine Kinases/*physiology ; Reactive Oxygen Species/metabolism ; Smad2 Protein/physiology ; Th17 Cells/*physiology ; }, abstract = {T helper type 17 cells (Th17 cells) are major contributors to many autoimmune diseases. In this study, we demonstrate that the germinal center kinase family member MINK1 (misshapen/NIK-related kinase 1) negatively regulates Th17 cell differentiation. The suppressive effect of MINK1 on induction of Th17 cells is mediated by the inhibition of SMAD2 activation through direct phosphorylation of SMAD2 at the T324 residue. The importance of MINK1 to Th17 cell differentiation was strengthened in the animal model of experimental autoimmune encephalomyelitis (EAE). Moreover, we show that the reactive oxygen species (ROS) scavenger N-acetyl cysteine boosts Th17 cell differentiation in a MINK1-dependent manner and exacerbates the severity of EAE. Thus, we have not only established MINK1 as a critical regulator of Th17 cell differentiation, but also clarified that accumulation of ROS may limit the generation of Th17 cells. The contribution of MINK1 to ROS-regulated Th17 cell differentiation may suggest an important mechanism for the development of autoimmune diseases influenced by antioxidant dietary supplements.}, }
@article {pmid28400046, year = {2017}, author = {Chen, W and Zhang, Q and Cheng, S and Huang, J and Diao, G and Han, J}, title = {Atgl gene deletion predisposes to proximal tubule damage by impairing the fatty acid metabolism.}, journal = {Biochemical and biophysical research communications}, volume = {487}, number = {1}, pages = {160-166}, doi = {10.1016/j.bbrc.2017.03.170}, pmid = {28400046}, issn = {1090-2104}, mesh = {Animals ; Apoptosis/*physiology ; Fatty Acids/*metabolism ; Gene Deletion ; Kidney Tubules, Proximal/*metabolism/pathology ; Lipase/genetics/*metabolism ; Lipid Metabolism ; Male ; Mice ; Mice, Knockout ; PPAR alpha/*metabolism ; Reactive Oxygen Species/metabolism ; Renal Insufficiency, Chronic/*metabolism/pathology ; }, abstract = {Fibrosis is the final common pathway of chronic kidney disease (CKD). Normal lipid metabolism is integral to renal physiology, and disturbances of renal lipid metabolism are increasingly being linked with CKD, including the fibrosis. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme of lipolysis. In the present study, we used Atgl[-/-] mice to investigate whether ATGL played a role in the regulation of proximal convoluted tubule (PCT) lipid metabolism and renal fibrosis development. ATGL deficiency led to lipid vacuolation of PCT and tubulointerstitial fibrosis, accompanied by massive albuminuria and decreased creatinine clearance rate (Ccr). In vitro experiments indicated that inhibition of ATGL in proximal tubular cell line HK-2 promoted intracellular lipid deposition, reactive oxygen species (ROS) accumulation and cell apoptosis. Both in vitro and in vivo experiments showed that ATGL inhibition decreased the renal peroxisome proliferator-activated receptorα(PPARα) expression, which implied the suppressed lipid metabolism. The antioxidant N-acetylcysteine (NAC) could partially reverse the effect of ROS accumulation and cell apoptosis, but could not restore the PPARαdecrease. These data raise the possibility that ATGL deficiency could impair the renal fatty acid metabolism though inhibiting PPARαexpression, which may lead to lipid deposition and cell apoptosis of PCT, and finally contribute to the renal fibrosis and dysfunction.}, }
@article {pmid28393248, year = {2017}, author = {Ma, SB and Zhang, R and Miao, S and Gao, B and Lu, Y and Hui, S and Li, L and Shi, XP and Wen, AD}, title = {Epigallocatechin-3-gallate ameliorates insulin resistance in hepatocytes.}, journal = {Molecular medicine reports}, volume = {15}, number = {6}, pages = {3803-3809}, doi = {10.3892/mmr.2017.6450}, pmid = {28393248}, issn = {1791-3004}, mesh = {Animals ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line, Tumor ; Glucose/metabolism ; Glycogen/metabolism ; Hep G2 Cells ; Hepatocytes/*drug effects/*metabolism ; Humans ; Insulin/metabolism ; *Insulin Resistance ; Male ; Mice ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Hyperglycemia is a typical pathogenic factor in a series of complications among patients with type II diabetes. Epigallocatechin-3-gallate (EGCG) is the major polyphenol extracted from green tea and is reported to be an antioxidant. The aim of the present study was to examine the effect of EGCG on insulin resistance in human HepG2 cells pretreated with high concentrations of glucose. The protein kinase B (AKT)/glycogen synthase kinase (GSK) pathways were analyzed using western blot analysis in HepG2 cells and primary mouse hepatocytes treated with high glucose and/or EGCG. Cellular glycogen content was determined using a glycogen assay kit. Reactive oxygen species (ROS) production was determined using dihydroethidium staining and flow cytometry. c‑JUN N‑terminal kinase (JNK)/insulin receptor substrate 1 (IRS1)/AKT/GSK signaling was explored using western blot analysis in HepG2 cells treated with high glucose and/or EGCG or N-acetyl-cysteine. High glucose significantly decreased the levels of phosphorylated AKT and GSK in HepG2 cells and mouse primary hepatocytes. Pretreatment with EGCG significantly restored the activation of AKT and GSK in HepG2 cells and primary hepatocytes exposed to high glucose. In HepG2 cells and primary hepatocytes, glycogen synthesis was improved by EGCG treatment in a dose‑dependent manner. High glucose significantly stimulated the production of ROS while EGCG protected high glucose‑induced ROS production. ROS is known to serve a major role in high glucose induced‑insulin resistance by increasing JNK and IRS1 serine phosphorylation. In the present study, EGCG was observed to enhance the insulin‑signaling pathway. EGCG ameliorated high glucose‑induced insulin resistance in the hepatocytes by potentially decreasing ROS‑induced JNK/IRS1/AKT/GSK signaling.}, }
@article {pmid28392212, year = {2017}, author = {Amen, F and Machin, A and Touriño, C and Rodríguez, I and Denicola, A and Thomson, L}, title = {N-acetylcysteine improves the quality of red blood cells stored for transfusion.}, journal = {Archives of biochemistry and biophysics}, volume = {621}, number = {}, pages = {31-37}, doi = {10.1016/j.abb.2017.02.012}, pmid = {28392212}, issn = {1096-0384}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Blood Preservation/*methods ; Cells, Cultured ; Dose-Response Relationship, Drug ; Erythrocyte Transfusion/*methods ; Erythrocytes/cytology/drug effects/*physiology ; Hemolysis/*drug effects/physiology ; Humans ; Hydrogen Peroxide/pharmacokinetics ; Male ; Organ Preservation Solutions/*administration &amp; dosage ; Oxidative Stress/drug effects/physiology ; }, abstract = {Storage inflicts a series of changes on red blood cells (RBC) that compromise the cell survival and functionality; largely these alterations (storage lesions) are due to oxidative modifications. The possibility of improving the quality of packed RBC stored for transfusion including N-acetylcysteine (NAC) in the preservation solution was explored. Relatively high concentrations of NAC (20-25 mM) were necessary to prevent the progressive leakage of hemoglobin, while lower concentrations (≥2.5 mM) were enough to prevent the loss of reduced glutathione during the first 21 days of storage. Peroxiredoxin-2 was also affected during storage, with a progressive accumulation of disulfide-linked dimers and hetero-protein complexes in the cytosol and also in the membrane of stored RBC. Although the presence of NAC in the storage solution was unable to avoid the formation of thiol-mediated protein complexes, it partially restored the capacity of the cell to metabolize H2O2, indicating the potential use of NAC as an additive in the preservation solution to improve RBC performance after transfusion.}, }
@article {pmid28389902, year = {2017}, author = {Pedroso, TF and Oliveira, CS and Fonseca, MM and Oliveira, VA and Pereira, ME}, title = {Effects of Zinc and N-Acetylcysteine in Damage Caused by Lead Exposure in Young Rats.}, journal = {Biological trace element research}, volume = {180}, number = {2}, pages = {275-284}, doi = {10.1007/s12011-017-1009-z}, pmid = {28389902}, issn = {1559-0720}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Animals, Newborn ; Biomarkers/blood/metabolism ; Blood-Brain Barrier/drug effects/metabolism ; Cerebrum/*drug effects/enzymology/metabolism ; Chlorides/administration &amp; dosage/metabolism/pharmacokinetics/*therapeutic use ; Drug Therapy, Combination ; Environmental Pollutants/blood/metabolism/toxicity ; GPI-Linked Proteins/antagonists &amp; inhibitors/metabolism ; Injections, Subcutaneous ; Lead/blood/metabolism/toxicity ; Lead Poisoning, Nervous System/blood/metabolism/*prevention &amp; control ; Nerve Tissue Proteins/antagonists &amp; inhibitors/metabolism ; Neurons/*drug effects/enzymology/metabolism ; Neuroprotective Agents/administration &amp; dosage/metabolism/pharmacokinetics/*therapeutic use ; Organometallic Compounds/administration &amp; dosage ; Porphobilinogen Synthase/antagonists &amp; inhibitors/blood ; Random Allocation ; Rats, Wistar ; Tissue Distribution/drug effects ; Toxicokinetics ; Zinc Compounds/administration &amp; dosage/metabolism/pharmacokinetics/*therapeutic use ; }, abstract = {This study investigated the toxicity of rats exposed to lead acetate (AcPb) during the second phase of brain development (8-12 days postnatal) in hematological and cerebral parameters. Moreover, the preventive effect of zinc chloride (ZnCl2) and N-acetylcysteine (NAC) was investigated. Pups were injected subcutaneously with saline (0.9% NaCl solution), ZnCl2 (27 mg/kg/day), NAC (5 mg/kg/day) or ZnCl2 plus NAC for 5 days (3rd-7th postnatal days), and with saline (0.9% NaCl solution) or AcPb (7 mg/kg/day) in the five subsequent days (8th-12th postnatal days). Animals were sacrificed 21 days after the last AcPb exposure. Pups exposed to AcPb presented inhibition of blood porphobilinogen-synthase (PBG-synthase) activity without changes in hemoglobin content. ZnCl2 pre-exposure partially prevented PBG-synthase inhibition. Regarding neurotoxicity biomarkers, animals exposed to AcPb presented a decrease in cerebrum acetylcholinesterase (AChE) activity and an increase in Pb accumulation in blood and cerebrum. These changes were prevented by pre-treatment with ZnCl2, NAC, and ZnCl2 plus NAC. AcPb exposure caused no alteration in behavioral tasks. In short, results show that AcPb inhibited the activity of two important enzymatic biomarkers up to 21 days after the end of the exposure. Moreover, ZnCl2 and NAC prevented the alterations induced by AcPb.}, }
@article {pmid28389245, year = {2017}, author = {Li, Y and Wen, JM and Du, CJ and Hu, SM and Chen, JX and Zhang, SG and Zhang, N and Gao, F and Li, SJ and Mao, XW and Miyamoto, H and Ding, KF}, title = {Thymol inhibits bladder cancer cell proliferation via inducing cell cycle arrest and apoptosis.}, journal = {Biochemical and biophysical research communications}, volume = {491}, number = {2}, pages = {530-536}, doi = {10.1016/j.bbrc.2017.04.009}, pmid = {28389245}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Antineoplastic Agents, Phytogenic/antagonists &amp; inhibitors/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/genetics/metabolism ; Caspase 9/genetics/metabolism ; Cell Line, Transformed ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytochromes c/metabolism ; Epithelial Cells/*drug effects/metabolism/pathology ; Free Radical Scavengers/pharmacology ; G2 Phase Cell Cycle Checkpoints/*drug effects ; *Gene Expression Regulation, Neoplastic ; Humans ; Imidazoles/pharmacology ; MAP Kinase Kinase 4/genetics/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Pyridines/pharmacology ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/metabolism ; Thymol/antagonists &amp; inhibitors/*pharmacology ; Urothelium/drug effects/metabolism/pathology ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Thymol is a phenolic compound with various pharmacological activities such as anti-inflammatory, anti-bacterial and anti-tumor effects. However, the effect of thymol on bladder cancer cell growth is still elusive. The purpose of this study is to investigate the efficacy of thymol in bladder cancer cells and its underlying mechanism. Thymol inhibited bladder cancer cell proliferation in a dose and time-dependent manner. We also observed cell cycle arrest at the G2/M phase after the treatment of thymol. Moreover, thymol could induce apoptosis in bladder cancer cells via the intrinsic pathway along with caspase-3/9 activation, release of cytochrome c and down-regulation of anti-apoptotic Bcl-2 family proteins. The activation of JNK and p38 was also critical for thymol-induced apoptosis since it was abrogated by the treatment of JNK inhibitor (SP600125), and p38 inhibitor (SB203580) but not ERK inhibitor (SCH772984). Furthermore, the generation of ROS (reactive oxygen species) was detected after the treatment of thymol. ROS scavenger NAC (N-acetyl cysteine) could block the thymol-triggered apoptosis and activation of MAPKs. These findings offer a novel therapeutic approach for bladder cancer.}, }
@article {pmid28388678, year = {2017}, author = {Zhang, L and Gan, X and He, Y and Zhu, Z and Zhu, J and Yu, H}, title = {Drp1-dependent mitochondrial fission mediates osteogenic dysfunction in inflammation through elevated production of reactive oxygen species.}, journal = {PloS one}, volume = {12}, number = {4}, pages = {e0175262}, pmid = {28388678}, issn = {1932-6203}, mesh = {3T3 Cells ; Acetylcysteine/administration &amp; dosage ; Animals ; Dynamins/*physiology ; Inflammation/metabolism/*physiopathology ; Mice ; Mitochondrial Dynamics/*physiology ; Osteogenesis/*physiology ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha/physiology ; }, abstract = {Although previous studies have implicated pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), to be detrimental for osteogenic activity, the related regulatory mechanisms are not yet fully validated. Since mitochondria host several essential metabolic processes and play a pivotal role in cellular functions, whether and how mitochondrial function contributes to inflammation-induced bone destruction needs further exploration. Our findings revealed that TNF-α impaired osteoblast function, including decreased mRNA levels of osteogenic markers, suppressed ALP expression and activity, and compromised cellular viability. Moreover, increased reactive oxygen species (ROS)-mediated oxidative stress in the TNF-α-treated group enhanced excessive mitochondrial fragmentation and disrupted mitochondrial function. However, treatment with antioxidant N-acetyl cysteine (NAC) or mitochondrial division inhibitor Mdivi-1 protected the cells from these adverse phenomena. These findings provide new insights into the role of the Drp1-dependent mitochondrial pathway in the osteogenic dysfunction during inflammation, indicating that this pathway may be a target for the development of new therapeutic approaches for the prevention and treatment of inflammation-induced bone destruction.}, }
@article {pmid28387735, year = {2017}, author = {Li, D and Zhao, K and Yang, X and Xiao, X and Tang, S}, title = {TCS2 Increases Olaquindox-Induced Apoptosis by Upregulation of ROS Production and Downregulation of Autophagy in HEK293 Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {22}, number = {4}, pages = {}, pmid = {28387735}, issn = {1420-3049}, mesh = {Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Survival/drug effects ; Down-Regulation ; HEK293 Cells ; Humans ; Oxidative Stress/drug effects ; Quinoxalines/*pharmacology ; Reactive Oxygen Species/*metabolism ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {Olaquindox, a feed additive, has drawn public attention due to its potential mutagenicity, genotoxicity, hepatoxicity and nephrotoxicity. The purpose of this study was to investigate the role of tuberous sclerosis complex (TSC2) pathways in olaquindox-induced autophagy in human embryonic kidney 293 (HEK293) cells. The results revealed that olaquindox treatment reduced the cell viability of HEK293 cells and downregulated the expression of TSC2 in a dose- and time-dependent manner. Meanwhile, olaquindox treatment markedly induced the production of reactive oxygen species (ROS), cascaded to autophagy, oxidative stress, and apoptotic cell death, which was effectively eliminated by the antioxidant N-acetylcysteine (NAC). Furthermore, overexpression of TSC2 attenuated olaquindox-induced autophagy in contrast to inducing the production of ROS, oxidative stress and apoptosis. Consistently, knockdown of TSC2 upregulated autophagy, and decreased olaquindox-induced cell apoptosis. In conclusion, our findings indicate that TSC2 partly participates in olaquindox-induced autophagy, oxidative stress and apoptosis, and demonstrate that TSC2 has a negative regulation role in olaquindox-induced autophagy in HEK293 cells.}, }
@article {pmid28382174, year = {2017}, author = {Jiang, Y and Cao, Y and Wang, Y and Li, W and Liu, X and Lv, Y and Li, X and Mi, J}, title = {Cysteine transporter SLC3A1 promotes breast cancer tumorigenesis.}, journal = {Theranostics}, volume = {7}, number = {4}, pages = {1036-1046}, pmid = {28382174}, issn = {1838-7640}, mesh = {Amino Acid Transport Systems, Basic/genetics/*metabolism ; Amino Acid Transport Systems, Neutral/genetics/*metabolism ; Animals ; Breast Neoplasms/pathology/*physiopathology ; *Carcinogenesis ; Cell Line, Tumor ; Cysteine/*metabolism ; Disease Models, Animal ; Gene Expression Profiling ; HEK293 Cells ; Heterografts ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; Survival Analysis ; }, abstract = {Cysteine is an essential amino acid for infants, aged people as well as patients with metabolic disorders. Although the thiol group of cysteine side chain is active in oxidative reactions, the role of cysteine in cancer remains largely unknown. Here, we report that the expression level of the solute carrier family 3, member 1 (SLC3A1), the cysteine carrier, tightly correlated with clinical stages and patients' survival. Elevated SLC3A1 expression accelerated the cysteine uptake and the accumulation of reductive glutathione (GSH), leading to reduced reactive oxygen species (ROS). ROS increased the stability and activity of PP2Ac, resulting in decreased AKT activity. Hence, SLC3A1 activated the AKT signaling through inhibiting PP2A phosphatase activity. Consistently, overexpression of SLC3A1 enhanced tumorigenesis of breast cancer cells, whereas blocking SLC3A1 either with specific siRNA or SLC3A1 specific inhibitor sulfasalazine suppressed tumor growth and also abolished dietary NAC-promoted tumor growth. Collectively, our data demonstrate that SLC3A1 promotes cysteine uptake and determines cellular response to antioxidant N-acetylcysteine, suggesting SLC3A1 is a potential therapeutic target for breast cancer.}, }
@article {pmid28377314, year = {2017}, author = {Manniello, MD and Del Gaudio, P and Aquino, RP and Russo, P}, title = {Clarithromycin and N-acetylcysteine co-spray-dried powders for pulmonary drug delivery: A focus on drug solubility.}, journal = {International journal of pharmaceutics}, volume = {533}, number = {2}, pages = {463-469}, doi = {10.1016/j.ijpharm.2017.03.079}, pmid = {28377314}, issn = {1873-3476}, mesh = {Acetylcysteine/*chemistry ; Administration, Inhalation ; Anti-Bacterial Agents/*chemistry ; Clarithromycin/*chemistry ; Drug Compounding/methods ; Drug Liberation ; *Dry Powder Inhalers ; Expectorants/*chemistry ; Powders ; Solubility ; }, abstract = {Cystic fibrosis (CF) lungs are usually susceptible to Pseudomonas aeruginosa colonization and this bacterium is resistant to immune system clearance and drug control. Particularly, the biofilm mode of growth protects several microorganisms from host defenses and antibacterial drugs, mainly due to a delayed penetration of the drug through the biofilm matrix. Biofilm, together with lung mucus viscosity and tenacity, reduces, therefore, the effectiveness of conventional antibiotic therapy in CF. The aim of this research was to design and develop a stable, portable, easy to use dry powder inhaler (DPI) for CF patients, able to release directly to the lung an association of macrolide antibiotics (clarithromycin) and a mucolytic agent (N-Acetyl-Cysteine). Its effectiveness is based on the counteracting of the characteristics of P. aeruginosa infections in CF (lung bacterial adhesion to lung epithelium, biofilm formation and mucus viscosity) and the ability to let the antimicrobial drug exert their pharmacological action. A solution of these two drugs, without any excipients, was spray-dried to obtain respirable microparticles, characterized by aerodynamic diameters suitable for inhalation (<5.0μm). The morphology evaluation evidenced particles shape dependent on water content in the spray drying feeds, with wrinkled particles more evident with higher water content. Moreover, thanks to the presence of N-acetylcysteine which can interact with clarithromycin dimethyl-amino group, a consistent enhancement of drug solubility was obtained, compared to raw material and to the drug sprayed alone. The mucolytic agent added in the DPI may improve the macrolide diffusion into the mucus, enabling its action.}, }
@article {pmid28377224, year = {2017}, author = {Jin, HO and Park, JA and Kim, HA and Chang, YH and Hong, YJ and Park, IC and Lee, JK}, title = {Piperlongumine downregulates the expression of HER family in breast cancer cells.}, journal = {Biochemical and biophysical research communications}, volume = {486}, number = {4}, pages = {1083-1089}, doi = {10.1016/j.bbrc.2017.03.166}, pmid = {28377224}, issn = {1090-2104}, mesh = {Antineoplastic Agents/administration &amp; dosage ; Apoptosis/drug effects ; Breast Neoplasms/*drug therapy/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Dioxolanes/*administration &amp; dosage ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; ErbB Receptors/*biosynthesis ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; MCF-7 Cells ; Reactive Oxygen Species/*metabolism ; }, abstract = {HER family receptors are frequently deregulated in breast cancer and the deregulation of these receptors is associated with poor prognosis. Thus, these receptors are considered therapeutic targets. In the present study, we found that piperlongumine (PL) downregulates the expression of HER family receptors HER1, HER2, and HER3 in breast cancer cells. Downregulation of these receptors by PL is mediated through the generation of reactive oxygen species (ROS), as N-acetyl-cysteine blocks it. Interestingly, the HER2-overexpressing cell lines BT474 and SkBr3 are somewhat more sensitive to PL than the low HER2-expressing cell line MCF7. In addition, the overexpression of HER2 increases the sensitivity of MCF7 cells to PL. Collectively, our data indicate the therapeutic potential of PL in the treatment of breast cancer.}, }
@article {pmid28376378, year = {2017}, author = {Huang, Y and He, Q}, title = {Inhibition of c-Src protects paraquat induced microvascular endothelial injury by modulating caveolin-1 phosphorylation and caveolae mediated transcellular permeability.}, journal = {Environmental toxicology and pharmacology}, volume = {52}, number = {}, pages = {62-68}, doi = {10.1016/j.etap.2017.01.023}, pmid = {28376378}, issn = {1872-7077}, mesh = {Acetylcysteine/pharmacology ; CSK Tyrosine-Protein Kinase ; Caveolae/drug effects/metabolism ; Caveolin 1/*metabolism ; Cell Line ; Cell Membrane Permeability/drug effects ; Endothelial Cells/*drug effects/metabolism ; Herbicides/*toxicity ; Humans ; Paraquat/*toxicity ; Phosphorylation ; Reactive Oxygen Species/metabolism ; src-Family Kinases/*antagonists &amp; inhibitors/metabolism ; }, abstract = {The mechanisms underlying paraquat induced acute lung injury (ALI) is still not clear. C-Src plays an important role in the regulation of microvascular endothelial barrier function and the pathogenesis of ALI. In the present study, we found that paraquat induced cell toxicity and an increase of reactive oxygen species (ROS) in endothelium. Paraquat exposure also induced significant increase of caveolin-1 phosphorylation, caveolae trafficking and albumin permeability in endothelial monolayers. C-Src depletion by siRNA significantly attenuate paraquat induced cell toxicity, caveolin-1 phosphorylation, caveolae formation and endothelial hyperpermeability. N-acetylcysteine (NAC) failed to protect endothelial monolayers against paraquat induced toxicity. Thus, our findings suggest that paraquat exposure increases paracellular endothelial permeability by increasing caveolin-1 phosphorylation in a c-Src dependant manner. The depletion of c-Src might protect microvascular endothelial function by regulating caveolin-1 phosphorylation and caveolae trafficking during paraquat exposure, and might have potential therapeutic effects on paraquat induced ALI.}, }
@article {pmid28369910, year = {2018}, author = {Zhu, Z and Huang, Y and Lv, L and Tao, Y and Shao, M and Zhao, C and Xue, M and Sun, J and Niu, C and Wang, Y and Kim, S and Cong, W and Mao, W and Jin, L}, title = {Acute ethanol exposure-induced autophagy-mediated cardiac injury via activation of the ROS-JNK-Bcl-2 pathway.}, journal = {Journal of cellular physiology}, volume = {233}, number = {2}, pages = {924-935}, doi = {10.1002/jcp.25934}, pmid = {28369910}, issn = {1097-4652}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; *Autophagy/drug effects ; Cardiomyopathy, Alcoholic/*enzymology/pathology ; Cardiotoxicity ; Cells, Cultured ; Disease Models, Animal ; *Ethanol ; Genetic Predisposition to Disease ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Microtubule-Associated Proteins/genetics/metabolism ; Myocytes, Cardiac/drug effects/*enzymology/pathology ; Phenotype ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Time Factors ; }, abstract = {Binge drinking is associated with increased cardiac autophagy, and often triggers heart injury. Given the essential role of autophagy in various cardiac diseases, this study was designed to investigate the role of autophagy in ethanol-induced cardiac injury and the underlying mechanism. Our study showed that ethanol exposure enhanced the levels of LC3-II and LC3-II positive puncta and promoted cardiomyocyte apoptosis in vivo and in vitro. In addition, we found that ethanol induced autophagy and cardiac injury largely via the sequential triggering of reactive oxygen species (ROS) accumulation, activation of c-Jun NH2-terminal kinase (JNK), phosphorylation of Bcl-2, and dissociation of the Beclin 1/Bcl-2 complex. By contrast, inhibition of ethanol-induced autophagic flux with pharmacologic agents in the hearts of mice and cultured cells significantly alleviated ethanol-induced cardiomyocyte apoptosis and heart injury. Elimination of ROS with the antioxidant N-acetyl cysteine (NAC) or inhibition of JNK with the JNK inhibitor SP600125 reduced ethanol-induced autophagy and subsequent autophagy-mediated apoptosis. Moreover, metallothionein (MT), which can scavenge reactive oxygen and nitrogen species, also attenuated ethanol-induced autophagy and cell apoptosis in MT-TG mice. In conclusion, our findings suggest that acute ethanol exposure induced autophagy-mediated heart toxicity and injury mainly through the ROS-JNK-Bcl-2 signaling pathway.}, }
@article {pmid28369600, year = {2017}, author = {Yoshino, H and Kashiwakura, I}, title = {Involvement of reactive oxygen species in ionizing radiation-induced upregulation of cell surface Toll-like receptor 2 and 4 expression in human monocytic cells.}, journal = {Journal of radiation research}, volume = {58}, number = {5}, pages = {626-635}, pmid = {28369600}, issn = {1349-9157}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cell Membrane/*metabolism/radiation effects ; Ceramides/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Monocytes/*metabolism/radiation effects ; Protein Biosynthesis/radiation effects ; *Radiation, Ionizing ; Reactive Oxygen Species/*metabolism ; Toll-Like Receptor 2/*metabolism ; Toll-Like Receptor 4/*metabolism ; Up-Regulation/*radiation effects ; }, abstract = {Toll-like receptors (TLRs) are pattern recognition receptors that recognize pathogen-associated molecular patterns and are indispensable for antibacterial and antiviral immunity. Our previous report showed that ionizing radiation increases the cell surface expressions of TLR2 and TLR4 and enhances their responses to agonists in human monocytic THP1 cells. The present study investigated how ionizing radiation increases the cell surface expressions of TLR2 and TLR4 in THP1 cells. The THP1 cells treated or not treated with pharmaceutical agents such as cycloheximide and N-acetyl-L-cysteine (NAC) were exposed to X-ray irradiation, following which the expressions of TLRs and mitogen-activated protein kinase were analyzed. X-ray irradiation increased the mRNA expressions of TLR2 and TLR4, and treatment with a protein synthesis inhibitor cycloheximide abolished the radiation-induced upregulation of their cell surface expressions. These results indicate that radiation increased those receptors through de novo protein synthesis. Furthermore, treatment with an antioxidant NAC suppressed not only the radiation-induced upregulation of cell surface expressions of TLR2 and TLR4, but also the radiation-induced activation of the c-Jun N-terminal kinase (JNK) pathway. Since it has been shown that the inhibitor for JNK can suppress the radiation-induced upregulation of TLR expression, the present results suggest that ionizing radiation increased the cell surface expressions of TLR2 and TLR4 through reactive oxygen species-mediated JNK activation.}, }
@article {pmid28367412, year = {2017}, author = {Mokhtari, V and Afsharian, P and Shahhoseini, M and Kalantar, SM and Moini, A}, title = {A Review on Various Uses of N-Acetyl Cysteine.}, journal = {Cell journal}, volume = {19}, number = {1}, pages = {11-17}, pmid = {28367412}, issn = {2228-5806}, abstract = {N-acetyl cysteine (NAC), as a nutritional supplement, is a greatly applied antioxidant in vivo and in vitro. NAC is a precursor of L-cysteine that results in glutathione elevation biosynthesis. It acts directly as a scavenger of free radicals, especially oxygen radicals. NAC is a powerful antioxidant. It is also recommended as a potential treatment option for different disorders resulted from generation of free oxygen radicals. Additionally, it is a protected and endured mucolytic drug that mellows tenacious mucous discharges. It has been used for treatment of various diseases in a direct action or in a combination with some other medications. This paper presents a review on various applications of NAC in treatment of several diseases.}, }
@article {pmid28367269, year = {2017}, author = {Ohashi, K and Kageyama, M and Shinomiya, K and Fujita-Koyama, Y and Hirai, SI and Katsuta, O and Nakamura, M}, title = {Spermidine Oxidation-Mediated Degeneration of Retinal Pigment Epithelium in Rats.}, journal = {Oxidative medicine and cellular longevity}, volume = {2017}, number = {}, pages = {4128061}, pmid = {28367269}, issn = {1942-0994}, mesh = {Acetylcysteine/chemistry/metabolism/pharmacology ; Aldehyde Dehydrogenase/metabolism ; Amine Oxidase (Copper-Containing)/antagonists &amp; inhibitors/metabolism ; Animals ; Cell Line ; Cell Survival/drug effects ; Female ; Fluorophotometry ; Humans ; Immunohistochemistry ; Microscopy, Electron, Transmission ; Oxidation-Reduction ; Photoreceptor Cells, Vertebrate/pathology ; Rats ; Rats, Inbred BN ; Retinal Degeneration/metabolism/pathology ; Retinal Pigment Epithelium/cytology/metabolism/pathology ; Spermidine/*chemistry/metabolism/pharmacology ; }, abstract = {Retinal pigment epithelium (RPE) degeneration is a crucial event in dry age-related macular degeneration and gyrate atrophy. The polyamine spermidine has been shown to induce RPE cell death in vitro. The present study aimed to establish a novel in vivo model of spermidine-induced RPE degeneration and to determine whether spermidine-induced RPE cell death involves oxidative mechanisms. In this study, spermidine caused ARPE-19 cell death in a concentration-dependent manner. This effect was prevented by removal of serum from the culture medium or treatment with amine oxidase inhibitors, N-acetylcysteine (NAC), or aldehyde dehydrogenase (ALDH). Intravitreal injection of spermidine into rats significantly increased the permeability of the blood-retinal barrier and decreased the amplitudes of scotopic electroretinogram a- and b-waves. Histological analysis revealed that spermidine induced vacuolation, atrophy, and dropout of RPE cells, leading to the disruption of photoreceptor outer segments. Simultaneous intravitreal administration of NAC and ALDH with spermidine prominently inhibited the functional and morphological changes induced by spermidine. In conclusion, this study demonstrated that the intravitreal administration of spermidine induced RPE cell dysfunction and death followed by photoreceptor degeneration in rats. These effects of spermidine are thought to be mediated by oxidative stress and a toxic aldehyde generated during spermidine oxidation.}, }
@article {pmid28363602, year = {2017}, author = {Salazar, G and Huang, J and Feresin, RG and Zhao, Y and Griendling, KK}, title = {Zinc regulates Nox1 expression through a NF-κB and mitochondrial ROS dependent mechanism to induce senescence of vascular smooth muscle cells.}, journal = {Free radical biology &amp; medicine}, volume = {108}, number = {}, pages = {225-235}, doi = {10.1016/j.freeradbiomed.2017.03.032}, pmid = {28363602}, issn = {1873-4596}, mesh = {Angiotensin II/metabolism ; Animals ; Aorta, Thoracic/*pathology ; Carrier Proteins/genetics/*metabolism ; Cation Transport Proteins ; Cells, Cultured ; Cellular Senescence ; Dactinomycin/pharmacology ; Ethylenediamines/pharmacology ; Gene Expression Regulation ; Membrane Proteins/genetics/*metabolism ; Membrane Transport Proteins ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/*metabolism ; Myocytes, Smooth Muscle/*physiology ; NADPH Oxidase 1/genetics/*metabolism ; NADPH Oxidase 4/genetics/metabolism ; NF-kappa B/metabolism ; Oxidative Stress ; RNA, Small Interfering/genetics ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Zinc/*metabolism ; }, abstract = {AIMS: The role of oxidative stress and inflammation in the development and progression of cardiovascular diseases (CVD) is well established. Increases in oxidative stress can further exacerbate the inflammatory response and lead to cellular senescence. We previously reported that angiotensin II (Ang II) and zinc increase reactive oxygen species (ROS) and cause senescence of vascular smooth muscle cells (VSMCs) and that senescence induced by Ang II is a zinc-dependent process. Zinc stimulated NADPH oxidase (Nox) activity; however, the role of Nox isoforms in zinc effects was not determined.<br><br>RESULTS: Here, we show that downregulation of Nox1, but not Nox4, by siRNA prevented both Ang II- and zinc-induced senescence in VSMCs. On the other hand, overexpression of Nox1 induced senescence, which was associated with reduced proliferation, reduced expression of telomerase and increased DNA damage. Zinc increased Nox1 protein expression, which was inhibited by chelation of zinc with TPEN and by overexpression of the zinc exporters ZnT3 and ZnT10. These transporters work to reduce cytosolic zinc, suggesting that increased cytosolic zinc mediates Nox1 upregulation. Other metals including copper, iron, cobalt and manganese failed to upregulate Nox1, suggesting that this pathway is zinc specific. Nox1 upregulation was inhibited by actinomycin D (ACD), an inhibitor of transcription, by inhibition of NF-&#x3ba;B, a known Nox1 transcriptional regulator and by N-acetyl cysteine (NAC) and MitoTEMPO, suggesting that NF-&#x3ba;B and mitochondrial ROS mediate zinc effects. Supporting this idea, we found that zinc increased NF-&#x3ba;B activation in the cytosol, stimulated the translocation of the p65 subunit to the nucleus, and that zinc accumulated in mitochondria increasing mitochondrial ROS, measured using MitoSox. Further, zinc-induced senescence was reduced by inhibition of NF-&#x3ba;B or reduction of mitochondrial ROS with MitoTEMPO. NF-&#x3ba;B activity was also reduced by MitoTEMPO, suggesting that mitochondrial ROS is upstream of NF-&#x3ba;B.<br><br>INNOVATION AND CONCLUSION: Our data demonstrate that altered zinc distribution leading to accumulation of zinc in the mitochondria increases mitochondrial ROS production causing NF-&#x3ba;B activation which in turn upregulates Nox1 expression inducing senescence of VSMCs.}, }
@article {pmid28359953, year = {2017}, author = {Benedikter, BJ and Volgers, C and van Eijck, PH and Wouters, EFM and Savelkoul, PHM and Reynaert, NL and Haenen, GRMM and Rohde, GGU and Weseler, AR and Stassen, FRM}, title = {Cigarette smoke extract induced exosome release is mediated by depletion of exofacial thiols and can be inhibited by thiol-antioxidants.}, journal = {Free radical biology &amp; medicine}, volume = {108}, number = {}, pages = {334-344}, doi = {10.1016/j.freeradbiomed.2017.03.026}, pmid = {28359953}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Acrolein/*metabolism ; Antioxidants/chemistry/*pharmacology ; Cell Line ; Cigarette Smoking/adverse effects/*metabolism ; Exosomes/*metabolism ; Extracellular Vesicles/*metabolism ; Flow Cytometry ; Humans ; Oxidation-Reduction ; Oxidative Stress ; Respiratory Mucosa/*metabolism ; Sulfhydryl Compounds/chemistry/*metabolism ; Tetraspanin 28/metabolism ; Tetraspanin 30/metabolism ; }, abstract = {INTRODUCTION: Airway epithelial cells have been described to release extracellular vesicles (EVs) with pathological properties when exposed to cigarette smoke extract (CSE). As CSE causes oxidative stress, we investigated whether its oxidative components are responsible for inducing EV release and whether this could be prevented using the thiol antioxidants N-acetyl-l-cysteine (NAC) or glutathione (GSH).<br><br>METHODS: BEAS-2B cells were exposed for 24h to CSE, H2O2, acrolein, 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB), bacitracin, rutin or the anti-protein disulfide isomerase (PDI) antibody clone RL90; with or without NAC or GSH. EVs in media were measured using CD63[+]CD81[+] bead-coupled flow cytometry or tunable resistive pulse sensing (TRPS). For characterization by Western Blotting, cryo-transmission electron microscopy and TRPS, EVs were isolated using ultracentrifugation. Glutathione disulfide and GSH in cells were assessed by a GSH reductase cycling assay, and exofacial thiols using Flow cytometry.<br><br>RESULTS: CSE augmented the release of the EV subtype exosomes, which could be prevented by scavenging thiol-reactive components using NAC or GSH. Among thiol-reactive CSE components, H2O2 had no effect on exosome release, whereas acrolein imitated the NAC-reversible exosome induction. The exosome induction by CSE and acrolein was paralleled by depletion of cell surface thiols. Membrane impermeable thiol blocking agents, but not specific inhibitors of the exofacially located thiol-dependent enzyme PDI, stimulated exosome release.<br><br>SUMMARY/CONCLUSION: Thiol-reactive compounds like acrolein account for CSE-induced exosome release by reacting with cell surface thiols. As acrolein is produced endogenously during inflammation, it may influence exosome release not only in smokers, but also in ex-smokers with chronic obstructive pulmonary disease. NAC and GSH prevent acrolein- and CSE-induced exosome release, which may contribute to the clinical benefits of NAC treatment.}, }
@article {pmid28356716, year = {2017}, author = {Abdel-Wahab, WM and Moussa, FI and Saad, NA}, title = {Synergistic protective effect of N-acetylcysteine and taurine against cisplatin-induced nephrotoxicity in rats.}, journal = {Drug design, development and therapy}, volume = {11}, number = {}, pages = {901-908}, pmid = {28356716}, issn = {1177-8881}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antineoplastic Agents/administration &amp; dosage/*adverse effects ; Cisplatin/administration &amp; dosage/*adverse effects/*antagonists &amp; inhibitors ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Kidney Function Tests ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Taurine/administration &amp; dosage/*pharmacology ; }, abstract = {Cisplatin (cis-diaminedichloroplatinum II; CDDP) is an effective anticancer drug, but it has limitations because of its nephrotoxicity. This study investigates the protective effect of N-acetylcysteine (NAC) and taurine (TAU), both individually and in combination, against CDDP nephrotoxicity in rats. For this purpose, 48 male rats were assigned into eight groups (n=6) as follows: 1) control group, 2) NAC group, 3) TAU group, 4) NAC-TAU group, 5) CDDP group, 6) CDDP-NAC group, 7) CDDP-TAU group, and 8) CDDP-NAC-TAU group. Cisplatin was administered as a single intraperitoneal injection at a concentration of 6 mg/kg. Three days after CDDP administration, NAC (50 mg/kg) and/or TAU (50 mg/kg) were administered three times weekly for four consecutive weeks. Kidney function markers in serum, urinary glucose and protein, as well as oxidant and antioxidant parameters in renal tissue were assessed. Administration of CDDP significantly elevated urinary glucose and protein, as well as serum creatinine, urea, and uric acid. Moreover, CDDP enhanced lipid peroxidation and suppressed the major enzymatic antioxidants in the kidney tissue. Treatment with NAC or TAU protected against the alterations in the serum, urine, and renal tissue when used individually along with CDDP. Furthermore, a combined therapy of both was more effective in ameliorating CDDP-induced nephrotoxicity, which points out to their synergistic effect.}, }
@article {pmid28356658, year = {2017}, author = {Sadineni, R and Karthik, KR and Swarnalatha, G and Das, U and Taduri, G}, title = {N-acetyl cysteine versus allopurinol in the prevention of contrast nephropathy in patients with chronic kidney disease: A randomized controlled trial.}, journal = {Indian journal of nephrology}, volume = {27}, number = {2}, pages = {93-98}, pmid = {28356658}, issn = {0971-4065}, abstract = {Contrast media administration can lead to acute deterioration in renal function particularly in patients with pre-existing chronic kidney disease. This prospective, randomized controlled open-label parallel group study was undertaken at Nizam's Institute of Medical Sciences, Hyderabad, from June to December 2015. A total of 95 patients were included, of which 35 received n-acetylcysteine (NAC) + normal saline (NS), 30 patients received allopurinol (ALL) + NS, and 30 patients received placebo. In our study, the overall incidence of CIN was 24%. Incidence of CIN in NAC + NS, ALL + NS, and placebo group were 20%, 16%, and 36%, respectively. The major finding of this study was there was no significant difference between NAC and allopurinol in the prevention of contrast nephropathy. However, only allopurinol was superior to placebo. In our study, hyperuricemia and baseline serum creatinine were the only risk factors associated with CIN.}, }
@article {pmid28352997, year = {2017}, author = {Ji, Y and Li, L and Tao, Q and Zhang, X and Luan, J and Zhao, S and Liu, H and Ju, D}, title = {Deprivation of asparagine triggers cytoprotective autophagy in laryngeal squamous cell carcinoma.}, journal = {Applied microbiology and biotechnology}, volume = {101}, number = {12}, pages = {4951-4961}, doi = {10.1007/s00253-017-8221-9}, pmid = {28352997}, issn = {1432-0614}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Asparaginase/metabolism/*pharmacology ; Asparagine/*metabolism ; Autophagy/*drug effects ; Carcinoma, Squamous Cell/drug therapy/*physiopathology ; Cell Line, Tumor ; Chloroquine/pharmacology ; Humans ; Laryngeal Neoplasms/*physiopathology/*therapy ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Laryngeal squamous cell carcinoma (LSCC), one of the most common malignancies in the head and neck, has poor prognosis and high mortality. The need of novel and effective treatment for LSCC is urgent. Asparaginase, an enzyme-depriving asparagine, has been employed for the treatment of various cancers. In this study, we reported for the first time that asparaginase could induce remarkable cytotoxicity and caspase-dependent apoptosis in human LSCC Tu212 and Tu686 cells. Meanwhile, autophagy was triggered by asparaginase in LSCC cells, which was confirmed by accumulation of autophagosomes and the conversion of light chain 3-I (LC3-I) to LC3-II. Importantly, inhibition of autophagy by chloroquine (CQ) significantly enhanced asparaginase-induced cytotoxicity, indicating that autophagy has a cytoprotective role in asparaginase-treated LSCC cells. Meanwhile, we found that mitochondrial-originated reactive oxygen species (ROS) participated in asparaginase-induced autophagy and cytotoxicity. N-acetyl-L-cysteine (NAC), a common antioxidant, was employed to scavenge ROS, and our results demonstrated that NAC could significantly block asparaginase-induced autophagy and attenuate asparaginase-induced cytotoxicity, indicating that intracellular ROS played a crucial role in asparagine deprivation therapy. Furthermore, western blot analysis showed that asparaginase-induced autophagy was mediated by inactivation of Akt/mTOR and activation of the Erk signaling pathway in Tu212 and Tu686 cells. Therefore, these results indicated the protective role of autophagy in asparaginase-treated LSCC cells and provided a new attractive therapeutic strategy for LSCC by asparaginase alone or in combination with autophagic inhibitors.}, }
@article {pmid28351307, year = {2017}, author = {Rao, PC and Begum, S and Sahai, M and Sriram, DS}, title = {Coptisine-induced cell cycle arrest at G2/M phase and reactive oxygen species-dependent mitochondria-mediated apoptosis in non-small-cell lung cancer A549 cells.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {39}, number = {3}, pages = {1010428317694565}, doi = {10.1177/1010428317694565}, pmid = {28351307}, issn = {1423-0380}, mesh = {A549 Cells ; Apoptosis/*drug effects ; Berberine/administration &amp; dosage/*analogs &amp; derivatives ; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/*drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mitochondria/drug effects/pathology ; Neoplasm Proteins/biosynthesis/genetics ; Reactive Oxygen Species/metabolism ; }, abstract = {This study aimed to explore the effect of coptisine on non-small-cell lung cancer and its mechanism through various in vitro cellular models (A549). Results claimed significant inhibition of proliferation by coptisine against A549, H460, and H2170 cells with IC50 values of 18.09, 29.50, and 21.60 µM, respectively. Also, coptisine exhibited upregulation of pH2AX, cell cycle arrest at G2/M phase, and downregulation of the expression of cyclin B1, cdc2, and cdc25C and upregulation of p21 dose dependently. Furthermore, induction of apoptosis in A549 cells by coptisine was characterized by the activation of caspase 9, caspase 8, and caspase 3, and cleavage of poly adenosine diphosphate ribose polymerase. In addition, coptisine was found to increase reactive oxygen species generation, upregulate Bax/Bcl-2 ratio, disrupt mitochondrial membrane potential, and cause cytochrome c release into the cytosol. Besides, treatment with a reactive oxygen species inhibitor (N-acetyl cysteine) abrogated coptisine-induced growth inhibition, apoptosis, reactive oxygen species generation, and mitochondrial dysfunction. Thus, the mediation of reactive oxygen species in the apoptosis-induced effect of coptisine in A549 cells was corroborated. These findings have offered new insights into the effect and mechanisms of action of coptisine against non-small-cell lung cancer.}, }
@article {pmid28350146, year = {2017}, author = {Rus, CP}, title = {[A girl with self-harm treated with N-acetylcysteine (NAC)].}, journal = {Tijdschrift voor psychiatrie}, volume = {59}, number = {3}, pages = {181-184}, pmid = {28350146}, issn = {0303-7339}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Attention Deficit Disorder with Hyperactivity/drug therapy ; Depression/drug therapy ; Female ; Humans ; Self-Injurious Behavior/*drug therapy ; Treatment Outcome ; }, abstract = {Deliberate and recurrent self-harm could be regarded as addictive behaviour that can be treated with medication. In addiction, the dopaminergic mesolimbic reward system is activated. Pain caused by cutting stimulates the reward system through the opioid system. Glutamatergic neurotransmission follows the same pathway and plays a role in addiction as well. In this case-study a 17-year-old girl was successfully treated with N-acetylcysteine (nac) in order to reduce the frequency of self-cutting. In addition, in this case nac reduced the symptoms of attention deficit/hyperactivity disorder and depression. nac modulates the glutamatergic neurotransmission. This article provides possible explanations for the effect of nac in this case.}, }
@article {pmid28350077, year = {2017}, author = {Li, C and Chang, Y and Li, Y and Chen, S and Chen, Y and Ye, N and Dai, D and Sun, Y}, title = {Advanced glycation end products promote the proliferation and migration of primary rat vascular smooth muscle cells via the upregulation of BAG3.}, journal = {International journal of molecular medicine}, volume = {39}, number = {5}, pages = {1242-1254}, pmid = {28350077}, issn = {1791-244X}, mesh = {Animals ; Apoptosis Regulatory Proteins/*genetics/metabolism ; Cell Movement/*drug effects ; Cell Proliferation/drug effects ; Gene Expression Regulation/*drug effects ; Gene Knockdown Techniques ; Glycation End Products, Advanced/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Muscle, Smooth, Vascular/*metabolism ; Myocytes, Smooth Muscle/*drug effects/*metabolism ; Oxidative Stress/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {The present study was aimed to investigate the role of reactive oxygen species (ROS) on advanced glycation end product (AGE)-induced proliferation and migration of vascular smooth muscle cells (VSMCs) and whether Bcl-2‑associated athanogene 3 (BAG3) is involved in the process. Primary rat VSMCs were extracted and cultured in vitro. Cell viability was detected by MTT assay and cell proliferation was detected by EdU incorporation assay. Cell migration was detected by wound healing and Transwell assays. BAG3 was detected using qPCR and western blot analysis. Transcriptional and translational inhibitors (actinomycin D and cycloheximide, respectively) were used to study the effect of AGEs on the expression of BAG3 in VSMCs. Lentiviral plasmids containing short hairpin RNA (shRNA) against rat BAG3 or control shRNA were transduced into VSMCs. Cellular ROS were detected by 2',7'-dichlorofluorescein diacetate (DCFH-DA) staining. Mitochondrial membrane potential was detected by tetramethylrhodamine methyl ester (TMRE) staining. AGEs significantly increased the expression of BAG3 in a dose-and time-dependent manner. Furthermore, AGEs mainly increased the expression of BAG3 mRNA by increasing the RNA synthesis rather than inhibiting the RNA translation. BAG3 knockdown reduced the proliferation and migration of VSMCs induced by AGEs. BAG3 knockdown reduced the generation of ROS and sustained the mitochondrial membrane potential of VSMCs. Reduction of ROS production by N-acetylcysteine (NAC), a potent antioxidant, also reduced the proliferation and migration of VSMCs. On the whole, the present study demonstrated for the first time that AGEs could increase ROS production and promote the proliferation and migration of VSMCs by upregulating BAG3 expression. This study indicated that BAG3 should be considered as a potential target for the prevention and/or treatment of vascular complications of diabetes.}, }
@article {pmid28347754, year = {2017}, author = {Liu, F and Wang, XY and Zhou, XP and Liu, ZP and Song, XB and Wang, ZY and Wang, L}, title = {Cadmium disrupts autophagic flux by inhibiting cytosolic Ca[2+]-dependent autophagosome-lysosome fusion in primary rat proximal tubular cells.}, journal = {Toxicology}, volume = {383}, number = {}, pages = {13-23}, doi = {10.1016/j.tox.2017.03.016}, pmid = {28347754}, issn = {1879-3185}, mesh = {Animals ; Autophagosomes/drug effects ; Autophagy/*drug effects ; Cadmium/*toxicity ; Calcium/metabolism ; Cells, Cultured ; Cytosol/metabolism ; Kidney Tubules, Proximal/*cytology ; Lysosomes/drug effects ; Male ; Microtubule-Associated Proteins/metabolism ; RNA-Binding Proteins/metabolism ; Rats ; Rats, Sprague-Dawley ; rab GTP-Binding Proteins/metabolism ; rab7 GTP-Binding Proteins ; }, abstract = {Previous studies have shown that subcellular Ca[2+] redistribution is involved in Cd-induced autophagy inhibition in primary rat proximal tubular (rPT) cells, but the mechanism remains unclear. In this study, the status of autophagic flux was monitored by the GFP and RFP tandemly tagged LC3 method. Pharmacological inhibition of cytosolic Ca[2+] concentration ([Ca[2+]]c) with 2-APB or BAPTA-AM significantly alleviated Cd-elevated yellow puncta formation and restored Cd-inhibited red puncta formation, while thapsigargin (TG) had the opposite regulatory effect, demonstrating that Cd-induced [Ca[2+]]c elevation inhibited the autophagic flux in rPT cells. Resultantly, Cd-induced autophagosomes accumulation was obviously modulated by 2-APB, BAPTA-AM and TG, respectively. Meanwhile, blockage of autophagosome-lysosome fusion and decreased recruitment of Rab7 to autophagosomes by Cd exposure was noticeably restored by 2-APB or BAPTA-AM, but co-treatment with Cd and TG further impaired Cd-induced autophagy arrest. Moreover, Cd-induced oxidative stress intimately correlated with cytosolic Ca[2+] mobilization, and N-acetylcysteine (NAC) markedly rescued Cd-blocked autophagosome-lysosome fusion and recruitment of Rab7 to autophagosomes in rPT cells, implying that Cd-induced autophagy inhibition was due to [Ca[2+]]c elevation-triggered oxidative stress. In summary, these results suggest that Cd-mediated autophagy inhibition in rPT cells is dependent on cytosolic Ca[2+] overload. Elevation of [Ca[2+]]c inhibited the autophagosome-lysosome fusion to block the degradation of autophagosomes, which aggravated Cd-induced cytotoxicity in rPT cells.}, }
@article {pmid28347704, year = {2017}, author = {Yu, CH and Suriguga,  and Gong, M and Liu, WJ and Cui, NX and Wang, Y and Du, X and Yi, ZC}, title = {High glucose induced endothelial to mesenchymal transition in human umbilical vein endothelial cell.}, journal = {Experimental and molecular pathology}, volume = {102}, number = {3}, pages = {377-383}, doi = {10.1016/j.yexmp.2017.03.007}, pmid = {28347704}, issn = {1096-0945}, mesh = {Acetylcysteine/pharmacology ; Actins/genetics/metabolism ; Antigens, CD/genetics/metabolism ; Cadherins/genetics/metabolism ; Cells, Cultured ; Epithelial-Mesenchymal Transition/*drug effects ; Flavonoids/pharmacology ; Gene Expression Regulation ; Glucose/*metabolism ; Human Umbilical Vein Endothelial Cells/*drug effects/metabolism ; Humans ; Mitogen-Activated Protein Kinase 3/genetics/metabolism ; Phosphorylation ; Platelet Endothelial Cell Adhesion Molecule-1/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Signal Transduction ; Transforming Growth Factor beta1/genetics/metabolism ; }, abstract = {BACKGROUND: Studies have shown that endothelial-to-mesenchymal transition (EndMT) could contribute to the progression of diabetic nephropathy, diabetic renal fibrosis, and cardiac fibrosis. The aim of this study was to investigate the influence of high glucose and related mechanism of MAPK inhibitor or specific antioxidant on the EndMT.<br><br>METHODS: In vitro human umbilical vein endothelial cells (HUVEC) were cultured with 11mM, 30mM, 60mM and 120mM glucose for 0, 24, 48, 72 and 168h. Endothelial cell morphology was observed with microscope, and RT-PCR was used to detect mRNA expression of endothelial markers VE-cadherin and CD31, mesenchymal markers &#x3b1;-SMA and collagen I, and transforming growth factor TGF-&#x3b2;1. Immunofluorescence staining was performed to detect the expression of CD31 and &#x3b1;-SMA. The concentration of TGF-&#x3b2;1 in the supernatant was detected by ELISA. ERK1/2 phosphorylation level was detected by Western blot analysis.<br><br>RESULTS: High glucose induced EndMT and increased the TGF-&#x3b2;1 level in HUVEC cells. Cells in high glucose for 7 days showed a significant decrease in mRNA expression of CD31 and VE-cadherin, and a significant increase in that of &#x3b1;-SMA and collagen I, while lost CD31 staining and acquired &#x3b1;-SMA staining. ERK signaling pathway blocker PD98059 significantly attenuated the high glucose-induced increase in the ERK1/2 phosphorylation level. PD98059 and NAC both inhibited high glucose-induced TGF-&#x3b2;1 expression and attenuated EndMT marker protein synthesis.<br><br>CONCLUSION: High glucose could induce HUVEC cells to undergo EndMT. NAC and ERK signaling pathway may play important role in the regulation of the TGF-&#x3b2;1 biosynthesis during high glucose-induced EndMT.}, }
@article {pmid28344907, year = {2017}, author = {Chang, P and Mo, B and Cauvi, DM and Yu, Y and Guo, Z and Zhou, J and Huang, Q and Yan, Q and Chen, G and Liu, Z}, title = {Grape seed proanthocyanidin extract protects lymphocytes against histone-induced apoptosis.}, journal = {PeerJ}, volume = {5}, number = {}, pages = {e3108}, pmid = {28344907}, issn = {2167-8359}, abstract = {Apoptosis of lymphocytes is associated with immunosuppression and poor prognosis in sepsis. Our previous report showed that histones, nuclear proteins released from damaged or dying cells in sepsis, can mediate lymphocyte apoptosis via mitochondria damage. Grape seed proanthocyanidin extract (GSPE), a natural substance with protective properties against oxidative stress, plays a vital role in cell and mitochondria protection. We thus hypothesized that GSPE may play a protective role in histone-induced lymphocyte apoptosis through its anti-oxidative properties. In this study, we investigated the protective efficacy of GSPE on lymphocyte apoptosis induced by extracellular histones, a main contributor of death in sepsis. Human blood lymphocytes were treated with 50 μg/ml histones, 2 μg/ml GSPE, or a combination of both. A total of 100 μM N-acetylcysteine (NAC), a reactive oxygen species (ROS) inhibitor, was used as a positive control for GSPE. Apoptosis, intracellular ROS levels, mitochondrial membrane potential, Bcl-2 expression, and caspase-3 cleavage were measured. Our data clearly indicate that GSPE significantly inhibited lymphocyte apoptosis, generation of ROS, the loss of mitochondrial membrane potential, the decrease in Bcl-2 expression, and caspase-3 activation induced by extracellular histones. In conclusion, we show that GSPE has a protective effect on lymphocyte apoptosis induced by extracellular histones. This study suggests GSPE as a potential therapeutic agent that could help reduce lymphocyte apoptosis, and thus the state of immunosuppression was observed in septic patients.}, }
@article {pmid28343997, year = {2017}, author = {Cho, MG and Ahn, JH and Choi, HS and Lee, JH}, title = {DNA double-strand breaks and Aurora B mislocalization induced by exposure of early mitotic cells to H2O2 appear to increase chromatin bridges and resultant cytokinesis failure.}, journal = {Free radical biology &amp; medicine}, volume = {108}, number = {}, pages = {129-145}, doi = {10.1016/j.freeradbiomed.2017.03.025}, pmid = {28343997}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Aurora Kinase B/*metabolism ; Catalase/genetics/metabolism ; *Chromatin Assembly and Disassembly ; *Cytokinesis ; *DNA Breaks, Double-Stranded ; HeLa Cells ; Humans ; Hydrogen Peroxide/*metabolism ; Mitosis ; Phenanthrenes/pharmacology ; Poly (ADP-Ribose) Polymerase-1/antagonists &amp; inhibitors/genetics/metabolism ; Protein Transport ; Proto-Oncogene Proteins p21(ras)/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Aneuploidy, an abnormal number of chromosomes that is a hallmark of cancer cells, can arise from tetraploid/binucleated cells through a failure of cytokinesis. Reactive oxygen species (ROS) have been implicated in various diseases, including cancer. However, the nature and role of ROS in cytokinesis progression and related mechanisms has not been clearly elucidated. Here, using time-lapse analysis of asynchronously growing cells and immunocytochemical analyses of synchronized cells, we found that hydrogen peroxide (H2O2) treatment at early mitosis (primarily prometaphase) significantly induced cytokinesis failure. Cytokinesis failure and the resultant formation of binucleated cells containing nucleoplasmic bridges (NPBs) seemed to be caused by increases in DNA double-strand breaks (DSBs) and subsequent unresolved chromatin bridges. We further found that H2O2 induced mislocalization of Aurora B during mitosis. All of these effects were attenuated by pretreatment with N-acetyl-L-cysteine (NAC) or overexpression of Catalase. Surprisingly, the PARP inhibitor PJ34 also reduced H2O2-induced Aurora B mislocalization and binucleated cell formation. Results of parallel experiments with etoposide, a topoisomerase IIα inhibitor that triggers DNA DSBs, suggested that both DNA DSBs and Aurora B mislocalization contribute to chromatin bridge formation. Aurora B mislocalization also appeared to weaken the "abscission checkpoint". Finally, we showed that KRAS-induced binucleated cell formation appeared to be also H2O2-dependent. In conclusion, we propose that a ROS, mainly H2O2 increases binucleation through unresolved chromatin bridges caused by DNA damage and mislocalization of Aurora B, the latter of which appears to augment the effect of DNA damage on chromatin bridge formation.}, }
@article {pmid28342871, year = {2019}, author = {Han, Y and Li, X and Yan, M and Yang, M and Wang, S and Pan, J and Li, L and Tan, J}, title = {Oxidative damage induces apoptosis and promotes calcification in disc cartilage endplate cell through ROS/MAPK/NF-κB pathway: Implications for disc degeneration.}, journal = {Biochemical and biophysical research communications}, volume = {516}, number = {3}, pages = {1026-1032}, doi = {10.1016/j.bbrc.2017.03.111}, pmid = {28342871}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Calcinosis/chemically induced/metabolism/prevention &amp; control ; Cartilage/cytology/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Chondrocytes/cytology/drug effects/*metabolism ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Intervertebral Disc/cytology/metabolism ; Intervertebral Disc Degeneration/metabolism ; *MAP Kinase Signaling System ; NF-kappa B/*metabolism ; Oxidants/pharmacology ; *Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cartilage endplate (CEP) cell calcification and apoptosis play a vital role in the intervertebral disc degeneration (IVDD). Oxidative stress is a key factor in inducing programmed cell death and cartilage calcification. However, the cell death and calcification of cartilage endplate cells under oxidative stress have never been described. The present study investigated the apoptosis and calcification in the cartilage endplate cell under oxidative stress induced by H2O2 to understand the underlying mechanism of IVDD. The cartilage endplate cells isolated from human lumbar discs were subjected to different concentrations of H2O2 for various time periods. The cell viability was determined by CCK-8 assay, whereas Western blot, immunofluorescence, and Alcian blue, Alizarin red, and Von Kossa staining evaluated the apoptosis and calcification. The level of mitochondria-specific reactive oxygen species (ROS) was quantified with an oxygen radical-sensitive probe-MitoSOX. The potential signaling pathways were investigated by Western blot after the addition of N-acetyl-l-cysteine (NAC). We found that the oxidative stress induced by H2O2 increased the apoptosis and subsequently the calcification in the cartilage endplate cells through the ROS/p38/ERK/p65 pathway. The apoptosis and the calcification of the cartilage endplate cells induced by H2O2 can be abolished by NAC. These results suggested that regulating the apoptosis and the calcification in the cartilage endplate cells under oxidative stress should be advantageous for the survival of cells and might delay the process of disc degeneration.}, }
@article {pmid28341536, year = {2017}, author = {Yuan, J and Zhu, C and Hong, Y and Sun, Z and Fang, X and Wu, B and Li, S}, title = {The role of cPLA2 in Methylglyoxal-induced cell apoptosis of HUVECs.}, journal = {Toxicology and applied pharmacology}, volume = {323}, number = {}, pages = {44-52}, doi = {10.1016/j.taap.2017.03.020}, pmid = {28341536}, issn = {1096-0333}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Human Umbilical Vein Endothelial Cells/*drug effects/enzymology/pathology ; Humans ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Oxidative Stress/drug effects ; Phosphodiesterase Inhibitors/pharmacology ; Phospholipases A2, Cytosolic/antagonists &amp; inhibitors/genetics/*metabolism ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyruvaldehyde/*toxicity ; RNA Interference ; Signal Transduction/drug effects ; Time Factors ; Transfection ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is mainly formed as a byproduct of glycolysis. Elevated MGO level is known to induce apoptosis of vascular endothelial cells, which is implicated with progression of atherosclerosis and diabetic complications. However, the underlying mechanisms have not been exhaustively investigated yet. Here, we further characterized the mechanisms how MGO induced apoptosis in human umbilical vein endothelial cells (HUVECs). Our data revealed that cytosolic phospholipase A2 (cPLA2) played an important role in MGO-induced cell apoptosis. It was found that MGO could increase both the activity and expression of cPLA2. Inhibition of cPLA2 by Pyrrophenone (PYR) or siRNA significantly attenuated the MGO-induced apoptosis. Additionally, MGO time-dependently decreased the phosphorylation of nuclear factor κB (NF-κB). Pretreatment of the cells with NF-κB inhibitor, BAY11-7082, further increased MGO-induced apoptosis of HUVECs, indicating that NF-κB played a survival role in this MGO-induced apoptosis. Furthermore, in the presence of si-cPLA2 or PYR, MGO no longer decreased NF-κB phosphorylation. Beyond that, the antioxidant N-acetyl cysteine (NAC) could reverse the changes of both cPLA2 and NF-κB caused by MGO. p38, the upstream of cPLA2, was also significantly phosphorylated by MGO. However, p38 inhibitor failed to reverse the apoptosis induced by MGO. This study gives an important insight into the downstream signaling mechanisms of MGO, cPLA2-NF-κB, in endothelial apoptosis.}, }
@article {pmid28341391, year = {2017}, author = {Preziosi, ME and Singh, S and Valore, EV and Jung, G and Popovic, B and Poddar, M and Nagarajan, S and Ganz, T and Monga, SP}, title = {Mice lacking liver-specific β-catenin develop steatohepatitis and fibrosis after iron overload.}, journal = {Journal of hepatology}, volume = {67}, number = {2}, pages = {360-369}, pmid = {28341391}, issn = {1600-0641}, support = {R01 DK062277/DK/NIDDK NIH HHS/United States ; R01 DK100287/DK/NIDDK NIH HHS/United States ; R01 HL130126/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Disease Models, Animal ; Fatty Liver/*etiology/*metabolism/prevention &amp; control ; Female ; Hemochromatosis/complications/metabolism ; Humans ; Iron Overload/*complications/drug therapy/*metabolism ; Liver/drug effects/metabolism/pathology ; Liver Cirrhosis/*etiology/*metabolism/prevention &amp; control ; Male ; Mice ; Mice, Knockout ; Oxidative Stress ; Signal Transduction ; beta Catenin/*deficiency/genetics ; }, abstract = {BACKGROUND &amp; AIMS: Iron overload disorders such as hereditary hemochromatosis and iron loading anemias are a common cause of morbidity from liver diseases and increase risk of hepatic fibrosis and hepatocellular carcinoma (HCC). Treatment options for iron-induced damage are limited, partly because there is lack of animal models of human disease. Therefore, we investigated the effect of iron overload in liver-specific β-catenin knockout mice (KO), which are susceptible to injury, fibrosis and tumorigenesis following chemical carcinogen exposure.<br><br>METHODS: Iron overload diet was administered to KO and littermate control (CON) mice for various times. To ameliorate an oxidant-mediated component of tissue injury, N-Acetyl-L-(+)-cysteine (NAC) was added to drinking water of mice on iron overload diet.<br><br>RESULTS: KO on iron diet (KO +Fe) exhibited remarkable inflammation, followed by steatosis, oxidative stress, fibrosis, regenerating nodules and occurrence of occasional HCC. Increased injury in KO +Fe was associated with activated protein kinase B (AKT), ERK, and NF-&#x3ba;B, along with reappearance of &#x3b2;-catenin and target gene Cyp2e1, which promoted lipid peroxidation and hepatic damage. Addition of NAC to drinking water protected KO +Fe from hepatic steatosis, injury and fibrosis, and prevented activation of AKT, ERK, NF-&#x3ba;B and reappearance of &#x3b2;-catenin.<br><br>CONCLUSIONS: The absence of hepatic &#x3b2;-catenin predisposes mice to hepatic injury and fibrosis following iron overload, which was reminiscent of hemochromatosis and associated with enhanced steatohepatitis and fibrosis. Disease progression was notably alleviated by antioxidant therapy, which supports its chemopreventive role in the management of chronic iron overload disorders.<br><br>LAY SUMMARY: Lack of animal models for iron overload disorders makes it hard to study the disease process for improving therapies. Feeding high iron diet to mice that lack the &#x3b2;-catenin gene in liver cells led to increased inflammation followed by fat accumulation, cell death and wound healing that mimicked human disease. Administration of an antioxidant prevented hepatic injury in this model.}, }
@article {pmid28337376, year = {2017}, author = {Zhang, J and Feng, Z and Wang, C and Zhou, H and Liu, W and Kanchana, K and Dai, X and Zou, P and Gu, J and Cai, L and Liang, G}, title = {Curcumin derivative WZ35 efficiently suppresses colon cancer progression through inducing ROS production and ER stress-dependent apoptosis.}, journal = {American journal of cancer research}, volume = {7}, number = {2}, pages = {275-288}, pmid = {28337376}, issn = {2156-6976}, abstract = {Colon cancer is characterized by its fast progression and poor prognosis, and novel agents of treating colon cancer are urgently needed. WZ35, a synthetic curcumin derivative, has been reported to exhibit promising antitumor activity. Here, we investigated the in vitro and in vivo activities of WZ35 and explored the underlying mechanisms in colon cancer cell lines. WZ35 treatment significantly decreased the cell viability associated with G2/M cell cycle arrest and apoptosis induction in colon cancer cell lines. We also show that WZ35 is highly effective in inhibiting tumor growth in a CT26 xenograft mouse model. Mechanistically, WZ35 treatment significantly induced reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress in CT26 cells. Abrogation of ROS production by N-acetylcysteine (NAC) co-treatment almost totally reversed the WZ35-induced cell apoptosis and ER stress activation. Inhibition of p-PERK by GSK2606414 can significantly reverse WZ35-induced cell apoptosis in CT26 cells. Taken together, the curcumin derivative WZ35 exhibited anti-tumor effects in colon cancer cells both in vitro and in vivo, via a ROS-ER stress-mediated mechanism. These findings indicate that activating ROS generation could be an important strategy for the treatment of colon cancers.}, }
@article {pmid28335665, year = {2017}, author = {Yu, L and Gan, X and Liu, X and An, R}, title = {Calcium oxalate crystals induces tight junction disruption in distal renal tubular epithelial cells by activating ROS/Akt/p38 MAPK signaling pathway.}, journal = {Renal failure}, volume = {39}, number = {1}, pages = {440-451}, pmid = {28335665}, issn = {1525-6049}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Calcium Oxalate/*metabolism ; Cells, Cultured ; Dogs ; Down-Regulation ; Epithelial Cells/*metabolism ; Heterocyclic Compounds, 3-Ring/pharmacology ; Humans ; Kidney Calculi/chemistry ; Kidney Tubules/*cytology ; Madin Darby Canine Kidney Cells ; Nephrolithiasis/*metabolism ; Occludin/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; *Signal Transduction ; Tight Junctions/*metabolism ; Zonula Occludens-1 Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Tight junction plays important roles in regulating paracellular transports and maintaining cell polarity. Calcium oxalate monohydrate (COM) crystals, the major crystalline composition of kidney stones, have been demonstrated to be able to cause tight junction disruption to accelerate renal cell injury. However, the cellular signaling involved in COM crystal-induced tight junction disruption remains largely to be investigated. In the present study, we proved that COM crystals induced tight junction disruption by activating ROS/Akt/p38 MAPK pathway. Treating Madin-Darby canine kidney (MDCK) cells with COM crystals induced a substantial increasing of ROS generation and activation of Akt that triggered subsequential activation of ASK1 and p38 mitogen-activated protein kinase (MAPK). Western blot revealed a significantly decreased expression of ZO-1 and occludin, two important structural proteins of tight junction. Besides, redistribution and dissociation of ZO-1 were observed by COM crystals treatment. Inhibition of ROS by N-acetyl-l-cysteine (NAC) attenuated the activation of Akt, ASK1, p38 MAPK, and down-regulation of ZO-1 and occludin. The redistribution and dissociation of ZO-1 were also alleviated by NAC treatment. These results indicated that ROS were involved in the regulation of tight junction disruption induced by COM crystals. In addition, the down-regulation of ZO-1 and occludin, the phosphorylation of ASK1 and p38 MAPK were also attenuated by MK-2206, an inhibitor of Akt kinase, implying Akt was involved in the disruption of tight junction upstream of p38 MAPK. Thus, these results suggested that ROS-Akt-p38 MAPK signaling pathway was activated in COM crystal-induced disruption of tight junction in MDCK cells.}, }
@article {pmid28335600, year = {2017}, author = {Markoutsa, E and Xu, P}, title = {Redox Potential-Sensitive N-Acetyl Cysteine-Prodrug Nanoparticles Inhibit the Activation of Microglia and Improve Neuronal Survival.}, journal = {Molecular pharmaceutics}, volume = {14}, number = {5}, pages = {1591-1600}, pmid = {28335600}, issn = {1543-8392}, support = {P20 GM109091/GM/NIGMS NIH HHS/United States ; R01 AG054839/AG/NIA NIH HHS/United States ; R15 CA188847/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*chemistry ; Animals ; Antioxidants/metabolism ; Cell Line ; Immunohistochemistry ; Interleukin-1beta/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; Microglia/*cytology/*drug effects/metabolism ; Nanoparticles/*chemistry ; Neurons/*cytology/*drug effects/metabolism ; Oxidation-Reduction/drug effects ; Prodrugs/*chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {One hallmark of neuroinflammation is the activation of microglia, which triggers the production and release of reactive oxygen species (ROS), nitrate, nitrite, and cytokines. N-Acetyl cysteine (NAC) is a free radical scavenger that is involved in the intracellular and extracellular detoxification of reactive oxygen species in the brain. However, the clinical application of NAC is limited by its low bioavailability and short half-life. Herein, NAC was conjugated to a polymer through a disulfide bond to form a NAC-prodrug nanoparticle (NAC-NP). Dynamic light scattering found that the NAC-NP has a size of around 50 nm. In vitro studies revealed that the release of NAC from NAC-NP is responsive to its environmental redox potential. For mimicking neuroinflammation in vitro, microglial cells were stimulated by a lipopolysaccharide (LPS), and the effect of NAC-NP on activated microglia was investigated. The study found that the morphology as well as the expression of microgliosis marker Iba-1 of the cells treated with NAC-NPs and LPS were close to those of control cells, indicating that NAC-NPs can inhibit the activation of microglia stimulated by LPS. Compared with free NAC, the production of ROS, NO3-, NO2-, tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β from the LPS-stimulated microglia was considerably decreased when the cells were pretreated with NAC-NPs. Furthermore, LPS-induced microglial phagocytocis of neurons was inhibited in the presence of NAC-NPs. These results indicated that NAC-NPs are more effective than free NAC for reversing the effect of LPS on microglia and subsequently protecting neurons.}, }
@article {pmid28323971, year = {2017}, author = {Lehnen, TE and Santos, MV and Lima, A and Maia, AL and Wajner, SM}, title = {N-Acetylcysteine Prevents Low T3 Syndrome and Attenuates Cardiac Dysfunction in a Male Rat Model of Myocardial Infarction.}, journal = {Endocrinology}, volume = {158}, number = {5}, pages = {1502-1510}, doi = {10.1210/en.2016-1586}, pmid = {28323971}, issn = {1945-7170}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Disease Models, Animal ; Euthyroid Sick Syndromes/*prevention &amp; control ; Male ; Myocardial Infarction/complications/*drug therapy/pathology ; Myocytes, Cardiac/drug effects/metabolism/pathology ; Protein Carbonylation/drug effects ; Rats ; Rats, Wistar ; Thyroid Hormones/metabolism ; Ventricular Dysfunction/*drug therapy/etiology/pathology ; }, abstract = {Nonthyroidal illness syndrome (NTIS) affects patients with myocardial infarction (MI). Oxidative stress has been implicated as a causative factor of NTIS, and reversed via N-acetylcysteine (NAC). Male Wistar rats submitted to left anterior coronary artery occlusion received NAC or placebo. Decreases in triiodothyronine (T3) levels were noted in MI-placebo at 10 and 28 days post-MI, but not in MI-NAC. Groups exhibited similar infarct areas whereas MI-NAC exhibited higher ejection fraction than did MI-placebo. Left ventricular systolic and diastolic diameters were also preserved in MI-NAC, but not in MI-placebo. Ejection fraction was positively correlated with T3 levels. Oxidative balance was deranged only in MI-placebo animals. Increased type 3 iodothyronine deiodinase expression was detected in the cardiomyocytes of MI-placebo compared with normal heart tissue. NAC was shown to diminish type 3 iodothyronine deiodinase expression and activity in MI-NAC. These results show that restoring redox balance by NAC treatment prevents NTIS- related thyroid hormone derangement and preserves heart function in rats subjected to MI.}, }
@article {pmid28321598, year = {2017}, author = {Soheyli, E and Sahraei, R and Nabiyouni, G}, title = {Preparation of Highly Biocompatible ZnSe Quantum Dots Using a New Source of Acetyl Cysteine as Capping Agent.}, journal = {Journal of fluorescence}, volume = {27}, number = {5}, pages = {1581-1586}, pmid = {28321598}, issn = {1573-4994}, abstract = {In this paper, we describe a facile method for preparation of ZnSe quantum dots (QDs) using an inexpensive and biocompatible source of acetyl cysteine in aqueous media. The structural properties of the ZnSe QDs have been characterized using XRD, FT-IR, and TEM techniques. The optical properties of the as-prepared QDs were found to be size-dependent, due to the strong confinement regime at relatively low refluxing time. Effect of solution pH and refluxing temperature on absorption and emission characteristics of the ZnSe QDs was studied. The empirical effective mass approximation also reveals that, both solution pH and refluxing temperature parameters would effect on ZnSe QDs growth, and increase their size. However, the influence of the solution pH was found to be more prominent. Water-solubility, high emission intensity and sub-10 nm nanocrystals size are the most essential features that suggest our synthesized aqueous-based ZnSe QDs (with a very cost-effective and biocompatible capping agent) can be utilized for biological intentions.}, }
@article {pmid28321046, year = {2017}, author = {Hirata, N and Yamada, S and Sekino, Y and Kanda, Y}, title = {Tobacco nitrosamine NNK increases ALDH-positive cells via ROS-Wnt signaling pathway in A549 human lung cancer cells.}, journal = {The Journal of toxicological sciences}, volume = {42}, number = {2}, pages = {193-204}, doi = {10.2131/jts.42.193}, pmid = {28321046}, issn = {1880-3989}, mesh = {A549 Cells ; Aldehyde Dehydrogenase/*metabolism ; Carcinogens/*toxicity ; Humans ; Lung Neoplasms/metabolism ; Nitrosamines/*toxicity ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Nicotiana ; Wnt Signaling Pathway/*drug effects ; }, abstract = {Epidemiological studies suggest that lung cancer, which is a major cause of cancer death, has a critical association with cigarette smoking. Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cigarette smoke is a major risk factor for carcinogenesis. However, the mechanisms by which NNK promotes cancer development have not been fully elucidated. Growing evidence suggests that lung cancer originates from cancer stem cells (CSCs), which are a minor population of lung cancer cells. In the present study, we investigated the effects of NNK on the CSCs in A549 human lung cancer cells using flow cytometry with aldehyde dehydrogenase (ALDH), a functional marker of CSCs. We found that NNK increased the proportion of ALDH-positive cells in a dose-dependent manner. A Wnt inhibitor PNU74654 reduced NNK-induced expression levels of Wnt target gene Dkk1 and increase in ALDH-positive cells. We next examined the signaling pathway that mediates the NNK-induced increase in ALDH-positive cells via Wnt signaling. DCF assay revealed that NNK induced reactive oxygen species (ROS) production. The ROS scavenger N-acetylcysteine (NAC) inhibited the NNK-induced Wnt activation and increase in ALDH-positive cells. These data suggest that NNK-induced ROS activate the Wnt signaling pathway in A549 cells. These findings would provide new insights into the role of NNK in the lung CSCs.}, }
@article {pmid28318471, year = {2017}, author = {Hasebe, K and Gray, L and Bortolasci, C and Panizzutti, B and Mohebbi, M and Kidnapillai, S and Spolding, B and Walder, K and Berk, M and Malhi, G and Dodd, S and Dean, OM}, title = {Adjunctive N-acetylcysteine in depression: exploration of interleukin-6, C-reactive protein and brain-derived neurotrophic factor.}, journal = {Acta neuropsychiatrica}, volume = {29}, number = {6}, pages = {337-346}, doi = {10.1017/neu.2017.2}, pmid = {28318471}, issn = {1601-5215}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Antidepressive Agents/*therapeutic use ; Biomarkers/blood ; Brain-Derived Neurotrophic Factor/*blood ; C-Reactive Protein/*analysis ; Depressive Disorder/blood/*drug therapy ; Female ; Humans ; Interleukin-6/*blood ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVE: This study aimed to explore effects of adjunctive N-acetylcysteine (NAC) treatment on inflammatory and neurogenesis markers in unipolar depression.<br><br>METHODS: We embarked on a 12-week clinical trial of NAC (2000 mg/day compared with placebo) as an adjunctive treatment for unipolar depression. A follow-up visit was conducted 4 weeks following the completion of treatment. We collected serum samples at baseline and the end of the treatment phase (week 12) to determine changes in interleukin-6 (IL6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) following NAC treatment.<br><br>RESULTS: NAC treatment significantly improved depressive symptoms on the Montgomery-Asberg Depression Rating Scale (MADRS) over 16 weeks of the trial. Serum levels of IL6 were associated with reductions of MADRS scores independent of treatment response. However, we found no significant changes in IL6, CRP and BDNF levels following NAC treatment.<br><br>CONCLUSION: Overall, this suggests that our results failed to support the hypothesis that IL6, CRP and BDNF are directly involved in the therapeutic mechanism of NAC in depression. IL6 may be a useful marker for future exploration of treatment response.}, }
@article {pmid28314261, year = {2017}, author = {Gümbel, D and Gelbrich, N and Napp, M and Daeschlein, G and Kramer, A and Sckell, A and Burchardt, M and Ekkernkamp, A and Stope, MB}, title = {Peroxiredoxin Expression of Human Osteosarcoma Cells Is Influenced by Cold Atmospheric Plasma Treatment.}, journal = {Anticancer research}, volume = {37}, number = {3}, pages = {1031-1038}, doi = {10.21873/anticanres.11413}, pmid = {28314261}, issn = {1791-7530}, mesh = {Apoptosis ; Ascorbic Acid/chemistry ; Atmosphere ; Cell Line, Tumor ; Cell Proliferation ; *Gene Expression Regulation, Neoplastic ; Homeostasis ; Humans ; Osteosarcoma/*metabolism ; Oxidation-Reduction ; Peroxiredoxins/*metabolism ; *Plasma Gases ; Protein Multimerization ; Signal Transduction ; }, abstract = {BACKGROUND/AIM: To evaluate the potential involvement of redox-specific signalling pathways in cold atmospheric plasma (CAP)-induced apoptosis on human osteosarcoma cells.<br><br>MATERIALS AND METHODS: Osteosarcoma cell lines were treated with CAP with or without antioxidative agents and seeded in cell culture plates. Cell proliferation was determined by counting viable cells. Carrier gas-treated cells served as control. Peroxiredoxin (PRX) 1-3 expression and secretion were assessed.<br><br>RESULTS: CAP treatment exhibited strongly attenuated proliferation rates. This effect was significantly attenuated by the addition of N-acetylcysteine (NAC). CAP-treated cells exhibited an increase of PRX 1 and 2 10 sec after treatment. The ratio of oxidized to reduced PRX1 and PRX2 was significantly altered with increasing cellular concentration of the oxidized dimer.<br><br>CONCLUSION: Antioxidant supplementation with NAC increases proliferation of CAP-treated osteosarcoma cells, implicating an involvement of redox signalling. Activation of PRX1 and -2 indicate CAP affects redox homeostasis.}, }
@article {pmid28303497, year = {2017}, author = {Schneider, R and Bandiera, S and Souza, DG and Bellaver, B and Caletti, G and Quincozes-Santos, A and Elisabetsky, E and Gomez, R}, title = {N-acetylcysteine Prevents Alcohol Related Neuroinflammation in Rats.}, journal = {Neurochemical research}, volume = {42}, number = {8}, pages = {2135-2141}, pmid = {28303497}, issn = {1573-6903}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alcohol Drinking/drug therapy/immunology/metabolism ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Brain/drug effects/*metabolism ; Ethanol/administration &amp; dosage/*toxicity ; Inflammation/drug therapy/immunology/metabolism ; Inflammation Mediators/antagonists &amp; inhibitors/*metabolism ; Male ; Rats ; Rats, Wistar ; }, abstract = {Alcoholism has been characterized as a systemic pro-inflammatory condition and alcohol withdrawal has been linked to various changes in the brain homeostasis, including oxidative stress and glutamate hyperactivity. N-acetylcysteine (NAC) is an anti-inflammatory and antioxidant multi-target drug with promising results in psychiatry, including drug addiction. We assessed the effects of NAC on the serum and brain inflammatory cytokines after cessation of chronic alcohol treatment in rats. Male Wistar rats received 2 g/kg alcohol or vehicle twice a day by oral gavage for 30 days. Rats were treated, from day 31 to 34, with NAC (60 or 90 mg/kg) or saline, intraperitoneally, once daily. Rats were sacrificed at day 35, trunk blood was collected and the frontal cortex and hippocampus dissected for assessment of TNF-α, IL-1β, IL-6, IL-18, IL-10. NAC prevented the increase of pro-inflammatory cytokines and the decrease of anti-inflammatory cytokine in the frontal cortex and hippocampus. No changes were observed on serum cytokines. We conclude that NAC protects against inflammation induced by chronic (30 days) alcohol ingestion followed by 5 days cessation in two rat brain areas. Because inflammation has been documented and associated with craving and relapse in alcoholics, the data revealed by this study points to the validity of NAC clinical evaluation in the context of alcohol detoxification and withdrawal.}, }
@article {pmid28301919, year = {2017}, author = {Zhang, P and Hong, J and Yoon, IN and Kang, JK and Hwang, JS and Kim, H}, title = {Clostridium difficile Toxin A Induces Reactive Oxygen Species Production and p38 MAPK Activation to Exert Cellular Toxicity in Neuronal Cells.}, journal = {Journal of microbiology and biotechnology}, volume = {27}, number = {6}, pages = {1163-1170}, doi = {10.4014/jmb.1702.02041}, pmid = {28301919}, issn = {1738-8872}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Bacterial Toxins/*pharmacology ; Caspase 3/biosynthesis ; Cell Line, Tumor ; Colitis/microbiology/physiopathology ; Colon/immunology/microbiology/physiopathology ; Down-Regulation ; Enterotoxins/*pharmacology ; Guinea Pigs ; Inflammation ; Neurons/*drug effects/metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Up-Regulation ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; rho GTP-Binding Proteins/genetics/metabolism ; }, abstract = {Clostridium difficile releases two exotoxins, toxin A and toxin B, which disrupt the epithelial cell barrier in the gut to increase mucosal permeability and trigger inflammation with severe diarrhea. Many studies have suggested that enteric nerves are also directly involved in the progression of this toxin-mediated inflammation and diarrhea. C. difficile toxin A is known to enhance neurotransmitter secretion, increase gut motility, and suppress sympathetic neurotransmission in the guinea pig colitis model. Although previous studies have examined the pathophysiological role of enteric nerves in gut inflammation, the direct effect of toxins on neuronal cells and the molecular mechanisms underlying toxin-induced neuronal stress remained to be unveiled. Here, we examined the toxicity of C. difficile toxin A against neuronal cells (SH-SY5Y). We found that toxin A treatment time- and dose-dependently decreased cell viability and triggered apoptosis accompanied by caspase-3 activation in this cell line. These effects were found to depend on the up-regulation of reactive oxygen species (ROS) and the subsequent activation of p38 MAPK and induction of p21[Cip1/Waf1]. Moreover, the N-acetyl-L-cysteine (NAC)-induced down-regulation of ROS could recover the viability loss and apoptosis of toxin A-treated neuronal cells. These results collectively suggest that C. difficile toxin A is toxic for neuronal cells, and that this is associated with rapid ROS generation and subsequent p38 MAPK activation and p21[Cip1/Waf1] up-regulation. Moreover, our data suggest that NAC could inhibit the toxicity of C. difficile toxin A toward enteric neurons.}, }
@article {pmid28299952, year = {2018}, author = {Chertoff, J}, title = {N-Acetylcysteine's Role in Sepsis and Potential Benefit in Patients With Microcirculatory Derangements.}, journal = {Journal of intensive care medicine}, volume = {33}, number = {2}, pages = {87-96}, doi = {10.1177/0885066617696850}, pmid = {28299952}, issn = {1525-1489}, mesh = {Acetylcysteine/*therapeutic use ; Acidosis, Lactic/etiology ; Free Radical Scavengers/*therapeutic use ; Humans ; Microcirculation/*physiology ; Mortality ; Multiple Organ Failure/etiology ; Regional Blood Flow ; Sepsis/complications/*drug therapy/mortality/physiopathology ; Vasodilation ; }, abstract = {OBJECTIVE: To review the data surrounding the utility of N-acetylcysteine (NAC) in sepsis and identify areas needed for additional research.<br><br>DATA SOURCES: A review of articles describing the mechanisms of action and clinical use of NAC in sepsis.<br><br>SUMMARY OF REVIEW: Despite many advances in critical care medicine, still as many as 50% of patients with septic shock die. Treatments thus far have focused on resuscitation and restoration of macrocirculatory targets in the early phases of sepsis, with less focus on microcirculatory dysfunction. N-acetylcysteine, due to its anti-inflammatory and antioxidative properties, has been readily investigated in sepsis and has yielded largely incongruous and disappointing results. In addition to its known anti-inflammatory and antioxidative roles, one underappreciated property of NAC is its ability to vasodilate the microcirculation and improve locoregional blood flow. Some investigators have sought to capitalize on this mechanism with promising results, as evidenced by microcirculatory vasodilation, improvements in regional blood flow and oxygen delivery, and reductions in lactic acidosis, organ failure, and mortality.<br><br>CONCLUSION: In addition to its antioxidant and anti-inflammatory properties, N-acetylcysteine possesses vasodilatory properties that could benefit the microcirculation in sepsis. It is imperative that we investigate these properties to uncover NAC's full potential for benefit in sepsis.}, }
@article {pmid28299863, year = {2017}, author = {Qui, S and Kano, J and Noguchi, M}, title = {Dickkopf 3 attenuates xanthine dehydrogenase expression to prevent oxidative stress-induced apoptosis.}, journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms}, volume = {22}, number = {4}, pages = {406-417}, doi = {10.1111/gtc.12484}, pmid = {28299863}, issn = {1365-2443}, mesh = {Adaptor Proteins, Signal Transducing ; *Apoptosis ; Cell Line ; Cell Line, Tumor ; Chemokines ; Gene Knockdown Techniques ; Humans ; Hydrogen Peroxide/metabolism ; Intercellular Signaling Peptides and Proteins/genetics/*metabolism ; Mitochondrial Membranes/metabolism ; *Oxidative Stress ; Xanthine Dehydrogenase/*genetics ; }, abstract = {Dickkopf (DKK) 3 is a DKK glycoprotein family member that controls cell fate during embryogenesis and exerts opposing effects on survival in a cell type-dependent manner; however, the mechanisms governing its pro-apoptosis versus pro-survival functions remain unclear. Here, we investigated DKK3 function in Li21 hepatoma cells and tPH5CH immortalized hepatocytes. DKK3 knockdown by siRNA resulted in reactive oxygen species accumulation and subsequent apoptosis, which were abrogated by administration of the antioxidant N-acetyl-cysteine. Moreover, forced DKK3 over-expression induced resistance to hydrogen peroxide (H2 O2)-induced apoptosis. Expression analysis by cDNA microarray showed that xanthine dehydrogenase (XDH) expression was significantly lower in Li21 and tPH5CHDKK3-over-expressing cells in response to H2 O2 treatment when compared to that in their respective mock-transfected controls, whereas a marked increase was observed in H2 O2 -treated DKK3 knockdown cells. Thus, these data suggest that DKK3 promotes cell survival during oxidative stress by suppressing the expression of the superoxide-producing enzyme XDH.}, }
@article {pmid28296042, year = {2017}, author = {Zou, L and Su, L and Sun, Y and Han, A and Chang, X and Zhu, A and Liu, F and Li, J and Sun, Y}, title = {Nickel sulfate induced apoptosis via activating ROS-dependent mitochondria and endoplasmic reticulum stress pathways in rat Leydig cells.}, journal = {Environmental toxicology}, volume = {32}, number = {7}, pages = {1918-1926}, doi = {10.1002/tox.22414}, pmid = {28296042}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Caspase 12/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cyclic N-Oxides/pharmacology ; Cytochromes c/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Heat-Shock Proteins/metabolism ; Leydig Cells/*drug effects/metabolism ; Male ; Mitochondria/*metabolism ; Nickel/*toxicity ; Rats, Wistar ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Signal Transduction ; Transcription Factor CHOP/metabolism ; }, abstract = {Nickel can induce apoptosis of testicular Leydig cells in mice, whereas the mechanisms remain unclear. In this study, we investigated the role of nickel-induced reactive oxygen species (ROS) generation in mitochondria and endoplasmic reticulum stress (ERS) mediated apoptosis pathways in rat Leydig cells. Fluorescent DCF and Annexin-V FITC/PI staining were performed to measure the production of ROS and apoptosis in Leydig cells. RT-qPCR and Western blot were conducted to analyze the key genes and proteins involved in mitochondria and ERS apoptotic pathways. The results showed that nickel sulfate induced ROS generation, consequently resulted in nucleolus deformation and apoptosis in testicular Leydig cells, which were then attenuated by ROS inhibitors of N-acetylcysteine (NAC) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). Nickel sulfate-triggered Leydig cells apoptosis via mitochondria and ERS pathways was characterized by the upregulated mRNA and proteins expression of Bak, cytochrome c, caspase 9, caspase 3, GRP78, GADD153, and caspase 12, which were inhibited by NAC and TEMPO respectively. The findings indicated that nickel-induced ROS generation was involved in apoptosis via mitochondria and ERS pathways in rat Leydig cells.}, }
@article {pmid28291959, year = {2017}, author = {Liang, W and Chen, M and Zheng, D and Li, J and Song, M and Zhang, W and Feng, J and Lan, J}, title = {The Opening of ATP-Sensitive K+ Channels Protects H9c2 Cardiac Cells Against the High Glucose-Induced Injury and Inflammation by Inhibiting the ROS-TLR4-Necroptosis Pathway.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {41}, number = {3}, pages = {1020-1034}, doi = {10.1159/000461391}, pmid = {28291959}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cell Line ; Decanoic Acids/pharmacology ; Diazoxide/pharmacology ; Gene Expression Regulation ; Glucose/*toxicity ; Glyburide/pharmacology ; Hydroxy Acids/pharmacology ; Imidazoles/pharmacology ; Indoles/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Myocytes, Cardiac/cytology/*drug effects/metabolism ; Necrosis/genetics/metabolism/prevention &amp; control ; Oxidative Stress ; Pinacidil/pharmacology ; Potassium Channels/agonists/*genetics/metabolism ; Rats ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/genetics/metabolism ; Signal Transduction ; Sulfonamides/pharmacology ; Toll-Like Receptor 4/antagonists &amp; inhibitors/*genetics/metabolism ; }, abstract = {BACKGROUND/AIMS: Hyperglycemia activates multiple signaling molecules, including reactive oxygen species (ROS), toll-like receptor 4 (TLR4), receptor-interacting protein 3 (RIP3, a kinase promoting necroptosis), which mediate hyperglycemia-induced cardiac injury. This study explored whether inhibition of ROS-TLR4-necroptosis pathway contributed to the protection of ATP-sensitive K+ (KATP) channel opening against high glucose-induced cardiac injury and inflammation.<br><br>METHODS: H9c2 cardiac cells were treated with 35 mM glucose (HG) to establish a model of HG-induced insults. The expression of RIP3 and TLR4 were tested by western blot. Generation of ROS, cell viability, mitochondrial membrane potential (MMP) and secretion of inflammatory cytokines were measured as injury indexes.<br><br>RESULTS: HG increased the expression of TLR4 and RIP3. Necrostatin-1 (Nec-1, an inhibitor of necroptosis) or TAK-242 (an inhibitor of TLR4) co-treatment attenuated HG-induced up-regulation of RIP3. Diazoxide (DZ, a mitochondrial KATP channel opener) or pinacidil (Pin, a non-selective KATP channel opener) or N-acetyl-L-cysteine (NAC, a ROS scavenger) pre-treatment blocked the up-regulation of TLR4 and RIP3. Furthermore, pre-treatment with DZ or Pin or NAC, or co-treatment with TAK-242 or Nec-1 attenuated HG-induced a decrease in cell viability, and increases in ROS generation, MMP loss and inflammatory cytokines secretion. However, 5-hydroxy decanoic acid (5-HD, a mitochondrial KATP channel blocker) or glibenclamide (Gli, a non-selective KATP channel blocker) pre-treatment did not aggravate HG-induced injury and inflammation.<br><br>CONCLUSION: KATP channel opening protects H9c2 cells against HG-induced injury and inflammation by inhibiting ROS-TLR4-necroptosis pathway.}, }
@article {pmid28291433, year = {2017}, author = {Göçer, H and Emir, D and Önger, ME and Dabak, N}, title = {Effects of bone cement loaded with teicoplanin, N-acetylcysteine or their combination on Staphylococcus aureus biofilm formation: an in vitro study.}, journal = {Eklem hastaliklari ve cerrahisi = Joint diseases &amp; related surgery}, volume = {28}, number = {1}, pages = {13-18}, doi = {10.5606/ehc.2017.52507}, pmid = {28291433}, issn = {1309-0313}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Bacterial Load ; Biofilms/*drug effects ; Bone Cements ; Expectorants/*pharmacology ; Staphylococcus aureus/*drug effects ; Teicoplanin/*pharmacology ; }, abstract = {OBJECTIVES: This study aims to demonstrate the antibiofilm effects of teicoplanin alone, N-acetyl cysteine (NAC) alone, or combination of both compounds when mixed with bone cement.<br><br>MATERIALS AND METHODS: A total of four groups were formed by using six cement samples in each, prepared with bone cement having different contents in each group. Group 1 (control group): cement alone without any drugs added. Group 2: 40 g cement, 400 mg teicoplanin. Group 3: 40 g cement, 6 g NAC. Group 4: 40 g cement, 6 g NAC, 400 mg teicoplanin. All cement samples were infected with Staphylococcus aureus for 48 hours at 36.5 &#xb0;C. Bacterial colonies were then counted by serial dilution method. Bacteria were counted using scanning electron microscopic (SEM) images.<br><br>RESULTS: Counts of bacteria colonies were 5.83&#xb1;1.60 [mean colony forming unit (cfu) x 105&#xb1;standard deviation (SD)] in group 1, 0.12&#xb1;0.56 in group 2, 0.11&#xb1;0.65 in group 3, and 0.01&#xb1;0.001 in group 4. Significant difference was found between group 1 and all other groups (p<0.05), and between group 4 and all other groups (p<0.05). According to SEM analysis, counts of bacteria (mean&#xb1;SD) were 1.88&#xb1;0.45, 0.75&#xb1;0.26, 0.21&#xb1;0.22, and 0.13&#xb1;0.25 in groups 1, 2, 3, and 4, respectively. Significant difference was found between group 1 and all other groups (p<0.05), and between group 4 and all other groups (p<0.05).<br><br>CONCLUSION: N-acetyl cysteine, teicoplanin, and their combination significantly reduced formation of biofilm compared to the control group. Also, combination of NAC and teicoplanin had the highest antibiofilm effect.}, }
@article {pmid28288879, year = {2017}, author = {Pérez-Miguelsanz, J and Vallecillo, N and Garrido, F and Reytor, E and Pérez-Sala, D and Pajares, MA}, title = {Betaine homocysteine S-methyltransferase emerges as a new player of the nuclear methionine cycle.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1864}, number = {7}, pages = {1165-1182}, doi = {10.1016/j.bbamcr.2017.03.004}, pmid = {28288879}, issn = {0167-4889}, mesh = {Active Transport, Cell Nucleus ; Animals ; Betaine-Homocysteine S-Methyltransferase/chemistry/genetics/*metabolism ; CHO Cells ; Cell Nucleus/*metabolism ; Cricetinae ; Cricetulus ; Cytoplasm/metabolism ; Glutathione/metabolism ; Liver/metabolism ; Male ; Methionine/*metabolism ; Oxidative Stress ; Protein Sorting Signals ; Rats ; Rats, Wistar ; }, abstract = {The paradigm of a cytoplasmic methionine cycle synthesizing/eliminating metabolites that are transported into/out of the nucleus as required has been challenged by detection of significant nuclear levels of several enzymes of this pathway. Here, we show betaine homocysteine S-methyltransferase (BHMT), an enzyme that exerts a dual function in maintenance of methionine levels and osmoregulation, as a new component of the nuclear branch of the cycle. In most tissues, low expression of Bhmt coincides with a preferential nuclear localization of the protein. Conversely, the liver, with very high Bhmt expression levels, presents a main cytoplasmic localization. Nuclear BHMT is an active homotetramer in normal liver, although the total enzyme activity in this fraction is markedly lower than in the cytosol. N-terminal basic residues play a role in cytoplasmic retention and the ratio of glutathione species regulates nucleocytoplasmic distribution. The oxidative stress associated with d-galactosamine (Gal) or buthionine sulfoximine (BSO) treatments induces BHMT nuclear translocation, an effect that is prevented by administration of N-acetylcysteine (NAC) and glutathione ethyl ester (EGSH), respectively. Unexpectedly, the hepatic nuclear accumulation induced by Gal associates with reduced nuclear BHMT activity and a trend towards increased protein homocysteinylation. Overall, our results support the involvement of BHMT in nuclear homocysteine remethylation, although moonlighting roles unrelated to its enzymatic activity in this compartment cannot be excluded.}, }
@article {pmid28288414, year = {2017}, author = {Pant, K and Yadav, AK and Gupta, P and Islam, R and Saraya, A and Venugopal, SK}, title = {Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells.}, journal = {Redox biology}, volume = {12}, number = {}, pages = {340-349}, pmid = {28288414}, issn = {2213-2317}, mesh = {Antineoplastic Agents/*pharmacology ; Butyric Acid/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Liver Neoplasms/drug therapy/*genetics/metabolism ; MicroRNAs/*genetics ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Sirtuin 1/*genetics ; }, abstract = {Butyrate is one of the short chain fatty acids, produced by the gut microbiota during anaerobic fermentation of dietary fibres. It has been shown that it can inhibit tumor progression via suppressing histone deacetylase and can induce apoptosis in cancer cells. However, the comprehensive pathway by which butyrate mediates apoptosis and growth arrest in cancer cells still remains unclear. In this study, the role of miR-22 in butyrate-mediated ROS release and induction of apoptosis was determined in hepatic cells. Intracellular expression of miR-22 was increased when the Huh 7 cells were incubated with sodium butyrate. Over-expression of miR-22 or addition of sodium butyrate inhibited SIRT-1 expression and enhanced the ROS production. Incubation of cells with anti-miR-22 reversed the effects of butyrate. Butyrate induced apoptosis via ROS production, cytochrome c release and activation of caspase-3, whereas addition of N-acetyl cysteine or anti-miR-22 reversed these butyrate-induced effects. Furthermore, sodium butyrate inhibited cell growth and proliferation, whereas anti-miR-22 inhibited these butyrate-mediated changes. The expression of PTEN and gsk-3 was found to be increased while p-akt and β-catenin expression was decreased significantly by butyrate. These data showed that butyrate modulated both apoptosis and proliferation via miR-22 expression in hepatic cells.}, }
@article {pmid28287621, year = {2017}, author = {Wongjaikam, S and Kumfu, S and Khamseekaew, J and Chattipakorn, SC and Chattipakorn, N}, title = {Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {44460}, pmid = {28287621}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Benzoates/pharmacology ; Calcium/metabolism ; Calcium Channels, T-Type/genetics/metabolism ; Cardiomyopathies/chemically induced/*drug therapy/genetics/pathology ; Deferasirox ; Deferiprone ; Deferoxamine/pharmacology ; Drug Combinations ; Drug Synergism ; Gene Expression Regulation ; Humans ; Iron/administration &amp; dosage/*metabolism ; Iron Chelating Agents/*pharmacology ; Iron Overload/chemically induced/*drug therapy/genetics/pathology ; Male ; Mitochondria/drug effects/metabolism/pathology ; Myocardium/metabolism/pathology ; Pyridones/*pharmacology ; Rats ; Rats, Wistar ; Sarcoplasmic Reticulum/drug effects/metabolism/pathology ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism ; Triazoles/pharmacology ; }, abstract = {Intracellular calcium [Ca[2+]]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca[2+]]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca[2+] ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca[2+]]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca[2+]]i homeostasis, only DFP + NAC restored cardiac [Ca[2+]]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca[2+]]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats.}, }
@article {pmid28286938, year = {2019}, author = {Kim, HR and Kim, KW and Kim, BM and Lee, KA and Lee, SH}, title = {N-acetyl-l-cysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL production in rheumatoid arthritis.}, journal = {The Korean journal of internal medicine}, volume = {34}, number = {1}, pages = {210-219}, pmid = {28286938}, issn = {2005-6648}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Arthritis, Rheumatoid/*drug therapy/immunology/pathology ; Cell Differentiation/drug effects/immunology ; Fibroblasts/drug effects/immunology/pathology ; Humans ; In Vitro Techniques ; Interleukin-17/metabolism ; Middle Aged ; Osteogenesis/*drug effects/immunology ; RANK Ligand/genetics/*metabolism ; Signal Transduction/drug effects ; Synovial Membrane/drug effects/immunology/pathology ; Th17 Cells/*drug effects/immunology/pathology ; }, abstract = {BACKGROUND/AIMS: This study aimed to determine the regulatory role of N-acetyl-l-cysteine (NAC), an antioxidant, in interleukin 17 (IL-17)-induced osteoclast differentiation in rheumatoid arthritis (RA).<br><br>METHODS: After RA synovial fibroblasts were stimulated by IL-17, the expression and production of receptor activator of nuclear factor &#x3ba;-B ligand (RANKL) was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Osteoclastogenesis was also determined after co-cultures of IL-17-stimulated RA synovial fibroblasts, Th17 cells and various concentrations of NAC with monocytes. After human peripheral CD4+ T cells were cultured with NAC under Th17 condition, IL-17, interferon &#x3b3;, IL-4, Foxp3, RANKL, and IL-2 expression and production was determined by flow cytometry or ELISA.<br><br>RESULTS: When RA synovial fibroblasts were stimulated by IL-17, IL-17 stimulated the production of RANKL, and NAC reduced the IL-17-induced RANKL production in a dose-dependent manner. NAC decreased IL-17-activated phosphorylation of mammalian target of rapamycin, c-Jun N-terminal kinase, and inhibitor of &#x3ba;B. When human peripheral blood CD14+ monocytes were cultured with macrophage colony-stimulating factor and IL-17 or RANKL, osteoclasts were differentiated, and NAC reduced the osteoclastogenesis. After human peripheral CD4+ T cells were co-cultured with IL-17-pretreated RA synovial fibroblasts or Th17 cells, NAC reduced their osteoclastogenesis. Under Th17 polarizing condition, NAC decreased Th17 cell differentiation and IL-17 and RANKL production.<br><br>CONCLUSION: NAC inhibits the IL-17-induced RANKL production in RA synovial fibroblasts and IL-17-induced osteoclast differentiation. NAC also reduced Th17 polarization. NAC could be a supplementary therapeutic option for inflammatory and bony destructive processes in RA.}, }
@article {pmid28281393, year = {2017}, author = {Murley, JS and Miller, RC and Senlik, RR and Rademaker, AW and Grdina, DJ}, title = {Altered expression of a metformin-mediated radiation response in SA-NH and FSa tumor cells treated under in vitro and in vivo growth conditions.}, journal = {International journal of radiation biology}, volume = {93}, number = {7}, pages = {665-675}, pmid = {28281393}, issn = {1362-3095}, support = {R01 CA132998/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Cell Line, Tumor ; Cell Proliferation/*drug effects/*radiation effects ; Dose-Response Relationship, Drug ; Emodin/administration &amp; dosage ; Female ; Metformin/*administration &amp; dosage ; Mice ; Mice, Inbred C3H ; Neoplasms, Experimental/*metabolism/pathology/*radiotherapy ; Radiation Dosage ; Radiation Tolerance/drug effects ; Radiation-Sensitizing Agents/administration &amp; dosage ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {PURPOSE: To assess the radiosensitizing effect of the biguanide drug metformin used alone or in combination with reactive oxygen species (ROS) modifying agents N-acetyl-L-cysteine (NAC) or emodin, and contrasted to the mitochondrial complex 1 inhibitor rotenone in altering the radiation responses of the p53 wild-type SA-NH and p53 mutant FSa mouse tumor lines grown either in vitro or in vivo.<br><br>MATERIALS AND METHODS: Tumor cells were grown to confluence in vitro and exposed to a single 4&#x2009;Gy dose in the presence or absence of metformin (5&#x2009;mM) and ROS modifiers or to 10&#x2009;Gy with or without metformin as tumors in the flanks of C3H mice using a tumor growth delay assay.<br><br>RESULTS: Both metformin and rotenone protected SA-NH (p&#x2009;<&#x2009;.001) while sensitizing FSa (p&#x2009;<&#x2009;.001) to 4&#x2009;Gy. Neither NAC nor emodin altered metformin's action. Metformin was also directly toxic to FSa cells (p&#x2009;=&#x2009;.002). In contrast, in vivo metformin (250&#x2009;mg/kg) sensitized both SA-NH (9-day growth delay, p&#x2009;<&#x2009;.05) and FSa (4-day growth delay, p&#x2009;<&#x2009;.05) tumors if administered 1&#x2009;h before irradiation.<br><br>CONCLUSION: Metformin effects on tumor cells measured under in vitro conditions may differ from those determined in vivo due to p53 and heterogeneous environmental factors.}, }
@article {pmid28280002, year = {2017}, author = {Zayed, MA and Wei, X and Park, KM and Belaygorod, L and Naim, U and Harvey, J and Yin, L and Blumer, K and Semenkovich, CF}, title = {N-Acetylcysteine accelerates amputation stump healing in the setting of diabetes.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {31}, number = {6}, pages = {2686-2695}, pmid = {28280002}, issn = {1530-6860}, support = {P30 DK056341/DK/NIDDK NIH HHS/United States ; R01 DK101392/DK/NIDDK NIH HHS/United States ; R01 DK076729/DK/NIDDK NIH HHS/United States ; K08 HL132060/HL/NHLBI NIH HHS/United States ; T32 DK007120/DK/NIDDK NIH HHS/United States ; P30 DK020579/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; *Amputation Stumps ; Animals ; *Diabetes Mellitus, Experimental ; Hindlimb/blood supply/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Reactive Oxygen Species/metabolism ; Wound Healing/*drug effects ; }, abstract = {Over 60% of lower extremity amputations are performed in patients with diabetes and peripheral arterial disease, and at least 25% require subsequent reamputation due to poor surgical site healing. The mechanisms underlying poor amputation stump healing in the setting of diabetes are not understood. N-acetylcysteine (NAC) is known to promote endothelial cell function and angiogenesis and may have therapeutic benefits in the setting of diabetes. We tested the hypothesis that NAC alters the vascular milieu to improve healing of amputation stumps in diabetes using a novel in vivo murine hindlimb ischemia-amputation model. Amputation stump tissue perfusion and healing were evaluated in C57BL/6J adult mice with streptozotocin-induced diabetes. Compared with controls, mice treated with daily NAC demonstrated improved postamputation stump healing, perfusion, adductor muscle neovascularization, and decreased muscle fiber damage. Additionally, NAC stimulated HUVEC migration and proliferation in a phospholipase C β-dependent fashion and decreased Gαq palmitoylation. Similarly, NAC treatment also decreased Gαq palmitoylation in ischemic and nonischemic hindlimbs in vivo In summary, we demonstrate that NAC accelerates healing of amputation stumps in the setting of diabetes and ischemia. The underlying mechanism appears to involve a previously unrecognized effect of NAC on Gαq palmitoylation and phospholipase C β-mediated signaling in endothelial cells.-Zayed, M. A., Wei, X., Park, K., Belaygorod, L., Naim, U., Harvey, J., Yin, L., Blumer, K., Semenkovich, C. F. N-acetylcysteine accelerates amputation stump healing in the setting of diabetes.}, }
@article {pmid28277986, year = {2017}, author = {Refaat, A and Pararasa, C and Arif, M and Brown, JE and Carmichael, A and Ali, SS and Sakurai, H and Griffiths, HR}, title = {Bardoxolone-methyl inhibits migration and metabolism in MCF7 cells.}, journal = {Free radical research}, volume = {51}, number = {2}, pages = {211-221}, doi = {10.1080/10715762.2017.1295452}, pmid = {28277986}, issn = {1029-2470}, mesh = {Antioxidants/metabolism ; Apoptosis/drug effects ; Blotting, Western ; Cell Movement/*drug effects ; Cell Proliferation/drug effects ; Glutathione/metabolism ; Humans ; MCF-7 Cells ; Mitochondria/drug effects/*metabolism ; Oleanolic Acid/*analogs &amp; derivatives/pharmacology ; Oxidative Stress/*drug effects ; RNA, Messenger/genetics ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; }, abstract = {Bardoxolone-methyl (BAR) is reported to have anti-inflammatory, anti-proliferative and anti-fibrotic effects. BAR activates Nrf2 and may ameliorate oxidative stress through induction of antioxidant genes. However, off-target effects, probably concentration and NFkB-dependent, have limited the clinical use of BAR. Nrf2 regulates expression of antioxidant and mitochondrial genes and has been proposed as a target for both obesity and breast cancer. Therefore, we explored whether BAR can alter migration and proliferation in the MCF7 cell line and whether metabolic function is affected by BAR. Incubation with BAR caused a time-dependent migratory inhibition and an associated decrease in mitochondrial respiration. Both migratory and mitochondrial inhibition by BAR were further enhanced in the presence of fatty acids. In addition to the activation of Nrf2, BAR altered the expression of target mRNA GCLC and UCP1. After 24 h, BAR inhibited both glycolytic capacity, reserve (p < 0.05) and oxidative phosphorylation (p < 0.001) with an associated increase in mitochondrial ROS and loss of intracellular glutathione in MCF7 cells; however, impairment of mitochondrial activity was prevented by N-acetyl cysteine. The fatty acid, palmitate, increased mitochondrial ROS, impaired migration and oxidative phosphorylation but palmitate toxicity towards MCF7 could not be inhibited by N-acetyl cysteine suggesting that they exert effects through different pathways. BAR-activated AKT, induced DNA damage and inhibited cell proliferation. When the proteasome was inhibited, there was loss of BAR-mediated changes in p65 phosphorylation and SOD2 expression suggesting non-canonical NFkB signaling effects. These data suggest that BAR-induced ROS are important in inhibiting MCF7 migration and metabolism by negatively affecting glycolytic capacity and mitochondrial function.}, }
@article {pmid28274308, year = {2017}, author = {Liu, Y and Li, S and Zhang, S and Cao, X and Zhang, Y}, title = {[Lipopolysaccharide of Porphyromonas gingivalis promotes the autophagy of human gingival fibroblasts].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {33}, number = {3}, pages = {315-319}, pmid = {28274308}, issn = {1007-8738}, mesh = {*Autophagy ; Bacteroidaceae Infections/metabolism/microbiology/*physiopathology ; Fibroblasts/*cytology/microbiology ; Gingiva/*cytology/metabolism/microbiology ; Humans ; Lipopolysaccharides/*metabolism ; Mitochondria/metabolism ; Porphyromonas gingivalis/genetics/*metabolism ; Ubiquinone/analogs &amp; derivatives/metabolism ; }, abstract = {Objective To investigate the impact of lipopolysaccharide of Porphyromonas gingivalis (Pg-LPS) on the autophagy of human gingival fibroblasts (HGFs). Methods Firstly, HGFs was stimulated with 10 μg/mL Pg-LPS for 12 hours or 24 hours. Rapamycin was used as a positive control. The expression of LC3B was detected by Western blotting and the distribution of autophagosomes was observed by indirect immunofluorescence staining. At the same time, mitochondrial ROS (mtROS) was labeled by MitoSOX Red. The levels of mtROS and mitochondrial autophagy were measured in HGFs after treated with Pg-LPS. Then, T-butyl-4 (BHA), N-acetylcysteine (NAC) and coenzyme Q10 (CoQ10) were used separately to block the ROS and the expression of LC3B in Pg-LPS-treated HGFs was tested by Western blotting. Results After treatment with Pg-LPS, the ratio of LC3BII/LC3BI and the number of autophagic cells significantly increased, and the increase in the 24-hour treatment group was the more obvious than that in the 12-hour treatment group. The mtROS production and mitochondrial autophagy were significantly promoted after Pg-LPS treatment. In addition, CoQ10 effectively reduced Pg-LPS-induced autophagy of HGFs. Conclusion Pg-LPS can induce the autophagy of HGFs by raising mtROS production, and autophagy is involved in the degradation of damaged mitochondria to maintain cellular homeostasis.}, }
@article {pmid28273962, year = {2017}, author = {Ghosh, R and Siddharth, M and Singh, N and Kare, PK and Banerjee, BD and Wadhwa, N and Tripathi, AK}, title = {Organochlorine Pesticide-Mediated Induction of NADPH Oxidase and Nitric-Oxide Synthase in Endothelial Cell.}, journal = {Journal of clinical and diagnostic research : JCDR}, volume = {11}, number = {1}, pages = {BC09-BC12}, pmid = {28273962}, issn = {2249-782X}, abstract = {INTRODUCTION: Organochlorine Pesticides (OCPs) are detected ubiquitously in human and have been shown to be associated with Cardiovascular Disease (CVD) and atherosclerosis.<br><br>AIM: To find out the effect of organochlorine pesticides in endothelial cell with regard to oxidative stress and associated expression of enzymes producing superoxide and Nitric Oxide (NO).<br><br>MATERIALS AND METHODS: Human Umbilical Vein Endothelial Cells (HUVEC) were cultured and treated with four OCPs which were found in human blood at a concentration of 0.1&#x3bc;M. The cells were tested for Reactive Oxygen Species (ROS) generation, NO production and mRNA expression of NAPDH oxidase (p47phox) and endothelial Nitric Oxide Synthase (eNOS). ROS generation was measured by using 2', 7'-dichlorodihydrofluorescein diacetate (H2DCFDA) method. NO was analysed by Bioxytech nitric oxide assay kit method and mRNA of NADPH oxidase and eNOS was quantified by real time PCR. Data were expressed as the mean&#xb1;SEM. Comparison between the groups were made by student's t-test (2-tailed) or one-way ANOVA with Tukey's post-hoc analysis depending on number of groups. For all statistical tests, p< 0.05 was considered to be significant.<br><br>RESULTS: All the four pesticides generated ROS accompanied by enhanced expression of NADPH oxidase. Maximum effect was observed with &#x3b2;-endosulfan. Level of NO was found to be decreased significantly in endothelial cells treated with these pesticides accompanied by enhanced expression of eNOS. The antioxidant N-acetylcysteine (NAC) reduced ROS generation and enhanced NO formation. Pesticide-mediated ROS generation possibly reacts with NO forming peroxinitrite and thereby reducing the bioavailability of NO although eNOS expression is increased.<br><br>CONCLUSION: OCPs induce endothelial dysfunction through increased ROS generation via NADPH oxidase expression and reduced bioavailability of nitric oxide.}, }
@article {pmid28273631, year = {2017}, author = {Alexandropoulos, D and Bazigos, GV and Doulamis, IP and Tzani, A and Konstantopoulos, P and Tragotsalou, N and Kondi-Pafiti, A and Kotsis, T and Arkadopoulos, N and Smyrniotis, V and Perrea, DN}, title = {Protective effects of N-acetylcystein and atorvastatin against renal and hepatic injury in a rat model of intestinal ischemia-reperfusion.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {89}, number = {}, pages = {673-680}, doi = {10.1016/j.biopha.2017.02.086}, pmid = {28273631}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/pathology/*prevention &amp; control ; Animals ; Antioxidants/*pharmacology ; Atorvastatin/*pharmacology ; Drug Therapy, Combination ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; Intestines/*blood supply ; Kidney Function Tests ; Liver Diseases/pathology/*prevention &amp; control ; Liver Function Tests ; Male ; Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; Reperfusion Injury/pathology/*prevention &amp; control ; }, abstract = {AIM OF THE STUDY: We sought to examine whether the separate and combined effect of N-acetylcystein (NAC) and atorvastatin prevented hepatic and renal tissue injury induced by intestinal ischemia-reperfusion (I/R).<br><br>MATERIAL AND METHODS: 40 male Wistar rats were allocated into 5 experimental groups; Control (n=8): sham, I/R (n=8): rats underwent occlusion of superior mesenteric artery for 45min, Atorvastatin (n=8): rats received 10mg/kg atorvastatin, NAC (n=8): rats received 160mg/kg NAC, NAC&amp;Atorvastatin (n=8): rats received both aforementioned agents. Administration of the agents was facilitated by oral gavage 24h before I/R. Serum levels of urea, creatinine, transaminases, IL-1&#x3b2;, IL-6, TNF-&#x3b1;, ICAM-1, as well as liver and kidney histopathological examination were evaluated.<br><br>RESULTS: Pretreatment with either NAC or Atorvastatin or their combination led to lower levels of transaminases and ICAM-1 (2.75&#xb1;0.46, 2.88&#xb1;0.84 and 1.5&#xb1;0.76 respectively for NAC, Atorvastatin and I/R groups), while only their combination led to lower ratios of IL-1, IL-6 and TNF-&#x3b1; than I/R group (1.3&#xb1;0.12 vs 1.94&#xb1;0.54, 1.21&#xb1;0.11 vs 2.12&#xb1;0.96 and 1.33&#xb1;0.11 vs 2.14&#xb1;0.77, respectively). NAC was associated with enhanced renal tissue histology, while atorvastatin was found superior in protecting hepatic tissue degenaration.<br><br>CONCLUSIONS: Both agents, seperately and combined, seem to exhibited tissue-specific protective activity against intestinal I/R induced injury.}, }
@article {pmid28273344, year = {2017}, author = {Uchida, M and Anderson, EL and Squillace, DL and Patil, N and Maniak, PJ and Iijima, K and Kita, H and O'Grady, SM}, title = {Oxidative stress serves as a key checkpoint for IL-33 release by airway epithelium.}, journal = {Allergy}, volume = {72}, number = {10}, pages = {1521-1531}, pmid = {28273344}, issn = {1398-9995}, support = {R01 AI071106/AI/NIAID NIH HHS/United States ; T32 HL007741/HL/NHLBI NIH HHS/United States ; R01 AI128729/AI/NIAID NIH HHS/United States ; T32 AI007425/AI/NIAID NIH HHS/United States ; R01 HL117823/HL/NHLBI NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Allergens/immunology ; Animals ; Antioxidants/metabolism ; Calcium/metabolism ; Epithelial Cells/metabolism ; Female ; Humans ; Interleukin-33/*metabolism ; Lung/drug effects/immunology/metabolism ; Mice ; Mice, Knockout ; NF-E2-Related Factor 2/metabolism ; Oleanolic Acid/analogs &amp; derivatives/pharmacology ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/immunology/metabolism ; }, abstract = {BACKGROUND: Interleukin (IL)-33 is implicated in the pathophysiology of asthma and allergic diseases. However, our knowledge is limited regarding how IL-33 release is controlled. The transcription factor nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a key role in antioxidant response regulation.<br><br>OBJECTIVE: The goal of this project was to investigate the role of cellular oxidative stress in controlling IL-33 release in airway epithelium.<br><br>METHODS: Complementary approaches were used that included human bronchial epithelial cells and mouse models of airway type-2 immunity that were exposed to fungus Alternaria extract. The clinically available Nrf2 activator 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me) was used to evaluate the role of Nrf2-induced antioxidant molecules.<br><br>RESULTS: Human bronchial epithelial cells produced reactive oxygen species (ROS) when they were exposed to Alternaria extract. ROS scavengers, such as glutathione (GSH) and N-acetyl cysteine, prevented extracellular secretion of ATP and increases in intracellular calcium concentrations that precede IL-33 release. Administration of CDDO-Me to mice enhanced expression of a number of antioxidant molecules in the lungs and elevated lung levels of endogenous GSH. Importantly, CDDO-Me treatment reduced allergen-induced ATP secretion and IL-33 release by airway epithelial cells in&#xa0;vitro and protected mice from IL-33 release and asthma-like pathological changes in the lungs.<br><br>CONCLUSIONS: The balance between oxidative stress and antioxidant responses plays a key role in controlling IL-33 release in airway epithelium. The therapeutic potential of Nrf2 activators needs to be considered for asthma and allergic airway diseases.}, }
@article {pmid28272477, year = {2017}, author = {Al Wafai, R and El-Rabih, W and Katerji, M and Safi, R and El Sabban, M and El-Rifai, O and Usta, J}, title = {Chemosensitivity of MCF-7 cells to eugenol: release of cytochrome-c and lactate dehydrogenase.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {43730}, pmid = {28272477}, issn = {2045-2322}, mesh = {Adenosine Triphosphate/metabolism ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Cytochromes c/*biosynthesis ; Dose-Response Relationship, Drug ; Eugenol/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; L-Lactate Dehydrogenase/*biosynthesis ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Phytochemicals have been extensively researched for their potential anticancer effects. In previous study, direct exposure of rat liver mitochondria to eugenol main ingredient of clove, uncoupled mitochondria and increased F0F1ATPase activity. In the present study, we further investigated the effects of eugenol on MCF-7 cells in culture. Eugenol demonstrated: a dose-dependent decrease in viability (MTT assay), and proliferation (real time cell analysis) of MCF-7 cells, (EC50: 0.9 mM); an increase in reactive oxygen species; a decrease in ATP level and mitochondrial membrane potential (MitoPT JC-1 assay); and a release of cytochrome-c and lactate dehydrogenase (Cytotoxicity Detection Kit [PLUS]) into culture media at eugenol concentration >EC50. Pretreatment with the antioxidants Trolox and N-acetyl cysteine partially restored cell viability and decreased ROS, with Trolox being more potent. Expression levels of both anti- and pro-apoptotic markers (Bcl-2 and Bax, respectively) decreased with increasing eugenol concentration, with no variation in their relative ratios. Eugenol-treated MCF-7 cells overexpressing Bcl-2 exhibited results similar to those of MCF-7. Our findings indicate that eugenol toxicity is non-apoptotic Bcl-2 independent, affecting mitochondrial function and plasma membrane integrity with no effect on migration or invasion. We report here the chemo-sensitivity of MCF-7 cells to eugenol, a phytochemical with anticancer potential.}, }
@article {pmid28271166, year = {2017}, author = {Yi, D and Hou, Y and Xiao, H and Wang, L and Zhang, Y and Chen, H and Wu, T and Ding, B and Hu, CA and Wu, G}, title = {N-Acetylcysteine improves intestinal function in lipopolysaccharides-challenged piglets through multiple signaling pathways.}, journal = {Amino acids}, volume = {49}, number = {12}, pages = {1915-1929}, doi = {10.1007/s00726-017-2389-2}, pmid = {28271166}, issn = {1438-2199}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dietary Supplements ; ErbB Receptors/metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Intestinal Mucosa/*drug effects/physiopathology ; Intestine, Small/*drug effects/physiopathology ; Lipopolysaccharides/*toxicity ; Oxidation-Reduction/drug effects ; Signal Transduction/*drug effects ; *Sus scrofa ; Swine ; Weaning ; }, abstract = {This study determined whether N-acetylcysteine (NAC) could improve intestinal function through phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), epithelial growth factor receptor (EGFR), toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), adenosine 5'-monophosphate-activated protein kinase (AMPK), and type I interferon (IFN) signaling pathways in a piglet model of lipopolysaccharides (LPS) challenge. Thirty-two piglets (24-day-old) were randomly allocated to one of four treatments, with eight replicates per treatment and one piglet per replicate. The experiment consisted of four treatments in a 2 × 2 factorial arrangement with two diets (supplemented with 0 or 500 mg NAC/kg diet) and saline or LPS administration. On day 20 of the trial, piglets in the LPS and LPS + NAC groups were intraperitoneally injected with 0 (saline) or 100 μg LPS/kg BW. Blood samples were obtained at 3 h and intestinal mucosae were collected at 6 h post LPS or saline injection. The growth performance was not affected by dietary NAC. LPS induced intestinal dysfunction, as indicated by: (1) reductions in the small-intestinal glutathione concentrations and plasma D-xylose levels; (2) elevations in plasma diamine oxidase activity, mucosal MMP3 mRNA levels and caspase-3 protein abundance; (3) reduced the activities of the small-intestinal mucosal maltase, sucrase and lactase. The adverse effects of LPS on porcine intestinal function and redox status were mitigated by NAC supplementation through the activation of multiple signaling pathways involving PI3K/Akt/mTOR, EGFR, TLR4/NF-κB, AMPK, and type I IFN. Our findings provide novel mechanisms for beneficial effects of NAC in protecting the intestine from inflammation in animals.}, }
@article {pmid28266127, year = {2017}, author = {Wang, S and Zhang, F and Zhao, G and Cheng, Y and Wu, T and Wu, B and Zhang, YE}, title = {Mitochondrial PKC-ε deficiency promotes I/R-mediated myocardial injury via GSK3β-dependent mitochondrial permeability transition pore opening.}, journal = {Journal of cellular and molecular medicine}, volume = {21}, number = {9}, pages = {2009-2021}, pmid = {28266127}, issn = {1582-4934}, mesh = {Aldehyde Dehydrogenase, Mitochondrial/deficiency/metabolism ; Animals ; Apoptosis ; Enzyme Activation ; Glycogen Synthase Kinase 3 beta/*metabolism ; Isoenzymes/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Heart/*enzymology ; Mitochondrial Membrane Transport Proteins/*metabolism ; Mitochondrial Permeability Transition Pore ; Models, Biological ; Myocardial Reperfusion Injury/*enzymology/pathology/physiopathology ; Myocardium/*enzymology/*pathology ; Myocytes, Cardiac/metabolism/pathology ; Protein Kinase C-delta/metabolism ; Protein Kinase C-epsilon/*deficiency/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Mitochondrial fission is critically involved in cardiomyocyte apoptosis, which has been considered as one of the leading causes of ischaemia/reperfusion (I/R)-induced myocardial injury. In our previous works, we demonstrate that aldehyde dehydrogenase-2 (ALDH2) deficiency aggravates cardiomyocyte apoptosis and cardiac dysfunction. The aim of this study was to elucidate whether ALDH2 deficiency promotes mitochondrial injury and cardiomyocyte death in response to I/R stress and the underlying mechanism. I/R injury was induced by aortic cross-clamping for 45 min. followed by unclamping for 24 hrs in ALDH2 knockout (ALDH2[-/-]) and wild-type (WT) mice. Then myocardial infarct size, cell apoptosis and cardiac function were examined. The protein kinase C (PKC) isoform expressions and their mitochondrial translocation, the activity of dynamin-related protein 1 (Drp1), caspase9 and caspase3 were determined by Western blot. The effects of N-acetylcysteine (NAC) or PKC-δ shRNA treatment on glycogen synthase kinase-3β (GSK-3β) activity and mitochondrial permeability transition pore (mPTP) opening were also detected. The results showed that ALDH2[-/-] mice exhibited increased myocardial infarct size and cardiomyocyte apoptosis, enhanced levels of cleaved caspase9, caspase3 and phosphorylated Drp1. Mitochondrial PKC-ε translocation was lower in ALDH2[-/-] mice than in WT mice, and PKC-δ was the opposite. Further data showed that mitochondrial PKC isoform ratio was regulated by cellular reactive oxygen species (ROS) level, which could be reversed by NAC pre-treatment under I/R injury. In addition, PKC-ε inhibition caused activation of caspase9, caspase3 and Drp1Ser[616] in response to I/R stress. Importantly, expression of phosphorylated GSK-3β (inactive form) was lower in ALDH2[-/-] mice than in WT mice, and both were increased by NAC pre-treatment. I/R-induced mitochondrial translocation of GSK-3β was inhibited by PKC-δ shRNA or NAC pre-treatment. In addition, mitochondrial membrane potential (∆Ψm) was reduced in ALDH2[-/-] mice after I/R, which was partly reversed by the GSK-3β inhibitor (SB216763) or PKC-δ shRNA. Collectively, our data provide the evidence that abnormal PKC-ε/PKC-δ ratio promotes the activation of Drp1 signalling, caspase cascades and GSK-3β-dependent mPTP opening, which results in mitochondrial injury-triggered cardiomyocyte apoptosis and myocardial dysfuction in ALDH2[-/-] mice following I/R stress.}, }
@article {pmid28265179, year = {2017}, author = {Wang, S and Wang, C and Yan, F and Wang, T and He, Y and Li, H and Xia, Z and Zhang, Z}, title = {N-Acetylcysteine Attenuates Diabetic Myocardial Ischemia Reperfusion Injury through Inhibiting Excessive Autophagy.}, journal = {Mediators of inflammation}, volume = {2017}, number = {}, pages = {9257291}, pmid = {28265179}, issn = {1466-1861}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Apoptosis/drug effects ; Autophagy/*drug effects ; Caspase 3/metabolism ; Diabetes Mellitus, Experimental/*drug therapy ; Dinoprost/analogs &amp; derivatives ; In Situ Nick-End Labeling ; Isoprostanes/pharmacology ; Male ; Myocardial Reperfusion Injury/*drug therapy ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Background. Excessive autophagy is a major mechanism of myocardial ischemia reperfusion injury (I/RI) in diabetes with enhanced oxidative stress. Antioxidant N-acetylcysteine (NAC) reduces myocardial I/RI. It is unknown if inhibition of autophagy may represent a mechanism whereby NAC confers cardioprotection in diabetes. Methods and Results. Diabetes was induced in Sprague-Dawley rats with streptozotocin and they were treated without or with NAC (1.5 g/kg/day) for four weeks before being subjected to 30-minute coronary occlusion and 2-hour reperfusion. The results showed that cardiac levels of 15-F2t-Isoprostane were increased and that autophagy was evidenced as increases in ratio of LC3 II/I and protein P62 and AMPK and mTOR expressions were significantly increased in diabetic compared to nondiabetic rats, concomitant with increased postischemic myocardial infarct size and CK-MB release but decreased Akt and eNOS activation. Diabetes was also associated with increased postischemic apoptotic cell death manifested as increases in TUNEL positive cells, cleaved-caspase-3, and ratio of Bax/Bcl-2 protein expression. NAC significantly attenuated I/RI-induced increases in oxidative stress and cardiac apoptosis, prevented postischemic autophagy formation in diabetes, and reduced postischemic myocardial infarction (all p < 0.05). Conclusions. NAC confers cardioprotection against diabetic heart I/RI primarily through inhibiting excessive autophagy which might be a major mechanism why diabetic hearts are less tolerant to I/RI.}, }
@article {pmid28263542, year = {2016}, author = {Vobornikova, I and Pohanka, M}, title = {Smartphone-based colorimetric detection of glutathione.}, journal = {Neuro endocrinology letters}, volume = {37}, number = {Suppl1}, pages = {139-143}, pmid = {28263542}, issn = {0172-780X}, mesh = {Antioxidants/*analysis ; Biological Assay/*methods ; Biomarkers ; Colorimetry ; Dithionitrobenzoic Acid ; Glutathione/*analysis ; Humans ; Smartphone/*statistics &amp; numerical data ; }, abstract = {OBJECTIVES: Glutathione belongs to the family of small-molecular weight antioxidants like ascorbic acid, cysteine, α-tocopherol, uric acid, etc. These molecules play important role in the neutralization of free radicals and reactive oxygen species (ROS). Oxidative stress may lead to ageing and the development of large scale of pathological states of organism. This low molecular weight antioxidant´s level can alter under pathological conditions from reduced (GSH, thiols) to oxidized (oxidized glutathione -GSSG, disulfides) form. A GSSG-to-GSH ratio is indicative marker of oxidative stress. There is a large scale of methods how to determine this biomarker. The trend of the analysis is to minimalize the instrument equipment, sample application volume and analysis cost.<br><br>DESIGN: Reduced glutathione (GSH) solutions were prepared in water in the concentration 0-16 mmol/L. Other small-molecular weight antioxidants like 0.25 mmol/L ascorbic acid, 0.15 mmol/L TROLOX and 0.02 mmol/L N-acetyl-cysteine (NAcCys) were studied as possible interferents. The samples were mixed with 5,5&#xb4;-dithiobis-(2-nitrobenzoic) acid (DTNB) resulting in yellow colored drops forming. Coloration was assayed using camera integrated in a smartphone and color channels analysis. The total volume of 10&#x2009;&#xb5;l of sample was applied for one analysis. The smartphone-based data were compared with the reference Ellman assay.<br><br>RESULTS: The calibration of glutathione was evaluated. The blue channel intensity data were decreasing according to the increasing glutathione concentration. Red and green channel intensities were stagnating during the whole concentration scale of glutathione. Limits of detection were 0.4 mmol/l for glutathione. Addition of 0.25 mmol/L of ascorbic acid, 0.15 mmol/L of TROLOX and 0.02mmol/L of N-acetylcysteine to GSH in final concentration 0-16 mmol/L had minimal influence on the assay. The results from smartphone-based analysis correlate with the standard Ellman method. The detection limit for GSH was 0.03 mmol/L.<br><br>CONCLUSION: The smartphone-based assay seems to be promising because of simplicity, reliability, robustness and low cost. In spite of the fact that there is a large scale for approaches for the glutathione determination, the main advantage of our colorimetric method is portability and easibility to perform the assay in the field and publically availability of smartphones for home applications.}, }
@article {pmid28263310, year = {2017}, author = {Misu, H and Takayama, H and Saito, Y and Mita, Y and Kikuchi, A and Ishii, KA and Chikamoto, K and Kanamori, T and Tajima, N and Lan, F and Takeshita, Y and Honda, M and Tanaka, M and Kato, S and Matsuyama, N and Yoshioka, Y and Iwayama, K and Tokuyama, K and Akazawa, N and Maeda, S and Takekoshi, K and Matsugo, S and Noguchi, N and Kaneko, S and Takamura, T}, title = {Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle.}, journal = {Nature medicine}, volume = {23}, number = {4}, pages = {508-516}, doi = {10.1038/nm.4295}, pmid = {28263310}, issn = {1546-170X}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Exercise ; Humans ; Low Density Lipoprotein Receptor-Related Protein-1 ; Mice ; Mice, Knockout ; Muscle Fibers, Skeletal/metabolism ; Muscle, Skeletal/*metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*genetics/metabolism ; Phosphorylation ; *Physical Conditioning, Animal ; Physical Conditioning, Human ; Physical Endurance/drug effects/*genetics ; Reactive Oxygen Species/*metabolism ; Receptors, LDL/*metabolism ; Selenoprotein P/*genetics/metabolism ; Tumor Suppressor Proteins/*metabolism ; Up-Regulation ; }, abstract = {Exercise has numerous health-promoting effects in humans; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly. This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) causes exercise resistance through its muscle receptor low-density lipoprotein receptor-related protein 1 (LRP1). SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a) expression in skeletal muscle. Supplementation with the anti-oxidant N-acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle-effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP-LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.}, }
@article {pmid28258325, year = {2017}, author = {Wang, L and Zhou, J and Hou, Y and Yi, D and Ding, B and Xie, J and Zhang, Y and Chen, H and Wu, T and Zhao, D and Hu, CA and Wu, G}, title = {N-Acetylcysteine supplementation alleviates intestinal injury in piglets infected by porcine epidemic diarrhea virus.}, journal = {Amino acids}, volume = {49}, number = {12}, pages = {1931-1943}, doi = {10.1007/s00726-017-2397-2}, pmid = {28258325}, issn = {1438-2199}, support = {31372319 and 31572416//National Natural Science Foundation of China/ ; 31402084//National Natural Science Foundation of China/ ; 2014ABA022//Hubei Provincial Key Project for Scientific and Technical Innovation/ ; 2010BB023//Hubei Provincial Research and Development Program/ ; 2013CFA097, 2012FFB04805 and 2011CDA131//Natural Science Foundation of Hubei Province/ ; 2016J08//Research and Innovation Initiatives of WHPU/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage/*pharmacology ; Animals ; Animals, Newborn ; Coronavirus Infections/drug therapy/*veterinary ; Dietary Supplements ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Intestinal Mucosa/*drug effects/pathology/physiopathology ; Intestine, Small/*drug effects/pathology/physiopathology ; Oxidation-Reduction/drug effects ; Plasma/drug effects/enzymology ; *Porcine epidemic diarrhea virus ; Sus scrofa ; Swine ; Swine Diseases/*drug therapy ; Weight Gain/drug effects ; }, abstract = {Porcine epidemic diarrhea virus (PEDV) infects the intestine of young pigs, but effective measures for prevention and treatment are lacking. N-Acetylcysteine (NAC) has been shown to reduce endotoxin-induced intestinal dysfunction. This study was conducted with the PEDV-infected neonatal piglet model to determine the effect of NAC supplementation on intestinal function. Thirty-two 7-day-old piglets were randomly allocated to one of four treatments in a 2 × 2 factorial design consisting of two liquid diets (0 or 50 mg/kg BW NAC supplementation) and oral administration of 0 or 10[4.5] TCID50 (50% tissue culture infectious dose) PEDV. On day 7 of the trial, half of the pigs (n = 8) in each dietary treatment received either sterile saline or PEDV (Yunnan province strain) solution at 10[4.5] TCID50 per pig. On day 10 of the trial, D-xylose (0.1 g/kg BW) was orally administrated to all pigs. One hour later, jugular vein blood samples were collected, and then all pigs were killed to obtain the small intestine. PEDV infection increased diarrhea incidence, while reducing ADG. PEDV infection also decreased plasma D-xylose concentration, small intestinal villus height, mucosal I-FABP and villin mRNA levels but increased mucosal MX1 and GCNT3 mRNA levels (P < 0.05). Dietary NAC supplementation ameliorated the PEDV-induced abnormal changes in all the measured variables. Moreover, NAC reduced oxidative stress, as indicated by decreases in plasma and mucosal H2O2 levels. Collectively, these novel results indicate that dietary supplementation with NAC alleviates intestinal mucosal damage and improves the absorptive function of the small intestine in PEDV-infected piglets.}, }
@article {pmid28255088, year = {2017}, author = {Hirai, DM and Jones, JH and Zelt, JT and da Silva, ML and Bentley, RF and Edgett, BA and Gurd, BJ and Tschakovsky, ME and O'Donnell, DE and Neder, JA}, title = {Oral N-acetylcysteine and exercise tolerance in mild chronic obstructive pulmonary disease.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {122}, number = {5}, pages = {1351-1361}, doi = {10.1152/japplphysiol.00990.2016}, pmid = {28255088}, issn = {1522-1601}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Antioxidants/pharmacology ; Cross-Over Studies ; Double-Blind Method ; Exercise/*physiology ; Exercise Tolerance/*drug effects ; Female ; Hemodynamics/drug effects ; Humans ; Locomotion/drug effects ; Male ; Muscle, Skeletal/drug effects/metabolism ; Oxygen/metabolism ; Pulmonary Disease, Chronic Obstructive/metabolism/*physiopathology ; Respiratory Function Tests/methods ; }, abstract = {Heightened oxidative stress is implicated in the progressive impairment of skeletal muscle vascular and mitochondrial function in chronic obstructive pulmonary disease (COPD). Whether accumulation of reactive oxygen species contributes to exercise intolerance in the early stages of COPD is unknown. The purpose of the present study was to determine the effects of oral antioxidant treatment with N-acetylcysteine (NAC) on respiratory, cardiovascular, and locomotor muscle function and exercise tolerance in patients with mild COPD. Thirteen patients [forced expiratory volume in 1 s (FEV1)-to-forced vital capacity ratio < lower limit of normal (LLN) and FEV1 ≥ LLN) were enrolled in a double-blind, randomized crossover study to receive NAC (1,800 mg/day) or placebo for 4 days. Severe-intensity constant-load exercise tests were performed with noninvasive measurements of central hemodynamics (stroke volume, heart rate, and cardiac output via impedance cardiography), arterial blood pressure, pulmonary ventilation and gas exchange, quadriceps muscle oxygenation (near-infrared spectroscopy), and estimated capillary blood flow. Nine patients completed the study with no major adverse clinical effects. Although NAC elevated plasma glutathione by ~27% compared with placebo (P < 0.05), there were no differences in exercise tolerance (placebo: 325 ± 47 s, NAC: 336 ± 51 s), central hemodynamics, arterial blood pressure, pulmonary ventilation or gas exchange, locomotor muscle oxygenation, or capillary blood flow from rest to exercise between conditions (P > 0.05 for all). In conclusion, modulation of plasma redox status with oral NAC treatment was not translated into beneficial effects on central or peripheral components of the oxygen transport pathway, thereby failing to improve exercise tolerance in nonhypoxemic patients with mild COPD.NEW &amp; NOTEWORTHY Acute antioxidant treatment with N-acetylcysteine (NAC) elevated plasma glutathione but did not modulate central or peripheral components of the O2 transport pathway, thereby failing to improve exercise tolerance in patients with mild chronic obstructive pulmonary disease (COPD).}, }
@article {pmid28253511, year = {2017}, author = {Du, JH and Li, X and Li, R and Cheng, BX and Kuerbanjiang, M and Ma, L}, title = {Role of Autophagy in Angiogenesis Induced by a High-Glucose Condition in RF/6A Cells.}, journal = {Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde}, volume = {237}, number = {2}, pages = {85-95}, doi = {10.1159/000455270}, pmid = {28253511}, issn = {1423-0267}, mesh = {*Apoptosis ; *Autophagy ; Blotting, Western ; Cell Movement ; Cell Survival ; Cells, Cultured ; Diabetic Retinopathy/*complications/pathology ; Glucose/*pharmacology ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Reactive Oxygen Species/metabolism ; Retinal Neovascularization/etiology/metabolism/*pathology ; }, abstract = {PURPOSE: To study the effect of autophagy on vitality, migration, and tube formation of RF/6A cells under the condition of D-glucose.<br><br>METHODS: Cultured RF/6A cells were randomly divided into 4 groups (control, low glucose, high glucose, and high glucose with 3-methyladenine [3-MA]). Autophagy-related proteins (Atg7, p62, and LC3) were monitored. Cell vitality, cell migration, tube formation, reactive oxygen species (ROS) production, and apoptosis were assessed.<br><br>RESULTS: Cell vitality significantly decreased and cell migration and tube formation significantly increased in the high-glucose group (p < 0.05). Pretreatment with 3-MA significantly increased cell viability and inhibited cell migration and tube formation (p < 0.05). ROS production increased in the high-glucose group and decreased in the high-glucose with N-acetylcysteine (NAC) group (p < 0.05). The level of apoptosis increased in the high-glucose group, while it was reduced in the high-glucose with 3-MA group.<br><br>CONCLUSION: Autophagy maybe participates in the formation of retinal neovascularization induced by high glucose.}, }
@article {pmid28249219, year = {2017}, author = {Al-Harbi, NO and Nadeem, A and Ansari, MA and Al-Harbi, MM and Alotaibi, MR and AlSaad, AM and Ahmad, SF}, title = {Psoriasis-like inflammation leads to renal dysfunction via upregulation of NADPH oxidases and inducible nitric oxide synthase.}, journal = {International immunopharmacology}, volume = {46}, number = {}, pages = {1-8}, doi = {10.1016/j.intimp.2017.02.018}, pmid = {28249219}, issn = {1878-1705}, mesh = {Acetylcysteine/therapeutic use ; Aminoquinolines ; Animals ; Antioxidants/therapeutic use ; Buthionine Sulfoximine/administration &amp; dosage ; Disease Models, Animal ; Humans ; Imiquimod ; Inflammation/chemically induced/drug therapy/*immunology ; Kidney/*metabolism/pathology ; Kidney Diseases/chemically induced/drug therapy/*immunology ; Male ; Membrane Glycoproteins/genetics/*metabolism ; Mice ; Mice, Inbred BALB C ; NADPH Oxidase 2 ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/*metabolism ; Nitric Oxide Synthase Type II/genetics/*metabolism ; Oxidative Stress/drug effects ; Psoriasis/chemically induced/drug therapy/*immunology ; }, abstract = {Psoriatic patients have systemic inflammation as well as oxidative stress, which are associated with cardiovascular disorders such as atherosclerosis, hypertension myocardial infarction, and stroke. Psoriasis has also been shown to be associated with kidney disease in several studies. Both disorders also have strong component of oxidative stress which usually emanates from NADPH oxidases (NOXs) and inducible nitric oxide synthase (iNOS). However, whether psoriatic inflammation leads to renal oxidative stress and dysfunction remains unexplored. Therefore, this study investigated the effect of imiquimod (IMQ)-induced psoriatic inflammation on kidney function and inflammation in a murine model. Mice were topically applied IMQ followed by various analyses in kidney/blood related to inflammation and kidney function. Psoriatic inflammation in mice was associated with kidney dysfunction as reflected by increased serum creatinine and blood urea nitrogen. Kidney dysfunction was paralleled by upregulation of ROS generating enzymes such as NOX2, NOX4 and iNOS with concomitant oxidative stress. Treatment either with general antioxidant, N-acetyl cysteine or NOX/iNOS inhibitors led to improvement of IMQ-induced renal dysfunction and oxidative stress. On the contrary, buthionine sulfoximine, oxidant inducer further aggravated IMQ-induced renal impairment and oxidant-antioxidant imbalance. Our data suggest that psoriatic inflammation causes kidney dysfunction where NOXs and iNOS play important roles. Treatment with antioxidants may be considered as adjunct therapy in psoriatic patients with kidney disease.}, }
@article {pmid28244691, year = {2017}, author = {Zhao, H and Duan, Q and Zhang, Z and Li, H and Wu, H and Shen, Q and Wang, C and Yin, T}, title = {Up-regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine-resistant pancreatic cancer cells.}, journal = {Journal of cellular and molecular medicine}, volume = {21}, number = {9}, pages = {2055-2067}, pmid = {28244691}, issn = {1582-4934}, mesh = {Aerobiosis ; Carcinogenesis/metabolism/pathology ; Cell Line, Tumor ; Deoxycytidine/*analogs &amp; derivatives/pharmacology ; Doublecortin-Like Kinases ; Drug Resistance, Neoplasm/*drug effects ; Epithelial-Mesenchymal Transition/*drug effects ; Glycolysis/*drug effects ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Neoplasm Metastasis ; Neoplastic Stem Cells/drug effects/metabolism/*pathology ; Pancreatic Neoplasms/metabolism/*pathology ; Phenotype ; Protein Serine-Threonine Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Up-Regulation/*drug effects ; Gemcitabine ; }, abstract = {Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT)-type cells are considered as underlying causes of chemoresistance, tumour recurrence and metastasis in pancreatic cancer. We aimed to describe the mechanisms - particularly glycolysis - involved in the regulation of the CSC and EMT phenotypes. We used a gemcitabine-resistant (GR) Patu8988 cell line, which exhibited clear CSC and EMT phenotypes and showed reliance on glycolysis. Inhibition of glycolysis using 2-deoxy-D-glucose (2-DG) significantly enhanced the cytotoxicity of gemcitabine and inhibited the CSC and EMT phenotypes in GR cells both in vitro and in vivo. Intriguingly, the use of the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) restored the CSC and EMT phenotypes. H2 O2 produced changes similar to those of 2-DG, indicating that ROS were involved in the acquired cancer stemness and EMT phenotypes of GR cells. Moreover, doublecortin-like kinase 1 (DCLK1), a pancreatic CSC marker, was highly expressed and regulated the stemness and EMT phenotypes in GR cell. Both 2-DG and H2 O2 treatment suppressed DCLK1 expression, which was also rescued by NAC. Together, these findings revealed that glycolysis promotes the expression of DCLK1 and maintains the CSC and EMT phenotypes via maintenance of low ROS levels in chemoresistant GR cells. The glycolysis-ROS-DCLK1 pathway may be potential targets for reversing the malignant behaviour of pancreatic cancer.}, }
@article {pmid28243583, year = {2017}, author = {Stavsky, M and Mor, O and Mastrolia, SA and Greenbaum, S and Than, NG and Erez, O}, title = {Cerebral Palsy-Trends in Epidemiology and Recent Development in Prenatal Mechanisms of Disease, Treatment, and Prevention.}, journal = {Frontiers in pediatrics}, volume = {5}, number = {}, pages = {21}, pmid = {28243583}, issn = {2296-2360}, abstract = {Cerebral palsy (CP) is the most common motor disability in childhood. This syndrome is the manifestation of intrauterine pathologies, intrapartum complications, and the postnatal sequel, especially among preterm neonates. A double hit model theory is proposed suggesting that an intrauterine condition along with intrapartum or postnatal insult lead to the development of CP. Recent reports demonstrated that treatment during the process of preterm birth such as magnesium sulfate and postnatal modalities such as cooling may prevent or reduce the prevalence of this syndrome. Moreover, animal models demonstrated that postnatal treatment with anti-inflammatory drugs coupled with nanoparticles may affect the course of the disease in pups with neuroinflammation. This review will describe the changes in the epidemiology of this disease, the underlying prenatal mechanisms, and possible treatments that may reduce the prevalence of CP and alter the course of the disease.}, }
@article {pmid28243354, year = {2017}, author = {Khor, SC and Wan Ngah, WZ and Mohd Yusof, YA and Abdul Karim, N and Makpol, S}, title = {Tocotrienol-Rich Fraction Ameliorates Antioxidant Defense Mechanisms and Improves Replicative Senescence-Associated Oxidative Stress in Human Myoblasts.}, journal = {Oxidative medicine and cellular longevity}, volume = {2017}, number = {}, pages = {3868305}, pmid = {28243354}, issn = {1942-0994}, mesh = {Antioxidants/*pharmacology ; Cell Survival/*drug effects ; Cells, Cultured ; Cellular Senescence/*drug effects ; Free Radicals/metabolism ; Glutathione/metabolism ; Humans ; Lipid Peroxidation/*drug effects ; Myoblasts/*drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Tocotrienols/*pharmacology ; }, abstract = {During aging, oxidative stress affects the normal function of satellite cells, with consequent regeneration defects that lead to sarcopenia. This study aimed to evaluate tocotrienol-rich fraction (TRF) modulation in reestablishing the oxidative status of myoblasts during replicative senescence and to compare the effects of TRF with other antioxidants (α-tocopherol (ATF) and N-acetyl-cysteine (NAC)). Primary human myoblasts were cultured to young, presenescent, and senescent phases. The cells were treated with antioxidants for 24 h, followed by the assessment of free radical generation, lipid peroxidation, antioxidant enzyme mRNA expression and activities, and the ratio of reduced to oxidized glutathione. Our data showed that replicative senescence increased reactive oxygen species (ROS) generation and lipid peroxidation in myoblasts. Treatment with TRF significantly diminished ROS production and decreased lipid peroxidation in senescent myoblasts. Moreover, the gene expression of superoxide dismutase (SOD2), catalase (CAT), and glutathione peroxidase (GPX1) was modulated by TRF treatment, with increased activity of superoxide dismutase and catalase and reduced glutathione peroxidase in senescent myoblasts. In comparison to ATF and NAC, TRF was more efficient in heightening the antioxidant capacity and reducing free radical insults. These results suggested that TRF is able to ameliorate antioxidant defense mechanisms and improves replicative senescence-associated oxidative stress in myoblasts.}, }
@article {pmid28237766, year = {2017}, author = {Eroshenko, D and Polyudova, T and Korobov, V}, title = {N-acetylcysteine inhibits growth, adhesion and biofilm formation of Gram-positive skin pathogens.}, journal = {Microbial pathogenesis}, volume = {105}, number = {}, pages = {145-152}, doi = {10.1016/j.micpath.2017.02.030}, pmid = {28237766}, issn = {1096-1208}, mesh = {Acetylcysteine/*pharmacology ; Adhesins, Bacterial/metabolism ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects ; Drug Resistance, Bacterial ; Gram-Negative Bacteria/cytology/*drug effects/metabolism/physiology ; Gram-Negative Bacterial Infections/microbiology ; Gram-Positive Bacteria/cytology/*drug effects/metabolism/physiology ; Gram-Positive Bacterial Infections/microbiology ; Humans ; Microbial Sensitivity Tests ; Skin/*microbiology ; Skin Diseases, Bacterial/microbiology ; }, abstract = {N-Acetylcysteine (NAC) is a non-antibiotic drug with antimicrobial properties against biofilm phenotypes of Gram-positive and Gram-negative bacteria. Our aim was to assess the effects of NAC on the growth of Gram-positive human skin and mucous membrane pathogens in the planktonic and biofilm phases. The minimum inhibitory concentrations (MICs) of NAC against Enterococcus faecalis, Corynebacterium ammoniagenes, Mycobacterium smegmatis, Propionibacterium acnes, Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes, and 14 clinical strains of coagulase-negative staphylococci (CNS) ranged from 0.098 to 25 mg/ml. We found that at sub-MICs of NAC the adherence of E. faecalis, S. epidermidis, and nine CNS strains significantly reduced. However, biofilm formation of E. faecalis, S. aureus and two CNS strains increased at sub-MICs of NAC. Furthermore, a dose-related decrease in biofilm formation of C. ammoniagenes, M. smegmatis, P. acnes, S. pyogenes, and S. epidermidis was observed. The effect of NAC on planktonic growth and biofilm formation of the M. smegmatis cell was also time-dependent. We have selected P. acnes VKM Ac-1450 Rif[r] strain with total resistance to rifampicin and used this microorganism for multispecies P. acnes - S. epidermidis biofilm model. The biofilm formation and growth of mixed culture of P. acnes and S. epidermidis was significantly slowed at 12.5 mg/ml of NAC. NAC also has a higher disruptive effect on both mature M. smegmatis and mixed P. acnes - S. epidermidis biofilm. Thus, NAC appears to be a promising, non-antibiotic alternative to prevent biofilm-associated infections.}, }
@article {pmid28231391, year = {2017}, author = {Huang, PC and Chiu, CC and Chang, HW and Wang, YS and Syue, HH and Song, YC and Weng, ZH and Tai, MH and Wu, CY}, title = {Prdx1-encoded peroxiredoxin is important for vascular development in zebrafish.}, journal = {FEBS letters}, volume = {591}, number = {6}, pages = {889-902}, doi = {10.1002/1873-3468.12604}, pmid = {28231391}, issn = {1873-3468}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Genetically Modified ; Blood Vessels/embryology/*metabolism ; Bone Morphogenetic Proteins/metabolism ; Embryo, Nonmammalian/blood supply/drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Developmental ; Gene Knockdown Techniques ; Hydrogen Peroxide/pharmacology ; In Situ Hybridization ; Microscopy, Confocal ; Oxidants/pharmacology ; Peroxiredoxins/*genetics/metabolism ; Receptors, Notch/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Zebrafish/embryology/*genetics/metabolism ; Zebrafish Proteins/*genetics/metabolism ; }, abstract = {Genetic signaling and redox homeostasis are required for proper growth of blood vessels. Here, we report a novel function of peroxiredoxin1 (Prdx1) in vascular development in zebrafish. Knockdown of prdx1 impairs the growth of intersegmental vessel and caudal vein plexus (CVP), and reduces the expression of vascular markers, thus suggesting a role for prdx1 in vasculature and indicating that the antioxidant function of prdx1 is important. We found that H2 O2 -treated embryos also have CVP defects and observed synergistic effects when prdx1 knockdown was combined with H2 O2 treatment. Moreover, N-acetyl-cysteine treatment rescues the vascular defects in prdx1 morphants. These results suggest that oxidative stress disturbs vascularization. Furthermore, we show that the regulation of prdx1 is mediated by Notch and BMP signals.}, }
@article {pmid28225868, year = {2017}, author = {Horst, A and de Souza, JA and Santos, MC and Riffel, AP and Kolberg, C and Ribeiro, MF and de Fraga, LS and Partata, WA}, title = {N-acetylcysteine downregulates phosphorylated p-38 expression but does not reverse the increased superoxide anion levels in the spinal cord of rats with neuropathic pain.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {50}, number = {2}, pages = {e5801}, pmid = {28225868}, issn = {1414-431X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Blotting, Western ; Constriction, Pathologic ; Disease Models, Animal ; Down-Regulation/drug effects ; Male ; Neuralgia/*drug therapy/etiology ; Pain Threshold ; Phosphorylation/drug effects ; Rats ; Rats, Wistar ; Spinal Cord/*drug effects/metabolism ; Superoxides/*metabolism ; p38 Mitogen-Activated Protein Kinases/*drug effects/metabolism ; }, abstract = {We determined the effect of N-acetylcysteine (NAC) on the expression of the phosphorylated p38 (p-p38) protein and superoxide anion generation (SAG), two important players in the processing of neuropathic pain, in the lumbosacral spinal cord of rats with chronic constriction injury (CCI)-induced neuropathic pain. The sciatic functional index (SFI) was also measured to assess the functional recovery post-nerve lesion. Thirty-six male Wistar rats were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received 2, 4, or 8 intraperitoneal injections of NAC (150 mg·kg-1·day-1) or saline beginning 4 h after CCI. Rats were sacrificed 1, 3, and 7 days after CCI. The SFI was measured on these days and the lumbosacral spinal cord was used for analysis of p-p38 expression and SAG. CCI induced a decrease in SFI as well as an increase in p-p38 expression and SAG in the spinal cord. The SFI showed a partial recovery at day 7 in saline-treated CCI rats, but recovery was improved in NAC-treated CCI rats. NAC induced a downregulation in p-p38 expression at all time-points evaluated, but did not reverse the increased SAG induced by CCI. Since p-p38 is a mediator in neuropathic pain and/or nerve regeneration, modulation of this protein may play a role in NAC-induced effects in CCI rats.}, }
@article {pmid28225005, year = {2017}, author = {Jiang, XS and Chen, XM and Wan, JM and Gui, HB and Ruan, XZ and Du, XG}, title = {Autophagy Protects against Palmitic Acid-Induced Apoptosis in Podocytes in vitro.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {42764}, pmid = {28225005}, issn = {2045-2322}, mesh = {Animals ; *Apoptosis ; *Autophagy ; Cell Line ; Chloroquine/pharmacology ; Membrane Potential, Mitochondrial ; Mice ; Palmitic Acid/*pharmacology ; Podocytes/drug effects/*metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Autophagy is a highly conserved degradation process that is involved in the clearance of proteins and damaged organelles to maintain intracellular homeostasis and cell integrity. Type 2 diabetes is often accompanied by dyslipidemia with elevated levels of free fatty acids (FFAs). Podocytes, as an important component of the filtration barrier, are susceptible to lipid disorders. The loss of podocytes causes proteinuria, which is involved in the pathogenesis of diabetic nephropathy. In the present study, we demonstrated that palmitic acid (PA) promoted autophagy in podocytes. We further found that PA increased the production of reactive oxygen species (ROS) in podocytes and that NAC (N-acetyl-cysteine), a potent antioxidant, significantly eliminated the excessive ROS and suppressed autophagy, indicating that the increased generation of ROS was associated with the palmitic acid-induced autophagy in podocytes. Moreover, we also found that PA stimulation decreased the mitochondrial membrane potential in podocytes and induced podocyte apoptosis, while the inhibition of autophagy by chloroquine (CQ) enhanced palmitic acid-induced apoptosis accompanied by increased ROS generation, and the stimulation of autophagy by rapamycin (Rap) remarkably suppressed palmitic acid-induced ROS generation and apoptosis. Taken together, these in vitro findings suggest that PA-induced autophagy in podocytes is mediated by ROS production and that autophagy plays a protective role against PA-induced podocyte apoptosis.}, }
@article {pmid28223539, year = {2017}, author = {Wu, H and Jiang, K and Yin, N and Ma, X and Zhao, G and Qiu, C and Deng, G}, title = {Thymol mitigates lipopolysaccharide-induced endometritis by regulating the TLR4- and ROS-mediated NF-κB signaling pathways.}, journal = {Oncotarget}, volume = {8}, number = {12}, pages = {20042-20055}, pmid = {28223539}, issn = {1949-2553}, mesh = {Animals ; Anti-Infective Agents/*pharmacology ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Cytokines/metabolism ; Endometritis/chemically induced/pathology/*prevention &amp; control ; Female ; Gene Expression Regulation/drug effects ; Interleukin-1beta/metabolism ; Lipopolysaccharides/*toxicity ; Mice ; Mice, Inbred BALB C ; NF-kappa B/*metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Thymol/*pharmacology ; Toll-Like Receptor 4/*metabolism ; }, abstract = {The purpose of this study was to investigate the effects of thymol on lipopolysaccharide (LPS)-induced inflammatory responses and to clarify the potential mechanism of these effects. LPS-induced mouse endometritis was used to confirm the anti-inflammatory action of thymol in vivo. RAW264.7 cells were used to examine the molecular mechanism and targets of thymol in vitro. In vivo, thymol markedly alleviated LPS-induced pathological injury, myeloperoxidase (MPO) activity, and the production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in mice. Further studies were performed to examine the expression of the Toll-like receptor 4 (TLR4) -mediated nuclear factor-κB (NF-κB) pathway. These results showed that the expression of the TLR4-mediated NF-κB pathway was inhibited by thymol treatment. In vitro, we observed that thymol dose-dependently inhibited the expression of TNF-α, IL-1β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 cells. Moreover, the results obtained from immunofluorescence assays also indicated that thymol dose-dependently suppressed LPS-induced reactive oxygen species (ROS) production. Silencing of TLR4 inhibited NF-κB pathway activation. Furthermore, H2O2 treatment increased the phosphorylation of p65 and IκBα, which were decreased when treated with N-acetyl cysteine or thymol. In conclusion, the anti-inflammatory effects of thymol are associated with activation of the TLR4 or ROS signaling pathways, contributing to NF-κB activation, thereby alleviating LPS-induced oxidative and inflammatory responses.}, }
@article {pmid28216620, year = {2017}, author = {Liu, PP and Liu, HH and Sun, SH and Shi, XX and Yang, WC and Su, GH and Zhao, J}, title = {Aspirin alleviates cardiac fibrosis in mice by inhibiting autophagy.}, journal = {Acta pharmacologica Sinica}, volume = {38}, number = {4}, pages = {488-497}, pmid = {28216620}, issn = {1745-7254}, mesh = {Animals ; Apoptosis/drug effects ; Aspirin/pharmacology/*therapeutic use ; Autophagy/*drug effects ; Cardiomyopathies/*drug therapy/pathology/physiopathology ; Cardiotonic Agents/pharmacology/*therapeutic use ; Cell Hypoxia ; Fibroblasts/drug effects/pathology ; Fibrosis/drug therapy/pathology ; Imidazoles/pharmacology ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors ; }, abstract = {Aspirin (ASA) is a cardioprotective drug with anti-cardiac fibrosis action in vivo. This study was aimed to clarify the anti-cardiac fibrosis action of ASA and the underlying mechanisms. Two heart injury models (injection of isoproterenol and ligation of the left anterior descending branch) were used in mice to induce cardiac fibrosis. The animals were treated with ASA (10 mg·kg[-1]·d[-1], ig) for 21 and 14 d, respectively. ASA administration significantly improved cardiac function, and ameliorated heart damage and fibrosis in the mice. The mechanisms underlying ASA's anti-fibrotic effect were further analyzed in neonatal cardiac fibroblasts (CFs) exposed to hypoxia in vitro. ASA (0.5-5 mmol/L) dose-dependently inhibited the proliferation and Akt phosphorylation in the CFs. In addition, ASA significantly inhibited CF apoptosis, and decreased the levels of apoptosis markers (cleaved caspase 3 and Parp1), which might serve as a side effect of anti-fibrotic effect of ASA. Furthermore, ASA dose-dependently inhibited the autophagy in the CFs, as evidenced by the reduced levels of autophagy marker LC3-II. The autophagy inhibitor Pepstatin A (PepA) promoted the inhibitory effect of ASA on CF proliferation, whereas the autophagy inducer rapamycin rescued ASA-caused inhibition of CF proliferation, suggesting an autophagy-dependent anti-proliferative effect of ASA. Both p38 inhibitor SB203580 and ROS scavenger N-acetyl-cysteine (NAC) significantly decreased Akt phosphorylation in CFs in the basal and hypoxic situations, but they both significantly increased LC3-II levels in the CFs. Our results suggest that an autophagy- and p38/ROS-dependent pathway mediates the anti-cardiac fibrosis effect of ASA in CFs. As PepA and SB203580 did not affect ASA-caused inhibition of CF apoptosis, the drug combination will enhance ASA's therapeutic effects.}, }
@article {pmid28216050, year = {2017}, author = {Sakamoto, Y and Yano, T and Hanada, Y and Takeshita, A and Inagaki, F and Masuda, S and Matsunaga, N and Koyanagi, S and Ohdo, S}, title = {Vancomycin induces reactive oxygen species-dependent apoptosis via mitochondrial cardiolipin peroxidation in renal tubular epithelial cells.}, journal = {European journal of pharmacology}, volume = {800}, number = {}, pages = {48-56}, doi = {10.1016/j.ejphar.2017.02.025}, pmid = {28216050}, issn = {1879-0712}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cardiolipins/*metabolism ; Cell Line ; Epithelial Cells/cytology/*drug effects/metabolism ; Intracellular Space/drug effects/metabolism ; Kidney Tubules/cytology ; Lipid Peroxidation/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Swine ; Vancomycin/*pharmacology ; }, abstract = {Vancomycin (VCM) is a first-line antibiotic for serious infections caused by methicillin-resistant Staphylococcus aureus. However, nephrotoxicity is one of the most complaint in VCM therapy. We previously reported that VCM induced apoptosis in a porcine proximal tubular epithelial cell line (LLC-PK1), in which mitochondrial complex I may generate superoxide, leading to cell death. In the present study, VCM caused production of mitochondrial reactive oxygen species and peroxidation of the mitochondrial phospholipid cardiolipin that was reversed by administration of the mitochondrial uncoupler carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP). FCCP also significantly suppressed VCM-induced depolarization of the mitochondrial membrane and apoptosis. Moreover, the lipophilic antioxidant vitamin E and a mitochondria-targeted antioxidant, mitoTEMPO, also significantly suppressed VCM-induced depolarization of mitochondrial membrane and apoptosis, whereas vitamin C, n-acetyl cysteine, or glutathione did not provide significant protection. These findings suggest that peroxidation of the mitochondrial membrane cardiolipin mediated the VCM-induced production of intracellular reactive oxygen species and initiation of apoptosis in LLC-PK1 cells. Furthermore, regulation of mitochondrial function using a mitochondria-targeted antioxidant, such as mitoTEMPO, may constitute a potential strategy for mitigation of VCM-induced proximal tubular epithelial cell injury.}, }
@article {pmid28214842, year = {2017}, author = {Yang, CT and Meng, FH and Chen, L and Li, X and Cen, LJ and Wen, YH and Li, CC and Zhang, H}, title = {Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {41}, number = {2}, pages = {742-754}, doi = {10.1159/000458734}, pmid = {28214842}, issn = {1421-9778}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Case-Control Studies ; Cell Adhesion/drug effects ; Cell Line ; Cell Movement/drug effects ; Cell Survival/drug effects ; Diabetes Mellitus, Type 2/metabolism/pathology ; Female ; Glycation End Products, Advanced/*analysis/blood ; Humans ; Interleukin-6/analysis ; Interleukin-8/analysis ; Male ; Matrix Metalloproteinase 9/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Middle Aged ; Mitochondria/drug effects/metabolism ; Protective Agents/*pharmacology ; Pyruvaldehyde/*pharmacology ; Receptor for Advanced Glycation End Products/*analysis/blood ; Up-Regulation/*drug effects ; }, abstract = {BACKGROUND/AIM: Accumulation of advanced glycation end products (AGEs) is a major cause of diabetes mellitus (DM) skin complications. Methylglyoxal (MGO), a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC), an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE) in NAC's dermal protection in human HaCaT keratinocytes.<br><br>METHODS: The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF)-&#x3ba;B activation, matrix metalloproteinase (MMP)-9 expression, as well as cellular behavioral function.<br><br>RESULTS: We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL)-6 and IL-8, activated NF-&#x3ba;B and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9, as well as the activation of NF-&#x3ba;B. Lastly, NAC blocked MGO-induced RAGE upregulation, and inhibition of RAGE with its neutralizing antibody significantly alleviated MGO-induced NF-&#x3ba;B activation, MMP-9 upregulation and inflammatory injury in HaCaT cells.<br><br>CONCLUSION: The present work indicates the administration of NAC can prevent MGO-induced dermal inflammatory injury through inhibition of AGEs/RAGE signal, which may provide a basal support for the treatment of diabetic skin complications with NAC-containing medicines in the future.}, }
@article {pmid28213190, year = {2017}, author = {Nocito Echevarria, MA and Andrade Reis, T and Ruffo Capatti, G and Siciliano Soares, V and da Silveira, DX and Fidalgo, TM}, title = {N-acetylcysteine for treating cocaine addiction - A systematic review.}, journal = {Psychiatry research}, volume = {251}, number = {}, pages = {197-203}, doi = {10.1016/j.psychres.2017.02.024}, pmid = {28213190}, issn = {1872-7123}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cocaine-Related Disorders/*drug therapy ; Female ; Free Radical Scavengers/*pharmacology ; Glutamic Acid/drug effects ; Humans ; Male ; Receptor, Metabotropic Glutamate 5/drug effects ; Receptors, Metabotropic Glutamate/drug effects ; Recurrence ; Secondary Prevention ; Treatment Outcome ; }, abstract = {The aim of this paper is to extensively review the current literature available on N-acetylcysteine (NAC) treatment for cocaine dependence (clinical and experimental studies). We screened all articles published before February 2016 reporting on the use of NAC as a pharmacological intervention for cocaine dependence or discussed its potential as a therapeutic approach for cocaine dependence. We described our results qualitatively. 21 studies matched our search criteria: 6 clinical trials and 15 animal studies. Four clinical studies showed NAC's capacity to reduce craving, desire to use cocaine, cocaine-cue viewing-time and cocaine-related spending. Studies in animal models also support this reinstatement prevention application of NAC. NAC reverses the disruption of glutamate homeostasis caused by long-term cocaine use restoring function of the cystine-glutamate exchanger in glial cells and reversing the downregulated GLT-1 receptor. Current data suggest promising potential for NAC as an anti-relapse agent, as a double-blind placebo trial was mainly negative, except in the subgroup of patients who were already abstinent. An optimal dose for relapse prevention may be one that restores extrasynaptic glutamate to physiological levels and predominantly activates mGluR2 and 3, but not mGluR5 receptors, which are linked to relapse. NAC may be better suited for avoiding relapse in already abstinent subjects.}, }
@article {pmid28208905, year = {2016}, author = {Salve, VT and Atram, JS}, title = {N-Acetylcysteine Combined with Home Based Physical Activity: Effect on Health Related Quality of Life in Stable COPD Patients- A Randomised Controlled Trial.}, journal = {Journal of clinical and diagnostic research : JCDR}, volume = {10}, number = {12}, pages = {OC16-OC19}, pmid = {28208905}, issn = {2249-782X}, abstract = {INTRODUCTION: Quality of life is adversely affected in Chronic Obstructive Pulmonary Disease (COPD), due to irreversible, progressive nature of the disease and limitations of current treatment options available. One of the important aim of treatment of COPD is to improve Quality of Life (QoL). Cigarette smoke contains numerous free radicals and other oxidants. Oxidative stress has been implicated in pathogenesis, progression of disease and exacerbation in COPD. Pulmonary tuberculosis, outdoor and indoor air pollution and many others are aetiologies of COPD in non-smokers. N-Acetylcysteine (NAC) is a precursor of endogenous anti-oxidant, Glutathione (GSH) and both agents act as free radical scavengers. Exercise limitation results in poor physical performance and eventually poor QoL in COPD.<br><br>AIM: To observe the combined effect of 600mg of NAC once daily and physical activity (home based) in addition to standard treatment for ten weeks, compared with placebo as control group with standard treatment.<br><br>MATERIALS AND METHODS: This randomised controlled trial was conducted at a tertiary care centre in Mumbai for two years from December 2011 to December 2013. Hundred patients diagnosed as stable COPD (as per Global Initiative against Obstructive Lung Disease (GOLD) 2010 guidelines) were enrolled in the study. There were 50 patients in study group and control group each. The QoL was assessed using Saint George Respiratory Questionnaire-C (SGRQ-C) initially and at the end of ten weeks. The study group was treated with NAC 600mg once a day combined with daily physical activity in addition to standard treatment. Control group patients were treated with placebo and standard treatment.<br><br>RESULTS: At the end of 10 weeks, it was observed that, mean change in SGRQ-C was significant in "study group" as compared to "control group". Mean change in score among study group was 4.72 and the same in control was 1.32, p-value=0.007. There was significant improvement in SGRQ-C score at the end of 10 weeks and QoL in the study group (p-value-0.0001 i.e., <0.05) while improvement in SGRQ-C score and QoL score in control group was not significant (p-value=0.118 i.e., >0.05). Overall, there was statistically significant improvement in SGRQ-C score and QoL (p-value=0.03 i.e., <0.05) in the study group.<br><br>CONCLUSION: From the current study, it can be concluded that N-acetylcysteine 600mg once a day and 20 minute daily walk in addition to regular treatment improves QoL in stable COPD patients.}, }
@article {pmid28208010, year = {2017}, author = {Cho, YE and Kim, SH and Lee, BH and Baek, MC}, title = {Circulating Plasma and Exosomal microRNAs as Indicators of Drug-Induced Organ Injury in Rodent Models.}, journal = {Biomolecules &amp; therapeutics}, volume = {25}, number = {4}, pages = {367-373}, pmid = {28208010}, issn = {1976-9148}, abstract = {This study was performed to evaluate whether microRNAs (miRNAs) in circulating exosomes may serve as biomarkers of drug-induced liver, kidney, or muscle-injury. Quantitative PCR analyses were performed to measure the amounts of liver-specific miRNAs (miR-122, miR-192, and miR-155), kidney-specific miR-146a, or muscle-specific miR-206 in plasma and exosomes from mice treated with liver, kidney or muscle toxicants. The levels of liver-specific miRNAs in circulating plasma and exosomes were elevated in acetaminophen-induced liver injury and returned to basal levels by treatment with antioxidant N-acetyl-cysteine. Circulating miR-146a and miR-206 were increased in cisplatin-induced nephrotoxicity and bupivacaine-induced myotoxicity, respectively. Taken together, these results indicate that circulating plasma and exosomal miRNAs can be used as potential biomarkers specific for drug-induced liver, kidney or muscle injury.}, }
@article {pmid28205121, year = {2017}, author = {Darweesh, SK and Ibrahim, MF and El-Tahawy, MA}, title = {Effect of N-Acetylcysteine on Mortality and Liver Transplantation Rate in Non-Acetaminophen-Induced Acute Liver Failure: A Multicenter Study.}, journal = {Clinical drug investigation}, volume = {37}, number = {5}, pages = {473-482}, pmid = {28205121}, issn = {1179-1918}, mesh = {*Acetaminophen ; Acetylcysteine/*administration &amp; dosage ; Administration, Intravenous ; Adult ; Cohort Studies ; Female ; Hospitalization/trends ; Humans ; Length of Stay/trends ; Liver Failure, Acute/drug therapy/*mortality ; Liver Transplantation/*mortality/*trends ; Male ; Middle Aged ; Mortality/*trends ; Prospective Studies ; Young Adult ; }, abstract = {INTRODUCTION AND AIM: Previous studies and systematic reviews have not provided conclusive evidence on the effect of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). We aimed to study the value of intravenous NAC in reducing liver transplantation and mortality in NAI-ALF.<br><br>PATIENTS AND METHODS: In a prospective, multicenter, observational study, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were enrolled. NAC infusion (in empirical dose) was given as 150&#xa0;mg/kg in 100&#xa0;ml dextrose 5% over half an hour, then 70&#xa0;mg/kg in 500&#xa0;ml dextrose 5% over 4&#xa0;h, then 70&#xa0;mg/kg in 500&#xa0;ml dextrose 5% over 16&#xa0;h. Thereafter continuous infusion was administered over 24&#xa0;h of 150&#xa0;mg/kg in 500&#xa0;ml dextrose 5% until up to two consecutive normal international normalized ratios (INRs) were obtained. Our endpoints were recovery, transplantation, or death. The primary outcome of the study was to assess reduction in mortality or liver transplantation. The secondary outcome was the evaluation of other clinical outcomes (length of ICU and hospital stays, organ system failure, and hepatic encephalopathy).<br><br>RESULTS: The study included a total of 155 adults; the NAC group (n&#xa0;=&#xa0;85) were given NAC between January 2011 to December 2013 and the control group (n&#xa0;=&#xa0;70) were not given NAC and were included from files dating between 2010 and 2011. Both groups (before NAC) were comparable with regard to etiology, age, sex, smoking, presence of co-morbidities, encephalopathy, liver profile, and INR. The success rate (transplant-free survival) in the NAC group was 96.4%. While in the control group, 17 patients (23.3%) recovered and 53 (76.6%) did not recover, of these 37 (53.3%) had liver transplantation and 16 (23.3%) died (p&#xa0;<&#xa0;0.01). The NAC group had significantly shorter hospital stays (p&#xa0;<&#xa0;0.001), less encephalopathy (p&#xa0;=&#xa0;0.02), and less bleeding (p&#xa0;<&#xa0;0.01) than the control group. The control group reported a higher ICU admission (p&#xa0;=&#xa0;0.01) rate and abnormal creatinine and electrolytes (p&#xa0;=&#xa0;0.002, p&#xa0;<&#xa0;0.01, respectively). Liver profile and INR (after NAC infusion) differed significantly between the two groups with regard to bilirubin (increased in controls, p&#xa0;=&#xa0;0.02), AST and INR (decreased in NAC group, p&#xa0;<&#xa0;0.001 for both), but the ALT decrease showed no statistical significance between the two groups.<br><br>CONCLUSIONS: When administered on admission, intravenous NAC caused a reduction in NAI-ALF mortality and need for transplantation. NAC decreased encephalopathy, hospital stay, ICU admission, and failure of other organs.}, }
@article {pmid28204833, year = {2017}, author = {Park, JS and Choi, HI and Bae, EH and Ma, SK and Kim, SW}, title = {Small heterodimer partner attenuates hydrogen peroxide-induced expression of cyclooxygenase-2 and inducible nitric oxide synthase by suppression of activator protein-1 and nuclear factor-κB in renal proximal tubule epithelial cells.}, journal = {International journal of molecular medicine}, volume = {39}, number = {3}, pages = {701-710}, doi = {10.3892/ijmm.2017.2883}, pmid = {28204833}, issn = {1791-244X}, mesh = {Animals ; Cyclooxygenase 2/*genetics/metabolism ; Epithelial Cells/drug effects/*metabolism ; *Gene Expression Regulation/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Kidney Diseases/genetics/metabolism/pathology ; Kidney Tubules, Proximal/drug effects/*metabolism ; Male ; Mice ; NF-kappa B/genetics/*metabolism ; Nitric Oxide Synthase Type II/*metabolism ; Promoter Regions, Genetic ; Protein Binding ; Proto-Oncogene Proteins c-jun/metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Reperfusion Injury/genetics/metabolism/pathology ; Transcription Factor AP-1/genetics/*metabolism ; Transcriptional Activation ; }, abstract = {The orphan nuclear receptor, small heterodimer partner (SHP), plays a negative regulatory role in innate immune responses and is involved in various inflammatory signaling pathways. In the present study, we aimed to ascertain whether SHP is effective in preventing hydrogen peroxide (H2O2)-induced kidney tubular inflammation and explored the molecular mechanisms underlying the protective effects of SHP. Renal ischemia/reperfusion (I/R) injury was induced in mice by clamping both renal pedicles for 30 min. The effects of H2O2 on cell viability in human renal proximal tubule (HK-2) cells were determined using MTT assays. 2',7'-DCF-DA was used to determine intracellular reactive oxygen species (ROS). SHP, cyclooxygenase-2 (COX-2) levels, and inducible nitric oxide synthase (iNOS) expression levels were determined by semi-quantitative immunoblotting and real-time polymerase chain reaction. In addition, SHP, nuclear factor-κB (NF-κB), and activator protein-1 (AP-1) promoter activities were determined by luciferase assays. SHP mRNA and protein expression levels were reduced, whereas COX-2 and iNOS levels were increased in mice subjected to renal I/R. H2O2 treatment in HK-2 cells decreased cell viability, increased ROS production, and induced COX-2 and iNOS expression. These changes were counteracted by transient transfection with SHP. H2O2 treatment decreased SHP luciferase activity, which was recovered by treatment with the NF-κB inhibitor Bay11-7082, transfection with dominant-negative c-Jun or treatment with N-acetyl cysteine (NAC). AP-1 and NF-κB promoter activities were increased by H2O2 and this increase was blocked by SHP transfection. To conclude, SHP protected HK-2 cells from H2O2-induced tubular injury by inhibition of COX-2 and iNOS through suppression of AP-1 and NF-κB promoter activities.}, }
@article {pmid28202418, year = {2017}, author = {Ye, X and Zuo, D and Yu, L and Zhang, L and Tang, J and Cui, C and Bao, L and Zan, K and Zhang, Z and Yang, X and Chen, H and Tang, H and Zu, J and Shi, H and Cui, G}, title = {ROS/TXNIP pathway contributes to thrombin induced NLRP3 inflammasome activation and cell apoptosis in microglia.}, journal = {Biochemical and biophysical research communications}, volume = {485}, number = {2}, pages = {499-505}, doi = {10.1016/j.bbrc.2017.02.019}, pmid = {28202418}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Blotting, Western ; Carrier Proteins/*metabolism ; Caspase 3/metabolism ; Cell Line ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Inflammasomes/drug effects/metabolism ; Mice ; Microglia/cytology/*drug effects/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Thioredoxins/*metabolism ; Thrombin/*pharmacology ; Time Factors ; bcl-2-Associated X Protein/metabolism ; }, abstract = {There is no effective therapy for intracerebral hemorrhage (ICH) because of poor understanding of the mechanisms of brain injury after hemorrhage. The NLRP3 inflammasome, as a vital component of innate immune system, which is associated with a wide range of human CNS disorders, including ICH. But its detailed mechanisms in ICH remain mainly unclear. In this study, BV2 cells with thrombin exposure were used to investigate the role of NLRP3 inflammasome in thrombin-induced brain injury. We used western blot to detect NLRP3 inflammasome activation and the expression of thioredoxin binding protein (TXNIP), DCFH-DA to investigate intracellular reactive oxygen species (ROS), flow cytometry to analyze apoptosis. Our results showed that ROS inhibitor N-acetyl-l-cysteine (NAC) suppressed the upregulation of intracellular ROS and TXNIP expression. Furthermore, the cell apoptosis and expression of apoptotic protein were significantly attenuated after treatment of thrombin with NAC or NLRP3 antagonist (MCC950). Thrombin activates ROS/TXNIP/NLRP3 signaling in BV2 cells, which may indicate a mechanism that pro-inflammatory and pro-apoptotic contributes to the development of ICH.}, }
@article {pmid28202395, year = {2017}, author = {Shi, S and Guo, Y and Lou, Y and Li, Q and Cai, X and Zhong, X and Li, H}, title = {Sulfiredoxin involved in the protection of peroxiredoxins against hyperoxidation in the early hyperglycaemia.}, journal = {Experimental cell research}, volume = {352}, number = {2}, pages = {273-280}, doi = {10.1016/j.yexcr.2017.02.015}, pmid = {28202395}, issn = {1090-2422}, mesh = {Animals ; Cell Line ; Cells, Cultured ; Diabetes Mellitus, Experimental/*metabolism ; Diabetic Cardiomyopathies/*metabolism ; Hyperglycemia/*metabolism ; MAP Kinase Kinase 4/metabolism ; Myocytes, Cardiac/metabolism ; *Oxidative Stress ; Oxidoreductases Acting on Sulfur Group Donors/genetics/*metabolism ; Peroxiredoxins/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {As a direct consequence of hyperglycaemia, the excessive generation of ROS is central to the pathogenesis of diabetic cardiomyopathy. We hypothesize that stimulation of high glucose (HG) results in an increased sulfiredoxin (Srx) expression, which regulates ROS signaling through reducing the hyperoxidized peroxiredoxins (Prxs). We show that hyperoxidized Prxs were initially reduced in the preliminary stage but then dramatically increased in advanced stage and these changes corresponded to a significant increase of Srx expression in the heart of diabetic rats. These time-dependent changes were also confirmed in neonatal cardiomyocytes and H9c2 cells treated with HG. Moreover, the reduction rate of hyperoxidized Prxs was greatly improved in the HG 24h group, which had an elevated expression of Srx. Our data also show that HG-induced AP1 activation and Srx expression were almost abolished by JNK inhibitor and N-acetylcysteine (NAC). In addition, siRNA-Srx suppressed HG-induced ANP and β-MHC gene expression. These observations suggest that activation of AP1 induced by HG is important for the expression of Srx and the reduction of hyperoxidized Prxs in cardiomyocytes. This Srx induction maybe is the pivotal compensatory protection mechanism against oxidative stress in diabetes or hyperglycaemia. Most interestingly, hyperoxidized Prxs/Srx pathway may be involved in the cardiac hypertrophy signaling of diabetes.}, }
@article {pmid28199982, year = {2017}, author = {Liu, Y and Ni, Y and Zhang, W and Sun, YE and Ma, Z and Gu, X}, title = {N-acetyl-cysteine attenuates remifentanil-induced postoperative hyperalgesia via inhibiting matrix metalloproteinase-9 in dorsal root ganglia.}, journal = {Oncotarget}, volume = {8}, number = {10}, pages = {16988-17001}, pmid = {28199982}, issn = {1949-2553}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Analgesics, Opioid/administration &amp; dosage/toxicity ; Animals ; Blotting, Western ; Enzyme Activation/drug effects ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Ganglia, Spinal/*drug effects/enzymology/metabolism ; Hyperalgesia/chemically induced/*prevention &amp; control ; Infusions, Subcutaneous ; Injections, Intraperitoneal ; Male ; Matrix Metalloproteinase 9/*metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Pain Measurement/methods ; Phosphorylation/drug effects ; Piperidines/administration &amp; dosage/toxicity ; Postoperative Period ; Protein Kinase C/metabolism ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; Remifentanil ; }, abstract = {Treatment of remifentanil-induced postoperative hyperalgesia (RIH) remains a clinical challenge because the mechanisms are not fully understood. Matrix metalloproteinase-9 (MMP-9) is a key component in neuroinflammation because of its facilitation of pro-inflammatory cytokine maturation. Therefore, inhibition of MMP-9 may represent a novel therapeutic approach to the treatment of RIH. Sprague-Dawley rats were randomly divided into three groups: Control, Incision and Remifentanil. A right plantar surgical incision was performed in Group Incision, and intraoperative remifentanil (0.04 mg/kg, 0.4 ml) was infused subcutaneously for 30 min in Group Remifentanil. The results indicated that intraoperative remifentanil induced an up-regulation and activation of MMP-9 in DRGs but not spinal cords. MMP-9 was expressed primarily in DRG neurons co-expressing mu opioid receptors (MOR), and elicited interleukin-1β (IL-1β) cleavage in DRG neurons and satellite glial cells (SGCs). Intraperitoneal injection of N-acetyl-cysteine (NAC), a broadly used safe drug, significantly attenuated RIH via suppressing the activation of MMP-9 in DRGs. NAC inhibited the cleavage of IL-1β in DRGs, which is a critical substrate of MMP-9, and markedly suppressed glial activation and neuron excitability in spinal dorsal horn induced by remifentanil. These results demonstrated that NAC can effectively alleviate RIH via powerfully inhibiting MMP-9 activation in DRGs.}, }
@article {pmid28197071, year = {2017}, author = {Katerji, M and Barada, K and Jomaa, M and Kobeissy, F and Makkawi, AK and Abou-Kheir, W and Usta, J}, title = {Chemosensitivity of U251 Cells to the Co-treatment of D-Penicillamine and Copper: Possible Implications on Wilson Disease Patients.}, journal = {Frontiers in molecular neuroscience}, volume = {10}, number = {}, pages = {10}, pmid = {28197071}, issn = {1662-5099}, abstract = {D-Penicillamine (PA), a copper chelator, and one of the recommended drugs for treatment of Wilson disease (WD) has been reported to worsen the symptoms of patients with neurologic presentations. However, the cause of this paradoxical response has not been fully elucidated and requires further investigations. Accordingly, we have studied the in vitro effect of Copper (Cu) and/or PA treatment on human glioblastoma U251 cells as an in vitro model of Cu cytotoxicity. Treatment of U251 cells with either Cu or PA exerted no significant effect on their morphology, viability or ROS level. In contrast, co-treatment with Cu-PA caused a decrease in viability, altered glutathione and ceruloplasmin expression coupled with marked increase in ROS; depolarization of mitochondrial membrane potential; and an increase in Sub G0 phase; along with alpha-Fodrin proteolysis. These findings along with the absence of LDH release in these assays, suggest that combined Cu-PA exposure induced apoptosis in U251 cells. In addition, pre-/or co-treatment with antioxidants showed a protective effect, with catalase being more effective than N-acetyl cysteine or trolox in restoring viability and reducing generated ROS levels. By comparison, a similar analysis using other cell lines showed that rat PC12 cells were resistant to Cu and/or PA treatment, while the neuroblastoma cell line SH-SY5Y was sensitive to either compound alone, resulting in decreased viability and increased ROS level. Taken together, this study shows that glioblastoma U251 cells provide a model for Cu-PA cytotoxicity mediated by H2O2. We postulate that PA oxidation in presence of Cu yields H2O2 which in turn permeates the plasma membrane and induced apoptosis. However, other cell lines exhibited different responses to these treatments, potentially providing a model for cell type- specific cytotoxic responses in the nervous system. The sensitivity of different neural and glial cell types to Cu-PA treatment may therefore underlie the neurologic worsening occurring in some PA-treated WD patients. Our results also raise the possibility that the side effects of PA treatment might be reduced or prevented by administering antioxidants.}, }
@article {pmid28193519, year = {2017}, author = {Wang, X and Xu, M and Frank, JA and Ke, ZJ and Luo, J}, title = {Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells.}, journal = {Toxicology and applied pharmacology}, volume = {320}, number = {}, pages = {26-31}, pmid = {28193519}, issn = {1096-0333}, support = {I01 BX001721/BX/BLRD VA/United States ; R01 AA015407/AA/NIAAA NIH HHS/United States ; R01 AA017226/AA/NIAAA NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology/therapeutic use ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects/*physiology ; Humans ; Induced Pluripotent Stem Cells/drug effects/*metabolism/pathology ; Neurons/drug effects/*metabolism/pathology ; Oxidative Stress/drug effects/*physiology ; Sulfonamides/pharmacology/therapeutic use ; Thiamine Deficiency/drug therapy/*metabolism/pathology ; Thiophenes/pharmacology/therapeutic use ; }, abstract = {Thiamine (vitamin B1) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells (hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration- and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration.}, }
@article {pmid28191279, year = {2017}, author = {Jiang, Y and Kou, J and Han, X and Li, X and Zhong, Z and Liu, Z and Zheng, Y and Tian, Y and Yang, L}, title = {ROS-Dependent Activation of Autophagy through the PI3K/Akt/mTOR Pathway Is Induced by Hydroxysafflor Yellow A-Sonodynamic Therapy in THP-1 Macrophages.}, journal = {Oxidative medicine and cellular longevity}, volume = {2017}, number = {}, pages = {8519169}, pmid = {28191279}, issn = {1942-0994}, mesh = {Autophagy/*drug effects ; Blotting, Western ; Cell Line ; Cell Survival/drug effects ; Chalcone/*analogs &amp; derivatives/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; Gene Knockdown Techniques ; Humans ; Macrophages/*drug effects ; Microscopy, Electron, Transmission ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Quinones/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/physiology ; TOR Serine-Threonine Kinases/metabolism ; Ultrasonic Therapy/*methods ; }, abstract = {Monocyte-derived macrophages participate in infaust inflammatory responses by secreting various types of proinflammatory factors, resulting in further inflammatory reactions in atherosclerotic plaques. Autophagy plays an important role in inhibiting inflammation; thus, increasing autophagy may be a therapeutic strategy for atherosclerosis. In the present study, hydroxysafflor yellow A-mediated sonodynamic therapy was used to induce autophagy and inhibit inflammation in THP-1 macrophages. Following hydroxysafflor yellow A-mediated sonodynamic therapy, autophagy was induced as shown by the conversion of LC3-II/LC3-I, increased expression of beclin 1, degradation of p62, and the formation of autophagic vacuoles. In addition, inflammatory factors were inhibited. These effects were blocked by Atg5 siRNA, the autophagy inhibitor 3-methyladenine, and the reactive oxygen species scavenger N-acetyl cysteine. Moreover, AKT phosphorylation at Ser473 and mTOR phosphorylation at Ser2448 decreased significantly after HSYA-SDT. These effects were inhibited by the PI3K inhibitor LY294002, the AKT inhibitor triciribine, the mTOR inhibitor rapamycin, mTOR siRNA, and N-acetyl cysteine. Our results demonstrate that HSYA-SDT induces an autophagic response via the PI3K/Akt/mTOR signaling pathway and inhibits inflammation by reactive oxygen species in THP-1 macrophages.}, }
@article {pmid28190473, year = {2017}, author = {Jian, KL and Zhang, C and Shang, ZC and Yang, L and Kong, LY}, title = {Eucalrobusone C suppresses cell proliferation and induces ROS-dependent mitochondrial apoptosis via the p38 MAPK pathway in hepatocellular carcinoma cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {25}, number = {}, pages = {71-82}, doi = {10.1016/j.phymed.2016.12.014}, pmid = {28190473}, issn = {1618-095X}, mesh = {Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Apoptosis/drug effects ; *Carcinoma, Hepatocellular/drug therapy/metabolism/pathology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Enzyme Inhibitors/pharmacology ; Eucalyptus/*chemistry ; Hep G2 Cells ; Humans ; Imidazoles/pharmacology ; *Liver Neoplasms/drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Phytotherapy ; Plant Extracts/*pharmacology/therapeutic use ; Pyridines/pharmacology ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {BACKGROUND: Eucalyptus extracts have anti-cancer activity against various cancer cells. Formyl-phloroglucinol meroterpenoids (FPMs), which are typical secondary metabolites of the genera Eucalyptus, have many important pharmacological activities.<br><br>PURPOSE: Eucalrobusone C (EC), a new bioactive phytochemical, was first isolated from the leaves of Eucalyptus robusta in our laboratory. EC is a FPM, and our previous research revealed that EC showed strongest cytotoxicity in three cancer models than other compounds isolated from the leaves of E. robusta. This study investigated its anti-tumor effects on human hepatocellular carcinoma (HCC) and its underlying mechanisms.<br><br>METHODS: Cell viability was measured by MTT assay. Cell cycle, apoptosis and mitochondrial transmembrane potential were determined by flow cytometry. Immunofluorescence was determined by a laser scanning confocal microscope. Protein levels were analyzed by Western blotting.<br><br>RESULTS: Our results showed that EC exerted strong anti-proliferative activity against HCC cells in a concentration- and time-dependent manner. EC markedly induced apoptosis through the caspase-dependent mitochondrial pathway, and the cell cycle was arrested at S phase. SB203580, a p38 MAPK inhibitor, effectively decreased cell death caused by EC. Moreover, the ROS scavenger N-acetyl cysteine (NAC) significantly attenuated apoptosis induced by EC and reversed EC-induced p38 MAPK activation.<br><br>CONCLUSION: Our findings indicate that EC induces mitochondrial-dependent apoptosis in HCC cells through ROS generation and p38 MAPK activation, making EC a promising candidate for further development as an anticancer agent for HCC cells.}, }
@article {pmid28190143, year = {2017}, author = {Abdel-Baky, RM and Ali, MA and Abuo-Rahma, GEAA and AbdelAziz, N}, title = {Inhibition of Urease Enzyme Production and some Other Virulence Factors Expression in Proteus mirabilis by N-Acetyl Cysteine and Dipropyl Disulphide.}, journal = {Advances in experimental medicine and biology}, volume = {973}, number = {}, pages = {99-113}, doi = {10.1007/5584_2016_197}, pmid = {28190143}, issn = {0065-2598}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Anti-Bacterial Agents/chemistry/*pharmacology ; Bacterial Proteins/*antagonists &amp; inhibitors/genetics/metabolism ; Biofilms/drug effects ; Disulfides/chemistry/*pharmacology ; Humans ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Proteus Infections/*microbiology ; Proteus mirabilis/*drug effects/enzymology/genetics/physiology ; Urease/*antagonists &amp; inhibitors/chemistry/genetics/metabolism ; Urinary Tract Infections/microbiology ; Virulence Factors/*antagonists &amp; inhibitors/chemistry/genetics/metabolism ; }, abstract = {UNLABELLED: Proteus mirabilis is one of the important pathogens that colonize the urinary tract and catheters resulting in various complications, such as blockage of the catheters and the formation of infective stones.<br><br>PURPOSE: In this study we evaluated the effect of N-acetyl cysteine (NAC) and dipropyl disulphide on some virulence factors expressed by a Proteus mirabilis strain isolated from a catheterized patient.<br><br>METHODS: Antibacterial activity of both compounds was determined by broth microdilution method. Their effect on different types of motility was determined by LB medium with variable agar content and sub-MIC of each drug. Their effect on adherence and mature biofilms was tested by tissue culture plate assay. Inhibitory effect on urease production was determined and supported by molecular docking studies.<br><br>RESULTS: The minimum inhibitory concentration (MIC) of NAC and dipropyl disulphide was 25 mM and 100 mM, respectively. Both compounds decreased the swarming ability and biofilm formation of the tested isolate in a dose-dependent manner. NAC had higher urease inhibitory activity (IC50 249 &#xb1;0.05 mM) than that shown by dipropyl disulphide (IC50 10&#xb1;0.2 mM). Results were supported by molecular docking studies which showed that NAC and dipropyl disulphide interacted with urease enzyme with binding free energy of -4.8 and -8.528 kcal/mol, respectively. Docking studies showed that both compounds interacted with Ni ion and several amino acids (His-138, Gly-279, Cysteine-321, Met-366 and His-322) which are essential for the enzyme activity.<br><br>CONCLUSION: NAC and dipropyl disulphide could be used in the control of P. mirabilis urinary tract infections.}, }
@article {pmid28189853, year = {2017}, author = {Ono, K and Jung, M and Zhang, T and Tsutsuki, H and Sezaki, H and Ihara, H and Wei, FY and Tomizawa, K and Akaike, T and Sawa, T}, title = {Synthesis of l-cysteine derivatives containing stable sulfur isotopes and application of this synthesis to reactive sulfur metabolome.}, journal = {Free radical biology &amp; medicine}, volume = {106}, number = {}, pages = {69-79}, doi = {10.1016/j.freeradbiomed.2017.02.023}, pmid = {28189853}, issn = {1873-4596}, mesh = {Acetylcysteine/*metabolism ; Cysteine/chemistry/*metabolism ; Cysteine Synthase/genetics/*metabolism ; HeLa Cells ; Humans ; Isotope Labeling ; *Metabolome ; Oxidation-Reduction ; Salmonella typhimurium/enzymology/*metabolism ; Sulfhydryl Compounds/chemistry/metabolism ; Sulfur/metabolism ; Sulfur Isotopes ; }, abstract = {Cysteine persulfide is an L-cysteine derivative having one additional sulfur atom bound to a cysteinyl thiol group, and it serves as a reactive sulfur species that regulates redox homeostasis in cells. Here, we describe a rapid and efficient method of synthesis of L-cysteine derivatives containing isotopic sulfur atoms and application of this method to a reactive sulfur metabolome. We used bacterial cysteine syntheses to incorporate isotopic sulfur atoms into the sulfhydryl moiety of L-cysteine. We cloned three cysteine synthases-CysE, CysK, and CysM-from the Gram-negative bacterium Salmonella enterica serovar Typhimurium LT2, and we generated their recombinant enzymes. We synthesized [34]S-labeled L-cysteine from O-acetyl-L-serine and [34]S-labeled sodium sulfide as substrates for the CysK or CysM reactions. Isotopic labeling of L-cysteine at both sulfur ([34]S) and nitrogen ([15]N) atoms was also achieved by performing enzyme reactions with [15]N-labeled L-serine, acetyl-CoA, and [34]S-labeled sodium sulfide in the presence of CysE and CysK. The present enzyme systems can be applied to syntheses of a series of L-cysteine derivatives including L-cystine, L-cystine persulfide, S-sulfo-L-cysteine, L-cysteine sulfonate, and L-selenocystine. We also prepared [34]S-labeled N-acetyl-L-cysteine (NAC) by incubating [34]S-labeled L-cysteine with acetyl coenzyme A in test tubes. Tandem mass spectrometric identification of low-molecular-weight thiols after monobromobimane derivatization revealed the endogenous occurrence of NAC in the cultured mammalian cells such as HeLa cells and J774.1 cells. Furthermore, we successfully demonstrated, by using [34]S-labeled NAC, metabolic conversion of NAC to glutathione and its persulfide, via intermediate formation of L-cysteine, in the cells. The approach using isotopic sulfur labeling combined with mass spectrometry may thus contribute to greater understanding of reactive sulfur metabolome and redox biology.}, }
@article {pmid28189848, year = {2017}, author = {Panchuk, RR and Lehka, LV and Terenzi, A and Matselyukh, BP and Rohr, J and Jha, AK and Downey, T and Kril, IJ and Herbacek, I and van Schoonhoven, S and Heffeter, P and Stoika, RS and Berger, W}, title = {Rapid generation of hydrogen peroxide contributes to the complex cell death induction by the angucycline antibiotic landomycin E.}, journal = {Free radical biology &amp; medicine}, volume = {106}, number = {}, pages = {134-147}, pmid = {28189848}, issn = {1873-4596}, support = {R01 CA091901/CA/NCI NIH HHS/United States ; R01 GM105977/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Aminoglycosides/*administration &amp; dosage ; Antibiotics, Antineoplastic/*administration &amp; dosage ; Apoptosis/drug effects ; Caspase 7/metabolism ; Caspase 9/metabolism ; Doxorubicin/administration &amp; dosage ; Humans ; Hydrogen Peroxide/toxicity ; Jurkat Cells/drug effects/*metabolism/pathology ; Leukemia/*drug therapy/metabolism/pathology ; Mitochondria/drug effects/pathology ; Oxidative Stress/*drug effects ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Reactive Oxygen Species/metabolism ; Streptomyces/chemistry ; Superoxides/toxicity ; }, abstract = {Landomycin E (LE) is an angucycline antibiotic produced by Streptomyces globisporus. Previously, we have shown a broad anticancer activity of LE which is, in contrast to the structurally related and clinically used anthracycline doxorubicin (Dx), only mildly affected by multidrug resistance-mediated drug efflux. In the present study, cellular and molecular mechanisms underlying the anticancer activity of landomycin E towards Jurkat T-cell leukemia cells were dissected focusing on the involvement of radical oxygen species (ROS). LE-induced apoptosis distinctly differed in several aspects from the one induced by Dx. Rapid generation of both extracellular and cell-derived hydrogen peroxide already at one hour drug exposure was observed in case of LE but not found before 24h for Dx. In contrast, Dx but not LE induced production of superoxide radicals. Mitochondrial damage, as revealed by JC-1 staining, was weakly enhanced already at 3h LE treatment and increased significantly with time. Accordingly, activation of the intrinsic apoptosis pathway initiator caspase-9 was not detectable before 12h exposure. In contrast, cleavage of the down-stream caspase substrate PARP-1 was clearly induced already at the three hour time point. Out of all caspases tested, only activation of effector caspase-7 was induced at this early time points paralleling the LE-induced oxidative burst. Accordingly, this massive cleavage of caspase-7 at early time points was inhibitable by the radical scavenger N-acetylcysteine (NAC). Additionally, only simultaneous inhibition of multiple caspases reduced LE-induced apoptosis. Specific scavengers of both H2O2 and OH[•] effectively decreased LE-induced ROS production, but only partially inhibited LE-induced apoptosis. In contrast, NAC efficiently blocked both parameters. Summarizing, rapid H2O2 generation and a complex caspase activation pattern contribute to the antileukemic effects of LE. As superoxide generation is considered as the main cardiotoxic mechanism of Dx, LE might represent a better tolerable drug candidate for further (pre)clinical development.}, }
@article {pmid28189104, year = {2017}, author = {den Braver, MW and Vermeulen, NPE and Commandeur, JNM}, title = {Generic method for the absolute quantification of glutathione S-conjugates: Application to the conjugates of acetaminophen, clozapine and diclofenac.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1046}, number = {}, pages = {185-194}, doi = {10.1016/j.jchromb.2017.02.004}, pmid = {28189104}, issn = {1873-376X}, mesh = {Acetaminophen/*blood/chemistry ; Animals ; Chromatography, Liquid ; Clozapine/*blood/chemistry ; Diclofenac/*blood/chemistry ; Glutathione/*blood/chemistry ; Male ; Mass Spectrometry ; Metabolomics/methods ; Principal Component Analysis ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; }, abstract = {Modification of cellular macromolecules by reactive drug metabolites is considered to play an important role in the initiation of tissue injury by many drugs. Detection and identification of reactive intermediates is often performed by analyzing the conjugates formed after trapping by glutathione (GSH). Although sensitivity of modern mass spectrometrical methods is extremely high, absolute quantification of GSH-conjugates is critically dependent on the availability of authentic references. Although [1]H NMR is currently the method of choice for quantification of metabolites formed biosynthetically, its intrinsically low sensitivity can be a limiting factor in quantification of GSH-conjugates which generally are formed at low levels. In the present study, a simple but sensitive and generic method for absolute quantification of GSH-conjugates is presented. The method is based on quantitative alkaline hydrolysis of GSH-conjugates and subsequent quantification of glutamic acid and glycine by HPLC after precolumn derivatization with o-phthaldialdehyde/N-acetylcysteine (OPA/NAC). Because of the lower stability of the glycine OPA/NAC-derivate, quantification of the glutamic acid OPA/NAC-derivate appeared most suitable for quantification of GSH-conjugates. The novel method was used to quantify the concentrations of GSH-conjugates of diclofenac, clozapine and acetaminophen and quantification was consistent with [1]H NMR, but with a more than 100-fold lower detection limit for absolute quantification.}, }
@article {pmid28187322, year = {2017}, author = {Finamor, I and Pérez, S and Bressan, CA and Brenner, CE and Rius-Pérez, S and Brittes, PC and Cheiran, G and Rocha, MI and da Veiga, M and Sastre, J and Pavanato, MA}, title = {Chronic aspartame intake causes changes in the trans-sulphuration pathway, glutathione depletion and liver damage in mice.}, journal = {Redox biology}, volume = {11}, number = {}, pages = {701-707}, pmid = {28187322}, issn = {2213-2317}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Aspartame/administration &amp; dosage/*adverse effects ; Chemical and Drug Induced Liver Injury/drug therapy/*metabolism/pathology ; Cystathionine gamma-Lyase/genetics ; Gene Expression Regulation/drug effects ; Glutamate-Cysteine Ligase/genetics ; Glutathione/*metabolism ; Humans ; Liver/metabolism/pathology ; Methionine Adenosyltransferase/genetics ; Mice ; Sweetening Agents/administration &amp; dosage/*adverse effects ; }, abstract = {No-caloric sweeteners, such as aspartame, are widely used in various food and beverages to prevent the increasing rates of obesity and diabetes mellitus, acting as tools in helping control caloric intake. Aspartame is metabolized to phenylalanine, aspartic acid, and methanol. Our aim was to study the effect of chronic administration of aspartame on glutathione redox status and on the trans-sulphuration pathway in mouse liver. Mice were divided into three groups: control; treated daily with aspartame for 90 days; and treated with aspartame plus N-acetylcysteine (NAC). Chronic administration of aspartame increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase activities and caused liver injury as well as marked decreased hepatic levels of reduced glutathione (GSH), oxidized glutathione (GSSG), γ-glutamylcysteine (γ-GC), and most metabolites of the trans-sulphuration pathway, such as cysteine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH). Aspartame also triggered a decrease in mRNA and protein levels of the catalytic subunit of glutamate cysteine ligase (GCLc) and cystathionine γ-lyase, and in protein levels of methionine adenosyltransferase 1A and 2A. N-acetylcysteine prevented the aspartame-induced liver injury and the increase in plasma ALT activity as well as the decrease in GSH, γ-GC, cysteine, SAM and SAH levels and GCLc protein levels. In conclusion, chronic administration of aspartame caused marked hepatic GSH depletion, which should be ascribed to GCLc down-regulation and decreased cysteine levels. Aspartame triggered blockade of the trans-sulphuration pathway at two steps, cystathionine γ-lyase and methionine adenosyltransferases. NAC restored glutathione levels as well as the impairment of the trans-sulphuration pathway.}, }
@article {pmid28185882, year = {2017}, author = {Tsikas, D and Böhmer, A}, title = {S-Transnitrosation reactions of hydrogen sulfide (H2S/HS[-]/S[2-]) with S-nitrosated cysteinyl thiols in phosphate buffer of pH 7.4: Results and review of the literature.}, journal = {Nitric oxide : biology and chemistry}, volume = {65}, number = {}, pages = {22-36}, doi = {10.1016/j.niox.2017.02.001}, pmid = {28185882}, issn = {1089-8611}, mesh = {Catalase/chemistry ; Cysteine/analogs &amp; derivatives/chemistry ; Humans ; Hydrogen Sulfide/*chemistry ; Hydrogen-Ion Concentration ; Kinetics ; Methemoglobin/chemistry ; Nitrates/analysis ; Nitrites/analysis ; Nitrosation ; Oxidation-Reduction ; Oxyhemoglobins/chemistry ; S-Nitrosothiols/*chemistry ; }, abstract = {Cysteine (CysSH) and its derivatives including N-acetylcysteine (NAC) and glutathione (GSH), and cysteine residues in proteins and enzymes are nitrosated with nitric oxide (NO) reaction products such as N2O3 to form S-nitrosated cysteine thiols (RCysSNO). RCysSNO undergo with cysteine thiols (RCysSH) S-transnitrosation reactions, thereby transferring reversibly their nitrosyl ([+]NO) group to RCysSH to form RCysSNO. [•]NO release from RCysSNO and S-transnitrosation are considered the most important features and signalling pathways of RCysSNO. Hydrogen sulfide (H2S: pKa1, 7; HS[-]: pKa2, 12.9) is an endogenous product of cysteine metabolism. We hypothesized that RCysSNO would also undergo S-transnitrosation reaction with H2S/HS[-]/S[2-] to form thionitrite (ONS[-]), the smallest S-nitrosated thiol. This article describes spectrophotometric and mass spectrometric investigations of S-transnitrosation reactions in phosphate buffered saline (PBS) of pH 7.4 between H2S/HS[-]/S[2-] (supplied as Na2S) and S-nitrosoglutathione (GSNO), S-nitroso-l-cysteine (CysSNO), S-nitroso-N-acetyl-l-cysteine (SNAC), and the synthetic S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET). For comparison, we also investigated the reactions of H2S/HS[-]/S[2-] with NO[+]BF4[-] and NO2[+]BF4[-], direct ON[+] and O2N[+] donors, respectively, and assumed formation of ONS[-] and thionitrate (O2NS[-]), respectively. Addition of Na2S (at 1 mM) to buffered RCysSNO solutions resulted in decreases of the absorbance at 340 nm and concomitant increases in the absorbance at 410 nm depending upon the nature and concentration of RCysSNO (range, 25-1000 μM). The reactivity order of RCysSNO against H2S/HS[-]/S[2-] was: CysSNO > SNACET > GSNO > SNAC. Our spectrophotometric and GC-MS analyses indicate that H2S/HS[-]/S[2-] and RCysSNO undergo multiple reactions. Major final reaction products were found to be nitrite and nitrate. ONS[-] and O2NS[-] were not detected by GC-MS, suggesting rapid and complete S/O-exchange from water at pH 7.4. GC-MS analyses of ethyl acetate extracts of reaction mixtures suggested formation of tetrasulfur (S4), the precursor of elemental sulfur (S8). The broad absorbance around 410 nm and the turbidity occurred in RCysSNO/Na2S reaction mixtures support formation of polysulfides (polysulfanes) and colloidal sulfur. The reaction of NO[+]BF4[-] and NO2[+]BF4[-] with H2S/HS[-]/S[2-] differed from the S-transnitrosation reactions of RCysSNO, with NO[+]BF4[-] being more reactive than NO2[+]BF4[-]. In this article, we also briefly review and discuss recent published work dealing with the reaction of H2S/HS[-]/S[2-] with low- and high-molecular-mass S-nitrosated thiols. This research area is highly challenging and controversial with respect to the primarily formed reaction products. The synthesis of structurally well-characterized, pure stable-isotope labelled species of putative reaction products, including ONS[-], O2NS[-] and ONSS[-], and their use in combination with mass spectrometry coupled to chromatography, e.g. GC-MS and LC-MS/MS, are indispensable in exploring the complex interaction of the two gasotransmitters, H2S and [•]NO.}, }
@article {pmid28185677, year = {2017}, author = {Yang, Y and He, X and Shi, J and Hickel, R and Reichl, FX and Högg, C}, title = {Effects of antioxidants on DNA double-strand breaks in human gingival fibroblasts exposed to dental resin co-monomer epoxy metabolites.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {33}, number = {4}, pages = {418-426}, doi = {10.1016/j.dental.2017.01.005}, pmid = {28185677}, issn = {1879-0097}, mesh = {Antioxidants/*pharmacology ; DNA ; DNA Breaks, Double-Stranded/*drug effects ; Fibroblasts ; Gingiva/cytology ; Histones ; Humans ; Resins, Synthetic/*adverse effects ; }, abstract = {OBJECTIVE: Eluted dental resin co-monomers can be metabolized to intermediate methacrylic acid (MA) and, further, to epoxy metabolites. Antioxidants have been studied previously, with the intention of decreasing the DNA double-strand breaks (DNA-DSBs) in human gingival fibroblasts (HGFs). In this study, the effects of the antioxidants, ascorbic acid (Asc) and N-acetylcysteine (NAC), were investigated on co-monomer metabolite-induced DNA-DSBs.<br><br>METHODS: HGFs were incubated with MA, 2,3-epoxy-2-methyl-propionicacid-methylester (EMPME) and 2,3-epoxy-2-methylpropionic acid (EMPA), respectively, in the presence or absence of antioxidants (Asc or NAC). EC50 Values were obtained from an XTT-based viability assay. DNA-DSBs were determined using a &#x3b3;-H2AX assay.<br><br>RESULTS: The cytotoxicity of the compounds could be ranked in the following order (mean&#xb1;SEM; n=4): EMPA>EMPME>MA. The average number of DSBs-foci/cell induced by each substance at EC50-concentration could be ranked in the following order (mean&#xb1;SD; n=4): EMPA>EMPME>MA. EMPA (1.72mM) and EMPME (2.58mM) induced the highest number of DSBs-foci, that is 21-fold and 13-fold, respectively, compared to control (0.48&#xb1;0.08 foci/cell). The addition of Asc (50; 100; 200&#x3bc;M) or NAC (50; 100; 200; 500&#x3bc;M) to MA (15.64; 5.21mM), EMPME (2.58mM), and EMPA (1.72; 0.57mM) significantly reduced the number of foci/cell in HGFs. The highest reduction could be found in HGFs with 1.72mM EMPA, the addition of NAC (50; 100; 200; 500&#x3bc;M) induced a 15-fold, 17-fold, 14-fold and 14-fold lower number of DSBs-foci/cell, respectively.<br><br>SIGNIFICANCE: Dental co-monomer epoxy metabolites, EMPME and EMPA, can induce DNA-DSBs. The addition of antioxidants (Asc or NAC) leads to reduction of DNA-DSBs, and NAC leads to more prominent reduction of DNA-DSBs compared to Asc.}, }
@article {pmid28182780, year = {2017}, author = {Wu, L and Pang, Y and Qin, G and Xi, G and Wu, S and Wang, X and Chen, T}, title = {Farnesylthiosalicylic acid sensitizes hepatocarcinoma cells to artemisinin derivatives.}, journal = {PloS one}, volume = {12}, number = {2}, pages = {e0171840}, pmid = {28182780}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Artemisinins/*pharmacology/toxicity ; Carcinoma, Hepatocellular/*metabolism ; Drug Synergism ; Farnesol/*analogs &amp; derivatives/pharmacology ; Hep G2 Cells ; Humans ; Liver Neoplasms/*metabolism ; Salicylates/*pharmacology ; }, abstract = {Dihydroartemisinin (DHA) and artesunate (ARS), two artemisinin derivatives, have efficacious anticancer activities against human hepatocarcinoma (HCC) cells. This study aims to study the anticancer action of the combination treatment of DHA/ARS and farnesylthiosalicylic acid (FTS), a Ras inhibitor, in HCC cells (Huh-7 and HepG2 cell lines). FTS pretreatment significantly enhanced DHA/ARS-induced phosphatidylserine (PS) externalization, Bak/Bax activation, mitochondrial membrane depolarization, cytochrome c release, and caspase-8 and -9 activations, characteristics of the extrinsic and intrinsic apoptosis. Pretreatment with Z-IETD-FMK (caspase-8 inhibitor) potently prevented the cytotoxicity of the combination treatment of DHA/ARS and FTS, and pretreatment with Z-VAD-FMK (pan-caspase inhibitor) significantly inhibited the loss of ΔΨm induced by DHA/ARS treatment or the combination treatment of DHA/ARS and FTS in HCC cells. Furthermore, silencing Bak/Bax modestly but significantly inhibited the cytotoxicity of the combination treatment of DHA/ARS and FTS. Interestingly, pretreatment with an antioxidant N-Acetyle-Cysteine (NAC) significantly prevented the cytotoxicity of the combination treatment of DHA and FTS instead of the combination treatment of ARS and FTS, suggesting that reactive oxygen species (ROS) played a key role in the anticancer action of the combination treatment of DHA and FTS. Similar to FTS, DHA/ARS also significantly prevented Ras activation. Collectively, our data demonstrate that FTS potently sensitizes Huh-7 and HepG2 cells to artemisinin derivatives via accelerating the extrinsic and intrinsic apoptotic pathways.}, }
@article {pmid28182160, year = {2017}, author = {Luo, CQ and Xing, L and Cui, PF and Qiao, JB and He, YJ and Chen, BA and Jin, L and Jiang, HL}, title = {Curcumin-coordinated nanoparticles with improved stability for reactive oxygen species-responsive drug delivery in lung cancer therapy.}, journal = {International journal of nanomedicine}, volume = {12}, number = {}, pages = {855-869}, pmid = {28182160}, issn = {1178-2013}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Curcumin/chemistry/*pharmacology ; *Drug Delivery Systems ; Humans ; Hydrogen Peroxide/pharmacology ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Nanoparticles/*administration &amp; dosage/chemistry ; Oxidants/pharmacology ; Polymers/chemistry ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND: The natural compound curcumin (Cur) can regulate growth inhibition and apoptosis in various cancer cell lines, although its clinical applications are restricted by extreme water insolubility and instability. To overcome these hurdles, we fabricated a Cur-coordinated reactive oxygen species (ROS)-responsive nanoparticle using the interaction between boronic acid and Cur.<br><br>MATERIALS AND METHODS: We synthesized a highly biocompatible 4-(hydroxymethyl) phenylboronic acid (HPBA)-modified poly(ethylene glycol) (PEG)-grafted poly(acrylic acid) polymer (PPH) and fabricated a Cur-coordinated ROS-responsive nanoparticle (denoted by PPHC) based on the interaction between boronic acid and Cur. The mean diameter of the Cur-coordinated PPHC nanoparticle was 163.8 nm and its zeta potential was -0.31 mV. The Cur-coordinated PPHC nanoparticle improved Cur stability in physiological environment and could timely release Cur in response to hydrogen peroxide (H2O2). PPHC nanoparticles demonstrated potent antiproliferative effect in vitro in A549 cancer cells. Furthermore, the viability of cells treated with PPHC nanoparticles was significantly increased in the presence of N-acetyl-cysteine (NAC), which blocks Cur release through ROS inhibition. Simultaneously, the ROS level measured in A549 cells after incubation with PPHC nanoparticles exhibited an obvious downregulation, which further proved that ROS depression indeed influenced the therapeutic effect of Cur in PPHC nanoparticles. Moreover, pretreatment with phosphate-buffered saline (PBS) significantly impaired the cytotoxic effect of Cur in A549 cells in vitro while causing less damage to the activity of Cur in PPHC nanoparticle.<br><br>CONCLUSION: The Cur-coordinated nanoparticles developed in this study improved Cur stability, which could further release Cur in a ROS-dependent manner in cancer cells.}, }
@article {pmid28182085, year = {2017}, author = {Tang, S and Gao, C and Long, Y and Huang, W and Chen, J and Fan, F and Jiang, C and Xu, Y}, title = {Maresin 1 Mitigates High Glucose-Induced Mouse Glomerular Mesangial Cell Injury by Inhibiting Inflammation and Fibrosis.}, journal = {Mediators of inflammation}, volume = {2017}, number = {}, pages = {2438247}, pmid = {28182085}, issn = {1466-1861}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Caspase 1/metabolism ; Cells, Cultured ; Docosahexaenoic Acids/*pharmacology ; Enzyme-Linked Immunosorbent Assay ; Fibrosis/*immunology/metabolism ; Glucose/*toxicity ; Inflammation/*immunology/metabolism ; Interleukin-1beta/metabolism ; Mesangial Cells/*drug effects/*immunology/metabolism ; Mice ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; }, abstract = {Background. Inflammation and fibrosis are the important pathophysiologic processes in diabetic nephropathy (DN). Maresin 1 is a potential anti-inflammatory lipid mediator, which has displayed powerful proresolving activities. Aim. We determine whether maresin 1 has protective effect on mouse glomerular mesangial cells (GMCs) induced by high glucose. Methods. We cultured GMCs stimulated by high glucose and categorized as follows: normal glucose group (5.6 mmol/L), high glucose group (30 mmol/L), mannitol group, maresin 1 intervention group (1, 10, and 100 nmol/L), maresin 1 and normal glucose group, and the N-acetylcysteine (NAC) intervention group (10 μmol/L NAC). After 24 h, the expression of ROS, NLRP3, caspase-1, procaspase-1, IL-1β, and pro-IL-1β was detected by western-blot, RT-PCR, and immunofluorescence. After 48 h, the expression of TGF-β1 and FN was detected by RT-PCR and ELISA. Results. Compared with normal glucose group, the expression of ROS, NLRP3, caspase-1, IL-1β, TGF-β1, and FN increased in high glucose group (P < 0.05), but it decreased after the treatment of maresin 1 in different concentrations. On the contrary, the expression of procaspase-1 and pro-IL-1β protein was restrained by high glucose and enhanced by maresin 1 in a dose-dependent manner (P < 0.05). Conclusion. Maresin 1 can inhibit NLRP3 inflammasome, TGF-β1, and FN in GMCs; it may have protective effect on DN by mitigating the inflammation and early fibrosis.}, }
@article {pmid28181495, year = {2017}, author = {Zheng, Y and Miyamoto, DT and Wittner, BS and Sullivan, JP and Aceto, N and Jordan, NV and Yu, M and Karabacak, NM and Comaills, V and Morris, R and Desai, R and Desai, N and Emmons, E and Milner, JD and Lee, RJ and Wu, CL and Sequist, LV and Haas, W and Ting, DT and Toner, M and Ramaswamy, S and Maheswaran, S and Haber, DA}, title = {Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination.}, journal = {Nature communications}, volume = {8}, number = {}, pages = {14344}, pmid = {28181495}, issn = {2041-1723}, support = {R01 CA129933/CA/NCI NIH HHS/United States ; R01 EB008047/EB/NIBIB NIH HHS/United States ; U01 EB012493/EB/NIBIB NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/metabolism ; Apoptosis/genetics ; Cell Line, Tumor ; Cell Survival/genetics ; Cytoprotection/genetics ; *Gene Expression Regulation, Neoplastic ; Humans ; Kruppel-Like Factor 4 ; Kruppel-Like Transcription Factors/metabolism ; Male ; Mice ; Neoplasms/*blood/*genetics/pathology ; Neoplastic Cells, Circulating/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Stress, Physiological ; Up-Regulation/genetics ; beta-Globins/*genetics/metabolism ; }, abstract = {Metastasis-competent circulating tumour cells (CTCs) experience oxidative stress in the bloodstream, but their survival mechanisms are not well defined. Here, comparing single-cell RNA-Seq profiles of CTCs from breast, prostate and lung cancers, we observe consistent induction of β-globin (HBB), but not its partner α-globin (HBA). The tumour-specific origin of HBB is confirmed by sequence polymorphisms within human xenograft-derived CTCs in mouse models. Increased intracellular reactive oxygen species (ROS) in cultured breast CTCs triggers HBB induction, mediated through the transcriptional regulator KLF4. Depletion of HBB in CTC-derived cultures has minimal effects on primary tumour growth, but it greatly increases apoptosis following ROS exposure, and dramatically reduces CTC-derived lung metastases. These effects are reversed by the anti-oxidant N-Acetyl Cysteine. Conversely, overexpression of HBB is sufficient to suppress intracellular ROS within CTCs. Altogether, these observations suggest that β-globin is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis.}, }
@article {pmid28180948, year = {2017}, author = {Chen, YW and Lan, KC and Tsai, JR and Weng, TI and Yang, CY and Liu, SH}, title = {Tributyltin exposure at noncytotoxic doses dysregulates pancreatic β-cell function in vitro and in vivo.}, journal = {Archives of toxicology}, volume = {91}, number = {9}, pages = {3135-3144}, doi = {10.1007/s00204-017-1940-y}, pmid = {28180948}, issn = {1432-0738}, support = {MOST103-2314-B-002-035//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Animals ; Blood Glucose/metabolism ; Calcium/metabolism ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Environmental Exposure/adverse effects ; Glucose/pharmacology ; Glucose Tolerance Test ; Insulin/blood/*metabolism ; Insulin Secretion ; Insulin-Secreting Cells/*drug effects/pathology/physiology ; Male ; Mice, Inbred ICR ; Rats ; Reactive Oxygen Species/metabolism ; Trialkyltin Compounds/*administration &amp; dosage/*toxicity ; }, abstract = {Tributyltin (TBT) is an endocrine disruptor. TBT can be found in food and in human tissues and blood. Several animal studies revealed that organotins induced diabetes with decreased insulin secretion. The detailed effect and mechanism of TBT on pancreatic β-cell function still remain unclear. We investigated the effect and mechanism of TBT exposure at noncytotoxic doses relevant to human exposure on β-cell function in vitro and in vivo. The β-cell-derived RIN-m5F cells and pancreatic islets from mouse and human were treated with TBT (0.05-0.2 μM) for 0.5-4 h. Adult male mice were orally exposed to TBT (25 μg/kg/day) with or without antioxidant N-acetylcysteine (NAC) for 1-3 weeks. Assays for insulin secretion and glucose metabolism were carried out. Unlike previous studies, TBT at noncytotoxic concentrations significantly increased glucose-stimulated insulin secretion and intracellular Ca[2+] ([Ca[2+]]i) in β-cells. The reactive oxygen species (ROS) production and phosphorylation of protein kinase C (PKC-pan) and extracellular signal-regulated kinase (ERK)1/2 were also increased. These TBT-triggered effects could be reversed by antiestrogen ICI182780 and inhibitors of ROS, [Ca[2+]]i, and PKC, but not ERK. Similarly, islets treated with TBT significantly increased glucose-stimulated insulin secretion, which could be reversed by ICI182780, NAC, and PKC inhibitor. Mice exposed to TBT for 3 weeks significantly increased blood glucose and plasma insulin and induced glucose intolerance and insulin resistance, which could be reversed by NAC. These findings suggest that low/noncytotoxic doses of TBT induce insulin dysregulation and disturb glucose homeostasis, which may be mediated through the estrogen receptor-regulated and/or oxidative stress-related signaling pathways.}, }
@article {pmid28178219, year = {2017}, author = {Jiang, C and Masood, M and Rasul, A and Wei, W and Wang, Y and Ali, M and Mustaqeem, M and Li, J and Li, X}, title = {Altholactone Inhibits NF-κB and STAT3 Activation and Induces Reactive Oxygen Species-Mediated Apoptosis in Prostate Cancer DU145 Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {22}, number = {2}, pages = {}, pmid = {28178219}, issn = {1420-3049}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Furans/*pharmacology ; Goniothalamus/chemistry ; Humans ; Male ; NF-kappa B/metabolism ; Prostatic Neoplasms/drug therapy ; Pyrones/*pharmacology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; }, abstract = {Altholactone, a natural compound isolated from Goniothalamus spp., has demonstrated anti-inflammatory and anticancer activities, but its molecular mechanisms are still not fully defined. Nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play pivotal roles in the cell survival of many human tumors. The objective of this study was to elucidate the mechanism of action of altholactone against prostate cancer DU145 cells and to evaluate whether its effects are mediated by inhibition of NF-κB and STAT3 activity. Altholactone inhibited proliferation of DU145 cells and induced cell cycle arrest in S phase and triggered apoptosis. Reporter assays revealed that altholactone repressed p65- and TNF-α-enhanced NF-κB transcriptional activity and also inhibited both constitutive and IL-6-induced transcriptional activity of STAT3. Consistent with this, altholactone down-regulated phosphorylation of STAT3 and moreover, decreased constitutively active mutant of STAT3 (STAT3C)-induced transcriptional activity. Altholactone treatment also results in down-regulation of STAT3 target genes such as survivin, and Bcl-2 followed by up regulation of pro-apoptotic Bax protein. However, pre-treatment with the antioxidant N-acetylcysteine (NAC) significantly inhibited the activation of Bax and prevented down-regulation of STAT3 target genes. Collectively, our findings suggest that altholactone induces DU145 cells death through inhibition of NF-κB and STAT3 activity.}, }
@article {pmid28177049, year = {2017}, author = {Gasparotto, J and Kunzler, A and Senger, MR and Souza, CD and Simone, SG and Bortolin, RC and Somensi, N and Dal-Pizzol, F and Moreira, JC and Abreu-Silva, AL and Calabrese, KD and Silva, FP and Gelain, DP}, title = {N-acetyl-cysteine inhibits liver oxidative stress markers in BALB/c mice infected with Leishmania amazonensis.}, journal = {Memorias do Instituto Oswaldo Cruz}, volume = {112}, number = {2}, pages = {146-154}, pmid = {28177049}, issn = {1678-8060}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/*pharmacology ; *Leishmania mexicana ; Leishmaniasis, Cutaneous/*metabolism/pathology ; Liver/*drug effects/enzymology ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/*drug effects/physiology ; }, abstract = {BACKGROUND: Leishmaniasis is a parasitosis caused by several species of the genus Leishmania. These parasites present high resistance against oxidative stress generated by inflammatory cells.<br><br>OBJECTIVES: To investigate oxidative stress and molecular inflammatory markers in BALB/c mice infected with L. amazonensis and the effect of antioxidant treatment on these parameters.<br><br>METHODS: Four months after infection, oxidative and inflammatory parameters of liver, kidneys, spleen, heart and lungs from BALB/c mice were assessed.<br><br>FINDINGS: In liver, L. amazonensis caused thiol oxidation and nitrotyrosine formation; SOD activity and SOD2 protein content were increased while SOD1 protein content decreased. The content of the cytokines IL-1&#x3b2;, IL-6, TNF-&#x3b1;, and the receptor of advanced glycation endproducts (RAGE) increased in liver. Treatment with the antioxidant N-acetyl-cysteine (20 mg/kg b.w) for five days inhibited oxidative stress parameters.<br><br>MAIN CONCLUSIONS: L. amazonensis induces significant alterations in the redox status of liver but not in other organs. Acute antioxidant treatment alleviates oxidative stress in liver, but it had no effect on pro-inflammatory markers. These results indicate that the pathobiology of leishmaniasis is not restricted to the cutaneous manifestations and open perspectives for the development of new therapeutic approaches to the disease, especially for liver function.}, }
@article {pmid28176233, year = {2017}, author = {Li, B and Lu, M and Jiang, XX and Pan, MX and Mao, JW and Chen, M}, title = {Inhibiting reactive oxygen species-dependent autophagy enhanced baicalein-induced apoptosis in oral squamous cell carcinoma.}, journal = {Journal of natural medicines}, volume = {71}, number = {2}, pages = {433-441}, pmid = {28176233}, issn = {1861-0293}, mesh = {Apoptosis ; Autophagy/*physiology ; Carcinoma, Squamous Cell/*drug therapy/pathology ; Flavanones/administration &amp; dosage/*therapeutic use ; Humans ; Medicine, Chinese Traditional/*methods ; Mouth Neoplasms/*drug therapy/pathology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Autophagy modulation has been considered a potential therapeutic strategy for oral squamous cell carcinoma (OSCC). A previous study confirmed that baicalein might possess significant anti-carcinogenic activity. However, whether baicalein induces autophagy and its role in cell death in OSCC are still unclear. The aim of this study was to investigate the anticancer activity and molecular targets of baicalein in OSCC in vitro. In this study, we found that baicalein induced significant apoptosis in OSCC cells Cal27. In addition to showing apoptosis induction, we also demonstrated baicalein-induced autophagic response in Cal27 cells. Moreover, pharmacologically or genetically blocking autophagy enhanced baicalein-induced apoptosis, indicating the cytoprotective role of autophagy in baicalein-treated Cal27 cells. Importantly, we found that baicalein triggered reactive oxygen species (ROS) generation in Cal27 cells. Furthermore, N-acetyl-cysteine, a ROS scavenger, abrogated the effects of baicalein on ROS-dependent autophagy. Therefore, we found that baicalein increased autophagy through the promotion of ROS signaling pathways in OSCC. These data also suggest that a strategy of blocking ROS-dependent autophagy to enhance the activity of baicalein warrants further attention for the treatment of OSCC.}, }
@article {pmid28165728, year = {2017}, author = {More, SS and Nugent, J and Vartak, AP and Nye, SM and Vince, R}, title = {Hepatoprotective Effect of ψ-Glutathione in a Murine Model of Acetaminophen-Induced Liver Toxicity.}, journal = {Chemical research in toxicology}, volume = {30}, number = {3}, pages = {777-784}, doi = {10.1021/acs.chemrestox.6b00291}, pmid = {28165728}, issn = {1520-5010}, mesh = {Acetaminophen/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; *Disease Models, Animal ; Glutathione/*pharmacology ; Mice ; }, abstract = {Ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios. While both agents appear to be equally efficacious when timely administered, ψ-GSH partly retains its efficacy even in the face of substantial delay in administration. Thus, implied is the ability of ψ-GSH to intercept secondary toxicology following APAP insult. Oral availability and complete lack of toxicity as evaluated by liver function tests and survival analysis underscored ψ-GSH as a safer and more efficacious alternative to NAC. Finally, the pharmacodynamic mimicry of GSH by ψ-GSH is illustrated through the isolation and chemical characterization of an entity that can arise only through direct encounter of ψ-GSH with N-acetyl-p-benzoquinoneimine, the primary toxic metabolite of APAP.}, }
@article {pmid28161963, year = {2017}, author = {Shankaran, P and Madlenakova, M and Hajkova, V and Jilich, D and Svobodova, I and Horinek, A and Fujikura, Y and Melkova, Z}, title = {Effects of heme degradation products on reactivation of latent HIV-1.}, journal = {Acta virologica}, volume = {61}, number = {1}, pages = {86-96}, doi = {10.4149/av_2017_01_86}, pmid = {28161963}, issn = {0001-723X}, mesh = {Arginine/*pharmacology ; Bilirubin/*pharmacology ; Carbon Monoxide ; Cell Line ; HIV-1/*drug effects/*physiology ; Heme/*pharmacology ; Humans ; RNA, Viral/genetics/metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Virus Latency/*physiology ; }, abstract = {Human immunodeficiency virus (HIV-1) infection can be currently controlled by combined antiretroviral therapy, but a sterilizing cure is not achievable as this therapy does not target persistent HIV-1 in latent reservoirs. Therefore, different latency reversal agents are intensively explored in various models. We have previously observed that heme arginate, a drug approved for human use, reveals a strong synergism with PKC inducers in reactivation of the latent provirus. Heme is physiologically decomposed by heme oxygenases into 3 degradation products: iron (Fe2+), carbon monoxide (CO) and biliverdin which is further converted to bilirubin by biliverdin reductase. In this paper, we have studied the effects of individual heme-degradation products on latent HIV-1 reactivation in ACH-2 cells harboring integrated HIV-1 provirus and in H12 clone of Jurkat cells harboring HIV-minivirus expressing EGFP. We employed addition of ascorbate to generate Fe2+, resulting in increased expression of both HIV-1 p24 Ag and EGFP in PMA-stimulated ACH-2 and H12 cells, respectively, as characterized on RNA and protein levels. On the other hand, addition of a CO-donor or bilirubin decreased the p24 expression. The reactivation of latent HIV-1 by iron or heme arginate was inhibited by antioxidant N-acetyl cysteine, or by an iron chelator desferrioxamine, suggesting that the effects were mediated by iron- or heme-induced redox stress. Finally, we demonstrated the stimulatory effects of heme arginate and PMA on HIV-1 expression in peripheral blood mononuclear cells of HIV-infected patients cultured ex vivo. These results may constitute a new direction in the latent HIV-1 reactivation and therapy.}, }
@article {pmid28157110, year = {2017}, author = {Chen, W and Guo, Y and Yang, W and Zheng, P and Zeng, J and Tong, W}, title = {Connexin40 correlates with oxidative stress in brains of traumatic brain injury rats.}, journal = {Restorative neurology and neuroscience}, volume = {35}, number = {2}, pages = {217-224}, doi = {10.3233/RNN-160705}, pmid = {28157110}, issn = {1878-3627}, mesh = {Acetylcysteine/therapeutic use ; Analysis of Variance ; Animals ; Brain/drug effects/*metabolism ; Brain Edema/etiology ; Brain Infarction/etiology ; Brain Injuries, Traumatic/drug therapy/*pathology/*physiopathology ; Connexins/*metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Male ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Wistar ; Time Factors ; Gap Junction alpha-5 Protein ; }, abstract = {BACKGROUND: Oxidative stress is an important factor in the pathophysiologic changes after traumatic brain injury (TBI). Connexin43 (Cx43) was reported to contribute to cerebral damage. However, the impacts of Cx40 have not been investigated in detail.<br><br>OBJECTIVE: In the present study, we hypothesized that Cx40 was involved in oxidative stress-induced brain injury after TBI.<br><br>METHODS: The controlled cortical impact (CCI) model was introduced to Wistar rats as a TBI model. Neurological deficits, oxidative stress and Cx40 were evaluated in TBI rats and N-acetylcysteine (NAC)-treated TBI rats. Neurological severity score (NSS) was used to assess neurological deficits. Brain infarction was measured by histo-staining. Brain edema was evaluated by measuring the brain water content. Cortex samples were collected to measure the tissue levels of malonyldialdehyde (MDA), nitric oxide (NO) and glutathione (GSH) and NADPH oxidase activity. Cx40 expression was determined by Western-blot.<br><br>RESULTS: TBI-induced brain injuries gradually increased from 6&#x200a;h to 24&#x200a;h post CCI, and the severity remained till 72&#x200a;h. The level of oxidative stress was consistent with the extent of neurological deficits. Cx40 was upregulated after TBI in a linear correlated manner with increased oxidative stress. With NAC intervention, both neurological deficits and oxidative stress were significantly attenuated. Meanwhile, elevated Cx40 expression in cortex was also prevented by NAC treatment.<br><br>CONCLUSION: These studies revealed the relationship between levels of Cx40 and oxidative stress after TBI. The cortex Cx40 expression was positively correlated with the cerebral oxidative stress, indicating the involvement of Cx40 in the progress of brain damage.}, }
@article {pmid28153047, year = {2017}, author = {Zhu, C and Yu, Y and Montani, JP and Ming, XF and Yang, Z}, title = {Arginase-I enhances vascular endothelial inflammation and senescence through eNOS-uncoupling.}, journal = {BMC research notes}, volume = {10}, number = {1}, pages = {82}, pmid = {28153047}, issn = {1756-0500}, mesh = {Acetylcysteine/pharmacology ; Adenoviridae/genetics ; Animals ; Arginase/genetics/*metabolism ; Cell Line, Tumor ; Cells, Cultured ; Cellular Senescence/genetics/*physiology ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Endothelium, Vascular/cytology/metabolism ; Free Radical Scavengers/pharmacology ; Genetic Vectors/genetics ; Human Umbilical Vein Endothelial Cells/drug effects/*metabolism ; Humans ; Immunoblotting ; Inflammation/genetics/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Mice ; Nitric Oxide Synthase Type III/*metabolism ; Transfection ; Tumor Suppressor Protein p53/metabolism ; Vascular Cell Adhesion Molecule-1/metabolism ; beta-Galactosidase/metabolism ; }, abstract = {BACKGROUND: Augmented arginase-II (Arg-II) is implicated in endothelial senescence and inflammation through a mutual positive regulatory circuit with S6K1. This study was conducted to investigate whether Arg-I, another isoform of arginase that has been also reported to play a role in vascular endothelial dysfunction, promotes endothelial senescence through similar mechanisms.<br><br>RESULTS: The non-senescent human endothelial cells from umbilical veins (passage 2 to 4) were transduced with empty recombinant adenovirus vector (rAd/CMV) as control or rAd/CMV-Arg-I to overexpress Arg-I. Overexpressing Arg-I promoted eNOS-uncoupling, enhanced senescence markers including p53-S15, p21 and senescence-associated &#x3b2;-galactosidase (SA-&#x3b2;-gal) staining, and increased inflammatory vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) as well as monocyte adhesion to endothelial cells without activating S6K1. All the effects of Arg-I were inhibited by the anti-oxidant N-acetylcysteine (NAC).<br><br>CONCLUSIONS: Our study demonstrates that Arg-I promotes endothelial senescence and inflammatory responses through eNOS-uncoupling unrelated to activation of the S6K1 pathway.}, }
@article {pmid28144054, year = {2017}, author = {Singh, S and Singh, N}, title = {Current trends of management of respiratory diseases by pulmonologists: Results of National Conference of Pulmonary Disease - 2015 survey.}, journal = {Lung India : official organ of Indian Chest Society}, volume = {34}, number = {1}, pages = {13-18}, pmid = {28144054}, issn = {0970-2113}, abstract = {CONTEXT: Respiratory diseases are a common problem in our country and these are associated with significant morbidity and mortality.<br><br>AIMS: The aim of the paper was to analyze the pattern of diagnostic tests used and treatment prescribed for common respiratory diseases.<br><br>SETTINGS AND DESIGN: A total of 1028 pulmonologists, either member of Indian Chest Society or delegate attending the National Conference of Pulmonary Diseases (NAPCON) 2015, participated in the online survey.<br><br>SUBJECTS AND METHODS: The survey included questions pertinent to common respiratory diseases such as pulmonary tuberculosis (PTB), bronchial asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pneumonia.<br><br>RESULTS: Investigation used for severity assessment and diagnosis of PTB, was sputum for acid-fast bacilli (83.5%), for IPF was high-resolution computed tomography chest (85.6%), for severe pneumonia was arterial blood gas analysis (69.3%), for asthma was spirometery and peak flow (96.8%) and for COPDs was spirometry (87.2%). The most popular choice of treatment for PTB was directly observed treatment short course (55.7%), for bronchial asthma, it was long-acting beta agonist with inhaled corticosteroids (LABA + ICSs) (41.1%), for COPD, it was LABA, ICS, and long-acting muscarinic antagonist (LABA + ICS + long-acting muscarinic antagonist) (32.4%) and for IPF, it was pirfenidone and N acetyl cysteine (38.3%). About 67.5% of doctors preferred hospitalization for patients with severe pneumonia. About 84.5% pulmonologists ordered diagnostic tests and 55.5% prescribed treatment as per current guidelines.<br><br>CONCLUSIONS: The majority of doctors (70.1%) in our survey followed recommended guidelines for respiratory disease diagnosis and treatment. However, there is a need for upgradation of treatment strategies currently used by doctors.}, }
@article {pmid28135835, year = {2017}, author = {Sarris, J}, title = {Clinical use of nutraceuticals in the adjunctive treatment of depression in mood disorders.}, journal = {Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists}, volume = {25}, number = {4}, pages = {369-372}, doi = {10.1177/1039856216689533}, pmid = {28135835}, issn = {1440-1665}, mesh = {*Bipolar Disorder/drug therapy ; *Depression/drug therapy ; *Depressive Disorder, Major/drug therapy ; *Dietary Supplements ; Eicosapentaenoic Acid/analogs &amp; derivatives ; Fatty Acids, Omega-3 ; Humans ; }, abstract = {OBJECTIVES: The aim of this paper is to detail a summary of the current evidence in this area, to better inform clinical practice. Our recent systematic reviews and meta-analyses of nutrient pharmacotherapies in the treatment unipolar depression revealed primarily positive results for replicated studies testing S-adenosyl methionine (SAMe), methylfolate, omega-3 (EPA or ethyl-EPA), and Vitamin D; with supportive isolated studies found for creatine and an amino acid combination. Mixed results were found for zinc, folic acid, Vitamin C, and tryptophan; and non-significant study results for inositol. In bipolar depression, omega-3 and N-acetyl cysteine (NAC) were found to have supportive evidence, with an isolated study using a chelated mineral formula also displaying efficacy. No major adverse effects were noted in the studies (aside from occasional minor digestive disturbances with omega-3 and NAC).<br><br>CONCLUSIONS: Several clinical considerations are needed when psychiatrists are considering prescribing nutrients, including knowledge of drug interactions, supplement safety and quality issues, individual psychological and biochemical individualities, in addition to cost factors.}, }
@article {pmid28130994, year = {2017}, author = {Tan, Y and Wang, Y and Li, M and Ye, X and Wu, T and Li, C}, title = {Enhanced photoelectrochemical immunosensing of cardiac troponin I based on energy transfer between N-acetyl-L-cysteine capped CdAgTe quantum dots and dodecahedral Au nanoparticles.}, journal = {Biosensors &amp; bioelectronics}, volume = {91}, number = {}, pages = {741-746}, doi = {10.1016/j.bios.2017.01.040}, pmid = {28130994}, issn = {1873-4235}, mesh = {Acetylcysteine/*chemistry ; Antibodies, Immobilized/*chemistry ; Biosensing Techniques/*methods ; Cadmium/chemistry ; Electrochemical Techniques/methods ; Energy Transfer ; Gold/*chemistry ; Humans ; Immunoassay/methods ; Light ; Limit of Detection ; Metal Nanoparticles/*chemistry/ultrastructure ; Quantum Dots/*chemistry/ultrastructure ; Reproducibility of Results ; Silver/chemistry ; Tellurium/chemistry ; Troponin I/*blood ; }, abstract = {An immunosensor was fabricated with an immobilized antibody for cardiac troponin I (anti-cTnI) on a photoresponsive composite material consisting of N-acetyl-L-cysteine capped CdAgTe quantum dots (NAC-CdAgTe QDs) and dodecahedral gold nanoparticles (AuNPs) stabilized by 1-(10-bromodecyl)-3-methylimidazolium bromide ionic liquid. Synthesized materials were characterized by TEM, SEM, UV-Vis, XRD, XPS, EIS, fluorescence, and photoelectrochemical method to confirm their morphology, elemental composition, and properties. The sensing element, anti-cTnI, was then covalently bound to the composite material coated on a glassy carbon electrode to complete the immunosensor, abbreviated as anti-cTnI(BSA)/NAC-CdAgTe QDs/AuNPs/GCE. Photocurrent was measured when the sensor was excited by a 405nm 100mW laser light. Optimal operating conditions, stability, reversibility, and reproducibility of the sensor have been studied. Performance of the aforementioned sensor was monitored with the photocurrent and the relative photocurrent variation, which is expressed as the changes in photocurrent upon the formation of antibody-antigen complex relative to the initial current measured in the unbound state of antibody. The experiment showed the relative photocurrent variation is directly proportional to the logarithm of cTnI concentration between 5.0pgmL[-1] and 20.0ngmL[-1] with a detection limit of 1.756pgmL[-1] (S/N=3). Performance of the immunosensor in common interferents and clinical human serum samples was investigated, showing comparable to ELISA with good selectivity, accuracy, and precision.}, }
@article {pmid28128878, year = {2017}, author = {Davis, BC and Tillman, H and Chung, RT and Stravitz, RT and Reddy, R and Fontana, RJ and McGuire, B and Davern, T and Lee, WM and , }, title = {Heat stroke leading to acute liver injury &amp; failure: A case series from the Acute Liver Failure Study Group.}, journal = {Liver international : official journal of the International Association for the Study of the Liver}, volume = {37}, number = {4}, pages = {509-513}, pmid = {28128878}, issn = {1478-3231}, support = {R01 DK058369/DK/NIDDK NIH HHS/United States ; U01 DK058369/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/etiology ; Adult ; Female ; Heat Stroke/*complications/*mortality ; Humans ; Liver/*physiopathology ; Liver Failure, Acute/etiology/*therapy ; Liver Transplantation ; Male ; Middle Aged ; Prospective Studies ; Registries ; Renal Replacement Therapy ; Rhabdomyolysis/etiology ; United States ; }, abstract = {BACKGROUND &amp; AIMS: In the United States, nearly 1000 annual cases of heat stroke are reported but the frequency and outcome of severe liver injury in such patients is not well described. The aim of this study was to describe cases of acute liver injury (ALI) or failure (ALF) caused by heat stroke in a large ALF registry.<br><br>METHODS: Amongst 2675 consecutive subjects enrolled in a prospective observational cohort of patients with ALI or ALF between January 1998 and April 2015, there were eight subjects with heat stroke.<br><br>RESULTS: Five patients had ALF and three had ALI. Seven patients developed acute kidney injury, all eight had lactic acidosis and rhabdomyolysis. Six patients underwent cooling treatments, three received N-acetyl cysteine (NAC), three required mechanical ventilation, three required renal replacement therapy, two received vasopressors, one underwent liver transplantation, and two patients died-both within 48&#xa0;hours of presentation. All cases occurred between May and August, mainly in healthy young men because of excessive exertion.<br><br>CONCLUSIONS: Management of ALI and ALF secondary to heat stroke should focus on cooling protocols and supportive care, with consideration of liver transplantation in refractory patients.}, }
@article {pmid28127704, year = {2017}, author = {Hu, DB and Li, ZS and Ali, I and Xu, LJ and Fang, NZ}, title = {Effect of potential role of p53 on embryo development arrest induced by H2O2 in mouse.}, journal = {In vitro cellular &amp; developmental biology. Animal}, volume = {53}, number = {4}, pages = {344-353}, pmid = {28127704}, issn = {1543-706X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzothiazoles/pharmacology ; Cell Cycle/genetics ; Cell Cycle Checkpoints/drug effects ; Embryo, Mammalian/cytology ; Embryonic Development/*drug effects ; Female ; Hydrogen Peroxide/*toxicity ; Intracellular Space/metabolism ; Male ; Mice ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Serine/metabolism ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/*metabolism ; Zygote/drug effects ; }, abstract = {During mammalian embryo development in vitro, mechanism of embryonic development arrest caused by oxidative stress has not been clear so far. The tumor suppressor protein p53 controls cell cycle and programmed cell death by regulating relevant signal pathway. Recent researches revealed that the concentration and distribution of p53 are closely related with reactive oxygen species (ROS). The main objective of this experiment was to explore the role of p53 on embryonic development arrest caused by oxidative stress. Results showed that embryo arrest at two-four-cell stage was significantly increased in the presence of 50 μM H2O2 (39.01 ± 2.74 vs. 77.20 ± 5.34%, p < 0.05). Supplementation of N-acetyl-L-cysteine (NAC) obviously reduced the ratio of development arrest (39.01 ± 2.74 vs. 71.18 ± 5.34%, p < 0.05), which was accompanied by an increase in ROS level, and H2O2 treatment sharply increased messenger RNA (mRNA) expression and protein levels of p53 and p53-ser15. Further increased transcription of GADD45a and p21, a downstream of p53, has an especially significant effect on the mRNA expression of GADD45a. However, expressions of cdc2 were reduced by H2O2. In addition, using Pifithrin-α (PFT-α), the suppresser of p53, the result showed that GADD45a and p21 were significantly downregulated, but the cell cycle gene cdc2 was significantly upregulated, while the protein level of p53 and p53-ser15 was significantly decreased. Taken together, these results demonstrate that ROS could activate p53 and regulate p53 target genes to influence early embryo development in in vitro culture.}, }
@article {pmid28124206, year = {2017}, author = {Xie, S and Tian, L and Niu, J and Liang, G and Liu, Y}, title = {Effect of N-acetyl cysteine and glycine supplementation on growth performance, glutathione synthesis, and antioxidative ability of grass carp, Ctenopharyngodon idella.}, journal = {Fish physiology and biochemistry}, volume = {43}, number = {4}, pages = {1011-1020}, pmid = {28124206}, issn = {1573-5168}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animal Feed/analysis ; Animal Nutritional Physiological Phenomena ; Animals ; Antioxidants/*metabolism ; Carps/*metabolism ; Diet/veterinary ; *Dietary Supplements ; Glutathione/*biosynthesis ; Glycine/administration &amp; dosage/*pharmacology ; }, abstract = {An 8-week feeding trial was conducted to evaluate the effect of N-acetyl cysteine (NAC) and glycine supplementation on growth performance, glutathione (GSH) synthesis, and antioxidative ability of grass carp, Ctenopharyngodon idella. Four practical diets were formulated: control, control + 0.2% NAC, control + 0.5% glycine, and control + 0.2% NAC + 0.5% glycine. Each diet was randomly assigned to quadruplicate groups of 30 fish (approximately 8.8 g). Weight gain and specific growth rate were significantly increased with the supplementation of NAC. Supplementation of NAC plus glycine significantly increased the feed efficiency. Glutathione peroxidase (GPx) and γ-glutamine cysteine synthase (γ-GCS) in plasma were significantly increased with the supplementation of NAC plus glycine. GSH in plasma increased and malondialdehyde (MDA) decreased in fish fed diets supplemented with NAC. Respiratory burst, superoxide dismutase (SOD), and catalase (CAT) activity were not affected by NAC or glycine. These results clearly indicated that NAC improved the growth performance and restored GSH of grass carp, supplemented NAC together with glycine enhanced GSH synthesis, and improved the antioxidative ability of grass carp.}, }
@article {pmid28123000, year = {2017}, author = {Bhushan, B and Chavan, H and Borude, P and Xie, Y and Du, K and McGill, MR and Lebofsky, M and Jaeschke, H and Krishnamurthy, P and Apte, U}, title = {Dual Role of Epidermal Growth Factor Receptor in Liver Injury and Regeneration after Acetaminophen Overdose in Mice.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {155}, number = {2}, pages = {363-378}, pmid = {28123000}, issn = {1096-0929}, support = {P20 GM103549/GM/NIGMS NIH HHS/United States ; R01 DK098414/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; T32 ES007079/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/metabolism/*toxicity ; Analgesics, Non-Narcotic/metabolism/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*enzymology ; Drug Overdose/*enzymology ; ErbB Receptors/antagonists &amp; inhibitors/*physiology ; Glutathione/metabolism ; Hepatocytes/*drug effects/enzymology ; Liver Failure, Acute/chemically induced/enzymology ; *Liver Regeneration ; Mice ; Mitochondria, Liver/drug effects/enzymology ; Oxidative Stress ; Protein Binding ; }, abstract = {Epidermal growth factor receptor (EGFR) plays a crucial role in hepatocyte proliferation. Its role in acetaminophen (APAP)-mediated hepatotoxicity and subsequent liver regeneration is completely unknown. Role of EGFR after APAP-overdose in mice was studied using pharmacological inhibition strategy. Rapid, sustained and dose-dependent activation of EGFR was noted after APAP-treatment in mice, which was triggered by glutathione depletion. EGFR-activation was also observed in primary human hepatocytes after APAP-treatment, preceding elevation of toxicity markers. Treatment of mice with an EGFR-inhibitor (EGFRi), Canertinib, 1h post-APAP resulted in robust inhibition of EGFR-activation and a striking reduction in APAP-induced liver injury. Metabolic activation of APAP, formation of APAP-protein adducts, APAP-mediated JNK-activation and its mitochondrial translocation were not altered by EGFRi. Interestingly, EGFR rapidly translocated to mitochondria after APAP-treatment. EGFRi-treatment abolished mitochondrial EGFR activity, prevented APAP-mediated mitochondrial dysfunction/oxidative-stress and release of endonucleases from mitochondria, which are responsible for DNA-damage/necrosis. Treatment with N-acetylcysteine (NAC), 4h post-APAP in mice did not show any protection but treatment of EGFRi in combination with NAC showed decrease in liver injury. Finally, delayed treatment with EGFRi, 12-h post-APAP, did not alter peak injury but caused impairment of liver regeneration resulting in sustained injury and decreased survival after APAP overdose in mice. Impairment of regeneration was due to inhibition of cyclinD1 induction and cell cycle arrest. Our study has revealed a new dual role of EGFR both in initiation of APAP-injury and in stimulation of subsequent compensatory regeneration after APAP-overdose.}, }
@article {pmid28118826, year = {2017}, author = {Cazzola, M and Calzetta, L and Facciolo, F and Rogliani, P and Matera, MG}, title = {Pharmacological investigation on the anti-oxidant and anti-inflammatory activity of N-acetylcysteine in an ex vivo model of COPD exacerbation.}, journal = {Respiratory research}, volume = {18}, number = {1}, pages = {26}, pmid = {28118826}, issn = {1465-993X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Airway Resistance/drug effects/immunology ; Anti-Inflammatory Agents/administration &amp; dosage ; Antioxidants/administration &amp; dosage ; Disease Progression ; Female ; Humans ; Lung/*drug effects/*physiopathology ; Male ; Organ Culture Techniques ; Oxidative Stress/drug effects/immunology ; Pulmonary Disease, Chronic Obstructive/*drug therapy/*physiopathology ; Reactive Oxygen Species/*immunology ; Treatment Outcome ; }, abstract = {BACKGROUND: Oxidative stress is recognized to be one of predisposing factor in the pathogenesis of COPD. The oxidant/antioxidant imbalance is significantly pronounced in patients with COPD exacerbation. N-acetylcysteine (NAC) seems to be able to reduce COPD exacerbations by modulating the oxidative stress in addition to its well-known mucolytic activity, but there are discordant findings on the actual anti-oxidant activity of NAC.<br><br>METHODS: The anti-oxidant effect of NAC and its impact on the inflammatory response have been pharmacologically characterized on a human ex vivo model of COPD exacerbation induced by lipopolysaccharide (LPS).<br><br>RESULTS: NAC prevented the desensitization induced by LPS incubation on the contractile tone in linear concentration-response manner. Concentrations of NAC &#x2265;1&#xa0;&#x3bc;M reduced the pro-oxidant response (peroxidase activity, hydrogen peroxide, malondialdehyde, nitric oxide), and improved the anti-oxidant response (total anti-oxidant capacity, glutathione, superoxide dismutase) induced by LPS. Lower concentrations of NAC (<1&#xa0;&#x3bc;M) did not modulate the bronchial oxidative imbalance. Concentrations of NAC &#x2265;300&#xa0;&#x3bc;M inhibited the inflammatory response (release of IL-1&#x3b2;, IL-8, and TNF-&#x3b1;) of human airways induced by the overnight stimulation with LPS, whereas lower concentrations of NAC (&#x2265;1&#xa0;&#x3bc;M) were sufficient to reduce the release of IL-6 elicited by LPS. Both the anti-oxidant effect and the anti-inflammatory effect of NAC were inversely correlated with the release of NKA.<br><br>CONCLUSIONS: The findings of this study suggest that NAC may have a role in modulating the detrimental effect induced by LPS in course of COPD exacerbation. It may elicit both anti-oxidant and anti-inflammatory effects when administered at high concentrations.}, }
@article {pmid28118671, year = {2017}, author = {Ahmadian, E and Babaei, H and Mohajjel Nayebi, A and Eftekhari, A and Eghbal, MA}, title = {Mechanistic Approach for Toxic Effects of Bupropion in Primary Rat Hepatocytes.}, journal = {Drug research}, volume = {67}, number = {4}, pages = {217-222}, doi = {10.1055/s-0042-123034}, pmid = {28118671}, issn = {2194-9387}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antidepressive Agents, Second-Generation/*adverse effects ; Antioxidants/pharmacology ; Bupropion/*toxicity ; Cell Death/drug effects ; Cell Survival/drug effects ; Cyclosporine/pharmacology ; Glutathione/metabolism ; Hepatocytes/*drug effects ; Lipid Peroxidation/*drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Oxidative Stress/drug effects ; Primary Cell Culture ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; alpha-Tocopherol/pharmacology ; }, abstract = {Bupropion is a widely prescribed antidepressant/smoke cessation drug. However, hepatotoxicity is one of its side effects reported in some recipients. The mechanisms by which bupropion induces hepatotoxicity is not clear yet. This experiment was intended to assess the cytotoxic mechanisms of bupropion toward primary rat hepatocytes. Additionally, the effect of α-tocopherol succinate (ALPHA-TOS) and N-acetyl cysteine (NAC) and mitochondrial permeability transition (MPT) pore sealing agent cyclosporine A (Cs A) on this toxicity was investigated. Cell death, LDH leakage, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), and mitochondrial depolarization were examined as toxicity indicators. Results revealed that bupropion led to a surge in ROS formation, depletion of intracellular glutathione, elevation of LPO, and mitochondrial collapse. ALPHA-TOS, NAC and Cs A administration diminished the intensity of cellular damage caused by bupropion. This experiment suggests the protective role of ALPHA-TOS, NAC and Cs A against bupropion-mediated cytotoxicity possibly through their reactive radical scavenging properties and their impacts on mitochondria. Furthermore, mitochondria might be contributed to the oxidative stress response and subsequent toxicological results observed by bupropion.}, }
@article {pmid28116600, year = {2017}, author = {Thatai, P and Sapra, B}, title = {Transungual Gel of Terbinafine Hydrochloride for the Management of Onychomycosis: Formulation, Optimization, and Evaluation.}, journal = {AAPS PharmSciTech}, volume = {18}, number = {6}, pages = {2316-2328}, doi = {10.1208/s12249-017-0711-7}, pmid = {28116600}, issn = {1530-9932}, mesh = {Animals ; Chemistry, Pharmaceutical/methods ; *Drug Delivery Systems ; Emulsions ; Naphthalenes/*administration &amp; dosage ; Onychomycosis/*drug therapy ; Particle Size ; Solubility ; Terbinafine ; }, abstract = {The present study was aimed to optimize, develop, and evaluate microemulsion and microemulsion-based gel as a vehicle for transungual drug delivery of terbinafine hydrochloride for the treatment of onychomycosis. D-optimal mixture experimental design was adopted to optimize the composition of microemulsion having amount of oil (X 1), Smix (mixture of surfactant and cosurfactant; X 2), and water (X 3) as the independent variables. The formulations were assessed for permeation (micrograms per square centimeter per hour; Y 1), particle size (nanometer; Y 2), and solubility of the drug in the formulation (milligrams per milliliter; Y 3). The microemulsion containing 3.05% oil, 24.98% Smix, and 71.96% water was selected as the optimized formulation. The microemulsion-based gel showed better penetration (∼5 folds) as well as more retention (∼9 fold) in the animal hoof as compared to the commercial cream. The techniques used to screen penetration enhancers (hydration enhancement factor, ATR-FTIR, SEM, and DSC) revealed the synergistic effect of combination of urea and n-acetyl cysteine in disruption of the structure of hoof and hence, leading to enhanced penetration of drug.}, }
@article {pmid28116245, year = {2017}, author = {Sato, Y and Ishihara, N and Nagayama, D and Saiki, A and Tatsuno, I}, title = {7-ketocholesterol induces apoptosis of MC3T3-E1 cells associated with reactive oxygen species generation, endoplasmic reticulum stress and caspase-3/7 dependent pathway.}, journal = {Molecular genetics and metabolism reports}, volume = {10}, number = {}, pages = {56-60}, pmid = {28116245}, issn = {2214-4269}, abstract = {Type 2 diabetes mellitus (T2DM) is associated with an increased risk of bone fractures without reduction of bone mineral density. The cholesterol oxide 7-ketocholesterol (7KCHO) has been implicated in numerous diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, cancer, age-related macular degeneration and T2DM. In the present study, 7KCHO decreased the viability of MC3T3-E1 cells, increased reactive oxygen species (ROS) production and apoptotic rate, and upregulated the caspase-3/7 pathway. Furthermore, these effects of 7KCHO were abolished by pre-incubation of the cells with N-acetylcysteine (NAC), an ROS inhibitor. Also, 7KCHO enhanced the mRNA expression of two endoplasmic reticulum (ER) stress markers; CHOP and GRP78, in MC3T3-E1 cells. Pre-incubation of the cells with NAC suppressed the 7KCHO-induced upregulation of CHOP, but not GRP78. In conclusion, we demonstrated that 7KCHO induced apoptosis of MC3T3-E1 cells associated with ROS generation, ER stress, and caspase-3/7 activity, and the effects of 7KCHO were abolished by the ROS inhibitor NAC. These findings may provide new insight into the relationship between oxysterol and pathophysiology of osteoporosis seen in T2DM.}, }
@article {pmid28115274, year = {2017}, author = {Feio-Azevedo, R and Costa, VM and Ferreira, LM and Branco, PS and Pereira, FC and Bastos, ML and Carvalho, F and Capela, JP}, title = {Toxicity of the amphetamine metabolites 4-hydroxyamphetamine and 4-hydroxynorephedrine in human dopaminergic differentiated SH-SY5Y cells.}, journal = {Toxicology letters}, volume = {269}, number = {}, pages = {65-76}, doi = {10.1016/j.toxlet.2017.01.012}, pmid = {28115274}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Amphetamine/chemistry/*toxicity ; Apoptosis/drug effects ; Carnitine/pharmacology ; Cell Differentiation/*drug effects ; Cell Line ; Cell Survival/drug effects ; Cycloheximide/pharmacology ; Dopaminergic Neurons/cytology/*drug effects ; Dose-Response Relationship, Drug ; Humans ; Lethal Dose 50 ; Methylphenidate/pharmacology ; Reactive Oxygen Species/chemistry ; p-Hydroxyamphetamine/chemistry/*toxicity ; p-Hydroxynorephedrine/chemistry/*toxicity ; }, abstract = {Amphetamine (AMPH) is a psychostimulant used worldwide by millions of patients in the clinical treatment of attention deficit hyperactivity disorder, narcolepsy or even obesity, and is also a drug of abuse. 4-Hydroxynorephedrine (4-OHNE) and 4-hydroxyamphetamine (4-OHAMPH) are two major metabolites known to persist in the brain longer than AMPH. The contribution of AMPH metabolites for its neurotoxicity is undetermined. We evaluated the toxicity of AMPH and its metabolites 4-OHNE and 4-OHAMPH, obtained by chemical synthesis, in human dopaminergic differentiated SH-SY5Y neurons. Cells were exposed to AMPH (concentration range 0-5mM) or 4-OHAMPH or 4-OHNE (concentration range 0-10mM) for 24 or 48h, and the viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) leakage assays. Results showed that for both AMPH and the metabolites a concentration-dependent toxicity was observed. The toxic concentration 50% (TC50) for AMPH and 4-OHNE following 24h exposure was circa 3.5mM and 8mM, respectively. For 4-OHAMPH the TC50 was not reached in the tested concentration range. N-acetyl cysteine, cycloheximide, l-carnitine, and methylphenidate were able to reduce cell death induced by AMPH TC50. Acridine orange/ethidium bromide staining showed evident signs of late apoptotic cells and necrotic cells following 24h exposure to AMPH 3.50mM. The 4-OHAMPH metabolite at 8.00mM originated few late apoptotic cells, whereas 4-OHNE at 8.00mM resulted in late apoptotic cells and necrotic cells, in a scenario similar to AMPH. In conclusion, the AMPH metabolite 4-OHNE is more toxic than 4-OHAMPH, nonetheless both are less toxic than the parent compound in vitro. The most toxic metabolite 4-OHNE has longer permanence in the brain, rendering likely its contribution for AMPH neurotoxicity.}, }
@article {pmid28115242, year = {2017}, author = {Jeong, CH and Seok, JS and Petriello, MC and Han, SG}, title = {Arsenic downregulates tight junction claudin proteins through p38 and NF-κB in intestinal epithelial cell line, HT-29.}, journal = {Toxicology}, volume = {379}, number = {}, pages = {31-39}, doi = {10.1016/j.tox.2017.01.011}, pmid = {28115242}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Arsenic/*toxicity ; Claudins/*genetics ; Down-Regulation ; Glutathione/metabolism ; HT29 Cells ; Humans ; Intestinal Mucosa/*drug effects/metabolism ; NF-kappa B/*physiology ; Oxidative Stress/drug effects ; Tight Junctions/drug effects ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*physiology ; }, abstract = {Arsenic is a naturally occurring metalloid that often is found in foods and drinking water. Human exposure to arsenic is associated with the development of gastrointestinal problems such as fluid loss, diarrhea and gastritis. Arsenic is also known to induce toxic responses including oxidative stress in cells of the gastrointestinal track. Tight junctions (TJs) regulate paracellular permeability and play a barrier role by inhibiting the movement of water, solutes and microorganisms in the paracellular space. Since oxidative stress and TJ damage are known to be associated, we examined whether arsenic produces TJ damage such as downregulation of claudins in the human colorectal cell line, HT-29. To confirm the importance of oxidative stress in arsenic-induced TJ damage, effects of the antioxidant compound (e.g., N-acetylcysteine (NAC)) were also determined in cells. HT-29 cells were treated with arsenic trioxide (40μM, 12h) to observe the modified expression of TJ proteins. Arsenic decreased expression of TJ proteins (i.e., claudin-1 and claudin-5) and transepithelial electrical resistance (TEER) whereas pretreatment of NAC (5-10mM, 1h) attenuated the observed claudins downregulation and TEER. Arsenic treatment produced cellular oxidative stress via superoxide generation and lowering glutathione (GSH) levels, while NAC restored cellular GSH levels and decreased oxidative stress. Arsenic increased phosphorylation of p38 and nuclear translocation of nuclear factor-kappa B (NF-κB) p65, while NAC attenuated these intracellular events. Results demonstrated that arsenic can damage intestinal epithelial cells by proinflammatory process (oxidative stress, p38 and NF-κB) which resulted in the downregulation of claudins and NAC can protect intestinal TJs from arsenic toxicity.}, }
@article {pmid28109565, year = {2017}, author = {Fowdar, K and Chen, H and He, Z and Zhang, J and Zhong, X and Zhang, J and Li, M and Bai, J}, title = {The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: A meta-analysis and systematic review.}, journal = {Heart &amp; lung : the journal of critical care}, volume = {46}, number = {2}, pages = {120-128}, doi = {10.1016/j.hrtlng.2016.12.004}, pmid = {28109565}, issn = {1527-3288}, mesh = {Acetylcysteine/*therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Forced Expiratory Volume/drug effects ; Free Radical Scavengers/therapeutic use ; Humans ; Inspiratory Capacity/drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology ; }, abstract = {N-acetylcysteine (NAC) is an antioxidant and anti-inflammatory. Its effects on chronic obstructive pulmonary (COPD) outcomes, including exacerbation of and changes in lung function parameters, are controversial. To investigate the effects of NAC on COPD exacerbation and changes in lung function parameters in patients with COPD. A meta-analysis of randomized controlled trials retrieved from PubMed and Medline databases (12 trials; 2691 patients). High-dose [relative ratio (RR) = 0.90, 95% confidence interval (CI) = 0.82-0.996, P = 0.041] and low-dose (RR = 0.83, 95% CI = 0.69-0.99, P = 0.043) NAC reduced COPD exacerbation prevalence. Long-term (≥6 months), but not short-term, NAC reduced exacerbation prevalence (RR = 0.85, 95% CI = 0.74-0.98, P = 0.024). NAC did not affect exacerbation rate, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), or inspiratory capacity (IC). Long-term NAC therapy may reduce risk of COPD exacerbation.}, }
@article {pmid28106298, year = {2017}, author = {Singh, A and Chagtoo, M and Tiwari, S and George, N and Chakravarti, B and Khan, S and Lakshmi, S and Godbole, MM}, title = {Inhibition of Inositol 1, 4, 5-Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics.}, journal = {Journal of cellular biochemistry}, volume = {118}, number = {8}, pages = {2333-2346}, doi = {10.1002/jcb.25891}, pmid = {28106298}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Autophagy/drug effects/genetics ; Autophagy-Related Protein 5/antagonists &amp; inhibitors/genetics/metabolism ; Blotting, Western ; Breast Neoplasms/*metabolism ; Cell Death/drug effects/genetics ; Cell Line, Tumor ; Energy Metabolism/drug effects/genetics ; Fluorescent Antibody Technique ; Humans ; Inositol 1,4,5-Trisphosphate Receptors/antagonists &amp; inhibitors/*metabolism ; MCF-7 Cells ; Macrolides/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Microtubule-Associated Proteins/genetics/metabolism ; RNA, Small Interfering/genetics/pharmacology ; }, abstract = {Inositol 1,4,5-trisphosphate receptors (IP3 Rs) regulate autophagy in normal cells and are associated with metastasis in cancer cells. In breast cancer, however, the regulation and role of IP3 Rs is not clear. To study this, we used MCF-7 breast cancer cell line and mouse model of breast cancer. Inhibiting IP3 R sub types resulted in compromised bioenergetics both in terms of glucose and mitochondrial metabolism. The siRNA mediated silencing of IP3 R or its blocking by its inhibitors Xestospongin C and 2-Amino-ethoxy diphenyl borate increased cell death and LC3II expression in MCF-7 cells as well as attenuated cellular bioenergetics. The level of Autophagy related gene, Atg5 was found to be up regulated after pharmacological as well as siRNA blocking of IP3 R. The specificity of its role in autophagy was confirmed through specific shRNA knockdown of the Atg5 along with IP3 R inhibitor. Inhibiting as well as silencing of IP3 R receptor also resulted in increase in ROS production which was abolished after pretreatment with N-acetyl cysteine. Its role in autophagy was confirmed through decrease in the levels of LC3 II after pretreatment with IP3 R inhibitor and N acetyl cysteine.Moreover, inhibiting as well as silencing IP3 R-induced cell death in MCF-7 cells was attenuated by autophagic inhibitors (Bafilomycin A1 or 3-Methyladeneine). In mice, blocking of IP3 Rs by 2-Amino-ethoxy diphenyl borate arrested tumor growth. Overall our findings indicate that IP3 R blocking resulted in autophagic cell death in breast cancer cells and provides a role of IP3 Rs in determining the breast cancer cell fate. J. Cell. Biochem. 118: 2333-2346, 2017. © 2017 Wiley Periodicals, Inc.}, }
@article {pmid28105252, year = {2016}, author = {Gong, X and Duan, Y and Zheng, J and Wang, Y and Wang, G and Norgren, S and Hei, TK}, title = {Nephroprotective Effects of N-Acetylcysteine Amide against Contrast-Induced Nephropathy through Upregulating Thioredoxin-1, Inhibiting ASK1/p38MAPK Pathway, and Suppressing Oxidative Stress and Apoptosis in Rats.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {8715185}, pmid = {28105252}, issn = {1942-0994}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Acute Kidney Injury/etiology/metabolism/*pathology ; Animals ; Apoptosis/*drug effects ; Contrast Media/toxicity ; Kidney/pathology/ultrastructure ; MAP Kinase Kinase Kinase 5/metabolism ; Male ; Microscopy, Electron, Transmission ; Oxidative Stress/*drug effects ; Phosphorylation/drug effects ; Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Superoxide Dismutase/genetics/metabolism ; Thioredoxins/genetics/metabolism ; Up-Regulation/*drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI) due to apoptosis induced in renal tubular cells. Our previous study demonstrated the novel N-acetylcysteine amide (NACA); the amide form of N-acetyl cysteine (NAC) prevented renal tubular cells from contrast-induced apoptosis through inhibiting p38 MAPK pathway in vitro. In the present study, we aimed to compare the efficacies of NACA and NAC in preventing CIN in a well-established rat model and investigate whether thioredoxin-1 (Trx1) and apoptosis signal-regulating kinase 1 (ASK1) act as the potential activator for p38 MAPK. NACA significantly attenuated elevations of serum creatinine, blood urea nitrogen, and biomarkers of AKI. At equimolar concentration, NACA was more effective than NAC in reducing histological changes of renal tubular injuries. NACA attenuated activation of p38 MAPK signal, reduced oxidative stress, and diminished apoptosis. Furthermore, we demonstrated that contrast exposure resulted in Trx1 downregulation and increased ASK1/p38 MAPK phosphorylation, which could be reversed by NACA and NAC. To our knowledge, this is the first report that Trx1 and ASK1 are involved in CIN. Our study highlights a renal protective role of NACA against CIN through modulating Trx1 and ASK1/p38 MAPK pathway to result in the inhibition of apoptosis among renal cells.}, }
@article {pmid28104914, year = {2017}, author = {Shin, SK and Kim, JH and Lee, JH and Son, YH and Lee, MW and Kim, HJ and Noh, SA and Kim, KP and Kim, IG and Lee, MJ}, title = {Docosahexaenoic acid-mediated protein aggregates may reduce proteasome activity and delay myotube degradation during muscle atrophy in vitro.}, journal = {Experimental &amp; molecular medicine}, volume = {49}, number = {1}, pages = {e287}, pmid = {28104914}, issn = {2092-6413}, mesh = {Animals ; Antioxidants/metabolism ; Cell Line ; Cell Survival ; Docosahexaenoic Acids/*pharmacology ; Humans ; Muscle Fibers, Skeletal/*metabolism ; Muscle Proteins/metabolism ; Muscular Atrophy/drug therapy/*metabolism/pathology ; Proteasome Endopeptidase Complex/*metabolism ; Protein Aggregates/*drug effects ; Protein Aggregation, Pathological/metabolism ; Proteolysis/drug effects ; Proto-Oncogene Protein c-fli-1/metabolism ; Reactive Oxygen Species/metabolism ; Recombinant Proteins ; Ubiquitin/metabolism ; Ubiquitination ; tau Proteins/metabolism ; }, abstract = {Proteasomes are the primary degradation machinery for oxidatively damaged proteins that compose a class of misfolded protein substrates. Cellular levels of reactive oxygen species increase with age and this cellular propensity is particularly harmful when combined with the age-associated development of various human disorders including cancer, neurodegenerative disease and muscle atrophy. Proteasome activity is reportedly downregulated in these disease conditions. Herein, we report that docosahexaenoic acid (DHA), a major dietary omega-3 polyunsaturated fatty acid, mediates intermolecular protein cross-linkages through oxidation, and the resulting protein aggregates potently reduce proteasomal activity both in vitro and in cultured cells. Cellular models overexpressing aggregation-prone proteins such as tau showed significantly elevated levels of tau aggregates and total ubiquitin conjugates in the presence of DHA, thereby reflecting suppressed proteasome activity. Strong synergetic cytotoxicity was observed when the cells overexpressing tau were simultaneously treated with DHA. Antioxidant N-acetyl cysteine significantly desensitized the cells to DHA-induced oxidative stress. DHA significantly delayed the proteasomal degradation of muscle proteins in a cellular atrophy model. Thus, the results of our study identified DHA as a potent inducer of cellular protein aggregates that inhibit proteasome activity and potentially delay systemic muscle protein degradation in certain pathologic conditions.}, }
@article {pmid28103509, year = {2017}, author = {Singh, MP and Han, J and Kang, SC}, title = {3',5-dihydroxy-3,4',7-trimethoxyflavone-induces ER-stress-associated HCT-116 programmed cell death via redox signaling.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {88}, number = {}, pages = {151-161}, doi = {10.1016/j.biopha.2017.01.027}, pmid = {28103509}, issn = {1950-6007}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Calcium/metabolism ; Cell Nucleus/drug effects/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Damage ; Endoplasmic Reticulum Stress/*drug effects ; Flavones/chemistry/*pharmacology ; HCT116 Cells ; Humans ; Intracellular Space/metabolism ; MAP Kinase Signaling System/drug effects ; Mitochondria/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Quercetin/*analogs &amp; derivatives/chemistry/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {Quercetin, a well cognized bioactive flavone possessing great medicinal value, has limited usage. The rapid gastrointestinal digestion of quercetin is also a major obstacle for its clinical implementation due to low bioavailability and poor aqueous solubility. 3',5-dihydroxy-3,4',7-trimethoxyflavone (DTMF), a novel semi-synthetic derivative of quercetin, is known to modulate several biological activities. Therefore, in the present study we examined the cytotoxic mechanism of DTMF in concentration-dependent manner (25, 50, and 100μM; 24h) against HCT-116 human colon carcinoma cells. The cytotoxic potential of DTMF was characterized based on deformed cell morphology, increased ROS accumulation, loss of mitochondrial membrane potential (ΔѰm), increased mitochondrial mass, chromatin condensation, and typical DNA-fragmentation in HCT-116 cells. The results showed that DTMF-induced enhanced ROS production at higher concentration (100μM) as evidenced by upregulated expression of ER stress and apoptotic proteins with concomitant increase in PERK, CHOP, and JNK levels, when compared to N-acetyl cysteine (NAC, ROS inhibitor) treated HCT-116 cells, which depicts that DTMF might act as a crucial mediator of apoptosis signaling. Collectively, our results suggest that DTMF stimulates ROS-mediated oxidative stress, which in turn induces PERK-CHOP and JNK pathway of apoptosis to promote HCT-116 cell death.}, }
@article {pmid28102849, year = {2017}, author = {Kou, JY and Li, Y and Zhong, ZY and Jiang, YQ and Li, XS and Han, XB and Liu, ZN and Tian, Y and Yang, LM}, title = {Berberine-sonodynamic therapy induces autophagy and lipid unloading in macrophage.}, journal = {Cell death &amp; disease}, volume = {8}, number = {1}, pages = {e2558}, pmid = {28102849}, issn = {2041-4889}, mesh = {Atherosclerosis/*drug therapy/genetics/pathology ; Autophagy/*drug effects/genetics ; Berberine/administration &amp; dosage ; Cell Survival/drug effects ; Cholesterol/genetics/*metabolism ; Chromones/administration &amp; dosage ; Humans ; Lipids/biosynthesis ; Macrophages/drug effects/metabolism ; Morpholines/administration &amp; dosage ; Oncogene Protein v-akt ; Phosphatidylinositol 3-Kinases/genetics ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/genetics ; Ultrasonography ; }, abstract = {Impaired autophagy in macrophages accompanies the progression of atherosclerosis and contributes to lipid loading in plaques and ineffective lipid degradation. Therefore, evoking autophagy and its associated cholesterol efflux may provide a therapeutic treatment for atherosclerosis. In the present study, berberine-mediated sonodynamic therapy (BBR-SDT) was used to induce autophagy and cholesterol efflux in THP-1 macrophages and derived foam cells. Following BBR-SDT, autophagy was increased in the macrophages, autophagy resistance in the foam cells was prevented, and cholesterol efflux was induced. The first two effects were blocked by the reactive oxygen species scavenger, N-acetyl cysteine. BBR-SDT also reduced the phosphorylation of Akt and mTOR, two key molecules in the PI3K/AKT/mTOR signaling pathway, which is responsible for inducing autophagy. Correspondingly, treatment with the autophagy inhibitor, 3-methyladenine, or the PI3K inhibitor, LY294002, abolished the autophagy-induced effects of BBR-SDT. Furthermore, induction of cholesterol efflux by BBR-SDT was reversed by an inhibition of autophagy by 3-methyladenine or by a small interfering RNA targeting Atg5. Taken together, these results demonstrate that BBR-SDT effectively promotes cholesterol efflux by increasing reactive oxygen species generation, and this subsequently induces autophagy via the PI3K/AKT/mTOR signaling pathway in both 'normal' macrophages and lipid-loaded macrophages (foam cells). Thus, BBR-SDT may be a promising atheroprotective therapy to inhibit the progression of atherosclerosis and should be further studied.}, }
@article {pmid28102488, year = {2017}, author = {Rhodes, K and Braakhuis, A}, title = {Performance and Side Effects of Supplementation with N-Acetylcysteine: A Systematic Review and Meta-Analysis.}, journal = {Sports medicine (Auckland, N.Z.)}, volume = {47}, number = {8}, pages = {1619-1636}, pmid = {28102488}, issn = {1179-2035}, mesh = {Acetylcysteine/administration &amp; dosage/*adverse effects ; Administration, Oral ; Antioxidants ; Athletic Performance/*physiology ; Dietary Supplements/*adverse effects ; Dose-Response Relationship, Drug ; Exercise/*physiology ; Humans ; Performance-Enhancing Substances ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) is a promising antioxidant supplement with potential as an acute strategy to enhance performance in elite sport, but there are concerns about its side effects with high doses.<br><br>OBJECTIVE: To review the current literature and evaluate the effects of NAC supplementation on sport performance and the risk of adverse effects.<br><br>METHODS: The literature up to May 2016 was searched on MEDLINE (PubMed), EMBASE, SPORTDiscus, Google Scholar and Scopus databases to identify all studies investigating the effects of NAC supplementation on exercise performance and/or side effects experienced. Performance outcomes from each study were converted to the percent effect equivalent to mean power output in a time trial. All pooled analyses were based on random-effects models generated by Review Manager (RevMan) [Computer program], version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, 2014).<br><br>RESULTS: A total of seven studies met criteria for inclusion in the sport performance meta-analysis, and 17 for inclusion in the side effects meta-analysis. The typical daily dose of NAC reported was 5.8&#xa0;g&#xb7;d[-1]; with a range between 1.2 and 20.0&#xa0;g&#xb7;d[-1]. The mean increase in performance was 0.29% (95% confidence interval -0.67 to 1.25). The difference in the odds ratio of side effects on NAC compared with placebo was 1.11 (95% confidence interval 0.88-1.39). The sub-analysis of NAC dose suggested an increase in side effects as the dosage of NAC increased; however, this observation requires further investigation.<br><br>CONCLUSIONS: Despite initial research publications reporting positive performance effects with NAC, at this stage it cannot be recommended further. The risk of side effects from NAC supplementation also remains unclear owing to significant variations in effects. Suboptimal reporting and documentation in the literature creates difficulties when meta-analysing outcomes and generating conclusions.}, }
@article {pmid28101470, year = {2016}, author = {Khalili Fard, J and Hamzeiy, H and Sattari, M and Eghbal, MA}, title = {Protective Roles of N-acetyl Cysteine and/or Taurine against Sumatriptan-Induced Hepatotoxicity.}, journal = {Advanced pharmaceutical bulletin}, volume = {6}, number = {4}, pages = {627-637}, pmid = {28101470}, issn = {2228-5881}, abstract = {Purpose: Triptans are the drug category mostly prescribed for abortive treatment of migraine. Most recent cases of liver toxicity induced by triptans have been described, but the mechanisms of liver toxicity of these medications have not been clear. Methods: In the present study, we obtained LC50 using dose-response curve and investigated cell viability, free radical generation, lipid peroxide production, mitochondrial injury, lysosomal membrane damage and the cellular glutathione level as toxicity markers as well as the beneficial effects of taurine and/or N-acetyl cysteine in the sumatriptan-treated rat parenchymal hepatocytes using accelerated method of cytotoxicity mechanism screening. Results: It was revealed that liver toxicity induced by sumatriptan in in freshly isolated parenchymal hepatocytes is dose-dependent. Sumatriptan caused significant free radical generation followed by lipid peroxide formation, mitochondrial injury as well as lysosomal damage. Moreover, sumatriptan reduced cellular glutathione content. Taurine and N-acetyl cysteine were able to protect hepatocytes against sumatriptan-induced harmful effects. Conclusion: It is concluded that sumatriptan causes oxidative stress in hepatocytes and the decreased hepatocytes glutathione has a key role in the sumatriptan-induced harmful effects. Also, N-acetyl cysteine and/or taurine could be used as treatments in sumatriptan-induced side effects.}, }
@article {pmid28101459, year = {2016}, author = {Ahmadian, E and Babaei, H and Mohajjel Nayebi, A and Eftekhari, A and Eghbal, MA}, title = {Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction.}, journal = {Advanced pharmaceutical bulletin}, volume = {6}, number = {4}, pages = {521-530}, pmid = {28101459}, issn = {2228-5881}, abstract = {Purpose: Depression is a public disorder worldwide. Despite the widespread use of venlafaxine in the treatment of depression, it has been associated with the incidence of toxicities. Hence, the goal of the current investigation was to evaluate the mechanisms of venlafaxine-induced cell death in the model of the freshly isolated rat hepatocytes. Methods: Collagenase-perfused rat hepatocytes were treated with venlafaxine and other agents. Cell damage, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential decline, lysosomal damage, glutathione (GSH) level were analyzed. Moreover, rat liver mitochondria were isolated through differential centrifugation to assess respiratory chain functionality. Results: Our results demonstrated that venlafaxine could induce ROS formation followed by lipid peroxidation, cellular GSH content depletion, elevated GSSG level, loss of lysosmal membrane integrity, MMP collapse and finally cell death in a concentration-dependent manner. N-acetyl cysteine, taurine and quercetine significantly decreased the aforementioned venlafaxine-induced cellular events. Also, radical scavenger (butylatedhydroxytoluene and α-tocopherol), CYP2E1 inhibitor (4-methylpyrazole), lysosomotropic agents (methylamine and chloroquine), ATP generators (L-gluthamine and fructose) and mitochondrial pore sealing agents (trifluoperazine and L-carnitine) considerably reduced cytotoxicity, ROS generation and lysosomal leakage following venlafaxine treatment. Mitochondrion dysfunction was concomitant with the blockade of the electron transfer complexes II and IV of the mitochondrial respiratory system. Conclusion: Therefore, our data indicate that venlafaxine induces oxidative stress towards hepatocytes and our findings provide evidence to propose that mitochondria and lysosomes are of the primary targets in venlafaxine-mediated cell damage.}, }
@article {pmid28100069, year = {2017}, author = {Kondakçı, G and Aydın, AF and Doğru-Abbasoğlu, S and Uysal, M}, title = {The effect of N-acetylcysteine supplementation on serum homocysteine levels and hepatic and renal oxidative stress in homocysteine thiolactone-treated rats.}, journal = {Archives of physiology and biochemistry}, volume = {123}, number = {2}, pages = {128-133}, doi = {10.1080/13813455.2016.1273365}, pmid = {28100069}, issn = {1744-4160}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; *Dietary Supplements ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Homocysteine/*analogs &amp; derivatives/*blood/pharmacology ; Kidney/drug effects/metabolism/*pathology ; Kidney Function Tests ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism/*pathology ; Liver Function Tests ; Male ; Malondialdehyde/metabolism ; Oxidants/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Radiation-Protective Agents/pharmacology ; Rats ; Rats, Wistar ; }, abstract = {The effect of N-acetylcysteine (NAC) (1 g/kg body weight/day) on serum homocysteine (Hcy) levels, insulin resistance (IR), and hepatic and renal prooxidant-antioxidant balance was evaluated in rats treated with homocysteine thiolactone (HcyT) (500 mg/kg body weight/day for 6 weeks). Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione, ferric reducing antioxidant power, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were determined in the liver and kidney. HcyT elevated serum Hcy levels and caused IR, but liver and kidney function tests remained unchanged. HcyT increased ROS and MDA without any change in hepatic antioxidants, but it elevated renal SOD and GSH-Px activities. NAC decreased serum Hcy, hepatic and renal ROS and MDA levels, and renal SOD and GSH-Px activities in rats with high Hcy levels. However, it did not ameliorate IR. Our results indicate that NAC supplementation may be effective in decreasing Hcy levels and Hcy-induced hepatic and renal oxidative stress.}, }
@article {pmid28097492, year = {2017}, author = {Nazıroğlu, M}, title = {Activation of TRPM2 and TRPV1 Channels in Dorsal Root Ganglion by NADPH Oxidase and Protein Kinase C Molecular Pathways: a Patch Clamp Study.}, journal = {Journal of molecular neuroscience : MN}, volume = {61}, number = {3}, pages = {425-435}, pmid = {28097492}, issn = {1559-1166}, mesh = {Acetophenones/pharmacology ; *Action Potentials ; Animals ; Calcium Signaling ; Capsaicin/analogs &amp; derivatives/pharmacology ; Cells, Cultured ; Cinnamates/pharmacology ; Ganglia, Spinal/*cytology/metabolism ; Indoles/pharmacology ; Male ; Maleimides/pharmacology ; NADPH Oxidases/*antagonists &amp; inhibitors/metabolism ; Neurons/drug effects/*metabolism/physiology ; Oxidative Stress ; Protein Kinase C/antagonists &amp; inhibitors/*metabolism ; Rats ; Rats, Wistar ; TRPM Cation Channels/antagonists &amp; inhibitors/genetics/*metabolism ; TRPV Cation Channels/antagonists &amp; inhibitors/genetics/*metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; ortho-Aminobenzoates/pharmacology ; }, abstract = {Despite considerable research, the mechanisms of neuropathic pain induced by excessive oxidative stress production and overload calcium ion (Ca[2+]) entry in dorsal root ganglion (DRG) remain substantially unidentified. The transient receptor potential melastatin 2 (TRPM2) and vanilloid 1 (TRPV1) channels are activated with different stimuli including oxidative stress. TRPM2 and TRPV1 have been shown to be involved in induction of neuropathic pain. However, the activation mechanisms of TRPM2 and TRPV1 via NADPH oxidase and protein kinase C (PKC) pathways are poorly understood. In this study, I investigated the roles of NADPH oxidase and PKC on Ca[2+] entry through TRPM2 and TRPV1 channels in in vitro DRG neurons of rats. Rat DRG neurons were used in whole-cell patch clamp experiments. The H2O2-induced TRPM2 current densities were decreased by N-(p-amylcinnamoyl)anthranilic acid (ACA), and dose-dependent capsaicin (CAP) and H2O2-induced TRPV1 currents were inhibited by capsazepine (CPZ). The TRPV1 channel is activated in the DRG neurons by 0.01 mM capsaicin but not 0.001 mM or 0.05 mM capsaicin. TRPM2 and TRPV1 currents were increased by the PKC activator, phorbol myristate acetate (PMA), although the currents were decreased by ACA, CPZ, and the PKC inhibitor, bisindolylmaleimide I (BIM). Both channel currents were further increased by PMA + H2O2 as compared to H2O2 only. In the combined presence of PMA + BIM, no TRPM2 or TRPV1 currents were observed. The CAP and H2O2-induced TRPM2 current densities were also decreased by the NADPH oxidase inhibitors apocynin and N-Acetylcysteine. In conclusion, these results demonstrate a protective role for NADPH oxidase and PKC inhibitors on Ca[2+] entry through TRPM2 and TRPV1 channels in DRG neurons. Since excessive oxidative stress production and Ca[2+] entry are implicated in the pathophysiology of neuropathic pain, the findings may be relevant to the etiology and treatment of neuropathology in DRG neurons.}, }
@article {pmid28092180, year = {2017}, author = {Soliman, NA and Zineldeen, DH and Katary, MA and Ali, DA}, title = {N-acetylcysteine a possible protector against indomethacin-induced peptic ulcer: crosstalk between antioxidant, anti-inflammatory, and antiapoptotic mechanisms.}, journal = {Canadian journal of physiology and pharmacology}, volume = {95}, number = {4}, pages = {396-403}, doi = {10.1139/cjpp-2016-0442}, pmid = {28092180}, issn = {1205-7541}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/therapeutic use ; Anti-Ulcer Agents/adverse effects/therapeutic use ; Antioxidants/*therapeutic use ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Chemical and Drug Induced Liver Injury/etiology ; Chemokines, CXC/metabolism ; Cytoprotection ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Gastric Mucosa/drug effects/metabolism/pathology ; Glucosephosphate Dehydrogenase/metabolism ; Humans ; Indomethacin/adverse effects ; Interferon-gamma/metabolism ; Interleukin-1beta/metabolism ; Male ; Oxidation-Reduction/*drug effects ; Pain/drug therapy ; Peroxidase/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Ranitidine/adverse effects/therapeutic use ; Rats ; Rats, Wistar ; Stomach Ulcer/chemically induced/*prevention &amp; control ; }, abstract = {This study investigated the gastroprotective effects of N-acetylcysteine (NAC) against indomethacin-induced gastric ulcer in rats. Ulceration was induced by a single oral administration of indomethacin (30 mg/kg). 50 male albino rats were allocated into 5 equal groups: control group received normal saline orally, indomethacin group rats received normal saline orally for 5 days and indomethacin (50 mg/kg) on the last day, ranitidine group received ranitidine (reference drug) orally for 5 days (50 mg/kg) before receiving indomethacin (50 mg/kg) on the last day, and NAC groups received NAC orally at 300 and 500 mg/kg, respectively, for 5 days before receiving indomethacin (50 mg/kg) on the last day. Gastric tissue interleukin-1β (IL-1β), interferon-γ (IFN-γ), and caspase-3 levels were immunoassayed. Total thiol (T-SH), myeloperoxidase (MPO), and glucose-6-phosphate dehydrogenase (G6PD) were determined by spectrophotometry. Cytokine-induced neutrophil chemoattractant 2α (CINC-2α) gene expression was evaluated in addition to Bcl-2 immunohistochemistry. Pretreatment with NAC improved the inflammatory, apoptotic, and redox status in a dose-dependent manner particularly in NAC 500 mg/kg pretreated group. These results show a role for NAC in improving indomethacin-induced gastric ulceration via antioxidative, antiapoptotic, and anti-inflammatory interactive mechanisms.}, }
@article {pmid28088644, year = {2017}, author = {Zhao, W and Feng, H and Sun, W and Liu, K and Lu, JJ and Chen, X}, title = {Tert-butyl hydroperoxide (t-BHP) induced apoptosis and necroptosis in endothelial cells: Roles of NOX4 and mitochondrion.}, journal = {Redox biology}, volume = {11}, number = {}, pages = {524-534}, pmid = {28088644}, issn = {2213-2317}, mesh = {Acetylcysteine/metabolism ; Apoptosis/drug effects/*genetics ; Autophagy/drug effects/*genetics ; Endothelial Cells/drug effects/metabolism ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Imidazoles/pharmacology ; NADPH Oxidase 4/antagonists &amp; inhibitors/*genetics ; Oxidative Stress/drug effects ; Pyrazoles/pharmacology ; Pyrazolones ; Pyridines/pharmacology ; Pyridones ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*genetics ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {Oxidative stress causes endothelial death while underlying mechanisms remain elusive. Herein, the pro-death effect of tert-butyl hydroperoxide (t-BHP) was investigated with low concentration (50μM) of t-BHP (t-BHPL) and high concentration (500μM) of t-BHP (t-BHPH). Both t-BHPL and t-BHPH induced endothelial cell death was determined. T-BHPL induced caspase-dependent apoptosis and reactive oxygen species (ROS) generation, which was inhibited by N-acetyl-L-cysteine (NAC). Furthermore, NADPH oxidase inhibitor diphenyleneiodonium (DPI), NOX4 siRNA, and NOX4 inhibitor GKT137831 reduced t-BHPL-induced ROS generation while mitochondrial respiratory chain inhibitors rotenone (Rot), 2-thenoyltrifluoroacetone (TTFA), and antimycin A (AA) failed to do so. NOX4 overexpression resulted in increased ROS generation and Akt expression but decreased sensitivity to t-BHPL. In contrast, T-BHPH induced LDH release, PI uptake, and cell translucent cytoplasm. RIP1 inhibitor necrostatin-1 (Nec-1), MLKL inhibitor necrosulfonamide (NSA) and silencing RIP1, RIP3, and MLKL inhibited t-BHPH-induced cell death while pan-caspase inhibitor Z-VAD-FMK showed no effect. T-BHPH-induced ROS production was inhibited by TTFA, AA and Rot while DPI showed no effect. T-BHPH induced RIP1/RIP3 interaction, which was decreased by Rot, TTFA, and AA. Silence RIP1 and RIP3 but not MLKL inhibited t-BHPH-induced mitochondrial membrane potential (MMP) decrease and ROS production. Moreover, P38MAPK inhibitor SB203580 reversed both t-BHPL and t-BHPH-induced cell death while inhibitors for ERKs and JNKs showed no obvious effect. These data suggested that t-BHP induced both apoptosis and necroptosis in endothelial cells which was mediated by ROS and p38MAPK. ROS derived from NADPH oxidase and mitochondria contributed to t-BHPL and t-BHPH-induced apoptosis and necroptosis, respectively.}, }
@article {pmid28087840, year = {2017}, author = {Ogura, K and Terasaki, Y and Miyoshi-Akiyama, T and Terasaki, M and Moss, J and Noda, M and Yahiro, K}, title = {Vibrio cholerae Cholix Toxin-Induced HepG2 Cell Death is Enhanced by Tumor Necrosis Factor-Alpha Through ROS and Intracellular Signal-Regulated Kinases.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {156}, number = {2}, pages = {455-468}, pmid = {28087840}, issn = {1096-0929}, mesh = {ADP-Ribosylation Factors/*toxicity ; Animals ; Apoptosis/*drug effects/immunology ; Bacterial Toxins/*toxicity ; Cell Survival/drug effects/immunology ; Chemical and Drug Induced Liver Injury/*etiology/immunology/metabolism ; Coculture Techniques ; Hep G2 Cells ; Humans ; Macrophages/drug effects/immunology ; Male ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/immunology/*toxicity ; }, abstract = {Cholix toxin (Cholix) from Vibrio cholerae is a potent virulence factor exhibiting ADP-ribosyltransferase activity on eukaryotic elongation factor 2 (eEF2) of host cells, resulting in the inhibition of protein synthesis. Administration of Cholix or its homologue Pseudomonas exotoxin A (PEA) to mice causes lethal hepatocyte damage. In this study, we demonstrate cytotoxicity of Cholix on human hepatocytes in the presence of tumor necrosis factor α (TNF-α), which has been reported to play a fatal role in PEA administered to mice. Compared with incubating HepG2 cells with Cholix alone, co-treatment with TNF-α and Cholix (TNF-α/Cholix) significantly enhanced the activation of caspases, cytochrome c release from mitochondria into cytoplasm, and poly-ADP-ribose polymerase (PARP) cleavage, while incubation with TNF-α alone or co-treatment with TNF-α/catalytically inactive Cholix did not. In the early stage of cell death, Cholix increased phosphorylation of mitogen-activated protein kinases (e.g., p38, ERK, JNK) and Akt, which was not affected by TNF-α alone. MAPK inhibitors (SP600125, SB20852, and U0126) suppressed PARP cleavage induced by TNF-α/Cholix. Protein kinase inhibitor Go6976 suppressed JNK phosphorylation and PARP cleavage by TNF-α/Cholix. In contrast, PKC activator PMA in the absence of TNF-α promoted Cholix-induced PARP cleavage. Reactive oxygen species (ROS) inhibitor, N-acetyl cysteine (NAC), suppressed TNF-α/Cholix-induced JNK and ERK phosphorylation, resulting in inhibition of PARP cleavage. These data suggest that ROS and JNK pathways are important mediators of TNF-α/Cholix-induced HepG2 cell death.}, }
@article {pmid28086830, year = {2017}, author = {Pati, ML and Hornick, JR and Niso, M and Berardi, F and Spitzer, D and Abate, C and Hawkins, W}, title = {Sigma-2 receptor agonist derivatives of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) induce cell death via mitochondrial superoxide production and caspase activation in pancreatic cancer.}, journal = {BMC cancer}, volume = {17}, number = {1}, pages = {51}, pmid = {28086830}, issn = {1471-2407}, support = {P50 CA196510/CA/NCI NIH HHS/United States ; R01 CA163764/CA/NCI NIH HHS/United States ; T32 CA009621/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Caspase 3/*metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Humans ; Ligands ; Mice ; Mice, Inbred C57BL ; Mitochondria/*drug effects/metabolism ; Pancreatic Neoplasms/*drug therapy/metabolism ; Piperazine ; Piperazines/*pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, sigma/*agonists ; Superoxides/*metabolism ; }, abstract = {BACKGROUND: Despite considerable efforts by scientific research, pancreatic cancer is the fourth leading cause of cancer related mortalities. Sigma-2 receptors, which are overexpressed in several tumors, represent promising targets for triggering selective pancreatic cancer cells death.<br><br>METHODS: We selected five differently structured high-affinity sigma-2 ligands (PB28, PB183, PB221, F281 and PB282) to study how they affect the viability of diverse pancreatic cancer cells (human cell lines BxPC3, AsPC1, Mia PaCa-2, and Panc1 and mouse Panc-02, KCKO and KP-02) and how this is reflected in vivo in a tumor model.<br><br>RESULTS: Important cytotoxicity was shown by the compounds in the aggressive Panc02 cells, where cytotoxic activity was caspase-3 independent for four of the five compounds. However, both cytotoxicity and caspase-3 activation involved generation of Reactive Oxygen Species (ROS), which could be partially reverted by the lipid antioxidant &#x3b1;-tocopherol, but not by the hydrophilic N-acetylcysteine (NAC) indicating crucial differences in the intracellular sites exposed to oxidative stress induced by sigma-2 receptor ligands. Importantly, all the compounds strongly increased the production of mitochondrial superoxide radicals except for PB282. Despite a poor match between in vitro and the in vivo efficacy, daily treatment of C57BL/6 mice bearing Panc02 tumors resulted in promising effects with PB28 and PB282 which were similar compared to the current standard-of-care chemotherapeutic gemcitabine without showing signs of systemic toxicities.<br><br>CONCLUSIONS: Overall, this study identified differential sensitivities of pancreatic cancer cells to structurally diverse sigma-2 receptor ligands. Of note, we identified the mitochondrial superoxide pathway as a previously unrecognized sigma-2 receptor-activated process, which encourages further studies on sigma-2 ligand-mediated cancer cell death for the targeted treatment of pancreatic tumors.}, }
@article {pmid28086233, year = {2017}, author = {Dai, X and Wang, L and Deivasigamni, A and Looi, CY and Karthikeyan, C and Trivedi, P and Chinnathambi, A and Alharbi, SA and Arfuso, F and Dharmarajan, A and Goh, BC and Hui, KM and Kumar, AP and Mustafa, MR and Sethi, G}, title = {A novel benzimidazole derivative, MBIC inhibits tumor growth and promotes apoptosis via activation of ROS-dependent JNK signaling pathway in hepatocellular carcinoma.}, journal = {Oncotarget}, volume = {8}, number = {8}, pages = {12831-12842}, pmid = {28086233}, issn = {1949-2553}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Benzimidazoles/*pharmacology ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism/*pathology ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Female ; Flow Cytometry ; Humans ; Immunohistochemistry ; Liver Neoplasms/metabolism/*pathology ; MAP Kinase Signaling System/*drug effects ; Mice ; Mice, Nude ; Reactive Oxygen Species ; Xenograft Model Antitumor Assays ; }, abstract = {A prior screening programme carried out using MTT assay by our group identified a series of novel benzimidazole derivatives, among which Methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) showed highest anticancer efficacy compared to that of chemotherapeutic agent, cisplatin. In the present study, we found that MBIC inhibited cell viability in different hepatocellular carcinoma (HCC) cell lines without exerting significant cytotoxic effects on normal liver cells. Annexin V-FITC/PI flow cytometry analysis and Western blotting results indicated that MBIC can induce apoptosis in HCC cells, which was found to be mediated through mitochondria associated proteins ultimately leading to the activation of caspase-3. The exposure to MBIC also resulted in remarkable impairment of HCC cell migration and invasion. In addition, treatment with MBIC led to a rapid generation of reactive oxygen species (ROS) and substantial activation of c-Jun-N-terminal kinase (JNK). The depletion of ROS by N-Acetyl cysteine (NAC) partially blocked MBIC-induced apoptosis and JNK activation in HCC cells. Finally, MBIC significantly inhibited tumor growth at a dose of 25 mg/kg in an orthotopic HCC mouse model. Taken together, these results demonstrate that MBIC may inhibit cell proliferation via ROS-mediated activation of the JNK signaling cascade in HCC cells.}, }
@article {pmid28081741, year = {2017}, author = {Wang, Z and Liao, K and Zuo, W and Liu, X and Qiu, Z and Gong, Z and Liu, C and Zeng, Q and Qian, Y and Jiang, L and Bu, Y and Hong, S and Hu, G}, title = {Depletion of NFBD1/MDC1 Induces Apoptosis in Nasopharyngeal Carcinoma Cells Through the p53-ROS-Mitochondrial Pathway.}, journal = {Oncology research}, volume = {25}, number = {1}, pages = {123-136}, pmid = {28081741}, issn = {1555-3906}, mesh = {Adaptor Proteins, Signal Transducing ; Adult ; Aged ; Animals ; Apoptosis/genetics ; Carcinoma ; Cell Cycle Proteins ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Disease Models, Animal ; Female ; Gene Expression ; Gene Silencing ; Heterografts ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Male ; Mice ; Middle Aged ; Mitochondria/*metabolism ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms/genetics/*metabolism/pathology ; Neoplasm Grading ; Neoplasm Staging ; Nuclear Proteins/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; Trans-Activators/genetics/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {NFBD1, a signal amplifier of the p53 pathway, is vital for protecting cells from p53-mediated apoptosis and the early phase of DNA damage response under normal culture conditions. Here we investigated its expression in patients with nasopharyngeal carcinoma (NPC), and we describe the biological functions of the NFBD1 gene. We found that NFBD1 mRNA and protein were more highly expressed in NPC tissues than in nontumorous tissues. To investigate the function of NFBD1, we created NFBD1-depleted NPC cell lines that exhibited decreased cellular proliferation and colony formation, an increase in their rate of apoptosis, and an enhanced sensitivity to chemotherapeutic agents compared with in vitro controls. However, N-acetyl cysteine (NAC) and downregulation of p53 expression could partially reverse the apoptosis caused by the loss of NFBD1. Further analysis showed that loss of NFBD1 resulted in increased production of intracellular reactive oxygen species (ROS) depending on p53, which subsequently triggered the mitochondrial apoptotic pathway. Using a xenograft model in nude mice, we showed that silencing NFBD1 also significantly inhibited tumor growth and led to apoptosis. Taken together, our data suggest that inhibition of NFBD1 in NPC could be therapeutically useful.}, }
@article {pmid28078487, year = {2017}, author = {Lu, W and Kang, J and Hu, K and Tang, S and Zhou, X and Xu, L and Li, Y and Yu, S}, title = {The role of the Nox4-derived ROS-mediated RhoA/Rho kinase pathway in rat hypertension induced by chronic intermittent hypoxia.}, journal = {Sleep &amp; breathing = Schlaf &amp; Atmung}, volume = {21}, number = {3}, pages = {667-677}, pmid = {28078487}, issn = {1522-1709}, support = {No.81070065, 81370181//The National Natural Science Foundation of China/ ; }, mesh = {Animals ; Hypertension/*metabolism ; Hypoxia/*metabolism ; Male ; NADPH Oxidase 4/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; Sleep Apnea, Obstructive/metabolism ; rho GTP-Binding Proteins/*metabolism ; rho-Associated Kinases/*metabolism ; }, abstract = {BACKGROUND: Obstructive sleep apnea syndrome, which is a risk factor for resistant hypertension, is characterized by chronic intermittent hypoxia (CIH) and is associated with many cardiovascular diseases. CIH elicits systemic oxidative stress and sympathetic hyperactivity, which lead to hypertension. Rho kinases (ROCKs) are considered to be major effectors of the small GTPase RhoA and have been extensively studied in the cardiovascular field. Upregulation of the RhoA/ROCK signaling cascade is observed in various cardiovascular disorders, such as atherosclerosis, pulmonary hypertension, and stroke. However, the exact molecular function of RhoA/ROCK in CIH remains unclear and requires further study.<br><br>OBJECTIVE: This study aimed to investigate the role of the NADPH oxidase 4 (Nox4)-induced ROS/RhoA/ROCK pathway in CIH-induced hypertension in rats.<br><br>METHODS: Male Sprague-Dawley rats were exposed to CIH for 21&#xa0;days (intermittent hypoxia of 21% O2 for 60&#xa0;s and 5% O2 for 30&#xa0;s, cyclically repeated for 8&#xa0;h/day). We randomly assigned 56 male rats to groups of normoxia (RA) or vertically implemented CIH together with vehicle (CIH-V), GKT137831 (CIH-G), N-acetyl cysteine (NAC) (CIH-N), or Y27632 (CIH-Y). The rats in the RA group were continuously exposed to room air, whereas the rats in the other groups were exposed to CIH. Systolic blood pressure (BP) was monitored at the beginning of each week. After the experiment, renal sympathetic nerve activity (RSNA) was recorded, and serum and renal tissues were subjected to molecular biological and biochemical analyses.<br><br>RESULTS: Compared with the BP of RA rats, the BP of CIH-V rats started to increase 2&#xa0;weeks after the beginning of the experiment, subsequently stabilizing at a high level at the end of the third week. CIH increased both RSNA and oxidative stress. This response was attenuated by treatment of the rats with GKT137831 or NAC. Inhibiting Nox4 activity or ROS production reduced RhoA/ROCK expression. Treatment with Y27632 reduced both BP and RSNA in rats exposed to CIH.<br><br>CONCLUSION: Hypertension can be induced by CIH in SD rats. The CIH-induced elevation of BP is at least partially mediated via the Nox4-induced ROS/RhoA/ROCK pathway.}, }
@article {pmid28075404, year = {2017}, author = {Garibaldi, S and Barisione, C and Marengo, B and Ameri, P and Brunelli, C and Balbi, M and Ghigliotti, G}, title = {Advanced Oxidation Protein Products-Modified Albumin Induces Differentiation of RAW264.7 Macrophages into Dendritic-Like Cells Which Is Modulated by Cell Surface Thiols.}, journal = {Toxins}, volume = {9}, number = {1}, pages = {}, pmid = {28075404}, issn = {2072-6651}, mesh = {Acetylcysteine/pharmacology ; Advanced Oxidation Protein Products/*metabolism/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Culture Techniques ; *Cell Differentiation/drug effects ; Cell Line ; Cell Survival/drug effects ; Dendritic Cells/*cytology/drug effects/metabolism ; Humans ; Macrophages/*cytology/drug effects/metabolism ; Mice ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Serum Albumin/*metabolism/pharmacology ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Local accumulation of Advanced Oxidation Protein Products (AOPP) induces pro-inflammatory and pro-fibrotic processes in kidneys and is an independent predictor of renal fibrosis and of rapid decline of eGFR in patients with chronic kidney disease (CKD). In addition to kidney damage, circulating AOPP may be regarded as mediators of systemic oxidative stress and, in this capacity, they might play a role in the progression of atherosclerotic damage of arterial walls. Atherosclerosis is a chronic inflammatory disease that involves activation of innate and adaptive immunity. Dendritic cells (DCs) are key cells in this process, due to their role in antigen presentation, inflammation resolution and T cell activation. AOPP consist in oxidative modifications of proteins (such as albumin and fibrinogen) that mainly occur through myeloperoxidase (MPO)-derived hypochlorite (HOCl). HOCl modified proteins have been found in atherosclerotic lesions. The oxidizing environment and the shifts in cellular redox equilibrium trigger inflammation, activate immune cells and induce immune responses. Thus, surface thiol groups contribute to the regulation of immune functions. The aims of this work are: (1) to evaluate whether AOPP-proteins induce activation and differentiation of mature macrophages into dendritic cells in vitro; and (2) to define the role of cell surface thiol groups and of free radicals in this process. AOPP-proteins were prepared by in vitro incubation of human serum albumin (HSA) with HOCl. Mouse macrophage-like RAW264.7 were treated with various concentrations of AOPP-HSA with or without the antioxidant N-acetyl cysteine (NAC). Following 48 h of HSA-AOPP treatment, RAW264.7 morphological changes were evaluated by microscopic observation, while markers of dendritic lineage and activation (CD40, CD86, and MHC class II) and allogeneic T cell proliferation were evaluated by flow cytometry. Cell surface thiols were measured by AlexaFluor-maleimide binding, and ROS production was assessed as DCF fluorescence by flow cytometry. HSA-AOPP induced the differentiation of RAW264.7 cells into a dendritic-like phenotype, as shown by morphological changes, by increased CD40, CD86 and MHC class II surface expression and by induction of T cell proliferation. The cell surface thiols dose dependently decreased following HSA-AOPP treatment, while ROS production increased. NAC pre-treatment enhanced the amount of cell surface thiols and prevented their reduction due to treatment with AOPP. Both ROS production and RAW264.7 differentiation into DC-like cells induced by HSA-AOPP were reduced by NAC. Our results highlight that oxidized plasma proteins modulate specific immune responses of macrophages through a process involving changes in the thiol redox equilibrium. We suggest that this mechanism may play a role in determining the rapid progression of the atherosclerotic process observed in CKD patients.}, }
@article {pmid28067673, year = {2017}, author = {Hu, Y and Zhao, C and Zheng, H and Lu, K and Shi, D and Liu, Z and Dai, X and Zhang, Y and Zhang, X and Hu, W and Liang, G}, title = {A novel STAT3 inhibitor HO-3867 induces cell apoptosis by reactive oxygen species-dependent endoplasmic reticulum stress in human pancreatic cancer cells.}, journal = {Anti-cancer drugs}, volume = {28}, number = {4}, pages = {392-400}, doi = {10.1097/CAD.0000000000000470}, pmid = {28067673}, issn = {1473-5741}, mesh = {Apoptosis/drug effects ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/*drug effects ; Humans ; MAP Kinase Signaling System/drug effects ; Pancreatic Neoplasms/*drug therapy/metabolism/pathology ; Piperidones/*pharmacology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Pancreatic cancer is the most commonly diagnosed malignancy among solid tumors and has shown an increasing trend year by year. Thus, there is an urgent need for the discovery of new anticancer drugs for the treatment of pancreatic cancer. In recent years, it has been reported that the compound HO-3867, a novel analog of the natural product curcumin, showed antitumor activity with low toxicity. However, the underlying mechanism of this compound's attack on cancer cells is not very clear. In the present study, it was found that HO-3867 showed good antitumor activity at the concentration of 2 μmol/l in PANC-1 and BXPC-3 cells. Importantly, it was also found that HO-3867 treatment significantly induced reactive oxygen species (ROS) production in human pancreatic cancer cell lines, inducing PANC-1 and BXPC-3 cells. Co-treatment with the ROS scavenger, N-acetyl cysteine, partially abrogated HO-3867-induced cell apoptosis. The activation of mitogen-activated protein kinase and endoplasmic reticulum stress indicated a downstream event of ROS generation in mediating the anticancer effect of the HO-3867. In addition, independent of the ROS pathway, direct STAT3 inhibition was observed in HO-3867-induced cell apoptosis. Taken together, the results of this work suggest that both the ROS-dependent ER stress and STAT3 pathways were implicated in the cell apoptosis induced by the novel compound HO-3867.}, }
@article {pmid28066832, year = {2016}, author = {Ahmadi, S and Bashiri, R and Ghadiri-Anari, A and Nadjarzadeh, A}, title = {Antioxidant supplements and semen parameters: An evidence based review.}, journal = {International journal of reproductive biomedicine}, volume = {14}, number = {12}, pages = {729-736}, pmid = {28066832}, issn = {2476-4108}, abstract = {Many studies have focused on male infertility. There is limited evidence about the influence of nutrition on quality of semen. Approximately, 30-80% of infertility cases are caused by oxidative stress and decreased level of seminal total antioxidant capacity. This study was aimed to review the effects of oral antioxidant supplements on improving major semen parameters such as sperm concentration, motility, morphology, DNA damage, and fertility rate. Data were extracted from PubMed and Google scholar database by using the terms "antioxidant", "multivitamin", "carnitine", "CoQ10", "vitamin C", "vitamin E", "zinc", "folic acid", "N-acetyl cysteine" and "selenium" combined with "male infertility", "semen", and "sperm" to generate a set of relevant citations. Supplements such as CoQ10 and alpha-tocopherol significantly improve sperm count. Also, carnitine has positive effects on sperm motility and morphology. Simultaneous administration of vitamin E and vitamin C reduces the sperm DNA damage. However, in some studies, one or more factors have not changed substantially. In most of the studies, antioxidant supplementation improved the number, motility, morphology and sometimes DNA integrity of sperm. The present study showed that antioxidant supplements, especially a combination of antioxidants such as vitamin C, vitamin E, and CoQ10 intake can effectively improve semen parameters in infertile men.}, }
@article {pmid28063998, year = {2017}, author = {He, ZJ and Zhu, FY and Li, SS and Zhong, L and Tan, HY and Wang, K}, title = {Inhibiting ROS-NF-κB-dependent autophagy enhanced brazilin-induced apoptosis in head and neck squamous cell carcinoma.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {101}, number = {}, pages = {55-66}, doi = {10.1016/j.fct.2017.01.002}, pmid = {28063998}, issn = {1873-6351}, mesh = {Apoptosis/*drug effects ; Autophagy/*drug effects ; Benzopyrans/*pharmacology ; Carcinoma, Squamous Cell/drug therapy/*pathology ; Cell Line, Tumor ; Head and Neck Neoplasms/drug therapy/*pathology ; Humans ; NF-kappa B/*antagonists &amp; inhibitors ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Autophagy modulation has been considered a potential therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). A previous study confirmed that brazilin might possess significant anti-carcinogenic activity. However, whether brazilin induces autophagy and its roles in cell death in HNSCC are still unclear. In this study, we have shown that brazilin induced significant apoptosis in the Cal27 HNSCC cell line but not in oral keratinocyte cell line (OKC). In addition to showing apoptosis induction, we demonstrated the brazilin-induced autophagic response in the Cal27 cells, as evidenced by the formation of GFP-LC3 puncta, and also showed the upregulation of LC3-II and Beclin-1. Moreover, pharmacologically or genetically blocking autophagy enhanced the brazilin-induced apoptosis, indicating the cytoprotective role of autophagy in brazilin-treated Cal27 cells. Moreover, brazilin activated nuclear factor kappa B (NF-κB p65) nuclear translocation and increased NF-κB p65 reporter activity, which contributed to the upregulation of autophagy-related genes, including LC3-II and Beclin-1. Importantly, we found that brazilin triggered reactive oxygen species (ROS) generation in Cal27 cells. Furthermore, N-acetyl-cysteine (NAC), a ROS scavenger, abrogated the effects of brazilin on the NF-κB p65-dependent autophagy. Taken together, our results demonstrated that brazilin increased the NF-κB p65-dependent autophagy through the promotion of ROS signalling pathways in HNSCC. These data also suggest that a strategy of blocking ROS-NF-κB p65-dependent autophagy to enhance the activity of brazilin warrants further attention for the treatment of HNSCC.}, }
@article {pmid28063010, year = {2017}, author = {Zhang, S and Yin, J and Zhong, J}, title = {Chaetocin reactivates the lytic replication of Epstein-Barr virus from latency via reactive oxygen species.}, journal = {Science China. Life sciences}, volume = {60}, number = {1}, pages = {66-71}, doi = {10.1007/s11427-016-0286-7}, pmid = {28063010}, issn = {1869-1889}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antigens, Viral/genetics/metabolism ; B-Lymphocytes/drug effects/metabolism/virology ; Blotting, Western ; Callithrix ; Cell Line, Transformed ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Glutathione Peroxidase/genetics/metabolism ; Herpesvirus 4, Human/*drug effects/genetics/physiology ; Histones/metabolism ; Host-Pathogen Interactions/drug effects ; Humans ; Lysine/metabolism ; Methylation/drug effects ; NADH Dehydrogenase/genetics/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Piperazines/pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Trans-Activators/genetics/metabolism ; Virus Activation/drug effects/genetics ; Virus Latency/drug effects/genetics ; Virus Replication/*drug effects/genetics ; }, abstract = {Oxidative stress, regarded as a negative effect of free radicals in vivo, takes place when organisms suffer from harmful stimuli. Some viruses can induce the release of reactive oxygen species (ROS) in infected cells, which may be closely related with their pathogenicity. In this report, chaetocin, a fungal metabolite reported to have antimicrobial and cytostatic activity, was studied for its effect on the activation of latent Epstein-Barr virus (EBV) in B95-8 cells. We found that chaetocin remarkably up-regulated EBV lytic transcription and DNA replication at a low concentration (50 nmol L[-1]). The activation of latent EBV was accompanied by an increased cellular ROS level. N-acetyl-L-cysteine (NAC), an ROS inhibitor, suppressed chaetocin-induced EBV activation. Chaetocin had little effect on histone H3K9 methylation, while NAC also significantly reduced H3K9 methylation. These results suggested that chaetocin reactivates latent EBV primarily via ROS pathways.}, }
@article {pmid28060555, year = {2018}, author = {Mei, M and Zhao, HW and Pan, QG and Pu, YM and Tang, MZ and Shen, BB}, title = {Efficacy of N-Acetylcysteine in Preventing Acute Kidney Injury After Cardiac Surgery: A Meta-Analysis Study.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {31}, number = {1}, pages = {14-23}, doi = {10.1080/08941939.2016.1269853}, pmid = {28060555}, issn = {1521-0553}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/blood/epidemiology/etiology/*prevention &amp; control ; Cardiac Surgical Procedures/*adverse effects ; Creatinine/blood ; Elective Surgical Procedures/adverse effects ; Free Radical Scavengers/*therapeutic use ; Hospital Mortality ; Humans ; Perioperative Care/adverse effects/methods ; Postoperative Complications/blood/epidemiology/etiology/*prevention &amp; control ; Treatment Outcome ; }, abstract = {PURPOSE: To evaluate whether perioperative N-acetylcysteine (NAC) administration reduces the risk of cardiac surgery associated acute kidney injury (CSA-AKI).<br><br>MATERIALS AND METHODS: A systematic literature review (Medline, PubMed, Cochrane, Biomedical central, Google Scholar) identified 10 studies (1391 patients; 695 NAC and 696 placebo) that compared the efficacy and adverse effects of perioperative NAC administration for CSA-AKI prevention in adults undergoing elective cardiac surgery. Meta-analysis was performed using Comprehensive Meta-Analysis statistical software.<br><br>RESULTS: Patients in the NAC-treated and placebo groups had similar rate of CSA-AKI occurrence, change in creatinine levels, as well as the in-hospital mortality rate (RR = 0.841, 95% CI = 0.691 to 1.023, p = 0.083; pooled difference in means = -0.328, 95% CI = -0.712 to 0.056, p = 0.094; RR = 0.741, 95% CI = 0.388 to 1.418, p = 0.366, respectively).<br><br>CONCLUSIONS: Our study does not support perioperative NAC administration as a mean to reduce the risk of CSA-AKI.}, }
@article {pmid28059653, year = {2017}, author = {Bijangi-Vishehsaraei, K and Reza Saadatzadeh, M and Wang, H and Nguyen, A and Kamocka, MM and Cai, W and Cohen-Gadol, AA and Halum, SL and Sarkaria, JN and Pollok, KE and Safa, AR}, title = {Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways.}, journal = {Journal of neurosurgery}, volume = {127}, number = {6}, pages = {1219-1230}, pmid = {28059653}, issn = {1933-0693}, support = {P30 CA082709/CA/NCI NIH HHS/United States ; R01 CA101743/CA/NCI NIH HHS/United States ; R01 CA138798/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Anticarcinogenic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/*drug effects ; DNA Damage/drug effects ; Glioblastoma/*metabolism/pathology ; Humans ; Isothiocyanates/*pharmacology ; Mice ; Neoplastic Stem Cells/*drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Sulfoxides ; }, abstract = {OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.}, }
@article {pmid28059488, year = {2017}, author = {Sadeghi, A and Seyyed Ebrahimi, SS and Golestani, A and Meshkani, R}, title = {Resveratrol Ameliorates Palmitate-Induced Inflammation in Skeletal Muscle Cells by Attenuating Oxidative Stress and JNK/NF-κB Pathway in a SIRT1-Independent Mechanism.}, journal = {Journal of cellular biochemistry}, volume = {118}, number = {9}, pages = {2654-2663}, doi = {10.1002/jcb.25868}, pmid = {28059488}, issn = {1097-4644}, mesh = {Animals ; Cell Line ; Inflammation/chemically induced/metabolism ; MAP Kinase Kinase 4/*metabolism ; MAP Kinase Signaling System/*drug effects ; Mice ; Muscle Fibers, Skeletal/*metabolism/pathology ; Muscle Proteins/*metabolism ; NF-kappa B/*metabolism ; Oxidative Stress/*drug effects ; Palmitic Acid/*toxicity ; Resveratrol ; Sirtuin 1/*metabolism ; Stilbenes/*pharmacology ; }, abstract = {Resveratrol has been shown to exert anti-inflammatory and anti-oxidant effects in a variety of cell types, however, its role in prevention of inflammatory responses mediated by palmitate in skeletal muscle cells remains unexplored. In the present study, we investigated the effects of resveratrol on palmitate-induced inflammation and elucidated the underlying mechanisms in skeletal muscle cells. The results showed that palmitate significantly enhanced TNF-α and IL-6 mRNA expression and protein secretion from C2C12 cells at 12, 24, and 36 h treatments. Increased expression of cytokines was accompanied by an enhanced phosphorylation of JNK, P38, ERK1/2, and IKKα/IKKβ. In addition, JNK and P38 inhibitors could significantly attenuate palmitate-induced mRNA expression of TNF-α and IL-6, respectively, whereas NF-κB inhibitor reduced the expression of both cytokines in palmitate-treated cells. Resveratrol pretreatment significantly prevented palmitate-induced TNF-α and IL-6 mRNA expression and protein secretion in C2C12 cells. Importantly, pre-treatment of the cells with resveratrol completely abrogated the phosphorylation of ERK1/2, JNK, and IKKα/IKKβ in palmitate treated cells. The protection from palmitate-induced inflammation by resveratrol was accompanied by a decrease in the generation of reactive oxygen species (ROS). N-acetyl cysteine (NAC), a known scavenger of ROS, could protect palmitate-induced expression of TNF-α and IL-6. Furthermore, inhibition of SIRT1 by shRNA or sirtinol demonstrated that the anti-inflammatory effect of resveratrol in muscle cells is mediated through a SIRT1-independent mechanism. Taken together, these findings suggest that resveratrol may represent a promising therapy for prevention of inflammation in skeletal muscle cells. J. Cell. Biochem. 118: 2654-2663, 2017. © 2017 Wiley Periodicals, Inc.}, }
@article {pmid28059455, year = {2017}, author = {Du, X and Shi, Z and Peng, Z and Zhao, C and Zhang, Y and Wang, Z and Li, X and Liu, G and Li, X}, title = {Acetoacetate induces hepatocytes apoptosis by the ROS-mediated MAPKs pathway in ketotic cows.}, journal = {Journal of cellular physiology}, volume = {232}, number = {12}, pages = {3296-3308}, doi = {10.1002/jcp.25773}, pmid = {28059455}, issn = {1097-4652}, mesh = {Acetoacetates/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cattle ; Cells, Cultured ; Female ; Hepatocytes/cytology/*drug effects/metabolism ; *Ketosis ; *MAP Kinase Signaling System ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {Dairy cows with ketosis are characterized by oxidative stress, hepatic damage, and hyperketonemia. Acetoacetate (AA) is the main component of ketone bodies in ketotic cows, and is associated with the above pathological process. However, the potential mechanism was not illuminated. Therefore, the aim of this study was to investigate the mechanism of AA-induced hepatic oxidative damage in ketotic cows. Compared with healthy cows, ketotic cows exhibited severe oxidative stress and hepatic damage. Moreover, the extent of hepatic damage and oxidative stress had a positive relationship with the AA levels. In vitro, AA treatment increased reactive oxygen species (ROS) content and further induced oxidative stress and apoptosis of bovine hepatocytes. In this process, AA treatment increased the phosphorylation levels of JNK and p38MAPK and decreased the phosphorylation level of ERK, which could increase p53 and inhibit nuclear factor E2-related factor 2 (Nrf2) expression, nuclear localization, and DNA-binding affinity, thereby inducing the overexpression of pro-apoptotic molecules Bax, Caspase 3, Caspase 9, PARP and inhibition of anti-apoptotic molecule Bcl-2. Antioxidant N-acetylcysteine (NAC) treatment or interference of MAPKs pathway could attenuate the hepatocytes apoptosis induced by AA. Collectively, these results indicate that AA triggers hepatocytes apoptosis via the ROS-mediated MAPKs pathway in ketotic cows.}, }
@article {pmid28058218, year = {2016}, author = {Abbas, FM and Julie, BM and Sharma, A and Halawa, A}, title = {"Contrast nephropathy" in renal transplantation: Is it real?.}, journal = {World journal of transplantation}, volume = {6}, number = {4}, pages = {682-688}, pmid = {28058218}, issn = {2220-3230}, abstract = {The risk of contrast-induced nephropathy (CIN) in renal transplant recipients is increased in diabetics, patients with impaired basal kidney function, patients in shock, patients presenting with acute emergency and in old age recipients. Approximately one-third of all hospitalized patients with acute kidney injury is attributed to CIN. In the United States, it is the third leading cause of hospital-acquired renal failure. Therefore, efforts should be directed to minimize CIN-related morbidity and mortality as well as to shorten hospital stay. While the role of peri-procedural prophylactic hydration with saline is unequivocal; the use of acetyl cysteine is not based on robust evidence. The utility of theophylline, aminophylline, calcium channel blockers, natriuretic peptide, and diuretics does not have proven role in attenuating CIN incidence. We aim to analyze the evidence for using various protocols in published literature to limit CIN-associated morbidity and mortality, particularly during surveillance of the renal allograft survival.}, }
@article {pmid28057548, year = {2017}, author = {Chi, X and Yu, D and Li, P and Lu, Q and Jiang, W and Hao, K}, title = {The protection effects of (1E,6E)-1,7-diphenylhepta-1,6-diene-3,5-dione, a curcumin analogue, against operative liver injury in rats.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {100}, number = {}, pages = {94-101}, doi = {10.1016/j.ejps.2016.12.042}, pmid = {28057548}, issn = {1879-0720}, mesh = {Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Curcumin/*analogs &amp; derivatives/pharmacology/*therapeutic use ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Liver/drug effects/metabolism/pathology/*surgery ; Male ; Protective Agents/pharmacology/*therapeutic use ; Rats, Sprague-Dawley ; Reperfusion Injury/blood/metabolism/pathology/*prevention &amp; control ; Succinate Dehydrogenase/metabolism ; }, abstract = {The relationship between the chemistry characteristic and the hepatoprotective effects of (1E,6E)-1,7-diphenylhepta-1,6-diene-3,5-dione (DDD), a curcumin analogue, in operative liver injury rats was investigated to reveal the mechanism of hepatic protection effects of DDD. DDD (1.2-4.8mmol/kg) was administrated 10min before reperfusion phase in hepatic ischemia-reperfusion injury (IRI) rats. DDD (4.8mmol/kg) administrated 10min before ischemia and N-acetylcysteine (NAC) (4.8mmol/kg) administrated 10min before reperfusion were included for comparative studies. The plasma liver enzyme activities, histopathological indices and markers of lipid peroxide were determined to evaluate the hepatic protection effects. Effects of DDD on succinate dehydrogenase (SDH) activity were also investigated. DDD showed dose-dependent hepatocyte protections when administrated 10min before reperfusion stages in hepatic IRI rats. DDD showed almost equivalent hepatoprotective effects when administrated 10min before ischemia phase demonstrating that DDD acted on the reperfusion stages selectively against the hepatic IRI, instead of ischemia phase. NAC was not effective against hepatic IRI when treated 10min before reperfusion because of the higher pKa of NAC. In additional, DDD had no effect on the SDH both in hepatic IRI rats and in mitochondria. In conclusion, DDD had dose-dependent hepatocyte protections in the reperfusion stages in hepatic IRI rats, while the observed hepatocyte protections of DDD did not involve SDH activities. β-Diketone structures of DDD were crucial for the hepatocyte protections. The abilities of DDD to clear up the unsaturated aldehydes related with the enolate nucleophilicity and the pKa. DDD might be a promising candidate to treat hepatic IRI.}, }
@article {pmid28056348, year = {2017}, author = {Flamm, SL and Yang, YX and Singh, S and Falck-Ytter, YT and , }, title = {American Gastroenterological Association Institute Guidelines for the Diagnosis and Management of Acute Liver Failure.}, journal = {Gastroenterology}, volume = {152}, number = {3}, pages = {644-647}, doi = {10.1053/j.gastro.2016.12.026}, pmid = {28056348}, issn = {1528-0012}, mesh = {Consensus ; Evidence-Based Medicine/standards ; Gastroenterology/*standards ; Humans ; Liver Failure, Acute/*diagnosis/etiology/*therapy ; Predictive Value of Tests ; Risk Factors ; Societies, Medical/*standards ; Treatment Outcome ; United States ; }, }
@article {pmid28049506, year = {2017}, author = {Al-Khayal, K and Alafeefy, A and Vaali-Mohammed, MA and Mahmood, A and Zubaidi, A and Al-Obeed, O and Khan, Z and Abdulla, M and Ahmad, R}, title = {Novel derivative of aminobenzenesulfonamide (3c) induces apoptosis in colorectal cancer cells through ROS generation and inhibits cell migration.}, journal = {BMC cancer}, volume = {17}, number = {1}, pages = {4}, pmid = {28049506}, issn = {1471-2407}, mesh = {Amides/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Movement/*drug effects ; Cell Proliferation/drug effects ; Colorectal Neoplasms/drug therapy/metabolism/*pathology ; Cytochromes c/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Sulfanilic Acids/*chemistry ; Tumor Cells, Cultured ; Wound Healing/drug effects ; }, abstract = {BACKGROUND: Colorectal cancer (CRC) is the 3[rd] most common type of cancer worldwide. New anti-cancer agents are needed for treating late stage colorectal cancer as most of the deaths occur due to cancer metastasis. A recently developed compound, 3c has shown to have potent antitumor effect; however the mechanism underlying the antitumor effect remains unknown.<br><br>METHODS: 3c-induced inhibition of proliferation was measured in the absence and presence NAC using MTT in HT-29 and SW620 cells and xCELLigence RTCA DP instrument. 3c-induced apoptotic studies were performed using flow cytometry. 3c-induced redox alterations were measured by ROS production using fluorescence plate reader and flow cytometry and mitochondrial membrane potential by flow cytometry; NADPH and GSH levels were determined by colorimetric assays. Bcl2 family protein expression and cytochrome c release and PARP activation was done by western blotting. Caspase activation was measured by ELISA. Cell migration assay was done using the real time xCELLigence RTCA DP system in SW620 cells and wound healing assay in HT-29.<br><br>RESULTS: Many anticancer therapeutics exert their effects by inducing reactive oxygen species (ROS). In this study, we demonstrate that 3c-induced inhibition of cell proliferation is reversed by the antioxidant, N-acetylcysteine, suggesting that 3c acts via increased production of ROS in HT-29 cells. This was confirmed by the direct measurement of ROS in 3c-treated colorectal cancer cells. Additionally, treatment with 3c resulted in decreased NADPH and glutathione levels in HT-29 cells. Further, investigation of the apoptotic pathway showed increased release of cytochrome c resulting in the activation of caspase-9, which in turn activated caspase-3 and -6. 3c also (i) increased p53 and Bax expression, (ii) decreased Bcl2 and BclxL expression and (iii) induced PARP cleavage in human colorectal cancer cells. Confirming our observations, NAC significantly inhibited induction of apoptosis, ROS production, cytochrome c release and PARP cleavage. The results further demonstrate that 3c inhibits cell migration by modulating EMT markers and inhibiting TGF&#x3b2;-induced phosphorylation of Smad2 and Samd3.<br><br>CONCLUSIONS: Our findings thus demonstrate that 3c disrupts redox balance in colorectal cancer cells and support the notion that this agent may be effective for the treatment of colorectal cancer.}, }
@article {pmid28045034, year = {2017}, author = {Khan, SY and Awad, EM and Oszwald, A and Mayr, M and Yin, X and Waltenberger, B and Stuppner, H and Lipovac, M and Uhrin, P and Breuss, JM}, title = {Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin.}, journal = {Scientific reports}, volume = {7}, number = {}, pages = {39501}, pmid = {28045034}, issn = {2045-2322}, support = {CH/16/3/32406/BHF_/British Heart Foundation/United Kingdom ; FS/13/2/29892/BHF_/British Heart Foundation/United Kingdom ; RG/16/14/32397/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Cellular Senescence/*drug effects ; Endothelial Cells/*drug effects/metabolism ; Free Radical Scavengers/*pharmacology ; Humans ; Inflammation/chemically induced ; NF-kappa B/metabolism ; Phenotype ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Cellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn's disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence.}, }
@article {pmid28043145, year = {2017}, author = {Jiao, Y and Ji, L and Kuang, Y and Yang, Q}, title = {Cytotoxic effect of oxaloacetate on HepG2-human hepatic carcinoma cells via apoptosis and ROS accumulation.}, journal = {Neoplasma}, volume = {64}, number = {2}, pages = {192-198}, doi = {10.4149/neo_2017_204}, pmid = {28043145}, issn = {0028-2685}, mesh = {Acetylcysteine ; Antineoplastic Agents/pharmacology ; *Apoptosis ; Carcinoma, Hepatocellular/*pathology ; Caspase 3/metabolism ; Glutathione ; Hep G2 Cells/drug effects ; Humans ; Liver Neoplasms/*pathology ; Oxaloacetic Acid/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Oxaloacetate (OA) is one of the intermediates of the Krebs cycle. In addition to its role in energy production, OA may have other effects on the cell. We report here that OA could have a cell type dependent cytotoxic effect on the human hepatic carcinoma cell line HepG2 through induction of apoptosis and reactive oxygen species (ROS) accumulation. In our study, OA decreased the viability and colony formation of HepG2 cells and induced cell death. Caspase-3 activity was increased, the pro-apoptotic protein Bax was up-regulated, and the anti-apoptotic protein Bcl-2 was down-regulated in OA-treated HepG2 cells indicating that apoptosis through the intrinsic pathway was involved in the cell death. The ROS level in OA-treated HepG2 cells was increased. The anti-oxidant N-acetylcysteine (NAC) and glutathione (GSH) prevented the OA-induced decrease in cell but did not alter the enhanced apoptotic Bax/Bcl-2 mRNA ratio. These results suggest that the OA-induced apoptosis of HepG2 cell is not driven by oxidative damage and at least two distinct mechanisms, one mediated by ROS and one involving apoptosis, result in the cytotoxic effects of OA on HepG2 cells. These studies expand the biological functional repertoire of OA and provide a mechanism by which hepatocellular carcinoma may be targeted by OA.}, }
@article {pmid28039148, year = {2017}, author = {Yan, J and Guo, Y and Fei, Y and Zhang, R and Han, Y and Lu, S}, title = {GPx1 knockdown suppresses chondrogenic differentiation of ATDC5 cells through induction of reductive stress.}, journal = {Acta biochimica et biophysica Sinica}, volume = {49}, number = {2}, pages = {110-118}, doi = {10.1093/abbs/gmw125}, pmid = {28039148}, issn = {1745-7270}, mesh = {Aggrecans/genetics/metabolism ; Animals ; Apoptosis/genetics ; Blotting, Western ; Cell Differentiation/*genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; Chondrocytes/*metabolism ; Chondrogenesis/genetics ; Collagen Type II/genetics/metabolism ; Gene Expression ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Glutathione Peroxidase/*genetics/metabolism ; Mice ; *Oxidative Stress ; *RNA Interference ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; SOX9 Transcription Factor/genetics/metabolism ; Glutathione Peroxidase GPX1 ; }, abstract = {Glutathione peroxidase 1 (GPx1) is a selenium (Se)-containing protein and is induced in cartilage formation. GPx1 eliminates reactive oxygen species (ROS), which are required for chondrogenic induction. The physiological properties of GPx1 in cartilage and the redox mechanisms involved are not known. The effects of GPx1 on chondrogenic differentiation of ATDC5 cells were examined through short hairpin RNA-mediated gene silencing. The results demonstrated that GPx1 knockdown impaired gene expression of sex determining region Y-box 9, collagen II (Col II), and aggrecan. GPx1 knockdown suppressed the accumulation of cartilage glycosaminoglycans (GAGs) and the proliferation of chondrocyte. GPx1 knockdown also induced cell apoptosis. However, cell sensitivity toward exogenous oxidative stress was not increased after GPx1 knockdown. Unexpectedly, GPx1 knockdown not only induced oxidative stress characterized by the increased production of ROS but also caused reductive stress indicated by an elevation of glutathione (GSH)/oxidized GSH (GSSG) ratio. Furthermore, GPx1 knockdown-mediated reductive and oxidative stress could be antagonized by a thiol-oxidizing agent diamide and a thiol-containing compound N-acetylcysteine (NAC), respectively. Moreover, NAC attenuated GPx1 knockdown-induced cell apoptosis, while diamide prevented GPx1 knockdown-suppressed chondrocyte proliferation. Finally, diamide but not NAC could rescue GPx1 knockdown-mediated impaired chondrogenic differentiation. In summary, GPx1 is essential for chondrogenic induction in ATDC5 cells mainly through modulation of intracellular GSH/GSSG ratio, rather than an antioxidant enzyme to detoxify ROS. In addition, GPx1 knockdown-induced impaired chondrogenesis may participate in the pathogenesis of the endemic osteoarthropathy due to Se deficiency. These observations offer novel insights for the development of therapeutic target during cartilage degeneration.}, }
@article {pmid28038427, year = {2017}, author = {Zhang, Z and Zhao, S and Yao, Z and Wang, L and Shao, J and Chen, A and Zhang, F and Zheng, S}, title = {Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell.}, journal = {Redox biology}, volume = {11}, number = {}, pages = {322-334}, pmid = {28038427}, issn = {2213-2317}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Autophagy/drug effects/*genetics ; Autophagy-Related Protein 5/agonists/antagonists &amp; inhibitors/genetics/metabolism ; Class III Phosphatidylinositol 3-Kinases/genetics/metabolism ; Gene Expression Regulation ; Glutathione/pharmacology ; Hepatic Stellate Cells/drug effects/*metabolism/pathology ; Lipid Droplets/drug effects/*metabolism ; Liver/drug effects/metabolism/pathology ; Liver Cirrhosis/drug therapy/*genetics/metabolism/pathology ; Male ; Mice ; Mice, Inbred ICR ; Primary Cell Culture ; Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; RNA, Small Interfering/genetics/metabolism ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/*metabolism ; Signal Transduction ; }, abstract = {Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, characterized by dramatic disappearance of lipid droplets (LDs). Although LD disappearance has long been considered one of the hallmarks of HSC activation, the underlying molecular mechanisms are largely unknown. In this study, we sought to investigate the role of autophagy in the process of LD disappearance, and to further examine the underlying mechanisms in this molecular context. We found that LD disappearance during HSC activation was associated with a coordinate increase in autophagy. Inhibition or depletion of autophagy by Atg5 siRNA impaired LD disappearance of quiescent HSCs, and also restored lipocyte phenotype of activated HSCs. In contrast, induction of autophagy by Atg5 plasmid accelerated LD loss of quiescent HSCs. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of autophagy activation. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, and in turn, prevented autophagosome generation and autophagic flux during HSC activation. Besides, we found that HSC activation triggered Rab25 overexpression, and promoted the combination of Rab25 and PI3KCIII, which direct autophagy to recognize, wrap and degrade LDs. Down-regulation of Rab25 activity, using Rab25 siRNA, blocked the target recognition of autophagy on LDs, and inhibited LD disappearance of quiescent HSCs. Moreover, the scavenging of excessive ROS could disrupt the interaction between autophagy and Rab25, and increase intracellular lipid content. Overall, these results provide novel implications to reveal the molecular mechanism of LD disappearance during HSC activation, and also identify ROS-Rab25-dependent autophagy as a potential target for the treatment of liver fibrosis.}, }
@article {pmid28035417, year = {2017}, author = {Park, WH}, title = {Gallic acid induces HeLa cell death via increasing GSH depletion rather than ROS levels.}, journal = {Oncology reports}, volume = {37}, number = {2}, pages = {1277-1283}, doi = {10.3892/or.2016.5335}, pmid = {28035417}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Death/drug effects ; Gallic Acid/*pharmacology ; Glutathione/*metabolism ; HeLa Cells/drug effects/metabolism ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Gallic acid (GA; 3,4,5-triphydroxyl-benzoic acid) is widely dispersed in various plants, fruits and foods and it shows various biological properties including anticancer effects. This study investigated the effects of GA on HeLa cervical cancer cells in relation to cell death, reactive oxygen species (ROS) and glutathione (GSH). GA dose-dependently inhibited the growth of HeLa cells and human umbilical vein endothelial cells (HUVEC) at 24 or 72 h. The susceptibility of HeLa cells to GA was higher than that of HUVEC. GA induced apoptosis in HeLa cells, which was accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm). GA increased ROS levels including O2•- in HeLa cells at 24 h and it also induced GSH depletion. N-acetyl cysteine (NAC) increased the growth inhibition of GA-treated HeLa cells and enhanced the death of these cells. NAC differently influenced ROS levels in GA-treated HeLa cells and significantly increased GSH depletion in these cells. L-buthionine sulfoximine (BSO) increased MMP (∆ψm) loss, ROS levels and GSH depletion in GA-treated HeLa cells. In conclusion, GA significantly inhibited the growth of HeLa cells. GA-induced HeLa cell death was tightly related to GSH depletion rather than ROS level changes.}, }
@article {pmid28032714, year = {2016}, author = {Liu, YK and Yang, HW and Wang, MH and Wang, W and Liu, F and Yang, HL}, title = {N-acetylcysteine Attenuates Cobalt Nanoparticle-Induced Cytotoxic Effects through Inhibition of Cell Death, Reactive Oxygen Species-related Signaling and Cytokines Expression.}, journal = {Orthopaedic surgery}, volume = {8}, number = {4}, pages = {496-502}, pmid = {28032714}, issn = {1757-7861}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Biomarkers/metabolism ; Blotting, Western ; Cell Line ; Cobalt/*toxicity ; Cytokines/*metabolism ; Free Radical Scavengers/*pharmacology ; Hip Prosthesis/adverse effects ; Metal-on-Metal Joint Prostheses/adverse effects ; Mice ; Nanoparticles/*toxicity ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {OBJECTIVE: Complex cobalt-chromium alloys, bearing surfaces of the second-generation metal-on-metal (MoM) hip prostheses, are subject to wear and generate cobalt nanoparticles (CoNPs). CoNPs could reduce cellular viability, activate the mitogen-activated protein kinase (MAPK) pathway and increase cell apoptosis via reactive oxygen species (ROS). However, the detailed mechanisms of ROS functioning on CoNP-mediated signaling molecules and cytotoxicity has not yet been fully demonstrated. The present study investigated the functional role of N-acetylcysteine (NAC) in reversing the activation of ROS signaling pathways triggered by CoNPs in normal mice kidney cells (TCMK-1 cells).<br><br>METHODS: After being pretreated with NAC, TCMK-1 cells were treated with 300-700&#x2009;&#x3bc;mol/L CoNPs, then, CCK-8 assay was used to verify the survival of TCMK-1 cells. Annexin V/PI staining was performed to investigate the apoptosis of TCMK-1 cells after NAC and different concentrations of CoNP treatments. In addition, western blot was performed to identify the cytokine (p-ERK, p-p38, and p-JNK) expression of the ROS-related MAPK signaling pathway.<br><br>RESULTS: Apoptosis rate of TCMK-1 cells was increased obviously after different concentrations of CoNP treatment. However, TCMK-1 cells, pretreated with NAC, exhibited a significantly decreased apoptosis rate. In addition, p-ERK, p-p38, and p-JNK expressions were increased with CoNP treatment, which indicated that CoNPs could activate the MAPK pathway. Interestingly, this entire stimulated phenomenon by CoNPs was reversed with NAC treatment.<br><br>CONCLUSIONS: These findings indicated that NAC could reverse CoNP-induced cytotoxicity by inhibiting ROS-induced cell death and cytokine expression. To our knowledge, this is the first report that describes how CoNP-induced cytotoxicity in TCMK-1 cells could be attenuated by anti-oxidative agents (NAC), which may function through inhibition of cell death and ROS.}, }
@article {pmid28025121, year = {2017}, author = {Li, R and Zhou, P and Guo, Y and Lee, JS and Zhou, B}, title = {Tris (1, 3-dichloro-2-propyl) phosphate induces apoptosis and autophagy in SH-SY5Y cells: Involvement of ROS-mediated AMPK/mTOR/ULK1 pathways.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {100}, number = {}, pages = {183-196}, doi = {10.1016/j.fct.2016.12.029}, pmid = {28025121}, issn = {1873-6351}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Autophagy-Related Protein-1 Homolog/*metabolism ; Blotting, Western ; Flow Cytometry ; Humans ; Intracellular Signaling Peptides and Proteins/*metabolism ; Microscopy, Fluorescence ; Neuroblastoma/drug therapy/metabolism/*pathology ; Organophosphorus Compounds/*pharmacology ; Reactive Oxygen Species/*metabolism ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in the environment and biota. Recent studies have shown that TDCIPP has neurotoxic effects. We hypothesized that the neurotoxicity might occur via the induction of the apoptosis and autophagy pathways. In the present study, we investigated TDCIPP-induced apoptotic death and autophagy in SH-SY5Y cells. Treatment with TDCIPP induced increased reactive oxygen species (ROS) generation and cell apoptosis, as well as autophagy. The autophagy inhibitor 3-methyladenine (3-MA) markedly decreased the expression of the autophagy marker beclin-1, microtubule-associated protein light chain 3-II (LC3II), p62/sequestosome 1 (SQSTM1) degradation, and promoted apoptosis. Conversely, the autophagy inducer rapamycin (Rapa) alleviated TDCIPP-induced apoptosis and markedly increased the expression of the autophagy markers. Pretreatment with N-acetyl cysteine (NAC) eliminated the increased ROS generation, resulting in increased cell viability. For further examination of the signaling pathways involved in TDCIPP-induced autophagy, compound C, a pharmacological inhibitor of adenosine monophosphate activated protein kinase (AMPK) was used. Western blotting showed that compound C markedly reduced the expression of phospho-AMPK (p-AMPK) and phospho-Unc-51-like kinase 1 (p-ULK1), increased phospho-mammalian target of rapamycin (p-mTOR) expression, and decreased beclin-1 and LC3II expression. These results suggested that the AMPK/mTOR/ULK1 signaling pathway was involved in TDCIPP-induced autophagy. The antioxidant NAC antagonized TDCIPP-induced activation of AMPK and autophagy. Taken together, our findings provide the first evidence that TDCIPP promotes apoptosis and autophagy simultaneously and that this process involves the ROS-mediated AMPK/mTOR/ULK1 pathways. Lastly, the induction of autophagy is a protective mechanism against TDCIPP-induced apoptosis.}, }
@article {pmid28024936, year = {2017}, author = {Akhtar, MJ and Ahamed, M and Alhadlaq, HA and Alshamsan, A}, title = {Nanotoxicity of cobalt induced by oxidant generation and glutathione depletion in MCF-7 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {40}, number = {}, pages = {94-101}, doi = {10.1016/j.tiv.2016.12.012}, pmid = {28024936}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Buthionine Sulfoximine/pharmacology ; Caspase 3/metabolism ; Cell Survival/drug effects ; Cobalt/chemistry/*toxicity ; Glutathione/antagonists &amp; inhibitors/metabolism ; Humans ; Lipid Peroxidation/drug effects ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/chemistry/*toxicity/ultrastructure ; Microscopy, Electron, Scanning ; Microscopy, Electron, Transmission ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Solubility ; X-Ray Diffraction ; }, abstract = {There are very few studies regarding the biological activity of cobalt-based nanoparticles (NPs) and, therefore, the possible mechanism behind the biological response of cobalt NPs has not been fully explored. The present study was designed to explore the potential mechanisms of the cytotoxicity of cobalt NPs in human breast cancer (MCF-7) cells. The shape and size of cobalt NPs were characterized by scanning and transmission electron microscopy (SEM and TEM). The crystallinity of NPs was determined by X-ray diffraction (XRD). The dissolution of NPs was measured in phosphate-buffered saline (PBS) and culture media by atomic absorption spectroscopy (AAS). Cytotoxicity parameters, such as [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT), neutral red uptake (NRU), and lactate dehydrogenase (LDH) release suggested that cobalt NPs were toxic to MCF-7 cells in a dose-dependent manner (50-200μg/ml). Cobalt NPs also significantly induced reactive oxygen species (ROS) generation, lipid peroxidation (LPO), mitochondrial outer membrane potential loss (MOMP), and activity of caspase-3 enzymes in MCF-7 cells. Moreover, cobalt NPs decreased intracellular antioxidant glutathione (GSH) molecules. The exogenous supply of antioxidant N-acetyl cysteine in cobalt NP-treated cells restored the cellular GSH level and prevented cytotoxicity that was also confirmed by microscopy. Similarly, the addition of buthionine-[S, R]-sulfoximine, which interferes with GSH biosynthesis, potentiated cobalt NP-mediated toxicity. Our data suggested that low solubility cobalt NPs could exert toxicity in MCF-7 cells mainly through cobalt NP dissolution to Co[2+].}, }
@article {pmid28012047, year = {2017}, author = {Jang, HS and Um, SI and Lee, SH and Whang, WK and Min, YS and Park, SY and Sohn, UD}, title = {The protective mechanism of QGC in feline esophageal epithelial cells by interleukin-1β treatment.}, journal = {Archives of pharmacal research}, volume = {40}, number = {2}, pages = {204-213}, doi = {10.1007/s12272-016-0858-x}, pmid = {28012047}, issn = {1976-3786}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cats ; Cell Survival/drug effects ; Cells, Cultured ; Cyclooxygenase 2/metabolism ; Epithelial Cells/*drug effects ; Esophageal Mucosa/cytology ; Flavonoids/pharmacology ; Fluoresceins/metabolism ; I-kappa B Kinase/metabolism ; Imidazoles/pharmacology ; Interleukin-1beta/*metabolism ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Phosphorylation ; Pyridines/pharmacology ; Quercetin/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species/*metabolism ; Rumex/chemistry ; Signal Transduction ; }, abstract = {In a previous study, Quercetin-3-O-β-D-glucuronopyranoside (QGC) has anti-oxidative and anti-inflammatory effects in vivo. QGC is a flavonoid glucoside extracted from Rumex Aquaticus. We investigated the downstream target proteins involved in IL-1β-stimulated ROS production and the ability of QGC to inhibit ROS production. Cell viability was determined using the MTT reduction assay. Western blot analysis was performed with antibodies to investigate the activation of three MAPKs, NF-κB, and phosphorylated IκB-α (pIB), and the expression of COX-2. 2',7'-dichlorofluorescin diacetate was used to detect the generation of intracellular ROS species. When the cells were exposed to media containing IL-1β for 18 h, cell viability was not affected. QGC did not reduce the COX-2 expression induced by IL-1β. However; QGC attenuated the production of intracellular ROS induced by IL-1β. IL-1β increased the expression of ERK, p38 MAPK, and pIB, and nuclear translocation of NF-κB were recovered by the ROS scavenger N-acetyl-L-cysteine (NAC) and QGC, but not by the NADPH oxidase inhibitor diphenylene iodonium. Pretreatment of cells with the ERK inhibitor PD98059, the p38 MAPK inhibitor SB202190, NAC, and QGC attenuated nuclear translocation of NF-κB and activation of pIB. QGC has a scavenging effect on cytokine-induced ROS production, thereby preventing its downstream effects, nuclear translocation of NF-κB, and activation of pIB is mediated by activation of ERK and p38 MAPK, although QGC does not inhibit IL-1β-stimulated COX-2 expression in feline esophageal epithelial cells. The data suggest that QGC exerts anti-oxidative effects and inhibitory effects against esophageal epithelial cells signals by the action of IL-1β treatment.}, }
@article {pmid28011677, year = {2017}, author = {Tersteeg, C and Roodt, J and Van Rensburg, WJ and Dekimpe, C and Vandeputte, N and Pareyn, I and Vandenbulcke, A and Plaimauer, B and Lamprecht, S and Deckmyn, H and Lopez, JA and De Meyer, SF and Vanhoorelbeke, K}, title = {N-acetylcysteine in preclinical mouse and baboon models of thrombotic thrombocytopenic purpura.}, journal = {Blood}, volume = {129}, number = {8}, pages = {1030-1038}, doi = {10.1182/blood-2016-09-738856}, pmid = {28011677}, issn = {1528-0020}, mesh = {ADAMTS13 Protein/genetics/metabolism ; Acetylcysteine/*therapeutic use ; Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Female ; Gene Deletion ; Male ; Mice ; Mice, Inbred C57BL ; Papio ; Protein Multimerization/*drug effects ; Purpura, Thrombotic Thrombocytopenic/drug therapy/genetics/metabolism/*prevention &amp; control ; von Willebrand Factor/chemistry/*metabolism ; }, abstract = {Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic disorder diagnosed by thrombocytopenia and hemolytic anemia, associated with a deficiency in von Willebrand factor (VWF)-cleaving protease ADAMTS13. Current treatment is based on plasma infusion for congenital TTP, or plasma exchange, often in combination with immunosuppressive agents, for acquired TTP. These treatment methods are not always effective; therefore, new treatment methods are highly necessary. N-acetylcysteine (NAC), an FDA-approved anti-mucolytic agent, is a possible new treatment strategy for TTP, as it was demonstrated to reduce disulfide bonds in VWF, thereby decreasing VWF multimers size and hence their prothrombotic potential. We investigated whether NAC, without concurrent plasma exchange and immunosuppressive therapy, is effective in preventing and resolving TTP signs, using well-established murine and baboon models for TTP. In mice, prophylactic administration of NAC was effective in preventing severe TTP signs. This in vivo finding was supported by in vitro data demonstrating the VWF multimer-reducing properties of NAC in solution. Nonetheless, in both mice and baboons, administration of NAC was not effective in resolving preexisting TTP signs; thrombocytopenia, hemolytic anemia, and organ damage could not be reversed, as thrombus resolution was not achieved. Failure to improve clinical outcome occurred even though a reduction in VWF multimers was observed, demonstrating that NAC was efficient in reducing disulfide bonds in circulating VWF multimers. In conclusion, prophylactic administration of NAC, without concurrent plasma exchange, was effective in preventing severe TTP signs in mice, but NAC was not effective in resolving preexistent acute TTP signs in mice and baboons.}, }
@article {pmid28005432, year = {2017}, author = {Zhang, T and Mu, Y and Yang, M and Al Maruf, A and Li, P and Li, C and Dai, S and Lu, J and Dong, Q}, title = {(+)-Catechin prevents methylglyoxal-induced mitochondrial dysfunction and apoptosis in EA.hy926 cells.}, journal = {Archives of physiology and biochemistry}, volume = {123}, number = {2}, pages = {121-127}, doi = {10.1080/13813455.2016.1263868}, pmid = {28005432}, issn = {1744-4160}, mesh = {Apoptosis/*drug effects ; Catechin/*pharmacology ; Cells, Cultured ; Endothelium, Vascular/*drug effects/metabolism/pathology ; Humans ; Hydrogen Peroxide/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism/*pathology ; Oxidants/metabolism ; Oxidative Stress/drug effects ; Pyruvaldehyde/*adverse effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {OBJECTIVE: To investigate whether (+)-catechin, a strong antioxidant, can prevent methylglyoxal (MGO)-induced cytotoxicity and its mechanism.<br><br>METHODS: Cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, hydrogen peroxide (H2O2) formation, mitochondrial membrane potential (MMP) and mitochondrial morphology were measured in EA.hy926 cells.<br><br>RESULT: MGO (4&#x2009;mM)-induced cytotoxicity was markedly inhibited by (+)-catechin (0.1-4&#x2009;mM) in 24&#x2009;h. 1&#x2009;mM MGO-induced apoptotic cell death (44.7%) was significantly inhibited by 4&#x2009;mM (+)-catechin (to 24.4%), 1&#x2009;mM aminoguanidine (AG) (to 28.8%) or 4&#x2009;mM N-acetylcysteine (NAC) (to 24.3%). (+)-Catechin (4&#x2009;mM) or AG (4&#x2009;mM) can inhibit the decrease of MMP induced by MGO (2-8&#x2009;mM) in 3&#x2009;h. (+)-Catechin (4&#x2009;mM) or AG (4&#x2009;mM) can inhibit MGO (4&#x2009;mM)-induced mitochondrial swelling in 3&#x2009;h. However, MGO (4&#x2009;mM)-induced ROS and H2O2 generation was not prevented by (+)-catechin (4&#x2009;mM).<br><br>CONCLUSIONS: (+)-Catechin prevents MGO-induced cytotoxicity in EA.Hy926 cells through inhibiting apoptosis and mitochondrial damage.}, }
@article {pmid28004071, year = {2016}, author = {Chen, QZ and Fu, ZD and Zhou, YB and Zhou, LF and Yang, CT and Li, JH}, title = {[N-acetyl-L-cysteine reduces the ozone-induced lung inflammation response in mice].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {68}, number = {6}, pages = {767-774}, pmid = {28004071}, issn = {0371-0874}, mesh = {Acetylcysteine ; Animals ; Antioxidants ; Bronchoalveolar Lavage Fluid ; Interleukin-6 ; Lung ; Mice ; Mice, Inbred C57BL ; NF-kappa B ; Neutrophils ; Ozone ; *Pneumonia ; }, abstract = {In this study, we investigated the protective effect of the antioxidant N-acetyl-L-cysteine (NAC) on the lung inflammation caused by ozone (O3) exposure in mice. Thirty-two C57BL/6 mice were randomly divided into control group, O3 group, O3+NAC group and NAC group. Mice were exposed to O3 (1.0 ppm) or fresh air for 3 h on the day 1, day 3 and day 5, respectively. NAC (100 mg/kg) was intraperitoneally applied to the mice 1 h before each exposure. At 24 h after the 3-time exposure, the alveolar wall structure was severely damaged and the infiltrated inflammatory cells were apparent perivascularly and peribronchiolarly. Significant increases in the total white blood cell count, macrophage, lymphocyte and neutrophil counts, as well as total protein concentration were observed in the bronchoalveolar lavage fluid (BALF) (P < 0.05). The IL-6, IL-8 (P < 0.01) and MDA levels (P < 0.05) in the lung homogenates were elevated coherently. Administration of NAC could attenuate the alveolar wall structure damage induced by O3 exposure and reduce the amount of infiltrated inflammatory cells, total and differential leukocyte counts (P < 0.05), as well as the IL-6, IL-8 (P < 0.01) and MDA release (P < 0.05). Western blotting results showed that the O3 exposure up-regulated the p38 MAPK and NF-κB p65 protein expression in the lung tissue of mice (P < 0.05), which could be alleviated by NAC (P < 0.05). These results indicated that NAC could protect against O3-induced pulmonary inflammation in mice. The beneficial effect of NAC might be related with the p38 MAPK and NF-κB p65 signal pathway.}, }
@article {pmid28003713, year = {2016}, author = {Xiao, H and Wu, M and Shao, F and Guan, G and Huang, B and Tan, B and Yin, Y}, title = {N-Acetyl-L-cysteine Protects the Enterocyte against Oxidative Damage by Modulation of Mitochondrial Function.}, journal = {Mediators of inflammation}, volume = {2016}, number = {}, pages = {8364279}, pmid = {28003713}, issn = {1466-1861}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/chemistry ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Proliferation ; Cell Survival ; Cytochromes c/metabolism ; DNA/metabolism ; Enterocytes/*drug effects ; Flow Cytometry ; Free Radical Scavengers/metabolism ; Hydrogen Peroxide/chemistry ; Mitochondria/drug effects/*metabolism ; *Oxidative Stress ; Swine ; bcl-X Protein/metabolism ; }, abstract = {The neonatal small intestine is susceptible to damage caused by oxidative stress. This study aimed to evaluate the protective role of antioxidant N-acetylcysteine (NAC) in intestinal epithelial cells against oxidative damage induced by H2O2. IPEC-J2 cells were cultured in DMEM-H with NAC and H2O2. After 2-day incubation, IPEC-J2 cells were collected for analysis of DNA synthesis, antioxidation capacity, mitochondrial respiration, and cell apoptosis. The results showed that H2O2 significantly decreased (P < 0.05) proliferation rate, mitochondrial respiration, and antioxidation capacity and increased cell apoptosis and the abundance of associated proteins, including cytochrome C, Bcl-XL, cleaved caspase-3, and total caspase-3. NAC supplementation remarkably increased (P < 0.05) proliferation rate, antioxidation capacity, and mitochondrial bioenergetics but decreased cell apoptosis. These findings indicate that NAC might rescue the intestinal injury induced by H2O2.}, }
@article {pmid28002632, year = {2017}, author = {Chen, CC and Hsia, CW and Ho, CW and Liang, CM and Chen, CM and Huang, KL and Kang, BH and Chen, YH}, title = {Hypoxia and hyperoxia differentially control proliferation of rat neural crest stem cells via distinct regulatory pathways of the HIF1α-CXCR4 and TP53-TPM1 proteins.}, journal = {Developmental dynamics : an official publication of the American Association of Anatomists}, volume = {246}, number = {3}, pages = {162-185}, doi = {10.1002/dvdy.24481}, pmid = {28002632}, issn = {1097-0177}, mesh = {Animals ; Apoptosis/genetics/physiology ; Blotting, Western ; Cell Proliferation/genetics/physiology ; Cell Survival/genetics/physiology ; Embryonic Stem Cells/cytology/*metabolism ; Female ; Fluorescent Antibody Technique ; Hair Follicle/cytology/metabolism ; Hyperoxia/*metabolism/physiopathology ; Hypoxia/*metabolism/physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Neural Crest/*cytology ; Oxidative Stress/genetics/physiology ; RNA, Small Interfering/genetics ; Rats ; Rats, Sprague-Dawley ; Receptors, CXCR4/genetics/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics/physiology ; Tropomyosin/genetics/*metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {BACKGROUND: Neural crest stem cells (NCSCs) are a population of adult multipotent stem cells. We are interested in studying whether oxygen tensions affect the capability of NCSCs to self-renew and repair damaged tissues. NCSCs extracted from the hair follicle bulge region of the rat whisker pad were cultured in vitro under different oxygen tensions.<br><br>RESULTS: We found significantly increased and decreased rates of cell proliferation in rat NCSCs (rNCSCs) cultured, respectively, at 0.5% and 80% oxygen levels. At 0.5% oxygen, the expression of both hypoxia-inducible factor (HIF) 1&#x3b1; and CXCR4 was greatly enhanced in the rNCSC nuclei and was suppressed by incubation with the CXCR4-specific antagonist AMD3100. In addition, the rate of cell apoptosis in the rNCSCs cultured at 80% oxygen was dramatically increased, associated with increased nuclear expression of TP53, decreased cytoplasmic expression of TPM1 (tropomyosin-1), and increased nuclear-to-cytoplasmic translocation of S100A2. Incubation of rNCSCs with the antioxidant N-acetylcysteine (NAC) overcame the inhibitory effect of 80% oxygen on proliferation and survival of rNCSCs.<br><br>CONCLUSIONS: Our results show for the first time that extreme oxygen tensions directly control NCSC proliferation differentially via distinct regulatory pathways of proteins, with hypoxia via the HIF1&#x3b1;-CXCR4 pathway and hyperoxia via the TP53-TPM1 pathway. Developmental Dynamics 246:162-185, 2017. &#xa9; 2016 Wiley Periodicals, Inc.}, }
@article {pmid27990559, year = {2017}, author = {Kho, AR and Choi, BY and Kim, JH and Lee, SH and Hong, DK and Lee, SH and Jeong, JH and Sohn, M and Suh, SW}, title = {Prevention of hypoglycemia-induced hippocampal neuronal death by N-acetyl-L-cysteine (NAC).}, journal = {Amino acids}, volume = {49}, number = {2}, pages = {367-378}, doi = {10.1007/s00726-016-2370-5}, pmid = {27990559}, issn = {1438-2199}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood-Brain Barrier/drug effects ; Cell Death/drug effects ; Glutathione/metabolism ; Hippocampus/drug effects/*pathology ; Hypoglycemia/drug therapy/metabolism/*pathology ; Male ; Microglia/drug effects ; Neurons/*drug effects/metabolism/pathology ; Rats, Sprague-Dawley ; Zinc/metabolism ; }, abstract = {Type 1 and type 2 diabetic patients who are treated with insulin or other blood glucose reducing agents for tight control of blood glucose levels are frequently at risk of experiencing severe hypoglycemia which can lead to seizures, loss of consciousness and death. Hypoglycemic neuronal cell death is not a simple result of low glucose supply to the brain, but, instead, results from a cell death signaling pathway that is started by the re-administration of glucose after glucose deprivation. Zinc is a biologically important element for physiological function of central nervous system. However, excessive zinc release from the presynaptic terminals and subsequent translocation into the postsynaptic neurons may contribute to neuronal death following hypoglycemia. N-acetyl-L-cysteine (NAC) acts as a zinc chelator that alleviates zinc-induced neuronal death processes. In addition, NAC restores levels of neuronal glutathione (GSH), a potent antioxidant, by providing a cell-permeable source of cysteine. Thus, we hypothesized that NAC treatment can reduce neuronal cell death, not only by increasing GSH concentration but also by zinc chelation. As a result, we found that NAC decreased the oxidative stress, zinc release and translocation, and improved the level of glutathione. Therefore, NAC administration alleviated hippocampal neuron death in hypoglycemia-induced rats.}, }
@article {pmid27989749, year = {2016}, author = {Zhang, Z and Guo, M and Zhao, S and Shao, J and Zheng, S}, title = {ROS-JNK1/2-dependent activation of autophagy is required for the induction of anti-inflammatory effect of dihydroartemisinin in liver fibrosis.}, journal = {Free radical biology &amp; medicine}, volume = {101}, number = {}, pages = {272-283}, doi = {10.1016/j.freeradbiomed.2016.10.498}, pmid = {27989749}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/pharmacology ; Artemisinins/*pharmacology ; Autophagy/*drug effects/genetics ; Carbon Tetrachloride ; Gene Expression Regulation ; Glutathione/pharmacology ; Hepatic Stellate Cells/*drug effects/metabolism/pathology ; Humans ; Liver ; Liver Cirrhosis/chemically induced/genetics/pathology/*prevention &amp; control ; Male ; Mitogen-Activated Protein Kinase 8/antagonists &amp; inhibitors/genetics/metabolism ; Mitogen-Activated Protein Kinase 9/antagonists &amp; inhibitors/genetics/metabolism ; Primary Cell Culture ; RNA, Small Interfering/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {Accumulating evidence identifies autophagy as an inflammation-related defensive mechanism against diseases including liver fibrosis. Therefore, autophagy may represent a new pharmacologic target for drug development to treat liver fibrosis. In this study, we sought to investigate the effect of dihydroartemisinin (DHA) on autophagy, and to further examine the molecular mechanisms of DHA-induced anti-inflammatory effects. We found that DHA appeared to play an essential role in controlling excessive inflammation. DHA suppressed inflammation in rat liver fibrosis model and inhibited the expression of proinflammatory cytokines in activated hepatic stellate cells (HSCs). Interestingly, DHA increased the autophagosome generation and autophagic flux in activated HSCs, which is underlying mechanism for the anti-inflammatory activity of DHA. Autophagy depletion impaired the induction of anti-inflammatory effect of DHA, while autophagy induction showed a synergistic effect with DHA. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of DHA-induced autophagy. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, and in turn, prevented DHA-induced autophagosome generation and autophagic flux. Besides, we found that c-Jun N-terminal kinase1/2 (JNK1/2) was a downstream signaling molecule of ROS that mediated the induction of autophagy by DHA. Down-regulation of JNK1/2 activity, using selective JNK1/2 inhibitor (SP600125) or siJNK1/2, led to an inhibition of DHA-induced autophagy. Overall, these results provide novel implications to reveal the molecular mechanism of DHA-induced anti-inflammatory effects, by which points to the possibility of using DHA based proautophagic drugs for the treatment of inflammatory diseases.}, }
@article {pmid27987315, year = {2017}, author = {Alund, AW and Mercer, KE and Pulliam, CF and Suva, LJ and Chen, JR and Badger, TM and Ronis, MJ}, title = {Partial Protection by Dietary Antioxidants Against Ethanol-Induced Osteopenia and Changes in Bone Morphology in Female Mice.}, journal = {Alcoholism, clinical and experimental research}, volume = {41}, number = {1}, pages = {46-56}, pmid = {27987315}, issn = {1530-0277}, support = {R37 AA018282/AA/NIAAA NIH HHS/United States ; T32 GM106999/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*administration &amp; dosage ; Bone Density/*drug effects/physiology ; Bone Diseases, Metabolic/*chemically induced/metabolism/*prevention &amp; control ; Ethanol/*toxicity ; Female ; Mice ; Random Allocation ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND: Chronic alcohol consumption leads to increased fracture risk and an elevated risk of osteoporosis by decreasing bone accrual through increasing osteoclast activity and decreasing osteoblast activity. We have shown that this mechanism involves the generation of reactive oxygen species (ROS) produced by NADPH oxidases. It was hypothesized that different dietary antioxidants, N-acetyl cysteine (NAC; 1.2 mg/kg/d), and α-tocopherol (Vit.E; 60 mg/kg/d) would be able to attenuate the NADPH oxidase-mediated ROS effects on bone due to chronic alcohol intake.<br><br>METHODS: To study the effects of these antioxidants, female mice received a Lieber-DeCarli liquid diet containing ethanol (EtOH) with or without additional antioxidant for 8&#xa0;weeks.<br><br>RESULTS: Tibias displayed decreased cortical bone mineral density in both the EtOH and EtOH&#xa0;+&#xa0;antioxidant groups compared to pair-fed (PF) and PF&#xa0;+&#xa0;antioxidant groups (p&#xa0;<&#xa0;0.05). However, there was significant protection from trabecular bone loss in mice fed either antioxidant (p&#xa0;<&#xa0;0.05). Microcomputed tomography analysis demonstrated a significant decrease in bone volume (bone volume/tissue volume) and trabecular number (p&#xa0;<&#xa0;0.05), along with a significant increase in trabecular separation in the EtOH compared to PF (p&#xa0;<&#xa0;0.05). In contrast, the EtOH&#xa0;+&#xa0;NAC and EtOH&#xa0;+&#xa0;Vit.E did not statistically differ from their respective PF controls. Ex vivo histologic sections of tibias were stained for nitrotyrosine, an indicator of intracellular damage by ROS, and tibias from mice fed EtOH exhibited significantly more staining than PF controls. EtOH treatment significantly increased the number of marrow adipocytes per mm as well as mRNA expression of aP2, an adipocyte marker in bone. Only NAC was able to reduce the number of marrow adipocytes to PF levels. EtOH-fed mice exhibited reduced bone length (p&#xa0;<&#xa0;0.05) and had a reduced number of proliferating chondrocytes within the growth plate. NAC and Vit.E prevented this (p&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: These data show that alcohol's pathological effects on bone extend beyond decreasing bone mass and suggest a partial protective effect of the dietary antioxidants NAC and Vit.E at these doses with regard to alcohol effects on bone turnover and bone morphology.}, }
@article {pmid27986611, year = {2017}, author = {Chang, CT and Hseu, YC and Thiyagarajan, V and Huang, HC and Hsu, LS and Huang, PJ and Liu, JY and Liao, JW and Yang, HL}, title = {Antrodia salmonea induces G2 cell-cycle arrest in human triple-negative breast cancer (MDA-MB-231) cells and suppresses tumor growth in athymic nude mice.}, journal = {Journal of ethnopharmacology}, volume = {196}, number = {}, pages = {9-19}, doi = {10.1016/j.jep.2016.12.018}, pmid = {27986611}, issn = {1872-7573}, mesh = {Animals ; Antineoplastic Agents/*pharmacology/*therapeutic use ; *Antrodia ; Apoptosis/drug effects ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cyclooxygenase 2 Inhibitors/pharmacology/therapeutic use ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; Poly(ADP-ribose) Polymerases/metabolism ; Triple Negative Breast Neoplasms/*drug therapy/metabolism/pathology ; Tumor Burden/drug effects ; }, abstract = {Antrodia salmonea (AS), is a well-known folk medicinal mushroom in Taiwan, has been reported to exhibit anti-oxidant, anti-angiogenic, and anti-inflammatory effects.<br><br>MATERIALS AND METHODS: In the present study, we examined the effects of AS on cell-cycle arrest in vitro in MDA-MB-231 cells and on tumor regression in vivo using an athymic nude mice model.<br><br>RESULTS: AS (0-200&#x3bc;g/mL) treatment significantly induced G2 cell-cycle arrest in MDA-MB-231 cells by reducing the levels of cyclin B1, cyclin A, cyclin E, and CDC2 proteins. In addition, N-acetylcysteine (NAC) pretreatment prevented AS induced G2 cell-cycle arrest, indicating that ROS accumulation and subsequent cell cycle arrest might be a major mechanism of AS-induced cytotoxicity. Further, AS treatment decreased COX-2 expression and induced PARP cleavage was significantly reversed by NAC pretreatment in MDA-MB-231 cells. The in vivo study results revealed that AS treatment was effective in terms of delaying the tumor incidence and reducing the tumor growth in MDA-MB-231-xenografted nude mice. TUNEL assay, immunohistochemical staining and Western blotting confirmed that AS significantly modulated the xenografted tumor progression as demonstrated by induction of apoptosis, autophagy, and cell-cycle arrest.<br><br>CONCLUSION: Our data strongly suggest that Antrodia salmonea could be an anti-cancer agent for human breast cancer.}, }
@article {pmid27981650, year = {2017}, author = {Zhao, T and Jin, W and Pan, H and Li, H and Zhao, Y and Feng, Y}, title = {Rosbin, a synthetic small molecule, induces A549 cells apoptosis through a ROS-mediated pathway.}, journal = {Cell biology international}, volume = {41}, number = {2}, pages = {221-226}, doi = {10.1002/cbin.10714}, pmid = {27981650}, issn = {1095-8355}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 7/metabolism ; Caspase 9/metabolism ; Flow Cytometry ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Piperidines/chemistry/*pharmacology/*toxicity ; Reactive Oxygen Species/*metabolism ; Thiophenes/chemistry/*toxicity ; }, abstract = {Rosbin (Thieno [2, 3-c] piperidine-3-carboxamide-2-[(3-methoxy-naphtha-lene-2-carbonyl)-amino]-6-(benzyl)-, hydrochloride), a synthetic piperidinothieno derivative compound obtained from chemical genetics screenings, significantly suppresses the viability of non-small cell lung cancer A549 cells with an IC50 of 2.05 ± 0.31 µM. It only decreases growth of non-tumour MRC-5 cells at the doses higher than 10 µM. Rosbin induces apoptosis in a dose-dependent manner by reducing the mitochondrial membrane potential (MMP) and increasing activities of caspases-3/7 and caspase-9 in A549 cells, without affecting the activity of caspase-8. Further studies showed that reactive oxygen species (ROS) induced apoptosis of A549 in the presence of rosbin as apoptosis was inhibited by N-acetyl cysteine (NAC). These results suggest that rosbin is a novel apoptosis inducer, and ROS played a significant role in the A549 apoptosis induced by rosbin.}, }
@article {pmid27974950, year = {2016}, author = {Sakelliou, A and Fatouros, IG and Athanailidis, I and Tsoukas, D and Chatzinikolaou, A and Draganidis, D and Jamurtas, AZ and Liacos, C and Papassotiriou, I and Mandalidis, D and Stamatelopoulos, K and Dimopoulos, MA and Mitrakou, A}, title = {Evidence of a Redox-Dependent Regulation of Immune Responses to Exercise-Induced Inflammation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {2840643}, pmid = {27974950}, issn = {1942-0994}, mesh = {Exercise/*physiology ; Humans ; Inflammation/*immunology ; Male ; *Oxidation-Reduction ; Young Adult ; }, abstract = {We used thiol-based antioxidant supplementation (n-acetylcysteine, NAC) to determine whether immune mobilisation following skeletal muscle microtrauma induced by exercise is redox-sensitive in healthy humans. According to a two-trial, double-blind, crossover, repeated measures design, 10 young men received either placebo or NAC (20 mg/kg/day) immediately after a muscle-damaging exercise protocol (300 eccentric contractions) and for eight consecutive days. Blood sampling and performance assessments were performed before exercise, after exercise, and daily throughout recovery. NAC reduced the decline of reduced glutathione in erythrocytes and the increase of plasma protein carbonyls, serum TAC and erythrocyte oxidized glutathione, and TBARS and catalase activity during recovery thereby altering postexercise redox status. The rise of muscle damage and inflammatory markers (muscle strength, creatine kinase activity, CRP, proinflammatory cytokines, and adhesion molecules) was less pronounced in NAC during the first phase of recovery. The rise of leukocyte and neutrophil count was decreased by NAC after exercise. Results on immune cell subpopulations obtained by flow cytometry indicated that NAC ingestion reduced the exercise-induced rise of total macrophages, HLA[+] macrophages, and 11B[+] macrophages and abolished the exercise-induced upregulation of B lymphocytes. Natural killer cells declined only in PLA immediately after exercise. These results indicate that thiol-based antioxidant supplementation blunts immune cell mobilisation in response to exercise-induced inflammation suggesting that leukocyte mobilization may be under redox-dependent regulation.}, }
@article {pmid27959381, year = {2017}, author = {Jayakumar, T and Lin, KC and Lu, WJ and Lin, CY and Pitchairaj, G and Li, JY and Sheu, JR}, title = {Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms.}, journal = {International journal of molecular medicine}, volume = {39}, number = {1}, pages = {174-182}, pmid = {27959381}, issn = {1791-244X}, mesh = {Acetylcysteine/pharmacology ; Blood Platelets/drug effects/*metabolism ; Cell Adhesion Molecules/*metabolism ; Citrus/*chemistry ; Electron Spin Resonance Spectroscopy ; Flavones/*pharmacology ; Flavonoids/*pharmacology ; Humans ; Hydroxyl Radical/metabolism ; Intracellular Space/drug effects/metabolism ; Microfilament Proteins/*metabolism ; Mitogen-Activated Protein Kinases/metabolism ; NADPH Oxidases/metabolism ; NF-kappa B/metabolism ; Nucleotides, Cyclic/*metabolism ; Phosphoproteins/*metabolism ; Phosphorylation/drug effects ; Protein Carbonylation/drug effects ; Protein Kinase C/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; }, abstract = {Nobiletin, a bioactive polymethoxylated flavone, has been described to possess a diversity of biological effects through its antioxidant and anti-inflammatory properties. Vasodilator-stimulated phosphoprotein (VASP) is a common substrate for cyclic AMP and cyclic GMP-regulated protein kinases [i.e., cyclic AMP-dependent protein kinase (PKA; also known as protein kinase A) and cyclic GMP-dependent protein kinase (PKG; also known as protein kinase G)] and it has been shown to be directly phosphorylated by protein kinase C (PKC). In the present study, we demonstrate that VASP is phosphorylated by nobiletin in human platelets via a non-cyclic nucleotide-related mechanism. This was confirmed by the use of inhibitors of adenylate cyclase (SQ22536) and guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)], since they prevented VASP phosphorylation induced by nobiletin. Furthormore, this event was also not affected by specific inhibitors of PKA (H-89), PKG (KT5823) and PKC (Ro318220), representing cyclic nucleotide-dependent pathways upon nobiletin-induced VASP phosphorylation. Similarly, inhibitors of p38 mitogen-activated protein kinase (MAPK; SB203580), extracellular signal-regulated kinase 2 (ERK2; PD98059), c-Jun N-terminal kinase 1 (JNK1; SP600125), Akt (LY294002) and nuclear factor-κB (NF-κB; Bay11-7082) did not affect nobiletin‑induced VASP phosphorylation. Moreover, electron spin resonance, dichlorofluorescein fluorescence and western blotting techniques revealed that nobiletin did not affect hydroxyl radicals (OH•), intracellular reactive oxygen species (ROS) and on protein carbonylation, respectively. Furthermore, the nobiletin‑induced VASP phosphorylation was surprisingly reversed by the intracellular antioxidant, N-acetylcysteine (NAC), but not by the inhibitor of NADPH oxidase, diphenyleneiodonium chloride (DPI). It was surprising to observe the differential effects of nobiletin and NAC on VASP phosphorylation in human platelets, since they both have been reported to have antioxidant properties. The likely explanation for this discrepancy is that NAC may bind to allosteric sites on the receptor different from those that nobiletin binds to in human platelets. Taken together, our findings suggest that nobiletin induces VASP phosphorylation in human platelets through non-cyclic nucleotide-related mechanisms. Nevertheless, the exact mechanisms responsible for these effects need to be further confirmed in future studies.}, }
@article {pmid27957685, year = {2018}, author = {Sun, Y and Sukumaran, P and Selvaraj, S and Cilz, NI and Schaar, A and Lei, S and Singh, BB}, title = {TRPM2 Promotes Neurotoxin MPP[+]/MPTP-Induced Cell Death.}, journal = {Molecular neurobiology}, volume = {55}, number = {1}, pages = {409-420}, pmid = {27957685}, issn = {1559-1182}, support = {DE017102/DE/NIDCR NIH HHS/United States ; R01 DE017102/DE/NIDCR NIH HHS/United States ; GM103442/GM/NIGMS NIH HHS/United States ; GM113123/GM/NIGMS NIH HHS/United States ; R21 DE024300/DE/NIDCR NIH HHS/United States ; P20 GM113123/GM/NIGMS NIH HHS/United States ; DE024300/DE/NIDCR NIH HHS/United States ; P20 GM103442/GM/NIGMS NIH HHS/United States ; }, mesh = {1-Methyl-4-phenylpyridinium/*toxicity ; Aged ; Animals ; Cell Death/drug effects/physiology ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Dopaminergic Neurons/drug effects/*metabolism/pathology ; Female ; Herbicides/toxicity ; Humans ; MPTP Poisoning/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Parkinson Disease/*metabolism/pathology ; TRPM Cation Channels/*biosynthesis/genetics ; }, abstract = {In neurons, Ca[2+] is essential for a variety of physiological processes that regulate gene transcription to neuronal growth and their survival. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ions (MPP[+]) are potent neurotoxins that selectively destroys the dopaminergic (DA) neurons and mimics Parkinson's disease (PD) like symptoms, but the mechanism as how MPP[+]/MPTP effects DA neuron survival is not well-understood. In the present study, we found that MPP[+] treatment increased the level of reactive oxygen species (ROS) that activates and upregulates the expression and function of melastatin-like transient receptor potential (TRPM) subfamily member, melastatin-like transient receptor potential channel 2 (TRPM2). Correspondingly, TRPM2 expression was also increased in substantia nigra of MPTP-induced PD mouse model and PD patients. ROS-mediated activation of TRPM2 resulted in an increased intracellular Ca[2+], which in turn promoted cell death in SH-SY5Y cells. Intracellular Ca[2+] overload caused by MPP[+]-induced ROS also affected calpain activity, followed by increased caspase 3 activities and activation of downstream apoptotic pathway. On the other hand, quenching of H2O2 by antioxidants, resveratrol (RSV), or N-acetylcysteine (NAC) effectively blocked TRPM2-mediated Ca[2+] influx, decreased intracellular Ca[2+] overload, and increased cell survival. Importantly, pharmacological inhibition of TRPM2 or knockdown of TRPM2 using siRNA, but not control siRNA, showed an increased protection by preventing MPP[+]-induced Ca[2+] increase and inhibited apoptosis. Taken together, we show here a novel role for TRPM2 expression and function in MPP[+]-induced dopaminergic neuronal cell death.}, }
@article {pmid27957238, year = {2016}, author = {Moura, FA and de Andrade, KQ and de Araújo, OR and Nunes-Souza, V and Santos, JC and Rabelo, LA and Goulart, MO}, title = {Colonic and Hepatic Modulation by Lipoic Acid and/or N-Acetylcysteine Supplementation in Mild Ulcerative Colitis Induced by Dextran Sodium Sulfate in Rats.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {4047362}, pmid = {27957238}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Body Weight/drug effects ; Colitis, Ulcerative/*chemically induced/*drug therapy/pathology ; Colon/drug effects/pathology ; Cytokines/metabolism ; Dextran Sulfate ; *Dietary Supplements ; Feeding Behavior/drug effects ; Inflammation/pathology ; Liver/drug effects/pathology ; Male ; Organ Size/drug effects ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Thioctic Acid/pharmacology/*therapeutic use ; }, abstract = {Lipoic acid (LA) and N-acetylcysteine (NAC) are antioxidant and anti-inflammatory agents that have not yet been tested on mild ulcerative colitis (UC). This study aims to evaluate the action of LA and/or NAC, on oxidative stress and inflammation markers in colonic and hepatic rat tissues with mild UC, induced by dextran sodium sulfate (DSS) (2% w/v). LA and/or NAC (100 mg·kg·day[-1], each) were given, once a day, in the diet, in a pretreatment phase (7 days) and during UC induction (5 days). Colitis induction was confirmed by histological and biochemical analyses (high performance liquid chromatography, spectrophotometry, and Multiplex®). A redox imbalance occurred before an immunological disruption in the colon. NAC led to a decrease in hydrogen peroxide (H2O2), malondialdehyde (MDA) levels, and myeloperoxidase activity. In the liver, DSS did not cause damage but treatments with both antioxidants were potentially harmful, with LA increasing MDA and LA + NAC increasing H2O2, tumor necrosis factor alpha, interferon gamma, and transaminases. In summary, NAC exhibited the highest colonic antioxidant and anti-inflammatory activity, while LA + NAC caused hepatic damage.}, }
@article {pmid27943387, year = {2017}, author = {Li, J and Wang, Q and Yang, R and Zhang, J and Li, X and Zhou, X and Miao, D}, title = {BMI-1 Mediates Estrogen-Deficiency-Induced Bone Loss by Inhibiting Reactive Oxygen Species Accumulation and T Cell Activation.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {32}, number = {5}, pages = {962-973}, doi = {10.1002/jbmr.3059}, pmid = {27943387}, issn = {1523-4681}, mesh = {Acetylcysteine/pharmacology ; Animals ; CD4-Positive T-Lymphocytes/*metabolism ; Estrogens/*deficiency ; Female ; Humans ; *Lymphocyte Activation ; Mice ; Mice, Transgenic ; Osteoporosis, Postmenopausal/drug therapy/genetics/*metabolism ; Ovariectomy ; Polycomb Repressive Complex 1/genetics/*metabolism ; Proto-Oncogene Proteins/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Estrogen/metabolism ; }, abstract = {Previous studies have shown that estrogen regulates bone homeostasis through regulatory effects on oxidative stress. However, it is unclear how estrogen deficiency triggers reactive oxygen species (ROS) accumulation. Recent studies provide evidence that the B lymphoma Mo-MLV insertion region 1 (BMI-1) plays a critical role in protection against oxidative stress and that this gene is directly regulated by estrogen via estrogen receptor (ER) at the transcriptional level. In this study, ovariectomized mice were given drinking water with/without antioxidant N-acetyl-cysteine (NAC, 1 mg/mL) supplementation, and compared with each other and with sham mice. Results showed that ovariectomy resulted in bone loss with increased osteoclast surface, increased ROS levels, T cell activation, and increased TNF and RANKL levels in serum and in CD4 T cells; NAC supplementation largely prevented these alterations. BMI-1 expression levels were dramatically downregulated in CD4 T cells from ovariectomized mice. We supplemented drinking water to BMI-1-deficient mice with/without NAC and compared them with each other and with wild-type (WT) mice. We found that BMI-1 deficiency mimicked alterations observed in ovariectomy whereas NAC supplementation reversed all alterations induced by BMI-1 deficiency. Because T cells are critical in mediating ovariectomy-induced bone loss, we further assessed whether BMI-1 overexpression in lymphocytes can protect against estrogen deficiency-induced osteoclastogenesis and bone loss by inhibiting oxidative stress, T cell activation, and RANKL production. When WT and Eμ-BMI-1 transgenic mice with BMI-1 specifically overexpressed in lymphocytes were ovariectomized and compared with each other and with WT sham mice, we found that BMI-1 overexpression in lymphocytes clearly reversed all alterations induced by ovariectomy. Results from this study indicate that estrogen deficiency downregulates BMI-1 and subsequently increases ROS, T cell activation, and RANKL production in T cells, thus enhancing osteoclastogenesis and accelerating bone loss. This study clarifies a novel mechanism regulating estrogen deficiency-induced bone loss. © 2016 American Society for Bone and Mineral Research.}, }
@article {pmid27941930, year = {2016}, author = {Chen, B and Liu, J and Ho, TT and Ding, X and Mo, YY}, title = {ERK-mediated NF-κB activation through ASIC1 in response to acidosis.}, journal = {Oncogenesis}, volume = {5}, number = {12}, pages = {e279}, pmid = {27941930}, issn = {2157-9024}, abstract = {Acidic microenvironment is a common feature of solid tumors. We have previously shown that neuron specific acid-sensing ion channel 1 (ASIC1) is expressed in breast cancer, and it is responsible for acidosis-induced cellular signaling through AKT, leading to nuclear factor-κB (NF-κB) activation, and cell invasion and metastasis. However, AKT is frequently activated in cancer. Thus, a key question is whether ASIC1-mediated cell signaling still takes place in the cancer cells carrying constitutively active AKT. In the present study, we show that among four prostate cancer cell lines tested, 22Rv1 cells express the highest level of phosphorylated AKT that is not impacted by acidosis. However, acidosis can still induce NF-κB activation during which extracellular signal-regulated kinase (ERK) serves as an alternative pathway for ASIC-mediated cell signaling. Inhibition of ERK by chemical inhibitors or small interfering RNAs suppresses the acidosis-induced NF-κB activity through regulation of the inhibitory subunit IκBα phosphorylation. Furthermore, suppression of ASIC1-mediated generation of reactive oxygen species (ROS) by ROS scavengers, such as glutathione or N-acetyl-cysteine causes a decrease in ERK phosphorylation and degradation of IκBα. Finally, ASIC1 is upregulated in a subset of prostate cancer cases and ASIC1 knockout by CRISPR/Cas9 significantly suppresses cell invasion, and castration resistance both in vitro and in vivo. Together, these results support the significance of ASIC1-ROS-ERK-IκBα-NF-κB axis in prostate tumorigenesis, especially in the constitutively active AKT background.}, }
@article {pmid27939630, year = {2017}, author = {Wei, J and Zhang, L and Ren, L and Zhang, J and Yu, Y and Wang, J and Duan, J and Peng, C and Sun, Z and Zhou, X}, title = {Endosulfan inhibits proliferation through the Notch signaling pathway in human umbilical vein endothelial cells.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {221}, number = {}, pages = {26-36}, doi = {10.1016/j.envpol.2016.08.083}, pmid = {27939630}, issn = {1873-6424}, mesh = {Acetylcysteine/metabolism ; Apoptosis/drug effects ; Cell Proliferation ; Cell Survival/drug effects ; Endosulfan/*toxicity ; Human Umbilical Vein Endothelial Cells ; Humans ; Insecticides/*toxicity ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Receptor, Notch1/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Our previous research showed that endosulfan triggers the extrinsic coagulation pathway by damaging endothelial cells and causes hypercoagulation of blood. To identify the mechanism of endosulfan-impaired endothelial cells, we treated human umbilical vein endothelial cells (HUVECs) with different concentrations of endosulfan, with and without an inhibitor for Notch, N-[N-(3, 5-difluorophenacetyl)-1-alanyl]S-Phenylglycinet-butylester (DAPT, 20 μM), or a reactive oxygen species (ROS) scavenger, N-Acetyl-l-cysteine (NAC, 3 mM), for 24 h. The results showed that endosulfan could inhibit cell viability/proliferation by increasing the release of lactate dehydrogenase (LDH), arresting the cell cycle in both S and G2/M phases, and inducing apoptosis in HUVECs. We also found that endosulfan can damage microfilaments, microtubules, and nuclei; arrest mitosis; remarkably increase the expressions of Dll4, Notch1, Cleaved-Notch1, Jagged1, Notch4, Hes1, and p21; and significantly induce ROS and malondialdehyde production in HUVECs. The presence of DAPT antagonized the above changes of cycle arrest, proliferation inhibition, and expressions of Dll4, Notch1, Cleaved-Notch1, Hes1, and p21 caused by endosulfan; however, NAC could attenuate LDH release; ROS and malondialdehyde production; apoptosis; and the expression levels of Dll4, Notch1, Cleaved-Notch1, Notch4, and Hes1 induced by endosulfan. These results demonstrated that endosulfan inhibited proliferation through the Notch signaling pathway as a result of oxidative stress. In addition, endosulfan can damage the cytoskeleton and block mitosis, which may add another layer of toxic effects on endothelial cells.}, }
@article {pmid27932980, year = {2016}, author = {Lin, CC and Lin, WN and Cho, RL and Wang, CY and Hsiao, LD and Yang, CM}, title = {TNF-α-Induced cPLA2 Expression via NADPH Oxidase/Reactive Oxygen Species-Dependent NF-κB Cascade on Human Pulmonary Alveolar Epithelial Cells.}, journal = {Frontiers in pharmacology}, volume = {7}, number = {}, pages = {447}, pmid = {27932980}, issn = {1663-9812}, abstract = {Tumor necrosis factor-α (TNF-α) triggers activation of cytosolic phospholipase A2 (cPLA2) and then enhancing the synthesis of prostaglandin (PG) in inflammatory diseases. However, the detailed mechanisms of TNF-α induced cPLA2 expression were not fully defined in human pulmonary alveolar epithelial cells (HPAEpiCs). We found that TNF-α-stimulated increases in cPLA2 mRNA (5.2 folds) and protein (3.9 folds) expression, promoter activity (4.3 folds), and PGE2 secretion (4.7 folds) in HPAEpiCs, determined by Western blot, real-time PCR, promoter activity assay and PGE2 ELISA kit. These TNF-α-mediated responses were abrogated by the inhibitors of NADPH oxidase [apocynin (APO) and diphenyleneiodonium chloride (DPI)], ROS [N-acetyl cysteine, (NAC)], NF-κB (Bay11-7082) and transfection with siRNA of ASK1, p47 [phox] , TRAF2, NIK, IKKα, IKKβ, or p65. TNF-α markedly stimulated NADPH oxidase activation and ROS including superoxide and hydrogen peroxide production which were inhibited by pretreatment with a TNFR1 neutralizing antibody, APO, DPI or transfection with siRNA of TRAF2, ASK1, or p47 [phox] . In addition, TNF-α also stimulated p47 [phox] phosphorylation and translocation in a time-dependent manner. On the other hand, TNF-α induced TNFR1, TRAF2, ASK1, and p47 [phox] complex formation in HPAEpiCs, which were attenuated by a TNF-α neutralizing antibody. We found that pretreatment with NAC, DPI, or APO also attenuated the TNF-α-stimulated IKKα/β and NF-κB p65 phosphorylation, NF-κB (p65) translocation, and NF-κB promoter activity in HPAEpiCs. Finally, we observed that TNF-α-stimulated NADPH oxidase activation and ROS generation activates NF-κB through the NIK/IKKα/β pathway. Taken together, our results demonstrated that in HPAEpiCs, up-regulation of cPLA2 by TNF-α is, at least in part, mediated through the cooperation of TNFR1, TRAF2, ASK1, and NADPH oxidase leading to ROS generation and ultimately activates NF-κB pathway.}, }
@article {pmid27926485, year = {2017}, author = {Morelli, MB and Amantini, C and Nabissi, M and Cardinali, C and Santoni, M and Bernardini, G and Santoni, A and Santoni, G}, title = {Axitinib induces senescence-associated cell death and necrosis in glioma cell lines: The proteasome inhibitor, bortezomib, potentiates axitinib-induced cytotoxicity in a p21(Waf/Cip1) dependent manner.}, journal = {Oncotarget}, volume = {8}, number = {2}, pages = {3380-3395}, pmid = {27926485}, issn = {1949-2553}, mesh = {Axitinib ; Bortezomib/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects/genetics ; Cellular Senescence/*drug effects/genetics ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; DNA Damage/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; G2 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression ; Glioma/genetics/metabolism ; Humans ; Imidazoles/*pharmacology ; Indazoles/*pharmacology ; Mitosis/drug effects/genetics ; Necrosis/genetics ; Proteasome Inhibitors/pharmacology ; Protein Kinase Inhibitors/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Glioblastoma is associated with a poor overall survival despite new treatment advances. Antiangiogenic strategies targeting VEGF based on tyrosine kinase inhibitors (TKIs) are currently undergoing extensive research for the treatment of glioma.Herein we demonstrated that the TKI axitinib induces DNA damage response (DDR) characterized by γ-H2AX phosphorylation and Chk1 kinase activation leading to G2/M cell cycle arrest and mitotic catastrophe in U87, T98 and U251 glioma cell lines. Moreover, we found that p21(Waf1/Cip1) increased levels correlates with induction of ROS and senescence-associated cell death in U87 and T98 cell lines, which are reverted by N-acetyl cysteine pretreatment. Conversely, U251 cell line showed a resistant phenotype in response to axitinib treatment, as evidenced by cell cycle arrest but no sign of cell death.The combinatorial use of axitinib with other therapies, with the aim of inhibiting multiple signaling pathways involved in tumor growth, can increase the efficiency of this TKI. Thus, we addressed the combined effects of axitinib with no toxic doses of the proteasome inhibitor bortezomib on the growth of U87 and T98 axitinib-sensitive and axitinib-resistant U251 cell lines. Compared to single treatments, combined exposure was more effective in inhibiting cell viability of all glioma cell lines, although with different cell death modalities. The regulation of key DDR and cell cycle proteins, including Chk1, γ-H2AX and p21(Waf1/Cip1) was also studied in glioma cell lines.Collectively, these findings provide new perspectives for the use of axitinib in combination with Bortezomib to overcome the therapy resistance in gliomas.}, }
@article {pmid27925012, year = {2016}, author = {Yue, SL and Zhang, YT and Wang, SW and Sun, M and Xing, YC and Wen, J and Zhou, JB}, title = {EFFECT OF NAC ON MOUSE GV OOCYTE SURVIVAL AND SUBSEQUENT EMBRYONIC DEVELOPMENT FOLLOWING VITRFICATION.}, journal = {Cryo letters}, volume = {37}, number = {4}, pages = {295-302}, pmid = {27925012}, issn = {0143-2044}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Cryopreservation/*methods ; Cryoprotective Agents/*pharmacology ; Embryonic Development/*drug effects ; Female ; Mice ; Mice, Inbred ICR ; Oocytes/drug effects ; Vitrification/*drug effects ; }, abstract = {BACKGROUND: Oocytes that survive cryopreservation may accumulate ROS which are known to bring harmful effects on embryonic development. NAC is an antioxidant which can be a supplement to reduce oxidative stress. However, whether NAC can improve the developmental competence of vitrified GV-oocytes remains unclear.<br><br>OBJECTIVE: The study was to investigate the effect of NAC on subsequent embryonic developmental competence of mice vitrified GV-oocytes.<br><br>MATERIALS AND METHODS: This study compared the effects of different concentration of NAC on the cleavage and blastocyst rates of mice vitrified GV-oocytes. Then the effects of NAC on mitochondria distribution, ROS level and embryonic development of vitrified oocytes were tested.<br><br>RESULTS: ROS activity of vitrified oocytes was significantly annihilated and mitochondrial distribution pattern was improved by 1.5 mM NAC (P<0.05). NAC supplementation throughout vitrification/warming and IVM media significantly improved the developmental competence of vitrified oocytes.<br><br>CONCLUSION: Supplementation of NAC could partially overcome the damages by vitrification and improve the development ability of mice vitrified GV-oocytes.}, }
@article {pmid27924409, year = {2017}, author = {Teodorak, BP and Scaini, G and Carvalho-Silva, M and Gomes, LM and Teixeira, LJ and Rebelo, J and De Prá, SD and Zeni, N and Schuck, PF and Ferreira, GC and Streck, EL}, title = {Antioxidants reverse the changes in energy metabolism of rat brain after chronic administration of L.-tyrosine.}, journal = {Metabolic brain disease}, volume = {32}, number = {2}, pages = {557-564}, pmid = {27924409}, issn = {1573-7365}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain Chemistry/*drug effects ; Citrate (si)-Synthase/metabolism ; Citric Acid Cycle/drug effects ; Creatine Kinase/metabolism ; Deferoxamine/pharmacology ; Electron Transport/drug effects ; Energy Metabolism/*drug effects ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Succinate Dehydrogenase/metabolism ; Tyrosine/*pharmacology ; Tyrosinemias/drug therapy/metabolism ; }, abstract = {Tyrosinemia type II is a rare autosomal recessive disease caused by deficiency of hepatic tyrosine aminotransferase and is associated with neurologic and development difficulties in numerous patients. Considering that the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly known and that high concentrations of tyrosine provoke mitochondrial dysfunction and oxidative stress, in the present study we investigated the in vivo influence of antioxidants (N-acetylcysteine, NAC; and deferoxamine, DFX) administration on the inhibitory effects on parameters of energy metabolism in cerebral cortex, hippocampus and striatum of rats, provoked by chronic administration of L.-tyrosine. Our results showed that chronic administration of L.-tyrosine results in a marked decrease in the activity of citrate synthase in all the analyzed structures and succinate dehydrogenase activities in hippocampus and striatum, and that antioxidants administration can prevent this inhibition in hippocampus and striatum. Moreover, chronic administration of L.-tyrosine inhibited the activity of complex I, II-III and IV in the striatum, which can be prevented by antioxidant treatment. However, the co-administration of NAC plus DFX could not prevent the inhibition of creatine kinase activity in the striatum. In conclusion, the present study demonstrates that the administration of antioxidants NAC and DFX attenuates the L.-tyrosine effects on enzymes of the Krebs cycle and the mitochondrial respiratory chain, suggesting that impairment of energy metabolism can be involved with oxidative stress. These results also indicate a possible neuroprotective role for NAC and DFX as a potential adjuvant therapy to the patients with Tyrosinemia type II.}, }
@article {pmid27920819, year = {2016}, author = {El-Lakkany, NM and Seif El-Din, SH and Sabra, AA and Hammam, OA and Ebeid, FA}, title = {Co-administration of metformin and N-acetylcysteine with dietary control improves the biochemical and histological manifestations in rats with non-alcoholic fatty liver.}, journal = {Research in pharmaceutical sciences}, volume = {11}, number = {5}, pages = {374-382}, pmid = {27920819}, issn = {1735-5362}, abstract = {Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health problem that affects 1/3 of the adult population and an increasing number of children in developed countries. Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. This study was conceived in a NAFLD rat model to evaluate the efficacy of both metformin (MTF) and N-acetylcysteine (NAC) with dietary control on biochemical and histologic liver manifestations. Rats were classified into nine groups; normal (I), NAFLD-induced by feeding high-fat diet (HFD; II) for 12 weeks, NAFLD switched to regular diet (RD; III), NAFLD-HFD or -RD treated with MTF in a dose of 150 mg/kg (IV, V), NAC in a dose of 500 mg/kg (VI, VII) or MTF+NAC (VIII, IX) respectively for 8 weeks. After 20 weeks, the rats in group II showed notable steatosis, lobular inflammation, fibrosis accompanied with elevated (P < 0.05) serum alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (γ-GT), cholesterol, triglycerides, LDL, VLDL, leptin, tumor necrosis factor (TNF-α), transforming growth factor (TGF-β1) and hepatic malondialdehyde (MDA) compared with group I. Meanwhile, hepatic superoxide dismutase (SOD), glutathione GSH with serum HDL, adiponectin were significantly decreased (P < 0.05). These changes were to a less extent in group III. MTF or NAC individually resulted in improvement of most of these biochemical and histological parameters. These improvements were more pronounced in the combined groups VIII and IX versus each drug alone. NAC supplementation concomitant with MTF could be beneficial for the treatment of NAFLD and prevention of nonalcoholic steatohepatitis (NASH).}, }
@article {pmid27920018, year = {2017}, author = {Cassidy, PB and Liu, T and Florell, SR and Honeggar, M and Leachman, SA and Boucher, KM and Grossman, D}, title = {A Phase II Randomized Placebo-Controlled Trial of Oral N-acetylcysteine for Protection of Melanocytic Nevi against UV-Induced Oxidative Stress In Vivo.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {10}, number = {1}, pages = {36-44}, pmid = {27920018}, issn = {1940-6215}, support = {P30 CA042014/CA/NCI NIH HHS/United States ; P30 CA069533/CA/NCI NIH HHS/United States ; R01 CA166710/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/metabolism/*therapeutic use ; Administration, Oral ; Antioxidants/administration &amp; dosage/adverse effects/metabolism/*therapeutic use ; Biomarkers/analysis ; Double-Blind Method ; Glutamate-Cysteine Ligase/analysis ; Guanine/analogs &amp; derivatives/analysis ; Humans ; Melanoma/etiology/*prevention &amp; control ; Mutation ; Nevus, Pigmented/complications/*drug therapy/genetics/pathology ; Oxidative Stress/*drug effects ; Pilot Projects ; Receptor, Melanocortin, Type 1/genetics ; Skin Neoplasms/complications/*drug therapy/genetics/pathology ; Sunlight/adverse effects ; Thioredoxin Reductase 1/analysis ; Ultraviolet Rays/*adverse effects ; }, abstract = {Oxidative stress plays a role in UV-induced melanoma, which may arise from melanocytic nevi. We investigated whether oral administration of the antioxidant N-acetylcysteine (NAC) could protect nevi from oxidative stress in vivo in the setting of acute UV exposure. The minimal erythemal dose (MED) was determined for 100 patients at increased risk for melanoma. Patients were randomized to receive a single dose (1,200 mg) of NAC or placebo, in double-blind fashion, and then one nevus was irradiated (1-2 MED) using a solar simulator. One day later, the MED was redetermined and the irradiated nevus and a control unirradiated nevus were removed for histologic analysis and examination of biomarkers of NAC metabolism and UV-induced oxidative stress. Increased expression of 8-oxoguanine, thioredoxin reductase-1, and γ-glutamylcysteine synthase modifier subunit were consistently seen in UV-treated compared with unirradiated nevi. However, no significant differences were observed in these UV-induced changes or in the pre- and postintervention MED between those patients receiving NAC versus placebo. Similarly, no significant differences were observed in UV-induced changes between subjects with germline wild-type versus loss-of-function mutations in the melanocortin-1 receptor. Nevi showed similar changes of UV-induced oxidative stress in an open-label post-trial study in 10 patients who received NAC 3 hours before nevus irradiation. Thus, a single oral dose of NAC did not effectively protect nevi from UV-induced oxidative stress under the conditions examined. Cancer Prev Res; 10(1); 36-44. ©2016 AACR.}, }
@article {pmid27919164, year = {2016}, author = {He, M and Ichinose, T and Yoshida, S and Shiba, F and Arashidani, K and Takano, H and Sun, G and Shibamoto, T}, title = {Differences in allergic inflammatory responses in murine lungs: comparison of PM2.5 and coarse PM collected during the hazy events in a Chinese city.}, journal = {Inhalation toxicology}, volume = {28}, number = {14}, pages = {706-718}, doi = {10.1080/08958378.2016.1260185}, pmid = {27919164}, issn = {1091-7691}, mesh = {Air Pollutants/*chemistry/*toxicity ; Allergens ; Animals ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Cell Count ; China ; Cities ; Cytokines/immunology ; Heme Oxygenase-1/genetics ; Immunoglobulin E/blood ; Immunoglobulin G/blood ; Lipopolysaccharides/analysis ; Lung/drug effects/pathology ; Male ; Membrane Proteins/genetics ; Mice ; Mice, Inbred BALB C ; Nitric Oxide Synthase Type II/genetics ; Ovalbumin ; Particle Size ; Particulate Matter/*chemistry/*toxicity ; *Pulmonary Eosinophilia/blood/etiology/immunology/pathology ; RAW 264.7 Cells ; *Respiratory Hypersensitivity/blood/etiology/immunology/pathology ; beta-Glucans/analysis ; }, abstract = {Urban particulate matter (PM) is associated with an increase in asthma. PM2.5 (<PM2.5 μm) and coarse PM (CPM: PM2.5-PM10 μm) were collected from the air in a Chinese city during haze events. The amounts of polycyclic aromatic hydrocarbons (PAHs) were higher in PM2.5 than in CPM. Conversely, microbial elements LPS and β-glucan were much higher in CPM than in PM2.5. Concentrations of Si, Al, Fe, and Ti in CPM were greater than in PM2.5, while Pb, Cu and As concentrations were lower than in PM2.5. When RAW264.7 cells were treated with PM2.5 and CPM, the pro-inflammatory response in the cells was associated with the microbial element levels and attenuated partly by both polymyxin B (PMB) and N-acetylcystein (NAC). The expression of the oxidative stress response gene heme oxygenase1 was associated with PAHs levels. The exacerbating effects of the two-types of PM on murine lung eosinophilia were compared to clarify the role of toxic materials. When BALB/c mice were intratracheally instilled with PM2.5 or CPM (total 0.4 mg) + ovalbumin (OVA), both exacerbated lung eosinophilia along with allergy-relevant biological indicators, such as OVA-specific IgE in serum; enhancement of lung pathology when compared with counterpart samples without OVA. The exacerbating effects were greater in microbial element-rich CPM than in organic chemical-rich PM2.5. These results indicate that microbial elements have more potently exacerbating effects on the development of lung eosinophilia than do organic chemicals. In addition, oxidative stress and transition metals might be associated with the exacerbation of this negative effect.}, }
@article {pmid27917341, year = {2016}, author = {Taghaddosinejad, F and Farzaneh, E and Ghazanfari-Nasrabad, M and Eizadi-Mood, N and Hajihosseini, M and Mehrpour, O}, title = {The effect of N-acetyl cysteine (NAC) on aluminum phosphide poisoning inducing cardiovascular toxicity: a case-control study.}, journal = {SpringerPlus}, volume = {5}, number = {1}, pages = {1948}, pmid = {27917341}, issn = {2193-1801}, abstract = {BACKGROUND: Aluminum phosphide (AlP) is a very effective indoor and outdoor pesticide. We investigated the effects of N-acetyl cysteine (NAC) on the survival time, hemodynamics, and cardiac biochemical parameters at various time intervals in some cases of AlP poisoning.<br><br>METHODS: This research was a case-control study to evaluate 63 AlP poisoned patients during 2010-2012. Patients with cardiovascular complications of AlP to be treated with intravenous NAC plus conventional treatment were considered as the case group and compared with patients who did not receive NAC. NAC infusion was administered to the case group at 300&#xa0;mg/kg for 20&#xa0;h. The data gathered included age, sex, heart rate, Systolic blood pressure (SBP), creatine phosphokinase (CPK), creatine kinase MB (CK-MB), and ECG at the admission time and 12, 18, and 24&#xa0;h after admission. Analysis of repeated measures was performed to check the variability of parameters over time.<br><br>RESULTS: The mean ages in the case and control groups were 26.65&#xa0;&#xb1;&#xa0;1.06 (19-37&#xa0;years) and 28.39&#xa0;&#xb1;&#xa0;1.11 (18-37&#xa0;years), respectively (P&#xa0;=&#xa0;0.266). Most of the patients were female (56.5%). CK-MB means were significantly different between the two groups, but no differences between the other variables were observed. Also, CK-MB, CPK, heart rate, and systolic blood pressure means became significantly different over time (0, 12, 18, and 24&#xa0;h) in both groups (P&#xa0;<&#xa0;0.001). NAC prevented sharp heart rate fluctuations in AlP patients in the case group. Regarding the outcomes, 17 patients died (10 patients in the control and 7 patients in the case groups). No side-effects of NAC were observed.<br><br>CONCLUSION: Our patients could be managed by the positive role of NAC as the biochemical index of cardiotoxicity was found to elevate in both the case and control groups. Therefore, for the management protocol optimization, NAC evaluation should be done in further cases.}, }
@article {pmid27916916, year = {2016}, author = {Wang, Y and Gao, H and Na, XL and Dong, SY and Dong, HW and Yu, J and Jia, L and Wu, YH}, title = {Aniline Induces Oxidative Stress and Apoptosis of Primary Cultured Hepatocytes.}, journal = {International journal of environmental research and public health}, volume = {13}, number = {12}, pages = {}, pmid = {27916916}, issn = {1660-4601}, mesh = {Acetylcysteine ; Aniline Compounds/*toxicity ; Animals ; Apoptosis/*drug effects ; Catalase/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Environmental Pollutants/*toxicity ; Glutathione/metabolism ; Hepatocytes/*drug effects/metabolism ; Humans ; Male ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {The toxicity and carcinogenicity of aniline in humans and animals have been well documented. However, the molecular mechanism involved in aniline-induced liver toxicity and carcinogenesis remains unclear. In our research, primary cultured hepatocytes were exposed to aniline (0, 1.25, 2.50, 5.0 and 10.0 μg/mL) for 24 h in the presence or absence of N-acetyl-l-cysteine (NAC). Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH), activities of superoxide dismutase (SOD) and catalase (CAT), mitochondrial membrane potential, DNA damage, cell viability, and apoptosis were detected. Levels of ROS and MDA were significantly increased and levels of GSH and CAT, activity of SOD, and mitochondrial membrane potential in hepatocytes were significantly decreased by aniline compared with the negative control group. The tail moment and DNA content of the tail in exposed groups were significantly higher than those in the negative control group. Cell viability was reduced and apoptotic death was induced by aniline in a concentration-dependent manner. The phenomena of ROS generation, oxidative damage, loss of mitochondrial membrane potential, DNA damage and apoptosis could be prevented if ROS inhibitor NAC was added. ROS generation is involved in the loss of mitochondrial membrane potential and DNA injury, which may play a role in aniline-induced apoptosis in hepatocytes. Our study provides insight into the mechanism of aniline-induced toxicity and apoptosis of hepatocytes.}, }
@article {pmid27915491, year = {2017}, author = {Kumar, SM and Haridoss, M and Swaminathan, K and Gopal, RK and Clemens, D and Dey, A}, title = {The effects of changes in glutathione levels through exogenous agents on intracellular cysteine content and protein adduct formation in chronic alcohol-treated VL17A cells.}, journal = {Toxicology mechanisms and methods}, volume = {27}, number = {2}, pages = {128-135}, doi = {10.1080/15376516.2016.1268229}, pmid = {27915491}, issn = {1537-6524}, mesh = {Alcohol Dehydrogenase/genetics ; Aldehydes/metabolism ; Cysteine/*metabolism ; Cytochrome P450 Family 2/genetics ; Ethanol/metabolism/*toxicity ; Glutathione/*metabolism ; Hep G2 Cells ; Hepatocytes/drug effects/metabolism ; Humans ; Oxidative Stress/*drug effects/genetics ; Transcriptome/drug effects ; }, abstract = {Alcohol-mediated liver injury is associated with changes in the level of the major cellular antioxidant glutathione (GSH). It is interesting to investigate if the changes in intracellular GSH level through exogenous agents affect the intracellular cysteine content and the protein adduct formation indicative of oxidative insult in chronic alcohol treated liver cells. In VL-17A cells treated with 2 mM N-acetyl cysteine (NAC) or 0.1 mM ursodeoxycholic acid (UDCA) plus 100 mM ethanol, an increase in cysteine concentration which was accompanied by decreases in hydroxynonenal (HNE) and glutathionylated protein adducts were observed. Pretreatment of 100 mM ethanol treated VL-17A cells with 0.4 mM buthionine sulfoximine (BSO) or 1 mM diethyl maleate (DEM) had opposite effects. Thus, altered GSH level through exogenous agents may either potentiate or ameliorate chronic alcohol-mediated protein adduct formation and change the cysteine level in chronic alcohol treated VL-17A cells. The gene expression of non-treated and ethanol-treated hepatocytes in 2 microarray datasets was also compared to locate differentially expressed genes involved in cysteine metabolism. The study demonstrates that increased protein adducts formation and changes in cysteine concentration occur under chronic alcohol condition in liver cells which may increase alcohol-mediated oxidative injury.}, }
@article {pmid27913221, year = {2017}, author = {Woolbright, BL and Jaeschke, H}, title = {Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure.}, journal = {Journal of hepatology}, volume = {66}, number = {4}, pages = {836-848}, pmid = {27913221}, issn = {1600-0641}, support = {R01 DK070195/DK/NIDDK NIH HHS/United States ; T32 ES007079/ES/NIEHS NIH HHS/United States ; R01 AA012916/AA/NIAAA NIH HHS/United States ; R56 AA012916/AA/NIAAA NIH HHS/United States ; P30 GM118247/GM/NIGMS NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*etiology/*immunology/pathology ; Humans ; Inflammasomes/*drug effects/*immunology ; Liver Failure, Acute/etiology/*immunology/pathology ; Mice ; Models, Immunological ; }, abstract = {Drug-induced acute liver failure carries a high morbidity and mortality rate. Acetaminophen overdose is the number one cause of acute liver failure and remains a major problem in Western medicine. Administration of N-acetyl cysteine is an effective antidote when given before the initial rise in toxicity; however, many patients present to the hospital after this stage occurs. As such, treatments which can alleviate late-stage acetaminophen-induced acute liver failure are imperative. While the initial mechanisms of toxicity are well described, a debate has recently occurred in the literature over whether there is a second phase of injury, mediated by inflammatory processes. Critical to this potential inflammatory process is the activation of caspase-1 and interleukin-1β by a molecular complex known as the inflammasome. Several different stimuli for the formation of multiple different inflammasome complexes have been identified. Formation of the NACHT, leucine-rich repeat (LRR) and pyrin (PYD) domains-containing protein 3 (Nalp3) inflammasome in particular, has directly been attributed to late-stage acetaminophen toxicity. In this review, we will discuss the mechanisms of acetaminophen-induced liver injury in mice and man with a particular focus on the role of inflammation and the inflammasome.}, }
@article {pmid27908784, year = {2017}, author = {Lomeli, N and Di, K and Czerniawski, J and Guzowski, JF and Bota, DA}, title = {Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats.}, journal = {Free radical biology &amp; medicine}, volume = {102}, number = {}, pages = {274-286}, pmid = {27908784}, issn = {1873-4596}, support = {T32 NS082174/NS/NINDS NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; P30 CA062203/CA/NCI NIH HHS/United States ; K08 NS072234/NS/NINDS NIH HHS/United States ; R25 GM055246/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage/*adverse effects ; Antioxidants/administration &amp; dosage ; Apoptosis/drug effects ; Cisplatin/administration &amp; dosage/*adverse effects ; Cognition/*drug effects ; Cognitive Dysfunction/chemically induced/*genetics/pathology ; Humans ; Mitochondria/drug effects/pathology ; Neoplasms/complications/drug therapy ; Neurons/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Rats ; }, abstract = {PURPOSE: Chemotherapy-related cognitive impairment (CRCI) is commonly reported following the administration of chemotherapeutic agents and comprises a wide variety of neurological problems. No effective treatments for CRCI are currently available. Here we examined the mechanisms involving cisplatin-induced hippocampal damage following cisplatin administration in a rat model and in cultured rat hippocampal neurons and neural stem/progenitor cells (NSCs). We also assessed the protective effects of the antioxidant, N-acetylcysteine in mitigating these damages.<br><br>EXPERIMENTAL DESIGN: Adult male rats received 6mg/kg cisplatin in the acute studies. In chronic studies, rats received 5mg/kg cisplatin or saline injections once per week for 4 weeks. N-acetylcysteine (250mg/kg/day) or saline was administered for five consecutive days during cisplatin treatment. Cognitive testing was performed 5 weeks after treatment cessation. Cisplatin-treated cultured hippocampal neurons and NSCs were examined for changes in mitochondrial function, oxidative stress production, caspase-9 activation, and neuronal dendritic spine density.<br><br>RESULTS: Acute cisplatin treatment reduced dendritic branching and spine density, and induced mitochondrial degradation. Rats receiving the chronic cisplatin regimen showed impaired performance in contextual fear conditioning, context object discrimination, and novel object recognition tasks compared to controls. Cisplatin induced mitochondrial DNA damage, impaired respiratory activity, increased oxidative stress, and activated caspase-9 in cultured hippocampal neurons and NSCs. N-acetylcysteine treatment prevented free radical production, ameliorated apoptotic cellular death and dendritic spine loss, and partially reversed the cisplatin-induced cognitive impairments.<br><br>CONCLUSIONS: Our results suggest that mitochondrial dysfunction and increased oxidative stress are involved in cisplatin-induced cognitive impairments. Therapeutic agents, such as N-acetylcysteine, may be effective in mitigating the deleterious effects of cisplatin.}, }
@article {pmid27908781, year = {2017}, author = {Zhang, A and Duan, H and Li, N and Zhao, L and Pu, F and Huang, B and Wu, C and Nan, Y and Du, T and Mu, Y and Zhao, Q and Sun, Y and Zhang, G and Hiscox, JA and Zhou, EM and Xiao, S}, title = {Heme oxygenase-1 metabolite biliverdin, not iron, inhibits porcine reproductive and respiratory syndrome virus replication.}, journal = {Free radical biology &amp; medicine}, volume = {102}, number = {}, pages = {149-161}, doi = {10.1016/j.freeradbiomed.2016.11.044}, pmid = {27908781}, issn = {1873-4596}, mesh = {Animals ; Biliverdine/metabolism ; Heme Oxygenase-1/genetics/*metabolism ; Iron/metabolism ; Porcine Reproductive and Respiratory Syndrome/*genetics/pathology/virology ; Porcine respiratory and reproductive syndrome virus/*genetics/pathogenicity ; Swine ; Virus Replication/*genetics ; }, abstract = {Porcinereproductiveandrespiratorysyndromevirus (PRRSV) causes significant economic losses to the pork industry worldwide. Previously, we demonstrated that heme oxygenase-1 (HO-1) interferes with PRRSV replication. To elucidate the mechanisms involved, here we assess whether the HO-1 downstream metabolites biliverdin (BV) and/or iron mediate the HO-1 antiviral effect. We demonstrate a BV concentration-dependent suppression of PRRSV replication and show that virions are not directly inactivated by BV. Additionally, BV or N-acetyl cysteine (NAC) significantly reduced reactive oxygen species (ROS) in PRRSV-infected MARC-145 cells; however, because NAC did not reduce viral load, the BV antiviral effect is independent of decreased ROS levels. Moreover, a secondary metabolite of BV, bilirubin (BR), specifically mediates this anti-PRRSV activity via a nitric oxide (NO)-dependent cGMP/PKG signaling pathway. While increased iron via addition of FeCl3 did not interfere with PRRSV replication, iron depletion by deferoxamine (DFO) after cobalt-protoporphyrin IX induction of HO-1 did not restore PRRSV replication. Collectively, our findings identify a HO-1-BV/BR-NO-cGMP/PKG cascade as a novel pathway underlying the host cell antiviral effect. These results provide a unique insight into the molecular mechanisms underlying the antiviral effects of the stress-responsive protein HO-1 during PRRSV infection.}, }
@article {pmid27907115, year = {2016}, author = {Li, T and Xu, Y and Liu, L and Huang, M and Wang, Z and Tong, Z and Zhang, H and Guo, F and Chen, C}, title = {Brucella Melitensis 16M Regulates the Effect of AIR Domain on Inflammatory Factors, Autophagy, and Apoptosis in Mouse Macrophage through the ROS Signaling Pathway.}, journal = {PloS one}, volume = {11}, number = {12}, pages = {e0167486}, pmid = {27907115}, issn = {1932-6203}, mesh = {Animals ; *Apoptosis/genetics ; Apoptosis Regulatory Proteins/genetics/metabolism ; *Autophagy/genetics ; Biomarkers ; Brucella melitensis/*physiology ; Brucellosis/genetics/metabolism/microbiology ; Cell Line ; Cells, Cultured ; Cytokines/genetics/metabolism ; Enzyme-Linked Immunosorbent Assay ; Gene Expression ; Gene Expression Profiling ; Humans ; Inflammasomes/metabolism ; Inflammation Mediators/chemistry/*metabolism ; Macrophages/immunology/*metabolism ; Mice ; Mitochondria/metabolism ; Protein Binding ; *Protein Domains ; Protein Transport ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; }, abstract = {Brucellosis is a highly contagious zoonosis caused by Brucella. Brucella can invade and persist inside host cells, which results in chronic infection. We constructed AIR interference and overexpression lentiviruses to acquire AIR interference, overexpression, and rescue stable expression cell lines. We also established a Brucella melitensis 16M-infected macrophage model, which was treated with either the vehicle control or NAC (ROS scavenger N-acetylcysteine (NAC) for 0, 3, 6, 12, and 24 h. Confocal laser microscopy, transmission electron microscopy, fluorescence quantitative PCR, flow cytometry, ELISA, and Western blot were used to detect inflammation, cell autophagy and apoptosis-related protein expression levels, ROS levels, and the distribution of mitochondria. It was found that after interference and overexpression of AIR, ROS release was significantly changed, and mitochondria became abnormally aggregated. B. melitensis 16M activated the NLRP3/AIM2 inflammatory complex, and induced RAW264.7 cells to secrete IL-1β and IL-18 through the ROS pathway. B. melitensis 16M also altered autophagy-related gene expression, increased autophagy activity, and induced cell apoptosis through the ROS pathway. The results showed that after B. melitensis 16M infection, ROS induced apoptosis, inflammation, and autophagy while AIR inhibited autophagosome maturation and autophagy initiation. Autophagy negatively regulated the activation of inflammasomes and prevented inflammation from occurring. In addition, mitophagy could promote cell apoptosis.}, }
@article {pmid27907022, year = {2016}, author = {Lan, X and Lederman, R and Eng, JM and Shoshtari, SS and Saleem, MA and Malhotra, A and Singhal, PC}, title = {Nicotine Induces Podocyte Apoptosis through Increasing Oxidative Stress.}, journal = {PloS one}, volume = {11}, number = {12}, pages = {e0167071}, pmid = {27907022}, issn = {1932-6203}, support = {R01 DA012111/DA/NIDA NIH HHS/United States ; R01 DK083931/DK/NIDDK NIH HHS/United States ; R01 DK084910/DK/NIDDK NIH HHS/United States ; R01 DK098074/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects/genetics ; Cell Line, Transformed ; Cell Proliferation/drug effects ; Cyclic N-Oxides/pharmacology ; Female ; Gene Expression Regulation ; Humans ; MAP Kinase Kinase 4/antagonists &amp; inhibitors/genetics/metabolism ; Male ; Membrane Proteins/genetics/metabolism ; Mice ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/genetics/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/genetics/metabolism ; Nicotine/antagonists &amp; inhibitors/*pharmacology ; Nicotinic Antagonists/pharmacology ; Oxidative Stress/*drug effects ; Podocytes/cytology/*drug effects/metabolism ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*agonists/antagonists &amp; inhibitors/metabolism ; Receptors, Nicotinic/genetics/metabolism ; Signal Transduction ; Spin Labels ; Tissue Culture Techniques ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {BACKGROUND: Cigarette smoking plays an important role in the progression of chronic kidney disease (CKD). Nicotine, one of the major components of cigarette smoking, has been demonstrated to increase proliferation of renal mesangial cells. In this study, we examined the effect of nicotine on podocyte injury.<br><br>METHODS: To determine the expression of nicotinic acetylcholine receptors (nAChR subunits) in podocytes, cDNAs and cell lysate of cultured human podocytes were used for the expression of nAChR mRNAs and proteins, respectively; and mouse renal cortical sections were subjected to immunofluorescant staining. We also studied the effect of nicotine on podocyte nephrin expression, reactive oxygen species (ROS) generation (via DCFDA loading followed by fluorometric analysis), proliferation, and apoptosis (morphologic assays). We evaluated the effect of nicotine on podocyte downstream signaling including phosphorylation of ERK1/2, JNK, and p38 and established causal relationships by using respective inhibitors. We used nAChR antagonists to confirm the role of nicotine on podocyte injury.<br><br>RESULTS: Human podocytes displayed robust mRNA and protein expression of nAChR in vitro studies. In vivo studies, mice renal cortical sections revealed co-localization of nAChRs along with synaptopodin. In vitro studies, nephrin expression in podocyte was decreased by nicotine. Nicotine stimulated podocyte ROS generation; nonetheless, antioxidants such as N-acetyl cysteine (NAC) and TEMPOL (superoxide dismutase mimetic agent) inhibited this effect of nicotine. Nicotine did not modulate proliferation but promoted apoptosis in podocytes. Nicotine enhanced podocyte phosphorylation of ERK1/2, JNK, and p38, and their specific inhibitors attenuated nicotine-induced apoptosis. nAChR antagonists significantly suppressed the effects of nicotine on podocyte.<br><br>CONCLUSIONS: Nicotine induces podocyte apoptosis through ROS generation and associated downstream MAPKs signaling. The present study provides insight into molecular mechanisms involved in smoking associated progression of chronic kidney disease.}, }
@article {pmid27904674, year = {2016}, author = {Yin, Y and Xue, X and Wang, Q and Chen, N and Miao, D}, title = {Bmi1 plays an important role in dentin and mandible homeostasis by maintaining redox balance.}, journal = {American journal of translational research}, volume = {8}, number = {11}, pages = {4716-4725}, pmid = {27904674}, issn = {1943-8141}, abstract = {To explore whether polycomb repressor Bmi1 plays an important role in dentin and mandible development homeostasis by maintaining redox balance, 3-week-old Bmi1 gene knockout (Bmi1[-/-]) mice were treated with the antioxidant N-acetylcysteine (NAC) for 2 weeks in their drinking water and phenotypes of the tooth and mandibles were compared with vehicle-treated Bmi1[-/-] mice and wild-type mice by radiograph, histochemistry and immunohistochemistry. Alterations of oxidative stress, DNA damage, cell proliferation and cell cycle-related parameters were also examined in mandibles. Results showed that the tooth volume and the dentin sialoprotein immunopositive areas, the cortical thickness, alveolar bone volume, osteoblast number and activity, and mRNA expression levels of Runx2, alkaline phosphatase and type I collagen were all reduced significantly in Bmi1[-/-] mice compared with their wild-type littermates, whereas these parameters were increased significantly in NAC-treated Bmi1[-/-] mice compared with vehicle-Bmi1[-/-] mice, although they were not normalized. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were reduced, DNA damage markers including γ-H2AX and 8-oxoguanine levels were increased, the number of Ki67 positive cells was decreased, whereas protein expression levels of p16, p19, p21, p27 and p53 were up-regulated in mandibles from Bmi1[-/-] mice compared with those from wild-type mice; alterations of these antioxidative enzyme activities, DNA damage markers, cell proliferation and cell cycle-related parameters were all partially rescued by the treatment with antioxidant NAC in Bmi1 deficient mice. These results demonstrated that Bmi1 deficiency resulted in defects in dentin and alveolar bone formation, while the treatment with antioxidant could improve these defects obviously. Therefore, our results indicate that Bmi1 plays an important role in stimulating dentin formation and alveolar bone formation by maintaining redox homeostasis, preventing DNA damage and inhibiting cyclin-dependent kinase inhibitors.}, }
@article {pmid27902864, year = {2017}, author = {Sun, Y and Yao, T and Li, H and Peng, Y and Zheng, J}, title = {In vitro and in vivo metabolic activation of berbamine to quinone methide intermediate.}, journal = {Journal of biochemical and molecular toxicology}, volume = {31}, number = {4}, pages = {}, doi = {10.1002/jbt.21876}, pmid = {27902864}, issn = {1099-0461}, mesh = {Activation, Metabolic ; Animals ; Benzylisoquinolines/*metabolism ; Cytochrome P-450 CYP3A/*metabolism ; Humans ; Indolequinones/*metabolism ; Male ; Microsomes, Liver/*enzymology ; Rats ; }, abstract = {Berbamine (BBM) is a bisbenzylisoquinoline alkaloid isolated from herbal medicine Berberis amurensis. BBM has been widely used for the treatment of leukemia. Recent studies demonstrated that exposure to BBM can give rise to cytotoxicity. The major objective of this study was to explore the metabolic activation of BBM in vitro and in vivo. Two oxidative metabolites (M1 and M2) and an N-acetylcysteine (NAC) conjugate (M3) were detected in human liver microsomal incubations of BBM supplemented with NAC, and the formation of all metabolites was NADPH dependent. Microsomal inhibition and recombinant P450 enzyme incubation studies demonstrated that P450 3A4 was the major enzyme responsible for the metabolic activation of BBM. In addition, a BBM-cysteine conjugate (M4) was detected in the urine of rats given BBM. The metabolism study will facilitate the understanding of the biochemical mechanisms of BBM-induced cytotoxicity.}, }
@article {pmid27902334, year = {2016}, author = {Qi, X and Zhang, H and Wang, Q and Wang, J}, title = {The NS1 protein of avian influenza virus H9N2 induces oxidative-stress-mediated chicken oviduct epithelial cells apoptosis.}, journal = {The Journal of general virology}, volume = {97}, number = {12}, pages = {3183-3192}, doi = {10.1099/jgv.0.000625}, pmid = {27902334}, issn = {1465-2099}, mesh = {Animals ; *Apoptosis ; Caspases/metabolism ; Chickens ; Epithelial Cells/cytology/*metabolism/virology ; Female ; Influenza A Virus, H9N2 Subtype/genetics/*metabolism ; Influenza in Birds/*metabolism/physiopathology/virology ; Mitochondria/metabolism ; Oviducts/*cytology/metabolism/virology ; *Oxidative Stress ; Poultry Diseases/*metabolism/physiopathology/virology ; Reactive Oxygen Species/metabolism ; Viral Nonstructural Proteins/genetics/*metabolism ; }, abstract = {The pathogenesis of H9N2 subtype avian influenza virus infection (AIV) in hens is often related to oviduct tissue damage. The viral non-structural NS1 protein is thought to play a key role in regulating the pathogenicity of AIV, but its exact function in this process remains elusive. In this study, the pro-apoptosis effect of H9N2 NS1 protein was examined on chicken oviduct epithelial cells (COECs) and our data indicated that NS1-induced oxidative stress was a contributing factor in apoptosis. Our data indicate that NS1 protein level was correlated with reactive oxygen species (ROS) in COECs transfected with NS1 expression plasmids. Interestingly, decreased activities of antioxidant enzymes, superoxide dismutase and catalase, were observed in NS1-transfected COECs. Treatment of COECs with antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), significantly inhibited NS1-induced apoptosis. Moreover, although antioxidant treatment has little effect on the activation of caspase-8 in NS1-transfected cells, the activation of caspase-3/9 and Bax/Bcl-2 were significantly downregulated. Taken together, the results of our study demonstrated that expression of H9N2 NS1 alone is sufficient to trigger oxidative stress in COECs. Additionally, NS1 protein can induce cellular apoptosis via activating ROS accumulation and mitochondria-mediated apoptotic signalling in COECs.}, }
@article {pmid27900814, year = {2017}, author = {Roy, SS and Mukherjee, S and Das, SK}, title = {Effects of intratracheal exposure of 2-chloroethyl ethyl sulfide (CEES) on the activation of CCAAT-enhancer-binding protein (C/EBP) and its protection by antioxidant liposome.}, journal = {Journal of biochemical and molecular toxicology}, volume = {31}, number = {5}, pages = {}, pmid = {27900814}, issn = {1099-0461}, support = {G12 MD007586/MD/NIMHD NIH HHS/United States ; U54 MD007593/MD/NIMHD NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*pharmacology ; CCAAT-Enhancer-Binding Proteins/*metabolism ; Guinea Pigs ; Intercellular Adhesion Molecule-1/metabolism ; Liposomes ; Lung Injury/chemically induced/drug therapy/*metabolism ; Male ; Mustard Gas/*toxicity ; }, abstract = {Exposure of 2-chloroethyl ethyl sulfide (CEES) to guinea pigs causes lung injury by infiltration of neutrophils in interstitial lung spaces. A unique MAPK-regulated transcription factor, C/EBP (CCAAT-enhancer-binding protein), regulates the expression of intracellular adhesion molecule-1 (ICAM-1), involved in recruiting neutrophils in lung. The present study was to determine if CEES exposure causes activation of C/EBP, in particular the predominant β-isoform and if so whether it can be prevented by intratracheal delivery of an antioxidant liposome containing N-acetyl cysteine and tocopherols. Lung injury was developed in guinea pigs by intratracheal exposure of CEES (0.5 mg/kg). The antioxidant liposome was given intratracheally 5 min after CEES exposure, and the animals were sacrificed after 30 days. CEES exposure caused a 2.3-fold increase in the activation of C/EBP accompanied with a 45% and 121% increase in the protein level of C/EBP β and ICAM-1, respectively, and this effect was counteracted by the antioxidant liposome.}, }
@article {pmid27900412, year = {2017}, author = {Chen, YY and Li, RY and Shi, MJ and Zhao, YX and Yan, Y and Xu, XX and Zhang, M and Zhao, XT and Zhang, YB}, title = {Demethyleneberberine alleviates inflammatory bowel disease in mice through regulating NF-κB signaling and T-helper cell homeostasis.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {66}, number = {2}, pages = {187-196}, pmid = {27900412}, issn = {1420-908X}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Berberine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Colon/drug effects/immunology/pathology ; Cytokines/immunology ; Dextran Sulfate ; Female ; Homeostasis/drug effects ; Immunoglobulin G/blood ; Inflammatory Bowel Diseases/blood/chemically induced/drug therapy/*immunology ; Mice ; Mice, Inbred C57BL ; NF-kappa B/*antagonists &amp; inhibitors/immunology ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Spleen/cytology ; T-Lymphocytes, Helper-Inducer/*drug effects/immunology ; }, abstract = {OBJECTIVE: The activation of NF-κB signaling and unbalance of T-helper (Th) cells have been reported to play a key role in the pathogenesis of colitis. Cortex Phellodendri Chinensis (CPC) is commonly used to treat inflammation and diarrhea. Demethyleneberberine (DMB), a component of CPC, was reported to treat alcoholic liver disease as a novel natural mitochondria-targeted antioxidant in our previous study. In this study, we investigated whether DMB could protect against dextran sulfate sodium (DSS)-induced inflammatory colitis in mice by regulation of NF-κB pathway and Th cells homeostatis.<br><br>METHODS: Inflammatory colitis mice were induced by 3% DSS, and DMB were orally administered on the doses of 150 and 300&#xa0;mg/kg. In vitro, DMB (10, 20, 40&#xa0;&#x3bc;M) and N-acetyl cysteine (NAC, 5&#xa0;mM) were co-cultured with RAW264.7 for 2&#xa0;h prior to lipopolysaccharide (LPS) stimulation, and splenocytes from the mice were cultured ex vivo for 48&#xa0;h for immune response test.<br><br>RESULTS: In vivo, DMB significantly alleviated the weight loss and diminished myeloperoxidase (MPO) activity, while significantly reduced the production of pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;), and inhibited the activation of NF-&#x3ba;B signaling pathway. Furthermore, DMB decreased interferon (IFN)-&#x3b3;, increased IL-4 concentration in the mice splenocytes and the ratio of IgG1/IgG2a in the serum. In vitro, ROS production and pro-inflammation cytokines were markedly inhibited by DMB in RAW264.7 cell.<br><br>CONCLUSIONS: Our findings revealed that DMB alleviated mice colitis and inhibited the inflammatory responses by inhibiting NF-&#x3ba;B pathway and regulating the balance of Th cells.}, }
@article {pmid27898405, year = {2016}, author = {Thieme, K and Da Silva, KS and Fabre, NT and Catanozi, S and Monteiro, MB and Santos-Bezerra, DP and Costa-Pessoa, JM and Oliveira-Souza, M and Machado, UF and Passarelli, M and Correa-Giannella, ML}, title = {N-Acetyl Cysteine Attenuated the Deleterious Effects of Advanced Glycation End-Products on the Kidney of Non-Diabetic Rats.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {40}, number = {3-4}, pages = {608-620}, doi = {10.1159/000452574}, pmid = {27898405}, issn = {1421-9778}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Diabetes Mellitus, Experimental/*pathology ; Gene Expression Regulation/drug effects ; Glycation End Products, Advanced/*toxicity ; Kidney/drug effects/*pathology ; Macrophages/drug effects/pathology ; Male ; RNA, Messenger/genetics/metabolism ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Serum Albumin/metabolism ; }, abstract = {AIM: To assess the renal effects of chronic exposure to advanced glycation end-products (AGEs) in the absence of diabetes and the potential impact of concomitant treatment with the antioxidant N-acetyl cysteine (NAC).<br><br>METHODS: Wistar rats received intraperitoneally 20 mg/kg/day of albumin modified (AlbAGE) or not (AlbC) by advanced glycation for 12 weeks and oral NAC (600mg/L; AlbAGE+NAC and AlbC+NAC, respectively). Biochemical, urinary and renal morphological analyses; carboxymethyl-lysine (CML, an AGE), CD68 (macrophage infiltration), and 4-hydroxynonenal (4-HNE, marker of oxidative stress) immunostaining; intrarenal mRNA expression of genes belonging to pathways related to AGEs (Ager, Ddost, Nfkb1), renin-angiotensin system (Agt, Ren, Ace), fibrosis (Tgfb1, Col4a1), oxidative stress (Nox4, Txnip), and apoptosis (Bax, Bcl2); and reactive oxidative species (ROS) content were performed.<br><br>RESULTS: AlbAGE significantly increased urine protein-to-creatinine ratio; glomerular area; renal CML content and macrophage infiltration; expression of Ager, Nfkb1, Agt, Ren, Tgfb1, Col4a1, Txnip, Bax/Bcl2 ratio; and 4-HNE and ROS contents. Some of these effects were attenuated by NAC concomitant treatment.<br><br>CONCLUSION: Because AGEs are highly consumed in modern diets and implicated in the progression of different kidney diseases, NAC could be a therapeutic intervention to decrease renal damage, considering that long-term restriction of dietary AGEs is difficult to achieve in practice.}, }
@article {pmid27897115, year = {2017}, author = {Martínez-Banaclocha, MA}, title = {Cysteinet Dysregulation in Muscular Dystrophies: A Pathogenic Network Susceptible to Therapy.}, journal = {Current medicinal chemistry}, volume = {24}, number = {3}, pages = {312-330}, doi = {10.2174/0929867323666161129124549}, pmid = {27897115}, issn = {1875-533X}, mesh = {Acetylcysteine/pharmacokinetics/pharmacology/therapeutic use ; Animals ; Cysteine/*metabolism ; Humans ; Muscular Dystrophies/drug therapy/*metabolism/*therapy ; }, abstract = {BACKGROUND: Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle degeneration without curative therapy. The specific defective protein in each type of muscular dystrophy has been associated with different deleterious factors that contribute to the progression of the disease. Among these factors, the impairment of calcium homeostasis, the ubiquitin-proteasome dysfunction, and the oxidative damage of cellular macromolecules seem to be of central importance. Can these different cellular dysfunctions be linked by a common pathogenic mechanism susceptible to therapy? A cellular cysteine network (CYSTEINET) has been proposed previously, as a matrix of interconnected sensitive cysteine-containing proteins (SCCPs) that in addition to reactive species and the cysteine/glutathione cycles can regulate metabolic, redox, and survival cellular pathways by a complex biochemical network of proteins with different functions, but sharing the same regulatory thiol group.<br><br>OBJECTIVE: Since there are many sensitive cysteine-containing proteins including cysteinedependent enzymes susceptible to redox modifications at cysteine residues that may contribute to muscular degeneration, the aim of this review is to propose that cysteinet dysregulation may explain oxidative damage, calcium disturbances and ubiquitin-proteasome dysfunctions associated with muscular dystrophies.<br><br>CONCLUSION: The present review proposes that cysteinet dysregulation in muscular dystrophies may represent a common pathogenic network contributing, in association with the specific protein dysfunction, to muscular degeneration. In this context, N-acetylcysteine may have an important role in the restoration of the proposed cysteinet dysregulation associated with these heterogeneous types of diseases.}, }
@article {pmid27895157, year = {2017}, author = {Dutta, RK and Kondeti, VK and Sharma, I and Chandel, NS and Quaggin, SE and Kanwar, YS}, title = {Beneficial Effects of Myo-Inositol Oxygenase Deficiency in Cisplatin-Induced AKI.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {28}, number = {5}, pages = {1421-1436}, pmid = {27895157}, issn = {1533-3450}, support = {P30 CA060553/CA/NCI NIH HHS/United States ; R01 DK060635/DK/NIDDK NIH HHS/United States ; R01 DK078314/DK/NIDDK NIH HHS/United States ; R01 HL124120/HL/NHLBI NIH HHS/United States ; }, mesh = {Acute Kidney Injury/*chemically induced/*enzymology ; Animals ; Cisplatin/*adverse effects ; Inositol Oxygenase/*deficiency/physiology ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; }, abstract = {Overexpression of the proximal tubular enzyme myo-inositol oxygenase (MIOX) induces oxidant stress in vitro However, the relevance of MIOX to tubular pathobiology remains enigmatic. To investigate the role of MIOX in cisplatin-induced tubular AKI, we generated conditional MIOX-overexpressing transgenic (MIOX-TG) mice and MIOX-knockout (MIOX[-/-]) mice with tubule-specific MIOX overexpression or knockout, respectively. Compared with cisplatin-treated wild-type (WT) mice, cisplatin-treated MIOX-TG mice had even greater increases in urea, creatinine, and KIM-1 levels and more tubular injury and apoptosis, but these effects were attenuated in cisplatin-treated MIOX[-/-] mice. Similarly, MIOX-TG mice had the highest and MIOX[-/-] mice had the lowest renal levels of Bax, cleaved caspase-3, and NADPH oxidase-4 expression and reactive oxygen species (ROS) generation after cisplatin treatment. In vitro, cisplatin dose-dependently increased ROS generation in LLC-PK1 cells. Furthermore, MIOX overexpression in these cells accentuated cisplatin-induced ROS generation and perturbations in the ratio of GSH to oxidized GSH, whereas MIOX-siRNA or N-acetyl cysteine treatment attenuated these effects. Additionally, the cisplatin-induced enhancement of p53 activation, NF-κB binding to DNA, and NF-κB nuclear translocation in WT mice was exacerbated in MIOX-TG mice but absent in MIOX[-/-] mice. In vitro, MIOX-siRNA or NAC treatment reduced the dose-dependent increase in p53 expression induced by cisplatin. We also observed a remarkable influx of inflammatory cells and upregulation of cytokines in kidneys of cisplatin-treated MIOX-TG mice. Finally, analysis of genomic DNA in WT mice revealed cisplatin-induced hypomethylation of the MIOX promoter. These data suggest that MIOX overexpression exacerbates, whereas MIOX gene disruption protects against, cisplatin-induced AKI.}, }
@article {pmid27894373, year = {2017}, author = {Rapado-Castro, M and Dodd, S and Bush, AI and Malhi, GS and Skvarc, DR and On, ZX and Berk, M and Dean, OM}, title = {Cognitive effects of adjunctive N-acetyl cysteine in psychosis.}, journal = {Psychological medicine}, volume = {47}, number = {5}, pages = {866-876}, doi = {10.1017/S0033291716002932}, pmid = {27894373}, issn = {1469-8978}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Attention/*drug effects ; Bipolar Disorder/*complications ; Cognitive Dysfunction/*drug therapy/etiology ; Executive Function/*drug effects ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Humans ; Male ; Memory, Short-Term/*drug effects ; Middle Aged ; Psychotic Disorders/*complications ; Schizophrenia/*complications ; Treatment Outcome ; }, abstract = {BACKGROUND: Cognitive deficits are predictors of functional outcome in patients with psychosis. While conventional antipsychotics are relatively effective on positive symptoms, their impact on negative and cognitive symptoms is limited. Recent studies have established a link between oxidative stress and neurocognitive deficits in psychosis. N-acetylcysteine (NAC), a glutathione precursor with glutamatergic properties, has shown efficacy on negative symptoms and functioning in patients with schizophrenia and bipolar disorder, respectively. However, there are few evidence-based approaches for managing cognitive impairment in psychosis. The present study aims to examine the cognitive effects of adjunctive NAC treatment in a pooled subgroup of participants with psychosis who completed neuropsychological assessment in two trials of both schizophrenia and bipolar disorder.<br><br>METHOD: A sample of 58 participants were randomized in a double fashion to receive 2 g/day of NAC (n = 27) or placebo (n = 31) for 24 weeks. Attention, working memory and executive function domains were assessed. Differences between cognitive performance at baseline and end point were examined using Wilcoxon's test. The Mann-Whitney test was used to examine the differences between the NAC and placebo groups at the end point.<br><br>RESULTS: Participants treated with NAC had significantly higher working memory performance at week 24 compared with placebo (U = 98.5, p = 0.027).<br><br>CONCLUSIONS: NAC may have an impact on cognitive performance in psychosis, as a significant improvement in working memory was observed in the NAC-treated group compared with placebo; however, these preliminary data require replication. Glutamatergic compounds such as NAC may constitute a step towards the development of useful therapies for cognitive impairment in psychosis.}, }
@article {pmid27891708, year = {2017}, author = {França, K and Lotti, T}, title = {N-acetyl cysteine in the treatment of trichotillomania.}, journal = {Dermatologic therapy}, volume = {30}, number = {3}, pages = {}, doi = {10.1111/dth.12446}, pmid = {27891708}, issn = {1529-8019}, mesh = {Acetylcysteine/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Treatment Outcome ; Trichotillomania/*drug therapy ; }, }
@article {pmid27889764, year = {2016}, author = {Luo, C and Lian, X and Hong, L and Zou, J and Li, Z and Zhu, Y and Huang, T and Zhang, Y and Hu, Y and Yuan, H and Wen, T and Zhuang, W and Cai, B and Zhang, X and Hisatome, I and Yamamoto, T and Huang, J and Cheng, J}, title = {High Uric Acid Activates the ROS-AMPK Pathway, Impairs CD68 Expression and Inhibits OxLDL-Induced Foam-Cell Formation in a Human Monocytic Cell Line, THP-1.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {40}, number = {3-4}, pages = {538-548}, doi = {10.1159/000452567}, pmid = {27889764}, issn = {1421-9778}, mesh = {AMP-Activated Protein Kinases/*metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 1/metabolism ; Acetylcysteine/pharmacology ; Antigens, CD/*metabolism ; Antigens, Differentiation, Myelomonocytic/*metabolism ; Cell Differentiation/drug effects ; Cell Line ; Cyclooxygenase 2/metabolism ; Foam Cells/*cytology/drug effects/metabolism ; Humans ; Lipoproteins, LDL/*pharmacology ; Models, Biological ; Monocytes/*cytology ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Tetradecanoylphorbol Acetate/pharmacology ; Time Factors ; Transcription Factor RelA/metabolism ; Uric Acid/*pharmacology ; }, abstract = {BACKGROUND/AIMS: Hyperuricemia is part of the metabolic-syndrome cluster of abdominal obesity, impaired glucose tolerance, insulin resistance, dyslipidemia, and hypertension. Monocytes/macrophages are critical in the development of metabolic syndrome, including gout, obesity and atherosclerosis. However, how high uric acid (HUA) exposure affects monocyte/macrophage function remains unclear. In this study, we investigated the molecular mechanism of HUA exposure in monocytes/macrophages and its impact on oxidized low-density lipoprotein (oxLDL)-induced foam-cell formation in a human monocytic cell line, THP-1.<br><br>METHODS: We primed THP-1 cells with phorbol-12-myristate-13-acetate (PMA) for differentiation, then exposed cells to HUA and detected the production of reactive oxygen species (ROS) and analyzed the level of phospho-AMPK&#x3b1;. THP-1 cells were pre-incubated with Compound C, an AMPK inhibitor, or N-acetyl-L-cysteine (NAC), a ROS scavenger, or HUA before PMA, to assess CD68 expression and phospho-AMPK&#x3b1; level. PMA-primed THP-1 cells were pre-treated with oxLDL before Compound C and HUA treatment. Western blot analysis was used to examine the levels of phospho-AMPK&#x3b1;, CD68, ABCG1, ABCA1, cyclooxygenase-2 (COX-2) and NF-&#x3ba;B (p65). Flow cytometry was used to assess ROS production and CD68 expression in live cells. Oil-red O staining was used to observe oxLDL uptake in cells.<br><br>RESULTS: HUA treatment increased ROS production in PMA-primed THP-1 cells; NAC blocked HUA-induced oxidative stress. HUA treatment time-dependently increased phospho-AMPK&#x3b1; level in PMA-primed THP-1 cells. The HUA-induced oxidative stress increased phospho-AMPK&#x3b1; levels, which was blocked by NAC. HUA treatment impaired CD68 expression during cell differentiation by activating the AMPK pathway, which was reversed by Compound C treatment. Finally, HUA treatment inhibited oxLDL uptake in the formation of foam cells in THP-1 cells, which was blocked by Compound C treatment. HUA treatment significantly increased the expression of ABCG1 and reversed the oxLDL-reduced ABCG1 expression but did not affect the expression of ABCA1, NF-&#x3ba;B (p65) or COX-2.<br><br>CONCLUSIONS: HUA exposure activated the ROS-AMPK pathway, impaired CD68 expression, and inhibited oxLDL-induced foam-cell formation in a human monocytic cell line, THP-1.}, }
@article {pmid27888799, year = {2017}, author = {Altaf, M and Monim-Ul-Mehboob, M and Kawde, AN and Corona, G and Larcher, R and Ogasawara, M and Casagrande, N and Celegato, M and Borghese, C and Siddik, ZH and Aldinucci, D and Isab, AA}, title = {New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status.}, journal = {Oncotarget}, volume = {8}, number = {1}, pages = {490-505}, pmid = {27888799}, issn = {1949-2553}, support = {R01 CA160687/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/chemistry/*pharmacology/therapeutic use ; Apoptosis/drug effects ; CRISPR-Cas Systems/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cisplatin/*pharmacology/therapeutic use ; Drug Resistance, Neoplasm ; Free Radical Scavengers/pharmacology ; Gene Knockdown Techniques/methods ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Neoplasms/*drug therapy/pathology ; Organogold Compounds/chemistry/*pharmacology/therapeutic use ; Pyridines/chemistry ; Reactive Oxygen Species/metabolism ; Thiocarbamates/chemistry ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes.}, }
@article {pmid27888692, year = {2017}, author = {Torres, S and Matías, N and Baulies, A and Nuñez, S and Alarcon-Vila, C and Martinez, L and Nuño, N and Fernandez, A and Caballeria, J and Levade, T and Gonzalez-Franquesa, A and Garcia-Rovés, P and Balboa, E and Zanlungo, S and Fabrías, G and Casas, J and Enrich, C and Garcia-Ruiz, C and Fernández-Checa, JC}, title = {Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease.}, journal = {Redox biology}, volume = {11}, number = {}, pages = {60-72}, pmid = {27888692}, issn = {2213-2317}, mesh = {Acetylcysteine/metabolism ; Animals ; Cerebellum/metabolism/pathology ; Cholesterol/metabolism ; Glutathione/*metabolism/pharmacology ; Humans ; Intracellular Signaling Peptides and Proteins ; Lysosomes/genetics/metabolism ; Mice ; Mice, Knockout ; Mitochondria/*metabolism/pathology ; Mutation ; Niemann-Pick C1 Protein ; Niemann-Pick Disease, Type C/genetics/*metabolism/pathology ; Oxidative Phosphorylation ; Proteins/*genetics/metabolism ; Purkinje Cells/metabolism ; Vesicular Transport Proteins/*genetics/metabolism ; }, abstract = {Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1[-/-] mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1[-/-] mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1[-/-] mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1[-/-] mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1[-/-] mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.}, }
@article {pmid27888451, year = {2017}, author = {Boşgelmez, I&#x130; and Güvendik, G}, title = {N-Acetyl-L-Cysteine Protects Liver and Kidney Against Chromium(VI)-Induced Oxidative Stress in Mice.}, journal = {Biological trace element research}, volume = {178}, number = {1}, pages = {44-53}, doi = {10.1007/s12011-016-0901-2}, pmid = {27888451}, issn = {1559-0720}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chromium/*toxicity ; Kidney/*metabolism/pathology ; Lipid Peroxidation/drug effects ; Liver/*metabolism/pathology ; Mice ; Oxidative Stress/*drug effects ; }, abstract = {Acute hexavalent chromium [Cr(VI)] compound exposure may lead to hepatotoxic and nephrotoxic effects. Cr(VI) reduction may generate reactive intermediates and radicals which might be associated with damage. We investigated effects of N-acetyl-l-cysteine (NAC) pre- or post-treatment on oxidative stress and accumulation of Cr in liver and kidney of Cr(VI)-exposed mice. Intraperitoneal potassium dichromate injection (20 mg Cr/kg) caused a significant elevation of lipid peroxidation in both tissues as compared to control (p < 0.05). Significant decreases in non-protein sulfhydryl (NPSH) level, as well as enzyme activities of catalase (CAT) and superoxide dismutase (SOD) along with significant accumulation of Cr in the tissues (p < 0.05) were of note. NAC pre-treatment (200 mg/kg, ip) provided a noticeable alleviation of lipid peroxidation (p < 0.05) in both tissues, whereas post-treatment exerted significant effect only in kidney. Similarly, Cr(VI)-induced NPSH decline was restored by NAC pre-treatment in both tissues (p < 0.05); however, NAC post-treatment could only replenish NPSH in liver (p < 0.05). Regarding enzyme activities, in liver tissue NAC pre-treatment provided significant restoration on Cr(VI)-induced CAT inhibition (p < 0.05), while SOD enzyme activity was regulated to some extent. In kidney, SOD activity was efficiently restored by both treatments (p < 0.05), whereas CAT enzyme alteration could not be totally relieved. Additionally, NAC pre-treatment in both tissues and post-treatment in liver exerted significant tissue Cr level decreases (p < 0.05). Overall, especially NAC pre-treatment seems to provide beneficial effects in regulating pro-oxidant/antioxidant balance and Cr accumulation caused by Cr(VI) in liver and kidney. This finding may be due to several mechanisms including extracellular reduction or chelation of Cr(VI) by readily available NAC.}, }
@article {pmid27886758, year = {2017}, author = {Gao, F and Ma, S and Xiao, X and Hu, Y and Zhao, D and He, Z}, title = {Sensing tyrosine enantiomers by using chiral CdSe/CdS quantum dots capped with N-acetyl-l-cysteine.}, journal = {Talanta}, volume = {163}, number = {}, pages = {102-110}, doi = {10.1016/j.talanta.2016.10.091}, pmid = {27886758}, issn = {1873-3573}, mesh = {Acetylcysteine/*chemistry ; Cadmium Compounds/*chemistry ; Quantum Dots/*chemistry ; Selenium Compounds/*chemistry ; Stereoisomerism ; Sulfides/*chemistry ; Tyrosine/*chemistry ; }, abstract = {Despite of the importance of enantiomers, the fluorescence sensing of enantiomers and the interpretation of the "preferential interaction" still remain insufficiently explored. In this study, we report the recognition of tyrosine (Tyr) enantiomers by chiral N-acetyl-L-cysteine (L-NAC) capped CdSe/CdS quantum dots (QDs) under alkaline experimental condition. L-Tyr could greatly quench the fluorescence of CdSe/CdS QDs, while D-Tyr displayed no effect on the fluorescence. The one-step synthesized chiral L-NAC-CdSe/CdS QDs demonstrated high selectivity for Tyr enantiomers. In particular, the mechanism of chiral recognition has been studied by UV/vis absorption spectra and circular dichroism (CD) spectra. The changes of intensity and sign of CD spectra corroborated the attachment of L-Tyr to the surface of QDs, which may be valuable aids in obtaining a better understanding of the possible mechanism of enantioselective recognition.}, }
@article {pmid27884591, year = {2017}, author = {Yamada, T and Ogi, K and Sakashita, M and Kanno, M and Kubo, S and Ito, Y and Imoto, Y and Tokunaga, T and Okamoto, M and Narita, N and Fujieda, S}, title = {Toll-like receptor ligands induce cytokine and chemokine production in human inner ear endolymphatic sac fibroblasts.}, journal = {Auris, nasus, larynx}, volume = {44}, number = {4}, pages = {398-403}, doi = {10.1016/j.anl.2016.10.007}, pmid = {27884591}, issn = {1879-1476}, mesh = {Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing/drug effects/metabolism ; B-Cell Activating Factor/drug effects/metabolism ; Chemokine CXCL10/drug effects/metabolism ; Chemokines/metabolism ; Cytokines/drug effects/*metabolism ; Endolymphatic Sac/cytology/*metabolism ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors ; Fibroblasts/*metabolism ; Free Radical Scavengers/pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors ; Poly I-C/pharmacology ; Toll-Like Receptor 2/metabolism ; Toll-Like Receptor 3/metabolism ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptor 9/metabolism ; Toll-Like Receptors/*metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors ; Thymic Stromal Lymphopoietin ; }, abstract = {OBJECTIVE: Against recent reports concerning cytokine or chemokine in mouse or rat inner ear cells, it is almost unknown whether human inner ear cells would produce cytokine or chemokine. We have for the first time established the human inner-ear-derived fibroblasts from endolymphatic sac.<br><br>METHODS: The expression levels of Toll-like receptors (TLRs) in human endolymphatic sac fibroblasts, and the effect on cytokine or chemokine production of the TLR ligands have been examined. To demonstrate the intracellular pathways involved in the regulation of cytokine-production, we used specific inhibitors of c-Jun N-terminal kinase (JNK), extracellular signal-related kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK)-signaling and N-acetyl-l-cysteine (NAC).<br><br>RESULTS: TLR 2, 3, 4 and 9 were highly expressed in human endolymphatic sac fibroblasts. The TLR 3 ligand, polyinosinic-polycytidylic acid (poly(I:C)) significantly enhanced the secretion of thymic stromal lymphopoietin (TSLP), B lymphocyte stimulator (BLyS), IFN&#x3b3;-inducible protein 10 (IP-10), and macrophage inflammatory protein 1 alpha (MIP-1&#x3b1;) from the cells. The inhibitor of JNK strongly reduced the poly(I:C)-induced TSLP-production. The antioxidant drug, NAC also reduced the TSLP-production in fibroblasts stimulated with poly(I:C).<br><br>CONCLUSION: Our findings suggest human inner-ear-endolymphatic sac derived fibroblasts can produce the cytokine and chemokine in response to TLR ligands and play a certain role during the initiation of an immune response.}, }
@article {pmid27884318, year = {2016}, author = {Kalimeris, K and Briassoulis, P and Ntzouvani, A and Nomikos, T and Papaparaskeva, K and Politi, A and Batistaki, C and Kostopanagiotou, G}, title = {N-acetylcysteine ameliorates liver injury in a rat model of intestinal ischemia reperfusion.}, journal = {The Journal of surgical research}, volume = {206}, number = {2}, pages = {263-272}, doi = {10.1016/j.jss.2016.08.049}, pmid = {27884318}, issn = {1095-8673}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Biomarkers/metabolism ; Hepatic Insufficiency/etiology/metabolism/pathology/*prevention &amp; control ; Injections, Intraperitoneal ; Intestines/*blood supply ; Liver/drug effects/metabolism/pathology ; Liver Function Tests ; Male ; Oxidative Stress/drug effects ; Random Allocation ; Rats ; Rats, Wistar ; Reperfusion Injury/*drug therapy/metabolism/physiopathology ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is an antioxidant with direct and indirect antioxidant actions used in the clinical setting. Oxidative stress is known to play a pivotal role in the intestinal ischemia reperfusion (IIR). Therefore, we studied the effect of different pretreatment regimens with NAC on the IIR injury in rats.<br><br>MATERIALS AND METHODS: Thirty-five male Wistar rats were randomly assigned to five groups. In group sham, only laparotomy was performed. Group control underwent IIR without NAC. In the other groups, NAC was administered intraperitoneally with different regimens: 150&#xa0;mg/kg before ischemia (NAC 150), 300&#xa0;mg/kg before ischemia (NAC 300), and 150&#xa0;mg/kg before ischemia plus 150&#xa0;mg/kg 5&#xa0;min before reperfusion (NAC 150&#xa0;+&#xa0;150). Measurements in tissues and blood were conducted at 4&#xa0;h of reperfusion following exsanguination.<br><br>RESULTS: Histological score of the liver was significantly improved in NAC 300 compared with control (1.7&#xa0;&#xb1;&#xa0;0.5 versus 2.9&#xa0;&#xb1;&#xa0;1.1, respectively, P&#xa0;=&#xa0;0.05). In addition, NAC treatment significantly reduced liver transaminases in all groups of treatment, mostly in group NAC 300. Plasma malondialdehyde levels were lower with NAC treatment, although not statistically significant. Lung glutathione peroxidase was significantly increased in group NAC 300 (P&#xa0;=&#xa0;0.04), while the other oxidation biomarkers showed no significant differences.<br><br>CONCLUSIONS: NAC exerts a significant protective role in liver injury following IIR, which seems to be independent of an intestinal protective effect. Additional administration of NAC before reperfusion was of no further benefit. The most effective regimen among the compared regimens was that of 300&#xa0;mg/kg before ischemia.}, }
@article {pmid27882134, year = {2016}, author = {Li, WH and Wang, L and He, HY and Chen, J and Yu, YR}, title = {Expression of neutrophil gelatinase-associated lipocalin in low osmolar contrast-induced nephropathy in rats and the effect of N-acetylcysteine.}, journal = {Experimental and therapeutic medicine}, volume = {12}, number = {5}, pages = {3175-3180}, pmid = {27882134}, issn = {1792-0981}, abstract = {Serum creatinine (Scr), which is a conventional indicator of contrast-induced nephropathy (CIN), is unable to reflect the damage of kidney promptly. The present study aimed to investigate the value of neutrophil gelatinase-associated lipocalin (NGAL) in kidney and serum of CIN rats to observe whether NGAL can be used as a superior indicator of CIN. Furthermore, N-acetylcysteine (NAC) was used to assess its effect on CIN. A total of 120 adult male Sprague Dawley rats were randomly divided into four groups (n=30/group): CIN rats (CIN), normal rats treated with NAC (NAC), CIN rats treated with NAC (NAC+CIN) and the control group (CON). Serum Scr and NGAL values were measured at 2, 12, 24, 48 and 72 h following the procedure. Immunohistochemistry and western blot analysis were used to detect NGAL within the kidney tissue. Hematoxylin and eosin staining were used to access the renal injury score. Oxidative stress within the kidney was analyzed via malondialdehyde (MDA) and superoxide dismutase (SOD). The level of NGAL in the serum and tissue of the CIN group increased significantly 2 h after the procedure (P<0.05). However, the Scr value did not exhibit a significantly change until 48 h later. Based on the renal injury scores, NAC reduced the kidney damage caused by the contrast. NAC treatment was associated with a decrease in SOD levels and an increase in MDA. These findings suggested that NGAL was a superior indicator of CIN than Scr, as NGAL was able to detect kidney damage much earlier. Furthermore, NAC treatment inhibited oxidative stress, thus protecting against CIN.}, }
@article {pmid27882116, year = {2016}, author = {Wang, G and Yin, T and Wang, Y}, title = {In vitro and in vivo assessment of high-dose vitamin C against murine tumors.}, journal = {Experimental and therapeutic medicine}, volume = {12}, number = {5}, pages = {3058-3062}, pmid = {27882116}, issn = {1792-0981}, abstract = {Vitamin C is widely used in clinical settings and is well known for its safety. Previous studies have shown the efficacy of intravenous vitamin C; however, intratumoral delivery of vitamin C has yet to be attempted. In the present study, the biological effects of high-dose vitamin C on tumor cells were investigated in vitro by using the MTT assay and flow cytometry. When administered in vitro, high-dose vitamin C inhibited the proliferation of murine colon and breast cancer cells, and induced tumor cell apoptosis. Cytotoxicity of vitamin C was partially reversed by N-acetyl-cysteine at a relatively low dosage. In addition, synergistic anti-tumor effects of vitamin C and cisplatin were observed. In vivo, intratumoral delivery of vitamin C delayed tumor growth in murine solid tumor models. Considering its low toxicity and availability, the present study indicates that vitamin C may be a novel therapeutic method for patients with advanced tumors.}, }
@article {pmid27875950, year = {2017}, author = {Khoeeniha, MK and Esfandyari-Manesh, M and Behrouz, H and Amini, M and Varnamkhasti, BS and Atyabi, F and Dinarvand, R}, title = {Targeted Delivery of Cabazitaxel by Conjugation to Albumin-PEG-folate Nanoparticles Using a Cysteine-acrylate Linker and Simple Synthesis Conditions.}, journal = {Current drug delivery}, volume = {14}, number = {8}, pages = {1120-1129}, doi = {10.2174/1567201814666161122150302}, pmid = {27875950}, issn = {1875-5704}, mesh = {Acrylates/chemistry ; Antineoplastic Agents/*administration &amp; dosage/*chemistry/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cysteine/chemistry ; *Drug Delivery Systems ; Drug Screening Assays, Antitumor ; Folic Acid/*chemistry ; HT29 Cells ; Humans ; Molecular Conformation ; Nanoparticles/*chemistry ; Polyethylene Glycols/*chemistry ; Serum Albumin/*chemistry ; Structure-Activity Relationship ; Taxoids/*administration &amp; dosage/*chemistry/pharmacology ; }, abstract = {BACKGROUND: Cabazitaxel (CBZ) is a new taxane approved by FDA for treatment of castration- resistant prostate cancer not responding to docetaxel. However, CBZ is not a suitable substrate for p-glycoprotein 60, an efflux pump which transports anticancer drugs out of malignant cells and is therefore a promising drug for treatment of multidrug resistant tumors. Similar to other taxanes, the presence of Tween 80 in the CBZ formulation shows that it is insoluble in water.<br><br>METHODS: In order to increase the solubility and circulation time of this drug, CBZ-human serum albumin (HSA) conjugate was synthesized. The designed linker was composed of methacrylic acid and N-acetyl cysteine to increase the solubility of CBZ and to increase the efficiency of conjugation. Targeting was performed by poly(ethylene glycol)-folic acid amide bound formation with carboxyl groups of HSA during in the step of nanoparticle formation. Cytotoxicity of nanoparticles was evaluated in vitro on HT-29, as a folate negative cell line, and MDA-MB-231, as a folate positive cell line.<br><br>RESULTS: H-NMR, Gel Permeation Chromatography, High Pressure Liquid Chromatography and UV spectrophotometry analysis confirmed the composition of conjugates. The resulting nanoparticles had a spherical shape, narrow size distribution and mean diameter of 138 nm. The efficiency of conjugation was 41.6 %. The IC50 of CBZ in targeted nanoparticles was 10.1 and 17.4% lower than that of the free CBZ for HT-29 and MDA-MB-231 cells, respectively.<br><br>CONCLUSION: This designed drug delivery system was more water-soluble and had enhanced in vitro characteristics and higher cytotoxic activity on cancer cells.}, }
@article {pmid27868128, year = {2016}, author = {Yi, X and Zhang, Y and Zhong, C and Zhong, X and Xiao, F}, title = {The role of STIM1 in the Cr(vi)-induced [Ca[2+]]i increase and cell injury in L-02 hepatocytes.}, journal = {Metallomics : integrated biometal science}, volume = {8}, number = {12}, pages = {1273-1282}, doi = {10.1039/c6mt00204h}, pmid = {27868128}, issn = {1756-591X}, mesh = {Acetylcysteine/pharmacology ; Calcium/*metabolism ; Cell Line, Transformed ; Chromium/*toxicity ; Gene Knockdown Techniques ; Hepatocytes/*drug effects/metabolism ; Homeostasis/drug effects ; Humans ; Neoplasm Proteins/genetics/*physiology ; Phosphorylation ; Stromal Interaction Molecule 1/genetics/*physiology ; }, abstract = {Hexavalent chromium [Cr(vi)] is a potent cytotoxin and carcinogen. In recent years, drinking water contamination with Cr(vi) has become a worldwide problem of significant public health importance, thus much attention has been paid to the investigation of Cr(vi)-induced hepatotoxicity. The concentration of intracellular calcium ions ([Ca[2+]]i) was found to be increased after Cr(vi) exposure, but the exact underlying mechanisms involved in the Ca[2+] homeostasis imbalance remain poorly characterized. In the present study, by utilizing the antagonist of store-operated calcium channels (SOCCs) 2-aminoethoxydiphenyl borate (2-APB), small interfering RNA against stromal interaction molecule 1 (si-STIM1) and antioxidant N-acetylcysteine (NAC), we found that Cr(vi) induces [Ca[2+]]i increase, cell viability loss and transaminase (AST/ALT) leakage, and that these could be suppressed by both 2-APB and si-STIM1. NAC significantly alleviated Cr(vi)-induced up-regulation of STIM1, phosphorylated-extracellular-signal-regulated kinases 1 and 2 (p-ERK1/2), ERK1/2 and nuclear factor κB (NF-κB). By utilizing the ERK inhibitor U0126 and the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that STIM1 can be regulated by ERK and NF-κB. Thus we concluded that STIM1 plays a role in the Cr(vi)-induced [Ca[2+]]i increase and cell injury. Our current data provide new insights into the mechanisms of STIM1 function in Cr(vi)-induced hepatotoxicity, and may provide experimental clues for the prevention and treatment of liver diseases in the occupational population exposed to Cr(vi).}, }
@article {pmid27863415, year = {2016}, author = {Ma, YC and Ke, Y and Zi, X and Zhao, F and Yuan, L and Zhu, YL and Fan, XX and Zhao, NM and Li, QY and Qin, YH and Liu, HM}, title = {Induction of the mitochondria-mediated apoptosis in human esophageal cancer cells by DS2, a newly synthetic diterpenoid analog, is regulated by Bax and caused by generation of reactive oxygen species.}, journal = {Oncotarget}, volume = {7}, number = {52}, pages = {86211-86224}, pmid = {27863415}, issn = {1949-2553}, support = {R01 CA122558/CA/NCI NIH HHS/United States ; R01 CA193967/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytochromes c/metabolism ; Diterpenes, Kaurane/chemistry/*pharmacology ; Esophageal Neoplasms/*drug therapy/metabolism/pathology ; Humans ; Mitochondria/*physiology ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein/*physiology ; }, abstract = {Ent-kaurane diterpene compounds have attracted considerable attention in recent years due to its antitumor, antibacterial, and antiviral activities. However, the clinical development of natural kaurane diterpenes, for example, oridonin for cancer therapy has been hampered by its relatively moderate potency, limited bioavailability. Herein, we report a newly synthetic analog of natural ent-kaurane diterpene, DS2, which exhibits significantly improved activity of antiproliferation against various cancer cell lines relative to oridonin. DS2 treatment triggers the mitochondria-mediated apoptosis and cell cycle arrest in human esophageal cancer cell lines (EC9706, EC109). Interestingly, normal human esophageal epithelial cells (HEECs) and normal human liver cells (HL-7702) are both significantly more resistant to the growth inhibition by DS2 compared with esophageal cancer cells. The DS2-induced apoptosis in EC9706 cells correlated with the drop of mitochondrial membrane potential (MMP), release of cytochrome c into the cytosol and activation of caspase-9 and -3. The induction of proapoptotic proteins p21 and Bax were also observed in DS2-treated cells. The DS2-induced apoptosis was significantly attenuated by knockdown of Bax proteins. Meanwhile, the DS2 treatment caused generation of reactive oxygen species (ROS) in human esophageal cancer cells, but not in HEECs, which was attenuated by pretreatment with ROS scavenger N-acetylcysteine (NAC). More interestingly, the antioxidants pretreatment completely attenuated DS2 mediated loss of the MMP and apoptosis, as well as Bax expression and growth inhibition. In conclusion, the present study reveals that the mitochondria-mediated cell death by DS2 is associated with Bax regulation and ROS generation, and understanding the function and mechanism of DS2 will help us to design better anti-cancer drugs.}, }
@article {pmid27856348, year = {2016}, author = {Kato, Y and Oki, K and Suga, N and Ono, S and Ishisaka, A and Miura, Y and Kanazawa, S and Naito, M and Kitamoto, N and Kettle, AJ}, title = {A novel quinone derived from 5-hydroxyindoleacetic acid reacts with protein: Possible participation of oxidation of serotonin and its metabolite in the development of atherosclerosis.}, journal = {Free radical biology &amp; medicine}, volume = {101}, number = {}, pages = {500-510}, doi = {10.1016/j.freeradbiomed.2016.11.023}, pmid = {27856348}, issn = {1873-4596}, mesh = {Acetylcysteine/chemistry ; Aged ; Antibodies, Monoclonal/biosynthesis/chemistry/isolation &amp; purification ; Aorta/chemistry/metabolism/pathology ; Atherosclerosis/*blood/pathology ; Glyceraldehyde-3-Phosphate Dehydrogenases/chemistry/metabolism ; Humans ; Hydroxyindoleacetic Acid/*chemistry/metabolism ; Immunohistochemistry ; Male ; Microtomy ; Peroxidase/chemistry/metabolism ; Phenylenediamines ; Quinones/*chemical synthesis/metabolism ; Serotonin/*chemistry/metabolism ; Xanthine Oxidase/chemistry/metabolism ; }, abstract = {The modification of 5-hydroxyindoleacetic acid (5HIAA) by myeloperoxidase with a xanthine oxidase system was investigated by chromatographic analyses. Two major products were identified as a dimer and quinone (indoleacetate dione) of 5HIAA. The formation of a quinone moiety was also confirmed by chemical trapping with o-phenylenediamine. In the presence of N-acetyl-cysteine (NAC), a quinone-NAC adduct was formed. When glyceraldehyde 3-phosphate dehydrogenase was exposed to the myeloperoxidase system with 5HIAA, quinone adducts were formed on the protein molecule. A monoclonal antibody was prepared using a quinone-modified protein as an immunogen to immunochemically detect the quinone on a protein. The established antibody recognized the quinone-NAC adduct, quinone-modified poly-L-lysine, and quinone-modified low-density lipoprotein. Quinone-modified proteins in human atherosclerotic lesions were immunohistochemically observed using the established antibody to the quinone and also a monoclonal antibody to tryptamine dione-modified protein, suggesting an occurrence of in vivo oxidation of serotonin and 5HIAA, accompanied by covalent adduction to biomolecules.}, }
@article {pmid27855364, year = {2016}, author = {Yang, C and Yang, QO and Kong, QJ and Yuan, W and Ou Yang, YP}, title = {Parthenolide Induces Reactive Oxygen Species-Mediated Autophagic Cell Death in Human Osteosarcoma Cells.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {40}, number = {1-2}, pages = {146-154}, doi = {10.1159/000452532}, pmid = {27855364}, issn = {1421-9778}, mesh = {Autophagy/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Humans ; Mitophagy/drug effects ; Osteosarcoma/enzymology/*pathology ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; }, abstract = {BACKGROUND AND AIM: Osteosarcoma is a devastating tumor of bone, primarily affecting adolescents. Parthenolide, a naturally occurring small molecule that interferes with NF-κB signaling, has recently attracted considerable attention because of its pharmacological action involving anti-cancer effects. However, the mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today.<br><br>METHODS: In this study, the effects of parthenolide were evaluated and characterized in human osteosarcoma cancer cell. Cell viability was assessed by CCK-8. Apoptosis was assessed by Annexin V-FITC/PI Flow cytometry assay. Relative quantitative real-time PCR and western blot were used to determine the expressions of genes and proteins.<br><br>RESULTS: Our results suggest that parthenolide did not cause caspase-dependent cell death in osteosarcoma cancer cells, as indicated by the absence of significant early apoptosis as well as caspase-3 cleavage. Instead, parthenolide increased the autophagy and mitophagy, as characterized by increased PINK1 and Parkin translocation to mitochondria and enhanced autophagy proteins. The induction of autophagy by parthenolide was associated with the increase of reactive oxygen species (ROS). ROS antioxidants N-acetylcysteine (NAC) attenuated parthenolide-induced autophagy activity.<br><br>CONCLUSIONS: Our findings unveil a novel mechanism of drug action by parthenolide in osteosarcoma cancer cells and suggest a potential value of treating osteosarcoma cancer through a caspase-independent autophagic cell death by ROS activation.}, }
@article {pmid27854233, year = {2016}, author = {Bartsakoulia, M and Mϋller, JS and Gomez-Duran, A and Yu-Wai-Man, P and Boczonadi, V and Horvath, R}, title = {Cysteine Supplementation May be Beneficial in a Subgroup of Mitochondrial Translation Deficiencies.}, journal = {Journal of neuromuscular diseases}, volume = {3}, number = {3}, pages = {363-379}, doi = {10.3233/JND-160178}, pmid = {27854233}, issn = {2214-3599}, support = {G1002570/MRC_/Medical Research Council/United Kingdom ; G1000848/MRC_/Medical Research Council/United Kingdom ; MR/N025431/1/MRC_/Medical Research Council/United Kingdom ; MC_PC_13071/MRC_/Medical Research Council/United Kingdom ; G0701386/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Carrier Proteins/genetics ; Cyclooxygenase 2/genetics ; Cysteine/*pharmacology ; Dietary Supplements ; Fibroblasts/*drug effects/metabolism ; Humans ; In Vitro Techniques ; MELAS Syndrome/*metabolism ; MERRF Syndrome/*metabolism ; Mitochondria/*drug effects/metabolism ; Mitochondrial Diseases/*metabolism ; Mitochondrial Proteins/genetics ; Mutation ; Neoplasm Proteins/genetics ; Oxygen Consumption/drug effects ; Protein Biosynthesis/*drug effects ; RNA-Binding Proteins ; tRNA Methyltransferases/genetics ; }, abstract = {BACKGROUND: Mitochondrial encephalomyopathies are severe, relentlessly progressive conditions and there are very few effective therapies available to date. We have previously suggested that in two rare forms of reversible mitochondrial disease (reversible infantile respiratory chain deficiency and reversible infantile hepatopathy) supplementation with L-cysteine can improve mitochondrial protein synthesis, since cysteine is required for the 2-thiomodification of mitochondrial tRNAs.<br><br>OBJECTIVES: We studied whether supplementation with L-cysteine or N-acetyl-cysteine (NAC) results in any improvement of the mitochondrial function in vitro in fibroblasts of patients with different genetic forms of abnormal mitochondrial translation.<br><br>METHODS: We studied in vitro in fibroblasts of patients carrying the common m.3243A>G and m.8344A>G mutations or autosomal recessive mutations in genes affecting mitochondrial translation, whether L-cysteine or N-acetyl-cysteine supplementation have an effect on mitochondrial respiratory chain function.<br><br>RESULTS: Here we show that supplementation with L-cysteine, but not with N-acetyl-cysteine partially rescues the mitochondrial translation defect in vitro in fibroblasts of patients carrying the m.3243A>G and m.8344A>G mutations. In contrast, N-acetyl-cysteine had a beneficial effect on mitochondrial translation in TRMU and MTO1 deficient fibroblasts.<br><br>CONCLUSIONS: Our results suggest that L-cysteine or N-acetyl-cysteine supplementation may be a potential treatment for selected subgroups of patients with mitochondrial translation deficiencies. Further studies are needed to explore the full potential of cysteine supplementation as a treatment for patients with mitochondrial disease.}, }
@article {pmid27853746, year = {2016}, author = {Basford, PJ and Brown, J and Gadeke, L and Fogg, C and Haysom-Newport, B and Ogollah, R and Bhattacharyya, R and Longcroft-Wheaton, G and Thursby-Pelham, F and Neale, JR and Bhandari, P}, title = {A randomized controlled trial of pre-procedure simethicone and N-acetylcysteine to improve mucosal visibility during gastroscopy - NICEVIS.}, journal = {Endoscopy international open}, volume = {4}, number = {11}, pages = {E1197-E1202}, pmid = {27853746}, issn = {2364-3722}, abstract = {Background and study aims: Mucosal views can be impaired by residual bubbles and mucus during gastroscopy. This study aimed to determine whether a pre-gastroscopy drink containing simethicone and N-acetylcysteine improves mucosal visualisation. Patients and methods: We conducted a randomized controlled trial recruiting 126 subjects undergoing routine gastroscopy. Subjects were randomized 1:1:1 to receive: A-pre-procedure drink of water, simethicone and N-acetylcysteine (NAC); B-water alone; or C-no preparation. Study endoscopists were blinded to group allocation. Digital images were taken at 4 locations (lower esophagus/upper gastric body/antrum/fundus), and rated for mucosal visibility (MV) using a 4-point scale (1 = best, 4 = worst) by 4 separate experienced endoscopists. The primary outcome measure was mean mucosal visibility score (MVS). Secondary outcome measures were procedure duration and volume of fluid flush required to achieve adequate mucosal views. Results: Mean MVS for Group A was significantly better than for Group B (1.35 vs 2.11, P < 0.001) and Group C (1.35 vs 2.21, P < 0.001). Mean flush volume required to achieve adequate mucosal views was significantly lower in Group A than Group B (2.0 mL vs 31.5 mL, P = 0.001) and Group C (2.0 mL vs 39.2 mL P < 0.001). Procedure duration did not differ significantly between any of the 3 groups. MV scores at each of the 4 locations demonstrated significantly better mucosal visibility in Group A compared to Group B and Group C (P < 0.0025 for all comparisons). Conclusions: A pre-procedure drink containing simethicone and NAC significantly improves mucosal visibility during gastroscopy and reduces the need for flushes during the procedure. Effectiveness in the lower esophagus demonstrates potential benefit in Barrett's oesophagus surveillance gastroscopy.}, }
@article {pmid27853743, year = {2016}, author = {Kwok, K and Chang, J and Lo, S and Giap, A and Lim, B and Wu, B}, title = {A novel adjunctive cleansing method to reduce colony-forming units on duodenoscopes.}, journal = {Endoscopy international open}, volume = {4}, number = {11}, pages = {E1178-E1182}, pmid = {27853743}, issn = {2364-3722}, abstract = {Background and study aims: Endoscopic retrograde cholangiopancreatography-related infections are of increasing global concern due to the emergence of multidrug-resistant bacteria such as carbapenem-resistant enterobacteriaceae (CRE), with bacterial biofilm production postulated as one cause of persistent infection from such virulent organisms. Because N-acetylcysteine (NAC) has been shown to possess antibacterial and biofilm-disruption properties, we aimed to evaluate if NAC would demonstrate clinical utility in reducing the colony forming units (CFU) at the elevator end of a duodenoscope, one of the hardest areas to clean. Patients and methods: This was a pilot study of 16 procedures involving the use of a duodenoscope. After use, the elevator tip of a duodenoscope was cultured and submerged for 30 minutes, either in 20 % NAC (200 mg/mL, intervention) or in sterile water (control). After 30 minutes, the elevator tip was re-cultured. Results: Submersion of the distal end of a duodenoscope in 20 % NAC (200 mg/mL) for 30 minutes resulted in a statistically significant reduction in bacterial colony forming units compared to control (average reduction 41.6 % vs 8.8 %, P = 0.001). There was no visible damage and no optical distortion to the duodenoscope after submersion in NAC. Conclusions: In summary, NAC may be a safe, simple, and useful adjunct to currently available methods of duodenoscope reprocessing. Further research may better define NAC's role in duodenoscope reprocessing, either broadly or specifically after procedures suspected to produce a high risk of bacterial contamination (e. g. choledocholithiasis).}, }
@article {pmid27846303, year = {2016}, author = {Chen, X and Tzekov, R and Su, M and Hong, H and Min, W and Han, A and Li, W}, title = {Auranofin Inhibits Retinal Pigment Epithelium Cell Survival through Reactive Oxygen Species-Dependent Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Signaling Pathway.}, journal = {PloS one}, volume = {11}, number = {11}, pages = {e0166386}, pmid = {27846303}, issn = {1932-6203}, support = {P30 CA016359/CA/NCI NIH HHS/United States ; R01 HL115148/HL/NHLBI NIH HHS/United States ; }, mesh = {Auranofin/*administration &amp; dosage ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival ; ErbB Receptors/*genetics ; Humans ; MAP Kinase Signaling System/drug effects ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/*drug effects ; Vitreoretinopathy, Proliferative/*drug therapy/genetics/pathology ; p38 Mitogen-Activated Protein Kinases/*genetics ; }, abstract = {Abnormal survival of retinal pigment epithelium (RPE) cells contributes to the pathogenesis of proliferative vitreoretinopathy (PVR), a sight-threatening disease. In this study, we explored the effect of the anti-rheumatic agent auranofin (AF) on RPE cell survival and studied the underlying signaling mechanisms in vitro. Our results showed that AF inhibited ARPE-19 cell survival in a dose and time-dependent manner. Application of AF induced several effects: a significant decrease in total epidermal growth factor receptor (EGFR) and an increase in phosphorylated EGFR and mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinase (ERK), P38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), c-Jun, mitogen activated protein kinase activated protein kinase 2(MAPKAPK2), and heat shock protein 27 (HSP27). AF also inhibited epidermal growth factor (EGF)-dependent cell proliferation and migration through affecting EGFR/MAPK signaling. The antioxidant N-acetylcysteine (NAC) blocked the AF-induced increase of reactive oxygen species (ROS) production, the reduction of total EGFR, and the phosphorylation of multiple nodes in EGFR/MAPK signaling pathway. P38MAPK inhibitor SB203580, but not inhibitors of EGFR (erlotinib), ERK (FR180204) and JNK (SP600125), suppressed AF-induced phosphorylation of EGFR/p38MAPK/MAPKAPK2/Hsp27. In conclusion, the ROS-dependent phosphorylation of EGFR/MAPK is an important signaling pathway for AF-induced inhibition of RPE cell survival, and AF may have the potential for treatment of abnormal survival of RPE cells in PVR.}, }
@article {pmid27845815, year = {2016}, author = {Höjer, J and Salmonson, H and Sjöberg, G and Tellerup, M and Brogren, J}, title = {[Overdose of modified-release paracetamol calls for changed treatment routines. New guidelines from the Swedish Poisons Information Centre].}, journal = {Lakartidningen}, volume = {113}, number = {}, pages = {}, pmid = {27845815}, issn = {1652-7518}, mesh = {Acetaminophen/administration &amp; dosage/*adverse effects/blood ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Analgesics, Non-Narcotic/administration &amp; dosage/*adverse effects/blood ; Antidotes/administration &amp; dosage/*therapeutic use ; Delayed-Action Preparations/*adverse effects ; Drug Overdose/*drug therapy/epidemiology ; Humans ; Male ; Poison Control Centers ; Practice Guidelines as Topic ; Sweden/epidemiology ; }, abstract = {Overdose of modified-release paracetamol calls for changed treatment routines. New guidelines from the Swedish Poisons Information Centre The sales of modified-release paracetamol tablets are steadily increasing in Sweden as are the number of overdose cases with this formulation. The Swedish Poisons Information Centre has noted that the standard treatment protocol with N-acetylcysteine (NAC), which is based on overdoses with immediate-release paracetamol formulations, is often inadequate in this setting. In this paper, an adult who overdosed on 66.5 grams of modified-release paracetamol tablets and developed severe liver impairment (max ALT 6,660 U/l) despite timely and rigorous NAC treatment is presented. The patient's peak S-paracetamol of 2,800 µmol/l was delayed to 19 hours post-ingestion. Moreover, a pharmacokinetic and clinical study of similar cases showed that seven (21%) of the 34 patients who received NAC treatment within 8 hours after ingestion developed liver impairment. Finally, new Swedish guidelines for management of these cases are presented. The guidelines are also available on www.giftinfo.se.}, }
@article {pmid27845722, year = {2016}, author = {Uhlig, S and Stanic, A and Hofgaard, IS and Kluger, B and Schuhmacher, R and Miles, CO}, title = {Glutathione-Conjugates of Deoxynivalenol in Naturally Contaminated Grain Are Primarily Linked via the Epoxide Group.}, journal = {Toxins}, volume = {8}, number = {11}, pages = {}, pmid = {27845722}, issn = {2072-6651}, mesh = {Cysteine/*metabolism ; Epoxy Compounds/metabolism ; Glutathione/*metabolism ; Trichothecenes/*metabolism ; Triticum/*chemistry ; }, abstract = {A glutathione (GSH) adduct of the mycotoxin 4-deoxynivalenol (DON), together with a range of related conjugates, has recently been tentatively identified by LC-MS of DON-treated wheat spikelets. In this study, we prepared samples of DON conjugated at the 10- and 13-positions with GSH, Cys, CysGly, γ-GluCys and N-acetylcysteine (NAC). The mixtures of conjugates were used as standards for LC-HRMS analysis of one of the DON-treated wheat spikelet samples, as well as 19 Norwegian grain samples of spring wheat and 16 grain samples of oats that were naturally-contaminated with DON at concentrations higher than 1 mg/kg. The artificially-contaminated wheat spikelets contained conjugates of GSH, CysGly and Cys coupled at the olefinic 10-position of DON, whereas the naturally-contaminated harvest-ripe grain samples contained GSH, CysGly, Cys, and NAC coupled mainly at the 13-position on the epoxy group. The identities of the conjugates were confirmed by LC-HRMS comparison with authentic standards, oxidation to the sulfoxides with hydrogen peroxide, and examination of product-ion spectra from LC-HRMS/MS analysis. No γ-GluCys adducts of DON were detected in any of the samples. The presence of 15-O-acetyl-DON was demonstrated for the first time in Norwegian grain. The results indicate that a small but significant proportion of DON is metabolized via the GSH-conjugation pathway in plants. To our knowledge, this is the first report of in vivo conjugation of trichothecenes via their epoxy group, which has generally been viewed as unreactive. Because conjugation at the 13-position of DON and other trichothecenes has been shown to be irreversible, this type of conjugate may prove useful as a biomarker of exposure to DON and other 12,13-epoxytrichothecenes.}, }
@article {pmid27845599, year = {2017}, author = {Shimizu, MH and Gois, PH and Volpini, RA and Canale, D and Luchi, WM and Froeder, L and Heilberg, IP and Seguro, AC}, title = {N-acetylcysteine protects against star fruit-induced acute kidney injury.}, journal = {Renal failure}, volume = {39}, number = {1}, pages = {193-202}, pmid = {27845599}, issn = {1525-6049}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/chemically induced/*drug therapy ; Animals ; Antioxidants/*pharmacology ; Averrhoa/*adverse effects ; Creatinine/metabolism ; Fruit/adverse effects ; Glomerular Filtration Rate ; Hyperoxaluria/drug therapy ; Kidney/physiopathology ; Male ; Oxalates/adverse effects ; Oxidative Stress/*drug effects ; Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Star fruit (SF) is a popular fruit, commonly cultivated in many tropical countries, that contains large amount of oxalate. Acute oxalate nephropathy and direct renal tubular damage through release of free radicals are the main mechanisms involved in SF-induced acute kidney injury (AKI). The aim of this study was to evaluate the protective effect of N-acetylcysteine (NAC) on SF-induced nephrotoxicity due to its potent antioxidant effect.<br><br>MATERIALS AND METHODS: Male Wistar rats received SF juice (4&#x2009;mL/100&#x2009;g body weight) by gavage after a 12&#x2009;h fasting and water deprivation. Fasting and water deprivation continued for 6&#x2009;h thereafter to warrant juice absorption. Thereafter, animals were allocated to three experimental groups: SF (n&#x2009;=&#x2009;6): received tap water; SF&#x2009;+&#x2009;NAC (n&#x2009;=&#x2009;6): received NAC (4.8&#x2009;g/L) in drinking water for 48&#x2009;h after gavage; and Sham (n&#x2009;=&#x2009;6): no interventions. After 48&#x2009;h, inulin clearance studies were performed to determine glomerular filtration rate. In a second series of experiment, rats were housed in metabolic cages for additional assessments.<br><br>RESULTS: SF rats showed markedly reduced inulin clearance associated with hyperoxaluria, renal tubular damage, increased oxidative stress and inflammation. NAC treatment ameliorated all these alterations. Under polarized light microscopy, SF rats exhibited intense calcium oxalate birefringence crystals deposition, dilation of renal tubules and tubular epithelial degeneration, which were attenuate by NAC therapy.<br><br>CONCLUSIONS: Our data show that therapeutic NAC attenuates renal dysfunction in a model of acute oxalate nephropathy following SF ingestion by reducing oxidative stress, oxaluria, and inflammation. This might represent a novel indication of NAC for the treatment of SF-induced AKI.}, }
@article {pmid27843711, year = {2016}, author = {Tian, Q and Wu, S and Dai, Z and Yang, J and Zheng, J and Zheng, Q and Liu, Y}, title = {Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway.}, journal = {PeerJ}, volume = {4}, number = {}, pages = {e2611}, pmid = {27843711}, issn = {2167-8359}, abstract = {BACKGROUND: Iron overload is recognized as a new pathogenfor osteoporosis. Various studies demonstrated that iron overload could induce apoptosis in osteoblasts and osteoporosis in vivo. However, the exact molecular mechanisms involved in the iron overload-mediated induction of apoptosis in osteoblasts has not been explored.<br><br>PURPOSE: In this study, we attempted to determine whether the mitochondrial apoptotic pathway is involved in iron-induced osteoblastic cell death and to investigate the beneficial effect of N-acetyl-cysteine (NAC) in iron-induced cytotoxicity.<br><br>METHODS: The MC3T3-E1 osteoblastic cell line was treated with various concentrations of ferric ion in the absence or presence of NAC, and intracellular iron, cell viability, reactive oxygen species, functionand morphology changes of mitochondria and mitochondrial apoptosis related key indicators were detected by commercial kits. In addition, to further explain potential mechanisms underlying iron overload-related osteoporosis, we also assessed cell viability, apoptosis, and osteogenic differentiation potential in bone marrow-derived mesenchymal stemcells(MSCs) by commercial kits.<br><br>RESULTS: Ferric ion demonstrated concentration-dependent cytotoxic effects on osteoblasts. After incubation with iron, an elevation of intracelluar labile iron levels and a concomitant over-generation of reactive oxygen species (ROS) were detected by flow cytometry in osteoblasts. Nox4 (NADPH oxidase 4), an important ROS producer, was also evaluated by western blot. Apoptosis, which was evaluated by Annexin V/propidium iodide staining, Hoechst 33258 staining, and the activation of caspase-3, was detected after exposure to iron. Iron contributed to the permeabilizatio of mitochondria, leading to the release of cytochrome C (cyto C), which, in turn, induced mitochondrial apoptosis in osteoblasts via activation of Caspase-3, up-regulation of Bax, and down-regulation of Bcl-2. NAC could reverse iron-mediated mitochondrial dysfunction and blocked the apoptotic events through inhibit the generation of ROS. In addition, iron could significantly promote apoptosis and suppress osteogenic differentiation and mineralization in bone marrow-derived MSCs.<br><br>CONCLUSIONS: These findings firstly demonstrate that the mitochondrial apoptotic pathway involved in iron-induced osteoblast apoptosis. NAC could relieved the oxidative stress and shielded osteoblasts from apoptosis casused by iron-overload. We also reveal that iron overload in bone marrow-derived MSCs results in increased apoptosis and the impairment of osteogenesis and mineralization.}, }
@article {pmid27841696, year = {2017}, author = {Zhou, W and Xu, G and Wang, Y and Xu, Z and Liu, X and Xu, X and Ren, G and Tian, K}, title = {Oxidative stress induced autophagy in cancer associated fibroblast enhances proliferation and metabolism of colorectal cancer cells.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {16}, number = {1}, pages = {73-81}, pmid = {27841696}, issn = {1551-4005}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; *Autophagy/drug effects ; Blotting, Western ; Cancer-Associated Fibroblasts/*metabolism/*pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Coculture Techniques ; Colorectal Neoplasms/*metabolism/*pathology ; Humans ; *Oxidative Stress/drug effects ; }, abstract = {Tumors are comprised of malignant cancer cells and stromal cells which constitute the tumor microenvironment (TME). Previous studies have shown that cancer associated fibroblast (CAF) in TME is an important promoter of tumor initiation and progression. However, the underlying molecular mechanisms by which CAFs influence the growth of colorectal cancer cells (CRCs) have not been clearly elucidated. In this study, by using a non-contact co-culture system between human colorectal fibroblasts (CCD-18-co) and CRCs (LoVo, SW480, and SW620), we found that fibroblasts existing in tumor microenvironment positively influenced the metabolism of colorectal cancer cells, through its autophagy and oxidative stress pathway which were initially induced by neighboring tumor cells. Therefore, our data provided a novel possibility to develop fibroblasts as a potential target to treat CRC.}, }
@article {pmid27835669, year = {2016}, author = {Wang, D and Meng, G and Zheng, M and Zhang, Y and Chen, A and Wu, J and Wei, J}, title = {The Glutaminase-1 Inhibitor 968 Enhances Dihydroartemisinin-Mediated Antitumor Efficacy in Hepatocellular Carcinoma Cells.}, journal = {PloS one}, volume = {11}, number = {11}, pages = {e0166423}, pmid = {27835669}, issn = {1932-6203}, mesh = {Acetylcysteine/antagonists &amp; inhibitors/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Artemisinins/*pharmacology ; Benzophenanthridines/*pharmacology ; Cell Line ; Cell Line, Tumor ; Drug Combinations ; Drug Synergism ; Endothelial Cells/cytology/drug effects/metabolism ; Enzyme Inhibitors/*pharmacology ; Gene Expression ; Glutaminase/*antagonists &amp; inhibitors/genetics/metabolism ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Hepatocytes/*drug effects/metabolism/pathology ; Humans ; Organ Specificity ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Reprogrammed metabolism and redox homeostasis are potential targets of cancer therapy. Our previous study demonstrated that the kidney form of glutaminase (GLS1) is highly expressed in hepatocellular carcinoma (HCC) cells and can be used as a target for effective anticancer therapy. Dihydroartemisinin (DHA) increases intracellular reactive oxygen species (ROS) levels leading to cytotoxicity in cancer cells. However, the heterogeneity of cancer cells often leads to differing responses to oxidative lesions. For instance, cancer cells with high ratio of GSH/GSSG, a critical ROS scavenger, are resistant to ROS-induced cytotoxicity. We postulate that a combinatorial strategy firstly disrupting redox homeostasis followed by DHA might yield a profound antitumor efficacy. In this study, when HCC cells were treated with a GLS1 inhibitor 968, the ROS elimination capacity was significantly reduced in HCC cells, which rendered HCC cells but not normal endothelial cells more sensitive to DHA-mediated cytotoxicity. We further confirmed that this synergistic antitumor efficacy was mediated by excessive ROS generation in HCC cells. NAC, a ROS inhibitor, partly rescued the combinatorial cytotoxic effect of 968 and DHA. Given that GLS1 is a potential antitumor target and DHA has been safely used in clinic, our findings provide new insight into liver cancer therapy targeting glutamine metabolism combined with the ROS generator DHA, which can be readily translated into cancer clinical trials.}, }
@article {pmid27833015, year = {2016}, author = {Sun, X and Jiao, X and Ma, Y and Liu, Y and Zhang, L and He, Y and Chen, Y}, title = {Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome.}, journal = {Biochemical and biophysical research communications}, volume = {481}, number = {1-2}, pages = {63-70}, doi = {10.1016/j.bbrc.2016.11.017}, pmid = {27833015}, issn = {1090-2104}, mesh = {Carrier Proteins/*immunology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelium, Vascular/drug effects/*immunology ; Human Umbilical Vein Endothelial Cells/drug effects/*immunology ; Humans ; Inflammasomes/*immunology ; Inflammation/chemically induced/*immunology ; Methylamines/*adverse effects ; NLR Family, Pyrin Domain-Containing 3 Protein/*immunology ; Reactive Oxygen Species/immunology ; }, abstract = {Recent research demonstrates that the choline-derived metabolite trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis and cardiovascular risks. The NLRP3 inflammasome responds to exogenous and endogenous danger signals involved in the development of atherosclerosis. Moreover, thioredoxin-interactive protein (TXNIP) activation is a key event linked to NLRP3 inflammasome via reactive oxygen species (ROS). Whether TMAO prime NLRP3 inflammasome via ROS-TXNIP pathway remains unclear. This study observed the expression of TXNIP-NLRP3 inflammasome stimulated by TMAO in human umbilical vein endothelial cells (HUVECs), aiming to elucidate the mechanism by which the TMAO may contribute to inflammation and endothelial dysfunction. Our data showed that TMAO significantly triggered oxidative stress and activated TXNIP-NLRP3 inflammasome whereat inflammatory cytokines interleukin (IL)-1β and IL-18 were released in a dose- and time-dependent manner, but endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) were inhibited. Moreover, TMAO-mediated effects were observably reversed by ROS inhibitor N-acetylcysteine (NAC) treatment or siRNA-mediated knockdown TXPIN and NLRP3. Taken together, our results firstly reveal that TMAO induces inflammation and endothelial dysfunction via activating ROS-TXNIP-NLRP3 inflammasome, suggest a likely mechanism for TMAO-dependent enhancement in atherosclerosis and cardiovascular risks.}, }
@article {pmid27832694, year = {2016}, author = {Abtahi, H and Peiman, S and Foroumandi, M and Safavi, E}, title = {Long Term Follow-Up of Sulfur Mustard Related Bronchiolitis Obliterans Treatment.}, journal = {Acta medica Iranica}, volume = {54}, number = {9}, pages = {605-609}, pmid = {27832694}, issn = {1735-9694}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Asthma/physiopathology ; Bronchiolitis Obliterans/chemically induced/*therapy ; Follow-Up Studies ; Humans ; Lung/physiopathology ; Male ; Middle Aged ; Mustard Gas/*toxicity ; Retrospective Studies ; Spirometry ; }, abstract = {Bronchiolitis obliterans (BO) is the most remarkable pulmonary sequels of war-related sulfur mustard inhalation. There is little if any data about long-term efficacy of associated BO treatment. Five years spirometric records of three groups of patients with obstructive pulmonary diseases (asthma, COPD, BO) and documented sulfur mustard inhalation were evaluated. The BO patients were treated with inhaled Seretide 125-250/25 (2 puffs BID), azithromycin (250 mg, three times/week) and N-acetylcysteine (1200-1800/day). Asthma and COPD patients were treated according to existing guidelines. Seventy-three (38 asthma, 16 COPD and 19 BO) patients completed the 5 years follow-up. Basal and final FEV1 in BO patients (2.69±0.81 and 2.39±0.65 respectively) were not significantly different from COPD patients (2.46±0.56 and 1.96±0.76 respectively). There was also no significant difference between the yearly FEV1 decline in BO patients compared to COPD patients (60±84 cc vs. 99±79 cc respectively, P=0.163). The non-significant difference of FEV1 decline in BO compared to COPD patients suggests the effectiveness of azithromycin, inhaled steroid and N-acetyl cysteine in BO patients. Considering safety and possible effectiveness, this treatment is recommended until more data is available from controlled clinical studies.}, }
@article {pmid27831562, year = {2016}, author = {Jiang, D and Gao, F and Zhang, Y and Wong, DS and Li, Q and Tse, HF and Xu, G and Yu, Z and Lian, Q}, title = {Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage.}, journal = {Cell death &amp; disease}, volume = {7}, number = {11}, pages = {e2467}, pmid = {27831562}, issn = {2041-4889}, mesh = {Animals ; Cell Respiration/drug effects ; Cytokines/metabolism ; *Cytoprotection/drug effects ; Epithelial Cells/drug effects/metabolism/*pathology ; Epithelium, Corneal/*pathology ; Humans ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*cytology/drug effects/metabolism ; Mitochondria/drug effects/*metabolism ; NF-kappa B/metabolism ; Nanotubes/chemistry ; Rabbits ; Reactive Oxygen Species/metabolism ; Rotenone/toxicity ; Sus scrofa ; Up-Regulation/drug effects ; Wound Healing/drug effects ; }, abstract = {Recent studies have demonstrated that mesenchymal stem cells (MSCs) can donate mitochondria to airway epithelial cells and rescue mitochondrial damage in lung injury. We sought to determine whether MSCs could donate mitochondria and protect against oxidative stress-induced mitochondrial dysfunction in the cornea. Co-culturing of MSCs and corneal epithelial cells (CECs) indicated that the efficiency of mitochondrial transfer from MSCs to CECs was enhanced by Rotenone (Rot)-induced oxidative stress. The efficient mitochondrial transfer was associated with increased formation of tunneling nanotubes (TNTs) between MSCs and CECs, tubular connections that allowed direct intercellular communication. Separation of MSCs and CECs by a transwell culture system revealed no mitochiondrial transfer from MSCs to CECs and mitochondrial function was impaired when CECs were exposed to Rot challenge. CECs with or without mitochondrial transfer from MSCs displayed a distinct survival capacity and mitochondrial oxygen consumption rate. Mechanistically, increased filopodia outgrowth in CECs for TNT formation was associated with oxidative inflammation-activated NFκB/TNFαip2 signaling pathways that could be attenuated by reactive oxygen species scavenger N-acetylcysteine (NAC) treatment. Furthermore, MSCs grown on a decellularized porcine corneal scaffold were transplanted onto an alkali-injured eye in a rabbit model. Enhanced corneal wound healing was evident following healthy MSC scaffold transplantation. And transferred mitochondria was detected in corneal epithelium. In conclusion, mitochondrial transfer from MSCs provides novel protection for the cornea against oxidative stress-induced mitochondrial damage. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.}, }
@article {pmid27830545, year = {2017}, author = {Bartlett, DC and Newsome, PN}, title = {A Modified Protocol for the Isolation of Primary Human Hepatocytes with Improved Viability and Function from Normal and Diseased Human Liver.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {1506}, number = {}, pages = {61-73}, doi = {10.1007/978-1-4939-6506-9_4}, pmid = {27830545}, issn = {1940-6029}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Cell Separation/instrumentation/*methods ; Cell Survival/drug effects ; Cell Transplantation/*methods ; Cells, Cultured ; Collagenases/pharmacology ; Hepatocytes/drug effects/metabolism/*transplantation ; Humans ; Liver/*cytology ; Liver Diseases/*surgery ; Primary Cell Culture ; Thermolysin/pharmacology ; Tissue Donors ; }, abstract = {Successful hepatocyte isolation is critical for continued development of cellular transplantation. However, most tissue available for research is from diseased liver and the results of hepatocyte isolation from such tissue are inferior compared to normal tissue. Here we describe a modified method, combining the use of Liberase and N-acetylcysteine (NAC), for the isolation of primary human hepatocytes with high viability from normal and diseased liver.}, }
@article {pmid27828984, year = {2016}, author = {Tang, B and Wang, K and Jia, YP and Zhu, P and Fang, Y and Zhang, ZJ and Mao, XH and Li, Q and Zeng, DZ}, title = {Fusobacterium nucleatum-Induced Impairment of Autophagic Flux Enhances the Expression of Proinflammatory Cytokines via ROS in Caco-2 Cells.}, journal = {PloS one}, volume = {11}, number = {11}, pages = {e0165701}, pmid = {27828984}, issn = {1932-6203}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Autophagy/drug effects ; Autophagy-Related Protein 12/antagonists &amp; inhibitors/genetics/immunology ; Autophagy-Related Protein 5/antagonists &amp; inhibitors/genetics/immunology ; Caco-2 Cells ; Cell Line, Tumor ; Epithelial Cells/cytology/drug effects/*immunology ; Free Radical Scavengers/pharmacology ; Fusobacterium Infections/genetics/*immunology/microbiology/pathology ; Fusobacterium nucleatum/*immunology ; Gene Expression Regulation ; Humans ; Interleukin-1beta/genetics/*immunology ; Interleukin-8/genetics/*immunology ; Macrolides/pharmacology ; Mice ; Mice, Inbred C57BL ; RNA, Small Interfering/genetics/metabolism ; Reactive Oxygen Species/*immunology/metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/genetics/*immunology ; }, abstract = {Fusobacterium nucleatum (F. nucleatum) plays a critical role in gastrointestinal inflammation. However, the exact mechanism by which F. nucleatum contributes to inflammation is unclear. In the present study, it was revealed that F. nucleatum could induce the production of proinflammatory cytokines (IL-8, IL-1β and TNF-α) and reactive oxygen species (ROS) in Caco-2 colorectal) adenocarcinoma cells. Furthermore, ROS scavengers (NAC or Tiron) could decrease the production of proinflammatory cytokines during F. nucleatum infection. In addition, we observed that autophagy is impaired in Caco-2 cells after F. nucleatum infection. The production of proinflammatory cytokines and ROS induced by F. nucleatum was enhanced with either autophagy pharmacologic inhibitors (3-methyladenine, bafilomycin A1) or RNA interference in essential autophagy genes (ATG5 or ATG12) in Caco-2 cells. Taken together, these results indicate that F. nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 Cells.}, }
@article {pmid27827950, year = {2016}, author = {Chen, CY and Yen, CY and Wang, HR and Yang, HP and Tang, JY and Huang, HW and Hsu, SH and Chang, HW}, title = {Tenuifolide B from Cinnamomum tenuifolium Stem Selectively Inhibits Proliferation of Oral Cancer Cells via Apoptosis, ROS Generation, Mitochondrial Depolarization, and DNA Damage.}, journal = {Toxins}, volume = {8}, number = {11}, pages = {}, pmid = {27827950}, issn = {2072-6651}, mesh = {4-Butyrolactone/*analogs &amp; derivatives/pharmacology ; Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; *Cinnamomum ; DNA Damage ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mouth Neoplasms/drug therapy ; Plant Stems ; Reactive Oxygen Species/metabolism ; }, abstract = {The development of drugs that selectively kill oral cancer cells but are less harmful to normal cells still provide several challenges. In this study, the antioral cancer effects of tenuifolide B (TFB), extracted from the stem of the plant Cinnamomum tenuifolium are evaluated in terms of their effects on cancer cell viability, cell cycle analysis, apoptosis, oxidative stress, and DNA damage. Cell viability of oral cancer cells (Ca9-22 and CAL 27) was found to be significantly inhibited by TFB in a dose-responsive manner in terms of ATP assay, yielding IC50 = 4.67 and 7.05 μM (24 h), but are less lethal to normal oral cells (HGF-1). Dose-responsive increases in subG1 populations as well as the intensities of flow cytometry-based annexin V/propidium iodide (PI) analysis and pancaspase activity suggested that apoptosis was inducible by TFB in these two types of oral cancer cells. Pretreatment with the apoptosis inhibitor (Z-VAD-FMK) reduced the annexin V intensity of these two TFB-treated oral cancer cells, suggesting that TFB induced apoptosis-mediated cell death to oral cancer cells. Cleaved-poly (ADP-ribose) polymerase (PARP) and cleaved-caspases 3, 8, and 9 were upregulated in these two TFB-treated oral cancer cells over time but less harmful for normal oral HGF-1 cells. Dose-responsive and time-dependent increases in reactive oxygen species (ROS) and decreases in mitochondrial membrane potential (MitoMP) in these two TFB-treated oral cancer cells suggest that TFB may generate oxidative stress as measured by flow cytometry. N-acetylcysteine (NAC) pretreatment reduced the TFB-induced ROS generation and further validated that ROS was relevant to TFB-induced cell death. Both flow cytometry and Western blotting demonstrated that the DNA double strand marker γH2AX dose-responsively increased in TFB-treated Ca9-22 cells and time-dependently increased in two TFB-treated oral cancer cells. Taken together, we infer that TFB can selectively inhibit cell proliferation of oral cancer cells through apoptosis, ROS generation, mitochondrial membrane depolarization, and DNA damage.}, }
@article {pmid27825965, year = {2016}, author = {Kim, J and Lee, GR and Kim, H and Jo, YJ and Hong, SE and Lee, J and Lee, HI and Jang, YS and Oh, SH and Lee, HJ and Lee, JS and Jeong, W}, title = {Effective killing of cancer cells and regression of tumor growth by K27 targeting sulfiredoxin.}, journal = {Free radical biology &amp; medicine}, volume = {101}, number = {}, pages = {384-392}, doi = {10.1016/j.freeradbiomed.2016.11.001}, pmid = {27825965}, issn = {1873-4596}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Adenocarcinoma, Bronchiolo-Alveolar/*drug therapy/metabolism/pathology ; Animals ; Antineoplastic Agents/chemical synthesis/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation ; Enzyme Inhibitors/chemical synthesis/*pharmacology ; Epithelial Cells/drug effects/metabolism/pathology ; Female ; Gene Expression ; Humans ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; Mitochondria/drug effects/metabolism/pathology ; Molecular Targeted Therapy ; Oxidative Stress/drug effects ; Oxidoreductases Acting on Sulfur Group Donors/*antagonists &amp; inhibitors/genetics/metabolism ; Quinazolines/chemical synthesis/*pharmacology ; Reactive Oxygen Species/*agonists/metabolism ; Xenograft Model Antitumor Assays ; beta-Alanine/*analogs &amp; derivatives/chemical synthesis/pharmacology ; }, abstract = {Cancer cells have been suggested to be more susceptible to oxidative damages and highly dependent on antioxidant capacity in comparison with normal cells, and thus targeting antioxidant enzymes has been a strategy for effective cancer treatment. Sulfiredoxin (Srx) is an enzyme that catalyzes the reduction of sulfinylated peroxiredoxins and thereby reactivates them. In this study we developed a Srx inhibitor, K27 (N-[7-chloro-2-(4-fluorophenyl)-4-quinazolinyl]-N-(2-phenylethyl)-β-alanine), and showed that it induces the accumulation of sulfinylated peroxiredoxins and oxidative stress, which leads to mitochondrial damage and apoptotic death of cancer cells. The effects of K27 were significantly reversed by ectopic expression of Srx or antioxidant N-acetyl cysteine. In addition, K27 led to preferential death of tumorigenic cells over non-tumorigenic cells, and suppressed the growth of xenograft tumor without acute toxicity. Our results suggest that targeting Srx might be an effective therapeutic strategy for cancer treatment through redox-mediated cell death.}, }
@article {pmid27825799, year = {2016}, author = {Hou, XB and Li, TH and Ren, ZP and Liu, Y}, title = {Combination of 2-deoxy d-glucose and metformin for synergistic inhibition of non-small cell lung cancer: A reactive oxygen species and P-p38 mediated mechanism.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {84}, number = {}, pages = {1575-1584}, doi = {10.1016/j.biopha.2016.10.037}, pmid = {27825799}, issn = {1950-6007}, mesh = {A549 Cells ; Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use ; Antioxidants/metabolism ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/*metabolism/pathology ; Caspase 3/metabolism ; Cell Survival/drug effects ; DNA Adducts/metabolism ; DNA Damage ; Deoxyglucose/pharmacology/*therapeutic use ; Drug Synergism ; Humans ; Intracellular Space/metabolism ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Metformin/pharmacology/*therapeutic use ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Targeting metabolism of lung cancer cells is a promising methodology for the treatment of lung cancer. In this regard, 2-Deoxy d-glucose (2-dDG) has been reported to inhibit cell proliferation by intervening the glycolytic pathway. However, phase I clinical trial of 2-dDG demonstrated cardiac side effects at higher dosage. Metformin (Met), on the other hand, has been reported to improve pathological response to chemotherapy in non-small cell lung cancer (NSCLC) patients. In this study, we propose that combination therapy of 2-dDG with Met will demonstrate enhanced cytotoxicity than either compound alone. Our results indicated that inhibition concentration 25 (IC25) for combined treatment of Met and 2-dDG showed more toxicity as compared to individual agents on a NSCLC cell line, A549. This augmented toxicity is associated with increased lipid peroxidation and decreased glutathione level as well as decreased super oxide dismutase and catalase activities. Combination of Met and 2-dDG also demonstrated enhanced DNA damage, DNA adduct formation, intracellular reactive oxygen species (ROS) level, and mitochondrial membrane potential alteration, as well as increased apoptosis, caspase-3 activity, P-p38 and P-AMP-activated protein kinase (AMPK) level. It was also shown that inhibition of caspase-3 and p38 kinase partially (75%-87%) reversed Met and 2-dDG induced cell death, without affecting the ROS levels. On the other hand, pre-treatment of cells with N-acetyl cysteine (NAC) reversed Met and 2-dDG induced cell death to >90%. Taken together, the results of this study demonstrated that combination of Met and 2-dDG showed better toxicity than individual compounds and cell death is ROS, P-p38 and caspase-3 mediated, thereby providing a proof of concept for the combination of Met and 2-dDG as a potential treatment protocol for NSCLC.}, }
@article {pmid27823620, year = {2016}, author = {Hsin, IL and Wang, SC and Li, JR and Ciou, TC and Wu, CH and Wu, HM and Ko, JL}, title = {Immunomodulatory proteins FIP-gts and chloroquine induce caspase-independent cell death via autophagy for resensitizing cisplatin-resistant urothelial cancer cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {23}, number = {13}, pages = {1566-1573}, doi = {10.1016/j.phymed.2016.09.003}, pmid = {27823620}, issn = {1618-095X}, mesh = {Amino Acid Chloromethyl Ketones/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Caspases/metabolism ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Chloroquine/administration &amp; dosage/*pharmacology ; Cisplatin/*pharmacology ; Drug Resistance, Neoplasm/drug effects ; Fungal Proteins/administration &amp; dosage/*pharmacology ; Ganoderma/chemistry ; Humans ; Immunologic Factors/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Urologic Neoplasms/*drug therapy/pathology ; }, abstract = {BACKGROUND: Chloroquine, a lysosomal inhibitor, is used for malaria, rheumatoid arthritis, and lupus erythematosus therapy. In our previous study, FIP-gts, an immunomodulatory protein from Ganoderma tsugae, inhibited cell viability in lung cancer cells and urothelial cancer cells. Urothelial carcinoma is the most common type of bladder cancer. Cisplatin resistance is an important issue in urothelial carcinoma therapy.<br><br>PURPOSE: The aim of this study is to investigate the effect of combination treatment with FIP-gts and chloroquine on cytotoxicity to resensitize the cisplatin-resistant cells.<br><br>METHODS: FIP-gts and chloroquine cytotoxicity were determined by evaluating CCK-8 assay. Cell death pathways, ROS and cell cycle arrested were analysed through flow cytometry and Western blot. ShRNA targeting to autophagy-related genes were tested to evaluate their autophagic cell death for resistant urothelial cells.<br><br>RESULTS: Using CCK-8 assay, chloroquine increased FIP-gts-induced cytotoxicity in parental and cisplatin-resistant urothelial cancer cell lines. On flow cytometry, chloroquine enhanced FIP-gts-mediated sub-G1 accumulation, annexin V positive signal and mitochondrial membrane potential loss. Caspase-3/PARP cascade and z-VAD-fmk were performed to prove that FIP-gts and chloroquine induced caspase-independent cell death. Using H2DCFDA staining and flow cytometry, FIP-gts and chloroquine did not induce ROS production. N-acetyl cysteine, a ROS scavenger, inhibited the cytotoxicity and LC3-II accumulation in FIP-gts and chloroquine-treated N/P cells. To elucidate the role of autophagy in caspase-independent cell death by FIP-gts and chloroquine, LC3 shRNA were used to inhibit autophagy in N/P cells. The capabilities of FIP-gts and chloroquine to induce cytotoxicity and sub-G1 phase accumulation were abolished in autophagy-defective cells. This is the first study to reveal the novel function of FIP-gts in triggering caspase-independent cell death in cisplatin-resistant urothelial cancer cells.<br><br>CONCLUSION: Chloroquine enhanced FIP-gts-induced autophagy dependent caspase-independent cell death via abundant autophagosome accumulation. Combination treatment with FIP-gts and chloroquine may provide a new strategy for urothelial cancer therapy.}, }
@article {pmid27821647, year = {2017}, author = {Ireland, DJ and Nathan, EA and Li, S and Charles, AK and Stinson, LF and Kemp, MW and Newnham, JP and Keelan, JA}, title = {Preclinical evaluation of drugs to block inflammation-driven preterm birth.}, journal = {Innate immunity}, volume = {23}, number = {1}, pages = {20-33}, doi = {10.1177/1753425916672313}, pmid = {27821647}, issn = {1753-4267}, mesh = {Adolescent ; Adult ; Amides/*pharmacology ; Amnion/*drug effects/pathology ; Bacterial Infections/*drug therapy/immunology ; Cells, Cultured ; Chorioamnionitis/*drug therapy/immunology ; Cyclooxygenase 2/genetics/metabolism ; Cytokines/metabolism ; Female ; Humans ; I-kappa B Kinase/antagonists &amp; inhibitors ; Inflammation Mediators/metabolism ; MAP Kinase Kinase Kinases/antagonists &amp; inhibitors ; Pregnancy ; Premature Birth/*drug therapy/immunology ; Thiophenes/*pharmacology ; Young Adult ; Zearalenone/*analogs &amp; derivatives/pharmacology ; }, abstract = {Intrauterine inflammation, the major cause of early preterm birth, can have microbial and sterile aetiologies. We assessed in a Transwell model the anti-inflammatory efficacies of five drugs on human extraplacental membranes delivered after preterm spontaneous labour (30-34 wk). Drugs [TPCA1 (IKKβ inhibitor), 5 z-7-oxozeaenol (OxZ, TAK1 inhibitor), inhibitor of NF-κB essential modulator binding domain (iNBD), SB239063 (p38 MAPK inhibitor) and N-acetyl cysteine (free radical scavenger free radicals)] were added after 12 h equilibration to the amniotic compartment. Concentrations of IL-6, TNF-α, MCP-1, IL-1β and PGE2 in the media, and IL6, TNFA and PTGS2 mRNA expression levels in membranes, were determined after 12 h. Data were analysed using mixed models analyses. Thirteen of the 28 membranes had histological chorioamnionitis (HCA[+]); five were positive for bacterial culture and six for fetal inflammatory reaction. Baseline PGE2 and cytokine production was similar between HCA[-] and HCA[+] membranes. Anti-inflammatory effects were also similar between HCA[-] and HCA[+] membranes. TPCA1 and OxZ were the most effective drugs; each inhibited amniotic secretion of 4/5 pro-inflammatory mediators and mRNA levels of 2/3, regardless of stimulus. We conclude that treatment with TPCA1 or OxZ, in combination with antibiotics, may minimise the adverse effects of intrauterine inflammation in pregnancy.}, }
@article {pmid27816822, year = {2016}, author = {Su, L and Lan, Q and Pritchard, HW and Xue, H and Wang, X}, title = {Reactive oxygen species induced by cold stratification promote germination of Hedysarum scoparium seeds.}, journal = {Plant physiology and biochemistry : PPB}, volume = {109}, number = {}, pages = {406-415}, doi = {10.1016/j.plaphy.2016.10.025}, pmid = {27816822}, issn = {1873-2690}, mesh = {Abscisic Acid/metabolism ; Acetylcysteine/pharmacology ; Cold Temperature ; Fabaceae/drug effects/growth &amp; development/*metabolism ; Germination/drug effects/physiology ; Gibberellins/metabolism ; Oxygen Consumption ; Paraquat/pharmacology ; Plant Growth Regulators/metabolism ; Plant Proteins/metabolism ; Protein Carbonylation ; Reactive Oxygen Species/metabolism ; Seeds/drug effects/metabolism ; }, abstract = {Seed germination is comprehensively regulated by multiple intrinsic and extrinsic factors, and reactive oxygen species (ROS) are relatively new among these factors. However, the role and underlying mechanisms of ROS in germination regulation remain largely unknown. In this study, we initially found that cold stratification could promote germination and respiration of Hedysarum scoparium seeds, especially at low temperature. We then noted that a ROS environment change induced by hydrogen peroxide (H2O2) or methylviologen (MV) could similarly promote seed germination. On the other hand, the ROS scavenger N-acetyl-L-cysteine (NAC) suppressed germination of cold-stratified H. scoparium seeds, indicating a stimulatory role of ROS upon seed germination. An increased accumulation of O2[-] was detected in embryonic axes of cold-stratified seeds, and stratification-induced ROS generation as well as progressive accumulation of ROS during germination was further confirmed at the cellular level by confocal microscopy. Moreover, protein carbonylation in cold-stratified seeds was enhanced during germination, which was reversed by NAC treatment. Finally, the relationship between ROS and abscisic acid (ABA) or gibberellin (GA) in germination regulation was investigated. ABA treatment significantly inhibited germination and reduced the H2O2 content in both cold-stratified and non-cold-stratified seeds. Furthermore, we found that cold stratification mediates the down-regulation of the ABA content and increase of GA, suggesting an interaction between ROS and ABA/GA. These results in H. scoparium shed new light on the positive role of ROS and their cross-talk between plant hormones in seed germination.}, }
@article {pmid27816613, year = {2017}, author = {Li, R and Zhou, P and Guo, Y and Lee, JS and Zhou, B}, title = {Tris (1,3-dichloro-2-propyl) phosphate-induced apoptotic signaling pathways in SH-SY5Y neuroblastoma cells.}, journal = {Neurotoxicology}, volume = {58}, number = {}, pages = {1-10}, doi = {10.1016/j.neuro.2016.10.018}, pmid = {27816613}, issn = {1872-9711}, mesh = {Analysis of Variance ; Apoptosis/*drug effects ; Calcium/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cholinesterase Inhibitors/toxicity ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Gene Expression Regulation/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Neuroblastoma/pathology ; Organophosphorus Compounds/*toxicity ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP, also known as TDCPP), an extensively used flame retardant, is frequently detected in the environment and biota. Recent studies have shown that TDCIPP has neurotoxic effects. In this study, we determined the mechanisms of TDCIPP-induced neurotoxicity in human neuroblastoma (SH-SY5Y) cells. By using morphological examination, flow cytometry, and mitochondrial membrane potential (ΔYm) measurement, we confirmed that exposure to TDCIPP caused apoptosis accompanied by the activation of apoptosis-related genes (e.g. Bax and Bcl-2) and caspase 3 protein in SH-SY5Y cells. Increased reactive oxygen species (ROS) formation and intracellular calcium ions ([Ca[2+]]i) were also observed in TDCIPP-treated SH-SY5Y cells. Exposure to TDCIPP led to the activation of protein markers of endoplasmic reticulum (ER) stress, including eukaryotic translation initiation factor 2a subunit (p-EIF2a), activation transcription factor (ATF4), glucose-regulated protein (GRP78), and the proapoptotic factor C/EBP homologous protein (CHOP). To determine the role of the ER in apoptosis, phenyl butyric acid (PBA), an ER stress inhibitor, was applied. Treatment with PBA effectively attenuated TDCIPP-induced ER stress and protected against apoptotic death in SH-SY5Y cells by inhibition of Bax expression and promotion of Bcl-2 expression. Furthermore, we found that pretreatment of the cells with the ROS scavenger N-acetyl cysteine (NAC) inhibited the ER stress response and prevented apoptosis. The combination of PBA and NAC pretreatment could further prevent TDCIPP induced ER-stress and apoptotic death compared with PBA or NAC pretreatment alone. Thus, in the present study, we demonstrated that TDCIPP induces cytotoxicity through a ROS-dependent mechanism involving ER stress and activation of mitochondrial apoptotic pathways in SH-SY5Y cells.}, }
@article {pmid27810491, year = {2016}, author = {Delos Santos, N and Azmat, S and Cuenca, Y and Drenth, J and Lauper, J and Tseng, AS}, title = {Effects of the biocide methylisothiazolinone on Xenopus laevis wound healing and tail regeneration.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {181}, number = {}, pages = {37-45}, doi = {10.1016/j.aquatox.2016.10.016}, pmid = {27810491}, issn = {1879-1514}, mesh = {Animals ; Antioxidants/metabolism ; Disinfectants/*toxicity ; Embryo, Nonmammalian/drug effects/physiology ; Immunohistochemistry ; Larva/drug effects/physiology ; Regeneration/*drug effects ; Thiazoles/*toxicity ; Water Pollutants, Chemical/chemistry/*toxicity ; Wound Healing/drug effects ; Xenopus laevis/growth &amp; development/metabolism/*physiology ; }, abstract = {The South African clawed frog, Xenopus laevis, has a strong history as a suitable model for environmental studies. Its embryos and transparent tadpoles are highly sensitive to the environment and their developmental processes are well described. It is also amenable for molecular studies. These characteristics enable its use for rapid identification and understanding of exposure-induced defects. To investigate the consequences of chemical exposure on aquatic animals, Xenopus laevis embryos and tadpoles were exposed to the biocide, methylisothiazolinone (MIT). Frog tadpoles exposed to MIT following tail amputation lost their natural regenerative ability. This inhibition of regeneration led to a failure to regrow tissues including the spinal cord, muscle, and notochord. This MIT-dependent regenerative defect is due to a failure to close the amputation wound. A wound healing assay revealed that while untreated embryos close their wounds within one day after injury, MIT-treated animals maintained open wounds that did not reduce in size and caused lethality. Concomitant exposure of MIT with chemicals containing thiol groups such as glutathione and N-acetyl cysteine restored normal wound healing and regeneration responses in tadpoles. Together these results indicate that exposure to MIT impairs developmental wound repair and tissue regeneration in Xenopus laevis. Thus, this study reveals new aspects of MIT activity and demonstrates that Xenopus laevis is a well-suited model for facilitating future research into chemical exposure effects on injury responses.}, }
@article {pmid27701048, year = {2016}, author = {Ahamed, M and Akhtar, MJ and Khan, MAM and Alhadlaq, HA and Alshamsan, A}, title = {Cobalt iron oxide nanoparticles induce cytotoxicity and regulate the apoptotic genes through ROS in human liver cells (HepG2).}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {148}, number = {}, pages = {665-673}, doi = {10.1016/j.colsurfb.2016.09.047}, pmid = {27701048}, issn = {1873-4367}, mesh = {Apoptosis/drug effects/*genetics ; Caspase 3/genetics ; Caspase 9/genetics ; Cell Survival/drug effects/genetics ; Cobalt/*chemistry ; Ferric Compounds/*chemistry ; Gene Expression Regulation, Neoplastic/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/genetics/metabolism/pathology ; Metal Nanoparticles/administration &amp; dosage/*chemistry/ultrastructure ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Proto-Oncogene Proteins c-bcl-2/genetics ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Spectrometry, X-Ray Emission ; Tumor Suppressor Protein p53/genetics ; X-Ray Diffraction ; bcl-2-Associated X Protein/genetics ; }, abstract = {Cobalt iron oxide (CoFe2O4) nanoparticles (CIO NPs) have been one of the most widely explored magnetic NPs because of their excellent chemical stability, mechanical hardness and heat generating potential. However, there is limited information concerning the interaction of CIO NPs with biological systems. In this study, we investigated the reactive oxygen species (ROS) mediated cytotoxicity and apoptotic response of CIO NPs in human liver cells (HepG2). Diameter of crystalline CIO NPs was found to be 23nm with a band gap of 1.97eV. CIO NPs induced cell viability reduction and membrane damage, and degree of induction was dose- and time-dependent. CIO NPs were also found to induce oxidative stress revealed by induction of ROS, depletion of glutathione and lower activity of superoxide dismutase enzyme. Real-time PCR data has shown that mRNA level of tumor suppressor gene p53 and apoptotic genes (bax, CASP3 and CASP9) were higher, while the expression level of anti-apoptotic gene bcl-2 was lower in cells following exposure to CIO NPs. Activity of caspase-3 and caspase-9 enzymes was also higher in CIO NPs exposed cells. Furthermore, co-exposure of N-acetyl-cysteine (ROS scavenger) efficiently abrogated the modulation of apoptotic genes along with the prevention of cytotoxicity caused by CIO NPs. Overall, we observed that CIO NPs induced cytotoxicity and apoptosis in HepG2 cells through ROS via p53 pathway. This study suggests that toxicity mechanisms of CIO NPs should be further investigated in animal models.}, }
@article {pmid27387968, year = {2016}, author = {Eftekhari, A and Ahmadian, E and Azarmi, Y and Parvizpur, A and Hamishehkar, H and Eghbal, MA}, title = {In vitro/vivo studies towards mechanisms of risperidone-induced oxidative stress and the protective role of coenzyme Q10 and N-acetylcysteine.}, journal = {Toxicology mechanisms and methods}, volume = {26}, number = {7}, pages = {520-528}, doi = {10.1080/15376516.2016.1204641}, pmid = {27387968}, issn = {1537-6524}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/metabolism/pathology/*prevention &amp; control ; Hepatocytes/drug effects/pathology ; Lipid Peroxidation/drug effects ; Liver/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Risperidone/*toxicity ; Ubiquinone/*analogs &amp; derivatives/pharmacology ; }, abstract = {The hepatotoxic effects of the antipsychotic agent, risperidone (RIS) were investigated for better understanding the pathogenesis of RIS in liver toxicity in vivo and in in vitro. Isolated rat hepatocytes were obtained by collagenase perfusion technique and were then incubated with RIS, different antioxidants in particular coenzyme Q10 (CoQ10), N-acetyl cysteine (NAC). Our results showed that RIS could induce cytotoxicity via rising reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation. All of these effects were significantly (p < 0.05) inhibited by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Similar outcomes were obtained from the in vivo experiments. Liver function enzyme test and histopathological evaluation confirmed RIS-(6 mg/kg) induced damage. Based on these results, it is suggested that RIS-induced liver toxicity is associated with mitochondrial/lysosomal cross-talk following the initiation of oxidative stress. Thus, the use of CoQ10 and/or NAC seems to be a safe therapeutic option in this context.}, }
@article {pmid27804000, year = {2017}, author = {Paul, M and Thushara, RM and Jagadish, S and Zakai, UI and West, R and Kemparaju, K and Girish, KS}, title = {Novel sila-amide derivatives of N-acetylcysteine protects platelets from oxidative stress-induced apoptosis.}, journal = {Journal of thrombosis and thrombolysis}, volume = {43}, number = {2}, pages = {209-216}, pmid = {27804000}, issn = {1573-742X}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Amides ; *Apoptosis ; Blood Platelets/*drug effects ; Cell Membrane Permeability ; Cells, Cultured ; Humans ; Hydrophobic and Hydrophilic Interactions ; *Oxidative Stress ; Protective Agents/chemistry ; Silanes/chemistry/pharmacology ; Structure-Activity Relationship ; }, abstract = {Oxidative stress-induced platelet apoptosis is one among the many causes for the development and progression of many disorders like cardiovascular diseases, arthritis, Alzheimer's disease and many chronic inflammatory responses. Many studies have demonstrated the less optimal effect of N-acetyl cysteine (NAC) in oxidative stress-induced cellular damage. This could be due to its less lipophilicity which makes it difficult to enter the cellular membrane. Therefore in the present study, lipophilic sila-amide derivatives (6a and 6b) synthesized through the reaction of NAC with 3-Aminopropyltrimethylsilane and aminomethyltrimethylsilane were used to determine their protective property against oxidative stress-induced platelet apoptosis. At a concentration of 10 µM, compound 6a and 6b were able to significantly inhibit Rotenone/H2O2 induced platelet apoptotic markers like reactive oxygen species, intracellular calcium level, mitochondrial membrane potential, cytochrome c release from mitochondrial to the cytosol, caspase-9 and -3 activity and phosphatidylserine externalization. Therefore, the compounds can be extrapolated as therapeutic agents to protect platelets from oxidative stress-induced platelet apoptosis and its associated complications.}, }
@article {pmid27766914, year = {2017}, author = {Minarini, A and Ferrari, S and Galletti, M and Giambalvo, N and Perrone, D and Rioli, G and Galeazzi, GM}, title = {N-acetylcysteine in the treatment of psychiatric disorders: current status and future prospects.}, journal = {Expert opinion on drug metabolism &amp; toxicology}, volume = {13}, number = {3}, pages = {279-292}, doi = {10.1080/17425255.2017.1251580}, pmid = {27766914}, issn = {1744-7607}, mesh = {Acetylcysteine/adverse effects/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism ; Free Radical Scavengers/adverse effects/pharmacology/*therapeutic use ; Glutathione/metabolism ; Humans ; Mental Disorders/*drug therapy/physiopathology ; }, abstract = {N-acetylcysteine (NAC) is widely known for its role as a mucolytic and as an antidote to paracetamol overdose. There is increasing interest in the use of NAC in the treatment of several psychiatric disorders. The rationale for the administration of NAC in psychiatric conditions is based on its role as a precursor to the antioxidant glutathione, and its action as a modulating agent of glutamatergic, dopaminergic, neurotropic and inflammatory pathways. Areas covered: This study reviews the available data regarding the use of NAC in different psychiatric disorders including substance use disorders, autism, obsessive-compulsive spectrum disorders, schizophrenia, depression, bipolar disorder. Promising results were found in trials testing the use of NAC, mainly as an add-on treatment, in cannabis use disorder in young people, depression in bipolar disorder, negative symptoms in schizophrenia, and excoriation (skin-picking) disorder. Despite initial optimism, recent findings regarding NAC efficacy in autism have been disappointing. Expert opinion: These preliminary positive results require further confirmation in larger samples and with longer follow-ups. Given its high tolerability and wide availability, NAC represents an important target to investigate in the field of new adjunctive treatments for psychiatric conditions.}, }
@article {pmid27314649, year = {2016}, author = {Madi, N and Dany, M and Abdoun, S and Usta, J}, title = {Moringa oleifera's Nutritious Aqueous Leaf Extract Has Anticancerous Effects by Compromising Mitochondrial Viability in an ROS-Dependent Manner.}, journal = {Journal of the American College of Nutrition}, volume = {35}, number = {7}, pages = {604-613}, doi = {10.1080/07315724.2015.1080128}, pmid = {27314649}, issn = {1541-1087}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; *Antineoplastic Agents, Phytogenic ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Caco-2 Cells ; Cell Survival/drug effects ; HEK293 Cells ; Hep G2 Cells ; Humans ; Jurkat Cells ; Mitochondria/*drug effects/physiology ; *Moringa oleifera ; Phytotherapy ; Plant Extracts/*pharmacology/therapeutic use ; Plant Leaves/*chemistry ; Plants, Medicinal ; Reactive Oxygen Species/analysis/*metabolism ; }, abstract = {INTRODUCTION: Moringa oleifera (MO) is an important dietary component for many populations in West Africa and the Indian subcontinent. In addition to its highly nutritious value, almost all parts of this plant have been widely used in folk medicine in curing infectious, cardiovascular, gastrointestinal, hepatic, and other diseases. Evidence-based research supported its versatile medicinal properties; however, more rigorous research is required to establish it in cancer therapy. As such, in this study we aim to investigate the in vitro anticancerous effect of Moringa oleifera's aqueous leaf extract.<br><br>METHODS: Moringa extract was prepared by soaking pulverized leaves in hot water mimicking the people's mode of the leaf drink preparation. Several assays were used to study the effect of different percentage concentrations of the extract on viability of A549 cells; levels of adenosine triphosphate (ATP), reactive oxygen species (ROS), and glutathione (GSH) generated; as well as percentage of lactate dehydrogenase (LDH) released at different time points. In addition to mitochondrial membrane potential, apoptotic events were assessed using western blotting for apoptotic markers and immunoflourescent flourescent labeled inhibitor of caspases (FLICA) assay.<br><br>RESULTS: MO extract treatment resulted in a significant decrease in mitochondrial membrane potential (1 hour) and ATP levels (3 hours), followed by an increase in (6 hours) ROS, caspase activation, proapoptotic proteins expression (p53, SMAC/Diablo, AIF), and PARP-1 cleavage. This eventually resulted in decreased GSH levels and a decrease in viability. The cytotoxic effect was prevented upon pretreatment with antioxidant N-acetyl-cysteine. MO decreased as well the viability of HepG2, CaCo2, Jurkat, and HEK293 cells.<br><br>CONCLUSION: Our findings identify a plant extract with an anticancerous effect on cancer cell lines. MO extract exerts its cytotoxic effect in A549 cancer cells by affecting mitochondrial viability and inducing apoptosis in an ROS-dependent manner.}, }
@article {pmid27799742, year = {2016}, author = {Abu El-Saad, AM and Al-Kahtani, MA and Abdel-Moneim, AM}, title = {N-acetylcysteine and meso-2,3-dimercaptosuccinic acid alleviate oxidative stress and hepatic dysfunction induced by sodium arsenite in male rats.}, journal = {Drug design, development and therapy}, volume = {10}, number = {}, pages = {3425-3434}, pmid = {27799742}, issn = {1177-8881}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/*therapeutic use ; Animals ; Arsenites/administration &amp; dosage/toxicity ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/*physiopathology ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Sodium Compounds/administration &amp; dosage/toxicity ; Succimer/administration &amp; dosage/*pharmacology/*therapeutic use ; }, abstract = {Environmental exposure to arsenic represents a serious challenge to humans and other animals. The aim of the present study was to test the protective effect of antioxidant N-acetylcysteine (NAC) either individually or in combination with a chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA), against sodium arsenite oral toxicity in male rats. Five groups were used: control; arsenic group (orally administrated in a concentration of 2 mg/kg body weight [b.w.]); the other three groups were orally administrated sodium arsenite in a concentration of 2 mg/kg b.w. followed by either NAC (10 mg/kg b.w., intraperitoneally [i.p.]), DMSA (50 mg/kg b.w., i.p.) or NAC plus DMSA. Arsenic toxicity caused significant rise in serum aspartate aminotransferase, alanine aminotransferase and total bilirubin, and a significant decrease in total protein (TP) and albumin levels after 3 weeks of experimental period. In addition, arsenic-treated rats showed significantly higher arsenic content in liver and significant rise in hepatic malondialdehyde level. By contrast, sharp decreases in glutathione content and catalase and glutathione reductase activities were discernible. NAC and/or DMSA counteracted most of these physiologic and biochemical defects. NAC monotherapy was more effective than DMSA in increasing TP, while DMSA was more effective in decreasing alanine aminotransferase. The combined treatment was superior over monotherapies in recovery of TP and glutathione. Biochemical data were well supported by histopathological and ultrastructural findings. In conclusion, the combination therapy of NAC and DMSA may be an ideal choice against oxidative insult induced by arsenic poisoning.}, }
@article {pmid27706848, year = {2017}, author = {Pei, HF and Hou, JN and Wei, FP and Xue, Q and Zhang, F and Peng, CF and Yang, Y and Tian, Y and Feng, J and Du, J and He, L and Li, XC and Gao, EH and Li, D and Yang, YJ}, title = {Melatonin attenuates postmyocardial infarction injury via increasing Tom70 expression.}, journal = {Journal of pineal research}, volume = {62}, number = {1}, pages = {}, doi = {10.1111/jpi.12371}, pmid = {27706848}, issn = {1600-079X}, mesh = {Animals ; Apoptosis/drug effects/physiology ; Disease Models, Animal ; Gene Knockdown Techniques ; Male ; Melatonin/*pharmacology ; Mice ; Mice, Inbred C57BL ; Mitochondrial Membrane Transport Proteins/*metabolism ; Mitochondrial Precursor Protein Import Complex Proteins ; Myocardial Infarction/metabolism/*pathology ; Myocardial Reperfusion Injury/metabolism/pathology ; Myocytes, Cardiac/drug effects ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; }, abstract = {Mitochondrial dysfunction leads to reactive oxygen species (ROS) overload, exacerbating injury in myocardial infarction (MI). As a receptor for translocases in the outer mitochondrial membrane (Tom) complex, Tom70 has an unknown function in MI, including melatonin-induced protection against MI injury. We delivered specific small interfering RNAs against Tom70 or lentivirus vectors carrying Tom70a sequences into the left ventricles of mice or to cultured neonatal murine ventricular myocytes (NMVMs). At 48 h post-transfection, the left anterior descending coronary arteries of mice were permanently ligated, while the NMVMs underwent continuous hypoxia. At 24 h after ischemia/hypoxia, oxidative stress was assessed by dihydroethidium and lucigenin-enhanced luminescence, mitochondrial damage by transmission electron microscopy and ATP content, and cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling and caspase-3 assay. At 4 weeks after ischemia, cardiac function and fibrosis were evaluated in mice by echocardiography and Masson's trichrome staining, respectively. Ischemic/hypoxic insult reduced Tom70 expression in cardiomyocytes. Tom70 downregulation aggravated post-MI injury, with increased mitochondrial fragmentation and ROS overload. In contrast, Tom70 upregulation alleviated post-MI injury, with improved mitochondrial integrity and decreased ROS production. PGC-1α/Tom70 expression in ischemic myocardium was increased with melatonin alone, but not when combined with luzindole. Melatonin attenuated post-MI injury in control but not in Tom70-deficient mice. N-acetylcysteine (NAC) reversed the adverse effects of Tom70 deficiency in mitochondria and cardiomyocytes, but at a much higher concentration than melatonin. Our findings showed that Tom70 is essential for melatonin-induced protection against post-MI injury, by breaking the cycle of mitochondrial impairment and ROS generation.}, }
@article {pmid27650197, year = {2017}, author = {Shi, XJ and Ding, L and Zhou, W and Ji, Y and Wang, J and Wang, H and Ma, Y and Jiang, G and Tang, K and Ke, Y and Zhao, W and Liu, HM}, title = {Pro-Apoptotic Effects of JDA-202, a Novel Natural Diterpenoid, on Esophageal Cancer Through Targeting Peroxiredoxin I.}, journal = {Antioxidants &amp; redox signaling}, volume = {27}, number = {2}, pages = {73-92}, pmid = {27650197}, issn = {1557-7716}, mesh = {Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Diterpenes, Kaurane/*administration &amp; dosage/pharmacology ; Drugs, Chinese Herbal/administration &amp; dosage/pharmacology ; Esophageal Neoplasms/*drug therapy/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hydrogen Peroxide/metabolism ; Isodon/*chemistry ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Peroxiredoxins/*antagonists &amp; inhibitors/metabolism ; Phosphorylation ; Xenograft Model Antitumor Assays ; }, abstract = {AIMS: Esophageal cancer (EC) is an aggressive malignancy and the most common solid tumor of gastrointestinal tract all over the world, with high incidence in Asia. The current study was designed to investigate the anticancer efficacy and mechanism that is involved in the action of a natural ent-kaurene diterpenoid, JDA-202, targeting EC.<br><br>RESULTS: We found that an antioxidant protein peroxiredoxin I (Prx I) was upregulated in human EC tissues as well as in EC cell lines. JDA-202, a novel natural compound isolated from Isodon rubescens (Labiatae), was proved to possess strong anti-proliferative activities on those cell lines. Importantly, JDA-202 does not only bind to Prx I directly and markedly inhibit the activity of Prx I in vitro, but it also significantly induces hydrogen peroxide (H2O2)-related cell death. Furthermore, overexpression of Prx I significantly reversed EC109 cell apoptosis caused by JDA-202, whereas short interfering RNA (siRNA)-induced Prx I knockdown resulted in marked cell death even without JDA-202 pretreatment. On the other hand, the increased phosphorylation of mitogen-activated protein kinase (MAPK) proteins (c-Jun N-terminal kinase [JNK], p38, and extracellular signal-regulated kinase [ERK]) by JDA-202 was suppressed by N-acetylcysteine (NAC) or catalase, a known reactive oxygen species (ROS) or H2O2 scavenger. JDA-202 also significantly inhibited the growth of EC109 tumor xenograft, without significant body weight loss and multi-organ toxicities. Innovation and Conclusion: Our findings, for the first time, demonstrated that JDA-202 may serve as a lead compound, targeting the overexpressed Prx I in EC cell lines and ROS accumulation as well as inhibiting the activation of their downstream targets in MAPKs. Antioxid. Redox Signal. 27, 73-92.}, }
@article {pmid27736757, year = {2016}, author = {Landini, G and Di Maggio, T and Sergio, F and Docquier, JD and Rossolini, GM and Pallecchi, L}, title = {Effect of High N-Acetylcysteine Concentrations on Antibiotic Activity against a Large Collection of Respiratory Pathogens.}, journal = {Antimicrobial agents and chemotherapy}, volume = {60}, number = {12}, pages = {7513-7517}, pmid = {27736757}, issn = {1098-6596}, mesh = {Acetylcysteine/*pharmacology ; Aminoglycosides/antagonists &amp; inhibitors/pharmacology ; Anti-Bacterial Agents/*pharmacology ; Ceftriaxone/antagonists &amp; inhibitors/pharmacology ; Drug Combinations ; Drug Interactions ; Enterobacter cloacae/drug effects/growth &amp; development/isolation &amp; purification ; Ertapenem ; Escherichia coli/drug effects/growth &amp; development/isolation &amp; purification ; Humans ; Imipenem/antagonists &amp; inhibitors/*pharmacology ; Klebsiella pneumoniae/drug effects/growth &amp; development/isolation &amp; purification ; Meropenem ; Microbial Sensitivity Tests ; Penicillins/agonists/pharmacology ; Pseudomonas aeruginosa/drug effects/growth &amp; development/isolation &amp; purification ; Respiratory Tract Infections/microbiology ; Staphylococcus aureus/drug effects/growth &amp; development/isolation &amp; purification ; Streptococcus pneumoniae/drug effects/growth &amp; development/isolation &amp; purification ; Streptococcus pyogenes/drug effects/growth &amp; development/isolation &amp; purification ; Thienamycins/antagonists &amp; inhibitors/*pharmacology ; beta-Lactams/antagonists &amp; inhibitors/*pharmacology ; }, abstract = {The effect of high N-acetylcysteine (NAC) concentrations (10 and 50 mM) on antibiotic activity against 40 strains of respiratory pathogens was investigated. NAC compromised the activity of carbapenems (of mostly imipenem and, to lesser extents, meropenem and ertapenem) in a dose-dependent fashion. We demonstrated chemical instability of carbapenems in the presence of NAC. With other antibiotics, 10 mM NAC had no major effects, while 50 mM NAC sporadically decreased (ceftriaxone and aminoglycosides) or increased (penicillins) antibiotic activity.}, }
@article {pmid27211910, year = {2017}, author = {Baek, MW and Cho, HS and Kim, SH and Kim, WJ and Jung, JY}, title = {Ascorbic Acid Induces Necrosis in Human Laryngeal Squamous Cell Carcinoma via ROS, PKC, and Calcium Signaling.}, journal = {Journal of cellular physiology}, volume = {232}, number = {2}, pages = {417-425}, doi = {10.1002/jcp.25438}, pmid = {27211910}, issn = {1097-4652}, mesh = {Apoptosis/drug effects ; Ascorbic Acid/*pharmacology ; Calcium/metabolism ; Calcium Signaling/*drug effects ; Carcinoma, Squamous Cell/*metabolism/*pathology ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Humans ; Laryngeal Neoplasms/*metabolism/*pathology ; Necrosis ; Protein Kinase C/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Ascorbic acid induces apoptosis, autophagy, and necrotic cell death in cancer cells. We investigated the mechanisms by which ascorbic acid induces death in laryngeal squamous cell carcinoma Hep2 cells. Ascorbic acid markedly reduced cell viability and induced death without caspase activation and an increase in cytochrome c. Hep2 cells exposed to ascorbic acid exhibited membrane rupture and swelling, the morphological characteristics of necrotic cell death. The generation of reactive oxygen species (ROS) was increased in Hep2 cells treated with ascorbic acid, and pretreatment with N-acetylcysteine blocked ascorbic acid-induced cell death. Ascorbic acid also stimulated protein kinase C (PKC) signaling, especially PKC α/β activation, and subsequently increased cytosolic calcium levels. However, ascorbic acid-induced necrotic cell death was inhibited by Ro-31-8425 (PKC inhibitor) and BAPTA-AM (cytosolic calcium-selective chelator). ROS scavenger NAC inhibited PKC activation induced by ascorbic acid and Ro-31-8425 suppressed the level of cytosolic calcium increased by ascorbic acid, indicating that ROS is represented as an upstream signal of PKC pathway and PKC activation leads to the release of calcium into the cytosol, which ultimately regulates the induction of necrosis in ascorbic acid-treated Hep2 cells. These data demonstrate that ascorbic acid induces necrotic cell death through ROS generation, PKC activation, and cytosolic calcium signaling in Hep2 cells. J. Cell. Physiol. 232: 417-425, 2017. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid27793104, year = {2016}, author = {Amaral, EP and Conceição, EL and Costa, DL and Rocha, MS and Marinho, JM and Cordeiro-Santos, M and D'Império-Lima, MR and Barbosa, T and Sher, A and Andrade, BB}, title = {N-acetyl-cysteine exhibits potent anti-mycobacterial activity in addition to its known anti-oxidative functions.}, journal = {BMC microbiology}, volume = {16}, number = {1}, pages = {251}, pmid = {27793104}, issn = {1471-2180}, support = {U01 AI069923/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Adult ; Animals ; Anti-Bacterial Agents/*pharmacology ; Antioxidants/*pharmacology ; Case-Control Studies ; Cell Death/drug effects ; Cell Line ; Disease Models, Animal ; Humans ; Latent Tuberculosis/blood/drug therapy/microbiology ; Lipid Peroxidation/drug effects ; Macrophages/drug effects/metabolism/microbiology ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Mycobacterium avium/drug effects/growth &amp; development/metabolism ; Mycobacterium bovis/drug effects/growth &amp; development/metabolism ; Mycobacterium tuberculosis/*drug effects ; NADPH Oxidases/deficiency/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Tuberculosis, Pulmonary/blood/drug therapy/microbiology ; Young Adult ; }, abstract = {BACKGROUND: Mycobacterium tuberculosis infection is thought to induce oxidative stress. N-acetyl-cysteine (NAC) is widely used in patients with chronic pulmonary diseases including tuberculosis due to its mucolytic and anti-oxidant activities. Here, we tested whether NAC exerts a direct antibiotic activity against mycobacteria.<br><br>METHODS: Oxidative stress status in plasma was compared between pulmonary TB (PTB) patients and those with latent M. tuberculosis infection (LTBI) or healthy uninfected individuals. Lipid peroxidation, DNA oxidation and cell death, as well as accumulation of reactive oxygen species (ROS) were measured in cultures of primary human monocyte-derived macrophages infected with M. tuberculosis and treated or not with NAC. M. tuberculosis, M. avium and M. bovis BCG cultures were also exposed to different doses of NAC with or without medium pH adjustment to control for acidity. The anti-mycobacterial effect of NAC was assessed in M. tuberculosis infected human THP-1 cells and bone marrow-derived macrophages from mice lacking a fully functional NADPH oxidase system. The capacity of NAC to control M. tuberculosis infection was further tested in vivo in a mouse (C57BL/6) model.<br><br>RESULTS: PTB patients exhibited elevated levels of oxidation products and a reduction of anti-oxidants compared with LTBI cases or uninfected controls. NAC treatment in M. tuberculosis-infected human macrophages resulted in a decrease of oxidative stress and cell death evoked by mycobacteria. Importantly, we observed a dose-dependent reduction in metabolic activity and in vitro growth of NAC treated M. tuberculosis, M. avium and M. bovis BCG. Furthermore, anti-mycobacterial activity in infected macrophages was shown to be independent of the effects of NAC on the host NADPH oxidase system in vitro. Short-term NAC treatment of M. tuberculosis infected mice in vivo resulted in a significant reduction of mycobacterial loads in the lungs.<br><br>CONCLUSIONS: NAC exhibits potent anti-mycobacterial effects and may limit M. tuberculosis infection and disease both through suppression of the host oxidative response and through direct antimicrobial activity.}, }
@article {pmid27791464, year = {2017}, author = {Tai, H and Wang, Z and Gong, H and Han, X and Zhou, J and Wang, X and Wei, X and Ding, Y and Huang, N and Qin, J and Zhang, J and Wang, S and Gao, F and Chrzanowska-Lightowlers, ZM and Xiang, R and Xiao, H}, title = {Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence.}, journal = {Autophagy}, volume = {13}, number = {1}, pages = {99-113}, pmid = {27791464}, issn = {1554-8635}, mesh = {Acetylcysteine/metabolism ; Adenosine Triphosphate/chemistry ; Animals ; Antioxidants/chemistry ; *Autophagy ; Cellular Senescence/*physiology ; Humans ; Hydrogen Peroxide/chemistry ; Lysosomes/*metabolism ; Mice ; Microscopy, Confocal ; Mitochondria/*metabolism ; NIH 3T3 Cells ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Sequestosome-1 Protein/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Macroautophagy/autophagy has profound implications for aging. However, the true features of autophagy in the progression of aging remain to be clarified. In the present study, we explored the status of autophagic flux during the development of cell senescence induced by oxidative stress. In this system, although autophagic structures increased, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence and the activity of lysosomal proteolytic enzymes all decreased in senescent cells, indicating impaired autophagic flux with lysosomal dysfunction. The influence of autophagy activity on senescence development was confirmed by both positive and negative autophagy modulators; and MTOR-dependent autophagy activators, rapamycin and PP242, efficiently suppressed cellular senescence through a mechanism relevant to restoring autophagic flux. By time-phased treatment of cells with the antioxidant N-acetylcysteine (NAC), the mitochondria uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and ambroxol, a reagent with the effect of enhancing lysosomal enzyme maturation, we found that mitochondrial dysfunction plays an initiating role, while lysosomal dysfunction is more directly responsible for autophagy impairment and senescence. Interestingly, the effect of rapamycin on autophagy flux is linked to its role in functional revitalization of both mitochondrial and lysosomal functions. Together, this study demonstrates that autophagy impairment is crucial for oxidative stress-induced cell senescence, thus restoring autophagy activity could be a promising way to retard senescence.}, }
@article {pmid27790250, year = {2016}, author = {Béchohra, L and Laraba-Djebari, F and Hammoudi-Triki, D}, title = {Cytotoxic activity of Androctonus australis hector venom and its toxic fractions on human lung cancer cell line.}, journal = {The journal of venomous animals and toxins including tropical diseases}, volume = {22}, number = {}, pages = {29}, pmid = {27790250}, issn = {1678-9199}, abstract = {BACKGROUND: Several studies have showed that animal venoms are a source of bioactive compounds that may inhibit the growth of cancer cells, which makes them useful agents for therapeutic applications. Recently, it was established that venom toxins from scorpions induced cytotoxic, antiproliferative and apoptogenic effects on cancer cells. Therefore, the present study aims to investigate the cytotoxic activity of Androctonus australis hector (Aah) scorpion venom and its toxic fractions (FtoxG-50 and F3) on NCI-H358 human lung cancer cells.<br><br>METHODS: The cytotoxic and antiproliferative activities were estimated using MTT assay, lactate dehydrogenase release and clonogenic assays. Apoptosis was evaluated by Hoechst 33258 staining, DNA fragmentation assay and caspase-3 activity. Oxidative stress was analyzed by reactive oxygen species, nitric oxide, malondialdehyde and protein carbonyl levels along with assessment of antioxidant status. In addition, alteration of mitochondrial membrane potential was analyzed by JC1 fluorescent dye.<br><br>RESULTS: The present findings showed that F3 fraction was more cytotoxic towards NCI-H358 lung cancer cells with an IC50 of 27.05&#x2009;&#xb1;&#x2009;0.70&#xa0;&#x3bc;g/mL than venom alone (396.60&#x2009;&#xb1;&#x2009;1.33&#xa0;&#x3bc;g/mL) and its toxic fraction FtoxG-50 (45.86&#x2009;&#xb1;&#x2009;0.91&#xa0;&#x3bc;g/mL). Nevertheless, F3 fraction was not cytotoxic at these concentrations on normal human lung fibroblast MRC-5 cells. Inhibition of NCI-H358 cell proliferation after F3 fraction exposure occurred mainly by apoptosis as evidenced by damaged nuclei, significant DNA fragmentation level and caspase-3 activation in a dose dependent manner. Moreover, F3 fraction enhanced oxidative and nitrosative stress biomarkers and dissipated mitochondrial membrane potential in lung cancer cells along with significant depletion in cellular enzymatic and non-enzymatic antioxidants. Further, the apoptosis induced by F3 fraction was markedly prevented by the antioxidant N-acetylcysteine (NAC) suggesting the potential mechanism of oxidative stress.<br><br>CONCLUSION: These findings suggest that F3 fraction could induce apoptosis in lung cancer cells through involvement of oxidative stress and mitochondrial dysfunction. Hence, these properties make F3 fraction a promising candidate for development of new anticancer agents.}, }
@article {pmid27652587, year = {2016}, author = {Mohamed, ZU and Krishnakumar, L and Sudhindran, S}, title = {N-acetyl cysteine in liver resection.}, journal = {Journal of surgical oncology}, volume = {114}, number = {6}, pages = {773}, doi = {10.1002/jso.24389}, pmid = {27652587}, issn = {1096-9098}, mesh = {Acetylcysteine/administration &amp; dosage/*adverse effects ; Delirium/*chemically induced/epidemiology ; Drug Administration Schedule ; Free Radical Scavengers/administration &amp; dosage/*adverse effects ; Hepatectomy/*methods ; Humans ; India ; Liver Transplantation ; *Living Donors ; Perioperative Care/*adverse effects/methods ; Postoperative Complications/*chemically induced/epidemiology ; }, }
@article {pmid27511942, year = {2016}, author = {Choi, JY and Won, NH and Park, JD and Jang, S and Eom, CY and Choi, Y and Park, YI and Dong, MS}, title = {From the Cover: Ethylmercury-Induced Oxidative and Endoplasmic Reticulum Stress-Mediated Autophagic Cell Death: Involvement of Autophagosome-Lysosome Fusion Arrest.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {154}, number = {1}, pages = {27-42}, doi = {10.1093/toxsci/kfw155}, pmid = {27511942}, issn = {1096-0929}, mesh = {Animals ; Autophagosomes/*drug effects ; *Autophagy ; Calcium/metabolism ; Cell Line ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/*drug effects ; Ethylmercury Compounds/*toxicity ; Humans ; Kidney/drug effects ; Kidney Tubules, Proximal/drug effects ; Lysosomes/*drug effects ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Unfolded Protein Response ; }, abstract = {Ethylmercury (EtHg) is derived from the degradation of thimerosal, the most widely used organomercury compound. In this study, EtHg-induced toxicity and autophagy in the mouse kidney was observed and then the mechanism of toxicity was explored in vitro in HK-2 cells. Low doses of EtHg induced autophagy without causing any histopathological changes in mouse kidneys. However, mice treated with high doses of EtHg exhibited severe focal tubular cell necrosis of the proximal tubules with autophagy. EtHg dose-dependently increased the production of reactive oxygen species, reduced the mitochondrial membrane potential, activated the unfolded protein response, and increased cytosolic Ca[2+ ]levels in HK-2 cells. Cell death induced by EtHg exposure was caused by autophagy and necrosis. N-acetyl cysteine and 4-phenylbutyric acid attenuated EtHg-induced stress and ameliorated the autophagic response in HK-2 cells. Furthermore, EtHg blocked autophagosome fusion with lysosomes, which was demonstrated via treatment with wortmannin and chloroquine. Low doses of EtHg and rapamycin, which resulted in minimal cytotoxicity, increased the levels of the autophagic SNARE complex STX17 (syntaxin 17)-VAMP8-SNAP29 without altering mRNA levels, but high dose of EtHg was cytotoxic. Inhibition of autophagic flux by chloroquin increased autophagosome formation and necrotic cell death in HK-2 cells. Collectively, our results show that EtHg induces autophagy via oxidative and ER stress and blockade of autophagic flux. Autophagy might play a dual role in EtHg-induced renal toxicity, being both protective following treatment with low doses of EtHg and detrimental following treatment with high doses.}, }
@article {pmid27786251, year = {2016}, author = {Du, J and Feng, W and Sun, J and Kang, C and Amizuka, N and Li, M}, title = {Ovariectomy upregulated the expression of Peroxiredoxin 1 &amp;5 in osteoblasts of mice.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {35995}, pmid = {27786251}, issn = {2045-2322}, mesh = {3T3 Cells ; Animals ; Apoptosis/drug effects ; CRISPR-Cas Systems ; Caspase 3/metabolism ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Estrogens/deficiency ; Female ; Gene Knockout Techniques ; Hydrogen Peroxide/pharmacology ; Mice ; Osteoblasts/drug effects/*metabolism/pathology ; Osteoporosis/etiology/metabolism/pathology ; Ovariectomy/adverse effects ; Peroxiredoxins/deficiency/genetics/*metabolism ; Up-Regulation ; }, abstract = {Peroxiredoxin (PRX), a family of peroxidases, is associated with various biological processes such as the detoxification of oxidants and cell apoptosis. Besides, the anti-apoptosis effect of estrogen results partially from its anti-oxidant function. The purpose of this study was to investigate the expression of PRXs in ovariectomy (OVX) mice and the related anti-oxidative mechanism of estrogen. Eight-week-old mice were subjected to ovariectomy. MC3T3-E1 cells were pretreatment with 17b-estradiol and N-acetyl cysteine followed by oxidative injury induced with H2O2. Western blot and real time-PCR were applied to clarify the expressions of PRX1 and caspase-3, with both wild-type and PRX1 knockout MC3T3-E1 cells generated by CRISPR/Cas9 technology. The results showed PRX1 and PRX5 were upregulated in osteoblasts in the proximal tibial metaphysis of ovariectomy mice. Interestingly, PRX1 and PRX5 showed different distribution patterns, with PRX1 mainly accumulated in cell nuclei and PRX5 in the cytoplasm. Gene expression analysis showed significantly reduced expressions of PRX1 and caspase-3 in the pretreatment groups when compared with cells treated with H2O2 alone. Also, a decrease of caspase-3 expressions was observed in PRX1 knockout MC3T3-E1 cells with or without H2O2 in comparison to wild-type cells. These findings suggested that PRX may play important roles in estrogen-deficient osteoporosis. (200 words).}, }
@article {pmid27725170, year = {2017}, author = {Santos, P and Herrmann, AP and Benvenutti, R and Noetzold, G and Giongo, F and Gama, CS and Piato, AL and Elisabetsky, E}, title = {Anxiolytic properties of N-acetylcysteine in mice.}, journal = {Behavioural brain research}, volume = {317}, number = {}, pages = {461-469}, doi = {10.1016/j.bbr.2016.10.010}, pmid = {27725170}, issn = {1872-7549}, mesh = {Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Anti-Anxiety Agents/*therapeutic use ; Anxiety/complications/*drug therapy ; Body Temperature/drug effects ; Dark Adaptation/drug effects ; Diazepam/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Exploratory Behavior/drug effects ; Fever/etiology ; Interpersonal Relations ; Male ; Maze Learning/drug effects ; Mice ; Time Factors ; }, abstract = {Anxiety disorders are highly prevalent and often result in poor quality of life. Available anxiolytics show significant adverse effects as well as partial efficacy in a sizable part of patients. Innovative treatments with more favorable risk-benefit ratio are sorely needed. A growing body of clinical data indicates the benefits of N-acetylcysteine (NAC) in psychiatric conditions. NAC modulates antioxidant, glutamatergic, inflammatory and neurotrophic pathways in the central nervous system, all of which are relevant to anxiety pathology. We evaluated the effects of NAC in mice models commonly used to characterize anxiolytic compounds. Male adult CF1 or BALB/c mice were treated (i.p.) acutely or subacutely (4 consecutive days) with NAC (60-150mg/kg) 60min before open field, light/dark, hole-board, social interaction, elevated T-maze or stress-induced hyperthermia tests. Diazepam (2mg/kg) was used as positive control. We found that NAC presents anxiolytic effects in all models, except for the elevated T-maze. Subacute treatments resulted in lower effective doses in comparison to acute treatment. The anxiolytic effects of NAC were comparable to diazepam. NAC is a safe and low cost medicine with suggested benefits in psychiatric conditions often presenting co-morbidity with anxiety. This study contributes evidence to support the validity of clinical trials with NAC in the context of anxiety disorders, especially considering the safety profile in comparison to the limitations of diazepam for long term treatment.}, }
@article {pmid27783328, year = {2017}, author = {Zhou, FM and Cheng, RX and Wang, S and Huang, Y and Gao, YJ and Zhou, Y and Liu, TT and Wang, XL and Chen, LH and Liu, T}, title = {Antioxidants Attenuate Acute and Chronic Itch: Peripheral and Central Mechanisms of Oxidative Stress in Pruritus.}, journal = {Neuroscience bulletin}, volume = {33}, number = {4}, pages = {423-435}, pmid = {27783328}, issn = {1995-8218}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Cell Line, Transformed ; Central Nervous System/*drug effects/metabolism ; Cyclic N-Oxides/therapeutic use ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Male ; Malondialdehyde/metabolism ; Mice ; Oxidative Stress/*drug effects ; Peripheral Nerves/*drug effects/metabolism ; Pruritus/chemically induced/*drug therapy/*pathology ; Reactive Oxygen Species/metabolism ; Skin/metabolism ; Superoxide Dismutase/metabolism ; Time Factors ; p-Methoxy-N-methylphenethylamine/toxicity ; }, abstract = {Itch (pruritus) is one of the most disabling syndromes in patients suffering from skin, liver, or kidney diseases. Our previous study highlighted a key role of oxidative stress in acute itch. Here, we evaluated the effects of antioxidants in mouse models of acute and chronic itch and explored the potential mechanisms. The effects of systemic administration of the antioxidants N-acetyl-L-cysteine (NAC) and N-tert-butyl-α-phenylnitrone (PBN) were determined by behavioral tests in mouse models of acute itch induced by compound 48/80 or chloroquine, and chronic itch by treatment with a mixture of acetone-diethyl-ether-water. We found that systemic administration of NAC or PBN significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner, attenuated dry skin-induced chronic itch, and suppressed oxidative stress in the affected skin. Antioxidants significantly decreased the accumulation of intracellular reactive oxygen species directly induced by compound 48/80 and chloroquine in the cultured dorsal root ganglia-derived cell line ND7-23. Finally, the antioxidants remarkably inhibited the compound 48/80-induced phosphorylation of extracellular signal-regulated kinase in the spinal cord. These results indicated that oxidative stress plays a critical role in acute and chronic itch in the periphery and spinal cord and antioxidant treatment may be a promising strategy for anti-itch therapy.}, }
@article {pmid27396856, year = {2016}, author = {Ryu, HM and Kim, YJ and Oh, EJ and Oh, SH and Choi, JY and Cho, JH and Kim, CD and Park, SH and Kim, YL}, title = {Hypoxanthine induces cholesterol accumulation and incites atherosclerosis in apolipoprotein E-deficient mice and cells.}, journal = {Journal of cellular and molecular medicine}, volume = {20}, number = {11}, pages = {2160-2172}, pmid = {27396856}, issn = {1582-4934}, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Animals ; Apolipoproteins E/*deficiency/metabolism ; Atherosclerosis/blood/*pathology ; Cholesterol/blood/*metabolism ; Down-Regulation/drug effects/genetics ; Hep G2 Cells ; Humans ; Hydrogen Peroxide/toxicity ; Hypercholesterolemia/pathology ; Hypoxanthine/*pharmacology ; Lipogenesis/drug effects/genetics ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Biological ; Plaque, Atherosclerotic/blood/metabolism/pathology ; Up-Regulation/drug effects ; }, abstract = {Reactive oxygen species (ROS) generation during purine metabolism is associated with xanthine oxidase and uric acid. However, the direct effect of hypoxanthine on ROS generation and atherosclerosis has not been evaluated. Smoking and heavy drinking are associated with elevated levels of hypoxanthine. In this study, we investigated the role of hypoxanthine on cholesterol synthesis and atherosclerosis development, particularly in apolipoprotein E (APOE)-deficient mice. The effect of hypoxanthine on the regulation of cholesterol synthesis and atherosclerosis were evaluated in Apoe knockout (KO) mice and cultured HepG2 cells. Hypoxanthine markedly increased serum cholesterol levels and the atherosclerotic plaque area in Apoe KO mice. In HepG2 cells, hypoxanthine increased intracellular ROS production. Hypoxanthine increased cholesterol accumulation and decreased APOE and ATP-binding cassette transporter A1 (ABCA1) mRNA and protein expression in HepG2 cells. Furthermore, H2 O2 also increased cholesterol accumulation and decreased APOE and ABCA1 expression. This effect was partially reversible by treatment with the antioxidant N-acetyl cysteine and allopurinol. Hypoxanthine and APOE knockdown using APOE-siRNA synergistically induced cholesterol accumulation and reduced APOE and ABCA1 expression. Hypoxanthine induces cholesterol accumulation in hepatic cells through alterations in enzymes that control lipid transport and induces atherosclerosis in APOE-deficient cells and mice. These effects are partially mediated through ROS produced in response to hypoxanthine.}, }
@article {pmid27776485, year = {2016}, author = {Okamoto, A and Tanaka, M and Sumi, C and Oku, K and Kusunoki, M and Nishi, K and Matsuo, Y and Takenaga, K and Shingu, K and Hirota, K}, title = {The antioxidant N-acetyl cysteine suppresses lidocaine-induced intracellular reactive oxygen species production and cell death in neuronal SH-SY5Y cells.}, journal = {BMC anesthesiology}, volume = {16}, number = {1}, pages = {104}, pmid = {27776485}, issn = {1471-2253}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Anesthetics, Local/pharmacology ; Antioxidants/administration &amp; dosage/*pharmacology ; Apoptosis/drug effects ; Bupivacaine/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Chromans/pharmacology ; Dose-Response Relationship, Drug ; HeLa Cells ; Humans ; Lidocaine/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mepivacaine/administration &amp; dosage ; Mitochondria/drug effects ; Neuroblastoma/metabolism ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {BACKGROUND: The local anesthetic lidocaine can affect intra- and extra-cellular signaling pathways in both neuronal and non-neuronal cells, resulting in long-term modulation of biological functions, including cell growth and death. Indeed, lidocaine was shown to induce necrosis and apoptosis in vitro. While several studies have suggested that lidocaine-induced apoptosis is mitochondrial pathway-dependent, it remains unclear whether reactive oxygen species (ROS) are involved in this process and whether the observed cell death can be prevented by antioxidant treatment.<br><br>METHODS: The effects of lidocaine and antioxidants on cell viability and death were evaluated using SH-SY5Y cells, HeLa cells, and HeLa cell derivatives. Cell viability was examined via MTS/PES ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt]/phenazine ethosulfate) assay. Meanwhile, cell apoptosis and necrosis were evaluated using a cell death detection assay with Annexin V-FITC and PI staining, as well as by assaying for caspase-3/7 and caspase-9 activity, and by measuring the release of lactate dehydrogenase, respectively. Mitochondrial transmembrane potential (&#x394;&#x3a8;m) was assessed using the fluorescent probe tetramethylrhodamine ethyl ester.<br><br>RESULTS: Lidocaine treatment resulted in suppression of the mitochondrial electron transport chain and subsequent attenuation of mitochondrial membrane potential, as well as enhanced ROS production, activation of caspase-3/7 and caspase-9, and induction of apoptosis and necrosis in SH-SY5Y cells in a dose- and time-dependent manner. Likewise, the anesthetics mepivacaine and bupivacaine also induced apoptosis in SH-SY5Y cells. Notably, the antioxidants N-acetyl cysteine (NAC) and Trolox successfully scavenged the mitochondria-derived ROS and suppressed local lidocaine-induced cell death.<br><br>CONCLUSIONS: Our findings demonstrate that the local anesthetics lidocaine, mepivacaine, and bupivacaine inhibited the activity of mitochondria and induced apoptosis and necrosis in a dose-dependent manner. Furthermore, they demonstrate that treatment with the antioxidants NAC, Trolox, and GGA resulted in preservation of mitochondrial voltage and inhibition of apoptosis via suppression of caspase activation.}, }
@article {pmid27725188, year = {2016}, author = {Patel, A and Zhang, S and Shrestha, AK and Maturu, P and Moorthy, B and Shivanna, B}, title = {Omeprazole induces heme oxygenase-1 in fetal human pulmonary microvascular endothelial cells via hydrogen peroxide-independent Nrf2 signaling pathway.}, journal = {Toxicology and applied pharmacology}, volume = {311}, number = {}, pages = {26-33}, pmid = {27725188}, issn = {1096-0333}, support = {R01 ES009132/ES/NIEHS NIH HHS/United States ; K08 HD073323/HD/NICHD NIH HHS/United States ; R01 ES019689/ES/NIEHS NIH HHS/United States ; R01 HL129794/HL/NHLBI NIH HHS/United States ; R01 HL087174/HL/NHLBI NIH HHS/United States ; R01 HL112516/HL/NHLBI NIH HHS/United States ; }, mesh = {Cells, Cultured ; Endothelium, Vascular/drug effects/enzymology ; Heme Oxygenase-1/*biosynthesis ; Humans ; Hydrogen Peroxide/metabolism/*pharmacology ; Lung/blood supply/*embryology ; Microvessels/*drug effects/enzymology ; NF-E2-Related Factor 2/*metabolism ; Omeprazole/*pharmacology ; *Signal Transduction ; }, abstract = {Omeprazole (OM) is an aryl hydrocarbon receptor (AhR) agonist and a proton pump inhibitor that is used to treat humans with gastric acid related disorders. Recently, we showed that OM induces NAD (P) H quinone oxidoreductase-1 (NQO1) via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent mechanism. Heme oxygenase-1 (HO-1) is another cytoprotective and antioxidant enzyme that is regulated by Nrf2. Whether OM induces HO-1 in fetal human pulmonary microvascular endothelial cells (HPMEC) is unknown. Therefore, we tested the hypothesis that OM will induce HO-1 expression via Nrf2 in HPMEC. OM induced HO-1 mRNA and protein expression in a dose-dependent manner. siRNA-mediated knockdown of AhR failed to abrogate, whereas knockdown of Nrf2 abrogated HO-1 induction by OM. To identify the underlying molecular mechanisms, we determined the effects of OM on cellular hydrogen peroxide (H2O2) levels since oxidative stress mediated by the latter is known to activate Nrf2. Interestingly, the concentration at which OM induced HO-1 also increased H2O2 levels. Furthermore, H2O2 independently augmented HO-1 expression. Although N-acetyl cysteine (NAC) significantly decreased H2O2 levels in OM-treated cells, we observed that OM further increased HO-1 mRNA and protein expression in NAC-pretreated compared to vehicle-pretreated cells, suggesting that OM induces HO-1 via H2O2-independent mechanisms. In conclusion, we provide evidence that OM transcriptionally induces HO-1 via AhR - and H2O2 - independent, but Nrf2 - dependent mechanisms. These results have important implications for human disorders where Nrf2 and HO-1 play a beneficial role.}, }
@article {pmid27774335, year = {2016}, author = {Cheng, B and Anand, P and Kuang, A and Akhtar, F and Scofield, VL}, title = {N-Acetylcysteine in Combination with IGF-1 Enhances Neuroprotection against Proteasome Dysfunction-Induced Neurotoxicity in SH-SY5Y Cells.}, journal = {Parkinson's disease}, volume = {2016}, number = {}, pages = {6564212}, pmid = {27774335}, issn = {2090-8083}, abstract = {Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson's disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells. Our results demonstrate that the proteasome inhibitor, MG132, initiates poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 activation, and nuclear condensation and fragmentation. In addition, MG132 treatment leads to endoplasmic reticulum (ER) stress and autophagy-mediated cell death. All of these events can be attenuated without obvious reduction of MG132 induced protein ubiquitination by first treating the cells with NAC and IGF-1 separately or simultaneously prior to exposure to MG132. Moreover, our data demonstrated that the combination of the two proved to be significantly more effective for neuronal protection. Therefore, we conclude that the simultaneous use of growth/neurotrophic factors and a free radical scavenger may increase overall protection against UPS dysfunction-mediated cytotoxicity and neurodegeneration.}, }
@article {pmid27643875, year = {2016}, author = {Rodman, SN and Spence, JM and Ronnfeldt, TJ and Zhu, Y and Solst, SR and O'Neill, RA and Allen, BG and Guan, X and Spitz, DR and Fath, MA}, title = {Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism.}, journal = {Radiation research}, volume = {186}, number = {4}, pages = {385-395}, pmid = {27643875}, issn = {1938-5404}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; R01 CA182804/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Animals ; Auranofin/pharmacology ; Breast Neoplasms/*pathology ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects/radiation effects ; Cell Survival/drug effects/radiation effects ; Cell Transformation, Neoplastic ; DNA Damage ; Drug Interactions ; Female ; Glutathione/biosynthesis/*metabolism ; Humans ; Mice ; Neoplasm Invasiveness ; Neoplastic Stem Cells/*drug effects/metabolism/pathology/*radiation effects ; Radiation-Sensitizing Agents/*pharmacology ; Sulfasalazine/pharmacology ; Survival Analysis ; Thiocarbamates/pharmacology ; Thioredoxin-Disulfide Reductase/antagonists &amp; inhibitors ; Thioredoxins/*metabolism ; }, abstract = {The goal of this study was to determine if depletion of glutathione (GSH) and inhibition of thioredoxin (Trx) reductase (TrxR) activity could enhance radiation responses in human breast cancer stem cells by a mechanism involving thiol-dependent oxidative stress. The following were used to inhibit GSH and Trx metabolism: buthionine sulfoximine (BSO), a GSH synthesis inhibitor; sulfasalazine (SSZ), an inhibitor of xc[-] cysteine/glutamate antiporter; auranofin (Au), a thioredoxin reductase inhibitor; or 2-AAPA, a GSH-reductase inhibitor. Clonogenic survival, Matrigel assays, flow cytometry cancer stem cell assays (CD44[+]CD24[-]ESA[+] or ALDH1) and human tumor xenograft models were used to determine the antitumor activity of drug and radiation combinations. Combined inhibition of GSH and Trx metabolism enhanced cancer cell clonogenic killing and radiation responses in human breast and pancreatic cancer cells via a mechanism that could be inhibited by N-acetylcysteine (NAC). Au, BSO and radiation also significantly decreased breast cancer cell migration and invasion in a thiol-dependent manner that could be inhibited by NAC. In addition, pretreating cells with Au sensitized breast cancer stem cell populations to radiation in vitro as determined by CD44[+]CD24[-]ESA[+] or ALDH1. Combined administration of Au and BSO, given prior to irradiation, significantly increased the survival of mice with human breast cancer xenografts, and decreased the number of ALDH1[+] cancer stem cells. These results indicate that combined inhibition of GSH- and Trx-dependent thiol metabolism using pharmacologically relevant agents can enhance responses of human breast cancer stem cells to radiation both in vitro and in vivo.}, }
@article {pmid27770431, year = {2017}, author = {Vliegenthart, A and Kimmitt, RA and Seymour, JH and Homer, NZ and Clarke, JI and Eddleston, M and Gray, A and Wood, DM and Dargan, PI and Cooper, JG and Antoine, DJ and Webb, DJ and Lewis, SC and Bateman, DN and Dear, JW}, title = {Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.}, journal = {Clinical pharmacology and therapeutics}, volume = {101}, number = {4}, pages = {531-540}, pmid = {27770431}, issn = {1532-6535}, support = {NC/K001485/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, mesh = {Acetaminophen/*blood/*toxicity ; Acetylcysteine/pharmacology ; Adult ; Alanine Transaminase/metabolism ; Analgesics, Non-Narcotic/*blood/*toxicity ; Antiemetics/adverse effects ; Area Under Curve ; Biomarkers/*blood ; Chemical and Drug Induced Liver Injury/*blood ; Cohort Studies ; Cytochrome P-450 Enzyme System/metabolism ; Drug Interactions ; Drug Overdose/metabolism/therapy ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Male ; Middle Aged ; Ondansetron/adverse effects ; ROC Curve ; Reproducibility of Results ; Toxicokinetics ; Young Adult ; }, abstract = {Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making.}, }
@article {pmid27567538, year = {2016}, author = {Abimannan, T and Peroumal, D and Parida, JR and Barik, PK and Padhan, P and Devadas, S}, title = {Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells.}, journal = {Free radical biology &amp; medicine}, volume = {99}, number = {}, pages = {352-363}, doi = {10.1016/j.freeradbiomed.2016.08.026}, pmid = {27567538}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Arthritis, Rheumatoid/genetics/*immunology/pathology ; Case-Control Studies ; Cell Differentiation ; Cytokines/genetics/*immunology ; Female ; Gene Expression Regulation/*immunology ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors/pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Middle Aged ; Mitogen-Activated Protein Kinase 1/genetics/immunology ; Mitogen-Activated Protein Kinase 3/genetics/immunology ; Naphthoquinones/antagonists &amp; inhibitors/pharmacology ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics/immunology ; Oxidants/antagonists &amp; inhibitors/pharmacology ; Oxidative Stress/*immunology ; Phosphorylation/drug effects ; Primary Cell Culture ; T-Box Domain Proteins/genetics/immunology ; Th1 Cells/*drug effects/immunology/pathology ; Th17 Cells/*drug effects/immunology/pathology ; }, abstract = {Reactive oxygen species (ROS) signaling is critical in T helper (Th) cell differentiation; however its role in differentiated Th cell functions is unclear. In this study, we investigated the role of oxidative stress on the effector functions of in vitro differentiated mouse Th17 and Th1 cells or CD4[+] T cells from patients with Rheumatoid Arthritis using pro-oxidants plumbagin (PB) and hydrogen peroxide. We found that in mouse Th cells, non-toxic concentration of pro-oxidants inhibited reactivation induced expression of IL-17A in Th17 and IFN-γ in Th1 cells by reducing the expression of their respective TFs, RORγt and T-bet. Interestingly, in both the subsets, PB increased the expression of IL-4 by enhancing reactivation induced ERK1/2 phosphorylation. We further investigated the cytokine modulatory effect of PB on CD4[+] T cells isolated from PBMCs of patients with Rheumatoid Arthritis, a well-known Th17 and or Th1 mediated disease. In human CD4[+] T cells from Rheumatoid Arthritis patients, PB reduced the frequencies of IL-17A[+] (Th17), IFN[-]γ[+] (Th1) and IL-17A[+]/IFN[-]γ[+] (Th17/1) cells and also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6. N-Acetyl Cysteine (NAC) an antioxidant completely reversed PB mediated cytokine modulatory effects in both mouse and human cells indicating a direct role for ROS. Together our data suggest that oxidative microenvironment can alter cytokine response of terminally differentiated cells and thus altering intracellular ROS could be a potential way to target Th17 and Th1 cells in autoimmune disorders.}, }
@article {pmid27554969, year = {2016}, author = {Banerjee, S and Aykin-Burns, N and Krager, KJ and Shah, SK and Melnyk, SB and Hauer-Jensen, M and Pawar, SA}, title = {Loss of C/EBPδ enhances IR-induced cell death by promoting oxidative stress and mitochondrial dysfunction.}, journal = {Free radical biology &amp; medicine}, volume = {99}, number = {}, pages = {296-307}, pmid = {27554969}, issn = {1873-4596}, support = {P20 GM103625/GM/NIGMS NIH HHS/United States ; P20 GM109005/GM/NIGMS NIH HHS/United States ; R15 ES022781/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/antagonists &amp; inhibitors/pharmacology ; Adenosine Triphosphate/antagonists &amp; inhibitors/biosynthesis ; Aldehydes/metabolism ; Animals ; Apoptosis/drug effects/radiation effects ; Buthionine Sulfoximine/pharmacology ; CCAAT-Enhancer-Binding Protein-delta/deficiency/*genetics ; Catalase/pharmacology ; DNA/*genetics/metabolism ; DNA Breaks, Double-Stranded/drug effects/*radiation effects ; Dose-Response Relationship, Radiation ; Embryo, Mammalian ; Fibroblasts/cytology/drug effects/metabolism/*radiation effects ; Gamma Rays ; Gene Expression Regulation ; Glutathione/metabolism ; Mice ; Mice, Knockout ; Mitochondria/drug effects/metabolism/*radiation effects ; Oxidative Stress ; Polyethylene Glycols/pharmacology ; Primary Cell Culture ; Reactive Oxygen Species/agonists/*metabolism ; Signal Transduction ; Superoxide Dismutase/pharmacology ; }, abstract = {Exposure of cells to ionizing radiation (IR) generates reactive oxygen species (ROS). This results in increased oxidative stress and DNA double strand breaks (DSBs) which are the two underlying mechanisms by which IR causes cell/tissue injury. Cells that are deficient or impaired in the cellular antioxidant response are susceptible to IR-induced apoptosis. The transcription factor CCAAT enhancer binding protein delta (Cebpd, C/EBPδ) has been implicated in the regulation of oxidative stress, DNA damage response, genomic stability and inflammation. We previously reported that Cebpd-deficient mice are sensitive to IR and display intestinal and hematopoietic injury, however the underlying mechanism is not known. In this study, we investigated whether an impaired ability to detoxify IR-induced ROS was the underlying cause of the increased radiosensitivity of Cebpd-deficient cells. We found that Cebpd-knockout (KO) mouse embryonic fibroblasts (MEFs) expressed elevated levels of ROS, both at basal levels and after exposure to gamma radiation which correlated with increased apoptosis, and decreased clonogenic survival. Pre-treatment of wild type (WT) and KO MEFs with polyethylene glycol-conjugated Cu-Zn superoxide dismutase (PEG-SOD) and catalase (PEG-CAT) combination prior to irradiation showed a partial rescue of clonogenic survival, thus demonstrating a role for increased intracellular oxidants in promoting IR-induced cell death. Analysis of mitochondrial bioenergetics revealed that irradiated KO MEFs showed significant reductions in basal, adenosine triphosphate (ATP)-linked, maximal respiration and reserved respiratory capacity and decrease in intracellular ATP levels compared to WT MEFs indicating they display mitochondrial dysfunction. KO MEFs expressed significantly lower levels of the cellular antioxidant glutathione (GSH) and its precursor- cysteine as well as methionine. In addition to its antioxidant function, GSH plays an important role in detoxification of lipid peroxidation products such as 4-hydroxynonenal (4-HNE). The reduced GSH levels observed in KO MEFs correlated with elevated levels of 4-HNE protein adducts in irradiated KO MEFs compared to respective WT MEFs. We further showed that pre-treatment with the GSH precursor, N-acetyl L-cysteine (NAC) prior to irradiation showed a significant reduction of IR-induced cell death and increases in GSH levels, which contributed to the overall increase in clonogenic survival of KO MEFs. In contrast, pre-treatment with the GSH synthesis inhibitor- buthionine sulfoximine (BSO) further reduced the clonogenic survival of irradiated KO MEFs. This study demonstrates a novel role for C/EBPδ in protection from basal as well as IR-induced oxidative stress and mitochondrial dysfunction thus promoting post-radiation survival.}, }
@article {pmid27427516, year = {2016}, author = {Miller, RC and Murley, JS and Rademaker, AW and Woloschak, GE and Li, JJ and Weichselbaum, RR and Grdina, DJ}, title = {Very low doses of ionizing radiation and redox associated modifiers affect survivin-associated changes in radiation sensitivity.}, journal = {Free radical biology &amp; medicine}, volume = {99}, number = {}, pages = {110-119}, pmid = {27427516}, issn = {1873-4596}, support = {R01 CA111423/CA/NCI NIH HHS/United States ; R01 CA132998/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects/radiation effects ; Dose-Response Relationship, Radiation ; Emodin/*pharmacology ; Female ; Fibrosarcoma/genetics/metabolism/pathology/*therapy ; Gamma Rays ; *Gene Expression Regulation, Neoplastic ; Hindlimb ; Inhibitor of Apoptosis Proteins/*genetics/metabolism ; Mice ; Mice, Inbred C3H ; Neoplasm Transplantation ; Oxidants/*pharmacology ; Protein Transport ; RNA, Small Interfering/genetics/metabolism ; Radiation Tolerance/*drug effects ; Reactive Oxygen Species/metabolism ; Repressor Proteins/*genetics/metabolism ; Survivin ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {Exposure of cells to a dose of ionizing radiation as low as 5mGy can induce changes in radiation sensitivity expressed by cells exposed to subsequent higher doses at later times. This is referred to as an adaptive effect. We describe a unique survivin-associated adaptive response in which increased radiation resistance or sensitization of cells can be induced by exposure to 5mGy or to the reactive oxygen species (ROS) generating drug Emodin (1,3,8-trihydroxy-6-methylanthraquinone), a naturally occurring anthraquinone. The purpose of this study was to determine the role of ROS generating processes in affecting both the intracellular localization of the inhibitor of apoptosis protein survivin and its subsequent effect on radiation response in the presence or absence of the anti-oxidant N-acetyl-L-cysteine (NAC). Experiments were performed using two well characterized murine sarcomas: SA-NH p53 wild-type (WT) and FSa p53 mutant (Mut), grown either in culture or as solid tumors in the right hind legs of C3H mice. Doses of 5mGy or 50μM Emodin were used to induce changes in the response of these tumor cells to higher radiation exposures using a multi-dosing paradigm. Effects on radiation sensitivity were determined for SA-NH and FSa cells as a function of survivin translocation either to the cytoplasm or nucleus in the presence or absence of 10mM NAC treatment. In vitro survival assays (2Gy per fraction, two once daily fractions) and tumor growth delay (TGD) (5Gy per fraction, five once daily fractions) studies were performed. Intracellular localization of survivin was determined by enzyme-linked immunosorbent assay (ELISA) and correlated to survival response and treatment conditions. 2Gy alone had no effect on intracellular translocation of survivin. When preceded 15min earlier by 5mGy or Emodin exposures, survivin became elevated in the cytoplasm of p53 WT SA-NH as compared to the nuclei of p53 Mut FSa cells. SA-NH cells transfected with p53 small interfering RNA (siRNA), in contrast, responded similarly to p53 Mut FSa cells by becoming more radiation sensitive if exposed to 5mGy prior to each 2Gy irradiation. In contrast to their respective responses to five once daily 5Gy fractions, SA-NH tumors were protected by 5mGy exposures administered 15min prior to each daily 5Gy dose as evidenced by a more rapid growth (1.9 day decrease in TGD, P=0.032), while FSa tumors were sensitized, growing at a much slower rate (4.5 day increase in TGD, P<0.001). Exposure of SA-NH and FSa tumor cells to 10mM NAC inhibited the ability of 5mGy and Emodin to induce intracellular translocation of survivin and the corresponding altered adaptive survival response. The survivin-associated adaptive response can be induced following a multi-dosing scheme in which very low radiation doses are followed shortly thereafter by higher doses consistent with a standard image guided radiotherapy protocol that is currently widely used in the treatment of cancer. While induced by exposure to ROS generating stresses, the ultimate expression of changes in radiation response is dependent upon the bi-functionality of the tumor associated protein survivin and its intracellular translocation.}, }
@article {pmid27765741, year = {2017}, author = {Baker, EH and Levin, SW and Zhang, Z and Mukherjee, AB}, title = {MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis.}, journal = {AJNR. American journal of neuroradiology}, volume = {38}, number = {2}, pages = {376-382}, pmid = {27765741}, issn = {1936-959X}, support = {Z99 CL999999//Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Aging/pathology ; Brain/*diagnostic imaging ; Brain Stem/diagnostic imaging ; Cerebellum/diagnostic imaging ; Cerebrum/diagnostic imaging ; Child ; Child, Preschool ; Cysteamine/therapeutic use ; Electroencephalography ; Female ; Follow-Up Studies ; Humans ; Infant ; Magnetic Resonance Imaging/*methods ; Male ; Neuronal Ceroid-Lipofuscinoses/*diagnostic imaging/drug therapy ; Thalamus/diagnostic imaging ; }, abstract = {BACKGROUND AND PURPOSE: Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N-acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging.<br><br>MATERIALS AND METHODS: Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population.<br><br>RESULTS: Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age.<br><br>CONCLUSIONS: Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions.}, }
@article {pmid27474782, year = {2016}, author = {Lundbäck, P and Lea, JD and Sowinska, A and Ottosson, L and Fürst, CM and Steen, J and Aulin, C and Clarke, JI and Kipar, A and Klevenvall, L and Yang, H and Palmblad, K and Park, BK and Tracey, KJ and Blom, AM and Andersson, U and Antoine, DJ and Erlandsson Harris, H}, title = {A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice.}, journal = {Hepatology (Baltimore, Md.)}, volume = {64}, number = {5}, pages = {1699-1710}, pmid = {27474782}, issn = {1527-3350}, support = {097826/Z/11/Z/WT_/Wellcome Trust/United Kingdom ; MR/L006758/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetaminophen/adverse effects ; Analgesics, Non-Narcotic/adverse effects ; Animals ; Antibodies, Neutralizing/*therapeutic use ; Antipyretics/adverse effects ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology ; HMGB1 Protein/*therapeutic use ; Inflammation/*drug therapy ; Male ; Mice ; Mice, Inbred C57BL ; }, abstract = {UNLABELLED: Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP-induced acute liver injury (APAP-ALI) and justifies development of anti-inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N-acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP-ALI. The anti-HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti-HMGB1 polyclonal antibody treatment improves survival in a model of APAP-ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti-HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP-ALI. The mouse anti-HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody-Fc backbones. Effector function-deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP-ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP-induced serum elevations of alanine aminotransferase and microRNA-122 and completely abrogated markers of APAP-induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C-X-C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy.<br><br>CONCLUSION: This is the first report describing the generation of a partly humanized HMGB1-neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP-ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1-specific therapy as a means to treat APAP-ALI and other inflammatory conditions. (Hepatology 2016;64:1699-1710).}, }
@article {pmid27667264, year = {2016}, author = {Lee, W and Woo, ER and Lee, DG}, title = {Phytol has antibacterial property by inducing oxidative stress response in Pseudomonas aeruginosa.}, journal = {Free radical research}, volume = {50}, number = {12}, pages = {1309-1318}, doi = {10.1080/10715762.2016.1241395}, pmid = {27667264}, issn = {1029-2470}, mesh = {Anti-Bacterial Agents/*pharmacology ; Apoptosis ; DNA Damage ; Oxidative Stress ; Phytol/administration &amp; dosage/*therapeutic use ; Pseudomonas aeruginosa/*pathogenicity ; }, abstract = {Phytol, isolated from Aster yomena, is widely distributed as a constituent of chlorophyll. In the present study, we confirmed the antibacterial activity of phytol and its mechanism inducing oxidative cell death in Pseudomonas aeruginosa. In phytol-treated cells, elevated level of intracellular reactive oxygen species (ROS) and transient NADH depletion were observed. These results demonstrated that phytol induced ROS accumulation and that the electron transport chain was involved in increase of ROS. Due to this ROS generation, the imbalance developed between intracellular ROS and the antioxidant defense system, leading to decrease of reduced glutathione (GSH). Moreover, severe DNA damage was shown after treatment with phytol. DNA electrophoresis and a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were conducted with pretreatment with the antioxidant N-acetylcysteine (NAC) to evaluate the cause of DNA damage. In NAC-pretreated cells, alleviated damage was confirmed and it supports that phytol induces oxidative stress-mediated DNA damage. In conclusion, phytol exerts the antibacterial property via inducing oxidative stress response in P. aeruginosa.}, }
@article {pmid27281491, year = {2016}, author = {Pieralisi, A and Martini, C and Soto, D and Vila, MC and Calvo, JC and Guerra, LN}, title = {N-acetylcysteine inhibits lipid accumulation in mouse embryonic adipocytes.}, journal = {Redox biology}, volume = {9}, number = {}, pages = {39-44}, pmid = {27281491}, issn = {2213-2317}, mesh = {3T3-L1 Cells ; Acetylcysteine/*pharmacology ; Adipocytes/*metabolism ; Adipogenesis ; Animals ; Cell Differentiation/drug effects ; Embryo, Mammalian ; Fibroblasts/cytology/drug effects/metabolism ; Lipid Metabolism/*drug effects ; Mice ; Phosphorylation ; Phosphotransferases/metabolism ; }, abstract = {Oxidative stress plays critical roles in the pathogenesis of diabetes, hypertension, and atherosclerosis; some authors reported that fat accumulation correlates to systemic oxidative stress in human and mice, but cellular redox environment effect on lipid accumulation is still unclear. In our laboratory we used mouse embryonic fibroblasts (undifferentiated cells: CC), which are capable of differentiating into mature adipocytes (differentiated cells: DC) and accumulate lipids, as obesity model. Here we analyzed the role of the well-known antioxidant and glutathione precursor N-acetylcysteine (NAC) in cellular MAPK modulation and lipid accumulation. We evaluated the effect of NAC on the adipogenic differentiation pathway using different doses: 0.01, 0.1, 1 and 5mM; no toxic doses in these cells. A dose of 5mM NAC [DCN-5] provoked a significant decrease in triglyceride accumulation (72±10 [DCN-5] vs 169±15 [DC], p<0.01), as well in Oil Red O stained neutral lipid content (120±2 [DCN-5] vs 139±12 [DC], p<0.01). Molecular mechanisms responsible for adipogenic differentiation involve increase of the expression of phosphoERK½ and phosphoJNK, 5mM NAC treatment inhibited both pERK½ and pJNK protein levels. We also evaluated the mitotic clonal expansion (MCE) which takes place during adipogenesis and observed an increase in DC at a rate of 1.5 cells number compared to CC at day 2, whereas the highest doses of NAC significantly inhibited MCE. Our results suggest that NAC inhibits lipid accumulation and the MAPK phosphorylation in mouse embryonic fibroblasts during adipogenic differentiation and further contribute to probe the importance of cellular redox environment in adipogenesis.}, }
@article {pmid27754725, year = {2017}, author = {Srivastava, A and Panduga, V and Saralaya, R and K R, P and Hameed, S and Solapure, S and Hosagrahara, VP}, title = {Evaluation of the metabolism, bioactivation and pharmacokinetics of triaminopyrimidine analogs toward selection of a potential candidate for antimalarial therapy.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {47}, number = {11}, pages = {962-972}, doi = {10.1080/00498254.2016.1247481}, pmid = {27754725}, issn = {1366-5928}, mesh = {Acetylcysteine/metabolism ; Animals ; Antimalarials/*metabolism ; Bile/metabolism ; Biotransformation ; Glutathione/metabolism ; Humans ; Microsomes, Liver/metabolism ; Quinones ; Rats ; Sulfhydryl Compounds/metabolism ; }, abstract = {1. During the course of metabolic profiling of lead Compound 1, glutathione (GSH) conjugates were detected in rat bile, suggesting the formation of reactive intermediate precursor(s). This was confirmed by the identification of GSH and N-acetylcysteine (NAC) conjugates in microsomal incubations. 2. It was proposed that bioactivation of Compound 1 occurs via the formation of a di-iminoquinone reactive intermediate through the involvement of the C-2 and C-5 nitrogens of the pyrimidine core. 3. To further investigate this hypothesis, structural analogs with modifications at the C-5 nitrogen were studied for metabolic activation in human liver microsomes supplemented with GSH/NAC. 4. Compounds 1 and 2, which bear secondary nitrogens at the C-5 of the pyrimidine core, were observed to form significant amounts of GSH/NAC-conjugates in vitro, whereas compounds with tertiary nitrogens at C-5 (Compound 3 and 4) formed no such conjugates. 5. These observations provide evidence that electron/hydrogen abstraction is required for the bioactivation of the triaminopyrimidines, potentially via a di-iminoquinone intermediate. The lack of a hydrogen and/or steric hindrance rendered Compound 3 and 4 incapable of forming thiol conjugates. 6. This finding enabled advancement of compound 4, with a desirable potency, safety and PK profile, as a lead candidate for further development in the treatment of malaria.}, }
@article {pmid27753160, year = {2017}, author = {Ishida, T and Suzuki, S and Lai, CY and Yamazaki, S and Kakuta, S and Iwakura, Y and Nojima, M and Takeuchi, Y and Higashihara, M and Nakauchi, H and Otsu, M}, title = {Pre-Transplantation Blockade of TNF-α-Mediated Oxygen Species Accumulation Protects Hematopoietic Stem Cells.}, journal = {Stem cells (Dayton, Ohio)}, volume = {35}, number = {4}, pages = {989-1002}, doi = {10.1002/stem.2524}, pmid = {27753160}, issn = {1549-4918}, mesh = {Acetylcysteine/pharmacology ; Animals ; Bone Marrow/drug effects/metabolism/pathology ; Cellular Microenvironment/drug effects ; *Cytoprotection/drug effects ; *Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*cytology/drug effects/*metabolism ; Indicators and Reagents ; Inflammation/pathology ; Mice, Inbred C57BL ; Reactive Oxygen Species/*metabolism ; Time Factors ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Hematopoietic stem cell (HSC) transplantation (HSCT) for malignancy requires toxic pre-conditioning to maximize anti-tumor effects and donor-HSC engraftment. While this induces bone marrow (BM)-localized inflammation, how this BM environmental change affects transplanted HSCs in vivo remains largely unknown. We here report that, depending on interval between irradiation and HSCT, residence within lethally irradiated recipient BM compromises donor-HSC reconstitution ability. Both in vivo and in vitro we demonstrate that, among inflammatory cytokines, TNF-α plays a role in HSC damage: TNF-α stimulation leads to accumulation of reactive oxygen species (ROS) in highly purified hematopoietic stem/progenitor cells (HSCs/HSPCs). Transplantation of flow-cytometry-sorted murine HSCs reveals damaging effects of accumulated ROS on HSCs. Short-term incubation either with an specific inhibitor of tumor necrosis factor receptor 1 signaling or an antioxidant N-acetyl-L-cysteine (NAC) prevents TNF-α-mediated ROS accumulation in HSCs. Importantly, pre-transplantation exposure to NAC successfully demonstrats protective effects in inflammatory BM on graft-HSCs, exhibiting better reconstitution capability than that of nonprotected control grafts. We thus suggest that in vivo protection of graft-HSCs from BM inflammation is a feasible and attractive approach, which may lead to improved hematopoietic reconstitution kinetics in transplantation with myeloablative conditioning that inevitably causes inflammation in recipient BM. Stem Cells 2017;35:989-1002.}, }
@article {pmid27751866, year = {2017}, author = {Adam, C and Wohlfarth, J and Haußmann, M and Sennefelder, H and Rodin, A and Maler, M and Martin, SF and Goebeler, M and Schmidt, M}, title = {Allergy-Inducing Chromium Compounds Trigger Potent Innate Immune Stimulation Via ROS-Dependent Inflammasome Activation.}, journal = {The Journal of investigative dermatology}, volume = {137}, number = {2}, pages = {367-376}, doi = {10.1016/j.jid.2016.10.003}, pmid = {27751866}, issn = {1523-1747}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Cells, Cultured ; Chromium Compounds/*toxicity ; Hypersensitivity/*etiology/immunology ; Immunity, Innate/*drug effects ; Interleukin-1beta/metabolism ; Mice ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein/*physiology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Chromium allergy is a common occupational skin disease mediated by chromium (VI)-specific T cells that induce delayed-type hypersensitivity in sensitized individuals. Additionally, chromium (VI) can act as an irritant. Both responses critically require innate immune activation, but if and how chromium (VI) elicits this signal is currently unclear. Using human monocytes, primary human keratinocytes, and murine dendritic cells we show that chromium (VI) compounds fail to trigger direct proinflammatory activation but potently induce processing and secretion of IL-1β. IL-1β release required priming by phorbol-ester or toll-like receptor stimulation and was prevented by inhibition of K[+] efflux, NLRP3 depletion or caspase-1 inhibition, identifying chromium (VI) as a hapten activator of the NLRP3 inflammasome. Inflammasome activation was initiated by mitochondrial reactive oxygen species production triggered by chromium (VI), as indicated by sensitivity to treatment with the ROS scavenger N-acetyl cysteine and a coinciding failure of K[+] efflux, caspase-1, or NLRP3 inhibition to prevent mitochondrial reactive oxygen species accumulation. IL-1β release further correlated with cytotoxicity that was secondary to reactive oxygen species, K[+] efflux, and NLRP3 activation. Trivalent chromium was unable to induce mitochondrial reactive oxygen species production, inflammasome activation, and cytotoxicity, suggesting that oxidation state-specific differences in mitochondrial reactivity may determine inflammasome activation and allergic/irritant capacity of different chromium compounds.}, }
@article {pmid27748853, year = {2016}, author = {Guo, L and Tan, K and Wang, H and Zhang, X}, title = {Pterostilbene inhibits hepatocellular carcinoma through p53/SOD2/ROS-mediated mitochondrial apoptosis.}, journal = {Oncology reports}, volume = {36}, number = {6}, pages = {3233-3240}, doi = {10.3892/or.2016.5151}, pmid = {27748853}, issn = {1791-2431}, mesh = {Animals ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/*drug therapy/pathology ; Hep G2 Cells ; Humans ; Liver Neoplasms/*drug therapy/pathology ; Mice, Inbred C57BL ; Mitochondria ; Reactive Oxygen Species/metabolism ; Stilbenes/*pharmacology ; Superoxide Dismutase/metabolism ; Tumor Burden ; Tumor Suppressor Protein p53/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Hepatocellular carcinoma (HCC) is one of the most common malignancies and the second cause of cancer-related deaths around the world. Pterostilbene (PTE), is a natural analog of resveratrol, possessing diverse pharmacological activities. In the present study, we aimed to examine the effect of PTE on tumor growth in mouse models of HCC and to elucidate the possible molecular mechanism in vivo and in vitro. We showed that PTE dose-dependently suppressed tumor growth in mice induced by diethylnitrosamine plus carbon tetrachloride, as evidenced by a decrease in the number of tumors and in the maximum size of the tumors. PTE concentration-dependently inhibited cell viability and proliferation in HepG2 cells. PTE increased caspase-3 activities and apoptosis in liver tumor tissues and cells, indicating the activation of the mitochondrial apoptotic pathway. PFTα, superoxide dismutase 2 (SOD2) lentivirus and N-acetylcysteine (NAC) significantly inhibited PTE-induced inhibition of tumor growth and cell proliferation and increase in apoptosis. PTE dose-dependently increased reactive oxygen species (ROS) levels both in liver tumor tissues and cells, which were inhibited by PFTα, SOD2 lentivirus and NAC. PTE resulted in a significant decrease in SOD2 expression in liver tumor tissues and cells, which were inhibited by PFTα, but not NAC, indicating that PTE-induced ROS generation was attributed to p53-mediated downregulation of SOD2. Collectively, PTE increased p53 expression, decreased SOD2 expression, and resulted in an increase in the ROS levels and the activation of the mitochondrial apoptotic pathway, leading to inhibition of tumor growth and cell proliferation. These data demonstrated that the p53/SOD2/ROS pathway is critical for PTE-mediated inhibition of tumor growth and HCC cell proliferation.}, }
@article {pmid27748827, year = {2016}, author = {Chen, G and Han, Y and He, W and Liang, F}, title = {Amentoflavone protects against high fat-induced metabolic dysfunction: Possible role of the regulation of adipogenic differentiation.}, journal = {International journal of molecular medicine}, volume = {38}, number = {6}, pages = {1759-1767}, pmid = {27748827}, issn = {1791-244X}, mesh = {3T3-L1 Cells ; Adipocytes/cytology/drug effects/metabolism ; Adipogenesis/*drug effects ; Adipose Tissue/*drug effects/*metabolism ; Animals ; Biflavonoids/*pharmacology ; CCAAT-Enhancer-Binding Protein-alpha/metabolism ; Cell Differentiation/*drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Diet, High-Fat ; Lipid Metabolism/*drug effects ; Male ; Mice ; PPAR gamma/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {In the present study, we evaluated the protective effects of amentoflavone (AMF) against high-fat (HF) diet-induced metabolic dysfunction and focused on the influence of AMF on adipogenic differentiation during 3T3-L1 adipocyte differentiation. For this purpose, male Wistar rats were fed a HF diet or a HF diet with AMF (10 or 50 mg/kg). We found that AMF protected against HF diet-induced metabolic dysfunction in a dose-dependent manner, as evidenced by a decrease in the fasting blood glucose levels, fasting insulin levels and the homeostatic model assessment-insulin resistance index (HOMA‑IR), as well as by a decrease in the glucose level, as shown by the intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test. Moreover, the results revealed that AMF significantly inhibited the increase in body weight, the weight of perirenal adipose tissues and the serum triglyceride (TG) content of the rats fed the HF diet in a dose-dependent manner. AMF also inhibited the accumulation of oil droplets in differentiated 3T3-L1 adipocytes in a concentration-dependent manner. The incubation of the cells with AMF for 0-8, 0-2, 2-4, or 4-8 days markedly inhibited adipogenesis. During the early phase of the adipocyte differentiation of 3T3-L1 cells, AMF decreased CCAAT/enhancer-binding protein (C/EBP) β expression in a concentration-dependent manner, leading to the inhibition of mitotic clonal expansion (MCE). Moreover, our results demonstrated that AMF significantly increased reactive oxygen species (ROS) generation in the cells and the antioxidant, N-acetylcysteine (NAC), markedly attenuated the inhibitory effects of AMF on adipogenesis. AMF also inhibited the expression of peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα and the expression of downstream targets in a concentration-dependent manner. The overexpression of PPARγ and C/EBPα (by transfection with respective overexpression plasmids) attentuated the inhibitory effects of AMF on the formation of oil droplets. The inhibitory effects of AMF on adipocyte differentiation may contribute to its protective effects against HF diet-induced metabolic dysfunction. Overall, the data in our study provide novel insight into the mechanisms responsible for the protective effects of AMF against HF diet-induced metabolic dysfunction and those for its inhibitory effect on adipocyte differentiation.}, }
@article {pmid27745551, year = {2016}, author = {Fraga, CM and Tomasi, CD and Damasio, DC and Vuolo, F and Ritter, C and Dal-Pizzol, F}, title = {N-acetylcysteine plus deferoxamine for patients with prolonged hypotension does not decrease acute kidney injury incidence: a double blind, randomized, placebo-controlled trial.}, journal = {Critical care (London, England)}, volume = {20}, number = {1}, pages = {331}, pmid = {27745551}, issn = {1466-609X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*drug therapy/epidemiology ; Adult ; Aged ; Critical Illness/epidemiology/*therapy ; Deferoxamine/*administration &amp; dosage ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/administration &amp; dosage ; Humans ; Hypotension/*drug therapy/epidemiology ; Incidence ; Intensive Care Units/trends ; Male ; Middle Aged ; }, abstract = {BACKGROUND: The aim was to test the primary hypothesis that in patients suffering from shock, treatment with N-acetylcysteine (NAC) plus deferoxamine (DFX) decreases the incidence of acute kidney injury (AKI).<br><br>METHODS: A double-blind, randomized, placebo-controlled trial was conducted in a general intensive care unit in an academic hospital. Patients were included if they had new-onset hypotension, defined as mean arterial blood pressure <60&#xa0;mmHg or requirement for vasopressor medication. A loading dose of NAC or placebo of 50&#xa0;mg/kg in 4&#xa0;h was administered intravenously. After the loading dose, patients received 100&#xa0;mg/kg/day for the next 48&#xa0;h. DFX or placebo was administered once at 1000&#xa0;mg at a rate of 15/mg/kg/h. The primary outcome was the incidence of AKI.<br><br>RESULTS: A total of 80 patients were enrolled in the study. The incidence of AKI was 67&#xa0;% in the placebo arm and 65&#xa0;% in the treatment group (relative risk (RR) 0.89 (0.35-2.2)). Furthermore, NAC plus DFX was effective in decreasing the severity and duration of AKI, and patients in the treatment group had lower serum creatinine levels at discharge. No severe adverse event associated with treatment was reported. The effects of NAC plus DFX could be secondary to the attenuation of early inflammatory response and oxidative damage.<br><br>CONCLUSION: The administration of NAC plus DFX to critically ill patients who had a new episode of hypotension did not decrease the incidence of AKI.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov NCT00870883 (Registered 25 March 2009.).}, }
@article {pmid27503687, year = {2016}, author = {Boeckler, GA and Paetz, C and Feibicke, P and Gershenzon, J and Unsicker, SB}, title = {Metabolism of poplar salicinoids by the generalist herbivore Lymantria dispar (Lepidoptera).}, journal = {Insect biochemistry and molecular biology}, volume = {78}, number = {}, pages = {39-49}, doi = {10.1016/j.ibmb.2016.08.001}, pmid = {27503687}, issn = {1879-0240}, mesh = {Animals ; Benzyl Alcohols/*metabolism ; Feeding Behavior ; Glucosides/*metabolism ; *Herbivory ; Larva/growth &amp; development/metabolism ; Moths/growth &amp; development/*physiology ; Plant Leaves/chemistry ; Populus/*chemistry ; Tissue Distribution ; }, abstract = {The survival of insect herbivores on chemically defended plants may often depend on their ability to metabolize these defense compounds. However, only little knowledge is available on how insects actually process most plant defense compounds. We investigated the metabolism of salicinoids, a major group of phenolic glycosides in poplar and willow species, by a generalist herbivore, the gypsy moth (Lymantria dispar). Seven salicinoid metabolites identified in gypsy moth caterpillar feces were mostly conjugates with glucose, cysteine or glycine. Two of the glucosides were phosphorylated, a feature not previously reported for insect metabolites of plant defense compounds. The origins of these metabolites were traced to specific moieties of three major poplar salicinoids ingested, salicin, salicortin and tremulacin. Based on the observed metabolite patterns we were able to deduce the initial steps of salicinoid breakdown in L. dispar guts, which involves cleavage of ester bonds. The conjugated molecules were effectively eliminated within 24 h after ingestion. Some of the initial breakdown products (salicin and catechol) demonstrated negative effects on insect growth and survival in bioassays on artificial diets. Gypsy moth caterpillars with prior feeding experience on salicinoid-containing poplar foliage converted salicinoids to the identified metabolites more efficiently than caterpillars pre-fed an artificial diet. The majority of the metabolites we identified were also produced by other common poplar-feeding insects. The conversion of plant defenses like salicinoids to a variety of water-soluble sugar, phosphate and amino acid conjugates and their subsequent excretion fits the general detoxification strategy found in insect herbivores and other animals.}, }
@article {pmid27742673, year = {2016}, author = {Scheffel, MJ and Scurti, G and Simms, P and Garrett-Mayer, E and Mehrotra, S and Nishimura, MI and Voelkel-Johnson, C}, title = {Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death.}, journal = {Cancer research}, volume = {76}, number = {20}, pages = {6006-6016}, pmid = {27742673}, issn = {1538-7445}, support = {C06 RR015455/RR/NCRR NIH HHS/United States ; P01 CA154778/CA/NCI NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Nucleus/metabolism ; Cells, Cultured ; DNA Damage ; Female ; Humans ; *Immunotherapy, Adoptive ; *Lymphocyte Activation ; Mice ; Neoplasms, Experimental/immunology/*therapy ; Phosphorylation ; Receptors, Antigen, T-Cell/physiology ; T-Lymphocytes/*immunology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Although adoptive transfer of autologous tumor antigen-specific T-cell immunotherapy can produce remarkable clinical efficacy, most patients do not achieve durable complete responses. We hypothesized that reducing susceptibility of T cells to activation-induced cell death (AICD), which increases during the rapid in vitro expansion of therapeutic T cells before their infusion, might improve the persistence of adoptively transferred cells. Our investigations revealed that repetitive stimulation of the T-cell receptor (TCR) induced AICD, as a result of activating the DNA damage response pathway through ATM-mediated Ser15 phosphorylation of p53. Activation of this DNA damage response pathway also occurred upon antigen-specific restimulation in TCR-transduced TIL1383I T cells prepared for adoptive transfer to patients as part of a clinical trial. Notably, treatment with the antioxidant N-acetyl cysteine (NAC) significantly reduced upregulation of the DNA damage marker γH2AX, subsequent ATM activation, and cell death. In the Pmel mouse model of melanoma, the presence of NAC during ex vivo T-cell expansion improved the persistence of adoptively transferred cells, reduced tumor growth, and increased survival. Taken together, our results offer a preclinical proof of concept for the addition of NAC to current therapeutic T-cell expansion protocols, offering immediate potential to improve the quality and therapeutic efficacy of adoptive T-cell therapeutics infused into patients. Cancer Res; 76(20); 6006-16. ©2016 AACR.}, }
@article {pmid27742300, year = {2016}, author = {Lauz Medeiros, SH and de Oliveira Menezes, A and Zogbi, L and Frasson de Souza Montero, E}, title = {N-Acetylcysteine Use in Hepatic Ischemia/Reperfusion in Rats Minimizing Bowel Injury.}, journal = {Transplantation proceedings}, volume = {48}, number = {7}, pages = {2371-2374}, doi = {10.1016/j.transproceed.2016.06.003}, pmid = {27742300}, issn = {1873-2623}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Intestinal Mucosa/*drug effects/*pathology ; Intestine, Small/drug effects/pathology ; Liver/*blood supply/surgery ; Liver Diseases/surgery ; Male ; Rats ; Rats, Wistar ; Reperfusion Injury/complications ; }, abstract = {BACKGROUND: The ischemia/reperfusion (I/R) phenomenon can cause the dysfunction of some transplanted organs and other distant organs. Liver surgery success, including transplantations, may depend on the adverse effects of intestinal mucosa injury arising from temporary porta triad occlusion. The study objective was to examine I/R liver effects on the small intestine in rats after N-acetylcysteine (NAC) treatment.<br><br>METHODS: Twenty-four male Wistar rats were randomly divided into 2 groups. After anesthesia, they underwent 30 minutes of hepatic ischemia by clamping the porta triad, followed by reperfusion for 30 minutes or 6 hours. Each group was divided into 2 subgroups (n&#xa0;= 6), with 1 group receiving 0.9% saline solution (control) and the other receiving 150 mg/kg of NAC, 15 minutes before hepatic ischemia. At the end of reperfusion, blood was collected for enzyme dosage (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], alkaline phosphatase [ALP]), and the terminal ileum was resected to study mucosal morphology by optical microscopy, computerized histomorphometry, and immunohistochemical assessment of apoptosis with caspase&#xa0;3.<br><br>RESULTS: After 30 minutes of reperfusion, animals receiving NAC had lower injury in the intestinal mucosa compared to the control subgroup (P&#xa0;< .05). After 6 hours, AST was higher in the control subgroup than in the NAC subgroup (P&#xa0;< .05), and AST, ALT and LDH values showed a significant increase in both subgroups (P&#xa0;< .05).<br><br>CONCLUSION: These findings show the deleterious effects of late (6-hour) reperfusion and the protective effect of NAC at 30 minutes, when evaluating the small intestine impact of I/R liver damage.}, }
@article {pmid27739590, year = {2017}, author = {Herrera, EA and Cifuentes-Zúñiga, F and Figueroa, E and Villanueva, C and Hernández, C and Alegría, R and Arroyo-Jousse, V and Peñaloza, E and Farías, M and Uauy, R and Casanello, P and Krause, BJ}, title = {N-Acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs.}, journal = {The Journal of physiology}, volume = {595}, number = {4}, pages = {1077-1092}, pmid = {27739590}, issn = {1469-7793}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Cells, Cultured ; *Cellular Reprogramming ; DNA Methylation ; Endothelial Cells/cytology/drug effects/*metabolism ; *Epigenesis, Genetic ; Female ; Fetal Growth Retardation/drug therapy/*metabolism ; Guinea Pigs ; Nitric Oxide Synthase Type III/genetics/metabolism ; Promoter Regions, Genetic ; Umbilical Arteries/drug effects/metabolism/pathology ; }, abstract = {KEY POINTS: Intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial epigenetic programming of the umbilical vessels. There is no evidence that this epigenetic programming is occurring on systemic fetal arteries. In IUGR guinea pigs we studied the functional and epigenetic programming of endothelial nitric oxide synthase (eNOS) (Nos3 gene) in umbilical and systemic fetal arteries, addressing the role of oxidative stress in this process by maternal treatment with N-acetylcysteine (NAC) during the second half of gestation. The present study suggests that IUGR endothelial cells have common molecular markers of programming in umbilical and systemic arteries. Notably, maternal treatment with NAC restores fetal growth by increasing placental efficiency and reverting the functional and epigenetic programming of eNOS in arterial endothelium in IUGR guinea pigs.<br><br>ABSTRACT: In humans, intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial programming in umbilical vessels. We aimed to determine the effects of maternal antioxidant treatment with N-acetylcysteine (NAC) on fetal endothelial function and endothelial nitric oxide synthase (eNOS) programming in IUGR guinea pigs. IUGR was induced by implanting ameroid constrictors on uterine arteries of pregnant guinea pigs at mid gestation, half of the sows receiving NAC in the drinking water (from day 34 until term). Fetal biometry and placental vascular resistance were followed by ultrasound throughout gestation. At term, umbilical arteries and fetal aortae were isolated to assess endothelial function by wire-myography. Primary cultures of endothelial cells (ECs) from fetal aorta, femoral and umbilical arteries were used to determine eNOS mRNA levels by quantitative PCR and analyse DNA methylation in the Nos3 promoter by pyrosequencing. Doppler ultrasound measurements showed that NAC reduced placental vascular resistance in IUGR (P&#xa0;<&#xa0;0.05) and recovered fetal weight (P&#xa0;<&#xa0;0.05), increasing fetal-to-placental ratio at term (&#x223c;40%) (P&#xa0;<&#xa0;0.001). In IUGR, NAC treatment restored eNOS-dependent relaxation in aorta and umbilical arteries (P&#xa0;<&#xa0;0.05), normalizing eNOS mRNA levels in EC fetal and umbilical arteries (P&#xa0;<&#xa0;0.05). IUGR-derived ECs had a decreased DNA methylation (&#x223c;30%) at CpG -170 (from the transcription start site) and this epigenetic signature was absent in NAC-treated fetuses (P&#xa0;<&#xa0;0.001). These data show that IUGR-ECs have common molecular markers of eNOS programming in umbilical and systemic arteries and this effect is prevented by maternal treatment with antioxidants.}, }
@article {pmid27738742, year = {2017}, author = {Stenger, B and Popp, T and John, H and Siegert, M and Tsoutsoulopoulos, A and Schmidt, A and Mückter, H and Gudermann, T and Thiermann, H and Steinritz, D}, title = {N-Acetyl-L-cysteine inhibits sulfur mustard-induced and TRPA1-dependent calcium influx.}, journal = {Archives of toxicology}, volume = {91}, number = {5}, pages = {2179-2189}, doi = {10.1007/s00204-016-1873-x}, pmid = {27738742}, issn = {1432-0738}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Calcium/*metabolism ; Chemical Warfare Agents/toxicity ; Dose-Response Relationship, Drug ; Glutathione/analysis/pharmacology ; HEK293 Cells ; Humans ; Mustard Gas/administration &amp; dosage/*toxicity ; Oximes/pharmacology ; Spectrometry, Mass, Electrospray Ionization/methods ; TRPA1 Cation Channel/antagonists &amp; inhibitors/*metabolism ; Tandem Mass Spectrometry/methods ; }, abstract = {Transient receptor potential family channels (TRPs) have been identified as relevant targets in many pharmacological as well as toxicological studies. TRP channels are ubiquitously expressed in different tissues and act among others as sensors for different external stimuli, such as mechanical stress or noxious impacts. Recent studies suggest that one member of this family, the transient receptor potential ankyrin 1 cation channel (TRPA1), is involved in pain, itch, and various diseases, suggesting TRPA1 as a potential therapeutic target. As a nociceptor, TRPA1 is mainly activated by noxious or electrophilic compounds, including alkylating substances. Previous studies already revealed an impact of 2-chloroethyl-ethyl sulfide on the ion channel TRPA1. In this study, we demonstrate that sulfur mustard (bis-(2-chloroethyl) sulfide, SM) activates the human TRPA1 (hTRPA1) in a dose-dependent manner measured by the increase in intracellular Ca[2+] concentration ([Ca[2+]]i). Besides that, SM-induced toxicity was attenuated by antioxidants. However, very little is known about the underlying mechanisms. Here, we demonstrate that N-acetyl-L-cysteine (NAC) prevents SM-induced hTRPA1-activation. HEK293-A1-E cells, overexpressing hTRPA1, show a distinct increase in [Ca[2+]]i immediately after SM exposure, whereas this increase is reduced in cells pretreated with NAC in a dose-dependent manner. Interestingly, glutathione, although being highly related to NAC, did not show an effect on hTRPA1 channel activity. Taken together, our results provide evidence that SM-dependent activation of hTRPA1 can be diminished by NAC treatment, suggesting a direct interaction of NAC and the hTRPA1 cation channel. Our previous studies already showed a correlation of hTRPA1-activation with cell damage after exposure to alkylating agents. Therefore, NAC might be a feasible approach mitigating hTRPA1-related dysregulations after exposure to SM.}, }
@article {pmid27738311, year = {2016}, author = {Wiraswati, HL and Hangen, E and Sanz, AB and Lam, NV and Reinhardt, C and Sauvat, A and Mogha, A and Ortiz, A and Kroemer, G and Modjtahedi, N}, title = {Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione.}, journal = {Oncotarget}, volume = {7}, number = {47}, pages = {76496-76507}, pmid = {27738311}, issn = {1949-2553}, mesh = {Apoptosis/drug effects ; Apoptosis Inducing Factor/*genetics/*metabolism ; Autophagy/drug effects ; Cell Line, Tumor ; Gene Expression ; Glutathione/metabolism ; Humans ; Mitochondria/drug effects/metabolism ; Oxidation-Reduction/*drug effects ; Oxidative Stress/*drug effects/*genetics ; Vitamin K 3/metabolism/*pharmacology ; }, abstract = {Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.}, }
@article {pmid27737524, year = {2017}, author = {Yao, CW and Kang, KA and Piao, MJ and Ryu, YS and Fernando, PMDJ and Oh, MC and Park, JE and Shilnikova, K and Na, SY and Jeong, SU and Boo, SJ and Hyun, JW}, title = {Reduced Autophagy in 5-Fluorouracil Resistant Colon Cancer Cells.}, journal = {Biomolecules &amp; therapeutics}, volume = {25}, number = {3}, pages = {315-320}, pmid = {27737524}, issn = {1976-9148}, abstract = {We investigated the role of autophagy in SNUC5/5-FUR, 5-fluorouracil (5-FU) resistant SNUC5 colon cancer cells. SNUC5/5- FUR cells exhibited low level of autophagy, as determined by light microscopy, confocal microscopy, and flow cytometry following acridine orange staining, and the decreased level of GFP-LC3 puncta. In addition, expression of critical autophagic proteins such as Atg5, Beclin-1 and LC3-II and autophagic flux was diminished in SNUC5/5-FUR cells. Whereas production of reactive oxygen species (ROS) was significantly elevated in SNUC5/5-FUR cells, treatment with the ROS inhibitor N-acetyl cysteine further reduced the level of autophagy. Taken together, these results indicate that decreased autophagy is linked to 5-FU resistance in SNUC5 colon cancer cells.}, }
@article {pmid27735147, year = {2016}, author = {Suraj, KP and Kumar, NK and Jyothi, E and Narayan, KV and Biju, G}, title = {Role of Pirfenidone in Idiopathic Pulmonary Fibrosis - A Longitudinal Cohort Study.}, journal = {The Journal of the Association of Physicians of India}, volume = {64}, number = {5}, pages = {36-41}, pmid = {27735147}, issn = {0004-5772}, mesh = {Acetylcysteine/*administration &amp; dosage/therapeutic use ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/*administration &amp; dosage/therapeutic use ; Antiviral Agents/*administration &amp; dosage/therapeutic use ; Cohort Studies ; Drug Therapy, Combination ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/diagnosis/*drug therapy ; Longitudinal Studies ; Male ; Middle Aged ; Proton Pump Inhibitors/therapeutic use ; Pyridones/*administration &amp; dosage/therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: But so far there is no proven pharmacological treatment for Idiopathic pulmonary fibrosis (IPF). As trials investigating different agents with different mechanisms of actions are going on, encouraging results have led to the licensing of the first IPF-specific drug, Pirfenidone.<br><br>OBJECTIVE: To assess the proportion of IPF among interstitial lung disease patients and to assess their treatment response to Pirfenidone.<br><br>MATERIAL AND METHODS: All consecutive patients attending the outpatient department from 1st January 2012 to 30th June 2012 with a proven diagnosis of Interstitial lung Disease (ILD) were included in this longitudinal cohort study. Out of the total ILDs, patients with IPF were identified. The disease, its natural course, available treatment options and the risks and benefits of drugs were discussed with each IPF patient along with their family members. After obtaining their consent, we started 23 patients on a combination of Pirfenidone, N-acetyl cysteine (NAC) and proton pump inhibitors (PPI). Patients were followed up for 52 weeks. Pirfenidone was discontinued in one patient due to an adverse effect 1 month after onset of treatment. Anova test using SPSS software and independent T test was used to analyse the data.<br><br>RESULTS: During the study period 69 patients with ILD attended our OPD which included 24 IPF patients representing 34.8% and 23 of these patients received treatment with Pirfenidone, NAC and PPI. One patient discontinued Pirfenidone due to adverse effects. After 12 months, 8 patients had worsening of FVC &#x2265;10%, the FVC of 7 patients remained stable, 8 patients could not repeat the tests and none of them had improvement. There was less than 15% decline in DLCO for 9 patients, 7 patients could not repeat the test and none improved. 8 patients had stable dyspnoea on exertion and 11 had worsening. Three patients died. Combining all the above parameters, only 4 patients had stable disease with the rest having no improvement.<br><br>CONCLUSIONS: The present study does not show any significant beneficial effect for Pirfenidone. Only four patients remained stable which cannot be attributed to the effect of any particular management strategy.}, }
@article {pmid27733157, year = {2016}, author = {Su, W and Zhang, Y and Zhang, Q and Xu, J and Zhan, L and Zhu, Q and Lian, Q and Liu, H and Xia, ZY and Xia, Z and Lei, S}, title = {N-acetylcysteine attenuates myocardial dysfunction and postischemic injury by restoring caveolin-3/eNOS signaling in diabetic rats.}, journal = {Cardiovascular diabetology}, volume = {15}, number = {1}, pages = {146}, pmid = {27733157}, issn = {1475-2840}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cardiomegaly/chemically induced/enzymology/physiopathology/*prevention &amp; control ; Caveolae/drug effects/enzymology/pathology ; Caveolin 3/genetics/*metabolism ; Cell Hypoxia ; Cell Line ; Cytoprotection ; Diabetes Mellitus, Experimental/chemically induced/*drug therapy ; Diabetic Cardiomyopathies/chemically induced/enzymology/physiopathology/*prevention &amp; control ; Heart Rate/drug effects ; Male ; Myocardial Reperfusion Injury/chemically induced/enzymology/physiopathology/*prevention &amp; control ; Myocytes, Cardiac/*drug effects/enzymology/metabolism/pathology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/genetics/*metabolism ; Oxidative Stress/drug effects ; Phosphorylation ; RNA Interference ; Rats, Sprague-Dawley ; Signal Transduction/*drug effects ; Streptozocin ; Transfection ; Ventricular Function, Left/drug effects ; }, abstract = {BACKGROUND: Patients with diabetes are prone to develop cardiac hypertrophy and more susceptible to myocardial ischemia-reperfusion (I/R) injury, which are concomitant with hyperglycemia-induced oxidative stress and impaired endothelial nitric oxide (NO) synthase (eNOS)/NO signaling. Caveolae are critical in the transduction of eNOS/NO signaling in cardiovascular system. Caveolin (Cav)-3, the cardiomyocytes-specific caveolae structural protein, is decreased in the diabetic heart in which production of reactive oxygen species are increased. We hypothesized that treatment with antioxidant N-acetylcysteine (NAC) could enhance cardiac Cav-3 expression and attenuate caveolae dysfunction and the accompanying eNOS/NO signaling abnormalities in diabetes.<br><br>METHODS: Control or streptozotocin-induced diabetic rats were either untreated or treated with NAC (1.5&#xa0;g/kg/day, NAC) by oral gavage for 4 weeks. Rats in subgroup were randomly assigned to receive 30&#xa0;min of left anterior descending artery ligation followed by 2&#xa0;h of reperfusion. Isolated rat cardiomyocytes or H9C2 cells were exposed to low glucose (LG, 5.5&#xa0;mmol/L) or high glucose (HG, 25&#xa0;mmol/L) for 36&#xa0;h before being subjected to 4&#xa0;h of hypoxia followed by 4&#xa0;h of reoxygenation (H/R).<br><br>RESULTS: NAC treatment ameliorated myocardial dysfunction and cardiac hypertrophy, and attenuated myocardial I/R injury and post-ischemic cardiac dysfunction in diabetic rats. NAC attenuated the reductions of NO, Cav-3 and phosphorylated eNOS and mitigated the augmentation of O2[-], nitrotyrosine and 15-F2t-isoprostane in diabetic myocardium. Immunofluorescence analysis demonstrated the colocalization of Cav-3 and eNOS in isolated cardiomyocytes. Immunoprecipitation analysis revealed that diabetic conditions decreased the association of Cav-3 and eNOS in isolated cardiomyocytes, which was enhanced by treatment with NAC. Disruption of caveolae by methyl-&#x3b2;-cyclodextrin or Cav-3 siRNA transfection reduced eNOS phosphorylation. NAC treatment attenuated the reductions of Cav-3 expression and eNOS phosphorylation in HG-treated cardiomyocytes or H9C2 cells. NAC treatment attenuated HG and H/R induced cell injury, which was abolished during concomitant treatment with Cav-3 siRNA or eNOS siRNA.<br><br>CONCLUSIONS: Hyperglycemia-induced inhibition of eNOS activity might be consequences of caveolae dysfunction and reduced Cav-3 expression. Antioxidant NAC attenuated myocardial dysfunction and myocardial I/R injury by improving Cav-3/eNOS signaling.}, }
@article {pmid27729002, year = {2017}, author = {Wang, J and Jiao, Y and Cui, L and Jiang, L}, title = {miR-30 functions as an oncomiR in gastric cancer cells through regulation of P53-mediated mitochondrial apoptotic pathway.}, journal = {Bioscience, biotechnology, and biochemistry}, volume = {81}, number = {1}, pages = {119-126}, doi = {10.1080/09168451.2016.1238294}, pmid = {27729002}, issn = {1347-6947}, mesh = {Apoptosis/*genetics ; Base Sequence ; Carcinogenesis/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; Down-Regulation/genetics ; Humans ; MicroRNAs/*genetics ; Mitochondria/*pathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/genetics ; Stomach Neoplasms/*pathology ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {The present study was designed to investigate the role of miR-30 in the development of Gastric cancer (GC). miR-30 expression was increased in GC tissues and cell lines. Downregulation of miR-30 inhibited cell proliferation and promoted apoptosis in HGC-27 cells. Upregulation of miR-30 enhanced the proliferation and inhibited apoptosis. P53 expression was decreased in GC tissues. P53 expression was correlated with miR-30 expression. Downregulation of miR-30 increased P53 expression. Knockdown of P53 inhibited miR-30-inhibitor-induced suppression of cell proliferation and increase of apoptosis. Downregulation of miR-30 increased ROS generation which was inhibited by shP53. miR-30 inhibitors induced a decrease in mitochondrial oxygen consumption, cytoplasmic release of cytochrome c, and activation of Caspase 3 and 9, activating mitochondrial apoptotic pathway. Downregulation of P53 and N-acetyl-cysteine suppressed miR-30 inhibitors-activated mitochondrial dysfunction and apoptotic events. In conclusion, we identified that miR-30 functioned as a potential oncomiR through P53/ROS-mediated regulation of mitochondrial apoptotic pathway.}, }
@article {pmid27726288, year = {2016}, author = {Shan, F and Shao, Z and Jiang, S and Cheng, Z}, title = {Erlotinib induces the human non-small-cell lung cancer cells apoptosis via activating ROS-dependent JNK pathways.}, journal = {Cancer medicine}, volume = {5}, number = {11}, pages = {3166-3175}, pmid = {27726288}, issn = {2045-7634}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/genetics/metabolism ; Carcinoma, Non-Small-Cell Lung/genetics/*metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; ErbB Receptors/metabolism ; Erlotinib Hydrochloride/chemistry/*pharmacology ; Gene Expression ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lung Neoplasms/genetics/*metabolism ; MAP Kinase Signaling System/*drug effects ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Although erlotinib (ERL) has drawn more and more attention toward its anticancer properties effect, the underlying mechanisms of ERL's anticancer properties effect remain unclear yet. So, the aim of this research was to explore the underlying anticancer mechanisms of ERL and to explore whether the reactive oxygen species (ROS)-dependent c-Jun N-terminal kinase (JNK) pathway contributed to the anticancer properties provided by ERL. In our study, we used MTT assay to detect the anticell growth ability of ERL on human non-small-cell lung cancer cell lines (A549). The extent of cell apoptosis was determined by Hoechst 33342 staining and fluorescence-activated cell sorter (FACS) assay. Then, DCFH-DA and JC-1 staining were used to monitor intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP), respectively. Finally, the effect of ERL on phosphorylation state of JNK protein and downstream apoptosis concerned proteins were detected by western blotting assay. Results showed that ERL significantly suppressed the growth and reproduction of A549 cells with the concentration rising up in vitro. Hoechst 33342 staining and FACS assay also confirmed the proapoptosis effect of ERL on A549 cells with the concentration rising up. Furthermore, exposure of A549 cells to ERL increased the intracellular ROS production. As expected, intracellular ROS activated the proapoptotic JNK signaling pathway and inhibited the activation of EFGR signaling pathway. Our results also revealed that ERL could induce cell-cycle arrest at G0/G1 period. Activation of JNK protein decreased MMP and downregulated content of antiapoptotic protein Bcl-2 concomitant with the upregulated content of proapoptotic protein Bax in A549 cells. In addition, c-Jun and cleaved caspase-3 were also activated by the phosphorylated JNK induced by ERL. All of these proapoptosis effect of ERL was reversed by administration of N-acetylcysteine (NAC), which performed as a ROS scavenger. Our results suggest that ERL induces A549 cells apoptosis via activating ROS-dependent JNK pathways in human non-small lung cancer cells that provide a new experimental foundation for cancer therapy.}, }
@article {pmid27722780, year = {2018}, author = {Zhang, H and Su, W and Ying, Z and Chen, Y and Zhou, L and Li, Y and Zhang, J and Zhang, L and Wang, T}, title = {N-acetylcysteine attenuates intrauterine growth retardation-induced hepatic damage in suckling piglets by improving glutathione synthesis and cellular homeostasis.}, journal = {European journal of nutrition}, volume = {57}, number = {1}, pages = {327-338}, pmid = {27722780}, issn = {1436-6215}, support = {2012CB124703//National Basic Research Program of People's Republic of China/ ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Alanine Transaminase/blood ; Animals ; Animals, Suckling/*metabolism ; Apoptosis ; Aspartate Aminotransferases/blood ; Fetal Growth Retardation/metabolism/pathology/*veterinary ; Gene Expression ; Genes, bcl-2/genetics ; Glutathione/*biosynthesis ; Homeostasis ; Liver/metabolism/pathology ; Liver Diseases/etiology/metabolism/*prevention &amp; control ; Male ; Malondialdehyde/analysis ; Necrosis ; Oxidation-Reduction ; *Sus scrofa ; }, abstract = {PURPOSE: The objective of the present study was to test the hypothesis that N-acetylcysteine (NAC) may play beneficial roles against intrauterine growth retardation (IUGR)-induced hepatic damage in suckling piglets.<br><br>METHODS: Fourteen IUGR and seven normal birth weight (NBW) neonatal male piglets were selected. Piglets were weaned at 7&#xa0;days of postnatal age and fed the control formula milk (NBW-CON and IUGR-CON groups) or the control formula milk supplemented with 1.2&#xa0;g/kg NAC (IUGR-NAC group) for 14&#xa0;days (n&#xa0;=&#xa0;7). The plasma and liver samples were analyzed for the parameters related to hepatic damage, redox status, apoptosis, and autophagy.<br><br>RESULTS: Compared with the NBW-CON group, IUGR-CON group exhibited increased activities of plasma aminotransferases, increased numbers of apoptotic hepatocytes, as well as higher concentrations of protein carbonyl, malondialdehyde (MDA), microtubule-associated protein 1 light chain 3 beta, and phospholipid-conjugated form (MAP1LC3B-II), along with a decrease in the content of reduced glutathione (GSH). NAC treatment increased GSH content and GSH-to-oxidized GSH ratio in the liver of IUGR-NAC group, most likely owing to the improved activities of &#x3b3;-glutamine-cysteine ligase, &#x3b3;-glutamine-cysteine synthetase, and glutathione reductase. The hepatic protein carbonyl and MDA contents were decreased in the IUGR-NAC group compared with the IUGR-CON group. In addition, NAC-treated piglets had an increased content of B cell lymphoma/leukemia 2 protein, whereas a decreased expression level of MAP1LC3B-II in the liver.<br><br>CONCLUSIONS: NAC may have beneficial effects in improving GSH synthesis and cellular homeostasis in the liver of IUGR suckling piglets.}, }
@article {pmid27720892, year = {2016}, author = {Yang, PM and Huang, YT and Zhang, YQ and Hsieh, CW and Wung, BS}, title = {Carbon monoxide releasing molecule induces endothelial nitric oxide synthase activation through a calcium and phosphatidylinositol 3-kinase/Akt mechanism.}, journal = {Vascular pharmacology}, volume = {87}, number = {}, pages = {209-218}, doi = {10.1016/j.vph.2016.09.010}, pmid = {27720892}, issn = {1879-3649}, mesh = {Androstadienes/pharmacology ; Animals ; Calcium/*metabolism ; Carbon Monoxide/*metabolism ; Cattle ; Chromones/pharmacology ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Endothelial Cells/metabolism ; Endothelium, Vascular/metabolism ; Morpholines/pharmacology ; Nitric Oxide Synthase Type III/*metabolism ; Organometallic Compounds/*pharmacology ; Phosphatidylinositol 3-Kinase/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Time Factors ; Wortmannin ; }, abstract = {The production of nitric oxide (NO) by endothelial NO synthase (eNOS) plays a major role in maintaining vascular homeostasis. This study elucidated the potential role of carbon monoxide (CO)-releasing molecules (CORMs) in NO production and explored the underlying mechanisms in endothelial cells. We observed that 25μM CORM-2 could increase NO production and stimulate an increase in the intracellular Ca[2+] level. Furthermore, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetra acetic acid caused CORM-2-induced NO production, which was abolished by 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), indicating that intracellular Ca[2+] release plays a major role in eNOS activation. The inhibition of the IP3 receptor diminished the CORM-2-induced intracellular Ca[2+] increase and NO production. Furthermore, CORM-2 induced eNOS Ser[1179] phosphorylation and eNOS dimerization, but it did not alter eNOS expression. CORM-2 (25μM) also prolonged Akt phosphorylation, lasting for at least 12h. Pretreatment with phosphatidylinositol 3-kinase inhibitors (wortmannin or LY294002) inhibited the increases in NO production and phosphorylation but did not affect eNOS dimerization. CORM-2-induced eNOS Ser[1179] phosphorylation was intracellularly calcium-dependent, because pretreatment with an intracellular Ca[2+] chelator (BAPTA-AM) inhibited this process. Although CORM-2 increases intracellular reactive oxygen species (ROS), pretreatment with antioxidant enzyme catalase and N-acetyl-cysteine did not abolish the CORM-2-induced eNOS activity or phosphorylation, signifying that ROS is not involved in this activity. Hence, CORM-2 enhances eNOS activation through intracellular calcium release, Akt phosphorylation, and eNOS dimerization.}, }
@article {pmid27718209, year = {2017}, author = {Escribano, BM and Medina-Fernández, FJ and Aguilar-Luque, M and Agüera, E and Feijoo, M and Garcia-Maceira, FI and Lillo, R and Vieyra-Reyes, P and Giraldo, AI and Luque, E and Drucker-Colín, R and Túnez, I}, title = {Lipopolysaccharide Binding Protein and Oxidative Stress in a Multiple Sclerosis Model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {14}, number = {1}, pages = {199-211}, pmid = {27718209}, issn = {1878-7479}, mesh = {Acetylcysteine/administration &amp; dosage ; Acute-Phase Proteins/*metabolism ; Adult ; Animals ; Brain/drug effects/metabolism ; Carrier Proteins/*metabolism ; Cell Count ; Dasyproctidae ; Dimethyl Fumarate/administration &amp; dosage ; Encephalomyelitis, Autoimmune, Experimental/metabolism ; Female ; Humans ; Lipid Peroxidation ; Lipopolysaccharides/metabolism ; Male ; Membrane Glycoproteins/*metabolism ; Middle Aged ; Multiple Sclerosis/*metabolism ; Natalizumab/administration &amp; dosage ; Neurons/drug effects ; *Oxidative Stress ; Rats ; Spinal Cord/drug effects/metabolism ; }, abstract = {Recent findings in experimental autoimmune encephalomyelitis (EAE) suggest that altering certain bacterial populations present in the gut may lead to a proinflammatory condition, that could result in the development of multiple sclerosis (MS). Also, Reactive Oxygen Species seem to be involved in the course of MS. In this study, it has been aimed to relate all these variables starting from an analysis of the lipopolysaccharide (LPS) and LPS-binding protein (LBP) with the determination of parameters related to oxidative stress in the blood, brain and spinal cord. For this purpose, samples obtained from EAE rats and relapsing-remitting (RRMS) MS patients were used. In addition, EAE rats were treated with Natalizumab, N-acetyl-cysteine and dimethyl fumarate. Natalizumab was also employed in RRMS. The results of this study revealed an improvement in the clinical symptoms of the EAE and MS with the treatments, as well as a reduction in the oxidative stress parameters and in LBP. Correlations between the clinical variables of the disease, i.e. oxidative damage and LBP, were established. Although the conclusions of this research are indeed relevant, further investigation would be necessary to establish the intrinsic mechanisms of the MS-oxidative stress-microbiota relationship.}, }
@article {pmid27717985, year = {2017}, author = {Abd-Elbaset, M and Arafa, EA and El Sherbiny, GA and Abdel-Bakky, MS and Elgendy, AN}, title = {Thymoquinone mitigate ischemia-reperfusion-induced liver injury in rats: a pivotal role of nitric oxide signaling pathway.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {390}, number = {1}, pages = {69-76}, pmid = {27717985}, issn = {1432-1912}, mesh = {Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Animals ; Antioxidants/*pharmacology ; Aspartate Aminotransferases/blood ; Benzoquinones/*pharmacology ; Biomarkers/blood ; Cytoprotection ; Disease Models, Animal ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Liver/*drug effects/metabolism/pathology ; Liver Diseases/metabolism/pathology/*prevention &amp; control ; Male ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Oxidative Stress/*drug effects ; Peroxidase/metabolism ; Rats, Wistar ; Reperfusion Injury/metabolism/pathology/*prevention &amp; control ; Signal Transduction/*drug effects ; }, abstract = {Oxidative and nitrosative stress-induced endothelial cell damage play an essential role in the pathogenesis of hepatic ischemia-reperfusion (IR) injury. IR is associated with reduced eNOS expression and exacerbated by superimposed stress. NOSTRIN induces intracellular endothelial nitric oxide synthase (eNOS) translocation and inducible nitric oxide synthase (iNOS) increases nitric oxide (NO) production. Our aim was to assess hepatic expression of iNOS, eNOS, and NOSTRIN in IR with or without N-acetylcysteine (NAC) or thymoquinone (TQ) pretreatment and to compare their hepatoprotective effects. Surgical induction of IR was performed by occlusion of hepatic pedicle for 30 min with mini-clamp and reperfused for 30 min. The effects of TQ (20 mg/kg/day) or NAC (300 mg/kg/day) administered orally for 10 days were evaluated by serum ALT and AST, oxidative stress parameters, NO production, and histopathological analysis. Also, localization and expression of iNOS, eNOS, and NOSTRIN were assessed by immunofluorescence. TQ or NAC pretreatment significantly decreased elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and myeloperoxidase (MPO) activities, malondialdehyde (MDA) level, and NO production. In addition, they restored the depleted GSH content and alleviated histopathological changes. Furthermore, they up-regulated eNOS and down-regulated iNOS and NOSTRIN expressions. TQ exerts its hepatoprotective effect, at least in part, by nitric oxide signaling pathway through modulation of iNOS, eNOS, and NOSTRIN expressions as well as suppression of oxidative stress.}, }
@article {pmid27715338, year = {2017}, author = {Mani, A and Staikou, C and Karmaniolou, I and Orfanos, N and Mylonas, A and Nomikos, T and Pafiti, A and Papalois, A and Arkadopoulos, N and Smyrniotis, V and Theodoraki, K}, title = {N-Acetylcysteine and Desferoxamine Reduce Pulmonary Oxidative Stress Caused by Hemorrhagic Shock in a Porcine Model.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {30}, number = {1}, pages = {33-40}, doi = {10.1080/08941939.2016.1215580}, pmid = {27715338}, issn = {1521-0553}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Biomarkers/analysis ; Colloids ; Crystalloid Solutions ; Deferoxamine/administration &amp; dosage/*therapeutic use ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Fluid Therapy/methods ; Free Radical Scavengers/*therapeutic use ; Glutathione Peroxidase/analysis ; Humans ; Infusions, Intravenous ; Isotonic Solutions/administration &amp; dosage ; Lung/enzymology/*metabolism/pathology ; Male ; Oxidative Stress/*drug effects ; Protein Carbonylation/drug effects ; Random Allocation ; Rehydration Solutions/administration &amp; dosage ; Shock, Hemorrhagic/complications/*drug therapy ; Siderophores/*therapeutic use ; Swine ; Thiobarbituric Acid Reactive Substances/analysis ; }, abstract = {AIM OF THE STUDY: To investigate the pulmonary oxidative stress and possible protective effect of N-Acetylcysteine (NAC) and Desferoxamine (DFX)in a porcine model subjected to hemorrhagic shock.<br><br>MATERIALS AND METHODS: Twenty-one pigs were randomly allocated to Group-A (sham, n = 5), Group-B (fluid resuscitation, n = 8) and Group-C (fluid, NAC and DFX resuscitation, n = 8). Groups B and C were subjected to a 40-min shock period induced by liver trauma, followed by a 60-min resuscitation period. During shock, the mean arterial pressure (MAP) was maintained at 30-40 mmHg. Resuscitation consisted of crystalloids (35&#xa0;mL/kg) and colloids (18&#xa0;mL/kg) targeting to MAP normalization (baseline values &#xb1; 10%). In addition, Group-C received pretreatment with NAC 200&#xa0;mg/kg plus DFX 2&#xa0;g as intravenous infusions. Thiobarbituric Acid Reactive Substances (TBARS), protein carbonyls and glutathione peroxidase (GPx) activity were determined in lung tissue homogenates. Also, histological examination of pulmonary tissue specimens was performed.<br><br>RESULTS: TBARS were higher in Group-B than in Group-A or Group-C: 2.90 &#xb1; 0.47, 0.57 &#xb1; 0.10, 1.78 &#xb1; 0.47 pmol/&#x3bc;g protein, respectively (p < 0.05). Protein carbonyls content was higher in Group-B than in Group-A or Group-C: 3.22 &#xb1; 0.68, 0.89 &#xb1; 0.30, 1.95 &#xb1; 0.54 nmol/mg protein, respectively (p > 0.05). GPx activity did not differ significantly between the three groups (p > 0.05). Lung histology was improved in Group-C versus Group-B, with less alveolar collapse, interstitial edema and inflammation.<br><br>CONCLUSION: NAC plus DFX prevented the increase of pulmonary oxidative stress markers and protein damage after resuscitated hemorrhagic shock and had beneficial effect on lung histology. NAC/DFX combination may be used in the multimodal treatment of hemorrhagic shock, since it may significantly prevent free radical injury in the lung.}, }
@article {pmid27714634, year = {2017}, author = {Sharma, AK and Singh, V and Gera, R and Purohit, MP and Ghosh, D}, title = {Zinc Oxide Nanoparticle Induces Microglial Death by NADPH-Oxidase-Independent Reactive Oxygen Species as well as Energy Depletion.}, journal = {Molecular neurobiology}, volume = {54}, number = {8}, pages = {6273-6286}, pmid = {27714634}, issn = {1559-1182}, support = {BSC0112//Council of Scientific and Industrial Research/ ; BSC0111//Council of Scientific and Industrial Research/ ; }, mesh = {Acetophenones/pharmacology ; Animals ; Apoptosis/drug effects ; Cell Death/*drug effects ; Cell Line ; Enzyme Inhibitors/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/*administration &amp; dosage ; Mice ; Microglia/*drug effects/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; Onium Compounds/pharmacology ; Oxidative Stress/drug effects ; Pyruvic Acid/pharmacology ; Reactive Oxygen Species/*metabolism ; Zinc Oxide/*administration &amp; dosage ; }, abstract = {Zinc oxide nanoparticle (ZnO-NP) is one of the most widely used engineered nanoparticles. Upon exposure, nanoparticle can eventually reach the brain through various routes, interact with different brain cells, and alter their activity. Microglia is the fastest glial cell to respond to any toxic insult. Nanoparticle exposure can activate microglia and induce neuroinflammation. Simultaneous to activation, microglial death can exacerbate the scenario. Therefore, we focused on studying the effect of ZnO-NP on microglia and finding out the pathway involved in the microglial death. The present study showed that the 24 h inhibitory concentration 50 (IC50) of ZnO-NP for microglia is 6.6 μg/ml. Early events following ZnO-NP exposure involved increase in intracellular calcium level as well as reactive oxygen species (ROS). Neither of NADPH oxidase inhibitors, apocynin, (APO) and diphenyleneiodonium chloride (DPIC) were able to reduce the ROS level and rescue microglia from ZnO-NP toxicity. In contrary, N-acetyl cysteine (NAC) showed opposite effect. Exogenous supplementation of superoxide dismutase (SOD) reduced ROS significantly even beyond control level but partially rescued microglial viability. Interestingly, pyruvate supplementation rescued microglia near to control level. Following 10 h of ZnO-NP exposure, intracellular ATP level was measured to be almost 50 % to the control. ZnO-NP-induced ROS as well as ATP depletion both disturbed mitochondrial membrane potential and subsequently triggered the apoptotic pathway. The level of apoptosis-inducing proteins was measured by western blot analysis and found to be upregulated. Taken together, we have deciphered that ZnO-NP induced microglial apoptosis by NADPH oxidase-independent ROS as well as ATP depletion.}, }
@article {pmid27709431, year = {2017}, author = {Zhang, L and Wei, J and Ren, L and Zhang, J and Yang, M and Jing, L and Wang, J and Sun, Z and Zhou, X}, title = {Endosulfan inducing apoptosis and necroptosis through activation RIPK signaling pathway in human umbilical vascular endothelial cells.}, journal = {Environmental science and pollution research international}, volume = {24}, number = {1}, pages = {215-225}, pmid = {27709431}, issn = {1614-7499}, mesh = {Acetylcysteine/metabolism ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Endosulfan/*toxicity ; Endothelial Cells/*drug effects ; Humans ; Insecticides/*toxicity ; Interleukin-33/metabolism ; MAP Kinase Kinase Kinases ; Necrosis ; Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Endosulfan, an organochlorine pesticide, was found in human blood, and its possible cardiovascular toxicity has been suggested. However, the mechanism about endothelial cell injuries induced by endosulfan has remained unknown. In the present study, human umbilical vein endothelial cells (HUVECs) were chosen to explore the toxicity mechanism and were treated with 0, 1, 6, and 12 μg/mL[-1] endosulfan for 24 h, respectively. The results showed that exposure to endosulfan could inhibit the cell viability, increase the release of lactate dehydrogenase (LDH), damage the ultrastructure, and lead to apoptosis and necroptosis in HUVECs. Furthermore, endosulfan upregulated the expressions of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), mixed lineage kinase domain-like (MLKL), caspase 8, and caspase 3, which means the activation of RIPK1 pathways. In addition, endosulfan promoted the increases of ROS, IL-1α, and IL-33 levels while antioxidant N-acetyl-L-cysteine (NAC) effectively attenuated the cytotoxicity from endosulfan. Taken together, these results have demonstrated that endosulfan induces the apoptosis and necroptosis of HUVECs, where the RIPK pathway plays a pro-necroptotic role and NAC plays an anti-necroptotic role. Our results may contribute to understanding cellular mechanisms for endosulfan-induced cardiovascular toxicity.}, }
@article {pmid27709270, year = {2017}, author = {Wang, HC and Zhou, Y and Huang, SK}, title = {SHP-2 phosphatase controls aryl hydrocarbon receptor-mediated ER stress response in mast cells.}, journal = {Archives of toxicology}, volume = {91}, number = {4}, pages = {1739-1748}, doi = {10.1007/s00204-016-1861-1}, pmid = {27709270}, issn = {1432-0738}, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 4/metabolism ; Animals ; Antioxidants/pharmacology ; Calcium Signaling ; Carbazoles/pharmacology ; Endoplasmic Reticulum Stress/*drug effects ; Gene Knockdown Techniques ; Humans ; Mast Cells/drug effects/*metabolism ; Mice ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/*metabolism ; Signal Transduction/drug effects ; eIF-2 Kinase/metabolism ; }, abstract = {Previously we reported that exposure of mouse and human mast cells to aryl hydrocarbon receptor (AhR) ligands resulted in reactive oxygen species (ROS)- and calcium (Ca[2+])-dependent activation of mast cells in vitro and in vivo. However, the mechanisms through which the AhR-ligand axis mediates stress response, Ca[2+] signaling and subsequent mast cell activation remain to be fully elucidated. Evidence is provided herein that SHP-2 is critical in regulating AhR-mediated ER stress response and intracellular Ca[2+] dynamics. We found that an AhR ligand, FICZ, induced significant reduction of intracellular GSH and an increased level of intracellular ROS. Significantly, we showed that in FICZ-treated mast cells, SHP-2 promoted, in a ROS-dependent manner, ER stress response involving primarily the PERK signaling pathway, ATF4 activation and eIF2α phosphorylation, which could be reversed by the addition of an antioxidant, NAC, and was inhibited in cells with SHP-2 knockdown. Our findings suggested that SHP-2 is critical in controlling ER stress signals in response to AhR activation, which provides a new mechanistic insight into how the AhR-ligand axis regulates cellular adaptation to the environmental insult in mast cells.}, }
@article {pmid27709231, year = {2016}, author = {Hara, J and Shankle, WR and Barrentine, LW and Curole, MV}, title = {Novel Therapy of Hyperhomocysteinemia in Mild Cognitive Impairment, Alzheimer's Disease, and Other Dementing Disorders.}, journal = {The journal of nutrition, health &amp; aging}, volume = {20}, number = {8}, pages = {825-834}, pmid = {27709231}, issn = {1760-4788}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; Case-Control Studies ; Cognitive Dysfunction/*drug therapy ; Dementia/*drug therapy ; Female ; Humans ; Hyperhomocysteinemia/*therapy ; Prospective Studies ; Treatment Outcome ; }, abstract = {OBJECTIVES: Studies have produced conflicting results assessing hyperhomocysteinemia (HYH) treatment with B vitamins in patients with normal cognition, Alzheimer's disease and related disorders (ADRD). This study examined the effect of HYH management with L-methylfolate (LMF), methylcobalamin (MeCbl; B12), and N-acetyl-cysteine (CFLN: Cerefolin®/Cerefolin-NAC®) on cognitive decline.<br><br>DESIGN: Prospective, case-control study of subjects followed longitudinally.<br><br>SETTING: Outpatient clinic for cognitive disorders.<br><br>PARTICIPANTS: 116 ADRD patients (34 with HYH, 82 with No-HYH) met inclusion and exclusion criteria to participate. No study participant took B vitamins.<br><br>INTERVENTION: HYH patients received CFLN, and No-HYH patients did not.<br><br>MEASUREMENTS: Cognitive outcome measures included MCI Screen (memory), CERAD Drawings (constructional praxis), Ishihara Number Naming (object recognition), Trails A and B (executive function), and F-A-S test (verbal fluency). Dependent or predictor measures included demographics, functional severity, CFLN and no CFLN treatment duration, ADRD diagnosis, memantine and cholinesterase inhibitor treatment. Linear mixed effects models with covariate adjustment were used to evaluate rate of change on cognitive outcomes.<br><br>RESULTS: The duration of CFLN treatment, compared to an equivalent duration without CFLN treatment, significantly slowed decline in learning and memory, constructional praxis, and visual-spatial executive function (Trails B). CFLN treatment slowed cognitive decline significantly more for patients with milder baseline severity. CFLN treatment effect increased as baseline functional severity decreased. The analytical model showed that treatment duration must exceed some minimum period of at least one year to slow the rate of cognitive decline.<br><br>CONCLUSION: After covariate adjustment, HYH+CFLN significantly slowed cognitive decline compared to No-HYH+No-CFLN. Longer CFLN treatment duration, milder baseline severity, and magnitude of homocysteine reduction from baseline were all significant predictors. There are a number of factors that could account for disagreement with other clinical trials of B vitamin treatment of HYH. Moreover, CFLN is chemically distinct from commonly used B vitamins as both LMF and MeCbl are the fully reduced and bioactive functional forms; CLFN also contains the glutathione precursor, N-acetyl-cysteine. The findings of other B vitamin trials of HYH can, therefore, only partly account for treatment effects of CFLN. These findings warrant further evaluation with a randomized, placebo-controlled trial.}, }
@article {pmid27707552, year = {2017}, author = {Su, X and Xie, X and Liu, L and Lv, J and Song, F and Perkovic, V and Zhang, H}, title = {Comparative Effectiveness of 12 Treatment Strategies for Preventing Contrast-Induced Acute Kidney Injury: A Systematic Review and Bayesian Network Meta-analysis.}, journal = {American journal of kidney diseases : the official journal of the National Kidney Foundation}, volume = {69}, number = {1}, pages = {69-77}, doi = {10.1053/j.ajkd.2016.07.033}, pmid = {27707552}, issn = {1523-6838}, mesh = {Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Bayes Theorem ; Contrast Media/*adverse effects ; Humans ; *Network Meta-Analysis ; Treatment Outcome ; }, abstract = {BACKGROUND: To simultaneously evaluate the relative efficacy of multiple pharmacologic strategies for preventing contrast-induced acute kidney injury (AKI).<br><br>STUDY DESIGN: Systematic review containing a Bayesian network meta-analysis of randomized controlled trials.<br><br>SETTING &amp; POPULATION: Participants undergoing diagnostic and/or interventional procedures with contrast media.<br><br>Randomized controlled trials comparing the active drug treatments with each other or with hydration alone.<br><br>INTERVENTION: Any of the following drugs in combination with hydration: N-acetylcysteine (NAC), theophylline (aminophylline), fenoldopam, iloprost, alprostadil, prostaglandin E1, statins, statins plus NAC, bicarbonate sodium, bicarbonate sodium plus NAC, ascorbic acid (vitamin C), tocopherol (vitamin E), &#x3b1;-lipoic acid, atrial natriuretic peptide, B-type natriuretic peptide, and carperitide.<br><br>OUTCOMES: The occurrence of contrast-induced AKI.<br><br>RESULTS: The trial network included 150 trials with 31,631 participants and 4,182 contrast-induced AKI events assessing 12 different interventions. Compared to hydration, ORs (95% credible intervals) for contrast-induced AKI were 0.31 (0.14-0.60) for high-dose statin plus NAC, 0.37 (0.19-0.64) for high-dose statin alone, 0.37 (0.17-0.72) for prostaglandins, 0.48 (0.26-0.82) for theophylline, 0.62 (0.40-0.88) for bicarbonate sodium plus NAC, 0.67 (0.54-0.81) for NAC alone, 0.64 (0.41-0.95) for vitamins and analogues, 0.70 (0.29-1.37) for natriuretic peptides, 0.69 (0.31-1.37) for fenoldopam, 0.78 (0.59-1.01) for bicarbonate sodium, and 0.98 (0.41-2.07) for low-dose statin. High-dose statin plus NAC or high-dose statin alone were likely to be ranked the best or the second best for preventing contrast-induced AKI. The overall results were not materially changed in metaregressions or subgroup and sensitivity analyses.<br><br>LIMITATIONS: Patient-level data were unavailable; unable to include some treatment agents; low event rates; imbalanced distribution of participants among treatment strategies.<br><br>CONCLUSIONS: High-dose statins plus hydration with or without NAC might be the preferred treatment strategy to prevent contrast-induced AKI in patients undergoing diagnostic and/or interventional procedures requiring contrast media.}, }
@article {pmid27704156, year = {2017}, author = {Romero, A and Ramos, E and Ares, I and Castellano, V and Martínez, M and Martínez-Larrañaga, MR and Anadón, A and Martínez, MA}, title = {Oxidative stress and gene expression profiling of cell death pathways in alpha-cypermethrin-treated SH-SY5Y cells.}, journal = {Archives of toxicology}, volume = {91}, number = {5}, pages = {2151-2164}, doi = {10.1007/s00204-016-1864-y}, pmid = {27704156}, issn = {1432-0738}, mesh = {Antioxidants/pharmacology ; Cell Death/drug effects/genetics ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Profiling ; Gene Expression Regulation/*drug effects ; Humans ; Insecticides/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; Neurons/*drug effects/pathology ; Neurotoxicity Syndromes/pathology ; Nitric Oxide/metabolism ; Oxidative Stress/*drug effects ; Pyrethrins/*toxicity ; }, abstract = {In this study, we investigated the induction of oxidative stress and apoptosis in human neuroblastoma cell line SH-SY5Y in response to alpha-cypermethrin (α-CYPER) exposure. MTT and LDH assays were carried out to assess the α-CYPER cytotoxicity. The IC50 value for α-CYPER was calculated to be 78.3 ± 2.98 µM for the MTT assay and 71.5 ± 3.94 µM for LDH assay. The pyrethroid α-CYPER (1-100 µM), in a dose-dependent manner, induced a significant increase in lipid peroxides measured as malondialdehyde (MDA) and in the levels of nitric oxide (NO). The neuroprotective role of three antioxidants, melatonin (MEL), Trolox and N-acetylcysteine (NAC) against α-CYPER-induced oxidative stress was examined. Compared to other antioxidants, MEL (1 µM) treatment showed the most effective protection against α-CYPER-induced lipid peroxidation and NO production. The effects of α-CYPER on gene expression profiling of cell death pathway in human neuroblastoma SH-SY5Y cells were also investigated. Of the 84 genes examined (P < 0.001; fold change >1.5), changes in mRNA levels were detected in 39 genes: 36 were up-regulated and 3 were down-regulated. A greater fold change reversion than 3.5-fold was observed on the up-regulated ATP6V1G2, BCL2, CASP9, FAS, GADD45A, SPATA2, SYCP2, ATG7, NFKB1, SNCA, ULK1 and JPH3 genes. The results demonstrated that α-CYPER alters the expression of apoptosis-, autophagy- and necrosis genes as well as induces oxidative stress which may lead to DNA damage. The detailed knowledge of the changes in gene expression obtained will provide a basis for further elucidating the molecular mechanisms of the α-CYPER-induced toxicity.}, }
@article {pmid27692686, year = {2016}, author = {Motawei, SM and Attalla, SM and Gouda, HE and Harouny, MA and Elmansoury, AM}, title = {The effects of N-acetyl cysteine on oxidative stress among patients with pre-eclampsia.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {135}, number = {2}, pages = {226-227}, doi = {10.1016/j.ijgo.2016.07.002}, pmid = {27692686}, issn = {1879-3479}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Antihypertensive Agents/therapeutic use ; Apgar Score ; Birth Weight ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Infant, Newborn ; Methyldopa/therapeutic use ; Oxidative Stress/*drug effects ; Pre-Eclampsia/*drug therapy ; Pregnancy ; Pregnancy Outcome ; Treatment Outcome ; }, }
@article {pmid27692298, year = {2016}, author = {Oommen, D and Dodd, NJ and Yiannakis, D and Moyeed, R and Jha, AN}, title = {Linking genotoxicity and cytotoxicity with membrane fluidity: A comparative study in ovarian cancer cell lines following exposure to auranofin.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {809}, number = {}, pages = {43-49}, doi = {10.1016/j.mrgentox.2016.09.003}, pmid = {27692298}, issn = {1879-3592}, mesh = {Antirheumatic Agents/*pharmacology ; Apoptosis/*drug effects ; Auranofin/*pharmacology ; DNA Damage/*drug effects ; Female ; Humans ; Membrane Fluidity/*drug effects ; Mutagenicity Tests/*methods ; Ovarian Neoplasms/drug therapy/*pathology ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, abstract = {Auranofin, an organogold compound classified as an anti-rheumatic agent is under phase 2 clinical trials for re-purposing to treat recurrent epithelial ovarian cancer. We have reported earlier that Breast cancer 1, early onset (BRCA1) mutant ovarian cancer cells exhibit increased sensitivity to auranofin. BRCA1 is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from DNA repair capability of cancer cells, membrane fluidity is also implicated in modulating resistance to chemotherapeutics. We report here that membrane fluidity influences the sensitivity of ovarian cancer cell lines, OVCAR5 and IGROV1, to auranofin. Electron spin resonance (ESR) analysis revealed a more fluidized membrane in IGROV1 compared to OVCAR5. Interestingly, IGROV1 cells were more sensitive to auranofin induced cytotoxicity than OVCAR5. In comparison to OVCAR5, IGROV1 cells also exhibited an increased number of DNA double strand breaks (DSBs) upon auranofin treatment as assessed by 53BP1 immunostaining. Furthermore, correlation analysis demonstrated a strong positive correlation (r=0.856) between membrane fluidity and auranofin sensitivity in these cell lines. Auranofin-treated IGROV1 cells also exhibited increased cellular oxidation and apoptosis. Anti-oxidant, N-acetyl cysteine (NAC) inhibited the cellular oxidation and apoptosis in auranofin-treated ovarian cancer cells suggesting reactive oxygen species (ROS) mediate the anti-cancer properties of auranofin. Overall, our study suggests that auranofin mediates its cytotoxicity via ROS production in ovarian cancer cells which correlates positively with membrane fluidity.}, }
@article {pmid27692001, year = {2016}, author = {Shi, X and Li, D and Deng, Q and Peng, Z and Zhao, C and Li, X and Wang, Z and Li, X and Liu, G}, title = {Acetoacetic acid induces oxidative stress to inhibit the assembly of very low density lipoprotein in bovine hepatocytes.}, journal = {The Journal of dairy research}, volume = {83}, number = {4}, pages = {442-446}, doi = {10.1017/S0022029916000546}, pmid = {27692001}, issn = {1469-7629}, mesh = {Acetoacetates/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/analysis ; *Cattle ; Cells, Cultured ; China ; Female ; Gene Expression/drug effects ; Hepatocytes/chemistry/drug effects/*metabolism ; Lipoproteins, VLDL/*biosynthesis ; Oxidative Stress/*drug effects ; RNA, Messenger/analysis ; Triglycerides/metabolism ; }, abstract = {Dairy cows with fatty liver or ketosis exhibit hyperketonemia, oxidative stress, and a low rate of very low density lipoprotein (VLDL) assembly, and there may be a potential link among these characteristics. Therefore, the objective of this study was to determine the effect of acetoacetic acid (AcAc) on the assembly of VLDL in cow hepatocytes. Cultured cow hepatocytes were treated with different concentrations of AcAc with or without N-acetylcysteine (NAC, an antioxidant). AcAc treatment decreased the mRNA expression and activities of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and significantly increased malondialdehyde (MDA) content, indicative of oxidative stress. Furthermore, AcAc treatment significantly down-regulated the mRNA expression of apolipoprotein B100 (ApoB100), apolipoprotein E (ApoE), and low density lipoprotein receptor (LDLR), which thus decreased VLDL assembly and increased triglyceride (TG) accumulation in these bovine hepatocytes. Importantly, NAC relieved AcAc-induced oxidative stress and increased VLDL assembly. In summary, these results suggest that AcAc-induced oxidative stress affects the assembly of VLDL, which increases TG accumulation in bovine hepatocytes.}, }
@article {pmid27690697, year = {2017}, author = {Zeren, S and Bayhan, Z and Koçak, C and Koçak, FE and Metineren, MH and Savran, B and Kocak, H and Algin, MC and Kahraman, C and Kocak, A and Cosgun, S}, title = {Antioxidant Effect of Ukrain Versus N-Acetylcysteine Against Acute Biliary Pancreatitis in An Experimental Rat Model.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {30}, number = {2}, pages = {116-124}, doi = {10.1080/08941939.2016.1230247}, pmid = {27690697}, issn = {1521-0553}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Alanine Transaminase/blood ; Amylases/blood ; Animals ; Antioxidants/administration &amp; dosage/adverse effects/*therapeutic use ; Aspartate Aminotransferases/blood ; Berberine Alkaloids/administration &amp; dosage/adverse effects/*therapeutic use ; Biliary Tract/*drug effects ; Bilirubin/blood ; Disease Models, Animal ; Humans ; Lipase/blood ; Male ; Malondialdehyde/blood ; Nitric Oxide/metabolism ; Oxidants/blood ; Oxidative Stress/drug effects ; Pancreas/metabolism/pathology ; Pancreatitis/blood/*drug therapy/metabolism/pathology ; Peroxidase/metabolism ; Phenanthridines/administration &amp; dosage/adverse effects/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {UNLABELLED: Purpose/Aim: Oxidative stress plays an important role in the pathogenesis of acute pancreatitis (AP). We compared the therapeutic effects of Ukrain (NSC 631570) and N-acetylcysteine (NAC) in rats with AP.<br><br>MATERIALS AND METHODS: Forty male Sprague Dawley rats were divided into four groups: controls; AP; AP with NAC; and AP with Ukrain. AP was induced via the ligation of the bile-pancreatic duct; drugs were administered intraperitoneally (i.p.) 30&#xa0;min and 12&#xa0;h after AP induction. Twenty-four hours after AP induction, animals were sacrificed and the pancreas was excised. Levels of malondialdehyde (MDA) and nitric oxide (NO), and activity levels of tumor necrosis factor (TNF)-&#x3b1;, and myeloperoxidase (MPO) were measured in tissue samples. Total oxidant status (TOS), total antioxidant status (TAS), and total bilirubin, as well as activity levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase and lipase were measured in serum samples. Pancreatic tissue histopathology was also evaluated.<br><br>RESULTS: Test drugs reduced levels of MDA, NO, TNF-&#x3b1;, total bilirubin, AST, ALT, TOS and MPO, amylase and lipase activities (P < 0.001), and increased TAS (P < 0.001). Rats treated with test drugs attenuated AP-induced morphologic changes and decreased pancreatic damage scores compared with the AP group (P < 0.05). Both test drugs attenuated pancreatic damage, but the therapeutic effect was more pronounced in rats that received Ukrain than in those receiving NAC.<br><br>CONCLUSIONS: These results suggest that treatment with Ukrain or NAC can reduce pancreatic damage via anti-inflammatory and antioxidant effects.}, }
@article {pmid27687220, year = {2016}, author = {Thomas, NO and Shay, KP and Kelley, AR and Butler, JA and Hagen, TM}, title = {Glutathione maintenance mitigates age-related susceptibility to redox cycling agents.}, journal = {Redox biology}, volume = {10}, number = {}, pages = {45-52}, pmid = {27687220}, issn = {2213-2317}, support = {P01 AT002034/AT/NCCIH NIH HHS/United States ; R01 AG017141/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aging/*metabolism ; Animals ; Gene Expression Regulation, Developmental/drug effects ; Glutathione/*metabolism ; Glutathione Peroxidase/metabolism ; Hepatocytes/cytology/*drug effects/metabolism ; Lipid Peroxidation/drug effects ; Male ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; Oxidation-Reduction/*drug effects ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Rats ; Rats, Inbred F344 ; Vitamin K 3/*toxicity ; }, abstract = {Isolated hepatocytes from young (4-6mo) and old (24-26mo) F344 rats were exposed to increasing concentrations of menadione, a vitamin K derivative and redox cycling agent, to determine whether the age-related decline in Nrf2-mediated detoxification defenses resulted in heightened susceptibility to xenobiotic insult. An LC50 for each age group was established, which showed that aging resulted in a nearly 2-fold increase in susceptibility to menadione (LC50 for young: 405μM; LC50 for old: 275μM). Examination of the known Nrf2-regulated pathways associated with menadione detoxification revealed, surprisingly, that NAD(P)H: quinone oxido-reductase 1 (NQO1) protein levels and activity were induced 9-fold and 4-fold with age, respectively (p=0.0019 and p=0.018; N=3), but glutathione peroxidase 4 (GPX4) declined by 70% (p=0.0043; N=3). These results indicate toxicity may stem from vulnerability to lipid peroxidation instead of inadequate reduction of menadione semi-quinone. Lipid peroxidation was 2-fold higher, and GSH declined by a 3-fold greater margin in old versus young rat cells given 300µM menadione (p<0.05 and p≤0.01 respectively; N=3). We therefore provided 400µMN-acetyl-cysteine (NAC) to hepatocytes from old rats before menadione exposure to alleviate limits in cysteine substrate availability for GSH synthesis during challenge. NAC pretreatment resulted in a >2-fold reduction in cell death, suggesting that the age-related increase in menadione susceptibility likely stems from attenuated GSH-dependent defenses. This data identifies cellular targets for intervention in order to limit age-related toxicological insults to menadione and potentially other redox cycling compounds.}, }
@article {pmid27683245, year = {2017}, author = {Desjardins, D and Cacho-Valadez, B and Liu, JL and Wang, Y and Yee, C and Bernard, K and Khaki, A and Breton, L and Hekimi, S}, title = {Antioxidants reveal an inverted U-shaped dose-response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans.}, journal = {Aging cell}, volume = {16}, number = {1}, pages = {104-112}, pmid = {27683245}, issn = {1474-9726}, mesh = {Acetylcysteine/pharmacology ; Aging/drug effects/*physiology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Caenorhabditis elegans/drug effects/*physiology ; Longevity/drug effects ; Mitochondria/drug effects/metabolism ; Models, Biological ; Mutation/genetics ; Oxidative Stress/drug effects ; Paraquat/pharmacology ; Reactive Oxygen Species/*metabolism ; Resveratrol ; Stilbenes/pharmacology ; Superoxide Dismutase/metabolism ; }, abstract = {Reactive oxygen species (ROS) are potentially toxic, but they are also signaling molecules that modulate aging. Recent observations that ROS can promote longevity have to be reconciled with the numerous claims about the benefits of antioxidants on lifespan. Here, three antioxidants [N-acetylcysteine (NAC), vitamin C, and resveratrol (RSV)] were tested on Caenorhabditis elegans mutants that alter drug uptake, mitochondrial function, and ROS metabolism. We observed that like pro-oxidants, antioxidants can both lengthen and shorten lifespan, dependent on concentration, genotypes, and conditions. The effects of antioxidants thus reveal an inverted U-shaped dose-response relationship between ROS levels and lifespan. In addition, we observed that RSV can act additively to both NAC and paraquat, to dramatically increase lifespan. This suggests that the effect of compounds that modulate ROS levels can be additive when their loci of action or mechanisms of action are sufficiently distinct.}, }
@article {pmid27683025, year = {2017}, author = {Clanton, RM and Wu, G and Akabani, G and Aramayo, R}, title = {Control of seizures by ketogenic diet-induced modulation of metabolic pathways.}, journal = {Amino acids}, volume = {49}, number = {1}, pages = {1-20}, doi = {10.1007/s00726-016-2336-7}, pmid = {27683025}, issn = {1438-2199}, mesh = {Amino Acids, Essential/administration &amp; dosage/metabolism ; Aspartic Acid/metabolism ; Demyelinating Diseases/*diet therapy/metabolism/physiopathology ; Diet, Ketogenic/*methods ; Epilepsy/*diet therapy/metabolism/physiopathology ; Fatty Acids, Volatile/administration &amp; dosage/metabolism ; Humans ; Ketone Bodies/metabolism ; Malates/metabolism ; Metabolic Networks and Pathways/*drug effects ; Mitochondria/metabolism ; Monocarboxylic Acid Transporters/metabolism ; Seizures/*diet therapy/metabolism/physiopathology ; }, abstract = {Epilepsy is too complex to be considered as a disease; it is more of a syndrome, characterized by seizures, which can be caused by a diverse array of afflictions. As such, drug interventions that target a single biological pathway will only help the specific individuals where that drug's mechanism of action is relevant to their disorder. Most likely, this will not alleviate all forms of epilepsy nor the potential biological pathways causing the seizures, such as glucose/amino acid transport, mitochondrial dysfunction, or neuronal myelination. Considering our current inability to test every individual effectively for the true causes of their epilepsy and the alarming number of misdiagnoses observed, we propose the use of the ketogenic diet (KD) as an effective and efficient preliminary/long-term treatment. The KD mimics fasting by altering substrate metabolism from carbohydrates to fatty acids and ketone bodies (KBs). Here, we underscore the need to understand the underlying cellular mechanisms governing the KD's modulation of various forms of epilepsy and how a diverse array of metabolites including soluble fibers, specific fatty acids, and functional amino acids (e.g., leucine, D-serine, glycine, arginine metabolites, and N-acetyl-cysteine) may potentially enhance the KD's ability to treat and reverse, not mask, these neurological disorders that lead to epilepsy.}, }
@article {pmid27682486, year = {2016}, author = {Wang, HQ and Li, T}, title = {[Research on the therapeutic effects of drugs on patients with pneumoconiosis in China].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {34}, number = {7}, pages = {510-516}, doi = {10.3760/cma.j.issn.1001-9391.2016.07.008}, pmid = {27682486}, issn = {1001-9391}, mesh = {Acetylcysteine/*therapeutic use ; Benzylisoquinolines/*therapeutic use ; Bronchoalveolar Lavage ; China ; Forced Expiratory Volume ; Humans ; Pneumoconiosis/*drug therapy ; Pulmonary Fibrosis ; Quinolines/*therapeutic use ; Research ; Respiratory Tract Infections ; *Treatment Outcome ; X-Ray Film ; }, abstract = {Objective: To review the clinical research on the main drugs which are used to treat pneumoconiosis in China, evaluate and analyze the efficacy, and give the suggestions on the study of pneumoconiosis treatment. Methods: The data of researches on the therapeutic effects of eight main drugs on patients with pneumoconiosis in China were retrieved from CNKI and Wanfang database before Jan. 1, 2016 including polyvinylpyridine, tetrandrine, piperaquine phosphate, hydroxypiperaquine phosphate, aluminium citrate, Xinin, Xifeining and N-acetyl cysteine (NAC) after consulting the related project files on the clinical treatment on the patients with pneumoconiosis, and a systematic analysis was made on the random control test (RCT) which conformed to the quality criteria in terms of five indices such as the improvement rate of respiratory system symptoms such as cough, expectoration, chest pain and dyspnea, the decrease of the respiratory system infection rate, the changes in FEV1.0% (forced expired volume in one second to forced vital capacity ratio) (ΔFEV1.0%) , index of stability and improvement rate of chest X-ray, and adverse reactions as well as the summary of descriptive efficacy. Results: Nine RCTs in the 15 papers were included; 2 097 patients with pneumoconiosis were included with 1215 in the treatment group and 882 in the control group. The medication modes were divided into four categories, monotherapy (such as polyvinylpyridine, hydroxypiperaquine phosphate, Xifeining and Xinin) , combination of tetrandrine with other drugs, hydroxypiperaquine phosphate and aluminium citrate, and lung lavage (added medications) ; the analysis indicated that the patients in the treatment group were obviously superior to those in the control group in terms of the improvement rate of respiratory system symptoms, the decrease rate of the respiratory tract infection, ΔFEV1.0%, the improvement rate of shadows as indicated in the X-ray chest film and the index of stability (P<0.01) ; after the mean values of the control group were deducted, the improvement rate of symptoms of the respiratory system within the treatment period of the patients with pneumoconiosis increased by 34.6% (95% CI 32.9%, 36.3%) in average, the mean value of the decrease in the respiratory tract infection rate was 26.0% (95% CI 24.0%, 28.0%) , the mean value of ΔFEV1.0% was 4.08 (95% CI 3.56, 4.60) , the improvement rate in X-ray chest film increased by 8.80% (95% CI 8.55%, 9.05%) in average, and the index of stability in the X-ray chest film increased by 10.6% (95% CI 9.18%, 12.0%) ; one-way analysis of variance indicated the presence of statistical difference in terms of efficacy of four categories of medication modes (Fthe improvement rate of symptoms of the respiratory system=482.2, P<0.01; Fthe decrease in the respiratory tract infection rate=72.01, P<0.01; FΔFEV1.0%=246.6, P<0.01; Fthe index of stability in the X-ray chest film=212.9, P<0.01; Fthe improvement rate of X-ray chest film=466.6, P<0.01) . Conclusion: Drugs such as polyvinylpyridine, tetrandrine, hydroxypiperaquine phosphate, aluminium citrate, Xinin, Xifeining and NAC have some efficacy in the treatment of pneumoconiosis. It is suggested that, in accordance with the mechanism of pneumosilicosis onset and the action mechanism of drugs and on the basis of the research on the traditional drugs, the latest clinical study results and the management experiences on the idiopathic pulmonary interstitial fibrosis be constantly traced and borrowed to strengthen the research on the drugs which are used to treat the pneumoconiosis and the patient health management.}, }
@article {pmid27679792, year = {2016}, author = {Giaglis, S and Hahn, S and Hasler, P}, title = {"The NET Outcome": Are Neutrophil Extracellular Traps of Any Relevance to the Pathophysiology of Autoimmune Disorders in Childhood?.}, journal = {Frontiers in pediatrics}, volume = {4}, number = {}, pages = {97}, pmid = {27679792}, issn = {2296-2360}, abstract = {Neutrophil extracellular trap (NET) formation represents a form of cell death distinct from apoptosis or necrosis, by which invading pathogens are simultaneously entangled and potentially eliminated. Increased NET formation is observed in systemic lupus erythematosus (SLE), rheumatoid arthritis, antineutrophil cytoplasmic antibody-associated small vessel vasculitis, antiphospholipid antibody syndrome (APS), and psoriasis. NETs contribute to the pathogenesis of autoimmunity by exposing cryptic autoepitopes, which may facilitate the generation of autoantibodies, induce the production of interferons, and activate the complement cascade. In SLE, augmented disease activity and renal disease are associated with increased NET formation, so that NETs could serve as a marker for the monitoring of disease activity. NETs can additionally cause endothelial cell damage and death and stimulate inflammation in atheromatous plaques, adding to the accelerated atherosclerosis witnessed in autoimmune disease. Since NETs induce production of interferons, assessing the extent of NET formation might facilitate the prediction of IFN-alpha levels and identification of SLE patients with presumably better responses to anti-IFN-alpha therapies or other novel therapeutic concepts, such as N-acetyl-cysteine and inhibitors of DNase 1 and peptidylarginine deiminase 4 (PAD4), which also target NETs. In summary, the study of NETs provides a novel approach to the understanding of autoimmune disease pathogenesis in childhood and opens new vistas in the development of sensitive disease markers and targeted therapies.}, }
@article {pmid27677293, year = {2017}, author = {Chou, HL and Fong, Y and Wei, CK and Tsai, EM and Chen, JY and Chang, WT and Wu, CY and Huang, HW and Chiu, CC}, title = {A Quinone-Containing Compound Enhances Camptothecin-Induced Apoptosis of Lung Cancer Through Modulating Endogenous ROS and ERK Signaling.}, journal = {Archivum immunologiae et therapiae experimentalis}, volume = {65}, number = {3}, pages = {241-252}, doi = {10.1007/s00005-016-0424-8}, pmid = {27677293}, issn = {1661-4917}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis ; Benzoquinones/chemistry ; Camptothecin/*pharmacology/therapeutic use ; Carcinoma, Non-Small-Cell Lung/*drug therapy ; Caspases/metabolism ; Cell Proliferation ; Drug Resistance, Neoplasm ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Lung Neoplasms/*drug therapy ; MAP Kinase Signaling System ; Mitochondria/*metabolism ; Putrescine/*analogs &amp; derivatives/chemistry/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {The natural compound camptothecin (CPT) derivatives have widely been used for anti-cancer treatments, including lung cancer. However, many chemoresistant cancer cells often develop a relatively higher threshold for inducing apoptosis, causing a limited efficacy of anti-cancer drugs. Likewise, lung cancer cells acquire chemoresistance against CPT analogs, such as irinotecan and topotecan, finally resulting in an unsatisfied outcome and poor prognosis of lung cancer patients. TFPP is a quinone-containing compound as a candidate for CPT-based combination chemotherapy. In this study, we examined the effect of TFPP and CPT cotreatment on non-small cell lung cancer (NSCLC) cells. Cell proliferation and flow cytometry-based Annexin-V/PI staining assays demonstrated the synergistic effect of TFPP on CPT-induced apoptosis in both NSCLC A549 and H1299 cells. The results of CPT and TFPP cotreatment cause the regulation of the ERK-Bim axis and the activation of mitochondrial-mediated caspase cascade, including caspase-9 and caspase-3. Besides, TFPP significantly enhanced CPT-induced endogenous reactive oxygen species (ROS) in the two NSCLC cells. In contrast, the treatment of N-acetyl-L-cysteine (NAC), an ROS scavenger, rescues the apoptosis of NSCLC cells induced by TFPP and CPT cotreatment, suggesting that the synergistic effect of TFPP on CPT-induced anti-NSCLC cells is through upregulating ROS production. Consequently, our results suggest that TFPP sensitizes NSCLC towards CPT-based chemotherapy may act through decreasing the apoptosis-initiating threshold. Therefore, TFPP may be a promising chemosensitizer for lung cancer treatment, and the underlying mechanism warrants further.}, }
@article {pmid27672280, year = {2016}, author = {Rabinowich, L and Wendon, J and Bernal, W and Shibolet, O}, title = {Clinical management of acute liver failure: Results of an international multi-center survey.}, journal = {World journal of gastroenterology}, volume = {22}, number = {33}, pages = {7595-7603}, pmid = {27672280}, issn = {2219-2840}, mesh = {Adult ; Europe ; Female ; Geography ; Hepatic Encephalopathy/*etiology ; Humans ; Intensive Care Units ; International Cooperation ; International Normalized Ratio ; Liver Failure, Acute/diagnosis/mortality/*therapy ; Liver Transplantation/*adverse effects ; Male ; Middle Aged ; Patient Admission ; Referral and Consultation ; Remission Induction ; Surveys and Questionnaires ; Time Factors ; }, abstract = {AIM: To assess the practice of caring for acute liver failure (ALF) patients in varying geographic locations and medical centers.<br><br>METHODS: Members of the European Acute Liver Failure Consortium completed an 88-item questionnaire detailing management of ALF. Responses from 22 transplantation centers in 11 countries were analyzed, treating between 300 and 500 ALF cases and performing over 100 liver transplants (LT) for ALF annually. The questions pertained to details of the institution and their clinical activity, standards of care, referral and admission, ward- based care versus intensive care unit (ICU) as well as questions regarding liver transplantation - including criteria, limitations, and perceived performance. Clinical data was also collected from 13 centres over a 3 mo period.<br><br>RESULTS: The interval between referral and admission of ALF patients to specialized units was usually less than 24 h and once admitted, treatment was provided by a multidisciplinary team. Principles of care of patients with ALF were similar among centers, particularly in relation to recognition of severity and care of the more critically ill. Centers exhibited similarities in thresholds for ICU admission and management of severe hepatic encephalopathy. Over 80% of centers administered n-acetyl-cysteine to ICU patients for non-paracetamol-related ALF. There was significant divergence in the use of prophylactic antibiotics and anti-fungals, lactulose, nutritional support and imaging investigations in admitted patients and in the monitoring and treatment of intra-cranial pressure (ICP). ICP monitoring was employed in 12 centers, with the most common indications being papilledema and renal failure. Most patients listed for transplantation underwent surgery within an average waiting time of 1-2 d. Over a period of 3 mo clinical data from 85 ALF patients was collected. Overall patient survival at 90-d was 76%. Thirty six percent of patients underwent emergency LT, with a 90% post transplant survival to hospital discharge, 42% survived with medical management alone.<br><br>CONCLUSION: Alongside similarities in principles of care of ALF patients, major areas of divergence were present in key areas of diagnosis, monitoring, treatment and decision to transplant.}, }
@article {pmid27671463, year = {2016}, author = {Schweikl, H and Widbiller, M and Krifka, S and Klement, J and Petzel, C and Bolay, C and Hiller, KA and Buchalla, W}, title = {Interaction between LPS and a dental resin monomer on cell viability in mouse macrophages.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {32}, number = {12}, pages = {1492-1503}, doi = {10.1016/j.dental.2016.09.009}, pmid = {27671463}, issn = {1879-0097}, mesh = {Animals ; Apoptosis/drug effects ; Cell Line ; *Cell Survival ; Macrophages ; Methacrylates/*toxicity ; Mice ; Reactive Oxygen Species ; Resins, Synthetic/*toxicity ; }, abstract = {OBJECTIVE: Lipopolysaccharide (LPS) from cariogenic microorganisms and resin monomers like HEMA (2-hydroxyethyl methacrylate) included in dentin adhesive are present in a clinical situation in deep dentinal cavity preparations. Here, cell survival, expression of proteins related to redox homeostasis, and viability of mouse macrophages exposed to LPS and HEMA were analyzed with respect to the influence of oxidative stress.<br><br>METHODS: Cell survival of RAW264.7 mouse macrophages was determined using a crystal violet assay, protein expression was detected by Western blotting, and HEMA- or LPS-induced apoptosis (cell viability) was analyzed by flow cytometry. Cells were exposed to HEMA (0-8mM), LPS (0.1&#x3bc;g/ml) or combinations of both substances for 24h. The influence of mitogen-activated protein kinases (MAPK) was analyzed using the specific inhibitors PD98059 (ERK1/2), SB203580 (p38) or SP600125 (JNK), and oxidative stress was identified by the antioxidant N-acetylcysteine (NAC).<br><br>RESULTS: Cell survival was reduced by HEMA. LPS, however, increased cell survival from 29% in cultures exposed to 8mM HEMA, to 46% in cultures co-exposed to 8mM HEMA/LPS. Notably, LPS-induced apoptosis was neutralized by 4-6mM HEMA but apoptosis caused by 8mM HEMA was counteracted by LPS. Expression of NOS (nitric oxide synthase), p47[phox] and p67[phox] subunits of NADPH oxidase, catalase or heme oxygenase (HO-1) was associated with HEMA- or LPS-induced apoptosis. While no influence of MAPK was detected, NAC inhibited cytotoxic effects of HEMA.<br><br>SIGNIFICANCE: HEMA- and LPS-triggered pathways may induce apoptosis and interfere with physiological tissue responses as a result of the differential formation of oxidative stress.}, }
@article {pmid27671340, year = {2016}, author = {Ergin, B and Guerci, P and Zafrani, L and Nocken, F and Kandil, A and Gurel-Gurevin, E and Demirci-Tansel, C and Ince, C}, title = {Effects of N-acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia.}, journal = {Intensive care medicine experimental}, volume = {4}, number = {1}, pages = {29}, pmid = {27671340}, issn = {2197-425X}, abstract = {BACKGROUND: Modulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI).<br><br>METHODS: Rats were randomized into five groups (n&#x2009;=&#x2009;8 per group): (1) control group, (2) control&#x2009;+&#x2009;NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS&#x2009;+&#x2009;fluid resuscitation, and (5) LPS&#x2009;+&#x2009;fluid resuscitation&#x2009;+&#x2009;NAC (150&#xa0;mg/kg/h). Fluid resuscitation was initiated at 120&#xa0;min and maintained at fixed volume for 2&#xa0;h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer's solution (Volulyte) with or without supplementation with NAC (150&#xa0;mg/kg/h). Oxygen tension in the renal cortex (C&#x3bc;PO2), outer medulla (M&#x3bc;PO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues.<br><br>RESULTS: Fluid resuscitation significantly improved the systemic and renal macrohemodynamic parameters after LPS. However, the addition of NAC further improved cortical renal oxygenation, oxygen delivery, and oxygen consumption (p&#x2009;<&#x2009;0.05). NAC supplementation dampened the accumulation of NGAL or L-FABP, hyaluronic acid, and nitric oxide in kidney tissue (p&#x2009;<&#x2009;0.01).<br><br>CONCLUSION: The addition of NAC to fluid resuscitation may improve renal oxygenation and attenuate microvascular dysfunction and AKI. Decreases in renal NO and hyaluronic acid levels may be involved in this beneficial effect. A therapeutic strategy combining initial fluid resuscitation with antioxidant therapies may prevent sepsis-induced AKI.}, }
@article {pmid27670786, year = {2017}, author = {Soto, D and Gomez-Serrano, M and Pieralisi, A and Calvo, JC and Peral, B and Guerra, LN}, title = {N-acetylcysteine inhibits kinase phosphorylation during 3T3-L1 adipocyte differentiation.}, journal = {Redox report : communications in free radical research}, volume = {22}, number = {6}, pages = {265-271}, pmid = {27670786}, issn = {1743-2928}, mesh = {3T3-L1 Cells ; Acetylcysteine/*pharmacology ; Adipocytes/cytology/*drug effects ; Animals ; Antioxidants/*pharmacology ; Cell Differentiation/drug effects ; Mice ; Monoamine Oxidase/metabolism ; Phosphorylation/drug effects ; }, abstract = {OBJECTIVES: Reports investigating the effects of antioxidants on obesity have provided contradictory results. We have previously demonstrated that treatment with the antioxidant N-acetylcysteine (NAC) inhibits cellular triglyceride (Tg) accumulation as well as total cellular monoamine oxidase A (MAOA) expression in 3T3-L1 mature adipocytes (Calzadilla et al., Redox Rep. 2013;210-218). Here we analyzed the role of NAC on adipogenic differentiation pathway.<br><br>METHODS: Assays were conducted using 3T3-L1 preadipocytes (undifferentiated cells: CC), which are capable of differentiating into mature adipocytes (differentiated cells: DC). We studied the effects of different doses of NAC (0.01 or 1&#x2005;mM) on DC, to evaluate cellular expression of phospho-JNK&#xbd; (pJNK&#xbd;), phospho-ERK&#xbd; (pERK&#xbd;) and, mitochondrial expression of citrate synthase, fumarate hydratase and MAOA.<br><br>RESULTS: Following the differentiation of preadipocytes, an increase in the expression levels of pJNK&#xbd; and pERK&#xbd; was observed, together with mitotic clonal expansion (MCE). We found that both doses of NAC decreased the expression of pJNK&#xbd; and pERK&#xbd;. Consistent with these results, NAC significantly inhibited MCE and modified the expression of different mitochondrial proteins.<br><br>DISCUSSION: Our results suggested that NAC could inhibit Tg and mitochondrial protein expression by preventing both MCE and kinase phosphorylation.}, }
@article {pmid27668024, year = {2016}, author = {Greene, SC and Noonan, PK and Sanabria, C and Peacock, WF}, title = {Effervescent N-Acetylcysteine Tablets versus Oral Solution N-Acetylcysteine in Fasting Healthy Adults: An Open-Label, Randomized, Single-Dose, Crossover, Relative Bioavailability Study.}, journal = {Current therapeutic research, clinical and experimental}, volume = {83}, number = {}, pages = {1-7}, pmid = {27668024}, issn = {0011-393X}, abstract = {BACKGROUND: Oral solution N-acetylcysteine (NAC) is an antidote for acetaminophen overdose, but its unpleasant taste and aroma can impede delivery even after the coadministration of antiemetic medications. Flavored effervescent NAC tablets dissolved in water might be a more palatable formulation than oral solution NAC diluted with soft drink.<br><br>OBJECTIVES: To evaluate the relative bioavailability of these 2 formulations and assess subjective preferences between them.<br><br>METHODS: Thirty healthy adult volunteers (mean [SD] = 35.2 [9.14] years) were enrolled in this open-label, randomized, single-dose, crossover study, with a 7-day washout period. Volunteers were randomized to receive 11 g effervescent test formulation or the reference product under fasting conditions, after which 19 serial blood samples were collected over 48 hours. Total plasma NAC concentrations were evaluated by LC-MS, and pharmacokinetic parameters were calculated. The 2 formulations were considered bioequivalent if the 90% CIs of log-transformed ratios of pharmacokinetic parameters were within the predetermined bioequivalence range (80%-125%) established by the US Food and Drug Administration. Within 15 minutes of dosing, subjects were also asked to rank formulation attributes on a 5-point hedonic scale, with mean group differences analyzed by Wilcoxon signed rank test. Safety-profile assessment included treatment-emergent adverse events, physical examination, chemistry, and hematology parameters.<br><br>RESULTS: The concentration-versus-time profiles were similar for the 2 formulations, with mean Cmax of 26.5 &#x3bc;g/mL for effervescent NAC tablets and 28.4 &#x3bc;g/mL for oral solution NAC. The 90% CIs for the pharmacokinetic parameters met the criteria for concluding bioequivalence, and subjects preferred effervescent NAC tablets in terms of taste (P = 0.0247), flavor (P = 0.0082), texture (P = 0.009), and overall likeability (P = 0.0012), but there was no difference for smell (P = 0.0533). All treatment-emergent adverse events were mild, with no differences between the treatment groups.<br><br>CONCLUSIONS: Data from this study of a single dose of 11 g oral NAC demonstrated that effervescent NAC tablets and oral solution NAC met the regulatory criteria for bioequivalence in fasting healthy adult subjects. Effervescent NAC tablets appear to be a more palatable alternative for treatment of acetaminophen overdose. ClinicalTrials.gov identifier: NCT02723669. (Curr Ther Res Clin Exp. 2016; 83C:1-7) &#xa9; 2016 Elsevier HS Journals, Inc.}, }
@article {pmid27665314, year = {2016}, author = {Liu, F and Li, ZF and Wang, ZY and Wang, L}, title = {Role of subcellular calcium redistribution in regulating apoptosis and autophagy in cadmium-exposed primary rat proximal tubular cells.}, journal = {Journal of inorganic biochemistry}, volume = {164}, number = {}, pages = {99-109}, doi = {10.1016/j.jinorgbio.2016.09.005}, pmid = {27665314}, issn = {1873-3344}, mesh = {Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cadmium/*pharmacology ; Calcium/*metabolism ; Endoplasmic Reticulum/*metabolism ; Kidney Tubules, Proximal/cytology/*metabolism ; Rats ; }, abstract = {Ca[2+] signaling plays a vital role in regulating apoptosis and autophagy. We previously proved that cytosolic Ca[2+] overload is involved in cadmium (Cd)-induced apoptosis in rat proximal tubular (rPT) cells, but the source of elevated cytosolic Ca[2+] concentration ([Ca[2+]]c) and the effect of potential subcellular Ca[2+] redistribution on apoptosis and autophagy remain to be elucidated. Firstly, data showed that Cd-induced elevation of [Ca[2+]]c was primarily generated intracellularly. Moreover, elevations of [Ca[2+]]c and mitochondrial Ca[2+] concentration ([Ca[2+]]mit) with depletion of endoplasmic reticulum (ER) Ca[2+] levels ([Ca[2+]]ER) were revealed in Cd-treated rPT cells, but this subcellular Ca[2+] redistribution was significantly suppressed by 2-Aminoethoxydiphenyl borate (2-APB). Elevated inositol 1,4,5-trisphosphate (IP3) levels with up-regulated IP3 receptor (IP3R) protein levels were shown in Cd-exposed cells, confirming that IP3R-mediated ER Ca[2+] release results in the elevation of [Ca[2+]]c. Up-regulated sequestosome 1 (p62) protein levels and autophagic flux assay demonstrated that Cd impaired autophagic degradation, while N-acetylcysteine (NAC) markedly attenuated Cd-induced p62 and microtubule-associated protein 1 light chain 3-II (LC3-II) accumulation, implying that the inhibition of autophagic flux was due to oxidative stress. Furthermore, pharmacological modulation of [Ca[2+]]c with 1,2-Bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) and 2-APB alleviated Cd-mediated apoptosis, inhibition of autophagic degradation and subsequent cytotoxicity, while thapsigargin (TG) had the opposite regulatory effect on them. In summary, cytosolic calcium overload originated from IP3R-mediated ER Ca[2+] release has a negative impact on Cd nephrotoxicity through its promotion of apoptosis and inhibition of autophagic flux.}, }
@article {pmid27663415, year = {2016}, author = {Xu, R and Tao, A and Bai, Y and Deng, Y and Chen, G}, title = {Effectiveness of N-Acetylcysteine for the Prevention of Contrast-Induced Nephropathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.}, journal = {Journal of the American Heart Association}, volume = {5}, number = {9}, pages = {}, pmid = {27663415}, issn = {2047-9980}, abstract = {BACKGROUND: Conflicting results have been obtained in trials that have evaluated the prophylactic efficacy of N-acetylcysteine (NAC) pretreatment in the prevention of contrast-induced nephropathy (CIN). In this meta-analysis of randomized controlled trials, we aimed to assess the effectiveness of NAC treatment for the prevention of CIN.<br><br>METHODS AND RESULTS: PubMed, EMBASE, and the Cochrane Library were electronically searched from inception to January 2016 for all relevant studies. The weighted relative risk (RR) and corresponding 95% CI for incident CIN were estimated using random effects models. Standard methods for assessing statistical heterogeneity and publication bias were used. The study included 11&#xa0;480 participants and 1653 cases of CIN. The incidence of CIN was 12.8% in the NAC group versus 16.0% in the control group (RR: 0.76, 95% CI: 0.66-0.88, P=0.0002). In the patients undergoing coronary angiography, the incidence of CIN in the NAC group versus the control group was 13.7% versus 17.2% (RR: 0.74, 95% CI: 0.63-0.87, P=0.0002); in those undergoing peripheral angiography, the incidence was 6.4% versus 5.8% (RR: 1.00, 95% CI: 0.42-2.40, P=1.00); in those undergoing computed tomography, the incidence was 7.7% versus 14.8% (RR: 0.51, 95% CI: 0.29-0.89, P=0.02).<br><br>CONCLUSIONS: Our meta-analysis showed an inverse and significant association between NAC supplementation and risk of CIN in patients undergoing coronary angiography and computed tomography, while a protective role for NAC in patients undergoing peripheral angiography was not obvious.}, }
@article {pmid27650929, year = {2016}, author = {Goyal, V and Bews, H and Cheung, D and Premecz, S and Mandal, S and Shaikh, B and Best, R and Bhindi, R and Chaudhary, R and Ravandi, A and Thliveris, J and Singal, PK and Niraula, S and Jassal, DS}, title = {The Cardioprotective Role of N-Acetyl Cysteine Amide in the Prevention of Doxorubicin and Trastuzumab-Mediated Cardiac Dysfunction.}, journal = {The Canadian journal of cardiology}, volume = {32}, number = {12}, pages = {1513-1519}, doi = {10.1016/j.cjca.2016.06.002}, pmid = {27650929}, issn = {1916-7075}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Antineoplastic Agents/administration &amp; dosage/adverse effects ; Antioxidants/pharmacology ; Cardiotonic Agents/pharmacology ; *Cardiotoxicity/diagnosis/etiology/prevention &amp; control ; Disease Models, Animal ; Doxorubicin/administration &amp; dosage/*adverse effects ; Drug Monitoring ; Echocardiography/methods ; Female ; Mice ; Oxidative Stress/drug effects ; Trastuzumab/administration &amp; dosage/*adverse effects ; Treatment Outcome ; }, abstract = {BACKGROUND: In the breast cancer setting, anticancer therapies including doxorubicin (DOX) and trastuzumab (TRZ) are associated with a significantly increased risk of cardiotoxicity. Despite the increasing support for the role of oxidative stress (OS) in its pathophysiology, we still do not have an optimal antioxidant for the prevention of DOX + TRZ-mediated cardiac dysfunction. The objective of this study was to investigate whether the novel antioxidant N-acetylcysteine amide (NACA) can attenuate DOX + TRZ-induced heart failure in a murine model.<br><br>METHODS: A total of 100 C57Bl/6 female mice received 1 of the following drug regimens: (1) saline, (2) NACA, (3) DOX, (4) TRZ, (5) DOX&#xa0;+ TRZ, (6) NACA&#xa0;+ DOX, (7) NACA&#xa0;+ TRZ, and (8) NACA&#xa0;+ DOX&#xa0;+ TRZ. Serial echocardiography was performed over a 10-day study period, after which the mice were killed for histologic and biochemical analyses.<br><br>RESULTS: In mice receiving DOX, the left ventricular ejection fraction (LVEF) decreased from 73% &#xb1; 4% to 43% &#xb1; 2% on day 10. In mice receiving DOX&#xa0;+ TRZ, the LVEF decreased from 72% &#xb1; 3% to 32% &#xb1; 2% on day 10. Prophylactic administration of NACA to mice receiving DOX or DOX&#xa0;+ TRZ was cardioprotective, with an LVEF of 62% &#xb1; 3% and 55% &#xb1; 3% on day 10, respectively. Histologic and biochemical analyses demonstrated a loss of cellular integrity, increased OS, and increased cardiac apoptosis in mice treated with DOX&#xa0;+ TRZ, which was attenuated by the prophylactic administration of NACA.<br><br>CONCLUSIONS: NACA attenuated the cardiotoxic side effects of DOX&#xa0;+ TRZ in a murine model of chemotherapy-induced cardiac dysfunction by decreasing OS and apoptosis.}, }
@article {pmid27648632, year = {2017}, author = {Kim, JY and Kim, HJ and Kim, N and Kwon, JH and Park, MJ}, title = {Effects of radiofrequency field exposure on glutamate-induced oxidative stress in mouse hippocampal HT22 cells.}, journal = {International journal of radiation biology}, volume = {93}, number = {2}, pages = {249-256}, doi = {10.1080/09553002.2017.1237058}, pmid = {27648632}, issn = {1362-3095}, mesh = {Animals ; Cell Line ; Cell Survival/drug effects/radiation effects ; Dose-Response Relationship, Radiation ; Glutamic Acid/*administration &amp; dosage ; Hippocampus/drug effects/physiology/radiation effects ; Mice ; Neurons/drug effects/*physiology/*radiation effects ; Oxidative Stress/*drug effects/physiology/*radiation effects ; Radiation Dosage ; *Radio Waves ; Reactive Oxygen Species/metabolism ; }, abstract = {PURPOSE: To define the impact of radiofrequency (RF) under in vitro experimental Alzheimer's disease conditions, we investigated the effect of RF radiation on glutamate-induced oxidative stress in mouse hippocampal neuronal HT22 cells.<br><br>MATERIALS AND METHODS: Cell survival rate was measured by MTT and trypan blue exclusion assays. Cell cycle distribution, cell death, and ROS production were analyzed using flow cytometry. Expression of proteins was analyzed by Western blot.<br><br>RESULTS: RF exposure alone had a marginal impact on cell proliferation; however, it significantly enhanced glutamate-induced cytotoxicity in HT22 cells. Glutamate augmented the subG1 fraction of cell cycle, annexin/propidium iodide positive cell population, and expression of cleaved poly (ADP ribose) polymerase, which were further increased by RF exposure. Glutamate induced reactive oxygen species (ROS) generation and RF exposure further upregulated it. N-acetylcysteine (NAC) treatment completely abrogated glutamate- and RF-induced ROS production followed by cell death and restored cell proliferation in HT22 cells. Finally, glutamate phosphorylated c-Jun N-terminal kinase (JNK) and RF increased this event further. Treatment with NAC and inhibitor of JNK decreased JNK phosphorylation and restored cell proliferation, respectively.<br><br>CONCLUSIONS: Our results demonstrate that RF exposure enhanced glutamate-induced cytotoxicity by further increase of ROS production in HT22 cells.}, }
@article {pmid27640177, year = {2016}, author = {Rao, KN and Sentir, AM and Engleman, EA and Bell, RL and Hulvershorn, LA and Breier, A and Chambers, RA}, title = {Toward early estimation and treatment of addiction vulnerability: radial arm maze and N-acetyl cysteine before cocaine sensitization or nicotine self-administration in neonatal ventral hippocampal lesion rats.}, journal = {Psychopharmacology}, volume = {233}, number = {23-24}, pages = {3933-3945}, pmid = {27640177}, issn = {1432-2072}, support = {R01 AA020396/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Behavior, Addictive/*drug therapy ; Behavior, Animal/*drug effects ; Cocaine/*pharmacology ; Cocaine-Related Disorders/*drug therapy ; Corpus Striatum/drug effects ; Disease Models, Animal ; Drug-Seeking Behavior/*drug effects ; Free Radical Scavengers/*pharmacology ; Hippocampus/drug effects ; Male ; Memory Disorders/pathology ; Memory, Short-Term/drug effects ; Nicotine/*pharmacology ; Nicotinic Agonists/*pharmacology ; Prefrontal Cortex/drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {RATIONAL: Prefrontal cortical (PFC)-hippocampal-striatal circuits, interconnected via glutamatergic signaling, are dysfunctional in mental illnesses that involve addiction vulnerability.<br><br>OBJECTIVES: In healthy and neurodevelopmentally altered rats, we examined how Radial Arm Maze (RAM) performance estimates addiction vulnerability, and how starting a glutamatergic modulating agent, N-acetyl cysteine (NAC) in adolescence alters adult mental illness and/or addiction phenotypes.<br><br>METHODS: Rats with neonatal ventral hippocampal lesions (NVHL) vs. SHAM-operated controls were randomized to NAC vs. saline in adolescence followed by cognitive testing (RAM) in early adulthood and then cocaine behavioral sensitization (experiment 1; n&#xa0;=&#xa0;80) or nicotine self-administration (experiment 2; n&#xa0;=&#xa0;12).<br><br>RESULTS: In experiment 1, NVHL rats showed over-consumption of food (Froot-Loops (FL)) baiting the RAM with poor working memory (low-arm entries to repeat (ETR)), producing an elevated FL to ETR ratio ("FLETR"; p&#xa0;<&#xa0;0.001). FLETR was the best linear estimator (compared to FL or ETR) of magnitude of long-term cocaine sensitization (R [2]&#xa0;=&#xa0;0.14, p&#xa0;<&#xa0;0.001). NAC treatment did not alter FL, ETR, FLETR, or cocaine sensitization. In experiment 2, FLETR also significantly and uniquely correlated with subsequent drug seeking during nicotine-induced reinstatement after extinction of nicotine self-administration (R [2]&#xa0;=&#xa0;0.47, p&#xa0;<&#xa0;0.01). NAC did not alter RAM performance, but significantly reversed NVHL-induced increases in nicotine seeking during extinction and reinstatement.<br><br>CONCLUSIONS: These findings demonstrate the utility of animal models of mental illness with addiction vulnerability for developing novel diagnostic measures of PFC-hippocampal-striatal circuit dysfunction that may reflect addiction risk. Such tests may direct pharmacological treatments prior to adulthood and addictive drug exposure, to prevent or treat adult addictions.}, }
@article {pmid27639126, year = {2016}, author = {Zhao, W and Wu, C and Li, S and Chen, X}, title = {Adiponectin protects palmitic acid induced endothelial inflammation and insulin resistance via regulating ROS/IKKβ pathways.}, journal = {Cytokine}, volume = {88}, number = {}, pages = {167-176}, doi = {10.1016/j.cyto.2016.09.005}, pmid = {27639126}, issn = {1096-0023}, mesh = {Adiponectin/*metabolism ; Cytokines/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; I-kappa B Kinase/*metabolism ; Inflammation/chemically induced/metabolism ; *Insulin Resistance ; Palmitic Acid/*toxicity ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Endothelial inflammation and insulin resistance (IR) has been closely associated with endothelial dysfunction. Adiponectin (APN), an adipocyte-secreted hormone from adipose tissues, showed cardioprotective effects. Here, the protective effect of APN on palmitic acid (PA)-induced endothelial inflammation and IR was investigated. Cultured human umbilical vein endothelial cells (HUVECs) were treated with PA without or without APN pretreatment. The expression of inflammatory cytokines TNF-α, IL-6, adhesion molecule ICAM-1 were determined by western blotting, ELISA, and real-time PCR. The protein expression and protein-protein interaction were determined by western blotting and immunoprecipitation. The intracellular reactive oxygen species (ROS) and nitric oxide (NO) production were monitored with fluorescence probes. PA-induced secretion of TNF-α, IL-6, and expression of ICAM-1 at protein and mRNA levels, which was significantly inhibited by APN. PA treatment caused increase of ROS generation, NOX2, p-IKKβ, p-IκBα, p-p65 expression, and p-IκBα-IKKβ interaction, which were all partly reversed by APN. ROS scavenger N-acetylcysteine (NAC) and NF-κB inhibitor PDTC showed similar effect on PA-induced secretion of TNF-α, IL-6, and expression of ICAM-1. Furthermore, APN and NAC pretreatment restored PA-induced increase of p-IRS-1(S307), decrease of p-IRS-1(Tyr). In addition, insulin-triggered expression of p-IRS-1(Tyr), p-PI3K, p-AKT, p-eNOS and NO generation were inhibited by PA, which were also restored by both APN and NAC. These results suggested that APN ameliorated endothelial inflammation and IR through ROS/IKKβ pathway. This study shed new insights into the mechanisms of APN's cardiovascular protective effect.}, }
@article {pmid27635524, year = {2017}, author = {Domínguez-Álvarez, M and Gea, J and Barreiro, E}, title = {Inflammatory Events and Oxidant Production in the Diaphragm, Gastrocnemius, and Blood of Rats Exposed to Chronic Intermittent Hypoxia: Therapeutic Strategies.}, journal = {Journal of cellular physiology}, volume = {232}, number = {5}, pages = {1165-1175}, doi = {10.1002/jcp.25600}, pmid = {27635524}, issn = {1097-4652}, mesh = {Animals ; Biomarkers/blood/metabolism ; Body Weight/drug effects ; Diaphragm/*metabolism/*pathology ; Hypoxia/*blood/metabolism/*therapy ; Inflammation/*pathology ; Interferon-gamma/blood/metabolism ; Interleukin-1beta/blood/metabolism ; Interleukin-6/blood/metabolism ; Male ; Muscle Fibers, Skeletal/pathology ; Muscle, Skeletal/*metabolism/*pathology ; Oxidants/*metabolism ; Rats, Wistar ; Superoxides/blood/metabolism ; Tumor Necrosis Factor-alpha/blood/metabolism ; }, abstract = {We hypothesized that inflammatory events and reactive oxygen species (ROS) production may be differentially expressed in respiratory and limb muscles, and blood of a chronic intermittent hypoxia (CIH) experimental model and that antioxidants and TNF-alpha blockade may influence those events. In blood, diaphragm, and gastrocnemius of rats non-invasively exposed to CIH (10% hypoxia, 2 h/day, 14 consecutive days) with/without concomitant treatment with either anti-TNF-alpha antibody (infliximab) or N-acetyl cysteine (NAC), inflammatory cytokines, superoxide anion production, muscle structural abnormalities, and fiber-type composition were assessed. Compared to non-exposed controls, in CIH-exposed rats, body weight gain was reduced, TNF-alpha, IL-1beta, IL-6, and interferon-gamma levels were increased in diaphragm, TNF-alpha, and IL-1 beta plasma levels were greater, systemic and muscle superoxide anion production was higher, diaphragm and gastrocnemius inflammatory cells and internal nuclei were higher, and muscle fiber-type and morphometry remained unmodified. CIH rats treated with infliximab further increased TNF-alpha, IL-1beta, IL-6, and interferon-gamma diaphragm levels, whereas NAC induced a reduction only in TNF-alpha and IL-1beta levels in diaphragm and plasma. Infliximab and NAC elicited a significant decline in superoxide anion production in diaphragm, gastrocnemius, and plasma, while inducing a further increase in inflammatory cells and internal nuclei in both muscles. Proinflammatory cytokines are differentially expressed in respiratory and limb muscles and plasma of CIH-exposed rats, while superoxide anion production increased in both muscle types and blood. Infliximab and NAC exerted different effects. These findings may help understand the biology underlying CIH in skeletal muscles and blood of patients with chronic respiratory diseases. J. Cell. Physiol. 232: 1165-1175, 2017. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid27634458, year = {2016}, author = {Komoike, Y and Matsuoka, M}, title = {Endoplasmic reticulum stress-mediated neuronal apoptosis by acrylamide exposure.}, journal = {Toxicology and applied pharmacology}, volume = {310}, number = {}, pages = {68-77}, doi = {10.1016/j.taap.2016.09.005}, pmid = {27634458}, issn = {1096-0333}, mesh = {Acrylamide/*toxicity ; Activating Transcription Factor 4/metabolism ; Animals ; Apoptosis/*drug effects ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/*drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Humans ; Neuroblastoma/metabolism/pathology ; Neurons/*drug effects/pathology ; RNA, Messenger/genetics ; Reactive Oxygen Species/metabolism ; Transcription Factor CHOP/genetics ; Zebrafish ; }, abstract = {Acrylamide (AA) is a well-known neurotoxic compound in humans and experimental animals. However, intracellular stress signaling pathways responsible for the neurotoxicity of AA are still not clear. In this study, we explored the involvement of the endoplasmic reticulum (ER) stress response in AA-induced neuronal damage in vitro and in vivo. Exposure of SH-SY5Y human neuroblastoma cells to AA increased the levels of phosphorylated form of eukaryotic translation initiation factor 2α (eIF2α) and its downstream effector, activating transcription factor 4 (ATF4), indicating the induction of the unfolded protein response (UPR) by AA exposure. Furthermore, AA exposure increased the mRNA level of c/EBP homologous protein (CHOP), the ER stress-dependent apoptotic factor, and caused the accumulation of reactive oxygen species (ROS) in SH-SY5Y cells. Treatments of SH-SY5Y cells with the chemical chaperone, 4-phenylbutyric acid and the ROS scavenger, N-acetyl-cysteine reduced the AA-induced expression of ATF4 protein and CHOP mRNA, and resulted in the suppression of apoptosis. In addition, AA-induced eIF2α phosphorylation was also suppressed by NAC treatment. In consistent with in vitro study, exposure of zebrafish larvae at 6-day post fertilization to AA induced the expression of chop mRNA and apoptotic cell death in the brain, and also caused the disruption of brain structure. These findings suggest that AA exposure induces apoptotic neuronal cell death through the ER stress and subsequent eIF2α-ATF4-CHOP signaling cascade. The accumulation of ROS by AA exposure appears to be responsible for this ER stress-mediated apoptotic pathway.}, }
@article {pmid27633119, year = {2016}, author = {Xie, P and Fujii, I and Zhao, J and Shinohara, M and Matsukura, M}, title = {A novel polysaccharide derived from algae extract induces apoptosis and cell cycle arrest in human gastric carcinoma MKN45 cells via ROS/JNK signaling pathway.}, journal = {International journal of oncology}, volume = {49}, number = {4}, pages = {1561-1568}, doi = {10.3892/ijo.2016.3658}, pmid = {27633119}, issn = {1791-2423}, abstract = {In recent years, interest in biological activities of compounds from marine organisms has intensified. Cancer is the most principal enemy for human life and health. For the first time, to the best of our knowledge, we investigated a novel algae-derived polysaccharide for its role in inducing apoptosis and cell cycle arrest in human gastric carcinoma MKN45 cells. We found that the novel polysaccharide suppressed MKN45 cell proliferation, induced cell apoptosis and arrested the cells at G2/M phase. Furthermore, we observed that the generation of reactive oxygen species (ROS) and the phosphorylation of Jun N-terminal kinase (JNK), p53, caspase-9 and -3 were induced in the polysaccharide-treated MKN45 cells. In addition, pretreatment with N-acetyl-cysteine (NAC) and SP600125, the inhibitor of ROS and JNK, induced MKN45 cell proliferation, prevented the cell apoptosis and released the cells from cycle arrest. Finally, we found that pretreatment with NAC prevented the JNK, p53, caspase-9 and -3 protein phosphorylation induced by the polysaccharide, however, pretreatment with SP600125 did not affect the generation of ROS, suggesting that ROS is upstream of JNK. Taken together, the novel polysaccharide induced cancer cell apoptosis and arrested cell cycle via ROS/JNK signaling pathway.}, }
@article {pmid27630715, year = {2016}, author = {Sacchinelli, A and Venturella, R and Lico, D and Di Cello, A and Lucia, A and Rania, E and Cirillo, R and Zullo, F}, title = {Corrigendum to "The Efficacy of Inositol and N-Acetyl Cysteine Administration (Ovaric HP) in Improving the Ovarian Function in Infertile Women with PCOS with or without Insulin Resistance".}, journal = {Obstetrics and gynecology international}, volume = {2016}, number = {}, pages = {2026056}, pmid = {27630715}, issn = {1687-9589}, abstract = {[This corrects the article DOI: 10.1155/2014/141020.].}, }
@article {pmid27629871, year = {2016}, author = {Rossell, SL and Francis, PS and Galletly, C and Harris, A and Siskind, D and Berk, M and Bozaoglu, K and Dark, F and Dean, O and Liu, D and Meyer, D and Neill, E and Phillipou, A and Sarris, J and Castle, DJ}, title = {N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms.}, journal = {BMC psychiatry}, volume = {16}, number = {1}, pages = {320}, pmid = {27629871}, issn = {1471-244X}, support = {N01AA21004/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Antipsychotic Agents/therapeutic use ; Australia ; *Clozapine ; Double-Blind Method ; Drug Resistance ; Female ; Follow-Up Studies ; Free Radical Scavengers/therapeutic use ; Humans ; Male ; Middle Aged ; New Zealand ; Quality of Life/psychology ; Schizophrenia/*drug therapy ; *Schizophrenic Psychology ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ.<br><br>METHODS: This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2&#xa0;g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes.<br><br>DISCUSSION: This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine.<br><br>TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registration Number: Current Randomised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015.}, }
@article {pmid27622324, year = {2016}, author = {Arora, D and Siddiqui, MH and Sharma, PK and Shukla, Y}, title = {Deltamethrin induced RIPK3-mediated caspase-independent non-apoptotic cell death in rat primary hepatocytes.}, journal = {Biochemical and biophysical research communications}, volume = {479}, number = {2}, pages = {217-223}, doi = {10.1016/j.bbrc.2016.09.042}, pmid = {27622324}, issn = {1090-2104}, mesh = {Animals ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/*metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cyclooxygenase 2/metabolism ; Hepatocytes/*drug effects/metabolism/ultrastructure ; Insecticides/pharmacology ; Male ; Microscopy, Confocal ; Microscopy, Electron, Transmission ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitriles/*pharmacology ; Primary Cell Culture ; Pyrethrins/*pharmacology ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Deltamethrin (DLM), a synthetic pyrethroid insecticide, is used all over the world for indoor and field pest management. In the present study, we investigated the elicited pathogenesis of DLM-induced hepatotoxicity in rat primary hepatocytes. DLM-induced cell death was accompanied with increased ROS generation, decreased mitochondrial membrane potential and G2/M arrest. Pre-treatment with N-acetyl cysteine/butylated hydroxyanisole/IM54 could partly rescue hepatocytes suggesting that ROS might play a role in DLM-induced toxicity. Interestingly, DLM treatment resulted in a caspase-independent but non-apoptotic cell death. Pre-treatment with pan-caspase inhibitor (ZVAD-FMK) could not rescue hepatocytes. Unaltered caspase-3 activity and absence of cleaved caspase-3 also corroborated our findings. Further, LDH release and Transmission electron microscopy (TEM) analysis demonstrated that DLM incites membrane disintegrity and necrotic damage. Immunochemical staining revealed an increased expression of inflammatory markers (TNFα, NFκB, iNOS, COX-2) following DLM treatment. Moreover, the enhanced RIPK3 expression in DLM treated groups and prominent rescue from cell death by GSK-872 indicated that DLM exposure could induce programmed necrosis in hepatocytes. The present study demonstrates that DLM could induce hepatotoxicity via non-apoptotic mode of cell death.}, }
@article {pmid27621939, year = {2016}, author = {Sitar, G and Kucuk, M and Erinc Sitar, M and Yasar, O and Aydin, S and Yanar, K and Cakatay, U and Buyukpınarbasili, N}, title = {Crucial Roles of Systemic and Tissue Lipid Peroxidation Levels and Anti-Oxidant Defences Following Contrast Agent Application.}, journal = {Iranian Red Crescent medical journal}, volume = {18}, number = {6}, pages = {e37331}, pmid = {27621939}, issn = {2074-1804}, abstract = {BACKGROUND: One of the most important side effects of contrast pharmaceutical agents, which are used very common in routine radiology practice, is contrast induced nephropathy. Even ischemia, oxidative stress and osmolality related cytotoxic effects are considered, the molecular mechanisms underlying this pathology have not been identified completely yet.<br><br>OBJECTIVES: The aim of the current study was to reveal the role of oxidative stress and antioxidant enzymatic defence mechanisms in the aetiopathogenesis of contrast-induced nephropathy. We also studied possible alleviating effects of N-acetylcysteine (NAC), a potent antioxidant, to obtain extra information regarding the molecular mechanisms underlying this pathology.<br><br>MATERIALS AND METHODS: This is an clinical-experimental study, This study was conducted of Istanbul/Turkey between September 15, 2012 and April 15, 2013. Three groups of male rats were randomly set up as a control group (C), a 100 mg/kg intraperitoneal NAC + 7 mL/kg contrast agent group (N + CIN) and a 7 mL/kg intraperitoneal contrast agent group (CIN). They were placed in individual metabolic cages 48 hours after agent administration to obtain 24-hour urine samples. Renal function tests (albumin, urea, creatinine, total protein) were conducted, oxidative stress parameters (Cu, Zn superoxide dismutase activity - Cu, Zn-SOD; advanced oxidation protein products - AOPP; protein carbonyls - PCO; total thiol groups - T-SH; and lipid hydroperoxides -LHP) were measured and tissues were analysed histopathologically.<br><br>RESULTS: Compared with the control group, groups CIN and N + CIN had significantly higher urea and LHP levels (P < 0.05 and P < 0.001, respectively) and significantly lower Cu, Zn-SOD activity and creatinine clearance (P < 0.05). There was no statistically significant difference between the groups in PCO or AOPP levels despite differences in descriptive statistics.<br><br>CONCLUSIONS: Contrast-agent-induced nephropathic changes are more closely related to the magnitude of lipid peroxidation than protein oxidation.}, }
@article {pmid27620528, year = {2016}, author = {Ji, Y and Dai, Z and Wu, G and Wu, Z}, title = {4-Hydroxy-2-nonenal induces apoptosis by activating ERK1/2 signaling and depleting intracellular glutathione in intestinal epithelial cells.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {32929}, pmid = {27620528}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/*pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects/physiology ; Caspase 3/metabolism ; Cell Line ; Dual Specificity Phosphatase 1/metabolism ; Glutathione/*metabolism ; Intestinal Mucosa/cytology/*drug effects/*metabolism ; MAP Kinase Signaling System/*drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Swine ; }, abstract = {Excessive reactive oxygen species (ROS) induces oxidative damage to cellular constituents, ultimately leading to induction of apoptotic cell death and the pathogenesis of various diseases. The molecular mechanisms for the action of ROS in intestinal diseases remain poorly defined. Here, we reported that 4-hydroxy-2-nonenal (4-HNE) treatment led to capses-3-dependent apoptosis accompanied by increased intracellular ROS level and reduced glutathione concentration in intestinal epithelial cells. These effects of 4-HNE were markedly abolished by the antioxidant L-cysteine derivative N-acetylcysteine (NAC). Further studies demonstrated that the protective effect of NAC was associated with restoration of intracellular redox state by Nrf2-related regulation of expression of genes involved in intracellular glutathione (GSH) biosynthesis and inactivation of 4-HNE-induced phosphorylation of extracellular signal-regulated protein kinases (ERK1/2). The 4-HNE-induced ERK1/2 activation was mediated by repressing mitogen-activated protein kinase phosphatase-1 (MKP-1), a negative regulator of ERK1/2, through a proteasome-dependent degradation mechanism. Importantly, either overexpression of MKP-1 or NAC treatment blocked 4-HNE-induced MKP-1 degradation, thereby protecting cell from apoptosis. These novel findings provide new insights into a functional role of MKP-1 in oxidative stress-induced cell death by regulating ERK1/2 MAP kinase in intestinal epithelial cells.}, }
@article {pmid27613482, year = {2016}, author = {Xie, H and Wu, J}, title = {Silica nanoparticles induce alpha-synuclein induction and aggregation in PC12-cells.}, journal = {Chemico-biological interactions}, volume = {258}, number = {}, pages = {197-204}, doi = {10.1016/j.cbi.2016.09.006}, pmid = {27613482}, issn = {1872-7786}, mesh = {Animals ; Autophagy/drug effects ; Biomarkers/metabolism ; Models, Biological ; Nanoparticles/*chemistry/ultrastructure ; PC12 Cells ; Phosphatidylinositol 3-Kinases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Aggregates/*drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Signal Transduction/drug effects ; Silicon Dioxide/*pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Ubiquitin/metabolism ; alpha-Synuclein/*chemistry/*metabolism ; }, abstract = {Silica nanoparticles (SiO2-NPs) are widely applied in diagnosis, imaging, and drug delivery of central nervous diseases. Previously, we found that SiO2-NPs enter the brain and, more specifically, the dopaminergic neurons in the striatum. Whether SiO2-NPs have neurotoxicity and contribute to development of Parkinson's disease (PD) remains unclear. In this study, we investigated the effect of SiO2-NPs on PC12 cells, a dopaminergic neuron-like cell line. We showed that SiO2-NPs up-regulated α-synuclein expression, and N-acetyl cysteine reduced α-synuclein. SiO2-NPs inhibited 20S proteasome activity and decreased ubiquitin, Parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) protein levels in the ubiquitin-proteasome system (UPS). SiO2-NPs induced autophagy as shown by transmission electron microscopy, and elevated LC3-II and Beclin 1 levels in PC12 cells. SiO2-NPs inhibited phosphorylation of PI3K, Akt, mTOR, and P70S6. These data suggest that SiO2-NPs induce oxidative stress and α-synuclein aggregation by inhibiting the UPS. SiO2-NPs also induce autophagy through inhibiting PI3K-Akt-mTOR signaling, which is known to negatively regulate autophagy. Amyloid aggregates of α-synuclein in dopaminergic neurons of the midbrain are considered the hallmark of PD. Our findings indicate that SiO2-NPs exposure induces neurotoxicity and may be a significant risk factor for the development of PD.}, }
@article {pmid27600005, year = {2016}, author = {Liu, B and Su, X and Zhang, Y and Huang, L and Pan, P and Hu, C}, title = {[Effect of chronic intermittent hypoxia on the expression of CXC chemokine ligand-10 in rat liver and the interventional effect of N-acetylcysteine].}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {41}, number = {8}, pages = {796-803}, doi = {10.11817/j.issn.1672-7347.2016.08.004}, pmid = {27600005}, issn = {1672-7347}, mesh = {Acetylcysteine ; Animals ; Chemokine CXCL10 ; Fatty Liver ; *Hypoxia ; Inflammation ; Male ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: To explore the effect of chronic intermittent hypoxia (CIH) on liver injury and to examine the expression of liver CXC chemokine ligand-10 (CXCL10) in the rats, and to explore the effect of N-acetylcysteine (NAC).<br><br>METHODS: A total of 21 male SD rats were randomly divided into a control group, a CIH group and a CIH+NAC group (n=7 in each group). The control group exposed to normal gaseous environment, the other 2 groups were exposed to CIH for 5 weeks (8 h/d); the control group and the CIH group were given daily saline lavage, the CIH+NAC group daily received NAC solution. After the end of 5 weeks, the rats were killed, and the MDA content and SOD activity in rat liver tissues were detected. The liver sections were stained with hematoxylin-eosin (HE) and the liver pathology was observed. The expression of CXCL10 in the liver tissues was detected by immunohistochemical method.&#x2029;<br><br>RESULTS: Compared with the control group, the MDA levels in rat liver tissues were increased (P<0.05), and the SOD levels were decreased (P<0.05) in the CIH group and the CIH+NAC group. Compared with the CIH group, the SOD levels in the rat liver tissues were increased (P<0.05), and the MDA levels were decreased in the CIH+NAC group. Compared with the control group, the hepatic steatosis and inflammatory reactions were more severe in the CIH group and the CIH+NAC group (both P<0.01). Compared with the CIH group, the hepatic steatosis and inflammatory reactions were reduced in the CIH+NAC group (P<0.05). The liver damage in the CIH+NAC group was less than that in the CIH group (P<0.05). Compared with the control group, the CXCL10 expression in the CIH group and the CIH+NAC group was increased (both P<0.01). The CXCL10 expression in the CIH+NAC group was down-regulated compared with that in the CIH group (P<0.01).&#x2029;<br><br>CONCLUSION: CIH can lead to liver injury and induce CXCL10 expression in rat liver tissues. The NAC can alleviate rat liver oxidative stress and inflammation caused by CIH, and in turn to improve the liver injury in rats.}, }
@article {pmid27597636, year = {2016}, author = {Bensignor, E and Fabriès, L and Bailleux, L}, title = {A split-body, randomized, blinded study to evaluate the efficacy of a topical spray composed of essential oils and essential fatty acids from plant extracts with antimicrobial properties.}, journal = {Veterinary dermatology}, volume = {27}, number = {6}, pages = {464-e123}, doi = {10.1111/vde.12374}, pmid = {27597636}, issn = {1365-3164}, mesh = {Administration, Topical ; Aerosols ; Animals ; Dog Diseases/*drug therapy ; Dogs ; Fatty Acids/administration &amp; dosage/chemistry/*therapeutic use ; Oils, Volatile/administration &amp; dosage/chemistry/*therapeutic use ; Plant Extracts/chemistry/*pharmacology ; Pyoderma/drug therapy/*veterinary ; }, abstract = {BACKGROUND: Bacterial pyoderma is a frequent presentation in dogs. Despite the widespread availability of effective systemic and topical antimicrobial products, good clinical practice currently recommends avoidance of long-term use to mitigate the development of bacterial resistance.<br><br>HYPOTHESIS/OBJECTIVES: To evaluate the speed of resolution of clinical signs of bacterial pyoderma in dogs treated with a systemic antimicrobial agent with or without the use of an adjunctive spray with antimicrobial properties.<br><br>ANIMALS: Twelve dogs with superficial bacterial pyoderma.<br><br>METHODS: In this controlled and blinded study, all dogs were treated with oral cefalexin and a topical spray (PYOClean Spray) for 4 weeks. The spray was applied to one half of each dog's body, whereas a placebo spray was applied to the other half.<br><br>RESULTS: Twelve dogs completed the study. Mean clinical scores were significantly reduced on spray-treated sites, for test product and placebo (respectively), by 47% and 34% at Week 1, 83% and 60% at Week 2, 95% and 82% at Week 3, and 100% and 96% at Week 4. Fifty percent of treated sites were considered clinically and cytologically cured at Week 2, 83% at Week 3, and 100% at Week 4 compared to 8%, 50% and 83% for the placebo sites, respectively.<br><br>These results demonstrate that use of a topical spray which contains plant-derived essential oils and fatty acids, and compounds with antimicrobial properties (Manuka oil and N-acetyl cysteine) may help to speed resolution of pyoderma and may allow for shorter antimicrobial treatment time.}, }
@article {pmid27596934, year = {2016}, author = {Li, Y and Wang, Y and Wu, Q and Li, L and Shi, Y and Bu, H and Bao, J}, title = {Comparison of methods for isolating primary hepatocytes from mini pigs.}, journal = {Xenotransplantation}, volume = {23}, number = {5}, pages = {414-420}, doi = {10.1111/xen.12259}, pmid = {27596934}, issn = {1399-3089}, mesh = {Animals ; *Cell Separation/methods ; Cells, Cultured ; Hepatocytes/*cytology ; Humans ; *Liver, Artificial ; Swine ; Swine, Miniature ; *Transplantation, Heterologous/methods ; }, abstract = {Successful porcine hepatocyte isolation is crucial for the development of bioartificial liver devices and hepatocyte transplantation. Serva collagenase NB grades are formulated collagenases that are suitable for various tissue isolation applications. N-acetylcysteine (NAC) can improve the viability of human hepatocytes. The aim of this study was to compare the effectiveness of two collagenases and effect of NAC on hepatocyte isolation from porcine liver tissue. Porcine hepatocytes were isolated using the perfusion method from Bama mini pigs assigned to the Serva NB 4 group (n=6), the Serva NB 8 group (n=6), or the NB 8+NAC group (n=6). Viability and yield were defined as fresh hepatocytes and their spheroids formation after 24-hour rocker culture in serum-free medium. Metabolic function was assessed by gene expression, albumin, and urea synthesis. All procedures resulted in successful hepatocyte isolation. Cells from the NB 8+NAC group had (97.8±1.9)% viability, which was higher than the NB 8 group with (94.4±2.4)% and the NB 4 group with (94.5±3.2)% (P<.001). The final cell yield reached (11.8±1.0)×10(9) cells in the NB 8+NAC group, compared to (9.5±2.1)×10(9) cells in the NB 8 group (P<.01) and (9.1±1.1) ×10(9) cells in the NB 4 group (P<.001). The secretion of albumin was superior in the NB 8+NAC group at a concentration of (425.8±35.3) ng/mL compared to the NB 8 group (339.1±32.6) ng/mL (P <.001) and NB 4 group (293.6±43.3) ng/mL (P <.01). The injury of hepatocytes also decreased in the NB 8+NAC group (P<.01). The data are presented as means ± SD. Formulated collagenase Serva NB 8 and NAC could improve the porcine hepatocyte isolation, resulting in higher yields of viable cells.}, }
@article {pmid27594528, year = {2016}, author = {Zhang, S and Li, T and Zhang, Y and Xu, H and Li, Y and Zi, X and Yu, H and Li, J and Jin, CY and Liu, HM}, title = {A new brominated chalcone derivative suppresses the growth of gastric cancer cells in vitro and in vivo involving ROS mediated up-regulation of DR5 and 4 expression and apoptosis.}, journal = {Toxicology and applied pharmacology}, volume = {309}, number = {}, pages = {77-86}, pmid = {27594528}, issn = {1096-0333}, support = {R01 CA122558/CA/NCI NIH HHS/United States ; R01 CA193967/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Bromine/chemistry ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Chalcones/chemistry/*pharmacology ; Heterografts ; Humans ; In Vitro Techniques ; Mice ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Stomach Neoplasms/metabolism/*pathology ; Up-Regulation/*drug effects ; }, abstract = {A new series of 20 brominated chalcone derivatives were designed, synthesized, and investigated for their effects against the growth of four cancer cell lines (EC109, SKNSH, HepG2, MGC803). Among them, compound 19 which given chemical name of H72, was the most potent one on gastric cancer cell lines (i.e. MGC803, HGC27, SGC7901) with IC50s ranged from 3.57 to 5.61μM. H72 exhibited less cytotoxicity to non-malignant gastric epithelial cells GES-1. H72 treatment of MGC803 and HGC27 induced generation of reactive oxygen species (ROS) leading to activation of caspase 9/3 cascade and mitochondria mediated apoptosis. H72 also up-regulated the expression of DR5, DR4 and BimEL, and down-regulated the expression of Bid, Bcl-xL, and XIAP. N-acetyl cysteine (NAC), a ROS scavenger completely blocked these effects of H72 in MGC803 cells. Intraperitoneal administration of H72 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that H72 is a lead brominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.}, }
@article {pmid27592553, year = {2016}, author = {Park, C and Kim, SJ and Lee, WK and Moon, SK and Kwak, S and Choe, SK and Park, R}, title = {Tetrabromobisphenol-A induces apoptotic death of auditory cells and hearing loss.}, journal = {Biochemical and biophysical research communications}, volume = {478}, number = {4}, pages = {1667-1673}, doi = {10.1016/j.bbrc.2016.09.001}, pmid = {27592553}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Blotting, Western ; Cell Line ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Flame Retardants/toxicity ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Hair Cells, Auditory/*drug effects/metabolism ; Hearing Loss/*chemically induced/physiopathology/prevention &amp; control ; Interleukin-6/genetics/metabolism ; Lateral Line System/drug effects/metabolism/physiopathology ; Mechanoreceptors/drug effects/metabolism ; Mice, Inbred ICR ; Microscopy, Fluorescence ; Organ of Corti/drug effects/metabolism/physiopathology ; Polybrominated Biphenyls/*toxicity ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Zebrafish ; }, abstract = {Phenolic tetrabromobisphenol-A (TBBPA) and its derivatives are commonly used flame-retardants, in spite of reported toxic effects including neurotoxicity, immunotoxicity, nephrotoxicity, and hepatotoxicity. However, the effects of TBBPA on ototoxicity have not yet been reported. In this study, we investigated the effect of TBBPA on hearing function in vivo and in vitro. Auditory Brainstem Response (ABR) threshold was markedly increased in mice after oral administration of TBBPA, indicating that TBBPA causes hearing loss. In addition, TBBPA induced the loss of both zebrafish neuromasts and hair cells in the rat cochlea in a dose-dependent manner. Mechanistically, hearing loss is largely attributed to apoptotic cell death, as TBBPA increased the expression of pro-apoptotic genes but decreased the expression of anti-apoptotic genes. We also found that TBBPA induced oxidative stress, and importantly, pretreatment with NAC, an anti-oxidant reagent, reduced TBBPA-induced reactive oxygen species (ROS) generation and partially prevented cell death. Our results show that TBBPA-mediated ROS generation induces ototoxicity and hearing loss. These findings implicate TBBPA as a potential environmental ototoxin by exerting its hazardous effects on the auditory system.}, }
@article {pmid27590588, year = {2016}, author = {Matsui, M and Tanaka, K and Higashiguchi, N and Okawa, H and Yamada, Y and Tanaka, K and Taira, S and Aoyama, T and Takanishi, M and Natsume, C and Takakura, Y and Fujita, N and Hashimoto, T and Fujita, T}, title = {Protective and therapeutic effects of fucoxanthin against sunburn caused by UV irradiation.}, journal = {Journal of pharmacological sciences}, volume = {132}, number = {1}, pages = {55-64}, doi = {10.1016/j.jphs.2016.08.004}, pmid = {27590588}, issn = {1347-8648}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Down-Regulation ; Female ; Fibroblasts/drug effects/metabolism/radiation effects ; Filaggrin Proteins ; Humans ; Intermediate Filament Proteins/genetics ; Mice ; Radiation-Protective Agents/pharmacology/*therapeutic use ; Reactive Oxygen Species/metabolism ; Skin/drug effects/pathology/radiation effects ; Sunburn/*drug therapy/metabolism/pathology ; Tretinoin/pharmacology ; Ultraviolet Rays/*adverse effects ; Xanthophylls/pharmacology/*therapeutic use ; }, abstract = {Mild exposure to ultraviolet (UV) radiation is also harmful and hazardous to the skin and often causes a photosensitivity disorder accompanied by sunburn. To understand the action of UV on the skin we performed a microarray analysis to isolate UV-sensitive genes. We show here that UV irradiation promoted sunburn and downregulated filaggrin (Flg); fucoxanthin (FX) exerted a protective effect. In vitro analysis showed that UV irradiation of human dermal fibroblasts caused production of intracellular reactive oxygen species (ROS) without cellular toxicity. ROS production was diminished by N-acetylcysteine (NAC) or FX, but not by retinoic acid (RA). In vivo analysis showed that UV irradiation caused sunburn and Flg downregulation, and that FX, but not NAC, RA or clobetasol, exerted a protective effect. FX stimulated Flg promoter activity in a concentration-dependent manner. Flg promoter deletion and chromatin immunoprecipitation analysis showed that caudal type homeo box transcription factor 1 (Cdx1) was a key factor for Flg induction. Cdx1 was also downregulated in UV-exposed skin. Therefore, our data suggested that the protective effects of FX against UV-induced sunburn might be exerted by promotion of skin barrier formation through induction of Flg, unrelated to quenching of ROS or an RA-like action.}, }
@article {pmid27581696, year = {2016}, author = {Grant, JE and Chamberlain, SR}, title = {Trichotillomania.}, journal = {The American journal of psychiatry}, volume = {173}, number = {9}, pages = {868-874}, pmid = {27581696}, issn = {1535-7228}, support = {110049//Wellcome Trust/United Kingdom ; }, mesh = {Female ; Humans ; Psychotherapy ; Trichotillomania/*diagnosis/epidemiology/psychology/therapy ; Young Adult ; }, abstract = {Trichotillomania, characterized by the repetitive pulling out of one’s own hair leading to hair loss and functional impairment, has been documented in the medical literature since the 19[th] century, but has received scant research attention. Community prevalence studies suggest that trichotillomania is a common disorder with point prevalence estimate of 0.5% to 2.0%. Although recently grouped with OCD in the DSM-5, clinicians need to be aware that trichotillomania and OCD may have less in common than originally thought. In fact, approaches to treating trichotillomania, which include habit reversal therapy and medication (n-acetyl cysteine or olanzapine), are quite different from those used to treat OCD; and some first-line treatments used for OCD appear ineffective for trichotillomania. Based on our clinical experience and research findings, the article recommends several management approaches to trichotillomania.}, }
@article {pmid27577752, year = {2016}, author = {Chao, MW and Chen, CP and Yang, YH and Chuang, YC and Chu, TY and Tseng, CY}, title = {N-acetylcysteine attenuates lipopolysaccharide-induced impairment in lamination of Ctip2-and Tbr1- expressing cortical neurons in the developing rat fetal brain.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {32373}, pmid = {27577752}, issn = {2045-2322}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Brain/drug effects/*growth &amp; development/metabolism ; Fetal Development/drug effects/genetics ; Gene Expression Regulation, Developmental/drug effects ; Humans ; Inflammation/*drug therapy/genetics/pathology ; Lipopolysaccharides/toxicity ; Male ; Matrix Attachment Region Binding Proteins/genetics ; Nerve Tissue Proteins/*genetics ; Neurons/drug effects/metabolism ; Oxidative Stress/drug effects/genetics ; Rats ; Repressor Proteins/*genetics ; T-Box Domain Proteins/*genetics ; Transcription Factors/genetics ; Tumor Suppressor Proteins/*genetics ; }, abstract = {Oxidative stress and inflammatory insults are the major instigating events of bacterial intrauterine infection that lead to fetal brain injury. The purpose of this study is to investigate the remedial effects of N-acetyl-cysteine (NAC) for inflammation-caused deficits in brain development. We found that lipopolysaccharide (LPS) induced reactive oxygen species (ROS) production by RAW264.7 cells. Macrophage-conditioned medium caused noticeable cortical cell damage, specifically in cortical neurons. LPS at 25 μg/kg caused more than 75% fetal loss in rats. An increase in fetal cortical thickness was noted in the LPS-treated group. In the enlarged fetal cortex, laminar positioning of the early born cortical cells expressing Tbr1 and Ctip2 was disrupted, with a scattered distribution. The effect was similar, but minor, in later born Satb2-expressing cortical cells. NAC protected against LPS-induced neuron toxicity in vitro and counteracted pregnancy loss and alterations in thickness and lamination of the neocortex in vivo. Fetal loss and abnormal fetal brain development were due to LPS-induced ROS production. NAC is an effective protective agent against LPS-induced damage. This finding highlights the key therapeutic impact of NAC in LPS-caused abnormal neuronal laminar distribution during brain development.}, }
@article {pmid27576730, year = {2016}, author = {Sato, N and Takasaka, N and Yoshida, M and Tsubouchi, K and Minagawa, S and Araya, J and Saito, N and Fujita, Y and Kurita, Y and Kobayashi, K and Ito, S and Hara, H and Kadota, T and Yanagisawa, H and Hashimoto, M and Utsumi, H and Wakui, H and Kojima, J and Numata, T and Kaneko, Y and Odaka, M and Morikawa, T and Nakayama, K and Kohrogi, H and Kuwano, K}, title = {Metformin attenuates lung fibrosis development via NOX4 suppression.}, journal = {Respiratory research}, volume = {17}, number = {1}, pages = {107}, pmid = {27576730}, issn = {1465-993X}, mesh = {AMP-Activated Protein Kinases/metabolism ; Animals ; Bleomycin ; Cell Differentiation/drug effects ; Cells, Cultured ; Cytoprotection ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Activation ; Humans ; Idiopathic Pulmonary Fibrosis/enzymology/genetics/pathology/*prevention &amp; control ; Lung/*drug effects/enzymology/pathology ; Metformin/*pharmacology ; Mice, Inbred C57BL ; Myofibroblasts/*drug effects/enzymology/pathology ; NADPH Oxidase 4/genetics/*metabolism ; Phosphorylation ; RNA Interference ; Reactive Oxygen Species/metabolism ; Smad Proteins/metabolism ; Time Factors ; Transfection ; Transforming Growth Factor beta/pharmacology ; }, abstract = {BACKGROUND: Accumulation of profibrotic myofibroblasts in fibroblastic foci (FF) is a crucial process for development of fibrosis during idiopathic pulmonary fibrosis (IPF) pathogenesis, and transforming growth factor (TGF)-β plays a key regulatory role in myofibroblast differentiation. Reactive oxygen species (ROS) has been proposed to be involved in the mechanism for TGF-β-induced myofibroblast differentiation. Metformin is a biguanide antidiabetic medication and its pharmacological action is mediated through the activation of AMP-activated protein kinase (AMPK), which regulates not only energy homeostasis but also stress responses, including ROS. Therefore, we sought to investigate the inhibitory role of metformin in lung fibrosis development via modulating TGF-β signaling.<br><br>METHODS: TGF-&#x3b2;-induced myofibroblast differentiation in lung fibroblasts (LF) was used for in vitro models. The anti-fibrotic role of metfromin was examined in a bleomycin (BLM)-induced lung fibrosis model.<br><br>RESULTS: We found that TGF-&#x3b2;-induced myofibroblast differentiation was clearly inhibited by metformin treatment in LF. Metformin-mediated activation of AMPK was responsible for inhibiting TGF-&#x3b2;-induced NOX4 expression. NOX4 knockdown and N-acetylcysteine (NAC) treatment illustrated that NOX4-derived ROS generation was critical for TGF-&#x3b2;-induced SMAD phosphorylation and myofibroblast differentiation. BLM treatment induced development of lung fibrosis with concomitantly enhanced NOX4 expression and SMAD phosphorylation, which was efficiently inhibited by metformin. Increased NOX4 expression levels were also observed in FF of IPF lungs and LF isolated from IPF patients.<br><br>CONCLUSIONS: These findings suggest that metformin can be a promising anti-fibrotic modality of treatment for IPF affected by TGF-&#x3b2;.}, }
@article {pmid27576004, year = {2016}, author = {Massarsky, A and Bone, AJ and Dong, W and Hinton, DE and Prasad, GL and Di Giulio, RT}, title = {AHR2 morpholino knockdown reduces the toxicity of total particulate matter to zebrafish embryos.}, journal = {Toxicology and applied pharmacology}, volume = {309}, number = {}, pages = {63-76}, doi = {10.1016/j.taap.2016.08.024}, pmid = {27576004}, issn = {1096-0333}, mesh = {Animals ; Embryo, Nonmammalian/*drug effects ; Gene Knockdown Techniques ; Morpholinos/*genetics ; Particulate Matter/*toxicity ; Receptors, Aryl Hydrocarbon/*genetics ; Zebrafish/*embryology ; }, abstract = {The zebrafish embryo has been proposed as a 'bridge model' to study the effects of cigarette smoke on early development. Previous studies showed that exposure to total particulate matter (TPM) led to adverse effects in developing zebrafish, and suggested that the antioxidant and aryl hydrocarbon receptor (AHR) pathways play important roles. This study investigated the roles of these two pathways in mediating TPM toxicity. The study consisted of four experiments. In experiment I, zebrafish embryos were exposed from 6h post fertilization (hpf) until 96hpf to TPM0.5 and TPM1.0 (corresponding to 0.5 and 1.0μg/mL equi-nicotine units) in the presence or absence of an antioxidant (N-acetyl cysteine/NAC) or a pro-oxidant (buthionine sulfoximine/BSO). In experiment II, TPM exposures were performed in embryos that were microinjected with nuclear factor erythroid 2-related factor 2 (Nrf2), AHR2, cytochrome P450 1A (CYP1A), or CYP1B1 morpholinos, and deformities were assessed. In experiment III, embryos were exposed to TPM, and embryos/larvae were collected at 24, 48, 72, and 96hpf to assess several genes associated with the antioxidant and AHR pathways. Lastly, experiment IV assessed the activity and protein levels of CYP1A and CYP1B1 after exposure to TPM. We demonstrate that the incidence of TPM-induced deformities was generally not affected by NAC/BSO treatments or Nrf2 knockdown. In contrast, AHR2 knockdown reduced, while CYP1A or CYP1B1 knockdowns elevated the incidence of some deformities. Moreover, as shown by gene expression the AHR pathway, but not the antioxidant pathway, was induced in response to TPM exposure, providing further evidence for its importance in mediating TPM toxicity.}, }
@article {pmid27572503, year = {2016}, author = {Cao, L and Liu, J and Zhang, L and Xiao, X and Li, W}, title = {Curcumin inhibits H2O2-induced invasion and migration of human pancreatic cancer via suppression of the ERK/NF-κB pathway.}, journal = {Oncology reports}, volume = {36}, number = {4}, pages = {2245-2251}, doi = {10.3892/or.2016.5044}, pmid = {27572503}, issn = {1791-2431}, mesh = {Apoptosis/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Curcumin/*administration &amp; dosage ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hydrogen Peroxide/toxicity ; MAP Kinase Signaling System/*drug effects ; Matrix Metalloproteinase 2/genetics ; Matrix Metalloproteinase 9/genetics ; NF-kappa B/antagonists &amp; inhibitors/genetics ; Neoplasm Invasiveness/genetics/pathology ; Pancreatic Neoplasms/*drug therapy/*genetics/pathology ; Signal Transduction/drug effects ; }, abstract = {Curcumin (diferuloylmethane), a natural polyphenol present in turmeric, possesses a wide spectrum of pharmacological properties, including antioxidant and antitumor metastatic activities. However, the underlying mechanisms by which curcumin suppresses the metastasis of pancreatic cancer are still not fully elucidated. Our previous study demonstrated that a moderate amount of hydrogen peroxide (H2O2) is able to promote pancreatic cancer invasion. The aim of this study was to determine whether curcumin can suppress H2O2-induced tumor invasive and migratory abilities. Human pancreatic cancer BxPC-3 and Panc-1 cells were exposed to H2O2 with or without curcumin or N-acetylcysteine (NAC; a scavenger of free radicals). The effects of curcumin on pancreatic cancer cell proliferation was analyzed using MTT assay. The intracellular reactive oxygen species (ROS) was determined using 2,7-dichlorodihydrofluorecein diacetate. The cellular invasive and migratory abilities were analyzed using Transwell Matrigel invasion assay and wound healing assay, respectively. The expressions of matrix metalloproteinase (MMP)-2 and MMP-9 were determined using qT-PCR and western blotting at mRNA and protein level. The activation of p-extracellular signal-regulated kinase (ERK) and p-nuclear factor-κB (NF-κB) were measured by western blotting. Our data showed that curcumin inhibited cancer cell proliferation in a dose-dependent manner. Curcumin and NAC were able to inhibit H2O2-induced ROS production, reduce the migration and invasion, and decrease the expression of MMP-2 and MMP-9 in pancreatic cancer cells. In addition, the H2O2‑induced elevation of p-ERK and p-NF-κB in BxPC-3 and Panc-1 cells were reduced by curcumin, NAC and PD 98059 (an ERK inhibitor). These data indicate that curcumin suppresses pancreatic cancer migration and invasion through the inhibition of the ROS/ERK/NF-κB signaling pathway. This study suggests that curcumin may be a potential anticancer agent for pancreatic cancer.}, }
@article {pmid27570977, year = {2016}, author = {Duan, F and Yu, Y and Guan, R and Xu, Z and Liang, H and Hong, L}, title = {Vitamin K2 Induces Mitochondria-Related Apoptosis in Human Bladder Cancer Cells via ROS and JNK/p38 MAPK Signal Pathways.}, journal = {PloS one}, volume = {11}, number = {8}, pages = {e0161886}, pmid = {27570977}, issn = {1932-6203}, mesh = {Anthracenes/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Humans ; Imidazoles/pharmacology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*metabolism ; Phosphorylation/drug effects ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Urinary Bladder Neoplasms/metabolism ; Vitamin K 2/*pharmacology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {The effects of vitamin K2 on apoptosis in a variety of cancer cells have been well established in previous studies. However, the apoptotic effect of vitamin K2 on bladder cancer cells has not been evaluated. The aim of this study is to examine the apoptotic activity of Vitamin K2 in bladder cancer cells and investigate the underlying mechanism. In this study, Vitamin K2 induced apoptosis in bladder cancer cells through mitochondria pathway including loss of mitochondria membrane potential, cytochrome C release and caspase-3 cascade. Furthermore, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK was detected in Vitamin K2-treated cells and both SP600125 (an inhibitor of JNK) and SB203580 (an inhibitor of p38 MAPK) completely abolished the Vitamin K2-induced apoptosis and loss of mitochondria membrane potential. Moreover, the generation of reactive oxygen species (ROS) was detected in bladder cancer cells, upon treatment of vitamin K2 and the anti-oxidant N-acetyl cysteine (NAC) almost blocked the Vitamin K2-triggered apoptosis, loss of mitochondria membrane potential and activation of JNK and p38 MAPK. Taken together, these findings revealed that Vitamin K2 induces apoptosis in bladder cancer cells via ROS-mediated JNK/p38 MAPK and Mitochondrial pathways.}, }
@article {pmid27567825, year = {2016}, author = {Shankle, WR and Hara, J and Barrentine, LW and Curole, MV}, title = {CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer's Disease and Cerebrovascular Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {54}, number = {3}, pages = {1073-1084}, doi = {10.3233/JAD-160241}, pmid = {27567825}, issn = {1875-8908}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Aged, 80 and over ; Alzheimer Disease/*diagnostic imaging/diet therapy ; Atrophy ; Cerebral Cortex/*diagnostic imaging ; Cerebrovascular Disorders/*diagnostic imaging/diet therapy ; Dietary Supplements ; Female ; Humans ; Hyperhomocysteinemia/*diagnostic imaging/diet therapy ; Male ; Middle Aged ; Tetrahydrofolates/administration &amp; dosage ; Vitamin B 12/administration &amp; dosage/analogs &amp; derivatives ; Vitamin B Complex/*administration &amp; dosage ; White Matter/*diagnostic imaging ; }, abstract = {We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ ± σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ ± σ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [μ ± σ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.}, }
@article {pmid27563219, year = {2016}, author = {Mohan, S and Abdelwahab, SI and Hobani, YH and Syam, S and Al-Zubairi, AS and Al-Sanousi, R and Oraiby, ME}, title = {Catha edulis Extract Induces H9c2 Cell Apoptosis by Increasing Reactive Oxygen Species Generation and Activation of Mitochondrial Proteins.}, journal = {Pharmacognosy magazine}, volume = {12}, number = {Suppl 3}, pages = {S321-6}, pmid = {27563219}, issn = {0973-1296}, abstract = {BACKGROUND: Catha edulis (Khat) is an evergreen shrub or small tree, traditionally used by various peoples of the Arabian Peninsula and Africa as an integral component of the socioeconomic traditions. It is believed that the psychostimulant nature and toxic nature of khat is primarily due to the presence of cathinone and cathine respectively. Studies have shown that khat chewing is closely associated with cardiac complications, especially myocardial infarction. Hence in this study, we exposed cathine-rich khat extract in a cardiomyoblast H9c2 (2-1) cell line to check the cell death mechanism.<br><br>MATERIALS AND METHODS: Extraction of Catha edulis leaves was done and the presence of cathine was confirmed with LC-MS-MS. The anti-proliferative activity was assayed using MTT and apoptosis detection by acridine orange/propidium iodide assay. The expression of Bcl-2 and Bax protein and caspase-3/7 expression were analyzed. The level of reactive oxygen species generation was also evaluated.<br><br>RESULTS: The khat extract showed an IC50 value of 86.5 &#x3bc;g/ml at 48 hours treatment. We have observed significant early apoptosis events by intervened acridine orange within the fragmented DNA with bright green fluorescence upon treatment. The Bcl-2 expression in the treatment with IC50 concentration of khat extract for 24, 48 and 72 hours of incubation significantly decreased with increase in bax level. The increased activation of caspase-3/7 was significantly observed upon treatment together with significant increase of ROS was detected at 24 and 48 hours treatment.<br><br>CONCLUSION: Collectively, our results provide insight into the mechanisms by which Catha edulis leaves mediate cell death in cardiomyocytes.<br><br>SUMMARY: Catha edulis (Khat) is an evergreen psychotropic shrub or small treeExtraction of khat leaves was done and the presence of cathine was confirmed with liquid chromatography-mass spectrometry-mass spectrometryThe khat extract showed an IC(50) value of 86.5 &#x3bc;g/ml at 48 h treatment in H9c2 (2-1) cell lineThe observed cell death was associated with increased expression of Bcl2 and caspase-3Significant increase of reactive oxygen species was also detected in the cell with treatment. Abbreviations used: CNS: central nervous system; AMI: acute myocardial infarction; TLC: thin layer chromatography; ESI: electrospray ionization; FBS: fetal bovine serum; DMSO: dimethylsulfoxide; AO; acridine orange; PI; propidium iodide; HRP: horseradish peroxidase; HBSS: hank's balanced salt solution; DCFH-DA: 2',7'-dichlorofluorescin diacetate; NAC, 10 mM: NAC: N-acetyl cysteine; ROS: reactive oxygen species.}, }
@article {pmid27558879, year = {2018}, author = {Moro, F and Orrù, A and Marzo, CM and Di Clemente, A and Cervo, L}, title = {mGluR2/3 mediates short-term control of nicotine-seeking by acute systemic N-acetylcysteine.}, journal = {Addiction biology}, volume = {23}, number = {1}, pages = {28-40}, doi = {10.1111/adb.12443}, pmid = {27558879}, issn = {1369-1600}, mesh = {Acetylcysteine/*pharmacology ; Amino Acids/pharmacology ; Animals ; Conditioning, Operant ; Cues ; Drug-Seeking Behavior/*drug effects ; Excitatory Amino Acid Antagonists/pharmacology ; Glutamic Acid/*drug effects/metabolism ; Locomotion/drug effects ; Male ; Nicotine/*administration &amp; dosage ; Nicotinic Agonists/*administration &amp; dosage ; Nucleus Accumbens/drug effects/metabolism ; Rats ; Rats, Wistar ; Receptors, Metabotropic Glutamate/antagonists &amp; inhibitors/*metabolism ; Self Administration ; Xanthenes/pharmacology ; }, abstract = {Chronic self-administration of nicotine induces maladaptive changes in the cortico-accumbal glutamate (Glu) network. Consequently, re-exposure to nicotine-associated cues raises extracellular Glu in the nucleus accumbens reinstating drug-seeking. Restoring basal concentrations of extracellular Glu, thereby increasing tonic activation of the presynaptic group II metabotropic Glu receptors (mGluR2/3) with N-acetylcysteine (N-AC), might offer a valid therapeutic approach for maintaining smoking abstinence. Although N-AC modulates nicotine-seeking behavior by drug-associated stimuli in abstinent rats, it is still unclear whether it occurs through activation of mGluR2/3. Male Wistar rats were trained to associate discriminative stimuli (S[D] s) with the availability of intravenous nicotine (0.03 mg/kg/65 µl/2-second/infusion) or oral saccharin (100 µl of 50 mg/l) self-administration versus non-reward. Reinforced response was followed by a cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent lever press extinction, without reinforcers, S[D] s and CSs. Re-exposure to nicotine or saccharin S[D+] /CS[+] , but not non-reward S[D-] /CS[-] , revived responding on the previously reinforced lever. Acute N-AC, 100 but not 60 or 30 mg/kg i.p., reduced cue-induced nicotine-seeking. N-AC 100 mg/kg did not modify cue-induced saccharin-seeking behavior or influenced locomotor activity. Blocking mGluR2/3 with the selective antagonist LY341495, 1 mg/kg i.p., completely prevented the antirelapse activity of N-AC. The finding that N-AC prevents cue-induced nicotine-seeking by stimulating mGluR2/3 might indicate a therapeutic opportunity for acute cue-controlled nicotine-seeking. Future studies could evaluate the persistent effects of chronic N-AC in promoting enduring suppression of nicotine-cue conditioned responding.}, }
@article {pmid27557522, year = {2016}, author = {Yao, H and Fan, R and Zhao, X and Zhao, W and Liu, W and Yang, J and Sattar, H and Zhao, J and Zhang, Z and Xu, S}, title = {Selenoprotein W redox-regulated Ca2+ channels correlate with selenium deficiency-induced muscles Ca2+ leak.}, journal = {Oncotarget}, volume = {7}, number = {36}, pages = {57618-57632}, pmid = {27557522}, issn = {1949-2553}, mesh = {Acetylcysteine/chemistry ; Animals ; Antioxidants/chemistry ; Calcinosis ; Calcium/*chemistry/metabolism ; Calcium Channels/*chemistry ; Chick Embryo ; Chickens ; Cytosol/metabolism ; Male ; Membrane Potentials ; Mitochondria/metabolism ; Muscle, Skeletal/metabolism ; Myoblasts/metabolism ; *Oxidation-Reduction ; Oxidative Stress ; Sarcoplasmic Reticulum/metabolism ; Selenium/*deficiency ; Selenoprotein W/*chemistry ; }, abstract = {Selenium (Se) deficiency induces Ca2+ leak and calcification in mammal skeletal muscles; however, the exact mechanism is still unclear. In the present study, both Se-deficient chicken muscle models and selenoprotein W (SelW) gene knockdown myoblast and embryo models were used to study the mechanism. The results showed that Se deficiency-induced typical muscular injuries accompanied with Ca2+ leak and oxidative stress (P < 0.05) injured the ultrastructure of the sarcoplasmic reticulum (SR) and mitochondria; decreased the levels of the Ca2+ channels, SERCA, SLC8A, CACNA1S, ORAI1, STIM1, TRPC1, and TRPC3 (P < 0.05); and increased the levels of Ca2+ channel PMCA (P < 0.05). Similarly, SelW knockdown also induced Ca2+ leak from the SR and cytoplasm; increased mitochondrial Ca2+ levels and oxidative stress; injured SR and mitochondrial ultrastructure; decreased levels of SLC8A, CACNA1S, ORA1, TRPC1, and TRPC3; and caused abnormal activities of Ca2+ channels in response to inhibitors in myoblasts and chicken embryos. Thus, both Se deficiency and SelW knockdown induced Ca2+ leak, oxidative stress, and Ca2+ channel reduction. In addition, Ca2+ levels and the expression of the Ca2+ channels, RyR1, SERCA, CACNA1S, TRPC1, and TRPC3 were recovered to normal levels by N-acetyl-L-cysteine (NAC) treatment compared with SelW knockdown cells. Thus, with regard to the decreased Ca2+ channels, SelW knockdown closely correlated Se deficiency with Ca2+ leak in muscles. The redox regulation role of SelW is crucial in Se deficiency-induced Ca2+ leak in muscles.}, }
@article {pmid27556437, year = {2016}, author = {Cai, L and Wang, LF and Pan, JP and Mi, XN and Zhang, Z and Geng, HJ and Wang, JH and Hu, SH and Zhang, W and Gao, Q and Wu, WT and Luo, HM}, title = {Neuroprotective Effects of Methyl 3,4-Dihydroxybenzoate against TBHP-Induced Oxidative Damage in SH-SY5Y Cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {21}, number = {8}, pages = {}, pmid = {27556437}, issn = {1420-3049}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival ; DNA Damage/*drug effects ; Gene Expression Regulation/drug effects ; Glutathione Peroxidase/metabolism ; Humans ; Hydroxybenzoates/*pharmacology ; Neurons/*cytology/drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Superoxide Dismutase/metabolism ; tert-Butylhydroperoxide/*adverse effects ; }, abstract = {This study investigated the neuroprotective effects of methyl 3,4-dihydroxybenzoate (MDHB) against t-butyl hydroperoxide (TBHP) induced oxidative damage in SH-SY5Y (human neuroblastoma cells) and the underlying mechanisms. SH-SY5Y were cultured in DMEM + 10% FBS for 24 h and pretreated with different concentrations of MDHB or N-acetyl-l-cysteine (NAC) for 4 h prior to the addition of 40 μM TBHP for 24 h. Cell viability was analyzed using the methylthiazolyltetrazolium (MTT) and lactate dehydrogenase (LDH) assays. An annexin V-FITC assay was used to detect cell apoptosis rates. The 2',7'-dichlorofluorescin diacetate (DCFH-DA) assay was used to determine intracellular ROS levels. The activities of antioxidative enzymes (GSH-Px and SOD) were measured using commercially available kits. The oxidative DNA damage marker 8-OHdG was detected using ELISA. Western blotting was used to determine the expression of Bcl-2, Bax, caspase 3, p-Akt and Akt proteins in treated SH-SY5Y cells. Our results showed that MDHB is an effective neuroprotective compound that can mitigate oxidative stress and inhibit apoptosis in SH-SY5Y cells.}, }
@article {pmid27553486, year = {2017}, author = {Chen, CH and Young, YH}, title = {N-acetylcysteine as a single therapy for sudden deafness.}, journal = {Acta oto-laryngologica}, volume = {137}, number = {1}, pages = {58-62}, doi = {10.1080/00016489.2016.1214981}, pmid = {27553486}, issn = {1651-2251}, mesh = {Acetylcysteine/*therapeutic use ; Adrenal Cortex Hormones/administration &amp; dosage ; Adult ; Audiometry ; Dextrans/administration &amp; dosage ; Female ; Free Radical Scavengers/*therapeutic use ; Hearing Loss, Sudden/*drug therapy ; Humans ; Male ; Middle Aged ; Plasma Substitutes/administration &amp; dosage ; Vestibular Evoked Myogenic Potentials ; }, abstract = {CONCLUSION: Like NAC ameliorates hearing loss from acoustic trauma in the inner ear, NAC may also rescue hearing loss from sudden deafness confined to the inner ear.<br><br>OBJECTIVE: This study assesses the effect of N-acetyl-L-cysteine (NAC) as a single therapy for sudden deafness.<br><br>METHODS: Thirty-five sudden deafness patients with neither systemic disorders nor central signs in electronystagmography were treated with NAC alone and assigned to Group A. For comparison, another 35 sudden deafness patients treated by corticosteroids and plasma expander were assigned to Group B. There were no significant differences between the two groups in terms of age, sex, laterality, and pre-treatment mean hearing level. All patients underwent an inner ear test battery comprising audiometry, and ocular vestibular-evoked myogenic potential (oVEMP), cervical VEMP (cVEMP), and caloric tests.<br><br>RESULTS: Groups A and B did not significantly differ in the pre-treatment mean hearing level, and percentages of abnormal oVEMP, cVEMP, and caloric tests, indicating that the involvement severity of sudden deafness between the two groups was similar. However, Group A (43&#x2009;&#xb1;&#x2009;27&#x2009;dB) showed significantly greater mean hearing gain than Group B (21&#x2009;&#xb1;&#x2009;28&#x2009;dB), and Group A (91%) revealed better improved rate of hearing than Group B (57%).}, }
@article {pmid27539775, year = {2016}, author = {Haseeb, A and Bilal, M and Khan, MA}, title = {N-Acetyl Cysteine: A Possible Treatment for Diabetic Cardiomyopathy.}, journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP}, volume = {26}, number = {8}, pages = {720}, pmid = {27539775}, issn = {1681-7168}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antiviral Agents/pharmacology/*therapeutic use ; Diabetic Cardiomyopathies/*drug therapy/pathology ; Fibrosis/pathology/prevention &amp; control ; Mice ; Oxidative Stress/drug effects/physiology ; }, }
@article {pmid27539140, year = {2017}, author = {Kao, SJ and Lee, WJ and Chang, JH and Chow, JM and Chung, CL and Hung, WY and Chien, MH}, title = {Suppression of reactive oxygen species-mediated ERK and JNK activation sensitizes dihydromyricetin-induced mitochondrial apoptosis in human non-small cell lung cancer.}, journal = {Environmental toxicology}, volume = {32}, number = {4}, pages = {1426-1438}, doi = {10.1002/tox.22336}, pmid = {27539140}, issn = {1522-7278}, mesh = {A549 Cells ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology ; Cell Survival/drug effects ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Drug Synergism ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavonols/*pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lung Neoplasms/*drug therapy/metabolism/pathology ; MAP Kinase Signaling System ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Protein Kinase Inhibitors/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer with a high mortality rate and still remains a therapeutic challenge. A strategy for targeting NSCLC is to identify agents that are effective against NSCLC cells while sparing normal cells. Dihydromyricetin (DHM) is the major flavonoid component derived from Ampelopsis grossedentata, which has a long history of use in medicine. Herein, the molecular mechanisms by which DHM exerts its anticancer effects against NSCLC cells were investigated. Results from MTS, colony formation, Western blot, flow cytometric, and JC-1 mitochondrial membrane potential assays revealed that DHM showed a selective cytotoxic effect against NSCLC cells (A549 and H1975), but not against normal lung (WI-38) fibroblasts, by inducing apoptosis. DHM-induced cell apoptosis occurred through Bcl-w suppression-mediated mitochondrial membrane depolarization, caspase-9/-7/-3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage in A549 and H1975 cells. Moreover, treatment of A549 and H1975 cells with DHM induced increase of intracellular peroxide and sustained activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK)1/2, and the reactive oxygen species scavenger, N-acetylcysteine (NAC), reversed DHM-induced ERK and JNK activation. Furthermore, treatment of cells with specific inhibitors of ERK and JNK or NAC significantly promoted the DHM-induced activation of caspase-9/-7/-3 and PARP cleavage and also sensitized the antitumorigenic effect of DHM on NSCLC cells. These findings define and support a novel function of DHM of inducing mitochondrion-derived apoptosis in human NSCLC cells, and a combination of DHM with ERK and JNK inhibitors should be a good strategy for preventing NSCLC proliferation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1426-1438, 2017.}, }
@article {pmid27535955, year = {2017}, author = {Dube, KM and Ditch, KL and Hills, L}, title = {Use of Nebulized Heparin, Nebulized N-Acetylcysteine, and Nebulized Epoprostenol in a Patient With Smoke Inhalational Injury and Acute Respiratory Distress Syndrome.}, journal = {Journal of pharmacy practice}, volume = {30}, number = {6}, pages = {663-667}, doi = {10.1177/0897190016663071}, pmid = {27535955}, issn = {1531-1937}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Anticoagulants/administration &amp; dosage ; Antihypertensive Agents/administration &amp; dosage ; Drug Therapy, Combination ; Epoprostenol/*administration &amp; dosage ; Expectorants/administration &amp; dosage ; Heparin/*administration &amp; dosage ; Humans ; Male ; Nebulizers and Vaporizers/*statistics &amp; numerical data ; Respiratory Distress Syndrome/complications/diagnostic imaging/*drug therapy ; Smoke Inhalation Injury/complications/diagnostic imaging/*drug therapy ; Young Adult ; }, abstract = {Smoke inhalation injury (SIJ) is associated with an increase in morbidity and mortality in patients with burns. SIJ causes airway damage, inflammation, and bronchial obstruction, resulting in decreased oxygenation and perfusion status in these patients. Retrospective studies have compared the use of nebulized heparin (NH) plus nebulized N-acetylcysteine (NAC) and albuterol in patients with SIJ to those who received standard ventilator support with bronchodilator therapy. These studies are associated with a decrease in mortality when NH and nebulized NAC are administered to patients with SIJ. Approximately 20% of patients who develop SIJ will also develop acute respiratory distress syndrome (ARDS). Epoprostenol, a selective pulmonary vasodilator, has been utilized in the treatment of ARDS with mixed results for improving gas exchange. To our knowledge, this is the first case report of the concomitant administration of NH, nebulized NAC, and nebulized epoprostenol following SIJ in a burn patient with ARDS.}, }
@article {pmid27531992, year = {2016}, author = {Bhat, PV and Pandareesh,  and Khanum, F and Tamatam, A}, title = {Cytotoxic Effects of Ochratoxin A in Neuro-2a Cells: Role of Oxidative Stress Evidenced by N-acetylcysteine.}, journal = {Frontiers in microbiology}, volume = {7}, number = {}, pages = {1142}, pmid = {27531992}, issn = {1664-302X}, abstract = {Ochratoxin-A (OTA), is toxic secondary metabolite and is found to be a source of vast range of toxic effects like hepatotoxicity, nephrotoxicity. However, the information available currently regarding neurotoxic effects exerted by OTA is scanty. Hence, the present study was aimed to evaluate the neurotoxic effects of OTA and the possible mechanisms of toxicity as well as the role of cytotoxic oxidative stress on neuronal (Neuro-2a) cell line was evaluated in vitro. Results of the MTT and LDH assay showed that, OTA induced dose-dependent cell death in Neuro-2a cells and EC50 value was determined as 500 nM. OTA induced high levels of reactive oxygen species (ROS) and elevated levels of malondialdehyde, also loss of mitochondrial membrane potential was observed in a dose depended manner. Effects of OTA on ROS induced chromosomal DNA damage was assessed by Comet assay and plasmid DNA damage assay in which increase in DNA damage was observed in Neuro-2a cells by increasing the OTA concentration. Further western blotting analysis of OTA treated Neuro-2a cells indicated elevated expression levels of c-Jun, JNK3 and cleaved caspase-3 leading to apoptotic cell death. Other hand realtime-Q-PCR analysis clearly indicates the suppressed expression of neuronal biomarker genes including AChE, BDNF, TH and NOS2. Further N-acetylcysteine (NAC) pretreatment to Neuro-2a cells followed by OTA treatment clearly evidenced that, the significant reversal of toxic effects exerted by OTA on Neuro-2a cells. In the present study, results illustrate that ROS a principle event in oxidative stress was elevated by OTA toxicity in Neuro-2a cells. However, further in vivo, animal studies are in need to conclude the present study reports and the use of NAC as a remedy for OTA induced neuronal stress.}, }
@article {pmid27525081, year = {2016}, author = {Oghabian, Z and Afshar, A and Rahimi, HR}, title = {Hepatotoxicity due to zinc phosphide poisoning in two patients: role of N-acetylcysteine.}, journal = {Clinical case reports}, volume = {4}, number = {8}, pages = {768-772}, pmid = {27525081}, issn = {2050-0904}, abstract = {Zinc phosphide (Zn3P2/ZnP) is used as a rodenticide. The most common signs of toxicity are nausea, vomiting, hypotension, and metabolic acidosis; patients presenting such signs are referred to the emergency department (ED) of the hospitals. Therefore, this study aimed to report two cases of hepatotoxicity following accidental and intentional ZnP poisoning and successful management with N-acetylcysteine (NAC).}, }
@article {pmid27524254, year = {2016}, author = {Yang, L and Kuang, H and Liu, Y and Xu, H and Aguilar, ZP and Xiong, Y and Wei, H}, title = {Mechanism of enhanced antibacterial activity of ultra-fine ZnO in phosphate buffer solution with various organic acids.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {218}, number = {}, pages = {863-869}, doi = {10.1016/j.envpol.2016.08.015}, pmid = {27524254}, issn = {1873-6424}, mesh = {Anti-Bacterial Agents/chemistry/*pharmacology ; Azides/chemistry ; Bacillus cereus/*drug effects/metabolism/ultrastructure ; Buffers ; Carboxylic Acids/*chemistry ; Dose-Response Relationship, Drug ; Escherichia coli O157/*drug effects/metabolism/ultrastructure ; Microbial Viability/drug effects ; Microscopy, Electron, Scanning ; Phosphates/*chemistry ; Propidium/analogs &amp; derivatives/chemistry ; Reactive Oxygen Species/metabolism ; Solubility ; Solutions ; Zinc Oxide/chemistry/*pharmacology ; }, abstract = {Ultra-fine-ZnO showed low toxicity in complex water matrix containing multiple components such as PBS buffer and the toxic mechanism of ultra-fine-ZnO has not been clearly elucidated. In present study, enhanced antibacterial activity of 200 nm diameter ultra-fine-ZnO in PBS buffer against Bacillus cereus and Escherichia coli were observed in the presence of several organic acids in comparison with ultra-fine-ZnO in PBS buffer alone. These findings indicated that the toxic effects of the ultra-fine-ZnO was dependent on the concentration of released Zn[2+] which was affected by organic acids. The production of reactive oxygen species (ROS) did not responsible to the toxic mechanism of ultra-fine-ZnO which was tested using the antioxidant N-Acetylcysteine (NAC). Indeed, ultra-fine-ZnO induced bacteria cell membrane leakages and cell morphology damages that eventually led to cell death, which were confirmed using propidium monoazide (PMA) in combination with PCR and scanning electron microscopy (SEM). All data gathered herein suggested that released Zn[2+] played a major role in the microbial toxicity of ultra-fine-ZnO.}, }
@article {pmid27521979, year = {2016}, author = {Squeglia, LM and Baker, NL and McClure, EA and Tomko, RL and Adisetiyo, V and Gray, KM}, title = {Alcohol use during a trial of N-acetylcysteine for adolescent marijuana cessation.}, journal = {Addictive behaviors}, volume = {63}, number = {}, pages = {172-177}, pmid = {27521979}, issn = {1873-6327}, support = {K01 DA036739/DA/NIDA NIH HHS/United States ; T32 AA007474/AA/NIAAA NIH HHS/United States ; R01 DA026777/DA/NIDA NIH HHS/United States ; K23 AA025399/AA/NIAAA NIH HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; UG1 DA013727/DA/NIDA NIH HHS/United States ; K12 DA031794/DA/NIDA NIH HHS/United States ; U01 DA031779/DA/NIDA NIH HHS/United States ; U10 DA013727/DA/NIDA NIH HHS/United States ; UL1 TR001450/TR/NCATS NIH HHS/United States ; /RA/ARRA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Marijuana Abuse/*drug therapy ; Treatment Outcome ; Underage Drinking/*statistics &amp; numerical data ; }, abstract = {AIMS: Current adolescent alcohol treatments have modest effects and high relapse rates. Evaluation of novel pharmacotherapy treatment is warranted. N-acetylcysteine (NAC), an over-the-counter antioxidant supplement with glutamatergic properties, is a promising treatment for marijuana cessation in adolescents; however, its effects on adolescent drinking have not been examined. To that end, this secondary analysis evaluated: (1) the effect of NAC vs. placebo on alcohol use over an eight-week adolescent marijuana cessation trial and (2) the role of marijuana cessation and reduction on subsequent alcohol use.<br><br>METHODS: Marijuana-dependent adolescents (ages 15-21; N=116) interested in treatment were randomized to NAC 1200mg or matched placebo twice daily for eightweeks. Participants were not required to be alcohol users or interested in alcohol cessation to qualify.<br><br>RESULTS: There were no demographic or baseline alcohol use differences between participants randomized to NAC vs. placebo (ps>0.05). Of the 89 participants returning for &#x2265;one visit following randomization, 77 reported &#x2265;one alcoholic drink in the 30days prior to study entry and averaged 1.3 (SD=1.4) binge drinking days per week. During treatment, less marijuana use (measured via urine cannabinoid levels) was associated with less alcohol use in the NAC-treated group but not in the placebo-treated group (p=0.016).<br><br>CONCLUSIONS: There was no evidence of compensatory alcohol use during marijuana treatment. In fact, in the NAC group, lower levels of marijuana use were associated with less alcohol use, suggesting NAC effects may generalize to other substances and could be useful in decreasing adolescent alcohol use. NAC trials specifically focused on alcohol-using adolescents are warranted.}, }
@article {pmid27516533, year = {2016}, author = {Guo, JY and Teng, X and Laddha, SV and Ma, S and Van Nostrand, SC and Yang, Y and Khor, S and Chan, CS and Rabinowitz, JD and White, E}, title = {Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells.}, journal = {Genes &amp; development}, volume = {30}, number = {15}, pages = {1704-1717}, pmid = {27516533}, issn = {1549-5477}, support = {P30 CA072720/CA/NCI NIH HHS/United States ; R01 CA193970/CA/NCI NIH HHS/United States ; K22 CA190521/CA/NCI NIH HHS/United States ; R01 CA163591/CA/NCI NIH HHS/United States ; R01 CA130893/CA/NCI NIH HHS/United States ; R01 CA188096/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Autophagy ; Autophagy-Related Protein 7/genetics/metabolism ; Cell Line, Tumor ; Energy Metabolism/drug effects/genetics ; Gene Deletion ; Genetic Variation ; Genome, Mitochondrial/genetics ; Glutamine/pharmacology ; Lung Neoplasms/*metabolism/physiopathology ; Mice ; Mitochondria/metabolism ; Nucleosides/pharmacology ; Nucleotides/*metabolism ; Oxidation-Reduction ; ras Proteins/*metabolism ; }, abstract = {Autophagy degrades and is thought to recycle proteins, other macromolecules, and organelles. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes malignancy. Autophagy-deficient tumor-derived cell lines are respiration-impaired and starvation-sensitive. However, to what extent their sensitivity to starvation arises from defective mitochondria or an impaired supply of metabolic substrates remains unclear. Here, we sequenced the mitochondrial genomes of wild-type or autophagy-deficient (Atg7(-/-)) Kras-driven lung tumors. Although Atg7 deletion resulted in increased mitochondrial mutations, there were too few nonsynonymous mutations to cause generalized mitochondrial dysfunction. In contrast, pulse-chase studies with isotope-labeled nutrients revealed impaired mitochondrial substrate supply during starvation of the autophagy-deficient cells. This was associated with increased reactive oxygen species (ROS), lower energy charge, and a dramatic drop in total nucleotide pools. While starvation survival of the autophagy-deficient cells was not rescued by the general antioxidant N-acetyl-cysteine, it was fully rescued by glutamine or glutamate (both amino acids that feed the TCA cycle and nucleotide synthesis) or nucleosides. Thus, maintenance of nucleotide pools is a critical challenge for starving Kras-driven tumor cells. By providing bioenergetic and biosynthetic substrates, autophagy supports nucleotide pools and thereby starvation survival.}, }
@article {pmid27516318, year = {2016}, author = {Aiassa, V and Zoppi, A and Becerra, MC and Albesa, I and Longhi, MR}, title = {Enhanced inhibition of bacterial biofilm formation and reduced leukocyte toxicity by chloramphenicol:β-cyclodextrin:N-acetylcysteine complex.}, journal = {Carbohydrate polymers}, volume = {152}, number = {}, pages = {672-678}, doi = {10.1016/j.carbpol.2016.07.013}, pmid = {27516318}, issn = {1879-1344}, mesh = {*Acetylcysteine/chemistry/pharmacology ; Biofilms/*drug effects ; *Chloramphenicol/chemistry/pharmacology ; Humans ; Leukocytes/*metabolism ; Staphylococcus aureus/*physiology ; *beta-Cyclodextrins/chemistry/pharmacology ; }, abstract = {The purpose of this study was to improve the physicochemical and biological properties of chloramphenicol (CP) by multicomponent complexation with β-cyclodextrin (β-CD) and N-acetylcysteine (NAC). The present work describes the ability of solid multicomponent complex (MC) to decrease biomass and cellular activity of Staphylococcus by crystal violet and XTT assay, and leukocyte toxicity, measuring the increase of reactive oxygen species by chemiluminescence, and using 123-dihydrorhodamine. In addition, MC was prepared by the freeze-drying or physical mixture methods, and then characterized by scanning electron microscopy and powder X-ray diffraction. Nuclear magnetic resonance and phase solubility studies provided information at the molecular level on the structure of the MC and its association binding constants, respectively. The results obtained allowed us to conclude that MC formation is an effective pharmaceutical strategy that can reduce CP toxicity against leukocytes, while enhancing its solubility and antibiofilm activity.}, }
@article {pmid27514995, year = {2016}, author = {Riegger, J and Joos, H and Palm, HG and Friemert, B and Reichel, H and Ignatius, A and Brenner, RE}, title = {Antioxidative therapy in an ex vivo human cartilage trauma-model: attenuation of trauma-induced cell loss and ECM-destructive enzymes by N-acetyl cysteine.}, journal = {Osteoarthritis and cartilage}, volume = {24}, number = {12}, pages = {2171-2180}, doi = {10.1016/j.joca.2016.07.019}, pmid = {27514995}, issn = {1522-9653}, mesh = {Acetylcysteine ; *Cartilage ; Chondrocytes ; Extracellular Matrix ; Humans ; Proteoglycans ; }, abstract = {OBJECTIVE: Mechanical trauma of articular cartilage results in cell loss and cytokine-driven inflammatory response. Subsequent accumulation of reactive oxygen (ROS) and nitrogen (RNS) species enhances the enzymatic degradation of the extracellular matrix (ECM). This study aims on the therapeutic potential of N-acetyl cysteine (NAC) in a human ex vivo cartilage trauma-model, focusing on cell- and chondroprotective features.<br><br>DESIGN: Human full-thickness cartilage explants were subjected to a defined impact trauma (0.59&#xa0;J) and treated with NAC. Efficiency of NAC administration was evaluated by following outcome parameters: cell viability, apoptosis rate, anabolic/catabolic gene expression, secretion and activity of matrix metalloproteinases (MMPs) and proteoglycan (PG) release.<br><br>RESULTS: Continuous NAC administration increased cell viability and reduced the apoptosis rate after trauma. It also suppressed trauma-induced gene expression of ECM-destructive enzymes, such as ADAMTS-4, MMP-1, -2, -3 and -13 in a dosage- and time-depending manner. Subsequent suppression of MMP-2 and MMP-13 secretion reflected these findings on protein level. Moreover, NAC inhibited proteolytic activity of MMPs and reduced PG release.<br><br>CONCLUSION: In the context of this ex&#xa0;vivo study, we showed not only remarkable cell- and chondroprotective features, but also revealed new encouraging findings concerning the therapeutically effective concentration and treatment-time regimen of NAC. Its defense against chondrocyte apoptosis and catabolic enzyme secretion recommends NAC as a multifunctional add-on reagent for pharmaceutical intervention after cartilage injury. Taken together, our data increase the knowledge on the therapeutic potential of NAC after cartilage trauma and presents a basis for future in&#xa0;vivo studies.}, }
@article {pmid27514409, year = {2016}, author = {Qin, QY and Zhang, YY and Sun, SQ and Zhu, H and Yang, XJ and Yan, HT}, title = {[Benzoquinone induce autophagy in HL60 cells and the role of reactive oxygen species in induced autophagy].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {34}, number = {5}, pages = {325-328}, doi = {10.3760/cma.j.issn.1001-9391.2016.05.002}, pmid = {27514409}, issn = {1001-9391}, mesh = {Acetylcysteine ; *Autophagy ; Benzoquinones ; Cell Cycle ; Cell Proliferation ; Cell Survival ; HL-60 Cells ; Humans ; Reactive Oxygen Species ; }, abstract = {OBJECTIVE: To investigate whether autophagy can be induced by 1, 4-benzoquinone (1, 4-BQ) in HL60 cells, as well as the role of reactive oxygen species (ROS) in induced autophagy.<br><br>METHODS: In order to determine a suitable 1, 4-BQ treatment concentration for autophagy detection in HL60 cells, the cell vitality were examined by CCK8 assay. Logarithmic-growth-phased cells were divided into control group, 1, 4-BQ group (10&#x3bc;mol/L 1, 4-BQ, 24 h) , NAC group (antioxidant n-acetyl cysteine, 5mmol/L, 24 h) and the 1, 4-BQ+NAC group (5 mmol/L NAC were preincubated for 1h prior to the treatment with 10 &#x3bc;mol/L 1, 4-BQ for 24 h). The autophagic acidic vesicle were inspected by acridine orange staining, LC3 were detected by immunofluorescence staining, and expressions of LC3 and Beclin1 were quantitatively detected by Western blot.<br><br>RESULTS: The results from cell viability test indicated that 1, 4-BQ exhibited a dose-dependent toxicity to HL60 cells. Compared with control group.the cell viability in 20.0&#x3001;40.0&#x3bc;mol/L concentration were decreased obviously, and the differences had statistical significance (P<0.05). Compare with contrd group acidic vesicle, LC3II, LC3II/LC3I and Beclin1 protein expressions were increased in 1, 4-BQ group, after both respectively 12.4% and 27%, the differences had statistital significance. While 1, 4-BQ+NAC group was observed that acidic vesicle, LC3 and Beclin1 protein level were markedly lower than 1, 4-BQ group, after both decreased 12.6% and 22.6% respectively, both the difference were statistically significant (P<0.05).<br><br>CONCLUSION: 1, 4-BQ can induce autophagy in HL60 cells, the induction of autophagy is at least partly resulted from ROS. Antioxidant can effectively suppress the occurrence of induced autophagy.}, }
@article {pmid27513568, year = {2016}, author = {Peter, T and Bissinger, R and Lang, F}, title = {Stimulation of Eryptosis by Caspofungin.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {39}, number = {3}, pages = {939-949}, doi = {10.1159/000447802}, pmid = {27513568}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Aniline Compounds ; Annexin A5 ; Antifungal Agents/*pharmacology ; Calcium/*metabolism ; Casein Kinases/antagonists &amp; inhibitors/genetics/metabolism ; Caspases/genetics/metabolism ; Caspofungin ; Cells, Cultured ; Ceramides/metabolism ; Echinocandins/*pharmacology ; Eryptosis/*drug effects ; Erythrocytes/chemistry/cytology/*drug effects ; Flow Cytometry ; Fluoresceins ; Fluorescent Dyes ; Gene Expression ; Hemolysis/drug effects ; Humans ; Lipopeptides/*pharmacology ; Oligopeptides/pharmacology ; Oxidative Stress ; Phosphatidylserines/metabolism ; Protein Kinase C/antagonists &amp; inhibitors/genetics/metabolism ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; Xanthenes ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {BACKGROUND/AIMS: The echinocandin antifungal agent caspofungin has been shown to trigger apoptosis of fungal cells. Beyond that, caspofungin is toxic for host mitochondria. Even though lacking mitochondria, erythrocytes may enter apoptosis-like suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in triggering of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, caspase activation and/or activation of p38 kinase, protein kinase C, and casein kinase. The present study explored, whether caspofungin induces eryptosis and, if so, to shed some light on the cellular mechanisms involved.<br><br>METHODS: Flow cytometry was employed to determine phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was quantified from hemoglobin concentration in the supernatant.<br><br>RESULTS: A 48 hours exposure of human erythrocytes to caspofungin (&#x2265; 30 &#xb5;g/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, significantly enhanced hemolysis, but did not significantly increase Fluo3-fluorescence, DCFDA fluorescence or ceramide abundance. The effect of caspofungin on annexin-V-binding was not significantly blunted by removal of extracellular Ca2+, by inhibition of caspases with pancaspase inhibitor zVAD (10 &#xb5;M), or by addition of the antioxidant N-acetyl-cysteine (1 mM), p38 kinase inhibitor SB203580 (2 &#xb5;M) or protein kinase C inhibitor staurosporine (1 &#xb5;M). The effect of caspofungin on annexin-V-binding was, however, significantly blunted in the presence of casein kinase inhibitor D4476 (10 &#xb5;M).<br><br>CONCLUSIONS: Caspofungin triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect possibly involving activation of casein kinase.}, }
@article {pmid27509531, year = {2017}, author = {Zhou, Y and Shi, X and Chen, H and Zhang, S and Salker, MS and Mack, AF and Föller, M and Mak, TW and Singh, Y and Lang, F}, title = {DJ-1/Park7 Sensitive Na[+] /H[+] Exchanger 1 (NHE1) in CD4[+] T Cells.}, journal = {Journal of cellular physiology}, volume = {232}, number = {11}, pages = {3050-3059}, doi = {10.1002/jcp.25516}, pmid = {27509531}, issn = {1097-4652}, mesh = {Animals ; Antioxidants/pharmacology ; CD4-Positive T-Lymphocytes/drug effects/*metabolism ; Cation Transport Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Cells, Cultured ; Genotype ; Hydrogen-Ion Concentration ; Mice, Inbred C57BL ; Mice, Knockout ; Phenotype ; Protein Deglycase DJ-1/deficiency/genetics/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Sodium-Hydrogen Exchanger 1 ; Sodium-Hydrogen Exchangers/antagonists &amp; inhibitors/genetics/*metabolism ; Time Factors ; Up-Regulation ; }, abstract = {DJ-1/Park7 is a redox-sensitive chaperone protein counteracting oxidation and presumably contributing to the control of oxidative stress responses and thus inflammation. DJ-1 gene deletion exacerbates the progression of Parkinson's disease presumably by augmenting oxidative stress. Formation of reactive oxygen species (ROS) is paralleled by activation of the Na[+] /H[+] exchanger 1 (NHE1). ROS formation in CD4[+] T cells plays a decisive role in regulating inflammatory responses. In the present study, we explored whether DJ-1 is expressed in CD4[+] T cells, and affects ROS production as well as NHE1 in those cells. To this end, DJ-1 and NHE1 transcript, and protein levels were quantified by qRT-PCR and Western blotting, respectively, intracellular pH (pHi) utilizing bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) fluorescence, NHE activity from realkalinization after an ammonium pulse, and ROS production utilizing 2',7' -dichlorofluorescin diacetate (DCFDA) fluorescence. As a result DJ-1 was expressed in CD4[+] T cells. ROS formation, NHE1 transcript levels, NHE1 protein, and NHE activity were higher in CD4[+] T cells from DJ-1 deficient mice than in CD4[+] T cells from wild type mice. Antioxidant N-acetyl-cysteine (NAC) and protein tyrosine kinase (PTK) inhibitor staurosporine decreased the NHE activity in DJ-1 deficient CD4[+] T cells, and blunted the difference between DJ-1[-/-] and DJ-1[+/+] CD4[+] T cells, an observation pointing to a role of ROS in the up-regulation of NHE1 in DJ-1[-/-] CD4[+] T cells. In conclusion, DJ-1 is a powerful regulator of ROS production as well as NHE1 expression and activity in CD4[+] T cells. J. Cell. Physiol. 232: 3050-3059, 2017. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid27507514, year = {2017}, author = {Pilipczuk, T and Kusznierewicz, B and Chmiel, T and Przychodzeń, W and Bartoszek, A}, title = {Simultaneous determination of individual isothiocyanates in plant samples by HPLC-DAD-MS following SPE and derivatization with N-acetyl-l-cysteine.}, journal = {Food chemistry}, volume = {214}, number = {}, pages = {587-596}, doi = {10.1016/j.foodchem.2016.07.125}, pmid = {27507514}, issn = {1873-7072}, mesh = {Acetylcysteine/*chemistry ; Chromatography, High Pressure Liquid/*methods ; Chromatography, Liquid/*methods ; Isothiocyanates/*chemistry ; Mass Spectrometry/*methods ; Plants/*chemistry ; Solid Phase Extraction/methods ; }, abstract = {The procedure for the isothiocyanates (ITCs) determination that involves derivatization with N-acetyl-l-cysteine (NAC) and separation by HPLC was developed. Prior to derivatization, plant ITCs were isolated and purified using solid-phase extraction (SPE). The optimum conditions of derivatization are: 500μL of isopropanolic eluate obtained by SPE combined with 500μL of derivatizing reagent (0.2M NAC and 0.2M NaHCO3 in water) and reaction time of 1h at 50°C. The formed dithiocarbamates are directly analyzed by HPLC coupled with diode array detector and mass spectrometer if required. The method was validated for nine common natural ITCs. Calibration curves were linear (R(2)⩾0.991) within a wide range of concentrations and limits of detection were below 4.9nmol/mL. The recoveries were in the range of 83.3-103.7%, with relative standard deviations <5.4%. The developed method has been successfully applied to determine ITCs in broccoli, white cabbage, garden cress, radish, horseradish and papaya.}, }
@article {pmid27502769, year = {2016}, author = {Skvarc, DR and Dean, OM and Byrne, LK and Gray, LJ and Ives, K and Lane, SE and Lewis, M and Osborne, C and Page, R and Stupart, D and Turner, A and Berk, M and Marriott, AJ}, title = {The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: study protocol for a randomised controlled trial.}, journal = {Trials}, volume = {17}, number = {}, pages = {395}, pmid = {27502769}, issn = {1745-6215}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Anti-Inflammatory Agents/*administration &amp; dosage/adverse effects ; Antioxidants/*administration &amp; dosage/adverse effects ; Biomarkers/blood ; Clinical Protocols ; Cognition/*drug effects ; Cognition Disorders/diagnosis/etiology/*prevention &amp; control/psychology ; Double-Blind Method ; Drug Administration Schedule ; Female ; Hospitals, University ; Humans ; Inflammation Mediators/blood ; Male ; Middle Aged ; Neuropsychological Tests ; Oxidative Stress/drug effects ; Research Design ; Surgical Procedures, Operative/*adverse effects ; Time Factors ; Treatment Outcome ; Victoria ; }, abstract = {BACKGROUND: Some degree of cognitive decline after surgery occurs in as many as one quarter of elderly surgical patients, and this decline is associated with increased morbidity and mortality. Cognition may be affected across a range of domains, including memory, psychomotor skills, and executive function. Whilst the exact mechanisms of cognitive change after surgery are not precisely known, oxidative stress and subsequent neuroinflammation have been implicated. N-acetylcysteine (NAC) acts via multiple interrelated mechanisms to influence oxidative homeostasis, neuronal transmission, and inflammation. NAC has been shown to reduce oxidative stress and inflammation in both human and animal models. There is clinical evidence to suggest that NAC may be beneficial in preventing the cognitive decline associated with both acute physiological insults and dementia-related disorders. To date, no trials have examined perioperative NAC as a potential moderator of postoperative cognitive changes in the noncardiac surgery setting.<br><br>METHODS AND DESIGN: This is a single-centre, randomised, double-blind, placebo-controlled clinical trial, with a between-group, repeated-measures, longitudinal design. The study will recruit 370 noncardiac surgical patients at the University Hospital Geelong, aged 60&#xa0;years or older. Participants are randomly assigned to receive either NAC or placebo (1:1 ratio), and groups are stratified by age and surgery type. Participants undergo a series of neuropsychological tests prior to surgery, 7&#xa0;days, 3&#xa0;months, and 12&#xa0;months post surgery. It is hypothesised that the perioperative administration of NAC will reduce the degree of postoperative cognitive changes at early and long-term follow-up, as measured by changes on individual measures of the neurocognitive battery, when compared with placebo. Serum samples are taken on the day of surgery and on day 2 post surgery to quantitate any changes in levels of biomarkers of inflammation and oxidative stress.<br><br>DISCUSSION: The PANACEA trial aims to examine the potential efficacy of perioperative NAC to reduce the severity of postoperative cognitive dysfunction in an elderly, noncardiac surgery population. This is an entirely novel approach to the prevention of postoperative cognitive dysfunction and will have high impact and translatable outcomes if NAC is found to be beneficial.<br><br>TRIAL REGISTRATION: The PANACEA trial has been registered with the Therapeutic Goods Administration, and the Australian New Zealand Clinical Trials Registry: ACTRN12614000411640 ; registered on 15 April 2014.}, }
@article {pmid27499574, year = {2016}, author = {Kanazawa, K and Sakamoto, M and Kanazawa, K and Ishigaki, Y and Aihara, Y and Hashimoto, T and Mizuno, M}, title = {Lipid peroxides as endogenous oxidants forming 8-oxo-guanosine and lipid-soluble antioxidants as suppressing agents.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {59}, number = {1}, pages = {16-24}, pmid = {27499574}, issn = {0912-0009}, abstract = {The oxidation of guanosine to 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA is closely associated with induction of various diseases, but the endogenous oxidant species involved remains unclear. Hydrogen peroxides (H2O2) have been considered to be the oxidant, while lipid peroxides are another possible oxidant because generated easily in bio-membranes surrounding DNA. The oxidant potency was compared between lipid peroxides and H2O2. Linoleic acid hydroperoxides (LOOH) formed 8-oxo-dG at a higher level than H2O2 in guanosine or double-stranded DNA. In the presence of a physiological concentration of Fe(2+) to produce hydroxyl radicals, LOOH was also a stronger oxidant. In a lipid micelle, LOOH markedly produced 8-oxo-dG at a concentration one-tenth of that of H2O2. Upon adding to rat hepatic mitochondria, phosphatidylcholine hydroperoxides produced 8-oxo-dG abundantly. Employing HepG2 cells after pretreated with glutathione peroxidase inhibitor, LOOH formed 8-oxo-dG more abundantly than H2O2. Then, antioxidants to suppress the 8-oxo-dG formation were examined, when the nuclei of pre-incubated HepG2 with antioxidants were exposed to LOOH. Water-soluble ascorbic acid, trolox, and N-acetyl cysteine showed no or weak antioxidant potency, while lipid-soluble 2,6-dipalmitoyl ascorbic acid, α-tocopherol, and lipid-soluble phytochemicals exhibited stronger potency. The present study shows preferential formation of 8-oxo-dG upon LOOH and the inhibition by lipid-soluble antioxidants.}, }
@article {pmid27496192, year = {2016}, author = {Han, G and Zhou, Q}, title = {Dimethylfumarate induces cell cycle arrest and apoptosis via regulating intracellular redox systems in HeLa cells.}, journal = {In vitro cellular &amp; developmental biology. Animal}, volume = {52}, number = {10}, pages = {1034-1041}, pmid = {27496192}, issn = {1543-706X}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Catalase/metabolism ; Cell Cycle Checkpoints/*drug effects ; Cell Proliferation/drug effects ; Dimethyl Fumarate/*pharmacology ; Glutathione/metabolism ; HeLa Cells ; Humans ; Intracellular Space/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Oxidation-Reduction/drug effects ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; }, abstract = {Dimethylfumarate (DMF) is cytotoxic to several kinds of cells and serves as an anti-tumor drug. This study was designed to investigate the effects and underlying mechanism of DMF on cervical cancer cells. HeLa cells were cultured and treated with 0, 50, 100, 150, and 200 μM DMF, respectively. After 24 h, cell growth was evaluated using Cell Counting Kit-8 (CCK-8) assay and the cell cycle was examined using flow cytometry. In addition, cell apoptosis was detected by Annexin V/propidium iodide (PI) staining and the expressions of caspase-3 and poly-ADP-ribose polymerase (PARP) were detected using western blotting. The redox-related factors were then assessed. Furthermore, all of the indicators were detected in HeLa cells after combined treatment of DMF and N-acetyl-L-cysteine (NAC, an oxygen-free radical scavenger). The cell number and cell growth of HeLa were obviously inhibited by DMF in a dose-dependent manner, as the cell cycle was arrested at G0/G1 phase (P < 0.05). The apoptotic HeLa cells were markedly increased, and the expression levels of caspase-3 and PARP were significantly increased in a DMF concentration-dependent way (P < 0.05). Meanwhile, loss of △Ψm, increase in reactive oxygen species and O2[·-], and the decrease in catalase activity and glutathione (GSH) level were found after DMF treatment (P < 0.05). All these changes were significantly attenuated and even completely disappeared by adding NAC (P < 0.05). In conclusion, the cytotoxicity of DMF on cell proliferation and apoptosis of HeLa cells was mainly related to the intracellular redox systems by depletion of intracellular GSH.}, }
@article {pmid27494339, year = {2016}, author = {Sharma, M and Sud, A and Kaur, T and Tandon, C and Singla, SK}, title = {N-acetylcysteine with apocynin prevents hyperoxaluria-induced mitochondrial protein perturbations in nephrolithiasis.}, journal = {Free radical research}, volume = {50}, number = {9}, pages = {1032-1044}, doi = {10.1080/10715762.2016.1221507}, pmid = {27494339}, issn = {1029-2470}, mesh = {Acetophenones/administration &amp; dosage/*therapeutic use ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/*therapeutic use ; Hyperoxaluria/*drug therapy ; Male ; Mice ; Mitochondria/*metabolism ; Nephrolithiasis/*genetics/*metabolism ; Rats, Inbred WF ; }, abstract = {Diminished mitochondrial activities were deemed to play an imperative role in surged oxidative damage perceived in hyperoxaluric renal tissue. Proteomics is particularly valuable to delineate the damaging effects of oxidative stress on mitochondrial proteins. The present study was designed to apply large-scale proteomics to describe systematically how mitochondrial proteins/pathways govern the renal damage and calcium oxalate crystal adhesion in hyperoxaluria. Furthermore, the potential beneficial effects of combinatorial therapy with N-acetylcysteine (NAC) and apocynin were studied to establish its credibility in the modulation of hyperoxaluria-induced alterations in mitochondrial proteins. In an experimental setup with male Wistar rats, five groups were designed for 9 d. At the end of the experiment, 24-h urine was collected and rats were euthanized. Urinary samples were analyzed for kidney injury marker and creatinine clearance. Transmission electron microscopy revealed distorted renal mitochondria in hyperoxaluria but combinatorial therapy restored the normal mitochondrial architecture. Mitochondria were isolated from renal tissue of experimental rats, and mitochondrial membrane potential was analyzed. The two-dimensional electrophoresis (2-DE) based comparative proteomic analysis was performed on proteins isolated from renal mitochondria. The results revealed eight differentially expressed mitochondrial proteins in hyperoxaluric rats, which were identified by Matrix-assisted laser desorption/ionization time of flight/time of flight (MALDI-TOF/TOF) analysis. Identified proteins including those involved in important mitochondrial processes, e.g. antioxidant defense, energy metabolism, and electron transport chain. Therapeutic administration of NAC with apocynin significantly expunged hyperoxaluria-induced discrepancy in the renal mitochondrial proteins, bringing them closer to the controls. The results provide insights to further understand the underlying mechanisms in the development of hyperoxaluria-induced nephrolithiasis and the therapeutic relevance of the combinatorial therapy.}, }
@article {pmid27492531, year = {2016}, author = {Blasi, F and Page, C and Rossolini, GM and Pallecchi, L and Matera, MG and Rogliani, P and Cazzola, M}, title = {The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections.}, journal = {Respiratory medicine}, volume = {117}, number = {}, pages = {190-197}, doi = {10.1016/j.rmed.2016.06.015}, pmid = {27492531}, issn = {1532-3064}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Inhalation ; Biofilms/*drug effects/growth &amp; development ; Bronchiectasis/complications/drug therapy ; Bronchitis/complications/drug therapy ; Bronchitis, Chronic/complications/drug therapy ; Cystic Fibrosis/complications/drug therapy ; Expectorants/therapeutic use ; Humans ; Injections, Intramuscular ; Pulmonary Disease, Chronic Obstructive/complications/drug therapy ; Respiratory Tract Infections/complications/*drug therapy ; }, abstract = {OBJECTIVES: In airway infections, biofilm formation has been demonstrated to be responsible for both acute and chronic events, and constitutes a genuine challenge in clinical practice. Difficulty in eradicating biofilms with systemic antibiotics has led clinicians to consider the possible role of non-antibiotic therapy. The aim of this review is to examine current evidence for the use of N-acetylcysteine (NAC) in the treatment of biofilm-related respiratory infections.<br><br>METHODS: Electronic searches of PUBMED up to September 2015 were conducted, searching for 'biofilm', 'respiratory tract infection', 'N-acetylcysteine', 'cystic fibrosis', 'COPD', 'bronchiectasis', 'otitis', and 'bronchitis' in titles and abstracts. Studies included for review were primarily in English, but a few in Italian were also selected.<br><br>RESULTS: Biofilm formation may be involved in many infections, including ventilator-associated pneumonia, cystic fibrosis, bronchiectasis, bronchitis, and upper respiratory airway infections. Many in&#xa0;vitro studies have demonstrated that NAC is effective in inhibiting biofilm formation, disrupting preformed biofilms (both initial and mature), and reducing bacterial viability in biofilms. There are fewer clinical studies on the use of NAC in disruption of biofilm formation, although there is some evidence that NAC alone or in combination with antibiotics can decrease the risk of exacerbations of chronic bronchitis, chronic obstructive pulmonary disease, and rhinosinusitis. However, the usefulness of NAC in the treatment of cystic fibrosis and bronchiectasis is still matter of debate. Most of the studies published to date have used oral or intramuscular NAC formulations.<br><br>CONCLUSIONS: Evidence from in&#xa0;vitro studies indicates that NAC has good antibacterial properties and the ability to interfere with biofilm formation and disrupt biofilms. Results from clinical studies have provided some encouraging findings that need to be confirmed and expanded using other routes of administration of NAC such as inhalation.}, }
@article {pmid27490835, year = {2016}, author = {Chen, AT and Chibnall, JT and Nasrallah, HA}, title = {Placebo-controlled augmentation trials of the antioxidant NAC in schizophrenia: A review.}, journal = {Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists}, volume = {28}, number = {3}, pages = {190-196}, pmid = {27490835}, issn = {1547-3325}, mesh = {Acetylcysteine/*therapeutic use ; Antipsychotic Agents/therapeutic use ; Double-Blind Method ; *Drug Therapy, Combination ; Free Radical Scavengers/*therapeutic use ; Humans ; Psychiatric Status Rating Scales ; *Randomized Controlled Trials as Topic ; Risperidone/therapeutic use ; Schizophrenia/*drug therapy ; Schizophrenic Psychology ; }, abstract = {BACKGROUND: Several studies have reported that schizophrenia is associated with mitochondrial abnormalities, glutathione deficit, and increased brain oxidative stress (free radicals). N-acetylcysteine (NAC) is a strong antioxidant with potential therapeutic benefit in schizophrenia, according to some reports. We conducted a review of the published controlled studies, with the goal of determining the efficacy profile of NAC as an adjunctive treatment for schizophrenia.<br><br>METHODS: An online search was conducted for all placebo-controlled, double-blind, randomized clinical trials of NAC in schizophrenia, and a review was conducted.<br><br>RESULTS: Two studies met the criteria for inclusion. Berk et al (2008) used NAC as an adjunctive treatment to atypical antipsychotics in subjects with chronic schizophrenia who were stable on antipsychotic medications. Treatment at 8 weeks was less efficacious than placebo, but at 24 weeks produced significant reductions vs placebo in Positive and Negative Syndrome Scale (PANSS) negative (d = 0.52), general (d = 0.46), and total (d = 0.57) scores. Farokhnia et al (2013) used NAC as an adjunctive treatment to risperidone in subjects with chronic schizophrenia who were experiencing an acute exacerbation episode. Eight weeks of treatment led to clinically significant reductions vs placebo in PANSS negative (d = 0.96), general (d = 0.59), and total (d = 0.88) scores.<br><br>CONCLUSIONS: The data suggest that adjunctive NAC may be efficacious in reducing negative and general symptoms in schizophrenia.}, }
@article {pmid27488560, year = {2016}, author = {Gomez-Ospina, N and Scott, AI and Oh, GJ and Potter, D and Goel, VV and Destino, L and Baugh, N and Enns, GM and Niemi, AK and Cowan, TM}, title = {Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl-L-cysteine.}, journal = {Journal of inherited metabolic disease}, volume = {39}, number = {6}, pages = {821-829}, pmid = {27488560}, issn = {1573-2665}, mesh = {Acetylcysteine/*therapeutic use ; Acidosis/pathology ; Amino Acid Metabolism, Inborn Errors/drug therapy/pathology ; Female ; Glutathione Synthase/deficiency ; Humans ; Infant, Newborn ; Male ; Mixed Function Oxygenases/*deficiency ; Phenotype ; Twins ; Tyrosinemias/*drug therapy/pathology ; }, abstract = {Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known. Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria. Treatment with N-acetyl-L-cysteine (NAC) restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria.}, }
@article {pmid27485363, year = {2017}, author = {Ali-Hasan-Al-Saegh, S and Mirhosseini, SJ and Ghodratipour, Z and Sarrafan-Chaharsoughi, Z and Rahimizadeh, E and Karimi-Bondarabadi, AA and Haddad, F and Shahidzadeh, A and Mahdavi, P and Dehghan, AM and Tahernejad, M and Shahidzadeh, A and Dehghan, H and Ghanei, A and Lotfaliani, M and Weymann, A and Zeriouh, M and Popov, AF and Sabashnikov, A}, title = {Strategies Preventing Contrast-Induced Nephropathy After Coronary Angiography: A Comprehensive Meta-Analysis and Systematic Review of 125 Randomized Controlled Trials.}, journal = {Angiology}, volume = {68}, number = {5}, pages = {389-413}, doi = {10.1177/0003319716661445}, pmid = {27485363}, issn = {1940-1574}, mesh = {Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Contrast Media/*adverse effects ; *Coronary Angiography ; Humans ; *Randomized Controlled Trials as Topic ; }, abstract = {This systematic review with meta-analysis sought to determine the strength of evidence for the effects of hydration (sodium bicarbonate [SB] and normal saline [NS]), supplementations (N-acetylcysteine [NAC] and vitamin C), and some common drugs (adenosine antagonists [AAs], statins, loop diuretics, and angiotensin-converting enzyme inhibitors [ACEIs]) on the incidence of contrast-induced nephropathy (CIN) and requirement for hemodialysis after coronary angiography. After screening, a total of 125 trials that reported outcomes were identified. Pooled analysis indicated beneficial effects of SB versus NS (odds ratio [OR] = 0.73; 95% confidence interval [CI]: 0.56-0.94; P = .01), NAC (OR = 0.79; 95% CI: 0.70-0.88; P = .001), vitamin C (OR = 0.64; 95% CI: 0.45-0.89; P = .01), statins (OR = 0.45; 95% CI: 0.35-0.57; P = .001), AA (OR = 0.28; 95% CI: 0.14-0.47; P = .001), loop diuretics (OR = 0.97; 95% CI: 0.33-2.85; P = .9), and ACEI (OR = 1.06; 95% CI: 0.69-1.61; P = .8). Overall, hydration with SB, use of supplements, such as NAC and vitamin C, and administration of statins and AA should always be considered for the prevention of CIN after coronary angiography.}, }
@article {pmid27485006, year = {2017}, author = {Yan, W and Wang, L and Huang, T and Xu, G}, title = {Treatment for non-thyroidal illness syndrome in advanced chronic kidney disease: a single-blind controlled study.}, journal = {Journal of nephrology}, volume = {30}, number = {4}, pages = {557-565}, pmid = {27485006}, issn = {1724-6059}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Chi-Square Distribution ; China ; Disease Progression ; Euthyroid Sick Syndromes/diagnosis/*drug therapy/etiology ; Female ; Glomerular Filtration Rate/drug effects ; Humans ; Kaplan-Meier Estimate ; Kidney/*drug effects/physiopathology ; Kidney Failure, Chronic/etiology/physiopathology/prevention &amp; control ; Male ; Middle Aged ; Proportional Hazards Models ; Renal Insufficiency, Chronic/complications/diagnosis/*drug therapy/physiopathology ; Risk Factors ; Single-Blind Method ; Sodium Bicarbonate/adverse effects/*therapeutic use ; Time Factors ; Treatment Outcome ; }, abstract = {AIM: Non-thyroidal illness syndrome (NTIS) is common among patients with advanced chronic kidney disease (CKD) and is strongly associated with poor prognosis. However, it remains unclear in how to correct this disorder and this study aimed to evaluate the effectiveness of sodium bicarbonate (SB) and N-acetyl-cysteine (NAC) for correcting NTIS status.<br><br>METHODS: Patients with CKD stage 3-4 were single-blind, placebo-controlled treated with placebo, SB, or NAC for 18&#xa0;weeks. The primary end points were the correction of NTIS and the occurrence of end-stage renal disease (ESRD). The secondary point was the change in estimated glomerular filtration rate (eGFR) after the follow-up.<br><br>RESULTS: The Kaplan-Meier survival analysis showed significant lower correcting ratio of NTIS in control group compared with SB group [Hazard ratio (HR) 0.19, 95&#xa0;% confidence interval (CI) 0.04-0.89, p&#xa0;=&#xa0;0.035] and NAC group (HR 0.09, 95&#xa0;% CI 0.02-0.38, p&#xa0;=&#xa0;0.001), and increased ESRD risk in control group than in SB group (HR 1.97, 95&#xa0;% CI 1.02-3.84, p&#xa0;=&#xa0;0.045) and NAC group (HR 5.50, 95&#xa0;% CI 2.23-13.57, p&#xa0;<&#xa0;0.001). The Cox regression analysis demonstrated significantly different effectiveness of placebo, SB and NAC on NTIS correction and ESRD risk, p&#xa0;<&#xa0;0.05, respectively. Variance analysis displayed a greater reduction in eGFR in controls than in SB (p&#xa0;=&#xa0;0.044) and NAC group (p&#xa0;<&#xa0;0.001).<br><br>CONCLUSION: SB and NAC are effective in promoting the recovery from NTIS status and delaying the deterioration of renal function in advanced CKD patients.}, }
@article {pmid27484511, year = {2016}, author = {Zhang, L and Zhang, Z and Chen, F and Chen, Y and Lin, Y and Wang, J}, title = {Aromatic heterocyclic esters of podophyllotoxin exert anti-MDR activity in human leukemia K562/ADR cells via ROS/MAPK signaling pathways.}, journal = {European journal of medicinal chemistry}, volume = {123}, number = {}, pages = {226-235}, doi = {10.1016/j.ejmech.2016.07.050}, pmid = {27484511}, issn = {1768-3254}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Antineoplastic Agents/chemistry/pharmacology ; Cell Cycle Checkpoints/drug effects ; Drug Resistance, Multiple/*drug effects ; Esters/*chemistry ; Gene Expression Regulation, Neoplastic/drug effects ; Heterocyclic Compounds/*chemistry ; Humans ; K562 Cells ; MAP Kinase Signaling System/*drug effects ; Podophyllotoxin/*chemistry/*pharmacology ; Reactive Oxygen Species/*metabolism ; Structure-Activity Relationship ; }, abstract = {Currently, multi-drug resistance (MDR) to antineoplastic drugs is a major obstacle to successful treatment of carcinoma. Looking for novel agents with anti-MDR activity is an effectively way to overcome cancer drug resistance. Our previous study showed that podophyllotoxin derivative exhibited potent anti-proliferative effect and down-regulated the expression level of P-gp in K562/ADR cells, which probably was related with the MAPK pathways. However, the relation of P-gp expression and MAPK pathways still remains unclear. In this study, a series of aromatic heterocyclic esters of podophyllotoxin were synthesized and their anticancer effects were evaluated against two human chronic myeloid leukemia cell lines (K562 and K562/ADR), simultaneously, the initial structure-activity relationship was summarized. The most potent compound, Z5, displayed an IC50 value of 0.032 ± 0.006 μM against K562/ADR cells, with a lower resistant factor value of 1.280. Treatment of K562/ADR cells with Z5 caused S cell cycle arrest through reductions in cyclinA, cyclinB1, CDK1 and CDK2 levels. Moreover, Z5 treatment resulted in the induction of apoptosis as characterized by DNA staining, flow cytometry analysis and cleavage of procaspases-3, -8, -9 and PARP. Notably, Z5 significantly inhibited P-gp expression in K562/ADR cells. Additionally, Z5 also caused reactive oxygen species (ROS) generation, which was further demonstrated by preincubation with the antioxidant N-acetylcysteine (NAC). Western blotting revealed that Z5 markedly stimulated the MAPK pathways, including ERK1/2, JNK and P38, however, the mechanisms were prevented by NAC. Finally, the employment of NAC and MAPK inhibitors (U0126, SP600125 and SB203580) remarkably blocked the S phase arrest, apoptosis and down-regulation of P-gp induced by Z5. Taken together, Z5 strongly possessed the potential anti-MDR activity in K562/ADR cells through ROS/MAPK pathways-dependent S phase arrest, apoptosis and down-regulation of P-gp expression.}, }
@article {pmid27481628, year = {2016}, author = {Rogliani, P and Calzetta, L and Cavalli, F and Matera, MG and Cazzola, M}, title = {Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {40}, number = {}, pages = {95-103}, doi = {10.1016/j.pupt.2016.07.009}, pmid = {27481628}, issn = {1522-9629}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Anti-Inflammatory Agents/adverse effects/therapeutic use ; Enzyme Inhibitors/adverse effects/therapeutic use ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/physiopathology ; Indoles/adverse effects/*therapeutic use ; Practice Guidelines as Topic ; Pyridones/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: The prevalence of idiopathic pulmonary fibrosis (IPF) is increasing every year. Pirfenidone and nintedanib were approved for treatment of IPF in 2014, but they received only a conditional recommendation for use and, thus, to date no drugs are strongly recommended for IPF. The aim of this study was to assess the effectiveness and safety of the currently approved drugs for IPF and N-acetylcysteine (NAC), the most debated drug in the last update of guidelines for IPF treatment.<br><br>METHODS: RCTs in IPF were identified searching from databases of published and unpublished studies. The influence of pirfenidone, nintedanib and NAC on clinical outcomes, safety, and mortality was assessed via pair-wise meta-analysis.<br><br>RESULTS: Ten papers (3847 IPF patients; 2254 treated; 1593 placebo) were included in this study. Our results showed that both pirfenidone and nintedanib, but not NAC, were significantly effective in reducing FVC decline and the risk of FVC &#x2265;10% decline in percent predicted over 12 months. Nintenadib significantly protected against the risk of acute exacerbation and mortality. Pirfenidone and nintedanib showed a similar and good safety profile, whereas NAC provided a signal for increased adverse events.<br><br>CONCLUSIONS: The rank of effectiveness emerging from this meta-analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib. Direct comparisons are necessary to assess this matter, and well designed bench-to-bedside studies would permit to understand the potential of combined, sequential, or adjunctive treatment regimens in which perhaps NAC may have a role for specific clusters of IPF patients.}, }
@article {pmid27477106, year = {2016}, author = {Singh, V and Gera, R and Kushwaha, R and Sharma, AK and Patnaik, S and Ghosh, D}, title = {Hijacking microglial glutathione by inorganic arsenic impels bystander death of immature neurons through extracellular cystine/glutamate imbalance.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {30601}, pmid = {27477106}, issn = {2045-2322}, mesh = {Amino Acid Transport System y+/metabolism ; Animals ; Arsenic/*adverse effects/pharmacology ; Cell Line ; Cell Survival/drug effects ; Cells, Cultured ; Coculture Techniques ; Cystine/*metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Glutamic Acid/*metabolism ; Glutathione/*metabolism ; Male ; Mice ; Microglia/cytology/*drug effects/metabolism ; Neurons/*cytology/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Arsenic-induced altered microglial activity leads to neuronal death, but the causative mechanism remains unclear. The present study showed, arsenic-exposed (10 μM) microglial (N9) culture supernatant induced bystander death of neuro-2a (N2a), which was further validated with primary microglia and immature neuronal cultures. Results indicated that arsenic-induced GSH synthesis by N9 unfavorably modified the extracellular milieu for N2a by lowering cystine and increasing glutamate concentration. Similar result was observed in N9-N2a co-culture. Co-exposure of arsenic and 250 μM glutamate, less than the level (265 μM) detected in arsenic-exposed N9 culture supernatant, compromised N2a viability which was rescued by cystine supplementation. Therefore, microglia executes bystander N2a death by competitive inhibition of system Xc(-) (xCT) through extracellular cystine/glutamate imbalance. We confirmed the role of xCT in mediating bystander N2a death by siRNA inhibition studies. Ex-vivo primary microglia culture supernatant from gestationally exposed mice measured to contain lower cystine and higher glutamate compared to control and N-acetyl cysteine co-treated group. Immunofluorescence staining of brain cryosections from treated group showed more dead immature neurons with no such effect on microglia. Collectively, we showed, in presence of arsenic microglia alters cystine/glutamate balance through xCT in extracellular milieu leading to bystander death of immature neurons.}, }
@article {pmid27475664, year = {2016}, author = {Ye, W and Zhong, Z and Zhu, S and Zheng, S and Xiao, J and Song, S and Yu, H and Wu, Q and Lin, Z and Chen, J}, title = {Advanced oxidation protein products induce catabolic effect through oxidant-dependent activation of NF-κ B pathway in human chondrocyte.}, journal = {International immunopharmacology}, volume = {39}, number = {}, pages = {149-157}, doi = {10.1016/j.intimp.2016.07.018}, pmid = {27475664}, issn = {1878-1705}, mesh = {Advanced Oxidation Protein Products/*metabolism ; Aged ; Arthritis, Rheumatoid/*metabolism ; Chondrocytes/*physiology ; Cyclic AMP Receptor Protein/*metabolism ; Cyclooxygenase 2 Inhibitors/metabolism ; Female ; Glycation End Products, Advanced/metabolism ; Glycosaminoglycans/metabolism ; Humans ; Male ; Matrix Metalloproteinase 13/metabolism ; Matrix Metalloproteinase 3/metabolism ; Middle Aged ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Nitriles/pharmacology ; Oxidation-Reduction ; Signal Transduction/drug effects ; Sulfones/pharmacology ; }, abstract = {Advanced oxidation protein products (AOPPs) have been shown to participate in the progression of rheumatoid arthritis (RA). However, the effect of AOPPs accumulation on catabolic effect in human chondrocyte and the underlying mechanism(s) remain unclear. The present study demonstrated that AOPPs inhibited cell viability and glycosaminoglycan (GAG) production in human chondrocyte. Exposure of chondrocyte to AOPPs significantly increased the production of catabolic factors, such as cyclooxygenase-2 (COX-2), matrix metalloproteinase 3 (MMPs)-3 and MMP-13. AOPPs stimulation induced ROS generation and NF-κ B p65 phosphorylation, which could be inhibited by soluble receptor for advanced glycan end products (sRAGE), NADPH oxidase inhibitor (apocynin), ROS scavenger (N-acetyl-cysteine, NAC). Furthermore, NF-κ B inhibitor Bay11-7082 significantly reversed the AOPPs-induced expression of catabolic factors and phosphorylation of NF-κ B p65. Targeting AOPPs-triggered catabolic effect might be as a promising option for patients with RA.}, }
@article {pmid27474283, year = {2016}, author = {Tang, J and Wu, P and Hou, X and Xu, K}, title = {Modification-free and N-acetyl-L-cysteine-induced colorimetric response of AuNPs: A mechanistic study and sensitive Hg(2+) detection.}, journal = {Talanta}, volume = {159}, number = {}, pages = {87-92}, doi = {10.1016/j.talanta.2016.05.068}, pmid = {27474283}, issn = {1873-3573}, mesh = {Acetylcysteine/*chemistry ; Chemistry Techniques, Analytical/*methods ; *Colorimetry ; Gold/*chemistry ; Mercury/*analysis ; Metal Nanoparticles/*chemistry ; }, abstract = {A facile yet sensitive and selective method was proposed for Hg(2+) detection based on N-acetyl-L-cysteine(NAC)-induced colorimetric response of AuNPs. The proposed method can be easily performed by introducing the premixing of NAC and Hg(2+) into as-prepared citrate-capped AuNPs solution. A combination of experimental and theoretical studies was applied to illustrate the mechanism of this AuNPs colorimetric system. The strong interaction of NAC and AuNPs through Au-S bond could lead to the aggregation of AuNPs, but the formation of NAC-Hg-NAC complex decreased the affinity between NAC and AuNPs and resulted in an anti-aggregation effect. Therefore, the color of the AuNPs solution would progress from purple to red with the increase of Hg(2+) concentration. The proposed method had a high sensitivity with a limit of detection of 9.9nM. Coexistent metal ions, including Cd(2+), Mn(2+), Al(3+), Ag(+), K(+), Mg(2+), Ca(2+), Cr(3+), Cu(2+), Fe(3+), Pb(2+), Ni(2+) and Zn(2+), did not interfere with the detection of Hg(2+). This method can be used to monitor Hg(2+) in tap water.}, }
@article {pmid27474168, year = {2016}, author = {Fan, TF and Wu, TF and Bu, LL and Ma, SR and Li, YC and Mao, L and Sun, ZJ and Zhang, WF}, title = {Dihydromyricetin promotes autophagy and apoptosis through ROS-STAT3 signaling in head and neck squamous cell carcinoma.}, journal = {Oncotarget}, volume = {7}, number = {37}, pages = {59691-59703}, pmid = {27474168}, issn = {1949-2553}, mesh = {Apoptosis/*drug effects ; Autophagy/*drug effects ; Blotting, Western ; Carcinoma, Squamous Cell/metabolism/pathology ; Cell Line, Tumor ; Flavonols/*pharmacology ; Head and Neck Neoplasms/metabolism/pathology ; Humans ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Chemotherapy is an effective weapon in the battle against cancer, but numerous cancer patients are either not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, an effective chemotherapy mechanism that enhances tumor sensitivity to chemotherapeutics is urgently needed. The aim of the present study was to determine the antitumor activity of dihydromyricetin (DHM) on head and neck squamous cell carcinoma (HNSCC) and its underlying mechanisms. We demonstrated that DHM can markedly induce apoptotic cell death and autophagy in HNSCC cells. Meanwhile, increased autophagy inhibited apoptosis. Pharmacological or genetic inhibition of autophagy further sensitized the HNSCC cells to DHM-induced apoptosis. Mechanistic analysis showed that the antitumor of DHM may be due to the activation phosphorylation of signal transducer and activator of transcription 3 (p-STAT3), which contributed to autophagy. Importantly, DHM triggered reactive oxygen species (ROS) generation in the HNSCC cells and the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger. Moreover, NAC abrogated the effects of DHM on STAT3-dependent autophagy. Overall, the following critical issues were observed: first, DHM increased the p-STAT3-dependent autophagy by generating ROS-signaling pathways in head and neck squamous cell carcinoma. Second, inhibiting autophagy could enhance DHM-induced apoptosis in head and neck squamous cell carcinoma.}, }
@article {pmid27469021, year = {2016}, author = {Jastrzębska, J and Frankowska, M and Filip, M and Atlas, D}, title = {N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement.}, journal = {Psychopharmacology}, volume = {233}, number = {18}, pages = {3437-3448}, pmid = {27469021}, issn = {1432-2072}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Behavior, Animal/*drug effects ; Cocaine/*administration &amp; dosage ; Cocaine-Related Disorders ; Cues ; Depression ; Dopamine Uptake Inhibitors/*administration &amp; dosage ; Drug-Seeking Behavior/*drug effects ; Extinction, Psychological/*drug effects ; Male ; Olfactory Bulb/surgery ; Rats ; Rats, Wistar ; Reward ; Self Administration ; }, abstract = {RATIONALE: Chronic exposure to drugs of abuse changes glutamatergic transmission in human addicts and animal models. N-acetylcysteine (NAC) is a cysteine prodrug that indirectly activates cysteine-glutamate antiporters. In the extrasynaptic space, NAC restores basal glutamate levels during drug abstinence and normalizes increased glutamatergic tone in rats during reinstatement to drugs of abuse. In initial clinical trials, repeated NAC administration seems to be promising for reduced craving in cocaine addicts.<br><br>OBJECTIVE: In this study, NAC-amide, called AD4 or NACA, was examined in intravenous cocaine self-administration and extinction/reinstatement procedures in rats. We investigated the behavioral effects of AD4 in the olfactory bulbectomized (OBX) rats, considered an animal model of depression. Finally, we tested rats injected with AD4 or NAC during 10-daily extinction training sessions to examine subsequent cocaine seeking.<br><br>RESULTS: AD4 (25-75&#xa0;mg&#xa0;kg(-1)) given acutely did not alter the rewarding effects of cocaine in OBX rats and sham-operated controls. However, at 6.25-50&#xa0;mg&#xa0;kg(-1), AD4 decreased dose-dependently cocaine seeking and relapse triggered by cocaine priming or drug-associated conditioned cues in both phenotypes. Furthermore, repeated treatment with AD4 (25&#xa0;mg&#xa0;kg(-1)) or NAC (100&#xa0;mg&#xa0;kg(-1)) during daily extinction trials reduced reinstatement of drug-seeking behavior in sham-operated controls. In the OBX rats only, AD4 effectively blocked cocaine-seeking behavior.<br><br>CONCLUSIONS: Our results demonstrate that AD4 is effective at blocking cocaine-seeking behavior, highlighting its potential clinical use toward cocaine use disorder.}, }
@article {pmid27457783, year = {2016}, author = {Goldman, JL and Koen, YM and Rogers, SA and Li, K and Leeder, JS and Hanzlik, RP}, title = {Bioactivation of Trimethoprim to Protein-Reactive Metabolites in Human Liver Microsomes.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {44}, number = {10}, pages = {1603-1607}, pmid = {27457783}, issn = {1521-009X}, support = {KL2 TR000119/TR/NCATS NIH HHS/United States ; T32 HD069038/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anti-Infective Agents, Urinary/adverse effects/*pharmacokinetics ; Biotransformation ; Humans ; Microsomes, Liver/*metabolism ; Proteins/*metabolism ; Trimethoprim/adverse effects/*pharmacokinetics ; }, abstract = {The formation of drug-protein adducts via metabolic activation and covalent binding may stimulate an immune response or may result in direct cell toxicity. Protein covalent binding is a potentially pivotal step in the development of idiosyncratic adverse drug reactions (IADRs). Trimethoprim (TMP)-sulfamethoxazole (SMX) is a combination antibiotic that commonly causes IADRs. Recent data suggest that the contribution of the TMP component of TMP-SMX to IADRs may be underappreciated. We previously demonstrated that TMP is bioactivated to chemically reactive intermediates that can be trapped in vitro by N-acetyl cysteine (NAC), and we have detected TMP-NAC adducts (i.e., mercapturic acids) in the urine of patients taking TMP-SMX. However, the occurrence and extent of TMP covalent binding to proteins was unknown. To determine the ability of TMP to form protein adducts, we incubated [(14)C]TMP with human liver microsomes in the presence and absence of NADPH. We observed protein covalent binding that was NADPH dependent and increased with incubation time and concentration of both protein and TMP. The estimated covalent binding was 0.8 nmol Eq TMP/mg protein, which is comparable to the level of covalent binding for several other drugs that have been associated with covalent binding-induced toxicity and/or IADRs. NAC and selective inhibitors of CYP2B6 and CYP3A4 significantly reduced TMP covalent binding. These results demonstrate for the first time that TMP bioactivation can lead directly to protein adduct formation, suggesting that TMP has been overlooked as a potential contributor of TMP-SMX IADRs.}, }
@article {pmid27449129, year = {2016}, author = {Kilanczyk, E and Saraswat Ohri, S and Whittemore, SR and Hetman, M}, title = {Antioxidant Protection of NADPH-Depleted Oligodendrocyte Precursor Cells Is Dependent on Supply of Reduced Glutathione.}, journal = {ASN neuro}, volume = {8}, number = {4}, pages = {}, pmid = {27449129}, issn = {1759-0914}, support = {R01 NS073584/NS/NINDS NIH HHS/United States ; }, mesh = {Adjuvants, Immunologic/pharmacology ; Animals ; Antibodies/pharmacology ; Antineoplastic Agents, Phytogenic/toxicity ; Antioxidants/*pharmacology ; Caspase 3/metabolism ; Cell Differentiation/drug effects ; Cells, Cultured ; Dehydroepiandrosterone/pharmacology ; Glutathione/*metabolism ; L-Lactate Dehydrogenase/metabolism ; Membrane Potential, Mitochondrial/drug effects ; NAD/analogs &amp; derivatives/toxicity ; NADP/immunology/*metabolism ; Oligodendroglia/*drug effects ; Rats ; Spinal Cord/cytology ; Stem Cells/drug effects ; Superoxides/metabolism ; Time Factors ; }, abstract = {The pentose phosphate pathway is the main source of NADPH, which by reducing oxidized glutathione, contributes to antioxidant defenses. Although oxidative stress plays a major role in white matter injury, significance of NADPH for oligodendrocyte survival has not been yet investigated. It is reported here that the NADPH antimetabolite 6-amino-NADP (6AN) was cytotoxic to cultured adult rat spinal cord oligodendrocyte precursor cells (OPCs) as well as OPC-derived oligodendrocytes. The 6AN-induced necrosis was preceded by increased production of superoxide, NADPH depletion, and lower supply of reduced glutathione. Moreover, survival of NADPH-depleted OPCs was improved by the antioxidant drug trolox. Such cells were also protected by physiological concentrations of the neurosteroid dehydroepiandrosterone (10(-8) M). The protection by dehydroepiandrosterone was associated with restoration of reduced glutathione, but not NADPH, and was sensitive to inhibition of glutathione synthesis. A similar protective mechanism was engaged by the cAMP activator forskolin or the G protein-coupled estrogen receptor (GPER/GPR30) ligand G1. Finally, treatment with the glutathione precursor N-acetyl cysteine reduced cytotoxicity of 6AN. Taken together, NADPH is critical for survival of OPCs by supporting their antioxidant defenses. Consequently, injury-associated inhibition of the pentose phosphate pathway may be detrimental for the myelination or remyelination potential of the white matter. Conversely, steroid hormones and cAMP activators may promote survival of NADPH-deprived OPCs by increasing a NADPH-independent supply of reduced glutathione. Therefore, maintenance of glutathione homeostasis appears as a critical effector mechanism for OPC protection against NADPH depletion and preservation of the regenerative potential of the injured white matter.}, }
@article {pmid27447560, year = {2016}, author = {Lemke, D and Pledl, HW and Zorn, M and Jugold, M and Green, E and Blaes, J and Löw, S and Hertenstein, A and Ott, M and Sahm, F and Steffen, AC and Weiler, M and Winkler, F and Platten, M and Dong, Z and Wick, W}, title = {Slowing down glioblastoma progression in mice by running or the anti-malarial drug dihydroartemisinin? Induction of oxidative stress in murine glioblastoma therapy.}, journal = {Oncotarget}, volume = {7}, number = {35}, pages = {56713-56725}, pmid = {27447560}, issn = {1949-2553}, mesh = {Animals ; Antimalarials/*administration &amp; dosage ; Artemisinins/*administration &amp; dosage ; Brain Neoplasms/drug therapy/*therapy ; Cell Line, Tumor ; Combined Modality Therapy ; Dacarbazine/administration &amp; dosage/*analogs &amp; derivatives ; Disease Progression ; Female ; Glioblastoma/drug therapy/*therapy ; Humans ; Mice ; Mice, Nude ; *Oxidative Stress ; *Physical Conditioning, Animal ; Reactive Oxygen Species/metabolism ; Temozolomide ; }, abstract = {Influencing cancer metabolism by lifestyle changes is an attractive strategy as - if effective - exercise-induced problems may be less severe than those induced by classical anti-cancer therapies. Pursuing this idea, clinical trials evaluated the benefit of e.g. different diets such as the ketogenic diet, intermittent caloric restriction and physical exercise (PE) in the primary and secondary prevention of different cancer types. PE proved to be beneficial in the context of breast and colon cancer.Glioblastoma has a dismal prognosis, with an average overall survival of about one year despite maximal safe resection, concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide therapy. Here, we focused on the influence of PE as an isolated and adjuvant treatment in murine GB therapy.PE did not reduce toxic side effects of chemotherapy in mice administered in a dose escalating scheme as shown before for starvation. Although regular treadmill training on its own had no obvious beneficial effects, its combination with temozolomide was beneficial in the treatment of glioblastoma-bearing mice. As PE might partly act through the induction of reactive oxygen species, dihydroartemisinin - an approved anti-malarial drug which induces oxidative stress in glioma cells - was further evaluated in vitro and in vivo. Dihydroartemisinin showed anti-glioma activity by promoting autophagy, reduced the clonogenic survival and proliferation capacity of glioma cells, and prolonged the survival of tumor bearing mice. Using the reactive oxygen species scavenger n-acetyl-cysteine these effects were in part reversible, suggesting that dihydroartemisinin partly acts through the generation of reactive oxygen species.}, }
@article {pmid27445100, year = {2016}, author = {Zhang, LL and Huang, S and Ma, XX and Zhang, WY and Wang, D and Jin, SY and Zhang, YP and Li, Y and Li, X}, title = {Angiotensin(1-7) attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1β/Smad circuit.}, journal = {Free radical biology &amp; medicine}, volume = {97}, number = {}, pages = {531-543}, doi = {10.1016/j.freeradbiomed.2016.07.014}, pmid = {27445100}, issn = {1873-4596}, mesh = {Angiotensin I/pharmacology/*physiology ; Angiotensin II/*physiology ; Animals ; Cells, Cultured ; Collagen Type I/genetics/metabolism ; Collagen Type I, alpha 1 Chain ; *Epithelial-Mesenchymal Transition ; Gene Expression ; Hepatocytes/*physiology ; Humans ; Hydrogen Peroxide/metabolism ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; Liver Cirrhosis/metabolism/pathology ; Male ; Mice ; NADPH Oxidase 4/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Peptide Fragments/pharmacology/*physiology ; Rats, Wistar ; *Signal Transduction ; Smad Proteins/metabolism ; }, abstract = {Epithelial-mesenchymal transition (EMT) is correlated with NAPDH oxidase (NOX)-derived reactive oxygen species (ROS). The ROS-induced NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a novel mechanism of EMT. Angiotensin II (AngII) induces EMT by regulating intracellular ROS. Nevertheless, it has not been reported whether AngII could induce hepatocyte EMT. Angiotensin-(1-7) [Ang-(1-7)] can inhibit the effects of AngII via a counter-regulatory mechanism. However, whether Ang-(1-7) attenuated the effects of AngII on hepatocyte EMT remains unclear. The aim of this study was to determine whether Ang-(1-7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived ROS-mediated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, two animal models were established. In the first model, rats were infused AngII. In the second model, Ang-(1-7) was constantly infused into double bile duct ligated (BDL) rats. In vitro, hepatocytes were pretreated with antioxidant, NLRP3 siRNA, NOX4 siRNA, or Ang-(1-7) before exposure to AngII. In vitro, AngII induced hepatocyte EMT, which was inhibited by N-acetylcysteine (NAC), diphenylene iodonium (DPI), and NOX4 siRNA. NLRP3 inflammasome, which was activated by hydrogen peroxide (H2O2), mediated AngII-induced hepatocyte EMT. Ang-(1-7) suppressed AngII-induced EMT by inhibiting the NOX-derived H2O2-activated NLRP3 inflammasome/IL-1ß/Smad circuit. In vivo, infusion of AngII induced activation of H2O2-correlated NLRP3 inflammasome in rat livers and accumulation of α-collagen I (Col1A1) in hepatocytes. Infusion of Ang-(1-7) alleviated BDL-induced liver fibrosis and inhibited the expression of Col1A1 and the activation of NLRP3 inflammasome in hepatocytes. Ang-(1-7) attenuated AngII-induced hepatocyte EMT by inhibiting the NOX-derived H2O2-activated NLRP3 inflammasome/IL-1ß/Smad circuit.}, }
@article {pmid27444578, year = {2016}, author = {Ahamed, M and Khan, MA and Akhtar, MJ and Alhadlaq, HA and Alshamsan, A}, title = {Role of Zn doping in oxidative stress mediated cytotoxicity of TiO2 nanoparticles in human breast cancer MCF-7 cells.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {30196}, pmid = {27444578}, issn = {2045-2322}, mesh = {A549 Cells ; Breast Neoplasms/*drug therapy/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Down-Regulation/drug effects ; Female ; Glutathione/metabolism ; Hep G2 Cells ; Humans ; MCF-7 Cells ; Nanoparticles/*administration &amp; dosage ; Oxidative Stress/*drug effects ; Particle Size ; Reactive Oxygen Species/metabolism ; Titanium/*pharmacology ; Up-Regulation/drug effects ; Zinc/*pharmacology ; }, abstract = {We investigated the effect of Zn-doping on structural and optical properties as well as cellular response of TiO2 nanoparticles (NPs) in human breast cancer MCF-7 cells. A library of Zn-doped (1-10 at wt%) TiO2 NPs was prepared. Characterization data indicated that dopant Zn was incorporated into the lattice of host TiO2. The average particle size of TiO2 NPs was decreases (38 to 28 nm) while the band gap energy was increases (3.35 eV-3.85 eV) with increasing the amount of Zn-doping. Cellular data demonstrated that Zn-doped TiO2 NPs induced cytotoxicity (cell viability reduction, membrane damage and cell cycle arrest) and oxidative stress (reactive oxygen species generation &amp;glutathione depletion) in MCF-7 cells and toxic intensity was increases with increasing the concentration of Zn-doping. Molecular data revealed that Zn-doped TiO2 NPs induced the down-regulation of super oxide dismutase gene while the up-regulation of heme oxygenase-1 gene in MCF-7 cells. Cytotoxicity induced by Zn-doped TiO2 NPs was efficiently prevented by N-acetyl-cysteine suggesting that oxidative stress might be the primarily cause of toxicity. In conclusion, our data indicated that Zn-doping decreases the particle size and increases the band gap energy as well the oxidative stress-mediated toxicity of TiO2 NPs in MCF-7 cells.}, }
@article {pmid27444019, year = {2016}, author = {Lao, T and Jiang, Z and Yun, J and Qiu, W and Guo, F and Huang, C and Mancini, JD and Gupta, K and Laucho-Contreras, ME and Naing, ZZ and Zhang, L and Perrella, MA and Owen, CA and Silverman, EK and Zhou, X}, title = {Hhip haploinsufficiency sensitizes mice to age-related emphysema.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {113}, number = {32}, pages = {E4681-7}, pmid = {27444019}, issn = {1091-6490}, support = {R01 HL075478/HL/NHLBI NIH HHS/United States ; R01 AI111475/AI/NIAID NIH HHS/United States ; R21 HL111835/HL/NHLBI NIH HHS/United States ; R01 HL111759/HL/NHLBI NIH HHS/United States ; R33 HL120794/HL/NHLBI NIH HHS/United States ; P01 HL105339/HL/NHLBI NIH HHS/United States ; R01 HL127200/HL/NHLBI NIH HHS/United States ; P01 HL114501/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Age Factors ; Animals ; Carrier Proteins/*genetics ; Emphysema/*etiology ; Glutathione/metabolism ; Glutathione S-Transferase pi/physiology ; *Haploinsufficiency ; Lung/pathology/physiology ; Lung Compliance ; Membrane Glycoproteins/*genetics ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; }, abstract = {Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip(+/-)), we observed increased lung compliance and spontaneous emphysema in Hhip(+/-) mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip(+/-) vs. Hhip(+/+) mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip(+/-) mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip(+/-) mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip(+/-) mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.}, }
@article {pmid27442797, year = {2016}, author = {Sun, Y and Yao, T and Guo, X and Peng, Y and Zheng, J}, title = {Simultaneous assessment of endogenous thiol compounds by LC-MS/MS.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1029-1030}, number = {}, pages = {213-221}, doi = {10.1016/j.jchromb.2016.06.024}, pmid = {27442797}, issn = {1873-376X}, mesh = {Acetylcysteine/*analysis/blood ; Animals ; Chromatography, High Pressure Liquid/*methods ; Cysteine/*analysis/blood ; Dipeptides/*analysis/blood ; Glutathione/*analysis/blood ; Homocysteine/*analysis/blood ; Limit of Detection ; Liver/*chemistry ; Male ; Mice ; Reproducibility of Results ; Sulfhydryl Compounds/analysis/blood ; Tandem Mass Spectrometry/methods ; }, abstract = {Biological thiol compounds are very important molecules that participate in various physiological events. Alteration in levels of endogenous thiols has been suggested as a biomarker of early stage of pathological changes. We reported a chemical derivatization- and LC-MS/MS-based approach to simultaneously determine thiol compounds including glutathione (GSH), cysteine (Cys), N-acetyl cysteine (NAC), homocysteine (Hcy), and cysteinylglycine (CysGly) in biological samples. Thiol-containing samples were derivatized with monobromobimane (mBrB) at room temperature, followed by LC-MS/MS analysis. Assessment of the analytes with baseline separation was completed within 10min, using a gradient elution on a C18 reversed-phase column. Excellent linearity was observed for all analytes over their concentration ranges of 1-400μM. The lowest limits of detection (S/N=3) in a range from 0.31fmol (for NAC) to 4.98fmol (for CysGly) were achieved. The results indicate that this approach was sensitive, selective, and well suited for high-throughput quantitative determination of the biological thiols.}, }
@article {pmid27441638, year = {2016}, author = {Raza, H and John, A and Shafarin, J}, title = {Potentiation of LPS-Induced Apoptotic Cell Death in Human Hepatoma HepG2 Cells by Aspirin via ROS and Mitochondrial Dysfunction: Protection by N-Acetyl Cysteine.}, journal = {PloS one}, volume = {11}, number = {7}, pages = {e0159750}, pmid = {27441638}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Aspirin/*pharmacology ; Cytochrome P-450 Enzyme System/metabolism ; Cytokines/metabolism ; Glutathione/metabolism ; Hep G2 Cells ; Humans ; Lipopolysaccharides/toxicity ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Liver/*drug effects/*metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cytotoxicity and inflammation-associated toxic responses have been observed to be induced by bacterial lipopolysaccharides (LPS) in vitro and in vivo respectively. Use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, has been reported to be beneficial in inflammation-associated diseases like cancer, diabetes and cardiovascular disorders. Their precise molecular mechanisms, however, are not clearly understood. Our previous studies on aspirin treated HepG2 cells strongly suggest cell cycle arrest and induction of apoptosis associated with mitochondrial dysfunction. In the present study, we have further demonstrated that HepG2 cells treated with LPS alone or in combination with aspirin induces subcellular toxic responses which are accompanied by increase in reactive oxygen species (ROS) production, oxidative stress, mitochondrial respiratory dysfunction and apoptosis. The LPS/Aspirin induced toxicity was attenuated by pre-treatment of cells with N-acetyl cysteine (NAC). Alterations in oxidative stress and glutathione-dependent redox-homeostasis were more pronounced in mitochondria compared to extra- mitochondrial cellular compartments. Pre-treatment of HepG2 cells with NAC exhibited a selective protection in redox homeostasis and mitochondrial dysfunction. Our results suggest that the altered redox metabolism, oxidative stress and mitochondrial function in HepG2 cells play a critical role in LPS/aspirin-induced cytotoxicity. These results may help in better understanding the pharmacological, toxicological and therapeutic properties of NSAIDs in cancer cells exposed to bacterial endotoxins.}, }
@article {pmid27437434, year = {2016}, author = {Tzounakas, VL and Kriebardis, AG and Georgatzakou, HT and Foudoulaki-Paparizos, LE and Dzieciatkowska, M and Wither, MJ and Nemkov, T and Hansen, KC and Papassideri, IS and D'Alessandro, A and Antonelou, MH}, title = {Data on how several physiological parameters of stored red blood cells are similar in glucose 6-phosphate dehydrogenase deficient and sufficient donors.}, journal = {Data in brief}, volume = {8}, number = {}, pages = {618-627}, pmid = {27437434}, issn = {2352-3409}, abstract = {This article contains data on the variation in several physiological parameters of red blood cells (RBCs) donated by eligible glucose-6-phosphate dehydrogenase (G6PD) deficient donors during storage in standard blood bank conditions compared to control, G6PD sufficient (G6PD(+)) cells. Intracellular reactive oxygen species (ROS) generation, cell fragility and membrane exovesiculation were measured in RBCs throughout the storage period, with or without stimulation by oxidants, supplementation of N-acetylcysteine and energy depletion, following incubation of stored cells for 24 h at 37 °C. Apart from cell characteristics, the total or uric acid-dependent antioxidant capacity of the supernatant in addition to extracellular potassium concentration was determined in RBC units. Finally, procoagulant activity and protein carbonylation levels were measured in the microparticles population. Further information can be found in "Glucose 6-phosphate dehydrogenase deficient subjects may be better "storers" than donors of red blood cells" [1].}, }
@article {pmid27431005, year = {2016}, author = {Sim, HJ and Kim, JH and Kook, SH and Lee, SY and Lee, JC}, title = {Glucose oxidase facilitates osteogenic differentiation and mineralization of embryonic stem cells through the activation of Nrf2 and ERK signal transduction pathways.}, journal = {Molecular and cellular biochemistry}, volume = {419}, number = {1-2}, pages = {157-163}, pmid = {27431005}, issn = {1573-4919}, mesh = {Animals ; Calcification, Physiologic/*drug effects ; Cell Differentiation/*drug effects ; Cell Line ; Core Binding Factor Alpha 1 Subunit/metabolism ; Glucose Oxidase/*pharmacology ; MAP Kinase Signaling System/*drug effects ; Mice ; Mouse Embryonic Stem Cells/cytology/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Osteogenesis/*drug effects ; Oxidative Stress/drug effects ; }, abstract = {Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signal is known to play important roles in controlling bone homeostasis. This study examined how oxidative stress affects the mineralization of embryonic stem (ES) cells by exposing them to glucose oxidase (GO), which continuously generates H2O2 at low concentrations. The roles of Nrf2/HO-1 and mitogen-activated protein kinases on osteogenesis in GO-exposed ES cells were also investigated. GO treatment at relatively low concentrations did not change the viability of ES cells, whereas it enhanced osteogenic differentiation and mineralization in the cells. GO treatment (1 mU/ml) augmented the induction of runt-related transcription factor 2 (Runx2), Nrf2, and HO-1 in ES cells. GO-mediated acceleration of Runx2 expression and mineralization was inhibited either by Nrf2 knockdown or by treating with 5 μM PD98059, an inhibitor of phospho-extracellular signal-regulated kinase (p-ERK). The GO-stimulated mineralization was also suppressed by treating the cells with reduced glutathione or catalase, but not by superoxide dismutase or N-acetyl-cysteine. Collectively, our results demonstrate that a mild oxidative stress activates Nrf2/HO-1 signaling and an ERK-mediated pathway, and facilitates the mineralization of ES cells with a corresponding increase in Runx2.}, }
@article {pmid27428953, year = {2016}, author = {Chiu, CH and Chang, CC and Lin, ST and Chyau, CC and Peng, RY}, title = {Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity.}, journal = {International journal of molecular sciences}, volume = {17}, number = {7}, pages = {}, pmid = {27428953}, issn = {1422-0067}, mesh = {Animals ; Antioxidants/metabolism ; Body Weight/drug effects ; Chemical and Drug Induced Liver Injury/etiology/metabolism/*prevention &amp; control ; Fibrinolytic Agents/pharmacology ; Glutathione/metabolism ; Interleukin-6/metabolism ; Lipopolysaccharides/*toxicity ; Liposomes/administration &amp; dosage/*chemistry ; Male ; Malondialdehyde/metabolism ; NF-kappa B/metabolism ; Nanocapsules/administration &amp; dosage/*chemistry ; Nitric Oxide Synthase Type II/metabolism ; Organ Size/drug effects ; Oxidative Stress ; Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Xanthophylls/pharmacology ; }, abstract = {Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA) apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group) were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10) for seven days and then were LPS-challenged (i.p., 5 mg/kg). The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), creatinine (CRE), hepatic malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS), suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day). Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity.}, }
@article {pmid27428732, year = {2016}, author = {Wongjaikam, S and Kumfu, S and Khamseekaew, J and Sripetchwandee, J and Srichairatanakool, S and Fucharoen, S and Chattipakorn, SC and Chattipakorn, N}, title = {Combined Iron Chelator and Antioxidant Exerted Greater Efficacy on Cardioprotection Than Monotherapy in Iron-Overloaded Rats.}, journal = {PloS one}, volume = {11}, number = {7}, pages = {e0159414}, pmid = {27428732}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Benzoates/*pharmacology ; Cardiomyopathies/chemically induced/*drug therapy/metabolism/pathology ; Cardiotonic Agents/pharmacology ; Deferasirox ; Deferiprone ; Deferoxamine/*pharmacology ; Drug Combinations ; Drug Synergism ; Humans ; Iron/blood ; Iron Chelating Agents/pharmacology ; Iron Overload/chemically induced/*drug therapy/metabolism/pathology ; Iron, Dietary/adverse effects ; Male ; Malondialdehyde/blood ; Mitochondria/drug effects/metabolism ; Pyridones/*pharmacology ; Rats ; Rats, Wistar ; Triazoles/*pharmacology ; Ventricular Function, Left/drug effects ; }, abstract = {BACKGROUND: Iron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated.<br><br>METHODS AND FINDINGS: Male Wistar rats were fed with either a normal diet or a high iron diet (HFe group) for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day) or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function.<br><br>CONCLUSIONS: The combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats.}, }
@article {pmid27427225, year = {2016}, author = {Denora, N and Lopedota, A and Perrone, M and Laquintana, V and Iacobazzi, RM and Milella, A and Fanizza, E and Depalo, N and Cutrignelli, A and Lopalco, A and Franco, M}, title = {Spray-dried mucoadhesives for intravesical drug delivery using N-acetylcysteine- and glutathione-glycol chitosan conjugates.}, journal = {Acta biomaterialia}, volume = {43}, number = {}, pages = {170-184}, doi = {10.1016/j.actbio.2016.07.025}, pmid = {27427225}, issn = {1878-7568}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Adhesives/*pharmacology ; Administration, Intravesical ; Animals ; Chitosan/*pharmacology ; Chromatography, Gel ; *Desiccation ; *Drug Delivery Systems ; Glutathione/chemistry/*pharmacology ; Microspheres ; Molecular Weight ; Mucins/*pharmacology ; Nanoparticles/chemistry/ultrastructure ; Nephelometry and Turbidimetry ; Photoelectron Spectroscopy ; Solubility ; Static Electricity ; Sulfhydryl Compounds/chemistry ; Sus scrofa ; }, abstract = {UNLABELLED: This work describes N-acetylcysteine (NAC)- and glutathione (GSH)-glycol chitosan (GC) polymer conjugates engineered as potential platform useful to formulate micro-(MP) and nano-(NP) particles via spray-drying techniques. These conjugates are mucoadhesive over the range of urine pH, 5.0-7.0, which makes them advantageous for intravesical drug delivery and treatment of local bladder diseases. NAC- and GSH-GC conjugates were generated with a synthetic approach optimizing reaction times and purification in order to minimize the oxidation of thiol groups. In this way, the resulting amount of free thiol groups immobilized per gram of NAC- and GSH-GC conjugates was 6.3 and 3.6mmol, respectively. These polymers were completely characterized by molecular weight, surface sulfur content, solubility at different pH values, substitution and swelling degree. Mucoadhesion properties were evaluated in artificial urine by turbidimetric and zeta (ζ)-potential measurements demonstrating good mucoadhesion properties, in particular for NAC-GC at pH 5.0. Starting from the thiolated polymers, MP and NP were prepared using both the Büchi B-191 and Nano Büchi B-90 spray dryers, respectively. The resulting two formulations were evaluated for yield, size, oxidation of thiol groups and ex-vivo mucoadhesion. The new spray drying technique provided NP of suitable size (<1μm) for catheter administration, low degree of oxidation, and sufficient mucoadhesion property with 9% and 18% of GSH- and NAC-GC based NP retained on pig mucosa bladder after 3h of exposure, respectively.<br><br>STATEMENT OF SIGNIFICANCE: The aim of the present study was first to optimize the synthesis of NAC-GC and GSH-GC, and preserve the oxidation state of the thiol moieties by introducing several optimizations of the already reported synthetic procedures that increase the mucoadhesive properties and avoid pH-dependent aggregation. Second, starting from these optimized thiomers, we studied the feasibility of manufacturing MP and NP by spray-drying techniques. The aim of this second step was to produce mucoadhesive drug delivery systems of adequate size for vesical administration by catheter, and comparable mucoadhesive properties with respect to the processed polymers, avoiding thiolic oxidation during the formulation. MP with acceptable size produced by spray-dryer B&#xfc;chi B-191 were compared with NP made with the apparatus Nano B&#xfc;chi B-90.}, }
@article {pmid27411777, year = {2016}, author = {Turedi, S and Erdem, E and Karaca, Y and Tatli, O and Sahin, A and Turkmen, S and Gunduz, A}, title = {The High Risk of Contrast-induced Nephropathy in Patients with Suspected Pulmonary Embolism Despite Three Different Prophylaxis: A Randomized Controlled Trial.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {23}, number = {10}, pages = {1136-1145}, doi = {10.1111/acem.13051}, pmid = {27411777}, issn = {1553-2712}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Aged, 80 and over ; Contrast Media/*adverse effects ; Coronary Angiography/*methods ; Creatinine ; Emergency Service, Hospital ; Female ; Hospital Mortality ; Humans ; Male ; Prospective Studies ; Pulmonary Embolism/*diagnostic imaging ; Renal Insufficiency/*chemically induced/*prevention &amp; control ; Risk Factors ; Sodium Bicarbonate/*therapeutic use ; Sodium Chloride/*therapeutic use ; Tomography, X-Ray Computed ; }, abstract = {OBJECTIVE: The objective was to compare the protective effects of N-acetylcysteine (NAC) plus normal saline (NS), sodium bicarbonate (NaHCO3) plus NS, and NS alone in the prevention of contrast-induced nephropathy (CIN) after computed tomography pulmonary angiography (CTPA) in emergency patients.<br><br>METHODS: This study was planned as a randomized, controlled clinical research. Patients undergoing contrast-enhanced CTPA on suspicion of pulmonary embolism (PE) in the emergency department and with at least one risk factor for development of CIN were included in one of three different prophylaxis groups. The groups received 3 mL/kg intravenous (IV) NAC+NS or NaHCO3 +NS solution or NS alone 1 hour before CTPA and 1 mL/kg IV per hour for a minimum of 6 hours after CTPA. CIN was evaluated as the primary outcome and moderate or severe renal insufficiency and in-hospital mortality as secondary outcomes.<br><br>RESULTS: A total of 257 patients were enrolled in the study. The total level of CIN development was 23.7% (61/257), the level of moderate and severe renal failure was 12.5% (32/257), and the in-hospital mortality rate was 12.8% (33/257). Rates of CIN development in the drug groups were 23.5% in the NAC group (20/85), 21.2% (18/85) in the NaHCO3 group, and 26.4% in the NS group (23/87). Rates of development of moderate or severe renal insufficiency were 9.4% in the NAC group (8/85), 10.6% in the NaHCO3 group (9/85), and 17.2% in the NS group (15/87). In-hospital mortality rates were 12.9% in the NAC group (11/85), 11.8% in the NaHCO3 group (10/85), and 13.8% in the NS group (12/87). No difference was determined between the drug groups in terms of CIN, moderate or severe renal injury, or hospital mortality.<br><br>CONCLUSIONS: Our results indicate that there is a high risk of CIN in patients with suspected PE despite three different types of prophylaxis being administered, and no statistically significant differences were observed among prophylactic NAC, NaHCO3 , and NS in prevention of CIN following contrast-enhanced CTPA.}, }
@article {pmid27406380, year = {2016}, author = {Saintigny, Y and Chevalier, F and Bravard, A and Dardillac, E and Laurent, D and Hem, S and Dépagne, J and Radicella, JP and Lopez, BS}, title = {A threshold of endogenous stress is required to engage cellular response to protect against mutagenesis.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {29412}, pmid = {27406380}, issn = {2045-2322}, mesh = {Animals ; CHO Cells ; Cricetulus ; *DNA Damage ; Genomic Instability/*genetics ; *Mutagenesis ; *Oxidative Stress ; Proteomics ; Thymidine/metabolism ; }, abstract = {Endogenous stress represents a major source of genome instability, but is in essence difficult to apprehend. Incorporation of labeled radionuclides into DNA constitutes a tractable model to analyze cellular responses to endogenous attacks. Here we show that incorporation of [(3)H]thymidine into CHO cells generates oxidative-induced mutagenesis, but, with a peak at low doses. Proteomic analysis showed that the cellular response differs between low and high levels of endogenous stress. In particular, these results confirmed the involvement of proteins implicated in redox homeostasis and DNA damage signaling pathways. Induced-mutagenesis was abolished by the anti-oxidant N-acetyl cysteine and plateaued, at high doses, upon exposure to L-buthionine sulfoximine, which represses cellular detoxification. The [(3)H]thymidine-induced mutation spectrum revealed mostly base substitutions, exhibiting a signature specific for low doses (GC > CG and AT > CG). Consistently, the enzymatic activity of the base excision repair protein APE-1 is induced at only medium or high doses. Collectively, the data reveal that a threshold of endogenous stress must be reached to trigger cellular detoxification and DNA repair programs; below this threshold, the consequences of endogenous stress escape cellular surveillance, leading to high levels of mutagenesis. Therefore, low doses of endogenous local stress can jeopardize genome integrity more efficiently than higher doses.}, }
@article {pmid27406060, year = {2016}, author = {Lin, CH and Lin, KF and Mar, K and Lee, SY and Lin, YM}, title = {Antioxidant N-Acetylcysteine and Glutathione Increase the Viability and Proliferation of MG63 Cells Encapsulated in the Gelatin Methacrylate/VA-086/Blue Light Hydrogel System.}, journal = {Tissue engineering. Part C, Methods}, volume = {22}, number = {8}, pages = {792-800}, doi = {10.1089/ten.TEC.2016.0025}, pmid = {27406060}, issn = {1937-3392}, mesh = {Acetamides/chemistry ; Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Azo Compounds/chemistry ; Bone Neoplasms/drug therapy/metabolism/*pathology ; Cell Proliferation/*drug effects ; Cell Survival ; Cross-Linking Reagents/chemistry ; Gelatin/chemistry ; Glutathione/*pharmacology ; Humans ; Hydrogel, Polyethylene Glycol Dimethacrylate/*chemistry ; Light ; Methacrylates ; Osteosarcoma/drug therapy/metabolism/*pathology ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, abstract = {Photoencapsulation of cells inside a hydrogel system can provide a suitable path to establish a gel in situ for soft tissue regeneration applications. However, the presence of photoinitiators and blue or UV light irradiation can result in cell damage and an increase of reactive oxygen species. We here evaluate the benefits of an antioxidant pretreatment on the photoencapsulated cells. We study this by evaluating proliferation and viability of MG63 cells, which we combined with a gelatin methacrylate (GelMA) hydrogel system, using the photoinitiator, VA-086, cured with 440 nm blue light. We found that blue light irradiation as well as the presence of 1% VA-086 reduced MG63 cell proliferation rates. Adding a short pretreatment step to the MG63 cells, consisting of the antioxidant molecules N-acetylcysteine (NAC) and reduced glutathione (GSH), and optimizing the GelMA encapsulation steps, we found that both NAC and GSH pretreatments of MG63 cells significantly increased both proliferation and viability of the cells, when using a 15% GelMA hydrogel, 1% VA-086, and 1-min blue light exposure. These findings suggest that the use of antioxidant pretreatment can counteract the negative presence of the photoinitiators and blue light exposure and result in a suitable environment for photoencapsulating cells in situ for tissue engineering and soft tissue applications.}, }
@article {pmid27405163, year = {2016}, author = {Gui, G and Meng, SS and Li, LJ and Liu, B and Liang, HX and Huangfu, CS}, title = {[Sodium nitrite enhanced the potentials of migration and invasion of human hepatocellular carcinoma SMMC-7721 cells through induction of mitophagy].}, journal = {Yao xue xue bao = Acta pharmaceutica Sinica}, volume = {51}, number = {1}, pages = {59-67}, pmid = {27405163}, issn = {0513-4870}, mesh = {Acetylcysteine/pharmacology ; Autophagy ; Carcinoma, Hepatocellular/*pathology ; Cell Line, Tumor ; Cell Movement ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Liver Neoplasms/*pathology ; *Mitophagy ; Neoplasm Invasiveness ; Nitrites/metabolism ; Reactive Oxygen Species/metabolism ; Sodium Nitrite/*pharmacology ; }, abstract = {Nitrites play multiple characteristic functions in invasion and metastasis of hepatic cancer cells, but the exact mechanism is not yet known. Cancer cells can maintain the malignant characteristics via clearance of excess mitochondria by mitophagy. The purpose of this article was to determine the roles of nitrite, reactive oxygen species (ROS) and hypoxia inducing factor 1 alpha (HIF-1 α) in mitophagy of hepatic cancer cells. After exposure of human hepatocellular carcinoma SMMC-7721 cells to a serial concentrations of sodium nitrite for 24 h under normal oxygen, the maximal cell vitality was increased by 16 mg x (-1) sodium nitrite. In addition, the potentials of migration and invasion for SMMC-7721 cells were increased significantly at the same time. Furthermore, sodium nitrite exposure displayed an increase of stress fibers, lamellipodum and perinuclear mitochondrial distribution by cell staining with Actin-Tracker Green and Mito-Tracker Red, which was reversed by N-acetylcysteine (NAC, a reactive oxygen scavenger). DCFH-DA staining with fluorescent microscopy showed that the intracellular level of ROS concentration was increased by the sodium nitrite treatment. LC3 immunostaining and Western blot results showed that sodium nitrite enhanced cell autophagy flux. Under the transmission electron microscopy (TEM), more autolysosomes formed after sodium nitrite treatment and NAC could prevent autophagosome degradation. RT-PCR results indicated that the expression levels of COX I and COXIV mRNA were decreased significantly after sodium nitrite treatment. Meanwhile, laser scanning confocal microscopy showed that sodium nitrite significantly reduced mitochondrial mass detected by Mito-Tracker Green staining. The expression levels of HIF-1α, Beclin-1 and Bnip3 (mitophagy marker molecular) increased remarkably after sodium nitrite treatment, which were reversed by NAC. Our results demonstrated that sodium nitrite (16 mg x L(-1)) increased the potentials of invasion and migration of hepatic cancer SMMC-7721 cells through induction of ROS and HIF-1α mediated mitophagy.}, }
@article {pmid27404685, year = {2016}, author = {Zhao, SJ and Zhong, ZS and Qi, GX and Tian, W}, title = {The efficacy of N-acetylcysteine plus sodium bicarbonate in the prevention of contrast-induced nephropathy after cardiac catheterization and percutaneous coronary intervention: A meta-analysis of randomized controlled trials.}, journal = {International journal of cardiology}, volume = {221}, number = {}, pages = {251-259}, doi = {10.1016/j.ijcard.2016.07.086}, pmid = {27404685}, issn = {1874-1754}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/chemically induced/epidemiology/*prevention &amp; control ; Cardiac Catheterization/*adverse effects/trends ; Contrast Media/administration &amp; dosage/*adverse effects ; Drug Therapy, Combination ; Humans ; Percutaneous Coronary Intervention/*adverse effects/trends ; Randomized Controlled Trials as Topic/methods ; Sodium Bicarbonate/*administration &amp; dosage ; Treatment Outcome ; }, abstract = {BACKGROUND: The efficacy of combining use of N-acetylcysteine (NAC) and sodium bicarbonate (SOB) in the prevention of contrast-induced nephropathy (CIN) after cardiac catheterization and percutaneous coronary intervention (PCI) is unclear.<br><br>METHODS: All relevant studies that compared the effect of combining the use of NAC and SOB with individual use on CIN in patients undergoing cardiac catheterization and PCI were identified by searching the databases including Pubmed, Embase, Cochrane Library, and Web of Science without time and language limitation. Only randomized controlled trials (RCTs) with full-text published were considered.<br><br>RESULTS: Sixteen RCTs involving 4432 cases were included into this meta-analysis. The results showed there were no additional benefit in reduction of CIN in COM group (COM versus NAC: RR 0.85, 95% CI 0.70-1.03, P=0.103; COM versus SOB: RR 0.91, 95% CI 0.71-1.16, P=0.449), even in patients with diabetes mellitus (COM versus NAC: RR 1.11, 95% CI 0.71-1.75, P=0.646; COM versus SOB: RR 1.06, 95% CI 0.45-2.47, P=0.893), undergoing PCI procedure (COM versus NAC: RR0.76, 95% CI 0.39-1.47, P=0.411; COM versus SOB: RR0.96, 95% CI 0.65-1.40, P=0.814), or with baseline renal dysfunction (COM versus NAC: RR 0.89, 95% CI 0.70-1.14, P=0.366; COM versus SOB: RR 0.95, 95% CI 0.67-1.36, P=0.788).<br><br>CONCLUSIONS: The present study demonstrated combining use of NAC and SOB was not significantly superior to individual use method in the prevention of CIN after cardiac catheterization and PCI.}, }
@article {pmid27403880, year = {2016}, author = {Sripetchwandee, J and Wongjaikam, S and Krintratun, W and Chattipakorn, N and Chattipakorn, SC}, title = {A combination of an iron chelator with an antioxidant effectively diminishes the dendritic loss, tau-hyperphosphorylation, amyloids-β accumulation and brain mitochondrial dynamic disruption in rats with chronic iron-overload.}, journal = {Neuroscience}, volume = {332}, number = {}, pages = {191-202}, doi = {10.1016/j.neuroscience.2016.07.003}, pmid = {27403880}, issn = {1873-7544}, mesh = {Acetylcysteine/pharmacology ; Amyloid beta-Peptides/metabolism ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/physiology ; Benzoates/pharmacology ; Brain/drug effects/metabolism/pathology ; Deferasirox ; Deferoxamine/pharmacology ; Dendrites/drug effects/metabolism/pathology ; Diet ; Disease Models, Animal ; Drug Therapy, Combination ; Iron/toxicity ; Iron Chelating Agents/*pharmacology ; Iron Overload/*drug therapy/metabolism/pathology ; Male ; Mitochondrial Dynamics/drug effects/physiology ; Neurodegenerative Diseases/*drug therapy/etiology/metabolism/pathology ; Phosphorylation/drug effects/physiology ; Random Allocation ; Rats, Wistar ; Triazoles/pharmacology ; tau Proteins/metabolism ; }, abstract = {Iron-overload can cause cognitive impairment due to blood-brain barrier (BBB) breakdown and brain mitochondrial dysfunction. Although deferiprone (DFP) has been shown to exert neuroprotection, the head-to-head comparison among iron chelators used clinically on brain iron-overload has not been investigated. Moreover, since antioxidant has been shown to be beneficial in iron-overload condition, its combined effect with iron chelator has not been tested. Therefore, the hypothesis is that all chelators provide neuroprotection under iron-overload condition, and that a combination of an iron chelator with an antioxidant has greater efficacy than monotherapy. Male Wistar rats (n=42) were assigned to receive a normal diet (ND) or a high-iron diet (HFe) for 4months. At the 2nd month, HFe-fed rats were treated with a vehicle, deferoxamine (DFO), DFP, deferasirox (DFX), n-acetyl cysteine (NAC) or a combination of DFP with NAC, while ND-fed rats received vehicle. At the end of the experiment, rats were decapitated and brains were removed to determine brain iron level and deposition, brain mitochondrial function, BBB protein expression, brain mitochondrial dynamic, brain apoptosis, tau-hyperphosphorylation, amyloid-β (Aβ) accumulation and dendritic spine density. The results showed that iron-overload induced BBB breakdown, brain iron accumulation, brain mitochondrial dysfunction, impaired brain mitochondrial dynamics, tau-hyperphosphorylation, Aβ accumulation and dendritic spine reduction. All treatments, except DFX, attenuated these impairments. Moreover, combined therapy provided a greater efficacy than monotherapy. These findings suggested that iron-overload induced brain iron toxicity and a combination of an iron chelator with an antioxidant provided a greatest efficacy for neuroprotection than monotherapy.}, }
@article {pmid27401659, year = {2016}, author = {Wu, Y and Zhang, M and Liu, R and Zhao, C}, title = {Oxidative Stress-Activated NHE1 Is Involved in High Glucose-Induced Apoptosis in Renal Tubular Epithelial Cells.}, journal = {Yonsei medical journal}, volume = {57}, number = {5}, pages = {1252-1259}, pmid = {27401659}, issn = {1976-2437}, mesh = {Antioxidants/metabolism ; Apoptosis/*drug effects ; Cation Transport Proteins/*metabolism ; Cell Cycle/drug effects ; Cell Line ; Dose-Response Relationship, Drug ; Epithelial Cells/*cytology/drug effects/*metabolism ; Glucose/*pharmacology ; Glutathione/metabolism ; Humans ; Kidney Tubules/*cytology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sodium-Hydrogen Exchanger 1 ; Sodium-Hydrogen Exchangers/*metabolism ; }, abstract = {PURPOSE: Diabetic nephropathy (DN) is a prevalent chronic microvascular complication of diabetes mellitus involving disturbances in electrolytes and the acid-base balance caused by a disorder of glucose metabolism. NHE1 is a Na[+]/H[+] exchanger responsible for keeping intracellular pH (pHi) balance and cell growth. Our study aimed to investigate roles of NHE1 in high glucose (HG)-induced apoptosis in renal tubular epithelial cells.<br><br>MATERIALS AND METHODS: Renal epithelial tubular cell line HK-2 was cultured in medium containing 5 mM or 30 mM glucose. Then, cell apoptosis, oxidative stress, NHE1 expression, and pHi were evaluated. NHE1 siRNA and inhibitor were used to evaluate its role in cell apoptosis.<br><br>RESULTS: HG significantly increased cell apoptosis and the production of reactive oxygen species (ROS) and 8-OHdG (p<0.05). Meanwhile, we found that HG induced the expression of NHE1 and increased the pHi from 7.0 to 7.6 after 48 h of incubation. However, inhibiting NHE1 using its specific siRNA or antagonist DMA markedly reduced cell apoptosis stimulated by HG. In addition, suppressing cellular oxidative stress using antioxidants, such as glutathione and N-acetyl cysteine, significantly reduced the production of ROS, accompanied by a decrease in NHE1. We also found that activated cyclic GMP-Dependent Protein Kinase Type I (PKG) signaling promoted the production of ROS, which contributed to the regulation of NHE1 functions.<br><br>CONCLUSION: Our study indicated that HG activates PKG signaling and elevates the production of ROS, which was responsible for the induction of NHE1 expression and dysfunction, as well as subsequent cell apoptosis, in renal tubular epithelial cells.}, }
@article {pmid27400421, year = {2016}, author = {Lu, Z and Zhang, Y and Gao, Y and Liu, B and Sun, X and He, F and Zhou, Q and Wu, Z}, title = {Effects of pyrogallic acid on Microcystis aeruginosa: oxidative stress related toxicity.}, journal = {Ecotoxicology and environmental safety}, volume = {132}, number = {}, pages = {413-419}, doi = {10.1016/j.ecoenv.2016.06.039}, pmid = {27400421}, issn = {1090-2414}, mesh = {Acetylcysteine/metabolism ; Antioxidants/*toxicity ; Ascorbic Acid/metabolism ; DNA Damage/drug effects ; Microcystis/*drug effects/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Pyrogallol/*toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {Pyrogallic acid (PA) is used in various industrial and consumer products. The molecular mechanisms underlying PA's toxicity was not fully understood. In this study, toxicity of PA on Microcystis aeruginosa with reactive oxygen species (ROS) generation as an end point was investigated. The results showed an increase in the percentage of cells with loss of membrane integrity and enhanced intracellular ROS production. Exposure to 50mgL(-1) PA for 48h caused the highest percentage of loss of membrane integrity (56.7%), and a 2.54-fold higher intracellular ROS level compared to control. Further investigation revealed that PA caused a dose-dependent increase in DNA strand breaks (DSB) of M. aeruginosa at exposure concentration from 2 to 50mgL(-1). The incubation of cells with ROS scavengers ascorbic acid, N-acetyl-l-cysteine (NAC) and tocopherol markedly alleviated the level of PA-induced DSB. Analysis of PA autoxidized products in culture solution showed that PA was quickly converted to purpurogallin (PG), and PG was further autoxidized to other polyphenolic compounds. PA and PG might participate a futile redox cycle, which mediated ROS production in M. aeruginosa. These results suggested DNA strands and cell membrane were two targets of ROS induced by PA, and oxidative damage was an important mechanism for the toxicity of PA against M. aeruginosa.}, }
@article {pmid27398384, year = {2016}, author = {Ortiz, MS and Forti, KM and Suárez Martinez, EB and Muñoz, LG and Husain, K and Muñiz, WH}, title = {Effects of Antioxidant N-acetylcysteine Against Paraquat-Induced Oxidative Stress in Vital Tissues of Mice.}, journal = {International journal of sciences, basic and applied research}, volume = {26}, number = {1}, pages = {26-46}, pmid = {27398384}, issn = {2307-4531}, support = {R25 GM082406/GM/NIGMS NIH HHS/United States ; U54 MD007579/MD/NIMHD NIH HHS/United States ; G12 MD007579/MD/NIMHD NIH HHS/United States ; R25 GM096955/GM/NIGMS NIH HHS/United States ; SC3 GM088087/GM/NIGMS NIH HHS/United States ; }, abstract = {Paraquat (PQ) is a commonly used herbicide that induces oxidative stress via reactive oxygen species (ROS) generation. This study aimed to investigate the effects of the antioxidant N-acetylcysteine (NAC) against PQ-induced oxidative stress in mice. Male Balb/C mice (24) were randomly divided into 4 groups and treated for 3 weeks: 1) control (saline), 2) NAC (0.5% in diet), 3) PQ (20 mg/kg, IP) and 4) combination (PQ + NAC). Afterwards mice were sacrificed and oxidative stress markers were analyzed. Our data showed no significant change in serum antioxidant capacity. PQ enhanced lipid peroxidation (MDA) levels in liver tissue compared to control whereas NAC decreased MDA levels (p<0.05). NAC significantly increased MDA in brain tissue (p<0.05). PQ significantly depleted glutathione (GSH) levels in liver (p=0.001) and brain tissue (p<0.05) but non-significant GSH depletion in lung tissue. NAC counteracted PQ, showing a moderate increase GSH levels in liver and brain tissues. PQ significantly increased 8-oxodeoxyguanosine (8-OH-dG) levels (p<0.05) in liver tissue compared to control without a significant change in brain tissue. NAC treatment ameliorated PQ-induced oxidative DNA damage in the liver tissue. PQ significantly decreased the relative mtDNA amplification and increased the frequency of lesions in liver and brain tissue (p<0.0001), while NAC restored the DNA polymerase activity in liver tissue but not in brain tissue. In conclusion, PQ induced lipid peroxidation, oxidative nuclear DNA and mtDNA damage in liver tissues and depleted liver and brain GSH levels. NAC supplementation ameliorated the PQ-induced oxidative stress response in liver tissue of mice.}, }
@article {pmid27390736, year = {2016}, author = {Choi, JS}, title = {Chrysophanic Acid Induces Necrosis but not Necroptosis in Human Renal Cell Carcinoma Caki-2 Cells.}, journal = {Journal of cancer prevention}, volume = {21}, number = {2}, pages = {81-87}, pmid = {27390736}, issn = {2288-3649}, abstract = {BACKGROUND: Chrysophanic acid, also known as chrysophanol, has a number of biological activities. It enhances memory and learning abilities, raises superoxide dismutase activity, and has anti-cancer effects in several model systems. According to previous reports, chrysophanic acid-induced cell death shares features of necrotic cell death. However, the molecular and cellular processes underlying chrysophanic acid-induced cell death remain poorly understood.<br><br>METHODS: Chrysophanic acid-induced cell death was monitored by cell viability assay and Annexin V-propidium iodide (PI) staining of renal cell carcinoma Caki-2 cells. The induction of intracellular reactive oxygen species (ROS) by chrysophanic acid and the suppression of ROS by anti-oxidants were evaluated by 2',7'-dichlorofluorescin diacetate staining. The expression and phosphorylation of proteins that are involved in apoptosis and necroptosis were detected by immunoblotting.<br><br>RESULTS: The extent of chrysophanic acid-induced cell death was concentration and time dependent, and dead cells mainly appeared in the PI-positive population, which is a major feature of necrosis, upon fluorescence-activated cell sorting analysis. Chrysophanic acid-induced cell death was associated with the generation of intracellular ROS, and this effect was reversed by pretreatment with N-acetyl cysteine. Chrysophanic acid-induced cell death was not associated with changes in apoptotic or necroptotic marker proteins.<br><br>CONCLUSIONS: The cell death induced by chrysophanic acid resembled neither apoptotic nor necroptotic cell death in human renal cell carcinoma Caki-2 cells.}, }
@article {pmid27387402, year = {2016}, author = {Ren, G and Luo, W and Sun, W and Niu, Y and Ma, DL and Leung, CH and Wang, Y and Lu, JJ and Chen, X}, title = {Psoralidin induced reactive oxygen species (ROS)-dependent DNA damage and protective autophagy mediated by NOX4 in breast cancer cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {23}, number = {9}, pages = {939-947}, doi = {10.1016/j.phymed.2016.05.008}, pmid = {27387402}, issn = {1618-095X}, mesh = {Antineoplastic Agents, Phytogenic/*toxicity ; Apoptosis/drug effects ; Autophagy/*drug effects ; Benzofurans/*toxicity ; Breast Neoplasms/*genetics ; Cadaverine/analogs &amp; derivatives ; Cell Proliferation/drug effects ; Coumarins/*toxicity ; *DNA Damage ; Dose-Response Relationship, Drug ; Female ; Fluorescent Dyes ; Gene Silencing ; Humans ; MCF-7 Cells ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/*metabolism ; RNA, Small Interfering/pharmacology ; *Reactive Nitrogen Species ; }, abstract = {BACKGROUND: Psoralidin (PSO), a natural phenolic coumarin, was reported to have anti-cancer activities. PSO induced reactive oxygen species (ROS) generation in cancer cells. The role of ROS in its anti-cancer effect remains unclear.<br><br>PURPOSE: This study was designed to investigate the potential roles of ROS in PSO-induced anti-cancer effect in MCF-7 breast cancer cells.<br><br>METHODS: Effect of PSO on cancer cell proliferation was determined by MTT assay. Comet assay was used to determine DNA damage. Protein expression was detected by Western blotting. Autophagic vacuoles were detected by monodansylcadaverine (MDC) staining. ROS generation was measured by fluorescent probe. NOX4 localization was determined by immunofluorescence staining.<br><br>RESULTS: PSO treatment caused proliferation inhibition in time- and dose- dependent manners, which was partially reversed by N-acetyl cysteine (NAC) and diphenyleneiodonium (DPI). PSO induced DNA damage and increased protein expression of &#x3b3;-H2AX, phosphorylation of ATM, ATR, Chk1, and Chk2. PSO induced autophagy as evidenced by the accumulation of autophagic vacuoles and alterations of autophagic protein expression. PSO-induced cell death was enhanced by autophagy inhibitor chloroquine (CQ). Furthermore, PSO treatment induced ROS formation, which was reversed by NAC or DPI pretreatment. The expression of NOX4 was significantly enhanced by PSO. Both NAC and DPI could reverse PSO-induced DNA damage and autophagic responses. In addition, silencing NOX4 by siRNA inhibited PSO-induced ROS generation, DNA damage, and autophagy.<br><br>CONCLUSIONS: Taken together, these results showed that PSO induced DNA damage and protective autophagy mediated by ROS generation in a NOX4-dependent manner in MCF-7 cells.}, }
@article {pmid27385396, year = {2016}, author = {Song, G and Napoli, E and Wong, S and Hagerman, R and Liu, S and Tassone, F and Giulivi, C}, title = {Altered redox mitochondrial biology in the neurodegenerative disorder fragile X-tremor/ataxia syndrome: use of antioxidants in precision medicine.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {22}, number = {}, pages = {548-559}, pmid = {27385396}, issn = {1528-3658}, support = {S10 RR023586/RR/NCRR NIH HHS/United States ; U54 HD079125/HD/NICHD NIH HHS/United States ; R01 HD040661/HD/NICHD NIH HHS/United States ; U50 DD000596/DD/NCBDD CDC HHS/United States ; R01 HD036071/HD/NICHD NIH HHS/United States ; R01 ES012691/ES/NIEHS NIH HHS/United States ; }, abstract = {A 55-200 expansion of the CGG nucleotide repeat in the 5'-UTR of the fragile X mental retardation 1 gene (FMR1) is the hallmark of the triplet nucleotide disease known as the "premutation" as opposed to those with >200 repeats, known as the full mutation or fragile X syndrome. Originally, premutation carriers were thought to be free of phenotypic traits; however, some are diagnosed with emotional and neurocognitive issues and, later in life, with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Considering that mitochondrial dysfunction has been observed in fibroblasts and post-mortem brain samples from carriers of the premutation, we hypothesized that mitochondrial dysfunction-derived ROS may result in cumulative oxidative-nitrative damage. Fibroblasts from premutation carriers (n=31, all FXTAS-free except 8), compared to age- and sex-matched controls (n=25), showed increased mitochondrial ROS production, impaired Complex I activity, lower expression of MIA40 (rate-limiting step of the redox-regulated mitochondrial-disulfide-relay-system), increased mtDNA deletions, and increased biomarkers of lipid and protein oxidative-nitrative damage. Most of the outcomes were more pronounced in FXTAS-affected individuals. Significant recovery of mitochondrial mass and/or function was obtained with superoxide or hydroxyl radicals' scavengers, a glutathione peroxidase analog, or by overexpressing MIA40. The effects of ethanol (a hydroxyl radical scavenger) were deleterious, while others (by N-acetyl-cysteine, quercetin and epigallocatechin-3-gallate) were outcome- and/or carrier-specifics. The use of antioxidants in the context of precision medicine is discussed with the goal of improving mitochondrial function in carriers with the potential of decreasing the morbidity and/or delaying FXTAS onset.}, }
@article {pmid27382365, year = {2016}, author = {Gómez, D and Muñoz, N and Guerrero, R and Acosta, O and Guerrero, CA}, title = {PPARγ Agonists as an Anti-Inflammatory Treatment Inhibiting Rotavirus Infection of Small Intestinal Villi.}, journal = {PPAR research}, volume = {2016}, number = {}, pages = {4049373}, pmid = {27382365}, issn = {1687-4757}, abstract = {Rotavirus infection has been reported to induce an inflammatory response in the host cell accompanied by the increased expression or activation of some cellular molecules including ROS, NF-κB, and COX-2. PPARγ stimulation and N-acetylcysteine (NAC) treatment have been found to interfere with viral infections including rotavirus infection. Small intestinal villi isolated from in vivo infected mice with rotavirus ECwt were analyzed for the percentage of ECwt-infected cells, the presence of rotavirus antigens, and infectious virion yield following treatment with pioglitazone. Isolated villi were also infected in vitro and treated with PPARγ agonists (PGZ, TZD, RGZ, DHA, and ALA), all-trans retinoic acid (ATRA), and NAC. After treatments, the expression of cellular proteins including PPARγ, NF-κB, PDI, Hsc70, and COX-2 was analyzed using immunochemistry, ELISA, immunofluorescence, and Western blotting. The results showed that rotavirus infection led to an increased accumulation of the cellular proteins studied and ROS. The virus infection-induced accumulation of the cellular proteins studied and ROS was reduced upon pioglitazone treatment, causing also a concomitant reduction of the infectious virion yield. We hypothesized that rotavirus infection is benefiting from the induction of a host cell proinflammatory response and that the interference of the inflammatory pathways involved leads to decreased infection.}, }
@article {pmid27375967, year = {2016}, author = {Sfara, V and Mougabure-Cueto, GA and González-Audino, PA}, title = {Modulation of the behavioral and electrical responses to the repellent DEET elicited by the pre-exposure to the same compound in Blattella germanica.}, journal = {PeerJ}, volume = {4}, number = {}, pages = {e2150}, pmid = {27375967}, issn = {2167-8359}, abstract = {Insects under different stimuli from the environment modify behavioural responses due to changes in the sensitivity of neurons at the peripheral and/or at the central level of the nervous system. This phenomenon is called neuronal plasticity, and sensory adaptation is an example of it. An insect repellent is a chemical that produces oriented movements of the insects away from its source. In this work we studied the modulation of the behavioural and electrical response to the repellent N, N-diethyl-3-methylbenzamide (DEET) in males of the German cockroach B. germanica produced by previous exposure to the same repellent. Methods. We determined repellency using a circular arena, one half of which was treated with DEET. The time spent by insects in each half of the arena was measured, and a repellency coefficient (RC) was calculated. The RCs of pre-exposed and non-pre-exposed insects were compared. To determine a possible role of nitric oxide in the modulation of the response to DEET after pre-exposure, the nitric oxide donor S-nitroso-acetyl-cysteine (SNAC) was applied on cockroaches' antennae. The electrical activity of the cockroaches' antennae in response to DEET was recorded using electroantennogram (EAG) technique. The response to DEET was recorded also after a long stimulation with the same repellent, and after topical application of SNAC and dbcGMP (a cGMP analogue) on the antennae. Results. We found that previous exposure of B. germanica males to the repellent DEET produced an increase of the repellency at the behavioural level, measured as RC. A possible role of nitric oxide (NO) in the transduction pathway of this phenomenon is suggested, since treatment of the cockroaches with the NO donor SNAC also produced an increase of the repellency elicited by DEET. On the other hand, the response of the cockroaches' antennae exposed to DEET was determined electrophysiologically. The electrical activity in response to DEET decreased when the insects' antennae were stimulated with a long pulse of the repellent. The activity of the antennae was restored after 10 min. Treatment of the antennae either with SNAC or dbGMPc also produced a decrease in the response of the antennae to the repellent. Discussion.The previous exposure to a chemical stimulus can modify the behaviour associated to the same stimulus, increasing or decreasing the behavioural response. In the case of DEET we found that pre-exposure increased DEET repellency in male cockroaches. We also found NO involvement in a similar phenomenon. On the other hand, the test showed that DEET is perceived by insects' antennae as an odour. A long exposure of the antennae to DEET caused a transient decrease in the response of the antennae to the same compound. The same effect was achieved by treating the antennae with SNAC or dbcGMP, suggesting the involvement of the NO/cGMP system in the transduction pathway of the sensory adaptation phenomenon elicited by an odour in this species.}, }
@article {pmid27374090, year = {2016}, author = {Doshi, KA and Trotta, R and Natarajan, K and Rassool, FV and Tron, AE and Huszar, D and Perrotti, D and Baer, MR}, title = {Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress.}, journal = {Oncotarget}, volume = {7}, number = {30}, pages = {48280-48295}, pmid = {27374090}, issn = {1949-2553}, support = {I01 BX002184/BX/BLRD VA/United States ; P30 CA134274/CA/NCI NIH HHS/United States ; R01 CA163800/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/drug effects ; Biphenyl Compounds/administration &amp; dosage/pharmacology ; Cytarabine/pharmacology ; *DNA Damage ; Drug Synergism ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/enzymology/genetics ; Oxidative Stress/*drug effects ; Protein Kinase Inhibitors/administration &amp; dosage/pharmacology ; Proto-Oncogene Proteins c-pim-1/*antagonists &amp; inhibitors/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Thiazolidines/administration &amp; dosage/pharmacology ; Topoisomerase II Inhibitors/administration &amp; dosage/*pharmacology ; fms-Like Tyrosine Kinase 3/*metabolism ; }, abstract = {Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD.}, }
@article {pmid27373489, year = {2016}, author = {Chen, KJ and Sabrina, S and El-Safory, NS and Lee, GC and Lee, CK}, title = {Constitutive expression of recombinant human hyaluronidase PH20 by Pichia pastoris.}, journal = {Journal of bioscience and bioengineering}, volume = {122}, number = {6}, pages = {673-678}, doi = {10.1016/j.jbiosc.2016.06.007}, pmid = {27373489}, issn = {1347-4421}, mesh = {Cell Adhesion Molecules/*genetics/metabolism ; Cloning, Molecular ; Gene Expression Regulation, Fungal ; Glycosylation ; Humans ; Hyaluronic Acid/metabolism ; Hyaluronoglucosaminidase/*genetics/metabolism ; Metabolic Engineering ; Molecular Weight ; Organisms, Genetically Modified ; Pichia/*genetics/*metabolism ; Recombinant Proteins/*genetics/metabolism ; Transfection ; }, abstract = {PH20 is known as sperm adhesion molecule 1 (SPAM1) and also has hyaluronidase function to preferentially hydrolyze the glycosidic linkage of hyaluronic acid (HA). A DNA fragment containing core domain of human PH20 gene was cloned into a constitutive expression plasmid (pGAPZαC) of Pichia pastoris to produce a fusion protein with α factor signal in the N-terminus and 6 × His as well as c-Myc tags in the C-terminus. The resulting plasmid pGAPZαC-PH20 was integrated into the genome of P. pastoris strain GS115. Functional recombinant human PH20 (rHuPH20) was successfully expressed and secreted by the recombinant P. pastoris transformant. Highest hyaluronidase activity of 2 mU/mL could be obtained at 3 day in an YPD culture. After purified by phenylboronic acid resin adsorption, rHuPH20 with a specific activity of 230 mU/mg was obtained. Via periodic acid-Schiff staining and zymogram analysis, the partially purified rHuPH20 was determined to be highly glycosylated to various extents with molecular mass in the range of 100-300 kDa. The enzyme showed a maximal activity at pH 5.0 but no appreciable activity at pH ≤3 and pH ≥8. The hyaluronidase activity could be stably maintained at 4°C but lost 40% after incubating at 30°C for 4 h. Both N-acetyl cysteine and glutathione showed a half maximal inhibitory concentration (IC50) of 8 mM against rHuPH20.}, }
@article {pmid27364593, year = {2016}, author = {Tao, S and Luo, Y and Bin He,  and Liu, J and Qian, X and Ni, Y and Zhao, R}, title = {Paraoxonase 2 modulates a proapoptotic function in LS174T cells in response to quorum sensing molecule N-(3-oxododecanoyl)-L-homoserine lactone.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {28778}, pmid = {27364593}, issn = {2045-2322}, mesh = {4-Butyrolactone/*analogs &amp; derivatives/pharmacology ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Aryldialkylphosphatase/antagonists &amp; inhibitors/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Colonic Neoplasms/genetics/metabolism/pathology ; Gene Expression Regulation, Neoplastic/drug effects ; HCT116 Cells ; Homoserine/*analogs &amp; derivatives/pharmacology ; Humans ; Microscopy, Electron, Transmission ; Mitochondria/drug effects/metabolism/ultrastructure ; Mucin-2/genetics/metabolism ; Quorum Sensing ; beta-Cyclodextrins/pharmacology ; }, abstract = {A mucus layer coats the gastrointestinal tract and serves as the first line of intestinal defense against infection. N-acyl-homoserine lactone (AHL) quorum-sensing molecules produced by gram-negative bacteria in the gut can influence the homeostasis of intestinal epithelium. In this study, we investigated the effects of two representative long- and short-chain AHLs, N-3-(oxododecanoyl)-homoserine lactone (C12-HSL) and N-butyryl homoserine lactone (C4-HSL), on cell viability and mucus secretion in LS174T cells. C12-HSL but not C4-HSL significantly decreased cell viability by inducing mitochondrial dysfunction and activating cell apoptosis which led to a decrease in mucin expression. Pretreatment with lipid raft disruptor (Methyl-β-cyclodextrin, MβCD) and oxidative stress inhibitor (N-acetyl-L-cysteine, NAC) slightly rescued the viability of cells damaged by C12-HSL exposure, while the paraoxonase 2 (PON2) inhibitor (Triazolo[4,3-a]quinolone, TQ416) significantly affected recovering cells viability and mucin secretion. When LS174T cells were treated with C12-HSL and TQ416 simultaneously, TQ416 showed the maximal positive effect on cells viability. However, if cells were first treated with C12-HSL for 40 mins, and then TQ46 was added, the TQ416 had no effect on cell viability. These results suggest that the C12-HSL-acid process acts at an early step to activate apoptosis as part of C12-HSL's effect on intestinal mucus barrier function.}, }
@article {pmid27364565, year = {2016}, author = {Zhao, B and Mei, Y and Yang, J and Ji, P}, title = {Erythropoietin-regulated oxidative stress negatively affects enucleation during terminal erythropoiesis.}, journal = {Experimental hematology}, volume = {44}, number = {10}, pages = {975-981}, pmid = {27364565}, issn = {1873-2399}, support = {P30 CA060553/CA/NCI NIH HHS/United States ; R00 HL102154/HL/NHLBI NIH HHS/United States ; R01 DK102718/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Apoptosis ; Biomarkers ; Cell Differentiation/*drug effects ; Erythroblasts/*cytology/*drug effects/metabolism ; Erythropoiesis/*drug effects ; Erythropoietin/*pharmacology ; Fetus ; Hematopoietic Cell Growth Factors/pharmacology ; Hemoglobins/metabolism ; Immunophenotyping ; Iron/metabolism ; Liver/cytology ; Mice ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Transferrin/metabolism ; }, abstract = {Differentiating erythroblasts are exposed to an oxidative environment. The dynamics of oxidative status during terminal erythropoiesis and how they affect cell differentiation in response to erythropoietin (Epo) are unclear. Here, we show that Epo induces reactive oxygen species (ROS) production in the early stages of terminal erythropoiesis. The levels of ROS correlate with CD71 surface expression and the uptake of iron and transferrin. ROS decreases in the late stages of terminal erythropoiesis, when the cells are preparing for enucleation. Consistently, treatment of erythroblasts with a low dose (5 mM) of N-acetyl-cysteine (NAC), a ROS scavenger, promotes enucleation. However, a high dose (20 mM) of NAC leads to significant cell death. Our study reveals an important function of Epo in regulating the dynamics of oxidative status and enucleation.}, }
@article {pmid27363620, year = {2016}, author = {Wrotek, S and Jędrzejewski, T and Piotrowski, J and Kozak, W}, title = {N-Acetyl-l-cysteine exacerbates generation of IL-10 in cells stimulated with endotoxin in vitro and produces antipyresis via IL-10 dependent pathway in vivo.}, journal = {Immunology letters}, volume = {177}, number = {}, pages = {1-5}, doi = {10.1016/j.imlet.2016.06.005}, pmid = {27363620}, issn = {1879-0542}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibodies, Blocking/administration &amp; dosage ; Antipyretics/*pharmacology ; Body Temperature ; Cells, Cultured ; Dinoprostone/metabolism ; Disease Models, Animal ; Fever/*drug therapy/immunology ; Interleukin-10/immunology/*metabolism ; Leukocytes, Mononuclear/*drug effects/physiology ; Lipopolysaccharides/immunology ; Male ; Rats ; Rats, Wistar ; }, abstract = {N-Acetyl-l-cysteine (NAC) is a well-known medication, primarily used as a mucolytic agent in pulmonary disease. Recently, we have found that NAC possesses antipyretic properties. The aim of the present study was to investigate the mechanism by which NAC attenuates fever. The concentration of interleukin (IL)-10 and prostaglandin (PG) E2 were measured using ELISA kit in the supernatants aspirated after stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS, 1μg/mL) and NAC (10mM). The body temperature of the Wistar rats was measured using biotelemetry system. To inhibit endotoxic fever, NAC (200mg/kg; i.p.) was injected into the rats one hour prior to the LPS administration (50μg/kg; i.p.). The pre-treatment of LPS-stimulated PBMCs with NAC resulted in a significant decrease in PGE2 concentration in comparison to the cells treated with LPS alone (PGE2 level was 386.1±61.9pg/mL vs. 2078.9±157.9pg/mL, respectively, p<0.001). Furthermore, in these cells we observed a significant increase in IL-10 level (142.1±2.62pg/mL in NAC+LPS stimulated cells vs. 54.4±0.6pg/mL in LPS stimulated cells, p<0.001). The injection of anti-IL-10 antibody into the rats abolished antipyretic properties of NAC. Body temperature in animals treated with anti-IL-10+NAC/LPS was 38.28±0.12°C vs. 37.73±0.06°C in IgG+NAC/LPS rats (p<0.001) and 38.31±0.20°C in NaCl/LPS-treated animals (n.s.). Based on these data, we conclude that NAC acts as an antipyretic via IL-10 stimulation. This finding provides a new insight into the immunopharmacology of NAC, and we believe that in a future it will contribute to the new and/or more accurate application of NAC in medicine.}, }
@article {pmid27363050, year = {2016}, author = {Mnaa, S and Shaker, ES and Mahmoud, HI}, title = {INHIBITORY ACTIVITY OF PROTECTED EDIBLE PLANTS ON OXIDATIVE STRESS INDUCED BY ORAL 1,4-DIOXANE.}, journal = {Journal of the Egyptian Society of Parasitology}, volume = {46}, number = {1}, pages = {135-143}, doi = {10.12816/0026159}, pmid = {27363050}, issn = {1110-0583}, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain/drug effects ; Catalase/metabolism ; Dioxanes/*toxicity ; Dose-Response Relationship, Drug ; Environmental Pollutants/toxicity ; Female ; Liver/drug effects/enzymology ; Malondialdehyde/metabolism ; Ovary/drug effects ; Oxidative Stress/*drug effects ; *Plants, Edible ; Rats ; Rats, Sprague-Dawley ; }, abstract = {1,4-Dioxane (DX) with two oxygen atoms make it hydrophilic and infinitely soluble in water. As a synthetic organic compound, it used widely throughout industry as a solvent. Dioxane causes numerous human ailments such as liver damage and kidney failure. It has been shown in research to be carcinogenic to animals, and is a potential carcinogen to humans. Daily administration for 1,4-dioxane (100 mg/kg body weight) in drinking water for rats weighing 120 g, except for normal control group. Experimental animal for 42 days was followed through body weight, serum alkaline phosphatase, serum creatinine, malondialdehyde, and catalase enzyme activity; beside histological patterns for liver, kidney, brain and ovary sections. Protection treatment has been offered using oral injection N-acetyl cysteine (100 mg/kg b.wt.), and fresh 200 mg/kg b.wt. in diet meal for each of nabk, husk, and sycamore in separated groups. Body weight and CAT activity have decreased by 25.8, and 68.7%, respectively. While increase has found in MDA, ALP and creatinine values by 76, 48.9, and 67.3%, respectively. NAC showed improvement especially for MDA peroxidation marker and creatinine for kidney disorder. On the other hand, nabk improved CAT activity and husk for ALP liver mutagenicity marker. Intoxicated DX showed edema, kupffer cell activation, atrophy of glomerular tuft, and necrosis of neurons in liver, kidney and brain sections. Obviously nabk showed highly improvement in liver toxicity which is the most sensitive organ to DX as found in research.}, }
@article {pmid27356027, year = {2016}, author = {Kita, K and Sugita, K and Sato, C and Sugaya, S and Sato, T and Kaneda, A}, title = {Extracellular Release of Annexin A2 is Enhanced upon Oxidative Stress Response via the p38 MAPK Pathway after Low-Dose X-Ray Irradiation.}, journal = {Radiation research}, volume = {186}, number = {1}, pages = {79-91}, doi = {10.1667/RR14277.1}, pmid = {27356027}, issn = {1938-5404}, mesh = {Acetylcysteine/pharmacology ; Annexin A2/*metabolism ; Dose-Response Relationship, Radiation ; Extracellular Space/drug effects/*metabolism/*radiation effects ; HeLa Cells ; Humans ; MAP Kinase Signaling System/drug effects/*radiation effects ; Oxidative Stress/drug effects/*radiation effects ; Ultraviolet Rays/adverse effects ; X-Rays/adverse effects ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {The extracellular microenvironment affects cellular responses to various stressors including radiation. Annexin A2, which was initially identified as an intracellular molecule, is also released into the extracellular environment and is known to regulate diverse cell surface events, however, the molecular mechanisms underlying its release are not well known. In this study, we found that in cultured human cancer and non-cancerous cells an extracellular release of annexin A2 was greatly enhanced 1-4 h after a single 20 cGy X-ray dose, but not after exposure to ultraviolet C (UVC) radiation. Extracellular release of annexin A2 was also enhanced after H2O2 and nicotine treatments, which was suppressed by pretreatment with the antioxidant, N-acetyl cysteine. Among the oxidative stress pathway molecules examined in HeLa cells, AMP-activated protein kinase α (AMPKα) and p38 mitogen-activated protein kinase (MAPK) were mostly activated by low-dose X-ray radiation, and the p38 MAPK inhibitor, SB203580, but not compound C (an AMPKα inhibitor), suppressed the enhancement of the annexin A2 extracellular release after low-dose X irradiation. In addition, the enhancement was suppressed in the cells in which p38α MAPK was downregulated by siRNA. HeLa cells and human cultured cells preirradiated with 20 cGy or precultured in media from low-dose X-irradiated cells showed an increase in resistance to radiation-induced cell death, and the increase was suppressed by treatment of the irradiated cell-derived media with anti-annexin A2 antibodies. In addition, extracellularly added recombinant annexin A2 conferred cellular radiation resistance. These results indicate that an oxidative stress-activated pathway via p38 MAPK was involved in the extracellular release of annexin A2, and this pathway was stimulated by low-dose X-ray irradiation. Furthermore, released annexin A2 may function in low-dose ionizing radiation-induced responses, such as radioresistance.}, }
@article {pmid27352350, year = {2015}, author = {Xiong, Y and Ren, L and Wang, Z and Hu, Z and Zhou, Y}, title = {Anti-proliferative Effect of Physcion on Human Gastric Cell Line via Inducing ROS-Dependent Apoptosis.}, journal = {Cell biochemistry and biophysics}, volume = {73}, number = {2}, pages = {537-543}, doi = {10.1007/s12013-015-0674-9}, pmid = {27352350}, issn = {1559-0283}, mesh = {AMP-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cytochromes c/metabolism ; Emodin/*analogs &amp; derivatives/toxicity ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Stomach Neoplasms/metabolism/pathology ; }, abstract = {In this study, the anti-proliferative effect of physcion, an anthraquinone derivative isolated and characterized from both terrestrial and marine sources, against human gastric cancer SGC-7901 cells was investigated and the underlying mechanisms were explored. Physcion reduced SGC-7901 cell viability in a dose- and time-dependent manner, as demonstrated by MTT assay. It triggered the mitochondrial/caspase apoptotic pathway indicated by loss of mitochondrial membrane potential and cytochrome c release. Moreover, physcion induced a sustained activation of the phosphorylation of AMPK, and compound C (an inhibitor of AMPK) significantly reversed physcion-induced apoptosis in SGC-7901 cells. In addition, physcion provoked the generation of reactive oxygen species (ROS) in SGC-7901 cells, while the antioxidant N-acetyl cysteine almost completely blocked physcion-induced AMPK activation and apoptosis. Taken together, these findings suggest that physcion induces apoptosis through a ROS/AMPK-dependent mitochondrial pathway.}, }
@article {pmid27351177, year = {2016}, author = {Martinez, PF and Bonomo, C and Guizoni, DM and Junior, SA and Damatto, RL and Cezar, MD and Lima, AR and Pagan, LU and Seiva, FR and Bueno, RT and Fernandes, DC and Laurindo, FR and Zornoff, LA and Okoshi, K and Okoshi, MP}, title = {Modulation of MAPK and NF-954;B Signaling Pathways by Antioxidant Therapy in Skeletal Muscle of Heart Failure Rats.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {39}, number = {1}, pages = {371-384}, doi = {10.1159/000445631}, pmid = {27351177}, issn = {1421-9778}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Echocardiography ; Gene Expression/drug effects ; Heart Failure/*drug therapy/genetics/metabolism ; Male ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Muscle, Skeletal/*drug effects/metabolism ; MyoD Protein/genetics/metabolism ; Myocardial Infarction/drug therapy/genetics/metabolism ; Myogenin/genetics/metabolism ; NF-kappa B/*metabolism ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*drug effects ; Ventricular Dysfunction, Left/drug therapy/genetics/physiopathology ; }, abstract = {BACKGROUND/AIMS: Although increased oxidative stress plays a role in heart failure (HF)-induced skeletal myopathy, signaling pathways involved in muscle changes and the role of antioxidant agents have been poorly addressed. We evaluated the effects of N-acetylcysteine (NAC) on intracellular signaling pathways potentially modulated by oxidative stress in soleus muscle from HF rats.<br><br>METHODS AND RESULTS: Four months after surgery, rats were assigned to Sham, myocardial infarction (MI)-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. Oxidative stress was evaluated in serum and soleus muscle; malondialdehyde was higher in MI-C than Sham and did not differ between MI-C and MI-NAC. Oxidized glutathione concentration in soleus muscle was similar in Sham and MI-C, and lower in MI-NAC than MI-C (Sham 0.168 &#xb1; 0.056; MI-C 0.223 &#xb1; 0.073; MI-NAC 0.136 &#xb1; 0.023 nmol/mg tissue; p = 0.014). Western blot showed increased p-JNK and decreased p38, ERK1/2, and p-ERK1/2 in infarcted rats. NAC restored ERK1/2. NF-954;B p65 subunit was reduced; p-Ser276 in p65 and I954;B was increased; and p-Ser536 unchanged in MI-C compared to Sham. NAC did not modify NF-954;B p65 subunit, but decreased p-Ser276 and p-Ser536.<br><br>CONCLUSION: N-acetylcysteine modulates MAPK and NF-954;B signaling pathways in soleus muscle of HF rats.}, }
@article {pmid27350943, year = {2016}, author = {Yoon, E and Babar, A and Choudhary, M and Kutner, M and Pyrsopoulos, N}, title = {Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update.}, journal = {Journal of clinical and translational hepatology}, volume = {4}, number = {2}, pages = {131-142}, pmid = {27350943}, issn = {2225-0719}, abstract = {Hepatic injury and subsequent hepatic failure due to both intentional and non-intentional overdose of acetaminophen (APAP) has affected patients for decades, and involves the cornerstone metabolic pathways which take place in the microsomes within hepatocytes. APAP hepatotoxicity remains a global issue; in the United States, in particular, it accounts for more than 50% of overdose-related acute liver failure and approximately 20% of the liver transplant cases. The pathophysiology, disease course and management of acute liver failure secondary to APAP toxicity remain to be precisely elucidated, and adverse patient outcomes with increased morbidity and mortality continue to occur. Although APAP hepatotoxicity follows a predictable timeline of hepatic failure, its clinical presentation might vary. N-acetylcysteine (NAC) therapy is considered as the mainstay therapy, but liver transplantation might represent a life-saving procedure for selected patients. Future research focus in this field may benefit from shifting towards obtaining antidotal knowledge at the molecular level, with focus on the underlying molecular signaling pathways.}, }
@article {pmid27350323, year = {2016}, author = {Liu, D and Li, J and Pan, H and He, F and Liu, Z and Wu, Q and Bai, C and Yu, S and Yang, X}, title = {Potential advantages of a novel chitosan-N-acetylcysteine surface modified nanostructured lipid carrier on the performance of ophthalmic delivery of curcumin.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {28796}, pmid = {27350323}, issn = {2045-2322}, mesh = {Acetylcysteine/*chemistry ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/chemistry/pharmacokinetics ; Chitosan/*analogs &amp; derivatives/chemistry ; Cornea/metabolism ; Curcumin/*administration &amp; dosage/chemistry/pharmacokinetics ; Drug Carriers/*chemistry ; Drug Delivery Systems/methods ; Drug Liberation ; Female ; Humans ; Lipids/*chemistry ; Male ; Nanostructures/*chemistry ; Ophthalmic Solutions/administration &amp; dosage/chemistry/pharmacokinetics ; Particle Size ; Rabbits ; Surface Properties ; }, abstract = {The transient precorneal retention time and low penetration capacity into intraocular tissues are the key obstacles that hinder the ophthalmic drug delivery of many therapeutic compounds, especially for drugs with poor solubility and permeability. To break the stalemate, N-acetyl-L-cysteine functionalized chitosan copolymer (CS-NAC), which exhibit marked bioadhesion and permeation enhancing effect, was synthesized. The curcumin encapsulated NLC (CUR-NLC) was produced and optimized followed by surface absorption of CS-NAC. After coating, changed particle size from 50.76 ± 2.21 nm to 88.64 ± 1.25 nm and reversed zeta potential from -20.38 ± 0.39 mV to 22.51 ± 0.34 mV was observed. The in vitro CUR release from NLC was slower than that of CUR-NLC and chitosan hydrochlorides (CH) coated NLC due to the inter and/or intramolecular disulfide formation of thiomers on the surface of nanocarriers. The modification also significantly enhanced transcorneal penetration compared with CH-NLC and the uncoated ones. The effect on bioadhesion and precorneal retention were evaluated by in vivo imaging technique and ocular pharmacokinetics studies revealing that the clearance of the formulations was significantly delayed in the presence of CS-NAC and the effect was positively related to the degree of thiolation. In summary, CS-NAC-NLC presented a series of notable advantages for ophthalmic drug application.}, }
@article {pmid27344977, year = {2016}, author = {Ali- Hasan- Al- Saegh, S and Mirhosseini, SJ and Tahernejad, M and Mahdavi, P and Shahidzadeh, A and Karimi-Bondarabadi, AA and Dehghan, AM and Rahimizadeh, E and Haddad, F and Ghodratipour, Z and Sarrafan-Chaharsoughi, Z and Shahidzadeh, A and Ghanei, A and Lotfaliani, M and Zeriouh, M and Weymann, A and Popov, AF and Sabashnikov, A}, title = {Impact of antioxidant supplementations on cardio-renal protection in cardiac surgery: an updated and comprehensive meta-analysis and systematic review.}, journal = {Cardiovascular therapeutics}, volume = {34}, number = {5}, pages = {360-370}, doi = {10.1111/1755-5922.12207}, pmid = {27344977}, issn = {1755-5922}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Acute Kidney Injury/diagnosis/mortality/*prevention &amp; control ; Antioxidants/adverse effects/*therapeutic use ; Ascorbic Acid/adverse effects/*therapeutic use ; Atrial Fibrillation/diagnosis/mortality/*prevention &amp; control ; Cardiac Surgical Procedures/*adverse effects/mortality ; *Dietary Supplements ; Fatty Acids, Unsaturated/adverse effects/*therapeutic use ; Humans ; Incidence ; Odds Ratio ; Risk Factors ; Treatment Outcome ; }, abstract = {This systematic review with meta-analysis sought to determine the strength of evidence in terms of the impact of common antioxidant supplementations, such as N-acetylcysteine (NAC), vitamin C, and polyunsaturated fatty acids (PUFA) on perioperative outcomes after cardiac surgery with particular focus on the incidence of atrial fibrillation (AF) and acute kidney injury (AKI) with associated mortality. A total of 29 trials were identified that reported incidence of AF and 17 trials that reported incidence of AKI. Pooled analysis reported that NAC (OR=0.5; P=.001), vitamin C (OR=0.4; P=.001), and PUFA (OR=0.8; P=.01) administration were associated with significantly reduced incidence of AF. In terms of postoperative AKI, only NAC was shown to be a beneficial supplement that was able to significantly reduce the incidence of AKI (OR=0.7; P=.01), and NAC could also significantly decrease overall mortality (OR=0.3; P=.03) following cardiac surgery. The use of NAC in patients undergoing cardiac surgery should be strongly recommended due to its combined cardio-renal protective effects and reduced mortality. Also, PUFA and vitamin C might be able to significantly decrease the incidence of arrhythmia; however, reno-protective effects and impact on overall mortality of these supplements seem to be less impressive.}, }
@article {pmid27339892, year = {2016}, author = {Junkunlo, K and Söderhäll, K and Söderhäll, I and Noonin, C}, title = {Reactive Oxygen Species Affect Transglutaminase Activity and Regulate Hematopoiesis in a Crustacean.}, journal = {The Journal of biological chemistry}, volume = {291}, number = {34}, pages = {17593-17601}, pmid = {27339892}, issn = {1083-351X}, mesh = {Animals ; Arthropod Proteins/*metabolism ; Astacoidea/*metabolism ; Hematopoiesis/*physiology ; Reactive Oxygen Species/*metabolism ; Transglutaminases/*metabolism ; }, abstract = {Reactive oxygen species (ROS) serve as a prime signal in the commitment to hematopoiesis in both mammals and Drosophila In this study, the potential function of ROS during hematopoiesis in the crayfish Pacifastacus leniusculus was examined. The antioxidant N-acetylcysteine (NAC) was used to decrease ROS in both in vivo and in vitro experiments. An increase in ROS was observed in the anterior proliferation center (APC) after LPS injection. In the absence of NAC, the LPS-induced increase in ROS levels resulted in the rapid restoration of the circulating hemocyte number. In the presence of NAC, a delay in the recovery rate of the hemocyte number was observed. NAC treatment also blocked the spread of APC and other hematopoietic tissue (HPT) cells, maintaining these cells at an undifferentiated stage. Extracellular transglutaminase (TGase) has been shown previously to play a role in maintaining HPT cells in an undifferentiated form. In this study, we show that extracellular TGase activity increased when the ROS level in HPT or APC cells was reduced after NAC treatment. In addition, collagen, a major component of the extracellular matrix and a TGase substrate were co-localized on the HPT cell surface. Taken together, the results of this study show that ROS are involved in crayfish hematopoiesis, in which a low ROS level is required to maintain hematopoietic progenitor cells in the tissue and to reduce hemocyte release. The potential roles of TGase in this process are investigated and discussed.}, }
@article {pmid27339615, year = {2016}, author = {Gruenbaum, SE and Zlotnik, A and Gruenbaum, BF and Hersey, D and Bilotta, F}, title = {Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury: A Systematic Review of the Clinical Literature.}, journal = {CNS drugs}, volume = {30}, number = {9}, pages = {791-806}, pmid = {27339615}, issn = {1179-1934}, support = {T32 GM086287/GM/NIGMS NIH HHS/United States ; UL1 TR000142/TR/NCATS NIH HHS/United States ; }, mesh = {Brain Injuries, Traumatic/*drug therapy/physiopathology ; Emergency Service, Hospital ; Humans ; *Intensive Care Units ; Intracranial Pressure ; Neuroprotective Agents/pharmacology/*therapeutic use ; Randomized Controlled Trials as Topic ; Time Factors ; Treatment Outcome ; }, abstract = {INTRODUCTION: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. The deleterious effects of secondary brain injury may be attenuated by early pharmacological therapy in the emergency room and intensive care unit (ICU). Current medical management of acute TBI is primarily supportive, aimed at reducing intracranial pressure (ICP) and optimizing cerebral perfusion. There are no pharmacological therapies to date that have been unequivocally demonstrated to improve neurological outcomes after TBI.<br><br>OBJECTIVES: The purpose of this systematic review was to evaluate the recent clinical studies from January 2013 through November 2015 that investigated neuroprotective functional outcomes of pharmacological agents after TBI.<br><br>METHODS: The following databases were searched for relevant studies: MEDLINE (OvidSP January Week 1, 2013-November Week 2 2015), Embase (OvidSP 2013 January 1-2015 November 24), and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health [NLM/NIH]). This systematic review included only full-length clinical studies and case series that included at least five patients and were published in the English language. Only studies that examined functional clinical outcomes were included.<br><br>RESULTS: Twenty-five of 527 studies met our inclusion criteria, which investigated 15 independent pharmacological therapies. Eight of these therapies demonstrated possible neuroprotective properties and improved functional outcomes, of which five were investigated with randomized clinical trials: statins, N-acetyl cysteine (NAC), Enzogenol, Cerebrolysin, and nitric oxide synthase inhibitor (VAS203). Three pharmacological agents did not demonstrate neuroprotective effects, and four agents had mixed results.<br><br>CONCLUSIONS: While there is currently no single pharmacological therapy that will unequivocally improve clinical outcomes after TBI, several agents have demonstrated promising clinical benefits for specific TBI patients and should be investigated further.}, }
@article {pmid27339432, year = {2016}, author = {Mateu-Jimenez, M and Fermoselle, C and Rojo, F and Mateu, J and Peña, R and Urtreger, AJ and Diament, MJ and Joffé, ED and Pijuan, L and Herreros, AG and Barreiro, E}, title = {Pharmacological Approaches in an Experimental Model of Non-Small Cell Lung Cancer: Effects on Tumor Biology.}, journal = {Current pharmaceutical design}, volume = {22}, number = {34}, pages = {5300-5310}, doi = {10.2174/1381612822666160623065523}, pmid = {27339432}, issn = {1873-4286}, mesh = {Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chemotherapy, Adjuvant ; Drug Screening Assays, Antitumor ; Female ; Lung Neoplasms/*drug therapy/pathology ; Mice ; Mice, Inbred BALB C ; Neoplasms, Experimental/drug therapy/pathology ; Oxidative Stress/drug effects ; }, abstract = {Lung cancer (LC) remains the leading cause of cancer mortality worldwide, and non-small cell LC (NSCLC) represents 80% of all LC. Oxidative stress and inflammation, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen activated protein kinases (MAPK) participate in LC pathophysiology. Currently available treatment for LC is limited and in vivo models are lacking. We hypothesized that antioxidants and NF- κB, MAPK, and proteasome inhibitors may exert an antitumoral response through attenuation of several key biological mechanisms that promote tumorigenesis and cancer cell growth. Body and tumor weights, oxidative stress, antioxidants, inflammation, NF-κB p65 expression, fibulins, apoptosis, autophagy, tumor and stroma histology were evaluated in the subcutaneous tumor of LC (LP07 adenocarcinoma) BALB/c mice, with and without concomitant treatment with NF-κB (sulfasalazine), MEK (U0126), and proteasome (bortezomib) inhibitors, and N-acetyl cysteine (NAC). Compared to LC control mice, in subcutanous tumors, the four pharmacological agents reduced oxidative stress markers and tumor proliferation (ki-67). Inflammation and NF-κB p65 expression were attenuated by NF-κB and MAPK inhibitors, and the latter also enhanced apoptotic markers. Catalase was induced by the three inhibitors, while bortezomib also promoted superoxide dismutase expression. NF-κB and MEK inhibitors significantly reduced tumor burden through several biological mechanisms that favored tumor degradation and attenuated tumor proliferation. These two pharmacological agents may enhance the anti-tumor activity of selectively targeted therapeutic strategies for LC. Proteasomal inhibition using bortezomib rather promotes tumor degradation, while treatment with antioxidants cannot be recommended. This experimental model supports the use of adjuvant drugs for the improvement of LC treatment.}, }
@article {pmid27338562, year = {2016}, author = {Rueda-Romero, C and Hernández-Pérez, G and Ramos-Godínez, P and Vázquez-López, I and Quintana-Belmares, RO and Huerta-García, E and Stepien, E and López-Marure, R and Montiel-Dávalos, A and Alfaro-Moreno, E}, title = {Titanium dioxide nanoparticles induce the expression of early and late receptors for adhesion molecules on monocytes.}, journal = {Particle and fibre toxicology}, volume = {13}, number = {1}, pages = {36}, pmid = {27338562}, issn = {1743-8977}, mesh = {Cell Adhesion Molecules/*metabolism ; Humans ; Metal Nanoparticles/chemistry/*toxicity ; Monocytes/cytology/*metabolism ; Titanium/*chemistry ; U937 Cells ; }, abstract = {BACKGROUND: There is growing evidence that exposure to titanium dioxide nanoparticles (TiO2 NPs) could be harmful. Previously, we have shown that TiO2 NPs induces endothelial cell dysfunction and damage in glial cells. Considering that inhaled particles can induce systemic effects and the evidence that nanoparticles may translocate out of the lungs, we evaluated whether different types of TiO2 NPs can induce the expression of receptors for adhesion molecules on monocytes (U937 cell line). We evaluated the role of reactive oxygen spices (ROS) on these effects.<br><br>METHODS: The expression of receptors for early (sLe(x) and PSGL-1) and late (LFA-1, VLA-4 and &#x3b1;V&#x3b2;3) adhesion molecules was evaluated in U937 cells on a time course (3-24&#xa0;h) using a wide range of concentrations (0.001-100&#xa0;&#x3bc;g/mL) of three types of TiO2 NPs (<25&#xa0;nm anatase, 50&#xa0;nm anatase-rutile or&#x2009;<&#x2009;100&#xa0;nm anatase). Cells exposed to TNF&#x3b1; were considered positive controls, and unexposed cells, negative controls. In some experiments we added 10 &#x3bc;molar of N-acetylcysteine (NAC) to evaluate the role of ROS.<br><br>RESULTS: All tested particles, starting at a concentration of 0.03&#xa0;&#x3bc;g/mL, induced the expression of receptors for early and late adhesion molecules. The largest increases were induced by the different molecules after 3&#xa0;h of exposure for sLe(x) and PSGL-1 (up to 3-fold of the positive controls) and after 18&#xa0;h of exposure for LFA-1, VLA-4 and &#x3b1;V&#x3b2;3 (up to 2.5-fold of the positive controls). Oxidative stress was observed as early as 10&#xa0;min after exposure, but the maximum peak was found after 4&#xa0;h of exposure. Adhesion of exposed or unexposed monocytes to unexposed or exposed endothelial cells was tested, and we observed that monocytes cells adhere in similar amounts to endothelial cells if one of the two cell types, or both were exposed. When NAC was added, the expression of the receptors was inhibited.<br><br>CONCLUSIONS: These results show that small concentrations of particles may activate monocytes that attach to endothelial cells. These results suggest that distal effects can be induced by small amounts of particles that may translocate from the lungs. ROS play a central role in the induction of the expression of these receptors.}, }
@article {pmid27338542, year = {2016}, author = {Moreira, MA and Irigoyen, MC and Saad, KR and Saad, PF and Koike, MK and Montero, EF and Martins, JL}, title = {N-acetylcysteine reduces the renal oxidative stress and apoptosis induced by hemorrhagic shock.}, journal = {The Journal of surgical research}, volume = {203}, number = {1}, pages = {113-120}, doi = {10.1016/j.jss.2016.02.020}, pmid = {27338542}, issn = {1095-8673}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Acute Kidney Injury/etiology/metabolism/*therapy ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Biomarkers/metabolism ; Combined Modality Therapy ; *Fluid Therapy ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Reperfusion Injury/etiology/metabolism/*therapy ; Resuscitation/*methods ; Shock, Hemorrhagic/*complications/metabolism ; Treatment Outcome ; }, abstract = {BACKGROUND: Renal ischemia/reperfusion injury induced by hemorrhagic shock (HS) and subsequent fluid resuscitation is a common cause of acute renal failure. The objective of this study was to evaluate the effect of combining N-acetylcysteine (NAC) with fluid resuscitation on renal injury in rats that underwent HS.<br><br>MATERIALS AND METHODS: Two groups of male Wistar rats were induced to controlled HS at 35&#xa0;mm Hg mean arterial pressure for 60&#xa0;min. After this period, the HS and fluid resuscitation (HS/R) group was resuscitated with lactate containing 50% of the blood that was withdrawn. The HS/R&#xa0;+&#xa0;NAC group was resuscitated with Ringer's lactate combined with 150&#xa0;mg/kg of NAC and blood. The sham group animals were catheterized but were not subjected to shock. All animals were kept under anesthesia and euthanized after 120&#xa0;min of fluid resuscitation or observation.<br><br>RESULTS: Animals treated with NAC presented attenuation of histologic lesions, reduced oxidative stress, and apoptosis markers when compared with animals from the HS/R group. The serum creatinine was similar in all the groups.<br><br>CONCLUSIONS: NAC is a promising drug for combining with fluid resuscitation to attenuate the kidney injury associated with HS.}, }
@article {pmid27333656, year = {2016}, author = {Miyake, N and Miyamoto, S}, title = {[Effectiveness of N-acetylcysteine in the treatment of schizophrenia].}, journal = {Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology}, volume = {36}, number = {2}, pages = {29-35}, pmid = {27333656}, issn = {1340-2544}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacokinetics/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents ; Antioxidants ; Clinical Trials as Topic ; Disease Models, Animal ; Glutathione ; Humans ; Microglia ; Neuroprotective Agents ; Oxidative Stress ; Schizophrenia/*drug therapy/etiology ; }, abstract = {Oxidative stress and neuroinflammation have recently been focused on the pathological hypotheses of schizophrenia. N-acetylcysteine (NAC) is a precursor of endogenous antioxidant glutathione and has antioxidant, anti-inflammatory, and neuroprotective properties. NAC is widely available as an over-the-counter nutritional supplement. Increasing lines of evidence suggest that NAC is effective for various mental disorders. In randomized controlled trials, treatment with NAC as an add-on to antipsychotics showed beneficial effects and safety profiles in patients with chronic schizophrenia. The results of a recent preclinical study using a neurodevelopmental model of schizophrenia suggest that NAC may have promising effects in an early stage of schizophrenia and an at-risk mental state. However, there is little clinical evidence for the efficacy and safety of NAC at these stages of schizophrenia. In this review, we summarize the evidence regarding the effectiveness of NAC for the treatment of schizophrenia and its prodromal stage. We also introduce the preliminary results of our research on NAC.}, }
@article {pmid27328773, year = {2016}, author = {Heintze, J and Costa, JR and Weber, M and Ketteler, R}, title = {Ribose 5-phosphate isomerase inhibits LC3 processing and basal autophagy.}, journal = {Cellular signalling}, volume = {28}, number = {9}, pages = {1380-1388}, pmid = {27328773}, issn = {1873-3913}, support = {MC_EX_G0800785//Medical Research Council/United Kingdom ; BB/J015881/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Aldose-Ketose Isomerases/*metabolism ; Animals ; Antioxidants/pharmacology ; Autophagosomes/drug effects/metabolism ; *Autophagy/drug effects ; Autophagy-Related Proteins/metabolism ; Base Sequence ; CRISPR-Cas Systems/genetics ; Cysteine Endopeptidases/metabolism ; Gene Knockdown Techniques ; Green Fluorescent Proteins/metabolism ; HeLa Cells ; Humans ; Mice ; Microtubule-Associated Proteins/*metabolism ; *Protein Processing, Post-Translational/drug effects ; }, abstract = {Autophagy and cellular metabolism are tightly linked processes, but how individual metabolic enzymes regulate the process of autophagy is not well understood. This study implicates ribose-5-phosphate isomerase (RPIA), a key regulator of the pentose phosphate pathway, in the control of autophagy. We used a dual gene deletion strategy, combining shRNA-mediated knockdown studies with CRISPR/Cas9 genome editing. Knockdown of RPIA by shRNA or genomic deletion by CRISPR/Cas9 genome editing, results in an increase of ATG4B-mediated LC3 processing and in the appearance of LC3-positive autophagosomes in cells. Increased LC3 processing upon knockdown of RPIA can be reversed by treatment with the antioxidant N-acetyl cysteine. The results are consistent with a model in which RPIA suppresses autophagy and LC3 processing by modulation of redox signaling.}, }
@article {pmid27325640, year = {2016}, author = {Lee, JS and Kim, JY and Kim, HJ and Kim, JC and Lee, JS and Kim, N and Park, MJ}, title = {Effects of combined radiofrequency field exposure on amyloid-beta-induced cytotoxicity in HT22 mouse hippocampal neurones.}, journal = {Journal of radiation research}, volume = {57}, number = {6}, pages = {620-626}, pmid = {27325640}, issn = {1349-9157}, mesh = {Acetylcysteine/chemistry ; Amyloid beta-Peptides/*adverse effects ; Animals ; Apoptosis ; Cell Cycle ; Cell Line ; Cell Proliferation ; Cell Survival/radiation effects ; DNA/chemistry ; Dose-Response Relationship, Radiation ; Glutathione/metabolism ; Hippocampus/*cytology/radiation effects ; Mice ; Neurons/metabolism/*radiation effects ; Oxidative Stress ; Radiation Dosage ; *Radio Waves ; Reactive Oxygen Species/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common progressive and irreversible neurodegenerative disease and it is caused by neuronal death in the brain. Recent studies have shown that non-ionizing radiofrequency (RF) radiation has some beneficial cognitive effects in animal models of AD. In this study, we examined the effect of combined RF radiation on amyloid-beta (Aβ)-induced cytotoxicity in HT22 rat hippocampal neurons. Treatment with Aβ suppressed HT22 cell proliferation in a concentration-dependent manner. RF exposure did not affect cell proliferation, and also had a marginal effect on Aβ-induced suppression of growth in HT22 cells. Cell cycle analysis showed that Aβ decreased the G1 fraction and increased the subG1 fraction, indicating increased apoptosis. Accordingly, Aβ increased the annexin V/propidium iodide (PI)-positive cell fraction and the degradation of poly (ADP ribose) polymerase and caspase-3 in HT22 cells. However, RF alone and the combination of Aβ and RF did not affect these events significantly. Aβ increased reactive oxygen species (ROS) generation, thereby suppressing cell proliferation. This was abrogated by N-acetylcysteine (NAC) treatment, indicating that Aβ-induced ROS generation is the main cause of suppression of proliferation. NAC also restored Aβ-induced annexin V/PI-positive cell populations. However, RF did not have a significant impact on these events. Finally, Aβ stimulated the ataxia telangiectasia and Rad3-related protein/checkpoint kinase 1 DNA single-strand breakage pathway, and enhanced beta-site amyloid precursor protein expression; RF had no effect on them. Taken together, our results demonstrate that RF exposure did not significantly affect the Aβ-induced decrease of cell proliferation, increase of ROS production, or induction of cell death in these cells.}, }
@article {pmid27324856, year = {2016}, author = {Turkmen, S and Cekic Gonenc, O and Karaca, Y and Mentese, A and Demir, S and Beyhun, E and Sahin, A and Gunduz, A and Yulug, E and Turedi, S}, title = {The effect of ethyl pyruvate and N-acetylcysteine on ischemia-reperfusion injury in an experimental model of ischemic stroke.}, journal = {The American journal of emergency medicine}, volume = {34}, number = {9}, pages = {1804-1807}, doi = {10.1016/j.ajem.2016.06.003}, pmid = {27324856}, issn = {1532-8171}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/*drug effects/pathology ; *Brain Ischemia ; Carotid Arteries ; Cell Count ; Female ; Free Radical Scavengers/*pharmacology ; Neurons/*drug effects/pathology ; Pyruvates/*pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; *Reperfusion Injury ; *Stroke ; }, abstract = {INTRODUCTION: Reperfusion therapies play an important role in early-period treatment for patients presenting to the emergency department due to stroke. However, the ischemia-reperfusion injury that may occur with reperfusion must then be considered. The purpose of this study was to determine the effectiveness of N-acetylcysteine (NAC) and ethyl pyruvate in preventing ischemia-reperfusion injury.<br><br>METHOD: This study is a randomized, controlled experimental study. In group 1, rats' left main carotid arteries were clamped. Reperfusion was established by releasing the clamp after 1.5 hours. In group 2, the left main carotid artery was clamped, and 20 mg/kg intraperitoneal NAC was administered after 1 hour. The clamp was released 0.5 hour after NAC administration. In group 3, rats' left carotid arteries were clamped, and 50 mg/kg ethyl pyruvate was administered intraperitoneally after 1 hour. The clamp was released 0.5 hour after ethyl pyruvate administration. All tissue samples were collected 2.5 hours after reperfusion. Brain tissues were compared histopathologically.<br><br>RESULTS: A higher percentage of degenerative neurons was determined in group 1 compared with groups 2 and 3 (P values: P(a) = .003 and P(c) = .003, respectively). A significant difference was also observed between groups 2 and 3 (P(b) = .003), with the percentage of degenerative neurons being lower in the NAC group than in the ethyl pyruvate group.<br><br>CONCLUSION: The use of NAC and ethyl pyruvate reduces injury resulting from ischemia-reperfusion in an experimental animal model of acute ischemic stroke and subsequent reperfusion.}, }
@article {pmid27322250, year = {2016}, author = {Huang, F and Liu, Q and Xie, S and Xu, J and Huang, B and Wu, Y and Xia, D}, title = {Cypermethrin Induces Macrophages Death through Cell Cycle Arrest and Oxidative Stress-Mediated JNK/ERK Signaling Regulated Apoptosis.}, journal = {International journal of molecular sciences}, volume = {17}, number = {6}, pages = {}, pmid = {27322250}, issn = {1422-0067}, mesh = {Animals ; *Apoptosis ; *Cell Cycle Checkpoints ; Cell Line ; Cyclin-Dependent Kinase 4/genetics/metabolism ; Cyclins/genetics/metabolism ; Insecticides/*toxicity ; MAP Kinase Signaling System ; Macrophages/cytology/*drug effects/metabolism ; Mice ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/genetics/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/genetics/metabolism ; *Oxidative Stress ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Protein Kinase Inhibitors/pharmacology ; Pyrethrins/*toxicity ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {Cypermethrin is one of the most highly effective synthetic pyrethroid insecticides. The toxicity of cypermethrin to the reproductive and nervous systems has been well studied. However, little is known about the toxic effect of cypermethrin on immune cells such as macrophages. Here, we investigated the cytotoxicity of cypermethrin on macrophages and the underlying molecular mechanisms. We found that cypermethrin reduced cell viability and induced apoptosis in RAW 264.7 cells. Cypermethrin also increased reactive oxygen species (ROS) production and DNA damage in a dose-dependent manner. Moreover, cypermethrin-induced G1 cell cycle arrest was associated with an enhanced expression of p21, wild-type p53, and down-regulation of cyclin D1, cyclin E and CDK4. In addition, cypermethrin treatment activated MAPK signal pathways by inducing c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 ERK1/2 phosphorylation, and increased the cleaved poly ADP-ribose polymerase (PARP). Further, pretreatment with antioxidant N-acetylcysteine (NAC) effectively abrogated cypermethrin-induced cell cytotoxicity, G1 cell cycle arrest, DNA damage, PARP activity, and JNK and ERK1/2 activation. The specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) effectively reversed the phosphorylation level of JNK and ERK1/2, and attenuated the apoptosis. Taken together, these data suggested that cypermethrin caused immune cell death via inducing cell cycle arrest and apoptosis regulated by ROS-mediated JNK/ERK pathway.}, }
@article {pmid27318358, year = {2016}, author = {Liu, T and Wu, L and Wang, D and Wang, H and Chen, J and Yang, C and Bao, J and Wu, C}, title = {Role of reactive oxygen species-mediated MAPK and NF-κB activation in polygonatum cyrtonema lectin-induced apoptosis and autophagy in human lung adenocarcinoma A549 cells.}, journal = {Journal of biochemistry}, volume = {160}, number = {6}, pages = {315-324}, doi = {10.1093/jb/mvw040}, pmid = {27318358}, issn = {1756-2651}, mesh = {Adenocarcinoma/*metabolism ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Humans ; Lung Neoplasms/*metabolism ; MAP Kinase Signaling System/*drug effects ; NF-kappa B/*metabolism ; Plant Lectins/chemistry/*pharmacology ; Polygonatum/*chemistry ; Reactive Oxygen Species/*metabolism ; }, abstract = {Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding lectin isolated from the rhizomes of Polygonatum cyrtonema Hua, has been reported to possess remarkable anti-tumour effects via inducing apoptosis and autophagy. The aim of this study was to investigate the molecular mechanisms mediating PCL-induced apoptosis and autophagy in A549 cells. Herein, we found that the treatment of A549 cells with PCL caused a remarkable generation of reactive oxygen species (ROS) and ROS scavenger N-acetyl-cysteine (NAC) inhibited PCL-induced apoptosis and autophagy. In addition, PCL treatment activated mitogen-activated protein kinase (MAPK) members extracellular signal-regulated kinase (ERK), JNK and p38, JNK inhibitor and p38 inhibitor partially reduced PCL-induced apoptosis and autophagy. Moreover, PCL administration activated NF-κB survival pathway in A549 cells, NF-κB inhibitor Bay11-7082 promoted PCL-induced apoptosis. Importantly, we found PCL may bind to the cell surface in a mannose-specific manner, and was then internalized and accumulated primarily onto the mitochondria. These findings may provide a new perspective of PCL as a potential anti-tumour drug targeting apoptosis and autophagy pathways for future cancer therapeutics.}, }
@article {pmid27318000, year = {2016}, author = {Debeljak Martacic, J and Borozan, S and Radovanovic, A and Popadic, D and Mojsilovic, S and Vucic, V and Todorovic, V and Kovacevic Filipovic, M}, title = {N-Acetyl-l-cysteine enhances ex-vivo amplification of deciduous teeth dental pulp stem cells.}, journal = {Archives of oral biology}, volume = {70}, number = {}, pages = {32-38}, doi = {10.1016/j.archoralbio.2016.06.002}, pmid = {27318000}, issn = {1879-1506}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Catalase/metabolism ; Cells, Cultured ; Child ; Dental Pulp/*cytology/*drug effects/metabolism ; Enzyme Activation ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/metabolism ; Isoenzymes/metabolism ; L-Lactate Dehydrogenase/metabolism ; Lactate Dehydrogenase 5 ; Lipid Peroxidation ; Osteogenesis/drug effects ; Oxidation-Reduction ; Stem Cells/*cytology/*drug effects/metabolism ; Sulfhydryl Compounds/pharmacology ; Superoxide Dismutase/metabolism ; Tooth, Deciduous/*cytology/*drug effects/metabolism ; beta-Galactosidase/metabolism ; }, abstract = {OBJECTIVE: Obtaining high number of stem cells is of interest for cell based therapies. N-Acetyl-l-cysteine (NAC) acts as a source of sulfhydryl groups and an anti-oxidative agent. The aim of this study was to test different NAC concentration on proliferation and differentiation of deciduous teeth dental pulp stem cells (DTSCs) in vitro as well as to define the possible underlining mechanism of its effect.<br><br>DESIGN: Number of viable, apoptotic and senescent DTSCs was determined after addition of NAC (0.1mM, 1.0mM, 2.0mM). Also, cell cycle analysis, HIF1-&#x3b1; expression, LDH isoenzymes, superoxide-dismutase (SOD) and catalase (CAT) activity, sulfhydryl groups content, the level of lipids' and proteins' oxidative damage and differentiation capacity of NAC treated DTSCs was determined.<br><br>RESULTS: DTSCs expressed HIF-1&#x3b1; in all conditions. The lowest NAC dose (0.1mM) increased the number of DTSCs by one fifth comparing to the control, most likely stimulating entry of cells into S phase of cell cycle and enhancing the activity of LDH5 isoenzyme. The highest NAC dose (2mM) inhibited DTSCs proliferation. Also, DTSCs had the lowest level of oxidative damage with 0.1mM NAC. All tested NAC concentrations enhanced DTSCs osteo-chondrogenesis.<br><br>CONCLUSION: The lowest NAC dose exerted significant positive effect on DTSCs proliferation as well as antioxidative protection creating beneficial environment for stem cells in vitro cultivation especially when their clinical use is important for stimulation of osteo-chondrogenesis.}, }
@article {pmid27316706, year = {2017}, author = {Dean, OM and Gray, KM and Villagonzalo, KA and Dodd, S and Mohebbi, M and Vick, T and Tonge, BJ and Berk, M}, title = {A randomised, double blind, placebo-controlled trial of a fixed dose of N-acetyl cysteine in children with autistic disorder.}, journal = {The Australian and New Zealand journal of psychiatry}, volume = {51}, number = {3}, pages = {241-249}, doi = {10.1177/0004867416652735}, pmid = {27316706}, issn = {1440-1614}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Autistic Disorder/*drug therapy ; Child ; Child, Preschool ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Humans ; Male ; Treatment Failure ; }, abstract = {OBJECTIVE: Oxidative stress, inflammation and heavy metals have been implicated in the aetiology of autistic disorder. N-acetyl cysteine has been shown to modulate these pathways, providing a rationale to trial N-acetyl cysteine for autistic disorder. There are now two published pilot studies suggesting efficacy, particularly in symptoms of irritability. This study aimed to explore if N-acetyl cysteine is a useful treatment for autistic disorder.<br><br>METHOD: This was a placebo-controlled, randomised clinical trial of 500&#x2009;mg/day oral N-acetyl cysteine over 6&#x2009;months, in addition to treatment as usual, in children with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of autistic disorder. The study was conducted in Victoria, Australia. The primary outcome measures were the Social Responsiveness Scale, Children's Communication Checklist-Second Edition and the Repetitive Behavior Scale-Revised. Additionally, demographic data, the parent-completed Vineland Adaptive Behavior Scales, Social Communication Questionnaire and clinician-administered Autism Diagnostic Observation Schedule were completed.<br><br>RESULTS: A total of 102 children were randomised into the study, and 98 (79 male, 19 female; age range: 3.1-9.9&#x2009;years) attended the baseline appointment with their parent/guardian, forming the Intention to Treat sample. There were no differences between N-acetyl cysteine and placebo-treated groups on any of the outcome measures for either primary or secondary endpoints. There was no significant difference in the number and severity of adverse events between groups.<br><br>CONCLUSION: This study failed to demonstrate any benefit of adjunctive N-acetyl cysteine in treating autistic disorder. While this may reflect a true null result, methodological issues particularly the lower dose utilised in this study may be confounders.}, }
@article {pmid27315604, year = {2016}, author = {Zhao, YT and Qi, YW and Hu, CY and Chen, SH and Liu, Y}, title = {Advanced glycation end products inhibit testosterone secretion by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress.}, journal = {International journal of molecular medicine}, volume = {38}, number = {2}, pages = {659-665}, doi = {10.3892/ijmm.2016.2645}, pmid = {27315604}, issn = {1791-244X}, mesh = {17-Hydroxysteroid Dehydrogenases/genetics/metabolism ; Acetylcysteine/pharmacology ; Animals ; Cell Survival/drug effects ; Cholesterol Side-Chain Cleavage Enzyme/genetics/metabolism ; Chorionic Gonadotropin/pharmacology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Glycation End Products, Advanced/*toxicity ; Humans ; Leydig Cells/*metabolism/*pathology ; Male ; Oxidative Stress/*drug effects ; Phosphoproteins/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Taurochenodeoxycholic Acid/pharmacology ; Testosterone/*metabolism ; Transcription Factor CHOP/metabolism ; }, abstract = {Diabetes severely impairs male reproduction. The present study assessed the effects and mechanisms of action of advanced glycation end products (AGEs), which play an important role in the development of diabetes complications, on testosterone secretion by rat Leydig cells. Primary rat Leydig cells were cultured and treated with AGEs (25, 50, 100 and 200 µg/ml). Testosterone production induced by human chorionic gonadotropin (hCG) was determined by ELISA. The mRNA and protein expression levels of steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (P450scc) and 3β-hydroxysteroid dehydrogenase (3β-HSD), which are involved in testosterone biosynthesis, were measured by reverse transcription-quantitative PCR and western blot analyssi, respectively. Reactive oxygen species (ROS) production in Leydig cells was measured using the dichlorofluorescein diacetate (DCFH-DA) probe. The expression levels of endoplasmic reticulum stress-related proteins [C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78)] in the Leydig cells were measured by western blot analysis. We found that the AGEs markedly suppressed testosterone production by rat Leydig cells which was induced by hCG in a concentration-dependent manner compared with the control (P<0.01). The mRNA and protein expression levels of StAR, 3β-HSD and P450scc were downregulated by the AGEs in a dose-dependent manner compared with the control (P<0.01). The antioxidant agent, N-acetyl‑L‑cysteine (NAC), and the endoplasmic reticulum stress inhibitor, tauroursodeoxycholic acid (TUDCA), reversed the inhibitory effects of AGEs. In addition, the content of ROS in Leydig cells treated with AGEs increased significantly. The expression levels of CHOP and GRP78 were markedly upregulated by the AGEs in the Leydig cells. From these findings, it can be concluded that AGEs inhibit testosterone production by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress.}, }
@article {pmid27311854, year = {2016}, author = {Song, Y and Baba, T and Mukaida, N}, title = {Gemcitabine induces cell senescence in human pancreatic cancer cell lines.}, journal = {Biochemical and biophysical research communications}, volume = {477}, number = {3}, pages = {515-519}, doi = {10.1016/j.bbrc.2016.06.063}, pmid = {27311854}, issn = {1090-2104}, mesh = {Cellular Senescence/*drug effects ; Deoxycytidine/*analogs &amp; derivatives/pharmacology ; Humans ; Pancreatic Neoplasms/*pathology ; Gemcitabine ; }, abstract = {Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they frequently develop metastatic disease or locally advanced tumors. Gemcitabine, an analogue of cytosine arabinoside, is commonly used for PDAC treatment. We observed that gemcitabine induced senescence phenotypes characterized by enhanced senescence-associated β-galactosidase (SA β-Gal) staining and increased expression of senescence-associated molecules in two human pancreatic cancer cell lines, Miapaca-2 and Panc-1, which exhibit resistance to gemcitabine but not L3.pl cells with a high sensitivity to gemcitabine. Gemcitabine-induced cell senescence can be inhibited by reactive oxygen species inhibitor, N-acetyl cysteine. Although gemcitabine also enhanced CXCL8 expression, anti-CXCL8 antibody failed to reduce gemcitabine-induced increases in SA β-Gal-positive cell numbers. These observations would indicate that cell senescence can proceed independently of CXCL8 expression, a characteristic feature of senescence-associated secretion phenotype.}, }
@article {pmid27309537, year = {2016}, author = {Monti, DA and Zabrecky, G and Kremens, D and Liang, TW and Wintering, NA and Cai, J and Wei, X and Bazzan, AJ and Zhong, L and Bowen, B and Intenzo, CM and Iacovitti, L and Newberg, AB}, title = {N-Acetyl Cysteine May Support Dopamine Neurons in Parkinson's Disease: Preliminary Clinical and Cell Line Data.}, journal = {PloS one}, volume = {11}, number = {6}, pages = {e0157602}, pmid = {27309537}, issn = {1932-6203}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Antioxidants/*therapeutic use ; Caudate Nucleus/diagnostic imaging/drug effects/metabolism/pathology ; Cell Differentiation ; Cell Survival/drug effects ; Dopamine/metabolism ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Dopaminergic Neurons/cytology/drug effects/metabolism ; Female ; Human Embryonic Stem Cells/cytology/metabolism ; Humans ; Male ; Mesencephalon/diagnostic imaging/drug effects/metabolism/pathology ; Middle Aged ; Neuroprotective Agents/*therapeutic use ; Neurotoxins/*antagonists &amp; inhibitors/toxicity ; Parkinson Disease/diagnostic imaging/*drug therapy/metabolism/pathology ; Pilot Projects ; Putamen/diagnostic imaging/drug effects/metabolism/pathology ; Rotenone/*antagonists &amp; inhibitors/toxicity ; Single Photon Emission Computed Tomography Computed Tomography ; Tissue Culture Techniques ; }, abstract = {BACKGOUND: The purpose of this study was to assess the biological and clinical effects of n-acetyl-cysteine (NAC) in Parkinson's disease (PD).<br><br>METHODS: The overarching goal of this pilot study was to generate additional data about potentially protective properties of NAC in PD, using an in vitro and in vivo approach. In preparation for the clinical study we performed a cell tissue culture study with human embryonic stem cell (hESC)-derived midbrain dopamine (mDA) neurons that were treated with rotenone as a model for PD. The primary outcome in the cell tissue cultures was the number of cells that survived the insult with the neurotoxin rotenone. In the clinical study, patients continued their standard of care and were randomized to receive either daily NAC or were a waitlist control. Patients were evaluated before and after 3 months of receiving the NAC with DaTscan to measure dopamine transporter (DAT) binding and the Unified Parkinson's Disease Rating Scale (UPDRS) to measure clinical symptoms.<br><br>RESULTS: The cell line study showed that NAC exposure resulted in significantly more mDA neurons surviving after exposure to rotenone compared to no NAC, consistent with the protective effects of NAC previously observed. The clinical study showed significantly increased DAT binding in the caudate and putamen (mean increase ranging from 4.4% to 7.8%; p<0.05 for all values) in the PD group treated with NAC, and no measurable changes in the control group. UPDRS scores were also significantly improved in the NAC group (mean improvement of 12.9%, p = 0.01).<br><br>CONCLUSIONS: The results of this preliminary study demonstrate for the first time a potential direct effect of NAC on the dopamine system in PD patients, and this observation may be associated with positive clinical effects. A large-scale clinical trial to test the therapeutic efficacy of NAC in this population and to better elucidate the mechanism of action is warranted.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT02445651.}, }
@article {pmid27302646, year = {2016}, author = {Grendar, J and Ouellet, JF and McKay, A and Sutherland, FR and Bathe, OF and Ball, CG and Dixon, E}, title = {Effect of N-acetylcysteine on liver recovery after resection: A randomized clinical trial.}, journal = {Journal of surgical oncology}, volume = {114}, number = {4}, pages = {446-450}, doi = {10.1002/jso.24312}, pmid = {27302646}, issn = {1096-9098}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Delirium/epidemiology ; Female ; Hepatectomy/*adverse effects ; Humans ; Liver Failure/epidemiology ; Male ; Middle Aged ; Postoperative Complications/*epidemiology ; Prospective Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: Liver failure following hepatic resection is a multifactorial complication. In experimental studies, infusion of N-acetylcysteine (NAC) can minimize hepatic parenchymal injury.<br><br>METHODS: Patients undergoing liver resection were randomized to postoperative care with or without NAC. No blinding was performed. Overall complication rate was the primary outcome; liver failure, length of stay, and mortality were secondary outcomes. Due to safety concerns, a premature multivariate analysis was performed and included within the model randomization to NAC, preoperative ASA, extent of resection, and intraoperative vascular occlusion as factors.<br><br>RESULTS: Two hundred and six patients were randomized (110 to conventional therapy; 96 to NAC). No significant differences were noted in overall complications (32.7% and 45.7%, P&#x2009;=&#x2009;0.06) or hepatic failure (3.6% and 5.4%, P&#x2009;=&#x2009;0.537) between treatment groups. There was significantly more delirium within the NAC group (2.7% and 9.8%, P&#x2009;<&#x2009;0.05) that caused early trial termination. In multivariate analysis, only randomization to NAC (OR&#x2009;=&#x2009;2.21, 95%CI&#x2009;=&#x2009;1.16-4.19) and extensive resections (OR&#x2009;=&#x2009;2.28, 95%CI&#x2009;=&#x2009;1.22-4.29) were predictive of postoperative complications.<br><br>CONCLUSIONS: Patients randomized to postoperative NAC received no benefit. There was a trend toward a higher rate of overall complications and a significantly higher rate of delirium in the NAC group. J. Surg. Oncol. 2016;114:446-450. &#xa9; 2016 Wiley Periodicals, Inc.}, }
@article {pmid27292614, year = {2016}, author = {Yang, JB and Khan, M and He, YY and Yao, M and Li, YM and Gao, HW and Ma, TH}, title = {Tubeimoside-1 induces oxidative stress-mediated apoptosis and G0/G1 phase arrest in human prostate carcinoma cells in vitro.}, journal = {Acta pharmacologica Sinica}, volume = {37}, number = {7}, pages = {950-962}, pmid = {27292614}, issn = {1745-7254}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Caspase 3 ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cinnamates/pharmacology ; Cyclin E/metabolism ; Cyclin-Dependent Kinase 2/metabolism ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/drug effects ; G1 Phase/*drug effects ; Humans ; Imidazoles/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Kinase Kinase 5/metabolism ; Male ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Prostatic Neoplasms/*pathology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Resting Phase, Cell Cycle/*drug effects ; Saponins/antagonists &amp; inhibitors/*pharmacology ; Thiourea/analogs &amp; derivatives/pharmacology ; Triterpenes/antagonists &amp; inhibitors/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {AIM: Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from the Chinese herbal medicine Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), has shown anticancer activities in various cancer cell lines. The aim of this study was to investigate the anticancer activity and molecular targets of TBMS1 in human prostate cancer cells in vitro.<br><br>METHODS: DU145 and P3 human prostate cancer cells were treated with TBMS1. Cell viability and apoptosis were detected. ROS generation, mitochondrial membrane potential and cell cycle profile were examined. Western blotting was used to measure the expression of relevant proteins in the cells.<br><br>RESULTS: TBMS1 (5-100 &#x3bc;mol/L) significantly suppressed the viability of DU145 and P3 cells with IC50 values of approximately 10 and 20 &#x3bc;mol/L, respectively. Furthermore, TBMS1 dose-dependently induced apoptosis and cell cycle arrest at G0/G1 phase in DU145 and P3 cells. In DU145 cells, TBMS1 induced mitochondrial apoptosis, evidenced by ROS generation, mitochondrial dysfunction, endoplasmic reticulum stress, modulated Bcl-2 family protein and cleaved caspase-3, and activated ASK-1 and its downstream targets p38 and JNK. The G0/G1 phase arrest was linked to increased expression of p53 and p21 and decreased expression of cyclin E and cdk2. Co-treatment with Z-VAD-FMK (pan-caspase inhibitor) could attenuate TBMS1-induced apoptosis but did not prevent G0/G1 arrest. Moreover, co-treatment with NAC (ROS scavenger), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor) or salubrinal (ER stress inhibitor) significantly attenuated TBMS1-induced apoptosis.<br><br>CONCLUSION: TBMS1 induces oxidative stress-mediated apoptosis in DU145 human prostate cancer cells in vitro via the mitochondrial pathway.}, }
@article {pmid27283928, year = {2016}, author = {Santos, JG and Aliaga, ME and Alarcón, K and Torres, A and Céspedes, D and Pavez, P}, title = {Reactivity and selectivity of the reaction of O,O-diethyl 2,4-dinitrophenyl phosphate and thionophosphate with thiols of low molecular weight.}, journal = {Organic &amp; biomolecular chemistry}, volume = {14}, number = {27}, pages = {6479-6486}, doi = {10.1039/c6ob00918b}, pmid = {27283928}, issn = {1477-0539}, abstract = {A reactivity and selectivity study of O,O-diethyl 2,4-dinitrophenyl phosphate () and O,O-diethyl 2,4-dinitrophenyl thionophosphate () with a series of thiols of low molecular weight: N-acetyl cysteine (NAC), l-cysteine (Cys), homocysteine (Hcys), glutathione (GSH), and d-penicillamine (Pen) was conducted. Results show that (i) these nucleophiles only attack at the aromatic moiety of both triester derivatives, (ii) a kinetic control product by sulfhydryl attack of thiols was observed in the reactions of both triesters with Cys and Hcys, followed by an intramolecular amine attack leading to a thermodynamic control product. The kinetic study leads to the proposal of Meisenheimer complex formation and then proton transfer to the reaction media as the mechanism of these reactions.}, }
@article {pmid27283193, year = {2016}, author = {Mikolka, P and Kopincova, J and Mikusiakova, LT and Kosutova, P and Calkovska, A and Mokra, D}, title = {Antiinflammatory Effect of N-Acetylcysteine Combined with Exogenous Surfactant in Meconium-Induced Lung Injury.}, journal = {Advances in experimental medicine and biology}, volume = {934}, number = {}, pages = {63-75}, doi = {10.1007/5584_2016_15}, pmid = {27283193}, issn = {0065-2598}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Cytokines/metabolism ; Disease Models, Animal ; Drug Therapy, Combination ; Lung/drug effects/metabolism ; Meconium Aspiration Syndrome/*drug therapy/metabolism ; Oxidative Stress/drug effects/physiology ; Pulmonary Surfactants/pharmacology/*therapeutic use ; Rabbits ; Treatment Outcome ; }, abstract = {Neonatal meconium aspiration syndrome (MAS) can be treated by exogenous surfactant (S). However, aspirated meconium initiates local inflammation and oxidation which may inactivate surfactant and reduce its action. This experimental study estimated whether combined use of surfactant and the antioxidant N-acetylcysteine (NAC) can enhance effectiveness of therapy. Meconium-instilled rabbits were non-treated (M), treated with monotherapies (M + S, M + NAC), combined therapy (M + S + NAC), or received saline instead of meconium (controls, C). Surfactant therapy consisted of two lung lavages (BAL) with diluted Curosurf (5 mg phospholipids/ml, 10 ml/kg) followed by undiluted Curosurf (100 mg phospholipids/kg). N-acetylcysteine (Acc Injekt, 10 mg/kg) was given intravenously in M + S + NAC group 10 min after surfactant therapy. Animals were oxygen-ventilated for additional 5 h. Then, differential white cell count in the blood (WBC) was determined. Left lung was saline-lavaged and differential cell count in BAL was determined. In right lung tissue, wet/dry weight ratio, oxidation markers (TBARS, 3NT) and interleukines (IL-2, IL-6, IL-13, and TNFα) using ELISA and RT-PCR were estimated. Combined S + NAC therapy significantly decreased W/D ratio, TBARS, 3NT, and IL, whereas the effect of monotherapies (either S or NAC) was less obvious. In conclusion, addition of NAC to surfactant treatment may enhance the therapeutic outcome in MAS.}, }
@article {pmid27282001, year = {2016}, author = {Espinosa, I and Báez, M and Lobo, E and Martínez, S and Gottschalk, M}, title = {Antimicrobial Activity of Penicillin G and N-acetylcystein on Planktonic and Sessile Cells of Streptococcus suis.}, journal = {Polish journal of microbiology}, volume = {65}, number = {1}, pages = {105-109}, doi = {10.5604/17331331.1197282}, pmid = {27282001}, issn = {1733-1331}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects/growth &amp; development ; Penicillin G/*pharmacology ; Streptococcus suis/*drug effects/*physiology ; }, abstract = {The aim of this study was to investigate the capacity of Streptococcus suis strains to form biofilms and to evaluate the antimicrobial activity of Penicillin G and N-acetylcystein (NAC) on both S. suis sessile and planktonic forms. Only non-typeable isolates of S. suis were correlated with a greater biofilm formation capacity. The MCI of Penicillin G and NAC required for inhibiting biofilm growth were higher than the required concentration for inhibiting planktonic growth. The combinations of NAC and Penicillin G showed a strong synergistic activity that inhibited biofilm formation and disrupted the pre-formed biofilm of S. suis.}, }
@article {pmid27278863, year = {2017}, author = {Rössler, OG and Thiel, G}, title = {Specificity of Stress-Responsive Transcription Factors Nrf2, ATF4, and AP-1.}, journal = {Journal of cellular biochemistry}, volume = {118}, number = {1}, pages = {127-140}, doi = {10.1002/jcb.25619}, pmid = {27278863}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 4/genetics/*metabolism ; Arsenites/pharmacology ; HEK293 Cells ; Humans ; NF-E2-Related Factor 2/genetics/*metabolism ; *Oxidative Stress ; Proto-Oncogene Proteins c-jun/genetics/*metabolism ; *Response Elements ; Tetradecanoylphorbol Acetate/pharmacology ; Transcription Factor AP-1/genetics/*metabolism ; *Transcription, Genetic ; Tunicamycin/pharmacology ; *Up-Regulation ; }, abstract = {Cellular stress leads to an upregulation of gene transcription. We asked if there is a specificity in the activation of the stress-responsive transcription factors Nrf2, ATF4, and AP-1/c-Jun, or if activation of these proteins is a redundant cellular answer toward extracellular stressors. Here, we show that oxidative stress, induced by stimulation of the cells with the oxidant arsenite, strongly activated gene transcription via the stress-responsive element (StRE), while phorbol ester or tunicamycin, activators of AP-1/c-Jun or ATF4, respectively, activated AP-1 or nutrient-sensing response element-mediated transcription. Preincubation of the cells with N-acetyl-cysteine or overexpression of thioredoxin selectively attenuated arsenite-induced upregulation of StRE-regulated transcription. Expression of either dominant-negative or constitutively active mutants of Nrf2, ATF4, or c-Jun confirmed that distinct transcription units are regulated by these transcription factors. Physiological stimuli involving the activation of either Gαq-coupled designer receptors or the protein kinases c-Jun N-terminal protein kinase or p38 strongly stimulated transcription via AP-1/c-Jun, with minimal effects on Nrf2 or ATF4-responsive promoters. Thus, activation of transcription by extracellular signaling molecules shows specificity at the level of the chemical nature of the signaling molecule, at the level of the intracellular transduction process, and at the level of signal-responsive transcription factors. J. Cell. Biochem. 118: 127-140, 2017. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid27278858, year = {2017}, author = {Hagos, FT and Daood, MJ and Ocque, JA and Nolin, TD and Bayir, H and Poloyac, SM and Kochanek, PM and Clark, RS and Empey, PE}, title = {Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {47}, number = {4}, pages = {346-353}, pmid = {27278858}, issn = {1366-5928}, support = {KL2 TR000146/TR/NCATS NIH HHS/United States ; R01 NS069247/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; Biological Transport ; Brain/*metabolism ; *Drug Interactions ; Organic Anion Transporters/*antagonists &amp; inhibitors ; Plasma/metabolism ; Probenecid/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {1. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses membrane barriers is unknown. We have attempted to understand how the transporter inhibitor, probenecid, affects NAC pharmacokinetics and to evaluate the interaction of NAC with transporters. 2. Juvenile Sprague-Dawley rats were administered NAC alone or in combination with probenecid intraperitoneally. Plasma and brain samples were collected serially and NAC concentrations were measured. Transporter studies were conducted with human embryonic kidney-293 cells that overexpress organic anion transporter (OAT)1 or OAT3 and with human multi-drug resistance-associated protein (MRP)1 or MRP4 membrane vesicles. 3. NAC area under the curve was increased in plasma (1.65-fold) and brain (2.41-fold) by probenecid. The apparent plasma clearance was decreased by 65%. Time- and concentration-dependent NAC uptake that was inhibitable by probenecid was observed with OAT1 and OAT3. No uptake of NAC was observed with MRP1 or MRP4. 4. Our results indicate for the first time that NAC is substrate for OAT1 and OAT3 and that probenecid increases NAC plasma and brain exposure in vivo. These data provide insight regarding how NAC crosses biological barriers and suggest a promising therapeutic strategy to increase NAC exposure.}, }
@article {pmid27278810, year = {2016}, author = {Park, WH}, title = {Pyrogallol induces the death of human pulmonary fibroblast cells through ROS increase and GSH depletion.}, journal = {International journal of oncology}, volume = {49}, number = {2}, pages = {785-792}, doi = {10.3892/ijo.2016.3543}, pmid = {27278810}, issn = {1791-2423}, mesh = {Antioxidants/*administration &amp; dosage ; Apoptosis/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Fibroblasts/*drug effects/metabolism/pathology ; Glutathione/*metabolism ; Humans ; Lung/drug effects/metabolism/pathology ; Pyrogallol/*administration &amp; dosage ; Reactive Oxygen Species/metabolism ; }, abstract = {Pyrogallol (PG) inhibits the growth of various cells via stimulating O2•--mediated death. This study investigated the effects of PG on cell death in human pulmonary fibroblast (HPF) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. PG inhibited the growth of HPF cells with an IC50 of ~50-100 µM at 24 h. PG induced a G1 phase arrest of the cell cycle and also triggered cell death accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm), Bcl-2 decrease, p53 increase and the activation of caspase-3. PG increased O2•- level in HPF cells and depleted GSH content in these cells. Z-VAD (a pan-caspase inhibitor) did not significantly change cell growth inhibition, death and MMP (∆ψm) loss in PG-treated HPF cells. N-acetylcysteine (NAC) attenuated growth inhibition, death and MMP (∆ψm) loss in PG-treated HPF cells and it decreased O2•- level in these cells as well. However, L-buthionine sulfoximine (BSO) strongly increased ROS level in PG-treated HPF cells and it intensified growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion in these cells. In conclusion, PG-induced HPF cell death was closely related to increases in ROS level and GSH depletion.}, }
@article {pmid27278736, year = {2016}, author = {Cao, L and Chen, X and Xiao, X and Ma, Q and Li, W}, title = {Resveratrol inhibits hyperglycemia-driven ROS-induced invasion and migration of pancreatic cancer cells via suppression of the ERK and p38 MAPK signaling pathways.}, journal = {International journal of oncology}, volume = {49}, number = {2}, pages = {735-743}, doi = {10.3892/ijo.2016.3559}, pmid = {27278736}, issn = {1791-2423}, mesh = {Acetylcysteine/administration &amp; dosage ; Cell Line, Tumor ; Cell Movement/drug effects ; Diabetes Complications/chemically induced/*drug therapy ; Flavonoids/administration &amp; dosage ; Free Radical Scavengers/administration &amp; dosage ; Gene Expression Regulation, Neoplastic/drug effects ; Glucose/toxicity ; Humans ; Hyperglycemia/chemically induced/complications/*drug therapy ; Imidazoles/administration &amp; dosage ; MAP Kinase Signaling System/drug effects ; Neoplasm Invasiveness/genetics ; Pancreatic Neoplasms/complications/*drug therapy/genetics/pathology ; Pyridines/administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/*administration &amp; dosage ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*biosynthesis ; }, abstract = {Increasing evidence suggests that there is a strong relationship between diabetes mellitus (DM) and pancreatic cancer. Our previous study revealed that hyperglycemia could enhance the invasive and migratory activities of pancreatic cancer cells. Resveratrol, a natural polyphenolic phytoalexin, has many biological and pharmaceutical properties, including antioxidant and anti-tumorigenic capabilities. The aim of the present study was to evaluate whether resveratrol affects hyperglycemia-induced reactive oxygen species (ROS) production as well as the invasion and migration of pancreatic cancer and its underlying mechanisms. Human pancreatic cancer Panc-1 cells were exposed to high glucose condition with or without resveratrol, N-acetylcysteine (NAC, a scavenger of free radicals), PD 98059 (an ERK inhibitor) or SB 203580 (a p38 MAPK inhibitor). The intracellular ROS and hydrogen peroxide (H2O2) were determined using 2,7-dichlorodihydrofluorecein diacetate and H2O2 assay. MTT, wound healing assay and transwell matrigel invasion assay were used to detect the proliferation, migration and invasion potential of cancer cells. The expressions of uPA, E-cadherin and Glut-1 were examined using QT-PCR and western blot analysis at mRNA and protein levels. The activation of p-ERK, p-p38 and p-NF-κB were measured by western blot analysis. The results of the present study showed that resveratrol could significantly decrease high glucose-induced production of ROS and H2O2 in Panc-1 cells. Resveratrol was also able to inhibit high glucose-induced proliferation, migration and invasion of pancreatic cancer cells. High glucose-modulated expression of uPA, E-cadherin and Glut-1 were inhibited by resveratrol. In addition, high glucose-induced activation of ERK and p38 MAPK signaling pathways as well as the transcription factor NF-κB could also be suppressed by resveratrol. Furthermore, resveratrol was able to suppress H2O2-induced migration and invasion abilities of pancreatic cancer cells. Taken together, these data indicate that resveratrol plays an important role in suppressing hyperglycemia-driven ROS-induced pancreatic cancer progression by inhibiting the ERK and p38 MAPK signaling pathways, providing evidence that resveratrol might be a potential candidate for chemoprevention of pancreatic cancer.}, }
@article {pmid27277871, year = {2016}, author = {Zhou, X and Chen, C and Zhang, F and Zhang, Y and Feng, Y and Ouyang, H and Xu, Y and Jiang, H}, title = {Metabolism and bioactivation of the tricyclic antidepressant amitriptyline in human liver microsomes and human urine.}, journal = {Bioanalysis}, volume = {8}, number = {13}, pages = {1365-1381}, doi = {10.4155/bio-2016-0025}, pmid = {27277871}, issn = {1757-6199}, mesh = {Acetylcysteine/analysis/metabolism/urine ; Amitriptyline/analysis/*metabolism/*urine ; Antidepressive Agents, Tricyclic/analysis/*metabolism/*urine ; Chromatography, High Pressure Liquid/methods ; Humans ; Metabolic Networks and Pathways ; Microsomes, Liver/*metabolism ; Tandem Mass Spectrometry/methods ; }, abstract = {AIM: Amitriptyline is a widely used tricyclic antidepressant, but the metabolic studies were conducted almost 20 years ago using high-performance liquid chromatography coupled with ultraviolet detector or radiolabeled methods.<br><br>RESULTS: First, multiple ion monitoring (MIM)- enhanced product ion (EPI) scan was used to obtain the diagnostic ions or neutral losses in human liver microsome incubations with amitriptyline. Subsequently, predicted multiple reaction monitoring (MRM)-EPI scan was used to identify the metabolites in human urine with the diagnostic ions or neutral losses. Finally, product ion filtering and neutral loss filtering were used as the data mining tools to screen metabolites. Consequently, a total of 28 metabolites were identified in human urine after an oral administration using LC-MS/MS.<br><br>CONCLUSION: An integrated workflow using LC-MS/MS was developed to comprehensively profile the metabolites of amitriptyline in human urine, in which five N-acetyl-l-cysteine conjugates were characterized as tentative biomarkers for idiosyncratic toxicity.}, }
@article {pmid27275268, year = {2015}, author = {Kasmi, I and Sallabanda, S and Kasmi, G}, title = {Fulminate Hepatic Failure in a 5 Year Old Female after Inappropriate Acetaminophen Treatment.}, journal = {Open access Macedonian journal of medical sciences}, volume = {3}, number = {3}, pages = {443-446}, pmid = {27275268}, issn = {1857-9655}, abstract = {BACKGROUND: Acetaminophen is a drug widely used in children because of its safety and efficacy. Although the risk of its toxicity is lower in children such reactions occur in pediatric patients from intentional overdoses and less frequently attributable to unintended inappropriate dosing. The aim of reporting this case is to attract the attention to the risk of the acetaminophen toxicity when administered in high doses.<br><br>CASE PRESENTATION: We report here a 5 year old girl who developed fulminate liver failure with renal impairment and acute pancreatitis, as a result of acetaminophen toxicity caused from unintentional repeated supratherapeutic ingestion, with a total administered dose of 4800 mg in three consecutive days, 1600 mg/day, approximately 90 mg/kg/day. The blood level of acetaminophen after 10 hours of the last administered dose was 32 mg/l. The patient presented with high fever, jaundice, lethargic, agitating with abdominal pain accompanied by encephalopathy. The liver function test revealed with high level of alanine aminotransferase 5794 UI/l and aspartate aminotransferase 6000 UI/l. Early initiation of oral N-acetylcysteine (NAC) after biochemical evidence of liver toxicity was beneficial with rapid improvement of liver enzymes, hepatic function and encephalopathy. During the course of the illness the child developed acute pancreatitis with hyperamylasemia 255 UI/L and hyperlypasemia 514 UI/L. Patient totally recovered within 29 days.<br><br>CONCLUSION: Healthcare providers should considered probable acetaminophen toxicity in any child who has received the drug and presented with liver failure. When there is a high index of suspicion of acetaminophen toxicity NAC should be initiated and continued until there are no signs of hepatic dysfunction.}, }
@article {pmid27259232, year = {2016}, author = {Suklabaidya, S and Das, B and Ali, SA and Jain, S and Swaminathan, S and Mohanty, AK and Panda, SK and Dash, P and Chakraborty, S and Batra, SK and Senapati, S}, title = {Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia.}, journal = {Oncotarget}, volume = {7}, number = {27}, pages = {41825-41842}, pmid = {27259232}, issn = {1949-2553}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Cell Line, Tumor ; Disulfiram/administration &amp; dosage ; Fibrosis/prevention &amp; control ; Guinea Pigs ; Humans ; Pancreas/drug effects/pathology ; Pancreatic Neoplasms/*drug therapy ; Pancreatic Stellate Cells/*drug effects ; Pyridones/administration &amp; dosage ; Rats ; Xenograft Model Antitumor Assays/*methods ; }, abstract = {Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC. Protein profiling of activated hamster pancreatic stellate cells (ha-PSCs) revealed expression of proteins involved in fibrosis, cancer cells growth and metastasis. Pirfenidone, suppressed growth of HapT1 cells and the desmoplastic response in vivo; these effects were enhanced by co-administration of NAC. Disulfiram alone or in combination with copper (Cu) was toxic to HapT1 cells and PSCs in vitro; but co-administration of DSF and Cu accelerated growth of HapT1 cells in vivo. Moreover, DSF had no effect on tumor-associated desmoplasia. Overall, this study identifies HapT1-derived orthotopic tumors as a useful model to study desmoplasia and tumor-directed therapeutics in PC. Pirfenidone in combination with NAC could be a novel combination therapy for PC and warrants investigation in human subjects.}, }
@article {pmid27255237, year = {2016}, author = {Lira, AB and de Sousa Rodrigues, CF}, title = {Evaluation of oxidative stress markers in obstructive sleep apnea syndrome and additional antioxidant therapy: a review article.}, journal = {Sleep &amp; breathing = Schlaf &amp; Atmung}, volume = {20}, number = {4}, pages = {1155-1160}, pmid = {27255237}, issn = {1522-1709}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Ascorbic Acid/therapeutic use ; Biomarkers/*blood ; Continuous Positive Airway Pressure ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Humans ; Lipid Peroxidation/drug effects/physiology ; Oxidative Stress/*drug effects/*physiology ; Reactive Oxygen Species/*blood ; Sleep Apnea, Obstructive/*drug therapy/*physiopathology ; }, abstract = {PURPOSE: The hypoxia and reoxygenation cycles in obstructive sleep apnea syndrome (OSAS) cause a change in the oxidative balance, leading to the formation of reactive oxygen species capable of reacting with other organic molecules impairing their functions. This study aimed to determine the best markers of oxidative stress in OSAS and what better antioxidant agent to be used to treat the disease.<br><br>METHODS: Searches were conducted in three different databases (PubMed, LILACS, SCIELO), using as descriptors the terms obstructive sleep apnea, oxidative stress, and antioxidant therapy. A total of 120 articles were found but only those considered of interest to the research were selected. Thus, 10 articles were included for further analysis regarding the biomarkers of oxidative stress in OSAS, and 6 articles to evaluate the antioxidant most often used for demonstration of efficacy.<br><br>RESULTS: The thioredoxin, malondialdehyde, superoxide dysmutase, and reduced iron were the most commonly used biomarkers and showed a more consistent relationship between increased oxidative stress and OSAS. As antioxidant therapy, vitamin C and N-acetylcysteine (NAC) presented interesting results as a reduction of oxidative stress, which may become an alternative to the complementary treatment of OSAS.<br><br>CONCLUSIONS: This review's findings agree mostly to measure that the markers of oxidative stress in OSAS may be a contributing aspect to assessment and monitoring of patient, and the antioxidant therapy appears to be beneficial in the treatment of OSAS.}, }
@article {pmid27254419, year = {2017}, author = {Sabarwal, A and Agarwal, R and Singh, RP}, title = {Fisetin inhibits cellular proliferation and induces mitochondria-dependent apoptosis in human gastric cancer cells.}, journal = {Molecular carcinogenesis}, volume = {56}, number = {2}, pages = {499-514}, doi = {10.1002/mc.22512}, pmid = {27254419}, issn = {1098-2744}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Flavonoids/*pharmacology ; Flavonols ; Gastric Mucosa/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Reactive Oxygen Species/metabolism ; Stomach/drug effects/pathology ; Stomach Neoplasms/*drug therapy/metabolism/pathology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {The anticancer effects of fisetin, a dietary agent, are largely unknown against human gastric cancer. Herein, we investigated the mechanisms of fisetin-induced inhibition of growth and survival of human gastric carcinoma AGS and SNU-1 cells. Fisetin (25-100 μM) caused significant decrease in the levels of G1 phase cyclins and CDKs, and increased the levels of p53 and its S15 phosphorylation in gastric cancer cells. We also observed that growth suppression and death of non-neoplastic human intestinal FHs74int cells were minimally affected by fisetin. Fisetin strongly increased apoptotic cells and showed mitochondrial membrane depolarization in gastric cancer cells. DNA damage was observed as early as 3 h after fisetin treatment which was accompanied with gamma-H2A.X(S139) phosphorylation and cleavage of PARP. Fisetin-induced apoptosis was observed to be independent of p53. DCFDA and MitoSOX analyses showed an increase in mitochondrial ROS generation in time- and dose-dependent fashion. It also increased cellular nitrite and superoxide generation. Pre-treatment with N-acetyl cysteine (NAC) inhibited ROS generation and also caused protection from fisetin-induced DNA damage. The formation of comets were observed in only fisetin treated cells which was blocked by NAC pre-treatment. Further investigation of the source of ROS, using mitochondrial respiratory chain (MRC) complex inhibitors, suggested that fisetin caused ROS generation specifically through complex I. Collectively, these results for the first time demonstrated that fisetin possesses anticancer potential through ROS production most likely via MRC complex I leading to apoptosis in human gastric carcinoma cells. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid27253411, year = {2016}, author = {Wang, H and Zhang, T and Sun, W and Wang, Z and Zuo, D and Zhou, Z and Li, S and Xu, J and Yin, F and Hua, Y and Cai, Z}, title = {Erianin induces G2/M-phase arrest, apoptosis, and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells in vitro and in vivo.}, journal = {Cell death &amp; disease}, volume = {7}, number = {6}, pages = {e2247}, pmid = {27253411}, issn = {2041-4889}, mesh = {Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Bibenzyls ; Cell Line, Tumor ; Cell Proliferation/drug effects ; G2 Phase Cell Cycle Checkpoints/*drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; MAP Kinase Signaling System/*drug effects ; Mice, Inbred BALB C ; Mice, Nude ; Osteosarcoma/*pathology ; Phenol ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Erianin, a natural product derived from Dendrobium chrysotoxum, has exhibited potential antitumor activity in various malignancies, including hepatocarcinoma, melanoma, and promyelocytic leukemia. Here we explored the effects of erianin on osteosarcoma (OS) in vitro and in vivo and further elucidated the underlying molecule mechanisms. In this study, we found that erianin potently suppressed cell viability in various OS cell lines. Treatment with erianin induced G2/M-phase arrest, apoptosis, and autophagy in OS cells. Further studies showed that erianin-induced apoptosis and autophagy was attributed to reactive oxygen species (ROS), as N-acetyl cysteine (NAC), an ROS scavenger, attenuated them. Moreover, we found that erianin induced activation of c-Jun N-terminal kinase (JNK) signal pathway, which was also blocked by NAC. Downregulation of JNK by its specific inhibitor SP600125 could attenuate apoptosis and autophagy induced by erianin. Finally, erianin in vivo markedly reduced the growth with little organ-related toxicity. In conclusion, erianin induced cell cycle G2/M-phase arrest, apoptosis, and autophagy via the ROS/JNK signaling pathway in human OS. In light of these results, erianin may be a promising agent for anticancer therapy against OS.}, }
@article {pmid27252377, year = {2016}, author = {Agarwal, S and Yadav, A and Tiwari, SK and Seth, B and Chauhan, LK and Khare, P and Ray, RS and Chaturvedi, RK}, title = {Dynamin-related Protein 1 Inhibition Mitigates Bisphenol A-mediated Alterations in Mitochondrial Dynamics and Neural Stem Cell Proliferation and Differentiation.}, journal = {The Journal of biological chemistry}, volume = {291}, number = {31}, pages = {15923-15939}, pmid = {27252377}, issn = {1083-351X}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Apoptosis/drug effects ; Benzhydryl Compounds/*toxicity ; Cell Differentiation/*drug effects ; Cell Proliferation/*drug effects ; Dynamins/*metabolism ; Hippocampus/*metabolism/pathology ; Male ; Membrane Potential, Mitochondrial/*drug effects ; Mitochondria/*metabolism/pathology ; Neural Stem Cells/*metabolism/pathology ; Phenols/*toxicity ; Protein Transport/drug effects ; Rats ; Rats, Wistar ; }, abstract = {The regulatory dynamics of mitochondria comprises well orchestrated distribution and mitochondrial turnover to maintain the mitochondrial circuitry and homeostasis inside the cells. Several pieces of evidence suggested impaired mitochondrial dynamics and its association with the pathogenesis of neurodegenerative disorders. We found that chronic exposure of synthetic xenoestrogen bisphenol A (BPA), a component of consumer plastic products, impaired autophagy-mediated mitochondrial turnover, leading to increased oxidative stress, mitochondrial fragmentation, and apoptosis in hippocampal neural stem cells (NSCs). It also inhibited hippocampal derived NSC proliferation and differentiation, as evident by the decreased number of BrdU- and β-III tubulin-positive cells. All these effects were reversed by the inhibition of oxidative stress using N-acetyl cysteine. BPA up-regulated the levels of Drp-1 (dynamin-related protein 1) and enhanced its mitochondrial translocation, with no effect on Fis-1, Mfn-1, Mfn-2, and Opa-1 in vitro and in the hippocampus. Moreover, transmission electron microscopy studies suggested increased mitochondrial fission and accumulation of fragmented mitochondria and decreased elongated mitochondria in the hippocampus of the rat brain. Impaired mitochondrial dynamics by BPA resulted in increased reactive oxygen species and malondialdehyde levels, disruption of mitochondrial membrane potential, and ATP decline. Pharmacological (Mdivi-1) and genetic (Drp-1siRNA) inhibition of Drp-1 reversed BPA-induced mitochondrial dysfunctions, fragmentation, and apoptosis. Interestingly, BPA-mediated inhibitory effects on NSC proliferation and neuronal differentiations were also mitigated by Drp-1 inhibition. On the other hand, Drp-1 inhibition blocked BPA-mediated Drp-1 translocation, leading to decreased apoptosis of NSC. Overall, our studies implicate Drp-1 as a potential therapeutic target against BPA-mediated impaired mitochondrial dynamics and neurodegeneration in the hippocampus.}, }
@article {pmid27251093, year = {2016}, author = {Tain, YL and Hsu, CN and Lee, CT and Lin, YJ and Tsai, CC}, title = {N-Acetylcysteine Prevents Programmed Hypertension in Male Rat Offspring Born to Suramin-Treated Mothers.}, journal = {Biology of reproduction}, volume = {95}, number = {1}, pages = {8}, doi = {10.1095/biolreprod.116.139766}, pmid = {27251093}, issn = {1529-7268}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Arginine/analogs &amp; derivatives/metabolism ; Blood Pressure/drug effects ; Female ; Fetal Development/*drug effects ; Hydrogen Sulfide/metabolism ; Hypertension/chemically induced/metabolism/*prevention &amp; control ; Kidney/*drug effects/metabolism ; Male ; Nitric Oxide/metabolism ; Pre-Eclampsia/metabolism/prevention &amp; control ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced/metabolism/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Renin-Angiotensin System/drug effects ; Suramin ; }, abstract = {Adulthood hypertension can be programmed by preeclampsia. Preeclampsia is associated with an imbalance in vasoactive factors, including nitric oxide (NO), hydrogen sulfide (H2S), and renin-angiotensin system (RAS). We examined whether maternal N-acetylcysteine (NAC) therapy prevented maternal suramin treatment-induced programmed hypertension in offspring and explored the effects of this therapy on NO, H2S, and RAS pathways in the kidneys. Pregnant Sprague-Dawley rats were intraperitoneally administered 60 mg/kg suramin alone on Gestational Days 10 and 11 and were treated with or without 1% NAC through drinking water during the entire pregnancy and lactation period. Male offspring were divided into four groups (n = 8-10/group): control, suramin, NAC, and suramin plus NAC. All rat offspring were euthanized at 12 wk of age. Maternal suramin treatment induced programmed hypertension in male offspring, which was prevented by maternal NAC therapy. Suramin-induced programmed hypertension was associated with increased plasma asymmetric dimethylarginine (ADMA, an NO synthase inhibitor) level, decreased plasma l-arginine-to-ADMA ratio, and decreased renal dimethylarginine dimethylaminohydrolase (an ADMA-metabolizing enzyme) activity. Protective effects of NAC against suramin-induced programmed hypertension were associated with an increase in plasma glutathione level, increase in renal 3-mercaptopyruvate sulfurtransferase level, and restoration of suramin-induced reduction in H2S synthesis in the kidneys. Suramin treatment exerted negligible effect on the RAS pathway in the adult male offspring kidneys. Our data suggested interplay among suramin, ADMA-NO pathway, and H2S synthesis pathway in programmed hypertension. Furthermore, NAC administration in pregnant rats with hypertension prevented programmed hypertension in adult offspring.}, }
@article {pmid27250492, year = {2017}, author = {Ozkol, H and Bulut, G and Balahoroglu, R and Tuluce, Y and Ozkol, HU}, title = {Protective Effects of Selenium, N-Acetylcysteine and Vitamin E Against Acute Ethanol Intoxication in Rats.}, journal = {Biological trace element research}, volume = {175}, number = {1}, pages = {177-185}, doi = {10.1007/s12011-016-0762-8}, pmid = {27250492}, issn = {1559-0720}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Alcoholic Intoxication/*metabolism/pathology/*prevention &amp; control ; Animals ; Male ; Organ Specificity/drug effects ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Selenium/*pharmacology ; Vitamin E/*pharmacology ; }, abstract = {The aim of this study was to determine possible protective influences of selenium (Se), N-acetylcysteine (NAC), and vitamin E (Vit E) against acute ethanol (EtOH) intoxication. Thirty-six rats were divided into six groups: I (control), II (EtOH), III (EtOH + Se), IV (EtOH + Vit E), V (EtOH + NAC), and VI (EtOH + mix). Except group I, EtOH was given the other pretreated (groups III, IV, V, and VI) and untreated groups (group II). Compared with the EtOH group, serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase, and creatine kinase-MB levels were significantly decreased in all pretreated groups, whereas slightly diminished amylase and lipase were observed. Compared with the control group, a remarkably lower total antioxidant status (TAS), but higher total oxidant status (TOS), and oxidative stress index (OSI) were seen in brain, liver, and kidney tissues. The values of these parameters were less affected from EtOH-exposed brain tissue of EtOH + NAC and liver of EtOH + mix groups. Both significant decrease of catalase activity and marked increases of adenosine deaminase and myeloperoxidase were determined only in liver tissue of the EtOH group. Activities of these enzymes were restored in almost all pretreated groups. Moreover, an increase of xanthine oxidase activity was prevented in brain tissue of pretreated groups. In histopathological examination of the liver, hydropic degeneration, sinusoidal dilatation, mononuclear cell infiltration, and marked congestion, which were seen in the EtOH group, were prevented in all pretreated groups. Relative protection against acute EtOH toxicity, in both single and combined pretreatments of Se, NAC, and Vit E supplementation, was probably through antioxidant and free radical-neutralizing effects of foregoing materials.}, }
@article {pmid27247025, year = {2016}, author = {Wang, J and Tan, X and Yang, Q and Zeng, X and Zhou, Y and Luo, W and Lin, X and Song, L and Cai, J and Wang, T and Wu, X}, title = {Inhibition of autophagy promotes apoptosis and enhances anticancer efficacy of adriamycin via augmented ROS generation in prostate cancer cells.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {77}, number = {Pt A}, pages = {80-90}, doi = {10.1016/j.biocel.2016.05.020}, pmid = {27247025}, issn = {1878-5875}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Doxorubicin/*pharmacology ; Humans ; Male ; Phosphatidylinositol 3-Kinases/metabolism ; Prostatic Neoplasms/*pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {The interplay between autophagy and apoptosis response to chemotherapy is still a subject of intense debate in recent years. More efforts have focused on the regulation effects of apoptosis on autophagy, whereas how autophagy affects apoptosis remains poorly understood. In this study performed on prostate cancer cells, we investigated the role of autophagy in adriamycin-induced apoptosis, as well as the mechanisms mediating the effects of autophagy on apoptosis response to adriamycin (ADM). The results show that ADM not only inhibited cell viability and enhanced apoptosis, but also promoted autophagy via PI3K/Akt(T308)/mTOR signal pathway. Inhibition of autophagy by either pharmacological inhibitor chloroquine (CQ) or RNA interference of Atg5 increased ADM-induced apoptosis and enhanced the chemosensitivity of prostate cancer cells. Moreover, blockade of autophagy augmented reactive oxygen species (ROS) generation induced by ADM. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the strengthened effects of CQ on ADM-induced apoptosis and rescued the cells from apoptosis. The results identified ROS as a potential mediator directing the modulation effects of the protective autophagy on apoptosis response to ADM. Suppression of the protective autophagy might provide a promising strategy to increase the anticancer efficacy of agents in the treatment of prostate cancer.}, }
@article {pmid27239415, year = {2016}, author = {de Lima Junior, EA and Yamashita, AS and Pimentel, GD and De Sousa, LG and Santos, RV and Gonçalves, CL and Streck, EL and de Lira, FS and Rosa Neto, JC}, title = {Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle.}, journal = {Journal of cachexia, sarcopenia and muscle}, volume = {7}, number = {5}, pages = {615-625}, pmid = {27239415}, issn = {2190-6009}, mesh = {Animals ; Anorexia/etiology/metabolism ; Antibiotics, Antineoplastic/*adverse effects/pharmacology ; Blood Glucose ; Cell Line ; Cytokines/metabolism ; Disease Models, Animal ; Doxorubicin/*adverse effects/pharmacology ; Fasting ; Glucose/metabolism ; Hyperglycemia/*chemically induced/*metabolism ; Inflammation/metabolism ; *Insulin Resistance ; MAP Kinase Signaling System/*drug effects ; Male ; Muscle Cells/metabolism ; Muscle, Skeletal/*drug effects/*metabolism/pathology ; Muscular Atrophy/etiology/metabolism/pathology ; Rats ; Sarcopenia/etiology/metabolism/pathology ; }, abstract = {BACKGROUND: Cancer is considered the second leading cause of death in the world, and for the treatment of this disease, pharmacological intervention strategies are frequently based on chemotherapy. Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents in clinical practice for treating a number of solid tumours. The treatment with DOX mimics some effects of cancer cachexia, such as anorexia, asthenia, decreases in fat and skeletal muscle mass and fatigue. We observed that treatment with DOX increased the systemic insulin resistance and caused a massive increase in glucose levels in serum. Skeletal muscle is a major tissue responsible for glucose uptake, and the positive role of AMPk protein (AMP-activated protein kinase) in GLUT-4 (Glucose Transporter type 4) translocation, is well established. With this, our aim was to assess the insulin sensitivity after treatment with DOX and involvement of AMPk signalling in skeletal muscle in this process.<br><br>METHODS: We used Wistar rats which received a single dose of doxorubicin (DOX group) or saline (CT group) intraperitoneally at a dose of 15&#x2009;mg/kg b.w. The expression of proteins involved in insulin sensitivity, glucose uptake, inflammation, and activity of electron transport chain was assessed in extensor digitorum longus muscle, as well as the histological evaluation. In vitro assays were performed in L6 myocytes to assess glucose uptake after treatment with DOX. Agonist of AMPk [5-aminoimidazole-4-carboxamide (AICAR)] and the antioxidant n-acetyl cysteine were used in L6 cells to evaluate its effect on glucose uptake and cell viability.<br><br>RESULTS: The animals showed a significant insulin resistance, hyperglycaemia, and hyperinsulinemia. A decrease in the expression of AMKP and GLUT-4 was observed in the extensor digitorum longus muscle. Also in L6 cells, DOX leads to a decrease in glucose uptake, which is reversed with AICAR.<br><br>CONCLUSIONS: DOX leads to conditions similar to cachexia, with severe glucose intolerance both in vivo and in vitro. The decrease of AMPk activity of the protein is modulated negatively with DOX, and treatment with agonist of AMPk (AICAR) has proved to be a possible therapeutic target, which is able to recover glucose sensitivity in skeletal muscle.}, }
@article {pmid27235905, year = {2016}, author = {Xie, S and Zhou, W and Tian, L and Niu, J and Liu, Y}, title = {Effect of N-acetyl cysteine and glycine supplementation on growth performance, glutathione synthesis, anti-oxidative and immune ability of Nile tilapia, Oreochromis niloticus.}, journal = {Fish &amp; shellfish immunology}, volume = {55}, number = {}, pages = {233-241}, doi = {10.1016/j.fsi.2016.05.033}, pmid = {27235905}, issn = {1095-9947}, mesh = {Acetylcysteine/analogs &amp; derivatives/analysis/*metabolism ; Animal Feed/analysis ; Animals ; Antioxidants/metabolism ; *Cichlids/growth &amp; development/metabolism ; Diet/veterinary ; Dietary Supplements/analysis ; Fish Diseases/*immunology/microbiology ; Glutathione/metabolism ; Glycine/*metabolism ; *Immunity, Innate ; Streptococcal Infections/immunology/microbiology/*veterinary ; Streptococcus iniae/physiology ; }, abstract = {An 8-week feeding trial was conducted to evaluate the effect of N-acetyl cysteine (NAC) and glycine supplementation on growth performance, glutathione (GSH) synthesis, anti-oxidative and immune ability of Nile tilapia, Oreochromis niloticus. Four practical diets were formulated, control, control +0.2% NAC, control +0.5% glycine, control +0.2% NAC +0.5% glycine. Each diet was randomly assigned to quadruplicate groups of 30 fish (approximately 9.5 g). The weight gain and specific growth rate were significantly increased with the supplementation of NAC and glycine. While they had no effect on feed efficiency feed intake and survival. Glutathion peroxidase (GPx) was increased by NAC and γ-glutamine cysteine synthase (γ-GCS) in plasma were increased by glycine. After the feeding trail, fish were challenged by Streptococcus iniae, fish fed the diet supplemented with NAC obtained significantly higher survival rate after 72 h challenge test. NAC also decreased malonaldehyde (MDA) in liver, increased glutathione S-transferase (GST) activity in plasma, up-regulated mRNA expression of Superoxide dismutase (SOD) and GPx in liver and headkidney. Dietary supplementation of glycine increased the anti-oxidative ability of tilapia through increase anti-oxidative enzyme activity (SOD, glutathione reductase, myeloperoxidase) and up-regulate anti-oxidative gene expression (SOD). Immune ability only enhanced by the supplementation of NAC through increased interleukin-1β (IL-1β) mRNA expression. These results clearly indicated that the supplementation of NAC and glycine can significantly improve the growth performance of tilapia, and NAC also enhance the anti-oxidative and immune capacity of tilapia, glycine could only enhance the anti-oxidative ability.}, }
@article {pmid27235709, year = {2016}, author = {Lee, JW and Park, S and Kim, SY and Um, SH and Moon, EY}, title = {Curcumin hampers the antitumor effect of vinblastine via the inhibition of microtubule dynamics and mitochondrial membrane potential in HeLa cervical cancer cells.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {23}, number = {7}, pages = {705-713}, doi = {10.1016/j.phymed.2016.03.011}, pmid = {27235709}, issn = {1618-095X}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Survival/drug effects ; Curcumin/*pharmacology ; Drug Synergism ; Female ; HeLa Cells ; Humans ; Male ; Membrane Potential, Mitochondrial/*drug effects ; Mice, Inbred C57BL ; Microtubules/*drug effects ; Reactive Oxygen Species/metabolism ; Tetrazolium Salts ; Thiazoles ; Vinblastine/*pharmacology ; }, abstract = {BACKGROUND: Curcumin, a major component of curry powder, which is a natural polyphenol product extracted from rhizoma curcumae longae, interacts with a specific binding site on microtubules. Vinblastine is an antitumor drug that induces microtubule depolymerization.<br><br>PURPOSE: We investigated whether curcumin influences the antitumor effect of vinblastine in HeLa human cervical cancer cells.<br><br>STUDY DESIGN: Changes in microtubule filaments were visualized by immuno-staining. Cell death was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) or water-soluble tetrazolium(WST) assay. Apoptotic cell formation was assessed by flow cytometry after staining cells with propidium iodide(PI) and/or Annexin V or with 6-diamidino-2-phenylindole(DAPI). Reactive oxygen species(ROS) were also measured by flow cytometry using dichloro-dihydro-fluorescein diacetate(DCF-DA). JC-1 was used to determine mitochondrial membrane potential (MMP).<br><br>RESULTS: When cells were pretreated with curcumin, microtubule filaments were disordered. Vinblastine-induced microtubule depolymerization and cell death were reduced in HeLa human cervical cancer cells pretreated with curcumin compared to the control. The decrease in cell death was much greater in cells pretreated with curcumin compared to cotreatment or post-treatment. DNA condensation by vinblastine was also decreased in curcumin-pretreated cells. Curcumin reduced ROS production by vinblastine. However, no changes in vinblastine-mediated microtubule depolymerization were detected upon N-acetylcysteine(NAC) treatment. In contrast, vinblastine-induced MMP collapse was inhibited by pretreatment with curcumin or NAC. These findings suggest that vinblastine-induced tumor cell death might be inhibited by curcumin via ROS-independent microtubule dynamics and ROS-dependent MMP collapse. It also suggests that microtubule dynamics could be necessary for the optimal antitumor activity of vinblastine. Our results suggest that patients treated with vinblastine should not consume curcumin.}, }
@article {pmid27226373, year = {2016}, author = {Brundu, S and Palma, L and Picceri, GG and Ligi, D and Orlandi, C and Galluzzi, L and Chiarantini, L and Casabianca, A and Schiavano, GF and Santi, M and Mannello, F and Green, K and Smietana, M and Magnani, M and Fraternale, A}, title = {Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics.}, journal = {Journal of virology}, volume = {90}, number = {16}, pages = {7118-7130}, pmid = {27226373}, issn = {1098-5514}, mesh = {Animals ; Cells, Cultured ; Cytokines/metabolism ; Female ; Glutathione/*deficiency ; Leukemia Virus, Murine/*pathogenicity ; Leukemia, Experimental/*complications/immunology/virology ; Lymphocyte Activation ; Macrophages, Peritoneal/immunology/metabolism/virology ; Mice ; Mice, Inbred C57BL ; Murine Acquired Immunodeficiency Syndrome/*etiology/metabolism/pathology ; Retroviridae Infections/*complications/immunology/virology ; Spleen/immunology/metabolism/virology ; Th1 Cells/immunology/metabolism/virology ; Th2 Cells/*immunology/metabolism/virology ; Tumor Virus Infections/*complications/immunology/virology ; }, abstract = {UNLABELLED: Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine (I-152), an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice.<br><br>IMPORTANCE: The first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/Th2 imbalance to be more effectively combated.}, }
@article {pmid27226127, year = {2016}, author = {Deo, P and Sahu, KK and Dhibar, DP and Varma, SC}, title = {Naphthalene ball poisoning: a rare cause of acquired methaemoglobinaemia.}, journal = {BMJ case reports}, volume = {2016}, number = {}, pages = {}, pmid = {27226127}, issn = {1757-790X}, mesh = {Acute Kidney Injury/chemically induced/therapy ; Adolescent ; Antioxidants/therapeutic use ; Ascorbic Acid/therapeutic use ; Cysteine/therapeutic use ; Hemolysis ; Humans ; Male ; Methemoglobinemia/blood/*chemically induced/*diagnosis ; Naphthalenes/*poisoning ; Renal Dialysis ; }, abstract = {A 15-year-old boy presented to emergency services with accidental naphthalene ball ingestion. Following consumption he developed methaemoglobinaemia, massive intravascular haemolysis and acute kidney injury. He had no history suggestive of congenital haemoglobin M disease. Development of severe methaemoglobinaemia and intravascular haemolysis is quite unusual after consumption of a single ball of naphthalene. The patient was managed with ascorbic acid and intravenous N-acetyl cysteine. He also required haemodialysis for acute kidney injury that developed secondary to pigment nephropathy.}, }
@article {pmid27222180, year = {2016}, author = {Xu, W and Guo, YB and Li, X and He, MR and Liu, SD}, title = {[Palmitic acid induces hepatocellular oxidative stress and activation of inflammasomes].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {36}, number = {5}, pages = {655-659}, pmid = {27222180}, issn = {1673-4254}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carrier Proteins/metabolism ; Caspase 1/metabolism ; Cells, Cultured ; Hepatocytes/*drug effects/metabolism ; Inflammasomes/*drug effects/metabolism ; Interleukin-1beta/metabolism ; Mice ; Mitochondria/drug effects ; NADPH Oxidase 4 ; NADPH Oxidases/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein ; *Oxidative Stress ; Palmitic Acid/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: To evaluate the effect of palmitic acid (PA) on oxidative stress and activation of inflammasomes in hepatocytes.<br><br>METHODS: To test the dose-dependent effect of PA on normal murine hepatocytes AML12, the cells were treated with 0, 0.15, 0.25 and 0.4 mmol/L of palmitic acid (PA). The cells were also divided into blank control group, 0.25 mmol/L PA group and 0.25 mmol/L PA+N-acetylcysteine (NAC) group to examine the effect of reactive oxygen species (ROS) on the activation of inflammasomes. After 24 h of treatment, lipid accumulation, total ROS, mitochondrial ROS, expression and localization of NOX4, and expressions of inflammasomes and IL-1&#x3b2; were detected in the hepatocytes.<br><br>RESULTS: Compared with the control cells, PA treatment of the cells significantly increased cytoplasmic lipid accumulation, concentrations of total ROS (12 463.09&#xb1;2.72 vs 6691.23&#xb1;2.45, P=0.00) and mitochondrial ROS (64.98&#xb1;0.94 vs 45.04&#xb1;0.92, P=0.00), and the expressions of NOX4, NLRP3, ASC, caspase-1, and IL-1&#x3b2; (1603.52&#xb1;1.32 vs 2629.33&#xb1;2.57, P=0.00). The mitochondria and NOX4 were found to be co-localized in the cytoplasm. NAC obviously reduced cellular ROS level stimulated by PA (7782.15&#xb1;2.87 vs 5445.6&#xb1;1.17, P=0.00) and suppressed the expressions of NLRP3, ASC and caspase-1.<br><br>CONCLUSION: PA treatment can stimulate lipid accumulation in hepatocytes and induce oxidative stress through NOX4 and mitochondria pathway to activate inflammasomes and stimulate the secretion of IL-1&#x3b2;.}, }
@article {pmid27221553, year = {2016}, author = {Lee, MH and Hong, SH and Park, C and Kim, GY and Leem, SH and Choi, SH and Keum, YS and Hyun, JW and Kwon, TK and Hong, SH and Choi, YH}, title = {Hwang-Heuk-San induces apoptosis in HCT116 human colorectal cancer cells through the ROS-mediated activation of caspases and the inactivation of the PI3K/Akt signaling pathway.}, journal = {Oncology reports}, volume = {36}, number = {1}, pages = {205-214}, doi = {10.3892/or.2016.4812}, pmid = {27221553}, issn = {1791-2431}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspases/*metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Colorectal Neoplasms/*drug therapy/metabolism ; Cytochromes c/metabolism ; Down-Regulation/drug effects ; HCT116 Cells ; Humans ; Medicine, Korean Traditional ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Phosphatidylinositol 3-Kinase/*metabolism ; Poly Adenosine Diphosphate Ribose/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Up-Regulation/drug effects ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Hwang-Heuk-San (HHS) is a polyherbal formulation that has been used in traditional Korean medicine for hundreds of years to treat gastrointestinal malignancy. However, to date, the mechanisms responsible for the anticancer effects remain unclear. In the present study, we investigated the anticancer effects of HHS using HCT116 human colorectal cancer (CRC) cells. Our results showed that HHS treatment significantly reduced cell survival and increased apoptotic cell death in a concentration-dependent manner. The treatment of HCT116 cells with HHS also significantly elevated the accumulation of reactive oxygen species (ROS), which was followed by the attenuation of the mitochondrial membrane potential through the upregulation of Bax and the downregulation of Bcl-2, which was accompanied by the release of cytochrome c to the cytosol. In addition, HHS treatment caused the truncation of Bid and activated the caspases (caspase-8, -9 and -3), which was associated with the induction of the Fas ligand, the death receptors (DRs), DR4 and DR5, downregulation of the inhibitors of protein expression in the apoptosis protein family, and the degradation of poly(ADP-ribose)-polymerase. However, a pan-caspase inhibitor reversed the HHS-induced apoptosis and growth suppression, indicating that HHS induces apoptosis though a caspase-dependent intrinsic and extrinsic apoptotic pathway in HCT116 cells. Moreover, HHS treatment inhibited the activation of phosphatidylinositol-3-kinase (PI3K)/Akt signaling, and a pharmacological inhibitor of PI3K significantly potentiated the apoptotic effects of HHS when employed in combination in HCT116 cells. Furthermore, the blocking of ROS generation by antioxidant N-acetyl cysteine attenuated the HHS-induced release of cytochrome c, caspase activation and PI3K/Akt inactivation, thereby preventing HHS-induced apoptosis and reduction in cell viability. These findings suggest that HHS-induced ROS generation is required for caspase-dependent apoptotic cell death involving inhibition of the PI3K/Akt signaling pathway in HCT116 cells. Overall, our findings suggest that HHS may be an effective treatment for CRC cancer, and further studies are required to identify the active compounds in HHS.}, }
@article {pmid27220315, year = {2016}, author = {Park, WH}, title = {Exogenous H2O2 induces growth inhibition and cell death of human pulmonary artery smooth muscle cells via glutathione depletion.}, journal = {Molecular medicine reports}, volume = {14}, number = {1}, pages = {936-942}, doi = {10.3892/mmr.2016.5307}, pmid = {27220315}, issn = {1791-3004}, mesh = {Apoptosis/drug effects ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Glutathione/*metabolism ; Humans ; Hydrogen Peroxide/*pharmacology ; Intracellular Space ; Myocytes, Smooth Muscle/*drug effects/*metabolism ; Oxidation-Reduction/drug effects ; Pulmonary Artery/*metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Reactive oxygen species (ROS) are associated with various pathophysiological processes of vascular smooth muscle cells (VSMCs). Pyrogallol (PG) induces the superoxide anion (O2•‑)‑mediated cell death of numerous cell types. The present study aimed to investigate the effects of exogenous hydrogen peroxide (H2O2) and PG treatment on the cell growth and death of human pulmonary artery smooth muscle cells (HPASMCs), with regards to intracellular ROS and glutathione (GSH) levels, as determined by MTT and cell number assays. H2O2 led to reduced growth of HPASMCs, with a half maximal inhibitory concentration of 250‑500 µM at 24 h, and induced apoptosis, as determined by Annexin V‑staining and benzyloxycarbonyl‑Val‑Ala‑Asp‑fluoromethylketone treatment. However, PG did not strongly induce growth inhibition and death of HPASMCs. In addition, H2O2 led to increased ROS levels, including mitochondrial O2•‑, and induced GSH depletion in HPASMCs. Treatment with N‑acetyl cysteine (NAC) attenuated apoptotic cell death and ROS levels in H2O2‑treated HPASMCs, and also prevented GSH depletion. Notably, PG treatment did not increase ROS levels, including mitochondrial O2•‑. Furthermore, NAC induced a significant increase in mitochondrial O2•‑ levels in PG‑treated HPASMCs, and cell death and GSH depletion were significantly increased. L‑buthionine sulfoximine intensified cell death and GSH depletion in PG‑treated HPASMCs. In conclusion, exogenous H2O2 induced growth inhibition and cell death of HPASMCs via GSH depletion.}, }
@article {pmid27219873, year = {2017}, author = {Bauer, AK and Fitzgerald, M and Ladzinski, AT and Lenhart Sherman, S and Maddock, BH and Norr, ZM and Miller, RR}, title = {Dual behavior of N-acetylcysteine during ethanol-induced oxidative stress in embryonic chick brains.}, journal = {Nutritional neuroscience}, volume = {20}, number = {8}, pages = {478-488}, doi = {10.1080/1028415X.2016.1185261}, pmid = {27219873}, issn = {1476-8305}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Brain/drug effects/*embryology/physiopathology ; Brain Chemistry/drug effects ; Cell Membrane/chemistry ; Chick Embryo ; Dose-Response Relationship, Drug ; Ethanol/*pharmacology ; Fatty Acids/analysis ; Fatty Acids, Unsaturated/analysis ; Glutathione/analysis ; Glutathione Peroxidase/analysis ; Lipid Peroxides/analysis ; Oxidative Stress/*drug effects ; Time Factors ; }, abstract = {OBJECTIVES: Ethanol (EtOH) causes oxidative stress in embryos. Because N-acetylcysteine (NAC) failures and successes in ameliorating EtOH-induced oxidative stress have been reported, the objective was to determine if exogenous NAC ameliorated EtOH-induced oxidative stress within embryonic chick brains.<br><br>METHODS: Control eggs were injected with approximately 25&#x2005;&#xb5;l of water on day 0, 1, and 2 of development (E0-2). Experimental eggs were injected with dosages of either 3.0&#x2005;mmol EtOH/kg egg; 747&#x2005;&#xb5;mol NAC/kg egg; 3.0&#x2005;mmol EtOH and 747&#x2005;&#xb5;mol NAC/kg egg; 1000&#x2005;&#xb5;mol NAC/kg egg; or 3.0&#x2005;mmol EtOH and 1000&#x2005;&#xb5;mol NAC/kg during the first 3 days of development (E0-2). At 11 days of development (E11; late embryogenesis), brains were harvested and subsequently assayed for oxidative stress markers including the loss of long-chain membrane polyunsaturated fatty acids (PUFAs); the accumulation of lipid hydroperoxides (LPO); decreased glutathione (GSH) and glutathione/glutathione disulfide (GSSG) levels; and decreased glutathione peroxidase (GPx) activities.<br><br>RESULTS: EtOH (3&#x2005;mmol/kg egg), medium NAC (747&#x2005;&#xb5;mol/kg egg), and EtOH and medium NAC promoted oxidative stress. These treatments caused decreased brain membrane long-chain PUFAs; increased LPO levels; decreased GSH levels and GSH/GSSG levels; and decreased Se-dependent GPx activities. High NAC dosages (1000&#x2005;&#xb5;mol/kg egg) attenuated EtOH-induced oxidative stress within EtOH and high NAC-treated chick brains.<br><br>DISCUSSION: Exogenous EtOH and/or medium NAC propagated oxidative stress. Meanwhile, high NAC ameliorated EtOH-induced oxidative stress.}, }
@article {pmid27216851, year = {2017}, author = {Balci, YI and Acer, S and Yagci, R and Kucukatay, V and Sarbay, H and Bozkurt, K and Polat, A}, title = {N-acetylcysteine supplementation reduces oxidative stress for cytosine arabinoside in rat model.}, journal = {International ophthalmology}, volume = {37}, number = {1}, pages = {209-214}, pmid = {27216851}, issn = {1573-2630}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Conjunctiva/*drug effects ; Cornea/*drug effects ; Cytarabine/*pharmacology ; Dietary Supplements ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Immunosuppressive Agents/*pharmacology ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Cytosine arabinoside (ARA-C) is a pyrimidine analog that may cause keratoconjunctivitis when used in high doses. The underlying mechanism may be the increased amounts of reactive oxygen radicals that may damage the DNA synthesis of corneal and conjunctival epithelial cells. Topical corticosteroids are one of the prophylactic treatments for keratoconjunctivitis induced by ARA-C. Forty Wistar-type albino rats were included in this study the rats were divided into four groups. The first group (Group 1) received only ARA-C, the second group (Group 2) received ARA-C and N-acetylcysteine (NAC), the third group (Group 3) received only NAC and the fourth group (Group 4) was the control group. The total oxidant status (TOS), the total antioxidant capacity and the oxidative stress index (OSI) measurements of the cornea and the conjunctiva were evaluated in these four groups. The mean TOS and OSI value was the highest in Group 1 and the lowest in Group 3. The differences in TOS and OSI values were statistically significant between Group 1 and Group 2. There are decreases in TOS and OSI values in rats which received ARA-C with NAC administration. NAC may have a protective effect on ARA-C-induced keratoconjunctivitis.}, }
@article {pmid27212445, year = {2016}, author = {Weinberger, B and Malaviya, R and Sunil, VR and Venosa, A and Heck, DE and Laskin, JD and Laskin, DL}, title = {Mustard vesicant-induced lung injury: Advances in therapy.}, journal = {Toxicology and applied pharmacology}, volume = {305}, number = {}, pages = {1-11}, pmid = {27212445}, issn = {1096-0333}, support = {P30 ES005022/ES/NIEHS NIH HHS/United States ; R01 ES004738/ES/NIEHS NIH HHS/United States ; U54 AR055073/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; Chemical Warfare Agents/*toxicity ; Fibrin/metabolism ; Humans ; Irritants/*toxicity ; Lung/drug effects/metabolism ; Lung Injury/*chemically induced/metabolism/*therapy ; Matrix Metalloproteinases/metabolism ; Mesenchymal Stem Cells ; Mustard Gas/*toxicity ; RNA, Untranslated ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta/metabolism ; Transient Receptor Potential Channels/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and, in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant.}, }
@article {pmid27208785, year = {2016}, author = {Youn, GS and Lee, KW and Choi, SY and Park, J}, title = {Overexpression of HDAC6 induces pro-inflammatory responses by regulating ROS-MAPK-NF-κB/AP-1 signaling pathways in macrophages.}, journal = {Free radical biology &amp; medicine}, volume = {97}, number = {}, pages = {14-23}, doi = {10.1016/j.freeradbiomed.2016.05.014}, pmid = {27208785}, issn = {1873-4596}, mesh = {Animals ; Gene Expression Regulation ; Histone Deacetylase 6/*genetics/metabolism ; Humans ; Inflammation/*genetics/metabolism/pathology ; Interleukin-1beta/genetics ; Interleukin-6/genetics ; Mice ; NADPH Oxidases/genetics ; NF-kappa B/metabolism ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Transcription Factor AP-1/*genetics ; Transcription Factor RelA/*genetics ; Tubulin/genetics ; Tumor Necrosis Factor-alpha/genetics ; p38 Mitogen-Activated Protein Kinases/*genetics ; }, abstract = {Although histone deacetylase 6 (HDAC6) has been implicated in inflammatory diseases, direct involvement and its action mechanism of HDAC6 in the transcriptional regulation of pro-inflammatory genes have been unclear. In this study, we investigated the possible role of HDAC6 in the expression of pro-inflammatory mediators, indicator of macrophage activation, in RAW 264.7 cells and primary mouse macrophages. HDAC6 overexpression significantly enhanced expression of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, with concomitant reduction in acetylated α-tubulin. HDAC6 overexpression significantly induced ROS generation via upregulation of NADPH oxidase expression and activity. Inhibition of ROS generation by N-acetyl cysteine, diphenyl iodonium and apocynin suppressed HDAC6-induced pro-inflammatory cytokines. An HDAC6 enzymatic inhibitor significantly inhibited ROS generation and expression of HDAC6-induced pro-inflammatory mediators, indicating the requirement of HDAC6 enzymatic activity for induction of pro-inflammatory cytokines. In addition, HDAC6 overexpression increased activation of MAPK species including ERK, JNK, and p38. Furthermore, HDAC6 overexpression resulted in activation of the NF-κB and AP-1 signaling pathways. Overall, our results provide the first evidence that HDAC6 is capable of inducing expression of pro-inflammatory genes by regulating the ROS-MAPK-NF-κB/AP-1 pathways and serves as a molecular target for inflammation.}, }
@article {pmid27208483, year = {2016}, author = {Jiang, X and An, Z and Lu, C and Chen, Y and Du, E and Qi, S and Yang, K and Zhang, Z and Xu, Y}, title = {The protective role of Nrf2-Gadd45b against antimony-induced oxidative stress and apoptosis in HEK293 cells.}, journal = {Toxicology letters}, volume = {256}, number = {}, pages = {11-18}, doi = {10.1016/j.toxlet.2016.05.016}, pmid = {27208483}, issn = {1879-3169}, mesh = {Antigens, Differentiation/genetics/*metabolism ; Antimony/*toxicity ; Apoptosis/*drug effects ; Binding Sites ; Dose-Response Relationship, Drug ; Enzyme Activation ; Gene Expression Regulation/drug effects ; Genes, Reporter ; HEK293 Cells ; Humans ; Kidney/*drug effects/metabolism/pathology ; Mitogen-Activated Protein Kinases/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidative Stress/*drug effects ; Phosphorylation ; Promoter Regions, Genetic ; RNA Interference ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Transcription, Genetic/drug effects ; Transfection ; }, abstract = {Antimony (Sb) is one of the most prevalent heavy metals and frequently causes biological toxicity. However, the specific mechanisms by which Sb elicits its toxic effects remains to be fully elucidated. In this study, we found antimony trioxide (Sb2O3) caused a dose-dependent cytotoxicity against HEK293 cells, and Sb2O3-induced excessive reactive oxygen species (ROS) was closely correlated with increased cell apoptosis. Mechanistic investigation manifested that nuclear factor NF-E2-related factor 2 (Nrf2) expression and nuclear translocation were significantly induced under Sb2O3 treatment in HEK293 cells, and Nrf2 knockdown aggregated Sb2O3-induced cell apoptosis. Moreover, elevated Gadd45b expression actives the phosphorylation of MAPKs upon Sb2O3 exposure, whereas Gadd45b knockdown diminished Sb2O3-induced activation of MAPKs and promoted cell apoptosis. In the meantime, however, the antioxidant N-acetylcysteine (NAC) was found to ameliorate Nrf2 expression and nuclear translocation as well as Gadd45b expression and MAPKs activation by repressing Sb2O3-induced ROS production. More importantly, we found Gadd45b was transcriptionally enhanced by Nrf2 through binding to three canonical antioxidant response elements (AREs) within its promoter region. Either Sb2O3 or TBHQ (a selective Nrf2 activator) treatment, Gadd45b expression was significantly increased by luciferase assay. Nrf2 inhibition greatly diminished Gadd45b expression due to reduced binding of Nrf2 in Gadd45b promoter under Sb2O3 treatment. To summarize, this study demonstrated the Nrf2-Gadd45b signaling axis exhibited a protective role in Sb-induced cell apoptosis.}, }
@article {pmid27208422, year = {2016}, author = {Bai, R and Guan, L and Zhang, W and Xu, J and Rui, W and Zhang, F and Ding, W}, title = {Comparative study of the effects of PM1-induced oxidative stress on autophagy and surfactant protein B and C expressions in lung alveolar type II epithelial MLE-12 cells.}, journal = {Biochimica et biophysica acta}, volume = {1860}, number = {12}, pages = {2782-2792}, doi = {10.1016/j.bbagen.2016.05.020}, pmid = {27208422}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Alveolar Epithelial Cells/cytology/*drug effects/metabolism ; Animals ; Autophagy/drug effects/genetics ; Beclin-1/genetics/metabolism ; Catalase/genetics/metabolism ; Cell Line ; Cell Survival/drug effects ; Gene Expression Regulation ; Hydrogen Peroxide/pharmacology ; L-Lactate Dehydrogenase/genetics/metabolism ; Lung/cytology/drug effects/metabolism ; Metallurgy ; Metals, Heavy/analysis/*toxicity ; Mice ; Microtubule-Associated Proteins/genetics/metabolism ; Oxidative Stress/drug effects ; Particle Size ; Particulate Matter/antagonists &amp; inhibitors/isolation &amp; purification/*toxicity ; Pulmonary Surfactant-Associated Protein B/antagonists &amp; inhibitors/*biosynthesis/genetics ; Pulmonary Surfactant-Associated Protein C/antagonists &amp; inhibitors/*biosynthesis/genetics ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {BACKGROUND: There is a strong link between smaller air pollution particles and a range of serious health conditions. Thus, there is a need for understanding the impacts of airborne fine particulate matter (PM) with an aerodynamic diameter of <1μm (PM1) on lung alveolar epithelial cells. In the present study, mouse lung epithelial type II cell MLE-12 cells were used to examine the intracellular oxidative responses and the surfactant protein expressions after exposure to various concentrations of PM1 collected from an urban site and a steel-factory site (referred as uPM1 and sPM1 hereafter, respectively).<br><br>METHODS: Physicochemical characterization of PM1 was performed by using scanning electron microscopy and transmission electron microscopy. Cytotoxicity and autophagy induced by PM1 were assessed by using comprehensive approaches after MLE-12 cells were exposed to different concentrations of PM1 for various times. Expression of surfactant proteins B and C in MLE-12 cells was determined by Western blotting.<br><br>RESULTS: All of the tested PM1 induced cytotoxicity evidenced by significant decrease of cell viability and increase of lactate dehydrogenase (LDH) release in a time- and concentration-dependent manner in the exposed cells compared with the unexposed cells. A similar pattern of increase of intercellular reactive oxygen species (ROS) generation and decrease of superoxide dismutase (SOD) and catalase (CAT) activities was also observed. PM1-induced autophagy was evidenced by an increase in microtubule-associated protein light chain-3 (LC3) puncta, accumulation of LC3II, and increased levels of beclin1. Data from Western blotting showed significant decrease of surfactant protein B and C expressions. Relatively high concentrations of transition metals, including Fe, Cu and Mn, may be responsible for the higher toxicity of sPM1 compared with uPM1. Moreover, pretreatment with N-acetylcysteine (NAC) or Chelex (a metal chelating agent, which removes a large suite of metals from PM1) prevented the increase of PM1-inudced ROS generation and autophagy, and down-regulated the expression of surfactant proteins B and C.<br><br>CONCLUSION: PM1, particularly PM1 with high concentrations of transition metals, such as Fe, Cu and Mn, induces oxidative damage and autophagy, as well as inhibits surfactant protein B and C expressions in lung alveolar type II epithelial cells.<br><br>GENERAL SIGNIFICANCE: This study will help to understand the mechanism underlying the toxicological effects of PM1 in lung alveolar type II epithelial cells. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.}, }
@article {pmid27206739, year = {2016}, author = {Toma, L and Sanda, GM and Deleanu, M and Stancu, CS and Sima, AV}, title = {Glycated LDL increase VCAM-1 expression and secretion in endothelial cells and promote monocyte adhesion through mechanisms involving endoplasmic reticulum stress.}, journal = {Molecular and cellular biochemistry}, volume = {417}, number = {1-2}, pages = {169-179}, pmid = {27206739}, issn = {1573-4919}, mesh = {Cell Adhesion/drug effects ; Cell Line ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Endothelial Cells/*metabolism ; Gene Expression Regulation/*drug effects ; Glycation End Products, Advanced ; Humans ; Lipoproteins, LDL/metabolism/*pharmacology ; Monocytes/*metabolism ; Vascular Cell Adhesion Molecule-1/*biosynthesis ; }, abstract = {Type 2 Diabetes Mellitus is a worldwide epidemic, and its atherosclerotic complications produce morbidity and mortality in affected patients. It is known that the vascular cell adhesion molecule-1 (VCAM-1) levels are increased in the sera of diabetic patients. Our aim was to investigate the impact of the endoplasmic reticulum stress (ERS) in VCAM-1 expression and secretion in human endothelial cells (HEC) exposed to glycated low-density lipoproteins (gLDL). The results showed that 24 h incubation of HEC with gLDL induces (i) stimulation of VCAM-1 expression and secretion, determining increased monocyte adhesion to HEC; (ii) RAGE up-regulation and free cholesterol loading; (iii) ERS activation (increased eIF2α phosphorylation and CHOP mRNA levels, and decreased GRP78 protein expression); and (iv) oxidative stress [increased levels of reactive oxygen species (ROS) and glutamate cysteine ligase catalytic unit gene expression]. Treatment of gLDL-exposed HEC with ERS inhibitors, salubrinal (Sal) and sodium phenylbutyrate (PBA), decreased intracellular ROS. Incubation of gLDL-exposed cells with the anti-oxidant N-acetyl-cysteine (NAC) reduced ERS, revealed by decreased eIF2α phosphorylation and CHOP gene expression and increased GRP78 expression, thus validating the interconnection between ERS and oxidative stress. Sal, PBA, NAC and inhibitors of p38 MAP kinase and NF-kB induced the decrease of VCAM-1 expression and of the ensuing monocyte adhesion induced by gLDL. In conclusion, in HEC, gLDL stimulate the expression of cellular VCAM-1, the secretion of soluble VCAM-1, and the adhesion of monocytes through mechanisms involving p38 MAP kinase and NF-kB signalling pathways activated by RAGE, ERS and oxidative stress, thus contributing to diabetic atherosclerosis.}, }
@article {pmid27206513, year = {2017}, author = {Ahmadi, F and Abbaszadeh, M and Razeghi, E and Maziar, S and Khoidaki, SD and Najafi, MT and Lessan-Pezeshki, M}, title = {Effectiveness of N-acetylcysteine for preserving residual renal function in patients undergoing maintenance hemodialysis: multicenter randomized clinical trial.}, journal = {Clinical and experimental nephrology}, volume = {21}, number = {2}, pages = {342-349}, pmid = {27206513}, issn = {1437-7799}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Administration, Oral ; Aged ; Antioxidants/*administration &amp; dosage/adverse effects ; Female ; Glomerular Filtration Rate/*drug effects ; Humans ; Intention to Treat Analysis ; Iran ; Kidney/*drug effects/physiopathology ; Kidney Failure, Chronic/diagnosis/physiopathology/*therapy ; Male ; Middle Aged ; Models, Biological ; *Renal Dialysis/adverse effects ; Time Factors ; Treatment Outcome ; Urination/drug effects ; Urodynamics/drug effects ; }, abstract = {BACKGROUND: To investigate the efficacy and safety of oral N-acetylcysteine (NAC) for preserving residual renal function in patients undergoing hemodialysis.<br><br>METHODS: Randomized, multi-center, parallel-group, open-label clinical trial (Registration No. IRCT 2014071418482N1). 54 patients who have been undergoing hemodialysis for at least 3&#xa0;months and had residual urine volume >100&#xa0;ml/24&#xa0;h were randomly allocated to NAC or no medication. Residual renal function evaluated by (1) estimated glomerular filtration rate (GFR), (2) 24&#xa0;h urine volume, and (3) renal Kt/V. GFR and Kt/V was determined at baseline and after 3&#xa0;months. 24&#xa0;h urine volume was measured at baseline, after 1, 2, and 3&#xa0;months.<br><br>RESULTS: Intention-to-treat analysis was performed on 47 patients (NAC&#xa0;=&#xa0;26, control&#xa0;=&#xa0;21). GFR in patients receiving NAC improved, whereas in the control arm a decline of 1.0&#xa0;ml/min/1.73&#xa0;m[2] was recorded (3.59 vs. 2.11&#xa0;ml/min/1.73&#xa0;m[2], effect size&#xa0;=&#xa0;17.0&#xa0;%, p&#xa0;=&#xa0;0.004). For 24&#xa0;h urine volume, the between-group difference after 1&#xa0;month was significant (669 vs. 533&#xa0;ml/24&#xa0;h, effect size&#xa0;=&#xa0;15.4&#xa0;%, p&#xa0;=&#xa0;0.004). After 3&#xa0;months, 24&#xa0;h urine volume in the NAC arm was on average 137&#xa0;ml higher than in the control group, and the difference reached near significance (673 vs. 536&#xa0;ml/24&#xa0;h, p&#xa0;=&#xa0;0.072). In the follow-up visit, Kt/V was higher in the NAC arm but the difference did not reach statistical significance (0.81 vs. 0.54, p&#xa0;=&#xa0;0.152).<br><br>CONCLUSION: Three months treatment with NAC appears to be effective in preserving renal function in patients undergoing hemodialysis and the medication is generally well-tolerated.}, }
@article {pmid27197028, year = {2016}, author = {Zhang, FF and Morioka, N and Kitamura, T and Fujii, S and Miyauchi, K and Nakamura, Y and Hisaoka-Nakashima, K and Nakata, Y}, title = {Lycopene ameliorates neuropathic pain by upregulating spinal astrocytic connexin 43 expression.}, journal = {Life sciences}, volume = {155}, number = {}, pages = {116-122}, doi = {10.1016/j.lfs.2016.05.021}, pmid = {27197028}, issn = {1879-0631}, mesh = {Animals ; Astrocytes/*metabolism ; Carotenoids/*pharmacology ; Cells, Cultured ; Connexin 43/*metabolism ; Lycopene ; Male ; Mice ; Neuralgia/*prevention &amp; control ; Rats ; Spinal Cord/cytology/*drug effects/metabolism ; Up-Regulation/*drug effects ; }, abstract = {AIM: Peripheral nerve injury upregulates tumor necrosis factor (TNF) expression. In turn, connexin 43 (Cx43) expression in spinal astrocytes is downregulated by TNF. Therefore, restoration of spinal astrocyte Cx43 expression to normal level could lead to the reduction of nerve injury-induced pain. While the non-provitaminic carotenoid lycopene reverses thermal hyperalgesia in mice with painful diabetic neuropathy, the antinociceptive mechanism is not entirely clear. The current study evaluated whether the antinociceptive effect of lycopene is mediated through the modulation of Cx43 expression in spinal astrocytes.<br><br>MAIN METHODS: The effect of lycopene on Cx43 expression was examined in cultured rat spinal astrocytes. The effect of intrathecal lycopene on Cx43 expression and neuropathic pain were evaluated in mice with partial sciatic nerve ligation (PSNL).<br><br>KEY FINDINGS: Treatment of cultured rat spinal astrocytes with lycopene reversed TNF-induced downregulation of Cx43 protein expression through a transcription-independent mechanism. By contrast, treatment of cultured spinal astrocytes with either pro-vitamin A carotenoid &#x3b2;-carotene or antioxidant N-acetyl cysteine had no effect on TNF-induced downregulation of Cx43 protein expression. In addition, repeated, but not single, intrathecal treatment with lycopene of mice with a partial sciatic nerve ligation significantly prevented not only the downregulation of Cx43 expression in spinal dorsal horn but mechanical hypersensitivity as well.<br><br>SIGNIFICANCE: The current findings suggest a significant spinal mechanism that mediates the analgesic effect of lycopene, through the restoration of normal spinal Cx43 expression.}, }
@article {pmid27195807, year = {2016}, author = {Dutta, P and Dey, T and Manna, P and Kalita, J}, title = {Antioxidant Potential of Vespa affinis L., a Traditional Edible Insect Species of North East India.}, journal = {PloS one}, volume = {11}, number = {5}, pages = {e0156107}, pmid = {27195807}, issn = {1932-6203}, mesh = {Animals ; Antioxidants/chemistry/*pharmacology ; Catalase/metabolism ; Glutathione Transferase/metabolism ; Humans ; Insecta/*chemistry ; Monocytes/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Tissue Extracts/chemistry/pharmacology ; }, abstract = {INTRODUCTION: Elevated oxidative stress plays an important role in the pathogenesis of health disorders, like arthritis. Traditionally, Vespa affinis L., a common edible insect among many tribes in North-East India, is believed to have a beneficial role in extenuating health disorders, such as arthritis. The present study investigated the molecular mechanism underlying medicinal benefit of the Aqueous Extract of Vespa affinis L. (AEVA) against oxidative stress pathophysiology.<br><br>METHODS: The free radical scavenging activities of AEVA were examined against DPPH, hydroxyl, and superoxide radicals and the effect on the activities of antioxidant enzyme (GST and CAT) was determined using both recombinant proteins and human plasma. The antioxidant potential of AEVA was again investigated using THP-1 monocytes.<br><br>RESULTS: AEVA possesses a significant free radical scavenging activity as evident from the DPPH, superoxide, and hydroxyl radical scavenging assay. Incubation of AEVA (2.5, 5, 7.5, and 10 &#x3bc;g/&#x3bc;L) with the recombinant antioxidant enzymes, rGST and rCAT significantly increased the enzyme activities compared to those observed in corresponding enzyme alone or AEVA itself. AEVA supplementation (5, 7.5, and 10 &#x3bc;g/&#x3bc;L) also stimulates the activities of GST and CAT when incubated with human plasma. A cell culture study also confirmed the beneficial role of AEVA (0.8 and 1.2 &#x3bc;g/&#x3bc;L) which enhances the activities of GST and CAT, and also reduces the intercellular ROS production in monocytes treated with or without H2O2 and the effects are at par with what is observed in N-acetyl cysteine-treated cells.<br><br>CONCLUSION: The antioxidant potential of the aqueous extract of Vespa affinis L. may mediate its therapeutic activities in oxidative stress-associated health disorders.}, }
@article {pmid27194299, year = {2017}, author = {Ni, C and Li, C and Dong, Y and Guo, X and Zhang, Y and Xie, Z}, title = {Anesthetic Isoflurane Induces DNA Damage Through Oxidative Stress and p53 Pathway.}, journal = {Molecular neurobiology}, volume = {54}, number = {5}, pages = {3591-3605}, pmid = {27194299}, issn = {1559-1182}, support = {R01 AG041274/AG/NIA NIH HHS/United States ; R01 GM088801/GM/NIGMS NIH HHS/United States ; R01 HD086977/HD/NICHD NIH HHS/United States ; R21 AG038994/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anesthetics, Inhalation/*pharmacology ; Animals ; Benzothiazoles/pharmacology ; Brain/metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; Cytosol/metabolism ; *DNA Damage ; Dactinomycin/pharmacology ; Deoxyribonucleases/metabolism ; Enzyme Activation/drug effects ; Histones/metabolism ; Humans ; Isoflurane/*pharmacology ; Mice ; Models, Biological ; Oligopeptides/pharmacology ; Oxidative Stress/*drug effects ; Signal Transduction/*drug effects ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {DNA damage is associated with aging and neurological disorders, including Alzheimer's disease. Isoflurane is a commonly used anesthetic. It remains largely unknown whether isoflurane induces DNA damage. Phosphorylation of the histone protein H2A variant X at Ser139 (γH2A.X) is a marker of DNA damage. We therefore set out to assess the effects of isoflurane on γH2A.X level in H4 human neuroglioma cells and in brain tissues of mice. Oxidative stress, caspase-activated DNase (CAD), and the p53 signaling pathway are involved in DNA damage. Thus, we determined the interaction of isoflurane with reactive oxygen species (ROS), CAD, and p53 to illustrate the underlying mechanisms. The cells were treated with 2 % isoflurane for 3 or 6 h. The mice were anesthetized with 1.4 % isoflurane for 2 h. Western blot, immunostaining and live cell fluorescence staining were used in the experiments. We showed that isoflurane increased levels of γH2A.X, cleaved caspase-3, and nucleus translocation of CAD and decreased levels of inhibitor of CAD (ICAD) and p53. Isoflurane enhanced the nucleus level of γH2A.X. Moreover, caspase inhibitor Z-VAD and ROS generation inhibitor N-acetyl-L-cysteine (NAC) attenuated the isoflurane-induced increase in γH2A.X level. However, NAC did not significantly alter the isoflurane-induced reduction in p53 level. Finally, p53 activator (actinomycin D) and inhibitor (pifithrin-α) attenuated and potentiated the isoflurane-induced increase in γH2A.X level, respectively. These findings suggest that isoflurane might induce DNA damage, as represented by increased γH2A.X level, via induction of oxidative stress and inhibition of the repair of DNA damage through the p53 signaling pathway.}, }
@article {pmid27193329, year = {2016}, author = {Dardis, A and Zampieri, S and Canterini, S and Newell, KL and Stuani, C and Murrell, JR and Ghetti, B and Fiorenza, MT and Bembi, B and Buratti, E}, title = {Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C.}, journal = {Acta neuropathologica communications}, volume = {4}, number = {1}, pages = {52}, pmid = {27193329}, issn = {2051-5960}, support = {GGP13183/TI_/Telethon/Italy ; P30 AG010133/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain/metabolism/pathology ; Cell Nucleus/drug effects/metabolism/pathology ; Cells, Cultured ; DNA-Binding Proteins/*metabolism ; Disease Models, Animal ; Fibroblasts/drug effects/metabolism/pathology ; Humans ; Intracellular Signaling Peptides and Proteins ; Male ; Mice, Inbred BALB C ; Mice, Transgenic ; Middle Aged ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology ; Niemann-Pick C1 Protein ; Niemann-Pick Disease, Type C/drug therapy/genetics/*metabolism/pathology ; Proteins/genetics/metabolism ; Spinal Cord/metabolism/pathology ; beta-Cyclodextrins/pharmacology ; }, abstract = {Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.}, }
@article {pmid27190866, year = {2016}, author = {Chogtu, B and Malik, DV and Magazine, R}, title = {Idiopathic Pulmonary Fibrosis and Myasthenia Gravis: An Unusual Association.}, journal = {Journal of clinical and diagnostic research : JCDR}, volume = {10}, number = {4}, pages = {OD06-7}, pmid = {27190866}, issn = {2249-782X}, abstract = {Idiopathic Pulmonary Fibrosis (IPF) is a chronic fibrosing lung condition with high morbidity and mortality, accounting for about 25% of the cases of interstitial lung diseases. It usually has a progressive course resulting in death due to respiratory failure. Myasthenia Gravis (MG) is an autoimmune neuromuscular disease, caused by antibody mediated activity against acetylcholine receptor at the neuromuscular junction. It is characterized by fluctuating muscle weakness and fatigue. Extensive literature search did not reveal any case report of an association between these two conditions. Here we present a case of a patient with IPF who also developed MG. The diagnosis of IPF was based on High Resolution Computed Tomography (HRCT) of the lung and that of MG was based on clinical criteria and electrophysiological testing. The case was successfully managed.}, }
@article {pmid27189055, year = {2017}, author = {Wang, C and Qi, S and Liu, C and Yang, A and Fu, W and Quan, C and Duan, P and Yu, T and Yang, K}, title = {Mitochondrial Dysfunction and Ca[2+] Overload in Injured Sertoli Cells Exposed to Bisphenol A.}, journal = {Environmental toxicology}, volume = {32}, number = {3}, pages = {823-831}, doi = {10.1002/tox.22282}, pmid = {27189055}, issn = {1522-7278}, mesh = {ATP Synthetase Complexes/metabolism ; Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Benzhydryl Compounds/*toxicity ; Calcium/metabolism ; Cells, Cultured ; Cytoplasm/metabolism ; Endocrine Disruptors/*toxicity ; Male ; Mitochondria/*drug effects/enzymology/metabolism ; Phenols/*toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sertoli Cells/cytology/drug effects/metabolism ; }, abstract = {Bisphenol-A (BPA) is well known as one of endocrine-disrupting chemicals and testicular toxicant. In this present study, we determined whether BPA caused cell injury through mitochondria impairment and ROS overproduction. The cellular ROS production, mitochondrial ATP synthetase activity and Ca[2+] concentration were examined. We have found BPA caused the cellular mitochondria dysfunction and followed by cell death in Sertoli cells. Moreover cytoplasm Ca[2+] overload was also involved. Furthermore, pretreatment with N-acetyl-L-cysteine (NAC) could alleviate the damage by causing a remarkable decrease in ROS production and mitochondrial dysfunction. Collectively, our results showed that BPA exposure induced Sertoli cell apoptosis because of excessive ROS generation and mitochondrial dysfunction. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 823-831, 2017.}, }
@article {pmid27186786, year = {2016}, author = {Onger, ME and Gocer, H and Emir, D and Kaplan, S}, title = {N-acetylcysteine eradicates Pseudomonas aeruginosa biofilms in bone cement.}, journal = {Scanning}, volume = {38}, number = {6}, pages = {766-770}, doi = {10.1002/sca.21326}, pmid = {27186786}, issn = {1932-8745}, mesh = {Acetylcysteine/*pharmacology ; Biofilms/*drug effects ; *Bone Cements ; Ciprofloxacin/pharmacology ; Microscopy, Electron, Scanning ; Pseudomonas aeruginosa/*drug effects/ultrastructure ; }, abstract = {Biofilm is an example of bacterial group behavior. We investigated the effect of N-acetylcysteine (NAC) alone and in combination with ciprofloxacin on Pseudomonas aeruginosa biofilm formation. Four groups (each contains six molds) of standardized bone cement molds were infected. NAC, ciprofloxacin each alone, and NAC/ciprofloxacin combination were evaluated in point of inhibiting and eradicating biofilm capacity using microbiological and electron microscopical evaluation techniques. Microbial counts and electron microscopical observations showed that the effect of NAC and ciprofloxacin combination on biofilm formation in bone cement is valuable. NAC enhances the beneficial effect of ciprofloxacin when used in combination with it in bone cement. SCANNING 38:766-770, 2016. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid27182794, year = {2017}, author = {Panda, PK and Behera, B and Meher, BR and Das, DN and Mukhopadhyay, S and Sinha, N and Naik, PP and Roy, B and Das, J and Paul, S and Maiti, TK and Agarwal, R and Bhutia, SK}, title = {Abrus Agglutinin, a type II ribosome inactivating protein inhibits Akt/PH domain to induce endoplasmic reticulum stress mediated autophagy-dependent cell death.}, journal = {Molecular carcinogenesis}, volume = {56}, number = {2}, pages = {389-401}, doi = {10.1002/mc.22502}, pmid = {27182794}, issn = {1098-2744}, support = {R01 CA195708/CA/NCI NIH HHS/United States ; }, mesh = {Abrus/chemistry ; Antineoplastic Agents/isolation &amp; purification/*pharmacology ; Autophagy/*drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Female ; HeLa Cells ; Humans ; Models, Molecular ; Plant Lectins/isolation &amp; purification/*pharmacology ; Pleckstrin Homology Domains/*drug effects ; Proto-Oncogene Proteins c-akt/chemistry/*metabolism ; Ribosome Inactivating Proteins, Type 2/isolation &amp; purification/*pharmacology ; Uterine Cervical Neoplasms/drug therapy/metabolism/pathology ; eIF-2 Kinase/metabolism ; }, abstract = {Abrus agglutinin (AGG), a type II ribosome-inactivating protein has been found to induce mitochondrial apoptosis. In the present study, we documented that AGG-mediated Akt dephosphorylation led to ER stress resulting the induction of autophagy-dependent cell death through the canonical pathway in cervical cancer cells. Inhibition of autophagic death with 3-methyladenine (3-MA) and siRNA of Beclin-1 and ATG5 increased AGG-induced apoptosis. Further, inhibiting apoptosis by Z-DEVD-FMK and N-acetyl cysteine (NAC) increased autophagic cell death after AGG treatment, suggesting that AGG simultaneously induced autophagic and apoptotic death in HeLa cells. Additionally, it observed that AGG-induced autophagic cell death in Bax knock down (Bax-KD) and 5-FU resistant HeLa cells, confirming as an alternate cell killing pathway to apoptosis. At the molecular level, AGG-induced ER stress in PERK dependent pathway and inhibition of ER stress by salubrinal, eIF2α phosphatase inhibitor as well as siPERK reduced autophagic death in the presence of AGG. Further, our in silico and colocalization study showed that AGG interacted with pleckstrin homology (PH) domain of Akt to suppress its phosphorylation and consequent downstream mTOR dephosphorylation in HeLa cells. We showed that Akt overexpression could not augment GRP78 expression and reduced autophagic cell death by AGG as compared to pcDNA control, indicating Akt modulation was the upstream signal during AGG's ER stress mediated autophagic cell death. In conclusion, we established that AGG stimulated cell death by autophagy might be used as an alternative tumor suppressor mechanism in human cervical cancer. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid27181592, year = {2017}, author = {Zheng, L and Wang, C and Luo, T and Lu, B and Ma, H and Zhou, Z and Zhu, D and Chi, G and Ge, P and Luo, Y}, title = {JNK Activation Contributes to Oxidative Stress-Induced Parthanatos in Glioma Cells via Increase of Intracellular ROS Production.}, journal = {Molecular neurobiology}, volume = {54}, number = {5}, pages = {3492-3505}, pmid = {27181592}, issn = {1559-1182}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis ; Brain Neoplasms/*enzymology/*pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Enzyme Activation/drug effects ; Glioma/*enzymology/*pathology ; Humans ; Hydrogen Peroxide/toxicity ; Intracellular Space/metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mitochondria/drug effects/metabolism ; *Oxidative Stress/drug effects ; Poly (ADP-Ribose) Polymerase-1/*metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Superoxides/metabolism ; }, abstract = {Parthanatos is a form of PARP-1-dependent programmed cell death. The induction of parthanatos is emerging as a new strategy to kill gliomas which are the most common type of primary malignant brain tumor. Oxidative stress is thought to be a critical factor triggering parthanatos, but its underlying mechanism is poorly understood. In this study, we used glioma cell lines and H2O2 to investigate the role of JNK in glioma cell parthanatos induced by oxidative stress. We found that exposure to H2O2 not only induced intracellular accumulation of ROS but also resulted in glioma cell death in a concentration- and incubation time-dependent manner, which was accompanied with cytoplasmic formation of PAR polymer, expressional upregulation of PARP-1, mitochondrial depolarization, and AIF translocation to nucleus. Pharmacological inhibition of PARP-1 with 3AB or genetic knockdown of its level with siRNA rescued glioma cell death, as well as suppressed cytoplasmic accumulation of PAR polymer and nuclear translocation of AIF, which were consistent with the definition of parthanatos. Moreover, the phosphorylated level of JNK increased markedly with the extension of H2O2 exposure time. Either attenuation of intracellular ROS with antioxidant NAC or inhibition of JNK phosphorylation with SP600125 or JNK siRNA could significantly prevent H2O2-induced parthanatos in glioma cells. Additionally, inhibition of JNK with SP600125 alleviated intracellular accumulation of ROS and attenuated mitochondrial generation of superoxide. Thus, we demonstrated that JNK activation contributes to glioma cell parthanatos caused by oxidative stress via increase of intracellular ROS generation.}, }
@article {pmid27180204, year = {2016}, author = {Zhang, L and Man, S and Wang, Y and Liu, J and Liu, Z and Yu, P and Gao, W}, title = {Paris Saponin II induced apoptosis via activation of autophagy in human lung cancer cells.}, journal = {Chemico-biological interactions}, volume = {253}, number = {}, pages = {125-133}, doi = {10.1016/j.cbi.2016.05.016}, pmid = {27180204}, issn = {1872-7786}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Blotting, Western ; Cell Line ; Chloroquine/toxicity ; Glutathione/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lung Neoplasms/metabolism/pathology ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Rhizome/chemistry/metabolism ; Saponins/*pharmacology ; Signal Transduction/drug effects ; }, abstract = {Paris Saponin II (PSII) has been shown anticancer activity against several cancer lines through the pro-apoptotic pathway. The aim of the study was to investigate the relationship between apoptosis and autophagy taking part in the anti-cancer mechanisms of PSII. In this study, PSII induced autophagy and apoptosis in dose- and time-dependent manners. Meanwhile, it induced autophagy as early as 2 h after exposure to 1 μM of PSII accompanying with apoptosis. Blockade of autophagy with chloroquine (CQ) attenuated apoptosis, while regulation of reactive oxygen species (ROS) by N-acetyl cysteine (NAC), gallic acid (GA) and H2O2 could not influence autophagy. In addition, PSII induced apoptosis via activation of autophagy, which might be associated with the activation of JNK and inhibition of PI3K/AKT/mTOR pathway. All in all, our research increased the understanding of the role of PSII regulating autophagy and apoptosis, which would hopefully provide prospective strategies for cancer therapy.}, }
@article {pmid27180073, year = {2017}, author = {Li, Y and Qin, T and Ingle, T and Yan, J and He, W and Yin, JJ and Chen, T}, title = {Differential genotoxicity mechanisms of silver nanoparticles and silver ions.}, journal = {Archives of toxicology}, volume = {91}, number = {1}, pages = {509-519}, doi = {10.1007/s00204-016-1730-y}, pmid = {27180073}, issn = {1432-0738}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cell Survival/drug effects ; Chelating Agents/pharmacology ; Chromans/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Humans ; Kinetics ; Lymphocytes/*drug effects/enzymology/metabolism ; Metal Nanoparticles/*toxicity ; Micronucleus Tests ; Mutagens/analysis/chemistry/*toxicity ; Oxidative Stress/*drug effects ; Particle Size ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/metabolism ; Silver/analysis/chemistry/*toxicity ; Silver Nitrate/antagonists &amp; inhibitors/toxicity ; Solubility ; Surface Properties ; }, abstract = {In spite of many reports on the toxicity of silver nanoparticles (AgNPs), the mechanisms underlying the toxicity are far from clear. A key question is whether the observed toxicity comes from the silver ions (Ag[+]) released from the AgNPs or from the nanoparticles themselves. In this study, we explored the genotoxicity and the genotoxicity mechanisms of Ag[+] and AgNPs. Human TK6 cells were treated with 5 nM AgNPs or silver nitrate (AgNO3) to evaluate their genotoxicity and induction of oxidative stress. AgNPs and AgNO3 induced cytotoxicity and genotoxicity in a similar range of concentrations (1.00-1.75 µg/ml) when evaluated using the micronucleus assay, and both induced oxidative stress by measuring the gene expression and reactive oxygen species in the treated cells. Addition of N-acetylcysteine (NAC, an Ag[+] chelator) to the treatments significantly decreased genotoxicity of Ag[+], but not AgNPs, while addition of Trolox (a free radical scavenger) to the treatment efficiently decreased the genotoxicity of both agents. In addition, the Ag[+] released from the highest concentration of AgNPs used for the treatment was measured. Only 0.5 % of the AgNPs were ionized in the culture medium and the released silver ions were neither cytotoxic nor genotoxic at this concentration. Further analysis using electron spin resonance demonstrated that AgNPs produced hydroxyl radicals directly, while AgNO3 did not. These results indicated that although both AgNPs and Ag[+] can cause genotoxicity via oxidative stress, the mechanisms are different, and the nanoparticles, but not the released ions, mainly contribute to the genotoxicity of AgNPs.}, }
@article {pmid27179791, year = {2016}, author = {Wright, DJ and Gray, LJ and Finkelstein, DI and Crouch, PJ and Pow, D and Pang, TY and Li, S and Smith, ZM and Francis, PS and Renoir, T and Hannan, AJ}, title = {N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.}, journal = {Human molecular genetics}, volume = {25}, number = {14}, pages = {2923-2933}, doi = {10.1093/hmg/ddw144}, pmid = {27179791}, issn = {1460-2083}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Autopsy ; Behavior, Animal/drug effects ; Chromosome Pairing/drug effects/genetics ; Cystathionine gamma-Lyase/biosynthesis/genetics ; Cystine/biosynthesis ; Depression/*drug therapy/genetics/physiopathology ; Disease Models, Animal ; Excitatory Amino Acid Transporter 2/biosynthesis/*genetics ; Glutamic Acid/genetics/metabolism ; Humans ; Huntington Disease/*drug therapy/genetics/physiopathology ; Mice ; Mice, Transgenic ; Receptors, N-Methyl-D-Aspartate/*genetics ; }, abstract = {Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington's disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system xc[-] In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine-γ-lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transporters, system xc[-] and GLT-1. We demonstrate that the R6/1 transgenic mouse model of HD has lower basal levels of cystine, and showed depressive-like behaviors in the forced-swim test. Administration of NAC reversed these behaviors. This effect was blocked by co-administration of the system xc[-] and GLT-1 inhibitors CPG and DHK, showing that glutamate transporter activity was required for the antidepressant effects of NAC. NAC was also able to specifically increase glutamate in HD mice, in a glutamate transporter-dependent manner. These in vivo changes reflect changes in glutamate transporter protein in HD mice and human HD post-mortem tissue. Furthermore, NAC was able to rescue changes in key glutamate receptor proteins related to excitotoxicity in HD, including NMDAR2B. Thus, we have shown that baseline reductions in cysteine underlie glutamatergic dysfunction and depressive-like behavior in HD and these changes can be rescued by treatment with NAC. These findings have implications for the development of new therapeutic approaches for depressive disorders.}, }
@article {pmid27177548, year = {2017}, author = {Liu, Y and Liu, WC and Sun, Y and Shen, X and Wang, X and Shu, H and Pan, R and Liu, CF and Liu, W and Liu, KJ and Jin, X}, title = {Normobaric Hyperoxia Extends Neuro- and Vaso-Protection of N-Acetylcysteine in Transient Focal Ischemia.}, journal = {Molecular neurobiology}, volume = {54}, number = {5}, pages = {3418-3427}, pmid = {27177548}, issn = {1559-1182}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Blood-Brain Barrier/drug effects/metabolism/pathology ; Brain Ischemia/complications/*drug therapy/metabolism/*pathology ; Hyperoxia/*metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Infarction, Middle Cerebral Artery/complications/drug therapy/metabolism/pathology ; Male ; *Neuroprotection/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Rats, Sprague-Dawley ; Reperfusion Injury/complications/drug therapy/metabolism/pathology ; Superoxides/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {N-acetylcysteine (NAC), a precursor of glutathione that reduces reperfusion-induced injury, has been shown protection when it was administered pre-ischemia. However, less is known about the effect when it was given post-ischemia and there is no positive result associated with anti-oxidant in clinical trials. This study investigated the neuro- and vaso-protection of post-ischemia NAC administration as well as combining NAC with normobaric hyperoxia (NBO). Male Sprague-Dawley rats were exposed to NBO or normoxia during 2-h occlusion of the middle cerebral artery, followed by 48-h reperfusion. NAC or vehicle was intraperitoneally administered to rats immediately before reperfusion onset. NAC and NBO treatments produced 1.2 and 30 % reduction of infarction volume, respectively, and combination treatment showed greater reduction (59.8 %) as well as more decrease of hemispheric swelling volume. Of note, combination therapy showed improved neurological assessment and motor function which were sustained for 7 days after reperfusion. We also determined that the combination therapy showed greater inhibitory effects on tight junction protein degradation accompanied by Evan's blue extravasation, hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) induction, and poly ADP-ribose polymerase (PARP)-1 activation in ischemic brain tissue. Our results showed that although post-ischemia NAC administration had limited protection, combination treatment of NAC plus NBO effectively prevented blood-brain barrier (BBB) damage and significantly improved the outcome of brain injury, providing new evidence to support the concept that "cocktail" treatment targeting different stages provides better neuro- and vaso-protection than current individual treatment that has all failed in their clinical trials.}, }
@article {pmid27177453, year = {2016}, author = {Zou, X and Liang, J and Sun, J and Hu, X and Lei, L and Wu, D and Liu, L}, title = {Allicin sensitizes hepatocellular cancer cells to anti-tumor activity of 5-fluorouracil through ROS-mediated mitochondrial pathway.}, journal = {Journal of pharmacological sciences}, volume = {131}, number = {4}, pages = {233-240}, doi = {10.1016/j.jphs.2016.04.017}, pmid = {27177453}, issn = {1347-8648}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/drug therapy/metabolism/pathology ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Disulfides ; Drug Synergism ; Fluorouracil/antagonists &amp; inhibitors/*pharmacology ; Humans ; Liver Neoplasms/*drug therapy/metabolism/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/*drug effects ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Sulfinic Acids/antagonists &amp; inhibitors/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {Drug resistance and hepatic dysfunction are the two major factors that limit the application of chemotherapy for hepatocellular carcinoma (HCC). It has been reported that allicin has the hepatic protective effect and antitumor activity. Hence allicin may be an ideal enhancer to chemotherapy regimen of HCC. In the present study, we demonstrated that allicin enhanced 5-fluorouracil (5-FU) inducing cytotoxicity in HCC cells. In vivo experiment, combined treatment group with allicin (5 mg/kg/d; every two days for 3 weeks) and 5-FU (20 mg/kg/d; 5 consecutive days) showed a dramatic inhibitory effect on the growth of HCC xenograft tumors in nude mice. The co-treatment group showed highly apoptotic level compared with 5-FU treated alone. Cells combined treatment with allicin and 5-FU increased intracellular reactive oxygen species (ROS) level, reduced mitochondrial membrane potential (ΔΨm), activated caspase-3 and PARP, and down-regulated Bcl-2 compared with DMSO, allicin and 5-FU treated alone. Moreover, the increase of activated caspase-3 and PARP was blocked by the ROS inhibitor antioxidant N-acetyl cysteine (NAC). In conclusion, this is the first study to demonstrate that allicin sensitized HCC cells to 5-FU induced apoptosis through ROS-mediated mitochondrial pathway. These results provided evidences for the combination used of allicin and 5-FU as a novel chemotherapy regimen in HCC.}, }
@article {pmid27177023, year = {2016}, author = {Zhang, SY and Li, XB and Hou, SG and Sun, Y and Shi, YR and Lin, SS}, title = {Cedrol induces autophagy and apoptotic cell death in A549 non-small cell lung carcinoma cells through the P13K/Akt signaling pathway, the loss of mitochondrial transmembrane potential and the generation of ROS.}, journal = {International journal of molecular medicine}, volume = {38}, number = {1}, pages = {291-299}, doi = {10.3892/ijmm.2016.2585}, pmid = {27177023}, issn = {1791-244X}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Autophagosomes/drug effects/metabolism/ultrastructure ; Autophagy/*drug effects ; Carcinoma, Non-Small-Cell Lung/enzymology/*pathology ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Humans ; L-Lactate Dehydrogenase/metabolism ; Lung Neoplasms/pathology ; Membrane Potential, Mitochondrial/*drug effects ; Phosphatidylinositol 3-Kinase/*metabolism ; Polycyclic Sesquiterpenes ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Terpenes/chemistry/*pharmacology ; }, abstract = {The objective of the present study was to determine the anticancer effects of cedrol in A549 human non-small cell lung cancer cells by examining the effects of cedrol on apoptosis induction, the phosphatidylinositol 3'-kinase (PI3K)/Akt signaling pathway, autophagy, reactive oxygen species (ROS) generation and mitochondrial transmembrane potential (MTP). The anticancer effects of cedrol were examined using A549 human lung carcinoma cells as an in vitro model. Cell viability was determined using MTT and lactate dehydrogenase (LDH) assays, and an inverted phase contrast microscope was used to examine the morphological changes in these cells. Cedrol‑triggered autophagy was confirmed by transmission electron microscopy (TEM) analysis of the cells, as well as by western blot analysis of microtubule-associated protein light-chain 3 (LC3)B expression. Intracellular ROS generation was measured by flow cytometry using 5-(6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (CM-DCFH2-DA) staining and MTP was measured using flow cytometry. The results demonstrated that cedrol reduced cell viability and induced cell apoptosis in a dose-dependent manner. Mechanistic evaluations indicated that cedrol induced apoptosis by reducing the MTP and by decreasing the levels of phosphorylated (p-)PI3K and p-Akt. Cedrol induced autophagy, which was confirmed by TEM analysis, by increasing intracellular ROS formation in a concentration-dependent manner, which was almost completely reversed by N-acetyl-L-cysteine (NAC) and tocopherol. Taken together, these findings reveal that cedrol inhibits cell proliferation and induces apoptosis in A549 cells through mitochondrial and PI3K/Akt signaling pathways. Our findings also reveal that cedrol induced pro-death autophagy by increasing intracellular ROS production.}, }
@article {pmid27175572, year = {2016}, author = {Liu, X and Zhang, Y and Wang, Y and Yan, Y and Wang, J and Gu, J and Chun, B and Liu, Z}, title = {Investigation of cadmium-induced apoptosis and the protective effect of N-acetylcysteine in BRL 3A cells.}, journal = {Molecular medicine reports}, volume = {14}, number = {1}, pages = {373-379}, doi = {10.3892/mmr.2016.5218}, pmid = {27175572}, issn = {1791-3004}, mesh = {Acetates/*pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cadmium/*pharmacology ; Caspase 3/metabolism ; Caspase 8/metabolism ; Caspase 9/metabolism ; Cell Line, Transformed ; Free Radical Scavengers/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism/ultrastructure ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; }, abstract = {The aims of the present study were to investigate the effect of cadmium (Cd)‑induced apoptosis and determine the protective effect of N‑acetylcysteine (NAC) in BRL 3A cells. The BRL 3A cells were treated with 0, 10, 20 or 40 µmol/l cadmium acetate (CdAc2) for 12 h. Another two groups of cells were preincubated with 2 mmol/l NAC for 30 min, and then either incubated with 20 µmol/l CdAc2 for 12 h, or treated with NAC alone. The levels of apoptosis and mitochondrial membrane potential (ΔΨm) were measured using flow cytometry. Mitochondrial ultrastructural changes were detected using transmission electron microscopy. The protein levels of caspase‑3, caspase‑9, poly (ADP‑ribose) polymerase (PARP), caspase‑8, and Fas ligand (FasL) protein were measured using immunoblotting. As the dose of Cd increased, there was a significant increase in the apoptotic ratio, a significant decrease in ΔΨm, mitochondrial swelling and degeneration, and blurring, deformation and eventual collapse of the mitochondrial cristae. The protein levels of caspase‑3, caspase‑9 and PARP decreased, whereas the levels of cleaved caspase‑3, cleaved caspase‑9, cleaved caspase‑8 and FasL increased dose‑dependently in relation to Cd. NAC effectively inhibited these changes. Cd induced apoptosis through the mitochondrial and FasL pathways in the BRL 3A cells, and NAC exerted a protective effect against Cd‑induced damage.}, }
@article {pmid27166184, year = {2016}, author = {Lu, B and Wang, B and Zhong, S and Zhang, Y and Gao, F and Chen, Y and Zheng, F and Shi, G}, title = {N-n-butyl haloperidol iodide ameliorates hypoxia/reoxygenation injury through modulating the LKB1/AMPK/ROS pathway in cardiac microvascular endothelial cells.}, journal = {Oncotarget}, volume = {7}, number = {23}, pages = {34800-34810}, pmid = {27166184}, issn = {1949-2553}, mesh = {AMP-Activated Protein Kinase Kinases ; AMP-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Cell Hypoxia/*drug effects ; Cell Survival/drug effects ; Endothelial Cells/*metabolism ; Haloperidol/*analogs &amp; derivatives/pharmacology ; Ischemia/drug therapy ; L-Lactate Dehydrogenase/metabolism ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Endothelial cells are highly sensitive to hypoxia and contribute to myocardial ischemia/reperfusion injury. We have reported that N-n-butyl haloperidol iodide (F2) can attenuate hypoxia/reoxygenation (H/R) injury in cardiac microvascular endothelial cells (CMECs). However, the molecular mechanisms remain unclear. Neonatal rat CMECs were isolated and subjected to H/R. Pretreatment of F2 leads to a reduction in H/R injury, as evidenced by increased cell viability, decreased lactate dehydrogenase (LDH) leakage and apoptosis, together with enhanced AMP-activated protein kinase (AMPK) and liver kinase B1 (LKB1) phosphorylation in H/R ECs. Blockade of AMPK with compound C reversed F2-induced inhibition of H/R injury, as evidenced by decreased cell viability, increased LDH release and apoptosis. Moreover, compound C also blocked the ability of F2 to reduce H/R-induced reactive oxygen species (ROS) generation. Supplementation with the ROS scavenger N-acetyl-L-cysteine (NAC) reduced ROS levels, increased cell survival rate, and decreased both LDH release and apoptosis after H/R. In conclusion, our data indicate that F2 may mitigate H/R injury by stimulating LKB1/AMPK signaling pathway and subsequent suppression of ROS production in CMECs.}, }
@article {pmid27164059, year = {2016}, author = {Horikoshi, Y and Takeo, T and Nakagata, N}, title = {N-acetyl cysteine prolonged the developmental ability of mouse two-cell embryos against oxidative stress at refrigerated temperatures.}, journal = {Cryobiology}, volume = {72}, number = {3}, pages = {198-204}, doi = {10.1016/j.cryobiol.2016.05.002}, pmid = {27164059}, issn = {1090-2392}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cold Temperature ; Cryopreservation/*methods ; *Embryo, Mammalian ; Female ; Glutathione/metabolism ; Male ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Oxidative Stress/drug effects ; }, abstract = {Cold storage of two-cell embryos at refrigerated temperatures is a useful means to ship genetically engineered mice. We previously reported that M2 medium maintained the developmental ability of two-cell embryos for 48 h at 4 °C, and offspring were obtained from embryos transported by a courier service under refrigerated temperatures. The limitation of 48 h practically restricts the shipping destination of the embryos. To enhance the applicability of the cold-storage technique, prolonging the time to maintain developmental ability of the embryos is required. Oxidative stress may be a cause of the declining developmental ability of cold-stored embryos. However, the effect of oxidative stress on developmental ability of embryos has not been investigated. We examined intracellular glutathione (GSH) levels of cold-stored two-cell embryos to evaluate the effect of oxidative and investigated the efficacy of adding N-acetyl cysteine (NAC) to the preservation medium on the developmental ability of cold-stored embryos and transported two-cell embryos at refrigerated temperatures. Intracellular GSH levels of two-cell embryos decreased by cold storage for longer than 72 h, whereas NAC recovered this reduction and improved the developmental ability of embryos cold-stored for 96 h. In the transport experiment, the developmental rate of transported two-cell embryos to offspring was increased by adding NAC to the preservation medium. We found that NAC prolonged the storage period of two-cell embryos and maintained the developmental ability by alleviating the reduction of intracellular GSH. These findings will improve the technique of cold-storage of two-cell embryos to facilitate efficient transport of genetically engineered mice worldwide.}, }
@article {pmid27162477, year = {2016}, author = {Shi, Y and Song, Q and Hu, D and Zhuang, X and Yu, S and Teng, D}, title = {Oleanolic acid induced autophagic cell death in hepatocellular carcinoma cells via PI3K/Akt/mTOR and ROS-dependent pathway.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {20}, number = {3}, pages = {237-243}, pmid = {27162477}, issn = {1226-4512}, abstract = {Oleanolic acid (OA) has a wide variety of bioactivities such as hepatoprotective, anti-inflammatory and anti-cancer activity and is used for medicinal purposes in many Asian countries. In the present study, the effect of OA on induction of autophagy in human hepatocellular carcinoma HepG2 and SMC7721 cells and the related mechanisms were investigated. MTT assay showed that OA significantly inhibited HepG2 and SMC7721 cells growth. OA treatment enhanced formation of autophagic vacuoles as revealed by monodansylcadaverine (MDC) staining. At the same time, increasing punctuate distribution of microtubule-associated protein 1 light chain 3 (LC3) and an increasing ratio of LC3-II to LC3-I were also triggered by OA incubation. In addition, OA-induced cell death was signifi cantly inhibited by autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) pretreatment. And we found out that OA can suppress the PI3K/Akt1/mTOR signaling pathway. Furthermore, our data suggested that OA-triggered autophagy was ROS-dependent as demonstrated by elevated cellular ROS levels by OA treatment. When ROS was cleared by N-acetylcysteine (NAC), OA-induced LC3-II convertsion and cell death were all reversed. Taken together, our results suggest that OA exerts anticancer eff ect via autophagic cell death in hepatocellular carcinoma.}, }
@article {pmid27161488, year = {2016}, author = {Ma, Y and Gao, M and Liu, D}, title = {N-acetylcysteine Protects Mice from High Fat Diet-induced Metabolic Disorders.}, journal = {Pharmaceutical research}, volume = {33}, number = {8}, pages = {2033-2042}, pmid = {27161488}, issn = {1573-904X}, support = {R01 HL098295/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Blood Glucose/drug effects/metabolism ; Diet, High-Fat/*adverse effects ; Insulin/blood ; Male ; Metabolic Diseases/*etiology/metabolism/*prevention &amp; control ; Mice ; Mice, Inbred C57BL ; Obesity/drug therapy/etiology/metabolism ; }, abstract = {PURPOSE: To study the effects of N-acetylcysteine (NAC, C5H9NO3S) on diet-induced obesity and obesity-related metabolic disorders.<br><br>METHODS: Six-week-old male C57BL/6 mice fed a chow or high-fat diet (HFD) were treated with NAC (2&#xa0;g/L) in drinking water for 11&#xa0;weeks. Its influences on body weight and food intake were manually measured, and influence on body composition were analyzed by magnetic residence imaging. Glucose meter and ELISA were used to determine serum glucose and insulin levels, as well as lipid content in the liver. The effects of NAC treatment on mRNA levels of genes involved in inflammation, thermogenesis, and lipid metabolism in various tissues were determined by real time PCR.<br><br>RESULTS: NAC supplementation inhibited the increase of fat mass and the development of obesity when mice were fed an HFD. NAC treatment significantly lowered HFD-induced macrophage infiltration, and enhanced adiponectin gene expression, resulting in reduced hyperglycemia and hyperinsulinemia, and improvement of insulin resistance. NAC oral administration suppressed hepatic lipid accumulation, as evidenced by lower levels of triglyceride and cholesterol in the liver. The beneficial effects are associated with a decrease of hepatic Ppar&#x3b3; and its target gene expression, and an increase in the expression of genes responsible for lipid oxidation and activation of farnesoid X receptor. Furthermore, NAC treatment also stimulates expression of thermogenic genes.<br><br>CONCLUSION: These results provide direct proof of the protective potential of NAC against HFD-induced obesity and obesity-associated metabolic disorders.}, }
@article {pmid27156686, year = {2016}, author = {Vasamsetti, SB and Karnewar, S and Gopoju, R and Gollavilli, PN and Narra, SR and Kumar, JM and Kotamraju, S}, title = {Resveratrol attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of intracellular GSH homeostasis: Relevance in atherosclerosis.}, journal = {Free radical biology &amp; medicine}, volume = {96}, number = {}, pages = {392-405}, doi = {10.1016/j.freeradbiomed.2016.05.003}, pmid = {27156686}, issn = {1873-4596}, mesh = {AMP-Activated Protein Kinases/metabolism ; Acetylcysteine/administration &amp; dosage ; Animals ; Antioxidants/administration &amp; dosage ; Apolipoproteins E/genetics ; Atherosclerosis/*drug therapy/metabolism/pathology ; Buthionine Sulfoximine/administration &amp; dosage ; Cell Differentiation/drug effects ; Glutathione/*metabolism ; Homeostasis/drug effects ; Humans ; Inflammation/chemically induced/*drug therapy/metabolism/pathology ; Macrophages/drug effects ; Matrix Metalloproteinase 9/biosynthesis ; Mice ; Mice, Knockout ; Monocytes/drug effects ; Resveratrol ; Stilbenes/*administration &amp; dosage/antagonists &amp; inhibitors ; Tetradecanoylphorbol Acetate/administration &amp; dosage ; }, abstract = {Monocyte-to-macrophage differentiation promotes an inflammatory environment within the arterial vessel wall that causes a mal-adaptive immune response, which contributes to the progression of atheromatous plaque formation. In the current study, we show that resveratrol, a well-known antioxidant, dose-dependently attenuated phorbol myristate acetate (PMA)-induced monocyte-to-macrophage differentiation, as measured by cell adhesion, increase in cell size, and scavenger receptor expression in THP-1 monocytes. Also, resveratrol significantly inhibited PMA-induced pro-inflammatory cytokine/chemokine and matrix metalloprotease (MMP-9) production. This inhibitory effect of resveratrol on monocyte differentiation results from its ability to restore intracellular glutathione (GSH) status, as resveratrol in the presence of buthionine sulfoximine (BSO) failed to affect monocyte differentiation. Furthermore, PMA-induced monocyte differentiation and inflammation was greatly inhibited when cells were co-treated with N-Acetyl-l-cysteine (NAC), a GSH precursor, while the presence of BSO aggravated these processes. These results also show that resveratrol mediated up-regulation of GSH is due to AMP-activated protein kinase (AMPK)-α activation, as compound C (AMPK inhibitor) treatment drastically depleted intracellular GSH and exacerbated PMA-induced monocyte differentiation and pro-inflammatory cytokine production. More importantly, chronic administration of resveratrol efficiently prevented monocyte infiltration and markedly diminished angiotensin (Ang)-II-induced atheromatous plaque formation in apolipoprotein-E knockout (ApoE(-/-)) mice. We conclude that, intracellular GSH status plays a critical role in regulating monocyte-to-macrophage differentiation and inflammation and resveratrol, by restoring GSH levels, inhibits these processes. Taken together, these results suggest that resveratrol can attenuate atherosclerosis, at least, in part, by inhibiting monocyte differentiation and pro-inflammatory cytokines production.}, }
@article {pmid27155098, year = {2016}, author = {Liu, G and Zhang, S and Yang, K and Zhu, L and Lin, D}, title = {Toxicity of perfluorooctane sulfonate and perfluorooctanoic acid to Escherichia coli: Membrane disruption, oxidative stress, and DNA damage induced cell inactivation and/or death.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {214}, number = {}, pages = {806-815}, doi = {10.1016/j.envpol.2016.04.089}, pmid = {27155098}, issn = {1873-6424}, mesh = {Alkanesulfonic Acids/*toxicity ; Caprylates/*toxicity ; Cell Membrane/*drug effects/genetics/metabolism/ultrastructure ; *DNA Damage ; Dose-Response Relationship, Drug ; Environmental Pollutants/*toxicity ; Escherichia coli K12/*drug effects/genetics/metabolism ; Fluorocarbons/*toxicity ; Gene Expression/drug effects ; Membrane Fluidity/drug effects ; Microbial Viability/drug effects/genetics ; Microscopy, Electron, Transmission ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Spectroscopy, Fourier Transform Infrared ; Superoxide Dismutase/metabolism ; Surface Properties ; }, abstract = {Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are two widely used polyfluorinated compounds (PFCs) and are persistent in the environment. This study for the first time systematically investigated their toxicities and the underlying mechanisms to Escherichia coli. Much higher toxicity was observed for PFOA than PFOS, with the 3 h half growth inhibition concentrations (IC50) determined to be 10.6 ± 1.0 and 374 ± 3 mg L(-1), respectively, while the bacterial accumulation of PFOS was much greater than that of PFOA. The PFC exposures disrupted cell membranes as evidenced by the dose-dependent variations of cell structures (by transmission electron microscopy observations), surface properties (electronegativity, hydrophobicity, and membrane fluidity), and membrane compositions (by gas chromatogram and Fourier transform infrared spectroscopy analyses). The increases in the contents of intracellular reactive oxygen species (ROS) and malondialdehyde and the activity of superoxide dismutase indicated the increment of oxidative stress induced by the PFCs in the bacterial cells. The fact that the cell growth inhibition was mitigated by the addition of ROS scavenger (N-acetyl cysteine) further evidenced the important role of oxidative damage in the toxicities of PFOS and PFOA. Eighteen genes involved in cell division, membrane instability, oxidative stress, and DNA damage of the exposed cells were up or down expressed, indicating the DNA damage by the PFCs. The toxicities of PFOS and PFOA to E. coli were therefore ascribed to the membrane disruption, oxidative stress, and DNA damage induced cell inactivation and/or death. The difference in the bactericidal effect between PFOS and PFOA was supposed to be related to their different dominating toxicity mechanisms, i.e., membrane disruption and oxidative damage, respectively. The outcomes will shed new light on the assessment of ecological effects of PFCs.}, }
@article {pmid27151894, year = {2016}, author = {Ronchetti, SA and Bianchi, MS and Duvilanski, BH and Cabilla, JP}, title = {In Vivo and In Vitro Arsenic Exposition Induces Oxidative Stress in Anterior Pituitary Gland.}, journal = {International journal of toxicology}, volume = {35}, number = {4}, pages = {463-475}, doi = {10.1177/1091581816645797}, pmid = {27151894}, issn = {1092-874X}, mesh = {Animals ; Apoptosis/drug effects ; Arsenic/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Gene Expression/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Metallothionein/genetics ; Oxidative Stress/drug effects ; Pituitary Gland, Anterior/*drug effects/metabolism ; Prolactin/blood ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Thioredoxins/genetics ; Water Pollutants, Chemical/*toxicity ; }, abstract = {Inorganic arsenic (iAs) is at the top of toxic metalloids. Inorganic arsenic-contaminated water consumption is one of the greatest environmental health threats worldwide. Human iAs exposure has been associated with cancers of several organs, neurological disorders, and reproductive problems. Nevertheless, there are no reports describing how iAs affects the anterior pituitary gland. The aim of this study was to investigate the mechanisms involved in iAs-mediated anterior pituitary toxicity both in vivo and in vitro. We showed that iAs administration (from 5 to 100 ppm) to male rats through drinking water increased messenger RNA expression of several oxidative stress-responsive genes in the anterior pituitary gland. Serum prolactin levels diminished, whereas luteinizing hormone (LH) levels were only affected at the higher dose tested. In anterior pituitary cells in culture, 25 µmol/L iAs significantly decreased prolactin release in a time-dependent fashion, whereas LH levels remained unaltered. Cell viability was significantly reduced mainly by apoptosis evidenced by morphological and phosphatidylserine externalization studies. This process is characterized by early depolarization of mitochondrial membrane potential and increased levels of reactive oxygen species. Expression of some key oxidative stress-responsive genes, such as heme oxygenase-1 and metallothionein-1, was also stimulated by iAs exposure. The antioxidant N-acetyl cysteine prevented iAs-induced effects on the expression of oxidative stress markers, prolactin release, and apoptosis. In summary, the present work demonstrates for the first time that iAs reduces prolactin release both in vivo and in vitro and induces apoptosis in anterior pituitary cells, possibly resulting from imbalanced cellular redox status.}, }
@article {pmid27149563, year = {2016}, author = {El-Hadidy, AR and El-Mohandes, EM and Asker, SA and Ghonaim, FM}, title = {A histological and immunohistochemical study of the effects of N-acetyl cysteine on retinopathy of prematurity by modifying insulin-like growth factor-1.}, journal = {Biotechnic &amp; histochemistry : official publication of the Biological Stain Commission}, volume = {91}, number = {6}, pages = {401-411}, doi = {10.1080/10520295.2016.1180428}, pmid = {27149563}, issn = {1473-7760}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Animals, Newborn ; Cell Line, Tumor ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/therapeutic use ; Gene Expression Regulation, Developmental/*drug effects ; Immunohistochemistry ; Insulin-Like Growth Factor I/*genetics/metabolism ; Rats ; Retinal Pigment Epithelium/chemistry/*drug effects/pathology ; Retinal Vessels/drug effects ; Retinopathy of Prematurity/drug therapy/*physiopathology/prevention &amp; control ; }, abstract = {Retinopathy of prematurity (ROP) is a vasoproliferative disorder that occurs in premature infants and may lead to permanent visual impairment. We investigated both the possible protective role of N-acetyl cysteine (NAC) for preventing ROP and the role of IGF-1 in the disorder. Forty-five newborn rats were divided into three groups. Group 1 was raised in room air as controls. Group 2 was exposed to 60% oxygen for 14 days after birth, then transferred to room air. Group 3 was exposed to the same conditions as group 2, but received intraperitoneal injections of NAC on postnatal days 7-17. After 35 days, both eyes of all rats were processed for histology. Some sections were stained with hematoxylin and eosin to assess structural changes and other sections were immunostained to determine the location of IGF-1. Frozen sections also were prepared and stained for adenosine triphosphatase to detect retinal blood vessels. Compared to the controls, more blood vessels, many of which were abnormal, and increased IGF-1 expression were observed in group 2. In group 3, abnormal blood vessels and IGF-1 expression were less evident. NAC appeared to be an effective vascular-protective agent for ROP by decreasing IGF-1 expression.}, }
@article {pmid27148463, year = {2016}, author = {Giampreti, A and Lonati, D and Ragghianti, B and Ronchi, A and Petrolini, VM and Vecchio, S and Locatelli, CA}, title = {N-Acetyl-Cysteine as Effective and Safe Chelating Agent in Metal-on-Metal Hip-Implanted Patients: Two Cases.}, journal = {Case reports in orthopedics}, volume = {2016}, number = {}, pages = {8682737}, pmid = {27148463}, issn = {2090-6749}, abstract = {Systemic toxicity associated with cobalt (Co) and chromium (Cr) containing metal hip alloy may result in neuropathy, cardiomyopathy, and hypothyroidism. However clinical management concerning chelating therapy is still debated in literature. Here are described two metal-on-metal hip-implanted patients in which N-acetyl-cysteine decreased elevated blood metal levels. A 67-year-old male who underwent Co/Cr hip implant in September 2009 referred to our Poison Control Centre for persisting elevated Co/Cr blood levels (from March 2012 to November 2014). After receiving oral high-dose N-acetyl-cysteine, Co/Cr blood concentrations dropped by 86% and 87% of the prechelation levels, respectively, and persisted at these latter concentrations during the following 6 months of follow-up. An 81-year-old female who underwent Co/Cr hip implant in January 2007 referred to our Centre for detection of high Co and Cr blood levels in June 2012. No hip revision was indicated. After a therapy with oral high-dose N-acetyl-cysteine Co/Cr blood concentrations decreased of 45% and 24% of the prechelation levels. Chelating agents reported in hip-implanted patients (EDTA, DMPS, and BAL) are described in few cases. N-acetyl-cysteine may provide chelating sites for metals and in our cases reduced Co and Cr blood levels and resulted well tolerable.}, }
@article {pmid27146087, year = {2016}, author = {Özcan, D and Seçkin, D}, title = {N-Acetylcysteine in the treatment of trichotillomania: remarkable results in two patients.}, journal = {Journal of the European Academy of Dermatology and Venereology : JEADV}, volume = {30}, number = {9}, pages = {1606-1608}, doi = {10.1111/jdv.13690}, pmid = {27146087}, issn = {1468-3083}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Female ; Humans ; Trichotillomania/*drug therapy ; }, abstract = {BACKGROUND: The management of trichotillomania is challenging. The limited efficacy and side-effects of pharmacological medications and difficulty in long-term maintenance of behavioural therapies necessitates alternative treatment options. A dysregulated glutamatergic system has been implicated in the pathophysiology of trichotillomania. A limited number of reports indicate that N-acetylcysteine (NAC), a glutamate modulator, may be a promising treatment for this disorder.<br><br>OBJECTIVES: We report two patients with trichotillomania for whom treatment with NAC was successful.<br><br>METHODS: The first patient was a 30-year-old female, and the second patient was a 14-year-old girl, both who were diagnosed with trichotillomania and prescribed NAC (1200 mg/d, p.o.).<br><br>RESULTS: Hair pulling behaviour subsided within 2 months and 2 weeks of initiating NAC in the first and second patient, respectively. Complete hair regrowth was observed after 4 and 6 months of NAC treatment in the first and second patient, respectively. No side-effects related to NAC were noted.<br><br>CONCLUSION: NAC could be a well-tolerated and effective treatment option for trichotillomania.}, }
@article {pmid27143871, year = {2016}, author = {Johnson, K and McEvoy, CE and Naqvi, S and Wendt, C and Reilkoff, RA and Kunisaki, KM and Wetherbee, EE and Nelson, D and Tirouvanziam, R and Niewoehner, DE}, title = {High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {11}, number = {}, pages = {799-807}, pmid = {27143871}, issn = {1178-2005}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Bronchitis, Chronic/complications/*drug therapy ; Double-Blind Method ; Female ; Health Status ; Humans ; Male ; Pulmonary Disease, Chronic Obstructive/complications/*drug therapy ; Treatment Failure ; }, abstract = {BACKGROUND: Clinical outcomes are worse in patients with COPD and chronic bronchitis. N-acetylcysteine (NAC) is commonly prescribed for such patients but with uncertain clinical benefits. We postulated that oral NAC, at much larger doses than those ordinarily prescribed, would improve clinical outcomes in a subset of patients with COPD and chronic bronchitis.<br><br>OBJECTIVE: The aim of this study was to determine whether very high-dose NAC would improve respiratory health status in patients with COPD and chronic bronchitis.<br><br>METHODS: Patients with COPD and chronic bronchitis were enrolled in a randomized, controlled, double-blinded trial. Patients received oral NAC (1,800 mg) or matching placebo twice daily for 8 weeks in addition to their usual respiratory medications. The primary outcome, respiratory health status, was assessed by changes in the St George's Respiratory Questionnaire. The effects of NAC on lung function and circulating markers of oxidative stress and inflammation were also evaluated.<br><br>RESULTS: We terminated the study prematurely because new external information suggested the possibility of a safety issue. Of the planned 130 patients, 51 were randomized and 45 (22 in the placebo arm and 23 in the NAC arm) completed the study. There was no statistically significant difference between changes in the St George's Respiratory Questionnaire total score, comparing NAC to placebo (adjusted mean difference, 0.1 U; 95% CI, -7.8 to 8.18 U; P=0.97). There were also no significant NAC-related improvements in any of the secondary outcomes.<br><br>CONCLUSION: In this 8-week trial, we were unable to show any clinical benefit from a very high dose of NAC in patients with COPD and chronic bronchitis.}, }
@article {pmid27142831, year = {2016}, author = {Arora, D and Siddiqui, MH and Sharma, PK and Singh, SP and Tripathi, A and Mandal, P and Singh, US and Singh, PK and Shukla, Y}, title = {Evaluation and physiological correlation of plasma proteomic fingerprints for deltamethrin-induced hepatotoxicity in Wistar rats.}, journal = {Life sciences}, volume = {160}, number = {}, pages = {72-83}, doi = {10.1016/j.lfs.2016.04.025}, pmid = {27142831}, issn = {1879-0631}, mesh = {Animals ; Blood Proteins/*metabolism ; Liver/*drug effects ; Male ; Nitriles/*toxicity ; Pesticides/*toxicity ; Pyrethrins/*toxicity ; Rats ; Rats, Wistar ; }, abstract = {AIMS: Uprising reports towards deltamethrin (DLM)-induced toxicity in non-target species including mammals have raised a worldwide concern. Moreover, in the absence of any identified marker, the prediction of DLM elicited early toxic manifestations in non-targets remains elusive.<br><br>MAIN METHODS: Comprehensive approach of proteome profiling along with conventional toxico-physiological correlation analysis was performed to classify novel protein based markers in the plasma of DLM exposed Wistar rats. Animals were exposed orally to DLM (low dose: 2.56mg/kg b.wt. and high dose: 5.12mg/kg b.wt.) up to seven consecutive days.<br><br>KEY FINDINGS: The UPLC-MS/MS analysis revealed a dose-dependent dissemination of DLM and its primary metabolite (3-Phenoxy benzoic acid) in rat plasma. Through 2-DE-MS/MS plasma profiling and subsequent verification at the transcriptional level, we found that 6 liver emanated acute phase proteins (Apolipoprotein-AIV, Apolipoprotein E, Haptoglobin, Hemopexin, Vitamin D Binding protein, and Fibrinogen gamma chain) were significantly (p<0.05) modulated in DLM treated groups in a dose-dependent manner. Accordingly, DLM exposure resulted in adverse effects on body growth (body weight &amp; relative organ weight), serum profile, liver function and histology, inflammatory changes (enhanced TNF-&#x251;, TGF-&#x3b2; and IL6 level), and oxidative stress. Moreover, these toxic manifestations were suppressed upon N-acetyl cysteine (NAC) supplementation in DLM treated animals. Thus, DLM-induced inflammatory response and subsequent oxidative injury to liver grounds the altered expression of identified acute phase proteins.<br><br>SIGNIFICANCE: In conclusion, we proposed these six liver emanated plasma proteins as novel candidate markers to assess the early DLM-induced hepatotoxicity in non-target species with a minimal invasive mean.}, }
@article {pmid27142208, year = {2016}, author = {Sarges, P and Steinberg, JM and Lewis, JH}, title = {Drug-Induced Liver Injury: Highlights from a Review of the 2015 Literature.}, journal = {Drug safety}, volume = {39}, number = {9}, pages = {801-821}, pmid = {27142208}, issn = {1179-1942}, mesh = {Animals ; Chemical and Drug Induced Liver Injury/*epidemiology ; Humans ; Liver Diseases/*complications ; Liver Function Tests ; Predictive Value of Tests ; Prognosis ; Risk Factors ; Severity of Illness Index ; Time Factors ; }, abstract = {Numerous publications contributed to the expanding knowledge base about drug-induced liver injury (DILI) in 2015. New findings from the US Drug Induced Liver Injury Network (DILIN) in their most recently updated registry include a 1- to 3-week delay in the appearance of acute DILI from short-course antibiotics such as cefazolin. They corroborated the finding that acute DILI in patients with underlying liver disease was far more severe and potentially fatal than in patients without liver disease. The only drug that seemed to have an increased risk of hepatotoxicity in these patients was azithromycin. While nearly one in six patients with acute DILI had persistently elevated liver tests at 6 months, and results for 75 % of these patients continued to be abnormal at 12 months, most of these "chronic" injury cases were relatively minor and the result of cholestatic hepatotoxins. Newly described DILI agents include tolvaptan, as well as some new direct-acting antiviral protease inhibitors for chronic hepatitis C. The latter have been associated with serious acute hepatitis, hyperbilirubinemia, and decompensation. Herbal hepatotoxicity continues to be increasingly reported, although applying causality assessment to these cases can, in fact, be more challenging than with prescription drugs. As important as cases with DILI, the class of PCSK9 inhibitors used to lower low-density lipoprotein (LDL) cholesterol have not been associated with significant liver injury, in contrast with other lipid-lowering agents. With respect to pharmacologic DILI risk factors, new data show that drugs metabolized by cytochrome P450 enzymes had a nearly four times higher likelihood of causing DILI. Interestingly, high lipophilicity, which was previously felt to be a risk factor for DILI, was not found to be associated, although more study is needed to confirm this observation. While human leukocyte antigen (HLA) genotypes have been linked to several specific agents, the role of such testing in the general population remains undefined due to the currently low positive and negative predictive values of the available tests. New DILI biomarkers, specifically microRNA-122 and keratin-18, among others, appear to have the necessary predictive value to determine the prognosis and outcome of patients with paracetamol (acetaminophen [AAP])-induced acute liver failure (ALF), and may be of great benefit in deciding who requires N-acetylcysteine (NAC), and for what duration. Treatment options for other forms of DILI remain limited; no firm conclusions can currently be drawn for the use of NAC in non-AAP ALF.}, }
@article {pmid27142143, year = {2016}, author = {Deng, Y and Zhao, L and Lu, X}, title = {A multidrug cocktail approach attenuates ischemic-type biliary lesions in liver transplantation from non-heart-beating donors.}, journal = {Medical hypotheses}, volume = {91}, number = {}, pages = {47-52}, doi = {10.1016/j.mehy.2016.04.013}, pmid = {27142143}, issn = {1532-2777}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Biliary Tract Diseases/complications/diagnosis ; Drug Therapy, Combination ; Epithelial Cells/cytology ; Epoprostenol/administration &amp; dosage ; Female ; Hemin/administration &amp; dosage ; Hepatocytes/cytology ; Humans ; Inflammation ; Ischemia/*drug therapy ; Kupffer Cells/cytology ; Liver/*drug effects ; Liver Failure/pathology/*surgery ; Liver Transplantation/*adverse effects/*methods ; Models, Theoretical ; Organ Preservation ; Reactive Oxygen Species/metabolism ; Reoperation ; Reperfusion Injury/*prevention &amp; control ; Streptokinase/administration &amp; dosage ; Swine ; Taurochenodeoxycholic Acid/administration &amp; dosage ; Thiazolidinediones/administration &amp; dosage ; Tissue Donors ; Warm Ischemia ; }, abstract = {Ischemic-type biliary lesions (ITBL) are the most troublesome biliary complication after liver transplantation (LT) from non-heart-beating donors (NHBD) and frequently result in death or re-transplantation. In transplantation process, warm ischemia (WI) in the donor, cold ischemia and reperfusion injury in the recipient altogether inducing ischemia-reperfusion injury (IRI) is strongly associated with ITBL. This is a cascading injury process, involving in a complex series of inter-connecting events causing variety of cells activation and damage associated with the massive release of inflammatory cytokines and generation of reactive oxygen species (ROS). These damaged cells such as sinusoidal endothelial cells (SECs), Kupffer cells (KCs), hepatocytes and biliary epithelial cells (BECs), coupled with immunological injury and bile salt toxicity altogether contribute to ITBL in NHBD LT. Developed therapeutic strategies to attenuate IRI are essential to improve outcome after LT. Among them, single pharmaceutical interventions blocking a specific pathway of IRI in rodent models play an absolutely dominant role, and show a beneficial effect in some given controlled experiments. But this will likely prove ineffective in complex clinical setting in which more risk parameters are involved. Therefore, we intend to design a multidrug cocktail approach to block different pathways on more than one stage (WI, cold ischemia and reperfusion) of the process of IRI-induced ITBL simultaneously. This multidrug cocktail will include six drugs containing streptokinase, epoprostenol, thiazolidinediones (TZDs), N-Acetylcysteine (NAC), hemin and tauroursodeoxycholic acid (TUDC). These drugs show protective effects by targeting the different key events of IRI, such as anti-inflammatory, anti-fibrosis, anti-oxidation, anti-apoptosis and reduced bile salt toxicity. Ideally, the compounds, dosage, and method of application of drugs included in cocktail should not be definitive. We can consider removing or adding some drugs to the proposed cocktail based on further research. But given the multitude of different combinations, it is extremely difficult to determent which combination is the optimization design. Nevertheless, regardless of the difficulty, our multidrug cocktail approach designed to block different mechanisms on more than one stage of IRI simultaneously may represent a future preventive and therapeutic avenue for ITBL.}, }
@article {pmid27137430, year = {2016}, author = {Fernandes, BS and Dean, OM and Dodd, S and Malhi, GS and Berk, M}, title = {N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis.}, journal = {The Journal of clinical psychiatry}, volume = {77}, number = {4}, pages = {e457-66}, doi = {10.4088/JCP.15r09984}, pmid = {27137430}, issn = {1555-2101}, mesh = {Acetylcysteine/*therapeutic use ; Activities of Daily Living/*classification/*psychology ; Depressive Disorder/diagnosis/*drug therapy/*psychology ; Follow-Up Studies ; Humans ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: To assess the utility of N-acetylcysteine administration for depressive symptoms in subjects with psychiatric conditions using a systematic review and meta-analysis.<br><br>DATA SOURCES: A computerized literature search was conducted in MEDLINE, Embase, the Cochrane Library, SciELO, PsycINFO, Scopus, and Web of Knowledge. No year or country restrictions were used. The Boolean terms used for the electronic database search were (NAC OR N-acetylcysteine OR acetylcysteine) AND (depression OR depressive OR depressed) AND (trial). The last search was performed in November 2014.<br><br>STUDY SELECTION: The literature was searched for double-blind, randomized, placebo-controlled trials using N-acetylcysteine for depressive symptoms regardless of the main psychiatric condition. Using keywords and cross-referenced bibliographies, 38 studies were identified and examined in depth. Of those, 33 articles were rejected because inclusion criteria were not met. Finally, 5 studies were included.<br><br>DATA EXTRACTION: Data were extracted independently by 2 investigators. The primary outcome measure was change in depressive symptoms. Functionality, quality of life, and manic and anxiety symptoms were also examined. A full review and meta-analysis were performed. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% CIs were calculated.<br><br>RESULTS: Five studies fulfilled our inclusion criteria for the meta-analysis, providing data on 574 participants, of whom 291 were randomized to receive N-acetylcysteine and 283 to placebo. The follow-up varied from 12 to 24 weeks. Two studies included subjects with bipolar disorder and current depressive symptoms, 1 included subjects with MDD in a current depressive episode, and 2 included subjects with depressive symptoms in the context of other psychiatric conditions (1 trichotillomania and 1 heavy smoking). Treatment with N-acetylcysteine improved depressive symptoms as assessed by Montgomery-Asberg Depression Rating Scale and Hamilton Depression Rating Scale when compared to placebo (SMD = 0.37; 95% CI = 0.19 to 0.55; P < .001). Subjects receiving N-acetylcysteine had better depressive symptoms scores on the Clinical Global Impressions-Severity of Illness scale at follow-up than subjects on placebo (SMD = 0.22; 95% CI = 0.03 to 0.41; P < .001). In addition, global functionality was better in N-acetylcysteine than in placebo conditions. There were no changes in quality of life. With regard to adverse events, only minor adverse events were associated with N-acetylcysteine (OR = 1.61; 95% CI = 1.01 to 2.59; P = .049).<br><br>CONCLUSIONS: Administration of N-acetylcysteine ameliorates depressive symptoms, improves functionality, and shows good tolerability.}, }
@article {pmid27135742, year = {2016}, author = {Wilhelm, T and Ragu, S and Magdalou, I and Machon, C and Dardillac, E and Técher, H and Guitton, J and Debatisse, M and Lopez, BS}, title = {Slow Replication Fork Velocity of Homologous Recombination-Defective Cells Results from Endogenous Oxidative Stress.}, journal = {PLoS genetics}, volume = {12}, number = {5}, pages = {e1006007}, pmid = {27135742}, issn = {1553-7404}, mesh = {Acetylcysteine/pharmacology ; Animals ; CHO Cells ; Centrosome/drug effects ; Cricetulus ; DNA Damage/genetics ; DNA Repair/genetics ; DNA Replication/*genetics ; DNA-Binding Proteins/genetics/metabolism ; Gene Regulatory Networks/genetics ; Histones/genetics ; Homologous Recombination/*genetics ; Hydrogen Peroxide/pharmacology ; Mitosis/*genetics ; Oxidative Stress/drug effects/*genetics ; Single Molecule Imaging ; X-ray Repair Cross Complementing Protein 1 ; }, abstract = {Replications forks are routinely hindered by different endogenous stresses. Because homologous recombination plays a pivotal role in the reactivation of arrested replication forks, defects in homologous recombination reveal the initial endogenous stress(es). Homologous recombination-defective cells consistently exhibit a spontaneously reduced replication speed, leading to mitotic extra centrosomes. Here, we identify oxidative stress as a major endogenous source of replication speed deceleration in homologous recombination-defective cells. The treatment of homologous recombination-defective cells with the antioxidant N-acetyl-cysteine or the maintenance of the cells at low O2 levels (3%) rescues both the replication fork speed, as monitored by single-molecule analysis (molecular combing), and the associated mitotic extra centrosome frequency. Reciprocally, the exposure of wild-type cells to H2O2 reduces the replication fork speed and generates mitotic extra centrosomes. Supplying deoxynucleotide precursors to H2O2-exposed cells rescued the replication speed. Remarkably, treatment with N-acetyl-cysteine strongly expanded the nucleotide pool, accounting for the replication speed rescue. Remarkably, homologous recombination-defective cells exhibit a high level of endogenous reactive oxygen species. Consistently, homologous recombination-defective cells accumulate spontaneous γH2AX or XRCC1 foci that are abolished by treatment with N-acetyl-cysteine or maintenance at 3% O2. Finally, oxidative stress stimulated homologous recombination, which is suppressed by supplying deoxynucleotide precursors. Therefore, the cellular redox status strongly impacts genome duplication and transmission. Oxidative stress should generate replication stress through different mechanisms, including DNA damage and nucleotide pool imbalance. These data highlight the intricacy of endogenous replication and oxidative stresses, which are both evoked during tumorigenesis and senescence initiation, and emphasize the importance of homologous recombination as a barrier against spontaneous genetic instability triggered by the endogenous oxidative/replication stress axis.}, }
@article {pmid27131451, year = {2016}, author = {Zeng, F and Sherry, JP and Bols, NC}, title = {Evaluating the toxic potential of benzothiazoles with the rainbow trout cell lines, RTgill-W1 and RTL-W1.}, journal = {Chemosphere}, volume = {155}, number = {}, pages = {308-318}, doi = {10.1016/j.chemosphere.2016.04.079}, pmid = {27131451}, issn = {1879-1298}, mesh = {Animals ; Benzothiazoles/metabolism/*toxicity ; Cell Death ; Cell Line ; Comet Assay ; DNA Damage ; Hydrazones ; Imidazoles ; Indoles ; Oncorhynchus mykiss/metabolism ; Reactive Oxygen Species/metabolism ; Toxicity Tests/*methods ; Water Pollutants, Chemical/*toxicity ; }, abstract = {Benzothiazole (BTHs) are environmental contaminants of emerging concern for which little toxicological information is available. Therefore the toxic potential of twelve BTHs was evaluated with two rainbow trout epithelial cell lines, RTgill-W1 and RTL-W1. The BTHs were benzothiazole (BTH), 3,3'-diethylthia dicarbocyanine iodide (DTDC), C.I. sulphur orange 1 (SO), 2-mercaptobenzothiazole (2MBTH), zinc 2-mercaptobenzothiazole (ZnMBTH), sodium 2-mercaptobenzothiazole (NaMBTH), 2-hydroxy-benzothiazole (OHBTH), 2- aminobenzothiazole (2ABTH), C.I. vat yellow 2 (VY), N,N-dicyclohexyl-2-benzothiazolsulfene amide (NNA), 2,2'-dithiobis (benzothiazole) (DBTH) and 2-(p-aminophenyl)-6-methylbenzothiazole-7-sulfonic acid (MBTHS). All BTHs, except for NNA, DBTH, and MBTHS, caused both cytotoxicity and a transitory elevation in reactive oxygen species (ROS) levels. Yet, neither N-acetyl cysteine (NAC) nor IM-54 inhibited cytotoxicity, suggesting that ROS imbalance did not contribute to cell death. Cell death was not blocked by Necrostatin-1 nor accompanied by DNA laddering, suggesting that neither necroptosis nor apoptosis took place. The comet assay revealed DNA strand breaks after exposures to 2ABTH and OHBTH for 1 day and to BTH for 12 days. In RTL-W1, cytochrome P4501A was induced noticeably by 2ABTH, OHBTH, and MBTHS and weakly by NaMBTH, ZnMBTH, SO, VY, and NNA, suggesting that these BTHs have the potential to alter xenobiotic metabolism and activate the aryl hydrocarbon receptor. In summary, several toxic actions were initiated in vitro by some but not all BTHs, warranting further study of these BTHs in vivo.}, }
@article {pmid27130472, year = {2017}, author = {Rodan, LH and Berry, GT}, title = {N-Acetylcysteine Therapy in an Infant with Transaldolase Deficiency Is Well Tolerated and Associated with Normalization of Alpha Fetoprotein Levels.}, journal = {JIMD reports}, volume = {31}, number = {}, pages = {73-77}, pmid = {27130472}, issn = {2192-8304}, abstract = {Transaldolase deficiency is a rare autosomal recessive disorder of the pentose phosphate pathway that presents clinically with infantile-onset hepatopathy progressing to cirrhosis, nephropathy, connective tissue abnormalities resembling cutis laxa, coagulopathy, cytopenias, and increased risk of hepatocellular carcinoma. In many cases, death occurs in infancy or early childhood. There is no established treatment for transaldolase deficiency in humans. Recent work in a knockout mouse model of transaldolase deficiency has demonstrated a benefit to supplementation with the glutathione precursor N-acetylcysteine (NAC). We describe an infant with genetically confirmed transaldolase deficiency with multisystem involvement, including liver enlargement and markedly elevated alpha fetoprotein. Acetaminophen was strictly avoided. Treatment with oral NAC over a 6-month period was well tolerated and was associated with a sustained normalization of alpha fetoprotein levels and stable clinical course. The clinical significance of normalized serum alpha fetoprotein in this patient is not certain, although it may reflect decreased hepatocyte injury and reduced hepatocarcinogenesis as has been suggested in the mouse disease model. NAC supplementation may provide benefit in humans with transaldolase deficiency. Longer follow-up and data on the response of additional patients with transaldolase deficiency to NAC supplementation will be required to further evaluate efficacy and optimize dosing.}, }
@article {pmid27129324, year = {2017}, author = {Livanos, P and Galatis, B and Quader, H and Apostolakos, P}, title = {ROS homeostasis as a prerequisite for the accomplishment of plant cytokinesis.}, journal = {Protoplasma}, volume = {254}, number = {1}, pages = {569-586}, pmid = {27129324}, issn = {1615-6102}, mesh = {*Cytokinesis ; Epitopes/metabolism ; *Homeostasis ; Membrane Fusion ; Meristem/cytology/metabolism/ultrastructure ; Plant Cells/metabolism ; Reactive Oxygen Species/*metabolism ; Transport Vesicles/metabolism ; Triticum/*cytology/*metabolism/ultrastructure ; }, abstract = {Reactive oxygen species (ROS) are emerging players in several biological processes. The present work investigates their potential involvement in plant cytokinesis by the application of reagents disturbing ROS homeostasis in root-tip cells of Triticum turgidum. In particular, the NADPH-oxidase inhibitor diphenylene iodonium, the ROS scavenger N-acetyl-cysteine, and menadione that leads to ROS overproduction were used. The effects on cytokinetic cells were examined using light, fluorescence, and transmission electron microscopy. ROS imbalance had a great impact on the cytokinetic process including the following: (a) formation of atypical "phragmoplasts" incapable of guiding vesicles to the equatorial plane, (b) inhibition of the dictyosomal and/or endosomal vesicle production that provides the developing cell plates with membranous and matrix polysaccharidic material, (c) disturbance of the fusion processes between vesicles arriving on the cell plate plane, (d) disruption of endocytic vesicle production that mediates the removal of the excess membrane material from the developing cell plate, and (e) the persistence of large callose depositions in treated cell plates. Consequently, either elevated or low ROS levels in cytokinetic root-tip cells resulted in a total inhibition of cell plate assembly or the formation of aberrant cell plates, depending on the stage of the affected cytokinetic cells. The latter failed to expand towards cell cortex and hence to give rise to complete daughter cell wall. These data revealed for the first time the necessity of ROS homeostasis for accomplishment of plant cytokinesis, since it seems to be a prerequisite for almost every aspect of this process.}, }
@article {pmid27127134, year = {2016}, author = {Kim, JK and Kang, KA and Ryu, YS and Piao, MJ and Han, X and Oh, MC and Boo, SJ and Jeong, SU and Jeong, YJ and Chae, S and Na, SY and Hyun, JW}, title = {Induction of Endoplasmic Reticulum Stress via Reactive Oxygen Species Mediated by Luteolin in Melanoma Cells.}, journal = {Anticancer research}, volume = {36}, number = {5}, pages = {2281-2289}, pmid = {27127134}, issn = {1791-7530}, mesh = {Activating Transcription Factor 6/antagonists &amp; inhibitors/genetics ; Apoptosis/drug effects ; Calcium/analysis ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/*drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Luteolin/*pharmacology ; Melanoma/*pathology ; Mitochondria/chemistry/drug effects ; Neoplasm Proteins/antagonists &amp; inhibitors/biosynthesis/genetics ; RNA, Small Interfering/genetics ; *Reactive Oxygen Species ; Staining and Labeling ; Transcription Factor CHOP/antagonists &amp; inhibitors/genetics ; Transfection ; Tumor Stem Cell Assay ; }, abstract = {BACKGROUND: This study aimed to investigate whether luteolin, a flavonoid, induces apoptosis in human melanoma cells via endoplasmic reticulum (ER) stress.<br><br>MATERIALS AND METHODS: To investigate the effects of luteolin in human melanoma cells, the anti-proliferation, apoptosis, ER stress induction and reactive oxygen species (ROS) generation were evaluated using MTT, Hoechst 33342, ER-tracker Blue White DPX and DCF-DA staining assays, respectively.<br><br>RESULTS: Luteolin inhibited cell proliferation and increased apoptotic body formation. Luteolin induced ER stress, as shown by ER staining and mitochondrial Ca(2+) overloading. Luteolin increased expression of the ER stress-related proteins; protein kinase RNA-like ER kinase, phospho eukaryotic translation initiation factor 2&#x3b1;, activating transcription factor (ATF) 6, CCAAT/enhancer-binding protein-homologous protein (CHOP), and cleaved caspase 12. Furthermore, luteolin increased the level of intracellular ROS, leading to ROS-mediated apoptosis and ER stress. However, N-acetyl cysteine, a ROS scavenger, decreased ROS levels, apoptosis, and ER stress induced by luteolin treatment. In addition, knockdown of CHOP and ATF6 by small-interfering RNA inhibited luteolin-induced cell death.<br><br>CONCLUSION: Luteolin induces apoptosis by ER stress via increasing ROS levels.}, }
@article {pmid27126918, year = {2016}, author = {Yamagata, K and Sone, N and Suguyama, S and Nabika, T}, title = {Different effects of arginine vasopressin on high-mobility group box 1 expression in astrocytes isolated from stroke-prone spontaneously hypertensive rats and congenic SHRpch1_18 rats.}, journal = {International journal of experimental pathology}, volume = {97}, number = {2}, pages = {97-106}, pmid = {27126918}, issn = {1365-2613}, mesh = {Animals ; Arginine Vasopressin/administration &amp; dosage/*pharmacology ; Astrocytes/*drug effects/metabolism ; Cell Hypoxia/physiology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; HMGB1 Protein/*biosynthesis/genetics ; Homeodomain Proteins/biosynthesis/genetics ; Hypertension/complications/metabolism/*pathology ; Rats, Inbred SHR ; Stroke/etiology/metabolism/*pathology ; Toll-Like Receptor 2/biosynthesis/genetics ; Transcription Factors/biosynthesis/genetics ; }, abstract = {Stroke-prone spontaneously hypertensive rats (SHRSP/Izm) develop severe hypertension and astrocytic oedema following ischaemic stimulation. During ischaemic stress high-mobility group box 1 (Hmgb1) expression in astrocytes is induced, and subsequently potentiates deterioration of the brain due to ischaemic injury, which manifests as both cerebral inflammation and astrocytic oedema. Arginine vasopressin (AVP) induces brain injury and increases astrocytic swelling. After stroke, Hmgb1 and peroxiredoxin (Prx) are released at different times and activate macrophages in the brain via Toll-like receptors (Tlr2s). The purpose of this study was to examine whether AVP and/or hypoxia and reoxygenation (H/R) contribute to Hmgb1 regulation following ischaemic stroke. Thus, Hmgb1, Prx2 and Tlr2 expression levels in astrocytes isolated from Wistar Kyoto rats (WKY/Izm), spontaneously hypertensive rats (SHR/Izm), SHRSP/Izm and congenic rat strain SHRpch1_18 treated with AVP and/or H/R were compared. Gene and protein expression levels were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time quantitative PCR, and Western blot. mRNA expression of Hmgb1, Prx2 and Tlr2 induced by AVP was dose-dependent, and Hmgb1 and Prx2 expression was higher in SHR/Izm, SHRSP/Izm and SHRch1_18 than in WKY/Izm. Tlr2 expression with AVP was reduced in SHR/Izm compared to WKY/Izm. In SHRpch1_18, Hmgb1 expression increased after AVP plus H/R. AVP-modulated expression of Hmgb1 protein was reduced by the addition of the antioxidant N-acetylcysteine (NAC). These results suggest that oxidative stress by AVP enhanced expression of Hmgb1, Prx2 and Tlr2 in astrocytes. We hypothesize that regulation of Hmgb1 by AVP during H/R might be related to induction of inflammation and stroke in SHRSP/Izm and SHRpch1_18 rats.}, }
@article {pmid27123164, year = {2016}, author = {Heidari, R and Esmailie, N and Azarpira, N and Najibi, A and Niknahad, H}, title = {Effect of Thiol-reducing Agents and Antioxidants on Sulfasalazine-induced Hepatic Injury in Normotermic Recirculating Isolated Perfused Rat Liver.}, journal = {Toxicological research}, volume = {32}, number = {2}, pages = {133-140}, pmid = {27123164}, issn = {1976-8257}, abstract = {Sulfasalzine is a widely administered drug against inflammatory-based disorders in human. However several cases of liver injury are associated with its administration. There is no stabilized safe protective agent against sulfasalazine-induced liver injury. Current investigation was designed to evaluate if N-acetylcysteine (NAC) and dithioteritol (DTT) as thiol reducing agents and/or vitamins C and E as antioxidants have any protective effects against sulfasalazine-induced hepatic injury in an ex vivo model of isolated rat liver. Rat liver was canulated and perfused via portal vein in a closed recirculating system. Different concentrations of sulfasalazine and/or thiol reductants and antioxidants were administered and markers of organ injury were monitored at different time intervals. It was found that 5 mM of sulfasalazine caused marked liver injury as judged by rise in liver perfusate level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) (p < 0.05). A significant amount of lipid peroxidation and hepatic glutathione depletion were detected in drug-treated livers, accompanied with significant histopathological changes of the organ. Administration of NAC (500 μM), DTT (400 μM), Vitamin C (200 μM), or vitamin E (200 μM) significantly alleviated sulfasalazine-induced hepatic injury in isolated perfused rat liver. The data obtained from current investigation indicate potential therapeutic properties of thiol reductants and antioxidants against sulfasalazine-induced liver injury.}, }
@article {pmid27122224, year = {2016}, author = {May, ER and Conklin, KA and Bemis, DA}, title = {Antibacterial effect of N-acetylcysteine on common canine otitis externa isolates.}, journal = {Veterinary dermatology}, volume = {27}, number = {3}, pages = {188-e47}, doi = {10.1111/vde.12313}, pmid = {27122224}, issn = {1365-3164}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Bacterial Agents/*therapeutic use ; Bacteria/*drug effects ; Dog Diseases/*microbiology ; Dogs ; Microbial Sensitivity Tests ; Otitis Externa/microbiology/*veterinary ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) has the potential to be a useful therapeutic agent for the treatment of otitis externa due to its antimicrobial and mucolytic properties, as well as its ability to disrupt bacterial biofilm.<br><br>HYPOTHESIS/OBJECTIVES: To determine the antibacterial activity of NAC against common bacterial isolates associated with canine otitis externa.<br><br>ANIMALS: Twenty two isolates from canine clinical cases of otitis externa were identified and tested, including five Staphylococcus pseudintermedius, six Pseudomonas aeruginosa, five Corynebacterium spp. and six &#x3b2;-haemolytic Streptococcus spp. isolates.<br><br>METHODS: Each isolate was grown on blood agar for 24&#xa0;h and transferred to Mueller Hinton Broth (MHB) to achieve a final concentration of 5&#xa0;&#xd7;&#xa0;10(5) &#xa0;CFU/mL. NAC was diluted in MHB to a starting concentration of 160 mg/mL and serial two-fold microdilution assays were performed in triplicate with negative controls for all isolates tested. Concentrations of NAC tested ranged from 0.125 to 80&#xa0;mg/mL. A 50&#xa0;&#x3bc;L volume of bacterial suspension was used to inoculate each well.<br><br>RESULTS: The minimum inhibitory concentration (MIC) of NAC for all isolates tested ranged from 5 to 20&#xa0;mg/mL.<br><br>N-Acetylcysteine inhibits clinically relevant and drug resistant bacteria in vitro, and has potential for use as a novel agent for treatment of otitis externa.}, }
@article {pmid27120594, year = {2016}, author = {Chen, SY and Liu, GH and Chao, WY and Shi, CS and Lin, CY and Lim, YP and Lu, CH and Lai, PY and Chen, HR and Lee, YR}, title = {Piperlongumine Suppresses Proliferation of Human Oral Squamous Cell Carcinoma through Cell Cycle Arrest, Apoptosis and Senescence.}, journal = {International journal of molecular sciences}, volume = {17}, number = {4}, pages = {}, pmid = {27120594}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Carcinoma, Squamous Cell/metabolism/pathology ; Caspase 3/metabolism ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Fragmentation/drug effects ; Dioxolanes/*pharmacology ; Humans ; Mouth Neoplasms/metabolism/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Oral squamous cell carcinoma (OSCC), an aggressive cancer originating in the oral cavity, is one of the leading causes of cancer deaths in males worldwide. This study investigated the antitumor activity and mechanisms of piperlongumine (PL), a natural compound isolated from Piper longum L., in human OSCC cells. The effects of PL on cell proliferation, the cell cycle, apoptosis, senescence and reactive oxygen species (ROS) levels in human OSCC cells were investigated. PL effectively inhibited cell growth, caused cell cycle arrest and induced apoptosis and senescence in OSCC cells. Moreover, PL-mediated anti-human OSCC behavior was inhibited by an ROS scavenger N-acetyl-l-cysteine (NAC) treatment, suggesting that regulation of ROS was involved in the mechanism of the anticancer activity of PL. These findings suggest that PL suppresses tumor growth by regulating the cell cycle and inducing apoptosis and senescence and is a potential chemotherapy agent for human OSCC cells.}, }
@article {pmid27120397, year = {2017}, author = {Li, S and Li, Y and Chen, G and Zhang, J and Xu, F and Wu, M}, title = {Restraining reactive oxygen species in Listeria monocytogenes promotes the apoptosis of glial cells.}, journal = {Redox report : communications in free radical research}, volume = {22}, number = {4}, pages = {190-196}, pmid = {27120397}, issn = {1743-2928}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects/genetics/*physiology ; Cell Line, Tumor ; Humans ; Listeria monocytogenes/*metabolism/physiology ; Neuroglia/*cytology/*metabolism ; Onium Compounds/pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {OBJECTIVES: Listeria monocytogenes is a facultative anaerobic foodborne pathogen that can traverse the blood-brain barrier and cause brain infection. L. monocytogenes infection induces host cell apoptosis in several cell types. In this study, we investigated the apoptosis of human glioma cell line U251 invaded by L. monocytogenes and evaluated the function of bacterial reactive oxygen species (ROS) during infection.<br><br>METHODS: Bacterial ROS level was reduced by carrying out treatment with N-acetyl cysteine (NAC) and diphenyleneiodonium chloride (DPI). After infection, the apoptosis of U251 cells was examined by flow cytometry assay and propidium iodide staining.<br><br>RESULTS: DPI and NAC efficiently decreased ROS level in L. monocytogenes without affecting bacterial growth. Moreover, the apoptosis of glial cells was enhanced upon invasion of DPI- and NAC-pretreated L. monocytogenes.<br><br>DISCUSSION: Results indicate that the apoptosis of glial cells can be induced by L. monocytogenes, and that the inhibition of bacterial ROS increases the apoptosis of host cells.}, }
@article {pmid27119348, year = {2016}, author = {Liang, L and Zhang, Z}, title = {Gambogic Acid Inhibits Malignant Melanoma Cell Proliferation Through Mitochondrial p66shc/ROS-p53/Bax-Mediated Apoptosis.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {38}, number = {4}, pages = {1618-1630}, doi = {10.1159/000443102}, pmid = {27119348}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Benzothiazoles/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; Male ; Melanoma/drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Mitochondria/*metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Src Homology 2 Domain-Containing, Transforming Protein 1/antagonists &amp; inhibitors/genetics/*metabolism ; Toluene/analogs &amp; derivatives/pharmacology ; Transplantation, Heterologous ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/*metabolism ; Xanthones/*pharmacology ; bcl-2-Associated X Protein/genetics/*metabolism ; }, abstract = {BACKGROUND/AIMS: Malignant melanoma has high metastatic potential, is highly resistant to chemotherapy, and has a poor survival rate. Gambogic acid (GA), a polyprenylated xanthone extracted from a traditional Chinese medicinal herb, has been proven to exhibit antitumor activity. The present study aimed to investigate the signaling pathways that mediated GA-induced inhibition of human malignant skin melanoma proliferation.<br><br>METHODS: The study was conducted using A375 cells and the corresponding tumor transplanted in nude mice.<br><br>RESULTS: Incubation of A375 cells with 1-10 &#x3bc;g/ml GA decreased cell viability and increased apoptosis. GA concentration-dependently increased p66shc expression and intracellular ROS levels. GA also decreased the oxygen consumption rate and the mitochondrial membrane potential (MMP) in A375 cells. Experimental inhibition of p66shc by siRNA suppressed GA-induced increase of ROS, decrease of oxygen consumption rate, MMP and cell viability, whilst suppressing GA-induced increase of apoptosis. GA concentration-dependently upregulated p53 and Bax expression in A375 cells. GA also increased p53-TA-luciferase activity and p53-binding to Bax promoter, which was inhibited by Sip53. Experimental inhibition of p53 with Sip53 blocked GA-induced decrease of the oxygen consumption rate and cell viability, and blocked the increase of apoptosis. In tumor-bearing nude mice, GA notably inhibited tumor growth, and this action was suppressed by N-acetylcysteine (NAC), a potent antioxidant, and by PFT-&#x3b1;, a p53 inhibitor. In A375 tumors transplanted in nude mice, GA increased both p66shc and p53 expression. NAC and PFT-&#x3b1; treatment did not significantly affect p66shc expression in tumors grown in mice treated with GA. In contrast, both NAC and PFT-&#x3b1; treatment inhibited GA-induced p53 expression in mouse tumors.<br><br>CONCLUSION: Results provided novel preclinical insights into the chemotherapeutic use of GA by highlighting the importance of p66shc/ROS-p53/Bax pathways in the antitumor effect of GA in malignant melanoma.}, }
@article {pmid27117852, year = {2016}, author = {Pirabbasi, E and Shahar, S and Manaf, ZA and Rajab, NF and Manap, RA}, title = {Efficacy of Ascorbic Acid (Vitamin C) and/N-Acetylcysteine (NAC) Supplementation on Nutritional and Antioxidant Status of Male Chronic Obstructive Pulmonary Disease (COPD) Patients.}, journal = {Journal of nutritional science and vitaminology}, volume = {62}, number = {1}, pages = {54-61}, doi = {10.3177/jnsv.62.54}, pmid = {27117852}, issn = {1881-7742}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Antioxidants/*administration &amp; dosage/*analysis ; Ascorbic Acid/*administration &amp; dosage ; Body Mass Index ; Dietary Carbohydrates/administration &amp; dosage ; Dietary Supplements ; Glutathione/blood ; Humans ; Malaysia ; Male ; Middle Aged ; Nutritional Status/*drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology ; Single-Blind Method ; Treatment Outcome ; Vitamin A/blood ; }, abstract = {Antioxidant therapy has a potential to be introduced as therapeutic modality for chronic obstructive pulmonary disease (COPD) patients. This study aimed to determine the effect of antioxidant supplementation [ascorbic acid and N-Acetylcysteine (NAC)] on nutritional and antioxidant status in male COPD patients. A parallel and single blind randomised controlled clinical trial (RCT) was conducted at two medical centers in Kuala Lumpur, Malaysia. Seventy-nine subjects were recruited and randomly divided into four trial arms (i.e., NAC, vitamin C, NAC+vitamin C and control groups) for six mo. The primary outcome was changes in body mass index by estimating power of 90% and significance level of p<0.05. Repeated Measure ANOVA showed that there was a significant interaction effect on BMI (p=0.046) and carbohydrate intake (p=0.030), especially in the NAC group. Plasma glutathione (GSH) increased significantly in all intervention groups, especially in vitamin C (p=0.005). A single supplementation of NAC or vitamin C improved nutritional and antioxidant status of subjects.}, }
@article {pmid27112894, year = {2016}, author = {Li, J and Liu, D and Tan, G and Zhao, Z and Yang, X and Pan, W}, title = {A comparative study on the efficiency of chitosan-N-acetylcysteine, chitosan oligosaccharides or carboxymethyl chitosan surface modified nanostructured lipid carrier for ophthalmic delivery of curcumin.}, journal = {Carbohydrate polymers}, volume = {146}, number = {}, pages = {435-444}, doi = {10.1016/j.carbpol.2016.03.079}, pmid = {27112894}, issn = {1879-1344}, mesh = {Acetylcysteine/chemistry ; Administration, Ophthalmic ; Animals ; Chitin/analogs &amp; derivatives/chemistry ; Chitosan/*analogs &amp; derivatives/chemistry ; Cornea/drug effects/*metabolism ; Curcumin/*administration &amp; dosage/pharmacokinetics ; Drug Carriers/*chemistry ; Drug Liberation ; Female ; Kinetics ; Lipids ; Male ; Nanostructures/*chemistry ; Oligosaccharides ; Particle Size ; Permeability ; Rabbits ; }, abstract = {To develop a potential nanocarrier for the topical ocular administration of curcumin (CUR), a novel thiolated chitosan was synthesized by the covalent binding between N-acetyl-l-cysteine (NAC) and chitosan (CS) to surface modify the nanostructured lipid carrier loaded CUR (CUR-NLC). And the superiorities of the CS-NAC co polymer coated CUR-NLC over chitosan oligosaccharides (COS) or carboxymethyl chitosan (CMCS) modification were also verified in detail. As expected, the increment in particle size and the reversal of zeta potential occurred after surface decorating, and the most prominent electropositivity was obtained for the CS-NAC-CUR-NLC group. Additionally, the utilization of the CS-NAC coating demonstrated an effectively controlled release over 72h and attained a 6.4 and 18.8 fold increase in apparent permeability coefficients (Papp) compared with the CUR-NLC and the self-made eye drops, respectively. Meanwhile, the clearance rate of the NLC labeled with Rhodamine B was significantly delayed in the presence of CS-NAC. By contrast, CS-NAC-CUR-NLC was superior to the COS and CMCS coated ones in view of in vitro release, drug permeability and corneal retention. Moreover, the results of the in-vivo and in-vitro characteristics demonstrated that the promoting effect of CMCS coating was relatively weaker than COS coated ones. Ocular irritation test was executed on the CS-NAC-CUR-NLC, neither a sign of toxicity nor irritation to the external ocular tissues was observed. In conclusion, CS-NAC-CUR-NLC possesses a greater potential as an ocular drug-delivery system comparing with the COS-CUR-NLC and CMCS-CUR-NLC.}, }
@article {pmid27108714, year = {2016}, author = {Cairney, DG and Beckwith, HK and Al-Hourani, K and Eddleston, M and Bateman, DN and Dear, JW}, title = {Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {54}, number = {5}, pages = {405-410}, doi = {10.3109/15563650.2016.1159309}, pmid = {27108714}, issn = {1556-9519}, mesh = {Acetaminophen/*blood/*poisoning ; Acetylcysteine/*therapeutic use ; Administration, Intravenous ; Adult ; Alanine Transaminase/blood ; Antidotes/therapeutic use ; Chemical and Drug Induced Liver Injury/*blood ; Dose-Response Relationship, Drug ; Drug Overdose/drug therapy ; Female ; Hospitalization ; Humans ; Male ; Nomograms ; Retrospective Studies ; Risk Factors ; United Kingdom ; }, abstract = {CONTEXT: Paracetamol (acetaminophen) overdose is a common reason for emergency hospital admission in the UK and the leading cause of acute liver failure in the Western world. Currently, the antidote acetylcysteine (NAC) is administered at a dose determined only by body weight without regard for the body burden of paracetamol.<br><br>OBJECTIVE: To determine whether higher plasma paracetamol concentrations are associated with increased risk of liver injury despite prompt treatment with intravenous NAC.<br><br>METHODS: Patients admitted to hospital for treatment with intravenous NAC following a single acute paracetamol overdose entered the study if NAC was commenced within 24&#x2009;h of drug ingestion (N&#x2009;=&#x2009;727 hospital presentations). Based on the plasma paracetamol concentration at first presentation to hospital, a series of nomograms were created: 0-100, 101-150, 151-200, 201-300, 301-500 and over 501&#x2009;mg/L. The primary endpoints were acute liver injury (ALI - peak serum ALT activity >150&#x2009;U/L and double the admission value) and hepatotoxicity (peak ALT&#x2009;>1000&#x2009;U/L).<br><br>RESULTS: ALI and hepatotoxicity were more common in patients with higher admission plasma paracetamol concentrations despite NAC treatment (ALI: nomogram 0-100: 6%, 101-150: 3%, 151-200: 3%, 201-300: 9%, 301-500: 13%, over 501&#x2009;mg/dL: 27%. p&#x2009;<&#x2009;0.0001). This dose-response relationship between paracetamol concentration and ALI persisted even in patients treated with NAC within 8&#x2009;h of overdose (nomogram 0-100: 0%, 101-150: 0.8%, 151-200: 2%, 201-300: 3.6%, 301-500: 12.5%, over 501mg/L: 33%. p&#x2009;<&#x2009;0.0001) and in patients with normal ALT activity at first presentation (nomogram: 0-100: 0%, 101-150: 1.2%, 151-200: 1.5%, 201-300: 5.3%, 301-500: 10.8% p&#x2009;<&#x2009;0.0001).<br><br>DISCUSSION: Patients with increased concentrations of plasma paracetamol at hospital presentation are at higher risk of liver injury even when intravenous NAC is promptly administered before there is biochemical evidence of toxicity.<br><br>CONCLUSION: This study supports theoretical concerns that the current intravenous dose of NAC may be too low in the setting of higher paracetamol exposure.}, }
@article {pmid28773431, year = {2016}, author = {Shen, YF and Ho, CC and Shie, MY and Wang, K and Fang, HY}, title = {Hinokitiol-Loaded Mesoporous Calcium Silicate Nanoparticles Induce Apoptotic Cell Death through Regulation of the Function of MDR1 in Lung Adenocarcinoma Cells.}, journal = {Materials (Basel, Switzerland)}, volume = {9}, number = {5}, pages = {}, pmid = {28773431}, issn = {1996-1944}, abstract = {Hinokitiol is a tropolone-related compound found in heartwood cupressaceous plants. Hinokitiol slows the growth of a variety of cancers through inhibition of cell proliferation. The low water solubility of hinokitiol leads to less bioavailability. This has been highlighted as a major limiting factor. In this study, mesoporous calcium silicate (MCS) nanoparticles, both pure and hinokitiol-loaded, were synthesized and their effects on A549 cells were analyzed. The results indicate that Hino-MCS nanoparticles induce apoptosis in higher concentration loads (>12.5 μg/mL) for A549 cells. Hino-MCS nanoparticles suppress gene and protein expression levels of multiple drug resistance protein 1 (MDR1). In addition, both the activity and the expression levels of caspase-3/-9 were measured in Hino-MCS nanoparticle-treated A549 cells. The Hino-MCS nanoparticles-triggered apoptosis was blocked by inhibitors of pan-caspase, caspase-3/-9, and antioxidant agents (N-acetylcysteine; NAC). The Hino-MCS nanoparticles enhance reactive oxygen species production and the protein expression levels of caspase-3/-9. Our data suggest that Hino-MCS nanoparticles trigger an intrinsic apoptotic pathway through regulating the function of MDR1 and the production of reactive oxygen species in A549 cells. Therefore, we believe that Hino-MCS nanoparticles may be efficacious in the treatment of drug-resistant human lung cancer in the future.}, }
@article {pmid27108012, year = {2016}, author = {Muramatsu, Y and Sugino, K and Ishida, F and Tatebe, J and Morita, T and Homma, S}, title = {Effect of inhaled N-acetylcysteine monotherapy on lung function and redox balance in idiopathic pulmonary fibrosis.}, journal = {Respiratory investigation}, volume = {54}, number = {3}, pages = {170-178}, doi = {10.1016/j.resinv.2015.11.004}, pmid = {27108012}, issn = {2212-5353}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Aged ; Disease Progression ; Female ; Glutathione/*metabolism ; Glutathione Disulfide/*metabolism ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/etiology/*metabolism/physiopathology ; Male ; ROC Curve ; Retrospective Studies ; *Vital Capacity ; }, abstract = {BACKGROUND: An oxidant-antioxidant imbalance is considered to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Therefore, administration of antioxidants, such as N-acetylcysteine (NAC), may represent a potential treatment option for IPF patients.<br><br>METHODS: The aim of this study was to evaluate the effect of inhaled NAC monotherapy on lung function and redox balance in patients with IPF. A retrospective observational study was done, involving 22 patients with untreated early IPF (19 men; mean [&#xb1;S.D.] age, 71.8 [&#xb1;6.3]y). At baseline and at 6 and 12 months after initiating inhaled NAC monotherapy, we assessed forced vital capacity (FVC) and measured the levels of total glutathione, oxidized glutathione (GSSG), and the ratio of reduced to oxidized glutathione in whole blood (hereafter referred to as the ratio), and of 8-hydroxy-2'-deoxyguanosine in urine. To evaluate response to treatment, we defined disease progression as a decrease in FVC of &#x2265;5% from baseline and stable disease as a decrease in FVC of <5%, over a period of 6 months.<br><br>RESULTS: Change in FVC in the stable group at 6 and 12 months were 95&#xb1;170mL and -70&#xb1;120mL, while those in the progressive group at 6 and 12 months were -210&#xb1;80mL, -320&#xb1;350mL, respectively. The serial mean change in GSSG from baseline decreased as the ratio of reduced to oxidized glutathione increased in patients with stable disease, while it increased as this ratio decreased in patients with progressive disease. Receiver operating characteristic curve analysis revealed that a baseline GSSG level of &#x2265;1.579&#x3bc;M was optimal for identifying treatment responders.<br><br>CONCLUSION: Inhaled NAC monotherapy was associated with improved redox imbalance in patients with early IPF.}, }
@article {pmid27107686, year = {2016}, author = {Yan, J and Xu, J and Fei, Y and Jiang, C and Zhu, W and Han, Y and Lu, S}, title = {TrxR2 deficiencies promote chondrogenic differentiation and induce apoptosis of chondrocytes through mitochondrial reactive oxygen species.}, journal = {Experimental cell research}, volume = {344}, number = {1}, pages = {67-75}, doi = {10.1016/j.yexcr.2016.04.014}, pmid = {27107686}, issn = {1090-2422}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; *Cell Differentiation/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chondrocytes/*cytology/drug effects/metabolism ; *Chondrogenesis/drug effects ; Humans ; Mitochondria/drug effects/*metabolism ; Reactive Oxygen Species/*metabolism ; Thioredoxin Reductase 2/*deficiency/metabolism ; }, abstract = {Thioredoxin reductase 2 (TrxR2) is a selenium (Se) containing protein. Se deficiency is associated with an endemic osteoarthropathy characterized by impaired cartilage formation. It is unclear whether TrxR2 have roles in cartilage function. We examined the effects of TrxR2 on chondrogenic ATDC5 cells through shRNA-mediated gene silencing of TrxR2. We demonstrated TrxR2 deficiencies could enhance chondrogenic differentiation and apoptosis of ATDC5 cells. TrxR2 deficiencies increased accumulation of cartilage glycosaminoglycans (GAGs) and mineralization. TrxR2 deficiencies also stimulated expression of extracellular (ECM) gene including Collagen II and Aggrecan. The enhanced chondrogenic properties were further confirmed by activation of Akt signaling which are required for chondrogenesis. In addition, TrxR2 deficiencies promoted chondrocyte proliferation through acceleration of cell cycle progression by increase in both S and G2/M phase cell distribution accompanied with induction of parathyroid hormone-related protein (PTHrP). Moreover, TrxR2 deficiencies induced chondrocyte death via apoptosis and increased cell sensitivity to exogenous oxidative stress. Furthermore, TrxR2 deficiencies induced emission of mitochondrial reactive oxygen species (ROS) without alteration of mitochondrial membrane potential and intracellular ATP content. Finally, treatment of TrxR2 deficiency cells with N-acetylcysteine (NAC) inhibited mitochondrial ROS production and chondrocyte apoptosis. NAC also prevented chondrogenic differentiation of TrxR2 deficiency cells by suppression of ECM gene expression, GAGs accumulation and mineralization, as well as attenuation of Akt signaling. Thus, TrxR2-mediated mitochondrial integrity is indispensable for chondrogenic differentiation of ATDC5 cells. TrxR2 deficiency-induced impaired proliferation and death of chondrocytes may be the pathological mechanism of the osteoarthropathy due to Se deficiency. Notably, this study also uncover the roles of mitochondrial ROS which could stimulate cartilage ECM synthesis that offer novel insights for development of therapeutic agent to prevent cartilage degeneration in human disease.}, }
@article {pmid27106722, year = {2016}, author = {Flores-López, LA and Martínez-Hernández, MG and Viedma-Rodríguez, R and Díaz-Flores, M and Baiza-Gutman, LA}, title = {High glucose and insulin enhance uPA expression, ROS formation and invasiveness in breast cancer-derived cells.}, journal = {Cellular oncology (Dordrecht)}, volume = {39}, number = {4}, pages = {365-378}, pmid = {27106722}, issn = {2211-3436}, mesh = {Blotting, Western ; Breast Neoplasms/*pathology ; Cell Line, Tumor ; Cell Movement/drug effects/physiology ; Cell Proliferation/drug effects/physiology ; Epithelial-Mesenchymal Transition/drug effects/physiology ; Female ; Glucose/*pharmacology ; Humans ; Hyperglycemia/physiopathology ; Hyperinsulinism/physiopathology ; Insulin/*pharmacology ; Neoplasm Invasiveness/*pathology/physiopathology ; Polymerase Chain Reaction ; Reactive Oxygen Species/*metabolism ; Urokinase-Type Plasminogen Activator/*biosynthesis ; }, abstract = {BACKGROUND: Accumulating evidence indicates that type 2 diabetes is associated with an increased risk to develop breast cancer. This risk has been attributed to hyperglycemia, hyperinsulinemia and chronic inflammation. As yet, however, the mechanisms underlying this association are poorly understood. Here, we studied the effect of high glucose and insulin on breast cancer-derived cell proliferation, migration, epithelial-mesenchymal transition (EMT) and invasiveness, as well as its relationship to reactive oxygen species (ROS) production and the plasminogen activation system.<br><br>METHODS: MDA-MB-231 cell proliferation, migration and invasion were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), scratch-wound and matrigel transwell assays, respectively. ROS production was determined using 2' 7'-dichlorodihydrofluorescein diacetate. The expression of E-cadherin, vimentin, fibronectin, urokinase plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1) were assessed using qRT-PCR and/or Western blotting assays, respectively. uPA activity was determined using gel zymography.<br><br>RESULTS: We found that high glucose stimulated MDA-MB-231 cell proliferation, migration and invasion, together with an increased expression of mesenchymal markers (i.e., vimentin and fibronectin). These effects were further enhanced by the simultaneous administration of insulin. In both cases, the invasion and growth responses were found to be associated with an increased expression of uPA, uPAR and PAI-1, as well as an increase in active uPA. An osmolality effect of high glucose was excluded by using mannitol at an equimolar concentration. We also found that all changes induced by high glucose and insulin were attenuated by the anti-oxidant N-acetylcysteine (NAC) and, thus, depended on ROS production.<br><br>CONCLUSIONS: From our data we conclude that hyperglycemia and hyperinsulinemia can promote breast cancer cell proliferation, migration and invasion. We found that these features were associated with increased expression of the mesenchymal markers vimentin and fibronectin, as well as increased uPA expression and activation through a mechanism mediated by ROS.}, }
@article {pmid27106530, year = {2016}, author = {Ma, G and Luo, W and Lu, J and Ma, DL and Leung, CH and Wang, Y and Chen, X}, title = {Cucurbitacin E induces caspase-dependent apoptosis and protective autophagy mediated by ROS in lung cancer cells.}, journal = {Chemico-biological interactions}, volume = {253}, number = {}, pages = {1-9}, doi = {10.1016/j.cbi.2016.04.028}, pmid = {27106530}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chloroquine/toxicity ; Drug Synergism ; Humans ; Lung Neoplasms/metabolism/pathology ; Macrolides/toxicity ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Triterpenes/*toxicity ; }, abstract = {Cucurbitacin E (CuE) is a triterpenoid with potent anticancer activities while the underlying mechanisms remain elusive. In the present study, the anticancer effects of CuE on 95D lung cancer cells were investigated. CuE decreased cell viability, inhibited colony formation, and increased reactive oxygen species (ROS) in a concentration-dependent manner, which were reversed by N-acetyl-l-cysteine (NAC). CuE induced apoptosis as determined by JC-1 staining, expression of Bcl-2 family proteins, cleavage of caspases, and TUNEL staining. NAC and Ac-DEVD-CHO partially reversed CuE-induced cleavage of caspase-3, caspase-7, and PARP. Furthermore, CuE caused accumulation of autophagic vacuoles and concentration- and time-dependent expression of LC3II protein. Autophagy inhibitors chloroquine and bafilomycin A1 enhanced CuE-induced LC3II expression and cell death. CuE-triggered protein expression of p-AKT, p-mTOR, Beclin-1, and p-ULK1 was partially reversed by NAC pretreatment. In addition, CuE treatment damaged F-actin without affecting β-tubulin as confirmed by immunofluorescence. In conclusion, CuE induced ROS-dependent apoptosis through Bcl-2 family and caspases in 95D lung cancer cells. Furthermore, CuE induced protective autophagy mediated by ROS through AKT/mTOR pathway. This study provides novel roles of ROS in the anticancer effect of CuE.}, }
@article {pmid27106252, year = {2017}, author = {Kanbay, M and Solak, Y and Afsar, B and Nistor, I and Aslan, G and Çağlayan, OH and Aykanat, A and Donciu, MD and Lanaspa, MA and Ejaz, AA and Johnson, RJ and Covic, A}, title = {Serum Uric Acid and Risk for Acute Kidney Injury Following Contrast.}, journal = {Angiology}, volume = {68}, number = {2}, pages = {132-144}, doi = {10.1177/0003319716644395}, pmid = {27106252}, issn = {1940-1574}, mesh = {Acute Kidney Injury/*blood/*chemically induced/epidemiology ; Biomarkers/*blood ; Clinical Trials as Topic ; Contrast Media/adverse effects ; Humans ; Risk Factors ; Uric Acid/*blood ; }, abstract = {Contrast-induced acute kidney injury (CI-AKI) is a common cause of hospital-acquired acute kidney injury (AKI). We evaluated the evidence that uric acid (UA) plays a pathogenic role in CI-AKI. Ten studies were eligible for inclusion for meta-analysis. Hyperuricemia predicted risk for cases with AKI in prospective cohort studies. Higher levels of serum UA (SUA), as defined by the authors, were associated with a 2-fold increased risk to develop AKI (pooled odds ratio 2.03; 95% confidence interval [CI] 1.48-2.78). Significant heterogeneity was found in cohort studies (P = .001, I[2] = 85.7%). In 2 clinical trials, lowering of SUA with saline hydration was significantly associated with reduced risk for AKI compared with saline hydration alone or saline hydration with N-acetyl cysteine. An analysis of 2 randomized controlled trials found that allopurinol with saline hydration had a significant protective effect on renal function (assessed by serum creatinine values) compared with hydration alone (mean difference: -0.52 mg/dL; 95% CI: -0.81 to -0.22). Hyperuricemia independently predicts CI-AKI. Two clinical trials suggest lowering SUA may prevent CI-AKI. The mechanism by which UA induces CI-AKI is likely related to acute uricosuria.}, }
@article {pmid27103982, year = {2016}, author = {Wink, LK and Adams, R and Wang, Z and Klaunig, JE and Plawecki, MH and Posey, DJ and McDougle, CJ and Erickson, CA}, title = {A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder.}, journal = {Molecular autism}, volume = {7}, number = {}, pages = {26}, pmid = {27103982}, issn = {2040-2392}, support = {UL1 TR001425/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Administration, Oral ; Autism Spectrum Disorder/*drug therapy ; Child ; Child, Preschool ; Comet Assay ; DNA Damage/drug effects ; Double-Blind Method ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Free Radical Scavengers/pharmacology/therapeutic use ; Glutathione/blood ; Homocysteine/blood ; Humans ; Male ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Pilot Projects ; Placebo Effect ; Social Behavior ; }, abstract = {BACKGROUND: Social impairment is a defining feature of autism spectrum disorder (ASD) with no demonstrated effective pharmacologic treatments. The goal of this study was to evaluate efficacy, safety, and tolerability of oral N-acetylcysteine (NAC), an antioxidant whose function overlaps with proposed mechanisms of ASD pathophysiology, targeting core social impairment in youth with ASD.<br><br>METHODS: This study was a 12-week randomized, double-blind, placebo-controlled trial of oral NAC in youth with ASD. Study participants were medically healthy youth age 4 to 12 years with ASD, weighing &#x2265;15 kg, and judged to be moderately ill based on the Clinical Global Impressions Severity scale. The participants were randomized via computer to active drug or placebo in a 1:1 ratio, with the target dose of NAC being 60 mg/kg/day in three divided doses. The primary outcome measure of efficacy was the Clinical Global Impressions Improvement (CGI-I) scale anchored to core social impairment. To investigate the impact of NAC on oxidative stress markers in peripheral blood, venous blood samples were collected at screen and week 12.<br><br>RESULTS: Thirty-one patients were enrolled (NAC = 16, placebo = 15). Three participants were lost to follow-up, and three left the trial due to adverse effects. The average daily dose of NAC at week 12 was 56.2 mg/kg (SD = 9.7) with dose ranging from 33.6 to 64.3 mg/kg. The frequency of adverse events was so low that comparisons between groups could not be conducted. At week 12, there was no statistically significant difference between the NAC and placebo groups on the CGI-I (p > 0.69) but the glutathione (GSH) level in blood was significantly higher in the NAC group (p < 0.05). The oxidative glutathione disulfide (GSSG) level increased in the NAC group, however only at a trend level of significance (p = 0.09). There was no significant difference between the NAC and placebo groups in the GSH/GSSG ratio, DNA strand break and oxidative damage, and blood homocysteine levels at week 12 (ps > 0.16).<br><br>CONCLUSIONS: The results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov NCT00453180.}, }
@article {pmid27103516, year = {2016}, author = {Rajagopal, S and Deb, I and Poddar, R and Paul, S}, title = {Aging is associated with dimerization and inactivation of the brain-enriched tyrosine phosphatase STEP.}, journal = {Neurobiology of aging}, volume = {41}, number = {}, pages = {25-38}, pmid = {27103516}, issn = {1558-1497}, support = {R01 NS083914/NS/NINDS NIH HHS/United States ; R21 NS065343/NS/NINDS NIH HHS/United States ; NS059962/NS/NINDS NIH HHS/United States ; R01 NS059962/NS/NINDS NIH HHS/United States ; NS083914/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aging/*genetics/*metabolism ; Animals ; Antioxidants/pharmacology ; Brain/enzymology/metabolism ; Cells, Cultured ; Enzyme Activation ; Glutamates/physiology ; Glutathione/metabolism ; Nervous System Diseases/*etiology ; Neuroprotection ; Oxidative Stress/physiology ; *Protein Multimerization ; Protein Tyrosine Phosphatases, Non-Receptor/metabolism/*physiology ; Rats, Sprague-Dawley ; Synaptic Transmission/genetics ; }, abstract = {The STriatal-Enriched tyrosine Phosphatase (STEP) is involved in the etiology of several age-associated neurologic disorders linked to oxidative stress and is also known to play a role in neuroprotection by modulating glutamatergic transmission. However, the possible effect of aging on STEP level and activity in the brain is still unclear. In this study, using young (1 month), adult (4 months), and aged (18 months) rats, we show that aging is associated with increase in dimerization and loss of activity of STEP. Increased dimerization of STEP is primarily observed in the cortex and hippocampus and is associated with depletion of both reduced and total glutathione levels, suggesting an increase in oxidative stress. Consistent with this interpretation, studies in cell culture models of glutathione depletion and oxidative stress also demonstrate formation of dimers and higher order oligomers of STEP that involve intermolecular disulfide bond formation between multiple cysteine residues. Conversely, administration of N-acetyl cysteine, a major antioxidant that enhances glutathione biosynthesis, attenuates STEP dimerization both in the cortex and hippocampus. The findings indicate that loss of this intrinsic protective response pathway with age-dependent increase in oxidative stress may be a contributing factor for the susceptibility of the brain to age-associated neurologic disorders.}, }
@article {pmid27103328, year = {2016}, author = {Song, SE and Jo, HJ and Kim, YW and Cho, YJ and Kim, JR and Park, SY}, title = {Delphinidin prevents high glucose-induced cell proliferation and collagen synthesis by inhibition of NOX-1 and mitochondrial superoxide in mesangial cells.}, journal = {Journal of pharmacological sciences}, volume = {130}, number = {4}, pages = {235-243}, doi = {10.1016/j.jphs.2016.03.005}, pmid = {27103328}, issn = {1347-8648}, mesh = {Animals ; Anthocyanins/*pharmacology ; Cell Proliferation/*drug effects ; Cells, Cultured ; Collagen/*biosynthesis ; Dose-Response Relationship, Drug ; Glucose/antagonists &amp; inhibitors/*pharmacology ; MAP Kinase Signaling System/drug effects ; Mesangial Cells/cytology/*metabolism ; Mice ; Mitochondria/*metabolism ; NADH, NADPH Oxidoreductases/antagonists &amp; inhibitors/*metabolism ; NADPH Oxidase 1 ; Reactive Oxygen Species/metabolism ; Superoxides/*antagonists &amp; inhibitors ; Up-Regulation/drug effects ; }, abstract = {This study examined the effect of delphinidin on high glucose-induced cell proliferation and collagen synthesis in mesangial cells. Glucose dose-dependently (5.6-25 mM) increased cell proliferation and collagen I and IV mRNA levels, whereas pretreatment with delphinidin (50 μM) prevented cell proliferation and the increased collagen mRNA levels induced by high glucose (25 mM). High glucose increased reactive oxygen species (ROS) generation, and this was suppressed by pretreating delphinidin or the antioxidant N-acetyl cysteine. NADPH oxidase (NOX) 1 was upregulated by high glucose, but pretreatment with delphinidin abrogated this upregulation. Increased mitochondrial superoxide by 25 mM glucose was also suppressed by delphinidin. The NOX inhibitor apocynin and mitochondria-targeted antioxidant Mito TEMPO inhibited ROS generation and cell proliferation induced by high glucose. Phosphorylation of extracellular signal regulated kinase (ERK)1/2 was increased by high glucose, which was suppressed by delphinidin, apocynin or Mito TEMPO. Furthermore, PD98059 (an ERK1/2 inhibitor) prevented the high glucose-induced cell proliferation and increased collagen mRNA levels. Transforming growth factor (TGF)-β protein levels were elevated by high glucose, and pretreatment with delphinidin or PD98059 prevented this augmentation. These results suggest that delphinidin prevents high glucose-induced cell proliferation and collagen synthesis by inhibition of NOX-1 and mitochondrial superoxide in mesangial cells.}, }
@article {pmid27102930, year = {2016}, author = {Siddiqui, MR and Wabaidur, SM and Ola, MS and AlOthman, ZA and Rafiquee, MZ and Khan, MA}, title = {High-Throughput UPLC-MS Method for the Determination of N-Acetyl-l-Cysteine: Application in Tissue Distribution Study in Wistar Rats.}, journal = {Journal of chromatographic science}, volume = {54}, number = {7}, pages = {1244-1252}, doi = {10.1093/chromsci/bmw060}, pmid = {27102930}, issn = {1945-239X}, mesh = {Acetylcysteine/*blood/pharmacokinetics ; Animals ; Antioxidants/*metabolism/pharmacokinetics ; Chromatography, High Pressure Liquid/methods/*standards ; Injections, Intraperitoneal ; Kidney/metabolism ; Limit of Detection ; Liver/metabolism ; Lung/metabolism ; Male ; Myocardium/metabolism ; Rats ; Rats, Wistar ; Reproducibility of Results ; Spleen/metabolism ; Tandem Mass Spectrometry/methods/*standards ; Tissue Distribution ; }, abstract = {N-Acetylcysteine (NAC) is the N-acetyl derivative of the amino acid l-cysteine and is extensively used as a medicine to treat a variety of diseases. High-throughput ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) method has been developed for the quantitative assessment of N-acetyl-l-cysteine. The method was further applied to study the distribution of the intraperitoneal injected drug into different tissues and plasma of Wistar rats, including liver, kidney, heart, lungs and spleen. The drug was having highest concentration in plasma and liver followed by kidney, lungs, heart and spleen. Method validation studies suggested being linear in the range of 1-15 µg mL(-1) for liver, kidney, heart, lungs and spleen and 1-120 µg mL(-1) for the plasma. The limit of detection and limit of quantitation were found to be 0.20 and 0.66 µg mL(-1), respectively. The recovery studies suggested that in all the cases, the obtained recovery was in the range of 98.51-101.88%. Our analyses provide a validated UPLC-MS method for the determination of NAC and its successful application for the analysis in plasma and tissues obtained from Wistar rats.}, }
@article {pmid27102814, year = {2016}, author = {Hu, Z and Lv, G and Li, Y and Li, E and Li, H and Zhou, Q and Yang, B and Cao, W}, title = {Enhancement of anti-tumor effects of 5-fluorouracil on hepatocellular carcinoma by low-intensity ultrasound.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {35}, number = {}, pages = {71}, pmid = {27102814}, issn = {1756-9966}, mesh = {Animals ; Antimetabolites, Antineoplastic/*administration &amp; dosage/pharmacology ; Carcinoma, Hepatocellular/metabolism/*therapy ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Combined Modality Therapy ; Down-Regulation ; Fluorouracil/*administration &amp; dosage/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/metabolism/*therapy ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Reactive Oxygen Species/metabolism ; Treatment Outcome ; Ultrasonic Therapy/*methods ; Up-Regulation ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND: Hepatocellular carcinoma (HCC) accounts for 75% of liver cancers and is the second most lethal cancer, associated with its multiple etiologies, poor prognosis and resistance to chemotherapy drugs. Chemotherapy treatment on HCC suffers low efficacy of drug uptake and can produce a range of side effects. Here we report an investigation on the effect of a combined treatment on human hepatocellular carcinoma BEL-7402 cells using low-intensity ultrasound (US) and 5-fluorouracil (5-FU).<br><br>METHODS: The uptake of 5-FU was measured by the high-performance liquid chromatography (HPLC). DNA damage was detected by the comet assay. MTT assay was used to examine cell viability. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (&#x394;&#x3c8;m) were respectively detected by the fluorescent probes DCFH-DA or JC-1. Endogenous apoptosis-associated proteins were analyzed by the western blot and immunohistochemistry. Histopathological changes were evaluated by the hematoxylin and eosin (H&amp;E) staining. Cell apoptosis was evaluated by the TUNEL and flow cytometry assays. Cell proliferation was measured using the immunohistochemical staining of PCNA.<br><br>RESULTS: Our results showed that low-intensity US (1.1 MHz, 1.0 W/cm2, 10% duty cycle) significantly enhanced the uptake of 5-FU, 5-FU-mediated DNA damage and reactive oxygen species (ROS) generation. The increased ROS production up-regulated the p53 protein level, which led to the up-regulation of Bax and down-regulation of Bcl-2. The enhancement of ROS generation and the activation of the apoptosis-associated proteins further triggered the collapse of mitochondrial membrane potential, released cytochrome c from mitochondria into cytosol and activated the mitochondria-caspase pathway, and cell apoptosis. Such enhanced effects could be partially blocked by the ROS scavenger N-acetylcysteine (NAC). Overall, low-intensity US combined with 5-FU led to an effective inhibition of tumor growth and prolonged overall survival of BEL-7402 HCC-bearing nude mice by more than 15% compared with 5-FU treatment alone.<br><br>CONCLUSIONS: Our results showed that low-intensity ultrasound combined with 5-FU produced much enhanced synergistic anti-tumor effects via enhanced ROS production in treating HCC.}, }
@article {pmid27102435, year = {2016}, author = {Zhang, X and Wang, YN and Zhu, JJ and Liu, XX and You, H and Gong, MY and Zou, M and Cheng, WH and Zhu, JH}, title = {N-acetylcysteine negatively regulates Notch3 and its malignant signaling.}, journal = {Oncotarget}, volume = {7}, number = {21}, pages = {30855-30866}, pmid = {27102435}, issn = {1949-2553}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Amyloid Precursor Protein Secretases/metabolism ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Catalase/metabolism ; Cell Cycle Proteins/metabolism ; Down-Regulation ; Gene Knockdown Techniques ; Glutathione/metabolism ; HeLa Cells ; Humans ; Lysosomes/*metabolism ; MCF-7 Cells ; Neoplasms/drug therapy ; Proteasome Endopeptidase Complex/metabolism ; Protein Domains ; RNA Interference ; RNA, Messenger/metabolism ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; Receptor, Notch1/metabolism ; Receptor, Notch3/genetics/*metabolism ; Signal Transduction/*drug effects ; Superoxide Dismutase/metabolism ; Transcription Factor HES-1/metabolism ; }, abstract = {Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors.}, }
@article {pmid27097965, year = {2016}, author = {Huang, D and Fang, F and Xu, F}, title = {Hyperoxia induces inflammation and regulates cytokine production in alveolar epithelium through TLR2/4-NF-κB-dependent mechanism.}, journal = {European review for medical and pharmacological sciences}, volume = {20}, number = {7}, pages = {1399-1410}, pmid = {27097965}, issn = {2284-0729}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cytokines/analysis/*metabolism ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; *Hyperoxia ; *Inflammation ; NF-kappa B/*metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Respiratory Mucosa/drug effects/metabolism ; Toll-Like Receptor 2/genetics/*metabolism ; Toll-Like Receptor 4/genetics/*metabolism ; }, abstract = {OBJECTIVE: It has been reported that inflammation of lung could be induced by proinflammatory factor under hyperoxia, which may be attributed by increasing generation of reactive oxygen species (ROS).<br><br>MATERIALS AND METHODS: In the present study, with human epithelial lung cancer cell line A549 treated with hyperoxia as in vitro model, we found that hyperoxia stimulation induced TLR2/4 activity in A549 cells. ROS inhibitor NAC was used to investigate the role of ROS in hyperoxia-induced inflammatory cytokines secretion.<br><br>RESULTS: Results of mRNA to protein level showed that elevated TLR2/4 activity and hyperoxia-induced inflammatory cytokines secretion could be significantly attenuated by NAC. EMSA results showed the activation of nuclear factor-&#x3ba;B (NF-&#x3ba;B) increased after 2-h hyperoxia stimulation, and the ROS inhibitor blocked TLR2/4 and NF-&#x3ba;B activity.<br><br>CONCLUSIONS: Data suggested that the TLR2/4-NF-&#x3ba;B pathway is involved in hyperoxia-induced inflammatory cytokines secretion in A549 human type II alveolar epithelial cells.}, }
@article {pmid27096074, year = {2016}, author = {Li, L and Li, M and Li, Y and Sun, W and Wang, Y and Bai, S and Li, H and Wu, B and Yang, G and Wang, R and Wu, L and Li, H and Xu, C}, title = {Exogenous H2S contributes to recovery of ischemic post-conditioning-induced cardioprotection by decrease of ROS level via down-regulation of NF-κB and JAK2-STAT3 pathways in the aging cardiomyocytes.}, journal = {Cell &amp; bioscience}, volume = {6}, number = {}, pages = {26}, pmid = {27096074}, issn = {2045-3701}, abstract = {BACKGROUND: Hydrogen sulfide (H2S), a third member of gasotransmitter family along with nitric oxide and carbon monoxide, generated from mainly catalyzed by cystathionine-lyase, possesses important functions in the cardiovascular system. Ischemic post-conditioning (PC) strongly protects against the hypoxia/reoxygenation (H/R)-induced injury and apoptosis of cardiomyocytes. However, PC protection is ineffective in the aging cardiomyocytes. Whether H2S restores PC-induced cardioprotection by decrease of reactive oxygen species (ROS) level in the aging cardiomyocytes is unknown.<br><br>METHODS: The aging cardiomyocytes were induced by treatment of primary cultures of neonatal cardiomyocytes using d-galactose and were exposed to H/R and PC protocols. Cell viability was observed by CCK-8 kit. Apoptosis was detected by Hoechst 33342 staining and flow cytometry. ROS level was analyzed using spectrofluorimeter. Related protein expressions were detected through Western blot.<br><br>RESULTS: Treatment of NaHS (a H2S donor) protected against H/R-induced apoptosis, cell damage, the expression of cleaved caspase-3 and cleaved caspase-9, the release of cytochrome c (Cyt c). The supplementation of NaHS also decreased the activity of LDH and CK, MDA contents, ROS levels and the phosphorylation of I&#x3ba;B&#x3b1;, NF-&#x3ba;B, JNK2 and STAT3, and increased cell viability, the expression of Bcl-2, the activity of SOD, CAT and GSH-PX. PC alone did not provide cardioprotection in H/R-treated aging cardiomyocytes, which was significantly restored by the addition of NaHS. The beneficial role of NaHS was similar to the supply of N-acetyl-cysteine (NAC, an inhibitor of ROS), Ammonium pyrrolidinedithiocarbamate (PDTC, an inhibitor of NF-&#x3ba;B) and AG 490 (an inhibitor of JNK2), respectively, during PC.<br><br>CONCLUSION: Our results suggest that exogenous H2S contributes to recovery of PC-induced cardioprotection by decrease of ROS level via down-regulation of NF-&#x3ba;B and JAK2/STAT3 pathways in the aging cardiomyocytes.}, }
@article {pmid27094558, year = {2016}, author = {Donadon, M and Molinari, AF and Corazzi, F and Rocchi, L and Zito, P and Cimino, M and Costa, G and Raimondi, F and Torzilli, G}, title = {Pharmacological Modulation of Ischemic-Reperfusion Injury during Pringle Maneuver in Hepatic Surgery. A Prospective Randomized Pilot Study.}, journal = {World journal of surgery}, volume = {40}, number = {9}, pages = {2202-2212}, pmid = {27094558}, issn = {1432-2323}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Alanine Transaminase/blood ; Bilirubin/blood ; Double-Blind Method ; Female ; Free Radical Scavengers ; Glucocorticoids ; Hepatectomy/*methods ; Humans ; Liver Function Tests ; Liver Neoplasms/surgery ; Male ; Methylprednisolone/*therapeutic use ; Middle Aged ; Pilot Projects ; Prospective Studies ; Reperfusion Injury/etiology/*prevention &amp; control ; Surgical Instruments ; *Tourniquets ; Young Adult ; }, abstract = {BACKGROUND: The Pringle maneuver, which is performed during liver surgery to reduce blood loss, may result in liver ischemia/reperfusion injury resulting in metabolic, immunological, and microvascular changes, which may lead to hepatocellular damage. The aim of this study was the investigation of the effects of N-acetylcysteine (NAC) and methylprednisolone (MET) in the modulation of liver warm ischemia during hepatic resection.<br><br>METHODS: Forty-eight patients were enrolled in a pilot double-blind, randomized clinical trial. The patients received either NAC, MET, or placebo. The primary endpoint was the reduction in postoperative alanine aminotransferase and bilirubin. The secondary endpoint was the difference in morbidity and mortality.<br><br>RESULTS: All the 48 patients had liver resection with no mortality. Morbidity was observed in 8 (16&#xa0;%) patients equally distributed among the groups. There was a significant favorable recovery of liver function tests in patients treated with NAC or MET compared with the placebo when the Pringle maneuver exceeded 70&#xa0;min.<br><br>CONCLUSIONS: The administration of NAC or MET prior to the Pringle maneuver during hepatic resection is associated with lower postoperative aberration in liver function tests compared with placebo when the Pringle maneuver exceeded 70&#xa0;min. Larger studies are required to validate our findings and to investigate the specific role of NAC and MET in liver surgery.}, }
@article {pmid27087133, year = {2016}, author = {Costa, M and Bernardi, J and Fiuza, T and Costa, L and Brandão, R and Pereira, ME}, title = {N-acetylcysteine protects memory decline induced by streptozotocin in mice.}, journal = {Chemico-biological interactions}, volume = {253}, number = {}, pages = {10-17}, doi = {10.1016/j.cbi.2016.04.026}, pmid = {27087133}, issn = {1872-7786}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/*pharmacology ; Alzheimer Disease/chemically induced/metabolism/pathology ; Animals ; Butyrylcholinesterase/metabolism ; Cerebral Cortex/drug effects/enzymology ; Energy Metabolism/drug effects ; Hippocampus/drug effects/enzymology ; Male ; Maze Learning/drug effects ; Memory/*drug effects ; Mice ; Neuroprotective Agents/*pharmacology ; Streptozocin/*toxicity ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment, associated with a reduced concentration of acetylcholine (ACh) in brain cortex and hippocampus. Recently we reported that the N-acetylcysteine (NAC) decreases brain acetylcholinesterase (AChE) activity in vitro. Thus, the aim of the current study was to investigate the effect of NAC against streptozotocin (STZ) induced AD in mice. Mice were divided into four groups: I) Sham, II) NAC, III) STZ and IV) NAC + STZ. Animals were daily treated with NAC (50 mg/kg/day, p.o.) for nine consecutive days and with STZ (2.5 mg/kg i.c.v.) at the first and third days. Step down passive avoidance (SDPA, days 7-8) and Morris water maze (MWM, days 6-9) task were assessed to evaluate learning and memory. On the tenth day animals were euthanized for AChE and butyrylcholinesterase (BChE) activities and ACh, energy-rich phosphate and brain glucose uptake levels evaluations. A learning and memory impairment was observed in SDPA and MWM in those animals that receive STZ. Nevertheless, the same was not observed in those animals that also received NAC. Brain cortex and hippocampus AChE and hippocampus BChE activities increase induced by STZ were also prevented by NAC treatment. The STZ induced a brain energy metabolism imbalance, decreasing adenosine triphosphate and increasing adenosine levels. The glucose uptake decrease in hippocampus was prevented by NAC. In conclusion, NAC treatment prevented the cognitive disturbance, by restoring the cholinergic system and brain energy metabolism disorders. NAC could modulate cholinergic imbalance without causing any changes per se in the same.}, }
@article {pmid27085456, year = {2016}, author = {Suha, T and Asli, M and Aynur, S and Yunus, K and Ahmet, M and Selim, D and Esin, Y and Ozgur, T and Ari, NS and Süleyman, T}, title = {Effects of N-acetylcysteine and ethyl pyruvate on ischemia-reperfusion injury in experimental electrical burn model.}, journal = {The American journal of emergency medicine}, volume = {34}, number = {7}, pages = {1217-1224}, doi = {10.1016/j.ajem.2016.03.032}, pmid = {27085456}, issn = {1532-8171}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Burns, Electric/*complications/pathology ; Disease Models, Animal ; Female ; Free Radical Scavengers/*therapeutic use ; Male ; Pyruvates/*therapeutic use ; Rats ; Rats, Wistar ; Reperfusion Injury/pathology/*prevention &amp; control ; }, abstract = {OBJECTIVES: This study was planned as a histopathologic evaluation of the effectiveness of ethyl pyruvate (EP) and N-acetylcysteine (NAC) in reducing electric burn-related organ damage in an experimental model.<br><br>METHODS: Four groups of 7 female Wister rats were established. The first was a sham group, the second an electrical burn control group receiving 600 V, the third group received NAC therapy of 20 mg/kg 1 hour after 600 V electrical burn, and the fourth group received 50 mg/kg EP 1 hour after 600 V electrical burn. Heart, kidney, striated muscle, brain, and lung tissues obtained 24 hours postprocedurally were subjected to histopathologic examination, and injury scores were determined. The values determined were then subjected to statistical analysis.<br><br>RESULTS: Electrical fire caused significant damage in heart, striated muscle, kidney, and brain tissues. A statistically significant decrease in injury scores in total striated muscle and heart tissue was observed in the 2 treatment groups administered NAC or EP compared to the control group (P= .001). Total kidney injury scores among the groups were significantly lower in the NAC and EP groups compared to the control group (P= .002 and P= .001, respectively). Brain injury examination revealed a significant decrease in injury scores with NAC and EP therapy, both antioxidant agents, in terms of neuron degeneration (P= .004 and P= .001, respectively).<br><br>CONCLUSIONS: Electrical burn was observed to cause injury in heart, striated muscle, kidney, and brain tissue. This injury was reduced by the administration of NAC and EP.}, }
@article {pmid27084536, year = {2016}, author = {Ashour, AE and Ahmed, AF and Kumar, A and Zoheir, KM and Aboul-Soud, MA and Ahmad, SF and Attia, SM and Abd-Allah, AR and Cheryan, VT and Rishi, AK}, title = {Thymoquinone inhibits growth of human medulloblastoma cells by inducing oxidative stress and caspase-dependent apoptosis while suppressing NF-κB signaling and IL-8 expression.}, journal = {Molecular and cellular biochemistry}, volume = {416}, number = {1-2}, pages = {141-155}, pmid = {27084536}, issn = {1573-4919}, mesh = {Apoptosis/*drug effects ; Benzoquinones/*pharmacology ; Caspases/genetics/*metabolism ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/*drug effects/genetics ; Humans ; Interleukin-8/*biosynthesis/genetics ; Medulloblastoma/genetics/*metabolism/pathology ; NF-kappa B/genetics/*metabolism ; Neoplasm Proteins/genetics/*metabolism ; Oxidative Stress/*drug effects ; Signal Transduction/*drug effects/genetics ; }, abstract = {Medulloblastoma (MB) is the most common malignant brain tumor of childhood. The transcription factor NF-κB is overexpressed in human MB and is a critical factor for MB tumor growth. NF-κB is known to regulate the expression of interleukin-8 (IL-8), the chemokine that enhances cancer cell growth and resistance to chemotherapy. We have recently shown that thymoquinone (TQ) suppresses growth of hepatocellular carcinoma cells in part by inhibiting NF-κB signaling. Here we sought to extend these studies in MB cells and show that TQ suppresses growth of MB cells in a dose- and time-dependent manner, causes G2M cell cycle arrest, and induces apoptosis. TQ significantly increased generation of reactive oxygen species (ROS), while pretreatment of MB cells with the ROS scavenger N-acetylcysteine (NAC) abrogated TQ-induced cell death and apoptosis, suggesting that TQ-induced cell death and apoptosis are oxidative stress-mediated. TQ inhibitory effects were associated with inhibition of NF-κB and altered expression of its downstream effectors IL-8 and its receptors, the anti-apoptotic Bcl-2, Bcl-xL, X-IAP, and FLIP, as well as the pro-apoptotic TRAIL-R1, caspase-8, caspase-9, Bcl-xS, and cytochrome c. TQ-triggered apoptosis was substantiated by up-regulation of the executioner caspase-3 and caspase-7, as well as cleavage of the death substrate poly(ADP-ribose)polymerase. Interestingly, pretreatment of MB cells with NAC or the pan-caspase inhibitor zVAD-fmk abrogated TQ-induced apoptosis, loss of cyclin B1 and NF-κB activity, suggesting that these TQ-mediated effects are oxidative stress- and caspase-dependent. These findings reveal that TQ induces both extrinsic and intrinsic pathways of apoptosis in MB cells, and suggest its potential usefulness in the treatment of MB.}, }
@article {pmid27084465, year = {2016}, author = {Oliveira, E and Saliba, JW and Oliveira, D and Dias, ES and Paz, GF}, title = {A prototype of the direct agglutination test kit (DAT-Canis) for the serological diagnosis of canine visceral leishmaniasis.}, journal = {Veterinary parasitology}, volume = {221}, number = {}, pages = {9-13}, doi = {10.1016/j.vetpar.2016.02.006}, pmid = {27084465}, issn = {1873-2550}, mesh = {Agglutination Tests/*veterinary ; Animals ; Antibodies, Protozoan/blood ; Dog Diseases/blood/*diagnosis ; Dogs ; Leishmaniasis, Visceral/blood/diagnosis/*veterinary ; Sensitivity and Specificity ; Serologic Tests/*veterinary ; }, abstract = {This report describes the stege I/II development of a new direct agglutination test (DAT) for the diagnosis of canine visceral leishmaniasis (CVL) using freeze-dried antigen produced Coomassie blue-stained Leishmania (Leishmania) infantum promastigotes. In stage I, 16 canine serum samples, collected from eight dogs carrying CVL and eight healthy dogs, were assessed with the DAT using 2-mercaptoethanol (2-ME), N-acetyl-cysteine (NAC), kaolin or NAC plus urea (NAC+U) to improve the assay conditions. Stage II assessed the diagnostic accuracy with 100 serum samples collected from dogs with symptomatic CVL and clinically healthy dogs, comparing the four different sample diluents. The CVL-DAT prototype kit showed equivalent performances when 2-ME, NAC or NAC+U were used: 97.1% sensitivity (CI: 83-99.8%), 97% specificity (CI: 88.5-99.5%) and a 97% diagnostic accuracy (CI: 90.8-99.2). With kaolin, a 94.1% sensitivity (CI: 79-99%), 97% specificity (CI: 88.5-99.5%) and 96% diagnostic accuracy were observed (CI: 89.5-98.7), with no statistically significant differences among the four reagents (p=1.0). The NAC plus urea in sample diluent decreased non-specific agglutination, promoted a better defined sharp-edged blue spot and was thus chosen as a component for the new DAT prototype to diagnose canine VL, designated DAT-Canis.}, }
@article {pmid27083693, year = {2016}, author = {Sahin Ersoy, G and Eken, M and Tal, R and Oztekin, D and Devranoglu, B and Isik Kaygusuz, E and Cevik, O}, title = {N-acetylcysteine leads to greater ovarian protection than enoxaparin sodium in a rat ovarian torsion model.}, journal = {Reproductive biomedicine online}, volume = {33}, number = {1}, pages = {93-101}, doi = {10.1016/j.rbmo.2016.03.009}, pmid = {27083693}, issn = {1472-6491}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*therapeutic use ; Animals ; Anti-Mullerian Hormone/blood ; Antioxidants/metabolism ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Enoxaparin/*therapeutic use ; Female ; Glutathione/metabolism ; In Situ Nick-End Labeling ; Malondialdehyde/metabolism ; Ovarian Diseases/*drug therapy ; Ovarian Follicle/drug effects ; Ovary/*drug effects ; Oxidative Stress ; Peroxidase/metabolism ; Pilot Projects ; Rats ; Rats, Wistar ; Reproductive Techniques, Assisted ; Superoxide Dismutase/metabolism ; }, abstract = {This study evaluated the effects of N-acetylcysteine (NAC) and enoxaparin on ovarian tissue preservation, ovarian reserve and oxidative damage following ovarian torsion/detorsion injury. Rats were divided into four groups (n = 6/group): control; ischaemia/reperfusion (I/R); I/R + NAC; I/R + enoxaparin. Twenty-four hours after detorsion, ovarian tissues were collected for histopathological analysis and measurement of tissue 8-OHdG, GSH, MDA, MPO and SOD concentrations, as well as pre- and post-operative circulating AMH concentrations. Administration of NAC resulted in more pre-antral follicles compared with enoxaparin treatment and haemorrhage and follicle cell degeneration were more pronounced in I/R + enoxaparin group than I/R + NAC group. Both NAC and enoxaparin led to a significant reduction in ovarian tissue 8-OHdG (P = 0.004 and P = 0.01, respectively) and MPO (P = 0.013 and P = 0.023, respectively) concentrations compared with I/R group, indicating a protective effect against I/R oxidative damage. Only NAC-treated animals showed a significant increase in GSH and SOD concentrations and decrease in MDA concentrations compared with I/R group (P = 0.007, P = 0.024 and P = 0.026, respectively). These results indicate that NAC is more effective than enoxaparin in minimizing ovarian damage and preserving ovarian reserve following ovarian torsion.}, }
@article {pmid27083477, year = {2016}, author = {Wang, B and Aw, TY and Stokes, KY}, title = {The protection conferred against ischemia-reperfusion injury in the diabetic brain by N-acetylcysteine is associated with decreased dicarbonyl stress.}, journal = {Free radical biology &amp; medicine}, volume = {96}, number = {}, pages = {89-98}, pmid = {27083477}, issn = {1873-4596}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/metabolism ; Blood-Brain Barrier/drug effects ; Brain/metabolism/pathology ; Cerebral Infarction/complications/drug therapy/metabolism/pathology ; Diabetes Mellitus, Experimental/complications/drug therapy/metabolism/pathology ; Diabetes Mellitus, Type 1/complications/*drug therapy/metabolism/pathology ; Glucose/metabolism ; Glutamate-Cysteine Ligase/genetics/metabolism ; Glutathione/metabolism ; Humans ; Mice ; Oxidative Stress/drug effects ; Pyruvaldehyde/metabolism ; Reperfusion Injury/complications/*drug therapy/metabolism/pathology ; Stroke/complications/*drug therapy/metabolism/pathology ; }, abstract = {Diabetes, a risk factor for stroke, leads to elevated blood methylglyoxal (MG) levels. This is due to increased MG generation from the high glucose levels, and because diabetes impairs the glutathione (GSH)-glyoxalase system for MG elimination. MG glycates proteins and causes dicarbonyl stress. We investigated the contribution of MG and GSH to stroke outcome. Cerebral ischemia/reperfusion was performed in chemical-induced (streptozotocin) and genetic Akita mouse models of Type 1 diabetes. Brain infarction and functions of the GSH-dependent MG elimination pathway were determined. Diabetes increased post-ischemia-reperfusion cerebral infarct area in association with elevated MG and diminished GSH levels. Infarct size correlated with brain MG-to-GSH ratio. Expression of glutamate-cysteine ligase catalytic subunit (GCLc) was increased in diabetic brain. GCL activity was unchanged. MG-adducts were elevated in the diabetic brain and, using immunoprecipitation, we identified one of the bands as glycated occludin. This was accompanied by increased blood-brain barrier permeability. Total protein carbonyls were elevated, indicative of oxidative/carbonyl stress. N-acetylcysteine (NAC) corrected MG-to-GSH ratio, and reduced diabetic brain infarct area, occludin glycation and permeability. In addition, protein carbonyls were decreased by NAC. We showed that the diabetic brain exhibited a lower GSH-dependent potential for MG elimination, which contributed to increased protein glycation, and oxidative/carbonyl stress. The consequence of these changes was aggravated post-stroke brain injury. NAC administration protected against the exacerbated brain damage via restored GSH generation and normalization of the MG-to-GSH ratio and possibly by attenuating oxidative/carbonyl stress. This treatment could contribute to the successful management of stroke risk/outcome in diabetes.}, }
@article {pmid27081862, year = {2016}, author = {Liu, MH and Zhang, Y and He, J and Tan, TP and Wu, SJ and Guo, DM and He, H and Peng, J and Tang, ZH and Jiang, ZS}, title = {Hydrogen sulfide protects H9c2 cardiac cells against doxorubicin-induced cytotoxicity through the PI3K/Akt/FoxO3a pathway.}, journal = {International journal of molecular medicine}, volume = {37}, number = {6}, pages = {1661-1668}, doi = {10.3892/ijmm.2016.2563}, pmid = {27081862}, issn = {1791-244X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Cardiotonic Agents/*pharmacology ; Cardiotoxicity/prevention &amp; control ; Cell Line ; Chromones/pharmacology ; Doxorubicin/*antagonists &amp; inhibitors/pharmacology ; Forkhead Box Protein O3/genetics/metabolism ; Gene Expression Regulation ; Hydrogen Sulfide/*pharmacology ; Models, Biological ; Morpholines/pharmacology ; Myocytes, Cardiac/cytology/*drug effects/metabolism ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/genetics/metabolism ; Rats ; Signal Transduction ; Sulfides/chemistry/*pharmacology ; }, abstract = {Doxorubicin (DOX) is an efficient drug used in cancer therapy that also produces reactive oxygen species (ROS) that induces severe cytotoxicity, which limits its clinical application. Hydrogen sulfide (H2S), a novel gasotransmitter, has been shown to exert cardioprotective effects. The present study aimed to determine whether exogenous H2S protects H9c2 cardiac cells against DOX-induced cytotoxicity and whether these protective effects are mediated through the PI3K/Akt/FoxO3a pathway. The H9c2 cardiac cells were exposed to 5 µM DOX for 24 h to establish a model of DOX-induced cardiotoxicity. The results showed that the treatment of H9c2 cardiac cells with sodium hydrosulfide (NaHS) for 30 min prior to DOX exposure markedly attenuated the phosphorylation of Akt and FoxO3a. Notably, pre-treatment of the H9c2 cells with NaHS significantly attenuated the nuclear localization of FoxO3a as well as the apoptosis of H9c2 cells induced by DOX. The treatment of H9c2 cells with N-acetyl-L-cysteine (NAC), a scavenger of ROS, prior to DOX exposure, also markedly increased the phosphorylation of Akt and FoxO3a which was inhibited by DOX alone. Furthermore, pre-treatment with LY294002, a selective inhibitor of PI3K/Akt, reversed the protective effect of H2S against DOX-induced injury of cardiomyocytes, as demonstrated by an increased number of apoptotic cells, a decrease in cell viability and the reduced phosphorylation of Akt and FoxO3a. These findings suggested that exogenous H2S attenuates DOX-induced cytotoxic effects in H9c2 cardiac cells through the PI3K/Akt/FoxO3a pathway.}, }
@article {pmid27080849, year = {2016}, author = {Taggart, LE and McMahon, SJ and Butterworth, KT and Currell, FJ and Schettino, G and Prise, KM}, title = {Protein disulphide isomerase as a target for nanoparticle-mediated sensitisation of cancer cells to radiation.}, journal = {Nanotechnology}, volume = {27}, number = {21}, pages = {215101}, doi = {10.1088/0957-4484/27/21/215101}, pmid = {27080849}, issn = {1361-6528}, mesh = {Acetylcysteine/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects/radiation effects ; Gene Expression Regulation, Neoplastic/drug effects/radiation effects ; Gold/chemistry/*pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects/radiation effects ; Metal Nanoparticles/*chemistry ; Mitochondria/drug effects/radiation effects ; Neoplasms/drug therapy/*enzymology/radiotherapy ; Oxidative Stress/radiation effects ; Protein Disulfide-Isomerases/*metabolism ; Radiation-Sensitizing Agents/*pharmacology ; }, abstract = {Radiation resistance and toxicity in normal tissues are limiting factors in the efficacy of radiotherapy. Gold nanoparticles (GNPs) have been shown to be effective at enhancing radiation-induced cell death, and were initially proposed to physically enhance the radiation dose deposited. However, biological responses of GNP radiosensitization based on physical assumptions alone are not predictive of radiosensitisation and therefore there is a fundamental research need to determine biological mechanisms of response to GNPs alone and in combination with ionising radiation. This study aimed to identify novel mechanisms of cancer cell radiosensitisation through the use of GNPs, focusing on their ability to induce cellular oxidative stress and disrupt mitochondrial function. Using N-acetyl-cysteine, we found mitochondrial oxidation to be a key event prior to radiation for the radiosensitisation of cancer cells and suggests the overall cellular effects of GNP radiosensitisation are a result of their interaction with protein disulphide isomerase (PDI). This investigation identifies PDI and mitochondrial oxidation as novel targets for radiosensitisation.}, }
@article {pmid27075430, year = {2016}, author = {Li, J and Xu, L and Deng, X and Jiang, C and Pan, C and Chen, L and Han, Y and Dai, W and Hu, L and Zhang, G and Cheng, Z and Liu, W}, title = {N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases.}, journal = {Pain}, volume = {157}, number = {8}, pages = {1711-1723}, doi = {10.1097/j.pain.0000000000000575}, pmid = {27075430}, issn = {1872-6623}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Hot Temperature ; Hyperalgesia/*drug therapy/metabolism ; Interleukin-1beta/metabolism ; Male ; Matrix Metalloproteinase Inhibitors/pharmacology/*therapeutic use ; Matrix Metalloproteinases/*metabolism ; Neuralgia/*drug therapy/metabolism ; Pain Measurement ; Pain Threshold/drug effects ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*drug effects/metabolism ; }, abstract = {The treatment of neuropathic pain remains a clinical challenge because of its unclear mechanisms and broad clinical morbidity. Matrix metalloproteinase (MMP)-9 and MMP-2 have previously been described as key components in neuropathic pain because of their facilitation of inflammatory cytokine maturation and induction of neural inflammation. Therefore, the inhibition of MMPs may represent a novel therapeutic approach to the treatment of neuropathic pain. In this study, we report that N-acetyl-cysteine (NAC), which is a broadly used respiratory drug, significantly attenuates neuropathic pain through a unique mechanism of MMP inhibition. Both the in vitro (0.1 mM) and in vivo application of NAC significantly suppressed the activity of MMP-9/2. Orally administered NAC (50, 100, and 200 mg/kg) not only postponed the occurrence but also inhibited the maintenance of chronic constrictive injury (CCI)-induced neuropathic pain in rats. The administration of NAC blocked the maturation of interleukin-1β, which is a critical substrate of MMPs, and markedly suppressed the neuronal activation induced by CCI, including inhibiting the phosphorylation of protein kinase Cγ, NMDAR1, and mitogen-activated protein kinases. Finally, NAC significantly inhibited CCI-induced microglia activation but elicited no notable effects on astrocytes. These results demonstrate an effective and safe approach that has been used clinically to alleviate neuropathic pain through the powerful inhibition of the activation of MMPs.}, }
@article {pmid27074587, year = {2016}, author = {Wang, Q and Xue, L and Zhang, X and Bu, S and Zhu, X and Lai, D}, title = {Autophagy protects ovarian cancer-associated fibroblasts against oxidative stress.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {15}, number = {10}, pages = {1376-1385}, pmid = {27074587}, issn = {1551-4005}, mesh = {Acetylcysteine/pharmacology ; Actins/metabolism ; Autophagy/*drug effects ; Autophagy-Related Protein 5/antagonists &amp; inhibitors/genetics/metabolism ; Cancer-Associated Fibroblasts/cytology/drug effects/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Female ; Fibroblasts/cytology/drug effects/metabolism ; Humans ; Hydrogen Peroxide/*toxicity ; Isoenzymes/metabolism ; L-Lactate Dehydrogenase/metabolism ; Lactate Dehydrogenase 5 ; Monocarboxylic Acid Transporters/metabolism ; Muscle Proteins/metabolism ; Ovarian Neoplasms/metabolism/pathology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; S Phase Cell Cycle Checkpoints/drug effects ; Superoxide Dismutase/metabolism ; }, abstract = {RNA-Seq and gene set enrichment anylysis revealed that ovarian cancer associated fibroblasts (CAFs) are mitotically active compared with normal fibroblasts (NFs). Cellular senescence is observed in CAFs treated with H2O2 as shown by elevated SA-β-gal activity and p21 (WAF1/Cip1) protein levels. Reactive oxygen species (ROS) production and p21 (WAF1/Cip1) elevation may account for H2O2-induced CAFs cell cycle arrest in S phase. Blockage of autophagy can increase ROS production in CAFs, leading to cell cycle arrest in S phase, cell proliferation inhibition and enhanced sensitivity to H2O2-induced cell death. ROS scavenger NAC can reduce ROS production and thus restore cell viability. Lactate dehydrogenase A (LDHA), monocarboxylic acid transporter 4 (MCT4) and superoxide dismutase 2 (SOD2) were up-regulated in CAFs compared with NFs. There was relatively high lactate content in CAFs than in NFs. Blockage of autophagy decreased LDHA, MCT4 and SOD2 protein levels in CAFs that might enhance ROS production. Blockage of autophagy can sensitize CAFs to chemotherapeutic drug cisplatin, implicating that autophagy might possess clinical utility as an attractive target for ovarian cancer treatment in the future.}, }
@article {pmid27074555, year = {2016}, author = {Gao, M and Chen, G and Wang, H and Xie, B and Hu, L and Kong, Y and Yang, G and Tao, Y and Han, Y and Wu, X and Zhang, Y and Dai, B and Shi, J}, title = {Therapeutic potential and functional interaction of carfilzomib and vorinostat in T-cell leukemia/lymphoma.}, journal = {Oncotarget}, volume = {7}, number = {20}, pages = {29102-29115}, pmid = {27074555}, issn = {1949-2553}, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Humans ; Hydroxamic Acids/administration &amp; dosage ; Leukemia-Lymphoma, Adult T-Cell/*pathology ; Mice ; Mice, Nude ; Oligopeptides/administration &amp; dosage ; Vorinostat ; Xenograft Model Antitumor Assays ; }, abstract = {We previously showed that the proteasome inhibitor carfilzomib and the histone deacetylase inhibitor (HDACI) vorinostat cooperated to induce cell apoptosis in one T-cell leukemia cell line in vitro, implying the possibility of the combination treatment of carfilzomib and vorinostat as a potential therapeutic strategy in human T-cell leukemia/lymphoma. Here we report that combination treatment of carfilzomib and vorinostat enhanced cell apoptosis and induced a marked increase in G2-M arrest, reactive oxygen species (ROS) generation, and activated the members of mitogen-activated protein kinases (MAPK) family, including the stress-activated kinases JNK, p38MAPK, and ERK1/2. Carfilzomib/vorinostat-mediated apoptosis was blocked by the ROS scavenger N-acetylcysteine (NAC). The JNK inhibitor SP600125 and the p38MAPK inhibitor SB203580 but not the MEK1/2 inhibitor U0126 significantly attenuated carfilzomib/vorinostat-induced apoptosis, suggesting that p38MAPK and JNK activation contribute to carfilzomib and vorinostat-induced apoptosis. This was further confirmed via short hairpin (shRNA) RNA knockdown of p38MAPK and JNK. Interestingly, the ROS scavenger NAC attenuated carfilzomib/vorinostat-mediated activation of p38MAPK and JNK. However, p38MAPK shRNA but not JNK shRNA diminished carfilzomib/vorinostat-mediated ROS generation. In contrast, overexpression of p38MAPK significantly increased carfilzomib/vorinostat-mediated ROS generation, suggesting that an amplification loop exists between ROS and p38MAPK pathway. Combination treatment of carfilzomib and vorinostat enhanced their individual antitumor activity in both a human xenograft model as well as human primary T-cell leukemia/lymphoma cells. These data suggest the potential clinical benefit and underlying molecular mechanism of combining carfilzomib with vorinostat in the treatment of human T-cell leukemia/lymphoma.}, }
@article {pmid27073589, year = {2016}, author = {Boonruamkaew, P and Chonpathompikunlert, P and Nagasaki, Y}, title = {Redox Nanoparticle Therapeutics for Acetaminophen-Induced Hepatotoxicity in Mice.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {4984597}, pmid = {27073589}, issn = {1942-0994}, mesh = {Acetaminophen/*adverse effects ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Animals ; Aspartate Aminotransferases/blood ; Glutathione Peroxidase/metabolism ; Liver/*pathology/physiopathology ; Liver Function Tests ; Male ; Malondialdehyde/metabolism ; Mice ; Nanoparticles/*chemistry ; Oxidation-Reduction/drug effects ; Particle Size ; Protective Agents/pharmacology ; Prothrombin Time ; Serum Albumin/metabolism ; Superoxides/metabolism ; }, abstract = {The purpose of this study was to evaluate the hepatoprotective effect of an antioxidative nanoparticle (RNP(N)) recently developed against APAP-induced hepatotoxicity in mice. The effects of oral administration of RNP(N) to APAP-treated mice were assessed for various biochemical liver function parameters: alanine transaminase (ALT) activity, aspartate transaminase (AST) activity, alkaline phosphatase (ALP) activity, prothrombin time, and serum albumin (ALB) level. The treatment effects were assessed in terms of free radical parameters: malondialdehyde (MDA) accumulation, glutathione peroxidase (GPx) activity, % inhibition of superoxide anion (O2 (-∙)), and histopathological examination. The N-acetylcysteine (NAC)-treated group exhibited an enhanced prothrombin time relative to the control group, while RNP(N) did not prolong prothrombin time. The RNP(N)-treated animals exhibited lower levels of ALT, AST, and ALP, while increased ALB levels were measured in these animals compared to those in the other groups. The RNP(N)-treated animals furthermore exhibited improved MDA levels, GPx activity, and % inhibition of O2 (-∙), which relate to oxidative damage. Histological staining of liver tissues from RNP(N)-treated animals did not reveal any microscopic changes relative to the other groups. The findings of this study suggest that RNP(N) possesses effective hepatoprotective properties and does not exhibit the notable adverse effects associated with NAC treatment.}, }
@article {pmid27071802, year = {2016}, author = {Xie, H and Wang, J and Jiang, L and Geng, C and Li, Q and Mei, D and Zhao, L and Cao, J}, title = {ROS-dependent HMGA2 upregulation mediates Cd-induced proliferation in MRC-5 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {34}, number = {}, pages = {146-152}, doi = {10.1016/j.tiv.2016.04.001}, pmid = {27071802}, issn = {1879-3177}, mesh = {Cadmium Chloride/*toxicity ; Cell Cycle/drug effects ; Cell Line ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Gene Expression/drug effects ; HMGA2 Protein/*biosynthesis/genetics ; Humans ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Up-Regulation ; }, abstract = {Cadmium (Cd) is a heavy metal widely found in a number of environmental matrices, and the exposure to Cd is increasing nowadays. In this study, the role of high mobility group A2 (HMGA2) in Cd-induced proliferation was investigated in MRC-5 cells. Exposure to Cd (2μM) for 48h significantly enhanced the growth of MRC-5 cells, increased reactive oxygen species (ROS) production, and induced both mRNA and protein expression of HMGA2. Evidence for Cd-induced reduction of the number of G0/G1 phase cells and an increase in the number of cells in S phase and G2/M phase was sought by flow cytometric analysis. Western blot analysis showed that cyclin D1, cyclin B1, and cyclin E were upregulated in Cd-treated cells. Further study revealed that N-acetyl cysteine (NAC) markedly prevented Cd-induced proliferation of MRC-5 cells, ROS generation, and the increasing protein level of HMGA2. Silencing of HMGA2 gene by siRNA blocked Cd-induced cyclin D1, cyclin B1, and cyclin E expression and reduction of the number of G0/G1 phase cells. Combining, our data showed that Cd-induced ROS formation provoked HMGA2 upregulation, caused cell cycle changes, and led to cell proliferation. This suggests that HMGA2 might be an important biomarker in Cd-induced cell proliferation.}, }
@article {pmid27069723, year = {2016}, author = {Awodele, O and Yemitan, O and Ise, PU and Ikumawoyi, VO}, title = {Modulatory potentials of aqueous leaf and unripe fruit extracts of Carica papaya Linn. (Caricaceae) against carbon tetrachloride and acetaminophen-induced hepatotoxicity in rats.}, journal = {Journal of intercultural ethnopharmacology}, volume = {5}, number = {1}, pages = {27-35}, pmid = {27069723}, issn = {2146-8397}, abstract = {INTRODUCTION: Carica papaya Linn is used in a traditional medicine for hepatobiliary disorders. This study investigated the hepatomodulatory effects of aqueous extracts of C. papaya leaf (CPL) and unripe fruit (CPF) at doses of 100 and 300 mg/kg on carbon tetrachloride (CCl4) and acetaminophen (ACM)-induced liver toxicities in rats.<br><br>MATERIALS AND METHODS: Rats were administered CCl4 (3 ml/kg in olive oil, i.p.) followed by oral administration of CPL and CPF at 2, 6 and 10 h intervals. The ACM model proceeded with the same method but inclusive of animals treated with N-acetyl cysteine (3 ml/kg i.p). At the end of the study, serum levels of liver biomarkers and antioxidant enzymes were assessed and histology of the liver tissues determined.<br><br>RESULTS: There was a significant (P < 0.05) reduction in CCl4 and ACM-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and direct bilirubin at 100 and 300 mg/kg, respectively. The levels of catalase (CAT), superoxide dismutase and reduced GSH were decreased in both models with corresponding significantly (P < 0.05) elevated level of malondialdehyde. However, these antioxidant enzymes were significantly (P < 0.05) increased in CPL and CPF-treated rats. Histopathological assessment of the liver confirmed the protective effects of CPL and CPF on CCl4 and ACM-induced hepatic damage evidenced by the normal presentation of liver tissue architecture.<br><br>CONCLUSION: These results indicate that aqueous extracts of C. papaya may be useful in preventing CCl4 and ACM-induced liver toxicities.}, }
@article {pmid27068641, year = {2016}, author = {Wang, X and Feng, Z and Li, J and Chen, L and Tang, W}, title = {High glucose induces autophagy of MC3T3-E1 cells via ROS-AKT-mTOR axis.}, journal = {Molecular and cellular endocrinology}, volume = {429}, number = {}, pages = {62-72}, doi = {10.1016/j.mce.2016.03.036}, pmid = {27068641}, issn = {1872-8057}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Autophagy/*drug effects ; Beclin-1/metabolism ; Blotting, Western ; Cell Line ; Cell Nucleus Shape/drug effects ; Cell Proliferation/drug effects ; Flow Cytometry ; Fluorescent Antibody Technique ; Glucose/*toxicity ; Mice ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Staining and Labeling ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {In the present study, we investigate the function of ROS-AKT-mTOR axis on the apoptosis, proliferation and autophagy of MC3T3-E1 cells, and the proliferation of MC3T3-E1 cells after autophagy inhibition under high glucose conditions. MC3T3-E1 cells cultured in vitro were divided into the following groups: normal control group, N-acetylcysteine (NAC) group, 11.0 mM high glucose group, 11.0 mM high glucose + NAC group, 22.0 mM high glucose group, 22.0 mM high glucose + NAC group, CQ group, 22.0 mM high glucose + CQ group, 3-MA group and 3-MA + 22.0 mM high glucose group. ROS production was measured by DCFH-DA fluorescent probe. Cell proliferation was measured by MTT assay. Cells in different groups were stained with Annexin V-FITC/PI, and then apoptosis rate was detected by flow cytometry. Nucleus morphology was observed under fluorescence microscope after being incubated with Honchest33258. Protein expression was measured using Western blotting and immunofluorescence. Cell apoptosis and proliferation in high glucose group were increased and decreased, respectively, in a dose-dependent manner. Autophagy was significantly induced in high glucose group, even though different concentration of glucose induced autophagy in different stages of autophagy. ROS production in MC3T3-E1 cells was remarkably increased in high glucose group, but not in a dose-dependent manner. NAC, as an antioxidant, reduced ROS production and ameliorated cell apoptosis, proliferation abnormity and autophagy caused by high glucose. Expression of p-AKT and p-mTOR proteins were dramatically decreased in high glucose group, and NAC reversed their expression. In addition, 3-MA, an inhibitor of autophagy, significantly decreased the proliferation of MC3T3-E1 cells. When cocultured with 22.0 mM glucose that induced autophagy, proliferation of MC3T3-E1 cells was not affected compared to 22.0 mM high glucose group. Our present findings reveal that high glucose affects apoptosis, proliferation and autophagy of MC3T3-E1 cells through ROS-AKT-mTOR axis. In addition, autophagy inhibition does not affect the proliferation of MC3T3-E1 cells under high glucose conditions.}, }
@article {pmid27067106, year = {2016}, author = {Romero, A and Ramos, E and Ares, I and Castellano, V and Martínez, M and Martínez-Larrañaga, MR and Anadón, A and Martínez, MA}, title = {Fipronil sulfone induced higher cytotoxicity than fipronil in SH-SY5Y cells: Protection by antioxidants.}, journal = {Toxicology letters}, volume = {252}, number = {}, pages = {42-49}, doi = {10.1016/j.toxlet.2016.04.005}, pmid = {27067106}, issn = {1879-3169}, mesh = {Antioxidants/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytoprotection ; Dose-Response Relationship, Drug ; Humans ; Inhibitory Concentration 50 ; Insecticides/*toxicity ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Nitric Oxide/metabolism ; Oxidative Stress/*drug effects ; Pyrazoles/*toxicity ; }, abstract = {Fipronil is a broad spectrum insecticide from the phenyl pyrazole family, which targets GABA receptor. Limited information is available about the metabolite fipronil sulfone cytotoxic actions. This study examined in vitro neurotoxicity of fipronil and fipronil sulfone and evaluated Trolox (vitamin E analog) (0.3, 1μM), N-acetyl-cysteine (0.5, 1mM), melatonin (0.1, 1μM) and Tempol (superoxide dismutase analog) (0.3, 0.5mM) protective role in SH-SY5Y cells. MTT and LDH assays were carried out to assess the cytotoxicity of fipronil and fipronil sulfone at 3-100μM concentrations. Fipronil sulfone was more toxic than fipronil. Tempol showed the best neuroprotectant profile against fipronil (50 and 150μM) and fipronil sulfone (3 and 10μM) reaching control levels. Fipronil (100μM) and fipronil sulfone (3μM) treatments induced a 4.7- and 5-fold increases in lipid peroxides measured as malondialdehyde (MDA) and a 2.2- and 2.0-fold increases in the levels of nitric oxide (NO). These results suggest that oxidative stress observed may be one of the major mechanisms of fipronil-induced neurotoxicity and it may be attributed in part to fipronil disposition and metabolism. Our results led us postulate that metabolite fipronil sulfone might be responsible for the fipronil-induced toxicity rather than fipronil itself.}, }
@article {pmid27062046, year = {2016}, author = {Quintanilla, ME and Rivera-Meza, M and Berríos-Cárcamo, P and Salinas-Luypaert, C and Herrera-Marschitz, M and Israel, Y}, title = {Beyond the "First Hit": Marked Inhibition by N-Acetyl Cysteine of Chronic Ethanol Intake But Not of Early Ethanol Intake. Parallel Effects on Ethanol-Induced Saccharin Motivation.}, journal = {Alcoholism, clinical and experimental research}, volume = {40}, number = {5}, pages = {1044-1051}, doi = {10.1111/acer.13031}, pmid = {27062046}, issn = {1530-0277}, mesh = {Acetylcysteine/*therapeutic use ; Alcohol Drinking/*drug therapy ; Animals ; Male ; Motivation/*drug effects ; Rats ; Saccharin/*administration &amp; dosage ; Self Administration ; Time Factors ; }, abstract = {BACKGROUND: A number of studies have shown that acetaldehyde synthesized in the brain is necessary to induce ethanol (EtOH) reinforcement in naïve animals (acquisition phase). However, after chronic intake is achieved (maintenance phase), EtOH intake becomes independent of acetaldehyde generation or its levels. Glutamate has been reported to be associated with the maintenance of chronic EtOH intake. The levels of brain extracellular glutamate are modulated by 2 glial processes: glutamate reabsorption via an Na(+) -glutamate transporter (GLT1) and a cystine-glutamate exchanger. Chronic EtOH intake lowers GLT1 levels and increases extracellular glutamate. The administration of N-acetyl cysteine (NAC), a precursor of cystine, has been shown to reduce the relapse of several drugs of abuse, while NAC has not been tested on chronic EtOH intake or on EtOH's influence on the motivation for another drug. These were investigated in the present study.<br><br>METHODS: (i) Rats bred for their high EtOH intake were allowed access to 10% EtOH and water up to 87&#xa0;days. NAC was administered (30 and 60&#xa0;mg/kg daily, intraperitoneally) for 14 consecutive days, either during the acquisition phase or the maintenance phase of EtOH drinking. (ii) In additional experiments, rats were allowed EtOH (10%) and water access for 61&#xa0;days, after which EtOH was replaced by saccharin (0.3%) to determine both if chronic EtOH consumption influences saccharin intake and whether NAC modifies the post chronic EtOH saccharin intake.<br><br>RESULTS: NAC did not influence the acquisition ("first hit") of chronic EtOH intake, but greatly inhibited (60 to 70%; p&#xa0;<&#xa0;0.0001) EtOH intake when NAC was administered to animals that were consuming EtOH chronically. NAC did not influence saccharin intake in na&#xef;ve animals. In animals that had consumed EtOH chronically and were thereafter offered a saccharin solution (0.3%), saccharin intake increased over 100% versus that of EtOH-untreated animals, an effect that was fully suppressed by NAC.<br><br>CONCLUSIONS: N-acetyl cysteine, a drug approved for use in humans, markedly reduces chronic EtOH intake and abolishes the increased intake of saccharin stimulated by chronic EtOH drinking.}, }
@article {pmid27061477, year = {2016}, author = {Pinar Karapinar, S and Ulum, YZ and Ozcelik, B and Dogan Buzoglu, H and Ceyhan, D and Balci Peynircioglu, B and Aksoy, Y}, title = {The effect of N-acetylcysteine and calcium hydroxide on TNF-α and TGF-β1 in lipopolysaccharide-activated macrophages.}, journal = {Archives of oral biology}, volume = {68}, number = {}, pages = {48-54}, doi = {10.1016/j.archoralbio.2016.03.017}, pmid = {27061477}, issn = {1879-1506}, mesh = {Acetylcysteine/*pharmacology ; Anti-Inflammatory Agents/pharmacology ; Calcium Hydroxide/*pharmacology ; Cell Death/drug effects ; Cell Line ; Enzyme-Linked Immunosorbent Assay/methods ; Flow Cytometry ; Humans ; Lipopolysaccharides/*pharmacology ; Macrophages/cytology/*drug effects/*metabolism ; Monocytes/cytology/drug effects/metabolism ; RNA, Messenger/genetics/metabolism ; Real-Time Polymerase Chain Reaction/methods ; Transforming Growth Factor beta1/genetics/*metabolism ; Tumor Necrosis Factor-alpha/genetics/*metabolism ; }, abstract = {OBJECTIVE: The present study was designed to evaluate the pro- and anti-inflammatory effects of NAC and calcium hydroxide (Ca(OH)2) on lipopolysaccharide-stimulated human macrophage cell lines.<br><br>DESIGN: THP-1 human monocyte precursor cells were differentiated into macrophage adherent cells. Cell cytotoxicity was measured by flow cytometry analysis. NAC and Ca(OH)2 were applied in the presence or absence of lipopolysaccharides (LPS) for time periods of 4, 8, and 24h. Protein and mRNA levels of tumor necrosis factor-alpha (TNF-&#x3b1;) and transforming growth factor-beta1 (TGF-&#x3b2;1) were determined using ELISA and qRT-PCR. The data were statistically analyzed by three-way ANOVA followed by Bonferroni test at &#x3b1;=0.05.<br><br>RESULTS: In LPS-stimulated cell lines, while the TNF-&#x3b1; protein and mRNA levels were reduced in the first 4h, only the TGF-&#x3b2;1 mRNA levels increased in the 24th hour following treatment with Ca(OH)2 and NAC when compared with the control group (p<0.001). In LPS-unstimulated cells, the TNF-&#x3b1; protein level was significantly decreased by NAC and Ca(OH)2 at the 4th hour. Additionally, while the TGF-&#x3b2;1 mRNA levels were significantly reduced, the protein level of TGF-&#x3b2;1 was increased at the 24th hour.<br><br>CONCLUSIONS: It was concluded that NAC, similar to Ca(OH)2, has anti-inflammatory properties and might be considered an alternate candidate therapeutical agent to Ca(OH)2.}, }
@article {pmid27059722, year = {2017}, author = {Rivkin, I and Galnoy-Glucksam, Y and Elron-Gross, I and Afriat, A and Eisenkraft, A and Margalit, R}, title = {Treatment of respiratory damage in mice by aerosols of drug-encapsulating targeted lipid-based particles.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {257}, number = {}, pages = {163-169}, doi = {10.1016/j.jconrel.2016.03.039}, pmid = {27059722}, issn = {1873-4995}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics ; Administration, Inhalation ; Aerosols/*chemistry ; Animals ; Dexamethasone/*administration &amp; dosage/pharmacokinetics ; Drug Delivery Systems ; Drug Liberation ; Expectorants/*administration &amp; dosage/pharmacokinetics ; Glucocorticoids/*administration &amp; dosage/pharmacokinetics ; Liposomes/*chemistry ; Male ; Mice ; Mice, Inbred BALB C ; Nebulizers and Vaporizers ; Respiratory Tract Diseases/chemically induced/drug therapy ; }, abstract = {The purpose of this study was to develop a treatment for respiratory damage caused by exposure to toxic industrial chemicals (TICs), including mass casualty events, by aerosols of dexamethasone and/or N-acetyl cysteine formulated in targeted lipid-based particles. Good encapsulation, performance as slow-release drug depots, conservation of matter, and retention of biological activity were obtained for the three drug-carrier formulations, pre- and post-aerosolization. Weight changes over a 2week period were applied, deliberately, as a non-invasive clinical parameter. Control mice gained weight continuously, whereas a non-lethal 30minute exposure of mice to 300ppm Cl2 in air showed a two-trend response. Weight loss over the first two days, reversing thereafter to weight gain, but at a rate and level significantly slower and smaller than those of the control mice, indicating the chlorine damage was long-term. The weight changes of Cl2-exposed mice given the inhalational treatments also showed the two-trend response, but the weight gain rates and levels were similar to those of the control mice, reaching the weight-gain range of the control mice. Following this proof of concept, studies are now extended to include additional TICs, and biochemical markers of injury and recovery.}, }
@article {pmid27058530, year = {2016}, author = {Martínez, MA and Úbeda, A and Moreno, J and Trillo, M&#xc1;}, title = {Power Frequency Magnetic Fields Affect the p38 MAPK-Mediated Regulation of NB69 Cell Proliferation Implication of Free Radicals.}, journal = {International journal of molecular sciences}, volume = {17}, number = {4}, pages = {510}, pmid = {27058530}, issn = {1422-0067}, mesh = {Cell Cycle ; Cell Line, Tumor ; *Cell Proliferation ; Humans ; *MAP Kinase Signaling System ; Magnetic Fields/*adverse effects ; Neuroblastoma/*etiology/*metabolism/pathology ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The proliferative response of the neuroblastoma line NB69 to a 100 µT, 50 Hz magnetic field (MF) has been shown mediated by activation of the MAPK-ERK1/2 pathway. This work investigates the MF effect on the cell cycle of NB69, the participation of p38 and c-Jun N-terminal (JNK) kinases in the field-induced proliferative response and the potential involvement of reactive oxygen species (ROS) in the activation of the MAPK-ERK1/2 and -p38 signaling pathways. NB69 cultures were exposed to the 100 µT MF, either intermittently for 24, 42 or 63 h, or continuously for periods of 15 to 120 min, in the presence or absence of p38 or JNK inhibitors: SB203580 and SP600125, respectively. Antioxidant N-acetylcysteine (NAC) was used as ROS scavenger. Field exposure induced transient activation of p38, JNK and ERK1/2. The MF proliferative effect, which was mediated by changes in the cell cycle, was blocked by the p38 inhibitor, but not by the JNK inhibitor. NAC blocked the field effects on cell proliferation and p38 activation, but not those on ERK1/2 activation. The MF-induced proliferative effects are exerted through sequential upregulation of MAPK-p38 and -ERK1/2 activation, and they are likely mediated by a ROS-dependent activation of p38.}, }
@article {pmid27057965, year = {2016}, author = {Smith, M and Hunter, R and Stellenboom, N and Kusza, DA and Parker, MI and Hammouda, AN and Jackson, G and Kaschula, CH}, title = {The cytotoxicity of garlic-related disulphides and thiosulfonates in WHCO1 oesophageal cancer cells is dependent on S-thiolation and not production of ROS.}, journal = {Biochimica et biophysica acta}, volume = {1860}, number = {7}, pages = {1439-1449}, doi = {10.1016/j.bbagen.2016.03.032}, pmid = {27057965}, issn = {0006-3002}, mesh = {Antineoplastic Agents, Phytogenic/chemical synthesis/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Disulfides/chemical synthesis/*pharmacology ; Dose-Response Relationship, Drug ; Esophageal Neoplasms/*drug therapy/metabolism/pathology ; Esophageal Squamous Cell Carcinoma ; G2 Phase Cell Cycle Checkpoints/drug effects ; *Garlic ; Humans ; Molecular Structure ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Structure-Activity Relationship ; Sulfhydryl Compounds/*metabolism ; Thiosulfonic Acids/chemical synthesis/*pharmacology ; Time Factors ; }, abstract = {BACKGROUND: Garlic has been used for centuries in folk medicine for its health promoting and cancer preventative properties. The bioactive principles in crushed garlic are allyl sulphur compounds which are proposed to chemically react through (i) protein S-thiolation and (ii) production of ROS.<br><br>METHODS: A collection of R-propyl disulphide and R-thiosulfonate compounds were synthesised to probe the importance of thiolysis and ROS generation in the cytotoxicity of garlic-related compounds in WHCO1 oesophageal cancer cells.<br><br>RESULTS: A significant correlation (R(2)=0.78, Fcrit (7,1) &#x3b1;=0.005) was found between the cytotoxicity IC(50) and the leaving group pK(a) of the R-propyl disulphides and thiosulfonates, supporting a mechanism that relies on the thermodynamics of a mixed disulphide exchange reaction. Disulphide (1) and thiosulfonate (11) were further evaluated mechanistically and found to induce G(2)/M cell-cycle arrest and apoptosis, inhibit cell proliferation, and generate ROS. When the ROS produced by 1 and 11 were quenched with Trolox, ascorbic acid or N-acetyl cysteine (NAC), only NAC was found to counter the cytotoxicity of both compounds. However, NAC was found to chemically react with 11 through mixed disulphide formation, providing an explanation for this apparent inhibitory result.<br><br>CONCLUSION: Cellular S-thiolation by garlic related disulphides appears to be the cause of cytotoxicity in WHCO1 cells. Generation of ROS appears to only play a secondary role.<br><br>GENERAL SIGNIFICANCE: Our findings do not support ROS production causing the cytotoxicity of garlic-related disulphides in WHCO1 cells. Importantly, it was found that the popular ROS inhibitor NAC interferes with the assay.}, }
@article {pmid27055427, year = {2016}, author = {Qu, D and Ren, XX and Guo, LY and Liang, JX and Xu, WJ and Han, YH and Zhu, YM}, title = {[Effect of N-acetylcysteine inhalation on ventilator-associated pneumonia caused by biofilm in endotracheal tubes].}, journal = {Zhonghua er ke za zhi = Chinese journal of pediatrics}, volume = {54}, number = {4}, pages = {278-282}, doi = {10.3760/cma.j.issn.0578-1310.2016.04.010}, pmid = {27055427}, issn = {0578-1310}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; *Biofilms ; Gram-Negative Bacteria/pathogenicity ; Humans ; Incidence ; Intubation, Intratracheal ; Pneumonia, Ventilator-Associated/*drug therapy/*microbiology ; Respiration, Artificial/adverse effects ; }, abstract = {OBJECTIVE: To observe the formation of the biofilm in endotracheal tubes, the characteristics of etiology, drug resistance and effect on the biofilm and ventilator-associated pneumonia (VAP) of inhaled N-acetylcysteine (NAC).<br><br>METHOD: We selected 117 tracheally intubated and undergoing mechanical ventilation for &#x2265;48 h in our hospital ICU from September 2010 to August 2012. All the cases were randomly divided into control group (60 cases) and study group (57 cases). The patients in the study group were treated with different doses of aerosolized NAC according to different ages, starting the first administration within 12 hours of mechanical ventilation, once every 8 hours, until stopping mechanical ventilation. Comparison was performed on the two groups in biofilm structure under the scanning electron microscopy, biofilm culture positive rate, VAP incidence, the etiology and drug resistance of the lower airway secretions and biofilms.<br><br>RESULT: (1) Electron microscopy showed that biofilm had formed in the endotracheal tube inner wall in early period of mechanical ventilation. With prolonged mechanical ventilation, biofilm structure improved. At the same time of mechanical ventilation, the thickness of biofilm in the study group decreased as compared with the control group. (2) Biofilm culture positive rate and incidence of ventilator-associated pneumonia decreased in the study group compared with in the control group (65%(37/57) vs. 80%(48/60), P<0.05; 11% (6/57)vs. 32%(19/60), P<0.01). (3) A large number of pathogenic bacteria colonized in the biofilm and gram-negative bacilli dominated. With prolonged mechanical ventilation, the cultured pathogens converged from the lower airway secretions and biofilm.<br><br>CONCLUSION: With prolonged mechanical ventilation, biofilm structure was improved. Inhalation of NAC can inhibit biofilm formation and reduce the incidence of VAP.}, }
@article {pmid27045874, year = {2016}, author = {Park, SH and Jeong, MH and Park, IH and Choi, JS and Rhee, JA and Kim, IS and Kim, MC and Cho, JY and Sim, DS and Hong, YJ and Park, HW and Kim, JH and Ahn, Y and Cho, JG and Park, JC and Kang, JC}, title = {Effects of combination therapy of statin and N-acetylcysteine for the prevention of contrast-induced nephropathy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.}, journal = {International journal of cardiology}, volume = {212}, number = {}, pages = {100-106}, doi = {10.1016/j.ijcard.2016.03.009}, pmid = {27045874}, issn = {1874-1754}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/chemically induced/diagnostic imaging/*prevention &amp; control ; Aged ; Contrast Media/*adverse effects ; Drug Therapy, Combination ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*administration &amp; dosage ; Male ; Middle Aged ; Percutaneous Coronary Intervention/*adverse effects ; Prospective Studies ; ST Elevation Myocardial Infarction/diagnostic imaging/*drug therapy/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: Acute myocardial infarction (AMI) is a risk factor for contrast-induced nephropathy (CIN). We investigated whether pretreatment with statin, N-acetylcysteine (NAC) and sodium bicarbonate (NaHCO3) reduces the risk of CIN.<br><br>METHODS: We conducted a prospective trial and enrolled a total of 334 ST-segment elevation myocardial infarction (STEMI) patients. Patients were divided into four groups: Group I (statin 40mg), Group II (statin 80mg), Group III (statin 80mg plus NAC 1200mg) and Group IV (regimen of group III plus NaHCO3 154mEq/L). CIN was defined as &#x2265;25% or &#x2265;0.5mg/dL increase in serum creatinine from the baseline within the 72h after PCI.<br><br>RESULTS: CIN occurred in 72 (21.6%) patients. The incidence of CIN was the lowest in the group III (14.3%), and multivariate analysis showed the lower incidence of CIN in group III compared to Group I [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.13-0.64, p=0.002]. Admission hyperglycemia [(AHG)>198mg/dL] (OR 2.20, 95% Cl 1.20-3.68, p=0.011) and the use of intra-aortic balloon pump (IABP) (OR 4.20, 95% CI 1.38-12.78, p=0.016) were independent predictors for CIN. The CIN (OR 9.00, 95% CI 1.30-62.06, p=0.026) was an independent predictor for in-hospital mortality.<br><br>CONCLUSIONS: Combination of high-dose statin plus NAC was associated with lower incidence of CIN in patients with STEMI who underwent primary PCI compared to statin only.}, }
@article {pmid27044854, year = {2016}, author = {Smith, JR and Broxterman, RM and Ade, CJ and Evans, KK and Kurti, SP and Hammer, SM and Barstow, TJ and Harms, CA}, title = {Acute supplementation of N-acetylcysteine does not affect muscle blood flow and oxygenation characteristics during handgrip exercise.}, journal = {Physiological reports}, volume = {4}, number = {7}, pages = {}, pmid = {27044854}, issn = {2051-817X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Biomarkers/blood ; Blood Flow Velocity/drug effects ; Brachial Artery/diagnostic imaging/*drug effects/physiology ; Cross-Over Studies ; *Dietary Supplements ; Double-Blind Method ; *Exercise ; Exercise Test ; *Hand Strength ; Hemoglobins/metabolism ; Humans ; Male ; Muscle Fatigue ; Muscle, Skeletal/blood supply/*drug effects/metabolism ; Myoglobin/metabolism ; Oxygen/*blood ; Oxygen Consumption/drug effects ; Physical Endurance/*drug effects ; Regional Blood Flow/drug effects ; Spectroscopy, Near-Infrared ; Time Factors ; Ultrasonography, Doppler ; Vasodilation/drug effects ; Young Adult ; }, abstract = {N-acetylcysteine (NAC; antioxidant and thiol donor) supplementation has improved exercise performance and delayed fatigue, but the underlying mechanisms are unknown. One possibility isNACsupplementation increases limb blood flow during severe-intensity exercise. The purpose was to determine ifNACsupplementation affected exercising arm blood flow and muscle oxygenation characteristics. We hypothesized thatNACwould lead to higher limb blood flow and lower muscle deoxygenation characteristics during severe-intensity exercise. Eight healthy nonendurance trained men (21.8 ± 1.2 years) were recruited and completed two constant power handgrip exercise tests at 80% peak power until exhaustion. Subjects orally consumed either placebo (PLA) orNAC(70 mg/kg) 60 min prior to handgrip exercise. Immediately prior to exercise, venous blood samples were collected for determination of plasma redox balance. Brachial artery blood flow (BABF) was measured via Doppler ultrasound and flexor digitorum superficialis oxygenation characteristics were measured via near-infrared spectroscopy. FollowingNACsupplementaiton, plasma cysteine (NAC: 47.2 ± 20.3 μmol/L vs.PLA: 9.6 ± 1.2 μmol/L;P = 0.001) and total cysteine (NAC: 156.2 ± 33.9 μmol/L vs.PLA: 132.2 ± 16.3 μmol/L;P = 0.048) increased. Time to exhaustion was not significantly different (P = 0.55) betweenNAC(473.0 ± 62.1 sec) andPLA(438.7 ± 58.1 sec). RestingBABFwas not different (P = 0.79) withNAC(99.3 ± 31.1 mL/min) andPLA(108.3 ± 46.0 mL/min).BABFwas not different (P = 0.42) during exercise or at end-exercise (NAC: 413 ± 109 mL/min;PLA: 445 ± 147 mL/min). Deoxy-[hemoglobin+myoglobin] and total-[hemoglobin+myoglobin] were not significantly different (P = 0.73 andP = 0.54, respectively) at rest or during exercise between conditions. We conclude that acuteNACsupplementation does not alter oxygen delivery during exercise in men.}, }
@article {pmid27043646, year = {2016}, author = {Scheer, MA and Schneider, KJ and Finnigan, RL and Maloney, EP and Wells, MA and Clemens, DL}, title = {The Involvement of Acetaldehyde in Ethanol-Induced Cell Cycle Impairment.}, journal = {Biomolecules}, volume = {6}, number = {2}, pages = {}, pmid = {27043646}, issn = {2218-273X}, mesh = {Acetaldehyde/metabolism/*toxicity ; Acetylcysteine/pharmacology ; Alcohol Dehydrogenase/metabolism ; Antioxidants/pharmacology ; CDC2 Protein Kinase/metabolism ; Cell Line ; Chromans/pharmacology ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Ethanol/*toxicity ; G2 Phase Cell Cycle Checkpoints/*drug effects ; Hep G2 Cells ; Humans ; Immunoblotting ; M Phase Cell Cycle Checkpoints/*drug effects ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent of these studies was to discern the roles of acetaldehyde and reactive oxygen, two of the major by-products of ethanol metabolism, in the G2/M cell cycle arrest.<br><br>METHODS: To investigate the role of ethanol metabolites in the cell cycle arrest, VA-13 and VL-17A cells were used. These are recombinant Hep G2 cells that express alcohol dehydrogenase or alcohol dehydrogenase and cytochrome P450 2E1, respectively. Cells were cultured with or without ethanol, lacking or containing the antioxidants N-acetylcysteine (NAC) or trolox, for three days. Cellular accumulation was monitored by the DNA content of the cultures. The accumulation of the cyclin-dependent kinase, Cdc2 in the inactive phosphorylated form (p-Cdc2) and the cyclin-dependent kinase inhibitor p21 were determined by immunoblot analysis.<br><br>RESULTS: Cultures maintained in the presence of ethanol demonstrated a G2/M cell cycle arrest that was associated with a reduction in DNA content and increased levels of p-Cdc2 and p21, compared with cells cultured in its absence. Inclusion of antioxidants in the ethanol containing media was unable to rescue the cells from the cell cycle arrest or these ethanol metabolism-mediated effects. Additionally, culturing the cells in the presence of acetaldehyde alone resulted in increased levels of p-Cdc2 and p21.<br><br>CONCLUSIONS: Acetaldehyde produced during ethanol oxidation has a major role in the ethanol metabolism-mediated G2/M cell cycle arrest, and the concurrent accumulation of p21 and p-Cdc2. Although reactive oxygen species are thought to have a significant role in ethanol-induced hepatocellular damage, they may have a less important role in the inability of hepatocytes to replace dead or damaged cells.}, }
@article {pmid27043622, year = {2016}, author = {Baali, N and Belloum, Z and Baali, S and Chabi, B and Pessemesse, L and Fouret, G and Ameddah, S and Benayache, F and Benayache, S and Feillet-Coudray, C and Cabello, G and Wrutniak-Cabello, C}, title = {Protective Activity of Total Polyphenols from Genista quadriflora Munby and Teucrium polium geyrii Maire in Acetaminophen-Induced Hepatotoxicity in Rats.}, journal = {Nutrients}, volume = {8}, number = {4}, pages = {193}, pmid = {27043622}, issn = {2072-6643}, mesh = {Acetaminophen/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Chromatography, Thin Layer ; Cytochrome P-450 CYP2E1/genetics/metabolism ; Gene Expression Regulation/drug effects ; Genista/*chemistry ; Male ; Mitochondria, Liver/drug effects ; Oxidative Stress/drug effects ; Plant Extracts/chemistry/pharmacology ; Polyphenols/chemistry/*pharmacology ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Wistar ; Teucrium/*chemistry ; Transaminases/blood/metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism ; }, abstract = {Oxidative stress is a major cause of drug-induced hepatic diseases and several studies have demonstrated that diet supplementation with plants rich in antioxidant compounds provides a variety of health benefits in these circumstances. Genista quadriflora Munby (Gq) and Teucrium polium geyrii Maire (Tp) are known to possess antioxidant and numerous biological properties and these endemic plants are often used for dietary or medicinal applications. Herein, we evaluated the beneficial effect of rich-polyphenol fractions of Gq and Tp to prevent Acetaminophen-induced liver injury and investigated the mechanisms involved in this protective action. Rats were orally administered polyphenolic extracts from Gq or Tp (300 mg/kg) or N-acetylcysteine (NAC: 200 mg/kg) once daily for ten days prior to the single oral administration of Acetaminophen (APAP: 1 g/kg). The results show that preventive administration of polyphenolic extracts from Gq or Tp exerts a hepatoprotective influence during APAP treatment by improving transaminases leakage and liver histology and stimulating antioxidant defenses. Besides, suppression of liver CYP2E1, GSTpi and TNF-α mRNA levels, with enhancement of mitochondrial bioenergetics may contribute to the observed hepatoprotection induced by Gq and Tp extracts. The effect of Tp extract is significantly higher (1.5-2 fold) than that of Gq extract and NAC regarding the enhancement of mitochondrial functionality. Overall, this study brings the first evidence that pretreatment with these natural extracts display in vivo protective activity against APAP hepatotoxicity through improving mitochondrial bioenergetics, oxidant status, phase I and II enzymes expression and inflammatory processes probably by virtue of their high total polyphenols content.}, }
@article {pmid27043357, year = {2016}, author = {Chen, X and Tan, M and Xie, Z and Feng, B and Zhao, Z and Yang, K and Hu, C and Liao, N and Wang, T and Chen, D and Xie, F and Tang, C}, title = {Inhibiting ROS-STAT3-dependent autophagy enhanced capsaicin-induced apoptosis in human hepatocellular carcinoma cells.}, journal = {Free radical research}, volume = {50}, number = {7}, pages = {744-755}, doi = {10.3109/10715762.2016.1173689}, pmid = {27043357}, issn = {1029-2470}, mesh = {Apoptosis/drug effects ; Autophagy/drug effects ; Capsaicin/*pharmacology ; Carcinoma, Hepatocellular/*drug therapy/*metabolism/pathology ; Hep G2 Cells ; Humans ; Liver Neoplasms/*drug therapy/*metabolism/pathology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/metabolism ; Transfection ; }, abstract = {Capsaicin, which is the pungent ingredient of red hot chili peppers, has been reported to possess anticancer activity, including that against hepatocellular carcinoma. However, the precise molecular mechanisms by which capsaicin exerts its anticancer effects remain poorly understood. Herein, we have tested the involvement of autophagy in the capsaicin mechanism of action in human hepatocellular carcinoma. HepG2 cancer cells were treated with different doses of capsaicin (50, 100 and 200μmol/L) for 6, 12, and 24 h. Flow cytometry and Caspase-3 activity assay were performed to determine cell apoptosis. Immunofluorescence was performed to visualize LC3-positive puncta. Western blotting was used to detect the expression of the hallmarks of apoptosis and autophagy. Capsaicin can induce apoptosis in HepG2 cells. The expression levels of CL-PARP and Bcl-2 were significantly increased. In line with the apoptosis, capsaicin can trigger autophagy in HepG2 cells. Capsaicin increased LC3-II and beclin-1 expression and GFP-LC3-positive autophagosomes. Pharmacological or genetic inhibition of autophagy further sensitized HepG2 cells to capsaicin-induced apoptosis. Mechanistically, capsaicin upregulated the Stat3 activity which contributed to autophagy. Importantly, we found that capsaicin triggered reactive oxygen species (ROS) generation in hepatoma cells and that the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger. Moreover, NAC abrogated the effects of capsaicin on Stat3-dependent autophagy. In this study, we demonstrated that capsaicin increased the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3)-dependent autophagy through the generation of ROS signaling pathways in human hepatoma. Inhibiting autophagy could enhance capsaicin-induced apoptosis in human hepatocellular carcinoma.}, }
@article {pmid27041464, year = {2016}, author = {Shen, Y and Miao, NJ and Xu, JL and Gan, XX and Xu, D and Zhou, L and Xue, H and Zhang, W and Lu, LM}, title = {N-acetylcysteine alleviates angiotensin II-mediated renal fibrosis in mouse obstructed kidneys.}, journal = {Acta pharmacologica Sinica}, volume = {37}, number = {5}, pages = {637-644}, pmid = {27041464}, issn = {1745-7254}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Angiotensin II/*metabolism/pharmacology ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Cell Line ; Fibroblasts/drug effects/pathology ; Fibrosis/drug therapy/etiology/pathology ; Kidney/drug effects/pathology ; Kidney Diseases/*drug therapy/etiology/pathology ; Male ; Mice, Inbred C57BL ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Renin-Angiotensin System/drug effects ; Ureteral Obstruction/complications/*drug therapy/pathology ; }, abstract = {AIM: To investigate the effects of ROS scavenger N-acetylcysteine (NAC) on angiotensin II (Ang II)-mediated renal fibrosis in vivo and in vitro.<br><br>METHODS: Mice were subjected to unilateral ureteral obstruction (UUO), and then treated with vehicle or NAC (250 mg/kg, ip) for 7 days. Histological changes of the obstructed kidneys were observed with Masson's trichrome staining. ROS levels were detected with DHE staining. The expression of relevant proteins in the obstructed kidneys was assessed using Western blotting assays. Cultured rat renal fibroblast NRK-49F cells were used for in vitro experiments.<br><br>RESULTS: In the obstructed kidneys, Ang II levels were significantly elevated, and collagen I was accumulated in the interstitial spaces. Furthermore, ROS production and the expression of p47 (a key subunit of NADPH oxidase complexes) were increased in a time-dependent manner; the expression of fibronectin, &#x3b1;-SMA and TGF-&#x3b2; were upregulated. Administration of NAC significantly alleviated the fibrotic responses in the obstructed kidneys. In cultured NRK-49F cells, treatment with Ang II (0.001-10 &#x3bc;mol/L) increased the expression of fibronectin, collagen I, &#x3b1;-SMA and TGF-&#x3b2; in dose-dependent and time-dependent manners. Ang II also increased ROS production and the phosphorylation of Smad3. Pretreatment with NAC (5 &#x3bc;mol/L) blocked Ang II-induced oxidative stress and ECM production in the cells.<br><br>CONCLUSION: In mouse obstructed kidneys, the fibrotic responses result from Ang II upregulation can be alleviated by the ROS scavenger N-acetylcysteine.}, }
@article {pmid27040821, year = {2016}, author = {Choi, BY and Kim, IY and Kim, JH and Lee, BE and Lee, SH and Kho, AR and Jung, HJ and Sohn, M and Song, HK and Suh, SW}, title = {Decreased cysteine uptake by EAAC1 gene deletion exacerbates neuronal oxidative stress and neuronal death after traumatic brain injury.}, journal = {Amino acids}, volume = {48}, number = {7}, pages = {1619-1629}, doi = {10.1007/s00726-016-2221-4}, pmid = {27040821}, issn = {1438-2199}, mesh = {*Acetylcysteine/pharmacokinetics/pharmacology ; Animals ; Brain Injuries, Traumatic/genetics/*metabolism/pathology ; Cell Death/drug effects/genetics ; Excitatory Amino Acid Transporter 3/*deficiency ; *Gene Deletion ; Mice ; Mice, Knockout ; Neurons/*metabolism/pathology ; Oxidative Stress/*drug effects/genetics ; }, abstract = {Excitatory amino acid carrier type 1 (EAAC1), a high-affinity glutamate transporter, can expend energy to move glutamate into neurons. However, under normal physiological conditions, EAAC1 does not have a great effect on glutamate clearance but rather participates in the neuronal uptake of cysteine. This process is critical to maintaining neuronal antioxidant function by providing cysteine for glutathione synthesis. Previous study showed that mice lacking EAAC1 show increased neuronal oxidative stress following transient cerebral ischemia. In the present study, we sought to characterize the role of EAAC1 in neuronal resistance after traumatic brain injury (TBI). Young adult C57BL/6 wild-type or EAAC1 (-/-) mice were subjected to a controlled cortical impact model for TBI. Neuronal death after TBI showed more than double the number of degenerating neurons in the hippocampus in EAAC1 (-/-) mice compared with wild-type mice. Superoxide production, zinc translocation and microglia activation similarly showed a marked increase in the EAAC1 (-/-) mice. Pretreatment with N-acetyl cysteine (NAC) reduced TBI-induced neuronal death, superoxide production and zinc translocation. These findings indicate that cysteine uptake by EAAC1 is important for neuronal antioxidant function and survival following TBI. This study also suggests that administration of NAC has therapeutic potential in preventing TBI-induced neuronal death.}, }
@article {pmid27038427, year = {2017}, author = {Kim, RJ and Kang, JR and Hah, YS and Park, HB}, title = {N-acetyl cysteine protects cells from chondrocyte death induced by local anesthetics.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {35}, number = {2}, pages = {297-303}, doi = {10.1002/jor.23254}, pmid = {27038427}, issn = {1554-527X}, mesh = {Acetylcysteine/*therapeutic use ; Anesthetics, Local/*adverse effects ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 7/metabolism ; Chondrocytes/*drug effects ; Drug Evaluation, Preclinical ; Free Radical Scavengers/*therapeutic use ; Humans ; Primary Cell Culture ; Reactive Oxygen Species/metabolism ; }, abstract = {Local anesthetics (LA) are among the drugs most frequently used for musculoskeletal problems, in procedures ranging from diagnosis to postoperative pain control. Chondrocyte toxicity induced by LA is an emerging area of concern. The purpose of this study was to determine whether N-acetyl cysteine (NAC), an antioxidant, will exert cytoprotective effects against chondrocyte death induced by LA. Primary cultured human chondrocytes were used for this study. This study used control, NAC, LA, and NAC-LA groups. Cytotoxicity was induced in the LA subgroups and their paired NAC-LA subgroups through exposure to ropivacaine (0.075%), bupivacaine (0.05%), or lidocaine (0.2%) for 24 h. The NAC-LA subgroups were exposed to 10 mM NAC for 1 h, before LA exposure. These study groups were evaluated for rates of cell viability, apoptosis, necrosis, intracellular ROS production, and caspase-3/7 activity. Cell viability in all LA subgroups was significantly lower than in the control group (p < 0.001). Cell viability in the NAC-LA subgroups was significantly higher than in their paired LA subgroups (p < 0.001). In the LA subgroups, rates of apoptosis and necrosis, intracellular ROS production, and caspase-3/7 activity were significantly higher than in the control group (p ≤ 0.029). In the NAC-LA subgroups, rates of apoptosis and necrosis, intracellular ROS production, and caspase-3/7 activity were significantly lower than in their paired LA subgroups (p ≤ 0.023). These results indicate that N-acetyl cysteine, an antioxidant, has cytoprotective effects against LA-induced toxicity to chondrocytes in vitro. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:297-303, 2017.}, }
@article {pmid27037130, year = {2016}, author = {Bodur, A and Alver, A and Kahraman, C and Altay, DU and İnce, &#x130;}, title = {Investigation of N-acetylcysteine on contralateral testis tissue injury by experimental testicular torsion: long-term effect.}, journal = {The American journal of emergency medicine}, volume = {34}, number = {6}, pages = {1069-1074}, doi = {10.1016/j.ajem.2016.03.021}, pmid = {27037130}, issn = {1532-8171}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Catalase/metabolism ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Male ; Malondialdehyde/metabolism ; Rats ; Spermatic Cord Torsion/*complications/metabolism/pathology ; Superoxide Dismutase/metabolism ; Testicular Diseases/etiology/*prevention &amp; control ; Time Factors ; }, abstract = {BACKGROUND: The aim of the study was to investigate long-term effects of N-acetylcysteine (NAC) on contralateral testes by experimental testicular torsion using histopathologic and biochemical parameters.<br><br>METHODS: Eighteen rats were randomized and divided into 3 groups. In group 1, the control group (C), laparotomy was performed and the left and right testes were excised 2 months later. In group 2, the torsion and detorsion group (T), the torsion was performed by rotating the left testis 720&#xb0; to clockwise direction, and then 4 hours later, detorsion was performed; 2 months later, contralateral testes were removed. In group 3, the NAC adding torsion and detorsion group (T+NAC), the torsion was performed by rotating the left testis 720&#xb0; to clockwise direction, and then 4 hours later, detorsion was performed. N-acetylcysteine was given intraperitoneally 30 minutes before detorsion and following 5 days after detorsion.<br><br>RESULTS: GPx activities were increased in the T and T+NAC groups compared with the control (P = .008 and P = .016, respectively). Seminiferous tubule diameter thickness is decreased in the torsion group compared with the control group and decreased in the T+NAC group compared with the torsion group (P < .05).<br><br>CONCLUSION: In the long term as implied from the histopathologic findings, NAC has beneficial effects against contralateral testis tissue injury induced by testicular torsion.}, }
@article {pmid27035545, year = {2016}, author = {Wang, H and Sun, N and Li, X and Li, K and Tian, J and Li, J}, title = {Diallyl trisulfide induces osteosarcoma cell apoptosis through reactive oxygen species-mediated downregulation of the PI3K/Akt pathway.}, journal = {Oncology reports}, volume = {35}, number = {6}, pages = {3648-3658}, doi = {10.3892/or.2016.4722}, pmid = {27035545}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Allyl Compounds/*pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Bone Neoplasms/drug therapy/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival ; Chromones/pharmacology ; Cyclin D1/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Morpholines/pharmacology ; Osteosarcoma/*drug therapy/pathology ; Phosphatidylinositol 3-Kinases/metabolism ; *Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-akt/*antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; Sulfides/*pharmacology ; }, abstract = {Diallyl trisulfide (DATS) is a natural organosulfur compound isolated from garlic, and has been reported to possess anticancer activities. However, the cancer growth inhibitory effects and molecular mechanisms in human osteosarcoma cells have not been well studied. The present study demonstrated that DATS significantly reduced cell viability in a dose- and time-dependent manner in MG63 and MNNG/HOS cells. DATS-induced G0/G1 phase arrest was found to correlate with a decrease in cyclin D1 in concomitance with an increase in p21 and p27. DATS induced a marked increase in reactive oxygen species (ROS) levels and collapse of mitochondrial membrane potential (Δψm) in the osteosarcoma cells. DATS induced apoptosis in the MG63 and MNNG/HOS cells via inhibition of the PI3K/Akt signaling pathway and through the mitochondrial apoptotic pathway. The efficiency of DATS basically approached the efficacy of LY294002, a specific PI3K inhibitor. However, N-acetylcysteine (NAC), a general ROS scavenger, completely blocked the DATS-induced ROS increase, inhibition of the PI3K/Akt pathway and cell apoptosis. Overall, DATS has the potential to be developed as a new anticancer drug. The mechanisms of action involve the ROS-mediated downregulation of the PI3K/Akt pathway.}, }
@article {pmid27035383, year = {2016}, author = {Zhu, Y and Li, S and Teng, X}, title = {The involvement of the mitochondrial pathway in manganese-induced apoptosis of chicken splenic lymphocytes.}, journal = {Chemosphere}, volume = {153}, number = {}, pages = {462-470}, doi = {10.1016/j.chemosphere.2016.03.081}, pmid = {27035383}, issn = {1879-1298}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Calmodulin/metabolism ; Caspase 3/metabolism ; Cells, Cultured ; Chickens/*metabolism ; Chlorides/*toxicity ; Glutathione Peroxidase/metabolism ; Lymphocytes/metabolism ; Malondialdehyde/metabolism ; Manganese Compounds ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*metabolism ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Spleen/cytology/metabolism ; Superoxide Dismutase/metabolism ; Tumor Suppressor Protein p53/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {The purpose of this study was to investigate the effect of excess manganese (Mn)-induced cytotoxicity on apoptosis in chicken splenic lymphocytes. Chicken splenic lymphocytes were cultured in medium in the absence and presence of manganese (II) chloride (MnCl2) (2 × 10(-4), 4 × 10(-4), 6 × 10(-4), 8 × 10(-4), 10 × 10(-4), and 12 × 10(-4) mM), in N-acetyl-l-cysteine (NAC) (1 mM), and the combination of MnCl2 and NAC for 12, 24, 36, and 48 h. Tests were performed on morphologic observation, reactive oxygen species (ROS) and malondialdehyde (MDA) content, manganese superoxide dismutase (Mn-SOD) and glutathione peroxidase (GSH-Px) activities, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), p53, and calmodulin (CaM) messenger RNA (mRNA) expression, Caspase-3 mRNA and protein expression, intracellular free Ca(2+) ([Ca(2+)]i), and mitochondrial transmembrane potential (ΔΨm). Our research indicated that excess Mn induced ROS and MDA content, inhibited Mn-SOD and GSH-Px activities, induced Bax and p53 mRNA expression, inhibited Bcl-2 and CaM mRNA expression, induced Caspase-3 mRNA and protein expression, upregulated [Ca(2+)]i, inhibited ΔΨm, and induced apoptosis in a dose effect. NAC relieved excess Mn-caused the changes of all above factors. Mn-induced oxidative injuries were alleviated by treatment with NAC, an ROS scavenger. The above results demonstrated that excess Mn caused oxidative stress and apoptosis via mitochondrial pathway in chicken splenic lymphocytes.}, }
@article {pmid27035222, year = {2016}, author = {Tu, P and Huang, Q and Ou, Y and Du, X and Li, K and Tao, Y and Yin, H}, title = {Aloe-emodin-mediated photodynamic therapy induces autophagy and apoptosis in human osteosarcoma cell line MG‑63 through the ROS/JNK signaling pathway.}, journal = {Oncology reports}, volume = {35}, number = {6}, pages = {3209-3215}, pmid = {27035222}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Anthraquinones/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/*drug effects ; Bone Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Osteosarcoma/*drug therapy/pathology ; Photochemotherapy ; Photosensitizing Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {The present study was carried out to investigate the effect and mechanisms of aloe‑emodin (AE)-mediated photodynamic therapy (AE-PDT) on the human osteosarcoma cell line MG-63. After treatment with AE-PDT, the human osteosarcoma cell line MG-63 was tested for levels of viability, autophagy, reactive oxygen species (ROS) and apoptosis and changes in cell morphology with the Cell Counting Kit-8 (CCK‑8), monodansylcadaverine (MDC) and Hoechst staining and transmission electron microscopy. The expression of proteins including LC-3, cleaved caspase-3, Beclin-1, Bcl-2, p-JNK, t-JNK and β-actin was examined with western blotting. AE-PDT significantly inhibited the viability of the MG-63 cells in an AE-concentration- and PDT energy density-dependent manner. Autophagy and apoptosis of MG-63 cells was substantially promoted in the AE-PDT group compared to the control group, the AE alone group and the light emitting diode (LED) alone group. Inhibition of autophagy by 3-methyladenine (3-MA) (5 mM) and chloroquine (CQ) (15 µM) significantly promoted the apoptosis rate and improved the sensitivity of the MG-63 cells to AE-PDT. AE-PDT was found to induce the expression of ROS and p-JNK. ROS scavenger, N-acetyl-L-cysteine (NAC, 5 mM), was able to hinder the autophagy, apoptosis and phosphorylation of JNK, and JNK inhibitor (SP600125, 10 µM) significantly inhibited the autophagy and apoptosis, and attenuated the sensitivity of MG63 cells to AE-PDT. In conclusion, AE-PDT induced the autophagy and apoptosis of human osteosarcoma cell line MG-63 through the activation of the ROS-JNK signaling pathway. Autophagy may play a protective role during the early stage following treatment of AE-PDT.}, }
@article {pmid27035109, year = {2016}, author = {Lu, J and Zhang, L and Xie, F and Zhu, L and Li, X and Ouyang, J and He, X and Han, S and Yi, C}, title = {Mild oxidative stress induced by a low dose of cisplatin contributes to the escape of TRAIL-mediated apoptosis in the ovarian cancer SKOV3 cell line.}, journal = {Oncology reports}, volume = {35}, number = {6}, pages = {3427-3434}, doi = {10.3892/or.2016.4702}, pmid = {27035109}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cisplatin/*pharmacology ; Drug Tolerance ; Female ; Humans ; Ovarian Neoplasms/*drug therapy/metabolism/pathology ; Oxidative Stress/*drug effects ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; }, abstract = {Tumor necrosis factor (TNF)-related apoptosis‑inducing ligand (TRAIL) is expressed in ovarian tissue and is widely thought to exhibit strong antitumor activity in a variety of tumor cell types. Therefore, we hypothesized that the cisplatin resistance of ovarian cancer is linked to the ability to escape from TRAIL-mediated apoptosis. We demonstrated that cisplatin-resistant ovarian cancer cell line SKOV3/DDP tolerated treatment with TRAIL, in contrast to the cisplatin‑sensitive ovarian cancer cell line SKOV3. SKOV3/DDP cells exhibited a much higher cell viability and a lower apoptosis rate than SKOV3 cells after treatment with TRAIL. To determine whether cisplatin induced the tolerance of TRAIL, we pretreated the SKOV3 cells with cisplatin in the presence of TRAIL. This revealed that a low dose of cisplatin (1 µM) increased the TRAIL tolerance of SKOV3 cells. Furthermore, cisplatin induced oxidative stress in both the SKOV3/DDP and SKOV3 cells, although the oxidative stress level of the SKOV3/DDP cells was generally much higher than that noted in the SKOV3 cells. Similarly, a low dose of hydrogen peroxide increased the TRAIL tolerance in SKOV3 cells. Notably, the TRAIL tolerance in the SKOV3 and SKOV3/DDP cells could be abrogated by the oxidative stress scavenger N-acetyl-cysteine. These results suggest that a low dose of cisplatin induces the tolerance of TRAIL in SKOV3 cells at least partly, depending on the oxidative stress signaling pathway.}, }
@article {pmid27035100, year = {2016}, author = {Jiang, Y and Wang, X and Li, Y and Mu, S and Zhou, S and Liu, Y and Zhang, B}, title = {GGsTOP increases migration of human periodontal ligament cells in vitro via reactive oxygen species pathway.}, journal = {Molecular medicine reports}, volume = {13}, number = {5}, pages = {3813-3820}, pmid = {27035100}, issn = {1791-3004}, mesh = {Adolescent ; Aminobutyrates/*pharmacology ; Animals ; Cell Movement/*drug effects ; Cells, Cultured ; Female ; Humans ; Male ; Mice ; Organophosphonates/*pharmacology ; Periodontal Ligament/cytology/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {GGsTOP is a novel and selective inhibitor of gamma-glutamyl transferase (GGT), a cell-surface enzyme that has a key role in glutathione homeostasis and the maintenance of cellular reactive oxygen species (ROS). ROS are essential for wound healing. However, little is known about the molecular mechanisms underlying the inhibition of GGT by GGsTOP in human periodontal ligament cells (hPLCs). The present study assessed GGT expression in mouse periodontal ligament tissues, GGT activity in hPLCs, and the potential physiological effect of GGsTOP on hPLC migration. Immunohistochemical analysis confirmed that GGT was widely expressed in mouse periodontal ligament tissue. Treatment with GGsTOP was associated with greater proliferation and migration of hPLCs, and higher levels of cellular ROS compared with untreated hPLCs. However, the increase in intracellular ROS was attenuated in hPLCs co‑cultured with the anti‑oxidant N‑acetylcysteine (NAC), a precursor of glutathione. The higher ROS levels associated with GGsTOP treatment were in parallel with increases in the levels of type I collagen and alpha smooth muscle actin, which was inhibited in hPLCs co‑cultured with NAC. Thus, GGsTOP may promote hPLC migration and participate in the maintenance of the periodontal ligament apparatus via the ROS pathway.}, }
@article {pmid27034735, year = {2016}, author = {Du, X and West, MB and Cheng, W and Ewert, DL and Li, W and Saunders, D and Towner, RA and Floyd, RA and Kopke, RD}, title = {Ameliorative Effects of Antioxidants on the Hippocampal Accumulation of Pathologic Tau in a Rat Model of Blast-Induced Traumatic Brain Injury.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {4159357}, pmid = {27034735}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Benzenesulfonates/pharmacology/*therapeutic use ; Blast Injuries/complications/*drug therapy/metabolism/pathology ; Brain Injuries, Traumatic/complications/*drug therapy/metabolism/pathology ; Cytoprotection/drug effects ; Disease Models, Animal ; Hippocampus/*drug effects/metabolism/pathology ; Male ; Neuroprotective Agents/pharmacology/therapeutic use ; Protein Aggregation, Pathological/metabolism/pathology/*prevention &amp; control ; Rats ; Rats, Long-Evans ; tau Proteins/*metabolism ; }, abstract = {Traumatic brain injury (TBI) can lead to early onset dementia and other related neurodegenerative diseases. We previously demonstrated that damage to the central auditory pathway resulting from blast-induced TBI (bTBI) could be significantly attenuated by a combinatorial antioxidant treatment regimen. In the current study, we examined the localization patterns of normal Tau and the potential blast-induced accumulation of neurotoxic variants of this microtubule-associated protein that are believed to potentiate the neurodegenerative effects associated with synaptic dysfunction in the hippocampus following three successive blast overpressure exposures in nontransgenic rats. We observed a marked increase in the number of both hyperphosphorylated and oligomeric Tau-positive hilar mossy cells and somatic accumulation of endogenous Tau in oligodendrocytes in the hippocampus. Remarkably, a combinatorial regimen of 2,4-disulfonyl α-phenyl tertiary butyl nitrone (HPN-07) and N-acetylcysteine (NAC) resulted in striking reductions in the numbers of both mossy cells and oligodendrocytes positively labeled for these pathological Tau immunoreactivity patterns in response to bTBI. This treatment strategy represents a promising therapeutic approach for simultaneously reducing or eliminating both primary auditory injury and nonauditory changes associated with bTBI-induced hippocampal neurodegeneration.}, }
@article {pmid27033208, year = {2016}, author = {Moon, JH and Choi, YS and Lee, HW and Heo, JS and Chang, SW and Lee, JY}, title = {Antibacterial effects of N-acetylcysteine against endodontic pathogens.}, journal = {Journal of microbiology (Seoul, Korea)}, volume = {54}, number = {4}, pages = {322-329}, pmid = {27033208}, issn = {1976-3794}, mesh = {Acetylcysteine/*pharmacology ; Actinomyces/*drug effects/physiology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/drug effects ; Calcium Hydroxide/pharmacology ; Chlorhexidine/pharmacology ; Dental Pulp Cavity/microbiology ; Durapatite ; Enterococcus faecalis/*drug effects/physiology ; Humans ; Lactobacillus/*drug effects/physiology ; Microbial Viability/drug effects ; Saliva ; Streptococcus mutans/*drug effects/physiology ; }, abstract = {The success of endodontic treatment depends on the eradication of microorganisms from the root canal system and the prevention of reinfection. The purpose of this investigation was to evaluate the antibacterial and antibiofilm efficacy of N-acetylcysteine (NAC), an antioxidant mucolytic agent, as an intracanal medicament against selected endodontic pathogens. Minimum inhibitory concentrations (MICs) of NAC for Actinomyces naeslundii, Lactobacillus salivarius, Streptococcus mutans, and Enterococcus faecalis were determined using the broth microdilution method. NAC showed antibacterial activity, with MIC values of 0.78-1.56 mg/ml. The effect of NAC on biofilm formation of each bacterium and a multispecies culture consisting of the four bacterial species was assessed by crystal violet staining. NAC significantly inhibited biofilm formation by all the monospecies and multispecies bacteria at minimum concentrations of 0.78-3.13 mg/ml. The efficacy of NAC for biofilm disruption was evaluated by scanning electron microscopy and ATP-bioluminescence quantification using mature multispecies biofilms. Preformed mature multispecies biofilms on saliva-coated hydroxyapatite disks were disrupted within 10 min by treatment with NAC at concentrations of 25 mg/ml or higher. After 24 h of treatment, the viability of mature biofilms was reduced by > 99% compared with the control. Moreover, the biofilm disrupting activity of NAC was significantly higher than that of saturated calcium hydroxide or 2% chlorhexidine solution. Within the limitations of this in vitro study, we conclude that NAC has excellent antibacterial and antibiofilm efficacy against endodontic pathogens and may be used as an alternative intracanal medicament in root canal therapies.}, }
@article {pmid27032906, year = {2016}, author = {Wei, B and Huang, Q and Huang, S and Mai, W and Zhong, X}, title = {Trichosanthin-induced autophagy in gastric cancer cell MKN-45 is dependent on reactive oxygen species (ROS) and NF-κB/p53 pathway.}, journal = {Journal of pharmacological sciences}, volume = {131}, number = {2}, pages = {77-83}, doi = {10.1016/j.jphs.2016.03.001}, pmid = {27032906}, issn = {1347-8648}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Autophagy/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; NF-kappa B/*metabolism ; Reactive Oxygen Species/*metabolism ; Stomach Neoplasms/drug therapy/*metabolism ; Trichosanthin/*pharmacology/therapeutic use ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Trichosanthin (TCS), isolated from the root tuber of Trichosanthes kirilowii tubers in the Cucurbitaceae family, owns a great deal of biological and pharmacological activities including anti-virus and anti-tumor. TCS has been reported to induce cell apoptosis of a diversity of cancers, including cervical cancer, choriocarcinoma, and gastric cancer, etc. However, whether TCS would induce autophagy in gastric cancer cells was seldom investigated. In current study, human gastric cancer MKN-45 cell growth was significantly inhibited by TCS. The anti-proliferation effect of TCS was due to an increased autophagy, which was confirmed by monodansylcadervarine (MDC) staining, up-regulation of Autophagy protein 5 (Atg5), and conversion of LC3 I to LC3 II (autophagosome marker). In addition, TCS induced reactive oxygen species (ROS) in MKN-45 cells and ROS scavenger N-acetylcysteine (NAC) significantly reversed TCS-induced autophagy. Furthermore, NF-κB/p53 pathway was activated during the process of autophagy induced by TCS and the ROS generation was mediated by it in MKN-45 cells. In vivo results showed that TCS exerted significantly anti-tumor effect on MKN-45 bearing mice. Considering the clinical usage of TCS on other human diseases, these research progresses provided a new insight into cancer research and new therapeutic avenues for patients with gastric cancer.}, }
@article {pmid27031525, year = {2015}, author = {Tie, G and Yan, J and Messina, JA and Raffai, RL and Messina, LM}, title = {Inhibition of p38 Mitogen-Activated Protein Kinase Enhances the Apoptosis Induced by Oxidized Low-Density Lipoprotein in Endothelial Progenitor Cells.}, journal = {Journal of vascular research}, volume = {52}, number = {6}, pages = {361-371}, doi = {10.1159/000443889}, pmid = {27031525}, issn = {1423-0135}, mesh = {Animals ; Apolipoproteins E/deficiency/genetics ; Apoptosis/*drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Endothelial Progenitor Cells/*drug effects/enzymology/pathology ; Humans ; Hypercholesterolemia/*enzymology/genetics/pathology ; Lipoproteins, LDL/*pharmacology ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphorylation ; Protein Kinase Inhibitors/*pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Scavenger Receptors, Class E/metabolism ; Signal Transduction/drug effects ; Time Factors ; p38 Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Oxidized low-density lipoprotein (oxLDL) is an important risk factor in the development of atherosclerosis. oxLDL has been shown to decrease endothelial progenitor cell (EPC) number by inducing apoptosis. p38 mitogen-activated protein kinase (MAPK) was shown to be activated by oxLDL and participated in the regulation of EPC number and function. However, the role of p38 remains unknown. Here, we show that oxLDL-induced p38 phosphorylation in EPCs is time and dose dependent. Treatment with antioxidant N-acetyl cysteine restored oxLDL-induced p38 phosphorylation to basal levels. LOX-1-blocking antibody also significantly decreased oxLDL-induced p38 phosphorylation. Interestingly, TUNEL staining showed that pretreatment with the p38 inhibitor SB203580 further increased oxLDL-induced apoptosis in EPCs. In accordance with these findings, pretreatment with SB203580 further attenuated Akt phosphorylation in EPCs challenged with oxLDL, indicating an interaction between Akt and p38 MAPK pathways. In agreement, inhibition of p38 MAPK further attenuated Akt phosphorylation and increased apoptosis in EPCs isolated from hypercholesterolemic ApoE-/- mice. In conclusion, p38 MAPK serves as an anti-apoptotic pathway by supporting Akt activity when EPCs are challenged with oxLDL.}, }
@article {pmid27029584, year = {2016}, author = {Geohagen, BC and Vydyanathan, A and Kosharskyy, B and Shaparin, N and Gavin, T and LoPachin, RM}, title = {Enolate-Forming Phloretin Pharmacophores: Hepatoprotection in an Experimental Model of Drug-Induced Toxicity.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {357}, number = {3}, pages = {476-486}, pmid = {27029584}, issn = {1521-0103}, support = {R01 ES003830/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/*metabolism/*toxicity ; Animals ; Benzoquinones/*metabolism ; Cytoprotection/*drug effects ; Imines/*metabolism ; Liver/cytology/*drug effects/metabolism ; Male ; Mice ; Phloretin/metabolism/*pharmacology ; }, abstract = {Drug-induced toxicity is often mediated by electrophilic metabolites, such as bioactivation of acetaminophen (APAP) to N-acetyl-p-benzoquinone imine (NAPQI). We have shown that APAP hepatotoxicity can be prevented by 2-acetylcyclopentanone (2-ACP). This 1,3-dicarbonyl compound ionizes to form an enolate nucleophile that scavenges NAPQI and other electrophilic intermediates. In this study, we expanded our investigation of enolate-forming compounds to include analyses of the phloretin pharmacophores, 2',4',6'-trihydroxyacetophenone (THA) and phloroglucinol (PG). Studies in a mouse model of APAP overdose showed that THA provided hepatoprotection when given either by intraperitoneal injection or oral administration, whereas PG was hepatoprotective only when given intraperitoneally. Corroborative research characterized the molecular pharmacology (efficacy, potency) of 2-ACP, THA, and PG in APAP-exposed isolated mouse hepatocytes. For comparative purposes, N-acetylcysteine (NAC) cytoprotection was also evaluated. Measurements of multiple cell parameters (e.g., cell viability, mitochondrial membrane depolarization) indicated that THA and, to a lesser extent, PG provided concentration-dependent protection against APAP toxicity, which exceeded that of 2-ACP or NAC. The enolate-forming compounds and NAC truncated ongoing APAP exposure and thereby returned intoxicated hepatocytes toward normal viability. The superior ability of THA to protect is related to multifaceted modes of action that include metal ion chelation, free radical trapping, and scavenging of NAPQI and other soft electrophiles involved in oxidative stress. The rank order of potency for the tested cytoprotectants was consistent with that determined in a parallel mouse model. These data suggest that THA or a derivative might be useful in treating drug-induced toxicities and other conditions that involve electrophile-mediated pathogenesis.}, }
@article {pmid27027616, year = {2016}, author = {Jouett, NP and Moralez, G and White, DW and Eubank, WL and Chen, S and Tian, J and Smith, ML and Zimmerman, MC and Raven, PB}, title = {N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects.}, journal = {Experimental physiology}, volume = {101}, number = {3}, pages = {387-396}, pmid = {27027616}, issn = {1469-445X}, support = {P30GM103335/GM/NIGMS NIH HHS/United States ; HL106431/HL/NHLBI NIH HHS/United States ; P20 RR017675/RR/NCRR NIH HHS/United States ; R21 HL106431/HL/NHLBI NIH HHS/United States ; P30 GM103335/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Blood Pressure/drug effects ; Female ; Humans ; Hypoxia/*physiopathology ; Male ; Muscles/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Respiration/drug effects ; Sleep Apnea, Obstructive/drug therapy/metabolism ; Superoxides/metabolism ; Sympathetic Nervous System/*drug effects/metabolism/physiopathology ; }, abstract = {What is the central question of this study? This study evaluated the following central question: does N-acetylcysteine (N-AC), an antioxidant that readily penetrates the blood-brain barrier, have the capability to reduce the increase in sympathetic nerve activity observed during hyperacute intermittent hypoxia? What is the main finding and its importance? We demonstrate that N-AC decreases muscle sympathetic nerve activity in response to hyperacute intermittent hypoxia versus placebo control. This finding suggests that antioxidants, such as N-AC, have therapeutic potential in obstructive sleep apnoea. This investigation tested the following hypotheses: that (i) N-acetylcysteine (N-AC) attenuates hyperacute intermittent hypoxia-induced sympathoexcitation, (ii) without elevating superoxide measured in peripheral venous blood. Twenty-eight healthy human subjects were recruited to the study. One hour before experimentation, each subject randomly ingested either 70 mg kg(-1) of N-AC (n = 16) or vehicle placebo (n = 12). Three-lead ECG and arterial blood pressure, muscle sympathetic nerve activity (n = 17) and whole-blood superoxide concentration (using electron paramagnetic resonance spectroscopy; n = 12) were measured. Subjects underwent a 20 min hyperacute intermittent hypoxia training (hAIHT) protocol that consisted of cyclical end-expiratory apnoeas with 100% nitrogen. N-AC decreased muscle sympathetic nerve activity after hAIHT compared with placebo (P < 0.02). However, N-AC did not alter superoxide concentrations in venous blood compared with placebo (P > 0.05). Moreover, hAIHT did not increase superoxide concentrations in the peripheral circulation as measured by electron paramagnetic resonance (P > 0.05). Based on these findings, we contend that (i) hAIHT and (ii) the actions of N-AC in hAIHT are primarily mediated centrally rather than peripherally, although central measurements of reactive oxygen species are difficult to obtain in human subjects, thus making this assertion difficult to verify. This investigation suggests the possibility of developing a pharmaceutical therapy to inhibit the sympathoexcitation associated with obstructive sleep apnoea.}, }
@article {pmid27027204, year = {2016}, author = {Bloch, MH and Panza, KE and Yaffa, A and Alvarenga, PG and Jakubovski, E and Mulqueen, JM and Landeros-Weisenberger, A and Leckman, JF}, title = {N-Acetylcysteine in the Treatment of Pediatric Tourette Syndrome: Randomized, Double-Blind, Placebo-Controlled Add-On Trial.}, journal = {Journal of child and adolescent psychopharmacology}, volume = {26}, number = {4}, pages = {327-334}, pmid = {27027204}, issn = {1557-8992}, support = {K23 MH091240/MH/NIMH NIH HHS/United States ; R01 HD070821/HD/NICHD NIH HHS/United States ; T32 MH018268/MH/NIMH NIH HHS/United States ; UL1 RR024139/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Anxiety/drug therapy ; Attention Deficit Disorder with Hyperactivity/drug therapy ; Child ; Depression/drug therapy ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Linear Models ; Male ; Obsessive-Compulsive Disorder/drug therapy ; Severity of Illness Index ; Tics/*drug therapy/etiology ; Tourette Syndrome/*drug therapy/physiopathology ; Treatment Outcome ; }, abstract = {BACKGROUND: Current pharmacological treatments for Tourette Syndrome (TS), such as antipsychotic agents and α-2 agonists, are moderately effective in the treatment of tics, but have substantial side effects that limit their use. N-acetylcysteine (NAC) modulates glutamatergic systems, and has been used safely as an antioxidant agent with minimal side effects for decades. NAC has been increasingly studied for the treatment of other obsessive-compulsive spectrum disorders. We aim to examine the efficacy of NAC for the treatment of pediatric TS in a double-blind, placebo-controlled, add-on study.<br><br>METHODS: Thirty-one children and adolescents 8-17 years of age with TS were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary outcome was change in severity of tics as measured by the Yale Global Tic Severity Scale (YGTSS), Total tic score. Secondary measures assessed comorbid obsessive-compulsive disorder (OCD), depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD). Linear mixed models in SAS were used to examine differences between NAC and placebo.<br><br>RESULTS: Of 31 randomized subjects, 14 were assigned to placebo (two females; 11.5 + 2.8 years) and 17 to active NAC (five females; 12.4 + 1.4 years) treatment. No significant difference between NAC and placebo was found in reducing tic severity or any secondary outcomes.<br><br>CONCLUSIONS: We found no evidence for efficacy of NAC in treating tic symptoms. Our findings stand in contrast to studies suggesting benefits of NAC in the treatment of other obsessive-compulsive spectrum disorders in adults, including OCD and trichotillomania, but are similar to a recent placebo-controlled trial of pediatric trichotillomania that found no benefit of NAC.}, }
@article {pmid27021842, year = {2016}, author = {Liu, X and Lu, YF and Guan, X and Zhao, M and Wang, J and Li, F}, title = {Characterizing novel metabolic pathways of melatonin receptor agonist agomelatine using metabolomic approaches.}, journal = {Biochemical pharmacology}, volume = {109}, number = {}, pages = {70-82}, doi = {10.1016/j.bcp.2016.03.020}, pmid = {27021842}, issn = {1873-2968}, support = {R01 GM115622/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetamides/chemistry/pharmacokinetics/*urine ; Animals ; Biotransformation ; Cytochrome P-450 Enzyme System/*metabolism ; Feces/chemistry ; Gene Expression Regulation ; Glutathione/chemistry ; Humans ; Hypnotics and Sedatives/chemistry/pharmacokinetics/*urine ; Isoenzymes/metabolism ; Metabolic Networks and Pathways/genetics ; Metabolomics ; Mice ; Mice, Inbred ICR ; Microsomes, Liver/drug effects/*metabolism ; Receptors, Melatonin/*agonists/genetics/metabolism ; Semicarbazides/chemistry ; Signal Transduction ; }, abstract = {Agomelatine (AGM), an analog of melatonin, is a potential agonist at melatonin receptors 1/2 and a selective antagonist at 5-hydroxytryptamine 2C receptors. AGM is widely used for the treatment of major depressive episodes in adults. However, multiple adverse effects associated with AGM have been reported in clinical practice. It is little known about AGM metabolism in vitro and in vivo, although metabolism plays a pivotal role in its efficacy and safety. To elucidate metabolic pathways of AGM, we systemically investigated AGM metabolism and its bioactivation in human liver microsomes (HLM) and mice using metabolomic approaches. We identified thirty-eight AGM metabolites and adducts, among which thirty-two are novel. In HLM, we uncovered five GSH-trapped adducts and two semicarbazide-trapped aldehydes. Moreover, we characterized three N-acetyl cysteine conjugated-AGM adducts in mouse urine and feces, which were formed from the degradation of AGM_GSH adducts. Using recombinant CYP450 isoenzymes and chemical inhibitors, we demonstrated that CYP1A2 and CYP3A4 are primary enzymes contributing to the formation of AGM_GSH adducts and AGM_hydrazones. This study provided a global view of AGM metabolism and identified the novel pathways of AGM bioactivation, which could be utilized for further understanding the mechanism of adverse effects related to AGM and possible drug-drug interactions.}, }
@article {pmid27016837, year = {2016}, author = {Yang, F and Liu, LH and Li, XP and Luo, JY and Zhang, Z and Yan, ZT and Zhang, SD and Li, HS}, title = {Short communication: N-Acetylcysteine-mediated modulation of antibiotic susceptibility of bovine mastitis pathogens.}, journal = {Journal of dairy science}, volume = {99}, number = {6}, pages = {4300-4302}, doi = {10.3168/jds.2015-10756}, pmid = {27016837}, issn = {1525-3198}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Bacterial Agents/pharmacology ; Cattle ; Female ; Mastitis, Bovine/*microbiology ; Microbial Sensitivity Tests ; Staphylococcus aureus/*drug effects ; Streptococcus/drug effects ; }, abstract = {The aim of this study was to investigate the effects of N-acetylcysteine (NAC) on antibiotic susceptibility of bovine mastitis pathogens including Staphylococcus aureus, Streptococcus dysgalactiae, Escherichia coli, and Streptococcus agalactiae. Minimum inhibitory concentrations (MIC) were tested by the agar-based E-test method. The presence of 10mM NAC reduced the MIC of penicillin and ampicillin but enhanced the MIC of erythromycin and ciprofloxacin for all of the strains. In addition, NAC-mediated modulation of MIC of kanamycin, tetracycline, and vancomycin was diverse, depending on the target bacterial pathogen and antibiotic being used. The results suggest that NAC is an important modulator of antibiotic activity against the major bovine mastitis pathogens.}, }
@article {pmid27014809, year = {2016}, author = {Wang, D and Qi, J and Pan, X and Yan, D and Yan, H}, title = {[The antagonistic effect and mechanism of N-acetylcysteine on acrylamide-induced hepatic and renal toxicity].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {34}, number = {1}, pages = {13-17}, doi = {10.3760/cma.j.issn.1001-9391.2016.01.003}, pmid = {27014809}, issn = {1001-9391}, mesh = {Acetylcysteine/*pharmacology ; Acrylamide/*toxicity ; Animals ; Cyclooxygenase 2/metabolism ; Female ; I-kappa B Proteins/metabolism ; Kidney/*drug effects/metabolism/pathology ; Liver/*drug effects/metabolism ; NF-KappaB Inhibitor alpha ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Transcription Factor RelA/metabolism ; }, abstract = {OBJECTIVE: The aim of this study is to investigate hepatic and renal toxicity of acrylamide (ACR) , the antagonistic effect and possible mechanism of N-acetylcysteine (NAC) on the toxicity.<br><br>METHODS: Forty female SD rats were randomly divided into four groups. All the rats were administrated by intraperitoneal(i.p.) injection and 1.5 hours later by gavage. The control group was administrated with 0.9% NaCl by i.p. injection and gavaged with 0.9% NaCl. The NAC group was administrated with 200 mg/kg NAC by injection and gavaged with 0.9% NaCl. The ACR group was administrated with 0.9% NaCl by injection and gavaged with 40 mg/kg ACR. The combined treatment group was administrated with 200 mg/kg NAC by i.p. injection and gavaged with 40 mg/kg ACR. The rats were administrated once a day for 2 weeks. After 24 hours of the last administration, the rats were decapitated. The blood was collected, the liver and kidney were separated. The body weight, organ coefficient and serum biochemical parameters were measured, and the pathological changes of the tissues were examined with a microscope. Then the expression of NF-&#x3ba;B p65, I&#x3ba;B-&#x3b1; and COX-2 were detected by Western blot.<br><br>RESULTS: From the second day to the end of the exposure, the body weight of rats in the ACR group was statistically lower than that in the control group (P<0.05) . Compared with the combined treatment group, the body weight in the ACR group statistically decreased in the second and third days (P < 0.05) . The liver and kidney organ coefficients in the ACR group were (4.159%&#xb1;.371%) and (0.764%&#xb1;0.068%) respectively, which increased statistically when compared with the control group (P < 0.05) . The contents of ALT, AST and Cr in the serum in the ACR group were (77.370&#xb1;16.397) U/L&#x3001;(379.410&#xb1;57.817) U/L and (77.812&#xb1;6.391) &#x3bc;mol/L respectively, which were not significantly different with those in the control group and the combined treatment group (P>0.05) . The content of BUN in the serum in the ACR group was (7.005&#xb1;1.009) mmol/L, which was statistically higher than that in the control group (P<0.05) . Histopathology results showed unclear boundary and nucleus pyknosis in hepatocytes, loose and disordered structures of hepatic cords in the ACR group, but no obvious pathology changes were observed in the kidneys of each group. In the Western blot results, the expression of nuclear NF-&#x3ba;B p65 and COX-2 in the liver in the ACR group was statistically higher than that in the control group and the combined treatment group (P<0.05) , and the expression of I&#x3ba;B-&#x3b1; in the liver in the ACR group statistically decreased compared with the control group and the combined treatment group (P<0.05) . The expression of total NF-&#x3ba;B p65 in the liver in the ACR group was statistically higher than that in the control group (P<0.05) .<br><br>CONCLUSION: Under the conditions of this experiment, ACR may induce hepatic toxicity through the activation of NF-&#x3ba;B signaling pathway, and NAC could antagonize the hepatic toxicity of ACR by inhibiting the NF-&#x3ba;B signaling pathway, whereas the toxic effect of ACR on kidney needs to be further studied.}, }
@article {pmid27012423, year = {2016}, author = {Yang, L and Yuan, Y and Fu, C and Xu, X and Zhou, J and Wang, S and Kong, L and Li, Z and Guo, Q and Wei, L}, title = {LZ-106, a novel analog of enoxacin, inducing apoptosis via activation of ROS-dependent DNA damage response in NSCLCs.}, journal = {Free radical biology &amp; medicine}, volume = {95}, number = {}, pages = {155-168}, doi = {10.1016/j.freeradbiomed.2016.03.007}, pmid = {27012423}, issn = {1873-4596}, mesh = {Acetylcysteine/metabolism ; Animals ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Damage/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Enoxacin/*administration &amp; dosage/analogs &amp; derivatives ; Humans ; Mice ; Mitochondria/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {Lung cancer, especially non-small-cell lung cancer (NSCLC), plays the leading role in cancer which is closely related to a myriad of fatal results. Unfortunately, current molecular mechanisms and clinical treatment of NSCLC still remain to be explored despite the fact that intensive investigations have been carried out in the last two decades. Recently, growing attention to finding exploitable sources of anticancer agents is refocused on quinolone compounds, an antibiotic with a long period of clinic application, for their remarkable cell-killing activity against not only bacteria, but eukaryotes as well. In this study, we found LZ-106, an analog of enoxacin, exhibiting potent inhibitory effects on NSCLC in both cultured cells and xenograft mouse model. We identified apoptosis-inducing action of LZ-106 in NSCLC cells through the mitochondrial and endoplasmic reticulum (ER)-stress apoptotic pathways via Annexin-V/PI double-staining assay, membrane potential detection, calcium level detection and the expression analysis of the key apoptotic proteins. Through comet assay, reactive oxygen species (ROS) detection, the expression analysis of DNA damage response (DDR) marker γ-H2AX and other DDR-related proteins, we also demonstrated that LZ-106 notably induced ROS overproduction and DDR. Interestingly, additional evidence in our findings revealed that DDR and apoptosis could be alleviated in the presence of ROS scavenger N-acetyl-cysteine (NAC), indicating ROS-dependent DDR involvement in LZ-106-induced apoptosis. Thus our data not only offered a new therapeutic candidate for NSCLC, but also put new insights into the pharmacological research of quinolones.}, }
@article {pmid27011171, year = {2016}, author = {Margaryan, NV and Gilgur, A and Seftor, EA and Purnell, C and Arva, NC and Gosain, AK and Hendrix, MJ and Strizzi, L}, title = {Melanocytes Affect Nodal Expression and Signaling in Melanoma Cells: A Lesson from Pediatric Large Congenital Melanocytic Nevi.}, journal = {International journal of molecular sciences}, volume = {17}, number = {3}, pages = {418}, pmid = {27011171}, issn = {1422-0067}, support = {R01 CA121205/CA/NCI NIH HHS/United States ; R37 CA059702/CA/NCI NIH HHS/United States ; R01CA121205/CA/NCI NIH HHS/United States ; R37CA59702/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cell Line, Tumor ; Child ; Female ; Humans ; Melanins/pharmacology ; Melanocytes/drug effects/*metabolism ; Melanoma/congenital/*metabolism/pathology ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Nodal Protein/genetics/*metabolism ; *Signal Transduction ; Smad2 Protein/metabolism ; }, abstract = {Expression of Nodal, a Transforming Growth Factor-beta (TGF-β) related growth factor, is associated with aggressive melanoma. Nodal expression in adult dysplastic nevi may predict the development of aggressive melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital melanocytic nevi (LCMN) has shown increased risk for development of melanoma. Here, we investigate whether Nodal expression can help identify the rare cases of LCMN that develop melanoma and shed light on why the majority of these patients do not. Immunohistochemistry (IHC) staining results show varying degree of Nodal expression in pediatric dysplastic nevi and LCMN. Moreover, median scores from Nodal IHC expression analysis were not significantly different between these two groups. Additionally, none of the LCMN patients in this study developed melanoma, regardless of Nodal IHC levels. Co-culture experiments revealed reduced tumor growth and lower levels of Nodal and its signaling molecules P-SMAD2 and P-ERK1/2 when melanoma cells were grown in vivo or in vitro with normal melanocytes. The same was observed in melanoma cells cultured with melanocyte conditioned media containing pigmented melanocyte derived melanosomes (MDM). Since MDM contain molecules capable of inactivating radical oxygen species, to investigate potential anti-oxidant effect of MDM on Nodal expression and signaling in melanoma, melanoma cells were treated with either N-acetyl-l-cysteine (NAC), a component of the anti-oxidant glutathione or synthetic melanin, which in addition to providing pigmentation can also exert free radical scavenging activity. Melanoma cells treated with NAC or synthetic melanin showed reduced levels of Nodal, P-SMAD2 and P-ERK1/2 compared to untreated melanoma cells. Thus, the potential role for Nodal in melanoma development in LCMN is less evident than in adult dysplastic nevi possibly due to melanocyte cross-talk in LCMN capable of offsetting or delaying the pro-melanoma effects of Nodal via anti-oxidant effects of MDM.}, }
@article {pmid27010918, year = {2016}, author = {Bose, D and Banerjee, S and Das, S and Chatterjee, N and Saha, KD}, title = {Heat Killed Attenuated Leishmania Induces Apoptosis of HepG2 Cells Through ROS Mediated p53 Dependent Mitochondrial Pathway.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {38}, number = {4}, pages = {1303-1318}, doi = {10.1159/000443125}, pmid = {27010918}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Calcium/metabolism ; Caspase 3/analysis/metabolism ; Caspase 9/analysis/metabolism ; Cytochromes c/metabolism ; DNA Fragmentation ; Down-Regulation ; G1 Phase Cell Cycle Checkpoints ; Hep G2 Cells ; Hot Temperature ; Humans ; Leishmania/*pathogenicity ; Membrane Potential, Mitochondrial ; Mitochondria/*metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; Up-Regulation/drug effects ; bcl-2-Associated X Protein/metabolism ; bcl-Associated Death Protein/metabolism ; }, abstract = {BACKGROUND/AIMS: Cytotoxic effect of attenuated Leishmania on liver cancer cells by inducing ROS generation.<br><br>METHODS: Spectrophotometric study to analyze cell death and levels of different active caspases. Flow cytometric study was done to analyze apoptosis induction and ROS generation and levels of different protein. Western blot analysis was performed to study the levels of protein. Confocal microscopy was done to ascertain the expression of different apoptotic markers.<br><br>RESULTS: We have now observed that attenuated Leishmania donovani UR6 also has potentiality towards growth inhibition of HepG2 cells and investigated the mechanism of action. The effect is associated with increased DNA fragmentation, rise in number of annexinV positive cells, and cell cycle arrest at G1 phase. The detection of unregulated levels of active PARP, cleaved caspases 3 and 9, cytosolic cytochrome C, Bax, and Bad, along with the observed downregulation of Bcl-2 and loss of mitochondrial membrane potential suggested the involvement of mitochondrial pathway. Enhanced ROS and p53 levels regulate the apoptosis of HepG2 cells. NAC was found to inhibit p53 production but PFT-&#x3b1; has no effect on ROS generation. In conclusion, Leishmania donovani UR6 efficiently induces apoptosis in HepG2 cells through ROS mediated p53 dependent mitochondrial pathway.<br><br>CONCLUSION: It has been reported earlier that some parasites show prominent cytotoxic effect and prevent tumor growth. From our study we found that Leishmania donovani UR6 efficiently induced apoptosis in HepG2 cells through ROS mediated p53 dependent mitochondrial pathway. This study has rejuvenated the age old idea of bio-therapy.}, }
@article {pmid27010086, year = {2016}, author = {Liu, S and Chen, F and Wang, L and Sun, W and Liu, Q and Chen, H and Su, D and Jiang, Y and Piao, F and Sun, X and Sun, W}, title = {2,5-hexanedione induced apoptosis of rat bone marrow mesenchymal stem cells by reactive oxygen species.}, journal = {Journal of occupational health}, volume = {58}, number = {2}, pages = {170-178}, pmid = {27010086}, issn = {1348-9585}, mesh = {Acetylcysteine ; Animals ; Antioxidants ; Apoptosis/*drug effects ; Bone Marrow Cells/*drug effects ; Caspase 3/metabolism ; Hexanones/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mesenchymal Stem Cells/*drug effects ; Mitochondrial Membranes/drug effects ; Rats ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVES: n-Hexane, a common industrial organic solvent, causes multiple organ damage, especially neurotoxicity, which is proved to be caused by its metabolite 2,5-hexanedione (2,5-HD). We previously showed that 2,5-HD induced apoptosis of rat bone marrow mesenchymal stem cells (BMSCs). In the current study, we explored the mechanism of 2,5-HD-induced apoptosis, especially the role played by reactive oxygen species (ROS).<br><br>METHODS: Intracellular ROS levels after 2,5-HD treatment were measured by the dichloro-dihydro-fluorescein diacetate (DCFH-DA) method, and the antioxidant N-acetyl cysteine (NAC) was used to scavenge ROS. Apoptosis, mitochondrial membrane potential (MMP), and caspase-3 activity were measured after 2,5-HD exposure with or without NAC pretreatment.<br><br>RESULTS: In rat BMSCs, 20 mM 2,5-HD significantly increased ROS levels and apoptosis. In addition, MMP activity was decreased and caspase-3 activity was increased. With NAC pretreatment, ROS increases were prevented, cells were rescued from apoptosis, and both MMP and caspase-3 activity returned to normal levels. Western blotting analysis of malondialdehyde-modified proteins and superoxide dismutase (SOD) 1 showed that after 2,5-HD exposure, BMSCs had oxidative damage and abnormal SOD1 expression. These returned to normal when cells were pretreated with NAC in addition to 20 mM 2,5-HD. Furthermore, the expressions of NF-&#x3ba;B p65/RelA and phospho-NF-&#x3ba;B p65/RelA (Ser536) were suppressed after 2,5-HD exposure and restored by NAC pretreatment.<br><br>CONCLUSIONS: 2,5-HD-induced apoptosis in rat BMSCs is potentially mediated by excessive ROS production.}, }
@article {pmid27008575, year = {2016}, author = {Taurà, P and Ibarzabal, A and Vendrell, M and Adelsdorfer, C and Delitala, A and de Lacy, B and Deulofeu, R and Delgado, S and Lacy, AM}, title = {Pretreatment with endothelium-derived nitric oxide synthesis modulators on gastrointestinal microcirculation during NOTES: an experimental study.}, journal = {Surgical endoscopy}, volume = {30}, number = {12}, pages = {5232-5238}, pmid = {27008575}, issn = {1432-2218}, mesh = {Abdomen/*blood supply ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Cholecystectomy/*methods ; Female ; Insufflation ; Microcirculation/*drug effects/physiology ; Models, Animal ; Natural Orifice Endoscopic Surgery/*methods ; Nitric Oxide/*antagonists &amp; inhibitors ; Preoperative Period ; Random Allocation ; Swine ; }, abstract = {BACKGROUND AND STUDY AIMS: On-demand endoscopic insufflation during natural orifice transluminal endoscopic surgery (NOTES) adversely affects microcirculatory blood flow (MBF), even with low mean intra-abdominal pressure, suggesting that shear stress caused by time-varying flow fluctuations has a great impact on microcirculation. As shear stress is inversely related to vascular diameter, nitric oxide (NO) production acts as a brake to vasoconstriction.<br><br>OBJECTIVE: To assess whether pretreatment by NO synthesis modulators protects gastrointestinal MBF during transgastric peritoneoscopy.<br><br>METHODS: Fourteen pigs submitted to cholecystectomy by endoscope CO2 insufflation for 60&#xa0;min were randomized into 2 groups: (1) 150&#xa0;mg/kg of N-acetyl cysteine (NAC, n&#xa0;=&#xa0;7) and (2) 4&#xa0;ml/kg of hypertonic saline 7.5&#xa0;% (HS, n&#xa0;=&#xa0;7), and compared to a non-treated NOTES group (n&#xa0;=&#xa0;7). Five animals made up a sham group. Colored microspheres were used to assess changes in MBF.<br><br>RESULTS: The average level of intra-abdominal pressure was similar in all groups (9&#xa0;mmHg). In NOTES group microcirculation decrease compared with baseline was greater in renal cortex, mesocolon, and mesentery (41, 42, 44&#xa0;%, respectively, p&#xa0;<&#xa0;0.01) than in renal medulla, colon, and small bowel (29, 32, 34, respectively, p&#xa0;<&#xa0;0.05). NAC avoided the peritoneoscopy effect on renal medulla and cortex (4 and 14&#xa0;% decrease, respectively) and reduced the impact on colon and small bowel (20&#xa0;% decrease). HS eliminated MBF changes in colon and small bowel (14&#xa0;% decrease) and modulated MBF in renal medulla and cortex (19&#xa0;% decrease). Neither treatment influenced mesentery MBF decrease.<br><br>CONCLUSIONS: Both pretreatments can effectively attenuate peritoneoscopy-induced deleterious effects on gastrointestinal MBF.}, }
@article {pmid27004703, year = {2016}, author = {Aldemir, M and Koca, HB and Doğan Bakı, E and Çarşanba, G and Öztürk Kavrut, N and Kavaklı, AS and Adalı, F and Emmiler, M and Darçın, OT}, title = {Effects of N-acetyl cysteine on renal functions evaluated by blood neutrophil gelatinase-associated lipocalin levels in geriatric patients undergoing coronary artery bypass grafting.}, journal = {Anatolian journal of cardiology}, volume = {16}, number = {7}, pages = {504-511}, pmid = {27004703}, issn = {2149-2271}, abstract = {OBJECTIVE: Recent conflicting studies on the renal effects of N-acetyl cysteine (NAC) after cardiac surgery have been published. The aim of this study was to evaluate the renal effects of NAC using neutrophil gelatinase-associated lipocalin (NGAL) blood levels in elderly patients undergoing coronary artery bypass grafting (CABG).<br><br>METHODS: This randomized, double-blinded, placebo-controlled study was conducted among geriatric patients (>65 years) scheduled to undergo CABG. A total of 60 consecutive patients were randomly assigned to 2 groups. The first group received I.V. NAC (n=30) and the second group received placebo (n=30) at induction of anesthesia and then for 20 h. NGAL values were determined and conventional renal function tests were performed. Statistical analysis was performed using SPSS 17.0 (IL, Chicago, USA). A p value of <0.05 was considered statistically significant.<br><br>RESULTS: Plasma creatinine levels at 24 h postoperatively were significantly higher in the placebo group than in the NAC group (1.41&#xb1;0.63 vs. 1.13&#xb1;0.35; p<0.05). The mean serum NGAL levels at 3 h postoperatively were higher in the placebo group than in the NAC group (104.94&#xb1;30.51 vs. 87.82&#xb1;25.18; p<0.05). NGAL levels were similar between the groups at all other measurement time points. Plasma creatinine levels of &#x2265;1.5 mg/dL or >25% of the baseline value at any time during the study period were observed in 27% of patients in the NAC group and 37% of patients in the placebo group; the difference was statistically significant (p<0.05).<br><br>CONCLUSION: In the present study, we found that I.V. NAC infusion in elderly patients undergoing CABG reduced the incidence of acute kidney injury as determined by blood NGAL and creatinine levels.}, }
@article {pmid27002509, year = {2017}, author = {Du, K and Farhood, A and Jaeschke, H}, title = {Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity.}, journal = {Archives of toxicology}, volume = {91}, number = {2}, pages = {761-773}, pmid = {27002509}, issn = {1432-0738}, support = {P20 GM103549/GM/NIGMS NIH HHS/United States ; P20 RR021940/RR/NCRR NIH HHS/United States ; R01 DK070195/DK/NIDDK NIH HHS/United States ; R01 DK102142/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Activation, Metabolic/drug effects ; Animals ; Antioxidants/pharmacology ; Chemical and Drug Induced Liver Injury/physiopathology ; Cyclic N-Oxides/pharmacology ; MAP Kinase Kinase 4/metabolism ; Male ; Mice, Inbred C57BL ; Mitochondria, Liver/*drug effects/metabolism ; Organophosphorus Compounds/*pharmacology ; Oxidative Stress/drug effects ; Piperidines/*pharmacology ; Protective Agents/*pharmacology ; }, abstract = {Acetaminophen (APAP) hepatotoxicity is characterized by an extensive mitochondrial oxidant stress. However, its importance as a drug target has not been clarified. To investigate this, fasted C57BL/6J mice were treated with 300 mg/kg APAP and the mitochondria-targeted antioxidant Mito-Tempo (MT) was given 1.5 h later. APAP caused severe liver injury in mice, as indicated by the increase in plasma ALT activities and centrilobular necrosis. MT dose-dependently reduced the injury. Importantly, MT did not affect APAP-protein adducts formation, glutathione depletion or c-jun N-terminal kinase activation and its mitochondrial translocation. In contrast, hepatic glutathione disulfide and peroxynitrite formation were dose-dependently reduced by MT, indicating its effective mitochondrial oxidant stress scavenging capacity. Consequently, mitochondrial translocation of Bax and release of mitochondrial intermembrane proteins such as apoptosis-inducing factor were prevented, and nuclear DNA fragmentation was eliminated. To demonstrate the importance of mitochondria-specific antioxidant property of MT, we compared its efficacy with Tempo, which has the same pharmacological mode of action as MT but lacks the mitochondria targeting moiety. In contrast to the dramatic protection by MT, the same molar dose of Tempo did not significantly reduce APAP hepatotoxicity. In contrast, even a 3 h post-treatment with MT reduced 70 % of the injury, and the combination of MT with N-acetylcysteine (NAC) provided superior protection than NAC alone. We conclude that MT protects against APAP overdose in mice by attenuating the mitochondrial oxidant stress and preventing peroxynitrite formation and the subsequent mitochondrial dysfunction. MT is a promising therapeutic agent for APAP overdose patients.}, }
@article {pmid27000859, year = {2016}, author = {Kang, N and Jian, JF and Cao, SJ and Zhang, Q and Mao, YW and Huang, YY and Peng, YF and Qiu, F and Gao, XM}, title = {Physalin A induces G2/M phase cell cycle arrest in human non-small cell lung cancer cells: involvement of the p38 MAPK/ROS pathway.}, journal = {Molecular and cellular biochemistry}, volume = {415}, number = {1-2}, pages = {145-155}, pmid = {27000859}, issn = {1573-4919}, mesh = {Acetylcysteine/administration &amp; dosage ; Carcinoma, Non-Small-Cell Lung/enzymology/metabolism/*pathology ; Cell Division/*drug effects ; Cell Line, Tumor ; G2 Phase/*drug effects ; Humans ; Lung Neoplasms/enzymology/metabolism/*pathology ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Withanolides/*pharmacology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Physalin A (PA) is an active withanolide isolated from Physalis alkekengi var. franchetii, a traditional Chinese herbal medicine named Jindenglong, which has long been used for the treatment of sore throat, hepatitis, and tumors in China. In the present study, we firstly investigated the effects of PA on proliferation and cell cycle distribution of the human non-small cell lung cancer (NSCLC) A549 cell line, and the potential mechanisms involved. Here, PA inhibited cell growth in dose- and time-dependent manners. Treatment of A549 cells with 28.4 μM PA for 24 h resulted in approximately 50 % cell death. PA increased the amount of intracellular ROS and the proportion of cells in G2/M. G2/M arrest was attenuated by the addition of ROS scavenger NAC. ERK and P38 were triggered by PA through phosphorylation in a time-dependent manner. The phosphorylation of ERK and P38 were not attenuated by the addition of NAC, but the use of the p38 inhibitor could reduce, at least in part, PA-induced ROS and the proportion of cells in G2/M. PA induces G2/M cell cycle arrest in A549 cells involving in the p38 MAPK/ROS pathway. This study suggests that PA might be a promising therapeutic agent against NSCLC.}, }
@article {pmid26998841, year = {2016}, author = {Roper, PM and Abbasnia, P and Vuchkovska, A and Natoli, RM and Callaci, JJ}, title = {Alcohol-related deficient fracture healing is associated with activation of FoxO transcription factors in mice.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {34}, number = {12}, pages = {2106-2115}, pmid = {26998841}, issn = {1554-527X}, support = {F31 AA021308/AA/NIAAA NIH HHS/United States ; R01 AA016138/AA/NIAAA NIH HHS/United States ; R21 AA021225/AA/NIAAA NIH HHS/United States ; T32 AA013527/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Bony Callus/*drug effects/metabolism ; Central Nervous System Depressants/*adverse effects ; Chondrogenesis/drug effects ; Drug Evaluation, Preclinical ; Ethanol/*adverse effects ; Forkhead Transcription Factors/*metabolism ; Fracture Healing/*drug effects ; Free Radical Scavengers/pharmacology/therapeutic use ; Male ; Mice, Inbred C57BL ; Random Allocation ; }, abstract = {The process of fracture healing is complex, and poor or incomplete healing remains a significant health problem. Proper fracture healing relies upon resident mesenchymal stem cell (MSC) differentiation into chondrocytes and osteoblasts, which are necessary for callus formation and ossification. Alcohol abuse is a leading contributor to poor fracture healing. Although the mechanism behind this action is unknown, excessive alcohol consumption is known to promote systemic oxidative stress. The family of FoxO transcription factors is activated by oxidative stress, and FoxO activation antagonizes Wnt signaling, which regulates mesenchymal stem cell differentiation. We hypothesize that alcohol exposure increases oxidative stress leading to deficient fracture repair by activating FoxO transcription factors within the fracture callus which disrupts chondrogenesis of mesenchymal stem cells. Our laboratory has developed an experimental model of delayed fracture union in mice using ethanol administration. We have found that ethanol administration significantly decreases external, cartilaginous callus formation, and hallmarks of endochondral ossification, and these changes are concomitant with increases in FoxO expression and markers of activation in fracture callus tissue of these mice. We were able to prevent these alcohol-induced effects with the administration of the antioxidant n-acetyl cysteine (NAC), suggesting that alcohol-induced oxidative stress produces the perturbed endochondral ossification and FoxO expression. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2106-2115, 2016.}, }
@article {pmid26996786, year = {2016}, author = {Lee, CA and Dhawan, A and Smith, RA and Mitry, RR and Fitzpatrick, E}, title = {Instant Blood-Mediated Inflammatory Reaction in Hepatocyte Transplantation: Current Status and Future Perspectives.}, journal = {Cell transplantation}, volume = {25}, number = {7}, pages = {1227-1236}, doi = {10.3727/096368916X691286}, pmid = {26996786}, issn = {1555-3892}, support = {MR/J006742/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Animals ; Hepatocytes/*transplantation ; Humans ; Inflammation/*blood/*pathology/therapy ; Inflammation Mediators/*metabolism ; Models, Biological ; }, abstract = {Hepatocyte transplantation (HT) is emerging as a promising alternative to orthotopic liver transplantation (OLT) in patients with certain liver-based metabolic disease and acute liver failure. Hepatocytes are generally infused into the portal venous system, from which they migrate into the liver cell plates of the native organ. One of the major hurdles to the sustained success of this therapy is early cell loss, with up to 70% of hepatocytes lost immediately following infusion. This is largely thought to be due to the instant blood-mediated inflammatory reaction (IBMIR), resulting in the activation of complement and coagulation pathways. Transplanted hepatocytes produce and release tissue factor (TF), which activates the coagulation pathway, leading to the formation of thrombin and fibrin clots. Thrombin can further activate a number of complement proteins, leading to the activation of the membrane attack complex (MAC) and subsequent hepatocyte cell death. Inflammatory cells including granulocytes, monocytes, Kupffer cells, and natural killer (NK) cells have been shown to cluster around transplanted hepatocytes, leading to their rapid clearance shortly after transplantation. Current research aims to improve cell engraftment and prevent early cell loss. This has been proven successful in vitro using pharmacological interventions such as melagatran, low-molecular-weight dextran sulphate, and N-acetylcysteine (NAC). Effective inhibition of IBMIR would significantly improve hepatocyte engraftment, proliferation, and function, providing successful treatment for patients with liver-based metabolic diseases.}, }
@article {pmid26993523, year = {2016}, author = {Gawlak, G and Son, S and Tian, Y and O'Donnell, JJ and Birukov, KG and Birukova, AA}, title = {Chronic high-magnitude cyclic stretch stimulates EC inflammatory response via VEGF receptor 2-dependent mechanism.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {310}, number = {11}, pages = {L1062-70}, pmid = {26993523}, issn = {1522-1504}, support = {R01 GM114171/GM/NIGMS NIH HHS/United States ; R01 HL076259/HL/NHLBI NIH HHS/United States ; R56 AG048231/AG/NIA NIH HHS/United States ; R56 HL107920/HL/NHLBI NIH HHS/United States ; T32 HL007605/HL/NHLBI NIH HHS/United States ; }, mesh = {Cells, Cultured ; Endothelial Cells/*physiology ; Humans ; Intercellular Adhesion Molecule-1/metabolism ; Interleukin-8/metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Cell Adhesion Molecule-1/metabolism ; Vascular Endothelial Growth Factor Receptor-2/*metabolism ; Ventilator-Induced Lung Injury/*immunology/metabolism ; }, abstract = {Ventilator-induced lung injury (VILI) is associated with activated inflammatory signaling, such as cytokine production by endothelial and epithelial cells and macrophages, although the precise mechanisms of inflammatory activation induced by VILI-relevant cyclic stretch (CS) amplitude remain poorly understood. We show that exposure of human pulmonary endothelial cells (EC) to chronic CS at 18% linear distension (18% CS), but not at physiologically relevant 5% CS, induces "EC-activated phenotype," which is characterized by time-dependent increase in ICAM1 and VCAM1 expression. A preconditioning of 18% CS also increased in a time-dependent fashion the release of soluble ICAM1 (sICAM1) and IL-8. Investigation of potential signaling mechanisms of CS-induced EC inflammatory activation showed that 18% CS, but not 5% CS, induced time-dependent upregulation of VEGF receptor 2 (VEGFR2), as monitored by increased protein expression and VEGFR2 tyrosine phosphorylation. Both CS-induced VEGFR2 expression and tyrosine phosphorylation were abrogated by cotreatment with reactive oxygen species inhibitor, N-acetyl cysteine. Molecular inhibition of VEGFR2 expression by gene-specific siRNA or treatment with VEGFR2 pharmacological inhibitor SU-1498 attenuated CS-induced activation of ICAM1 and VCAM1 expression and sICAM1 release. Chronic EC preconditioning at 18% CS augmented EC inflammation and barrier-disruptive response induced by proinflammatory cytokine TNF-α. This effect of chronic 18% CS preconditioning was attenuated by siRNA-induced VEGFR2 knockdown. This study demonstrates for the first time a VEGFR2-dependent mechanism of EC inflammatory activation induced by pathological CS. We conclude that, despite the recognized role of VEGF as a prosurvival and angiogenic factor, excessive activation of VEGFR2 signaling by high-tidal-volume lung mechanical ventilation may contribute to ventilator-induced (biotrauma) lung inflammation and barrier dysfunction by augmenting cell response to VILI-associated inflammatory mediators.}, }
@article {pmid26992751, year = {2016}, author = {Raciti, M and Ong, J and Weis, L and Edoff, K and Battagli, C and Falk, A and Ceccatelli, S}, title = {Glucocorticoids alter neuronal differentiation of human neuroepithelial-like cells by inducing long-lasting changes in the reactive oxygen species balance.}, journal = {Neuropharmacology}, volume = {107}, number = {}, pages = {422-431}, doi = {10.1016/j.neuropharm.2016.03.022}, pmid = {26992751}, issn = {1873-7064}, mesh = {Cell Differentiation/drug effects/*physiology ; Cell Line ; Cell Proliferation/drug effects/physiology ; Dexamethasone/pharmacology ; Glucocorticoids/*pharmacology ; Humans ; Induced Pluripotent Stem Cells/drug effects/metabolism ; Neural Stem Cells/drug effects/*metabolism ; Neurogenesis/drug effects/*physiology ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {Prenatal exposure to excess glucocorticoid has been shown to have adverse effects on the developing nervous system that may lead to alterations of fetal and adult neurogenesis, resulting in behavioral changes. In addition, an imbalance of the redox state, with an increased susceptibility to oxidative stress, has been observed in rodent neural stem cells exposed to the synthetic glucocorticoid analog dexamethasone (Dex). In the present study, we used the induced pluripotent stem cells (IPSC)-derived lt-NES AF22 cell line, representative of the neuroepithelial stage in central nervous system development, to investigate the heritable effects of Dex on reactive oxygen species (ROS) balance and its impact on neuronal differentiation. By analysing gene expression in daughter cells that were never directly exposed to Dex, we could observe a downregulation of four key antioxidant enzymes, namely Catalase, superoxide dismutase 1, superoxide dismutase 2 and glutathione peroxidase7, along with an increased intracellular ROS concentration. The imbalance in the intracellular REDOX state was associated to a significant downregulation of major neuronal markers and a concomitant increase of glial cells. Interestingly, upon treatment with the antioxidant N-acetyl-cysteine (NAC), the misexpression of both neuronal and glial markers analyzed was recovered. These novel findings point to the increased ROS concentration playing a direct role in the heritable alterations of the differentiation potential induced by Dex exposure. Moreover, the data support the hypothesis that early insults may have detrimental long-lasting consequences on neurogenesis. Based on the positive effects exerted by NAC, it is conceivable that therapeutic strategies including antioxidants may be effective in the treatment of neuropsychiatric disorders that have been associated to increased ROS and impaired neurogenesis.}, }
@article {pmid26990051, year = {2016}, author = {Rosenblat, JD and Kakar, R and Berk, M and Kessing, LV and Vinberg, M and Baune, BT and Mansur, RB and Brietzke, E and Goldstein, BI and McIntyre, RS}, title = {Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.}, journal = {Bipolar disorders}, volume = {18}, number = {2}, pages = {89-101}, doi = {10.1111/bdi.12373}, pmid = {26990051}, issn = {1399-5618}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; *Bipolar Disorder/diagnosis/drug therapy/physiopathology ; Depression/*drug therapy ; Humans ; *Inflammation/drug therapy/psychology ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine the overall antidepressant effect of adjunctive anti-inflammatory agents in the treatment of bipolar depression.<br><br>METHODS: Completed and ongoing clinical trials of anti-inflammatory agents for BD published prior to 15 May 15 2015 were identified through searching the PubMed, Embase, PsychINFO, and Clinicaltrials.gov databases. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with standard therapy alone.<br><br>RESULTS: Ten RCTs were identified for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size of adjunctive anti-inflammatory agents on depressive symptoms was -0.40 (95% confidence interval -0.14 to -0.65, p = 0.002), indicative of a moderate and statistically significant antidepressant effect. The heterogeneity of the pooled sample was low (I&#xb2; = 14%, p = 0.32). No manic/hypomanic induction or significant treatment-emergent adverse events were reported.<br><br>CONCLUSIONS: Overall, a moderate antidepressant effect was observed for adjunctive anti-inflammatory agents compared with conventional therapy alone in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.}, }
@article {pmid26988587, year = {2016}, author = {Belmokhtar, K and Robert, T and Ortillon, J and Braconnier, A and Vuiblet, V and Boulagnon-Rombi, C and Diebold, MD and Pietrement, C and Schmidt, AM and Rieu, P and Touré, F}, title = {Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {36}, number = {5}, pages = {800-809}, doi = {10.1161/ATVBAHA.115.306349}, pmid = {26988587}, issn = {1524-4636}, mesh = {Animals ; Antioxidants/pharmacology ; Aorta/metabolism/pathology ; Aortic Diseases/etiology/genetics/*metabolism/pathology ; Apolipoproteins E/deficiency/genetics ; Atherosclerosis/etiology/genetics/*metabolism/pathology ; Cell Movement ; Cells, Cultured ; Disease Models, Animal ; Genetic Predisposition to Disease ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Mitogen-Activated Protein Kinases/metabolism ; Muscle, Smooth, Vascular/drug effects/*metabolism/pathology ; Myocytes, Smooth Muscle/drug effects/*metabolism/pathology ; Nephrectomy ; Oxidative Stress ; Phenotype ; Phosphorylation ; Plaque, Atherosclerotic ; Protein Binding ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Receptor for Advanced Glycation End Products/deficiency/genetics/metabolism ; Serum Amyloid A Protein/*metabolism ; Signal Transduction ; Uremia/*complications/genetics/metabolism ; }, abstract = {OBJECTIVE: Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis.<br><br>APPROACH AND RESULTS: We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe(-/-) background. Sham-operated mice were used as controls. Primary cultures of Ager(+/+) and Ager(-/-) vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe(-/-) than in sham-operated Apoe(-/-) mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of &#x3b1;-SMA. Ager transcript levels in the aorta were 6&#xd7; higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe(-/-) Ager(-/-) mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager(+/+) but not of Ager(-/-) VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogen-activated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases, rather than of AKT, was subject to specific redox-regulation by SAA and S100B. Furthermore, human aortic atherosclerotic sections were positively stained for RAGE and SAA.<br><br>CONCLUSIONS: Uremia upregulates SAA and RAGE expression in the aortic wall and in atherosclerotic lesions in mice. Ager(-/-) animals are protected against the uremia-induced acceleration of atherosclerosis. SAA modulates the functions of murine and human VSMCs in vitro in a RAGE-dependent manner. This study, therefore, identifies SAA as a potential new uremic toxin involved in uremia-related atherosclerosis through interaction with RAGE.}, }
@article {pmid26987028, year = {2016}, author = {Wang, R and Ma, L and Weng, D and Yao, J and Liu, X and Jin, F}, title = {Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway.}, journal = {Oncology reports}, volume = {35}, number = {5}, pages = {3075-3083}, doi = {10.3892/or.2016.4690}, pmid = {26987028}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Cell Line, Tumor ; Cell Shape ; Cell Survival/drug effects ; Cisplatin/*pharmacology ; Drug Screening Assays, Antitumor ; Drug Synergism ; Gallic Acid/*pharmacology ; Humans ; Lung Neoplasms/drug therapy ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Reactive Oxygen Species/*metabolism ; Small Cell Lung Carcinoma/drug therapy ; }, abstract = {Small cell lung cancer (SCLC) is the most aggressive lung cancer subtype and accounts for more than 15% of all lung cancer cases. Cisplatin [cis-diamminedichloroplatinum (CDDP)]-based combination chemotherapy is the cornerstone for all stages of SCLC. However, acquired multidrug resistance (MDR) and intolerable toxicities lead to a high mortality rate in SCLC patients. Gallic acid [3,4,5-trihydroxybenzoic acid (GA)] is a natural botanic phenolic compound which can induce cell apoptosis in several types of cancers. In the present study, we aimed to explore the anticancer effects of GA on human SCLC H446 cells and its promotive effects on the anticancer activities of cisplatin. The viability of the H446 cells was analyzed by MTT assay. Morphological changes in the H446 cells were observed under an inverted microscope. Apoptosis induction was determined by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. The level of reactive oxygen species (ROS) was assessed by 2'7'-dichlorofluorescein diacetate (DCFH‑DA), mitochondrial membrane potential (MMP) by JC-1, and western blotting was used to examine the expression of mitochondrial apoptosis-related proteins. The results showed that both GA and cisplatin changed the morphology, inhibited the growth and induced apoptosis in the H446 cells by inducing generation of ROS, disruption of MMP, downregulation of XIAP expression, and upregulation of Bax, Apaf-1, DIABLO and p53 expression. More importantly, GA combined with cisplatin exhibited synergistic effects on inducing of these pro-apoptotic mediators and modulating the activation of apoptosis-related molecules. However, inhibition of the generation of ROS by N-acetyl-l-cysteine (NAC), a specific ROS inhibitor, reversed the cell apoptosis induced by cisplatin combined with GA. In conclusion, the results from the present study revealed that GA exhibited an anticancer effect on human SCLC H446 cells and enhanced the antitumor activities of cisplatin via the ROS-dependent mitochondrial apoptotic pathway.}, }
@article {pmid26986653, year = {2016}, author = {Patel, SJ and Luther, J and Bohr, S and Iracheta-Vellve, A and Li, M and King, KR and Chung, RT and Yarmush, ML}, title = {A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity.}, journal = {Clinical and translational gastroenterology}, volume = {7}, number = {3}, pages = {e153}, pmid = {26986653}, issn = {2155-384X}, abstract = {OBJECTIVES: Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response. Because of this, NAC is less effective if given at later stages in the disease course. Resolvins, a novel group of lipid mediators shown to attenuate host inflammation, may be a therapeutic intervention for APAP hepatotoxicity.<br><br>METHODS: The temporal patterns of liver injury and neutrophil activation were investigated in a murine model of APAP hepatotoxicity. In addition, the effect of neutrophil depletion and resolvin administration on the severity of liver injury induced by APAP was studied. In vitro studies to investigate the mechanism of resolvin effect on hepatocyte injury and neutrophil adhesion were performed.<br><br>RESULTS: We demonstrate that hepatic neutrophil activation occurs secondary to the initial liver injury induced directly by APAP. We also show that neutrophil depletion attenuates APAP-induced liver injury, and administration of resolvins hours after APAP challenge not only attenuates liver injury, but also extends the therapeutic window eightfold compared to NAC. Mechanistic in vitro analysis highlights resolvins' ability to inhibit neutrophil attachment to endothelial cells in the presence of the reactive metabolite of APAP.<br><br>CONCLUSIONS: This study highlights the ability of resolvins to protect against APAP-induced liver injury and extend the therapeutic window compared to NAC. Although the mechanism for resolvin-mediated hepatoprotection is likely multifactorial, inhibition of neutrophil infiltration and activation appears to play an important role.}, }
@article {pmid26984266, year = {2016}, author = {Lee, CF and Yang, JS and Tsai, FJ and Chiang, NN and Lu, CC and Huang, YS and Chen, C and Chen, FA}, title = {Kaempferol induces ATM/p53-mediated death receptor and mitochondrial apoptosis in human umbilical vein endothelial cells.}, journal = {International journal of oncology}, volume = {48}, number = {5}, pages = {2007-2014}, doi = {10.3892/ijo.2016.3420}, pmid = {26984266}, issn = {1791-2423}, mesh = {Apoptosis ; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Human Umbilical Vein Endothelial Cells/*drug effects/metabolism ; Humans ; Kaempferols/*pharmacology ; Mitochondria/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Signal Transduction/drug effects ; Time Factors ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Kaempferol is a member of the flavonoid compounds found in vegetables and fruits. It is shown to exhibit biological impact and anticancer activity, but no report exists on the angiogenic effect of kaempferol and induction of cell apoptosis in vitro. In this study, we investigated the role of kaempferol on anti-angiogenic property and the apoptotic mechanism of human umbilical vein endothelial cells (HUVECs). Our results demonstrated that kaempferol decreased HUVEC viability in a time- and concentration-dependent manner. Kaempferol also induced morphological changes and sub-G1 phase cell population (apoptotic cells). Kaempferol triggered apoptosis of HUVECs as detecting by DNA fragmentation, comet assay and immunofluorescent staining for activated caspase-3. The caspase signals, including caspase-8, -9 and -3, were time-dependently activated in HUVECs after kaempferol exposure. Furthermore, pre-treatment with a specific inhibitor of caspase-8 (Z-IETD-FMK) significantly reduced the activity of caspase-8, -9 and -3, indicating that extrinsic pathway is a major signaling pathway in kaempferol-treated HUVECs. Importantly, kaempferol promoted reactive oxygen species (ROS) evaluated using flow cytometric assay in HUVECs. We further investigated the upstream extrinsic pathway and showed that kaempferol stimulated death receptor signals [Fas/CD95, death receptor 4 (DR4) and DR5] through increasing the levels of phosphorylated p53 and phosphorylated ATM pathways in HUVECs, which can be individually confirmed by N-acetylcysteine (NAC), ATM specific inhibitor (caffeine) and p53 siRNA. Based on these results, kaempferol-induced HUVEC apoptosis was involved in an ROS-mediated p53/ATM/death receptor signaling. Kaempferol might possess therapeutic effects on cancer treatment in anti-vascular targeting.}, }
@article {pmid26982035, year = {2016}, author = {Takhtfooladi, HA and Hesaraki, S and Razmara, F and Takhtfooladi, MA and Hajizadeh, H}, title = {Effects of N-acetylcysteine and pentoxifylline on remote lung injury in a rat model of hind-limb ischemia/reperfusion injury.}, journal = {Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia}, volume = {42}, number = {1}, pages = {9-14}, pmid = {26982035}, issn = {1806-3756}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology/therapeutic use ; Glutathione/analysis ; Hindlimb/blood supply ; Ischemia/*prevention &amp; control ; Lung/*blood supply/drug effects/pathology ; Lung Injury/pathology/*prevention &amp; control ; Male ; Malondialdehyde/analysis ; Oxidative Stress ; Pentoxifylline/*pharmacology/therapeutic use ; Random Allocation ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; Reproducibility of Results ; Superoxide Dismutase/analysis ; Time Factors ; }, abstract = {OBJECTIVE: To investigate the effects of N-acetylcysteine (NAC) and pentoxifylline in a model of remote organ injury after hind-limb ischemia/reperfusion (I/R) in rats, the lungs being the remote organ system.<br><br>METHODS: Thirty-five male Wistar rats were assigned to one of five conditions (n = 7/group), as follows: sham operation (control group); hind-limb ischemia, induced by clamping the left femoral artery, for 2 h, followed by 24 h of reperfusion (I/R group); and hind-limb ischemia, as above, followed by intraperitoneal injection (prior to reperfusion) of 150 mg/kg of NAC (I/R+NAC group), 40 mg/kg of pentoxifylline (I/R+PTX group), or both (I/R+NAC+PTX group). At the end of the trial, lung tissues were removed for histological analysis and assessment of oxidative stress.<br><br>RESULTS: In comparison with the rats in the other groups, those in the I/R group showed lower superoxide dismutase activity and glutathione levels, together with higher malondialdehyde levels and lung injury scores (p < 0.05 for all). Interstitial inflammatory cell infiltration of the lungs was also markedly greater in the I/R group than in the other groups. In addition, I/R group rats showed various signs of interstitial edema and hemorrhage. In the I/R+NAC, I/R+PTX, and I/R+NAC+PTX groups, superoxide dismutase activity, glutathione levels, malondialdehyde levels, and lung injury scores were preserved (p < 0.05 for all). The differences between the administration of NAC or pentoxifylline alone and the administration of the two together were not significant for any of those parameters (p > 0.05 for all).<br><br>CONCLUSIONS: Our results suggest that NAC and pentoxifylline both protect lung tissue from the effects of skeletal muscle I/R. However, their combined use does not appear to increase the level of that protection.}, }
@article {pmid26982591, year = {2016}, author = {Feng, Y and Yang, Y and Fan, C and Di, S and Hu, W and Jiang, S and Li, T and Ma, Z and Chao, D and Feng, X and Xin, Z and Pang, S and Li, X and Yan, X}, title = {Pterostilbene Inhibits the Growth of Human Esophageal Cancer Cells by Regulating Endoplasmic Reticulum Stress.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {38}, number = {3}, pages = {1226-1244}, doi = {10.1159/000443071}, pmid = {26982591}, issn = {1421-9778}, mesh = {Animals ; Antineoplastic Agents/*administration &amp; dosage/pharmacology ; Cell Adhesion/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Esophageal Neoplasms/*drug therapy/*metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice ; Signal Transduction/drug effects ; Stilbenes/*administration &amp; dosage/pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND/AIMS: Pterostilbene (PTE), a natural dimethylated resveratrol analog from blueberries, is known to have diverse pharmacological activities, including anticancer properties. In this study, we investigated the anticancer activity of PTE against human esophageal cancer cells both in vitro and in vivo and explored the role of endoplasmic reticulum (ER) stress (ERS) signaling in this process.<br><br>METHODS: Cell viability, the apoptotic index, Caspase 3 activity, adhesion, migration, reactive oxygen species (ROS) levels, and glutathione (GSH) levels were detected to explore the effect of PTE on human EC109 esophageal cancer cells. Furthermore, siRNA transfection and a chemical inhibitor were employed to confirm the role of ERS.<br><br>RESULTS: PTE treatment dose- and time-dependently decreased the viability of human esophageal cancer EC109 cells. PTE also decreased tumor cell adhesion, migration and intracellular GSH levels while increasing the apoptotic index, Caspase 3 activity and ROS levels, which suggest the strong anticancer activity of PTE. Furthermore, PTE treatment increased the expression of ERS-related molecules (GRP78, ATF6, p-PERK, p-eIF2&#x3b1; and CHOP), upregulated the pro-apoptosis-related protein PUMA and downregulated the anti-apoptosis-related protein Bcl-2 while promoting the translocation of cytochrome c from mitochondria to cytosol and the activation of Caspase 9 and Caspase 12. The downregulation of ERS signaling by CHOP siRNA desensitized esophageal cancer cells to PTE treatment, whereas upregulation of ERS signaling by thapsigargin (THA) had the opposite effect. N-Acetylcysteine (NAC), a ROS scavenger, also desensitized esophageal cancer cells to PTE treatment.<br><br>CONCLUSIONS: Overall, the results indicate that PTE is a potent anti-cancer pharmaceutical against human esophageal cancer, and the possible mechanism involves the activation of ERS signaling pathways.}, }
@article {pmid26977590, year = {2016}, author = {Ding, D and Jiang, H and Chen, GD and Longo-Guess, C and Muthaiah, VP and Tian, C and Sheppard, A and Salvi, R and Johnson, KR}, title = {N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in γ-glutamyl transferase 1 deficient mice.}, journal = {Aging}, volume = {8}, number = {4}, pages = {730-750}, pmid = {26977590}, issn = {1945-4589}, support = {R01 DC005827/DC/NIDCD NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Evoked Potentials, Auditory, Brain Stem/physiology ; Hair Cells, Auditory, Inner/*drug effects/pathology ; Mice ; Otoacoustic Emissions, Spontaneous/physiology ; Presbycusis/genetics/pathology/*prevention &amp; control ; gamma-Glutamyltransferase/*genetics ; }, abstract = {Genetic factors combined with oxidative stress are major determinants of age-related hearing loss (ARHL), one of the most prevalent disorders of the elderly. Dwarf grey mice, Ggt1dwg/dwg, are homozygous for a loss of function mutation of the g-glutamyl transferase 1 gene, which encodes an important antioxidant enzyme critical for the resynthesis of glutathione (GSH). Since GSH reduces oxidative damage, we hypothesized that Ggt1dwg/dwg mice would be susceptible to ARHL. Surprisingly, otoacoustic emissions and cochlear microphonic potentials, which reflect cochlear outer hair cell (OHC) function, were largely unaffected in mutant mice, whereas auditory brainstem responses and the compound action potential were grossly abnormal. These functional deficits were associated with an unusual and selective loss of inner hair cells (IHC), but retention of OHC and auditory nerve fibers. Remarkably, hearing deficits and IHC loss were completely prevented by N-acetyl-L-cysteine, which induces de novo synthesis of GSH; however, hearing deficits and IHC loss reappeared when treatment was discontinued. Ggt1dwg/dwg mice represent an important new model for investigating ARHL, therapeutic interventions, and understanding the perceptual and electrophysiological consequences of sensory deprivation caused by the loss of sensory input exclusively from IHC.}, }
@article {pmid26976749, year = {2016}, author = {Charvat, RA and Arrizabalaga, G}, title = {Oxidative stress generated during monensin treatment contributes to altered Toxoplasma gondii mitochondrial function.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {22997}, pmid = {26976749}, issn = {2045-2322}, support = {R01 AI089808/AI/NIAID NIH HHS/United States ; R01 AI 89808-01/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Fibroblasts/cytology/drug effects/parasitology ; Foreskin/cytology ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Glutaredoxins/genetics/metabolism ; Golgi Apparatus/drug effects ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Fluorescence ; Mitochondria/*drug effects/metabolism ; Monensin/*pharmacology ; Oxidative Stress/*drug effects ; Peroxiredoxins/genetics/metabolism ; Proton Ionophores/pharmacology ; Protozoan Proteins/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Toxoplasma/*drug effects/genetics/metabolism ; }, abstract = {The ionophore monensin displays potent activities against several coccidian parasites of veterinary and medical importance including the opportunistic pathogen of humans, Toxoplasma gondii. While monensin is used widely in animals, toxicity impedes its use in humans. Nonetheless, given its potency, understanding its mode of action would reveal vulnerable aspects of the parasite that can be exploited for drug development. We previously established that monensin induces Toxoplasma to undergo cell cycle arrest and an autophagy-like cell death. Interestingly, these effects are dependent on the mitochondrion-localized TgMSH-1 protein, suggesting that monensin disrupts mitochondrial function. We demonstrate that monensin treatment results in decreased mitochondrial membrane potential and altered morphology. These effects are mitigated by the antioxidant compound N-acetyl-cysteine suggesting that monensin causes an oxidative stress, which was indeed the case based on direct detection of reactive oxygen species. Moreover, over-expression of the antioxidant proteins glutaredoxin and peroxiredoxin 2 protect Toxoplasma from the deleterious effects of monensin. Thus, our studies show that the effects of monensin on Toxoplasma are due to a disruption of mitochondrial function caused by the induction of an oxidative stress and implicate parasite redox biology as a viable target for the development of drugs against Toxoplasma and related pathogenic parasites.}, }
@article {pmid26975440, year = {2016}, author = {Hurley, MM and Resch, JM and Maunze, B and Frenkel, MM and Baker, DA and Choi, S}, title = {N-acetylcysteine decreases binge eating in a rodent model.}, journal = {International journal of obesity (2005)}, volume = {40}, number = {7}, pages = {1183-1186}, pmid = {26975440}, issn = {1476-5497}, support = {R01 DK074734/DK/NIDDK NIH HHS/United States ; R21 DA035088/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Binge-Eating Disorder/*drug therapy ; Conditioning, Operant/drug effects ; Diet, High-Fat ; *Disease Models, Animal ; Feeding Behavior/*drug effects/*psychology ; Injections, Intraventricular ; Male ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Binge-eating behavior involves rapid consumption of highly palatable foods leading to increased weight gain. Feeding in binge disorders resembles other compulsive behaviors, many of which are responsive to N-acetylcysteine (NAC), which is a cysteine prodrug often used to promote non-vesicular glutamate release by a cystine-glutamate antiporter. To examine the potential for NAC to alter a form of compulsive eating, we examined the impact of NAC on binge eating in a rodent model. Specifically, we monitored consumption of standard chow and a high-fat, high carbohydrate western diet (WD) in a rodent limited-access binge paradigm. Before each session, rats received either a systemic or intraventricular injection of NAC. Both systemic and central administration of NAC resulted in significant reductions of binge eating the WD without decreasing standard chow consumption. The reduction in WD was not attributable to general malaise as NAC did not produce condition taste aversion. These results are consistent with the clinical evidence of NAC to reduce or reverse compulsive behaviors, such as, drug addiction, skin picking and hair pulling.}, }
@article {pmid26971627, year = {2016}, author = {Nass, N and Sel, S and Ignatov, A and Roessner, A and Kalinski, T}, title = {Oxidative stress and glyoxalase I activity mediate dicarbonyl toxicity in MCF-7 mamma carcinoma cells and a tamoxifen resistant derivative.}, journal = {Biochimica et biophysica acta}, volume = {1860}, number = {6}, pages = {1272-1280}, doi = {10.1016/j.bbagen.2016.03.006}, pmid = {26971627}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/*toxicity ; Drug Resistance, Neoplasm ; Humans ; Lactoylglutathione Lyase/*physiology ; MAP Kinase Signaling System ; MCF-7 Cells ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Tamoxifen/*pharmacology ; }, abstract = {BACKGROUND: Acquired tamoxifen resistance is a significant problem in estrogen receptor positive breast cancer. In a cellular model, tamoxifen resistance was associated with increased sensitivity towards toxic dicarbonyls and reduced free sulfhydryl group content. We here analyzed the role of oxidative stress and glyoxalase I activity on dicarbonyl resistance and the significance of glyoxalase I expression for survival.<br><br>METHODS: Reactive oxygen species were determined by 2,7-dihydrochlorofluorescein diacetate. Inhibitors for NADPH-oxidase (diphenyleneiodonium), p38 MAPK (SB203580) and ERK1/2 (UO126) were applied to investigate interactions of these signaling molecules. N-acetyl cysteine was used to evaluate the effect of oxidative stress on cell viability, which was assessed by the resazurin assay. Gene expression was analyzed by real time qRT-PCR. Glyoxalase activity was inhibited by the specific inhibitor CS-0683 and siRNA. The relevance of glyoxalase 1 mRNA abundance on survival of breast cancer patients was evaluated by the KM-plotter web interface.<br><br>RESULTS: &#x3b1;-Oxo-aldehydes caused an immediate increase in reactive oxygen species where the tamoxifen resistant cell line (TamR) responded at lower concentrations than the MCF-7 parental cell line. Inhibitor studies placed ROS production by NADPH-oxidase downstream of p38 MAPK. The antioxidant N-acetyl cysteine (NAC) increased survival, whereas glyoxalase (GLO1) inhibition increased dicarbonyl toxicity. GLO1 mRNA abundance was correlated with unfavorable prognosis of breast cancer patients.<br><br>CONCLUSIONS: Dicarbonyl toxicity was mediated by oxidative stress and GLO1 activity determines aldehyde toxicity in tamoxifen resistant cells.<br><br>GENERAL SIGNIFICANCE: Glyoxalases might be predictive biomarkers for tamoxifen resistance and a putative target for the treatment of tamoxifen resistant breast cancer patients.}, }
@article {pmid26967219, year = {2016}, author = {Remington, R and Bechtel, C and Larsen, D and Samar, A and Page, R and Morrell, C and Shea, TB}, title = {Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer's Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {51}, number = {4}, pages = {991-995}, doi = {10.3233/JAD-151098}, pmid = {26967219}, issn = {1875-8908}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*complications ; Cognition Disorders/*diet therapy/etiology ; *Dietary Supplements ; Disease Progression ; Female ; Folic Acid/therapeutic use ; Follow-Up Studies ; Humans ; Male ; Mood Disorders/*diet therapy/etiology ; Neuropsychological Tests ; Psychiatric Status Rating Scales ; Time Factors ; Vitamin B 12/therapeutic use ; alpha-Tocopherol/therapeutic use ; }, abstract = {Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer's disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo-controlled studies with NF, and contrast with the routine decline for participants receiving placebo.}, }
@article {pmid26965709, year = {2017}, author = {Tseng, CY and Wang, JS and Chao, MW}, title = {Causation by Diesel Exhaust Particles of Endothelial Dysfunctions in Cytotoxicity, Pro-inflammation, Permeability, and Apoptosis Induced by ROS Generation.}, journal = {Cardiovascular toxicology}, volume = {17}, number = {4}, pages = {384-392}, doi = {10.1007/s12012-016-9364-0}, pmid = {26965709}, issn = {1559-0259}, support = {NSC-102-2320-B-033-001-MY3//Ministry of Science and Technology, Taiwan (TW)/International ; }, mesh = {Animals ; Apoptosis/drug effects/physiology ; Capillary Permeability/drug effects/*physiology ; Cytotoxins/toxicity ; Endothelium, Vascular/drug effects/*metabolism/pathology ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism/pathology ; Humans ; Inflammation/chemically induced/metabolism/pathology ; Inflammation Mediators/*metabolism ; Oxidative Stress/drug effects/physiology ; Particulate Matter/*toxicity ; Reactive Oxygen Species/*metabolism ; Vehicle Emissions/*toxicity ; }, abstract = {Epidemiological studies suggest that an increase of diesel exhaust particles (DEP) in ambient air corresponds to an increase in hospital-recorded myocardial infarctions within 48 h after exposure. Among the many theories to explain this data are endothelial dysfunction and translocation of DEP into vasculature. The mechanisms for such DEP-induced vascular permeability remain unknown. One of the major mechanisms underlying the effects of DEP is suggested to be oxidative stress. Experiments have shown that DEP induce the generation of reactive oxygen species (ROS), such as superoxide anion and H2O2 in the HUVEC tube cells. Transcription factor Nrf2 is translocated to the cell nucleus, where it activates transcription of the antioxidative enzyme HO-1 and sequentially induces the release of vascular permeability factor VEGF-A. Furthermore, a recent study shows that DEP-induced intracellular ROS may cause the release of pro-inflammatory TNF-α and IL-6, which may induce endothelial permeability as well by promoting VEGF-A secretion independently of HO-1 activation. These results demonstrated that the adherens junction molecule, VE-cadherin, becomes redistributed from the membrane at cell-cell borders to the cytoplasm in response to DEP, separating the plasma membranes of adjacent cells. DEP were occasionally found in endothelial cell cytoplasm and in tube lumen. In addition, the induced ROS is cytotoxic to the endothelial tube-like HUVEC. Acute DEP exposure stimulates ATP depletion, followed by depolarization of their actin cytoskeleton, which sequentially inhibits PI3K/Akt activity and induces endothelial apoptosis. Nevertheless, high-dose DEP augments tube cell apoptosis up to 70 % but disrupts the p53 negative regulator Mdm2. In summary, exposure to DEP affects parameters influencing vasculature permeability and viability, i.e., oxidative stress and its upregulated antioxidative and pro-inflammatory responses, which sequentially induce vascular permeability factor, VEGF-A release and disrupt cell-cell junction integrity. While exposure to a low dose of DEP actin triggers cytoskeleton depolarization, reduces PI3K/Akt activity, and induces a p53/Mdm2 feedback loop, a high dose causes apoptosis by depleting Mdm2. Addition of ROS scavenger N-acetyl cysteine suppresses DEP-induced oxidative stress efficiently and reduces subsequent damages by increasing endogenous glutathione.}, }
@article {pmid26964642, year = {2016}, author = {Wang, Z and Li, H and Guo, R and Wang, Q and Zhang, D}, title = {Antioxidants inhibit advanced glycosylation end-product-induced apoptosis by downregulation of miR-223 in human adipose tissue-derived stem cells.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {23021}, pmid = {26964642}, issn = {2045-2322}, mesh = {Acetylcysteine/administration &amp; dosage ; Adipose Tissue/cytology/drug effects ; Antioxidants/*administration &amp; dosage ; Apoptosis/*drug effects ; Ascorbic Acid/administration &amp; dosage/analogs &amp; derivatives ; Caspase 3/biosynthesis ; Cell Proliferation/drug effects ; Gene Expression Regulation, Developmental/drug effects ; Glycation End Products, Advanced/administration &amp; dosage ; Humans ; Mesenchymal Stem Cells/*cytology/drug effects ; MicroRNAs/*biosynthesis/genetics ; Reactive Oxygen Species/metabolism ; Serum Albumin/administration &amp; dosage ; Serum Albumin, Human ; }, abstract = {Advanced glycosylation end products (AGEs) are endogenous inflammatory mediators that induce apoptosis of mesenchymal stem cells. A potential mechanism includes increased generation of reactive oxygen species (ROS). MicroRNA-223 (miR-223) is implicated in the regulation of cell growth and apoptosis in several cell types. Here, we tested the hypothesis that antioxidants N-acetylcysteine (NAC) and ascorbic acid 2-phosphate (AAP) inhibit AGE-induced apoptosis via a microRNA-dependent mechanism in human adipose tissue-derived stem cells (ADSCs). Results showed that AGE-HSA enhanced apoptosis and caspase-3 activity in ADSCs. AGE-HSA also increased ROS generation and upregulated the expression of miR-223. Interestingly, reductions in ROS generation and apoptosis, and upregulation of miR-223 were found in ADSCs treated with antioxidants NAC and AAP. Furthermore, miR-223 mimics blocked antioxidant inhibition of AGE-induced apoptosis and ROS generation. Knockdown of miR-223 amplified the protective effects of antioxidants on apoptosis induced by AGE-HSA. miR-223 acted by targeting fibroblast growth factor receptor 2. These results indicate that NAC and AAP suppress AGE-HSA-induced apoptosis of ADSCs, possibly through downregulation of miR-223.}, }
@article {pmid26958800, year = {2016}, author = {Orfanos, NF and Mylonas, AI and Karmaniolou, II and Stergiou, IP and Lolis, ED and Dimas, C and Papalois, AE and Kondi-Pafiti, AI and Smyrniotis, VE and Arkadopoulos, NF}, title = {The effects of antioxidants on a porcine model of liver hemorrhage.}, journal = {The journal of trauma and acute care surgery}, volume = {80}, number = {6}, pages = {964-971}, doi = {10.1097/TA.0000000000001026}, pmid = {26958800}, issn = {2163-0763}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis ; Crystalloid Solutions ; Deferoxamine/*pharmacology ; Disease Models, Animal ; *Hepatectomy ; Immunohistochemistry ; Isotonic Solutions/pharmacology ; Liver/*blood supply ; Male ; Random Allocation ; Resuscitation/methods ; Shock, Hemorrhagic/*drug therapy ; Swine ; }, abstract = {PURPOSE: The aim of this study is to assess the efficacy of the combination of N-acetylcysteine (NAC) and deferoxamine (DFO) in the resuscitation from hemorrhagic shock in a porcine model of bleeding during hepatectomy.<br><br>METHODS: Twenty-one pigs were divided randomly to three groups: Sham (S) group, n = 5; fluid (F) resuscitation group, n = 8; and fluid plus NAC plus DFO (NAC&amp;DFO) resuscitation group, n = 8. The animals of groups F and NAC&amp;DFO were subjected to left hepatectomy and controlled hemorrhage from the traumatic liver surface. Shock was established within 10 minutes and maintained for 30 minutes at mean arterial pressure (MAP) of 30 to 40 mm Hg. Resuscitation followed the shock period with crystalloids and colloids. Group NAC&amp;DFO received additionally NAC and DFO in doses of 200 mg/kg and 65 mg/kg, respectively. The total time of the experiment was 6 hours.<br><br>RESULTS: Animal weight, blood loss, excised liver mass, and MAP at the end of the shock period were comparable between experimental groups. Group NAC&amp;DFO received significantly lower volume of both crystalloids and colloids (35% and 42% less, respectively) compared to group F. Hepatocellular proliferation (proliferating cell nuclear antigen) was higher in the antioxidant group. Apoptosis, measured by caspase-3, was restored to sham group levels when NAC and DFO were administered.<br><br>CONCLUSIONS: Our experimental study showed that coadministration of NAC and DFO during liver hemorrhage can decrease the amounts of fluids needed for resuscitation. Moreover, the antioxidant combination restores the energy dependent apoptosis and proliferation of the hepatocytes.}, }
@article {pmid26957787, year = {2016}, author = {Palaniswamy, U and Lakkam, SR and Arya, S and Aravelli, S}, title = {Effectiveness of N-acetyl cysteine, 2% chlorhexidine, and their combination as intracanal medicaments on Enterococcus faecalis biofilm.}, journal = {Journal of conservative dentistry : JCD}, volume = {19}, number = {1}, pages = {17-20}, pmid = {26957787}, issn = {0972-0707}, abstract = {AIM: The purpose of this study was to evaluate the antibacterial efficacies of 2% chlorhexidine (CHX), N-acetyl cysteine (NAC) and assess their synergistic or antagonist action as intracanal medicament.<br><br>MATERIALS AND METHODS: Agar diffusion test was performed with 2% CHX, NAC, and their combination against E. faecalis planktonic cells. The diameters of the zones of bacterial inhibition were measured and recorded for each solution. The assay was further extended to 2 weeks old E. faecalis dentinal biofilm. Sixteen freshly extracted teeth were vertically sectioned into two halves resulting in a total of 32 samples. The samples were inoculated with bacterial suspension and incubated at 37&#xb0;C for 2 weeks for biofilm formation. The samples were then divided into four experimental groups with 8 samples in each group. The samples were gently washed in saline and placed in culture wells containing the test solutions, i.e., 2% CHX, NAC, a combination of 2% CHX and NAC in 1:1 ratio, and a control group containing saline. The biofilm formed on the root canal surface were removed with a sterile scalpel and inoculated on blood agar plates to check for the formation of E. faecalis colonies.<br><br>STATISTICAL ANALYSIS: For agar diffusion test, data were analyzed statistically using one-way analysis of variance and then by post-hoc Scheffe's test to compare the antimicrobial efficacy between the groups. Statistical analysis was not done for the cultures obtained from the biofilm as there was no growth in all the three test groups except the control group, i.e., saline.<br><br>RESULTS: In agar diffusion test, among the three groups tested, 2% CHX and NAC showed almost equal zones of inhibition whereas maximum inhibition was shown by a combination of NAC and 2% CHX suggesting a synergistic action. The results obtained were highly significant (P < 0.001) for the combination of medicament when compared to individual test group. In culture analysis, which was done for the biofilm, no growth was observed in all the three test groups. The results obtained were biologically significant but statistically insignificant.<br><br>CONCLUSION: NAC has almost equal antimicrobial property as 2% CHX whereas their combination showed a synergistic action.}, }
@article {pmid26957510, year = {2017}, author = {, }, title = {ACMT Position Statement: Duration of Intravenous Acetylcysteine Therapy Following Acetaminophen Overdose.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {13}, number = {1}, pages = {126-127}, pmid = {26957510}, issn = {1937-6995}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Analgesics, Non-Narcotic/*poisoning ; Antioxidants/*administration &amp; dosage ; Clinical Decision-Making ; Drug Administration Schedule ; Drug Overdose/diagnosis/*drug therapy ; Humans ; Infusions, Intravenous ; Toxicology/*standards ; Treatment Outcome ; }, }
@article {pmid26956915, year = {2016}, author = {Canayakin, D and Bayir, Y and Kilic Baygutalp, N and Sezen Karaoglan, E and Atmaca, HT and Kocak Ozgeris, FB and Keles, MS and Halici, Z}, title = {Paracetamol-induced nephrotoxicity and oxidative stress in rats: the protective role of Nigella sativa.}, journal = {Pharmaceutical biology}, volume = {54}, number = {10}, pages = {2082-2091}, doi = {10.3109/13880209.2016.1145701}, pmid = {26956915}, issn = {1744-5116}, mesh = {*Acetaminophen ; Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents/isolation &amp; purification/*pharmacology ; Antioxidants/isolation &amp; purification/*pharmacology ; Biomarkers/blood ; Creatinine/blood ; Cytoprotection ; Disease Models, Animal ; Ethanol/chemistry ; Female ; Glutathione/metabolism ; Kidney/*drug effects/metabolism/pathology ; Kidney Diseases/blood/chemically induced/pathology/*prevention &amp; control ; Malondialdehyde/metabolism ; *Nigella sativa/chemistry ; Phytotherapy ; Plant Extracts/isolation &amp; purification/*pharmacology ; Plants, Medicinal ; Rats, Wistar ; Seeds ; Solvents/chemistry ; Superoxide Dismutase/metabolism ; Urea/blood ; }, abstract = {Context Nigella sativa L. (Ranunculaceae) (NS) is traditionally used to treat many conditions such as inflammation. Objective This study evaluates the effects of NS seeds ethanol extract in paracetamol-induced acute nephrotoxicity in rats. Materials and methods Forty-eight female Wistar Albino rats were divided into eight groups: I = sham; II = sham + 1000 mg/kg NS; III = sham + 140 mg/kg (N-acetyl cysteine) NAC; IV = 2 g/kg paracetamol; V = 2 g/kg paracetamol + 140 mg/kg NAC; VI, VII and VIII = 2 g/kg paracetamol + 250, 500 and 1000 mg/kg NS, respectively. Paracetamol administration (oral) was carried out 1 h after NS and NAC administrations (oral), and all animals were sacrificed 24 h later. Results Paracetamol administration significantly increased serum urea (88.05 U/L) and creatinine (0.80 U/L) when compared with the sham group (49.80 and 0.31 U/L, respectively). However, serum urea level was reduced to 65.60, 56.00 and 54.18 U/L, with 250, 500 and 1000 mg/kg doses of the extract, respectively. Also, serum creatinine level was reduced to 0.64, 0.57 and 0.52 U/L with 250, 500 and 1000 mg/kg doses of the extract, respectively. NS administration increased superoxide dismutase and glutathione, and decreased malondialdehyde levels in the kidneys. Kidney histopathological examinations showed that NS administration antagonized paracetamol-induced kidney pathological damage. Discussion and conclusions The results suggest NS has a significant nephroprotective activity on paracetamol-induced nephrotoxicity. It may be suggested that the antiinflammatory and antioxidant effects of NS ethanolic extract originated from different compounds of its black seeds.}, }
@article {pmid26953647, year = {2016}, author = {Al-Harbi, NO and Nadeem, A and Al-Harbi, MM and Ansari, MA and AlSharari, SD and Bahashwan, SA and Attia, SM and Al-Hosaini, KA and Al Hoshani, AR and Ahmad, SF}, title = {Airway oxidative stress causes vascular and hepatic inflammation via upregulation of IL-17A in a murine model of allergic asthma.}, journal = {International immunopharmacology}, volume = {34}, number = {}, pages = {173-182}, doi = {10.1016/j.intimp.2016.03.003}, pmid = {26953647}, issn = {1878-1705}, mesh = {Allergens/immunology ; Animals ; Asthma/*immunology ; Cockroaches/immunology ; Disease Models, Animal ; Hepatitis/*immunology ; Humans ; Hydrogen Peroxide/metabolism ; Interleukin-17/genetics/*metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/*physiology ; STAT3 Transcription Factor/metabolism ; Th1 Cells/immunology ; Th17 Cells/*immunology ; Th2 Cells/immunology ; Up-Regulation ; Vasculitis/*immunology ; }, abstract = {Oxidants are generated in asthmatic airways due to infiltration of inflammatory leukocytes and resident cells in the lung. Reactive oxygen species (ROS) such as hydrogen peroxide and superoxide radical may leak into systemic circulation when generated in uncontrolled manner and may impact vasculature. Our previous studies have shown an association between airway inflammation and systemic inflammation; however so far none has investigated the impact of airway oxidative inflammation on hepatic oxidative stress and Th1/Th2/Th17 cytokine markers in liver/vasculature in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of systemic/hepatic Th1/Th2/Th17 cytokines balance and hepatic oxidative stress. Mice were sensitized intraperitoneally with cockroach extract (CE) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with CE. Mice were then assessed for systemic/hepatic inflammation through assessment of Th1/Th2/Th17 cytokines and oxidative stress (iNOS, protein nitrotyrosine, lipid peroxides and myeloperoxidase activity). Challenge with CE led to increased Th2/Th17 cytokines in blood/liver and hepatic oxidative stress. However, only Th17 related pro-inflammatory markers were upregulated by hydrogen peroxide (H2O2) inhalation in vasculature and liver, whereas antioxidant treatment, N-acetyl cysteine (NAC) downregulated them. Hepatic oxidative stress was also upregulated by H2O2 inhalation, whereas NAC attenuated it. Therefore, our study shows that airway oxidative inflammation may contribute to systemic inflammation through upregulation of Th17 immune responses in blood/liver and hepatic oxidative stress. This might predispose these patients to increased risk for the development of cardiovascular disorders.}, }
@article {pmid26951077, year = {2016}, author = {Kurashige, T and Shimamura, M and Nagayama, Y}, title = {Differences in quantification of DNA double-strand breaks assessed by 53BP1/γH2AX focus formation assays and the comet assay in mammalian cells treated with irradiation and N-acetyl-L-cysteine.}, journal = {Journal of radiation research}, volume = {57}, number = {3}, pages = {312-317}, pmid = {26951077}, issn = {1349-9157}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Cell Survival/drug effects/radiation effects ; Comet Assay/*methods ; *DNA Breaks, Double-Stranded/drug effects/radiation effects ; Histones/*metabolism ; Humans ; Micronucleus Tests ; Phosphoproteins/*metabolism ; *Radiation, Ionizing ; Rats ; Reactive Oxygen Species/metabolism ; Time Factors ; Tumor Suppressor p53-Binding Protein 1/*metabolism ; }, abstract = {The biological effect of ionizing radiation (IR) on genomic DNA is thought to be either direct or indirect; the latter is mediated by IR induction of free radicals and reactive oxygen species (ROS). This study was designed to evaluate the effect of N-acetyl-L-cysteine (NAC), a well-known ROS-scavenging antioxidant, on IR induction of genotoxicity, cytotoxicity and ROS production in mammalian cells, and aimed to clarify the conflicting data in previous publications. Although we clearly demonstrate the beneficial effect of NAC on IR-induced genotoxicity and cytotoxicity (determined using the micronucleus assay and cell viability/clonogenic assays), the data on NAC's effect on DNA double-strand break (DSB) formation were inconsistent in different assays. Specifically, mitigation of IR-induced DSBs by NAC was readily detected by the neutral comet assay, but not by the γH2AX or 53BP1 focus assays. NAC is a glutathione precursor and exerts its effect after conversion to glutathione, and presumably it has its own biological activity. Assuming that the focus assay reflects the biological responses to DSBs (detection and repair), while the comet assay reflects the physical status of genomic DNA, our results indicate that the comet assay could readily detect the antioxidant effect of NAC on DSB formation. However, NAC's biological effect might affect the detection of DSB repair by the focus assays. Our data illustrate that multiple parameters should be carefully used to analyze DNA damage when studying potential candidates for radioprotective compounds.}, }
@article {pmid26948886, year = {2016}, author = {Thursz, M and Morgan, TR}, title = {Treatment of Severe Alcoholic Hepatitis.}, journal = {Gastroenterology}, volume = {150}, number = {8}, pages = {1823-1834}, pmid = {26948886}, issn = {1528-0012}, support = {U01 AA018389/AA/NIAAA NIH HHS/United States ; U01 AA021884/AA/NIAAA NIH HHS/United States ; U01 AA021886/AA/NIAAA NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Biopsy ; Free Radical Scavengers/*therapeutic use ; Glucocorticoids/*therapeutic use ; Hepatitis, Alcoholic/*drug therapy/pathology ; Humans ; Liver/pathology ; Prednisolone/*therapeutic use ; Prognosis ; }, abstract = {Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history of heavy alcohol use, findings from blood tests, and exclusion of other liver diseases by blood and imaging analyses. Liver biopsy specimens, usually collected via the transjugular route, should be analyzed to confirm a diagnosis of AH in patients with an atypical history or presentation. The optimal treatment for patients with severe AH is prednisolone, possibly in combination with N-acetyl cysteine. At present, only short-term increases in survival can be expected-no treatment has been found to increase patient survival beyond 3 months. Abstinence is essential for long-term survival. New treatment options, including liver transplantation, are being tested in trials and results eagerly are awaited.}, }
@article {pmid26946308, year = {2016}, author = {Elbini Dhouib, I and Jallouli, M and Annabi, A and Gharbi, N and Elfazaa, S and Lasram, MM}, title = {A minireview on N-acetylcysteine: An old drug with new approaches.}, journal = {Life sciences}, volume = {151}, number = {}, pages = {359-363}, doi = {10.1016/j.lfs.2016.03.003}, pmid = {26946308}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/therapeutic use ; Humans ; Models, Biological ; Oxidative Stress/*drug effects ; Prodrugs/pharmacology/*therapeutic use ; }, abstract = {N-acetylcysteine (NAC), a cysteine pro-drug and glutathione precursor has been used in therapeutic practices for several decades, as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication. There is a growing interest concerning the beneficial effects of NAC against the early stages of toxicity-induced by pesticides. Nevertheless, the mechanisms underlying the therapeutic and clinical applications of NAC are not fully understood. In this review we aimed to focus on the protective effects of NAC against oxidative stress caused by pesticide in many organs. The possible mechanisms of action may be associated to its antioxidant properties. The anti-oxidative activity of NAC has been attributed to the fast reaction with free radicals as well as the restitution of reduced glutathione (GSH).}, }
@article {pmid26945669, year = {2016}, author = {Wang, WH and He, EM and Chen, J and Guo, Y and Chen, J and Liu, X and Zheng, HL}, title = {The reduced state of the plastoquinone pool is required for chloroplast-mediated stomatal closure in response to calcium stimulation.}, journal = {The Plant journal : for cell and molecular biology}, volume = {86}, number = {2}, pages = {132-144}, doi = {10.1111/tpj.13154}, pmid = {26945669}, issn = {1365-313X}, mesh = {Chloroplasts/*metabolism ; Hydrogen Peroxide/metabolism ; Oxygen/metabolism ; Plant Leaves/*metabolism ; Plant Stomata/*metabolism ; Plants/classification/*metabolism ; Plastoquinone/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Besides their participation in photosynthesis, leaf chloroplasts function in plant responses to stimuli, yet how they direct stimulus-induced stomatal movement remains elusive. Here, we showed that over-reduction of the plastoquinone (PQ) pool by dibromothymoquinone (DBMIB) was closely associated with stomatal closure in plants which required chloroplastic H2O2 generation in the mesophyll. External application of H2 O2 reduced the PQ pool, whereas the cell-permeable reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) reversed the DBMIB-induced over-reduction of the PQ pool and stomatal closure. Mesophyll chloroplasts are key players of extracellular Ca(2+) (Ca(2+)o)-induced stomatal closure, but when treated with either 3-(3',4'-dichlorophenyl)-1,1-dimethylurea (DCMU) or NAC they failed to facilitate Ca(2+)o-induced stomatal closure due to the inhibition of chloroplastic H2 O2 synthesis in mesophyll. Similarly, the Arabidopsis electron transfer chain-related mutants npq4-1, stn7 and cas-1 exhibited diverse responses to Ca(2+)o or DBMIB. Transcriptome analysis also demonstrated that the PQ pool signaling pathway shared common responsive genes with the H2 O2 signaling pathway. These results implicated a mechanism for chloroplast-mediated stomatal closure involving the generation of mesophyll chloroplastic H2O2 based on the reduced state of the PQ pool, which is calcium-sensing receptor (CAS) and LHCII phosphorylation dependent.}, }
@article {pmid26943028, year = {2016}, author = {Shan, Y and Guan, F and Zhao, X and Wang, M and Chen, Y and Wang, Q and Feng, X}, title = {Macranthoside B Induces Apoptosis and Autophagy Via Reactive Oxygen Species Accumulation in Human Ovarian Cancer A2780 Cells.}, journal = {Nutrition and cancer}, volume = {68}, number = {2}, pages = {280-289}, doi = {10.1080/01635581.2016.1142587}, pmid = {26943028}, issn = {1532-7914}, mesh = {AMP-Activated Protein Kinases/metabolism ; Antineoplastic Agents, Phytogenic/administration &amp; dosage/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Female ; Humans ; Oleanolic Acid/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Ovarian Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Saponins/administration &amp; dosage/*pharmacology ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Macranthoside B (MB), a saponin compound in Lonicera macranthoides, can block cell proliferation and induce cell death in several types of cancer cells; however, the precise mechanisms by which MB exerts its anticancer effects remain poorly understood. MB blocked A2780 human ovarian carcinoma cell proliferation both dose- and time-dependently. MB induced apoptosis, with increased poly (ADP-ribose) polymerase (PARP) and caspase-3/9 cleavage. MB also caused autophagy in A2780 cells, with light chain 3 (LC3)-II elevation. Inhibiting MB-induced autophagy with the autophagy inhibitor 3-methyladenine (3-MA) significantly decreased apoptosis, with a reduction of growth inhibition; inhibiting MB-induced apoptosis with the pan-caspase inhibitor Z-VAD-FMK did not decrease autophagy but elevated LC3-II levels, indicating that MB-induced autophagy is cytotoxic and may be upstream of apoptosis. Furthermore, MB increased intracellular reactive oxygen species (ROS) levels, with activated 5' adenosine monophosphate-activated protein kinase (AMPK), decreased mammalian target of rapamycin (mTOR) and P70S6 kinase phosphorylation, and increased PARP and caspase-3/9 cleavage, and LC3-II elevation; treatment with the ROS scavenger N-acetyl cysteine and the AMPK inhibitor Compound C diminished this effect. Therefore, the ROS/AMPK/mTOR pathway mediates the effect of MB on induction of apoptosis via autophagy in human ovarian carcinoma cells.}, }
@article {pmid26941168, year = {2016}, author = {Rios, FJ and Lopes, RA and Neves, KB and Camargo, LL and Montezano, AC and Touyz, RM}, title = {Off-Target Vascular Effects of Cholesteryl Ester Transfer Protein Inhibitors Involve Redox-Sensitive and Signal Transducer and Activator of Transcription 3-Dependent Pathways.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {357}, number = {2}, pages = {415-422}, doi = {10.1124/jpet.115.230748}, pmid = {26941168}, issn = {1521-0103}, support = {CH/12/4/27962//British Heart Foundation/United Kingdom ; RG/13/7/30099//British Heart Foundation/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Cholesterol Ester Transfer Proteins/*antagonists &amp; inhibitors ; Free Radical Scavengers/pharmacology ; Male ; Mitogen-Activated Protein Kinases/drug effects ; Myocytes, Smooth Muscle/drug effects ; NADPH Oxidases/metabolism ; Oxidation-Reduction ; Phosphorylation ; Protein Phosphatase 1/drug effects ; Pyrazoles/pharmacology ; Pyrazolones ; Pyridines/pharmacology ; Pyridones ; Rats ; Rats, Inbred WKY ; STAT3 Transcription Factor/*antagonists &amp; inhibitors ; Vascular Resistance/drug effects/genetics ; Vasoconstriction/drug effects/genetics ; Vasodilator Agents/pharmacology ; }, abstract = {Elevated blood pressure was an unexpected outcome in some cholesteryl ester transfer protein (CETP) inhibitor trials, possibly due to vascular effects of these drugs. We investigated whether CETP inhibitors (torcetrapib, dalcetrapib, anacetrapib) influence vascular function and explored the putative underlying molecular mechanisms. Resistance arteries and vascular smooth muscle cells (VSMC) from rats, which lack the CETP gene, were studied. CETP inhibitors increased phenylephrine-stimulated vascular contraction (logEC50 (:) 6.6 ± 0.1; 6.4 ± 0.06, and 6.2 ± 0.09 for torcetrapib, dalcetrapib, and anacetrapib, respectively, versus control 5.9 ± 0.05). Only torcetrapib reduced endothelium-dependent vasorelaxation. The CETP inhibitor effects were ameliorated by N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, and by S3I-201 [2-hydroxy-4-[[2-(4-methylphenyl)sulfonyloxyacetyl]amino]benzoic acid], a signal transducer and activator of transcription 3 (STAT3) inhibitor. CETP inhibitors increased the phosphorylation (2- to 3-fold) of vascular myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1) (procontractile proteins) and stimulated ROS production. CETP inhibitors increased the phosphorylation of STAT3 (by 3- to 4-fold), a transcription factor important in cell activation. Activation of MLC was reduced by NAC, GKT137831 [2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione] (Nox1/4 inhibitor), and S3I-201. The phosphorylation of STAT3 was unaffected by NAC and GKT137831. CETP inhibitors did not influence activation of mitogen-activated proteins kinases (MAPK) or c-Src. Our data demonstrate that CETP inhibitors influence vascular function and contraction through redox-sensitive, STAT3-dependent, and MAPK-independent processes. These phenomena do not involve CETP because the CETP gene is absent in rodents. Findings from our study indicate that CETP inhibitors have vasoactive properties, which may contribute to the adverse cardiovascular effects of these drugs such as hypertension.}, }
@article {pmid26941030, year = {2016}, author = {Wang, LL and Huang, YH and Yan, CY and Wei, XD and Hou, JQ and Pu, JX and Lv, JX}, title = {N-acetylcysteine Ameliorates Prostatitis via miR-141 Regulating Keap1/Nrf2 Signaling.}, journal = {Inflammation}, volume = {39}, number = {2}, pages = {938-947}, pmid = {26941030}, issn = {1573-2576}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Carrageenan ; Cyclooxygenase 2/biosynthesis ; Disease Models, Animal ; Kelch-Like ECH-Associated Protein 1/*metabolism ; Male ; MicroRNAs/*genetics ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress/drug effects ; Prostatitis/chemically induced/*drug therapy ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; }, abstract = {Chronic prostatitis was the most common type of prostatitis and oxidative stress was reported to be highly elevated in prostatitis patients. In this study, we determined the effect of N-acetylcysteine (NAC) on prostatitis and the molecular mechanism involved in it. Male Sprague-Dawley rats were divided into three groups: control group (group A, n = 20), carrageenan-induced chronic nonbacterial prostatitis (CNP) model group (group B, n = 20), and carrageenan-induced CNP model group with NAC injection (group C, n = 20). Eye score, locomotion score, inflammatory cell count, cyclooxygenase 2 (COX2) expression, and Evans blue were compared in these three groups. The expression of miR-141 was determined by quantitative real-time PCR (qRT-PCR). Moreover, protein expressions of Kelch-like ECH-associated protein-1 (Keap1) and nuclear factor erythroid-2 related factor 2 (Nrf2) and its target genes were examined by Western blot. Luciferase reporter assay was performed in RWPE-1 cells transfected miR-141 mimic or inhibitor and the plasmid carrying 3'-UTR of Keap1. The value of eye score, locomotion score, inflammatory cell count, and Evans blue were significantly decreased in group C, as well as the expression of COX2, when comparing to that of group B. These results indicated that NAC relieved the carrageenan-induced CNP. Further, we found that NAC increased the expression of miR-141 and activated the Keap1/Nrf2 signaling. Luciferase reporter assay revealed that miR-141 mimic could suppress the activity of Keap1 and stimulate the downstream target genes of Nrf2. In addition, miR-141 inhibitor could reduce the effect of NAC on prostatitis. NAC ameliorates the carrageenan-induced prostatitis and prostate inflammation pain through miR-141 regulating Keap1/Nrf2 signaling.}, }
@article {pmid26936454, year = {2016}, author = {Park, JE and Park, B and Chae, IG and Kim, DH and Kundu, J and Kundu, JK and Chun, KS}, title = {Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma Caki cells.}, journal = {Oncology reports}, volume = {35}, number = {5}, pages = {2723-2732}, doi = {10.3892/or.2016.4642}, pmid = {26936454}, issn = {1791-2431}, mesh = {Abietanes/*pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Renal Cell/drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Inhibitory Concentration 50 ; Kidney Neoplasms/drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/*drug effects ; src-Family Kinases/metabolism ; }, abstract = {Carnosic acid (CA), the major bioactive compound of Rosmarinus officinalis L., has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of CA remain poorly understood. In the present study, we investigated that CA significantly reduced the viability of human renal carcinoma Caki cells. CA-induced apoptosis was connected with the cleavage of caspase-9, -7 and -3, and that of PARP. Moreover, CA increased the expression of pro-apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2 and Bcl-xL, thereby releasing cytochrome c into the cytosol. Treatment with CA in Caki cells also induced the expression of p53 and its target gene product, p27, through down-regulation of Murine double minute-2 (Mdm2). Furthermore, CA generated reactive oxygen species (ROS), and pretreatment with ROS scavenger N-acetyl cysteine (NAC) abrogated CA-induced cleavage of PARP and expression of p53. One of the key oncogenic signals is mediated through signal transducer and activator of transcription-3 (STAT3), which promotes abnormal cell proliferation. Incubation of cells with CA markedly diminished the phosphorylation of STAT3 and its upstream, Src, and reduced the expression of STAT3 responsive gene products, such as D-series of cyclins and survivin. Taken together, the present study revealed that CA induced apoptosis in Caki cells by induction of p53 and suppression of STAT3 signaling.}, }
@article {pmid26936390, year = {2016}, author = {You, BR and Park, WH}, title = {The levels of HDAC1 and thioredoxin1 are related to the death of mesothelioma cells by suberoylanilide hydroxamic acid.}, journal = {International journal of oncology}, volume = {48}, number = {5}, pages = {2197-2204}, doi = {10.3892/ijo.2016.3402}, pmid = {26936390}, issn = {1791-2423}, mesh = {Apoptosis ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Histone Deacetylase 1/*metabolism ; Histone Deacetylase Inhibitors/*pharmacology ; Humans ; Hydroxamic Acids/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mesothelioma/drug therapy/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Thioredoxins/*metabolism ; Vorinostat ; }, abstract = {Mesothelioma is an aggressive tumor which is mainly derived from the pleura of lung. In the present study, we evaluated the anticancer effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor on human mesothelioma cells in relation to the levels of HDAC1, reactive oxygen species (ROS) and thioredoxin (Trx). While 1 µM SAHA inhibited cell growth in Phi and ROB cells at 24 h, it did not affect the growth in ADA and Mill cells. Notably, the level of HDAC1 was relatively overexpressed among Phi, REN and ROB cells. SAHA induced necrosis and apoptosis, which was accompanied by the cleavages of PARP and caspase-3 in Phi cells. This agent also increased the loss of mitochondrial membrane potential (MMP, ΔΨm) in Phi cells. All the tested caspase inhibitors attenuated apoptosis in SAHA-treated Phi cells whereas HDAC1 siRNA enhanced the apoptotic cell death. SAHA increased intracellular ROS levels including O2•- in Phi cells. N-acetyl cysteine (NAC) and vitamin C (Vit.C) significantly reduced the growth inhibition and death of Phi cells caused by SAHA. This drug decreased the mRNA and protein levels of Trx1 in Phi and ROB cells. Furthermore, Trx1 siRNA increased cell death and O2•- level in SAHA-treated Phi cells. In conclusion, SAHA selectively inhibited the growth of Phi and ROB mesothelioma cells, which showed the higher basal level of HDAC1. SAHA-induced Phi cell death was related to oxidative stress and Trx1 levels.}, }
@article {pmid26936198, year = {2016}, author = {Zhao, W and Lu, M and Zhang, Q}, title = {Chloride intracellular channel 1 regulates migration and invasion in gastric cancer by triggering the ROS-mediated p38 MAPK signaling pathway.}, journal = {Molecular medicine reports}, volume = {13}, number = {4}, pages = {3711}, doi = {10.3892/mmr.2016.4972}, pmid = {26936198}, issn = {1791-3004}, abstract = {Mol Med Rep 12:[Related article:] 8041–8047, 2015; DOI: 10.3892/mmr.2015.4459 Following the publication of this article, an interested reader drew to our attention anomalies associated with the presentation of Fig. 4A. In the original presentation of the Figure, different representations of the same photomicrograph were inadvertently used for the panels labelled 'N', 'H-R', 'H-R + NAC' and 'H-R + SB203580'. This error arose as a consequence of an incorrect ordering of our original image numbers. A corrected version of Fig. 4A is provided below, featuring the appropriate data for each of the five panels listed above. This Figure was intended to show how, compared with the normoxic control group, the invasiveness of the SGC-7901 gastric cancer cells was markedly increased under hypoxia-reoxygenation (H-R) conditions, although pretreatment with N-acetyl cysteine (NAC; 30 mmol/l) or indanyloxyacetic acid 94 (IAA-94; 40 μmol/l), inhibited the invasiveness resulting from H-R exposure. Similarly, treatment with the inhibitor of p38 mitogen-activated protein kinase, SB203580 (10 μmol/l), also inhibited the cell invasiveness induced under the H-R conditions. We sincerely apologize for this mistake, and thank the reader of our article who drew this matter to our attention. Furthermore, we regret any inconvenience this mistake has caused.}, }
@article {pmid26935921, year = {2016}, author = {Wang, P and Shehu, AI and Liu, K and Lu, J and Ma, X}, title = {Biotransformation of Cobicistat: Metabolic Pathways and Enzymes.}, journal = {Drug metabolism letters}, volume = {10}, number = {2}, pages = {111-123}, pmid = {26935921}, issn = {1874-0758}, support = {R01 DK090305/DK/NIDDK NIH HHS/United States ; R56 AI095425/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Anti-HIV Agents/pharmacokinetics ; Cobicistat/*pharmacokinetics ; Cytochrome P-450 CYP2D6/*metabolism ; Cytochrome P-450 CYP3A/*metabolism ; Humans ; Male ; Mice ; Mice, Knockout ; Microsomes, Liver/*metabolism ; }, abstract = {BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer for antiretroviral therapy.<br><br>OBJECTIVE: The current study was designed to profile the metabolic pathways of COBI and to determine the enzymes that contribute to COBI metabolism.<br><br>METHOD: We screened COBI metabolites in mice and human liver microsomes. We also used cDNAexpressed human cytochromes P450 (CYPs) to explore the role of human enzymes in COBI metabolism.<br><br>RESULTS: Twenty new and three known metabolites of COBI were identified in mouse urine and feces. These new metabolic pathways of COBI include glycine conjugation, N-acetyl cysteine conjugation, morpholine ring-opening, and thiazole ring-opening. Twelve of COBI metabolites were further confirmed in mouse and human liver microsomes, including nine new metabolites. Consistent with the previous report, CYP3A4 and CYP2D6 were determined as the major enzymes that contribute to COBI metabolism.<br><br>CONCLUSION: This study provided a full map of COBI metabolism. These results can be used to manage CYP-mediated drug-drug interactions and adverse drug reactions that are associated with COBI-containing regimens in human.}, }
@article {pmid26934478, year = {2016}, author = {Heinemann, SD and Posimo, JM and Mason, DM and Hutchison, DF and Leak, RK}, title = {Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual-hit hypothesis of neurodegeneration.}, journal = {Hippocampus}, volume = {26}, number = {8}, pages = {980-994}, pmid = {26934478}, issn = {1098-1063}, support = {R03 NS088395/NS/NINDS NIH HHS/United States ; R15 NS093539/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Glutathione/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Hippocampus/drug effects/pathology/*physiopathology ; Leupeptins/toxicity ; Microtubule-Associated Proteins/metabolism ; Models, Neurological ; Neurodegenerative Diseases/drug therapy/pathology/physiopathology ; Neurons/drug effects/pathology/*physiology ; Neuroprotective Agents/pharmacology ; Oxidative Stress/physiology ; Paraquat/toxicity ; Proteasome Endopeptidase Complex/metabolism ; Rats, Sprague-Dawley ; Stress, Physiological/drug effects/*physiology ; }, abstract = {The dual-hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, a relatively high-throughput dual-hit model of stress synergy was developed in primary hippocampal neurons. In order to increase the rigor of the study and strengthen the interpretations, three independent, unbiased viability assays were employed at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48 h. MG132 and paraquat only elicited additive effects 24 h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48 h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. These findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, a new model of hippocampal vulnerability was developed for the testing of therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic. © 2016 Wiley Periodicals, Inc.}, }
@article {pmid26934053, year = {2016}, author = {Adhami, N and Starck, SR and Flores, C and Martins Green, M}, title = {A Health Threat to Bystanders Living in the Homes of Smokers: How Smoke Toxins Deposited on Surfaces Can Cause Insulin Resistance.}, journal = {PloS one}, volume = {11}, number = {3}, pages = {e0149510}, pmid = {26934053}, issn = {1932-6203}, mesh = {Air Pollutants/*adverse effects ; Animals ; Antioxidants/pharmacology ; Catalase/pharmacology ; DNA Damage/drug effects ; Diabetes Mellitus, Type 2/metabolism ; Glutathione Peroxidase/metabolism ; Hydrogen Peroxide/metabolism ; Insulin Resistance/*physiology ; Lipid Peroxidation/drug effects ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Superoxide Dismutase/metabolism ; Nicotiana/adverse effects ; Tobacco Smoke Pollution/*adverse effects ; alpha-Tocopherol/pharmacology ; }, abstract = {Thirdhand smoke (THS) is the accumulation of secondhand smoke on environmental surfaces. THS is found on the clothing and hair of smokers as well as on surfaces in homes and cars of smokers. Exposure occurs by ingestion, inhalation and dermal absorption. Children living in homes of smokers are at highest risk because they crawl on the floor, touch parents' clothing/hair and household objects. Using mice exposed to THS under conditions that mimic exposure of humans, we show that THS increases cellular oxidative stress by increasing superoxide dismutase (SOD) activity and hydrogen peroxide (H2O2) levels while reducing the activity of antioxidant enzymes catalase and glutathione peroxidase (GPx) that break down H2O2 into H2O and O2. This results in lipid peroxidation, protein nitrosylation and DNA damage. Consequences of these cell and molecular changes are hyperglycemia and insulinemia. Indeed, we found reduced levels of insulin receptor, PI3K, AKT, all important molecules in insulin signaling and glucose uptake by cells. To determine whether these effects on THS-induced insulin resistance are due to increase in oxidative stress, we treated mice exposed to THS with the antioxidants N-acetyl cysteine (NAC) and alpha-tocopherol (alpha-toc) and showed that the oxidative stress, the molecular damage, and the insulin resistance, were significantly reversed. Conversely, feeding the mice with chow that mimics "western diet", which is known to increase oxidative stress, while exposing the mice to THS, further increased the oxidative stress and aggravated hyperglycemia and insulinemia. In conclusion, THS exposure results in insulin resistance in the form of non-obese type II diabetes (NODII) through oxidative stress. If confirmed in humans, these studies could have a major impact on how people view exposure to environmental tobacco toxins, in particular to children, elderly and workers in environments where tobacco smoke has taken place.}, }
@article {pmid26931055, year = {2016}, author = {Paydary, K and Akamaloo, A and Ahmadipour, A and Pishgar, F and Emamzadehfard, S and Akhondzadeh, S}, title = {N-acetylcysteine augmentation therapy for moderate-to-severe obsessive-compulsive disorder: randomized, double-blind, placebo-controlled trial.}, journal = {Journal of clinical pharmacy and therapeutics}, volume = {41}, number = {2}, pages = {214-219}, doi = {10.1111/jcpt.12370}, pmid = {26931055}, issn = {1365-2710}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Double-Blind Method ; Drug Interactions ; Drug Therapy, Combination/methods ; Female ; Fluvoxamine/therapeutic use ; Humans ; Iran ; Male ; Obsessive-Compulsive Disorder/*drug therapy ; Psychiatric Status Rating Scales ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Treatment Outcome ; }, abstract = {WHAT IS KNOWN AND OBJECTIVE: N-acetylcysteine (NAC) has been proposed as a potential therapy for obsessive-compulsive disorder (OCD) as it may regulate the exchange of glutamate and prevent its pre-oxidant effects. The aim of the present double-blind, placebo-controlled trial was to assess the efficacy and tolerability of NAC augmentation in moderate-to-severe (OCD) treatment.<br><br>METHODS: In this randomized, double-blind, two-centre, placebo-controlled, 10-week trial, patients with moderate-to-severe OCD were enrolled. Patients were randomized into two parallel groups to receive fluvoxamine (200 mg daily) plus placebo or fluvoxamine (200 mg daily) plus NAC (2000 mg daily). A total of 44 patients (22 in each group) were visited to evaluate response to therapy using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) at baseline, and at weeks 4, 8 and 10. Side effects were recorded using predesigned checklists upon each visit.<br><br>RESULTS AND DISCUSSION: Repeated-measures ANOVA showed a significant effect for time &#xd7; treatment interaction (Greenhouse-Geisser corrected: F = 5&#xb7;14, d.f. = 1&#xb7;64, P = 0&#xb7;012) in the Y-BOCS total score and a significant effect for time &#xd7; treatment interaction (Greenhouse-Geisser corrected: F = 5&#xb7;44, d.f. = 1&#xb7;54, P = 0&#xb7;011) in the Y-BOCS obsession subscale between the two groups.<br><br>WHAT IS NEW AND CONCLUSION: Our results showed that NAC might be effective as an augmentative agent in the treatment of moderate-to-severe OCD.<br><br>TRIAL REGISTRATION: Iranian Registry of Clinical Trials (www.irct.ir): IRCT201405271556N60.}, }
@article {pmid26929671, year = {2016}, author = {Brown, CJ}, title = {Preservation of retinal structure and function after cilioretinal artery occlusion: a case report.}, journal = {International medical case reports journal}, volume = {9}, number = {}, pages = {29-34}, pmid = {26929671}, issn = {1179-142X}, abstract = {Cilioretinal artery occlusion is a cause of sudden, often catastrophic loss of central vision. There are no established effective treatments. Recently, a patient presented 24 hours after a cilioretinal artery occlusion, following a cardiac catheterization prior to which her blood thinners had been discontinued. Lacking an effective way to address the severe retinal ischemic oxidative stress, she was offered, under compassionate use, a multivitamin complex designed to address retinal ischemia and oxidative stress. Significant components of this product are L-methylfolate and n-acetyl cysteine. The patient experienced a rapid unexpected improvement in vision and preservation of retinal structure, suggesting that marked improvement in retinal artery occlusions outcomes may be possible as late as 24 hours postocclusion. This is the third reported case of cilioretinal artery occlusion associated with cardiac catheterization.}, }
@article {pmid26925725, year = {2016}, author = {Ahamed, M and Akhtar, MJ and Alhadlaq, HA and Alshamsan, A}, title = {Copper ferrite nanoparticle-induced cytotoxicity and oxidative stress in human breast cancer MCF-7 cells.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {142}, number = {}, pages = {46-54}, doi = {10.1016/j.colsurfb.2016.02.043}, pmid = {26925725}, issn = {1873-4367}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/genetics/metabolism ; Caspase 9/genetics/metabolism ; Cell Cycle/drug effects ; Cell Membrane/drug effects ; Cell Survival/drug effects ; Copper/chemistry/*pharmacology ; Dose-Response Relationship, Drug ; Ferrous Compounds/antagonists &amp; inhibitors/chemistry/*pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression ; Glutathione/antagonists &amp; inhibitors/metabolism ; Humans ; L-Lactate Dehydrogenase/genetics/metabolism ; MCF-7 Cells ; Magnetite Nanoparticles/*chemistry/ultrastructure ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Oxidative Stress/*drug effects ; Particle Size ; Reactive Oxygen Species/agonists/metabolism ; }, abstract = {Copper ferrite (CuFe2O4) nanoparticles (NPs) are important magnetic materials currently under research due to their applicability in nanomedicine. However, information concerning the biological interaction of copper ferrite NPs is largely lacking. In this study, we investigated the cellular response of copper ferrite NPs in human breast cancer (MCF-7) cells. Copper ferrite NPs were prepared by co-precipitation technique with the thermal effect. Prepared NPs were characterized by X-ray diffraction (XRD), field emission transmission electron microscopy (FETEM) and dynamic light scattering (DLS). Characterization data showed that copper ferrite NPs were crystalline, spherical with smooth surfaces and average diameter of 15nm. Biochemical studies showed that copper ferrite NPs induce cell viability reduction and membrane damage in MCF-7 cells and degree of induction was dose- and time-dependent. High SubG1 cell population during cell cycle progression and MMP loss with a concomitant up-regulation of caspase-3 and caspase-9 genes suggested that copper ferrite NP-induced cell death through mitochondrial pathway. Copper ferrite NP was also found to induce oxidative stress in MCF-7 cells as indicated by reactive oxygen species (ROS) generation and glutathione depletion. Cytotoxicity due to copper ferrite NPs exposure was effectively abrogated by N-acetyl-cysteine (ROS scavenger) suggesting that oxidative stress could be the plausible mechanism of copper ferrite NPs toxicity. Further studies are underway to explore the toxicity mechanisms of copper ferrite NPs in different types of human cells. This study warrants further generation of extensive biointeraction data before their application in nanomedicine.}, }
@article {pmid26924495, year = {2016}, author = {Abdelzaher, LA and Imaizumi, T and Suzuki, T and Tomita, K and Takashina, M and Hattori, Y}, title = {Astaxanthin alleviates oxidative stress insults-related derangements in human vascular endothelial cells exposed to glucose fluctuations.}, journal = {Life sciences}, volume = {150}, number = {}, pages = {24-31}, doi = {10.1016/j.lfs.2016.02.087}, pmid = {26924495}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Glucose/metabolism/*pharmacology ; Human Umbilical Vein Endothelial Cells/drug effects/*metabolism ; Humans ; Inflammation/genetics ; Mitogen-Activated Protein Kinases/biosynthesis/genetics ; NADPH Oxidases/biosynthesis/genetics ; Nitric Oxide Synthase Type III/biosynthesis ; Oxidative Stress/*drug effects ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Reactive Oxygen Species/metabolism ; Transcription Factors/biosynthesis/genetics ; Xanthophylls/pharmacology ; }, abstract = {Glycemic fluctuations may play a critical role in the pathogenesis of diabetic complications, such as cardiovascular disease. We investigated whether the oxycarotenoid astaxanthin can reduce the detrimental effects of fluctuating glucose on vascular endothelial cells. Human umbilical venous endothelial cells were incubated for 3 days in media containing 5.5mM glucose, 22 mM glucose, or 5.5mM glucose alternating with 22 mM glucose in the absence or presence of astaxanthin or N-acetyl-L-cysteine (NAC). Constant high glucose increased reactive oxygen species (ROS) generation, but such an effect was more pronounced in fluctuating glucose. This was associated with up-regulated p22(phox) expression and down-regulated peroxisome proliferator activated receptor-γ coactivator (PGC-1α) expression. Astaxanthin inhibited ROS generation, p22(phox) up-regulation, and PGC-1α down-regulation by the stimuli of glucose fluctuation. Fluctuating glucose, but not constant high glucose, significantly decreased the endothelial nitric oxide synthase (eNOS) phosphorylation level at Ser-1177 without affecting total eNOS expression, which was prevented by astaxanthin as well as by the anti-oxidant NAC. Transferase-mediated dUTP nick end labeling (TUNEL) showed increased cell apoptosis in fluctuating glucose. Glucose fluctuation also resulted in up-regulating gene expression of pro-inflammatory mediators, interleukin-6 and intercellular adhesion molecule-1. These adverse changes were subdued by astaxanthin. The phosphorylation levels of c-Jun N-terminal kinase (JNK) and p38 were significantly increased by glucose fluctuations, and astaxanthin significantly inhibited the increase in JNK and p38 phosphorylation. Taken together, our results suggest that astaxanthin can protect vascular endothelial cells against glucose fluctuation by reducing ROS generation.}, }
@article {pmid26923246, year = {2016}, author = {Shang, CH and Zhang, QQ and Zhou, JH}, title = {Oridonin Inhibits Cell Proliferation and Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.}, journal = {Inflammation}, volume = {39}, number = {2}, pages = {873-880}, pmid = {26923246}, issn = {1573-2576}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis/*drug effects ; Arthritis, Rheumatoid/*drug therapy ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Diterpenes, Kaurane/*pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibroblasts/drug effects ; Humans ; Interleukin-1beta/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*metabolism ; Phosphorylation/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; Synoviocytes/*drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Oridonin, an active diterpenoid compound from Rabdosia rubescens, has anti-tumor effects. Rheumatoid arthritis fibroblast-like synoviocytes (RAFLS), a pathological hallmark of RA, exhibits "tumor-like" phenotype. Here, we investigated the effects of oridonin on the proliferation and apoptosis of RAFLS. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Apoptosis and mitochondrial membrane potential were detected by flow cytometry. Western blot analysis was performed to examine the phosphorylation of extra-cellular regulated kinases (ERK1/2), C-Jun N-Terminal Kinase (JNK), and p38 mitogen-activated protein kinases and the expression of apoptosis-related proteins. Oridonin inhibited cell proliferation and induced cell apoptosis in interleukin-1β (IL-1β)-treated FLS. z-VAD-fmk, a pan-caspase inhibitor, significantly (P < 0.05) attenuated oridonin-induced apoptosis of FLS. Oridonin suppressed IL-1β-mediated phosphorylation of ERK1/2 and JNK in a dose-dependent manner. Meanwhile, oridonin alone dose-dependently suppressed FLS proliferation, triggered cell apoptosis, and reduced mitochondrial membrane potential (ΔΨm) through activating caspase-3, caspase-9, and PARP, leading to translocation of cytochrome c into cytoplasm. z-VAD-fmk significantly (P < 0.05) inhibited oridonin-induced apoptosis. The accumulation of cellular reactive oxygen species (ROS) was about sevenfold increase in oridonin-treated cells. Pretreatment of N-acetylcysteine (NAC), an inhibitor of ROS, significantly attenuated oridonin-triggered apoptosis, indicating the involvement of ROS production in oridonin-induced mitochondrial apoptosis. Oridonin inhibits cell proliferation, induces cell apoptosis, and decreases the phosphorylation of ERK1/2 and JNK in IL-1β-exposed RAFLS. Oridonin induces mitochondrial apoptosis by enhancing the production of ROS in FLS.}, }
@article {pmid26923123, year = {2016}, author = {Ali, F and Khan, M and Khan, SN and Riazuddin, S}, title = {N-Acetyl cysteine protects diabetic mouse derived mesenchymal stem cells from hydrogen-peroxide-induced injury: A novel hypothesis for autologous stem cell transplantation.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {79}, number = {3}, pages = {122-129}, doi = {10.1016/j.jcma.2015.09.005}, pmid = {26923123}, issn = {1728-7731}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Diabetes Mellitus, Experimental/*metabolism ; Hydrogen Peroxide/*toxicity ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/*drug effects/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Streptozocin ; Transplantation, Autologous ; }, abstract = {BACKGROUND: Stem cell transplantation is one of the therapeutic options available to repair damaged organs. However, transplanted cells entail several challenges including their survival in diabetes-affected injured tissue. This study was designed to determine the effects of preconditioning of mesenchymal stem cells (MSCs) with N-acetyl cysteine (NAC), a widely used antioxidant drug.<br><br>METHODS: Diabetic-mouse-derived MSCs (blood glucose &#x2265; 300 mg/dL) were preconditioned with 30 mM NAC for 1 hour followed by oxidative injury with 100 &#x3bc;M hydrogen peroxide (H2O2) for 1 hour.<br><br>RESULTS: Gene expression analysis showed marked upregulation of prosurvival genes (Akt and Bcl-2) and significantly downregulated expression of proapoptotic and stress genes (Capase-3, Bax, Bak, p53, p38, and NF-&#x3ba;B) in the 30 mM-NAC-treated group when compared with those cells treated with H2O2 alone. NAC preconditioning improved cell viability, decreased lactate dehydrogenase release, &#x3b2;-galactosidase activity, and Annexin-V-positive cells. Also, amelioration of oxidative stress, as shown by a decrease in malondialdehyde level and an increase in superoxide dismutase and catalase activities and glutathione level, was observed in the 30 mM-NAC-treated group in comparison to cells treated with H2O2 alone.<br><br>CONCLUSION: This study demonstrates the potential benefits of pharmacological preconditioning of diabetic-mouse-derived MSCs with NAC for amelioration of apoptosis and oxidative stress in H2O2 induced injury.}, }
@article {pmid26922582, year = {2016}, author = {Szkudlinska, MA and von Frankenberg, AD and Utzschneider, KM}, title = {The antioxidant N-Acetylcysteine does not improve glucose tolerance or β-cell function in type 2 diabetes.}, journal = {Journal of diabetes and its complications}, volume = {30}, number = {4}, pages = {618-622}, pmid = {26922582}, issn = {1873-460X}, support = {P30 DK017047/DK/NIDDK NIH HHS/United States ; T32 HL007028/HL/NHLBI NIH HHS/United States ; P30DK017047/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Antioxidants/administration &amp; dosage/*therapeutic use ; Biomarkers/blood/urine ; Body Mass Index ; Combined Modality Therapy ; Diabetes Mellitus, Type 2/complications/*diet therapy/metabolism/therapy ; *Dietary Supplements ; F2-Isoprostanes/urine ; Fructosamine/blood ; Glucose Tolerance Test ; Glycated Hemoglobin/analysis ; Humans ; Hyperglycemia/*prevention &amp; control ; Insulin/blood/*metabolism ; Insulin Secretion ; Insulin-Secreting Cells/*metabolism ; Middle Aged ; Obesity/complications ; Oxidative Stress ; Pilot Projects ; Washington ; }, abstract = {UNLABELLED: Hyperglycemia induces oxidative stress and thereby may exacerbate β-cell dysfunction in type 2 diabetes (T2DM). Notably, glutathione (GSH), synthesized from N-Acetylcysteine (NAC), neutralizes reactive oxygen species within cells and is low in individuals with diabetes.<br><br>AIM: Determine if NAC supplementation improves &#x3b2;-cell function and glucose tolerance by decreasing oxidative stress in T2DM.<br><br>METHODS: Thirteen subjects (6M/7F) with T2DM (duration: 0-13 years, median: 2 years), treated with diet/exercise alone (n=7) or metformin (n=6), underwent a 2-h oral glucose tolerance test (OGTT) at baseline, after 2 weeks supplementation with 600 mg NAC orally twice daily, and again after 2 weeks supplementation with 1200 mg NAC twice daily. The following measurements were made: fasting glucose and fructosamine for glycemic control, incremental AUC glucose (0-120 min) for glucose tolerance, and &#x394; insulin/&#x394; glucose (0-30 min) for the early insulin response to glucose. Fasting erythrocyte GSH and GSSG (oxidized glutathione) levels, plasma thiobarbituric acid reactive substances (TBARS), and urine F2&#x3b1; isoprostanes were measured to assess oxidative status.<br><br>RESULTS: Subjects were middle aged (mean &#xb1; SEM: 53.9 &#xb1; 3.2 years), obese (BMI 37.3 &#xb1; 2.8 kg/m(2)), and relatively well-controlled (HbA1c 6.7 &#xb1; 0.3%, 50 mmol/mol). Glycemic control, glucose tolerance, insulin release, and oxidative markers did not change with either dose of NAC.<br><br>CONCLUSIONS: Based on the lack of any short-term benefit from NAC supplementation on markers of glucose metabolism, &#x3b2;-cell response, and oxidative status, it is unlikely to be a valuable therapeutic approach for treatment of type 2 diabetes.}, }
@article {pmid26922293, year = {2016}, author = {Wang, N and Qian, P and Kumar, S and Yan, TD and Phan, K}, title = {The effect of N-acetylcysteine on the incidence of contrast-induced kidney injury: A systematic review and trial sequential analysis.}, journal = {International journal of cardiology}, volume = {209}, number = {}, pages = {319-327}, doi = {10.1016/j.ijcard.2016.02.083}, pmid = {26922293}, issn = {1874-1754}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*chemically induced/*drug therapy/epidemiology ; Contrast Media/*adverse effects ; Free Radical Scavengers/therapeutic use ; Humans ; Incidence ; Randomized Controlled Trials as Topic/methods ; Treatment Outcome ; }, abstract = {BACKGROUND: There have been a myriad of studies investigating the effectiveness of N-acetylcysteine (NAC) in the prevention of contrast induced nephropathy (CIN) in patients undergoing coronary angiography (CAG) with or without percutaneous coronary intervention (PCI). However the consensus is still out about the effectiveness of NAC pre-treatment due to vastly mixed results amongst the literature.<br><br>OBJECTIVES: The aim of this study was to conduct a meta-analysis and trial sequential analysis to determine the effects of pre-operative NAC in lowering the incidence of CIN in patients undergoing CAG and/or PCI.<br><br>METHODS: A systematic literature search was performed to include all randomized controlled trials (RCTs) comparing NAC versus control as pretreatment for CAG and/or PCI. A traditional meta-analysis and several subgroup analyses were conducted using traditional meta-analysis with relative risk (RR), trial sequential analysis, and meta-regression analysis.<br><br>RESULTS: 43 RCTs met our inclusion criteria giving a total of 3277 patients in both control and treatment arms. There was a significant reduction in the risk of CIN in the NAC treated group compared to control (OR 0.666; 95% CI, 0.532-0.834; I2=40.11%; p=0.004). Trial sequential analysis, using a relative risk reduction threshold of 15%, indicates that the evidence is firm.<br><br>CONCLUSIONS: The results of the present paper support the use of NAC in the prevention of CIN in patients undergoing CAG&#xb1;PCI. Future studies should focus on the benefits of NAC amongst subgroups of high-risk patients.}, }
@article {pmid26918336, year = {2016}, author = {Xiao, D and Wang, L and Huang, X and Li, Y and Dasgupta, C and Zhang, L}, title = {Protective Effect of Antenatal Antioxidant on Nicotine-Induced Heart Ischemia-Sensitive Phenotype in Rat Offspring.}, journal = {PloS one}, volume = {11}, number = {2}, pages = {e0150557}, pmid = {26918336}, issn = {1932-6203}, support = {R01 HL118861/HL/NHLBI NIH HHS/United States ; R03 DA032510/DA/NIDA NIH HHS/United States ; HL118861/HL/NHLBI NIH HHS/United States ; DA032510/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Coronary Circulation/drug effects ; Disease Susceptibility ; Drug Evaluation, Preclinical ; Female ; Fetus/drug effects ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Infusion Pumps, Implantable ; Male ; Models, Biological ; Myocardial Ischemia/*etiology/prevention &amp; control ; Myocardial Reperfusion Injury/etiology/prevention &amp; control ; Nicotine/administration &amp; dosage/*toxicity ; Oxidative Stress/drug effects ; Phenotype ; Phosphorylation/drug effects ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Protein Kinase C-epsilon/biosynthesis ; Protein Processing, Post-Translational/drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Recovery of Function ; Ventricular Dysfunction, Left/*etiology/prevention &amp; control ; }, abstract = {Fetal nicotine exposure increased risk of developing cardiovascular disease later in life. The present study tested the hypothesis that perinatal nicotine-induced programming of heart ischemia-sensitive phenotype is mediated by enhanced reactive oxygen species (ROS) in offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps from day 4 of gestation to day 10 after birth, in the absence or presence of a ROS inhibitor, N-acetyl-cysteine (NAC) in drinking water. Experiments were conducted in 8 month old age male offspring. Isolated hearts were perfused in a Langendorff preparation. Perinatal nicotine treatment significantly increased ischemia and reperfusion-induced left ventricular injury, and decreased post-ischemic recovery of left ventricular function and coronary flow rate. In addition, nicotine enhanced cardiac ROS production and significantly attenuated protein kinase Cε (PKCε) protein abundance in the heart. Although nicotine had no effect on total cardiac glycogen synthase kinase-3β (GSK3β) protein expression, it significantly increased the phosphorylation of GSK3β at serine 9 residue in the heart. NAC inhibited nicotine-mediated increase in ROS production, recovered PKCε gene expression and abrogated increased phosphorylation of GSK3β. Of importance, NAC blocked perinatal nicotine-induced increase in ischemia and reperfusion injury in the heart. These findings provide novel evidence that increased oxidative stress plays a causal role in perinatal nicotine-induced developmental programming of ischemic sensitive phenotype in the heart, and suggest potential therapeutic targets of anti-oxidative stress in the treatment of ischemic heart disease.}, }
@article {pmid26913679, year = {2016}, author = {Rababa'h, AM and Deo, SV and Altarabsheh, SE and De Caro, J and Tarboush, NA and Alzoubi, KH and Ababneh, M and McConnell, BK and Markowitz, AH and Park, SJ}, title = {N-Acetyl Cysteine Therapy Does Not Prevent Renal Failure in High-Risk Patients Undergoing Open-Heart Surgery.}, journal = {The heart surgery forum}, volume = {19}, number = {1}, pages = {E16-22}, doi = {10.1532/hsf.1424}, pmid = {26913679}, issn = {1522-6662}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*mortality/*prevention &amp; control ; Aged ; Cardiac Surgical Procedures/*mortality/statistics &amp; numerical data ; Female ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Hospital Mortality ; Hospitalization/statistics &amp; numerical data ; Humans ; Male ; Middle Aged ; Postoperative Complications/*mortality/*prevention &amp; control ; Prevalence ; Randomized Controlled Trials as Topic ; Renal Agents ; Risk Factors ; Survival Rate ; Treatment Failure ; Treatment Outcome ; }, abstract = {BACKGROUND: Renal dysfunction is a common complication after cardiovascular surgery. Controversial issues have been discussed regarding the role of N-acetyl cysteine in the prevention of postoperative renal dysfunction. The purpose of this meta-analysis is to assess whether N-acetyl cysteine offers any protection against the development of acute renal dysfunction after cardiac surgery.<br><br>METHODS: Multiple databases were searched for randomized trials comparing the role of N-acetyl cysteine and placebo in human patients undergoing cardiac surgery. End-points studied were: the incidence of acute renal failure, hemodialysis, early mortality, duration of hospital stay, and maximal change in creatinine values. Dichotomous variables were compared using the risk difference (RD) calculated with inverse weighting; continuous data was pooled as (standardized) mean difference. Results are presented with 95% confidence interval (P < .05 is significant); results are presented within 95% confidence interval.<br><br>RESULTS: Thirteen randomized trials (713 and 707 patients in the N-acetyl cysteine and control groups, respectively) were included in the present analysis; nine dealing with patients at high-risk for acute renal failure. The incidence of postoperative acute renal dysfunction was 23% and 36% in the N-acetyl cysteine and control cohorts, respectively. N-acetyl cysteine therapy did not reduce acute renal dysfunction in the high-risk cohort [RD -0.03 (-0.09 to 0.02); P = .22; I2 = 24%]. Maximal change in creatinine levels after surgery was also comparable [standardized mean difference 0.07 (-0.23, 0.09); P = .39]. Early mortality was 2.9% and 3.7% in the N-acetyl cysteine and control cohorts respectively; [RD 0 (-0.03 to 0.02); P = .63; I2 = 20%]. Hospital stay (mean length of stay 10.4 and 10.1 days in the N-acetyl cysteine and control cohorts, respectively) was also similar in both cohorts [WMD 0.17 (-0.02 to 0.37) days; P = .81].<br><br>CONCLUSION: Prophylactic N-acetyl cysteine therapy does not reduce the incidence of renal dysfunction in high-risk patients undergoing cardiac surgery.}, }
@article {pmid26912034, year = {2016}, author = {Mason, SA and Morrison, D and McConell, GK and Wadley, GD}, title = {Muscle redox signalling pathways in exercise. Role of antioxidants.}, journal = {Free radical biology &amp; medicine}, volume = {98}, number = {}, pages = {29-45}, doi = {10.1016/j.freeradbiomed.2016.02.022}, pmid = {26912034}, issn = {1873-4596}, mesh = {Animals ; Antioxidants/*physiology ; Athletes ; Exercise/*physiology ; Humans ; Muscle Contraction ; Muscle, Skeletal/*metabolism/physiology ; Oxidation-Reduction ; *Signal Transduction ; }, abstract = {Recent research highlights the importance of redox signalling pathway activation by contraction-induced reactive oxygen species (ROS) and nitric oxide (NO) in normal exercise-related cellular and molecular adaptations in skeletal muscle. In this review, we discuss some potentially important redox signalling pathways in skeletal muscle that are involved in acute and chronic responses to contraction and exercise. Specifically, we discuss redox signalling implicated in skeletal muscle contraction force, mitochondrial biogenesis and antioxidant enzyme induction, glucose uptake and muscle hypertrophy. Furthermore, we review evidence investigating the impact of major exogenous antioxidants on these acute and chronic responses to exercise. Redox signalling pathways involved in adaptive responses in skeletal muscle to exercise are not clearly elucidated at present, and further research is required to better define important signalling pathways involved. Evidence of beneficial or detrimental effects of specific antioxidant compounds on exercise adaptations in muscle is similarly limited, particularly in human subjects. Future research is required to not only investigate effects of specific antioxidant compounds on skeletal muscle exercise adaptations, but also to better establish mechanisms of action of specific antioxidants in vivo. Although we feel it remains somewhat premature to make clear recommendations in relation to application of specific antioxidant compounds in different exercise settings, a bulk of evidence suggests that N-acetylcysteine (NAC) is ergogenic through its effects on maintenance of muscle force production during sustained fatiguing events. Nevertheless, a current lack of evidence from studies using performance tests representative of athletic competition and a potential for adverse effects with high doses (>70mg/kg body mass) warrants caution in its use for performance enhancement. In addition, evidence implicates high dose vitamin C (1g/day) and E (≥260 IU/day) supplementation in impairments to some skeletal muscle cellular adaptations to chronic exercise training. Thus, determining the utility of antioxidant supplementation in athletes likely requires a consideration of training and competition periodization cycles of athletes in addition to type, dose and duration of antioxidant supplementation.}, }
@article {pmid26908203, year = {2016}, author = {Kumar, A and Shalmanova, L and Hammad, A and Christmas, SE}, title = {Induction of IL-8(CXCL8) and MCP-1(CCL2) with oxidative stress and its inhibition with N-acetyl cysteine (NAC) in cell culture model using HK-2 cell.}, journal = {Transplant immunology}, volume = {35}, number = {}, pages = {40-46}, doi = {10.1016/j.trim.2016.02.003}, pmid = {26908203}, issn = {1878-5492}, mesh = {Acetylcysteine/*pharmacology ; Cell Culture Techniques ; Cell Line ; Chemokine CCL2/*immunology ; Humans ; Interleukin-1beta/immunology ; Interleukin-8/*immunology ; *Kidney Transplantation ; Oxidative Stress/*drug effects/immunology ; Reperfusion Injury/*drug therapy/immunology ; }, abstract = {Renal transplantation can often be complicated due to delayed graft function, which is a direct sequel of ischaemia reperfusion injury. The adverse outcome of delayed graft function is not only short term but the long-term function of the graft is also affected. Therefore, it is important to understand the mechanisms of ischaemia reperfusion injury. Reactive oxygen species are the key mediators in ischaemia reperfusion injury causing direct cell damage which also initiate inflammation by inducing chemokines. The presence of inflammation is a marker of severe delayed graft function. However, the effect of oxidative stress on the expression of key chemokines has not been fully established yet. Therefore, the aim of this study was to measure the oxidative stress response and the secretion of chemokines in a cell culture model that mimics the effects of ischaemia reperfusion injury in immortalised human renal proximal tubular epithelial cells, HK-2. Cells were treated with varying concentrations of hydrogen peroxide and markers of oxidative stress response and chemokine release were measured. Exposure to hydrogen peroxide induced a significant increase in the activity of the antioxidant enzyme glutathione peroxidase and the levels of the chemokines Interleukin-8 (IL-8; CXCL8) and MCP-1 (CCL2). A dose related increase of chemokine secretion was also observed. The cytokine Interleukin-1β (IL-1β) at 1 ng/ml significantly potentiated the expression of both IL-8 (CXCL8) and MCP-1 (CCL2) which showed synergistic response in the presence of hydrogen peroxide. Pre-incubation of the cells with the anti-oxidant N-acetyl cysteine (NAC) strongly suppressed the induction of both IL-8 and MCP-1 when stimulated with hydrogen peroxide and IL-1β. This study demonstrates the potential of anti-oxidants like N-acetyl cysteine in ameliorating the effects of ischaemia reperfusion injury thus suggesting a new therapeutic approach in renal transplantation. These findings can have potential implications for clinical use to prevent ischaemia reperfusion injury in renal transplantation.}, }
@article {pmid26906511, year = {2016}, author = {Cheng, F and Lan, J and Xia, W and Tu, C and Chen, B and Li, S and Pan, W}, title = {Folic Acid Attenuates Vascular Endothelial Cell Injury Caused by Hypoxia via the Inhibition of ERK1/2/NOX4/ROS Pathway.}, journal = {Cell biochemistry and biophysics}, volume = {74}, number = {2}, pages = {205-211}, doi = {10.1007/s12013-016-0723-z}, pmid = {26906511}, issn = {1559-0283}, mesh = {Coronary Artery Disease/pathology ; Cytoprotection/*drug effects ; Folic Acid/*pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Human Umbilical Vein Endothelial Cells/cytology/*drug effects/metabolism ; Humans ; MAP Kinase Signaling System/*drug effects ; Mitogen-Activated Protein Kinase 3/*metabolism ; NADPH Oxidase 4 ; NADPH Oxidases/*metabolism ; Nitric Oxide/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Coronary artery disease is a disease with high morbidity and mortality, in which vascular endothelial dysfunction plays an important role. Hypoxia leads to the inflammation and oxidative stress in endothelial cells, which results in the endothelial injury. The present study was designed to investigate the protective effect and mechanism of folic acid on hypoxia-induced injury in human umbilical vein endothelial cells (HUVEC). Cell counting Kit was used to detect cell survival rate, and apoptotic cells were detected by Hoechst 33258 staining. Intracellular reactive oxygen species (ROS) level was measured using dichloro-dihydro-fluorescein diacetate staining. Western blot was used to determine the protein expressions of extracellular signal protein kinase 1/2 (ERK1/2) and phosphorylated ERK1/2 (p-ERK1/2), NOX4 subunit of NAPDH and endothelial nitric oxide synthase (eNOS). Folic acid significantly increased the cell survival rate and decreased the apoptosis of HUVECs treated with folic acid compared with hypoxia-treated HUVEC. Folic acid also decreased ROS level, while it increased the nitrite content in HUVECs. In addition, folic acid decreased protein expressions of NOX4 and p-ERK1/2, while it increased the protein expression of eNOS in HUVECs. Furthermore, N-acetyl cysteine (NAC), the antioxidant, had similar effect on the cell survival rate and the apoptosis. In addition, DPI (NOX4 inhibitor) and U0126 (ERK1/2 inhibitor) rather than NAC decreased the protein expression of NOX4. NAC, DPI, and U0126 increased the protein expression of eNOS. Furthermore, U0126 rather than DPI and NAC decreased the protein expression of p-ERK1/2. Taken together, the results suggested that hypoxia decreased the cell survival rate and induced apoptosis via ERK1/2/NOX4/ROS pathway, which could be the target of folic acid in protecting the HUVECs from injury caused by hypoxia.}, }
@article {pmid26905757, year = {2016}, author = {Molina-Manso, D and Del-Prado, G and Gómez-Barrena, E and Cordero-Ampuero, J and Fernandez-Roblas, R and Esteban, J}, title = {Effect of different agents with potential antibiofilm activity on antimicrobial susceptibility of biofilms formed by Staphylococcus spp. isolated from implant-related infections.}, journal = {The Journal of antibiotics}, volume = {69}, number = {9}, pages = {686-688}, pmid = {26905757}, issn = {1881-1469}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Anti-Bacterial Agents/administration &amp; dosage/*pharmacology ; Biofilms/*drug effects ; Erythromycin/administration &amp; dosage/*pharmacology ; Humans ; Microbial Sensitivity Tests ; Prosthesis-Related Infections/*drug therapy/microbiology ; Species Specificity ; Staphylococcus aureus/drug effects/isolation &amp; purification ; Staphylococcus epidermidis/drug effects/isolation &amp; purification ; }, abstract = {An in vitro study aimed to evaluate the effect of N-acetyl cysteine (NAC) or sub-ICs of erythromycin on antimicrobial susceptibility of staphylococcal biofilms was performed. Staphylococcus aureus and Staphylococcus epidermidis strains were isolated from patients with prosthetic joint infections using a previously published sonication procedure. Conventional susceptibility studies were performed using microdilution according to the CLSI procedures. Biofilm susceptibility was performed using the Calgary methodology. The addition of NAC showed no effect with the S. aureus strains, and a strain-dependent effect with the S. epidermidis strains. No effect was detected with erythromycin for almost all tested strains.}, }
@article {pmid26903511, year = {2016}, author = {Yang, L and Meng, H and Yang, M}, title = {Autophagy protects osteoblasts from advanced glycation end products-induced apoptosis through intracellular reactive oxygen species.}, journal = {Journal of molecular endocrinology}, volume = {56}, number = {4}, pages = {291-300}, doi = {10.1530/JME-15-0267}, pmid = {26903511}, issn = {1479-6813}, mesh = {Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Antioxidants/pharmacology ; *Apoptosis/drug effects ; *Autophagy ; Cell Line ; Cell Survival/drug effects ; Glycation End Products, Advanced/*metabolism/pharmacology ; Intracellular Space/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/metabolism ; Osteoblasts/drug effects/*metabolism ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {Patients with type II diabetes are susceptible to fracture; however, these patients typically have normal bone mineral density. Thus, such fractures cannot be entirely explained by advanced glycation end products (AGEs)-induced osteoblast apoptosis. Autophagy is a molecular process allowing cells to degrade unnecessary or dysfunctional cellular organelles, and closely interacts with apoptosis. The aim of this study was to determine whether autophagy participated in the pathology of AGEs-treated osteoblasts, and the possible mechanism of such an involvement. Osteoblastic MC3T3-E1 cells were used. Autophagy was evaluated by detecting the level of LC3 via western blotting and immunofluorescence. p62/SQSTM1 expression was also assessed by western blotting. The autophagy inducer rapamycin (RA) and the autophagy inhibitor 3-methyladenine were used to determine whether autophagy has effect on AGEs-induced apoptosis. N-Acetylcysteine (NAC), reactive oxygen species (ROS) inhibitor, was used to determine whether ROS and mitochondrial damage were involved in autophagy regulation. The results showed that the autophagy level was increased in MC3T3-E1 cells treated with AGEs, as represented by an increase in both the total LC3 level and the LC3II/LC3I ratio, as well as a decrease in p62/SQSTMI expression. Further inducing autophagy by RA attenuated AGEs-induced apoptosis. The antioxidant NAC suppresses AGEs-induced autophagy in osteoblastic MC3T3-E1 cells. These results demonstrate that autophagy participates in the pathology of AGEs-treated osteoblasts, and may play a protective role in AGEs-induced apoptosis in osteoblastic MC3T3-E1 cells. ROS and mitochondrial damage are essential in upregulating AGEs-induced autophagy.}, }
@article {pmid26899537, year = {2016}, author = {Li, H and Wang, C and Liu, C and Li, R and Zou, M and Cheng, G}, title = {Efficacy of Short-Term Statin Treatment for the Prevention of Contrast-Induced Acute Kidney Injury in Patients Undergoing Coronary Angiography/Percutaneous Coronary Intervention: A Meta-Analysis of 21 Randomized Controlled Trials.}, journal = {American journal of cardiovascular drugs : drugs, devices, and other interventions}, volume = {16}, number = {3}, pages = {201-219}, doi = {10.1007/s40256-016-0164-5}, pmid = {26899537}, issn = {1179-187X}, mesh = {Acute Kidney Injury/chemically induced/epidemiology/*prevention &amp; control ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; *Evidence-Based Medicine ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Iatrogenic Disease/epidemiology/prevention &amp; control ; Percutaneous Coronary Intervention/*adverse effects ; Randomized Controlled Trials as Topic ; Risk ; }, abstract = {BACKGROUND: The results of previous studies have been contradictory in terms of the efficacy of statin treatment in preventing contrast-induced acute kidney injury (CI-AKI) and clinical adverse events (AEs).<br><br>OBJECTIVE: This meta-analysis was undertaken to assess the role of short-term statin treatment in the prevention of CI-AKI and clinical AEs.<br><br>METHODS: We searched the Cochrane Library, EMBASE, and PubMed databases for randomized controlled trials (RCTs) with the development of CI-AKI as a primary outcome. Secondary outcomes were the post-procedural serum creatinine (SCr) level, estimated glomerular filtration rate (eGFR), and development of AEs. We also performed prespecified subgroup analyses.<br><br>RESULTS: A total of 21 RCTs involving 7746 patients were included. Short-term statin treatment significantly reduced the risk of CI-AKI [risk ratio (RR) 0.57; 95&#xa0;% confident interval (CI) 0.47-0.69; p&#xa0;<&#xa0;0.00001) and was associated with a lower post-procedural SCr level and a higher eGFR. High-dose statins resulted in a lower incidence of CI-AKI than the lower-dose statins. In addition, the benefit was seen across various subgroups for patients at risk of CI-AKI, statin-na&#xef;ve patients, and East Asians, regardless of statin type, definition of CI-AKI, use of N-acetylcysteine (NAC) and hydration, and osmolality of contrast. However, there was no significant difference between the two groups in terms of the incidence of AEs.<br><br>CONCLUSIONS: The meta-analysis suggests that short-term statin treatment can effectively prevent CI-AKI, and the benefit is also observed in high-risk patients, statin-na&#xef;ve patients, and an East Asian population. However, the effect of simvastatin for the prevention of CI-AKI, of statins for the prevention of AEs, and whether high-dose statins have a better effect than lower-dose statins are all still uncertain.}, }
@article {pmid26899513, year = {2016}, author = {Lucyk, SN and Yarema, MC and Sivilotti, ML and Johnson, DW and Nettel-Aguirre, A and Victorino, C and Bailey, B and Dart, RC and Heard, K and Spyker, DA and Rumack, BH}, title = {Outcomes of Patients With Premature Discontinuation of the 21-h Intravenous N-Acetylcysteine Protocol After Acute Acetaminophen Overdose.}, journal = {The Journal of emergency medicine}, volume = {50}, number = {4}, pages = {629-637}, doi = {10.1016/j.jemermed.2015.12.004}, pmid = {26899513}, issn = {0736-4679}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Intravenous ; Adolescent ; Adult ; Female ; Humans ; Male ; Retrospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: The minimum recommended treatment duration for i.v. N-acetylcysteine (NAC) after an acute, single acetaminophen (APAP) overdose is 21 h. Some have questioned whether shorter courses may be sufficient in carefully selected cases.<br><br>OBJECTIVE: We sought to describe the incidence of hepatotoxicity in a cohort of acute APAP overdose patients who received <21 h of i.v. NAC for any reason.<br><br>METHODS: We performed a secondary analysis of a large multicenter retrospective cohort of patients hospitalized for APAP poisoning. We selected patients with a potentially toxic serum APAP concentration measured between 4 and 24 h post ingestion, in whom i.v. NAC was initiated but discontinued before completing the full 21-h course. We further characterized outcomes in these patients as a function of two novel risk-prediction tools, the psi (&#x3c8;) parameter and APAP &#xd7; aminotransferase (AT) product. The &#x3c8; parameter is an estimate of the cellular burden of injury based on the area under the concentration-time curve before treatment, and calculated with respect to the APAP concentration and time to initiation of NAC.<br><br>RESULTS: Fifty-nine patients met inclusion criteria. Intravenous NAC was initiated a median of 11.3 h post ingestion and administered for a median of 11.0 h. Hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 1,000 IU/L) occurred in one patient (1.7%; 95% confidence interval 0.04-9.1), and eight additional patients developed hepatic injury (AST or ALT > 100 IU/L). No fatalities occurred. A multiplication product of APAP and AT (APAP &#xd7; AT) that falls below 10,000 &#x3bc;mol/L/IU-L, or pretreatment &#x3c8; < 5 mmol/L-h suggested a low risk of hepatic injury.<br><br>CONCLUSIONS: In this retrospective analysis of patients treated with < 21 h of i.v. NAC for acute APAP overdose, the incidence of hepatotoxicity and coagulopathy was low, despite delays to NAC treatment.}, }
@article {pmid26898612, year = {2016}, author = {Li, D and Zhang, L and Zhou, J and Chen, H}, title = {Cigarette smoke extract exposure induces EGFR-TKI resistance in EGFR-mutated NSCLC via mediating Src activation and EMT.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {93}, number = {}, pages = {35-42}, doi = {10.1016/j.lungcan.2015.12.007}, pmid = {26898612}, issn = {1872-8332}, mesh = {Antineoplastic Agents/pharmacology ; Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics/*metabolism/pathology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; *Drug Resistance, Neoplasm ; Enzyme Activation ; *Epithelial-Mesenchymal Transition ; ErbB Receptors/*genetics ; Humans ; Lung Neoplasms/drug therapy/*genetics/*metabolism/pathology ; *Mutation ; Phenotype ; Protein Kinase Inhibitors/pharmacology ; Smoking/*adverse effects ; src-Family Kinases/*metabolism ; }, abstract = {OBJECTIVES: The study aims to explore the molecular basis for the poor response of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with smoking history. Novel agent overcoming EGFR-TKI resistance had also been investigated.<br><br>METHODS: The impact of cigarette smoke extract (CSE) on gefitinib sensitive PC-9 cells was evaluated using quantitative real-time PCR (qRT-PCR), western blot, CCK-8 assays, immunofluorescence staining, matrigel invasion assays and wound healing assays.<br><br>RESULTS: Western blot and qRT-PCR presented that CSE stimulated the up-regulation of Vimentin and down-regulation of E-cadherin in PC-9 cells in concentration-and time-dependent manners through modulating Src phosphorylation. N-acetylcysteine (NAC) was capable of decreasing Src phosphorylation, abrogating changes of epithelial to mesenchymal transition (EMT) markers instigated by CSE. Immunofluorescence staining found that PC-9 cells displayed features of mesenchymal cells after CSE exposure, while PP2 and NAC could recover these changes. CCK-8 assays showed that CSE could increase the IC50 of PC-9 cells, while PP2 and NAC could abort the elevation of IC50 caused by CSE. Matrigel invasion assays and wound healing assays showed that CSE could increase the invasion and migration ability of PC-9 cells, which could be suppressed by NAC and PP2.<br><br>CONCLUSION: CSE exposure induced EGFR-TKI resistance via mediating Src activation and EMT in NSCLC. NAC may alleviate smoking induced EGFR-TKI resistance through inhibiting Src activation and EMT reversal. NAC may be a promising adjuvant to reinforce the effect of EGFR-TKI.}, }
@article {pmid26896612, year = {2016}, author = {Liu, J and Quan, J and Feng, J and Zhang, Q and Xu, Y and Liu, J and Huang, W and Liu, J and Tian, L}, title = {High glucose regulates LN expression in human liver sinusoidal endothelial cells through ROS/integrin αvβ3 pathway.}, journal = {Environmental toxicology and pharmacology}, volume = {42}, number = {}, pages = {231-236}, doi = {10.1016/j.etap.2016.01.021}, pmid = {26896612}, issn = {1872-7077}, mesh = {Acetylcysteine ; Cells, Cultured ; Endothelial Cells/*physiology ; Fluoresceins ; Glucose/*metabolism ; Humans ; Integrin alphaVbeta3/*metabolism ; Laminin/*metabolism ; Liver/*physiology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Diabetes mellitus can cause a wide variety of vascular complications and is one of the major risk factors for Non Alcoholic Fatty Liver Disease (NAFLD). The present study was designed investigate the expression of laminin (LN) in human liver sinusoidal endothelial cells (HLSECs) induced by high glucose and the role of reactive oxygen species (ROS) and integrin αvβ3 in the regulation of LN expression. HLSECs were cultured and treated with media containing 25 mM glucose in the presence or absence of N-acetylcysteine (NAC) or clone LM609. The level of intracellular ROS of HLSECs was measured with 2',7' dichloro-fluorescein diacetate (DCFH-DA) probe. Expression of integrin αvβ3 was measured using RT-PCR and Western blot. Expression of LN was testified by immunofluorescence assay. Compared with that in control group, ROS level and the expression of integrin αvβ3 and LN increased in high glucose group. Compared with that in high glucose group, antioxidant NAC inhibited the expression of integrin αvβ3, NAC and the anti-body for blocking integrin αvβ3 (clone LM609) down-regulated the expression of LN. However, the above parameters did not differ between control and mannitol groups. High glucose up-regulates expression of LN in HLSECs through ROS/integrin αvβ3 pathway.}, }
@article {pmid28856191, year = {2016}, author = {de Jong, L and Knapen, DG and Oude Munnink, TH and Henstra, MJ and Veneman, TF}, title = {False positive acetaminophen concentrations in icteric serum.}, journal = {Practical laboratory medicine}, volume = {4}, number = {}, pages = {38-40}, pmid = {28856191}, issn = {2352-5517}, abstract = {INTRODUCTION: Serum concentrations of acetaminophen are measured to predict the risk of hepatotoxicity in cases of acetaminophen overdose and to identify acetaminophen use in patients with acute liver injury without a known cause. The acetaminophen concentration determines if treatment with N-acetyl cysteine, the antidote for acetaminophen poisoning, is warranted.<br><br>DESCRIPTION: A 49-year-old woman was admitted to our hospital with a hepatic encephalopathy and a total serum bilirubin concentration of 442&#xa0;&#xb5;mol/l. The acetaminophen concentration of 11.5&#xa0;mg/l was measured with an enzymatic-colorimetric assay, thus treatment with N-acetyl cysteine was started. Interestingly, the acetaminophen concentration remained unchanged (11.5-12.3&#xa0;mg/l) during a period of 4 consecutive days. In contrast, the acetaminophen concentration measured by HPLC, a chromatographic technique, remained undetectable.<br><br>DISCUSSION: In the presented case, elevated bilirubin was the most likely candidate to interfere with acetaminophen assay causing false positive results. Bilirubin has intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum and for that reason it causes interference in an enzymatic-colorimetric assay.<br><br>CONCLUSION: False positive acetaminophen laboratory test results may be found in icteric serum, when enzymatic-colorimetric assays are used for determination of an acetaminophen concentration. Questionable acetaminophen results in icteric serum should be confirmed by a non-enzymatic method, by means of ultrafiltration of the serum, or by dilution studies.}, }
@article {pmid28962440, year = {2015}, author = {Rosic, G and Srejovic, I and Zivkovic, V and Selakovic, D and Joksimovic, J and Jakovljevic, V}, title = {The effects of N-acetylcysteine on cisplatin-induced cardiotoxicity on isolated rat hearts after short-term global ischemia.}, journal = {Toxicology reports}, volume = {2}, number = {}, pages = {996-1006}, pmid = {28962440}, issn = {2214-7500}, abstract = {The aim of this study was to estimate the protective effect of N-acetyl-l-cysteine (NAC) against cisplatin-induced cardiotoxicity under conditions of ischemic-reperfusion injury. Wistar albino rats were randomly divided into three groups (n = 8): control, cisplatin (5 mg/kg/w, i.p., 5 weeks) and cisplatin + NAC group (cisplatin - 5 mg/kg/w, i.p. and NAC - 500 mg/kg/w, i.p., 5 weeks). Isolated hearts were perfused according to the modified Langendorff technique at constant pressure (70 cmH2O). Following cardiodynamic parameters were measured: maximum rate of left ventricular pressure development, minimum rate of left ventricular pressure development, left ventricular systolic pressure (SLVP), left ventricular diastolic pressure and heart rate. The ischemic vasodilation episodes were induced by the complete interruption of coronary inflow for 30, 60 and 120 s. The samples of the coronary venous effluent (CVE) were continuously collected during the reperfusion period for determination of coronary flow (CF) rate and oxidative stress markers (H2O2, O2[-], NO2[-] and thiobarbituric acid reactive substances - TBARS). Cisplatin reduced CF, heart rate and overflow (total, maximal and duration of overflow) during reperfusion, and increased SLVP (under basal conditions and after global ischemias). Cisplatin increased levels of H2O2 (under basal conditions), O2[-] and TBARS (under basal conditions and after ischemia), but decreased NO2[-] levels (during reperfusion) in CVE, and decreased superoxide dismutase and reduced glutathione in serum. NAC attenuated cisplatin-induced changes of cardiodynamic parameters (except CF under basal conditions) and oxidative stress parameters. Those results suggest that NAC, by decreasing oxidative stress, may be useful in cardioprotection during cisplatin therapy.}, }
@article {pmid27418761, year = {2015}, author = {Giannikouris, I}, title = {The effect of N-acetylcysteine on oxidative serum biomarkers of hemodialysis patients.}, journal = {Hippokratia}, volume = {19}, number = {2}, pages = {131-135}, pmid = {27418761}, issn = {1108-4189}, abstract = {BACKGROUND: The aim of the study was to determine the effect of oral N-acetylcysteine (NAC) on levels of serum oxidative stress biomarkers in hemodialysis patients.<br><br>METHODS: Forty eight hemodialysis patients were administered NAC orally for six months. Hematological, biochemical parameters and levels of asymmetric dimethylarginine (ADMA), malondialdehyde (MDA), myeloperoxidase (MPO) and nitrogen oxide (NO) were determined prior to and upon completion of the study period.<br><br>RESULTS: At the end of the study period white blood cells, neutrophil percentage and C-reactive protein levels were significantly lower. Uric acid, albumin and hemoglobin were significantly higher compared to pre-treatment values. Statistically significant increase in NO, and decrease in MDA and ADMA levels were observed. Serum MPO demonstrated a measurable decrease trend, though not significant.<br><br>CONCLUSION: It is suggested that treatment with NAC appears to be associated with restoration of important parameters of antioxidant defence and reduction in the levels of mediators of oxidative cellular damage. Hippokratia 2015; 19 (2):131-135.}, }
@article {pmid27551466, year = {2015}, author = {Yahiro, K and Akazawa, Y and Nakano, M and Suzuki, H and Hisatune, J and Isomoto, H and Sap, J and Noda, M and Moss, J and Hirayama, T}, title = {Helicobacter pylori VacA induces apoptosis by accumulation of connexin 43 in autophagic vesicles via a Rac1/ERK-dependent pathway.}, journal = {Cell death discovery}, volume = {1}, number = {}, pages = {15035}, pmid = {27551466}, issn = {2058-7716}, abstract = {Helicobacter pylori (H. pylori) produces vacuolating cytotoxin (VacA), a potent protein toxin, which is associated with gastric inflammation and ulceration. Recent studies demonstrated that connexins (Cxs), which are responsible for intracellular communication at gap junctions (GJs) as well as cell homeostasis, participate in VacA-induced cell death. We now demonstrate in AZ-521 cells that VacA increased cytoplasmic Cx43, accompanied by LC3-II generation in a time- and dose-dependent manner without induction of Cx43 mRNA expression. Inhibition of VacA-induced Rac1 activity prevented ERK phosphorylation and the increase in Cx43. Suppression of ERK activity and addition of N-acetyl-cysteine inhibited VacA-dependent increase in Cx43 and LC3-II. DIDS, an anion-selective inhibitor, suppressed VacA-dependent increase in Cx43, suggesting that VacA channel activity was involved in this pathway. By confocal microscopy, Cx43 increased by VacA was predominately localized in cholesterol-rich, detergent-resistant membranes including GJs, and a fraction of Cx43 was incorporated in endocytotic vesicles and autophagolysosomes. Accumulation of Cx43 was also observed in gastric mucosa from H. pylori-infected patients compared with healthy controls, suggesting that the pathogen caused a similar effect in vivo. Our findings show that VacA-mediated effects on autophagy inhibits turnover of Cx43, resulting in increased levels in the cytoplasm, leading eventually to apoptotic cell death.}, }
@article {pmid27103891, year = {2015}, author = {Ko, EY and Lee, SH and Ko, JY and Moon, JY and Yoon, WJ and Ahn, G and Roh, SW and Cho, K and Jeon, YJ and Kim, D and Kim, KN}, title = {Trans-1,3-diphenyl-2,3-epoxypropan-1-one, a chalcone derivative, induces apoptosis via ROS-mediated down-regulation of Bcl-xL in human leukemia HL-60 cells.}, journal = {EXCLI journal}, volume = {14}, number = {}, pages = {900-907}, pmid = {27103891}, issn = {1611-2156}, abstract = {The anticancer effects of trans-1,3-diphenyl-2,3-epoxypropan-1-one (DPEP), a chalcone derivative, were investigated in human leukemia HL-60 cells. Treatment of HL-60 cells with various concentration of DPEP resulted in a sequence of events characteristic of apoptosis, including loss of cell viability, morphological changes, and increased sub-G1 DNA content. We demonstrated that DPEP elevates reactive oxygen species (ROS) levels in HL-60 cells, and that the ROS scavenger N-acetylcysteine (NAC) could block DPEP-induced ROS generation and apoptosis. Western blot analysis revealed that DPEP inhibits Bcl-xL expression, leading to caspase-3 activation and poly-ADP-ribose polymerase (PARP) cleavage, thereby inducing apoptosis. However, NAC pre-treatment significantly inhibited the activation of caspase-3 and PARP cleavage and reduced Bcl-xL levels. These findings provide the first evidence that DPEP may inhibit the growth of HL-60 cells and induce apoptosis through a ROS-mediated Bcl-xL pathway.}, }
@article {pmid28962324, year = {2014}, author = {Christen, V and Camenzind, M and Fent, K}, title = {Silica nanoparticles induce endoplasmic reticulum stress response, oxidative stress and activate the mitogen-activated protein kinase (MAPK) signaling pathway.}, journal = {Toxicology reports}, volume = {1}, number = {}, pages = {1143-1151}, pmid = {28962324}, issn = {2214-7500}, abstract = {Application of silica nanoparticles (SiO2-NPs) may result in human exposure. Here we investigate unexplored modes of action by which SiO2-NPs with average size of 225 nm act on human hepatoma cells (Huh7). We focused on the endoplasmic (ER) stress response and on mitogen-activated protein kinase (MAPK) signaling pathways. Both pathways were induced. ER stress and the associated three unfolded protein response (UPR) pathways were activated as demonstrated by significant inductions of BiP and XBP-1s and a moderate but significant induction of ATF-4 at 0.05 and 0.5 mg/ml. In addition to activation of NFкB interferon stimulated genes IP-10, IRF-9, and ISG-15 were up-regulated. As a consequence of ER stress, the pro-inflammatory cytokine TNFα and PP2Ac were induced following exposure to 0.05 mg/ml SiO2-NPs. Additionally, this occurred at 0.005 mg/ml SiO2-NPs for TNFα at 24 h. This in turn led to a strong transcriptional induction of MAP-kinases and its target genes cJun, cMyc and CREB. A strong transcriptional down-regulation of the proapoptotic gene p53 occurred at 0.05 and 0.5 mg/ml SiO2-NP. Exposure of Huh7 cells to the anti-oxidant N-acetyl cysteine reduced transcriptional induction of ER stress markers demonstrating a link between the induction of oxidative stress and ER stress. Our study demonstrates that SiO2-NPs lead to strong ER stress and UPR induction, oxidative stress, activation of MAPK signaling and down-regulation of p53. All of these activated pathways, which are analyzed here for the first time in detail, inhibit apoptosis and induce cell proliferation, which may contribute to a hepatotoxic, inflammatory and tumorigenic action of SiO2-NPs.}, }
@article {pmid28962293, year = {2014}, author = {Li, N and Bhattacharya, P and Karavalakis, G and Williams, K and Gysel, N and Rivera-Rios, N}, title = {Emissions from commercial-grade charbroiling meat operations induce oxidative stress and inflammatory responses in human bronchial epithelial cells.}, journal = {Toxicology reports}, volume = {1}, number = {}, pages = {802-811}, pmid = {28962293}, issn = {2214-7500}, abstract = {Commercial charbroiling emissions are a significant source of ambient particulate matter (PM) in urban settings. The objective of this study was to determine whether organic extract of PM emissions from commercial charbroiling meat operations could induce an inflammatory response in human bronchial epithelial cells and whether this effect was mediated by oxidative stress. PM samples were collected during cooking hamburgers on a commercial-grade under-fired charbroiler and sequentially extracted with water and methanol to obtain the aqueous PM suspension (AqPM) and organic extract (OE). The pro-oxidative and pro-inflammatory effects of OE were assessed using human bronchial epithelial cell line BEAS-2B. While AqPM did not have any effect, OE effectively induced the expression of heme oxygennase-1 and cyclooxygenase-2 in BEAS-2B cells. OE also up-regulated the levels of IL-6, IL-8, and prostaglandin E2. OE-induced cellular inflammatory response could be effectively suppressed by the antioxidant N-acetyl cysteine, nuclear factor (erythroid-derived 2)-like 2 activator sulforaphane and p38 MAPK inhibitor SB203580. In conclusion, organic chemicals emitted from commercial charbroiling meat operations could induce an inflammatory response in human bronchial epithelial cells, which was mediated by oxidative stress and p38 MAPK.}, }
@article {pmid28989945, year = {2014}, author = {Beckman, SA and Sekiya, N and Chen, WCW and Mlakar, L and Tobita, K and Huard, J}, title = {The cardiac regenerative potential of myoblasts remains limited despite improving their survival via antioxidant treatment.}, journal = {CellR4-- repair, replacement, regeneration, &amp; reprogramming}, volume = {2}, number = {2}, pages = {}, pmid = {28989945}, issn = {2329-7042}, support = {T32 HL076124/HL/NHLBI NIH HHS/United States ; U54 AR050733/AR/NIAMS NIH HHS/United States ; }, abstract = {INTRODUCTION: Since myoblasts have been limited by poor cell survival after cellular myoplasty, the major goal of the current study was to determine whether improving myoblast survival with an antioxidant could improve cardiac function after the transplantation of the myoblasts into an acute myocardial infarction.<br><br>BACKGROUND: We previously demonstrated that early myogenic progenitors such as muscle-derived stem cells (MDSCs) exhibited superior cell survival and improved cardiac repair after transplantation into infarcted hearts compared to myoblasts, which we partially attributed to MDSC's higher antioxidant levels.<br><br>AIM: To determine if antioxidant treatment could increase myoblast survival, subsequently improving cardiac function after myoblast transplantation into infarcted hearts.<br><br>MATERIALS AND METHODS: Myoblasts were pre-treated with the antioxidant N-acetylcysteine (NAC) or the glutathione depleter, diethyl maleate (DEM), and injected into infarcted murine hearts. Regenerative potential was monitored by cell survival and cardiac function.<br><br>RESULTS: At early time points, hearts injected with NAC-treated myoblasts exhibited increased donor cell survival, greater cell proliferation, and decreased cellular apoptosis, compared to untreated myoblasts. NAC-treated myoblasts significantly improved cardiac contractility, reduced fibrosis, and increased vascular density compared to DEM-treated myoblasts, but compared to untreated myoblasts, no difference was noted.<br><br>DISCUSSION: While early survival of myoblasts transplanted into infarcted hearts was augmented by NAC pre-treatment, cardiac function remained unchanged compared to non-treated myoblasts.<br><br>CONCLUSION: Despite improving cell survival with NAC treated myoblast transplantation in a MI heart, cardiac function remained similar to untreated myoblasts. These results suggest that the reduced cardiac regenerative potential of myoblasts, when compared to MDSCs, is not only attributable to cell survival but is probably also related to the secretion of paracrine factors by the MDSCs.}, }
@article {pmid27785204, year = {2012}, author = {Kazemifar, AM and Hajaghamohammadi, AA and Samimi, R and Alavi, Z and Abbasi, E and Asl, MN}, title = {Hepatoprotective Property of Oral Silymarin is Comparable to N-Acetyl Cysteine in Acetaminophen Poisoning.}, journal = {Gastroenterology research}, volume = {5}, number = {5}, pages = {190-194}, pmid = {27785204}, issn = {1918-2805}, abstract = {BACKGROUND: N-Acetyl Cysteine (NAC) is usually used as antidote for prevention of acetaminophen-induced hepatotoxicity. In present study we have evaluated efficacy of oral silymarin in its prevention in rats intoxicated with lethal dose of acetaminophen.<br><br>METHODS: A total of 50 Male Sprague-Dawley rats were randomly divided into five groups. The first group received only vehicle of acetaminophen and served as control. The second group was given 800 mg/kg acetaminophen by gavage with an orogastric canula. The third, fourth and fifth groups were given 300 mg/kg NAC and 150 and 300 mg/kg silymarin respectively. Analysis of serum AST, ALT, and ALP and liver histopathology were employed for assessment of hepatotoxicity.<br><br>RESULTS: Mean serum ALT levels were significantly increased in the APAP group rats. The mean serum ALT levels returned to normal in both NAC treated and silymarin treated groups. Silymarin (150 mg/kg) had prevented hepatocytes necrosis similar to NAC. No severe hepatotoxicity were seen in groups 3 and 4; while it is seen in 70% of animals in group 2.<br><br>CONCLUSION: We found that a single dose of orally administered silymarin (150 mg/kg) significantly attenuated acetaminophen-induced liver damage in rat. Oral silymarin can be used in these patients instead of NAC.}, }
@article {pmid26952834, year = {2010}, author = {Berk, M and Dodd, S and Dean, OM and Kohlmann, K and Berk, L and Malhi, GS}, title = {The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder.}, journal = {Acta neuropsychiatrica}, volume = {22}, number = {5}, pages = {237-242}, doi = {10.1111/j.1601-5215.2010.00472.x}, pmid = {26952834}, issn = {0924-2708}, abstract = {UNLABELLED: Berk M, Dodd S, Dean OM, Kohlmann K, Berk L, Malhi GS. The validity and internal structure of the Bipolar Depression Rating Scale: data from a clinical trial of N-acetylcysteine as adjunctive therapy in bipolar disorder.<br><br>BACKGROUND: The phenomenology of unipolar and bipolar disorders differ in a number of ways, such as the presence of mixed states and atypical features. Conventional depression rating instruments are designed to capture the characteristics of unipolar depression and have limitations in capturing the breadth of bipolar disorder.<br><br>METHOD: The Bipolar Depression Rating Scale (BDRS) was administered together with the Montgomery Asberg Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) in a double-blind randomised placebo-controlled clinical trial of N-acetyl cysteine for bipolar disorder (N = 75).<br><br>RESULTS: A factor analysis showed a two-factor solution: depression and mixed symptom clusters. The BDRS has strong internal consistency (Cronbach's alpha = 0.917), the depression cluster showed robust correlation with the MADRS (r = 0.865) and the mixed subscale correlated with the YMRS (r = 0.750).<br><br>CONCLUSION: The BDRS has good internal validity and inter-rater reliability and is sensitive to change in the context of a clinical trial.}, }
@article {pmid26952771, year = {2009}, author = {Bernardo, M and Dodd, S and Gama, CS and Copolov, DL and Dean, O and Kohlmann, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Bush, AI and Berk, M}, title = {Effects of N-acetylcysteine on substance use in bipolar disorder: a randomised placebo-controlled clinical trial.}, journal = {Acta neuropsychiatrica}, volume = {21}, number = {5}, pages = {239-245}, doi = {10.1111/j.1601-5215.2009.00415.x}, pmid = {26952771}, issn = {0924-2708}, abstract = {OBJECTIVE: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU).<br><br>METHODS: Participants were randomised to 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using the Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU.<br><br>RESULTS: Amongst the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumer caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared with placebo at week 2 of treatment but not at other study visits.<br><br>CONCLUSION: NAC appeared to have little effect on substance use in this population. A larger study on a substance using population will be necessary to determine if NAC may be a useful treatment for substance use.}, }
@article {pmid28140232, year = {2000}, author = {Woo, OF and Mueller, PD and Olson, KR and Anderson, IB and Kim, SY}, title = {Shorter duration of oral N -Acetylcysteine therapy for acute acetaminophen overdose.}, journal = {Annals of emergency medicine}, volume = {35}, number = {4}, pages = {363-368}, pmid = {28140232}, issn = {1097-6760}, abstract = {STUDY OBJECTIVE: We sought to evaluate the safety and efficacy of a shorter N -acetylcysteine (NAC) regimen in the treatment of acute acetaminophen overdose.<br><br>METHODS: We performed a retrospective case series in a large urban county hospital. Of 305 patients identified through the emergency department, 75 patients met the criteria inclusion: an acute overdose ingestion, serum acetaminophen concentration in toxic range according to the Rumack-Matthew nomogram, and oral NAC treatment initiated within 24 hours of the ingestion. The regional poison control center recommended oral treatment with NAC 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours until the serum acetaminophen level was no longer detectable, rather than the standard 72-hour treatment regimen.<br><br>RESULTS: The primary outcome measure was the development of hepatotoxicity. Twenty-five (33.3%) patients were treated for a period of less than 24 hours, 25 (33.3%) were treated for 24 to 36 hours, and 25 (33.3%) were treated for 37 to 64 hours; the mean and median duration of treatment was 31 hours. None of the patients treated for less than 24 hours had evidence of hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] level >1,000 IU/L); hepatotoxicity developed in 2 (8%) patients treated for 24 to 36 hours and 4 (16%) patients treated for 37 to 64 hours. There were no deaths or patients who received liver transplantation. The overall incidence of hepatotoxicity in our patients was similar to that found in other protocols with administration of oral NAC for 72 hours or intravenous NAC for 20 or 48 hours.<br><br>CONCLUSION: This observational study suggests that a shorter course of oral NAC therapy in patients who do not show evidence of hepatotoxicity within 36 hours of an acute acetaminophen overdose is safe and effective. [Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY. Shorter duration of oral N -acetylcysteine therapy for acute acetami-nophen overdose. Ann Emerg Med . April 2000;35:363-368.].}, }
@article {pmid27406960, year = {1997}, author = {Rivabene, R and Straface, E and Giammarioli, AM and Rainaldi, G and Malorni, W}, title = {Combined effect of 3-aminobenzamide and N-acetylcysteine on HIV replication in chronically infected U937 cells.}, journal = {Redox report : communications in free radical research}, volume = {3}, number = {3}, pages = {145-151}, doi = {10.1080/13510002.1997.11747102}, pmid = {27406960}, issn = {1351-0002}, abstract = {The existence of a close relationship between apoptosis associated with oxidative stress and the increase of viral progeny in chronically HIV-infected cells has been previously reported. The possibility of modulating both phenomena by using an antioxidant such as N-acetylcysteine (NAC) has also been demonstrated. The present investigation was designed to study the role of the nuclear enzyme poly-(ADP-ribose)-polymerase (PARP) when HIV- infected cells are treated with tumour necrosis factor alpha (TNFα), a cytokine capable of inducing both apoptosis and intracellular oxygen free radical production. PARP overexpression may result in a rapid drop of intracellular NAD(+) and ATP concentration, thus contributing to cellular redox imbalance. We have used the specific PARP inhibitor 3- aminobenzamide (3-ABA), alone or in a combination with NAC. 3-ABA was only partially capable of inhibiting viral replication and apoptosis induced by TNFα. In contrast, the combination of NAC and 3-ABA led to an inhibition of apoptosis as well as to a marked decrease in viral particle production, with a parallel replenishment of intracellular reduced glutathione content. The results reported here confirm the potential role of antioxidant drug treatment in specific phases of HIV infection.}, }
@article {pmid27414772, year = {1997}, author = {Marini, M and Musiani, D and Raggi, MA and Schiavone, P and Levine, RL}, title = {Oxidative stress does not mediate heat shock-induced cell damage and apoptosis.}, journal = {Redox report : communications in free radical research}, volume = {3}, number = {1}, pages = {57-63}, doi = {10.1080/13510002.1997.11747091}, pmid = {27414772}, issn = {1351-0002}, abstract = {The hypothesis that oxidative damage arising from heat shock might significantly contribute to cell death and in particular to apoptosis has been tested in human peripheral blood lymphocytes. Cellular glutathione content and protein carbonyl groups were measured as indicators of oxidative injury. Cell viability and proliferative capacity were evaluated as measures of irreversible damage. Heat shock caused dose-dependent decreases in cell viability, and apoptotic cell death was found to be a major component of heat-shock-mediated mortality. However, only the more severe heat treatment (1 h, 45°C) caused an immediate decrease in glutathione content. The content in carbonyl groups was not significantly affected by heat shock. N-acetyl-cysteine, when added before the hyperthermic treatment, did increase the glutathione content of the cells, but this did not favourably affect the survival of heat-shocked lymphocytes. It is suggested that oxidative damage is not a significant component of heat shock-mediated cell injury, and that, at least in this experimental model, apoptosis is triggered by stimuli other than an altered redox state of the cell.}, }
@article {pmid27405831, year = {1995}, author = {Hybertson, BM and Lampey, AS and Clarke, JH and Koh, Y and Repine, JE}, title = {N-acetylcysteine pretreatment attenuates paraquat-induced lung leak in rats.}, journal = {Redox report : communications in free radical research}, volume = {1}, number = {5}, pages = {337-342}, doi = {10.1080/13510002.1995.11747008}, pmid = {27405831}, issn = {1351-0002}, abstract = {We investigated the effects of N-acetylcysteine (NAC) pretreatment on paraquat-induced lung inflammation and leak. We found that administering a single intravenous dose (60 mg/kg) of paraquat rapidly (2 h) increased lung leak, lung lavage cytokine-induced neutrophil chemoattractant (CINC) levels, and lung myeloperoxidase (MPO) activity in rats. Rats pretreated with NAC (150 mg/kg, intraperitoneally) had increased lung tissue glutathione (GSH + GSSG) levels compared to saline-pretreated rats. In addition, rats pretreated with NAC and then given paraquat 2.5 h later had decreased lung leak compared to saline-pretreated rats given paraquat. In contrast, NAC pretreated rats given paraquat had the same lung lavage CINC levels and lung tissue MPO activity as saline-pretreated rats given paraquat. Our results indicate that paraquat causes an oxidative injury which may be decreased by the GSH-increasing or other properties of NAC.}, }
@article {pmid27414179, year = {1994}, author = {Malorni, W and Rivabene, R and Santini, MT and Rainaldi, G and Donelli, G}, title = {N-acetylcysteine prevents TNF-induced mitochondrial damage, apoptosis and viral particle production in HIV-infected U937 cells.}, journal = {Redox report : communications in free radical research}, volume = {1}, number = {1}, pages = {57-64}, doi = {10.1080/13510002.1994.11746957}, pmid = {27414179}, issn = {1351-0002}, abstract = {It has been hypothesized that reactive oxygen intermediates (ROI) can activate human immunodeficiency virus (HIV) replication and that HIV can trigger programmed cell death (PCD). In this work, we studied PCD in U937 cultured cells chronically infected with HIV and exposed to tumor necrosis factor alpha (TNFα). This cytokine has been shown to induce apoptosis in some cell types and to produce intracellular free radical species including ROI. In addition, it was also demonstrated that HIV-induced PCD observable in U937 infected cells can be favored by TNF exposure. In one of our recent works, evidence was presented that the thiol supplier N-acetylcysteine (NAC) can 'protect', at least partially, HIV-infected cells from PCD and determine a significant decrease in viral progeny. In the present work, we demonstrate (a) that apoptosis can be easily induced by TNF only in infected U937 cells and not in control wild-type cells, (b) that daily treatment of TNF-exposed cells with low concentrations of NAC is able to impair viral progeny formation as early as 24 h, (c) that the mitochondrial damage induced by TNF is counteracted by preexposure to NAC, and (d) that NAC alone exerts changes in mitochondria which may be responsible for the protective effects exerted by this compound. Because of the radical producing capacity of TNF, these results seem to indicate that the protective effects of NAC may be due to the specific antioxidant nature of this substance which appears to be capable of impairing both the apoptotic machinery and viral replication by an intracellular mechanism involving mitochondrial integrity and function.}, }
@article {pmid26541884, year = {2016}, author = {de Miranda Ramos, V and Zanotto-Filho, A and de Bittencourt Pasquali, MA and Klafke, K and Gasparotto, J and Dunkley, P and Gelain, DP and Moreira, JCF}, title = {NRF2 Mediates Neuroblastoma Proliferation and Resistance to Retinoic Acid Cytotoxicity in a Model of In Vitro Neuronal Differentiation.}, journal = {Molecular neurobiology}, volume = {53}, number = {9}, pages = {6124-6135}, pmid = {26541884}, issn = {1559-1182}, mesh = {Acetylcysteine/pharmacology ; Cell Death/drug effects ; Cell Differentiation/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; *Models, Biological ; NF-E2-Related Factor 2/*metabolism ; Neuroblastoma/*metabolism/*pathology ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Tretinoin/*pharmacology ; }, abstract = {Retinoic acid (RA) morphogenetic properties have been used in different kinds of therapies, from neurodegenerative disorders to some types of cancer such as promyelocytic leukemia and neuroblastoma. However, most of the pathways responsible for RA effects remain unknown. To investigate such pathways, we used a RA-induced differentiation model in the human neuroblastoma cells, SH-SY5Y. Our data showed that n-acetyl-cysteine (NAC) reduced cells' proliferation rate and increased cells' sensitivity to RA toxicity. Simultaneously, NAC pre-incubation attenuated nuclear factor erythroid 2-like factor 2 (NRF2) activation by RA. None of these effects were obtained with Trolox[®] as antioxidant, suggesting a cysteine signalization by RA. NRF2 knockdown increased cell sensibility to RA after 96 h of treatment and diminished neuroblastoma proliferation rate. Conversely, NRF2 overexpression limited RA anti-proliferative effects and increased cell proliferation. In addition, a rapid and non-genomic activation of the ERK 1/2 and PI3K/AKT pathways revealed to be equally required to promote NRF2 activation and necessary for RA-induced differentiation. Together, we provide data correlating NRF2 activity with neuroblastoma proliferation and resistance to RA treatments; thus, this pathway could be a potential target to optimize neuroblastoma chemotherapeutic response as well as in vitro neuronal differentiation protocols.}, }
@article {pmid26830358, year = {2016}, author = {Du, L and Empey, PE and Ji, J and Chao, H and Kochanek, PM and Bayır, H and Clark, RS}, title = {Probenecid and N-Acetylcysteine Prevent Loss of Intracellular Glutathione and Inhibit Neuronal Death after Mechanical Stretch Injury In Vitro.}, journal = {Journal of neurotrauma}, volume = {33}, number = {20}, pages = {1913-1917}, pmid = {26830358}, issn = {1557-9042}, support = {R01 NS069247/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain Injuries, Traumatic/metabolism ; Cell Death/drug effects ; Cells, Cultured ; Female ; Glutathione/metabolism ; Male ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Probenecid/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Stress, Mechanical ; }, abstract = {Probenecid and N-acetylcysteine (NAC) can preserve intracellular levels of the vital antioxidant glutathione (GSH) via two distinct biochemical pathways. Probenecid inhibits transporter-mediated GSH efflux and NAC serves as a cysteine donor for GSH synthesis. We hypothesized that probenecid and NAC alone would maintain intracellular GSH concentrations and inhibit neuronal death after traumatic stretch injury, and that the drugs in combination would produce additive effects. Sex-segregated rat primary cortical neurons were treated with probenecid (100 μM) and NAC (50 μM), alone and in combination (Pro-NAC), then subjected to mechanical stretch (10s[-1] strain rate, 50% membrane deformation). At 24 h, both probenecid and NAC inhibited trauma-induced intracellular GSH depletion, lactate dehydrogenase (LDH) release, and propidium iodide (PI) uptake in both XY- and XX-neurons. Combined Pro-NAC treatment was superior to probenecid or NAC alone in maintenance of intracellular GSH and neuronal death assessed by PI uptake. Interestingly, caspase 3 activity 24 h after mechanical trauma was more prominent in XX-neurons, and treatment effects (probenecid, NAC, and Pro-NAC) were observed in XX- but not XY-neurons; however, XY-neurons were ultimately more vulnerable to mechanical stretch-induced injury than their XX counterparts, as was evidenced by more neuronal death detected by LDH release and PI uptake. In addition, after stretch injury in HT22 hippocampal cells, both NAC and probenecid were highly effective at reducing oxidative stress detected by dichlorofluorescein fluorescence. These in vitro data support further testing of this drug combination in models of traumatic neuronal injury in vivo.}, }
@article {pmid26138014, year = {2016}, author = {Odewumi, CO and Latinwo, LM and Ruden, ML and Badisa, VL and Fils-Aime, S and Badisa, RB}, title = {Modulation of cytokines and chemokines expression by NAC in cadmium chloride treated human lung cells.}, journal = {Environmental toxicology}, volume = {31}, number = {11}, pages = {1612-1619}, pmid = {26138014}, issn = {1522-7278}, support = {G12 MD007582/MD/NIMHD NIH HHS/United States ; G12 RR003020/RR/NCRR NIH HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cadmium Chloride/*toxicity ; Cell Survival/drug effects ; Chemokines/analysis ; Cytokines/analysis ; Humans ; Interleukin-1alpha/analysis ; Lung/*drug effects/immunology ; Protective Agents/pharmacology ; }, abstract = {Cadmium (Cd), is one of the most hazardous metals found in the environment. Cd exposure through inhalation has been linked to various diseases in lungs. It was shown that Cd induces proinflammatory cytokines through oxidative stress mechanism. In this report, we studied the immunomodulatory effect of a well known antioxidant, N-acetylcysteine (NAC) on cadmium chloride (CdCl2) treated human lung A549 cells through human cytokine array 6. The lung cells were treated with 0 or 75 µM CdCl2 alone, 2.5 mM NAC alone, or co-treated with 2.5 mM NAC and 75 µM CdCl2 for 24 h. The viability of cells was measured by crystal violet dye. The array results were validated by human IL-1alpha enzyme- linked immunosorbent assay (ELISA) kit. The viability of the 75 µM CdCl2 alone treated cells was decreased to 44.5%, while the viability of the co-treated cells with 2.5 mM NAC was increased to 84.1% in comparison with untreated cells. In the cell lysate of CdCl2 alone treated cells, 19 and 8 cytokines were up and down-regulated, while in the medium 15 and 3 cytokines were up and downregulated in comparison with the untreated cells. In the co-treated cells, all these cytokines expression was modulated by the NAC treatment. The IL-1α ELISA result showed the same pattern of cytokine expression as the cytokine array. This study clearly showed the modulatory effect of NAC on cytokines and chemokines expression in CdCl2- treated cells and suggests the use of NAC as protective agent against cadmium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1612-1619, 2016.}, }
@article {pmid25846798, year = {2016}, author = {Ahamed, M and Akhtar, MJ and Khan, MA and Alhadlaq, HA and Alrokayan, SA}, title = {Cytotoxic response of platinum-coated gold nanorods in human breast cancer cells at very low exposure levels.}, journal = {Environmental toxicology}, volume = {31}, number = {11}, pages = {1344-1356}, doi = {10.1002/tox.22140}, pmid = {25846798}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/metabolism/pathology ; Caspase 3/genetics/metabolism ; Caspase 9/genetics/metabolism ; Down-Regulation/drug effects ; Female ; G1 Phase Cell Cycle Checkpoints/drug effects ; Gold/*chemistry ; Humans ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Nanotubes/*chemistry/toxicity ; Particle Size ; Platinum/*chemistry ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Up-Regulation/drug effects ; }, abstract = {Because of unique optical behavior gold nanorods (GNRs) have attracted attention for the application in biomedical field such as bio-sensing, bio-imaging and hyperthermia. However, toxicological response of GNRs is controversial due to their different surface coating. Therefore, a comprehensive knowledge about toxicological profile of GNRs is necessary before their biomedical applications. First time, we investigated the toxic response of GNRs coated with platinum (GNRs-Pt) in human breast carcinoma (MCF-7) cells. Platinum coating further improves the optical and catalytic properties of GNRs. Assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT), neutral red uptake (NRU) and lactate dehydroganase (LDH) assays have shown that GNRs-Pt induced cytotoxicity at very low exposure levels (0.1-0.8 μg mL[-1]). Accumulation of cells in SubG1 phase and low mitochondrial membrane potential (JC-1 probe) in treated cells suggest that GNRs-Pt induced cell death via apoptotic pathway. Quantitative real-time PCR data demonstrated that mRNA expression of apoptotic genes (bax, caspase-3 and caspase-9) were up-regulated while anti-apoptotic gene bcl-2 was down-regulated in cells exposed to GNRs-Pt. We further observed the higher activity of caspase-3 and caspase-9 enzymes in GNRs-Pt treated cells supporting mRNA data. Moreover, N-acetyl cysteine (NAC) significantly attenuated the ROS generation and cytotoxicity induced by GNRs-Pt in MCF-7 cells suggesting that ROS might plays a crucial role in GNRs-Pt induced toxicity. This study warns of possible toxicity of GNRs even at very low exposure levels. Further investigations needed to explore potential mechanisms of this low dose toxicity phenomenon. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1344-1356, 2016.}, }
@article {pmid25758670, year = {2016}, author = {Lin, BH and Tsai, MH and Lii, CK and Wang, TS}, title = {IP3 and calcium signaling involved in the reorganization of the actin cytoskeleton and cell rounding induced by cigarette smoke extract in human endothelial cells.}, journal = {Environmental toxicology}, volume = {31}, number = {11}, pages = {1293-1306}, doi = {10.1002/tox.22133}, pmid = {25758670}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Actin Cytoskeleton/drug effects/*metabolism ; Antioxidants/pharmacology ; *Calcium Signaling/drug effects ; Cell Line ; Chelating Agents/pharmacology ; Endothelial Cells/cytology/drug effects/metabolism ; Estrenes/pharmacology ; Glutathione/metabolism ; Humans ; Indoles/pharmacology ; Inositol 1,4,5-Trisphosphate Receptors/antagonists &amp; inhibitors/*metabolism ; Macrocyclic Compounds/pharmacology ; Maleimides/pharmacology ; Microscopy, Fluorescence ; Nitrendipine/analogs &amp; derivatives/pharmacology ; Oxazoles/pharmacology ; Oxidative Stress/drug effects ; Protein Kinase C/antagonists &amp; inhibitors/metabolism ; Pyrrolidinones/pharmacology ; Reactive Oxygen Species/metabolism ; *Smoke ; Nicotiana/*chemistry/metabolism ; Type C Phospholipases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Smoking increases the risk of cardiovascular disorders and leads to damage caused by inflammation and oxidative stress. The actin cytoskeleton is a key player in the response to inflammatory stimuli and is an early target of cellular oxidative stress. The purpose of this study was to investigate the changes in actin cytoskeleton dynamics in human endothelial EA.hy926 cells exposed to cigarette smoke extract (CSE). Immunostaining revealed that CSE exposure resulted in modification of the actin cytoskeleton and led to cell rounding in a dose- and time-dependent manner. In addition, the intracellular calcium concentration was increased by treatment with CSE. Pretreatment with antioxidants (lipoic acid, glutathione, N-acetyl cysteine, aminoguanidine, α-tocopherol, and vitamin C) significantly attenuated the CSE-induced actin cytoskeleton reorganization and cell rounding. Calcium ion chelators (EGTA, BAPTA-AM AM) and a potent store-operated calcium channel inhibitor (MRS 1845) also reduced CSE-induced intracellular calcium changes and attenuated actin cytoskeleton reorganization and cell morphology change. Moreover, the CSE-induced intracellular calcium increase was suppressed by pretreatment with the inositol trisphosphate receptor (IP3R) inhibitor xestospongin C, the phospholipase C (PLC) inhibitor U-73122, and the protein kinase C (PKC) inhibitor GF109203X. These results suggest that reactive oxygen species production and intracellular calcium increase play an essential role in CSE-induced actin disorganization and cell rounding through a PLC-IP3-PKC signaling pathway. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1293-1306, 2016.}, }
@article {pmid26895214, year = {2016}, author = {Yang, P and Li, Y and Xu, G}, title = {Antioxidant therapy improves non-thyroidal illness syndrome in uremic rats.}, journal = {Renal failure}, volume = {38}, number = {4}, pages = {514-520}, doi = {10.3109/0886022X.2016.1145515}, pmid = {26895214}, issn = {1525-6049}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Euthyroid Sick Syndromes/*drug therapy/etiology ; Female ; Free Radical Scavengers/*therapeutic use ; Male ; Pyrrolidines/*therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Thiocarbamates/*therapeutic use ; Uremia/complications ; }, abstract = {BACKGROUND: The roles of antioxidant therapy on non-thyroidal illness syndrome (NTIS) in uremic rats is still unclear.<br><br>MATERIALS AND METHODS: Twenty-four Sprague-Dawley (SD) rats were randomly divided into blank, 5/6 nephrectomy (Nx), pyrrolidine dithiocarbamate (PDTC, 10&#x2009;mg/100&#x2009;g), sodium bicarbonate (SB, 0.1&#x2009;g/100&#x2009;g), N-acetylcysteine (NAC, 80&#x2009;mg/100&#x2009;g) and thyroid hormones (TH, levothyroxine 2&#x2009;&#x3bc;g/100&#x2009;g) groups. The serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), advanced oxidation protein products (AOPP), interleukin (IL)-1&#x3b2;, free triiodothyronine (FT3), and thyroid stimulating hormone (TSH) were detected in the sixth week. The expressions of IL-1&#x3b2; and deiodinase type 1 (DIO1) were assessed by western blotting. The nuclear factor kappa B (NF-&#x3ba;B) inflammatory signal pathway was confirmed by electrophoretic mobility shift assay (EMSA).<br><br>RESULTS: Compared with 5/6 Nx group, PDTC and NAC significantly reduced the levels (p&#x2009;<&#x2009;0.01, respectively) of serum MDA, AOPP, TSH, and elevated levels of serum SOD (p&#x2009;<&#x2009;0.01, respectively) and FT3 (p&#x2009;=&#x2009;0.016 and p&#x2009;<&#x2009;0.01). Neither had significant effects on serum IL-1&#x3b2; content (p&#x2009;=&#x2009;0.612 and p&#x2009;=&#x2009;0.582). PDTC and NAC markedly decreased the protein expression of IL-1&#x3b2; (p&#x2009;<&#x2009;0.01) and increased the protein expression of DIO1 (p&#x2009;<&#x2009;0.01), respectively. Both had been considerably blunted NF-&#x3ba;B activity (p&#x2009;<&#x2009;0.01).<br><br>CONCLUSIONS: In uremic rat model, PDTC and NAC can effectively improve oxidative stress level and NTIS. In terms of improving oxidative stress level, NAC is probably superior to PDTC.}, }
@article {pmid26891662, year = {2016}, author = {Réus, GZ and Bernardini Dos Santos, MA and Abelaira, HM and Maciel, AL and Arent, CO and Matias, BI and Bruchchen, L and Ignácio, ZM and Michels, M and Dal-Pizzol, F and Carvalho, AF and Zugno, AI and Quevedo, J}, title = {Antioxidant Therapy Alters Brain MAPK-JNK and BDNF Signaling Path-ways in Experimental Diabetes Mellitus.}, journal = {Current neurovascular research}, volume = {13}, number = {2}, pages = {107-114}, doi = {10.2174/1567202613666160219115832}, pmid = {26891662}, issn = {1875-5739}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Analysis of Variance ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Brain/*drug effects/metabolism ; Brain-Derived Neurotrophic Factor/*metabolism ; Deferoxamine/pharmacology/therapeutic use ; Diabetes Mellitus, Experimental/*drug therapy/pathology ; MAP Kinase Kinase 4/*metabolism ; Rats ; Rats, Wistar ; Signal Transduction/*drug effects ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {This study was designed to investigate the effects of treatment with the antioxidants N-acetylcysteine (NAC) and deferoxamine (DFX) in intracellular pathways in the brain of diabetic rats. To conduct this study we induced diabetes in Wistar rats with a single injection of alloxan, and afterwards rats were treated with NAC or DFX for 14 days. Following treatment completion, the immunocontent of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase-38 (MAPK38), brain-derived neurotrophic factor (BDNF), and protein kinases A and C (PKA and PKC) were determined in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). DFX treatment increased JNK content in the PFC and NAc of diabetic rats. In the amygdala, JNK was increased in diabetics treated with saline or NAC. MAPK38 was decreased in the PFC of control and in diabetic rats treated with NAC or DFX; and in the NAc in all groups. PKA was decreased in the PFC with DFX treatment. In the amygdala, PKA content was increased in diabetic rats treated with either saline or NAC, compared to controls; and it was decreased in either NAC or DFX-treated groups, compared to saline-treated diabetic animals. In the NAc, PKA was increased in NAC-treated diabetic rats. PKC was increased in the amygdala of NAC-treated diabetic rats. In the PFC, the BDNF levels were decreased following treatment with DFX in diabetic rats. In the hippocampus of diabetic rats the BDNF levels were decreased. However, treatment with DFX reversed this effect. In the amygdala the BDNF increased with DFX in non-diabetic rats. In the NAc DFX treatment increased the BDNF levels in diabetic rats. In conclusion, both diabetes and treatment with antioxidants were able to alter intracellular pathways involved in the regulation of cell survival in a brain area and treatment-dependent fashion.}, }
@article {pmid26890139, year = {2016}, author = {Frazzini, V and Guarnieri, S and Bomba, M and Navarra, R and Morabito, C and Mariggiò, MA and Sensi, SL}, title = {Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.}, journal = {Cell death &amp; disease}, volume = {7}, number = {2}, pages = {e2100}, pmid = {26890139}, issn = {2041-4889}, mesh = {Alzheimer Disease/*metabolism/pathology ; Animals ; Calcium/metabolism ; Cells, Cultured ; Disease Models, Animal ; Female ; Hippocampus/drug effects/*metabolism/pathology ; Male ; Mice ; Neurons/drug effects/*metabolism/pathology ; Reactive Oxygen Species/metabolism ; Shab Potassium Channels/antagonists &amp; inhibitors/*metabolism ; Synapses/drug effects/metabolism ; }, abstract = {Altered neuronal excitability is emerging as an important feature in Alzheimer's disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca(2+)]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative-dependent oligomerization, and loss of function of Kv2.1 channels. These processes can be part on the increased neuronal excitability of these neurons. These steps may set a deleterious vicious circle that eventually helps to promote excitotoxic damage found in the AD brain.}, }
@article {pmid26882067, year = {2016}, author = {Conway, GE and Casey, A and Milosavljevic, V and Liu, Y and Howe, O and Cullen, PJ and Curtin, JF}, title = {Non-thermal atmospheric plasma induces ROS-independent cell death in U373MG glioma cells and augments the cytotoxicity of temozolomide.}, journal = {British journal of cancer}, volume = {114}, number = {4}, pages = {435-443}, pmid = {26882067}, issn = {1532-1827}, mesh = {Antineoplastic Agents, Alkylating/*pharmacology ; Apoptosis/drug effects/physiology ; Brain Neoplasms/*drug therapy/*pathology ; Cell Line, Tumor ; Dacarbazine/*analogs &amp; derivatives/pharmacology ; Drug Synergism ; Glioma/*drug therapy/*pathology ; HeLa Cells ; Humans ; Plasma Gases/*pharmacology ; Reactive Oxygen Species/*metabolism ; Temozolomide ; }, abstract = {BACKGROUND: Non-thermal atmospheric plasma (NTAP) is an ionised gas produced under high voltage that can generate short-lived chemically active species and induce a cytotoxic insult in cancer cells. Cell-specific resistance to NTAP-mediated cytotoxicity has been reported in the literature. The aim of this study was to determine whether resistance against NTAP could be overcome using the human glioma cell line U373MG.<br><br>METHODS: Non-thermal atmospheric plasma was generated using a Dielectric Barrier Device (DBD) system with a maximum voltage output of 120&#x2009;kV at 50&#x2009;Hz. The viability of U373MG GBM cells and HeLa cervical carcinoma cells was determined using morphology, flow cytometry and cytotoxicity assays. Fluorescent probes and inhibitors were used to determine the mechanisms of cytotoxicity of cells exposed to the plasma field. Combinational therapy with temozolomide (TMZ) and multi-dose treatments were explored as mechanisms to overcome resistance to NTAP.<br><br>RESULTS: Non-thermal atmospheric plasma decreased cell viability in a dose (time)-dependent manner. U373MG cells were shown to be resistant to NTAP treatment when compared with HeLa cells, and the levels of intracellular reactive oxygen species (ROS) quantified in U373MG cells were much lower than in HeLa cells following exposure to the plasma field. Reactive oxygen species inhibitor N-acetyl cysteine (NAC) only alleviated the cytotoxic effects in HeLa cells and not in the relatively NTAP-resistant cell line U373MG. Longer exposures to NTAP induced a cell death independent of ROS, JNK and caspases in U373MG. The relative resistance of U373MG cells to NTAP could be overcome when used in combination with low concentrations of the GBM chemotherapy TMZ or exposure to multiple doses.<br><br>CONCLUSIONS: For the very first time, we report that NTAP induces an ROS-, JNK- and caspase-independent mechanism of cell death in the U373MG GBM cell line that can be greatly enhanced when used in combination with low doses of TMZ. Further refinement of the technology may facilitate localised activation of cytotoxicity against GBM when used in combination with new and existing chemotherapeutic regimens.}, }
@article {pmid26879220, year = {2016}, author = {Nouraei, N and Zarger, L and Weilnau, JN and Han, J and Mason, DM and Leak, RK}, title = {Investigation of the therapeutic potential of N-acetyl cysteine and the tools used to define nigrostriatal degeneration in vivo.}, journal = {Toxicology and applied pharmacology}, volume = {296}, number = {}, pages = {19-30}, pmid = {26879220}, issn = {1096-0333}, support = {R03 NS088395/NS/NINDS NIH HHS/United States ; R15 NS093539/NS/NINDS NIH HHS/United States ; R03NS088395/NS/NINDS NIH HHS/United States ; R15NS093539/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Corpus Striatum/drug effects/*pathology ; Male ; Mice ; Nerve Degeneration/chemically induced/*pathology/*prevention &amp; control ; Neuroprotective Agents/pharmacology/*therapeutic use ; Oxidopamine/toxicity ; Substantia Nigra/drug effects/*pathology ; }, abstract = {The glutathione precursor N-acetyl-L-cysteine (NAC) is currently being tested on Parkinson's patients for its neuroprotective properties. Our studies have shown that NAC can elicit protection in glutathione-independent manners in vitro. Thus, the goal of the present study was to establish an animal model of NAC-mediated protection in which to dissect the underlying mechanism. Mice were infused intrastriatally with the oxidative neurotoxicant 6-hydroxydopamine (6-OHDA; 4 μg) and administered NAC intraperitoneally (100mg/kg). NAC-treated animals exhibited higher levels of the dopaminergic terminal marker tyrosine hydroxylase (TH) in the striatum 10d after 6-OHDA. As TH expression is subject to stress-induced modulation, we infused the tracer FluoroGold into the striatum to retrogradely label nigrostriatal projection neurons. As expected, nigral FluoroGold staining and cell counts of FluoroGold(+) profiles were both more sensitive measures of nigrostriatal degeneration than measurements relying on TH alone. However, NAC failed to protect dopaminergic neurons 3 weeks following 6-OHDA, an effect verified by four measures: striatal TH levels, nigral TH levels, nigral TH(+) cell counts, and nigral FluoroGold levels. Some degree of mild toxicity of FluoroGold and NAC was evident, suggesting that caution must be exercised when relying on FluoroGold as a neuron-counting tool and when designing experiments with long-term delivery of NAC--such as clinical trials on patients with chronic disorders. Finally, the strengths and limitations of the tools used to define nigrostriatal degeneration are discussed.}, }
@article {pmid26874726, year = {2016}, author = {Duan, C and Zhang, B and Deng, C and Cao, Y and Zhou, F and Wu, L and Chen, M and Shen, S and Xu, G and Zhang, S and Duan, G and Yan, H and Zou, X}, title = {Piperlongumine induces gastric cancer cell apoptosis and G2/M cell cycle arrest both in vitro and in vivo.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {37}, number = {8}, pages = {10793-10804}, pmid = {26874726}, issn = {1423-0380}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Cycle Proteins/antagonists &amp; inhibitors/physiology ; Cell Division/drug effects ; Cell Line, Tumor ; Dioxolanes/*pharmacology/therapeutic use ; Endoplasmic Reticulum Stress/drug effects ; G2 Phase Cell Cycle Checkpoints/drug effects ; Glutathione/pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Neoplasm Proteins/antagonists &amp; inhibitors/physiology ; Nuclear Proteins/antagonists &amp; inhibitors/physiology ; RNA Interference ; RNA, Small Interfering/genetics ; STAT3 Transcription Factor/antagonists &amp; inhibitors ; Stomach Neoplasms/drug therapy/*pathology ; Telomerase/biosynthesis/genetics ; Tumor Stem Cell Assay ; X-Linked Inhibitor of Apoptosis Protein/biosynthesis/genetics ; Xenograft Model Antitumor Assays ; }, abstract = {Recently, several studies have shown that piperlongumine (PL) can selectively kill cancer cells by targeting reactive oxygen species (ROS). However, the potential therapeutic effects and detailed mechanism of PL in gastric cancer are still not clear. In the current report, we found that PL significantly suppressed gastric cancer both in vitro and in vivo. PL obviously increased ROS generation in gastric cancer cells. Anti-oxidant glutathione (GSH) and N-acetyl-L-cysteine (NAC) can abrogate PL-induced gastric cancer cell death and proliferation inhibition. GADD45α was induced in PL-treated cancer cells and led to G2/M phase arrest, whereas genetic depletion of GADD45α by small interfering RNAs (siRNAs) could partly reverse PL-induced cell cycle arrest in gastric cancer cells. Interestingly, we also found that PL treatment decreased the expression of telomerase reverse transcriptase (TERT) gene, which plays an essential role in cancer initiation and progression. Our findings thus revealed a potential anti-tumor effect of PL on gastric cancer cells and may have therapeutic implications.}, }
@article {pmid26867644, year = {2016}, author = {Kim, M and Baek, HS and Lee, M and Park, H and Shin, SS and Choi, DW and Lim, KM}, title = {Rhododenol and raspberry ketone impair the normal proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {32}, number = {}, pages = {339-346}, doi = {10.1016/j.tiv.2016.02.003}, pmid = {26867644}, issn = {1879-3177}, mesh = {Animals ; Butanols/*toxicity ; Butanones/*toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Melanocytes/*drug effects/metabolism ; Mice, Inbred C57BL ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/genetics ; GADD45 Proteins ; }, abstract = {Rhododenol or rhododendrol (RD, 4-(4-hydroxyphenyl)-2-butanol) occurs naturally in many plants along with raspberry ketone (RK, 4-(4-hydroxyphenyl)-2-butanone), a ketone derivative, which include Nikko maple tree (Acer nikoense) and white birch (Betula platyphylla). De-pigmenting activity of RD was discovered and it was used as a brightening ingredient for the skin whitening cosmetics. Recently, cosmetics containing RD were withdrawn from the market because a number of consumers developed leukoderma, inflammation and erythema on their face, neck and hands. Here, we explored the mechanism underlying the toxicity of RD and RK against melanocytes using B16F10 murine melanoma cells and human primary epidermal melanocytes. Treatment with RD or RK resulted in the decreased cell viability in a dose-dependent manner which appeared from cell growth arrest. Consistently, ROS generation was significantly increased by RD or RK as determined by DCF-enhanced fluorescence. An antioxidant enzyme, glutathione peroxidase was depleted as well. In line with ROS generation, oxidative damages and the arrest of normal cell proliferation, GADD genes (Growth Arrest and DNA Damage) that include GADD45 and GADD153, were significantly up-regulated. Prevention of ROS generation with an anti-oxidant, N-acetylcysteine (NAC) significantly rescued RD and RK-suppressed melanocyte proliferation. Consistently, up-regulation of GADD45 and GADD153 was significantly attenuated by NAC, suggesting that increased ROS and the resultant growth arrest of melanocytes may contribute to RD and RK-induced leukoderma.}, }
@article {pmid26863770, year = {2015}, author = {Bozhokina, ES and Kever, LV and Komissarchik, YY and Khaitlina, SY and Efremova, TN}, title = {[ENTRY OF FACULTATIVE PATHOGEN SERRATIA GRIMESII INTO HELA CELLS. ELECTRON MICROSCOPIC ANALYSIS].}, journal = {Tsitologiia}, volume = {57}, number = {10}, pages = {714-719}, pmid = {26863770}, issn = {0041-3771}, mesh = {Acetylcysteine/pharmacology ; Adhesins, Bacterial/metabolism ; Cytoplasm/drug effects/*ultrastructure ; Eukaryotic Cells/drug effects/*ultrastructure ; HeLa Cells ; *Host-Pathogen Interactions ; Humans ; Microscopy, Electron ; Serratia/metabolism/pathogenicity/*ultrastructure ; }, abstract = {Facultative pathogens Serratia grimesii are able to invade eukaryotic cells where they have been found in vacuoles and free in the cytoplasm (Efremova et al., 2001; Bozhokina et al., 2011). However, efficiency of this invasion is low, and the mechanisms of the invasion related to the initial steps of the process are not known. In the present study, we have increased the invasion efficiency by incubation of HeLa cells with N-acetylcysteine (NAC) preceding the infection. In the NAC-pretreated cells, two modes of S. grimesii to enter HeLa cells were observed. In the most cases, the penetration of S. grimesii into the cell was consistent with the "zipper mechanism", involving specific interaction of bacterial invasin with a host cell surface receptor. However, in some cases, bacteria were trapped by membrane ruffling probably produced by injected bacterial proteins that trigger the bacterial uptake process, as described in the "trigger mechanism". Further elucidation of bacterial and cellular factors involved in the bacteria-host cell interaction should clarify whether two different mechanisms or a predominant one operate during S. grimesii invasion.}, }
@article {pmid26862576, year = {2016}, author = {Vilas-Boas, F and Bagulho, A and Jerónimo, A and Tenente, R and Real, C}, title = {Data on intracellular localization of RPSA upon alteration of its redox state.}, journal = {Data in brief}, volume = {6}, number = {}, pages = {311-315}, pmid = {26862576}, issn = {2352-3409}, abstract = {Ribosomal Protein SA (RPSA), a component of the 40S ribosomal subunit, was identified as a H2O2 target in HeLa cells [1]. In order to analyze the intracellular localization of RPSA in different redox states we overexpressed wild-type RPSA (RPSAwt) or RPSA containing two cysteine to serine residue substitutions at positions 148 and 163 (RPSAmut) in HeLa cells. The transfected cells were exposed to H2O2 or N-acetylcysteine (NAC) and RPSA subcellular localization was assessed by immunofluorescence in permeabilized cells. In addition, co-immunofluorescence for RPSA and Ribosomal Protein S6 (RPS6) was performed in cells overexpressing RPSAwt or RPSAmut. Finally, the ribosomal expression of endogenous RPSA in the presence or absence of H2O2 was analyzed by Western blot. The data presented in this work is related to the research article entitled "Hydrogen peroxide regulates cell adhesion through the redox sensor RPSA" [1].}, }
@article {pmid26862259, year = {2015}, author = {Gheshlaghi, F and Lavasanijou, MR and Moghaddam, NA and Khazaei, M and Behjati, M and Farajzadegan, Z and Sabzghabaee, AM}, title = {N-acetylcysteine, Ascorbic Acid, and Methylene Blue for the Treatment of Aluminium Phosphide Poisoning: Still Beneficial?.}, journal = {Toxicology international}, volume = {22}, number = {1}, pages = {40-44}, pmid = {26862259}, issn = {0971-6580}, abstract = {OBJECTIVES: Intentional and accidental intoxication with aluminium phosphide (ALP) remains a clinical problem, especially in the Middle East region. Considering the high mortality rate besides lack of any recommended first option drug for its treatment, this study was aimed to compare the therapeutic effects of N-acetylcysteine (NAC), vitamin C (Vit C), and methylene blue; both in isolate and also in combination, for the treatment of ALP intoxication in a rat model.<br><br>MATERIALS AND METHODS: In this experimental animal study, 80 male Wistar rats in eight groups were intoxicated with ALP (12.5 mg/kg) and treated with a single dose of NAC (100 mg/kg) or Vit C (500-1,000 mg/kg) or methylene blue (1 mg/kg/5 min, 0.1%) or two of these agents or all three of them (controls were not treated). Rats were monitored regarding the parameters of drug efficacy as increased survival time and reduced morbidity and mortality rate for 3 consecutive days to ensure toxin neutralization. Macroscopic changes were recorded and biopsy sections were taken from brain, cerebellum, kidney, liver, and heart for microscopic evaluation regarding cellular hypoxia.<br><br>RESULTS: The mean survival times of rats exposed to ALP and treated with VitC + NAC was 210.55&#xb1;236.22 minutes. In analysis of survival times, there was a significant difference between Group 5 which received VitC + NAC and the other groups (P < 0.01). Serum magnesium levels after death were higher than normal (P = 0.01).<br><br>CONCLUSIONS: Despite the higher survival rate of antioxidant-treated rats compared with controls, this difference was not statistically significant.}, }
@article {pmid26861954, year = {2016}, author = {Krzyzanowska, W and Pomierny, B and Budziszewska, B and Filip, M and Pera, J}, title = {N-Acetylcysteine and Ceftriaxone as Preconditioning Strategies in Focal Brain Ischemia: Influence on Glutamate Transporters Expression.}, journal = {Neurotoxicity research}, volume = {29}, number = {4}, pages = {539-550}, pmid = {26861954}, issn = {1476-3524}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Analysis of Variance ; Animals ; Brain/drug effects/metabolism/pathology ; Brain Edema/etiology/prevention &amp; control ; Brain Infarction/etiology/prevention &amp; control ; Ceftriaxone/*pharmacology/*therapeutic use ; Disease Models, Animal ; Drug Administration Schedule ; Enzyme-Linked Immunosorbent Assay ; Excitatory Amino Acid Transporter 2/genetics/*metabolism ; Gene Expression Regulation/*drug effects ; Infarction, Middle Cerebral Artery/complications/*drug therapy/pathology ; Male ; Nervous System Diseases/etiology/prevention &amp; control ; Neuroprotective Agents/pharmacology/therapeutic use ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; }, abstract = {Glutamate (Glu) plays a key role in excitotoxicity-related injury in cerebral ischemia. In the brain, Glu homeostasis depends on Glu transporters, including the excitatory amino acid transporters and the cysteine/Glu antiporter (xc-). We hypothesized that drugs acting on Glu transporters, such as ceftriaxone (CEF, 200 mg/kg, i.p.) and N-acetylcysteine (NAC, 150 mg/kg, i.p.), administered repeatedly for 5 days before focal cerebral ischemia in rats and induced by a 90-min middle cerebral artery occlusion (MCAO), may induce brain tolerance to ischemia. We compared the effects of these drugs on brain infarct volume, neurological deficits and the mRNA and protein expression of the Glu transporter-1 (GLT-1) and xc- with the effects of ischemic preconditioning and chemical preconditioning using 3-nitropropionic acid. Administration of CEF and NAC significantly reduced infarct size and neurological deficits caused by a 90-min MCAO. These beneficial effects were accompanied by changes in GLT-1 expression caused by a 90-min MCAO at both the mRNA and protein levels in the frontal cortex, hippocampus, and dorsal striatum. Thus, the results of this study suggest that the regulation of GLT-1 and xc- plays a role in the development of cerebral tolerance to ischemia and that this regulation may be a novel approach in the therapy of brain ischemia.}, }
@article {pmid26861788, year = {2016}, author = {Yamada, K and Asai, K and Nagayasu, F and Sato, K and Ijiri, N and Yoshii, N and Imahashi, Y and Watanabe, T and Tochino, Y and Kanazawa, H and Hirata, K}, title = {Impaired nuclear factor erythroid 2-related factor 2 expression increases apoptosis of airway epithelial cells in patients with chronic obstructive pulmonary disease due to cigarette smoking.}, journal = {BMC pulmonary medicine}, volume = {16}, number = {}, pages = {27}, pmid = {26861788}, issn = {1471-2466}, mesh = {Aged ; Apoptosis/*genetics ; Blotting, Western ; Breath Tests ; Bronchi/cytology/metabolism ; Case-Control Studies ; Cell Line, Tumor ; Epithelial Cells/*metabolism ; Female ; Gene Knockdown Techniques ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Male ; Middle Aged ; NF-E2-Related Factor 2/*genetics/metabolism ; Oxidative Stress/*genetics ; Pulmonary Disease, Chronic Obstructive/etiology/*genetics/metabolism ; RNA, Messenger/*metabolism ; Real-Time Polymerase Chain Reaction ; Respiratory Mucosa/cytology/metabolism ; Smoke/*adverse effects ; Smoking/adverse effects/*genetics/metabolism ; Time-Lapse Imaging ; *Nicotiana ; }, abstract = {BACKGROUND: Cigarette smoking-induced oxidative stress is known to be a key mechanism in COPD pathogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central transcription factor that regulates the antioxidant defense system. The aim of this study was to compare Nrf2 expression in COPD subjects and control subjects, and to determine the role of Nrf2 in protecting against oxidative stress-induced apoptosis.<br><br>METHODS: We enrolled 8 COPD subjects and 7 control subjects in this study. We performed bronchial brushing by bronchoscopy and obtained bronchial epithelial cells from the airways. Nrf2 expression in bronchial epithelial cells was evaluated by real-time PCR and Western blotting. We examined the effect of 10 or 15 % cigarette smoke extract (CSE) induced A549 cells apoptosis using a time-lapse cell imaging assay with caspase-3/7 activation detecting reagent and performed Terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling assay for confirming A549 cells apoptosis. We also examined the effects of Nrf2 knockdown and, 0.1, 0.5, and 1.0 mM N-acetyl cysteine on CSE-induced apoptosis. Statistical analyses were performed using t-test, paired t-test or an analysis of variance followed by the Tukey-Kramer method.<br><br>RESULTS: Nrf2 mRNA expression in COPD subjects was significantly lower than that in control subjects and Nrf2 mRNA were negatively correlated with pack year. Nrf2 protein in COPD subjects was significantly lower than that in control subjects. CSE-induced A549 cells apoptosis was increased in a time-, concentration-dependent manner, and was significantly increased by Nrf2 knockdown. N-acetyl cysteine significantly ameliorated CSE-induced apoptosis.<br><br>CONCLUSIONS: Nrf2 expression was lower in COPD patients than in control subjects. Nrf2 might have a protective role against apoptosis caused by CSE-induced oxidative stress. These results suggest an involvement of Nrf2 in COPD and administration of antioxidants to patients with COPD might be a basic therapeutic option.}, }
@article {pmid26859482, year = {2016}, author = {Pereboeva, L and Hubbard, M and Goldman, FD and Westin, ER}, title = {Robust DNA Damage Response and Elevated Reactive Oxygen Species in TINF2-Mutated Dyskeratosis Congenita Cells.}, journal = {PloS one}, volume = {11}, number = {2}, pages = {e0148793}, pmid = {26859482}, issn = {1932-6203}, mesh = {Antioxidants/pharmacology ; *DNA Damage ; Dyskeratosis Congenita/*genetics/*metabolism ; Female ; Humans ; In Vitro Techniques ; Lymphocytes/drug effects/metabolism ; Male ; *Mutation ; Pedigree ; RNA/genetics ; Reactive Oxygen Species/*metabolism ; Telomerase/genetics ; Telomere-Binding Proteins/*genetics ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Dyskeratosis Congenita (DC) is an inherited multisystem premature aging disorder with characteristic skin and mucosal findings as well as a predisposition to cancer and bone marrow failure. DC arises due to gene mutations associated with the telomerase complex or telomere maintenance, resulting in critically shortened telomeres. The pathogenesis of DC, as well as several congenital bone marrow failure (BMF) syndromes, converges on the DNA damage response (DDR) pathway and subsequent elevation of reactive oxygen species (ROS). Historically, DC patients have had poor outcomes following bone marrow transplantation (BMT), perhaps as a consequence of an underlying DNA hypersensitivity to cytotoxic agents. Previously, we demonstrated an activated DDR and increased ROS, augmented by chemotherapy and radiation, in somatic cells isolated from DC patients with a mutation in the RNA component of telomerase, TERC. The current study was undertaken to determine whether previous findings related to ROS and DDR in TERC patients' cells could be extended to other DC mutations. Of particular interest was whether an antioxidant approach could counter increased ROS and decrease DC pathologies. To test this, we examined lymphocytes from DC patients from different DC mutations (TERT, TINF2, and TERC) for the presence of an active DDR and increased ROS. All DC mutations led to increased steady-state p53 (2-fold to 10-fold) and ROS (1.5-fold to 2-fold). Upon exposure to ionizing radiation (XRT), DC cells increased in both DDR and ROS to a significant degree. Exposing DC cells to hydrogen peroxide also revealed that DC cells maintain a significant oxidant burden compared to controls (1.5-fold to 3-fold). DC cell culture supplemented with N-acetylcysteine, or alternatively grown in low oxygen, afforded significant proliferative benefits (proliferation: maximum 2-fold increase; NAC: 5-fold p53 decrease; low oxygen: maximum 3.5-fold p53 decrease). Together, our data supports a mechanism whereby telomerase deficiency and subsequent shortened telomeres initiate a DDR and create a pro-oxidant environment, especially in cells carrying the TINF2 mutations. Finally, the ameliorative effects of antioxidants in vitro suggest this could translate to therapeutic benefits in DC patients.}, }
@article {pmid26857738, year = {2016}, author = {Li, S and Lu, L and Liao, X and Gao, T and Wang, F and Zhang, L and Xi, L and Liu, S and Luo, X}, title = {Manganese elevates manganese superoxide dismutase protein level through protein kinase C and protein tyrosine kinase.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {29}, number = {2}, pages = {265-274}, doi = {10.1007/s10534-016-9913-9}, pmid = {26857738}, issn = {1572-8773}, mesh = {Animals ; Avian Proteins/*metabolism ; Cells, Cultured ; Chickens ; Enzyme Activation ; Male ; Manganese/*pharmacology ; Phosphorylation ; Protein Biosynthesis ; Protein Kinase C/*metabolism ; Protein Processing, Post-Translational ; Protein-Tyrosine Kinases/*metabolism ; Superoxide Dismutase/*metabolism ; }, abstract = {Three experiments were conducted to investigate the effects of inorganic and organic Mn sources on MnSOD mRNA, protein and enzymatic activity and the possible signal pathways. The primary broiler myocardial cells were treated with MnCl2 (I) or one of organic chelates of Mn and amino acids with weak, moderate (M) or strong (S) chelation strength for 12 and 48 h. Cells were preincubated with superoxide radical anions scavenger N-acetylcysteine (NAC) or specific inhibitors for MAPKs and protein tyrosine kinase (PTK) or protein kinase C (PKC) for 30 min before treatments of I and M. The MnSOD mRNA, protein and enzymatic activity, phosphorylated MAPKs or protein kinases activations were examined. The results showed that additions of Mn increased (P < 0.05) MnSOD mRNA levels and M was more effective than I. Additions of Mn elevated (P < 0.05) MnSOD protein levels and enzymatic activities, and no differences were found among I and M. Addition of NAC did not decrease (P > 0.05) Mn-induced MnSOD mRNA and protein levels. None of the three MAPKs was phosphorylated (P > 0.05) by Mn. Additions of Mn decreased (P < 0.05) the PTK activities and increased (P < 0.05) the membrane PKC contents. Inhibitors for PTK or PKC decreased (P < 0.05) Mn-induced MnSOD protein levels. The results suggested that Mn-induced MnSOD mRNA and protein expressions be not related with NAC, and MAPK pathways might not involve in Mn-induced MnSOD mRNA expression. PKC and PTK mediated the Mn-induced MnSOD protein expression.}, }
@article {pmid26855803, year = {2015}, author = {Kumar, S and Kishore, L and Sharma, AP and Garg, N and Singh, SK}, title = {Efficacy of holmium laser urethrotomy and intralesional injection of Santosh PGI tetra-inject (Triamcinolone, Mitomycin C, Hyaluronidase and N-acetyl cysteine) on the outcome of urethral strictures.}, journal = {Central European journal of urology}, volume = {68}, number = {4}, pages = {462-465}, pmid = {26855803}, issn = {2080-4806}, abstract = {INTRODUCTION: To study the efficacy of holmium laser urethrotomy with intralesional injection of Santosh PGI tetra-inject (Triamcinolone, Mitomycin C, Hyaluronidase and N-acetyl cysteine) in the treatment of urethral strictures.<br><br>MATERIAL AND METHODS: A total of 50 patients with symptomatic urethral stricture were evaluated by clinical history, physical examination, uroflowmetry and retrograde urethrogram preoperatively. All patients were treated with holmium laser urethrotomy, followed by injection of tetra-inject at the urethrotomy site. Tetra-inject was prepared by diluting acombination of 40 mg Triamcinolone, 2 mg Mitomycin, 3000 UHyaluronidase and 600 mg N-acetyl cysteine in 5-10 ml of saline, according to the stricture length. An indwelling 18 Fr silicone catheter was left in place for 7-10 days.All patients were followed-up for 6-18 months postoperatively by history, uroflowmetry, and if required, retrograde urethrogram and micturating urethrogram every 3 months.<br><br>RESULTS: 41 (82%) patients had asuccessful outcome,whereas 9 (18%) had recurrences during a follow-up ranging from 6-18 months. In <1 cm length strictures, the success rate was 100%, while in 1-3 cm and >3 cm lengthsthe success rates were 81.2% and 66.7% respectively. This modality, thus, has an encouraging success rate, especially in those with short segment urethral strictures (<3 cm).<br><br>CONCLUSIONS: Holmium laser urethrotomy with intralesional injection ofSantosh PGI tetra-inject (Triamcinolone, Mitomycin C, Hyaluronidase, N-acetyl cysteine) is a safe and effective minimally-invasive therapeutic modality for short segment urethral strictures.}, }
@article {pmid26855777, year = {2015}, author = {Sanguinetti, CM}, title = {N-acetylcysteine in COPD: why, how, and when?.}, journal = {Multidisciplinary respiratory medicine}, volume = {11}, number = {}, pages = {8}, pmid = {26855777}, issn = {1828-695X}, abstract = {Oxidants have long been recognized to have an important role in the pathogenesis of COPD, and in this cigarette smoke has a strong responsibility, because it generates a conspicuous amount of oxidant radicals able to modify the structure of the respiratory tract and to enhance several mechanisms that sustain lung inflammation in COPD. In fact, oxidative stress is highly increased in COPD and natural antioxidant capacities, mainly afforded by reduced glutathione, are often overcome. Thus an exogenous supplementation of antioxidant compounds is mandatory to at least partially counteract the oxidative stress. For this purpose N-acetylcysteine has great potentialities due to its capacity of directly contrasting oxidants with its free thiols, and to the possibility it has of acting as donor of cysteine precursors aimed at glutathione restoration. Many studies in vitro and in vivo have already demonstrated the antioxidant capacity of NAC. Many clinical studies have long been performed to explore the efficacy of NAC in COPD with altern results, especially when the drug was used at very low dosage and/or for a short period of time. More recently, several trials have been conducted to verify the appropriateness of using high-dose NAC in COPD, above all to decrease the exacerbations rate. The results have been encouraging, even if some of the data come from the most widely sized trials that have been conducted in Chinese populations. Although other evidence should be necessary to confirm the results in other populations of patients, high-dose oral NAC nevertheless offers interesting perspectives as add-on therapy for COPD patients.}, }
@article {pmid26854864, year = {2016}, author = {Pals, JA and Wagner, ED and Plewa, MJ}, title = {Energy of the Lowest Unoccupied Molecular Orbital, Thiol Reactivity, and Toxicity of Three Monobrominated Water Disinfection Byproducts.}, journal = {Environmental science &amp; technology}, volume = {50}, number = {6}, pages = {3215-3221}, pmid = {26854864}, issn = {1520-5851}, support = {T32 ES007326/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetamides/chemistry ; Acetates/*chemistry ; Acetonitriles/chemistry ; Acetylcysteine/chemistry ; Animals ; CHO Cells ; Computer Simulation ; Cricetulus ; Disinfectants/*chemistry/*toxicity ; Disinfection ; Drinking Water/chemistry ; Sulfhydryl Compounds/chemistry ; Water Purification/*methods ; }, abstract = {Disinfection of drinking water protects public health against waterborne pathogens. However, during disinfection, toxic disinfection byproducts (DBPs) are formed. Exposure to DBPs was associated with increased risk of bladder cancer in humans. DBPs are generated at concentrations below their carcinogenic potencies; it is unclear how exposure leads to adverse health outcomes. We used computational estimates of the energy of the lowest unoccupied molecular orbital (ELUMO) to predict thiol reactivity and additive toxicity among soft electrophile DBPs. Bromoacetic acid (BAA) was identified as non-thiol-reactive, which was supported by in chemico and in vitro data. Bromoacetonitrile (BAN) and bromoacetamide (BAM) were thiol-reactive. Genotoxicity induced by these compounds was reduced by increasing the thiol pool with N-acetyl L-cysteine (NAC), while NAC had little effect on BAA. BAN and BAM shared depletion of glutathione (GSH) or cellular thiols as a molecular initiating event (MIE), whereas BAA induces toxicity through another pathway. Binary mixtures of BAM and BAN expressed a potentiating effect in genotoxicity. We found that soft electrophile DBPs could be an important predictor of common mechanism groups that demonstrated additive toxicity. In silico estimates of ELUMO could be used to identify the most relevant DBPs that are the forcing factors of the toxicity of finished drinking waters.}, }
@article {pmid26854005, year = {2016}, author = {Eshraghi, AA and Roell, J and Shaikh, N and Telischi, FF and Bauer, B and Guardiola, M and Bas, E and Van De Water, T and Rivera, I and Mittal, J}, title = {A novel combination of drug therapy to protect residual hearing post cochlear implant surgery.}, journal = {Acta oto-laryngologica}, volume = {136}, number = {4}, pages = {420-424}, doi = {10.3109/00016489.2015.1134809}, pmid = {26854005}, issn = {1651-2251}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Cochlear Implantation ; Dexamethasone/pharmacology/*therapeutic use ; Drug Therapy, Combination ; Free Radical Scavengers/pharmacology/*therapeutic use ; Hair Cells, Auditory/drug effects ; Hearing Loss/*prevention &amp; control ; Mannitol/pharmacology/*therapeutic use ; Postoperative Complications/*prevention &amp; control ; Rats, Sprague-Dawley ; }, abstract = {UNLABELLED: Conclusions A cocktail combining NAC, Mannitol, and Dexamethasone may be used to prevent loss of residual hearing post-implantation. There is a window of opportunity to treat the cochlea before the onset of cell death in HCs. Objective Inner ear trauma caused by cochlear implant electrode insertion trauma (EIT) initiates multiple molecular mechanisms in hair cells (HCs) or support cells (SCs), resulting in initiation of programmed cell death within the damaged tissues of the cochlea, which leads to loss of residual hearing. In earlier studies L-N-acetylcysteine (L-NAC), Mannitol, and dexamethasone have been shown independently to protect the HCs loss against different types of inner ear trauma. These three molecules have different otoprotective effects. The goal of this preliminary study is to test the efficacy of a combination of these molecules to enhance the otoprotection of HCs against EIT. Methods OC explants were dissected from P-3 rats and placed in serum-free media. Explants were divided into control and experimental groups.<br><br>CONTROL GROUP: (1) untreated controls; (2) EIT. Experimental group: (1) EIT&#x2009;+&#x2009;L-NAC (5, 2, or 1&#x2009;mM); (2) EIT&#x2009;+&#x2009;Mannitol (100, 50, or 10&#x2009;mM); (3) EIT&#x2009;+&#x2009;Dex (20, 10, or 5&#x2009;&#x3bc;g/mL); (4) EIT&#x2009;+&#x2009;L-NAC&#x2009;+&#x2009;Mannitol&#x2009;+&#x2009;Dex. After EIT was caused in an in-vitro model of CI, explants were cultured in media containing L-NAC alone, Mannitol alone, or Dex alone at decreasing concentrations. Concentrations of L-NAC, Mannitol, and Dex that showed 50% protection of hair cell loss individually were used as a combination in experimental group 4. Results There was an increase of total hair cell (THC) loss in the EIT OC explants when compared with control group HC counts or the tri-therapy cochlea. This study defined the dosage of L-NAC, Mannitol, and Dex for the survival of 50% protection of hair cells in vitro. Their combination provided close to 96% protection, demonstrating an additive effect.}, }
@article {pmid26852701, year = {2016}, author = {Botsakis, K and Theodoritsi, S and Grintzalis, K and Angelatou, F and Antonopoulos, I and Georgiou, CD and Margarity, M and Matsokis, NA and Panagopoulos, NT}, title = {17β-Estradiol/N-acetylcysteine interaction enhances the neuroprotective effect on dopaminergic neurons in the weaver model of dopamine deficiency.}, journal = {Neuroscience}, volume = {320}, number = {}, pages = {221-229}, doi = {10.1016/j.neuroscience.2016.01.068}, pmid = {26852701}, issn = {1873-7544}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Dopaminergic Neurons/*drug effects/pathology ; Drug Synergism ; Estradiol/*administration &amp; dosage ; Female ; Immunohistochemistry ; Male ; Mice ; Mice, Neurologic Mutants ; Nerve Degeneration/pathology ; Neuroprotective Agents/*administration &amp; dosage ; Parkinsonian Disorders/*pathology ; }, abstract = {The weaver mouse, is a phenocopy of Parkinson's disease (PD) in which dopaminergic neurons degenerate gradually during development, reaching at P21 a neurodegeneration of 55%. Thus, the weaver mouse constitutes an appropriate in vivo PD model for investigating the effect of neuroprotective agents. In the present study, long-term treatment (from P1 to P21) with 17β-estradiol (17β-estradiol) significantly protected the dopaminergic neurons in the substantia nigra (SN) of weaver mouse by 54%, as was detected by immunohistochemical experiments, using the specific antibody against tyrosine hydroxylase (TH). This dopaminergic neuroprotection is in line with our biochemical results showing that 17β-estradiol treatment significantly decreased the high lipid peroxidation levels seen in the SN of weaver mouse, indicating high oxidative stress. Interestingly, co-administration of 17β-estradiol with N-acetylcysteine (NAC, precursor molecule of glutathione (GSH)) further significantly increased the survival of dopaminergic neurons in the SN (by 85%), with a parallel further decrease of lipid peroxidation to normal levels. Our results show the in vivo neuroprotective effect of 17β-estradiol, which is strongly enhanced by co administration of NAC, indicating a strong synergistic effect of the two drugs. Furthermore, the main mechanism underlying this neuroprotective action seems to be the reversal of the oxidative stress shown by the high peroxidation levels. These results could be of clinical relevance since both drugs are already used separately in the clinic, 17β-estradiol for treatment of PD and NAC as a mucolytic agent and for the treatment of several disorders.}, }
@article {pmid26851769, year = {2016}, author = {Nie, X and Lowe, DW and Rollins, LG and Bentzley, J and Fraser, JL and Martin, R and Singh, I and Jenkins, D}, title = {Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia.}, journal = {Neuroscience research}, volume = {108}, number = {}, pages = {24-33}, pmid = {26851769}, issn = {1872-8111}, support = {R01 NS022576/NS/NINDS NIH HHS/United States ; R01 NS052448/NS/NINDS NIH HHS/United States ; R01 NS034741/NS/NINDS NIH HHS/United States ; R37 NS022576/NS/NINDS NIH HHS/United States ; R01 NS037766/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Animals, Newborn ; Antioxidants/administration &amp; dosage/*therapeutic use ; Brain/drug effects/metabolism/pathology ; Brain Infarction/pathology/therapy ; Caspase 3/metabolism ; Cell Death ; Dose-Response Relationship, Drug ; Enzyme Activation ; Female ; *Hypothermia, Induced ; Hypoxia-Ischemia, Brain/pathology/physiopathology/*therapy ; Inflammation Mediators/metabolism ; Male ; Motor Skills/drug effects ; Nitric Oxide Synthase Type II/metabolism ; Rats, Sprague-Dawley ; Sex Factors ; Time Factors ; }, abstract = {Approximately half of moderate to severely hypoxic-ischemic (HI) newborns do not respond to hypothermia, the only proven neuroprotective treatment. N-acetylcysteine (NAC), an antioxidant and glutathione precursor, shows promise for neuroprotection in combination with hypothermia, mitigating post-HI neuroinflammation due to oxidative stress. As mechanisms of HI injury and cell death differ in males and females, sex differences must be considered in translational research of neuroprotection. We assessed the potential toxicity and efficacy of NAC in combination with hypothermia, in male and female neonatal rats after severe HI injury. NAC 50mg/kg/d administered 1h after initiation of hypothermia significantly decreased iNOS expression and caspase 3 activation in the injured hemisphere versus hypothermia alone. However, only females treated with hypothermia +NAC 50mg/kg showed improvement in short-term infarct volumes compared with saline treated animals. Hypothermia alone had no effect in this severe model. When NAC was continued for 6 weeks, significant improvement in long-term neuromotor outcomes over hypothermia treatment alone was observed, controlling for sex. Antioxidants may provide insufficient neuroprotection after HI for neonatal males in the short term, while long-term therapy may benefit both sexes.}, }
@article {pmid26848926, year = {2016}, author = {Magalhães, PV and Dean, O and Andreazza, AC and Berk, M and Kapczinski, F}, title = {Antioxidant treatments for schizophrenia.}, journal = {The Cochrane database of systematic reviews}, volume = {2}, number = {2}, pages = {CD008919}, pmid = {26848926}, issn = {1469-493X}, mesh = {Acetylcysteine/therapeutic use ; Allopurinol/therapeutic use ; Antioxidants/*therapeutic use ; Antipsychotic Agents/*therapeutic use ; Ascorbic Acid/therapeutic use ; Dehydroepiandrosterone/therapeutic use ; Drug Therapy, Combination/methods ; Free Radical Scavengers/*therapeutic use ; Ginkgo biloba ; Humans ; Oxidative Stress/*drug effects ; Randomized Controlled Trials as Topic ; Schizophrenia/*drug therapy/metabolism ; Selegiline/therapeutic use ; Vitamin E/therapeutic use ; Vitamins/therapeutic use ; }, abstract = {BACKGROUND: There is accumulating evidence that progressive changes in brain structure and function take place as schizophrenia unfolds. Among many possible candidates, oxidative stress may be one of the mediators of neuroprogression, grey matter loss and subsequent cognitive and functional impairment. Antioxidants are exogenous or endogenous molecules that mitigate any form of oxidative stress or its consequences. They may act from directly scavenging free radicals to increasing anti-oxidative defences. There is evidence that current treatments impact oxidative pathways and may to some extent reverse pro-oxidative states in schizophrenia. The existing literature, however, indicates that these treatments do not fully restore the deficits in antioxidant levels or restore levels of oxidants in schizophrenia. As such, there has been interest in developing interventions aimed at restoring this oxidative balance beyond the benefits of antipsychotics in this direction. If antioxidants are to have a place in the treatment of this serious condition, the relevant and up-to-date information should be available to clinicians and investigators.<br><br>OBJECTIVES: To evaluate the effect of antioxidants as add-on treatments to standard antipsychotic medication for improving acute psychotic episodes and core symptoms, and preventing relapse in people with schizophrenia.<br><br>SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran this search in November 2010, and again on 8 January 2015. We also inspected references of all identified studies for further trials and contacted authors of trials for additional information.<br><br>SELECTION CRITERIA: We included reports if they were randomised controlled trials (RCTs) involving people with schizophrenia who had been allocated to either a substance with antioxidant potential or to a placebo as an adjunct to standard antipsychotic treatment.<br><br>DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.<br><br>MAIN RESULTS: The review includes 22 RCTs of varying quality and sample size studying Ginkgo biloba, N-acetyl cysteine (NAC), allopurinol, dehydroepiandrosterone (DHEA), vitamin C, vitamin E or selegiline. Median follow-up was eight weeks. Only three studies including a minority of the participants reported our a priori selected primary outcome of clinically important response. Short-term data for this outcome (measured as at least 20% improvement in scores on Positive and Negative Syndrome Scale (PANSS)) were similar (3 RCTs, n = 229, RR 0.77, 95% CI 0.53 to 1.12, low quality evidence). Studies usually reported only endpoint psychopathology rating scale scores. Psychotic symptoms were lower in those using an adjunctive antioxidant according to the PANSS (7 RCTS, n = 584, MD -6.00, 95% CI -10.35 to -1.65, very low quality evidence) and the Brief Psychiatric Rating Scale (BPRS) (8 RCTS, n = 843, MD -3.20, 95% CI -5.63 to -0.78, low quality evidence). There was no overall short-term difference in leaving the study early (16 RCTs, n = 1584, RR 0.73, 95% CI 0.48 to 1.11, moderate quality evidence), or in general functioning (2 RCTs, n = 52, MD -1.11, 95% CI -8.07 to 5.86, low quality evidence). Adverse events were generally poorly reported. Three studies reported useable data for 'any serious adverse effect', results were equivocal (3 RCTs, n = 234, RR 0.65, 95% CI 0.19 to 2.27, low quality evidence). No evidence was available for relapse, quality of life or service use.<br><br>AUTHORS' CONCLUSIONS: Although 22 trials could be included in this review, the evidence provided is limited and mostly not relevant to clinicians or consumers. Overall, although there was low risk of attrition and selective data reporting bias within the trials, the trials themselves were not adequately powered and need more substantial follow-up periods. There is a need for larger trials with longer periods of follow-up to be conducted. Outcomes should be meaningful for those with schizophrenia, and include measures of improvement and relapse (not just rating scale scores), functioning and quality of life and acceptability and, importantly, safety data.}, }
@article {pmid26848099, year = {2016}, author = {Zhou, L and Jiang, L and Xu, M and Liu, Q and Gao, N and Li, P and Liu, EH}, title = {Miltirone exhibits antileukemic activity by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction pathways.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {20585}, pmid = {26848099}, issn = {2045-2322}, mesh = {Animals ; Antineoplastic Agents/*administration &amp; dosage/pharmacology ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Leukemia/*drug therapy/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Mitochondria/*metabolism ; Phenanthrenes/*administration &amp; dosage/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {In this study, we investigated the effects of miltirone in human leukemia cell lines, primary leukemia cells, and nude mice U937 xenograft. Treatment of cells with miltirone resulted in apoptosis, mitochondria membrane potential (MMP) collapses, increase of Bax/Bcl-2 ratio, and cytochrome c release. Miltirone triggered the endoplasmic reticulum (ER) stress identified through several key molecules of the unfolded protein response, including phosphorylated PERK, eIF2a, GRP78, GRP94, and caspase-12. Miltrone treatment also resulted in the release of Ca(2+) from the ER stores and mitochondrial Ca(2+) loading in the cells. Further research revealed that miltirone resulted in dose-dependent decrease in complex III activity and elevated reactive oxygen species (ROS) production in these cells. Miltirone-induced apoptosis, dissipation of MMP and ER stress were dramatically blocked by pretreatment with antioxidant N-acetylcysteine (NAC). In contrast, treatment with ER stress inhibitor TUDCA significantly attenuated miltirone-induced ROS and apoptosis in leukemia cells. Moreover, our in vivo findings showed that administration of miltirone markedly inhibited tumor growth and induced apoptosis in U937 xenograft model with low systemic toxicity. Taken together, these findings indicate that miltirone may exert its antileukemic activity by inducing apoptosis through a ROS-dependent destructive cycle involving ER stress and mitochondrial dysfunction.}, }
@article {pmid26847865, year = {2016}, author = {Handigund, M and Bae, TW and Lee, J and Cho, YG}, title = {Evaluation of in vitro storage characteristics of cold stored platelet concentrates with N acetylcysteine (NAC).}, journal = {Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis}, volume = {54}, number = {1}, pages = {127-138}, doi = {10.1016/j.transci.2016.01.006}, pmid = {26847865}, issn = {1473-0502}, mesh = {Acetylcysteine/*pharmacology ; Biomarkers/metabolism ; Blood Platelets/drug effects/*metabolism ; *Cold Temperature ; Cryopreservation/*methods ; Cryoprotective Agents/pharmacology ; Glucose/analysis ; Humans ; Hydrogen-Ion Concentration ; Neuraminidase/metabolism ; Platelet Activation/drug effects ; Platelet Count ; Platelet Function Tests ; Rewarming ; Time Factors ; }, abstract = {Platelets play a vital role in hemostasis and thrombosis, and their demand and usage has multiplied many folds over the years. However, due to the short life span and storage constraints on platelets, it is allowed to store them for up to 7 days at room temperature (RT); thus, there is a need for an alternative storage strategy for extension of shelf life. Current investigation involves the addition of 50 mM N acetylcysteine (NAC) in refrigerated concentrates. Investigation results revealed that addition of NAC to refrigerated concentrates prevented platelet activation and reduced the sialidase activity upon rewarming as well as on prolonged storage. Refrigerated concentrates with 50 mM NAC expressed a 23.91 ± 6.23% of CD62P (P-Selectin) and 22.33 ± 3.42% of phosphotidylserine (PS), whereas RT-stored platelets showed a 46.87 ± 5.23% of CD62P and 25.9 ± 6.48% of phosphotidylserine (PS) after 5 days of storage. Further, key metabolic parameters such as glucose and lactate accumulation indicated reduced metabolic activity. Taken together, investigation and observations indicate that addition of NAC potentially protects refrigerated concentrates by preventing platelet activation, stabilizing sialidase activity, and further reducing the metabolic activity. Hence, we believe that NAC can be a good candidate for an additive solution to retain platelet characteristics during cold storage and may pave the way for extension of storage shelf life.}, }
@article {pmid26847810, year = {2016}, author = {Cai, G and Yang, X and Lai, Q and Yu, X and Zhang, H and Li, Y and Chen, Z and Lei, X and Zheng, W and Xu, H and Zheng, T}, title = {Lysing bloom-causing alga Phaeocystis globosa with microbial algicide: An efficient process that decreases the toxicity of algal exudates.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {20081}, pmid = {26847810}, issn = {2045-2322}, mesh = {Anti-Infective Agents/isolation &amp; purification/metabolism/*pharmacology ; Catalase/metabolism ; Cell Membrane Permeability/drug effects ; Exudates and Transudates/drug effects/metabolism ; Flow Cytometry ; Fluorometry ; Haptophyta/*drug effects/metabolism/ultrastructure ; Harmful Algal Bloom/drug effects ; Microscopy, Electron, Transmission ; Oxidative Stress/drug effects ; Oxidoreductases/metabolism ; Photosynthesis/drug effects ; Reactive Oxygen Species/metabolism ; Streptomyces/*metabolism ; }, abstract = {Algicidal microbes could effectively remove the harmful algae from the waters. In this study, we were concerned with the ecological influence of an algicide extracted from Streptomyces alboflavus RPS, which could completely lyse the Phaeocystis globosa cells within two days. In microcosms, 4 μg/mL of the microbial algicide could efficiently remove P. globosa cells without suppressing other aquatic organisms. Bioluminescent assays confirmed that the toxicity of microbial algicide at this concentration was negligible. Interestingly, the toxicity of P. globosa exudates was also significantly reduced after being treated with the algicide. Further experiments revealed that the microbial algicide could instantly increase the permeability of the plasma membrane and disturb the photosynthetic system, followed by the deformation of organelles, vacuolization and increasing oxidative stress. The pre-incubation of N-acetyl cysteine (NAC) verified that the rapid damages to the plasma membrane and photosynthetic system caused the algal death in the early phase, and the increasing oxidative stress killed the rest. The late accumulation and possible release of CAT also explained the decreasing toxicity of the algal culture. These results indicated that this microbial algicide has great potential in controlling the growth of P. globosa on site.}, }
@article {pmid26845511, year = {2016}, author = {Guo, X and Lin, D and Li, W and Wang, K and Peng, Y and Zheng, J}, title = {Electrophilicities and Protein Covalent Binding of Demethylation Metabolites of Colchicine.}, journal = {Chemical research in toxicology}, volume = {29}, number = {3}, pages = {296-302}, doi = {10.1021/acs.chemrestox.5b00461}, pmid = {26845511}, issn = {1520-5010}, mesh = {Animals ; Binding Sites/drug effects ; Carrier Proteins/*metabolism ; Colchicine/chemistry/metabolism/*pharmacology ; Humans ; Methylation/drug effects ; Microsomes, Liver/*drug effects/metabolism ; Molecular Structure ; Rats ; Structure-Activity Relationship ; }, abstract = {Colchicine, an alkaloid existing in plants of Liliaceous colchicum, has been widely used in the treatment of gout and familial Mediterranean fever. The administration of colchicine was found to cause liver injury in humans. The mechanisms of colchicine-induced liver toxicity remain unknown. The objectives of this study were to determine the electrophilicities of demethylation metabolites of colchicine and investigate the protein adductions derived from the reactive metabolites of colchicine. Four demethylated colchicine (1-, 2-, 3-, and 10-DMCs), namely, M1-M4, were detected in colchicine-fortified microsomal incubations. Four N-acetyl cysteine (NAC) conjugates (M5-M8) derived from colchicine were detected in the microsomes in the presence of NAC. M5 and M6 were derived from 10-DMC. M7 resulted from the reaction of 2-DMC or 3-DMC with NAC, and M8 originated from 10-DMC. Microsomal protein covalent binding was observed after exposure to colchicine. Two cysteine adducts (CA-1 and CA-2) derived from 10-DMC were found in proteolytically digested microsomal protein samples after incubation with colchicine. The findings allow us to define the chemical property of demethylation metabolites of colchicine and the interaction between protein and the reactive metabolites of colchicine generated in situ.}, }
@article {pmid26844634, year = {2016}, author = {Gil, JA and Wawrzynski, J and Waryasz, GR}, title = {Orthopedic Manifestations of Ochronosis: Pathophysiology, Presentation, Diagnosis, and Management.}, journal = {The American journal of medicine}, volume = {129}, number = {5}, pages = {536.e1-6}, doi = {10.1016/j.amjmed.2016.01.010}, pmid = {26844634}, issn = {1555-7162}, mesh = {Disease Management ; Humans ; Joint Diseases/diagnostic imaging/*etiology ; Ochronosis/*complications ; }, abstract = {Ochronotic arthropathy occurs in patients with alkaptonuria, manifesting first in the intervertebral discs of the lumbar spine, with subsequent degeneration most often observed in the knee, hip, and shoulder joints. Efforts at treatment are targeted at minimizing the damaging effects of the underlying metabolic disorder on the articular cartilage. Vitamin E and N-acetyl cysteine are potential therapies because of their scavenging of free radicals and consequent limitation of oxidative damage to joint tissue. Arthroscopy has been found to be an effective diagnostic tool in cases of suspected ochronosis. Arthroplasty performed in patients with ochronotic arthropathy suggests that the procedure is effective in the alleviation of joint pain and the improvement of mobility. Perioperative management of these patients may require more careful consideration pertinent to the associated comorbidities of this disorder.}, }
@article {pmid26839632, year = {2016}, author = {da Silva, RF and Borges, Cdos S and Villela E Silva, P and Missassi, G and Kiguti, LR and Pupo, AS and Barbosa Junior, F and Anselmo-Franci, JA and Kempinas, Wde G}, title = {The Coadministration of N-Acetylcysteine Ameliorates the Effects of Arsenic Trioxide on the Male Mouse Genital System.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {4257498}, pmid = {26839632}, issn = {1942-0994}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Arsenic/blood ; Arsenic Trioxide ; Arsenicals/*administration &amp; dosage/adverse effects ; Body Weight ; Epididymis/*drug effects/physiology ; Male ; Mice ; Organ Size ; Oxides/*administration &amp; dosage/adverse effects ; Random Allocation ; Reactive Oxygen Species/metabolism ; Sperm Motility/drug effects ; Spermatogenesis/drug effects ; Spermatozoa/physiology ; Testis/*drug effects/physiology ; Testosterone/blood/*metabolism ; }, abstract = {Arsenic trioxide (As2O3) has shown effectiveness in treatment of leukemia but is also associated with reproductive toxicity. Since remediation with N-acetylcysteine (NAC) may mitigate the adverse effects caused by exposure, we assessed the effects of As2O3 and its potential reversibility after exposure cessation or coadministration of NAC. Animals received 0.3 or 3.0 mg/Kg/day of As2O3 subcutaneously and 40 mM of NAC in tap water. As2O3 treatment impaired spermatogenesis and sperm motility and decreased seminal vesicle weight and testosterone serum levels; after suspension of treatment, these parameters remained altered. When NAC was administered, animals showed improvement in sperm parameters and seminal vesicle weight. In vitro epididymal contractility was increased in As2O3-treated animals. We concluded that As2O3 is toxic to the male mouse genital system by compromising sperm quality and quantity; these effects persisted even after suspension of the treatment. However, the coadministration of NAC ameliorates the harmful effects of the drug on the male genital system.}, }
@article {pmid26834733, year = {2016}, author = {Asmar, S and Chatellier, S and Mirande, C and van Belkum, A and Canard, I and Raoult, D and Drancourt, M}, title = {A Chlorhexidine- Agar Plate Culture Medium Protocol to Complement Standard Broth Culture of Mycobacterium tuberculosis.}, journal = {Frontiers in microbiology}, volume = {7}, number = {}, pages = {30}, pmid = {26834733}, issn = {1664-302X}, abstract = {The culture of Mycobacterium tuberculosis using parallel inoculation of a solid culture medium and a liquid broth provides the gold standard for the diagnosis of tuberculosis. Here, we evaluated a chlorhexidine decontamination-MOD9 solid medium protocol versus the standard NALC-NaOH-Bactec 960 MGIT protocol for the diagnosis of pulmonary tuberculosis by culture. Three-hundred clinical specimens comprising 193 sputa, 30 bronchial aspirates, 10 broncho-alveolar lavages, 47 stools, and 20 urines were prospectively submitted for the routine diagnosis of tuberculosis. The contamination rates were 5/300 (1.7%) using the MOD9 protocol and 17/300 (5.7%) with the Bactec protocol, respectively (P < 0.05, Fisher exact test). Of a total of 50 Mycobacterium isolates (48 M. tuberculosis and two Mycobacterium abscessus) were cultured. Out of these 50, 48 (96%) isolates were found using the MOD9 protocol versus 35 (70%) when using the Bactec protocol (P < 0.05, Fisher exact test). The time to positivity was 10.1 ± 3.9 days versus 14.7 ± 7.3 days, respectively, (P < 0.05, Student's t-test). These data confirmed the usefulness of parallel inoculation of a solid culture medium with broth for the recovery of M. tuberculosis in agreement with current recommendations. More specifically, chlorhexidine decontamination and inoculation of the MOD9 solid medium could be proposed to complement the standard Bactec 960 MGIT broth protocol.}, }
@article {pmid26832829, year = {2016}, author = {Ercan, UK and Smith, J and Ji, HF and Brooks, AD and Joshi, SG}, title = {Chemical Changes in Nonthermal Plasma-Treated N-Acetylcysteine (NAC) Solution and Their Contribution to Bacterial Inactivation.}, journal = {Scientific reports}, volume = {6}, number = {}, pages = {20365}, pmid = {26832829}, issn = {2045-2322}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Anti-Bacterial Agents/chemistry/*pharmacology ; Hydrogen-Ion Concentration ; Magnetic Resonance Spectroscopy ; Microbial Viability/drug effects ; Nitrates/chemistry ; Nitrites/chemistry ; Pharmaceutical Solutions/chemistry/*pharmacology ; *Plasma Gases/chemistry ; Reactive Nitrogen Species/chemistry ; Reactive Oxygen Species/chemistry ; Spectroscopy, Fourier Transform Infrared ; }, abstract = {In continuation of our previous reports on the broad-spectrum antimicrobial activity of atmospheric non-thermal dielectric barrier discharge (DBD) plasma treated N-Acetylcysteine (NAC) solution against planktonic and biofilm forms of different multidrug resistant microorganisms, we present here the chemical changes that mediate inactivation of Escherichia coli. In this study, the mechanism and products of the chemical reactions in plasma-treated NAC solution are shown. UV-visible spectrometry, FT-IR, NMR, and colorimetric assays were utilized for chemical characterization of plasma treated NAC solution. The characterization results were correlated with the antimicrobial assays using determined chemical species in solution in order to confirm the major species that are responsible for antimicrobial inactivation. Our results have revealed that plasma treatment of NAC solution creates predominantly reactive nitrogen species versus reactive oxygen species, and the generated peroxynitrite is responsible for significant bacterial inactivation.}, }
@article {pmid26831695, year = {2016}, author = {Jiang, L and Yu, Y and Li, Y and Yu, Y and Duan, J and Zou, Y and Li, Q and Sun, Z}, title = {Oxidative Damage and Energy Metabolism Disorder Contribute to the Hemolytic Effect of Amorphous Silica Nanoparticles.}, journal = {Nanoscale research letters}, volume = {11}, number = {1}, pages = {57}, pmid = {26831695}, issn = {1931-7573}, abstract = {Amorphous silica nanoparticles (SiNPs) have been extensively used in biomedical applications due to their particular characteristics. The increased environmental and iatrogenic exposure of SiNPs gained great concerns on the biocompatibility and hematotoxicity of SiNPs. However, the studies on the hemolytic effects of amorphous SiNPs in human erythrocytes are still limited. In this study, amorphous SiNPs with 58 nm were selected and incubated with human erythrocytes for different times (30 min and 2 h) at various concentrations (0, 10, 20, 50, and 100 μg/mL). SiNPs induced a dose-dependent increase in percent hemolysis and significantly increased the malondialdehyde (MDA) content and decreased the superoxide dismutase (SOD) activity, leading to oxidative damage in erythrocytes. Hydroxyl radical (·OH) levels were detected by electron spin resonance (ESR), and the decreased elimination rates of ·OH showed SiNPs induced low antioxidant ability in human erythrocytes. Na(+)-K(+) ATPase activity and Ca(2+)-Mg(2+) ATPase activity were found remarkably inhibited after SiNP treatment, possibly causing energy sufficient in erythrocytes. Percent hemolysis of SiNPs was significantly decreased in the presence of N-acetyl-cysteine (NAC) and adenosine diphosphate (ADP). It was concluded that amorphous SiNPs caused dose-dependent hemolytic effects in human erythrocytes. Oxidative damage and energy metabolism disorder contributed to the hemolytic effects of SiNPs in vitro.}, }
@article {pmid26831541, year = {2016}, author = {Hamzeh, N and Li, L and Barkes, B and Huang, J and Canono, B and Gillespie, M and Maier, L and Day, B}, title = {The effect of an oral anti-oxidant, N-Acetyl-cysteine, on inflammatory and oxidative markers in pulmonary sarcoidosis.}, journal = {Respiratory medicine}, volume = {112}, number = {}, pages = {106-111}, doi = {10.1016/j.rmed.2016.01.011}, pmid = {26831541}, issn = {1532-3064}, support = {5U01HL112707/HL/NHLBI NIH HHS/United States ; UL1TR001082/TR/NCATS NIH HHS/United States ; }, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*therapeutic use ; Administration, Oral ; Adult ; Aged ; Antioxidants/*therapeutic use ; Bronchoalveolar Lavage Fluid/cytology/*immunology ; DNA/*metabolism ; Deoxyguanosine/*analogs &amp; derivatives/metabolism ; Double-Blind Method ; Female ; Glutathione/*metabolism ; Humans ; Inflammation ; Lipopolysaccharides/pharmacology ; Male ; Middle Aged ; Oxidation-Reduction ; *Oxidative Stress ; Sarcoidosis, Pulmonary/*drug therapy/immunology/metabolism ; Tumor Necrosis Factor-alpha/drug effects/*immunology ; }, abstract = {BACKGROUND: Oxidative stress (OS) has been shown to play a role in the pathogenesis of sarcoidosis and previous studies have shown that anti-oxidants can reduce markers of oxidative stress and inflammation in the peripheral blood of sarcoidosis subjects. We investigated the effect of N-Acetyl-Cysteine (NAC) on oxidative stress and inflammatory markers in the lungs of sarcoidosis patients.<br><br>METHODS: We randomized 11 sarcoidosis subjects to active therapy and 3 to placebo for 8 weeks in a double blinded study. Bronchoscopy with bronchoalveolar lavage was performed pre and post therapy. Our primary endpoint was TNF-&#x3b1; production from stimulated and unstimulated BAL cells. Secondary outcomes included measures of oxidative stress (GSH, 8-OHdG) levels in the BAL. In-vitro studies were also performed to assess the effect of NAC on lipopolysaccharide stimulated BAL cell production of TNF-&#x3b1;.<br><br>RESULTS: Eight subjects in the active group and 2 in the placebo group completed the study protocol. Eight weeks of oral NAC did not have a significant impact on TNF-&#x3b1; levels from BAL cells in-vivo in spite of a 59% increase in BAL GSH levels. Our in vitro studies showed a significant decline in TNF-&#x3b1; production from LPS stimulated BAL cells treated with 5 and 10 mM of NAC.<br><br>CONCLUSIONS: Oral NAC increased GSH levels but failed to suppress in-vivo TNF-&#x3b1; production in contrast to effects in-vitro. Anti-oxidant therapy may still play a role in the management of sarcoidosis but therapy with better bioavailability or potency is needed to suppress the lung inflammatory response.}, }
@article {pmid26830534, year = {2016}, author = {Böhmer, A and Pich, A and Schmidt, M and Haghikia, A and Tsikas, D}, title = {Evidence by chromatography and mass spectrometry that inorganic nitrite induces S-glutathionylation of hemoglobin in human red blood cells.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1019}, number = {}, pages = {72-82}, doi = {10.1016/j.jchromb.2016.01.032}, pmid = {26830534}, issn = {1873-376X}, mesh = {Chromatography, High Pressure Liquid/*methods ; Erythrocytes/chemistry/metabolism ; Female ; Glutathione/blood/*metabolism ; Hemoglobins/chemistry/*metabolism ; Humans ; Male ; Nitrites/blood/*chemistry ; Oxidation-Reduction ; Tandem Mass Spectrometry/*methods ; }, abstract = {Previously we found by HPLC with fluorescence detection that inorganic nitrite induces oxidation of glutathione (GSH) to its disulfide (GSSG) in intact and more abundantly in lyzed red blood cells (RBCs) from healthy humans. In the present work, we performed MS-based protein analysis and observed that nitrite (range, 0-20mM) induces formation of S-glutathionyl hemoglobin (HbSSG) at cysteine (Cys) β93 and β112 of oxyhemoglobin (HbO2) in lyzed human RBCs (range, 6-8mM HbO2). Hemoglobin species were isolated from incubation mixtures of nitrite in lyzed RBCs by ultrafiltration or affinity chromatography and analyzed by HPLC and LC-MS/MS. The mechanism likely involves inhibition of catalase activity by nitrite (IC50, 9 μM), which allows H2O2 to accumulate and oxidize Cys moieties of oxyhemoglobin and erythrocytic GSH to form HbSSG in addition to GSSG. In freshly prepared hemolysate samples, nitrite induced release of superoxide and molecular oxygen. In the presence of paracetamol and nitrite in hemolysate samples, 3-nitro-paracetamol was detected. Nitrite also induced S-nitroso hemoglobin (HbSNO) formation in low yield (i.e., 0.1%). Synthetic cysteine (Cys), glutathione (GSH), N-acetylcysteine (NAC) and N-acetylcysteine ethyl ester (NACET) inhibited nitrite-induced modifications of oxyhemoglobin including methemoglobin, HbSSG (CysSH >> NACET >> GSH ≈ NAC; thiol concentration, 50 μM) and HbSNO. Nitrite-induced oxidative modifications may alter physiological hemoglobin functions and may require alternative treatments for conditions associated with oxidized hemoglobin like in nitrite-induced methemoglobinemia. Accumulation of soluble Cys in RBCs via oral administration of NACET could be a new promising strategy to prevent nitrite-induced methemoglobinemia by nitrite and other oxidants.}, }
@article {pmid26828938, year = {2016}, author = {Zheng, X and Wu, J and Shao, Q and Li, X and Kou, J and Zhu, X and Zhong, Z and Jiang, Y and Liu, Z and Li, H and Tian, Y and Yang, L}, title = {Apoptosis of THP-1 Macrophages Induced by Pseudohypericin-Mediated Sonodynamic Therapy Through the Mitochondria-Caspase Pathway.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {38}, number = {2}, pages = {545-557}, doi = {10.1159/000438649}, pmid = {26828938}, issn = {1421-9778}, mesh = {Apoptosis/*drug effects ; Caspases/*metabolism ; Cell Line ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Humans ; Hypericum/chemistry ; Macrophages/*drug effects/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism/pathology ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Perylene/*analogs &amp; derivatives/chemistry/pharmacology ; Plaque, Atherosclerotic/metabolism/pathology/therapy ; Reactive Oxygen Species/metabolism ; Ultrasonic Therapy ; }, abstract = {BACKGROUND/AIMS: Pseudohypericin (P-HY) and its congener hypericin are the major hydroxylated phenanthroperylenediones present in Hypericum species. Our previous study indicated that hypericin was able to function as a sonosensitizer. The potential use of P-HY as a sonosensitizer for sonodynamic therapy (SDT) requires further exploration. Thus, this study aimed to investigate the effects of P-HY-SDT on THP-1 macrophages.<br><br>METHODS: THP-1 macrophages were incubated with P-HY, and cell viability was measured using a CCK-8 assay. Fluorescence microscopy assessed the intracellular reactive oxygen species (ROS), mitochondrial membrane potential (&#x394;&#x3a8;m) and mitochondrial permeability transition pore (mPTP) opening. Apoptotic and necrotic cell levels were measured by the flow cytometry analysis. Western blots were employed to assay BAX, Cytochrome C expression and apoptosis-related proteins.<br><br>RESULTS: P-HY-SDT induced THP-1 macrophage apoptosis. The levels of ROS were significantly increased in the SDT group, resulting in both mPTP opening and &#x394;&#x3a8;m loss, which led to apoptosis. In addition, the translocation of BAX, release of Cytochrome C and the upregulated expression of apoptosis-related proteins after P-HY-SDT were observed, all of which were reversed by N-acetyl cysteine (NAC).<br><br>CONCLUSION: P-HY-SDT induced THP-1 macrophage apoptosis through the mitochondria-caspase pathway via ROS generation, the translocation of BAX and the release of Cytochrome C to regulate the mPTP opening.}, }
@article {pmid26827257, year = {2016}, author = {Bentzley, JP and Tomko, RL and Gray, KM}, title = {Low Pretreatment Impulsivity and High Medication Adherence Increase the Odds of Abstinence in a Trial of N-Acetylcysteine in Adolescents with Cannabis Use Disorder.}, journal = {Journal of substance abuse treatment}, volume = {63}, number = {}, pages = {72-77}, pmid = {26827257}, issn = {1873-6483}, support = {R01 DA026777/DA/NIDA NIH HHS/United States ; R01 DA038700/DA/NIDA NIH HHS/United States ; T32 AA007474/AA/NIAAA NIH HHS/United States ; U01 DA031779/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Female ; Humans ; *Impulsive Behavior ; Male ; Marijuana Abuse/*drug therapy ; Medication Adherence/*psychology ; Young Adult ; }, abstract = {BACKGROUND: In light of recent progress toward pharmacologic interventions to treat adolescent cannabis use disorder, it is important to consider which adolescent characteristics may be associated with a favorable response to treatment. This study presents secondary analyses from a parent randomized controlled trial of N-acetylcysteine (NAC) in adolescents with cannabis use disorder. We hypothesized that high pretreatment impulsivity and medication non-adherence would be associated with reduced abstinence rates.<br><br>METHODS: Participants were treatment-seeking adolescents (N=115) who met criteria for cannabis use disorder and were assessed for pretreatment impulsivity. They received 1200 mg NAC or placebo orally twice daily for 8 weeks. An intent-to-treat analysis using a repeated-measures logistic regression model was used to relate pretreatment impulsivity (Barratt Impulsiveness Scale) and treatment group to abstinence rates, measured by urine cannabinoid tests. To explore mechanisms by which NAC may reduce cannabis use, relationships between impulsivity, adherence, and abstinence were assessed in a second statistical model using data from participants with recorded adherence and urine cannabinoid test results (n=54).<br><br>RESULTS: In the intent-to-treat analysis, low pretreatment impulsivity, NAC treatment, and negative baseline urine cannabinoid test results independently increased the odds of having negative urine cannabinoid tests during treatment (OR=2.1, 2.3, and 5.3 respectively). In the sample of participants with adherence data (n=54), adherence tripled the odds of abstinence. Notably, the effect of adherence on abstinence was only observed in the NAC treatment group. Lastly, although the highly impulsive participants had reduced rates of abstinence, highly impulsive individuals adherent to NAC treatment had increased abstinence rates compared to non-adherent individuals.<br><br>CONCLUSION: Low impulsivity, NAC treatment, medication adherence, and baseline negative cannabinoid testing were associated with increased rates of abstinence in adolescents seeking treatment for cannabis use disorder. Efforts to optimize pharmacotherapy adherence may be particularly crucial for highly impulsive individuals. Understanding and addressing factors, such as impulsivity and adherence, which may affect outcomes, may aid in the successful evaluation and development of potentially promising pharmacotherapies.}, }
@article {pmid26825874, year = {2016}, author = {Abrigo, J and Rivera, JC and Simon, F and Cabrera, D and Cabello-Verrugio, C}, title = {Transforming growth factor type beta (TGF-β) requires reactive oxygen species to induce skeletal muscle atrophy.}, journal = {Cellular signalling}, volume = {28}, number = {5}, pages = {366-376}, doi = {10.1016/j.cellsig.2016.01.010}, pmid = {26825874}, issn = {1873-3913}, mesh = {Animals ; Antioxidants/pharmacology ; Atrophy ; Cell Line ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Fibers, Skeletal/metabolism/ultrastructure ; Muscle Proteins/metabolism ; Muscle, Skeletal/drug effects/*metabolism/pathology/ultrastructure ; NADPH Oxidases/metabolism ; Reactive Oxygen Species/*metabolism ; Transforming Growth Factor beta1/*physiology/toxicity ; Tripartite Motif Proteins/metabolism ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {Transforming growth factor beta 1 (TGF-β1) is a classical modulator of skeletal muscle and regulates several processes, such as myogenesis, regeneration, and muscle function in skeletal muscle diseases. Skeletal muscle atrophy, characterised by the loss of muscle strength and mass, is one of the pathological conditions regulated by TGF-β. Atrophy also results in increased myosin heavy chain (MHC) degradation and the expression of two muscle-specific E3 ubiquitin ligases, atrogin-1 and MuRF-1. Reactive oxygen species (ROS) are modulators of muscle wasting, and NAD(P)H oxidase (NOX) is one of the main sources of ROS. While it was recently found that TGF-β1 induces atrophy in skeletal muscle, the underlying mechanism is not fully understood. In this study, the role of NOX-derived ROS in skeletal muscle atrophy induced by TGF-β was assessed. TGF-β1 induced an atrophic effect in C2C12 myotubes, as evidenced by decreased myotube diameter and MHC levels, together with increased MuRF-1 levels. Concomitantly, TGF-β increased NOX-induced ROS contents. Interestingly, NOX inhibition through apocynin and the antioxidant treatment with N-acetyl cysteine (NAC) decreased increased ROS levels in myotubes. Additionally, both apocynin and NAC completely prevented the decreased MHC, decreased myotube diameter, and increased MuRF-1 induced by TGF-β. Injection of TGF-β1 into the tibialis anterior muscle induced atrophy, as observed by decreased fibre diameter and MHC levels, together with increased MuRF-1 levels. Likewise, TGF-β increased the ROS contents in the smaller fibres of skeletal muscle. Additionally, the administration of NAC to mice prevented all atrophic effects and the increase in ROS induced by TGF-β in the tibialis anterior. This is the first study to report that TGF-β has an atrophic effect dependent on NOX-induced ROS in skeletal muscle.}, }
@article {pmid26822914, year = {2016}, author = {Shukla, PK and Gangwar, R and Manda, B and Meena, AS and Yadav, N and Szabo, E and Balogh, A and Lee, SC and Tigyi, G and Rao, R}, title = {Rapid disruption of intestinal epithelial tight junction and barrier dysfunction by ionizing radiation in mouse colon in vivo: protection by N-acetyl-l-cysteine.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {310}, number = {9}, pages = {G705-15}, pmid = {26822914}, issn = {1522-1547}, support = {R01 CA092160/CA/NCI NIH HHS/United States ; R01 DK055532/DK/NIDDK NIH HHS/United States ; U01 AI107331/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/therapeutic use ; Actin Cytoskeleton/metabolism ; Animals ; Colon/drug effects/metabolism/*radiation effects ; Dietary Supplements ; Female ; Free Radical Scavengers/administration &amp; dosage/pharmacology/*therapeutic use ; Intestinal Absorption ; Intestinal Mucosa/drug effects/metabolism/*radiation effects ; Inulin/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Radiation Injuries/drug therapy/*prevention &amp; control ; *Radiation, Ionizing ; Radiation-Protective Agents/administration &amp; dosage/pharmacology/*therapeutic use ; Sulfhydryl Compounds/metabolism ; Tight Junction Proteins/metabolism ; Tight Junctions/metabolism/*radiation effects ; }, abstract = {The goals of this study were to evaluate the effects of ionizing radiation on apical junctions in colonic epithelium and mucosal barrier function in mice in vivo. Adult mice were subjected to total body irradiation (4 Gy) with or without N-acetyl-l-cysteine (NAC) feeding for 5 days before irradiation. At 2-24 h postirradiation, the integrity of colonic epithelial tight junctions (TJ), adherens junctions (AJ), and the actin cytoskeleton was assessed by immunofluorescence microscopy and immunoblot analysis of detergent-insoluble fractions for TJ and AJ proteins. The barrier function was evaluated by measuring vascular-to-luminal flux of fluorescein isothiocyanate (FITC)-inulin in vivo and luminal-to-mucosal flux in vitro. Oxidative stress was evaluated by measuring protein thiol oxidation. Confocal microscopy showed that radiation caused redistribution of occludin, zona occludens-1, claudin-3, E-cadherin, and β-catenin, as well as the actin cytoskeleton as early as 2 h postirradiation, and this effect was sustained for at least 24 h. Feeding NAC before irradiation blocked radiation-induced disruption of TJ, AJ, and the actin cytoskeleton. Radiation increased mucosal permeability to inulin in colon, which was blocked by NAC feeding. The level of reduced-protein thiols in colon was depleted by radiation with a concomitant increase in the level of oxidized-protein thiol. NAC feeding blocked the radiation-induced protein thiol oxidation. These data demonstrate that radiation rapidly disrupts TJ, AJ, and the actin cytoskeleton by an oxidative stress-dependent mechanism that can be prevented by NAC feeding.}, }
@article {pmid26822174, year = {2016}, author = {Yeh, CC and Ko, HH and Hsieh, YP and Wu, KJ and Kuo, MY and Deng, YT}, title = {Phenethyl isothiocyanate enhances TRAIL-induced apoptosis in oral cancer cells and xenografts.}, journal = {Clinical oral investigations}, volume = {20}, number = {9}, pages = {2343-2352}, pmid = {26822174}, issn = {1436-3771}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cell Line, Tumor ; Cell Survival ; Drug Resistance, Neoplasm ; Heterografts ; Humans ; In Situ Nick-End Labeling ; Isothiocyanates/*pharmacology ; Mice ; Mouth Neoplasms/*drug therapy ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; }, abstract = {OBJECTIVES: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been regarded as a promising candidate for cancer therapy. However, most of oral cancer cell lines are resistant to the TRAIL-induced cytotoxicity. The aim of this study was to investigate the ability of phenethyl isothiocyanate (PEITC) to sensitize TRAIL-induced apoptosis in TRAIL-resistant oral cancer cells and xenografts.<br><br>MATERIALS AND METHODS: Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, Western blotting, and a mouse xenograft model were used to study the effects of PEITC and TRAIL on two TRAIL-resistant human oral cancer cells, SAS and Ca9-22.<br><br>RESULTS: PEITC upregulated death receptor 4 (DR4) and DR5 protein expression and increased reactive oxygen species (ROS) production in both SAS and Ca9-22 cells. Antioxidant N-acetyl-L-cysteine (NAC) and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 inhibited PEITC-induced DR4 and DR5 expression. Inhibitor experiments showed that PEITC induced apoptosis through ROS-mediated JNK activation and upregulation of DR4 and DR5. Furthermore, treatment with PEITC significantly increased TRAIL-induced apoptosis in both cells. Combined treatment with PEITC and TRAIL had greater effect on the inhibition of tumor growth than either agent alone.<br><br>CONCLUSIONS: We showed for the first time that PEITC overcomes TRAIL resistance in oral cancer cells and enhance the therapeutic potential of TRAIL in vivo.<br><br>CLINICAL RELEVANCE: PEITC, either alone or in combination with TRAIL, can be used as a new therapeutic approach for the treatment of oral cancers.}, }
@article {pmid26821200, year = {2016}, author = {Kane, AE and Huizer-Pajkos, A and Mach, J and McKenzie, C and Mitchell, SJ and de Cabo, R and Jones, B and Cogger, V and Le Couteur, DG and Hilmer, SN}, title = {N-Acetyl cysteine does not prevent liver toxicity from chronic low-dose plus subacute high-dose paracetamol exposure in young or old mice.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {30}, number = {3}, pages = {263-275}, pmid = {26821200}, issn = {1472-8206}, support = {Z99 AG999999//Intramural NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*pharmacology/therapeutic use ; Age Factors ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*metabolism/pathology/*prevention &amp; control ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Free Radical Scavengers/pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Random Allocation ; }, abstract = {Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute overexposures. The risk of hepatotoxicity from nonacute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for nonacute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and subacute paracetamol overexposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33 g/kg food) or control diet for 6 weeks. Mice were then dosed orally eight times over 3 days with additional paracetamol (250 mg/kg) or saline, followed by either one or two doses of oral NAC (1200 mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Subacute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from subacute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for subacute paracetamol toxicity.}, }
@article {pmid26820529, year = {2016}, author = {Tsuchiya, H and Hohjoh, H and Fujiwara, Y and Sugimoto, Y and Koshimizu, TA}, title = {Prostaglandin D2 elicits the reversible neurite retraction in hypothalamic cell line.}, journal = {Biochemical and biophysical research communications}, volume = {470}, number = {4}, pages = {804-810}, doi = {10.1016/j.bbrc.2016.01.091}, pmid = {26820529}, issn = {1090-2104}, mesh = {Animals ; Cell Enlargement/*drug effects ; Cell Line ; Dose-Response Relationship, Drug ; Hypothalamus/*cytology/drug effects/*metabolism ; Mice ; Neurites/drug effects/*physiology/ultrastructure ; Prostaglandin D2/*administration &amp; dosage ; Reactive Oxygen Species/*metabolism ; }, abstract = {Prostaglandins (PGs) play important roles in diverse physiological processes in the central nervous system. PGD2 is the most abundant PG in the brain and acts through specific receptors, DP1 and CRTH2. We investigated the effects of PGD2 on the morphology of the hypothalamic cell line mHypoE-N37 (N37). In N37 cells, serum starvation induced neurite outgrowth and PGD2 elicited neurite retraction, although we failed to detect transcripts for DP1 and CRTH2. Such an effect of PGD2 was efficiently mimicked by its metabolite, 15-deoxy-Δ(12,14)-prostaglandin J2. N-acetyl cysteine completely abolished the effect of PGD2, and reactive oxygen species (ROS) were considered to be important. Notably, neurite outgrowth was restored by PGD2 removal. These results suggest that PGD2 induces reversible neurite retraction in a ROS-mediated mechanism that does not involve any known receptor.}, }
@article {pmid26813472, year = {2016}, author = {Erdil, N and Eroglu, T and Akca, B and Disli, OM and Yetkin, O and Colak, MC and Erdil, F and Battaloglu, B}, title = {The effects of N-acetylcysteine on pulmonary functions in patients undergoing on-pump coronary artery surgery: a double blind placebo controlled study.}, journal = {European review for medical and pharmacological sciences}, volume = {20}, number = {1}, pages = {180-187}, pmid = {26813472}, issn = {2284-0729}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Blood Gas Analysis ; Cardiopulmonary Bypass/*adverse effects ; Coronary Artery Bypass/*adverse effects ; Coronary Artery Disease/*surgery ; Double-Blind Method ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Lung Diseases/diagnosis/etiology/*prevention &amp; control ; Male ; Middle Aged ; Prospective Studies ; Respiratory Function Tests ; }, abstract = {OBJECTIVE: To investigate the effects of N-acetylcysteine (NAC) on pulmonary function tests and arterial blood gases in patients undergoing on-pump coronary artery surgery.<br><br>PATIENTS AND METHODS: The effect of NAC was assessed within the scope of a prospective, single center, double-blind, placebo-controlled, parallel group study. Eighty-two patients undergoing coronary artery bypass grafting were randomized into two groups to receive either placebo (group 1, n = 40) or NAC (group 2, n=42). Both the NAC group and the placebo-receiving control group also included a COPD subgroup consisting of patients with an FEV1/FVC ratio of < 0.7 and an FEV1 value of 50-80%. Pulmonary function tests were performed preoperatively and on postoperative day 60.<br><br>RESULTS: Both groups were similar with respect to age, gender, preoperative risk factors, ejection fraction (EF), mean cross-clamp time, ventilation time, intensive care unit (ICU) stay, atrial fibrillation (AF) and hospital stay (p > 0.05). Postoperative FVC and FEV1 values in group 1 and the postoperative FEV1, FEV1/FVC and FEF 25-75 values in group 2 were lower in comparison to their preoperative values. However, in both group 1 and 2, the decreases observed in these parameters were not statistically significant (p > 0.05). In the COPD subgroup of group 1, a postoperative decrease was observed in the FEV1 and FEF25-75 values, with the FEV1 decreasing by 4.55%, and the FEF25-75 decreasing by 4.2% (p < 0.05). In the COPD subgroup of group 2, no significant decrease was observed in the pulmonary function test values (p > 0.05).<br><br>CONCLUSIONS: This study demonstrated that NAC administration in COPD patients undergoing on-pump coronary artery surgery resulted in the preservation of pulmonary functions.}, }
@article {pmid26812248, year = {2016}, author = {Okamura, AM and Gomes, PX and de Oliveira, GV and de Araújo, FY and Tomaz, VS and Chaves Filho, AJ and de Sousa, FC and Vasconcelos, SM and de Lucena, DF and Macêdo, D}, title = {N-acetylcysteine attenuates nicotine-induced kindling in female periadolescent rats.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {67}, number = {}, pages = {58-65}, doi = {10.1016/j.pnpbp.2016.01.010}, pmid = {26812248}, issn = {1878-4216}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dose-Response Relationship, Drug ; Drug Interactions ; Estradiol/blood ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Kindling, Neurologic/*drug effects ; Lipid Peroxidation/drug effects ; Nicotine/*pharmacology ; Nicotinic Agonists/*pharmacology ; Nitrites/metabolism ; Rats ; Rats, Wistar ; Statistics, Nonparametric ; Superoxide Dismutase/metabolism ; }, abstract = {Kindling is a form of behavioral sensitization that is related to the progression of several neuropsychiatric disorders such as bipolar disorder. We recently demonstrated that female periadolescent rats are more vulnerable to nicotine (NIC)-induced kindling than their male counterparts. Furthermore, we evidenced that decreases in brain antioxidative defenses may contribute to this gender difference. Here we aimed to determine the preventive effects of the antioxidant N-acetyl cysteine (NAC) against NIC-kindling in female periadolescent rats. To do this female Wistar rats at postnatal day 30 received repeated injections of NIC 2mg/kg, i.p. every weekday for up to 19 days. NAC90, 180 or 270 mg/kg, i.p. was administered 30 min before NIC. The levels of glutathione (GSH), superoxide dismutase (SOD) activity, lipid peroxidation (LP) and nitrite were determined in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). The development of kindling occurred at a median time of 16.5 days with 87.5% of NIC animals presenting stage 5 seizures in the last day of drug administration. NAC270 prevented the occurrence of kindling. NIC-kindled animals presented decreased levels of GSH and increased LP in the PFC, HC and ST, while SOD activity was decreased in the ST. NAC180 or 270 prevented the alterations in GSH induced by NIC, but only NAC270 prevented the alterations in LP. Nitrite levels increased in the ST of NAC270 pretreated NIC-kindled animals. Taken together we demonstrated that NAC presents anti-kindling effects in female animals partially through the restoration of oxidative alterations.}, }
@article {pmid26811594, year = {2015}, author = {Singh, R and Shah, R and Turner, C and Regueira, O and Vasylyeva, TL}, title = {N-acetylcysteine renoprotection in methotrexate induced nephrotoxicity and its effects on B-cell lymphoma.}, journal = {Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical &amp; Paediatric Oncology}, volume = {36}, number = {4}, pages = {243-248}, pmid = {26811594}, issn = {0971-5851}, abstract = {BACKGROUND: Nephrotoxicity is one of the known side effects of methotrexate (MTX) therapy despite the use of conventional protective measures. Our objectives were to evaluate the effects of N-acetylcysteine (NAC) on MTX-induced toxicity in renal tubular cells and to evaluate whether adjunctive use of NAC interferes with MTX antitumor activity in the B-cell lymphoma.<br><br>METHODS: Kidney Epithelial (Madin-Darby canine kidney [MDCK]) cells were exposed to MTX (10 &#x3bc;M or 100 &#x3bc;M) alone and with NAC (0.2 mM or 0.4 mM). Reactive oxygen species (ROS) generation at 1, 2, 4, and 24 h was measured by flow cytometer. Quantification of total glutathione (GSH) was performed by using GSH assay kit. To measure the impact of NAC on the antitumor activity of MTX, B lymphoma cells were exposed to MTX alone and with NAC. A percentage of apoptosis was measured using fluorescein isothiocyanate in both cell lines. Quantitative data was presented as a means &#xb1; standard deviation, and P values were analyzed using the Student's t-test.<br><br>RESULTS: Apoptosis in MDCK cells were observed after 24 h of incubation with both 10 &#x3bc;M and 100 &#x3bc;M MTX. Maximum ROS generation was observed at 4 h and corresponded to GSH production. Treatment with 0.2 and 0.4 mM of NAC led to decrease percentages of apoptotic MDCK cells. NAC did not change either proliferation or apoptosis of B-cell lymphoma.<br><br>CONCLUSION: Using NAC for kidney protection may not interfere with the antitumor activity of MTX. Further in vivo studies are warranted to confirm noninterference between MTX and NAC and assess synergistic antitumor effects.}, }
@article {pmid26809688, year = {2016}, author = {Martínez, I and García-Carpizo, V and Guijarro, T and García-Gomez, A and Navarro, D and Aranda, A and Zambrano, A}, title = {Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus.}, journal = {Virulence}, volume = {7}, number = {4}, pages = {427-442}, pmid = {26809688}, issn = {2150-5608}, mesh = {A549 Cells ; Acetylcysteine/pharmacology ; Animals ; Cell Line ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/genetics ; Cyclin-Dependent Kinase Inhibitor p18/genetics ; *DNA Breaks, Double-Stranded ; DNA Damage/*genetics ; Glutathione/analogs &amp; derivatives/pharmacology ; Histones/genetics ; *Host-Pathogen Interactions/genetics ; Humans ; Mice ; Oxidative Stress/genetics ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/virology ; Respiratory Syncytial Virus Infections/virology ; Respiratory Syncytial Virus, Human/*physiology ; }, abstract = {Human respiratory syncytial virus (HRSV) accounts for the majority of lower respiratory tract infections during infancy and childhood and is associated with significant morbidity and mortality. HRSV provokes a proliferation arrest and characteristic syncytia in cellular systems such as immortalized epithelial cells. We show here that HRSV induces the expression of DNA damage markers and proliferation arrest such as P-TP53, P-ATM, CDKN1A and γH2AFX in cultured cells secondary to the production of mitochondrial reactive oxygen species (ROS). The DNA damage foci contained γH2AFX and TP53BP1, indicative of double-strand breaks (DSBs) and could be reversed by antioxidant treatments such as N-Acetylcysteine (NAC) or reduced glutathione ethyl ester (GSHee). The damage observed is associated with the accumulation of senescent cells, displaying a canonical senescent phenotype in both mononuclear cells and syncytia. In addition, we show signs of DNA damage and aging such as γH2AFX and CDKN2A expression in the respiratory epithelia of infected mice long after viral clearance. Altogether, these results show that HRSV triggers a DNA damage-mediated cellular senescence program probably mediated by oxidative stress. The results also suggest that this program might contribute to the physiopathology of the infection, tissue remodeling and aging, and might be associated to long-term consequences of HRSV infections.}, }
@article {pmid26809061, year = {2016}, author = {Lee, YJ and Lim, SS and Baek, BJ and An, JM and Nam, HS and Woo, KM and Cho, MK and Kim, SH and Lee, SH}, title = {Nickel(II)-induced nasal epithelial toxicity and oxidative mitochondrial damage.}, journal = {Environmental toxicology and pharmacology}, volume = {42}, number = {}, pages = {76-84}, doi = {10.1016/j.etap.2016.01.005}, pmid = {26809061}, issn = {1872-7077}, mesh = {Acetylcysteine ; Annexin A5/metabolism ; Apoptosis ; Caspase 3/metabolism ; Cell Cycle/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Down-Regulation ; Hazardous Substances/*toxicity ; Nasal Mucosa/*drug effects/physiology ; Nickel/*toxicity ; Oxidative Stress ; Phosphorylation ; Signal Transduction ; Up-Regulation ; }, abstract = {In probing the underlying mechanisms of nickel(II)-induced cytotoxicity on nasal epithelium, we investigated the effects of nickel(II) acetate on nasal epithelial RPMI-2650 cells. Nickel(II) elicited apoptosis, as signified by pyknotic and fragmented nuclei, increased caspase-3/7 activity, and an increase in annexin V binding, hypodiploid DNA, and Bax/Bcl-2 protein ratio. Nickel(II)-induced G2/M arrest was associated with up-regulation of p21(WAF1/CIP1) expression, decrease in phosphorylation at Thr(161) of Cdc2, and down-regulation of cyclin B1. Associated with these responses, ROS generation and mitochondrial depolarization increased in a nickel(II) concentration-dependent fashion. Pretreatment with N-acetylcysteine (NAC) attenuated these changes. p53 reporter gene assay and analyses of p53, Puma, Bax, and Bcl-2 protein levels indicated that NAC inhibited nickel(II)-induced activation of p53-mediated mitochondrial apoptotic pathway. Collectively, our study provides evidences that nickel(II) may induce oxidative damage on nasal epithelium in which antioxidant NAC protects cells against nickel(II)-induced apoptosis through the prevention of oxidative stress-mediated mitochondrial damage.}, }
@article {pmid26808507, year = {2016}, author = {Jiao, Y and Ma, S and Wang, Y and Li, J and Shan, L and Liu, Q and Liu, Y and Song, Q and Yu, F and Yu, H and Liu, H and Huang, L and Chen, J}, title = {N-Acetyl Cysteine Depletes Reactive Oxygen Species and Prevents Dental Monomer-Induced Intrinsic Mitochondrial Apoptosis In Vitro in Human Dental Pulp Cells.}, journal = {PloS one}, volume = {11}, number = {1}, pages = {e0147858}, pmid = {26808507}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Dental Pulp/cytology/metabolism/*pathology ; Humans ; In Vitro Techniques ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {PURPOSE: To investigate the involvement of intrinsic mitochondrial apoptosis in dental monomer-induced cytotoxicity and the influences of N-acetyl cysteine (NAC) on this process.<br><br>METHODS: Human dental pulp cells (hDPCs) were exposed to several dental monomers in the absence or presence of NAC, and cell viability, intracellular redox balance, morphology and function of mitochondria and key indicators of intrinsic mitochondrial apoptosis were evaluated using various commercial kits.<br><br>RESULTS: Dental monomers exerted dose-dependent cytotoxic effects on hDPCs. Concomitant to the over-production of reactive oxygen species (ROS) and depletion of glutathione (GSH), differential changes in activities of superoxide dismutase, glutathione peroxidase, and catalase were detected. Apoptosis, as indicated by positive Annexin V/propidium iodide (PI) staining and activation of caspase-3, was observed after dental monomer treatment. Dental monomers impaired the morphology and function of mitochondria, and induced intrinsic mitochondrial apoptosis in hDPCs via up-regulation of p53, Bax and cleaved caspase-3, and down-regulation of Bcl-2. NAC restored cell viability, relieved oxidative stress and blocked the apoptotic effects of dental monomers.<br><br>CONCLUSIONS: Dental monomers induced oxidative stress and mitochondrial intrinsic apoptosis in hDPCs. NAC could reduce the oxidative stress and thus protect hDPCs against dental monomer-induced apoptosis.}, }
@article {pmid26805894, year = {2016}, author = {Menon, S and Lu, C and Menon, R and Schwartz, J and Guan, Y}, title = {Effects of Antioxidants in Human Cancers: Differential Effects on Non-Coding Intronic RNA Expression.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {5}, number = {1}, pages = {}, pmid = {26805894}, issn = {2076-3921}, abstract = {The notion that dietary antioxidants can help fight cancer is popular. However, the mechanism(s) behind the effect of antioxidants in cancer is still unclear. Previous studies indicate that supplements can influence gene expression; however, all of these studies were focused on the coding/exonic gene expression. Studies are now emerging to highlight critical functional roles for RNAs expressed from the non-coding regions. This project was designed to study the effect of antioxidant supplements on non-coding intronic RNA expression in human cancers. Vitamin E, N-Acetyl cysteine (NAC) and Sulforaphane are commonly used supplements to prevent diseases including cancers. We studied the effect of these antioxidant supplements on the non-coding intronic RNA expression using publicly available datasets from a mouse model for lung cancer and prostate cancer cell lines. Although high throughput polyA-enriched RNA-Seq data characterize spliced coding mRNA regions, recent studies reveal the expression of reads from the non-coding intronic regions. Our analyses indicate that cancer cells have higher expression of introns compared to that of normal cells and that treatment with antioxidant supplements reduces the increased expression of introns of several genes. However, we did find high expression of introns of multiple genes including many oncogenes in the supplement treated groups compared to that of the control; this effect was distinct depending on the cell type and the supplement studied. Using RT-PCRs, we validated the expression of introns of two oncogenes, DLK1 and LRG1, known to be key players in lung cancer progression, and demonstrate changed intronic expression with supplement treatment in cancer cells. With regard to the antioxidant system, supplements did not change the intronic RNAs for endogenous antioxidant enzymes except for a significant decrease in the expression of superoxide dismutase (SOD) intronic RNA. Concurrently, we also found that a prolonged (48 h) exposure to Vitamin C, Vitamin E and Green tea extract reduced the enzymatic activity of SOD in lung cancer cells. The results from this study reveal that the antioxidant supplements have a significant effect on the intronic RNA expression of many genes including cancer genes that are not directly linked to the body's antioxidant system. It is important to study this novel effect of antioxidant supplements in detail as it may have a significant role in disease progression.}, }
@article {pmid26803479, year = {2016}, author = {Kosten, L and Verhaeghe, J and Verkerk, R and Thomae, D and De Picker, L and Wyffels, L and Van Eetveldt, A and Dedeurwaerdere, S and Stroobants, S and Staelens, S}, title = {Multiprobe molecular imaging of an NMDA receptor hypofunction rat model for glutamatergic dysfunction.}, journal = {Psychiatry research. Neuroimaging}, volume = {248}, number = {}, pages = {1-11}, doi = {10.1016/j.pscychresns.2016.01.013}, pmid = {26803479}, issn = {1872-7506}, mesh = {Animals ; Brain/drug effects/*metabolism ; Disease Models, Animal ; Dizocilpine Maleate/administration &amp; dosage/*pharmacology ; Excitatory Amino Acid Antagonists/administration &amp; dosage/*pharmacology ; Glutamic Acid/*metabolism ; Kynurenine/*metabolism ; Male ; Molecular Imaging ; Positron-Emission Tomography/methods ; Rats ; Rats, Sprague-Dawley ; Receptor, Metabotropic Glutamate 5/*metabolism ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Schizophrenia/*metabolism ; Tryptophan/*metabolism ; }, abstract = {There are many indications of a connection between abnormal glutamate transmission through N-methyl-d-aspartate (NMDA) receptor hypofunction and the occurrence of schizophrenia. The importance of metabotropic glutamate receptor subtype 5 (mGluR5) became generally recognized due to its physical link through anchor proteins with NMDAR. Neuroinflammation as well as the kynurenine (tryptophan catabolite; TRYCAT) pathway are equally considered as major contributors to the pathology. We aimed to investigate this interplay between glutamate release, neuronal activation and inflammatory markers, by using small-animal positron emission tomography (PET) in a rat model known to induce schizophrenia-like symptoms. Daily intraperitoneal injection of MK801 or saline were administered to induce the model together with N-Acetyl-cysteine (NAc) or saline as the treatment in 24 male Sprague Dawley rats for one month. Biweekly in vivo [(11)C]-ABP688 microPET was performed together with mGluR5 immunohistochemistry. Simultaneously, weekly in vivo [(18)F]-FDG microPET imaging data for glucose metabolism was acquired and microglial activation was investigated with biweekly in vivo [(18)F]-PBR111 scans versus OX42 immunohistochemistry. Finally, plasma samples were analyzed for TRYCAT metabolites. We show that chronic MK801 administration (and thus elevated endogenous glutamate) causes significant tissue loss in rat brain, enhances neuroinflammatory pathways and may upregulate mGluR5 expression.}, }
@article {pmid26801986, year = {2016}, author = {Palabiyik, SS and Karakus, E and Halici, Z and Cadirci, E and Bayir, Y and Ayaz, G and Cinar, I}, title = {The protective effects of carvacrol and thymol against paracetamol-induced toxicity on human hepatocellular carcinoma cell lines (HepG2).}, journal = {Human &amp; experimental toxicology}, volume = {35}, number = {12}, pages = {1252-1263}, doi = {10.1177/0960327115627688}, pmid = {26801986}, issn = {1477-0903}, mesh = {Acetaminophen/*toxicity ; Anti-Inflammatory Agents/administration &amp; dosage/*pharmacology ; Antioxidants/administration &amp; dosage/*pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cymenes ; Cytokines/genetics/metabolism ; Dose-Response Relationship, Drug ; Drug Synergism ; Gene Expression/drug effects ; Hep G2 Cells ; Humans ; Monoterpenes/administration &amp; dosage/*pharmacology ; Oxidative Stress/drug effects ; Thymol/administration &amp; dosage/*pharmacology ; }, abstract = {Acetaminophen (APAP) overdose could induce liver damage and lead to acute liver failure. The treatment of APAP overdoses could be improved by new therapeutic strategies. Thymus spp., which has many beneficial effects and has been used in folk medicine, is one such potential strategy. In the present study, the hepatoprotective activity of the main constituents of Thymus spp., carvacrol and thymol, were evaluated in light of APAP-induced hepatotoxicity. We hoped to understand the hepatoprotective mechanism of these agents on the antioxidant system and pro-inflammatory cytokines in vitro. Dose-dependent effects of thymol and carvacrol (25, 50, and 100 µM) were tested on cultured HepG2 cells. N-Acetylcysteine (NAC) was tested as positive control. We showed that APAP inhibited HepG2 cell growth by inducing inflammation and oxidative stress. Incubating APAP-exposed HepG2 cells with carvacrol and thymol for 24 h ameliorated this inflammation and oxidative stress. We also evaluated alanine transaminase and lactate dehydrogenase levels of HepG2 cells. We found that thymol and carvacrol protected against APAP-induced toxicity in HepG2 cells by increasing antioxidant activity and reducing pro-inflammatory cytokines, such as tumor necrosis factor α and interleukin 1β. Taking together high-dose thymol and carvacrol treatment has an effect close to NAC treatment in APAP toxicity, but thymol has better treatment effect than carvacrol.}, }
@article {pmid26799635, year = {2017}, author = {Heywood, HK and Lee, DA}, title = {Bioenergetic reprogramming of articular chondrocytes by exposure to exogenous and endogenous reactive oxygen species and its role in the anabolic response to low oxygen.}, journal = {Journal of tissue engineering and regenerative medicine}, volume = {11}, number = {8}, pages = {2286-2294}, pmid = {26799635}, issn = {1932-7005}, support = {/WT_/Wellcome Trust/United Kingdom ; 080440/WT_/Wellcome Trust/United Kingdom ; R339/0214/DMT_/The Dunhill Medical Trust/United Kingdom ; }, mesh = {Animals ; *Cartilage, Articular/cytology/metabolism ; Cattle ; Cell Hypoxia/drug effects ; *Cellular Reprogramming Techniques ; *Chondrocytes/cytology/metabolism ; *Energy Metabolism ; *Reactive Oxygen Species/metabolism/pharmacology ; }, abstract = {Monolayer culture is integral to many cell-based cartilage repair strategies, but chondrocytes lose regenerative potential with increasing duration in vitro. This coincides with elevated reactive oxygen species (ROS) levels and a bioenergetic transformation characterized by increasing mitochondrial function. This study investigates ROS as stimuli for bioenergetic reprogramming and the effect of antioxidants on the propensity of chondrocytes to regenerate a cartilaginous matrix. Articular chondrocytes were cultured in monolayer under a 2% O2 atmosphere. Oxidative stress was increased using 50 μm H2 O2 or a 20% O2 culture atmosphere, or decreased using the antioxidant N-acetyl-cysteine (NAC). Mitochondrial function was characterized using 200 nm Mitotracker green and an oxygen biosensor. After two population doublings ± NAC, chondrocytes were encapsulated in alginate beads (1 × 10[7] cells/ml) for an additional 10 days before DMB assay of glycosaminoglycan content. The beads were cultured under both 20% O2 and the more physiological 5% O2 condition. Chondrocytes expanded in 20% O2 exhibited elevated mitochondrial mass and functional capacity, which was partially mimicked by the exogenous ROS, H2 O2 . Oligomycin treatment revealed that the increased oxygen consumption was coupled to oxidative phosphorylation. NAC limited these markers of bioenergetic reprogramming during culture-expansion with no significant effect on subsequent GAG production under 20% O2 . However, NAC treatment in monolayer abolished the hypoxic induction of GAG in alginate beads. This supports the hypothesis of a causal relationship between exposure to ROS and acquired mitochondrial function in chondrocytes. Additionally, mitochondrial function may be required for the hypoxic induction of GAG synthesis by chondrocytes. © 2015 The Authors. Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley &amp; Sons, Ltd.}, }
@article {pmid26798412, year = {2016}, author = {Wu, H and Li, R and Wei, ZH and Zhang, XL and Chen, JZ and Dai, Q and Xie, J and Xu, B}, title = {Diabetes-Induced Oxidative Stress in Endothelial Progenitor Cells May Be Sustained by a Positive Feedback Loop Involving High Mobility Group Box-1.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {1943918}, pmid = {26798412}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood Glucose/metabolism ; Body Weight/drug effects ; Bone Marrow Cells/drug effects/pathology ; Cells, Cultured ; Diabetes Mellitus, Experimental/*pathology ; Endothelial Progenitor Cells/drug effects/metabolism/*pathology ; *Feedback, Physiological ; Glycation End Products, Advanced/metabolism ; Glycyrrhizic Acid/pharmacology ; HMGB1 Protein/blood/*metabolism ; Male ; Mice, Inbred C57BL ; Models, Biological ; Monocytes/pathology ; *Oxidative Stress/drug effects ; Shc Signaling Adaptor Proteins/metabolism ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; Up-Regulation/drug effects ; }, abstract = {Oxidative stress is considered to be a critical factor in diabetes-induced endothelial progenitor cell (EPC) dysfunction, although the underlying mechanisms are not fully understood. In this study, we investigated the role of high mobility group box-1 (HMGB-1) in diabetes-induced oxidative stress. HMGB-1 was upregulated in both serum and bone marrow-derived monocytes from diabetic mice compared with control mice. In vitro, advanced glycation end productions (AGEs) induced, expression of HMGB-1 in EPCs and in cell culture supernatants in a dose-dependent manner. However, inhibition of oxidative stress with N-acetylcysteine (NAC) partially inhibited the induction of HMGB-1 induced by AGEs. Furthermore, p66shc expression in EPCs induced by AGEs was abrogated by incubation with glycyrrhizin (Gly), while increased superoxide dismutase (SOD) activity in cell culture supernatants was observed in the Gly treated group. Thus, HMGB-1 may play an important role in diabetes-induced oxidative stress in EPCs via a positive feedback loop involving the AGE/reactive oxygen species/HMGB-1 pathway.}, }
@article {pmid26794940, year = {2016}, author = {Miles, KB and Ball, RL and Matthew, HW}, title = {Chitosan films with improved tensile strength and toughness from N-acetyl-cysteine mediated disulfide bonds.}, journal = {Carbohydrate polymers}, volume = {139}, number = {}, pages = {1-9}, doi = {10.1016/j.carbpol.2015.11.052}, pmid = {26794940}, issn = {1879-1344}, mesh = {Acetylcysteine/*chemistry ; Chitosan/*analogs &amp; derivatives/chemistry ; Crystallization ; Disulfides/chemistry ; Elastic Modulus ; Hydrogen-Ion Concentration ; Tensile Strength ; Tissue Engineering ; }, abstract = {To improve the mechanical properties of chitosan (Ct) materials without the use of cytotoxic crosslinkers, disulfide cross-linkable Ct was synthesized by grafting N-acetyl-cysteine (NAC) to Ct using carbodiimide chemistry. Cast films of NAC-Ct conjugates were prepared with degrees of substitution (DS) of 0%, 6%, 15%, and 20%, and the disulfide bond formation was induced by increasing the reaction media pH to 11. The tensile strength, breaking strain, elastic moduli and toughness of disulfide cross-linked polymers were analyzed by monotonic tensile testing of hydrated NAC-Ct films. Crystallinity was determined via XRD. Results demonstrated that NAC incorporation and crosslinking in chitosan produced tougher polymer films with 4-fold higher tensile strength (10 MPa) and 6-fold greater elongation (365%), but reduced crystallinity, compared to unmodified chitosan. The resilience of NAC-Ct films was evaluated by cyclic testing, and results demonstrate that increasing NAC content produced a more resilient material that dissipated less energy when deformed. These improved mechanical properties broaden chitosan's applicability towards the construction of mechanically robust implantable scaffolds for tissue regeneration.}, }
@article {pmid26794139, year = {2016}, author = {Pati, R and Das, I and Mehta, RK and Sahu, R and Sonawane, A}, title = {Zinc-Oxide Nanoparticles Exhibit Genotoxic, Clastogenic, Cytotoxic and Actin Depolymerization Effects by Inducing Oxidative Stress Responses in Macrophages and Adult Mice.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {150}, number = {2}, pages = {454-472}, doi = {10.1093/toxsci/kfw010}, pmid = {26794139}, issn = {1096-0929}, mesh = {Actin Depolymerizing Factors/*genetics ; Animals ; Cell Culture Techniques ; Cell Cycle/drug effects ; Cell Line ; Cell Movement/drug effects ; Cell Survival/drug effects ; Chromosomal Instability/drug effects ; Comet Assay ; *DNA Damage ; Dose-Response Relationship, Drug ; Macrophages/*drug effects/enzymology/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; Micronuclei, Chromosome-Defective/chemically induced ; Mutagens/*toxicity ; Nanoparticles/chemistry/*toxicity ; Oxidative Stress/*drug effects/genetics ; Zinc Oxide/chemistry/*toxicity ; }, abstract = {Zinc oxide nanoparticles (ZnO-NPs) have wide biological applications, which have raised serious concerns about their impact on the health and environment. Although, various studies have shown ZnO-NP toxicity on different cells underin vitroconditions, sufficient information is lacking regarding toxicity and underlying mechanisms underin vivoconditions. In this work, we investigated genotoxic, clastogenic, and cytotoxic effects of ZnO-NPs on macrophages and in adult mice. ZnO-NP-treated mice showed signs of toxicity such as loss in body weight, passive behavior and reduced survival. Further mechanistic studies revealed that administration of higher dose caused severe DNA damage in peripheral blood and bone marrow cells as evident by the formation of COMET tail, micronuclei, chromosomal fragmentation, and phosphorylation of H2A histone family member X. Moreover, ZnO-NPs inhibited DNA repair mechanism by downregulating the expression offen-1andpolBproteins. Histopathological examinations showed severe inflammation and damage to liver, lungs, and kidneys. Cell viability and wound healing assays revealed that ZnO-NPs killed macrophages in a dose-dependent manner, caused severe wounds and inhibited cellular migration by irreversible actin depolymerization and degradation. Reduction in the viability of macrophages was due to the arrest of the cell cycle at the G0/G1 phase, inhibition of superoxide dismutase and catalase and eventually reactive oxygen species. Furthermore, treatment with an antioxidant drug N-acetyl cysteine significantly reduced the ZnO-NP induced genotoxicity bothin vitroandin vivo Altogether, this study gives detailed pathological insights of ZnO-NP that impair cellular functions, thus will enable to arbitrate their biological applications.}, }
@article {pmid26792818, year = {2016}, author = {Wang, K and Wang, H and Peng, Y and Zheng, J}, title = {Identification of Epoxide-Derived Metabolite(s) of Benzbromarone.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {44}, number = {4}, pages = {607-615}, doi = {10.1124/dmd.115.066803}, pmid = {26792818}, issn = {1521-009X}, mesh = {Animals ; Benzbromarone/chemistry/*metabolism ; Epoxy Compounds/chemistry/*metabolism ; Humans ; Male ; Mice ; Microsomes, Liver/metabolism ; Uricosuric Agents/chemistry/*metabolism ; }, abstract = {Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury. BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate. The present study reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR. The NAC conjugate was identified as 6-NAC BBR. Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR.}, }
@article {pmid26792697, year = {2016}, author = {Cao, XL and Zhao, MF and Li, DG and Xing, Y and Zhang, YC and Chen, J and He, XY and Cui, R and Meng, JX and Xiao, X and Mu, J and Jiang, YY and Wu, RM}, title = {[Establishment of macrophage model of iron overload in vitro and the injury induced by oxidative stress on macrophage with iron overload].}, journal = {Zhonghua yi xue za zhi}, volume = {96}, number = {2}, pages = {129-133}, doi = {10.3760/cma.j.issn.0376-2491.2016.02.012}, pmid = {26792697}, issn = {0376-2491}, mesh = {Acetylcysteine ; Antioxidants ; Down-Regulation ; Ferric Compounds ; Humans ; Iron ; *Iron Overload ; *Macrophages ; *Oxidative Stress ; Phosphatidylinositol 3-Kinases ; Quaternary Ammonium Compounds ; Reactive Oxygen Species ; Signal Transduction ; }, abstract = {OBJECTIVE: To establish macrophage iron overload model in vitro by co-culture macrophages with iron, and to explore the effect of iron overload on cell reactive oxygen species (ROS) and the impact of ROS on macrophages.<br><br>METHOD: Iron overload group were treated with different concentrations (0, 5, 10, 20, 40, 80 &#x3bc;mol/L respectively) of ferric ammonium citrate (FAC). The control group was the group of macrophages without FAC treatment. We detected the number and state of cells, metabolic activity, the change of phagocytosis, the levels of ROS and reactive nitrogen, and changes of related oxidative stress signaling pathways in different groups. Changes in the above indexes were detected after application of deferasirox (DFX) to remove iron and the antioxidant N -acetylcysteine (NAC) to clear excess oxidative stress.<br><br>RESULTS: (1)The levels of labile iron pool (LIP) in macrophages co-cultivated with iron was increased with the increase of iron concentration in a dose-dependent manner. The LIP levels was the highest in the macrophages treated with 80 &#x3bc;mol/L. (2)The increase of FAC concentration, the metabolic activity of macrophages in the 5 FAC-treated groups decreased to 51.58%, 40.98%, 16.23%, 3.46%, and 0.05% of the activity level of the control group (all P< 0.05). The group with the metabolic activity decreased to 16.23% (20 &#x3bc;mol/L) was selected as the iron overload group for the following experiments. (3)Compared with the control group, the number of macrophages in the iron overload group reduced to 32.80% (P<0.05), and the state of cells changed from adherence to partial suspension. The phagocytosis of macrophages in the iron overload group reduced to 20.40% of the control group (P<0.05). (4)Our further experiment showed that the levels of ROS and the activity nitrogen in the iron overload group increased by 7.71-and 1.45-fold compared with the control group (both P<0.05). The RT-PCR showed up-regulated mRNA expression of genes related with ROS production, i. e. nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX 4) gene related with ROS production and inducible nitric oxide synthase (iNOS) gene related with reactive nitrogen production, down-regulated mRNA expression of glutathione peroxidase 1 (GPX1) gene which participated in ROS clearance. Moreover, mRNA expression of phosphatidylinositol-3-kinase (PI3K) gene involved in oxidative stress signaling pathway in the iron overload group was up-regulated, while fork head protein O3 (FOXO3) which regulated oxidative stress through negative feedback showed a down-regulation level of mRNA expression compared with the control group. (5)After iron chelation and antioxidant treatment, the above-mentioned damage in the iron overload group were partially reversed.<br><br>CONCLUSIONS: The damages of iron overload on macrophages may be mediated by inducing oxidative stress and activating oxidative stress signaling pathways. Our established model provides a method to explore the mechanism of iron overload on macrophage, and may shed some new light on possible therapeutic target in treating iron overload patients.}, }
@article {pmid26787572, year = {2016}, author = {Shahbazian, H and Shayanpour, S and Ghorbani, A}, title = {Evaluation of administration of oral N-acetylcysteine to reduce oxidative stress in chronic hemodialysis patients: A double-blind, randomized, controlled clinical trial.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {27}, number = {1}, pages = {88-93}, doi = {10.4103/1319-2442.174084}, pmid = {26787572}, issn = {1319-2442}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage ; Humans ; Kidney Failure, Chronic/metabolism/*therapy ; Male ; Oxidative Stress/*drug effects ; Prospective Studies ; *Renal Dialysis ; Time Factors ; Treatment Outcome ; }, abstract = {This study was designed to assess the efficacy of N-acetylcysteine (NAC) on the reduction of oxidative stress in chronic hemodialysis (HD) patients through measurement of total serum anti-oxidant capacity. In this randomized, double-blind, controlled clinical trial, the efficacy and safety of NAC in reduction of oxidative stress was evaluated in 40 chronic HD patients. The study was conducted at the HD Department of the Golestan Hospital, Ahvaz, Iran. Data were analyzed using SPSS version 19. Paired samples test showed that the mean score of the serum level of total anti-oxidant capacity (TAC) increased from 26.39±17.03 to 33.26±18.8 (Pvalue=0.01) and from 24.02±16.47 to 25.38±17.04 (P=0.1) in the NAC and placebo groups, respectively. Difference in the mean TAC changes between groups was statistically significant (P=0.042). In our study, NAC administration could reduce oxidative stress in chronic HD patients. No major side-effects were observed.}, }
@article {pmid26787567, year = {2016}, author = {Habib, M and Hillis, A and Hammad, A}, title = {N-acetylcysteine and/or ascorbic acid versus placebo to prevent contrast-induced nephropathy in patients undergoing elective cardiac catheterization: The NAPCIN trial; A single-center, prospective, randomized trial.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {27}, number = {1}, pages = {55-61}, doi = {10.4103/1319-2442.174072}, pmid = {26787567}, issn = {1319-2442}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Antioxidants/administration &amp; dosage ; Ascorbic Acid/*administration &amp; dosage ; *Cardiac Catheterization ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Free Radical Scavengers/administration &amp; dosage ; Humans ; Kidney Diseases/chemically induced/metabolism/*prevention &amp; control ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; }, abstract = {Several protective measures have been described to prevent contrast-induced nephropathy (CIN). This study is aimed to evaluate the effect of a high dose of N-acetylcysteine (NAC) plus hydration, a low dose of NAC plus ascorbic acid and hydration or hydration alone on the prevention of CIN in high-risk patients undergoing elective coronary artery intervention. We conducted a randomized, prospective, placebo-controlled trial of 105 high-risk patients undergoing elective cardiac catheterization. The patients were divided into three different groups: Group A (n=30), NAC 1200 mg orally before angiography and 1200 mg orally twice daily for three doses along with good hydration; Group B (n=30), NAC 600 mg before angiography and 600 mg orally twice daily for three doses plus ascorbic acid (3000 mg one dose) before angiography and 2000 mg two doses after angiography and good hydration; and Group C (n=45), hydration with 0.9% saline started just before contrast media injection and continued for 12 h at a rate 1.0 mL/kg//min after angiography or 0.5 mL/kg/h in cases with overt heart failure for 12 h. CIN was defined as an increase in serum creatinine of >25% of baseline or an absolute increase of 0.5 mg/dL above baseline after 48 h. The incidence of CIN was significantly lower in Group A (6.66%) compared with Group B (16.66%) or Group C (17.77%). The difference between Groups A and B and between Groups A and C was also highly significant (P=0.001). In contrast, the difference between Groups B and C was not statistically significant (P=0.37). Our study indicates that high doses of NAC plus hydration provide better protection against CIN than combination therapy of NAC and ascorbic acid plus hydration, or hydration alone.}, }
@article {pmid26786042, year = {2016}, author = {El-Ebiary, AA and Elsharkawy, RE and Soliman, NA and Soliman, MA and Hashem, AA}, title = {N-acetylcysteine in Acute Organophosphorus Pesticide Poisoning: A Randomized, Clinical Trial.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {119}, number = {2}, pages = {222-227}, doi = {10.1111/bcpt.12554}, pmid = {26786042}, issn = {1742-7843}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Atropine/therapeutic use ; Dose-Response Relationship, Drug ; Egypt ; Female ; Glutathione/blood ; Hospitalization ; Humans ; Length of Stay ; Male ; Malondialdehyde/blood ; Middle Aged ; Organophosphate Poisoning/*drug therapy ; Oxidative Stress/drug effects ; Pesticides/*poisoning ; Respiration, Artificial ; Treatment Outcome ; Young Adult ; }, abstract = {Organophosphorus poisoning is a major global health problem with hundreds of thousands of deaths each year. Research interest in N-acetylcysteine has grown among increasing evidence of the role of oxidative stress in organophosphorus poisoning. We aimed to assess the safety and efficacy of N-acetylcysteine as an adjuvant treatment in patients with acute organophosphorus poisoning. This was a randomized, controlled, parallel-group trial on 30 patients suffering from acute organophosphorus poisoning, who were admitted to the Poison Control Center of Tanta University Emergency Hospital, Tanta, Egypt, between April and September 2014. Interventions included oral N-acetylcysteine (600 mg three times daily for 3 days) as an added treatment to the conventional measures versus only the conventional treatment. Outcome measures included mortality, total dose of atropine administered, duration of hospitalization and the need for ICU admission and/or mechanical ventilation. A total of 46 patients were screened and 30 were randomized. No significant difference was found between both groups regarding demographic characteristics and the nature or severity of baseline clinical manifestations. No major adverse effects to N-acetylcysteine therapy were reported. Malondialdehyde significantly decreased and reduced glutathione significantly increased only in the NAC-treated patients. The patients on NAC therapy required less atropine doses than those who received only the conventional treatment; however, the length of hospital stay showed no significant difference between both groups. The study concluded that the use of N-acetylcysteine as an added treatment was apparently safe, and it reduced atropine requirements in patients with acute organophosphorus pesticide poisoning.}, }
@article {pmid26779856, year = {2016}, author = {Ali-Hasan-Al-Saegh, S and Mirhosseini, SJ and Ghodratipour, Z and Sarafan-Chaharsoughi, Z and Dehghan, AM and Rahimizadeh, E and Shahidzadeh, A and Lotfaliani, MR and Sedaghat-Hamedani, F and Kayvanpour, E and Sabashnikov, A and Popov, AF}, title = {Protective effects of anti-oxidant supplementations on contrast-induced nephropathy after coronary angiography: an updated and comprehensive meta-analysis and systematic review.}, journal = {Kardiologia polska}, volume = {74}, number = {7}, pages = {610-626}, doi = {10.5603/KP.a2016.0007}, pmid = {26779856}, issn = {1897-4279}, mesh = {Aged ; Antioxidants/pharmacology/*therapeutic use ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; *Dietary Supplements ; Female ; Humans ; Incidence ; Kidney Diseases/chemically induced/epidemiology/*prevention &amp; control ; Kidney Function Tests ; Male ; Middle Aged ; }, abstract = {BACKGROUND AND AIM: This systematic review with meta-analysis sought to determine the strength of evidence for effects of antioxidants (AO) such as N-acetyl cysteine (NAC), vitamin C, vitamin E, and alpha-lipoic acid on the incidence of contrast-in-duced nephropathy (CIN), requirement for haemodialysis, level of serum creatinine, and mortality after coronary angiography.<br><br>METHODS AND RESULTS: After Medline, Embase, Elsevier, Sciences online database, and Google Scholar literature searches, studies with randomised controlled design were selected for the meta-analysis. The effect sizes measured were odds ratio (OR) for categorical variables and standard mean difference (SMD) with 95% confidence interval (CI) for calculating differences between mean changes of serum creatinine in intervention and control groups. A value of p < 0.1 for Q test or I2 > 50% indicated significant heterogeneity between the studies. Literature search of all major databases retrieved 2350 studies. After screening, a total of 49 trials were identified that reported outcomes. Pooled treatment effect analysis revealed that NAC (OR of 0.79; 95% CI 0.69-0.9; p = 0.000), vitamin C (0.63; 95% CI 0.45-0.89; p = 0.000), and vitamin E (OR of 0.5; 95% CI 0.27-0.92; p = 0.026) could significantly reduce the incidence of CIN. NAC (SMD of -0.119; 95% CI -0.191 - 0.046; p = 0.000), but not vitamin C (SMD of -0.08; 95% CI -0.22-0.04; p = 0.1) and vitamin E (-0.25; 95% CI -0.46-0.05; p = 0.1), could significantly reduce mean levels of serum creatinine. Nevertheless, AO could not reduce the incidence of mortality, with an OR of 0.94 (95% CI 0.69-1.28; p = 0.7).<br><br>CONCLUSIONS: Overall, antioxidants such as NAC, vitamin C, and vitamin E can reduce the incidence of CIN, while only NAC might be able to significantly lower serum creatinine levels. There is no impact of AO supplementation on mortality.}, }
@article {pmid26779823, year = {2016}, author = {Sharma, M and Kaur, T and Singla, SK}, title = {Role of mitochondria and NADPH oxidase derived reactive oxygen species in hyperoxaluria induced nephrolithiasis: therapeutic intervention with combinatorial therapy of N-acetyl cysteine and Apocynin.}, journal = {Mitochondrion}, volume = {27}, number = {}, pages = {15-24}, doi = {10.1016/j.mito.2016.01.002}, pmid = {26779823}, issn = {1872-8278}, mesh = {Acetophenones/*therapeutic use ; Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Disease Models, Animal ; Drug Therapy, Combination/methods ; Hyperoxaluria/complications/*drug therapy ; Male ; Mitochondria/*metabolism ; NADPH Oxidases/*metabolism ; Nephrolithiasis/drug therapy/physiopathology ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Treatment Outcome ; }, abstract = {The interactions between the main cellular sources of ROS, such as mitochondria and NADPH oxidase, are known to play an imperative role in the pathogenesis of hyperoxaluria-induced nephrolithiasis. The present study was designed to investigate the protective effect of a combinatorial therapy based on the attenuation of oxidative stress with antioxidant (N-acetyl cysteine), and NADPH oxidase inhibitor (apocynin), that might be required to effectively eliminate hyperoxaluric manifestations. Hyperoxaluria was induced in male Wistar rats by administering 0.4% ethylene glycol with 1% ammonium chloride in drinking water for 9 days. Hyperoxaluria accentuated renal oxidative stress in terms of increased ROS production and lipid peroxidation. Mitochondrial dysfunction, a central deleterious event in renal stone crystallization, was evident by decreased activities of electron transport chain complex I, II and IV, augmented mitochondrial ROS, reduced GSH/GSSG ratio, which resulted in the mitochondrial permeability transition pore (mPTP) opening as indicated by increased mitochondrial swelling in hyperoxaluric rats. Furthermore, NADPH oxidase activity was significantly increased, with raised expression of NOX1, NOX2, NOX4, p38MAPK and MnSOD, in the renal tissue of hyperoxaluric rats compared to control. However, combinatorial therapy with N-acetyl cysteine (50mg/kg/day) and apocynin (200mg/kg/day), intraperitoneally, significantly improved renal functions in hyperoxaluric rats and considerably ameliorated mitochondrial dysfunction. NAC with apocynin was also found to be effective in reducing the redundant activity of NADPH oxidase in renal tissue of hyperoxaluric rats. Hence, our investigation provides novel mechanistic insights that combinatorial approaches using targeted modulators of ROS offer therapeutic benefits in hyperoxaluria-induced nephrolithiasis.}, }
@article {pmid26779540, year = {2016}, author = {Bo, J and Xie, S and Guo, Y and Zhang, C and Guan, Y and Li, C and Lu, J and Meng, QH}, title = {Methylglyoxal Impairs Insulin Secretion of Pancreatic β-Cells through Increased Production of ROS and Mitochondrial Dysfunction Mediated by Upregulation of UCP2 and MAPKs.}, journal = {Journal of diabetes research}, volume = {2016}, number = {}, pages = {2029854}, pmid = {26779540}, issn = {2314-6753}, mesh = {Animals ; Apoptosis/drug effects ; Cell Line, Tumor ; Insulin/*metabolism ; Insulin Secretion ; Insulin-Secreting Cells/*drug effects/metabolism ; Ion Channels/*metabolism ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Mitochondrial Proteins/*metabolism ; Pyruvaldehyde/*pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Uncoupling Protein 2 ; Up-Regulation/*drug effects ; }, abstract = {Methylglyoxal (MG) is a highly reactive glucose metabolic intermediate and a major precursor of advanced glycation end products. MG level is elevated in hyperglycemic disorders such as diabetes mellitus. Substantial evidence has shown that MG is involved in the pathogenesis of diabetes and diabetic complications. We investigated the impact of MG on insulin secretion by MIN6 and INS-1 cells and the potential mechanisms of this effect. Our study demonstrates that MG impaired insulin secretion by MIN6 or ISN-1 cells in a dose-dependent manner. It increased reactive oxygen species (ROS) production and apoptosis rate in MIN6 or ISN-1 cells and inhibited mitochondrial membrane potential (MMP) and ATP production. Furthermore, the expression of UCP2, JNK, and P38 as well as the phosphorylation JNK and P38 was increased by MG. These effects of MG were attenuated by MG scavenger N-acetyl cysteine. Collectively, these data indicate that MG impairs insulin secretion of pancreatic β-cells through increasing ROS production. High levels of ROS can damage β-cells directly via JNK/P38 upregulation and through activation of UCP2 resulting in reduced MMP and ATP production, leading to β-cell dysfunction and impairment of insulin production.}, }
@article {pmid26774701, year = {2016}, author = {Guo, D and Gu, J and Jiang, H and Ahmed, A and Zhang, Z and Gu, Y}, title = {Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to the development of pulmonary arterial hypertension.}, journal = {Journal of molecular and cellular cardiology}, volume = {91}, number = {}, pages = {179-187}, doi = {10.1016/j.yjmcc.2016.01.009}, pmid = {26774701}, issn = {1095-8584}, support = {RG/09/001/25940/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Calcium/metabolism ; Calcium Channels, L-Type/genetics/metabolism ; Cell Proliferation/drug effects ; Gene Expression Regulation ; Hypertension, Pulmonary/chemically induced/*enzymology/genetics/pathology ; Hypertrophy, Right Ventricular/chemically induced/*enzymology/genetics/pathology ; Male ; Metalloporphyrins/pharmacology ; Monocrotaline ; Myocytes, Smooth Muscle/drug effects/*enzymology/pathology ; Organ Culture Techniques ; Pentose Phosphate Pathway ; Phosphorylation ; Primary Cell Culture ; Pulmonary Artery/drug effects/*enzymology/pathology ; Pyruvate Kinase/*genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Serine/pharmacology ; }, abstract = {AIMS: Pulmonary arterial hypertension [1] is a proliferative disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMCs). Reactive oxygen species (ROS) is implicated in the development of PAH and regulates the vascular tone and functions. However, which cellular signaling mechanisms are triggered by ROS in PAH is still unknown. Hence, here we wished to characterize the signaling mechanisms triggered by ROS.<br><br>METHODS AND RESULTS: By Western blots, we showed that increased intracellular ROS caused inhibition of the glycolytic pyruvate kinase M2 (PKM2) activity through promoting the phosphorylation of PKM2. Monocrotaline (MCT)-induced rats developed severe PAH and right ventricular hypertrophy, with a significant increase in the P-PKM2 and decrease in pyruvate kinase activity which could be attenuated with the treatments of PKM2 activators, FBP and l-serine. The antioxidant NAC, apocynin and MnTBAP had the similar protective effects in the development of PAH. In vitro assays confirmed that inhibition of PKM2 activity could modulate the flux of glycolytic intermediates in support of cell proliferation through the increased pentose phosphate pathway (PPP). Increased ROS and decreased PKM2 activity also promoted the Cav1.2 expression and intracellular calcium.<br><br>CONCLUSION: Our data provide new evidence that PKM2 makes a critical regulatory contribution to the PAHs for the first time. Decreased pyruvate kinase M2 activity confers additional advantages to rat PASMCs by allowing them to sustain anti-oxidant responses and thereby support cell survival in PAH. It may become a novel treatment strategy in PAH by using of PKM2 activators.}, }
@article {pmid26769589, year = {2016}, author = {Jallouli, M and El Bini Dhouib, I and Dhouib, H and Lasram, M and Gharbi, N and El Fazaa, S}, title = {Disruption of steroidogenesis after dimethoate exposure and efficacy of N-acetylcysteine in rats: an old drug with new approaches.}, journal = {Environmental science and pollution research international}, volume = {23}, number = {8}, pages = {7975-7984}, pmid = {26769589}, issn = {1614-7499}, mesh = {17-Hydroxysteroid Dehydrogenases/metabolism ; Acetylcysteine/*pharmacology ; Animals ; Dimethoate/*toxicity ; Environmental Pollutants/*toxicity ; Free Radical Scavengers/*pharmacology ; Free Radicals/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Male ; Phosphoproteins/metabolism ; Rats ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Testis/*drug effects/enzymology/metabolism ; Testosterone/*blood ; }, abstract = {Organophosphates (OPs) like dimethoate (DMT), are pesticides used worldwide, which can affect both animals and human. Whereas their toxicity is due to acetylcholinesterase inhibition, their secondary toxic effects have been related to free oxygen radical biosynthesis. The present study was designed to investigate the reprotoxic effects of DMT and the protective role of N-acetylcysteine (NAC) in male rat. DMT (20 mg/ kg/body weight) was administered daily to rats via gavage in corn oil and NAC (2 g/l) was added to drinking water for 30 days. Rats were sacrificed on the 30th day, 2 h after the last administration. Markers of testis injury (steroidogenesis impairment) and oxidative stress (lipid peroxidation, reduced glutathione, and antioxidant status) were assessed. In DMT-exposed rats, the serum level of testosterone was decreased. Further, a significant increase in lipid peroxidation level and a significant decrease in the activities of antioxidant enzymes were observed in the testis of rats during DMT intoxication. Real-time PCR (RT-PCR) analysis demonstrated a decrease in messenger RNA (mRNA) levels for testicular steroidogenic acute regulatory StAR protein, cytochrome P450scc, 3β-hydroxysteroid dehydrogenase (3β-HSD), and 17β hydroxysteroid dehydrogenase (17β-HSD) in the testis after DMT exposure. No significant changes in the oxidative stress status and selected reproductive variables were observed on CTN group, whereas NAC restored the oxidative stress and the steroidogenesis on NAC group. Dimethoate induces reprotoxicity and oxidative stress. N-acetylcysteine showed therapeutic recovery effects against dimethoate toxicity.}, }
@article {pmid26768878, year = {2016}, author = {Gurcay, AG and Gurcan, O and Kazanci, A and Bozkurt, I and Senturk, S and Bodur, E and Turkoglu, OF and Bavbek, M}, title = {Comparative Biochemical and Motor Function Analysis of Alpha Lipoic Acid and N-Acetyl Cysteine Treatment on Rats with Experimental Spinal Cord Injury.}, journal = {Turkish neurosurgery}, volume = {26}, number = {1}, pages = {119-126}, doi = {10.5137/1019-5149.JTN.14594-15.0}, pmid = {26768878}, issn = {2651-5032}, mesh = {Animals ; Cysteine/*pharmacology ; Disease Models, Animal ; Male ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Recovery of Function/*drug effects ; Spinal Cord Injuries/*pathology ; Thioctic Acid/*pharmacology ; }, abstract = {AIM: Spinal Cord Injury (SCI) is a devastating health problem both for the patient and the clinician. Numerous treatment modalities have been studied to reverse the effects of spinal cord injury. Herein is reported the effects and the comparison of Alpha Lipoic Acid and N-Acetyl Cysteine on rats with SCI.<br><br>MATERIAL AND METHODS: 38 adult male Sprague-Dawley rats were randomly divided into 5 groups: only laminectomy, laminectomy and trauma, laminectomy trauma and Alpha Lipoic Acid 100 mg/kg IP administration, laminectomy trauma and N-Acetyl Cysteine 300 mg/kg IP administration, and vehicle group (PEG). The trauma model was the Modified Allen Weight drop method. After the procedure, the rats' motor function was evaluated using the modified Tarlov Scale and consequently they were sacrificed and the spinal cord tissue was analyzed biochemically for inflammation markers.<br><br>RESULTS: Both Alpha Lipoic Acid and N-Acetyl Cysteine administration after the injury significantly improved the results. There was no statistically significant difference in between the agents.<br><br>CONCLUSION: Although these agents both proven to be effective in ameliorating the effects of SCI, there was not enough evidence in this research to conclude the benefit of one agent over the other.}, }
@article {pmid26757427, year = {2016}, author = {Chughlay, MF and Kramer, N and Spearman, CW and Werfalli, M and Cohen, K}, title = {N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review.}, journal = {British journal of clinical pharmacology}, volume = {81}, number = {6}, pages = {1021-1029}, pmid = {26757427}, issn = {1365-2125}, mesh = {Acetylcysteine/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy ; Free Radical Scavengers/therapeutic use ; Humans ; }, abstract = {AIMS: N-acetylcysteine (NAC) may be useful in the management of non-paracetamol drug-induced liver injury (DILI). Our objective was to review systematically evidence for the use of NAC as a therapeutic option for non-paracetamol DILI.<br><br>METHODS: We searched for randomized controlled trials (RCTs) and prospective cohort studies. We searched several bibliographic databases, grey literature sources, conference proceedings and ongoing trials. Our pre-specified primary outcomes were all cause and DILI related mortality, time to normalization of liver biochemistry and adverse events. Secondary outcomes were proportion receiving liver transplant, time to transplantation, transplant-free survival and hospitalization duration.<br><br>RESULTS: We identified one RCT of NAC vs. placebo in patients with non-paracetamol acute liver failure. There was no difference in the primary outcomes of overall survival at 3&#xa0;weeks between NAC [70%, 95% confidence interval (CI)&#xa0;=&#xa0;60%, 81%, n&#xa0;=&#xa0;81] and placebo (66%, 95% CI&#xa0;=&#xa0;56%, 77%, n&#xa0;=&#xa0;92). NAC significantly improved the secondary outcomes of transplant-free survival compared with placebo: 40% NAC (95% CI&#xa0;=&#xa0;28%, 51%) vs. 27% placebo (95% CI&#xa0;=&#xa0;18%, 37%). A subgroup analysis according to aetiology found improved transplant-free survival in patients with non-paracetamol DILI, NAC (58%, n&#xa0;=&#xa0;19) vs. placebo (27%, n&#xa0;=&#xa0;26), odds ratio (OR) 0.27 (95% CI&#xa0;=&#xa0;0.076, 0.942). Overall survival was similar, NAC (79%) vs. placebo (65%);, OR 0.50 (95% CI&#xa0;=&#xa0;0.13, 1.98).<br><br>CONCLUSION: Current available evidence is limited and does not allow for any firm conclusions to be made regarding the role of NAC in non-paracetamol DILI. We therefore highlight the need for further research in this area.}, }
@article {pmid26752183, year = {2016}, author = {Mallela, SK and Almeida, R and Ejsing, CS and Conzelmann, A}, title = {Functions of Ceramide Synthase Paralogs YPR114w and YJR116w of Saccharomyces cerevisiae.}, journal = {PloS one}, volume = {11}, number = {1}, pages = {e0145831}, pmid = {26752183}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Alkaline Ceramidase/genetics/metabolism ; Amidohydrolases/genetics/metabolism ; Antifungal Agents/pharmacology ; Antioxidants/pharmacology ; Cations, Divalent ; Ceramides/*biosynthesis ; Copper/toxicity ; Fatty Acids, Monounsaturated/pharmacology ; Gene Deletion ; *Gene Expression Regulation, Fungal ; Membrane Proteins/genetics/metabolism ; Mitochondria/metabolism ; Oxidoreductases/genetics/metabolism ; Oxygen/pharmacology ; Phylogeny ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae/classification/drug effects/*genetics/metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Vacuoles/metabolism ; }, abstract = {Ceramide is synthesized in yeast by two redundant acyl-CoA dependent synthases, Lag1 and Lac1. In lag1∆ lac1∆ cells, free fatty acids and sphingoid bases are elevated, and ceramides are produced through the redundant alkaline ceramidases Ypc1 and Ydc1, working backwards. Even with all four of these genes deleted, cells are surviving and continue to contain small amounts of complex sphingolipids. Here we show that these residual sphingolipids are not synthesized by YPR114w or YJR116w, proteins of unknown function showing a high degree of homology to Lag1 and Lac1. Indeed, the hextuple lag1∆ lac1∆ ypc1∆ ydc1∆ ypr114w∆ yjr116w∆ mutant still contains ceramides and complex sphingolipids. Yjr116w∆ exhibit an oxygen-dependent hypersensitivity to Cu2+ due to an increased mitochondrial production of reactive oxygen species (ROS) and a mitochondrially orchestrated programmed cell death in presence of copper, but also a general copper hypersensitivity that cannot be counteracted by the antioxidant N-acetyl-cysteine (NAC). Myriocin efficiently represses the synthesis of sphingoid bases of ypr114w∆, but not its growth. Both yjr116w∆ and ypr114w∆ have fragmented vacuoles and produce less ROS than wild type, before and after diauxic shift. Ypr114w∆/ypr114w∆ have an increased chronological life span. Thus, Yjr116w and Ypr114w are related, but not functionally redundant.}, }
@article {pmid26747500, year = {2016}, author = {Atef, ME and Anand-Srivastava, MB}, title = {Oxidative stress contributes to the enhanced expression of Gqα/PLCβ1 proteins and hypertrophy of VSMC from SHR: role of growth factor receptor transactivation.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {310}, number = {5}, pages = {H608-18}, doi = {10.1152/ajpheart.00659.2015}, pmid = {26747500}, issn = {1522-1539}, support = {MOP-53074//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Antioxidants/pharmacology ; Cell Size ; Cells, Cultured ; Disease Models, Animal ; ErbB Receptors/metabolism ; GTP-Binding Protein alpha Subunits, Gq-G11/*metabolism ; Hypertension/*enzymology/genetics/pathology ; Hypertrophy ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Muscle, Smooth, Vascular/drug effects/*enzymology/pathology ; Myocytes, Smooth Muscle/drug effects/*enzymology/pathology ; *Oxidative Stress/drug effects ; Phospholipase C beta/*metabolism ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins pp60(c-src)/antagonists &amp; inhibitors/metabolism ; RNA Interference ; Rats, Inbred SHR ; Rats, Inbred WKY ; Receptor, IGF Type 1/metabolism ; Receptors, Growth Factor/antagonists &amp; inhibitors/genetics/*metabolism ; Receptors, Platelet-Derived Growth Factor/metabolism ; Signal Transduction ; Transfection ; Up-Regulation ; }, abstract = {We showed previously that vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) exhibit overexpression of Gqα/PLCβ1 proteins, which contribute to increased protein synthesis through the activation of MAP kinase signaling. Because oxidative stress has been shown to be increased in hypertension, the present study was undertaken to examine the role of oxidative stress and underlying mechanisms in enhanced expression of Gqα/PLCβ1 proteins and VSMC hypertrophy. Protein expression was determined by Western blotting, whereas protein synthesis and cell volume, markers for VSMC hypertrophy, were determined by [(3)H]-leucine incorporation and three-dimensional confocal imaging, respectively. The increased expression of Gqα/PLCβ1 proteins, increased protein synthesis, and augmented cell volume exhibited by VSMCs from SHRs were significantly attenuated by antioxidants N-acetyl-cysteine (NAC), a scavenger of superoxide anion, DPI, an inhibitor of NAD(P)H oxidase. In addition, PP2, AG1024, AG1478, and AG1295, inhibitors of c-Src, insulin-like growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), respectively, also attenuated the enhanced expression of Gqα/PLCβ1 proteins and enhanced protein synthesis in VSMCs from SHRs toward control levels. Furthermore, the levels of IGF-1R and EGFR proteins and not of PDGFR were also enhanced in VSMCs from SHRs, which were attenuated significantly by NAC, DPI, and PP2. In addition, NAC, DPI, and PP2 also attenuated the enhanced phosphorylation of IGF-1R, PDGFR, EGFR, c-Src, and EKR1/2 in VSMCs from SHRs. These data suggest that enhanced oxidative stress in VSMCs from SHRs activates c-Src, which through the transactivation of growth factor receptors and MAPK signaling contributes to enhanced expression of Gqα/PLCβ1 proteins and resultant VSMC hypertrophy.}, }
@article {pmid26744324, year = {2016}, author = {Julien, C and Lissouba, A and Madabattula, S and Fardghassemi, Y and Rosenfelt, C and Androschuk, A and Strautman, J and Wong, C and Bysice, A and O'sullivan, J and Rouleau, GA and Drapeau, P and Parker, JA and Bolduc, FV}, title = {Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms.}, journal = {Human molecular genetics}, volume = {25}, number = {6}, pages = {1088-1099}, pmid = {26744324}, issn = {1460-2083}, support = {P40 OD010440/OD/NIH HHS/United States ; //Canadian Institutes of Health Research/Canada ; }, mesh = {Adenosine Triphosphatases/genetics ; Animals ; Caenorhabditis elegans ; *Disease Models, Animal ; Drosophila ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum Stress/drug effects/genetics ; Female ; Humans ; Locomotion/drug effects/genetics ; Microtubules/drug effects/metabolism ; Mutation ; Phenazines/pharmacology ; Phenotype ; Spastic Paraplegia, Hereditary/*drug therapy/genetics ; Zebrafish ; }, abstract = {Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans, Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N-acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP.}, }
@article {pmid26743493, year = {2016}, author = {Tai, IH and Sheen, JM and Lin, YJ and Yu, HR and Tiao, MM and Chen, CC and Huang, LT and Tain, YL}, title = {Maternal N-acetylcysteine therapy regulates hydrogen sulfide-generating pathway and prevents programmed hypertension in male offspring exposed to prenatal dexamethasone and postnatal high-fat diet.}, journal = {Nitric oxide : biology and chemistry}, volume = {53}, number = {}, pages = {6-12}, doi = {10.1016/j.niox.2015.12.006}, pmid = {26743493}, issn = {1089-8611}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dexamethasone ; Diet, High-Fat/*adverse effects ; Female ; Hydrogen Sulfide/*metabolism ; Hypertension/chemically induced/*prevention &amp; control ; Male ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Nitric oxide (NO) and hydrogen sulfide (H2S) pathways are involved in the development of hypertension, a condition that can originate from early life. We examined whether asymmetric dimethylarginine (ADMA, a nitric oxide synthase inhibitor)/NO and H2S generating pathway contributed to programmed hypertension in offspring exposed to prenatal dexamethasone (DEX) and postnatal high-fat (HF) and whether N-acetylcysteine (NAC) therapy prevented this process. We examined 16-week-old male rat offspring from five groups: control, DEX (0.1 mg/kg i.p. from gestational day 16-22), HF (58% high-fat diet from weaning to 4 months of age), DEX+HF, and NAC (1% in drinking water during lactation). Prenatal DEX and postnatal HF diet synergistically induced programmed hypertension in adult offspring, which was prevented by maternal NAC therapy. We attributed the protective effects of NAC on two-hit induced programmed hypertension to the reduction of plasma ADMA, restoration of plasma l-arginine-to-ADMA ratio, upregulation of gene expression of H2S-generating enzymes, restoration of renal 3-mercaptopyruvate sulphurtransferase (3MST) protein levels and activity, induction of plasma glutathione level, and reduction of oxidative stress. Manipulation of the ADMA-NO and H2S-generating pathways by maternal NAC therapy may be a potential approach to prevent programmed hypertension induced by two-hit insults.}, }
@article {pmid26740270, year = {2016}, author = {Elliott, TR and Symes, T and Kannourakis, G and Angus, P}, title = {Resolution of norfloxacin-induced acute liver failure after N-acetylcysteine therapy: further support for the use of NAC in drug-induced ALF?.}, journal = {BMJ case reports}, volume = {2016}, number = {}, pages = {}, pmid = {26740270}, issn = {1757-790X}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Anti-Bacterial Agents/*adverse effects ; Chemical and Drug Induced Liver Injury/*drug therapy ; Female ; Humans ; Liver/pathology ; Liver Failure, Acute/chemically induced ; Norfloxacin/*adverse effects ; }, abstract = {Liver injury due to idiosyncratic drug reactions can be difficult to diagnose and may lead to acute liver failure (ALF), which has a high mortality rate. N-acetylcysteine (NAC) is effective treatment for paracetamol toxicity, but its role in non-paracetamol drug-induced ALF is controversial. We report on the use of a validated bedside tool to establish causality for drug-induced liver injury (DILI) and describe the first case of resolution of norfloxacin-induced ALF after NAC therapy. NAC is easy to administer and generally has a good safety profile. We discuss the evidence to support the use of NAC in ALF secondary to DILI and possibilities for further clinical research in this field.}, }
@article {pmid26731315, year = {2016}, author = {Oommen, D and Yiannakis, D and Jha, AN}, title = {BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin.}, journal = {Mutation research}, volume = {784-785}, number = {}, pages = {8-15}, doi = {10.1016/j.mrfmmm.2015.11.002}, pmid = {26731315}, issn = {1873-135X}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/genetics ; Auranofin/*pharmacology ; BRCA1 Protein/*genetics/metabolism ; Carcinoma, Ovarian Epithelial ; Cell Line, Tumor/drug effects ; DNA Breaks, Double-Stranded/drug effects ; DNA Damage/drug effects/genetics ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; NF-E2-Related Factor 2/genetics/metabolism ; Neoplasms, Glandular and Epithelial/drug therapy/genetics/pathology ; Ovarian Neoplasms/*drug therapy/genetics/pathology ; }, abstract = {Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) via direct protein-protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.}, }
@article {pmid26724531, year = {2016}, author = {Afonso, P and Auclair, M and Boccara, F and Vantyghem, MC and Katlama, C and Capeau, J and Vigouroux, C and Caron-Debarle, M}, title = {LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: Role of ZMPSTE24 downregulation.}, journal = {Atherosclerosis}, volume = {245}, number = {}, pages = {200-211}, doi = {10.1016/j.atherosclerosis.2015.12.012}, pmid = {26724531}, issn = {1879-1484}, mesh = {Cells, Cultured ; Cellular Senescence/drug effects ; DNA/genetics ; DNA Mutational Analysis ; *Down-Regulation ; HIV Protease Inhibitors/*pharmacology ; Humans ; Lamin Type A/*genetics/metabolism ; Lipodystrophy/drug therapy/*genetics/metabolism ; Membrane Proteins/biosynthesis/*genetics ; Metalloendopeptidases/biosynthesis/*genetics ; *Mutation ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Calcification/drug therapy/*genetics/metabolism ; }, abstract = {BACKGROUND: Some LMNA mutations responsible for lipodystrophies, and some HIV-protease inhibitors (PIs) induce accumulation of farnesylated prelamin A and premature senescence in some cell types. Patients with LMNA mutations or under PI-based therapy suffer from early atherosclerosis. The metalloprotease ZMPSTE24 is the key enzyme in prelamin A maturation.<br><br>AIM: We studied whether altered expression of ZMPSTE24 could contribute to vascular cell dysfunction in response to LMNA mutations or PI treatments.<br><br>METHODS: Protein expression of prelamin A and ZMPSTE24 were evaluated in patients' cells and in human cultured VSMCs. Oxidative stress, inflammation, senescence and transdifferentiation/calcification were evaluated in VSMCs.<br><br>RESULTS: Fibroblasts from LMNA-mutated lipodystrophic patients (mutations R482W, D47Y or R133L) and peripheral blood mononuclear cells from PI-treated-HIV-infected patients expressed increased prelamin A and decreased ZMPSTE24, which was also observed in VSMCs overexpressing mutant LMNA or treated with PIs. These alterations correlated with oxidative stress, inflammation, senescence and calcification (all p < 0.05). ZMPSTE24 silencing in native VSMCs recapitulated the mutant LMNA- and PI-induced accumulation of farnesylated prelamin A, oxidative stress, inflammation, senescence and calcification. A negative regulator of ZMPSTE24, miRNA-141-3p, was enhanced in LMNA-mutated or PI-treated VSMCs. The farnesylation inhibitors pravastatin and FTI-277, or the antioxidant N-acetyl cysteine, partly restored ZMPSTE24 expression, and concomitantly decreased oxidative stress, inflammation, senescence, and calcification of PI-treated VSCMs.<br><br>CONCLUSIONS: ZMPSTE24 downregulation is a major contributor in VSMC dysfunctions resulting from LMNA mutations or PI treatments that could translate in early atherosclerosis at the clinical level. These novel pathophysiological mechanisms could open new therapeutic perspectives for cardiovascular aging.}, }
@article {pmid26721593, year = {2016}, author = {Kim, H and Lee, GR and Kim, J and Baek, JY and Jo, YJ and Hong, SE and Kim, SH and Lee, J and Lee, HI and Park, SK and Kim, HM and Lee, HJ and Chang, TS and Rhee, SG and Lee, JS and Jeong, W}, title = {Sulfiredoxin inhibitor induces preferential death of cancer cells through reactive oxygen species-mediated mitochondrial damage.}, journal = {Free radical biology &amp; medicine}, volume = {91}, number = {}, pages = {264-274}, doi = {10.1016/j.freeradbiomed.2015.12.023}, pmid = {26721593}, issn = {1873-4596}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Benzoates/*pharmacology ; Cell Line, Tumor ; Female ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/*drug effects ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Oxidoreductases Acting on Sulfur Group Donors/*antagonists &amp; inhibitors ; Reactive Oxygen Species/*metabolism ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {Recent studies have shown that many types of cancer cells have increased levels of reactive oxygen species (ROS) and enhance antioxidant capacity as an adaptation to intrinsic oxidative stress, suggesting that cancer cells are more vulnerable to oxidative insults and are more dependent on antioxidant systems compared with normal cells. Thus, disruption of redox homeostasis caused by a decline in antioxidant capacity may provide a method for the selective death of cancer cells. Here we show that ROS-mediated selective death of tumor cells can be caused by inhibiting sulfiredoxin (Srx), which reduces hyperoxidized peroxiredoxins, leading to their reactivation. Srx inhibitor increased the accumulation of sulfinic peroxiredoxins and ROS, which led to oxidative mitochondrial damage and caspase activation, resulting in the death of A549 human lung adenocarcinoma cells. Srx depletion also inhibited the growth of A549 cells like Srx inhibition, and the cytotoxic effects of Srx inhibitor were considerably reversed by Srx overexpression or antioxidants such as N-acetyl cysteine and butylated hydroxyanisol. Moreover, Srx inhibitor rendered tumorigenic ovarian cells more susceptible to ROS-mediated death compared with nontumorigenic cells and significantly suppressed the growth of A549 xenografts without acute toxicity. Our results suggest that Srx might serve as a novel therapeutic target for cancer treatment based on ROS-mediated cell death.}, }
@article {pmid26720166, year = {2016}, author = {Cabanillas, G and Popescu-Martinez, A}, title = {N-Acetylcysteine for Relapsing Thrombotic Thrombocytopenic Purpura: More Evidence of a Promising Drug.}, journal = {American journal of therapeutics}, volume = {23}, number = {5}, pages = {e1277-9}, doi = {10.1097/MJT.0000000000000386}, pmid = {26720166}, issn = {1536-3686}, mesh = {Acetylcysteine/*administration &amp; dosage/therapeutic use ; Combined Modality Therapy ; Humans ; Male ; Middle Aged ; Plasma Exchange/methods ; Platelet Count ; Purpura, Thrombotic Thrombocytopenic/diagnostic imaging/physiopathology/*therapy ; Recurrence ; Remission Induction/methods ; Rituximab/administration &amp; dosage ; Steroids/*administration &amp; dosage/therapeutic use ; Tomography, X-Ray Computed ; Treatment Outcome ; }, abstract = {Thrombotic thrombocytopenic purpura (TTP) is a microangiopatic thrombotic state associated with a deficiency on the cleavage function of the Von Willebrand factor polymers by a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13. We report a patient with relapsing TTP successfully treated with N-acetylcysteine (NAC) after failure of plasma exchange (PE) with steroids, rituximab, cyclophosphamide, vincristine, and azathioprine. A 51-year-old male who had an altered mental status while he was on rehabilitation for a previously treated TTP with a subsequent neurologic deficit. He was treated 7 days ago with PE plus steroids and subsequently discharged to our facility for rehabilitation. He was found to have a platelet level of 153,000/mm, hemoglobin decreased from 9.2 to 6.2 g/dL, creatinine raised from 1.0 to 2.4 mg/dL, and the peripheral smear showed schistocytes. A brain computed tomography showed a subacute infarction in the left frontal lobe and an abdominal-pelvic computed tomography disclosed a retroperitoneal hematoma. PE and steroids were started for 14 days. On day 15th, rituximab was added weekly for 10 cycles. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 activity level was 95% without platelet count improvement. We started cyclophosphamide, then vincristine, and finally azathioprine. His platelet were maintained above 150,000/mm for a few days. He had several episodes of sepsis after every chemotherapeutic drug. On day 135th, NAC was commenced at 150 mg/kg for 10 days along with PE and low-dose steroids for 10 days. Complete recover of platelet count was achieved and the patient was successfully discharged. Relapsing TTP is often difficult to manage and may last longer than expected carrying several comorbidities and complications. PE plus steroids are the mainstay of TTP treatment and Rituximab is the drug of choice after they have failed. The patient had a complete remission after NAC therapy. Hence, NAC likely can be considered an earlier choice of treatment after rituximab, before the use of chemotherapeutic agents, considering its toxic and adverse effects.}, }
@article {pmid26718128, year = {2016}, author = {Zhao, Z and Sun, YS and Chen, W and Lv, LX and Li, YQ}, title = {Hispolon inhibits breast cancer cell migration by reversal of epithelial-to-mesenchymal transition via suppressing the ROS/ERK/Slug/E-cadherin pathway.}, journal = {Oncology reports}, volume = {35}, number = {2}, pages = {896-904}, doi = {10.3892/or.2015.4445}, pmid = {26718128}, issn = {1791-2431}, mesh = {Antineoplastic Agents/*pharmacology ; Blotting, Western ; Breast Neoplasms/*pathology ; Cadherins/metabolism ; Catechols/*pharmacology ; Cell Movement/drug effects ; Epithelial-Mesenchymal Transition/*drug effects ; Humans ; MAP Kinase Signaling System/physiology ; MCF-7 Cells ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {Hispolon has been shown to have anticancer effects on various tumors. However, whether hispolon exerts anti-migration activity in breast cancer cells and the underlying mechanisms, have not been elucidated yet. In the present study, our data demonstrated that hispolon inhibited TPA-induced breast cancer MCF-7 cell migration at sub-toxic concentrations in vitro. Hispolon decreased the level of cellular ROS significantly and repressed TPA-induced phosphorylation of extracellular signal-regulated kinase (ERK), accompanied by upregulation of E-cadherin and downregulation of the transcriptional repressor Slug. Furthermore, N-acetyl-cysteine, an antioxidant agent, markedly suppressed TPA-induced epithelial-to-mesenchymal transition, cell migration and activation of ERK. Taken together, our results indicated that hispolon suppressed the migration of breast cancer cells via suppressing the ROS/ERK/Slug/E‑cadherin pathway. Hispolon may be developed as a potential antimetastasis agent to breast cancer.}, }
@article {pmid26716647, year = {2016}, author = {Wei, W and Ma, C and Cao, Y and Yang, L and Huang, Z and Qin, D and Chen, Y and Liu, C and Xia, L and Wang, T and Lei, H and Yu, Y and Huang, M and Tong, Y and Xu, H and Gao, F and Zhang, J and Wu, YL}, title = {Identification of H7 as a novel peroxiredoxin I inhibitor to induce differentiation of leukemia cells.}, journal = {Oncotarget}, volume = {7}, number = {4}, pages = {3873-3883}, pmid = {26716647}, issn = {1949-2553}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Blotting, Western ; Cell Differentiation/*drug effects ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Female ; High-Throughput Screening Assays ; Humans ; Leukemia, Myeloid, Acute/drug therapy/metabolism/*pathology ; Leukemia, Promyelocytic, Acute/drug therapy/metabolism/*pathology ; Mice ; Mice, Transgenic ; Peroxiredoxins/*antagonists &amp; inhibitors ; Small Molecule Libraries/*pharmacology ; Sulfonamides/*pharmacology ; Surface Plasmon Resonance ; Tumor Cells, Cultured ; }, abstract = {Identifying novel targets to enhance leukemia-cell differentiation is an urgent requirement. We have recently proposed that inhibiting the antioxidant enzyme peroxiredoxin I (Prdx I) may induce leukemia-cell differentiation. However, this concept remains to be confirmed. In this work, we identified H7 as a novel Prdx I inhibitor through virtual screening, in vitro activity assay, and surface plasmon resonance assay. Cellular thermal shift assay showed that H7 directly bound to Prdx I but not to Prdxs II-V in cells. H7 treatment also increased reactive oxygen species (ROS) level and cell differentiation in leukemia cells, as reflected by the upregulation of the cell surface differentiation marker CD11b/CD14 and the morphological maturation of cells. The differentiation-induction effect of H7 was further observed in some non-acute promyelocytic leukemia (APL) and primary leukemia cells apart from APL NB4 cells. Moreover, the ROS scavenger N-acetyl cysteine significantly reversed the H7-induced cell differentiation. We demonstrated as well that H7-induced cell differentiation was associated with the activation of the ROS-Erk1/2-C/EBPβ axis. Finally, we showed H7 treatment induced cell differentiation in an APL mouse model. All of these data confirmed that Prdx I was novel target for inducing leukemia-cell differentiation and that H7 was a novel lead compound for optimizing Prdx I inhibition.}, }
@article {pmid26711827, year = {2015}, author = {Huang, T and He, R and Zhou, M and Zhang, J and Lin, Z and Ye, Q and Chen, X}, title = {[Possible effect of N-Acetyl-L-cysteine on Aβ(25-35)-induced tau hyperphosphorylation].}, journal = {Zhonghua yi xue za zhi}, volume = {95}, number = {33}, pages = {2701-2704}, pmid = {26711827}, issn = {0376-2491}, mesh = {Acetylcysteine ; Amyloid beta-Peptides ; Cyclin-Dependent Kinase 5 ; *Neurons ; Peptide Fragments ; Phosphorylation ; tau Proteins ; }, abstract = {OBJECTIVE: To investigate the possible effect and mechanism of N-Acetyl-L-cysteine (NAC) on fibrillar Aβ(25-35)-induced tau hyperphosphorylation.<br><br>METHODS: The phosphorylation of tau was induced by A&#x3b2;(25-35) in primary cortical neuron. Neurons were incubated in the absent or present A&#x3b2;(25-35), or pre-incubated NAC then co-incubated in A&#x3b2;. The measurement of ROS was performed on a microplate fluorometer. The proteins of p35/p25, cdk5, pT205 and pS404 were detected by Western blot.<br><br>RESULTS: In A&#x3b2; treated group, the ROS, pT205 and pS404 level were obviously higher than that in non-treated with A&#x3b2; group for 12 h (t=-6.35, P<0.05; t=-5, P<0.05; t=-4.57, P<0.05). However, in neurons pre-incubated with (10 mmol/L) NAC and then co-incubated with 20 &#xb5;mol/L A&#x3b2;, the ROS, pT205 and pS404 level were significantly decreased compared with that of A&#x3b2; group (t=3.47, P<0.05; t=3.88, P<0.05 and t=3.64, P<0.05); Upon A&#x3b2; exposure for 12 h, cortical neurons showed a statistically significant increase in p25 when compared to the control group (t=-6.20, P<0.05). However, pre-treatment with NAC showed a decrease in p25 as compared to neurons treated with A&#x3b2; alone for 12 h (t=4.72, P<0.05).<br><br>CONCLUSION: NAC attenuated the A&#x3b2;(25-35)-induced tau hyperphosphorylation through CDK5 pathway.}, }
@article {pmid26707483, year = {2016}, author = {Park, SH and Shin, MJ and Kim, DW and Park, J and Choi, SY and Kang, YH}, title = {Blockade of monocyte-endothelial trafficking by transduced Tat-superoxide dismutase protein.}, journal = {International journal of molecular medicine}, volume = {37}, number = {2}, pages = {387-397}, pmid = {26707483}, issn = {1791-244X}, mesh = {Atherosclerosis/*genetics/pathology ; Cyclic AMP Response Element-Binding Protein ; Endothelium, Vascular/drug effects/pathology ; Human Umbilical Vein Endothelial Cells ; Humans ; Inflammation/*genetics/pathology ; Monocytes/metabolism/pathology ; NF-kappa B/biosynthesis ; Oxidation-Reduction/drug effects ; Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis/metabolism ; Protein Transport/drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/biosynthesis/*genetics ; Superoxide Dismutase-1 ; Transcriptional Activation ; Transduction, Genetic ; Tumor Necrosis Factor-alpha/biosynthesis ; Vascular Cell Adhesion Molecule-1/biosynthesis ; }, abstract = {It has previously been suggested that reactive oxygen species (ROS) are involved in the pathogenesis of chronic inflammatory diseases, which entails the initial activation of pro-inflammatory cytokines to facilitate leukocyte transmigration. The present study investigated whether intracellular superoxide dismutase (SOD) suppressed monocyte endothelial trafficking and transmigration. Human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes were activated by the cytokine tumor necrosis factor-α (TNF-α) in the absence and presence of cell-permeable transactivator of transcription (Tat)-SOD protein. External stimulation with SOD was conducted using endothelial cells and monocytes. Purified cell-permeable Tat-SOD, but not non-targeted SOD, at 1-3 µM was transduced into endothelial cells in a time‑ and dose-dependent manner. Non-toxic Tat-SOD at ≤0.5 µM, but not 1 µM SOD, blocked the monocyte-endothelium interactions by inhibiting the TNF-α-induced stimulation of vascular cell adhesion molecule-1 (VCAM-1) in HUVECs and integrin β1 in THP-1 cells. Endothelial VCAM-1 induction by TNF-α was responsible for superoxide anion production being quenched by N-acetyl-cysteine and Tat-SOD. SOD treatment markedly inhibited superoxide anion production induced by TNF-α, but no inhibition of endothelial transmigration was noted. Tat-SOD prevented transendothelial monocyte migration by firmly localizing occludin-1, platelet/endothelial cell adhesion molecule‑1 (PECAM-1) and vascular endothelial‑cadherin present in paracellular junctions and inhibiting endothelial induction and activation of matrix-degrading membrane type-1 (MT-1) matrix metalloproteinase (MMP), MMP-2 and MMP-9. By contrast, treatment with 1 µM SOD did not have such effects. Furthermore, transduced Tat-SOD hindered nuclear transactivation of nuclear factor-κB (NF-κB), modulating the induction of paracellular junction proteins and matrix‑degrading MMP in TNF-α‑stimulated HUVECs. Transduced Tat-SOD, but not external SOD, impeded cytokine-induced endothelial adhesion and the transmigration of monocytes. Thus, we suggest that transduced Tat-SOD qualifies as an atheroprotective agent against oxidation-driven and inflammation-associated atherosclerosis.}, }
@article {pmid26707376, year = {2016}, author = {Li, W and Cao, L and Chen, X and Lei, J and Ma, Q}, title = {Resveratrol inhibits hypoxia-driven ROS-induced invasive and migratory ability of pancreatic cancer cells via suppression of the Hedgehog signaling pathway.}, journal = {Oncology reports}, volume = {35}, number = {3}, pages = {1718-1726}, doi = {10.3892/or.2015.4504}, pmid = {26707376}, issn = {1791-2431}, mesh = {Cell Hypoxia/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Regulation, Neoplastic/drug effects ; Hedgehog Proteins/genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis/genetics ; Matrix Metalloproteinase 2/*biosynthesis/genetics ; Neoplasm Invasiveness/genetics ; Pancreatic Neoplasms/*drug therapy/genetics/pathology ; Reactive Oxygen Species/metabolism ; Resveratrol ; Signal Transduction/drug effects ; Stilbenes/*administration &amp; dosage ; Urokinase-Type Plasminogen Activator/*biosynthesis/genetics ; }, abstract = {A hypoxic microenvironment is commonly found in the central region of solid tumors, including pancreatic cancer. Our previous study revealed that resveratrol plays an important role in suppressing the proliferation and EMT of pancreatic cancer cells. However, whether resveratrol could suppress hypoxia-induced cancer progression and the underlying mechanisms have not been fully elucidated. The aim of the present study was to evaluate whether resveratrol affects hypoxia-induced reactive oxygen species (ROS) production and the activation of the Hedgehog (Hh) signaling pathway as well as the invasion of pancreatic cancer. The human pancreatic cancer cell lines, BxPC-3 and Panc-1, were subjected to a hypoxic condition and three different concentrations of resveratrol. The intracellular ROS were determined using 2,7-dichlorodihydrofluorecein diacetate. Wound healing and Transwell invasion assays were used to detect the migratory and invasive potential of the cancer cells. Metastatic-related and Hh signaling-related factors were detected by qRT-PCR and western blot analysis. Immunofluorescence staining was used to test the nuclear translocation of GLI1. The results showed that the hypoxia-induced production of ROS was decreased by resveratrol in a concentration-dependent manner. Resveratrol significantly inhibited the hypoxia-stimulated invasion and migration of pancreatic cancer cells. Resveratrol inhibited hypoxia-induced HIF-1α protein expression. Resveratrol also suppressed hypoxia‑induced expression of metastatic-related factors, uPA and MMP2. In addition, resveratrol markedly inhibited hypoxia-mediated activation of the Hh signaling pathway. Furthermore, the antioxidant N-acetylcysteine (NAC) significantly suppressed the invasive and migratory ability of pancreatic cancer cells during hypoxia. Taken together, these data indicate that resveratrol plays an important role in suppressing hypoxia-driven ROS-induced pancreatic cancer progression by inhibiting the Hh signaling pathway, providing evidence that resveratrol may be a potential candidate for the chemoprevention of cancer.}, }
@article {pmid26703449, year = {2016}, author = {Huang, M and Zeng, S and Qiu, Q and Xiao, Y and Shi, M and Zou, Y and Yang, X and Xu, H and Liang, L}, title = {Niclosamide induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes.}, journal = {International immunopharmacology}, volume = {31}, number = {}, pages = {45-49}, doi = {10.1016/j.intimp.2015.11.002}, pmid = {26703449}, issn = {1878-1705}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Arthritis, Rheumatoid/*immunology ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cells, Cultured ; Fibroblasts/*drug effects/pathology ; Gene Expression Regulation/drug effects ; Humans ; Niclosamide/*administration &amp; dosage ; Oncogene Protein v-akt/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Synovial Membrane/*pathology ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {To explore the effects of niclosamide on the viability and apoptosis of rheumatoid arthritis of fibroblast-like synoviocytes (rheumatoid arthritis (RA)fibroblast-like synoviocytes (FLS)), FLS obtained from RA patients were treated with niclosamide. Niclosamide significantly inhibited the viability of RA FLS in a concentration-dependent manner. Niclosamide treated FLS showed a significant increase in the percentage of apoptosis and higher intracellular ROS levels. N-acetyl-l-cysteine (NAC) pretreatment significantly attenuated niclosamide-induced apoptosis. The apoptotic response was due to the up-regulation of pro-apoptotic protein, Bax, and down-regulation of antiapoptotic protein, B cell lymphoma 2 (Bcl-2). The activation of mitochondrial pathway in niclosamide-treated RA FLS induced the cytochrome C, cleavage of caspase-9 and caspase-3. Additionally, niclosamide inhibited the phosphorylation of Akt. Collectively, our results reveal that niclosamide inhibits cell proliferation and induces mitochondrial apoptosis of RAFLSs, which is associated with the modulation of Akt signaling pathways.}, }
@article {pmid26702595, year = {2016}, author = {Usmiani, T and Andreis, A and Budano, C and Sbarra, P and Andriani, M and Garrone, P and Fanelli, AL and Calcagnile, C and Bergamasco, L and Biancone, L and Marra, S}, title = {AKIGUARD (Acute Kidney Injury GUARding Device) trial: in-hospital and one-year outcomes.}, journal = {Journal of cardiovascular medicine (Hagerstown, Md.)}, volume = {17}, number = {7}, pages = {530-537}, doi = {10.2459/JCM.0000000000000348}, pmid = {26702595}, issn = {1558-2035}, mesh = {Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Aged ; Aged, 80 and over ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Female ; Fluid Therapy/*methods ; Furosemide/therapeutic use ; Glomerular Filtration Rate ; Humans ; Intention to Treat Analysis ; Italy ; Kaplan-Meier Estimate ; Male ; *Percutaneous Coronary Intervention ; Prospective Studies ; Renal Insufficiency, Chronic/diagnosis/surgery ; Sodium Bicarbonate/therapeutic use ; Sodium Chloride/therapeutic use ; }, abstract = {AIMS: Contrast-induced acute kidney injury (CIAKI) in patients with chronic kidney disease undergoing coronary angiography or percutaneous coronary intervention is a common iatrogenic complication associated with increased morbidity and mortality. This study compares sodium bicarbonate/isotonic saline/N-acetylcysteine/vitamin C prophylaxis (BS-NAC) against high-volume forced diuresis with matched hydration in CIAKI prevention.<br><br>METHODS: One-hundred and thirty-three consecutive patients undergoing coronary angiography or percutaneous coronary intervention with estimated glomerular filtration rate less than 60&#x200a;mL/min/1.73m were randomized to the study group receiving matched hydration (MHG) or to the control group receiving BS-NAC. MHG received in vein (i.v.) 250&#x200a;mL isotonic saline bolus, followed by a 0.5&#x200a;mg/kg furosemide i.v. bolus to forced diuresis. A dedicated device automatically matched the isotonic saline i.v. infusion rate to the urinary output for 1&#x200a;h before, during and 4&#x200a;h after the procedure.<br><br>RESULTS: MHG had the lowest incidence of CIAKI (7 vs. 25%, P&#x200a;=&#x200a;0.01), major adverse cardiac and cerebrovascular events at 1 year (7 vs. 32%, P&#x200a;<&#x200a;0.01) and readmissions to cardiology/nephrology departments (8 vs. 25%, P&#x200a;=&#x200a;0.03; hospitalization days 1.0&#x200a;&#xb1;&#x200a;3.8 vs. 4.9&#x200a;&#xb1;&#x200a;12.5, P&#x200a;=&#x200a;0.01). Three months after the procedure the decrease in the estimated glomerular filtration rate was 0.02% for MHG versus 15% for the control group.<br><br>CONCLUSION: Matched hydration was more effective than BS-NAC in CIAKI prevention. One-year follow-up showed that matched hydration was associated also with limited chronic kidney disease progression, major adverse cardiac and cerebrovascular events and hospitalizations.}, }
@article {pmid26697327, year = {2015}, author = {Lambros, MP and DeSalvo, MK and Moreno, J and Mulamalla, HC and Kondapalli, L}, title = {Transcriptional profiling of radiation damage and preventive treatments in a 3-dimensional (3D) human cell culture model of oral mucositis.}, journal = {Genomics data}, volume = {6}, number = {}, pages = {40-43}, pmid = {26697327}, issn = {2213-5960}, abstract = {Cancer patients who receive radiation are often afflicted by oral mucositis, a debilitating disease, characterized by mouth sores and difficulty in swallowing. Oftentimes, cancer patients afflicted with mucositis must stop life-saving therapies. Thus it is very important to prevent mucositis before it develops. Using a validated organotypic model of human oral mucosa, a 3-dimensional cell culture model of human oral keratinocytes, it has been shown that a mixture (NAC-QYD) of N-acetyl cysteine (NAC) and a traditional Chinese medicine, Qingre Liyan decoction (QYD), prevented radiation damage (Lambros et al., 2014). Here we provide detailed methods and analysis of microarray data for non-irradiated and irradiated human oral mucosal tissue with and without pretreatment with NAC, QYD and NAC-QYD. The microarray data been deposited in Gene Expression Omnibus (GEO): GSE62397. These data can be used to further elucidate the mechanisms of irradiation damage in oral mucosa and its prevention.}, }
@article {pmid26696857, year = {2015}, author = {Durieux, AM and Fernandes, C and Murphy, D and Labouesse, MA and Giovanoli, S and Meyer, U and Li, Q and So, PW and McAlonan, G}, title = {Targeting Glia with N-Acetylcysteine Modulates Brain Glutamate and Behaviors Relevant to Neurodevelopmental Disorders in C57BL/6J Mice.}, journal = {Frontiers in behavioral neuroscience}, volume = {9}, number = {}, pages = {343}, pmid = {26696857}, issn = {1662-5153}, abstract = {An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span.}, }
@article {pmid26694382, year = {2015}, author = {de Andrade, KQ and Moura, FA and dos Santos, JM and de Araújo, OR and de Farias Santos, JC and Goulart, MO}, title = {Oxidative Stress and Inflammation in Hepatic Diseases: Therapeutic Possibilities of N-Acetylcysteine.}, journal = {International journal of molecular sciences}, volume = {16}, number = {12}, pages = {30269-30308}, pmid = {26694382}, issn = {1422-0067}, mesh = {Acetylcysteine/chemistry/*pharmacology/*therapeutic use ; Animals ; Biomarkers/metabolism ; Humans ; Inflammation/*pathology ; Liver Diseases/*pathology ; Models, Biological ; Oxidative Stress/*drug effects ; }, abstract = {Liver disease is highly prevalent in the world. Oxidative stress (OS) and inflammation are the most important pathogenetic events in liver diseases, regardless the different etiology and natural course. N-acetyl-l-cysteine (the active form) (NAC) is being studied in diseases characterized by increased OS or decreased glutathione (GSH) level. NAC acts mainly on the supply of cysteine for GSH synthesis. The objective of this review is to examine experimental and clinical studies that evaluate the antioxidant and anti-inflammatory roles of NAC in attenuating markers of inflammation and OS in hepatic damage. The results related to the supplementation of NAC in any form of administration and type of study are satisfactory in 85.5% (n = 59) of the cases evaluated (n = 69, 100%). Within this percentage, the dosage of NAC utilized in studies in vivo varied from 0.204 up to 2 g/kg/day. A standard experimental design of protection and treatment as well as the choice of the route of administration, with a broader evaluation of OS and inflammation markers in the serum or other biological matrixes, in animal models, are necessary. Clinical studies are urgently required, to have a clear view, so that, the professionals can be sure about the effectiveness and safety of NAC prescription.}, }
@article {pmid26693496, year = {2015}, author = {Pezeshgi, A and Parsamanesh, N and Farhood, G and Mahmoodi, K}, title = {Evaluation of the protective effect of N-acetylcysteine on contrast media nephropathy.}, journal = {Journal of renal injury prevention}, volume = {4}, number = {4}, pages = {109-112}, pmid = {26693496}, issn = {2345-2781}, abstract = {INTRODUCTION: Intravenous contrast agents can cause acute decline in kidney function, especially in patients with risk factors.<br><br>OBJECTIVES: In this study, we aimed to examine the ameliorative effect N-acetylcysteine (NAC) to reduce the incidence of contrast nephropathy.<br><br>PATIENTS AND METHODS: This study was a prospective, randomized, double-blind clinical trial on 150 patients who underwent coronary angiography. The study was carried out on patients undergoing coronary angiography. Patients were randomly assigned into 2 groups of intervention group and control subjects. Intervention group took NAC 600 mg orally twice a day. It was administered one day before angiography and continued until the second day after angiography. Control subjects received saline only. Serum creatinine was measured before and three days after coronary angiography.<br><br>RESULTS: There was no significant difference between intervention and control groups at baseline (P > 0.05). However, there was a significant decline in creatinine level among NAC patients (P = 0.001). Saline group had significantly higher proportion of nephropathy cases than NAC patients Conclusion: We found that the consumption of NAC is useful for contrast induced nephropathy (CIN) prevention.}, }
@article {pmid26691320, year = {2016}, author = {Schmid, RD and Hovda, LR}, title = {Acute Hepatic Failure in a Dog after Xylitol Ingestion.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {12}, number = {2}, pages = {201-205}, pmid = {26691320}, issn = {1937-6995}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Animals, Inbred Strains ; Antidotes/therapeutic use ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/blood/physiopathology/therapy/*veterinary ; Combined Modality Therapy/veterinary ; Disseminated Intravascular Coagulation/etiology/prevention &amp; control/veterinary ; Dogs ; Hypoglycemia/etiology/prevention &amp; control/veterinary ; Liver Failure, Acute/etiology/prevention &amp; control/*veterinary ; Male ; S-Adenosylmethionine/therapeutic use ; Sweetening Agents/chemistry/*poisoning ; Treatment Outcome ; Xylitol/antagonists &amp; inhibitors/*poisoning ; }, abstract = {Xylitol is a five-carbon sugar alcohol produced from natural resources frequently used as a sugar substitute for humans. We report the development and successful treatment of acute hepatic failure and coagulopathy in a dog after xylitol ingestion. A 9-year-old 4.95 kg (10.9 lb) neutered male Chihuahua was evaluated at a veterinary clinic for vomiting after ingesting 224 g (45 g/kg, 20.5 g/lb) of granulated xylitol. Hypoglycemia developed within 1-2 h, elevated liver values, suggesting the development of acute hepatic failure, within 12 h and coagulopathy less than 24 h after ingestion. Treatment included maropitant, intravenous dextrose, phytonadione, metronidazole, and fresh frozen plasma. N-acetylcysteine (NAC) and S-adensoyl-L-methionine (SAMe) provided hepatic detoxification and support. The dog survived and liver values returned to normal within 1 month post ingestion. No adverse effects to hepatic function have been identified 2 years after acute xylitol toxicity. This paper is one of the few reports of successful management of a dog with hypoglycemia, hepatic failure, and coagulopathy caused by xylitol toxicity. To date, this is the highest published xylitol dose survived by a dog, as well as the only reported case that documents laboratory changes throughout the course of toxicity and includes normal hepatic indices for 7 months following xylitol toxicity. The rapidly expanding use of xylitol in a variety of products intended for human consumption has led to a rise in xylitol toxicity cases reported in dogs, and clinicians should be aware that more dogs may potentially be exposed and develop similar manifestations.}, }
@article {pmid26689740, year = {2016}, author = {Fantacuzzi, M and Maccallini, C and Di Matteo, M and Ammazzalorso, A and Bruno, I and De Filippis, B and Giampietro, L and Mollica, A and Amoroso, R}, title = {Screening of NOS activity and selectivity of newly synthesized acetamidines using RP-HPLC.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {120}, number = {}, pages = {419-424}, doi = {10.1016/j.jpba.2015.11.045}, pmid = {26689740}, issn = {1873-264X}, mesh = {Amidines/*chemical synthesis/pharmacokinetics ; Chromatography, High Pressure Liquid/methods ; Enzyme Activation/drug effects/physiology ; Enzyme Inhibitors/*analysis/pharmacokinetics ; Nitric Oxide Synthase Type II/*analysis/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Nitric Oxide Synthase (NOS) inhibitors could play a powerful role in inflammatory and neurodegenerative diseases. In this work, novel acetamidine derivatives of NOS were synthesized and the inhibitor activity was evalued. To screen the activity and selectivity, the l-citrulline residue, after the enzymatic NOS assay, was derivatized with o-phthaldialdehyde/N-acetyl cysteine (OPA/NAC) and then evaluated by RP-HPLC method with fluorescence detection. All compounds did not affect the activity of endothelial and neuronal isoforms, while nine of them possessed a percentage of iNOS activity at 10μM lower than 50%, and were selected for IC50 evaluation. Among them, a compound emerged as a very potent (IC50 of 53nM) and selective iNOS inhibitor.}, }
@article {pmid26687918, year = {2016}, author = {Li, C and Han, X and Zhang, H and Wu, J and Li, B}, title = {The interplay between autophagy and apoptosis induced by tanshinone IIA in prostate cancer cells.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {37}, number = {6}, pages = {7667-7674}, pmid = {26687918}, issn = {1423-0380}, mesh = {Abietanes/*pharmacology ; Acetylcysteine/pharmacology ; Adenocarcinoma/*pathology ; Amino Acid Chloromethyl Ketones/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Beclin-1/biosynthesis/genetics ; Caspase 3/metabolism ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Humans ; Male ; Microtubule-Associated Proteins/biosynthesis/genetics ; Neoplasm Proteins/biosynthesis/genetics ; Prostatic Neoplasms/*pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Tanshinone IIA (T2A), a derivative of phenanthrenequinone and also the major active ingredient of Danshen, has been paid extensive attention as a promising cancer therapy for its potential anti-cancer activities. In this study, the apoptosis and autophagy of human prostate cancer PC-3 cells were observed after 5 μM T2A treatment, as well as their relevance. Mitochondrial-dependent apoptosis was firstly detected through morphological observation and biochemical analysis. Meanwhile, 5 μM T2A successfully triggered the autophagy of PC-3 cells, indicated by increased expression of Beclin1, and LC3 II. Validation experiments were conducted to further consolidate T2A's contribution to autophagy: Pretreatment with autophagy inhibitor 3-methyladenine (3-MA) provided protection against autophagy and enhanced T2A-induced apoptosis. Besides, the apoptosis suppressor z-VAD-fmk failed to facilitate the formation of autophagic vacuoles, which also proved the T2A-induced autophagy independent of apoptosis. Moreover, the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) efficiently inhibited the expression of Beclin1, LC3-II, and cleaved caspase-3, which indicated apoptosis and autophagy with dependence on intracellular ROS production. Taken together, these results demonstrated that autophagy is the cytoprotective mechanism in this experimental system, and the ROS resulted from T2A treatment played a critical role in apoptosis and autophagy initiation.}, }
@article {pmid26683224, year = {2016}, author = {García, V and Lara-Chica, M and Cantarero, I and Sterner, O and Calzado, MA and Muñoz, E}, title = {Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells.}, journal = {Oncotarget}, volume = {7}, number = {4}, pages = {4490-4506}, pmid = {26683224}, issn = {1949-2553}, mesh = {Animals ; Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Blotting, Western ; Cell Cycle Checkpoints/*drug effects ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Comet Assay ; DNA Damage/drug effects ; Fluorescent Antibody Technique ; Humans ; Immunoenzyme Techniques ; Lactones/*pharmacology ; Male ; Mice ; Mice, Nude ; Phosphorylation/drug effects ; Prostatic Neoplasms/drug therapy/metabolism/*pathology ; Tumor Cells, Cultured ; Wound Healing/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {Galiellalactone (GL) is a fungal metabolite that presents antitumor activities on prostate cancer in vitro and in vivo. In this study we show that GL induced cell cycle arrest in G2/M phase, caspase-dependent apoptosis and also affected the microtubule organization and migration ability in DU145 cells. GL did not induce double strand DNA break but activated the ATR and ATM-mediated DNA damage response (DDR) inducing CHK1, H2AX phosphorylation (fH2AX) and CDC25C downregulation. Inhibition of the ATM/ATR activation with caffeine reverted GL-induced G2/M cell cycle arrest, apoptosis and DNA damage measured by fH2AX. In contrast, UCN-01, a CHK1 inhibitor, prevented GL-induced cell cycle arrest but enhanced apoptosis in DU145 cells. Furthermore, we found that GL did not increase the levels of intracellular ROS, but the antioxidant N-acetylcysteine (NAC) completely prevented the effects of GL on fH2AX, G2/M cell cycle arrest and apoptosis. In contrast to NAC, other antioxidants such as ambroxol and EGCG did not interfere with the activity of GL on cell cycle. GL significantly suppressed DU145 xenograft growth in vivo and induced the expression of fH2AX in the tumors. These findings identify for the first time that GL activates DDR in prostate cancer.}, }
@article {pmid26681765, year = {2016}, author = {Di, K and Lloyd, GK and Abraham, V and MacLaren, A and Burrows, FJ and Desjardins, A and Trikha, M and Bota, DA}, title = {Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier.}, journal = {Neuro-oncology}, volume = {18}, number = {6}, pages = {840-848}, pmid = {26681765}, issn = {1523-5866}, support = {P30 CA062203/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Blood-Brain Barrier/*drug effects/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Glioma/*drug therapy ; Lactones/*pharmacology ; Mice, Inbred BALB C ; Mice, Nude ; Proteasome Inhibitors/*pharmacology ; Pyrroles/*pharmacology ; }, abstract = {BACKGROUND: The proteasome plays a vital role in the physiology of glioblastoma (GBM), and proteasome inhibition can be used as a strategy for treating GBM. Marizomib is a second-generation, irreversible proteasome inhibitor with a more lipophilic structure that suggests the potential for penetrating the blood-brain barrier. While bortezomib and carfilzomib, the 2 proteasome inhibitors approved for treatment of multiple myeloma, have little activity against malignant gliomas in vivo, marizomib could be a novel therapeutic strategy for primary brain tumors.<br><br>METHODS: The in-vitro antitumor activity of marizomib was studied in glioma cell lines U-251 and D-54. The ability of marizomib to cross the blood-brain barrier and regulate proteasome activities was evaluated in cynomolgus monkeys and rats. The antitumor effect of marizomib in vivo was tested in an orthotopic xenograft model of human GBM.<br><br>RESULTS: Marizomib inhibited the proteasome activity, proliferation, and invasion of glioma cells. Meanwhile, free radical production and apoptosis induced by marizomib could be blocked by antioxidant N-acetyl cysteine. In animal studies, marizomib distributed into the brain at 30% of blood levels in rats and significantly inhibited (>30%) baseline chymotrypsin-like proteasome activity in brain tissue of monkeys. Encouragingly, the immunocompromised mice, intracranially implanted with glioma xenografts, survived significantly longer than the control animals (P < .05) when treated with marizomib.<br><br>CONCLUSIONS: These preclinical studies demonstrated that marizomib can cross the blood-brain barrier and inhibit proteasome activity in rodent and nonhuman primate brain and elicit a significant antitumor effect in a rodent intracranial model of malignant glioma.}, }
@article {pmid26681636, year = {2016}, author = {Lewis, P and Sheehan, D and Soares, R and Coelho, AV and O'Halloran, KD}, title = {Redox Remodeling Is Pivotal in Murine Diaphragm Muscle Adaptation to Chronic Sustained Hypoxia.}, journal = {American journal of respiratory cell and molecular biology}, volume = {55}, number = {1}, pages = {12-23}, doi = {10.1165/rcmb.2015-0272OC}, pmid = {26681636}, issn = {1535-4989}, mesh = {*Adaptation, Physiological ; Animals ; Antioxidants/metabolism ; Chronic Disease ; Diaphragm/*metabolism/*physiopathology ; Disease Models, Animal ; Hypoxia/*metabolism/*physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinases/metabolism ; Muscle Contraction ; Oxidation-Reduction ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Protein Carbonylation ; Proteomics ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Sulfhydryl Compounds/metabolism ; }, abstract = {Mechanisms underpinning chronic sustained hypoxia (CH)-induced structural and functional adaptations in respiratory muscles are unclear despite the clinical relevance to respiratory diseases. The objectives of the present study were to thoroughly assess the putative role of CH-induced redox remodeling in murine diaphragm muscle over time and the subsequent effects on metabolic enzyme activities, catabolic signaling and catabolic processes, and diaphragm muscle contractile function. C57Bl6/J mice were exposed to normoxia or normobaric CH (fraction of inspired oxygen = 0.1) for 1, 3, or 6 weeks. A second cohort was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine). After CH exposure, we performed two-dimensional redox proteomics with mass spectrometry, enzyme activity assays, and cell-signaling assays on diaphragm homogenates. We also assessed diaphragm isotonic contractile and endurance properties ex vivo. Global protein redox changes in the diaphragm after CH are indicative of oxidation. Remodeling of proteins key to contractile, metabolic, and homeostatic functions was observed. Several oxidative and glycolytic enzyme activities were decreased by CH. Redox-sensitive chymotrypsin-like proteasome activity of the diaphragm was increased. CH decreased phospho-forkhead box O3a (FOXO3a) and phospho-mammalian target of rapamycin content. Hypoxia-inducible factor-1α and phospho-p38 mitogen-activated protein kinase content was increased in CH diaphragm, and this was attenuated by antioxidant treatment. CH exposure decreased force- and power-generating capacity of the diaphragm, and this was prevented by antioxidant supplementation with N-acetyl cysteine but not tempol. Redox remodeling is pivotal for diaphragm adaptation to CH, affecting metabolic activity, atrophy signaling, and functional performance. Antioxidant supplementation may be useful as an adjunctive therapy in respiratory-related diseases characterized by hypoxic stress.}, }
@article {pmid26680088, year = {2015}, author = {Cusumano, G and Romagnoli, J and Liuzzo, G and Ciavarella, LP and Severino, A and Copponi, G and Manchi, M and Giubilato, S and Zannoni, GF and Stigliano, E and Caristo, ME and Crea, F and Citterio, F}, title = {N-Acetylcysteine and High-Dose Atorvastatin Reduce Oxidative Stress in an Ischemia-Reperfusion Model in the Rat Kidney.}, journal = {Transplantation proceedings}, volume = {47}, number = {9}, pages = {2757-2762}, doi = {10.1016/j.transproceed.2015.09.035}, pmid = {26680088}, issn = {1873-2623}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Atorvastatin/administration &amp; dosage/*pharmacology ; Catalase/metabolism ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione Peroxidase/metabolism ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration &amp; dosage/*pharmacology ; Kidney/blood supply/injuries/pathology ; Kidney Diseases/*drug therapy/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Peroxidase/metabolism ; Rats ; Reperfusion Injury/*drug therapy/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: To investigate the effects of N-acetylcysteine (NAC) and high-dose atorvastatin (ATOR) in reducing oxidative stress in a rat kidney model of ischemia-reperfusion injury.<br><br>METHODS: Forty female rats underwent clamping of the left renal artery for 30 minutes, followed by reperfusion. The effects of pre-ischemic administration of NAC and/or ATOR were evaluated within 4 groups: a) control (no NAC, no ATOR); b) NAC (intraperitoneal NAC administration); c) ATOR (oral ATOR administration); and d) NAC+ATOR (both drugs). Oxidative stress was assessed by measuring the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and myeloperoxidase (MPO). Post-ischemia-reperfusion injury was evaluated by means of renal histology.<br><br>RESULTS: NAC, ATOR, and NAC+ATOR in rats showed lower MPO (P&#xa0;< .05) and higher GPx activity (P&#xa0;< .05) versus control; SOD activity was lower in NAC versus ATOR (P&#xa0;< .05). No difference among groups was found at histology. However, a lower rate of tubular ischemic lesions was evident in NAC+ATOR versus control (P&#xa0;= .07).<br><br>CONCLUSIONS: Atorvastatin pretreatment provides protection against oxidative stress in a rat kidney model of ischemia-reperfusion injury, reinforcing the evidence of a beneficial effect of statins beyond their cholesterol-lowering properties.}, }
@article {pmid26674585, year = {2015}, author = {Zhang, JQ and Zhang, JQ and Fang, LZ and Liu, L and Fu, WP and Dai, LM}, title = {Effect of oral N-acetylcysteine on COPD patients with microsatellite polymorphism in the heme oxygenase-1 gene promoter.}, journal = {Drug design, development and therapy}, volume = {9}, number = {}, pages = {6379-6387}, pmid = {26674585}, issn = {1177-8881}, mesh = {Acetylcysteine/*administration &amp; dosage/*therapeutic use ; Administration, Oral ; Aged ; Alleles ; DNA/genetics ; Dose-Response Relationship, Drug ; Female ; Genotype ; Heme Oxygenase-1/*genetics/metabolism ; Humans ; Male ; Microsatellite Repeats/*genetics ; Polymorphism, Genetic/*genetics ; Promoter Regions, Genetic/*genetics ; Pulmonary Disease, Chronic Obstructive/diagnosis/*drug therapy/*genetics ; }, abstract = {BACKGROUND: Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung, and HO-1 gene promoter polymorphism has been shown to be associated with the severity and prognosis of COPD patients. N-acetylcysteine (NAC), an antioxidant/mucous modifier, has shown an uncertain benefit in COPD patients. We hypothesized that this polymorphism could be associated with the effectiveness of oral NAC.<br><br>METHODS: A total of 368 patients with COPD were recruited and the polymorphisms of their HO-1 gene promoter were classified into three subclasses according to the number of (GT)n repeats, as previously reported: class S (<27 (GT)n repeats), class M (27-32 (GT)n repeats), and class L (>32 (GT)n repeats). These subjects were then classified as L+ group (with the L allele: L/L, L/M, L/S) and L- group (without the L allele: M/M, M/S, S/S). All the patients were allocated to standard therapy plus NAC 600 mg bid over a 1-year period and were observed over that year.<br><br>RESULTS: The L- group saw improvements in forced expiratory volume in 1 second (FEV1) (from 1.44&#xb1;0.37 to 1.58&#xb1;0.38, P=0.04) and FEV1% predicted (from 56.6&#xb1;19.2 to 59.7&#xb1;17.2, P=0.03). No improvement was found in forced vital capacity of each group and the decline of forced vital capacity in both of the groups was not statistical significant. The number of yearly COPD exacerbations of the L- group was 1.5&#xb1;0.66 which was lower than the 2.1&#xb1;0.53 of the L+ group (P<0.01). For the changes of St George's Respiratory Questionnaire (SGRQ) score, only the activity score of the L- group was more significant than that of the L+ group (P=0.02). The improvement of the outcome of 6-minute walking distance test in L- group (from 290.1&#xb1;44.9 meters to 309.7&#xb1;46.9 m) was higher than that in the L+ group (from 289.7&#xb1;46.2 m to 300.3&#xb1;44.2 m) (P=0.03).<br><br>CONCLUSION: A 600 mg bid oral NAC treatment for 1-year on COPD patients without the L allele can improve the FEV1, FEV1% predicted, the SGRQ activity score, and the result of 6-minute walking distance test, and the exacerbation rate of the L allele carrier in COPD patients is much higher than in the COPD patients without the L allele.}, }
@article {pmid26671656, year = {2016}, author = {Mao, G and Goswami, M and Kalen, AL and Goswami, PC and Sarsour, EH}, title = {N-acetyl-L-cysteine increases MnSOD activity and enhances the recruitment of quiescent human fibroblasts to the proliferation cycle during wound healing.}, journal = {Molecular biology reports}, volume = {43}, number = {1}, pages = {31-39}, pmid = {26671656}, issn = {1573-4978}, support = {R01 CA111365/CA/NCI NIH HHS/United States ; 2R01 CA111365/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Fibroblasts/cytology/*drug effects/metabolism ; Humans ; Mice ; Mice, Knockout ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*metabolism ; Wound Healing/*drug effects ; }, abstract = {The rebuilding of the connective tissue during wound healing requires the recruitment of fibroblasts to the wound area as well as reentry of quiescent fibroblasts to the proliferative cycle. Whether this process can be modulated by a small molecular weight thiol antioxidant N-acetyl-L-cysteine (NAC) was tested in normal human skin fibroblasts (NHFs) using a uni-directional wound healing assay. NAC treated cells demonstrated a decreased migration rate but increased number of proliferating cells recruited into the wound area post wounding. Fifteen day quiescent control and NAC treated NHFs were re-plated at a lower density and cell numbers counted at different days post-plating. Interestingly, NAC treated cells exhibited increased cellular proliferation indicated by both decreased cell population doubling time and increased S phase cells. NAC treated cells demonstrated decreased steady state levels of reactive oxygen species as well as increased protein and activity levels of manganese superoxide dismutase (MnSOD). NAC treatment failed to induce proliferation in quiescent cells lacking MnSOD expression. These results demonstrate that NAC enhanced the recruitment of quiescent NHFs into proliferation cycle during wound healing. Our results also suggest that the wound healing properties of NAC might be due to its ability to induce and enhance MnSOD expression and activity. Altogether, these findings suggest NAC might be potentially developed as a dietary intervention to improve tissue injury in animals and humans.}, }
@article {pmid26670322, year = {2015}, author = {Kartha, RV and Zhou, J and Basso, L and Schröder, H and Orchard, PJ and Cloyd, J}, title = {Mechanisms of Antioxidant Induction with High-Dose N-Acetylcysteine in Childhood Cerebral Adrenoleukodystrophy.}, journal = {CNS drugs}, volume = {29}, number = {12}, pages = {1041-1047}, pmid = {26670322}, issn = {1179-1934}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Adolescent ; Adrenoleukodystrophy/*drug therapy/*metabolism ; Antioxidants/*administration &amp; dosage/pharmacology ; Blood Chemical Analysis ; Cells, Cultured ; Child ; Child, Preschool ; Enzyme-Linked Immunosorbent Assay ; Ferritins/*metabolism ; Fibroblasts/drug effects/metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Male ; RNA, Messenger/metabolism ; Treatment Outcome ; }, abstract = {BACKGROUND: Childhood cerebral adrenoleukodystrophy (CCALD), a progressive demyelinating disease affecting school-aged boys, causes death within a few years. Oxidative stress is an important contributing factor. N-acetylcysteine (NAC; 280 mg/kg/day) added as adjunctive therapy to reduced-intensity hematopoietic cell transplantation (HCT) improves survival in advanced cases. However, the mechanisms underlying the benefits of NAC are unclear.<br><br>OBJECTIVE: The aim of this study was to understand the mechanism of action of NAC in the setting of HCT in CCALD.<br><br>METHODS: Immunoassays were carried out to determine changes in heme oxygenase-1 (HO-1) and ferritin expression in plasma samples collected from boys with CCALD at three different timepoints during the course of transplantation. In addition, the induction of HO-1 was also confirmed in normal fibroblasts following incubation with 10-100&#xa0;&#xb5;mol/L NAC for 4&#xa0;h.<br><br>RESULTS: Following NAC therapy we observed an increase in expression of the antioxidants HO-1 (~4-fold) and its effector ferritin (~160-fold) in patient samples as compared with baseline. We also observed that NAC exposure significantly increased HO-1 expression in fibroblasts.<br><br>CONCLUSION: Our data suggest that HO-1 is a possible target protein of NAC and a mediator of its cytoprotective effects in these patients.}, }
@article {pmid26667036, year = {2015}, author = {Huggins, CJ and Mayekar, MK and Martin, N and Saylor, KL and Gonit, M and Jailwala, P and Kasoji, M and Haines, DC and Quiñones, OA and Johnson, PF}, title = {C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4.}, journal = {Molecular and cellular biology}, volume = {36}, number = {5}, pages = {693-713}, pmid = {26667036}, issn = {1098-5549}, support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, mesh = {Activating Transcription Factor 4/analysis/genetics/*metabolism ; Animals ; CCAAT-Enhancer-Binding Proteins/analysis/genetics/*metabolism ; Cell Line ; Female ; Fetus/abnormalities/metabolism ; Gene Deletion ; Gene Expression Regulation ; Glutathione/metabolism ; Humans ; Male ; Mice, Inbred C57BL ; Neoplasms/genetics/metabolism ; *Oxidative Stress ; Protein Multimerization ; Response Elements ; Transcription Factor CHOP/metabolism ; }, abstract = {The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances, and endoplasmic reticulum (ER) stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here, we show that C/EBPγ:ATF4 heterodimers, but not C/EBPβ:ATF4 dimers, are the predominant CARE-binding species in stressed cells. C/EBPγ and ATF4 associate with genomic CAREs in a mutually dependent manner and coregulate many ISR genes. In contrast, the C/EBP family members C/EBPβ and C/EBP homologous protein (CHOP) were largely dispensable for induction of stress genes. Cebpg(-/-) mouse embryonic fibroblasts (MEFs) proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg(-/-) mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPγ-deficient newborns die from atelectasis and respiratory failure, which can be mitigated by in utero exposure to the antioxidant, N-acetyl-cysteine. Cebpg(-/-) mice on a mixed strain background showed improved viability but, upon aging, developed significantly fewer malignant solid tumors than WT animals. Our findings identify C/EBPγ as a novel antioxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells.}, }
@article {pmid26664414, year = {2015}, author = {Mund, ME and Quarcoo, D and Gyo, C and Brüggmann, D and Groneberg, DA}, title = {Paracetamol as a toxic substance for children: aspects of legislation in selected countries.}, journal = {Journal of occupational medicine and toxicology (London, England)}, volume = {10}, number = {}, pages = {43}, pmid = {26664414}, issn = {1745-6673}, abstract = {Paracetamol is used widely in pediatrics because it has a high drug safety when used in therapeutic dosages. In case of overdose the majority of paracetamol is metabolized to N-acetyl-p-benzoquinone imine (NAPQI), which is responsible for the severe toxic effects. The covalent connection between NAPQI and hepatic proteins leads to hepatocellular damage and possibly to severe liver failure. The antidote for paracetamol is N-acetylcysteine (NAC). It is a precursor of glutathione and aids to fill glutathione stores. The Rumack-Matthew nomogram should be used to decide on antidote treatment. Pediatric drug metabolism differs from adult metabolism. Children have a larger liver size compared to their body weight than adults, resulting in a higher metabolism rate. Young children seem to be less sensitive to acute intoxication than adults. One hypothesis to explain the lower rate refers to the larger liver size. The acute toxic dosage for children is more than 200 mg/kg body weight. There seems to be a global increase in accidental pediatric paracetamol overdose. Governmental websites of various European Union (EU) countries were searched for legal information on paracetamol availability in pharmacies and non-pharmacy stores. Various EU countries permit prescription-free sales of paracetamol in pharmacies and non-pharmacy stores. In Sweden paracetamol 500 mg may be sold in both pharmacies and non-pharmacies in a maximum pack size of 20 units. In the United Kingdom (UK) paracetamol 500 mg is listed in the general sales list with a maximum pack size of 30 effervescent tablets or 16 tablets. In Ireland paracetamol 500 mg may be sold in a maximum pack size of 12 units in a non-pharmacy. In the Netherlands paracetamol 500 mg is legal to be sold in a maximum pack size of 50 units in a drug store and with a maximum of 20 units in any other non-pharmacy. Several countries in the European Union are permitted to offer paracetamol prescription-free in pharmacies and non-pharmacy stores without legal guidance on the storage position within the store. Further research is needed to investigate whether paracetamol is located directly accessible to young children within the stores in EU countries which permit prescription-free sales of paracetamol.}, }
@article {pmid26659826, year = {2016}, author = {Terrill, JR and Pinniger, GJ and Graves, JA and Grounds, MD and Arthur, PG}, title = {Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy.}, journal = {The Journal of physiology}, volume = {594}, number = {11}, pages = {3095-3110}, pmid = {26659826}, issn = {1469-7793}, mesh = {Animals ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscle Contraction/drug effects/physiology ; Muscle, Skeletal/*drug effects/*physiology ; Muscular Dystrophy, Duchenne/*diet therapy/genetics/*metabolism ; Pyrrolidonecarboxylic Acid/administration &amp; dosage ; Taurine/*administration &amp; dosage/*biosynthesis ; Thiazolidines/administration &amp; dosage ; }, abstract = {KEY POINTS: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation, oxidative stress and myofibre necrosis. Cysteine precursor antioxidants such as N-acetyl cysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) reduce dystropathology in the mdx mouse model for DMD, and we propose this is via increased synthesis of the amino acid taurine. We compared the capacity of OTC and taurine treatment to increase taurine content of mdx muscle, as well as effects on in vivo and ex vivo muscle function, inflammation and oxidative stress. Both treatments increased taurine in muscles, and improved many aspects of muscle function and reduced inflammation. Taurine treatment also reduced protein thiol oxidation and was overall more effective, as OTC treatment reduced body and muscle weight, suggesting some adverse effects of this drug. These data suggest that increasing dietary taurine is a better candidate for a therapeutic intervention for DMD.<br><br>ABSTRACT: Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease for which there is no widely available cure. Whilst the mechanism of loss of muscle function in DMD and the mdx mouse model are not fully understood, disruptions in intracellular calcium homeostasis, inflammation and oxidative stress are implicated. We have shown that protein thiol oxidation is increased in mdx muscle, and that the indirect thiol antioxidant l-2-oxothiazolidine-4-carboxylate (OTC), which increases cysteine availability, decreases pathology and increases in vivo strength. We propose that the protective effects of OTC are a consequence of conversion of cysteine to taurine, which has itself been shown to be beneficial to mdx pathology. This study compares the efficacy of taurine with OTC in decreasing dystropathology in mdx mice by measuring in vivo and ex vivo contractile function and measurements of inflammation and protein thiol oxidation. Increasing the taurine content of mdx muscle improved both in vivo and ex vivo muscle strength and function, potentially via anti-inflammatory and antioxidant effects of taurine. OTC treatment increased taurine synthesis in the liver and taurine content of mdx muscle, improved muscle function and decreased inflammation. However, OTC was less effective than taurine treatment, with OTC also decreasing body and EDL muscle weights, suggesting that OTC had some detrimental effects. These data support continued research into the use of taurine as a therapeutic intervention for DMD, and suggest that increasing dietary taurine is the better strategy for increasing taurine content and decreasing severity of dystropathology.}, }
@article {pmid26659493, year = {2016}, author = {Reyes, RC and Cittolin-Santos, GF and Kim, JE and Won, SJ and Brennan-Minnella, AM and Katz, M and Glass, GA and Swanson, RA}, title = {Erratum to: Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {13}, number = {1}, pages = {239}, doi = {10.1007/s13311-015-0413-3}, pmid = {26659493}, issn = {1878-7479}, }
@article {pmid26658309, year = {2015}, author = {Horie, M and Warabi, E and Komine, S and Oh, S and Shoda, J}, title = {Cytoprotective Role of Nrf2 in Electrical Pulse Stimulated C2C12 Myotube.}, journal = {PloS one}, volume = {10}, number = {12}, pages = {e0144835}, pmid = {26658309}, issn = {1932-6203}, mesh = {Animals ; Antioxidants/metabolism ; Apoptosis/physiology ; Cell Line ; Cell Survival/physiology ; Cytoprotection ; Electric Stimulation ; Mice ; Muscle Fibers, Skeletal/metabolism ; Muscle, Skeletal/cytology/*metabolism ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress/physiology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Regular physical exercise is central to a healthy lifestyle. However, exercise-related muscle contraction can induce reactive oxygen species and reactive nitrogen species (ROS/RNS) production in skeletal muscle. The nuclear factor-E2-related factor-2 (Nrf2) transcription factor is a cellular sensor for oxidative stress. Regulation of nuclear Nrf2 signaling regulates antioxidant responses and protects organ structure and function. However, the role of Nrf2 in exercise- or contraction-induced ROS/RNS production in skeletal muscle is not clear. In this study, using differentiated C2C12 cells and electrical pulse stimulation (EPS) of muscle contraction, we explored whether Nrf2 plays a role in the skeletal muscle response to muscle contraction-induced ROS/RNS. We found that EPS (40 V, 1 Hz, 2 ms) stimulated ROS/RNS accumulation and Nrf2 activation. We also showed that expression of NQO1, HO-1 and GCLM increased after EPS-induced muscle contraction and was remarkably suppressed in cells with Nrf2 knockdown. We also found that the antioxidant N-acetylcysteine (NAC) significantly attenuated Nrf2 activation after EPS, whereas the nitric oxide synthetase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) did not. Furthermore, Nrf2 knockdown after EPS markedly decreased ROS/RNS redox potential and cell viability and increased expression of the apoptosis marker Annexin V in C2C12 myotubes. These results indicate that Nrf2 activation and expression of Nrf2 regulated-genes protected muscle against the increased ROS caused by EPS-induced muscle contraction. Thus, our findings suggest that Nrf2 may be a key factor for preservation of muscle function during muscle contraction.}, }
@article {pmid26658004, year = {2016}, author = {Barnado, A and Crofford, LJ and Oates, JC}, title = {At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases.}, journal = {Journal of leukocyte biology}, volume = {99}, number = {2}, pages = {265-278}, pmid = {26658004}, issn = {1938-3673}, support = {T32 AR059039/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy/immunology ; Antibodies, Monoclonal/therapeutic use ; Antimalarials/therapeutic use ; Apoptosis/immunology ; Atherosclerosis/etiology/prevention &amp; control ; Autoantigens/immunology ; Autoimmune Diseases/drug therapy/*immunology ; Biomarkers ; Deoxyribonuclease I/therapeutic use ; Extracellular Traps/drug effects/*immunology ; Female ; Humans ; Hydrolases/antagonists &amp; inhibitors ; Immunosuppressive Agents/therapeutic use ; Interferon-alpha/antagonists &amp; inhibitors/biosynthesis ; Lupus Erythematosus, Systemic/complications/drug therapy/immunology ; *Molecular Targeted Therapy ; Neutrophils/drug effects/*immunology ; Pregnancy ; Pregnancy Complications/immunology/prevention &amp; control ; Protein Processing, Post-Translational/drug effects ; Protein-Arginine Deiminase Type 4 ; Protein-Arginine Deiminases ; Thrombophilia/etiology/immunology ; Thrombosis/prevention &amp; control ; Translational Research, Biomedical/methods/trends ; Vitamin D/therapeutic use ; }, abstract = {Neutrophil extracellular traps are associated with a unique form of cell death distinct from apoptosis or necrosis, whereby invading microbes are trapped and killed. Neutrophil extracellular traps can contribute to autoimmunity by exposing autoantigens, inducing IFN-α production, and activating the complement system. The association of neutrophil extracellular traps with autoimmune diseases, particularly systemic lupus erythematosus, will be reviewed. Increased neutrophil extracellular trap formation is seen in psoriasis, antineutrophil cytoplasmic antibody-associated vasculitis, antiphospholipid antibody syndrome rheumatoid arthritis, and systemic lupus erythematosus. Neutrophil extracellular traps may promote thrombus formation in antineutrophil cytoplasmic antibody-associated vasculitis and antiphospholipid antibody syndrome. In systemic lupus erythematosus, increased neutrophil extracellular trap formation is associated with increased disease activity and renal disease, suggesting that neutrophil extracellular traps could be a disease activity marker. Neutrophil extracellular traps can damage and kill endothelial cells and promote inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus. As neutrophil extracellular traps induce IFN-α production, measuring neutrophil extracellular traps may estimate IFN-α levels and identify which systemic lupus erythematosus patients have elevated levels and may be more likely to respond to emerging anti-IFN-α therapies. In addition to anti-IFN-α therapies, other novel agents, such as N-acetyl-cysteine, DNase I, and peptidylarginine deiminase inhibitor 4, target neutrophil extracellular traps. Neutrophil extracellular traps offer insight into the pathogenesis of autoimmune diseases and provide promise in developing disease markers and novel therapeutic agents in systemic lupus erythematosus. Priority areas for basic research based on clinical research insights will be identified, specifically the potential role of neutrophil extracellular traps as a biomarker and therapeutic target in systemic lupus erythematosus.}, }
@article {pmid26656795, year = {2016}, author = {Rosic, G and Selakovic, D and Joksimovic, J and Srejovic, I and Zivkovic, V and Tatalović, N and Orescanin-Dusic, Z and Mitrovic, S and Ilic, M and Jakovljevic, V}, title = {The effects of N-acetylcysteine on cisplatin-induced changes of cardiodynamic parameters within coronary autoregulation range in isolated rat hearts.}, journal = {Toxicology letters}, volume = {242}, number = {}, pages = {34-46}, doi = {10.1016/j.toxlet.2015.11.028}, pmid = {26656795}, issn = {1879-3169}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biomarkers/metabolism ; Cardiotonic Agents/*pharmacology ; *Cisplatin ; Coronary Circulation/*drug effects ; Coronary Vessels/*drug effects/pathology/physiopathology ; Cytoprotection ; Disease Models, Animal ; Heart Diseases/chemically induced/metabolism/pathology/physiopathology/*prevention &amp; control ; Heart Rate/drug effects ; Homeostasis ; Isolated Heart Preparation ; Male ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Rats, Wistar ; Ventricular Function, Left/*drug effects ; Ventricular Pressure/drug effects ; }, abstract = {The aim of this study was to evaluate the effects of chronic NAC administration along with cisplatin on cisplatin-induced cardiotoxicity by means of coronary flow (CF), cardiodynamic parameters, oxidative stress markers and morphological changes in isolated rat heart. Isolated hearts of Wistar albino rats (divided into four groups: control, cisplatin, NAC and cisplatin+NAC group) were perfused according to Langendorff technique at constant coronary perfusion pressure starting at 50 and gradually increased to 65, 80, 95 and 110 cm H2O to evaluate cardiodynamic parameters within autoregulation range. Samples of coronary venous effluent (CVE) were collected for determination of CF and biochemical assays, and heart tissue samples for biochemical assays and histopathological examination. Cisplatin treatment decreased CF and heart rate, and increased left ventricular systolic pressure and maximum left ventricular pressure development rate. Cisplatin increased H2O2 and TBARS, but decreased NO2(-) levels in CVE. In tissue samples, cisplatin reduced pathological alterations in myocardium and coronary vessels, with no changes in the amount of total glutathione, as well as in activity of glutathione peroxidase and glutathione reductase. NAC coadministration, by reducing oxidative damage, attenuated cisplatin-induced changes of cardiodynamic and oxidative stress parameters, as well as morphological changes in myocardium and coronary vasculature.}, }
@article {pmid26656160, year = {2016}, author = {Cort, A and Ozben, T and Melchiorre, M and Chatgilialoglu, C and Ferreri, C and Sansone, A}, title = {Effects of bleomycin and antioxidants on the fatty acid profile of testicular cancer cell membranes.}, journal = {Biochimica et biophysica acta}, volume = {1858}, number = {2}, pages = {434-441}, doi = {10.1016/j.bbamem.2015.12.005}, pmid = {26656160}, issn = {0006-3002}, mesh = {Acetylcysteine/*pharmacology ; Bleomycin/*pharmacology ; Cell Line, Tumor ; Curcumin/*pharmacology ; Fatty Acids/*metabolism ; Free Radical Scavengers/*pharmacology ; Humans ; MAP Kinase Kinase 4/metabolism ; MAP Kinase Signaling System/drug effects ; Male ; Neoplasm Proteins/metabolism ; Testicular Neoplasms/*drug therapy/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Bleomycin is used in chemotherapy regimens for the treatment of patients having testicular germ-cell tumor (TGCT). There is no study in the literature investigating the effects of bleomycin on membrane lipid profile in testicular cancer cells. We investigated membrane fatty acid (FA) profiles isolated, derivatized and analyzed by gas chromatography of NTera-2 testicular cancer cells incubated with bleomycin (Bleo) for 24 h in the absence and presence of N-Acetyl-L-Cysteine (NAC) and curcumin (Cur) as commonly used antioxidant adjuvants. At the same time the MAPK pathway and EGFR levels were followed up. Bleomycin treatment increased significantly saturated fatty acids (SFA) of phospholipids at the expense of monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). Bleomycin also led to a significant increase in the trans lipid isomers of oleic and arachidonic acids due to its free radical producing effect. Incubation with bleomycin increased the p38 MAPK and JNK levels and downregulated EGFR pathway. Coincubation of bleomycin with NAC reversed effects caused by bleomycin. Our results highlight the important role of membrane fatty acid remodeling occurring during the use of bleomycin and its concurrent use with antioxidants which can adjuvate the cytotoxic effects of the chemotherapeutic agents.}, }
@article {pmid26655191, year = {2015}, author = {Singhal, R and Myneedu, VP}, title = {Microscopy as a diagnostic tool in pulmonary tuberculosis.}, journal = {International journal of mycobacteriology}, volume = {4}, number = {1}, pages = {1-6}, doi = {10.1016/j.ijmyco.2014.12.006}, pmid = {26655191}, issn = {2212-554X}, mesh = {Humans ; Microscopy, Fluorescence/economics/methods ; Sensitivity and Specificity ; Tuberculosis, Pulmonary/*diagnosis ; }, abstract = {Tuberculosis continues to cast a huge impact on humanity with its high incidence and mortality, especially in developing countries. For tuberculosis case detection, microscopy continues to be indispensible, given its low cost, rapidity, simplicity of procedure and high specificity. Modifications have attempted to improve the sensitivity of microscopy which include: concentration methods such as centrifugation, N-acetyl cysteine-sodium hydroxide, bleach, ammonium sulfate or chitin. Furthermore, classical Ziehl-Neelsen (ZN) staining has been subjected to varying carbol fuchsin concentrations or replaced by Kinyoun staining, fluorescent microscopy or immune-fluorescence. Currently, light emitting diode fluorescence is recognizably the most plausible method as an alternative to ZN staining.}, }
@article {pmid26654980, year = {2016}, author = {Marazita, MC and Dugour, A and Marquioni-Ramella, MD and Figueroa, JM and Suburo, AM}, title = {Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration.}, journal = {Redox biology}, volume = {7}, number = {}, pages = {78-87}, pmid = {26654980}, issn = {2213-2317}, mesh = {Cell Line ; Cell Survival/drug effects ; Cellular Senescence/drug effects ; Complement Factor H/genetics/metabolism ; Gene Expression Regulation ; Humans ; Hydrogen Peroxide/*adverse effects ; Interleukins/metabolism ; Macular Degeneration/etiology/immunology/metabolism/pathology ; Oxidative Stress ; Retinal Pigment Epithelium/*cytology/drug effects/metabolism ; Smoke/*adverse effects ; Nicotiana/chemistry ; Vascular Endothelial Growth Factor A/genetics/*metabolism ; }, abstract = {Oxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress-induced premature cellular senescence (SIPS) is postulated to contribute to this condition. In this study, we hypothesized that oxidative damage, promoted by endogenous or exogenous sources, could elicit a senescence response in RPE cells, which would in turn dysregulate the expression of major players in AMD pathogenic mechanisms. We showed that exposure of a human RPE cell line (ARPE-19) to a cigarette smoke concentrate (CSC), not only enhanced Reactive Oxygen Species (ROS) levels, but also induced 8-Hydroxydeoxyguanosine-immunoreactive (8-OHdG) DNA lesions and phosphorylated-Histone 2AX-immunoreactive (p-H2AX) nuclear foci. CSC-nuclear damage was followed by premature senescence as shown by positive senescence associated-β-galactosidase (SA-β-Gal) staining, and p16(INK4a) and p21(Waf-Cip1) protein upregulation. N-acetylcysteine (NAC) treatment, a ROS scavenger, decreased senescence markers, thus supporting the role of oxidative damage in CSC-induced senescence activation. ARPE-19 senescent cultures were also established by exposure to hydrogen peroxide (H2O2), which is an endogenous stress source produced in the retina under photo-oxidation conditions. Senescent cells upregulated the proinflammatory cytokines IL-6 and IL-8, the main markers of the senescence-associated secretory phenotype (SASP). Most important, we show for the first time that senescent ARPE-19 cells upregulated vascular endothelial growth factor (VEGF) and simultaneously downregulated complement factor H (CFH) expression. Since both phenomena are involved in AMD pathogenesis, our results support the hypothesis that SIPS could be a principal player in the induction and progression of AMD. Moreover, they would also explain the striking association of this disease with cigarette smoking.}, }
@article {pmid26654742, year = {2015}, author = {Ozkaya, H and Bahat, G and Tufan, A and Dogan, H and Bilicen, Z and Karan, MA}, title = {Successful treatment of non-healing pressure ulcers with topical n-acetyl cysteine.}, journal = {Journal of wound care}, volume = {24}, number = {12}, pages = {606, 608-11}, doi = {10.12968/jowc.2015.24.12.606}, pmid = {26654742}, issn = {0969-0700}, mesh = {Administration, Topical ; Aged, 80 and over ; Antioxidants/*therapeutic use ; Cysteine/*therapeutic use ; Female ; Homes for the Aged ; Humans ; Nursing Homes ; Pressure Ulcer/*drug therapy ; Prospective Studies ; Treatment Outcome ; Vasodilator Agents/*therapeutic use ; Wound Healing/*drug effects ; }, abstract = {OBJECTIVE: N-acetyl cysteine (NAC) is a thiol compound with antioxidant and vasodilatory properties. It has multiple potential uses-including as an aid to wound healing-supported by varying levels of evidence. Pressure ulcers (PUs) are a major problem affecting older and bed-bound patients, and are associated with significant morbidity, mortality, and health-care costs. We aimed to study whether topical NAC treatment may be useful in non-healing PUs in a prospective case study in two debilitated nursing home residents suffering from a total of three treatment-resistant PUs.<br><br>METHOD: PUs were staged as described by the National Pressure Ulcer Advisory Panel. The ulcers were measured at the beginning and weekly thereafter with a standard wound measuring paper ruler.<br><br>RESULTS: The first patient had a category 3 pressure ulcer and the second patient had one category 3 and one category 4 ulcer. Topical NAC vial administration significantly improved healing in all three PUs without any side effects.<br><br>CONCLUSION: Our data indicate that NAC may be used in treatment-resistant PUs successfully.}, }
@article {pmid26654154, year = {2016}, author = {Javanmanesh, F and Kashanian, M and Rahimi, M and Sheikhansari, N}, title = {A comparison between the effects of metformin and N-acetyl cysteine (NAC) on some metabolic and endocrine characteristics of women with polycystic ovary syndrome.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {32}, number = {4}, pages = {285-289}, doi = {10.3109/09513590.2015.1115974}, pmid = {26654154}, issn = {1473-0766}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Blood Glucose/drug effects ; Double-Blind Method ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Humans ; Hypoglycemic Agents/pharmacology/*therapeutic use ; Insulin/blood ; Lipid Metabolism/drug effects ; Metformin/pharmacology/*therapeutic use ; Polycystic Ovary Syndrome/blood/*drug therapy ; Young Adult ; }, abstract = {OBJECTIVE: To compare N-acetyl cysteine (NAC) and metformin on polycystic ovary syndrome (PCOS).<br><br>METHOD: Study was performed as a randomized double-blind clinical trial on women with diagnosis of PCOS without additional complications. In one group, oral NAC 600&#x2009;mg, three times a day and in the other group, 500&#x2009;mg oral metformin, three times a day were prescribed. Duration of treatment was 24 weeks, and after finishing this period of treatment, fasting blood glucose (FBS) and insulin, lipid profile and Homeostasis Model Assessment (HOMA) index were measured (all the blood samples were taken while fasting) and were compared in the two groups.<br><br>RESULTS: Forty-six women in NAC group and 48 women in metformin group finished the study. The two groups did not show significant difference according to age, body mass index (BMI) of more than 30; mean BMI, AUB, FBS, fasting blood insulin, lipid profile and HOMA index before treatment. After 24 weeks of treatment; BMI >30 [17 (35.4%) versus 7 (15.2%), p&#x2009;=&#x2009;0.033], mean BMI [(28.36&#x2009;&#xb1;&#x2009;2.27) versus (27.11&#x2009;&#xb1;&#x2009;3.55), p&#x2009;=&#x2009;0.44], number of women with the complain of abnormal uterine bleeding (AUB) [24 (50%) versus 13 (28.3%), p&#x2009;=&#x2009;0.037], FBS [(90.02&#x2009;&#xb1;&#x2009;6.24) versus (86.61&#x2009;&#xb1;&#x2009;7.81), p&#x2009;=&#x2009;0.021], fasting insulin (10.40&#x2009;&#xb1;&#x2009;2.64 versus 8.89&#x2009;&#xb1;&#x2009;2.20, p&#x2009;=&#x2009;0.004), HOMA Index (2.09&#x2009;&#xb1;&#x2009;0.69 versus 1.71&#x2009;&#xb1;&#x2009;0.45, p&#x2009;=&#x2009;0.001), low density lipoprotein (LDL) (141.83&#x2009;&#xb1;&#x2009;26.98 versus 127.89&#x2009;&#xb1;&#x2009;28.70, p&#x2009;=&#x2009;0.017) were less in NAC group. Triglyceride (TG) and total cholesterol did not show significant difference between the two groups after treatment. High-density lipoprotein (HDL) was higher in NAC group.<br><br>CONCLUSION: NAC can improve lipid profile and fasting blood sugar (FBS) and fasting blood insulin better than metformin.}, }
@article {pmid26653983, year = {2015}, author = {Kesari, KK and Luukkonen, J and Juutilainen, J and Naarala, J}, title = {Genomic instability induced by 50Hz magnetic fields is a dynamically evolving process not blocked by antioxidant treatment.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {794}, number = {}, pages = {46-51}, doi = {10.1016/j.mrgentox.2015.10.004}, pmid = {26653983}, issn = {1879-3592}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cell Line, Tumor ; Genomic Instability/*drug effects ; Humans ; Lipid Peroxidation/drug effects ; *Magnetic Fields ; Micronucleus Tests ; Reactive Oxygen Species/metabolism ; Vitamin K 3/pharmacology ; }, abstract = {Increased level of micronuclei was observed in SH-SY5Y cells in a previous study at 8 and 15 days after exposure to extremely low frequency (ELF) magnetic fields (MF), indicating possible induction of genomic instability in the progeny of the exposed cells. The aim of this study was to further explore the induction of genomic instability by ELF MFs by increasing the follow-up time up to 45 days after exposure. Human SH-SY5Y neuroblastoma cells were exposed to a 50Hz, 100μT MF for 24h with or without co-exposure to menadione (MQ), a chemical agent that increases cellular superoxide production. Micronuclei, reactive oxygen species (ROS) and lipid peroxidation (LPO) were measured at 15, 30 and 45 days after exposure. To study the possible causal role of ROS in the delayed effects of MF, the antioxidant N-acetylcysteine (NAC) was administered before MF exposure. Consistently with the previous study, the level of micronuclei was statistically significantly elevated 15 days after exposure. A similar effect was observed at 30 days, but not at 45 days after exposure. The level of LPO was statically significantly decreased 30 and 45 days after exposure. Consistently with our previous findings, the MF effect did not depend on co-exposure to MQ. Treatment with NAC effectively decreased cellular ROS level and suppressed the effect of MQ on ROS, but it did not block the MF effect, indicating that increase in ROS is not needed as a causal link between MF exposure and induction of delayed effects. The results presented here are consistent with genomic instability that persists in the progeny of MF-exposed cells up to at least 30 days after exposure. Changes in LPO observed at 30 and 45 days after exposure indicates that the MF-initiated process may continue up to at least 45 days after exposure.}, }
@article {pmid26653649, year = {2015}, author = {Xiao, Y and Xia, H and Zhu, L and Li, X and Chen, R and Yin, X and Jiang, Z and Feng, L and Chen, J and Yu, M and Lou, J and Zhang, X}, title = {[Study on the therapeutic effects of tetrandrine combined with N-acetylcysteine on experimental silicosis of rats].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {33}, number = {7}, pages = {519-522}, pmid = {26653649}, issn = {1001-9391}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Benzylisoquinolines/*pharmacology ; Disease Models, Animal ; Dust ; Hydroxyproline/metabolism ; Interleukin-6/metabolism ; Lung/pathology ; Malondialdehyde/metabolism ; Pulmonary Fibrosis/chemically induced/*drug therapy ; Quartz/toxicity ; Rats ; Rats, Wistar ; Silicon Dioxide/*toxicity ; Silicosis/*drug therapy ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVE: To compare the effects of oral treatment with tetrandrine (TD) and N-acetylcys-teine (NAC) separately or jointly on silica-exposed rats.<br><br>METHODS: 40 sprague-Dawly (SD) rats were randomly divided into normal saline group, quartz group, TD treatment group (50 mg/kg), NAC treatment group (500 mg/kg) and combined treatment group (TD: 50 mg/kg + NAC: 500 mg/kg). Rats in normal saline group and other groups received intratracheal instillation of normal saline and quartz dust suspension respectively. Treatment groups were given TD, NAC separately or jointly via esophagus the next day after instillation, once a day and six times a week for 30 consecutive days. At the end of experiment, the pathological changes of lung tissues were evaluated by the methods of Foot, HE and Masson staining, the level of hydroxyproline (HYP), malondjalde-hyde (MDA), tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) and interleukin-6 (IL-6) in lung tissues were measured by alkaline hydrolysis method, the barbituric acid method and enzyme-linked immunosorbent assay (ELISA) respectively.<br><br>RESULTS: Compared with the quartz group, lymph nodes/body coefficients in all treatment groups and lung/body coefficient in combined treatment group were significantly decreased (P < 0.05). Pathology results showed that the normal saline group demonstrated no obvious evidence of lung damage. The quartz group lungs silicotic lesions focused on II~III level, the TD treatment group was mainly with I level, the NAC treatment group was mainly with I~II level, and the combined treatment group only showed little silicotic nodule, no obvious fibrosis. HYP content in TD treatment group and combined treatment group were significantly lower than that in the quartz group (P < 0.05), while it showed no obvious change in NAC treatment group. MDA content in lung tissues of each treatment group (TD treatment group, NAC treatment group and combined treatment group) were 18.80 &#xb1; 2.94, 20.13 &#xb1; 4.01 and 17.05 &#xb1; 3.52 nmol/ml respectively, which lower than in the quartz group (23.99 &#xb1; 3.26 nmol/ml). The level of IL-6 in lung tissues of the quartz group were 89.57 &#xb1; 8.78 pg/ml. After TD and NAC monotherapy, the IL-6 content decreased to 79.22 &#xb1; 9.65 pg/ml and 81.63 &#xb1; 5.72 pg/ml, and it decreased more significantly after combined medication (74.37 &#xb1; 3.17 pg/ml). The level of TNF-&#x3b1; in the quartz group were 59.05 &#xb1; 4.48 pg/ml. After TD and NAC monotherapy, the TNF-&#x3b1; content decreased to 50.48 &#xb1; 2.76 pg/ml and 54.28 &#xb1; 4.30 pg/ml, and it decreased more significantly after combined medication (49.10 &#xb1; 4.98 pg/ml).<br><br>CONCLUSION: NAC and TD could reduce MDA, TNF-&#x3b1; and IL-6 levels in lung tissue, and alleviate SiO2-induced pulmonary fibrosis in rats. Combined treatment with TD and NAC was more effective than TD or NAC treatment separately.}, }
@article {pmid26651980, year = {2016}, author = {AlMatar, M and Batool, T and Makky, EA}, title = {Therapeutic Potential of N-Acetylcysteine for Wound Healing, Acute Bronchiolitis, and Congenital Heart Defects.}, journal = {Current drug metabolism}, volume = {17}, number = {2}, pages = {156-167}, doi = {10.2174/1389200217666151210124713}, pmid = {26651980}, issn = {1875-5453}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism ; Bronchiolitis/*drug therapy/metabolism ; Heart Defects, Congenital/*drug therapy/metabolism ; Humans ; Reactive Oxygen Species/metabolism ; Wound Healing/*drug effects ; }, abstract = {BACKGROUND: Wound healing is a composite and vital process in which devitalized tissue layers and cellular structures repair themselves. Bronchiolitis is generally prompted by respiratory syncytial virus or human metapneumovirus; this condition is an acute inflammatory injury of bronchioles. Heart problems that develop before birth are known as congenital heart defects (CHDs), and pregestational diabetes is considered a major predisposing factor of CHDs. N-Acetylcysteine (NAC) is a transformed kind of amino acid cysteine which restores the intracellular levels of the natural antioxidant glutathione when taken internally, thereby assisting the cells' ability to diminish the damaging effects of reactive oxygen species (ROS).<br><br>OBJECTIVE: In the present communication, NAC's therapeutic potential for wound healing, acute bronchiolitis, and congenital heart defects (CHDs) is critically analyzed by reviewing its effect on the various targets of these diseases. The multifunctional nature of NAC is outlined in a review of evidence from in vitro and in vivo studies.<br><br>CONCLUSION: In conclusion, NAC could be used as a therapeutic agent in the treatment of wound healing, acute bronchiolitis and congenital heart defects (CHDs). The focus of future research should be the following; (1) to examine NAC clinically to be considered in the treatment of wound healing; (2) to investigate whether NAC could be used alone or with insulin to prevent CHDs in infants with pregestational diabetes; (3) to evaluate the application of NAC as a potential agent for PAH treatment.}, }
@article {pmid26651262, year = {2016}, author = {Birdsall, RE and McCarthy, SM and Janin-Bussat, MC and Perez, M and Haeuw, JF and Chen, W and Beck, A}, title = {A sensitive multidimensional method for the detection, characterization, and quantification of trace free drug species in antibody-drug conjugate samples using mass spectral detection.}, journal = {mAbs}, volume = {8}, number = {2}, pages = {306-317}, pmid = {26651262}, issn = {1942-0870}, mesh = {Acetylcysteine/*chemistry ; Chromatography, Reverse-Phase ; Fluorescent Dyes/*chemistry ; Humans ; Mass Spectrometry ; Protein Stability ; Trastuzumab/*chemistry ; }, abstract = {Conjugation processes and stability studies associated with the production and shelf life of antibody-drug conjugates (ADCs) can result in free (non-conjugated) drug species. These free drug species can increase the risk to patients and reduce the efficacy of the ADC. Despite stringent purification steps, trace levels of free drug species may be present in formulated ADCs, reducing the therapeutic window. The reduction of sample preparation steps through the incorporation of multidimensional techniques has afforded analysts more efficient methods to assess trace drug species. Multidimensional methods coupling size-exclusion and reversed phase liquid chromatography with ultra-violet detection (SEC-RPLC/UV) have been reported, but offer limited sensitivity and can limit method optimization. The current study addresses these challenges with a multidimensional method that is specific, sensitive, and enables method control in both dimensions via coupling of an on-line solid phase extraction column to RPLC with mass spectral detection (SPE-RPLC/MS). The proposed method was evaluated using an antibody-fluorophore conjugate (AFC) as an ADC surrogate to brentuximab vedotin and its associated parent maleimide-val-cit-DSEA payload and the derived N-acetylcysteine adduct formed during the conjugation process. Assay sensitivity was found to be 2 orders more sensitive using MS detection in comparison to UV-based detection with a nominal limit of quantitation of 0.30 ng/mL (1.5 pg on-column). Free-drug species were present in an unadulterated ADC surrogate sample at concentrations below 7 ng/mL, levels not detectable by UV alone. The proposed SPE-RPLC/MS method provides a high degree of specificity and sensitivity in the assessment of trace free drug species and offers improved control over each dimension, enabling straightforward integration into existing or novel workflows.}, }
@article {pmid26648023, year = {2016}, author = {Jang, JH and Kim, JY and Sung, EG and Kim, EA and Lee, TJ}, title = {Gambogic acid induces apoptosis and sensitizes TRAIL-mediated apoptosis through downregulation of cFLIPL in renal carcinoma Caki cells.}, journal = {International journal of oncology}, volume = {48}, number = {1}, pages = {376-384}, doi = {10.3892/ijo.2015.3249}, pmid = {26648023}, issn = {1791-2423}, mesh = {Acetylcysteine/administration &amp; dosage ; Apoptosis/drug effects ; CASP8 and FADD-Like Apoptosis Regulating Protein/*biosynthesis/genetics ; Carcinoma, Renal Cell/*drug therapy/genetics/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Reactive Oxygen Species/metabolism ; TNF-Related Apoptosis-Inducing Ligand/*genetics/metabolism ; Xanthones/*administration &amp; dosage ; }, abstract = {Gambogic acid (GA) is a natural compound derived from brownish gamboge resin that shows a range of bioactivity, such as antitumor and antimicrobial properties. Although, GA is already known to induce cell death in a variety of cancer cells, the molecular basis for GA-induced cell death in renal cancer cells is unclear. In this study, a treatment with GA induced cell death in human renal carcinoma Caki cells in a dose-dependent manner. Treatment of Caki cells with GA decreased the levels of antiapoptotic proteins, such as Bcl-2 and XIAP in a dose-dependent manner. In addition, GA decreased the expression of the cFLIPL protein, which was downregulated at the transcriptional level without any change in the levels of cFLIPs expression. z-VAD (pan-caspase inhibitor) partially blocked GA-mediated cell death. GA-induced apoptotic cell death in Caki cells is mediated partly by the AIF translocation from the mitochondria into the nucleus via a caspase-independent pathway. In contrast, N-acetylcysteine (NAC), a ROS scavenger, had no effect on GA-induced cell death. The restoration of cFLIPL attenuated GA-induced cell death in Caki cells. Furthermore, a sub-toxic dose of GA sensitized TRAIL-mediated apoptosis in Caki cells. Pretreatment with z-VAD completely blocked GA plus TRAIL-mediated apoptosis. On the contrary, pretreatment with NAC partially inhibited GA plus TRAIL-induced apoptosis. Our findings suggested that GA induces apoptosis via the downregulation of cFLIPL and sensitized TRAIL-mediated apoptosis in Caki cells.}, }
@article {pmid26647857, year = {2016}, author = {Park, WH and You, BR}, title = {Antimycin A induces death of the human pulmonary fibroblast cells via ROS increase and GSH depletion.}, journal = {International journal of oncology}, volume = {48}, number = {2}, pages = {813-820}, doi = {10.3892/ijo.2015.3276}, pmid = {26647857}, issn = {1791-2423}, mesh = {Acetylcysteine/pharmacology ; Antimycin A/*pharmacology ; Antioxidants/metabolism ; Apoptosis/drug effects ; Ascorbic Acid/metabolism ; Caspase Inhibitors/pharmacology ; Cell Death/*drug effects ; Cell Line ; Cell Proliferation/drug effects ; Fibroblasts/*drug effects/metabolism ; G1 Phase/drug effects ; Glutathione/*metabolism ; Growth Inhibitors/pharmacology ; Humans ; Lung/*drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Antimycin A (AMA) inhibits the growth of various cells via stimulating oxidative stress-mediated death. However, little is known about the anti-growth effect of AMA on normal primary lung cells. Here, we investigated the effects of AMA on cell growth inhibition and death in human pulmonary fibroblast (HPF) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. AMA inhibited the growth of HPF cells with an IC50 of ~150 µM at 24 h. AMA induced a G1 phase arrest of the cell cycle and it also triggered apoptosis accompanied by the loss of mitochondrial membrane potential (MMP; ∆Ψm). AMA increased ROS levels including O2᛫- in HPF cells from the early time point of 25 min. It induced GSH depletion in HPF cells in a dose-dependent manner. Z-VAD (a pan-caspase inhibitor) did not significantly prevent cell death and MMP (∆Ψm) loss induced by AMA. N-acetylcysteine (NAC; an antioxidant) attenuated cell growth inhibition, death and MMP (∆Ψm) loss in AMA-treated HPF cells and NAC generally decreased the ROS level in these cells as well. Vitamin C enhanced cell growth inhibition, death, GSH depletion and O2᛫- levels in 100 µM AMA-treated HPF cells whereas this agent strongly attenuated these effects in 200 µM AMA-treated cells. In conclusion, AMA inhibited the growth of HPF cells via apoptosis as well as a G1 phase arrest of the cell cycle. AMA-induced HPF cell death was related to increased ROS levels and GSH depletion.}, }
@article {pmid26646579, year = {2015}, author = {Fazio, A and Briglia, M and Faggio, C and Alzoubi, K and Lang, F}, title = {Oxaliplatin Induced Suicidal Death of Human Erythrocytes.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {37}, number = {6}, pages = {2393-2404}, doi = {10.1159/000438592}, pmid = {26646579}, issn = {1421-9778}, mesh = {Antineoplastic Agents/*pharmacology ; Calcium/metabolism ; Cell Death/*drug effects ; Erythrocytes/*drug effects/metabolism ; Humans ; In Vitro Techniques ; Ion Transport ; Organoplatinum Compounds/*pharmacology ; Oxaliplatin ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND/AIMS: The alkylating drug oxaliplatin is widely used for chemotherapy of malignancy. Oxaliplatin is effective by inducing both, necrosis and apoptosis. Similar to necrosis or apoptosis of nucleated cells, erythrocytes may enter hemolysis, which is apparent from hemoglobin release or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress and/or Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether and how oxaliplatin induces eryptosis.<br><br>METHODS: Phosphatidylserine exposure at the cell surface was quantified utilizing annexin-V-binding, cell volume estimated from forward scatter, hemolysis deduced from hemoglobin release, [Ca2+]i determined utilizing Fluo-3 fluorescence, and reactive oxygen species (ROS) abundance visualized using 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) dependent fluorescence.<br><br>RESULTS: A 48 hours exposure of human erythrocytes to oxaliplatin (10 &#xb5;g/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, significantly increased Fluo-3 fluorescence, and significantly increased DCFDA fluorescence. The effect of oxaliplatin on annexin-V-binding and forward scatter was rather augmented by removal of extracellular Ca2+, but was significantly blunted in the presence of the antioxidant N-acetyl-cysteine (1 mM).<br><br>CONCLUSIONS: Oxaliplatin triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect partially dependent on ROS formation.}, }
@article {pmid26635914, year = {2016}, author = {Dyugovskaya, L and Berger, S and Polyakov, A and Lavie, P and Lavie, L}, title = {Intermittent Hypoxia Affects the Spontaneous Differentiation In Vitro of Human Neutrophils into Long-Lived Giant Phagocytes.}, journal = {Oxidative medicine and cellular longevity}, volume = {2016}, number = {}, pages = {9636937}, pmid = {26635914}, issn = {1942-0994}, mesh = {Adult ; Antigens, Differentiation/metabolism ; *Cell Differentiation ; Cell Hypoxia ; Cells, Cultured ; Female ; Giant Cells/cytology/*metabolism ; Humans ; Male ; Neutrophils/cytology/*metabolism ; *Signal Transduction ; }, abstract = {Previously we identified, for the first time, a new small-size subset of neutrophil-derived giant phagocytes (Gϕ) which spontaneously develop in vitro without additional growth factors or cytokines. Gϕ are CD66b(+)/CD63(+)/MPO(+)/LC3B(+) and are characterized by extended lifespan, large phagolysosomes, active phagocytosis, and reactive oxygen species (ROS) production, and autophagy largely controls their formation. Hypoxia, and particularly hypoxia/reoxygenation, is a prominent feature of many pathological processes. Herein we investigated Gϕ formation by applying various hypoxic conditions. Chronic intermittent hypoxia (IH) (29 cycles/day for 5 days) completely abolished Gϕ formation, while acute IH had dose-dependent effects. Exposure to 24 h (56 IH cycles) decreased their size, yield, phagocytic ability, autophagy, mitophagy, and gp91-phox/p22-phox expression, whereas under 24 h sustained hypoxia (SH) the size and expression of LC3B and gp91-phox/p22-phox resembled Gϕ formed in normoxia. Diphenyl iodide (DPI), a NADPH oxidase inhibitor, as well as the PI3K/Akt and autophagy inhibitor LY294002 abolished Gϕ formation at all oxygen conditions. However, the potent antioxidant, N-acetylcysteine (NAC) abrogated the effects of IH by inducing large CD66b(+)/LC3B(+) Gϕ and increased both NADPH oxidase expression and phagocytosis. These findings suggest that NADPH oxidase, autophagy, and the PI3K/Akt pathway are involved in Gϕ development.}, }
@article {pmid26635415, year = {2016}, author = {Li, S and Chen, G and Wu, M and Zhang, J and Wu, S}, title = {Restraining of reactive oxygen species promotes invasion of Listeria monocytogenes into glia cells.}, journal = {FEMS microbiology letters}, volume = {363}, number = {2}, pages = {fnv228}, doi = {10.1093/femsle/fnv228}, pmid = {26635415}, issn = {1574-6968}, mesh = {Cell Line ; Host-Pathogen Interactions ; Humans ; Listeria monocytogenes/genetics/*physiology ; Listeriosis/*metabolism/microbiology ; Neuroglia/*metabolism/microbiology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Listeria monocytogenes is a foodborne pathogen that could cause severe infection in the central nervous system of humans and animals. However, the molecular mechanism of the pathogenesis is not fundamentally assessed. This study aimed to analyze the role of reactive oxygen species (ROS) in L. monocytogenes during its invasion into glia cells. The ROS level in L. monocytogenes was manipulated using NAD(P)H oxidase inhibitor diphenyleneiodonium chloride (DPI) and ROS scavenger N-acetyl cysteine (NAC). Results showed that the invasiveness of L. monocytogenes was elevated when ROS was downregulated by DPI and NAC treatment. Expression profiles of proinflammatory factors in glia cells were also examined because they play important roles in the functions of glia cells in the brain immune system. The expression levels of proinflammatory factors (tumor necrosis factor α and interleukin-1β) in host glia cells were downregulated when invaded by L. monocytogenes with lower ROS level. This finding indicates that ROS may function as negative regulator during the invasion of L. monocytogenes in brain infection.}, }
@article {pmid26635070, year = {2017}, author = {Bhardwaj, JK and Saraf, P}, title = {N-acetyl cysteine-mediated effective attenuation of methoxychlor-induced granulosa cell apoptosis by counteracting reactive oxygen species generation in caprine ovary.}, journal = {Environmental toxicology}, volume = {32}, number = {1}, pages = {156-166}, doi = {10.1002/tox.22221}, pmid = {26635070}, issn = {1522-7278}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism/*pharmacology ; Apoptosis/*drug effects ; Dose-Response Relationship, Drug ; Female ; *Goats ; Granulosa Cells/*drug effects/pathology ; Insecticides/*toxicity ; Lipid Peroxidation/drug effects ; Methoxychlor/*antagonists &amp; inhibitors/*toxicity ; Ovary/*drug effects/pathology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Methoxychlor (MXC), an organochloride insecticide, is a potent toxicant-targeting female reproductive system and known to cause follicular atresia by inducing apoptosis within granulosa cells. Oxidative stress plays a pivotal role in apoptosis; thus, this study focuses on the ameliorative action of N-acetyl cysteine (NAC) on MXC-induced oxidative stress and apoptosis within granulosa cell of caprine ovary. Classic histology, fluorescence assay, and biochemical parameters were employed to evaluate the effect of varied concentration of NAC (1, 5, and 10 mM) on granulosa cell apoptosis after 24, 48, and 72 h exposure duration. Histomorphological studies revealed that NAC diminished the incidence of apoptotic attributes like condensed or marginated chromatin, pyknosis, crescent-shaped nucleus, empty cell spaces, and degenerated cellular structure along with the presence of cytoplasmic processes within granulosa cells in dose- and time-dependent manner. NAC significantly downregulated the percentage of MXC-induced granulosa cell apoptosis within healthy ovarian follicle with its increasing dose, maximum at 10 mM concentration. It also significantly (p < 0.05) upregulated the activity of antioxidant enzymes, namely catalase, superoxide dismutase, and glutathione-s-transferase, along with ferric reducing antioxidant power further declining lipid peroxidation in the MXC-treated caprine ovary. The results revealed a negative correlation between apoptosis frequency and antioxidant enzymes' activity (rCAT = -0.67, rSOD = -0.56, rGST = -0.31; p < 0.05) while a positive correlation was observed with lipid peroxidation (r = 0.63; p < 0.05) after NAC supplementation. Thus, NAC supplementation reduces the MXC-generated oxidative stress that perhaps declines the ROS generating signal transduction pathway of apoptosis, thereby preventing MXC-induced granulosa cell apoptosis and follicular atresia. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 156-166, 2017.}, }
@article {pmid26633044, year = {2016}, author = {Stine, JG and Lewis, JH}, title = {Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review.}, journal = {Expert review of gastroenterology &amp; hepatology}, volume = {10}, number = {4}, pages = {517-536}, pmid = {26633044}, issn = {1747-4132}, support = {T32 DK007769/DK/NIDDK NIH HHS/United States ; T32DK007769/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Adrenal Cortex Hormones/therapeutic use ; Antidotes/adverse effects/*therapeutic use ; Antioxidants/therapeutic use ; Chelating Agents/therapeutic use ; Chemical and Drug Induced Liver Injury/etiology/genetics/*prevention &amp; control/*therapy ; Cholagogues and Choleretics/therapeutic use ; Genetic Predisposition to Disease ; Humans ; Liver Transplantation ; Liver, Artificial ; Patient Selection ; Pharmacogenomic Testing ; Phenotype ; Precision Medicine ; Risk Factors ; Therapeutic Irrigation ; Treatment Outcome ; }, abstract = {While the pace of discovery of new agents, mechanisms and risk factors involved in drug-induced liver injury (DILI) remains brisk, advances in the treatment of acute DILI seems slow by comparison. In general, the key to treating suspected DILI is to stop using the drug prior to developing irreversible liver failure. However, predicting when to stop is an inexact science, and commonly used ALT monitoring is an ineffective strategy outside of clinical trials. The only specific antidote for acute DILI remains N-acetylcysteine (NAC) for acetaminophen poisoning, although NAC is proving to be beneficial in some cases of non-acetaminophen DILI in adults. Corticosteroids can be effective for DILI associated with autoimmune or systemic hypersensitivity features. Ursodeoxycholic acid, silymarin and glycyrrhizin have been used to treat DILI for decades, but success remains anecdotal. Bile acid washout regimens using cholestyramine appear to be more evidenced based, in particular for leflunomide toxicity. For drug-induced acute liver failure, the use of liver support systems is still investigational in the United States and emergency liver transplant remains limited by its availability. Primary prevention appears to be the key to avoiding DILI and the need for acute treatment. Pharmacogenomics, including human leukocyte antigen genotyping and the discovery of specific DILI biomarkers offers significant promise for the future. This article describes and summarizes the numerous and diverse treatment and prevention modalities that are currently available to manage DILI.}, }
@article {pmid26629962, year = {2016}, author = {Smith, L and Tracy, DK and Giaroli, G}, title = {What Future Role Might N-Acetyl-Cysteine Have in the Treatment of Obsessive Compulsive and Grooming Disorders?: A Systematic Review.}, journal = {Journal of clinical psychopharmacology}, volume = {36}, number = {1}, pages = {57-62}, doi = {10.1097/JCP.0000000000000431}, pmid = {26629962}, issn = {1533-712X}, mesh = {Acetylcysteine/adverse effects/pharmacology/*therapeutic use ; Adult ; Child ; Free Radical Scavengers/adverse effects/pharmacology/*therapeutic use ; Humans ; Obsessive-Compulsive Disorder/*drug therapy/physiopathology ; Oxidative Stress/drug effects ; Randomized Controlled Trials as Topic ; }, abstract = {Licensed pharmacological treatments for obsessive-compulsive disorders include selective serotonin reuptake inhibitors and tricyclic antidepressants. However, a large proportion of patients show minimal or no therapeutic response to these treatments. The glutamatergic system has been implicated in the etiology of obsessive-compulsive spectrum disorders, and it has been postulated that n-acetyl-cysteine (NAC) could have a therapeutic effect on these conditions through its actions on the glutamatergic system and the reduction of oxidative stress. A systematic review was conducted on the existing methodologically robust literature regarding the efficacy of NAC on obsessive-compulsive spectrum disorders in adults and children. Four randomized, double-blind placebo-controlled studies were identified, investigating the effects of NAC on obsessive-compulsive disorder, trichotillomania, and onychophagia. Results remain inconclusive, but NAC may still be useful as a treatment for obsessive-compulsive spectrum disorders on an individual level, particularly as the compound has a relatively benign side-effect profile. The dearth of methodologically robust work is clinically important: larger randomized controlled trials are required to inform of any meaningful clinical effectiveness, and to better determine which, if any, clinical populations might most benefit.}, }
@article {pmid26625315, year = {2016}, author = {Ramos-Torres, &#xc1; and Bort, A and Morell, C and Rodríguez-Henche, N and Díaz-Laviada, I}, title = {The pepper's natural ingredient capsaicin induces autophagy blockage in prostate cancer cells.}, journal = {Oncotarget}, volume = {7}, number = {2}, pages = {1569-1583}, pmid = {26625315}, issn = {1949-2553}, mesh = {Antineoplastic Agents, Phytogenic/isolation &amp; purification/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Capsaicin/isolation &amp; purification/*pharmacology ; Capsicum/chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Humans ; Lysosomes/drug effects/metabolism ; Male ; Microtubule-Associated Proteins/metabolism ; Phosphatidylinositol 3-Kinase/metabolism ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Time Factors ; }, abstract = {Capsaicin, the pungent ingredient of red hot chili peepers, has been shown to have anti-cancer activities in several cancer cells, including prostate cancer. Several molecular mechanisms have been proposed on its chemopreventive action, including ceramide accumulation, endoplasmic reticulum stress induction and NFκB inhibition. However, the precise mechanisms by which capsaicin exerts its anti-proliferative effect in prostate cancer cells remain questionable. Herein, we have tested the involvement of autophagy on the capsaicin mechanism of action on prostate cancer LNCaP and PC-3 cells.The results showed that capsaicin induced prostate cancer cell death in a time- and concentration-dependent manner, increased the levels of microtubule-associated protein light chain 3-II (LC3-II, a marker of autophagy) and the accumulation of the cargo protein p62 suggesting an autophagy blockage. Moreover, confocal microscopy revealed that capsaicin treatment increased lysosomes which co-localized with LC3 positive vesicles in a similar extent to that produced by the lysosomal protease inhibitors E64 and pepstatin pointing to an autophagolysosomes breakdown inhibition. Furthermore, we found that capsaicin triggered ROS generation in cells, while the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger. Co-treatment of cells with NAC and capsaicin abrogated the effects of capsaicin on autophagy and cell death. Normal prostate PNT2 and RWPE-1 cells were more resistant to capsaicin-induced cytotoxicity and did not accumulate p62 protein.Taken together, these results suggest that ROS-mediated capsaicin-induced autophagy blockage contributes to antiproliferation in prostate cancer cells, which provides new insights into the anticancer molecular mechanism of capsaicin.}, }
@article {pmid26625143, year = {2015}, author = {Lin, CP and Huang, PH and Lai, CF and Chen, JW and Lin, SJ and Chen, JS}, title = {Simvastatin Attenuates Oxidative Stress, NF-κB Activation, and Artery Calcification in LDLR-/- Mice Fed with High Fat Diet via Down-regulation of Tumor Necrosis Factor-α and TNF Receptor 1.}, journal = {PloS one}, volume = {10}, number = {12}, pages = {e0143686}, pmid = {26625143}, issn = {1932-6203}, mesh = {Animals ; Arteriosclerosis/*metabolism/pathology ; Calcinosis/*metabolism ; Diet, High-Fat ; Down-Regulation ; Gene Knockout Techniques ; Humans ; Male ; Mice ; Mice, Knockout ; NF-kappa B/*metabolism ; Oxidative Stress/*drug effects ; Receptors, LDL/genetics ; Receptors, Tumor Necrosis Factor, Type I/drug effects/*genetics/metabolism ; Simvastatin/*pharmacology ; Tumor Necrosis Factor-alpha/drug effects/genetics/*metabolism ; }, abstract = {Simvastatin (SIM) is anti-inflammatory. We used low density lipoprotein receptor knockout (LDLR-/-) mice and human aortic smooth muscle cells (HASMCs) as model systems to study the effect of SIM on arterial calcification and to explore the potential mechanisms contributing to this protective effect. High-fat diet (HFD) caused the LRLR -/- to develop dyslipidemia, diabetics, atherosclerosis and aortic smooth muscle calcification. SIM, N-acetyl cysteine (NAC, a ROS scavenger) and apocynin (APO, a NADPH oxidase inhibitor) did not significantly retard the development of dyslipidemia or diabetic. However, those treatments were still effective in attenuating the HFD-induced atherosclerosis and aortic smooth muscle calcification. These findings suggest that the protective effect of SIM against aortic calcification is not contributed by the cholesterol lowering effect. SIM, NAC and APO were found to attenuate the HFD induced elevation of serum TNF-α, soluble TNFR1 (sTNFR1), 3-nitro-tyrosine. We hypothesized that the pro-inflammatory cytokine, oxidative stress and TNFR1 played a role in inducing aortic calcification. We used HASMC to investigate the role of TNF-α, oxidative stress and TNFR1 in inducing aortic calcification and to elucidate the mechanism contributes the protective effect of SIM against aortic calcification. We demonstrated that treating HASMC with TNF-α induced cell Ca deposit and result in an increase in ALP, NADPH oxidase activity, NF-kB subunit p65, BMP2, MSX2, and RUNX2 expression. SIM suppressed the TNF-α induced activation of NADPH oxidase subunit p47, the above-mentioned bone markers and TNFR1 expression. Furthermore, p65, p47 and TNFR1 siRNAs inhibited the TNF-α-mediated stimulation of BMP-2, MSX2, RUNX2 expression. SIM, APO, and NAC either partially inhibit or completely block the TNF-α induced H2O2 or superoxide production. These results suggest that SIM may, independent of its cholesterol-lowering effect, suppresses the progression of vascular diseases through the inhibition of the inflammation mediators TNF-α and TNFR1.}, }
@article {pmid26624959, year = {2015}, author = {Sisombath, NS and Jalilehvand, F}, title = {Similarities between N-Acetylcysteine and Glutathione in Binding to Lead(II) Ions.}, journal = {Chemical research in toxicology}, volume = {28}, number = {12}, pages = {2313-2324}, pmid = {26624959}, issn = {1520-5010}, support = {P41 GM103393/GM/NIGMS NIH HHS/United States ; P41GM103393/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*chemistry ; Binding Sites ; Coordination Complexes/*chemistry ; Glutathione/*chemistry ; Lead/*chemistry ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {N-Acetylcysteine is a natural thiol-containing antioxidant, a precursor for cysteine and glutathione, and a potential detoxifying agent for heavy metal ions. However, previous accounts of the efficiency of N-acetylcysteine (H2NAC) in excretion of lead are few and contradicting. Here, we report results on the nature of lead(II) complexes formed with N-acetylcysteine in aqueous solution, which were obtained by combining information from several spectroscopic methods, including (207)Pb, (13)C, and (1)H NMR, Pb LIII-edge X-ray absorption, ultraviolet-visible (UV-vis) spectroscopy, and electro-spray ionization mass spectrometry (ESI-MS). Two series of solutions were used containing CPb(II) = 10 and 100 mM, respectively, varying the H2NAC/Pb(II) mole ratios from 2.1 to 10.0 at pH 9.1-9.4. The coordination environments obtained resemble those previously found for the Pb(II) glutathione system: at a ligand-to-lead mole ratio of 2.1, dimeric or oligomeric Pb(II) N-acetylcysteine complexes are formed, while a trithiolate [Pb(NAC)3](4-) complex dominates in solutions with H2NAC/Pb(II) mole ratios >3.0.}, }
@article {pmid26622376, year = {2015}, author = {Li, M and Gao, W and Ma, J and Zhu, Y and Li, X}, title = {Early-stage lupus nephritis treated with N-acetylcysteine: A report of two cases.}, journal = {Experimental and therapeutic medicine}, volume = {10}, number = {2}, pages = {689-692}, pmid = {26622376}, issn = {1792-0981}, abstract = {The oxidative-antioxidative status is closely associated with the progression of systemic lupus erythematosus (SLE), and oxidative stress is customarily found in patients with SLE. N-acetylcysteine (NAC), a typical antioxidant, is reliable and often applied for clinical treatment. Lupus nephritis (LN) is a kidney disorder associated with SLE, but the treatment of LN with antioxidants is rarely documented. The present report describes two cases of early-stage LN that were orally treated with 1,200 mg NAC in addition to the standard therapy with hydroxychloroquine and calcitriol. Following the NAC administration, the glutathione level largely increased while the level of the lipid peroxidation biomarker 8-iso-prostaglandin F2α declined in both cases. In addition, the routine blood counts, 24-h urine protein, erythrocyte sedimentation rate and the SLE disease activity index were markedly improved. In conclusion, the present report of two cases has shown that NAC, as an antioxidant, may exert a beneficial effect to modulate the oxidative status in LN; however, the underlying mechanisms require further investigation.}, }
@article {pmid26621689, year = {2016}, author = {Becker, K and Saurugger, EM and Kienberger, D and Lopes, D and Haack, D and Köberle, M and Stehr, M and Lochmann, D and Zimmer, A and Salar-Behzadi, S}, title = {Advanced stable lipid-based formulations for a patient-centric product design.}, journal = {International journal of pharmaceutics}, volume = {497}, number = {1-2}, pages = {136-149}, doi = {10.1016/j.ijpharm.2015.11.039}, pmid = {26621689}, issn = {1873-3476}, mesh = {Acetylcysteine/*chemistry/pharmacology ; Adult ; Chemistry, Pharmaceutical/*methods ; Computer Simulation ; Drug Liberation ; Drug Stability ; Excipients/chemistry ; Female ; Humans ; Male ; Middle Aged ; Particle Size ; Polysorbates/*chemistry ; Solubility ; Taste/drug effects ; Technology, Pharmaceutical/*methods ; Triglycerides/*chemistry ; Young Adult ; }, abstract = {Multiparticulate dosage forms are a recent strategy to meet the special needs of children, elderly people and patients suffering from dysphagia. Our study presents a novel and cost-efficient approach for the manufacturing of a taste-masked multiparticulate system with a stable immediate release profile by applying lipid-based excipients in a solvent-free hot melt coating process. The thermosensitive N-acetylcysteine (N-ac) was used as model drug and hot-melt coated with a mixture of tripalmitin and polysorbate 65. A predictive in vitro method for the evaluation of the taste masking efficiency was developed based on the deprotonation of the carboxyl group of N-ac and the decline of pH, responsible for the unpleasant sour taste of the compound. The method was confirmed using in vivo studies. Differential scanning calorimetry and X-ray scattering experiments revealed polymorphic transformation and its dependency on transformation time, temperature and emulsifier concentration. During the process, the coating was transformed almost completely into the stable β-polymorph, leading to an unaltered dissolution profile during storage. A statistical design was conducted that revealed the critical process parameters affecting the taste masking efficiency and drug release. This study shows the successful application of solvent-free hot-melt coating in the development of a taste-masked and stable formulation.}, }
@article {pmid26620190, year = {2016}, author = {Saito, Y and Ishii, KA and Aita, Y and Ikeda, T and Kawakami, Y and Shimano, H and Hara, H and Takekoshi, K}, title = {Loss of SDHB Elevates Catecholamine Synthesis and Secretion Depending on ROS Production and HIF Stabilization.}, journal = {Neurochemical research}, volume = {41}, number = {4}, pages = {696-706}, pmid = {26620190}, issn = {1573-6903}, mesh = {Animals ; Apoptosis ; Catecholamines/*biosynthesis/metabolism ; Cell Survival ; Electron Transport Complex II/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Mitochondria/metabolism ; Mutation ; PC12 Cells ; Paraganglioma/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA, Small Interfering/genetics ; Rats ; Reactive Oxygen Species/*metabolism ; Succinate Dehydrogenase/genetics/*metabolism ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Germline mutations in genes encoding succinate dehydrogenase subunits are associated with the development of familial pheochromocytomas and paragangliomas [hereditary paraganglioma/pheochromocytoma syndrome (HPPS)]. In particular, a mutation in succinate dehydrogenase subunit B (SDHB) is highly associated with abdominal paraganglioma and subsequent distant metastasis (malignant paraganglioma), indicating the importance of SDHB genetic testing. The discovery of HPPS suggests an association among genetic mitochondrial defects, tumor development, and catecholamine oversecretion. To investigate this association, we transfected pheochromocytoma cells (PC12) with SDHB-specific siRNA. SDHB silencing virtually abolished complex II activity, demonstrating the utility of this in vitro model for investigating the pseudo-hypoxic drive hypothesis. Lack of complex II activity resulting from RNA interference of SDHB increased tyrosine hydroxylase (TH; the rate-limiting enzyme in catecholamine biosynthesis) activity and catecholamine secretion. Reduced apoptosis was observed accompanied by Bcl-2 accumulation in PC12 cells, consistent with the phenotypes of paragangliomas with SDHB mutations. In addition, SDHB silencing increased reactive oxygen species (ROS) production and nuclear HIF1α stabilization under normoxic conditions. Furthermore, phenotypes induced by complex II activity knockdown were abolished by pretreatment with N-acetyl cysteine (an ROS scavenger) and by prior HIF1α knockdown, indicating an ROS- and HIF1α-dependent mechanism. Our results indicate that increased ROS may act as signal transduction messengers that induce HIF1α stabilization and may be necessary for the pseudo-hypoxic states observed in our experimental model. To our knowledge, this is the first study demonstrating that pseudo-hypoxic states resulting from SDHB knockdown are associated with increased TH activity and catecholamine oversecretion.}, }
@article {pmid26612354, year = {2016}, author = {Syed, M and Skonberg, C and Hansen, SH}, title = {Inhibition of ATP synthesis by fenbufen and its conjugated metabolites in rat liver mitochondria.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {31}, number = {}, pages = {23-29}, doi = {10.1016/j.tiv.2015.11.013}, pmid = {26612354}, issn = {1879-3177}, mesh = {2,4-Dinitrophenol/pharmacology ; Adenosine Triphosphate/*antagonists &amp; inhibitors/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Cyclosporine/pharmacology ; Egtazic Acid/pharmacology ; Glutathione/pharmacology ; Male ; Mitochondria, Liver/*drug effects/metabolism ; NADP/pharmacology ; Oxidative Phosphorylation/drug effects ; Phenylbutyrates/*pharmacology ; Rats, Sprague-Dawley ; Rotenone/pharmacology ; }, abstract = {Fenbufen is an arylpropionic acid derivative belonging to the group of non-steroidal anti-inflammatory drugs (NSAIDs). Even though fenbufen is considered a safe drug, some adverse reactions including hepatic events have been reported. To investigate whether mitochondrial damage could be involved in the drug induced liver injury (DILI) by fenbufen, the inhibitory effect of fenbufen and its conjugated metabolites on oxidative phosphorylation (ATP synthesis) in rat liver mitochondria was investigated. Fenbufen glucuronide (F-GlcA), fenbufen-N-acetyl cysteine-thioester (F-NAC) and fenbufen-S-glutathione thioester (F-SG) were found to be more potent inhibitors compared to parent fenbufen (F), whereas fenbufen-O-carnitine (F-carn), fenbufen-glycine (F-gly) and fenbufen-N-acetyl lysine amide (F-NAL) were less potent compared to fenbufen. Fenbufen-CoA thioester (F-CoA) was equally potent as fenbufen in inhibiting ATP synthesis. Fenbufen showed time and concentration dependent inhibition of ATP synthesis with Kinact of 4.4 min(-1) and KI of 0.88 μM and Kinact/KI ratio of 5.01 min(-1) μM(-1). Data show that fenbufen did not act through opening MPT pore, nor did incubation of mitochondria with reduced GSH and fenbufen show any protective effect on fenbufen mediated inhibition of oxidative phosphorylation. Inclusion of NADPH in mitochondrial preparations with fenbufen did not modulate the inhibitory effects, suggesting no role of CYP mediated oxidative metabolites on the ATP synthesis in isolated mitochondria. The results from the present experiments provide evidence that fenbufen and its metabolites could be involved in mitochondrial toxicity through inhibition of ATP synthesis.}, }
@article {pmid26612073, year = {2016}, author = {Sözbir, E and Nazıroğlu, M}, title = {Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain.}, journal = {Metabolic brain disease}, volume = {31}, number = {2}, pages = {385-393}, pmid = {26612073}, issn = {1573-7365}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Brain/metabolism ; Calcium/metabolism ; Diabetes Mellitus, Experimental/*metabolism ; Female ; Ganglia, Spinal/*drug effects ; Glutathione/metabolism ; Hydrogen Peroxide/pharmacology ; Lipid Peroxidation/drug effects ; Neurons/metabolism ; Oxidative Stress/drug effects ; Rats, Wistar ; TRPM Cation Channels/*metabolism ; }, abstract = {N-acetylcysteine (NAC) is a sulfhydryl donor antioxidant that contributes to the regeneration of glutathione (GSH) and also scavengers via a direct reaction with free oxygen radicals. Recently, we observed a modulatory role of NAC on GSH-depleted dorsal root ganglion (DRG) cells in rats. NAC may have a protective role on oxidative stress and calcium influx through regulation of the TRPM2 channel in diabetic neurons. Therefore, we investigated the effects of NAC on DRG TRPM2 channel currents and brain oxidative stress in streptozotocin (STZ)-induced diabetic rats. Thirty-six rats divided into four groups: control, STZ, NAC and STZ + NAC. Diabetes was induced in the STZ and STZ + NAC groups by intraperitoneal STZ (65 mg/kg) administration. After the induction of diabetes, rats in the NAC and STZ + NAC groups received NAC (150 mg/kg) via gastric gavage. After 2 weeks, DRG neurons and the brain cortex were freshly isolated from rats. In whole-cell patch clamp experiments, TRPM2 currents in the DRG following diabetes induction with STZ were gated by H2O2. TRPM2 channel current densities in the DRG and lipid peroxidation levels in the DRG and brain were higher in the STZ groups than in controls; however, brain GSH, GSH peroxidase (GSH-Px), vitamin C and vitamin E concentrations and DRG GSH-Px activity were decreased by diabetes. STZ + H2O2-induced TRPM2 gating was totally inhibited by NAC and partially inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2-APB). GSH-Px activity and lipid peroxidation levels were also attenuated by NAC treatment. In conclusion, we observed a modulatory role of NAC on oxidative stress and Ca(2+) entry through the TRPM2 channel in the diabetic DRG and brain. Since excessive oxidative stress and overload Ca(2+) entry are common features of neuropathic pain, our findings are relevant to the etiology and treatment of pain neuropathology in DRG neurons.}, }
@article {pmid26609913, year = {2016}, author = {Wang, Z and Zhao, X and Gong, X}, title = {Costunolide induces lung adenocarcinoma cell line A549 cells apoptosis through ROS (reactive oxygen species)-mediated endoplasmic reticulum stress.}, journal = {Cell biology international}, volume = {40}, number = {3}, pages = {289-297}, doi = {10.1002/cbin.10564}, pmid = {26609913}, issn = {1095-8355}, mesh = {Adenocarcinoma/metabolism/pathology ; Adenocarcinoma of Lung ; Antineoplastic Agents, Phytogenic/*toxicity ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Endoribonucleases/antagonists &amp; inhibitors/genetics/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lung Neoplasms/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*toxicity ; }, abstract = {Costunolide is an active sesquiterpene lactone derived from many herbal medicines. It has a broad spectrum of bioactivities, including anti-inflammatory and potential anti-tumor effects. The aims of the present study were to evaluate the inhibitory effects of costunolide on A549 cell growth and to explore the underlying molecular mechanisms. Annexin V-FITC/PI flow cytometry analysis revealed that costunolide induced apoptosis. To study the mechanism, we found that costunolide exposure activated the unfolded protein response (UPR) signaling pathways, as shown by the up-regulation of GRP78 and IRE1α and the activation of ASK1 and JNK. Meanwhile, siRNA knockdown of IRE1α significantly attenuated costunolide-induced apoptosis and partly restored the mitochondrial membrane potential. ER stress-activated JNK phosphorylated Bcl-2 at Ser70, which changes the anti-apoptotic function of Bcl-2, resulting in mitochondrial dysfunction and leading to mitochondrial activation of apoptosis. Furthermore, costunolide induced ROS generation, while the antioxidant N-acetyl cysteine (NAC) effectively blocked ER stress and apoptosis activation, suggesting that ROS acts as an upstream signaling molecule in triggering ER stress and mitochondrial apoptotic pathways. Taken together, our research demonstrates that costunolide exhibits its anti-tumor activity though inducing apoptosis, which is mediated by ER stress. We further confirm that Bcl-2 is a key molecule connecting the ER stress and mitochondrial pathways.}, }
@article {pmid26604642, year = {2015}, author = {Licks, F and Hartmann, RM and Marques, C and Schemitt, E and Colares, JR and Soares, Mdo C and Reys, J and Fisher, C and da Silva, J and Marroni, NP}, title = {N-acetylcysteine modulates angiogenesis and vasodilation in stomach such as DNA damage in blood of portal hypertensive rats.}, journal = {World journal of gastroenterology}, volume = {21}, number = {43}, pages = {12351-12360}, pmid = {26604642}, issn = {2219-2840}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Blotting, Western ; Comet Assay ; DNA Damage/*drug effects ; Disease Models, Animal ; Gastric Mucosa/metabolism ; Hypertension, Portal/blood/*drug therapy/genetics/physiopathology ; Immunohistochemistry ; Male ; *Neovascularization, Pathologic ; Nitric Oxide Synthase Type III/metabolism ; Portal Pressure/drug effects ; Rats, Wistar ; Stomach/*blood supply/*drug effects ; Tyrosine/analogs &amp; derivatives/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Vasodilation/*drug effects ; }, abstract = {AIM: To evaluate the antioxidant effect of N-acetylcysteine (NAC) on the stomach of rats with portal hypertension.<br><br>METHODS: Twenty-four male Wistar rats weighing &#xb1; 250 g were divided into four experimental groups (n = 6 each): Sham-operated (SO), SO + NAC, partial portal vein ligation (PPVL), and PPVL + NAC. Treatment with NAC in a dose of 10 mg/kg (i.p.) diluted in 0.6 mL of saline solution was administered daily for 7 d starting 8 d after the surgery. Animals from the PPVL and SO group received saline solution (0.6 mL) for the same period of time as the PPVL + NAC and SO + NAC group. On the 15(th) day the animals were anesthetized and we evaluated portal pressure by cannulating mesenteric artery. After, we removed the stomach for further analysis. We performed immunohistochemical analysis for endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), and nitrotirosine (NTT) proteins in stomach. We also evaluated eNOS and VEGF by Western blot analysis and assessed DNA damage in blood samples by the comet assay.<br><br>RESULTS: The portal hypertension group exhibited increases in portal pressure when compared to SO group (29.8 &#xb1; 1.8 vs 12.0 &#xb1; 0.3 mmHg) (P < 0.001). The same was observed when we compared the eNOS (56.8 &#xb1; 3.7 vs 13.46 &#xb1; 2.8 pixels) (P < 0.001), VEGF (34.9 &#xb1; 4.7 vs 17.46 &#xb1; 2.6 pixels) (P < 0.05), and NTT (39.01 &#xb1; 4.0 vs 12.77 &#xb1; 2.3 pixels) (P < 0.05) expression by immunohistochemistry of the PPVL animals with the SO group. The expression of eNOS (0.39 &#xb1; 0.03 vs 0.25 &#xb1; 0.03 a.&#x3bc;) (P < 0.01) and VEGF (0.38 &#xb1; 0.04 vs 0.26 &#xb1; 0.04 a.&#x3bc;) (P < 0.01) were also evaluated by Western blot analysis, and we observed an increase of both proteins on PPVL animals. We also evaluated the DNA damage by comet assay, and observed an increase on damage index and damage frequency on those animals. NAC decreased portal pressure values in PPVL + NAC animals (16.46 &#xb1; 2 vs 29.8 &#xb1; 1.8 mmHg) (P < 0.001) when compared to PPVL. The expression of eNOS (14.60 &#xb1; 4.1 vs 56.8 &#xb1; 3.7 pixels) (P < 0.001), VEGF (19.53 &#xb1; 3.2 vs 34.9 &#xb1; 4.7 pixels) (P < 0.05) and NTT (21.84 &#xb1; 0.7 vs 39.01 &#xb1; 4.0 pixels) (P < 0.05) evaluated by immunohistochemistry were also reduced in PPVL + NAC animals. Also, when evaluated by Western blot eNOS expression (0.32 &#xb1; 0.03 vs 0.39 &#xb1; 0.03 a.&#x3bc;) (P < 0.05) and VEGF expression (0.31 &#xb1; 0.09 vs 0.38 &#xb1; 0.04 a.&#x3bc;) (P < 0.01). Furthermore, NAC modulated DNA damage in PPVL + NAC animals.<br><br>CONCLUSION: In view of these results, we believe NAC is able to protect the stomach from the alterations induced by the PPVL procedure.}, }
@article {pmid26602814, year = {2016}, author = {Khameneh, B and Fazly Bazzaz, BS and Amani, A and Rostami, J and Vahdati-Mashhadian, N}, title = {Combination of anti-tuberculosis drugs with vitamin C or NAC against different Staphylococcus aureus and Mycobacterium tuberculosis strains.}, journal = {Microbial pathogenesis}, volume = {93}, number = {}, pages = {83-87}, doi = {10.1016/j.micpath.2015.11.006}, pmid = {26602814}, issn = {1096-1208}, mesh = {Acetylcysteine/*pharmacology ; Antitubercular Agents/*pharmacology ; Ascorbic Acid/*pharmacology ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Isoniazid/pharmacology ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/*drug effects/physiology ; Rifampin/pharmacology ; Staphylococcal Infections/drug therapy/*microbiology ; Staphylococcus aureus/*drug effects/physiology ; Tuberculosis/drug therapy/*microbiology ; }, abstract = {BACKGROUNDS: Hepatotoxicity due to anti tuberculosis drugs, rifampin and isoniazid, is a major problem in tuberculosis patients. Vitamin C, an antioxidant, and N-acetyl cysteine (NAC), a scavenger of active metabolites, reduce the hepatotoxicity. The aim of present study was to investigate the effect of vitamin C and NAC individually on the antibacterial activity of anti tuberculosis drugs against Mycobacterium tuberculosis and Staphylococcus aureus strains.<br><br>METHODS: The MICs of each compound against all strains were determined in 96 wells plate. Rifampin was tested at serial two fold concentrations alone or in combination with NAC or vitamin C.<br><br>RESULTS: The MIC of rifampin against different strains of S. aureus was 0.008-0.032 &#x3bc;g/ml. The MIC of rifampin and isoniazid against M. tuberculosis strains were 40 and 0.2 &#x3bc;g/ml, respectively. Vitamin C and NAC had no antibacterial activity against all strains. MIC of rifampin was reduced two fold by combination with vitamin C for all S. aureus strains, while NAC did not affect the antibacterial activity of rifampin. Vitamin C and NAC had remarkable effects on the antibacterial activity of anti-tuberculosis drugs against M. tuberculosis.<br><br>CONCLUSIONS: Synergistic effects were observed between rifampin or isoniazid and vitamin C against all tested strains. However, combination therapy of rifampin and isoniazid with NAC was not being effective. This study highlighted the advantages of combination of anti-tuberculosis drugs and vitamin C to eradicate the microbial infections.}, }
@article {pmid26602168, year = {2016}, author = {Khayyat, A and Tobwala, S and Hart, M and Ercal, N}, title = {N-acetylcysteine amide, a promising antidote for acetaminophen toxicity.}, journal = {Toxicology letters}, volume = {241}, number = {}, pages = {133-142}, doi = {10.1016/j.toxlet.2015.11.008}, pmid = {26602168}, issn = {1879-3169}, support = {T32 OD011126/OD/NIH HHS/United States ; }, mesh = {Acetaminophen/*antagonists &amp; inhibitors/*toxicity ; Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Alanine Transaminase/metabolism ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Antidotes/*pharmacology ; Antioxidants/pharmacology ; Chemical and Drug Induced Liver Injury/prevention &amp; control ; Glutamate Dehydrogenase/metabolism ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria, Liver/drug effects/metabolism ; Oxidative Stress/drug effects ; Survival Analysis ; }, abstract = {Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over the counter antipyretic and analgesic medications. It is safe at therapeutic doses, but its overdose can result in severe hepatotoxicity, a leading cause of drug-induced acute liver failure in the USA. Depletion of glutathione (GSH) is one of the initiating steps in APAP-induced hepatotoxicity; therefore, one strategy for restricting organ damage is to restore GSH levels by using GSH prodrugs. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an acetaminophen overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and I.V. administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteine amide (NACA), a novel antioxidant with higher bioavailability, and compared it with NAC in APAP-induced hepatotoxicity in C57BL/6 mice. Our results showed that NACA is better than NAC at a low dose (106mg/kg) in preventing oxidative stress and protecting against APAP-induced damage. NACA significantly increased GSH levels and the GSH/GSSG ratio in the liver to 66.5% and 60.5% of the control, respectively; and it reduced the level of ALT by 30%. However, at the dose used, NAC was not effective in combating the oxidative stress induced by APAP. Thus, NACA appears to be better than NAC in reducing the oxidative stress induced by APAP. It would be of great value in the health care field to develop drugs like NACA as more effective and safer options for the prevention and therapeutic intervention in APAP-induced toxicity.}, }
@article {pmid26599235, year = {2015}, author = {Tsai, CC and Wu, SB and Chang, PC and Wei, YH}, title = {Alteration of Connective Tissue Growth Factor (CTGF) Expression in Orbital Fibroblasts from Patients with Graves' Ophthalmopathy.}, journal = {PloS one}, volume = {10}, number = {11}, pages = {e0143514}, pmid = {26599235}, issn = {1932-6203}, mesh = {Adult ; Antioxidants/metabolism/pharmacology ; Cells, Cultured ; Connective Tissue Growth Factor/*genetics/metabolism ; Female ; Fibroblasts/drug effects/*metabolism ; Fibrosis/genetics ; *Gene Expression ; Gene Expression Regulation ; Graves Ophthalmopathy/*genetics/pathology ; Humans ; Hydrogen Peroxide/pharmacology ; Male ; Middle Aged ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Up-Regulation ; Young Adult ; }, abstract = {Graves' ophthalmopathy (GO) is a disfiguring and sometimes blinding disease, which is characterized by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. The aim of this study is to investigate whether the expression levels of fibrosis-related genes, especially that of connective tissue growth factor (CTGF), are altered in orbital fibroblasts of patients with GO. The role of oxidative stress in the regulation of CTGF expression in GO orbital fibroblasts is also examined. By a SYBR Green-based real time quantitative PCR (RT-QPCR), we demonstrated that the mRNA expression levels of fibronectin, apolipoprotein J, and CTGF in cultured orbital fibroblasts from patients with GO were significantly higher than those of age-matched normal controls (p = 0.007, 0.037, and 0.002, respectively). In addition, the protein expression levels of fibronectin, apolipoprotein J, and CTGF analyzed by Western blot were also significantly higher in GO orbital fibroblasts (p = 0.046, 0.032, and 0.008, respectively) as compared with the control. Furthermore, after treatment of orbital fibroblasts with a sub-lethal dose of hydrogen peroxide (200 μM H2O2), we found that the H2O2-induced increase of CTGF expression was more pronounced in the GO orbital fibroblasts as compared with those in normal controls (20% vs. 7%, p = 0.007). Importantly, pre-incubation with antioxidants including N-acetylcysteine (NAC) and vitamin C, respectively, resulted in significant attenuation of the induction of CTGF in GO orbital fibroblasts in response to H2O2 (p = 0.004 and 0.015, respectively). Taken together, we suggest that oxidative stress plays a role in the alteration of the expression of CTGF in GO orbital fibroblasts that may contribute to the pathogenesis and progression of GO. Antioxidants may be used in combination with the therapeutic agents for effective treatment of GO.}, }
@article {pmid26597719, year = {2016}, author = {Monroy, N and Herrero, L and Carrasco, L and González, ME}, title = {Influence of glutathione availability on cell damage induced by human immunodeficiency virus type 1 viral protein R.}, journal = {Virus research}, volume = {213}, number = {}, pages = {116-123}, doi = {10.1016/j.virusres.2015.11.017}, pmid = {26597719}, issn = {1872-7492}, mesh = {Adenosine Triphosphate/metabolism ; Glutathione/*metabolism ; *Oxidative Stress ; Saccharomycetales/genetics/growth &amp; development/*physiology ; vpr Gene Products, Human Immunodeficiency Virus/*metabolism ; }, abstract = {The human immunodeficiency virus type 1 (HIV-1) encodes for accessory viral protein R (Vpr), which arrests the cell cycle of host cells at G2 and causes mitochondrial dysfunction and alterations in glycolysis. High-level expression of Vpr protein correlates with increased viral production and disease progression. Vpr causes structural and functional injury in many types of eukaryotic cells, whether or not they are permissive for viral replication; among them is the budding yeast Saccharomyces cerevisiae. We hypothesized that the dramatic Vpr-induced injuries in yeast could be prevented by strengthening their redox response capacity. We show that exogenous addition of glutathione (GSH) or its prodrug, N-acetylcysteine (NAC), protected budding yeasts from Vpr-induced cytopathic effects. Moreover, addition of adenosine triphosphate (ATP) to growing cultures of Vpr-producing yeast returned cellular growth to control levels, whereas the addition dehydroascorbic acid (DHA) had only a minor protective effect. The diminished protein levels of Cox2p and Cox4p in wild typeVpr-producing yeasts together with the acute sensitivity of petite yeasts to Vpr activity may have been caused by low intracellular ATP levels. As a consequence of this energy deficit, eukaryotic cells would be unable to synthetize adequate supplies of GSH or to signal the mitochondrial retrograde response. Our findings strongly suggest that the cytopathogenic effect of Vpr protein in eukaryotic cells can be prevented by increasing intracellular antioxidant stores or, alternatively, supplying external ATP. Furthermore, these results support a potentially promising future for S. cerevisiae expression as a modality to search for Vpr-targeted inhibitors.}, }
@article {pmid26596265, year = {2016}, author = {Saify, K and Saadat, I and Saadat, M}, title = {Down-regulation of antioxidant genes in human SH-SY5Y cells after treatment with morphine.}, journal = {Life sciences}, volume = {144}, number = {}, pages = {26-29}, doi = {10.1016/j.lfs.2015.11.014}, pmid = {26596265}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Analgesics, Opioid/*pharmacology ; Antioxidants/*metabolism/pharmacology ; Cell Line ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Morphine/*pharmacology ; RNA, Messenger/biosynthesis/genetics ; Reactive Oxygen Species/metabolism ; }, abstract = {AIMS: Morphine strongly induces reactive oxygen species (ROS). The deleterious actions of morphine can be countered by antioxidant system. In the present study, we investigated the expression levels of nine antioxidant genes in human SH-SY5Y cells treated with morphine.<br><br>MAIN METHODS: The cells were treated with three final concentrations of morphine (1, 5, and 10 &#x3bc;mol) for four exposure times (1 h, 24 h, 72 h and 18 days). The mRNA levels were determined using quantitative real-time RCR.<br><br>KEY FINDINGS: Based on the alterations of mRNA levels, the genes might be categorized into three different groups: In the first group, the mRNA levels of the CAT, SOD1 and GSTM3 genes were significantly down-regulated in all examined experimental conditions. In the second group, the mRNA levels of SOD2, NQO1, GSTM2 and GSTO1 were initially increased and then decreased. In the third group, the mRNA levels of NQO2 and GSTP1, were initially increased and then reached to the control levels. The number of down-regulated genes were significantly increased as a function of exposure time (&#x3c7;(2)=7.52, P=0.006). We investigated the effect of morphine (10 &#x3bc;mol) in the absence and presence of N-acetyl-cysteine (NAC, 1 mmol). The mRNA levels revealed significant differences between cells exposed to morphine and cells co-treated with morphine plus NAC. In cases that morphine increased the level of mRNAs, morphine plus NAC, result in decreased mRNA levels and vice versa.<br><br>SIGNIFICANCE: These findings suggested that there are different pathways for regulation of antioxidant genes after SH-SY5Y cells exposed to morphine and morphine might act through inducing ROS.}, }
@article {pmid26594846, year = {2016}, author = {Wong, A and Graudins, A}, title = {Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {54}, number = {2}, pages = {115-119}, doi = {10.3109/15563650.2015.1115055}, pmid = {26594846}, issn = {1556-9519}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; *Administration, Intravenous ; Adolescent ; Adult ; Anaphylaxis ; Drug Overdose/drug therapy ; Drug-Related Side Effects and Adverse Reactions/drug therapy/*epidemiology ; Female ; Humans ; Incidence ; Male ; Retrospective Studies ; Young Adult ; }, abstract = {CONTEXT: Adverse reactions to intravenous (IV) acetylcysteine treatment in paracetamol overdose, are common. Previous studies suggest the incidence and severity of non-allergic anaphylactic reactions (NAARs) are influenced by the rate of acetylcysteine infusion.<br><br>OBJECTIVE: We compared the incidence of adverse drug events of a two-bag IV acetylcysteine regimen with that of the traditional three-bag regimen.<br><br>MATERIALS AND METHODS: This was a retrospective analysis of patients presenting with paracetamol overdose requiring treatment with acetylcysteine to three emergency departments. We prospectively identified all presentations where IV acetylcysteine was administered using a 20 h, two-bag regimen (200 mg/kg over 4 h followed by 100 mg/kg over 16 h) from February 2014 to June 2015. We compared this to an historical cohort treated with the 21 h three-bag IV regimen (150 mg/kg over 1 h, 50 mg/kg over 4 h and 100 mg/kg over 16 h) from October 2009 to October 2013. Medical and nursing notes were searched retrospectively for entries suggesting the presence of an adverse reaction. The primary outcome was incidence of NAARs and gastrointestinal reactions in each group.<br><br>RESULTS: 389 presentations were treated with the three-bag regimen and 210 presentations received the two-bag regimen. NAARs were recorded more commonly with the three-bag acetylcysteine regimen than the two-bag regimen (10% vs 4.3%, p = 0.02, OR 2.5, 95% CI 1.1-5.8). There was no difference in reports of gastrointestinal reactions between cohorts (three-bag 39% vs two-bag 41%, p = 0.38, OR 1.17 95% CI (0.83-1.65)).<br><br>DISCUSSION: The incidence of NAARs was significantly reduced by combining the first two bags of the traditional three-bag regimen and infusing these over 4 h at 50 mg/kg/hr. Simplifying the administration of acetylcysteine may have other benefits such as better utilisation of nursing time and reduced infusion administration errors.<br><br>CONCLUSIONS: A two-bag 20 h acetylcysteine regimen was well tolerated and resulted in significantly fewer and milder NAARs than the standard three-bag regimen.}, }
@article {pmid26593907, year = {2015}, author = {Hoirisch-Clapauch, S and Nardi, AE}, title = {Improvement of Psychotic Symptoms and the Role of Tissue Plasminogen Activator.}, journal = {International journal of molecular sciences}, volume = {16}, number = {11}, pages = {27550-27560}, pmid = {26593907}, issn = {1422-0067}, mesh = {Animals ; Antipsychotic Agents/therapeutic use ; Brain/metabolism ; Dietary Supplements ; Electroconvulsive Therapy ; Hormones/metabolism ; Humans ; Life Style ; Neuropeptides/metabolism ; *Phenotype ; Plasminogen Activator Inhibitor 1/metabolism ; Protein Binding ; Psychotic Disorders/*diagnosis/*metabolism/therapy ; Schizophrenia/diagnosis/diet therapy/metabolism/therapy ; Serpins/metabolism ; Smoking ; Tissue Plasminogen Activator/antagonists &amp; inhibitors/*metabolism ; Neuroserpin ; }, abstract = {Tissue plasminogen activator (tPA) mediates a number of processes that are pivotal for synaptogenesis and remodeling of synapses, including proteolysis of the brain extracellular matrix, degradation of adhesion molecules, activation of neurotrophins, and activation of the N-methyl-d-aspartate receptor. Abnormalities in these processes have been consistently described in psychotic disorders. In this paper, we review the physiological roles of tPA, focusing on conditions characterized by low tPA activity, which are prevalent in schizophrenia. We then describe how tPA activity is influenced by lifestyle interventions and nutritional supplements that may ameliorate psychotic symptoms. Next, we analyze the role of tPA in the mechanism of action of hormones and medications effective in mitigating psychotic symptoms, such as pregnenolone, estrogen, oxytocin, dopamine D3 receptor antagonists, retinoic acid, valproic acid, cannabidiol, sodium nitroprusside, N-acetyl cysteine, and warfarin. We also review evidence that tPA participates in the mechanism by which electroconvulsive therapy and cigarette smoking may reduce psychotic symptoms.}, }
@article {pmid26592462, year = {2016}, author = {Ducret, E and Puaud, M and Lacoste, J and Belin-Rauscent, A and Fouyssac, M and Dugast, E and Murray, JE and Everitt, BJ and Houeto, JL and Belin, D}, title = {N-acetylcysteine Facilitates Self-Imposed Abstinence After Escalation of Cocaine Intake.}, journal = {Biological psychiatry}, volume = {80}, number = {3}, pages = {226-234}, pmid = {26592462}, issn = {1873-2402}, support = {MR/N02530X/1/MRC_/Medical Research Council/United Kingdom ; G1002231/MRC_/Medical Research Council/United Kingdom ; G1000183/MRC_/Medical Research Council/United Kingdom ; 093875//Wellcome Trust/United Kingdom ; G0001354/MRC_/Medical Research Council/United Kingdom ; G0701500/MRC_/Medical Research Council/United Kingdom ; G9536855/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cocaine/*administration &amp; dosage/pharmacology ; Cocaine-Related Disorders/*drug therapy/rehabilitation ; Corpus Striatum/metabolism ; Early Growth Response Protein 1/metabolism ; Electroshock ; Excitatory Amino Acid Transporter 2/metabolism ; Male ; Nucleus Accumbens/metabolism ; Punishment ; Rats ; Reinforcement Schedule ; Self Administration ; Time Factors ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) has been suggested to prevent relapse to cocaine seeking. However, the psychological processes underlying its potential therapeutic benefit remain largely unknown.<br><br>METHODS: We investigated the hallmark features of addiction that were influenced by chronic NAC treatment in rats given extended access to cocaine: escalation, motivation, self-imposed abstinence in the face of punishment, or propensity to relapse. For this, Sprague Dawley rats were given access either to 1 hour (short access) or 6 hours (long access [LgA]) self-administration (SA) sessions until LgA rats displayed a robust escalation. Rats then received daily saline or NAC (60 mg/kg, intraperitoneal) treatment and were tested under a progressive ratio and several consecutive sessions in which lever presses were punished by mild electric foot shocks.<br><br>RESULTS: NAC increased the sensitivity to punishment in LgA rats only, thereby promoting abstinence. Following the cessation of punishment, NAC-treated LgA rats failed to recover fully their prepunishment cocaine intake levels and resumed cocaine SA at a lower rate than short access and vehicle-treated LgA rats. However, NAC altered neither the escalation of SA nor the motivation for cocaine. At the neurobiological level, NAC reversed cocaine-induced decreases in the glutamate type 1 transporter observed in both the nucleus accumbens and the dorsolateral striatum. NAC also increased the expression of Zif268 in the nucleus accumbens and dorsolateral striatum of LgA rats.<br><br>CONCLUSIONS: Our results indicate that NAC contributes to the restoration of control over cocaine SA following adverse consequences, an effect associated with plasticity mechanisms in both the ventral and dorsolateral striatum.}, }
@article {pmid26591569, year = {2015}, author = {Kirpichnikova, KM and Petrov, YP and Filatova, NA and Gamaley, IA}, title = {[CELLS FORM AND THEIR SENSITIVITY TO LYTIC ACTIVITY OF NATURAL KILLER CELLS UNDER THE ANTIOXIDANT ACTION].}, journal = {Tsitologiia}, volume = {57}, number = {8}, pages = {578-583}, pmid = {26591569}, issn = {0041-3771}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies, Monoclonal/pharmacology ; Antioxidants/*pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cell Line, Transformed ; Cell Shape/*drug effects ; Coculture Techniques ; Cytotoxicity, Immunologic/*drug effects ; Enzyme Repression ; Killer Cells, Natural/cytology/*drug effects/immunology ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Mice ; NIH 3T3 Cells ; Pyrrolidonecarboxylic Acid/pharmacology ; Thiazolidines/pharmacology ; Thioctic Acid/pharmacology ; }, abstract = {The present paper is an attempt to estimate the influence of cell surface morphology changes to functional activity under the effect of antioxidant, N-acetylcysteine (NAC), and alpha-lipoic asid (ALA). Two experimental parameters were used to characterize transformed fibroblasts 3T3-SV40 status. The functional one was the cell sensitivity to lysis by natural killer (NK) mouse splenocytes, and morphology index (cell form index) was a cell area. We showed that addition of NAC or ALA to the cell medium caused fast decrease of cell area and changes of cell form. On the other hand, their sensitivity to lysis NK cells gradually and significantly decreased. Then we compared NAC or ALA effect with the effects of other substances, which were non-antioxidants but caused cell responses which concurred with of antioxidants, at least partly. They were: latrunculin B, desorganizing actin filaments (as both antioxidants), OTZ reducing ROS level in the cell (as NAC), BSO (inhibitor of glutathione synthesis), increasing ROS level in the cell (as ALA), antibodies to gelatinases, MMP-2 and MMP-9 inactivating their activities (as both antioxidants). The results obtained showed a correlation between changes of morphology index and functional activity, sensitivity to lysis by NK cells. We suppose that geometry of cell surface might be a functional indicator of cell reaction to the antioxidant.}, }
@article {pmid26588882, year = {2017}, author = {Park, YS and Park, JH and Ko, J and Shin, IC and Koh, HC}, title = {mTOR inhibition by rapamycin protects against deltamethrin-induced apoptosis in PC12 Cells.}, journal = {Environmental toxicology}, volume = {32}, number = {1}, pages = {109-121}, doi = {10.1002/tox.22216}, pmid = {26588882}, issn = {1522-7278}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology ; Apoptosis/*drug effects ; Autophagy/drug effects ; Cell Survival ; Dopamine/metabolism ; Humans ; Insecticides/*toxicity ; Nitriles/*antagonists &amp; inhibitors/*toxicity ; PC12 Cells ; Pyrethrins/*antagonists &amp; inhibitors/*toxicity ; Rats ; Reactive Oxygen Species ; Sirolimus/*pharmacology ; TOR Serine-Threonine Kinases/*antagonists &amp; inhibitors ; }, abstract = {The autophagy pathway can be induced and upregulated in response to intracellular reactive oxygen species (ROS). In this study, we explored a novel pharmacotherapeutic approach involving the regulation of autophagy to prevent deltamethrin (DLM) neurotoxicity. We found that DLM-induced apoptosis in PC12 cells, as demonstrated by the activation of caspase-3 and -9 and by nuclear condensation. DLM treatment significantly decreased dopamine (DA) levels in PC12 cells. In addition, we observed that cells treated with DLM underwent autophagic cell death, by monitoring the expression of LC3-II, p62, and Beclin-1. Exposure of PC12 cells to DLM led to the production of ROS. Treatment with N-acetyl cysteine (NAC) effectively blocked both apoptosis and autophagy. In addition, mitogen-activated protein kinase (MAPK) inhibitors attenuated apoptosis as well as autophagic cell death. We also investigated the modulation of DLM-induced apoptosis in response to autophagy regulation. Pretreatment with the autophagy inducer, rapamycin, significantly enhanced the viability of DLM-exposed cells, and this enhancement of cell viability was partially due to alleviation of DLM-induced apoptosis via a decrease in levels of cleaved caspase-3. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), significantly increased DLM toxicity in these cells. Our results suggest that DLM-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against DLM-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 109-121, 2017.}, }
@article {pmid26586529, year = {2016}, author = {Xu, CC and Denton, KR and Wang, ZB and Zhang, X and Li, XJ}, title = {Abnormal mitochondrial transport and morphology as early pathological changes in human models of spinal muscular atrophy.}, journal = {Disease models &amp; mechanisms}, volume = {9}, number = {1}, pages = {39-49}, pmid = {26586529}, issn = {1754-8411}, support = {R21 NS089042/NS/NINDS NIH HHS/United States ; R21NS089042/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Animals ; Biological Transport ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Differentiation ; Cells, Cultured ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells/cytology ; Karyotyping ; Membrane Potentials ; Mice ; Mice, SCID ; Mitochondria/*pathology ; Motor Neurons/*pathology ; Muscular Atrophy, Spinal/*pathology ; Polymerase Chain Reaction ; Prosencephalon/physiopathology ; }, abstract = {Spinal muscular atrophy (SMA), characterized by specific degeneration of spinal motor neurons, is caused by mutations in the survival of motor neuron 1, telomeric (SMN1) gene and subsequent decreased levels of functional SMN. How the deficiency of SMN, a ubiquitously expressed protein, leads to spinal motor neuron-specific degeneration in individuals affected by SMA remains unknown. In this study, we examined the role of SMN in mitochondrial axonal transport and morphology in human motor neurons by generating SMA type 1 patient-specific induced pluripotent stem cells (iPSCs) and differentiating these cells into spinal motor neurons. The initial specification of spinal motor neurons was not affected, but these SMA spinal motor neurons specifically degenerated following long-term culture. Moreover, at an early stage in SMA spinal motor neurons, but not in SMA forebrain neurons, the number of mitochondria, mitochondrial area and mitochondrial transport were significantly reduced in axons. Knocking down of SMN expression led to similar mitochondrial defects in spinal motor neurons derived from human embryonic stem cells, confirming that SMN deficiency results in impaired mitochondrial dynamics. Finally, the application of N-acetylcysteine (NAC) mitigated the impairment in mitochondrial transport and morphology and rescued motor neuron degeneration in SMA long-term cultures. Furthermore, NAC ameliorated the reduction in mitochondrial membrane potential in SMA spinal motor neurons, suggesting that NAC might rescue apoptosis and motor neuron degeneration by improving mitochondrial health. Overall, our data demonstrate that SMN deficiency results in abnormal mitochondrial transport and morphology and a subsequent reduction in mitochondrial health, which are implicated in the specific degeneration of spinal motor neurons in SMA.}, }
@article {pmid26585821, year = {2015}, author = {Bielli, A and Scioli, MG and Mazzaglia, D and Doldo, E and Orlandi, A}, title = {Antioxidants and vascular health.}, journal = {Life sciences}, volume = {143}, number = {}, pages = {209-216}, doi = {10.1016/j.lfs.2015.11.012}, pmid = {26585821}, issn = {1879-0631}, mesh = {Animals ; Antioxidants/*metabolism/pharmacology ; Endothelium, Vascular/drug effects/*metabolism ; *Health Status ; Humans ; Mitochondria/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Oxygen free radicals and other reactive oxygen species (ROS) are common products of normal aerobic cellular metabolism, but high levels of ROS lead to oxidative stress and cellular damage. Increased production of ROS favors vascular dysfunction, inducing altered vascular permeability and inflammation, accompanied by the loss of vascular modulatory function, the imbalance between vasorelaxation and vasoconstriction, and the aberrant expression of inflammatory adhesion molecules. Inflammatory stimuli promote oxidative stress generated from the increased activity of mitochondrial nicotinamide adenine dinucleotide phosphate oxidase, particularly of the Nox4 isoform, with the consequent impairment of mitochondrial β-oxidation. Vascular dysfunction due to the increase in Nox4 activity and ROS overproduction leads to the progression of cardiovascular diseases, diabetes, inflammatory bowel disease, and neurological disorders. Considerable research into the development of effective antioxidant therapies using natural derivatives or new synthetic molecules has been conducted. Antioxidants may prevent cellular damage by reducing ROS overproduction or interfering in reactions that involve ROS. Vitamin E and ascorbic acid are well known as natural antioxidants that counteract lipid peroxidative damage by scavenging oxygen-derived free radicals, thus restoring vascular function. Recently, preliminary studies on natural antioxidants such as goji berries, thymus, rosemary, green tea ginseng, and garlic have been conducted for their efficacy in preventing vascular damage. N-acetyl-cysteine and propionyl-L-carnitine are synthetic compounds that regulate ROS production by replacing endogenous antioxidants in both endothelial and smooth muscle cells. In this review, we consider the molecular mechanisms underlying the generation of oxidative stress-induced vascular dysfunction as well as the beneficial effects of antioxidant therapies.}, }
@article {pmid26584571, year = {2016}, author = {Bonnot, O and Cohen, D and Thuilleaux, D and Consoli, A and Cabal, S and Tauber, M}, title = {Psychotropic treatments in Prader-Willi syndrome: a critical review of published literature.}, journal = {European journal of pediatrics}, volume = {175}, number = {1}, pages = {9-18}, pmid = {26584571}, issn = {1432-1076}, mesh = {Adolescent ; Child ; Child, Preschool ; Cystine/analogs &amp; derivatives/therapeutic use ; Fructose/analogs &amp; derivatives/therapeutic use ; Humans ; Prader-Willi Syndrome/*drug therapy ; Psychotropic Drugs/*therapeutic use ; Risperidone/therapeutic use ; Topiramate ; }, abstract = {UNLABELLED: Prader-Willi syndrome (PWS) is a rare genetic syndrome. The phenotype includes moderate to intellectual disability, dysmorphia, obesity, and behavioral disturbances (e.g., hetero and self-injurious behaviors, hyperphagia, psychosis). Psychotropic medications are widely prescribed in PWS for symptomatic control. We conducted a systematic review of published literature to examine psychotropic medications used in PWS. MEDLINE was searched to identify articles published between January 1967 and December 2014 using key words related to pharmacological treatments and PWS. Articles with original data were included based on a standardized four-step selection process. The identification of studies led to 241 records. All selected articles were evaluated for case descriptions (PWS and behavioral signs) and treatment (type, titration, efficiency, and side effects). Overall, 102 patients were included in these studies. Treatment involved risperidone (three reports, n = 11 patients), fluoxetine (five/n = 6), naltrexone (two/n = 2), topiramate (two/n = 16), fluvoxamine (one/n = 1), mazindol (one/n = 2), N-acetyl cysteine (one/n = 35), rimonabant (one/n = 15), and fenfluramine (one/n = 15).<br><br>CONCLUSION: We identified promising treatment effects with topiramate for self-injury and impulsive/aggressive behaviors, risperidone for psychotic symptoms associated with uniparental disomy (UPD), and N-acetyl cysteine for skin picking. The pharmacological approach of behavioral impairment in PWS has been poorly investigated to date. Further randomized controlled studies are warranted.<br><br>WHAT IS KNOWN: Behavioral disturbances in Prader-Willi syndrome including aggressive reactions, skin picking, and hyperphagia might be very difficult to manage. Antipsychotic drugs are widely prescribed, but weight gain and increased appetite are their major side effects.<br><br>WHAT IS NEW: Topiramate might be efficient for self-injury and impulsive/aggressive behaviors, N-acetyl cysteine is apromising treatment for skin picking and Antidepressants are indicated for OCD symptoms. Risperidone is indicated in case of psychotic symptoms mainly associated with uniparental disomy.}, }
@article {pmid26584462, year = {2016}, author = {Zeng, F and Sherry, JP and Bols, NC}, title = {Use of the rainbow trout cell lines, RTgill-W1 and RTL-W1 to evaluate the toxic potential of benzotriazoles.}, journal = {Ecotoxicology and environmental safety}, volume = {124}, number = {}, pages = {315-323}, doi = {10.1016/j.ecoenv.2015.11.003}, pmid = {26584462}, issn = {1090-2414}, mesh = {Animals ; Cell Death ; Cell Line ; Comet Assay ; Cytochrome P-450 Enzyme System/metabolism ; DNA Damage ; Gills/cytology/drug effects/metabolism ; Liver/cytology/drug effects/metabolism ; Oncorhynchus mykiss ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Toxicity Tests/*methods ; Triazoles/*toxicity ; }, abstract = {Epithelial cell lines, RTgill-W1 and RTL-W1 from respectively gill and liver of rainbow trout, Onchorhynchus mykiss (Walbaum), were used to evaluate the toxic potential of six benzotriazoles (BTRs) and tolytriazole (TT), which is a commercial mixture of 4-methyl-1H-benzotriazole (4MBTR) and 5-methyl-1H-benzotriazole (5MBTR). The other BTRs were 1H-benzotriazole (1H-BTR), 5-chlorobenzotriazole (5CBTR), 1-hydroxybenzotriazole (1OHBTR) and 5,6-dimethyl-1H-benzotriazole monohydrate (DM). Except for DM, all BTRs were cytotoxic at concentrations above 15mg/L and transitorily elevated reactive oxygen species (ROS) levels. Neither N-acetyl cysteine (NAC) nor IM-54 inhibited cytotoxicity, suggesting that ROS were not the major cause of the cell death. Cell death was not blocked by Necrostatin nor accompanied by DNA laddering, suggesting that the cell death mechanism was neither necroptosis nor apoptosis. As judged by the comet assay, DNA strand breaks were detected with three BTRs: 4MBTR, 5MBTR and 5CBTR. In RTL-W1, the BTRs weakly induced cytochrome P4501A, suggesting that they have the potential to alter xenobiotic metabolism and activate the aryl hydrocarbon receptor. In summary, the toxic potential of BTRs appears to be limited to only high concentrations, which are higher than have been measured in the environment to date.}, }
@article {pmid26577769, year = {2016}, author = {Acosta-Zaldívar, M and Andrés, MT and Rego, A and Pereira, CS and Fierro, JF and Côrte-Real, M}, title = {Human lactoferrin triggers a mitochondrial- and caspase-dependent regulated cell death in Saccharomyces cerevisiae.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {21}, number = {2}, pages = {163-173}, doi = {10.1007/s10495-015-1199-9}, pmid = {26577769}, issn = {1573-675X}, mesh = {Antifungal Agents/*pharmacology ; *Apoptosis ; Humans ; Lactoferrin/*pharmacology ; Microbial Sensitivity Tests ; Microbial Viability/drug effects ; Mitochondria/drug effects/metabolism ; Saccharomyces cerevisiae/*cytology/drug effects ; }, abstract = {We have previously shown that the antifungal activity of human lactoferrin (hLf) against Candida albicans relies on its ability to induce cell death associated with apoptotic markers. To gain a deeper understanding of the mechanisms underlying hLf-induced apoptosis, we characterized this cell death process in the well-established Saccharomyces cerevisiae model. Our results indicate that hLf induces cell death in S. cerevisiae in a manner that requires energy and de novo protein synthesis. Cell death is associated with nuclear chromatin condensation, preservation of plasma membrane integrity, and is Yca1p metacaspase-dependent. Lactoferrin also caused mitochondrial dysfunction associated with ROS accumulation and release of cytochrome c. Pre-incubation with oligomycin, an oxidative phosphorylation inhibitor, increased resistance to hLf and, accordingly, mutants deficient in the F1F0-ATP synthase complex were more resistant to death induced by hLf. This indicates that mitochondrial energetic metabolism plays a key role in the killing effect of hLf, though a direct role of F1F0-ATP synthase cannot be precluded. Overexpression of the anti-apoptotic protein Bcl-xL or pre-incubation with N-acetyl cysteine reduced the intracellular level of ROS and increased resistance to hLf, confirming a ROS-mediated mitochondrial cell death process. Mitochondrial involvement was further reinforced by the higher resistance of cells lacking mitochondrial DNA, or other known yeast mitochondrial apoptosis regulators, such as, Aif1p, Cyc3p and Aac1/2/3p. This study provides new insights into a detailed understanding at the molecular level of hLf-induced apoptosis, which may allow the design of new strategies to overcome the emergence of resistance of clinically relevant fungi to conventional antifungals.}, }
@article {pmid26577174, year = {2016}, author = {Vessoni, AT and Quinet, A and de Andrade-Lima, LC and Martins, DJ and Garcia, CC and Rocha, CR and Vieira, DB and Menck, CF}, title = {Chloroquine-induced glioma cells death is associated with mitochondrial membrane potential loss, but not oxidative stress.}, journal = {Free radical biology &amp; medicine}, volume = {90}, number = {}, pages = {91-100}, doi = {10.1016/j.freeradbiomed.2015.11.008}, pmid = {26577174}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Chloroquine/*pharmacology ; Glioma/*drug therapy/metabolism/pathology ; Humans ; Membrane Potential, Mitochondrial/*drug effects ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Chloroquine (CQ), a quinolone derivative widely used to treat and prevent malaria, has been shown to exert a potent adjuvant effect when combined with conventional glioblastoma therapy. Despite inducing lysosome destabilization and activating p53 in human glioma cells, the mechanisms underlying cell death induced by this drug are poorly understood. Here, we analyzed in a time- and dose-dependent manner, the effects of CQ upon mitochondria integrity, autophagy regulation and redox processes in four human glioma cell lines that differ in their resistance to this drug. NAC-containing media protected cells against CQ-induced loss of mitochondrial membrane potential (MMP), autophagic vacuoles (LC3II) accumulation and loss of cell viability induced by CQ. However, we noticed that part of this protection was due to media acidification in NAC preparations, alerting for problems in experimental procedures using NAC. The results indicate that although CQ induces accumulation of LC3II, mitochondria, and oxidative stress, neither of these events is clearly correlated to cell death induced by this drug. The only event elicited in all cell lines at equitoxic doses of CQ was the loss of MMP, indicating that mitochondrial stability is important for cells resistance to this drug. Finally, the data indicate that higher steady-state MMP values can predict cell resistance to CQ treatment.}, }
@article {pmid26576075, year = {2015}, author = {Han, S and Cai, W and Yang, X and Jia, Y and Zheng, Z and Wang, H and Li, J and Li, Y and Gao, J and Fan, L and Hu, D}, title = {ROS-Mediated NLRP3 Inflammasome Activity Is Essential for Burn-Induced Acute Lung Injury.}, journal = {Mediators of inflammation}, volume = {2015}, number = {}, pages = {720457}, pmid = {26576075}, issn = {1466-1861}, mesh = {Acute Lung Injury/*etiology/prevention &amp; control ; Animals ; Burns/*complications ; Carrier Proteins/antagonists &amp; inhibitors/genetics/*physiology ; Caspase 1/genetics/physiology ; Cells, Cultured ; Inflammasomes/*physiology ; Interleukin-18/analysis/physiology ; Interleukin-1beta/analysis/physiology ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nitriles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sulfones/pharmacology ; }, abstract = {The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI.}, }
@article {pmid26573561, year = {2016}, author = {Kim, KC and Piao, MJ and Madduma Hewage, SR and Han, X and Kang, KA and Jo, JO and Mok, YS and Shin, JH and Park, Y and Yoo, SJ and Hyun, JW}, title = {Non-thermal dielectric-barrier discharge plasma damages human keratinocytes by inducing oxidative stress.}, journal = {International journal of molecular medicine}, volume = {37}, number = {1}, pages = {29-38}, pmid = {26573561}, issn = {1791-244X}, mesh = {Argon/*adverse effects ; Cell Line ; Cell Survival ; Humans ; Keratinocytes/cytology/metabolism/*pathology ; Lipid Peroxidation ; *Oxidative Stress ; Oxygen/*adverse effects ; Plasma Gases/*adverse effects ; Reactive Oxygen Species/metabolism ; }, abstract = {The aim of this study was to identify the mechanisms through which dielectric-barrier discharge plasma damages human keratinocytes (HaCaT cells) through the induction of oxidative stress. For this purpose, the cells were exposed to surface dielectric-barrier discharge plasma in 70% oxygen and 30% argon. We noted that cell viability was decreased following exposure of the cells to plasma in a time-dependent manner, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The levels of intracellular reactive oxygen species (ROS) were determined using 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium was used to monitor superoxide anion production. Plasma induced the generation of ROS, including superoxide anions, hydrogen peroxide and hydroxyl radicals. N-acetyl cysteine, which is an antioxidant, prevented the decrease in cell viability caused by exposure to plasma. ROS generated by exposure to plasma resulted in damage to various cellular components, including lipid membrane peroxidation, DNA breaks and protein carbonylation, which was detected by measuring the levels of 8-isoprostane and diphenyl-1-pyrenylphosphine assay, comet assay and protein carbonyl formation. These results suggest that plasma exerts cytotoxic effects by causing oxidative stress-induced damage to cellular components.}, }
@article {pmid26573558, year = {2016}, author = {Huang, YT and Chen, YY and Lai, YH and Cheng, CC and Lin, TC and Su, YS and Liu, CH and Lai, PC}, title = {Resveratrol alleviates the cytotoxicity induced by the radiocontrast agent, ioxitalamate, by reducing the production of reactive oxygen species in HK-2 human renal proximal tubule epithelial cells in vitro.}, journal = {International journal of molecular medicine}, volume = {37}, number = {1}, pages = {83-91}, pmid = {26573558}, issn = {1791-244X}, mesh = {Antioxidants/*pharmacology ; Cell Line ; Cell Survival/drug effects ; Contrast Media/*adverse effects ; DNA Fragmentation/drug effects ; Epithelial Cells/cytology/*drug effects/metabolism ; Humans ; Iothalamic Acid/adverse effects/*analogs &amp; derivatives ; Kidney Tubules, Proximal/cytology/*drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Resveratrol ; Stilbenes/*pharmacology ; }, abstract = {Radiocontrast-induced nephropathy (RIN) is one of the leading causes of hospital-acquired acute kidney injury (AKI). The clinical strategies currently available for the prevention of RIN are insufficient. In this study, we aimed to determine whether resveratrol, a polyphenol phytoalexin, can be used to prevent RIN. For this purpose, in vitro experiments were performed using a human renal proximal tubule epithelial cell line (HK-2 cells). Following treatment for 48 h, the highly toxic radiocontrast agent, ioxitalamate, exerted cytotoxic effects on the HK-2 cells in a concentration-dependent manner, as shown by MTT assay. The half maximal inhibitory concentration (IC50) was found to be approximately 30 mg/ml. Flow cytometry also revealed a marked increase in the number of apoptotic cells following exposure to ioxitalamate. In addition, the number of necrotic, but not necroptotic cells was increased. However, treatment with resveratrol (12.5 µM) for 48 h significantly alleviated ioxitalamate (30 mg/ml)-induced cytotoxicity, by reducing cytosolic DNA fragmentation, increasing the expression of the anti-apoptotic protein, Bcl-2 (B-cell lymphoma 2), and survivin, activating caspase-3, preventing autophagic death and suppressing the production of reactive oxygen species (ROS). Resveratrol also suppressed the ioxitalamate-induced formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage. N-acetylcysteine (NAC), a ROS scavenger commonly used to prevent RIN, also reduced ioxitalamate-induced cytotoxicity, but at a high concentration of 1 mM. Sirtuin (SIRT)1 and SIRT3 were not found to play a role in these effects. Overall, our findings suggest that resveratrol may prove to be an effective adjuvant therapy for the prevention of RIN.}, }
@article {pmid26572666, year = {2016}, author = {Reyes, RC and Cittolin-Santos, GF and Kim, JE and Won, SJ and Brennan-Minnella, AM and Katz, M and Glass, GA and Swanson, RA}, title = {Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {13}, number = {1}, pages = {217-225}, pmid = {26572666}, issn = {1878-7479}, support = {R01 NS041421/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/cerebrospinal fluid ; Animals ; Antioxidants/analysis ; Brain Chemistry/drug effects ; Dose-Response Relationship, Drug ; Glutathione/*cerebrospinal fluid ; Humans ; Mice ; Mice, Inbred C57BL ; Rats ; Rats, Sprague-Dawley ; }, abstract = {N-acetyl cysteine (NAC) supports the synthesis of glutathione (GSH), an essential substrate for fast, enzymatically catalyzed oxidant scavenging and protein repair processes. NAC is entering clinical trials for adrenoleukodystrophy, Parkinson's disease, schizophrenia, and other disorders in which oxidative stress may contribute to disease progression. However, these trials are hampered by uncertainty about the dose of NAC required to achieve biological effects in human brain. Here we describe an approach to this issue in which mice are used to establish the levels of NAC in cerebrospinal fluid (CSF) required to affect brain neurons. NAC dosing in humans can then be calibrated to achieve these NAC levels in human CSF. The mice were treated with NAC over a range of doses, followed by assessments of neuronal GSH levels and neuronal antioxidant capacity in ex vivo brain slices. Neuronal GSH levels and antioxidant capacity were augmented at NAC doses that produced peak CSF NAC concentrations of ≥50 nM. Oral NAC administration to humans produced CSF concentrations of up to 10 μM, thus demonstrating that oral NAC administration can surpass the levels required for biological activity in brain. Variations of this approach may similarly facilitate and rationalize drug dosing for other agents targeting central nervous system disorders.}, }
@article {pmid26572172, year = {2015}, author = {Wang, LS and Hu, Y and Li, CL and Li, Y and Wei, YR and Yin, ZF and Du, YK and Min, Z and Weng, D and Chen, JM and Li, HP}, title = {N-acetylcysteine attenuates cigaret smoke-induced pulmonary exacerbation in a mouse model of emphysema.}, journal = {Inhalation toxicology}, volume = {27}, number = {14}, pages = {802-809}, doi = {10.3109/08958378.2015.1110217}, pmid = {26572172}, issn = {1091-7691}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bronchoalveolar Lavage Fluid/chemistry ; Emphysema/*chemically induced/*drug therapy ; Female ; Gene Expression Regulation/drug effects ; Interleukin-10/chemistry/metabolism ; Interleukin-1beta/chemistry/metabolism ; Mice ; Mice, Inbred C57BL ; Smoke/*adverse effects ; Tobacco Products/*adverse effects ; }, abstract = {OBJECTIVE: The purpose of this study was to investigate the effects of cigaret smoke (CS) on a mouse model of emphysema and examine the protective role of N-acetylcysteine (NAC) in the CS-induced exacerbation of pulmonary damage in the mice.<br><br>METHOD: Particulate matter (PM) in sidestream cigaret smoke aerosol was analyzed by a scanning mobility particle sizer spectrometer. A mouse model of emphysema was established by an injection of porcine pancreatic elastase (PPE) into the trachea. Mice with emphysema were then exposed to filtered air, or sidestream CS with intragastric administration of NAC or normal saline. Mouse body weight, survival, pulmonary tissue histology, total antioxidant capacity (T-AOC) and malonaldehyde (MDA) contents in lung tissue, and inflammatory responses were examined.<br><br>RESULTS: Particles with a size of &#x2264;346&#x2009;nm constituted 99.06% of CS PM. Mice exhibited ruptured alveolar septal, alveolar fusion, significantly increased mean lining interval, and reduced mean alveolar number (all p&#x2009;<&#x2009;0.05), 21&#x2009;d after PPE injection. Exposure of mice with emphysema to CS exacerbated the pulmonary tissue damage, caused weight loss, significantly increased mortality, decreased T-AOC, elevated MDA contents in lung tissue, and increased interleukin (IL)-1&#x3b2; levels in bronchoalveolar lavage (BAL) fluids (all p&#x2009;<&#x2009;0.05). Administration of NAC attenuated those CS-induced adverse effects in the mice and increased anti-inflammatory factor IL-10 levels in BAL fluids significantly (all p&#x2009;<&#x2009;0.05).<br><br>CONCLUSIONS: Exposure of mice with emphysema to CS exacerbated the pulmonary damage, and NAC reduced the CS-mediated pulmonary damage by preventing oxidative damage and reducing inflammatory responses.}, }
@article {pmid26567752, year = {2016}, author = {Matera, MG and Calzetta, L and Cazzola, M}, title = {Oxidation pathway and exacerbations in COPD: the role of NAC.}, journal = {Expert review of respiratory medicine}, volume = {10}, number = {1}, pages = {89-97}, doi = {10.1586/17476348.2016.1121105}, pmid = {26567752}, issn = {1747-6356}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Expectorants/therapeutic use ; Glutathione/pharmacology ; Humans ; Lung ; Oxidative Stress/*drug effects/physiology ; Patient Selection ; Pulmonary Disease, Chronic Obstructive/*drug therapy/*physiopathology/prevention &amp; control ; }, abstract = {Oxidative stress is an important trait in the pathogenesis of chronic obstructive pulmonary disease (COPD). Consequently, targeting oxidative stress is likely to be beneficial as a treatment in COPD. Glutathione (GSH) is an intracellular antioxidant that protects against a variety of different antioxidant species. The increase of lung GSH in COPD is an attempt to counter excess oxidant production but it is inadequate during exacerbations due to the excessive production of ROS. N-acetyl-l-cysteine (NAC) acts as a precursor for the substrate cysteine in synthesis of GSH and also as a mucolytic and anti-inflammatory agent. NAC prevents COPD exacerbations at high dosage (≥1200 mg daily), while a regular treatment with 600 mg daily is enough in chronic bronchitis. Nonetheless, we must still establish whether the level of bronchial obstruction may influence its effects, the effect of high-dose NAC in Caucasian patients with COPD, and the role of NAC in the escalation and de-escalation of therapy in COPD.}, }
@article {pmid26567351, year = {2016}, author = {Ghanizadeh Kazerouni, E and Franklin, CE and Seebacher, F}, title = {UV-B exposure reduces locomotor performance by impairing muscle function but not mitochondrial ATP production.}, journal = {The Journal of experimental biology}, volume = {219}, number = {Pt 1}, pages = {96-102}, doi = {10.1242/jeb.131615}, pmid = {26567351}, issn = {1477-9145}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/pharmacology ; Cyprinodontiformes/*physiology ; Lipid Peroxidation ; Mitochondria/metabolism ; Muscle Contraction ; Muscle, Skeletal/physiology/*radiation effects ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Swimming ; Ultraviolet Rays ; }, abstract = {Ultraviolet B radiation (UV-B) can reduce swimming performance by increasing reactive oxygen species (ROS) formation. High concentrations of ROS can damage mitochondria, resulting in reduced ATP production. ROS can also damage muscle proteins, thereby leading to impaired muscle contractile function. We have shown previously that UV-B exposure reduces locomotor performance in mosquitofish (Gambusia holbrooki) without affecting metabolic scope. Our aim was therefore to test whether UV-B influences swimming performance of mosquitofish by ROS-induced damage to muscle proteins without affecting mitochondrial function. In a fully factorial design, we exposed mosquitofish to UV-B and no-UV-B controls in combination with exposure to N-acetylcysteine (NAC) plus no-NAC controls. We used NAC, a precursor of glutathione, as an antioxidant to test whether any effects of UV-B on swimming performance were at least partly due to UV-B-induced ROS. UV-B significantly reduced critical sustained swimming performance and tail beat frequencies, and it increased ROS-induced damage (protein carbonyl concentrations and lipid peroxidation) in muscle. However, UV-B did not affect the activity of sarco-endoplasmic reticulum ATPase (SERCA), an enzyme associated with muscle calcium cycling and muscle relaxation. UV-B did not affect ADP phosphorylation (state 3) rates of mitochondrial respiration, and it did not alter the amount of ATP produced per atom of oxygen consumed (P:O ratio). However, UV-B reduced the mitochondrial respiratory control ratio. Under UV-B exposure, fish treated with NAC showed greater swimming performance and tail beat frequencies, higher glutathione concentrations, and lower protein carbonyl concentrations and lipid peroxidation than untreated fish. Tail beat amplitude was not affected by any treatment. Our results showed, firstly, that the effects of UV-B on locomotor performance were mediated by ROS and, secondly, that reduced swimming performance was not caused by impaired mitochondrial ATP production. Instead, reduced tail beat frequencies indicate that muscle of UV-B exposed fish were slower, which was likely to have been caused by slower contraction rates, because SERCA activities remained unaffected.}, }
@article {pmid26567248, year = {2016}, author = {Lee, ES and Kim, HM and Kang, JS and Lee, EY and Yadav, D and Kwon, MH and Kim, YM and Kim, HS and Chung, CH}, title = {Oleanolic acid and N-acetylcysteine ameliorate diabetic nephropathy through reduction of oxidative stress and endoplasmic reticulum stress in a type 2 diabetic rat model.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {31}, number = {3}, pages = {391-400}, doi = {10.1093/ndt/gfv377}, pmid = {26567248}, issn = {1460-2385}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; *Diabetes Mellitus, Experimental ; Diabetes Mellitus, Type 2/*complications/metabolism ; Diabetic Nephropathies/*drug therapy/etiology/metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Inbred OLETF ; Reactive Oxygen Species ; }, abstract = {BACKGROUND: Hyperglycemia-induced endoplasmic reticulum (ER) stress and oxidative stress could be causes of renal fibrosis in diabetes. Oleanolic acid (OA) naturally occurs in fruits and vegetables. It has anti-inflammatory, antihyperlipidemic and antioxidant effects. N-acetylcysteine (NAC) is a precursor of glutathione, which has a strong antioxidant effect in the body. In this study, we investigated the therapeutic effects of OA and NAC in diabetic nephropathy (DN).<br><br>METHODS: Otsuka Long-Evans Tokushima Fatty rats were treated with OA (100 mg/kg/day) or NAC (300 mg/kg/day) for 20 weeks by oral gavage.<br><br>RESULTS: The OA or NAC administration increased blood insulin secretion and superoxide dismutase levels, and decreased triglycerides and urinary albumin/creatinine levels. In the kidney, the damaged renal structure recovered with OA or NAC administration, through an increase in nephrin and endothelial selective adhesion molecules and a decrease in transforming growth factor-&#x3b2;/p-smad2/3 and ER stress. Reactive oxygen species and ER stress were increased by high glucose and ER stress inducers in cultured mesangial cells, and these levels recovered with OA (5.0 &#x3bc;M) or NAC (2.5 mM) treatment.<br><br>CONCLUSION: The findings in this study suggest that OA and NAC have therapeutic effects for DN through an antioxidant effect and ER stress reduction.}, }
@article {pmid26566191, year = {2015}, author = {Thakkar, K and Billa, G and Rane, J and Chudasama, H and Goswami, S and Shah, R}, title = {The rise and fall of felbamate as a treatment for partial epilepsy--aplastic anemia and hepatic failure to blame?.}, journal = {Expert review of neurotherapeutics}, volume = {15}, number = {12}, pages = {1373-1375}, doi = {10.1586/14737175.2015.1113874}, pmid = {26566191}, issn = {1744-8360}, mesh = {Anemia, Aplastic/*etiology ; Anticonvulsants/adverse effects/therapeutic use ; Drug Resistant Epilepsy/drug therapy ; Epilepsies, Partial/*drug therapy ; Felbamate ; Humans ; Liver Failure/*etiology ; Phenylcarbamates/*adverse effects/*therapeutic use ; Propylene Glycols/*adverse effects/*therapeutic use ; }, abstract = {Felbamate has been approved for refractory partial seizures since the early nineties. Due to safety concerns regarding its use, namely, in aplastic anemia and hepatic failure, felbamate's use has been restricted and a 'Black Box' warning has been inserted. Nonetheless, it is a useful drug in refractory cases of partial epilepsy. There are certain precautions which can prevent and minimize the serious idiosyncratic reactions associated with felbamate, thereby providing an option in refractory cases where no other drug works.}, }
@article {pmid26564153, year = {2016}, author = {Cheng, KC and Hung, CT and Chen, KJ and Wu, WC and Suen, JL and Chang, CH and Lu, CY and Tseng, CH and Chen, YL and Chiu, CC}, title = {Quinoline-Based Compound BPIQ Exerts Anti-Proliferative Effects on Human Retinoblastoma Cells via Modulating Intracellular Reactive Oxygen Species.}, journal = {Archivum immunologiae et therapiae experimentalis}, volume = {64}, number = {2}, pages = {139-147}, doi = {10.1007/s00005-015-0368-4}, pmid = {26564153}, issn = {1661-4917}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Growth Inhibitors/*pharmacology ; Humans ; Imidazoles/*pharmacology ; Inhibitor of Apoptosis Proteins/genetics/metabolism ; Oxidation-Reduction/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Quinazolines/*pharmacology ; Reactive Oxygen Species/*metabolism ; Retinoblastoma/*drug therapy ; Survivin ; X-Linked Inhibitor of Apoptosis Protein/genetics/metabolism ; }, abstract = {Retinoblastoma (Rb) is the most common primary intraocular malignant tumor of childhood. It is important to develop the strategy for Rb treatment. We have tested a quinolone derivative 2,9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11H-indeno[1,2-c]quinolin-11-one (BPIQ) for its anti-cancer effects against Rb via cultured human Rb cell line Y79. Our results showed that BPIQ significantly inhibits cell growth of Y79. Furthermore, the flow cytometer-based assays and Western blotting showed that BPIQ induces the apoptosis of Y79 via increasing the level of reactive oxygen species (ROS). Besides, the activation of γH2AX, a DNA damage sensor in human Y79 cells was also observed, indicating the potential of BPIQ for causing DNA damage of Rb cells. On the contrary, BPIQ-induced apoptosis of Y79 cells was attenuated significantly by N-acetyl-L-cysteine (NAC), an ROS scavenger. The results of Western blot showed that BPIQ down-regulates the levels of anti-apoptotic proteins Bcl-2, survivin and XIAP while up-regulates the pro-apoptotic proteins Bad, Bax and Bid. Our present study demonstrated the anti-proliferative effect of BPIQ in human Y79 cells. The inhibitory effect of BPIQ on the proliferation of Y79 cells is, at least, partly mediated by the regulation of ROS and DNA damage pathway. In conclusion, BPIQ may provide an alternative option in the chemotherapeutics or chemoprevention on the Rb therapy in the future.}, }
@article {pmid26557254, year = {2015}, author = {Rad, P and Karlsson, CA and Janson, C}, title = {Idiopathic fibrotic lung disease at a university hospital setting: management and prognostic factors.}, journal = {European clinical respiratory journal}, volume = {2}, number = {}, pages = {}, pmid = {26557254}, issn = {2001-8525}, abstract = {BACKGROUND: Idiopathic fibrosing interstitial pneumonia consists of many subtypes, most associated with a poor prognosis. The aim of the study was to evaluate diagnostic procedures and treatment as well as survival in patients with idiopathic fibrosing interstitial pneumonia.<br><br>METHODS: This study comprised 175 patients with idiopathic fibrosing interstitial pneumonia (ICD 10 code J84) that had been diagnosed at Uppsala University Hospital, during 2005 to 2012. Patient records were reviewed concerning: gender, age, smoking, occupational exposure, comorbidities, procedures, lung function, and treatment. Information on survival and cause of death was collected.<br><br>RESULTS: A total of 98% had been examined with computed tomography, 93% with spirometry, 49% with measurement of diffusion capacity, 48% with bronchoalveolar lavage, and 23% with lung biopsy. Prednisolone had been prescribed to 74% while N-acetylcysteine (NAC) and omeprazole were prescribed to 54%, respectively. Five-year survival was 46%. Mortality was associated with high age, low diffusion capacity, and the use of NAC.<br><br>CONCLUSION: High age and a low diffusion capacity are related to shorter survival in idiopathic fibrosing interstitial pneumonia. We also unexpectedly found that the use of NAC was related to shorter survival. A relatively low proportion of the patients were examined with diffusion capacity measurement. Thus, there is a possibility to improve diagnostic procedures and thereby improve estimation of prognosis in fibrotic lung disease.}, }
@article {pmid26557253, year = {2015}, author = {Myllärniemi, M and Kaarteenaho, R}, title = {Pharmacological treatment of idiopathic pulmonary fibrosis - preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine.}, journal = {European clinical respiratory journal}, volume = {2}, number = {}, pages = {}, pmid = {26557253}, issn = {2001-8525}, abstract = {Three recent clinical trials on the pharmacologic treatment of idiopathic pulmonary fibrosis (IPF) mark a new chapter in the management of patients suffering from this very severe fibrotic lung disease. This review article summarizes the published investigations on the preclinical studies of three novel IPF drugs, namely pirfenidone, nintedanib, and N-acetylcysteine (NAC). In addition, the study protocols, differences, and the main findings in the recent clinical trials of these pharmacological treatments are reviewed. The strategy for drug development and the timeline from the discovery to the clinical use have been very different in these regimens. Pirfenidone was discovered in 1976 but only recently received approval in most countries, and even now its exact mechanism of action is unknown. On the contrary, nintedanib (BIBF1120) was identified in large drug screening tests as a very specific inhibitor of certain tyrosine kinases, but no published data on preclinical tests existed until 2014. NAC, a mucolytic drug with an antioxidant mechanism of action was claimed to possess distinct antifibrotic properties in several experimental models but proved to be ineffective in a recent randomized placebo-controlled trial. At present, no curative treatment is available for IPF. A better understanding of the molecular mechanisms of IPF as well as relevant preclinical tests including animal models and in vitro experiments on human lung cells are needed to promote the development of therapeutic drugs.}, }
@article {pmid26552352, year = {2015}, author = {Allameh, Z and Karimi, A and Rafiei Tabatabaei, S and Sharifian, M and Salamzadeh, J}, title = {Effect of N-acetylcysteine on inflammation biomarkers in pediatric acute pyelonephritis: a randomized controlled trial.}, journal = {Iranian journal of kidney diseases}, volume = {9}, number = {6}, pages = {454-462}, pmid = {26552352}, issn = {1735-8604}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Calcitonin/blood ; Calcitonin Gene-Related Peptide ; Child ; Child, Preschool ; Creatinine/blood ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Inflammation/blood ; Leukocyte Count ; Male ; Protein Precursors/blood ; Pyelonephritis/*blood/complications/*drug therapy ; }, abstract = {INTRODUCTION: This study was designed to investigate the effect of N-acetylcysteine (NAC), as a potent and safe antioxidant, on inflammatory biomarkers of acute pyelonephritis in pediatric patients.<br><br>MATERIALS AND METHODS: Children (< 15 years old) admitted with a diagnosis of pyelonephritis were recruited in a randomized placebo-controlled trial. They were randomly allocated to 2 groups and recieved placebo or NAC effervescent tablets with daily dose based on their weight, for 5 days. The children were evaluated for serum procalcitonin level, leukocyte count, C-reactive protein (CRP), serum creatinine, and clinical symptoms on the 1st and the 5th days.<br><br>RESULTS: Seventy patients, 35 in each group, with a mean age of 5.54 &#xb1; 3.10 years completed the study. There was no significant difference between the two groups in the amount of changes in procalcitonin levels after 5 days (P = .90). Within-group analysis confirmed CRP reduction in both groups (P < .001); however, between-group analysis did not show significant difference in CRP reductions, either (P = .65). No significant differences were found between the two groups in the day of resolving pyuria (P = .46), day of resolving bacteriuria (P = .81), or reductions in leukocyte count (P = .64) and neutrophil count (P = .49).<br><br>CONCLUSIONS: A short period of NAC administration with the recommended doses could not lead to a significant decrease in inflammation biomarkers. Studies on higher doses and longer duration of NAC administration along with evaluation of the long-term effects of the intervention by tools such as renal scntigraphy are suggested.}, }
@article {pmid26549707, year = {2016}, author = {Chen, TC and Yu, MC and Chien, CC and Wu, MS and Lee, YC and Chen, YC}, title = {Nilotinib reduced the viability of human ovarian cancer cells via mitochondria-dependent apoptosis, independent of JNK activation.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {31}, number = {}, pages = {1-11}, doi = {10.1016/j.tiv.2015.11.002}, pmid = {26549707}, issn = {1879-3177}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; DNA Fragmentation ; Female ; Humans ; Imatinib Mesylate/pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/physiology ; Niacinamide/analogs &amp; derivatives/pharmacology ; Ovarian Neoplasms/metabolism ; Phenylurea Compounds/pharmacology ; Protein-Tyrosine Kinases/*antagonists &amp; inhibitors ; Pyrimidines/*pharmacology ; Reactive Oxygen Species/metabolism ; Sorafenib ; }, abstract = {Nilotinib (AMN) induces apoptosis in various cancer cells; however the effect of AMN on human ovarian cancer cells is still unclear. A reduction in cell viability associated with the occurrence of apoptotic characteristics was observed in human SKOV-3 ovarian cancer cells under AMN but not sorafenib (SORA) or imatinib (STI) stimulation. Activation of apoptotic pathway including increased caspase (Casp)-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein cleavage by AMN was detected with disrupted mitochondrial membrane potential (MMP) accompanied by decreased Bcl-2 protein and increased cytosolic cytochrome (Cyt) c/cleaved Casp-9 protein expressions was found, and AMN-induced cell death was inhibited by peptidyl Casp inhibitors, VAD, DEVD and LEHD. Increased phosphorylated c-Jun N-terminal kinase (JNK) protein expression was detected in AMN- but not SORA- or STI-treated SKOV-3 cells, and the JNK inhibitors, SP600125 and JNKI, showed slight but significant enhancement of AMN-induced cell death in SKOV-3 cells. The intracellular peroxide level was elevated by AMN and H2O2, and N-acetylcysteine (NAC) prevented H2O2- but not AMN-induced peroxide production and apoptosis in SKOV-3 cells. AMN induction of apoptosis with increased intracellular peroxide production and JNK protein phosphorylation was also identified in human A2780 ovarian cancer cells, cisplatin-resistant A2780CP cells, and clear ES-2 cells. The evidence supporting AMN effectively reducing the viability of human ovarian cancer cells via mitochondrion-dependent apoptosis is provided.}, }
@article {pmid26549478, year = {2015}, author = {Tang, FY and Chen, CY and Shyu, HW and Hong, S and Chen, HM and Chiou, YH and Lin, KH and Chou, MC and Wang, LY and Wang, YF}, title = {Resveratrol induces cell death and inhibits human herpesvirus 8 replication in primary effusion lymphoma cells.}, journal = {Chemico-biological interactions}, volume = {242}, number = {}, pages = {372-379}, doi = {10.1016/j.cbi.2015.10.025}, pmid = {26549478}, issn = {1872-7786}, mesh = {Apoptosis/*drug effects ; Autophagy/*drug effects ; CASP8 and FADD-Like Apoptosis Regulating Protein/genetics ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Activation/drug effects ; Herpesvirus 8, Human/*drug effects/genetics/*physiology ; Humans ; Lymphoma, Primary Effusion/*pathology/virology ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/*pharmacology ; Virus Replication/*drug effects ; }, abstract = {Resveratrol (3,4',5-trihydroxy-trans-stilbene) has been reported to inhibit proliferation of various cancer cells. However, the effects of resveratrol on the human herpesvirus 8 (HHV8) harboring primary effusion lymphoma (PEL) cells remains unclear. The anti-proliferation effects and possible mechanisms of resveratrol in the HHV8 harboring PEL cells were examined in this study. Results showed that resveratrol induced caspase-3 activation and the formation of acidic vacuoles in the HHV8 harboring PEL cells, indicating resveratrol treatment could cause apoptosis and autophagy in PEL cells. In addition, resveratrol treatment increased ROS generation but did not lead to HHV8 reactivation. ROS scavenger (N-acetyl cysteine, NAC) could attenuate both the resveratrol induced caspase-3 activity and the formation of acidic vacuoles, but failed to attenuate resveratrol induced PEL cell death. Caspase inhibitor, autophagy inhibitors and necroptosis inhibitor could not block resveratrol induced PEL cell death. Moreover, resveratrol disrupted HHV8 latent infection, inhibited HHV8 lytic gene expression and decreased virus progeny production. Overexpression of HHV8-encoded viral FLICE inhibitory protein (vFLIP) could partially block resveratrol induced cell death in PEL cells. These data suggest that resveratrol-induced cell death in PEL cells may be mediated by disruption of HHV8 replication. Resveratrol may be a potential anti-HHV8 drug and an effective treatment for HHV8-related tumors.}, }
@article {pmid26548469, year = {2015}, author = {Fischer, T}, title = {[Pharmacological therapy of age-related macular degeneration based on etiopathogenesis].}, journal = {Orvosi hetilap}, volume = {156}, number = {46}, pages = {1847-1858}, doi = {10.1556/650.2015.30207}, pmid = {26548469}, issn = {0030-6002}, mesh = {Aged ; Aged, 80 and over ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Antioxidants/administration &amp; dosage ; Aspirin/administration &amp; dosage/analogs &amp; derivatives ; Bosentan ; *Dietary Supplements ; Docosahexaenoic Acids/administration &amp; dosage ; Eicosapentaenoic Acid/administration &amp; dosage ; Folic Acid/administration &amp; dosage ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration &amp; dosage ; Infliximab/administration &amp; dosage ; Lutein/administration &amp; dosage ; Macular Degeneration/*drug therapy/*metabolism ; Melatonin/administration &amp; dosage ; PPAR gamma/agonists ; Receptor, Angiotensin, Type 1/drug effects ; Renin/antagonists &amp; inhibitors ; Renin-Angiotensin System/*drug effects ; Resveratrol ; Stilbenes/administration &amp; dosage ; Sulfonamides/administration &amp; dosage ; Trimetazidine/administration &amp; dosage ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors ; Ubiquinone/administration &amp; dosage/analogs &amp; derivatives ; Vitamin D/administration &amp; dosage ; Xanthophylls/administration &amp; dosage ; }, abstract = {It is of great therapeutic significance that disordered function of the vascular endothelium which supply the affected ocular structures plays a major role in the pathogenesis and development of age-related macular degeneration. Chronic inflammation is closely linked to diseases associated with endothelial dysfunction, and age-related macular degeneration is accompanied by a general inflammatory response. According to current concept, age-related macular degeneration is a local manifestation of systemic vascular disease. This recognition could have therapeutic implications because restoration of endothelial dysfunction can restabilize the condition of chronic vascular disease including age-related macular degeneration as well. Restoration of endothelial dysfunction by pharmaacological or non pharmacological interventions may prevent the development or improve endothelial dysfunction, which result in prevention or improvement of age related macular degeneration as well. Medicines including inhibitors of the renin-angiotensin system (converting enzyme inhibitors, angiotensin-receptor blockers and renin inhibitors), statins, acetylsalicylic acid, trimetazidin, third generation beta-blockers, peroxisome proliferator-activated receptor gamma agonists, folate, vitamin D, melatonin, advanced glycation end-product crosslink breaker alagebrium, endothelin-receptor antagonist bosentan, coenzyme Q10; "causal" antioxidant vitamins, N-acetyl-cysteine, resveratrol, L-arginine, serotonin receptor agonists, tumor necrosis factor-alpha blockers, specific inhibitor of the complement alternative pathway, curcumin and doxycyclin all have beneficial effects on endothelial dysfunction. Restoration of endothelial dysfunction can restabilize chronic vascular disease including age-related macular degeneration as well. Considering that the human vascular system is consubstantial, medicines listed above should be given to patients (1) who have no macular degeneration but have risk factors for the disease and are older than 50 years; (2) who have been diagnosed with unilateral age-related macular degeneration in order to prevent damage of the contralateral eye; (3) who have bilateral age-related macular degeneration in order to avert deterioration and in the hope of a potential improvement. However, randomised prospective clinical trials are still needed to elucidate the potential role of these drug treatments in the prevention and treatment of age-related macular degeneration.}, }
@article {pmid26547317, year = {2015}, author = {Feng, T and Pi, B and Li, B and Jiang, L and Wang, YM and Zhu, XS and Yang, HL}, title = {N-Acetyl cysteine (NAC)-mediated reinforcement of alpha-tricalcium phosphate/silk fibroin (α-TCP/SF) cement.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {136}, number = {}, pages = {892-899}, doi = {10.1016/j.colsurfb.2015.10.021}, pmid = {26547317}, issn = {1873-4367}, mesh = {Acetylcysteine/*chemistry ; Animals ; Biocompatible Materials ; Calcium Phosphates/*chemistry ; Fibroins/*chemistry ; Rats ; }, abstract = {Calcium phosphate cements (CPCs) are popular bone filling materials and drug carriers. However poor mechanical properties and lack of osteoinduction restrict their clinical applications. Recent studies suggested the osteogenic properties of NAC. In our study, we incorporated NAC with α-TCP/SF. We found that the compressive strength of α-TCP/SF-NAC composites increased with increase in NAC concentration, possibly due to complex three-dimensional networks of SF induced by NAC, which was large and chemically heterogeneous and induced compact oriented growth of HA crystals. However the setting time increased slightly with the addition of NAC, due to the ruptured disulfide bonds in SF. The α-TCP/SF-NAC composites also showed decent biocompatibility in vitro. As a result, these composites hold great potential as bone filling materials for clinical applications, including minimally invasive surgeries.}, }
@article {pmid26545726, year = {2016}, author = {Jenkins, DD and Wiest, DB and Mulvihill, DM and Hlavacek, AM and Majstoravich, SJ and Brown, TR and Taylor, JJ and Buckley, JR and Turner, RP and Rollins, LG and Bentzley, JP and Hope, KE and Barbour, AB and Lowe, DW and Martin, RH and Chang, EY}, title = {Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis.}, journal = {The Journal of pediatrics}, volume = {168}, number = {}, pages = {67-76.e6}, pmid = {26545726}, issn = {1097-6833}, support = {R01 NS052448/NS/NINDS NIH HHS/United States ; NS52448/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Cerebrovascular Circulation/drug effects ; Chorioamnionitis/*drug therapy ; Double-Blind Method ; Echoencephalography ; Electroencephalography ; Female ; Fetus ; Humans ; Infant ; Infant, Newborn ; Magnetic Resonance Imaging ; Male ; Mothers ; Neuroprotective Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Pregnancy ; Prospective Studies ; Ultrasonography, Doppler ; }, abstract = {OBJECTIVE: To evaluate the clinical safety of antenatal and postnatal N-acetylcysteine (NAC) as a neuroprotective agent in maternal chorioamnionitis in a randomized, controlled, double-blinded trial.<br><br>STUDY DESIGN: Twenty-two mothers >24&#xa0;weeks gestation presenting within 4&#xa0;hours of diagnosis of clinical chorioamnionitis were randomized with their 24 infants to NAC or saline treatment. Antenatal NAC (100&#xa0;mg/kg/dose) or saline was given intravenously every 6&#xa0;hours until delivery. Postnatally, NAC (12.5-25&#xa0;mg/kg/dose, n&#xa0;=&#xa0;12) or saline (n&#xa0;=&#xa0;12) was given every 12&#xa0;hours for 5 doses. Doppler studies of fetal umbilical and fetal and infant cerebral blood flow, cranial ultrasounds, echocardiograms, cerebral oxygenation, electroencephalograms, and serum cytokines were evaluated before and after treatment, and 12, 24, and 48&#xa0;hours after birth. Magnetic resonance spectroscopy and diffusion imaging were performed at term age equivalent. Development was followed for cerebral palsy or autism to 4&#xa0;years of age.<br><br>RESULTS: Cardiovascular measures, cerebral blood flow velocity and vascular resistance, and cerebral oxygenation did not differ between treatment groups. Cerebrovascular coupling was disrupted in infants with chorioamnionitis treated with saline but preserved in infants treated with NAC, suggesting improved vascular regulation in the presence of neuroinflammation. Infants treated with NAC had higher serum anti-inflammatory interleukin-1 receptor antagonist and lower proinflammatory vascular endothelial growth factor over time vs controls. No adverse events related to NAC administration were noted.<br><br>CONCLUSIONS: In this cohort of newborns exposed to chorioamnionitis, antenatal and postnatal NAC was safe, preserved cerebrovascular regulation, and increased an anti-inflammatory neuroprotective protein.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT00724594.}, }
@article {pmid26545472, year = {2015}, author = {Ciftci, Z and Deniz, M and Yilmaz, I and Ciftci, HG and Sirin, DY and Gultekin, E}, title = {In vitro analysis of a novel controlled release system designed for intratympanic administration of N-acetylcysteine: a preliminary report.}, journal = {American journal of otolaryngology}, volume = {36}, number = {6}, pages = {786-793}, doi = {10.1016/j.amjoto.2015.08.004}, pmid = {26545472}, issn = {1532-818X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Biocompatible Materials ; Borates ; Chitosan ; *Delayed-Action Preparations ; *Drug Delivery Systems ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Hydrogel, Polyethylene Glycol Dimethacrylate ; Hydrogen-Ion Concentration ; In Vitro Techniques ; Injections ; Microscopy, Electron, Scanning ; Polyvinyl Alcohol ; Spectrophotometry ; *Tympanic Membrane ; }, abstract = {The aim of this in-vitro experimental study was to design a novel drug delivery system that may permit controlled release of N-acetylcysteine (NAC) following intratympanic administration. The system was composed of two different solutions that attained a hydrogel form within seconds after getting into contact with each other. The authors performed swelling, pH and temperature tests and analysis of controlled release of NAC from this novel controlled release system. For the structure and porosity analysis of the hydrogel, an environmental scanning electron microscope (SEM) was used. The diameter of designed hydrogel showed an increase when pH was increased. In addition, in comparison to acidic values, the pore diameter of the hydrogel increased significantly especially in physiological level. The increase in the pore diameter was also directly proportional to the increase in temperature. Spectrophotometric analysis showed that the amount of NAC released into the medium was statistically significant (p=0.038, t=-2.18, 95% CI; DF: 27). SEM analysis of the samples revealed a smooth surface topography and numerous porous structures. The authors are of the opinion that the designed hydrogel may be used as an alternative method for intratympanic delivery of NAC for otoprotective purposes. The disadvantages of intratympanic injection of the drug in its liquid form, including leakage through eustachian tube, restraining the patient in an uncomfortable position, necessity for repetitive injections and dose dependent inflammation of the middle ear epithelium, may also be avoided. Further in vivo studies should be conducted to assess its tolerability and effectivity.}, }
@article {pmid26542776, year = {2015}, author = {Suzuki, S and Fujita, N and Hosogane, N and Watanabe, K and Ishii, K and Toyama, Y and Takubo, K and Horiuchi, K and Miyamoto, T and Nakamura, M and Matsumoto, M}, title = {Excessive reactive oxygen species are therapeutic targets for intervertebral disc degeneration.}, journal = {Arthritis research &amp; therapy}, volume = {17}, number = {}, pages = {316}, pmid = {26542776}, issn = {1478-6362}, mesh = {Acetylcysteine/pharmacology ; Adult ; Aged ; Animals ; Antioxidants/*pharmacology ; Blotting, Western ; Female ; Flow Cytometry ; Humans ; Intervertebral Disc/drug effects/metabolism ; Intervertebral Disc Degeneration/*pathology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; }, abstract = {INTRODUCTION: Oxidative stress has been reported to be involved in numerous human diseases, including musculoskeletal disorders such as osteoarthritis. However, the interaction between intervertebral disc (IVD) degeneration and oxidative stress is not well understood. The purpose of the present study was to elucidate the contribution of oxidative stress to IVD degeneration and the efficacy of antioxidant treatment for degenerative discs.<br><br>METHODS: The expression level of an oxidative stress marker, nitrotyrosine, was assessed by immunohistochemistry and Western blotting. For evaluating intracellular reactive oxygen species (ROS) levels and oxidative stress in rat annulus fibrosus (AF) cells, flow cytometry and luciferase assay with an OKD48 construct were performed. The grade of IVD degeneration was assessed by magnetic resonance imaging and histological analysis.<br><br>RESULTS: A high frequency of nitrotyrosine-positive cells was observed in rat and human degenerative discs. mRNA expression of catabolic factors such as tumor necrosis factor-alpha (TNF-alpha), matrix metalloprotease-3 (MMP-3), and cyclooxygenase-2 (COX-2) was significantly induced by treatment with H2O2 or buthionine sulfoximine, whereas that of aggrecan, an important chondrogenic proteoglycan, was reduced in a dose-dependent manner. Treatment with mitogen-activated protein kinase (MAPK) inhibitors blocked the inductive effect of excessive ROS on COX-2 mRNA expression. Western blotting confirmed the phosphorylation of MAPKs in H2O2 and BSO-treated AF cells. Conversely, we showed that TNF-&#x3b1; induced oxidative stress with increased intracellular ROS levels in AF cells. Treatment with the antioxidant N-acetyl cysteine (NAC) abrogated the catabolic effect of excessive ROS and TNF-alpha in vitro. Finally, we showed that oral administration of NAC prevented IVD degeneration in rat degenerative model.<br><br>CONCLUSIONS: A positive feedback loop was formed between excessive ROS and TNF-alpha in AF cells. Thus, oxidative stress contributes to the progression of IVD degeneration and NAC can be a therapeutic option for IVD degeneration.}, }
@article {pmid26538833, year = {2015}, author = {Bjørn, ME and Hasselbalch, HC}, title = {The Role of Reactive Oxygen Species in Myelofibrosis and Related Neoplasms.}, journal = {Mediators of inflammation}, volume = {2015}, number = {}, pages = {648090}, pmid = {26538833}, issn = {1466-1861}, mesh = {Acetylcysteine/chemistry ; Animals ; Antioxidants/chemistry ; Disease Progression ; Hepatitis C/*pathology ; Humans ; Inflammation ; Mice ; Myeloproliferative Disorders/metabolism/*pathology ; Neoplasms/metabolism/*pathology ; Oxidative Stress ; Primary Myelofibrosis/metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Reactive oxygen species (ROS) have been implicated in a wide variety of disorders ranging between traumatic, infectious, inflammatory, and malignant diseases. ROS are involved in inflammation-induced oxidative damage to cellular components including regulatory proteins and DNA. Furthermore, ROS have a major role in carcinogenesis and disease progression in the myeloproliferative neoplasms (MPNs), where the malignant clone itself produces excess of ROS thereby creating a vicious self-perpetuating circle in which ROS activate proinflammatory pathways (NF-κB) which in turn create more ROS. Targeting ROS may be a therapeutic option, which could possibly prevent genomic instability and ultimately myelofibrotic and leukemic transformation. In regard to the potent efficacy of the ROS-scavenger N-acetyl-cysteine (NAC) in decreasing ROS levels, it is intriguing to consider if NAC treatment might benefit patients with MPN. The encouraging results from studies in cystic fibrosis, systemic lupus erythematosus, and chronic obstructive pulmonary disease warrant such studies. In addition, the antioxidative potential of the widely used agents, interferon-alpha2, statins, and JAK inhibitors, should be investigated as well. A combinatorial approach using old agents with anticancer properties together with novel JAK1/2 inhibitors may open a new era for patients with MPNs, the outlook not only being "minimal residual disease" and potential cure but also a marked improvement in inflammation-mediated comorbidities.}, }
@article {pmid26536848, year = {2016}, author = {Lachance, C and Goupil, S and Tremblay, RR and Leclerc, P}, title = {The immobilization of human spermatozoa by STAT3 inhibitory compound V results from an excessive intracellular amount of reactive oxygen species.}, journal = {Andrology}, volume = {4}, number = {1}, pages = {133-142}, doi = {10.1111/andr.12123}, pmid = {26536848}, issn = {2047-2927}, mesh = {Acetylcysteine/pharmacology ; Acrosome Reaction/drug effects ; Adenosine Triphosphate/metabolism ; Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis/*physiology ; Calcium/metabolism ; Caspase Inhibitors/pharmacology ; Cyclic S-Oxides/*pharmacology ; Humans ; Leupeptins/pharmacology ; Male ; Membrane Potential, Mitochondrial ; Mitochondria/metabolism ; Oxidation-Reduction ; Oxidative Stress/physiology ; Phosphorylation/drug effects ; Proteasome Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors ; Sperm Motility/*drug effects ; Spermatozoa/*physiology ; }, abstract = {We previously showed that Stattic V (Stat3 inhibitory compound V) reduces human sperm motility and cellular ATP levels, increases intracellular Ca(2+) concentration, and promotes mitochondrial membrane depolarization resulting in increased levels of extracellular reactive oxygen species (ROS). As these alterations in cellular function are highly similar to what is observed in a cell undergoing apoptosis, our goal was to determine if the immobilizing effect of Stattic V on spermatozoa results from apoptosis or was because of an oxidative stress. To address this question, spermatozoa were incubated with Stattic V in combination with a caspase inhibitor, a proteasome inhibitor or a cell permeant ROS scavenger. Following incubation in different conditions, sperm motility was evaluated by CASA, acrosomal integrity by FITC conjugated Pisum sativum agglutinin (PSA-FITC) labeling, intracellular pH, and mitochondrial superoxide production by flow cytometry using BCECF and MitoSoxRed dye, respectively. Levels of reduced thiols were assessed by iodoacetamidofluorescein staining on total and on sperm surface proteins, and protein tyrosine phosphorylation was evaluated by western blot. The loss in sperm motility induced by Stattic V was associated with a slight intracellular acidification and an important increase in intracellular superoxide anion. Unlike caspase and proteasome inhibitors, low molecular weight thiols, such as N-acetyl-L-cysteine (NAC), prevented Stattic V-induced sperm immobilization and increase responsiveness to acrosome reaction inducers. NAC also efficiently prevented the production of superoxide anion, mitochondrial membrane depolarization, intracellular acidification and the oxidation of protein free thiols caused by Stattic V. These results show that the deleterious effects of Stattic V on sperm functions are caused directly or indirectly by excessive intracellular ROS production without causing sperm apoptosis or necrosis.}, }
@article {pmid26536834, year = {2015}, author = {Cui, Y and Narasimhulu, CA and Liu, L and Zhang, Q and Liu, PZ and Li, X and Xiao, Y and Zhang, J and Hao, H and Xie, X and He, G and Cui, L and Parthasarathy, S and Liu, Z}, title = {N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {16339}, pmid = {26536834}, issn = {2045-2322}, support = {R01 HL094650/HL/NHLBI NIH HHS/United States ; R01 HL124122/HL/NHLBI NIH HHS/United States ; R01HL124122/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Atherosclerosis/metabolism ; Humans ; Hyperlipidemias/metabolism ; Lipoproteins, LDL/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction/*drug effects ; Reactive Oxygen Species/metabolism ; Receptors, LDL/metabolism ; }, abstract = {Low-density lipoprotein (LDL) is non-atherogenic, while oxidized LDL (ox-LDL) is critical to atherosclerosis. N-acetylcysteine (NAC) has anti-atherosclerotic effect with largely unknown mechanisms. The present study aimed to determine if NAC could attenuate in vivo LDL oxidation and inhibit atherosclerosis. A single dose of human native LDL was injected intravenously into male C57BL/6 mice with and without NAC treatment. Serum human ox-LDL was detected 30 min after injection, reached the peak in 3 hours, and became undetectable in 12 hours. NAC treatment significantly reduced serum ox-LDL level without detectable serum ox-LDL 6 hours after LDL injection. No difference in ox-LDL clearance was observed in NAC-treated animals. NAC treatment also significantly decreased serum ox-LDL level in patients with coronary artery diseases and hyperlipidemia without effect on LDL level. Intracellular and extracellular reactive oxidative species (ROS) production was significantly increased in the animals treated with native LDL, or ox-LDL and in hyperlipidemic LDL receptor knockout (LDLR(-/-)) mice that was effectively prevented with NAC treatment. NAC also significantly reduced atherosclerotic plaque formation in hyperlipidemic LDLR(-/-) mice. NAC attenuated in vivo oxidation of native LDL and ROS formation from ox-LDL associated with decreased atherosclerotic plaque formation in hyperlipidemia.}, }
@article {pmid26535414, year = {2015}, author = {Elgawish, MS and Kishikawa, N and Kuroda, N}, title = {Quinones as novel chemiluminescent probes for the sensitive and selective determination of biothiols in biological fluids.}, journal = {The Analyst}, volume = {140}, number = {24}, pages = {8148-8156}, doi = {10.1039/c5an01604e}, pmid = {26535414}, issn = {1364-5528}, mesh = {Acetylcysteine/analysis/blood ; Chemistry Techniques, Analytical/*methods ; Chromatography, High Pressure Liquid ; Fluorescent Dyes/*chemistry ; Glutathione/analysis/blood ; Homocysteine/analysis/blood ; Humans ; Limit of Detection ; Luminescence ; Molecular Structure ; Quinones/*chemistry ; Sulfhydryl Compounds/*analysis/blood ; }, abstract = {Altered plasma aminothiol concentrations are thought to be a valuable risk indicator and are interestingly utilized for routine clinical diagnosis and for the monitoring of various metabolic disorders and human diseases, and accordingly there is a need for an accurate and reliable assay capable of simultaneously determining aminothiols including glutathione (GSH), N-acetylcysteine (NAC), homocysteine (Hcys), and cysteine (Cys) in human plasma. Herein, a highly sensitive, selective, and very fast HPLC-chemiluminescence (HPLC-CL) coupled method is reported, exploiting for the first time the strong nucleophilicity and high reactivity of aminothiols toward quinones for a CL assay. The unique redox-cycling capability of quinone and/or Michael addition adducts, thioether-quinone conjugates, was utilized to establish a novel analytical method based on the reaction of adducts with dithiothreitol (DTT) to liberate reactive oxygen species (ROS), which are detected by using a luminol-CL assay. Specimen preparation involved the derivatization of aminothiols with menadione (MQ) for 5 minutes at room temperature. A unique green chemistry synthesis of thioether-quinones in HEPES buffer (pH 8.5) was introduced by using our reaction methodology without needing any hazardous organic solvent or catalyst. The aminothiol-MQ adducts were separated using solid-phase extraction followed by isocratic elution on an ODS column. Linearity was observed in the range of 2.5-500, 5-500, 10-1500, and 20-2000 nM with detection limits (S/N of 3) of 3.8, 4.2, 8, and 16 (fmol per injection) for GSH, NAC, Hcys, and Cys, respectively. The method was successfully applied for the selective determination of aminothiols in human plasma from healthy people and patients with rheumatic arthritis and diabetes mellitus. The obtained results postulated the usefulness of our method for investigating the relationship between aminothiol metabolism and related human disorders.}, }
@article {pmid26530353, year = {2016}, author = {You, BR and Park, WH}, title = {Auranofin induces mesothelioma cell death through oxidative stress and GSH depletion.}, journal = {Oncology reports}, volume = {35}, number = {1}, pages = {546-551}, doi = {10.3892/or.2015.4382}, pmid = {26530353}, issn = {1791-2431}, mesh = {Apoptosis ; Auranofin/*pharmacology ; Caspases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Glutathione/*metabolism ; Humans ; Mesothelioma/*metabolism ; Oxidative Stress/*drug effects ; Thioredoxin Reductase 1/metabolism ; }, abstract = {Mesothelioma is an aggressive tumor associated with asbestos exposure. Auranofin as an inhibitor of thioredoxin reductase (TrxR) affects many biological processes such as inflammation and proliferation. In the present study, we investigated the cellular effects of auranofin on patient-derived mesothelioma cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Basal TrxR1 levels have no difference between mesothelial cells and certain mesothelioma cells. In particular, ADA, CON and Hmeso mesothelioma cells showed lower levels of TrxR1 expression. Auranofin inhibited the proliferation of mesothelioma cells in a dose-dependent manner. Among mesothelioma cells were ADA and CON cells sensitive to auranofin. This agent also induced caspase-independent apoptosis and necrosis in ADA cells. In addition, auranofin increased ROS levels including O2(•-) and induced GSH depletion in mesothelioma cells. While N-acetyl cysteine (NAC) prevented cell death and decreased ROS levels in auranofin-treated mesothelioma cells, L-buthionine sulfoximine (BSO) intensified apoptosis and GSH depletion in these cells. In conclusion, auranofin induced mesothelioma cell death through oxidative stress and the death was regulated by the status of GSH content.}, }
@article {pmid26530247, year = {2016}, author = {Barreiro, E and Puig-Vilanova, E and Marin-Corral, J and Chacón-Cabrera, A and Salazar-Degracia, A and Mateu, X and Puente-Maestu, L and García-Arumí, E and Andreu, AL and Molina, L}, title = {Therapeutic Approaches in Mitochondrial Dysfunction, Proteolysis, and Structural Alterations of Diaphragm and Gastrocnemius in Rats With Chronic Heart Failure.}, journal = {Journal of cellular physiology}, volume = {231}, number = {7}, pages = {1495-1513}, doi = {10.1002/jcp.25241}, pmid = {26530247}, issn = {1097-4652}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Bortezomib/*administration &amp; dosage ; Diaphragm/drug effects/metabolism/pathology ; Heart Failure/chemically induced/*drug therapy/metabolism ; Humans ; Mitochondria/metabolism ; Monocrotaline/toxicity ; Muscle, Skeletal/drug effects/metabolism/pathology ; NF-kappa B/metabolism ; Oxidative Stress/*drug effects ; Proteolysis/drug effects ; Rats ; }, abstract = {Patients with chronic heart failure (CHF) experience exercise intolerance, fatigue and muscle wasting, which negatively influence their survival. We hypothesized that treatment with either the antioxidant N-acetyl cysteine (NAC) or the proteasome inhibitor bortezomib of rats with monocrotaline-induced CHF may restore inspiratory and limb muscle mass, function, and structure through several molecular mechanisms involved in protein breakdown and metabolism in the diaphragm and gastrocnemius. In these muscles of CHF-cachectic rats with and without treatment with NAC or bortezomib (N = 10/group) and non-cachectic controls, proteolysis (tyrosine release, proteasome activities, ubiquitin-proteasome markers), oxidative stress, inflammation, mitochondrial function, myosin, NF-κB transcriptional activity, muscle structural abnormalities, and fiber morphometry were analyzed together with muscle and cardiac functions. In diaphragm and gastrocnemius of CHF-cachectic rats, tyrosine release, proteasome activity, protein ubiquitination, atrogin-1, MURF-1, NF-κB activity, oxidative stress, inflammation, and structural abnormalities were increased, while muscle and cardiac functions, myosin content, slow- and fast-twitch fiber sizes, and mitochondrial activity were decreased. Concomitant treatment of CHF-cachectic rats with NAC or bortezomib improved protein catabolism, oxidative stress, inflammation, muscle fiber sizes, function and damage, superoxide dismutase and myosin levels, mitochondrial function (complex I, gastrocnemius), cardiac function and decreased NF-κB transcriptional activity in both muscles. Treatment of CHF-cachectic animals with NAC or bortezomib attenuated the functional (heart, muscles), biological, and structural alterations in muscles. Nonetheless, future studies conducted in actual clinical settings are warranted in order to assess the potential beneficial effects and safety concerns of these pharmacological agents on muscle mass loss and wasting in CHF-cachectic patients.}, }
@article {pmid26521983, year = {2016}, author = {Butterworth, RF}, title = {Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited.}, journal = {Metabolic brain disease}, volume = {31}, number = {6}, pages = {1211-1215}, pmid = {26521983}, issn = {1573-7365}, mesh = {Ammonia/antagonists &amp; inhibitors/metabolism ; Animals ; Antioxidants/pharmacology/therapeutic use ; Energy Metabolism/drug effects/physiology ; Glutamate-Ammonia Ligase/antagonists &amp; inhibitors/*metabolism ; Hepatic Encephalopathy/drug therapy/etiology/*metabolism ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors/*metabolism ; Liver Cirrhosis/drug therapy/etiology/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {The concept of synergistic mechanisms as the pathophysiologic basis of hepatic encephalopathy started with the pioneering work of Les Zieve in Minneapolis some 60 years ago where synergistic actions of the liver-derived toxins ammonia, methanethiol, and octanoic acid were described. More recently, synergistic actions of ammonia and manganese, a toxic metal that is normally eliminated via the hepatobiliary route and shown to accumulate in brain in liver failure, on the glutamatergic neurotransmitter system were described. The current upsurge of interest in brain inflammation (neuroinflammation) in relation to the CNS complications of liver failure has added a third dimension to the synergy debate. The combined actions of ammonia, manganese and pro-inflammatory cytokines in brain in liver failure result in oxidative/nitrosative stress resulting from activation of glutamate (NMDA) receptors and consequent nitration of key brain proteins. One such protein, glutamine synthetase, the sole enzyme responsible for brain ammonia removal is nitrated and inactivated in brain in liver failure. Consequently, brain ammonia levels increase disproportionately resulting in alterations of brain excitability, impaired brain energy metabolism, encephalopathy and brain swelling. Experimental therapeutic approaches for which proof-of-principle has been established include the NMDA receptor antagonist memantine, N-acetyl cysteine (recently shown to have antioxidant properties at both hepatic and cerebral levels) and probiotics.}, }
@article {pmid26519795, year = {2016}, author = {Zhu, B and Wang, Q and Shi, X and Guo, Y and Xu, T and Zhou, B}, title = {Effect of combined exposure to lead and decabromodiphenyl ether on neurodevelopment of zebrafish larvae.}, journal = {Chemosphere}, volume = {144}, number = {}, pages = {1646-1654}, doi = {10.1016/j.chemosphere.2015.10.056}, pmid = {26519795}, issn = {1879-1298}, mesh = {Animals ; Axons/*drug effects/metabolism ; Central Nervous System/drug effects/growth &amp; development/metabolism ; Gene Expression Regulation, Developmental/*drug effects ; Halogenated Diphenyl Ethers/*toxicity ; Lead/*toxicity ; Motor Activity/drug effects ; Motor Neurons/drug effects/metabolism ; Oxidative Stress ; Random Allocation ; Reactive Oxygen Species/metabolism ; Water Pollutants, Chemical/*toxicity ; Zebrafish/genetics/growth &amp; development/*metabolism ; }, abstract = {The effect of combined exposure to decabromodiphenyl ether (BDE-209) and lead (Pb) on neurodevelopment of zebrafish (Danio rerio) larvae was investigated. Zebrafish embryos were exposed to Pb (0, 5, 10, 20 µg/L) and BDE-209 (0, 50, 100, 200 µg/L), either alone or in combination (Mix1: 5 + 50 µg/L, Mix2: 10 + 100 µg/L, Mix3: 20 + 200 µg/L) for up to 144 h post-fertilization. Growth of secondary motoneuron axons and expression of genes related to central nervous system development was significantly inhibited in Mix3 co-exposure group. A significant increase in reactive oxygen species (ROS), lipid peroxidation, DNA damage, and perturbation of the antioxidant system was detected in the Mix3 group compared to single-toxicant treatments or control. Depressed locomotor activity was recorded in the Mix2 and Mix3 groups. Addition of N-acetyl cysteine to Mix3 eliminated excessive ROS, and protected against lipid peroxidation, DNA damage, and locomotor dysfunction. Pb uptake was increased in the presence of BDE-209, but BDE-209 bioconcentration and the ability to metabolize BDE-209 were decreased in the presence of Pb. These results suggest that BDE-209 and Pb have a synergistic disruptive effect on neurodevelopment in zebrafish larvae by enhanced generation of ROS, which is a major factor that contributes to developmental neurotoxicity.}, }
@article {pmid26518358, year = {2016}, author = {Rasmussen, K and Nikrad, J and Reilly, C and Li, Y and Jones, RS}, title = {N-Acetyl-l-cysteine effects on multi-species oral biofilm formation and bacterial ecology.}, journal = {Letters in applied microbiology}, volume = {62}, number = {1}, pages = {30-38}, pmid = {26518358}, issn = {1472-765X}, support = {UL1 TR000114/TR/NCATS NIH HHS/United States ; UL1TR000114/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Bacterial Adhesion/*drug effects ; Biofilms/drug effects/*growth &amp; development ; Dental Caries/microbiology/*prevention &amp; control ; Dental Plaque/microbiology/*prevention &amp; control ; Microbial Viability/drug effects ; RNA, Ribosomal, 16S ; }, abstract = {UNLABELLED: Future therapies for the treatment of dental decay have to consider the importance of preserving bacterial ecology while reducing biofilm adherence to teeth. A multi-species plaque-derived (MSPD) biofilm model was used to assess how concentrations of N-acetyl-l-cysteine (NAC) (0, 0·1, 1, 10%) affected the growth of complex oral biofilms. Biofilms were grown (n = 96) for 24 h on hydroxyapatite discs in BMM media with 0·5% sucrose. Bacterial viability and biomass formation was examined on each disc using a microtitre plate reader. In addition, fluorescence microscopy and Scanning Electron Microscopy was used to qualitatively examine the effect of NAC on bacterial biofilm aggregation, extracellular components and bacterial morphology. The total biomass was significantly decreased after exposure of both 1% (from 0·48, with a 95% confidence interval of (0·44, 0·57) to 0·35, with confidence interval (0·31, 0·38)) and 10% NAC (0·14 with confidence interval (0·11, 0·17)). 16S rRNA amplicon sequencing analysis indicated that 1% NAC reduced biofilm adherence while preserving biofilm ecology.<br><br>As a compound with a wide safety margin, N-acetyl-l-cysteine (NAC) has the potential to be used as a long term anti-plaque bacteriostatic agent for managing chronic dental decay without substantially altering biofilm's bacterial ecology. The potential anti-caries benefit of NAC is directly related to reducing the biofilm coverage which reduces the degree of acid generation and the amount of time that the surface is exposed to a lower pH.}, }
@article {pmid26517353, year = {2015}, author = {Gu, Y and Barzegar, M and Chen, X and Wu, Y and Shang, C and Mahdavian, E and Salvatore, BA and Jiang, S and Huang, S}, title = {Fusarochromanone-induced reactive oxygen species results in activation of JNK cascade and cell death by inhibiting protein phosphatases 2A and 5.}, journal = {Oncotarget}, volume = {6}, number = {39}, pages = {42322-42333}, pmid = {26517353}, issn = {1949-2553}, support = {P20 RR016456/RR/NCRR NIH HHS/United States ; R01 CA115414/CA/NCI NIH HHS/United States ; 5P20RR016456-11/RR/NCRR NIH HHS/United States ; 8 P20 GM103424-11/GM/NIGMS NIH HHS/United States ; P20 GM103424/GM/NIGMS NIH HHS/United States ; CA115414/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Blotting, Western ; COS Cells ; Cell Death/drug effects ; Cell Survival/drug effects ; Chlorocebus aethiops ; Chromones/*pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; HEK293 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; MAP Kinase Signaling System/*drug effects ; Nuclear Proteins/*antagonists &amp; inhibitors/metabolism ; Phosphoprotein Phosphatases/*antagonists &amp; inhibitors/metabolism ; Protein Phosphatase 2/*antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Recent studies have shown that fusarochromanone (FC101), a mycotoxin, is cytotoxic in a variety of cell lines. However, the molecular mechanism underlying its cytotoxicity remains elusive. Here we found that FC101 induced cell death in COS7 and HEK293 cells in part by activating JNK pathway. This is evidenced by the findings that inhibition of JNK with SP600125 or expression of dominant negative c-Jun partially prevented FC101-induced cell death. Furthermore, we observed that FC101-activated JNK pathway was attributed to induction of reactive oxygen species (ROS). Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, suppressed FC101-induced activation of JNK and cell death. Moreover, we noticed that FC101 inhibited the serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5) in the cells, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented FC101-induced activation of JNK and cell death. The results indicate that FC101-induced ROS inhibits PP2A and PP5, leading to activation of JNK pathway and consequently resulting in cell death.}, }
@article {pmid26516435, year = {2015}, author = {Ebrahimi, M and Mousavi, SR and Toussi, AG and Reihani, H and Bagherian, F}, title = {Comparing the Therapeutic Effectiveness of N-acetylcysteine with the Combination of N-acetyl Cysteine and Cimetidine in Acute Acetaminophen Toxicity: A Double-Blinded Clinical Trial.}, journal = {Electronic physician}, volume = {7}, number = {6}, pages = {1310-1317}, pmid = {26516435}, issn = {2008-5842}, abstract = {BACKGROUND: N-acetylcysteine (NAC) has been used as a classic treatment for hepatotoxicity induced by N-acetyl-p-benzoquinone imine (NAPQI) as a metabolite of acetaminophen. However, cimetidine theoretically can reduce the production of toxic metabolites through the inhibition of cytochrome p450, and it recently was proposed as a complementary treatment for acetaminophen toxicity.<br><br>OBJECTIVE: The aim of this study was to compare the effects of treating acute acetaminophen toxicity with NAC alone and with a combination of NAC and cimetidine.<br><br>METHODS: From October 2013 to March 2014, 105 patients suspected of acetaminophen toxicity who had paraclinical confirmation of toxicity requiring medical treatment (based on the risk assessment nomogram of acetaminophen serum level) were enrolled in this double-blind, randomized, controlled trial at Imam Reza Hospital in Mashhad, Iran. The patients were divided into two groups, i.e., 1) patients who were treated with NAC alone (group A) and 2) patients who were treated with a combination of NAC and cimetidine (group B). The primary outcomes were 1) the serum level of acetaminophen and 2) the serum level of aminotransferases at the time of admission and 4, 12, 24, and 48 hours after admission. Exclusion criteria included multiple toxicities, concurrent diseases that could affect liver enzymes, the use of other drugs, and dissatisfaction with the project. For measuring quantitative data, SPSS version 16 was used for t-test analysis and for analyzing the qualitative data with chi-squared analysis.<br><br>RESULTS: Sixty patients (32 females and 28 males) with a mean age of 25.2 &#xb1; 7.3 years were classified in two groups of 30.. There was no difference between the groups in terms of their admission information. The average levels of acetaminophen in both groups at admission, 12, 24, and 48 hours after hospitalization were not significantly different from each other. Twelve hours after hospitalization, the aspartate aminotransferase (AST) level in the group treated with NAC was significantly higher than in the group treated with the combination of NAC and cimetidine (IU/L30.1 &#xb1; 110.0 versus IU/L26.38 &#xb1; 94.93, p = 0.044). At the other times that the level of liver enzymes was assessed, the serum levels of urea and creatinine were not significantly different in the two groups (p > 0.05).<br><br>CONCLUSION: The intravenous administration of 300 mg of cimetidine every six hours with NAC did not improve the level of hepatoprotective action significantly compared with the NAC treatment protocol alone.}, }
@article {pmid26515652, year = {2016}, author = {Ulusoy, AT and Kalyoncuoğlu, E and Reis, A and Cehreli, ZC}, title = {Antibacterial effect of N-acetylcysteine and taurolidine on planktonic and biofilm forms of Enterococcus faecalis.}, journal = {Dental traumatology : official publication of International Association for Dental Traumatology}, volume = {32}, number = {3}, pages = {212-218}, doi = {10.1111/edt.12237}, pmid = {26515652}, issn = {1600-9657}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents ; *Biofilms ; Dental Pulp Cavity/microbiology ; Dentin ; Enterococcus faecalis/*drug effects/growth &amp; development ; Humans ; Taurine/*analogs &amp; derivatives/pharmacology ; Thiadiazines/*pharmacology ; }, abstract = {AIM: This study investigated the antimicrobial activity of taurolidine and N-acetylcysteine (NAC) on planktonic and biofilm Enterococcus faecalis phenotypes.<br><br>MATERIALS AND METHODS: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of NAC and taurolidine were determined using broth microdilution, utilizing calcium hydroxide (CH), sodium hypochlorite, and chlorhexidine for comparisons. Thereafter, the ability of dentin powder to neutralize the antibacterial activity of NAC and taurolidine was studied. The efficacy of both antimicrobial agents on E.&#xa0;faecalis biofilms was examined quantitatively by exposure of 21-day-old E.&#xa0;faecalis biofilms on dentin disks. The cytotoxicity of human dental pulp fibroblast cells in contact with the extracts was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay.<br><br>RESULTS: The MIC and MBC of NAC, taurolidine, and CH were not affected by pre-incubation in dentin powder. As verified by qualitative assay of E.&#xa0;faecalis biofilms, CH was the strongest bactericidal agent at all test dilutions, regardless of the presence of dentin powder. The antibacterial effect of NAC and taurolidine was significantly lower than that of CH at all test dilutions. At 48&#xa0;h, all test agents showed similar, but high levels of cytotoxicity.<br><br>CONCLUSION: NAC and taurolidine were effective against E.&#xa0;faecalis in planktonic state, at the expense of demonstrating cytotoxic effects. For both planktonic and biofilm forms of E.&#xa0;faecalis, neither NAC nor taurolidine offered any advantage over CH.}, }
@article {pmid26515054, year = {2015}, author = {Fulbright, JM and Egas-Bejar, DE and Huh, WW and Chandra, J}, title = {Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy.}, journal = {Cancer chemotherapy and pharmacology}, volume = {76}, number = {6}, pages = {1297-1307}, pmid = {26515054}, issn = {1432-0843}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA115811/CA/NCI NIH HHS/United States ; P30CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Adolescent ; Animals ; Anthracyclines/*adverse effects ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cardiotonic Agents/*pharmacology ; Cell Line ; Cell Line, Tumor ; Child, Preschool ; Female ; Heart Diseases/chemically induced/*prevention &amp; control ; Humans ; Jurkat Cells ; Leukemia/blood/drug therapy/pathology ; Leukocytes, Mononuclear/drug effects/metabolism ; Male ; Mice, Inbred BALB C ; Mice, SCID ; Myocytes, Cardiac/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {PURPOSE: Cardiotoxic side effects of anthracyclines limit their use as effective chemotherapeutics. One mechanistic model of anthracycline-induced cardiotoxicity is attributed to the generation of intracellular reactive oxygen species (ROS). However, this theory has been questioned because several cardioprotective strategies have included the use of antioxidants without significant clinical benefit. We sought to determine whether measurement of intracellular reactive oxygen species after anthracycline exposure in vivo and in vitro could provide a means for designing more effective antioxidant-based cardioprotective schemes.<br><br>METHODS: Intracellular levels of ROS were assessed in peripheral blood mononuclear cells from leukemia bearing mice exposed to anthracyclines and in patients receiving anthracyclines. Comparison of cell death induction and ROS levels were also conducted in vitro in cardiomyocyte and leukemia lines. ROS blockade using antioxidants was conducted, and effects on cell death were assessed.<br><br>RESULTS: Elevated ROS in blood of mice and representative patient samples correlated with cardiomyocyte necrosis and decreased ejection fraction. In vitro, comparison of the cytotoxic effects of anthracyclines in acute leukemia cells and in cardiomyocytes revealed distinct kinetics of cell death induction and dependence upon oxidative stress. Although apoptotic cell death was observed in both acute leukemia cells and cardiomyocytes, the antioxidant N-acetylcysteine protected cardiomyocytes but not acute leukemia cells from anthracycline cytotoxicity.<br><br>CONCLUSIONS: Our findings point toward revisiting the use of NAC as a cardioprotective agent since it does not appear to interfere with the cytotoxic action of anthracyclines. NAC has been evaluated clinically for cardioprotective activity but future trials must ensure that adequate dose, scheduling and incorporation of markers of oxidative stress are included.}, }
@article {pmid26513129, year = {2016}, author = {Soliman, E and Van Dross, R}, title = {Anandamide-induced endoplasmic reticulum stress and apoptosis are mediated by oxidative stress in non-melanoma skin cancer: Receptor-independent endocannabinoid signaling.}, journal = {Molecular carcinogenesis}, volume = {55}, number = {11}, pages = {1807-1821}, doi = {10.1002/mc.22429}, pmid = {26513129}, issn = {1098-2744}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Arachidonic Acids/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Chromans/pharmacology ; Endocannabinoids/*pharmacology ; *Endoplasmic Reticulum Stress ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice ; *Oxidative Stress ; Polyunsaturated Alkamides/*pharmacology ; Receptors, Cannabinoid/*metabolism ; Signal Transduction/drug effects ; Skin Neoplasms/drug therapy/*metabolism ; }, abstract = {Endocannabinoids are neuromodulatory lipids that regulate central and peripheral physiological functions. Endocannabinoids have emerged as effective antitumor drugs due to their ability to induce apoptosis in various cancer studies. The G-protein coupled cannabinoid receptors (CB1 and CB2) and the TRPV1 ion channel were reported to mediate the antiproliferative activity of endocannabinoids. However, receptor-independent effects also account for their activity. Our previous studies showed that the antiproliferative activity of anandamide (AEA) was regulated by cyclooxygenase-2 (COX-2) via induction of endoplasmic reticulum (ER) stress. We also determined that AEA induced oxidative stress. However, the role of oxidative stress, the cannabinoid receptors, and TRPV1 in AEA-induced ER stress-apoptosis was unclear. Therefore, the current study examines the role of oxidative stress in ER stress-apoptosis and investigates whether this effect is modulated by CB1, CB2, or TRPV1. In non-melanoma skin cancer (NMSC) cells, AEA reduced the total intracellular level of glutathione and induced oxidative stress. To evaluate the importance of oxidative stress in AEA-induced cell death, the antioxidants, N-acetylcysteine (NAC) and Trolox, were utilized. Each antioxidant ameliorated the antiproliferative effect of AEA. Furthermore, Trolox inhibited AEA-induced CHOP10 expression and caspase 3 activity, indicating that oxidative stress was required for AEA-induced ER stress-apoptosis. On the other hand, selective blockade of CB1, CB2, and TRPV1 did not inhibit AEA-induced oxidative stress or ER stress-apoptosis. These findings suggest that AEA-induced ER stress-apoptosis in NMSC cells is mediated by oxidative stress through a receptor-independent mechanism. Hence, receptor-independent AEA signaling pathways may be targeted to eliminate NMSC. © 2015 Wiley Periodicals, Inc.}, }
@article {pmid26512993, year = {2016}, author = {Shirkhanloo, H and Ghazaghi, M and Mousavi, HZ}, title = {Chromium speciation in human blood samples based on acetyl cysteine by dispersive liquid-liquid biomicroextraction and in-vitro evaluation of acetyl cysteine/cysteine for decreasing of hexavalent chromium concentration.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {118}, number = {}, pages = {1-8}, doi = {10.1016/j.jpba.2015.10.018}, pmid = {26512993}, issn = {1873-264X}, mesh = {Acetylcysteine/*blood/chemistry ; Chromium/*blood/chemistry ; Cysteine/*blood/chemistry ; Drug Evaluation, Preclinical/methods ; Environmental Pollutants/blood/chemistry ; Humans ; Liquid Phase Microextraction/*methods ; Prodrugs/*analysis/chemistry ; }, abstract = {A rapid and efficient method based on ionic liquid dispersive liquid-liquid biomicroextraction (IL-DLLBME) was used for speciation and preconcentration of Chromium (III, VI) in human blood samples before determination by electro-thermal atomic absorption spectrometer (ET-AAS). In this method, 1-hexyl-3-methylimidazolium hexafluorophosphate as a ionic liquid was dissolved in acetone as a dispersant solvent and then the binary solution was rapidly injected by a syringe into the blood samples containing Cr(III), which have already complexed by acetyl cysteine (NAC) at optimized pH. Under the optimal conditions, the linear range (LR), limit of detection (LOD) and preconcentration factor (PF) were obtained 0.03-4.4 μg L(-1), 0.005 μg L(-1) and 10 respectively (RSD <5%). In vitro study show us, the cysteine (Cys) as a prodrug of NAC can decrease the concentration of Cr(VI) in blood samples and human body. Validation of methodology was confirmed by standard reference material (SRM).}, }
@article {pmid26506860, year = {2016}, author = {Uesugi, S and Fujisawa, N and Yoshida, J and Watanabe, M and Dan, S and Yamori, T and Shiono, Y and Kimura, K}, title = {Pyrrocidine A, a metabolite of endophytic fungi, has a potent apoptosis-inducing activity against HL60 cells through caspase activation via the Michael addition.}, journal = {The Journal of antibiotics}, volume = {69}, number = {3}, pages = {133-140}, pmid = {26506860}, issn = {1881-1469}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Anti-Infective Agents/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Bridged-Ring Compounds/*pharmacology ; Caspase Inhibitors/pharmacology ; DNA Fragmentation/drug effects ; HL-60 Cells ; Humans ; Hypocreales/chemistry ; Oligopeptides/pharmacology ; Pyrrolidinones/*pharmacology ; Reactive Oxygen Species ; Tandem Mass Spectrometry ; }, abstract = {Pyrrocidine A is a known antimicrobial compound produced by endophytic fungi and has a unique 13-membered macrocyclic alkaloid structure with an α,β-unsaturated carbonyl group. We have previously reported that pyrrocidine A shows potent cytotoxicity against human acute promyelocytic leukemia HL60 cells, and the activity is 70-fold higher than that of pyrrocidine B which is the analog lacking the α,β-unsaturated carbonyl group. Pyrrocidine A induced nuclear condensation, DNA fragmentation and caspase activation in HL60 cells. Since the DNA fragmentation was suppressed by pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (z-VAD-fmk), caspase-mediated apoptosis contributes to pyrrocidine A-induced cytotoxicity. JFCR39 human cancer cells panel indicated that the mechanism of action of pyrrocidine A is different from other clinical anticancer drugs, and this compound broadly inhibited the growth of various cancer cell lines. The apoptosis induction by pyrrocidine A was suppressed by both N-acetyl-l-cysteine (NAC) and glutathione, both of which are thiol-containing antioxidants. Furthermore, pyrrocidine A directly bound to N-acetyl-l-cysteine methyl ester (NACM) through the Michael-type addition at the α,β-unsaturated carbonyl group and was detected by HPLC and liquid chromatography-ESI-tandem MS (LC-ESI-MS/MS) analyses. This indicates that this moiety is crucial for the potent apoptosis-inducing activity of pyrrocidine A.}, }
@article {pmid26504962, year = {2015}, author = {Jahanshahi, B and Raoof, JB and Amiri-Aref, M and Ojani, R}, title = {A Voltammetric Sensor Based on Modified Multi-Walled Carbon Nanotubes for N-Acetyl-L-Cysteine Determination in the Presence of Tryptophan Using 4-Chlorocatechol as a Homogenous Electrochemical Catalyst.}, journal = {Journal of nanoscience and nanotechnology}, volume = {15}, number = {5}, pages = {3429-3436}, doi = {10.1166/jnn.2015.10212}, pmid = {26504962}, issn = {1533-4880}, mesh = {Acetylcysteine/*analysis ; Catechols/*chemistry ; Electrochemical Techniques/*methods ; Electrodes ; Limit of Detection ; Nanotubes, Carbon/*chemistry ; Oxidation-Reduction ; Tryptophan/*chemistry ; }, abstract = {Simultaneous determination of N-acetyl-L-cysteine (NAC) and Tryptophan (Trp) has been studied at the surface of glassy carbon electrode (GCE) modified with multi-walled carbon nanotubes (MWCNTs) in the presence of 4-chlorocatechol as homogenous electrochemical catalyst in aqueous media. The electrocatalytic properties of GCE modified with MWCNTs in the presence of 4-chlorocatechol toward the electrocatalytic oxidation of NAC and Trp was studied using cyclic voltammetry (CV), double-step potential chronoamperometry and differential pulse voltammetry (DPV). The results has shown that NAC participates in Michael type addition reaction with electrogenerated quinone from electrooxidation of 4-chlorocatechol at MWCNT/GCE to form the corresponding thioquinone derivative. The reoxidation of the adduct leads to increase in the oxidative current which is proportional to the concentration of NAC. Differential pulse voltammogram peak currents of NAC and Trp increased linearly with their concentration at the ranges of 5-60 μM and 5-50 μM, respectively and the detection limits for NAC and Trp were sequentially 3.427 μM and 2.494 μM. The proposed method was successfully used for the determination of NAC in pharmaceutical samples and the obtained results were found to be reasonable.}, }
@article {pmid26504357, year = {2015}, author = {Lin, AH and Liu, MH and Ko, HK and Perng, DW and Lee, TS and Kou, YR}, title = {Lung Epithelial TRPA1 Transduces the Extracellular ROS into Transcriptional Regulation of Lung Inflammation Induced by Cigarette Smoke: The Role of Influxed Ca[2+].}, journal = {Mediators of inflammation}, volume = {2015}, number = {}, pages = {148367}, pmid = {26504357}, issn = {1466-1861}, mesh = {Acetanilides/chemistry ; Acetophenones/chemistry ; Animals ; Biomarkers/metabolism ; Bronchoalveolar Lavage Fluid ; Calcium/*metabolism ; Calcium Channels/genetics/*metabolism ; Chelating Agents/chemistry ; Chemokine CXCL2/metabolism ; Egtazic Acid/chemistry ; Enzyme Activation ; Gene Expression Regulation, Neoplastic ; Humans ; Inflammation ; Interleukin-8/metabolism ; Lung/*pathology ; MAP Kinase Signaling System ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; NADPH Oxidases/metabolism ; Nerve Tissue Proteins/genetics/*metabolism ; Oxidative Stress ; Purines/chemistry ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Smoke/*adverse effects ; TRPA1 Cation Channel ; Transient Receptor Potential Channels/genetics/*metabolism ; }, abstract = {The mechanism underlying the inflammatory role of TRPA1 in lung epithelial cells (LECs) remains unclear. Here, we show that cigarette smoke extract (CSE) sequentially induced several events in LECs. The Ca(2+) influx was prevented by decreasing extracellular reactive oxygen species (ROS) with the scavenger N-acetyl-cysteine, removing extracellular Ca(2+) with the chelator EGTA, or treating with the TRPA1 antagonist HC030031. NADPH oxidase activation was abolished by its inhibitor apocynin, EGTA, or HC030031. The increased intracellular ROS was halted by apocynin, N-acetyl-cysteine, or HC030031. The activation of the MAPKs/NF-κB signaling was suppressed by EGTA, N-acetyl-cysteine, or HC030031. IL-8 induction was inhibited by HC030031 or TRPA1 siRNA. Additionally, chronic cigarette smoke (CS) exposure in wild-type mice induced TRPA1 expression in LECs and lung tissues. In CS-exposure trpa1 (-/-) mice, the increased BALF level of ROS was similar to that of CS-exposure wild-type mice; yet lung inflammation was lessened. Thus, in LECs, CSE may initially increase extracellular ROS, which activate TRPA1 leading to an increase in Ca(2+) influx. The increased intracellular Ca(2+) contributes to activation of NADPH oxidase, resulting in increased intracellular ROS, which activate the MAPKs/NF-κB signaling leading to IL-8 induction. This mechanism may possibly be at work in mice chronically exposed to CS.}, }
@article {pmid26503030, year = {2015}, author = {Farias, CF and Massaoka, MH and Girola, N and Azevedo, RA and Ferreira, AK and Jorge, SD and Tavares, LC and Figueiredo, CR and Travassos, LR}, title = {Benzofuroxan derivatives N-Br and N-I induce intrinsic apoptosis in melanoma cells by regulating AKT/BIM signaling and display anti metastatic activity in vivo.}, journal = {BMC cancer}, volume = {15}, number = {}, pages = {807}, pmid = {26503030}, issn = {1471-2407}, mesh = {Animals ; Antineoplastic Agents/chemistry/pharmacology/therapeutic use ; Apoptosis/*drug effects/physiology ; Apoptosis Regulatory Proteins/antagonists &amp; inhibitors/*metabolism ; Bcl-2-Like Protein 11 ; Benzoxazoles/*chemistry/pharmacology/*therapeutic use ; Cell Line, Tumor ; HeLa Cells ; Humans ; Male ; Melanoma, Experimental/drug therapy/*metabolism ; Membrane Proteins/antagonists &amp; inhibitors/*metabolism ; Mice ; Mice, Inbred C57BL ; Oncogene Protein v-akt/antagonists &amp; inhibitors/*metabolism ; Proto-Oncogene Proteins/antagonists &amp; inhibitors/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {BACKGROUND: Malignant melanoma is an aggressive type of skin cancer, and despite recent advances in treatment, the survival rate of the metastatic form remains low. Nifuroxazide analogues are drugs based on the substitution of the nitrofuran group by benzofuroxan, in view of the pharmacophore similarity of the nitro group, improving bioavailability, with higher intrinsic activity and less toxicity. Benzofuroxan activity involves the intracellular production of free-radical species. In the present work, we evaluated the antitumor effects of different benzofuroxan derivatives in a murine melanoma model.<br><br>METHODS: B16F10-Nex2 melanoma cells were used to investigate the antitumor effects of Benzofuroxan derivatives in vitro and in a syngeneic melanoma model in C57Bl/6 mice. Cytotoxicity, morphological changes and reactive oxygen species (ROS) were assessed by a diphenyltetrasolium reagent, optical and fluorescence microscopy, respectively. Annexin-V binding and mitochondrial integrity were analyzed by flow cytometry. Western blotting and colorimetry identified cell signaling proteins.<br><br>RESULTS: Benzofuroxan N-Br and N-I derivatives were active against murine and human tumor cell lines, exerting significant protection against metastatic melanoma in a syngeneic model. N-Br and N-I induce apoptosis in melanoma cells, evidenced by specific morphological changes, DNA condensation and degradation, and phosphatidylserine translocation in the plasma membrane. The intrinsic mitochondrial pathway in B16F10-Nex2 cells is suggested owing to reduced outer membrane potential in mitochondria, followed by caspase -9, -3 activation and cleavage of PARP. The cytotoxicity of N-Br and N-I in B16F10-Nex2 cells is mediated by the generation of ROS, inhibited by pre-incubation of the cells with N-acetylcysteine (NAC). The induction of ROS by N-Br and N-I resulted in the inhibition of AKT activation, an important molecule related to tumor cell survival, followed by upregulation of BIM.<br><br>CONCLUSION: We conclude that N-Br and N-I are promising agents aiming at cancer treatment. They may be useful in melanoma therapy as inducers of intrinsic apoptosis and by exerting significant antitumor activity against metastatic melanoma, as presently shown in syngeneic mice.}, }
@article {pmid26501381, year = {2015}, author = {Tsai, MS and Chien, CC and Lin, TH and Liu, CC and Liu, RH and Su, HL and Chiu, YT and Wang, SH}, title = {Galangin Prevents Acute Hepatorenal Toxicity in Novel Propacetamol-Induced Acetaminophen-Overdosed Mice.}, journal = {Journal of medicinal food}, volume = {18}, number = {11}, pages = {1187-1197}, doi = {10.1089/jmf.2014.3328}, pmid = {26501381}, issn = {1557-7600}, mesh = {Acetaminophen/administration &amp; dosage/*adverse effects/analogs &amp; derivatives ; Acetylcysteine/therapeutic use ; Alanine Transaminase/blood ; Alpinia/chemistry ; Animals ; Antioxidants/metabolism/pharmacology/therapeutic use ; Chemical and Drug Induced Liver Injury/metabolism/pathology/*prevention &amp; control ; Cytochrome P-450 CYP2E1/metabolism ; Disease Models, Animal ; Flavonoids/pharmacology/*therapeutic use ; Glutathione/metabolism ; Helichrysum/chemistry ; Liver/*drug effects/metabolism/pathology ; Male ; Mice, Inbred BALB C ; Oxidative Stress/*drug effects ; *Phytotherapy ; Plant Extracts/pharmacology/*therapeutic use ; Protective Agents/pharmacology/therapeutic use ; Silymarin/therapeutic use ; }, abstract = {Acetaminophen (APAP) overdose causes severe liver and kidney damage. APAP-induced liver injury (AILI) represents the most frequent cause of drug-induced liver failure. APAP is relatively insoluble and can only be taken orally; however, its prodrug, propacetamol, is water soluble and usually injected directly. In this study, we examined the time-dependent effects of AILI after propacetamol injection in mice. After analyses of alanine aminotransferase and aspartate aminotransferase activities and liver histopathology, we demonstrated that a novel AILI mouse model can be established by single propacetamol injection. Furthermore, we compared the protective and therapeutic effects of galangin with a known liver protective extract, silymarin, and the only clinical agent for treating APAP toxicity, N-acetylcysteine (NAC), at the same dose in the model mice. We observed that galangin and silymarin were more effective than NAC for protecting against AILI. However, only NAC greatly improved both the survival time and rate consequent to a lethal dose of propacetamol. To decipher the hepatic protective mechanism(s) of galangin, galangin pretreatment significantly decreased the hepatic oxidative stress, increased hepatic glutathione level, and decreased hepatic microsomal CYP2E1 levels induced by propacetamol injection. In addition, propacetamol injection also reproduced the probability of APAP-induced kidney injury (AIKI), appearing similar to a clinical APAP overdose. Only galangin pretreatment showed the protective effect of AIKI. Thus, we have established a novel mouse model for AILI and AIKI using a single propacetamol injection. We also demonstrated that galangin provides significant protection against AILI and AIKI in this mouse model.}, }
@article {pmid26500648, year = {2015}, author = {Allen, M and Bailey, C and Cahatol, I and Dodge, L and Yim, J and Kassissa, C and Luong, J and Kasko, S and Pandya, S and Venketaraman, V}, title = {Mechanisms of Control of Mycobacterium tuberculosis by NK Cells: Role of Glutathione.}, journal = {Frontiers in immunology}, volume = {6}, number = {}, pages = {508}, pmid = {26500648}, issn = {1664-3224}, abstract = {Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), continues to be one of the most prevalent infectious diseases in the world. There is an upward trend in occurrence due to emerging multidrug resistant strains and an increasingly larger proportion of immunocompromised patient populations as a result of the acquired immunodeficiency syndrome pandemic. The complex and often deadly combination of multidrug resistant M. tb (MDR-M. tb) along with human immunodeficiency virus (HIV) puts a significant number of people at high risk for pulmonary and extra-pulmonary TB without sufficient therapeutic options available. Natural killer (NK) cells and macrophages are major components of the body's innate immune system, contributing significantly to the body's ability to synergistically inhibit the growth of M. tb in immune compromised individuals lacking a sufficient T cell response. Direct mechanisms of control are largely through the secretory products perforin, granulysin, and granzymes, as well as multiple membrane-bound death receptors that facilitate target directed lysis. NK cells also have a role in indirectly stimulating an immune response through activation of macrophages and monocytes with multiple signaling pathways, including both reactive oxygen species and reactive nitrogen species. Glutathione (GSH) has been shown to play a part in inhibiting the growth of intracellular M. tb through bacteriostatic mechanisms. Enhancing cellular GSH through several cytokines and N-acetyl cysteine has been shown to increase these effects, at least in part, through their action on NK cells. Taken together, there is substantial evidence for a mechanistic correlation between NK cell activity and functionality in combating M. tb in HIV infection mediated through adequate GSH production and use.}, }
@article {pmid26500003, year = {2016}, author = {Genzen, JR and Hunsaker, JJ and Nelson, LS and Faine, BA and Krasowski, MD}, title = {N-acetylcysteine interference of Trinder-based assays.}, journal = {Clinical biochemistry}, volume = {49}, number = {1-2}, pages = {100-104}, doi = {10.1016/j.clinbiochem.2015.10.005}, pmid = {26500003}, issn = {1873-2933}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/blood/*therapeutic use ; Ferric Compounds/*chemistry ; Humans ; Poisoning/drug therapy ; Retrospective Studies ; }, abstract = {OBJECTIVES: The primary objective of this study was to evaluate potential interference of Trinder-based chemistry assays by N-acetylcysteine (NAC). A secondary objective was to look for evidence of interference in patients treated with NAC for acetaminophen (APAP) overdose.<br><br>DESIGN AND METHODS: Dilutions of NAC in plasma were tested for interference using the following Roche Diagnostics Trinder-based assays on a cobas 8000 system: enzymatic creatinine (Cr), cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), triglycerides (TRIG), and uric acid (UA). Two non-Trinder Roche assays - urea nitrogen (BUN) and glucose (GLUC) - were tested as controls. Sekisui N-geneous&#xae; low-density lipoprotein cholesterol (LDL-C) reagent was also evaluated. Retrospective chart review of APAP overdose cases over 49months was conducted to look for differences in plasma Cr before and after intravenous (IV) NAC administration.<br><br>RESULTS: NAC concentrations (shown in parentheses) that caused &#x2265;10% inhibition for individual assays were (in order of sensitivity to interference): TRIG (570mg/L)>CHOL (740mg/L)&#x2248;Cr (790mg/L)>UA (1100mg/L)>HDL-C (1760mg/L)>LDL-C (2900mg/L). Neither BUN nor GLUC achieved significant inhibition up to 10,000mg/L NAC. Evidence for relatively minor inhibition of Cr was observed in patients after NAC administration.<br><br>CONCLUSIONS: NAC inhibition of the assays investigated typically occurs at concentrations higher than expected during IV and oral NAC therapy.}, }
@article {pmid26498924, year = {2015}, author = {Yu, Y and Cai, Z and Cui, M and Nie, P and Sun, Z and Sun, S and Chu, S and Wang, X and Hu, L and Yi, J and Shen, L and He, B}, title = {The orphan nuclear receptor Nur77 inhibits low shear stress-induced carotid artery remodeling in mice.}, journal = {International journal of molecular medicine}, volume = {36}, number = {6}, pages = {1547-1555}, pmid = {26498924}, issn = {1791-244X}, mesh = {Animals ; Blotting, Western ; Carotid Arteries/metabolism/*physiology ; Cell Movement/drug effects/genetics ; Cell Proliferation/drug effects/genetics ; Cells, Cultured ; Gene Expression/drug effects ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Confocal ; Muscle, Smooth, Vascular/cytology ; Myocytes, Smooth Muscle/metabolism ; Neointima/genetics/metabolism ; Nuclear Receptor Subfamily 4, Group A, Member 1/genetics/*metabolism ; Platelet-Derived Growth Factor/pharmacology ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Shear Strength ; *Stress, Mechanical ; Vascular Remodeling/genetics/*physiology ; }, abstract = {Shear stress, particularly low and oscillatory shear stress, plays a critical pathophysiological role in vascular remodeling-related cardiovascular diseases. Growing evidence suggests that the orphan nuclear receptor Nur77 [also known as TR3 or nuclear receptor subfamily 4, group A, member 1 (NR4A1)] is expressed in diseased human vascular tissue and plays an important role in vascular physiology and pathology. In the present study, we used a mouse model of flow-dependent remodeling by partial ligation of the left common carotid artery (LCCA) to define the exact role of Nur77 in vascular remodeling induced by low shear stress. Following vascular remodeling, Nur77 was highly expressed in neointimal vascular smooth muscle cells (VSMCs) in the ligated carotid arteries. The reactive oxygen species (ROS) levels were elevated in the remodeled arteries in vivo and in primary rat VSMCs in vitro following stimulation with platelet-derived growth factor (PDGF). Further in vitro experiments revealed that Nur77 expression was rapidly increased in the VSMCs following stimulation with PDGF and H2O2, whereas treatment with N-acetyl cysteine (NAC, a ROS scavenger) reversed the increase in the protein level of Nur77 induced by H2O2. Moreover, Nur77 overexpression markedly inhibited the proliferation and migration of VSMCs, induced by PDGF. Finally, to determine the in vivo role of Nur77 in low shear stress-induced vascular remodeling, wild-type (WT) and Nur77-deficient mice were subjected to partial ligation of the LCCA. Four weeks following surgery, in the LCCAs of the Nur77‑deficient mice, a significant increase in the intima-media area and carotid intima-media thickness was noted, as well as more severe elastin disruption and collagen deposition compared to the WT mice. Immunofluorescence staining revealed an increase in VSMC proliferation [determined by the expression of proliferating cell nuclear antigen (PCNA)] and matrix metalloproteinase 9 (MMP-9) production in the Nur77-deficient mice. There was no difference in the number of intimal apoptotic cells between the groups. Taken together, our results indicate that Nur77 may be a sensor of oxidative stress and an inhibitor of vascular remodeling induced by low shear stress. Nur77, as well as its downstream cell signals, may thus be a potential therapeutic target for the suppression of vascular remodeling.}, }
@article {pmid26498383, year = {2015}, author = {Sobarzo, CM and Rosana, Nde M and Livia, L and Berta, D and Schteingart, HF}, title = {Mono-(2-ethylhexyl) phthalate (MEHP) affects intercellular junctions of Sertoli cell: A potential role of oxidative stress.}, journal = {Reproductive toxicology (Elmsford, N.Y.)}, volume = {58}, number = {}, pages = {203-212}, doi = {10.1016/j.reprotox.2015.10.010}, pmid = {26498383}, issn = {1873-1708}, mesh = {Animals ; Antioxidants/pharmacology ; Cadherins/metabolism ; Cell Shape/drug effects ; Cells, Cultured ; Claudin-1/metabolism ; Connexin 43/metabolism ; Cytoprotection ; Diethylhexyl Phthalate/*analogs &amp; derivatives/toxicity ; Glutathione/metabolism ; Glutathione Transferase/metabolism ; Intercellular Junctions/*drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Male ; Nerve Tissue Proteins/metabolism ; Occludin/metabolism ; Oxidative Stress/*drug effects ; Rats, Sprague-Dawley ; Sertoli Cells/*drug effects/metabolism/pathology ; Zonula Occludens-1 Protein/metabolism ; alpha Catenin/metabolism ; }, abstract = {We analyzed the potential role of oxidative stress induced by mono (2-ethylhexyl) phthalate (MEHP) in adherent cell junction protein expression of prepubertal rat Sertoli cells (SC) in vitro. Five-day SC cultures were treated with MEHP (200μM) for 24h and compared to cells in basal conditions. Western blot and immunofluorescent (IF) analyses showed that MEHP induced increase of N-cadherin and catenin expression, modifying its distribution. Concomitantly, Cx-43 expression decreased significantly and delocalization of the IF signal for tight junction proteins (occludin, claudin-11 and ZO-1) occurred. Indicative of oxidative stress, MEHP induced in SC an increase of lipoperoxides, a decrease in glutathione (GSH) levels and a concomitant increase in Glutathione S-Transferases (GST) activity. Antioxidant N-acetyl-cysteine (1mM) treatment prevented GSH decrease and N-cadherin and α-catenin up-regulation induced by MEHP. Our data suggest that oxidative stress signaling is a mechanism involved in adherent cell junctions disruption induced by MEHP in SC cultures.}, }
@article {pmid26497999, year = {2015}, author = {Qin, W and Li, C and Zheng, W and Guo, Q and Zhang, Y and Kang, M and Zhang, B and Yang, B and Li, B and Yang, H and Wu, Y}, title = {Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells.}, journal = {Oncotarget}, volume = {6}, number = {37}, pages = {39839-39854}, pmid = {26497999}, issn = {1949-2553}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis Regulatory Proteins/genetics/metabolism ; Autophagy/drug effects/*genetics ; Beclin-1 ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation/drug effects/genetics ; Epithelial-Mesenchymal Transition/drug effects/genetics ; Free Radical Scavengers ; Glycolysis/drug effects/*genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Male ; Membrane Proteins/genetics/metabolism ; Mice, Nude ; Microscopy, Confocal ; Neoplasm Metastasis ; RNA Interference ; RNAi Therapeutics/methods ; Reactive Oxygen Species/*metabolism ; Stomach Neoplasms/drug therapy/*genetics/metabolism ; Transcription Factor RelA/genetics/metabolism ; Xenograft Model Antitumor Assays/methods ; }, abstract = {Autophagy defect has been shown to be correlated with malignant phenotype and poor prognosis of human cancers, however, the detailed mechanisms remain obscure. In this study, we investigated the biological changes induced by autophagy inhibition in gastric cancer. We showed that inhibition of autophagy in gastric cancer cells promotes epithelial-mesenchymal transition (EMT) and metastasis, alters metabolic phenotype from mitochondrial oxidative phosphorylation to aerobic glycolysis and converts cell phenotype toward malignant, which maybe further contribute to chemoresistance and poor prognosis of gastric cancer. We also identified that the EMT and metabolism alterations induced by autophagy inhibition were dependent on ROS-NF-κB-HIF-1α pathway. More importantly, scavenging of ROS by the antioxidant N-acetylcysteine (NAC) attenuated activation of NF-κB and HIF-1α in autophagy-deficient gastric cancer cells, and autophagy inhibition induced metastasis and glycolysis were also diminished by NAC in vivo. Taken together, our findings suggested that autophagy defect promotes metastasis and glycolysis of gastric cancer, and antioxidants could be used to improve disease outcome for gastric cancer patients with autophagy defect.}, }
@article {pmid26497050, year = {2015}, author = {Zhao, W and Lu, M and Zhang, Q}, title = {Chloride intracellular channel 1 regulates migration and invasion in gastric cancer by triggering the ROS-mediated p38 MAPK signaling pathway.}, journal = {Molecular medicine reports}, volume = {12}, number = {6}, pages = {8041-8047}, pmid = {26497050}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects ; Chloride Channels/antagonists &amp; inhibitors/*metabolism ; Down-Regulation/drug effects ; Glycolates/pharmacology ; Humans ; Imidazoles/pharmacology ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Stomach Neoplasms/metabolism/pathology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Chloride intracellular channel 1 (CLIC1) has been demonstrated to be overexpressed in gastric cancer, and elevated CLIC1 expression levels are markedly associated with the processes of tumor cell migration and invasion. However, the regulatory mechanism and signaling pathway underlying these processes have remained to be elucidated. The present study examined the impact of N-acetyl cysteine (NAC), indanyloxyacetic acid (IAA)-94 and SB203580, inhibitors of reactive oxygen species (ROS), as well as CLIC1 and p38 mitogen-activated protein kinase (MAPK) on the migration and invasion of SGC-7901 gastric cancer cells in a hypoxia‑reoxygenation (H-R) microenvironment. The results demonstrated that intracellular ROS and CLIC1 levels were increased under H‑R conditions, and that functional inhibition of CLIC1 significantly decreased the H‑R‑elevated ROS generation and p‑p38 MAPK levels in SGC‑7901 cells, as well as inhibited the migration and invasion of SGC‑7901 cells. In addition, the expression levels of MMP‑2 and MMP‑9 were inhibited by NAC, IAA‑94 and SB203580. These results indicated that CLIC1 regulates gastric cancer-cell migration and invasion via the ROS-mediated p38 MAPK signaling pathway.}, }
@article {pmid26496265, year = {2015}, author = {Huang, H and Dai, HP and Kang, J and Chen, BY and Sun, TY and Xu, ZJ}, title = {Double-Blind Randomized Trial of Pirfenidone in Chinese Idiopathic Pulmonary Fibrosis Patients.}, journal = {Medicine}, volume = {94}, number = {42}, pages = {e1600}, pmid = {26496265}, issn = {1536-5964}, mesh = {Asian People ; Double-Blind Method ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy ; Male ; Middle Aged ; Pyridones/*therapeutic use ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) lacks effective treatment. Pirfenidone has been used to treat IPF patients. N-acetylcysteine (NAC) exerts antioxidant and antifibrotic effects on IPF cases.This study is a double-blind, modified placebo-controlled, randomized phase II trial of pirfenidone in Chinese IPF patients. We randomly assigned the enrolled Chinese IPF patients with mild to moderate impairment of pulmonary function to receive either oral pirfenidone (1800 mg per day) and NAC (1800 mg per day) or placebo and NAC (1800 mg per day) for 48 weeks. The primary endpoints were the changes in forced vital capacity (FVC) and walking distance and the lowest SPO2 during the 6-minute walk test (6MWT) at week 48. The key secondary endpoint was the progression-free survival time. This study is registered in ClinicalTrials.gov as number NCT01504334.Eighty-six patients were screened, and 76 cases were enrolled (pirfenidone + NAC: 38; placebo + NAC: 38). The effect of pirfenidone treatment was significant at the 24th week, but this effect did not persist to the 48th week. At the 24th week, the mean decline in both FVC and ΔSPO2 (%) during the 6MWT in the pirfenidone group was lower than that in the control group (-0.08 ± 0.20 L vs -0.22 ± 0.29 L, P = 0.02 and -3.44% ± 4.51% vs -6.29% ± 6.06%, P = 0.03, respectively). However, there was no significant difference between these 2 groups at the 48th week (-0.15 ± 0.25 L vs -0.25 ± 0.28 L, P = 0.11 and -4.25% ± 7.27% vs -5.31% ± 5.49%, P = 0.51, respectively). The pirfenidone treatment group did not achieve the maximal distance difference on the 6MWT at either the 24th or the 48th week. But pirfenidone treatment prolonged the progression-free survival time in the IPF patients (hazard ratio = 1.88, 95% confidence interval: 1.092-3.242, P = 0.02). In the pirfenidone group, the adverse event (AE) rate (52.63%) was higher than that in the control group (26.3%, P = 0.03). Rash was more common in the pirfenidone group (39.5% vs 13.2%, P = 0.02).Compared with placebo combined with high-dose NAC, pirfenidone combined with high-dose NAC prolonged the progression-free survival of Chinese IPF patients with mild to moderate impairment of pulmonary function. (ClinicalTrials.gov number, NCT01504334).}, }
@article {pmid26496199, year = {2015}, author = {Pi, J and Cai, H and Jin, H and Yang, F and Jiang, J and Wu, A and Zhu, H and Liu, J and Su, X and Yang, P and Cai, J}, title = {Qualitative and Quantitative Analysis of ROS-Mediated Oridonin-Induced Oesophageal Cancer KYSE-150 Cell Apoptosis by Atomic Force Microscopy.}, journal = {PloS one}, volume = {10}, number = {10}, pages = {e0140935}, pmid = {26496199}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/antagonists &amp; inhibitors/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Diterpenes, Kaurane/antagonists &amp; inhibitors/*pharmacology ; Dose-Response Relationship, Drug ; Epithelial Cells/*drug effects/metabolism/ultrastructure ; Esophagus/drug effects/metabolism/ultrastructure ; Free Radical Scavengers/pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Atomic Force ; Mitochondria/drug effects/metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/*metabolism ; }, abstract = {High levels of intracellular reactive oxygen species (ROS) in cells is recognized as one of the major causes of cancer cell apoptosis and has been developed into a promising therapeutic strategy for cancer therapy. However, whether apoptosis associated biophysical properties of cancer cells are related to intracellular ROS functions is still unclear. Here, for the first time, we determined the changes of biophysical properties associated with the ROS-mediated oesophageal cancer KYSE-150 cell apoptosis using high resolution atomic force microscopy (AFM). Oridonin was proved to induce ROS-mediated KYSE-150 cell apoptosis in a dose dependent manner, which could be reversed by N-acetylcysteine (NAC) pretreatment. Based on AFM imaging, the morphological damage and ultrastructural changes of KYSE-150 cells were found to be closely associated with ROS-mediated oridonin-induced KYSE-150 cell apoptosis. The changes of cell stiffness determined by AFM force measurement also demonstrated ROS-dependent changes in oridonin induced KYSE-150 cell apoptosis. Our findings not only provided new insights into the anticancer effects of oridonin, but also highlighted the use of AFM as a qualitative and quantitative nanotool to detect ROS-mediated cancer cell apoptosis based on cell biophysical properties, providing novel information of the roles of ROS in cancer cell apoptosis at nanoscale.}, }
@article {pmid26490979, year = {2016}, author = {Chen, Z and Wang, B and Yu, F and Chen, Q and Tian, Y and Ma, S and Liu, X}, title = {The roles of mitochondria in radiation-induced autophagic cell death in cervical cancer cells.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {37}, number = {3}, pages = {4083-4091}, pmid = {26490979}, issn = {1423-0380}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Autophagy/*radiation effects ; Female ; HeLa Cells ; Humans ; Mitochondria/*physiology/radiation effects ; Reactive Oxygen Species/metabolism ; Uterine Cervical Neoplasms/radiotherapy ; }, abstract = {Mitochondria as the critical powerhouse of eukaryotic cells play important roles in regulating cell survival or cell death. Under numerous stimuli, impaired mitochondria will generate massive reactive oxygen species (ROS) which participate in the regulation of vital signals and could even determine the fate of cancer cells. While the roles of mitochondria in radiation-induced autophagic cell death still need to be elucidated. Human cervical cancer cell line, Hela, was used, and the SOD2 silencing model (SOD2-Ri) was established by gene engineering. Cell viability was detected by methyl thiazolyl tetrazolium (MTT) assays, MitoTracker Green staining was used to detect mitochondrial mass, Western blot was used to detect protein expression, and the level of ROS, autophagy, and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. Ionizing radiation (IR) could induce the increase of MAPLC3-II/MAPLC3-I ratio, Beclin1 expression, and ROS generation but decrease the MMP in a time-dependent manner. After SOD2 silencing, the IR-induced changes of ROS and the MMP were significantly enhanced. Moreover, both the radio sensitivity and autophagy increased in SOD2-Ri cells. Whereas, compared with SOD2-Ri, the opposite results were obtained by NAC, an antioxidant. After the treatment with the inhibitor of mitochondrial electron-transport chain complex II, thenoyltrifluoroacetone (TTFA), the rate of autophagy, ROS, and the total cell death induced by IR increased. In addition, the decrease of MMP was more obvious. However, these results were reversed by cyclosporine A (CsA). IR could induce ROS generation and mitochondrial damage which lead to autophagic cell death in Hela cells.}, }
@article {pmid26488897, year = {2015}, author = {Chang, CY and Li, JR and Wu, CC and Ou, YC and Chen, WY and Kuan, YH and Wang, WY and Chen, CJ}, title = {Valproic acid sensitizes human glioma cells to gefitinib-induced autophagy.}, journal = {IUBMB life}, volume = {67}, number = {11}, pages = {869-879}, doi = {10.1002/iub.1445}, pmid = {26488897}, issn = {1521-6551}, mesh = {Adenylate Kinase/metabolism ; Antineoplastic Agents/*pharmacology ; Apoptosis ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Drug Synergism ; Enzyme Activation ; Gefitinib ; Glioma/*drug therapy ; Humans ; Oxidative Stress ; Quinazolines/*pharmacology ; Reactive Oxygen Species/metabolism ; Valproic Acid/*pharmacology ; }, abstract = {Autophagy and apoptosis represent important cellular processes involved in cancer cell killing mechanisms. Epidermal growth factor receptor inhibitor gefitinib and valproic acid have been implicated in the treatment of malignancies including glioma involving autophagic and apoptotic mechanisms. Therefore, it is interesting to investigate whether a combination of gefitinib and valproic acid shows better cancer cell killing effect on human glioma cells. We found that a nontoxic concentration of valproic acid sensitized U87 and T98G glioma cells to gefitinib cytotoxicity by inhibiting cell growth and long-term clonogenic survival. The augmented consequences were accompanied by the formation of autophagic vacuoles, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), and degradation of p62. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 but not broad-spectrum caspase inhibitor attenuated gefitinib/valproic acid-induced growth inhibition. Gefitinib/valproic acid-induced autophagy was accompanied by the activation of liver kinase-B1 (LKB1)/AMP-activated protein kinase (AMPK)/ULK1. Silencing of AMPK and ULK1 suppressed gefitinib/valproic acid-induced autophagy and growth inhibition. Mechanistic studies showed that gefitinib/valproic acid increased intracellular reactive oxygen species generation and N-acetyl cysteine attenuated gefitinib/valproic acid-caused autophagy and growth inhibition. In addition to demonstrating the autophagic mechanisms of gefitinib/valproic acid, the results of this study further suggest that intracellular oxidative stress and the LKB1/AMPK signaling might be a potential target for the development of therapeutic strategy against glioma.}, }
@article {pmid26484027, year = {2015}, author = {Yu, M and Shin, HS and Lee, HK and Ryu, DR and Kim, SJ and Choi, KB and Kang, DH}, title = {Effect of aldosterone on epithelial-to-mesenchymal transition of human peritoneal mesothelial cells.}, journal = {Kidney research and clinical practice}, volume = {34}, number = {2}, pages = {83-92}, pmid = {26484027}, issn = {2211-9132}, abstract = {BACKGROUND: Peritoneal fibrosis is one of the major causes of technical failure in patients on peritoneal dialysis. Epithelial-to-mesenchymal transition (EMT) of the peritoneum is an early and reversible mechanism of peritoneal fibrosis. Human peritoneal mesothelial cells (HPMCs) have their own renin-angiotensin-aldosterone system (RAAS), however, it has not been investigated whether aldosterone, an end-product of the RAAS, induces EMT in HPMCs, and which mechanisms are responsible for aldosterone-induced EMT.<br><br>METHODS: EMT of HPMCs was evaluated by comparing the expression of epithelial cell marker, E-cadherin, and mesenchymal cell marker, &#x3b1;-smooth muscle actin after stimulation with aldosterone (1-100nM) or spironolactone. Activation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) and generation of reactive oxygen species (ROS) were assessed by western blotting and 2',7'-dichlorofluororescein diacetate staining, respectively. The effects of MAPK inhibitors or antioxidants (N-acetyl cysteine, apocynin, and rotenone) on aldosterone-induced EMT were evaluated.<br><br>RESULTS: Aldosterone induced EMT in cultured HPMCs, and spironolactone blocked aldosterone-induced EMT. Aldosterone induced activation of both ERK1/2 and p38 MAPK from 1 hour. Either PD98059, an inhibitor of ERK1/2, or SB20358, an inhibitor of p38 MAPK, attenuated aldosterone-induced EMT. Aldosterone induced ROS in HPMCs from 5 minutes, and antioxidant treatment ameliorated aldosterone-induced EMT. N-acetyl cysteine and apocynin alleviated activation of ERK and p38 MAPK.<br><br>CONCLUSION: Aldosterone induced EMT in HPMCs by acting through the mineralocorticoid receptor. Aldosterone-induced generation of ROS followed by activation of ERK, and p38 MAPK served as one of the mechanisms of aldosterone-induced EMT of HPMCs.}, }
@article {pmid26481639, year = {2016}, author = {Butterworth, RF}, title = {The concept of "the inflamed brain" in acute liver failure: mechanisms and new therapeutic opportunities.}, journal = {Metabolic brain disease}, volume = {31}, number = {6}, pages = {1283-1287}, pmid = {26481639}, issn = {1573-7365}, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Brain/*metabolism ; Brain Edema/genetics/metabolism/*therapy ; Genetic Therapy/*trends ; Hepatic Encephalopathy/genetics/*metabolism/*therapy ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors/*metabolism ; Liver Failure, Acute/genetics/metabolism/therapy ; }, abstract = {The presence and severity of a systemic inflammatory response is a major predictor of brain edema and encephalopathy in acute liver failure (ALF) and polymorphisms of the gene coding for the proinflammatory cytokine TNF-alpha are known to influence the clinical outcome in ALF. Recent reports provide robust evidence for a role of neuroinflammation(inflammation of the brain per se) in ALF with the cardinal features of neuroinflammation including activation of microglial cells and increased production in situ of pro-inflammatory cytokines such as TNF-alpha and interleukins IL-1beta and IL-6. Multiple liver-brain signalling pathways have been proposed to explain the phenomenon of neuroinflammation in liver failure and these include direct effects of systemically-derived cytokines, recruitment of monocytes relating to microglial activation as well as effects of liver failure-derived toxins and altered permeability of the blood-brain barrier. Synergistic mechanisms involving ammonia and cytokines have been proposed. Currently-available strategies aimed at lowering of blood ammonia such as lactulose, probiotics and rifaximin have the potential to dampen systemic inflammation as does the anti-oxidant N-acetyl cysteine, mild hypothermia and albumin dialysis. Experimental studies demonstrate that deletion of genes coding for TNF-alpha or IL-1 leads to attenuation of the CNS consequences of ALF and administration of the TNF-alpha receptor antagonist etanercept has comparable beneficial effects in experimental ALF. Together, these findings confirm a major role for central neuroinflammatory mechanisms in general and mechanisms involving TNF-alpha in particular in the pathogenesis of the cerebral consequences of ALF and open the door to novel therapeutic interventions in this often fatal disorder.}, }
@article {pmid26479898, year = {2016}, author = {Heidari, R and Taheri, V and Rahimi, HR and Shirazi Yeganeh, B and Niknahad, H and Najibi, A}, title = {Sulfasalazine-induced renal injury in rats and the protective role of thiol-reductants.}, journal = {Renal failure}, volume = {38}, number = {1}, pages = {137-141}, doi = {10.3109/0886022X.2015.1096731}, pmid = {26479898}, issn = {1525-6049}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Acute Kidney Injury/chemically induced/*prevention &amp; control ; Animals ; Antirheumatic Agents/*adverse effects ; Dithiothreitol/pharmacology/*therapeutic use ; Drug Evaluation, Preclinical ; Free Radical Scavengers/pharmacology/*therapeutic use ; Male ; Random Allocation ; Rats, Sprague-Dawley ; Sulfasalazine/*adverse effects ; }, abstract = {Sulfasalazine is widely used for inflammatory-mediated disorders in human. Renal damage is a serious adverse effect accompanied sulfasalazine administration. No specific therapeutic option is available against this complication so far. Oxidative stress seems to play a role in sulfasalazine-induced renal injury. Current investigation was designed to evaluate the effect of N-acetyl cysteine (NAC) and dithiothreitol (DTT) as thiol reductants against sulfasalazine-induced renal injury in rats. Oral administration of sulfasalazine (600 mg/kg for 14 consecutive days) caused renal injury as judged by increase in serum level of creatinine and blood urea nitrogen. Furthermore, the level of reactive oxygen species and lipid peroxidation were raised in kidney tissue after sulfasalazine administration. Additionally, it was also found that renal glutathione reservoirs were significantly depleted in sulfasalazine-treated animals. Histopathological examination of kidney endorsed organ injury in drug-treated rats. Daily intraperitoneal administration of NAC (250 and 500 mg/kg/day) and/or DTT (15 and 30 mg/kg/day) effectively alleviated renal damage induced by sulfasalazine. Data suggested that thiol reductants could serve as potential protective agents with therapeutic capabilities against sulfasalazine adverse effect toward kidney.}, }
@article {pmid26478730, year = {2015}, author = {Khaledifar, A and Momeni, A and Ebrahimi, A and Kheiri, S and Mokhtari, A}, title = {Comparison of N-acetylcysteine, ascorbic acid, and normal saline effect in prevention of contrast-induced nephropathy.}, journal = {ARYA atherosclerosis}, volume = {11}, number = {4}, pages = {228-232}, pmid = {26478730}, issn = {1735-3955}, abstract = {BACKGROUND: Considering the crucial role of appropriate preventative strategies in reducing the rate of contrast-induced nephropathy (CIN) occurrence and its related morbidity and mortality, the effect of N-acetylcysteine (NAC), ascorbic acid (AA), and normal saline (NS) was investigated in the patient's undergone coronary angiography.<br><br>METHODS: In this clinical trial, 120 patients scheduled for elective coronary angiography with serum creatinine (Cr) level > 1.5 mg/dl or glomerular filtration rate (GFR) &#x2265; 60 selected by convenience method. Selected patients were allocated in three treatment groups randomly to receive oral NAC (600 mg/twice daily) plus NS (100 ml/hour) (Group A), oral AA (250 mg/twice daily) plus NS (100 ml/hour) (Group B) and NS (100 ml/hour) (Group C), respectively. The occurrence of CIN was evaluated based on serum Cr and GFR in three studied groups, before and after angiography procedure. The analysis of variance and paired t-test were used for data analysis by SPSS.<br><br>RESULTS: The serum Cr increased and GFR decreased significantly during the intervention in three groups (P < 0.010). However, the amounts of these changes were equal between groups (P > 0.050).<br><br>CONCLUSION: The study showed that nor the addition of NAC neither the addition of AA to sodium chloride infusion has more beneficial effect than hydration with sodium chloride, in the prevention of CIN.}, }
@article {pmid26477273, year = {2015}, author = {Maharani, N and Ting, YK and Cheng, J and Hasegawa, A and Kurata, Y and Li, P and Nakayama, Y and Ninomiya, H and Ikeda, N and Morikawa, K and Yamamoto, K and Makita, N and Yamashita, T and Shirayoshi, Y and Hisatome, I}, title = {Molecular Mechanisms Underlying Urate-Induced Enhancement of Kv1.5 Channel Expression in HL-1 Atrial Myocytes.}, journal = {Circulation journal : official journal of the Japanese Circulation Society}, volume = {79}, number = {12}, pages = {2659-2668}, doi = {10.1253/circj.CJ-15-0416}, pmid = {26477273}, issn = {1347-4820}, mesh = {Animals ; Cell Line ; Gene Expression Regulation/*drug effects ; Heart Atria/metabolism/pathology ; Hyperuricemia/*metabolism/pathology ; Kv1.5 Potassium Channel/*biosynthesis/genetics ; MAP Kinase Signaling System/drug effects ; Mice ; Muscle Proteins/*metabolism ; Myocytes, Cardiac/*metabolism/pathology ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Uric Acid/*pharmacology ; }, abstract = {BACKGROUND: Hyperuricemia induces endothelial dysfunction, oxidative stress and inflammation, increasing cardiovascular morbidities. It also raises the incidence of atrial fibrillation; however, underlying mechanisms are unknown.<br><br>The effects of urate on expression of Kv1.5 in cultured mouse atrial myocytes (HL-1 cells) using reverse transcriptase-PCR, immunoblots, flow cytometry and patch-clamp experiments were studied. Treatment with urate at 7 mg/dl for 24 h increased the Kv1.5 protein level, enhanced ultra-rapid delayed-rectifier K(+)channel currents and shortened action potential duration in HL-1 cells. HL-1 cells expressed the influx uric acid transporter (UAT), URATv1, and the efflux UATs, ABCG2 and MRP4. An inhibitor against URATv1, benzbromarone, abolished the urate effects, whereas an inhibitor against ABCG2, KO143, augmented them. Flow cytometry showed that urate induced an increase in reactive oxygen species, which was abolished by the antioxidant, N-acetylcysteine (NAC), and the NADPH-oxidase inhibitor, apocynin. Both NAC and apocynin abolished the enhancing effects of urate on Kv1.5 expression. A urate-induced increase in the Kv1.5 proteins was accompanied by phosphorylation of extracellular signal-regulated kinase (ERK), and was abolished by an ERK inhibitor, PD98059. NAC abolished phosphorylation of ERK by urate.<br><br>CONCLUSIONS: Intracellular urate taken up by UATs enhanced Kv1.5 protein expression and function in HL-1 atrial myocytes, which could be attributable to ERK phosphorylation and oxidative stress derived from nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase.}, }
@article {pmid26474608, year = {2015}, author = {Jia, SS and Li, WY and Liu, X and Li, LY}, title = {[Transforming growth factor-β1 induces differentiation of bone marrow-derived mesenchymal stem cells into myofibroblasts via production of reactive oxygen species].}, journal = {Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences}, volume = {47}, number = {5}, pages = {737-742}, pmid = {26474608}, issn = {1671-167X}, mesh = {Actins/metabolism ; Animals ; *Cell Differentiation ; Collagen/metabolism ; Mesenchymal Stem Cells/*cytology ; Mice ; Myofibroblasts/*cytology ; Reactive Oxygen Species/*metabolism ; Transforming Growth Factor beta1/*pharmacology ; }, abstract = {OBJECTIVE: The aim of this study was to investigate the mechanism underlying transforming growth factor-β1 (TGF-β1) induced differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into myofibroblasts.<br><br>METHODS: Primary mouse BMSCs were isolated from bone marrow by flushing the tibias and femurs of mice, and passage 3 to passage 5 of BMSCs were used in the experiments. BMSCs differentiation into myofibroblast was induced by different doses of TGF-&#x3b2;1. In addition, reactive oxygen species (ROS) inhibitor (N-acetylcysteine, NAC) was added to test its effect on the action of TGF-&#x3b2;1. Expressions of BMSCs differentiation parameters, &#x3b1;-smooth muscle actin (&#x3b1;-SMA), collagen &#x3b1;1(I) [Col &#x3b1;1(I)] and collagen &#x3b1;1(III) [Col &#x3b1;1(III)] were measured by real-time quantitative PCR (RT-qPCR) and Western blot analysis. BMSCs were preloaded for 15 min with 2', 7'-dichlorohydrofluorescein diacetate (DCFH-DA), then stimulated with TGF-&#x3b2;1 for different times, and fluorescence of ROS was measured using high content analysis.<br><br>RESULTS: TGF-&#x3b2;1 stimulated differentiation of BMSCs into myofibroblasts and up-regulated expression of &#x3b1;-SMA, Col &#x3b1;1(I) and Col &#x3b1;1(III) in a dose-dependent manner, which blocked by ROS inhibitor NAC. In addition, TGF-&#x3b2;1 could induce a significant rapid and transient increase in ROS production in BMSCs, and the effect of TGF-&#x3b2;1 on ROS production was peaked at 30 min.<br><br>CONCLUSION: TGF-&#x3b2;1 induced differentiation of BMSCs into myofibroblasts via production of ROS.}, }
@article {pmid26474283, year = {2015}, author = {Morelli, MB and Amantini, C and Santoni, M and Soriani, A and Nabissi, M and Cardinali, C and Santoni, A and Santoni, G}, title = {Axitinib induces DNA damage response leading to senescence, mitotic catastrophe, and increased NK cell recognition in human renal carcinoma cells.}, journal = {Oncotarget}, volume = {6}, number = {34}, pages = {36245-36259}, pmid = {26474283}, issn = {1949-2553}, mesh = {Apoptosis/drug effects/genetics ; Axitinib ; Carcinoma, Renal Cell/*drug therapy/genetics/immunology ; Cell Line, Tumor ; Cellular Senescence/drug effects ; *DNA Damage ; Humans ; Imidazoles/*pharmacology ; Indazoles/*pharmacology ; Kidney Neoplasms/*drug therapy/genetics/immunology ; Killer Cells, Natural/drug effects/immunology ; Mitosis/drug effects/genetics ; Protein Kinase Inhibitors/administration &amp; dosage/*therapeutic use ; }, abstract = {Tyrosine kinase inhibitors (TKIs) including axitinib have been introduced in the treatment of renal cell carcinoma (RCC) because of their anti-angiogenic properties. However, no evidence are presently available on a direct cytotoxic anti-tumor activity of axitinib in RCC.Herein we reported by western blot analysis that axitinib treatment induces a DNA damage response (DDR) initially characterized by γ-H2AX phosphorylation and Chk1 kinase activation and at later time points by p21 overexpression in A-498 and Caki-2 RCC cells although with a different potency. Analysis by immunocytochemistry for the presence of 8-oxo-7,8-dihydro-2'-deoxyguanosine in cellular DNA and flow cytometry using the redox-sensitive fluorescent dye DCFDA, demonstrated that DDR response is accompanied by the presence of oxidative DNA damage and reactive oxygen species (ROS) generation. This response leads to G2/M cell cycle arrest and induces a senescent-like phenotype accompanied by enlargement of cells and increased senescence-associated β-galactosidase activity, which are abrogated by N-acetyl cysteine (NAC) pre-treatment. In addition, axitinib-treated cells undergo to cell death through mitotic catastrophe characterized by micronucleation and abnormal microtubule assembly as assessed by fluorescence microscopy.On the other hand, axitinib, through the DDR induction, is also able to increase the surface NKG2D ligand expression. Accordingly, drug treatment promotes NK cell recognition and degranulation in A-498 RCC cells in a ROS-dependent manner.Collectively, our results indicate that both cytotoxic and immunomodulatory effects on RCC cells can contribute to axitinib anti-tumor activity.}, }
@article {pmid26474275, year = {2015}, author = {Capasso, A and Cerchia, C and Di Giovanni, C and Granato, G and Albano, F and Romano, S and De Vendittis, E and Ruocco, MR and Lavecchia, A}, title = {Ligand-based chemoinformatic discovery of a novel small molecule inhibitor targeting CDC25 dual specificity phosphatases and displaying in vitro efficacy against melanoma cells.}, journal = {Oncotarget}, volume = {6}, number = {37}, pages = {40202-40222}, pmid = {26474275}, issn = {1949-2553}, mesh = {Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Discovery/*methods ; Dual-Specificity Phosphatases/*antagonists &amp; inhibitors/metabolism ; Enzyme Inhibitors/*pharmacology ; Humans ; Kinetics ; Ligands ; Melanoma/metabolism/pathology ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/*pharmacology ; Tumor Suppressor Protein p53/metabolism ; cdc25 Phosphatases/*antagonists &amp; inhibitors/metabolism ; }, abstract = {CDC25 phosphatases are important regulators of the cell cycle and represent promising targets for anticancer drug discovery. We recently identified NSC 119915 as a new quinonoid CDC25 inhibitor with potent anticancer activity. In order to discover more active analogs of NSC 119915, we performed a range of ligand-based chemoinformatic methods against the full ZINC drug-like subset and the NCI lead-like set. Nine compounds (3, 5-9, 21, 24, and 25) were identified with Ki values for CDC25A, -B and -C ranging from 0.01 to 4.4 μM. One of these analogs, 7, showed a high antiproliferative effect on human melanoma cell lines, A2058 and SAN. Compound 7 arrested melanoma cells in G2/M, causing a reduction of the protein levels of CDC25A and, more consistently, of CDC25C. Furthermore, an intrinsic apoptotic pathway was induced, which was mediated by ROS, because it was reverted in the presence of antioxidant N-acetyl-cysteine (NAC). Finally, 7 decreased the protein levels of phosphorylated Akt and increased those of p53, thus contributing to the regulation of chemosensitivity through the control of downstream Akt pathways in melanoma cells. Taken together, our data emphasize that CDC25 could be considered as a possible oncotarget in melanoma cells and that compound 7 is a small molecule CDC25 inhibitor that merits to be further evaluated as a chemotherapeutic agent for melanoma, likely in combination with other therapeutic compounds.}, }
@article {pmid26472863, year = {2015}, author = {Wang, Q and Mazur, A and Guerrero, F and Lambrechts, K and Buzzacott, P and Belhomme, M and Theron, M}, title = {Antioxidants, endothelial dysfunction, and DCS: in vitro and in vivo study.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {119}, number = {12}, pages = {1355-1362}, doi = {10.1152/japplphysiol.00167.2015}, pmid = {26472863}, issn = {1522-1601}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/metabolism ; Animals ; Antioxidants/*metabolism ; Ascorbic Acid/pharmacology ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Decompression Sickness/*physiopathology ; Diving/injuries ; Endothelium, Vascular/*physiopathology ; Glutathione/metabolism ; Male ; Nitric Oxide/metabolism ; Oxidative Stress ; Peptidyl-Dipeptidase A/metabolism ; Peroxynitrous Acid/metabolism ; Rats ; Rats, Sprague-Dawley ; Superoxides/metabolism ; Thiobarbituric Acid Reactive Substances ; }, abstract = {Reactive oxygen species (ROS) production is a well-known effect in individuals after an undersea dive. This study aimed to delineate the links between ROS, endothelial dysfunction, and decompression sickness (DCS) through the use of antioxidants in vitro and in vivo. The effect of N-acetylcysteine (NAC) on superoxide and peroxynitrite, nitric oxide (NO) generation, and cell viability during in vitro diving simulation were analyzed. Also analyzed was the effect of vitamin C and NAC on plasma glutathione thiol and thiobarbituric acid reactive substances (TBARS), plasma angiotensin-converting enzyme (ACE) activity, and angiotensin-II and DCS morbidity during in vivo diving simulation. During an in vitro diving simulation, vascular endothelial cells showed overproduction of superoxide and peroxynitrite, obvious attenuation of NO generation, and promotion of cell death, all of which were reversed by NAC treatment. After in vivo diving simulation, plasma ACE activity and angiotensin-II level were not affected. The plasma level of glutathione thiol was downregulated after the dive, which was attenuated partially by NAC treatment. Plasma TBARS level was upregulated; however, either NAC or vitamin C treatment failed to prevent DCS morbidity. During in vitro simulation, endothelial superoxide and peroxynitrite-mediated oxidative stress were involved in the attenuation of NO availability and cell death. This study is the first attempt to link oxidative stress and DCS occurrence, and the link could not be confirmed in vivo. Even in the presence of antioxidants, ROS and bubbles generated during diving and/or decompression might lead to embolic or biochemical stress and DCS. Diving-induced oxidative stress might not be the only trigger of DCS morbidity.}, }
@article {pmid26472194, year = {2015}, author = {Pallichankandy, S and Rahman, A and Thayyullathil, F and Galadari, S}, title = {ROS-dependent activation of autophagy is a critical mechanism for the induction of anti-glioma effect of sanguinarine.}, journal = {Free radical biology &amp; medicine}, volume = {89}, number = {}, pages = {708-720}, doi = {10.1016/j.freeradbiomed.2015.10.404}, pmid = {26472194}, issn = {1873-4596}, mesh = {Antineoplastic Agents/*pharmacology ; Autophagy/*drug effects ; Benzophenanthridines/*pharmacology ; Blotting, Western ; Brain Neoplasms/*pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Glioma/*pathology ; Humans ; Isoquinolines/*pharmacology ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Transfection ; }, abstract = {Malignant gliomas are notoriously resistant to therapies that induce apoptosis, but are less resistant to therapies that induce autophagy. Therefore, drugs targeting autophagy are promising candidates in the treatment of malignant gliomas. In this study, we investigated the anti-glioma potential of sanguinarine (SNG) in vitro, and further examined the molecular mechanisms of SNG-induced cell death. In human malignant glioma cells SNG activated autophagic cell death pathway characterized by increased acidic vesicular organelles formation, GFP-LC3 punctate formation, LC3-II conversion, and expression of autophagy related proteins, such as Atg5 and Beclin-1. The autophagy inhibitor bafilomycin A1 or knockdown of Atg5 markedly inhibited the SNG-induced autophagic cell death. Apart from inducing autophagic cell death, SNG has also been shown to induce apoptotic cell death in these cell lines. Importantly, the study also identified the crucial role of reactive oxygen species (ROS)-dependent activation of the extracellular signal-regulated kinase1/2 (ERK1/2) in the facilitation of SNG-induced autophagic cell death. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, ERK1/2 activation, and in turn, prevented SNG-induced autophagic cell death. Moreover, scavengers of H2O2 (sodium pyruvate and catalase) significantly attenuated the activity of SNG. Down-regulation of ERK1/2 activity, by using selective ERK1/2 inhibitor (U0126) or siERK1/2, led to an inhibition of SNG-induced autophagic cell death. Furthermore, tumor cells transfected with constitutively active ERK2-MEK1-LA fusion protein accentuated SNG-induced autophagic cell death. Overall, our findings unveil a novel anti-tumor mechanism of action of SNG in human malignant glioma cells, opening up the possibility of using SNG based pro-autophagic drugs for the treatment of malignant glioma.}, }
@article {pmid26472193, year = {2015}, author = {Murray, TV and Dong, X and Sawyer, GJ and Caldwell, A and Halket, J and Sherwood, R and Quaglia, A and Dew, T and Anilkumar, N and Burr, S and Mistry, RK and Martin, D and Schröder, K and Brandes, RP and Hughes, RD and Shah, AM and Brewer, AC}, title = {NADPH oxidase 4 regulates homocysteine metabolism and protects against acetaminophen-induced liver damage in mice.}, journal = {Free radical biology &amp; medicine}, volume = {89}, number = {}, pages = {918-930}, pmid = {26472193}, issn = {1873-4596}, support = {RG/13/11/30384/BHF_/British Heart Foundation/United Kingdom ; PG/11/124/29318/BHF_/British Heart Foundation/United Kingdom ; RE/13/2/30182/BHF_/British Heart Foundation/United Kingdom ; RG/08/110/25922/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Acetaminophen/*toxicity ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Betaine/metabolism ; Blotting, Western ; Cells, Cultured ; Cysteine/metabolism ; Female ; Glutathione/metabolism ; Hep G2 Cells ; Homocysteine/*metabolism ; Humans ; Immunoenzyme Techniques ; Liver/drug effects/*metabolism/pathology ; Liver Diseases/etiology/*prevention &amp; control ; Methionine/metabolism ; Mice ; Mice, Knockout ; NADPH Oxidase 4 ; NADPH Oxidases/*physiology ; Reactive Oxygen Species/metabolism ; S-Adenosylmethionine/metabolism ; }, abstract = {Glutathione is the major intracellular redox buffer in the liver and is critical for hepatic detoxification of xenobiotics and other environmental toxins. Hepatic glutathione is also a major systemic store for other organs and thus impacts on pathologies such as Alzheimer's disease, Sickle Cell Anaemia and chronic diseases associated with aging. Glutathione levels are determined in part by the availability of cysteine, generated from homocysteine through the transsulfuration pathway. The partitioning of homocysteine between remethylation and transsulfuration pathways is known to be subject to redox-dependent regulation, but the underlying mechanisms are not known. An association between plasma Hcy and a single nucleotide polymorphism within the NADPH oxidase 4 locus led us to investigate the involvement of this reactive oxygen species- generating enzyme in homocysteine metabolism. Here we demonstrate that NADPH oxidase 4 ablation in mice results in increased flux of homocysteine through the betaine-dependent remethylation pathway to methionine, catalysed by betaine-homocysteine-methyltransferase within the liver. As a consequence NADPH oxidase 4-null mice display significantly lowered plasma homocysteine and the flux of homocysteine through the transsulfuration pathway is reduced, resulting in lower hepatic cysteine and glutathione levels. Mice deficient in NADPH oxidase 4 had markedly increased susceptibility to acetaminophen-induced hepatic injury which could be corrected by administration of N-acetyl cysteine. We thus conclude that under physiological conditions, NADPH oxidase 4-derived reactive oxygen species is a regulator of the partitioning of the metabolic flux of homocysteine, which impacts upon hepatic cysteine and glutathione levels and thereby upon defence against environmental toxins.}, }
@article {pmid26472041, year = {2015}, author = {Yuan, S and Lu, Y and Yang, J and Chen, G and Kim, S and Feng, L and Ogasawara, M and Hammoudi, N and Lu, W and Zhang, H and Liu, J and Colman, H and Lee, JS and Li, XN and Xu, RH and Huang, P and Wang, F}, title = {Metabolic activation of mitochondria in glioma stem cells promotes cancer development through a reactive oxygen species-mediated mechanism.}, journal = {Stem cell research &amp; therapy}, volume = {6}, number = {}, pages = {198}, pmid = {26472041}, issn = {1757-6512}, support = {R01 CA100428/CA/NCI NIH HHS/United States ; R01 CA172724/CA/NCI NIH HHS/United States ; CA100428/CA/NCI NIH HHS/United States ; }, mesh = {Activation, Metabolic ; Animals ; Antioxidants/pharmacology ; Brain Neoplasms/metabolism/pathology ; Cell Differentiation ; Cell Line, Tumor ; Culture Media ; Electron Transport ; Glioblastoma/metabolism ; Glioma/*metabolism/pathology ; Humans ; Mice ; Mice, Nude ; Mice, SCID ; Mitochondria/drug effects/*metabolism ; NF-kappa B/metabolism ; Neoplastic Stem Cells/drug effects/*metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {INTRODUCTION: Cancer stem cells (CSCs) possess characteristics associated with normal stem cells, specifically the abilities to renew themselves and to give rise to all cell types (differentiation). It is assumed that induction of differentiation in CSCs would reduce their ability to form tumors. What triggers CSC differentiation and the role of "differentiation" in tumorigenesis remain elusive.<br><br>METHODS: Glioma stem cell (GSC) lines and subcutaneous as well as orthotopic xenografts established from fresh surgical specimens of glioblastoma multiforme were used.<br><br>RESULTS: Exposure of GSCs to serum activates mitochondrial respiration and causes an increase in mitochondrial reactive oxygen species (ROS) as well as oxidative stress responses, leading to the appearance of differentiation morphology and a deceased expression of CSC markers. Chemical perturbation of the mitochondrial electron transport chain causes ROS increase and further downregulation of stem cell markers, while antioxidant N-acetyl-cysteine reduces ROS and suppresses the differentiation of GSCs. Surprisingly, the serum-induced differentiated GSCs exhibit greater ability to form tumor in both orthotopic and subcutaneous xenograft models, which can be suppressed by N-acetyl-cysteine. Mitochondrial ROS from the serum-stimulated cells triggered the activation of nuclear factor-kappa-B (NF&#x3ba;B) pathway, which is a potential mechanism for the promotion of tumorigenesis.<br><br>CONCLUSION: This study suggests that ROS generated from active mitochondrial respiration in the presence of serum is critical in CSCs activation, which promotes tumor development in vivo.}, }
@article {pmid26469940, year = {2016}, author = {Campbell, A and Bushman, J and Munger, J and Noble, M and Pröschel, C and Mayer-Pröschel, M}, title = {Mutation of ataxia-telangiectasia mutated is associated with dysfunctional glutathione homeostasis in cerebellar astroglia.}, journal = {Glia}, volume = {64}, number = {2}, pages = {227-239}, pmid = {26469940}, issn = {1098-1136}, support = {R01 AI081773/AI/NIAID NIH HHS/United States ; R03 NS061339/NS/NINDS NIH HHS/United States ; R21 HD055550/HD/NICHD NIH HHS/United States ; R56 AI081773/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Adolescent ; Amino Acid Transport System y+/metabolism ; Animals ; Astrocytes/*metabolism ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Cell Survival/physiology ; Cerebellum/*metabolism ; Coculture Techniques ; Cystine/metabolism ; Extracellular Space/metabolism ; Glutathione/*metabolism ; Glutathione Reductase/metabolism ; Homeostasis/*physiology ; Humans ; Intracellular Space/metabolism ; Mice, 129 Strain ; Mice, Transgenic ; Mutation ; Neurons/physiology ; }, abstract = {Astroglial dysfunction plays an important role in neurodegenerative diseases otherwise attributed to neuronal loss of function. Here we focus on the role of astroglia in ataxia-telangiectasia (A-T), a disease caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. A hallmark of A-T pathology is progressive loss of cerebellar neurons, but the mechanisms that impact neuronal survival are unclear. We now provide a possible mechanism by which A-T astroglia affect the survival of cerebellar neurons. As astroglial functions are difficult to study in an in vivo setting, particularly in the cerebellum where these cells are intertwined with the far more numerous neurons, we conducted in vitro coculture experiments that allow for the generation and pharmacological manipulation of purified cell populations. Our analyses revealed that cerebellar astroglia isolated from Atm mutant mice show decreased expression of the cystine/glutamate exchanger subunit xCT, glutathione (GSH) reductase, and glutathione-S-transferase. We also found decreased levels of intercellular and secreted GSH in A-T astroglia. Metabolic labeling of l-cystine, the major precursor for GSH, revealed that a key component of the defect in A-T astroglia is an impaired ability to import this rate-limiting precursor for the production of GSH. This impairment resulted in suboptimal extracellular GSH supply, which in turn impaired survival of cerebellar neurons. We show that by circumventing the xCT-dependent import of L-cystine through addition of N-acetyl-L-cysteine (NAC) as an alternative cysteine source, we were able to restore GSH levels in A-T mutant astroglia providing a possible future avenue for targeted therapeutic intervention.}, }
@article {pmid26467067, year = {2015}, author = {Homma, T and Fujii, J}, title = {Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs.}, journal = {Current drug metabolism}, volume = {16}, number = {7}, pages = {560-571}, doi = {10.2174/1389200216666151015114515}, pmid = {26467067}, issn = {1875-5453}, mesh = {Aging/*drug effects/metabolism ; Animals ; Antioxidants/chemistry/*pharmacology ; Cell Death/drug effects/physiology ; Glutathione/chemistry/*pharmacology ; Humans ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects/physiology ; }, abstract = {Glutathione (GSH), an abundant tripeptidyl molecule, plays pivotal roles in protecting cells against oxidative stress-induced cellular damage and in detoxifying xenobiotics and drug metabolism. GSH is now entering a new era of therapeutic applications. Decreased GSH levels are associated with the common features of aging as well as of a wide range of pathological conditions, including neurodegenerative disorders. Notably, GSH depletion and/or alterations in its metabolism appear to be crucial in the onset of Parkinson's disease. Despite the fact that GSH is required for cell survival, the molecular mechanism that links GSH depletion to cell death remains poorly understood. Recently, considerable attention has been focused on a newly defined type of cell death: irondependent cell death, also referred to as "ferroptosis". The iron chelator deferoxamine nearly abolishes ferroptosis induced by inhibiting GSH synthesis or cystine uptake by the xCT transporter. Deferoxamine preferentially abrogates the intralysosomal accumulation of iron and inhibits oxidative stress-induced lysosomal membrane permeabilization and cell death. The use of GSH and a prodrug derived from it can be useful, since the dysfunction of the GSH redox system appears to cause a variety of diseases including neurodegenerative disorders. However, the effectiveness of GSH as a therapeutic agent is limited because of its low bioavailability. We also review trials that have been designed to cope with this difficulty; e.g. the use of precursors such as N-acetyl cysteine and chemical modification such as methylation.}, }
@article {pmid26466556, year = {2016}, author = {Tsai, WY and Tsai, RY and Liu, CC and Wu, JL and Wong, CS}, title = {Sulfasalazine attenuates ACL transection and medial menisectomy-induced cartilage destruction by inhibition of cystine/glutamate antiporter.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {34}, number = {4}, pages = {650-657}, doi = {10.1002/jor.23069}, pmid = {26466556}, issn = {1554-527X}, mesh = {Animals ; Anterior Cruciate Ligament Injuries ; Antiporters/*antagonists &amp; inhibitors/metabolism ; Antirheumatic Agents/pharmacology/*therapeutic use ; Cells, Cultured ; Chondrocytes/drug effects ; Drug Evaluation, Preclinical ; Knee Injuries/*complications/metabolism ; Male ; Osteoarthritis, Knee/etiology/*prevention &amp; control ; Rats, Wistar ; Sulfasalazine/pharmacology/*therapeutic use ; Tibial Meniscus Injuries ; }, abstract = {We had previously demonstrated that excitatory amino acid glutamate plays a role in the progression and severity of knee osteoarthritis (OA), and early hyaluronic acid injection attenuates the OA progression by attenuation of knee joint glutamate level, which was also related to the cystine/glutamate antiporter system X (system XC-) expression. System XC- uptakes cystine into chondrocytes for glutathione (GSH) synthesis, but the role of system XC- in OA is rarely addressed. Sulfasalazine (SSZ) is a system XC- inhibitor; SSZ was applied intra-articularly to study the function of system XC- in the development of OA in rats subjected to anterior cruciate ligament transection and medial meniscectomy (ACLT + MMx). Moerover, the system XC- activator N-acetylcysteine (NAC) was also applied to verify the role of system XC-. The intra-articular injection of SSZ significantly attenuated knee swelling and cartilage destruction in the knees of ACLT + MMx rats and this effect was blocked by NAC. The results showed that inhibition of system XC- function can attenuate ACLT + MMx-induced cartilage destruction. In the present study, system XC- inhibitor SSZ was shown to reduce glutamate content in synovial fluid and GSH in chondrocytes. It was also showed SSZ could attenuate ACLT + MMx-induced cartilage destruction, and treatment of NAC reversed the protective effect of SSZ.}, }
@article {pmid26466512, year = {2016}, author = {Unal, F and Yuksel, MA and Boran, B and Yuksel, IT and Abali, R}, title = {The role of N-Acetylcysteine in preventing cyclophosphamide-induced gonadotoxicity: An experimental study in rats.}, journal = {Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology}, volume = {36}, number = {3}, pages = {372-375}, doi = {10.3109/01443615.2015.1065236}, pmid = {26466512}, issn = {1364-6893}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Mullerian Hormone/blood ; Antineoplastic Agents, Alkylating/*adverse effects ; Cyclophosphamide/*adverse effects ; Drug Evaluation, Preclinical ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Glutathione/metabolism ; Infertility, Female/chemically induced/*prevention &amp; control ; Ovarian Reserve/drug effects ; Rats, Sprague-Dawley ; }, abstract = {This study assessed whether NAC could prevent cyclophosphamide (CY)-induced damage, by measuring the anti-Müllerian hormone (AMH) levels. Forty-eight Sprague-Dawley female rats were divided into four groups: CY + NAC, CY, NAC and control, each including 12 rats. There was no significant difference among the 24-h AMH values of the groups (p = 0.452), whereas a significant difference was found in terms of 72-h values (p = 0.003). Paired comparisons revealed no significant difference between CY and CY + NAC (p>0.699) and NAC (p = 0.065) groups regarding 72-h AMH values. However, AMH concentrations of the CY group at 72 hours were significantly lower than those of the control group (p = 0.015). AMH concentrations of the CY + NAC group at 72 hours were also significantly lower than those of the NAC group (p = 0.002) and the control group (p = 0.002). The AMH levels of CY and CY + NAC groups at 72 hours were significantly lower than those at 24 hours. The 24-h and 72-h AMH levels in the NAC and control groups were similar. In the present study, a single dose of NAC failed to prevent the cytotoxic effects of CY.}, }
@article {pmid26466148, year = {2017}, author = {Finkelstein, Y and Goel, G and Hutson, JR and Armstrong, J and Baum, CR and Wax, P and Brent, J and , }, title = {Drug Misuse in Adolescents Presenting to the Emergency Department.}, journal = {Pediatric emergency care}, volume = {33}, number = {7}, pages = {451-456}, doi = {10.1097/PEC.0000000000000571}, pmid = {26466148}, issn = {1535-1815}, mesh = {Adolescent ; Cohort Studies ; Drug Misuse/*trends ; Emergency Service, Hospital/*trends ; Female ; Humans ; Male ; Registries ; United States/epidemiology ; }, abstract = {OBJECTIVES: Drug misuse is a disturbing, common practice among youth. One in 4 American adolescents reports consuming prescription medications without a clinical indication. We sought to explore current trends of drug misuse in adolescents.<br><br>METHODS: Using the 37 participating sites of the ToxIC (Toxicology Investigators Consortium) Case Registry, a cross-country surveillance tool, we conducted an observational cohort study of all adolescents (aged 13-18 years) who presented to emergency departments with drug misuse and required a bedside medical toxicology consultation between January 2010 and June 2013.<br><br>RESULTS: Of 3043 poisonings, 202 (7%) involved drug misuse (139 [69%] were males). Illicit drugs (primarily synthetic cannabinoids and "bath salts") were encountered in 101 (50%), followed by prescription medications (56 [28%]) and over-the-counter (OTC) drugs (51 [25%]). Dextromethorphan was the most commonly misused legal medication (24 [12%]). Polypharmacy exposure was documented in 74 (37%). One hundred sixty-three adolescents (81%) were symptomatic; of these, 81% had central nervous system impairments: psychosis (38%), agitation (30%), coma (26%), myoclonus (11%), and seizures (10%); and 66 (41%) displayed a specific toxidrome, most commonly sedative-hypnotic. Benzodiazepines were the most frequently administered medications (46%). Antidotes were administered to 28% of adolescents, primarily naloxone, physostigmine, N-acetyl-cysteine, and flumazenil. No deaths were recorded.<br><br>CONCLUSIONS: Adolescents presenting with drug misuse may be exposed to a wide range and combinations of therapeutics or illicit substances and frequently display central nervous system abnormalities, compromising the ability to obtain a reliable history. Frontline clinicians should maintain a high index of suspicion, as routine toxicology screenings fail to detect most contemporary misused legal and designer drugs.}, }
@article {pmid26462568, year = {2016}, author = {İçer, M and Zengin, Y and Gunduz, E and Dursun, R and Durgun, HM and Turkcu, G and Yuksel, H and Üstündağ, M and Guloglu, C}, title = {Is montelukast as effective as N-acetylcysteine in hepatic injury due to acetaminophen intoxication in rats?.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {68}, number = {1}, pages = {55-59}, doi = {10.1016/j.etp.2015.09.008}, pmid = {26462568}, issn = {1618-1433}, mesh = {Acetaminophen/*toxicity ; Acetates/*pharmacology ; Acetylcysteine/pharmacology ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Cyclopropanes ; Cytochrome P-450 CYP1A2 Inducers/*pharmacology ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Male ; Quinolines/*pharmacology ; Rats ; Rats, Wistar ; Sulfides ; }, abstract = {This study aims to investigate the acute protective effect of montelukast sodium in hepatic injury secondary to acetaminophen (APAP) intoxication. This study used 60 rats. The rats were grouped into 6 groups. The control group was administered oral distilled water 10 ml/kg, the APAP group oral APAP 1 g/kg, the montelukast sodium (MK) group oral MK 30 mg/kg, the acetaminophen+N-acetylcysteine (APAP+NAC) group oral APAP 1 g/kg, followed by a single dose of intraperitoneal NAC 1.5 g/kg three hours later, the acetaminophen+montelukast sodium (APAP+MK) group oral APAP 1 g/kg, followed by oral MK 30 mg/kg 3 h later, the acetaminophen+N-acetylcysteine+montelukast sodium (APAP+NAC+MK) group oral APAP 1 g/kg, followed by a single intraperitoneal NAC 1.5 g/kg plus oral MK 30 mg/kg 3 h later. Blood and liver tissue samples were taken 24h after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin were studied from the blood samples. Liver tissue samples were used for histopathological examination. Compared with the control group, serum AST and ALT activities were higher in the APAP and APAP+NAC groups. APAP+NAC, APAP+MK, and APAP+NAC+MK groups had reduced serum ALT and AST activities than the group administered APAP alone. APAP+MK and APAP+NAC+MK groups had a lower serum ALP activity than the control group. Histopathologically, there was a difference between the group administered APAP alone and the APAP+MK and APAP+NAC+MK groups. MK is as protective as NAC in liver tissue in APAP intoxication in rats.}, }
@article {pmid26461335, year = {2014}, author = {Finamor, I and Pavanato, MA and Pês, T and Ourique, G and Saccol, E and Schiefelbein, S and Llesuy, S and Partata, W}, title = {N-acetylcysteine protects the rat kidney against aspartame-induced oxidative stress.}, journal = {Free radical biology &amp; medicine}, volume = {75 Suppl 1}, number = {}, pages = {S30}, doi = {10.1016/j.freeradbiomed.2014.10.759}, pmid = {26461335}, issn = {1873-4596}, abstract = {Long-term intake of aspartame at the acceptable daily ingestion dose causes oxidative stress in the rat kidney through the dysregulation of glutathione homeostasis. N-acetylcysteine (NAC) provides the cystein required for the production of GSH, being effective in treating disorders associated with oxidative stress. The aim of this research was to investigate the effects of NAC on the aspartame-induced oxidative stress in the rat kidney. The animals received aspartame by gavage for six weeks (40mg/kg). From the 5th week, NAC (1mmol/kg, via intraperitoneal) was injected for two weeks. Then, they were anaesthetized for blood sample and euthanized for the kidney collection. The blood was centrifuged at 1800g for 15min and the serum was separated for creatinine measurement. The tissue was homogenized in 1.15% KCl buffer and centrifuged at 700g for 10min at 4°C. The supernatant fraction obtained was used to the measurements of oxidative stress biomarkers. The creatinine levels were enhanced in the serum of aspartame-treated rats. NAC caused a reduction in the thiobarbituric acid reactive substances, lipid hydroperoxides, carbonyl protein and hydrogen peroxide levels, which were increased in the kidney of aspartame-treated animals. Additionally, NAC caused an elevation in the glutathione peroxidase and glutathione reductase activities, total glutathione, ascorbic acid, and total reactive antioxidant potential levels, which were decreased in the kidney of aspartame-treated rats. In conclusion, NAC may be useful for the protection of the rat kidney against aspartame-induced oxidative stress.}, }
@article {pmid26461300, year = {2014}, author = {Tormos Ana, M and Taléns-Visconti, R and Jorques, M and Pérez-Garrido, S and Bonora-Centelles, A and Nebreda Ángel, R and Sastre, J}, title = {p38α deficiency and oxidative stress cause cytokinesis failure in hepatocytes.}, journal = {Free radical biology &amp; medicine}, volume = {75 Suppl 1}, number = {}, pages = {S19}, doi = {10.1016/j.freeradbiomed.2014.10.633}, pmid = {26461300}, issn = {1873-4596}, abstract = {Cytokinesis is the last step in mitosis and it implies re-organization of the actin cytoskeleton. Its failure is one of the major mechanisms of polyploidy and binucleation in mammals. Our aims were 1) to assess the role of redox-sensitive p38α MAPK in cytokinesis by studying the liver of wild type mice or liver-specific p38α knock-out mice; 2) to assess the role of oxidative stress associated with hepatocyte isolation on cytokinesis. When p38α was down-regulated in hepatocytes, MK2 phosphorylation on threonine 334 was completely abrogated. Activation of MNK-1, required for abscission of the intercellular bridge, was diminished. Key proteins of the RhoA pathway (phospho-PRK2, nuclear phosphorylated cofilin, and cytosolic p27) were assessed confirming the impairment of this pathway. The absence of p38α in aging liver also led to a decrease in HSP27 phosphorylation, which is required for actin polymerization. Indeed, a severe impairment in the F-actin filamentous structure was found in the liver of old mice upon p38α deficiency. Consequently, long-term p38α MAPK down-regulation markedly affects the RhoA pathway and actin cytoskeleton dynamics inducing actin disassembly and cytokinesis failure upon aging. On the other hand, hepatocyte isolation caused marked glutathione depletion, increased generation of reactive oxygen species, and activated cell cycle entry. Addition of N-acetyl cysteine to isolation media prevented glutathione depletion, restrained the cell cycle entry, and abrogated defective cytokinesis and the formation of binucleated hepatocytes during isolation. Our results show that hepatocytes do enter into S phase but they do not complete cell division with age upon p38α deficiency or upon oxidative stress associated with isolation leading in both cases to cytokinesis failure and binucleation.}, }
@article {pmid26458509, year = {2015}, author = {Qiu, M and Chen, L and Tan, G and Ke, L and Zhang, S and Chen, H and Liu, J}, title = {A reactive oxygen species activation mechanism contributes to JS-K-induced apoptosis in human bladder cancer cells.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {15104}, pmid = {26458509}, issn = {2045-2322}, mesh = {Adenosine Triphosphate/metabolism ; Apoptosis/*drug effects ; Azo Compounds/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Doxorubicin/pharmacology ; Drug Resistance, Neoplasm ; Glutathione/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Models, Biological ; Nitric Oxide/metabolism ; Oxidation-Reduction/drug effects ; Piperazines/*pharmacology ; Reactive Oxygen Species/*metabolism ; Urinary Bladder Neoplasms/metabolism ; }, abstract = {Reactive oxygen species (ROS) and cellular oxidant stress are regulators of cancer cells. The alteration of redox status, which is induced by increased generation of ROS, results in increased vulnerability to oxidative stress. The aim of this study is to investigate the influence of O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, C13H16N6O8) on proliferation and apoptosis in bladder cancer cells and explored possible ROS-related mechanisms. Our results indicated that JS-K could suppress bladder cancer cell proliferation in a concentration- and time-dependent manner and induce apoptosis and ROS accumulation in a concentration-dependent manner. With increasing concentrations of JS-K, expression of proteins that are involved in cell apoptosis increased in a concentration-dependent manner. Additionally, the antioxidant N-acetylcysteine (NAC) reversed JS-K-induced cell apoptosis; conversely, the prooxidant oxidized glutathione (GSSG) exacerbated JS-K-induced cell apoptosis. Furthermore, we found that nitrites, which were generated from the oxidation of JS-K-released NO, induced apoptosis in bladder cancer cells to a lower extent through the ROS-related pathway. In addition, JS-K was shown to enhance the chemo-sensitivity of doxorubicin in bladder cancer cells. Taken together, the data suggest that JS-K-released NO induces bladder cancer cell apoptosis by increasing ROS levels, and nitrites resulting from oxidation of NO have a continuous apoptosis-inducing effect.}, }
@article {pmid26458505, year = {2015}, author = {Kang, X and Hu, DY and Li, CB and Ai, ZS and Peng, A}, title = {N-acetylcysteine for the prevention of contrast-induced nephropathy in patients with pre-existing renal insufficiency or diabetes: a systematic review and meta-analysis.}, journal = {Renal failure}, volume = {37}, number = {10}, pages = {297-303}, doi = {10.3109/0886022X.2015.1012985}, pmid = {26458505}, issn = {1525-6049}, mesh = {Acetylcysteine/*therapeutic use ; Contrast Media/*adverse effects ; Diabetic Nephropathies/complications ; Humans ; Kidney Diseases/*chemically induced/prevention &amp; control ; Randomized Controlled Trials as Topic ; Renal Insufficiency/complications ; }, abstract = {PURPOSE: To identify benefit of N-acetylcysteine (NAC) on patients with pre-existing renal insufficiency or diabetes.<br><br>BACKGROUND: NAC administration is a common method for prevention of contrast-induced nephropathy (CIN). Nevertheless, its benefit on patients with pre-existing renal insufficiency or diabetes remains uncertain and controversial.<br><br>METHODS: Randomized controlled trials (RCTs) to evaluate the efficacy of NAC for the prevention of CIN in patients with pre-existing renal insufficiency or diabetes were searched from the databases of MEDLINE, EMBASE, and Cochrane library. Pooled odds ratio (OR) with 95% confidence interval (95% CI) were calculated using fixed-effects model by the Mantel-Haenszel test.<br><br>RESULTS: Twenty RCTs involving 3466 subjects (1756 assigned to NAC and 1710 assigned to the control) were included in the pre-existing renal dysfunction group. Pooled analysis suggested a significant reduction in CIN among this group (OR, 0.76; 95% CI, 0.61-0.93; p&#x2009;=&#x2009;0.008). However, the nine trials comparing NAC versus control among patients with diabetes (NAC, 367 subjects; control, 358 subjects) showed no benefit of NAC for prevention of CIN (OR&#x2009;=&#x2009;0.87; 95% CI, 0.58-1.30; p&#x2009;=&#x2009;0.50). No significant heterogeneity was detected (p&#x2009;=&#x2009;0.07; I2&#x2009;=&#x2009;34% for the group of pre-existing renal dysfunction; p&#x2009;=&#x2009;0.40; I2&#x2009;=&#x2009;5% for the group of diabetes).<br><br>CONCLUSION: Our results suggest that NAC decreases the incidence of contrast-induced nephropathy among patients with pre-existing renal insufficiency. The benefit was not existed in patients with diabetes.}, }
@article {pmid26455407, year = {2015}, author = {Di Bari, M and Tombolillo, V and Conte, C and Castigli, E and Sciaccaluga, M and Iorio, E and Carpinelli, G and Ricordy, R and Fiore, M and Degrassi, F and Tata, AM}, title = {Cytotoxic and genotoxic effects mediated by M2 muscarinic receptor activation in human glioblastoma cells.}, journal = {Neurochemistry international}, volume = {90}, number = {}, pages = {261-270}, doi = {10.1016/j.neuint.2015.09.008}, pmid = {26455407}, issn = {1872-9754}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Brain Neoplasms/metabolism ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Glioblastoma/*metabolism ; Humans ; Muscarinic Agonists/*pharmacology ; Receptor, Muscarinic M2/*genetics/*metabolism ; Receptors, Muscarinic/genetics/metabolism ; }, abstract = {Glioblastomas are the most common brain tumors in humans. Previously, we demonstrated that the muscarinic receptor agonist, arecaidine propargyl ester, via M2 receptors, inhibits cell proliferation in a time and dose-dependent manner and induces a severe apoptosis in human U251 and U87 glioblastoma cell lines. In order to clarify the mechanisms causing apoptosis after arecaidine treatment, we analyzed the ability of arecaidine to induce oxidative stress. By dichloro-dihydro-fluorescein diacetate (DCFDA) staining, we demonstrated that arecaidine increased the intracellular ROS levels. ROS accumulation was completely counteracted by the ROS scavenger, N-acetyl-l-cysteine (NAC). Apoptotic cell death appeared directly correlated to ROS production since NAC was able to counteract this effect. Although there was an up-regulation of some detoxifying enzyme expression such as superoxide dismutase (MnSOD) and sirtuin-1 (SIRT1), the cytotoxic effect caused by arecaidine treatment caused DNA damage, as demonstrated by the increase of histone γ-H2AX positive cells, and chromosomal aberrations. These effects were mediated by M2 receptor activation; in fact after silencing of M2 receptors by siRNA, the increase of γ-H2AX positive cells was abolished. In conclusion, in addition to a cytostatic effect previously described, in the present study we have better characterized the mechanisms causing the cytotoxic effects and the apoptotic cell death in glioblastoma cells after M2 receptor activation. These data allow to consider this receptor a new interesting therapeutic tool for the glioblastoma treatment.}, }
@article {pmid26452072, year = {2016}, author = {Borgas, D and Chambers, E and Newton, J and Ko, J and Rivera, S and Rounds, S and Lu, Q}, title = {Cigarette Smoke Disrupted Lung Endothelial Barrier Integrity and Increased Susceptibility to Acute Lung Injury via Histone Deacetylase 6.}, journal = {American journal of respiratory cell and molecular biology}, volume = {54}, number = {5}, pages = {683-696}, pmid = {26452072}, issn = {1535-4989}, support = {R37 AA011431/AA/NIAAA NIH HHS/United States ; R01 HL130230/HL/NHLBI NIH HHS/United States ; P20 GM103652/GM/NIGMS NIH HHS/United States ; R25 HL088992/HL/NHLBI NIH HHS/United States ; I01 BX002622/BX/BLRD VA/United States ; T32 ES007272/ES/NIEHS NIH HHS/United States ; }, mesh = {Acute Lung Injury/*enzymology/microbiology/*pathology ; Animals ; Cattle ; Cell Membrane Permeability/drug effects ; Disease Susceptibility ; Endothelial Cells/drug effects/enzymology/microbiology/pathology ; Endothelium, Vascular/enzymology/*pathology ; Glycogen Synthase Kinase 3 beta/metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/*metabolism ; Humans ; Lipopolysaccharides/pharmacology ; Lung/*pathology ; Male ; Mice, Inbred C57BL ; Microvessels/pathology ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Pseudomonas aeruginosa/drug effects/physiology ; Smoking/*adverse effects ; }, abstract = {Epidemiologic evidence indicates that cigarette smoke (CS) is associated with the development of acute lung injury (ALI). We have previously shown that brief CS exposure exacerbates lipopolysaccharide (LPS)-induced ALI in vivo and endothelial barrier dysfunction in vitro. In this study, we found that CS also exacerbated Pseudomonas-induced ALI in mice. We demonstrated that lung microvascular endothelial cells (ECs) isolated from mice exposed to CS had a greater permeability or incomplete recovery after challenges by LPS and thrombin. Histone deacetylase (HDAC) 6 deacetylates proteins essential for maintenance of endothelial barrier function. We found that HDAC6 phosphorylation at serine-22 was increased in lung tissues of mice exposed to CS and in lung ECs exposed to cigarette smoke extract (CSE). Inhibition of HDAC6 attenuated CSE-induced increases in EC permeability and CS priming of ALI. Similar barrier protection was provided by the microtubule stabilizer taxol, which preserved α-tubulin acetylation. CSE decreased α-tubulin acetylation and caused microtubule depolymerization. In coordination with increased HDAC6 phosphorylation, CSE inhibited Akt and activated glycogen synthase kinase (GSK)-3β; these effects were ameliorated by the antioxidant N-acetyl cysteine. Our results suggest that CS increases lung EC permeability, thereby enhancing susceptibility to ALI, likely through oxidative stress-induced Akt inactivation and subsequent GSK-3β activation. Activated GSK-3β may activate HDAC6 via phosphorylation of serine-22, leading to α-tubulin deacetylation and microtubule disassembly. Inhibition of HDAC6 may be a novel therapeutic option for ALI in cigarette smokers.}, }
@article {pmid26451628, year = {2015}, author = {Song, X and Li, L and Shi, Q and Lehmler, HJ and Fu, J and Su, C and Xia, X and Song, E and Song, Y}, title = {Polychlorinated Biphenyl Quinone Metabolite Promotes p53-Dependent DNA Damage Checkpoint Activation, S-Phase Cycle Arrest and Extrinsic Apoptosis in Human Liver Hepatocellular Carcinoma HepG2 Cells.}, journal = {Chemical research in toxicology}, volume = {28}, number = {11}, pages = {2160-2169}, doi = {10.1021/acs.chemrestox.5b00320}, pmid = {26451628}, issn = {1520-5010}, support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; }, mesh = {Apoptosis/drug effects ; Benzoquinones/*toxicity ; Carcinoma, Hepatocellular/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Cycle Proteins/metabolism ; Cell Survival/drug effects ; Checkpoint Kinase 1 ; Checkpoint Kinase 2/metabolism ; *DNA Damage ; Hep G2 Cells ; Humans ; Liver Neoplasms/metabolism ; Polychlorinated Biphenyls/*toxicity ; Protein Kinases/metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants. The toxic behavior and mechanism of PCBs individuals and congeners have been extensively investigated. However, there is only limited information on their metabolites. Our previous studies have shown that a synthetic PCB metabolite, PCB29-pQ, causes oxidative damage with the evidence of cytotoxicity, genotoxicity, and mitochondrial-derived intrinsic apoptosis. Here, we investigate the effects of PCB29-pQ on DNA damage checkpoint activation, cell cycle arrest, and death receptor-related extrinsic apoptosis in human liver hepatocellular carcinoma HepG2 cells. Our results illustrate that PCB29-pQ increases the S-phase cell population by down-regulating cyclins A/D1/E, cyclin-dependent kinases (CDK 2/4/6), and cell division cycle 25A (CDC25A) and up-regulating p21/p27 protein expressions. PCB29-pQ also induces apoptosis via the up-regulation of Fas/FasL and the activation of caspase 8/3. Moreover, p53 plays a pivotal role in PCB29-pQ-induced cell cycle arrest and apoptosis via the activation of ATM/Chk2 and ATR/Chk1 checkpoints. Cell cycle arrest and apoptotic cell death were attenuated by the pretreatment with antioxidant N-acetyl-cysteine (NAC). Taken together, these results demonstrate that PCB29-pQ induces oxidative stress and promotes p53-dependent DNA damage checkpoint activation, S-phase cycle arrest, and extrinsic apoptosis in HepG2 cells.}, }
@article {pmid26449828, year = {2016}, author = {Wu, D and Zhang, J and Wang, J and Li, J and Liao, F and Dong, W}, title = {Hesperetin induces apoptosis of esophageal cancer cells via mitochondrial pathway mediated by the increased intracellular reactive oxygen species.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {37}, number = {3}, pages = {3451-3459}, pmid = {26449828}, issn = {1423-0380}, mesh = {Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Esophageal Neoplasms/*drug therapy/metabolism/pathology ; Female ; Glutathione/metabolism ; Hesperidin/*pharmacology ; Humans ; Mice ; Mice, Inbred BALB C ; Mitochondria/*physiology ; Proto-Oncogene Proteins c-bcl-2/analysis ; Reactive Oxygen Species/*metabolism ; }, abstract = {Esophageal cancer is of high prevalence and poor prognosis. Hesperetin has been reported to exert antitumor ability by inducing apoptosis in many cancers in vitro and in vivo without obvious toxicity. However, there is no study concerning about the effect of hesperetin on esophageal cancer. In this study, we aimed to investigate whether hesperetin could induce apoptosis in esophageal cancer cells and explore its potential mechanism. We found that hesperetin induced esophageal cancer cells apoptosis in a concentration-dependent and time-dependent manner compared with the untreated cells. Hoechst 33258 staining and flow cytometry analysis showed more apoptotic cells in the hesperetin-treated group (p < 0.05, respectively). The intracellular reactive oxygen species (ROS) increased significantly, and glutathione (GSH) was depleted. The loss of △Ψ m was more tremendous in the hesperetin-treated cells. N-acetylcysteine (NAC) reduced the proapoptotic ability of hesperetin, while DL-buthionine-S, R-sulfoximine (BSO) enhanced the anticancer effect. Western blotting showed that the expression levels of cytochrome C (Cyt C) and apoptosis-inducing factor (AIF) decreased in mitochondria and increased in cytoplasm (p < 0.05). The levels of intracellular cleaved caspase-9, cleaved caspase-3, Apaf-1, Bcl-2-associated X protein (Bax), and suppressor of fused (SuFu) increased, while B cell lymphoma 2 (Bcl-2) and Survivin decreased. What is more, in xenograft tumor model, hesperetin inhibited the tumor growth significantly via induction of cell apoptosis which was detected by TUNEL assay (p < 0.05). Taken together, our study demonstrated that hesperetin could induce cell apoptosis in esophageal cancer cells via mitochondrial-mediated intrinsic pathway by accumulation of ROS.}, }
@article {pmid26449771, year = {2016}, author = {Sinthorn, W and Chatuphonprasert, W and Chulasiri, M and Jarukamjorn, K}, title = {Thai red rice extract provides liver protection in paracetamol-treated mice by restoring the glutathione system.}, journal = {Pharmaceutical biology}, volume = {54}, number = {5}, pages = {770-779}, doi = {10.3109/13880209.2015.1079725}, pmid = {26449771}, issn = {1744-5116}, mesh = {Acetaminophen/*toxicity ; Animals ; Antioxidants/isolation &amp; purification/pharmacology ; Drugs, Chinese Herbal/isolation &amp; purification/*pharmacology ; Female ; Glutathione/*metabolism ; Liver/*drug effects/*metabolism ; Mice ; Mice, Inbred ICR ; *Oryza ; Thailand ; }, abstract = {CONTEXT: The incidence of drug-induced liver disease associated with oxidant-antioxidant imbalance is increasing. Colored rice can potentially improve these hepatic disorders through antioxidative and glutathione-restoring effects.<br><br>OBJECTIVES: The objective of this study is to determine the in vitro antioxidant properties of extracts from red (Hom-Dang and Hom-Kularb-Dang) and black (Hom-Dum-Sukhothai and Kum-Doi-Saket) Thai rice cultivars [Oryza sativa L. (Poaceae)] and to examine the in vivo hepatoprotective potential of Hom-Dang extract in paracetamol-treated mice.<br><br>MATERIALS AND METHODS: The in vitro antioxidant properties of the extracts were determined by ABTS, [Formula: see text], [Formula: see text], metal chelating capacity, and lipid peroxidation assays. To investigate hepatoprotective effects in vivo, mice administered 60&#x2009;mg/kg/d paracetamol were given Hom-Dang extract (128, 256, and 512&#x2009;mg/kg/d) and/or control antioxidant N-acetyl-cysteine (NAC, 150&#x2009;mg/kg/d) for 7 and 30 d. Liver health was ascertained by measuring levels of hepatic transaminases (GPT/GOT), determining the glutathione profile (GSH/GSSG ratio), and histomorphological examination of liver tissue.<br><br>RESULTS: Hom-Dang extract showed the highest in vitro antioxidant potency (an IC50 value of 36.50&#x2009;&#xb1;&#x2009;0.46, 12.98&#x2009;&#xb1;&#x2009;0.23, 21.83&#x2009;&#xb1;&#x2009;2.58, 15.87&#x2009;&#xb1;&#x2009;0.30, and 86.21&#x2009;&#xb1;&#x2009;2.45&#x2009;mg/mL for ABTS, OH(&#x2022;), [Formula: see text], metal chelating, and lipid peroxidation, respectively). Mice administered paracetamol exhibited increases in GPT/GOT with decreases in GSH and GSH/GSSG ratio followed by histomorphological signs of liver injury. In the presence of the Hom-Dang extract, the GPT/GOT values were normalized, GSH production was induced, and the GSH/GSSG ratio was increased.<br><br>CONCLUSION: Thai colored rice cultivars, especially the Hom-Dang variety, are promising candidates for health supplements due to their antioxidative and hepatoprotective properties.}, }
@article {pmid26447555, year = {2016}, author = {Huang, CC and Pan, WY and Tseng, MT and Lin, KJ and Yang, YP and Tsai, HW and Hwang, SM and Chang, Y and Wei, HJ and Sung, HW}, title = {Enhancement of cell adhesion, retention, and survival of HUVEC/cbMSC aggregates that are transplanted in ischemic tissues by concurrent delivery of an antioxidant for therapeutic angiogenesis.}, journal = {Biomaterials}, volume = {74}, number = {}, pages = {53-63}, doi = {10.1016/j.biomaterials.2015.09.043}, pmid = {26447555}, issn = {1878-5905}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Antioxidants/*administration &amp; dosage ; *Cell Adhesion ; *Cell Survival ; Cell Transplantation ; Human Umbilical Vein Endothelial Cells ; Humans ; Ischemia/*therapy ; Male ; Mesenchymal Stem Cells/*cytology ; Mice ; Mice, Inbred BALB C ; Neovascularization, Physiologic/*drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {A recurring obstacle in cell-base strategies for treating ischemic diseases is the significant loss of viable cells that is caused by the elevated levels of regional reactive oxygen species (ROS), which ultimately limits therapeutic capacity. In this study, aggregates of human umbilical vein endothelial cells (HUVECs) and cord-blood mesenchymal stem cells (cbMSCs), which are capable of inducing therapeutic angiogenesis, are prepared. We hypothesize that the concurrent delivery of an antioxidant N-acetylcysteine (NAC) may significantly increase cell retention following the transplantation of HUVEC/cbMSC aggregates in a mouse model with hindlimb ischemia. Our in vitro results demonstrate that the antioxidant NAC can restore ROS-impaired cell adhesion and recover the reduced angiogenic potential of HUVEC/cbMSC aggregates under oxidative stress. In the animal study, we found that by scavenging the ROS generated in ischemic tissues, NAC is likely to be able to establish a receptive cell environment in the early stage of cell transplantation, promoting the adhesion, retention, and survival of cells of engrafted aggregates. Therapeutic angiogenesis is therefore enhanced and blood flow recovery and limb salvage are ultimately achieved. The combinatory strategy that uses an antioxidant and HUVEC/cbMSC aggregates may provide a new means of boosting the therapeutic efficacy of cell aggregates for the treatment of ischemic diseases.}, }
@article {pmid26447155, year = {2015}, author = {Hildebrandt, W and Sauer, R and Bonaterra, G and Dugi, KA and Edler, L and Kinscherf, R}, title = {Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status.}, journal = {The American journal of clinical nutrition}, volume = {102}, number = {5}, pages = {1014-1024}, doi = {10.3945/ajcn.114.101964}, pmid = {26447155}, issn = {1938-3207}, mesh = {Acetylcysteine/administration &amp; dosage/blood/pharmacokinetics/*therapeutic use ; Administration, Oral ; Adult ; Antihypertensive Agents/administration &amp; dosage/blood/pharmacokinetics/*therapeutic use ; Antioxidants/administration &amp; dosage/analysis/pharmacokinetics/*therapeutic use ; Biotransformation ; Cholesterol/blood ; Cysteine/blood ; Double-Blind Method ; Glutathione/blood ; Homocysteine/*antagonists &amp; inhibitors/blood ; Humans ; Hyperhomocysteinemia/blood/complications/metabolism/*prevention &amp; control ; Hyperlipidemias/complications ; Hypertension/blood/complications/metabolism/*prevention &amp; control ; Leukocytes, Mononuclear/drug effects/metabolism ; Male ; Middle Aged ; Smoking/adverse effects ; Triglycerides/blood ; }, abstract = {BACKGROUND: Elevated total plasma homocysteine (tHcy) is considered to be an independent cardiovascular disease risk factor, although tHcy lowering by B-vitamins improves only certain clinical endpoints. N-acetylcysteine (NAC), a thiol-containing antioxidant, acutely lowers tHcy and possibly also blood pressure. However, to our knowledge, at present no conclusive long-term evaluation exists that controls for factors such as hyperlipidemia, smoking, medication, and disease stage, all of which affect the thiol redox state, including tHcy.<br><br>OBJECTIVE: We reanalyzed 2 double-blind, placebo-controlled trials in unmedicated middle-aged men, one in a hyperlipidemic group (HYL group; n = 40) and one in a normolipidemic group (NOL group; n = 42), each stratified for smokers and nonsmokers.<br><br>DESIGN: We evaluated the effect of 4 wk of oral NAC (1.8 g/d) on tHcy (primary endpoint), plasma thiol (cysteine), and intracellular glutathione concentrations as well as on blood pressure. The HYL group had total cholesterol >220 mg/dL or triglycerides >150 mg/dL.<br><br>RESULTS: NAC treatment significantly (P = 0.001, multivariate analysis of variance for repeated measures) lowered postabsorptive plasma concentrations of tHcy by -11.7% &#xb1; 3.0% (placebo: 4.1% &#xb1; 3.6%) while increasing those of cysteine by 28.1% &#xb1; 5.7% (placebo: 4.0% &#xb1; 3.4%) with no significant impact of hyperlipidemia or smoking. Moreover, NAC significantly decreased systolic (P = 0.003) and diastolic (P = 0.017) blood pressure within all subjects with a significant reduction in diastolic pressure in the HYL group (P = 0.008) but not in the NOL group. An explorative stepwise multiple regression analysis identified 1) post-treatment cysteine as well as 2) pretreatment tHcy and 3) albumin plasma concentrations as being significant contributors to tHcy reduction.<br><br>CONCLUSIONS: Four weeks of oral NAC treatment significantly decreased plasma tHcy concentrations, irrespective of lipid or smoking status, and lowered systolic blood pressure in both normolipidemic and hyperlipidemic men, with significant diastolic blood pressure reductions in the HYL group only. Increased oral intake of cysteine may therefore be considered for primary or secondary prevention of vascular events with regard to the 2 independent risk factors of hyperhomocysteinemia and arterial hypertension.}, }
@article {pmid26446958, year = {2015}, author = {Le Gal, K and Ibrahim, MX and Wiel, C and Sayin, VI and Akula, MK and Karlsson, C and Dalin, MG and Akyürek, LM and Lindahl, P and Nilsson, J and Bergo, MO}, title = {Antioxidants can increase melanoma metastasis in mice.}, journal = {Science translational medicine}, volume = {7}, number = {308}, pages = {308re8}, doi = {10.1126/scitranslmed.aad3740}, pmid = {26446958}, issn = {1946-6242}, mesh = {Acetylcysteine/adverse effects/pharmacology ; Animals ; Antioxidants/adverse effects/*pharmacology ; Cell Line, Tumor ; Chromans/adverse effects/pharmacology ; Dietary Supplements/adverse effects ; Disease Models, Animal ; Glutathione/metabolism ; Humans ; Male ; Melanoma/*chemically induced/pathology ; Mice ; Neoplasm Metastasis/pathology ; }, abstract = {Antioxidants in the diet and supplements are widely used to protect against cancer, but clinical trials with antioxidants do not support this concept. Some trials show that antioxidants actually increase cancer risk and a study in mice showed that antioxidants accelerate the progression of primary lung tumors. However, little is known about the impact of antioxidant supplementation on the progression of other types of cancer, including malignant melanoma. We show that administration of N-acetylcysteine (NAC) increases lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. Similarly, NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the glutathione system play a previously unappreciated role in malignant melanoma progression.}, }
@article {pmid26446137, year = {2015}, author = {Zhang, F and Cui, J and Liu, X and Lv, B and Liu, X and Xie, Z and Yu, B}, title = {Roles of microRNA-34a targeting SIRT1 in mesenchymal stem cells.}, journal = {Stem cell research &amp; therapy}, volume = {6}, number = {}, pages = {195}, pmid = {26446137}, issn = {1757-6512}, mesh = {Animals ; Apoptosis ; Cells, Cultured ; Cellular Senescence ; Male ; Mesenchymal Stem Cells/*metabolism/physiology ; MicroRNAs/*genetics ; Rats ; Rats, Sprague-Dawley ; Sirtuin 1/*genetics/metabolism ; }, abstract = {INTRODUCTION: Mesenchymal stem cell (MSC)-based therapies have had positive outcomes both in animal models of cardiovascular diseases and in clinical patients. However, the number and function of MSCs decline during hypoxia and serum deprivation (H/SD), reducing their ability to contribute to endogenous injury repair. MicroRNA-34a (miR-34a) is originally identified as a TP53-targeted miRNA that modulates cell functions, including apoptosis, proliferation, and senescence via several signaling pathways, and hence is an appealing target for MSC-based therapy for myocardial infarction.<br><br>METHODS: Bone marrow-derived MSCs were isolated from 60-80&#xa0;g male donor rats. Expression levels of miR-34a were determined by qRT-PCR. The roles of miR-34a in regulating cell vitality, apoptosis and senescence were investigated using the cell counting kit (CCK-8) assay, flow cytometric analysis of Annexin V-FITC/PI staining and senescence-associated &#x3b2;-galactosidase (SA-&#x3b2;-gal) staining, respectively. The expression of silent information regulator 1 (SIRT1) and forkhead box class O 3a (FOXO3a) and of apoptosis- and senescence-associated proteins in MSCs were analyzed by western blotting.<br><br>RESULTS: The results of the current study showed that miR-34a was significantly up-regulated under H/SD conditions in MSCs, while overexpression of miR-34a was significantly associated with increased apoptosis, impaired cell vitality and aggravated senescence. Moreover, we found that the mechanism underlying the proapoptotic function of miR-34a involves activation of the SIRT1/FOXO3a pathway, mitochondrial dysfunction and finally, activation of the intrinsic apoptosis pathway. Further study showed that miR-34a can also aggravate MSC senescence, an effect which was partly abolished by the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC).<br><br>CONCLUSIONS: Our study demonstrates for the first time that miR-34a plays pro-apoptotic and pro-senescence roles in MSCs by targeting SIRT1. Thus, inhibition of miR-34a might have important therapeutic implications in MSC-based therapy for myocardial infarction.}, }
@article {pmid26439053, year = {2015}, author = {Buyukserbetci, M and Dadali, M and Aydogmus, Y and Huri, E and Hascicek, AM and Ozer, E and Ogus, E and Kilinc, AS and Eroglu, M}, title = {Oral misoprostol does not protect the kidneys from diclofenac induced toxicity: data from an unilateral ureteral obstructive rat model.}, journal = {European review for medical and pharmacological sciences}, volume = {19}, number = {18}, pages = {3528-3535}, pmid = {26439053}, issn = {2284-0729}, mesh = {Administration, Oral ; Animals ; Diclofenac/*adverse effects ; Disease Models, Animal ; Female ; Kidney/*drug effects/pathology ; Misoprostol/administration &amp; dosage/*therapeutic use ; Rats ; Rats, Wistar ; Ureteral Obstruction/*physiopathology ; }, abstract = {OBJECTIVE: Ureteral obstruction leads to permanent changes in the structure of the kidney by several mechanisms. In this study, it was hypothesized that there would be a protective effect of misoprostol against diclofenac in rats with unilateral ureteral obstruction (UUO).<br><br>MATERIALS AND METHODS: Twenty-two female rats were randomized into 5 groups of 4 and 2 rats for the control group. The right ureter was sutured. The rats were grouped as control, contrast agent, contrast agent +N-acetylcysteine (NAC),&#xa0; diclofenac and diclofenac + misoprostol groups.Radiographic contrast agent was given iv on the 3rd day and other agents were administered orally for 1 week. The rats were sacrified after 1 week and histopathological and biochemical oxidative stress markers were evaluated.<br><br>RESULTS: The contrast agent and NAC&#xa0; group&#xa0; had lower rates of hemorrhage, inflammation, obstructive dilatation and fatty degeneration compared to the contrast agent only group (p < 0.05). No differences were seen in the normal kidneys. Between all the groups, there was no difference for tubule epithelium damage (p > 0.05). The contrast agent and NAC group had higher rates of antioxidant SH level compared to the contrast agent only group (p < 0.05) and lower rates of oxidative end product carbonyl groups (p < 0.05). For normal kidneys no difference was seen. No statistical difference was seen in MDA levels (p > 0.05). Statistically no difference was seen between the diclofenac group and the diclofenac and misoprostol group neither pathologically nor chemically (p > 0.05).<br><br>CONCLUSIONS: These results showed that NAC is protective against radiographic contrast agent toxicity when given before and after administration in obstructed kidneys as in previous data. Misoprostol was not observed to have any protective effect against diclofenac in obstructed kidneys.}, }
@article {pmid26436698, year = {2015}, author = {Amini, A and Masoumi-Moghaddam, S and Ehteda, A and Liauw, W and Morris, DL}, title = {Depletion of mucin in mucin-producing human gastrointestinal carcinoma: Results from in vitro and in vivo studies with bromelain and N-acetylcysteine.}, journal = {Oncotarget}, volume = {6}, number = {32}, pages = {33329-33344}, pmid = {26436698}, issn = {1949-2553}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adenocarcinoma/*drug therapy/genetics/metabolism/pathology ; Animals ; Bromelains/administration &amp; dosage/*therapeutic use ; Female ; Gastrointestinal Neoplasms/*drug therapy/genetics/metabolism/pathology ; Humans ; Injections, Intraperitoneal ; Mice ; Mice, Nude ; Mucin 5AC/antagonists &amp; inhibitors ; Mucin-2/antagonists &amp; inhibitors ; Mucins/*antagonists &amp; inhibitors/genetics/metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {Aberrant expression of membrane-associated and secreted mucins, as evident in epithelial tumors, is known to facilitate tumor growth, progression and metastasis, and to provide protection against adverse growth conditions, chemotherapy and immune surveillance. Emerging evidence provides support for the oncogenic role of MUC1 in gastrointestinal carcinomas and relates its expression to an invasive phenotype. Similarly, mucinous differentiation of gastrointestinal tumors, in particular increased or de novo expression of MUC2 and/or MUC5AC, is widely believed to imply an adverse clinicopathological feature. Through formation of viscous gels, too, MUC2 and MUC5AC significantly contribute to the biology and pathogenesis of mucin-secreting gastrointestinal tumors. Here, we investigated the mucin-depleting effects of bromelain (BR) and N-acetylcysteine (NAC), in nine different regimens as single or combination therapy, in in vitro (MKN45, KATOIII and LS174T cell lines) and in vivo (female nude mice bearing intraperitoneal MKN45 and LS174T) settings. The inhibitory effects of the treatment on cancer cell growth and proliferation were also evaluated in vivo. Our results suggest that a combination of BR and NAC with dual effects on growth and mucin products of mucin-expressing tumor cells is a promising candidate towards the development of novel approaches to gastrointestinal malignancies with the involvement of mucin pathology. This capability supports the use of this combination formulation in locoregional approaches for reducing the adverse effects of the aberrantly secreted gel-forming mucins, as in pseudomyxoma peritonei and similar pathologies with ectopic production of mucin.}, }
@article {pmid26436146, year = {2015}, author = {Deng, HH and Wu, GW and He, D and Peng, HP and Liu, AL and Xia, XH and Chen, W}, title = {Fenton reaction-mediated fluorescence quenching of N-acetyl-L-cysteine-protected gold nanoclusters: analytical applications of hydrogen peroxide, glucose, and catalase detection.}, journal = {The Analyst}, volume = {140}, number = {22}, pages = {7650-7656}, doi = {10.1039/c5an01284h}, pmid = {26436146}, issn = {1364-5528}, mesh = {Acetylcysteine/*chemistry ; Biosensing Techniques/*methods ; Blood Glucose/*analysis ; Catalase/*analysis ; Glucose/analysis ; Humans ; Hydrogen Peroxide/*analysis/chemistry ; Iron/*chemistry ; Limit of Detection ; Metal Nanoparticles/*chemistry ; Models, Molecular ; Saliva/chemistry/enzymology ; }, abstract = {Given the importance of hydrogen peroxide (H2O2) in many biological processes and its wide application in various industries, the demand for sensitive, accurate, and economical H2O2 sensors is high. In this study, we used Fenton reaction-stimulated fluorescence quenching of N-acetyl-L-cysteine-protected gold nanoclusters (NAC-AuNCs) as a reporter system for the determination of H2O2. After the experimental conditions were optimized, the sensing platform enabled the analysis of H2O2 with a limit of detection (LOD) as low as 0.027 μM. As the glucose oxidase cascade leads to the generation of H2O2 and catalase catalyzes the decomposition of H2O2, these two biocatalytic procedures can be probed by the Fenton reaction-mediated quenching of NAC-AuNCs. The LOD for glucose was found to be 0.18 μM, and the linear range was 0.39-27.22 μM. The LOD for catalase was 0.002 U mL(-1), and the linear range was 0.01-0.3 U mL(-1). Moreover, the proposed sensing methods were successfully applied for human serum glucose detection and the non-invasive determination of catalase activity in human saliva, demonstrating their great potential for practical applications.}, }
@article {pmid26434549, year = {2015}, author = {Agbor, TA and Brown, M and Clark, L and Kavsak, PA}, title = {Negative interference of N-acetyl cysteine (NAC) on selected chemistries on the Abbott architect platform.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {451}, number = {Pt B}, pages = {219-221}, doi = {10.1016/j.cca.2015.09.032}, pmid = {26434549}, issn = {1873-3492}, mesh = {Acetylcysteine/*analysis/metabolism ; *Artifacts ; Clinical Chemistry Tests/*methods ; Humans ; }, }
@article {pmid26433892, year = {2016}, author = {Yi, D and Hou, Y and Wang, L and Long, M and Hu, S and Mei, H and Yan, L and Hu, CA and Wu, G}, title = {N-acetylcysteine stimulates protein synthesis in enterocytes independently of glutathione synthesis.}, journal = {Amino acids}, volume = {48}, number = {2}, pages = {523-533}, doi = {10.1007/s00726-015-2105-z}, pmid = {26433892}, issn = {1438-2199}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Cell Proliferation/*drug effects ; Cysteine/metabolism ; Enterocytes/*metabolism ; Eukaryotic Initiation Factors/metabolism ; Glutathione/analogs &amp; derivatives/*metabolism/pharmacology ; Maleates/pharmacology ; Protein Biosynthesis/*drug effects ; Real-Time Polymerase Chain Reaction ; Sus scrofa ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Dietary supplementation with N-acetylcysteine (NAC) has been reported to improve intestinal health and treat gastrointestinal diseases. However, the underlying mechanisms are not fully understood. According to previous reports, NAC was thought to exert its effect through glutathione synthesis. This study tested the hypothesis that NAC enhances enterocyte growth and protein synthesis independently of cellular glutathione synthesis. Intestinal porcine epithelial cells were cultured for 3 days in Dulbecco's modified Eagle medium containing 0 or 100 μM NAC. To determine a possible role for GSH (the reduced form of glutathione) in mediating the effect of NAC on cell growth and protein synthesis, additional experiments were conducted using culture medium containing 100 μM GSH, 100 μM GSH ethyl ester (GSHee), diethylmaleate (a GSH-depletion agent; 10 μM), or a GSH-synthesis inhibitor (buthionine sulfoximine, BSO; 20 μM). NAC increased cell proliferation, GSH concentration, and protein synthesis, while inhibiting proteolysis. GSHee enhanced cell proliferation and GSH concentration without affecting protein synthesis but inhibited proteolysis. Conversely, BSO or diethylmaleate reduced cell proliferation and GSH concentration without affecting protein synthesis, while promoting protein degradation. At the signaling level, NAC augmented the protein abundance of total mTOR, phosphorylated mTOR, and phosphorylated 70S6 kinase as well as mRNA levels for mTOR and p70S6 kinase in IPEC-1 cells. Collectively, these results indicate that NAC upregulates expression of mTOR signaling proteins to stimulate protein synthesis in enterocytes independently of GSH generation. Our findings provide a hitherto unrecognized biochemical mechanism for beneficial effects of NAC in intestinal cells.}, }
@article {pmid26433260, year = {2015}, author = {Feng, D and Huang, H and Yang, Y and Yan, T and Jin, Y and Cheng, X and Cui, L}, title = {Ameliorative effects of N-acetylcysteine on fluoride-induced oxidative stress and DNA damage in male rats' testis.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {792}, number = {}, pages = {35-45}, doi = {10.1016/j.mrgentox.2015.09.004}, pmid = {26433260}, issn = {1879-3592}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*chemistry ; Animals ; Body Weight ; Catalase/blood ; *DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/chemistry ; Electrodes ; Fluorides/adverse effects/*chemistry ; Immunohistochemistry ; Lipid Peroxidation/drug effects ; Male ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Sodium Fluoride/chemistry ; Sperm Count ; Spermatozoa/pathology ; Testis/metabolism/pathology ; Testosterone/*blood ; }, abstract = {This study was to elucidate DNA damage in rats treated with sodium fluoride (NaF) by performing 8-Hydroxy-2-deoxyguanosine (8-OHdG) immunohistochemical staining assays on seminiferous tubules of rats' testis, and also to evaluate the protective effects of N-acetylcysteine (NAC) on spermatogenesis. Male Sprague Dawley (SD) rats were exposed to a single dose of NaF (25mg/kg/day) with or without NAC (150mg/kg/day) for 7 weeks (7W) by gastric gavage. Testicular fluorine content was detected by fluorine ion selective electrode method. Oxidative damage to DNA was evaluated by measuring the increase in 8-OHdG formation in testicular tissue through immunohistochemical staining assays and also the effects of NAC pretreatment. The biochemical indicators about oxidative stress were detected by colorimetric assays, sperm parameters and the morphological changes of testis were studied. NaF significantly increased serum levels of oxidative stress, markedly elevated testicular fluorine and 8-OHdG expression levels as well as the rate of sperm aberration compared to saline group. Testosterone in serum, sperm counts and the mobility of sperm were lower than those of the rats in control group. The pathological morphological changes in testicular seminiferous tubule were also obvious in the rats with NaF treatment. Pretreatment with NAC did not reduce the contents of fluoride content in testis, but significantly reduced 8-OHdG formation and lipid peroxidation. This study suggests that NAC may have certain antagonism on the reproductive damage induced by NaF.}, }
@article {pmid26432840, year = {2015}, author = {Wilder, T and Ryba, DM and Wieczorek, DF and Wolska, BM and Solaro, RJ}, title = {N-acetylcysteine reverses diastolic dysfunction and hypertrophy in familial hypertrophic cardiomyopathy.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {309}, number = {10}, pages = {H1720-30}, pmid = {26432840}, issn = {1522-1539}, support = {P01 HL062426/HL/NHLBI NIH HHS/United States ; P01-HL-62426/HL/NHLBI NIH HHS/United States ; T32-HL-007692/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/metabolism ; Calcium-Binding Proteins/drug effects/metabolism ; Cardiomyopathy, Hypertrophic, Familial/genetics/*metabolism/physiopathology ; Carrier Proteins/drug effects/metabolism ; Diastole/*drug effects ; Disease Models, Animal ; Female ; Free Radical Scavengers/*pharmacology ; Heart Ventricles/*drug effects/metabolism/physiopathology ; Male ; Mice ; Mice, Transgenic ; Mitogen-Activated Protein Kinase 1/drug effects/metabolism ; Mitogen-Activated Protein Kinase 3/drug effects/metabolism ; Myofibrils/*drug effects/metabolism ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/drug effects/metabolism ; Tropomyosin/genetics ; }, abstract = {S-glutathionylation of cardiac myosin-binding protein C (cMyBP-C) induces Ca(2+) sensitization and a slowing of cross-bridge kinetics as a result of increased oxidative signaling. Although there is evidence for a role of oxidative stress in disorders associated with hypertrophic cardiomyopathy (HCM), this mechanism is not well understood. We investigated whether oxidative myofilament modifications may be in part responsible for diastolic dysfunction in HCM. We administered N-acetylcysteine (NAC) for 30 days to 1-mo-old wild-type mice and to transgenic mice expressing a mutant tropomyosin (Tm-E180G) and nontransgenic littermates. Tm-E180G hearts demonstrate a phenotype similar to human HCM. After NAC administration, the morphology and diastolic function of Tm-E180G mice was not significantly different from controls, indicating that NAC had reversed baseline diastolic dysfunction and hypertrophy in our model. NAC administration also increased sarco(endo)plasmic reticulum Ca(2+) ATPase protein expression, reduced extracellular signal-related kinase 1/2 phosphorylation, and normalized phosphorylation of phospholamban, as assessed by Western blot. Detergent-extracted fiber bundles from NAC-administered Tm-E180G mice showed nearly nontransgenic (NTG) myofilament Ca(2+) sensitivity. Additionally, we found that NAC increased tension cost and rate of cross-bridge reattachment. Tm-E180G myofilaments were found to have a significant increase in S-glutathionylation of cMyBP-C, which was returned to NTG levels upon NAC administration. Taken together, our results indicate that oxidative myofilament modifications are an important mediator in diastolic function, and by relieving this modification we were able to reverse established diastolic dysfunction and hypertrophy in HCM.}, }
@article {pmid26432613, year = {2016}, author = {Uysal, HB and Dağlı, B and Yılmaz, M and Kahyaoğlu, F and Gökçimen, A and Ömürlü, &#x130;K and Demirci, B}, title = {Biochemical and Histological Effects of Thiamine Pyrophosphate against Acetaminophen-Induced Hepatotoxicity.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {118}, number = {1}, pages = {70-76}, doi = {10.1111/bcpt.12496}, pmid = {26432613}, issn = {1742-7843}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/administration &amp; dosage/therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Catalase/metabolism ; Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology/*prevention &amp; control ; Drug Therapy, Combination ; Female ; Glutathione/metabolism ; Liver/*drug effects/metabolism/pathology ; Liver Function Tests ; Malondialdehyde/metabolism ; Nitric Oxide/metabolism ; Oxidative Stress/*drug effects ; Peroxidase/metabolism ; Rats, Wistar ; Thiamine Pyrophosphate/administration &amp; dosage/*therapeutic use ; }, abstract = {The aim of this study was to investigate whether thiamine pyrophosphate (TPP) has biochemical and histological preventive effects on oxidative liver damage induced by paracetamol (APAP). Rats were divided into the following groups: healthy control (HG), APAP (AG, 1500 mg/kg, orally), thiamine pyrophosphate (TPPG, 100 mg/kg, intraperitoneally), APAP+NAC (ANAC, 100 mg/kg, intraperitoneally), APAP+TPP (ATPG) and APAP+NAC+TPP (ANTG). Oxidant, antioxidant parameters, liver function tests and histological assessment were performed between groups. Malondialdehyde levels in the AG, HG, TPPG, ANAC, ATPG and ANTG groups were 0.470 ± 0.210, 0.213 ± 0.004, 0.194 ± 0.001, 0.197 ± 0.06, 0.199 ± 0.008 and 0.173 ± 0.010 μmol/g protein, respectively. Total glutathione levels were 7.787 ± 0.395, 14.925 ± 0.932, 13.200 ± 0.984, 13.162 ± 0.486, 13.287 ± 0.787 and 13.500 ± 0.891 μm/g protein, respectively. In the AG group, marked liver damage occurred with the elevation of liver function tests and oxidative stress markers, such as malondialdehyde, myeloperoxidase and nitric oxide (p < 0.05). Biochemical results were congruent with the histological changes of oxidative damage. Compared to the AG group (p < 0.05), TPP significantly reduced oxidant parameter levels in the ATPG group and simultaneously increased the antioxidant parameter levels of catalase and glutathione. The histological changes were improved to almost normal hepatic structure. Moreover, TPP had nearly the same hepatoprotective effect as NAC, and there was statistically no additional benefit with NAC co-treatment. There was no statistically significant difference (p > 0.05) among the ANAC, ANTG and ATPG groups in terms of oxidant/antioxidant levels. TPP proved to be as efficacious as standard therapy and may be beneficial in APAP-induced hepatotoxicity.}, }
@article {pmid26431905, year = {2015}, author = {Suzuki, M and Bandoski, C and Bartlett, JD}, title = {Fluoride induces oxidative damage and SIRT1/autophagy through ROS-mediated JNK signaling.}, journal = {Free radical biology &amp; medicine}, volume = {89}, number = {}, pages = {369-378}, pmid = {26431905}, issn = {1873-4596}, support = {R01 DE018106/DE/NIDCR NIH HHS/United States ; R01DE018106/DE/NIDCR NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; *Autophagy ; Blotting, Western ; Cell Proliferation/drug effects ; Cells, Cultured ; DNA Damage/drug effects ; Fluorescent Antibody Technique ; Fluorides/*pharmacology ; Immunoenzyme Techniques ; JNK Mitogen-Activated Protein Kinases/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Phosphates/*pharmacology ; Phosphorylation ; RNA, Messenger/genetics ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Sirtuin 1/genetics/*metabolism ; }, abstract = {Fluoride is an effective caries prophylactic, but at high doses can also be an environmental health hazard. Acute or chronic exposure to high fluoride doses can result in dental enamel and skeletal and soft tissue fluorosis. Dental fluorosis is manifested as mottled, discolored, porous enamel that is susceptible to dental caries. Fluoride induces cell stress, including endoplasmic reticulum stress and oxidative stress, which leads to impairment of ameloblasts responsible for dental enamel formation. Recently we reported that fluoride activates SIRT1 and autophagy as an adaptive response to protect cells from stress. However, it still remains unclear how SIRT1/autophagy is regulated in dental fluorosis. In this study, we demonstrate that fluoride exposure generates reactive oxygen species (ROS) and the resulting oxidative damage is counteracted by SIRT1/autophagy induction through c-Jun N-terminal kinase (JNK) signaling in ameloblasts. In the mouse-ameloblast-derived cell line LS8, fluoride induced ROS, mitochondrial damage including cytochrome-c release, up-regulation of UCP2, attenuation of ATP synthesis, and H2AX phosphorylation (γH2AX), which is a marker of DNA damage. We evaluated the effects of the ROS inhibitor N-acetylcysteine (NAC) and the JNK inhibitor SP600125 on fluoride-induced SIRT1/autophagy activation. NAC decreased fluoride-induced ROS generation and attenuated JNK and c-Jun phosphorylation. NAC decreased SIRT1 phosphorylation and formation of the autophagy marker LC3II, which resulted in an increase in the apoptosis mediators γH2AX and cleaved/activated caspase-3. SP600125 attenuated fluoride-induced SIRT1 phosphorylation, indicating that fluoride activates SIRT1/autophagy via the ROS-mediated JNK pathway. In enamel organs from rats or mice treated with 50, 100, or 125 ppm fluoride for 6 weeks, cytochrome-c release and the DNA damage markers 8-oxoguanine, p-ATM, and γH2AX were increased compared to those in controls (0 ppm fluoride). These results suggest that fluoride-induced ROS generation causes mitochondrial damage and DNA damage, which may lead to impairment of ameloblast function. To counteract this impairment, SIRT1/autophagy is induced via JNK signaling to protect cells/ameloblasts from fluoride-induced oxidative damage that may cause dental fluorosis.}, }
@article {pmid26430188, year = {2015}, author = {Blackmore, L and Bernal, W}, title = {Acute liver failure.}, journal = {Clinical medicine (London, England)}, volume = {15}, number = {5}, pages = {468-472}, pmid = {26430188}, issn = {1473-4893}, mesh = {Humans ; *Liver Failure, Acute/complications/etiology/therapy ; }, abstract = {Acute liver failure (ALF) is a rare critical illness with high mortality whose successful management requires early recognition and effective initial management. Though it may result from a wide variety of causes, in the UK and much of the developed world most cases result from paracetamol-induced hepatotoxicity, and administration of antidotal N-acetyl cysteine at first recognition is key. Involvement of local critical care services should occur at an early stage for stabilisation, monitoring and supportive care with parallel discussion with specialist liver centres to identify those patients who may benefit from transfer. Prognostic criteria are applied to identify patients for emergency liver transplantation, and candidates for surgery are prioritised on waitlisting schemes. Outcomes now approach that of elective surgery. However, the majority of cases, and particularly those with paracetamol-induced disease, recover with supportive medical care alone. Overall outcomes for patients with ALF have improved dramatically over the last three decades, but mortality remains unacceptable and further advances in care are required.}, }
@article {pmid26429951, year = {2015}, author = {Zyoud, SH and Al-Jabi, SW and Sweileh, WM and Awang, R and Waring, WS}, title = {Global research productivity of N-acetylcysteine use in paracetamol overdose: A bibliometric analysis (1976-2012).}, journal = {Human &amp; experimental toxicology}, volume = {34}, number = {10}, pages = {1006-1016}, doi = {10.1177/0960327114565494}, pmid = {26429951}, issn = {1477-0903}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal/*poisoning ; *Bibliometrics ; Biomedical Research/*statistics &amp; numerical data ; Drug Overdose ; Humans ; Publishing/*statistics &amp; numerical data ; }, abstract = {PURPOSE: The main objective of this study was to examine the publication pattern of N-acetylcysteine (NAC) research output for paracetamol overdose at the global level.<br><br>METHODS: Data were searched for documents that contained specific words regarding NAC and paracetamol as keywords in the title and/or abstract and/or keywords. Scientific output was evaluated based on a methodology developed and used in other bibliometric studies. Research productivity was adjusted to the national population and nominal gross domestic product per capita.<br><br>RESULTS: The criteria were met by 367 publications from 33 countries. The highest number of articles associated with the use of NAC in paracetamol overdose was from the United States of America (USA; 39.78%), followed by the United Kingdom (UK; 11.99%). After adjusting for economy and population power, USA (2.822), Iran (1.784) and UK (1.125) had the highest research productivity. The total number of citations at the time of data analysis (14 March 2014) was 8785 with an average of 23.9 citations per document and a median (interquartile range) of 6 (1-22). The h-index of the retrieved documents was 48. The highest h-index was 32 for USA, followed by 20 for UK. Furthermore, the highest number of collaborations with international authors for each country was held by USA with 11 countries, followed by Canada with 7 countries.<br><br>CONCLUSION: The amount of NAC-based research activity was low in some countries, and more effort is needed to bridge this gap and to promote better evaluation of NAC use worldwide. Our findings demonstrate that NAC use for paracetamol overdose remains a hot issue in scientific research and may have a larger audience compared with other toxicological aspects. Editors and authors in the field of toxicology might usefully promote the submission of work on NAC in future to improve their journal's impact.}, }
@article {pmid26421191, year = {2015}, author = {Hamidian, SM and Aletaha, NS and Taslimi, R and Montazeri, M}, title = {An Additive Effect of Oral N-Acetyl Cysteine on Eradication of Helicobacter pylori.}, journal = {Journal of pathogens}, volume = {2015}, number = {}, pages = {540271}, pmid = {26421191}, issn = {2090-3057}, abstract = {Background. Helicobacter pylori is highly adapted to the gastric environment where it lives within or beneath the gastric mucous layer. The aim of this study was to evaluate whether the addition of N-acetyl cysteine to the treatment regimen of H. pylori infection would affect eradication rates of the disease. Methods. A total of 79 H. pylori positive patients were randomized to two therapeutic groups. Both groups received a 14-day course of three-drug regimen including amoxicillin/clarithromycin/omeprazole. Experimental group (38 subjects) received NAC, and control group (41 subjects) received placebo, besides three-drug regimen. H. pylori eradication was evaluated by urea breath test at least 4 weeks after the cessation of therapy. Results. The rate of H. pylori eradication was 72.9% and 60.9% in experimental and control groups, respectively (P = 0.005). By logistic regression modeling, female gender (OR 3.68, 95% CI: 1.06-5.79; P = 0.040) and treatment including NAC (OR 1.88, 95% CI: 0.68-3.15; P = 0.021) were independent factors associated with H. pylori eradication. Conclusion. The results of the present study show that NAC has an additive effect on the eradication rates of H. pylori obtained with three-drug regimen and appears to be a promising means of eradicating H. pylori infection.}, }
@article {pmid26420761, year = {2016}, author = {Belgaumkar, AP and Carswell, KA and Hughes, RD and Quaglia, A and Dhawan, A and Mitry, RR and Patel, AG}, title = {The Effect of Intraoperative N-Acetylcysteine on Hepatocellular Injury During Laparoscopic Bariatric Surgery. A Randomised Controlled Trial.}, journal = {Obesity surgery}, volume = {26}, number = {6}, pages = {1254-1265}, pmid = {26420761}, issn = {1708-0428}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Bariatric Surgery/*adverse effects/methods ; Body Mass Index ; Comorbidity ; Cytokines/blood ; Female ; Free Radical Scavengers/therapeutic use ; Gastrectomy ; Humans ; Intraoperative Care/methods ; Intraoperative Complications/blood/prevention &amp; control ; Keratin-18/blood ; Laparoscopy/adverse effects ; Liver/*injuries/pathology ; Male ; Middle Aged ; Obesity, Morbid/physiopathology/*surgery ; Postoperative Period ; Single-Blind Method ; Treatment Outcome ; Weight Loss ; Young Adult ; }, abstract = {BACKGROUND: The combination of pneumoperitoneum and intraoperative retraction of the left lobe of the liver leads to hepatocellular injury during laparoscopic gastric surgery. Fatty livers are more susceptible to ischaemic insults. This trial investigated whether the antioxidant N-acetylcysteine (NAC) reduced liver injury during laparoscopic sleeve gastrectomy (LSG).<br><br>METHODS: Patients undergoing LSG were randomised (single blinded) to receive intraoperative NAC infusion or standard anaesthetic treatment. Blood samples were taken before and after surgery (days 0 to 4). Primary endpoints included serum aminotransferases. Secondary measures were C-reactive protein, weight cell count (WCC), cytokines (interleukin 6 and 10) and cytokeratin-18 as markers of apoptosis. Intraoperative liver biopsy samples were assessed using a locally developed injury score.<br><br>RESULTS: Twenty patients (14 females, mean age 44.5 (SEM&#x2009;&#xb1;&#x2009;2.9)&#x2009;years, mean BMI 60.8 (SEM&#x2009;&#xb1;&#x2009;2.4)&#x2009;kg/m(2)) were recruited (NAC n&#x2009;=&#x2009;10, control n&#x2009;=&#x2009;10). The trial was stopped early after a planned interim analysis. Baseline liver function was similar. The peak rise in liver enzymes was on day 1, but levels were not significantly different between the groups. Rates of complications and length of stay were not significantly different. Secondary outcome measures, including white cell count (WCC), cytokines and cytokeratin (CK)-18 fragments, were not different between groups. Liver injury scores did not differ significantly.<br><br>CONCLUSIONS: NAC did not reduce intraoperative liver injury in this small number of patients. The heterogenous nature of the study population, with differences in co-morbidities, body mass index and intraabdominal anatomy, leads to a varied post-operative inflammatory response. Significant hepatocyte injury occurs through both necrosis and apoptosis.}, }
@article {pmid26415619, year = {2015}, author = {Liao, H and Bao, X and Zhu, J and Qu, J and Sun, Y and Ma, X and Wang, E and Guo, X and Kang, Q and Zhen, Y}, title = {O-Alkylated derivatives of quercetin induce apoptosis of MCF-7 cells via a caspase-independent mitochondrial pathway.}, journal = {Chemico-biological interactions}, volume = {242}, number = {}, pages = {91-98}, doi = {10.1016/j.cbi.2015.09.022}, pmid = {26415619}, issn = {1872-7786}, mesh = {Apoptosis/*drug effects ; Apoptosis Inducing Factor/metabolism ; Caspases/metabolism ; Drug Screening Assays, Antitumor/methods ; Endodeoxyribonucleases/metabolism ; Endoplasmic Reticulum/drug effects ; Humans ; MCF-7 Cells/drug effects ; Mitochondria/drug effects/metabolism ; Quercetin/analogs &amp; derivatives/chemistry/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {The aim of this study was to investigate the antitumor effects of two novel alkylated derivatives of quercetin, 7-O-butylquercetin (BQ) and 7-O-geranylquercetin (GQ), in MCF-7 human breast cancer cells and explore the possible cellular mechanism of the related apoptotic effects. Our data showed that BQ and GQ were more toxic to MCF-7 cells and had better accumulation ability in MCF-7 cells than quercetin. Morphological observations and DNA fragmentation pattern suggested that the derivatives could induce apoptosis in MCF-7 cells. Derivatives-induced apoptosis could not be reversed by Z-VAD-FMK and N-acetyl cysteine demonstrated that the apoptosis was independent on caspase and reactive oxygen species. Western blot assay showed that endonuclease G and apoptosis inducing factor might be relative to the apoptosis. Alkylation of quercetin at 7-O position can enhance the apoptosis inducing effect and cell accumulation ability relative to quercetin. This structural alteration brings changes on apoptosis pathway as well.}, }
@article {pmid26411723, year = {2016}, author = {Taşkınlar, H and Naycı, A and Çömelekoğlu, &#xdc; and Polat, G and Zorludemir, S and Avlan, D}, title = {Intestinal ischemia-reperfusion induced diaphragm contractility dysfunction: Electrophysiological and ultrastructural study in a neonatal rat model.}, journal = {Journal of pediatric surgery}, volume = {51}, number = {3}, pages = {354-359}, doi = {10.1016/j.jpedsurg.2015.08.013}, pmid = {26411723}, issn = {1531-5037}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Biomarkers/metabolism ; Diaphragm/drug effects/metabolism/pathology/*physiopathology ; Electromyography ; Intestines/*blood supply/pathology ; Male ; Microscopy, Electron, Transmission ; Muscle Contraction/drug effects/*physiology ; Phrenic Nerve/drug effects/pathology/physiopathology ; Random Allocation ; Rats ; Rats, Wistar ; Reperfusion Injury/drug therapy/*physiopathology ; Treatment Outcome ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {AIM: To evaluate the remote effect of intestinal ischemia reperfusion (IR) injury mediated by tumor necrosis factor alpha (TNF-α) on diaphragm contractility functions and whether administration of NAC may counteract the possible detrimental effects in an experimental neonatal rat model.<br><br>METHODS: 40 Wistar rat pups were randomized into four groups; ten animals in each. Intestinal ischemia was conducted by obstructing mesentery of intestines by a silk loop. In the control group; only laparotomy was performed. After 1h ischemia, reperfusion was conducted for 1h in 1h group, 24h for 24h group and 24h for 24h+NAC group but administration of NAC (150mg/kg/day) intraperitoneally twice a day was performed. Inflammatory response was evaluated by tissue TNF-&#x3b1; level and contractility functions by mechanic activity studies of the diaphragm. Electrophysiology of the diaphragm and the phrenic nerve was conducted to determine neuropathy or myopathy and transmission electron microscopy was performed to evaluate ultrastructural changes in the phrenic nerve.<br><br>RESULTS: Diaphragm tissue TNF-&#x3b1; level significantly increased in 1h and 24h groups (P=0.004, P=0.0001; respectively). Diaphragm mechanic activation force and duration significantly decreased at 1h and 24h (P=0.004, P=0.02 and P=0.0001, P=0.0001; respectively). NAC administration significantly prevented decrease in the maximal contraction and the duration (P<0.001). Phrenic nerve compound action potential (CMAP) amplitude significantly decreased in 1h group (P<0.0001) and NAC administration significantly prevented this decrease when compared with 24h group (P<0.001). In diaphragmatic needle electromyography, the duration of motor unit potentials (MUP) was prolonged significantly when compared with control group. Contractility and electrophysiological studies were indicating primarily neuropathy in diaphragm dysfunction. Histopathology revealed axonal and myelin degeneration in the 1h and 24h group, but less injury in the NAC administered group.<br><br>CONCLUSIONS: Intestinal IR induced elevation of TNF-&#x3b1; level in the diaphragm. Impairment in the diaphragm contractility and neuropathic changes in the phrenic nerve occurred even in the first hour of reperfusion. NAC administration prevented these detrimental effects.}, }
@article {pmid26409646, year = {2015}, author = {Yu, B and Changsheng, Y and Wenjun, Z and Ben, L and Hai, Q and Jing, M and Guangwei, X and Shuhua, W and Fang, L and Aschner, M and Rongzhu, L}, title = {Differential protection of pre- versus post-treatment with curcumin, Trolox, and N-acetylcysteine against acrylonitrile-induced cytotoxicity in primary rat astrocytes.}, journal = {Neurotoxicology}, volume = {51}, number = {}, pages = {58-66}, doi = {10.1016/j.neuro.2015.09.011}, pmid = {26409646}, issn = {1872-9711}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acrylonitrile/*toxicity ; Animals ; Antioxidants/*administration &amp; dosage ; Astrocytes/*drug effects/*metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Chromans/*administration &amp; dosage ; Curcumin/*administration &amp; dosage ; Cytotoxins ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; NF-E2-Related Factor 2/metabolism ; Neuroprotective Agents/*administration &amp; dosage ; Oxidative Stress/drug effects ; Rats ; Reactive Oxygen Species ; }, abstract = {OBJECTIVE: This study was designed to examine the differential protection of pre- versus post-treatment with three different antioxidants, curcumin (CUR), Trolox, and N-acetylcysteine (NAC), on acrylonitrile (AN)-induced cytotoxicity in primary rat astrocytes.<br><br>METHODS: Primary astrocyte cultures were treated with CUR, Trolox and NAC for 4h prior to, or following 24h treatment with AN (2.5mM). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) release, lipid peroxidation, glutathione, reactive oxygen species (ROS) and mitochondrial membrane potential were measured to evaluate protection associated with the three antioxidants. Knockdown of Nrf2 expression by liposome transfection with siRNA was used to confirm the role of Nrf2 activation in the protection associated with the three antioxidants.<br><br>RESULTS: Compared with AN treatment alone, pre-treatment with CUR at either concentration significantly increased cell viability and mitochondrial membrane potential, and reduced glutathione levels; lipid peroxidation and ROS production were significantly decreased as well. NAC also showed significant efficacy in attenuating AN-induced toxicity at higher concentration. However, pre-treatment with Trolox failed to ameliorate the AN-induced toxicity. When post-treatment with Trolox, this antioxidant led to significant protective effects at both concentrations, while CUR and NAC were efficacious only at the higher concentrations. Knockdown of Nrf2 only abolished the protective effects of CUR pre-treatment on AN-induced cytotoxicity, while the protective effects of NAC and Trolox pre-treatment groups showed no differences between the Nrf2-knockdown and non-knockdown treatments.<br><br>CONCLUSIONS: The selected antioxidants exert differential cellular protection when administered prior or subsequent to AN-induced cytotoxic events in decreasing cellular viability, antioxidative capacity and mitochondrial function, enhanced cytotoxicity and ROS production. These results suggest that antioxidants should be carefully chosen for their efficacy in preventing or diminishing oxidative damage caused by AN. The differential effect of pre- and post-treatment may be attributed to activation of the Nrf2 signaling pathway.}, }
@article {pmid26408630, year = {2015}, author = {Wang, N and Wei, RB and Li, QP and Yang, X and Li, P and Huang, MJ and Wang, R and Cai, GY and Chen, XM}, title = {Renal Protective Effect of Probucol in Rats with Contrast-Induced Nephropathy and its Underlying Mechanism.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {21}, number = {}, pages = {2886-2892}, pmid = {26408630}, issn = {1643-3750}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/chemistry ; Animals ; Antioxidants/chemistry ; Contrast Media/*adverse effects ; Creatinine/blood ; Deoxyguanosine/analogs &amp; derivatives/chemistry ; Disease Models, Animal ; Immunohistochemistry ; Kidney/metabolism ; Kidney Diseases/*chemically induced ; Male ; Malondialdehyde/chemistry/metabolism ; Nitrogen/urine ; Oxidative Stress ; Probucol/*chemistry ; Rats ; Rats, Wistar ; Superoxide Dismutase/chemistry ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) refers to acute renal damage that occurs after the use of contrast agents. This study investigated the renal protective effect of probucol in a rat model of contrast-induced nephropathy and the mechanism of its effect.<br><br>MATERIAL AND METHODS: Twenty-eight Wistar rats were randomly divided into the control group, model group, N-acetylcysteine(NAC) group, and probucol group. We used a rat model of iopromide-induced CIN. One day prior to modeling, the rats received gavage. At 24 h after the modeling, blood biochemistry and urine protein were assessed. Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in renal tissue. Kidney sections were created for histopathological examination.<br><br>RESULTS: The model group of rats showed significantly elevated levels of blood creatinine, urea nitrogen, 24-h urine protein, histopathological scores, and parameters of oxidative stress (P<0.05). Both the NAC and probucol groups demonstrated significantly lower Scr, BUN, and urine protein levels compared to the model group (P<0.05), with no significant difference between these 2 groups. The NAC group and the probucol group had significantly lower MDA and higher SOD than the model group at 24 h after modeling (P<0.05). The 8-OHdG-positive tubule of the probucol group and NAC group were significantly lower than those of the model group (p=0.046, P=0.0008), with significant difference between these 2 groups (P=0.024).<br><br>CONCLUSIONS: Probucol can effectively reduce kidney damage caused by contrast agent. The underlying mechanism may be that probucol accelerates the recovery of renal function and renal pathology by reducing local renal oxidative stress.}, }
@article {pmid26407525, year = {2015}, author = {Iorio, R and Castellucci, A and Rossi, G and Cinque, B and Cifone, MG and Macchiarelli, G and Cecconi, S}, title = {Mancozeb affects mitochondrial activity, redox status and ATP production in mouse granulosa cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {30}, number = {1 Pt B}, pages = {438-445}, doi = {10.1016/j.tiv.2015.09.018}, pmid = {26407525}, issn = {1879-3177}, mesh = {Adenosine Triphosphate/*biosynthesis ; Animals ; Cells, Cultured ; DNA Damage ; Female ; Fungicides, Industrial/*toxicity ; Glutathione/metabolism ; Granulosa Cells/*drug effects/metabolism ; Maneb/*toxicity ; Mice ; Mitochondria/drug effects ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-akt/physiology ; Tumor Suppressor Protein p53/analysis ; Zineb/*toxicity ; }, abstract = {BACKGROUND: Mancozeb (MZ) is a fungicide that belongs to the subclass of metal (Mn/Zn) ethylene-bis-dithiocarbamate pesticides. In mouse and human granulosa cells (GCs) exposed to MZ (0.01 μg/ml), morphological modifications and significant alterations of p53 expression level in comparison with control GCs were recorded.<br><br>OBJECTIVES: To investigate if MZ (0.01 &#x3bc;g/ml) induces oxidative stress and alters energy metabolism in exposed mouse GCs.<br><br>RESULTS: Following fungicide exposure, GCs showed low p53 content, a depolarized mitochondrial membrane potential (&#x394;&#x3a8;m), as well as low ATP and reduced glutathione (GSH) levels associated with increased reactive oxygen species (ROS) generation. No remarkable differences on other parameters such as ATP/ADP ratio, energy charge, as well as induction of apoptosis and DNA damage were found. The activation of AKT and PDK1 kinases in MZ-treated cells was observed. Inhibition of ROS generation by the antioxidant N-acetylcysteine (NAC) restored a normal expression level of p53.<br><br>CONCLUSIONS: Our results demonstrate that the low dose of MZ here used induces a mild oxidative stress in GCs, and provides evidence for the possible involvement of AKT/PKB signaling pathway in triggering adaptive and survival response.}, }
@article {pmid26407170, year = {2015}, author = {Kaur, G and Leslie, EM and Tillman, H and Lee, WM and Swanlund, DP and Karvellas, CJ and , }, title = {Detection of Ophthalmic Acid in Serum from Acetaminophen-Induced Acute Liver Failure Patients Is More Frequent in Non-Survivors.}, journal = {PloS one}, volume = {10}, number = {9}, pages = {e0139299}, pmid = {26407170}, issn = {1932-6203}, support = {MOP-272075//Canadian Institutes of Health Research/Canada ; U-01 58369//PHS HHS/United States ; }, mesh = {Acetaminophen/*adverse effects ; Adult ; Case-Control Studies ; Demography ; Female ; Humans ; Liver Failure, Acute/*blood/*chemically induced ; Male ; Oligopeptides/*blood ; *Survivors ; }, abstract = {BACKGROUND/AIM: Acetaminophen (APAP) hepatotoxicity is related to the formation of N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). Ophthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate. Metabolomics studies of mice with APAP-induced acute liver failure (APAP-ALF) identified OA as a marker of oxidative stress and hepatic GSH consumption. The aim of the current study was to determine whether OA is detectable in APAP-ALF human patients either early (day 2) or late (day 4) and whether OA levels were associated with in-hospital survival in the absence of liver transplant.<br><br>METHODS: Serum samples from 130 APAP-ALF patients (82 survivors, 48 non-survivors) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and correlated with clinical data from the United States Acute Liver Failure Study Group (US ALFSG) Registry (2004-2011).<br><br>RESULTS: Survivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl) and lactate levels (3.3 vs. 6.5 &#x3bc;mol/l, p<0.05 for all). During the first 7 days of the study, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p< 0.001 for all). Non-survivors were more likely to have detectable OA levels early (31% vs. 15%, p = 0.034) and late (27% vs. 11%, p = 0.02). However there were no significant differences in mean OA levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for all).<br><br>CONCLUSION: OA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could replenish GSH levels and prevent OA production.}, }
@article {pmid26402075, year = {2015}, author = {Remington, R and Lortie, JJ and Hoffmann, H and Page, R and Morrell, C and Shea, TB}, title = {A Nutritional Formulation for Cognitive Performance in Mild Cognitive Impairment: A Placebo-Controlled Trial with an Open-Label Extension.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {48}, number = {3}, pages = {591-595}, doi = {10.3233/JAD-150057}, pmid = {26402075}, issn = {1875-8908}, mesh = {Aged ; Cognitive Dysfunction/*diet therapy ; Cohort Studies ; *Dietary Supplements ; Follow-Up Studies ; Humans ; Middle Aged ; Psychiatric Status Rating Scales ; Treatment Outcome ; }, abstract = {Thirty-four individuals with mild cognitive impairment were randomized for 6 months to a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or indistinguishable placebo, followed by a 6-month open-label extension in which all individuals received NF. The NF cohort improved in the Dementia Rating Scale (DRS; effect size >0.7) and maintained baseline performance in CLOX-1. The placebo cohort did not improve in DRS and declined in CLOX-1, but during the open-label extension improved in DRS and ceased declining in CLOX-1. These findings extend prior studies of NF efficacy for individuals without cognitive impairment and with Alzheimer's disease.}, }
@article {pmid26401392, year = {2015}, author = {Jaccob, AA}, title = {Protective effect of N-acetylcysteine against ethanol-induced gastric ulcer: A pharmacological assessment in mice.}, journal = {Journal of intercultural ethnopharmacology}, volume = {4}, number = {2}, pages = {90-95}, pmid = {26401392}, issn = {2146-8397}, abstract = {AIM: Since there is an increasing need for gastric ulcer therapies with optimum benefit-risk profile. This study was conducted to investigate gastro-protective effects of N-acetylcysteine (NAC) against ethanol-induced gastric ulcer models in mice.<br><br>MATERIALS AND METHODS: A total of 41 mice were allocated into six groups consisted of 7 mice each. Groups 1 (normal control) and 2 (ulcer control) received distilled water at a dose of 10 ml/kg, groups 3, 4 and 5 were given NAC at doses 100, 300 and 500 mg/kg, respectively, and the 6(th) group received ranitidine (50 mg/kg). All drugs administered orally once daily for 7 days, on the 8(th) day absolute ethanol (7 ml/kg) was administrated orally to all mice to induce the acute ulcer except normal control group. Then 3 h after, all animals were sacrificed then consequently the stomachs were excised for examination.<br><br>RESULTS: NAC administration at the tested doses showed a dose-related potent gastro-protective effect with significant increase in curative ratio, PH of gastric juice and mucus content viscosity seen with the highest dose of NAC and it is comparable with that observed in ranitidine group.<br><br>CONCLUSION: The present findings demonstrate that, oral NAC shows significant gastro-protective effects comparable to ranitidine confirmed by anti-secretory, cytoprotective, histological and biochemical data, but the molecular mechanisms behind such protection are complex.}, }
@article {pmid26394653, year = {2015}, author = {Gao, H and Sun, W and Zhao, W and Hao, W and Leung, CH and Lu, J and Chen, X}, title = {Total Tanshinones-Induced Apoptosis and Autophagy Via Reactive Oxygen Species in Lung Cancer 95D Cells.}, journal = {The American journal of Chinese medicine}, volume = {43}, number = {6}, pages = {1265-1279}, doi = {10.1142/S0192415X1550072X}, pmid = {26394653}, issn = {1793-6853}, mesh = {Abietanes/*pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/genetics/metabolism ; Autophagy/*drug effects ; Beclin-1 ; Caspase 3/genetics/metabolism ; Cell Line, Tumor ; Drugs, Chinese Herbal/*pharmacology ; Humans ; Lung Neoplasms/drug therapy/genetics/metabolism/*physiopathology ; Membrane Proteins/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Up-Regulation ; }, abstract = {Tanshinones are a group of bioactive constituents isolated from Salvia miltiorrhiza Bunge, a widely prescribed traditional Chinese herb. In the current study, the anticancer properties of total tanshinones (TDT) were evaluated using 95D lung cancer cells. Tanshinone IIA was identified as the main component of TDT. Compared with tanshinone IIA, TDT showed more cytotoxic effects on the 95D cells. Annexin V/7-AAD double staining, the depolarization of mitochondrial membrane potential (MMP) (Δψ), the up-regulation of pro-apoptotic proteins, such as cleaved-PARP, cleaved-caspase-3, Bax, and Bad, and the down-regulation of anti-apoptotic protein Bcl-2 were evidence of TDT-induced apoptosis. Furthermore, TDT-induced autophagy as demonstrated by monodansylcadaverine (MDC) staining and the up-regulation of autophagy-associated proteins, such as LC3-II, Beclin-1, Atg3, Atg5, Atg7, and Atg12. Autophagy inhibitors, 3-methyladenine (3-MA) and bafilomycin A1, enhanced TDT-induced cell death. 3-MA pretreatment enhanced the TDT-induced up-regulation of Bax and cleaved-PARP. In addition, TDT induced the generation of reactive oxygen species (ROS), which was reversed by N-acetylcysteine (NAC). NAC also reversed TDT-induced depolarization of Δψ, MDC staining, up-regulation of Bax, cleaved-PARP, Beclin-1, LC3-II, and cell viability. In conclusion, our findings showed that TDT-induced apoptosis and protective autophagy in 95D cells mediated by increasing intracellular ROS production.}, }
@article {pmid26392121, year = {2015}, author = {Pathak, S and Stern, C and Vambutas, A}, title = {N-Acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune inner ear disease patients.}, journal = {Immunologic research}, volume = {63}, number = {1-3}, pages = {236-245}, pmid = {26392121}, issn = {1559-0755}, support = {R21 DC011827/DC/NIDCD NIH HHS/United States ; R33 DC011827/DC/NIDCD NIH HHS/United States ; R21DC011827/DC/NIDCD NIH HHS/United States ; R33DC011827/DC/NIDCD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Autoimmune Diseases/*drug therapy/immunology ; Humans ; Interleukin-8/metabolism ; Labyrinth Diseases/*drug therapy/immunology ; Leukocytes, Mononuclear/*drug effects/immunology ; Molecular Targeted Therapy ; Peroxidase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Autoimmune inner ear disease (AIED) is a poorly understood disease marked by bilateral, rapidly progressive hearing loss triggered by unknown stimuli, which is corticosteroid responsive in 60 % of patients. Although the mechanism of the disease is not precisely understood, a complex interaction of cytokines is believed to contribute toward the inflammatory disease process and hearing loss. Previously, we showed the role of TNF-α in steroid-sensitive and IL-1β in steroid-resistant immune-mediated hearing loss. N-Acetylcysteine (NAC), a broad spectrum antioxidant, has been effective in other autoimmune disorders. Other studies have shown NAC to have a protective adjunct role in human idiopathic sudden hearing loss, where the addition of NAC resulted in better hearing recovery than with steroids alone, although the mechanism of this protection was not elucidated. In the present study, we observed PBMCs from AIED patients exhibited higher baseline TNF-α and MPO levels compared with normal healthy controls. NAC effectively abrogates LPS-mediated TNF-α release from PBMC of both AIED patients and controls. We demonstrated that in AIED patients, the TNF-α downstream signaling pathway appears aberrantly regulated, influencing both MPO and IL-8 expression. Given that NAC effectively abrogated LPS-mediated TNF-α release and exerted minimal effects on the downstream targets of this pathway, we feel NAC may be a rational adjunct therapy for this enigmatic disease, worthy of clinical exploration.}, }
@article {pmid26389000, year = {2015}, author = {Bishayee, K and Mondal, J and Sikdar, S and Khuda-Bukhsh, AR}, title = {Condurango (Gonolobus condurango) Extract Activates Fas Receptor and Depolarizes Mitochondrial Membrane Potential to Induce ROS-dependent Apoptosis in Cancer Cells in vitro: CE-treatment on HeLa: a ROS-dependent mechanism.}, journal = {Journal of pharmacopuncture}, volume = {18}, number = {3}, pages = {32-41}, pmid = {26389000}, issn = {2093-6966}, abstract = {OBJECTIVES: Condurango (Gonolobus condurango) extract is used by complementary and alternative medicine (CAM) practitioners as a traditional medicine, including homeopathy, mainly for the treatment of syphilis. Condurango bark extract is also known to reduce tumor volume, but the underlying molecular mechanisms still remain unclear.<br><br>METHODS: Using a cervical cancer cell line (HeLa) as our model, the molecular events behind condurango extract's (CE's) anticancer effect were investigated by using flow cytometry, immunoblotting and reverse transcriptase-polymerase chain reaction (RT-PCR). Other included cell types were prostate cancer cells (PC3), transformed liver cells (WRL-68), and peripheral blood mononuclear cells (PBMCs).<br><br>RESULTS: Condurango extract (CE) was found to be cytotoxic against target cells, and this was significantly deactivated in the presence of N-acetyl cysteine (NAC), a scavenger of reactive oxygen species (ROS), suggesting that its action could be mediated through ROS generation. CE caused an increase in the HeLa cell population containing deoxyribonucleic acid (DNA) damage at the G zero/Growth 1 (G0/G1) stage. Further, CE increased the tumor necrosis factor alpha (TNF-&#x3b1;) and the fas receptor (FasR) levels both at the ribonucleic acid (RNA) and the protein levels, indicating that CE might have a cytotoxic mechanism of action. CE also triggered a sharp decrease in the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-&#x3ba;B) both at the RNA and the protein levels, a possible route to attenuation of B-cell lymphoma 2 (Bcl-2), and caused an opening of the mitochondrial membrane's permeability transition (MPT) pores, thus enhancing caspase activities.<br><br>CONCLUSION: Overall, our results suggest possible pathways for CE mediated cytotoxicity in model cancer cells.}, }
@article {pmid26388990, year = {2015}, author = {Alhadlaq, HA and Akhtar, MJ and Ahamed, M}, title = {Zinc ferrite nanoparticle-induced cytotoxicity and oxidative stress in different human cells.}, journal = {Cell &amp; bioscience}, volume = {5}, number = {}, pages = {55}, pmid = {26388990}, issn = {2045-3701}, abstract = {BACKGROUND: Zinc ferrite nanoparticles (NPs) have shown potential to be used in biomedical field such as magnetic resonance imaging and hyperthermia. However, there is limited information concerning the biological response of zinc ferrite NPs. This study was designed to evaluate the cytotoxicity of zinc ferrite NPs in three widely used in vitro cell culture models: human lung epithelial (A549), skin epithelial (A431) and liver (HepG2) cells. Zinc ferrite NPs were characterized by electron microscopy and dynamic light scattering. Cell viability, cell membrane damage, reactive oxygen species (ROS), glutathione (GSH), mitochondrial membrane potential (MMP), transcriptional level of apoptotic genes were determined in zinc ferrite NPs exposed cells.<br><br>RESULTS: Zinc ferrite NPs were almost spherical shaped with an average size of 44&#xa0;nm. Zinc ferrite NPs induced dose-dependent cytotoxicity (MTT and LDH) and oxidative stress (ROS and GSH) in all three types of cells in the dosage range of 10-40&#xa0;&#xb5;g/ml. Transcriptional level of tumor suppressor gene p53 and apoptotic genes (bax, caspase-3 and caspase-9) were up-regulated while the anti-apoptotic gene bcl-2 was down-regulated in cells after zinc ferrite NPs exposure. Furthermore, higher activity of caspase-3 and caspase-9 enzymes was also observed in zinc ferrite NPs treated cells. ROS generation, MMP loss and cell death in all three types of cells were abrogated by N-acetyl cysteine (ROS scavenger), which suggests that oxidative stress might be one of the plausible mechanisms of zinc ferrite NPs cytotoxicity. It is worth mentioning that there was marginally difference in the sensitivity of three cell lines against zinc ferrite NPs exposure. Cytotoxicity of zinc ferrite NPs were in following order; A549&#xa0;>&#xa0;HepG2&#xa0;>&#xa0;A431.<br><br>CONCLUSION: Altogether, zinc ferrite NPs induced cytotoxicity and oxidative stress in A549, A431 and HepG2 cells, which is likely to be mediated through ROS generation. This study warrants further investigation to explore the potential mechanisms of toxicity of zinc ferrite NPs in normal cells as well as in animal models.}, }
@article {pmid26387535, year = {2015}, author = {Wang, L and Zhang, Y and Li, X and Xie, Y and He, J and Yu, J and Song, Y}, title = {The MIL-88A-Derived Fe3O4-Carbon Hierarchical Nanocomposites for Electrochemical Sensing.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {14341}, pmid = {26387535}, issn = {2045-2322}, abstract = {Metal or metal oxides/carbon nanocomposites with hierarchical superstructures have become one of the most promising functional materials in sensor, catalysis, energy conversion, etc. In this work, novel hierarchical Fe3O4/carbon superstructures have been fabricated based on metal-organic frameworks (MOFs)-derived method. Three kinds of Fe-MOFs (MIL-88A) with different morphologies were prepared beforehand as templates, and then pyrolyzed to fabricate the corresponding novel hierarchical Fe3O4/carbon superstructures. The systematic studies on the thermal decomposition process of the three kinds of MIL-88A and the effect of template morphology on the products were carried out in detail. Scanning electron microscopy, transmission electron microscopy, X-ray powder diffraction, X-ray photoelectron spectroscopy and thermal analysis were employed to investigate the hierarchical Fe3O4/carbon superstructures. Based on these resulted hierarchical Fe3O4/carbon superstructures, a novel and sensitive nonenzymatic N-acetyl cysteine sensor was developed. The porous and hierarchical superstructures and large surface area of the as-formed Fe3O4/carbon superstructures eventually contributed to the good electrocatalytic activity of the prepared sensor towards the oxidation of N-acetyl cysteine. The proposed preparation method of the hierarchical Fe3O4/carbon superstructures is simple, efficient, cheap and easy to mass production. It might open up a new way for hierarchical superstructures preparation.}, }
@article {pmid26386189, year = {2015}, author = {Lai, FN and Ma, JY and Liu, JC and Wang, JJ and Cheng, SF and Sun, XF and Li, L and Li, B and Nyachoti, CM and Shen, W}, title = {The influence of N-acetyl-l-cysteine on damage of porcine oocyte exposed to zearalenone in vitro.}, journal = {Toxicology and applied pharmacology}, volume = {289}, number = {2}, pages = {341-348}, doi = {10.1016/j.taap.2015.09.010}, pmid = {26386189}, issn = {1096-0333}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; C-Reactive Protein/genetics/metabolism ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Cells, Cultured ; Connexin 43/genetics/metabolism ; Cytoprotection ; Female ; Gene Expression Regulation, Developmental ; Glucuronosyltransferase/genetics/metabolism ; Glutathione/metabolism ; In Vitro Oocyte Maturation Techniques ; Meiosis/*drug effects ; Mitochondria/drug effects/metabolism ; Oocytes/*drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Serum Amyloid P-Component/genetics/metabolism ; Swine ; Zearalenone/*toxicity ; }, abstract = {Zearalenone (ZEA), one of the mycotoxins produced by Fusarium fungi, impacts porcine reproduction by interfering with the estrogen signaling pathway. Previous studies have shown that ZEA inhibits porcine oocyte maturation through the formation of aberrant spindle. To explore the effect of ZEA on porcine oocyte meiotic maturation, the extent of both nuclear and cytoplasmic maturation was examined in this study. Compared with control group, presence of ZEA (3 μM) during oocyte maturation, significantly inhibited the polar body extrusions from 71% to 51%, and significantly increased intracellular reactive oxygen species (ROS) level (12.01 vs. 5.89). Intracellular glutathione (GSH) content in ZEA treatment group was lower than in the control group (1.08 pmol/oocyte vs. 0.18 pmol/oocyte), and cortical granules of cortical area distributed oocytes were reduced (88% vs. 62%). ZEA decreases cumulus expansion in both morphology and mRNA level (HAS2, PTX3, TNFAIP6 and CX43). Addition of N-acetyl-l-cysteine (NAC) to the oocyte maturation media reversed the ZEA-induced inhibition of polar body extrusion (from 69% to 81%), up-regulated ROS (from 7.9 to 6.5), down-regulated GSH content (from 0.16 to 0.82 pmol/oocyte) and recovered cumulus cells expansion in morphology and mRNA level. It is concluded that ZEA affects both oocyte nucleus and cytoplasmic maturation during in vitro maturation, and NAC can reverse these damages to some extent.}, }
@article {pmid26382946, year = {2015}, author = {Yao, N and Li, YJ and Zhang, DM and Liu, DL and Tang, MK and Yiu, A and Li, Y and Chen, WM and Lan, P and Yao, Z and Chen, ZS and Ye, WC}, title = {B4G2 induces mitochondrial apoptosis by the ROS-mediated opening of Ca(2+)-dependent permeability transition pores.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {37}, number = {3}, pages = {838-852}, doi = {10.1159/000430212}, pmid = {26382946}, issn = {1421-9778}, mesh = {Apoptosis/drug effects ; Calcium/*metabolism ; Carcinoma, Hepatocellular/*metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondrial Membrane Transport Proteins/*metabolism ; Mitochondrial Permeability Transition Pore ; Reactive Oxygen Species/metabolism ; Triterpenes/*pharmacology ; }, abstract = {BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. At present, only sorafenib is approved to treat HCC. In this study, we found that a 23-hydroxybetulinic acid derivative, B4G2, exhibited potent antiproliferative activity in HCC cell lines.<br><br>METHODS: We used four HCC cell lines (HepG2, HepG2/ADM, Hep3B and Bel-7402) to evaluate the anti-tumour activity and explore underlying mechanisms by which B4G2 induces apoptosis.<br><br>RESULTS: Among these cell lines, HepG2 showed the highest sensitivity to B4G2. HepG2 cells treated with B4G2 showed a depolarized mitochondrial membrane potential, released cytochrome c, activated caspase-9 and caspase-3 and cleaved poly ADP-ribose polymerase (PARP). However, Z-VAD-FMK, a pan-caspase inhibitor, did not attenuate B4G2-induced apoptosis, implying that the induction of mitochondrial apoptosis by B4G2 may be independent of caspases. Moreover, pre-treatment with MgCl2, a blocker of Ca2+-dependent permeability transition (PT) pores, attenuated the depolarization of the mitochondrial potential and decreased the population of apoptotic cells, indicating that B4G2-induced apoptosis was partly dependent on the opening of the Ca2+-dependent PT pores. B4G2 also increased the levels of intracellular calcium and reactive oxygen species (ROS). Furthermore, an ROS scavenger, N-acetyl-cysteine (NAC), markedly decreased the accumulation of intracellular calcium and apoptosis.<br><br>CONCLUSION: This is the first demonstration that B4G2 inhibits the growth of HCC cells and induces mitochondrial apoptosis in hepatocellular carcinoma cells by the ROS-mediated opening of Ca2+-dependent permeability transition pores.}, }
@article {pmid26374743, year = {2015}, author = {Sarris, J and Oliver, G and Camfield, DA and Dean, OM and Dowling, N and Smith, DJ and Murphy, J and Menon, R and Berk, M and Blair-West, S and Ng, CH}, title = {N-Acetyl Cysteine (NAC) in the Treatment of Obsessive-Compulsive Disorder: A 16-Week, Double-Blind, Randomised, Placebo-Controlled Study.}, journal = {CNS drugs}, volume = {29}, number = {9}, pages = {801-809}, pmid = {26374743}, issn = {1179-1934}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Analysis of Variance ; Double-Blind Method ; Female ; Follow-Up Studies ; Free Radical Scavengers ; Humans ; Male ; Middle Aged ; Obsessive-Compulsive Disorder/*drug therapy ; Psychiatric Status Rating Scales ; Retrospective Studies ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: Obsessive-compulsive disorder (OCD) is a disabling mental illness for which pharmacological and psychosocial interventions are all too often inadequate. Recent preclinical and clinical studies have implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of OCD. The amino acid-based nutraceutical N-acetyl cysteine (NAC) is a safe and readily available agent that has been found to modify the synaptic release of glutamate in subcortical brain regions via modulation of the cysteine-glutamate antiporter.<br><br>OBJECTIVE: The aim of this study was to assess the efficacy and safety of NAC in treating OCD.<br><br>METHODS: A 16-week, double-blind, placebo-controlled, randomised trial using 3 g/day of NAC (1.5 g twice daily) in 44 participants (aged 18-70 years) with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)-diagnosed OCD, during 2013-2015. The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (YBOCS), conducted every 4 weeks.<br><br>RESULTS: Analysis of the full sample (intention-to-treat) with repeated measures mixed linear modelling revealed a nonsignificant time &#xd7; treatment interaction for the YBOCS scale total score (p = 0.39). A per-protocol analysis removing protocol violators also failed to show a significant time &#xd7; treatment interaction for YBOCS total score (p = 0.15). However, a significant time &#xd7; treatment interaction was observed for the YBOCS 'Compulsions' subscale in favour of NAC (p = 0.013), with a significant reduction observed at week 12 (dissipating at week 16). At 16 weeks, only four (20%) participants were considered 'responders' (YBOCS &#x2265;35% reduction at endpoint) versus four (27%) in the placebo group. The NAC was well-tolerated, aside from more cases of heartburn occurring compared with placebo (p = 0.045).<br><br>CONCLUSION: Further research involving NAC for OCD may require larger samples to detect moderate or small effect sizes, involve dosage or formulation differences, use in concert with exposure therapy, or an additional post-study observational period to mitigate study withdrawal.<br><br>TRIAL REGISTRATION: ACTRN12613000310763.}, }
@article {pmid26370073, year = {2016}, author = {Hung, JH and Chen, CY and Omar, HA and Huang, KY and Tsao, CC and Chiu, CC and Chen, YL and Chen, PH and Teng, YN}, title = {Reactive oxygen species mediate Terbufos-induced apoptosis in mouse testicular cell lines via the modulation of cell cycle and pro-apoptotic proteins.}, journal = {Environmental toxicology}, volume = {31}, number = {12}, pages = {1888-1898}, doi = {10.1002/tox.22190}, pmid = {26370073}, issn = {1522-7278}, mesh = {Animals ; Antinematodal Agents/*toxicity ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/*metabolism ; Cell Cycle/drug effects ; Cell Division/drug effects ; Cell Line ; Insecticides/*toxicity ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Organothiophosphorus Compounds/*toxicity ; Reactive Oxygen Species/*metabolism ; Testis/cytology/*drug effects/metabolism ; }, abstract = {Terbufos (S-t-butylthiomethyl-O,O-diethyl phosphorodithioate) is a highly toxic organophosphate which is extensively used as an insecticide and nematicide. Chronic exposure to terbufos causes neuronal injury and predisposes to neurodegenerative diseases. Accumulating evidence has shown that the exposure to terbufos, as an occupational risk factor, may also cause reproductive disorders. However, the exact mechanisms of reproductive toxicity remain unclear. The present study aimed to investigate the toxic effect of terbufos on testicular cells and to explore the mechanism of toxicity on a cellular level. The cytotoxic effects of terbufos on mouse immortalized spermatogonia (GC-1), spermatocytes (GC-2), Leydig (TM3), and Sertoli (TM4) cell lines were assessed by MTT assays, caspase activation, flow cytometry, TUNEL assay, Western blot, and cell cycle analysis. The exposure to different concentrations of terbufos ranging from 50 to 800 μM for 6 h caused significant death in all the used testicular cell lines. Terbufos increased reactive oxygen species (ROS) production, reduced mitochondrial membrane potential, and initiated apoptosis, which was confirmed by a dose-dependent increase in the number of TUNEL-positive apoptotic cells. Blocking ROS production by N-acetyl cysteine (NAC) protected GC-1 cells from terbufos-induced cell death. The results demonstrated that terbufos induces ROS, apoptosis, and DNA damage in testicular cell lines and it should be considered potentially hazardous to testis. Together, this study provided potential molecular mechanisms of terbufos-induced toxicity in testicular cells and suggests a possible protective measure. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1888-1898, 2016.}, }
@article {pmid26370061, year = {2016}, author = {Shema-Didi, L and Kristal, B and Eizenberg, S and Marzuq, N and Sussan, M and Feldman-Idov, Y and Ofir, P and Atar, S}, title = {Prevention of contrast-induced nephropathy with single bolus erythropoietin in patients with diabetic kidney disease: A randomized controlled trial.}, journal = {Nephrology (Carlton, Vic.)}, volume = {21}, number = {4}, pages = {295-300}, doi = {10.1111/nep.12609}, pmid = {26370061}, issn = {1440-1797}, mesh = {Acetylcysteine/administration &amp; dosage ; Acute Kidney Injury/chemically induced/diagnosis/*prevention &amp; control ; Aged ; Aged, 80 and over ; Biomarkers/blood/urine ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Cystatin C/blood ; Cytoprotection ; Diabetic Nephropathies/complications/diagnosis/*drug therapy ; Double-Blind Method ; Drug Administration Schedule ; Erythropoietin/*administration &amp; dosage ; Female ; Humans ; Infusions, Intravenous ; Iohexol/adverse effects/*analogs &amp; derivatives ; Israel ; Lipocalin-2/urine ; Male ; Middle Aged ; Prospective Studies ; Protective Agents/*administration &amp; dosage ; Recombinant Proteins/administration &amp; dosage ; Renal Insufficiency, Chronic/complications/diagnosis/*drug therapy ; Risk Factors ; Time Factors ; Treatment Outcome ; Triiodobenzoic Acids/*adverse effects ; }, abstract = {AIM: Contrast-induced-nephropathy (CIN) is associated with poor outcomes, thus prevention of CIN may be of clinical value. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in experimental models and in clinical studies of acute kidney injury. We therefore evaluated its effectiveness for prevention of CIN after coronary angiography (CA) ± percutaneous coronary intervention (PCI) in diabetic patients with chronic kidney disease.<br><br>METHODS: A prospective, randomized, controlled trial was carried out in 138 diabetic patients with eGFR <60 mL/min who underwent non-urgent CA &#xb1; PCI. Patients received normal saline and n-acetyl cysteine before CA, with or without 50,000&#x2009;U of EPO administered 30 min prior to CA. CIN was defined as an increase in serum creatinine of at least 0.5 mg/dL during the first 2 days after exposure to contrast media. Primary outcome was the incidence of CIN. Secondary outcomes were the sensitivity and positive predictive value (PPV) of Cystatin C (CC) and Neutrophil-gelatinase-associated-lipocalin (NGAL) for diagnosis of CIN.<br><br>RESULTS: The observed incidence of CIN was 8.7%, significantly lower than the expected for such high-risk population. The administration of EPO prior to CA did not reduce the incidence of CIN (9.7% vs. 7.6%, P = 0.65). CC and NGAL demonstrated a low sensitivity (16.6%) and low PPV (6.7 and 33.3%, respectively) for detecting CIN.<br><br>CONCLUSION: The administration of EPO prior to CA did not reduce the incidence of CIN. Additional prospective research with a larger sample size and in other patient categories is essential to further define the potential protective effect of EPO on prevention of CIN.}, }
@article {pmid26366134, year = {2015}, author = {Perl, A and Hanczko, R and Lai, ZW and Oaks, Z and Kelly, R and Borsuk, R and Asara, JM and Phillips, PE}, title = {Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycin.}, journal = {Metabolomics : Official journal of the Metabolomic Society}, volume = {11}, number = {5}, pages = {1157-1174}, pmid = {26366134}, issn = {1573-3882}, support = {R01 DK078922/DK/NIDDK NIH HHS/United States ; R01 AI122176/AI/NIAID NIH HHS/United States ; U01 AR076092/AR/NIAMS NIH HHS/United States ; P30 CA006516/CA/NCI NIH HHS/United States ; P01 CA120964/CA/NCI NIH HHS/United States ; R01 AT004332/AT/NCCIH NIH HHS/United States ; R01 AI048079/AI/NIAID NIH HHS/United States ; R21 AI061066/AI/NIAID NIH HHS/United States ; R01 AI072648/AI/NIAID NIH HHS/United States ; }, abstract = {Systemic lupus erythematosus (SLE) patients exhibit depletion of the intracellular antioxidant glutathione and downstream activation of the metabolic sensor, mechanistic target of rapamycin (mTOR). Since reversal of glutathione depletion by the amino acid precursor, N-acetylcysteine (NAC), is therapeutic in SLE, its mechanism of impact on the metabolome was examined within the context of a double-blind placebo-controlled trial. Quantitative metabolome profiling of peripheral blood lymphocytes (PBL) was performed in 36 SLE patients and 42 healthy controls matched for age, gender, and ethnicity of patients using mass spectrometry that covers all major metabolic pathways. mTOR activity was assessed by western blot and flow cytometry. Metabolome changes in lupus PBL affected 27 of 80 KEGG pathways at FDR p < 0.05 with most prominent impact on the pentose phosphate pathway (PPP). While cysteine was depleted, cystine, kynurenine, cytosine, and dCTP were the most increased metabolites. Area under the receiver operating characteristic curve (AUC) logistic regression approach identified kynurenine (AUC = 0.859), dCTP (AUC = 0.762), and methionine sulfoxide (AUC = 0.708), as top predictors of SLE. Kynurenine was the top predictor of NAC effect in SLE (AUC = 0.851). NAC treatment significantly reduced kynurenine levels relative to placebo in vivo (raw p = 2.8 × 10[-7], FDR corrected p = 6.6 × 10[-5]). Kynurenine stimulated mTOR activity in healthy control PBL in vitro. Metabolome changes in lupus PBL reveal a dominant impact on the PPP that reflect greater demand for nucleotides and oxidative stress. The PPP-connected and NAC-responsive accumulation of kynurenine and its stimulation of mTOR are identified as novel metabolic checkpoints in lupus pathogenesis.}, }
@article {pmid26364141, year = {2015}, author = {Wei, M and Li, Z and Xiao, L and Yang, Z}, title = {Effects of ROS-relative NF-κB signaling on high glucose-induced TLR4 and MCP-1 expression in podocyte injury.}, journal = {Molecular immunology}, volume = {68}, number = {2 Pt A}, pages = {261-271}, doi = {10.1016/j.molimm.2015.09.002}, pmid = {26364141}, issn = {1872-9142}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line, Transformed ; Chemokine CCL2/genetics/*immunology ; Gene Expression Regulation ; Glucose/*toxicity ; Inflammation ; Mice ; NF-kappa B/antagonists &amp; inhibitors/genetics/*immunology ; Podocytes/*drug effects/immunology/pathology ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/*metabolism ; Signal Transduction ; Thiocarbamates/pharmacology ; Toll-Like Receptor 4/genetics/*immunology ; }, abstract = {High glucose (HG) induced inflammation is central to progression in diabetic nephropathy (DN). Recent studies have suggested that nuclear factor-kappa B (NF-κB) signaling activation is associated with DN, and podocyte damage may be involved in orchestrating these effects. Therefore, the aim of this study was to investigate the effects of NF-κB signaling on podocytes under HG conditions. The effects of HG and NF-κB signaling on podocytes were assessed by CCK-8 assay, cellular NF-κB translocation assay, measurement of reactive oxygen species (ROS) and Western blot analysis. We found that HG reduced cell viability, activated NF-κB signaling and up-regulated toll-like receptor 4 (TLR4) and monocyte chemoattractant protein-1 (MCP-1). In these cells, NF-κB inhibition with ammonium pyrrolidinethiocarbamate (PDTC) resulted in effectively constraining TLR4 and MCP-1 up-regulation, indicating that protective effects associated with the inhibition of NF-κB were linked to TLR4 and MCP-1 down-regulation in podocytes. Furthermore, HG significantly increased the production of intracellular ROS. Pretreatment with N-acetyl-l-cysteine (NAC) significantly inhibited intracellular ROS generation and increased cell viability, accompanied by a significant NF-κB inhibition and suppression of TLR4 and inflammatory cytokine MCP-1 expression. Collectively, our novel data suggest that HG induces the over-experssion of TLR-4 and MCP-1 through a NF-κB-dependent signaling. NF-κB-mediated increased inflammation is possibly via ROS and contributes to the cell injury. These results may provide potential therapeutic target for diabetic nephropathy in the future.}, }
@article {pmid26362762, year = {2015}, author = {McCarty, MF and DiNicolantonio, JJ}, title = {An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly.}, journal = {Age (Dordrecht, Netherlands)}, volume = {37}, number = {5}, pages = {96}, pmid = {26362762}, issn = {1574-4647}, mesh = {Aged ; Aging/*metabolism ; Cysteine/*pharmacology ; Diet, Protein-Restricted/*adverse effects ; Dietary Supplements ; Global Health ; Glutathione/*biosynthesis/drug effects ; Humans ; *Nutrition Surveys ; Risk Factors ; Survival Rate/trends ; }, abstract = {Restricted dietary intakes of protein or essential amino acids tend to slow aging and boost lifespan in rodents, presumably because they downregulate IGF-I/Akt/mTORC1 signaling that acts as a pacesetter for aging and promotes cancer induction. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) III cohort has revealed that relatively low protein intakes in mid-life (under 10 % of calories) are indeed associated with decreased subsequent risk for mortality. However, in those over 65 at baseline, such low protein intakes were associated with increased risk for mortality. This finding accords well with other epidemiology correlating relatively high protein intakes with lower risk for loss of lean mass and bone density in the elderly. Increased efficiency of protein translation reflecting increased leucine intake and consequent greater mTORC1 activity may play a role in this effect; however, at present there is little solid evidence that leucine supplementation provides important long-term benefits to the elderly. Aside from its potential pro-anabolic impact, higher dietary protein intakes may protect the elderly in another way-by providing increased amino acid substrate for synthesis of key protective factors. There is growing evidence, in both rodents and humans, that glutathione synthesis declines with increasing age, likely reflecting diminished function of Nrf2-dependent inductive mechanisms that boost expression of glutamate cysteine ligase (GCL), rate-limiting for glutathione synthesis. Intracellular glutathione blunts the negative impact of reactive oxygen species (ROS) on cell health and functions both by acting as an oxidant scavenger and by opposing the pro-inflammatory influence of hydrogen peroxide on cell signaling. Fortunately, since GCL's K m for cysteine is close to intracellular cysteine levels, increased intakes of cysteine-achieved from whole proteins or via supplementation with N-acetylcysteine (NAC)-can achieve a compensatory increase in glutathione synthesis, such that more youthful tissue levels of this compound can be restored. Supplementation with phase 2 inducers-such as lipoic acid-can likewise increase glutathione levels by promoting increased GCL expression. In aging humans and/or rodents, NAC supplementation has exerted favorable effects on vascular health, muscle strength, bone density, cell-mediated immunity, markers of systemic inflammation, preservation of cognitive function, progression of neurodegeneration, and the clinical course of influenza-effects which could be expected to lessen mortality and stave off frailty. Hence, greater cysteine availability may explain much of the favorable impact of higher protein intakes on mortality and frailty risk in the elderly, and joint supplementation with NAC and lipoic acid could be notably protective in the elderly, particularly in those who follow plant-based diets relatively low in protein. It is less clear whether the lower arginine intake associated with low-protein diets has an adverse impact on vascular health.}, }
@article {pmid26361990, year = {2016}, author = {Balszuweit, F and Menacher, G and Schmidt, A and Kehe, K and Popp, T and Worek, F and Thiermann, H and Steinritz, D}, title = {Protective effects of the thiol compounds GSH and NAC against sulfur mustard toxicity in a human keratinocyte cell line.}, journal = {Toxicology letters}, volume = {244}, number = {}, pages = {35-43}, doi = {10.1016/j.toxlet.2015.09.002}, pmid = {26361990}, issn = {1879-3169}, mesh = {Acetylcysteine/*pharmacology ; Antidotes/*pharmacology ; Apoptosis/drug effects ; Cell Line ; Chemical Warfare Agents/*toxicity ; Cytoprotection ; Dose-Response Relationship, Drug ; Glutathione/*pharmacology ; Humans ; Inflammation Mediators/metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Keratinocytes/*drug effects/metabolism/pathology ; Mustard Gas/*toxicity ; Necrosis ; Sulfhydryl Compounds/*pharmacology ; Time Factors ; }, abstract = {Sulfur mustard (SM) is a chemical warfare agent causing blistering, inflammation and ulceration of the skin. Thiol compounds such as glutathione (GSH) and N-acetylcysteine (NAC) have been suggested as potential antidotes. We investigated SM toxicity in a human keratinocyte cell line (HaCaT) and used GSH and NAC to counteract its cytotoxic effects. Cells were treated with 1, 5 or 10mM GSH or NAC and exposed to 30, 100 or 300μM SM. Different treatment regimens were applied to model extra- and intra-cellular GSH/NAC effects on SM toxicity. Necrosis, apoptosis and interleukin-6 and -8 levels were determined 24h post-exposure. Necrosis and apoptosis increased with SM dose. Interleukin-6 and -8 production peaked at 100μM and decreased at 300μM probably due to reduced ability for interleukin biosynthesis. Intracellular GSH/NAC diminished necrosis induced by 100μM SM. Extracellular GSH/NAC protected against necrosis and apoptosis induced by 100 and 300μM SM. Interleukin-6 and -8 production, induced by 100μM SM was reduced by GSH/NAC. However, low-dose GSH/NAC treatment of cells exposed to 300μM SM led to increased interleukin production. Thus, moderately poisoned cells are mostly responsible for SM-induced secretion of pro-inflammatory cytokines. GSH and NAC treatment can reduce SM-induced toxic effects. Protective effects were more pronounced by extracellular GSH or NAC administration. Rescue of severely poisoned cells may result in a strong secretion of pro- inflammatory cytokines. In summary, thiol compounds such as GSH or NAC constitute a promising approach to improve the therapy for SM injury. Additional intervention to prevent adverse effects of interleukin production might be beneficial.}, }
@article {pmid26354371, year = {2015}, author = {Ochi, M and Tanaka, Y and Toyoda, H}, title = {Protective effect of N-acetylcysteine against nicardipine hydrochloride-induced autophagic cell death of human vascular endothelial cells.}, journal = {The Journal of toxicological sciences}, volume = {40}, number = {5}, pages = {551-558}, doi = {10.2131/jts.40.551}, pmid = {26354371}, issn = {1880-3989}, mesh = {Acetylcysteine/*pharmacology ; Autophagy/*drug effects ; Cells, Cultured ; Endothelial Cells/*drug effects/*physiology/ultrastructure ; Humans ; Nicardipine/*antagonists &amp; inhibitors/*pharmacology ; }, abstract = {Nicardipine hydrochloride (NIC) injection has been widely used for emergency treatment of abnormally high blood pressure. However, NIC injection often causes severe peripheral vascular injury. The purpose of the present study was to reduce the NIC-induced cell injury in human vascular endothelial cells by use of clinical agents. The mechanism of NIC-induced cell injury was evaluated by time-lapse microscopic imaging, autophagosome staining with monodansylcadaverine, immunostaining of light chain 3 isoform B (LC-3B) and assessment of cell viability after exposure to NIC with or without an inhibitor of autophagosome formation (3-methyladenine, 3-MA). Results from autophagosome labeling and immunostaining of LC-3B revealed an increase of autophagosomes and LC-3B in NIC-treated cells. NIC-mediated reduction of cell viability was inhibited by 3-methyladenine. Moreover, we found that N-acetylcysteine (NAC) reduced NIC-induced cell injury in human vascular endothelial cells. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy with NAC could contribute to the reduction of NIC-induced vascular injury.}, }
@article {pmid26352668, year = {2015}, author = {Schiller, PW and Nguyen, TM and Saray, A and Poon, AW and Laferrière, A and Coderre, TJ}, title = {The bifunctional μ opioid agonist/antioxidant [Dmt(1)]DALDA is a superior analgesic in an animal model of complex regional pain syndrome-type i.}, journal = {ACS chemical neuroscience}, volume = {6}, number = {11}, pages = {1789-1793}, pmid = {26352668}, issn = {1948-7193}, support = {MOP-119279//Canadian Institutes of Health Research/Canada ; R01 DA004443/DA/NIDA NIH HHS/United States ; MOP-89716//Canadian Institutes of Health Research/Canada ; R37 DA004443/DA/NIDA NIH HHS/United States ; DA004443/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Analgesics, Opioid/chemistry/*pharmacology ; Animals ; Antioxidants/chemistry/*pharmacology ; Area Under Curve ; Chronic Pain/drug therapy/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drug Synergism ; Hot Temperature ; Hyperalgesia/drug therapy/metabolism ; Male ; Morphine/pharmacology ; Oligopeptides/chemistry/*pharmacology ; Rats, Long-Evans ; Receptors, Opioid, mu/*agonists/metabolism ; Reflex Sympathetic Dystrophy/*drug therapy/metabolism ; Touch ; }, abstract = {Reactive oxygen species (ROS) play an important role in the development of complex regional pain syndrome-Type I (CRPS-I), as also demonstrated with the chronic post ischemia pain (CPIP) animal model of CRPS-I. We show that morphine and the antioxidant N-acetylcysteine (NAC) act synergistically to reduce mechanical allodynia in CPIP rats. The tetrapeptide amide [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) is a potent and selective μ opioid receptor (MOR) agonist with favorable pharmacokinetic properties and with antioxidant activity due to its N-terminal Dmt (2',6'-dimethyltyrosine) residue. In the CPIP model, [Dmt(1)]DALDA was 15-fold more potent than morphine in reversing mechanical allodynia and 4.5-fold more potent as analgesic in the heat algesia test. The results indicate that bifunctional compounds with MOR agonist/antioxidant activity have therapeutic potential for the treatment of CRPS-I.}, }
@article {pmid26351772, year = {2015}, author = {Hattori, N and Yamada, S and Torii, K and Takeda, S and Nakamura, K and Tanaka, H and Kajiyama, H and Kanda, M and Fujii, T and Nakayama, G and Sugimoto, H and Koike, M and Nomoto, S and Fujiwara, M and Mizuno, M and Hori, M and Kodera, Y}, title = {Effectiveness of plasma treatment on pancreatic cancer cells.}, journal = {International journal of oncology}, volume = {47}, number = {5}, pages = {1655-1662}, pmid = {26351772}, issn = {1791-2423}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Nucleus/*drug effects/metabolism ; Cell Proliferation/drug effects ; Humans ; Mice ; Pancreatic Neoplasms/pathology/*therapy ; Plasma Gases/*administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Non-equilibrium atmospheric pressure plasma (NEAPP) has attracted attention in cancer therapy. We explored the indirect effect of NEAPP through plasma-activated medium (PAM) on pancreatic cancer cells in vitro and in vivo. In this study, four pancreatic cancer cell lines were used and the antitumor effects of PAM treatment were evaluated using a cell proliferation assay. To explore functional mechanisms, morphological change and caspase-3/7 activation in cells were also assessed. Furthermore, reactive oxygen species (ROS) generation in cells was examined and N-acetyl cysteine (NAC), an intracellular ROS scavenger, was tested. Finally, the antitumor effect of local injection of PAM was investigated in a mouse xenograft model. We found that PAM treatment had lethal effect on pancreatic cancer cells. Typical morphological findings suggestive of apoptosis such as vacuolization of cell membranes, small and round cells and aggregation of cell nuclei, were observed in the PAM treated cells. Caspase-3/7 activation was detected in accordance with the observed morphological changes. Additionally, ROS uptake was observed in all cell lines tested, while the antitumor effects of PAM were completely inhibited with NAC. In the mouse xenograft model, the calculated tumor volume on day 28 in the PAM treatment group was significantly smaller compared with the control group [28 ± 22 vs. 89 ± 38 (mm(3) ± SD), p=0.0031]. These results show that PAM treatment of pancreatic cancer might be a promising therapeutic strategy.}, }
@article {pmid26350063, year = {2015}, author = {Uetaki, M and Tabata, S and Nakasuka, F and Soga, T and Tomita, M}, title = {Metabolomic alterations in human cancer cells by vitamin C-induced oxidative stress.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {13896}, pmid = {26350063}, issn = {2045-2322}, mesh = {Ascorbic Acid/*metabolism/pharmacology/toxicity ; Cell Survival/drug effects ; Energy Metabolism/drug effects ; Humans ; Hydrogen Peroxide/metabolism ; MCF-7 Cells ; *Metabolome ; *Metabolomics/methods ; NAD/metabolism ; Neoplasms/*metabolism ; *Oxidative Stress/drug effects ; }, abstract = {Intravenous administration of high-dose vitamin C has recently attracted attention as a cancer therapy. High-dose vitamin C induces pro-oxidant effects and selectively kills cancer cells. However, the anticancer mechanisms of vitamin C are not fully understood. Here, we analyzed metabolic changes induced by vitamin C in MCF7 human breast adenocarcinoma and HT29 human colon cancer cells using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). The metabolomic profiles of both cell lines were dramatically altered after exposure to cytotoxic concentrations of vitamin C. Levels of upstream metabolites in the glycolysis pathway and tricarboxylic acid (TCA) cycle were increased in both cell lines following treatment with vitamin C, while adenosine triphosphate (ATP) levels and adenylate energy charges were decreased concentration-dependently. Treatment with N-acetyl cysteine (NAC) and reduced glutathione (GSH) significantly inhibited vitamin C-induced cytotoxicity in MCF7 cells. NAC also suppressed vitamin C-dependent metabolic changes, and NAD treatment prevented vitamin C-induced cell death. Collectively, our data suggests that vitamin C inhibited energy metabolism through NAD depletion, thereby inducing cancer cell death.}, }
@article {pmid26350014, year = {2015}, author = {Yang, ML and Ye, ZM}, title = {[Extremely low frequency electromagnetic field induces apoptosis of osteosarcoma cells via oxidative stress].}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {44}, number = {3}, pages = {323-328}, pmid = {26350014}, issn = {1008-9292}, mesh = {Acetylcysteine ; *Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; *Electromagnetic Fields ; Humans ; Imidazoles ; Osteosarcoma/*pathology ; *Oxidative Stress ; Phosphorylation ; Pyridines ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {OBJECTIVE: To investigate the effects of extremely low frequency electromagnetic field (ELF-EMF) on human osteosarcoma cells and its mechanisms.<br><br>METHODS: Human osteosarcoma MG-63 cells were exposed to 50 Hz,1 mT ELF-EMF for 1, 2 and 3 h in vitro, with or without pretreatment by reactive oxygen species (ROS) inhibitor N acetylcysteine (NAC) or p38MAPK inhibitor SB203580. The proliferation of MG-63 cells was determined by MTT method; the apoptosis rate and ROS level in MG-63 cells were detected by flow cytometry. The expression of p38MAPK in MG-63 cells was determined by Western blotting.<br><br>RESULTS: ELF-EMF decreased the viability of MG-63 cells, inhibited cell growth, induced cell apoptosis and increased the level of ROS significantly. The apoptosis rate declined significantly after treatment with ROS inhibitor NAC or p38MAPK inhibitor SB203580. After exposure to ELF-EMF, p38MAPK in MG-63 cells was activated, and the phosphorylation level was also inhibited after treatment with NAC.<br><br>CONCLUSION: ELF-EMF can induce the apoptosis of MG-63 cells. Increased ROS and p38MAPK activation may be involved in the mechanism.}, }
@article {pmid26349602, year = {2015}, author = {Kim, JK and Kang, KA and Piao, MJ and Kumara, MH and Jeong, YJ and Ko, MH and Hyun, JW}, title = {Generation of Reactive Oxygen Species and Endoplasmic Reticulum Stress by Dictyopteris undulata Extract Leads to Apoptosis in Human Melanoma Cells.}, journal = {Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer}, volume = {34}, number = {3}, pages = {191-200}, doi = {10.1615/jenvironpatholtoxicoloncol.2015013074}, pmid = {26349602}, issn = {2162-6537}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/*drug effects ; Humans ; Phaeophyceae/*chemistry ; Reactive Oxygen Species/*metabolism ; }, abstract = {In this study, we evaluated the hypothesis that a marine brown algae, Dictyopteris undulata ethanol extract (DUE), provokes apoptosis in a human melanoma cell line, A2058, via reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. DUE inhibited A2058 cell proliferation and increased apoptotic body formation, as indicated by the presence of fragmented nuclei and the activation of caspase-3. Moreover, DUE-treated cells showed elevated ER staining, mitochondrial calcium cation (Ca2+) overloading, augmented levels of ER stress-related and cell death modulatory proteins, including RNA-dependent protein kinase-related ER kinase, phospho-inositol-requiring enzyme 1α, phospho-eukaryotic translation initiation factor 2α, and CCAAT/enhancer-binding protein-homologous protein, as well as increased intracellular ROS levels. However, the antioxidant N-acetyl cysteine reversed the elevated ROS levels, decreased apoptosis, and mitigated ER stress in A2058 cells following DUE treatment. These findings suggest that DUE treatment triggers apoptosis in human melanoma cells through a mechanism involving ER stress and ROS.}, }
@article {pmid26347514, year = {2016}, author = {Yoon, H and Lee, DH and Jang, ES and Kim, J and Shin, CM and Park, YS and Hwang, JH and Kim, JW and Jeong, SH and Kim, N}, title = {Effects of N-acetylcysteine on First-Line Sequential Therapy for Helicobacter pylori Infection: A Randomized Controlled Pilot Trial.}, journal = {Gut and liver}, volume = {10}, number = {4}, pages = {520-525}, pmid = {26347514}, issn = {2005-1212}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Amoxicillin/administration &amp; dosage ; Anti-Bacterial Agents/*administration &amp; dosage ; Clarithromycin/administration &amp; dosage ; Drug Administration Schedule ; Drug Therapy, Combination ; Female ; Helicobacter Infections/*drug therapy/microbiology ; *Helicobacter pylori ; Humans ; Intention to Treat Analysis ; Male ; Metronidazole/administration &amp; dosage ; Middle Aged ; Pilot Projects ; Rabeprazole/administration &amp; dosage ; Treatment Outcome ; }, abstract = {BACKGROUND/AIMS: To evaluate the adjuvant effects of N-acetylcysteine (NAC) on first-line sequential therapy (SQT) for Helicobacter pylori infection.<br><br>METHODS: Patients with H. pylori infections were randomly assigned to receive sequential therapy with (SQT+NAC group, n=49) or without (SQT-only group, n=50) NAC. Sequential therapy consisted of rabeprazole 20 mg and amoxicillin 1 g for the first 5 days, followed by rabeprazole 20 mg, clarithromycin 500 mg and metronidazole 500 mg for the remaining 5 days; all drugs were administered twice daily. For the SQT+NAC group, NAC 400 mg bid was added for the first 5 days of sequential therapy. H. pylori eradication was evaluated 4 weeks after the completion of therapy.<br><br>RESULTS: The eradication rates by intention-to-treat analysis were 58.0% in the SQT-only group and 67.3% in the SQT+NAC group (p=0.336). The eradication rates by per-protocol analysis were 70.0% in the SQT-only group and 80.5% in the SQT+NAC group (p=0.274). Compliance was very good in both groups (SQT only/SQT+NAC groups: 95.2%/100%, p=0.494). There was no significant difference in the adverse event rates between groups (SQT-only/SQT+NAC groups: 26.2%/26.8%, p=0.947).<br><br>CONCLUSIONS: The H. pylorieradication rate was numerically higher in the SQT+NAC group than in the SQT-only group. As our data did not reach statistical significance, larger trials are warranted.}, }
@article {pmid26347391, year = {2015}, author = {Kranzer, K and Elamin, WF and Cox, H and Seddon, JA and Ford, N and Drobniewski, F}, title = {A systematic review and meta-analysis of the efficacy and safety of N-acetylcysteine in preventing aminoglycoside-induced ototoxicity: implications for the treatment of multidrug-resistant TB.}, journal = {Thorax}, volume = {70}, number = {11}, pages = {1070-1077}, doi = {10.1136/thoraxjnl-2015-207245}, pmid = {26347391}, issn = {1468-3296}, mesh = {Acetylcysteine/*therapeutic use ; Aminoglycosides/*adverse effects ; Ear Diseases/*chemically induced/*prevention &amp; control ; Free Radical Scavengers/therapeutic use ; Humans ; Tuberculosis, Multidrug-Resistant/*drug therapy ; }, abstract = {BACKGROUND: Ototoxicity is a severe side effect of aminoglycoside antibiotics. Aminoglycosides are recommended for the treatment of multidrug-resistant TB (MDR-TB). N-Acetylcysteine (NAC) appears to protect against drug- and noise-induced hearing loss. This review aimed to determine if coadministering NAC with aminoglycoside affected ototoxicity development, and to assess the safety and tolerability of prolonged NAC administration.<br><br>METHODS: Eligible studies reported on the efficacy of concomitant NAC and aminoglycoside administration for ototoxicity prevention or long-term (&#x2265; 6 weeks) administration of NAC regardless of indication. Pooled estimates were calculated using a fixed-effects model. Heterogeneity was assessed using the I(2) statistic.<br><br>RESULTS: Three studies reported that NAC reduced ototoxicity in 146 patients with end-stage renal failure receiving aminoglycosides. Pooled relative risk for otoprotection at 4-6 weeks was 0.14 (95% CI 0.05 to 0.45), and the risk difference was -33.3% (95% CI 45.5% to 21.2%). Eighty-three studies (N=9988) described the administration of NAC for >6 weeks. Abdominal pain, nausea and vomiting, diarrhoea and arthralgia were increased 1.4-2.2 times.<br><br>DISCUSSION: This review provides evidence for the safety and otoprotective effect of NAC when coadministered with aminoglycoside. It represents a strong justification for a clinical trial to investigate the effect of concomitant NAC treatment in patients receiving aminoglycosides as part of MDR-TB treatment.}, }
@article {pmid26346736, year = {2014}, author = {Sanchez-Alavez, M and Bortell, N and Galmozzi, A and Conti, B and Marcondes, MC}, title = {Reactive oxygen species scavenger N-acetyl cysteine reduces methamphetamine-induced hyperthermia without affecting motor activity in mice.}, journal = {Temperature (Austin, Tex.)}, volume = {1}, number = {3}, pages = {227-241}, pmid = {26346736}, issn = {2332-8940}, support = {R01 DA036164/DA/NIDA NIH HHS/United States ; R03 DA027936/DA/NIDA NIH HHS/United States ; R21 DA029491/DA/NIDA NIH HHS/United States ; }, abstract = {Hyperthermia is a potentially lethal side effect of Methamphetamine (Meth) abuse, which involves the participation of peripheral thermogenic sites such as the Brown Adipose Tissue (BAT). In a previous study we found that the anti-oxidant N-acetyl cysteine (NAC) can prevent the high increase in temperature in a mouse model of Meth-hyperthermia. Here, we have further explored the ability of NAC to modulate Meth-induced hyperthermia in correlation with changes in BAT. We found that NAC treatment in controls causes hypothermia, and, when administered prior or upon the onset of Meth-induced hyperthermia, can ameliorate the temperature increase and preserve mitochondrial numbers and integrity, without affecting locomotor activity. This was different from Dantrolene, which decreased motor activity without affecting temperature. The effects of NAC were seen in spite of its inability to recover the decrease of mitochondrial superoxide induced in BAT by Meth. In addition, NAC did not prevent the Meth-induced decrease of BAT glutathione. Treatment with S-adenosyl-L-methionine, which improves glutathione activity, had an effect in ameliorating Meth-induced hyperthermia, but also modulated motor activity. This suggests a role for the remaining glutathione for controlling temperature. However, the mechanism by which NAC operates is independent of glutathione levels in BAT and specific to temperature. Our results show that, in spite of the absence of a clear mechanism of action, NAC is a pharmacological tool to examine the dissociation between Meth-induced hyperthermia and motor activity, and a drug of potential utility in treating the hyperthermia associated with Meth-abuse.}, }
@article {pmid26346162, year = {2015}, author = {Kook, SH and Kim, KA and Ji, H and Lee, D and Lee, JC}, title = {Irradiation inhibits the maturation and mineralization of osteoblasts via the activation of Nrf2/HO-1 pathway.}, journal = {Molecular and cellular biochemistry}, volume = {410}, number = {1-2}, pages = {255-266}, pmid = {26346162}, issn = {1573-4919}, mesh = {3T3 Cells ; Animals ; Antioxidants/pharmacology ; Biomarkers/metabolism ; Calcification, Physiologic/drug effects/*radiation effects ; Calcium/metabolism ; Cell Differentiation/drug effects/*radiation effects ; Dose-Response Relationship, Radiation ; Enzyme Induction ; Enzyme Inhibitors/pharmacology ; Heme Oxygenase-1/antagonists &amp; inhibitors/*biosynthesis/genetics ; Membrane Proteins/antagonists &amp; inhibitors/*biosynthesis/genetics ; Mice ; NF-E2-Related Factor 2/genetics/*metabolism ; Osteoblasts/drug effects/enzymology/pathology/*radiation effects ; Osteogenesis/drug effects/*radiation effects ; Oxidative Stress/radiation effects ; RNA Interference ; Reactive Oxygen Species/metabolism ; Signal Transduction/radiation effects ; Transfection ; }, abstract = {Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the induction of antioxidant gene expression and protects cells against oxidative injury. However, there are controversial findings regarding the roles of Nrf2 on bone metabolism under oxidative stress. The role of Nrf2 on the differentiation of radiation-exposed osteoblasts is also unclear. We investigated whether Nrf2 negatively or positively affects osteoblast differentiation in response to irradiation. Irradiation inhibited osteoblast differentiation of MC3T3-E1 cells in a dose-dependent manner. This inhibition was evidenced by the irradiation-mediated decreases in bone-like nodule formation, alkaline phosphatase (ALP) activity, calcium accumulation, and expression of osteoblast markers, such as ALP, osteocalcin, osteopontin, bone sialoprotein, osterix, and Runx2. These reductions were accompanied by increased induction of Nrf2 and heme oxygenase-1 (HO-1), accumulation of cellular oxidants, and depletion of antioxidant defense enzymes. siRNA-mediated silencing of Nrf2 markedly reversed the negative effect of irradiation on osteoblast differentiation of the cells, leading to a decrease in HO-1 and an increase in Runx2 levels. Irradiation-mediated decreases in the levels of Runx2 and osteocalcin mRNA, but not of Nrf2 protein, were also significantly inhibited by HO-1 inhibitor, zinc protoporphyrin IX. Furthermore, N-acetyl cysteine restored all of the changes induced by irradiation to near-normal levels in the cells. These results demonstrate that irradiation inhibits osteoblast differentiation and mineralization of MC3T3-E1 cells through the oxidative stress-mediated activation of Nrf2/HO-1 pathway.}, }
@article {pmid26344001, year = {2015}, author = {Liu, SC and Lee, HP and Hung, CY and Tsai, CH and Li, TM and Tang, CH}, title = {Berberine attenuates CCN2-induced IL-1β expression and prevents cartilage degradation in a rat model of osteoarthritis.}, journal = {Toxicology and applied pharmacology}, volume = {289}, number = {1}, pages = {20-29}, doi = {10.1016/j.taap.2015.08.020}, pmid = {26344001}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Berberine/*pharmacology ; Cartilage/drug effects/metabolism ; Cells, Cultured ; Connective Tissue Growth Factor/*pharmacology ; Disease Models, Animal ; Fibroblasts/drug effects/metabolism ; Humans ; Interleukin-1beta/genetics/*metabolism ; MAP Kinase Kinase Kinase 5/genetics/metabolism ; NF-kappa B/metabolism ; Osteoarthritis/*drug therapy ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Receptors, Vitronectin/genetics/metabolism ; Recombinant Proteins/pharmacology ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Connective tissue growth factor (CTGF; also known as CCN2) is an inflammatory mediator that is abundantly expressed in osteoarthritis (OA). Interleukin-1β (IL-1β) plays a pivotal role in OA pathogenesis. Berberine exhibits an anti-inflammatory effect, but the mechanisms by which it modulates CCN2-induced IL-1β expression in OA synovial fibroblasts (OASFs) remain unknown. We showed that CCN2-induced IL-1β expression is mediated by the activation of αvβ3/αvβ5 integrin-dependent reactive oxygen species (ROS) generation, and subsequent activation of apoptosis signal-regulating kinase 1 (ASK1), p38/JNK, and nuclear factor-κB (NF-κB) signaling pathways. This IL-1β expression in OASFs is attenuated by N-acetylcysteine (NAC), inhibitors of ASK1, p38, or JNK, or treatment with berberine. Furthermore, berberine also reverses cartilage damage in an experimental model of collagenase-induced OA (CIOA). We observed that CCN2 increased IL-1β expression via αvβ3/αvβ5 integrins, ROS, and ASK1, p38/JNK, and NF-κB signaling pathways. Berberine was found to inhibit these signaling components in OASFs in vitro and prevent cartilage degradation in vivo. We suggest a novel therapeutic strategy of using berberine for managing OA.}, }
@article {pmid26343756, year = {2015}, author = {Zhu, Y and Gu, YX and Mo, JJ and Shi, JY and Qiao, SC and Lai, HC}, title = {N-acetyl cysteine protects human oral keratinocytes from Bis-GMA-induced apoptosis and cell cycle arrest by inhibiting reactive oxygen species-mediated mitochondrial dysfunction and the PI3K/Akt pathway.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {29}, number = {8}, pages = {2089-2101}, doi = {10.1016/j.tiv.2015.09.002}, pmid = {26343756}, issn = {1879-3177}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Bisphenol A-Glycidyl Methacrylate/*toxicity ; Caspase 3/genetics/metabolism ; Cell Cycle Checkpoints/*drug effects ; Gene Expression Regulation/drug effects ; Humans ; Keratinocytes/*drug effects ; Mitochondria/drug effects ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Resins, Synthetic/toxicity ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Bisphenol-A-glycidyl methacrylate (Bis-GMA) released from dental resin materials causes various toxic effects on gingival epithelium. Thus the underlying mechanisms of its cytotoxicity should be elucidated for safety use. One potential cause of cell damage is the generation of reactive oxygen species (ROS) beyond the capacity of a balanced redox regulation. In this study, we found that exposure of human oral keratinocytes (HOKs) to Bis-GMA caused apoptosis and G1/S cell cycle arrest in parallel with an increased ROS level. Moreover, Bis-GMA induced a depletion of mitochondrial membrane potential, an increase in the Bax/Bcl-2 ratio, an activation of caspase-3 and altered expressions of cell cycle-related proteins (p21, PCNA, cyclinD1). Furthermore, the co-treatment of the ROS scavenger N-acetyl cysteine (NAC) obviously attenuated Bis-GMA-induced toxicity. Here we also evaluated the effects of Bis-GMA on the ROS-related PI3k/Akt pathway. We found that Bis-GMA inhibited the phosphorylation of Akt, whereas the amount of phosphorylated Akt was reverted to the control level in the presence of NAC. Our findings suggested that the toxic effects of Bis-GMA were related to ROS production and the antioxidant NAC effectively reduced Bis-GMA-mediated cytotoxicity.}, }
@article {pmid26342050, year = {2016}, author = {Giorgi, VS and Da Broi, MG and Paz, CC and Ferriani, RA and Navarro, PA}, title = {N-Acetyl-Cysteine and l-Carnitine Prevent Meiotic Oocyte Damage Induced by Follicular Fluid From Infertile Women With Mild Endometriosis.}, journal = {Reproductive sciences (Thousand Oaks, Calif.)}, volume = {23}, number = {3}, pages = {342-351}, doi = {10.1177/1933719115602772}, pmid = {26342050}, issn = {1933-7205}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Adult ; Animals ; Carnitine/*pharmacology/therapeutic use ; Cattle ; Endometriosis/*pathology/prevention &amp; control ; Female ; *Follicular Fluid ; Humans ; Infertility, Female/*pathology/prevention &amp; control ; Meiosis/drug effects/physiology ; Oocytes/*drug effects/pathology ; Ovulation Induction/methods ; }, abstract = {This study evaluated the potential protective effect of the antioxidants, l-carnitine (LC) and N-acetyl-cysteine (NAC), in preventing meiotic oocyte damage induced by follicular fluid (FF) from infertile women with mild endometriosis (ME). We performed an experimental study. The FF samples were obtained from 22 infertile women undergoing stimulated cycles for intracytoplasmic sperm injection (11 with ME and 11 without endometriosis). Immature bovine oocytes were submitted to in vitro maturation (IVM) divided into 9 groups: no-FF (No-FF); with FF from control (CFF) or ME (EFF) groups; and with LC (C + LC and E + LC), NAC (C + NAC and E + NAC), or both antioxidants (C + 2Ao and E + 2Ao). After IVM, oocytes were immunostained for visualization of microtubules and chromatin by confocal microscopy. The percentage of meiotically normal metaphase II (MII) oocytes was significantly lower in the EFF group (51.35%) compared to No-FF (86.36%) and CFF (83.52%) groups. The E + NAC (62.22%), E + LC (80.61%), and E + 2Ao (61.40%) groups showed higher percentage of normal MII than EFF group. The E + LC group showed higher percentage of normal MII than E + NAC and E + 2Ao groups and a similar percentage to No-FF and CFF groups. Therefore, FF from infertile women with ME causes meiotic abnormalities in bovine oocytes, and, for the first time, we demonstrated that the use of NAC and LC prevents these damages. Our findings elucidate part of the pathogenic mechanisms involved in infertility associated with ME and open perspectives for further studies investigating whether the use of LC could improve the natural fertility and/or the results of in vitro fertilization of women with ME.}, }
@article {pmid26341012, year = {2015}, author = {Hwang, GH and Ryu, JM and Jeon, YJ and Choi, J and Han, HJ and Lee, YM and Lee, S and Bae, JS and Jung, JW and Chang, W and Kim, LK and Jee, JG and Lee, MY}, title = {The role of thioredoxin reductase and glutathione reductase in plumbagin-induced, reactive oxygen species-mediated apoptosis in cancer cell lines.}, journal = {European journal of pharmacology}, volume = {765}, number = {}, pages = {384-393}, doi = {10.1016/j.ejphar.2015.08.058}, pmid = {26341012}, issn = {1879-0712}, mesh = {Antineoplastic Agents, Phytogenic/chemistry/*pharmacology ; Apoptosis/drug effects/*physiology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Glutathione Reductase/*physiology ; Hep G2 Cells ; Humans ; Naphthoquinones/chemistry/*pharmacology ; Reactive Oxygen Species/*metabolism ; Thioredoxin-Disulfide Reductase/*physiology ; }, abstract = {Plumbagin is a secondary metabolite that was first identified in the Plumbago genus of plants. It is a naphthoquinone compound with anti-atherosclerosis, anticancer, anti-inflammatory, antimicrobial, contraceptive, cardiotonic, immunosuppressive, and neuroprotective activities. However, the mechanisms of plumbagin's activities are largely unknown. In this study, we examined the effect of plumbagin on HepG2 hepatocellular carcinoma cells as well as LLC lung cancer cells, SiHa cervical carcinoma cells. Plumbagin significantly decreased HepG2 cell viability in a dose-dependent manner. Additionally, treatment with plumbagin significantly increased the Bax/Bcl-2 ratio and caspase-3/7 activity. Using the similarity ensemble approach (SEA)-a state-of-the-art cheminformatic technique-we identified two previously unknown cellular targets of plumbagin: thioredoxin reductase (TrxR) and glutathione reductase (GR). This was then confirmed using protein- and cell-based assays. We found that plumbagin was directly reduced by TrxR, and that this reduction was inhibited by the TrxR inhibitor, sodium aurothiomalate (ATM). Plumbagin also decreased the activity of GR. Plumbagin, and the GR inhibitor sodium arsenite all increased intracellular reactive oxygen species (ROS) levels and this increase was significantly attenuated by pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) in HepG2 cells. Plumbagin increased TrxR-1 and heme oxygenase (HO)-1 expression and pretreatment with NAC significantly attenuated the plumbagin-induced increase of TrxR-1 and HO-1 expression in HepG2 cells, LLC cells and SiHa cells. Pretreatment with NAC significantly prevented the plumbagin-induced decrease in cell viability in these cell types. In conclusion, plumbagin exerted its anticancer effect by directly interacting with TrxR and GR, and thus increasing intracellular ROS levels.}, }
@article {pmid26339453, year = {2015}, author = {Cai, Z and Lou, Q and Wang, F and Li, E and Sun, J and Fang, H and Xi, J and Ju, L}, title = {N-acetylcysteine protects against liver injure induced by carbon tetrachloride via activation of the Nrf2/HO-1 pathway.}, journal = {International journal of clinical and experimental pathology}, volume = {8}, number = {7}, pages = {8655-8662}, pmid = {26339453}, issn = {1936-2625}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biomarkers/metabolism ; Carbon Tetrachloride ; Chemical and Drug Induced Liver Injury/enzymology/genetics/pathology/*prevention &amp; control ; Cytoprotection ; Disease Models, Animal ; Heme Oxygenase (Decyclizing)/genetics/*metabolism ; Liver/*drug effects/enzymology/pathology ; Male ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidative Stress/drug effects ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; Signal Transduction/*drug effects ; Up-Regulation ; }, abstract = {Chronic liver injury is an important clinical problem which eventually leads to cirrhosis, hepatocellular carcinoma and end-stage liver failure. It is well known that cell damage induced by reactive oxygen species (ROS) is an important mechanism of hepatocyte injure. N-acetylcysteine (NAC), a precursor of glutathione (GSH), is well-known role as the antidote to acetaminophen toxicity in clinic. NAC is now being utilized more widely in the clinical setting for non-acetaminophen (APAP) related causes of liver injure. However, the mechanisms underlying its beneficial effects are poorly defined. Thus, Aim of the present study was to investigate potential hepatic protective role of NAC and to delineate its mechanism of action against carbon tetrachloride (CCl4)-induced liver injury in models of rat. Our results showed that the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as malondialdehyde (MDA) contents decreased significantly in CCl4-induced rats with NAC treatment. GSH content and superoxide dismutase (SOD) activities remarkably increased in the NAC groups compared with those in CCl4-induced group. Treatment with NAC had been shown to an increase in nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA levels. In conclusion, these results suggested that NAC upregulated HO-1 through the activation of Nrf2 pathway and protected rat against CCl4-induced liver injure. The results of this study provided pharmacological evidence to support the clinical application of NAC.}, }
@article {pmid26338258, year = {2016}, author = {Bhilare, NV and Dhaneshwar, SS and Sinha, AJ and Kandhare, AD and Bodhankar, SL}, title = {Novel Thioester Prodrug of N-acetylcysteine for Odor Masking and Bioavailability Enhancement.}, journal = {Current drug delivery}, volume = {13}, number = {4}, pages = {611-620}, doi = {10.2174/1567201812666150904144607}, pmid = {26338258}, issn = {1875-5704}, mesh = {Acetylcysteine/pharmacokinetics/*pharmacology ; Animals ; Biological Availability ; Chromatography, High Pressure Liquid ; Expectorants/pharmacokinetics/*pharmacology ; Hydrolysis ; Male ; *Odorants ; Prodrugs/pharmacokinetics/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: The mucolytic N-acetylcysteine (NAC) is used to control the excessive mucus secretion if mucus is the underlying cause of broncho-constriction. Its major drawbacks are poor bioavailability due to extensive first pass effect, poor lipophilicity, high protein binding and offensive odor.<br><br>METHODS: For minimizing above shortcomings of NAC, in present study thioester (A1) prodrug of NAC was synthesized by conventional as well as microwave-assisted methods. Release studies of A-1 were carried out using HPLC and pharmacological evaluation was performed in ovalbumin-induced model of pulmonary inflammation in Sprague dawley rats.<br><br>RESULTS: A-1 was found to be stable in HCl buffer, phosphate buffer, stomach homogenates but furnished 30% NAC in 6h and 1.7% of NAC in 4h when incubated with small intestinal and liver homogenates respectively. Upon oral administration of A-1 to rats, 4.85% NAC was detected in blood at 8h. Urine samples pooled over a period of 24h exhibited 0.75% NAC while negligible concentration was found in 24 h pooled samples of feces.<br><br>CONCLUSION: The findings of this preliminary investigation demonstrated significant effects of thioester prodrug A-1 as compared to NAC through reduction of lung inflammation, airway eosinophilia and reversal of lung function parameters in ovalbumin- challenged rats at half the equimolar dose of NAC. Interestingly masking thiol group through thioester formation resulted in odorless prodrug. We propose that thioester prodrug using palmitic acid as a carrier is a promising strategy to enhance bioavailability of NAC by increasing its lipophilicity/ absorption and minimizing its first pass metabolism.}, }
@article {pmid26338072, year = {2016}, author = {Valayil, JM and Kuriakose, GC and Jayabaskaran, C}, title = {Isolation, Purification and Characterization of a Novel Steroidal Saponin Cholestanol Glucoside from Lasiodiplodia theobromae that Induces Apoptosis in A549 Cells.}, journal = {Anti-cancer agents in medicinal chemistry}, volume = {16}, number = {7}, pages = {865-874}, doi = {10.2174/1871520615666150904104325}, pmid = {26338072}, issn = {1875-5992}, mesh = {Apoptosis/*drug effects ; Ascomycota/*chemistry ; Cell Line, Tumor ; Cholestanol/chemistry/*isolation &amp; purification/pharmacology ; Glucosides/chemistry/*isolation &amp; purification/pharmacology ; Humans ; }, abstract = {Search for novel anticancer lead molecules continues to be a major focus of cancer research due to the limitations of existing drugs such as lack of tumor selectivity, narrow therapeutic index and multidrug resistance of cancer types. Natural molecules often possess better pharmacokinetic traits compared to synthetic molecules as they continually evolve by natural selection process to interact with biological macromolecules. Microbial metabolites constitute nearly half of the pharmaceuticals in market today. Endophytic fungi, owing to its rich chemical diversity, are viewed as attractive sources of novel bioactive compounds. In the present study, we report the purification and characterization of a novel steroidal saponin, cholestanol glucoside (CG) from Saraca asoca endophytic fungus Lasiodiplodia theobromae. The compound was assessed for its cytotoxic potentialities in six human cancer cell lines, A549, PC3, HepG2, U251, MCF7 and OVCAR3. CG exhibited significant cytotoxicities towards A549, PC3 and HepG2 among which A549 cells were most vulnerable to CG treatment. However, CG treatment exhibited negligible cytotoxicity in non malignant human lung fibroblast cell line (WI-38). Induction of cell death by CG treatment in A549 cells was further investigated. CG induced the generation of reactive oxygen species (ROS) and mitochondrial membrane permeability loss followed by apoptotic cell death. Mitochondrial membrane depolarization and apoptotic cell death in CG treated A549 cells were completely blocked in presence of an antioxidant, N-acetyl cysteine (NAC). Hence it could be concluded that CG initiates apoptosis in cancer cells by augmenting the basal oxidative stress and that the generation of intracellular ROS is crucial for the induction of apoptosis.}, }
@article {pmid26337463, year = {2015}, author = {Liu, Y and Zhou, G and Wang, Z and Guo, X and Xu, Q and Huang, Q and Su, L}, title = {NF-κB signaling is essential for resistance to heat stress-induced early stage apoptosis in human umbilical vein endothelial cells.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {13547}, pmid = {26337463}, issn = {2045-2322}, mesh = {Apoptosis/*physiology ; Cells, Cultured ; Cytoprotection/physiology ; Endothelial Cells/cytology/*physiology ; Heat-Shock Proteins/*metabolism ; Heat-Shock Response/*physiology ; Humans ; NF-kappa B/*metabolism ; Reactive Oxygen Species/metabolism ; Umbilical Veins/cytology/*physiology ; }, abstract = {Cell apoptosis induced by heat stress is regulated by a complex signaling network. We previously reported that a p53-dependent pathway is involved. Here, we present evidence that NF-κB signaling plays a crucial role in preventing heat stress-induced early apoptosis. Human umbilical vein endothelial cells (HUVECs) were examined and increased phosphorylation of p65 and IκBα were detected, without IκBα degradation. When NF-κB signaling was inhibited by BAY11-7082, or a small interference RNA (siRNA) targeting p65, a significant increase in cell apoptosis and caspase-3 activity was observed, as well as reduced expression and translocation of HSP27 into the nucleus, an accumulation of reactive oxygen species, and prolonged phosphorylation of mitogen-activated protein kinases (MAPKs). In addition, an association between HSP27 and p65 was identified which may enhance NF-κB activation. When HSP27 was overexpressed, pretreatment of HUVECs with the antioxidant, apocynin, or N-acetyl cysteine, suppressed apoptosis. Similarly, inhibition of JNK and p38 with SP600125 and SB203580, respectively, also suppressed apoptosis, whereas siRNA-mediated HSP27 knockdown and treatment with the ERK 1/2 inhibitor PD98059 did otherwise. In conclusion, these findings suggest a novel role for an NF-κB signaling pathway involving HSP27, ROS, and MAPKs that confers a protective effect against heat stress-induced cell apoptosis.}, }
@article {pmid26336810, year = {2016}, author = {Lee, SS and Chen, YJ and Tsai, CH and Huang, FM and Chang, YC}, title = {Elevated transglutaminase-2 expression mediates fibrosis in areca quid chewing-associated oral submucocal fibrosis via reactive oxygen species generation.}, journal = {Clinical oral investigations}, volume = {20}, number = {5}, pages = {1029-1034}, pmid = {26336810}, issn = {1436-3771}, mesh = {Acetylcysteine/pharmacology ; *Areca ; Arecoline/pharmacology ; Blotting, Western ; Catechin/analogs &amp; derivatives/pharmacology ; Dose-Response Relationship, Drug ; GTP-Binding Proteins/*metabolism ; Humans ; Immunohistochemistry ; Oral Submucous Fibrosis/*enzymology/*prevention &amp; control ; Protein Glutamine gamma Glutamyltransferase 2 ; Reactive Oxygen Species/*metabolism ; Transglutaminases/*metabolism ; }, abstract = {OBJECTIVES: Transglutaminase-2 (TGM-2) protein is involved in the cross-linking of matrix proteins resulting in several fibrotic disorders and can be induced by reactive oxygen species (ROS). Little is known about its role in the development of oral submucocal fibrosis (OSF). Hence, we hypothesize that TGM-2 may have a role in the pathogenesis of areca quid chewing-associated OSF and arecoline, a major areca nut alkaloid, could regulate TGM-2 via ROS generation.<br><br>MATERIALS: Forty OSF specimens from areca quid chewing-associated OSF and ten normal buccal mucosa biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The expression of TGM-2 from fibroblasts cultured from OSF and normal buccal mucosa was evaluated by Western blot. The effect of arecoline on normal buccal mucosa fibroblasts (BMFs) was used to elucidate whether TGM-2 expression could be affected by arecoline by using 2', 7'-dichlorofluorescein diacetate assay and Western blot. In addition, glutathione precursor N-acetyl-L-cysteine (NAC) and epigallocatechin-3 gallate (EGCG) were added to find the possible regulatory mechanisms.<br><br>RESULTS: TGM-2 expression was significantly higher in OSF specimens than normal specimens (p&#xa0;<&#xa0;0.05). Fibroblasts derived from OSF were found to exhibit higher TGM-2 expression than BMFs in protein levels (p&#xa0;<&#xa0;0.05). Arecoline significantly upregulated the intracellular ROS generation in a dose-dependent manner (p&#xa0;<&#xa0;0.05). TGM-2 protein induced by arecoline was found in BMFs in a dose-dependent manner (p&#xa0;<&#xa0;0.05). Treatment with NAC and EGCG markedly inhibited TGM-2 expression induced by arecoline (p&#xa0;<&#xa0;0.05).<br><br>CONCLUSIONS: Our results suggest that TGM-2 expression is significantly upregulated in OSF tissues from areca quid chewers. Arecoline-upregulated TGM-2 expression may be mediated by ROS generation.<br><br>CLINICAL RELEVANCE: TGM-2 protein is upregulated in areca quid chewing-associated OSF. Using this in vitro model, antioxidants could inhibit arecoline-upregulated TGM-2 expression. NAC and EGCG may serve as a useful agent in controlling OSF.}, }
@article {pmid26335900, year = {2015}, author = {Enciu, AM and Popescu, LM}, title = {Telopodes of telocytes are influenced in vitro by redox conditions and ageing.}, journal = {Molecular and cellular biochemistry}, volume = {410}, number = {1-2}, pages = {165-174}, pmid = {26335900}, issn = {1573-4919}, mesh = {Antioxidants/pharmacology ; Cell Movement ; Cell Proliferation ; Cell Shape ; Cells, Cultured ; *Cellular Senescence ; Dose-Response Relationship, Drug ; Female ; Humans ; Microscopy, Video ; Myometrium/cytology/drug effects/*metabolism ; Oxidants/pharmacology ; Oxidation-Reduction ; *Oxidative Stress/drug effects ; Telocytes/drug effects/*metabolism ; Telopodes/drug effects/*metabolism ; Time Factors ; }, abstract = {Telocytes (TCs) are a novel cell type identified among interstitial cells in various organs. TCs are characterized by very long cell processes (tens to hundreds micrometres) named telopodes (Tps) with uneven calibre: dilations (podoms) and very thin segments (podomers). However, little is known about the factors which influence Tps conformation. Recently, extracellular matrix proteins were found to influence Tps extension, adherence and spreading. Here, we show that oxidative stress and ageing influence formation of new Tps of TCs cultivated from human non-pregnant myometrium. Using real-time videomicroscopy, we found that ageing the TCs to passage 21 increased the ratio of Tps/TC number with about 50 %, whereas oxidative stress hindered formation of new Tps in both aged and young TCs (passage 7). Under oxidative stress, newly formed cell processes were up to 25 % shorter. Migration pathway length was decreased by 30-40 % for both young and aged cells in an oxidative stress environment. Contrary, addition of N-acetyl cysteine in cell culture medium shifted TCs morphology to a long and slender profile. In conclusion, we showed that TCs specific morphology in vitro is influenced by oxidative status balance, as well as ageing.}, }
@article {pmid26335060, year = {2015}, author = {Sudo, K and Takezawa, Y and Kohsaka, S and Nakajima, K}, title = {Involvement of nitric oxide in the induction of interleukin-1 beta in microglia.}, journal = {Brain research}, volume = {1625}, number = {}, pages = {121-134}, doi = {10.1016/j.brainres.2015.08.030}, pmid = {26335060}, issn = {1872-6240}, mesh = {Animals ; Astrocytes/drug effects ; Brain/cytology ; Enzyme Inhibitors/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Female ; Glial Fibrillary Acidic Protein/metabolism ; Interleukin-1beta/*metabolism ; Microglia/drug effects ; Nerve Growth Factor/metabolism ; Nitric Oxide/*metabolism ; Polysaccharides/pharmacology ; Pregnancy ; Rats ; Rats, Wistar ; Superoxides/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {In response to in vitro stimulation with lipopolysaccharide (LPS), microglia induce the production of the inflammatory cytokine interleukin-1 beta (IL-1β) together with nitric oxide (NO) and superoxide anion (O2(-)). Here we investigated the role of NO and O2(-) in the signaling mechanism by which IL-1β is induced in microglia. The LPS-inducible IL-1β was significantly suppressed by pretreatment with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide, but not by pretreatment with the O2(-) scavenger N-acetyl cysteine, suggesting the close association of NO with IL-1β induction. The pretreatment of microglia with the inducible NO synthase inhibitor 1400W prior to LPS stimulation significantly reduced the production of IL-1β, and the addition of the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) into microglia led to the induction of IL-1β. These results suggested that NO induces IL-1β through a specific signaling cascade. LPS-dependent IL-1β induction was significantly suppressed by inhibitors of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor kappaB (NFκB), indicating that ERK/JNK and NFκB serve in the cascade of IL-1β induction. As expected, ERK/JNK and NFκB were all activated in the SNAP-stimulated microglia. Taken together, these results indicate that NO is an important signaling molecule for the ERK/JNK and NFκB activations, which are requisite to the induction of IL-1β in microglia.}, }
@article {pmid26334094, year = {2015}, author = {Zhuang, L and Xu, L and Wang, P and Jiang, Y and Yong, P and Zhang, C and Zhang, H and Meng, Z and Yang, P}, title = {Na+/K+-ATPase α1 subunit, a novel therapeutic target for hepatocellular carcinoma.}, journal = {Oncotarget}, volume = {6}, number = {29}, pages = {28183-28193}, pmid = {26334094}, issn = {1949-2553}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects/genetics ; Blotting, Western ; Carcinoma, Hepatocellular/drug therapy/*genetics/metabolism ; Cell Cycle Checkpoints/drug effects/genetics ; Cell Line, Tumor ; Cell Movement/drug effects/genetics ; Cell Proliferation/drug effects/genetics ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects/*genetics ; Hep G2 Cells ; Humans ; Liver Neoplasms/drug therapy/*genetics/metabolism ; Molecular Targeted Therapy ; RNA Interference ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sodium-Potassium-Exchanging ATPase/antagonists &amp; inhibitors/*genetics/metabolism ; }, abstract = {We aimed to identify the expression patterns of Na+/K+-ATPase (NKA) α subunits in human hepatocellular carcinoma (HCC) samples and evaluate these subunits as potential targets for HCC treatment. The mRNA expression profiles of NKA α subunits in human HCC samples were analyzed. We found that the mRNA expression for NKA α1 subunit (ATP1A1) was higher than that for other NKA α subunits. Also, ATP1A1 gene expression was markedly higher in HCC samples than in adjacent nontumor tissue samples. Western blotting data suggested that 6 of 14 (43%) HCC samples had elevated ATP1A1 protein expression. Furthermore, knockdown of ATP1A1 expression in human HCC HepG2 and MHCC97H cells markedly reduced their proliferation in vitro and suppressed the tumorigenicity of MHCC97H cells in vivo. Downregulation of ATP1A1 expression resulted in cell-cycle arrest at G2/M phase and apoptosis in HepG2 cells as well as decreased migration in Hep3B cells. We further validated that ATP1A1 downregulation caused intracellular accumulation of reactive oxygen species. Pretreatment with N-acetyl cysteine blocked cell-growth inhibition induced by ATP1A1 downregulation. Collectively, these data suggested that targeting ATP1A1 is a novel approach to the treatment of HCC.}, }
@article {pmid26332274, year = {2016}, author = {Pu, X and Wang, Z and Zhou, S and Klaunig, JE}, title = {Protective effects of antioxidants on acrylonitrile-induced oxidative stress in female F344 rats.}, journal = {Environmental toxicology}, volume = {31}, number = {12}, pages = {1808-1818}, doi = {10.1002/tox.22182}, pmid = {26332274}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Acrylonitrile/*toxicity ; Animals ; Antioxidants/*pharmacology ; Biomarkers/metabolism ; Brain/*drug effects/metabolism ; Camellia sinensis/chemistry ; Carcinogens/*toxicity ; DNA Damage/drug effects ; Dietary Supplements ; Female ; Oxidative Stress/*drug effects ; Polyphenols/pharmacology ; Rats, Inbred F344 ; Selenium/pharmacology ; Taurine/pharmacology ; Vitamin E/pharmacology ; }, abstract = {The induction of oxidative stress and damage appears to be involved in acrylonitrile induction of brain astrocytomas in rat. The present study examined the effects of dietary antioxidant supplementation on acrylonitrile-induced oxidative stress and oxidative damage in rats in vivo. To assess the effects of antioxidants on biomarkers of acrylonitrile-induced oxidative stress, female F344 rats were provided with diets containing vitamin E (0.05%), green tea polyphenols (GTP, 0.4%), N-acetyl cysteine (NAC, 0.3%), sodium selenite (0.1mg/kg), and taurine (10g/kg) for 7 days, and then co-administered with 0 and 100 ppm acrylonitrile in drinking water for 28 days. Significant increase in oxidative DNA damage in brain, evidenced by elevated 8OHdG levels, was seen in acrylonitrile-exposed rats. Supplementation with vitamin E, GTP, and NAC reduced acrylonitrile-induced oxidative DNA damage in brain while no protective effects were seen with the selenium or taurine supplementation. Acrylonitrile increased oxidative DNA damage, measured by the fpg-modified alkaline Comet assay in rat WBCs, which was reduced by supplementation of Vitamin E, GTP, NAC, selenium, and taurine. In addition to stimulation of oxidative DNA damage, acrylonitrile triggered induction of pro-inflammatory cytokines Tnfα, Il-1β, and Ccl2, and the growth stimulatory cyclin D1 and cyclin D2 genes, which were effectively down-regulated with antioxidant treatment. Antioxidant treatment also was able to stimulate the pro-apoptotic genes Bad, Bax, and FasL and DNA repair genes Xrcc6 and Gadd45α. The results of this study support the involvement of oxidative stress in the development of acrylonitrile-induced astrocytomas and suggest that antioxidants block acrylonitrile-mediated damage through mechanisms that may involve in the suppression of inflammatory responses, inhibition of cell proliferation and stimulation of apoptosis. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1808-1818, 2016.}, }
@article {pmid26331942, year = {2015}, author = {Oldham, JM and Ma, SF and Martinez, FJ and Anstrom, KJ and Raghu, G and Schwartz, DA and Valenzi, E and Witt, L and Lee, C and Vij, R and Huang, Y and Strek, ME and Noth, I and , }, title = {TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis.}, journal = {American journal of respiratory and critical care medicine}, volume = {192}, number = {12}, pages = {1475-1482}, pmid = {26331942}, issn = {1535-4970}, support = {UL1 TR000430/TR/NCATS NIH HHS/United States ; T32 HL007605/HL/NHLBI NIH HHS/United States ; U10 HL080513/HL/NHLBI NIH HHS/United States ; R01 HL097163/HL/NHLBI NIH HHS/United States ; R33 HL120770/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Cohort Studies ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/*genetics/immunology ; Intracellular Signaling Peptides and Proteins/*genetics/immunology ; Male ; Mucin-5B/*genetics/immunology ; Polymorphism, Single Nucleotide/genetics/immunology ; Risk ; }, abstract = {RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease of unknown etiology. The genes TOLLIP and MUC5B play important roles in lung host defense, which is an immune process influenced by oxidative signaling. Whether polymorphisms in TOLLIP and MUC5B modify the effect of immunosuppressive and antioxidant therapy in individuals with IPF is unknown.<br><br>OBJECTIVES: To determine whether single-nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B modify the effect of interventions in subjects participating in the Evaluating the Effectiveness of Prednisone, Azathioprine, and N-Acetylcysteine in Patients with Idiopathic Pulmonary Fibrosis (PANTHER-IPF) clinical trial.<br><br>METHODS: SNPs within TOLLIP (rs5743890/rs5743894/rs5743854/rs3750920) and MUC5B (rs35705950) were genotyped. Interaction modeling was conducted with multivariable Cox regression followed by genotype-stratified survival analysis using a composite endpoint of death, transplantation, hospitalization, or a decline of &#x2265; 10% in FVC.<br><br>MEASUREMENTS AND MAIN RESULTS: Significant interaction was observed between N-acetylcysteine (NAC) therapy and rs3750920 within TOLLIP (P interaction = 0.001). After stratifying by rs3750920 genotype, NAC therapy was associated with a significant reduction in composite endpoint risk (hazard ratio, 0.14; 95% confidence interval, 0.02-0.83; P = 0.03) in those with a TT genotype, but a nonsignificant increase in composite endpoint risk (hazard ratio, 3.23; 95% confidence interval, 0.79-13.16; P = 0.10) was seen in those with a CC genotype. These findings were then replicated in an independent IPF cohort.<br><br>CONCLUSIONS: NAC may be an efficacious therapy for individuals with IPF with an rs3750920 (TOLLIP) TT genotype, but it was associated with a trend toward harm in those with a CC genotype. A genotype-stratified prospective clinical trial should be conducted before any recommendation regarding the use of off-label NAC to treat IPF.}, }
@article {pmid26331632, year = {2015}, author = {Fu, J and Zhu, Y and Yerke, A and Wise, ML and Johnson, J and Chu, Y and Sang, S}, title = {Oat avenanthramides induce heme oxygenase-1 expression via Nrf2-mediated signaling in HK-2 cells.}, journal = {Molecular nutrition &amp; food research}, volume = {59}, number = {12}, pages = {2471-2479}, doi = {10.1002/mnfr.201500250}, pmid = {26331632}, issn = {1613-4133}, mesh = {Antioxidants/pharmacology ; Avena/*chemistry ; Cell Line ; Dose-Response Relationship, Drug ; Heme Oxygenase-1/*metabolism ; Humans ; Kidney Tubules, Proximal/cytology/*drug effects/metabolism ; NF-E2-Related Factor 2/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Transport/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; ortho-Aminobenzoates/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {SCOPE: Numerous studies have shown that avenanthramides (AVAs), unique compounds found in oats, are strong antioxidants, though the mechanism of action remains unclear. Here, we investigated whether AVAs affect heme oxygenase-1 (HO-1) expression through the activation of Nrf2 translocation.<br><br>METHODS AND RESULTS: We investigated the effects AVA 2c, 2f, and 2p on HK-2 cells, and found that AVAs could significantly increase HO-1 expression in both a dose- and time-dependent manner. Furthermore, we found that AVA-induced HO-1 expression is mediated by Nrf2 translocation. The addition of N-acetylcysteine (NAC), but not specific inhibitors of p38 (SB202190), PI3K (LY294002), and MEK1 (PD098059) attenuated AVA-induced HO-1 expression, demonstrating an important role for reactive oxygen species, but not PI3K or MAPK activation, in activating the HO-1 pathway. Moreover, hydrogenation of the double bond of the functional &#x3b1;,&#x3b2;-unsaturated carbonyl group of AVAs eliminated their effects on HO-1 expression, suggesting that this group is crucial for the antioxidant activity of AVAs.<br><br>CONCLUSION: Our results suggest a novel mechanism whereby AVAs exert an antioxidant function on human health. Further investigation of these markers in human is warranted to explore the beneficial health effects of whole grain oat intake.}, }
@article {pmid26324807, year = {2015}, author = {Cazzola, M and Calzetta, L and Page, C and Jardim, J and Chuchalin, AG and Rogliani, P and Matera, MG}, title = {Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis.}, journal = {European respiratory review : an official journal of the European Respiratory Society}, volume = {24}, number = {137}, pages = {451-461}, pmid = {26324807}, issn = {1600-0617}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Bronchitis, Chronic/diagnosis/*drug therapy/physiopathology ; Bronchodilator Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Disease Progression ; Humans ; Lung/*drug effects/physiopathology ; Pulmonary Disease, Chronic Obstructive/diagnosis/*drug therapy/physiopathology ; Treatment Outcome ; }, abstract = {In order to clarify the possible role of N-acetylcysteine (NAC) in the treatment of patients with chronic bronchitis and chronic obstructive pulmonary disease (COPD), we have carried out a meta-analysis testing the available evidence that NAC treatment may be effective in preventing exacerbations of chronic bronchitis or COPD and evaluating whether there is a substantial difference between the responses induced by low (≤ 600 mg per day) and high (> 600 mg per day) doses of NAC. The results of the present meta-analysis (13 studies, 4155 COPD patients, NAC n = 1933; placebo or controls n = 2222) showed that patients treated with NAC had significantly and consistently fewer exacerbations of chronic bronchitis or COPD (relative risk 0.75, 95% CI 0.66-0.84; p < 0.01), although this protective effect was more apparent in patients without evidence of airway obstruction. However, high doses of NAC were also effective in patients suffering from COPD diagnosed using spirometric criteria (relative risk 0.75, 95% CI 0.68-0.82; p = 0.04). NAC was well tolerated and the risk of adverse reactions was not dose-dependent (low doses relative risk 0.93, 95% CI 0.89-0.97; p = 0.40; high doses relative risk 1.11, 95% CI 0.89-1.39; p = 0.58). The strong signal that comes from this meta-analysis leads us to state that if a patient suffering from chronic bronchitis presents a documented airway obstruction, NAC should be administered at a dose of ≥ 1200 mg per day to prevent exacerbations, while if a patient suffers from chronic bronchitis, but is without airway obstruction, a regular treatment of 600 mg per day seems to be sufficient.}, }
@article {pmid26321125, year = {2015}, author = {Saify, K and Saadat, M}, title = {Expression patterns of antioxidant genes in human SH-SY5Y cells after treatment with methadone.}, journal = {Psychiatry research}, volume = {230}, number = {1}, pages = {116-119}, doi = {10.1016/j.psychres.2015.08.027}, pmid = {26321125}, issn = {1872-7123}, mesh = {Antioxidants/*physiology ; Cell Line, Tumor ; Cell Survival/*drug effects/physiology ; Dose-Response Relationship, Drug ; Down-Regulation/physiology ; *Gene Expression Regulation, Neoplastic ; Growth Inhibitors/*pharmacology ; Humans ; Methadone/*pharmacology ; Reactive Oxygen Species/metabolism ; Treatment Outcome ; }, abstract = {The expression levels of nine antioxidant genes in SH-SY5Y cells exposed to methadone (final concentrations 1-20µM) were investigated. Based on this study the genes could be categorized on three different groups. The number of down-regulated genes were increased as a function of exposure time (P=0.004). The methadone associated mRNA alterations were modulated by N-acetyl-cysteine. These findings suggested that different pathways for regulation of antioxidant genes could be active after exposing of SH-SY5Y cells to methadone; and also suggested that methadone might act by inducing the reactive oxygen species.}, }
@article {pmid26320741, year = {2016}, author = {Singh, A and Singh, V and Tiwari, RL and Chandra, T and Kumar, A and Dikshit, M and Barthwal, MK}, title = {The IRAK-ERK-p67phox-Nox-2 axis mediates TLR4, 2-induced ROS production for IL-1β transcription and processing in monocytes.}, journal = {Cellular &amp; molecular immunology}, volume = {13}, number = {6}, pages = {745-763}, pmid = {26320741}, issn = {2042-0226}, mesh = {Cell Line ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Interleukin-1 Receptor-Associated Kinases/*metabolism ; Interleukin-1beta/*genetics/metabolism ; Lipopeptides/pharmacology ; Lipopolysaccharides/pharmacology ; Membrane Glycoproteins/*metabolism ; Monocytes/drug effects/*metabolism ; NADPH Oxidase 2 ; NADPH Oxidases/*metabolism ; Phosphoproteins/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 2/*metabolism ; Toll-Like Receptor 4/*metabolism ; Transcription Factor AP-1/metabolism ; *Transcription, Genetic/drug effects ; }, abstract = {In monocytic cells, Toll-like receptor 4 (TLR4)- and TLR2-induced reactive oxygen species (ROS) cause oxidative stress and inflammatory response; however, the mechanism is not well understood. The present study investigated the role of interleukin-1 receptor-associated kinase (IRAK), extracellular signal-regulated kinase (ERK), p67phox and Nox-2 in TLR4- and TLR2-induced ROS generation during interleukin-1 beta (IL-1β) transcription, processing, and secretion. An IRAK1/4 inhibitor, U0126, PD98059, an NADPH oxidase inhibitor (diphenyleneiodonium (DPI)), and a free radical scavenger (N-acetyl cysteine (NAC))-attenuated TLR4 (lipopolysaccharide (LPS))- and TLR2 (Pam3csk4)-induced ROS generation and IL-1β production in THP-1 and primary human monocytes. An IRAK1/4 inhibitor and siRNA-attenuated LPS- and Pam3csk4-induced ERK-IRAK1 association and ERK phosphorylation and activity. LPS and Pam3csk4 also induced IRAK1/4-, ERK- and ROS-dependent activation of activator protein-1 (AP-1), IL-1β transcription, and IL-1β processing because significant inhibition in AP-1 activity, IL-1β transcription, Pro- and mature IL-β expression, and caspase-1 activity was observed with PD98059, U0126, DPI, NAC, an IRAK1/4 inhibitor, tanshinone IIa, and IRAK1 siRNA treatment. IRAK-dependent ERK-p67phox interaction, p67phox translocation, and p67phox-Nox-2 interaction were observed. Nox-2 siRNA significantly reduced secreted IL-1β, IL-1β transcript, pro- and mature IL-1β expression, and caspase-1 activity indicating a role for Nox-2 in LPS- and Pam3csk4-induced IL-1β production, transcription, and processing. In the present study, we demonstrate that the TLR4- and TLR2-induced IRAK-ERK pathway cross-talks with p67phox-Nox-2 for ROS generation, thus regulating IL-1β transcription and processing in monocytic cells.}, }
@article {pmid26317351, year = {2015}, author = {Kim, YJ and Lee, DH and Ahn, J and Chung, WJ and Jang, YJ and Seong, KS and Moon, JH and Ha, TY and Jung, CH}, title = {Pharmacokinetics, Tissue Distribution, and Anti-Lipogenic/Adipogenic Effects of Allyl-Isothiocyanate Metabolites.}, journal = {PloS one}, volume = {10}, number = {8}, pages = {e0132151}, pmid = {26317351}, issn = {1932-6203}, mesh = {3T3 Cells ; Acetylcysteine/metabolism ; Adipogenesis/*drug effects ; Administration, Oral ; Animals ; Gene Expression Regulation/drug effects ; Glutathione/metabolism ; Isothiocyanates/*administration &amp; dosage/*pharmacokinetics/urine ; Lipid Metabolism/*drug effects ; Lipogenesis/*drug effects ; Male ; Mice ; Oleic Acid/pharmacology ; Rats ; Tissue Distribution ; }, abstract = {Allyl-isothiocyanate (AITC) is an organosulfur phytochemical found in abundance in common cruciferous vegetables such as mustard, wasabi, and cabbage. Although AITC is metabolized primarily through the mercapturic acid pathway, its exact pharmacokinetics remains undefined and the biological function of AITC metabolites is still largely unknown. In this study, we evaluated the inhibitory effects of AITC metabolites on lipid accumulation in vitro and elucidated the pharmacokinetics and tissue distribution of AITC metabolites in rats. We found that AITC metabolites generally conjugate with glutathione (GSH) or N-acetylcysteine (NAC) and are distributed in most organs and tissues. Pharmacokinetic analysis showed a rapid uptake and complete metabolism of AITC following oral administration to rats. Although AITC has been reported to exhibit anti-tumor activity in bladder cancer, the potential bioactivity of its metabolites has not been explored. We found that GSH-AITC and NAC-AITC effectively inhibit adipogenic differentiation of 3T3-L1 preadipocytes and suppress expression of PPAR-γ, C/EBPα, and FAS, which are up-regulated during adipogenesis. GSH-AITC and NAC-AITC also suppressed oleic acid-induced lipid accumulation and lipogenesis in hepatocytes. Our findings suggest that AITC is almost completely metabolized in the liver and rapidly excreted in urine through the mercapturic acid pathway following administration in rats. AITC metabolites may exert anti-obesity effects through suppression of adipogenesis or lipogenesis.}, }
@article {pmid26316066, year = {2015}, author = {Seixas, JD and Chaves-Ferreira, M and Montes-Grajales, D and Gonçalves, AM and Marques, AR and Saraiva, LM and Olivero-Verbel, J and Romão, CC and Bernardes, GJ}, title = {An N-Acetyl Cysteine Ruthenium Tricarbonyl Conjugate Enables Simultaneous Release of CO and Ablation of Reactive Oxygen Species.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {21}, number = {42}, pages = {14708-14712}, pmid = {26316066}, issn = {1521-3765}, abstract = {We have designed and synthesised a [Ru(CO)3 Cl2 (NAC)] pro-drug that features an N-acetyl cysteine (NAC) ligand. This NAC carbon monoxide releasing molecule (CORM) conjugate is able to simultaneously release biologically active CO and to ablate the concurrent formation of reactive oxygen species (ROS). Complexes of the general formulae [Ru(CO)3 (L)3 ](2+) , including [Ru(CO)3 Cl(glycinate)] (CORM-3), have been shown to produce ROS through a water-gas shift reaction, which contributes significantly, for example, to their antibacterial activity. In contrast, NAC-CORM conjugates do not produce ROS or possess antibacterial activity. In addition, we demonstrate the synergistic effect of CO and NAC both for the inhibition of nitric oxide (formation) and in the expression of tumour-necrosis factor (TNF)-α. This work highlights the advantages of combining a CO-releasing scaffold with the anti-oxidant and anti-inflammatory drug NAC in a unique pro-drug.}, }
@article {pmid26313520, year = {2015}, author = {Koizumi, C and Yamada, M and Ishizaki, K and Ueda, T and Sakurai, K}, title = {Anti-infective control in human bronchiolar epithelial cells by mucin phenotypic changes following uptake of N-acetyl-L-cysteine.}, journal = {Free radical research}, volume = {49}, number = {12}, pages = {1449-1458}, doi = {10.3109/10715762.2015.1087642}, pmid = {26313520}, issn = {1029-2470}, mesh = {Acetylcysteine/immunology/*metabolism ; Bronchioles/immunology/metabolism ; Cells, Cultured ; Coculture Techniques ; Epithelial Cells/immunology/*metabolism ; Fluorescent Antibody Technique ; Humans ; In Vitro Techniques ; Mucins/*biosynthesis/immunology ; Oxidation-Reduction ; Phenotype ; Pneumonia, Aspiration/immunology/metabolism ; Pneumonia, Pneumococcal/immunology/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Streptococcus pneumoniae ; }, abstract = {PURPOSE: Aspiration pneumonia is infection of the respiratory tract resulting from accumulation of sputum in the larynx. N-acetyl-L-cysteine (NAC) might regulate mucin (MUC) expression and activate inherent anti-infective system in bronchiolar epithelial cells after cellular uptake, and therefore, serve as the preventative agent for chronic lung disease including aspiration pneumonia. The purpose of this in vitro study was to evaluate the effect of uptake of NAC by human bronchiolar epithelial cells on bacterial infection and regulations of mucin expression in association with cellular redox status under co-culture with a representative pathogen for hospital- and community-acquired pneumonia, Streptococcus pneumoniae.<br><br>MATERIALS AND METHODS: Human bronchiolar epithelial cells preincubated with or without 20 mM NAC for 3 h were co-cultured with or without bacteria for 8 h and evaluated with respect to cellular redox balance, expressions of various types of MUC, proinflammatory cytokines and mediators, and bacterial infection state by biochemical, genetic, and immunofluorescent assays.<br><br>RESULTS: Markedly increased intracellular reactive oxygen species and oxidized glutathione levels plus increased release and expression of proinflammatory cytokines and mediators were observed in cells co-cultured with bacteria. These bacteria-induced cellular redox disturbance and proinflammatory events were prevented and alleviated by pretreatment with NAC. Cells co-cultured with bacteria did not increase expression of anti-infective membranous MUC4 but exhibited increases in gel-forming MUC5AC expression and bacterial infection. However, NAC-pretreated cells avoided bacterial infection along with enhancement of MUC4, but not MUC5AC, expression.<br><br>CONCLUSION: Uptake of NAC by human bronchiolar epithelial cells prevented bacterial infection and upregulated membranous, but not gel-forming, MUC expression along with the increase in intracellular antioxidant level under co-culture conditions with S. pneumoniae.}, }
@article {pmid26309524, year = {2015}, author = {Yu, WC and Tian, LY and Cheng, W}, title = {Efficacy study of edaravone and acetylcysteine towards bleomycin-induced rat pulmonary fibrosis.}, journal = {International journal of clinical and experimental medicine}, volume = {8}, number = {6}, pages = {8730-8739}, pmid = {26309524}, issn = {1940-5901}, abstract = {The aim of this study was to investigate the interventional effects of Edaravone (EDA) and Acetylcysteine (NAC) towards the Bleomycin (BLM)-induced pulmonary fibrosis. 48 Wistar rats were divided into the control group, the BLM group, the hormone group, the EDA group, the NAC group and the combination group. After performing the BLM intratracheal injection to prepare the pulmonary fibrosis model, the rats were administrated EDA, dexamethasone (DEX), NAC and EDA+NAC combined intervention, the lung HRCT examination was performed on the 7(th), 21(st) and 31(st) day. On the 31(st) day, the rats were killed for the detection of serum malondialdehyde (MDA) and superoxide dismutase (SOD) contents; the lung tissues were performed the HE and Masson staining and determined the hydroxyproline content. The rats of the intervention group exhibited mild hypoxic phenomenon, with less ground-glass shadow and consolidated shadow than the BLM group, the MDA content decreased while the SOD content increased, and the degrees of alveolar inflammatory cell infiltration and fibrosis were low. The results of the EDA group and the NAC group were similar, and those of the combination group were better. EDA could inhibit the BLM-induced pulmonary fibrosis through adjusting the oxidant/antioxidant imbalance, with the effect similar to NAC, and the combined application of these 2 drugs were much more effective.}, }
@article {pmid26305534, year = {2015}, author = {Park, JH and Kang, SS and Kim, JY and Tchah, H}, title = {The Antioxidant N-Acetylcysteine Inhibits Inflammatory and Apoptotic Processes in Human Conjunctival Epithelial Cells in a High-Glucose Environment.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {56}, number = {9}, pages = {5614-5621}, doi = {10.1167/iovs.15-16909}, pmid = {26305534}, issn = {1552-5783}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cells, Cultured ; Conjunctiva/drug effects/metabolism/*pathology ; Epithelial Cells/drug effects/*metabolism/pathology ; Flow Cytometry ; Glucose/*pharmacology ; Humans ; Hyperglycemia/metabolism/*pathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {PURPOSE: We evaluated the effects of N-acetylcysteine (NAC), which is known to inhibit reactive oxygen species (ROS)-dependent apoptosis, on high glucose-induced ROS, apoptosis, inflammation, and delayed-wounding closure in primary cultured human conjunctival epithelial cells (pHCECs), and the regulatory effects of cleaved caspase-3, BAX, nuclear factor κB (NF-κB), IL-6, and TNF-α on these processes.<br><br>METHODS: High glucose-induced ROS generation was measured using 2',7'-dichlorofluorescein diacetate (DCFH-DA). The effects of NAC on high glucose-induced apoptosis were investigated in pHCECs using Annexin-V and PI staining, and cleaved caspase-3 and BAX expression levels using immunoblotting. To evaluate the inflammatory response, IL-6 and TNF-&#x3b1; expression levels were quantified by multiplex cytokine analysis, and NF-&#x3ba;B activation and IkB-&#x3b1; degradation were assessed by Western blot analysis. The effects of NAC on high glucose-delayed conjunctival epithelial wound healing were assessed by a scratch-induced directional wounding assay.<br><br>RESULTS: Compared to the untreated control and normal glucose (5 mM), high glucose at 25 mM stimulated ROS generation, apoptosis, and release of inflammatory cytokines, and delayed wound healing in pHCECs. The addition of NAC markedly reduced the high glucose-induced ROS activation, Annexin-PI-positive cells, and levels of cleaved caspase-3, BAX, IL-6, and TNF-&#x3b1;. N-acetylcysteine also prevented high glucose-delayed wound healing.<br><br>CONCLUSIONS: High glucose levels promote apoptosis by affecting mitochondria-dependent caspase activity through elevation of ROS production, a process that can be reversed by the antioxidant NAC. These findings demonstrate that NAC has a beneficial effect on conjunctival epithelial cell wound healing, antiapoptosis, and anti-inflammation in the conjunctival epithelial cell.}, }
@article {pmid26303969, year = {2015}, author = {Lee, D and Kook, SH and Ji, H and Lee, SA and Choi, KC and Lee, KY and Lee, JC}, title = {N-acetyl cysteine inhibits H2O2-mediated reduction in the mineralization of MC3T3-E1 cells by down-regulating Nrf2/HO-1 pathway.}, journal = {BMB reports}, volume = {48}, number = {11}, pages = {636-641}, pmid = {26303969}, issn = {1976-670X}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology/*therapeutic use ; Animals ; Cell Differentiation/drug effects ; Core Binding Factor Alpha 1 Subunit/metabolism ; Down-Regulation/drug effects ; Heme Oxygenase-1/metabolism ; Humans ; Hydrogen Peroxide/*antagonists &amp; inhibitors/*pharmacology ; Mice ; NF-E2-Related Factor 2/*metabolism ; Osteoblasts ; Osteocalcin/metabolism ; Osteogenesis/drug effects ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; }, abstract = {There are controversial findings regarding the roles of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway on bone metabolism under oxidative stress. We investigated how Nrf2/HO-1 pathway affects osteoblast differentiation of MC3T3-E1 cells in response to hydrogen peroxide (H2O2), N-acetyl cysteine (NAC), or both. Exposing the cells to H2O2 decreased the alkaline phosphatase activity, calcium accumulation, and expression of osteoblast markers, such as osteocalcin and runt-related transcription factor-2. In contrast, H2O2 treatment increased the expression of Nrf2 and HO-1 in the cells. Treatment with hemin, a chemical HO-1 inducer, mimicked the inhibitory effect of H2O2 on osteoblast differentiation by increasing the HO-1 expression and decreasing the osteogenic marker genes. Pretreatment with NAC restored all changes induced by H2O2 to near normal levels in the cells. Collectively, our findings suggest that H2O2-mediated activation of Nrf2/HO-1 pathway negatively regulates the osteoblast differentiation, which is inhibited by NAC.}, }
@article {pmid26303504, year = {2016}, author = {Yan, Z and Wang, J and Li, J and Jiang, N and Zhang, R and Yang, W and Yao, W and Wu, W}, title = {Oxidative stress and endocytosis are involved in upregulation of interleukin-8 expression in airway cells exposed to PM2.5.}, journal = {Environmental toxicology}, volume = {31}, number = {12}, pages = {1869-1878}, doi = {10.1002/tox.22188}, pmid = {26303504}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/*toxicity ; Antioxidants/pharmacology ; Bronchi/cytology/*drug effects/metabolism ; Cell Line ; *Endocytosis ; Epithelial Cells/drug effects ; Humans ; Interleukin-8/*metabolism ; Macrophages/cytology/drug effects/metabolism ; *Oxidative Stress ; Particulate Matter/*toxicity ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/cytology/*drug effects/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation ; }, abstract = {Inhaled PM2.5 (particulate matter with an aerodynamic diameter of 2.5 μm or less) can induce lung inflammation through released inflammatory mediators from airway cells, such as interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α). However, the mechanisms underlying PM2.5-induced IL-8 gene expression have not been fully characterized. BEAS-2B cells (a human bronchial epithelial cell line) and THP-1 cells (a human macrophage-like cell line) were used as the in vitro models to investigate the underlying mechanism in this study. IL-8 expression was increased in the cells treated with PM2.5 in a dose-dependent manner. The water-soluble and insoluble fractions of PM2.5 suspension were both shown to induce IL-8 expression. PM2.5 exposure could obviously induce ROS (reactive oxygen species) generation, indicative of oxidative stress. Pretreatment with the antioxidant N-acetyl-l-cysteine (NAC) potently inhibited PM2.5-induced IL-8 expression. Employment of the transition metal chelators including TPEN (N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine) or DFO (desferrioxamine) inhibited IL-8 expression induced by PM2.5 by over 20% in BEAS-2B cells, but had minimal effect in THP-1 cells. Pretreatment with the endocytosis inhibitor CytD markedly blocked IL-8 expression induced by PM2.5 in both BEAS-2B and THP-1 cells. In summary, exposure to PM2.5 induced IL-8 gene expression through oxidative stress induction and endocytosis in airway cells. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1869-1878, 2016.}, }
@article {pmid26302927, year = {2015}, author = {Oliveira, VA and Oliveira, CS and Mesquita, M and Pedroso, TF and Costa, LM and Fiuza, Tda L and Pereira, ME}, title = {Zinc and N-acetylcysteine modify mercury distribution and promote increase in hepatic metallothionein levels.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {32}, number = {}, pages = {183-188}, doi = {10.1016/j.jtemb.2015.06.006}, pmid = {26302927}, issn = {1878-3252}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Creatinine/blood ; Female ; Kidney/drug effects/metabolism ; Liver/drug effects/*metabolism ; Mercury/*blood ; Metallothionein/*metabolism ; Porphobilinogen Synthase/metabolism ; Rats, Wistar ; Sulfhydryl Compounds/metabolism ; Urea/blood ; Zinc/blood/*pharmacology ; }, abstract = {This study investigated the ability of zinc (Zn) and N-acetylcysteine (NAC) in preventing the biochemical alterations caused by mercury (Hg) and the retention of this metal in different organs. Adult female rats received ZnCl2 (27mg/kg) and/or NAC (5mg/kg) or saline (0.9%) subcutaneously and after 24h they received HgCl2 (5mg/kg) or saline (0.9%). Twenty-four hours after, they were sacrificed and analyses were performed. Hg inhibited hepatic, renal, and blood δ-aminolevulinic acid dehydratase (δ-ALA-D) activity, decreased renal total thiol levels, as well as increased serum creatinine and urea levels and aspartate aminotransferase activity. HgCl2-exposed groups presented an important retention of Hg in all the tissues analyzed. All pre-treatments demonstrated tendency in preventing hepatic δ-ALA-D inhibition, whereas only ZnCl2 showed this effect on blood enzyme. Moreover, the combination of these compounds completely prevented liver and blood Hg retention. The exposure to Zn and Hg increased hepatic metallothionein levels. These results show that Zn and NAC presented promising effects against the toxicity caused by HgCl2.}, }
@article {pmid26302043, year = {2015}, author = {de Vasconcellos, JF and Laranjeira, AB and Leal, PC and Bhasin, MK and Zenatti, PP and Nunes, RJ and Yunes, RA and Nowill, AE and Libermann, TA and Zerbini, LF and Yunes, JA}, title = {SB225002 Induces Cell Death and Cell Cycle Arrest in Acute Lymphoblastic Leukemia Cells through the Activation of GLIPR1.}, journal = {PloS one}, volume = {10}, number = {8}, pages = {e0134783}, pmid = {26302043}, issn = {1932-6203}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Cell Cycle/*drug effects ; Cell Death/*drug effects ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Silencing ; Humans ; Jurkat Cells ; Membrane Proteins ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Proteins/*drug effects ; Neoplasm Transplantation ; Nerve Tissue Proteins/*drug effects ; Oligonucleotide Array Sequence Analysis ; Phenylurea Compounds/*pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; }, abstract = {Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1, a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1, seems to underlie the anti-leukemic effect of SB225002.}, }
@article {pmid26301645, year = {2015}, author = {Chong, E and Poh, KK and Lu, Q and Zhang, JJ and Tan, N and Hou, XM and Ong, HY and Azan, A and Chen, SL and Chen, JY and Ali, RM and Fang, WY and Lau, TW and Tan, HC}, title = {Comparison of combination therapy of high-dose oral N-acetylcysteine and intravenous sodium bicarbonate hydration with individual therapies in the reduction of Contrast-induced Nephropathy during Cardiac Catheterisation and Percutaneous Coronary Intervention (CONTRAST): A multi-centre, randomised, controlled trial.}, journal = {International journal of cardiology}, volume = {201}, number = {}, pages = {237-242}, doi = {10.1016/j.ijcard.2015.07.108}, pmid = {26301645}, issn = {1874-1754}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Cardiac Catheterization/adverse effects/*methods ; China/epidemiology ; Contrast Media/*adverse effects ; Coronary Angiography/adverse effects ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Fluid Therapy/*methods ; Follow-Up Studies ; Glomerular Filtration Rate/physiology ; Humans ; Incidence ; Infusions, Intravenous ; Kidney Function Tests ; Malaysia/epidemiology ; Male ; Percutaneous Coronary Intervention/adverse effects/*methods ; Prognosis ; Renal Insufficiency/chemically induced/*drug therapy/epidemiology ; Singapore/epidemiology ; Sodium Bicarbonate/*administration &amp; dosage ; Survival Rate/trends ; }, abstract = {INTRODUCTION: N-acetylcysteine (NAC) and sodium bicarbonate (SOB) therapies may prevent contrast-induced nephropathy (CIN). However, the efficacy of using combination over individual therapies was not established, and there was no large randomised study comparing abbreviated SOB therapy with conventional sustained saline pre-hydration with oral NAC.<br><br>METHODS: In a multi-centre, open-label, randomised, controlled trial (NCT00497328), we prospectively enrolled 548 patients with at least moderate renal impairment undergoing cardiac catheterisation with or without percutaneous coronary intervention. Patients were randomly assigned to 3 groups: 1) NAC: 154 mEq/L sustained sodium chloride regime (1 mL/kg/h 12 h before, during and 6h after the procedure) with oral NAC at 1.2g bid for 3 days (n=185); 2) SOB: 154 mEq/L abbreviated SOB regime at 3 mL/kg/h 1h before the procedure, and 1 mL/kg/h during and 6h after the procedure (n=182); and 3) COM: combination of abbreviated SOB regime and oral NAC (n=181). The primary end point was incidence of CIN. The secondary end points were rise in serum creatinine, hospitalisation duration, haemodialysis, morbidity and mortality within 30 days.<br><br>RESULTS: The 3 groups had similar baseline characteristics: age 68 &#xb1; 10 years, 76% male, 48% diabetic and baseline glomerular filtration rate (GFR) 47.7 &#xb1; 13.0 mL/min. There were 41 (8.8%) patients with GFR<30. The CIN incidences were NAC 6.5%, SOB 12.8% and COM 10.6%. The COM regimen was not superior to either the NAC (relative risk (RR)=1.61, 95% confidence interval (CI): 0.76 to 3.45, p=0.225) or SOB (RR=0.83, 95% CI: 0.44 to 1.56, p=0.593) regimens. The CIN incidence was lower in the NAC group than the SOB group (adjusted odds ratio (OR)=0.40, 95% CI: 0.17 to 0.92; p=0.032). Multivariate analysis showed contrast volume (OR=1.99, 95% CI: 1.33 to 2.96, p<0.001 per 100mL), female (OR=2.47, 95% CI: 1.22 to 5.00, p=0.012) and diabetes (OR=2.03, 95% CI: 1.03 to 3.99, p=0.041) were independent risk predictors. There were no differences in the secondary outcomes among the 3 groups.<br><br>CONCLUSION: The combination regimen was not superior to individual regimens in preventing CIN in patients with baseline renal impairment. There was a trend suggesting that the 12-hour sustained sodium chloride pre-hydration regimen was more protective than the 1-hour abbreviated SOB regimen.}, }
@article {pmid26298721, year = {2016}, author = {Shin, SH and Choi, YJ and Lee, H and Kim, HS and Seo, SW}, title = {Oxidative stress induced by low-dose doxorubicin promotes the invasiveness of osteosarcoma cell line U2OS in vitro.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {37}, number = {2}, pages = {1591-1598}, pmid = {26298721}, issn = {1423-0380}, mesh = {Antineoplastic Agents/*pharmacology ; Bone Neoplasms/*pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Doxorubicin/*pharmacology ; Humans ; In Vitro Techniques ; Matrix Metalloproteinase 9/metabolism ; Neoplasm Invasiveness/pathology ; Osteosarcoma/*pathology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; }, abstract = {Reactive oxygen species (ROS) are known to mediate doxorubicin (DOX)-induced apoptosis and are the major cause of DOX toxicity. We introduce a novel in vitro phenomenon of osteosarcoma (OS) cell line caused by low-dose DOX-induced oxidative stress. Human osteosarcoma cell line U2OS was used for the experiments. Hydrogen peroxide (H2O2) and the antioxidant compound N-acetylcysteine (NAC) were used to investigate the involvement of oxidative stress. In proliferation assays, low dose of DOX (below 200 nM) did not affect U2OS proliferation significantly for up to 48 h. In Matrigel(TM) invasion assay, DOX increased the invasiveness of U2OS at around 100 nM, which is a subclinical concentration. Quantitative real-time polymerase chain reaction and gelatin zymography showed increased MMP-9 expression and increased MMP-9 enzymatic activity, respectively, in the presence of DOX doses that increased the invasiveness of U2OS. H2O2, a representative source of ROS, also increased the invasiveness of U2OS as DOX did, with similar patterns. However, when the cells were pre-treated with NAC, no DOX- or H2O2-mediated increase of invasiveness or MMP-9 expression was evident. The results suggest that oxidative stress induced by low-dose DOX promotes the invasiveness of osteosarcoma cell line U2OS in vitro, through MMP-9 induction.}, }
@article {pmid26296767, year = {2015}, author = {Deng, L and Chen, M and Tanaka, M and Ku, Y and Itoh, T and Shoji, I and Hotta, H}, title = {HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis.}, journal = {The Journal of general virology}, volume = {96}, number = {9}, pages = {2670-2683}, doi = {10.1099/jgv.0.000221}, pmid = {26296767}, issn = {1465-2099}, mesh = {*Apoptosis ; Apoptosis Regulatory Proteins/*genetics/metabolism ; Bcl-2-Like Protein 11 ; Caspase 3/genetics/metabolism ; Cell Line, Tumor ; Cytochromes c/genetics/metabolism ; Hepacivirus/genetics/*physiology ; Hepatitis C/enzymology/*metabolism/physiopathology/virology ; Humans ; MAP Kinase Kinase 4/genetics/*metabolism ; Membrane Proteins/*genetics/metabolism ; Mitochondria/enzymology/metabolism ; Proto-Oncogene Proteins/*genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Transcriptional Activation ; bcl-2-Associated X Protein/genetics/*metabolism ; }, abstract = {We previously reported that hepatitis C virus (HCV) infection induces Bax-triggered, mitochondrion-mediated apoptosis by using the HCV J6/JFH1 strain and Huh-7.5 cells. However, it was still unclear how HCV-induced Bax activation. In this study, we showed that the HCV-induced activation and mitochondrial accumulation of Bax were significantly attenuated by treatment with a general antioxidant, N-acetyl cysteine (NAC), or a specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, with the result suggesting that the reactive oxygen species (ROS)/JNK signalling pathway is upstream of Bax activation in HCV-induced apoptosis. We also demonstrated that HCV infection transcriptionally activated the gene for the pro-apoptotic protein Bim and the protein expression of three major splice variants of Bim (BimEL, BimL and BimS). The HCV-induced increase in the Bim mRNA and protein levels was significantly counteracted by treatment with NAC or SP600125, suggesting that the ROS/JNK signalling pathway is involved in Bim upregulation. Moreover, HCV infection led to a marked accumulation of Bim on the mitochondria to facilitate its interaction with Bax. On the other hand, downregulation of Bim by siRNA (small interfering RNA) significantly prevented HCV-mediated activation of Bax and caspase 3. Taken together, these observations suggest that HCV-induced ROS/JNK signalling transcriptionally activates Bim expression, which leads to Bax activation and apoptosis induction.}, }
@article {pmid26294195, year = {2015}, author = {Curtis, RM and Sivilotti, ML}, title = {A descriptive analysis of aspartate and alanine aminotransferase rise and fall following acetaminophen overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {53}, number = {9}, pages = {849-855}, doi = {10.3109/15563650.2015.1077968}, pmid = {26294195}, issn = {1556-9519}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Adult ; Aged ; Alanine Transaminase/*blood ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/therapeutic use ; Aspartate Aminotransferases/*blood ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/blood/*diagnosis/etiology/mortality/therapy ; *Clinical Enzyme Tests ; *Decision Support Techniques ; Drug Overdose ; Female ; Humans ; Kaplan-Meier Estimate ; Liver Transplantation ; Male ; Middle Aged ; Models, Biological ; Predictive Value of Tests ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {CONTEXT: Risk prediction following acetaminophen (paracetamol, APAP) overdose is based on serum APAP, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels. One recently proposed risk stratification tool, the APAPxAT multiplication product, uses either AST or ALT, whichever is higher, yet their interrelation is not well known following APAP-induced hepatic injury.<br><br>OBJECTIVE: To describe the kinetics of AST and ALT release into and disappearance from the circulation following APAP overdose.<br><br>MATERIALS AND METHODS: An observational case series of adult patients with peak AST or ALT > 100 IU/L attributable to APAP toxicity. Cases were identified by electronic search of hospital laboratory database and by discharge diagnosis corroborated by structured explicit medical record review.<br><br>RESULTS: Of 68 cases identified (mean age (SD): 39 (18) years, 63% female, and 21% ethanol co-ingested), 28 (41%) developed hepatotoxicity (peak AST or ALT > 1000 IU/L), 28 (41%) coagulopathy (international normalized ratio or INR > 2), and 21 (31%) both. Three patients (4%) were transferred for liver transplantation and ultimately six (8.8%) died. Serum AST and ALT activity rose in a closely aligned 1:1 AST:ALT ratio, but fell at distinctly different rates: AST activity fell with a half-life (interquartile range [IQR]) of 15.1 (12.2, 19.4) hours, and ALT 39.6 (32.9, 47.6) hours. Using an aminotransferase falling to below 50% of peak as the basis for discontinuing acetylcysteine would have resulted in antidotal treatment being stopped 24 (IQR: 9.6, 40) hours earlier (and in no cases later) using AST rather than ALT. Only six patients had an AST:ALT ratio greater than 2:1 at the time of acetylcysteine administration; of these six, four died and one survivor developed coagulopathy.<br><br>DISCUSSION: AST and ALT release into the circulation appears tightly linked and numerically similar, except in the sickest patients. Once the aminotransferases peak, AST returns to baseline more quickly.<br><br>CONCLUSION: Either AST or ALT can be used for early risk stratification tools when only one is known. Any criterion for N-AC discontinuation should be based on the decline of AST rather than ALT, with a potential benefit measured in days.}, }
@article {pmid26291957, year = {2016}, author = {Nguyen, HD and Choo, YY and Nguyen, TD and Nguyen, HN and Chau, VM and Lee, JH}, title = {7-Methoxy-(9H-β-Carbolin-1-il)-(E)-1-Propenoic Acid, a β-Carboline Alkaloid From Eurycoma longifolia, Exhibits Anti-Inflammatory Effects by Activating the Nrf2/Heme Oxygenase-1 Pathway.}, journal = {Journal of cellular biochemistry}, volume = {117}, number = {3}, pages = {659-670}, doi = {10.1002/jcb.25315}, pmid = {26291957}, issn = {1097-4644}, mesh = {Acrylates/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Carbolines/*pharmacology ; Cell Survival/drug effects ; Cyclooxygenase 2/metabolism ; Dinoprostone/metabolism ; Drug Evaluation, Preclinical ; Eurycoma/chemistry ; Heme Oxygenase-1/*metabolism ; Interleukin-6/metabolism ; Lipopolysaccharides/pharmacology ; MAP Kinase Signaling System ; Membrane Proteins/*metabolism ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/*metabolism ; NF-kappa B/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Plant Extracts/*pharmacology ; RAW 264.7 Cells ; Signal Transduction/immunology ; }, abstract = {Eurycoma longifolia is an herbal medicinal plant popularly used in Southeast Asian countries. In the present study, we show that 7-methoxy-(9H-β-carbolin-1-il)-(E)-1-propenoic acid (7-MCPA), a β-carboline alkaloid isolated from E. longifolia, exerted anti-inflammatory effects by activating the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. 7-MCPA inhibited lipopolysaccharide (LPS)-induced production of nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-6 (IL-6) in RAW264.7 cells and rescued C57BL/6 mice from LPS-induced lethality in vivo. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and IL-6 was also significantly suppressed by treatment of 7-MCPA in RAW264.7 cells. 7-MCPA induced nuclear translocation of Nrf2 and increased transcription of its target genes, such as HO-1. Treating RAW264.7 cells with 7-MCPA increased the intracellular level of reactive oxygen species (ROS) and the phosphorylation level of p38 mitogen-activated protein kinase (MAPK); however, co-treatment with the antioxidant N-acetyl-cysteine (NAC) blocked 7-MCPA-induced p38 MAPK phosphorylation. Moreover, NAC or SB203580 (p38 MAPK inhibitor) blocked 7-MCPA-induced nuclear translocation of Nrf2, suggesting that 7-MCPA activated Nrf2 via a ROS-dependent p38 pathway. 7-MCPA induced HO-1 protein and mRNA expression and knockdown of Nrf2 with siRNA or SB203580 blocked 7-MCPA-mediated induction of HO-1 expression. Inhibiting Nrf2 or HO-1 abrogated the anti-inflammatory effects of 7-MCPA in LPS-stimulated RAW264.7 cells. We also demonstrated that 7-MCPA suppressed LPS-induced nuclear factor κB (NF-κB) activation. These results provide the first evidence that 7-MCPA exerts its anti-inflammatory effect by modulating the Nrf2 and NF-κB pathways and may be a potential Nrf2 activator to prevent or treat inflammatory diseases.}, }
@article {pmid26291797, year = {2015}, author = {Maged, AM and Elsawah, H and Abdelhafez, A and Bakry, A and Mostafa, WA}, title = {The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with Polycystic Ovary Syndrome.}, journal = {Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology}, volume = {31}, number = {8}, pages = {635-638}, doi = {10.3109/09513590.2015.1037269}, pmid = {26291797}, issn = {1473-0766}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Clomiphene/pharmacology/*therapeutic use ; Drug Therapy, Combination ; Female ; Fertility Agents, Female/therapeutic use ; Humans ; Infertility, Female/*drug therapy/etiology ; Metformin/pharmacology/*therapeutic use ; Ovulation/drug effects ; Ovulation Induction/*methods ; Polycystic Ovary Syndrome/complications/*drug therapy ; Pregnancy ; Pregnancy Rate ; Treatment Outcome ; }, abstract = {OBJECTIVES: To assess the adjuvant effect of metformin and N-acetylcysteine (NAC) to clomiphene citrate (CC) in induction of ovulation in Polycystic Ovary Syndrome (PCOS) patients.<br><br>STUDY DESIGN: 120 women with PCOS were randomly divided into three equal groups: group I received CC only, group II received CC plus NAC and group III received CC plus metformin.<br><br>RESULTS: There was a significant difference between group II and other two groups regarding average number of ovulatory follicles >18&#x2009;mm (2.25 versus 1.75 and 1.89, respectively), but no significant difference between the three study groups regarding number of intermediate follicles 14-18&#x2009;mm (4, 10 and 4, respectively). There was no significant difference between the three study groups regarding occurrence and laterality of ovulation, pregnancy rate per cycle but a significant difference between group II and other two groups regarding pregnancy rate per patient (20% versus 10% and 10%, respectively, p value 0.05). There was a highly statistically significant difference between group II and other two groups regarding peak endometrial thickness (7.3&#x2009;&#xb1;&#x2009;1.1 versus 5.4&#x2009;&#xb1;&#x2009;0.6 and 5.3&#x2009;&#xb1;&#x2009;0.6, respectively).<br><br>CONCLUSIONS: NAC as an adjuvant to CC for induction of ovulation improves ovulation and pregnancy rates in PCOS patients with beneficial impacts on endometrial thickness.}, }
@article {pmid26291594, year = {2016}, author = {Eshraghi, A and Talasaz, AH and Salamzadeh, J and Salarifar, M and Pourhosseini, H and Nozari, Y and Bahremand, M and Jalali, A and Boroumand, MA}, title = {Evaluating the Effect of Intracoronary N-Acetylcysteine on Platelet Activation Markers After Primary Percutaneous Coronary Intervention in Patients With ST-Elevation Myocardial Infarction.}, journal = {American journal of therapeutics}, volume = {23}, number = {1}, pages = {e44-51}, doi = {10.1097/MJT.0000000000000309}, pmid = {26291594}, issn = {1536-3686}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Biomarkers ; Electrocardiography ; Female ; Humans ; Male ; Middle Aged ; Myocardial Infarction/blood/*therapy ; *Percutaneous Coronary Intervention ; Platelet Activation/*drug effects ; Platelet Aggregation Inhibitors/*pharmacology ; }, abstract = {During percutaneous coronary intervention (PCI), trauma occurs in the arterial endothelium, resulting in platelet activation and aggregation. As platelet aggregation may lead to coronary thrombosis, antiplatelet agents are essential adjunctive therapies in patients undergoing PCI. The aim of this study was to determine the effect of the intracoronary administration of high-dose N-acetylcysteine (NAC) for the evaluation of its antiplatelet effects in human subjects. In this triple-blind trial, 147 patients undergoing primary PCI were enrolled. Finally, 100 patients were randomized to receive high-dose intracoronary NAC (100 mg/kg bolus, followed by 10 mg·kg[-1]·h[-1] intracoronary continued intravenously for 12 hours) (n = 50) or dextrose solution (n = 50). Platelet activation biomarkers were measured before and 24 hours after the procedure. Secondary end points, comprising all-cause death, reinfarction, and target-vessel revascularization, were assessed at 30 days and 2 years. In comparison with the placebo, NAC could not reduce the level of platelet activation biomarkers within a 24-hour period after its prescription. Major adverse clinical events at 30 days and 2 years were infrequent and not statistically different between the 2 groups. Our results revealed that NAC, compared with the placebo, did not provide an additional clinical benefit as an effective antiplatelet agent after PCI.}, }
@article {pmid26291278, year = {2015}, author = {Ray, PD and Huang, BW and Tsuji, Y}, title = {Coordinated regulation of Nrf2 and histone H3 serine 10 phosphorylation in arsenite-activated transcription of the human heme oxygenase-1 gene.}, journal = {Biochimica et biophysica acta}, volume = {1849}, number = {10}, pages = {1277-1288}, pmid = {26291278}, issn = {0006-3002}, support = {T32 ES007046/ES/NIEHS NIH HHS/United States ; T32ES007046/ES/NIEHS NIH HHS/United States ; R01 GM095550/GM/NIGMS NIH HHS/United States ; R01 GM088392/GM/NIGMS NIH HHS/United States ; R01GM088392/GM/NIGMS NIH HHS/United States ; R01GM095550/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Antioxidant Response Elements/*genetics ; Arsenites/pharmacology ; Gene Expression Regulation, Enzymologic ; Heme Oxygenase-1/*biosynthesis/genetics/metabolism ; Histones/*genetics/metabolism ; Humans ; Keratinocytes/metabolism ; Mice ; NF-E2-Related Factor 2/*genetics/metabolism ; Oxidative Stress/genetics ; Phosphorylation ; Promoter Regions, Genetic ; Protein Binding ; Signal Transduction ; Transcriptional Activation/drug effects/*genetics ; }, abstract = {Expression of the antioxidant gene heme oxygenase-1 (HO-1) is primarily induced through NF-E2-related factor 2 (Nrf2)-mediated activation of the antioxidant response element (ARE). Gene transcription is coordinately regulated by transcription factor activity at enhancer elements and epigenetic alterations such as the posttranslational modification of histone proteins. However, the role of histone modifications in the Nrf2-ARE axis remains largely uncharacterized. The environmental contaminant arsenite is a potent inducer of both HO-1 expression and phosphorylation of histone H3 serine 10 (H3S10); therefore, we investigated the relationships between Nrf2 and H3S10 phosphorylation in arsenite-induced, ARE-dependent, transcriptional activation of the human HO-1 gene. Arsenite increased phosphorylation of H3S10 both globally and at the HO-1 promoter concomitantly with HO-1 transcription in human HaCaT keratinocytes. Conversely, arsenite-induced H3S10 phosphorylation and HO-1 expression were blocked by N-acetylcysteine (NAC), the c-Jun N-terminal kinase (JNK) inhibitor SP600125, and JNK knockdown (siJNK). Interestingly, ablation of arsenite-induced H3S10 phosphorylation by SP600125 or siJNK did not inhibit Nrf2 nuclear accumulation nor ARE binding, despite inhibiting HO-1 expression. In response to arsenite, binding of Nrf2 to the HO-1 ARE preceded phosphorylation of H3S10 at the HO-1 ARE. Furthermore, arsenite-mediated occupancy of phosphorylated H3S10 at the HO-1 ARE was decreased in Nrf2-deficient mouse embryonic fibroblasts. These results suggest the involvement of H3S10 phosphorylation in the Nrf2-ARE axis by proposing that Nrf2 may influence H3S10 phosphorylation at the HO-1 ARE and additional promoter regions. Our data highlights the complex interplay between Nrf2 and H3S10 phosphorylation in arsenite-activated HO-1 transcription.}, }
@article {pmid26278389, year = {2017}, author = {Leung, TM and Lu, Y}, title = {Alcoholic Liver Disease: from CYP2E1 to CYP2A5.}, journal = {Current molecular pharmacology}, volume = {10}, number = {3}, pages = {172-178}, pmid = {26278389}, issn = {1874-4702}, support = {R21 AA020877/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/metabolism ; Chemical and Drug Induced Liver Injury/enzymology/pathology ; Cytochrome P-450 CYP2E1/metabolism ; Cytochrome P450 Family 2/*metabolism ; Humans ; Hyperglycemia/chemically induced/enzymology/pathology ; Liver Diseases, Alcoholic/*enzymology/pathology ; Signal Transduction ; Up-Regulation ; }, abstract = {This article reviews recent studies on CYP2E1-mediated alcoholic liver injury, the induction of CYP2A5 by alcohol and the mechanism for this upregulation, especially the permissive role of CYP2E1 in the induction of CYP2A5 by alcohol and the CYP2E1-ROS-Nrf2 pathway, and protective effects of CYP2A5 against ethanol-induced oxidative liver injury. Ethanol can induce CYP2E1, an active generator of reactive oxygen species (ROS), and CYP2E1 is a contributing factor for alcoholinduced oxidative liver injury. CYP2A5, another isoform of cytochrome P450, can also be induced by ethanol. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity, protein and mRNA levels as compared to pair-fed controls. This induction was blunted in CYP2E1 knockout (cyp2e1-/-) mice but was restored when human CYP2E1 was reintroduced and expressed in cyp2e1-/- mice. Ethanol-induced CYP2E1 co-localized with CYP2A5 and preceded the elevation of CYP2A5. The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol elevation of ROS and blunted the alcohol induction of CYP2A5, but not CYP2E1, suggesting ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. The antioxidants blocked the activation of Nrf2, a transcription factor known to upregulate expression of CYP2A5. When alcohol-induced liver injury was enhanced in Nrf2 knockout (Nrf2-/-) mice, alcohol elevation of CYP2A5 but not CYP2E1 was also lower in Nrf2-/- mice. CYP2A5 knockout (cyp2a5-/-) mice exhibited an enhanced alcoholic liver injury compared with WT mice as indicated by serum ALT, steatosis and necroinflammation. Alcohol-induced hyperglycemia were observed in cyp2a5-/- mice but not in WT mice.}, }
@article {pmid26274909, year = {2015}, author = {Jiao, Y and Ma, S and Li, J and Shan, L and Wang, Y and Tian, M and Yang, Y and Sun, J and Ban, J and Chen, J}, title = {N-Acetyl Cysteine (NAC)-Directed Detoxification of Methacryloxylethyl Cetyl Ammonium Chloride (DMAE-CB).}, journal = {PloS one}, volume = {10}, number = {8}, pages = {e0135815}, pmid = {26274909}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Adult ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Dental Pulp/*metabolism/pathology ; Female ; Humans ; Male ; Mass Spectrometry ; Methacrylates/*toxicity ; Oxidative Stress/*drug effects ; Quaternary Ammonium Compounds/*toxicity ; }, abstract = {Methacryloxylethyl cetyl ammonium chloride (DMAE-CB) is a polymerizable antibacterial monomer and has been proved as an effective strategy to achieve bioactive bonding with reliable bacterial inhibitory effects. However, the toxicity of DMAE-CB may hamper its wide application in clinical situations. Thus, this study was designed to investigate the toxicity of DMAE-CB and explore the possible protective effects of N-acetyl cysteine (NAC). High performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) analysis showed that chemical binding of NAC and DMAE-CB occurred in a time dependent manner. Pre-incubation of fourty-eight hours is required for adequate reaction between DMAE-CB and NAC. DMAE-CB reduced human dental pulp cells (hDPCs) viability in a dose-dependent manner. The toxic effects of DMAE-CB were accompanied by increased reactive oxygen species (ROS) level and reduced glutathione (GSH) content. NAC alleviated DMAE-CB-induced oxidative stress. Annexin V/ Propidium Iodide (PI) staining and Hoechst 33342 staining indicated that DMAE-CB induced apoptosis. Collapsed mitochondrial membrane potential (MMP) and activation of caspase-3 were also observed after DMAE-CB treatment. NAC rescued hDPCs from DMAE-CB-induced apoptosis, accompanied by lower level of MMP loss and caspase-3 activity. This study assists to elucidate the mechanism underlying the cytotoxic effects of DMAE-CB and provides theoretical supports for the searching of effective strategies to reduce toxicity of quaternary ammonium dental monomers.}, }
@article {pmid26269112, year = {2016}, author = {Shen, J and Hong, Y and Zhao, Q and Zhang, JL}, title = {Preclinical evaluation of perifosine as a potential promising anti-rhabdomyosarcoma agent.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {37}, number = {1}, pages = {1025-1033}, pmid = {26269112}, issn = {1423-0380}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Mice ; Mice, SCID ; Phosphorylcholine/*analogs &amp; derivatives/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Rhabdomyosarcoma/drug therapy/metabolism/pathology ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {Rhabdomyosarcoma (RMS) is a highly malignant and metastatic pediatric cancer that arises from the skeletal muscle. Recent studies have identified an important role of AKT signaling in RMS progression. In the current study, we investigated the activity of perifosine, an oral alkylphospholipid AKT inhibitor, against human RMS cells (RD and Rh-30 lines) both in vivo and in vitro, and studied the underlying mechanisms. We showed that perifosine significantly inhibited RMS cell growth in concentration- and time-dependent manners. Meanwhile, perifosine induced dramatic apoptosis in RMS cells. At the signaling level, perifosine blocked AKT activation, while inducing reactive oxygen species (ROS) production as well as JNK and P38 phosphorylations in RMS cells. Restoring AKT activation by introducing a constitutively active-AKT (CA-AKT) only alleviated (not abolished) perifosine-induced cytotoxicity in RD cells. Yet, the ROS scavenger N-acetyl cysteine (NAC) as well as pharmacological inhibitors against JNK (SP-600125) or P38 (SB-203580) suppressed perifosine-induced cytotoxicity in RMS cells. Thus, perifosine induces growth inhibition and apoptosis in RMS cells through mechanisms more than just blocking AKT. In vivo, oral administration of perifosine significantly inhibited growth of Rh-30 xenografts in severe combined immunodeficient (SCID) mice. Our data indicate that perifosine might be further investigated as a promising anti-RMS agent.}, }
@article {pmid26265456, year = {2015}, author = {Zanin, RF and Bergamin, LS and Morrone, FB and Coutinho-Silva, R and de Souza Wyse, AT and Battastini, AM}, title = {Pathological concentrations of homocysteine increases IL-1β production in macrophages in a P2X7, NF-ĸB, and erk-dependent manner.}, journal = {Purinergic signalling}, volume = {11}, number = {4}, pages = {463-470}, pmid = {26265456}, issn = {1573-9546}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Homocysteine/*toxicity ; Hyperhomocysteinemia/*metabolism ; Interleukin-1beta/*biosynthesis ; MAP Kinase Signaling System/*drug effects ; Macrophages/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B/*metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Purinergic P2X7/*metabolism ; Toll-Like Receptor 4/genetics ; }, abstract = {Elevated plasma levels of homocysteine (Hcy) are associated with the development of coronary artery disease (CAD), peripheral vascular disease, and atherosclerosis. Hyperhomocysteinemia is likely related to the enhanced production of pro-inflammatory cytokines including IL-1β. However, the mechanisms underlying the effects of Hcy in immune cells are not completely understood. Recent studies have established a link between macrophage accumulation, cytokine IL-1β, and the advance of vascular diseases. The purpose of the present study is to investigate the effects of Hcy on IL-1β secretion by murine macrophages. Hcy (100 μM) increases IL-1β synthesis via enhancement of P2X7 expression and NF-ĸB and ERK activation in murine macrophages. In addition, the antioxidant agent N-acetylcysteine (NAC) reduces NF-κB activation, ERK phosphorylation, and IL-1β production in Hcy-exposed macrophages, indicating the importance of ROS in this pro-inflammatory process. In summary, our results show that Hcy may be involved in the synthesis and secretion of IL-1β via NF-ĸB, ERK, and P2X7 stimulation in murine macrophages.}, }
@article {pmid26262996, year = {2015}, author = {Schmitt, B and Vicenzi, M and Garrel, C and Denis, FM}, title = {Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study.}, journal = {Redox biology}, volume = {6}, number = {}, pages = {198-205}, pmid = {26262996}, issn = {2213-2317}, mesh = {Acetylcysteine/blood/*pharmacokinetics ; Administration, Oral ; Antioxidants/metabolism ; Biological Availability ; Biomarkers/blood ; Blood Pressure/drug effects ; Body Mass Index ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; Cross-Over Studies ; *Dietary Supplements ; Female ; Glutathione/blood/*pharmacokinetics ; Humans ; Male ; Metabolic Syndrome/*blood/*diet therapy/pathology ; Middle Aged ; Oxidative Stress/drug effects ; Tablets ; Triglycerides/blood ; Vitamin E/blood ; }, abstract = {Glutathione (GSH) is critical to fight against oxidative stress. Its very low bioavailability limits the interest of a supplementation. The purpose of this study was to compare the bioavailability, the effect on oxidative stress markers and the safety of a new sublingual form of GSH with two commonly used dietary supplements, N-acetylcysteine (NAC) and oral GSH. The study was a three-week randomized crossover trial. 20 Volunteers with metabolic syndrome were enrolled. GSH levels and several oxidative stress markers were determined at different times during each 21-days period. Compared to oral GSH group, an increase of total and reduced GSH levels in plasma and a higher GSH/GSSG ratio (p=0.003) was observed in sublingual GSH group. After 3 weeks of administration, there was a significant increase of vitamin E level in plasma only in sublingual GSH group (0.83 µmol/g; p=0.04). Our results demonstrate the superiority of a new sublingual form of GSH over the oral GSH form and NAC in terms of GSH supplementation.}, }
@article {pmid26262887, year = {2015}, author = {Mansour, HH and El Kiki, SM and Hasan, HF}, title = {Protective effect of N-acetylcysteine on cyclophosphamide-induced cardiotoxicity in rats.}, journal = {Environmental toxicology and pharmacology}, volume = {40}, number = {2}, pages = {417-422}, doi = {10.1016/j.etap.2015.07.013}, pmid = {26262887}, issn = {1872-7077}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Cardiotoxicity/etiology/metabolism/prevention &amp; control ; Cyclophosphamide/*adverse effects ; Disease Models, Animal ; Gene Expression Regulation, Enzymologic/drug effects ; Heart Diseases/chemically induced/metabolism/*prevention &amp; control ; Male ; Malondialdehyde/metabolism ; Nitric Oxide/*metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Cyclophosphamide (CP) is an oxazaphosphorine nitrogen mustard alkylating drug used for the treatment of chronic and acute leukemias, lymphoma, myeloma, and cancers of the breast and ovary. It is known to cause severe cardiac toxicity. This study investigated the protective effect of N-Acetylcysteine (NAC) on CP-induced cardiotoxicity in rats. CP resulted in a significant increase in serum aminotransferases, creatine kinase (CK), lactate dehydrogenase(LDH) enzymes, asymmetric dimethylarginine and tumor necrosis factor-α and significant decrease in total nitrate/nitrite(NOx). In cardiac tissues, a single dose of CP (200mg/kg, i.p.) resulted in significant increase in malondialdehyde and NOx and a significant decrease in reduced glutathione content, glutathione peroxidase, catalase, and superoxide dismutase activities. Interestingly, Administration of NAC (200mg/kg, i.p.) for 5 days prior to CP attenuates all the biochemical changes induced by CP. These results revealed that NAC attenuates CP-induced cardiotoxicity by inhibiting oxidative and nitrosative stress and preserving the activity of antioxidant enzymes.}, }
@article {pmid26261285, year = {2015}, author = {Mao, X and Peng, Y and Zheng, J}, title = {In Vitro and In Vivo Characterization of Reactive Intermediates of Corynoline.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {43}, number = {10}, pages = {1491-1498}, doi = {10.1124/dmd.115.065813}, pmid = {26261285}, issn = {1521-009X}, mesh = {Animals ; Berberine Alkaloids/*metabolism/*pharmacology/urine ; Cytochrome P-450 Enzyme Inhibitors/metabolism/pharmacology ; Cytochrome P-450 Enzyme System/metabolism ; Humans ; Male ; Microsomes, Liver/drug effects/*metabolism ; Rats ; Rats, Sprague-Dawley ; Tandem Mass Spectrometry/methods ; }, abstract = {Corynoline is a 1,3-benzodioxole-containing isoquinoline alkaloid isolated from Corydalis bugeana Turcz., a traditional herbal medicine. Corynoline has reportedly demonstrated multiple pharmacologic properties. Previous studies have also shown that corynoline induced cytotoxicity and inhibited cytochrome P450 (CYP) enzymes, but the mechanisms of the adverse effects remain unknown. The major objective of the present study was to identify reactive metabolites of corynoline responsible for the cytotoxicity and enzyme inhibition. Three oxidative metabolites (M1-M3) were detected by liquid chromatography-tandem mass spectrometry in rat liver microsomal incubations after exposure to corynoline. M1 and M2 were two isomers of catechol derivatives, and M3 was a di-catechol. The M1-M3 metabolites were also observed in urine of rats given corynoline. A total of four N-acetylcysteine (NAC) conjugates (M4-M7) were detected in microsomes containing corynoline, NAC, and NADPH. Apparently, M4 and M5 were derived from M1, M6 resulted from M2, and M7 was a M3-derived NAC conjugate. This indicates that corynoline was bioactivated to ortho-quinone derivatives. No corynoline-derived NAC conjugates (M4-M7) were detected in urine of rats given corynoline; however, three corresponding cysteinylglycine conjugates (M8-M10) were observed instead. Recombinant P450 enzyme incubations demonstrated that the CYPs 2C9, 3A4, and 2C19 were mainly involved in metabolic activation of corynoline. The metabolism study facilitates the understanding of corynoline-induced cytotoxicity and P450 enzyme inhibition.}, }
@article {pmid26261019, year = {2015}, author = {Mocelin, R and Herrmann, AP and Marcon, M and Rambo, CL and Rohden, A and Bevilaqua, F and de Abreu, MS and Zanatta, L and Elisabetsky, E and Barcellos, LJ and Lara, DR and Piato, AL}, title = {N-acetylcysteine prevents stress-induced anxiety behavior in zebrafish.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {139 Pt B}, number = {}, pages = {121-126}, doi = {10.1016/j.pbb.2015.08.006}, pmid = {26261019}, issn = {1873-5177}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Anxiety Agents/*pharmacology ; Anxiety/*prevention &amp; control ; Behavior, Animal/drug effects ; Disease Models, Animal ; Female ; Humans ; Male ; Stress, Physiological ; Translational Research, Biomedical ; Zebrafish/*physiology ; }, abstract = {Despite the recent advances in understanding the pathophysiology of anxiety disorders, the pharmacological treatments currently available are limited in efficacy and induce serious side effects. A possible strategy to achieve clinical benefits is drug repurposing, i.e., discovery of novel applications for old drugs, bringing new treatment options to the market and to the patients who need them. N-acetylcysteine (NAC), a commonly used mucolytic and paracetamol antidote, has emerged as a promising molecule for the treatment of several neuropsychiatric disorders. The mechanism of action of this drug is complex, and involves modulation of antioxidant, inflammatory, neurotrophic and glutamate pathways. Here we evaluated the effects of NAC on behavioral parameters relevant to anxiety in zebrafish. NAC did not alter behavioral parameters in the novel tank test, prevented the anxiety-like behaviors induced by an acute stressor (net chasing), and increased the time zebrafish spent in the lit side in the light/dark test. These data may indicate that NAC presents an anti-stress effect, with the potential to prevent stress-induced psychiatric disorders such as anxiety and depression. The considerable homology between mammalian and zebrafish genomes invests the current data with translational validity for the further clinical trials needed to substantiate the use of NAC in anxiety disorders.}, }
@article {pmid26257840, year = {2015}, author = {Zhao, L and Xie, F and Wang, TT and Liu, MY and Li, JL and Shang, L and Deng, ZX and Zhao, PX and Ma, XM}, title = {Chlorpyrifos Induces the Expression of the Epstein-Barr Virus Lytic Cycle Activator BZLF-1 via Reactive Oxygen Species.}, journal = {Oxidative medicine and cellular longevity}, volume = {2015}, number = {}, pages = {309125}, pmid = {26257840}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Catalase/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Chlorpyrifos/*toxicity ; DNA Damage/drug effects ; Herpesvirus 4, Human/*drug effects/metabolism ; Humans ; Insecticides/*toxicity ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; Trans-Activators/*metabolism ; Up-Regulation/drug effects ; }, abstract = {Organophosphate pesticides (OPs) are among the most widely used synthetic chemicals for the control of a wide variety of pests, and reactive oxygen species (ROS) caused by OPs may be involved in the toxicity of various pesticides. Previous studies have demonstrated that a reactivation of latent Epstein-Barr virus (EBV) could be induced by oxidative stress. In this study, we investigated whether OPs could reactivate EBV through ROS accumulation. The Raji cells were treated with chlorpyrifos (CPF), one of the most commonly used OPs. Oxidative stress indicators and the expression of the EBV immediate-early gene BZLF-1 were determined after CPF treatment. Our results show that CPF induces oxidative stress as evidenced by decreased malondialdehyde (MDA) level, accompanied by an increase in ROS production, DNA damage, glutathione (GSH) level, and superoxide dismutase (SOD) and catalase (CAT) activity. Moreover, CPF treatment significantly enhances the expression of BZLF-1, and the increased BZLF-1 expression was ameliorated by N-acetylcysteine (NAC) incubation. These results suggest that OPs could contribute to the reactivation of the EBV lytic cycle through ROS induction, a process that may play an important role in the development of EBV-associated diseases.}, }
@article {pmid26250417, year = {2015}, author = {Owumi, SE and Andrus, JP and Herzenberg, LA and Herzenberg, LA}, title = {Co-administration of N-Acetylcysteine and Acetaminophen Efficiently Blocks Acetaminophen Toxicity.}, journal = {Drug development research}, volume = {76}, number = {5}, pages = {251-258}, doi = {10.1002/ddr.21262}, pmid = {26250417}, issn = {1098-2299}, mesh = {Acetaminophen/*administration &amp; dosage/*adverse effects ; Acetylcysteine/*administration &amp; dosage/therapeutic use ; Administration, Oral ; Animals ; Chemical and Drug Induced Liver Injury/enzymology/etiology/*prevention &amp; control ; Disease Models, Animal ; Drug Combinations ; Gene Expression Regulation, Enzymologic/drug effects ; Male ; Mice ; Transaminases/metabolism ; }, abstract = {Preclinical Research Although acetaminophen (APAP) is an effective analgesic and anti-pyretic, APAP overdose is the most frequent cause of serious, often lethal, drug-induced hepatotoxicity. Administration of N-acetyl cysteine (NAC) within 8 hours of APAP overdose effectively mitigates APAP-induced hepatotoxicity. Thus, preventing APAP toxicity before it occurs by formulating APAP with NAC is logical and, as we show here in a mouse model, is effective in preventing APAP toxicity. Thus, toxic oral APAP doses sufficient to cause severe widespread liver damage do not cause significant damage when administered concurrently with equal amounts of NAC, that is, in the NAC-APAP treated animals, hepatic transaminases increase only marginally and liver architecture remains fully intact. Thus, we conclude that concomitant oral dosing with APAP and NAC can provide a convenient and effective way of preventing toxicity associated with large dosage of APAP. From a public health perspective, these findings support the concept that a co-formulation of APAP plus NAC is a viable over-the-counter (OTC) alternative to the current practice of providing APAP OTC and treating APAP toxicity if/when it occurs. In essence, our findings indicate that replacing the current OTC APAP with a safe and functional APAP/NAC formulation could prevent the accidental and intentional APAP toxicity that occurs today.}, }
@article {pmid26250135, year = {2016}, author = {Livanos, P and Galatis, B and Apostolakos, P}, title = {Deliberate ROS production and auxin synergistically trigger the asymmetrical division generating the subsidiary cells in Zea mays stomatal complexes.}, journal = {Protoplasma}, volume = {253}, number = {4}, pages = {1081-1099}, pmid = {26250135}, issn = {1615-6102}, mesh = {*Asymmetric Cell Division ; Indoleacetic Acids/*metabolism ; Plant Stomata/cytology/*metabolism ; Reactive Oxygen Species/*metabolism ; Zea mays/cytology/*metabolism ; }, abstract = {Subsidiary cell generation in Poaceae is an outstanding example of local intercellular stimulation. An inductive stimulus emanates from the guard cell mother cells (GMCs) towards their laterally adjacent subsidiary cell mother cells (SMCs) and triggers the asymmetrical division of the latter. Indole-3-acetic acid (IAA) immunolocalization in Zea mays protoderm confirmed that the GMCs function as local sources of auxin and revealed that auxin is polarly accumulated between GMCs and SMCs in a timely-dependent manner. Besides, staining techniques showed that reactive oxygen species (ROS) exhibit a closely similar, also time-dependent, pattern of appearance suggesting ROS implication in subsidiary cell formation. This phenomenon was further investigated by using the specific NADPH-oxidase inhibitor diphenylene iodonium, the ROS scavenger N-acetyl-cysteine, menadione which leads to ROS overproduction, and H2O2. Treatments with diphenylene iodonium, N-acetyl-cysteine, and menadione specifically blocked SMC polarization and asymmetrical division. In contrast, H2O2 promoted the establishment of SMC polarity and subsequently subsidiary cell formation in "younger" protodermal areas. Surprisingly, H2O2 favored the asymmetrical division of the intervening cells of the stomatal rows leading to the creation of extra apical subsidiary cells. Moreover, H2O2 altered IAA localization, whereas synthetic auxin analogue 1-napthaleneacetic acid enhanced ROS accumulation. Combined treatments with ROS modulators along with 1-napthaleneacetic acid or 2,3,5-triiodobenzoic acid, an auxin efflux inhibitor, confirmed the crosstalk between ROS and auxin functioning during subsidiary cell generation. Collectively, our results demonstrate that ROS are critical partners of auxin during development of Z. mays stomatal complexes. The interplay between auxin and ROS seems to be spatially and temporarily regulated.}, }
@article {pmid26246867, year = {2015}, author = {Gan, X and Xing, D and Su, G and Li, S and Luo, C and Irwin, MG and Xia, Z and Li, H and Hei, Z}, title = {Propofol Attenuates Small Intestinal Ischemia Reperfusion Injury through Inhibiting NADPH Oxidase Mediated Mast Cell Activation.}, journal = {Oxidative medicine and cellular longevity}, volume = {2015}, number = {}, pages = {167014}, pmid = {26246867}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Degranulation/*drug effects ; Cell Line ; Cell Survival/drug effects ; Female ; Hydrogen Peroxide/toxicity ; Intestinal Mucosa/enzymology/metabolism/*pathology ; Mast Cells/cytology/drug effects/*physiology ; Membrane Glycoproteins/metabolism ; NADPH Oxidase 2 ; NADPH Oxidases/*metabolism ; Oxidative Stress/drug effects ; Propofol/*pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/chemically induced/drug therapy/mortality ; Tryptases/metabolism ; Up-Regulation/drug effects ; beta-N-Acetylhexosaminidases/blood ; p-Methoxy-N-methylphenethylamine/toxicity ; }, abstract = {Both oxidative stress and mast cell (MC) degranulation participate in the process of small intestinal ischemia reperfusion (IIR) injury, and oxidative stress induces MC degranulation. Propofol, an anesthetic with antioxidant property, can attenuate IIR injury. We postulated that propofol can protect against IIR injury by inhibiting oxidative stress subsequent from NADPH oxidase mediated MC activation. Cultured RBL-2H3 cells were pretreated with antioxidant N-acetylcysteine (NAC) or propofol and subjected to hydrogen peroxide (H2O2) stimulation without or with MC degranulator compound 48/80 (CP). H2O2 significantly increased cells degranulation, which was abolished by NAC or propofol. MC degranulation by CP further aggravated H2O2 induced cell degranulation of small intestinal epithelial cell, IEC-6 cells, stimulated by tryptase. Rats subjected to IIR showed significant increases in cellular injury and elevations of NADPH oxidase subunits p47(phox) and gp91(phox) protein expression, increases of the specific lipid peroxidation product 15-F2t-Isoprostane and interleukin-6, and reductions in superoxide dismutase activity with concomitant enhancements in tryptase and β-hexosaminidase. MC degranulation by CP further aggravated IIR injury. And all these changes were attenuated by NAC or propofol pretreatment, which also abrogated CP-mediated exacerbation of IIR injury. It is concluded that pretreatment of propofol confers protection against IIR injury by suppressing NADPH oxidase mediated MC activation.}, }
@article {pmid26245827, year = {2016}, author = {Rottenstreich, A and Hochberg-Klein, S and Rund, D and Kalish, Y}, title = {The role of N-acetylcysteine in the treatment of thrombotic thrombocytopenic purpura.}, journal = {Journal of thrombosis and thrombolysis}, volume = {41}, number = {4}, pages = {678-683}, pmid = {26245827}, issn = {1573-742X}, mesh = {ADAMTS13 Protein ; Acetylcysteine/*administration &amp; dosage ; Autoantibodies/blood ; Female ; Humans ; Male ; Middle Aged ; Purpura, Thrombotic Thrombocytopenic/blood/*drug therapy ; }, abstract = {Thrombotic thrombocytopenic purpura (TTP) is an acute, thrombotic microangiopathy with a high mortality rate if left untreated. Plasma exchange (PEX) is the current standard of care. However, a significant number of patients are refractory to this treatment. N-acetylcysteine (NAC) was recently suggested as a potential therapeutic adjunct for patients with TTP. This study reports a series of three patients with TTP successfully treated with NAC in addition to standard therapy. Detailed chart reviews on these patients were conducted. We discuss clinical features, laboratory findings and management of three patients who presented with microangiopathic hemolytic anemia and thrombocytopenia. Anti-ADAMTS13 antibodies and low levels of ADAMTS13 were detected and confirmed the diagnosis of acquired TTP. Based upon their severe presentation or lack of response to initial treatment with PEX, corticosteroids and other immunosuppressive agents, NAC was added. Under this combined treatment, all three patients hada significant clinical improvement of symptoms with concurrent normalization of platelet count and ADAMTS13 activity level. This report highlights the potential therapeutic utility of NAC in the treatment of TTP. Randomized controlled studies will be required to better characterize the risk-to-benefit ratio of NAC in the treatment of TTP.}, }
@article {pmid26242742, year = {2015}, author = {Liu, C and Lu, XZ and Shen, MZ and Xing, CY and Ma, J and Duan, YY and Yuan, LJ}, title = {N-Acetyl Cysteine improves the diabetic cardiac function: possible role of fibrosis inhibition.}, journal = {BMC cardiovascular disorders}, volume = {15}, number = {}, pages = {84}, pmid = {26242742}, issn = {1471-2261}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Cells, Cultured ; Diabetes Mellitus, Experimental/*drug therapy/metabolism/pathology ; Diabetic Cardiomyopathies/*drug therapy/metabolism/pathology ; Fibrosis/metabolism/pathology/prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects/physiology ; }, abstract = {BACKGROUND: Diabetic cardiomyopathy is one of the leading causes of death in diabetes mellitus (DM) patients. This study aimed to explore the therapeutic implication of N-acetyl-L-cysteine (NAC, an antioxidant and glutathione precursor) and the possible underlying mechanism.<br><br>METHODS: Thirty five 12-week-old male C57BL/6 mice were included. Twenty-five diabetic mice were induced by intraperitoneal injection of streptozocin (STZ, 150&#xa0;mg/kg, Sigma-Aldrich) dissolved in a mix of citrate buffer after overnight fast. Mice with a blood glucose level above 13.5&#xa0;mmol/L were considered diabetic. As a non-DM (diabetic) control, mice were injected with equal volume of citrate buffer. The 25 diabetic mice were divided into 5 groups with 5 animals in each group: including DM (diabetes without NAC treatment), and 4 different NAC treatment groups, namely NAC1, NAC3, NAC5 and NAC7, with the number defining the start time point of NAC treatment. In the 10 non-DM mice, mice were either untreated (Ctrl) or treated with NAC for 5&#xa0;weeks (NAC only). Echocardiography was performed 12&#xa0;weeks after STZ injection. Heart tissue were collected after echocardiography for Hematoxylin Eosin (HE) and Trichrome staining and ROS staining. Cardiac fibroblast cells were isolated, cultured and treated with high glucose plus NAC or the vehicle. qPCR analysis and CCK-8 assay were performed to observe fibrotic gene expression and cell proliferation.<br><br>RESULTS: We found that both cardiac systolic function and diastolic function were impaired, coupled with excessive reactive oxygen stress and cardiac fibrosis 12&#xa0;weeks after STZ induction. NAC significantly reduced ROS generation and fibrosis, together with improved cardiac systolic function and diastolic function. Strikingly, NAC1 treatment, which had the earlier and longer treatment, produced significant improvement of cardiac function and less fibrosis. In the cardiac fibroblasts, NAC blocked cardiac fibroblast proliferation and collagen synthesis induced by hyperglycemia.<br><br>CONCLUSIONS: Our study indicates that NAC treatment in diabetes effectively protects from diabetic cardiomyopathy, possibly through inhibiting the ROS production and fibrosis, which warrants further clarification.}, }
@article {pmid26240545, year = {2015}, author = {Ibrahim, ES and Sharawy, A}, title = {Effectiveness of intravenous infusion of N-acetylcysteine in cirrhotic patients undergoing major abdominal surgeries.}, journal = {Saudi journal of anaesthesia}, volume = {9}, number = {3}, pages = {272-278}, pmid = {26240545}, issn = {1658-354X}, abstract = {BACKGROUND: Postoperative acute kidney injury (AKI) is common in patients with chronic liver disease. We prospectively evaluated effectiveness of the N-acetylcysteine (NAC) in preserving postoperative renal functions in cirrhotic patients undergoing major abdominal surgeries.<br><br>MATERIALS AND METHODS: A total of 60 cirrhotic patients child A to B were randomized into two groups of 30 each. NAC groupwas received intravenous infusion of NAC (1200 mg/12h starting immediately before surgery and continued for 72h h postoperative) and controls group received a similar volume of glucose 5% solution as a a placebo. Systemic hemodynamics, hepatic and renal functions, serum cystatin C and cystatin C glomerular filtration rate (GFR) (GFR) were compared between both groups.<br><br>RESULTS: Serum level of cystatin C was raised significantly above the basal value at postoperative day 1 and day 3 associated with significantly decreased in cystatin C GFR below the basal value in the control group (P = 0.001). 6 (20%) (PP = 0.03) in control group developed AKI based on cystatin C GFR criteria (GFR <55 ml/min/1.73m(2)). Mean values of alanine aminotransferase and aspartate aminotransferase were increased significantly above the basal values in both groups, but the increases were significantly lower in NAC group (P = 0.00). Chest infection was significantly lower associated with shorter hospital stay in the NAC group than the control group.<br><br>CONCLUSION: Intravenous administration of NAC NAC in cirrhotic patients undergoing major abdominal surgeries reduces the incidence of cystatin C GFR-based AKI, postoperative renal and liver functions were well-preserved and improved outcome.}, }
@article {pmid26238284, year = {2015}, author = {Tanaka, M and Miura, Y and Numanami, H and Karnan, S and Ota, A and Konishi, H and Hosokawa, Y and Hanyuda, M}, title = {Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species.}, journal = {Oncology reports}, volume = {34}, number = {4}, pages = {1726-1732}, doi = {10.3892/or.2015.4155}, pmid = {26238284}, issn = {1791-2431}, mesh = {Acetylcysteine/administration &amp; dosage ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Lung Neoplasms/*genetics/pathology ; Mesothelioma/*genetics/pathology ; Mesothelioma, Malignant ; NADPH Oxidase 4 ; NADPH Oxidases/*biosynthesis/genetics ; Onium Compounds/administration &amp; dosage ; Oxidative Stress/*genetics ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Malignant pleural mesothelioma (MPM) is an aggressive tumor that is characterized by dysregulated growth and resistance to apoptosis. Reactive oxygen species (ROS)-generating NADPH oxidase (Nox) family enzymes have been suggested to be involved in neoplastic proliferation. Both the antioxidant N-acetylcysteine (NAC) and the inhibitor of flavoprotein-dependent oxidase, diphenylene iodonium (DPI), inhibited the cell viability of MPM cells in a dose-dependent manner. To examine whether Nox-mediated ROS generation confers antiapoptotic activity and thus a growth advantage to MPM cells, we analyzed the mRNA expression of Nox family members using quantitative RT-PCR in 7 MPM cell lines and a normal mesothelial cell line. Nox4 mRNA was expressed in all of the examined MPM cell lines, whereas little or no Nox2, Nox3 and Nox5 mRNA expression was detected. In 2 MPM cell lines, Nox4 mRNA expression was significantly higher than that in a normal mesothelial cell line. siRNAs targeting Nox4 suppressed ROS generation and cell viability in the MPM cell lines. In addition, DPI treatment and knockdown of Nox4 attenuated phosphorylation of AKT and ERK. Taken together, our results indicate that Nox4-mediated ROS, at least in part, transmit cell survival signals and their depletion leads to apoptosis, thus highlighting the Nox4-ROS-AKT signaling pathway as a potential therapeutic target for MPM treatment.}, }
@article {pmid26238021, year = {2015}, author = {Ye, L and Yu, G and Wang, C and Du, B and Sun, D and Liu, J and Qi, T and Yu, X and Wei, W and Cheng, J and Jiang, Y}, title = {MicroRNA‑128a, BMI1 polycomb ring finger oncogene, and reactive oxygen species inhibit the growth of U‑87 MG glioblastoma cells following exposure to X‑ray radiation.}, journal = {Molecular medicine reports}, volume = {12}, number = {4}, pages = {6247-6254}, doi = {10.3892/mmr.2015.4175}, pmid = {26238021}, issn = {1791-3004}, mesh = {Apoptosis/radiation effects ; Cell Cycle ; Cell Line, Tumor/radiation effects ; Cell Proliferation/radiation effects ; Dose-Response Relationship, Radiation ; Down-Regulation ; Glioblastoma/metabolism/*pathology ; Humans ; MicroRNAs/genetics/*metabolism ; Polycomb Repressive Complex 1/genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; Radiation Tolerance ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; X-Rays ; }, abstract = {Radiotherapy is an important therapeutic strategy for the treatment of numerous types of malignant tumors, including glioma. However, radioresistance and anti‑apoptotic mechanisms decrease the efficacy of radiotherapy in many patients with glioma. BMI1 polycomb ring finger oncogene (Bmi‑1) is an oncogene associated with radioresistance in tumor cells. MicroRNA (miRNA)‑128a is a brain-specific miRNA, which suppresses Bmi‑1 expression. The present study investigated the effects of various radiation intensities on U‑87 MG glioma cells, as well as the role of reactive oxygen species (ROS), Bmi‑1, and miRNA‑128a in the cellular response to radiotherapy. The response of U‑87 MG cells following exposure to X‑ray radiation was assessed using a cell growth curve and inhibition ratio. Cell cycle distribution and the levels of intracellular ROS were evaluated by flow cytometry. The mRNA expression levels of Bmi‑1 and those of miRNA‑128a in U‑87 MG cells exposed to X‑ray radiation were evaluated by reverse transcription‑quantitative polymerase chain reaction. X‑ray radiation did not decrease the number of U‑87 MG cells; however, it did inhibit cellular growth in a dose‑dependent manner. Following exposure to X‑ray radiation for 24 h, cell cycle distribution was altered, with an increase in the number of cells in G0/G1 phase. The mRNA expression levels of Bmi‑1 were downregulated in the 1 and 2 Gy groups, and upregulated in the 6 and 8 Gy groups. The expression levels of miRNA‑128a were upregulated in the 1 and 2 Gy groups, and downregulated in the 8 Gy group. The levels of ROS were increased following exposure to ≥2 Gy, and treatment with N-acetyl cysteine was able to induce radioresistance. These results suggested that U‑87 MG cells exhibited radioresistance. High doses of X‑ray radiation increased the expression levels of Bmi‑1, which may be associated with the evasion of cellular senescence. miRNA‑128a and its downstream target gene Bmi‑1 may have an important role in the radioresistance of U‑87 MG glioma cells. In addition, ROS may be involved in the mechanisms underlying the inhibitory effects of X‑ray radiation in U‑87 MG cells, and the downregulation of ROS may induce radioresistance.}, }
@article {pmid26235743, year = {2015}, author = {Chen, K and Chu, BZ and Liu, F and Li, B and Gao, CM and Li, LL and Sun, QS and Shen, ZF and Jiang, YY}, title = {New benzimidazole acridine derivative induces human colon cancer cell apoptosis in vitro via the ROS-JNK signaling pathway.}, journal = {Acta pharmacologica Sinica}, volume = {36}, number = {9}, pages = {1074-1084}, pmid = {26235743}, issn = {1745-7254}, mesh = {Acridines/chemistry/*pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis ; Benzimidazoles/chemistry/*pharmacology ; Caspases/metabolism ; Cell Line, Tumor ; Colon/drug effects/metabolism/pathology ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; HCT116 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {AIM: To investigate the mechanisms underlying anticancer action of the benzimidazole acridine derivative N-{(1H-benzo[d]imidazol-2-yl)methyl}-2-butylacridin-9-amine(8m) against human colon cancer cells in vitro.<br><br>METHODS: Human colon cancer cell lines SW480 and HCT116 were incubated in the presence of 8m, and then the cell proliferation and apoptosis were measured. The expression of apoptotic/signaling genes and proteins was detected using RT-PCR and Western blotting. ROS generation and mitochondrial membrane depolarization were visualized with fluorescence microscopy.<br><br>RESULTS: 8m dose-dependently suppressed the proliferation of SW480 and HCT116 cells with IC50 values of 6.77 and 3.33 &#x3bc;mol/L, respectively. 8m induced apoptosis of HCT116 cells, accompanied by down-regulation of Bcl-2, up-regulation of death receptor-5 (DR5), truncation of Bid, cleavage of PARP, and activation of caspases (including caspase-8 and caspase-9 as well as the downstream caspases-3 and caspase-7). Moreover, 8m selectively activated JNK and p38 without affecting ERK in HCT116 cells. Knockout of JNK1, but not p38, attenuated 8m-induced apoptosis. In addition, 8m induced ROS production and mitochondrial membrane depolarization in HCT116 cells. Pretreatment with the antioxidants N-acetyl cysteine or glutathione attenuated 8m-induced apoptosis and JNK activation in HCT116 cells.<br><br>CONCLUSION: The new benzimidazole acridine derivative, 8m exerts anticancer activity against human colon cancer cells in vitro by inducing both intrinsic and extrinsic apoptosis pathways via the ROS-JNK1 pathway.}, }
@article {pmid26235215, year = {2015}, author = {Ma, G and Wu, Q and Wu, X and Arnesano, F and Natile, G and Sletten, E and Liu, Y}, title = {The reaction of a platinated methionine motif of CTR1 with cysteine and histidine is dependent upon the type of precursor platinum complex.}, journal = {Journal of inorganic biochemistry}, volume = {153}, number = {}, pages = {239-246}, doi = {10.1016/j.jinorgbio.2015.07.010}, pmid = {26235215}, issn = {1873-3344}, mesh = {Amino Acid Motifs ; Amino Acid Sequence ; Antineoplastic Agents/*chemistry/pharmacology ; Binding Sites ; Cation Transport Proteins/*chemistry/metabolism ; Cisplatin/*chemistry/pharmacology ; Copper Transporter 1 ; Cysteine/chemistry ; Histidine/chemistry ; Methionine/chemistry ; Molecular Sequence Data ; Organoplatinum Compounds/*chemistry/pharmacology ; Oxaliplatin ; Protein Binding ; Saccharomyces cerevisiae/chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism ; }, abstract = {The human copper protein (hCTR1) is believed to facilitate the cellular uptake of cisplatin. Cisplatin likely binds to the methionine (Met)-rich motifs located in the N-terminus of hCTR1, and ligand exchange would be essential if cisplatin has to pass through the hCTR1 channel. In this work, we investigated the reaction between platinated adducts of a methionine-rich motif of yeast CTR1 (Mets7) and N-acetyl-cysteine (AcCys) or N-acetyl-histidine (AcHis), mimicking metal-binding residues downstream the CTR1 channel. Platination involved two cis-compounds, cisplatin and oxaliplatin, and one monofunctional complex, cis-diammine(pyridine)chloridoplatinum(II) (cDPCP). The reactions were monitored by HPLC and the products were characterized by ESI-MS. The results indicate different reactivities depending upon the platinum complex. The cisplatin/Mets7 adduct reacts readily with both cysteine and histidine (t1/2<2min). In contrast, the oxaliplatin/Mets7 adduct reacts with cysteine but not with histidine, whereas cDPCP/Mets7 adduct reacts with histidine but not with cysteine. Hence, Mets7 adducts of these platinum complexes exhibit different reactivities towards downstream coordinating amino acids. These results suggest that each platinum complex possesses different reactivities and consequently may lead to differences in their cellular distribution and bioactivity.}, }
@article {pmid26234406, year = {2016}, author = {Murad, HA and Habib, H and Kamel, Y and Alsayed, S and Shakweer, M and Elshal, M}, title = {Thearubigins protect against acetaminophen-induced hepatic and renal injury in mice: biochemical, histopathological, immunohistochemical, and flow cytometry study.}, journal = {Drug and chemical toxicology}, volume = {39}, number = {2}, pages = {190-198}, doi = {10.3109/01480545.2015.1070170}, pmid = {26234406}, issn = {1525-6014}, mesh = {Acetaminophen/*toxicity ; Acute Kidney Injury/chemically induced/metabolism/pathology/*prevention &amp; control ; Animals ; Apoptosis/drug effects ; Camellia sinensis/*chemistry ; Catechin/administration &amp; dosage/*analogs &amp; derivatives/isolation &amp; purification/therapeutic use ; Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology/*prevention &amp; control ; Flow Cytometry ; Immunohistochemistry ; Kidney Function Tests ; Liver Function Tests ; Male ; Mice ; Plant Leaves/chemistry ; Polyphenols/administration &amp; dosage/isolation &amp; purification/*therapeutic use ; }, abstract = {CONTEXT: Acetaminophen toxicity is used as a model for studying chemical toxicity. N-acetylcysteine (NAC) is used for the treatment of hepatotoxicity; however, there is no specific therapy for nephrotoxicity.<br><br>OBJECTIVE: This study was designed to investigate the potential protective effect of black tea extract (BTE) and its main phenolic pigment, thearubigins (TRs), against acetaminophen (APAP)-induced hepatic and renal injury in mice.<br><br>MATERIALS AND METHODS: Besides control groups, six groups (n&#x2009;=&#x2009;8) were given intraperitoneally APAP (300&#x2009;mg/kg) and then after 1.5 hours were treated intraperitoneally as follows: NAC (318&#x2009;mg/kg), BTE (3%, 4.5%), and TRs (50, 60, and 70&#x2009;mg/kg). Six hours post-APAP injection, blood was collected for biochemical measurements. Later, liver and kidneys were removed for histopathological, immunohistochemical, and flow cytometry studies.<br><br>RESULTS: APAP increased alanine aminotransferase and malondialdehyde and decreased glutathione levels in blood. Treatments significantly reversed these changes mostly with NAC and TRs70. TRs showed dose-dependent significant differences. The APAP-induced central lobular hepatic necrosis and increased TUNEL positivity were mild with co-administration of NAC and TRs (60,&#x2009;70) while moderate with co-administration of BTE (3,&#x2009;4.5) and TRs50. The APAP-increased serum creatinine level was significantly reversed by treatments (mostly TRs60,&#x2009;70). The APAP-induced renal tubular epithelial degeneration and necrosis were mild with co-administration of TRs (60,&#x2009;70) while moderate with co-administration of NAC, BTE (3,&#x2009;4.5), and TRs50. The APAP-accumulated apoptotic cells in sub-G1 phase were significantly decreased by treatments, mostly by NAC and TRs70 in the liver and TRs (60,&#x2009;70) in kidneys.<br><br>CONCLUSION: Thearubigins protected against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice possibly through their antioxidant activity.}, }
@article {pmid26230185, year = {2015}, author = {Bulacio, RP and Anzai, N and Ouchi, M and Torres, AM}, title = {Organic Anion Transporter 5 (Oat5) Urinary Excretion Is a Specific Biomarker of Kidney Injury: Evaluation of Urinary Excretion of Exosomal Oat5 after N-Acetylcysteine Prevention of Cisplatin Induced Nephrotoxicity.}, journal = {Chemical research in toxicology}, volume = {28}, number = {8}, pages = {1595-1602}, doi = {10.1021/acs.chemrestox.5b00176}, pmid = {26230185}, issn = {1520-5010}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Biomarkers/*urine ; Cisplatin/toxicity ; Dicarboxylic Acid Transporters/*urine ; Electrophoresis ; Immunoblotting ; Kidney/drug effects/*injuries ; Male ; Nephrosis/*diagnosis/drug therapy/prevention &amp; control ; Organic Anion Transporters/urine ; Rats ; Rats, Wistar ; }, abstract = {Cisplatin is a commonly used chemotherapeutic agent. Its main side-effect is nephrotoxicity. It was reported that the organic anion transporter 5 (Oat5) urinary excretion is elevated, implying renal perturbation, when no modifications of traditional markers of renal damage are still observed in cisplatin-induced acute kidney injury (AKI). It was also demonstrated that Oat5 is excreted in urine by the exosomal pathway. This study was designated to demonstrate the specific response of the urinary excretion of exosomal Oat5 to kidney injury independently of other cisplatin toxic effects, in order to strengthen Oat5 urinary levels as a specific biomarker of AKI. To accomplish that aim, we evaluated if urinary excretion of exosomal Oat5 returns to its basal levels when cisplatin renal damage is prevented by the coadministration of the renoprotective compound N-acetylcysteine. Four days after cisplatin administration, AKI was induced in cisplatin-treated male Wistar rats (Cis group), as it was corroborated by increased urea and creatinine plasma levels. Tubular damage was also observed. In cotreated animals (Cis + NAC group), plasma urea and creatinine concentrations tended to return to their basal values, and tubular damage was improved. Urinary excretion of exosomal Oat5 was notably increased in the Cis group, but when renal injury was ameliorated by N-acetylcysteine coadministration, that increase was undetected. So, in this work we observed that urinary excretion of exosomal Oat5 was only increased if renal insult is produced, demonstrating its specificity as a renal injury biomarker.}, }
@article {pmid26228975, year = {2016}, author = {Chen, H and Pan, J and Wang, JD and Liao, QM and Xia, XR}, title = {Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Induces Apoptosis in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.}, journal = {Inflammation}, volume = {39}, number = {1}, pages = {39-46}, pmid = {26228975}, issn = {1573-2576}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Arthritis, Rheumatoid/*drug therapy ; Caspase 3/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Fibroblasts/*metabolism ; Histone Deacetylase Inhibitors/*pharmacology ; Humans ; Hydroxamic Acids/*pharmacology ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; NF-KappaB Inhibitor alpha/metabolism ; Reactive Oxygen Species/metabolism ; Synovial Membrane/cytology/*metabolism ; Transcription Factor RelA/metabolism ; Vorinostat ; bcl-X Protein/metabolism ; }, abstract = {Here, we explored the effects of suberoylanilide hydroxamic acid (SAHA) on the viability and apoptosis of rheumatoid arthritis of fibroblast-like synoviocytes (rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS)). FLS obtained from RA patients were treated with SAHA. SAHA significantly inhibited the viability of RA FLS in a concentration-dependent manner up to 5 μM. SAHA-treated FLS showed a significant increase in the percentage of apoptosis and the expression and activity of caspase-3 and higher intracellular ROS levels. N-acetyl-l-cysteine (NAC) pretreatment significantly attenuated SAHA-induced apoptosis, decreasing the percentage of apoptosis by about 60 %. A significant decline in phosphorylated IκBα and nuclear factor kappa B (NF-κB) p65 and concomitant increase in total IκBα were shown in SAHA-treated FLS. Additionally, the levels of anti-apoptotic Bcl-2 proteins (Bcl-xL and Mcl-1) were significantly reduced by SAHA. Collectively, SAHA induces apoptosis of RA FLS, at least partially, through generation of ROS and suppression of NF-κB activation and Bcl-xL and Mcl-1 expression.}, }
@article {pmid26224008, year = {2015}, author = {Xiao, D and Huang, X and Li, Y and Dasgupta, C and Wang, L and Zhang, L}, title = {Antenatal Antioxidant Prevents Nicotine-Mediated Hypertensive Response in Rat Adult Offspring.}, journal = {Biology of reproduction}, volume = {93}, number = {3}, pages = {66}, pmid = {26224008}, issn = {1529-7268}, support = {R01 HL110125/HL/NHLBI NIH HHS/United States ; R01 HL118861/HL/NHLBI NIH HHS/United States ; R03 DA032510/DA/NIDA NIH HHS/United States ; HL118861/HL/NHLBI NIH HHS/United States ; DA032510/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/pharmacology ; Animals ; Antioxidants/*pharmacology ; Body Weight/drug effects ; Enzyme Activation/drug effects ; Female ; Humans ; Hypertension/*chemically induced ; Muscle Relaxation/drug effects ; Muscle, Smooth, Vascular/drug effects ; Nicotine/*antagonists &amp; inhibitors/*toxicity ; Nicotinic Agonists/*toxicity ; Phorbol 12,13-Dibutyrate/pharmacology ; Pregnancy ; Prenatal Exposure Delayed Effects/prevention &amp; control ; Protein Kinase C/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/antagonists &amp; inhibitors ; }, abstract = {Previous studies have demonstrated that perinatal nicotine exposure increased blood pressure (BP) in adult offspring. However, the underlying mechanisms were unclear. The present study tested the hypothesis that perinatal nicotine-induced programming of hypertensive response is mediated by enhanced reactive oxygen species (ROS) in the vasculature. Nicotine was administered to pregnant rats via subcutaneous osmotic mini-pumps from Day 4 of gestation to Day 10 after birth, in the absence or presence of the ROS inhibitor N-acetyl-cysteine (NAC) in the drinking water. Experiments were conducted in 8-mo-old male offspring. Perinatal nicotine treatment resulted in a significant increase in arterial ROS production in offspring, which was abrogated by NAC. Angiotensin II (Ang II)-induced BP responses were significantly higher in nicotine-treated group than in saline-treated control group, and NAC treatment blocked the nicotine-induced increase in BP response. Consistent with that, the nicotine treatment significantly increased both Ang II-induced and phorbol [12, 13]-dibutyrate (PDBu, a Prkc activator)-induced arterial contractions in adult offspring, which were blocked by NAC treatment. In addition, perinatal nicotine treatment significantly attenuated acetylcholine-induced arterial relaxation in offspring, which was also inhibited by NAC treatment. Results demonstrate that inhibition of ROS blocks the nicotine-induced increase in arterial reactivity and BP response to vasoconstrictors in adult offspring, suggesting a key role for increased oxidative stress in nicotine-induced developmental programming of hypertensive phenotype in male offspring.}, }
@article {pmid26223711, year = {2015}, author = {Somdaş, MA and Korkmaz, F and Gürgen, SG and Sagit, M and Akçadağ, A}, title = {N-acetylcysteine Prevents Gentamicin Ototoxicity in a Rat Model.}, journal = {The journal of international advanced otology}, volume = {11}, number = {1}, pages = {12-18}, doi = {10.5152/iao.2015.650}, pmid = {26223711}, issn = {1308-7649}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cochlea/drug effects/*pathology/physiopathology ; Disease Models, Animal ; Ear Diseases/chemically induced/pathology/*prevention &amp; control ; Evoked Potentials, Auditory, Brain Stem ; Female ; Free Radical Scavengers/pharmacology ; Gentamicins/*toxicity ; Otoacoustic Emissions, Spontaneous/*drug effects ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; }, abstract = {OBJECTIVE: The possible preventive effect of N-acetylcysteine (NAC) in gentamicin ototoxicity was studied with auditory brain stem responses (ABRs), otoacoustic emissions (OAEs), and histopathological investigation of the cochlea.<br><br>MATERIALS AND METHODS: This study is conducted on 36 rats in three groups. Gentamicin, gentamicin plus NAC, and NAC alone were intraperitoneally administered for 15 days. The rats were sacrificed to study the cochleas after testing hearing levels.<br><br>RESULTS: ABR thresholds and OAEs were attenuated in the gentamicin group, in which apoptosis was detected with histopathological investigation. The group that received NAC in addition to gentamicin had better ABR thresholds and better OAEs. The histopathological evidence of apoptosis in was considerably less in this group.<br><br>CONCLUSION: Gentamicin ototoxicity can be detected by ABR and OAE testing in rats, and NAC may protect the cochlear cells from apoptosis.}, }
@article {pmid26220902, year = {2015}, author = {Yang, X and Dong, QF and Li, LW and Huo, JL and Li, PQ and Fei, Z and Zhen, HN}, title = {The cap-translation inhibitor 4EGI-1 induces mitochondrial dysfunction via regulation of mitochondrial dynamic proteins in human glioma U251 cells.}, journal = {Neurochemistry international}, volume = {90}, number = {}, pages = {98-106}, doi = {10.1016/j.neuint.2015.07.019}, pmid = {26220902}, issn = {1872-9754}, mesh = {Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Glioma/drug therapy ; Humans ; Hydrazones/*pharmacology ; Mitochondria/*drug effects/metabolism ; Mitochondrial Dynamics/*drug effects ; Protein Biosynthesis/*drug effects ; Protein Synthesis Inhibitors/*pharmacology ; Thiazoles/*pharmacology ; }, abstract = {Translation initiation factors (eIFs) are over-activated in many human cancers and may contribute to their progression. The small molecule 4EGI-1, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anti-cancer effects in human cancer cells. The goal of the present study was to evaluate the anti-cancer effects of 4EGI-1 in human glioma U251 cells. We found that 4EGI-1 impaired the assembly of the eIF4F complex, and inhibited proliferation of U251 cells via inducing apoptosis. 4EGI-1 treatment induced collapse of mitochondrial membrane potential (MMP) and production of intracellular reactive oxygen species (ROS), which were prevented by the ROS scavenger N-acetyl-cysteine (NAC). In addition, 4EGI-1 inhibited mitochondrial ATP synthesis via suppressing complex I activity, but had no effects on mitochondrial biogenesis. The results of fluorescence staining showed that 4EGI-1 indeed fragmented the mitochondrial network of U251 cells. We found a significant decrease in optic atrophy type 1 (Opa-1) and mitofusin 1 (Mfn-1) related to fusion proteins as well as an increase in fission protein dynamin-related protein 1 (Drp-1). Furthermore, the anti-cancer effects of 4GI-1 were partially nullified by knock down of Drp-1 using siRNA. These data indicate that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for human glioma therapy.}, }
@article {pmid26219228, year = {2015}, author = {Zhang, X and Wang, X and Wu, T and Li, B and Liu, T and Wang, R and Liu, Q and Liu, Z and Gong, Y and Shao, C}, title = {Isoliensinine induces apoptosis in triple-negative human breast cancer cells through ROS generation and p38 MAPK/JNK activation.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {12579}, pmid = {26219228}, issn = {2045-2322}, mesh = {Apoptosis/*drug effects ; Benzylisoquinolines/pharmacology ; Cell Line, Tumor ; Enzyme Activation/*drug effects ; Female ; Humans ; Isoquinolines/*pharmacology ; MAP Kinase Signaling System/*drug effects ; MCF-7 Cells ; Phenols/pharmacology ; Reactive Oxygen Species/*metabolism ; Triple Negative Breast Neoplasms/*drug therapy/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Isoliensinine, liensinine and neferine are major bisbenzylisoquinoline alkaloids in the seed embryo of lotus (Nelumbo nucifera), and exhibit potential anti-cancer activity. Here, we explored the effects of these alkaloids on triple-negative breast cancer cells and found that among the three alkaloids isoliensinine possesses the most potent cytotoxic effect, primarily by inducing apoptosis. Interestingly, isoliensinine showed a much lower cytotoxicity against MCF-10A, a normal human breast epithelial cell line. Further studies showed that isoliensinine could significantly increase the production of reactive oxygen species (ROS) in triple-negative breast cancer cells, but not in MCF-10A cells. The isoliensinine-induced apoptosis could be attenuated by radical oxygen scavenger N-acetyl cysteine, suggesting that the cytotoxic effect of isoliensinine on cancer cells is at least partially achieved by inducing oxidative stress. We found that both p38 MAPK and JNK signaling pathways were activated by isoliensinine treatment and contributed to the induction of apoptosis. Furthermore, inhibitors or specific siRNAs of p38 MAPK and JNK could attenuate apoptosis induced by isoliensinine. However, only the p38 inhibitor or p38-specific siRNA blocked the elevation of ROS in isoliensinine-treated cells. Our findings thus revealed a novel antitumor effect of isoliensinine on breast cancer cells and may have therapeutic implications.}, }
@article {pmid26215453, year = {2015}, author = {Gopi, V and Subramanian, V and Manivasagam, S and Vellaichamy, E}, title = {Angiotensin II down-regulates natriuretic peptide receptor-A expression and guanylyl cyclase activity in H9c2 (2-1) cardiac myoblast cells: Role of ROS and NF-κB.}, journal = {Molecular and cellular biochemistry}, volume = {409}, number = {1-2}, pages = {67-79}, pmid = {26215453}, issn = {1573-4919}, mesh = {Angiotensin II/metabolism/*pharmacology ; Animals ; Atrial Natriuretic Factor/metabolism ; Cell Line ; Enzyme Activation ; Guanylate Cyclase/*metabolism ; Myoblasts, Cardiac/*metabolism ; NADPH Oxidases/metabolism ; NF-kappa B/*metabolism ; Proto-Oncogene Proteins c-fos/biosynthesis ; Proto-Oncogene Proteins c-jun/biosynthesis ; Proto-Oncogene Proteins c-myc/biosynthesis ; Rats ; Reactive Oxygen Species/*metabolism ; Receptors, Atrial Natriuretic Factor/*biosynthesis ; }, abstract = {Atrial natriuretic peptide (ANP)/natriuretic peptide receptor-A (NPR-A) system is suggested as an endogenous anti-hypertrophic protective mechanism of the heart. We have shown previously that Angiotensin II (ANG II), an effector molecule of renin-angiotensin-aldosterone system, down-regulates NPR-A expression and its activity in vivo rat heart. However, the underlying mechanism by which ANG II down-regulates NPR-A expression in the heart is not well understood. Hence, the present investigation was aimed to determine whether ANG II-stimulated reactive oxygen species (ROS) and NF-κB are involved in the down-regulation of NPR-A activity in H9c2 (2-1) cardiac myoblast cells. The H9c2 (2-1) cardiac myoblast cells were exposed to ANG II (10(-7) M for 20 h) with/or without blocker treatment (losartan-10 µM, N-acetyl cysteine (NAC)-10 mM and pyrrolidine dithiocarbamate (PDTC)-100 µM). On exposure, ANG II induced a significant decrease (P < 0.001) in the expression of Npr1 (coding for NPR-A) gene and NPR-A receptor-dependent guanylyl cyclase (GC) activity. The level of expression of proto-oncogenes (c-fos, c-myc, and c-jun) and natriuretic peptides (ANP and BNP) was increased in ANG II-treated cells when compared with control cells. Interestingly, ANG II-dependent repression of Npr1 gene expression and guanylyl cyclase (GC) activity was completely restored on treatment with losartan, while only a partial reversal was observed in NAC- and PDTC-co-treated cells. In conclusion, the results of this study suggest that ROS-mediated NF-κB activation mechanism is critically involved in the ANG II-mediated down-regulation of NPR-A expression and its GC activity.}, }
@article {pmid26209138, year = {2015}, author = {Zhao, C and She, T and Wang, L and Su, Y and Qu, L and Gao, Y and Xu, S and Cai, S and Shou, C}, title = {Daucosterol inhibits cancer cell proliferation by inducing autophagy through reactive oxygen species-dependent manner.}, journal = {Life sciences}, volume = {137}, number = {}, pages = {37-43}, doi = {10.1016/j.lfs.2015.07.019}, pmid = {26209138}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Glutathione/pharmacology ; Humans ; Mice ; Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Sitosterols/antagonists &amp; inhibitors/*pharmacology ; Tumor Stem Cell Assay ; }, abstract = {AIMS: This study aims to evaluate the anti-cancer effect of daucosterol and explore its possible mechanism.<br><br>MAIN METHODS: MTT and colony formation assay were performed to determine the effect of daucosterol on cancer cell proliferation in vitro. H22 allograft model was used for the assessment of its anti-cancer activity in vivo. Intracellular generation of reactive oxygen species (ROS) was measured using DCFH-DA probe with flow cytometry system and a laser scanning confocal microscope. LC3 (microtubule-associated protein 1 light chain 3)-II conversion was monitored with immunofluorescence and immunoblotting to demonstrate daucosterol-induced autophagy.<br><br>KEY FINDINGS: We found that daucosterol inhibits the proliferation of human breast cancer cell line MCF-7 and gastric cancer cell lines MGC803, BGC823 and AGS in a dose-dependent manner. Furthermore, daucosterol inhibits murine hepatoma H22 cell growth in ICR mice. Daucosterol treatment induces intracellular ROS generation and autophagy, but not apoptotic cell death. Treatment with ROS scavenger GSH (reduced glutathione), NAC (N-acetyl-l-cysteine) or autophagy inhibitor 3-Methyladenine (3-MA) counteracted daucosterol-induced autophagy and growth inhibition in BGC823 and MCF-7 cancer cells.<br><br>SIGNIFICANCE: Daucosterol inhibits cancer cell proliferation by inducing autophagy through ROS-dependent manner and could be potentially developed as an anti-cancer agent.}, }
@article {pmid26208145, year = {2016}, author = {Muñoz-Egea, MC and García-Pedrazuela, M and Mahillo-Fernandez, I and Esteban, J}, title = {Effect of Antibiotics and Antibiofilm Agents in the Ultrastructure and Development of Biofilms Developed by Nonpigmented Rapidly Growing Mycobacteria.}, journal = {Microbial drug resistance (Larchmont, N.Y.)}, volume = {22}, number = {1}, pages = {1-6}, doi = {10.1089/mdr.2015.0124}, pmid = {26208145}, issn = {1931-8448}, mesh = {Acetylcysteine/pharmacology ; Amikacin/pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects ; Ciprofloxacin/pharmacology ; Clarithromycin/pharmacology ; Microbial Sensitivity Tests/methods ; Microscopy, Confocal/methods ; Mycobacterium/*drug effects ; Polysorbates/pharmacology ; }, abstract = {We analyze the effect of amikacin, ciprofloxacin, and clarithromycin, alone and associated with N-acetylcysteine (NAC) and Tween 80, at different times and concentrations in nonpigmented rapidly growing mycobacteria (NPRGM) biofilms. For this purpose, confocal laser scanning microscopy and image analysis were used to study the development and behavior of intrinsic autofluorescence, covered area, thickness, and cell viability in NPRGM biofilms after adding antibiotics alone and associated with antibiofilm agents. In this study, ciprofloxacin is the most active antibiotic against this type of biofilm and thickness is the most affected parameter. NAC and Tween 80 combined with antibiotics exert a synergistic effect in increasing the percentage of dead bacteria and also reducing the percentage of covered surface and thickness of NPRGM biofilms. Tween 80 seems to be an antibiofilm agent more effective than NAC due to its higher reduction in the percentage of cover surface and thickness. In conclusion, the results obtained in this work show that phenotypic parameters (thickness, percentage of covered surface, autofluorescence, percentage of live/dead bacteria) are affected by combining antibiotics and antibiofilm agents, ciprofloxacin and Tween 80 being the most active agents against NPRGM biofilms.}, }
@article {pmid26206888, year = {2015}, author = {Monti, L and Paganini, C and Lecci, S and De Leonardis, F and Hay, E and Cohen-Solal, M and Villani, S and Superti-Furga, A and Tenni, R and Forlino, A and Rossi, A}, title = {N-acetylcysteine treatment ameliorates the skeletal phenotype of a mouse model of diastrophic dysplasia.}, journal = {Human molecular genetics}, volume = {24}, number = {19}, pages = {5570-5580}, doi = {10.1093/hmg/ddv289}, pmid = {26206888}, issn = {1460-2083}, support = {GGP06076/TI_/Telethon/Italy ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Animals, Newborn ; Antioxidants/*administration &amp; dosage ; Bone and Bones/*drug effects/pathology ; Cell Proliferation/drug effects ; Chondrocytes/cytology/*drug effects ; Disease Models, Animal ; Dwarfism/*drug therapy/pathology ; Embryo, Mammalian/drug effects ; Female ; Growth and Development/drug effects ; Humans ; Male ; Mice ; Pregnancy ; Proteoglycans/metabolism ; }, abstract = {Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by mutations in SLC26A2, a cell membrane sulfate-chloride antiporter. Sulfate uptake impairment results in low cytosolic sulfate, leading to cartilage proteoglycan (PG) undersulfation. In this work, we used the dtd mouse model to study the role of N-acetyl-l-cysteine (NAC), a well-known drug with antioxidant properties, as an intracellular sulfate source for macromolecular sulfation. Because of the important pre-natal phase of skeletal development and growth, we administered 30 g/l NAC in the drinking water to pregnant mice to explore a possible transplacental effect on the fetuses. When cartilage PG sulfation was evaluated by high-performance liquid chromatography disaccharide analysis in dtd newborn mice, a marked increase in PG sulfation was observed in newborns from NAC-treated pregnancies when compared with the placebo group. Morphometric studies of the femur, tibia and ilium after skeletal staining with alcian blue and alizarin red indicated a partial rescue of abnormal bone morphology in dtd newborns from treated females, compared with pups from untreated females. The beneficial effect of increased macromolecular sulfation was confirmed by chondrocyte proliferation studies in cryosections of the tibial epiphysis by proliferating cell nuclear antigen immunohistochemistry: the percentage of proliferating cells, significantly reduced in the placebo group, reached normal values in dtd newborns from NAC-treated females. In conclusion, NAC is a useful source of sulfate for macromolecular sulfation in vivo when extracellular sulfate supply is reduced, confirming the potential of therapeutic approaches with thiol compounds to improve skeletal deformity and short stature in human DTD and related disorders.}, }
@article {pmid26206453, year = {2015}, author = {Zhu, D and Deng, Y and Pan, Y and Wang, Z and Yuan, X and Guo, X and Wang, Y and Liu, H}, title = {N-acetylcysteine Ameliorates the Erectile Dysfunction Caused by Chronic Intermittent Hypoxia in Rats: Partly Involvement of Endoplasmic Reticulum Stress.}, journal = {Urology}, volume = {86}, number = {4}, pages = {844.e7-844.e14}, doi = {10.1016/j.urology.2015.07.013}, pmid = {26206453}, issn = {1527-9995}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Blotting, Western ; Disease Models, Animal ; Endoplasmic Reticulum Stress/*drug effects ; Erectile Dysfunction/*drug therapy/etiology/metabolism ; Free Radical Scavengers/pharmacology ; Hypoxia/*complications/pathology ; Immunohistochemistry ; Male ; Nitric Oxide Synthase/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: To conduct a study using a rodent model of chronic intermittent hypoxia (CIH) to define whether endoplasmic reticulum stress (ERS) is involved in the CIH-induced apoptosis of penile tissue and erectile dysfunction (ED), and whether treatment with N-acetylcysteine (NAC) alleviates pathological variations in corpus cavernosa. Previous work has prompted that CIH acted as the major trigger linking obstructive sleep apnea syndrome and ED.<br><br>MATERIALS AND METHODS: Five-month-old Sprague-Dawley male rats were subjected to 8 hours of intermittent hypoxia per day, with or without NAC for 5 weeks. Erectile function, apoptosis of penile tissue, levels of ERS-associated proapoptotic effectors, and nitric oxide (NO) and nitric oxide synthase (NOS) activity were determined.<br><br>RESULTS: Treatment with NAC inhibited apoptosis of penile tissue, the expressions of ERS-related products: BIP, CHOP, caspase12, and Bax, NO, and endothelial NOS. Administration of NAC before CIH significantly improved the CIH-induced impaired erectile function.<br><br>CONCLUSION: Our results show that pre-CIH NAC administration ameliorates the ED following CIH partly by alleviating CIH-induced ERS and cell apoptosis via regulating the expressions of BIP, CHOP, caspase12, and Bax.}, }
@article {pmid26203910, year = {2015}, author = {Rosani, U and Tarricone, E and Venier, P and Brun, P and Deligianni, V and Zuin, M and Martines, E and Leonardi, A and Brun, P}, title = {Atmospheric-Pressure Cold Plasma Induces Transcriptional Changes in Ex Vivo Human Corneas.}, journal = {PloS one}, volume = {10}, number = {7}, pages = {e0133173}, pmid = {26203910}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Aged ; Air ; Antioxidants/pharmacology ; Atmospheric Pressure ; Cold Temperature ; Cornea/*drug effects/metabolism ; DNA Damage ; DNA Glycosylases/biosynthesis/genetics ; Disinfection/*methods ; Enzyme Induction/drug effects ; Equipment Design ; Eye Proteins/genetics ; Gene Expression Profiling ; Helium ; Humans ; In Vitro Techniques ; Middle Aged ; Oxidative Stress/genetics ; Plasma Gases/*pharmacology ; RNA, Messenger/biosynthesis/genetics ; Time Factors ; Transcription, Genetic/*drug effects ; Transcriptome/*drug effects ; }, abstract = {BACKGROUND: Atmospheric pressure cold plasma (APCP) might be considered a novel tool for tissue disinfection in medicine since the active chemical species produced by low plasma doses, generated by ionizing helium gas in air, induces reactive oxygen species (ROS) that kill microorganisms without substantially affecting human cells.<br><br>OBJECTIVES: In this study, we evaluated morphological and functional changes in human corneas exposed for 2 minutes (min) to APCP and tested if the antioxidant n-acetyl l-cysteine (NAC) was able to inhibit or prevent damage and cell death.<br><br>RESULTS: Immunohistochemistry and western blotting analyses of corneal tissues collected at 6 hours (h) post-APCP treatment demonstrated no morphological tissue changes, but a transient increased expression of OGG1 glycosylase that returned to control levels in 24 h. Transcriptome sequencing and quantitative real time PCR performed on different corneas revealed in the treated corneas many differentially expressed genes: namely, 256 and 304 genes showing expression changes greater than &#xb1; 2 folds in the absence and presence of NAC, respectively. At 6 h post-treatment, the most over-expressed gene categories suggested an active or enhanced cell functioning, with only a minority of genes specifically concerning oxidative DNA damage and repair showing slight over-expression values (<2 folds). Moreover, time-related expression analysis of eight genes up-regulated in the APCP-treated corneas overall demonstrated the return to control expression levels after 24 h.<br><br>CONCLUSIONS: These findings of transient oxidative stress accompanied by wide-range transcriptome adjustments support the further development of APCP as an ocular disinfectant.}, }
@article {pmid26203774, year = {2015}, author = {Gao, Y and Huang, R and Gong, Y and Park, HS and Wen, Q and Almosnid, NM and Chippada-Venkata, UD and Hosain, NA and Vick, E and Farone, A and Altman, E}, title = {The antidiabetic compound 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione, isolated from Averrhoa carambola L., demonstrates significant antitumor potential against human breast cancer cells.}, journal = {Oncotarget}, volume = {6}, number = {27}, pages = {24304-24319}, pmid = {26203774}, issn = {1949-2553}, mesh = {Acetylcysteine/chemistry ; Antineoplastic Agents/*chemistry ; Antioxidants/chemistry ; Apoptosis ; Averrhoa/*chemistry ; Bone Neoplasms/metabolism/pathology ; Breast Neoplasms/metabolism/*pathology ; Caspases/metabolism ; Cell Cycle ; Cell Line, Tumor/drug effects ; Cell Proliferation ; Cyclohexenes/*chemistry ; Cytochromes c/metabolism ; Drug Screening Assays, Antitumor ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Hypoglycemic Agents/*chemistry ; Inhibitory Concentration 50 ; Lung Neoplasms/metabolism/pathology ; MCF-7 Cells/drug effects ; NF-kappa B/metabolism ; Oxidative Stress ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) is a cyclohexanedione found in the roots of Averrhoa carambola L., commonly known as starfruit. Researchers have shown that DMDD has significant therapeutic potential for the treatment of diabetes; however, the effects of DMDD on human cancers have never been reported. We investigated the cytotoxic effects of DMDD against human breast, lung and bone cancer cells in vitro and further examined the molecular mechanisms of DMDD-induced apoptosis in human breast cancer cells. DMDD suppressed the growth of breast carcinoma cells, but not normal mammary epithelial cells, via induction of G1 phase cell cycle arrest, oxidative stress and apoptosis. DMDD increased the level of intracellular reactive oxygen species (ROS) and DMDD-induced ROS generation was found to be associated with the mitochondrial activity. The cytotoxicity that was induced by DMDD was attenuated by co-treatment with the antioxidant N-acetyl-L-cysteine (NAC). DMDD-induced cell apoptosis involved the activation of both the intrinsic mitochondrial pathway and the extrinsic receptor pathway. In addition, DMDD inhibited the canonical NF-κB signaling pathway at all steps, including TNF-α production, phosphorylation of NF-κB p65 and IκBα, as well as TNF-α activated NF-κB p65 nuclear translocation.Collectively, our studies indicate that DMDD has significant potential as a safe and efficient therapeutic agent for the treatment of breast cancer.}, }
@article {pmid26203575, year = {2015}, author = {Sepulveda-Martinez, A and Romero, C and Juarez, G and Hasbun, J and Parra-Cordero, M}, title = {[Causes and management of severe acute liver damage during pregnancy].}, journal = {Revista medica de Chile}, volume = {143}, number = {5}, pages = {627-636}, doi = {10.4067/S0034-98872015000500011}, pmid = {26203575}, issn = {0717-6163}, mesh = {*Fatty Liver/etiology/therapy ; Female ; Gestational Age ; *HELLP Syndrome/etiology/therapy ; Humans ; *Liver Failure, Acute/etiology/therapy ; Pregnancy ; *Pregnancy Complications/etiology ; Pregnancy Trimester, Third ; }, abstract = {Abnormalities in liver function tests appear in 3% of pregnancies. Severe acute liver damage can be an exclusive condition of pregnancy (dependent or independent of pre-eclampsia) or a concomitant disease. HELLP syndrome and acute fatty liver of pregnancy are the most severe liver diseases associated with pregnancy. Both appear during the third trimester and have a similar clinical presentation. Acute fatty liver may be associated with hypoglycemia and HELLP syndrome is closely linked with pre-eclampsia. Among concomitant conditions, fulminant acute hepatitis caused by medications or virus is the most severe disease. Its clinical presentation may be hyper-acute with neurological involvement and severe coagulation disorders. It has a high mortality and patients should be transplanted. Fulminant hepatic failure caused by acetaminophen overdose can be managed with n-acetyl cysteine. Because of the high fetal mortality rate, the gestational age at diagnosis is crucial.}, }
@article {pmid26199914, year = {2015}, author = {Mushtaq, S and Ali, T and Javed, Q and Tabassum, S and Murtaza, I}, title = {N-Acetyl Cysteine Inhibits Endothelin-1-Induced ROS Dependent Cardiac Hypertrophy through Superoxide Dismutase Regulation.}, journal = {Cell journal}, volume = {17}, number = {2}, pages = {355-360}, pmid = {26199914}, issn = {2228-5806}, abstract = {OBJECTIVE: Oxidative stress down regulates antioxidant enzymes including superoxide dismutase (SOD) and contributes to the development of cardiac hypertrophy. N-Acetyl cysteine (NAC) can enhance the SOD activity, so the aim of this study is to highlight the inhibitory role of NAC against endothelin-1 (ET-1)-induced cardiac hypertrophy.<br><br>MATERIALS AND METHODS: In this experimental study at QAU from January, 2013 to March, 2013. ET-1 (50 &#xb5;g/kg) and NAC (50 mg/kg) were given intraperitoneally to 6-day old neonatal rats in combination or alone. All rats were sacrificed 15 days after the final injection. Histological analysis was carried out to observe the effects caused by both drugs. Reactive oxygen species (ROS) analysis and SOD assay were also carried out. Expression level of hyper- trophic marker, brain natriuretic peptide (BNP), was detected by western blotting.<br><br>RESULTS: Our findings showed that ET-1-induced cardiac hypertrophy leading towards heart failure was due to the imbalance of different parameters including free radical-induced oxidative stress and antioxidative enzymes such as SOD. Furthermore NAC acted as an antioxidant and played inhibitory role against ROS-dependent hypertrophy via regulatory role of SOD as a result of oxidative response associated with hypertrophy.<br><br>CONCLUSION: ET-1-induced hypertrophic response is associated with increased ROS production and decreased SOD level, while NAC plays a role against free radicals-induced oxidative stress via SOD regulation.}, }
@article {pmid26196721, year = {2015}, author = {Akhtar, MJ and Ahamed, M and Alhadlaq, HA and Alshamsan, A and Khan, MA and Alrokayan, SA}, title = {Antioxidative and cytoprotective response elicited by molybdenum nanoparticles in human cells.}, journal = {Journal of colloid and interface science}, volume = {457}, number = {}, pages = {370-377}, doi = {10.1016/j.jcis.2015.07.034}, pmid = {26196721}, issn = {1095-7103}, mesh = {Antioxidants/chemistry/*pharmacology ; Cell Survival/drug effects ; Cytoprotection/*drug effects ; Dose-Response Relationship, Drug ; Humans ; Hydrogen Peroxide/chemistry/pharmacology ; MCF-7 Cells ; Molybdenum/chemistry/*pharmacology ; Nanoparticles/*chemistry ; Oxidants/chemistry/pharmacology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Particle Size ; Structure-Activity Relationship ; Surface Properties ; Tumor Cells, Cultured ; }, abstract = {Nanotechnology based therapeutics can offer an alternative platform in a wide variety of biomedical applications. Here we report novel cytotoxicity preventive potential of molybdenum nanoparticles (Mo NPs) in human breast (MCF-7) and fibrosarcoma (HT-1080) cells compromised with oxidant exposure. Physicochemical properties such as size, crystallinity, purity and band gap (an optical characteristic) of Mo NPs were characterized respectively by field emission transmission electron microscopy (FETEM), X-ray diffraction (XRD), energy dispersive spectrum (EDS) and UV-vis absorption spectroscopy. The average size of crystalline Mo NPs was found to be 35 nm with a band gap of 1.4 eV. Potential cytotoxicity of Mo NPs was evaluated by a battery of cell viability and oxidative stress parameters. Cell viability and oxidative stress data suggested Mo NPs to be reasonably non-cytotoxic. Cytotoxic preventive and GSH restoring potential of Mo NPs was determined against cytotoxicity and oxidative stress induced by H2O2 (and ZnO NPs) in two cells. Mo NPs significantly increased GSH level in MCF-7 and HT-1080 cells, an activity that was comparable to antioxidant N-acetyl cysteine (NAC). GSH level was increased 1.56 times in MCF-7 cells and 1.25 times in HT-1080 cells by 100 μg/ml of Mo NPs relative to control cells in 24 h. End-point data clearly suggest that Mo NPs significantly protected cells against cytotoxicity induced by H2O2 and ZnO (NPs) (p<0.05). Our study warrants further investigation about Mo NPs that could be exploited in myriads of nanotechnology applications.}, }
@article {pmid26196532, year = {2015}, author = {Morry, J and Ngamcherdtrakul, W and Gu, S and Goodyear, SM and Castro, DJ and Reda, MM and Sangvanich, T and Yantasee, W}, title = {Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis.}, journal = {Biomaterials}, volume = {66}, number = {}, pages = {41-52}, pmid = {26196532}, issn = {1878-5905}, support = {HHSN261201300078C/CA/NCI NIH HHS/United States ; R01 GM089918/GM/NIGMS NIH HHS/United States ; HHSN261201300078C//PHS HHS/United States ; R01GM089918/GM/NIGMS NIH HHS/United States ; }, mesh = {Administration, Cutaneous ; Animals ; Cell Survival/drug effects/genetics ; Gene Silencing ; Genetic Therapy/methods ; HSP47 Heat-Shock Proteins/*genetics ; Mice ; Mice, Inbred C3H ; NADPH Oxidase 4 ; NADPH Oxidases/*genetics ; Nanocapsules/administration &amp; dosage/*chemistry/ultrastructure ; Nanopores/ultrastructure ; Particle Size ; Porosity ; RNA, Small Interfering/administration &amp; dosage/*genetics ; Scleroderma, Diffuse/*genetics/*therapy ; Silicon Dioxide/chemistry ; Treatment Outcome ; }, abstract = {Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an in vitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the in vitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. In vivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice.}, }
@article {pmid26194066, year = {2015}, author = {Yi, MH and Kim, HP and Jeong, KY and Kim, CR and Kim, TY and Yong, TS}, title = {House dust mite allergen Der f 1 induces IL-8 in human basophilic cells via ROS-ERK and p38 signal pathways.}, journal = {Cytokine}, volume = {75}, number = {2}, pages = {356-364}, doi = {10.1016/j.cyto.2015.07.011}, pmid = {26194066}, issn = {1096-0023}, mesh = {Acetylcysteine/pharmacology ; Antigens, Dermatophagoides/*immunology ; Arthropod Proteins/*immunology ; Basophils/*immunology ; Cell Line, Tumor ; Cloning, Molecular ; Cysteine Endopeptidases/*immunology ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/*metabolism ; Humans ; Immunoglobulin E/immunology ; Inflammation/immunology ; Interleukin-8/*biosynthesis/genetics ; Phosphorylation/drug effects/immunology ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/*metabolism ; Signal Transduction/immunology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Der f 1, a major house dust mite allergen and member of the papain-like cysteine protease family, can provoke immune responses with its proteolytic activity. To understand the role of Der f 1 in inflammatory immune responses, we studied the mechanism of the regulation of interleukin (IL)-8 expressions in human basophilic cell KU812 by proteolytically active recombinant Der f 1. Not only production of IL-8 mRNA was induced but also the DNA binding activity of activator protein-1 (AP-1) and phosphorylation of NF-κB p65 were increased in Der f 1-treated KU812. Furthermore, Der f 1 induction of IL-8 expression was sensitive to pharmacological inhibition of ERK and p38 mitogen activated protein kinase (MAPK) pathways. Der f 1 also activated ERK and p38 MAPK phosphorylation and rapidly induced reactive oxygen species (ROS) production. The antioxidant N-acetyl-cysteine (NAC) inhibited phosphorylation of ERK, but not p38, suggesting that secretion of IL-8 in KU812 cells treated with Der f 1 is dependent on ROS, ERK MAPK and p38 MAPK. We describe the mechanism of Der f 1-induced IL-8 secretion from human basophilic cells, which are thought to be important for allergic inflammation independent of IgE antibodies. These findings improve our understanding of the inflammatory immune response in human basophils to protease allergens.}, }
@article {pmid26189548, year = {2015}, author = {Choudhury, S and Ghosh, S and Gupta, P and Mukherjee, S and Chattopadhyay, S}, title = {Inflammation-induced ROS generation causes pancreatic cell death through modulation of Nrf2/NF-κB and SAPK/JNK pathway.}, journal = {Free radical research}, volume = {49}, number = {11}, pages = {1371-1383}, doi = {10.3109/10715762.2015.1075016}, pmid = {26189548}, issn = {1029-2470}, mesh = {Animals ; Cell Death/drug effects ; Cell Survival ; Humans ; Inflammation/*metabolism ; Male ; Mice ; NF-E2-Related Factor 2/*metabolism ; NF-kappa B/*metabolism ; Pancreas/*pathology ; Pancreatitis, Chronic/*genetics ; Reactive Oxygen Species ; Signal Transduction ; }, abstract = {Chronic pancreatitis is characterized by progressive loss of exocrine and endocrine functions of the pancreas and is considered to be the single most important cause for development of pancreatic cancer. Recent evidence suggests that inflammation and oxidative stress play pivotal roles in the development of clinical conditions like pancreatitis, type 2 diabetes mellitus, and metabolic syndrome. Nonetheless, molecular signaling pathways linking inflammation, oxidative stress, and pancreatic cell death are not yet well defined. In this study, bacterial lipopolysaccharide (LPS) was used (injected twice a week for three weeks) to emulate a chronic systemic inflammatory state in experimental Swiss albino mice. Using this model, we traced the genesis of inflammation-induced pancreatic dysfunction and mapped the signaling events which contribute to the induction of this state. Histopathological studies revealed the appearance of cell injuries and increased collagen content in LPS-exposed group, indicative of fibrosis. Assays for intraperitoneal glucose tolerance, insulin levels, and insulin receptor mRNA expression signified inflammation-induced insulin insensitivity. For the first time we present evidence that cellular inflammation and subsequent oxidative stress modulate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/NF-E2-related factor 2 or Nuclear factor (erythroid-derived 2)-like 2 pathway and initiates pancreatic cell death by activation of stress-responsive Rho/stress-activated protein kinase or SAPK/Jun-N-terminal kinase (JNK) pathway. Scavenging of intracellular reactive oxygen species (ROS) by a standard antioxidant N-acetyl cysteine led to pancreatic cell survival. The data obtained strongly indicates that the LPS/toll-like receptor-4 or TLR-4/ROS/NF-κB pathway is critically involved in the initiation of inflammation, oxidative stress, and pancreatic cell death and might prove to be an excellent choice as a target for novel therapeutic strategies in the management of metabolic disorders.}, }
@article {pmid26189301, year = {2015}, author = {Yao, Y and Li, J and Jiang, CS and Zhao, XX and Miao, ZH and Liu, HT and Zheng, P and Ya, WX and Li, WQ}, title = {Trichodimerol and sorbicillin induced apoptosis of HL-60 cells is mediated by reactive oxygen species.}, journal = {Die Pharmazie}, volume = {70}, number = {6}, pages = {394-398}, pmid = {26189301}, issn = {0031-7144}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Bridged-Ring Compounds/*pharmacology ; Free Radical Scavengers/pharmacology ; HL-60 Cells ; Humans ; MAP Kinase Signaling System/drug effects ; Reactive Oxygen Species/*metabolism ; Resorcinols/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {In this study, two secondary metabolite compounds, trichodimerol and sorbicillin were isolated from the mycelial mass of the marine fungus Trichothecium sp.. It was found that trichodimerol and sorbicillin exhibited strong cytotoxic activity with IC50 values from 6.55 μM to 28.55 μM on three cancer cell lines, HL-60, U937 and T47D. Then HL-60 cells were employed for apoptotic assay. The two compounds could significantly increase the levels of activated caspase-3/7 in a dose-dependent manner and remarkably increase sub-G1 fraction in the cell cycle using flow cytometry, indicating that trichodimerol and sorbicillin potently induced apoptosis in HL-60 cells. Trichodimerol or sorbicillin induced ROS levels also showed dose-dependent increases in HL-60 cells as measured by 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA), while trichodimerol or sorbicillin induced apoptosis was effectively blocked by the ROS inhibitor N-acetyl-L-cysteine (NAC). Western blot results showed that trichodimerol or sorbicillin could increase phosphorylated p38 levels and decrease ERK and phosphorylated ERK levels in a concentration-dependent manner. Our findings suggest that the pro-apoptosis effects of trichodimerol and sorbicillin were mediated by ROS, while activation of p38 and inhibition of ERK may be involved in these effects.}, }
@article {pmid26187465, year = {2015}, author = {Yang, X and Yao, H and Chen, Y and Sun, L and Li, Y and Ma, X and Duan, S and Li, X and Xiang, R and Han, J and Duan, Y}, title = {Inhibition of Glutathione Production Induces Macrophage CD36 Expression and Enhances Cellular-oxidized Low Density Lipoprotein (oxLDL) Uptake.}, journal = {The Journal of biological chemistry}, volume = {290}, number = {36}, pages = {21788-21799}, pmid = {26187465}, issn = {1083-351X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimetabolites/pharmacology ; Blotting, Western ; Buthionine Sulfoximine/pharmacology ; CD36 Antigens/genetics/*metabolism ; Cell Line ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Glutathione/antagonists &amp; inhibitors/*biosynthesis/metabolism ; Glutathione Disulfide/metabolism ; Lipoproteins, LDL/*metabolism/pharmacokinetics ; Macrophages/drug effects/*metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; PPAR gamma/genetics/metabolism ; Protein Biosynthesis/drug effects/genetics ; RNA Interference ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {The glutathione (GSH)-dependent antioxidant system has been demonstrated to inhibit atherosclerosis. Macrophage CD36 uptakes oxidized low density lipoprotein (oxLDL) thereby facilitating foam cell formation and development of atherosclerosis. It remains unknown if GSH can influence macrophage CD36 expression and cellular oxLDL uptake directly. Herein we report that treatment of macrophages with l-buthionine-S,R-sulfoximine (BSO) decreased cellular GSH production and ratios of GSH to glutathione disulfide (GSH/GSSG) while increasing production of reactive oxygen species. Associated with decreased GSH levels, macrophage CD36 expression was increased, which resulted in enhanced cellular oxLDL uptake. In contrast, N-acetyl cysteine and antioxidant enzyme (catalase or superoxide dismutase) blocked BSO-induced CD36 expression as well as oxLDL uptake. In vivo, administration of mice with BSO increased CD36 expression in peritoneal macrophages and kidneys. BSO had no effect on CD36 mRNA expression and promoter activity but still induced CD36 protein expression in macrophages lacking peroxisome proliferator-activated receptor γ expression, suggesting it induced CD36 expression at the translational level. Indeed, we determined that BSO enhanced CD36 translational efficiency. Taken together, our study demonstrates that cellular GSH levels and GSH/GSSG status can regulate macrophage CD36 expression and cellular oxLDL uptake and demonstrate an important anti-atherogenic function of the GSH-dependent antioxidant system by providing a novel molecular mechanism.}, }
@article {pmid26184564, year = {2015}, author = {Barajas-Espinosa, A and Basye, A and Angelos, MG and Chen, CA}, title = {Modulation of p38 kinase by DUSP4 is important in regulating cardiovascular function under oxidative stress.}, journal = {Free radical biology &amp; medicine}, volume = {89}, number = {}, pages = {170-181}, pmid = {26184564}, issn = {1873-4596}, support = {K99 HL103846/HL/NHLBI NIH HHS/United States ; R00 HL103846/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Aorta/cytology/*physiology ; Apoptosis ; Blotting, Western ; Cell Proliferation ; Cells, Cultured ; Endothelium, Vascular/cytology/*physiology ; Gene Expression Regulation ; Heart/*physiopathology ; Immunoenzyme Techniques ; Mice ; Mice, Knockout ; Myocardial Ischemia/*physiopathology ; Myocardial Reperfusion Injury/physiopathology ; *Oxidative Stress ; Phosphorylation ; Protein Tyrosine Phosphatases/*physiology ; RNA, Messenger/genetics ; Rats ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Over-activation of p38 is implicated in many cardiovascular diseases (CVDs), including myocardial infarction, hypertrophy, heart failure, and ischemic heart disease. Numerous therapeutic interventions for CVDs have been directed toward the inhibition of the p38 mitogen-activated protein kinase activation that contributes to the detrimental effect after ischemia/reperfusion (I/R) injuries. However, the efficacy of these treatments is far from ideal, as they lack specificity and are associated with high toxicity. Previously, we demonstrated that N-acetyl cysteine (NAC) pretreatment up-regulates DUSP4 expression in endothelial cells, regulating p38 and ERK1/2 activities, and thus providing a protective effect against oxidative stress. Here, endothelial cells under hypoxia/reoxygenation (H/R) insult and isolated heart I/R injury were used to investigate the role of DUSP4 in the modulation of the p38 pathway. In rat endothelial cells, DUSP4 is time-dependently degraded by H/R (0.25 ± 0.07-fold change of control after 2h H/R). Its degradation is closely associated with hyperphosphorylation of p38 (2.1 ± 0.36-fold change) and cell apoptosis, as indicated by the increase in cells immunopositive for cleaved caspase-3 (12.59 ± 3.38%) or TUNEL labeling (29.46 ± 3.75%). The inhibition of p38 kinase activity with 20 µM SB203580 during H/R prevents H/R-induced apoptosis, assessed via TUNEL (12.99 ± 1.89%). Conversely, DUSP4 gene silencing in endothelial cells augments their sensitivity to H/R-induced apoptosis (45.81 ± 5.23%). This sensitivity is diminished via the inhibition of p38 activity (total apoptotic cells drop to 17.47 ± 1.45%). Interestingly, DUSP4 gene silencing contributes to the increase in superoxide generation from cells. Isolated Langendorff-perfused mouse hearts were subjected to global I/R injury. DUSP4(-/-) hearts had significantly larger infarct size than WT. The increase in I/R-induced infarct in DUSP4(-/-) mice significantly correlates with reduced functional recovery (assessed by RPP%, LVDP%, HR%, and dP/dtmax) as well as lower CF% and a higher initial LVEDP. From immunoblotting analysis, it is evident that p38 is significantly overactivated in DUSP4(-/-) mice after I/R injury. The activation of cleaved caspase-3 is seen in both WT and DUSP4(-/-) I/R hearts. Infusion of a p38 inhibitor prior to ischemia and during the reperfusion improves both WT and DUSP4(-/-) cardiac function. Therefore, the identification of p38 kinase modulation by DUSP4 provides a novel therapeutic target for oxidant-induced diseases, especially myocardial infarction.}, }
@article {pmid26184135, year = {2015}, author = {Nath, N and Chattopadhyay, M and Rodes, DB and Nazarenko, A and Kodela, R and Kashfi, K}, title = {Nitric Oxide-Releasing Aspirin Suppresses NF-κB Signaling in Estrogen Receptor Negative Breast Cancer Cells in Vitro and in Vivo.}, journal = {Molecules (Basel, Switzerland)}, volume = {20}, number = {7}, pages = {12481-12499}, pmid = {26184135}, issn = {1420-3049}, support = {R24 DA018055/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Aspirin/*analogs &amp; derivatives/pharmacology ; Breast Neoplasms/*drug therapy/genetics/metabolism/pathology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; *Gene Expression Regulation, Neoplastic ; Genes, Reporter ; Humans ; Inhibitory Concentration 50 ; Injections, Subcutaneous ; Luciferases/genetics/metabolism ; Mice ; Mice, Nude ; NF-kappa B/*antagonists &amp; inhibitors/genetics/metabolism ; Proliferating Cell Nuclear Antigen/genetics/metabolism ; Reactive Oxygen Species/agonists/metabolism ; Receptor, ErbB-2/*deficiency/genetics ; Receptors, Estrogen/*deficiency/genetics ; Signal Transduction ; Xenograft Model Antitumor Assays ; }, abstract = {Estrogen receptor negative (ER(-)) breast cancer is aggressive, responds poorly to current treatments and has a poor prognosis. The NF-κB signaling pathway is implicated in ER(-) tumorigenesis. Aspirin (ASA) is chemopreventive against ER(+) but not for ER(-) breast cancers. Nitric oxide-releasing aspirin (NO-ASA) is a safer ASA where ASA is linked to an NO-releasing moiety through a spacer. In vitro, we investigated anti-proliferation effects of NO-ASA (para- and meta-isomers) against ER(-) breast cancer cells MDA-MB-231 and SK-BR-23, effects on NF-κB signaling, and reactive oxygen species by standard techniques. In vivo, effects of NO-ASA were evaluated in a mouse xenograft model using MDA-MB-231 cells. p-NO-ASA inhibited the growth of MDA-MB-231 and SK-BR-3 cells at 24 h, the respective IC50s were 13 ± 2 and 17 ± 2 μM; ASA had an IC50 of >3000 μM in both cell lines. The IC50s for m-NO-ASA in MDA-MB-231 and SK-BR-3 were 173 ± 15 and 185 ± 12 μM, respectively, therefore, implying p-NO-ASA as a stronger inhibitor of growth p-NO-ASA reduced cell growth by inhibiting proliferation, inducing apoptosis and causing G0/G1 cell cycle block. Activation of NF-κB was inhibited by both isomers as demonstrated by decreases in NF-κB-DNA binding and luciferase activity at 24 h, However, m-NO-ASA produced transient effects at 3 h such as increased NF-κB-DNA-binding, increased levels of nuclear p50, even though both isomers inhibited IκB degradation. Increase in nuclear p50 by m-NO-ASA was associated with translocation of p50 in to the nucleus as observed by immunoflouresence at 3 h. NO-ASA induced reactive oxygen species (ROS) as evidenced by overall increases in both H2DCFDA (2',7'-dichlorodihydrofluorescein) and DHE (dihydroethidium)-derived fluorescence. Inhibition of ROS by N-acetyl-cysteine reversed the m-NO-ASA-mediated translocation of p50 in to the nucleus. In xenografts, p-NO-ASA inhibited tumor growth by inhibiting proliferation (PCNA and tumor volume), inducing apoptosis (TUNEL positive cells) and reducing NF-κB expression. Both isomers inhibit cancer cells, inhibit NF-κB pathway and induce ROS, and have potential as anticancer compounds.}, }
@article {pmid26184052, year = {2015}, author = {Nance, E and Porambo, M and Zhang, F and Mishra, MK and Buelow, M and Getzenberg, R and Johnston, M and Kannan, RM and Fatemi, A and Kannan, S}, title = {Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {214}, number = {}, pages = {112-120}, pmid = {26184052}, issn = {1873-4995}, support = {R01 EY025304/EY/NEI NIH HHS/United States ; R01HD069562/HD/NICHD NIH HHS/United States ; R01 EB018306/EB/NIBIB NIH HHS/United States ; K08NS063956/NS/NINDS NIH HHS/United States ; R01 HD069562/HD/NICHD NIH HHS/United States ; R01EB018306/EB/NIBIB NIH HHS/United States ; K08 NS063956/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Animals ; Animals, Newborn ; Astrocytes/pathology ; Brain/metabolism ; Brain Ischemia/*drug therapy/pathology ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cytokines/antagonists &amp; inhibitors ; Dendrimers/*chemistry/pharmacokinetics ; Densitometry ; Drug Delivery Systems ; Female ; Mice ; Microglia/drug effects ; Myelin Sheath/metabolism ; Oligodendroglia/drug effects ; Pregnancy ; RNA/biosynthesis/genetics ; White Matter/*pathology ; }, abstract = {Extreme prematurity is a major risk factor for perinatal and neonatal brain injury, and can lead to white matter injury that is a precursor for a number of neurological diseases, including cerebral palsy (CP) and autism. Neuroinflammation, mediated by activated microglia and astrocytes, is implicated in the pathogenesis of neonatal brain injury. Therefore, targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes in models of perinatal white matter injury. In this work, we use a mouse model of ischemia-induced neonatal white matter injury to study the biodistribution of generation 4, hydroxyl-functionalized polyamidoamine dendrimers. Following systemic administration of the Cy5-labeled dendrimer (D-Cy5), we demonstrate dendrimer uptake in cells involved in ischemic injury, and in ongoing inflammation, leading to secondary injury. The sub-acute response to injury is driven by astrocytes. Within five days of injury, microglial proliferation and migration occurs, along with limited differentiation of oligodendrocytes and oligodendrocyte death. From one day to five days after injury, a shift in dendrimer co-localization occurred. Initially, dendrimer predominantly co-localized with astrocytes, with a subsequent shift towards microglia. Co-localization with oligodendrocytes reduced over the same time period, demonstrating a region-specific uptake based on the progression of the injury. We further show that systemic administration of a single dose of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either sub-acute or delayed time points after injury results in sustained attenuation of the 'detrimental' pro-inflammatory response up to 9days after injury, while not impacting the 'favorable' anti-inflammatory response. The D-NAC therapy also led to improvement in myelination, suggesting reduced white matter injury. Demonstration of treatment efficacy at later time points in the postnatal period provides a greater understanding of how microglial activation and chronic inflammation can be targeted to treat neonatal brain injury. Importantly, it may also provide a longer therapeutic window.}, }
@article {pmid26182369, year = {2015}, author = {Yang, R and Zhang, M and Gustafson, AR and Wang, E and Cole, MP and Tooley, CE and Cheng, A}, title = {Loss of protein targeting to glycogen sensitizes human hepatocellular carcinoma cells towards glucose deprivation mediated oxidative stress and cell death.}, journal = {Bioscience reports}, volume = {35}, number = {3}, pages = {}, pmid = {26182369}, issn = {1573-4935}, support = {1R56DK093847/DK/NIDDK NIH HHS/United States ; }, mesh = {Autophagy ; Carcinoma, Hepatocellular/metabolism/pathology ; Carrier Proteins/genetics/*metabolism ; Cell Death/genetics ; DNA-Binding Proteins/metabolism ; Gene Knockdown Techniques ; Glucose/*metabolism ; Glycogen/metabolism ; Glycogen Debranching Enzyme System/genetics/metabolism ; Heme Oxygenase-1/metabolism ; Hep G2 Cells/*metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Liver Neoplasms/metabolism/pathology ; *Oxidative Stress ; Phosphoprotein Phosphatases/genetics/*metabolism ; Transcription Factors/metabolism ; }, abstract = {Protein targeting to glycogen (PTG) is a ubiquitously expressed scaffolding protein that critically regulates glycogen levels in many tissues, including the liver, muscle and brain. However, its importance in transformed cells has yet to be explored in detail. Since recent studies have demonstrated an important role for glycogen metabolism in cancer cells, we decided to assess the effect of PTG levels on the ability of human hepatocellular carcinoma (HepG2) cells to respond to metabolic stress. Although PTG expression did not significantly affect the proliferation of HepG2 cells under normal culture conditions, we determined that PTG plays an important role during glucose deprivation. Overexpression of PTG protected cells from cell death in the absence of glucose, whereas knocking down PTG further promoted cytotoxicity, as measured by the release of lactate dehydrogenase (LDH) into the media. Additionally, we demonstrated that PTG attenuates glucose deprivation induced haeme oxygenase-1 (HO-1) expression, suggesting that PTG protects against glucose deprivation-induced oxidative stress. Indeed, treating cells with the antioxidant N-acetyl cysteine (NAC) rescued cells from cytotoxicity caused by glucose deprivation. Finally, we showed that loss of PTG resulted in enhanced autophagy. In control cells, glucose deprivation suppressed autophagy as determined by the increase in the levels of p62, an autophagy substrate. However, in knockdown cells, this suppression was relieved. Blockade of autophagy also attenuated cytotoxicity from glucose deprivation in PTG knockdown cells. Taken together, our findings identify a novel role for PTG in protecting hepatocellular carcinoma cells from metabolic stress, in part by regulating oxidative stress and autophagy.}, }
@article {pmid26180585, year = {2015}, author = {Mileo, AM and Di Venere, D and Abbruzzese, C and Miccadei, S}, title = {Long Term Exposure to Polyphenols of Artichoke (Cynara scolymus L.) Exerts Induction of Senescence Driven Growth Arrest in the MDA-MB231 Human Breast Cancer Cell Line.}, journal = {Oxidative medicine and cellular longevity}, volume = {2015}, number = {}, pages = {363827}, pmid = {26180585}, issn = {1942-0994}, mesh = {Acetylcysteine/toxicity ; Breast Neoplasms/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cynara scolymus/*chemistry/metabolism ; Female ; HCT116 Cells ; Humans ; Polyphenols/chemistry/*toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {Polyphenolic extracts from the edible part of artichoke (Cynara scolymus L.) have been shown to be potential chemopreventive and anticancer dietary compounds. High doses of polyphenolic extracts (AEs) induce apoptosis and decrease the invasive potential of the human breast cancer cell line, MDA-MB231. However, the molecular mechanism underlying AEs antiproliferative effects is not completely understood. We demonstrate that chronic and low doses of AEs treatment at sublethal concentrations suppress human breast cancer cell growth via a caspases-independent mechanism. Furthermore, AEs exposure induces a significant increase of senescence-associated β-galactosidase (SA-β-gal) staining and upregulation of tumour suppressor genes, p16(INK4a) and p21(Cip1/Waf1) in MDA-MB231 cells. AEs treatment leads to epigenetic alterations in cancer cells, modulating DNA hypomethylation and lysine acetylation levels in total proteins. Cell growth arrest correlates with increased reactive oxygen species (ROS) production in AEs treated breast cancer cells. Inhibition of ROS generation by N-acetylcysteine (NAC) attenuates the antiproliferative effect. These findings demonstrate that chronic AEs treatment inhibits breast cancer cell growth via the induction of premature senescence through epigenetic and ROS-mediated mechanisms. Our results suggest that artichoke polyphenols could be a promising dietary tool either in cancer chemoprevention or/and in cancer treatment as a nonconventional, adjuvant therapy.}, }
@article {pmid26180538, year = {2015}, author = {Marthandan, S}, title = {Effects of ebselen and N-acetyl cysteine on replicative aging of primary human fibroblast strains.}, journal = {Immunity &amp; ageing : I &amp; A}, volume = {12}, number = {}, pages = {8}, pmid = {26180538}, issn = {1742-4933}, abstract = {Administration of selected concentrations of ebselen and N-acetyl cysteine have been proven to display an antioxidant potential based on their effect on markers of T cell integrity and function in human peripheral blood mononuclear cells and CD4(+) T cell clones. Here we assessed the impact of various antioxidant concentrations on replicative aging of primary human fibroblast strains derived from embryonic lung (MRC-5) and foreskin (HFF). None of the antioxidant concentrations affected the cumulative population doublings, levels of oxidative DNA damage, intracellular GSH:GSSG ratio, potency of heat shock responses and the induction of senescence in both fibroblast strains. Our results showed no effect of both antioxidants on primary fibroblast strains and reveal their cell type specific antioxidant potential.}, }
@article {pmid26178977, year = {2015}, author = {Kloypan, C and Srisa-art, M and Mutirangura, A and Boonla, C}, title = {LINE-1 hypomethylation induced by reactive oxygen species is mediated via depletion of S-adenosylmethionine.}, journal = {Cell biochemistry and function}, volume = {33}, number = {6}, pages = {375-385}, doi = {10.1002/cbf.3124}, pmid = {26178977}, issn = {1099-0844}, mesh = {Antioxidants/*pharmacology ; Cell Line ; *DNA Methylation ; Glutathione/metabolism ; Homocysteine/metabolism ; Humans ; Hydrogen Peroxide/pharmacology/toxicity ; Kidney/cytology ; *Long Interspersed Nucleotide Elements ; Oxidants/pharmacology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; S-Adenosylmethionine/*pharmacology ; Urothelium/cytology ; }, abstract = {Whether long interspersed nuclear element-1 (LINE-1) hypomethylation induced by reactive oxygen species (ROS) was mediated through the depletion of S-adenosylmethionine (SAM) was investigated. Bladder cancer (UM-UC-3 and TCCSUP) and human kidney (HK-2) cell lines were exposed to 20 μM H2O2 for 72 h to induce oxidative stress. Level of LINE-1 methylation, SAM and homocysteine (Hcy) was measured in the H2O2 -exposed cells. Effects of α-tocopheryl acetate (TA), N-acetylcysteine (NAC), methionine, SAM and folic acid on oxidative stress and LINE-1 methylation in the H2O2 -treated cells were explored. Viabilities of cells treated with H2O2 were not significantly changed. Intracellular ROS production and protein carbonyl content were significantly increased, but LINE-1 methylation was significantly decreased in the H2O2 -treated cells. LINE-1 methylation was restored by TA, NAC, methionine, SAM and folic acid. SAM level in H2O2 -treated cells was significantly decreased, while total glutathione was significantly increased. SAM level in H2O2 -treated cells was restored by NAC, methionine, SAM and folic acid; while, total glutathione level was normalized by TA and NAC. Hcy was significantly decreased in the H2O2 -treated cells and subsequently restored by NAC. In conclusion, in bladder cancer and normal kidney cells exposed to H2O2 , SAM and Hcy were decreased, but total glutathione was increased. Treatments with antioxidants (TA and NAC) and one-carbon metabolites (SAM, methionine and folic acid) restored these changes. This pioneer finding suggests that exposure of cells to ROS activates glutathione synthesis via the transsulfuration pathway leading to deficiency of Hcy, which consequently causes SAM depletion and eventual hypomethylation of LINE-1.}, }
@article {pmid26177712, year = {2016}, author = {Fontani, F and Domazetovic, V and Marcucci, T and Vincenzini, MT and Iantomasi, T}, title = {Tumor Necrosis Factor-Alpha Up-Regulates ICAM-1 Expression and Release in Intestinal Myofibroblasts by Redox-Dependent and -Independent Mechanisms.}, journal = {Journal of cellular biochemistry}, volume = {117}, number = {2}, pages = {370-381}, doi = {10.1002/jcb.25279}, pmid = {26177712}, issn = {1097-4644}, mesh = {ADAM Proteins/metabolism ; ADAM17 Protein ; Cell Line ; Humans ; Intercellular Adhesion Molecule-1/*genetics/metabolism ; Intestinal Mucosa/metabolism ; Intestines/cytology ; Matrix Metalloproteinases/metabolism ; Myofibroblasts/*metabolism ; NADPH Oxidases/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Transcriptional Activation ; Tumor Necrosis Factor-alpha/*physiology ; Up-Regulation ; }, abstract = {Intercellular adhesion molecule-1 (ICAM-1) is distributed and expressed on cell surface and is present in circulation as soluble form (sICAM-1). Tumor necrosis factor-alpha (TNFα) and radical oxygen species (ROS) up-regulate the expression of ICAM-1. This study demonstrates for the first time in 18 Co cells, a myofibroblast cell line derived from human colonic mucosa, an up-regulation of ICAM-1 expression and sICAM-1 release induced by oxidative stress and TNFα stimulation. The intracellular redox state was modulated by L-buthionine-S,R-sulfoximine (BSO) or N-acetylcysteine (NAC), inhibitor and precursor respectively of GSH synthesis. ROS production increases in cells treated with BSO or TNFα, and this has been related to an up-regulation of ICAM-1 expression and sICAM-1 release. The involvement of metalloproteinases in ICAM-1 release has been demonstrated. Moreover, also expression and activation of A disintegrin and metalloproteinase 17, a membrane-bound enzyme known as TNFα-converting enzyme (TACE), have been related to ROS levels. This suggests the possible involvement of TACE in the cleavage of ICAM-1 on cell surface in condition of oxidative stress. NAC down-regulates the expression and release of ICAM-1 as well as the expression and activation of TACE. However, in TNFα stimulated cells NAC treatment reduces only in part ICAM-1 expression and sICAM-1 release. Given this TNFα may also act on these events by a redox-independent mechanism.}, }
@article {pmid26172395, year = {2015}, author = {Alfonso, H and Franklin, P and Ching, S and Croft, K and Burcham, P and Olsen, N and Reid, A and Joyce, D and de Klerk, N and Musk, AB}, title = {Effect of N-acetylcysteine supplementation on oxidative stress status and alveolar inflammation in people exposed to asbestos: a double-blind, randomized clinical trial.}, journal = {Respirology (Carlton, Vic.)}, volume = {20}, number = {7}, pages = {1102-1107}, doi = {10.1111/resp.12592}, pmid = {26172395}, issn = {1440-1843}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Asbestos/*adverse effects ; Dietary Supplements ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage ; Humans ; *Inflammation/drug therapy/metabolism ; Male ; Middle Aged ; Occupational Exposure/*adverse effects ; Oxidative Stress/*drug effects ; *Pneumonia/chemically induced/drug therapy/metabolism ; Treatment Outcome ; }, abstract = {BACKGROUND AND OBJECTIVE: Many of the pathological consequences in the lung following inhalation of asbestos fibres arise as a consequence of persistent oxidative stress and inflammation. Inflammatory responses can be observed in asymptomatic asbestos-exposed individuals. There are currently no interventions to reduce inflammatory or oxidative responses to asbestos before disease develops. We investigated the effects of oral N-acetylcysteine (NAC) on indicators of inflammation or oxidative stress in asymptomatic people previously exposed to asbestos.<br><br>METHODS: A double-blind, randomized, placebo-controlled study was conducted to assess the effectiveness and safety of 1800&#x2009;mg of NAC given orally over a period of 4 months. This was a proof of principle study. Effectiveness was assessed using indicators of inflammation or oxidation as primary end-points. Serum levels of total combined thiols (cysteine, cysteinylglycine, glutathione and homocysteine) were used to monitor the NAC supplementation.<br><br>RESULTS: Thirty-four subjects were randomly allocated to NAC and 32 to placebo. Serum levels of total combined thiols were similar between the groups after intervention. There were no differences in levels of inflammatory or oxidative stress end-points between the groups. No adverse effects were identified.<br><br>CONCLUSIONS: No evidence was found that NAC supplementation replenishes total combined thiols in the blood of healthy subjects with a history of asbestos exposure. There was also no evidence of reduced indicators of inflammation or oxidative stress. Further studies should determine the conditions required to increase levels of total anti-oxidant capacity in the blood and in the lungs of subjects with either asbestos-related diseases or subclinical lung inflammation.}, }
@article {pmid26172216, year = {2015}, author = {Inoue, K and Fukuda, K and Yoshimura, T and Kusano, K}, title = {Comparison of the Reactivity of Trapping Reagents toward Electrophiles: Cysteine Derivatives Can Be Bifunctional Trapping Reagents.}, journal = {Chemical research in toxicology}, volume = {28}, number = {8}, pages = {1546-1555}, doi = {10.1021/acs.chemrestox.5b00129}, pmid = {26172216}, issn = {1520-5010}, mesh = {Chromatography, Liquid ; Clozapine/chemistry ; Cross-Linking Reagents/*chemistry ; Cysteine/*chemistry ; Imidazoles/chemistry ; Mass Spectrometry ; Molecular Structure ; Pyridines/chemistry ; Sulfhydryl Compounds/chemistry ; }, abstract = {Trapping reagents are powerful tools to detect unstable reactive metabolites. There are a variety of trapping reagents based on chemical reactivity to electrophiles, and we investigated the reactivity of thiol and amine trapping reagents to metabolically generated electrophiles and commercially available electrophilic compounds. Glutathione (GSH) and N-acetylcysteine (Nac) trapped soft electrophiles, and amine derivatives such as semicarbazide (SC) and methoxyamine (MeA) reacted as hard nucleophiles to trap aldehydes as imine derivatives. Cysteine (Cys) and homocysteine (HCys) captured both soft electrophiles and hard electrophilic aldehydes. There were no qualitative differences in trapping soft electrophiles among Cys, HCys, GSH, and Nac, although quantitative reactivity to trap soft electrophiles varied likely depending on the pKa values of their thiol group. In the reactivity with aldehydes, Cys and HCys showed relatively lower reactivity as compared with SC and MeA. Nonetheless, they can trap aldehydes, and the resulting conjugates were stable and detected easily because their amino group formed imines after reaction with aldehydes, which are successively attacked by the intramolecular thiol group to form stable ring structures. This report demonstrated that Cys and HCys are advantageous to evaluate the formations of both soft electrophiles and aldehyde-type derivatives from a lot of drug candidates at early drug discovery by their unique structural characteristics.}, }
@article {pmid26170942, year = {2015}, author = {Salama, M and Elgamal, M and Abdelaziz, A and Ellithy, M and Magdy, D and Ali, L and Fekry, E and Mohsen, Z and Mostafa, M and Elgamal, H and Sheashaa, H and Sobh, M}, title = {Toll-like receptor 4 blocker as potential therapy for acetaminophen-induced organ failure in mice.}, journal = {Experimental and therapeutic medicine}, volume = {10}, number = {1}, pages = {241-246}, pmid = {26170942}, issn = {1792-0981}, abstract = {Acetaminophen (APAP, 4-hydroxyacetanilide) is the most common cause of acute liver failure in the United States. In addition to exhibiting hepatotoxicity, APAP exerts a nephrotoxic effect may be independent of the induced liver damage. Toll-like receptors (TLRs) have been suggested as a potential class of novel therapeutic targets. The aim of the present study was to investigate the potential of the TLR-4 blocker TAK-242 in the prevention of APAP-induced hepato-renal failure. Four groups of C57BL mice were studied: Vehicle-treated/control (VEH), APAP-treated (APAP), N-acetyl cysteine (NAC)-pretreated plus APAP (APAP + NAC) and TAK-242-pretreated plus APAP (APAP + TAK) groups. Mice were clinically assessed then perfused 4 h later. Liver and kidney tissues were collected and examined histologically using basic hematoxylin and eosin staining to detect signs of necrosis and inflammation. Plasma samples were collected to measure the levels of alanine transaminase, aspartate transaminase and serum creatinine. In addition, liver and kidney tissues were assayed to determine the levels of reduced glutathione. The results of the present study indicate the potential role of TLR-4 in APAP-induced organ toxicity. In the APAP + TAK and APAP + NAC groups, histopathological examination indicated that pretreatment with TAK-242 or NAC afforded protection against APAP-induced injury. However, this protective effect was more clinically evident in the APAP + TAK group compared with the APAP + NAC group. The various biochemical parameters (serum enzymes and reduced glutathione) revealed no significant protection in either of the pretreated groups. Therefore, the present study indicated that the TLR-4 blocker had protective effects against acute APAP toxicity in liver and kidney tissues. These effects were identified clinically, histologically and biochemically. Furthermore, the TLR-4 blocker TAK-242 exhibited antioxidant properties in addition to anti-inflammatory effects.}, }
@article {pmid26170769, year = {2015}, author = {Pauley, KA and Sandritter, TL and Lowry, JA and Algren, DA}, title = {Evaluation of an Alternative Intravenous N-Acetylcysteine Regimen in Pediatric Patients.}, journal = {The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG}, volume = {20}, number = {3}, pages = {178-185}, pmid = {26170769}, issn = {1551-6776}, abstract = {OBJECTIVE: Conventionally, intravenous N-acetylcysteine (IV-NAC) administration is a 3-bag regimen administered over the course of 21 hours, which increases the risk of reconstitution and administration errors. To minimize errors, an alternative IV-NAC regimen consists of a loading dose (150 mg/kg) followed by a maintenance infusion (15 mg/kg/hr) until termination criteria are met. The aim was to determine the clinical outcomes of an alternative IV-NAC regimen in pediatric patients.<br><br>METHODS: A retrospective review of pharmacy dispensing records and diagnostic codes at a pediatric hospital identified patients who received alternative IV-NAC dosing from March 1, 2008, to September 10, 2012, for acetaminophen overdoses. Exclusion criteria included chronic liver disease, initiation of oral or other IV-NAC regimens, and initiation of standard IV-NAC infusion prior to facility transfer. Clinical and laboratory data were abstracted from the electronic medical record. Descriptive statistics were utilized. Clinical outcomes and adverse drug reaction incidences were compared between the alternative and Food and Drug Administration (FDA)-approved IV-NAC regimens.<br><br>RESULTS: Fifty-nine patients (mean age 13.4 &#xb1; 4.3 years; range: 2 months-18 years) with acetaminophen overdoses were identified. Upon IV-NAC discontinuation, 45 patients had normal alanine transaminase (ALT) concentrations, while 14 patients' ALT concentrations remained elevated (median 140 units/L) but were trending downward. Two patients (3.4%) developed hepatotoxicity (aspartate transaminase/ALT > 1000 units/L). No patients developed hepatic failure, were listed for a liver transplant, were intubated, underwent hemodialysis, or died. Two patients (3.4%) developed anaphylactoid reactions. No known medication or administration errors occurred. Clinical outcome incidences of the studied endpoints with the alternative IV-NAC regimen are at the lower end of published incidence ranges compared to the FDA IV-NAC regimen for acetaminophen overdoses.<br><br>CONCLUSIONS: This alternative IV-NAC regimen appears to be effective and well tolerated among pediatric patients when compared to the FDA-approved regimen. It may also result in fewer reconstitution and administration errors, leading to improved patient safety.}, }
@article {pmid26170516, year = {2015}, author = {Masoompour, SM and Anushiravani, A and Tafaroj Norouz, A}, title = {Evaluation of the Effect of Nebulized N-Acetylcysteine on Respiratory Secretions in Mechanically Ventilated Patients: Randomized Clinical Trial.}, journal = {Iranian journal of medical sciences}, volume = {40}, number = {4}, pages = {309-315}, pmid = {26170516}, issn = {0253-0716}, abstract = {BACKGROUND: The purpose of our study was to evaluate an inexpensive and available method to reduce mucous impactions in mechanically ventilated patients.<br><br>METHODS: This randomized clinical trial was conducted on 40 mechanically ventilated patients aged 15-90 years. The patients were randomly allocated into two arms; 20 cases and 20 controls. The cases received N-acetylcysteine via their nebulizers, and the control group received normal saline three times a day for one day. We measured the density of respiratory secretion, plateau and peak airway pressures, and O2 saturation at baseline, 12 and 24 hours later.<br><br>RESULTS: Although the mean secretion density was significantly lower in the NAC group (F (1, 38)=8.61, P=0.006), but a repeated measures ANOVA with a Greenhouse-Geisser correction determined that the effect of NAC on mean secretion density did not differ significantly between time points (F (1, 38)=3.08, P=0.087). NAC increased O2 saturation significantly between time points (F (1.92, 73.1)=4.6, P=0.014). The plateau airway pressures were relatively stable throughout the study in the normal saline and NAC groups (F (1.95, 37.1)=0.67, P=0.513). The peak airway pressure did not change significantly during the study in the normal saline and NAC groups (F (1.52, 56.4)=0.91, P=0.384).<br><br>CONCLUSION: Considering the limitations of the study, nebulized NAC in mechanically ventilated patients was not effective more than normal saline nebulization in reducing the density of mucous plugs. The peak and plateau airway pressures were relatively stable throughout the study in both groups.<br><br>TRIAL REGISTRATION NUMBER: IRCT201104276312N1.}, }
@article {pmid26169035, year = {2015}, author = {Wang, J and Liu, L and Cen, J and Ji, B}, title = {BME, a novel compound of anthraquinone, down regulated P-glycoprotein expression in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells via generation of reactive oxygen species.}, journal = {Chemico-biological interactions}, volume = {239}, number = {}, pages = {139-145}, doi = {10.1016/j.cbi.2015.07.003}, pmid = {26169035}, issn = {1872-7786}, mesh = {ATP Binding Cassette Transporter, Subfamily B/*metabolism ; Anthraquinones/*chemistry/*pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Cell Cycle/drug effects ; Down-Regulation/drug effects ; Doxorubicin/pharmacokinetics/*pharmacology ; Drug Resistance, Neoplasm/*drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; K562 Cells/drug effects/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Reactive Oxygen Species/*metabolism ; Rhodamine 123/metabolism ; }, abstract = {P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor cells is still a main obstacle for the chemotherapeutic treatment of cancers. Thus, development of effective MDR reversing agents is an important approach in the clinic. The present study revealed that BME, a novel compound of anthraquinone, elevated intracellular accumulation of the P-gp substrates and reduced concentration resulting in 50% inhibition of cell growth (IC50) values for doxorubicin (DOX) in doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. Further more, BME was also reported to down regulated P-gp expression accompanying with generation of nontoxic low level of intracellular reactive oxygen species (iROS) and activation of extracellular signal-regulated kinase (ERK)1/2 as well as c-JUN N-terminal kinase (JNK). However, treatment with N-acetyl-cysteine (NAC), U0216 and SP600125 almost abolished actions of the BME mentioned above. These results indicated that the effect of the BME on the P-gp may be involved in generation of nontoxic low level of iROS and activation of ERK1/2 or JNK, which suggested valuable clues to screen and develop P-gp reversing agents.}, }
@article {pmid26168893, year = {2015}, author = {Alkholifi, FK and Albers, DS}, title = {Attenuation of rotenone toxicity in SY5Y cells by taurine and N-acetyl cysteine alone or in combination.}, journal = {Brain research}, volume = {1622}, number = {}, pages = {409-413}, doi = {10.1016/j.brainres.2015.06.041}, pmid = {26168893}, issn = {1872-6240}, mesh = {Acetylcysteine/*pharmacology ; Aconitate Hydratase/metabolism ; Cell Death/drug effects/physiology ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Humans ; L-Lactate Dehydrogenase/metabolism ; Neuroprotective Agents/*pharmacology ; Rotenone/*toxicity ; Taurine/*pharmacology ; }, abstract = {There is accumulating evidence that supports the involvement of reactive oxygen species (ROS), mitochondrial dysfunction and inflammation in the pathogenesis of neurodegenerative diseases. Thus, it is plausible that a multi-targeted therapeutic approach may be a more effective strategy to retard or even potentially halt the progression of the disease. Taurine is an organic acid that has a role in the regulation of oxidative stress and promoting mitochondrial normal functions, and N-Acetyl cysteine (NAC) is a well-known anti-oxidant and glutathione precursor. The main purpose of this study was to examine the cytoprotective effects of taurine alone or in combination with NAC against rotenone-induced toxicity in the SH-SY5Y neuroblastoma cell line. Taurine treatment produced a concentration-dependent reduction in rotenone-induced cell death. From this, we tested sub-effective concentrations of taurine in combination with low, sub-effective concentrations of NAC against rotenone toxicity, and found the combined treatment afforded greater cytoprotection than either treatment alone. The combined taurine/NAC treatment also attenuated rotenone-induced reductions in aconitase activity suggesting the cytoprotection afforded by the combined treatment may be associated with anti-oxidative mechanisms. Together, our data suggest that a multi-targeted approach may yield new avenues of research exploring the utility of combining therapeutic agents with different mechanisms of actions at concentrations lower than previously tested and shown to be cytoprotective.}, }
@article {pmid26168733, year = {2015}, author = {Shaunak, S}, title = {Perspective: Dendrimer drugs for infection and inflammation.}, journal = {Biochemical and biophysical research communications}, volume = {468}, number = {3}, pages = {435-441}, doi = {10.1016/j.bbrc.2015.07.033}, pmid = {26168733}, issn = {1090-2104}, mesh = {Animals ; Anti-Inflammatory Agents/*administration &amp; dosage/chemistry ; Dendrimers/*administration &amp; dosage/*chemistry ; Humans ; Infections/*drug therapy ; Inflammation/*drug therapy ; Nanoparticles/chemistry/*therapeutic use/ultrastructure ; }, abstract = {Biologists are dissecting complex biological pathways at breath taking speed. It is opening up new opportunities for the therapeutic evaluation of novel dendrimer drugs. This review focuses on studies of small dendrimers decorated with sulfate, phosphonate, N-acetyl-cysteine, glucosamine and mannose in animal model studies of infection and inflammation. It highlights those animal model studies which have demonstrated the most promising dendrimer drug constructs as potential new medicines. The issues relating to their analytical chemistry that are slowing the progress of dendrimer drugs into the clinic are highlighted. It should be possible to solve these with additional analytical expertise because it is small dendrimers with only 16-32 peripheral groups that make for the best infection and inflammation related medicines. Public-private partnerships are now needed to progress these dendrimer drugs into proof-of-concept clinical trials.}, }
@article {pmid26167240, year = {2015}, author = {Nurulain, SM and Ojha, S and Tekes, K and Shafiullah, M and Kalasz, H and Adem, A}, title = {Efficacy of N-Acetylcysteine, Glutathione, and Ascorbic Acid in Acute Toxicity of Paraoxon to Wistar Rats: Survival Study.}, journal = {Oxidative medicine and cellular longevity}, volume = {2015}, number = {}, pages = {329306}, pmid = {26167240}, issn = {1942-0994}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Glutathione/*pharmacology ; Insecticides/*toxicity ; Male ; Oxidative Stress/*drug effects ; Paraoxon/*toxicity ; Pralidoxime Compounds/toxicity ; Rats ; Rats, Wistar ; Risk ; }, abstract = {There are a great number of reports with assertions that oxidative stress is produced by organophosphorus compound (OPC) poisoning and is a cofactor of mortality and morbidity in OPC toxicity. In addition, antioxidants have been suggested as adjuncts to standard therapy. However, there is no substantial evidence for the benefit of the use of antioxidants in survival after acute intoxication of OPCs. The present study was conducted to assess the effectiveness of three non-enzymatic antioxidants (NEAOs), N-acetylcysteine (NAC), glutathione (GSH), and ascorbic acid (AA), in acute intoxication of adult male Wister rats with paraoxon. The efficacy of the antioxidants was estimated as both a pretreatment and a concurrent application along with the standard oxime, pralidoxime (2-PAM). Relative risk of death after 48 hours of application was estimated by Cox regression analysis. The results revealed no benefit of either tested NEAO to the improvement in survival of experimental rats. The application of these antioxidants was found to be deleterious when administered along with pralidoxime compared to the treatment with pralidoxime alone. It has been concluded that the tested non-enzymatic antioxidants are not useful in acute toxicity for improving survival rates. However, the individual toxic dynamics of diversified OPCs should not be overlooked and further studies with different OPCs are suggested.}, }
@article {pmid26166235, year = {2015}, author = {Schipper, HM and Arnold, D and GrandʼMaison, F and Melmed, C and Moore, F and Levental, M and Su, H and Constantin, M and Stril, JL and Godin, J}, title = {Tolerability and Safety of Combined Glatiramer Acetate and N-Acetylcysteine in Relapsing-Remitting Multiple Sclerosis.}, journal = {Clinical neuropharmacology}, volume = {38}, number = {4}, pages = {127-131}, doi = {10.1097/WNF.0000000000000090}, pmid = {26166235}, issn = {1537-162X}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Free Radical Scavengers/*therapeutic use ; Glatiramer Acetate/*therapeutic use ; Glutathione/blood ; Humans ; Immunosuppressive Agents/*therapeutic use ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/blood/*drug therapy ; Outcome Assessment, Health Care ; Pilot Projects ; Young Adult ; }, abstract = {INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system where inflammation and neurodegeneration play key roles. Mounting evidence implicates oxidative stress in the development of irreversible neuronal and glial injury in this condition. N-acetylcysteine (NAC) is a sulfhydryl amino acid derivative with antioxidant and antiapoptotic properties. Administration of NAC to mice attenuated the induction of or improved experimental autoimmune encephalomyelitis (an MS model).<br><br>METHODS: We performed an open-label study to explore the tolerability and safety of the combination of glatiramer acetate (GA) and NAC in patients with relapsing-remitting multiple sclerosis at the outpatient MS clinics of the Jewish General Hospital and H&#xf4;pital Charles Lemoyne, Montreal, Canada. Seven patients with relapsing-remitting multiple sclerosis with at least one T1 gadolinium-enhancing lesion on screening magnetic resonance imaging were recruited. Treatment consisted of a 10-week run-in period followed by 36-week treatment with a combination of GA 20 mg subcutaneously once daily plus NAC 2.5 g orally twice daily. Outcome measures included safety and tolerability, redox biochemistry, and magnetic resonance imaging effect.<br><br>RESULTS: Treatment with the combination of GA and NAC was safe and well tolerated.<br><br>CONCLUSIONS: In light of the favorable safety profile, an efficacy-demonstrating study may be considered.}, }
@article {pmid26163948, year = {2015}, author = {Yoshida, A and Shiotsu-Ogura, Y and Wada-Takahashi, S and Takahashi, SS and Toyama, T and Yoshino, F}, title = {Blue light irradiation-induced oxidative stress in vivo via ROS generation in rat gingival tissue.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {151}, number = {}, pages = {48-53}, doi = {10.1016/j.jphotobiol.2015.07.001}, pmid = {26163948}, issn = {1873-2682}, mesh = {Acetylcysteine/pharmacology ; Animals ; Gingiva/drug effects/*metabolism/*radiation effects ; Glutathione/metabolism ; Light ; Lipid Peroxidation/radiation effects ; Male ; Oxidative Stress/drug effects/*radiation effects ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Singlet Oxygen/metabolism ; }, abstract = {It has been reported that oxidative stress with reactive oxygen species (ROS) generation is induced by blue light irradiation to a living body. Only limited research has been reported in dental field on the dangers of blue light, mostly focusing on cytotoxicity associated with heat injury of dental pulp. We thus performed an in vivo study on oral tissue exposed to blue light. ROS generated upon blue light irradiation of flavin adenine dinucleotide were measured by electron spin resonance spectroscopy. After blue light irradiation, the palatal gingiva of Wistar rats were isolated. Collected samples were subjected to biochemical analysis of lipid peroxidation and glutathione. Singlet oxygen was generated by blue light irradiation, but was significantly quenched in an N-acetyl-L-cysteine (NAC) concentration-dependent manner. Blue light significantly accelerated oxidative stress and increased the oxidized glutathione levels in gingival tissue. These effects were also inhibited by NAC pre-administration. The results suggest that blue light irradiation at clinical levels of tooth bleaching treatment may enhance lipid peroxidation by the induction of oxidative stress and the consumption of a significant amount of intracellular glutathione. In addition, NAC might be an effective supplement for the protection of oral tissues against blue light irradiation-induced oxidative damage.}, }
@article {pmid26163453, year = {2015}, author = {Cui, ZG and Ogawa, R and Tsuneyama, K and Yan, G and Tao, L and Shimomura, A and Inadera, H}, title = {Insight into the molecular mechanism of heme oxygenase-1 induction by docosahexaenoic acid in U937 cells.}, journal = {Chemico-biological interactions}, volume = {238}, number = {}, pages = {180-188}, doi = {10.1016/j.cbi.2015.07.005}, pmid = {26163453}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Butadienes/pharmacology ; Docosahexaenoic Acids/*pharmacology ; Down-Regulation/drug effects ; Heme Oxygenase-1/genetics/*metabolism ; Humans ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; NF-E2-Related Factor 2/metabolism ; Nitriles/pharmacology ; Oxidative Stress/drug effects ; Promoter Regions, Genetic ; Protein Binding ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Response Elements ; U937 Cells ; Up-Regulation/*drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Heme oxygenase-1 (HO-1) has anti-inflammatory effects on myeloid cells in response to various stimuli. To date, little is known about whether fatty acids can affect HO-1 induction. Here, we report the induction of HO-1 by docosahexaenoic acid (DHA) and the associated molecular mechanisms in human myelomonocytic lymphoma U937 cells. When U937 cells were treated with DHA, eicosapentaenoic acid, palmitic acid or oleic acid, DHA was the most effective inducer of HO-1. The activation of AKT and glycogen synthase kinase-3β did not significantly change after DHA treatment. However, DHA increased the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), but not of other mitogen-activated protein kinases such as p38 and JNK. The increase in HO-1 expression was significantly inhibited by U0126, an ERK1/2 inhibitor. Nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and its binding to the HO-1 promoter significantly increased upon DHA treatment. An increase in intracellular reactive oxygen species was detected by dichlorofluorescein diacetate, but not by hydroethidium or 2-[6-(4-hydroxy)phenoxy-3H-xanthen-3-on-9-yl] benzoic acid after DHA treatment. Pretreatment with NAC dramatically inhibited the ERK1/2 activation, binding of Nrf-2 to antioxidant response elements (AREs) located in the HO-1 promoter and the induction of HO-1 by DHA. In conclusion, DHA increased HO-1 expression in U937 cells via activation of ERK1/2 and increased Nrf-2 binding to ARE in the HO-1 promoter. These findings will help develop better strategies for treating inflammatory disorders with DHA.}, }
@article {pmid26161242, year = {2015}, author = {Liu, ZJ and Zhao, W and Zhang, QG and Li, L and Lai, LY and Jiang, S and Xu, SY}, title = {OGG1 Involvement in High Glucose-Mediated Enhancement of Bupivacaine-Induced Oxidative DNA Damage in SH-SY5Y Cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2015}, number = {}, pages = {683197}, pmid = {26161242}, issn = {1942-0994}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Bupivacaine/*toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Comet Assay ; DNA Damage/*drug effects ; DNA Glycosylases/genetics/*metabolism ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Glucose/*pharmacology ; Humans ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; }, abstract = {Hyperglycemia can inhibit expression of the 8-oxoG-DNA glycosylase (OGG1) which is one of the key repair enzymes for DNA oxidative damage. The effect of hyperglycemia on OGG1 expression in response to local anesthetics-induced DNA damage is unknown. This study was designed to determine whether high glucose inhibits OGG1 expression and aggravates bupivacaine-induced DNA damage via reactive oxygen species (ROS). SH-SY5Y cells were cultured with or without 50 mM glucose for 8 days before they were treated with 1.5 mM bupivacaine for 24 h. OGG1 expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. ROS was estimated using the redox-sensitive fluorescent dye DCFH-DA. DNA damage was investigated with immunostaining for 8-oxodG and comet assays. OGG1 expression was inhibited in cells exposed to high glucose with concomitant increase in ROS production and more severe DNA damage as compared to control culture conditions, and these changes were further exacerbated by bupivacaine. Treatment with the antioxidant N-acetyl-L-cysteine (NAC) prevented high glucose and bupivacaine mediated increase in ROS production and restored functional expression of OGG1, which lead to attenuated high glucose-mediated exacerbation of bupivacaine neurotoxicity. Our findings indicate that subjects with diabetes may experience more detrimental effects following bupivacaine use.}, }
@article {pmid26159509, year = {2015}, author = {Sun, Y and Qi, Z and He, Q and Cui, D and Qian, S and Ji, L and Ding, S}, title = {The effect of treadmill training and N-acetyl-l-cysteine intervention on biogenesis of cytochrome c oxidase (COX).}, journal = {Free radical biology &amp; medicine}, volume = {87}, number = {}, pages = {326-335}, doi = {10.1016/j.freeradbiomed.2015.06.035}, pmid = {26159509}, issn = {1873-4596}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antioxidants/*metabolism ; Apoptosis/drug effects ; Cytochromes c/metabolism ; Electron Transport Complex IV/*biosynthesis ; Male ; Mice ; Mitochondria/*metabolism ; *Oxidative Stress ; Physical Conditioning, Animal ; RNA, Messenger/biosynthesis ; }, abstract = {Mitochondrial biogenesis refers to increased content of mitochondria, which has been shown to be promoted by aerobic exercise. During this process, oxidative stress is considered the essential initiator. Even though some studies have addressed the issue as to whether antioxidants would hamper the effects of exercise on mitochondrial biogenesis, no consensus has been achieved. Therefore, the purpose of the present study was to investigate the effects of exercise and antioxidant intervention on mitochondrial biogenesis, as well as COX biogenesis. Thirty-two clean-grade male ICR mice were randomly assigned to a control group (Con), exercise group (Ex), N-acetyl-l-cysteine group (NAC), or NAC plus exercise group (NEx). The NAC and NEx groups were injected with NAC (0.1 mg/g/2 days) intraperitoneally for 3 weeks, whereas the Con and Ex groups were administered saline for the same period of time. Mice assigned to Ex and NEx groups started exercise training 1 week before drug intervention was initiated. After 1 week of acclimatization, the mice were allowed to run at a speed of 28 m/min for 60 min, 6 days a week. The results showed that exercise training caused an increase in mRNA and protein levels of COXIV, whereas NAC intervention lowered the two so significantly that even exercise training could not reverse the effect of NAC intervention. Our data suggest that even though antioxidant intervention could alleviate oxidative damage caused by exercise, it was not necessarily beneficial for mitochondrial biogenesis.}, }
@article {pmid26158396, year = {2016}, author = {Ishibashi, Y and Matsui, T and Yamagishi, S}, title = {Tofogliflozin, A Highly Selective Inhibitor of SGLT2 Blocks Proinflammatory and Proapoptotic Effects of Glucose Overload on Proximal Tubular Cells Partly by Suppressing Oxidative Stress Generation.}, journal = {Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme}, volume = {48}, number = {3}, pages = {191-195}, doi = {10.1055/s-0035-1555791}, pmid = {26158396}, issn = {1439-4286}, mesh = {Apoptosis/*drug effects/genetics ; Benzhydryl Compounds/pharmacology/*therapeutic use ; Cell Line ; Chemokine CCL2/genetics/metabolism ; Gene Expression Regulation/drug effects ; Glucose/*pharmacology ; Glucosides/pharmacology/*therapeutic use ; Humans ; Inflammation/*drug therapy/pathology ; Kidney Tubules, Proximal/drug effects/*pathology ; Oxidative Stress/*drug effects/genetics ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Sodium-Glucose Transporter 2/metabolism ; *Sodium-Glucose Transporter 2 Inhibitors ; }, abstract = {Ninety percent of glucose filtered by the glomerulus is reabsorbed by a sodium-glucose cotransporter 2 (SGLT2), which is mainly expressed on S1 and S2 segment of renal proximal tubules. Since SGLT-2-mediated glucose reabsorption is increased under diabetic conditions, selective inhibition of SGLT2 is a potential therapeutic target for the treatment of diabetes. We have recently shown that an inhibitor of SGLT2 has anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing advanced glycation end products formation and oxidative stress generation in the kidney. However, the direct effects of SGLT2 inhibitor on tubular cell damage remain unclear. In this study, we investigated the effects of tofogliflozin, a highly selective inhibitor of SGLT2 on oxidative stress generation, inflammatory and proapoptotic reactions in cultured human proximal tubular cells exposed to high glucose. Tofogliflozin dose-dependently suppressed glucose entry into tubular cells. High glucose exposure (30 mM) for 4 and 24 h significantly increased oxidative stress generation in tubular cells, which were suppressed by the treatment of tofogliflozin or an antioxidant N-acetylcysteine (NAC). Monocyte chemoattractant protein-1 (MCP-1) gene expression and apoptotic cell death were induced by 4 h- and 8 day-exposure to high glucose, respectively, both of which were also blocked by tofogliflozin or NAC. The present study suggests that SGLT2-mediated glucose entry into tubular cells could stimulate oxidative stress and evoke inflammatory and proapoptotic reactions in this cell type. Blockade of glucose reabsorption in tubular cells by SGLT2 inhibitor might exert beneficial effects on tubulointerstitial damage in diabetic nephropathy.}, }
@article {pmid26156407, year = {2015}, author = {Chen, C and Guan, X and Quinn, DA and Ouyang, B}, title = {N-Acetylcysteine Inhibits Ventilation-Induced Collagen Accumulation in the Rat Lung.}, journal = {The Tohoku journal of experimental medicine}, volume = {236}, number = {4}, pages = {255-261}, doi = {10.1620/tjem.236.255}, pmid = {26156407}, issn = {1349-3329}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Analysis of Variance ; Animals ; Collagen/drug effects/*metabolism ; Injections, Intravenous ; Lung/metabolism/*pathology ; Pulmonary Fibrosis/etiology/*pathology/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Respiration, Artificial/*adverse effects ; Tidal Volume ; Time Factors ; }, abstract = {Mechanical ventilation is the most important life supportive therapy for patients with acute respiratory distress syndrome (ARDS). However, increasing evidence from clinical studies suggests that mechanical ventilation can cause lung fibrosis, which may significantly contribute to morbidity and mortality. Recent studies also found fibroproliferation occurred in early stage of ARDS with poor outcome. We have hypothesized that mechanical ventilation-induced lung injury may be a major contributor to lung fibrosis, and antioxidant could be a potential therapeutic agent for the treatment to mechanic ventilation induced fibroproliferation. We therefore used Sprague-Dawley rats that were ventilated with large tidal volume (20 ml/kg) or low tidal volume (7 ml/kg). We analyzed the time course of collagen level in the lung and the effect of N-acetylcysteine (NAC), a thiol antioxidant, on mechanical ventilation-induced collagen accumulation. In addition, normal human lung fibroblasts (NHLF) were exposed to mechanical stretch, which mimics ventilator-induced lung inflation, to evaluate the collagen secretion in culture medium. We found that ventilation-induced collagen accumulation occurred even after 2-hour ventilation. Pretreatment with NAC (140 mg/kg) inhibited collagen accumulation in lungs of rats ventilated with large tidal volume. Moreover, mechanical stretch caused the accumulation of collagen in the culture medium of NHLF, the magnitude of which was decreased with the pretreatment with NAC (1 mM). These results indicate that mechanical ventilation can induce collagen accumulation within 2 hours. NAC alleviated the collagen accumulation induced by mechanical ventilation with high tidal volume. Therefore, NAC can be considered as a good candidate in preventing ventilation-induced lung fibrosis.}, }
@article {pmid26155892, year = {2016}, author = {Wu, X and Lehmler, HJ}, title = {Effects of thiol antioxidants on the atropselective oxidation of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) by rat liver microsomes.}, journal = {Environmental science and pollution research international}, volume = {23}, number = {3}, pages = {2081-2088}, pmid = {26155892}, issn = {1614-7499}, support = {ES017425/ES/NIEHS NIH HHS/United States ; ES013661/ES/NIEHS NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; ES05605/ES/NIEHS NIH HHS/United States ; ES06694/ES/NIEHS NIH HHS/United States ; P30 ES006694/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; R01 ES017425/ES/NIEHS NIH HHS/United States ; R01 ES014901/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*metabolism ; Glutathione/metabolism ; Hydroxylation ; Male ; Microsomes, Liver/chemistry/*metabolism ; Oxidation-Reduction ; Polychlorinated Biphenyls/chemistry/*metabolism ; Rats ; Stereoisomerism ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Chiral polychlorinated biphenyl (PCB) congeners, such as PCB 136, are atropselectively metabolized to various hydroxylated PCB metabolites (HO-PCBs). The present study investigates the effect of two thiol antioxidants, glutathione and N-acetyl-cysteine (NAC), on profiles and chiral signatures of PCB 136 and its HO-PCB metabolites in rat liver microsomal incubations. Liver microsomes prepared from rats pretreated with phenobarbital were incubated with PCB 136 (5 μM) in the presence of the respective antioxidant (0-10 mM), and levels and chiral signatures of PCB 136 and its HO-PCB metabolites were determined. Three metabolites, 5-136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol), 4-136 (2,2',3,3',6,6'-hexachlorobiphenyl-4-ol), and 4,5-136 (2,2',3,3',6,6'-hexachlorobiphenyl-4,5-diol), were detected in all incubations, with 5-136 being the major metabolite. Compared to microsomal incubations without antioxidant, levels of 4,5-136 increased with increasing antioxidant concentration, whereas levels of PCB 136 and both mono-HO-PCBs were not affected by the presence of either antioxidant. PCB 136, 4-136, and 5-136 displayed significant atropisomeric enrichment; however, the direction and extent of the atropisomeric enrichment was not altered in the presence of an antioxidant. Because 4,5-136 can either be conjugated to a sulfate or glucuronide metabolite that is readily excreted or further oxidized a potentially toxic PCB 136 quinone, the effect of both thiol antioxidants on 4,5-136 formation suggests that disruptions of glutathione homeostasis may alter the balance between both metabolic pathways and, thus, PCB 136 toxicity in vivo.}, }
@article {pmid26154615, year = {2015}, author = {Chang, HT and Chou, CT and Kuo, DH and Shieh, P and Jan, CR and Liang, WZ}, title = {The Mechanism of Ca(2+) Movement in the Involvement of Baicalein-Induced Cytotoxicity in ZR-75-1 Human Breast Cancer Cells.}, journal = {Journal of natural products}, volume = {78}, number = {7}, pages = {1624-1634}, doi = {10.1021/acs.jnatprod.5b00173}, pmid = {26154615}, issn = {1520-6025}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Boron Compounds ; Breast Neoplasms ; Calcium/*metabolism ; Caspase 3/metabolism ; Caspase 9 ; Cytosol/metabolism ; Egtazic Acid/analogs &amp; derivatives ; Endoplasmic Reticulum/drug effects ; Female ; Flavanones/*pharmacology ; Humans ; Indoles ; Maleimides ; Molecular Structure ; Reactive Oxygen Species/pharmacology ; Thapsigargin/pharmacology ; Type C Phospholipases ; }, abstract = {Baicalein (5,6,7-trihydroxyflavone) (1) has been found to be active against a wide variety of cancer cells. However, the molecular mechanism underlying the effects of 1 on the induction of Ca(2+) movement and cytotoxicity in human breast cancer cells is unknown. This study examined the relationship between 1-induced Ca(2+) signaling and cytotoxicity in ZR-75-1 human breast cancer cells. The in vitro investigations reported herein produced the following results: (i) Compound 1 increased intracellular Ca(2+) concentration ([Ca(2+)]i) in a concentration-dependent manner. The signal was decreased by approximately 50% by removal of extracellular Ca(2+). (ii) Compound 1-triggered [Ca(2+)]i increases were significantly suppressed by store-operated Ca(2+) channel blockers 2-aminoethoxydiphenyl borate (2-APB) and the PKC inhibitor GF109203X. (iii) In Ca(2+)-free medium, compound 1-induced [Ca(2+)]i increases were also inhibited by GF109203X. Furthermore, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) or 2,5-ditert-butylhydroquinone (BHQ) abolished 1-induced [Ca(2+)]i increases. Inhibition of phospholipase C (PLC) with U73122 abolished 1-induced [Ca(2+)]i increases. (iv) Compound 1 (20-40 μM) caused cytotoxicity, increased reactive oxygen species (ROS) production, and activated caspase-9/caspase-3. Furthermore, compound 1-induced apoptosis was significantly inhibited by prechelating cytosolic Ca(2+) with BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester) or by decreasing ROS with the antioxidant NAC (N-acetylcysteine). Together, baicalein (1) induced a [Ca(2+)]i increase by inducing PLC-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via PKC-dependent, 2-APB-sensitive store-operated Ca(2+) channels. Moreover, baicalein (1) induced Ca(2+)-associated apoptosis involved ROS production in ZR-75-1 cells.}, }
@article {pmid26153346, year = {2015}, author = {Zhao, Y and Wang, X and Sun, Y and Zhou, Y and Yin, Y and Ding, Y and Li, Z and Guo, Q and Lu, N}, title = {LYG-202 exerts antitumor effect on PI3K/Akt signaling pathway in human breast cancer cells.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {20}, number = {9}, pages = {1253-1269}, doi = {10.1007/s10495-015-1145-x}, pmid = {26153346}, issn = {1573-675X}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Breast Neoplasms/*metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Female ; Flavones/chemistry/*pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Heterografts ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred BALB C ; Mice, Nude ; Oncogene Protein v-akt/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Piperazines/chemistry/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {In this study, we aimed to investigate the antitumor effect of LYG-202, a newly synthesized piperazine-substituted derivative of flavonoid on human breast cancer cells and illustrate the potential mechanisms. LYG-202 induced apoptosis in MCF-7, MDA-MB-231 and MDA-MB-435 cells. LYG-202 triggered the activation of mitochondrial apoptotic pathway through multiple steps: increasing Bax/Bcl-2 ratio, decreasing mitochondrial membrane potential (ΔΨ(m)), activating caspase-9 and caspase-3, inducing cleavage of poly(ADP-ribose) polymerase, cytochrome c release and apoptosis-inducing factor translocation. Furthermore, LYG-202 inhibited cell cycle progression at the G1/S transition via targeting Cyclin D, CDK4 and p21(Waf1/Cip1). Additionally, LYG-202 increased the generation of intracellular ROS. N-Acetyl cysteine, an antioxidant, reversed LYG-202-induced apoptosis suggesting that LYG-202 induces apoptosis by accelerating ROS generation. Further, we found that LYG-202 deactivated the PI3K/Akt pathway, activated Bad phosphorylation, increased Cyclin D and Bcl-xL expression, and inhibited NF-κB nuclear translocation. Activation of PI3K/Akt pathway by IGF-1 attenuated LYG-202-induced apoptosis and cell cycle arrest. Our in vivo study showed that LYG-202 exhibited a potential antitumor effect in nude mice inoculated with MCF-7 tumor through similar mechanisms identified in cultured cells. In summary, our results demonstrated that LYG-202 induced apoptosis and cell cycle arrest via targeting PI3K/Akt pathway, indicating that LYG-202 is a potential anticancer agent for breast cancer.}, }
@article {pmid26152521, year = {2016}, author = {Kim, DH and Park, KW and Chae, IG and Kundu, J and Kim, EH and Kundu, JK and Chun, KS}, title = {Carnosic acid inhibits STAT3 signaling and induces apoptosis through generation of ROS in human colon cancer HCT116 cells.}, journal = {Molecular carcinogenesis}, volume = {55}, number = {6}, pages = {1096-1110}, doi = {10.1002/mc.22353}, pmid = {26152521}, issn = {1098-2744}, mesh = {Abietanes/*pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Colonic Neoplasms/drug therapy/*metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; HCT116 Cells ; HT29 Cells ; Humans ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Carnosic acid (CA), the main antioxidant compound of Rosmarinus officinalis L., has been reported to possess anticancer activity. However, the molecular mechanisms underlying the anticancer effects of CA remain poorly understood. Our study revealed that CA treatment significantly reduced the viability of human colon cancer HCT116, SW480, and HT-29 cells. Treatment with CA induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, activation of caspase-9, and -3, and the cleavage of PARP in HCT116 cells. CA inhibited the constitutive phosphorylation, the DNA binding and the reporter gene activity of STAT3 in HCT116 cells by blocking the phosphorylation of upstream JAK2 and Src kinases. Moreover, CA attenuated the expression of STAT3 target gene products, such as survivin, cyclin D1, D2, and D3. In STAT3-overexpressed HCT116 cells, CA inhibited cell viability and the expression of cyclin D1 and survivin. Furthermore, CA treatment induced the generation of ROS in these colon cancer cells. Pretreatment of cells with ROS scavenger N-acetyl cysteine abrogated the inhibitory effect of CA on the JAK2-STAT3/Src-STAT3 signaling and rescued cells from CA-induced apoptosis by blocking the induction of p53 and the cleavage of caspase-3 and PARP in HCT116 cells. However, L-buthionine-sulfoximine, a pharmacological inhibitor of GSH synthesis, increased CA-induced ROS production, thereby potentiating apoptotic effect of CA. In conclusion, our study provides the first report that CA induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases, and inhibition of STAT3 signaling pathway. © 2015 Wiley Periodicals, Inc.}, }
@article {pmid26151790, year = {2015}, author = {Landriscina, A and Musaev, T and Rosen, J and Ray, A and Nacharaju, P and Nosanchuk, JD and Friedman, AJ}, title = {N-acetylcysteine S-nitrosothiol Nanoparticles Prevent Wound Expansion and Accelerate Wound Closure in a Murine Burn Model.}, journal = {Journal of drugs in dermatology : JDD}, volume = {14}, number = {7}, pages = {726-732}, pmid = {26151790}, issn = {1545-9616}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Cutaneous ; Animals ; Burns/*drug therapy ; Disease Models, Animal ; Mice ; Mice, Inbred BALB C ; Nanoparticles/*therapeutic use ; S-Nitrosothiols/administration &amp; dosage/*therapeutic use ; Wound Healing/*drug effects ; }, abstract = {BACKGROUND: The treatment of cutaneous wounds in the clinical setting continues to be a clinical challenge and economic burden, with burn wounds being especially formidable. Direct mechanical injury coupled with the transfer of thermal energy leads to tissue necrosis, pro-inflammatory cytokine release and the eventual expansion of an initial wound. Our current therapeutic armamentarium falls short of options to help prevent wound expansion, and therefore new modalities are required. Nitrosating substances such as RSNOs have been proven to be effective in promoting wound closure due to their ability to modulate inflammation, cytokine production and vascular function.<br><br>OBJECTIVE: We aim to evaluate the efficacy of n-actetylcysteine s-nitrosothiol nanoparticles (NAC-SNO-np) on thermal burn wounds and associated expansion.<br><br>METHODS: A multi-burn model was utilized to induce three burn wounds on the dorsal surface of BALB/c mice, allowing for evaluation of the burn itself and peripheral tissue. Wounds were excised and processed for histology and immunohistochemistry on day 7 following wounding.<br><br>RESULTS: Following treatment with NAC-SNO-np, burn wound expansion was attenuated and wound healing was accelerated. Histological analysis revealed increased collagen deposition as well as increased macrophage and decreased neutrophil infiltration into the wound bed.<br><br>CONCLUSION: NAC-SNO-np represents a platform that harnesses the nitrosative properties of NAC-SNO in order to accelerate the transition from inflammatory to proliferative wound healing. Further studies are needed in order to translate to the clinical setting.}, }
@article {pmid26148434, year = {2015}, author = {Al-Anati, L and Viluksela, M and Strid, A and Bergman, &#xc5; and Andersson, PL and Stenius, U and Högberg, J}, title = {Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene.}, journal = {Chemico-biological interactions}, volume = {239}, number = {}, pages = {164-173}, doi = {10.1016/j.cbi.2015.07.002}, pmid = {26148434}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzo(a)pyrene/*toxicity ; Checkpoint Kinase 1 ; Cytochrome P-450 CYP1A1/genetics ; DNA Damage/*drug effects ; Drug Synergism ; Estradiol/pharmacology ; Female ; Hep G2 Cells/drug effects ; Histones ; Humans ; Hydroxyl Radical/metabolism ; Liver/drug effects/metabolism ; Male ; Polychlorinated Biphenyls/metabolism/pharmacokinetics/*pharmacology/*toxicity ; Protein Kinases/metabolism ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000mg/kgbw) for 28days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and γH2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1μM of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5μM). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and γH2AX. CYP1A1 mRNA induction was seen at 1h, and γH2AX at 3h. The anti-oxidant N-Acetyl-l-Cysteine (NAC) completely prevented, and 17β-estradiol amplified the γH2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.}, }
@article {pmid26148005, year = {2015}, author = {Tseng, CY and Chang, JF and Wang, JS and Chang, YJ and Gordon, MK and Chao, MW}, title = {Protective Effects of N-Acetyl Cysteine against Diesel Exhaust Particles-Induced Intracellular ROS Generates Pro-Inflammatory Cytokines to Mediate the Vascular Permeability of Capillary-Like Endothelial Tubes.}, journal = {PloS one}, volume = {10}, number = {7}, pages = {e0131911}, pmid = {26148005}, issn = {1932-6203}, mesh = {Adherens Junctions/drug effects/metabolism ; Antigens, CD/metabolism ; Cadherins/metabolism ; Capillaries/drug effects ; Capillary Permeability/drug effects ; Cells, Cultured ; Cysteine/*pharmacology ; Cytokines/*metabolism ; Heme Oxygenase-1/metabolism ; Human Umbilical Vein Endothelial Cells/*drug effects/metabolism ; Humans ; Inflammation/chemically induced/*metabolism ; Interleukin-6/metabolism ; Oxidative Stress/drug effects ; Particulate Matter/adverse effects ; Protective Agents/*pharmacology ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Vehicle Emissions/*toxicity ; }, abstract = {Exposure to diesel exhaust particles (DEP) is associated with pulmonary and cardiovascular diseases. Previous studies using in vitro endothelial tubes as a simplified model of capillaries have found that DEP-induced ROS increase vascular permeability with rearrangement or internalization of adherens junctional VE-cadherin away from the plasma membrane. This allows DEPs to penetrate into the cell and capillary lumen. In addition, pro-inflammatory cytokines are up-regulated and mediate vascular permeability in response to DEP. However, the mechanisms through which these DEP-induced pro-inflammatory cytokines increase vascular permeability remain unknown. Hence, we examined the ability of DEP to induce permeability of human umbilical vein endothelial cell tube cells to investigate these mechanisms. Furthermore, supplementation with NAC reduces ROS production following exposure to DEP. HUVEC tube cells contributed to a pro-inflammatory response to DEP-induced intracellular ROS generation. Endothelial oxidative stress induced the release of TNF-α and IL-6 from tube cells, subsequently stimulating the secretion of VEGF-A independent of HO-1. Our data suggests that DEP-induced intracellular ROS and release of the pro-inflammatory cytokines TNF- α and IL-6, which would contribute to VEGF-A secretion and disrupt cell-cell borders and increase vasculature permeability. Addition of NAC suppresses DEP-induced ROS efficiently and reduces subsequent damages by increasing endogenous glutathione.}, }
@article {pmid26140672, year = {2015}, author = {Castro, B and Palomares, T and Azcoitia, I and Bastida, F and del Olmo, M and Soldevilla, JJ and Alonso-Varona, A}, title = {Development and preclinical evaluation of a new galactomannan-based dressing with antioxidant properties for wound healing.}, journal = {Histology and histopathology}, volume = {30}, number = {12}, pages = {1499-1512}, doi = {10.14670/HH-11-646}, pmid = {26140672}, issn = {1699-5848}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*administration &amp; dosage/*therapeutic use ; *Bandages/adverse effects ; Curcumin/pharmacology ; Cytokines/biosynthesis/genetics ; Fibroblasts/drug effects ; Galactans ; Galactose/analogs &amp; derivatives ; Humans ; Inflammation/drug therapy/genetics ; Irritants ; Mannans/*administration &amp; dosage/adverse effects/*therapeutic use ; Materials Testing ; Oxidative Stress/drug effects ; Plant Gums ; Reactive Oxygen Species/metabolism ; Sus scrofa ; Wound Healing/*drug effects ; }, abstract = {We describe a novel wound dressing (HR006) with two components: a lyophilized matrix of the galactomannan from locust bean gum (LBG) and an antioxidant hydration solution (AHsol) containing curcumin and N-acetyl-L-cysteine (NAC). Physico-structural analyses of the LBG matrix revealed homogeneous interconnected pores with high absorbing capacity showing excellent properties for moist wound care (MWC). In an in vitro oxidative stress fibroblast injury model, the AHsol showed relevant protective effects reducing intracellular reactive oxygen species (ROS) production, rescuing cell viability, and regulating expression of inflammation-related genes (COX-2, TNF-α, IL-1α, IL-1β). The new dressing showed good biocompatibility profile as demonstrated by cytotoxicity, hemocompatibility, and skin irritation tests. Moreover, in an in vivo skin wound model in pigs, this dressing enhanced the production of healthy and organized granulation tissue and re-epithelization. In summary, HR006 exhibits significant antioxidant activity, good biocompatibility, and excellent repair capabilities improving tissue remodeling and the healing of wounds.}, }
@article {pmid26139573, year = {2015}, author = {Jahanban-Esfahlan, A and Panahi-Azar, V and Sajedi, S}, title = {Spectroscopic and molecular docking studies on the interaction between N-acetyl cysteine and bovine serum albumin.}, journal = {Biopolymers}, volume = {103}, number = {11}, pages = {638-645}, doi = {10.1002/bip.22697}, pmid = {26139573}, issn = {1097-0282}, mesh = {Animals ; Binding Sites ; Cysteine/*chemistry ; Protein Binding ; Serum Albumin, Bovine/*chemistry ; Spectrometry, Fluorescence ; Thermodynamics ; }, abstract = {The interaction between N-acetyl cysteine (NAC) and bovine serum albumin (BSA) was investigated by UV-vis, fluorescence spectroscopy, and molecular docking methods. Fluorescence study at three different temperatures indicated that the fluorescence intensity of BSA was reduced upon the addition of NAC by the static quenching mechanism. Binding constant (K(b)) and the number of binding sites (n) were determined. The binding constant for the interaction of NAC and BSA was in the order of 10(3) M(-1), and the number of binding sites was obtained to be equal to 1. Enthalpy (ΔH), entropy (ΔS), and Gibb's free energy (ΔG) as thermodynamic values were also achieved by van't Hoff equation. Hydrogen bonding and van der Waals force were the major intermolecular forces in the interaction process and it was spontaneous. Finally, the binding mode and the binding sites were clarified using molecular docking which were in good agreement with the results of spectroscopy experiments.}, }
@article {pmid26139231, year = {2015}, author = {Schumer, MC and Panza, KE and Mulqueen, JM and Jakubovski, E and Bloch, MH}, title = {LONG-TERM OUTCOME IN PEDIATRIC TRICHOTILLOMANIA.}, journal = {Depression and anxiety}, volume = {32}, number = {10}, pages = {737-743}, pmid = {26139231}, issn = {1520-6394}, support = {K23 MH091240/MH/NIMH NIH HHS/United States ; R25 MH077823/MH/NIMH NIH HHS/United States ; UL1 RR024139/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Anxiety/epidemiology ; *Behavior Therapy ; Child ; Comorbidity ; Depression/epidemiology ; Double-Blind Method ; Female ; Humans ; Male ; Severity of Illness Index ; Treatment Outcome ; Trichotillomania/drug therapy/psychology/*therapy ; }, abstract = {OBJECTIVE: To examine long-term outcome in children with trichotillomania.<br><br>METHOD: We conducted follow-up clinical assessments an average of 2.8 &#xb1; 0.8 years after baseline evaluation in 30 of 39 children who previously participated in a randomized, double-blind, placebo-controlled trial of N-acetylcysteine (NAC) for pediatric trichotillomania. Our primary outcome was change in hairpulling severity on the Massachusetts General Hospital Hairpulling Hospital Hairpulling Scale (MGH-HPS) between the end of the acute phase and follow-up evaluation. We also obtained secondary measures examining styles of hairpulling, comorbid anxiety and depressive symptoms, as well as continued treatment utilization. We examined both correlates and predictors of outcome (change in MGH-HPS score) using linear regression.<br><br>RESULTS: None of the participants continued to take NAC at the time of follow-up assessment. No significant changes in hairpulling severity were reported over the follow-up period. Subjects reported significantly increased anxiety and depressive symptoms but improvement in automatic pulling symptoms. Increased hairpulling symptoms during the follow-up period were associated with increased depression and anxiety symptoms and increased focused pulling. Older age and greater focused pulling at baseline assessment were associated with poor long-term prognosis.<br><br>CONCLUSIONS: Our findings suggest that few children with trichotillomania experience a significant improvement in trichotillomania symptoms if behavioral treatments are inaccessible or have failed to produce adequate symptom relief. Our findings also confirm results of previous cross-sectional studies that suggest an increased risk of depression and anxiety symptoms with age in pediatric trichotillomania. Increased focused pulling and older age among children with trichotillomania symptoms may be associated with poorer long-term prognosis.}, }
@article {pmid26138612, year = {2015}, author = {Goldman, JL and Leeder, JS and Van Haandel, L and Pearce, RE}, title = {In Vitro Hepatic Oxidative Biotransformation of Trimethoprim.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {43}, number = {9}, pages = {1372-1380}, pmid = {26138612}, issn = {1521-009X}, support = {KL2 TR000119/TR/NCATS NIH HHS/United States ; T32 HD069038/HD/NICHD NIH HHS/United States ; TL1 TR000120/TR/NCATS NIH HHS/United States ; }, mesh = {Anti-Infective Agents, Urinary/*pharmacokinetics ; Biotransformation ; Humans ; In Vitro Techniques ; Methylation ; Microsomes, Liver/*metabolism ; Oxidation-Reduction ; Trimethoprim/*pharmacokinetics ; }, abstract = {Trimethoprim (TMP) has been widely used since the 1960s, both alone and in combination with sulfamethoxazole. Unfortunately, information regarding the role that cytochrome P450 enzymes (P450s) play in the formation of TMP primary metabolites is scarce. Hence, we undertook in vitro studies to identify and more fully characterize the P450s that catalyze formation of six TMP primary metabolites: TMP 1-N-oxide (1-NO-TMP) and 3-N-oxide (3-NO-TMP), 3'- and 4'-desmethyl-TMP, a benzylic alcohol (Cα-OH-TMP), and an N-acetyl cysteine (NAC) adduct of TMP (Cα-NAC-TMP). Formation kinetics for each TMP metabolite in human liver microsomes (HLMs) were consistent with single-enzyme Michaelis-Menten kinetics, and Km values were markedly above (≥10-fold) the therapeutic concentrations of TMP (50 µM). The combined results from correlation studies between rates of metabolite formation and marker P450 activities in a panel of HLMs along with inhibition studies utilizing selective P450 inhibitors incubated with pooled HLMs suggested that 1-NO-TMP, Cα-NAC-TMP, and Cα-OH-TMP were predominantly formed by CYP3A4. In contrast, 3-NO-TMP was formed predominantly by CYP1A2 in HLMs and inhibited by α-naphthoflavone. 4'-Desmethyl-TMP, which is believed to be a reactive TMP metabolite precursor, was formed by several P450s, including CYP3A4, correlated with multiple P450 activities, but was inhibited primarily by ketoconazole (up to 50%), suggesting that CYP3A4 makes a major contribution to TMP 4'-demethylation. TMP 3'-demethylation was catalyzed by multiple P450s, including CYP2C9, correlated with CYP2C9 activity, and was inhibited by sulfaphenazole (up to 40%). Overall, CYP2C9 and CYP3A4 appear to be the most significant contributors to TMP primary metabolism.}, }
@article {pmid26137628, year = {2015}, author = {Xu, Z and Zhang, Z and Ma, X and Ping, F and Zheng, X}, title = {[Effect of PM2.5 on oxidative stress-JAK/STAT signaling pathway of human bronchial epithelial cells].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {44}, number = {3}, pages = {451-455}, pmid = {26137628}, issn = {1000-8020}, mesh = {Acetylcysteine ; Cytokines ; Epithelial Cells/*metabolism ; Gene Expression ; Humans ; Interleukin-6/blood ; Janus Kinase 2/*metabolism ; Oxidative Stress/*physiology ; Tyrphostins ; }, abstract = {OBJECTIVE: To investigate the regulation of oxidative stress-JAK/STAT signaling pathway on cytokines in human bronchial epithelial cells induced by PM2.5.<br><br>METHODS: Bronchial epithelial cells 16HBE were cultured using traditional invasive methods. Two aspects were explored, one is the relationship among PM2.5, oxidative stress, JAK/STAT signaling pathway. There were the following groups, control group, N-acetyl-L-cysteine (NAC, 5 mmol/L) group, 50 &#x3bc;g/ml PM2.5 group, 100 &#x3bc;g/ml PM2.5 group, 50 &#x3bc;g/ml PM2.5 + 5 mmol/L NAC group, 100 &#x3bc;g/ml PM2.5 + 5 mmol/L NAC group. Intracellular ROS levels and the gene expression of JAK2 and STAT3 were detected after all groups were exposed for 24 h. The other one is to explore the relationship among PM2.5, JAK/STAT signaling pathway and cytokine. The groups were arranged the following, control group, 6 &#x3bc;mol/L AG490 group, 100 &#x3bc;g/ml PM2.5 group, 6 &#x3bc;mol/L AG490 + 100 &#x3bc;g/ml PM2.5 group. The level of IL-6 was determined after all groups were exposed for 24h.<br><br>RESULTS: After 24 h exposure, intracellular ROS levels and the gene expression of JAK2 and STAT3 in 50 &#x3bc;g/ml PM2.5, 100 &#x3bc;g/ml PM2.5 exposure group were higher than the control group. Intracellular ROS levels and the gene expression of JAK2 and STAT3 in PM2.5 + NAC protection group were lower than the respective PM2.5 exposure group, the differences were statistically significant (P < 0.05). IL-6 levels of cellular supernatant in 6 &#x3bc;mol/L AG490 + 100 &#x3bc;g/ml PM2.5 group were lower than 100 &#x3bc;g/M PM2. group, the differences were statistically significant (P < 0.05).<br><br>CONCLUSION: PM2.5 could cause oxidative damage on bronchial epithelial cells, and then regulate JAK/STAT signaling pathway and relative cytokines of epithelial cells through oxidative stress.}, }
@article {pmid26134947, year = {2015}, author = {Quast, SA and Steinhorst, K and Plötz, M and Eberle, J}, title = {Sensitization of Melanoma Cells for Death Ligand TRAIL Is Based on Cell Cycle Arrest, ROS Production, and Activation of Proapoptotic Bcl-2 Proteins.}, journal = {The Journal of investigative dermatology}, volume = {135}, number = {11}, pages = {2794-2804}, pmid = {26134947}, issn = {1523-1747}, mesh = {Apoptosis Regulatory Proteins/*metabolism ; Blotting, Western ; Cell Cycle Checkpoints/*physiology ; Cell Death/genetics ; Humans ; Melanoma/*genetics/pathology ; Membrane Potential, Mitochondrial/physiology ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*genetics ; Sensitivity and Specificity ; Transfection ; Tumor Cells, Cultured ; }, abstract = {The death ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) represents a promising strategy for melanoma due to significant expression of TRAIL receptor 1 in melanoma metastases and high TRAIL sensitivity through this receptor. However, prevalent and inducible resistance are limiting its clinical use. In previous work, we and others have described multiple strategies leading to TRAIL sensitization; however, the common principles of these strategies remained elusive. Here, we demonstrate in melanoma cell lines (TRAIL-sensitive, TRAIL-resistant, and TRAIL-selected cells with acquired resistance) that cell cycle arrest clearly correlates with enhanced TRAIL sensitivity. Cell cycle arrest was induced by high cell confluence, serum starvation, or cyclin-dependent kinase (CDK) 4/6 inhibition. Addressing the signaling pathways revealed disruption of mitochondrial membrane potential and production of reactive oxygen species (ROS) in response to antiproliferative conditions alone. Activation of the proapoptotic Bcl-2 protein Bax and inhibition of apoptosis by Bcl-2 overexpression or by the antioxidant N-acetyl cysteine underlined the critical involvement of mitochondrial apoptosis pathways and of ROS, respectively. Most pronounced was the upregulation of small proapoptotic Bcl-2 proteins (Puma and Bcl-xS). These data provide a general understanding on TRAIL sensitization as well as an alternative view on CDK inhibitors and may suggest selective targeting of melanoma cells by cell cycle inhibition and TRAIL.}, }
@article {pmid26134756, year = {2016}, author = {Ali, MH and Messiha, BA and Abdel-Latif, HA}, title = {Protective effect of ursodeoxycholic acid, resveratrol, and N-acetylcysteine on nonalcoholic fatty liver disease in rats.}, journal = {Pharmaceutical biology}, volume = {54}, number = {7}, pages = {1198-1208}, doi = {10.3109/13880209.2015.1060247}, pmid = {26134756}, issn = {1744-5116}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biomarkers/blood ; Choline Deficiency/complications ; Cytoprotection ; Disease Models, Animal ; Hypolipidemic Agents/*pharmacology ; Lipids/blood ; Liver/*drug effects/metabolism/pathology ; Male ; Methionine/deficiency ; Non-alcoholic Fatty Liver Disease/blood/etiology/pathology/*prevention &amp; control ; Oxidative Stress/drug effects ; Rats, Wistar ; Resveratrol ; Stilbenes/*pharmacology ; Ursodeoxycholic Acid/*pharmacology ; }, abstract = {CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Resveratrol (RSV) and N-acetylcysteine (NAC) are safe representatives of natural and synthetic antioxidants, respectively.<br><br>OBJECTIVE: The objective of this study was to evaluate protective effects of RSV and NAC, compared with ursodeoxycholic acid (UDCA), on experimental NAFLD.<br><br>MATERIALS AND METHODS: NAFLD was induced by feeding rats a methionine choline-deficient diet (MCDD) for four cycles, each of 4&#x2009;d of MCDD feeding and 3&#x2009;d of fasting. Animals were divided into normal control, steatosis control, and five treatment groups, receiving UDCA (25&#x2009;mg/kg/d), RSV (10&#x2009;mg/kg/d), NAC (20&#x2009;mg/kg/d), UDCA&#x2009;+&#x2009;RSV, and UDCA&#x2009;+&#x2009;NAC orally for 28&#x2009;d. Liver integrity markers (liver index and serum transaminases), serum tumor necrosis factor-&#x3b1; (TNF-&#x3b1;), glucose, albumin, renal functions (urea, creatinine), lipid profile (total cholesterol; TC, triglycerides, high density lipoproteins, low density lipoproteins; LDL-C, very low density lipoproteins, leptin), and oxidative stress markers (hepatic malondialdehyde; MDA, glutathione; GSH, glutathione-S-transferase; GST) were measured using automatic analyzer, colorimetric kits, and ELISA kits, supported by a liver histopathological study.<br><br>RESULTS: RSV and NAC administration significantly improved liver index (RSV only), alanine transaminase (52, 52%), TNF-&#x3b1; (70, 70%), glucose (69, 80%), albumin (122, 114%), MDA (55, 63%), GSH (160, 152%), GST (84, 84%), TC (86, 86%), LDL-C (83, 81%), and leptin (59, 70%) levels compared with steatosis control values. A combination of RSV or NAC with UDCA seems to ameliorate their effects.<br><br>DISCUSSION AND CONCLUSION: RSV and NAC are effective on NAFLD through antioxidant, anti-inflammatory, and lipid-lowering potentials, where as RSV seems better than UDCA or NAC.}, }
@article {pmid26134032, year = {2015}, author = {Zhang, Y and Liao, H and Zhong, S and Gao, F and Chen, Y and Huang, Z and Lu, S and Sun, T and Wang, B and Li, W and Xu, H and Zheng, F and Shi, G}, title = {Effect of N-n-butyl haloperidol iodide on ROS/JNK/Egr-1 signaling in H9c2 cells after hypoxia/reoxygenation.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {11809}, pmid = {26134032}, issn = {2045-2322}, mesh = {Acetylcysteine/administration &amp; dosage ; Antipyrine/administration &amp; dosage/analogs &amp; derivatives ; Cell Hypoxia/drug effects ; Cell Line ; Early Growth Response Protein 1/*biosynthesis/genetics ; Edaravone ; Gene Expression Regulation/drug effects ; Haloperidol/administration &amp; dosage/analogs &amp; derivatives ; Humans ; MAP Kinase Kinase 4/*biosynthesis/metabolism ; MAP Kinase Signaling System/*drug effects ; Myocardial Reperfusion Injury/genetics/*metabolism/pathology ; Myocytes, Cardiac/metabolism/pathology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Xanthine Oxidase/metabolism ; }, abstract = {Reactive oxygen species (ROS)-induced oxidative stress in cells is an important pathophysiological process during myocardial ischemia/reperfusion (I/R) injury, and the transcription factor Egr-1 is a master switch for various damage pathways during reperfusion injury. An in vitro model of myocardial I/R injury and H9c2 cardiomyoblast cells hypoxia/reoxygenation (H/R) was used to assess whether there is abnormal intracellular ROS/JNK/Egr-1 signaling. We also assessed whether N-n-butyl haloperidol (F2), which exerts protective effects during myocardial I/R injury, can modulate this pathway. H/R induced ROS generation, JNK activation, and increased the expression of Egr-1 protein in H9c2 cells. The ROS scavengers edaravone (EDA) and N-acetyl-L-cysteine (NAC) reduced ROS level, downregulated JNK activation, and Egr-1 expression in H9c2 cells after H/R. The JNK inhibitor SP600125 inhibited Egr-1 overexpression in H9c2 cells caused by H/R. F2 could downregulate H/R-induced ROS level, JNK activation, and Egr-1 expression in H9c2 cells in a dose-dependent manner. The ROS donor hypoxanthine-xanthine oxidase (XO/HX) and the JNK activator ANISO antagonized the effects of F2. Therefore, H/R activates ROS/Egr-1 signaling pathway in H9c2 cells, and JNK activation plays an important role in this pathway. F2 regulates H/R-induced ROS/JNK/Egr-1 signaling, which might be an important mechanism by which it antagonizes myocardial I/R injury.}, }
@article {pmid26134009, year = {2015}, author = {Yang, Y and Hu, R and Zhu, K and Li, Y and Li, J and Miao, M and Wang, H and Yao, K and Liu, Z}, title = {[Involvement of oxidative stress in embelin-induced cell death in leukemia HL-60 cells].}, journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi}, volume = {36}, number = {6}, pages = {465-468}, pmid = {26134009}, issn = {0253-2727}, mesh = {Acetylcysteine ; Apoptosis ; Benzoquinones ; Cell Survival ; Comet Assay ; DNA Damage ; Fluoresceins ; HL-60 Cells ; Humans ; *Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {OBJECTIVE: To evaluate the effects of Embelin on HL-60 cells by the impact of oxidative stress on DNA double-strain breaks (DSBs).<br><br>METHODS: HL-60 cells were treated with Embelin in different concentration (3, 10, 30, 100, and 300 &#x3bc;g/ml) for 24 h, and inhibitory effects was examined by CCK-8 assay. Reactive oxygen species (ROS) levels were evaluated by flow cytometry using DCFH-DA. Comet assay was used to detect the extent of DSBs.<br><br>RESULTS: Embelin inhibited proliferation of HL-60 cells in a dose-dependent manner. At the concentration of 10, 30, 100, and 300 &#x3bc;g/ml, the inhibition rate was (12.74 &#xb1; 2.27)%, (23.49 &#xb1; 1.96)%, (30.30&#xb1;1.89)%, and (57.55 &#xb1; 3.59)% (P<0.05). Embelin also lead to high level of intracellular ROS and deterioration of DNA damage (P<0.05). When HL-60 cells were pretreated with ROS scavenger N-acetyl-l-cysteine (NAC) for 2 h and then treated with 300 &#x3bc;g/ml Embelin for 24 h, the intracellular ROS level declined and DSBs relieved (P<0.05). Meanwhile, embelin-induced cell viability significantly declined to (32.75 &#xb1; 2.70)% (P<0.05).<br><br>CONCLUSION: Embelin induced the death of HL-60 cells by increasing the generation of intracellular oxidation and the oxidative stress, which drived the damage of DNA double-strand.}, }
@article {pmid26133975, year = {2015}, author = {Ruenraroengsak, P and Tetley, TD}, title = {Differential bioreactivity of neutral, cationic and anionic polystyrene nanoparticles with cells from the human alveolar compartment: robust response of alveolar type 1 epithelial cells.}, journal = {Particle and fibre toxicology}, volume = {12}, number = {}, pages = {19}, pmid = {26133975}, issn = {1743-8977}, support = {G0700926//Medical Research Council/United Kingdom ; }, mesh = {Alveolar Epithelial Cells/*drug effects/metabolism/ultrastructure ; Anions ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Biological Transport ; Cations ; Cell Line ; Cell Shape ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; *Drug Carriers ; Glutathione Disulfide/metabolism ; Humans ; Macrophages, Alveolar/*drug effects/metabolism/ultrastructure ; Mitochondria/drug effects/metabolism/pathology ; *Nanoparticles ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Polystyrenes/chemistry/metabolism/*toxicity ; Primary Cell Culture ; Pulmonary Alveoli/*drug effects/metabolism/ultrastructure ; Reactive Oxygen Species/metabolism ; Surface Properties ; Time Factors ; }, abstract = {BACKGROUND: Engineered nanoparticles (NP) are being developed for inhaled drug delivery. This route is non-invasive and the major target; alveolar epithelium provides a large surface area for drug administration and absorption, without first pass metabolism. Understanding the interaction between NPs and target cells is crucial for safe and effective NP-based drug delivery. We explored the differential effect of neutral, cationic and anionic polystyrene latex NPs on the target cells of the human alveolus, using primary human alveolar macrophages (MAC) and primary human alveolar type 2 (AT2) epithelial cells and a unique human alveolar epithelial type I-like cell (TT1). We hypothesized that the bioreactivity of the NPs would relate to their surface chemistry, charge and size as well as the functional role of their interacting cells in vivo.<br><br>METHODS: Amine- (ANP) and carboxyl- surface modified (CNP) and unmodified (UNP) polystyrene NPs, 50 and 100 nm in diameter, were studied. Cells were exposed to 1-100 &#x3bc;g/ml (1.25-125 &#x3bc;g/cm(2); 0 &#x3bc;g/ml control) NP for 4 and 24 h at 37 &#xb0;C with or without the antioxidant, N-acetyl cysteine (NAC). Cells were assessed for cell viability, reactive oxygen species (ROS), oxidised glutathione (GSSG/GSH ratio), mitochondrial integrity, cell morphology and particle uptake (using electron microscopy and laser scanning confocal microscopy).<br><br>RESULTS: ANP-induced cell death occurred in all cell types, inducing increased oxidative stress, mitochondrial disruption and release of cytochrome C, indicating apoptotic cell death. UNP and CNP exhibited little cytotoxicity or mitochondrial damage, although they induced ROS in AT2 and MACs. Addition of NAC reduced epithelial cell ROS, but not MAC ROS, for up to 4 h. TT1 and MAC cells internalised all NP formats, whereas only a small fraction of AT2 cells internalized ANP (not UNP or CNP). TT1 cells were the most resistant to the effects of UNP and CNP.<br><br>CONCLUSION: ANP induced marked oxidative damage and cell death via apoptosis in all cell types, while UNP and CNP exhibited low cytotoxicity via oxidative stress. MAC and TT1 cell models show strong particle-internalization compared to the AT2 cell model, reflecting their cell function in vivo. The 50 nm NPs induced a higher bioreactivity in epithelial cells, whereas the 100 nm NPs show a stronger effect on phagocytic cells.}, }
@article {pmid26133502, year = {2015}, author = {Jayakumar, S and Pal, D and Sandur, SK}, title = {Nrf2 facilitates repair of radiation induced DNA damage through homologous recombination repair pathway in a ROS independent manner in cancer cells.}, journal = {Mutation research}, volume = {779}, number = {}, pages = {33-45}, doi = {10.1016/j.mrfmmm.2015.06.007}, pmid = {26133502}, issn = {1873-135X}, mesh = {DNA Breaks, Double-Stranded/radiation effects ; DNA Damage/radiation effects ; DNA End-Joining Repair/genetics/*radiation effects ; Free Radical Scavengers/metabolism ; Histones/genetics/metabolism ; Humans ; MCF-7 Cells ; NF-E2-Related Factor 2/antagonists &amp; inhibitors/*genetics ; Rad51 Recombinase/*genetics/metabolism ; Radiation Tolerance/genetics/radiation effects ; Radiation, Ionizing ; Reactive Oxygen Species/metabolism ; Recombinational DNA Repair/genetics/*radiation effects ; Tretinoin/administration &amp; dosage ; }, abstract = {Nrf2 is a redox sensitive transcription factor that is involved in the co-ordinated transcription of genes involved in redox homeostasis. But the role of Nrf2 in DNA repair is not investigated in detail. We have employed A549 and MCF7 cells to study the role of Nrf2 on DNA repair by inhibiting Nrf2 using all-trans retinoic acid (ATRA) or by knock down approach prior to radiation exposure (4 Gy). DNA damage and repair analysis was studied by γH2AX foci formation and comet assay. Results suggested that the inhibition of Nrf2 in A549 or MCF7 cells led to significant slowdown in DNA repair as compared to respective radiation controls. The persistence of residual DNA damage even in the presence of free radical scavenger N-acetyl cysteine, suggested that the influence of Nrf2 on DNA repair was not linked to its antioxidant functions. Further, its influence on non-homologous end joining repair pathway was studied by inhibiting both Nrf2 and DNA-PK together. This led to synergistic reduction of survival fraction, indicating that Nrf2 may not be influencing the NHEJ pathway. To investigate the role of homologous recombination repair (HR) pathway, RAD51 foci formation was monitored. There was a significant reduction in the foci formation in cells treated with ATRA or shRNA against Nrf2 as compared to their respective radiation controls. Further, Nrf2 inhibition led to significant reduction in mRNA levels of RAD51. BLAST analysis was also performed on upstream regions of DNA repair genes to identify antioxidant response element and found that many repair genes that are involved in HR pathway may be regulated by Nrf2. Together, these results suggest the involvement of Nrf2 in DNA repair, a hitherto unknown function of Nrf2, putatively through its influence on HR pathway.}, }
@article {pmid26133055, year = {2015}, author = {Kruh, JN and Kruh-Garcia, NA and Foster, CS}, title = {Evaluation of the Effect of N-Acetylcysteine on Protein Deposition on Contact Lenses in Patients with the Boston Keratoprosthesis Type I.}, journal = {Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics}, volume = {31}, number = {6}, pages = {314-322}, doi = {10.1089/jop.2015.0010}, pmid = {26133055}, issn = {1557-7732}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biofilms/drug effects ; *Contact Lenses ; Eye Proteins/*metabolism ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Proteome/*drug effects ; Proteomics/methods ; Stevens-Johnson Syndrome/metabolism/pathology/*therapy ; Tears/*metabolism ; Treatment Outcome ; Trichiasis/metabolism/pathology/*therapy ; Visual Acuity/drug effects ; Young Adult ; }, abstract = {PURPOSE: To establish the efficacy of topical N-acetylcysteine (NAC) as a treatment to reduce protein deposition on the contact lens surface.<br><br>METHODS: In this prospective, nonrandomized clinical trial, a total of 10 eyes (9 patients) were enrolled from a single center. All patients had a prior ocular history of either a Boston Keratoprosthesis type I or trichiasis from Stevens-Johnson syndrome, which necessitated full-time contact lens wear. Four visits were required to complete the study. During visit 1, a new contact lens was inserted and a baseline examination was performed. Visit 2 served as the control month, whereas visits 3 and 4 were month 1 and 2 on treatment with 20% NAC. At the end of each visit the contact lens was replaced. The lenses from visit 2 (control month-without NAC) and from visit 3 (treatment month-with NAC) were collected for proteomic analysis. The main outcome measures were to quantify protein deposition, as well as to assess the visual acuity and ocular surface symptoms before and after treatment.<br><br>RESULTS: Topical NAC resulted in a 20% decrease in protein deposition. This correlated with a trend for improvement in visual acuity and increased subjective improvement in vision at month 1 (P=0.0153) and 2 (P=0.0016).<br><br>CONCLUSIONS: NAC reduced protein deposition, decreased ocular surface symptoms, and improved contact lens transparency, thereby providing increased optical clarity.}, }
@article {pmid26132846, year = {2015}, author = {Weiss, M and Gümbel, D and Hanschmann, EM and Mandelkow, R and Gelbrich, N and Zimmermann, U and Walther, R and Ekkernkamp, A and Sckell, A and Kramer, A and Burchardt, M and Lillig, CH and Stope, MB}, title = {Cold Atmospheric Plasma Treatment Induces Anti-Proliferative Effects in Prostate Cancer Cells by Redox and Apoptotic Signaling Pathways.}, journal = {PloS one}, volume = {10}, number = {7}, pages = {e0130350}, pmid = {26132846}, issn = {1932-6203}, mesh = {Apoptosis/*drug effects ; Cell Line ; Cell Proliferation/*drug effects ; Free Radicals/metabolism ; Humans ; Male ; Plasma Gases/*pharmacology ; Prostatic Neoplasms/*metabolism ; Signal Transduction ; }, abstract = {One of the promising possibilities of the clinical application of cold plasma, so-called cold atmospheric plasma (CAP), is its application on malignant cells and cancer tissue using its anti-neoplastic effects, primarily through the delivery of reactive oxygen and nitrogen species (ROS, RNS). In this study, we investigated the impact of CAP on cellular proliferation and consecutive molecular response mechanisms in established prostate cancer (PC) cell lines. PC cells showed a significantly reduced cell growth following CAP treatment as a result of both an immediate increase of intracellular peroxide levels and through the induction of apoptosis indicated by annexin V assay, TUNEL assay, and the evaluation of changes in nuclear morphology. Notably, co-administration of N-acetylcysteine (NAC) completely neutralized CAP effects by NAC uptake and rapid conversion to glutathione (GSH). Vitamin C could not counteract the CAP induced effects on cell growth. In summary, relatively short treatments with CAP of 10 seconds were sufficient to induce a significant inhibition of cancer proliferation, as observed for the first time in urogenital cancer. Therefore, it is important to understand the mode of CAP related cell death and clarify and optimize CAP as cancer therapy. Increased levels of peroxides can alter redox-regulated signaling pathways and can lead to growth arrest and apoptosis. We assume that the general intracellular redox homeostasis, especially the levels of cellular GSH and peroxidases such as peroxiredoxins affect the outcome of the CAP treatment.}, }
@article {pmid26132720, year = {2015}, author = {Michelucci, A and Paolini, C and Canato, M and Wei-Lapierre, L and Pietrangelo, L and De Marco, A and Reggiani, C and Dirksen, RT and Protasi, F}, title = {Antioxidants protect calsequestrin-1 knockout mice from halothane- and heat-induced sudden death.}, journal = {Anesthesiology}, volume = {123}, number = {3}, pages = {603-617}, pmid = {26132720}, issn = {1528-1175}, support = {MDA275574//PHS HHS/United States ; AR059646/AR/NIAMS NIH HHS/United States ; GGP13213/TI_/Telethon/Italy ; R01 AR059646/AR/NIAMS NIH HHS/United States ; R01 AR053349/AR/NIAMS NIH HHS/United States ; AR053349/AR/NIAMS NIH HHS/United States ; }, mesh = {Anesthetics, Inhalation/*toxicity ; Animals ; Antioxidants/*therapeutic use ; Calcium-Binding Proteins/*deficiency ; Calsequestrin ; Death, Sudden/*prevention &amp; control ; Halothane/*toxicity ; Hot Temperature/*adverse effects ; Male ; Mice ; Mice, Knockout ; }, abstract = {BACKGROUND: Mice lacking calsequestrin-1 (CASQ1-null), a Ca-binding protein that modulates the activity of Ca release in the skeletal muscle, exhibit lethal hypermetabolic episodes that resemble malignant hyperthermia in humans when exposed to halothane or heat stress.<br><br>METHODS: Because oxidative species may play a critical role in malignant hyperthermia crises, we treated CASQ1-null mice with two antioxidants, N-acetylcysteine (NAC, Sigma-Aldrich, Italy; provided ad libitum in drinking water) and (&#xb1;)-6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox, Sigma-Aldrich; administered by intraperitoneal injection), before exposure to halothane (2%, 1 h) or heat (41&#xb0;C, 1 h).<br><br>RESULTS: NAC and Trolox significantly protected CASQ1-null mice from lethal episodes, with mortality being 79% (n = 14), 25% (n = 16), and 20% (n = 5) during halothane exposure and 86% (n = 21), 29% (n = 21), and 33% (n = 6) during heat stress in untreated, NAC-treated, and Trolox-treated mice, respectively. During heat challenge, an increase in core temperature in CASQ1-null mice (42.3&#xb0; &#xb1; 0.1&#xb0;C, n=10) was significantly reduced by both NAC and Trolox (40.6&#xb0; &#xb1; 0.3&#xb0;C, n = 6 and 40.5&#xb0; &#xb1; 0.2&#xb0;C, n = 6). NAC treatment of CASQ1-null muscles/mice normalized caffeine sensitivity during in vitro contracture tests, Ca transients in single fibers, and significantly reduced the percentage of fibers undergoing rhabdomyolysis (37.6 &#xb1; 2.5%, 38/101 fibers in 3 mice; 11.6 &#xb1; 1.1%, 21/186 fibers in 5 mice). The protective effect of antioxidant treatment likely resulted from mitigation of oxidative stress, because NAC reduced mitochondrial superoxide production, superoxide dismutase type-1 expression, and 3-nitrotyrosine expression, and increased both reduced glutathione and reduced glutathione/oxidized glutathione ratio.<br><br>CONCLUSION: These studies provide a deeper understanding of the mechanisms that underlie hyperthermic crises in CASQ1-deficient muscle and demonstrate that antioxidant pretreatment may prevent them.}, }
@article {pmid26131064, year = {2015}, author = {Xue, L and Li, J and Li, Y and Chu, C and Xie, G and Qin, J and Yang, M and Zhuang, D and Cui, L and Zhang, H and Fu, X}, title = {N-acetylcysteine protects Chinese Hamster ovary cells from oxidative injury and apoptosis induced by microcystin-LR.}, journal = {International journal of clinical and experimental medicine}, volume = {8}, number = {4}, pages = {4911-4921}, pmid = {26131064}, issn = {1940-5901}, abstract = {This study aimed to investigate the MC-LR induced oxidative injury and apoptosis in Chinese hamster ovary (CHO) cells, and the protective effects of N-acetylcysteine (NAC) on these cells. Cell viability was determined by MTT assay after exposure to NAC at various concentrations (0, 1, 5, 10, 20, 30, 40, 50, 60 and 80 mmol/L) alone, or NAC (0, 1 and 5 mmol/L) plus MC-LR (0, 2.5, 5 and 10 μg/ml) for 24 h. The reactive oxygen species (ROS) in CHO cells were measured by DCFH-DA, mitochondrial membrane potential (MMP) by fluorescence probe JC-1 staining, and apoptosis index determined by Annexin V-PI staining. Results showed, following exposure to NAC alone for 24 h, cell viability remains higher than 80% at 1 and 5 mmol/L. After exposure to NAC at different concentrations plus MC-LR, cell viability increased, ROS decreased, MMP elevated, and apoptosis index reduced to a certain extent. In conclusion, MC-LR may induce the apoptosis of CHO cells by inducing ROS production which is protected by NAC.}, }
@article {pmid26120766, year = {2015}, author = {Li, R and Jen, N and Wu, L and Lee, J and Fang, K and Quigley, K and Lee, K and Wang, S and Zhou, B and Vergnes, L and Chen, YR and Li, Z and Reue, K and Ann, DK and Hsiai, TK}, title = {Disturbed Flow Induces Autophagy, but Impairs Autophagic Flux to Perturb Mitochondrial Homeostasis.}, journal = {Antioxidants &amp; redox signaling}, volume = {23}, number = {15}, pages = {1207-1219}, pmid = {26120766}, issn = {1557-7716}, support = {DE014183/DE/NIDCR NIH HHS/United States ; HL118650/HL/NHLBI NIH HHS/United States ; DE010742/DE/NIDCR NIH HHS/United States ; P01 HL090553/HL/NHLBI NIH HHS/United States ; HL083015/HL/NHLBI NIH HHS/United States ; HL111437/HL/NHLBI NIH HHS/United States ; }, mesh = {Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Aorta, Thoracic/metabolism/pathology/physiopathology ; *Autophagy ; Biomechanical Phenomena ; DNA Damage ; DNA, Mitochondrial/genetics ; Homeostasis ; MAP Kinase Signaling System ; Mitochondria/*metabolism ; Oxidative Stress ; Oxygen Consumption ; Phagosomes/metabolism ; Rabbits ; Regional Blood Flow ; }, abstract = {AIM: Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. Autophagy is tightly regulated in intracellular bulk degradation/recycling system for maintaining cellular homeostasis. We postulated that disturbed flow modulates autophagy with an implication in mitochondrial superoxide (mtO2(•-)) production.<br><br>RESULTS: In the disturbed flow or oscillatory shear stress (OSS)-exposed aortic arch, we observed prominent staining of p62, a reverse marker of autophagic flux, whereas in the pulsatile shear stress (PSS)-exposed descending aorta, p62 was attenuated. OSS significantly increased (i) microtubule-associated protein light chain 3 (LC3) II to I ratios in human aortic endothelial cells, (ii) autophagosome formation as quantified by green fluorescent protein (GFP)-LC3 dots per cell, and (iii) p62 protein levels, whereas manganese superoxide dismutase (MnSOD) overexpression by recombinant adenovirus, N-acetyl cysteine treatment, or c-Jun N-terminal kinase (JNK) inhibition reduced OSS-mediated LC3-II/LC3-I ratios and mitochondrial DNA damage. Introducing bafilomycin to Earle's balanced salt solution or to OSS condition incrementally increased both LC3-II/LC3-I ratios and p62 levels, implicating impaired autophagic flux. In the OSS-exposed aortic arch, both anti-phospho-JNK and anti-8-hydroxy-2'-deoxyguanosine (8-OHdG) staining for DNA damage were prominent, whereas in the PSS-exposed descending aorta, the staining was nearly absent. Knockdown of ATG5 with siRNA increased OSS-mediated mtO2(&#x2022;-), whereas starvation or rapamycin-induced autophagy reduced OSS-mediated mtO2(&#x2022;-), mitochondrial respiration, and complex II activity.<br><br>INNOVATION: Disturbed flow-mediated oxidative stress and JNK activation induce autophagy.<br><br>CONCLUSION: OSS impairs autophagic flux to interfere with mitochondrial homeostasis. Antioxid. Redox Signal. 23, 1207-1219.}, }
@article {pmid26118633, year = {2015}, author = {Ma, X and Dang, C and Kang, H and Dai, Z and Lin, S and Guan, H and Liu, X and Wang, X and Hui, W}, title = {Saikosaponin-D reduces cisplatin-induced nephrotoxicity by repressing ROS-mediated activation of MAPK and NF-κB signalling pathways.}, journal = {International immunopharmacology}, volume = {28}, number = {1}, pages = {399-408}, doi = {10.1016/j.intimp.2015.06.020}, pmid = {26118633}, issn = {1878-1705}, mesh = {Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Cell Line ; Cell Survival/drug effects ; *Cisplatin ; Cytokines/metabolism ; Humans ; Kidney Diseases/chemically induced/*drug therapy/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; Oleanolic Acid/*analogs &amp; derivatives/pharmacology/therapeutic use ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Saponins/pharmacology/*therapeutic use ; Signal Transduction/drug effects ; }, abstract = {The nephrotoxicity induced by cisplatin (DDP) severely limits the clinical efficacy of this widely used anticancer agent. The observed nephrotoxicity may be the result of DDP-induced inflammation and apoptosis. Saikosaponin-D (SSD), a triterpenoid saponin, has numerous pharmacological properties. The goal of the present study was to investigate whether and how SSD protected against DDP-induced nephrotoxicity. Non-cytotoxic levels of SSD significantly increased the viability rate, improved the nuclear morphology, and attenuated the caspase-3 activation and programmed apoptosis of DDP-treated HK-2 cells. In addition, SSD treatment markedly inhibited the release of tumour necrosis factor (TNF)-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as the production of nitric oxide and the expression of inducible nitric oxide synthase (iNOS) by these cells. More importantly, SSD effectively blocked the DDP-induced activation of NF-κB, P38, JNK, and MAPKs. Furthermore, we found that U0126 (a specific inhibitor of MAPKs) strongly inhibited the IKK/IκB/NF-κB-dependent release of pro-inflammatory cytokines and iNOS gene expression. Finally, we demonstrated that SSD decreased the level of reactive oxygen species (ROS) accumulation and that the specific ROS scavenger N-acetylcysteine (NAC) markedly inhibited the DDP-induced activation of MAPK and phosphorylation of the downstream signal NF-κB, which in turn reduced the levels of pro-inflammatory cytokine release and iNOS gene expression. Our results suggest that the SSD-mediated alleviation of DDP-induced nephrotoxicity was due to uncoupling of the ROS, P38, and JNK/NF-κB signalling pathways.}, }
@article {pmid26116711, year = {2015}, author = {da Silva, ND and Roseguini, BT and Chehuen, M and Fernandes, T and Mota, GF and Martin, PK and Han, SW and Forjaz, CL and Wolosker, N and de Oliveira, EM}, title = {Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {309}, number = {5}, pages = {H897-905}, doi = {10.1152/ajpheart.00158.2015}, pmid = {26116711}, issn = {1522-1539}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Aged ; Antioxidants/administration &amp; dosage/*therapeutic use ; Chemokine CCL2/blood ; Endothelins/blood ; Humans ; Hyperemia/blood/*drug therapy ; Inflammation/blood/drug therapy ; Intermittent Claudication/blood/*drug therapy ; Leg/blood supply ; Male ; MicroRNAs/blood ; Middle Aged ; Nitric Oxide Synthase Type III/blood ; Phosphatidylinositol 3-Kinases/blood ; Vascular Cell Adhesion Molecule-1/blood ; Vascular Endothelial Growth Factor A/blood ; *Walking ; }, abstract = {Increased oxidative stress and inflammation contribute to impaired walking capacity and endothelial dysfunction in patients with intermittent claudication (IC). The goal of the study was to determine the effects of oral treatment with the antioxidant N-acetylcysteine (NAC) on walking capacity, leg postocclusive reactive hyperemia, circulating levels of inflammatory mediators, and whole blood expression of angiogenic mediators in patients with IC. Following a double-blinded randomized crossover design, 10 patients with IC received NAC (1,800 mg/day for 4 days plus 2,700 mg before the experimental session) and placebo (PLA) before undergoing a graded treadmill exercise test. Leg postocclusive reactive hyperemia was assessed before and after the test. Blood samples were taken before and after NAC or PLA ingestions and 5 and 30 min after the exercise test for the analysis of circulating inflammatory and angiogenic markers. Although NAC increased the plasma ratio of reduced to oxidized glutathione, there were no differences between experimental sessions for walking tolerance and postocclusive reactive hyperemia. Plasma concentrations of soluble vascular cell adhesion protein-1, monocyte chemotactic protein-1, and endothelin-1 increased similarly following maximal exercise after PLA and NAC (P < 0.001). Whole blood expression of pro-angiogenic microRNA-126 increased after maximal exercise in the PLA session, but treatment with NAC prevented this response. Similarly, exercise-induced changes in whole blood expression of VEGF, endothelial nitric oxide synthase and phosphatidylinositol 3-kinase R2 were blunted after NAC. In conclusion, oral NAC does not increase walking tolerance or leg blood flow in patients with IC. In addition, oral NAC prevents maximal exercise-induced increase in the expression of circulating microRNA-126 and other angiogenic mediators in patients with IC.}, }
@article {pmid26115910, year = {2015}, author = {Shi, J and Wang, L and Zhang, H and Jie, Q and Li, X and Shi, Q and Huang, Q and Gao, B and Han, Y and Guo, K and Liu, J and Yang, L and Luo, Z}, title = {Glucocorticoids: Dose-related effects on osteoclast formation and function via reactive oxygen species and autophagy.}, journal = {Bone}, volume = {79}, number = {}, pages = {222-232}, doi = {10.1016/j.bone.2015.06.014}, pmid = {26115910}, issn = {1873-2763}, mesh = {Animals ; Autophagy/*drug effects/physiology ; Blotting, Western ; Cell Differentiation ; Cells, Cultured ; Dose-Response Relationship, Drug ; Glucocorticoids/*administration &amp; dosage ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Confocal ; Microscopy, Electron, Transmission ; Osteoclasts/cytology/*drug effects/*metabolism ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; X-Ray Microtomography ; }, abstract = {Whether glucocorticoids directly enhance or interrupt osteoclastogenesis is still a controversial subject. In this study, we ascertained the dose-dependent positive effects of glucocorticoids on osteoclastogenesis in vivo and in vitro as well as investigated the mechanism in vitro. As the dose of glucocorticoids increased, osteoclastogenesis was stimulated at 0.1 μM, a peak was achieved at 1 μM and a corresponding decrease occurred at 10 μM. Reactive oxygen species (ROS), which play a crucial role in osteoclastogenesis, and autophagy flux activity, a cellular recycling process, were consistently up-regulated along with the dose-dependent effects of the glucocorticoids on osteoclast formation and function. N-acetyl-cysteine (NAC), a ROS scavenger, abrogated the effects of the glucocorticoids on autophagy and osteoclastogenesis. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, interrupted osteoclastogenesis stimulation by the glucocorticoids. These results implied that with glucocorticoid administration, ROS and autophagy, as a downstream factor of ROS, played vital roles in osteoclast formation and function. 3-MA administration did not enhance ROS accumulation, so that autophagy had no effect on ROS induced by glucocorticoids. Our investigation demonstrated that glucocorticoids had dose-dependent positive effects on osteoclast formation and function via ROS and autophagy. These results provide support for ROS and autophagy as therapeutic targets in glucocorticoid-related bone loss diseases such as glucocorticoid-induced osteoporosis.}, }
@article {pmid26115783, year = {2015}, author = {Mlejnek, P and Dolezel, P}, title = {Loss of mitochondrial transmembrane potential and glutathione depletion are not sufficient to account for induction of apoptosis by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone in human leukemia K562 cells.}, journal = {Chemico-biological interactions}, volume = {239}, number = {}, pages = {100-110}, doi = {10.1016/j.cbi.2015.06.033}, pmid = {26115783}, issn = {1872-7786}, mesh = {Acetylcysteine/chemistry/pharmacology ; Apoptosis/*drug effects ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/chemistry/*pharmacology ; Glutathione/chemistry/*metabolism ; Humans ; K562 Cells/drug effects/metabolism ; Membrane Potential, Mitochondrial/*drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; }, abstract = {Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), an uncoupler of mitochondrial oxidative phosphorylation, inhibits cell proliferation and induces cell death with apoptotic features. It was reported that the cytotoxic effects of FCCP are preceded by a rapid glutathione (GSH) depletion with a subsequent loss of mitochondrial transmembrane potential (ΔΨ). The GSH depletion was suggested as the cause of apoptosis in FCCP treated cells. This conclusion was further supported by the finding that all adverse effects of FCCP including cell death can be prevented by N-acetylcysteine (NAC) a precursor of GSH synthesis (Han and Park, 2011). Here, we argue that neither loss of ΔΨ nor GSH depletion is sufficient to account for induction of apoptosis in FCCP treated leukemia K562 cells. Indeed, the lowest concentration of FCCP that brings about the permanent loss of ΔΨ and the extensive decrease in GSH level induces cell death in minor population of cells. Only much higher concentrations of FCCP, that exceed the range to achieve permanent collapse of ΔΨ, induce extensive apoptosis. The low proapoptotic activity of FCCP could be explained by hyperactivation of protein kinase B/Akt. A detailed LC/MS/MS analysis of cell extracts revealed extensive formation of FCCP adducts with GSH. This effect could explain the mechanism of GSH depletion, which is currently unknown. Although NAC induces an increase in the GSH pool, this effect is not crucial for abrogation of FCCP cytotoxicity. Indeed, the presence of NAC in the growth medium causes a rapid clearance of FCCP due to its quantitative conversion into the FCCP-NAC adduct, which is the real cause of abrogated FCCP cytotoxicity.}, }
@article {pmid26114584, year = {2015}, author = {Hrabe, JE and O'Leary, BR and Fath, MA and Rodman, SN and Button, AM and Domann, FE and Spitz, DR and Mezhir, JJ}, title = {Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor β-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells.}, journal = {Redox biology}, volume = {5}, number = {}, pages = {319-327}, pmid = {26114584}, issn = {2213-2317}, support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; R01CA115438/CA/NCI NIH HHS/United States ; R01CA182804/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; R21CA161182/CA/NCI NIH HHS/United States ; R01 CA182804/CA/NCI NIH HHS/United States ; NIHP30CA086862/CA/NCI NIH HHS/United States ; T32CA148062/CA/NCI NIH HHS/United States ; T32 CA148062/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/chemistry/therapeutic use/toxicity ; Auranofin/chemistry/therapeutic use/toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; Colonic Neoplasms/drug therapy/metabolism/pathology ; Female ; Glutathione/metabolism ; HCT116 Cells ; Humans ; MAP Kinase Kinase Kinases/antagonists &amp; inhibitors/*metabolism ; Mice ; Mice, Nude ; Mutation ; Oxidative Stress/drug effects ; Thioredoxin-Disulfide Reductase/antagonists &amp; inhibitors/metabolism ; Thioredoxins/*metabolism ; Transplantation, Heterologous ; Zearalenone/analogs &amp; derivatives/chemistry/therapeutic use/toxicity ; ras Proteins/*genetics/metabolism ; }, abstract = {Transforming growth factor β-activated kinase 1 (TAK1) is critical for survival of many KRAS mutated colorectal cancer cells, and TAK1 inhibition with 5Z-7-oxozeaenol has been associated with oxidative stress leading to tumor cell killing. When SW 620 and HCT 116 human colon cancer cells were treated with 5µM 5Z-7-oxozeaenol, cell viability, growth, and clonogenic survival were significantly decreased. Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress, 10mM N-acetylcysteine (NAC) partially reversed the growth inhibitory effects of 5Z-7-oxozeaenol. In addition, 5Z-7-oxozeaenol also increased steady-state levels of H2DCFDA oxidation as well as increased levels of total glutathione (GSH) and glutathione disulfide (GSSG). Interestingly, depletion of GSH using buthionine sulfoximine did not significantly potentiate 5Z-7-oxozeaenol toxicity in either cell line. In contrast, pre-treatment of cells with auranofin (Au) to inhibit thioredoxin reductase activity significantly increased levels of oxidized thioredoxin as well as sensitized cells to 5Z-7-oxozeaenol-induced growth inhibition and clonogenic cell killing. These results were confirmed in SW 620 murine xenografts, where treatment with 5Z-7-oxozeaenol or with Au plus 5Z-7-oxozeaenol significantly inhibited growth, with Au plus 5Z-7-oxozeaenol trending toward greater growth inhibition compared to 5Z-7-oxozeaenol alone. These results support the hypothesis that thiol-mediated oxidative stress is causally related to TAK1-induced colon cancer cell killing. In addition, these results support the hypothesis that thioredoxin metabolism is a critical target for enhancing colon cancer cell killing via TAK1 inhibition and could represent an effective therapeutic strategy in patients with these highly resistant tumors.}, }
@article {pmid26114497, year = {2015}, author = {Nishikawa, T and Miyahara, E and Kurauchi, K and Watanabe, E and Ikawa, K and Asaba, K and Tanabe, T and Okamoto, Y and Kawano, Y}, title = {Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention.}, journal = {PloS one}, volume = {10}, number = {6}, pages = {e0131394}, pmid = {26114497}, issn = {1932-6203}, mesh = {Animals ; Apoptosis/*drug effects ; *Cardiotoxins/administration &amp; dosage/pharmacokinetics/pharmacology ; Cell Line ; *Cyclophosphamide/adverse effects/pharmacokinetics/pharmacology ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Myocytes, Cardiac/*metabolism/pathology ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {Observed only after administration of high doses, cardiotoxicity is the dose-limiting effect of cyclophosphamide (CY). We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2-thiazolyl)¬2,5-diphenyl¬2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and CYP inhibitor β-ionone (BIO). Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125-500 μM) did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 μM or more. After 250 μM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 ± 8.0 μM, 4-hydroxy-cyclophosphamide (HCY) 17.6 ± 4.3, o-carboxyethyl-phosphoramide (CEPM) 26.6 ± 5.3 μM, and acrolein 26.7 ± 2.5 μM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity.}, }
@article {pmid26111556, year = {2015}, author = {Ware, KM and Feinstein, DL and Rubinstein, I and Weinberg, G and Rovin, BH and Hebert, L and Muni, N and Cianciolo, RE and Satoskar, AA and Nadasdy, T and Brodsky, SV}, title = {Brodifacoum induces early hemoglobinuria and late hematuria in rats: novel rapid biomarkers of poisoning.}, journal = {American journal of nephrology}, volume = {41}, number = {4-5}, pages = {392-399}, pmid = {26111556}, issn = {1421-9670}, support = {U01 NS083457/NS/NINDS NIH HHS/United States ; }, mesh = {4-Hydroxycoumarins/*poisoning ; Acetylcysteine/pharmacology ; Animals ; Biomarkers/urine ; Disease Progression ; Free Radical Scavengers/pharmacology ; Hematuria/*chemically induced ; Hemoglobins/drug effects ; Hemoglobinuria/*chemically induced ; Rats ; Rats, Sprague-Dawley ; Rodenticides/*poisoning ; }, abstract = {INTRODUCTION: Brodifacoum (BDF) is a superwarfarin that is used primarily as a rodenticide. There have been increasing numbers of reports of human cases of accidental or intentional BDF ingestion with high mortality rate. Its broad availability and high lethality suggest that BDF should be considered a potential chemical threat. Currently, there is no biomarker for early detection of BDF ingestion in humans; patients typically present with severe coagulopathy. Since we demonstrated earlier that warfarin can induce acute kidney injury with hematuria, we tested whether BDF would also lead to change in urinary biomarkers.<br><br>MATERIAL AND METHODS: BDF was administered to Sprague Dawley rats via oral gavage. N-acetylcysteine (NAC) was given per os in drinking water 24 h prior to BDF. Urinalysis was performed at different times after BDF administration. Anticoagulation and serum creatinine levels were analyzed in the blood.<br><br>RESULTS: We observed that within a few hours the animals developed BDF-dose-dependent transient hemoglobinuria, which ceased within 24 h. This was accompanied by a transient decrease in hematocrit, gross hemolysis and an increase in free hemoglobin in the serum. At later times, animals developed true hematuria with red blood cells in the urine, which was associated with BDF anticoagulation. NAC prevented early hemoglobinuria, but not late hematuria associated with BDF.<br><br>CONCLUSIONS: We propose that transient early hemoglobinuria (associated with oxidative stress) with consecutive late hematuria (associated with anticoagulation) are novel biomarkers of BDF poisoning, and they can be used in clinical setting or in mass casualty with BDF to identify poisoned patients.}, }
@article {pmid26109726, year = {2015}, author = {Shigemura, T and Shiohara, M and Kato, M and Furuta, S and Kaneda, K and Morishita, K and Hasegawa, H and Fujii, M and Gorlach, A and Koike, K and Kamata, T}, title = {Superoxide-Generating Nox5α Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype.}, journal = {Journal of virology}, volume = {89}, number = {17}, pages = {9080-9089}, pmid = {26109726}, issn = {1098-5514}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Transformed ; Cell Movement/genetics ; Cell Proliferation/drug effects/genetics ; Cell Survival/genetics ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Viral/*genetics ; Human T-lymphotropic virus 1/*metabolism ; Humans ; Interleukin-2/metabolism ; Janus Kinases/metabolism ; Leukemia-Lymphoma, Adult T-Cell/*pathology/virology ; Membrane Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; NADPH Oxidase 5 ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/*metabolism ; Onium Compounds/pharmacology ; RNA Interference ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; STAT5 Transcription Factor/metabolism ; Tumor Suppressor Proteins/metabolism ; Up-Regulation ; }, abstract = {UNLABELLED: Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and transforms T cells in vitro. To our knowledge, the functional role of reactive oxygen species (ROS)-generating NADPH oxidase 5 (Nox5) in HTLV-1 transformation remains undefined. Here, we found that Nox5α expression was upregulated in 88% of 17 ATL patient samples but not in normal peripheral blood T cells. Upregulation of the Nox5α variant was transcriptionally sustained by the constitutive Janus family tyrosine kinase (Jak)-STAT5 signaling pathway in interleukin-2 (IL-2)-independent HTLV-1-transformed cell lines, including MT1 and MT2, whereas it was transiently induced by the IL-2-triggered Jak-STAT5 axis in uninfected T cells. A Nox inhibitor, diphenylene iodonium, and antioxidants such as N-acetyl cysteine blocked proliferation of MT1 and MT2 cells. Ablation of Nox5α by small interfering RNAs abrogated ROS production, inhibited cellular activities, including proliferation, migration, and survival, and suppressed tumorigenicity in immunodeficient NOG mice. The findings suggest that Nox5α is a key molecule for redox-signal-mediated maintenance of the HTLV-1 transformation phenotype and could be a potential molecular target for therapeutic intervention in cancer development.<br><br>IMPORTANCE: HTLV-1 is the first human oncogenic retrovirus shown to be associated with ATL. Despite the extensive study over the years, the mechanism underlying HTLV-1-induced cell transformation is not fully understood. In this study, we addressed the expression and function of ROS-generating Nox family genes in HTLV-1-transformed cells. Our report provides the first evidence that the upregulated expression of Nox5&#x3b1; is associated with the pathological state of ATL peripheral blood mononuclear cells and that Nox5&#x3b1; is an integral component of the Jak-STAT5 signaling pathway in HTLV-1-transformed T cells. Nox5&#x3b1;-derived ROS are critically involved in the regulation of cellular activities, including proliferation, migration, survival, and tumorigenicity, in HTLV-1-transformed cells. These results indicate that Nox5&#x3b1;-derived ROS are functionally required for maintenance of the HTLV-1 transformation phenotype. The finding provides new insight into the redox-dependent mechanism of HTLV-1 transformation and raises an intriguing possibility that Nox5&#x3b1; serves as a potential molecular target to treat HTLV-1-related leukemia.}, }
@article {pmid26105008, year = {2015}, author = {Trewin, AJ and Lundell, LS and Perry, BD and Patil, KV and Chibalin, AV and Levinger, I and McQuade, LR and Stepto, NK}, title = {Effect of N-acetylcysteine infusion on exercise-induced modulation of insulin sensitivity and signaling pathways in human skeletal muscle.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {309}, number = {4}, pages = {E388-97}, doi = {10.1152/ajpendo.00605.2014}, pmid = {26105008}, issn = {1522-1555}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Cross-Over Studies ; Double-Blind Method ; Exercise/*physiology ; Exercise Test ; Female ; Glucose Clamp Technique ; Humans ; Infusions, Intravenous ; Insulin/*metabolism ; *Insulin Resistance ; Male ; Muscle Contraction/drug effects ; Muscle, Skeletal/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Young Adult ; }, abstract = {-Reactive oxygen species (ROS) produced in skeletal muscle may play a role in potentiating the beneficial responses to exercise; however, the effects of exercise-induced ROS on insulin action and protein signaling in humans has not been fully elucidated. Seven healthy, recreationally active participants volunteered for this double-blind, randomized, repeated-measures crossover study. Exercise was undertaken with infusion of saline (CON) or the antioxidant N-acetylcysteine (NAC) to attenuate ROS. Participants performed two 1-h cycling exercise sessions 7-14 days apart, 55 min at 65% V̇o2peak plus 5 min at 85%V̇o2peak, followed 3 h later by a 2-h hyperinsulinemic euglycemic clamp (40 mIU·min(-1)·m(2)) to determine insulin sensitivity. Four muscle biopsies were taken on each trial day, at baseline before NAC infusion (BASE), after exercise (EX), after 3-h recovery (REC), and post-insulin clamp (PI). Exercise, ROS, and insulin action on protein phosphorylation were evaluated with immunoblotting. NAC tended to decrease postexercise markers of the ROS/protein carbonylation ratio by -13.5% (P = 0.08) and increase the GSH/GSSG ratio twofold vs. CON (P < 0.05). Insulin sensitivity was reduced (-5.9%, P < 0.05) by NAC compared with CON without decreased phosphorylation of Akt or AS160. Whereas p-mTOR was not significantly decreased by NAC after EX or REC, phosphorylation of the downstream protein synthesis target kinase p70S6K was blunted by 48% at PI with NAC compared with CON (P < 0.05). We conclude that NAC infusion attenuated muscle ROS and postexercise insulin sensitivity independent of Akt signaling. ROS also played a role in normal p70S6K phosphorylation in response to insulin stimulation in human skeletal muscle.}, }
@article {pmid26104799, year = {2015}, author = {Yu, F and Gong, P and Hu, Z and Qiu, Y and Cui, Y and Gao, X and Chen, H and Li, J}, title = {Cu(II) enhances the effect of Alzheimer's amyloid-β peptide on microglial activation.}, journal = {Journal of neuroinflammation}, volume = {12}, number = {}, pages = {122}, pmid = {26104799}, issn = {1742-2094}, mesh = {Alzheimer Disease/*metabolism ; Amyloid beta-Peptides/*pharmacology ; Animals ; Cell Line ; Copper/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Macrophage Activation/drug effects ; Mice ; Microglia/*drug effects ; NADPH Oxidases/antagonists &amp; inhibitors ; NF-kappa B/antagonists &amp; inhibitors ; Neurons/drug effects ; Nitric Oxide/metabolism ; Superoxides/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND: Aggregated forms of amyloid-β (Aβ) peptides are important triggers for microglial activation, which is an important pathological component in the brains of Alzheimer's patients. Cu(II) ions are reported to be coordinated to monomeric Aβ, drive Aβ aggregation, and potentiate Aβ neurotoxicity. Here we investigated whether Cu(II) binding modulates the effect of Aβ on microglial activation and the subsequent neurotoxicity.<br><br>METHODS: A&#x3b2; peptides were incubated with Cu(II) at an equimolar ratio to obtain the Cu(II)-A&#x3b2; complex. Primary and BV-2 microglial cells were treated with Cu(II)-A&#x3b2;, A&#x3b2;, or Cu(II). The tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) and nitric oxide levels in the media were determined. Extracellular hydrogen peroxide was quantified by a fluorometric assay with Amplex Red. Mitochondrial superoxide was detected by MitoSOX oxidation.<br><br>RESULTS: Incubation of Cu(II) with A&#x3b2; confers different chemical properties on the resulting complex. At the subneurotoxic concentrations, Cu(II)-A&#x3b2; (but not A&#x3b2; or Cu(II) alone) treatment induced an activating morphological phenotype of microglia and induced the microglial release of TNF-&#x3b1; and nitric oxide as well as microglia-mediated neuronal damage. Cu(II)-A&#x3b2;-triggered microglial activation was blocked by nuclear factor (NF)-&#x3ba;B inhibitors and was accompanied with NF-&#x3ba;B activation. Moreover, Cu(II)-A&#x3b2; induced hydrogen peroxide release, which was not affected by NADPH oxidase inhibitors. Mitochondrial superoxide production was increased after Cu(II)-A&#x3b2; stimulation. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), inhibited Cu(II)-A&#x3b2;-elicited microglial release of TNF-&#x3b1; and nitric oxide as well as the microglia-mediated neurotoxic effect.<br><br>CONCLUSION: Our observations suggest that Cu(II) enhances the effect of A&#x3b2; on microglial activation and the subsequent neurotoxicity. The Cu(II)-A&#x3b2;-triggered microglial activation involves NF-&#x3ba;B activation and mitochondrial ROS production.}, }
@article {pmid26100161, year = {2015}, author = {Günther, M and Davidsson, J and Plantman, S and Norgren, S and Mathiesen, T and Risling, M}, title = {Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {22}, number = {9}, pages = {1477-1483}, doi = {10.1016/j.jocn.2015.03.025}, pmid = {26100161}, issn = {1532-2653}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Apoptosis/*drug effects ; Brain/drug effects/physiopathology ; Brain Injuries/*pathology ; Head Injuries, Penetrating/pathology ; In Situ Nick-End Labeling ; Male ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {We examined the effects of N-acetylcysteine amide (NACA) in the secondary inflammatory response following a novel method of focal penetrating traumatic brain injury (TBI) in rats. N-acetylcysteine (NAC) has limited but well-documented neuroprotective effects after experimental central nervous system ischemia and TBI, but its bioavailability is very low. We tested NACA, a modified form of NAC with higher membrane and blood-brain barrier permeability. Focal penetrating TBI was produced in male Sprague-Dawley rats randomly selected for NACA treatment (n=5) and no treatment (n=5). In addition, four animals were submitted to sham surgery. After 2 hours or 24 hours the brains were removed, fresh frozen, cut in 14 μm coronal sections and subjected to immunohistochemistry, immunofluorescence, Fluoro-Jade and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses. All treated animals were given 300 mg/kg NACA intraperitoneally (IP) 2 minutes post trauma. The 24 hour survival group was given an additional bolus of 300 mg/kg IP after 4 hours. NACA treatment decreased neuronal degeneration by Fluoro-Jade at 24 hours with a mean change of 35.0% (p<0.05) and decreased TUNEL staining indicative of apoptosis at 2 hours with a mean change of 38.7% (p<0.05). Manganese superoxide dismutase (MnSOD) increased in the NACA treatment group at 24 hours with a mean change of 35.9% (p<0.05). Levels of migrating macrophages and activated microglia (Ox-42/CD11b), nitric oxide-producing inflammatory enzyme iNOS, peroxynitrite marker 3-nitrotyrosine, NFκB translocated to the nuclei, cytochrome C and Bcl-2 were not affected. NACA treatment decreased neuronal degeneration and apoptosis and increased levels of antioxidative enzyme MnSOD. The antiapoptotic effect was likely regulated by pathways other than cytochrome C. Therefore, NACA prevents brain tissue damage after focal penetrating TBI, warranting further studies towards a clinical application.}, }
@article {pmid26093296, year = {2015}, author = {Bai, D and Ge, L and Gao, Y and Lu, X and Wang, H and Yang, G}, title = {Cytoplasmic translocation of HuR contributes to angiotensin II induced cardiac fibrosis.}, journal = {Biochemical and biophysical research communications}, volume = {463}, number = {4}, pages = {1273-1277}, doi = {10.1016/j.bbrc.2015.06.101}, pmid = {26093296}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/*pharmacology ; Animals ; Collagen/biosynthesis ; Cytoplasm/*metabolism ; Dose-Response Relationship, Drug ; ELAV Proteins/*metabolism ; Heart Diseases/*chemically induced/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Protein Transport ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta/metabolism ; }, abstract = {Cardiac fibrosis is one of the key structural changes of the hypertrophied left ventricle in hypertensive heart disease. Increased angiotensin II was found to be important in the hypertension related fibrosis, while the underlying mechanism is unknown. In this study, we found that angiotensin II dose-dependently increased the expression of Col1a1, Col3a1 and α-smooth muscle actin, which were blocked by ROS (reactive oxygen species) scavenger N-acetyl cysteine (NAC). Mechanistically, angiotensin II induced robust ROS generation, which in turn induced cytoplasmic translocation of RNA binding protein HuR. Cytoplasmic translocated HuR increased TGFβ pathway activity and subsequent collagen synthesis. In contrast, knockdown of HuR nearly blocked angiotensin II induced TGFβ activation and collagen synthesis. Taken together, we here identified that angiotensin II promotes collagen synthesis in cardiac fibroblast through ROS-HuR-TGFβ pathway.}, }
@article {pmid26091937, year = {2015}, author = {Singh, S and Murad, MH and Chandar, AK and Bongiorno, CM and Singal, AK and Atkinson, SR and Thursz, MR and Loomba, R and Shah, VH}, title = {Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis.}, journal = {Gastroenterology}, volume = {149}, number = {4}, pages = {958-70.e12}, doi = {10.1053/j.gastro.2015.06.006}, pmid = {26091937}, issn = {1528-0012}, support = {08/14/44/DH_/Department of Health/United Kingdom ; K23 DK090303/DK/NIDDK NIH HHS/United States ; MR/M003132/1/MRC_/Medical Research Council/United Kingdom ; U01AA021788/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adrenal Cortex Hormones/adverse effects/*therapeutic use ; Comparative Effectiveness Research ; Disease Progression ; Drug Therapy, Combination ; Free Radical Scavengers/adverse effects/*therapeutic use ; Hepatitis, Alcoholic/complications/diagnosis/*drug therapy/mortality ; Humans ; Pentoxifylline/adverse effects/*therapeutic use ; Risk Factors ; Severity of Illness Index ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND &amp; AIMS: Severe alcoholic hepatitis (AH) has high mortality. We assessed the comparative effectiveness of pharmacological interventions for severe AH, through a network meta-analysis combining direct and indirect treatment comparisons.<br><br>METHODS: We conducted a systematic literature review, through February 2015, for randomized controlled trials of adults with severe AH (discriminant function &#x2265;32 and/or hepatic encephalopathy) that compared the efficacy of active pharmacologic interventions (corticosteroids, pentoxifylline, and N-acetylcysteine [NAC], alone or in combination) with each other or placebo, in reducing short-term mortality (primary outcome) and medium-term mortality, acute kidney injury, and/or infections (secondary outcomes). We performed direct and Bayesian network meta-analysis for all treatments, and used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence.<br><br>RESULTS: We included 22 randomized controlled trials (2621 patients) comparing 5 different interventions. In a direct meta-analysis, only corticosteroids decreased risk of short-term mortality. In a network meta-analysis, moderate quality evidence supported the use of corticosteroids alone (relative risk [RR], 0.54; 95% credible interval [CrI], 0.39-0.73) or in combination with pentoxifylline (RR, 0.53; 95% CrI, 0.36-0.78) or NAC (RR, 0.15; 95% CI, 0.05-0.39), to reduce short-term mortality; low quality evidence showed that pentoxifylline also decreased short-term mortality (RR, 0.70; 95% CrI, 0.50-0.97). The addition of NAC, but not pentoxifylline, to corticosteroids may be superior to corticosteroids alone for reducing short-term mortality. No treatment was effective in reducing medium-term mortality. Imprecise estimates and the small number of direct trials lowered the confidence in several comparisons.<br><br>CONCLUSIONS: In patients with severe AH, pentoxifylline and corticosteroids (alone and in combination with pentoxifylline or NAC) can reduce short-term mortality. No treatment decreases risk of medium-term mortality.}, }
@article {pmid26091056, year = {2015}, author = {Yilmaz, B and Türkçü, G and Şengül, E and Gül, A and Özkurt, FE and Akdağ, M}, title = {Efficacy of N-Acetylcysteine on Wound Healing of Nasal Mucosa.}, journal = {The Journal of craniofacial surgery}, volume = {26}, number = {5}, pages = {e422-6}, doi = {10.1097/SCS.0000000000001880}, pmid = {26091056}, issn = {1536-3732}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage/*therapeutic use ; Antioxidants/administration &amp; dosage/therapeutic use ; Epithelium/injuries/pathology ; Goblet Cells/drug effects/pathology ; Injections, Intraperitoneal ; Male ; Nasal Cavity/drug effects/injuries/pathology ; Nasal Mucosa/drug effects/*injuries/pathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Rhinitis/pathology ; Time Factors ; Wound Healing/drug effects ; }, abstract = {Postoperative nasal mucosa healing is a highly complex and organized process, and the success rates of endoscopic sinus surgery and septoplasty surgeries are closely associated with the postoperative wound healing processes. In this experimental study, the authors' aim was to use histopathologic examination to investigate the effects of N-Acetylcysteine (NAC) on the wound healing of rat nasal mucosa after mechanical trauma. Twenty-one Sprague-Dawley rats were randomly divided into 3 groups: the nontreated group (N = 7), the control saline group (N = 7), and the NAC group (N = 7). No treatment was given to the nontreated group for 15 days. The control saline group received intraperitoneal injection of saline (2.5 mL/kg, intraperitoneal) for 15 days and the NAC group was intraperitoneally injected with NAC at a dose of 300 mg/kg/day for 15 days. At the beginning of the study, unilateral mechanical nasal trauma was induced with an interdental brush inserted through the right nostril in all rats. Samples were stained using hematoxylin and eosin solution, and were examined by a pathologist using a light microscope. The severity of inflammation was milder in the NAC group compared with that in the nontreated and saline groups (P < 0.05). The subepithelial thickness index was lower in the experimental group (P < 0.05). Goblet cell loss was reduced in the experimental group compared with the nontreated and saline groups (P < 0.05). NAC decreases inflammation and goblet cell loss. Therefore, NAC has potential beneficial effects on the wound healing of nasal mucosa in rats.}, }
@article {pmid26089925, year = {2015}, author = {Khaledifar, A and Mobasheri, M and Kheiri, S and Zamani, Z}, title = {Comparison of N-acetylcysteine and angiotensin converting enzyme inhibitors in blood pressure regulation in hypertensive patients.}, journal = {ARYA atherosclerosis}, volume = {11}, number = {1}, pages = {5-13}, pmid = {26089925}, issn = {1735-3955}, abstract = {BACKGROUND: Hypertension (HTN) is the most prevalent non-infectious disease worldwide and can lead to mortality. This trial aimed to compare the effect of N-acetylcysteine (NAC) and angiotensin-converting enzyme inhibitors (ACEIs) on controlling blood pressure in hypertensive patients.<br><br>METHODS: This cross-sectional clinical trial was conducted in Hajar Hospital, Shahrekord, Iran, in 2009. A sample of 126 patients with HTN was selected and randomly divided into 2 groups (group A and group B). First, group A was treated with ACEI alone and group B with ACEI + NAC for 2 months. Blood pressure of all patients was evaluated each week. After a 2 week period of washout, the drugs were changed. In the second period of the trial, group A was treated with ACEI + NAC and group B with NAC alone and their blood pressure was evaluated in the same manner as the previous period. The data were analyzed using SPSS.<br><br>RESULTS: A significant reduction was observed in systolic and diastolic blood pressure of patients (P < 0.050). However, during both periods of the trial, the group receiving NAC + ACEI experienced a more significant reduction in blood pressure compared with the ACEI group (P < 0.050).<br><br>CONCLUSION: NAC accompanied with ACEI decreased the patients' systolic and diastolic blood pressure significantly; however, ACEI alone did not have any significant effects on blood pressure. Systolic blood pressure decreased 7 mmHg on average and fluctuated during the trial.}, }
@article {pmid26088922, year = {2015}, author = {Zhu, Y and Paul, P and Lee, S and Craig, BT and Rellinger, EJ and Qiao, J and Gius, DR and Chung, DH}, title = {Antioxidant inhibition of steady-state reactive oxygen species and cell growth in neuroblastoma.}, journal = {Surgery}, volume = {158}, number = {3}, pages = {827-836}, pmid = {26088922}, issn = {1532-7361}, support = {T32 CA106183/CA/NCI NIH HHS/United States ; R01 DK61470/DK/NIDDK NIH HHS/United States ; R01 DK061470/DK/NIDDK NIH HHS/United States ; R01 CA152601/CA/NCI NIH HHS/United States ; R01 CA168292/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Biomarkers, Tumor/*metabolism ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Humans ; Immunohistochemistry ; Neuroblastoma/*metabolism ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND: Reactive oxygen species (ROS) contribute to adult tumorigenesis; however, their roles in pediatric solid tumors are unknown. Here, we sought to define the steady-state ROS levels in neuroblastoma and to examine whether aggressive cellular behavior, which may predict treatment failure, is regulated by ROS.<br><br>METHODS: Neuroblastoma sections were assessed for 4-hydroxynonenal (4-HNE), a marker of intracellular lipid peroxidation and a byproduct of increased levels of ROS. Human neuroblastoma cell lines, MYCN-amplified BE(2)-C and MYCN-nonamplified SK-N-SH, were examined in our study. Superoxide and hydroperoxide oxidation products were detected by staining for dihydroethidium (DHE) and 5, 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate (CDCFH2), using the oxidation-insensitive analog CDCF as a negative control. Cells were treated with N-acetylcysteine (NAC; 10&#xa0;mmol/L) daily for 5&#xa0;days and analyzed.<br><br>RESULTS: Greater expression of 4-HNE was observed in undifferentiated tumor sections as compared with the more differentiated tumors. Interestingly, increased levels of ROS were detected in MYCN-amplified BE(2)-C cells. Moreover, gastrin-releasing peptide receptor-induced ROS production stimulated upregulation of the hypoxia inducible factor (HIF)-1&#x3b1;/vascular endothelial growth factor (VEGF) pathway and an increase in cell growth. Antioxidant NAC decreased HIF-1&#x3b1;/VEGF expression and inhibited BE(2)-C cell growth.<br><br>CONCLUSION: We report a novel observation that shifting the redox balance toward greater ROS levels results in a more aggressive neuroblastoma phenotype. Our data suggest that ROS play a critical role in refractory neuroblastoma.}, }
@article {pmid26085187, year = {2015}, author = {Phaelante, A and Rohde, LE and Lopes, A and Olsen, V and Tobar, SA and Cohen, C and Martinelli, N and Biolo, A and Dal-Pizzol, F and Clausell, N and Andrades, M}, title = {N-acetylcysteine Plus Deferoxamine Improves Cardiac Function in Wistar Rats After Non-reperfused Acute Myocardial Infarction.}, journal = {Journal of cardiovascular translational research}, volume = {8}, number = {5}, pages = {328-337}, pmid = {26085187}, issn = {1937-5395}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aldehydes ; Animals ; Antioxidants/*administration &amp; dosage ; Deferoxamine/*administration &amp; dosage ; Echocardiography ; Immunohistochemistry ; Iron/blood ; Iron Chelating Agents/*administration &amp; dosage ; Male ; Myocardial Infarction/*drug therapy/pathology/physiopathology ; Myocardium/pathology ; Oxidative Stress/physiology ; Random Allocation ; Rats ; Rats, Wistar ; Stroke Volume/physiology ; Sulfhydryl Compounds/blood ; Troponin I/blood ; Ventricular Function/*drug effects ; }, abstract = {The antioxidant N-acetycysteine can turn into a prooxidant molecule in presence of iron ions. Thus, our goal was to test if the association of N-acetylcysteine (NAC) and an iron chelator (deferoxamine--DFX) in a rodent model of acute myocardial infarction (AMI) improves cardiac function. Male Wistar rats were subjected to a SHAM surgery or AMI. The animals were randomized: vehicle, NAC (25 mg/kg for 28 days), DFX (40 mg/kg for 7 days), or NAC plus DFX (NAC plus DFX, respectively). Animals were killed 28 days after the AMI. Animals treated with NAC/DFX showed an increase in left ventricular ejection fraction at 28 days when compared with vehicle group (45.2 ± 10.9 % vs. 34.7 ± 8.7 %, p = 0.03). Antioxidant effect of NAC/DFX treatment decreased 4-hydroxynonenal when compared to AMI group (p = 0.06). In conclusion, we showed beneficial effect of NAC/DFX association in improving left ventricle function in an experimental AMI.}, }
@article {pmid26083398, year = {2015}, author = {Paul, M and Hemshekhar, M and Thushara, RM and Sundaram, MS and NaveenKumar, SK and Naveen, S and Devaraja, S and Somyajit, K and West, R and Basappa,  and Nayaka, SC and Zakai, UI and Nagaraju, G and Rangappa, KS and Kemparaju, K and Girish, KS}, title = {Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviation by N-Acetylcysteine and N-Acetylcysteine Amide.}, journal = {PloS one}, volume = {10}, number = {6}, pages = {e0127558}, pmid = {26083398}, issn = {1932-6203}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacology ; Antimetabolites, Antineoplastic/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; BH3 Interacting Domain Death Agonist Protein/genetics/metabolism ; Blood Platelets/cytology/drug effects/metabolism ; Gene Expression Regulation ; Humans ; MAP Kinase Kinase 4/*genetics/metabolism ; Membrane Potential, Mitochondrial ; Methotrexate/antagonists &amp; inhibitors/*pharmacology ; Mitochondria/drug effects/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Phosphorylation ; Primary Cell Culture ; Signal Transduction ; bcl-2-Associated X Protein/genetics/metabolism ; bcl-Associated Death Protein/genetics/metabolism ; }, abstract = {Thrombocytopenia in methotrexate (MTX)-treated cancer and rheumatoid arthritis (RA) patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 μM) induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading to ΔΨm dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC) and its derivative N-acetylcysteine amide (NACA) proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions.}, }
@article {pmid26081590, year = {2015}, author = {Gu, S and Yang, XC and Xiang, XY and Wu, Y and Zhang, Y and Yan, XY and Xue, YN and Sun, LK and Shao, GG}, title = {Sanguinarine-induced apoptosis in lung adenocarcinoma cells is dependent on reactive oxygen species production and endoplasmic reticulum stress.}, journal = {Oncology reports}, volume = {34}, number = {2}, pages = {913-919}, doi = {10.3892/or.2015.4054}, pmid = {26081590}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/drug therapy/*metabolism ; Adenocarcinoma of Lung ; Apoptosis ; Benzophenanthridines/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Chaperone BiP ; *Endoplasmic Reticulum Stress/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Isoquinolines/*pharmacology ; Lung Neoplasms/drug therapy/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Sanguinarine (SAN), an alkaloid isolated from plants of the Papaveraceae family, is a compound with multiple biological activities. In the present study, we explored the anticancer properties of SAN in lung cancer using the human lung adenocarcinoma cell line SPC-A1. Our results revealed that SAN inhibited SPC-A1 cell growth and induced apoptosis in a dose-dependent manner. We found that SAN triggered reactive oxygen species (ROS) production, while elimination of ROS by N-acetylcysteine (NAC) reversed the growth inhibition and apoptosis induced by SAN. SAN-induced endoplasmic reticulum (ER) stress resulted in the upregulation of many genes and proteins involved in the unfolded protein response (UPR) pathway, including glucose-regulated protein 78 (GRP78), p-protein kinase R (PKR)-like ER kinase (PERK), p-eukaryotic translation initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4) and CCAAT/enhancer binding protein homologous protein (CHOP). Blocking ER stress with tauroursodeoxycholic acid (TUDCA) markedly reduced SAN-induced inhibition of growth and apoptosis. Furthermore, TUDCA decreased SAN-induced ROS production, and NAC attenuated SAN-induced GRP78 and CHOP expression. Overall, our data indicate that the anticancer effects of SAN in lung cancer cells depend on ROS production and ER stress and that SAN may be a potential agent against lung cancer.}, }
@article {pmid26081152, year = {2016}, author = {Pavlin, M and Repič, M and Vianello, R and Mavri, J}, title = {The Chemistry of Neurodegeneration: Kinetic Data and Their Implications.}, journal = {Molecular neurobiology}, volume = {53}, number = {5}, pages = {3400-3415}, pmid = {26081152}, issn = {1559-1182}, mesh = {Animals ; Free Radicals/metabolism ; Glutamic Acid/metabolism ; Humans ; Inflammation/pathology ; Kinetics ; Nerve Degeneration/*metabolism ; Polyamines/metabolism ; }, abstract = {We collected experimental kinetic rate constants for chemical processes responsible for the development and progress of neurodegeneration, focused on the enzymatic and non-enzymatic degradation of amine neurotransmitters and their reactive and neurotoxic metabolites. A gross scheme of neurodegeneration on the molecular level is based on two pathways. Firstly, reactive species oxidise heavy atom ions, which enhances the interaction with alpha-synuclein, thus promoting its folding to the beta form and giving rise to insoluble amyloid plaques. The latter prevents the function of vesicular transport leading to gradual neuronal death. In the second pathway, radical species, OH(·) in particular, react with the methylene groups of the apolar part of the lipid bilayer of either the cell or mitochondrial wall, resulting in membrane leakage followed by dyshomeostasis, loss of resting potential and neuron death. Unlike all other central neural system (CNS)-relevant biogenic amines, dopamine and noradrenaline are capable of a non-enzymatic auto-oxidative reaction, which produces hydrogen peroxide. This reaction is not limited to the mitochondrial membrane where scavenging enzymes, such as catalase, are located. On the other hand, dopamine and its metabolites, such as dopamine-o-quinone, dopaminechrome, 5,6-dihydroxyindole and indo-5,6-quinone, also interact directly with alpha-synuclein and reversibly inhibit plaque formation. We consider the role of the heavy metal ions, selected scavengers and scavenging enzymes, and discuss the relevance of certain foods and food supplements, including curcumin, garlic, N-acetyl cysteine, caffeine and red wine, as well as the long-term administration of non-steroid anti-inflammatory drugs and occasional tobacco smoking, that could all act toward preventing neurodegeneration. The current analysis can be employed in developing strategies for the prevention and treatment of neurodegeneration, and, hopefully, aid in the building of an overall kinetic molecular model of neurodegeneration itself.}, }
@article {pmid26079211, year = {2015}, author = {Mitra, S and Siddiqui, WA and Khandelwal, S}, title = {C-Phycocyanin protects against acute tributyltin chloride neurotoxicity by modulating glial cell activity along with its anti-oxidant and anti-inflammatory property: A comparative efficacy evaluation with N-acetyl cysteine in adult rat brain.}, journal = {Chemico-biological interactions}, volume = {238}, number = {}, pages = {138-150}, doi = {10.1016/j.cbi.2015.06.016}, pmid = {26079211}, issn = {1872-7786}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Blood-Brain Barrier/drug effects/metabolism ; Glutathione/metabolism ; Male ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Oxidoreductases/metabolism ; Permeability/drug effects ; Phycocyanin/*pharmacology ; Protein Carbonylation/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Trialkyltin Compounds/toxicity ; }, abstract = {Spirulina is a widely used health supplement and is a dietary source of C-Phycocyanin (CPC), a potent anti-oxidant. We have previously reported the neurotoxic potential of tributyltin chloride (TBTC), an environmental pollutant and potent biocide. In this study, we have evaluated the protective efficacy of CPC against TBTC induced neurotoxicity. To evaluate the extent of neuroprotection offered by CPC, its efficacy was compared with the degree of protection offered by N-acetylcysteine (NAC) (a well known neuroprotective drug, taken as a positive control). Male Wistar rats (28 day old) were administered with 20mg/kg TBTC (oral) and 50mg/kg CPC or 50mg/kg NAC (i.p.), alone or in combination, and various parameters were evaluated. These include blood-brain barrier (BBB) damage; redox parameters (ROS, GSH, redox pathway associated enzymes, oxidative stress markers); inflammatory, cellular, and stress markers; apoptotic proteins and in situ cell death assay (TUNEL). We observed increased CPC availability in cortical tissue following its administration. Although BBB associated proteins like claudin-5, p-glycoprotein and ZO-1 were restored, CPC/NAC failed to protect against TBTC induced overall BBB permeability (Evans blue extravasation). Both CPC and NAC remarkably reduced oxidative stress and inflammation. NAC effectively modulated redox pathway associated enzymes whereas CPC countered ROS levels efficiently. Interestingly, CPC and NAC were equivalently capable of reducing apoptotic markers, astroglial activation and cell death. This study illustrates the various pathways involved in CPC mediated neuroprotection against this environmental neurotoxicant and highlights its capability to modulate glial cell activity.}, }
@article {pmid26074713, year = {2015}, author = {Fuentes-Orozco, C and Dávalos-Cobián, C and García-Correa, J and Ambriz-González, G and Macías-Amezcua, MD and García-Rentería, J and Rendón-Félix, J and Chávez-Tostado, M and Cuesta-Márquez, LA and Alvarez-Villaseñor, AS and Cortés-Flores, AO and González-Ojeda, A}, title = {Antioxidant drugs to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis: What does evidence suggest?.}, journal = {World journal of gastroenterology}, volume = {21}, number = {21}, pages = {6745-6753}, pmid = {26074713}, issn = {2219-2840}, mesh = {Antioxidants/*therapeutic use ; Chi-Square Distribution ; Cholangiopancreatography, Endoscopic Retrograde/*adverse effects ; Evidence-Based Medicine ; Humans ; Incidence ; Pancreatitis/diagnosis/epidemiology/*prevention &amp; control ; Randomized Controlled Trials as Topic ; Risk Factors ; Treatment Outcome ; }, abstract = {AIM: To determine whether or not the use of antioxidant supplementation aids in the prevention of post- endoscopic retrograde cholangiopancreatography pancreatitis.<br><br>METHODS: A systematic review of randomized controlled trials (RCTs) was made to evaluate the preventive effect of prophylactic antioxidant supplementation in post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The inclusion criteria included: acute post-endoscopic retrograde cholangiopancreatography pancreatitis in adults; randomized clinical trials with the use of any antioxidant as an intervention compared with placebo, to reduce PEP. The outcome measure was the incidence and severity of PEP. Twelve RCTs involving 3110 patients since 1999 were included. The antioxidants used were selenite, &#x3b2;-carotene, and pentoxifylline (each one in one trial), N-acetylcysteine (NAC) in three trials, and allopurinol in six trials. The group of patients treated with NAC received different doses; either oral or intravenous, and allopurinol-treated patients received five different oral doses in two different administration periods. The results are expressed with raw numbers, proportions, as well as mean and standard deviations. The incidence of pancreatitis between groups was analyzed with Pearson's &#x3c7;(2) test or Fisher's exact test (F). The main outcome is expressed as relative risks and 95%CI.<br><br>RESULTS: The incidence of pancreatitis in all antioxidant treatment groups was 8.6%, whereas it was 9.7% in the control group. The antioxidants used were selenite, &#x3b2;-carotene, and pentoxifylline (each one in one trial), NAC in three trials, and allopurinol in six trials. In allopurinol trials, three different dosifications were used; two trials reported a low dosage (of less than 400 mg), two trials reported a moderate dose (600 mg) and the remaining two employed higher doses (more than 900 mg). Supplementation was not associated with a significant reduction in the incidence of PEP [relative risk (RR) = 0.93; 95%CI: 0.82-1.06; P = 0.28]. In addition, the incidences of PEP in patients treated with allopurinol and those treated with other antioxidants were similar to that observed in patients who received the placebo (RR for trials with allopurinol, 0.92; 95%CI: 0.78-1.08; P = 0.31) and, with the use of other antioxidants, the incidence of PEP was 8.9%, whereas it was 9.7% in the control group (RR = 0.95; 95%CI: 0.77-1.18; P = 0.19).<br><br>CONCLUSION: Antioxidant supplementation shows no beneficial effect on the incidence of PEP. There is a lack of robust trials to support the use of antioxidants for prevention.}, }
@article {pmid26066646, year = {2015}, author = {Chughlay, MF and Kramer, N and Werfalli, M and Spearman, W and Engel, ME and Cohen, K}, title = {N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review protocol.}, journal = {Systematic reviews}, volume = {4}, number = {}, pages = {84}, pmid = {26066646}, issn = {2046-4053}, mesh = {Acetylcysteine/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy ; *Clinical Protocols ; Free Radical Scavengers/therapeutic use ; Humans ; *Research Design ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND: Drug-induced liver injury (DILI) refers to acute or chronic liver injury that may occur as a consequence of using drugs and herbal or dietary supplements. Specific therapies for DILI are limited. There is considerable evidence for efficacy and safety of N-acetylcysteine (NAC) in management of paracetamol-induced liver injury. More recently, research has explored the use of NAC in non-paracetamol drug-induced liver injury. It is important to summarise the evidence of NAC for non-paracetamol DILI to determine if NAC may be considered a therapeutic option in this condition.<br><br>METHODS/DESIGN: We will conduct a systematic review of the benefit and harm of NAC in non-paracetamol drug-induced liver injury. Primary and secondary outcomes of interest are pre-specified. Primary outcomes include all-cause mortality, mortality due to DILI, time to normalisation of liver biochemistry (e.g. return of alanine transaminase to <100 U/l and/or international normalized ratio (INR) <1.5) and adverse events. Secondary outcomes include transplantation rate, time to transplantation, transplant-free survival and duration of hospitalisation. We will include randomized controlled trials (RCTs) and prospective cohort studies. RCTs will contribute to the evaluation of safety and efficacy of NAC, whereas, the cohort studies will contribute exclusively to the evaluation of safety. We will search several bibliographic databases (including PubMed, Scopus, CINAHL, CENTRAL), grey literature sources, conference proceedings and ongoing trials. Following data extraction and assessment of the risk of bias, we will conduct a meta-analysis if feasible, as well as subgroup analyses. We will assess and explore clinical and statistical heterogeneity.<br><br>DISCUSSION: The aim of this review is to provide evidence on the effectiveness and safety of NAC in non-paracetamol DILI. We anticipate that the results could aid health care practitioners, researchers and policymakers in the decision-making regarding the use of NAC in patients with non-paracetamol DILI.<br><br>PROSPERO CRD42014008771.}, }
@article {pmid26061948, year = {2015}, author = {Inagaki, Y and Matsumoto, Y and Ishii, M and Uchino, K and Sezutsu, H and Sekimizu, K}, title = {Fluorescence imaging for a noninvasive in vivo toxicity-test using a transgenic silkworm expressing green fluorescent protein.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {11180}, pmid = {26061948}, issn = {2045-2322}, mesh = {Animals ; Animals, Genetically Modified ; Bombyx/*drug effects/*genetics/metabolism ; Catalysis ; Cytochrome P-450 Enzyme System/metabolism ; Drug Evaluation, Preclinical/methods ; *Gene Expression ; Green Fluorescent Proteins/*genetics/metabolism ; Hemolymph/metabolism ; Phenotype ; *Toxicity Tests/methods ; }, abstract = {In drug development, the toxicity of candidate chemicals must be carefully examined in an animal model. Here we developed a live imaging technique using silkworms for a noninvasive toxicity test applicable for drug screening. Injection of carbon tetrachloride, a tissue-injuring chemical, into transgenic silkworms expressing green fluorescent protein (GFP) induced leakage of GFP from the tissues into the hemolymph. The leakage of GFP was suppressed by pre-administration of either cimetidine, a cytochrome P450 inhibitor, or N-acetyl cysteine, a free-radical scavenger. The transgenic silkworm was made transparent by feeding a diet containing chemicals that inhibit uric acid deposition in the epithelial cells. In the transparent silkworms, GFP fluorescence in the fat body could be observed from outside the body. Injection of salicylic acid or iron sulfate, tissue-injuring chemicals, into the transparent silkworms decreased the fluorescence intensity of the GFP in the fat body. These findings suggest that the transparent GFP-expressing silkworm model is useful for evaluating the toxicity of chemicals that induce tissue injury.}, }
@article {pmid26060353, year = {2015}, author = {Orihuela-Campos, RC and Tamaki, N and Mukai, R and Fukui, M and Miki, K and Terao, J and Ito, HO}, title = {Biological impacts of resveratrol, quercetin, and N-acetylcysteine on oxidative stress in human gingival fibroblasts.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {56}, number = {3}, pages = {220-227}, pmid = {26060353}, issn = {0912-0009}, abstract = {In periodontitis, production of reactive oxygen species (ROS) by neutrophils induces oxidative stress and deteriorates surrounding tissues. Antioxidants reduce damage caused by ROS and are used to treat diseases involving oxidative stress. This study summarizes the different effects of resveratrol, quercetin, and N-acetylcysteine (NAC) on human gingival fibroblasts (HGFs) under oxidative stress induced by hydrogen peroxide. Real-time cytotoxicity analyses reveals that resveratrol and quercetin enhanced cell proliferation even under oxidative stress. Of the antioxidants tested, resveratrol is the most effective at inhibiting ROS production. HGFs incubated with resveratrol and quercetin up-regulate the transcription of type I collagen gene after 3 h, but only resveratrol sustained this up-regulation for 24 h. A measurement of the oxygen consumption rate (OCR, mitochondrial respiration) shows that resveratrol generates the highest maximal respiratory capacity, followed by quercetin and NAC. Simultaneous measurement of OCR and the extracellular acidification rate (non-mitochondrial respiration) reveals that resveratrol and quercetin induce an increase in mitochondrial respiration when compared with untreated cells. NAC treatment consumes less oxygen and enhances more non-mitochondrial respiration. In conclusion, resveratrol is the most effective antioxidant in terms of real-time cytotoxicity analysis, reduction of ROS production, and enhancement of type I collagen synthesis and mitochondrial respiration in HGFs.}, }
@article {pmid26058063, year = {2015}, author = {Cui, Y and Jia, F and He, J and Xie, X and Li, Z and Fu, M and Hao, H and Liu, Y and Liu, DZ and Cowan, PJ and Zhu, H and Sun, Q and Liu, Z}, title = {Ambient Fine Particulate Matter Suppresses In Vivo Proliferation of Bone Marrow Stem Cells through Reactive Oxygen Species Formation.}, journal = {PloS one}, volume = {10}, number = {6}, pages = {e0127309}, pmid = {26058063}, issn = {1932-6203}, support = {R01 ES026200/ES/NIEHS NIH HHS/United States ; R01 HL094650/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Bone Marrow Cells/*cytology ; Cell Proliferation/drug effects ; Intracellular Space/metabolism ; Male ; Mice, Inbred C57BL ; Particulate Matter/*toxicity ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Stem Cells/cytology/drug effects/*metabolism ; }, abstract = {AIMS: Some environmental insults, such as fine particulate matter (PM) exposure, significantly impair the function of stem cells. However, it is unknown if PM exposure could affect the population of bone marrow stem cells (BMSCs). The present study was to investigate the effects of PM on BMSCs population and related mechanism(s).<br><br>MAIN METHEODS: PM was intranasally distilled into male C57BL/6 mice for one month. Flow cytometry with antibodies for BMSCs, Annexin V and BrdU ware used to determine the number of BMSCs and the levels of their apoptosis and proliferation in vivo. Phosphorylated Akt (P-Akt) level was determined in the BM cells with western blotting. Intracellular reactive oxygen species (ROS) formation was quantified using flow cytometry analysis. To determine the role of PM-induced ROS in BMSCs population, proliferation, and apotosis, experiments were repeated using N-acetylcysteine (NAC)-treated wild type mice or a triple transgenic mouse line with overexpression of antioxidant network (AON) composed of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase-1 with decreased in vivo ROS production.<br><br>KEY FINDINGS: PM treatment significantly reduced BMSCs population in association with increased ROS formation, decreased P-Akt level, and inhibition of proliferation of BMSCs without induction of apoptosis. NAC treatment or AON overexpression with reduced ROS formation effectively prevented PM-induced reduction of BMSCs population and proliferation with partial recovery of P-Akt level.<br><br>SIGNIFICANCE: PM exposure significantly decreased the population of BMSCs due to diminished proliferation via ROS-mediated mechanism (could be partially via inhibition of Akt signaling).}, }
@article {pmid26057332, year = {2015}, author = {Wright, CR and Brown, EL and Della Gatta, PA and Fatouros, IG and Karagounis, LG and Terzis, G and Mastorakos, G and Michailidis, Y and Mandalidis, D and Spengos, K and Chatzinikolaou, A and Methenitis, S and Draganidis, D and Jamurtas, AZ and Russell, AP}, title = {Regulation of Granulocyte Colony-Stimulating Factor and Its Receptor in Skeletal Muscle is Dependent Upon the Type of Inflammatory Stimulus.}, journal = {Journal of interferon &amp; cytokine research : the official journal of the International Society for Interferon and Cytokine Research}, volume = {35}, number = {9}, pages = {710-719}, doi = {10.1089/jir.2014.0159}, pmid = {26057332}, issn = {1557-7465}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants/pharmacology ; Chemokine CCL2/metabolism ; Exercise/physiology ; Granulocyte Colony-Stimulating Factor/*metabolism ; Humans ; Inflammation/chemically induced/*metabolism ; Interleukin-6/metabolism ; Lipopolysaccharides/pharmacology ; Male ; Muscle, Skeletal/drug effects/*metabolism ; Myoblasts/drug effects/metabolism ; Neutrophils/drug effects/metabolism ; RNA, Messenger/metabolism ; Receptors, Granulocyte Colony-Stimulating Factor/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Young Adult ; }, abstract = {The cytokine granulocyte colony-stimulating factor (G-CSF) binds to its receptor (G-CSFR) to stimulate hematopoietic stem cell mobilization, myelopoiesis, and the production and activation of neutrophils. In response to exercise-induced muscle damage, G-CSF is increased in circulation and G-CSFR has recently been identified in skeletal muscle cells. While G-CSF/G-CSFR activation mediates pro- and anti-inflammatory responses, our understanding of the role and regulation in the muscle is limited. The aim of this study was to investigate, in vitro and in vivo, the role and regulation of G-CSF and G-CSFR in skeletal muscle under conditions of muscle inflammation and damage. First, C2C12 myotubes were treated with lipopolysaccharide (LPS) with and without G-CSF to determine if G-CSF modulates the inflammatory response. Second, the regulation of G-CSF and its receptor was measured following eccentric exercise-induced muscle damage and the expression levels we investigated for redox sensitivity by administering the antioxidant N-acetylcysteine (NAC). LPS stimulation of C2C12 myotubes resulted in increases in G-CSF, interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNFα) messenger RNA (mRNA) and an increase in G-CSF, IL-6, and MCP-1 release from C2C12 myotubes. The addition of G-CSF following LPS stimulation of C2C12 myotubes increased IL-6 mRNA and cytokine release into the media, however it did not affect MCP-1 or TNFα. Following eccentric exercise-induced muscle damage in humans, G-CSF levels were either marginally increased in circulation or remain unaltered in skeletal muscle. Similarly, G-CSFR levels remained unchanged in response to damaging exercise and G-CSF/G-CSFR did not change in response to NAC. Collectively, these findings suggest that G-CSF may cooperate with IL-6 and potentially promote muscle regeneration in vitro, whereas in vivo aseptic inflammation induced by exercise did not change G-CSF and G-CSFR responses. These observations suggest that different models of inflammation produce a different G-CSF response.}, }
@article {pmid26055939, year = {2014}, author = {Shaughnessy, F and Mariotti, E and Shaw, KP and Eykyn, TR and Blower, PJ and Siow, R and Southworth, R}, title = {Modification of intracellular glutathione status does not change the cardiac trapping of (64)Cu(ATSM).}, journal = {EJNMMI research}, volume = {4}, number = {1}, pages = {40}, pmid = {26055939}, issn = {2191-219X}, support = {PG/10/20/28211/BHF_/British Heart Foundation/United Kingdom ; }, abstract = {BACKGROUND: The trapping mechanisms of the PET hypoxia imaging agent copper(II)-diacetyl-bis(N (4)-methylthiosemicarbazone) ((64)Cu(ATSM)) remain unresolved, although its reduction prior to dissociation may be mediated by intracellular thiols. Glutathione (GSH) is the most abundant intracellular thiol, and its redox status changes in cancer cells and ischaemic myocardium (two prime applications for (64)Cu(ATSM) PET). We therefore investigated whether modification of intracellular GSH content affects the hypoxia selectivity of (64)Cu(ATSM).<br><br>METHODS: Isolated rat hearts (n&#x2009;=&#x2009;five per group) were perfused with aerobic buffer (equilibrated with 95%O2/5%CO2) for 15&#xa0;min, then hypoxic buffer (95%N2/5%CO2) for 20&#xa0;min. Cardiac glutathione was depleted by buthionine sulphoximine (BSO, 4&#xa0;mmol/kg/ 48&#xa0;h intraperitoneal), or augmented by N-acetyl cysteine (NAC, 4&#xa0;mmol/L) in the perfusion buffer. Cardiac (64)Cu retention from three 2-MBq bolus injections of (64)Cu(ATSM) before and during hypoxia was then monitored by NaI detectors.<br><br>RESULTS: Cardiac GSH content was elevated by NAC and depleted by BSO (from 7.9&#x2009;&#xb1;&#x2009;2.0 to 59.3&#x2009;&#xb1;&#x2009;8.3&#xa0;nmol/mg and 3.7&#x2009;&#xb1;&#x2009;1.0&#xa0;nmol/mg protein, respectively; p&#x2009;<&#x2009;0.05). Hypoxia did not affect cardiac GSH content in any group. During normoxia, tracer washed out bi-exponentially, with 13.1%&#x2009;&#xb1;&#x2009;1.7% injected dose being retained; this was not affected by GSH augmentation or depletion. Hypoxia significantly increased tracer retention (to 59.1%&#x2009;&#xb1;&#x2009;6.3%, p&#x2009;<&#x2009;0.05); this effect was not modified by GSH augmentation or depletion.<br><br>CONCLUSION: Modification of GSH levels had no impact upon the pharmacokinetics or hypoxia selectivity of (64)Cu(ATSM). While thiols may yet prove essential for the intracellular trapping of (64)Cu(ATSM), they are not the determinants of its hypoxia selectivity.}, }
@article {pmid26053925, year = {2015}, author = {Xiao, J and Deng, J and Lv, L and Kang, Q and Ma, P and Yan, F and Song, X and Gao, B and Zhang, Y and Xu, J}, title = {Hydrogen Peroxide Induce Human Cytomegalovirus Replication through the Activation of p38-MAPK Signaling Pathway.}, journal = {Viruses}, volume = {7}, number = {6}, pages = {2816-2833}, pmid = {26053925}, issn = {1999-4915}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Cells, Cultured ; Cytomegalovirus/*drug effects/*physiology ; Cytomegalovirus Infections/virology ; Disease Models, Animal ; Fibroblasts/virology ; Genes, Immediate-Early ; Humans ; Hydrogen Peroxide/*metabolism ; Male ; Mice, Inbred BALB C ; Oxidants/metabolism ; Promoter Regions, Genetic/drug effects ; *Signal Transduction ; Transcription, Genetic ; Virus Replication/*drug effects ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H2O2, the most common reactive oxygen species, is the main byproduct of oxidative metabolism. However, the function of H2O2 on HCMV infection is not yet fully understood and the effect and mechanism of N-acetylcysteine (NAC) on H2O2-stimulated HCMV replication is unclear. We, therefore, examined the effect of NAC on H2O2-induced HCMV production in human foreskin fibroblast cells. In the present study, we found that H2O2 enhanced HCMV lytic replication through promoting major immediate early (MIE) promoter activity and immediate early (IE) gene transcription. Conversely, NAC inhibited H2O2-upregulated viral IE gene expression and viral replication. The suppressive effect of NAC on CMV in an acute CMV-infected mouse model also showed a relationship between antioxidants and viral lytic replication. Intriguingly, the enhancement of HCMV replication via supplementation with H2O2 was accompanied with the activation of the p38 mitogen-activated protein kinase pathway. Similar to NAC, the p38 inhibitor SB203580 inhibited H2O2-induced p38 phosphorylation and HCMV upregulation, while upregulation of inducible ROS was unaffected. These results directly relate HCMV replication to H2O2, suggesting that treatment with antioxidants may be an attractive preventive and therapeutic strategy for HCMV.}, }
@article {pmid26052837, year = {2015}, author = {Zhou, J and Coles, LD and Kartha, RV and Nash, N and Mishra, U and Lund, TC and Cloyd, JC}, title = {Intravenous Administration of Stable-Labeled N-Acetylcysteine Demonstrates an Indirect Mechanism for Boosting Glutathione and Improving Redox Status.}, journal = {Journal of pharmaceutical sciences}, volume = {104}, number = {8}, pages = {2619-2626}, doi = {10.1002/jps.24482}, pmid = {26052837}, issn = {1520-6017}, mesh = {Acetylcysteine/*administration &amp; dosage/metabolism/pharmacokinetics/pharmacology ; Animals ; Antioxidants/*administration &amp; dosage/metabolism/pharmacokinetics/pharmacology ; Blood-Brain Barrier/drug effects/metabolism ; Brain/*drug effects/metabolism ; Carbon Isotopes ; Erythrocytes/drug effects/metabolism ; Female ; Glutathione/*agonists/chemistry/metabolism ; Half-Life ; Injections, Intravenous ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Nitrogen Isotopes ; Nootropic Agents/*administration &amp; dosage/metabolism/pharmacokinetics/pharmacology ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Prodrugs/*administration &amp; dosage/metabolism/pharmacokinetics/pharmacology ; Random Allocation ; Tissue Distribution ; }, abstract = {There is an increasing interest in using N-acetylcysteine (NAC) as a treatment for neurodegenerative disorders to increase glutathione (GSH) levels and its redox status. The purpose of this study was to characterize the biosynthesis of NAC to GSH using a novel stable isotope-labeled technique, and investigate the pharmacodynamics of NAC in vivo. Female wild-type mice were given a single intravenous bolus dose of 150 mg kg(-1) stable-labeled NAC. Plasma, red blood cells (RBC), and brain tissues were collected at predesignated time points. Stable-labeled NAC and its metabolite GSH (both labeled and unlabeled forms) were quantified in blood and brain samples. Molar ratios of the reduced and oxidized forms of GSH (GSH divided by glutathione disulfide, redox ratio) were also determined. The elimination phase half-life of NAC was approximately 34 min. Both labeled and unlabeled GSH in RBC were found to increase; however, the area under the curve above baseline (AUCb0-280) of labeled GSH was only 1% of the unlabeled form. These data indicate that NAC is not a direct precursor of GSH. In addition, NAC has prolonged effects in brain even when the drug has been eliminated from systemic circulation.}, }
@article {pmid26051462, year = {2015}, author = {Partyka, A and Niżański, W and Bratkowska, M and Maślikowski, P}, title = {Effects of N-acetyl-L-cysteine and catalase on the viability and motility of chicken sperm during liquid storage.}, journal = {Reproductive biology}, volume = {15}, number = {2}, pages = {126-129}, doi = {10.1016/j.repbio.2015.03.001}, pmid = {26051462}, issn = {2300-732X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Inbred Strains ; Antioxidants/*pharmacology ; Catalase/metabolism ; Cell Survival/drug effects ; Chickens ; Fertility Agents, Male/*pharmacology ; Male ; Osmolar Concentration ; Poland ; Refrigeration/veterinary ; Semen Preservation/*veterinary ; Sperm Motility/drug effects ; Spermatozoa/cytology/*drug effects ; Time Factors ; }, abstract = {The purpose of the current study was to investigate the effects of N-acetyl-L-cysteine (NAC) and catalase (CAT) on chicken sperm parameters during liquid storage for up to 48 h at 5 °C. Supplementation of EK extender with NAC (15 mM) increased sperm motility after 24h. After 48 h, an increase in sperm viability with NAC (5, 15 mM) and CAT (100, 300 U/mL) was observed, but only treatment with 15 mM NAC improved sperm progressive motility.}, }
@article {pmid26050706, year = {2015}, author = {Karimzadeh, I and Khalili, H and Sagheb, MM and Farsaei, S}, title = {A double-blinded, placebo-controlled, multicenter clinical trial of N-acetylcysteine for preventing amphotericin B-induced nephrotoxicity.}, journal = {Expert opinion on drug metabolism &amp; toxicology}, volume = {11}, number = {9}, pages = {1345-1355}, doi = {10.1517/17425255.2015.1042363}, pmid = {26050706}, issn = {1744-7607}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amphotericin B/*adverse effects/therapeutic use ; Antifungal Agents/*adverse effects/therapeutic use ; Cystatin C/urine ; Double-Blind Method ; Female ; Hepatitis A Virus Cellular Receptor 1 ; Humans ; Kidney Diseases/chemically induced/*prevention &amp; control ; Kidney Function Tests ; Male ; Membrane Glycoproteins/urine ; Middle Aged ; Receptors, Virus ; Young Adult ; }, abstract = {OBJECTIVE: To evaluate the effectiveness of oral N-acetylcysteine (NAC) co-treatment in preventing amphotericin B (AmB)-induced nephrotoxicity (AIN), including creatinine clearance and biomarkers of renal function (cystatin C [Cys C] and kidney injury molecule-1 [KIM-1]).<br><br>METHODS: Either placebo or 600 mg oral NAC was given twice daily during the treatment course of AmB. Renal function test, serum as well as urinary level of Cys C and urinary KIM-1 were determined.<br><br>RESULTS: Among the study population (n = 54), 23 (42.59%) patients developed AmB nephrotoxicity during their treatment course. NAC co-treatment was significantly associated with mitigating AmB nephrotoxicity (OR = 0.286, 95% CI: 0.082 - 0.993; p = 0.049). No statistically significant difference regarding accuracy of measured biomarkers including serum creatinine, serum and urine Cys C and urine KIM-1 at days 0 and 7 of treatment in predicting and detecting AmB nephrotoxicity was identified. The changes in mean serum and urine Cys C and urine KIM during AmB treatment within and between treatment groups were not statistically significant.<br><br>CONCLUSIONS: Co-treatment with 600 mg oral NAC twice a day during AmB treatment, after adjusting for multiple variables, was associated with prevention of AIN. However, significantly higher adverse reactions developed in the patients who were treated with NAC.}, }
@article {pmid26046640, year = {2015}, author = {Llanos, P and Contreras-Ferrat, A and Barrientos, G and Valencia, M and Mears, D and Hidalgo, C}, title = {Glucose-Dependent Insulin Secretion in Pancreatic β-Cell Islets from Male Rats Requires Ca2+ Release via ROS-Stimulated Ryanodine Receptors.}, journal = {PloS one}, volume = {10}, number = {6}, pages = {e0129238}, pmid = {26046640}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Caffeine/pharmacology ; Calcium/*metabolism ; Carbachol/pharmacology ; Cell Line, Tumor ; Cells, Cultured ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Glucose/*pharmacology ; Hydrogen Peroxide/pharmacology ; Immunohistochemistry ; Insulin/*metabolism ; Insulin Secretion ; Insulin-Secreting Cells/*drug effects/metabolism ; Islets of Langerhans/drug effects/metabolism ; Male ; Mice ; Microscopy, Confocal ; Oxidants/pharmacology ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Ryanodine/pharmacology ; Ryanodine Receptor Calcium Release Channel/genetics/*metabolism ; }, abstract = {Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells requires an increase in intracellular free Ca2+ concentration ([Ca2+]). Glucose uptake into β-cells promotes Ca2+ influx and reactive oxygen species (ROS) generation. In other cell types, Ca2+ and ROS jointly induce Ca2+ release mediated by ryanodine receptor (RyR) channels. Therefore, we explored here if RyR-mediated Ca2+ release contributes to GSIS in β-cell islets isolated from male rats. Stimulatory glucose increased islet insulin secretion, and promoted ROS generation in islets and dissociated β-cells. Conventional PCR assays and immunostaining confirmed that β-cells express RyR2, the cardiac RyR isoform. Extended incubation of β-cell islets with inhibitory ryanodine suppressed GSIS; so did the antioxidant N-acetyl cysteine (NAC), which also decreased insulin secretion induced by glucose plus caffeine. Inhibitory ryanodine or NAC did not affect insulin secretion induced by glucose plus carbachol, which engages inositol 1,4,5-trisphosphate receptors. Incubation of islets with H2O2 in basal glucose increased insulin secretion 2-fold. Inhibitory ryanodine significantly decreased H2O2-stimulated insulin secretion and prevented the 4.5-fold increase of cytoplasmic [Ca2+] produced by incubation of dissociated β-cells with H2O2. Addition of stimulatory glucose or H2O2 (in basal glucose) to β-cells disaggregated from islets increased RyR2 S-glutathionylation to similar levels, measured by a proximity ligation assay; in contrast, NAC significantly reduced the RyR2 S-glutathionylation increase produced by stimulatory glucose. We propose that RyR2-mediated Ca2+ release, induced by the concomitant increases in [Ca2+] and ROS produced by stimulatory glucose, is an essential step in GSIS.}, }
@article {pmid26046347, year = {2015}, author = {Jarazo Dietrich, S and Fass, MI and Jacobo, PV and Sobarzo, CM and Lustig, L and Theas, MS}, title = {Inhibition of NOS-NO System Prevents Autoimmune Orchitis Development in Rats: Relevance of NO Released by Testicular Macrophages in Germ Cell Apoptosis and Testosterone Secretion.}, journal = {PloS one}, volume = {10}, number = {6}, pages = {e0128709}, pmid = {26046347}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Adjuvants, Immunologic ; Animals ; Apoptosis/drug effects ; Autoimmune Diseases/chemically induced/immunology/pathology/*prevention &amp; control ; Coculture Techniques ; Complex Mixtures ; Enzyme Inhibitors/*pharmacology ; Gene Expression Regulation ; Humans ; Leydig Cells/drug effects/immunology/*metabolism/pathology ; Luteinizing Hormone/blood/genetics ; Macrophages/drug effects/immunology/pathology ; Male ; NG-Nitroarginine Methyl Ester/*pharmacology ; Nitric Oxide/*antagonists &amp; inhibitors/biosynthesis ; Nitric Oxide Donors/pharmacology ; Nitric Oxide Synthase Type II/genetics/metabolism ; Orchitis/chemically induced/immunology/pathology/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Spermatozoa/drug effects/immunology/*metabolism/pathology ; Testosterone/biosynthesis/metabolism ; Triazenes/pharmacology ; }, abstract = {BACKGROUND: Although the testis is considered an immunoprivileged organ it can orchestrate immune responses against pathological insults such as infection and trauma. Experimental autoimmune orchitis (EAO) is a model of chronic inflammation whose main histopathological features it shares with human orchitis. In EAO an increased number of macrophages infiltrate the interstitium concomitantly with progressive germ cell degeneration and impaired steroidogenesis. Up-regulation of nitric oxide (NO)-NO synthase (NOS) system occurs, macrophages being the main producers of NO.<br><br>OBJECTIVE: The aim of our study was to evaluate the role of NO-NOS system in orchitis development and determine the involvement of NO released by testicular macrophages on germ cell apoptosis and testosterone secretion.<br><br>METHOD AND RESULTS: EAO was induced in rats by immunization with testicular homogenate and adjuvants (E group) and a group of untreated normal rats (N) was also studied. Blockage of NOS by i.p. injection of E rats with a competitive inhibitor of NOS, L-NAME (8mg/kg), significantly reduced the incidence and severity of orchitis and lowered testicular nitrite content. L-NAME reduced germ cell apoptosis and restored intratesticular testosterone levels, without variations in serum LH. Co-culture of N testicular fragments with testicular macrophages obtained from EAO rats significantly increased germ cell apoptosis and testosterone secretion, whereas addition of L-NAME lowered both effects and reduced nitrite content. Incubation of testicular fragments from N rats with a NO donor DETA-NOnoate (DETA-NO) induced germ cell apoptosis through external and internal apoptotic pathways, an effect prevented by N-acetyl-L-cysteine (NAC). DETA-NO inhibited testosterone released from Leydig cells, whereas NAC (from 2.5 to 15 mM) did not prevent this effect.<br><br>CONCLUSIONS: We demonstrated that NO-NOS system is involved in the impairment of testicular function in orchitis. NO secreted mainly by testicular macrophages could promote oxidative stress inducing ST damage and interfering in Leydig cell function.}, }
@article {pmid26043815, year = {2015}, author = {Santos, CL and Bobermin, LD and Souza, DG and Bellaver, B and Bellaver, G and Arús, BA and Souza, DO and Gonçalves, CA and Quincozes-Santos, A}, title = {Lipoic acid and N-acetylcysteine prevent ammonia-induced inflammatory response in C6 astroglial cells: The putative role of ERK and HO1 signaling pathways.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {29}, number = {7}, pages = {1350-1357}, doi = {10.1016/j.tiv.2015.05.023}, pmid = {26043815}, issn = {1879-3177}, mesh = {Acetylcysteine/*pharmacology ; Ammonia/toxicity ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Astrocytes/*drug effects/metabolism ; Cell Line ; Cytokines/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Glutathione/metabolism ; Heme Oxygenase (Decyclizing)/metabolism ; Nitrites/metabolism ; Rats ; S100 Calcium Binding Protein beta Subunit/metabolism ; Signal Transduction/drug effects ; Thioctic Acid/*pharmacology ; }, abstract = {Hyperammonemia induces significant changes in the central nervous system (CNS) in direct association with astroglial functions, such as oxidative damage, glutamatergic excitotoxicity, and impaired glutamine synthetase (GS) activity and pro-inflammatory cytokine release. Classically, lipoic acid (LA) and N-acetylcysteine (NAC) exhibit antioxidant and anti-inflammatory activities by increasing glutathione (GSH) biosynthesis and decreasing pro-inflammatory mediator levels in glial cells. Thus, we evaluated the protective effects of LA and NAC against ammonia cytotoxicity in C6 astroglial cells. Ammonia decreased GSH levels and increased cytokine release and NFκB transcriptional activation. LA and NAC prevented these effects by the modulation of ERK and HO1 pathways. Taken together, these observations show that LA and NAC prevent the ammonia-induced inflammatory response.}, }
@article {pmid26041966, year = {2015}, author = {Butterworth, RF}, title = {Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure.}, journal = {Journal of clinical and experimental hepatology}, volume = {5}, number = {Suppl 1}, pages = {S96-S103}, pmid = {26041966}, issn = {0973-6883}, abstract = {Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepato-protective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited.}, }
@article {pmid26041950, year = {2015}, author = {Shalimar,  and Acharya, SK}, title = {Management in acute liver failure.}, journal = {Journal of clinical and experimental hepatology}, volume = {5}, number = {Suppl 1}, pages = {S104-15}, pmid = {26041950}, issn = {0973-6883}, abstract = {Acute liver failure (ALF) is a rare, potentially fatal complication of severe hepatic illness resulting from various causes. In a clinical setting, severe hepatic injury is usually recognised by the appearance of jaundice, encephalopathy and coagulopathy. The central and most important clinical event in ALF is occurrence of hepatic encephalopathy (HE) and cerebral edema which is responsible for most of the fatalities in this serious clinical syndrome. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a central role in the pathogenesis. The role of newer ammonia lowering agents is still evolving. Liver transplant is the only effective therapy that has been identified to be of promise in those with poor prognostic factors, whereas in the others, aggressive intensive medical management has been documented to salvage a substantial proportion of patients. A small fraction of patients undergo liver transplant and the remaining are usually treated with medical therapy. Therefore, identification of the complications and causes of death in such patients, and use of appropriate prognostic models to identify those who need liver transplant and those who can be managed with medical treatment is a vital component of therapeutic strategy. In this review, we discuss the various pathogenetic mechanisms and treatment options available.}, }
@article {pmid26041154, year = {2015}, author = {Wang, T and Wang, Q and Song, R and Zhang, Y and Zhang, K and Yuan, Y and Bian, J and Liu, X and Gu, J and Liu, Z}, title = {Autophagy Plays a Cytoprotective Role During Cadmium-Induced Oxidative Damage in Primary Neuronal Cultures.}, journal = {Biological trace element research}, volume = {168}, number = {2}, pages = {481-489}, doi = {10.1007/s12011-015-0390-8}, pmid = {26041154}, issn = {1559-0720}, mesh = {Acetylcysteine/chemistry ; Animals ; Antioxidants/chemistry ; *Autophagy ; Cadmium/*toxicity ; Cells, Cultured ; Cerebral Cortex/embryology ; Chloroquine/chemistry ; L-Lactate Dehydrogenase/metabolism ; Membrane Potential, Mitochondrial ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/metabolism ; Neurons/*cytology/drug effects ; *Oxidative Stress ; Primary Cell Culture ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cadmium (Cd) induces significant oxidative damage in cells. Recently, it was reported that autophagy could be induced by Cd in neurons. However, little is known about the role of reactive oxygen species (ROS) during Cd-induced autophagy. In our study, we examined the cross-talk between ROS and autophagy by using N-acetyl cysteine (NAC, an antioxidant) and chloroquine (CQ, a pharmacological inhibitor of autophagy) in a primary rat neuronal cell cultures. We observed accumulation of acidic vesicular organelles and the increased expression of endogenous protein light chain 3 (LC3) in Cd-treated neurons, revealing that Cd induced a high level of autophagy. Moreover, increased levels of ROS were observed in neurons treated with Cd, showing that ROS accumulation was closely associated with neuron's exposure to Cd. Furthermore, we found that autophagy was inhibited by using CQ and/or NAC with further aggravation of mitochondrial damage, lactate dehydrogenase (LDH) leakage and hypoploid apoptotic cell number in Cd-treated neurons. These results proved that autophagy has a cytoprotective role during Cd-induced toxicity in neurons, and it can prevent the oxidative damage. These findings may enable the development of novel therapeutic strategies for neurological diseases.}, }
@article {pmid26035204, year = {2015}, author = {Waterdrinker, A and Berk, M and Venugopal, K and Rapado-Castro, M and Turner, A and Dean, OM}, title = {Effects of N-Acetyl cysteine on suicidal ideation in bipolar depression.}, journal = {The Journal of clinical psychiatry}, volume = {76}, number = {5}, pages = {665}, doi = {10.4088/JCP.14l09378}, pmid = {26035204}, issn = {1555-2101}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Bipolar Disorder/*drug therapy/physiopathology ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Humans ; Randomized Controlled Trials as Topic ; *Suicidal Ideation ; }, }
@article {pmid26032963, year = {2015}, author = {Manna, A and Bauri, AK and Chattopadhyay, S and Chatterjee, M}, title = {Generation of Redox Imbalance Mediates the Cytotoxic Effect of Malabaricone-A in a Multidrug Resistant Cell Line.}, journal = {Anti-cancer agents in medicinal chemistry}, volume = {15}, number = {9}, pages = {1156-1163}, doi = {10.2174/1871520615666150602093004}, pmid = {26032963}, issn = {1875-5992}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; *Drug Resistance, Neoplasm ; Drug Synergism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Resorcinols/*pharmacology ; }, abstract = {Multidrug resistance (MDR) refers to cross-resistance to a range of structurally and functionally unrelated compounds, and is accompanied by an elevated expression of ATP driven cell-membrane transporters. The cytotoxicity of Malabaricone-A (MAL-A), a diarylnonanoid derived from Myristica malabarica was demonstrated in leukemic cell lines, but its effectiveness in drug-resistant cancer cell lines has not been evaluated. Accordingly, this study tested its cytotoxic potential in a T-lymphoblastic leukemic cell line, CCRF CEM and its MDR counterpart, CEM/ADR5000. The effectiveness of MAL-A was 1.8 fold higher in CEM/ADR5000 than CCRF CEM cell line, the IC50 being value 5.40 ± 1.41 vs. 9.72 ± 1.08 µg/ml, respectively, suggesting that MAL-A demonstrated 'collateral sensitivity'. This cytotoxicity of MAL-A was attributed to an enhanced generation of oxidative stress, as the IC50 value increased following the addition of an anti-oxidant, N-acetyl cysteine (NAC). Furthermore, MAL-A depleted glutathione and inhibited glutathione peroxidase activity, which too contributed towards generation of a redox imbalance. This culminated in an apoptosis mediated cell death as evident by mitochondrial membrane depolarization, enhanced caspase-3 activity, increased externalization of phosphatidylserine and an increase in the sub G0/G1 population. Collectively, compounds with pro-oxidant activity have promising therapeutic potential in drug resistant phenotypes, worthy of future pharmacological consideration.}, }
@article {pmid26032180, year = {2016}, author = {Rodriguez, I and Diaz, A and Vaamonde, D}, title = {Assessment of the effect of prolonged forced swimming on CD-1 mice sperm morphology with and without antioxidant supplementation.}, journal = {Andrologia}, volume = {48}, number = {3}, pages = {277-281}, doi = {10.1111/and.12443}, pmid = {26032180}, issn = {1439-0272}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Shape/drug effects/*physiology ; Male ; Mice ; Physical Conditioning, Animal/physiology ; Resveratrol ; Spermatozoa/*cytology/drug effects ; Stilbenes/*pharmacology ; Swimming/*physiology ; }, abstract = {As physical exercise has been shown to negatively affect sperm morphology, this study was undertaken to assess the effect of a 3-min forced swimming protocol during 50 days, with and without administration of antioxidants [N-acetylcysteine (NAC) and trans-resveratrol], on sperm morphology in CD-1 mice. Forty-four 13-week-old CD-1 mice were randomly allocated to four different groups: mice not submitted to exercise, control group (CG), mice submitted to swimming without administration of antioxidants (EX), mice submitted to swimming that received trans-resveratrol supplementation [exercise group (EX)+Resv] and mice submitted to swimming exercise that received NAC supplementation (EX+NAC). The EX showed 30.5% of spermatozoa with normal morphology, showing significant differences with regard to the CG, which showed 58.5%. The groups receiving antioxidant supplements showed significantly higher percentages of spermatozoa with normal morphology in comparison with the EX group (EX+Resv: 64.1%, EX+NAC: 48.2%). The imposed model of forced swimming caused alterations in sperm morphology. The antioxidants employed seem to be suitable antioxidants for avoiding exercise-associated sperm morphology anomalies in prolonged forced swimming exercise. Trans-resveratrol has proven to be more efficient for this purpose.}, }
@article {pmid26028291, year = {2015}, author = {Ranieri, D and Avitabile, D and Shiota, M and Yokomizo, A and Naito, S and Bizzarri, M and Torrisi, MR}, title = {Nuclear redox imbalance affects circadian oscillation in HaCaT keratinocytes.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {65}, number = {}, pages = {113-124}, doi = {10.1016/j.biocel.2015.05.018}, pmid = {26028291}, issn = {1878-5875}, mesh = {ARNTL Transcription Factors/genetics/metabolism ; Acetylcysteine/pharmacology ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Circadian Rhythm/drug effects/*physiology ; Gene Expression ; Humans ; Keratinocytes/cytology/drug effects/*metabolism ; Melatonin/pharmacology ; Niacinamide/pharmacology ; Oxidation-Reduction ; Peroxiredoxins/biosynthesis/metabolism ; Protein Biosynthesis ; Reactive Oxygen Species ; Resveratrol ; Sirtuin 1/antagonists &amp; inhibitors/metabolism ; Stilbenes/pharmacology ; Transcription, Genetic ; }, abstract = {Circadian clock is regulated by a transcriptional/translational feedback loop (TTFL) lasting ∼24 h. Circadian oscillation of peroxiredoxins (PRDX1-6) redox status has been shown in mature erythrocytes. We have recently reported that nuclear levels of PRDX2 are circadian regulated in the HaCaT keratinocytes. In this study, we addressed whether PRDX2 translocation could influence the TTFL. A reporter HaCaT cell line stably expressing the luciferase gene under control of Bmal1 promoter was lentivirally transduced either with an empty vector (EV), a vector carrying a myc-tagged wild type PRDX2 (PRDX2-Myc) or the same gene with a nuclear localization sequence (PRDX2-MycNuc). PRDX2 overexpressing cells were protected from H2O2-induced oxidative stress. The amplitude of the Bmal1 promoter activity was significantly dampened in PRDX2-MycNuc versus EV cells when synchronized either by dexamethasone treatment or temperature cycles. Clock synchronization was not affected in PRDX2 silenced cells. N-acetyl cysteine or melatonin treatments, significantly dampened the Bmal1 promoter activity suggesting that sustained scavenging of ROS impairs clock synchronization. Noteworthy, H2O2 treatment rescued proper oscillation of the clock in synchronized PRDX2-MycNuc HaCaT cells. Since the histone deacetylase Sirtuin 1 (Sirt1) modulates clock gene expression amplitude, the effect of Sirt1 activator resveratrol or Sirt1 inhibitor nicotinamide were also investigated. Interestingly, NAM enhanced the molecular clock synchronization in PRDX2-MycNuc cells. Our findings demonstrate that PRDX2 regulates the TTFL oscillation by finely tuning the cellular redox status of the nucleus likely influencing the deacetilase activity of SIRT1 enzyme.}, }
@article {pmid26027766, year = {2015}, author = {Baykara, M and Silici, S and Özçelik, M and Güler, O and Erdoğan, N and Bilgen, M}, title = {In vivo nephroprotective efficacy of propolis against contrast-induced nephropathy.}, journal = {Diagnostic and interventional radiology (Ankara, Turkey)}, volume = {21}, number = {4}, pages = {317-321}, pmid = {26027766}, issn = {1305-3612}, mesh = {Acetylcysteine/pharmacology ; Animals ; Biomarkers/metabolism ; Calpain/pharmacology ; Contrast Media/*adverse effects ; Diatrizoate/*adverse effects ; Disease Models, Animal ; Kidney Diseases/chemically induced/metabolism/*prevention &amp; control ; Male ; Propolis/*pharmacology ; Random Allocation ; Rats ; Treatment Outcome ; }, abstract = {PURPOSE: Contrast agents administered in diagnostic imaging or interventional procedures of clinical radiology may cause contrast-induced nephropathy (CIN). Preventive measures against CIN involve pharmaceutical pretreatments, such as N-acetylcystein (NAC) or calpain, but alternative medicines can also be helpful. This study aims to assess the prospects of a natural compound, propolis, as a potential nephroprotector against a specific contrast agent, diatrizoate.<br><br>METHODS: In vivo experiments were performed on 35 male rats in five groups: control, diatrizoate alone, and pretreatments with propolis, NAC, or calpain one hour before diatrizoate administration. Three days later, blood and renal tissue samples were collected and quantitatively processed for determining induced changes in critical biomarkers malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), as well as serum creatinine and plasma urea.<br><br>RESULTS: Diatrizoate increased creatinine (113%), urea (400%), and MDA (162%) levels and decreased GSH (-71%), SOD (-69%), GSH-Px (-77%), and CAT (-73%) levels. Evaluating the response of each pretreatment provided sufficient evidence that propolis was as effective as either NAC or calpain, but consistently more prominent in restoring the MDA, GSH, SOD, and GSH-Px levels close to their normal range. This outcome demonstrated the nephroprotective effect of propolis against CIN.<br><br>CONCLUSION: Propolis protects renal tissue against toxicity, free radicals, and other adverse effects induced by diatrizoate. This function is most likely exerted through the antioxidant and antitoxic activities of propolis.}, }
@article {pmid26024834, year = {2015}, author = {Martínez-González, JJ and Guevara-Flores, A and Rendón, JL and Arenal, IPD}, title = {Auranofin-induced oxidative stress causes redistribution of the glutathione pool in Taenia crassiceps cysticerci.}, journal = {Molecular and biochemical parasitology}, volume = {201}, number = {1}, pages = {16-25}, doi = {10.1016/j.molbiopara.2015.05.001}, pmid = {26024834}, issn = {1872-9428}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Auranofin/*toxicity ; Buthionine Sulfoximine/metabolism ; Cysticercus/chemistry/drug effects/physiology ; Glutathione/*analysis ; Oxidants/*toxicity ; *Oxidative Stress ; Reactive Oxygen Species/analysis ; Survival Analysis ; Taenia/*chemistry/*drug effects/physiology ; }, abstract = {Previously, we have studied the effect of the gold-compound auranofin (AF) on both thioredoxin-glutathione reductasa (TGR) activity and viability of Taenia crassiceps cysticerci. It was demonstrated that micromolar concentrations of AF were high enough to fully inhibit TGR and kill the parasites. In this work, the dynamics of changes in the glutathione pool of T. crassiceps cysticerci following the addition of AF, was analyzed. A dose-dependent decrease in the internal glutathione concentration, concomitant with an increase in ROS production was observed. These changes were simultaneous with the formation of glutathione-protein complexes and the export of glutathione disulfide (GSSG) to the culture medium. Incubation of cysticerci in the presence of both AF and N-acetyl cysteine (NAC) prevents all the above changes, maintaining cysticerci viability. By contrast, the presence of both AF and buthionine sulfoximine (BSO) resulted in a potentiation of the effects of the gold compound, jeopardizing cysticerci viability. These results suggest the lethal effect of AF on T. crassiceps cysticerci, observed at micromolar concentrations, can be explained as a consequence of major changes in the glutathione status, which results in a significant increase in the oxidative stress of the parasites.}, }
@article {pmid26024660, year = {2015}, author = {Qin, LS and Jia, PF and Zhang, ZQ and Zhang, SM}, title = {ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {34}, number = {1}, pages = {57}, pmid = {26024660}, issn = {1756-9966}, mesh = {Apoptosis ; Cell Death ; Cell Line, Tumor ; Cell Survival ; Peptidyl-Prolyl Isomerase F ; Cyclophilins/*metabolism ; Glioma/*chemically induced/genetics ; Humans ; Pyrans/*adverse effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {BACKGROUND: The primary glioblastoma multiforme (GBM) is the most malignant form of astrocytic tumor with an average survival of approximately 12-14 months. The search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects; however, its role in GBM and the underlying mechanism are not clear.<br><br>RESULTS: Here we found that salinomycin induced both apoptosis and necrosis in cultured glioma cells, and necrosis played a major role in contributing salinomycin's cytotoxicity. Salinomycin induced p53 translocation to mitochondria, where it formed a complex with cyclophilin-D (CyPD). This complexation was required for mitochondrial permeability transition pore (mPTP) opening and subsequent programmed necrosis. Blockade of Cyp-D by siRNA-mediated depletion or pharmacological inhibitors (cyclosporin A and sanglifehrin A) significantly suppressed salinomycin-induced glioma cell necrosis. Meanwhile, p53 stable knockdown alleviated salinomycin-induced necrosis in glioma cells. Reactive oxygen species (ROS) production was required for salinomycin-induced p53 mitochondrial translocation, mPTP opening and necrosis, and anti-oxidants n-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) inhibited p53 translocation, mPTP opening and glioma cell death.<br><br>CONCLUSIONS: Thus, salinomycin mainly induces programmed necrosis in cultured glioma cells.}, }
@article {pmid26024013, year = {2015}, author = {Annabi, A and Dhouib, IB and Lamine, AJ and El Golli, N and Gharbi, N and El Fazâa, S and Lasram, MM}, title = {Recovery by N-acetylcysteine from subchronic exposure to Imidacloprid-induced hypothalamic-pituitary-adrenal (HPA) axis tissues injury in male rats.}, journal = {Toxicology mechanisms and methods}, volume = {25}, number = {7}, pages = {524-531}, doi = {10.3109/15376516.2015.1045663}, pmid = {26024013}, issn = {1537-6524}, mesh = {Acetylcysteine/*isolation &amp; purification/metabolism ; Adrenal Glands/pathology ; Animals ; Antioxidants/metabolism ; Calcium/metabolism ; Cholesterol/blood ; Hypothalamo-Hypophyseal System/drug effects/*injuries/metabolism ; Imidazoles/*toxicity ; Insecticides/*toxicity ; Male ; Neonicotinoids ; Nitro Compounds/*toxicity ; Organ Size ; Oxidative Stress/drug effects ; Parasympathetic Nervous System/drug effects ; Pituitary-Adrenal System/drug effects/*injuries/metabolism ; Rats ; Rats, Wistar ; Synaptic Transmission/drug effects ; }, abstract = {Imidacloprid is the most important example of the neonicotinoid insecticides known to target the nicotinic acetylcholine receptor in insects, and potentially in mammals. N-Acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the recovery effect of NAC against Imidacloprid-induced oxidative stress and cholinergic transmission alteration in hypothalamic-pituitary-adrenal (HPA) axis of male rats following subchronic exposure. About 40 mg/kg of Imidacloprid was administered daily by intragastric intubation and 28 days later, the rats were sacrificed and HPA axis tissues were removed for different analyses. Imidacloprid increased adrenal relative weight and cholesterol level indicating an adaptive stage of the general alarm reaction to stress. Moreover, Imidacloprid caused a significant increase in malondialdehyde level, the antioxidants catalase, superoxide dismutase and glutathione-S-transferase showed various alterations following administration and significant depleted thiols content was only recorded in hypothalamic tissue. Furthermore, the hypothalamic and pituitary acetylcholinesterase activity and calcium level were significantly increased highlighting the alteration of cholinergic activity. The present findings revealed that HPA axis is a sensitive target to Imidacloprid (IMI). Interestingly, the use of NAC for only 7 days post-exposure to IMI showed a partial therapeutic effect against Imidacloprid toxicity.}, }
@article {pmid26023743, year = {2015}, author = {Chen, L and Zong, R and Zhou, J and Ge, L and Zhou, T and Ma, JX and Liu, Z and Zhou, Y}, title = {The oxidant role of 4-hydroxynonenal in corneal epithelium.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {10630}, pmid = {26023743}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/*metabolism/pharmacology ; Animals ; Cells, Cultured ; Drug Antagonism ; Epithelial Cells/drug effects/metabolism ; Epithelium, Corneal/drug effects/*metabolism ; Humans ; Male ; NADPH Oxidase 4 ; NADPH Oxidases/metabolism ; NF-E2-Related Factor 2/metabolism ; Oxidants/*metabolism/pharmacology ; Oxidative Stress/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {4-Hydroxynonenal (4-HNE or HNE) is a main endogenous product of cellular lipid peroxidation in tissues and is reported to play pathogenic roles in eye diseases. Here we investigated the association between 4-HNE and oxidative stress in the corneal epithelium. 4-HNE suppressed the cell viability of human corneal epithelial cells (HCE) in a concentration dependent manner. 4-HNE significantly increased the level of 3-Nitrotyrosine (3-NT), a marker of oxidative stress, in HCE cells and corneal epithelium of rats by immunofluorescent staining and Western blot analysis. To its underlying mechanistic on ROS system, 4-HNE elevated the ROS generation enzyme NADPH oxidase 4 (NOX4) and induced the activation of NF-E2-related factor-2 (NRF2) and its downstream effectors: NAD(P)H dehydrogenase (quinone 1) (NQO1) and glutathione S-transferase P (GSTP). Furthermore, N-acetylcysteine (NAC), an antioxidant and ROS scavenger, antagonized the inhibitory and oxidant effects of 4-HNE on the corneal epithelial cells. In conclusion, 4-HNE plays an oxidant role in the corneal epithelium and this work provides a new strategy for the pathogenesis and treatment of corneal diseases.}, }
@article {pmid26022125, year = {2015}, author = {Tanti, GK and Pandey, S and Goswami, SK}, title = {SG2NA enhances cancer cell survival by stabilizing DJ-1 and thus activating Akt.}, journal = {Biochemical and biophysical research communications}, volume = {463}, number = {4}, pages = {524-531}, doi = {10.1016/j.bbrc.2015.05.069}, pmid = {26022125}, issn = {1090-2104}, mesh = {Animals ; Autoantigens/*physiology ; Calmodulin-Binding Proteins/*physiology ; Cell Line ; Cell Line, Tumor ; Cell Survival/*physiology ; Enzyme Activation ; Humans ; Intracellular Signaling Peptides and Proteins/*metabolism ; Mice ; Neoplasms/enzymology/metabolism/pathology ; Oncogene Proteins/*metabolism ; Peroxiredoxins/*metabolism ; Protein Deglycase DJ-1 ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {SG2NA in association with striatin and zinedin forms a striatin family of WD-40 repeat proteins. This family of proteins functions as scaffold in different signal transduction pathways. They also act as a regulatory subunit of protein phosphatase 2A. We have shown that SG2NA which evolved first in the metazoan evolution among the striatin family members expresses different isoforms generated out of alternative splicing. We have also shown that SG2NA protects cells from oxidative stress by recruiting DJ-1 and Akt to mitochondria and membrane in the post-mitotic neuronal cells. DJ-1 is both cancer and Parkinson's disease related protein. In the present study we have shown that SG2NA protects DJ-1 from proteasomal degradation in cancer cells. Hence, downregulation of SG2NA reduces DJ-1/Akt colocalization in cancer cells resulting in the reduction of anchorage dependent and independent growth. Thus SG2NA enhances cancer cell survival. Reactive oxygen species enhances SG2NA, DJ-1 and Akt trimerization. Removal of the reactive oxygen species by N-acetyl-cysteine thus reduces cancer cell growth.}, }
@article {pmid26019894, year = {2015}, author = {Rahmani, F and Ebrahimi Bakhtavar, H and Ghavidel, A}, title = {Acute hepatorenal failure in a patient following consumption of mushrooms: a case report.}, journal = {Iranian Red Crescent medical journal}, volume = {17}, number = {3}, pages = {e17973}, pmid = {26019894}, issn = {2074-1804}, abstract = {INTRODUCTION: One of the highly toxic mushrooms that are common in the northwest region of Iran is Amanita phalloides, which might result in renal or liver failure.<br><br>CASE PRESENTATION: This is a case report of a patient referred a few days after consumption of wild mushrooms to emergency department having gastrointestinal complaint whose experiments indicated liver and renal failure. The supportive treatment was given to the patient prescribing N-acetyl cysteine (NAC) and Livergol (silymarin) along with hemodialysis. A few days after admission to the hospital, the patient died due to severe clinical symptoms.<br><br>CONCLUSIONS: The patient was poisoned by A. phalloides complaining gastrointestinal symptoms including nausea; vomiting and watery diarrhea about six hours after consumption and then, amatoxin in the mushroom caused damage to hepatocytes and renal cells and finally led to hepatorenal failure. Deaths caused by this type of mushroom are extremely high and necessary trainings should be provided to the people by the health system not to consume wild mushrooms, especially in spring and summer.}, }
@article {pmid26018652, year = {2015}, author = {Fan, HQ and He, W and Xu, KF and Wang, ZX and Xu, XY and Chen, H}, title = {FTO Inhibits Insulin Secretion and Promotes NF-κB Activation through Positively Regulating ROS Production in Pancreatic β cells.}, journal = {PloS one}, volume = {10}, number = {5}, pages = {e0127705}, pmid = {26018652}, issn = {1932-6203}, mesh = {Acetylcysteine/metabolism ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Animals ; Diabetes Mellitus, Type 2/metabolism ; Gene Expression Regulation/physiology ; Glucose/metabolism ; Insulin/*metabolism ; Insulin Resistance/physiology ; Insulin-Secreting Cells/*metabolism ; Islets of Langerhans/*metabolism ; Mice ; Mice, Inbred C57BL ; Mixed Function Oxygenases/*metabolism ; NF-kappa B/*metabolism ; Oxo-Acid-Lyases/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction/physiology ; }, abstract = {FTO (Fat mass and obesity-associated) is associated with increased risk of obesity and type 2 diabetes incurrence. Pancreas islet β cells dysfunction and insulin resistance are major causes of type 2 diabetes. However, whether FTO plays an important functional role in pancreatic β cells as well as the related molecular mechanism is still unclear. In the present study, the tissue expression profile of FTO was firstly determined using quantitative PCR and western blot. FTO is widely expressed in various tissues and presented with relative high expression in pancreas tissue, especially in endocrine pancreas. FTO overexpression in MIN6 cells achieved by lentivirus delivery significantly inhibits insulin secretion in the presence of glucose stimulus as well as KCl. FTO silence has no effect on insulin secretion of MIN6 cells. However, FTO overexpression doesn't affect the transcription of insulin gene. Furthermore, reactive oxygen species (ROS) production and NF-κB activation are significantly promoted by FTO overexpression. Inhibition of intracellular ROS production by N-acetyl-L-cysteine (NAC) can alleviate NF-κB activation and restore the insulin secretion mediated by FTO overexpression. A whole transcript-microarray is employed to analyze the differential gene expression mediated by FTO overexpression. The genes which are modulated by FTO are involved in many important biological pathways such as G-protein coupled receptor signaling and NF-κB signaling. Therefore, our study indicates that FTO may contribute to pancreas islet β cells dysfunction and the inhibition of FTO activity is a potential target for the treatment of diabetes.}, }
@article {pmid26013662, year = {2015}, author = {Lee, WJ and Chien, MH and Chow, JM and Chang, JL and Wen, YC and Lin, YW and Cheng, CW and Lai, GM and Hsiao, M and Lee, LM}, title = {Nonautophagic cytoplasmic vacuolation death induction in human PC-3M prostate cancer by curcumin through reactive oxygen species -mediated endoplasmic reticulum stress.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {10420}, pmid = {26013662}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Curcumin/*pharmacology ; Cycloheximide/pharmacology ; Disease Models, Animal ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Heat-Shock Proteins/metabolism ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, SCID ; Microtubule-Associated Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Prostatic Neoplasms/metabolism/pathology ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/metabolism ; Transplantation, Heterologous ; Vacuoles/metabolism ; }, abstract = {The antiapoptotic and antiautophagic abilities of cancer cells constitute a major challenge for anticancer drug treatment. Strategies for triggering nonapoptotic or nonautophagic cell death may improve therapeutic efficacy against cancer. Curcumin has been reported to exhibit cancer chemopreventive properties. Herein, we report that curcumin induced apoptosis in LNCaP, DU145, and PC-3 cells but triggered extensive cytoplasmic vacuolation in PC-3M cells. Electron microscopic images showed that the vacuoles lacked intracellular organelles and were derived from the endoplasmic reticulum (ER). Moreover, curcumin-induced vacuolation was not reversed by an apoptosis- or autophagy-related inhibitor, suggesting that vacuolation-mediated cell death differs from classical apoptotic and autophagic cell death. Mechanistic investigations revealed that curcumin treatment upregulated the ER stress markers CHOP and Bip/GRP78 and the autophagic marker LC3-II. In addition, curcumin induced ER stress by triggering ROS generation, which was supported by the finding that treating cells with the antioxidant NAC alleviated curcumin-mediated ER stress and vacuolation-mediated death. An in vivo PC-3M orthotopic prostate cancer model revealed that curcumin reduced tumor growth by inducing ROS production followed by vacuolation-mediated cell death. Overall, our results indicated that curcumin acts as an inducer of ROS production, which leads to nonapoptotic and nonautophagic cell death via increased ER stress.}, }
@article {pmid26011614, year = {2015}, author = {Yang, X and Yin, Z and Chen, F and Hu, J and Yang, Y}, title = {Organic matter induced mobilization of polymer-coated silver nanoparticles from water-saturated sand.}, journal = {The Science of the total environment}, volume = {529}, number = {}, pages = {182-190}, doi = {10.1016/j.scitotenv.2015.05.066}, pmid = {26011614}, issn = {1879-1026}, mesh = {Adsorption ; Edetic Acid ; Metal Nanoparticles/*chemistry ; *Models, Chemical ; Polymers/*chemistry ; Silicon Dioxide/chemistry ; Silver/*chemistry ; }, abstract = {Mobilization of polymer-coated silver nanoparticles (AgNPs) by anionic surfactant (sodium dodecylbenzenesulphonate: SDBS), amino acid derivative (N-acetylcysteine: NAC), and chelate (ethylenediaminetetraacetic acid: EDTA) in water-saturated sand medium was explored based on carefully designed column tests. Exposure experiments monitoring the size evolution of polyvinylpyrrolidone (PVP) coated AgNPs in organic solutions confirm the capacity of SDBS, NAC and EDTA to partly displace PVP. Single Pulse Column Experiment (SPCE) results show both the PVP polymer and the silver core controlled AgNP deposition while the effect of the PVP was dominant. Results of Co-injected Pulse Column Experiments (CPCEs) where AgNP and SDBS or NAC were co-injected into the column following a very short mixing (<1 s) disprove our hypothesis that coating-alternation by particle associated organic would mobilize irreversibly deposited particles from the uncoated sand, while surface charge modification by adsorbed NAC was identified as a potential mobilizing mechanism for AgNP from the iron-oxide-coated sand. Triple Pulse Column Experiment (TPCE) results confirm that such a charging effect of the adsorbed organic molecules may enable SDBS and NAC to mobilize AgNPs from the iron-oxide-coated sands. TPCE results with five distinct levels of SDBS indicate that concentration-stimulated change in the SDBS format from an individual to a micelle significantly increased the mobilizing efficiency and site blockage of SDBS. Although being an electrolyte, EDTA did not mobilize AgNPs, as the case with SDBS or NAC, as it dissolved the iron oxides which in turn prevented EDTA adsorption on sand. The findings have implications for better understanding the behavior of polymer-coated nanoparticles in organic-presented groundwater systems, i.e., detachment-associated uncertainty in exposure prediction of the nanomaterials.}, }
@article {pmid26008662, year = {2015}, author = {Saleem, AF and Abbas, Q and Haque, AU}, title = {Use of N-acetylcysteine in children with fulminant hepatic failure caused by acute viral hepatitis.}, journal = {Journal of the College of Physicians and Surgeons--Pakistan : JCPSP}, volume = {25}, number = {5}, pages = {354-358}, pmid = {26008662}, issn = {1681-7168}, support = {1 D43 TW00758501/TW/FIC NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Adolescent ; Analysis of Variance ; Antiviral Agents/*therapeutic use ; Child ; Child, Preschool ; Female ; Hepatitis, Viral, Human/complications/*diagnosis/immunology ; Humans ; Infant ; Jaundice/etiology ; Liver Failure, Acute/*drug therapy/etiology ; Liver Function Tests ; Male ; Retrospective Studies ; Risk Factors ; Treatment Outcome ; Vomiting/etiology ; }, abstract = {OBJECTIVE: To determine the efficacy of N-acetylcysteine (NAC) in children aged > 1 month to 16 years admitted with Fulminant Hepatic Failure (FHF) secondary to Acute Viral Hepatitis (AVH) in a tertiary care center of a developing country.<br><br>STUDY DESIGN: Analytical study.<br><br>PLACE AND DURATION OF STUDY: Department of Paediatrics, The Aga Khan University Hospital, Karachi, Pakistan, from January 2007 to December 2011.<br><br>METHODOLOGY: Medical records of children (> 1 month - 16 years) with FHF admitted with AVH of known etiology who received NAC were reviewed retrospectively. Liver function tests (mean &#xb1; SD) at baseline, 24 hours after NAC and before or at the time of discharge/death were recorded and compared via using repeated measures ANOVA(r-ANOVA). Efficacy of NAC is defined in improvement in biochemical markers, liver function test and discharge disposition (survived or died). Mortality associated risk factors were identified by using logistic regression analysis. P-value and 95% confidence interval were recorded.<br><br>RESULTS: Forty children (mean age was 80 &#xb1; 40 months) with FHF secondary to AVH received NAC. Majority were males (n=25; 63%). Vomiting (75%) and jaundice (65%) were the main presenting symptoms, one-third had hypoglycemic, while 40% had altered sensorium at the time of admission. There was significant statistical difference in liver enzymes and prothrombin time on admission comparing at discharge in children received NAC (p < 0.001). Fifteen (38%) children died. Severe vomiting {Odds Ratio (OR) 0.22, 95% Confidence Interval (CI) 0.05 - 0.8}, jaundice (OR 9.3, CI 1.1 - 82.6), inotropic support (OR 20.6, CI 3.5 - 118.3) and mechanical ventilation (OR 4.3, CI 1.1 - 16.6) at the time of admission are associated with risk factors for mortality in children with FHF secondary to AVH.<br><br>CONCLUSION: NAC used in children with FHF secondary to AVH is associated with markedly improved liver function tests and recovery. FHF with complications is high risk for mortality.}, }
@article {pmid26006043, year = {2015}, author = {Muniroh, M and Khan, N and Koriyama, C and Akiba, S and Vogel, CF and Yamamoto, M}, title = {Suppression of methylmercury-induced IL-6 and MCP-1 expressions by N-acetylcysteine in U-87MG human astrocytoma cells.}, journal = {Life sciences}, volume = {134}, number = {}, pages = {16-21}, doi = {10.1016/j.lfs.2015.04.024}, pmid = {26006043}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology ; Astrocytes/metabolism/pathology ; Astrocytoma/*metabolism/pathology ; Cell Line, Tumor ; Chemokine CCL2/*biosynthesis ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Hydrogen Peroxide/metabolism ; Interleukin-6/*biosynthesis ; Methylmercury Compounds/*pharmacology ; Neoplasm Proteins/*biosynthesis ; Oxidative Stress/drug effects ; Superoxides/metabolism ; }, abstract = {AIMS: The aim of this study was to clarify the involvement of oxidative stress in methylmercury (MeHg)-induced pro-inflammatory cytokine expressions and the suppressive effects of N-acetylcysteine (NAC) in MeHg-induced cytokine expression.<br><br>MATERIALS AND METHODS: Using U-87-MG human astrocytoma cell line, interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 expressions induced by 4 &#x3bc;M MeHg were measured at mRNA and protein levels. Hydrogen peroxide (H2O2) and superoxide anion (O2(-)) were quantified by flow-cytometry analysis. To examine the suppressive effects of NAC on the cytokine expressions among different timing of NAC treatment, cells were treated with 0.5 or 5mM NAC before, simultaneously, or after MeHg administration.<br><br>KEY FINDINGS: MeHg exposure at 4 &#x3bc;M, a non-cytotoxic concentration, significantly induced MCP-1 and IL-6 expressions at both mRNA and protein levels. A significant increase of H2O2 production but not O2(-) was observed. MeHg-induced expression of MCP-1 and IL-6 mRNA was reduced by 10-20% in the presence of 5mM NAC (co-treatment experiment) compared to cells treated with MeHg only. Pre-treatment of cells with 0.5 or 5mM NAC at 0.5 or 1h and its subsequent washout before MeHg addition suppressed MCP-1 and IL-6 cytokine expressions. Post-treatment of cells with NAC after MeHg addition also suppressed the cytokine induction, but the magnitude of suppression was evidently lower than in co-treated cells even though the H2O2 generation was almost completely suppressed by NAC.<br><br>SIGNIFICANCE: NAC may effectively suppress the MeHg-induced cytokine production through both, inhibition of reactive oxygen species as well as extracellular chelation of MeHg in astrocytes.}, }
@article {pmid26000607, year = {2015}, author = {Zhang, M and Harashima, N and Moritani, T and Huang, W and Harada, M}, title = {The Roles of ROS and Caspases in TRAIL-Induced Apoptosis and Necroptosis in Human Pancreatic Cancer Cells.}, journal = {PloS one}, volume = {10}, number = {5}, pages = {e0127386}, pmid = {26000607}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Annexin A5/metabolism ; Apoptosis/drug effects/*physiology ; Caspases/*metabolism ; Cell Death/drug effects/*physiology ; Cell Line, Tumor ; Cyclic N-Oxides/pharmacology ; Humans ; Imidazoles/pharmacology ; Indoles/pharmacology ; Pancreatic Neoplasms/*metabolism/pathology ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/metabolism ; Spin Labels ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; }, abstract = {Death signaling provided by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) can induce death in cancer cells with little cytotoxicity to normal cells; this cell death has been thought to involve caspase-dependent apoptosis. Reactive oxygen species (ROS) are also mediators that induce cell death, but their roles in TRAIL-induced apoptosis have not been elucidated fully. In the current study, we investigated ROS and caspases in human pancreatic cancer cells undergoing two different types of TRAIL-induced cell death, apoptosis and necroptosis. TRAIL treatment increased ROS in two TRAIL-sensitive pancreatic cancer cell lines, MiaPaCa-2 and BxPC-3, but ROS were involved in TRAIL-induced apoptosis only in MiaPaCa-2 cells. Unexpectedly, inhibition of ROS by either N-acetyl-L-cysteine (NAC), a peroxide inhibitor, or Tempol, a superoxide inhibitor, increased the annexin V-/propidium iodide (PI)+ early necrotic population in TRAIL-treated cells. Additionally, both necrostatin-1, an inhibitor of receptor-interacting protein kinase 1 (RIP1), and siRNA-mediated knockdown of RIP3 decreased the annexin V-/PI+ early necrotic population after TRAIL treatment. Furthermore, an increase in early apoptosis was induced in TRAIL-treated cancer cells under inhibition of either caspase-2 or -9. Caspase-2 worked upstream of caspase-9, and no crosstalk was observed between ROS and caspase-2/-9 in TRAIL-treated cells. Together, these results indicate that ROS contribute to TRAIL-induced apoptosis in MiaPaCa-2 cells, and that ROS play an inhibitory role in TRAIL-induced necroptosis of MiaPaCa-2 and BxPC-3 cells, with caspase-2 and -9 playing regulatory roles in this process.}, }
@article {pmid26000292, year = {2015}, author = {Gao, L and Gao, M and Yang, G and Tao, Y and Kong, Y and Yang, R and Meng, X and Ai, G and Wei, R and Wu, H and Wu, X and Shi, J}, title = {Synergistic Activity of Carfilzomib and Panobinostat in Multiple Myeloma Cells via Modulation of ROS Generation and ERK1/2.}, journal = {BioMed research international}, volume = {2015}, number = {}, pages = {459052}, pmid = {26000292}, issn = {2314-6141}, mesh = {Apoptosis/drug effects ; Caspases/metabolism ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Synergism ; Enzyme Activation/drug effects ; Humans ; Hydroxamic Acids/*pharmacology ; Indoles/*pharmacology ; MAP Kinase Signaling System/drug effects ; Mitochondria/drug effects/metabolism ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3/*metabolism ; Multiple Myeloma/*drug therapy/enzymology/*metabolism/pathology ; Oligopeptides/*pharmacology ; Panobinostat ; Reactive Oxygen Species/*metabolism ; }, abstract = {Relapse of disease and subsequent resistance to established therapies remain as major challenges in the treatment of multiple myeloma (MM). New therapeutic options are needed for these extensively pretreated patients. To explore an optimized combinational therapy, interactions between the irreversible proteasome inhibitor carfilzomib exhibiting a well-tolerated side-effect profile and histone deacetylase inhibitor (HDACi) panobinostat (LBH589) were examined in MM cells. Coadministration of carfilzomib and LBH589 led to a synergistic inhibition of proliferation in MM cells. Further studies showed that the combined treatment synergistically increased mitochondrial injury, caspase activation, and apoptosis in MM cells. Lethality of the carfilzomib/LBH589 combination was associated with the reactive oxygen species (ROS) generation and ERK1/2 inactivation. In addition, the free radical scavenger N-acetylcysteine (NAC) could block carfilzomib and LBH589-induced oxidative stress and the subsequent apoptosis. Together, these findings argue that the strategy of combining carfilzomib and LBH589 warrants attention in MM.}, }
@article {pmid25999707, year = {2015}, author = {Zhang, JQ and Zhang, JQ and Liu, H and Zhao, ZH and Fang, LZ and Liu, L and Fu, WP and Shu, JK and Feng, JG and Dai, LM}, title = {Effect of N-acetylcysteine in COPD patients with different microsomal epoxide hydrolase genotypes.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {10}, number = {}, pages = {917-923}, pmid = {25999707}, issn = {1178-2005}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Antioxidants/*administration &amp; dosage ; Disease Progression ; Drug Administration Schedule ; Epoxide Hydrolases/*genetics/metabolism ; Female ; Forced Expiratory Volume ; Humans ; Lung/*drug effects/physiopathology ; Male ; Middle Aged ; Pharmacogenetics ; Phenotype ; *Polymorphism, Genetic ; Pulmonary Disease, Chronic Obstructive/diagnosis/*drug therapy/enzymology/genetics/physiopathology ; Recovery of Function ; Severity of Illness Index ; Spirometry ; Surveys and Questionnaires ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: The role of the antioxidant N-acetylcysteine (NAC) in the treatment of chronic obstructive pulmonary disease (COPD) has not been clarified as yet. In early studies, we found that the proportion of smokers with COPD having extremely slow/slow microsomal epoxide hydrolase (EPHX1) enzyme activity is significantly higher than that in healthy smokers. The purpose of this study was to evaluate whether different EPHX1 enzyme activity is related to differential therapeutic effects of treatment with NAC in COPD.<br><br>METHODS: A total of 219 patients with COPD were randomly allocated to an extremely slow/slow EPHX1 enzyme activity group (n=157) or a fast/normal EPHX1 enzyme activity group (n=62) according to their EPHX1 enzyme activity. Both groups were treated with NAC 600 mg twice daily for one year. The main study parameters, including forced expiratory volume in one second (FEV1), St George's Respiratory Questionnaire (SGRQ), and yearly exacerbation rate, were measured at baseline and at 6-month intervals for one year.<br><br>RESULTS: Both FEV1 and SGRQ symptom scores were improved after treatment with NAC in the slow activity group when compared with the fast activity group. Further, changes in FEV1 and SGRQ symptom score in patients with mild-to-moderate COPD were more significant than those in patients with severe-to-very severe COPD. The yearly exacerbation rates were reduced in both groups, but the reduction in the slow activity group was significantly lower than in the fast activity group.<br><br>CONCLUSION: NAC treatment in COPD patients with extremely slow/slow EPHX1 enzyme activity improves FEV1 and the SGRQ symptom score, especially in those with mild-to-moderate COPD, and polymorphism in the EPHX1 gene may have a significant role in differential responses to treatment with NAC in patients with COPD.}, }
@article {pmid25998848, year = {2015}, author = {Göder, A and Nagel, G and Kraus, A and Dörsam, B and Seiwert, N and Kaina, B and Fahrer, J}, title = {Lipoic acid inhibits the DNA repair protein O 6-methylguanine-DNA methyltransferase (MGMT) and triggers its depletion in colorectal cancer cells with concomitant autophagy induction.}, journal = {Carcinogenesis}, volume = {36}, number = {8}, pages = {817-831}, doi = {10.1093/carcin/bgv070}, pmid = {25998848}, issn = {1460-2180}, mesh = {Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Autophagy/*drug effects ; Colorectal Neoplasms/*drug therapy/metabolism/pathology ; Cysteine/metabolism ; DNA Modification Methylases/antagonists &amp; inhibitors/genetics/*metabolism ; DNA Repair/drug effects ; DNA Repair Enzymes/antagonists &amp; inhibitors/genetics/*metabolism ; Dacarbazine/analogs &amp; derivatives/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Female ; Glutathione/metabolism ; Guanine/analogs &amp; derivatives/metabolism ; HCT116 Cells/drug effects ; Humans ; Male ; Mice, Inbred BALB C ; Molecular Targeted Therapy ; Temozolomide ; Thioctic Acid/analogs &amp; derivatives/*pharmacology ; Tumor Suppressor Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Alkylating agents are present in food and tobacco smoke, but are also used in cancer chemotherapy, inducing the DNA lesion O (6)-methylguanine. This critical adduct is repaired by O (6)-methylguanine-DNA methyltransferase (MGMT), resulting in MGMT inactivation and degradation. In the present study, we analyzed the effects of the natural disulfide compound lipoic acid (LA) on MGMT in vitro and in colorectal cancer cells. We show that LA, but not its reduced form dihydrolipoic acid, potently inhibits the activity of recombinant MGMT by interfering with its catalytic Cys-145 residue, which was partially reversible by N-acetyl cysteine. Incubation of HCT116 colorectal cancer cells with LA altered their glutathione pool and caused a decline in MGMT activity. This was mirrored by LA-induced depletion of MGMT protein, which was not attributable to changes in MGMT messenger RNA levels. Loss of MGMT protein coincided with LA-induced autophagy, a process resulting in lysosomal degradation of proteins, including presumably MGMT. LA-stimulated autophagy in a p53-independent manner as revealed by the response of isogenic HCT116 cell lines. Knockdown of the crucial autophagy component beclin-1 and chemical inhibitors blocked LA-induced autophagy, but did not abrogate LA-triggered MGMT degradation. Concomitant with MGMT depletion, LA pretreatment resulted in enhanced O (6)-methylguanine levels in DNA. It also increased the cytotoxicity of the alkylating anticancer drug temozolomide in temozolomide-resistant colorectal cancer cells. Taken together, our study showed that the natural compound LA inhibits MGMT and induces autophagy. Furthermore, LA enhanced the cytotoxic effects of temozolomide, which makes it a candidate for a supplement in cancer therapy.}, }
@article {pmid25998424, year = {2015}, author = {Collins, JA and Moots, RJ and Clegg, PD and Milner, PI}, title = {Resveratrol and N-acetylcysteine influence redox balance in equine articular chondrocytes under acidic and very low oxygen conditions.}, journal = {Free radical biology &amp; medicine}, volume = {86}, number = {}, pages = {57-64}, pmid = {25998424}, issn = {1873-4596}, support = {MR/K006312/1/MRC_/Medical Research Council/United Kingdom ; BB/F017502/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cartilage, Articular/cytology ; Cell Hypoxia ; Cells, Cultured ; Chondrocytes/drug effects/*metabolism ; Glutathione/metabolism ; Glycosaminoglycans/metabolism ; Horses ; Hydrogen-Ion Concentration ; Interleukin-1/physiology ; Membrane Potential, Mitochondrial ; Resveratrol ; Stilbenes/*pharmacology ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Mature articular cartilage is an avascular tissue characterized by a low oxygen environment. In joint disease, acidosis and further reductions in oxygen levels occur, compromising cartilage integrity.This study investigated how acidosis and very low oxygen levels affect components of the cellular redox system in equine articular chondrocytesand whether the antioxidants resveratrol and N-acetylcysteine could modulate this system. We used articular chondrocytes isolated from nondiseased equine joints and cultured them in a 3-D alginate bead system for 48h in <1, 2, 5, and 21% O2 at pH 7.2 or 6.2 in the absence or presence of the proinflammatory cytokine, interleukin-1β (10ng/ml).In addition, chondrocytes were cultured with resveratrol (10µM) or N-acetylcysteine (NAC) (2mM).Cell viability, glycosaminoglycan (GAG) release, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS), GSH:GSSG ratio, and SOD1 and SOD2 protein expression were measured. Very low levels of oxygen (<1%), acidosis (pH 6.2), and exposure to IL-1β led to reductions in cell viability, increased GAG release, alterations in ΔΨm and ROS levels, and reduced GSH:GSSG ratio. In addition, SOD1 and SOD2 protein expressions were reduced. Both resveratrol and NAC partially restored ΔΨm and ROS levels and prevented GAG release and cell loss and normalized SOD1 and SOD2 protein expression. In particular NAC was highly effective at restoring the GSH:GSSG ratio.These results show that the antioxidants resveratrol and N-acetylcysteine can counteract the redox imbalance in articular chondrocytes induced by low oxygen and acidic conditions.}, }
@article {pmid25998312, year = {2015}, author = {Hu, KH and Li, WX and Sun, MY and Zhang, SB and Fan, CX and Wu, Q and Zhu, W and Xu, X}, title = {Cadmium Induced Apoptosis in MG63 Cells by Increasing ROS, Activation of p38 MAPK and Inhibition of ERK 1/2 Pathways.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {36}, number = {2}, pages = {642-654}, doi = {10.1159/000430127}, pmid = {25998312}, issn = {1421-9778}, mesh = {Apoptosis/*drug effects ; Cadmium/*toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Environmental Pollutants/*toxicity ; Humans ; MAP Kinase Signaling System/*drug effects ; Osteoblasts/cytology/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {BACKGROUND/AIMS: Cadmium (Cd) induces apoptosis in different kinds of cells, including osteoblasts, both in vivo and in vitro. However, little is known about the mechanisms by which Cd induces apoptosis.<br><br>METHODS: In the present study, we used the human osteosarcoma cell line MG63, which has characteristics similar to human osteoblasts, as an in vitro model to determine the cellular mechanisms by which Cd induces apoptosis.<br><br>RESULTS: We found that short-term exposure to CdCl2 induced apoptosis in MG63 cells. Furthermore, the incubation of cells with CdCl2 significantly increased the level of phosphorylated p38MAPK and significantly decreased the phosphorylation of ERK1/2 in a concentration-dependent manner. Additionally, the inhibition of the phosphorylation of p38 MAPK by SB202190 protected MG63 cells from Cd-induced apoptosis. The incubation of MG63 cells with the ERK1/2 inhibitor PD98059 significantly increased apoptosis in MG63 cells. CdCl2 also significantly increased the intracellular levels of ROS. N-acetylcysteine (NAC) significantly reduced ROS levels and reversed the effects of CdCl2 on MAPK signaling.<br><br>CONCLUSION: Our results suggested that Cd induced apoptosis in MG63 cells by increasing ROS, activation of p38 MAPK and inhibition of ERK1/2 pathways.}, }
@article {pmid25997958, year = {2015}, author = {Bu, HQ and Cai, K and Shen, F and Bao, XD and Xu, Y and Yu, F and Pan, HQ and Chen, CH and Du, ZJ and Cui, JH}, title = {Induction of apoptosis by capsaicin in hepatocellular cancer cell line SMMC-7721 is mediated through ROS generation and activation of JNK and p38 MAPK pathways.}, journal = {Neoplasma}, volume = {62}, number = {4}, pages = {582-591}, doi = {10.4149/neo_2015_070}, pmid = {25997958}, issn = {0028-2685}, abstract = {Capsaicin, one of the major pungent ingredients found in red peppers, has been shown to have anti-carcinogenic effect on various cancer cells through multiple mechanisms. In this study, we investigated the apoptotic effect of capsaicin on human hepatocellular cancer cell line SMMC-7721, as well as the possible mechanisms involved. Treatment of SMMC-7721 cells with capsaicin resulted in a dose-dependent inhibition of cell-viability and induction of apoptosis which was associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. These effects were significantly blocked when cells were pretreated with a general antioxidant N-acetyl cysteine (NAC). We also found that capsaicin induced JNK and p38 MAPK phosphorylation. JNK and p38 MAPK inhibitor effectively blocked capsaicin-induced SMMC-7721 cell apoptosis. In addition, NAC completely blocked phosphorylation of JNK and p38 MAPK induced by capsaicin. Our results indicate that capsaicin induced in SMMC-7721 cell apoptosis through generation of intracellular ROS and activation of JNK and p38 MAPK pathways.}, }
@article {pmid25994759, year = {2016}, author = {Woo, SH and Yang, LP and Chuang, HC and Fitzgerald, A and Lee, HY and Pickering, C and Myers, JN and Skinner, HD}, title = {Down-regulation of malic enzyme 1 and 2: Sensitizing head and neck squamous cell carcinoma cells to therapy-induced senescence.}, journal = {Head &amp; neck}, volume = {38 Suppl 1}, number = {}, pages = {E934-40}, doi = {10.1002/hed.24129}, pmid = {25994759}, issn = {1097-0347}, mesh = {Carcinoma, Squamous Cell/*metabolism/pathology ; Cell Line, Tumor ; Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Head and Neck Neoplasms/*metabolism/pathology ; Humans ; Malate Dehydrogenase/genetics/*metabolism ; Metformin/pharmacology ; Radiation, Ionizing ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {BACKGROUND: The purpose of this study was to present the results of our investigation of malic enzyme (ME) expression and the induction of senescence in head and neck squamous cell carcinoma (HNSCC).<br><br>METHODS: P53, ME1, ME2, and aspects of cellular metabolism, such as reactive oxygen species (ROS) were investigated in HNSCC cell lines.<br><br>RESULTS: Both metformin and ionizing radiation inhibited the expression of ME2, but not ME1, in HNSCC. Knockdown of ME1 or ME2 potentiated therapy-induced senescence in HNSCC cells regardless of p53 status, and led to increased p21 and generation of ROS. Therapy-induced senescence in ME-depleted cells was blocked by the antioxidant N-acetyl cysteine. Finally, high expression of ME2 was associated with poorer overall survival (OS) in patients with HNSCC.<br><br>CONCLUSION: Depletion of ME enhances therapy-induced senescence and seems driven largely by ROS. ME2 expression in HNSCC may be associated with poor outcome, providing a possible link between therapy-induced senescence and patient outcome, and indicating a potential therapeutic benefit of targeting ME2. &#xa9; 2015 Wiley Periodicals, Inc. Head Neck 38: E934-E940, 2016.}, }
@article {pmid25988491, year = {2015}, author = {Guo, X and Jiang, X and Ren, X and Sun, H and Zhang, D and Zhang, Q and Zhang, J and Huang, Y}, title = {The Galvanotactic Migration of Keratinocytes is Enhanced by Hypoxic Preconditioning.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {10289}, pmid = {25988491}, issn = {2045-2322}, mesh = {Animals ; Cell Hypoxia/*physiology ; Cell Movement/*physiology ; Cells, Cultured ; Electricity ; *Ischemic Preconditioning ; Keratinocytes/*physiology ; Mice ; Mice, Inbred BALB C ; Re-Epithelialization/*physiology ; Reactive Oxygen Species/metabolism ; Skin/injuries ; Wound Healing/physiology ; }, abstract = {The endogenous electric field (EF)-directed migration of keratinocytes (galvanotaxis) into wounds is an essential step in wound re-epithelialization. Hypoxia, which occurs immediately after injury, acts as an early stimulus to initiate the healing process; however, the mechanisms for this effect, remain elusive. We show here that the galvanotactic migration of keratinocytes was enhanced by hypoxia preconditioning as a result of the increased directionality rather than the increased motility of keratinocytes. This enhancement was both oxygen tension- and preconditioning time-dependent, with the maximum effects achieved using 2% O2 preconditioning for 6 hours. Hypoxic preconditioning (2% O2, 6 hours) decreased the threshold voltage of galvanotaxis to < 25 mV/mm, whereas this value was between 25 and 50 mV/mm in the normal culture control. In a scratch-wound monolayer assay in which the applied EF was in the default healing direction, hypoxic preconditioning accelerated healing by 1.38-fold compared with the control conditions. Scavenging of the induced ROS by N-acetylcysteine (NAC) abolished the enhanced galvanotaxis and the accelerated healing by hypoxic preconditioning. Our data demonstrate a novel and unsuspected role of hypoxia in supporting keratinocyte galvanotaxis. Enhancing the galvanotactic response of cells might therefore be a clinically attractive approach to induce improved wound healing.}, }
@article {pmid25985305, year = {2015}, author = {Checconi, P and Salzano, S and Bowler, L and Mullen, L and Mengozzi, M and Hanschmann, EM and Lillig, CH and Sgarbanti, R and Panella, S and Nencioni, L and Palamara, AT and Ghezzi, P}, title = {Redox proteomics of the inflammatory secretome identifies a common set of redoxins and other glutathionylated proteins released in inflammation, influenza virus infection and oxidative stress.}, journal = {PloS one}, volume = {10}, number = {5}, pages = {e0127086}, pmid = {25985305}, issn = {1932-6203}, mesh = {Animals ; Antioxidants/pharmacology ; Blotting, Western ; Cell Line ; Dexamethasone/pharmacology ; Down-Regulation/drug effects ; Glutathione/*metabolism ; Humans ; Inflammation/complications/*metabolism/pathology ; Influenza, Human/complications/*metabolism/pathology ; Lipopolysaccharides/pharmacology ; Mice ; Oxidation-Reduction/drug effects ; *Oxidative Stress/drug effects ; Peroxiredoxins/metabolism ; Profilins/metabolism ; Proteins/*metabolism ; *Proteomics ; RAW 264.7 Cells ; Sulfhydryl Compounds/pharmacology ; Thioredoxins/metabolism ; Vimentin/metabolism ; }, abstract = {Protein cysteines can form transient disulfides with glutathione (GSH), resulting in the production of glutathionylated proteins, and this process is regarded as a mechanism by which the redox state of the cell can regulate protein function. Most studies on redox regulation of immunity have focused on intracellular proteins. In this study we have used redox proteomics to identify those proteins released in glutathionylated form by macrophages stimulated with lipopolysaccharide (LPS) after pre-loading the cells with biotinylated GSH. Of the several proteins identified in the redox secretome, we have selected a number for validation. Proteomic analysis indicated that LPS stimulated the release of peroxiredoxin (PRDX) 1, PRDX2, vimentin (VIM), profilin1 (PFN1) and thioredoxin 1 (TXN1). For PRDX1 and TXN1, we were able to confirm that the released protein is glutathionylated. PRDX1, PRDX2 and TXN1 were also released by the human pulmonary epithelial cell line, A549, infected with influenza virus. The release of the proteins identified was inhibited by the anti-inflammatory glucocorticoid, dexamethasone (DEX), which also inhibited tumor necrosis factor (TNF)-α release, and by thiol antioxidants (N-butanoyl GSH derivative, GSH-C4, and N-acetylcysteine (NAC), which did not affect TNF-α production. The proteins identified could be useful as biomarkers of oxidative stress associated with inflammation, and further studies will be required to investigate if the extracellular forms of these proteins has immunoregulatory functions.}, }
@article {pmid25983264, year = {2015}, author = {Sachdeva, S and Pant, SC and Kushwaha, P and Bhargava, R and Flora, SJ}, title = {Sodium tungstate induced neurological alterations in rat brain regions and their response to antioxidants.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {82}, number = {}, pages = {64-71}, doi = {10.1016/j.fct.2015.05.003}, pmid = {25983264}, issn = {1873-6351}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/pharmacology ; Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Brain/*drug effects/metabolism ; Dopamine/metabolism ; Flavanones/pharmacology ; Glutathione Peroxidase/metabolism ; Glutathione Transferase/metabolism ; Male ; Monoamine Oxidase/metabolism ; Neurotransmitter Agents/metabolism ; Oxidative Stress/drug effects ; Rats, Wistar ; Toxicity Tests, Subchronic/methods ; Tungsten Compounds/administration &amp; dosage/*toxicity ; }, abstract = {Tungsten, recognized recently as an environmental contaminant, is being used in arms and ammunitions as substitute to depleted uranium. We studied the effects of sodium tungstate on oxidative stress, few selected neurological variables like acetylcholinesterase, biogenic amines in rat brain regions (cerebral cortex, hippocampus and cerebellum) and their prevention following co-administration of N-acetylcysteine (NAC), naringenin and quercetin. Animals were sub-chronically exposed to sodium tungstate (100 ppm in drinking water) and orally co-supplemented with different antioxidants (0.30 mM) for three months. Sodium tungstate significantly decreased the activity of acetylcholinesterase, dopamine, nor-epinephrine and 5-hydroxytryptamine levels while it increased monoamine oxidase activity in different brain regions. Tungstate exposure produced a significant increase in biochemical variables indicative of oxidative stress while, neurological alterations were more pronounced in the cerebral cortex compared to other regions. Co-administration of NAC and flavonoids with sodium tungstate significantly restored glutathione, prevented changes in the brain biogenic amines, reactive oxygen species (ROS) and TBARS levels in the different brain regions. The protection was more prominent in the animals co-administered with NAC. We can thus conclude that sodium tungstate induced brain oxidative stress and the alterations in some neurological variables can effectively be reduced by co-supplementation of NAC.}, }
@article {pmid25981694, year = {2015}, author = {Park, Y and Choi, J and Lim, JW and Kim, H}, title = {β-Carotene-induced apoptosis is mediated with loss of Ku proteins in gastric cancer AGS cells.}, journal = {Genes &amp; nutrition}, volume = {10}, number = {4}, pages = {467}, pmid = {25981694}, issn = {1555-8932}, abstract = {High dietary intakes and high blood levels of β-carotene are associated with a decreased incidence of various cancers. The anticancer effect of β-carotene is related to its pro-oxidant activity. DNA repair Ku proteins, as a heterodimer of Ku70 and Ku80, play a crucial role in DNA double-strand break repair. Reductions in Ku70/80 contribute to apoptosis. Previously, we showed that reactive oxygen species (ROS) activate caspase-3 which induces degradation of Ku proteins. In the present study, we investigated the mechanism of β-carotene-induced apoptosis of gastric cancer AGS cells by determining cell viability, DNA fragmentation, apoptotic indices (increases in cytochrome c and Bax, decrease in Bcl-2), ROS levels, mitochondrial membrane potential, caspase-3 activity, Ku70/80 levels, and Ku-DNA-binding activity of the cells treated with or without antioxidant N-acetyl cysteine and caspase-3 inhibitor z-DEVED-fmk. As a result, β-carotene induced apoptosis (decrease in cell viability, increases in DNA fragmentation and apoptotic indices) and caspase-3 activation, but decreased Ku70/80 levels and Ku-DNA-binding activity. β-Carotene-induced alterations (increase in caspase-3 activity, decrease in Ku proteins) and apoptosis were inhibited by N-acetyl cysteine and z-DEVED-fmk. Increment of intracellular and mitochondrial ROS levels and loss of mitochondrial membrane potential were suppressed by N-acetyl cysteine, but not by z-DEVED-fmk in β-carotene-treated cells. Therefore, β-carotene-induced increases in ROS and caspase-3 activity may lead to reduction of Ku70/80 levels, which results in apoptosis in gastric cancer cells. Loss of Ku proteins might be the underlying mechanism for β-carotene-induced apoptosis in gastric cancer cells.}, }
@article {pmid25981581, year = {2015}, author = {Hao, W and Yuan, X and Yu, L and Gao, C and Sun, X and Wang, D and Zheng, Q}, title = {Licochalcone A-induced human gastric cancer BGC-823 cells apoptosis by regulating ROS-mediated MAPKs and PI3K/AKT signaling pathways.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {10336}, pmid = {25981581}, issn = {2045-2322}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chalcones/*pharmacology ; Disease Models, Animal ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mice ; Mitogen-Activated Protein Kinases/*metabolism ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Stomach Neoplasms/drug therapy/*metabolism/pathology ; Xenograft Model Antitumor Assays ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Both phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK) signaling cascades play an important role in cell proliferation, survival, angiogenesis, and metastasis of tumor cells. In the present report, we investigated the effects of licochalcone A (LA), a flavonoid extracted from licorice root, on the PI3K/AKT/mTOR and MAPK activation pathways in human gastric cancer BGC-823 cells. LA increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding and activation of caspase-3, and cleavage of poly-ADP-ribose polymerase (PARP). Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented LA-induced apoptosis. Interestingly, we also observed that LA caused the activation of ERK, JNK, and p38 MAPK in BGC-823 cells. The antitumour activity of LA-treated BGC-823 cells was significantly distinct in KM mice in vivo. All the findings from our study suggest that LA can interfere with MAPK signaling cascades, initiate ROS generation, induce oxidative stress and consequently cause BGC cell apoptosis.}, }
@article {pmid25976678, year = {2015}, author = {Shen, K and Xie, J and Wang, H and Zhang, H and Yu, M and Lu, F and Tan, H and Xu, H}, title = {Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells.}, journal = {Molecular cancer therapeutics}, volume = {14}, number = {7}, pages = {1738-1749}, doi = {10.1158/1535-7163.MCT-14-1048}, pmid = {25976678}, issn = {1538-8514}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Blotting, Western ; Breast Neoplasms/*drug therapy/genetics/metabolism ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Electrophoresis, Gel, Two-Dimensional ; *Epigenesis, Genetic ; Female ; Free Radical Scavengers/pharmacology ; HeLa Cells ; Hep G2 Cells ; Humans ; MAP Kinase Signaling System/*drug effects ; MCF-7 Cells ; Mice, Inbred BALB C ; Mice, Nude ; Microscopy, Fluorescence ; Proteomics/methods ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Terpenes/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {Cambogin is a polycyclic polyprenylated acylphoroglucinol (PPAP) from the Garcinia genus, which has been used traditionally for cancer treatment across Southeastern Asia. In this study, we found that cambogin inhibited breast cancer cell proliferation and induced cell apoptosis in vitro. Cambogin induced the activation of the caspase-independent mitochondrial apoptotic pathway, as indicated by an increase in the ratio of Bax/Bcl-2 and the nuclear translocation of apoptosis inducing factor (AIF). Two-dimensional gel electrophoresis and mass spectrometry revealed that the expression of proteins involving in the radical oxygen species (ROS) pathway was among the most affected upon cambogin treatment. Cambogin enhanced cellular ROS production, and induced the activation of the ASK1-MKK4/MKK7-JNK/SAPK signaling pathway. Pretreatment with ROS scavenger N-acetylcysteine (NAC), an antioxidant, or the JNK inhibitor SP600125 was able to restore cell viability in the presence of cambogin. Importantly, cambogin treatment led to the activation of activating transcription factor-2 (ATF-2) and the trimethylation of histone H3K9 in the activator protein 1 (AP-1) binding region of the Bcl-2 gene promoter. Finally, cambogin exhibited a potential antitumor effect in MCF-7 breast cancer xenografts without apparent toxicity. Taken in conjunction, the present study indicates that cambogin can induce breast adenocarcinoma cell apoptosis and therefore represents therapeutic potential for cancer treatment.}, }
@article {pmid25976560, year = {2015}, author = {Huang, C and Yuan, L and Cao, S}, title = {Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets.}, journal = {International journal of molecular medicine}, volume = {36}, number = {1}, pages = {173-185}, pmid = {25976560}, issn = {1791-244X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; *Diet, High-Fat ; Glucagon-Like Peptide 1/*metabolism ; Glucagon-Like Peptide-1 Receptor/agonists/antagonists &amp; inhibitors ; Glucagon-Secreting Cells/*cytology ; Homeodomain Proteins/antagonists &amp; inhibitors ; Inflammation/pathology ; Insulin-Secreting Cells/*metabolism ; Liraglutide/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/physiology ; Palmitates/*pharmacology ; Peptide Fragments/pharmacology ; Proprotein Convertase 1/biosynthesis/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Trans-Activators/antagonists &amp; inhibitors ; Transcription Factor RelA/biosynthesis ; }, abstract = {The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.}, }
@article {pmid25974890, year = {2015}, author = {Oyman Eyrilmez, G and Doran, S and Murtezi, E and Demir, B and Odaci Demirkol, D and Coskunol, H and Timur, S and Yagci, Y}, title = {Selective Cell Adhesion and Biosensing Applications of Bio-Active Block Copolymers Prepared by CuAAC/Thiol-ene Double Click Reactions.}, journal = {Macromolecular bioscience}, volume = {15}, number = {9}, pages = {1233-1241}, doi = {10.1002/mabi.201500099}, pmid = {25974890}, issn = {1616-5195}, mesh = {Animals ; *Biosensing Techniques ; *Cell Adhesion ; Cell Line, Tumor ; Click Chemistry ; Humans ; Keratinocytes/physiology ; Methylmethacrylates/*chemistry ; Oligopeptides/*metabolism ; Polyesters/*chemistry ; Protein Binding ; Surface Properties ; *Tissue Scaffolds ; }, abstract = {N-Acetyl-l-cysteine (NAC)-capped poly(methyl methacrylate)-b-polycaprolactone block copolymer (PMMA-b-PCL-NAC) was prepared using the previously described one-pot photoinduced sequential CuAAC/thiol-ene double click procedure. PMMA-b-PCL-NAC had previously shown good applicability as a matrix for cell adhesion of cells from the Vero cell line (African green monkey kidney epithelial). Here, in this work, PMMA-b-PCL-NAC served as an excellent immobilization matrix for biomolecule conjugation. Covalent binding of RGD (R: arginine, G: glycine, and D: aspartic acid) peptide sequence onto the PMMA-b-PCL-NAC-coated surface was performed via EDC chemistry. RGD-modified PMMA-b-PCL-NAC (PMMA-b-PCL-NAC-RGD) as a non-toxic cell proliferation platform was used for selective "integrin αvβ3-mediated cell adhesion and biosensing studies. Both optical and electrochemical techniques were used to monitor the adhesion differences between "integrin αvβ3" receptor positive and negative cell lines on to the designed biofunctional surfaces.}, }
@article {pmid25972196, year = {2015}, author = {Luo, Q and Li, Y and Lai, Y and Zhang, Z}, title = {The role of NF-κB in PARP-inhibitor-mediated sensitization and detoxification of arsenic trioxide in hepatocellular carcinoma cells.}, journal = {The Journal of toxicological sciences}, volume = {40}, number = {3}, pages = {349-363}, doi = {10.2131/jts.40.349}, pmid = {25972196}, issn = {1880-3989}, mesh = {1-Naphthylamine/*analogs &amp; derivatives/pharmacology ; Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Carcinoma, Hepatocellular/*metabolism/*pathology ; DNA Damage ; Hep G2 Cells ; Humans ; Inactivation, Metabolic/drug effects ; Liver Neoplasms/*metabolism/*pathology ; NF-kappa B/*physiology ; Naphthalimides/*pharmacology ; Oxidative Stress ; Oxides/*pharmacology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors/*pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Quinolones/*pharmacology ; Reactive Oxygen Species ; }, abstract = {The therapeutic efficacy of arsenic trioxide (ATO) for treatments of solid tumors is restricted by its drug resistance and chemotoxicity. In this study, we investigated ATO sensitization and detoxification effect of the Poly (ADP ribose) polymerase-1 (PARP-1) inhibitor 4-Amino-1,8-naphthalimide (4AN) in the hepatocellular carcinoma cell line HepG2. We firstly reported that ATO treatment induced the activation of Nuclear factor of κB (NF-κB) and its downstream anti-apoptosis and pro-inflammatory effectors in a PARP-1-dependent manner and thus conferred HepG2 cells with ATO resistance and toxicity. 4AN significantly suppressed the ATO-induced NF-κB activation, which promotes the apoptotic response and alleviates the inflammatory reaction induced by ATO, resulting in sensitization and detoxification against ATO. We also demonstrated that the ATO-induced activation of PARP-1 and NF-κB was closely associated with the oxidative DNA damage mediated by the generated reactive oxygen species (ROS). Furthermore, the attenuation of ATO-induced ROS and the resulting oxidative DNA damage by N-acetyl-L-cysteine (NAC), a potent antioxidant, significantly reduced the activation of PARP-1 and NF-κB in ATO-treated cells. Our study provides novel insights into the mechanism of the PARP-1-mediated NF-κB signaling pathway in ATO resistance and toxicity in anticancer treatments. This study also highlights the application potential of PARP-1 inhibitors in ATO-based anti-cancer treatments and in prevention of NF-κB-mediated therapeutic resistance and toxicity.}, }
@article {pmid25971771, year = {2015}, author = {Quadros Gomes, BA and da Silva, LF and Quadros Gomes, AR and Moreira, DR and Dolabela, MF and Santos, RS and Green, MD and Carvalho, EP and Percário, S}, title = {N-acetyl cysteine and mushroom Agaricus sylvaticus supplementation decreased parasitaemia and pulmonary oxidative stress in a mice model of malaria.}, journal = {Malaria journal}, volume = {14}, number = {}, pages = {202}, pmid = {25971771}, issn = {1475-2875}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Agaricus/*chemistry ; Animals ; Dietary Supplements/*analysis ; Disease Models, Animal ; Lung/drug effects ; Malaria/*diet therapy/parasitology ; Male ; Mice ; Oxidative Stress/*drug effects ; Parasitemia/diet therapy/parasitology ; Plasmodium berghei/*physiology ; }, abstract = {BACKGROUND: Malaria infection can cause high oxidative stress, which could lead to the development of severe forms of malaria, such as pulmonary malaria. In recent years, the role of reactive oxygen species in the pathogenesis of the disease has been discussed, as well as the potential benefit of antioxidants supplementation. The aim of this study was to investigate the effects of N-acetyl cysteine (NAC) or mushroom Agaricus sylvaticus supplementation on the pulmonary oxidative changes in an experimental model of malaria caused by Plasmodium berghei strain ANKA.<br><br>METHODS: Swiss male mice were infected with P. berghei and treated with NAC or AS. Samples of lung tissue and whole blood were collected after one, three, five, seven or ten days of infection for the assessment of thiobarbituric acid reactive substances (TBARS), trolox equivalent antioxidant capacity (TEAC), nitrites and nitrates (NN) and to assess the degree of parasitaemia.<br><br>RESULTS: Although parasitaemia increased progressively with the evolution of the disease in all infected groups, there was a significant decrease from the seventh to the tenth day of infection in both antioxidant-supplemented groups. Results showed significant higher levels of TEAC in both supplemented groups, the highest occurring in the group supplemented with A. sylvaticus. In parallel, TBARS showed similar levels among all groups, while levels of NN were higher in animals supplemented with NAC in relation to the positive control groups and A. sylvaticus, whose levels were similar to the negative control group.<br><br>CONCLUSION: Oxidative stress arising from plasmodial infection was attenuated by supplementation of both antioxidants, but A. sylvaticus proved to be more effective and has the potential to become an important tool in the adjuvant therapy of malaria.}, }
@article {pmid25970706, year = {2015}, author = {Tang, S and Hou, Y and Zhang, H and Tu, G and Yang, L and Sun, Y and Lang, L and Tang, X and Du, YE and Zhou, M and Yu, T and Xu, L and Wen, S and Liu, C and Liu, M}, title = {Oxidized ATM promotes abnormal proliferation of breast CAFs through maintaining intracellular redox homeostasis and activating the PI3K-AKT, MEK-ERK, and Wnt-β-catenin signaling pathways.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {14}, number = {12}, pages = {1908-1924}, pmid = {25970706}, issn = {1551-4005}, mesh = {Antioxidants/chemistry ; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Breast Neoplasms/*metabolism ; Cell Line, Tumor ; Cell Proliferation ; DNA Breaks, Double-Stranded ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Fibroblasts/*metabolism ; Homeostasis ; Humans ; MAP Kinase Kinase 1/metabolism ; Mitochondria/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Oxygen/chemistry ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; *Wnt Signaling Pathway ; beta Catenin/metabolism ; }, abstract = {Abnormal proliferation is one characteristic of cancer-associated fibroblasts (CAFs), which play a key role in tumorigenesis and tumor progression. Oxidative stress (OS) is the root cause of CAFs abnormal proliferation. ATM (ataxia-telangiectasia mutated protein kinase), an important redox sensor, is involved in DNA damage response and cellular homeostasis. Whether and how oxidized ATM regulating CAFs proliferation remains unclear. In this study, we show that there is a high level of oxidized ATM in breast CAFs in the absence of double-strand breaks (DSBs) and that oxidized ATM plays a critical role in CAFs proliferation. The effect of oxidized ATM on CAFs proliferation is mediated by its regulation of cellular redox balance and the activity of the ERK, PI3K-AKT, and Wnt signaling pathways. Treating cells with antioxidant N-acetyl-cysteine (NAC) partially rescues the proliferation defect of the breast CAFs caused by ATM deficiency. Administrating cells with individual or a combination of specific inhibitors of the ERK, PI3K-AKT, and Wnt signaling pathways mimics the effect of ATM deficiency on breast CAF proliferation. This is mainly ascribed to the β-catenin suppression and down-regulation of c-Myc, thus further leading to the decreased cyclinD1, cyclinE, and E2F1 expression and the enhanced p21(Cip1) level. Our results reveal an important role of oxidized ATM in the regulation of the abnormal proliferation of breast CAFs. Oxidized ATM could serve as a potential target for treating breast cancer.}, }
@article {pmid25970225, year = {2015}, author = {Dansette, PM and Levent, D and Hessani, A and Mansuy, D}, title = {Bioactivation of clopidogrel and prasugrel: factors determining the stereochemistry of the thiol metabolite double bond.}, journal = {Chemical research in toxicology}, volume = {28}, number = {6}, pages = {1338-1345}, doi = {10.1021/acs.chemrestox.5b00133}, pmid = {25970225}, issn = {1520-5010}, mesh = {Antithrombins/chemistry/*metabolism ; Clopidogrel ; Glutathione/chemistry/metabolism ; Humans ; Microsomes, Liver/metabolism ; Molecular Structure ; Prasugrel Hydrochloride/*chemistry/*metabolism ; Prodrugs/chemistry/*metabolism ; Stereoisomerism ; Sulfhydryl Compounds/chemistry/*metabolism ; Ticlopidine/*analogs &amp; derivatives/chemistry/metabolism ; }, abstract = {The antithrombotics of the tetrahydrothienopyridine series, clopidogrel and prasugrel, are prodrugs that must be metabolized in two steps to become pharmacologically active. The first step is the formation of a thiolactone metabolite. The second step is a further oxidation with the formation of a thiolactone sulfoxide whose hydrolytic opening leads to a sulfenic acid that is eventually reduced into the corresponding active cis thiol. Very few data were available on the formation of the isomer of the active cis thiol having a trans configuration of the double bond, the most striking result in that regard being that both cis and trans thiols were formed upon the metabolism of clopidogrel by human liver microsomes in the presence of glutathione (GSH), whereas only the cis thiol was detected in the sera of patients treated with this drug. This article shows that trans thiols are also formed upon the microsomal metabolism of prasugrel or its thiolactone metabolite in the presence of GSH and that metabolites having the trans configuration of the double bond are only formed when microsomal incubations are done in the presence of thiols, such as GSH, N-acetyl-cysteine, and mercaptoethanol. Intermediate formation of thioesters resulting from the reaction of GSH with the thiolactone sulfoxide metabolite appears to be responsible for trans thiol formation. Addition of human liver cytosol to the microsomal incubations led to a dramatic decrease of the formation of the trans thiol metabolites. These data suggest that cytosolic esterases would accelerate the hydrolytic opening of thiolactone sulfoxide intermediates and disfavor the formation of thioesters resulting from the reaction of these intermediates with GSH that is responsible for trans isomer formation. This would explain why trans thiols have not been detected in the sera of patients treated with clopidogrel.}, }
@article {pmid25966046, year = {2015}, author = {Ahamed, M and Akhtar, MJ and Alhadlaq, HA and Khan, MA and Alrokayan, SA}, title = {Comparative cytotoxic response of nickel ferrite nanoparticles in human liver HepG2 and breast MFC-7 cancer cells.}, journal = {Chemosphere}, volume = {135}, number = {}, pages = {278-288}, doi = {10.1016/j.chemosphere.2015.03.079}, pmid = {25966046}, issn = {1879-1298}, mesh = {Apoptosis ; Caspase 3/metabolism ; Caspase 9/metabolism ; Ferric Compounds/*toxicity ; Glutathione/metabolism ; Hep G2 Cells ; Humans ; Lipid Peroxidation ; Liver/metabolism ; MCF-7 Cells ; Membrane Potential, Mitochondrial ; Metal Nanoparticles/*toxicity ; Neutral Red/metabolism ; Nickel/*toxicity ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Nickel ferrite nanoparticles (NPs) have received much attention for their potential applications in biomedical fields such as magnetic resonance imaging, drug delivery and cancer hyperthermia. However, little is known about the toxicity of nickel ferrite NPs at the cellular and molecular levels. In this study, we investigated the cytotoxic responses of nickel ferrite NPs in two different types of human cells (i.e., liver HepG2 and breast MCF-7). Nickel ferrite NPs induced dose-dependent cytotoxicity in both types of cells, which was demonstrated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide (MTT), neutral red uptake (NRU) and lactate dehydrogenase (LDH) assays. Nickel ferrite NPs were also found to induce oxidative stress, which was evident by the depletion of glutathione and the induction of reactive oxygen species (ROS) and lipid peroxidation. The mitochondrial membrane potential due to nickel ferrite NP exposure was also observed. The mRNA levels for the tumor suppressor gene p53 and the apoptotic genes bax, CASP3 and CASP9 were up-regulated, while the anti-apoptotic gene bcl-2 was down-regulated following nickel ferrite NP exposure. Furthermore, the activities of apoptotic enzymes (caspase-3 and caspase-9) were also higher in both types of cells treated with nickel ferrite NPs. Cytotoxicity induced by nickel ferrite was efficiently prevented by N-acetyl cysteine (ROS scavenger) treatment, which suggested that oxidative stress might be one of the possible mechanisms of nickel ferrite NP toxicity. We also observed that MCF-7 cells were slightly more susceptible to nickel ferrite NP exposure than HepG2 cells. This study warrants further investigation to explore the potential mechanisms of different cytotoxic responses of nickel ferrite NPs in different cell lines.}, }
@article {pmid25965428, year = {2015}, author = {Akhtar, MJ and Ahamed, M and Alhadlaq, HA and Khan, MAM and Alrokayan, SA}, title = {Glutathione replenishing potential of CeO2 nanoparticles in human breast and fibrosarcoma cells.}, journal = {Journal of colloid and interface science}, volume = {453}, number = {}, pages = {21-27}, doi = {10.1016/j.jcis.2015.04.049}, pmid = {25965428}, issn = {1095-7103}, mesh = {Antioxidants/chemistry/*pharmacology ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cerium/chemistry/*pharmacology ; Female ; Fibrosarcoma/metabolism ; Glutathione/*metabolism ; Humans ; *Nanoparticles/chemistry/ultrastructure ; Reactive Oxygen Species/metabolism ; }, abstract = {Recently, cerium oxide nanoparticles (CeO2 NPs) has been reported for multi-enzyme mimetic activities like that of superoxide dismutase and catalase. Here, we report glutathione (GSH) replenishing response by CeO2 NPs in human breast (MCF-7) and fibrosarcoma (HT-1080) cells. CeO2 NPs were found to be mostly cuboidal in shape with average diameter of 25 nm. Effects on cell viability, reactive oxygen species (ROS) generation, and mitochondrial outer membrane potential (MOMP) suggested CeO2 NPs to be reasonably non-cytotoxic. Data on membrane damage and lipid peroxidation correlated well with the cell viability results suggesting NPs of CeO2 to be biocompatible. Interestingly, CeO2 NPs significantly increased intracellular GSH in cells challenged with oxidants. Replenishment of depleted GSH in oxidatively challenged cells was comparable with the GSH restoring potential of known antioxidant N-acetyl cysteine (NAC), a precursor of GSH. Like NAC, CeO2 NPs significantly replenished depleted GSH in both cell types challenged with hydrogen peroxide (H2O2) and zinc oxide (ZnO) NPs. Moreover, CeO2 NPs treated cells were significantly protected from cytotoxicity caused by H2O2 and ZnO NPs. Our findings, therefore, suggest CeO2 NPs as a potential antioxidant rather than a toxic material.}, }
@article {pmid25965123, year = {2015}, author = {Abu Hashim, H and Foda, O and Ghayaty, E}, title = {Combined metformin-clomiphene in clomiphene-resistant polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials.}, journal = {Acta obstetricia et gynecologica Scandinavica}, volume = {94}, number = {9}, pages = {921-930}, doi = {10.1111/aogs.12673}, pmid = {25965123}, issn = {1600-0412}, mesh = {Clomiphene/*therapeutic use ; Drug Therapy, Combination ; Female ; Fertility Agents, Female/*therapeutic use ; Humans ; Hypoglycemic Agents/*therapeutic use ; Metformin/*therapeutic use ; Polycystic Ovary Syndrome/*therapy ; Pregnancy ; Pregnancy Rate ; }, abstract = {OBJECTIVE: Our objective was to compare the effectiveness of metformin plus clomiphene citrate vs. gonadotrophins, laparoscopic ovarian diathermy, aromatase inhibitors, N-acetyl-cysteine and other insulin sensitizers+clomiphene for improving fertility outcomes in women with clomiphene-resistant polycystic ovary syndrome.<br><br>DESIGN: PubMed, SCOPUS and CENTRAL databases were searched until April 2014 with the key words: PCOS, polycystic ovary syndrome, metformin, clomiphene citrate, ovulation induction and pregnancy. The search was limited to articles conducted with humans and published in English.<br><br>SAMPLE: The PRISMA statement was followed. Twelve randomized controlled trials (n = 1411 women) were included.<br><br>MAIN OUTCOME MEASURES: Ovulation and clinical pregnancy rates per woman randomized.<br><br>RESULTS: Compared with gonadotrophins, the metformin+clomiphene combination resulted in significantly fewer ovulations (odds ratio 0.25; 95% confidence interval 0.15-0.41; p < 0.00001, 3 trials, I(2) = 85%, n = 323) and pregnancies (odds ratio 0.45; 95% confidence interval 0.27-0.75; p = 0.002, 3 trials, I(2) = 0%, n = 323). No significant differences were found when metformin+clomiphene was compared with laparoscopic ovarian diathermy (odds ratio 0.88; 95% confidence interval 0.53-1.47; p = 0.62, 1 trial, n = 282; odds ratio 0.96; 95% confidence interval 0.60-1.54; p = 0.88, 2 trials, I(2) = 0%, n = 332, for ovulation and pregnancy rates, respectively). Likewise, no differences were observed in comparison with aromatase inhibitors (odds ratio 0.88; 95% confidence interval 0.58-1.34; p = 0.55, 3 trials, I(2) = 3%, n = 409; odds ratio 0.85; 95% confidence interval 0.53-1.36; p = 0.50, 2 trials, n = 309, for ovulation and pregnancy rates, respectively).<br><br>CONCLUSIONS: There is evidence for the superiority of gonadotrophins, but the metformin+clomiphene combination is mainly relevant for clomiphene-resistant polycystic ovary syndrome patients and, if not effective, a next step could be gonadotrophins. More attempts with metformin+clomiphene are only relevant if there is limited access to gonadotrophins.}, }
@article {pmid25961745, year = {2015}, author = {Chang, TC and Hsu, MF and Wu, KK}, title = {High glucose induces bone marrow-derived mesenchymal stem cell senescence by upregulating autophagy.}, journal = {PloS one}, volume = {10}, number = {5}, pages = {e0126537}, pmid = {25961745}, issn = {1932-6203}, mesh = {Autophagy/*drug effects ; Blotting, Western ; Bone Marrow Cells/*cytology ; Cells, Cultured ; Glucose/*pharmacology ; Humans ; In Situ Nick-End Labeling ; Interleukin-6/metabolism ; Mesenchymal Stem Cells/*cytology/*drug effects ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; }, abstract = {Hyperglycemia was reported to cause bone marrow hematopoietic niche dysfunction, and high glucose (HG) in the cultured medium induces MSC senescence. The underlying mechanism is unclear. Here, we investigated the role of HG-induced autophagy in bone-marrow-derived mesenchymal stem cell (BMSC) senescence. HG (25 mM) increased expression of Beclin-1, Atg 5, 7 and 12, generation of LC3-II and autophagosome formation which was correlated with development of cell senescence. Pretreatment of HG-MSC with 3-methyladenine (3-MA) prevented senescence but increased apoptosis. N-acetylcysteine (NAC) was effective in abrogating HG-induced autophagy accompanied by prevention of senescence. Diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, blocked autophagy and senescence in a manner comparable to NAC. 3-MA, NAC and DPI inhibited HG-induced interleukin-6 production in BMSCs. These results suggest that hyperglycemia induces MSC senescence and local inflammation via a novel oxidant-mediated autophagy which contributes to bone marrow niche dysfunction and hematopoietic impairment.}, }
@article {pmid25960622, year = {2015}, author = {Agostinis, C and Zorzet, S and De Leo, R and Zauli, G and De Seta, F and Bulla, R}, title = {The combination of N-acetyl cysteine, alpha-lipoic acid, and bromelain shows high anti-inflammatory properties in novel in vivo and in vitro models of endometriosis.}, journal = {Mediators of inflammation}, volume = {2015}, number = {}, pages = {918089}, pmid = {25960622}, issn = {1466-1861}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage ; Apoptosis ; Bromelains/*administration &amp; dosage ; Cells, Cultured ; Disease Models, Animal ; Endometriosis/*drug therapy ; Endothelial Cells/drug effects ; Female ; Humans ; Inflammation/metabolism ; Mice ; Mice, SCID ; Microscopy, Fluorescence ; Thioctic Acid/*administration &amp; dosage ; Tumor Necrosis Factor-alpha/metabolism ; Uterus/cytology ; Vascular Cell Adhesion Molecule-1/metabolism ; }, abstract = {To evaluate the efficacy of an association of N-acetyl cystein, alpha-lipoic acid, and bromelain (NAC/LA/Br) in the treatment of endometriosis we set up a new in vivo murine model. We explored the anti-inflammatory and proapoptotic effect of this combination on human endometriotic endothelial cells (EECs) and on endothelial cells isolated from normal uterus (UtMECs). We implanted fragments of human endometriotic cysts intraperitoneally into SCID mice to evaluate the efficacy of NAC/LA/Br treatment. UtMECs and EECs, untreated or treated with NAC/LA/Br, were activated with the proinflammatory stimulus TNF-α and their response in terms of VCAM1 expression was evaluated. The proapoptotic effect of higher doses of NAC/LA/Br on UtMECs and EECs was measured with a fluorogenic substrate for activated caspases 3 and 7. The preincubation of EECs with NAC/LA/Br prior to cell stimulation with TNF-α prevents the upregulation of the expression of the inflammatory "marker" VCAM1. Furthermore NAC/LA/Br were able to induce EEC, but not UtMEC, apoptosis. Finally, the novel mouse model allowed us to demonstrate that mice treated with NAC/LA/Br presented a lower number of cysts, smaller in size, compared to untreated mice. Our findings suggest that these dietary supplements may have potential therapeutic uses in the treatment of chronic inflammatory diseases like endometriosis.}, }
@article {pmid25957927, year = {2015}, author = {Deepmala,  and Slattery, J and Kumar, N and Delhey, L and Berk, M and Dean, O and Spielholz, C and Frye, R}, title = {Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review.}, journal = {Neuroscience and biobehavioral reviews}, volume = {55}, number = {}, pages = {294-321}, doi = {10.1016/j.neubiorev.2015.04.015}, pmid = {25957927}, issn = {1873-7528}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Clinical Trials as Topic ; Female ; Humans ; Male ; Mental Disorders/*drug therapy ; Nervous System Diseases/*drug therapy ; Neurology ; Psychiatry ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Young Adult ; }, abstract = {N-acetylcysteine (NAC) is recognized for its role in acetaminophen overdose and as a mucolytic. Over the past decade, there has been growing evidence for the use of NAC in treating psychiatric and neurological disorders, considering its role in attenuating pathophysiological processes associated with these disorders, including oxidative stress, apoptosis, mitochondrial dysfunction, neuroinflammation and glutamate and dopamine dysregulation. In this systematic review we find favorable evidence for the use of NAC in several psychiatric and neurological disorders, particularly autism, Alzheimer's disease, cocaine and cannabis addiction, bipolar disorder, depression, trichotillomania, nail biting, skin picking, obsessive-compulsive disorder, schizophrenia, drug-induced neuropathy and progressive myoclonic epilepsy. Disorders such as anxiety, attention deficit hyperactivity disorder and mild traumatic brain injury have preliminary evidence and require larger confirmatory studies while current evidence does not support the use of NAC in gambling, methamphetamine and nicotine addictions and amyotrophic lateral sclerosis. Overall, NAC treatment appears to be safe and tolerable. Further well designed, larger controlled trials are needed for specific psychiatric and neurological disorders where the evidence is favorable.}, }
@article {pmid25953698, year = {2015}, author = {Xie, X and Zhao, Y and Ma, CY and Xu, XM and Zhang, YQ and Wang, CG and Jin, J and Shen, X and Gao, JL and Li, N and Sun, ZJ and Dong, DL}, title = {Dimethyl fumarate induces necroptosis in colon cancer cells through GSH depletion/ROS increase/MAPKs activation pathway.}, journal = {British journal of pharmacology}, volume = {172}, number = {15}, pages = {3929-3943}, pmid = {25953698}, issn = {1476-5381}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Colonic Neoplasms/enzymology/metabolism/*pathology ; Dimethyl Fumarate/*adverse effects ; Fumarates/adverse effects ; Glutathione/*metabolism ; HMGB1 Protein/metabolism ; Humans ; L-Lactate Dehydrogenase/metabolism ; MAP Kinase Signaling System/*drug effects ; Maleates/adverse effects ; Membrane Potential, Mitochondrial/drug effects ; Methanol/adverse effects ; Mice ; Mitogen-Activated Protein Kinases/*metabolism ; Necrosis/*chemically induced/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Dimethyl fumarate (DMF) is a newly approved drug for the treatment of relapsing forms of multiple sclerosis and relapsing-remitting multiple sclerosis. Here, we investigated the effects of DMF and its metabolites mono-methylfumarate (MMF and methanol) on different gastrointestinal cancer cell lines and the underlying molecular mechanisms involved.<br><br>EXPERIMENTAL APPROACH: Cell viability was measured by the MTT or CCK8 assay. Protein expressions were measured by Western blot analysis. LDH release, live- and dead-cell staining, intracellular GSH levels, and mitochondrial membrane potential were examined by using commercial kits.<br><br>KEY RESULTS: DMF but not MMF induced cell necroptosis, as demonstrated by the pharmacological tool necrostatin-1, transmission electron microscopy, LDH and HMGB1 release in CT26 cells. The DMF-induced decrease in cellular GSH levels as well as cell viability and increase in reactive oxygen species (ROS) were inhibited by co-treatment with GSH and N-acetylcysteine (NAC) in CT26 cells. DMF activated JNK, p38 and ERK MAPKs in CT26 cells and JNK, p38 and ERK inhibitors partially reversed the DMF-induced decrease in cell viability. GSH or NAC treatment inhibited DMF-induced JNK, p38, and ERK activation in CT26 cells. DMF but not MMF increased autophagy responses in SGC-7901, HCT116, HT29 and CT26 cancer cells, but autophagy inhibition did not prevent the DMF-induced decrease in cell viability.<br><br>CONCLUSION AND IMPLICATIONS: DMF but not its metabolite MMF induced necroptosis in colon cancer cells through a mechanism involving the depletion of GSH, an increase in ROS and activation of MAPKs.}, }
@article {pmid25949858, year = {2015}, author = {Draghiciu, O and Lubbers, J and Nijman, HW and Daemen, T}, title = {Myeloid derived suppressor cells-An overview of combat strategies to increase immunotherapy efficacy.}, journal = {Oncoimmunology}, volume = {4}, number = {1}, pages = {e954829}, pmid = {25949858}, issn = {2162-4011}, abstract = {Myeloid-derived suppressor cells (MDSCs) contribute to tumor-mediated immune escape and negatively correlate with overall survival of cancer patients. Nowadays, a variety of methods to target MDSCs are being investigated. Based on the intervention stage of MDSCs, namely development, expansion and activation, function and turnover, these methods can be divided into: (I) prevention or differentiation to mature cells, (II) blockade of MDSC expansion and activation, (III) inhibition of MDSC suppressive activity or (IV) depletion of intratumoral MDSCs. This review describes effective mono- or multimodal-therapies that target MDSCs for the benefit of cancer treatment.}, }
@article {pmid25948264, year = {2015}, author = {Won, SJ and Kim, JE and Cittolin-Santos, GF and Swanson, RA}, title = {Assessment at the single-cell level identifies neuronal glutathione depletion as both a cause and effect of ischemia-reperfusion oxidative stress.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {35}, number = {18}, pages = {7143-7152}, pmid = {25948264}, issn = {1529-2401}, support = {R01 NS081149/NS/NINDS NIH HHS/United States ; NS081149/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Brain Ischemia/*metabolism/pathology ; Glutathione/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/*metabolism/pathology ; Oxidative Stress/*physiology ; Reperfusion Injury/etiology/*metabolism/pathology ; }, abstract = {Oxidative stress contributes to neuronal death in brain ischemia-reperfusion. Tissue levels of the endogenous antioxidant glutathione (GSH) are depleted during ischemia-reperfusion, but it is unknown whether this depletion is a cause or an effect of oxidative stress, and whether it occurs in neurons or other cell types. We used immunohistochemical methods to evaluate glutathione, superoxide, and oxidative stress in mouse hippocampal neurons after transient forebrain ischemia. GSH levels in CA1 pyramidal neurons were normally high relative to surrounding neuropil, and exhibited a time-dependent decrease during the first few hours of reperfusion. Colabeling for superoxide in the neurons showed a concurrent increase in detectable superoxide over this interval. To identify cause-effect relationships between these changes, we independently manipulated superoxide production and GSH metabolism during reperfusion. Mice in which NADPH oxidase activity was blocked to prevent superoxide production showed preservation of neuronal GSH content, thus demonstrating that neuronal GSH depletion is result of oxidative stress. Conversely, mice in which neuronal GSH levels were maintained by N-acetyl cysteine treatment during reperfusion showed less neuronal superoxide signal, oxidative stress, and neuronal death. At 3 d following ischemia, GSH content in reactive astrocytes and microglia was increased in the hippocampal CA1 relative to surviving neurons. Results of these studies demonstrate that neuronal GSH depletion is both a result and a cause of neuronal oxidative stress after ischemia-reperfusion, and that postischemic restoration of neuronal GSH levels can be neuroprotective.}, }
@article {pmid25941492, year = {2015}, author = {Lewis, P and Sheehan, D and Soares, R and Varela Coelho, A and O'Halloran, KD}, title = {Chronic sustained hypoxia-induced redox remodeling causes contractile dysfunction in mouse sternohyoid muscle.}, journal = {Frontiers in physiology}, volume = {6}, number = {}, pages = {122}, pmid = {25941492}, issn = {1664-042X}, abstract = {Chronic sustained hypoxia (CH) induces structural and functional adaptations in respiratory muscles of animal models, however the underlying molecular mechanisms are unclear. This study explores the putative role of CH-induced redox remodeling in a translational mouse model, with a focus on the sternohyoid-a representative upper airway dilator muscle involved in the control of pharyngeal airway caliber. We hypothesized that exposure to CH induces redox disturbance in mouse sternohyoid muscle in a time-dependent manner affecting metabolic capacity and contractile performance. C57Bl6/J mice were exposed to normoxia or normobaric CH (FiO2 = 0.1) for 1, 3, or 6 weeks. A second cohort of animals was exposed to CH for 6 weeks with and without antioxidant supplementation (tempol or N-acetyl cysteine in the drinking water). Following CH exposure, we performed 2D redox proteomics with mass spectrometry, metabolic enzyme activity assays, and cell-signaling assays. Additionally, we assessed isotonic contractile and endurance properties ex vivo. Temporal changes in protein oxidation and glycolytic enzyme activities were observed. Redox modulation of sternohyoid muscle proteins key to contraction, metabolism and cellular homeostasis was identified. There was no change in redox-sensitive proteasome activity or HIF-1α content, but CH decreased phospho-JNK content independent of antioxidant supplementation. CH was detrimental to sternohyoid force- and power-generating capacity and this was prevented by chronic antioxidant supplementation. We conclude that CH causes upper airway dilator muscle dysfunction due to redox modulation of proteins key to function and homeostasis. Such changes could serve to further disrupt respiratory homeostasis in diseases characterized by CH such as chronic obstructive pulmonary disease. Antioxidants may have potential use as an adjunctive therapy in hypoxic respiratory disease.}, }
@article {pmid25941092, year = {2016}, author = {Atalay, F and Odabasoglu, F and Halici, M and Cadirci, E and Aydin, O and Halici, Z and Cakir, A}, title = {N-Acetyl Cysteine Has Both Gastro-Protective and Anti-Inflammatory Effects in Experimental Rat Models: Its Gastro-Protective Effect Is Related to Its In Vivo and In Vitro Antioxidant Properties.}, journal = {Journal of cellular biochemistry}, volume = {117}, number = {2}, pages = {308-319}, doi = {10.1002/jcb.25193}, pmid = {25941092}, issn = {1097-4644}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Antioxidants/*pharmacology/therapeutic use ; Carrageenan ; Catalase/metabolism ; Drug Evaluation, Preclinical ; Edema/chemically induced/drug therapy/metabolism ; Glutathione Transferase/metabolism ; Indomethacin ; Lipid Peroxidation ; Oxidative Stress ; Peroxidase/metabolism ; Rats, Wistar ; Stomach/drug effects/enzymology ; Stomach Ulcer/chemically induced/*drug therapy/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {N-acetyl cysteine (NAC), a metabolite of sulphur-containing amino acid cysteine, is used as an antioxidant and a mucolytic agent. Therefore, we aimed to investigate anti-inflammatory and anti-ulcerative effects of NAC. We also intended to determine the relation between antiulcer effect of NAC and its antioxidant properties by biochemical evaluation. In this study a total of 15 rat groups (n = 6 per group) were used for inflammation and ulcer experiments. Anti-inflammatory effects of NAC have been investigated on six rat groups with carrageenan (CAR)-induced paw oedema model. Antiulcer effects of NAC have been investigated on 24 h fasted nine rat groups with IND-induced ulcer model in the presence of positive (LAN, RAN, FAM, and OMEP), negative (untreated IND group) and intact control groups. In biochemical analyses of stomach tissues; glutathione S-transferase (GST), catalase (CAT), myeloperoxidase (MPO), and superoxide dismutase (SOD) enzyme activities and lipid peroxidation (LPO) and the glutathione (GSH) levels were determined. All doses of NAC exerted significant anti-inflammatory effect; even the effect of 900 mg/kg NAC was similar with that of DIC and IND. In gastric tissues NAC administration decreased the level of LPO and activity of CAT, which were increased by IND. Furthermore, NAC increased the GSH level and SOD and GST activities, which decreased in ulcerous stomach tissues. Only MPO activity increased in both IND and NAC groups when compared to healthy rat group. We determined that NAC has both anti-inflammatory and anti-ulcerative effects.}, }
@article {pmid25940290, year = {2015}, author = {Liu, W and Su, W and Yang, X and Bai, J and Zhong, X and He, Z}, title = {[Cigarette smoke extract induces senescence of murine skeletal muscle cells by oxidative stress-induced down-regulation of histone deacetylase 2].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {31}, number = {5}, pages = {630-3, 638}, pmid = {25940290}, issn = {1007-8738}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cellular Senescence/*drug effects ; Down-Regulation/*drug effects ; Histone Deacetylase 2/*genetics ; Mice ; Muscle, Skeletal/*cytology/drug effects/metabolism ; Oxidative Stress/*drug effects ; Pulmonary Disease, Chronic Obstructive/pathology ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Smoke/*adverse effects ; Nicotiana/*chemistry ; beta-Galactosidase/metabolism ; }, abstract = {OBJECTIVE: To investigate whether cigarette smoke extract (CSE) induces the senescence of skeletal muscle cells by oxidative stress-induced down-regulation of histone deacetylase 2 (HDAC2).<br><br>METHODS: C2C12 myoblasts were induced to differentiate into skeletal muscle cells. H2O2 and N-acetyl cysteine (NAC) were used to investigate the effects of CSE on oxidative stress, cell senescence and the expression of HDAC2 in skeletal muscle cells, and detect the changes of the activities of malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS) and glutathione peroxidase (GSH-Px). Cell senescence was identified by senescence-associated &#x3b2;-galactosidase staining. The expressions of HDAC2 mRNA and protein were measured by real-time quantitative PCR and Western blotting, respectively.<br><br>RESULTS: Compared with the control group, MDA concentration and ROS activity significantly increased, the activities of SOD and GSH-Px significantly decreased, the expression of &#x3b2;-galactosidase was up-regulated, and the expressions of HDAC2 mRNA and protein were down-regulated in the CSE group and the H2O2 group. However, the changes in the CSE group were reversed after the pretreatment of NAC.<br><br>CONCLUSION: CSE may lead to the senescence of murine skeletal muscle cells by oxidative stress-induced down-regulation of HDAC2.}, }
@article {pmid25939976, year = {2015}, author = {Guzmán, R and Campos, C and Yuguero, R and Masegù, C and Gil, P and Moragón, &#xc1;C}, title = {Protective effect of sulfurous water in peripheral blood mononuclear cells of Alzheimer's disease patients.}, journal = {Life sciences}, volume = {132}, number = {}, pages = {61-67}, doi = {10.1016/j.lfs.2015.04.006}, pmid = {25939976}, issn = {1879-0631}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*prevention &amp; control ; Antioxidants/*pharmacology ; Cell Survival ; Comet Assay ; DNA Damage/genetics ; Drug Evaluation, Preclinical ; Female ; Humans ; Hydrogen Sulfide/chemistry/*pharmacology ; In Vitro Techniques ; Leukocytes, Mononuclear/*drug effects ; Male ; Tetrazolium Salts ; Thiazoles ; Water/chemistry ; }, abstract = {AIMS: One of the main features of sulfurous water (SW) is the presence of hydrogen sulfide (H2S), which confers its antioxidant activity. Since oxidative stress plays an important role in Alzheimer's disease (AD) we hypothesize that SW could have a protective effect in these patients.<br><br>MATERIAL AND METHODS: A therapeutic in vitro approach of SW was performed in peripheral blood mononuclear cells (PBMCs) of AD patients and in age-matched healthy non-demented controls using one modification of the comet assay (to measure oxidative DNA damage) and the MTT assay (as an indicator of cell viability). Hydrogen peroxide and homocysteine were used to induce oxidative DNA damage, and vitamin C, Trolox and N-acetyl-cysteine were selected as antioxidants of reference to compare SW treatment results.<br><br>KEY FINDINGS: SW did not increase per se the oxidative DNA damage of PBMC. Furthermore, SW protected them against enhanced oxidative stress in AD and control populations after pro-oxidant stimuli, with similar results to those observed when using the antioxidants of reference. Nevertheless, SW was the only treatment that could avoid the loss of viability of PBMC for all pro-oxidant stimuli in both populations, suggesting that H2S could confer to SW a more antioxidant capacity than other known antioxidants.<br><br>SIGNIFICANCE: The protective effect of SW was proved for the first time not only in DNA stability but also in cell viability preservation in AD, indicating that further research in other in vitro and in vivo models could lead to include SW as a possible therapy for AD.}, }
@article {pmid25937502, year = {2015}, author = {Arent, CO and Valvassori, SS and Steckert, AV and Resende, WR and Dal-Pont, GC and Lopes-Borges, J and Amboni, RT and Bianchini, G and Quevedo, J}, title = {The effects of n-acetylcysteine and/or deferoxamine on manic-like behavior and brain oxidative damage in mice submitted to the paradoxal sleep deprivation model of mania.}, journal = {Journal of psychiatric research}, volume = {65}, number = {}, pages = {71-79}, doi = {10.1016/j.jpsychires.2015.04.011}, pmid = {25937502}, issn = {1879-1379}, mesh = {Acetylcysteine/*therapeutic use ; Aldehydes/metabolism ; Analysis of Variance ; Animals ; Antimanic Agents/*therapeutic use ; *Bipolar Disorder/drug therapy/etiology/pathology ; *Brain/drug effects/metabolism/pathology ; Deferoxamine/*therapeutic use ; Disease Models, Animal ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Lipid Peroxidation/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Sleep Deprivation/*complications ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Bipolar disorder (BD) is a severe psychiatric disorder associated with social and functional impairment. Some studies have strongly suggested the involvement of oxidative stress in the pathophysiology of BD. Paradoxal sleep deprivation (PSD) in mice has been considered a good animal model of mania because it induces similar manic-like behavior, as well as producing the neurochemical alterations which have been observed in bipolar patients. Thus, the objective of the present study was to evaluate the effects of the antioxidant agent's n-acetylcysteine (Nac) and/or deferoxamine (DFX) on behavior and the oxidative stress parameters in the brains of mice submitted to the animal model of mania induced by PSD. The mice were treated for a period of seven days with saline solution (SAL), Nac, DFX or Nac plus DFX. The animals were subject to the PSD protocol for 36 h. Locomotor activity was then evaluated using the open-field test, and the oxidative stress parameters were subsequently evaluated in the hippocampus and frontal cortex of mice. The results showed PSD induced hyperactivity in mice, which is considered a manic-like behavior. In addition to this, PSD increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of mice. The Nac plus DFX adjunctive treatment prevented both the manic-like behavior and oxidative damage induced by PSD. Improving our understanding relating to oxidative damage in biomolecules, and the antioxidant mechanisms presented in the animal models of mania are important in helping to improve our knowledge concerning the pathophysiology and development of new therapeutical treatments for BD.}, }
@article {pmid25935303, year = {2015}, author = {Moon, JH and Jang, EY and Shim, KS and Lee, JY}, title = {In vitro effects of N-acetyl cysteine alone and in combination with antibiotics on Prevotella intermedia.}, journal = {Journal of microbiology (Seoul, Korea)}, volume = {53}, number = {5}, pages = {321-329}, pmid = {25935303}, issn = {1976-3794}, mesh = {Acetylcysteine/*pharmacology ; Ampicillin/pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects/growth &amp; development ; Ciprofloxacin/pharmacology ; Metronidazole/pharmacology ; Microbial Sensitivity Tests ; Prevotella intermedia/*drug effects/growth &amp; development/ultrastructure ; Tetracycline/pharmacology ; }, abstract = {N-acetyl cysteine (NAC) is an antioxidant that possesses anti-inflammatory activities in tissues. In the field of dentistry, NAC was demonstrated to prevent the expression of LPS-induced inflammatory mediators in phagocytic cells and gingival fibroblasts during the inflammatory process, but the effect of NAC on oral pathogens has been rarely studied. Here, we examined the effect of NAC against planktonic and biofilm cells of Prevotella intermedia, a major oral pathogen. NAC showed antibacterial activity against the planktonic P. intermedia with MIC value of 3 mg/ml and significantly decreased biofilm formation by the bacterium even at sub MIC. NAC did not affect the antibiotic susceptibility of planktonic P. intermedia, showing indifference (fractional inhibitory concentration index of 0.5-4) results against the bacterium in combination with ampicillin, ciprofloxacin, tetracycline or metronidazole. On the other hand, viability of the pre-established bacterial biofilm exposed to the antibiotics except metronidazole was increased in the presence of NAC. Collectively, NAC may be used for prevention of the biofilm formation by P. intermedia rather than eradication of the pre-established bacterial biofilm. Further studies are required to explore antibacterial and anti-biofilm activity of NAC against mixed population of oral bacteria and its modulatory effect on antibiotics used for oral infectious diseases.}, }
@article {pmid25935150, year = {2015}, author = {Lamoke, F and Mazzone, V and Persichini, T and Maraschi, A and Harris, MB and Venema, RC and Colasanti, M and Gliozzi, M and Muscoli, C and Bartoli, M and Mollace, V}, title = {Amyloid β peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation.}, journal = {Journal of neuroinflammation}, volume = {12}, number = {}, pages = {84}, pmid = {25935150}, issn = {1742-2094}, support = {R01 EY022416/EY/NEI NIH HHS/United States ; R01 HL108719/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amyloid beta-Peptides/*pharmacology ; Animals ; Cattle ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Interactions ; Endothelial Cells ; Endothelium, Vascular/cytology ; Free Radical Scavengers/pharmacology ; HSP90 Heat-Shock Proteins/*metabolism ; Immunoprecipitation ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type III/*metabolism ; Oxidative Stress/*drug effects ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; Serine/metabolism ; Signal Transduction/drug effects ; Vascular Endothelial Growth Factor A/pharmacology ; }, abstract = {BACKGROUND: Amyloid β (Aβ)-induced vascular dysfunction significantly contributes to the pathogenesis of Alzheimer's disease (AD). Aβ is known to impair endothelial nitric oxide synthase (eNOS) activity, thus inhibiting endothelial nitric oxide production (NO).<br><br>METHOD: In this study, we investigated A&#x3b2;-effects on heat shock protein 90 (HSP90) interaction with eNOS and Akt in cultured vascular endothelial cells and also explored the role of oxidative stress in this process.<br><br>RESULTS: Treatments of endothelial cells (EC) with A&#x3b2; promoted the constitutive association of HSP90 with eNOS but abrogated agonist (vascular endothelial growth factor (VEGF))-mediated HSP90 interaction with Akt. This effect resulted in blockade of agonist-mediated phosphorylation of Akt and eNOS at serine 1179. Furthermore, A&#x3b2; stimulated the production of reactive oxygen species in endothelial cells and concomitant treatments of the cells with the antioxidant N-acetyl-cysteine (NAC) prevented A&#x3b2; effects in promoting HSP90/eNOS interaction and rescued agonist-mediated Akt and eNOS phosphorylation.<br><br>CONCLUSIONS: The obtained data support the hypothesis that oxidative damage caused by A&#x3b2; results in altered interaction of HSP90 with Akt and eNOS, therefore promoting vascular dysfunction. This mechanism, by contributing to A&#x3b2;-mediated blockade of nitric oxide production, may significantly contribute to the cognitive impairment seen in AD patients.}, }
@article {pmid25932150, year = {2015}, author = {Jiang, L and Wang, L and Chen, L and Cai, GH and Ren, QY and Chen, JZ and Shi, HJ and Xie, YH}, title = {As2O3 induces apoptosis in human hepatocellular carcinoma HepG2 cells through a ROS-mediated mitochondrial pathway and activation of caspases.}, journal = {International journal of clinical and experimental medicine}, volume = {8}, number = {2}, pages = {2190-2196}, pmid = {25932150}, issn = {1940-5901}, abstract = {Arsenic trioxide (As2O3) has been shown to induce apoptosis in hepatocellular carcinoma cells. However, the molecular mechanism of As2O3-induced apoptosis in the hepatocellular carcinoma cells remains poorly understood. Here, we investigated the impact of As2O3 exposure on the human hepatocellular carcinoma cell line HepG2 and examined the underlying mechanism of cell death. As2O3 induced apoptosis of HepG2 cells in a dose- and time-dependent manner and caused a massive production of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was able to prevent As2O3-induced cell death, implying an involvement of ROS in the induction of As2O3-triggered apoptosis. Furthermore, As2O3 initiated apoptosis by triggering of the mitochondria apoptotic pathway as indicated by inhibited Bcl-2 expression, a collapse of the mitochondrial membrane potential (MMP), release of cytochrome c and activation of the caspase cascade. However, these As2O3-induced events can be prevented by NAC. Taken together, these findings suggest that the As2O3 induced apoptosis through a ROS-mediated mitochondrial pathway and activation of caspases.}, }
@article {pmid25929180, year = {2015}, author = {Muroi, M and Tanamoto, K}, title = {Zinc- and oxidative property-dependent degradation of pro-caspase-1 and NLRP3 by ziram in mouse macrophages.}, journal = {Toxicology letters}, volume = {235}, number = {3}, pages = {199-205}, doi = {10.1016/j.toxlet.2015.04.012}, pmid = {25929180}, issn = {1879-3169}, mesh = {Animals ; Carrier Proteins/genetics/*metabolism ; Caspase 1/genetics/*metabolism ; Cell Line ; Fungicides, Industrial/*toxicity ; Gene Expression Regulation/drug effects ; Interleukin-18/genetics/metabolism ; Interleukin-1beta/genetics/metabolism ; Macrophages/*drug effects ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein ; Oxidation-Reduction ; Zinc/*pharmacology ; Ziram/*toxicity ; }, abstract = {The NLRP3 inflammasome, composed of caspase-1, NLRP3 and ASC, plays a critical role in the clearance of microbial pathogens. Here, we found that the treatment of mouse macrophages with the zinc-containing dithiocarbamate ziram, a widely used fungicide in agriculture, caused a decrease in pro-caspase-1 and NLRP3 levels while not affecting ASC level. Ziram did not affect levels of pro-caspase-1 and NLRP3 mRNA, and no cleavage products of pro-caspase-1 including p10 subunit, which is an autocleavage product of pro-caspase-1, were detected, indicating that the decrease was associated with degradation of these proteins. The decrease was inhibited by SH-type antioxidants, N-acetyl cysteine, dithiothreitol and 2-mercaptoethanol, or a metal chelator EDTA but not by inhibitors of proteasome, lysosomes, autophagy and matrix metalloproteases. Thiram, a comparator for ziram that does not contain zinc, showed a weaker decrease in protein levels. Furthermore, the zinc-containing dithiocarbamate, zinc diethyldithiocarbamate, efficiently decreased the levels of pro-caspase-1 and NLRP3, whereas dithiocarbamates, dimethyldithiocarbamate and diethyldithiocarbamate without zinc, were less active. The organic zinc compound [3,4-toluenedithiolato(2-)]zinc hydrate did not induce a decrease in protein levels. Ziram also inhibited IL-1β production by macrophages in response to lipopolysaccharide and bacterial clearance during Salmonella infection of macrophage cells. These results indicate that ziram causes degradation of pro-caspase-1 and NLRP3 in a zinc- and oxidative property-dependent manner and suggest that exposure to ziram may compromise the clearance of microbial pathogens.}, }
@article {pmid25928540, year = {2015}, author = {Wu, L and Chen, X and Huang, L and Tian, J and Ke, F and Xu, J and Chen, Y and Zheng, M}, title = {A Novobiocin Derivative, XN4, Inhibits the Proliferation of Chronic Myeloid Leukemia Cells by Inducing Oxidative DNA Damage.}, journal = {PloS one}, volume = {10}, number = {4}, pages = {e0123314}, pmid = {25928540}, issn = {1932-6203}, mesh = {Antigens, CD34/genetics/metabolism ; Apoptosis/drug effects/genetics ; Cell Cycle/drug effects/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects/genetics ; Cell Survival/drug effects/genetics ; DNA Damage/*drug effects/genetics ; Flow Cytometry ; Humans ; K562 Cells ; Membrane Proteins/genetics/metabolism ; NADPH Oxidase 4 ; NADPH Oxidase 5 ; NADPH Oxidases/genetics/metabolism ; Novobiocin/analogs &amp; derivatives/*pharmacology ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; }, abstract = {XN4 might induce DNA damage and apoptotic cell death through reactive oxygen species (ROS). The inhibition of proliferation of K562 and K562/G01 cells was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide). The mRNA levels of NADPH oxidase 1-5 (Nox1-5) genes were evaluated by qRT-PCR. The levels of extracellular reactive oxygen species (ROS), DNA damage, apoptosis, and cell cycle progression were examined by flow cytometry (FCM). Protein levels were analyzed by immunoblotting. XN4 significantly inhibited the proliferation of K562 and K562/G01 cells, with IC50 values of 3.75±0.07 µM and 2.63±0.43 µM, respectively. XN4 significantly increased the levels of Nox4 and Nox5 mRNA, stimulating the generation of intracellular ROS, inducing DNA damage and activating ATM-γ-H2AX signaling, which increased the number of cells in the S and G2/M phase of the cell cycle. Subsequently, XN4 induced apoptotic cell death by activating caspase-3 and PARP. Moreover, the above effects were all reversed by the ROS scavenger N-acetylcysteine (NAC). Additionally, XN4 can induce apoptosis in progenitor/stem cells isolated from CML patients' bone marrow. In conclusion, XN4-induced DNA damage and cell apoptosis in CML cells is mediated by the generation of ROS.}, }
@article {pmid25926552, year = {2015}, author = {El-Bini Dhouib, I and Annabi, A and Jrad, A and El-Golli, N and Gharbi, N and Lasram, MM and El-Fazaa, S}, title = {Carbosulfan-induced oxidative damage following subchronic exposure and the protective effects of N-acetylcysteine in rats.}, journal = {General physiology and biophysics}, volume = {34}, number = {3}, pages = {249-261}, doi = {10.4149/gpb_2015005}, pmid = {25926552}, issn = {0231-5882}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Carbamates/*poisoning ; Chemical and Drug Induced Liver Injury/etiology/*metabolism/*prevention &amp; control ; Drug Interactions ; Drug Synergism ; Kidney Diseases/*chemically induced/*metabolism/prevention &amp; control ; Oxidative Stress/drug effects ; Pesticides/poisoning ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Treatment Outcome ; }, abstract = {Carbosulfan (CB)-induced oxidative stress leads to the inevitable accumulation of free radicals and eventual alteration of antioxidant enzymes in various biological systems. The present study is designed to investigate the preventive effect of N-acetylcysteine (NAC) on carbosulfan-induced hepatic and renal dysfunction in rats. Rats exposed to CB and NAC were examined for toxicity by assessing various biochemical alteration and stress markers including in liver and kidney. Significant increases of blood alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), creatinine and urea were detected in CB-treated rats. In addition, the levels of antioxidative enzymes such as catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH) also were assessed. According to the results, rats exposed to carbosulfan showed a significant increase in the accumulation of stress markers and an alteration in the antioxidative enzymes activity, when compared to their respective controls. Interestingly, administration of NAC to CB-treated rats attenuates the toxicity of this compound, objectified by biochemical and oxidative improvement of liver and kidney. Thus, the present study reports for the first time that NAC could be a promising therapeutic agent against CB induced oxidative stress.}, }
@article {pmid25925316, year = {2015}, author = {Chen, Z and Dai, T and Chen, X and Tan, L and Shi, C}, title = {Activation and regulation of the granulation tissue derived cells with stemness-related properties.}, journal = {Stem cell research &amp; therapy}, volume = {6}, number = {1}, pages = {85}, pmid = {25925316}, issn = {1757-6512}, mesh = {Acetylcysteine/chemistry ; Animals ; Cell Differentiation ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Dermis/cytology ; Disease Models, Animal ; Gene Knock-In Techniques ; Granulation Tissue/*cytology ; Mice ; Mice, Inbred C57BL ; MicroRNAs/antagonists &amp; inhibitors/metabolism ; Oligonucleotides, Antisense/metabolism ; Reactive Oxygen Species/chemistry ; Skin Diseases/therapy ; Stem Cell Transplantation ; Stem Cells/*cytology/metabolism ; Wound Healing ; }, abstract = {INTRODUCTION: Skin as the largest and easily accessible organ of the body represents an abundant source of adult stem cells. Among them, dermal stem cells hold great promise in tissue repair and the skin granulation tissue has been recently proposed as a promising source of dermal stem cells, but their biological characteristics have not been well investigated.<br><br>METHODS: The 5-bromo-2'-deoxyuridine (BrdU) lineage tracing approach was employed to chase dermal stem cells in vivo. Granulation tissue derived cells (GTCs) were isolated and their in vitro proliferation, self-renewing, migration, and multi-differentiation capabilities were assessed. Combined radiation and skin wound model was used to investigate the therapeutic effects of GTCs. MicroRNA-21 (miR-21) antagomir was used to antagonize miR-21 expression. Reactive oxygen species (ROS) were scavenged by N-acetyl cysteine (NAC).<br><br>RESULTS: The quiescent dermal stem/progenitor cells were activated to proliferate upon injury and enriched in granulation tissues. GTCs exhibited enhanced proliferation, colony formation and multi-differentiation capacities. Topical transplantation of GTCs into the combined radiation and skin wound mice accelerated wound healing and reduced tissue fibrosis. Blockade of the miR-21 expression in GTCs inhibited cell migration and differentiation, but promoted cell proliferation and self-renewing at least partially via a ROS dependent pathway.<br><br>CONCLUSIONS: The granulation tissue may represent an alternative adult stem cell source in tissue replacement therapy and miR-21 mediated ROS generation negatively regulates the stemness-related properties of granulation tissue derived cells.}, }
@article {pmid25922788, year = {2015}, author = {Jiao, Y and Ma, S and Li, J and Shan, L and Yang, Y and Li, M and Chen, J}, title = {The influences of N-acetyl cysteine (NAC) on the cytotoxicity and mechanical properties of Poly-methylmethacrylate (PMMA)-based dental resin.}, journal = {PeerJ}, volume = {3}, number = {}, pages = {e868}, pmid = {25922788}, issn = {2167-8359}, abstract = {Objectives. This study aimed to investigate the influences of N-acetyl cysteine (NAC) on cytotoxicity and mechanical properties of Poly-methylmethacrylate (PMMA) dental resins. Methods. Experimental PMMA resin was prepared by incorporating various concentrations of NAC (0, 0.15, 0.3, 0.6 and 0.9 wt.%). MTT assay was performed to investigate viability of human dental pulp cells after exposure to extract of PMMA resin with or without NAC. Cell adhesion on resin specimens was examined with scanning electron microscopy. Degree of conversion was studied with Fourier Transform Infrared Spectroscopy (FTIR). Flexural strength, microhardness and surface roughness was evaluated using a universal testing machine, microhardness tester and optical profilometer, respectively. Results. Incorporation of NAC into PMMA resin significantly reduced its cytotoxicity and enhanced cell adhesion on its surface. NAC induced negative influences on the mechanical and physical properties of PMMA resin in a dose-dependent manner. The degree of conversion for all experimental PMMA resins reached as high as 72% after 24 h of polymerization. All the tested properties were maintained when the concentration of incorporated NAC was 0.15 wt.%. Conclusion. The addition of 0.15 wt.% NAC remarkably improved biocompatibility of PMMA resin without exerting significant negative influence on its mechanical and physical properties.}, }
@article {pmid25922640, year = {2015}, author = {Cromie, MM and Gao, W}, title = {Epigallocatechin-3-gallate enhances the therapeutic effects of leptomycin B on human lung cancer a549 cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2015}, number = {}, pages = {217304}, pmid = {25922640}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; Cytochrome P-450 CYP3A/genetics/metabolism ; Down-Regulation/drug effects ; Fatty Acids, Unsaturated/pharmacology ; Glutathione Peroxidase/genetics/metabolism ; Humans ; Inhibitor of Apoptosis Proteins/genetics/metabolism ; Lung Neoplasms/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/metabolism ; Survivin ; Up-Regulation/drug effects ; Glutathione Peroxidase GPX1 ; }, abstract = {Our previous studies have shown Leptomycin B (LMB) is a promising antilung cancer drug. Epigallocatechin-3-gallate (EGCG) has antitumor properties but a debatable clinical application. The objective of this study is to evaluate the combination therapeutic effect of LMB and EGCG and its molecular mechanisms in human lung cancer A549 cells. Increased cytotoxicity was observed in LMB+EGCG-treated cells compared to LMB-treated cells. Elevated ROS was maximized 2 h after treatment, and LMB+EGCG-treated cells had higher ROS levels compared to LMB. N-Acetyl-L-cysteine (NAC) studies confirmed the oxidative role of LMB and/or EGCG treatment. In comparison to the control, CYP3A4, SOD, GPX1, and p21 mRNA expression levels were increased 7.1-, 2.0-, 4.6-, and 13.1-fold in LMB-treated cells, respectively, while survivin was decreased 42.6-fold. Additionally, these increases of CYP3A4, SOD, and GPX1 were significantly reduced, while p21 was significantly increased in LMB+EGCG-treated cells compared to LMB-treated cells. The qRT-PCR results for p21 and survivin were further confirmed by Western blot. Our study first shows that LMB produces ROS and is possibly metabolized by CYP3A4, GPX1, and SOD in A549 cells, and combination treatment of LMB and EGCG augments LMB-induced cytotoxicity through enhanced ROS production and the modulation of drug metabolism and p21/survivin pathways.}, }
@article {pmid25920891, year = {2015}, author = {Lasram, MM and Dhouib, IB and Annabi, A and El Fazaa, S and Gharbi, N}, title = {A review on the possible molecular mechanism of action of N-acetylcysteine against insulin resistance and type-2 diabetes development.}, journal = {Clinical biochemistry}, volume = {48}, number = {16-17}, pages = {1200-1208}, doi = {10.1016/j.clinbiochem.2015.04.017}, pmid = {25920891}, issn = {1873-2933}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Diabetes Mellitus, Type 2/*prevention &amp; control ; Humans ; Insulin Resistance/*physiology ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC), a cysteine pro-drug and glutathione precursor has been used in therapeutic practices for several decades, as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication. There is a growing interest concerning the beneficial effects of NAC against the early stages of type-2 diabetes development. Nevertheless, the mechanisms underlying the therapeutic and clinical applications of NAC are not fully understood. In this review we aimed to focus on the protective effects of NAC against insulin resistance.<br><br>DESIGN AND METHODS: The possible mechanisms of action were reviewed using the major findings of more than 100 papers relating to the antioxidant, anti-inflammatory and anti-apoptotic properties of NAC.<br><br>RESULTS: The anti-oxidative activity of NAC has been attributed to its fast reactions with free radicals as well as the restitution of reduced glutathione. Further, NAC has anti-inflammatory and anti-apoptotic properties which can have positive effects during the inflammatory process in insulin resistance. Moreover, NAC can modulate certain signaling pathways in both insulin target cells and &#x3b2; cells.<br><br>CONCLUSIONS: The diverse biological effects of NAC may make it a potential adjuvant or therapeutic target in the treatment of type-2 diabetes. So, further studies are required for determining its ability to alleviate insulin resistance and to improve insulin sensitivity.}, }
@article {pmid25917538, year = {2015}, author = {Paula, MM and Petronilho, F and Vuolo, F and Ferreira, GK and De Costa, L and Santos, GP and Effting, PS and Dal-Pizzol, F and Dal-Bó, AG and Frizon, TE and Silveira, PC and Pinho, RA}, title = {Gold nanoparticles and/or N-acetylcysteine mediate carrageenan-induced inflammation and oxidative stress in a concentration-dependent manner.}, journal = {Journal of biomedical materials research. Part A}, volume = {103}, number = {10}, pages = {3323-3330}, doi = {10.1002/jbm.a.35469}, pmid = {25917538}, issn = {1552-4965}, mesh = {*Acetylcysteine/chemistry/pharmacology ; Animals ; Carrageenan/*adverse effects/pharmacology ; Dose-Response Relationship, Drug ; Gold/*chemistry ; Inflammation/chemically induced/metabolism/pathology ; Interleukin-10/metabolism ; Interleukin-1beta/metabolism ; Male ; Metal Nanoparticles/*chemistry ; Oxidative Stress/*drug effects ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {We report the effect of gold nanoparticles (AuNP) in an acute inflammation model induced by carrageenan (CG) and compared this effect with those induced by the antioxidant N-acetylcysteine (NAC) alone and by the synergistic effect of NAC and AuNP together. Male Wistar rats received saline or saline containing CG administered into the pleural cavity, and some rats also received NAC (20 mg/kg) subcutaneously and/or AuNP administered into the pleural cavity immediately after surgery. Four hours later, the rats were sacrificed and pleural exudates obtained for evaluation of cytokine levels and myeloperoxidase activities. Oxidative stress parameters were also evaluated in the lungs. The results demonstrated that the inflammatory process caused by the administration of CG into the pleural cavity resulted in a substantial increase in the levels of tumor necrosis factor-α, interleukin-1β, and myeloperoxidase and a reduction in interleukin-10 levels. These levels seem to be reversed after different treatments in animals. Antioxidant enzymes exhibited positive responses after treatment of NAC + AuNP, and all treatments were effective at reducing lipid peroxidation and oxidation of thiol groups induced by CG. These findings suggest that small compounds, such as NAC plus AuNP, may be useful in the treatment of conditions associated with local inflammation.}, }
@article {pmid25916659, year = {2015}, author = {Heim, J and Felder, E and Tahir, MN and Kaltbeitzel, A and Heinrich, UR and Brochhausen, C and Mailänder, V and Tremel, W and Brieger, J}, title = {Genotoxic effects of zinc oxide nanoparticles.}, journal = {Nanoscale}, volume = {7}, number = {19}, pages = {8931-8938}, doi = {10.1039/c5nr01167a}, pmid = {25916659}, issn = {2040-3372}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Chlorides/chemistry/toxicity ; DNA Breaks, Double-Stranded/drug effects ; Humans ; Metal Nanoparticles/*chemistry/toxicity ; Microscopy, Electron, Transmission ; Reactive Oxygen Species/metabolism ; Zinc Compounds/chemistry/toxicity ; Zinc Oxide/*chemistry ; }, abstract = {The potential toxicity of nanoparticles has currently provoked public and scientific discussions, and attempts to develop generally accepted handling procedures for nanoparticles are under way. The investigation of the impact of nanoparticles on human health is overdue and reliable test systems accounting for the special properties of nanomaterials must be developed. Nanoparticular zinc oxide (ZnO) may be internalised through ambient air or the topical application of cosmetics, only to name a few, with unpredictable health effects. Therefore, we analysed the determinants of ZnO nanoparticle (NP) genotoxicity. ZnO NPs (15-18 nm in diameter) were investigated at concentrations of 0.1, 10 and 100 μg mL(-1) using the cell line A549. Internalised NPs were only infrequently detectable by TEM, but strongly increased Zn(2+) levels in the cytoplasm and even more in the nuclear fraction, as measured by atom absorption spectroscopy, indicative of an internalised zinc and nuclear accumulation. We observed a time and dosage dependent reduction of cellular viability after ZnO NP exposure. ZnCl2 exposure to cells induced similar impairments of cellular viability. Complexation of Zn(2+) with diethylene triamine pentaacetic acid (DTPA) resulted in the loss of toxicity of NPs, indicating the relevant role of Zn(2+) for ZnO NP toxicity. Foci analyses showed the induction of DNA double strand breaks (DSBs) by ZnO NPs and increased intracellular reactive oxygen species (ROS) levels. Treatment of the cells with the ROS scavenger N-acetyl-l-cysteine (NAC) resulted in strongly decreased intracellular ROS levels and reduced DNA damage. However, a slow increase of ROS after ZnO NP exposure and reduced but not quashed DSBs after NAC-treatment suggest that Zn(2+) may exert genotoxic activities without the necessity of preceding ROS-induction. Our data indicate that ZnO NP toxicity is a result of cellular Zn(2+) intake. Subsequently increased ROS-levels cause DNA damage. However, we found evidence for the assumption that DNA-DSBs could be caused by Zn(2+) without the involvement of ROS.}, }
@article {pmid25916122, year = {2015}, author = {Petrushanko, IIu and Simonenko, OV and Burnysheva, KM and Klimanova, EA and Dergousova, EA and Mit'kevich, VA and Lopina, OD and Makarov, AA}, title = {[The ability of cells to adjust to the low oxigen content associated with Na,K-ATPase glutationilation].}, journal = {Molekuliarnaia biologiia}, volume = {49}, number = {1}, pages = {175-183}, pmid = {25916122}, issn = {0026-8984}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Catalytic Domain/drug effects ; Cell Hypoxia ; Cell Line ; Cell Membrane/chemistry/metabolism ; Cell Survival/drug effects ; Glutathione/chemistry/*metabolism ; Glutathione Disulfide/pharmacology ; Humans ; Ischemia/drug therapy/*metabolism/pathology ; Mice ; Oxidative Stress/*drug effects ; Oxygen/*metabolism ; Oxygen Consumption/drug effects ; Sodium-Potassium-Exchanging ATPase/chemistry/drug effects/*metabolism ; }, abstract = {Decreasing the amount of oxygen in the tissues under hypoxic and ischemic conditions, observed at a number of pathologic processes, inevitably leads to their damage. One of the main causes of cell damage and death is a violation of the systems maintaining ionic balance. Na,K-ATPaseis a basic ion-transporting protein of animal cell plasma membrane and inhibition of the Na,K-ATPase activity at lower concentrations of oxygen is one of the earliest and most critical events for cell viability. Currently there is an active search for modulators of Na,K-ATPase activity. For this purpose traditionally used cardiac glycosides but the existence of serious adverse effects forced to look for alternative inhibitors of Na,K-ATPase. Previously we have found that the glutathionylation of Na,K-ATPase catalytic subunit leads to a complete-inhibition of the enzyme. In this paper it is shown that the agents which increase the level of Na,K-ATPase glutathionylation: ethyl glutathione (et-GSH), oxidized glutathione (GSSG) and N-acetyl cysteine (NAC), increase cell survival under oxygen deficiency conditions, prevent decline of ATP in the cells and normalize their redox status. Concentration range in which these substances have a maximum protective effect, and does not exhibit cytotoxic properties was defined: for et-GSH 0.2-0.5 mM, for GSSG 0.2-1 mM, for NAC 10 to 15 mM. The results show prospects for development of methods for tissues protection from damage caused by oxygen starvation by varying the degree of Na,K-ATPase glutathionylation.}, }
@article {pmid25915766, year = {2015}, author = {Rajah, T and Chow, SC}, title = {Suppression of Human T Cell Proliferation Mediated by the Cathepsin B Inhibitor, z-FA-FMK Is Due to Oxidative Stress.}, journal = {PloS one}, volume = {10}, number = {4}, pages = {e0123711}, pmid = {25915766}, issn = {1932-6203}, support = {P30 AI064518/AI/NIAID NIH HHS/United States ; }, mesh = {Cathepsin B/antagonists &amp; inhibitors ; *Cell Proliferation ; Cells, Cultured ; Cysteine Proteinase Inhibitors/*pharmacology ; Dipeptides/*pharmacology ; Humans ; Ketones/*pharmacology ; *Oxidative Stress ; T-Lymphocytes/*drug effects/metabolism/physiology ; }, abstract = {The cathepsin B inhibitor, benzyloxycarbonyl-phenylalanine-alanine-fluoromethyl ketone (z-FA-FMK) readily inhibits anti-CD3-induced human T cell proliferation, whereas the analogue benzyloxycarbonyl-phenylalanine-alanine-diazomethyl ketone (z-FA-DMK) had no effect. In contrast, benzyloxycarbonyl-phenylalanine-alanine-chloromethyl ketone (z-FA-CMK) was toxic. The inhibition of T cell proliferation mediated by z-FA-FMK requires not only the FMK moiety, but also the benzyloxycarbonyl group at the N-terminal, suggesting some degree of specificity in z-FA-FMK-induced inhibition of primary T cell proliferation. We showed that z-FA-FMK treatment leads to a decrease in intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) levels in activated T cells. The inhibition of anti-CD3-induced T cell proliferation mediated by z-FA-FMK was abolished by the presence of low molecular weight thiols such as GSH, N-acetylcysteine (NAC) and L-cysteine, whereas D-cysteine which cannot be metabolised to GSH has no effect. The inhibition of anti-CD3-induced up-regulation of CD25 and CD69 expression mediated by z-FA-FMK was also attenuated in the presence of exogenous GSH. Similar to cell proliferation, GSH, NAC and L-cysteine but not D-cysteine, completely restored the processing of caspase-8 and caspase-3 to their respective subunits in z-FA-FMK-treated activated T cells. Our collective results demonstrated that the inhibition of T cell activation and proliferation mediated by z-FA-FMK is due to oxidative stress via the depletion of GSH.}, }
@article {pmid25915728, year = {2015}, author = {Nishimiya, H and Yamada, M and Ueda, T and Sakurai, K}, title = {N-acetyl cysteine alleviates inflammatory reaction of oral epithelial cells to poly (methyl methacrylate) extract.}, journal = {Acta odontologica Scandinavica}, volume = {73}, number = {8}, pages = {616-625}, doi = {10.3109/00016357.2015.1021834}, pmid = {25915728}, issn = {1502-3850}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Antioxidants/analysis ; Cadherins/analysis ; Cell Adhesion/drug effects ; Cell Count ; Cell Survival/drug effects ; Cells, Cultured ; Cytokines/analysis ; Epithelial Cells/drug effects/immunology ; Formaldehyde/analysis ; Glutathione/analysis ; Humans ; Inflammation Mediators/analysis ; L-Lactate Dehydrogenase/analysis ; Lysosomes/drug effects ; Male ; Mouth Mucosa/cytology/*drug effects/immunology ; Oxidation-Reduction ; Polymethyl Methacrylate/chemistry/*toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/analysis ; Time Factors ; }, abstract = {OBJECTIVES: The purpose of this in vitro study was to determine whether the cytotoxicity of self-curing polymethyl methacrylate (PMMA) dental resin to oral epithelial cells was eliminated by mixing the antioxidant amino acid derivative, N-acetyl cysteine (NAC) with the material.<br><br>MATERIALS AND METHODS: Rat and human oral epithelial cells cultured on polystyrene were incubated in culture medium with or without extract from self-curing PMMA dental resin, with or without pre-mixing with NAC. On day 1, the cultures were evaluated for cellular damage, intracellular formaldehyde invasion, cellular redox status and pro-inflammatory cytokine production. Formaldehyde content and the amount of released NAC in the extract were evaluated.<br><br>RESULTS: Rat epithelial cells cultured with PMMA extract showed marked increases in lactate dehydrogenase (LDH) release, intracellular formaldehyde and lysosomal levels and reductions in attached cell number and the amount of E-cadherin compared with those in the culture without the extract; these adverse biological effects were alleviated or prevented by pre-mixing the resin with NAC. In human oral epithelial cells cultured with PMMA extract, the addition of NAC into the resin prevented the intracellular elevation of reactive oxygen species and the reduction in cellular glutathione levels. Human cell cultures with the extract produced higher levels of various pro-inflammatory cytokines than cultures without the extract; this was prevented by mixing the resin with NAC. The extract from PMMA pre-mixed with NAC contained a lower concentration of formaldehyde and a substantial amount of antioxidants.<br><br>CONCLUSION: The cytotoxicity of self-curing PMMA dental resin to oral epithelial cells was eliminated by mixing the resin with NAC.}, }
@article {pmid25913522, year = {2015}, author = {Hoque, M and Nanduri, R and Gupta, J and Mahajan, S and Gupta, P and Saleemuddin, M}, title = {Oleic acid complex of bovine α-lactalbumin induces eryptosis in human and other erythrocytes by a Ca(2+)-independent mechanism.}, journal = {Biochimica et biophysica acta}, volume = {1850}, number = {9}, pages = {1729-1739}, doi = {10.1016/j.bbagen.2015.04.009}, pmid = {25913522}, issn = {0006-3002}, mesh = {Amiloride/pharmacology ; Animals ; Calcium/*pharmacology ; Cattle ; Chickens ; Erythrocytes/*drug effects ; Goats ; Hemolysis/drug effects ; Humans ; Lactalbumin/*pharmacology ; Oleic Acids/*pharmacology ; }, abstract = {BACKGROUND: Complexes of oleic acid (OA) with milk α-lactalbumin, received remarkable attention in view of their selective toxicity towards a spectrum of tumors during the last two decades. OA complexes of some structurally related/unrelated proteins are also tumoricidal. Erythrocytes are among the few differentiated cells that are sensitive and undergo hemolysis when exposed to the complexes.<br><br>METHODS: The effects of OA complex of bovine &#x3b1;-lactalbumin (Bovine Alpha-lactalbumin Made LEthal to Tumor cells, BAMLET) on human, goat and chicken erythrocytes on calcein leakage, phosphatidylserine exposure, morphological changes and hemolysis were studied by confocal microscopy, FACS analysis, scanning electron microscopy and measuring hemoglobin release.<br><br>RESULTS: Erythrocytes exposed to BAMLET undergo eryptosis-like alterations as revealed by calcein leakage, surface phosphatidylserine exposure and transformation to echinocytes at low concentrations and hemolysis when the concentration of the complex was raised. Ca(2+) was not essential and restricted the alterations when included in the medium. The BAMLET-induced alterations in human erythrocytes were prevented by the cation channel inhibitors, amiloride and BaCl2 but not by inhibitors of thiol proteases, sphingomyelinase and by the antioxidant N-acetyl cysteine.<br><br>CONCLUSIONS: The work shows for the first time that low concentrations of BAMLET induces eryptosis in erythrocytes by a novel mechanism not requiring Ca(2+) and hemolysis by detergent-like action by the released OA at higher concentrations.<br><br>GENERAL SIGNIFICANCE: The study points out to the need for a comprehensive evaluation of the toxicity of OA complexes of &#x3b1;-lactalbumin and other proteins towards erythrocytes and other differentiated cells before being considered for therapy.}, }
@article {pmid25913086, year = {2015}, author = {Xu, X and He, L and Zhang, A and Li, Q and Hu, W and Chen, H and Du, J and Shen, J}, title = {Toxoplasma gondii isolate with genotype Chinese 1 triggers trophoblast apoptosis through oxidative stress and mitochondrial dysfunction in mice.}, journal = {Experimental parasitology}, volume = {154}, number = {}, pages = {51-61}, doi = {10.1016/j.exppara.2015.04.008}, pmid = {25913086}, issn = {1090-2449}, mesh = {Animals ; Apoptosis ; Female ; Genotype ; Male ; Membrane Potentials ; Mice ; Mice, Inbred BALB C ; Mitochondria/pathology/physiology ; Oxidative Stress ; Placenta/metabolism/physiopathology ; Pregnancy ; Pregnancy Complications, Parasitic/metabolism/parasitology/*pathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Toxoplasma/classification/genetics/*physiology ; Toxoplasmosis, Animal/metabolism/parasitology/*pathology ; Transcriptome ; Trophoblasts/*pathology ; }, abstract = {Congenital toxoplasmosis may result in abortion, severe mental retardation and neurologic damage in the offspring. Placental damage is considered as the key event in this disease. Here we show that maternal infection with Toxoplasma gondii Wh3 isolate of genotype Chinese 1, which is predominantly prevalent in China, induced trophoblast apoptosis of pregnant mouse. PCR array analysis of 84 key genes in the biogenesis and functions of mouse mitochondrion revealed that ten genes were up-regulated at least 2-fold in the Wh3 infection group, compared with those in the control. The elevated levels of reactive oxygen species (ROS), malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG), as well as the decreased glutathione (GSH), were observed in the infected mice. The mRNA levels of NADPH oxidase 1 and glutathione peroxidase 6 (GPx6) were significantly increased. The production of excessive ROS was NADPH oxidase-dependent, which contributed to mitochondrial structural damage and mitochondrial dysfunction in placentas, followed by the cleavage of caspase-9 and caspase-3, and finally resulted in apoptosis of trophoblasts. All the above-mentioned phenomena were inhibited by pretreatment with the antioxidant of N-acetylcysteine (NAC). Taken together, we concluded that Wh3 infection during pregnancy may contribute to trophoblast apoptosis by oxidative stress-induced mitochondrial dysfunction and activation of the downstream signaling pathway.}, }
@article {pmid25912534, year = {2015}, author = {Oliver, G and Dean, O and Camfield, D and Blair-West, S and Ng, C and Berk, M and Sarris, J}, title = {N-acetyl cysteine in the treatment of obsessive compulsive and related disorders: a systematic review.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {13}, number = {1}, pages = {12-24}, pmid = {25912534}, issn = {1738-1088}, abstract = {OBJECTIVE: Obsessive compulsive and related disorders are a collection of debilitating psychiatric disorders in which the role of glutamate dysfunction in the underpinning neurobiology is becoming well established. N-acetyl cysteine (NAC) is a glutamate modulator with promising therapeutic effect. This paper presents a systematic review of clinical trials and case reports exploring the use of NAC for these disorders. A further objective was to detail the methodology of current clinical trials being conducted in the area.<br><br>METHODS: PubMed, Web of Science and Cochrane Library Database were searched for human clinical trials or case reports investigating NAC in the treatment of obsessive compulsive disorder (OCD) or obsessive compulsive related disorders. Researchers with known involvement in NAC studies were contacted for any unpublished data.<br><br>RESULTS: Four clinical trials and five case reports/series were identified. Study durations were commonly 12-weeks, using 2,400-3,000 mg/day of NAC. Overall, NAC demonstrates activity in reducing the severity of symptoms, with a good tolerability profile and minimal adverse effects. Currently there are three ongoing randomized controlled trials using NAC for OCD (two adults and one pediatric), and one for excoriation.<br><br>CONCLUSIONS: Encouraging results have been demonstrated from the few pilot studies that have been conducted. These results are detailed, in addition to a discussion of future potential research.}, }
@article {pmid25912358, year = {2015}, author = {Sun, M and Wang, L and Jiang, S and Liu, R and Zhao, D and Chen, H and Song, X and Song, L}, title = {CpG ODNs induced autophagy via reactive oxygen species (ROS) in Chinese mitten crab, Eriocheir sinensis.}, journal = {Developmental and comparative immunology}, volume = {52}, number = {1}, pages = {1-9}, doi = {10.1016/j.dci.2015.04.008}, pmid = {25912358}, issn = {1879-0089}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Aquaculture ; *Autophagy/drug effects ; Brachyura/*immunology ; Gene Expression Regulation/drug effects ; Hemocytes/drug effects/*physiology ; Immunity, Innate ; Immunization ; Microtubule-Associated Proteins/genetics/metabolism ; Oligodeoxyribonucleotides/*administration &amp; dosage ; Reactive Oxygen Species/*metabolism ; }, abstract = {Autophagy is a highly conserved intracellular homeostatic process involved in numerous responses in both vertebrate and invertebrate. In the present study, autophagy in hemocytes of Chinese mitten crab Eriocheir sinensis was observed by Western-blot and immunofluorescence assay, and its induction by CpG oligodeoxynucleotides (ODNs) was investigated. The increase of LC3-conversion (LC3-II/LC3-I) and LC3-puncta formation were observed in hemocytes of crabs after rapamycin injection. And the ratio of LC3-conversion and the percentage of LC3-puncta formation were also significantly increased after CpG ODNs stimulation, and the highest values were 1.89-fold and 3.77-fold compared to that in pUC57 group at 24 h post-injection. Moreover, the mRNA expression levels of autophagy-related genes, EsGabarap and EsAtg7, both dramatically increased after CpG ODNs injection, and reached the peak at 6 h post-injection, which were 2.66- and 2.82-fold (P <0.01) for EsGabarap, and 6.16-fold and 6.10-fold (P <0.01) for EsAtg7 compared to saline and pUC57 groups, respectively. The generation of ROS in hemocytes was induced and reached peak at 6 h post-injection in CpG-pUC57 group, which was 1.30-fold (P <0.01) and 1.66-fold (P <0.01) of that in saline and pUC57 group, respectively. The increased ROS generation and autophagy triggered by CpG ODNs were abolished after the treatment of the ROS scavenger, N-acetyl-L-cysteine (NAC). It was suggested that CpG ODNs could induce autophagy and up-regulate the expression levels of autophagy-related genes in crabs via the activation of ROS generation in the hemocytes. The results provided useful information to understand autophagy in crab, and they were also helpful for the application of CpG ODNs as the novel immune stimulants in aquaculture.}, }
@article {pmid25910366, year = {2014}, author = {Takhtfooladi, MA and Jahanshahi, G and Jahanshahi, A and Sotoudeh, A and Samiee Amlashi, O and Allahverdi, A}, title = {Effects of N-acetylcysteine on liver remote injury after skeletal muscle ischemia reperfusion in rats.}, journal = {The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology}, volume = {25 Suppl 1}, number = {}, pages = {43-47}, doi = {10.5152/tjg.2014.6008}, pmid = {25910366}, issn = {2148-5607}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Liver Diseases/metabolism/pathology/*prevention &amp; control ; Male ; Malondialdehyde/metabolism ; Muscle, Skeletal/blood supply/*pathology ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Reperfusion Injury/*complications ; }, abstract = {BACKGROUND/AIMS: This study evaluated the effects of N-acetylcysteine as a scavenger of radical oxygen species on liver injury as a remote organ after skeletal muscle ischemia reperfusion.<br><br>MATERIALS AND METHODS: Twenty male Wistar rats were allocated randomly into two experimental groups: ischemia reperfusion (I/R) and ischemia reperfusion + N-acetylcysteine (I/R+NAC). All animals were undergone 2h of ischemia by occlusion femoral artery and 24h of reperfusion. Rats that were treated with N-acetylcysteine given intravenously at a dose of 150 mg/kg, immediately before reperfusion. Serum levels of aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured. Livers were harvested for histopathological and biochemical studies. Liver tissue malondialdehyde (MDA), glutathione (GSH) and myeloperoxidase (MPO) activity were assayed.<br><br>RESULTS: The ALT and AST values were significantly lower in I/R+NAC group. Hepatic MDA level and MPO activity were significantly increased in I/R group. The levels of GSH in liver tissue were significantly depressed by ischemia reperfusion. Liver histopathologic study in I/R group showed enlarged sinusoids, sinusoidal congestion, cytoplasmic vacuolation, cellular degenerative changes and necrosis. Histopathologically, there was a significant difference between two groups.<br><br>CONCLUSION: Histopatological and biochemical results have shown that N-acetylcysteine was able to protect liver from skeletal muscle ischemia reperfusion injury.}, }
@article {pmid25909282, year = {2015}, author = {Li, CJ and Sun, LY and Pang, CY}, title = {Synergistic protection of N-acetylcysteine and ascorbic acid 2-phosphate on human mesenchymal stem cells against mitoptosis, necroptosis and apoptosis.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {9819}, pmid = {25909282}, issn = {2045-2322}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor/metabolism ; Ascorbic Acid/*analogs &amp; derivatives/pharmacology ; Cell Proliferation/drug effects ; Cells, Cultured ; Cytochromes c/metabolism ; Drug Synergism ; Dynamins ; GTP Phosphohydrolases/metabolism ; Histones/metabolism ; Humans ; Hydrogen Peroxide/toxicity ; Mesenchymal Stem Cells/cytology/drug effects/metabolism ; Microtubule-Associated Proteins/metabolism ; Mitochondria/*drug effects/metabolism ; Mitochondrial Proteins/metabolism ; Necrosis ; Oxidative Stress/drug effects ; Protective Agents/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Human mesenchymal stem cells (hMSCs) contribute to ischemic tissue repair, regeneration, and possess ability to self-renew. However, poor viability of transplanted hMSCs within ischemic tissues has limited its therapeutic efficiency. Therefore, it is urgent to explore new method to improve the viability of the grafted cells. By using a systematic analysis, we reveal the mechanism of synergistic protection of N-acetylcysteine (NAC) and ascorbic acid 2-phosphate (AAP) on hMSCs that were under H2O2-induced oxidative stress. The combined treatment of NAC and AAP (NAC/AAP) reduces reactive oxygen species (ROS) generation, stabilizes mitochondrial membrane potential and decreases mitochondrial fission/fragmentation due to oxidative stress. Mitochondrial fission/fragmentation is a major prologue of mitoptosis. NAC/AAP prevents apoptotic cell death via decreasing the activation of BAX, increasing the expression of BCL2, and reducing cytochrome c release from mitochondria that might lead to the activation of caspase cascade. Stabilization of mitochondria also prevents the release of AIF, and its nuclear translocation which may activate necroptosis via H2AX pathway. The decreasing of mitoptosis is further studied by MicroP image analysis, and is associated with decreased activation of Drp1. In conclusion, NAC/AAP protects mitochondria from H2O2-induced oxidative stress and rescues hMSCs from mitoptosis, necroptosis and apoptosis.}, }
@article {pmid25908761, year = {2015}, author = {Lin, JR and Shen, WL and Yan, C and Gao, PJ}, title = {Downregulation of dynamin-related protein 1 contributes to impaired autophagic flux and angiogenic function in senescent endothelial cells.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {35}, number = {6}, pages = {1413-1422}, doi = {10.1161/ATVBAHA.115.305706}, pmid = {25908761}, issn = {1524-4636}, mesh = {Animals ; *Autophagy ; Cellular Senescence/*physiology ; Down-Regulation ; Dynamins ; Endothelial Cells/*metabolism ; GTP Phosphohydrolases/*metabolism ; Humans ; Microtubule-Associated Proteins/*metabolism ; Mitochondria, Muscle/metabolism ; Mitochondrial Proteins/*metabolism ; Muscle, Smooth, Vascular/cytology ; Rats, Inbred WKY ; Reactive Oxygen Species/metabolism ; Umbilicus/blood supply ; Veins ; }, abstract = {OBJECTIVE: Recent studies have shown that altered mitochondrial dynamics impairs the function in senescent endothelial cells (ECs). However, the underlying molecular mechanism remains to be elucidated. Herein, we investigated the role and underlying mechanism of mitochondrial fission protein dynamin-related protein 1 (DRP1) in vascular aging.<br><br>APPROACH AND RESULTS: We found that DRP1 expression is decreased in senescent ECs, accompanied with long interconnected mitochondria and impaired angiogenic function. In addition, there was marked increase of autophagosomes but not of autolysosomes (assessed as punctate dual fluorescent mCherry-GFP (green fluorescent protein) tandem-tagged light chain 3 expression) in senescent ECs, indicating impaired autophagic flux. DRP1 knockdown or pharmacological inhibition in young ECs resulted in elongated mitochondria, suppressed autophagic flux, premature senescence, and impaired angiogenic function. In contrast, adenoviral-mediated overexpression of DRP1 in senescent ECs restored autophagic flux and improved angiogenic function. EC senescence was associated with the increase of mitochondrial reactive oxygen species and antioxidant N-acetyl-cysteine restored autophagosome clearance and improved angiogenic function. Consistently, en face staining of old rat thoracic aorta revealed a decrease of DRP1 expression and increase of autophagosomes accumulation. Furthermore, in vivo knockdown of Drp1 in common carotid arteries significantly impaired the autophagosome clearance. Importantly, downregulation of Drp1 directly abrogated microvessels outgrowth from ex vivo aortic rings.<br><br>CONCLUSIONS: These results suggest that loss of DRP1 during senescence exacerbates ECs dysfunction by increasing mitochondrial reactive oxygen species and subsequently inhibiting autophagic flux.}, }
@article {pmid25906049, year = {2015}, author = {Srivastava, R and Bhattacharya, S and Chakraborty, A and Chattopadhyay, A}, title = {Differential in vivo genotoxicity of arsenic trioxide in glutathione depleted mouse bone marrow cells: expressions of Nrf2/Keap1/P62.}, journal = {Toxicology mechanisms and methods}, volume = {25}, number = {3}, pages = {223-228}, doi = {10.3109/15376516.2015.1034334}, pmid = {25906049}, issn = {1537-6524}, mesh = {Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing/agonists/antagonists &amp; inhibitors/genetics/*metabolism ; Animals ; Arsenic Trioxide ; Arsenicals/administration &amp; dosage/antagonists &amp; inhibitors ; Bone Marrow Cells/*drug effects/metabolism/pathology ; Buthionine Sulfoximine/pharmacology ; Chromatids/drug effects/pathology ; Chromosome Aberrations/chemically induced ; Cytoskeletal Proteins/agonists/antagonists &amp; inhibitors/genetics/*metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors/metabolism ; Glutathione/agonists/antagonists &amp; inhibitors/metabolism ; Kelch-Like ECH-Associated Protein 1 ; Male ; Membrane Glycoproteins/agonists/antagonists &amp; inhibitors/genetics/*metabolism ; Mice ; Mutagens/administration &amp; dosage/chemistry/*toxicity ; NF-E2-Related Factor 2/agonists/antagonists &amp; inhibitors/genetics/*metabolism ; Neoplasm Proteins/agonists/antagonists &amp; inhibitors/genetics/metabolism ; Nuclear Pore Complex Proteins/agonists/antagonists &amp; inhibitors/genetics/*metabolism ; Oxides/administration &amp; dosage/antagonists &amp; inhibitors/*toxicity ; }, abstract = {Generation of reactive oxygen species is one of the major contributors in arsenic-induced genotoxicity where reduced glutathione (GSH) could be an important determining factor. To understand the role of endogenous GSH, arsenic trioxide (As2O3) was administered in buthionine sulfoximine (BSO)- and N-acetyl-L-cysteine (NAC)-treated mice. As2O3-induced significant chromosome aberrations (CAs) in all treatment groups compared with the control. BSO-treated mouse bone marrow cells showed significant CAs at a dose of 2 mg As2O3 kg(-1) b.w. Similar induction was not evident at 4 mg As2O3 kg(-1) b.w. and exhibited antagonistic effect at 8 mg As2O3 kg(-1) b.w. To understand this differential effect, expression pattern of Nrf2 was observed. Nrf2 expression increased following As2O3 treatment in a dose-dependent manner up to 4 mg As2O3 kg(-1) b.w after which no further increase was noticed. NAC pre-treatment significantly reduced the extent of As2O3-induced CAs suggesting the protective role of endogenous GSH against arsenic-induced genotoxicity.}, }
@article {pmid25904217, year = {2015}, author = {Kadowaki, D and Anraku, M and Sakaya, M and Hirata, S and Maruyama, T and Otagiri, M}, title = {Olmesartan protects endothelial cells against oxidative stress-mediated cellular injury.}, journal = {Clinical and experimental nephrology}, volume = {19}, number = {6}, pages = {1007-1014}, pmid = {25904217}, issn = {1437-7799}, mesh = {Angiotensin II Type 1 Receptor Blockers/*pharmacology ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Endothelial Cells/*drug effects ; Female ; Human Umbilical Vein Endothelial Cells/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Imidazoles/*pharmacology ; NADPH Oxidases/antagonists &amp; inhibitors ; Oxidants/pharmacology ; Oxidative Stress/*drug effects ; Protein Kinase C/antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; Tetrazoles/*pharmacology ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {BACKGROUND: The primary cause of death of hemodialysis (HD) patients is cardiovascular disease, and increased oxidative stress has been proposed to be involved in the disease pathogenesis. In this study, we examined the effect of olmesartan on oxidative stress induced by angiotensin II, lipopolysaccharide, indoxyl sulfate, advanced oxidation protein products (AOPP) or hydrogen peroxide (H2O2), which are known to be present at higher concentrations in the blood of HD patients, using human umbilical vein endothelial cells (HUVECs).<br><br>METHODS: Oxidative stress was evaluated by measuring the mean fluorescence intensity of CM-H2DCFCA, an ROS-sensitive fluorescent dye, in HUVECs. HUVECs were incubated with each of the above compounds in the presence or absence of olmesartan. Moreover, these oxidant-stimulated cells were also treated with the reactive oxygen species (ROS) inhibitor N-acetyl-cysteine (NAC), NADPH oxidase inhibitor diphenylene iodonium (DPI) or PKC inhibitor calphostin C. In addition, we investigated the effects of olmesartan on cytotoxicity and vascular endothelial growth factor (VEGF) secretion, which is involved in vascular inflammation in HUVECs induced by AOPP or H2O2.<br><br>RESULTS: The treatment of these oxidant-stimulated cells with olmesartan resulted in a significant reduction in intracellular ROS production to an extent that was nearly equivalent to that of NAC, DPI or calphostin C. Furthermore, olmesartan reduced the cytotoxicity and VEGF secretion induced by AOPP or H2O2.<br><br>CONCLUSIONS: These results demonstrated that the antioxidant activity of olmesartan might contribute to both its vasculoprotective and anti-hypertensive effects.}, }
@article {pmid25899473, year = {2015}, author = {Wang, X and Jiang, L and Ge, L and Chen, M and Yang, G and Ji, F and Zhong, L and Guan, Y and Liu, X}, title = {Oxidative DNA damage induced by di-(2-ethylhexyl) phthalate in HEK-293 cell line.}, journal = {Environmental toxicology and pharmacology}, volume = {39}, number = {3}, pages = {1099-1106}, doi = {10.1016/j.etap.2015.03.016}, pmid = {25899473}, issn = {1872-7077}, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; *DNA Damage/drug effects ; Diethylhexyl Phthalate/*toxicity ; Glutathione/antagonists &amp; inhibitors/*metabolism ; HEK293 Cells ; Humans ; Lysosomes/drug effects ; Mitochondria/drug effects ; Oxidative Stress ; Plasticizers/*toxicity ; }, abstract = {Di-(2-ethylhexyl) phthalate (DEHP) is commonly employed as a plasticizer. We have found that exposure of human embryonic kidney cell line 293 (HEK-293) to DEHP resulted in a crucial dose-dependent increase of DNA strand breaks in a comet assay. To elucidate the role of glutathione (GSH) in the DNA damage, the cells were pretreated with buthionine-(S,R)-sulfoximine (BSO) and pretreated with N-acetylcysteine (NAC), a GSH precursor. Here we show that depletion of GSH in HEK-293 cells with BSO dramatically increased the susceptibility of HEK-293 cells to DEHP-induced DNA damage. Furthermore, when the intracellular GSH content was elevated by NAC, the DNA damage induced by DEHP was almost completely abolished. In addition, DEHP had effect on lysosomal or mitochondrial damage at high dose level. These results indicate that DEHP exerts genotoxic effects in HEK-293 cells, probably through DNA damage induced by oxidative stress; GSH is responsible for cellular defense against DEHP-induced DNA damage; lysosome and mitochondria may be the vital targets in DEHP-induced DNA damage.}, }
@article {pmid25894720, year = {2015}, author = {Chen, J and Solomides, C and Parekh, H and Simpkins, F and Simpkins, H}, title = {Cisplatin resistance in human cervical, ovarian and lung cancer cells.}, journal = {Cancer chemotherapy and pharmacology}, volume = {75}, number = {6}, pages = {1217-1227}, doi = {10.1007/s00280-015-2739-2}, pmid = {25894720}, issn = {1432-0843}, support = {R01-CA098804/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Cisplatin/*therapeutic use ; Drug Resistance, Neoplasm/*drug effects ; Female ; Humans ; Lung Neoplasms/*drug therapy/metabolism ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Ovarian Neoplasms/*drug therapy/metabolism ; Oxidative Stress/drug effects ; Oxidoreductases/metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; Thioredoxins/metabolism ; Uterine Cervical Neoplasms/*drug therapy/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {PURPOSE: This study was performed to determine whether or not in cervical, ovarian and lung cancer cell lines, free radicals (ROS) play a role in cisplatin cytotoxicity and activation of the mitochondrial and JNK/p38 pathways. The role of the enzyme, dihydrodiol dehydrogenase (DDH1), in the activation/deactivation of this pathway and how this may be related to the development of resistance was also investigated.<br><br>METHODS: Mitochondrial membrane potential and ROS analysis were performed by flow cytometry, P-JNK and P-p38 by western blotting and mRNA by RT-PCR. Dihydrodiol dehydrogenase (DDH1) and thioredoxin knockdowns were prepared by standard techniques.<br><br>RESULTS: Cisplatin treatment of a cervical cancer cell line resulted in ROS production with mitochondrial membrane depolarization and phosphorylation of JNK and p38. N-acetyl-cysteine, a free radical scavenger, ameliorated these effects. Treatment of the sensitive cells with H2O2 produced similar effects but at shorter incubation times. Similar results were observed with an ovarian cell line. Downregulation of dihydrodiol dehydrogenase in the cisplatin-resistant cervical and lung cancer cell lines resulted in increased drug sensitivity with detectable production of ROS and activation of the JNK/p38 pathways; however, downregulation of thioredoxin&#xa0;in the cervical cells had minimal effect.<br><br>CONCLUSION: Dihydrodiol dehydrogenase appears to play a role in cisplatin resistance in cervical, ovarian and lung cancer cells which includes mitochondrial membrane depolarization, ROS production and activation of the JNK pathway. However, its mode of action cannot be mimicked by an ROS scavenger so its mechanism of action is more complex (a not unexpected finding considering its role in xenobiotic activation/countering oxidative stress).}, }
@article {pmid25889381, year = {2015}, author = {Truini, A and Piroso, S and Pasquale, E and Notartomaso, S and Di Stefano, G and Lattanzi, R and Battaglia, G and Nicoletti, F and Cruccu, G}, title = {N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive transmission in humans.}, journal = {Molecular pain}, volume = {11}, number = {}, pages = {14}, pmid = {25889381}, issn = {1744-8069}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Amino Acids/therapeutic use ; Analgesics/*therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Pain/*drug therapy ; Receptors, Metabotropic Glutamate/*antagonists &amp; inhibitors ; Treatment Outcome ; Xanthenes/therapeutic use ; Young Adult ; }, abstract = {BACKGROUND: Emerging research seeking novel analgesic drugs focuses on agents targeting group-II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors). N-Acetylcysteine (NAC) enhances the endogenous activation of mGlu2/3 receptors by activating the glial glutamate:cystine membrane exchanger. Here, we examined whether NAC inhibits nociceptive responses in humans and animals. We tested the effect of oral NAC (1.2 g) on thermal-pain thresholds and laser-evoked potentials in 10 healthy volunteers, according to a crossover, double-blind, placebo-controlled design, and the effect of NAC (100 mg/kg, i.p.) on the tail-flick response evoked by radiant heat stimulation in mice.<br><br>RESULTS: In healthy subjects, NAC treatment left thermal-pain thresholds unchanged, but significantly reduced pain ratings to laser stimuli and amplitudes of laser-evoked potentials. NAC induced significantly greater changes in these measures than placebo. In the tail-flick test, NAC strongly reduced the nocifensive reflex response to radiant heat. The action of NAC was abolished by the preferential mGlu2/3 receptor antagonist, LY341495 (1&#xa0;mg/kg, i.p.).<br><br>CONCLUSIONS: Our findings show for the first time that NAC inhibits nociceptive transmission in humans, and does the same in mice by activating mGlu2/3 receptors. These data lay the groundwork for investigating the therapeutic potential of NAC in patients with chronic pain.}, }
@article {pmid25889084, year = {2015}, author = {Sulaiman, MK and Chu, Z and Blanco, VM and Vallabhapurapu, SD and Franco, RS and Qi, X}, title = {SapC-DOPS nanovesicles induce Smac- and Bax-dependent apoptosis through mitochondrial activation in neuroblastomas.}, journal = {Molecular cancer}, volume = {14}, number = {}, pages = {78}, pmid = {25889084}, issn = {1476-4598}, support = {R01 CA158372/CA/NCI NIH HHS/United States ; 1R01CA158372/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Peptidyl-Prolyl Isomerase F ; Cyclophilins/metabolism ; Cyclosporine/metabolism ; Cytochromes c/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Mitochondria/*drug effects/metabolism ; Mitochondrial Proteins/*metabolism ; Nanoparticles/administration &amp; dosage ; Neuroblastoma/*drug therapy/metabolism ; Phosphatidylserines/*pharmacology ; Reactive Oxygen Species/metabolism ; Saposins/*metabolism ; bcl-2-Associated X Protein/*metabolism ; }, abstract = {BACKGROUND: High toxicity, morbidity and secondary malignancy render chemotherapy of neuroblastoma inefficient, prompting the search for novel compounds. Nanovesicles offer great promise in imaging and treatment of cancer. SapC-DOPS, a stable nanovesicle formed from the lysosomal protein saposin C and dioleoylphosphatidylserine possess strong affinity for abundantly exposed surface phosphatidylserine on cancer cells. Here, we show that SapC-DOPS effectively targets and suppresses neuroblastoma growth and elucidate the molecular mechanism of SapC-DOPS action in neuroblastoma in vitro.<br><br>METHODS: In vivo targeting of neuroblastoma was assessed in xenograft mice injected intravenously with fluorescently-labeled SapC-DOPS. Xenografted tumors were also used to demonstrate its therapeutic efficacy. Apoptosis induction in vivo was evaluated in tumor sections using the TUNEL assay. The mechanisms underlying the induction of apoptosis by SapC-DOPS were addressed through measurements of cell viability, mitochondrial membrane potential (&#x394;&#x3a8;M), flow cytometric DNA fragmentation assays and by immunoblot analysis of second mitochondria-derived activator of caspases (Smac), Bax, Cytochrome c (Cyto c) and Caspase-3 in the cytosol or in mitochondrial fractions of cultured neuroblastoma cells.<br><br>RESULTS: SapC-DOPS showed specific targeting and prevented the growth of human neuroblastoma xenografts in mice. In neuroblastoma cells in vitro, apoptosis occurred via a series of steps that included: (1) loss of &#x394;&#x3a8;M and increased mitochondrial superoxide formation; (2) cytosolic release of Smac, Cyto c, AIF; and (3) mitochondrial translocation and polymerization of Bax. ShRNA-mediated Smac knockdown and V5 peptide-mediated Bax inhibition decreased cytosolic Smac and Cyto c release along with caspase activation and abrogated apoptosis, indicating that Smac and Bax are critical mediators of SapC-DOPS action. Similarly, pretreatment with the mitochondria-stabilizing agent bongkrekic acid decreased apoptosis indicating that loss of &#x394;&#x3a8;M is critical for SapC-DOPS activity. Apoptosis induction was not critically dependent on reactive oxygen species (ROS) production and Cyclophilin D, since pretreatment with N-acetyl cysteine and cyclosporine A, respectively, did not prevent Smac or Cyto c release.<br><br>CONCLUSIONS: Taken together, our results indicate that SapC-DOPS acts through a mitochondria-mediated pathway accompanied by an early release of Smac and Bax. Specific tumor-targeting capacity and anticancer efficacy of SapC-DOPS supports its potential as a dual imaging and therapeutic agent in neuroblastoma therapy.}, }
@article {pmid25885549, year = {2016}, author = {Khanna, S and Mitra, S and Lakhera, PC and Khandelwal, S}, title = {N-acetylcysteine effectively mitigates cadmium-induced oxidative damage and cell death in Leydig cells in vitro.}, journal = {Drug and chemical toxicology}, volume = {39}, number = {1}, pages = {74-80}, doi = {10.3109/01480545.2015.1028068}, pmid = {25885549}, issn = {1525-6014}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cadmium/administration &amp; dosage/*toxicity ; Calcium/metabolism ; Cell Death/drug effects ; Glutathione/metabolism ; Leydig Cells/drug effects ; Male ; Mitochondrial Membranes/drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Time Factors ; }, abstract = {CONTEXT: Cadmium (Cd) is known to cause severe damage to various organs including lung, liver, kidney, brain and reproductive system. Several studies have reported the induction of oxidative stress pathways following Cd exposure.<br><br>OBJECTIVE: Since oxidative stress is also deemed responsible for inducing male infertility, a growing worldwide concern, we tried to understand whether the antioxidant N-acetylcysteine (NAC) can be a potential therapeutic agent to counter Cd toxicity using primary Leydig cells.<br><br>MATERIALS AND METHODS: This study highlights the initial cellular alterations which culminate in cell death induction. Primary Leydig cells were isolated from 28-day-old male Wistar rats, exposed to various concentrations of Cd in vitro and biochemical and cell death parameters were evaluated to understand the effect of Cd. NAC pre-treatment was done to understand its protective efficacy.<br><br>RESULTS: Following Cd exposure to Leydig cells in vitro, we found simultaneous intracellular calcium (Ca(2+)) increase and reduction in mitochondrial membrane polarization at 30 min, followed by significant induction of reactive oxygen species and MAPK-extracellular-regulated kinases with concurrent glutathione depletion at 1 h, and significant cell death (both necrotic and apoptotic) at 6 and 18 h, respectively. Pre-treatment with NAC abrogated all these toxic manifestations and showed significantly reduced cell death. NAC also rescued the expression of 3-&#x3b2;HSD, a major steroidogenic protein.<br><br>DISCUSSION AND CONCLUSION: Taken together, these data illustrated that NAC can be used as a potential protective agent against Cd-induced testicular toxicity, especially with regards to oxidative stress-induced Leydig cell toxicity.}, }
@article {pmid25877653, year = {2015}, author = {Xing, Y and Wei, RB and Tang, L and Yang, Y and Zheng, XY and Wang, ZC and Gao, YW}, title = {Protective effect of salidroside on contrast-induced nephropathy in comparison with N-acetylcysteine and its underlying mechanism.}, journal = {Chinese journal of integrative medicine}, volume = {21}, number = {4}, pages = {266-273}, pmid = {25877653}, issn = {1993-0402}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Contrast Media/*adverse effects ; Cytoprotection/*drug effects ; Glucosides/*pharmacology ; Kidney/drug effects/pathology ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Oxidative Stress/drug effects ; Phenols/*pharmacology ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; }, abstract = {OBJECTIVE: To study the prevention effect of salidroside on contrast-induced-nephropathy (CIN) and its underlying mechanism.<br><br>METHODS: A total of 24 Wistar rats were randomly divided into 4 groups with 6 in each group. Rats were firstly administrated with normal saline (control and model groups), N-acetylcysteine (NAC, NAC group) and salidroside (salidroside group) for 7 days before model establishment in each group, respectively. Histopathological analysis was performed by periodic acid-Schiff (PAS) staining. Oxidative stress related parameters including superoxide dismutase (SOD) and methane dicarboxylic aldehyde (MDA), nitric oxide (NO), angiotensin II (Ang II), 8-hydroxy-2'-deoxyguanosine (8-OHdG), mRNA and protein levels of endothelial nitric oxide synthase (eNOS), and nitric oxide synthase (NOS) activity were measured.<br><br>RESULTS: Compared with the control group, the levels of MDA, Ang II and 8-OHdG were all significantly increased and levels of SOD, NO, and eNOS mRNA and protein were decreased significantly in the model group (P<0.05). Meanwhile, the NOS activity was also significantly decreased in the model group (P<0.05). In addition, the levels of these parameters were all improved in the NAC (P<0.05) and salidroside groups and no significant different was found between these two groups (P>0.05).<br><br>CONCLUSION: Salidroside can be the potential substitute of NAC to prevent CIN. The underlying mechanism may be associated with oxidative stress damage caused by contrast agents.}, }
@article {pmid25876967, year = {2015}, author = {Zhao, L and Wei, Z and Yang, F and Sun, Y}, title = {[Transforming growth factor-β1 induced cellular proliferation and collagen synthesis was mediated by reactive oxygen species in pulmonary fibroblasts].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {33}, number = {1}, pages = {15-19}, pmid = {25876967}, issn = {1001-9391}, mesh = {Acetylcysteine ; *Cell Proliferation ; Collagen/*biosynthesis ; Collagen Type I ; Fibroblasts/*cytology ; Hydrogen Peroxide ; Lung/*cytology ; *MAP Kinase Signaling System ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta1/*metabolism ; }, abstract = {OBJECTIVE: This study will explore whether reactive oxygen species (ROS) is involved in TGF-β1-induced JNK activation, pulmonary fibroblast proliferation and collagen type I and III synthesis.<br><br>METHODS: Pulmonary fibroblasts were randomly divided into control (0.4% serum) and TGF-&#x3b2;1 (5 &#xb5;g/L) groups to detect whether TGF-&#x3b2;1 could induce pulmonary fibroblast proliferation, synthesis of collagen I and III, phosphorylated-JNK (p-JNK) and 8-OHdG (indicator of ROS); while in the part to explore whether NAC (N-acetyl-L-cysteine, antioxidants) has the inhibitory role in TGF-&#x3b2;1-induced pulmonary fibroblast, it did control (0.4% serum), H2O2 (0.1 mmol/L, positive control), H2O2+NAC (10 mmol/L), TGF-&#x3b2;1 (5 &#xb5;g/L), TGF-&#x3b2;1+NAC groups. Pulmonary fibroblast proliferation, 8-OHdG levels, expressions of JNK and collagen I and III were used by MTT assay, immunofluorescence and western blot respectively.<br><br>RESULTS: In the experiments to detect the effect of TGF-&#x3b2;1 on pulmonary fibroblasts, compared with control, TGF-&#x3b2;1 significantly stimulated pulmonary fibroblast proliferation and increased collagen I and III protein, p-JNK and 8-OHdG levels. In the next experiments to explore whether NAC has the inhibitory role in TGF-&#x3b2;1-induced pulmonary fibroblasts, compared with control, pulmonary fibroblast proliferation and the levels of collagen I and II, p-JNK, 8-OHdG were all significantly increased in H2O2 and TGF-&#x3b2;1 groups; while these changes were markedly blocked with the treatment of NAC.<br><br>CONCLUSION: TGF-&#x3b2;1 induces pulmonary fibroblasts to generate ROS, which contributes to JNK activation and pulmonary fibroblast proliferation as well as collagen synthesis, while ROS inhibition suppresses this effet of TGF-&#x3b2;1 in pulmonary fibroblasts.}, }
@article {pmid25876056, year = {2016}, author = {Rui, W and Guan, L and Zhang, F and Zhang, W and Ding, W}, title = {PM2.5-induced oxidative stress increases adhesion molecules expression in human endothelial cells through the ERK/AKT/NF-κB-dependent pathway.}, journal = {Journal of applied toxicology : JAT}, volume = {36}, number = {1}, pages = {48-59}, doi = {10.1002/jat.3143}, pmid = {25876056}, issn = {1099-1263}, mesh = {Cell Adhesion/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Endothelial Cells/drug effects/*metabolism ; Extracellular Signal-Regulated MAP Kinases/*drug effects ; Humans ; Intercellular Adhesion Molecule-1/*analysis ; Oxidative Stress/*drug effects ; Particulate Matter/*pharmacology ; Protein Serine-Threonine Kinases/*physiology ; Proto-Oncogene Proteins c-akt/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Vascular Cell Adhesion Molecule-1/*analysis ; NF-kappaB-Inducing Kinase ; }, abstract = {The aim of this study was to explore the intracellular mechanisms underlying the cardiovascular toxicity of air particulate matter (PM) with an aerodynamic diameter of less than 2.5 µm (PM2.5) in a human umbilical vein cell line, EA.hy926. We found that PM2.5 exposure triggered reactive oxygen species (ROS) generation, resulting in a significant decrease in cell viability. Data from Western blots showed that PM2.5 induced phosphorylation of Jun N-terminal kinase (JNK), extracellular signal regulatory kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and protein kinase B (AKT), and activation of nuclear factor kappa B (NF-κB). We further observed a significant increase in expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in a time- and dose-dependent manner. Moreover, the adhesion of monocytic THP-1 cells to EA.hy926 cells was greatly enhanced in the presence of PM2.5 . However, N-acetylcysteine (NAC), a scavenger of ROS, prevented the increase of ROS generation, attenuated the phosphorylation of the above kinases, and decreased the NF-κB activation as well as the expression of ICAM-1 and VCAM-1. Furthermore, ERK inhibitor (U0126), AKT inhibitor (LY294002) and NF-κB inhibitor (BAY11-7082) significantly down-regulated PM2.5 -induced ICAM-1 and VCAM-1 expression as well as adhesion of THP-1 cells, but not JNK inhibitor (SP600125) and p38 MAPK inhibitor (SB203580), indicating that ERK/AKT/NF-κB is involved in the signaling pathway that leads to PM2.5 -induced ICAM-1 and VCAM-1 expression. These findings suggest PM2.5 -induced ROS may function as signaling molecules triggering ICAM-1 and VCAM-1 expressions through activating the ERK/AKT/NF-κB-dependent pathway, and further promoting monocyte adhesion to endothelial cells.}, }
@article {pmid25872712, year = {2015}, author = {Yang, Y and Lin, X and Huang, H and Feng, D and Ba, Y and Cheng, X and Cui, L}, title = {Sodium fluoride induces apoptosis through reactive oxygen species-mediated endoplasmic reticulum stress pathway in Sertoli cells.}, journal = {Journal of environmental sciences (China)}, volume = {30}, number = {}, pages = {81-89}, doi = {10.1016/j.jes.2014.11.004}, pmid = {25872712}, issn = {1001-0742}, mesh = {Acetylcysteine/metabolism ; Animals ; Apoptosis/*drug effects ; Biomarkers/metabolism ; Dose-Response Relationship, Drug ; *Endoplasmic Reticulum Stress ; Gene Knockdown Techniques ; Male ; Oxidative Stress/drug effects ; Rats ; *Reactive Oxygen Species ; Sertoli Cells ; Sodium Fluoride/*toxicity ; Testis ; Transcription Factor CHOP/genetics/metabolism ; }, abstract = {Excessive fluoride exposure is known to contribute to reproductive system dysfunction, ultimately leading to pathological damage and apoptosis in cells. Although both oxidative and endoplasmic reticulum (ER) stresses have been implicated in fluorosis, the signaling pathways and their roles in sodium fluoride (NaF)-induced apoptosis of Sertoli cells have been sparsely described. In this study, oxidative damage, ER stress, and apoptosis were analyzed after Sertoli cells were treated with varying doses of NaF for 24hr. Moreover, the antioxidant N-acetylcysteine (NAC) and pro-apoptotic transcription factor CHOP knockdown were used to clarify the precise interplay between reactive oxygen species (ROS), ER stress and their roles in NaF-induced apoptosis in Sertoli cells. The present study indicated that NaF significantly decreased cell viability and induced apoptosis in Sertoli cells. In addition, NaF exposure facilitated the accumulation of ROS and increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in Sertoli cells. Treatment with NAC caused remarkable recovery from these NaF-induced responses. Meanwhile, excessive NaF triggered ER stress as evidenced by up-regulated glucose-regulated protein 78 kDa (GRP78), PKR-like ER kinase (PERK), phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) and CCAAT/enhancer-binding protein-homologous protein (CHOP), without affecting total eukaryotic translation initiation factor 2α (eIF2α). NAC effectively blocked the activation of ER stress, suggesting that NaF-induced ROS is an early event that triggers ER stress. Taken together, the results demonstrate that the ROS-mediated ER stress pathway is the crucial mechanistic event involved in NaF-induced apoptosis of Sertoli cells.}, }
@article {pmid25871324, year = {2015}, author = {Saleh, AM and Aljada, A and El-Abadelah, MM and Sabri, SS and Zahra, JA and Nasr, A and Aziz, MA}, title = {The pyridone-annelated isoindigo (5'-Cl) induces apoptosis, dysregulation of mitochondria and formation of ROS in leukemic HL-60 cells.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {35}, number = {5}, pages = {1958-1974}, doi = {10.1159/000374004}, pmid = {25871324}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; HL-60 Cells ; Humans ; Indoles/chemistry/pharmacology ; Leukemia, Promyelocytic, Acute/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/*metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyridones/*chemistry/pharmacology ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/*metabolism ; Thiocarbamates/pharmacology ; bcl-2-Associated X Protein/metabolism ; }, abstract = {BACKGROUND/AIMS: In our quest to develop an isoindigo with improved efficacy and bioavailability, we recently synthesized a series of novel substituted pyridone-annelated isoindigo and evaluated their antiproliferative effects. We identified the compound [(E)-1-(5'-Chloro-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f] quinoline-8-carboxylic acid], abbreviated as 5'-Cl, which shows selective antiproliferative activities against various cancer cell lines mediated through apoptosis. Here we have investigated the molecular mechanisms underlying the apoptotic activity of 5'-Cl in the human promyelocytic leukemia HL-60 cells.<br><br>METHODS: We employed different methods to determine the apoptotic pathways triggered by 5'-Cl in HL-60 cells, using flow cytometry, nuclear staining, caspases activation, mitochondria functioning, generation of reactive oxygen species (ROS) and Western blotting techniques.<br><br>RESULTS: Low concentrations (1-8 &#xb5;M) of 5'-Cl inhibited the growth of HL-60 cells in a dose and time-dependent manner. Cytotoxicity of this compound is found to be mediated by a caspase-dependent apoptosis. Also, there were indications of caspase independent apoptosis as z-VAD-FMK failed to fully rescue the cells from 5'-Cl-induced apoptosis. In addition, the compound triggered generation of Reactive Oxygen Species (ROS), caused depolarization of the mitochondrial inner membrane, decreased the level of cellular ATP, modulated the expression and phosphorylation of Bcl-2 leading to loss of its association with Bax and increased the release of cytochrome c to the cytosol of treated cells. The effects of 5'-Cl on mitochondria and apoptosis were substantially blocked in the presence of a combination between z-VAD-FMK and either of the ROS scavenger N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC).<br><br>CONCLUSION: We demonstrated that the growth inhibitory effects of 5'-Cl in HL-60 cells involve multiple pathways of apoptosis and dysregulation of mitochondrial functions.}, }
@article {pmid25869245, year = {2015}, author = {Gautam, N and Thakare, R and Rana, S and Natarajan, A and Alnouti, Y}, title = {Irreversible binding of an anticancer compound (BI-94) to plasma proteins.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {45}, number = {10}, pages = {858-873}, pmid = {25869245}, issn = {1366-5928}, support = {P01 DA028555/DA/NIDA NIH HHS/United States ; R01 CA127239/CA/NCI NIH HHS/United States ; CA127239/CA/NCI NIH HHS/United States ; DA028555-01/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Antineoplastic Agents/chemistry/metabolism/*pharmacokinetics ; Blood Proteins/*metabolism ; Drug Stability ; Glutathione/metabolism ; Humans ; Hydrogen-Ion Concentration ; Male ; Mice, Inbred BALB C ; Molecular Structure ; Oxadiazoles/*metabolism ; Serum Albumin/metabolism ; Sulfones/*metabolism ; Tandem Mass Spectrometry ; }, abstract = {1. We investigated the mechanisms responsible for the in vivo instability of a benzofurazan compound BI-94 (NSC228148) with potent anti-cancer activity. 2. BI-94 was stable in MeOH, water, and in various buffers at pHs 2.5-5, regardless of the buffer composition. In contrast, BI-94 was unstable in NaOH and at pHs 7-9, regardless of the buffer composition. BI-94 disappeared immediately after spiking into mice, rat, monkey, and human plasma. BI-94 stability in plasma can be only partially restored by acidifying it, which indicated other mechanisms in addition to pH for BI-94 instability in plasma. 3. BI-94 formed adducts with the trapping agents, glutathione (GSH) and N-acetylcysteine (NAC), in vivo and in vitro via nucleophilic aromatic substitution reaction. The kinetics of adduct formation showed that neutral or physiological pHs enhanced and accelerated GSH and NAC adduct formation with BI-94, whereas acidic pHs prevented it. Therefore, physiological pHs not only altered BI-94 chemical stability but also enhanced adduct formation with endogenous nucleophiles. In addition, adduct formation with human serum albumin-peptide 3 (HSA-T3) at the Cys34 position was demonstrated. 4. In conclusion, BI-94 was unstable at physiological conditions due to chemical instability and irreversible binding to plasma proteins.}, }
@article {pmid25868875, year = {2015}, author = {Lablanche, S and Cottet-Rousselle, C and Argaud, L and Laporte, C and Lamarche, F and Richard, MJ and Berney, T and Benhamou, PY and Fontaine, E}, title = {Respective effects of oxygen and energy substrate deprivation on beta cell viability.}, journal = {Biochimica et biophysica acta}, volume = {1847}, number = {6-7}, pages = {629-639}, doi = {10.1016/j.bbabio.2015.04.002}, pmid = {25868875}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cells, Cultured ; Energy Metabolism/drug effects ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Humans ; Hypoglycemic Agents/pharmacology ; Hypoxia ; Islets of Langerhans/*drug effects/*metabolism/pathology ; Metformin/pharmacology ; Microscopy, Confocal ; Mitochondria/*drug effects/metabolism ; Mitochondrial Membrane Transport Proteins/*drug effects ; Mitochondrial Permeability Transition Pore ; Oxidative Stress/drug effects ; Oxygen/*pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Deficit in oxygen and energetic substrates delivery is a key factor in islet loss during islet transplantation. Permeability transition pore (PTP) is a mitochondrial channel involved in cell death. We have studied the respective effects of oxygen and energy substrate deprivation on beta cell viability as well as the involvement of oxidative stress and PTP opening. Energy substrate deprivation for 1h followed by incubation in normal conditions led to a cyclosporin A (CsA)-sensitive-PTP-opening in INS-1 cells and human islets. Such a procedure dramatically decreased INS-1 cells viability except when transient removal of energy substrates was performed in anoxia, in the presence of antioxidant N-acetylcysteine (NAC) or when CsA or metformin inhibited PTP opening. Superoxide production increased during removal of energy substrates and increased again when normal energy substrates were restored. NAC, anoxia or metformin prevented the two phases of oxidative stress while CsA prevented the second one only. Hypoxia or anoxia alone did not induce oxidative stress, PTP opening or cell death. In conclusion, energy substrate deprivation leads to an oxidative stress followed by PTP opening, triggering beta cell death. Pharmacological prevention of PTP opening during islet transplantation may be a suitable option to improve islet survival and graft success.}, }
@article {pmid25867911, year = {2015}, author = {Li, W and Maloney, RE and Aw, TY}, title = {High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature.}, journal = {Redox biology}, volume = {5}, number = {}, pages = {80-90}, pmid = {25867911}, issn = {2213-2317}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; DK44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain/*metabolism ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Diabetes Mellitus, Experimental/chemically induced/metabolism/pathology ; Endothelial Cells/cytology/metabolism ; Free Radical Scavengers/pharmacology ; Glucose/*pharmacology ; Glutathione/antagonists &amp; inhibitors/metabolism ; Glycosylation/drug effects ; Humans ; Lactoylglutathione Lyase/metabolism ; Male ; Microvessels/*metabolism ; Occludin/metabolism ; Oxidative Stress/*drug effects ; Pyruvaldehyde/analysis/blood/toxicity ; Rats ; Rats, Wistar ; Thiolester Hydrolases/metabolism ; }, abstract = {We previously demonstrated that in normal glucose (5mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG-occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG-occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes.}, }
@article {pmid25865073, year = {2016}, author = {Zhao, J and Tang, C and Nie, X and Xi, H and Jiang, S and Jiang, J and Liu, S and Liu, X and Liang, L and Wan, C and Yang, J}, title = {Autophagy potentially protects against 2,3,7,8-tetrachlorodibenzo-p-Dioxin induced apoptosis in SH-SY5Y cells.}, journal = {Environmental toxicology}, volume = {31}, number = {9}, pages = {1068-1079}, doi = {10.1002/tox.22116}, pmid = {25865073}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Oxidative Stress/drug effects ; Phenotype ; Polychlorinated Dibenzodioxins/*toxicity ; Protective Agents/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {The environmental toxicant TCDD may elicit cytotoxic effects by inducing reactive oxygen species (ROS) generation. Autophagy is one of the first lines of defense against oxidative stress damage. Herein, we investigated whether autophagy played a regulatory role in TCDD-induced neurotoxicity. Here, we showed that TCDD exposure caused marked autophagy in SH-SY5Y cells, whose dose range was close to that inducing apoptosis. Electron microscopic and Western blot analyses revealed that TCDD induced autophagy at a starting dose of approximate 100 nM. Interestingly, 100-200 nM TCDD exposure resulted in obviously decreased cell viability and evident apoptotic phenotype. Furthermore, the levels of pro-apoptotic molecules, Bax and cleaved-PARP, increased significantly, whereas Bcl2 declined after exposed to 100 nM TCDD. In addition, the apoptosis was verified using flow cytometrical analysis. These data strongly suggested that TCDD induced both autophagy and apoptosis at a similar dose range in SH-SY5Y cells. Interestingly, pretreatment with ROS scavenger, N-acetyl-cysteine (NAC), could effectively block both TCDD-induced apoptosis and autophagy. More surprisingly, inhibition of autophagy with 3-methyladenine (3MA), remarkably augmented TCDD-induced apoptosis. The findings implicated that the onset of autophagy might serve as a protective mechanism to ameliorate ROS-triggered cytotoxic effects in human SH-SY5Y neuronal cells under TCDD exposure. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1068-1079, 2016.}, }
@article {pmid25863775, year = {2015}, author = {Zhang, A and Wang, P and Ma, X and Yin, X and Li, J and Wang, H and Jiang, W and Jia, Q and Ni, L}, title = {Mechanisms that lead to the regulation of NLRP3 inflammasome expression and activation in human dental pulp fibroblasts.}, journal = {Molecular immunology}, volume = {66}, number = {2}, pages = {253-262}, doi = {10.1016/j.molimm.2015.03.009}, pmid = {25863775}, issn = {1872-9142}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/pharmacology ; Bicuspid/cytology/drug effects/immunology ; Carrier Proteins/antagonists &amp; inhibitors/genetics/*immunology ; Caspase 1/genetics/immunology ; Dental Pulp/cytology/drug effects/immunology ; Fibroblasts/cytology/*drug effects/immunology ; Gene Expression Regulation ; Humans ; I-kappa B Proteins/antagonists &amp; inhibitors/genetics/*immunology ; Inflammasomes/*drug effects/immunology ; Interleukin-1beta/genetics/immunology ; Lipopolysaccharides/*pharmacology ; Myeloid Differentiation Factor 88/antagonists &amp; inhibitors/genetics/*immunology ; NF-KappaB Inhibitor alpha ; NLR Family, Pyrin Domain-Containing 3 Protein ; Peptides/pharmacology ; Phosphorylation/drug effects ; Primary Cell Culture ; RNA, Small Interfering/genetics/metabolism ; Reactive Oxygen Species/immunology/metabolism ; Signal Transduction ; Toll-Like Receptor 4/genetics/*immunology ; Tooth Extraction ; }, abstract = {BACKGROUND: The NLRP3 inflammasome plays an important role in the cellular defense against invading pathogens and is reported to be expressed in human dental pulp fibroblasts (HDPFs). However, the role of the NLRP3 inflammasome in HDPFs during pulpal infection and inflammation remains unclear.<br><br>OBJECTIVES: To elucidate the function of the NLRP3 inflammasome and the mechanisms that lead to its expression and activation in HDPFs.<br><br>METHODS: The test model used lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to simulate an inflammatory environment. Lentiviral vectors encoding short hairpin RNAs were used to knock down NLRP3 and caspase-1 in HDPFs. Specific inhibitors were used to determine whether the toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), or nuclear factor-kappa B (NF-&#x3ba;B) pathways were involved in the regulation of NLRP3 expression. Reactive oxygen species (ROS) production was measured by fluorescent microscopy and flow cytometry using the total ROS/superoxide detection kit. Gene and protein expression were quantified by real-time polymerase chain reaction and Western blot, while cytokine release was measured by an enzyme-linked immunosorbent assay.<br><br>RESULTS: LPS up-regulated NLRP3 and IL-1&#x3b2; expression while ATP induced the activation of caspase-1 and the release of IL-1&#x3b2; in LPS-primed HDPFs. The knockdown of NLRP3 or caspase-1 expression significantly inhibited IL-1&#x3b2; secretion. Pretreatment with a TLR4 inhibitor, a MyD88 inhibitory peptide, or an I Kappa B alpha (I&#x3ba;B&#x3b1;) phosphorylation inhibitor significantly inhibited LPS-induced NLRP3 and IL-1&#x3b2; expression. ATP potently promoted ROS generation in HDPFs; N-acetyl cysteine inhibited ROS production, caspase-1 activation and IL-1&#x3b2; secretion induced by ATP.<br><br>CONCLUSIONS: Our results demonstrated that the NLRP3 inflammasome in HDPFs is crucial for IL-1&#x3b2; secretion in response to LPS plus ATP. LPS engaged the TLR4/MyD88/NF-&#x3ba;B pathway to enhance NLRP3 and pro-IL-1&#x3b2; expression in HDPFs. ATP promoted the generation of ROS and activated the NLRP3 inflammasome in a ROS-dependent manner.}, }
@article {pmid25862169, year = {2015}, author = {Alpay, M and Backman, LR and Cheng, X and Dukel, M and Kim, WJ and Ai, L and Brown, KD}, title = {Oxidative stress shapes breast cancer phenotype through chronic activation of ATM-dependent signaling.}, journal = {Breast cancer research and treatment}, volume = {151}, number = {1}, pages = {75-87}, doi = {10.1007/s10549-015-3368-5}, pmid = {25862169}, issn = {1573-7217}, support = {R03 CA125824/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis/genetics ; Ataxia Telangiectasia Mutated Proteins/antagonists &amp; inhibitors/*genetics ; Breast Neoplasms/*genetics/pathology ; Cell Line, Tumor ; DNA Damage/genetics ; Female ; Gene Expression Regulation, Neoplastic ; HeLa Cells ; Humans ; NF-kappa B/biosynthesis/genetics ; Oxidative Stress/genetics ; Reactive Oxygen Species/metabolism ; Signal Transduction/genetics ; Transcription Factor RelA/*biosynthesis/genetics ; Transcriptional Activation/*genetics ; Tumor Suppressor Proteins/biosynthesis/genetics ; }, abstract = {Reactive oxygen species (ROS) are thought to be among the initiating insults that drive carcinogenesis; however, beyond the mutagenic properties of ROS, it is unclear how reactive oxygen species and response to redox imbalance may shape cancer phenotype. We have previously observed that basal activity of the powerfully oncogenic transcription factor NF-κB in cultured breast cancer and other tumor cell lines is dependent upon the DNA damage-responsive kinase ATM. Here we show that, in MDA-MB-231 and HeLa cells, basal ATM-dependent NF-κB activation occurs through a canonical DNA damage-responsive signaling pathway as knockdown of two proteins involved in this signaling pathway, ERC1 and TAB1, results in loss of NF-κB basal activity. We further show that knockdown of ATM in MDA-MB-231, a breast cancer line with a pronounced mesenchymal phenotype, results in the reversion of these cells to an epithelial morphology and gene expression pattern. Culture of MDA-MB-231 and HeLa cells on the antioxidant N-acetyl cysteine (NAC) blunted NF-κB transcriptional activity, and long-term culture on low doses of NAC resulted in coordinate reductions in steady-state ROS levels, acquisition of an epithelial morphology, as well as upregulation of epithelial and downregulation of mesenchymal marker gene expression. Moreover, these reversible effects are attributable, at least in part, to downregulation of ATM-dependent NF-κB signaling in MDA-MB-231 cells as RNAi-mediated knockdown of the NF-κB subunit RelA or its upstream activator TG2 produced similar alterations in phenotype. We conclude that chronic activation of ATM in response to persistent ROS insult triggers continual activation of the oncogenic NF-κB transcriptional complex that, in turn, promotes aggressive breast cancer phenotype.}, }
@article {pmid25862124, year = {2015}, author = {Thit, A and Selck, H and Bjerregaard, HF}, title = {Toxic mechanisms of copper oxide nanoparticles in epithelial kidney cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {29}, number = {5}, pages = {1053-1059}, doi = {10.1016/j.tiv.2015.03.020}, pmid = {25862124}, issn = {1879-3177}, mesh = {Animals ; Apoptosis/drug effects ; Cell Line ; Cell Survival/drug effects ; Copper/*toxicity ; DNA Damage ; Epithelial Cells/*drug effects/metabolism ; Glutathione/metabolism ; Kidney/cytology ; Metal Nanoparticles/*toxicity ; Particle Size ; Reactive Oxygen Species/metabolism ; Xenopus laevis ; }, abstract = {CuO NPs have previously been reported as toxic to a range of cell cultures including kidney epithelial cells from the frog, Xenopus laevis (A6). Here we examine the molecular mechanisms affecting toxicity of Cu in different forms and particle sizes. A6 cells were exposed to ionic Cu (Cu2+) or CuO particles of three different sizes: CuO NPs of 6 nm (NP6), larger Poly-dispersed CuO NPs of <100 nm (Poly) and CuO Micro particles of <5 μm (Micro), at 200 μM, equal to 12.7 mg Cu/L. Poly was significantly more toxic than NP6, Micro and Cu2+ to A6 cells, causing DNA damage, decreased cell viability and levels of reduced glutathione (GSH) and eventually cell death. We show that ROS (Reactive Oxygen Species) generation plays a key role and occurs early in Poly toxicity as Poly-induced DNA damage and cell death could be mitigated by the antioxidant NAC (N-acetyl-cysteine). Here we propose a model of the sequence of events explaining Poly toxicity. Briefly, the events include: cellular uptake, most likely via endocytosis, production of ROS, which cause DNA damage that activates a signaling pathway which eventually leads to cell death, mainly via apoptosis.}, }
@article {pmid25851054, year = {2015}, author = {Sukumari-Ramesh, S and Prasad, N and Alleyne, CH and Vender, JR and Dhandapani, KM}, title = {Overexpression of Nrf2 attenuates Carmustine-induced cytotoxicity in U87MG human glioma cells.}, journal = {BMC cancer}, volume = {15}, number = {}, pages = {118}, pmid = {25851054}, issn = {1471-2407}, support = {R01 NS065172/NS/NINDS NIH HHS/United States ; R21 NS075774/NS/NINDS NIH HHS/United States ; R01NS065172/NS/NINDS NIH HHS/United States ; R21NS075774/NS/NINDS NIH HHS/United States ; }, mesh = {Antineoplastic Agents, Alkylating/*pharmacology/toxicity ; Antioxidants/pharmacology ; Carmustine/*pharmacology/toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/*genetics ; *Gene Expression ; Glioma/*genetics/metabolism ; Humans ; Hydroquinones/pharmacology ; NF-E2-Related Factor 2/*genetics/metabolism ; Oxidative Stress/drug effects ; Up-Regulation/drug effects ; }, abstract = {BACKGROUND: Malignant glioma is one of the most devastating tumors in adults with poor patient prognosis. Notably, glioma often exhibits resistance to conventional chemotherapeutic approaches, complicating patient treatments. However, the molecular mediators involved in tumor chemoresistance remain poorly defined, creating a barrier to the successful management of glioma. In the present study, we hypothesized that the antioxidant transcription factor, Nrf2 (nuclear factor erythroid-derived 2 like 2), attenuates glioma cytotoxicity to Carmustine (BCNU), a widely used chemotherapeutic agent known to modulate cellular oxidative balance.<br><br>METHODS: To test the hypothesis, we employed human malignant glioma cell line, U87MG and overexpression of Nrf2 in glioma cells was achieved using both pharmacological and genetic approaches.<br><br>RESULTS: Notably, induction of Nrf2 was associated with increased expression of heme oxygenase-1 (HO-1), a stress inducible enzyme involved in anti-oxidant defense. In addition, over expression of Nrf2 in U87MG cells significantly attenuated the cytotoxicity of Carmustine as evidenced by both cellular viability assay and flow cytometry analysis. Consistent with this, antioxidants such as glutathione and N-acetyl cysteine significantly reduced Carmustine mediated glioma cytotoxicity.<br><br>CONCLUSIONS: Taken together, these data strongly implicate an unexplored role of Nrf2 in glioma resistance to Carmustine and raise the possible use of Nrf2 inhibitors as adjunct to Carmustine for the treatment of malignant glioma.}, }
@article {pmid25847297, year = {2015}, author = {Beaupere, C and Garcia, M and Larghero, J and Fève, B and Capeau, J and Lagathu, C}, title = {The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation.}, journal = {Aging cell}, volume = {14}, number = {4}, pages = {534-546}, pmid = {25847297}, issn = {1474-9726}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Autophagy/drug effects ; Bone Marrow Cells/drug effects/metabolism/pathology ; Cell Differentiation/*drug effects ; Cell Proliferation/drug effects ; Cellular Senescence/*drug effects ; Gene Expression Regulation ; Humans ; Interleukin-6/genetics/metabolism ; Interleukin-8/genetics/metabolism ; Mesenchymal Stem Cells/*drug effects/metabolism/pathology ; Mitochondria/drug effects/metabolism/pathology ; NF-kappa B/antagonists &amp; inhibitors/genetics/metabolism ; Osteoblasts/*drug effects/metabolism/pathology ; Osteocalcin/genetics/metabolism ; Oxidative Stress/drug effects ; Primary Cell Culture ; Recombinant Proteins/pharmacology ; Sesquiterpenes/pharmacology ; Signal Transduction ; Sirolimus/pharmacology ; nef Gene Products, Human Immunodeficiency Virus/*pharmacology ; tat Gene Products, Human Immunodeficiency Virus/*pharmacology ; }, abstract = {To maintain bone mass turnover and bone mineral density (BMD), bone marrow (BM) mesenchymal stem cells (MSCs) are constantly recruited and subsequently differentiated into osteoblasts. HIV-infected patients present lower BMD than non-HIV infected individuals and a higher prevalence of osteopenia/osteoporosis. In antiretroviral treatment (ART)-naive patients, encoded HIV proteins represent pathogenic candidates. They are released by infected cells within BM and can impact on neighbouring cells. In this study, we tested whether HIV proteins Tat and/or Nef could induce senescence of human BM-MSCs and reduce their capacity to differentiate into osteoblasts. When compared to nontreated cells, MSCs chronically treated with Tat and/or Nef up to 30 days reduced their proliferative activity and underwent early senescence, associated with increased oxidative stress and mitochondrial dysfunction. The antioxidant molecule N-acetyl- cysteine had no or minimal effects on Tat- or Nef-induced senescence. Tat but not Nef induced an early increase in NF-κB activity and cytokine/chemokine secretion. Tat-induced effects were prevented by the NF-κB inhibitor parthenolide, indicating that Tat triggered senescence via NF-κB activation leading to oxidative stress. Otherwise, Nef- but not Tat-treated cells displayed early inhibition of autophagy. Rapamycin, an autophagy inducer, reversed Nef-induced senescence and oxidative stress. Moreover, Tat+Nef had cumulative effects. Finally, Tat and/or Nef decreased the MSC potential of osteoblastic differentiation. In conclusion, our in vitro data show that Tat and Nef could reduce the number of available precursors by inducing MSC senescence, through either enhanced inflammation or reduced autophagy. These results offer new insights into the pathophysiological mechanisms of decreased BMD in HIV-infected patients.}, }
@article {pmid25845505, year = {2015}, author = {Keir, I and Kellum, JA}, title = {Acute kidney injury in severe sepsis: pathophysiology, diagnosis, and treatment recommendations.}, journal = {Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001)}, volume = {25}, number = {2}, pages = {200-209}, doi = {10.1111/vec.12297}, pmid = {25845505}, issn = {1476-4431}, mesh = {Acute Kidney Injury/complications/diagnosis/*veterinary ; Animals ; Biomarkers/blood/urine ; Critical Care ; Critical Illness ; Dog Diseases/blood/*diagnosis/physiopathology/therapy/urine ; Dogs ; Humans ; Hydroxyethyl Starch Derivatives/adverse effects ; Practice Guidelines as Topic ; Sepsis/complications/diagnosis/*veterinary ; Veterinary Medicine ; }, abstract = {OBJECTIVE: To review the unique pathophysiology of sepsis-induced acute kidney injury (AKI) and highlight the relevant aspects of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury that may apply to veterinary patients.<br><br>DATA SOURCES: Electronic search of MEDLINE database.<br><br>HUMAN DATA SYNTHESIS: Sepsis-induced AKI is diagnosed in up to 47% of human ICU patients and is seen as a major public health concern associated with increased mortality and increased progression to chronic kidney disease (CKD). Consensus criteria for the definition and classification of AKI has allowed for accurate description of the epidemiology of patients with AKI. AKI develops from a complex relationship between the initial insult and activation of inflammation and coagulation. In contrast to the traditional view, clinical and experimental data dispute the role of renal ischemia-reperfusion in the development of sepsis-induced AKI. Renal tubular dysfunction with activation of the tubuloglomerular feedback mechanism appears to be a crucial contributor to sepsis-induced AKI. Furosemide and n-acetylcysteine (NAC) do not appear to be helpful in the treatment of AKI. Hydroxyethyl starches (HES), dopamine, and supraphysiological concentrations of chloride are harmful in patients with AKI.<br><br>VETERINARY DATA SYNTHESIS: Community and hospital-acquired AKI is a significant factor affecting survival in critical ill patients. Sepsis-induced AKI occurs in 12% of dogs with abdominal sepsis and is an important contributor to mortality. Early detection of AKI in hospitalized patients currently offers the best opportunity to improve patient outcome. The use of urinary biomarkers to diagnose early AKI should be evaluated in critical care patients.<br><br>CONCLUSION: Veterinary clinical trials comparing treatment choices with the development of AKI are needed to make evidence-based recommendations for the prevention and treatment of AKI.}, }
@article {pmid25845326, year = {2015}, author = {Lee, DH and Nam, YJ and Lee, CS}, title = {Quercetin-3-O-(2″-galloyl)-α-L-rhamnopyranoside attenuates cholesterol oxidation product-induced apoptosis by suppressing NF-κB-mediated cell death process in differentiated PC12 cells.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {388}, number = {8}, pages = {869-881}, pmid = {25845326}, issn = {1432-1912}, mesh = {Animals ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/metabolism ; Cell Death/drug effects ; Cell Survival/drug effects ; DNA Fragmentation ; Glutathione/metabolism ; Hydroxycholesterols/*toxicity ; Ketocholesterols/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; NF-kappa B/metabolism ; Oxidation-Reduction ; PC12 Cells ; Quercetin/*analogs &amp; derivatives/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Cholesterol oxidation products are suggested to be involved in neuronal cell degeneration. We examined the preventive effect of quercetin-3-O-(2″-galloyl)-α-L-rhamnopyranoside (QGR), a quercetin derivative, on the cholesterol oxidation product-induced neuronal cell death using differentiated PC12 cells in relation to nuclear factor (NF)-κB-mediated apoptotic process. 7-Ketocholesterol and 25-hydroxycholesterol induced a decrease in the levels of BH3 interacting-domain death agonist (Bid) and B cell lymphoma 2 (Bcl-2), increase in the levels of Bcl-2-associated X protein (Bax) and p53, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases, and cleavage of poly(ADP-ribose) polymerase 1 (PARP-1). 7-Ketocholesterol induced increase in cytosolic and nuclear NF-κB p65, nuclear phospho-NF-κB p65, cytosolic NF-κB p50, and cytosolic phospho-IκB-α levels. The addition of QGR, N-acetyl cysteine, or Bay 11-7085 attenuated the cholesterol oxidation product-induced changes in the apoptosis-related protein levels, activation of NF-κB, formation of reactive oxygen species, depletion of glutathione (GSH), nuclear damage, and cell death. The results show that QGR may attenuate the cholesterol oxidation product-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways that is mediated by NF-κB activation. The preventive effect appears to be associated with the inhibitory effect on the formation of reactive oxygen species and depletion of GSH.}, }
@article {pmid25843257, year = {2015}, author = {Al-Harbi, NO and Nadeem, A and Al-Harbi, MM and Imam, F and Al-Shabanah, OA and Ahmad, SF and Sayed-Ahmed, MM and Bahashwan, SA}, title = {Oxidative airway inflammation leads to systemic and vascular oxidative stress in a murine model of allergic asthma.}, journal = {International immunopharmacology}, volume = {26}, number = {1}, pages = {237-245}, doi = {10.1016/j.intimp.2015.03.032}, pmid = {25843257}, issn = {1878-1705}, mesh = {Animals ; Antioxidants/metabolism/*therapeutic use ; Aorta/*drug effects/immunology/metabolism ; Asthma/drug therapy/*immunology/metabolism ; Disease Models, Animal ; Female ; Hydrogen Peroxide/*toxicity ; Inhalation Exposure ; Lipid Peroxidation/drug effects/immunology ; Ovalbumin/immunology ; Oxidative Stress/*drug effects/immunology ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Respiratory Hypersensitivity/drug therapy/*immunology/metabolism ; }, abstract = {Oxidant-antioxidant imbalance plays an important role in repeated cycles of airway inflammation observed in asthma. It is when reactive oxygen species (ROS) overwhelm antioxidant defenses that a severe inflammatory state becomes apparent and may impact vasculature. Several studies have shown an association between airway inflammation and cardiovascular complications; however so far none has investigated the link between airway oxidative stress and systemic/vascular oxidative stress in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of vascular/systemic oxidant-antioxidant balance. Rats were sensitized intraperitoneally with ovalbumin (OVA) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with OVA. Rats were then assessed for airway and vascular inflammation, oxidative stress (ROS, lipid peroxides) and antioxidants measured as total antioxidant capacity (TAC) and thiol content. Challenge with OVA led to increased airway inflammation and oxidative stress with a concomitant increase in vascular inflammation and oxidative stress. Oxidative stress in the vasculature was significantly inhibited by antioxidant treatment, N-acetyl cysteine; whereas hydrogen peroxide (H2O2) inhalation worsened it. Therefore, our study shows that oxidative airway inflammation is associated with vascular/systemic oxidative stress which might predispose these patients to increased cardiovascular risk.}, }
@article {pmid25841782, year = {2015}, author = {Sharaf, MS and van den Heuvel, MR and Stevens, D and Kamunde, C}, title = {Zinc and calcium modulate mitochondrial redox state and morphofunctional integrity.}, journal = {Free radical biology &amp; medicine}, volume = {84}, number = {}, pages = {142-153}, doi = {10.1016/j.freeradbiomed.2015.03.017}, pmid = {25841782}, issn = {1873-4596}, mesh = {Animals ; Calcium/*pharmacology ; Membrane Potential, Mitochondrial ; Mitochondria, Liver/drug effects/*metabolism/ultrastructure ; Mitochondrial Size ; Oncorhynchus mykiss ; Oxidation-Reduction ; Oxidative Phosphorylation ; Oxidative Stress ; Reactive Oxygen Species ; Zinc/*pharmacology ; }, abstract = {Zinc and calcium have highly interwoven functions that are essential for cellular homeostasis. Here we first present a novel real-time flow cytometric technique to measure mitochondrial redox state and show it is modulated by zinc and calcium, individually and combined. We then assess the interactions of zinc and calcium on mitochondrial H2O2 production, membrane potential (ΔΨm), morphological status, oxidative phosphorylation (OXPHOS), complex I activity, and structural integrity. Whereas zinc at low doses and both cations at high doses individually and combined promoted H2O2 production, the two cations individually did not alter mitochondrial redox state. However, when combined at low and high doses the two cations synergistically suppressed and promoted, respectively, mitochondrial shift to a more oxidized state. Surprisingly, the antioxidants vitamin E and N-acetylcysteine showed pro-oxidant activity at low doses, whereas at high antioxidant doses NAC inhibited OXPHOS and dyscoupled mitochondria. Individually, zinc was more potent than calcium in inhibiting OXPHOS, whereas calcium more potently dissipated the ΔΨm and altered mitochondrial volume and ultrastructure. The two cations synergistically inhibited OXPHOS but antagonistically dissipated ΔΨm and altered mitochondrial volume and morphology. Overall, our study highlights the importance of zinc and calcium in mitochondrial redox regulation and functional integrity. Importantly, we uncovered previously unrecognized bidirectional interactions of zinc and calcium that reveal distinctive foci for modulating mitochondrial function in normal and disease states because they are potentially protective or damaging depending on conditions.}, }
@article {pmid25835550, year = {2015}, author = {Burelle, Y and Bemeur, C and Rivard, ME and Thompson Legault, J and Boucher, G and ,  and Morin, C and Coderre, L and Des Rosiers, C}, title = {Mitochondrial vulnerability and increased susceptibility to nutrient-induced cytotoxicity in fibroblasts from leigh syndrome French canadian patients.}, journal = {PloS one}, volume = {10}, number = {3}, pages = {e0120767}, pmid = {25835550}, issn = {1932-6203}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Adenosine Triphosphate/metabolism ; Adolescent ; Adult ; Calcium/metabolism ; Canada ; Case-Control Studies ; Cell Membrane Permeability ; Child ; Fibroblasts/*metabolism ; Humans ; Leigh Disease/genetics/*metabolism ; Membrane Potential, Mitochondrial ; Mitochondria/genetics/*metabolism ; Mutation ; Neoplasm Proteins/genetics ; Oxidative Phosphorylation ; Phenotype ; Reactive Oxygen Species ; Stress, Physiological ; Superoxides/metabolism ; Young Adult ; }, abstract = {Mutations in LRPPRC are responsible for the French Canadian variant of Leigh Syndrome (LSFC), a severe disorder characterized biochemically by a tissue-specific deficiency of cytochrome c oxidase (COX) and clinically by the occurrence of severe and deadly acidotic crises. Factors that precipitate these crises remain unclear. To better understand the physiopathology and identify potential treatments, we performed a comprehensive analysis of mitochondrial function in LSFC and control fibroblasts. Furthermore, we have used this cell-based model to screen for conditions that promote premature cell death in LSFC cells and test the protective effect of ten interventions targeting well-defined aspects of mitochondrial function. We show that, despite maintaining normal ATP levels, LSFC fibroblasts present several mitochondrial functional abnormalities under normal baseline conditions, which likely impair their capacity to respond to stress. This includes mitochondrial network fragmentation, impaired oxidative phosphorylation capacity, lower membrane potential, increased sensitivity to Ca2+-induced permeability transition, but no changes in reactive oxygen species production. We also show that LSFC fibroblasts display enhanced susceptibility to cell death when exposed to palmitate, an effect that is potentiated by high lactate, while high glucose or acidosis alone or in combination were neutral. Furthermore, we demonstrate that compounds that are known to promote flux through the electron transport chain independent of phosphorylation (methylene blue, dinitrophenol), or modulate fatty acid (L-carnitine) or Krebs cycle metabolism (propionate) are protective, while antioxidants (idebenone, N-acetyl cysteine, resveratrol) exacerbate palmitate plus lactate-induced cell death. Collectively, beyond highlighting multiple alterations in mitochondrial function and increased susceptibility to nutrient-induced cytotoxicity in LSFC fibroblasts, these results raise questions about the nature of the diets, particularly excess fat intake, as well as on the use of antioxidants in patients with LSFC and, possibly, other COX defects.}, }
@article {pmid25834818, year = {2015}, author = {Tiryakioglu, O and Erkoc, K and Tunerir, B and Uysal, O and Altin, HF and Gunes, T and Aydin, S}, title = {The effect of iloprost and N-acetylcysteine on skeletal muscle injury in an acute aortic ischemia-reperfusion model: an experimental study.}, journal = {BioMed research international}, volume = {2015}, number = {}, pages = {453748}, pmid = {25834818}, issn = {2314-6141}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Aorta, Abdominal/*drug effects/pathology ; Humans ; Iloprost/*administration &amp; dosage ; Male ; Muscle, Skeletal/drug effects/injuries ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*drug therapy/pathology ; }, abstract = {OBJECTIVE: The objective of this study was to examine the effects of iloprost and N-acetylcysteine (NAC) on ischemia-reperfusion (IR) injuries to the gastrocnemius muscle, following the occlusion-reperfusion period in the abdominal aorta of rats.<br><br>MATERIALS AND METHODS: Forty male Sprague-Dawley rats were randomly divided into four equal groups. Group 1: control group. Group 2 (IR): aorta was occluded. The clamp was removed after 1 hour of ischemia. Blood samples and muscle tissue specimens were collected following a 2-hour reperfusion period. Group 3 (IR + iloprost): during a 1-hour ischemia period, iloprost infusion was initiated from the jugular catheter. During a 2-hour reperfusion period, the iloprost infusion continued. Group 4 (IR + NAC): similar to the iloprost group.<br><br>FINDINGS: The mean total oxidant status, CK, and LDH levels were highest in Group 2 and lowest in Group 1. The levels of these parameters in Group 3 and Group 4 were lower compared to Group 2 and higher compared to Group 1 (P < 0.05). The histopathological examination showed that Group 3 and Group 4, compared to Group 2, had preserved appearance with respect to hemorrhage, necrosis, loss of nuclei, infiltration, and similar parameters.<br><br>CONCLUSION: Iloprost and NAC are effective against ischemia-reperfusion injury and decrease ischemia-related tissue injury.}, }
@article {pmid25834143, year = {2015}, author = {Li, X and Liu, S and Luo, J and Liu, A and Tang, S and Liu, S and Yu, M and Zhang, Y}, title = {Helicobacter pylori induces IL-1β and IL-18 production in human monocytic cell line through activation of NLRP3 inflammasome via ROS signaling pathway.}, journal = {Pathogens and disease}, volume = {73}, number = {4}, pages = {}, doi = {10.1093/femspd/ftu024}, pmid = {25834143}, issn = {2049-632X}, mesh = {Blotting, Western ; Carrier Proteins/*metabolism ; Caspase 1/analysis ; Cell Line ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Gene Expression Profiling ; Helicobacter pylori/*immunology ; Humans ; Inflammasomes/*metabolism ; Interleukin-18/*metabolism ; Interleukin-1beta/*metabolism ; Monocytes/*immunology/microbiology ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction ; }, abstract = {This study investigated whether Helicobacter pylori could activate the nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome in human macrophages and the involvement of reactive oxygen species (ROS) in inflammasome activation. Phorbol-12-myristate-13-acetate (PMA)-differentiated human acute monocytic leukemia cell line THP-1 was infected with H. pylori. The levels of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 in supernatant were measured by ELISA. Intracellular ROS level was analyzed by flow cytometry. Quantitative real-time PCR and western blot analysis were employed to determine the mRNA and protein expression levels of NLRP3 and caspase-1 in THP-1 cells, respectively. Our results showed that H. pylori infection could induce IL-1β and IL-18 production in PMA-differentiated THP-1 cells in a dose- and time-dependent manner. Moreover, secretion of IL-1β and IL-18 in THP-1 cells following H. pylori infection was remarkably reduced by NLRP3-specific small interfering RNA treatment. In addition, the intracellular ROS level was elevated by H. pylori infection, which could be eliminated by the ROS scavenger N-acetylcysteine (NAC). Furthermore, NAC treatment could inhibit NLRP3 inflammasome formation and caspase-1 activation and suppress the release of IL-1β and IL-18 from H. pylori-infected THP-1 cells. These findings provide novel insights into the innate immune response against H. pylori infection, which could potentially be used for the prevention and treatment of H. pylori-related diseases.}, }
@article {pmid25826445, year = {2015}, author = {Lee, HJ and Lee, JO and Kim, N and Kim, JK and Kim, HI and Lee, YW and Kim, SJ and Choi, JI and Oh, Y and Kim, JH and Suyeon-Hwang,  and Park, SH and Kim, HS}, title = {Irisin, a Novel Myokine, Regulates Glucose Uptake in Skeletal Muscle Cells via AMPK.}, journal = {Molecular endocrinology (Baltimore, Md.)}, volume = {29}, number = {6}, pages = {873-881}, pmid = {25826445}, issn = {1944-9917}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Cell Differentiation/drug effects ; Cells, Cultured ; Enzyme Activation/drug effects ; Fibronectins/*pharmacology ; Glucose/*metabolism ; Glucose Transporter Type 4/metabolism ; Muscle, Skeletal/*cytology ; Myoblasts/*drug effects/enzymology/*metabolism ; Protein Transport/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Irisin is a novel myokine produced by skeletal muscle. However, its metabolic role is poorly understood. In the present study, irisin induced glucose uptake in differentiated skeletal muscle cells. It increased AMP-activated protein kinase (AMPK) phosphorylation and the inhibition of AMPK blocked glucose uptake. It also increased reactive oxygen species (ROS) generation. N-acetyl cysteine, a ROS scavenger, blocked irisin-induced AMPK phosphorylation. Moreover, irisin activated p38 MAPK in an AMPK-dependent manner. The inhibition and knockdown of p38 MAPK blocked irisin-induced glucose uptake. A colorimetric absorbance assay showed that irisin stimulated the translocation of glucose transporter type 4 to the plasma membrane and that this effect was suppressed in cells pretreated with a p38 MAPK inhibitor or p38 MAPK small interfering RNA. In primary cultured myoblast cells, irisin increased the concentration of intracellular calcium. STO-609, a calcium/calmodulin-dependent protein kinase kinase inhibitor, blocked irisin-induced AMPK phosphorylation, implying that calcium is involved in irisin-mediated signaling. Our results suggest that irisin plays an important role in glucose metabolism via the ROS-mediated AMPK pathway in skeletal muscle cells.}, }
@article {pmid25825088, year = {2015}, author = {Liu, S and Li, X}, title = {Autophagy inhibition enhances sensitivity of endometrial carcinoma cells to paclitaxel.}, journal = {International journal of oncology}, volume = {46}, number = {6}, pages = {2399-2408}, doi = {10.3892/ijo.2015.2937}, pmid = {25825088}, issn = {1791-2423}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/*drug effects ; Beclin-1 ; Cell Line, Tumor ; Chloroquine/*pharmacology ; Drug Synergism ; Endometrial Neoplasms/*metabolism/pathology ; Female ; Humans ; Membrane Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Paclitaxel/*pharmacology ; RNA-Binding Proteins/metabolism ; Tubulin Modulators/pharmacology ; }, abstract = {Autophagy has been shown to be involved in cancer cell resistance to chemotherapy. Paclitaxel, a widely used chemotherapeutic drug, was demonstrated to induce autophagy in various cancer cells. Therefore, we sought to evaluate the role of autophagy on the paclitaxel-induced cell death in endometrial carcinoma. In this study, we found that paclitaxel induced autophagy in paclitaxel-insensitive HEC-1A and JEC cells, exhibiting an increased microtubule associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, a decrease in p62/SQSTM1 abundance, the upregulation of Beclin 1 expression and punctate dots of yellow fluorescent protein (YFP)-LC3 in the cytosol. Paclitaxel-mediated cell death was further potentiated by pretreatment with autophagy inhibitor chloroquine (CQ) or shRNA against the autophagic gene beclin 1. Moreover, paclitaxel stimulated reactive oxygen species (ROS) generation, and inhibition of the ROS by antioxidant N-acetyl-cysteine (NAC) blocked paclitaxel-induced autophagy, indicating that paclitaxel-induced autophagy in endometrial carcinoma cells is mediated by ROS. These findings suggest that paclitaxel-elicited autophagic response plays a protective role that impedes the eventual death of endometrial carcinoma cell, and that autophagy-inhibitor therapy could be an effective and potent strategy to improve paclitaxel treatment outcomes in the treatment of endometrial carcinoma.}, }
@article {pmid25823877, year = {2015}, author = {El Rahi, C and Thompson-Moore, N and Mejia, P and De Hoyos, P}, title = {Successful use of N-acetylcysteine to treat severe hepatic injury caused by a dietary fitness supplement.}, journal = {Pharmacotherapy}, volume = {35}, number = {6}, pages = {e96-e101}, doi = {10.1002/phar.1572}, pmid = {25823877}, issn = {1875-9114}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy ; Dietary Supplements/*poisoning ; Humans ; Male ; *Physical Fitness ; Vasodilator Agents/*therapeutic use ; Young Adult ; }, abstract = {In the absence of adequate premarketing efficacy and safety evaluations, adverse events from over-the-counter supplements are emerging as a public health concern. Specifically, bodybuilding products are being identified as a frequent cause of drug-induced liver injury. We present a case of a 20-year-old Hispanic male who presented with acute nausea and vomiting accompanied by severe right upper quadrant abdominal pain, shivering, and shortness of breath. Laboratory data pointed to mixed cholestatic and hepatocellular damage, and after exclusion of known alternate etiologies, the patient was diagnosed with acute drug-induced liver injury secondary to the use of "Friction," a bodybuilding supplement. Treatment with N-acetylcysteine (NAC) 20% oral solution was initiated empirically at a dose of 4000 mg [DOSAGE ERROR CORRECTED] (70 mg/kg) every 4 hours and was continued once the diagnosis was made. Within 48 hours of admission to our hospital, the patient began to show clinical resolution of right abdominal pain and tolerance to oral diet associated with a significant decline toward normal in his liver function tests and coagulopathy. The WHO-UMC causality assessment system suggested a "certain causality" between exposure to the supplement and the acute liver injury. In the event of suspected drug-induced liver injury, treatment with NAC should be considered given its favorable risk-benefit profile.}, }
@article {pmid25822013, year = {2015}, author = {Elatrech, I and Marzaioli, V and Boukemara, H and Bournier, O and Neut, C and Darfeuille-Michaud, A and Luis, J and Dubuquoy, L and El-Benna, J and My-Chan Dang, P and Marie, JC}, title = {Escherichia coli LF82 differentially regulates ROS production and mucin expression in intestinal epithelial T84 cells: implication of NOX1.}, journal = {Inflammatory bowel diseases}, volume = {21}, number = {5}, pages = {1018-1026}, doi = {10.1097/MIB.0000000000000365}, pmid = {25822013}, issn = {1536-4844}, mesh = {Colorectal Neoplasms/immunology/metabolism/microbiology ; Epithelial Cells/immunology/*metabolism/microbiology ; Escherichia coli/*pathogenicity ; Escherichia coli Infections/immunology/metabolism/microbiology ; Humans ; Ileum/immunology/*metabolism/microbiology ; Immunoenzyme Techniques ; Interleukin-8/genetics/metabolism ; Intestinal Mucosa/*metabolism ; Intestines/immunology/microbiology ; Mucin 5AC/genetics/*metabolism ; Mucin-2/genetics/*metabolism ; NADPH Oxidase 1 ; NADPH Oxidases/genetics/*metabolism ; RNA, Messenger/genetics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND: Increased reactive oxygen species (ROS) production is associated with inflamed ileal lesions in Crohn's disease colonized by pathogenic adherent-invasive Escherichia coli LF82. We investigated whether such ileal bacteria can modulate ROS production by epithelial cells, thus impacting on inflammation and mucin expression.<br><br>METHODS: Ileal bacteria from patients with Crohn's disease were incubated with cultured epithelial T84 cells, and ROS production was assayed using the luminol-amplified chemiluminescence method. The gentamicin protection assay was used for bacterial invasion of T84 cell. The expression of NADPH oxidase (NOX) subunits, mucin, and IL-8 was analyzed by quantitative real-time PCR and Western blots. Involvement of NOX and ROS was analyzed using diphenyleneiodonium (DPI) and N-acetylcysteine (NAC).<br><br>RESULTS: Among different bacteria tested, only LF82 induced an increase of ROS production by T84 cells in a dose-dependent manner. This response was inhibited by DPI and NAC. Heat- or ethanol-attenuated LF82 bacteria and the mutant LF82&#x394;FimA, which does not express pili type 1 and poorly adheres to epithelial cells, did not induce the oxidative response. The LF82-induced oxidative response coincides with its invasion in T84 cells, and both processes were inhibited by DPI. Also, we observed an increased expression of NOX1 and NOXO1 in response to LF82 bacteria versus the mutant LF82&#x394;FimA. Furthermore, LF82 inhibited mucin gene expression (MUC2 and MUC5AC) in T84 cells while increasing the chemotactic IL-8 expression, both in a DPI-sensitive manner.<br><br>CONCLUSIONS: Adherent-invasive E. coli LF82 induced ROS production by intestinal NADPH oxidase and altered mucin and IL-8 expression, leading to perpetuation of inflammatory lesions in Crohn's disease.}, }
@article {pmid25821351, year = {2015}, author = {Wang, C and Xia, Y and Zheng, Y and Dai, W and Wang, F and Chen, K and Li, J and Li, S and Zhu, R and Yang, J and Yin, Q and Zhang, H and Wang, J and Lu, J and Zhou, Y and Guo, C}, title = {Protective effects of N-acetylcysteine in concanavalin A-induced hepatitis in mice.}, journal = {Mediators of inflammation}, volume = {2015}, number = {}, pages = {189785}, pmid = {25821351}, issn = {1466-1861}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Concanavalin A/*pharmacology ; Cytokines/metabolism ; Hepatitis/*prevention &amp; control ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; NF-kappa B/physiology ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/physiology ; }, abstract = {This study was designed to study the protective effects and mechanisms of N-acetylcysteine (NAC) in concanavalin A-induced hepatitis in mice. In this study, pretreatment with NAC ameliorated the histopathological changes and suppressed inflammatory cytokines in ConA-induced hepatitis. The expression of IL-2, IL-6, TNF-α, and IFN-γ was significantly reduced in the NAC-treated groups. NAC activated PI3K/Akt pathway and inhibited the activation of NF-κB. Additionally, NAC reduced autophagosome formation, as assessed by detecting the expression of LC3 and Beclin 1. Our results demonstrate that NAC can alleviate ConA-induced hepatitis by regulating the PI3K/Akt pathway and reducing the late stages of autophagy. Our results described a new pharmaceutical to provide more effective therapies for immune hepatitis.}, }
@article {pmid25821291, year = {2015}, author = {Zaeri, S and Emamghoreishi, M}, title = {Acute and Chronic Effects of N-acetylcysteine on Pentylenetetrazole-induced Seizure and Neuromuscular Coordination in Mice.}, journal = {Iranian journal of medical sciences}, volume = {40}, number = {2}, pages = {118-124}, pmid = {25821291}, issn = {0253-0716}, abstract = {BACKGROUND: N-acetylcysteine (NAC) has been indicated against experimental seizures, but with relatively inconclusive results. This study was undertaken to evaluate whether NAC exerts a dose-dependent anticonvulsant effect and to determine NAC safe therapeutic dose range and its muscle-relaxant activity in both acute and chronic uses.<br><br>METHODS: Following intraperitoneal (i.p.) administration of N-acetylcysteine acutely (50-300 mg/kg) or chronically for 8 days (25-300 mg/kg), mice were injected with PTZ (90 mg/kg, i.p.) and latency times to the onset of myoclonic and clonic seizures and protection against death were recorded. Changes in body weight and mortality rate were considered as parameters for drug safety. The muscle-relaxant activity of NAC was assessed by rotarod test.<br><br>RESULTS: Acute and chronic treatment with NAC delayed latency times to myoclonic and clonic seizures in a dose-dependent manner, but with no significant prevention against PTZ-induced death. Chronic administration of 300 mg/kg NAC was fully lethal while lower doses (100 and 150 mg/kg) resulted in a significant weight loss and decreased stay time on rotarod. Acute treatment with NAC had no significant effect on stay time on rotarod at all studied doses.<br><br>CONCLUSION: NAC exerts a dose-dependent anticonvulsant effect in acute and chronic uses, with no muscle relaxant activity. NAC has higher efficacy in preventing seizure in chronic than acute treatment, but its chronic use at higher doses of 75 mg/kg may be associated with side effects and/or toxicity. These findings suggest that low doses of NAC may have a potential use as a prophylactic treatment for absence seizure in human.}, }
@article {pmid25820767, year = {2015}, author = {Hou, Y and Jia, S and Nawaratna, G and Hu, S and Dahanayaka, S and Bazer, FW and Wu, G}, title = {Analysis of L-homoarginine in biological samples by HPLC involving precolumn derivatization with o-phthalaldehyde and N-acetyl-L-cysteine.}, journal = {Amino acids}, volume = {47}, number = {9}, pages = {2005-2014}, doi = {10.1007/s00726-015-1962-9}, pmid = {25820767}, issn = {1438-2199}, mesh = {Acetylcysteine/*chemistry ; Animals ; Chromatography, High Pressure Liquid/methods ; Homoarginine/*blood ; Male ; Rats ; Rats, Sprague-Dawley ; o-Phthalaldehyde/*chemistry ; }, abstract = {L-Homoarginine (hArg) may play a role in regulating the metabolism of its structural homologue L-arginine via multiple pathways (including nitric oxide synthase) in animals. Accurate measurement of hArg is essential for studying its synthesis and utilization by cells and the whole body. Here, we describe a simple, sensitive and automated method for analysis of hArg in biological samples by high-performance liquid chromatography involving precolumn derivatization with o-phthalaldehyde (OPA) and N-acetyl-L-cysteine (NAC) as the thiol. The hArg-OPA-NAC derivative was separated at 25 °C on a reversed-phase C18 material and detected by fluorescence at excitation and emission wavelengths of 340 and 450 nm, respectively. The total running time for one sample (including the time for column regeneration) was 20 min, with the retention time for hArg being 10.03 min. The limit of detection was 188 fmol hArg, which was equivalent to 12 nM hArg in the 160-µl assay mixture. The assay was linear between 1.0 and 80 pmol hArg injected into the HPLC column (equivalent to 0.0625 and 5 µM hArg in the 160-µl assay mixture, respectively). The precision (relative deviation, %) and bias (relative error, %) of the HPLC method were 0.52-1.16 and 0.42-1.12, respectively, for aqueous solutions of hArg and for various biological samples (e.g., plasma, liver, brain and kidney). This is a highly sensitive, accurate, efficient and easily automated method for analysis of hArg in biological samples and provides a useful tool for studying the biochemistry, nutrition, physiology and pharmacology of hArg and arginine in animals and humans.}, }
@article {pmid25817791, year = {2015}, author = {Bozhokina, E and Khaitlina, S and Gamaley, I}, title = {Dihydrolipoic but not alpha-lipoic acid affects susceptibility of eukaryotic cells to bacterial invasion.}, journal = {Biochemical and biophysical research communications}, volume = {460}, number = {3}, pages = {697-702}, doi = {10.1016/j.bbrc.2015.03.092}, pmid = {25817791}, issn = {1090-2104}, mesh = {Base Sequence ; Cadherins/metabolism ; Cell Line, Tumor ; DNA Primers ; Escherichia coli/*pathogenicity ; Eukaryotic Cells/microbiology ; Humans ; Real-Time Polymerase Chain Reaction ; Serratia/*pathogenicity ; Thioctic Acid/*analogs &amp; derivatives/*pharmacology ; beta Catenin/metabolism ; }, abstract = {Sensitivity of eukaryotic cells to facultative pathogens can depend on physiological state of host cells. Previously we have shown that pretreatment of HeLa cells with N-acetylcysteine (NAC) makes the cells 2-3-fold more sensitive to invasion by the wild-type Serratia grimesii and recombinant Escherichia coli expressing gene of actin-specific metalloprotease grimelysin [1]. To evaluate the impact of chemically different antioxidants, in the present work we studied the effects of α-Lipoic acid (LA) and dihydrolipoic acid (DHLA) on efficiency of S. grimesii and recombinant E. coli expressing grimelysin gene to penetrate into HeLa and CaCo cells. Similarly to the effect of NAC, pretreatment of HeLa and CaCo cells with 0.6 or 1.25 mM DHLA increased the entry of grimelysin producing bacteria by a factor of 2.5 and 3 for the wild-type S. grimesii and recombinant E. coli, respectively. In contrast, pretreatment of the cells with 0.6 or 1.25 mM LA did not affect the bacteria uptake. The increased invasion of HeLa and CaCo cells correlated with the enhanced expression of E-cadherin and β-catenin genes, whereas expression of these genes in the LA-treated cells was not changed. Comparison of these results suggests that it is sulfhydryl group of DHLA that promotes efficient modification of cell properties assisting bacterial uptake. We assume that the NAC- and DHLA-induced stimulation of the E-cadherin-catenin pathway contributes to the increased internalization of the grimelysin producing bacteria within transformed cells.}, }
@article {pmid25815442, year = {2015}, author = {Lee, C}, title = {Overexpression of Tyro3 receptor tyrosine kinase leads to the acquisition of taxol resistance in ovarian cancer cells.}, journal = {Molecular medicine reports}, volume = {12}, number = {1}, pages = {1485-1492}, doi = {10.3892/mmr.2015.3542}, pmid = {25815442}, issn = {1791-3004}, mesh = {Acetylcysteine/administration &amp; dosage ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Oncogene Protein v-akt/*biosynthesis/genetics ; Ovarian Neoplasms/*drug therapy/genetics/pathology ; Paclitaxel/*administration &amp; dosage ; Phosphorylation/drug effects ; RNA, Messenger/biosynthesis ; Receptor Protein-Tyrosine Kinases/*biosynthesis/genetics ; Signal Transduction/drug effects ; }, abstract = {The majority of patients with ovarian cancer are diagnosed at the advanced stages (III/IV) and their 5-year-survival rate is relatively low. One of the major causes of the poor prognosis of ovarian cancer is the development of resistance to first-line chemotherapy, including platinum and taxol. Therefore, improvements in current understanding of chemoresistance is required for the successful treatment of ovarian cancer. In the present study, taxol-resistant ovarian cancer cells, SKOV3/TR, were established by exposing parental SKOV3 cells to increasing concentrations of taxol. . Briefly, cells were treated with 1.5 nM (for 4 weeks), 3 nM (for 4 weeks), 6 nM (for 5 weeks), 12 nM (for 5 weeks) and 24 nM taxol (for 8 weeks) over 6 months. The SKOV3/TR cells were found to be smaller in size and rounder in shape compared with their parental cells. Cell viability and colony formation assays demonstrated an increase in the population doubling time of the SKOV3/TR cells, indicating a reduction in the proliferative capacity of these cells. Reverse transcription-polymerase chain reaction and western blot analysis revealed that, among the TAM receptor tyrosine kinases (RTKs), the mRNA and protein expression levels of Tyro3 RTK were increased, while those of Axl and Mer RTK were decreased in the SKOV3/TR cells. In addition, restoration of the level of Tyro3 by transfecting Tyro3-specific small interfering RNA into the SKOV3/TR cells reduced the proliferative capacity of the cells, indicating that upregulation of the expression of Tyro3 in SKOV3/TR cells may promote survival in the presence of taxol, which eventually resulted in the acquisition of resistance upon taxol treatment. The present study subsequently found that, in the SKOV3/TR cells, the level of intracellular reactive oxygen species (ROS) was elevated, and antioxidant treatment with N-acetyl cysteine (NAC) exerted more profound antiproliferative effects compared with the parental cells. The western blot analysis demonstrated that treatment of the SKOV3/TR cells with NAC reduced the protein expression of Tyro3, and the inhibitory effect of NAC on the phosphorylation of Akt was increased, which may have had a positive effect on the proliferation of the SKOV3/TR cells. The levels of phosphorylation and protein expression of signal transducers and activators of transcription 3 (STAT3) were not affected by NAC treatment, indicating that the phosphorylation of Akt, but not expression or phosphorylation of STAT3, was associated with the increased intracellular ROS level in the SKOV3/TR cells. Taken together, the results of the present study demonstrated that the acquired taxol resistance of ovarian cancer cells was associated with ROS-dependent upregulation in the expression of Tyro3 RTK and the subsequent activation of Akt.}, }
@article {pmid25809591, year = {2015}, author = {Nakagawa, Y and Inomata, A and Ogata, A and Nakae, D}, title = {Comparative effects of sulfhydryl compounds on target organellae, nuclei and mitochondria, of hydroxylated fullerene-induced cytotoxicity in isolated rat hepatocytes.}, journal = {Journal of applied toxicology : JAT}, volume = {35}, number = {12}, pages = {1465-1472}, doi = {10.1002/jat.3137}, pmid = {25809591}, issn = {1099-1263}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/pharmacology ; Cell Culture Techniques ; Cell Nucleus/drug effects/metabolism/ultrastructure ; Cell Survival/drug effects ; Cells, Cultured ; Cysteine/pharmacology ; DNA Damage/*drug effects ; Fullerenes/*toxicity ; Hepatocytes/*drug effects/metabolism/ultrastructure ; Male ; Membrane Potential, Mitochondrial/*drug effects ; Methionine/pharmacology ; Organelles/*drug effects/metabolism/ultrastructure ; Rats, Inbred F344 ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {DNA damage and cytotoxicity induced by a hydroxylated fullerene [C60 (OH)24 ], which is a spherical nanomaterial and/or a water-soluble fullerene derivative, and their protection by sulfhydryl compounds were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C60 (OH)24 at a concentration of 50 μM caused time (0 to 3 h)-dependent cell death accompanied by the formation of cell surface blebs, the loss of cellular levels of ATP and reduced glutathione, accumulation of glutathione disulfide, and induction of DNA fragmentation assayed using alkali single-cell agarose-gel electrophoresis. C60 (OH)24 -induced cytotoxicity was effectively prevented by pretreatment with sulfhydryl compounds. N-acetyl-L-cysteine (NAC), L-cysteine and L-methionine, at a concentration of 2.5 mM, ameliorated cell death, accompanied by a decrease in cellular ATP levels, formation of cell surface blebs, induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential caused by C60 (OH)24 . In addition, DNA fragmentation caused by C60 (OH)24 was also inhibited by NAC, whereas an antioxidant ascorbic acid did not affect C60 (OH)24 -induced cell death and DNA damage in rat hepatocytes. Taken collectively, these results indicate that incubation of rat hepatocytes with C60 (OH)24 elicits DNA damage, suggesting that nuclei as well as mitochondria are target sites of the hydroxylated fullerene; and induction of DNA damage and oxidative stress is ameliorated by an increase in cellular GSH levels, suggesting that the onset of toxic effects may be partially attributable to a thiol redox-state imbalance caused by C60 (OH)24 .}, }
@article {pmid25805996, year = {2015}, author = {Weiland, A and Garcia, S and Knackstedt, LA}, title = {Ceftriaxone and cefazolin attenuate the cue-primed reinstatement of alcohol-seeking.}, journal = {Frontiers in pharmacology}, volume = {6}, number = {}, pages = {44}, pmid = {25805996}, issn = {1663-9812}, support = {P50 AA010761/AA/NIAAA NIH HHS/United States ; R01 DA033436/DA/NIDA NIH HHS/United States ; }, abstract = {Alcohol consumption and the reinstatement of alcohol-seeking rely on glutamate and GABA transmission. Modulating these neurotransmitters may be a viable treatment strategy to prevent alcohol relapse. N-acetylcysteine (NAC) and the antibiotic ceftriaxone (CEF) alter the glial reuptake and release of glutamate while the antibiotic cefazolin (CEFAZ) modulates GABA signaling without affecting glutamate. Here, we used the extinction-reinstatement model of relapse to test the ability of these compounds to attenuate the reinstatement of alcohol-seeking. Male Sprague-Dawley rats were trained to self-administer 20% (v/v) alcohol in the home cage using an intermittent schedule (24 h on, 24 h off) for 12 sessions. Subsequently, animals self-administered alcohol during daily 45-min operant sessions for 26 sessions, followed by extinction training. We tested whether chronic administration of NAC, CEF, or CEFAZ attenuated the cue-primed reinstatement of alcohol-seeking. CEF and CEFAZ attenuated cue-primed reinstatement of alcohol-seeking while NAC had no effect. We subsequently investigated whether CEF and CEFAZ alter the self-administration of sucrose and chow pellets and if CEFAZ attenuates the reinstatement of cocaine-seeking. The operant self-administration of regular chow and sucrose was not altered by either CEF or CEFAZ. CEFAZ had no effect on cocaine reinstatement, a behavior that has been strongly tied to altered glutamate homeostasis in the nucleus accumbens. Thus the ability of CEFAZ to attenuate alcohol reinstatement likely does not involve the glial modulation of glutamate levels. The dampening of GABA transmission may be a common mechanism of action of cefazolin and ceftriaxone.}, }
@article {pmid25801561, year = {2015}, author = {Rodríguez-Beltrán, J and Cabot, G and Valencia, EY and Costas, C and Bou, G and Oliver, A and Blázquez, J}, title = {N-acetylcysteine selectively antagonizes the activity of imipenem in Pseudomonas aeruginosa by an OprD-mediated mechanism.}, journal = {Antimicrobial agents and chemotherapy}, volume = {59}, number = {6}, pages = {3246-3251}, pmid = {25801561}, issn = {1098-6596}, mesh = {Acetylcysteine/*pharmacology ; Acinetobacter baumannii/drug effects ; Anti-Bacterial Agents/*pharmacology ; Escherichia coli/drug effects ; Gene Expression Regulation, Bacterial/drug effects ; Imipenem/*pharmacology ; Microbial Sensitivity Tests ; Porins/*metabolism ; Pseudomonas aeruginosa/*drug effects/*metabolism ; }, abstract = {The modulating effect of N-acetylcysteine (NAC) on the activity of different antibiotics has been studied in Pseudomonas aeruginosa. Our results demonstrate that, in contrast to previous reports, only the activity of imipenem is clearly affected by NAC. MIC and checkerboard determinations indicate that the NAC-based modulation of imipenem activity is dependent mainly on OprD. SDS-PAGE of outer membrane proteins (OMPs) after NAC treatments demonstrates that NAC does not modify the expression of OprD, suggesting that NAC competitively inhibits the uptake of imipenem through OprD. Similar effects on imipenem activity were obtained with P. aeruginosa clinical isolates. Our results indicate that imipenem-susceptible P. aeruginosa strains become resistant upon simultaneous treatment with NAC and imipenem. Moreover, the generality of the observed effects of NAC on antibiotic activity was assessed with two additional bacterial species, Escherichia coli and Acinetobacter baumannii. Caution should be taken during treatments, as the activity of imipenem may be modified by physiologically attainable concentrations of NAC, particularly during intravenous and nebulized regimes.}, }
@article {pmid25798044, year = {2015}, author = {Hwang, GH and Jeon, YJ and Han, HJ and Park, SH and Baek, KM and Chang, W and Kim, JS and Kim, LK and Lee, YM and Lee, S and Bae, JS and Jee, JG and Lee, MY}, title = {Protective effect of butylated hydroxylanisole against hydrogen peroxide-induced apoptosis in primary cultured mouse hepatocytes.}, journal = {Journal of veterinary science}, volume = {16}, number = {1}, pages = {17-23}, pmid = {25798044}, issn = {1976-555X}, mesh = {Animals ; Apoptosis/*drug effects ; Butylated Hydroxyanisole/chemistry/*pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Hepatocytes/*drug effects ; Hydrogen Peroxide/*toxicity ; Male ; Mice ; Mice, Inbred ICR ; Molecular Structure ; }, abstract = {Butylated hydroxyanisole (BHA) is a synthetic phenolic compound consisting of a mixture of two isomeric organic compounds: 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole. We examined the effect of BHA against hydrogen peroxide (H2O2)-induced apoptosis in primary cultured mouse hepatocytes. Cell viability was significantly decreased by H2O2 in a dose-dependent manner. Additionally, H2O2 treatment increased Bax, decreased Bcl-2, and promoted PARP-1 cleavage in a dose-dependent manner. Pretreatment with BHA before exposure to H2O2 significantly attenuated the H2O2-induced decrease of cell viability. H2O2 exposure resulted in an increase of intracellular reactive oxygen species (ROS) generation that was significantly inhibited by pretreatment with BHA or N-acetyl-cysteine (NAC, an ROS scavenger). H2O2-induced decrease of cell viability was also attenuated by pretreatment with BHA and NAC. Furthermore, H2O2-induced increase of Bax, decrease of Bcl-2, and PARP-1 cleavage was also inhibited by BHA. Taken together, results of this investigation demonstrated that BHA protects primary cultured mouse hepatocytes against H2O2-induced apoptosis by inhibiting ROS generation.}, }
@article {pmid25793216, year = {2014}, author = {Nguyen, H and Romani, A}, title = {Effect of Alcohol Administration on Mg[2+] Homeostasis in H9C2 Cells.}, journal = {Journal of cardiovascular diseases &amp; diagnosis}, volume = {2}, number = {6}, pages = {179}, pmid = {25793216}, issn = {2329-9517}, support = {R01 AA011593/AA/NIAAA NIH HHS/United States ; }, abstract = {Alcoholic cardiomyopathy represents one of the main clinical complications in chronic alcoholics. This pathology contrasts the seemingly beneficial effect of small doses of alcohol on the cardiovascular system. Studies carried out in liver cells exposed acutely or chronically to varying doses of EtOH indicate that intrahepatic alcohol metabolism results in a major loss of cellular Mg[2+]. To investigate whether EtOH administration also induced Mg[2+] extrusion in cardiac cells, H9C2 cells were exposed to varying doses of EtOH for short- or ling-term periods of time. The results indicate that H9C2 cells exposed to EtOH doses higher than 0.1% (v/v, or 15 mM) extruded Mg[2+] into the extracellular medium on a time- and dose-dependent manner. Consistent with the involvement of cyP4502E1 in metabolizing EtOH, administration of chloro-methiazole (CMZ) as an inhibitor of the cytochrome prevented EtOH-induced Mg[2+] loss to a large extent. EtOH-induced Mg[2+] extrusion was also prevented by the administration of di-thio-treitol (DTT) and n-acetyl-cysteine (NAC), two agents that prevent the negative effects of ROS formation and free radicals generation associated with EtOH metabolism by cyP4502E1. Taken together, our data indicate that Mg[2+] extrusion also occur in cardiac cells exposed to EtOH as a result of alcohol metabolism by cyP4502E1 and associated free radical formation. Interestingly, Mg[2+] extrusion only occurs at doses of EtOH higher than 0.1% administered for an extended period of time. The significance of Mg[2+] extrusion for the onset of alcoholic cardiomyopathy remains to be elucidated.}, }
@article {pmid25790792, year = {2015}, author = {Braakhuis, AJ and Hopkins, WG}, title = {Impact of Dietary Antioxidants on Sport Performance: A Review.}, journal = {Sports medicine (Auckland, N.Z.)}, volume = {45}, number = {7}, pages = {939-955}, pmid = {25790792}, issn = {1179-2035}, mesh = {Acetylcysteine/administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Athletic Performance/*physiology ; Beta vulgaris ; Beverages ; *Dietary Supplements ; Humans ; Quercetin/administration &amp; dosage ; Resveratrol ; Spirulina ; Stilbenes/administration &amp; dosage ; Vitamin E/administration &amp; dosage ; }, abstract = {Many athletes supplement with antioxidants in the belief this will reduce muscle damage, immune dysfunction and fatigue, and will thus improve performance, while some evidence suggests it impairs training adaptations. Here we review the effect of a range of dietary antioxidants and their effects on sport performance, including vitamin E, quercetin, resveratrol, beetroot juice, other food-derived polyphenols, spirulina and N-acetylcysteine (NAC). Older studies suggest vitamin E improves performance at altitude, with possible harmful effects on sea-level performance. Acute intake of vitamin E is worthy of further consideration, if plasma levels can be elevated sufficiently. Quercetin has a small beneficial effect for exercise of longer duration (>100 min), but it is unclear whether this benefits athletes. Resveratrol benefits trained rodents; more research is needed in athletes. Meta-analysis of beetroot juice studies has revealed that the nitrate component of beetroot juice had a substantial but unclear effect on performance when averaged across athletes, non-athletes and modes of exercise (single dose 1.4 ± 2.0%, double dose 0.5 ± 1.9%). The effect of addition of polyphenols and other components to beetroot juice was trivial but unclear (single dose 0.4 ± 3.2%, double dose -0.5 ± 3.3%). Other food-derived polyphenols indicate a range of performance outcomes from a large improvement to moderate impairment. Limited evidence suggests spirulina enhances endurance performance. Intravenous NAC improved endurance cycling performance and reduced muscle fatigue. On the basis of vitamin E and NAC studies, acute intake of antioxidants is likely to be beneficial. However, chronic intakes of most antioxidants have a harmful effect on performance.}, }
@article {pmid25789157, year = {2015}, author = {Li, H and Wang, Y and Wei, C and Bai, S and Zhao, Y and Li, H and Wu, B and Wang, R and Wu, L and Xu, C}, title = {Mediation of exogenous hydrogen sulfide in recovery of ischemic post-conditioning-induced cardioprotection via down-regulating oxidative stress and up-regulating PI3K/Akt/GSK-3β pathway in isolated aging rat hearts.}, journal = {Cell &amp; bioscience}, volume = {5}, number = {}, pages = {11}, pmid = {25789157}, issn = {2045-3701}, abstract = {The physiological and pathological roles of hydrogen sulfide (H2S) in the regulation of cardiovascular functions have been recognized. Cystathionine gamma-lyase (CSE) is a major H2S-producing enzyme in cardiovascular system. Ischemic post-conditioning (PC) provides cadioprotection in young hearts but lost in the aging hearts. The involvement of H2S in the recovery of PC-induced cardioprotection in the aging hearts is unclear. In the present study, we demonstrated that ischemia/reperfusion (I/R) decreased H2S production rate and CSE expression, aggravated cardiomyocytes damage, apoptosis and myocardial infarct size, reduced cardiac function, increased the levels of Bcl-2, caspase-3 and caspase-9 mRNA, enhanced oxidative stress in isolated young and aging rat hearts. I/R also increased the release of cytochrome c and down-regulated the phosphorylation of PI3K, Akt and GSK-3β in the aging rat hearts. We further found that PC increased H2S production rate and CSE expressions, and protected young hearts from I/R-induced cardiomyocytes damage, all of which were disappeared in the aging hearts. Supply of NaHS not only increased PC-induced cardioprotection in the young hearts, but also lightened I/R induced-myocardial damage and significantly recovered the cardioprotective role of PC against I/R induced myocardial damage in the aging hearts. LY294002 (a PI3K inhibitor) abolished but N-acetyl-cysteine (NAC, an inhibitor of reactive oxygen species, ROS) further enhanced the protective role of H2S against I/R induced myocardial damage in the aging hearts. In conclusion, these results demonstrate that exogenous H2S recovers PC-induced cardioprotection via inhibition of oxidative stress and up-regulation of PI3K-Akt-GSK-3β pathway in the aging rat hearts. These findings suggested that H2S might be a novel target for the treatment of aging cardiovascular diseases.}, }
@article {pmid25785867, year = {2015}, author = {Mo, C and Zhao, R and Vallejo, J and Igwe, O and Bonewald, L and Wetmore, L and Brotto, M}, title = {Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {14}, number = {10}, pages = {1507-1516}, pmid = {25785867}, issn = {1551-4005}, support = {P01 AG039355/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Alprostadil/analogs &amp; derivatives/pharmacology ; Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; Dinoprostone/*pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/cytology/*drug effects/metabolism ; Myoblasts/*drug effects ; Reactive Oxygen Species/metabolism ; Receptors, Prostaglandin E, EP1 Subtype/agonists/genetics/metabolism ; Receptors, Prostaglandin E, EP2 Subtype/agonists/genetics/metabolism ; Receptors, Prostaglandin E, EP3 Subtype/agonists/genetics/metabolism ; Receptors, Prostaglandin E, EP4 Subtype/agonists/genetics/*metabolism ; Signal Transduction/drug effects ; Thiophenes/pharmacology ; Triazoles/pharmacology ; }, abstract = {We recently demonstrated that conditioned media (CM) from osteocytes enhances myogenic differentiation of myoblasts, suggesting that signaling from bone may be important for skeletal muscle myogenesis. The effect of CM was closely mimicked by prostaglandin E2 (PGE2), a bioactive lipid mediator in various physiological or pathological conditions. PGE2 is secreted at high levels by osteocytes and such secretion is further enhanced under loading conditions. Although four types of receptors, EP1 to EP4, mediate PGE2 signaling, it is unknown whether these receptors play a role in myogenesis. Therefore, in this study, the expression of EPs in mouse primary myoblasts was characterized, followed by examination of their roles in myoblast proliferation by treating myoblasts with PGE2 or specific agonists. All four PGE2 receptor mRNAs were detectable by quantitative real-time PCR (qPCR), but only PGE2 and EP4 agonist CAY 10598 significantly enhance myoblast proliferation. EP1/EP3 agonist 17-phenyl trinor PGE2 (17-PT PGE2) and EP2 agonist butaprost did not have any significant effects. Moreover, treatment with EP4 antagonist L161,982 dose-dependently inhibited myoblast proliferation. These results were confirmed by cell cycle analysis and the gene expression of cell cycle regulators. Concomitant with the inhibition of myoblast proliferation, treatment with L161,982 significantly increased intracellular reactive oxygen species (ROS) levels. Cotreatment with antioxidant N-acetyl cysteine (NAC) or sodium ascorbate (SA) successfully reversed the inhibition of myoblast proliferation and ROS overproduction caused by L161,982. Therefore, PGE2 signaling via the EP4 receptor regulates myogenesis by promoting myoblast proliferation and blocking this receptor results in increased ROS production in myoblasts.}, }
@article {pmid25776470, year = {2015}, author = {Li, J and Meng, Z and Zhang, G and Xing, Y and Feng, L and Fan, S and Fan, F and Buren, B and Liu, Q}, title = {N-acetylcysteine relieves oxidative stress and protects hippocampus of rat from radiation-induced apoptosis by inhibiting caspase-3.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {70}, number = {}, pages = {1-6}, doi = {10.1016/j.biopha.2014.12.029}, pmid = {25776470}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects/*radiation effects ; Caspase 3/*metabolism ; Caspase Inhibitors/pharmacology ; Gamma Rays/adverse effects ; Hippocampus/cytology/*drug effects/*radiation effects ; In Situ Nick-End Labeling ; Male ; Oxidative Stress/*drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {It has been recognized that radiation-induced effects remain a significant risk. An accumulation of reactive oxygen species (ROS) is considered to be one factor that contributes to neurodegenerative changes. The aim of our study was to investigate the potential radioprotective effects of NAC. Male Sprague-Dawley rats underwent radiation. Irradiation was performed at room temperature with a 4-Gy dose of radiation. A dose of N-acetylcysteine (NAC) was performed 15 min prior to irradiation intraperitoneally. The methods of immunohistochemistry, TUNEL staining, Nissl staining, qRT-PCR, analysis of reactive oxygen species and Western blot were performed. In conclusion, our results demonstrate that NAC inhibits apoptosis induced by irradiation via the inhibition of caspase-3. We demonstrated a decrease in caspase-3 mRNA that was present at 24h of NAC treatment. Such mRNA decrease was accompanied by a decrease of protein. In the present study, NAC effectively antagonized oxidation induced by irradiation. These results provide evidence that the neural protective effect and the antioxidant effect of NAC contribute to metabolic activity.}, }
@article {pmid25773954, year = {2015}, author = {Altinoz, E and Turkoz, Y and Vardi, N}, title = {The protective effect of N-acetylcysteine against acrylamide toxicity in liver and small and large intestine tissues.}, journal = {Bratislavske lekarske listy}, volume = {116}, number = {4}, pages = {252-258}, doi = {10.4149/bll_2015_049}, pmid = {25773954}, issn = {0006-9248}, mesh = {Acetylcysteine/*pharmacology ; Acrylamide/*toxicity ; Animals ; Antioxidants/pharmacology ; Chemical and Drug Induced Liver Injury/pathology/*prevention &amp; control ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Intestinal Diseases/chemically induced/pathology/*prevention &amp; control ; Intestine, Large/*drug effects/pathology ; Liver/*drug effects/pathology ; Male ; Rats ; Rats, Wistar ; }, abstract = {The aim of this study was to investigate the protective effects of N-acetylcysteine against acrylamide toxicity in liver and small and large intestine tissues in rats.The rats were divided into four groups. Acrylamide administration increased MDA levels in all tissues significantly (p < 0.05). But acrylamide+NAC administration decreased MDA levels significantly as compared to the acrylamide group, and lowered it to a level close to the control group values (p < 0.05). GSH levels in liver and small intestine tissues reduced significantly in the acrylamide group (p < 0.05). But acrylamide+NAC administration increased GSH levels significantly in all tissues. Whereas GST activity decreased significantly in the acrylamide group in liver and small intestine tissues as compared to the other groups (p < 0.05), the GST activity increased significantly in the acrylamide+NAC group in all tissues as compared to the acrylamide group (p < 0.05). Liver histopathology showed that the liver epithelial cells were damaged significantly in the acrylamide group. Small intestine histopathology showed that the intestinal villous epithelial cells were damaged significantly in the acrylamide group.Our results indicate that a high level of acrylamide causes oxidative damage in liver and small and large intestine tissues, while N-acetylcysteine administration in a pharmacological dose shows to have an antioxidant effect in preventing this damage (Tab. 2, Fig. 2, Ref. 66).}, }
@article {pmid25772235, year = {2015}, author = {Strohecker, AM and Joshi, S and Possemato, R and Abraham, RT and Sabatini, DM and White, E}, title = {Identification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase as a novel autophagy regulator by high content shRNA screening.}, journal = {Oncogene}, volume = {34}, number = {45}, pages = {5662-5676}, pmid = {25772235}, issn = {1476-5594}, support = {K22 CA187931/CA/NCI NIH HHS/United States ; R01 CA163591/CA/NCI NIH HHS/United States ; R37 CA053370/CA/NCI NIH HHS/United States ; R01 CA130893/CA/NCI NIH HHS/United States ; RC1 CA147961/CA/NCI NIH HHS/United States ; P30 CA072720/CA/NCI NIH HHS/United States ; R01CA130893/CA/NCI NIH HHS/United States ; R37 CA53370/CA/NCI NIH HHS/United States ; }, mesh = {Adaptor Proteins, Signal Transducing/biosynthesis/genetics ; *Autophagy ; Cell Line, Tumor ; Gene Deletion ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Neoplasm Proteins/genetics/*metabolism ; Neoplasms/genetics/*metabolism/pathology ; *Oxidative Stress ; Phosphofructokinase-2/genetics/*metabolism ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Sequestosome-1 Protein ; Up-Regulation ; }, abstract = {Deregulation of autophagy has been linked to multiple degenerative diseases and cancer, thus the identification of novel autophagy regulators for potential therapeutic intervention is important. To meet this need, we developed a high content image-based short hairpin RNA screen monitoring levels of the autophagy substrate p62/SQSTM1. We identified 186 genes whose loss caused p62 accumulation indicative of autophagy blockade, and 67 genes whose loss enhanced p62 elimination indicative of autophagy stimulation. One putative autophagy stimulator, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), drives flux through pentose phosphate pathway. Knockdown of PFKFB4 in prostate cancer cells increased p62 and reactive oxygen species (ROS), but surprisingly increased autophagic flux. Addition of the ROS scavenger N-acetyl cysteine prevented p62 accumulation in PFKFB4-depleted cells, suggesting that the upregulation of p62 and autophagy was a response to oxidative stress caused by PFKFB4 elimination. Thus, PFKFB4 suppresses oxidative stress and p62 accumulation, without which autophagy is stimulated likely as a ROS detoxification response.}, }
@article {pmid25771838, year = {2015}, author = {Pérez, L and Arias, ME and Sánchez, R and Felmer, R}, title = {N-acetyl-L-cysteine pre-treatment protects cryopreserved bovine spermatozoa from reactive oxygen species without compromising the in vitro developmental potential of intracytoplasmic sperm injection embryos.}, journal = {Andrologia}, volume = {47}, number = {10}, pages = {1196-1201}, doi = {10.1111/and.12412}, pmid = {25771838}, issn = {1439-0272}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cattle ; Cryopreservation/*methods ; Cryoprotective Agents/*pharmacology ; DNA Fragmentation ; Embryonic Development/drug effects ; Fertilization in Vitro ; Male ; Reactive Oxygen Species/*adverse effects ; Semen Preservation/*methods ; Sperm Injections, Intracytoplasmic/*methods ; Spermatozoa/*drug effects/metabolism ; }, abstract = {Excess of reactive oxygen species (ROS) on in vitro embryo production systems negatively affects the quality and developmental potential of embryos, as result of a decreased sperm quality and increased DNA fragmentation. This issue is of major importance in assisted fertilisation procedures such as intracytoplasmic sperm injection (ICSI), because this technique does not allow the natural selection of competent spermatozoa, and therefore, DNA-damaged spermatozoa might be used to fertilise an egg. The aim of this study was to investigate a new strategy to prevent the potential deleterious effect of ROS on cryopreserved bovine spermatozoa. We evaluated the effect of a sperm pre-treatment with different concentrations of N-acetyl-L-cysteine (NAC) on ROS production, viability and DNA fragmentation and assessed the effect of this treatment on the in vitro developmental potential and quality of embryos generated by ICSI. The results show a strong scavenging effect of 1 and 10 mm NAC after exposure of spermatozoa to a ROS inducer, without compromising the viability and DNA integrity. Importantly, in vitro developmental potential and quality of embryos generated by ICSI with spermatozoa treated with NAC were not affected, confirming the feasibility of using this treatment before an ICSI cycle.}, }
@article {pmid25771148, year = {2015}, author = {Schneider, R and Santos, CF and Clarimundo, V and Dalmaz, C and Elisabetsky, E and Gomez, R}, title = {N-acetylcysteine prevents behavioral and biochemical changes induced by alcohol cessation in rats.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {49}, number = {3}, pages = {259-263}, doi = {10.1016/j.alcohol.2015.01.009}, pmid = {25771148}, issn = {1873-6823}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anxiety/chemically induced/*psychology ; Behavior, Animal/*drug effects ; Central Nervous System Depressants/adverse effects ; Corticosterone/*metabolism ; Ethanol/adverse effects ; Free Radical Scavengers/*pharmacology ; Leptin/*metabolism ; Motor Activity/*drug effects ; Rats ; Rats, Wistar ; Substance Withdrawal Syndrome/etiology/*metabolism/psychology ; }, abstract = {N-acetylcysteine (NAC), a glutamate-modulating agent with antioxidant and anti-inflammatory properties, has been considered as a potential anti-addictive drug. Beneficial effects were reported for cocaine, cannabis, and tobacco addicts, but the effect of NAC in alcoholics or in alcohol animal models is unknown. The aggravation of alcohol withdrawal symptoms, such as anxiety, has been associated with increased levels of serum corticosterone and leptin. Thus, the aim of this study was to assess the effects of NAC on anxiety, as well as corticosterone and leptin serum levels, after cessation of chronic alcohol treatment in rats. Male Wistar rats were treated with 2 g/kg ethanol, twice daily, by gavage for 30 days; control animals received an appropriate dose of glucose to balance caloric intake. Rats were treated for 4 days with NAC (60 and 90 mg/kg, intra-peritoneally [i.p.]) or saline after alcohol cessation. Twenty-four hours after the last treatment, rats were exposed to a 5-min session in the open-field test (OF). Corticosterone and leptin serum levels were determined by ELISA in samples collected within 30 min after the OF. Results showed that rats were hypoactive (decreased rearing, peripheral, and total crossings), and that corticosterone and leptin levels were increased 5 days after alcohol cessation. Four days of NAC prevented the behavioral and biochemical changes brought about by alcohol cessation. We suggest that, in addition to the anti-addictive properties reported for other drugs of abuse, NAC is potentially useful in the management of alcohol withdrawal.}, }
@article {pmid25770664, year = {2015}, author = {Liu, H and Gooneratne, R and Huang, X and Lai, R and Wei, J and Wang, W}, title = {A rapid in vivo zebrafish model to elucidate oxidative stress-mediated PCB126-induced apoptosis and developmental toxicity.}, journal = {Free radical biology &amp; medicine}, volume = {84}, number = {}, pages = {91-102}, doi = {10.1016/j.freeradbiomed.2015.03.002}, pmid = {25770664}, issn = {1873-4596}, mesh = {Animals ; Antioxidants/pharmacology ; *Apoptosis ; Cystine/analogs &amp; derivatives/pharmacology ; Environmental Pollutants/*toxicity ; Gene Expression Regulation, Developmental/drug effects ; Genes, Reporter ; Glutathione/metabolism ; Green Fluorescent Proteins/biosynthesis/genetics ; NF-E2-Related Factor 2/biosynthesis/genetics ; *Oxidative Stress ; Polychlorinated Biphenyls/*toxicity ; Promoter Regions, Genetic ; Reactive Oxygen Species/metabolism ; Sequence Analysis, DNA ; Zebrafish ; Zebrafish Proteins/biosynthesis/genetics ; }, abstract = {Dioxin-like 3,3',4,4',5-pentachlorobiphenyl (PCB126) is one of the most potent and widespread environmental pollutants. Although PCB126-induced toxicity is related to the aryl hydrocarbon receptor pathway, there is still no study that has constructed an in vivo visual model to clarify the role of the Nrf2/ARE signaling pathway in the oxidative stress mechanism of PCB126-induced toxicity. In the present study, an in vivo zebrafish model of nrf2a fused to enhanced green fluorescent protein (nrf2a-eGFP) was constructed. The zebrafish embryos microinjected with nrf2a-eGFP (72h postfertilization) were exposed to various concentrations of PCB126 (0, 25, 50, 100, 200μg/L) or 30mMN-acetylcysteine (NAC)+200μg/L PCB126. After 72h exposure, PCB126 significantly increased the malformation rates and induced eGFP expression in a dose-dependent manner in several zebrafish tissue types. The distribution of eGFP fluorescence coincided with developmental deformity sites. NAC pretreatment effectively counteracted PCB126-induced developmental toxicity including heart rate, pericardial edema, and body length. The highest PCB126 dose, 200μg/L, produced marked apoptosis in the eye, gill, and trunk detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. At 48 and 72h exposure, 200μg/L PCB126 affected glutathione metabolism as evidenced by decreased glutathione and increased glutathione disulfide concentrations, indicative of oxidative stress. These effects were also counteracted by NAC pretreatment. Furthermore, the Nrf2-regulated genes gclc, gpx, gstp1, and hmox1 were significantly induced at 24, 48, and 72h at the highest PCB126 exposures but not in the NAC-pretreated group. In addition, a significant increase in ROS generation was detected in zebrafish larvae at 72h PCB126 exposure, which might offer a link for future mechanistic studies. Collectively, these data suggest that PCB126-induced developmental toxicity and apoptosis in the nrf2a-eGFP-injected zebrafish model are due to oxidative stress mediated by disruption to glutathione metabolism and changes in Nrf2-regulated gene expression.}, }
@article {pmid25769432, year = {2015}, author = {Singh, F and Charles, AL and Schlagowski, AI and Bouitbir, J and Bonifacio, A and Piquard, F and Krähenbühl, S and Geny, B and Zoll, J}, title = {Reductive stress impairs myoblasts mitochondrial function and triggers mitochondrial hormesis.}, journal = {Biochimica et biophysica acta}, volume = {1853}, number = {7}, pages = {1574-1585}, doi = {10.1016/j.bbamcr.2015.03.006}, pmid = {25769432}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Respiration/drug effects ; Cell Survival/drug effects ; Cytoprotection/drug effects ; *Hormesis/drug effects ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Mitochondria/drug effects/*metabolism ; Mitochondrial Turnover/drug effects ; Myoblasts/drug effects/*metabolism ; Oxidation-Reduction/drug effects ; Protective Agents/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; *Stress, Physiological/drug effects ; Time Factors ; }, abstract = {Even though oxidative stress damage from excessive production of ROS is a well known phenomenon, the impact of reductive stress remains poorly understood. This study tested the hypothesis that cellular reductive stress could lead to mitochondrial malfunction, triggering a mitochondrial hormesis (mitohormesis) phenomenon able to protect mitochondria from the deleterious effects of statins. We performed several in vitro experiments on L6 myoblasts and studied the effects of N-acetylcysteine (NAC) at different exposure times. Direct NAC exposure (1mM) led to reductive stress, impairing mitochondrial function by decreasing maximal mitochondrial respiration and increasing H2O2production. After 24h of incubation, the reactive oxygen species (ROS) production was increased. The resulting mitochondrial oxidation activated mitochondrial biogenesis pathways at the mRNA level. After one week of exposure, mitochondria were well-adapted as shown by the decrease of cellular ROS, the increase of mitochondrial content, as well as of the antioxidant capacities. Atorvastatin (ATO) exposure (100μM) for 24h increased ROS levels, reduced the percentage of live cells, and increased the total percentage of apoptotic cells. NAC exposure during 3days failed to protect cells from the deleterious effects of statins. On the other hand, NAC pretreatment during one week triggered mitochondrial hormesis and reduced the deleterious effect of statins. These results contribute to a better understanding of the redox-dependant pathways linked to mitochondria, showing that reductive stress could trigger mitochondrial hormesis phenomenon.}, }
@article {pmid25769104, year = {2015}, author = {Rodríguez-Cotto, RI and Ortiz-Martínez, MG and Jiménez-Vélez, BD}, title = {Organic extracts from African dust storms stimulate oxidative stress and induce inflammatory responses in human lung cells through Nrf2 but not NF-κB.}, journal = {Environmental toxicology and pharmacology}, volume = {39}, number = {2}, pages = {845-856}, pmid = {25769104}, issn = {1872-7077}, support = {2G12RR003051/RR/NCRR NIH HHS/United States ; R25 GM061838/GM/NIGMS NIH HHS/United States ; R25GM061838/GM/NIGMS NIH HHS/United States ; G12 RR003051/RR/NCRR NIH HHS/United States ; G12 MD007600/MD/NIMHD NIH HHS/United States ; 8G12-MD007600/MD/NIMHD NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Africa ; Air Movements ; Air Pollutants/*toxicity ; Cell Line ; Deferoxamine/metabolism ; *Dust ; Glutathione S-Transferase pi/genetics ; Heme Oxygenase-1/genetics ; Humans ; Inflammation/metabolism ; Interleukin-6/genetics ; Interleukin-8/genetics ; Lung/cytology ; NF-E2-Related Factor 2/*metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Puerto Rico ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {The health impact of the global African dust event (ADE) phenomenon in the Caribbean has been vaguely investigated. Heavy metals in ADE and non-ADE extracts were evaluated for the formation of reactive oxygen species (ROS) and antioxidant capacity by cells using, deferoxamine mesylate (DF) and N-acetyl-l-cysteine (NAC). Results show that ADE particulate matter 2.5 (PM2.5) induces ROS and stimulates oxidative stress. Pre-treatment with DF reduces ROS in ADE and Non-ADE extracts and in lung cells demonstrating that heavy metals are of utmost importance. Glutathione-S-transferase and Heme Oxygenase 1 mRNA levels are induced with ADE PM and reduced by DF and NAC. ADE extracts induced Nrf2 activity and IL-8 mRNA levels significantly more than Non-ADE. NF-κB activity was not detected in any sample. Trace elements and organic constituents in ADE PM2.5 enrich the local environment load, inducing ROS formation and activating antioxidant-signaling pathways increasing pro-inflammatory mediator expressions in lung cells.}, }
@article {pmid25767408, year = {2015}, author = {Mahmoudi, GA and Astaraki, P and Mohtashami, AZ and Ahadi, M}, title = {N-acetylcysteine overdose after acetaminophen poisoning.}, journal = {International medical case reports journal}, volume = {8}, number = {}, pages = {65-69}, pmid = {25767408}, issn = {1179-142X}, abstract = {N-acetylcysteine (NAC) is used widely and effectively in oral and intravenous forms as a specific antidote for acetaminophen poisoning. Here we report a rare case of iatrogenic NAC overdose following an error in preparation of the solution, and describe its clinical symptoms. Laboratory results and are presented and examined. A 23-year-old alert female patient weighing 65 kg presented to the emergency ward with weakness, lethargy, extreme fatigue, nausea, and dizziness. She had normal arterial blood gas and vital signs. An excessive dosage of NAC over a short period of time can lead to hemolysis, thrombocytopenia, and acute renal failure in patients with normal glucose-6-phosphate dehydrogenase, and finally to death. Considering the similarity between some of the clinical symptoms of acetaminophen overdose and NAC overdose, it is vitally important for the administration phases and checking of the patient's symptoms to be carried out attentively and cautiously.}, }
@article {pmid25767260, year = {2015}, author = {Sun, Q and Zhong, W and Zhang, W and Li, Q and Sun, X and Tan, X and Sun, X and Dong, D and Zhou, Z}, title = {Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {308}, number = {9}, pages = {G757-66}, pmid = {25767260}, issn = {1522-1547}, support = {R01 AA014623/AA/NIAAA NIH HHS/United States ; R01 AA016013/AA/NIAAA NIH HHS/United States ; R01AA018844/AA/NIAAA NIH HHS/United States ; R01AA020212/AA/NIAAA NIH HHS/United States ; }, mesh = {Activating Transcription Factor 4/metabolism ; Animals ; Antioxidants/pharmacology ; *Apoptosis/drug effects ; Carrier Proteins/metabolism ; Caspase 3/metabolism ; Cation Transport Proteins/metabolism ; Cell Line, Tumor ; Chelating Agents/pharmacology ; Deficiency Diseases/blood/*etiology/pathology ; Disease Models, Animal ; Endoplasmic Reticulum/drug effects/*metabolism/pathology ; *Ethanol ; Eukaryotic Initiation Factor-2/metabolism ; Liver/drug effects/*metabolism/pathology ; Liver Diseases, Alcoholic/blood/*etiology/pathology ; Male ; Membrane Transport Proteins ; Mitochondria, Liver/drug effects/*metabolism/pathology ; Oxidative Stress ; Phosphorylation ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Time Factors ; Transcription Factor CHOP/metabolism ; Zinc/blood/*deficiency ; }, abstract = {Hepatic zinc deficiency has been well documented in alcoholic patients, but the mechanisms by which zinc deficiency mediates cell death have not been well defined. The objectives of this study were to determine whether alcohol perturbs subcellular zinc homeostasis and how organelle zinc depletion may link with cell death pathways. Wistar rats were pair-fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure significantly reduced zinc level in isolated hepatic endoplasmic reticulum (ER) and mitochondria. Among the detected zinc transporters, ER Zrt/Irt-like protein (ZIP)13 and mitochondrial ZIP8, which transport zinc from ER and mitochondria to cytosol, were significantly increased. Mitochondrial zinc transporter (ZnT) 4, which transports zinc from cytosol to mitochondria, was also increased. ER phosphorylated eukaryotic initiation factor 2α, activating transcription factor 4, and C/EBP homologous protein were significantly upregulated, and mitochondrial cytochrome c release and Bax insertion were detected in association with caspase-3 activation and apoptotic cell death. To define the role of zinc deficiency in ER and mitochondrial stress, H4IIEC3 cells were treated with 3 μM N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine for 6 h with or without supplementation with zinc or N-acetylcysteine (NAC). The results demonstrated that zinc deprivation induced caspase-3 activation and apoptosis in association with ER and mitochondria dysfunction, which were inhibited by zinc as low as 10 μM but not by 2 mM NAC. These results suggest that chronic ethanol exposure induced in ER and mitochondrial zinc deficiency might activate intrinsic cell death signaling pathway, which could not be effectively rescued by antioxidant treatment.}, }
@article {pmid25766794, year = {2015}, author = {Zhang, GL and Liang, Y and Zhu, JY and Jia, Q and Gan, WQ and Sun, LM and Hou, HM}, title = {Oxidative stress-mediated antiproliferative effects of furan-containing sulfur flavors in human leukemia Jurkat cells.}, journal = {Food chemistry}, volume = {180}, number = {}, pages = {1-8}, doi = {10.1016/j.foodchem.2015.01.122}, pmid = {25766794}, issn = {1873-7072}, mesh = {Apoptosis ; Cell Survival ; Furans/*pharmacology ; Humans ; Jurkat Cells/*chemistry ; Leukemia ; Oxidative Stress ; Sulfur/*pharmacology ; }, abstract = {Antiproliferative effects of 15 sulfides were investigated in human leukemia Jurkat cells. Treatment with 5-50 μM of nine monosulfides and two linear disulfides did not induce DNA fragmentation. Whereas, furan-containing sulfur flavors including methyl 2-methyl-3-furyl disulfide (MMFDS), bis (2-methyl-3-furyl) disulfide (BMFDS), methyl furfuryl disulfide (MFDS) and difurfuryl disulfide (DFDS) induced DNA fragmentation to a varying extent in Jurkat cells. The cell viability-reduction effect of these sulfur flavors was in the following order: DFDS>BMFDS>MMFDS>>MFDS based on the IC50 values. MMFDS and BMFDS, but not DFDS, significantly increased the intracellular ROS level by 1.90- and 3.02-fold, respectively. Addition of N-acetylcysteine (NAC) or glutathione (GSH) partially suppressed induction of DNA fragmentation, apoptosis and caspase-3 activation by MMFDS and BMFDS. These results suggest that the furan-containing disulfides have a strong antiproliferative effect, and the oxidative stress and subsequent caspase-3 activation are involved in antiproliferative effect induced by MMFDS and BMFDS in Jurkat cells.}, }
@article {pmid25765302, year = {2015}, author = {Katz, M and Won, SJ and Park, Y and Orr, A and Jones, DP and Swanson, RA and Glass, GA}, title = {Cerebrospinal fluid concentrations of N-acetylcysteine after oral administration in Parkinson's disease.}, journal = {Parkinsonism &amp; related disorders}, volume = {21}, number = {5}, pages = {500-503}, doi = {10.1016/j.parkreldis.2015.02.020}, pmid = {25765302}, issn = {1873-5126}, mesh = {Acetylcysteine/*administration &amp; dosage/*cerebrospinal fluid ; Administration, Oral ; Aged ; Aged, 80 and over ; Biomarkers/cerebrospinal fluid ; Blood-Brain Barrier/drug effects/metabolism ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Parkinson Disease/*cerebrospinal fluid/*drug therapy ; }, abstract = {INTRODUCTION: Depletion of neuronal glutathione may contribute to the pathogenesis of Parkinson's disease (PD). N-acetylcysteine (NAC) can restore neuronal glutathione levels, but it has not been established whether NAC can cross the blood-brain barrier in humans.<br><br>METHODS: Twelve patients with PD were given oral NAC twice daily for 2 days. Three doses were compared: 7&#xa0;mg/kg, 35&#xa0;mg/kg, and 70&#xa0;mg/kg. NAC, cysteine, and glutathione were measured in the cerebrospinal fluid (CSF) at baseline and 90&#xa0;min after the last dose. Cognitive and motor functions were assessed pre- and post-NAC administration using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson's Disease Rating Scale part III motor subscore (UPDRS-III).<br><br>RESULTS: Oral NAC produced a dose-dependent increase in CSF NAC concentrations (p&#xa0;<&#xa0;0.001), with the highest dose producing a CSF concentration of 9.26&#xa0;&#xb1;&#xa0;1.62&#xa0;&#x3bc;M. There were no significant adverse events. NAC had no acute effect on motor or cognitive function.<br><br>CONCLUSION: Orally administered NAC produces biologically relevant CSF NAC concentrations at doses that are well tolerated. The findings support the feasibility of NAC as a potential disease-modifying therapy for PD.}, }
@article {pmid25761907, year = {2015}, author = {Wimana, Z and Gebhart, G and Guiot, T and Vanderlinden, B and Morandini, R and Doumont, G and Sherer, F and Van Simaeys, G and Goldman, S and Ghanem, G and Flamen, P}, title = {Mucolytic Agents Can Enhance HER2 Receptor Accessibility for [(89)Zr]Trastuzumab, Improving HER2 Imaging in a Mucin-Overexpressing Breast Cancer Xenograft Mouse Model.}, journal = {Molecular imaging and biology}, volume = {17}, number = {5}, pages = {697-703}, pmid = {25761907}, issn = {1860-2002}, mesh = {Acetylcysteine ; Animals ; Antibodies, Monoclonal, Humanized/*pharmacokinetics ; Antineoplastic Agents/pharmacokinetics ; Cell Line, Tumor ; Expectorants/*pharmacology ; Female ; Humans ; Mammary Neoplasms, Experimental/diagnostic imaging/metabolism/*pathology ; Mice ; Mice, Nude ; Mice, Transgenic ; Molecular Imaging/*methods ; Mucin-4/genetics/metabolism ; Mucins/*drug effects ; Positron-Emission Tomography/methods ; Receptor, ErbB-2/*metabolism ; Tissue Distribution ; Xenograft Model Antitumor Assays ; }, abstract = {PURPOSE: Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([(89)Zr]T) binding/uptake.<br><br>PROCEDURES: The effect of N-acetylcysteine (NAC) and MUC4 knockdown/stimulation on [(89)Zr]T binding/uptake were evaluated in MCF7(HER2-), BT474 and SKBr3(HER2+/MUC4-), and JIMT1(HER2+/MUC4+) cell lines. The results were then validated in SKBR3 and JIMT1 tumor-bearing nude mice with a microPET-CT and ex vivo analysis.<br><br>RESULTS: Significant increases in [(89)Zr]T binding/uptake were observed in JIMT1 cells following MUC4 knockdown (62.4&#x2009;&#xb1;&#x2009;6.5%) and exposure to NAC (62.8&#x2009;&#xb1;&#x2009;19.4%). Compared to controls, mice treated with NAC showed a significant increase in [(89)Zr]T uptake in MUC4 tumors on microPET-CT (SUVmean (18.3&#x2009;&#xb1;&#x2009;4.7%), SUVmax (41.7&#x2009;&#xb1;&#x2009;8.4%)) and individual organ counting (37.3&#x2009;&#xb1;&#x2009;18.3%). In contrast, no significant differences were observed in SKBr3.<br><br>CONCLUSION: NAC can enhance [(89)Zr]T accumulation and improve the HER2 imaging of MUC4-overexpressing tumors. The potential positive impact on trastuzumab-based treatment deserves further investigation.}, }
@article {pmid25760991, year = {2015}, author = {Loveman, E and Copley, VR and Colquitt, J and Scott, DA and Clegg, A and Jones, J and O'Reilly, KM and Singh, S and Bausewein, C and Wells, A}, title = {The clinical effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: a systematic review and economic evaluation.}, journal = {Health technology assessment (Winchester, England)}, volume = {19}, number = {20}, pages = {i-xxiv, 1-336}, doi = {10.3310/hta19200}, pmid = {25760991}, issn = {2046-4924}, support = {10/50/06/DH_/Department of Health/United Kingdom ; }, mesh = {Cost-Benefit Analysis ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/economics ; Models, Economic ; Treatment Outcome ; }, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a life-limiting lung disease that generally affects people over 60 years old. The main symptoms are shortness of breath and cough, and as the disease progresses there is a considerable impact on day-to-day life. Few treatments are currently available.<br><br>OBJECTIVES: To conduct a systematic review of clinical effectiveness and an analysis of cost-effectiveness of treatments for IPF based on an economic model informed by systematic reviews of cost-effectiveness and quality of life.<br><br>DATA SOURCES: Eleven electronic bibliographic databases, including MEDLINE, EMBASE, Web of Science, and The Cochrane Library and the Centre for Reviews and Dissemination databases, were searched from database inception to July 2013. Reference lists of relevant publications were also checked and experts consulted.<br><br>METHODS: Two reviewers independently screened references for the systematic reviews, extracted and checked data from the included studies and appraised their risk of bias. An advisory group was consulted about the choice of interventions until consensus was reached about eligibility. A narrative review with meta-analysis was undertaken, and a network meta-analysis (NMA) was performed. A decision-analytic Markov model was developed to estimate cost-effectiveness of pharmacological treatments for IPF. Parameter values were obtained from NMA and systematic reviews. Univariate and probabilistic sensitivity analyses were undertaken. The model perspective is NHS and Personal Social Services, and discount rate is 3.5% for costs and health benefits.<br><br>RESULTS: Fourteen studies were included in the review of clinical effectiveness, of which one evaluated azathioprine, three N-acetylcysteine (NAC) (alone or in combination), four pirfenidone, one BIBF 1120, one sildenafil, one thalidomide, two pulmonary rehabilitation, and one a disease management programme. Study quality was generally good, with a low risk of bias. The current evidence suggests that some treatments appear to be clinically effective. The model base-case results show increased survival for five pharmacological treatments, compared with best supportive care, at increased cost. General recommendations cannot be made of their cost-effectiveness owing to limitations in the evidence base.<br><br>LIMITATIONS: Few direct comparisons of treatments were identified. An indirect comparison through a NMA was performed; however, caution is recommended in the interpretation of these results. In relation to the economic model, there is an assumption that pharmacological treatments have a constant effect on the relative rate of per cent predicted forced vital capacity decline.<br><br>CONCLUSIONS: Few interventions have any statistically significant effect on IPF and a lack of studies on palliative care approaches was identified. Research is required into the effects of symptom control interventions, in particular pulmonary rehabilitation and thalidomide. Other research priorities include a well-conducted randomised controlled trial on inhaled NAC therapy and an updated evidence synthesis once the results of ongoing studies are reported.<br><br>STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002116.<br><br>FUNDING: The National Institute for Health Research Health Technology Assessment programme.}, }
@article {pmid25760137, year = {2015}, author = {Yao, XM and Ye, SD and Xiao, CC and Gu, JF and Yang, D and Wang, S}, title = {Metformin alleviates high glucose-mediated oxidative stress in rat glomerular mesangial cells by modulation of p38 mitogen-activated protein kinase expression in vitro.}, journal = {Molecular medicine reports}, volume = {12}, number = {1}, pages = {520-526}, doi = {10.3892/mmr.2015.3446}, pmid = {25760137}, issn = {1791-3004}, mesh = {Animals ; Diabetic Nephropathies/*drug therapy/genetics/pathology ; Gene Expression Regulation/drug effects ; Glucose/pharmacology ; Mesangial Cells/metabolism/pathology ; Metformin/*administration &amp; dosage ; Oxidative Stress/*drug effects ; Rats ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/*biosynthesis/metabolism ; }, abstract = {The aim of the current study was to investigate the effects and mechanism of metformin in oxidative stress and p38 mitogen-activated protein kinase (p38MAPK) expression in rat glomerular mesangial cells (MCs) cultured in a high glucose medium. Rat glomerular MCs (HBZY-1) were cultured in complete medium and divided into the following five groups: Normal control (NC), high glucose (HG), metformin-treated, SB203580-treated (SB) and N-acetylcysteine-treated (NAC). The production of intracellular reactive oxygen species (ROS) in rat glomerular MCs was measured using flow cytometry. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in the supernatant was detected using colorimetric analysis and an ELISA, respectively. p22phox mRNA levels in rat glomerular MCs were determined using reverse transcription-quantitative polymerase chain reaction. The levels of p22phox protein and phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK) protein in rat glomerular MCs were determined by western blot analysis. Compared with the NC group, the activity of SOD in the supernatant was significantly reduced, whereas the levels of MDA in the supernatant, intracellular p22phox mRNA and protein, p-p38MAPK protein in addition to ROS production in rat glomerular MCs were significantly increased in the HG group (P<0.05). When metformin was added to the high glucose medium, the activity of SOD in supernatant fluid was increased significantly, whereas a significant reduction (P<0.05) was observed in the levels of MDA in the supernatant, intracellular p22phox mRNA and protein, p-p38MAPK protein in addition to ROS production in rat glomerular MCs. These results were similar to those obtained when SB203580 or N-acetylcysteine was added to the high glucose medium (P<0.05). In conclusion, metformin was suggested to alleviate high glucose-induced oxidative stress and p-p38MAPK protein expression in rat glomerular MCs, which may contribute to its reno‑protective abilities in diabetes.}, }
@article {pmid25759554, year = {2015}, author = {Mudalel, ML and Dave, KP and Hummel, JP and Solga, SF}, title = {N-acetylcysteine treats intravenous amiodarone induced liver injury.}, journal = {World journal of gastroenterology}, volume = {21}, number = {9}, pages = {2816-2819}, pmid = {25759554}, issn = {2219-2840}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Amiodarone/administration &amp; dosage/*adverse effects ; Anti-Arrhythmia Agents/administration &amp; dosage/*adverse effects ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/blood/diagnosis/*drug therapy/etiology ; Fatal Outcome ; Female ; Humans ; Infusions, Intravenous ; Injections, Intravenous ; Liver/*drug effects/metabolism/pathology ; Liver Function Tests ; Oxidative Stress/drug effects ; Time Factors ; Treatment Outcome ; }, abstract = {We report a case of intravenous (IV) amiodarone drug induced liver injury (DILI). The patient received IV N-acetylcysteine (NAC) which resulted in a rapid improvement in liver enzymes. While the specific mechanisms for the pathogenesis of IV amiodarone DILI and the therapeutic action of IV NAC are both unknown, this case strongly implies at least some commonality. Because IV amiodarone is indicated for the treatment of serious cardiac arrhythmias in an intensive care unit setting, some degree of ischemic hepatitis is likely a cofactor in most cases.}, }
@article {pmid25756909, year = {2015}, author = {Maggioni, D and Monfrini, M and Ravasi, M and Tredici, G and Scuteri, A}, title = {Neurobasal medium toxicity on mature cortical neurons.}, journal = {Neuroreport}, volume = {26}, number = {6}, pages = {320-324}, doi = {10.1097/WNR.0000000000000343}, pmid = {25756909}, issn = {1473-558X}, mesh = {Animals ; Cell Survival/drug effects ; Cerebral Cortex/*drug effects ; Culture Media, Conditioned/*toxicity ; Cysteine/analogs &amp; derivatives/toxicity ; Glycine/analogs &amp; derivatives/toxicity ; Neurons/*drug effects ; Primary Cell Culture/*methods ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; }, abstract = {Neurobasal medium (NBM) is a widely used medium for neuronal cultures, originally formulated to support survival of rat hippocampal neurons, but then optimized for several other neuronal subtypes. In the present study, the toxic effect of NBM on long-term cortical neuron cultures has been reported and investigated. A significant neuronal cell loss was observed 24 h after the total medium change performed at days in vitro 10. The neurotoxic effect was specifically because of NBM-A, a commercially derived modification of classic NBM, as neurons exposed to minimum essential medium for 24 h did not show the same mortality rate. We showed that the toxic effect was mediated by the N-methyl-D-aspartate receptor (NMDAr) as its inactivation partly prevented NBM-induced neuronal loss, and the addition of NMDAr activators, such as L-cysteine or glycine to minimum essential medium, reproduced the same toxicity rate observed in NBM. Besides the toxicity associated with NMDAr activation, the decreased antioxidative defenses also worsen (because of glutathione depletion) neuronal death, thus amplifying the effect of excitotoxic amino acids. Indeed, glutathione supplementation by the addition of its precursor N-acetyl-cysteine resulted in an increase in neuronal survival that partially prevented NBM-A toxicity. These results evidenced, on the one hand, the unsuitability of NBM-A for long-term neuronal culture, and on the other, they highlight the importance of selection of more suitable culture conditions.}, }
@article {pmid25754379, year = {2015}, author = {Gao, X and Zhang, X and Wang, Y and Wang, Y and Peng, S and Fan, C}, title = {An in vitro study on the cytotoxicity of bismuth oxychloride nanosheets in human HaCaT keratinocytes.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {80}, number = {}, pages = {52-61}, doi = {10.1016/j.fct.2015.02.018}, pmid = {25754379}, issn = {1873-6351}, mesh = {Bismuth/administration &amp; dosage/*toxicity ; Cell Line ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Humans ; Keratinocytes/*drug effects/ultrastructure ; Nanostructures/chemistry/*toxicity ; }, abstract = {As an emerging nanomaterial, bismuth oxychloride (BiOCl) has attracted explosive interests in diverse areas. However, how it interfaces with biological systems, particularly its interaction with human cells and the resulting effects are completely unknown. In this paper, the cytotoxicity of BiOCl nanosheets (NSs) was investigated toward a human skin derived cell line (HaCaT). It was found that BiOCl-NSs had no cytotoxicity at low concentrations (<0.5 µg/mL), whereas higher concentrations (5-100 µg/mL) of BiOCl-NSs could trigger toxic effects on HaCaT cells, with changes in cell morphology and impairment of intracellular structures (mitochondria and cytoskeleton). BiOCl-NSs also led to cell apoptosis and cells cycle arrest in G0/G1 phase. Flow cytometric data showed that BiOCl-NSs were effectively incorporated into HaCaT cells. Transmission electron microscope (TEM) images further revealed that BiOCl-NSs sequestered in the lysosomes, mitochondria, nuclei, and vesicles. Results of DCFH-DA assay and nutritional antioxidant N-acetylcysteine (NAC) experiments suggested that an oxidative stress mechanism was involved in the cytotoxic effects of BiOCl-NSs. Taken together, this work represents the first study on the behavior of BiOCl-NSs on human cells, and constitutes the first and essential step for the risk assessment of BiOCl nanomaterials.}, }
@article {pmid25753204, year = {2015}, author = {Ding, H and Wang, T and Xu, D and Cha, B and Liu, J and Li, Y}, title = {Dexamethasone-induced apoptosis of osteocytic and osteoblastic cells is mediated by TAK1 activation.}, journal = {Biochemical and biophysical research communications}, volume = {460}, number = {2}, pages = {157-163}, doi = {10.1016/j.bbrc.2015.02.161}, pmid = {25753204}, issn = {1090-2104}, mesh = {Apoptosis/*drug effects ; Cell Line ; Dexamethasone/*pharmacology ; Enzyme Activation ; Humans ; MAP Kinase Kinase Kinases/antagonists &amp; inhibitors/*metabolism ; Osteoblasts/cytology/*drug effects ; Osteocytes/cytology/*drug effects ; Protein Kinase Inhibitors/pharmacology ; }, abstract = {Increased apoptosis of osteoblasts and osteocytes is the main mechanism of glucocorticoid (GC)-induced osteonecrosis. In the current study, we investigated whether dexamethasone (Dex)-induced osteoblastic and osteocytic cell apoptosis is mediated through activation of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1), and whether TAK1 inhibition could promote survival opposing the deleterious effects of Dex. We found that TAK1 was activated by Dex in both osteocytic MLO-Y4 and osteoblastic OB-6 cells, which was prevented by two known anti-oxidants N-acetylcysteine (NAC) and ebselen. TAK1 inhibitors, including LYTAK1 and 5Z-7-oxozeaenol (57-OZ), inhibited Dex-induced apoptosis of MLO-Y4 and OB-6 cells. Meanwhile shRNA-mediated knockdown of TAK1 also suppressed Dex-induced damages to MLO-Y4 and OB-6 cells. On the other hand, exogenously over-expressing TAK1 enhanced Dex-induced MLO-Y4 and OB-6 cell apoptosis. At the molecular level, we found that TAK1 mediated Dex-induced pro-apoptotic Pyk2-JNK activation. Inhibition or silencing of TAK1 almost abolished Pyk2-JNK phosphorylations by Dex in MLO-Y4 and OB-6 cells. TAK1 over-expression, on the other hand, increased Dex's activity on Pyk2-JNK phosphorylations in above cells. We conclude that part of the pro-apoptotic actions of Dex on osteoblastic and osteocytic cells are mediated through TAK1 activation, and that inhibition of TAK1 might protect from GC-induced damages to osteoblasts and osteocytes.}, }
@article {pmid25752743, year = {2015}, author = {Graudins, A}, title = {Paracetamol poisoning in adolescents in an Australian setting: not quite adults.}, journal = {Emergency medicine Australasia : EMA}, volume = {27}, number = {2}, pages = {139-144}, doi = {10.1111/1742-6723.12373}, pmid = {25752743}, issn = {1742-6723}, mesh = {Acetaminophen/*poisoning ; Adolescent ; Adult ; Alcohol Drinking/epidemiology ; Analgesics, Non-Narcotic/*poisoning ; Drug Overdose ; Female ; Humans ; Length of Stay ; Male ; Young Adult ; }, abstract = {OBJECTIVE: To describe and compare the characteristics of paracetamol poisoning in adolescent and adult patients.<br><br>METHOD: Descriptive retrospective case series of adolescent (12-17 years) and adult (>18 years) patients presenting to a metropolitan hospital network ED, diagnosed with paracetamol poisoning from October 2009 to September 2013.<br><br>RESULTS: There were 220 adolescent (median age 16 years, 47% treated with acetylcysteine [NAC]) and 647 adult presentations (median age 27 years, 42% treated with NAC) for paracetamol poisoning in the study period. Adolescent patients were more frequently women (89% vs 76%; odds ratio [OR] 2.4; 95% confidence interval [CI] 1.5-3.8) and ingested similar amounts of paracetamol (18&#x2009;g) when requiring NAC treatment. Adolescents were more likely to ingest paracetamol as a single agent (53% vs 34%; OR 2.2; 95% CI 1.6-3.0) and less likely to ingest compound paracetamol products than adults (18% vs 29%; OR 0.54; 95% CI 0.36-0.79). Adolescents were less likely to report accidental supratherapeutic ingestion of paracetamol (0.02% vs 10%; OR 0.23; 95% CI 0.09-0.58), or co-ingestion of prescription medications (25% vs 43%; OR 0.4; 95% CI 0.31-0.62). Adolescents had more frequent histamine release reactions to NAC than adults (17% vs 8%; OR 2.3; 95% CI 1.2-4.5). No cases required liver transplantation or resulted in death.<br><br>CONCLUSION: Adolescents ingested comparable amounts of paracetamol to adults, when presenting with deliberate self-poisoning. However, there were significant differences in co-ingested medications and the reason for ingestion of paracetamol. Histamine reactions to NAC were more common in adolescents; however, most were mild. Overall, outcome was favourable in both cohorts.}, }
@article {pmid25749517, year = {2015}, author = {Hambright, HG and Meng, P and Kumar, AP and Ghosh, R}, title = {Inhibition of PI3K/AKT/mTOR axis disrupts oxidative stress-mediated survival of melanoma cells.}, journal = {Oncotarget}, volume = {6}, number = {9}, pages = {7195-7208}, pmid = {25749517}, issn = {1949-2553}, support = {T32 DE014318/DE/NIDCR NIH HHS/United States ; R01 AT007448/AT/NCCIH NIH HHS/United States ; R21 CA125719/CA/NCI NIH HHS/United States ; 2P30CA054174-17/CA/NCI NIH HHS/United States ; P30 CA046934/CA/NCI NIH HHS/United States ; 1R21CA125719/CA/NCI NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; UL1 TR001120/TR/NCATS NIH HHS/United States ; R01 CA149516/CA/NCI NIH HHS/United States ; TL1 TR001119/TR/NCATS NIH HHS/United States ; }, mesh = {Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Cell Separation ; Cell Survival ; Flow Cytometry ; Glutathione/metabolism ; Homeostasis ; Humans ; Melanocytes/metabolism ; Melanoma/*metabolism ; Membrane Potential, Mitochondrial ; *Oxidative Stress ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation ; Plant Extracts/chemistry ; Proto-Oncogene Proteins c-akt/*metabolism ; RNA Interference ; Reactive Oxygen Species/metabolism ; Skin Neoplasms/*metabolism ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Elevated oxidative stress in cancer cells contributes to hyperactive proliferation and enhanced survival, which can be exploited using agents that increase reactive oxygen species (ROS) beyond a threshold level. Here we show that melanoma cells exhibit an oxidative stress phenotype compared with normal melanocytes, as evidenced by increased total cellular ROS, KEAP1/NRF2 pathway activity, protein damage, and elevated oxidized glutathione. Our overall objective was to test whether augmenting this high oxidative stress level in melanoma cells would inhibit their dependence on oncogenic PI3K/AKT/mTOR-mediated survival. We report that NexrutineR augmented the constitutively elevated oxidative stress markers in melanoma cells, which was abrogated by N-acetyl cysteine (NAC) pre-treatment. NexrutineR disrupted growth homeostasis by inhibiting proliferation, survival, and colony formation in melanoma cells without affecting melanocyte cell viability. Increased oxidative stress in melanoma cells inhibited PI3K/AKT/mTOR pathway through disruption of mTORC1 formation and phosphorylation of downstream targets p70S6K, 4EBP1 and rpS6. NAC pre-treatment reversed inhibition of mTORC1 targets, demonstrating a ROS-dependent mechanism. Overall, our results illustrate the importance of disruption of the intrinsically high oxidative stress in melanoma cells to selectively inhibit their survival mediated by PI3K/AKT/mTOR.}, }
@article {pmid25747728, year = {2015}, author = {Schneider, D and Hernández, C and Farías, M and Uauy, R and Krause, BJ and Casanello, P}, title = {Oxidative stress as common trait of endothelial dysfunction in chorionic arteries from fetuses with IUGR and LGA.}, journal = {Placenta}, volume = {36}, number = {5}, pages = {552-558}, doi = {10.1016/j.placenta.2015.02.003}, pmid = {25747728}, issn = {1532-3102}, mesh = {Adult ; Antioxidants/metabolism ; Arteries/metabolism/*physiopathology ; Case-Control Studies ; Endothelium, Vascular/*physiopathology ; Female ; Fetal Growth Retardation/*physiopathology ; Fetal Macrosomia/*physiopathology ; Glutathione Peroxidase/metabolism ; Humans ; In Vitro Techniques ; NADPH Oxidase 4 ; NADPH Oxidases/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Obesity/*physiopathology ; Oxidative Stress ; Placenta/physiopathology ; Pregnancy ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Glutathione Peroxidase GPX1 ; }, abstract = {INTRODUCTION: Fetal macrosomia and intrauterine growth restriction (IUGR) associate with increased morbidity in the neonate. Placental vascular relaxation is impaired in fetal macrosomia, as well as in IUGR, and this could result from increased oxidative stress present in both conditions. We determined the role of pro- and anti-oxidants on NOS dependent relaxation in placental chorionic arteries from pregnancies with LGA babies from overweight and/or obese mothers (LOOM) and IUGR fetuses from normal BMI women.<br><br>METHODS: Chorionic arteries were mounted in a wire-myograph, where responses to the NOS-dependent agent CGRP in presence or absence of the antioxidant N-acetyl cysteine (NAC), the pro-oxidant SIN-1, the SOD inhibitor DDC, and the GPx inhibitor MS were determined. Additionally the presence of pro- and antioxidant enzymes (NOX-4, SOD-1, SOD-2 and GPx-1) and eNOS in chorionic and umbilical vessels were addressed by immunohistochemistry.<br><br>RESULTS: Maximal CGRP-induced relaxation was comparable to controls but presented a reduced potency in chorionic arteries from LOOM placentae, whilst in IUGR vessels both maximal response and potency were reduced. NAC increased maximal relaxation in controls, IUGR and LOOM arteries, whilst SIN-1 completely abolished the CGRP-induced relaxation only in IUGR and LOOM samples, the later effect was paralleled by SOD or GPx inhibition. These responses associated with the presence of NOX-4, SOD-1 and GPx-1 in the endothelium and vascular wall of chorionic and umbilical arteries in the different groups studied.<br><br>DISCUSSION: These data suggest that NOS dependent relaxation in placental vessels from IUGR and LOOM pregnancies present a higher sensitivity to oxidative stress.}, }
@article {pmid25747710, year = {2015}, author = {Hua, P and Sun, M and Zhang, G and Zhang, Y and Tian, X and Li, X and Cui, R and Zhang, X}, title = {Cepharanthine induces apoptosis through reactive oxygen species and mitochondrial dysfunction in human non-small-cell lung cancer cells.}, journal = {Biochemical and biophysical research communications}, volume = {460}, number = {2}, pages = {136-142}, doi = {10.1016/j.bbrc.2015.02.131}, pmid = {25747710}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Benzylisoquinolines/*pharmacology ; Carcinoma, Non-Small-Cell Lung/metabolism/*pathology/physiopathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; Lung Neoplasms/metabolism/*pathology/physiopathology ; Membrane Potential, Mitochondrial/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cepharanthine is a medicinal plant-derived natural compound which possesses potent anti-cancer properties. However, there is little report about its effects on lung cancer cells. In this study, we investigated the effects of cepharanthine on the cell viability and apoptosis in human non-small-cell lung cancer H1299 and A549 cells. It was found that cepharanthine inhibited the growth of H1299 and A549 cells in a dose-dependent manner which was associated with the generation of reactive oxygen species(ROS) and the dissipation of mitochondrial membrane potential (Δψm). These effects were markedly abrogated when cells were pretreated with N-acetylcysteine (NAC), a specific ROS inhibitor, indicating that the apoptosis-inducing effect of cepharanthine in lung cancer cells was mediated by ROS. In addition, cepharanthine triggered apoptosis in non-small lung cancer cells via the upregulation of Bax, downregulation of Bcl-2 and significant activation of caspase-3 and PARP. These results provide the rationale for further research and preclinical investigation of cepharanthine's anti-tumor effect against human non-small-cell lung cancer.}, }
@article {pmid25746829, year = {2015}, author = {Sharma, S and Raghuvanshi, S and Jaswal, A and Shrivastava, S and Shukla, S}, title = {Lead acetate-induced hepatoxicity in Wistar rats: possible protective role of combination therapy.}, journal = {Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer}, volume = {34}, number = {1}, pages = {23-34}, doi = {10.1615/jenvironpatholtoxicoloncol.2015012006}, pmid = {25746829}, issn = {2162-6537}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adenosine Triphosphatases/metabolism ; Animals ; DNA Damage ; Drug Therapy, Combination ; Lipid Peroxidation/drug effects ; Liver/*drug effects/metabolism/pathology/ultrastructure ; Male ; Organometallic Compounds/*toxicity ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Selenium/administration &amp; dosage/*pharmacology ; }, abstract = {Experimental studies have shown that sulphur-containing antioxidants have beneficial effects against the detrimental properties of Pb. In the present study, we investigated the therapeutic potential of combined administration of N-acetyl cysteine (NAC; 50 mg/kg p.o.) and selenium (Se; 0.5 mg/kg p.o.) against lead acetate intoxication (Pb; 0.2% in water ad libitum) in a male rat model for 12 wk. The exposure of rats to lead acetate produced significant (P < 0.05) alterations in cytochrome P450 (CYP) activity, microsomal lipid peroxidation, reduced glutathione, and proteins. In addition, significant elevation in liver markers transaminases, triglycerides, cholesterol, and bilirubin as well as a decline in albumin were also compared with the experimental control rats. Combined treatment of lead-exposed animals with NAC and Se showed marked improvement of the biochemical, molecular, and histopathological findings. These experimental results strongly indicate the protective effect of NAC alone with Se against toxic effects of lead on liver tissue.}, }
@article {pmid25744598, year = {2015}, author = {Tormos, AM and Taléns-Visconti, R and Bonora-Centelles, A and Pérez, S and Sastre, J}, title = {Oxidative stress triggers cytokinesis failure in hepatocytes upon isolation.}, journal = {Free radical research}, volume = {49}, number = {8}, pages = {927-934}, doi = {10.3109/10715762.2015.1016019}, pmid = {25744598}, issn = {1029-2470}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Cycle Proteins/genetics/metabolism ; Cell Separation ; Cells, Cultured ; *Cytokinesis ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Gene Expression ; Hepatocytes/drug effects/*physiology ; Male ; Mice, Inbred C57BL ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Primary hepatocytes are highly differentiated cells and proliferatively quiescent. However, the stress produced during liver digestion seems to activate cell cycle entry by proliferative/dedifferentiation programs that still remain unclear. The aim of this work was to assess whether the oxidative stress associated with hepatocyte isolation affects cell cycle and particularly cytokinesis, the final step of mitosis. Hepatocytes were isolated from C57BL/6 mice by collagenase perfusion in the absence and presence of N-acetyl cysteine (NAC). Polyploidy, cell cycle, and reactive oxygen species (ROS) were studied by flow cytometry (DNA, phospho-histone 3, and CellROX(®) Deep Red) and Western blotting (cyclins B1 and D1, and proliferating cell nuclear antigen). mRNA expression of cyclins A1, B1, B2, D1, and F by reverse transcription (RT)-PCR was also assessed. Glutathione levels were measured by mass spectrometry. Here we show that hepatocyte isolation enhanced cell cycle entry, increased hepatocyte binucleation, and caused marked glutathione oxidation. Addition of 5 mM NAC to the hepatocyte isolation media prevented glutathione depletion, partially blocked ROS production and cell cycle entry of hepatocytes, and avoided the blockade of mitosis progression, abrogating defective cytokinesis and diminishing the formation of binucleated hepatocytes during isolation. Therefore, addition of NAC to the isolation media decreased the generation of polyploid hepatocytes confirming that oxidative stress occurs during hepatocyte isolation and it is responsible, at least in part, for cytokinesis failure and hepatocyte binucleation.}, }
@article {pmid25741219, year = {2015}, author = {Xu, H and Li, X and Ding, W and Zeng, X and Kong, H and Wang, H and Xie, W}, title = {Deguelin induces the apoptosis of lung cancer cells through regulating a ROS driven Akt pathway.}, journal = {Cancer cell international}, volume = {15}, number = {}, pages = {25}, pmid = {25741219}, issn = {1475-2867}, abstract = {BACKGROUND: Duguelin is a rotenoid extracted from plants and has potent antitumor effects in vitro and in vivo. However, the mechanism underlying the antitumor effect remains unclear. Our preliminary study showed that Deguelin is effective to stimulate the generation of Reactive Oxygen Species (ROS). In the current study, we evaluated the in vitro cytotoxicity of Deguelin against lung cancer cells and studied whether a ROS scavenger, N-acetyl-cysteine (NAC), can reverse the inhibitory effect of Deguelin.<br><br>RESULTS: We showed that the dose-dependent apoptotic inducing effect of Deguelin could be partially reversed by the co-administration of NAC. Moreover, Deguelin reduced the phosphorylation of Akt protein and induced the apoptotic protein Caspase-3 in a dose-dependent manner. Co-treatment with NAC partially attenuated this effect and rescued some cells from apoptosis.<br><br>CONCLUSION: Deguelin induces the apoptosis of cancer cells through a ROS driven Akt pathway, which could translate into a promising therapeutic for lung cancer.}, }
@article {pmid25740810, year = {2015}, author = {Billard, JM}, title = {D-Serine in the aging hippocampus.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {116}, number = {}, pages = {18-24}, doi = {10.1016/j.jpba.2015.02.013}, pmid = {25740810}, issn = {1873-264X}, mesh = {Aging/*metabolism/pathology ; Animals ; Hippocampus/*metabolism/pathology ; Humans ; Memory/physiology ; Oxidative Stress/physiology ; Receptors, N-Methyl-D-Aspartate/metabolism ; Serine/chemistry/*metabolism ; Stereoisomerism ; }, abstract = {Experimental evidences now indicate that memory formation relies on the capacity of neuronal networks to manage long-term changes in synaptic communication. This property is driven by N-methyl-D-aspartate receptors (NMDAR), which requires the binding of glutamate but also the presence of the co-agonist D-serine at the glycine site. Defective memory function and impaired brain synaptic plasticity observed in aging are rescued by partial agonist acting at this site suggesting that this gating process is targeted to induce age-related cognitive defects. This review aims at compelling recent studies characterizing the role of D-serine in changes in functional plasticity that occur in the aging hippocampus since deficits are rescued by D-serine supplementation. The impaired efficacy of endogenous D-serine is not due to changes in the affinity to glycine-binding site but to a decrease in tissue levels of the amino acid resulting from a weaker expression of the producing enzyme serine racemase (SR). Interestingly, neither SR expression, D-serine levels, nor NMDAR activation is affected in aged LOU/C rats, a model of healthy aging in which memory deficits do not occur. These old animals do not develop oxidative stress suggesting that the D-serine-related pathway could be targeted by the age-related accumulation of reactive oxygen species. Accordingly, senescent rats chronically treated with the reducing agent N-acetyl-cysteine to prevent oxidative damage, show intact NMDAR activation linked to preserved D-serine levels and SR expression. These results point to a significant role of D-serine in age-related functional alterations underlying hippocampus-dependent memory deficits, at least within the CA1 area since the amino acid does not appear as critical in changes affecting the dentate gyrus.}, }
@article {pmid25739837, year = {2015}, author = {Silva, E and Greene, AF and Strauss, K and Herrick, JR and Schoolcraft, WB and Krisher, RL}, title = {Antioxidant supplementation during in vitro culture improves mitochondrial function and development of embryos from aged female mice.}, journal = {Reproduction, fertility, and development}, volume = {27}, number = {6}, pages = {975-983}, doi = {10.1071/RD14474}, pmid = {25739837}, issn = {1448-5990}, mesh = {Acetylcysteine/pharmacology ; Age Factors ; Animals ; Antioxidants/*pharmacology ; Embryo Culture Techniques ; Embryonic Development/*drug effects/physiology ; Female ; Gene Expression/drug effects ; Mice ; Mitochondria/*drug effects/metabolism ; Oxidative Stress/drug effects ; Sirtuins/pharmacology ; Taurine/analogs &amp; derivatives/pharmacology ; Thioctic Acid/pharmacology ; alpha-Tocopherol/pharmacology ; }, abstract = {Maternal aging results in reduced oocyte and blastocyst quality, thought to be due, in part, to mitochondrial dysfunction and accumulation of reactive oxygen species. To reduce oxidative stress, the antioxidants α-lipoic acid (ALA; 10µM), α-tocopherol (250µM), hypotaurine (1mM) and N-acetylcysteine (NAC; 1mM), and sirtuin (100ngmL(-1)) were added to embryo culture medium (AntiOX) and compared with a control (CON) without antioxidants to assess blastocyst development after in vitro maturation and fertilisation of oocytes from aged B6D2F1 female mice (13.5 months). Development to the blastocyst stage increased in the AntiOX compared with CON group (87.6% vs 72.7%, respectively; P<0.01), in addition to higher mitochondrial membrane potential and ATP levels in the AntiOX group. Expression of genes associated with oxidative stress (PI3K, FOXO3A and GLRX2) was upregulated in the CON compared with AntiOX group. In addition to AntiOX, a medium containing only NAC and ALA (rAntiOX) was used to culture embryos from young CF1 females (6-8 weeks). More blastocysts developed in the rAntiOX compared with CON group (64.1% vs 43.3%, respectively; P<0.01), although AntiOX (48.0% blastocysts) did not result in improved development in young mice. Antioxidants improved mitochondrial activity, gene expression and development in embryos of older female mice, whereas a reduced level of antioxidants during culture was beneficial to embryos from young mice.}, }
@article {pmid25738883, year = {2015}, author = {Guo, J and Li, Y and Chen, Z and He, Z and Zhang, B and Li, Y and Hu, J and Han, M and Xu, Y and Li, Y}, title = {N-acetylcysteine treatment following spinal cord trauma reduces neural tissue damage and improves locomotor function in mice.}, journal = {Molecular medicine reports}, volume = {12}, number = {1}, pages = {37-44}, pmid = {25738883}, issn = {1791-3004}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Disease Models, Animal ; Humans ; Mice ; Motor Activity/*drug effects ; Neurons/drug effects/metabolism ; Neuroprotective Agents/*administration &amp; dosage ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Recovery of Function/drug effects ; Spinal Cord Injuries/*drug therapy/metabolism/physiopathology ; }, abstract = {Following spinal cord trauma, mitochondrial dysfunction associated with increased oxidative stress is a critical event leading to leukocyte inflammatory responses, neuronal cell death and demyelination, contributing to permanent locomotor and neurological disability. The present study demonstrated that the mitochondrial enhancer N-acetylcysteine (NAC) may restore redox balance via enhancement of mitochondrial respiratory activity following traumatic spinal cord injury (SCI). In addition, NAC ameliorates oxidative stress-induced neuronal loss, demyelination, leukocyte infiltration and inflammatory mediator expression and improves long-term locomotor function. Furthermore, neuronal survival and neurological recovery are significantly correlated with increased mitochondrial bioenergetics in SCI following treatment with NAC. Therefore, NAC may represent a potential therapeutic agent for preserving mitochondrial dynamics and integrity following traumatic SCI.}, }
@article {pmid25738249, year = {2015}, author = {Hwang, KE and Kim, YS and Hwang, YR and Kwon, SJ and Park, DS and Cha, BK and Kim, BR and Yoon, KH and Jeong, ET and Kim, HR}, title = {Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1.}, journal = {Oncology reports}, volume = {33}, number = {5}, pages = {2411-2419}, doi = {10.3892/or.2015.3830}, pmid = {25738249}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Non-Small-Cell Lung/*genetics/metabolism ; Cell Line, Tumor ; Cytochromes c/drug effects/metabolism ; Down-Regulation ; Free Radical Scavengers/pharmacology ; Humans ; Lung Neoplasms/*genetics/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mesothelioma/*genetics/metabolism ; Mesothelioma, Malignant ; Mitochondria/drug effects/metabolism ; Pemetrexed/*pharmacology ; Reactive Oxygen Species/*metabolism ; Sirtuin 1/*drug effects/genetics/metabolism ; }, abstract = {Pemetrexed is a multitargeted antifolate used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). However, the mechanism by which pemetrexed induces apoptosis remains unclear. In the present study, we investigated the involvement of reactive oxygen species (ROS) and sirtuin 1 (SIRT1) in pemetrexed-induced apoptosis in MSTO-211 malignant mesothelioma cells and A549 NSCLC cells. Pemetrexed enhanced caspase-dependent apoptosis, induced intracellular ROS generation, and downregulated SIRT1 in the MSTO-211 and A549 cells. Pemetrexed-induced apoptosis, which was prevented by pretreatment with N-acetyl-cysteine (NAC), was mediated by effects on the mitochondria, including mitochondrial membrane potential transition (MPT) and cytosolic release of cytochrome c, and also involved regulation of SIRT1 expression. Interference with SIRT1 expression using siRNA enhanced pemetrexed-induced apoptosis through mitochondrial dysfunction and ROS generation, whereas resveratrol, an activator of SIRT1, protected against pemetrexed-induced apoptosis. These results show that pemetrexed induces apoptosis in MSTO-211 mesothelioma cells and A549 NSCLC cells through mitochondrial dysfunction mediated by ROS accumulation and SIRT1 downregulation.}, }
@article {pmid25738016, year = {2015}, author = {Bhat, S and Kenchetty, KP}, title = {N-acetyl cysteine in the management of rodenticide consumption - life saving?.}, journal = {Journal of clinical and diagnostic research : JCDR}, volume = {9}, number = {1}, pages = {OC10-3}, pmid = {25738016}, issn = {2249-782X}, abstract = {BACKGROUND AND AIM OF STUDY: Rodenticide is a commonly ingested poison in India. Many rodenticides contain hepatotoxic agents and can cause acute liver failure (ALF). There is no antidote for rodenticide poison, and consumption is often fatal. The Role of N acetyl cysteine (NAC) in acetaminophen induced ALF is well established. Additionally some studies have shown that it may be useful in non-acetaminophen induced ALF also. Cases with ALF secondary to suicidal rodenticide consumption have been reported, and some reports show that NAC is beneficial in these cases. Our study was a retrospective analysis of patients admitted with rodenticide consumption, comparing outcomes in those receiving standard of care management and those who were treated with NAC also.<br><br>MATERIALS AND METHODS: Case sheets of all inpatients of a tertiary medical college hospital between January 2010 and December 2012 admitted with an alleged history of rodenticide consumption were surveyed and data was extracted and analysed.<br><br>STATISTICAL ANALYSIS: Patients were analysed with respect to age, sex, mode of presentation, interval between consumption of rodenticide and starting NAC; the outcome in patients treated with acetylcysteine was compared to outcomes in those not treated with acetylcysteine<br><br>RESULTS: A total of 100 patients were studied out of which 18 died. Sixteen of the deaths were in patients who had not been treated with NAC. We found that patients who had received NAC had lower mortality, lower peak values of AST/ALT, and shorter hospital stay.<br><br>CONCLUSION: NAC may have a role in the management of ALF associated with rodenticide consumption.}, }
@article {pmid25732608, year = {2015}, author = {Hu, J and Zhang, Q and Ren, X and Sun, Z and Quan, Q}, title = {Efficacy and safety of acetylcysteine in "non-acetaminophen" acute liver failure: A meta-analysis of prospective clinical trials.}, journal = {Clinics and research in hepatology and gastroenterology}, volume = {39}, number = {5}, pages = {594-599}, doi = {10.1016/j.clinre.2015.01.003}, pmid = {25732608}, issn = {2210-741X}, mesh = {Acetaminophen/adverse effects ; Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Clinical Trials as Topic ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Infusions, Intravenous ; Liver Failure, Acute/*drug therapy/mortality ; Prospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: Acute liver failure (ALF) is a rare but highly mortal condition without liver transplantation (LT). N-acetylcysteine (NAC), a glutathione precursor that detoxifies the reactive metabolite of acetaminophen and replenishes hepatic glutathione stores, is a highly effective drug for the prevention of ALF caused by acetaminophen. However, therapeutic use of NAC in non-acetaminophen-induced ALF (NAI-ALF) including alcohol intoxication, hepatitis virus infection, or drug and toxin-related hepatotoxicity is still inconclusive. The aim of this article is using meta-analysis method to analyze recent prospective clinical trials for the safety and efficacy of NAC in patients with ALF not caused by acetaminophen poisoning.<br><br>METHODS: Prospective clinical trials comparing efficacy and safety between NAC and control in the treatment of NAI-ALF were identified by searching Pubmed (2000-2014) and EMBASE (2000-2014) using the search terms acetylcysteine or NAC and NAI-ALF. The primary outcome was overall survival. Secondary outcomes included liver transplantation-free survival, post transplantation survival, length of ICU and hospital stays, and the relationship with coma grade. The safety profiles were also analyzed.<br><br>RESULTS: Four clinical trials were selected for meta-analysis. A total of 331 patients receiving treatment with NAC (oral or intravenously) and 285 patients in control group were included for meta-analysis. No statistical difference was identified between NAC group and control group for overall survival [236/331 (71%) vs 191/285 (67%); 95% CI 1.16 (0.81-1.67); P=0.42]. However, there were significant differences between NAC group and control group regarding the survival with native liver [112/273 (41%) vs 68/226 (30%); 95% CI 1.61 (1.11-2.34); P=0.01] and post-transplantation survival [78/91 (85.7%) vs 50/70 (71.4%); 95% CI 2.44 (1.11-5.37); P=0.03]. The identified side effects of NAC included nausea, vomiting, and diarrhea or constipation. Rarely, it could cause rashes, fever, headache, drowsiness, low blood pressure, and elevated serum transaminase levels in a patient with cystic fibrosis. At the dose used for acetaminophen toxicity, acetylcysteine does not have hepatotoxic effects.<br><br>CONCLUSION: NAC is safe for NAI-ALF. It can prolong patients' survival with native liver without transplantation and survival after transplantation, but it cannot improve the overall survival.}, }
@article {pmid25732260, year = {2015}, author = {Zhang, Y and Shen, GL and Shangguan, LJ and Yu, Y and He, ML}, title = {Involvement of NFκB signaling in mediating the effects of GRK5 on neural stem cells.}, journal = {Brain research}, volume = {1608}, number = {}, pages = {31-39}, doi = {10.1016/j.brainres.2015.02.041}, pmid = {25732260}, issn = {1872-6240}, mesh = {AMP-Activated Protein Kinase Kinases ; Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Drug Interactions ; Embryo, Mammalian ; Enzyme Inhibitors/pharmacology ; G-Protein-Coupled Receptor Kinase 5/genetics/*metabolism ; Gene Expression Regulation/*drug effects ; Hippocampus/cytology ; NF-kappa B/*metabolism ; Neoplasm Proteins/metabolism ; Nestin/metabolism ; Neural Stem Cells/drug effects/*metabolism ; Nucleocytoplasmic Transport Proteins/metabolism ; Protein Serine-Threonine Kinases/metabolism ; RNA, Small Interfering/pharmacology ; Rats ; Signal Transduction/drug effects/*physiology ; Tetradecanoylphorbol Acetate/pharmacology ; }, abstract = {Nuclear factor κB (NFκB) signaling plays ubiquitous roles in inflammation, immune response and neurogenesis. G protein-coupled receptor kinase 5 (GRK5) can protect neurons from degeneration. GRK5 also mediates tumor necrosis factor-α (TNFα)-induced NFκB signaling through the phosphorylation of IκBα. Here, we show that NFκB signaling is involved in neural stem cell (NSC) differentiation. The IκBα/p65 pathway was activated by phorbol myristate acetate (PMA), a stimulator of protein kinase C (PKC). Once the NFκB was activated, the initial stage of neural differentiation was induced, with an increased level of GRK5 in NSCs. This finding was reversed in response to the NFκB inhibitor N-acetyl cysteine (NAC). To evaluate the effect of GRK5-NFκB signaling crosstalk on NSC neurogenesis and apoptosis, GRK5 was knocked down by siRNAs in cell culture. SiRNAs against GRK5 not only impaired neural differentiation and axogenesis, but also induced apoptosis of NSC. GRK5 knockdown affected the transcription of NFκB, phosphorylation of the liver kinase B1 (LKB1) and the activity of caspase 3, thereby modulated neurogenesis and apoptosis. Taken together, our findings reveal a novel function of GRK5 in neurogenesis and provide insight into the molecular mechanisms underlying neurodevelopmental disorders and neurodegenerative diseases.}, }
@article {pmid25732255, year = {2015}, author = {She, T and Qu, L and Wang, L and Yang, X and Xu, S and Feng, J and Gao, Y and Zhao, C and Han, Y and Cai, S and Shou, C}, title = {Sarsaparilla (Smilax Glabra Rhizome) Extract Inhibits Cancer Cell Growth by S Phase Arrest, Apoptosis, and Autophagy via Redox-Dependent ERK1/2 Pathway.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {8}, number = {5}, pages = {464-474}, doi = {10.1158/1940-6207.CAPR-14-0372}, pmid = {25732255}, issn = {1940-6215}, mesh = {Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Proliferation/*drug effects ; Down-Regulation/drug effects ; Female ; HT29 Cells ; HeLa Cells ; Hep G2 Cells ; Humans ; MAP Kinase Signaling System/drug effects/physiology ; MCF-7 Cells ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms/*pathology ; Oxidation-Reduction/drug effects ; Plant Extracts/*pharmacology ; Rhizome/chemistry ; S Phase/drug effects ; Smilax/*chemistry ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {Cancer is still the major cause of death across the world. Regular approaches cannot effectively solve the emerging problems, including drug/radiation resistance, side effects, and therapeutic ineffectiveness. Natural dietary supplements have shown effectiveness in the prevention and treatment of cancer. Sarsaparilla (Smilax Glabra Rhizome) has growth-inhibitory effects on several cancer cell lines in vitro and in vivo, with little toxicity on normal cells. However, the mechanism underlying its function remains elusive. In the present study, we examined the anticancer activity of the supernatant of the water-soluble extract (SW) from sarsaparilla. Liquid chromatography/mass spectrometry-ion trap-time-of-flight (LC/MS-IT-TOF) analysis identified flavonoids, alkaloids, and phenylpropanoids as the major bioactive components of SW. SW was shown to markedly inhibit the growth of a broad spectrum of cancer cell lines in the in vitro and in vivo assays. S phase arrest, autophagy, or/and apoptosis were partly responsible for SW-induced growth inhibition. Results of microarray analysis and validation by quantitative RT-PCR indicated the involvement of oxidative stress and the MAPK1 pathway in SW-treated cells. We further found that SW destroyed intracellular-reduced glutathione/oxidized glutathione (GSH/GSSG) balance, and supplement with N-acetylcysteine (NAC) or glutathione (GSH) significantly antagonized SW-induced S phase arrest, apoptosis, and autophagy. In addition, SW-induced GSH/GSSG imbalance activated the ERK1/2 pathway, which contributed to SW-induced S phase arrest, apoptosis, autophagy, and resultant growth-inhibitory effect. Together, our results provide a molecular basis for sarsaparilla as an anticancer agent.}, }
@article {pmid25732239, year = {2015}, author = {Rahimmi, A and Khosrobakhsh, F and Izadpanah, E and Moloudi, MR and Hassanzadeh, K}, title = {N-acetylcysteine prevents rotenone-induced Parkinson's disease in rat: An investigation into the interaction of parkin and Drp1 proteins.}, journal = {Brain research bulletin}, volume = {113}, number = {}, pages = {34-40}, doi = {10.1016/j.brainresbull.2015.02.007}, pmid = {25732239}, issn = {1873-2747}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Corpus Striatum/drug effects/metabolism ; Disease Models, Animal ; Dopamine/metabolism ; Dopaminergic Neurons/metabolism ; Drug Interactions ; Dynamins/*metabolism ; Male ; Oxidative Stress/drug effects ; Parkinsonian Disorders/*chemically induced/metabolism/*prevention &amp; control ; Protein Binding ; Random Allocation ; Rats ; Rats, Wistar ; Rotarod Performance Test ; Rotenone/*antagonists &amp; inhibitors/pharmacology ; Substantia Nigra/drug effects/metabolism ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {There are convincing evidences that oxidative stress has an important role in both the initiation and progression of Parkinson's disease. N-acetylcysteine (NAC) is shown to have antioxidant properties via fortifying glutathione which is one of the main endogenous antioxidant systems. Therefore our study was aimed to evaluate the effect of NAC in management of Parkinson's disease. To this aim, male Wistar rats (10-12 months) received rotenone 2.5mg/kg/48 h intraperitoneally (ip) to induce a Parkinson's disease model. Pretreatment with NAC (25 and 50mg/kg/48 h ip) was administered 1h before the rotenone injection. Three behavioral tests (rotarod, rearing and bar tests) were performed for motor function assessment. Dopamine levels of dopaminergic areas in rat brain including substantia nigra (SN) and striatum (ST) were assessed using high performance liquid chromatography analysis to measure the loss of dopamine. Western blot analysis was also done for parkin and Drp1 (dynamin related protein-1) proteins quantification in SN and ST. Our results indicated that NAC significantly ameliorated the rotenone-induced motor dysfunction and dopamine loss. Furthermore, NAC was able to prevent the rotenone-induced changes in parkin and Drp1 levels in the both studied areas. In conclusion we found that NAC delayed the Parkinson's disease induction by rotenone and this effect might be related to its proved antioxidant effect.}, }
@article {pmid25731901, year = {2016}, author = {Kasperczyk, S and Dobrakowski, M and Kasperczyk, A and Romuk, E and Rykaczewska-Czerwińska, M and Pawlas, N and Birkner, E}, title = {Effect of N-acetylcysteine administration on homocysteine level, oxidative damage to proteins, and levels of iron (Fe) and Fe-related proteins in lead-exposed workers.}, journal = {Toxicology and industrial health}, volume = {32}, number = {9}, pages = {1607-1618}, doi = {10.1177/0748233715571152}, pmid = {25731901}, issn = {1477-0393}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Air Pollutants, Occupational/toxicity ; Anemia, Iron-Deficiency/etiology/*prevention &amp; control ; Antioxidants/administration &amp; dosage/*therapeutic use ; *Dietary Supplements ; Haptoglobins/analysis ; Homocysteine/blood ; Humans ; Hyperhomocysteinemia/etiology/*prevention &amp; control ; Inhalation Exposure/adverse effects ; Iron/blood ; Lead/blood/toxicity ; Lead Poisoning/blood/physiopathology/*prevention &amp; control ; Male ; Middle Aged ; Occupational Diseases/blood/physiopathology/*prevention &amp; control ; Occupational Exposure/adverse effects ; Oxidative Stress/drug effects ; Poland ; Protein Carbonylation ; Protoporphyrins/blood ; Transferrin/analysis ; }, abstract = {N-Acetylcysteine (NAC) could be included in protocols designed for the treatment of lead toxicity. Therefore, in this study, we decided to investigate the influence of NAC administration on homocysteine (Hcy) levels, oxidative damage to proteins, and the levels of iron (Fe), transferrin (TRF), and haptoglobin (HPG) in lead (Pb)-exposed workers. The examined population (n = 171) was composed of male employees who worked with Pb. They were randomized into four groups. Workers who were not administered any antioxidants, drugs, vitamins, or dietary supplements were classified as the reference group (n = 49). The remaining three groups consisted of workers who were treated orally with NAC at three different doses (1 × 200, 2 × 200, or 2 × 400 mg) for 12 weeks. After the treatment, blood Pb levels significantly decreased in the groups receiving NAC compared with the reference group. The protein concentration was not affected by NAC administration. In contrast, Hcy levels significantly decreased or showed a strong tendency toward lower values depending on the NAC dose. Levels of the protein carbonyl groups were significantly decreased in all of the groups receiving NAC. Conversely, glutamate dehydrogenase activity was significantly elevated in all of the groups receiving NAC, while the level of protein thiol groups was significantly elevated only in the group receiving 200 mg of NAC. Treatment with NAC did not significantly affect Fe and TRF levels, whereas HPG levels showed a tendency toward lower values. Treatment with NAC normalized the level of Hcy and decreased oxidative stress as measured by the protein carbonyl content; this effect occurred in a dose-dependent manner. Moreover, small doses of NAC elevated the levels of protein thiol groups. Therefore, NAC could be introduced as an alternative therapy for chronic Pb toxicity in humans.}, }
@article {pmid25729878, year = {2015}, author = {Prado, E and Maes, M and Piccoli, LG and Baracat, M and Barbosa, DS and Franco, O and Dodd, S and Berk, M and Vargas Nunes, SO}, title = {N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study.}, journal = {Redox report : communications in free radical research}, volume = {20}, number = {5}, pages = {215-222}, pmid = {25729878}, issn = {1743-2928}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adolescent ; Adult ; Aged ; Double-Blind Method ; Female ; Glutathione/metabolism ; Humans ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Pilot Projects ; Tobacco Use Disorder/*drug therapy/metabolism ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION: N-Acetylcysteine (NAC) may have efficacy in treating tobacco use disorder (TUD) by reducing craving and smoking reward. This study examines whether treatment with NAC may have a clinical efficacy in the treatment of TUD.<br><br>METHODS: A 12-week double blind randomized controlled trial was conducted to compare the clinical efficacy of NAC 3 g/day versus placebo. We recruited 34 outpatients with therapy resistant TUD concurrently treated with smoking-focused group behavioral therapy. Participants had assessments of daily cigarette use (primary outcome), exhaled carbon monoxide (CO(EXH)) (secondary outcome), and quit rates as defined by CO(EXH) < 6 ppm. Depression was measured with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using conventional and modified intention-to-treat endpoint analyses.<br><br>RESULTS: NAC treatment significantly reduced the daily number of cigarettes used (&#x394; mean &#xb1; SD = -10.9 &#xb1; 7.9 in the NAC-treated versus -3.2 &#xb1; 6.1 in the placebo group) and CO(EXH) (&#x394; mean &#xb1; SD = -10.4 &#xb1; 8.6 ppm in the NAC-treated versus -1.5 &#xb1; 4.5 ppm in the placebo group); 47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking as defined by CO(EXH) < 6 ppm. NAC treatment significantly reduced the HDRS score in patients with tobacco use disorder.<br><br>CONCLUSIONS: These data show that treatment with NAC may have a clinical efficacy in TUD. NAC combined with appropriate psychotherapy appears to be an efficient treatment option for TUD.}, }
@article {pmid25729577, year = {2015}, author = {Hall, SR and Blundon, HL and Ladda, MA and Robertson, AW and Martinez-Farina, CF and Jakeman, DL and Goralski, KB}, title = {Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism.}, journal = {Pharmacology research &amp; perspectives}, volume = {3}, number = {2}, pages = {e00110}, pmid = {25729577}, issn = {2052-1707}, abstract = {Jadomycins are natural products biosynthesized by the bacteria Streptomyces venezuelae which kill drug-sensitive and multidrug-resistant breast cancer cells in culture. Currently, the mechanisms of jadomycin cytotoxicity are poorly understood; however, reactive oxygen species (ROS)-induced DNA cleavage is suggested based on bacterial plasmid DNA cleavage studies. The objective of this study was to determine if and how ROS contribute to jadomycin cytotoxicity in drug-sensitive MCF7 (MCF7-CON) and taxol-resistant MCF7 (MCF7-TXL) breast cancer cells. As determined using an intracellular, fluorescent, ROS-detecting probe, jadomycins B, S, SPhG, and F dose dependently increased intracellular ROS activity 2.5- to 5.9-fold. Cotreatment with the antioxidant N-acetyl cysteine lowered ROS concentrations to below baseline levels and decreased the corresponding cytotoxic potency of the four jadomycins 1.9- to 3.3-fold, confirming a ROS-mediated mechanism. Addition of CuSO4 enhanced, whereas addition of the Cu(II)-chelator d-penicillamine reduced, the ROS generation and cytotoxicity of each jadomycin. Specific inhibitors of the antioxidant enzymes, superoxide dismutase 1, glutathione S-transferase, and thioredoxin reductase, but not catalase, enhanced jadomycin-mediated ROS generation and anticancer activity. In conclusion, the results indicate that jadomycin cytotoxicity involves the generation of cytosolic superoxide via a Cu(II)-jadomycin reaction, a mechanism common to all jadomycins tested and observed in MCF7-CON and drug-resistant MCF7-TXL cells. The superoxide dismutase 1, glutathione, and peroxiredoxin/thioredoxin cellular antioxidant enzyme pathways scavenged intracellular ROS generated by jadomycin treatment. Blocking these antioxidant pathways could serve as a strategy to enhance jadomycin cytotoxic potency in drug-sensitive and multidrug-resistant breast cancers.}, }
@article {pmid25724285, year = {2015}, author = {Kumar, A and Shukla, S and Chauhan, AK and Singh, D and Pandey, HP and Singh, C}, title = {The manganese-salen compound EUK-134 and N-acetyl cysteine rescue from zinc- and paraquat-induced toxicity in rat polymorphonuclear leukocytes.}, journal = {Chemico-biological interactions}, volume = {231}, number = {}, pages = {18-26}, doi = {10.1016/j.cbi.2015.02.012}, pmid = {25724285}, issn = {1872-7786}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Glutathione Peroxidase/metabolism ; Glutathione Transferase/metabolism ; Granulocytes/*drug effects/metabolism ; Herbicides/*toxicity ; Isoenzymes/metabolism ; Lipid Peroxidation/drug effects ; Male ; Organometallic Compounds/*pharmacology ; Oxidative Stress/drug effects ; Paraquat/*toxicity ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Salicylates/*pharmacology ; Superoxide Dismutase/metabolism ; Zinc/*toxicity ; }, abstract = {Oxidative stress is implicated in toxicant-induced inflammation leading to chronic diseases. Polymorphonuclear leukocytes (PMNs) offer the first line of defense against infection in the mammals and protect against inflammation-mediated pathological anomalies. Conversely, activated PMNs contribute to the oxidative stress-mediated damage and inflammation. The study aimed to investigate the status of oxidative stress and antioxidant defense system in the PMNs of rats treated with/without zinc (Zn) and/or paraquat (PQ) in the presence or absence of a synthetic superoxide dismutase/catalase mimetic, a manganese-salen compound-EUK-134 and/or a glutathione precursor, N-acetyl cysteine (NAC). While Zn and/or PQ elevated the total free radical generation, lipid peroxidation (LPO) and catalytic activity of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione S-transferase alpha 4-4 (GSTA4-4), a pronounced decrease in reduced glutathione (GSH) and glutathione reductase (GR) activity was also observed. Zn and/or PQ augmented the expression of metallothionein-I and II and GSTA4-4. Pre-treatment of EUK-134 or NAC alone altered the level of total free radical generation, LPO, GSH content and catalytic activity of MPO, SOD, GR and GPx and the expression of metallothionein I and II towards normalcy. The alterations were more pronounced in the PMNs of rats treated with EUK-134 and NAC in combination. Catalytic activity/expression of GSTA4-4 remained unchanged in the PMNs of EUK-134 or NAC treated rats. The results demonstrate that EUK-134 and NAC protect PMNs from the toxic effects of Zn and PQ in rats and also suggest that metallothioneins I/II might contribute to antioxidant defense under GSH depleted conditions.}, }
@article {pmid25721381, year = {2015}, author = {Sun, C and Wang, H and Mao, S and Liu, J and Li, S and Wang, J}, title = {Reactive oxygen species involved in CT26 immunogenic cell death induced by Clostridium difficile toxin B.}, journal = {Immunology letters}, volume = {164}, number = {2}, pages = {65-71}, doi = {10.1016/j.imlet.2015.02.007}, pmid = {25721381}, issn = {1879-0542}, mesh = {Apoptosis/drug effects/immunology ; Bacterial Proteins/*metabolism/pharmacology ; Bacterial Toxins/*metabolism/pharmacology ; *Cell Death/drug effects/immunology ; Cell Line, Tumor ; Humans ; Reactive Oxygen Species/*metabolism ; Recombinant Proteins/pharmacology ; }, abstract = {Immunogenic cell death (ICD) is a new concept appeared in recent years. Despite growing interests of research on ICD, the circumstances that trigger immune responses against dying tumor cells remain largely unknown. It was demonstrated that recombinant Clostridium difficile toxin B (rTcdB) can induce ICD in intoxicated cells, but its mechanism remains unclear. This work aims at exploring whether reactive oxygen species (ROS) involved in rTcdB induced ICD using the chemical agent N-acetyl cysteine (NAC), diphenylene iodonium (DPI) and Antimycin A (Anti.A). The results suggested that ROS involved in rTcdB induced apoptosis and autophagy. DPI and Anti.A successfully inhibited the antitumor immune effect induced by rTcdB. As ICD is determined by a variety of factors, rTcdB is a potential tool for further exploring the circumstances that trigger ICD, which may offer us a good choice for designing the new chemotherapeutic drugs with immunogenic properties.}, }
@article {pmid25721293, year = {2015}, author = {Amin, PJ and Shankar, BS}, title = {Sulforaphane induces ROS mediated induction of NKG2D ligands in human cancer cell lines and enhances susceptibility to NK cell mediated lysis.}, journal = {Life sciences}, volume = {126}, number = {}, pages = {19-27}, doi = {10.1016/j.lfs.2015.01.026}, pmid = {25721293}, issn = {1879-0631}, mesh = {Anticarcinogenic Agents/*pharmacology ; Female ; Gene Expression Regulation, Neoplastic/drug effects/physiology ; Histocompatibility Antigens Class I/immunology ; Humans ; Immunity, Cellular/drug effects ; Isothiocyanates/*pharmacology ; Killer Cells, Natural/*immunology/pathology ; Male ; NK Cell Lectin-Like Receptor Subfamily K/*immunology ; Neoplasms/drug therapy/*immunology/pathology ; Reactive Oxygen Species/*immunology ; Sulfoxides ; U937 Cells ; }, abstract = {AIMS: The goal of this study is to investigate the tumor cytotoxic effects of sulforaphane (SFN) and ionizing radiation (IR) as well as their ability to up-regulate natural killer group 2, member D (NKG2D) ligands and modulate the susceptibility of tumor cells to natural killer (NK) cell-mediated killing.<br><br>MAIN METHODS: Expression of MHC class I-related chain molecules A and B (MICA/MICB) and total reactive oxygen species (ROS) were assessed by flow cytometry following labeling with appropriate dyes or antibodies. NK cell cytotoxicity was determined by calcein release of target cells.<br><br>KEY FINDINGS: The expression of NKG2D ligands MICA/MICB was found to vary in all the four tumor cell lines tested (MCF7 < A549 < MDA-MB-231 < U937). Exposure of these cells to IR and SFN resulted in a differential induction of these ligands. IR induced an increase in expression of MICA/MICB in MCF7 cells and SFN induced MICA/MICB expression in A549 and MDA-MB-231 cells. This SFN induced increase in receptor expression resulted in increased susceptibility to NK cell mediated killing of tumor cells which was abrogated by blocking with anti-MICA/MICB antibody. SFN induced increase in MICA/MICB expression as well as increased susceptibility to NK cell mediated killing was abrogated by N-acetyl cysteine in A549 and MDA-MB-231 cells suggesting a ROS mediated mechanism.<br><br>SIGNIFICANCE: Our results indicate that SFN has an immunotherapeutic potential to be used in cancer therapy.}, }
@article {pmid25720821, year = {2015}, author = {Winefield, RD and Heemskerk, AA and Kaul, S and Williams, TD and Caspers, MJ and Prisinzano, TE and McCance-Katz, EF and Lunte, CE and Faiman, MD}, title = {N-acetyl-S-(N,N-diethylcarbamoyl) cysteine in rat nucleus accumbens, medial prefrontal cortex, and in rat and human plasma after disulfiram administration.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {107}, number = {}, pages = {518-525}, pmid = {25720821}, issn = {1873-264X}, support = {K24 DA023359/DA/NIDA NIH HHS/United States ; R01 DA024982/DA/NIDA NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; DA 023359/DA/NIDA NIH HHS/United States ; DA 021727/DA/NIDA NIH HHS/United States ; DA 024982/DA/NIDA NIH HHS/United States ; R21 DA021727/DA/NIDA NIH HHS/United States ; P20GM103418/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/blood/metabolism ; Animals ; Disulfiram/*blood/*metabolism ; Female ; Humans ; Male ; Microdialysis/methods ; Nucleus Accumbens/*metabolism ; Prefrontal Cortex/*metabolism ; Prodrugs/metabolism ; Rats ; Rats, Sprague-Dawley ; Thiocarbamates/blood/*metabolism ; }, abstract = {Disulfiram (DSF), a treatment for alcohol use disorders, has shown some clinical effectiveness in treating addiction to cocaine, nicotine, and pathological gambling. The mechanism of action of DSF for treating these addictions is unclear but it is unlikely to involve the inhibition of liver aldehyde dehydrogenase (ALDH2). DSF is a pro-drug and forms a number of metabolites, one of which is N-acetyl-S-(N,N-diethylcarbamoyl) cysteine (DETC-NAC). Here we describe a LCMS/MS method on a QQQ type instrument to quantify DETC-NAC in plasma and intracellular fluid from mammalian brain. An internal standard, the N,N-di-isopropylcarbamoyl homolog (MIM: 291>128) is easily separable from DETC-NAC (MIM: 263>100) on C18 RP media with a methanol gradient. The method's linear range is 0.5-500 nM from plasma and dialysate salt solution with all precisions better than 10% RSD. DETC-NAC and internal standards were recovered at better than 95% from all matrices, perchloric acid precipitation (plasma) or formic acid addition (salt) and is stable in plasma or salt at low pH for up to 24 h. Stability is observed through three freeze-thaw cycles per day for 7 days. No HPLC peak area matrix effect was greater than 10%. A human plasma sample from a prior analysis for S-(N,N-diethylcarbamoyl) glutathione (CARB) was found to have DETC NAC as well. In other human plasma samples from 62.5 mg/d and 250 mg/d dosing, CARB concentration peaks at 0.3 and 4 nM at 3 h followed by DETC-NAC peaks of 11 and 70 nM 2 h later. Employing microdialysis sampling, DETC-NAC levels in the nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and plasma of rats treated with DSF reached 1.1, 2.5 and 80 nM at 6h. The correlation between the appearance and long duration of DETC-NAC concentration in rat brain and the persistence of DSF-induced changes in neurotransmitters observed by Faiman et al. (Neuropharmacology, 2013, 75C, 95-105) is discussed.}, }
@article {pmid25717100, year = {2015}, author = {Yuan, S and Hollinger, M and Lachowicz-Scroggins, ME and Kerr, SC and Dunican, EM and Daniel, BM and Ghosh, S and Erzurum, SC and Willard, B and Hazen, SL and Huang, X and Carrington, SD and Oscarson, S and Fahy, JV}, title = {Oxidation increases mucin polymer cross-links to stiffen airway mucus gels.}, journal = {Science translational medicine}, volume = {7}, number = {276}, pages = {276ra27}, pmid = {25717100}, issn = {1946-6242}, support = {P01 HL107202/HL/NHLBI NIH HHS/United States ; P30 DK072517/DK/NIDDK NIH HHS/United States ; P01 HL081064/HL/NHLBI NIH HHS/United States ; P50HL107191/HL/NHLBI NIH HHS/United States ; P01HL103453/HL/NHLBI NIH HHS/United States ; R01 HL080414/HL/NHLBI NIH HHS/United States ; U10 HL109146/HL/NHLBI NIH HHS/United States ; U10 HL109250/HL/NHLBI NIH HHS/United States ; R01HL080414/HL/NHLBI NIH HHS/United States ; P50 HL107191/HL/NHLBI NIH HHS/United States ; UL1 TR000439/TR/NCATS NIH HHS/United States ; R24 HL123767/HL/NHLBI NIH HHS/United States ; P01 HL103453/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Biomechanical Phenomena/drug effects ; Cross-Linking Reagents/*metabolism ; Cystic Fibrosis/pathology/physiopathology ; DNA/metabolism ; Disulfides/metabolism ; Elasticity/drug effects ; Expectorants/pharmacology ; Galactose/chemistry/pharmacology ; Gels/*metabolism ; Humans ; Lung/drug effects/*physiology ; Mice, Inbred C57BL ; Mucins/*metabolism ; Mucus/*metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Polymers/*metabolism ; Reducing Agents/pharmacology ; Sputum/drug effects ; Sulfhydryl Compounds/chemistry/pharmacology ; }, abstract = {Airway mucus in cystic fibrosis (CF) is highly elastic, but the mechanism behind this pathology is unclear. We hypothesized that the biophysical properties of CF mucus are altered because of neutrophilic oxidative stress. Using confocal imaging, rheology, and biochemical measures of inflammation and oxidation, we found that CF airway mucus gels have a molecular architecture characterized by a core of mucin covered by a web of DNA and a rheological profile characterized by high elasticity that can be normalized by chemical reduction. We also found that high levels of reactive oxygen species in CF mucus correlated positively and significantly with high concentrations of the oxidized products of cysteine (disulfide cross-links). To directly determine whether oxidation can cross-link mucins to increase mucus elasticity, we exposed induced sputum from healthy subjects to oxidizing stimuli and found a marked and thiol-dependent increase in sputum elasticity. Targeting mucin disulfide cross-links using current thiol-amino structures such as N-acetylcysteine (NAC) requires high drug concentrations to have mucolytic effects. We therefore synthesized a thiol-carbohydrate structure (methyl 6-thio-6-deoxy-α-D-galactopyranoside) and found that it had stronger reducing activity than NAC and more potent and fast-acting mucolytic activity in CF sputum. Thus, oxidation arising from airway inflammation or environmental exposure contributes to pathologic mucus gel formation in the lung, which suggests that it can be targeted by thiol-modified carbohydrates.}, }
@article {pmid25716970, year = {2015}, author = {Mokra, D and Drgova, A and Mokry, J and Antosova, M and Durdik, P and Calkovska, A}, title = {N-acetylcysteine effectively diminished meconium-induced oxidative stress in adult rabbits.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {66}, number = {1}, pages = {101-110}, pmid = {25716970}, issn = {1899-1505}, mesh = {Acetylcysteine/*pharmacology ; Age Factors ; Animals ; Antioxidants/*pharmacology ; Biomarkers/metabolism ; Disease Models, Animal ; Humans ; Infant, Newborn ; Inflammation Mediators/metabolism ; Leukocytes/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Lung/*drug effects/immunology/metabolism ; Lung Injury/chemically induced/immunology/metabolism/*prevention &amp; control ; *Meconium ; Meconium Aspiration Syndrome/chemically induced/immunology/metabolism/*prevention &amp; control ; Mitochondria/drug effects/metabolism ; Oxidative Stress/*drug effects ; Pneumonia/chemically induced/immunology/metabolism/*prevention &amp; control ; Pulmonary Edema/metabolism/prevention &amp; control ; Rabbits ; Thiobarbituric Acid Reactive Substances/metabolism ; Time Factors ; }, abstract = {Since inflammation and oxidative stress are fundamental in the pathophysiology of neonatal meconium aspiration syndrome (MAS), various anti-inflammatory drugs have been used in experimental and clinical studies on MAS. This pilot study evaluated therapeutic potential of N-acetylcysteine in modulation of meconium-induced inflammation and oxidative lung injury. Oxygen-ventilated adult rabbits were intratracheally given 4 ml/kg of meconium (25 mg/ml) or saline (Sal, n = 6). Thirty minutes later, meconium-instilled animals were treated with intravenous N-acetylcysteine (10 mg/kg, Mec + NAC, n=6) or were non-treated (Mec, n = 6). All animals were oxygen-ventilated for additional 5 hours. Total and differential blood leukocyte counts were determined at baseline, and at 1, 3 and 5 h of the treatment. After sacrificing animals, left lung was saline-lavaged and total and differential cell counts in the bronchoalveolar lavage fluid were determined. Right lung was used for biochemical analyses and for estimation of wet-dry weight ratio. In lung tissue homogenate, thiobarbituric acid-reactive substances (TBARS), dityrosine, lysine-lipid peroxidation (LPO) products, and total antioxidant status (TAS) were detected. In isolated lung mitochondria, TBARS, dityrosine, lysine-LPO products, thiol group content, conjugated dienes, and activity of cytochrome c oxidase were estimated. To evaluate systemic effects of meconium instillation and NAC treatment, TBARS and TAS were determined also in plasma. To evaluate participation of eosinophils in the meconium-induced inflammation, eosinophil cationic protein (ECP) was detected in plasma and lung homogenate. Meconium instillation increased oxidation markers and ECP in the lung and decreased TAS (all P<0.05). NAC treatment reduced ECP and oxidation markers (all P<0.05, except of dityrosine in homogenate and conjugated dienes in mitochondria) and prevented a decrease in TAS (P<0.01) in lung homogenate compared to Mec group. In plasma, NAC decreased TBARS (P<0.001) and ECP, and increased TAS (both P<0.05) compared to Mec group. Concluding, N-acetylcysteine diminished meconium-induced inflammation and oxidative lung injury.}, }
@article {pmid25715791, year = {2015}, author = {Takeo, T and Horikoshi, Y and Nakao, S and Sakoh, K and Ishizuka, Y and Tsutsumi, A and Fukumoto, K and Kondo, T and Haruguchi, Y and Takeshita, Y and Nakamuta, Y and Tsuchiyama, S and Nakagata, N}, title = {Cysteine analogs with a free thiol group promote fertilization by reducing disulfide bonds in the zona pellucida of mice.}, journal = {Biology of reproduction}, volume = {92}, number = {4}, pages = {90}, pmid = {25715791}, issn = {1529-7268}, support = {5R21HL093605-02/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amino Acids/chemistry ; Animals ; Cysteine/*analogs &amp; derivatives/*pharmacology ; Disulfides/*chemistry ; Embryo Transfer ; Fertilization in Vitro/*drug effects ; Glutathione/metabolism ; In Vitro Techniques ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Proteins/chemistry ; Spermatozoa/drug effects ; Sulfhydryl Compounds/*chemistry ; Zona Pellucida/chemistry/*drug effects ; }, abstract = {Archives of cryopreserved sperm harvested from genetically engineered mice, in mouse resource centers, are a readily accessible genetic resource for the scientific community. We previously reported that exposure of oocytes to reduced glutathione (GSH) greatly improves the fertilization rate of frozen-thawed mouse sperm. Application of GSH to in vitro fertilization techniques is widely accepted as a standard protocol to produce sufficient numbers of mice from cryopreserved sperm. However, the detailed mechanism of the enhancement of fertilization mediated by GSH in vitro is not fully understood. Here we focused on the chemical by determining the effects of its amino acid constituents and cysteine analogs on the fertilization of oocytes by frozen-thawed sperm. Furthermore, we determined the stability of these compounds in aqueous solution. We show here that l-cysteine (l-Cys), d-cysteine (d-Cys), or N-acetyl-l-cysteine (NAC) increased the rate of fertilization when added to the medium but did not adversely affect embryo development in vitro or in vivo. The levels of thiol groups of proteins in the zona pellucida (ZP) and the expansion of the ZP were increased by l-Cys, d-Cys, and NAC. These effects were abrogated by the methylation of the thiol group of l-Cys. NAC was the most stable of these compounds in the fertilization medium at 4°C. These results suggest that the thiol groups of cysteine analogs markedly enhance the fertilization rate of mouse oocytes.}, }
@article {pmid25715308, year = {2015}, author = {Nadkarni, GN and Konstantinidis, I and Patel, A and Yacoub, R and Kumbala, D and Patel, RA and Annapureddy, N and Pakanati, KC and Simoes, PK and Javed, F and Benjo, AM}, title = {Trimetazidine Decreases Risk of Contrast-Induced Nephropathy in Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials.}, journal = {Journal of cardiovascular pharmacology and therapeutics}, volume = {20}, number = {6}, pages = {539-546}, doi = {10.1177/1074248415573320}, pmid = {25715308}, issn = {1940-4034}, mesh = {Aged ; Contrast Media/*adverse effects ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; Renal Insufficiency, Chronic/*complications ; Trimetazidine/*therapeutic use ; Vasodilator Agents/*therapeutic use ; }, abstract = {OBJECTIVES: We sought to synthesize and analyze the available data from randomized controlled trials (RCTs) for trimetazidine (TMZ) in the prevention of contrast-induced nephropathy (CIN).<br><br>BACKGROUND: Contrast-induced nephropathy after coronary angiography is associated with poor outcomes. Trimetazidine is an anti-ischemic drug that might reduce incidence of CIN, but current data are inconclusive.<br><br>METHODS: We searched MEDLINE/PubMed, EMBASE, Scopus, Cochrane Library, Web of Science, and ScienceDirect electronic databases for RCTs comparing intravenous hydration with normal saline (NS) and/or N-acetyl cysteine (NAC) versus TMZ plus NS &#xb1; NAC for prevention of CIN. We used RevMan 5.2 for statistical analysis with the fixed effects model.<br><br>RESULTS: Of the 808 studies, 3 RCTs met criteria with 290 patients in the TMZ plus NS &#xb1; NAC group and 292 patients in the NS &#xb1; NAC group. The mean age of patients was 59.5 years, and baseline serum creatinine ranged from 1.3 to 2 mg/dL. Trimetazidine significantly reduced the incidence of CIN by 11% (risk difference 0.11; 95% confidence interval, 0.16-0.06; P < .01). There was no significant heterogeneity between the studies (I(2) statistic = 0). The number needed to treat to prevent 1 episode of CIN was 9.<br><br>CONCLUSIONS: The addition of TMZ to NS &#xb1; NAC significantly decreased the incidence of CIN in patients undergoing coronary angiography. In conclusion, TMZ could be considered as a potential tool for prevention of CIN in patients with renal dysfunction.}, }
@article {pmid25714760, year = {2015}, author = {Ito, S and Araya, J and Kurita, Y and Kobayashi, K and Takasaka, N and Yoshida, M and Hara, H and Minagawa, S and Wakui, H and Fujii, S and Kojima, J and Shimizu, K and Numata, T and Kawaishi, M and Odaka, M and Morikawa, T and Harada, T and Nishimura, SL and Kaneko, Y and Nakayama, K and Kuwano, K}, title = {PARK2-mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis.}, journal = {Autophagy}, volume = {11}, number = {3}, pages = {547-559}, pmid = {25714760}, issn = {1554-8635}, mesh = {Adult ; Aged ; Autophagy ; Bronchi/cytology ; *Cellular Senescence ; Epithelial Cells/*pathology ; Female ; Humans ; Immunohistochemistry ; Lung/physiopathology ; Male ; Microscopy, Electron ; Middle Aged ; Mitochondria/pathology ; *Mitophagy ; Protein Kinases/*physiology ; Pulmonary Disease, Chronic Obstructive/immunology/*physiopathology ; Reactive Oxygen Species/metabolism ; Smoking/adverse effects ; Tobacco Products ; Ubiquitin-Protein Ligases/*physiology ; }, abstract = {Cigarette smoke (CS)-induced mitochondrial damage with increased reactive oxygen species (ROS) production has been implicated in COPD pathogenesis by accelerating senescence. Mitophagy may play a pivotal role for removal of CS-induced damaged mitochondria, and the PINK1 (PTEN-induced putative kinase 1)-PARK2 pathway has been proposed as a crucial mechanism for mitophagic degradation. Therefore, we sought to investigate to determine if PINK1-PARK2-mediated mitophagy is involved in the regulation of CS extract (CSE)-induced cell senescence and in COPD pathogenesis. Mitochondrial damage, ROS production, and cell senescence were evaluated in primary human bronchial epithelial cells (HBEC). Mitophagy was assessed in BEAS-2B cells stably expressing EGFP-LC3B, using confocal microscopy to measure colocalization between TOMM20-stained mitochondria and EGFP-LC3B dots as a representation of autophagosome formation. To elucidate the involvement of PINK1 and PARK2 in mitophagy, knockdown and overexpression experiments were performed. PINK1 and PARK2 protein levels in lungs from patients were evaluated by means of lung homogenate and immunohistochemistry. We demonstrated that CSE-induced mitochondrial damage was accompanied by increased ROS production and HBEC senescence. CSE-induced mitophagy was inhibited by PINK1 and PARK2 knockdown, resulting in enhanced mitochondrial ROS production and cellular senescence in HBEC. Evaluation of protein levels demonstrated decreased PARK2 in COPD lungs compared with non-COPD lungs. These results suggest that PINK1-PARK2 pathway-mediated mitophagy plays a key regulatory role in CSE-induced mitochondrial ROS production and cellular senescence in HBEC. Reduced PARK2 expression levels in COPD lung suggest that insufficient mitophagy is a part of the pathogenic sequence of COPD.}, }
@article {pmid25713720, year = {2015}, author = {Mullan, A and Cocker, D and Taylor, G and Millar, C and Ranganath, L}, title = {Fatal oxidative haemolysis and methaemoglobinaemia in a patient with alkaptonuria and acute kidney injury.}, journal = {Clinical kidney journal}, volume = {8}, number = {1}, pages = {109-112}, pmid = {25713720}, issn = {2048-8505}, abstract = {Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism, which leads to an accumulation of homogentisic acid (HGA) and is associated with a progressive arthropathy. Fatal complications are unusual and usually result from cardiac disease or progressive renal impairment; rapidly fatal haematological complications are exceptionally rare and described in only a handful of case reports. This case involves a 63-year-old male with AKU and modest chronic kidney disease who developed rapidly fatal haemolysis and methaemoglobinuria following an episode of acute kidney injury triggered by an obstructing ureteric calculus and urosepsis. The patient succumbed despite aggressive antioxidant therapy with ascorbic acid and n-acetyl cysteine. A rapid build-up of HGA due to reduced renal clearance, triggering oxidative haemolysis and methaemoglobinuria is proposed as the mechanism. Alternative strategies to consider when conventional antioxidants fail are discussed including the potent inhibitor of HGA production, nitisonone.}, }
@article {pmid25711080, year = {2014}, author = {Voronkina, IV and Vakhromova, EA and Kirpichnikova, KM and Smagina, LV and Gamaleĭ, IA}, title = {[Activity of matrix metalloproteinases of transformed fibroblasts under the antioxidant action].}, journal = {Tsitologiia}, volume = {56}, number = {10}, pages = {717-724}, pmid = {25711080}, issn = {0041-3771}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Line, Transformed ; Collagen Type I/genetics/metabolism ; Extracellular Matrix/*drug effects/enzymology/ultrastructure ; Gene Expression Regulation/*drug effects ; Matrix Metalloproteinase 1/genetics/metabolism ; Matrix Metalloproteinase 2/genetics/metabolism ; Matrix Metalloproteinase 8/genetics/metabolism ; Matrix Metalloproteinase 9/genetics/metabolism ; Mice ; NIH 3T3 Cells ; Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism ; Tissue Inhibitor of Metalloproteinase-2/genetics/metabolism ; }, abstract = {We have shown that antioxidant N-acetylcysteine (NAC, 2-10 mM) quickly (for 2 hours) and completely inactivates the activity of matrix metalloproteinases (gelatinases MMP-2 and MMP-9, and collagenases MMP-1 and MMP-8) secreted by transformed mouse fibroblasts 3T3-SV40 into the medium. The same MMP inhibition took place in the cell-free conditioned medium of HT-1080 fibroblasts, which suggests a direct chemical interaction between NAC and MMP resulting in the loss of MMP activity. Besides inhibitory effect, NAC decreased MMP-1 and MMP-9 (but not MMP-2) production in the cell medium. However, the level of MMP-1 and MMP-9 inhibitor (TIMP-1) remained normal, indicating a shift in the balance between the enzyme and inhibitor. The correlation between MMP-2 level and tissue enzyme inhibitor TIMP-2 was similar in control and NAC treated cells. At the same time, reorganization of type I collagen at the cell surface occurred. All together permits the conclusion that NAC action results in the extracellular matrix remodeling and changing in cellular functions.}, }
@article {pmid25709111, year = {2015}, author = {Naeem, M and McEnteggart, GE and Murphy, TP and Prince, E and Ahn, S and Soares, G}, title = {Fenoldopam for the prevention of contrast-induced nephropathy (CIN)-do we need more trials? A meta-analysis.}, journal = {Clinical imaging}, volume = {39}, number = {5}, pages = {759-764}, doi = {10.1016/j.clinimag.2015.02.003}, pmid = {25709111}, issn = {1873-4499}, mesh = {Contrast Media/*adverse effects ; Dopamine Agonists/*therapeutic use ; Fenoldopam/*therapeutic use ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; }, abstract = {We conducted a pooled analysis of clinical trials comparing intravenous Fenoldopam (FP) with Saline/Placebo/N-acetyl cysteine (NAC) for the prevention of contrast-induced nephropathy (CIN). Five studies were eligible. Quantitative analyses were done with Review Manager (RevMan version 5.2.). A total of 85 out of 353 patients in Fenoldopam group while 73 among 366 in the control group were affected due to CIN. The risk ratio for the development of CIN in the Fenoldopam group was 1.19 compared to the control group. This was not statistically significant. Fenoldopam is no better than Placebo/Saline or NAC in preventing CIN, but more studies are required.}, }
@article {pmid25705238, year = {2015}, author = {Lambros, MP and Kondapalli, L and Parsa, C and Mulamalla, HC and Orlando, R and Pon, D and Huang, Y and Chow, MS}, title = {Molecular signatures in the prevention of radiation damage by the synergistic effect of N-acetyl cysteine and qingre liyan decoction, a traditional chinese medicine, using a 3-dimensional cell culture model of oral mucositis.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2015}, number = {}, pages = {425760}, pmid = {25705238}, issn = {1741-427X}, abstract = {Qingre Liyan decoction (QYD), a Traditional Chinese medicine, and N-acetyl cysteine (NAC) have been used to prevent radiation induced mucositis. This work evaluates the protective mechanisms of QYD, NAC, and their combination (NAC-QYD) at the cellular and transcriptional level. A validated organotypic model of oral mucosal consisting of a three-dimensional (3D) cell tissue-culture of primary human keratinocytes exposed to X-ray irradiation was used. Six hours after the irradiation, the tissues were evaluated by hematoxylin and eosin (H and E) and a TUNEL assay to assess histopathology and apoptosis, respectively. Total RNA was extracted and used for microarray gene expression profiling. The tissue-cultures treated with NAC-QYD preserved their integrity and showed no apoptosis. Microarray results revealed that the NAC-QYD caused the upregulation of genes encoding metallothioneins, HMOX1, and other components of the Nrf2 pathway, which protects against oxidative stress. DNA repair genes (XCP, GADD45G, RAD9, and XRCC1), protective genes (EGFR and PPARD), and genes of the NFκB pathway were upregulated. Finally, tissue-cultures treated prophylactically with NAC-QYD showed significant downregulation of apoptosis, cytokines and chemokines genes, and constrained damage-associated molecular patterns (DAMPs). NAC-QYD treatment involves the protective effect of Nrf2, NFκB, and DNA repair factors.}, }
@article {pmid25703423, year = {2015}, author = {Mollace, V and Gliozzi, M and Musolino, V and Carresi, C and Muscoli, S and Mollace, R and Tavernese, A and Gratteri, S and Palma, E and Morabito, C and Vitale, C and Muscoli, C and Fini, M and Romeo, F}, title = {Oxidized LDL attenuates protective autophagy and induces apoptotic cell death of endothelial cells: Role of oxidative stress and LOX-1 receptor expression.}, journal = {International journal of cardiology}, volume = {184}, number = {}, pages = {152-158}, doi = {10.1016/j.ijcard.2015.02.007}, pmid = {25703423}, issn = {1874-1754}, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Autophagy/drug effects/*physiology ; Cattle ; Cell Death/drug effects/physiology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects/*metabolism ; Gene Expression Regulation ; Lipoproteins, LDL/*toxicity ; Oxidative Stress/drug effects/*physiology ; Scavenger Receptors, Class E/*biosynthesis ; }, abstract = {BACKGROUND: Overproduction of oxidized-low density lipoproteins (oxyLDLs) has been found to contribute in endothelial cell (EC) dysfunction thereby leading to atherosclerosis development and progression. In particular, oxyLDLs lead to apoptotic cell death of EC via oxidative stress production, mostly subsequent to the overexpression of the scavenger receptor LOX-1. Here, we hypothesize that LOX-1 expression in EC represents a crucial event which attenuates protective autophagic response, thereby enhancing programmed endothelial cell death.<br><br>METHODS AND RESULTS: Bovine aortic endothelial cells (BAECs) in culture were exposed to oxyLDL (1-100 &#x3bc;M). After 48 h incubation, oxyLDL produced pronounced malondialdehyde (MDA) elevation and apoptotic cell death of BAEC as detected by FACS analysis, an effect counteracted by antioxidant N-acetyl-cysteine (NAC) as well as by the NO-donor SNAP. OxyLDL-induced apoptotic cell death was also accompanied by reduced VEGF-dependent phosphorylation of constitutive NO synthase (cNOS) in BAEC and consistent attenuation of autophagic response as detected by the expression of Beclin-1 and LC3, two reliable biomarkers of autophagy. Moreover, silencing LOX-1 receptor significantly restored LC3 expression in oxyLDL-treated BAEC, thus suggesting a key role of LOX-1 overproduction in oxyLDL-induced endothelial dysfunction.<br><br>CONCLUSIONS: OxyLDL leads to impaired NO generation and apoptotic cell death in BAECs. This effect occurs via the overexpression of LOX-1 and subsequent attenuation of protective autophagic response thereby contributing to the pathophysiology of oxyLDL-induced endothelial dysfunction which characterizes early stages of atherosclerotic process.}, }
@article {pmid25701684, year = {2015}, author = {Zheng, Q and Ren, Y and Reinach, PS and Xiao, B and Lu, H and Zhu, Y and Qu, J and Chen, W}, title = {Reactive oxygen species activated NLRP3 inflammasomes initiate inflammation in hyperosmolarity stressed human corneal epithelial cells and environment-induced dry eye patients.}, journal = {Experimental eye research}, volume = {134}, number = {}, pages = {133-140}, doi = {10.1016/j.exer.2015.02.013}, pmid = {25701684}, issn = {1096-0007}, mesh = {Acetylcysteine/pharmacology ; Adult ; Blotting, Western ; Carrier Proteins/*metabolism ; Caspase 1/metabolism ; Cell Line ; Dry Eye Syndromes/*metabolism ; Enzyme-Linked Immunosorbent Assay ; Epithelium, Corneal/*metabolism ; Female ; Gene Knockdown Techniques ; Humans ; Inflammasomes/*metabolism ; Inflammation/metabolism ; Interleukin-1beta/metabolism ; Keratitis/*metabolism ; Male ; Middle Aged ; NLR Family, Pyrin Domain-Containing 3 Protein ; Osmotic Pressure/drug effects ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction ; Transfection ; Young Adult ; }, abstract = {In studies on dry eye (DE) disease, an association has been identified between tear film hyperosmolarity and inflammation severity elicited through receptor-induced increases in proinflammatory cytokine and chemokine release. These immune reactions might be mediated by inflammasomes, macromolecular complexes mounted around the NLRP3 protein and can be activated by reactive oxygen species (ROS) over-generation. Hence in this study we determine whether: a) ROS activated NLRP3 inflammasomes mediate hyperosmotic stress-induced inflammation in human corneal epithelial cells (HCECs); b) the ROS-NLRP3-IL-1β axis activation is associated with environment-induced DE. Immortalized HCECs were exposed to 500 mOsm medium in the presence and absence of a ROS inhibitor, N-acetyl-l-cysteine (NAC). HCECs transfected with NLRP3 siRNA or a negative control (NC) siRNA. Intracellular ROS was measured by fluorometric analysis using the probe 2',7'-dichlorofluorescin diacetate (DCFH-DA). Real-time PCR evaluated NLRP3, ASC, pro-caspase-1 and pro-IL-1β mRNA levels. Western blot analysis assessed NLRP3 protein expression whereas caspase-1 activity was determined with a fluorometric assay. Bioactive IL-1β release was assessed by ELISA. ROS production, NLRP3 inflammasome and pro-IL-1β gene expression as well as IL-1β secretion were also evaluated in the conjunctival epithelial cells and tear fluid samples of environment-induced DE patients and normal subjects. NAC suppressed hyperosmolarity-induced rises in ROS levels, NLRP3 inflammasome formation and activation, caspase-1 activity and IL-1β release. On the other hand, NLRP3 siRNA knockdown inhibited hyperosmotic stress-induced NLRP3 activation, which led to ASC, pro-caspase-1 and pro-IL-1β mRNA down-regulation followed by suppression of associated caspase-1 activity and IL-1β secretion. In addition, in ocular surface samples of environment-induced DE patients, ROS generation, NLRP3, ASC, pro-caspase-1 and pro-IL-1β gene expression as well as IL-1β secretion were upregulated. Taken together, NLRP3 mediated innate immune responses triggered by rises in ROS generation induce inflammation in hyperosmotic stressed HCECs. ROS-NLRP3-IL-1β signaling pathway might play a priming role in environment-induced DE development.}, }
@article {pmid25700738, year = {2015}, author = {Jabir, MS and Hopkins, L and Ritchie, ND and Ullah, I and Bayes, HK and Li, D and Tourlomousis, P and Lupton, A and Puleston, D and Simon, AK and Bryant, C and Evans, TJ}, title = {Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy.}, journal = {Autophagy}, volume = {11}, number = {1}, pages = {166-182}, pmid = {25700738}, issn = {1554-8635}, support = {/WT_/Wellcome Trust/United Kingdom ; 103830/WT_/Wellcome Trust/United Kingdom ; G1001998/MRC_/Medical Research Council/United Kingdom ; WT094779MA/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Apoptosis Regulatory Proteins/metabolism ; *Autophagy ; Bone Marrow Cells/pathology ; Calcium-Binding Proteins/metabolism ; DNA, Mitochondrial/metabolism ; DNA-Binding Proteins/metabolism ; *Down-Regulation ; Female ; HEK293 Cells ; Humans ; Inflammasomes/*metabolism ; Macrophages/metabolism/ultrastructure ; Mice, Inbred C57BL ; Mitochondria/*metabolism/ultrastructure ; Mitophagy ; Protein Binding ; Pseudomonas Infections/metabolism/microbiology/pathology ; Pseudomonas aeruginosa/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {The nucleotide-binding domain, leucine-rich repeat containing family caspase recruitment domain containing 4 (NLRC4) inflammasome can be activated by pathogenic bacteria via products translocated through the microbial type III secretion apparatus (T3SS). Recent work has shown that activation of the NLRP3 inflammasome is downregulated by autophagy, but the influence of autophagy on NLRC4 activation is unclear. We set out to determine how autophagy might influence this process, using the bacterium Pseudomonas aeruginosa, which activates the NLRC4 inflammasome via its T3SS. Infection resulted in T3SS-dependent mitochondrial damage with increased production of reactive oxygen intermediates and release of mitochondrial DNA. Inhibiting mitochondrial reactive oxygen release or degrading intracellular mitochondrial DNA abrogated NLRC4 inflammasome activation. Moreover, macrophages lacking mitochondria failed to activate NLRC4 following infection. Removal of damaged mitochondria by autophagy significantly attenuated NLRC4 inflammasome activation. Mitochondrial DNA bound specifically to NLRC4 immunoprecipitates and transfection of mitochondrial DNA directly activated the NLRC4 inflammasome; oxidation of the DNA enhanced this effect. Manipulation of autophagy altered the degree of inflammasome activation and inflammation in an in vivo model of P. aeruginosa infection. Our results reveal a novel mechanism contributing to NLRC4 activation by P. aeruginosa via mitochondrial damage and release of mitochondrial DNA triggered by the bacterial T3SS that is downregulated by autophagy.}, }
@article {pmid25700359, year = {2014}, author = {Hu, L and Li, LL and Lin, ZG and Jiang, ZC and Li, HX and Zhao, SG and Yang, KB}, title = {Blockage of potassium channel inhibits proliferation of glioma cells via increasing reactive oxygen species.}, journal = {Oncology research}, volume = {22}, number = {1}, pages = {57-65}, pmid = {25700359}, issn = {1555-3906}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Brain Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Glioma/*drug therapy/pathology ; Humans ; Potassium Channel Blockers/*pharmacology ; Potassium Channels/metabolism ; Reactive Oxygen Species/*metabolism ; Tetraethylammonium/*pharmacology ; Tumor Suppressor Protein p53/genetics/metabolism ; Up-Regulation ; }, abstract = {The potassium (K(+)) channel plays an important role in the cell cycle and proliferation of tumor cells, while its role in brain glioma cells and the signaling pathways remains unclear. We used tetraethylammonium (TEA), a nonselective antagonist of big conductance K(+) channels, to block K(+) channels in glioma cells, and antioxidant N-acetyl-l-cysteine (NAC) to inhibit production of intracellular reactive oxygen species (ROS). TEA showed an antiproliferation effect on C6 and U87 glioma cells in a time-dependent manner, which was accompanied by an increased intracellular ROS level. Antioxidant NAC pretreatment reversed TEA-mediated antiproliferation and restored ROS level. TEA treatment also caused significant increases in mRNA and protein levels of tumor-suppressor proteins p53 and p21, and the upregulation was attenuated by pretreatment of NAC. Our results suggest that K(+) channel activity significantly contributes to brain glioma cell proliferation via increasing ROS, and it might be an upstream factor triggering the activation of the p53/p21(Cip1)-dependent signaling pathway, consequently leading to glioma cell cycle arrest.}, }
@article {pmid25688267, year = {2015}, author = {Rose, S and Wynne, R and Frye, RE and Melnyk, S and James, SJ}, title = {Increased susceptibility to ethylmercury-induced mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines.}, journal = {Journal of toxicology}, volume = {2015}, number = {}, pages = {573701}, pmid = {25688267}, issn = {1687-8191}, abstract = {The association of autism spectrum disorders with oxidative stress, redox imbalance, and mitochondrial dysfunction has become increasingly recognized. In this study, extracellular flux analysis was used to compare mitochondrial respiration in lymphoblastoid cell lines (LCLs) from individuals with autism and unaffected controls exposed to ethylmercury, an environmental toxin known to deplete glutathione and induce oxidative stress and mitochondrial dysfunction. We also tested whether pretreating the autism LCLs with N-acetyl cysteine (NAC) to increase glutathione concentrations conferred protection from ethylmercury. Examination of 16 autism/control LCL pairs revealed that a subgroup (31%) of autism LCLs exhibited a greater reduction in ATP-linked respiration, maximal respiratory capacity, and reserve capacity when exposed to ethylmercury, compared to control LCLs. These respiratory parameters were significantly elevated at baseline in the ethylmercury-sensitive autism subgroup as compared to control LCLs. NAC pretreatment of the sensitive subgroup reduced (normalized) baseline respiratory parameters and blunted the exaggerated ethylmercury-induced reserve capacity depletion. These findings suggest that the epidemiological link between environmental mercury exposure and an increased risk of developing autism may be mediated through mitochondrial dysfunction and support the notion that a subset of individuals with autism may be vulnerable to environmental influences with detrimental effects on development through mitochondrial dysfunction.}, }
@article {pmid25681790, year = {2015}, author = {Hoffman, JD and Ward, WM and Loo, G}, title = {Effect of antioxidants on the genotoxicity of phenethyl isothiocyanate.}, journal = {Mutagenesis}, volume = {30}, number = {3}, pages = {421-430}, doi = {10.1093/mutage/gev003}, pmid = {25681790}, issn = {1464-3804}, mesh = {Apoptosis ; Ascorbic Acid/*pharmacology ; Biphenyl Compounds/chemistry ; Chromans/*pharmacology ; DNA Damage ; Drug Evaluation, Preclinical ; Free Radical Scavengers/chemistry/*pharmacology ; Glutathione/metabolism ; HCT116 Cells ; HT29 Cells ; Humans ; Isothiocyanates/*toxicity ; Mutagens/*toxicity ; Picrates/chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {Isothiocyanates are plant-derived compounds that may be beneficial in the prevention of certain chronic diseases. Yet, by stimulating the production of reactive oxygen species (ROS), isothiocyanates can be genotoxic. Whether antioxidants influence isothiocyanate-induced genotoxicity is unclear, but this situation was clarified appreciably herein. In HCT116 cells, phenethyl isothiocyanate (PEITC) increased ROS production, which was inhibited by N-acetylcysteine (NAC) and deferoxamine (DFO) but not by ascorbic acid (ASC) and trolox (TRX) that were found to be more potent radical scavengers. Surprisingly, ASC and TRX each intensified the DNA damage that was caused by PEITC, but neither ASC nor TRX by themselves caused any DNA damage. In contrast, NAC and DFO each not only attenuated PEITC-induced DNA damage but also attenuated the antioxidant-intensified, PEITC-induced DNA damage. To determine if the DNA damage could be related to possible changes in the major antioxidant defence system, glutathione (GSH) was investigated. PEITC lowered GSH levels, which was prevented by NAC, whereas ASC, TRX and DFO neither inhibited nor enhanced the GSH-lowering effect of PEITC. The GSH synthesis inhibitor, buthionine sulphoxime, intensified PEITC-induced DNA damage, although by itself buthionine sulphoxime did not directly cause DNA damage. The principal findings suggest that ASC and TRX make PEITC more genotoxic, which might be exploited in killing cancer cells as one approach in killing cancer cells is to extensively damage their DNA so as to initiate apoptosis.}, }
@article {pmid25681565, year = {2015}, author = {Qi, W and Niu, J and Qin, Q and Qiao, Z and Gu, Y}, title = {Glycated albumin triggers fibrosis and apoptosis via an NADPH oxidase/Nox4-MAPK pathway-dependent mechanism in renal proximal tubular cells.}, journal = {Molecular and cellular endocrinology}, volume = {405}, number = {}, pages = {74-83}, doi = {10.1016/j.mce.2015.02.007}, pmid = {25681565}, issn = {1872-8057}, mesh = {Acetophenones/pharmacology ; Animals ; *Apoptosis ; Cell Line ; Fibronectins/genetics/metabolism ; Fibrosis ; Gene Expression ; Glycation End Products, Advanced ; Kidney Tubules, Proximal/enzymology/*pathology ; MAP Kinase Signaling System ; NADPH Oxidase 4 ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/*metabolism ; Rats ; Serum Albumin/*physiology ; Transforming Growth Factor beta/genetics/metabolism ; Glycated Serum Albumin ; }, abstract = {Glycated albumin (GA), an Amadori product used as a marker of hyperglycemia and the early-stage glycation products compared to AGEs, might further promote kidney lesions in diabetic nephropathy (DN). However, the mechanisms how GA cause proximal tubular cells damage remain poorly understood. In this study, we investigated the effects of GA on fibrosis and apoptosis of renal proximal tubular cells (NRK-52E) in vitro experiments. Our results showed that GA promoted α-SMA, fibronectin (FN) and TGF-β expressions in NRK-52E cells. GA also increased cell apoptosis and stimulated the expressions of pro-caspase 3/cleaved-caspase 3. GA overloading enhanced the phosphorylation of MAPK pathway. GA-induced α-SMA, FN, TGF-β and caspase 3 expressions were completely suppressed by the NADPH oxidase inhibitor apocynin (Apo), the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the latent antioxidant Astragaloside IV (AS-IV). Real-time PCR showed that GA increased Nox1, Nox2 and Nox4 mRNA expressions, especially the Nox4 expression. Furthermore, Nox4 siRNA blocked GA-induced tubular damages and the MAPK pathway activation. These results demonstrate that GA increases the permissiveness of proximal tubular cells to fibrosis and apoptosis in vitro by triggering a pathway that involves NADPH oxidase/Nox4-MAPK signaling pathway. This event may represent a key cellular effect in increasing the susceptibility of tubular cells to fibrosis and apoptosis when the tubules cope with a high GA load. This effect is instrumental to renal damage and disease progression in patients with DN.}, }
@article {pmid25681429, year = {2015}, author = {Satonaka, H and Nagata, D and Takahashi, M and Kiyosue, A and Myojo, M and Fujita, D and Ishimitsu, T and Nagano, T and Nagai, R and Hirata, Y}, title = {Involvement of P2Y12 receptor in vascular smooth muscle inflammatory changes via MCP-1 upregulation and monocyte adhesion.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {308}, number = {8}, pages = {H853-61}, doi = {10.1152/ajpheart.00862.2013}, pmid = {25681429}, issn = {1522-1539}, mesh = {Adenosine Diphosphate/pharmacology ; Animals ; Cell Adhesion ; Cells, Cultured ; Chemokine CCL2/genetics/*metabolism ; Inflammation/metabolism ; Male ; Monocytes/drug effects/*metabolism/physiology ; Muscle, Smooth, Vascular/*metabolism/pathology ; NF-kappa B/metabolism ; Purinergic P2Y Receptor Antagonists/pharmacology ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptors, Purinergic P2Y12/*metabolism ; *Up-Regulation ; }, abstract = {Antiplatelet drugs, frequently used for cardiovascular events with thrombotic involvement, are also regarded as possible promising agents for cardiovascular primary prevention. The roles of P2Y12, an ADP receptor and the target of thienopyridine antiplatelet drugs, are not satisfactorily known in the vascular wall. We investigated the hypothesis that vascular smooth muscle cell (VSMC) P2Y12 is involved in vascular wall inflammatory changes by upregulating monocyte chemoattractant protein-1 (MCP-1) and promoting monocyte adhesion. ADP at 10(-5) M induced a 3.6 ± 0.3-fold upregulation of MCP-1 mRNA in cultured rat VSMCs, which was significantly inhibited by R-138727, the active metabolite of P2Y12 inhibitor prasugrel and siRNAs against P2Y12. ADP also induced MCP-1 protein upregulation, which was diminished by R-138727 and P2Y12 siRNAs. JNK (c-Jun NH2-terminal kinase) inhibition attenuated ADP-induced MCP-1 mRNA and protein upregulation. R-138727 and P2Y12 siRNAs inhibited ADP-induced JNK activation. The reactive oxygen species (ROS) inhibitors N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and Tempol also diminished MCP-1 upregulation and JNK activation induced by ADP. ADP induced MCP-1 promoter activation, which was inhibited by R-138727 and P2Y12 siRNAs. Nuclear factor-κB (NF-κB) consensus sites in the MCP-1 promoter region were involved in this activation. ADP-induced NF-κB pathway activation, examined by a plasmid containing multiple NF-κB sites, was diminished by P2Y12 inhibition. For cellular function analysis, stimulation of VSMC with ADP increased subsequent THP-1 monocyte adhesion. P2Y12 siRNAs and CCR2 antagonism diminished this ADP-induced monocyte adhesion. These data suggested that ADP, via the VSMC P2Y12 receptor, induces vascular inflammatory changes by upregulating MCP-1 and promoting monocyte adhesion.}, }
@article {pmid25673499, year = {2015}, author = {Loxham, M and Morgan-Walsh, RJ and Cooper, MJ and Blume, C and Swindle, EJ and Dennison, PW and Howarth, PH and Cassee, FR and Teagle, DA and Palmer, MR and Davies, DE}, title = {The effects on bronchial epithelial mucociliary cultures of coarse, fine, and ultrafine particulate matter from an underground railway station.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {145}, number = {1}, pages = {98-107}, pmid = {25673499}, issn = {1096-0929}, support = {G0900453/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Bronchi/cytology/*drug effects ; Cells, Cultured ; Cilia/*drug effects ; Epithelial Cells/cytology ; Humans ; Particle Size ; Particulate Matter/*toxicity ; *Transportation ; }, abstract = {We have previously shown that underground railway particulate matter (PM) is rich in iron and other transition metals across coarse (PM10-2.5), fine (PM2.5), and quasi-ultrafine (PM0.18) fractions and is able to generate reactive oxygen species (ROS). However, there is little knowledge of whether the metal-rich nature of such particles exerts toxic effects in mucus-covered airway epithelial cell cultures or whether there is an increased risk posed by the ultrafine fraction. Monolayer and mucociliary air-liquid interface (ALI) cultures of primary bronchial epithelial cells (PBECs) were exposed to size-fractionated underground railway PM (1.1-11.1 µg/cm(2)) and release of lactate dehydrogenase and IL-8 was assayed. ROS generation was measured, and the mechanism of generation studied using desferrioxamine (DFX) and N-acetylcysteine (NAC). Expression of heme oxygenase-1 (HO-1) was determined by RT-qPCR. Particle uptake was studied by transmission electron microscopy. Underground PM increased IL-8 release from PBECs, but this was diminished in mucus-secreting ALI cultures. Fine and ultrafine PM generated a greater level of ROS than coarse PM. ROS generation by ultrafine PM was ameliorated by DFX and NAC, suggesting an iron-dependent mechanism. Despite the presence of mucus, ALI cultures displayed increased HO-1 expression. Intracellular PM was observed within vesicles, mitochondria, and free in the cytosol. The results indicate that, although the mucous layer appears to confer some protection against underground PM, ALI PBECs nonetheless detect PM and mount an antioxidant response. The combination of increased ROS-generating ability of the metal-rich ultrafine fraction and ability of PM to penetrate the mucous layer merits further research.}, }
@article {pmid25671543, year = {2015}, author = {Nogueira, NP and Saraiva, FM and Sultano, PE and Cunha, PR and Laranja, GA and Justo, GA and Sabino, KC and Coelho, MG and Rossini, A and Atella, GC and Paes, MC}, title = {Proliferation and differentiation of Trypanosoma cruzi inside its vector have a new trigger: redox status.}, journal = {PloS one}, volume = {10}, number = {2}, pages = {e0116712}, pmid = {25671543}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Heme/pharmacology ; Hydrogen Peroxide/pharmacology ; Insect Vectors/*parasitology ; Oxidation-Reduction/drug effects ; Rhodnius/parasitology ; Trypanosoma cruzi/*cytology/drug effects/metabolism/*physiology ; Uric Acid/pharmacology ; }, abstract = {Trypanosoma cruzi proliferate and differentiate inside different compartments of triatomines gut that is the first environment encountered by T. cruzi. Due to its complex life cycle, the parasite is constantly exposed to reactive oxygen species (ROS). We tested the influence of the pro-oxidant molecules H2O2 and the superoxide generator, Paraquat, as well as, metabolism products of the vector, with distinct redox status, in the proliferation and metacyclogenesis. These molecules are heme, hemozoin and urate. We also tested the antioxidants NAC and GSH. Heme induced the proliferation of epimastigotes and impaired the metacyclogenesis. β-hematin, did not affect epimastigote proliferation but decreased parasite differentiation. Conversely, we show that urate, GSH and NAC dramatically impaired epimastigote proliferation and during metacyclogenesis, NAC and urate induced a significant increment of trypomastigotes and decreased the percentage of epimastigotes. We also quantified the parasite loads in the anterior and posterior midguts and in the rectum of the vector by qPCR. The treatment with the antioxidants increased the parasite loads in all midgut sections analyzed. In vivo, the group of vectors fed with reduced molecules showed an increment of trypomastigotes and decreased epimastigotes when analyzed by differential counting. Heme stimulated proliferation by increasing the cell number in the S and G2/M phases, whereas NAC arrested epimastigotes in G1 phase. NAC greatly increased the percentage of trypomastigotes. Taken together, these data show a shift in the triatomine gut microenvironment caused by the redox status may also influence T. cruzi biology inside the vector. In this scenario, oxidants act to turn on epimastigote proliferation while antioxidants seem to switch the cycle towards metacyclogenesis. This is a new insight that defines a key role for redox metabolism in governing the parasitic life cycle.}, }
@article {pmid25669981, year = {2015}, author = {Serguienko, A and Grad, I and Wennerstrøm, AB and Meza-Zepeda, LA and Thiede, B and Stratford, EW and Myklebost, O and Munthe, E}, title = {Metabolic reprogramming of metastatic breast cancer and melanoma by let-7a microRNA.}, journal = {Oncotarget}, volume = {6}, number = {4}, pages = {2451-2465}, pmid = {25669981}, issn = {1949-2553}, mesh = {Apoptosis/drug effects/genetics ; Blotting, Western ; Breast Neoplasms/genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects/genetics ; Cellular Reprogramming/*genetics ; Doxorubicin/pharmacology ; Energy Metabolism/*genetics ; Enzymes/genetics/metabolism ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Glycolysis/genetics ; Humans ; Melanoma/genetics/metabolism/pathology ; MicroRNAs/*genetics/metabolism ; Mitochondria/genetics/metabolism ; Neoplasm Metastasis ; Oxidative Phosphorylation ; Oxidative Stress/genetics ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Let-7 microRNAs (miRNAs) are highly conserved well-established promoters of terminal differentiation that are expressed in healthy adult tissues and frequently repressed in cancer cells. The tumor suppressive role of let-7 in a variety of cancers in vitro and in vivo has been widely documented and prompted these miRNAs to be candidate genes for miRNA replacement therapy. In this study we described a new role of let-7a in reprogramming cancer metabolism, recently identified as a new hallmark of cancer. We show that let-7a down-regulates key anabolic enzymes and increases both oxidative phosphorylation and glycolysis in triple-negative breast cancer and metastatic melanoma cell lines. Strikingly, the accelerated glycolysis coexists with drastically reduced cancer features. Moreover, let-7a causes mitochondrial ROS production concomitant with the up-regulation of oxidative stress responsive genes. To exploit these increased ROS levels for therapeutic purposes, we combined let-7a transfection with the chemotherapeutic drug doxorubicin. In both cancer types let-7a increased cell sensitivity to doxorubicin. Pre-treatment with N-acetyl cysteine (NAC) totally abolished this effect, indicating that the increased doxorubicin sensitivity of let-7a cells depends on the redox pathway. We thus have demonstrated that let-7a plays a prominent role in regulating energy metabolism in cancer cells, further expanding its therapeutic potential.}, }
@article {pmid25669694, year = {2014}, author = {Kopincová, J and Mokrá, D and Mikolka, P and Kolomazník, M and Čalkovská, A}, title = {N-acetylcysteine advancement of surfactant therapy in experimental meconium aspiration syndrome: possible mechanisms.}, journal = {Physiological research}, volume = {63}, number = {Suppl 4}, pages = {S629-42}, doi = {10.33549/physiolres.932938}, pmid = {25669694}, issn = {1802-9973}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Animals, Newborn ; Bronchoalveolar Lavage Fluid/immunology ; Cell Migration Assays, Leukocyte ; Cytokines/metabolism ; Drug Evaluation, Preclinical ; Drug Therapy, Combination ; Edema/prevention &amp; control ; Expectorants/pharmacology/*therapeutic use ; Leukocyte Count ; Lung/drug effects/metabolism ; Meconium Aspiration Syndrome/immunology/metabolism/*prevention &amp; control ; Pilot Projects ; Pulmonary Surfactants/pharmacology/*therapeutic use ; Rabbits ; Random Allocation ; Respiratory Function Tests ; Thiobarbituric Acid Reactive Substances/metabolism ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Meconium aspiration syndrome (MAS) is meconium-induced respiratory failure of newborns associated with activation of inflammatory and oxidative pathways. For severe MAS, exogenous surfactant treatment is used which improves respiratory functions but does not treat the inflammation. Oxidative process can lead to later surfactant inactivation; hence, surfactant combination with antioxidative agent may enhance the therapeutic effect. Young New Zealand rabbits were instilled by meconium suspension and treated by surfactant alone, N-acetylcysteine (NAC) alone or by their combination and oxygen-ventilated for 5 h. Blood samples were taken before and 30 min after meconium application and 30 min, 1, 3 and 5 h after the treatment for evaluating of oxidative damage, total leukocyte count, leukocyte differential count and respiratory parameters. Leukocyte differential was assessed also in bronchoalveolar lavage fluid. NAC alone had only mild therapeutic effect on MAS. However, the combination of NAC and surfactant facilitated rapid onset of therapeutic effect in respiratory parameters (oxygenation index, PaO(2)/FiO(2)) compared to surfactant alone and was the only treatment which prevented neutrophil migration into the lungs, oxidative damage and lung edema. Moreover, NAC suppressed IL-8 and IL-beta formation and thus seems to be favorable agent for improving surfactant therapy in MAS.}, }
@article {pmid25666878, year = {2015}, author = {Köse, SA and Nazıroğlu, M}, title = {N-acetyl cysteine reduces oxidative toxicity, apoptosis, and calcium entry through TRPV1 channels in the neutrophils of patients with polycystic ovary syndrome.}, journal = {Free radical research}, volume = {49}, number = {3}, pages = {338-346}, doi = {10.3109/10715762.2015.1006214}, pmid = {25666878}, issn = {1029-2470}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Calcium/*metabolism ; Cytokines/drug effects ; Female ; Humans ; Neutrophils/*drug effects/metabolism ; Oxidative Stress/drug effects ; Polycystic Ovary Syndrome/*metabolism ; TRPM Cation Channels/metabolism ; TRPV Cation Channels/drug effects/*metabolism ; Young Adult ; }, abstract = {Polycystic ovary syndrome (PCOS) is a common inflammatory and oxidant disease with an uncertain pathogenesis. N-acetyl cysteine (NAC) decreases oxidative stress, intracellular free calcium ion [Ca(2+)]i, and apoptosis levels in human neutrophil. We aimed to investigate the effects of NAC on apoptosis, oxidative stress, and Ca(2+) entry through transient receptor potential vanilloid 1 (TRPV1) and TRP melastatin 2 (TRPM2) channels in neutrophils from patients with PCOS. Neutrophils isolated from PCOS group were investigated in three settings: (1) after incubation with TRPV1 channel blocker capsazepine or TRPM2 channel blocker 2-aminoethyl diphenylborinate (2-APB), (2) after supplementation with NAC (for 6 weeks), and (3) with combination (capsazepine + 2-APB + NAC) exposure. The neutrophils in TRPM2 and TRPV1 experiments were stimulated by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP; 1 μM) and capsaicin (10 μM) as concentration agonists, respectively. Neutrophil lipid peroxidation and capsaicin-induced increase in [Ca(2+)]i concentrations were reduced by capsazepine and NAC treatments. However, the [Ca(2+)]i concentration did not change by fMLP stimulation. Neutrophil lipid peroxidation, apoptosis, caspase-3, caspase-9, cytosolic reactive oxygen species production, and mitochondrial membrane depolarization values were decreased by NAC treatment although neutrophil glutathione peroxidase and reduced glutathione levels were increased by the NAC treatment. Serum lipid peroxidation, luteinizing hormone, testosterone, insulin, interleukin-1 beta, and homocysteine levels were decreased by NAC treatment although serum vitamin A, beta-carotene, vitamin E, and total antioxidant status were increased by the NAC treatment. In conclusion, NAC reduced oxidative stress, apoptosis, cytokine levels, and Ca(2+) entry through TRPV1 channel, which provide supportive evidence that oxidative stress and TRPV1 channel plays a key role in etiology of PCOS.}, }
@article {pmid25665792, year = {2015}, author = {Thuy, le TT and Matsumoto, Y and Thuy, TT and Hai, H and Suoh, M and Urahara, Y and Motoyama, H and Fujii, H and Tamori, A and Kubo, S and Takemura, S and Morita, T and Yoshizato, K and Kawada, N}, title = {Cytoglobin deficiency promotes liver cancer development from hepatosteatosis through activation of the oxidative stress pathway.}, journal = {The American journal of pathology}, volume = {185}, number = {4}, pages = {1045-1060}, doi = {10.1016/j.ajpath.2014.12.017}, pmid = {25665792}, issn = {1525-2191}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Antioxidants/metabolism ; Cytoglobin ; Diet ; Globins/*deficiency/metabolism ; Hepatic Stellate Cells/drug effects/metabolism/pathology ; Humans ; Inflammation/pathology ; Liver/drug effects/metabolism/pathology ; Liver Cirrhosis/metabolism/*pathology ; Liver Neoplasms/*metabolism/*pathology ; Macrophages/drug effects/pathology ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/metabolism/pathology ; Oxidation-Reduction/drug effects ; *Oxidative Stress/drug effects ; Precancerous Conditions/*metabolism/*pathology ; }, abstract = {This study was conducted to clarify the role of cytoglobin (Cygb), a globin expressed in hepatic stellate cells (HSCs), in the development of liver fibrosis and cancer in nonalcoholic steatohepatitis (NASH). Cygb expression was assessed in patients with NASH and hepatocellular carcinoma. Mouse NASH model was generated in Cygb-deficient (Cygb(-/-)) or wild-type (WT) mice by giving a choline-deficient amino acid-defined diet and, in some of them, macrophage deletion and N-acetyl cysteine treatment were used. Primary-cultured mouse HSCs isolated from WT (HSCs(Cygb-wild)) or Cygb(-/-) (HSCs(Cygb-null)) mice were characterized. As results, the expression of CYGB was reduced in patients with NASH and hepatocellular carcinoma. Choline-deficient amino acid treatment for 8 weeks induced prominent inflammation and fibrosis in Cygb(-/-) mice, which was inhibited by macrophage deletion. Surprisingly, at 32 weeks, despite no tumor formation in the WT mice, all Cygb(-/-) mice developed liver cancer, which was ameliorated by N-acetyl cysteine treatment. Altered expression of 31 genes involved in the metabolism of reactive oxygen species was notable in Cygb(-/-) mice. Both HSCs(Cygb-null) and Cygb siRNA-transfected-HSCs(Cygb-wild) exhibited the preactivation condition. Our findings provide important insights into the role that Cygb, expressed in HSCs during liver fibrosis, plays in cancer development with NASH.}, }
@article {pmid25663549, year = {2015}, author = {Usenko, CY and Abel, EL and Kudela, M and Janise, A and Bruce, ED}, title = {Comparison of PBDE congeners as inducers of oxidative stress in zebrafish.}, journal = {Environmental toxicology and chemistry}, volume = {34}, number = {5}, pages = {1154-1160}, doi = {10.1002/etc.2922}, pmid = {25663549}, issn = {1552-8618}, mesh = {Acetylcysteine/toxicity ; Animals ; Down-Regulation/drug effects ; Electron Transport Complex IV/metabolism ; Glutamate-Cysteine Ligase/metabolism ; Glutathione/metabolism ; Glutathione S-Transferase pi/metabolism ; Halogenated Diphenyl Ethers/chemistry/*toxicity ; Oxidative Stress/*drug effects ; Polybrominated Biphenyls/toxicity ; TNF Receptor-Associated Factor 1/metabolism ; Toxicity Tests ; Up-Regulation/drug effects ; Zebrafish/growth &amp; development/*metabolism ; }, abstract = {A proposed primary pathway through which polybrominated diphenyl ethers (PBDEs) disrupt normal biological functions is oxidative stress. In the present study, 4 PBDE congeners were evaluated for their potential to initiate oxidative stress in zebrafish during development: BDE 28, BDE 47, BDE 99, and BDE 100. N-acetylcysteine (NAC) was used to increase intracellular glutathione concentrations and only decreased the effects of BDE 28 at 10 ppm and 20 ppm and BDE 47 at 20 ppm. N-acetylcysteine coexposure did not alter the rates of mortality or curved body axis compared with PBDE exposure alone. The activity of glutathione-S-transferase (GST) was not altered at 24 h postfertilization (hpf), but increased following 10 ppm BDE 28 exposure at 120 hpf. Transcription of several genes associated with stress was also evaluated. At 24 hpf, cytochrome c oxidase subunit 6a (COX6a) transcription was up-regulated in embryos exposed to BDE 99, and BDE 28 exposure up-regulated the transcription of Glutathione-S-transferase-pi (GSTpi). At 24 hpf, glutamate-cysteine ligase (GCLC) was slightly down-regulated by all congeners evaluated. At 120 hpf, TNF receptor-associated protein 1 (TRAP1) and COX6A were up-regulated by all congeners, however GSTpi was down-regulated by all congeners. The results of quantitative real-time transcription polymerase chain reaction are mixed and do not strongly support a transcriptional response to oxidative stress. According to the authors' data, PBDEs do not induce oxidative stress. Oxidative stress may occur at high exposure concentrations; however, this does not appear to be a primary mechanism of action for the PBDE congeners tested.}, }
@article {pmid25663373, year = {2015}, author = {Ahamed, M and Alhadlaq, HA and Ahmad, J and Siddiqui, MA and Khan, ST and Musarrat, J and Al-Khedhairy, AA}, title = {Comparative cytotoxicity of dolomite nanoparticles in human larynx HEp2 and liver HepG2 cells.}, journal = {Journal of applied toxicology : JAT}, volume = {35}, number = {6}, pages = {640-650}, doi = {10.1002/jat.3097}, pmid = {25663373}, issn = {1099-1263}, mesh = {Apoptosis/drug effects ; Calcium Carbonate/*toxicity ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line ; Cell Survival ; Dose-Response Relationship, Drug ; Glutathione/analysis ; Hep G2 Cells/chemistry/*drug effects ; Humans ; Laryngeal Mucosa/chemistry/cytology/*drug effects ; Magnesium/*toxicity ; Metal Nanoparticles/*toxicity ; Oxidative Stress/drug effects ; Reactive Oxygen Species/analysis ; Real-Time Polymerase Chain Reaction ; Tumor Suppressor Protein p53/analysis ; }, abstract = {Dolomite is a natural mineral of great industrial and commercial importance. With the advent of nanotechnology, natural minerals including dolomite in the form of nanoparticles (NPs) are being utilized in various applications to improve the quality of products. However, safety or toxicity information of dolomite NPs is largely lacking. This study evaluated the cytotoxicity of dolomite NPs in two widely used in vitro cell culture models: human airway epithelial (HEp2) and human liver (HepG2) cells. Concentration-dependent decreased cell viability and damaged cell membrane integrity revealed the cytotoxicity of dolomite NPs. We further observed that dolomite NPs induce oxidative stress in a concentration-dependent manner, as indicated by depletion of glutathione and induction of reactive oxygen species (ROS) and lipid peroxidation. Quantitative real-time PCR data demonstrated that the mRNA level of tumor suppressor gene p53 and apoptotic genes (bax, CASP3 and CASP9) were up-regulated whereas the anti-apoptotic gene bcl-2 was down-regulated in HEp2 and HepG2 cells exposed to dolomite NPs. Moreover, the activity of apoptotic enzymes (caspase-3 and caspase-9) was also higher in both kinds of cells treated with dolomite NPs. It is also worth mentioning that HEp2 cells seem to be marginally more susceptible to dolomite NPs exposure than HepG2 cells. Cytotoxicity induced by dolomite NPs was efficiently prevented by N-acetyl cysteine treatment, which suggests that oxidative stress is primarily responsible for the cytotoxicity of dolomite NPs in both HEp2 and HepG2 cells. Toxicity mechanisms of dolomite NPs warrant further investigations at the in vivo level.}, }
@article {pmid25658320, year = {2015}, author = {Moretti, D and Del Bello, B and Allavena, G and Corti, A and Signorini, C and Maellaro, E}, title = {Calpain-3 impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells.}, journal = {PloS one}, volume = {10}, number = {2}, pages = {e0117258}, pmid = {25658320}, issn = {1932-6203}, mesh = {Benzothiazoles/pharmacology ; Calpain/analysis/genetics/*metabolism ; Cell Death ; Cell Line, Tumor ; *Cell Proliferation ; Humans ; Melanoma/genetics/metabolism/*pathology ; Muscle Proteins/analysis/genetics/*metabolism ; Mutation ; Oxidation-Reduction ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation ; }, abstract = {Calpain-3 is an intracellular cysteine protease, belonging to Calpain superfamily and predominantly expressed in skeletal muscle. In human melanoma cell lines and biopsies, we previously identified two novel splicing variants (hMp78 and hMp84) of Calpain-3 gene (CAPN3), which have a significant lower expression in vertical growth phase melanomas and, even lower, in metastases, compared to benign nevi. In the present study, in order to investigate the pathophysiological role played by the longer Calpain-3 variant, hMp84, in melanoma cells, we over-expressed it in A375 and HT-144 cells. In A375 cells, the enforced expression of hMp84 induces p53 stabilization, and modulates the expression of a few p53- and oxidative stress-related genes. Consistently, hMp84 increases the intracellular production of ROS (Reactive Oxygen Species), which lead to oxidative modification of phospholipids (formation of F2-isoprostanes) and DNA damage. Such events culminate in an adverse cell fate, as indicated by the decrease of cell proliferation and by cell death. To a different extent, either the antioxidant N-acetyl-cysteine or the p53 inhibitor, Pifithrin-α, recover cell viability and decrease ROS formation. Similarly to A375 cells, hMp84 over-expression causes inhibition of cell proliferation, cell death, and increase of both ROS levels and F2-isoprostanes also in HT-144 cells. However, in these cells no p53 accumulation occurs. In both cell lines, no significant change of cell proliferation and cell damage is observed in cells over-expressing the mutant hMp84C42S devoid of its enzymatic activity, suggesting that the catalytic activity of hMp84 is required for its detrimental effects. Since a more aggressive phenotype is expected to benefit from down-regulation of mechanisms impairing cell growth and survival, we envisage that Calpain-3 down-regulation can be regarded as a novel mechanism contributing to melanoma progression.}, }
@article {pmid25657778, year = {2014}, author = {Heidari, R and Babaei, H and Eghbal, MA}, title = {Amodiaquine-induced toxicity in isolated rat hepatocytes and the cytoprotective effects of taurine and/or N-acetyl cysteine.}, journal = {Research in pharmaceutical sciences}, volume = {9}, number = {2}, pages = {97-105}, pmid = {25657778}, issn = {1735-5362}, abstract = {Amodiaquine is an antimalarial drug used in the prophylaxis and treatment of this disease. However, hepatotoxicity as a life-threatening adverse effect is associated with its clinical use. We evaluated amodiaquine-induced toxicity in isolated rat hepatocytes as an in vitro model for studying drug-induced hepatotoxicity. This study attempts to investigate the protective effects of taurine and N-acetyl cysteine against the cytotoxicity induced by amodiaquine. Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. This technique is based on liver perfusion with collagenase after removal of calcium ion (Ca(2+)) with a chelator (ethylene glycol tetraacetic acid (EGTA) 0.5 mM). Cells were treated with different concentrations of amodiaquine, taurine and N-acetyl cysteine. Cell death, protein carbonylation, reactive oxygen species formation, lipid peroxidation, and mitochondrial depolarization were assessed as toxicity markers. Amodiaquine cytotoxic mechanism involved protein carbonylation as well as reactive oxygen species formation and lipid peroxidation. In addition, mitochondria seem to be a target for amodiaquine to induce cellular damage. Administration of taurine (200 μM) and/or N-acetyl cysteine (200 μM) reduced oxidative stress, lipid peroxidation and protein carbonylation caused by amodiaquine. Furthermore, amodiaquine-induced mitochondrial injury was significantly mitigated by taurine and/or N-acetyl cysteine. In glutathione-depleted cells, only N-acetyl cysteine protected hepatocytes against amodiaquine, and taurine showed no protective properties in this situation. Taurine and N-acetyl cysteine protect hepatocytes against amodiaquine probably via their antioxidant properties and counteracting oxidative stress.}, }
@article {pmid25653965, year = {2014}, author = {Kumar, A and Bhawani, G and Kumari, N and Murthy, KS and Lalwani, V and Raju, ChN}, title = {Comparative study of renal protective effects of allopurinol and N-acetyl-cysteine on contrast induced nephropathy in patients undergoing cardiac catheterization.}, journal = {Journal of clinical and diagnostic research : JCDR}, volume = {8}, number = {12}, pages = {HC03-7}, pmid = {25653965}, issn = {2249-782X}, abstract = {UNLABELLED: Objectives : To evaluate the difference in the renal protective effects of allopurinol and n-acetyl cysteine along with saline hydration in patients of contrast induced nephropathy (CIN) post cardiac interventions.<br><br>BACKGROUND: CIN remains a common complication of cardiac procedures. Radio contrast agents can cause a reduction in renal function that may be related to oxidative stress underlining various patho- physiologies. Conflicting evidence suggests that administration of allopurinol, a xanthine oxidase inhibitor can prevent CIN.<br><br>MATERIALS AND METHODS: This is a study of 500 patients undergoing angiography and coronary revascularisation in patients showing significant coronary block. The angiography positive patients (275) were prospectively randomised to different treatment protocol to study for their reno-protective effect. The patients received either of the three drugs saline hydration (SH, 1ml/kg/hr), n-acetylcysteine (SH+NAC, 600 mg bd) or Allopurinol (SH+ALLP, 300 mg/day) 12 hours before and after administration of radio contrast agent. Levels of serum creatinine and blood urea of the 275 patients recorded at 24 hour interval were noted post angioplasty over a course of 5 days in patients receiving either omnipaque (125) or visipaque (150) contrast media. All the 500 patients were also assessed for development of any kind of adverse drug effects/reactions with the two contrast media.<br><br>RESULTS: CIN occurred in 56 of 500 the patients (10.6%) who underwent angiography and 49 of 275 patients (17.8%) who underwent angioplasty. In the omnipaque group CIN occurred in 16/40, 8/40, nil/45 in patients receiving SH, NAC plus SH and SH plus ALLP respectively. In the visipaque group CIN occurred in 15/50, 10/50, nil/50 in the three treatments groups respectively. Allopurinol maintained a consistent fall in the serum creatinine &amp; blood urea levels from the baseline values from the end of the 1(st) day (p < .01 &amp; .001) in both the category. Visipaque proved to be better dye than omnipaque with less adverse drug effects/ reactions.<br><br>CONCLUSION: Prophylactic oral administration of allopurinol (300 mg/day) along with hydration is better than n-acetylcysteine and saline hydration alone for protection against CIN in patients undergoing coronary procedures.}, }
@article {pmid25653680, year = {2015}, author = {Thakker, D and Raval, A and Patel, I and Walia, R}, title = {N-acetylcysteine for polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled clinical trials.}, journal = {Obstetrics and gynecology international}, volume = {2015}, number = {}, pages = {817849}, pmid = {25653680}, issn = {1687-9589}, abstract = {Objective. To review the benefits and harms of N-acetylcysteine (NAC) in women with polycystic ovary syndrome (PCOS). Method. Literature search was conducted using the bibliographic databases, MEDLINE (Ovid), CINAHL, EMBASE, Scopus, PsyInfo, and PROQUEST (from inception to September 2013) for the studies on women with PCOS receiving NAC. Results. Eight studies with a total of 910 women with PCOS were randomized to NAC or other treatments/placebo. There were high risk of selection, performance, and attrition bias in two studies and high risk of reporting bias in four studies. Women with NAC had higher odds of having a live birth, getting pregnant, and ovulation as compared to placebo. However, women with NAC were less likely to have pregnancy or ovulation as compared to metformin. There was no significant difference in rates of the miscarriage, menstrual regulation, acne, hirsutism, and adverse events, or change in body mass index, testosterone, and insulin levels with NAC as compared to placebo. Conclusions. NAC showed significant improvement in pregnancy and ovulation rate as compared to placebo. The findings need further confirmation in well-designed randomized controlled trials to examine clinical outcomes such as live birth rate in longer follow-up periods. Systematic review registration number is CRD42012001902.}, }
@article {pmid25653669, year = {2015}, author = {Amini, L and Tehranian, N and Movahedin, M and Ramezani Tehrani, F and Ziaee, S}, title = {Antioxidants and management of polycystic ovary syndrome in Iran: A systematic review of clinical trials.}, journal = {Iranian journal of reproductive medicine}, volume = {13}, number = {1}, pages = {1-8}, pmid = {25653669}, issn = {1680-6433}, abstract = {BACKGROUND: Recently there is a focus on the antioxidants as adjuvant treatment of polycystic ovary syndrome (PCOS), the most endocrinopathy in reproductive age women.<br><br>OBJECTIVE: The aim of this review is answer to the question whether antioxidants are effective for managing of hormonal and metabolic problems in women with PCOS based on first degree evidences from Iran.<br><br>MATERIALS AND METHODS: A systematic review of clinical trials was done in Persian and international databases including PubMed, Scientific Information Database, Google Scholar, Iran Medex, and Magiran up to 2013. Keywords were including polycystic ovary syndrome, Iran, vitamin, antioxidant. From 440 potential studies found electronically, 11 studies; including 444 women in intervention and 390 women in control groups. Intervention in three studies was Calcium-vitamin D or calcitriol; in three studies was &#x3c9;-3 fatty acids; in two studies was N-acetyl cysteine; in one study was folic acid; in one study was Zinc; and in one study was Soy.<br><br>RESULTS: Finally, 11 studies that were relevant and met the inclusion criteria reviewed. There were 7 studies in English and 4 studies in Persian. We couldn't include all studies because all full texts were not accessible.<br><br>CONCLUSION: The results showed that antioxidants and vitamins have positive effects on management of PCOS women. Although it seems more studies is necessary in this field.}, }
@article {pmid25653524, year = {2015}, author = {Li, X and Gao, L and Zheng, L and Kou, J and Zhu, X and Jiang, Y and Zhong, Z and Dan, J and Xu, H and Yang, Y and Li, H and Shi, S and Cao, W and Zhao, Y and Tian, Y and Yang, L}, title = {The efficacy and mechanism of apoptosis induction by hypericin-mediated sonodynamic therapy in THP-1 macrophages.}, journal = {International journal of nanomedicine}, volume = {10}, number = {}, pages = {821-838}, pmid = {25653524}, issn = {1178-2013}, mesh = {Anthracenes ; Apoptosis/*drug effects/radiation effects ; Blotting, Western ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Survival/drug effects/radiation effects ; Cytochromes c/metabolism ; Cytosol/metabolism ; Humans ; Macrophages/drug effects/*pathology/radiation effects ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Electron, Transmission ; Mitochondria/metabolism/*pathology ; Perylene/*analogs &amp; derivatives/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Radiation-Sensitizing Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; *Ultrasonic Therapy ; }, abstract = {PURPOSE: To investigate the sonoactivity of hypericin (HY), together with its sonodynamic effect on THP-1 macrophages and the underlying mechanism.<br><br>MATERIALS AND METHODS: CCK-8 was used to examine cell viability. Confocal laser scanning microscopy was performed to assess the localization of HY in cells, reactive oxygen species (ROS) generation, and opening of the mitochondrial permeability transition pore (mPTP) after different treatments. Apoptosis was analyzed using Hoechst-propidium iodide and transmission electron microscopy. Mitochondrial membrane potential (&#x394;&#x3a8;m) collapse was detected via fluorescence microscopy. Lipoprotein oxidation was determined in malondialdehyde (MDA) assays. Western blotting was conducted to determine the translocation of BAX and cytochrome C and the expression of apoptosis-related proteins.<br><br>RESULTS: HY was sublocalized among the nuclei and the mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosome in the cytosol of THP-1 macrophages. Under low-intensity ultrasound irradiation, HY significantly decreased cell viability and induced apoptosis. Furthermore, greater ROS generation, higher MDA levels, and greater &#x394;&#x3a8;m loss were observed in the sonodynamic therapy (SDT) group. Both ROS generation and MDA levels were significantly reduced by the ROS scavenger N-acetyl cysteine (NAC) and the singlet oxygen scavenger sodium azide. Most of the loss of &#x394;&#x3a8;m was inhibited by pretreatment with NAC, sodium azide, and the mPTP inhibitor cyclosporin A (CsA). mPTP opening was induced upon SDT but was reduced by pretreatment with bongkrekic acid, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium, CsA, and NAC. Western blot analyses revealed translocation of BAX and cytochrome C, downregulated expression of Bcl-2, and upregulated expression of cleaved caspase-9, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase in the SDT group, which were reversed by NAC.<br><br>CONCLUSION: HY mediated SDT-induced apoptosis in THP-1 macrophages via ROS generation. Then, the proapoptotic factor BAX translocated from the cytosol to the mitochondria, increasing the ratio of BAX/Bcl-2, and the mPTP opened to release cytochrome C. This study demonstrated the great potential of HY-mediated SDT for treating atherosclerosis.}, }
@article {pmid25652861, year = {2015}, author = {He, L and You, X and Li, G and Zeng, Y and Li, R and Zhu, C and Yu, M and Wu, Y}, title = {[Mycoplasma genitalium-derived lipid-associated membrane proteins negatively regulate cytokine secretion by inducing HO-1 expression in placental trophoblast cells].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {31}, number = {2}, pages = {194-198}, pmid = {25652861}, issn = {1007-8738}, mesh = {Adult ; Bacterial Proteins/genetics/*metabolism ; Cells, Cultured ; Female ; Gene Expression Regulation ; Heme Oxygenase-1/*genetics/metabolism ; Humans ; Mycoplasma Infections/*enzymology/genetics/microbiology ; Mycoplasma genitalium/genetics/*metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; NF-kappa B/genetics/*metabolism ; Placenta/*cytology/enzymology/microbiology ; Pregnancy ; Reactive Oxygen Species/metabolism ; Trophoblasts/cytology/*enzymology/microbiology ; Tumor Necrosis Factor-alpha/genetics/*metabolism ; }, abstract = {OBJECTIVE: To observe the expression of heme oxygenase-1 (HO-1) in regulation of cytokines response induced by Mycoplasma genitalium-derived lipid-associated membrane proteins (LAMPs) in placental trophoblast cells.<br><br>METHODS: Placental trophoblast cells were cultured in vitro and stimulated by 0.5-5 &#x3bc;g/mL LAMPs for 4 to 12 hours. Expression of HO-1 mRNA and protein, and nuclear translocation of nuclear factor erythroid-2 related factor 2 (Nrf2) were detected by real-time quantitative PCR and Western blotting, respectively. The intracellular formation of reactive oxygen species (ROS) was detected by the fluorescent probe H2DCFDA. N-acetyl-cysteine (NAC) and nuclear factor erythroid-2 related factor 2 (Nrf2) siRNA were respectively used to analyze the roles of ROS and Nrf2 in mediating HO-1 expression. Finally, placental trophoblast cells were transfected with HO-1 siRNA, or preincubated by the HO-1 agonist cobalt protoporphyrin (CoPP) or its inhibitor zinc protoporphyrin (ZnPP), and LAMPs-induced secretion of TNF-&#x3b1; and IL-1&#x3b2; were detected by ELISA.<br><br>RESULTS: M. genitalium LAMPs induced the expression of HO-1 mRNA and protein, the accumulation of ROS and the nuclear translocation of Nrf2 in placental trophoblast cells. NAC treatment inhibited LAMPs-induced HO-1 expression and Nrf2 nuclear translocation, and the transfection of Nrf2 siRNA significantly abrogated HO-1 expression. Furthermore, HO-1 siRNA and ZnPP treatment increased LAMPs-induced TNF-&#x3b1; and IL-1&#x3b2; secretion, while the HO-1 agonist CoPP treatment further decreased their production.<br><br>CONCLUSION: M. genitalium LAMPs could induce placental trophoblast cells to express HO-1 through ROS/Nrf2 pathways. Up-regulation of HO-1 negatively regulates excessive production of cytokines.}, }
@article {pmid25652258, year = {2015}, author = {McGovern, AJ and Vitkovitsky, IV and Jones, DL and Mullins, ME}, title = {Can AST/ALT ratio indicate recovery after acute paracetamol poisoning?.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {53}, number = {3}, pages = {164-167}, doi = {10.3109/15563650.2015.1006399}, pmid = {25652258}, issn = {1556-9519}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Alanine Transaminase/*blood ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/therapeutic use ; Aspartate Aminotransferases/*blood ; Chemical and Drug Induced Liver Injury/blood/*diagnosis/drug therapy/etiology ; *Clinical Enzyme Tests ; Humans ; Predictive Value of Tests ; Recovery of Function ; Retrospective Studies ; Severity of Illness Index ; Time Factors ; Treatment Outcome ; }, abstract = {CONTEXT: Paracetamol (acetaminophen or APAP) is the most common pharmaceutical exposure in the US. Elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels indicate hepatic toxicity. AST and ALT levels rise in similar proportions but later decline at different rates, with AST falling more rapidly than ALT.<br><br>OBJECTIVE: To determine whether the AST/ALT ratio can indicate that a patient has passed the time of peak AST concentration.<br><br>METHODS: We retrospectively identified cases of patients hospitalized for acute APAP poisoning by querying the pharmacy database of all patients treated with acetylcysteine (NAC) from January 1, 2001 to March 19, 2013. We included all patients with severe APAP poisoning, defined as AST or ALT greater than 1000 IU/L. Patients who were given NAC for other indications, those without APAP poisoning, and those receiving liver transplantation were excluded. We then recorded paired AST and ALT concentrations from each patient's hospital course. We classified each pair as clearly post-peak or not, and calculated the AST/ALT ratio for each pair of values. We compared different thresholds of AST/ALT ratio in increments of 0.1 to find the optimal value that reliably indicated resolving transaminases.<br><br>RESULTS: We identified 1820 patients who received NAC during the study period. Of these, 333 received NAC for suspected poisoning by APAP. After excluding patients without severe APAP poisoning, other diagnoses explaining transaminase elevations, and patients who underwent liver transplantation, we had 37 evaluable patients with 343 evaluable pairs of AST and ALT concentrations. An AST/ALT ratio less than or equal to 0.4 was 99% sensitive for identifying patients with resolving transaminases.<br><br>CONCLUSION: An AST/ALT ratio less than or equal to 0.4 following severe hepatoxicity from paracetamol poisoning appears to be highly predictive of recovery in patients treated with NAC. This has potential to be an indicator of safe discontinuation of NAC treatment.}, }
@article {pmid25650867, year = {2015}, author = {Kung, HJ and Changou, CA and Li, CF and Ann, DK}, title = {Chromatophagy: autophagy goes nuclear and captures broken chromatin during arginine-starvation.}, journal = {Autophagy}, volume = {11}, number = {2}, pages = {419-421}, doi = {10.1080/15548627.2015.1009789}, pmid = {25650867}, issn = {1554-8635}, mesh = {Arginine/*metabolism ; Autophagy/*physiology ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Chromatin/*metabolism ; DNA/metabolism ; *DNA Damage ; Humans ; }, }
@article {pmid25649257, year = {2015}, author = {Jiang, A and Li, Y and Wang, P and Shan, X and Jiang, P and Wang, X and Feng, Q}, title = {Mechanism of Dose-Dependent Regulation of UBE1L by Polyphenols in Human Bronchial Epithelial Cells.}, journal = {Journal of cellular biochemistry}, volume = {116}, number = {8}, pages = {1553-1562}, doi = {10.1002/jcb.25109}, pmid = {25649257}, issn = {1097-4644}, mesh = {Antineoplastic Agents/*pharmacology ; Bronchi/cytology/*drug effects ; Catechin/analogs &amp; derivatives/pharmacology ; Cell Line ; Cell Survival/drug effects ; Curcumin/pharmacology ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects ; Gene Expression Regulation/drug effects ; Humans ; Polyphenols/*pharmacology ; Reactive Oxygen Species/metabolism ; Resveratrol ; Signal Transduction/drug effects ; Stilbenes/pharmacology ; Ubiquitin-Activating Enzymes/*genetics/*metabolism ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {Ubiquitin activating enzyme E1-like (UBE1L) is the activating enzyme for ISG15ylation (ISG15, interferon stimulated gene 15). UBE1L is thought to be a candidate tumor suppressor gene and has positive activity against stress responses such as viral infections. Both type I interferon and retinoic acid are known to induce UBE1L expression. However, the molecular mechanism of UBE1L regulation is unclear. Here, the effect of several chemopreventive polyphenols on UBE1L expression in human bronchial epithelial cells (Beas-2B) was investigated. Lower concentrations of curcumin, (-)-epigallocatechin-3-gallate (EGCG) and resveratrol upregulated UBE1L, while high concentrations of curcumin, EGCG and resveratrol downregulated UBE1L levels. Interestingly, curcumin, EGCG and resveratrol diminished intracellular reactive oxygen species (ROS) at lower concentrations but generated ROS at higher concentrations. The antioxidant N-acetylcysteine (NAC) increased UBE1L protein levels, while pro-oxidants such as hydrogen peroxide and tert-butyl hydroperoxide (tBHP) decreased UBE1L protein levels, indicating that the intracellular redox status is associated with UBE1L expression. Kinase inhibitors were used to examine the contribution of mitogen-activated protein kinase (MAPK) activity to the polyphenol-regulated UBE1L. Only the inhibition of c-Jun N-terminal kinase (JNK) significantly reduced UBE1L expression. Knockdown of nuclear factor erythroid-2 related factor-2 (Nrf2) caused a concomitant decrease in UBE1L protein levels. It is concluded from the above mentioned results that JNK/Nrf2 signal pathway is involved in the regulation of UBE1L via intracellular ROS status when cells came in contact with polyphenols.}, }
@article {pmid25645871, year = {2015}, author = {Saptarshi, SR and Feltis, BN and Wright, PF and Lopata, AL}, title = {Investigating the immunomodulatory nature of zinc oxide nanoparticles at sub-cytotoxic levels in vitro and after intranasal instillation in vivo.}, journal = {Journal of nanobiotechnology}, volume = {13}, number = {}, pages = {6}, pmid = {25645871}, issn = {1477-3155}, mesh = {Acetylcysteine/pharmacology ; Administration, Intranasal ; Animals ; Cell Line/drug effects ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects/immunology ; Female ; Heme Oxygenase-1/genetics ; Humans ; Immunologic Factors/administration &amp; dosage/*pharmacology ; Inflammation/genetics ; Interleukin-8/genetics ; MAP Kinase Signaling System/drug effects ; Metal Nanoparticles/*administration &amp; dosage/*toxicity ; Mice, Inbred BALB C ; NF-kappa B/metabolism ; Toxicity Tests/methods ; Zinc Oxide/administration &amp; dosage/*pharmacology ; }, abstract = {BACKGROUND: This study evaluates the time-dependent pro-inflammatory response of the model human lung epithelial cells (A549) to industrially relevant zinc oxide nanoparticles (ZnO NPs). In terms of toxicity, ZnO-NPs are categorised into the group of high toxicity nanomaterials. However information on pro-inflammatory potential of these NPs at sub-toxic concentrations is limited. Understanding how cellular defense mechanisms function in the presence of sub-cytotoxic concentrations of these NPs is vital. Moreover, there is an urgent need for additional in vivo studies addressing pulmonary toxicity due to accidental inhalation of ZnO NPs.<br><br>RESULTS: Exposure to sub-cytotoxic ZnO NP concentrations (20 &#x3bc;g/mL) induced significant up-regulation of mRNA for the pro-inflammatory cytokine IL-8 and redox stress marker heme oxygenase-1, along with increased release of IL-8. The highest pro-inflammatory response was recorded after 4 to 6 hr exposure to ZnO NPs over a 24 hr period. Pre-treatment of A549 cells with the sulfhydryl antioxidant N-acetyl cysteine (at 5 mM) resulted in significant reduction of the up-regulation of inflammatory markers, confirming the role of reactive oxygen species in the observed immunomodulatory effects, independent of cytotoxicity. Furthermore, we report for the first time that, intranasal instillation of a single dose (5 mg/kg) of pristine or surfactant-dispersed ZnO NPs can cause pulmonary inflammation, already after 24 hr in a murine model. This was confirmed by up-regulation of eotaxin mRNA in the lung tissue and release of pro-inflammatory cytokines in the sera of mice exposed to ZnO NPs.<br><br>CONCLUSION: Our study highlights that even at sub-cytotoxic doses ZnO NPs can stimulate a strong inflammatory and antioxidant response in A549 cells. ZnO NP mediated cytotoxicity may be the outcome of failure of cellular redox machinery to contain excessive ROS formation. Moreover exposure to a single but relatively high dose of ZnO NPs via intranasal instillation may provoke acute pulmonary inflammatory reactions in vivo.}, }
@article {pmid25640478, year = {2015}, author = {Gao, Y and Chu, SF and Li, JP and Zhang, Z and Yan, JQ and Wen, ZL and Xia, CY and Mou, Z and Wang, ZZ and He, WB and Guo, XF and Wei, GN and Chen, NH}, title = {Protopanaxtriol protects against 3-nitropropionic acid-induced oxidative stress in a rat model of Huntington's disease.}, journal = {Acta pharmacologica Sinica}, volume = {36}, number = {3}, pages = {311-322}, pmid = {25640478}, issn = {1745-7254}, support = {K22 AA020303/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*pharmacology ; Basal Ganglia/*drug effects/metabolism/pathology/physiopathology ; Behavior, Animal/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; HSP70 Heat-Shock Proteins/metabolism ; Heme Oxygenase (Decyclizing)/metabolism ; Humans ; Huntington Disease/chemically induced/metabolism/pathology/physiopathology/*prevention &amp; control ; Male ; Mitochondria/drug effects/metabolism ; Motor Activity/drug effects ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-E2-Related Factor 2/metabolism ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; *Nitro Compounds ; *Propionates ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sapogenins/*pharmacology ; Signal Transduction/drug effects ; Time Factors ; Weight Loss/drug effects ; }, abstract = {AIM: Protopanaxtriol (Ppt) is extracted from Panax ginseng Mayer. In the present study, we investigated whether Ppt could protect against 3-nitropropionic acid (3-NP)-induced oxidative stress in a rat model of Huntington's disease (HD) and explored the mechanisms of action.<br><br>METHODS: Male SD rats were treated with 3-NP (20 mg/kg on d 1, and 15 mg/kg on d 2-5, ip). The rats received Ppt (5, 10, and 20 mg/kg, po) daily prior to 3-NP administration. Nimodipine (12 mg/kg, po) or N-acetyl cysteine (NAC, 100 mg/kg, po) was used as positive control drugs. The body weight and behavior were monitored within 5 d. Then the animals were sacrificed, neuronal damage in striatum was estimated using Nissl staining. Hsp70 expression was detected with immunohistochemistry. Reactive oxygen species (ROS) generation was measured using dihydroethidium (DHE) staining. The levels of components in the Nrf2 pathway were measured with immunohistochemistry and Western blotting.<br><br>RESULTS: 3-NP resulted in a marked reduction in the body weight and locomotion activity accompanied by progressive striatal dysfunction. In striatum, 3-NP caused ROS generation mainly in neurons rather than in astrocytes and induced Hsp70 expression. Administration of Ppt significantly alleviated 3-NP-induced changes of body weight and behavior, decreased ROS production and restored antioxidant enzymes activities in striatum. Moreover, Ppt directly scavenged free radicals, increased Nrf2 entering nucleus, and the expression of its downstream products heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidase 1 (NQO1) in striatum. Similar effects were obtained with the positive control drugs nimodipine or NAC.<br><br>CONCLUSION: Ppt exerts a protective action against 3-NP-induced oxidative stress in the rat model of HD, which is associated with its anti-oxidant activity.}, }
@article {pmid25639750, year = {2015}, author = {Sakamoto, S and Muramatsu, Y and Satoh, K and Ishida, F and Kikuchi, N and Sano, G and Sugino, K and Isobe, K and Takai, Y and Homma, S}, title = {Effectiveness of combined therapy with pirfenidone and inhaled N-acetylcysteine for advanced idiopathic pulmonary fibrosis: a case-control study.}, journal = {Respirology (Carlton, Vic.)}, volume = {20}, number = {3}, pages = {445-452}, doi = {10.1111/resp.12477}, pmid = {25639750}, issn = {1440-1843}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Aged ; Aged, 80 and over ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage ; Disease-Free Survival ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/administration &amp; dosage ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/physiopathology ; Male ; Middle Aged ; Pyridones/*administration &amp; dosage ; Retrospective Studies ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND AND OBJECTIVE: Treatment with pirfenidone may slow the decline in vital capacity and increase progression-free survival (PFS) in idiopathic pulmonary fibrosis (IPF). The effects of combination therapy with inhaled N-acetylcysteine (NAC) and pirfenidone are unclear. We assessed the effects of this combination therapy in patients with advanced IPF.<br><br>METHODS: Patients with a diagnosis of advanced IPF (Japanese Respiratory Society stage III/IV IPF) and a relative decline in forced vital capacity (FVC) of &#x2265; 10% within the previous 6 (&#xb1; 2) months were enrolled. Outcomes were evaluated in a 12-month follow-up pulmonary function test. Treatment was considered ineffective if the decline in FVC was &#x2265; 10% and effective if the decline was <10%. We compared clinical characteristics, effectiveness and PFS between patients receiving inhaled NAC plus pirfenidone (n = 24) and those receiving pirfenidone alone (control; n = 10).<br><br>RESULTS: Data from 34 IPF patients (age range, 59-82 years) were analysed. At the 12-month follow-up examination, treatment was deemed effective in 8 of 17 (47%) patients receiving NAC plus pirfenidone and in 2 of 10 (20%) receiving pirfenidone alone. The annual rate of change in FVC was -610 mL in the NAC plus pirfenidone group and -1320 mL in the pirfenidone group (P < 0.01). PFS was longer (304 days) in the NAC plus pirfenidone group than in the pirfenidone group (168 days; P = 0.016).<br><br>CONCLUSIONS: Combination treatment with inhaled NAC and oral pirfenidone reduced the rate of annual FVC decline and improved PFS in patients with advanced IPF.}, }
@article {pmid25638384, year = {2014}, author = {Urban, M and Cagáňová, B and Plačková, S and Kurcová, I and Pelclova, D}, title = {Paracetamol poisonings in the Czech and Slovak Republic and N-acetylcysteine treatment. Data analysis.}, journal = {Neuro endocrinology letters}, volume = {35 Suppl 2}, number = {}, pages = {180-185}, pmid = {25638384}, issn = {0172-780X}, mesh = {Acetaminophen/administration &amp; dosage/*poisoning ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Non-Narcotic/administration &amp; dosage/*poisoning ; Child ; Child, Preschool ; Czech Republic/epidemiology ; Drug Overdose/*epidemiology ; Drug-Related Side Effects and Adverse Reactions/*epidemiology ; Humans ; Infant ; Middle Aged ; Slovakia/epidemiology ; Young Adult ; }, abstract = {OBJECTIVES: Paracetamol overdose belongs to frequent calls to Toxicological Information Centre (TIC) in the Czech Republic and to the National Toxicological Information Centre (NTIC) in Slovakia. The aim of the study was to evaluate outcomes and side effects of paracetamol overdose in both countries.<br><br>METHODS: Data concerning paracetamol poisoning extracted from TIC and NTIC databases 2000-2013 and discharge reports were analysed. Numbers and outcomes in patients presenting within 24 hours of a single paracetamol overdose were compared in relation to 3 paracetamol concentration bands (&#x2264; 100 mg/l, 100-149 mg/l, and 150 mg/l).<br><br>RESULTS: 5397 inquiries concerning paracetamol were recorded in TIS and NTIC. Data from 196 discharge reports with plasma level were studied. Median age of the patients was 18 (0.2-86) years. Eight/196 (4.1%) patients developed side effects after N-acetylcysteine (NAC) administration. 120 cases fulfilled time criteria of the study and were divided into 3 groups, where 55.7%, 73.1% and 96.9% patients have been treated with NAC. Among these 120 patients, favourable outcome was seen in 100%, 100%, and 92.8%, respectively. One death due to suicidal attempt with plasma level 407 mg/l presenting at 20 hours has been recorded among 120 patients. No patient without NAC treatment died due to acute overdose and plasma concentration &#x2264; 150 mg/I at 4 hours.<br><br>CONCLUSIONS: These data support the opinion that NAC should not be used in patients with < 149 mg/l levels in absence of higher risk factors because of very low risk of hepatotoxicity on one side, and side effects on the other side.}, }
@article {pmid25631537, year = {2015}, author = {Furmaga, J and Wax, P and Kleinschmidt, K}, title = {N-Acetylcysteine (NAC)-Induced Hyponatremia Caused by an Electronic Medical Record (EMR) Order Error.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {11}, number = {3}, pages = {355-358}, pmid = {25631537}, issn = {1937-6995}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects ; Antidotes/administration &amp; dosage/*adverse effects ; Biomarkers/blood ; *Electronic Health Records ; Epilepsy, Tonic-Clonic/blood/chemically induced/diagnosis ; Female ; Humans ; Hyponatremia/blood/*chemically induced/diagnosis ; Infant ; Infusions, Intravenous ; *Medical Order Entry Systems ; *Medication Errors ; Poisoning/blood/diagnosis/*drug therapy ; Risk Factors ; Sodium/blood ; Time Factors ; }, abstract = {INTRODUCTION: Intravenous N-acetylcysteine (NAC) causes few adverse drug events, with mild anaphylactoid reactions being the most common. Hyponatremia as a complication of hypoosmolar NAC solution has been reported. We describe how a locally constructed electronic medical record (EMR) order set for IV NAC resulted in a seizure from hyponatremia due to excess free water administration.<br><br>CASE REPORT: A 13-month-old female with no past medical history presented to a hospital after ingesting an unknown number of acetaminophen 500 mg tablets. The 4-h acetaminophen concentration was 343 mcg/mL, and she was started on IV NAC. 8.2 h into her 21-h IV NAC protocol, she developed a tonic-clonic seizure. Repeat serum sodium was 124 mEq/L, a decrease from 142 mEq/L at the time of admission. She was treated with hypertonic saline, lorazepam, and levetiracetam and had no further seizures. A brain MRI and EEG were both normal. After the seizure was stabilized, the providers noticed that the patient had receive a total of 900 mL of D5W (112.5 mL/kg) in the first 9 h of hospitalization. This was caused by a poorly constructed, restrictive, EMR order set that did not allow customization of the IV NAC preparation.<br><br>DISCUSSION: Because the 21-h IV NAC administration involves preparation of 3 different doses infused over 3 different time intervals, an order set was developed to reduce ordering errors. However, error in its construction caused the pharmacist to prepare a solution containing too much free water, decreasing patient's intravascular sodium and resulting in a seizure.<br><br>CONCLUSION: The purposes of our case report were to highlight the dangers of overreliance on EMR order sets and to recognize hyponatremic seizures as an adverse reaction of an inappropriately prepared IV NAC.}, }
@article {pmid25630265, year = {2015}, author = {Cheng, AJ and Bruton, JD and Lanner, JT and Westerblad, H}, title = {Antioxidant treatments do not improve force recovery after fatiguing stimulation of mouse skeletal muscle fibres.}, journal = {The Journal of physiology}, volume = {593}, number = {2}, pages = {457-472}, pmid = {25630265}, issn = {1469-7793}, mesh = {Animals ; Antioxidants/*pharmacology ; Calcium/metabolism ; Female ; Mice ; Mice, Inbred C57BL ; *Muscle Fatigue ; Muscle Fibers, Skeletal/*drug effects/metabolism/physiology ; NADPH Oxidases/antagonists &amp; inhibitors ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; *Recovery of Function ; }, abstract = {The contractile performance of skeletal muscle declines during intense activities, i.e. fatigue develops. Fatigued muscle can enter a state of prolonged low-frequency force depression (PLFFD). PLFFD can be due to decreased tetanic free cytosolic [Ca(2+) ] ([Ca(2+) ]i) and/or decreased myofibrillar Ca(2+) sensitivity. Increases in reactive oxygen and nitrogen species (ROS/RNS) may contribute to fatigue-induced force reductions. We studied whether pharmacological ROS/RNS inhibition delays fatigue and/or counteracts the development of PLFFD. Mechanically isolated mouse fast-twitch fibres were fatigued by sixty 150 ms, 70 Hz tetani given every 1 s. Experiments were performed in standard Tyrode solution (control) or in the presence of: NADPH oxidase (NOX) 2 inhibitor (gp91ds-tat); NOX4 inhibitor (GKT137831); mitochondria-targeted antioxidant (SS-31); nitric oxide synthase (NOS) inhibitor (l-NAME); the general antioxidant N-acetylcysteine (NAC); a cocktail of SS-31, l-NAME and NAC. Spatially and temporally averaged [Ca(2+) ]i and peak force were reduced by ∼20% and ∼70% at the end of fatiguing stimulation, respectively, with no marked differences between groups. PLFFD was similar in all groups, with 30 Hz force being decreased by ∼60% at 30 min of recovery. PLFFD was mostly due to decreased tetanic [Ca(2+) ]i in control fibres and in the presence of NOX2 or NOX4 inhibitors. Conversely, in fibres exposed to SS-31 or the anti ROS/RNS cocktail, tetanic [Ca(2+) ]i was not decreased during recovery so PLFFD was only caused by decreased myofibrillar Ca(2+) sensitivity. The cocktail also increased resting [Ca(2+) ]i and ultimately caused cell death. In conclusion, ROS/RNS-neutralizing compounds did not counteract the force decline during or after induction of fatigue.}, }
@article {pmid25627470, year = {2015}, author = {Khan, SS and Ghouse, SS and Chandran, P}, title = {Toxic effect of environmentally relevant concentration of silver nanoparticles on environmentally beneficial bacterium Pseudomonas putida.}, journal = {Bioprocess and biosystems engineering}, volume = {38}, number = {7}, pages = {1243-1249}, doi = {10.1007/s00449-015-1365-z}, pmid = {25627470}, issn = {1615-7605}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Catalase/metabolism ; Glutathione Reductase/metabolism ; Lipid Peroxidation ; Metal Nanoparticles/chemistry/*toxicity ; Pseudomonas putida/*drug effects/enzymology/metabolism ; Reactive Oxygen Species/metabolism ; Silver/*chemistry ; Superoxide Dismutase/metabolism ; }, abstract = {Silver nanoparticles (Ag NPs) are being increasingly used in many consumer products owing to their excellent antimicrobial properties. The continuous use of Ag NPs in consumer products will lead to environmental release. The present study evaluated the toxic effects and the possible underlying mechanism of Ag NPs on Pseudomonas putida. Ag NP exposure inhibited growth of the cells. Increased lipid peroxidation occurred coincident with suppression of the antioxidant defense system. Ag NP exposure caused reactive oxygen species (ROS) production, glutathione depletion and inactivation of the antioxidant enzyme superoxide dismutase, catalase and glutathione reductase. The addition of superoxide dismutase or pretreatment of P. putida with N-acetyl cysteine that quenches ROS reduced toxicity of the NPs.}, }
@article {pmid25627108, year = {2015}, author = {Usai, C and Ravera, S and Cuccarolo, P and Panfoli, I and Dufour, C and Cappelli, E and Degan, P}, title = {Dysregulated Ca2+ homeostasis in Fanconi anemia cells.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {8088}, pmid = {25627108}, issn = {2045-2322}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Calcium/*metabolism ; Calcium-Transporting ATPases/metabolism ; Carbocyanines/metabolism ; Cell Line ; Fanconi Anemia/*metabolism/*pathology ; Fanconi Anemia Complementation Group Proteins/metabolism ; Fibroblasts/drug effects/*metabolism/pathology ; Heterocyclic Compounds, 3-Ring/metabolism ; *Homeostasis/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Kinetics ; Microscopy, Confocal ; Mitochondria/drug effects/metabolism ; Models, Biological ; Resveratrol ; Stilbenes/pharmacology ; Thapsigargin/pharmacology ; }, abstract = {Fanconi Anemia (FA) is a rare and complex inherited blood disorder associated with bone marrow failure and malignancies. Many alterations in FA physiology appear linked to red-ox unbalance including alterations in the morphology and structure of nuclei, intermediate filaments and mitochondria, defective respiration, reduced ATP production and altered ATP/AMP ratio. These defects are consistently associated with impaired oxygen metabolism indeed treatment with antioxidants N-acetylcysteine (NAC) and resveratrol (RV) does rescue FA physiology. Due to the importance of the intracellular calcium signaling and its key function in the control of intracellular functions we were interested to study calcium homeostasis in FA. We found that FANCA cells display a dramatically low intracellular calcium concentration ([Ca(2+)]i) in resting conditions. This condition affects cellular responses to stress. The flux of Ca(2+) mobilized by H2O2 from internal stores is significantly lower in FANCA cells in comparison to controls. The low basal [Ca(2+)]i in FANCA appears to be an actively maintained process controlled by a finely tuned interplay between different intracellular Ca(2+) stores. The defects associated with the altered Ca(2+) homeostasis appear consistently overlapping those related to the unbalanced oxidative metabolism in FA cells underlining a contiguity between oxidative stress and calcium homeostasis.}, }
@article {pmid25625649, year = {2015}, author = {Takano, H and Momota, Y and Kani, K and Aota, K and Yamamura, Y and Yamanoi, T and Azuma, M}, title = {γ-Tocotrienol prevents 5-FU-induced reactive oxygen species production in human oral keratinocytes through the stabilization of 5-FU-induced activation of Nrf2.}, journal = {International journal of oncology}, volume = {46}, number = {4}, pages = {1453-1460}, pmid = {25625649}, issn = {1791-2423}, mesh = {Antimetabolites, Antineoplastic/*adverse effects ; Antioxidants/*pharmacology ; Cell Line ; Cell Nucleus/metabolism ; Cell Proliferation/drug effects ; Fluorouracil/*adverse effects ; Gene Expression Regulation/drug effects ; Humans ; Keratinocytes/cytology/*drug effects/metabolism ; Mouth/cytology ; NF-E2-Related Factor 2/metabolism ; Reactive Oxygen Species/metabolism ; Stomatitis/chemically induced/prevention &amp; control ; Tocotrienols/*pharmacology ; }, abstract = {UNLABELLED: Chemotherapy-induced oral mucositis is a common adverse event in patients with oral squamous cell carcinoma, and is initiated through a variety of mechanisms, including the generation of reactive oxygen species (ROS). In this study, we examined the preventive effect of γ-tocotrienol on the 5-FU-induced ROS production in human oral keratinocytes (RT7). We treated RT7 cells with 5-FU and γ-tocotrienol at concentrations of 10 µg/ml and 10 nM, respectively. When cells were treated with 5-FU alone, significant growth inhibition was observed as compared to untreated cells. This inhibition was, in part, due to the ROS gene-rated by 5-FU treatment, because N-acetyl cysteine (NAC), a ROS scavenger, significantly ameliorated the growth of RT7 cells. γ-tocotrienol showed no cytotoxic effect on the growth of RT7 cells. Simultaneous treatment of cells with these agents resulted in the significant recovery of cell growth, owing to the suppression of ROS generation by γ-tocotrienol. Whereas 5-FU stimulated the expression of NF-E2-related factor 2 (Nrf2) protein in the nucleus up to 12 h after treatment of RT7 cells, γ-tocotrienol had no obvious effect on the expression of nuclear Nrf2 protein. Of note, the combined treatment with both agents stabilized the 5-FU-induced nuclear Nrf2 protein expression until 24 h after treatment. In addition, expression of Nrf2-dependent antioxidant genes, such as heme oxygenase-1 (HO-1) and<br><br>NAD(P)H: quinone oxidoreductase-1 (NQO-1), was significantly augmented by treatment of cells with both agents. These findings suggest that &#x3b3;-tocotrienol could prevent 5-FU-induced ROS generation by stabilizing Nrf2 activation, thereby leading to ROS detoxification and cell survival in human oral keratinocytes.}, }
@article {pmid25620313, year = {2015}, author = {Kopke, R and Slade, MD and Jackson, R and Hammill, T and Fausti, S and Lonsbury-Martin, B and Sanderson, A and Dreisbach, L and Rabinowitz, P and Torre, P and Balough, B}, title = {Efficacy and safety of N-acetylcysteine in prevention of noise induced hearing loss: a randomized clinical trial.}, journal = {Hearing research}, volume = {323}, number = {}, pages = {40-50}, doi = {10.1016/j.heares.2015.01.002}, pmid = {25620313}, issn = {1878-5891}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Audiometry, Pure-Tone ; Auditory Threshold ; Cytoprotection ; Double-Blind Method ; Hearing ; Hearing Loss, Noise-Induced/diagnosis/etiology/physiopathology/*prevention &amp; control/psychology ; Humans ; Male ; Military Personnel ; Noise/*adverse effects ; Occupational Diseases/diagnosis/etiology/physiopathology/*prevention &amp; control/psychology ; Occupational Exposure/*adverse effects ; Prospective Studies ; Protective Agents/adverse effects/*therapeutic use ; Time Factors ; Treatment Outcome ; *Weapons ; Young Adult ; }, abstract = {Despite a robust hearing conservation program, military personnel continue to be at high risk for noise induced hearing loss (NIHL). For more than a decade, a number of laboratories have investigated the use of antioxidants as a safe and effective adjunct to hearing conservation programs. Of the antioxidants that have been investigated, N-acetylcysteine (NAC) has consistently reduced permanent NIHL in the laboratory, but its clinical efficacy is still controversial. This study provides a prospective, randomized, double-blinded, placebo-controlled clinical trial investigating the safety profile and the efficacy of NAC to prevent hearing loss in a military population after weapons training. Of the 566 total study subjects, 277 received NAC while 289 were given placebo. The null hypothesis for the rate of STS was not rejected based on the measured results. While no significant differences were found for the primary outcome, rate of threshold shifts, the right ear threshold shift rate difference did approach significance (p = 0.0562). No significant difference was found in the second primary outcome, percentage of subjects experiencing an adverse event between placebo and NAC groups (26.7% and 27.4%, respectively, p = 0.4465). Results for the secondary outcome, STS rate in the trigger hand ear, did show a significant difference (34.98% for placebo-treated, 27.14% for NAC-treated, p-value = 0.0288). Additionally, post-hoc analysis showed significant differences in threshold shift rates when handedness was taken into account. While the secondary outcomes and post-hoc analysis suggest that NAC treatment is superior to the placebo, the present study design failed to confirm this. The lack of significant differences in overall hearing loss between the treatment and placebo groups may be due to a number of factors, including suboptimal dosing, premature post-exposure audiograms, or differences in risk between ears or subjects. Based on secondary outcomes and post hoc analyses however, further studies seem warranted and are needed to clarify dose response and the factors that may have played a role in the observed results.}, }
@article {pmid25619687, year = {2015}, author = {Roussel, J and Thireau, J and Brenner, C and Saint, N and Scheuermann, V and Lacampagne, A and Le Guennec, JY and Fauconnier, J}, title = {Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes: Role of adenine nucleotide translocase.}, journal = {Biochimica et biophysica acta}, volume = {1852}, number = {5}, pages = {749-758}, doi = {10.1016/j.bbadis.2015.01.011}, pmid = {25619687}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Animals ; Bongkrekic Acid/pharmacology ; Calcium/*metabolism ; Cells, Cultured ; Free Radical Scavengers/pharmacology ; Immunoblotting ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred C57BL ; Microscopy, Confocal ; Mitochondria, Heart/drug effects/metabolism/physiology ; Mitochondrial ADP, ATP Translocases/*antagonists &amp; inhibitors/metabolism ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Myocytes, Cardiac/cytology/*drug effects/metabolism ; Nitric Oxide/metabolism ; Oxidation-Reduction/drug effects ; Palmitoylcarnitine/*pharmacology ; Reactive Oxygen Species/metabolism ; Ryanodine Receptor Calcium Release Channel/*metabolism ; Sarcoplasmic Reticulum/*drug effects/metabolism ; Tacrolimus Binding Proteins/metabolism ; }, abstract = {Long chain fatty acids bind to carnitine and form long chain acyl carnitine (LCAC), to enter into the mitochondria. They are oxidized in the mitochondrial matrix. LCAC accumulates rapidly under metabolic disorders, such as acute cardiac ischemia, chronic heart failure or diabetic cardiomyopathy. LCAC accumulation is associated with severe cardiac arrhythmia including ventricular tachycardia or fibrillation. We thus hypothesized that palmitoyl-carnitine (PC), alters mitochondrial function leading to Ca(2+) dependent-arrhythmia. In isolated cardiac mitochondria from C57Bl/6 mice, application of 10μM PC decreased adenine nucleotide translocase (ANT) activity without affecting mitochondrial permeability transition pore (mPTP) opening. Mitochondrial reactive oxygen species (ROS) production, measured with MitoSOX Red dye in isolated ventricular cardiomyocytes, increased significantly under PC application. Inhibition of ANT by bongkrekic acid (20 μM) prevented PC-induced mitochondrial ROS production. In addition, PC increased type 2 ryanodine receptor (RyR2) oxidation, S-nitrosylation and dissociation of FKBP12.6 from RyR2, and therefore increased sarcoplasmic reticulum (SR) Ca(2+) leak. ANT inhibition or anti-oxidant strategy (N-acetylcysteine) prevented SR Ca(2+) leak, FKBP12.6 depletion and RyR2 oxidation/S-nitrosylation induced by PC. Finally, both bongkrekic acid and NAC significantly reduced spontaneous Ca(2+) wave occurrences under PC. Altogether, these results suggest that an elevation of PC disturbs ANT activity and alters Ca(2+) handling in a ROS-dependent pathway, demonstrating a new pathway whereby altered FA metabolism may contribute to the development of ventricular arrhythmia in pathophysiological conditions.}, }
@article {pmid25618603, year = {2015}, author = {Ye, F and Wang, H and Zhang, L and Zou, Y and Han, H and Huang, J}, title = {Baicalein induces human osteosarcoma cell line MG-63 apoptosis via ROS-induced BNIP3 expression.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {36}, number = {6}, pages = {4731-4740}, pmid = {25618603}, issn = {1423-0380}, mesh = {Acetylcysteine/metabolism ; Apoptosis/drug effects ; Bone Neoplasms/*drug therapy/genetics/pathology ; Cell Line, Tumor ; Flavanones/*administration &amp; dosage ; Gene Expression Regulation, Neoplastic/drug effects ; Glutathione/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Membrane Proteins/*biosynthesis/genetics ; Osteosarcoma/*drug therapy/genetics/pathology ; Proto-Oncogene Proteins/*biosynthesis/genetics ; Reactive Oxygen Species/metabolism ; }, abstract = {Baicalein, a flavonoid compound, is one of the active constituents of the root of Scutellariae Radix. Its antitumor effects have attracted widespread attention worldwide. One of its major functions is to induce the apoptosis of tumor cells, but the antitumor mechanism is currently unclear. In the present study, we found that baicalein increased MG-63 cell mortality in a dose-dependent manner. Meanwhile, baicalein activated apoptosis through induced intracellular reactive oxygen species (ROS) generation, and that ROS scavenger N-acetyl-cysteine (NAC), glutathione (GSH), and superoxide dismutase (SOD) apparently inhibited intracellular ROS production, consequently attenuating the baicalein-induced apoptosis. Baicalein also induce the mitochondrial fragmentation which precedes the cell apoptosis. This morphological alteration is accompanied by an increase in the expression of the protein BNIP3 as well as Mul1 and Drp1. Furthermore, we show that the inhibition of BNIP3 expression can inhibit cell apoptosis by baicalein treatment. Taken together, our results bring the evidence of a mechanism that links apoptosis and ROS-induced BNIP3 expression in MG-63 cells with bacalein treatment and suggest that baicalein has a good potential as an anti-osteosarcoma drug.}, }
@article {pmid25617894, year = {2015}, author = {Badisa, RB and Kumar, SS and Mazzio, E and Haughbrook, RD and Allen, JR and Davidson, MW and Fitch-Pye, CA and Goodman, CB}, title = {N-acetyl cysteine mitigates the acute effects of cocaine-induced toxicity in astroglia-like cells.}, journal = {PloS one}, volume = {10}, number = {1}, pages = {e0114285}, pmid = {25617894}, issn = {1932-6203}, support = {G12 MD007582/MD/NIMHD NIH HHS/United States ; G12 RR003020/RR/NCRR NIH HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; G12MD007582/MD/NIMHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Astrocytes/*drug effects ; Cell Line ; Cell Membrane/drug effects ; Cell Survival/drug effects ; Cocaine/*toxicity ; Cytoskeleton/drug effects ; Glutathione/metabolism ; Histones/drug effects ; Methylation ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Cocaine has a short half-life of only about an hour but its effects, predominantly on the central nervous system (CNS), are fairly long-lasting. Of all cells within the CNS, astrocytes may be the first to display cocaine toxicity owing to their relative abundance in the brain. Cocaine entry could trigger several early response changes that adversely affect their survival, and inhibiting these changes could conversely increase their rate of survival. In order to identify these changes and the minimal concentrations of cocaine that can elicit them in vitro, rat C6 astroglia-like cells were treated with cocaine (2-4 mM for 1h) and assayed for alterations in gross cell morphology, cytoplasmic vacuolation, viability, reactive oxygen species (ROS) generation, glutathione (GSH) levels, cell membrane integrity, F-actin cytoskeleton, and histone methylation. We report here that all of the above identified features are significantly altered by cocaine, and may collectively represent the key pathology underlying acute toxicity-mediated death of astroglia-like cells. Pretreatment of the cells with the clinically available antioxidant N-acetyl cysteine (NAC, 5 mM for 30 min) inhibited these changes during subsequent application of cocaine and mitigated cocaine-induced toxicity. Despite repeated cocaine exposure, NAC pretreated cells remained highly viable and post NAC treatment also increased viability of cocaine treated cells to a smaller yet significant level. We show further that this alleviation by NAC is mediated through an increase in GSH levels in the cells. These findings, coupled with the fact that astrocytes maintain neuronal integrity, suggest that compounds which target and mitigate these early toxic changes in astrocytes could have a potentially broad therapeutic role in cocaine-induced CNS damage.}, }
@article {pmid25617880, year = {2014}, author = {Maes, M and Leunis, JC}, title = {Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome.}, journal = {Neuro endocrinology letters}, volume = {35}, number = {7}, pages = {577-585}, pmid = {25617880}, issn = {0172-780X}, mesh = {Adult ; Antioxidants/metabolism ; Autoimmune Diseases/*immunology/*metabolism ; Bacterial Translocation/immunology ; Epitopes/immunology/metabolism ; Fatigue Syndrome, Chronic/*immunology/*metabolism ; Female ; Humans ; Immunoglobulin M/immunology/metabolism ; Male ; Middle Aged ; Nitroso Compounds/immunology/metabolism ; Oxidative Stress/*immunology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Young Adult ; }, abstract = {OBJECTIVES: There is evidence that inflammatory, oxidative and nitrosative stress (IO&amp;NS) pathways participate in the pathophysiology of a subgroup of patients with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Increased IgM-related autoimmune responses to oxidative specific epitopes (OSEs), including malondialdehyde (MDA), oleic acid and phosphatidyl inositol (Pi), and nitroso-(NO)-adducts, including NO-tryptophan (NOW), NO-arginine and NO-cysteinyl, are frequently observed in ME/CFS. Autoimmune responses in ME/CFS may be driven by increased bacterial translocation as measured by IgM and IgA responses to LPS of gram negative bacteria.<br><br>METHODS: The aim of this study is to examine whether IgM responses to OSEs and NO-adducts are related to a better outcome as measured by the Fibromyalgia and Fatigue Rating Scale (FF). 76 ME/CFS patients with initially abnormal autoimmune responses were treated with care-as-usual, including nutraceuticals with anti-IO&amp;NS effects (NAIOS), such as L-carnitine, coenzyme Q10, taurine + lipoic acid, with or without curcumine + quercitine or N-acetyl-cysteine, zinc + glutamine.<br><br>RESULTS: We found that use of these NAIOS was associated with highly significant reductions in initially increased IgM-mediated autoimmune responses to OSEs and NO-adducts. A greater reduction in autoimmune responses to OSEs during intake of these NAIOS was associated with a lower FF score. Reductions in IgM responses to oleic acid, MDA and Pi, but not in any of the NO-adducts, were associated with reductions in severity of illness. These associations remained significant after adjusting for possible effects of increased bacterial translocation (leaky gut).<br><br>CONCLUSIONS: Our results show that autoimmune responses to OSEs are involved in the pathophysiology of ME/CFS and that these pathways are a new drug target in a subgroup of ME/CFS patients. Although hypernitrosylation and nitrosative stress play a role in ME/CFS, reductions in these pathways are not associated with lowered severity of illness. Randomized controlled trials with NAIOS should be carried out in the subgroup of ME/CFS patients with initially increased autoimmune responses to OSEs.}, }
@article {pmid25609734, year = {2015}, author = {Pereira, S and Shah, A and George Fantus, I and Joseph, JW and Giacca, A}, title = {Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation.}, journal = {The Journal of endocrinology}, volume = {225}, number = {1}, pages = {1-7}, doi = {10.1530/JOE-14-0676}, pmid = {25609734}, issn = {1479-6805}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers ; Blood Glucose ; Emulsions/administration &amp; dosage ; Fatty Acids, Nonesterified/*blood ; Female ; Free Radical Scavengers/pharmacology ; Glucose/metabolism ; Heparin/administration &amp; dosage ; Insulin Resistance/*physiology ; Oxidative Stress/drug effects/physiology ; Phospholipids/*administration &amp; dosage ; Rats ; Rats, Wistar ; Soybean Oil/*administration &amp; dosage ; }, abstract = {Circulating free fatty acids (FFAs) are elevated in obesity and cause insulin resistance. The objective of the current study was to determine whether the antioxidant N-acetyl-l-cysteine (NAC) prevented hepatic and peripheral insulin resistance caused by prolonged elevation of plasma FFAs. Chronically cannulated Wistar rats received saline (SAL), Intralipid plus heparin (IH), IH plus NAC, or NAC i.v. infusion for 48 h. Insulin sensitivity was determined using the hyperinsulinemic-euglycemic clamp with tritiated glucose tracer. IH induced hepatic and peripheral insulin resistance (P<0.05). NAC co-infusion did not prevent insulin resistance in the liver, although it was able to prevent peripheral insulin resistance. Prolonged IH infusion did not appear to induce oxidative stress in the liver because hepatic content of protein carbonyl, malondialdehyde, and reduced to oxidized glutathione ratio did not differ across treatment groups. In alignment with our insulin sensitivity results, IH augmented skeletal muscle protein carbonyl content and this was prevented by NAC co-infusion. Taken together, our results indicate that oxidative stress mediates peripheral, but not hepatic, insulin resistance resulting from prolonged plasma FFA elevation. Thus, in states of chronic plasma FFA elevation, such as obesity, antioxidants may protect against peripheral but not hepatic insulin resistance.}, }
@article {pmid25607831, year = {2015}, author = {Wang, H and Wei, L and Li, C and Zhou, J and Li, Z}, title = {CDK5RAP1 deficiency induces cell cycle arrest and apoptosis in human breast cancer cell line by the ROS/JNK signaling pathway.}, journal = {Oncology reports}, volume = {33}, number = {3}, pages = {1089-1096}, doi = {10.3892/or.2015.3736}, pmid = {25607831}, issn = {1791-2431}, mesh = {Apoptosis/*physiology ; Blotting, Western ; Breast Neoplasms/*metabolism/pathology ; Cell Cycle Checkpoints/*physiology ; Female ; Flow Cytometry ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists &amp; inhibitors/*biosynthesis ; MAP Kinase Signaling System/*physiology ; MCF-7 Cells ; Nerve Tissue Proteins/antagonists &amp; inhibitors/*biosynthesis ; RNA, Small Interfering/antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; Transfection ; }, abstract = {Cyclin-dependent kinase 5 regulatory subunit associated protein 1 (CDK5RAP1) is an enzyme which post-synthetically converts the RNA modification N6-iso-pentenyladenosine (i6A) into 2-methylthio-N6-isopentenyladenosine (ms2i6A). However, the interaction between CDK5RAP1 deficiency and cell apoptosis has not been studied. Breast cancer has long been a leading cause of mortality in the world. Therefore, in the present study, CDK5RAP1 deficiency in a human breast cancer cell line was investigated. CDK5RAP1 small interfering RNA (siRNA) and negative control siRNA were transfected into MCF-7 cells, and the cells were further incubated for 48 h. CDK5RAP1 deficiency suppressed tumor growth in MCF-7 cells and arrested the cells at G2/M phase. CDK5RAP1 deficiency also induced cell apoptosis and reactive oxygen species (ROS) generation. Furthermore, western blot analysis showed that the expression of phospho-c-Jun N-terminal kinase (p-JNK), p53, caspase-9 and caspase-3 were upregulated in CDK5RAP1-deficient MCF-7 cells. Pretreatment with N-acetyl-cysteine (NAC), the inhibitor of ROS, or with SP600125, the inhibitor of JNK, prevented the apoptosis and the high expression of p-JNK, p53, caspase-9 and caspase-3 in CDK5RAP1-deficient MCF-7 cells. Taken together, these data indicated that CDK5RAP1 deficiency induced cell cycle arrest and apoptosis in human breast cancer MCF-7 cells by the ROS/JNK signaling pathway. Our findings indicated a novel therapeutic strategy for cancer.}, }
@article {pmid25604962, year = {2015}, author = {Liu, J and Guo, W and Li, J and Li, X and Geng, J and Chen, Q and Gao, J}, title = {Tumor-targeting novel manganese complex induces ROS-mediated apoptotic and autophagic cancer cell death.}, journal = {International journal of molecular medicine}, volume = {35}, number = {3}, pages = {607-616}, pmid = {25604962}, issn = {1791-244X}, mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Female ; Humans ; Manganese/administration &amp; dosage/chemistry/*pharmacology ; Mice ; Mitochondria/drug effects/metabolism ; Neoplasms/drug therapy/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Receptors, Transferrin/metabolism ; Signal Transduction/drug effects ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {In this study, the antitumor activity of the novel manganese (II) compound, Adpa-Mn {[(Adpa)Mn(Cl)(H(2)O)] (Adpa=bis(2-pyridylmethyl)amino-2-propionic acid)}, and its possible mechanisms of action were investigated. In vitro, the growth inhibitory effects of Adpa-Mn (with IC(50) values lower than 15 µM) on tumor cell lines were examined by MTT assay. We found that this compound was more selective against cancer cells than the popular chemotherapeutic reagent, cisplatin. We then found that Adpa-Mn achieved its selectivity against cancer cells through the transferrin (Tf)-transferrin receptor (TfR) system, which is highly expressed in tumor cells. Furthermore, Adpa-Mn induced both apoptosis and autophagy, as indicated by chromatin condensation, the activation of poly(ADP-ribose) polymerase (PARP), Annexin V/propidium iodide staining, an enhanced fluorescence intensity of monodansylcadaverine (MDC), as well as the elevated expression of the autophagy-related protein, microtubule-associated protein 1 light chain 3 (LC3). In addition, Adpa-Mn induced the generation of intracellular reactive oxygen species (ROS) and its anticancer effects were significantly reduced following pre-treatment with the antioxidant, N-acetyl cysteine, indicating that ROS triggered cell death. In vivo, the induction of apoptosis and autophagy in tumor tissue was confirmed following treatment with Adpa-Mn, which contributed to its significant antitumor activity against hepatocellular carcinoma (Hep-A cell) xenografts at 10 mg/kg. Taken together, these data suggest the possible use of Adpa-Mn as a novel anticancer drug.}, }
@article {pmid25600293, year = {2015}, author = {Tang, HM and Pan, K and Kong, KY and Hu, L and Chan, LC and Siu, KL and Sun, H and Wong, CM and Jin, DY}, title = {Loss of APD1 in yeast confers hydroxyurea sensitivity suppressed by Yap1p transcription factor.}, journal = {Scientific reports}, volume = {5}, number = {}, pages = {7897}, pmid = {25600293}, issn = {2045-2322}, support = {R01 TW008298/TW/FIC NIH HHS/United States ; R01TW008298/TW/FIC NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Cell Cycle/drug effects/genetics ; Cell Proliferation/drug effects/genetics ; DNA Replication/drug effects/*genetics ; Ferredoxins/chemistry/*genetics ; Hydroxyurea/*pharmacology ; Iron/chemistry ; Oxidation-Reduction ; Phenotype ; Saccharomyces cerevisiae/chemistry/*genetics ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; }, abstract = {Ferredoxins are iron-sulfur proteins that play important roles in electron transport and redox homeostasis. Yeast Apd1p is a novel member of the family of thioredoxin-like ferredoxins. In this study, we characterized the hydroxyurea (HU)-hypersensitive phenotype of apd1Δ cells. HU is an inhibitor of DNA synthesis, a cellular stressor and an anticancer agent. Although the loss of APD1 did not influence cell proliferation or cell cycle progression, it resulted in HU sensitivity. This sensitivity was reverted in the presence of antioxidant N-acetyl-cysteine, implicating a role for intracellular redox. Mutation of the iron-binding motifs in Apd1p abrogated its ability to rescue HU sensitivity in apd1Δ cells. The iron-binding activity of Apd1p was verified by a color assay. By mass spectrometry two irons were found to be incorporated into one Apd1p protein molecule. Surprisingly, ribonucleotide reductase genes were not induced in apd1Δ cells and the HU sensitivity was unaffected when dNTP production was boosted. A suppressor screen was performed and the expression of stress-regulated transcription factor Yap1p was found to effectively rescue the HU sensitivity in apd1Δ cells. Taken together, our work identified Apd1p as a new ferredoxin which serves critical roles in cellular defense against HU.}, }
@article {pmid25600149, year = {2015}, author = {Kwak, JY and Ham, HJ and Kim, CM and Hwang, ES}, title = {Nicotinamide exerts antioxidative effects on senescent cells.}, journal = {Molecules and cells}, volume = {38}, number = {3}, pages = {229-235}, pmid = {25600149}, issn = {0219-1032}, mesh = {Antioxidants/*pharmacology ; Cell Cycle Checkpoints ; Cellular Senescence/*drug effects ; Fibroblasts/drug effects/*physiology ; Humans ; Infant, Newborn ; MCF-7 Cells ; Male ; Niacinamide/*pharmacology ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Nicotinamide (NAM) has been shown to suppress reactive oxygen species (ROS) production in primary human fibroblasts, thereby extending their replicative lifespan when added to the medium during long-term cultivation. Based on this finding, NAM is hypothesized to affect cellular senescence progression by keeping ROS accumulation low. In the current study, we asked whether NAM is indeed able to reduce ROS levels and senescence phenotypes in cells undergoing senescence progression and those already in senescence. We employed two different cellular models: MCF-7 cells undergoing senescence progression and human fibroblasts in a state of replicative senescence. In both models, NAM treatment substantially decreased ROS levels. In addition, NAM attenuated the expression of the assessed senescence phenotypes, excluding irreversible growth arrest. N-acetyl cysteine, a potent ROS scavenger, did not have comparable effects in the tested cell types. These data show that NAM has potent antioxidative as well as anti-senescent effects. Moreover, these findings suggest that NAM can reduce cellular deterioration caused by oxidative damage in postmitotic cells in vivo.}, }
@article {pmid25599738, year = {2015}, author = {Sahraei, Z and Salamzadeh, J and Nafar, M}, title = {Effect of N-acetyl cysteine and vitamin C on kidney allograft function biomarkers interleukin-18 and neutrophil gelatinase-associated lipocalin.}, journal = {Iranian journal of kidney diseases}, volume = {9}, number = {1}, pages = {56-62}, pmid = {25599738}, issn = {1735-8604}, mesh = {Acetylcysteine/*therapeutic use ; Acute-Phase Proteins/*urine ; Adolescent ; Adult ; Allografts ; Antioxidants/*therapeutic use ; Ascorbic Acid/*therapeutic use ; Biomarkers/urine ; Delayed Graft Function/diagnosis/*prevention &amp; control/urine ; Drug Therapy, Combination ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Interleukin-18/*urine ; Iran ; Kidney Transplantation/*adverse effects/methods ; Lipocalin-2 ; Lipocalins/*urine ; Living Donors ; Male ; Middle Aged ; Predictive Value of Tests ; Proto-Oncogene Proteins/*urine ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION: Delayed graft function (DGF) is a consequence of ischemia-reperfusion injuries in kidney allografts, for which no definite treatment is available. The neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) are introduced as the most promising urine biomarkers to detect DGF. N-acetylcysteine (NAC) and vitamin C, well-known potent antioxidants that scavenge free radicals, may alleviate kidney injury. This study investigated the protective effects of NAC alone and in combination with vitamin C on DGF, by measuring IL-18 and NGAL in living donor kidney transplantations.<br><br>MATERIALS AND METHODS: Patients transplanted between January 2011 and February 2013 were randomly divided into 3 groups to receive routine anti-rejection medication only (n = 32), NAC plus routine immunosuppressive regimen (NAC group; n = 33), and NAC and vitamin C plus routine regimen (NAC and vitamin C group; n = 19). Urine samples were taken 4 hours and 24 hours after transplantation. Enzyme-linked immunosorbent assay kits were utilized for measuring urine NGAL and IL-18.<br><br>RESULTS: There were no significant differences in the DGF prevalence and its duration between the study arms. Although the levels of NGAL and IL-18 decreased in the NAC and NAC and vitamin C groups, these reductions were not significant. Glomerular filtration rate at 30 and 60 days after transplantation were not significantly different between study groups, either.<br><br>CONCLUSIONS: Our results showed that NAC is a safe drug without significant adverse effects in kidney transplant recipients; however, its potential useful effects on urinary biomarkers of DGF were not illustrated in the present study.}, }
@article {pmid25596737, year = {2015}, author = {Cusimano, A and Puleio, R and D'Alessandro, N and Loria, GR and McCubrey, JA and Montalto, G and Cervello, M}, title = {Cytotoxic activity of the novel small molecule AKT inhibitor SC66 in hepatocellular carcinoma cells.}, journal = {Oncotarget}, volume = {6}, number = {3}, pages = {1707-1722}, pmid = {25596737}, issn = {1949-2553}, mesh = {Animals ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/*drug therapy/enzymology/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclohexanones/*pharmacology ; Humans ; Liver Neoplasms/*drug therapy/enzymology/pathology ; Male ; Mice ; Mice, Nude ; Protein Kinase Inhibitors/*pharmacology ; Proto-Oncogene Proteins c-akt/*antagonists &amp; inhibitors/metabolism ; Pyridines/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {Hepatocellular carcinoma (HCC) is characterized by limited response to current drug therapies. Here, we report that SC66, a novel AKT inhibitor, reduced cell viability in a dose- and time-dependent manner, inhibited colony formation and induced apoptosis in HCC cells. SC66 treatment led to a reduction in total and phospho-AKT levels. This was associated with alterations in cytoskeleton organization, a reduction in expression levels of E-cadherin, β-catenin and phospho-FAK, together with up-regulation of Snail protein levels. All these alterations were coupled with anoikis cell death induction. In addition, SC66 induced the production of reactive oxygen species (ROS) and DNA damage. Pre-treatment with the ROS scavenger N-Acetyl-cysteine (NAC) prevented SC66-induced cell growth inhibition and anoikis. SC66 significantly potentiated the effects of both conventional chemotherapeutic and targeted agents, doxorubicin and everolimus, respectively. In vivo, SC66 inhibited tumor growth of Hep3B cells in xenograft models, with a similar mechanism observed in the in vitro model. Taken together, these data indicate that the AKT inhibitor SC66 had antitumor effects on HCC cells. This was mediated by ROS production, induction of anoikis-mediated cell death and inhibition of the AKT cell survival pathway. Our results provide a rational basis for the use of SC66 in HCC treatment.}, }
@article {pmid25595415, year = {2015}, author = {Eren, Y and Dirik, E and Neşelioğlu, S and Erel, &#xd6;}, title = {Oxidative stress and decreased thiol level in patients with migraine: cross-sectional study.}, journal = {Acta neurologica Belgica}, volume = {115}, number = {4}, pages = {643-649}, doi = {10.1007/s13760-015-0427-y}, pmid = {25595415}, issn = {2240-2993}, mesh = {Adult ; Antioxidants/metabolism ; Cross-Sectional Studies ; Female ; Humans ; Male ; Migraine Disorders/*blood/*physiopathology ; Oxidative Stress/*physiology ; Sulfhydryl Compounds/*blood ; Young Adult ; }, abstract = {Although migraine is a neurological disorder known since long, its physiopathology remains unclear. Recent studies suggest that migraine is associated with oxidative stress; however, they report divergent results. The aim of the present study was to evaluate total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), and serum thiol level in migraine patients with or without aura. The study group consisted of 141 migraine patients. The control group included 70 healthy subjects. TAS, TOS, OSI were evaluated using a method developed by Erel. Serum thiol level was measured using the Hu method. No difference was found in TAS, TOS, OSI between the patients and controls. The level of thiol was significantly lower in patients than in controls. Negative correlations were detected between thiol level and Migraine Disability Assessment score in patients. Although TAS, TOS, and OSI were similar to those of the control group, serum thiol level, an important marker of antioxidant capacity, was significantly lower in migraines compared with controls, and caused more serious disability. Novel treatment approaches may be developed based on these data, and compounds containing thiol, such as alpha lipoic acid and N-acetyl cysteine, may be used in prophylaxis.}, }
@article {pmid25595117, year = {2015}, author = {Ayfer Aytemur, Z and Baysak, A and Ozdemir, O and Köse, T and Sayiner, A}, title = {N-acetylcysteine in patients with COPD exacerbations associated with increased sputum.}, journal = {Wiener klinische Wochenschrift}, volume = {127}, number = {7-8}, pages = {256-261}, pmid = {25595117}, issn = {1613-7671}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Double-Blind Method ; Expectorants/therapeutic use ; Female ; Humans ; Male ; Placebo Effect ; Pulmonary Disease, Chronic Obstructive/*diagnosis/*drug therapy ; Sputum/*drug effects ; Treatment Outcome ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) has been shown not to alter the clinical outcome in chronic obstructive pulmonary disease (COPD) exacerbations. However, NAC may improve symptoms through its mucolytic effect in the subgroup of patients with increased sputum production. The aims of this study were to determine whether NAC improves symptoms and pulmonary function in patients with COPD exacerbation and increased sputum production.<br><br>METHODS: This was a placebo-controlled study, where patients with severe COPD and increased sputum production, who were hospitalized for an exacerbation, were included. They were randomized to receive either NAC 200&#xa0;mg tid or placebo in addition to the usual treatment.<br><br>RESULTS: Forty-two patients were included and were equally distributed to NAC and placebo groups. The symptoms, namely, ease of sputum production and dyspnea at rest and on exertion significantly improved in both groups; but there was no difference in improvement between NAC and placebo groups (p&#x2009;=&#x2009;0.96, 0.62, 0.31, respectively). Similarly, forced expiratory volume-one second (FEV1) and PaO2 levels improved significantly in NAC (964&#x2009;&#xb1;&#x2009;599-1239&#x2009;&#xb1;&#x2009;543&#xa0;ml, p&#x2009;<&#x2009;0.001, and 57.5&#x2009;&#xb1;&#x2009;14.5-70.5&#x2009;&#xb1;&#x2009;16.0&#xa0;mmHg, p&#x2009;<&#x2009;0.001, respectively) and placebo groups (981&#x2009;&#xb1;&#x2009;514-1180&#x2009;&#xb1;&#x2009;535&#xa0;ml, p&#x2009;<&#x2009;0.001 and 57.9&#x2009;&#xb1;&#x2009;14.3-68.7&#x2009;&#xb1;&#x2009;19.0&#xa0;mmHg, p&#x2009;<&#x2009;0.001, respectively), without any difference between the two groups (p&#x2009;=&#x2009;0.52 and 0.57). There was no difference in the number of exacerbations during the 6-month follow-up period.<br><br>CONCLUSION: NAC does not have any beneficial effect on clinical outcomes in patients with severe COPD exacerbation associated with increased and/or viscous mucus production.}, }
@article {pmid25593971, year = {2014}, author = {Poels, J and Abou-Ghannam, G and Herman, S and Van Langendonckt, A and Wese, FX and Wyns, C}, title = {In Search of Better Spermatogonial Preservation by Supplementation of Cryopreserved Human Immature Testicular Tissue Xenografts with N-acetylcysteine and Testosterone.}, journal = {Frontiers in surgery}, volume = {1}, number = {}, pages = {47}, pmid = {25593971}, issn = {2296-875X}, abstract = {Controlled slow-freezing is the procedure currently applied for immature testicular tissue (ITT) cryobanking in clinical practice. Vitrification has been proposed as a promising alternative, with a view to better preserve the spermatogonial stem cells for future fertility restoration by autografting in young boys suffering from cancer. It appears that besides the potential influence of the cryopreservation technique used, the transplantation procedure itself has a significant impact on spermatogonial loss observed in ITT xenografts. Eighteen ITT pieces issued from 6 patients aged 2-15 years were used. Fragments of fresh tissue (serving as ungrafted controls), frozen-thawed tissue, frozen-thawed tissue supplemented with N-acetylcysteine (NAC), and frozen-thawed tissue supplemented with testosterone xenografted to nude mice for 5 days were compared. Upon graft removal, histological and immunohistochemical analyses were performed to evaluate spermatogonia, intratubular proliferation, and intrinsic and extrinsic apoptosis. A significant decrease in the integrity of intact seminiferous tubules was found in all three grafted groups. Spermatogonia were observed by immunohistochemistry in all grafted groups, with recovery rates of 67, 63, and 53%, respectively, for slow-frozen tissue, slow-frozen tissue supplemented with NAC, and slow-frozen tissue supplemented with testosterone. Apoptosis evidenced by active caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was similar in all grafts. The study is limited by the low availability of ITT samples of human origin, and no clear impact of graft supplementation was found. The mouse xenotransplantation model needs to be refined to investigate human spermatogenesis in human ITT grafts.}, }
@article {pmid25591776, year = {2015}, author = {Cui, Y and Xie, X and Jia, F and He, J and Li, Z and Fu, M and Hao, H and Liu, Y and Liu, JZ and Cowan, PJ and Zhu, H and Sun, Q and Liu, Z}, title = {Ambient fine particulate matter induces apoptosis of endothelial progenitor cells through reactive oxygen species formation.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {35}, number = {1}, pages = {353-363}, pmid = {25591776}, issn = {1421-9778}, support = {R01 HL094650/HL/NHLBI NIH HHS/United States ; R01ES018900/ES/NIEHS NIH HHS/United States ; NIH R01 HL094650/HL/NHLBI NIH HHS/United States ; R01 ES018900/ES/NIEHS NIH HHS/United States ; R01 ES026200/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Bone Marrow Cells/cytology ; Cells, Cultured ; Endothelial Progenitor Cells/cytology/drug effects/metabolism ; Enzyme-Linked Immunosorbent Assay ; Glutathione Peroxidase/genetics/metabolism ; Interleukin-1beta/blood ; Lung/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Particulate Matter/*toxicity ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND/AIMS: Bone marrow (BM)-derived endothelial progenitor cells (EPCs) play a critical role in angiogenesis and vascular repair. Some environmental insults, like fine particulate matter (PM) exposure, significantly impair cardiovascular functions. However, the mechanisms for PM-induced adverse effects on cardiovascular system remain largely unknown. The present research was to study the detrimental effects of PM on EPCs and explore the potential mechanisms.<br><br>METHODS: PM was intranasal-distilled into male C57BL/6 mice for one month. Flow cytometry was used to measure the number of EPCs, apoptosis level of circulating EPCs and intracellular reactive oxygen species (ROS) formation. Serum TNF-&#x3b1; and IL-1&#x3b2; were measured using ELISA. To determine the role of PM-induced ROS in EPC apoptosis, PM was co-administrated with the antioxidant N-acetylcysteine (NAC) in wild type mice or used in a triple transgenic mouse line (TG) with overexpression of antioxidant enzyme network (AON) composed of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase (Gpx-1) with decreased in vivo ROS production.<br><br>RESULTS: PM treatment significantly decreased circulating EPC population, promoted apoptosis of EPCs in association with increased ROS production and serum TNF-&#x3b1; and IL-1&#x3b2; levels, which could be effectively reversed by either NAC treatment or overexpression of AON.<br><br>CONCLUSION: PM exposure significantly decreased circulating EPCs population due to increased apoptosis via ROS formation in mice.}, }
@article {pmid25591758, year = {2015}, author = {Martinez, PF and Bonomo, C and Guizoni, DM and Junior, SA and Damatto, RL and Cezar, MD and Lima, AR and Pagan, LU and Seiva, FR and Fernandes, DC and Laurindo, FR and Novelli, EL and Matsubara, LS and Zornoff, LA and Okoshi, K and Okoshi, MP}, title = {Influence of N- acetylcysteine on oxidative stress in slow-twitch soleus muscle of heart failure rats.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {35}, number = {1}, pages = {148-159}, doi = {10.1159/000369683}, pmid = {25591758}, issn = {1421-9778}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ethidium/analogs &amp; derivatives/analysis ; Free Radical Scavengers/*pharmacology ; Glutathione Peroxidase/metabolism ; Heart Failure/epidemiology/metabolism/pathology ; Heart Ventricles/physiopathology ; Male ; Malondialdehyde/blood ; Muscle, Skeletal/drug effects/metabolism ; Myocardial Infarction/etiology/metabolism ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Tyrosine/analogs &amp; derivatives/analysis ; }, abstract = {BACKGROUND: Chronic heart failure is characterized by decreased exercise capacity with early exacerbation of fatigue and dyspnea. Intrinsic skeletal muscle abnormalities can play a role in exercise intolerance. Causal or contributing factors responsible for muscle alterations have not been completely defined. This study evaluated skeletal muscle oxidative stress and NADPH oxidase activity in rats with myocardial infarction (MI) induced heart failure.<br><br>METHODS AND RESULTS: Four months after MI, rats were assigned to Sham, MI-C (without treatment), and MI-NAC (treated with N-acetylcysteine) groups. Two months later, echocardiogram showed left ventricular dysfunction in MI-C; NAC attenuated diastolic dysfunction. In soleus muscle, glutathione peroxidase and superoxide dismutase activity was decreased in MI-C and unchanged by NAC. 3-nitrotyrosine was similar in MI-C and Sham, and lower in MI-NAC than MI-C. Total reactive oxygen species (ROS) production was assessed by HPLC analysis of dihydroethidium (DHE) oxidation fluorescent products. The 2-hydroxyethidium (EOH)/DHE ratio did not differ between Sham and MI-C and was higher in MI-NAC. The ethidium/DHE ratio was higher in MI-C than Sham and unchanged by NAC. NADPH oxidase activity was similar in Sham and MI-C and lower in MI-NAC. Gene expression of p47(phox) was lower in MI-C than Sham. NAC decreased NOX4 and p22(phox) expression.<br><br>CONCLUSIONS: We corroborate the case that oxidative stress is increased in skeletal muscle of heart failure rats and show for the first time that oxidative stress is not related to increased NADPH oxidase activity.}, }
@article {pmid25589719, year = {2015}, author = {Remington, R and Bechtel, C and Larsen, D and Samar, A and Doshanjh, L and Fishman, P and Luo, Y and Smyers, K and Page, R and Morrell, C and Shea, TB}, title = {A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {45}, number = {2}, pages = {395-405}, doi = {10.3233/JAD-142499}, pmid = {25589719}, issn = {1875-8908}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*complications ; Caregivers/psychology ; Cognition Disorders/*diet therapy/*etiology ; Cohort Studies ; *Dietary Supplements ; Double-Blind Method ; Female ; Folic Acid/administration &amp; dosage ; Humans ; Male ; Middle Aged ; Mood Disorders/*diet therapy/*etiology ; Time Factors ; Vitamin B 12/administration &amp; dosage ; alpha-Tocopherol/administration &amp; dosage ; }, abstract = {BACKGROUND: Increasing evidence points toward the efficacy of nutritional modifications in delaying cognitive decline and mood/behavioral difficulties in Alzheimer's disease (AD). Nutritional supplementation with individual agents has shown varied results suggesting the need for combinatorial intervention.<br><br>OBJECTIVE: We set out to determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for individuals diagnosed with AD.<br><br>METHODS: A double-blind, multi-site, phase II study (ClinicalTrials.gov NCT01320527; Alzheimer's Association Trialmatch) was conducted in which 106 individuals with AD were randomized to a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for 3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months.<br><br>RESULTS: The NF cohort improved versus the placebo cohort within 3 months (Clox-1 p = 0.0083, 95%CI [0.4481, 2.9343]; Dementia Rating Scale p = 0.0266, 95%CI [0.1722, 2.7171]). Caregivers reported non-significant improvements in Neuropsychiatric Inventory. Both cohorts improved or maintained baseline performance during open-label extensions. Activities of Daily Living did not change for either cohort.<br><br>CONCLUSIONS: These findings extend phase I studies where NF maintained or improved cognitive performance and mood/behavior.}, }
@article {pmid25588957, year = {2015}, author = {Larom, S and Kallmann, D and Saper, G and Pinhassi, R and Rothschild, A and Dotan, H and Ankonina, G and Schuster, G and Adir, N}, title = {The Photosystem II D1-K238E mutation enhances electrical current production using cyanobacterial thylakoid membranes in a bio-photoelectrochemical cell.}, journal = {Photosynthesis research}, volume = {126}, number = {1}, pages = {161-169}, pmid = {25588957}, issn = {1573-5079}, mesh = {Acetylcysteine/chemistry ; *Bioelectric Energy Sources ; Cytochromes c/metabolism ; Electrochemical Techniques ; Electrodes ; Hydrogen/metabolism ; *Mutation ; Oxidation-Reduction ; Photochemical Processes ; Photosystem II Protein Complex/*genetics/metabolism ; Synechocystis/genetics/*metabolism ; Thylakoids/*metabolism ; }, abstract = {The conversion of solar energy (SEC) to storable chemical energy by photosynthesis has been performed by photosynthetic organisms, including oxygenic cyanobacteria for over 3 billion years. We have previously shown that crude thylakoid membranes from the cyanobacterium Synechocytis sp. PCC 6803 can reduce the electron transfer (ET) protein cytochrome c even in the presence of the PSII inhibitor DCMU. Mutation of lysine 238 of the Photosystem II D1 protein to glutamic acid increased the cytochrome reduction rates, indicating the possible position of this unknown ET pathway. In this contribution, we show that D1-K238E is rather unique, as other mutations to K238, or to other residues in the same vicinity, are not as successful in cytochrome c reduction. This observation indicates the sensitivity of ET reactions to minor changes. As the next step in obtaining useful SEC from biological material, we describe the use of crude Synechocystis membranes in a bio-photovoltaic cell containing an N-acetyl cysteine-modified gold electrode. We show the production of significant current for prolonged time durations, in the presence of DCMU. Surprisingly, the presence of cytochrome c was not found to be necessary for ET to the bio-voltaic cell.}, }
@article {pmid25581647, year = {2014}, author = {Caro, AA and Bell, M and Ejiofor, S and Zurcher, G and Petersen, DR and Ronis, MJ}, title = {N-acetylcysteine inhibits the up-regulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically.}, journal = {Alcoholism, clinical and experimental research}, volume = {38}, number = {12}, pages = {2896-2906}, pmid = {25581647}, issn = {1530-0277}, support = {P20 GM103429/GM/NIGMS NIH HHS/United States ; R01 AA009300/AA/NIAAA NIH HHS/United States ; P20RR016460/RR/NCRR NIH HHS/United States ; R37 AA009300/AA/NIAAA NIH HHS/United States ; P20 RR016460/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Ethanol/*administration &amp; dosage ; Liver/drug effects/*metabolism ; Male ; Mitochondria, Liver/drug effects/*genetics/*metabolism ; Oxidative Stress/drug effects/physiology ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Rats ; Rats, Sprague-Dawley ; Transcription Factors/antagonists &amp; inhibitors/biosynthesis/genetics ; Up-Regulation/drug effects/*physiology ; }, abstract = {BACKGROUND: Chronic ethanol (EtOH) administration to experimental animals induces hepatic oxidative stress and up-regulates mitochondrial biogenesis. The mechanisms by which chronic EtOH up-regulates mitochondrial biogenesis have not been fully explored. In this work, we hypothesized that oxidative stress is a factor that triggers mitochondrial biogenesis after chronic EtOH feeding. If our hypothesis is correct, co-administration of antioxidants should prevent up-regulation of mitochondrial biogenesis genes.<br><br>METHODS: Rats were fed an EtOH-containing diet intragastrically by total enteral nutrition for 150&#xa0;days, in the absence or presence of the antioxidant N-acetylcysteine (NAC) at 1.7&#xa0;g/kg/d; control rats were administered isocaloric diets where carbohydrates substituted for EtOH calories.<br><br>RESULTS: EtOH administration significantly increased hepatic oxidative stress, evidenced as decreased liver total glutathione and reduced glutathione/glutathione disulfide ratio. These effects were inhibited by co-administration of EtOH and NAC. Chronic EtOH increased the expression of mitochondrial biogenesis genes including peroxisome proliferator-activated receptor gamma-coactivator-1 alpha and mitochondrial transcription factor A, and mitochondrial DNA; co-administration of EtOH and NAC prevented these effects. Chronic EtOH administration was associated with decreased mitochondrial mass, inactivation and depletion of mitochondrial complex I and complex IV, and increased hepatic mitochondrial oxidative damage, effects that were not prevented by NAC.<br><br>CONCLUSIONS: These results suggest that oxidative stress caused by chronic EtOH triggered the up-regulation of mitochondrial biogenesis genes in rat liver, because an antioxidant such as NAC prevented both effects. Because NAC did not prevent liver mitochondrial oxidative damage, extra-mitochondrial effects of reactive oxygen species may regulate mitochondrial biogenesis. In spite of the induction of hepatic mitochondrial biogenesis genes by chronic EtOH, mitochondrial mass and function decreased probably in association with mitochondrial oxidative damage. These results also predict that the effectiveness of NAC as an antioxidant therapy for chronic alcoholism will be limited by its limited antioxidant effects in mitochondria, and its inhibitory effect on mitochondrial biogenesis.}, }
@article {pmid25581610, year = {2015}, author = {Chen, S and Zheng, S and Liu, Z and Tang, C and Zhao, B and Du, J and Jin, H}, title = {Endogeous sulfur dioxide protects against oleic acid-induced acute lung injury in association with inhibition of oxidative stress in rats.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {95}, number = {2}, pages = {142-156}, pmid = {25581610}, issn = {1530-0307}, mesh = {Acetylcysteine/pharmacology ; Acute Lung Injury/*chemically induced/*physiopathology ; Analysis of Variance ; Animals ; Apoptosis/drug effects/physiology ; Asparagine/analogs &amp; derivatives/pharmacology ; Aspartate Aminotransferases/metabolism ; Blotting, Western ; Colorimetry ; Fluorescence ; Glutathione/pharmacology ; Immunohistochemistry ; In Situ Nick-End Labeling ; Oleic Acid/*adverse effects ; Oxidative Stress/*physiology ; Rats ; Reactive Oxygen Species/metabolism ; Sulfur Dioxide/*metabolism ; }, abstract = {The role of endogenous sulfur dioxide (SO2), an efficient gasotransmitter maintaining homeostasis, in the development of acute lung injury (ALI) remains unidentified. We aimed to investigate the role of endogenous SO2 in the pathogenesis of ALI. An oleic acid (OA)-induced ALI rat model was established. Endogenous SO2 levels, lung injury, oxidative stress markers and apoptosis were examined. OA-induced ALI rats showed a markedly downregulated endogenous SO2/aspartate aminotransferase 1 (AAT1)/AAT2 pathway and severe lung injury. Chemical colorimetry assays demonstrated upregulated reactive oxygen species generation and downregulated antioxidant capacity in OA-induced ALI rats. However, SO2 increased endogenous SO2 levels, protected against oxidative stress and alleviated ALI. Moreover, compared with OA-treated cells, in human alveolar epithelial cells SO2 downregulated O2(-) and OH(-) generation. In contrast, L-aspartic acid-β-hydroxamate (HDX, Sigma-Aldrich Corporation), an inhibitor of endogenous SO2 generating enzyme, promoted free radical generation, upregulated poly (ADP-ribose) polymerase expression, activated caspase-3, as well as promoted cell apoptosis. Importantly, apoptosis could be inhibited by the free radical scavengers glutathione (GSH) and N-acetyl-L-cysteine (NAC). The results suggest that SO2/AAT1/AAT2 pathway might protect against the development of OA-induced ALI by inhibiting oxidative stress.}, }
@article {pmid25581570, year = {2015}, author = {Hong, FY and Bao, JF and Hao, J and Yu, Q and Liu, J}, title = {Methylglyoxal and advanced glycation end-products promote cytokines expression in peritoneal mesothelial cells via MAPK signaling.}, journal = {The American journal of the medical sciences}, volume = {349}, number = {2}, pages = {105-109}, doi = {10.1097/MAJ.0000000000000394}, pmid = {25581570}, issn = {1538-2990}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cell Proliferation/drug effects ; Chemokine CCL2/*biosynthesis ; Enzyme Inhibitors ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/*drug effects ; Glucose/metabolism ; Glycation End Products, Advanced/*pharmacology ; Humans ; Imidazoles/pharmacology ; MAP Kinase Signaling System/*drug effects ; Peritoneal Dialysis ; Peritoneum/cytology/*metabolism ; Pyridines/pharmacology ; Pyruvaldehyde/*pharmacology ; Real-Time Polymerase Chain Reaction ; Vascular Endothelial Growth Factor A/*biosynthesis ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND: Peritoneal dialysis fluid degrades glucose into glucose degradation products that impair peritoneal mesothelial cell functions. These compounds are known to interfere with many cellular functions and to promote the formation of advanced glycation end products (AGEs). This study aimed to investigate the biological effects and the underlying mechanism of glucose degradation products and AGEs on mesothelial cells.<br><br>METHODS: Cell proliferation was determined using [3H]-thymidine incorporation assay. Real-time polymerase chain reaction and enzyme linked immunosorbent assay (ELISA) were used to determine the mRNA and protein expression of cytokines. Reactive oxygen species production in mesothelial cells was determined by flow cytometry. Western blot was used to measure the protein expression of p38 MAPK.<br><br>RESULTS: Methylglyoxal (MGO) and AGE-human serum albumin (AGE-HSA) inhibited human peritoneal mesothelial cells proliferation in a dose- and time-dependent manner. The mRNA and protein expression of cytokines including vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) was significantly increased after treatment with MGO and AGE-HSA. Also, the antioxidant N-acetylcysteine (NAC) inhibited MGO- or AGE-HSA-induced reactive oxygen species generation. Western blot showed that MGO and AGE increased the phosphorylation levels of p38 MAPK, which was significantly attenuated after treatment of NAC or p38 MAPK inhibitor SB203580. Furthermore, AGE- or MGO-induced increased expression of VEGF and MCP-1 was significantly reduced in the presence of NAC or SB203580.<br><br>CONCLUSIONS: Together, this study suggested that AGE or MGO promoted VEGF and MCP-1 expression through activation of p38 MAPK signaling.}, }
@article {pmid25581126, year = {2015}, author = {Sun, B and Wang, X and Ji, Z and Wang, M and Liao, YP and Chang, CH and Li, R and Zhang, H and Nel, AE and Xia, T}, title = {NADPH Oxidase-Dependent NLRP3 Inflammasome Activation and its Important Role in Lung Fibrosis by Multiwalled Carbon Nanotubes.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {11}, number = {17}, pages = {2087-2097}, pmid = {25581126}, issn = {1613-6829}, support = {R01 ES022698/ES/NIEHS NIH HHS/United States ; S10 RR023057/RR/NCRR NIH HHS/United States ; U19 ES019528/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Carrier Proteins/*metabolism ; Cathepsin B/metabolism ; Cell Line ; Cytochrome b Group/metabolism ; Humans ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; Lung/pathology ; Lysosomes/metabolism ; Macrophages/metabolism ; Male ; Metal Nanoparticles/chemistry ; Mice ; Mice, Inbred C57BL ; NADH, NADPH Oxidoreductases/*metabolism ; NADPH Oxidase 1 ; NADPH Oxidases/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nanotubes, Carbon/*chemistry ; Oxidative Stress ; Oxygen/chemistry ; Pulmonary Fibrosis/*pathology ; Reactive Oxygen Species/metabolism ; Respiratory Burst ; Silver/chemistry ; }, abstract = {The purpose of this paper is to elucidate the key role of NADPH oxidase in NLRP3 inflammasome activation and generation of pulmonary fibrosis by multi-walled carbon nanotubes (MWCNTs). Although it is known that oxidative stress plays a role in pulmonary fibrosis by single-walled CNTs, the role of specific sources of reactive oxygen species, including NADPH oxidase, in inflammasome activation remains to be clarified. In this study, three long aspect ratio (LAR) materials (MWCNTs, single-walled carbon nanotubes, and silver nanowires) are used to compare with spherical carbon black and silver nanoparticles for their ability to trigger oxygen burst activity and NLRP3 assembly. All LAR materials but not spherical nanoparticles induce robust NADPH oxidase activation and respiratory burst activity in THP-1 cells, which are blunted in p22(phox) -deficient cells. The NADPH oxidase is directly involved in lysosomal damage by LAR materials, as demonstrated by decreased cathepsin B release and IL-1β production in p22(phox) -deficient cells. Reduced respiratory burst activity and inflammasome activation are also observed in bone marrow-derived macrophages from p47(phox) -deficient mice. Moreover, p47(phox) -deficient mice have reduced IL-1β production and lung collagen deposition in response to MWCNTs. Lung fibrosis is also suppressed by N-acetyl-cysteine in wild-type animals exposed to MWCNTs.}, }
@article {pmid25580997, year = {2015}, author = {Ono, T and Ota, A and Ito, K and Nakaoka, T and Karnan, S and Konishi, H and Furuhashi, A and Hayashi, T and Yamada, Y and Hosokawa, Y and Kazaoka, Y}, title = {Plumbagin suppresses tumor cell growth in oral squamous cell carcinoma cell lines.}, journal = {Oral diseases}, volume = {21}, number = {4}, pages = {501-511}, doi = {10.1111/odi.12310}, pmid = {25580997}, issn = {1601-0825}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*drug therapy/pathology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Humans ; Mouth Neoplasms/*drug therapy/pathology ; Naphthoquinones/*pharmacology ; }, abstract = {OBJECTIVES: Plumbagin (PL), a naturally occurring quinoid, exerts antitumoral effects in diverse types of cancer cells. However, the effect of PL on tumor cell proliferation in oral squamous cell carcinoma (OSCC) remains poorly understood. In this study, we assessed the efficacy of PL, in human OSCC cells.<br><br>METHODS: The effect of PL on the cell growth and apoptosis of OSCC cell lines was evaluated using MTT and Annexin V assays, respectively. The effect of PL on mitochondrial membrane potential loss and reactive oxygen species (ROS) generation was evaluated using flow cytometry analysis.<br><br>RESULTS: MTT assay showed that PL dose-dependently suppressed OSCC cell growth, with IC50 values ranging from 3.87 to 14.6 &#x3bc;M. Flow cytometry analysis revealed that PL treatment resulted in a significant decrease in mitochondrial membrane potential and an increase in the number of apoptotic cells. Notably, ROS generation was significantly elevated after PL treatment. Furthermore, a ROS scavenger, N-acetylcysteine (NAC), clearly suppressed the decrease in mitochondrial membrane potential, increase of caspase-3/7 activity, and apoptosis after PL treatment.<br><br>CONCLUSION: This study provides the considerable evidence of the tumor-suppressive effect of PL, thereby highlighting its therapeutic potential for OSCC treatment.}, }
@article {pmid25580916, year = {2015}, author = {Nikoo, M and Radnia, H and Farokhnia, M and Mohammadi, MR and Akhondzadeh, S}, title = {N-acetylcysteine as an adjunctive therapy to risperidone for treatment of irritability in autism: a randomized, double-blind, placebo-controlled clinical trial of efficacy and safety.}, journal = {Clinical neuropharmacology}, volume = {38}, number = {1}, pages = {11-17}, doi = {10.1097/WNF.0000000000000063}, pmid = {25580916}, issn = {1537-162X}, mesh = {Acetylcysteine/*therapeutic use ; Antipsychotic Agents/*therapeutic use ; Autistic Disorder/drug therapy/*physiopathology ; Child ; Child, Preschool ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Free Radical Scavengers/*therapeutic use ; Humans ; Irritable Mood/*drug effects ; Male ; Psychiatric Status Rating Scales ; Risperidone/*therapeutic use ; Treatment Outcome ; }, abstract = {OBJECTIVES: According to the proposed interference of N-acetylcysteine (NAC) with pathophysiologic processes of autistic disorders (ADs), we aimed to assess the effectiveness and safety of NAC as an adjunct to risperidone in the treatment of ADs in a randomized, double-blind, clinical trial.<br><br>METHODS: The participants were referred outpatients between 4 and 12 years of age with the diagnosis of ADs and a score of more than 12 on Aberrant Behavior Checklist-Community (ABC-C) Irritability subscale score. The participants were randomized into 2 groups. One group received risperidone plus NAC, and the other group received risperidone plus placebo. The dose of risperidone was titrated between 1 and 2.0 mg/d, and the dose of NAC was 600 to 900 mg/d. The main outcome was mean decrease in the ABC-C irritability subscale score from baseline at 5 and 10 weeks. Changes in other subscales were considered as secondary outcome measures.<br><br>RESULTS: Forty patients completed the 10-week trial. Baseline characteristics including age, sex and body weight, as well as baseline scores in 5 subscales did not demonstrate statistically significant difference between the 2 groups. Repeated-measures analysis showed significant effect for time &#xd7; treatment interaction in irritability (P = 0.01) and hyperactivity/noncompliance (P = 0.02) subscales. By week 10, the NAC group showed significantly more reduction in irritability (P = 0.02) and hyperactivity/noncompliance (P = 0.01) subscales scores.<br><br>CONCLUSIONS: N-acetylcysteine can be considered as an adjuvant therapy for ADs with beneficial therapeutic outcomes.}, }
@article {pmid25580427, year = {2014}, author = {Ma, J and Yang, J and Wang, C and Zhang, N and Dong, Y and Wang, C and Wang, Y and Lin, X}, title = {Emodin augments cisplatin cytotoxicity in platinum-resistant ovarian cancer cells via ROS-dependent MRP1 downregulation.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {107671}, pmid = {25580427}, issn = {2314-6141}, mesh = {Acetylcysteine/administration &amp; dosage ; Cell Line, Tumor ; Drug Resistance, Neoplasm/*drug effects ; Emodin/*administration &amp; dosage ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Multidrug Resistance-Associated Proteins/*biosynthesis/genetics ; Ovarian Neoplasms/*drug therapy/genetics/pathology ; Reactive Oxygen Species ; }, abstract = {The intracellular level of reactive oxygen species (ROS) is closely associated with chemosensitivity of cancer cells. Overexpression of ATP binding cassette transporter MRP1 is correlated with resistance to platinum drugs. In this study, we tested the hypothesis that emodin, a potent ROS generator, may increase sensitivity of cisplatin-(cDDP-) resistant ovarian carcinoma cells to cDDP cytotoxicity via ROS-mediated suppression of MRP1 expression. Using the isogenic pair of the human ovarian carcinoma cell line COC1 and its cDDP resistant variant COC1/DDP, we found that ROS level in the cDDP-sensitive ovarian cancer cells was significantly higher than that in the cDDP-resistant cells. Emodin enhanced ROS production in COC1/DDP cells and consequently sensitized them to cDDP-induced apoptosis. These effects were reversed by addition of the antioxidant N-acetyl-L-cysteine (NAC). Cotreatment with emodin and cDDP inhibited the tumor growth in vivo by increasing tumor cell apoptosis. The emodin-enhanced cDDP cytotoxicity was attributable to downregulation of multidrug resistance-related protein 1 (MRP1) expression. Together, these results suggest that emodin could act as an adjunct to enhance the anticancer effect of cDDP likely through ROS-related downregulation of MRP1 expression, and may be of therapeutic potential in cDDP-refractory ovarian carcinomas.}, }
@article {pmid25580390, year = {2014}, author = {Hwang, ES}, title = {Effects of benzyl isothiocyanate and its N-acetylcysteine conjugate on induction of detoxification enzymes in hepa1c1c7 mouse hepatoma cells.}, journal = {Preventive nutrition and food science}, volume = {19}, number = {4}, pages = {268-273}, pmid = {25580390}, issn = {2287-1098}, abstract = {The induction of detoxification enzymes by benzyl isothiocyanate (BITC) and its synthetic N-acetyl-L-cysteine (NAC) conjugate (NAC-BITC) was examined in Hepa1c1c7 murine hepatoma cells. BITC and NAC-BITC inhibited Hepa1c1c7 cell growth in a dose-dependent manner. Cell growth was 4.5~57.2% lower in Hepa1c1c7 cells treated with 0.1~10 μM BITC than in control-treated Hepa1c1c7 cells. The NAC-BITC treatment had a similar inhibitory pattern on Hepa1c1c7 cell growth; 0.5 μM and 10 μM NAC-BITC decreased cell growth by 13.6% and 47.4%, respectively. Treatment of Hepa1c1c7 cells with 0.1~2.0 μM BITC also elicited a dose-response effect on the induction of quinone reductase quinone reductase (QR) activity and QR mRNA expression. Treatment with 1 μM and 2 μM BITC caused 1.8- and 2.8-fold inductions of QR mRNA, respectively. By comparison, treatment with 1 μM and 2 μM NAC-BITC caused 1.6- and 1.9-fold inductions of QR mRNA, respectively. Cytochrome P450 (CYP) 1A1 and CYP2E1 induction were lower in 0.1~2 μM BITC-treated cells than in control-treated cells. CYP2E1 activity was 1.2-fold greater in 0.1 μM NAC-BITC-treated cells than in control-treated cells. However, the CYP2E1 activity of cells treated with higher concentrations (i.e., 1~2 μM) of NAC-BITC was similar to the activity of control-treated cells. Considering the potential of isothiocyanatesto prevent cancer, these results provide support for the use of BITC and NAC-BITC conjugates as chemopreventive agents.}, }
@article {pmid25578562, year = {2015}, author = {Su, X and Wang, P and Yang, S and Zhang, K and Liu, Q and Wang, X}, title = {Sonodynamic therapy induces the interplay between apoptosis and autophagy in K562 cells through ROS.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {60}, number = {}, pages = {82-92}, doi = {10.1016/j.biocel.2014.12.023}, pmid = {25578562}, issn = {1878-5875}, mesh = {Apoptosis/drug effects/radiation effects ; Autophagy/drug effects/*radiation effects ; Cell Survival/drug effects/radiation effects ; Humans ; K562 Cells ; Protoporphyrins/pharmacology ; Reactive Oxygen Species/*metabolism ; Ultrasonic Therapy ; }, abstract = {Sonodynamic therapy (SDT) is a relatively new approach in the treatment of various cancers including leukemia cells. The aim of this study is to investigate the occurrence of apoptosis and autophagy after treated by protoporphyrin IX (PpIX)-mediated SDT (PpIX-SDT) on human leukemia K562 cells as well as the relationship between them. Firstly, mitochondrial-dependent apoptosis was observed through morphological observation and biochemical analysis. Meanwhile, SDT was shown to induce autophagy in K562 cells, which caused an increase in EGFP-LC3 puncta cells, a conversion of LC3 II/I, formation of acidic vesicular organelles (AVOs) and co-localization between LC3 and LAMP2 (a lysosome marker). Besides, pretreatment with autophagy inhibitor 3-MA or bafilomycin A1 was shown to provide protection against autophagy and to enhance SDT-induced apoptosis and necrosis, while the apoptosis suppressor z-VAD-fmk failed to affect formation of autophagic vacuoles or partially prevented SDT-induced cytotoxicity, which suggested that SDT-induced autophagy functioned as a survival mechanism. Additionally, this study reported apparent apoptosis and autophagy with dependence on intracellular reactive oxygen species (ROS) production. Preliminary data showed that ROS scavenger N-acetylcysteine (NAC) effectively blocked the SDT induced accumulation of ROS, reversed sono-damage, cell apoptosis and autophagy. Taken together, these data indicate that autophagy may be cytoprotective in our experimental system, and the ROS caused by PpIX-SDT treatment may play an important role in initiating apoptosis and autophagy.}, }
@article {pmid25577879, year = {2014}, author = {Zhu, HY and Zhu, JP and Xie, AM and Yuan, J and Hua, Y and Zhang, W}, title = {[Preparation and characterization of tumor targeted CdTe quantum dots modified with functional polymer].}, journal = {Yao xue xue bao = Acta pharmaceutica Sinica}, volume = {49}, number = {10}, pages = {1457-1465}, pmid = {25577879}, issn = {0513-4870}, mesh = {Acetylcysteine/chemistry ; Cadmium Compounds/*pharmacology ; Humans ; Neoplasms/*drug therapy ; Polymers/chemistry ; Quantum Dots/*chemistry ; Spectrophotometry, Ultraviolet ; Tellurium/*pharmacology ; }, abstract = {N-acetyl-L-cysteine (NAC) capped quantum dots (QDs) were synthesized by a hydrothermal method and coated with 2-amino-2-deoxy-D-glucose (DG), polyethylene glycol (PEG), and 9-D-arginine (9R). The optical properties, morphology and structure of 9R/DG-coated CdTe QDs were characterized by ultraviolet-visible spectrometry, fluorescence spectrum, Fourier transform infrared (FTIR), proton nuclear magnetic resonance (1H NMR), liquid chromatography-mass spectrometer (LC-MS), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transmission electron micrographs (TEM). Furthermore, the biocompatibility, tumor targeted ability and transmembrane action of 9R/DG-coated CdTe QDs were studied. Results indicated that 9R/DG-coated CdTe QDs was constructed successfully by ligand exchange. The 9R/DG-coated CdTe QDs with the size of 8-10 nm had good dispersity and the absorbance and fluorescence peaks of CdTe QDs after modification were red shifted from 480 nm to 510 nm and 627 nm to 659 nm, respectively. In addition, the CdTe QDs modified by PEG, DG and 9R displayed good biocompatibility, high targeted ability to the cancer cells with glucose transporter type 1 (GLUT1) receptor high expression and obvious transmembrane ability.}, }
@article {pmid25577197, year = {2015}, author = {Boussabbeh, M and Ben Salem, I and Prola, A and Guilbert, A and Bacha, H and Abid-Essefi, S and Lemaire, C}, title = {Patulin induces apoptosis through ROS-mediated endoplasmic reticulum stress pathway.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {144}, number = {2}, pages = {328-337}, doi = {10.1093/toxsci/kfu319}, pmid = {25577197}, issn = {1096-0929}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Endoplasmic Reticulum/*drug effects/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Humans ; Oxidative Stress/*drug effects ; Patulin/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Patulin (PAT) is a toxic metabolite produced by several filamentous fungi of the genera of Penicillium, Aspergillus, and Byssochlamys. PAT is the most common mycotoxin found in apples and apple-based products including juice, compotes, cider, and baby food. Exposure to this mycotoxin has been reported to induce intestinal and kidney injuries. This study investigated the mechanism of PAT-induced toxicity in human colon carcinoma (HCT116) and embryonic kidney cells (HEK293). We demonstrated that PAT activated endoplasmic reticulum (ER) and unfolded protein response as evidenced by up-regulation of GRP78 and GADD34, splicing of XBP1 mRNA, and expression of the proapoptotic factor CHOP. This ER stress response was accompanied by the induction of the mitochondrial apoptotic pathway. Apoptosis occurred with ROS production, drop in mitochondrial membrane potential and caspase activation. Further, we showed that deficiency of the proapoptotic protein Bax or Bak protected cells against PAT-induced apoptosis. The treatment of cells with the ROS scavenger N-acetyl cysteine inhibits the ER stress response and prevents mitochondrial apoptosis. Collectively, our data provide new mechanistic insights in the signaling pathways of the cell death induced by PAT and demonstrate that PAT induces cytotoxicity through a ROS-dependent mechanism involving ER stress and activation of mitochondrial apoptotic pathway in human intestinal and kidney cells.}, }
@article {pmid25576706, year = {2015}, author = {Zhang, W and Chen, L and Zhang, L and Xiao, M and Ding, J and Goltzman, D and Miao, D}, title = {Administration of exogenous 1,25(OH)2D3 normalizes overactivation of the central renin-angiotensin system in 1α(OH)ase knockout mice.}, journal = {Neuroscience letters}, volume = {588}, number = {}, pages = {184-189}, doi = {10.1016/j.neulet.2015.01.013}, pmid = {25576706}, issn = {1872-7972}, mesh = {Acetylcysteine/administration &amp; dosage ; Angiotensin II/metabolism ; Animals ; Antioxidants/administration &amp; dosage ; Blood Pressure/drug effects ; Brain/drug effects/metabolism ; Calcitriol/*pharmacology ; Calcium/administration &amp; dosage ; Diet ; Mice, Knockout ; Oxidative Stress/drug effects ; Phosphorus/administration &amp; dosage ; Receptor, Angiotensin, Type 1/metabolism ; Renin/metabolism ; Renin-Angiotensin System/*drug effects/physiology ; Steroid Hydroxylases/*genetics ; Vitamins/*pharmacology ; }, abstract = {Previously, we reported that active vitamin D deficiency in mice causes secondary hypertension and cardiac dysfunction, but the underlying mechanism remains largely unknown. To clarify whether exogenous active vitamin D rescues hypertension by normalizing the altered central renin-angiotensin system (RAS) via an antioxidative stress mechanism, 1-alpha-hydroxylase [1α(OH)ase] knockout mice [1α(OH)ase(-/-)] and their wild-type littermates were fed a normal diet alone or with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a high-calcium, high-phosphorus "rescue" diet with or without antioxidant N-acetyl-l-cysteine (NAC) supplementation for 4 weeks. Compared with their wild-type littermates, 1α(OH)ase(-/-)mice had high mean arterial pressure, increased levels of renin, angiotensin II (Ang II), and Ang II type 1 receptor, and increased malondialdehyde levels, but decreased anti-peroxiredoxin I and IV proteins and the antioxidative genes glutathione reductase (Gsr) and glutathione peroxidase 4 (Gpx4) in the brain samples. Except Ang II type 1 receptor, these pathophysiological changes were rescued by exogenous 1,25(OH)2D3 or NAC plus rescue diet, but not by rescue diet alone. We conclude that 1,25(OH)2D3 normalizes the altered central RAS in 1α(OH)ase(-/-)mice, at least partially, through a central antioxidative mechanism.}, }
@article {pmid25575547, year = {2015}, author = {Liu, Y and Yao, W and Xu, J and Qiu, Y and Cao, F and Li, S and Yang, S and Yang, H and Wu, Z and Hou, Y}, title = {The anti-inflammatory effects of acetaminophen and N-acetylcysteine through suppression of the NLRP3 inflammasome pathway in LPS-challenged piglet mononuclear phagocytes.}, journal = {Innate immunity}, volume = {21}, number = {6}, pages = {587-597}, doi = {10.1177/1753425914566205}, pmid = {25575547}, issn = {1753-4267}, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Carrier Proteins/genetics/immunology/*metabolism ; Caspase 1/genetics/metabolism ; Cells, Cultured ; Drug Combinations ; Drug Synergism ; Gene Expression Regulation/drug effects ; Inflammasomes/immunology/*metabolism ; Interleukin-18/genetics/metabolism ; Interleukin-1beta/genetics/metabolism ; Leukocytes, Mononuclear/drug effects/*immunology ; Lipopolysaccharides/immunology ; Mononuclear Phagocyte System/drug effects ; *Swine ; }, abstract = {Acetaminophen (AAP) and N-acetylcysteine (NAC) have been found to have anti-inflammatory effects via the TLR-NF-κB pathway in LPS-challenged piglets. However, the action mechanisms employed by AAP and NAC have yet to be completely understood. This study investigated the anti-inflammatory effects and mechanisms of AAP and NAC on LPS-induced inflammatory responses via the NLRP3 inflammasome pathway in piglet mononuclear phagocytes. The results show that mRNA expression levels of IL-1β, IL-18 and NLRP3, as well as the protein level of cleaved caspase-1, are significantly increased after LPS challenge in vitro. LPS stimulation did not change ASC and caspase-1 mRNA levels, which were components of NLRP3 inflammasome complex. AAP (0.5-1.0 mM) and NAC (0.5-1.0 mM) used individually or in combination could down-regulate protein expression of cleaved caspase-1 and mRNA expression of IL-1β, IL-18 and NLRP3. NAC could significantly enhance the above inhibition actions of AAP. The combined use of AAP plus NAC had better inhibition action on the NLRP3 inflammasome pathway. These results indicate that the anti-inflammatory effects of AAP and NAC occur via the regulation on mRNA expression of NLRP3 and activation of caspase-1. The anti-inflammatory activity of AAP and NAC could be related to the suppression of NLRP3 inflammasome pathway under LPS stimulation.}, }
@article {pmid25572399, year = {2015}, author = {Tapryal, N and Vivek G, V and Mukhopadhyay, CK}, title = {Catecholamine stress hormones regulate cellular iron homeostasis by a posttranscriptional mechanism mediated by iron regulatory protein: implication in energy homeostasis.}, journal = {The Journal of biological chemistry}, volume = {290}, number = {12}, pages = {7634-7646}, pmid = {25572399}, issn = {1083-351X}, mesh = {Animals ; Catecholamines/*physiology ; Cell Line, Tumor ; DNA Primers ; *Energy Metabolism ; *Homeostasis ; Humans ; Iron/*metabolism ; Iron-Regulatory Proteins/*physiology ; Liver/cytology/metabolism ; Mice ; Muscle, Skeletal/cytology/metabolism ; *RNA Processing, Post-Transcriptional ; }, abstract = {Adequate availability of iron is important for cellular energy metabolism. Catecholamines such as epinephrine and norepinephrine promote energy expenditure to adapt to conditions that arose due to stress. To restore the energy balance, epinephrine/norepinephrine-exposed cells may face higher iron demand. So far, no direct role of epinephrine/norepinephrine in cellular iron homeostasis has been reported. Here we show that epinephrine/norepinephrine regulates iron homeostasis components such as transferrin receptor-1 and ferritin-H in hepatic and skeletal muscle cells by promoting the binding of iron regulatory proteins to iron-responsive elements present in the UTRs of transferrin receptor-1 and ferritin-H transcripts. Increased transferrin receptor-1, decreased ferritin-H, and increased iron-responsive element-iron regulatory protein interaction are also observed in liver and muscle tissues of epinephrine/norepinephrine-injected mice. We demonstrate the role of epinephrine/norepinephrine-induced generation of reactive oxygen species in converting cytosolic aconitase (ACO1) into iron regulatory protein-1 to bind iron-responsive elements present in UTRs of transferrin receptor-1 and ferritin-H. Our study further reveals that mitochondrial iron content and mitochondrial aconitase (ACO2) activity are elevated by epinephrine/norepinephrine that are blocked by the antioxidant N-acetyl cysteine and iron regulatory protein-1 siRNA, suggesting involvement of reactive oxygen species and iron regulatory protein-1 in this mechanism. This study reveals epinephrine and norepinephrine as novel regulators of cellular iron homeostasis.}, }
@article {pmid25568806, year = {2014}, author = {Alam, J and Baek, KJ and Choi, YS and Kim, YC and Choi, Y}, title = {N-acetylcysteine and the human serum components that inhibit bacterial invasion of gingival epithelial cells prevent experimental periodontitis in mice.}, journal = {Journal of periodontal &amp; implant science}, volume = {44}, number = {6}, pages = {266-273}, pmid = {25568806}, issn = {2093-2278}, abstract = {PURPOSE: We previously reported that human serum significantly reduces the invasion of various oral bacterial species into gingival epithelial cells in vitro. The aims of the present study were to characterize the serum component(s) responsible for the inhibition of bacterial invasion of epithelial cells and to examine their effect on periodontitis induced in mice.<br><br>METHODS: Immortalized human gingival epithelial (HOK-16B) cells were infected with various 5- (and 6-) carboxy-fluorescein diacetate succinimidyl ester-labeled oral bacteria, including Fusobacterium nucleatum, Provetella intermedia, Porphyromonas gingivalis, and Treponiema denticola, in the absence or presence of three major serum components (human serum albumin [HSA], pooled human IgG [phIgG] and &#x3b1;1-antitrypsin). Bacterial adhesion and invasion were determined by flow cytometry. The levels of intracellular reactive oxygen species (ROS) and activation of small GTPases were examined. Experimental periodontitis was induced by oral inoculation of P. gingivalis and T. denticola in Balb/c mice.<br><br>RESULTS: HSA and phIgG, but not &#x3b1;1-antitrypsin, efficiently inhibited the invasion of various oral bacterial species into HOK-16B cells. HSA but not phIgG decreased the adhesion of F. nucleatum onto host cells and the levels of intracellular ROS in HOK-16B cells. N-acetylcysteine (NAC), a ROS scavenger, decreased both the levels of intracellular ROS and invasion of F. nucleatum into HOK-16B cells, confirming the role of ROS in bacterial invasion. Infection with F. nucleatum activated Rac1, a regulator of actin cytoskeleton dynamics. Not only HSA and NAC but also phIgG decreased the F. nucleatum-induced activation of Rac1. Furthermore, both HSA plus phIgG and NAC significantly reduced the alveolar bone loss in the experimental periodontitis induced by P. gingivalis and T. denticola in mice.<br><br>CONCLUSIONS: NAC and the serum components HSA and phIgG, which inhibit bacterial invasion of oral epithelial cells in vitro, can successfully prevent experimental periodontitis.}, }
@article {pmid25568320, year = {2015}, author = {Huang, C and Wang, JJ and Ma, JH and Jin, C and Yu, Q and Zhang, SX}, title = {Activation of the UPR protects against cigarette smoke-induced RPE apoptosis through up-regulation of Nrf2.}, journal = {The Journal of biological chemistry}, volume = {290}, number = {9}, pages = {5367-5380}, pmid = {25568320}, issn = {1083-351X}, support = {R01 EY019949/EY/NEI NIH HHS/United States ; R21 EY025061/EY/NEI NIH HHS/United States ; EY019949/EY/NEI NIH HHS/United States ; EY025061/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects/genetics/*physiology ; Blotting, Western ; Cell Line ; Cell Survival/drug effects/genetics/physiology ; DNA-Binding Proteins/genetics/metabolism ; Endoplasmic Reticulum Stress/physiology ; Epithelial Cells/drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Humans ; Methylamines/pharmacology ; Mitochondria/drug effects/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; RNA Interference ; Reactive Oxygen Species/metabolism ; Regulatory Factor X Transcription Factors ; Retinal Pigment Epithelium/cytology ; Reverse Transcriptase Polymerase Chain Reaction ; *Smoke ; Nicotiana/*chemistry ; Transcription Factor CHOP/genetics/metabolism ; Transcription Factors/genetics/metabolism ; Unfolded Protein Response/drug effects/genetics/*physiology ; *Up-Regulation ; X-Box Binding Protein 1 ; }, abstract = {Recent studies have revealed a role of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) in the regulation of RPE cell activity and survival. Herein, we examined the mechanisms by which the UPR modulates apoptotic signaling in human RPE cells challenged with cigarette smoking extract (CSE). Our results show that CSE exposure induced a dose- and time-dependent increase in ER stress markers, enhanced reactive oxygen species (ROS), mitochondrial fragmentation, and apoptosis of RPE cells. These changes were prevented by the anti-oxidant NAC or chemical chaperone TMAO, suggesting a close interaction between oxidative and ER stress in CSE-induced apoptosis. To decipher the role of the UPR, overexpression or down-regulation of XBP1 and CHOP genes was manipulated by adenovirus or siRNA. Overexpressing XBP1 protected against CSE-induced apoptosis by reducing CHOP, p-p38, and caspase-3 activation. In contrast, XBP1 knockdown sensitized the cells to CSE-induced apoptosis, which is likely through a CHOP-independent pathway. Surprisingly, knockdown of CHOP reduced p-eIF2α and Nrf2 resulting in a marked increase in caspase-3 activation and apoptosis. Furthermore, Nrf2 inhibition increased ER stress and exacerbated cell apoptosis, while Nrf2 overexpression reduced CHOP and protected RPE cells. Our data suggest that although CHOP may function as a pro-apoptotic gene during ER stress, it is also required for Nrf2 up-regulation and RPE cell survival. In addition, enhancing Nrf2 and XBP1 activity may help reduce oxidative and ER stress and protect RPE cells from cigarette smoke-induced damage.}, }
@article {pmid25562842, year = {2015}, author = {Wright, DJ and Renoir, T and Smith, ZM and Frazier, AE and Francis, PS and Thorburn, DR and McGee, SL and Hannan, AJ and Gray, LJ}, title = {N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease.}, journal = {Translational psychiatry}, volume = {5}, number = {1}, pages = {e492}, pmid = {25562842}, issn = {2158-3188}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Behavior, Animal/*drug effects ; Brain/drug effects/pathology ; Disease Models, Animal ; Disease Progression ; Excitatory Amino Acid Transporter 2/drug effects/metabolism ; Free Radical Scavengers/*pharmacology ; Gait/drug effects ; Huntington Disease/*metabolism ; Mice ; Mice, Transgenic ; Mitochondria/*drug effects/metabolism ; Motor Activity/drug effects ; Organ Size ; Oxidative Stress/*drug effects ; }, abstract = {Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy.}, }
@article {pmid25560241, year = {2015}, author = {Li, L and Fath, MA and Scarbrough, PM and Watson, WH and Spitz, DR}, title = {Combined inhibition of glycolysis, the pentose cycle, and thioredoxin metabolism selectively increases cytotoxicity and oxidative stress in human breast and prostate cancer.}, journal = {Redox biology}, volume = {4}, number = {}, pages = {127-135}, pmid = {25560241}, issn = {2213-2317}, support = {R01CA133114/CA/NCI NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; R01 CA133114/CA/NCI NIH HHS/United States ; R01CA182804/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; P30CA086862/CA/NCI NIH HHS/United States ; T32 CA078586/CA/NCI NIH HHS/United States ; T32CA078586/CA/NCI NIH HHS/United States ; R01 CA100045/CA/NCI NIH HHS/United States ; R21CA139182/CA/NCI NIH HHS/United States ; R01 CA182804/CA/NCI NIH HHS/United States ; R21 CA139182/CA/NCI NIH HHS/United States ; R01CA100045/CA/NCI NIH HHS/United States ; }, mesh = {Antioxidants/administration &amp; dosage ; Breast Neoplasms/drug therapy/*metabolism/pathology ; Cell Line, Tumor ; Dehydroepiandrosterone/administration &amp; dosage ; Deoxyglucose/administration &amp; dosage ; Drug Synergism ; Female ; Glycolysis/drug effects ; Humans ; Male ; Oxidative Stress/drug effects ; Pentose Phosphate Pathway/drug effects ; Prostatic Neoplasms/drug therapy/*metabolism/pathology ; Thioredoxins/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Inhibition of glycolysis using 2-deoxy-d-glucose (2DG, 20mM, 24-48h) combined with inhibition of the pentose cycle using dehydroepiandrosterone (DHEA, 300µM, 24-48h) increased clonogenic cell killing in both human prostate (PC-3 and DU145) and human breast (MDA-MB231) cancer cells via a mechanism involving thiol-mediated oxidative stress. Surprisingly, when 2DG+DHEA treatment was combined with an inhibitor of glutathione (GSH) synthesis (l-buthionine sulfoximine; BSO, 1mM) that depleted GSH>90% of control, no further increase in cell killing was observed during 48h exposures. In contrast, when an inhibitor of thioredoxin reductase (TrxR) activity (Auranofin; Au, 1µM), was combined with 2DG+DHEA or DHEA-alone for 24h, clonogenic cell killing was significantly increased in all three human cancer cell lines. Furthermore, enhanced clonogenic cell killing seen with the combination of DHEA+Au was nearly completely inhibited using the thiol antioxidant, N-acetylcysteine (NAC, 20mM). Redox Western blot analysis of PC-3 cells also supported the conclusion that thioredoxin-1 (Trx-1) oxidation was enhanced by treatment DHEA+Au and inhibited by NAC. Importantly, normal human mammary epithelial cells (HMEC) were not as sensitive to 2DG, DHEA, and Au combinations as their cancer cell counterparts (MDA-MB-231). Overall, these results support the hypothesis that inhibition of glycolysis and pentose cycle activity, combined with inhibition of Trx metabolism, may provide a promising strategy for selectively sensitizing human cancer cells to oxidative stress-induced cell killing.}, }
@article {pmid25559659, year = {2015}, author = {Kuyumcu, A and Akyol, A and Buyuktuncer, Z and Ozmen, MM and Besler, HT}, title = {Improved oxidative status in major abdominal surgery patients after N-acetyl cystein supplementation.}, journal = {Nutrition journal}, volume = {14}, number = {}, pages = {4}, pmid = {25559659}, issn = {1475-2891}, mesh = {Abdomen/*surgery ; Acetylcysteine/*administration &amp; dosage ; Aged ; Antioxidants/*analysis ; Colonic Neoplasms/surgery ; Female ; Glutathione/blood ; Humans ; Male ; Malondialdehyde/blood ; Middle Aged ; Nitrates/urine ; Oxidative Stress/*drug effects ; Pancreatic Neoplasms/surgery ; Preoperative Care/*methods ; Reactive Oxygen Species/blood ; Rectal Neoplasms/surgery ; Stomach Neoplasms/surgery ; }, abstract = {BACKGROUND: Increased levels of reactive oxygen species during and after surgery may affect inflammatory response, post-operative adhesion molecule formation, and hemodynamic stability. The glutathione redox cycle is an important regulator in oxidative stress and its reduced forms scavenge free radicals. N-acetyl cysteine, a precursor of reduced glutathione, is considered as a potentially therapeutic wide spectrum agent in clinical practice. We therefore examined whether N-acetyl cysteine improves some biochemical parameters in cancer patients undergoing major abdominal surgery.<br><br>METHODS: Thirty-three patients diagnosed with pancreas, stomach, rectum, colon malignancies, and undergoing major abdominal surgery at Ankara Numune Training and Research Hospital were randomly divided into two groups; control (CON) and N-acetyl cysteine (NAC). The NAC group had 1,200&#xa0;mg&#xa0;N-acetyl cysteine starting two days before the operation day, in addition to isonitrogenous and isocaloric total parenteral nutrition of 1.2&#xa0;g/kg protein, 25&#xa0;kcal/kg, and 60:40 carbohydrate/fat ratio. Blood and urine samples were drawn two days before the operation, on operation day, and on the first, third, and fifth days post-operation.<br><br>RESULTS: Plasma malondialdehyde was significantly lower in the NAC group (P&#x2009;<&#x2009;0.001). N-acetyl cysteine treatment did not affect plasma levels of vitamin A, C or E. The NAC group exhibited a higher ratio of reduced glutathione to oxidised glutathione (P&#x2009;=&#x2009;0.019). Urinary nitrate level was also significantly lower in the NAC group (P&#x2009;=&#x2009;0.016).<br><br>CONCLUSION: The study demonstrated the clinical importance of N-acetyl cysteine supplementation on antioxidant parameters in abdominal surgery patients. In these patients N-acetyl cysteine and vitamin administration can be considered as an effective method for improvement of oxidative status.}, }
@article {pmid25556383, year = {2015}, author = {Mousavi, SG and Sharbafchi, MR and Salehi, M and Peykanpour, M and Karimian Sichani, N and Maracy, M}, title = {The efficacy of N-acetylcysteine in the treatment of methamphetamine dependence: a double-blind controlled, crossover study.}, journal = {Archives of Iranian medicine}, volume = {18}, number = {1}, pages = {28-33}, pmid = {25556383}, issn = {1735-3947}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Amphetamine-Related Disorders/*drug therapy ; Central Nervous System Stimulants/adverse effects ; Craving ; Cross-Over Studies ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Methamphetamine/adverse effects ; Substance Withdrawal Syndrome/*drug therapy/etiology ; Surveys and Questionnaires ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVE: Preclinical studies and early pilot clinical investigations have suggested that N-acetylcysteine (NAC) may be useful in treatment of methamphetamine (METH) dependence. The present study evaluated whether NAC would suppress craving to the METH.<br><br>METHODS: In a double-blind, controlled crossover clinical trial, 32 METH-dependent volunteers were chosen to receive either NAC (1200 mg/day) or placebo, randomly. They were intervened in two four-week sessions. During first session they received either 1200 mg/day of NAC (group A) or placebo (group B). After three days of washout period, next session started with the crossover intervention of the previous regimen. During these eight weeks, all participants received standardized, and Matrix Model of treatment. Craving was assessed using the Cocaine Craving Questionnaire-Brief (CCQ-Brief). The data were analyzed using SPSS version 20.0 (SPSS Inc. Chicago, Illinois, USA).<br><br>RESULTS: In 23 subjects who completed the study, the mean score of CCQ-Brief reduced in four consecutive weeks with NAC treatment. The mean (SD) scores of carving in group A and B were 3.38 (1.16) and 5.96 (1.03), at the end of first session; and 4.57 (1.88) and 3.2 (0.86), at the end of the second session, respectively. Our findings indicate that the main effect was significant for NAC (P < 0.001). Across placebo and NAC conditions, only mild side effects were noted, and the number of subjects who reported side effects did not differ.<br><br>CONCLUSION: The NAC showed good efficacy in suppressing METH craving, and may be a useful pharmacological treatment for METH dependency.}, }
@article {pmid25553484, year = {2015}, author = {Hou, Y and Wang, L and Yi, D and Wu, G}, title = {N-acetylcysteine and intestinal health: a focus on its mechanism of action.}, journal = {Frontiers in bioscience (Landmark edition)}, volume = {20}, number = {5}, pages = {872-891}, doi = {10.2741/4342}, pmid = {25553484}, issn = {2768-6698}, mesh = {Acetylcysteine/*pharmacology ; Growth/drug effects ; Humans ; Intestines/*drug effects/physiology ; }, abstract = {The integrity of the intestinal epithelium ensures its normal physiological function. Consequently, damage to the mucosal epithelium can impair the absorption of nutrients, thereby reducing the growth performance and compromising the health of animals. N-acetylcysteine (NAC) is pharmaceutically available either intravenously, orally, or by inhalation for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification, and transplant prolongation. NAC is rapidly metabolized by the small intestine to produce glutathione and can not be detected in animals without supplementation. The physiologic functions and therapeutic effects of NAC are largely associated with maintaining intracellular concentrations of reduced glutathione. Results from recent studies indicate that NAC reduces inflammation, alleviates oxidative stress, improves energy status, and ameliorates tissue damage in the intestine of lipopolysaccharide-challenged piglets. Moreover, dietary supplementation with NAC ameliorates acetic acid-induced colitis in a porcine model. The effects of NAC are associated with some intestinal cell signaling pathways, such as EGFR, TLR4, apoptosis and tight junction signaling. The current review focuses on the protective effects of NAC on intestinal health and the molecular mechanisms of its action.}, }
@article {pmid25553408, year = {2015}, author = {Ayorech, Z and Tracy, DK and Baumeister, D and Giaroli, G}, title = {Taking the fuel out of the fire: evidence for the use of anti-inflammatory agents in the treatment of bipolar disorders.}, journal = {Journal of affective disorders}, volume = {174}, number = {}, pages = {467-478}, doi = {10.1016/j.jad.2014.12.015}, pmid = {25553408}, issn = {1573-2517}, mesh = {Acetylcysteine/adverse effects/therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/*therapeutic use ; Antidepressive Agents/adverse effects/therapeutic use ; Antimanic Agents/adverse effects/therapeutic use ; Bipolar Disorder/*drug therapy ; Fatty Acids, Omega-3/adverse effects/therapeutic use ; Humans ; }, abstract = {BACKGROUND: Inflammation has emerged as a potentially important factor - and thus putative pharmacological target - in the pathology of bipolar disorders. However to date no systematic evaluations of the efficacy of add on anti-inflammatory treatment for the depressive and manic episodes have been carried out.<br><br>METHODS: Sixteen articles were ultimately identified - by computer searches of databases (including PsycINFO, MEDLINE, and EMBASE), supplemented by hand searches and personal communication - as meeting study inclusion criteria.<br><br>RESULTS: Anti-manic effects were evaluated in two trials, one of adjunctive n-acetyl cysteine (NAC), one of omega-3 fatty acids (O3FA), and significant improvements only emerged for NAC. Celecoxib had a rapid but short-lived antidepressant effect. Despite limited effects of O3FA on symptoms, imaging data demonstrated alterations in neuronal functioning that might have longer-term therapeutic effects. Evidence was strongest for adjunctive NAC in bipolar depression though conclusions are limited by small sample sizes.<br><br>LIMITATIONS: Definitive conclusions are limited by the paucity of data, small study sizes, and the variability in methodology used.<br><br>CONCLUSIONS: Current evidence for aspirin or celecoxib is insufficient though further investigation of the potential of celecoxib in early illness onset is warranted. Variable evidence exists for add-on O3FA though an indication of short-term treatment effects on membrane fluidity and neuronal activity suggest longer follow-up assessment is needed. The strongest evidence emerged for NAC in depression and future studies must address the role of illness duration and patients&#x5f3; baseline medications on outcomes. Careful consideration of lithium toxicity in the elderly and renal impaired is essential.}, }
@article {pmid25549853, year = {2015}, author = {Ibie, C and Knott, R and Thompson, CJ}, title = {In-vitro evaluation of the effect of polymer structure on uptake of novel polymer-insulin polyelectrolyte complexes by human epithelial cells.}, journal = {International journal of pharmaceutics}, volume = {479}, number = {1}, pages = {103-117}, doi = {10.1016/j.ijpharm.2014.12.058}, pmid = {25549853}, issn = {1873-3476}, mesh = {*Acetylcysteine/chemistry/pharmacology ; *Amidines/chemistry/pharmacology ; Biological Transport ; Caco-2 Cells ; Cell Survival/drug effects ; Epithelial Cells/drug effects ; Humans ; *Insulin/chemistry/pharmacology ; Microscopy, Fluorescence ; *Polyamines/chemistry/pharmacology ; *Quaternary Ammonium Compounds/chemistry/pharmacology ; }, abstract = {The biocompatibility and cellular uptake of polymer, insulin polyelectrolyte complexes (PECs) prepared using polyallylamine-based polymers was evaluated in-vitro using Caco-2 cell monolayers as a predictive model for human small intestinal epithelial cells. Poly(allyl amine) (PAA) and Quaternised PAA (QPAA) were thiolated using either carbodiimide mediated conjugation to N-acetylcysteine (NAC) or reaction with 2-iminothiolane hydrochloride yielding their NAC and 4-thiobutylamidine (TBA) conjugates, respectively. The effect of polymer quaternisation and/or thiolation on the IC50 of PAA was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay carried out on Caco-2 cells (with and without a 24 h recovery period after samples were removed). Uptake of PECs by Caco-2 cells was monitored by microscopy using fluorescein isothiocyanate (FITC) labelled insulin and rhodamine-labelled polymers at polymer:insulin ratios (4:5) after 0.5, 1, 2 and 4 h incubation in growth media (±calcium) and following pre-incubation with insulin. MTT results indicated that quaternisation of PAA was associated with an improvement in IC50 values; cells treated with QPAA (0.001-4 mg mL(-1)) showed no signs of toxicity following a 24 h cell recovery period, while thiolation of QPAA resulted in a decrease in the IC50. Cellular uptake studies showed that within 2-4 h, QPAA and QPAA-TBA insulin PECs were taken up intracellularly, with PECs being localised within the perinuclear area of cells. Further investigation showed that uptake of PECs was unaffected when calcium-free media was used, while presaturating insulin receptors affected the uptake of QPAA, insulin PECs, but not QPAA-TBA PECs. The biocompatibility of PAA and uptake of insulin was improved by both thiol and quaternary substitution.}, }
@article {pmid25545158, year = {2015}, author = {Heidari, R and Niknahad, H and Jamshidzadeh, A and Azarpira, N and Bazyari, M and Najibi, A}, title = {Carbonyl traps as potential protective agents against methimazole-induced liver injury.}, journal = {Journal of biochemical and molecular toxicology}, volume = {29}, number = {4}, pages = {173-181}, doi = {10.1002/jbt.21682}, pmid = {25545158}, issn = {1099-0461}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Carnosine/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology ; Male ; Metformin/*therapeutic use ; Methimazole/*toxicity ; Mice ; Necrosis ; Oxidative Stress/drug effects ; Protective Agents/therapeutic use ; }, abstract = {Liver injury is a deleterious adverse effect associated with methimazole administration, and reactive intermediates are suspected to be involved in this complication. Glyoxal is an expected reactive intermediate produced during methimazole metabolism. Current investigation was undertaken to evaluate the role of carnosine, metformin, and N-acetyl cysteine as putative glyoxal (carbonyl) traps, against methimazole-induced hepatotoxicity. Methimazole (100 mg/kg, intraperitoneally) was administered to intact and/or glutathione (GSH)-depleted mice and the role of glyoxal trapping agents was investigated. Methimazole caused liver injury as revealed by an increase in serum alanine aminotransferase and aspartate aminotransferase. Moreover, lipid peroxidation and protein carbonylation occurred significantly in methimazole-treated animals' liver. Hepatic GSH reservoirs were decreased, and inflammatory cells infiltration was observed in liver histopathology. Methimazole-induced hepatotoxicity was severe in GSH-depleted mice and accompanied with interstitial hemorrhage and necrosis of the liver. Glyoxal trapping agents effectively diminished methimazole-induced liver injury both in intact and/or GSH-depleted animals.}, }
@article {pmid25545035, year = {2015}, author = {da Silva, DG and Ricci, O and de Almeida, EA and Bonini-Domingos, CR}, title = {Potential utility of melatonin as an antioxidant therapy in the management of sickle cell anemia.}, journal = {Journal of pineal research}, volume = {58}, number = {2}, pages = {178-188}, doi = {10.1111/jpi.12204}, pmid = {25545035}, issn = {1600-079X}, mesh = {Adult ; Anemia, Sickle Cell/blood/*drug therapy/metabolism ; Antioxidants/*therapeutic use ; Catalase/blood ; Female ; Glutathione/blood ; Glutathione Peroxidase/blood ; Glutathione Reductase/blood ; Hemoglobin, Sickle/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/blood ; Melatonin/*therapeutic use ; Oxidative Stress/drug effects ; Superoxide Dismutase/blood ; }, abstract = {This study aimed to assess antioxidant effects of melatonin treatment compared to N-acetylcysteine (NAC) and to their combination in a sickle cell suspension. Sickle erythrocytes were suspended in phosphate-buffered saline, pH 7.4, composing external control group. They were also suspended and incubated at 37°C either in the absence (experimental control group) or in the presence of NAC, melatonin and their combination at concentrations of 100 pm, 100 nm and 100 μm for 1 hr (treatment groups). The melatonin influences were evaluated by spectrophotometric [hemolysis degree, catalase (CAT), glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PDH), and superoxide dismutase (SOD) activities] and chromatographic methods [glutathione (GSH) and malondialdehyde (MDA) levels]. Incubation period was able to cause a rise about 64% on hemolysis degree as well as practically doubled the lipid peroxidation levels (P < 0.01). However, almost all antioxidants tested treatments neutralized this incubation effect observed in MDA levels. Among the antioxidant biomarkers evaluated, we observed a modulating effect of combined treatment on GPx and SOD activities (P < 0.01), which showed ~25% decrease in their activities. In addition, we found an antioxidant dose-dependent effect for melatonin on lipid peroxidation (r = -0.29; P = 0.03) and for combined antioxidant treatments also on MDA levels (r = -0.37; P = 0.01) and on SOD activity (r = -0.54; P < 0.01). Hence, these findings contribute with important insight that melatonin individually or in combination with NAC may be useful for sickle cell anemia management.}, }
@article {pmid25542361, year = {2015}, author = {Bian, W and Wang, F and Wei, Y and Wang, L and Liu, Q and Dong, W and Shuang, S and Choi, MM}, title = {Doped zinc sulfide quantum dots based phosphorescence turn-off/on probe for detecting histidine in biological fluid.}, journal = {Analytica chimica acta}, volume = {856}, number = {}, pages = {82-89}, doi = {10.1016/j.aca.2014.11.037}, pmid = {25542361}, issn = {1873-4324}, mesh = {Acetylcysteine/*chemistry ; Adsorption ; Adult ; Cobalt/chemistry ; Histidine/chemistry/*urine ; Humans ; Hydrogen-Ion Concentration ; Limit of Detection ; Luminescent Agents/*chemistry ; Luminescent Measurements ; Manganese/chemistry ; Quantum Dots/*chemistry ; Sulfides/*chemistry ; Time Factors ; Urinalysis/*methods ; Zinc Compounds/*chemistry ; }, abstract = {We report a turn-on phosphorescence probe for detection of histidine based on Co(2+)-adsorbed N-acetyl-L-cysteine (NAC) capped Mn: ZnS quantum dots (QDs) which is directly synthesized by the hydrothermal method. The phosphorescence of NAC-Mn: ZnS QDs is effectively quenched by Co(2+) attributing to the adsorption of Co(2+) onto the surface of QDs with a concomitant in suppressing the recombination process of hole and electron of QDs. The phosphorescence of Co(2+)-adsorbed NAC-Mn: ZnS QDs can be recovered by binding of Co(2+) with histidine. The quenching and regeneration of the phosphorescence of NAC-Mn: ZnS QDs have been studied in detail. The as-prepared QDs-based probe is applied to determine histidine with a linear range of 1.25-30 μM and a detection limit of 0.74 μM. The relative standard deviation for eleven repeat detections of 20 μM histidine is 0.65%. Co(2+)-adsorbed NAC-Mn: ZnS QDs show high sensitivity and good selectivity to histidine over other amino acids, metal ions and co-existing substances. The proposed QDs probe has been successfully applied to determination of histidine in human urine samples with good recoveries of 98.5-103%.}, }
@article {pmid25541725, year = {2015}, author = {Fabbri, R and Sapone, A and Paolini, M and Vivarelli, F and Franchi, P and Lucarini, M and Pasquinelli, G and Vicenti, R and Macciocca, M and Venturoli, S and Canistro, D}, title = {Effects of N-acetylcysteine on human ovarian tissue preservation undergoing cryopreservation procedure.}, journal = {Histology and histopathology}, volume = {30}, number = {6}, pages = {725-735}, doi = {10.14670/HH-30.725}, pmid = {25541725}, issn = {1699-5848}, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Adult ; Cryopreservation/*methods ; Female ; Humans ; Ovary/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Young Adult ; }, abstract = {The aim of the study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC), added in freezing/thawing solutions, on reactive oxygen species (RRS) levels and on ovarian tissue preservation after cryopreservation. Ovarian samples from 10 subjects suffering from cancer diseases were cryopreserved using the slow freezing/rapid thawing standard protocol without or with NAC supplementation. RRS levels produced during cryopreservation were monitored by electron paramagnetic resonance (EPR) spectroscopy. The preservation of fresh ovarian tissue (t0), thawed tissue (t1 and t1 NAC) and thawed tissue maintained at 4°C for 2 hrs (t2 and t2 NAC) was analysed by light microscopy, transmission electron microscopy, Ki67 immunohistochemical and TUNEL analysis. It was possible to design a maximum peak for RRS production at t1, which slightly decreased at t2. NAC reduced the extent of RRS levels in cryopreserved ovarian tissues if compared with non-supplemented ones, although not restoring RRS production to baseline values. Comparative analysis between the two cryopreservation protocols showed that a better preservation of morphological characteristics, proliferation index and DNA integrity of ovarian tissue was obtained using NAC and no differences between t1NAC and t2NAC were observed. The employment of NAC during cryopreservation procedure could be an useful strategy for preserving the function of endogenous cellular systems. Nevertheless, further studies on the viability of thawed ovarian tissue are needed to support the feasibility of this approach in clinical settings.}, }
@article {pmid25541714, year = {2014}, author = {Khadaroo, RG and Fortis, S and Salim, SY and Streutker, C and Churchill, TA and Zhang, H}, title = {I-FABP as biomarker for the early diagnosis of acute mesenteric ischemia and resultant lung injury.}, journal = {PloS one}, volume = {9}, number = {12}, pages = {e115242}, pmid = {25541714}, issn = {1932-6203}, support = {69042-1//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Biomarkers/metabolism ; Disease Models, Animal ; Early Diagnosis ; Fatty Acid-Binding Proteins/*metabolism ; Lung Injury/diagnosis/*metabolism ; Male ; Mesenteric Ischemia/chemically induced/complications/*diagnosis/metabolism ; Mice ; Mice, Inbred C57BL ; alpha-Defensins/*metabolism ; }, abstract = {Acute mesenteric ischemia (AMI) is a life-threatening condition that can result in multiple organ injury and death. A timely diagnosis and treatment would have a significant impact on the morbidity and mortality in high-risk patient population. The purpose of this study was to investigate if intestinal fatty acid binding protein (I-FABP) and α-defensins can be used as biomarkers for early AMI and resultant lung injury. C57BL/6 mice were subjected to intestinal ischemia by occlusion of the superior mesenteric artery. A time course of intestinal ischemia from 0.5 to 3 h was performed and followed by reperfusion for 2 h. Additional mice were treated with N-acetyl-cysteine (NAC) at 300 mg/kg given intraperitoneally prior to reperfusion. AMI resulted in severe intestinal injury characterized by neutrophil infiltrate, myeloperoxidase (MPO) levels, cytokine/chemokine levels, and tissue histopathology. Pathologic signs of ischemia were evident at 1 h, and by 3 h of ischemia, the full thickness of the intestine mucosa had areas of coagulative necrosis. It was noted that the levels of α-defensins in intestinal tissue peaked at 1 h and I-FABP in plasma peaked at 3 h after AMI. Intestinal ischemia also resulted in lung injury in a time-dependent manner. Pretreatment with NAC decreased the levels of intestinal α-defensins and plasma I-FABP, as well as lung MPO and cytokines. In summary, the concentrations of intestinal α-defensins and plasma I-FABP predicted intestinal ischemia prior to pathological evidence of ischemia and I-FABP directly correlated with resultant lung injury. The antioxidant NAC reduced intestinal and lung injury induced by AMI, suggesting a role for oxidants in the mechanism for distant organ injury. I-FABP and α-defensins are promising biomarkers, and may guide the treatment with antioxidant in early intestinal and distal organ injury.}, }
@article {pmid25539742, year = {2014}, author = {Wu, Y and Wang, KY and Li, Z and Liu, YP and Izumi, H and Uramoto, H and Nakayama, Y and Ito, K and Kohno, K}, title = {Y-box binding protein 1 enhances DNA topoisomerase 1 activity and sensitivity to camptothecin via direct interaction.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {33}, number = {1}, pages = {112}, pmid = {25539742}, issn = {1756-9966}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Binding Sites ; Camptothecin/*pharmacology ; Catalysis ; Cell Line, Tumor ; DNA Topoisomerases, Type I/genetics/*metabolism ; Down-Regulation ; Drug Resistance, Neoplasm ; Enzyme Activation ; Gene Expression Regulation, Neoplastic ; Humans ; Nucleic Acid Conformation ; Oxidative Stress/drug effects ; Protein Binding ; Protein Interaction Domains and Motifs ; RNA Interference ; Topoisomerase I Inhibitors/*pharmacology ; Transfection ; Y-Box-Binding Protein 1/genetics/*metabolism ; }, abstract = {BACKGROUND: The Y-box binding protein 1 (YB-1) possesses pleiotropic functions through its interactions with various cellular proteins, and its high expression levels make it a potential useful prognostic biomarker for cancer cells. Eukaryotic DNA topoisomerases, such as DNA topoisomerase 1 (TOPO1) and DNA topoisomerase 2 (TOPO2), are the essential DNA metabolism regulators that usually overexpressed in cancer cells, and multiple proteins have been reported to regulate the enzyme activity and the clinical efficacy of their inhibitors. The present study unraveled the interaction of YB-1 with TOPO1, and further investigated the related function and potential mechanisms during the interaction.<br><br>METHODS: The direct association of TOPO1 with specific domain of YB-1 was explored by co-immunoprecipitation and GST pull-down assays. The interaction function was further clarified by DNA relaxation assays, co-immunoprecipitation and WST-8 assays with in vitro gain- and loss- of function models.<br><br>RESULTS: We found that YB-1 interacts directly with TOPO1 (but not with TOPO2) and promotes TOPO1 catalytic activity. Interactions between YB-1 and TOPO1 increased when cancer cells were treated with the TOPO1 inhibitor, camptothecin (CPT), but not with the TOPO2 inhibitor, adriamycin (ADM). Furthermore, we found that the interaction is prevented by pretreatment with the antioxidant agent, N-acetyl cysteine, and that YB-1 downregulation renders cells resistant to CPT.<br><br>CONCLUSIONS: Our findings suggest that nuclear YB-1 serves as an intracellular promoter of TOPO1 catalytic activity that enhances CPT sensitivity through its direct interaction with TOPO1.}, }
@article {pmid25537089, year = {2015}, author = {You, BR and Kim, SH and Park, WH}, title = {Reactive oxygen species, glutathione, and thioredoxin influence suberoyl bishydroxamic acid-induced apoptosis in A549 lung cancer cells.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {36}, number = {5}, pages = {3429-3439}, pmid = {25537089}, issn = {1423-0380}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Glutathione/analysis/*physiology ; Histone Deacetylase Inhibitors/*pharmacology ; Humans ; Hydroxamic Acids/*pharmacology ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Thioredoxins/analysis/*physiology ; }, abstract = {Suberoyl bishydroxamic acid (SBHA) as a histone deacetylase (HDAC) inhibitor can induce apoptosis through the formation of reactive oxygen species (ROS). However, there is no report about the regulation of ROS and antioxidant enzymes in SBHA-treated lung cancer cells. Here, we investigated the toxicological effects of SBHA on the regulations of ROS, glutathione (GSH), and antioxidant enzymes, especially thioredoxin (Trx) in A549 lung cancer cells. SBHA inhibited the growth of A549 cells in time- and dose-dependent manners, and it induced apoptosis which accompanied by the loss of mitochondrial membrane potential (MMP; ΔΨm). SBHA significantly increased ROS levels including O2 (•-) level at 72 h whereas it decreased ROS levels at the early time points (30 min to 3 h). SBHA also induced GSH depletion at 24 and 72 h. N-acetyl cysteine (NAC; a well-known antioxidant) prevented apoptotic cell death and GSH depletion via decreasing ROS in SBHA-treated A549 cells. In addition, SBHA changed the levels of antioxidant-related proteins, especially Trx1. The expression and activity of Trx1 in A549 cells were reduced by SBHA. While the downregulation of Trx1 enhanced cell death, ROS level, and GSH depletion in SBHA-treated A549 cells, the overexpression of Trx1 decreased ROS level in these cells without the prevention of cell death and GSH depletion. In conclusion, SBHA-induced A549 cell death was influenced by changes in ROS and GSH levels. The basal status of Trx1 among other antioxidant proteins was closely correlated with the survival of A549 cells.}, }
@article {pmid25535147, year = {2014}, author = {Bulut, F and Meric, F and Yorgancilar, E and Nergiz, Y and Akkus, M and Nergiz, S and Nasir, Y}, title = {Effects of N-acetyl-cysteine and acetylsalicylic acid on the tonsil bacterial biofilm tissues by light and electron microscopy.}, journal = {European review for medical and pharmacological sciences}, volume = {18}, number = {23}, pages = {3720-3725}, pmid = {25535147}, issn = {2284-0729}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Adolescent ; Adult ; Aspirin/*pharmacology/therapeutic use ; Biofilms/*drug effects ; Child ; Child, Preschool ; Female ; Humans ; Male ; Microscopy, Electron/methods ; Microscopy, Polarization/methods ; Palatine Tonsil/*drug effects/microbiology/*pathology ; Tonsillitis/diagnosis/drug therapy ; Young Adult ; }, abstract = {OBJECTIVE: The present study aimed to investigate the effects of the bacterial biofilm formation on the tonsil surface exposed N-acetyl-cysteine (NAC) and acetylsalicylic acid (ASA) of patients undergoing tonsillectomy by light and electron microscopy. The general process of biofilm formation comprises adhesion of free-living or planktonic bacteria to a surface, which subsequently develop into microcolonies and form a biofilm. Based on studies that have shown the presence of biofilms in common sites of chronic infections, it has become clear that bacteria may persist on mucosal surfaces through formation of biofilms.<br><br>PATIENTS AND METHODS: Ten patients between 4 and 39 years of age (mean, 11.9 &#xb1; 11.2 years). In all cases, periodic acide Schiff (PAS) staining was found to be an accurate predictor of the presence or absence of biofilm using light microscopy as a control standard. Therapeutic doses of NAC and ASA were identificated as the effective on the tonsil bacterial biofilm using light and electron microscopy.<br><br>RESULTS: Biofilm formation was detected on all samples. Tonsils removed from patients with ASA-10 had showed higher-grade inhibitory effect at the biofilm formation than the other group (p &#x2264; 0.0001). The correlation was found between drug dose and decrease at the biofilm formation.<br><br>CONCLUSIONS: In chronic or recurrent tonsillitis patients, decrease on the tonsils surface biofilm formation may be associated with ASA dose. Whether effect on the tonsils surface biofilm formation of other agent have a role is not known. Key Words: Acetylsalicylic acid, Chronic tonsillitis, In vitro, Mucosal biofilm, N-Acetyl-cysteine.}, }
@article {pmid25534813, year = {2016}, author = {Kumar, A and Sasmal, D and Bhaskar, A and Mukhopadhyay, K and Thakur, A and Sharma, N}, title = {Deltamethrin-induced oxidative stress and mitochondrial caspase-dependent signaling pathways in murine splenocytes.}, journal = {Environmental toxicology}, volume = {31}, number = {7}, pages = {808-819}, doi = {10.1002/tox.22091}, pmid = {25534813}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Caspases/*drug effects ; Glutathione/metabolism ; Immune System/drug effects ; Insecticides/*toxicity ; Mice ; Mitochondria/drug effects/*enzymology/immunology ; Molecular Docking Simulation ; Nitriles/antagonists &amp; inhibitors/*toxicity ; Oxidative Stress/*drug effects ; Pyrethrins/antagonists &amp; inhibitors/*toxicity ; Signal Transduction/*drug effects/immunology ; Spleen/cytology/*drug effects ; }, abstract = {Deltamethrin (DLM) is a well-known pyrethroid insecticide used extensively in pest control. Exposure to DLM has been demonstrated to cause apoptosis in various cells. However, the immunotoxic effects of DLM on mammalian system and its mechanism is still an open question to be explored. To explore these effects, this study has been designed to first observe the interactions of DLM to immune cell receptors and its effects on the immune system. The docking score revealed that DLM has strong binding affinity toward the CD45 and CD28 receptors. In vitro study revealed that DLM induces apoptosis in murine splenocytes in a concentration-dependent manner. The earliest markers of apoptosis such as enhanced reactive oxygen species and caspase 3 activation are evident as early as 1 h by 25 and 50 µM DLM. Western blot analysis demonstrated that p38 MAP kinase and Bax expression is increased in a concentration-dependent manner, whereas Bcl 2 expression is significantly reduced after 3 h of DLM treatment. Glutathione depletion has been also observed at 3 and 6 h by 25 and 50 µM concentration of DLM. Flow cytometry results imply that the fraction of hypodiploid cells has gradually increased with all the concentrations of DLM at 18 h. N-acetyl cysteine effectively reduces the percentage of apoptotic cells, which is increased by DLM. In contrast, buthionine sulfoxamine causes an elevation in the percentage of apoptotic cells. Phenotyping data imply the effect of DLM toxicity in murine splenocytes. In brief, the study demonstrates that DLM causes apoptosis through its interaction with CD45 and CD28 receptors, leading to oxidative stress and activation of the mitochondrial caspase-dependent pathways which ultimately affects the immune functions. This study provides mechanistic information by which DLM causes toxicity in murine splenocytes. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 808-819, 2016.}, }
@article {pmid25534769, year = {2015}, author = {Fan, X and Chen, P and Jiang, Y and Wang, Y and Tan, H and Zeng, H and Wang, Y and Qu, A and Gonzalez, FJ and Huang, M and Bi, H}, title = {Therapeutic efficacy of Wuzhi tablet (Schisandra sphenanthera Extract) on acetaminophen-induced hepatotoxicity through a mechanism distinct from N-acetylcysteine.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {43}, number = {3}, pages = {317-324}, pmid = {25534769}, issn = {1521-009X}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/*metabolism ; Animals ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism ; Drugs, Chinese Herbal/*pharmacology ; Glutathione/metabolism ; Hepatocytes/drug effects/metabolism ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Plant Extracts/chemistry/*pharmacology ; Schisandra/*chemistry ; Signal Transduction/drug effects ; Tablets/*pharmacology ; }, abstract = {Acetaminophen (APAP) hepatotoxicity is the most common cause of drug-induced liver injury and N-acetylcysteine (NAC) is the primary antidote of APAP poisoning. Wuzhi tablet (WZ), the active constituents well identified and quantified, is a preparation of an ethanol extract of Schisandra sphenanthera and exerts a protective effect toward APAP-induced hepatotoxicity in mice. However, the clinical use of WZ to rescue APAP-induced acute liver injury and the mechanisms involved in the therapeutic effect of WZ remain unclear. Therefore, the effect of WZ on APAP hepatotoxicity was compared with NAC in mice, and molecular pathways contributing to its therapeutic action were investigated. Administration of WZ 4 hours after APAP treatment significantly attenuated APAP hepatotoxicity and exerted much better therapeutic effect than NAC, as revealed by morphologic, histologic, and biochemical assessments. Both WZ and NAC prevented APAP-induced c-Jun N-terminal protein kinase activation and mitochondrial glutathione depletion in livers. The protein expression of nuclear factor erythroid 2-related factor 2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was increased by WZ administration. Furthermore, p53 and p21 levels were upregulated upon APAP exposure, which were completely reversed by postdosing of WZ 4 hours after APAP treatment over 48 hours. In comparison with NAC, WZ significantly increased the expression of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration in APAP-injured livers. This study demonstrated that WZ possessed a therapeutic efficacy against APAP-induced liver injury by inhibiting oxidative stress and stimulating a regenerative response after liver injury. Thus WZ may represent a new therapy for APAP-induced acute liver injury.}, }
@article {pmid25534168, year = {2015}, author = {Nikolayevskyy, V and Miotto, P and Pimkina, E and Balabanova, Y and Kontsevaya, I and Ignatyeva, O and Ambrosi, A and Skenders, G and Ambrozaitis, A and Kovalyov, A and Sadykhova, A and Simak, T and Kritsky, A and Mironova, S and Tikhonova, O and Dubrovskaya, Y and Rodionova, Y and Cirillo, D and Drobniewski, F}, title = {Utility of propidium monoazide viability assay as a biomarker for a tuberculosis disease.}, journal = {Tuberculosis (Edinburgh, Scotland)}, volume = {95}, number = {2}, pages = {179-185}, doi = {10.1016/j.tube.2014.11.005}, pmid = {25534168}, issn = {1873-281X}, mesh = {Adult ; Antitubercular Agents/pharmacology/therapeutic use ; *Azides ; Bacterial Load ; Drug Monitoring/methods ; Humans ; Microbial Viability/*drug effects ; Mycobacterium tuberculosis/*drug effects/isolation &amp; purification ; Propidium/*analogs &amp; derivatives ; Specimen Handling/methods ; Sputum/microbiology ; Tuberculosis, Pulmonary/*diagnosis/drug therapy ; Young Adult ; }, abstract = {Reliable laboratory diagnosis of tuberculosis (TB), including laboratory biomarkers of cure, remains a challenge. In our study we evaluated the performance of a Propidium Monoazide (PMA) assay for the detection of viable TB bacilli in sputum specimens during anti-TB chemotherapy and its potential use as a TB biomarker. The study was conducted at three centres on 1937 sputum specimens from 310 adult bacteriologically confirmed pulmonary TB patients obtained before commencing anti-TB treatment and at regular intervals afterwards. Performance of the PMA assay was assessed using various readout assays with bacteriology culture results and time to positivity on liquid media used as reference standards. Treatment of sputum with N-acetyl-cysteine was found to be fully compatible with the PMA assay. Good sensitivity and specificity (97.5% and 70.7-80.0%) for detection of live TB bacilli was achieved using the Xpert(®) MTB/RIF test as a readout assay. Tentative Ct and ΔCt thresholds for the Xpert(®) MTB/RIF system were proposed. Good correlation (r = 0.61) between Ct values and time to positivity of TB cultures on liquid media was demonstrated. The PMA method has potential in monitoring bacterial load in sputum specimens and so may have a role as a biomarker of cure in TB treatment.}, }
@article {pmid25529445, year = {2015}, author = {Zhang, Y and Han, L and Qi, W and Cheng, D and Ma, X and Hou, L and Cao, X and Wang, C}, title = {Eicosapentaenoic acid (EPA) induced apoptosis in HepG2 cells through ROS-Ca(2+)-JNK mitochondrial pathways.}, journal = {Biochemical and biophysical research communications}, volume = {456}, number = {4}, pages = {926-932}, doi = {10.1016/j.bbrc.2014.12.036}, pmid = {25529445}, issn = {1090-2104}, mesh = {Apoptosis/*drug effects ; Calcium/*metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Shape/drug effects ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Cytoplasm/drug effects/metabolism ; Eicosapentaenoic Acid/*pharmacology ; Hep G2 Cells ; Humans ; Intracellular Space/drug effects/metabolism ; MAP Kinase Signaling System/*drug effects ; Mitochondria/drug effects/*metabolism ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Reactive Oxygen Species/*metabolism ; }, abstract = {Eicosapentaenoic acid (EPA), a well-known dietary n-3 PUFAS, has been considered to inhibit proliferation of tumor cells. However, the molecular mechanism related to EPA-induced liver cancer cells apoptosis has not been reported. In this study, we investigated the effect of EPA on HepG2 cells proliferation and apoptosis mechanism through mitochondrial pathways. EPA inhibited proliferation of HepG2 cells in a dose-dependent manner and had no significant effect on the cell viability of humor normal liver L-02 cells. It was found that EPA initially evoked ROS formation, leading to [Ca(2+)]c accumulation and the mitochondrial permeability transition pore (MPTP) opening; EPA-induced HepG2 cells apoptosis was inhibited by N-acetylcysteine (NAC, an inhibitor of ROS), 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM, a chelator of calcium) and CsA (inhibitor of MPTP). The relationship between ROS production, the increase of cytoplasmic Ca and MPTP opening was detected. It seems that ROS may act as an upstream regulator of EPA-induced [Ca(2+)]c generation, moreover, generation of ROS, overload of mitochondrial [Ca(2+)]c, and JNK activated cause the opening of MPTP. Western blotting results showed that EPA elevated the phosphorylation status of JNK, processes associated with the ROS generation. Simultaneously, the apoptosis induced by EPA was related to release of cytochrome C from mitochondria to cytoplasm through the MPTP and activation of caspase-9 and caspase-3. These results suggest that EPA induces apoptosis through ROS-Ca(2+)-JNK mitochondrial pathways.}, }
@article {pmid25527729, year = {2015}, author = {Rinna, A and Magdolenova, Z and Hudecova, A and Kruszewski, M and Refsnes, M and Dusinska, M}, title = {Effect of silver nanoparticles on mitogen-activated protein kinases activation: role of reactive oxygen species and implication in DNA damage.}, journal = {Mutagenesis}, volume = {30}, number = {1}, pages = {59-66}, doi = {10.1093/mutage/geu057}, pmid = {25527729}, issn = {1464-3804}, mesh = {Analysis of Variance ; Blotting, Western ; Comet Assay/methods ; DNA Damage/*drug effects/genetics ; Enzyme Activation/*drug effects ; Epithelial Cells ; Humans ; Metal Nanoparticles/*toxicity ; Microscopy, Electron ; Mitogen-Activated Protein Kinases/*metabolism ; Nitroblue Tetrazolium ; Onium Compounds ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Silver/*toxicity ; }, abstract = {Large quantities of engineered nanoparticles (NP), such as nanosilver (AgNP), have been widely applied, leading to an increased exposure and potential health concerns. Herein, we have examined the ability of AgNP to induce reactive oxygen species (ROS), their role in genotoxic effects and the involvement of mitogen-activated protein kinases (MAPK). AgNP exposure induced ROS production in human epithelial embryonic cells which could be decreased by diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation, induced by AgNP, was an early response but not sustained in time. Furthermore, JNK and ERK activation could be inhibited by both DPI and a free radicals scavenger N-acetyl cysteine. We also investigated the role of MAPK in the DNA damage. Using a modified comet assay for the specific detection of hOGG1 sensitive sites, we showed that AgNP induced DNA oxidation after 30-min treatment, whereas no response was observed after 2h. In conclusion, AgNP seem to induce DNA damage via a mechanism involving ROS formation. The oxidative DNA damage observed was transient, likely due to DNA repair; furthermore, higher damage was achieved upon inhibition of ERK activation by pre-treatment with U0126, suggesting a role for ERK in DNA damage repair. Activation of different MAPK might play an important role in the NP toxicity outcomes; understanding this process may be helpful for the identification of NP toxicity.}, }
@article {pmid25525113, year = {2014}, author = {Lutz, A and Sfara, V and Alzogaray, RA}, title = {Repellence produced by monoterpenes on Rhodnius prolixus (Hemiptera: Reduviidae) decreases after continuous exposure to these compounds.}, journal = {Journal of insect science (Online)}, volume = {14}, number = {}, pages = {}, pmid = {25525113}, issn = {1536-2442}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Animals ; Arthropod Antennae/drug effects ; Insect Repellents/*pharmacology ; Monoterpenes/*pharmacology ; Motor Activity/drug effects ; Nymph/drug effects/physiology ; Rhodnius/*drug effects/physiology ; }, abstract = {Botanical monoterpenes are secondary metabolites present in essential oils produced by plants. Some of them are insect repellents. The bloodsucking bug Rhodnius prolixus Ståhl (Hemiptera: Reduviidae) is one of the main vectors of Chagas disease in the north of South America and some countries in Central America. In this study, we studied the repellence produced by two monoterpenes, menthyl acetate and geraniol, on fifth instar nymphs of R. prolixus. In the absence of other stimuli, both menthyl acetate and geraniol produced a repellent effect from 740 μg/cm(2) and 74 μg/cm(2), respectively. Pre-exposure to each monoterpene reduced the repellent activity produced by the same substance. Additionally, pre-exposure to one monoterpene decreased the behavioral response of the nymphs to the other one. The repellent effect of both monoterpenes also decreased when nymphs' antennae were previously treated with the nitric oxide donor S-nitroso-N-acetyl-cysteine.}, }
@article {pmid25524555, year = {2015}, author = {Zhao, Z and Han, F and Yang, S and Wu, J and Zhan, W}, title = {Oxamate-mediated inhibition of lactate dehydrogenase induces protective autophagy in gastric cancer cells: involvement of the Akt-mTOR signaling pathway.}, journal = {Cancer letters}, volume = {358}, number = {1}, pages = {17-26}, doi = {10.1016/j.canlet.2014.11.046}, pmid = {25524555}, issn = {1872-7980}, mesh = {Adult ; Aged ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/biosynthesis ; Autophagy/drug effects ; Beclin-1 ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; L-Lactate Dehydrogenase/antagonists &amp; inhibitors/*biosynthesis ; Male ; Membrane Proteins/biosynthesis ; Middle Aged ; Oncogene Protein v-akt/*genetics ; Oxalic Acid/*administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Stomach Neoplasms/drug therapy/*enzymology/genetics ; TOR Serine-Threonine Kinases/*genetics ; }, abstract = {Cancer cells produce a substantial amount of energy through aerobic glycolysis even in the presence of adequate oxygen. Lactate dehydrogenase (LDH), a key regulator of glycolysis, reversibly catalyzes the conversion of pyruvate to lactate. Recently, oxamate, an inhibitor of LDH, has been shown to be a promising anticancer agent. However, the detailed mechanism remains largely unclear. In this study, we demonstrate that oxamate inhibits the viability of human gastric cancer cells in a dose- and time-dependent manner. In addition, treatment with oxamate induces protective autophagy in gastric cancer cells. Moreover, autophagy inhibited by chloroquine or Beclin 1 small interfering RNA (siRNA) enhances oxamate-induced apoptosis and proliferation inhibition. Further study has shown that oxamate treatment significantly augments reactive oxygen species (ROS) production. Furthermore, cells pretreated with N-acetyl cysteine (NAC), a ROS inhibitor, display significantly reduced ROS production and attenuated oxamate-induced autophagy. Finally, functional studies reveal that the Akt-mTOR signaling pathway, a major negative regulator of autophagy, is inhibited by oxamate. Together, our results provide new insights regarding the biological and anti-proliferative activities of oxamate against gastric cancer, and may offer a promising therapeutic strategy for gastric cancer.}, }
@article {pmid25517489, year = {2014}, author = {Brito, MV and Costa, FD and Vasconcelos, DM and Costa, LA and Yasojima, EY and Teixeira, RK and Yamaki, VN}, title = {Attenuation of copaiba oil in hepatic damage in rats.}, journal = {Acta cirurgica brasileira}, volume = {29}, number = {12}, pages = {776-780}, doi = {10.1590/S0102-86502014001900002}, pmid = {25517489}, issn = {1678-2674}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/therapeutic use ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Animals ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism ; Corn Oil/therapeutic use ; Disease Models, Animal ; Fabaceae/*chemistry ; Male ; Plant Oils/administration &amp; dosage/*therapeutic use ; Random Allocation ; Rats, Wistar ; Treatment Outcome ; gamma-Glutamyltransferase/blood ; }, abstract = {PURPOSE: To investigate the copaiba oil on the hepatic damage induced by acetaminophen, comparing against corn oil.<br><br>METHODS: Fifty four rats were distributed into nine study groups (N=6): control group, that didn't receive the acetaminophen; Acetaminophen Group, that only received the acetaminophen; Prophylactic Copaiba Group 1, that received copaiba oil two hours before the acetaminophen; Prophylactic Copaiba Group 7, that received copaiba oil seven days, once by day, before the acetaminophen; Therapy Copaiba Group, that received the copaiba oil two hours after the acetaminophen, the corn's groups were similar than copaiba oil groups; and N-Acetyl-Cysteine Group, that received the N-Acetyl-Cysteine two hours after the acetaminophen. Euthanasia was performed after 24 hours. The serum levels transaminases, bilirubin and canalicular enzymes were analyzed.<br><br>RESULTS: The prophylactic copaiba group 7, therapy copaiba group and N-Acetyl-Cysteine Group showed amounts of AST and ALT similar to the control group; and the prophylactic copaiba group 1 and corn's groups showed similar levels to the acetaminophen group. There was no significant difference between the groups regarding the amount of alkaline phosphatase and &#x264; GT (p>0.05). The therapy copaiba group showed the highest levels of total bilirubin and was statistically different from the other groups (p<0.01).<br><br>CONCLUSIONS: Copaiba oil administered prophylactically for seven days and therapeutically 2 hours after the acetaminophen acute intoxication offered a potential hepato protection against paracetamol-induced hepatic damage, normalizing the biochemical parameters similarly to N-Acetyl-Cysteine, and the treatment with corn oil shows no effect on the liver damage.}, }
@article {pmid25517291, year = {2015}, author = {Liem-Nguyen, V and Bouchet, S and Björn, E}, title = {Determination of sub-nanomolar levels of low molecular mass thiols in natural waters by liquid chromatography tandem mass spectrometry after derivatization with p-(hydroxymercuri) benzoate and online preconcentration.}, journal = {Analytical chemistry}, volume = {87}, number = {2}, pages = {1089-1096}, doi = {10.1021/ac503679y}, pmid = {25517291}, issn = {1520-6882}, mesh = {Chromatography, Liquid/*methods ; Hydroxymercuribenzoates/*chemistry ; Online Systems ; Solid Phase Extraction/*methods ; Spectrometry, Mass, Electrospray Ionization/*methods ; Sulfhydryl Compounds/*analysis ; Tandem Mass Spectrometry/*methods ; Water/*chemistry ; Water Pollutants, Chemical/analysis ; }, abstract = {Low molecular mass (LMM) thiols is a diverse group of compounds, which play several important roles in aquatic ecosystems, even though they typically occur at low concentrations. Comprehensive studies of LMM thiols in natural waters have so far been hampered by selectivity and limit of detection constraints of previous analytical methods. Here, we describe a selective and robust method for the quantification of 16 LMM thiols in natural waters. Thiols were derivatized with 4-(hydroxymercuri)benzoate (PHMB) and preconcentrated online by solid-phase extraction (SPE) before separation by liquid chromatography and determination by electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Their quantification was performed by selective reaction monitoring (SRM), while the presence of a product ion at m/z 355, specific for thiols and common for the investigated compounds, also allows to screen samples for unknown thiols by a precursor ion scan approach. The robustness of the method was validated for aqueous matrices with different pH, sulfide, and dissolved organic carbon (DOC) concentrations. The limits of detection for the thiols were in the sub-nanomolar range (0.06-0.5 nM) and the methodology allowed determination of both reduced and total thiol concentrations (using tris(2-carboxyethyl)phosphine (TCEP) as reducing agent). Six thiols (mercaptoacetic acid, cysteine, homocysteine, N-acetyl-cysteine, mercaptoethane-sulfonate, and glutathione) were detected with total concentrations of 7-153 nM in boreal lake or wetland pore waters while four thiols (mercaptoacetic acid, cysteine, homocysteine, and N-acetyl-cysteine) were detected in their reduced form at concentrations of 5-80 nM.}, }
@article {pmid25516653, year = {2014}, author = {Videla, LA and Fernández, V and Cornejo, P and Vargas, R and Morales, P and Ceballo, J and Fischer, A and Escudero, N and Escobar, O}, title = {T3-induced liver AMP-activated protein kinase signaling: redox dependency and upregulation of downstream targets.}, journal = {World journal of gastroenterology}, volume = {20}, number = {46}, pages = {17416-17425}, pmid = {25516653}, issn = {2219-2840}, mesh = {3-Hydroxybutyric Acid/blood ; AMP-Activated Protein Kinases/genetics/*metabolism ; Animals ; Antioxidants/pharmacology ; Dinoprost/analogs &amp; derivatives/metabolism ; Enzyme Activation ; Fatty Acids/*metabolism ; Gene Expression Regulation, Enzymologic ; Injections, Intraperitoneal ; Liver/*drug effects/enzymology ; Male ; Oxidation-Reduction ; Phosphorylation ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Time Factors ; Triiodothyronine/administration &amp; dosage/*pharmacology ; }, abstract = {AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T3)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver.<br><br>METHODS: Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T3/kg or T3 vehicle (NaOH 0.1 N; controls) and studied at 8 or 24 h after treatment. Separate groups of animals received 500 mg N-acetylcysteine (NAC)/kg or saline ip 30 min prior T3. Measurements included plasma and liver 8-isoprostane and serum &#x3b2;-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA).<br><br>RESULTS: T3 upregulates AMPK signaling, including the upstream kinases Ca(2+)-calmodulin-dependent protein kinase kinase-&#x3b2; and transforming growth factor-&#x3b2;-activated kinase-1, with T3-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1&#x3b1; (CPT-1&#x3b1;) activation and higher expression of peroxisome proliferator-activated receptor-&#x3b3; co-activator-1&#x3b1; and that of the fatty acid oxidation (FAO)-related enzymes CPT-1&#x3b1;, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T3 induced a significant increase in the serum levels of &#x3b2;-hydroxybutyrate, a surrogate marker for hepatic FAO.<br><br>CONCLUSION: T3 administration activates liver AMPK signaling in a redox-dependent manner, leading to FAO enhancement as evidenced by the consequent ketogenic response, which may constitute a key molecular mechanism regulating energy dynamics to support T3 preconditioning against ischemia-reperfusion injury.}, }
@article {pmid25515895, year = {2015}, author = {Bao, J and Lin, L}, title = {Platelet apoptosis in patients with acute coronary syndromes.}, journal = {Journal of thrombosis and thrombolysis}, volume = {39}, number = {4}, pages = {539-546}, pmid = {25515895}, issn = {1573-742X}, mesh = {Acute Coronary Syndrome/*metabolism/pathology ; *Apoptosis ; Blood Platelets/*metabolism/pathology ; Female ; Humans ; Male ; }, abstract = {Platelet apoptosis occurs commonly under various conditions such as physical and chemical stimuli. Acute coronary syndrome (ACS), one of most important cardiovascular and cerebrovascular diseases, severely threats people's health and is usually accompanied with various complications especially bleeding. There might be platelet apoptosis in ACS, which might be responsible for the complication of bleeding. The objective of the present study was to explore whether there were apoptotic platelets in ACS patients. Vein blood was drawn from eleven ACS patients and eleven health people. Platelet-rich plasma was prepared and subjected to apoptotic events analysis including increased expression of pro-apoptotic proteins and decreased expression of anti-apoptotic proteins, exposure of phosphatidylserine (PS), mitochondrial inner membrane potential depolarization and caspase-3 activation by Western blot and flow cytometry. In addition, washed platelets from the normal people were prepared and treated with the platelet-poor plasma (PPP) of the ACS patients, and were further examined apoptotic cascades. Paired Student's t test was used in the data comparisons. There were more platelets with depolarized mitochondrial inner membrane potential in the ACS patients than those of the health donors. Levels of Bax and Bak increased, while expression of Bcl-2 and Bcl-XL decreased in platelets from ACS patients. Caspase-3 activation was observed in platelets from the patients with ACS. Interestingly, there were significant differences in PS exposure between the platelets from the ACS patients and the normal controls. Furthermore, apoptotic events were observed in the normal platelets incubated with PPP from the ACS patients. In addition, pretreatment of healthy platelets with anti-oxidants N-acetyl cysteine (NAC) or dithiothreitol (DTT) significantly reduced ACS patients-derived PPP-induced platelet apoptosis. Platelets from the ACS patients are incurred apoptosis. Antioxidants NAC or DTT can reduce ACS patients-derived PPP-induced platelet apoptosis in vitro.}, }
@article {pmid25511268, year = {2014}, author = {Zhang, Z and Zhai, J}, title = {[Protective effects of n-acetylcysteine against decabromodiphenyl ether-induced brain oxidative injury in mice].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {32}, number = {9}, pages = {674-678}, pmid = {25511268}, issn = {1001-9391}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism/*pharmacology ; Brain/*drug effects/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Glutathione/metabolism ; Halogenated Diphenyl Ethers/toxicity ; Hippocampus/metabolism ; Male ; Malondialdehyde/metabolism ; Mice, Inbred BALB C ; Mitogen-Activated Protein Kinases/metabolism ; Oxidation-Reduction ; Phosphorylation ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {OBJECTIVE: To study the protective effects of N-acetylcysteine (NAC) against oxidative injury in the brain tissue of mice induced by decabromodiphenyl ether (PBDE-209) and the expression of mitogen activated protein kinase (MAPK)-related proteins in the hippocampus.<br><br>METHODS: Twenty-one male BALB/c mice were randomly divided into three groups with seven mice in each group: solvent control group, PBDE-209 group with gavage of 500 mg/kg PBDE-209, and PBDE-209 +NAC group which received intraperitoneal injection of 100 mg/kg NAC 0.5 h before exposure to PBDE-209. Mice were sacrificed 6 weeks after exposure. Malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and glutathione (GSH) level in the cerebral cortex, hippocampus, cerebellum, and striatum, as well as the protein expression of extracellular signal-regulated kinase (ERK), phosphorylated ERK (p-ERK), p38 MAPK (p38), and phosphorylated p38 (p-p38) in the hippocampus, were determined by Western blot.<br><br>RESULTS: Compared with the hippocampal and cerebellar levels of MDA in control group [(4.91&#xb1;1.60) and (2.42&#xb1;1.41) nmol/mg pro] and PBDE-209+NAC group [(6.16&#xb1;1.03) and (2.83&#xb1;0.85) nmol/mg pro], the MDA levels in PBDE-209 group [(12.12&#xb1;6.39) and (4.24&#xb1;1.15) nmol/mg pro] were significantly increased (P < 0.05). The striatum MDA level in PBDE-209 group [(12.92&#xb1;4.30) nmol/mg pro] was significantly increased as compared with that of the control group [(4.05&#xb1;2.23) nmol/mg pro] (P < 0.05). The hippocampal SOD activity of PBDE-209 group [(59.29&#xb1;37.09) U/mg pro] was reduced significantly as compared with those of the control group [(93.28&#xb1;21.75) U/mg pro] and PBDE-209+NAC group [(98.92&#xb1;21.54) U/mgpro] (P < 0.05). The GSH levels in the cerebral cortex, striatum, and cerebellum in PBDE-209 group [(40.98&#xb1;13.19), (24.46&#xb1;11.30), and (3.55&#xb1;1.55) mg GSH/g pro] were significantly reduced as compared with those of the control group [(75.79&#xb1;26.51), (44.52&#xb1;13.15) and (8.01&#xb1;3.23) mg GSH/g pro] and the PBDE-209+NAC group [(89.86&#xb1;28.39), (39.01&#xb1;9.05) and (10.34&#xb1;2.58) mg GSH/g pro] (P < 0.05). Western blot results showed that the ratios of p-p38/p38 and p-ERK/ERK in the hippocampus were significantly higher in the PBDE-209 group than in the control group and PBDE-209+NAC group (P < 0.05).<br><br>CONCLUSION: Antioxidant NAC has a protective effect against PBDE-209-induced brain injury in mice to some extent, and reduces the expression of MAPK-related proteins.}, }
@article {pmid25510360, year = {2015}, author = {Koren Carmi, I and Haj, R and Yehuda, H and Tamir, S and Reznick, AZ}, title = {The role of oxidation in FSL-1 induced signaling pathways of an atopic dermatitis model in HaCaT keratinocytes.}, journal = {Advances in experimental medicine and biology}, volume = {849}, number = {}, pages = {1-10}, doi = {10.1007/5584_2014_98}, pmid = {25510360}, issn = {0065-2598}, mesh = {Cell Line ; Cytokines/metabolism ; Dermatitis, Atopic/*drug therapy ; Diglycerides/*pharmacology ; Humans ; Keratinocytes/*drug effects ; NF-kappa B/metabolism ; Oligopeptides/*pharmacology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Oxidative stress (OS) is common in inflammatory conditions and may be important in atopic dermatitis (AD) etiology. The aim of this project was to study the involvement of oxidation in FSL-1 (deacylated lipoprotein)-triggered signaling pathways leading to AD-typical cytokine expression in HaCaT keratinocytes. HaCaT keratinocytes, pretreated with the inhibitor to OS N-acetylcysteine (NAC), were exposed to FSL-1, a stimulator of AD-related cytokines. Cytokines expression was studied by real time polymerase chain reaction (PCR); nuclear factor-kappa B (NF-κB) and p38 mitogen activated protein kinase (MAPK) activities were studied by western blotting; and the oxidative state of cells was determined by the dichlorofluorescein (DCF) assay. We found that endogenous OS in keratinocytes appeared 4 h after FSL-1 administration. OS activated NF-κB, but not p38 MAPK, and the inhibition of OS reduced FSL-1 induced interleukin (IL) 33, thymic stromal lymphopoietin (TSLP) and TNFα mRNA expression. We conclude that FSL-1 triggers an OS reaction in HaCaT keratinocytes, which is probably a secondary event affecting the expression of specific AD typical cytokines, possibly through the NF-κB pathways. This role of OS in the inflammatory response in AD is worth further investigating.}, }
@article {pmid25509183, year = {2014}, author = {Vadzyuk, OB and Kosterin, SA}, title = {Activation of glybenclamide-sensitive mitochondrial swelling under induction of cyclosporin of A-sensitive mitochondrial pore.}, journal = {Ukrainian biochemical journal}, volume = {86}, number = {4}, pages = {51-60}, doi = {10.15407/ubj86.04.051}, pmid = {25509183}, issn = {2409-4943}, mesh = {Animals ; Calcium Chloride/*pharmacology ; Cyclosporine/*pharmacology ; Dose-Response Relationship, Drug ; Female ; Glyburide/*pharmacology ; In Vitro Techniques ; KATP Channels/metabolism ; Mitochondria, Muscle/*drug effects/metabolism ; Mitochondrial Membrane Transport Proteins/*metabolism ; Mitochondrial Permeability Transition Pore ; Mitochondrial Swelling/*drug effects ; Myometrium/drug effects/metabolism ; Rats ; Uterus/*drug effects/metabolism ; }, abstract = {Induction of mitochondrial swelling and increased generation of reactive oxygen forms by Ca ions have been shown in suspension of mitochondria from rat uterus. These effects were suppressed by the blocker of mitochondrial Ca2+-uniporter ruthenium red and MPTP inhibitor cyclosporin A, that evidences that the induction of mitochondrial permeability transition pore by Ca ions takes place. Ca2+-induced mitochondrial swelling was blocked by ATP-sensitive channel blocker glybenclamide but only if K+ was present in the incubation medium. We also demonstrated that Ca2+-induced mitochondrial swelling can be eliminated in the presence of ROS scavengers N-acetyl cysteine and ascorbate. This effect of scavengers was also sensitive to K+ and was not revealed in the medium that contained equimolar NaCl instead of KCl. Thus, our data gave us grounds to assume that the induction of MPTP by Ca ions evokes the activation of mitochondrial ATPsensitive K+-channels, which are mediated by ROS.}, }
@article {pmid25505928, year = {2014}, author = {Marthandan, S and Freeburn, R and Steinbrecht, S and Pawelec, G and Barnett, Y}, title = {SENIEUR status of the originating cell donor negates certain 'anti-immunosenescence' effects of ebselen and N-acetyl cysteine in human T cell clone cultures.}, journal = {Immunity &amp; ageing : I &amp; A}, volume = {11}, number = {1}, pages = {17}, pmid = {25505928}, issn = {1742-4933}, abstract = {BACKGROUND: Damage to T cells of the immune system by reactive oxygen species may result in altered cell function or cell death and thereby potentially impact upon the efficacy of a subsequent immune response. Here, we assess the impact of the antioxidants Ebselen and N-acetyl cysteine on a range of biological markers in human T cells derived from a SENIEUR status donor. In addition, the impact of these antioxidants on different MAP kinase pathways in T cells from donors of different ages was also examined.<br><br>METHODS: T cell clones were derived from healthy 26, 45 and SENIEUR status 80 year old people and the impact of titrated concentrations of Ebselen or N-acetyl cysteine on their proliferation and in vitro lifespan, GSH:GSSG ratio as well as levels of oxidative DNA damage and on MAP kinase signaling pathways was examined.<br><br>RESULTS: In this investigation neither Ebselen nor N-acetyl cysteine supplementation had any impact on the biological endpoints examined in the T cells derived from the SENIEUR status 80 year old donor. This is in contrast to the anti-immunosenescent effects of these antioxidants on T cells from donors of 26 or 45 years of age. The analysis of MAP kinases showed that pro-apoptotic pathways become activated in T cells with increasing in vitro age and that Ebselen or N-acetyl cysteine could decrease activation (phosphorylation) in T cells from 26 or 45 year old donors, but not from the SENIEUR status 80 year old donor.<br><br>CONCLUSIONS: The results of this investigation demonstrate that the biological phenotype of SENIEUR status derived human T cells negates the anti-immunosenescence effects of Ebselen and also N-acetyl cysteine. The results highlight the importance of pre-antioxidant intervention evaluation to determine risk-benefit.}, }
@article {pmid25505594, year = {2014}, author = {Porte, J and Jenkins, G}, title = {Assessment of the effect of potential antifibrotic compounds on total and αVβ6 integrin-mediated TGF-β activation.}, journal = {Pharmacology research &amp; perspectives}, volume = {2}, number = {4}, pages = {e00030}, pmid = {25505594}, issn = {2052-1707}, support = {G0901226/MRC_/Medical Research Council/United Kingdom ; G1100564/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; }, abstract = {Transforming growth factor-β (TGF-β) plays an important role in the development of tissue fibrosis, and molecules inhibiting this pathway are attractive therapeutic targets for fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Activation of TGF-β is the rate-limiting step in TGF-β bioavailability, and activation by the αVβ6 integrin is important in fibrosis of the lung, liver, and kidney. Activation of TGF-β by αVβ6 requires direct cell-cell contact and measurable release of active TGF-β in extracellular fluid compartments does not reflect tissue specific activation. The aim of this study was to determine the effect of antifibrotic compounds on both total, and specific αVβ6 integrin-mediated TGF-β activity. Using a transformed mink lung cell (TMLC) TGF-β reporter, the effects of potential antifibrotic therapies including an activin-like kinase (Alk5) inhibitor, Dexamethasone, Pirfenidone, N-acetylcysteine (NAC), and BIBF1120 were assessed. Effects due to αVβ6 integrin-mediated TGF-β activity were measured using reporter cells cocultured with cells expressing αVβ6 integrins. These high-throughput studies were validated using a phosphorylated Smad2 Enzyme-Linked Immunosorbent Assay. Alk5 inhibitors are potent inhibitors of TGF-β activity, whereas the novel antifibrotics, Pirfenidone, BIBF1120, and NAC are only moderate inhibitors, and Dexamethasone does not specifically affect TGF-βactivity, but inhibits TGF-β-induced gene expression. None of the current small molecular inhibitors inhibit αVβ6-mediated TGF-β activity. These results demonstrate the potential of this high-throughput assay of αVβ6-specific TGF-β activity and illustrate that currently available antifibrotics have limited effects on αVβ6 integrin-mediated TGF-β activity.}, }
@article {pmid25503516, year = {2015}, author = {Ko, HK and Lee, HF and Lin, AH and Liu, MH and Liu, CI and Lee, TS and Kou, YR}, title = {Regulation of Cigarette Smoke Induction of IL-8 in Macrophages by AMP-activated Protein Kinase Signaling.}, journal = {Journal of cellular physiology}, volume = {230}, number = {8}, pages = {1781-1793}, doi = {10.1002/jcp.24881}, pmid = {25503516}, issn = {1097-4652}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Blotting, Western ; Cell Line ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Immunohistochemistry ; Interleukin-8/*biosynthesis ; Macrophages/*metabolism ; Mice ; NF-kappa B/metabolism ; Pneumonia/metabolism ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*drug effects ; Smoke/*adverse effects ; Tobacco Products/*adverse effects ; Transfection ; }, abstract = {Inhaled cigarette smoke (CS) causes persistent lung inflammation in smokers. Interleukin 8 (IL-8) released from macrophages is a key chemokine during initiation and progression of CS-induced lung inflammation, yet its regulation is largely unknown. AMP-activated protein kinase (AMPK), a crucial energy homeostasis regulator, may modulate inflammation. Here we report that CS extract (CSE) increased the level of intracellular reactive oxygen species (ROS), activating AMPK, mitogen-activated protein kinases (MAPKs), and NF-κB, as well as inducing IL-8, in human macrophages. N-acetyl-cysteine (ROS scavenger) or hexamethonium [nicotinic acetylcholine receptor (nAChR) antagonist] attenuated the CSE-induced increase in intracellular ROS, activation of AMPK and NF-κB, as well as IL-8 induction, which suggests that nAChRs and ROS are important. Prevention of AMPK activation by compound C or AMPK siRNA reduced CSE-induced IL-8 production, confirming the role of AMPK. Compound C or AMPK siRNA also inhibited the activation of MAPKs and NF-κB by CSE, which suggests that these molecules are downstream of AMPK. Additionally, exposure of human macrophages to nicotine activated AMPK and induced IL-8 and that these effects were lessened by hexamethonium or compound C, implying that nicotine in CS may be causative. Furthermore, chronic CS exposure in mice promoted AMPK phosphorylation and expression of MIP-2 (an IL-8 homolog) in infiltrated macrophages and in lung tissues, as well as induced lung inflammation, all of which were reduced by compound C treatment. Thus, we identified a novel nAChRs-dependent, ROS-sensitive, AMPK/MAPKs/NF-κB signaling pathway, which seems to be important to CS-induced macrophage IL-8 production and possibly to lung inflammation.}, }
@article {pmid25502879, year = {2014}, author = {Xu, H and Sun, Y and Zhang, Y and Wang, W and Dan, J and Yao, J and Chen, H and Tian, F and Sun, X and Guo, S and Tian, Z and Tian, Y}, title = {Protoporphyrin IX induces a necrotic cell death in human THP-1 macrophages through activation of reactive oxygen species/c-Jun N-terminal protein kinase pathway and opening of mitochondrial permeability transition pore.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {34}, number = {6}, pages = {1835-1848}, doi = {10.1159/000366383}, pmid = {25502879}, issn = {1421-9778}, mesh = {Anthracenes/administration &amp; dosage ; Cell Death/genetics ; Cell Line ; Cell Survival/drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Macrophages/metabolism/pathology ; Mitochondria/metabolism/pathology ; Mitochondrial Membrane Transport Proteins/genetics/*metabolism ; Mitochondrial Permeability Transition Pore ; Necrosis/genetics/*metabolism ; Protoporphyrins/*administration &amp; dosage/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND: Protoporphyrin IX (PpIX) and its derivatives are widely used in photodynamic therapy (PDT) to kill cancer cells. Studies showed that the application of these drugs could cause systemic toxic effects in human. However, the molecular pathways involved in PpIX-induced cytotoxicity are not well-defined. Macrophages represent the primary system for protecting tissues from toxicants and initiating the resolution of inflammation. Thus, this study aims to investigate the toxicity of PpIX on macrophages and provide strategies to prevent the toxic effects.<br><br>METHODS: THP-1 macrophages were incubated with PpIX and cell death was measured by MTT assay and Annexin V-PI staining. Intracellular reactive oxygen species (ROS) were evaluated by 2', 7'-Dichlorodihydrofluorescin diacetate (DCFH-DA) and MitoSOX&#xae; Red staining and mitochondrial membrane potential (&#x394;&#x3a8;m) was detected by tetramethylrhodamine methyl ester (TMRM) staining. Mitogen-activated protein (MAP) kinase activation was assayed by western blotting. Mitochondrial permeability transition pore (mPTP) opening was measured by calcein loading/Co(2+) quenching technique and evaluating the release of mitochondrial content.<br><br>RESULTS: PpIX reduced cell viability in a dose- and time-dependent manner. The cell death was characterized by increasing PI-positive cells, ATP depletion, LDH releasing and rapid &#x394;&#x3a8;m loss favoring necrotic features. In addition, PpIX successively induced ROS production, c-Jun N-terminal protein kinase (JNK) activation and mPTP opening. ROS scavengers, N-acetylcysteine (NAC) and deferoxamine (DFX), JNK inhibitor, SP600125, and mPTP inhibitor, cyclosporin A (CsA), all significantly rescued this cell death. Furthermore, mPTP opening was directly regulated by ROS/JNK pathway.<br><br>CONCLUSION: PpIX induces a necrotic cell death in THP-1 macrophages through ROS production, JNK activation, and mPTP opening. It is tempting to speculate that blocking the pathways involved in the cytotoxic effects of PpIX will alleviate its side effects.}, }
@article {pmid25500303, year = {2015}, author = {Rodrigues, SD and França, KC and Dallin, FT and Fujihara, CK and Nascimento, AJ and Pecoits-Filho, R and Nakao, LS}, title = {N-acetylcysteine as a potential strategy to attenuate the oxidative stress induced by uremic serum in the vascular system.}, journal = {Life sciences}, volume = {121}, number = {}, pages = {110-116}, doi = {10.1016/j.lfs.2014.11.024}, pmid = {25500303}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Animals ; Biomarkers/metabolism ; Blood Vessels/*drug effects/metabolism/pathology ; Cells, Cultured ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Humans ; Male ; Middle Aged ; Myocytes, Smooth Muscle/drug effects/pathology ; Nephrectomy ; Oxidative Stress/*drug effects ; Rabbits ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Renal Insufficiency, Chronic/blood/drug therapy ; Uremia/*blood ; }, abstract = {AIMS: Chronic kidney disease (CKD) progression is accompanied by systemic oxidative stress, which contributes to an increase in the risk of cardiovascular diseases (CVDs). N-acetylcysteine (NAC) is among the most studied antioxidants, but its therapeutic benefits in CKD-associated CVDs remain controversial. Here, we investigated whether NAC could inhibit the oxidative stress induced by uremia in vitro and in vivo.<br><br>MAIN METHODS: Endothelial and smooth muscle cells were challenged with human uremic or non-uremic sera, and the effects of a pre-treatment with 2mM NAC were evaluated. Reactive oxygen species (ROS) production, protein oxidation and total glutathione/glutathione disulfide (tGSH/GSSG) ratios were measured. Five-sixths nephrectomized or sham-operated rats were orally treated (in the drinking water) with 60 mg/kg/day NAC or not treated for 53 days. Plasma cysteine/cystine reduction potential Eh(Cyss/2Cys) was determined as a novel marker of the systemic oxidative stress.<br><br>KEY FINDINGS: NAC inhibited all the determined oxidative stress parameters, likely by increasing the tGSH/GSSG ratio, in both cell lines exposed to uremic serum. Orally administered NAC attenuated the systemic oxidative stress in uremic rats.<br><br>SIGNIFICANCE: The present results indicate that NAC, by preventing GSH depletion in vascular cells exposed to uremic serum and by attenuating the systemic oxidative stress during CKD progression, emerges as a potential strategy to prevent the oxidative stress induced by uremic toxicity in the vascular system.}, }
@article {pmid25499330, year = {2014}, author = {Tsikas, D and Niemann, J and Flentje, M and Schwarz, A and Tossios, P}, title = {N-Acetylcysteine (NAC) inhibits renal nitrite and nitrate reabsorption in healthy subjects and in patients undergoing cardiac surgery: risk of nitric oxide (NO) bioavailability loss by NAC?.}, journal = {International journal of cardiology}, volume = {177}, number = {1}, pages = {30-33}, doi = {10.1016/j.ijcard.2014.09.109}, pmid = {25499330}, issn = {1874-1754}, mesh = {Acute Kidney Injury/metabolism/*prevention &amp; control ; Adult ; Biological Availability ; *Cardiac Surgical Procedures ; Disaccharides/administration &amp; dosage/*pharmacokinetics ; Female ; Follow-Up Studies ; Healthy Volunteers ; Heart Diseases/*surgery ; Humans ; Injections, Intravenous ; Male ; Nitric Oxide/*blood ; Postoperative Complications/etiology/metabolism/*prevention &amp; control ; Prognosis ; Renal Reabsorption/*drug effects ; Risk Factors ; Young Adult ; }, }
@article {pmid25497111, year = {2015}, author = {Wigenstam, E and Koch, B and Bucht, A and Jonasson, S}, title = {N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury.}, journal = {Toxicology}, volume = {328}, number = {}, pages = {40-47}, doi = {10.1016/j.tox.2014.12.008}, pmid = {25497111}, issn = {1879-3185}, mesh = {Acetylcysteine/*pharmacology ; Acute Lung Injury/blood/chemically induced/immunology/physiopathology/*prevention &amp; control ; Adrenal Cortex Hormones/*pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/*pharmacology ; Bronchial Hyperreactivity/blood/chemically induced/immunology/physiopathology/*prevention &amp; control ; Bronchoalveolar Lavage Fluid/cytology/immunology ; *Chlorine ; Cytoprotection ; Dexamethasone/*pharmacology ; Disease Models, Animal ; Drug Synergism ; Drug Therapy, Combination ; Female ; Fibrinogen/metabolism ; Gases ; Inhalation Exposure ; Lung/*drug effects/immunology/physiopathology ; Mice, Inbred BALB C ; Neutrophil Infiltration/drug effects ; Plasminogen Activator Inhibitor 1/blood ; Time Factors ; }, abstract = {Chlorine (Cl2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1h after Cl2-exposure could improve protection against acute lung injury in Cl2-exposed mice. BALB/c mice were exposed to 300 ppm Cl2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated.}, }
@article {pmid25496785, year = {2015}, author = {Taracha, E and Kaniuga, E and Chrapusta, SJ and Boguszewski, PM and Lehner, M and Krząścik, P and Płaźnik, A}, title = {N-acetyl cysteine does not modify the sensitization of the rewarding effect of amphetamine as assessed with frequency-modulated 50-kHz vocalization in the rat.}, journal = {Behavioural brain research}, volume = {280}, number = {}, pages = {141-148}, doi = {10.1016/j.bbr.2014.12.005}, pmid = {25496785}, issn = {1872-7549}, mesh = {Acetylcysteine/*pharmacology ; Amphetamine/*pharmacology ; Animals ; Central Nervous System Stimulants/*pharmacology ; Excitatory Amino Acid Agents/*pharmacology ; Male ; Motor Activity/drug effects ; Random Allocation ; Rats, Sprague-Dawley ; Reward ; Ultrasonics ; Vocalization, Animal/*drug effects ; }, abstract = {A satisfactory pharmacological cure for addictions to psychostimulants has not yet been developed. Because of the well-known role of changes in the corticoaccumbal and corticostriatal glutamatergic system(s) in drug seeking and relapses in psychostimulant addiction, much hope is presently linked to the use of agents that restore glutamate homeostasis. In this regard, one of the most promising agents is N-acetyl cysteine, which has been shown to reverse some changes in neuroplasticity associated with psychostimulant addiction/dependence. In this study, we used the enhancement of locomotor activity and the induction of frequency-modulated 50-kHz ultrasonic vocalization (FM 50-kHz USV) to test the possible stimulant properties of N-acetyl cysteine itself in various experimental settings (acute and subchronic administration in amphetamine-naïve and amphetamine-pretreated rats) and the capacity of N-acetyl cysteine to attenuate both the rewarding effects of amphetamine and the behavioral sensitization to this stimulant in rats showing considerable differences in their susceptibility to the FM 50-kHz USV sensitization. Our data showed no stimulant properties of N-acetyl cysteine and no acute effect of the drug on the rewarding properties of amphetamine. Moreover, no effect of N-acetyl cysteine on the pre-existing sensitization of the FM 50-kHz USV and locomotor activity responses to amphetamine were observed, independent of the susceptibility of the rats to the FM 50-kHz USV sensitization. Hence, N-acetyl cysteine seems to be ineffective at reversing the neurobiological changes underlying the sensitization of these responses to amphetamine in rats.}, }
@article {pmid25489974, year = {2015}, author = {Rains, JL and Jain, SK}, title = {Effect of hyperketonemia (Acetoacetate) on nuclear factor-κB and p38 mitogen-activated protein kinase activation mediated intercellular adhesion molecule 1 upregulation in endothelial cells.}, journal = {Metabolic syndrome and related disorders}, volume = {13}, number = {2}, pages = {71-77}, pmid = {25489974}, issn = {1557-8518}, support = {R01 DK072433/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetoacetates/*pharmacology ; Acetylcysteine/pharmacology ; Blotting, Western ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; Human Umbilical Vein Endothelial Cells/*metabolism ; Humans ; Intercellular Adhesion Molecule-1/*metabolism ; NF-kappa B/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/*metabolism ; Reactive Oxygen Species/metabolism ; Up-Regulation/drug effects ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*blood ; }, abstract = {BACKGROUND: Hyperketonemia is a pathological condition observed in patients with type 1 diabetes and ketosis-prone diabetes (KPD), which results in increased blood levels of acetoacetate (AA) and β-hydroxybutyrate (BHB). Frequent episodes of hyperketonemia are associated with a higher incidence of vascular disease. We examined the hypothesis that hyperketonemia activates the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that regulate intercellular adhesion molecule 1 (ICAM-1) expression in endothelial cells.<br><br>METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured with AA (0-8&#x2009;mM) or BHB (0-10&#x2009;mM) for 0-24&#x2009;hr. Western blotting was used to determine NF-&#x3ba;B activation in whole-cell lysates. ICAM-1 expression was measured using flow cytometry.<br><br>RESULTS: RESULTS show a 2.4-fold increase in NF-&#x3ba;B activation in cells treated with 8&#x2009;mM AA compared to the control. BHB had little or no effect on NF-&#x3ba;B activation. Pretreatment with a reactive oxygen species (ROS) inhibitor [N-acetyl-l-cysteine (NAC)] reduced NF-&#x3ba;B to near-control levels. The expression of AA-induced ICAM-1 was significantly reduced when cells were pretreated with either NAC or p38 MAPK inhibitor.<br><br>CONCLUSIONS: These results suggest that NF-&#x3ba;B and p38 MAPK mediate upregulation of ICAM-1 expression in endothelial cells exposed to elevated levels of AA, which may contribute to the development of vascular disease in diabetes.}, }
@article {pmid25488805, year = {2015}, author = {Tseng, CY and Wang, JS and Chang, YJ and Chang, JF and Chao, MW}, title = {Exposure to High-Dose Diesel Exhaust Particles Induces Intracellular Oxidative Stress and Causes Endothelial Apoptosis in Cultured In Vitro Capillary Tube Cells.}, journal = {Cardiovascular toxicology}, volume = {15}, number = {4}, pages = {345-354}, doi = {10.1007/s12012-014-9302-y}, pmid = {25488805}, issn = {1559-0259}, mesh = {Adenosine Triphosphate/metabolism ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Capillaries/*drug effects/metabolism/pathology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Energy Metabolism/drug effects ; Human Umbilical Vein Endothelial Cells/*drug effects/metabolism/pathology ; Humans ; Mitochondria/drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Particulate Matter/*toxicity ; Phosphatidylinositol 3-Kinase/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-mdm2/metabolism ; Signal Transduction/drug effects ; Superoxides/metabolism ; Tumor Suppressor Protein p53/metabolism ; Vehicle Emissions/*toxicity ; }, abstract = {Previous studies suggest a direct correlation between exposure to diesel exhaust particles (DEP) and the onset of vascular permeability, presumably through the disruption of the adherens junctions. This would lead to deleterious effects on vasculature, such as acute myocardial infarction and atherosclerosis. Although the mechanism remains unclear, we demonstrate DEP-induced mitochondrial reactive oxygen species generation, which may be a central cause of the above vascular disorders. In vitro capillary-like HUVEC tube cells are used in this study and show that acute DEP exposure stimulates ATP depletion, followed by depolarization of their actin cytoskeleton, which sequentially inhibits PI3K/Akt activity and induces endothelial apoptosis. These events are accompanied by induction of p53/Mdm2 feedback regulation at 10 µg/mL DEP and produce 20 % cell apoptosis. Nevertheless, 100 µg/mL DEP augments tube cell apoptosis up to 70 % but disrupts the p53 negative regulator Mdm2. Addition of N-acetylcysteine provides substantial protection against the cytotoxic effects of DEP. In summary, exposure to a low dose of DEP actin triggers cytoskeleton depolarization, reduces PI3K/Akt activity, and induces a p53/Mdm2 feedback loop, and a high dose causes apoptosis by depleting Mdm2.}, }
@article {pmid25483961, year = {2014}, author = {Lo Verso, F and Carnio, S and Vainshtein, A and Sandri, M}, title = {Autophagy is not required to sustain exercise and PRKAA1/AMPK activity but is important to prevent mitochondrial damage during physical activity.}, journal = {Autophagy}, volume = {10}, number = {11}, pages = {1883-1894}, pmid = {25483961}, issn = {1554-8635}, support = {TCP04009/TI_/Telethon/Italy ; TCR09003/TI_/Telethon/Italy ; }, mesh = {AMP-Activated Protein Kinases/genetics/*metabolism ; Animals ; Antioxidants/chemistry ; Autophagy/*physiology ; Autophagy-Related Protein 7 ; Female ; Glucose/metabolism ; Homeostasis ; Male ; Mice ; Mice, Knockout ; Microtubule-Associated Proteins/*genetics ; Mitochondria/*physiology ; Muscle Contraction ; Oxidative Stress ; Physical Conditioning, Animal ; }, abstract = {Physical activity has been recently documented to play a fundamental physiological role in the regulation of autophagy in several tissues. It has also been reported that autophagy is required for exercise itself and for training-induced adaptations in glucose homeostasis. These autophagy-mediated metabolic improvements are thought to be largely dependent on the activation of the metabolic sensor PRKAA1/AMPK. However, it is unknown whether these important benefits stem from systemic adaptations or are due solely to alterations in skeletal muscle metabolism. To address this we utilized inducible, muscle-specific, atg7 knockout mice that we have recently generated. Our findings indicate that acute inhibition of autophagy in skeletal muscle just prior to exercise does not have an impact on physical performance, PRKAA1 activation, or glucose homeostasis. However, we reveal that autophagy is critical for the preservation of mitochondrial function during damaging muscle contraction. This effect appears to be gender specific affecting primarily females. We also establish that basal oxidative stress plays a crucial role in mitochondrial maintenance during normal physical activity. Therefore, autophagy is an adaptive response to exercise that ensures effective mitochondrial quality control during damaging physical activity.}, }
@article {pmid25482950, year = {2014}, author = {Gang, BP and Dilda, PJ and Hogg, PJ and Blackburn, AC}, title = {Targeting of two aspects of metabolism in breast cancer treatment.}, journal = {Cancer biology &amp; therapy}, volume = {15}, number = {11}, pages = {1533-1541}, pmid = {25482950}, issn = {1555-8576}, mesh = {Apoptosis/drug effects ; Arsenicals/pharmacology ; Breast Neoplasms/*drug therapy/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Dichloroacetic Acid/*pharmacology ; Drug Resistance, Neoplasm ; Drug Synergism ; Female ; Humans ; Inhibitory Concentration 50 ; Mitochondria/drug effects/metabolism ; *Molecular Targeted Therapy ; Reactive Oxygen Species/metabolism ; }, abstract = {Deregulated metabolism is gaining recognition as a hallmark of cancer cells, and is being explored for therapeutic potential. The Warburg effect is a metabolic phenotype that occurs in 90% of tumors, where glycolysis is favored despite the presence of oxygen. Dichloroacetate (DCA) is a pyruvate dehydrogenase kinase (PDK) inhibitor that can reverse the Warburg effect. PENAO (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) is a novel anti-mitochondrial agent that targets the adenine nucleotide transporter in mitochondria and is currently in clinical trials for solid tumors. We have investigated the targeting of two aspects of metabolism, using DCA to promote mitochondrial activity combined with PENAO to inhibit mitochondrial activity, in breast and other carcinoma cell lines. PENAO was effective at low uM concentrations in luminal (T-47D) and triple negative (MDA-MB-231) breast cancer cells, in normoxia and hypoxia. The cytotoxicity of PENAO was enhanced by DCA by a mechanism involving increased reactive oxygen species in both T-47D and MDA-MB-231 cells, however further investigations found it did not always involve PDK2 inhibition or reduction of the mitochondrial membrane potential, which are the accepted mechanisms for DCA induction of apoptosis. Nevertheless, DCA sensitized all cancer cell lines tested toward apoptosis of PENAO. DCA and PENAO are both currently in clinical trials and targeting cancer metabolism with these drugs may offer options for difficult to treat cancers.}, }
@article {pmid25482371, year = {2016}, author = {Cheraghi, E and Mehranjani, MS and Shariatzadeh, MA and Esfahani, MH and Ebrahimi, Z}, title = {N-Acetylcysteine improves oocyte and embryo quality in polycystic ovary syndrome patients undergoing intracytoplasmic sperm injection: an alternative to metformin.}, journal = {Reproduction, fertility, and development}, volume = {28}, number = {6}, pages = {723-731}, doi = {10.1071/RD14182}, pmid = {25482371}, issn = {1448-5990}, mesh = {Academic Medical Centers ; Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/therapeutic use ; Antioxidants/adverse effects/*therapeutic use ; Drug Therapy, Combination ; Ectogenesis/*drug effects ; Female ; Follicular Fluid/drug effects ; Humans ; Hypoglycemic Agents/adverse effects/therapeutic use ; Infertility, Female/etiology/*prevention &amp; control ; Iran ; Metformin/adverse effects/therapeutic use ; Oocyte Retrieval ; Oocytes/drug effects/pathology ; Oogenesis/*drug effects ; Ovulation Induction ; Patient Dropouts ; Pilot Projects ; Polycystic Ovary Syndrome/*drug therapy/physiopathology ; *Sperm Injections, Intracytoplasmic ; }, abstract = {Polycystic ovary syndrome (PCOS) is associated with low-quality oocytes. The aim of the present study was to investigate the effects of metformin (MET), N-acetylcysteine (NAC) and their combination on follicular fluid parameters, oocytes and embryo quality in PCOS patients. A prospective randomised placebo-controlled pilot study on 60 Iranian women with PCOS (aged 25-35 years) undergoing intracytoplasmic sperm injection (ICSI) was designed. Women were divided into four groups (n=15 in each): (1) an MET, administered 1500mg day(-1) MET; (2) an NAC group, administered 1800mg day(-1) NAC; (3) an NAC + MET group; and (4) a placebo group. Drugs were administered from the 3rd day of previous cycle until the day of oocyte aspiration (6 weeks treatment in total). Data were analysed by one-way ANOVA, with significance set at P<0.05. The number of immature and abnormal oocytes decreased significantly in the NAC compared with placebo group, with a concomitant increase in the number of good-quality embryos in the NAC group (P<0.05). Malondialdehyde levels decreased significantly in the NAC and NAC + MET groups compared with the placebo-treated group (P<0.02). In addition, there were significant decreases in leptin levels in the NAC, MET and NAC + MET groups compared with the placebo group (P<0.001). Insulin and LH levels were significantly lower in the MET and NAC groups compared with the placebo-treated group (P<0.02). We concluded that NAC improves oocyte and embryo quality and could be administered as an alternative to MET.}, }
@article {pmid25482261, year = {2015}, author = {Hall, A and Parhamifar, L and Lange, MK and Meyle, KD and Sanderhoff, M and Andersen, H and Roursgaard, M and Larsen, AK and Jensen, PB and Christensen, C and Bartek, J and Moghimi, SM}, title = {Polyethylenimine architecture-dependent metabolic imprints and perturbation of cellular redox homeostasis.}, journal = {Biochimica et biophysica acta}, volume = {1847}, number = {3}, pages = {328-342}, doi = {10.1016/j.bbabio.2014.12.002}, pmid = {25482261}, issn = {0006-3002}, mesh = {Adenosine Triphosphate/metabolism ; Antioxidants/metabolism/pharmacology ; Cell Line ; Cell Membrane/*drug effects/metabolism ; Cell Respiration/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Energy Metabolism/*drug effects ; Glutathione/metabolism ; Homeostasis ; Humans ; Kinetics ; Mitochondrial Membranes/*drug effects/metabolism ; Molecular Structure ; Molecular Weight ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Oxygen Consumption/drug effects ; Polyethyleneimine/chemistry/*toxicity ; Reactive Oxygen Species/metabolism ; Structure-Activity Relationship ; Transfection/*methods ; }, abstract = {Polyethylenimines (PEIs) are among the most efficient polycationic non-viral transfectants. PEI architecture and size not only modulate transfection efficiency, but also cytotoxicity. However, the underlying mechanisms of PEI-induced multifaceted cell damage and death are largely unknown. Here, we demonstrate that the central mechanisms of PEI architecture- and size-dependent perturbations of integrated cellular metabolomics involve destabilization of plasma membrane and mitochondrial membranes with consequences on mitochondrial oxidative phosphorylation (OXPHOS), glycolytic flux and redox homeostasis that ultimately modulate cell death. In comparison to linear PEI, the branched architectures induced greater plasma membrane destabilization and were more detrimental to glycolytic activity and OXPHOS capacity as well as being a more potent inhibitor of the cytochrome c oxidase. Accordingly, the branched architectures caused a greater lactate dehydrogenase (LDH) and ATP depletion, activated AMP kinase (AMPK) and disturbed redox homeostasis through diminished availability of nicotinamide adenine dinucleotide phosphate (NADPH), reduced antioxidant capacity of glutathione (GSH) and increased burden of reactive oxygen species (ROS). The differences in metabolic and redox imprints were further reflected in the transfection performance of the polycations, but co-treatment with the GSH precursor N-acetyl-cysteine (NAC) counteracted redox dysregulation and increased the number of viable transfected cells. Integrated biomembrane integrity and metabolomic analysis provides a rapid approach for mechanistic understanding of multifactorial polycation-mediated cytotoxicity, and could form the basis for combinatorial throughput platforms for improved design and selection of safer polymeric vectors.}, }
@article {pmid25481834, year = {2015}, author = {Prajapati, P and Sripada, L and Singh, K and Bhatelia, K and Singh, R and Singh, R}, title = {TNF-α regulates miRNA targeting mitochondrial complex-I and induces cell death in dopaminergic cells.}, journal = {Biochimica et biophysica acta}, volume = {1852}, number = {3}, pages = {451-461}, doi = {10.1016/j.bbadis.2014.11.019}, pmid = {25481834}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Amino Acid Chloromethyl Ketones/pharmacology ; Cell Death/drug effects ; Cell Line ; Dopaminergic Neurons/*enzymology/pathology ; Electron Transport Complex I/*metabolism ; Free Radical Scavengers/pharmacology ; Humans ; MicroRNAs/*metabolism ; Mitochondria/*enzymology/pathology ; Parkinson Disease/*enzymology/pathology ; Protease Inhibitors/pharmacology ; Tumor Necrosis Factor-alpha/metabolism/*pharmacology ; }, abstract = {Parkinson's disease (PD) is a complex neurological disorder of the elderly population and majorly shows the selective loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) region of the brain. The mechanisms leading to increased cell death of DAergic neurons are not well understood. Tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine is elevated in blood, CSF and striatum region of the brain in PD patients. The increased level of TNF-α and its role in pathogenesis of PD are not well understood. In the current study, we investigated the role of TNF-α in the regulation of cell death and miRNA mediated mitochondrial functions using, DAergic cell line, SH-SY5Y (model of dopaminergic neuron degeneration akin to PD). The cells treated with low dose of TNF-α for prolonged period induce cell death which was rescued in the presence of zVAD.fmk, a caspase inhibitor and N-acetyl-cysteine (NAC), an antioxidant. TNF-α alters mitochondrial complex-I activity, decreases adenosine triphosphate (ATP) levels, increases reactive oxygen species levels and mitochondrial turnover through autophagy. TNF-α differentially regulates miRNA expression involved in pathogenesis of PD. Bioinformatics analysis revealed that the putative targets of altered miRNA included both pro/anti apoptotic genes and subunits of mitochondrial complex. The cells treated with TNF-α showed decreased level of nuclear encoded transcript of mitochondrial complexes, the target of miRNA. To our knowledge, the evidences in the current study demonstrated that TNF-α is a potential regulator of miRNAs which may regulate mitochondrial functions and neuronal cell death, having important implication in pathogenesis of PD.}, }
@article {pmid25478815, year = {2015}, author = {Van Laar, VS and Roy, N and Liu, A and Rajprohat, S and Arnold, B and Dukes, AA and Holbein, CD and Berman, SB}, title = {Glutamate excitotoxicity in neurons triggers mitochondrial and endoplasmic reticulum accumulation of Parkin, and, in the presence of N-acetyl cysteine, mitophagy.}, journal = {Neurobiology of disease}, volume = {74}, number = {}, pages = {180-193}, pmid = {25478815}, issn = {1095-953X}, support = {T32 NS007391/NS/NINDS NIH HHS/United States ; K08NS059576/NS/NINDS NIH HHS/United States ; R01NS077954/NS/NINDS NIH HHS/United States ; R01 NS077954/NS/NINDS NIH HHS/United States ; K08 NS059576/NS/NINDS NIH HHS/United States ; NS07391/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*metabolism ; Animals ; Calcium/metabolism ; Cells, Cultured ; Cerebral Cortex/drug effects/pathology/physiopathology ; Chaperonin 60/metabolism ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/drug effects/*metabolism/pathology ; GTP Phosphohydrolases ; Glutamic Acid/administration &amp; dosage/*toxicity ; Humans ; Membrane Potential, Mitochondrial/drug effects/physiology ; Membrane Proteins/metabolism ; Mitochondria/drug effects/pathology/*physiology ; Mitochondrial Proteins/metabolism ; Mitophagy/drug effects/physiology ; Neurons/drug effects/pathology/*physiology ; Oxidative Stress/drug effects/physiology ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/metabolism ; Transfection ; Ubiquitin-Protein Ligases/genetics/*metabolism ; }, abstract = {Disruption of the dynamic properties of mitochondria (fission, fusion, transport, degradation, and biogenesis) has been implicated in the pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD). Parkin, the product of gene PARK2 whose mutation causes familial PD, has been linked to mitochondrial quality control via its role in regulating mitochondrial dynamics, including mitochondrial degradation via mitophagy. Models using mitochondrial stressors in numerous cell types have elucidated a PINK1-dependent pathway whereby Parkin accumulates on damaged mitochondria and targets them for mitophagy. However, the role Parkin plays in regulating mitochondrial homeostasis specifically in neurons has been less clear. We examined whether a stressor linked to neurodegeneration, glutamate excitotoxicity, elicits Parkin-mitochondrial translocation and mitophagy in neurons. We found that brief, acute exposure to glutamate causes Parkin translocation to mitochondria in neurons, in a calcium- and N-methyl-d-aspartate (NMDA) receptor-dependent manner. In addition, we found that Parkin accumulates on endoplasmic reticulum (ER) and mitochondrial/ER junctions following excitotoxicity, supporting a role for Parkin in mitochondrial-ER crosstalk in mitochondrial homeostasis. Despite significant Parkin-mitochondria translocation, however, we did not observe mitophagy under these conditions. To further investigate, we examined the role of glutamate-induced oxidative stress in Parkin-mitochondria accumulation. Unexpectedly, we found that glutamate-induced accumulation of Parkin on mitochondria was promoted by the antioxidant N-acetyl cysteine (NAC), and that co-treatment with NAC facilitated Parkin-associated mitophagy. These results suggest the possibility that mitochondrial depolarization and oxidative damage may have distinct pathways associated with Parkin function in neurons, which may be critical in understanding the role of Parkin in neurodegeneration.}, }
@article {pmid25465095, year = {2015}, author = {Wang, P and Li, C and Wang, X and Xiong, W and Feng, X and Liu, Q and Leung, AW and Xu, C}, title = {Anti-metastatic and pro-apoptotic effects elicited by combination photodynamic therapy with sonodynamic therapy on breast cancer both in vitro and in vivo.}, journal = {Ultrasonics sonochemistry}, volume = {23}, number = {}, pages = {116-127}, doi = {10.1016/j.ultsonch.2014.10.027}, pmid = {25465095}, issn = {1873-2828}, mesh = {Animals ; Apoptosis/*drug effects/*radiation effects ; Biological Transport ; Breast Neoplasms/drug therapy/*pathology/*therapy ; Cell Line, Tumor ; Chlorophyllides ; Combined Modality Therapy ; Female ; Humans ; Intracellular Space/drug effects/metabolism/radiation effects ; Lung Neoplasms/secondary ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mitochondria/drug effects/radiation effects ; Neoplasm Metastasis ; *Photochemotherapy ; Photosensitizing Agents/metabolism/pharmacology ; Porphyrins/metabolism/*pharmacology ; Reactive Oxygen Species/metabolism ; *Ultrasonic Therapy ; Vascular Endothelial Growth Factor A/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Sono-Photodynamic therapy (SPDT), a new modality for cancer treatment, is aimed at enhancing anticancer effects by the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we investigated the antitumor effect and possible mechanisms of Chlorin e6 (Ce6) mediated SPDT (Ce6-SPDT) on breast cancer both in vitro and in vivo. MTT assay revealed that the combined therapy markedly enhanced cell viability loss of breast cancer cell lines (MDA-MB-231, MCF-7 and 4T1) compared with SDT and PDT alone. Propidium iodide/hoechst33342 double staining reflected that 4T1 cells with apoptotic morphological characteristics were significantly increased in groups given combined therapy. Besides, the combined therapy caused obvious mitochondrial membrane potential (MMP) loss at early 1 h post SPDT treatment. The generation of intracellular reactive oxygen species (ROS) detected by flow cytometry was greatly increased in 4T1 cells treated with the combination therapy, and the loss of cell viability and MMP could be effectively rescued by pre-treatment with the ROS scavenger N-acetylcysteine (NAC). Further, Ce6-SPDT markedly inhibited the tumor growth (volume and weight) and lung metastasis in 4T1 tumor-bearing mice, but had no effect on the body weight. Hematoxylin and eosin staining revealed obvious tissue destruction with large spaces in the Ce6-SPDT groups, and TUNEL staining indicated tumor cell apoptosis after treatment. Immunohistochemistry analysis showed that the expression level of VEGF and MMP were significantly decreased in the combined groups. These results indicated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, loss of MMP and generation of ROS might be involved. In addition, Ce6-mediated SPDT significantly inhibited tumor growth and metastasis in mouse breast cancer 4T1 xenograft model, in which MMP-9 and VEGF may play a crucial role.}, }
@article {pmid25464205, year = {2015}, author = {Wei, X and Qi, Y and Zhang, X and Gu, X and Cai, H and Yang, J and Zhang, Y}, title = {ROS act as an upstream signal to mediate cadmium-induced mitophagy in mouse brain.}, journal = {Neurotoxicology}, volume = {46}, number = {}, pages = {19-24}, doi = {10.1016/j.neuro.2014.11.007}, pmid = {25464205}, issn = {1872-9711}, mesh = {Acetylcarnitine/pharmacology ; Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Brain/*drug effects/metabolism/ultrastructure ; Cadmium/*toxicity ; Collagenases/metabolism ; Dose-Response Relationship, Drug ; Male ; Mice ; Mice, Inbred Strains ; Microscopy, Electron, Transmission ; Microtubule Proteins ; Microtubule-Associated Proteins/metabolism ; Mitochondrial Diseases/*chemically induced/*pathology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Ubiquitin-Protein Ligases/metabolism ; }, abstract = {As a well known generator of reactive oxygen species (ROS), cadmium (Cd) is found to be an effective inducer of mitophagy in mouse kidney and liver cells. Here, we aim to elucidate whether Cd can also initiate mitophagy in mouse brain and what role ROS play in this process. Our results showed that Cd caused overproduction of ROS. Meanwhile, Cd induced mitophagy, as indicated by the collapse of mitochondrial membrane potential (MMP), formation of mitophagosomes, increases of PINK1 level and LC3-II/LC3-I ratio and decrease of mitochondrial mass. Scavenging of ROS by N-acetyl-L-cysteine (NAC) or acetyl-L-carnitine (ALC) rescued MMP and mitochondrial mass, and squelched PINK1 level, mitochondrial accumulation of Parkin and LC3-II/LC3-I ratio, suggesting that ROS were associated with Cd-induced mitophagy. Cyclosporine A (CsA), an inhibitor of mitophagy, blocked Cd-induced mitophagy and PINK1/Parkin pathway but failed to suppress ROS increase, revealing that ROS are the causes rather than the results of Cd-induced mitophagy. In conclusion, this study suggested that ROS functioned on the upstream of PINK1/Parkin pathway to mediate Cd-induced mitophagy.}, }
@article {pmid25463279, year = {2015}, author = {Yan, S and Zhang, X and Zheng, H and Hu, D and Zhang, Y and Guan, Q and Liu, L and Ding, Q and Li, Y}, title = {Clematichinenoside inhibits VCAM-1 and ICAM-1 expression in TNF-α-treated endothelial cells via NADPH oxidase-dependent IκB kinase/NF-κB pathway.}, journal = {Free radical biology &amp; medicine}, volume = {78}, number = {}, pages = {190-201}, doi = {10.1016/j.freeradbiomed.2014.11.004}, pmid = {25463279}, issn = {1873-4596}, mesh = {Blotting, Western ; Cell Adhesion ; Cell Proliferation ; Cells, Cultured ; Gene Expression Regulation/drug effects ; Human Umbilical Vein Endothelial Cells/*metabolism ; Humans ; I-kappa B Kinase/genetics/*metabolism ; Immunoprecipitation ; Intercellular Adhesion Molecule-1/genetics/*metabolism ; Leukocytes/cytology/metabolism ; Monocytes/cytology/metabolism ; NADPH Oxidases/genetics/*metabolism ; NF-kappa B/genetics/*metabolism ; RNA, Messenger/genetics ; Reactive Oxygen Species ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Saponins/*pharmacology ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/*pharmacology ; Vascular Cell Adhesion Molecule-1/genetics/*metabolism ; }, abstract = {Proinflammatory cytokine TNF-α-induced adhesion of leukocytes to endothelial cells plays a critical role in the early stage of atherosclerosis. Oxidative stress and redox-sensitive transcription factors are implicated in the process. Thus, compounds that mediate intracellular redox status and regulate transcription factors are of great therapeutic interest. Clematichinenoside (AR), a triterpene saponin isolated from the root of Clematis chinensis Osbeck, was previously demonstrated to have anti-inflammatory and antioxidative properties. However, little is known about the exact mechanism underlying these actions. Thus we performed a detailed study on its effect on leukocytes-endothelial cells adhesion with TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) and cell-free systems. First, we found that AR reduced TNF-α-induced VCAM-1 and ICAM-1 expression and their promoter activity, inhibited translocation of p65 and phosphorylation of IκBα, suppressed IκB kinase-β (IKK-β) activity, lowered O2(∙-) and H2O2 levels, tackled p47(phox) translocation, and decreased NOX4 NADPH oxidase expression. Second, we showed that AR exhibited no direct free radical scavenging ability in cell-free systems at concentrations that were used in intact cells. Besides, AR had no direct effect on the activity of IKK-β that was extracted from TNF-α-stimulated HUVECs. We also found that p47 translocation, NOX4 expression, and reactive oxygen species (ROS) levels were up-regulated before IκB phosphorylation in TNF-α-induced HUVECs. Moreover, TNF-α-enhanced IKK-β activity was also inhibited by (polyethylene glycol) PEG-catalase, N-acetylcysteine (NAC), and vitamin E. In conclusion, these results suggest that AR reduces VCAM-1 and ICAM-1 expression through NADPH oxidase-dependent IKK/NF-κB pathways in TNF-α-induced HUVECs, which finally suppress monocyte-HUVECs adhesion. This compound is potentially beneficial for early-stage atherosclerosis.}, }
@article {pmid25463117, year = {2014}, author = {Şentürk, T and Çavun, S and Avcı, B and Yermezler, A and Serdar, Z and Savcı, V}, title = {Effective inhibition of cardiomyocyte apoptosis through the combination of trimetazidine and N-acetylcysteine in a rat model of myocardial ischemia and reperfusion injury.}, journal = {Atherosclerosis}, volume = {237}, number = {2}, pages = {760-766}, doi = {10.1016/j.atherosclerosis.2014.10.091}, pmid = {25463117}, issn = {1879-1484}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Apoptosis/*drug effects ; Blood Pressure ; Caspase 3/metabolism ; Cell Death ; Coronary Vessels/pathology ; Disease Models, Animal ; Fatty Acids/chemistry ; Glucose/chemistry ; Glutathione/chemistry ; Inflammation ; Male ; Malondialdehyde/chemistry ; Myocardial Ischemia/*drug therapy ; Myocardium/pathology ; Myocytes, Cardiac/*cytology ; Oxidative Stress ; Oxygen/chemistry ; Rats ; Rats, Wistar ; Reperfusion Injury/*drug therapy ; S100 Calcium Binding Protein beta Subunit/blood ; Trimetazidine/*administration &amp; dosage ; }, abstract = {OBJECTIVE: Apoptosis is the early and predominant form of cell death in infarcted myocardia. The aim of the study was to investigate the effects of trimetazidine (TMZ) and N-acetylcysteine (NAC), used alone or in combination, on oxidative stress, infarct size, and ischemia-reperfusion (IR)-induced cardiomyocyte apoptosis in a rat model of myocardial IR.<br><br>METHODS AND RESULTS: Myocardial IR was established by ligating an area under the left main coronary artery for 30 min followed by 3 h of reperfusion. Saline (1 ml/kg), NAC (50, 150 mg/kg), or TMZ (3, 5 mg/kg) was intravenously injected during the middle of the ischemic period. At the end of the reperfusion, blood samples were collected from the animals to measure serum M30 and M65 levels, which are markers of cell death, the S100b level, which is a marker of inflammation, and the malondialdehyde (MDA) level, which is a marker of oxidative stress. The infarct size was evaluated as the ratio of the infarct area to the risk area. Apoptotic activation was assessed by caspase-3 immunostaining and a TUNEL assay. TMZ and NAC, either alone or in combination, significantly reduced serum MDA levels, infarct area and apoptotic activity compared to those observed in saline group. Interestingly, the infarct area was more smaller in TMZ (3 and 5 mg/kg) injected groups (9.72 &#xb1; 1.3% and 9.96 &#xb1; 2.3%) than those observed in NAC (50 and 150 mg/kg) (16.1 &#xb1; 2.5% and 19.1 &#xb1; 2.14%) or TMZ (5 mg/kg)- NAC (150 mg/kg) combination groups (16.9 &#xb1; 1.6%). However, the apoptotic activity was reduced more significantly in the combination of TMZ (5 mg/kg)-NAC (50 mg/kg) compared to TMZ-only group. Neither TMZ or NAC treatments nor the combination of the drugs significantly affected serum M30, M65 and S100B levels.<br><br>CONCLUSION: Intravenous NAC and TMZ administration decreased oxidative stress, infarct area and apoptotic activity in a rat model of IR. Although the combination treatment was more effective in reducing the apoptotic activity than either treatment groups alone, TMZ treatment was more successful in reducing the infarct area than NAC or combination treatments. Present results suggest that, in addition to mechanical attempts to secure myocardial reperfusion, the use of TMZ and NAC may help to reduce IR injury.}, }
@article {pmid25460548, year = {2015}, author = {Li, ZY and Jiang, WY and Cui, ZJ}, title = {An essential role of NAD(P)H oxidase 2 in UVA-induced calcium oscillations in mast cells.}, journal = {Photochemical &amp; photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology}, volume = {14}, number = {2}, pages = {414-428}, doi = {10.1039/c4pp00304g}, pmid = {25460548}, issn = {1474-9092}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Bone Marrow Cells ; Calcium Signaling/drug effects/physiology/*radiation effects ; Cell Line ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Mast Cells/drug effects/*metabolism/*radiation effects ; Membrane Glycoproteins/antagonists &amp; inhibitors/*metabolism ; Mice, Inbred ICR ; NADPH Oxidase 2 ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; Onium Compounds/pharmacology ; Periodicity ; Peritoneal Cavity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; *Ultraviolet Rays ; }, abstract = {Solar UVA radiation (320-400 nm) is known to have immunomodulatory effects, but the detailed mechanisms involved are not fully elucidated. UVA irradiation has been shown to induce calcium oscillations in rat peritoneal mast cells due to NAD(P)H oxidase (NOX) activation, but the specific NOX isoforms have not been identified. In the present work effects of UVA irradiation were investigated in isolated rat peritoneal mast cells, in cultured rat mast cell line RBL-2H3, and in mouse bone marrow-derived mast cells (BMMC). It was found that UVA irradiation by alternate 340/380 nm (3.2-5.6 μW cm(-2)) or by LED (380 nm, 80 μW cm(-2)) induced calcium oscillations in isolated rat peritoneal mast cells, in RBL-2H3, and in BMMC. Such UVA-induced calcium oscillations resembled closely those induced by surface IgE receptor (FcεRI) activation. It was found that RBL-2H3 expressed high levels of gp91(phox) (NOX2), p22(phox), p67(phox), p47(phox), p40(phox), Rac1, Rac2, moderate levels of DUOX2, but did not express NOX1, NOX3, NOX4, or DUOX1. The specific cellular localizations of gp91(phox) (NOX2), p22(phox), p47(phox), p67(phox), p40(phox) and Rac1/2 were confirmed by immunocytochemistry. UVA-induced reactive oxygen species (ROS) production in RBL-2H3 was completely suppressed by the NOX inhibitor diphenyleneiodonium chloride (DPI) or by the antioxidant N-acetyl-l-cysteine (NAC). siRNA suppression of gp91(phox) (NOX2), p22(phox) and p47(phox) expression inhibited markedly UVA-induced calcium oscillations, ROS and IL-6/LTC4 production in RBL-2H3. Taken together these data indicate that NOX2 plays an essential role in UVA irradiation-induced calcium oscillations, ROS and mediator production in mast cells.}, }
@article {pmid25458850, year = {2015}, author = {Mahmoodi, M and Soleimani Mehranjani, M and Shariatzadeh, SM and Eimani, H and Shahverdi, A}, title = {N-acetylcysteine improves function and follicular survival in mice ovarian grafts through inhibition of oxidative stress.}, journal = {Reproductive biomedicine online}, volume = {30}, number = {1}, pages = {101-110}, doi = {10.1016/j.rbmo.2014.09.013}, pmid = {25458850}, issn = {1472-6491}, mesh = {Acetylcysteine/*chemistry ; Animals ; Apoptosis ; Autografts ; Estradiol/*chemistry ; Female ; Malondialdehyde/chemistry ; Mice ; Ovarian Follicle/metabolism/physiology ; Ovary/physiology/*transplantation ; Oxidative Stress ; Transplantation, Heterotopic ; Vagina/cytology ; }, abstract = {The effect of N-acetylcysteine (NAC) on mouse ovary heterotopic autotransplantation was investigated. Mice (age 4-5 weeks) were divided into the following groups: control; autograft plus NAC (150 mg/kg daily intraperitoneal injection) and autograft plus saline (n = 6 per group). Groups were treated from 1 day before until 7 days after transplantation. After 28 days, ovary compartments were estimated stereologically. Plasma malondialdehyde, progesterone, oestradiol concentrations and the percentage of apoptotic follicles were measured to evaluate the rate of oxidative stress and ovarian graft function. The mean total volume of ovary, cortex and the number of follicles was significantly higher (all P < 0.001) in the autografts plus NAC group compared with the saline group. In the autografts plus NAC group, the mean percentage of apoptotic follicles (P < 0.001) and malondialdehyde concentration (P < 0.001 day 7; P < 0.05 day 28) were significantly lower, whereas oestradiol concentration was significantly higher (P < 0.05) compared with the saline group. Although NAC cannot compensate the above parameters to the control level, it considerably improves follicular survival and development and also the structure and function of transplanted ovaries, through reducing oxidative stress and apoptosis.}, }
@article {pmid25458464, year = {2015}, author = {Skov, M and Pressler, T and Lykkesfeldt, J and Poulsen, HE and Jensen, P&#xd8; and Johansen, HK and Qvist, T and Kræmer, D and Høiby, N and Ciofu, O}, title = {The effect of short-term, high-dose oral N-acetylcysteine treatment on oxidative stress markers in cystic fibrosis patients with chronic P. aeruginosa infection -- a pilot study.}, journal = {Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society}, volume = {14}, number = {2}, pages = {211-218}, doi = {10.1016/j.jcf.2014.09.015}, pmid = {25458464}, issn = {1873-5010}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Antioxidants/administration &amp; dosage ; Ascorbic Acid/*metabolism ; Chronic Disease ; *Cystic Fibrosis/complications/drug therapy/metabolism ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Monitoring ; Female ; Forced Expiratory Volume/drug effects ; Humans ; Inflammation/drug therapy/metabolism ; *Lung/drug effects/metabolism ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; *Pseudomonas Infections/complications/physiopathology ; Reactive Oxygen Species/metabolism ; Treatment Outcome ; }, abstract = {BACKGROUND: Patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa lung infection have increased oxidative stress as a result of an imbalance between the production of reactive oxygen species caused by inflammation and their inactivation by the impaired antioxidant systems. Supplementation with anti-oxidants is potentially beneficial for CF patients.<br><br>METHODS: The effect of 4 weeks of oral N-acetylcysteine (NAC) treatment (2400 mg/day divided into two doses) on biochemical parameters of oxidative stress was investigated in an open-label, controlled, randomized trial on 21 patients; 11 patients in the NAC group and 10 in the control group. Biochemical parameters of oxidative burden and plasma levels of antioxidants were assessed at the end of the study and compared to the baseline values in the two groups.<br><br>RESULTS: A significant increase in the plasma levels of the antioxidant ascorbic acid (p=0.037) and a significant decrease in the levels of the oxidized form of ascorbic acid (dehydroascorbate) (p=0.004) compared to baseline were achieved after NAC treatment. No significant differences were observed in the control group. The parameters of oxidative burden did not change significantly compared to baseline in either of the groups. A better lung function was observed in the NAC treated group with a mean (SD) change compared to baseline of FEV1% predicted of 2.11 (4.6), while a decrease was observed in the control group (change -1.4 (4.6)), though not statistically significant.<br><br>CONCLUSION: Treatment with N-acetylcysteine 1200 mg&#xd7;2/day for 30 days significantly decreased the level of oxidized vitamin C and increased the level of vitamin C (primary end-points) and a not statistically significant improvement of lung function was observed in this group of patients.}, }
@article {pmid25458027, year = {2014}, author = {Correa, MJ and Mariz, HA and Andrade, LE and Kayser, C}, title = {[Oral N-acetylcysteine in the treatment of Raynaud's phenomenon secondary to systemic sclerosis: a randomized, double-blind, placebo-controlled clinical trial].}, journal = {Revista brasileira de reumatologia}, volume = {54}, number = {6}, pages = {452-458}, doi = {10.1016/j.rbr.2014.07.001}, pmid = {25458027}, issn = {1809-4570}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Double-Blind Method ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Male ; Microcirculation ; Middle Aged ; Raynaud Disease/*drug therapy/etiology/physiopathology ; Regional Blood Flow ; Scleroderma, Systemic/complications ; }, abstract = {OBJECTIVE: To evaluate the safety and efficacy of N-acetylcysteine (NAC) orally on digital microcirculation blood flow in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc).<br><br>METHODS: This was a randomized, double-blind, placebo-controlled trial in which 42 patients with SSc received oral NAC at a dose of 600mg tid (21 patients, mean age 45.6&#xb1;9.5 years) or placebo (21 patients, mean age 45.0&#xb1;12.7 years) for four weeks. The primary endpoint was the change in cutaneous microcirculation blood flow before and after cold stimulation measured by laser Doppler imaging (LDI) at weeks 0 and 4. The frequency and severity of RP and the number of digital ulcers were also measured at weeks 0 and 4. The adverse events were recorded in the fourth week.<br><br>RESULTS: There was no significant change in digital blood flow assessed by LDI before or after cold stimulus after four weeks of NAC or placebo. Both groups showed significant improvement in the frequency and severity of RP attacks, with no difference between the two groups. At the end of the study, the placebo group had three digital ulcers, while the NAC group showed no ulcers. NAC was well tolerated and no patient discontinued the treatment.<br><br>CONCLUSIONS: NAC orally at a dose of 1800mg/day showed no vasodilator effect on hands' microcirculation after four weeks of treatment in patients with RP secondary to SSc.}, }
@article {pmid25457945, year = {2014}, author = {Miranda, RU and Gómez-Quiroz, LE and Mendoza, M and Pérez-Sánchez, A and Fierro, F and Barrios-González, J}, title = {Reactive oxygen species regulate lovastatin biosynthesis in Aspergillus terreus during submerged and solid-state fermentations.}, journal = {Fungal biology}, volume = {118}, number = {12}, pages = {979-989}, doi = {10.1016/j.funbio.2014.09.002}, pmid = {25457945}, issn = {1878-6146}, mesh = {Acetylcysteine/metabolism ; Aspergillus/genetics/*metabolism ; Culture Media ; *Fermentation ; Gene Expression Regulation, Fungal ; Genes, Fungal ; Hydrogen Peroxide/metabolism ; Lovastatin/*biosynthesis ; Reactive Oxygen Species/*metabolism ; Transcription Factors/genetics/metabolism ; }, abstract = {In a previous work we detected an important increase in reactive oxygen species (ROS) concentrations during idiophase in lovastatin fermentations. Hence, the objective of the present work was to determine if ROS contributes to the regulation of lovastatin biosynthesis. Exogenous antioxidants were used to reduce ROS accumulation. The addition of N-Acetyl-L-cysteine (NAC) decreased ROS accumulation and concurrent lovastatin production. In solid-state fermentation (SSF), the addition of 100 mM of NAC lowered ROS accumulation by 53%, together with a 79% decrease in lovastatin biosynthesis. A similarly, situation was observed in submerged fermentation (SmF). Decreased lovastatin production was due to a lower expression of the regulatory gene lovE, and gene lovF. Moreover, the addition of H2O2 to the culture caused precocious gene expression and lovastatin biosynthesis. These results indicate that ROS accumulation in idiophase contributes to the regulation of the biosynthetic genes. It was considered that Yap1 (Atyap1) could be a transcription factor linking ROS with lovastatin biosynthesis. In a Northern analysis, Aspergillus terreus yap1 gene (Atyap1) was highly expressed during trophophase but down regulated during idiophase. Conversely, expression pattern of srrA gene, suggested that SrrA could positively control lovastatin biosynthesis, and also explaining the characteristics of the biosynthesis in SSF.}, }
@article {pmid25451595, year = {2015}, author = {Lu, TH and Su, CC and Tang, FC and Chen, CH and Yen, CC and Fang, KM and Lee, kI and Hung, DZ and Chen, YW}, title = {Chloroacetic acid triggers apoptosis in neuronal cells via a reactive oxygen species-induced endoplasmic reticulum stress signaling pathway.}, journal = {Chemico-biological interactions}, volume = {225}, number = {}, pages = {1-12}, doi = {10.1016/j.cbi.2014.10.022}, pmid = {25451595}, issn = {1872-7786}, mesh = {Acetates/*metabolism/toxicity ; Animals ; Apoptosis/*physiology ; Calpain/genetics/metabolism ; Caspases/genetics/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*physiology ; Flow Cytometry ; Heat-Shock Proteins/genetics/metabolism ; Membrane Glycoproteins/genetics/metabolism ; Mice ; Neurons/*metabolism ; RNA/chemistry/genetics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction/*physiology ; Transcription Factor CHOP/genetics/metabolism ; }, abstract = {Chloroacetic acid (CA), a chlorinated analog of acetic acid and an environmental toxin that is more toxic than acetic, dichloroacetic, or trichloroacetic acids, is widely used in chemical industries. Furthermore, CA has been found to be the major disinfection by-products (DBPs) of drinking water. CA has been reported to be highly corrosive and to induce severe tissue injuries (including nervous system) that lead to death in mammals. However, the effects and underlying mechanisms of CA-induced neurotoxicity remain unknown. In the present study, we found that CA (0.5-2.0 mM) significantly increased LDH release, decreased the number of viable cells (cytotoxicity) and induced apoptotic events (including: increases in the numbers of apoptotic cells, the membrane externalization of phosphatidylserine (PS), and caspase-3/-7 activity) in Neuro-2a cells. CA (1.5 mM; the approximate to LD50) also triggered ER stress, which was identified by monitoring several key molecules that are involved in the unfolded protein responses (including the increase in the expressions of p-PERK, p-IRE-1, p-eIF2α, ATF-4, ATF-6, CHOP, XBP-1, GRP 78, GRP 94, and caspase-12) and calpain activity. Transfection of GRP 78- and GRP 94-specific si-RNA effectively abrogated CA-induced cytotoxicity, caspase-3/-7 and caspase-12 activity, and GRP 78 and GRP 94 expression in Neuro-2a cells. Additionally, pretreatment with 2.5 mM N-acetylcysteine (NAC; a glutathione (GSH) precursor) dramatically suppressed the increase in lipid peroxidation, cytotoxicity, apoptotic events, calpain and caspase-12 activity, and ER stress-related molecules in CA-exposed cells. Taken together, these results suggest that the higher concentration of CA exerts its cytotoxic effects in neuronal cells by triggering apoptosis via a ROS-induced ER stress signaling pathway.}, }
@article {pmid25451294, year = {2015}, author = {Chen, H and Tian, M and Jin, L and Jia, H and Jin, Y}, title = {PUMA is invovled in ischemia/reperfusion-induced apoptosis of mouse cerebral astrocytes.}, journal = {Neuroscience}, volume = {284}, number = {}, pages = {824-832}, doi = {10.1016/j.neuroscience.2014.10.059}, pmid = {25451294}, issn = {1873-7544}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Apoptosis/drug effects/*physiology ; Apoptosis Regulatory Proteins/genetics/*metabolism ; Astrocytes/drug effects/*physiology ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Hypoxia/drug effects/*physiology ; Cell Survival/physiology ; Cells, Cultured ; Cytochromes c/metabolism ; Free Radical Scavengers/pharmacology ; Gene Knockdown Techniques ; Glucose/*deficiency ; Mice, Inbred C57BL ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/drug therapy/*physiopathology ; Transfection ; Tumor Suppressor Proteins/genetics/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {PUMA (p53-upregulated modulator of apoptosis), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and p53-independent forms of apoptosis. PUMA has been invovled in the onset and progress of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. Although many studies have shown that ischemia and reperfusion (I/R) can induce the apoptosis of astrocytes, the role of PUMA in I/R-mediated apoptosis of cerebral astrocyte apoptosis remains unclear. To mimic in vivo I/R conditions, primary mouse cerebral astrocytes were incubated in a combinational cultural condition of oxygen, glucose, and serum deprivation (OSGD) for 1 h followed by reperfusion (OSGD/R). Cell death determination assays and cell viability assays indicated that OSGD and OSGD/R induce the apoptosis of primary cerebral astrocytes. The expression of PUMA was significantly elevated in primary cerebral astrocytes during OSGD/R. Moreover, targeted down-regulation of PUMA by siRNA transfection significantly decreased the OSGD/R-induced apoptosis of primary cerebral astrocytes. We also found that OSGD and OSGD/R triggered the release of cytochrome c in astrocytes, indicating the dependence on a mitochondrial apoptotic pathway. Reactive oxygen species (ROS) was extremely generated during OSGD and OSGD/R, and the elimination of ROS by treated with N-acetyl-L-cysteine (NAC) remarkably inhibited the expression of PUMA and the apoptosis of primary cerebral astrocytes. The activation of Caspase 3 and Caspase 9 was extremely elevated in primary cerebral astrocytes during OSGD. In addition, we found that knockdown of PUMA led to the depressed expression of Bax, cleaved caspase-9 and caspase-3 during OSGD/R. These results indicate that PUMA is invovled in the apoptosis of cerebral astrocytes upon I/R injury.}, }
@article {pmid25451261, year = {2014}, author = {Lu, G and Xu, S and Peng, L and Huang, Z and Wang, Y and Gao, X}, title = {Angiotensin II upregulates Kv1.5 expression through ROS-dependent transforming growth factor-beta1 and extracellular signal-regulated kinase 1/2 signalings in neonatal rat atrial myocytes.}, journal = {Biochemical and biophysical research communications}, volume = {454}, number = {3}, pages = {410-416}, doi = {10.1016/j.bbrc.2014.10.088}, pmid = {25451261}, issn = {1090-2104}, mesh = {Adaptor Proteins, Signal Transducing/genetics ; Angiotensin II/*metabolism ; Animals ; Cells, Cultured ; Heart Atria/cytology/metabolism ; Kv1.5 Potassium Channel/*genetics ; *MAP Kinase Signaling System ; Membrane Proteins/genetics ; Myocytes, Cardiac/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Receptor, Angiotensin, Type 1/metabolism ; Signal Transduction ; Smad2 Protein/genetics ; Smad3 Protein/genetics ; Transforming Growth Factor beta1/*metabolism ; *Up-Regulation ; }, abstract = {Kv1.5 potassium channel represents a promising target for atrial fibrillation (AF) therapy. During AF, the renin-angiotensin system is markedly activated. Recent evidence indicates that angiotensin II (Ang II) can upregulate Kv1.5 channel, but the mechanism remains unknown. In this study, we report that Ang II-mediated transforming growth factor-beta1 (TGF-β1)/Smad2/3 and extracellular signal-regulated kinase (ERK) 1/2 signalings are involved in atrial Kv1.5 expression. In neonatal rat atrial myocytes, quantitative PCR and Western blotting revealed that Ang II upregulated TGF-β1, synapse-associated protein 97 (SAP97) and Kv1.5 expression in a time- and concentration-dependent manner. The Ang II-induced upregulation of Kv1.5, SAP97 and phosphorylated Smad2/3 (P-Smad2/3) were reversed by the Ang II type 1 (AT1) receptor antagonist losartan, an anti-TGF-β1 antibody and the ERK 1/2 inhibitor PD98059 but not by the AT2 receptor antagonist PD123319. mRNA knockdown of either Smad2 or Smad3 blocked Ang II-induced expression of Kv1.5 and SAP97. These data suggest that AT1 receptor/TGF-β1/P-Smad2/3 and ERK 1/2 signalings are involved in Ang II-induced Kv1.5 and SAP97 expression. Flow cytometry and Western blotting revealed that losartan and the anti-TGF-β1 antibody diminished Ang II-induced reactive oxygen species (ROS) generation and that the antioxidants diphenyleneiodonium and N-acetyl cysteine inhibited Ang II-induced expression of P-Smad2/3, phosphorylated ERK (P-ERK) 1/2, Kv1.5, SAP97, suggesting that ROS participate in Kv1.5 and SAP97 regulation by modulating Ang II-induced P-Smad2/3 and P-ERK 1/2 expression. In conclusion, we demonstrate that ROS-dependent Ang II/AT1 receptor/TGF-β1/P-Smad2/3 and Ang II/ERK 1/2 signalings are involved in atrial Kv1.5 and SAP97 expression. Antioxidants would be beneficial for AF treatment through inhibiting atrial Kv1.5 expression.}, }
@article {pmid25451090, year = {2014}, author = {Ha, JS and Dho, SH and Youm, TH and Kwon, KS and Park, SS}, title = {Astrocytic phospholipase A2 contributes to neuronal glutamate toxicity.}, journal = {Brain research}, volume = {1590}, number = {}, pages = {97-106}, doi = {10.1016/j.brainres.2014.10.015}, pmid = {25451090}, issn = {1872-6240}, mesh = {Animals ; Astrocytes/*enzymology ; Cell Survival/drug effects ; Coculture Techniques ; Gene Knockdown Techniques ; Glutamic Acid/*toxicity ; Hydrogen Peroxide/toxicity ; Lipoxygenase/metabolism ; Mice ; Mice, Inbred ICR ; Neurons/*drug effects ; Oxidants/toxicity ; Phospholipases A2/genetics/*metabolism ; Primary Cell Culture ; Prostaglandin-Endoperoxide Synthases/metabolism ; }, abstract = {The role of astrocytes in glutamate toxicity has been controversial. Here, we show that astrocytes in neuron-astrocyte co-cultures increased neuronal sensitivity to chronic glutamate exposure but not to acute exposure. Enhanced neuronal toxicity by chronic exposure was dependent on astrocyte cell numbers. A reduced generation of extracellular H2O2 induced by glutamate was observed in co-cultures. Further, neuronal glutamate toxicity was not suppressed by NADPH oxidase (Nox) inhibitors, catalase or Nox4 knockdown in co-cultures, whereas these compounds effectively reduced the toxicity in pure neuron cultures. Instead, the intracellular scavenger of reactive oxygen species, N-acetylcysteine (NAC), reduced neuronal cytotoxicity in co-cultures, whereas catalase worked in pure neuron cultures. Lipoxygenase (LOX) inhibitors attenuated neuronal glutamate toxicity in co-cultures but not in pure neuron cultures. Neuronal 5-LOX activity was increased only in co-cultures, whereas 12-LOX activity was increased in both types of cultures. The cyclooxygenase (COX) inhibitors, indomethacin and NS-398, and the phospholipase A2 (PLA2) inhibitors, LY311727 and MAFP, more effectively reduced neuronal glutamate toxicity in co-cultures than in pure neuron cultures. However, in co-cultures, pre-treating neurons and astrocytes with the same inhibitors generated opposite results. COX inhibitors suppressed neuronal glutamate toxicity in pre-treated neurons rather than astrocytes, whereas PLA2 inhibitors reduced the toxicity in pre-treated astrocytes rather than neurons. Gene-specific knockdown of PLA2 confirmed these results. Knockdown of cPLA2α and/or sPLA2-V in astrocytes rather than in neurons more effectively reduced glutamate toxicity in co-cultures. These findings suggest that astrocytic PLA2 activity increases neuronal sensitivity to chronic glutamate exposure in neuron-astrocyte co-cultures.}, }
@article {pmid25449180, year = {2015}, author = {Lasram, MM and El-Golli, N and Lamine, AJ and Douib, IB and Bouzid, K and Annabi, A and El Fazaa, S and Abdelmoula, J and Gharbi, N}, title = {Changes in glucose metabolism and reversion of genes expression in the liver of insulin-resistant rats exposed to malathion. The protective effects of N-acetylcysteine.}, journal = {General and comparative endocrinology}, volume = {215}, number = {}, pages = {88-97}, doi = {10.1016/j.ygcen.2014.10.002}, pmid = {25449180}, issn = {1095-6840}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Biomarkers/analysis ; Cholinesterase Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/*drug effects ; Glucose/*metabolism ; Glycerol Kinase/metabolism ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Insulin/*metabolism ; *Insulin Resistance ; Intracellular Signaling Peptides and Proteins/metabolism ; Liver/drug effects/*metabolism ; Malathion/*pharmacology ; Male ; Oxidative Stress/drug effects ; Phosphoenolpyruvate Carboxykinase (GTP)/metabolism ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; }, abstract = {Organophosphorus pesticides are known to disturb glucose homeostasis and increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on insulin signaling pathways and the protective effects of N-acetylcysteine (NAC). Malathion (200 mg/kg) and NAC (2 g/l) were administered orally to rats, during 28 consecutive days. Malathion increases plasma glucose, plasma insulin and glycated hemoglobin levels. Further, we observed an increase of insulin resistance biomarkers and a decrease of insulin sensitivity indices. The GP, GSK3β and PEPCK mRNA expressions were amplified by malathion while, the expression of glucokinase gene is down-regulated. On the basis of biochemical and molecular findings, it is concluded that malathion impairs glucose homeostasis through insulin resistance and insulin signaling pathways disruptions in a way to result in a reduced function of insulin into hepatocytes. Otherwise, when malathion-treated rats were compared to NAC supplemented rats, fasting glucose and insulin levels, as well as insulin resistance indices were reduced. Furthermore, NAC restored liver GP and PEPCK expression. N-acetylcysteine showed therapeutic effects against malathion-induced insulin signaling pathways disruption in liver. These data support the concept that antioxidant therapies attenuate insulin resistance and ameliorate insulin sensitivity.}, }
@article {pmid25447593, year = {2015}, author = {Bullón, P and Román-Malo, L and Marín-Aguilar, F and Alvarez-Suarez, JM and Giampieri, F and Battino, M and Cordero, MD}, title = {Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial dysfunction through mitochondrial biogenesis improvement.}, journal = {Pharmacological research}, volume = {91}, number = {}, pages = {1-8}, doi = {10.1016/j.phrs.2014.10.007}, pmid = {25447593}, issn = {1096-1186}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Animals ; Antioxidants/*pharmacology ; Cells, Cultured ; Citrate (si)-Synthase/metabolism ; Fibroblasts/drug effects/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Lipopolysaccharides ; Male ; Mice, Inbred C57BL ; Mitochondria/*drug effects/metabolism ; Oxidative Stress/drug effects ; Oxygen Consumption/drug effects ; Reactive Oxygen Species/metabolism ; Ubiquinone/*analogs &amp; derivatives/pharmacology ; }, abstract = {Oxidative stress is implicated in several infectious diseases. In this regard, lipopolysaccharide (LPS), an endotoxic component, induces mitochondrial dysfunction and oxidative stress in several pathological events such as periodontal disease or sepsis. In our experiments, LPS-treated fibroblasts provoked increased oxidative stress, mitochondrial dysfunction, reduced oxygen consumption and mitochondrial biogenesis. After comparing coenzyme Q10 (CoQ10) and N-acetylcysteine (NAC), we observed a more significant protection of CoQ10 than of NAC, which was comparable with other lipophilic and hydrophilic antioxidants such as vitamin E or BHA respectively. CoQ10 improved mitochondrial biogenesis by activating PGC-1α and TFAM. This lipophilic antioxidant protection was observed in mice after LPS injection. These results show that mitochondria-targeted lipophilic antioxidants could be a possible specific therapeutic strategy in pharmacology in the treatment of infectious diseases and their complications.}, }
@article {pmid25445966, year = {2015}, author = {Dilshara, MG and Lee, KT and Lee, CM and Choi, YH and Lee, HJ and Choi, IW and Kim, GY}, title = {New compound, 5-O-isoferuloyl-2-deoxy-D-ribono-γ-lacton from Clematis mandshurica: Anti-inflammatory effects in lipopolysaccharide-stimulated BV2 microglial cells.}, journal = {International immunopharmacology}, volume = {24}, number = {1}, pages = {14-23}, doi = {10.1016/j.intimp.2014.10.030}, pmid = {25445966}, issn = {1878-1705}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Cell Line, Transformed ; *Clematis ; Cyclooxygenase 2/genetics/metabolism ; Dinoprostone/metabolism ; Down-Regulation/drug effects ; Heme Oxygenase-1/genetics/metabolism ; Lactones/chemistry/pharmacology ; Lipopolysaccharides/immunology ; Membrane Proteins/genetics/metabolism ; Mice ; Microglia/*drug effects/immunology ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/*metabolism ; Nervous System Diseases/*drug therapy ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; *Phytotherapy ; Plant Roots ; Proline/analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species/metabolism ; Ribose/analogs &amp; derivatives/chemistry/pharmacology ; Signal Transduction/drug effects ; Thiocarbamates/pharmacology ; }, abstract = {Microglia are main immune cells to exacerbate neural disorders in persistent overactivating. Therefore, it is a good strategy to regulate microglia for the treatment of neural disorders. In the present study, we isolated and characterized a novel compound, 5-O-isoferuloyl-2-deoxy-D-ribono-γ-lacton (5-DRL) from Clematis mandshurica, and evaluated its anti-inflammatory effect in lipopolysaccharide (LPS)-treated BV2 microglial cells. 5-DRL inhibited the expression of LPS-stimulated proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2), as well as their regulatory genes inducible NO syntheses (iNOS) and cyclooxygenase-2 (COX-2). 5-DRL also downregulated the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) through suppression of the nuclear translocation of the NF-κB subunits, p65 and p50. Consistent with the inhibition of iNOS and COX-2 via NF-κB activity with 5-DRL, an inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC), also led to the suppression of LPS-induced iNOS and COX-2 expression. Additionally, 5-DRL corresponding with antioxidants, N-acetylcysteine (NAC) and glutathione (GSH), remarkably inhibited reactive oxygen species (ROS) generation. Both NAC and GSH, thus attenuated the expression of iNOS and COX-2 by suppressing NF-κB activation, indicating that 5-DRL suppresses LPS-induced iNOS and COX-2 expression through downregulation of the ROS-dependent NF-κB signaling pathway. The present study also indicated that 5-DRL suppresses NO and PGE2 production by inducing heme oxygenase-1 (HO-1) via nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, the present data indicate that 5-DRL attenuates the production of proinflammatory mediators such as NO and PGE2 as well as their regulatory genes in LPS-stimulated BV2 microglial cells by inhibiting ROS-dependent NF-κB activation and stimulating the Nrf2/HO-1 signal pathway. These data may be implicated in the application of 5-DRL in LPS-stimulated inflammatory disease.}, }
@article {pmid25444896, year = {2015}, author = {Clark, O and Park, I and Di Florio, A and Cichon, AC and Rustin, S and Jugov, R and Maeshima, R and Stoker, AW}, title = {Oxovanadium-based inhibitors can drive redox-sensitive cytotoxicity in neuroblastoma cells and synergise strongly with buthionine sulfoximine.}, journal = {Cancer letters}, volume = {357}, number = {1}, pages = {316-327}, doi = {10.1016/j.canlet.2014.11.039}, pmid = {25444896}, issn = {1872-7980}, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Buthionine Sulfoximine/administration &amp; dosage/*pharmacology ; Cell Line, Tumor ; Drug Synergism ; Fibroblasts/drug effects ; Humans ; Mice ; Neuroblastoma/*drug therapy/metabolism ; Oxidation-Reduction ; Pyrones/administration &amp; dosage/*pharmacology ; Signal Transduction ; Transfection ; Vanadates/administration &amp; dosage/*pharmacology ; }, abstract = {In a wide range of neuroblastoma-derived lines oxovanadium compounds such as bis(maltolato)oxovanadium(IV) (BMOV) are cytotoxic. This is not explained by oxidative stress or inhibition of ion channels. Genotoxicity is unlikely given that a p53 response is absent and p53-mutant lines are also sensitive. Cytotoxicity is inhibited by N-acetyl cysteine and glutathione ester, indicating that BMOV action is sensitive to cytoplasmic redox and thiol status. Significantly, combining BMOV with glutathione synthesis inhibition greatly enhances BMOV-induced cell death. This combination treatment triggers high AKT pathway activation, highlighting the potential functional importance of PTP inhibition by BMOV. AKT activation itself, however, is not required for cytotoxicity. Oxovanadium compounds may thus represent novel leads as p53-independent therapeutics for neuroblastoma.}, }
@article {pmid25443718, year = {2014}, author = {McLean, LS and Crane, L and Baziard-Mouysset, G and Edwards, LP}, title = {Antiproliferative effect induced by novel imidazoline S43126 in PC12 cells is mediated by ROS, stress activated MAPKs and caspases.}, journal = {Pharmacological reports : PR}, volume = {66}, number = {6}, pages = {937-945}, doi = {10.1016/j.pharep.2014.06.003}, pmid = {25443718}, issn = {2299-5684}, mesh = {Animals ; Anisoles/administration &amp; dosage/*pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Proliferation/*drug effects ; Dose-Response Relationship, Drug ; Imidazoline Receptors/metabolism ; Imidazolines/administration &amp; dosage/*pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; PC12 Cells ; Rats ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {BACKGROUND: Some imidazoline compounds have pleiotropic effects including cell death in vitro. We examined the antiproliferative action of a novel imidazoline compound S43126, and the role of the I1-imidazoline receptor, ROS, MAPKs and caspases in S43126-induced cell death.<br><br>METHODS: PC 12 cells were treated with various concentrations of S43126 in the presence or absence of several ligands, and the effects on cell proliferation, ROS levels, and apoptosis were evaluated using Trypan Blue, Alamar Blue, Western blot and microscopy.<br><br>RESULTS: We showed that S43126 reduced PC12 cell proliferation by greater than 50%, increased cell death by greater than 40% and increased apoptotic body formation. These effects were reversed by I1R-antagonist, efaroxan. S43126 also increased intracellular ROS levels by greater than 2.5-fold relative to vehicle-treated control. These effects were significantly inhibited by N-acetyl-cysteine. In addition, pharmacologic inhibitors of ERK, JNK and p38 MAPK, significantly reduced S43126-induced antiproliferative activity. Caspases 3, 8 and 9 were all activated in a time-dependent manner by S43126. Pan caspase inhibitor z-VAD-fmk, ameliorated the effects of S43126 on cell death and cell proliferation.<br><br>CONCLUSION: Our data showed that the effects of S43126 on PC12 cell death were partly mediated by ROS production, MAPK and caspase activation. These results further indicate an emerging role for I1R in apoptotic processes.}, }
@article {pmid25438539, year = {2014}, author = {Yang, Y and Huang, H and Feng, D and Liu, W and Cheng, X and Ba, Y and Cui, L}, title = {[Effects. of N-acetylcysteine on fluoride-induced endoplasmic reticulum stress in sertoli cells].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {43}, number = {5}, pages = {805-8, 813}, pmid = {25438539}, issn = {1000-8020}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Survival/*drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Fluoresceins ; Heat-Shock Proteins ; Humans ; Male ; Oxidative Stress ; Rats ; Reactive Oxygen Species/adverse effects ; Sertoli Cells/drug effects ; Signal Transduction ; Sodium Fluoride ; }, abstract = {OBJECTIVE: Investigated the effects of N-acetylcysteine (NAC) on endoplasmic reticulum stress of sertoli cells induced by sodium fluoride (NaF).<br><br>METHODS: Rat sertoli cells were exposed to various concentration of (0, 6, 12, 24 &#xb5;g/ml) sodium fluoride with or without 2 mmol/L NAC for 24 hours. The cell viability was evaluated using trypan blue exclusion test. Intracellular reactive oxygen species (ROS) was measured using the fluorescent probe DCFH-DA. Western blot was used to test the expression of GRP78, PERK and CHOP.<br><br>RESULTS: It was found that treatment with NAC (2 mmol/L) restored the reduced cell viability and excessive oxidative stress (P < 0.01). Moreover, fluoride exposure upregulated the expression of GRP7 8, PERK and CHOP protein (P <0. 01). NAC was also found to suppress the levels of GRP78, PERK and CHOP expression in NaF-treated cells (p<0.01).<br><br>CONCLUSION: Endoplasmic reticulum stress signaling pathways were activated by ROS, and NAC attenuate endoplasmic reticulum stress through inhibiting the levels of ROS in NaF-treated sertoli cells.}, }
@article {pmid25437876, year = {2015}, author = {Gerriets, VA and Kishton, RJ and Nichols, AG and Macintyre, AN and Inoue, M and Ilkayeva, O and Winter, PS and Liu, X and Priyadharshini, B and Slawinska, ME and Haeberli, L and Huck, C and Turka, LA and Wood, KC and Hale, LP and Smith, PA and Schneider, MA and MacIver, NJ and Locasale, JW and Newgard, CB and Shinohara, ML and Rathmell, JC}, title = {Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.}, journal = {The Journal of clinical investigation}, volume = {125}, number = {1}, pages = {194-207}, pmid = {25437876}, issn = {1558-8238}, support = {R56AI102074/AI/NIAID NIH HHS/United States ; R56 AI102074/AI/NIAID NIH HHS/United States ; R01AI110613/AI/NIAID NIH HHS/United States ; R00CA168997/CA/NCI NIH HHS/United States ; R01 HL108006/HL/NHLBI NIH HHS/United States ; R01HL108006/HL/NHLBI NIH HHS/United States ; R00 CA168997/CA/NCI NIH HHS/United States ; R01 AI110613/AI/NIAID NIH HHS/United States ; P30 CA014236/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; CD4-Positive T-Lymphocytes/*enzymology ; Cell Differentiation ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Encephalomyelitis, Autoimmune, Experimental/*enzymology/immunology ; Energy Metabolism ; Glycolysis ; Mice, Inbred C57BL ; Protein Serine-Threonine Kinases/*physiology ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; T-Lymphocytes, Regulatory/enzymology ; Th17 Cells/enzymology ; Transcriptome ; }, abstract = {Activation of CD4+ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4+ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4+ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4+ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4+ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.}, }
@article {pmid25437431, year = {2014}, author = {Zhu, J and Bi, Z and Yang, T and Wang, W and Li, Z and Huang, W and Wang, L and Zhang, S and Zhou, Y and Fan, N and Bai, Y and Song, W and Wang, C and Wang, H and Bi, Y}, title = {Regulation of PKM2 and Nrf2-ARE pathway during benzoquinone induced oxidative stress in yolk sac hematopoietic stem cells.}, journal = {PloS one}, volume = {9}, number = {12}, pages = {e113733}, pmid = {25437431}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzoquinones/*pharmacology ; Carrier Proteins/genetics/*metabolism ; Dose-Response Relationship, Drug ; Female ; Gene Expression Regulation, Developmental/drug effects ; Hematopoietic Stem Cells/*metabolism ; Membrane Proteins/genetics/*metabolism ; Mice ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects ; Pregnancy ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Thyroid Hormones/genetics/*metabolism ; Yolk Sac/*cytology/*metabolism ; Thyroid Hormone-Binding Proteins ; }, abstract = {Benzene is an occupational toxicant and an environmental pollutant that is able to induce the production of reactive oxygen species (ROS), causing oxidative stress and damages of the macromolecules in target cells, such as the hematopoietic stem cells. We had previously found that embryonic yolk sac hematopoietic stem cells (YS-HSCs) are more sensitive to benzene toxicity than the adult bone marrow hematopoietic stem cells, and that nuclear factor-erythroid-2-related factor 2 (Nrf2) is the major regulator of cytoprotective responses to oxidative stress. In the present report, we investigated the effect of PKM2 and Nrf2-ARE pathway on the cellular antioxidant response to oxidative stress induced by benzene metabolite benzoquinone (BQ) in YS-HSC isolated from embryonic yolk sac and enriched by magnetic-activated cell sorting (MACS). Treatment of the YS-HSC with various concentrations of BQ for 6 hours induces ROS generation in a dose-dependent manner. Additional tests showed that BQ is also capable of inducing expression of NADPH oxidase1 (NOX1), and several other antioxidant enzymes or drug-metabolizing enzymes, including heme oxygenase 1 (HMOX1), superoxide dismutase (SOD), catalase and NAD(P)H dehydrogenase quinone 1 (NQO1). Concomitantly, only the expression of PKM2 protein was decreased by the treatment of BQ but not the PKM2 mRNA, which suggested that BQ may induce PKM2 degradation. Pretreatment of the cells with antioxidant N-acetylcysteine (NAC) decreased ROS generation and prevented BQ-induced PKM2 degradation, suggesting involvement of ROS in the PKM2 protein degradation in cellular response to BQ. These findings suggest that BQ is a potent inducer of ROS generation and the subsequent antioxidant responses of the YS-HSC. The accumulated ROS may attenuate the expression of PKM2, a key regulator of the pyruvate metabolism and glycolysis.}, }
@article {pmid25435376, year = {2015}, author = {Yu, SM and Kim, SJ}, title = {The thymoquinone-induced production of reactive oxygen species promotes dedifferentiation through the ERK pathway and inflammation through the p38 and PI3K pathways in rabbit articular chondrocytes.}, journal = {International journal of molecular medicine}, volume = {35}, number = {2}, pages = {325-332}, pmid = {25435376}, issn = {1791-244X}, mesh = {Animals ; Benzoquinones/*toxicity ; Cartilage, Articular/*metabolism/pathology ; Cell Dedifferentiation/*drug effects ; Cells, Cultured ; Chondrocytes/*metabolism/pathology ; Inflammation/chemically induced/metabolism/pathology ; MAP Kinase Signaling System/*drug effects ; Phosphatidylinositol 3-Kinases/*metabolism ; Rabbits ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Dedifferentiation and inflammation are major features of cartilage degeneration during the pathogenesis of osteoarthritis (OA). Thymoquinone (TQ) is the major compound of black seed oil isolated from Nigella sativa with various beneficial or harmful effects on several diseases; however, its effects on the dedifferentiation and inflammation of chondrocytes have not yet been characterized. In the present study, we investigated whether TQ regulates the dedifferentiation and inflammation of rabbit articular chondrocytes, focusing on the production of reactive oxygen species (ROS) in rabbit articular chondrocytes. TQ induced the generation of ROS in a dose-dependent manner, as shown by staining with the fluorescent probe, 2'-7'-dichlorofluorescein diacetate. We confirmed that TQ induced dedifferentiation by measuring the loss of type II collagen and the reduction in chondroitin sulfate proteoglycan levels. TQ also caused inflammation by inducing the expression of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). The antioxidant, N-acetyl cysteine (NAC), prevented the dedifferentiation and inflammation which was generated by the TQ-induced production of ROS. Furthermore, TQ caused a dose-dependent increase in p38, phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphoinositide 3-kinase (PI3K) expression. NAC abrogated this effect and attenuated the dedifferentiation and inflammation which was generated by the TQ-induced production of ROS. To identify the ROS-regulated pathways, we treated the chondrocytes with the p38 inhibitor, SB203580, the MEK inhibitor, PD98059, and the PI3K inhibitor, LY294002. PD98059 inhibited the TQ-induced dedifferentiation and SB203580 and LY294002 prevented the TQ-induced inflammation. These findings suggest that the TQ-induced production of ROS causes dedifferentiation through the ERK pathway and inflammation through the PI3K and p38 pathways in rabbit articular chondrocytes.}, }
@article {pmid25434308, year = {2015}, author = {Deng, S and Tang, S and Zhang, S and Zhang, C and Wang, C and Zhou, Y and Dai, C and Xiao, X}, title = {Furazolidone induces apoptosis through activating reactive oxygen species-dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {75}, number = {}, pages = {173-186}, doi = {10.1016/j.fct.2014.11.019}, pmid = {25434308}, issn = {1873-6351}, mesh = {Acetylcysteine/metabolism ; Apoptosis/*drug effects ; Caspase 3/genetics/metabolism ; Caspase 7/genetics/metabolism ; Caspase 9/genetics/metabolism ; Furazolidone/*pharmacology ; Hep G2 Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; }, abstract = {Furazolidone (FZD), a synthetic nitrofuran with a broad spectrum of antimicrobial activities, has been shown to be genotoxic and potentially carcinogenic in several types of cells. However, the proper molecular mechanisms of FZD toxicity remain unclear. This study was aimed to explore the effect of FZD on apoptosis in HepG2 cells and uncover signaling pathway underlying the cytotoxicity of FZD. The results showed that FZD induced apoptosis in HepG2 cells in a dose-dependent manner characterized by nuclei morphology changes, cell membrane phosphatidylserine translocation, poly (ADP-ribose) polymerase (PARP) cleavage and a cascade activation of caspase-9 and -3. FZD could enhance reactive oxygen species (ROS) generation, up-regulate Bax/Bcl-2 ratio, disrupt mitochondrial membrane potential (MMP) and subsequently cause cytochrome c release. Both ROS scavenger (N-acetyl cysteine, NAC) and caspase inhibitors suppressed FZD-induced apoptosis. Furthermore, NAC attenuated FZD-induced ROS generation and mitochondrial dysfunction. Meanwhile, FZD treatment inhibited both the activation and expression of Akt, and PI3K/Akt inhibitor LY294002 promoted FZD-induced apoptosis. On the contrary, PI3K/Akt activator insulin-like growth factor-1 (IGF-1) attenuated lethality of FZD in HepG2 cells. In conclusion, it is first demonstrated that FZD-induced apoptosis in HepG2 cells might be mediated through ROS-dependent mitochondrial signaling pathway and involves PI3K/Akt signaling.}, }
@article {pmid25431587, year = {2014}, author = {Gunay, Y and Altaner, S and Ekmen, N}, title = {The Role of e-NOS in Chronic Cholestasis-Induced Liver and Renal Injury in Rats: The Effect of N-Acetyl Cysteine.}, journal = {Gastroenterology research and practice}, volume = {2014}, number = {}, pages = {564949}, pmid = {25431587}, issn = {1687-6121}, abstract = {Introduction. The role of chronic cholestasis (CC) in liver injury and fibrosis remains unclear. The aims of this study were to define the role of endothelial nitric oxide synthase (e-NOS) in CC and the protective effect of N-acetyl-L-cysteine (NAC) in liver and kidney injury. Materials and Methods. Group A (sham group); Group B (CBDL); and Group C (CBDL + NAC). Group C received daily dosage of NAC (100 mg/kg) intraperitoneally for up to 4 weeks. Results. The rate of bridging fibrosis was higher (100% versus 20%, P = .025), but the intensity of e-NOS in liver was lower in rats that received NAC (1.3 versus 2.7, P = .046). The necrotic area in the kidneys among rats that received NAC was lower at week 4 (48% versus 57%; P < .001). The numbers of e-NOS stained cells in kidney were similar in sham group and the two groups with CBDL. Discussion. NAC reduced the stimulus for liver fibrosis in this rat model of CC and attenuated liver and kidney injury. Our study showed that e-NOS expression increased in liver tissue of rats with CC and that this was reversed by NAC. Treatment with NAC might restore e-NOS protein expression and prevent liver injury in CC.}, }
@article {pmid25430819, year = {2014}, author = {Schwenck, J and Griessinger, CM and Fuchs, K and Bukala, D and Bauer, N and Eichner, M and Röcken, M and Pichler, BJ and Kneilling, M}, title = {In vivo optical imaging of matrix metalloproteinase activity detects acute and chronic contact hypersensitivity reactions and enables monitoring of the antiinflammatory effects of N-acetylcysteine.}, journal = {Molecular imaging}, volume = {13}, number = {}, pages = {}, doi = {10.2310/7290.2014.00044}, pmid = {25430819}, issn = {1536-0121}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage/pharmacology ; Dermatitis, Allergic Contact/*metabolism/*pathology ; Disease Models, Animal ; Ear/pathology ; Female ; Gene Expression Regulation/drug effects ; Matrix Metalloproteinases/*metabolism ; Mice ; Mice, Inbred C57BL ; Picryl Chloride/adverse effects ; }, abstract = {The aim of this study was to determine whether the severity of contact hypersensitivity reactions (CHSRs) can be observed by noninvasive in vivo optical imaging of matrix metalloproteinase (MMP) activity and whether this is an appropriate tool for monitoring an antiinflammatory effect. Acute and chronic CHSRs were elicited by application of a 1% trinitrochlorobenzene (TNCB) solution for up to five times on the right ear of TNCB-sensitized mice. N-Acetylcysteine (NAC)-treated and sham-treated mice were monitored by measuring ear swelling and optical imaging of MMP activity. In addition, we performed hematoxylin-eosin staining and CD31 immunohistochemistry for histopathologic analysis of the antiinflammatory effects of NAC. The ear thickness and the MMP activity increased in line with the increasing severity of the CHSR. MMP activity was enhanced 2.5- to 2.7-fold during acute CHSR and 3.1- to 4.1-fold during chronic CHSR. NAC suppressed ear swelling and MMP signal intensity in mice with acute and chronic CHSR. During chronic CHSR, the vessel density was significantly reduced in ear sections derived from NAC-treated compared to sham-treated mice. In vivo optical imaging of MMP activity measures acute and chronic CHSR and is useful to monitor antiinflammatory effects.}, }
@article {pmid25428294, year = {2015}, author = {Samadi-Maybodi, A and Akhoondi, R}, title = {Trace analysis of N-acetyl-L-cysteine using luminol-H2O2 chemiluminescence system catalyzed by silver nanoparticles.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {30}, number = {6}, pages = {775-779}, doi = {10.1002/bio.2819}, pmid = {25428294}, issn = {1522-7243}, mesh = {Acetylcysteine/*analysis ; Catalysis ; Hydrogen Peroxide/chemistry ; Limit of Detection ; Luminescent Measurements/*methods ; Luminol/chemistry ; Metal Nanoparticles/*chemistry ; Silver/*chemistry ; Tablets/*analysis/chemistry ; }, abstract = {N-Acetyl-L-cysteine (NAC) can inhibit the luminol-H2 O2 , reaction, which is catalyzed by silver nanoparticles. Based on this phenomenon a new method was developed for NAC determination. Under optimum conditions, a linear relationship between chemiluminescence intensity and NAC concentration was found in the range 0.034-0.98 µg/mL. The detection limit was 0.010 µg/mL (S/N =3), and the relative standard deviation (RSD) was <5% for 0.480 µg/mL NAC (n =5). This simple, sensitive and inexpensive method has been applied to measure the concentration of NAC in pharmaceutical tablets.}, }
@article {pmid25426938, year = {2014}, author = {Yu, R and Cui, Z and Li, M and Yang, Y and Zhong, J}, title = {Dimer-dependent intrinsic/basal activity of the class B G protein-coupled receptor PAC1 promotes cellular anti-apoptotic activity through Wnt/β-catenin pathways that are associated with dimer endocytosis.}, journal = {PloS one}, volume = {9}, number = {11}, pages = {e113913}, pmid = {25426938}, issn = {1932-6203}, mesh = {Animals ; *Apoptosis ; CHO Cells ; Cricetinae ; Cricetulus ; Endocytosis ; Mice ; Mutation ; Protein Multimerization ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/genetics/*metabolism ; Wnt Proteins/*metabolism ; *Wnt Signaling Pathway ; beta Catenin/metabolism ; }, abstract = {The high expression of PACAP (pituitary adenylate cyclase-activating polypeptide)-preferring receptor PAC1 is associated with nerve injury and tumors. Our previous report (Yu R, et al. PLoS One 2012; 7: e51811) confirmed the dimerization of PAC1 and found that the M-PAC1 mutation in the N-terminal first Cys/Ala lost the ability to form dimers. In this study, Chinese hamster ovary (CHO-K1) cells overexpressing wild-type PAC1 (PAC1-CHO) had significantly higher anti-apoptotic activities against serum withdrawal-induced apoptosis associated with a lower caspase 3 activity and a higher Bcl-2 level in a ligand-independent manner than those of CHO cells overexpressing the mutant M-PAC1 (M-PAC1-CHO). PAC1-CHO had significantly higher β-catenin, cyclin D1 and c-myc levels corresponding to the Wnt/β-catenin signal than did M-PAC1-CHO. In addition, the Wnt/β-catenin pathway inhibitor XAV939 significantly inhibited the anti-apoptotic activities of PAC1-CHO. Top-flash assays demonstrated that PAC1-CHO had a significantly stronger Wnt/β-catenin signal than did M-PAC1-CHO. Acetylcysteine (NAC) as an inhibitor of the dimerization of PAC1 inhibited the anti-apoptotic activities that were endowed by PAC1 and decreased the Wnt/β-catenin signal in Top-flash assays. In the PAC1 Tet (tetracycline)-on inducible gene expression system by doxycycline (Dox), higher expression levels of PAC1 resulted in higher anti-apoptotic activities that were associated with a stronger Wnt/β-catenin signal. A similar correlation was also found with the down-regulation of PAC1 in the Neuro2a neuroblastoma cell. BiFC combined with fluorescence confocal imaging indicated that during serum-withdrawal-induced apoptosis, PAC1 dimers displayed significant endocytosis. These findings indicate that PAC1 has ligand-independent and dimer-dependent intrinsic/basal activity, conferring cells with anti-apoptotic activities against serum withdrawal, which is involved in the Wnt/β-catenin signal and is associated with the endocytosis of PAC1 dimers. The discovery and study of the dimer-dependent basal activity of PAC1 not only help us understand the physiological and pathological role of PAC1 but also promote the development of drugs targeting PAC1.}, }
@article {pmid25422104, year = {2015}, author = {Moazzen, H and Lu, X and Liu, M and Feng, Q}, title = {Pregestational diabetes induces fetal coronary artery malformation via reactive oxygen species signaling.}, journal = {Diabetes}, volume = {64}, number = {4}, pages = {1431-1443}, doi = {10.2337/db14-0190}, pmid = {25422104}, issn = {1939-327X}, mesh = {Aldehyde Dehydrogenase 1 Family ; Aldehydes/metabolism ; Animals ; Blood Glucose ; Cadherins/metabolism ; Coronary Vessel Anomalies/*etiology/metabolism ; Diabetes Mellitus, Experimental/*complications/metabolism ; Epithelial-Mesenchymal Transition ; Female ; Fibroblast Growth Factor 2/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Isoenzymes/metabolism ; Mice ; Myocardium/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects/*metabolism ; Reactive Oxygen Species/*metabolism ; Retinal Dehydrogenase/metabolism ; Signal Transduction/physiology ; }, abstract = {Hypoplastic coronary artery disease is a congenital coronary artery malformation associated with a high risk of sudden cardiac death. However, the etiology and pathogenesis of hypoplastic coronary artery disease remain undefined. Pregestational diabetes increases reactive oxygen species (ROS) levels and the risk of congenital heart defects. We show that pregestational diabetes in mice induced by streptozotocin significantly increased 4-hydroxynonenal production and decreased coronary artery volume in fetal hearts. Pregestational diabetes also impaired epicardial epithelial-to-mesenchymal transition (EMT) as shown by analyses of the epicardium, epicardial-derived cells, and fate mapping. Additionally, the expression of hypoxia-inducible factor 1α (Hif-1α), Snail1, Slug, basic fibroblast growth factor (bFgf), and retinaldehyde dehydrogenase (Aldh1a2) was decreased and E-cadherin expression was increased in the hearts of fetuses of diabetic mothers. Of note, these abnormalities were all rescued by treatment with N-acetylcysteine (NAC) in diabetic females during gestation. Ex vivo analysis showed that high glucose levels inhibited epicardial EMT, which was reversed by NAC treatment. We conclude that pregestational diabetes in mice can cause coronary artery malformation through ROS signaling. This study may provide a rationale for further clinical studies to investigate whether pregestational diabetes could cause hypoplastic coronary artery disease in humans.}, }
@article {pmid25421417, year = {2014}, author = {Himmerich, H and Erbguth, F}, title = {[Nutrition and dietary supplements in psychiatric diseases].}, journal = {Der Nervenarzt}, volume = {85}, number = {12}, pages = {1512-1520}, pmid = {25421417}, issn = {1433-0407}, mesh = {*Dietary Supplements ; Evidence-Based Medicine ; Humans ; Mental Disorders/*diet therapy/*prevention &amp; control ; Nutrition Therapy/*methods ; *Risk Reduction Behavior ; }, abstract = {Nutrition and specific nutritional supplements can have prophylactic or therapeutic properties with respect to certain psychiatric disorders. A traditional Mediterranean diet, for example, seems to have prophylactic benefits against depression and dementia, whereas overeating and obesity increase the risk for both.Although evidence for nutritional supplements in the treatment of psychiatric disorders is not sufficient for general recommendations, data from observational studies and randomized controlled trials (RCT) seem to point to their use for specific indications. Folate, S-adenosylmethionine (SAM) and eicosapentaenoic acid (EPA), for instance, seem to have antidepressant properties, zinc may be beneficial in attention deficit hyperactivity disorder (ADHD), vitamin B6 (pyridoxine) could reduce extrapyramidal side effects of antipsychotics and N-acetylcysteine (NAC) seems to be effective against negative symptoms, abnormal movements and akathisia in schizophrenia.Psychiatric disorders, in turn, may lead to deficiency of mineral nutrients and vitamins. For instance, vitamin B1 (thiamine) deficiency is common in alcohol-dependent patients and should therefore be considered during withdrawal treatment. Although vitamin malnutrition is uncommon in developed countries, vitamin deficiency syndromes, such as pernicious anemia or Wernicke's encephalopathy are still relevant differential diagnoses.Some psychopharmacological drugs may additionally change the nutritional habits of the patients in an unfavorable way leading to weight gain and obesity and the risk for further psychiatric problems.}, }
@article {pmid25411097, year = {2015}, author = {Muldoon, LL and Wu, YJ and Pagel, MA and Neuwelt, EA}, title = {N-acetylcysteine chemoprotection without decreased cisplatin antitumor efficacy in pediatric tumor models.}, journal = {Journal of neuro-oncology}, volume = {121}, number = {3}, pages = {433-440}, pmid = {25411097}, issn = {1573-7373}, support = {CA137488/CA/NCI NIH HHS/United States ; R37 NS044687/NS/NINDS NIH HHS/United States ; NS44687/NS/NINDS NIH HHS/United States ; R01 NS044687/NS/NINDS NIH HHS/United States ; R01 CA137488/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antineoplastic Agents/*toxicity ; Antioxidants/*administration &amp; dosage ; Brain Neoplasms/pathology ; Cells, Cultured ; Child ; Cisplatin/*toxicity ; Disease Models, Animal ; Female ; Humans ; Male ; Medulloblastoma/pathology ; Neoplasm Transplantation ; Neoplasms, Experimental/*drug therapy ; Neuroblastoma/pathology ; Oxidative Stress/drug effects ; Rats ; Rats, Nude ; }, abstract = {Decreasing oxidative damage with the antioxidant agent N-acetylcysteine (NAC) can block the side effects of chemotherapy, but may diminish anti-tumor efficacy. We tested the potential for interactions of high dose NAC against a minimally effective cisplatin chemotherapy regimen in rat models of human pediatric cancers. Athymic rats received subcutaneous implantation of human SK-N-AS neuroblastoma cells or intra-cerebellar implantation of human D283-MED medulloblastoma cells. Rats were untreated or treated with cisplatin (3 or 4 mg/kg IV) with or without NAC (1,000 mg/kg IV) 30 min before or 4 h after cisplatin treatment. Blood urea nitrogen (BUN) and tumor volumes were measured. Cisplatin decreased the growth of SK-N-AS neuroblastoma subcutaneous tumors from 17.7 ± 4.9 to 6.4 ± 2.5 fold over baseline 2 weeks after treatment (P < 0.001). Pretreatment with NAC decreased cisplatin efficacy, while 4 h delayed NAC did not significantly affect cisplatin anti-tumor effects (relative tumor volume 6.8 ± 2.0 fold baseline, P < 0.001). In D283-MED medulloblastoma brain tumors, cisplatin decreased final tumor volume to 3.9 ± 2.3 mm(3) compared to untreated tumor volume of 45.9 ± 38.7 (P = 0.008). Delayed NAC did not significantly alter cisplatin efficacy (tumor volume 6.8 ± 8.1 mm(3), P = 0.014 versus control). Cisplatin was minimally nephrotoxic in these models. NAC decreased cisplatin-induced elevations in BUN (P < 0.02). NAC chemoprotection did not alter cisplatin therapy, if delayed until 4 h after chemotherapy. These data support a Phase I/II clinical trial of delayed NAC to reduce ototoxicity in children with localized pediatric cancers.}, }
@article {pmid25410913, year = {2015}, author = {Dalvie, D and Kalgutkar, AS and Chen, W}, title = {Practical approaches to resolving reactive metabolite liabilities in early discovery.}, journal = {Drug metabolism reviews}, volume = {47}, number = {1}, pages = {56-70}, doi = {10.3109/03602532.2014.984813}, pmid = {25410913}, issn = {1097-9883}, mesh = {Animals ; Biotransformation/physiology ; Drug Discovery/*methods ; Drug-Related Side Effects and Adverse Reactions/*metabolism ; Glutathione/metabolism ; Humans ; Microsomes, Liver/*metabolism ; Pharmaceutical Preparations/chemistry/*metabolism ; }, abstract = {Idiosyncratic toxicity is one of the principal causes for withdrawal of marketed drugs after launch. Circumstantial evidence suggests that several drug-induced adverse effects are a result of transformation of a drug to electrophilic reactive metabolites (RMs) that can covalently bind to vital macromolecules in the body. Strategies have been implemented in early discovery to examine (and minimize) the formation of RMs. A common technique involves incubation of a new chemical entity with NADPH-supplemented human liver microsomes (HLMs) in the presence of soft nucleophilic trapping agents, such as glutathione (GSH) or N-acetylcysteine (NAC). Advances in mass spectrometry and the advent of very sensitive mass spectrometers ensure facile identification of the resulting GSH or NAC adducts of the reactive species. Detection of sulfhydryl conjugates in in vitro incubations, however, raise more questions regarding the path forward for RM-positive drug candidates. One approach that can assist in mitigating RM formation is assessment of their total body burden. Computation of dose using in vitro intrinsic clearance (Clint), potency data (Ceff) and the fractional contribution of RM pathway (frm), can provide an initial read of the daily burden of RM. This overview attempts to provide practical ways of assessing these factors and assist in putting the risk of RM formation into perspective.}, }
@article {pmid25410822, year = {2014}, author = {Loveman, E and Copley, VR and Colquitt, JL and Scott, DA and Clegg, AJ and Jones, J and O'Reilly, KM and Singh, S and Bausewein, C and Wells, A}, title = {The effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: systematic review, network meta-analysis and health economic evaluation.}, journal = {BMC pharmacology &amp; toxicology}, volume = {15}, number = {}, pages = {63}, pmid = {25410822}, issn = {2050-6511}, support = {10/50/06/DH_/Department of Health/United Kingdom ; }, mesh = {Cost-Benefit Analysis ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/*economics ; Models, Economic ; Quality of Life ; Treatment Outcome ; }, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a life-limiting lung disease with considerable impact on patients and carers as the disease progresses. Currently few treatments are available. We aimed to evaluate the clinical and cost-effectiveness of available treatments for IPF.<br><br>METHODS: Systematic reviews of clinical effectiveness, quality of life and cost effectiveness were undertaken. Eleven bibliographic databases were searched from inception to July 2013 and studies were assessed for eligibility against a set of pre-defined criteria. Two reviewers screened references, extracted data from included studies and appraised their quality. An advisory group was consulted about the choice of interventions. A narrative review was undertaken and where feasible fixed effect and random effects meta-analysis were undertaken including a network meta-analysis (NMA). A decision-analytic Markov model was developed to estimate cost-effectiveness of pharmacological treatments for IPF. Following best practice recommendations, the model perspective was of the national health service and personal social services, a discount rate of 3.5% for costs and health benefits was applied and outcomes were expressed as cost per quality adjusted life-year gained. Parameter values were obtained from the NMA and systematic reviews. Sensitivity analyses were undertaken.<br><br>RESULTS: Fourteen studies were included in the review of clinical effectiveness, of which one evaluated azathioprine, three N-acetylcysteine [NAC] (alone or in combination), four pirfenidone, one nintedanib, one sildenafil, one thalidomide, two pulmonary rehabilitation, and one a disease management programme. Study quality was generally good. Evidence suggests that some effective treatments are available. In NMA only nintedanib and pirfenidone show statistically significant improvements. The model results show increased survival for five pharmacological treatments (NAC triple therapy, inhaled NAC, nintedanib, pirfenidone, and sildenafil) compared with best supportive care, at increased cost. Only inhaled NAC was cost-effective at current willingness to pay thresholds but it may not be clinically effective.<br><br>CONCLUSIONS: Few interventions have any statistically significant effect and the cost-effectiveness of treatments is uncertain. A lack of studies on palliative care approaches was identified and there is a need for further research into pulmonary rehabilitation and thalidomide in particular. A well conducted RCT on inhaled NAC therapy should also be considered.}, }
@article {pmid25407538, year = {2014}, author = {Tao, YY and Yan, XC and Zhou, T and Shen, L and Liu, ZL and Liu, CH}, title = {Fuzheng Huayu recipe alleviates hepatic fibrosis via inhibiting TNF-α induced hepatocyte apoptosis.}, journal = {BMC complementary and alternative medicine}, volume = {14}, number = {}, pages = {449}, pmid = {25407538}, issn = {1472-6882}, mesh = {Actins/metabolism ; Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Apoptosis/*drug effects ; Carbon Tetrachloride ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism ; Drugs, Chinese Herbal/pharmacology/*therapeutic use ; Enzyme Inhibitors/pharmacology ; Hepatic Stellate Cells/drug effects ; Hepatocytes/drug effects/metabolism ; Hydroxyproline/metabolism ; Liver/cytology/*drug effects/metabolism ; Liver Cirrhosis/chemically induced/*drug therapy/metabolism ; Male ; Mice, Inbred C57BL ; *Phytotherapy ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Tumor Necrosis Factor-alpha/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {BACKGROUND: What was the relationship of Fuzheng Huayu recipe (FZHY) inhibiting hepatocyte apoptosis and HSC activation at different stage of liver fibrosis? In order to answer this question, the study was carried out to dynamically observe FZHY's effect on hepatocyte apoptosis and HSC activation and further explored underling mechanism of FZHY against hepatocyte apoptosis.<br><br>METHODS: Mice were randomly divided into four groups: normal, model, FZHY, and N-acetylcystein (NAC) groups. Acute hepatic injury and liver fibrosis in mice were induced by CCl4. Three days before the first CCl4 injection, treatment with FZHY powder or NAC respectively was started. In vitro, primary hepatocytes were pretreated with FZHY medicated serum or Z-VAD-FMK and then incubated with ActD and TNF-&#x3b1;. Primary HSCs were treated with DNA from apoptotic hepatocytes incubated by Act D/TNF-&#x3b1; or FZHY medicated. Liver sections were analyzed for HE staining and immunohistochemical evaluation of apoptosis. Serum ALT and AST, Alb content and TNF-&#x3b1; expression in liver tissue were detected. Hyp content was assayed and collagen deposition was visualized. Expressions of &#x3b1;-SMA and type I collagen were analyzed by immunofluorescence and immunoblotting. Flow cytometry, immunofluorescence, and DNA ladder for hepatocyte apoptosis and immunoblotting for TNF-R1, Bcl-2 and Bax were also analyzed.<br><br>RESULTS: Mice showed characteristic features of massive hepatocytes apoptosis in early stage of liver injury and developed severe hepatic fibrosis in later phase. FZHY treatment significantly alleviated acute liver injury and hepatocyte apoptosis, and inhibited liver fibrosis by decreasing &#x3b1;-SMA expression and hepatic Hyp content. In vitro, primary hepatocytes were induced by TNF-&#x3b1; and Act D. The anti-apoptotic effect of FZHY was generated by reducing TNFR1 expression and balancing the expressions of Bcl-2 and Bax. Meanwhile, the nuclear DNA from apoptotic hepatocytes stimulated HSC activation in a dose dependent manner, and the DNA from apoptotic hepatocytes treated with FZHY or Z-VAD-FMK reduced HSC activation and type I collagen expression.<br><br>CONCLUSION: These findings suggested that FZHY suppressed hepatocyte apoptosis through regulating mediators in death receptor and mitochondrial pathways, and the effect of FZHY on hepatocyte apoptosis might play an important role in inhibiting liver fibrosis.}, }
@article {pmid25403798, year = {2015}, author = {Khojastehfar, A and Aghaei, M and Gharagozloo, M and Panjehpour, M}, title = {Cadmium induces reactive oxygen species-dependent apoptosis in MCF-7 human breast cancer cell line.}, journal = {Toxicology mechanisms and methods}, volume = {25}, number = {1}, pages = {48-55}, doi = {10.3109/15376516.2014.985353}, pmid = {25403798}, issn = {1537-6524}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms/*metabolism/*pathology ; Cadmium Chloride/*toxicity ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Cell Survival/drug effects ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Female ; Humans ; MCF-7 Cells ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {CONTEXT AND OBJECTIVE: Although low concentrations of cadmium exposure may enhance growth of human cultured cells, high and long term of this heavy metal leads to cell death through apoptosis or necrosis. This study was conducted to define the underlying biochemical mechanism of Cd-induced cell death in MCF-7 human breast cancer cell line.<br><br>METHODS: The MCF-7 breast cancer cells were treated with different concentrations of CdCl2 and cell viability was assessed using the MTT assay. A propidium iodide (PI) and annexin-V staining flow cytometric method was used for apoptosis detection. Hoechst 33342 staining was used to observe the morphological changes of cell apoptosis. The cellular DNA was isolated using DNA kit extraction and analyzed electrophoretically. Intracellular reactive oxygen species (ROS) levels were quantified using the fluorescent dye (DCFH-DA).<br><br>RESULTS: A progressive loss in cell viability and an increased number of apoptotic cells were observed upon 48&#x2009;h exposure to CdCl2. N-acetylcysteine (NAC) administration reversed the cadmium cytotoxicity effects and protected cells from apoptotic death. Simultaneously, significant elevations of ROS levels were revealed in a dose-dependent manner during the exposure. Typical morphological changes of apoptosis were observed with Hoechst staining after cadmium treatment.<br><br>CONCLUSION: These results suggest that during the apoptosis mediated by cadmium chloride, ROS production and oxidative damage may be an initiating event and responsible for the mechanism of MCF-7 human breast cell death.}, }
@article {pmid25402962, year = {2014}, author = {Feng, J and Chen, X and Sun, X and Wang, F and Sun, X}, title = {Expression of endoplasmic reticulum stress markers GRP78 and CHOP induced by oxidative stress in blue light-mediated damage of A2E-containing retinal pigment epithelium cells.}, journal = {Ophthalmic research}, volume = {52}, number = {4}, pages = {224-233}, doi = {10.1159/000363387}, pmid = {25402962}, issn = {1423-0259}, mesh = {Biomarkers/*metabolism ; Blotting, Western ; Cell Line ; Cell Survival ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*physiology ; Flow Cytometry ; Heat-Shock Proteins/genetics/*metabolism ; Humans ; Light ; Microscopy, Confocal ; Oxidative Stress ; RNA, Messenger/genetics ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Retinal Pigment Epithelium/*drug effects/metabolism/*radiation effects ; Retinoids/*toxicity ; Transcription Factor CHOP/genetics/*metabolism ; Transfection ; }, abstract = {AIMS: Age-related lipofuscin N-retinylidene-N-retinylethanolamine (A2E) accumulated in human retinal pigment epithelium (RPE) cells confers susceptibility to blue light-mediated damage, which represents one pathogenesis of age-related macular degeneration. This study investigated the expression of 2 best-characterized endoplasmic reticulum (ER) stress markers, glucose-related protein 78 (GRP78) and C/EBP homologous protein (CHOP), as well as their regulation by oxidative stress after blue light-mediated damage of A2E-containing RPE cells.<br><br>METHODS: ARPE-19 cells were incubated with A2E (10, 25, 50 &#x3bc;M) for 2 h and exposed to blue light for 20 min. A2E distributions in RPE cells were assessed via laser scanning confocal microscope and liquid chromatography-mass spectrometry. Cell viability was measured by a Cell Titer 96 Aqueous One Solution cell proliferation assay. The quantity of intracellular reactive oxygen species (ROS) was detected by dihydroethidium fluorescence using flow cytometry. Expressions of GRP78 and CHOP were measured at both mRNA and protein levels. To examine the role of oxidative stress in regulating GRP78 and CHOP expression, RPE cells were pretreated with the antioxidant N-acetylcysteine (NAC) for 2 h. RNA interference of GRP78 performed by short hairpin RNA was used to evaluate the effect of GRP78 in blue light-mediated damage of RPE cells.<br><br>RESULTS: After blue light exposure, A2E-treated RPE cells showed a gradual decrease in cell viability and a particular increase in ROS levels. Meanwhile, the expressions of GRP78 and CHOP in A2E-treated RPE cells were significantly increased at different time points after illumination. Pretreatment with NAC attenuated the expression of 2 ER stress markers, especially CHOP in A2E and blue light-treated RPE cells. Silencing of GRP78 by RNA interference upregulated CHOP and caspase-12 expression as well as aggravated the blue light-mediated damage of A2E-laden RPE cells.<br><br>CONCLUSION: RPE cells exhibited ROS accumulation and subsequent elevation of GRP78 and CHOP expression after A2E and blue light-induced damage. The ROS scavenger NAC diminished ER stress protein expression, suggesting a connection between ER and oxidative stress in blue light-mediated damage of A2E-containing RPE cells. Besides, GRP78 may play a protective role in it.}, }
@article {pmid25400395, year = {2014}, author = {Manoj, EM and Ranasinghe, G and Ragunathan, MK}, title = {Successful use of N-acetyl cysteine and activated recombinant factor VII in fulminant hepatic failure and massive bleeding secondary to dengue hemorrhagic fever.}, journal = {Journal of emergencies, trauma, and shock}, volume = {7}, number = {4}, pages = {313-315}, pmid = {25400395}, issn = {0974-2700}, abstract = {Consensus on management of complicated cases of dengue infection is evolving. Dengue hemorrhagic fever (DHF) occasionally progress to fulminant liver failure with high fatality rate. Inadvertent use of blood products to control massive bleeding in dengue shock syndrome may worsen fluid overload and subsequently the multi-organ dysfunction. We report a case of 37-years-old Sri Lankan man who developed fulminant liver failure and massive bleeding associated with DHF, subsequently recovered completely with supportive measures including administration of N-acetyl cysteine and activated recombinant factor VII. In conclusion, prevention of ischemic injury to liver and adoption of early aggressive supportive measures in complicated cases of dengue hemorrhagic fever is crucial for a favorable outcome. Indications for rFVIIa to arrest uncontrolled internal bleeding and use of NAC in non-acetaminophen-induced acute liver failure in complicated DHF are a platform for discussion.}, }
@article {pmid25398315, year = {2015}, author = {Avezov, K and Reznick, AZ and Aizenbud, D}, title = {Time and dose effects of cigarette smoke and acrolein on protein carbonyl formation in HaCaT keratinocytes.}, journal = {Advances in experimental medicine and biology}, volume = {849}, number = {}, pages = {57-64}, doi = {10.1007/5584_2014_91}, pmid = {25398315}, issn = {0065-2598}, mesh = {Acetylcysteine/pharmacology ; Acrolein/chemistry/*toxicity ; Aldehydes/chemistry/toxicity ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Humans ; Keratinocytes/*drug effects/*metabolism ; Protein Carbonylation/*drug effects ; Smoking ; *Tobacco Products ; Tobacco Smoke Pollution/*adverse effects/analysis ; }, abstract = {Cigarette smoke (CS) is an important environmental source of human exposure to a highly toxic and chemically active α,β-unsaturated aldehyde: acrolein. It is capable of causing protein carbonylation and dysfunction, especially in oral tissues of smokers, constantly exposed to CS toxic constituents. The foremost damage is considered to be cumulative, but even a short exposure can be potentially harmful. The objectives of the current study were to examine the short time and dose effects of direct CS and acrolein exposure on intracellular protein carbonylation in epithelial cells. HaCaT-keratinocytes were exposed to different doses of acrolein and whole phase CS using a unique smoking simulator apparatus that mimics the exposure in smokers. The rate of intracellular protein carbonyl modification was examined 10-60 min after the exposure by Western blot. In addition, the effect of pre-incubation with a thiol scavenger N-acetylcysteine (NAC) was also assessed. We found that intracellular protein carbonyls increased as fast as 10 min after CS exposure and their concentration doubled after 20 min, with a slight elevation afterwards. Also, carbonyl levels increased gradually as CS and acrolein doses were elevated. Addition of 1 mM NAC neutralized part of the damage. We conclude that CS and acrolein intracellular protein carbonylation is dose- and time- dependent. Even a short time exposure to CS and its aldehydic constituents can be potentially harmful.}, }
@article {pmid25398242, year = {2015}, author = {Maeda, H and Hirata, K and Watanabe, H and Ishima, Y and Chuang, VT and Taguchi, K and Inatsu, A and Kinoshita, M and Tanaka, M and Sasaki, Y and Otagiri, M and Maruyama, T}, title = {Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {352}, number = {2}, pages = {244-257}, doi = {10.1124/jpet.114.219493}, pmid = {25398242}, issn = {1521-0103}, mesh = {Acetaminophen/pharmacology ; Acute Disease ; Albumins/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Animals ; Antigens, CD/*metabolism ; Antigens, Differentiation, Myelomonocytic/*metabolism ; Antioxidants/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/metabolism/pathology ; Concanavalin A/pharmacology ; Disease Models, Animal ; Flow Cytometry ; Glycoproteins/administration &amp; dosage/pharmacokinetics/*therapeutic use ; Kupffer Cells/*drug effects/metabolism/pathology ; Lectins, C-Type/*metabolism ; Male ; Mannose Receptor ; Mannose-Binding Lectins/*metabolism ; Mice, Inbred C57BL ; Nanoparticles/*chemistry ; Receptors, Cell Surface/*metabolism ; }, abstract = {Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD68(+) KC, play a key role in the induction of hepatic oxidative stress and injuries, we developed a polythiolated- and mannosylated human serum albumin (SH-Man-HSA), which functions as a novel nanoantioxidant for delivering thiol to CD68(+) KC. In vitro electron paramagnetic resonance coupled with pharmacokinetics and immunohistochemical studies showed that SH-Man-HSA possessed powerful radical-scavenging activity and rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) on CD68(+) cells. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A)-treated mice. Moreover, SH-Man-HSA exhibited excellent hepatoprotective functions, not by decreasing tumor necrosis factor or interferon-γ production that is closely associated with Con-A-induced hepatitis, but by suppressing ROS production. Interestingly, the protective effect of SH-Man-HSA was superior to N-acetyl cysteine (NAC). This could be attributed to the difference in the inhibition of hepatic oxidative stress between the two antioxidants depending on their potential for thiol delivery to the liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase in F4/80(+)/ROS(+) cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited a profound hepatoprotective action against these hepatitis models, whereas this was not observed for NAC. It can be concluded therefore that SH-Man-HSA has great potential for use in a rescue therapy for hepatopathy as a nanoantioxidant because of its ability to efficiently and rapidly deliver thiols to CD68(+)/CD206(+) KC.}, }
@article {pmid25394438, year = {2014}, author = {Yeganehkhah, MR and Iranirad, L and Dorri, F and Pazoki, S and Akbari, H and Miryounesi, M and Vahedian, M and Nazeri, A and Hosseinzadeh, F and Vafaeimanesh, J}, title = {Comparison between three supportive treatments for prevention of contrast-induced nephropathy in high-risk patients undergoing coronary angiography.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {25}, number = {6}, pages = {1217-1223}, doi = {10.4103/1319-2442.144255}, pmid = {25394438}, issn = {1319-2442}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; Blood Urea Nitrogen ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Female ; Fluid Therapy/*methods ; Humans ; Hydrogen-Ion Concentration ; Iohexol/*adverse effects ; Iran ; Kidney Diseases/blood/chemically induced/*prevention &amp; control/urine ; Male ; Middle Aged ; Risk Factors ; Sodium Bicarbonate/*administration &amp; dosage ; Sodium Chloride/*administration &amp; dosage ; Time Factors ; Treatment Outcome ; }, abstract = {Contrast-induced nephropathy is the third most common cause of acute renal failure in hospitalized patients. The purpose of this study was to compare three supportive treatments for prevention of contrast-induced nephropathy in high-risk patients undergoing coronary angiography. In this randomized clinical trial study, 150 patients with at least one risk factor, such as, congestive heart failure, history of diabetes mellitus, age>65 years or renal failure were randomly assigned to three equal groups: First group (Sodium (Na) bicarbonate infusion), second group [(N-Acetylcysteine (NAC)+Sodium Chloride (Nacl)], third group (Nacl). Angiography was performed with 350 mgI/mL of Iohexol (Omnipaque). Serum creatinine (Cr), blood blood urea nitrogen (BUN), and urine pH were measured at the start of angiography and 48 hours later. The three groups had no significant difference in demographic characteristics or other risk factors before intervention (P>0.05). Forty eight hours after exposure, the Cr level increased significantly in the Nacl group (P=0.039), while these changes were not significant in the other groups (P>0.05). The incidence of contrast-induced nephropathy was not statistically significant between all the groups (P=0.944). Although the Cr clearance had no statistically significant difference, it was lower in the NaCl group. Therefore, Na bicarbonate may be the treatment of choice in the prevention of contrast-induced nephropathy, because of less prescribed fluid volume and a lesser time required for infusion of the fluid.}, }
@article {pmid25393956, year = {2015}, author = {Arab, HA and Walker, NI and Cheung, K and Hickman, PE and Potter, JM and Kadkhodaee, M and Roberts, MS}, title = {Free radical scavengers improve liver function but not morphological changes induced by reperfusion injury.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {28}, number = {2}, pages = {77-85}, doi = {10.3109/08941939.2014.971205}, pmid = {25393956}, issn = {1521-0553}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aspartate Aminotransferases/metabolism ; Chromans/pharmacology ; Disease Models, Animal ; Female ; Free Radical Scavengers/*pharmacology ; Gentisates/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Liver/blood supply/*drug effects/*physiopathology ; Rats ; Rats, Sprague-Dawley ; Regional Blood Flow/drug effects/physiology ; Reperfusion Injury/*complications/metabolism/*physiopathology ; Superoxides/metabolism ; }, abstract = {OBJECTIVE: Reperfusion injury (RI) is associated with high generation of reactive oxygen species (ROS), but the extent of involvement of these agents in the injury remains controversial. The present study aimed to examine the effectiveness of ROS scavengers against hepatic reperfusion injury in the rat.<br><br>METHODS: The RI was induced in the liver using an isolated slow-flow, reflow perfused rat liver in both anterograde and retrograde perfusion. The effects of gentisic acid, N-acetyl cysteine, and trolox C on the superoxide production, liver function, and morphological changes were examined using different biochemical and histological assays.<br><br>RESULTS: The hepatic RI caused a significant (p < 0.05) increase in superoxide production and enzyme releases and a decrease in bile flow in both directions. Histological changes induced by RI include apoptosis, necrosis, pale cytoplasm, cell vacuolation, and attenuation of cell cords. Although the production of superoxide in retrograde direction was significantly less than the anterograde, the extent of the injury in the retrograde was greater than the anterograde direction. Pretreatment of the livers with each of the test compounds significantly reduced the release of lactate dehydrogenase and aspartate aminotransferase and improved bile flow in the liver exposed to hypoxia/reperfusion. However, they failed to protect the liver against the structural alterations induced by RI.<br><br>CONCLUSION: ROS scavengers can reduce superoxide-induced damage and improve the liver function, but they are not able to prevent the structural changes. It shows that ROS are not the sole causative mechanism of hepatic RI and other mechanisms and mediators may be involved.}, }
@article {pmid25393477, year = {2014}, author = {Wang, X and Li, H and Zheng, A and Yang, L and Liu, J and Chen, C and Tang, Y and Zou, X and Li, Y and Long, J and Liu, J and Zhang, Y and Feng, Z}, title = {Mitochondrial dysfunction-associated OPA1 cleavage contributes to muscle degeneration: preventative effect of hydroxytyrosol acetate.}, journal = {Cell death &amp; disease}, volume = {5}, number = {11}, pages = {e1521}, pmid = {25393477}, issn = {2041-4889}, mesh = {Acetates/isolation &amp; purification/*pharmacology ; Acetylcysteine/pharmacology ; Animals ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/antagonists &amp; inhibitors/pharmacology ; Catechols/isolation &amp; purification/*pharmacology ; Cell Differentiation ; Electron Transport Complex I/genetics/metabolism ; Electron Transport Complex II/genetics/metabolism ; GTP Phosphohydrolases/*genetics/metabolism ; Gene Expression Regulation ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/*metabolism/pathology ; Muscle Fibers, Skeletal/drug effects/*metabolism/pathology ; Myoblasts/cytology/drug effects/metabolism ; Myosin Heavy Chains/*genetics/metabolism ; Olive Oil ; Oxidative Stress ; Plant Oils/chemistry ; Proteolysis ; RNA, Messenger/*genetics/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; tert-Butylhydroperoxide/antagonists &amp; inhibitors/pharmacology ; }, abstract = {Mitochondrial dysfunction contributes to the development of muscle disorders, including muscle wasting, muscle atrophy and degeneration. Despite the knowledge that oxidative stress closely interacts with mitochondrial dysfunction, the detailed mechanisms remain obscure. In this study, tert-butylhydroperoxide (t-BHP) was used to induce oxidative stress on differentiated C2C12 myotubes. t-BHP induced significant mitochondrial dysfunction in a time-dependent manner, accompanied by decreased myosin heavy chain (MyHC) expression at both the mRNA and protein levels. Consistently, endogenous reactive oxygen species (ROS) overproduction triggered by carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a mitochondrial oxidative phosphorylation inhibitor, was accompanied by decreased membrane potential and decreased MyHC protein content. However, the free radical scavenger N-acetyl-L-cysteine (NAC) efficiently reduced the ROS level and restored MyHC content, suggesting a close association between ROS and MyHC expression. Meanwhile, we found that both t-BHP and FCCP promoted the cleavage of optic atrophy 1 (OPA1) from the long form into short form during the early stages. In addition, the ATPase family gene 3-like 2, a mitochondrial inner membrane protease, was also markedly increased. Moreover, OPA1 knockdown in myotubes was accompanied by decreased MyHC content, whereas NAC failed to prevent FCCP-induced MyHC decrease with OPA1 knockdown, suggesting that ROS might affect MyHC content by modulating OPA1 cleavage. In addition, hydroxytyrosol acetate (HT-AC), an important compound in virgin olive oil, could significantly prevent t-BHP-induced mitochondrial membrane potential and cell viability loss in myotubes. Specifically, HT-AC inhibited t-BHP-induced OPA1 cleavage and mitochondrial morphology changes, accompanied by improvement on mitochondrial oxygen consumption capacity, ATP productive potential and activities of mitochondrial complex I, II and V. Moreover, both t-BHP- and FCCP-induced MyHC decrease was sufficiently inhibited by HT-AC. Taken together, our data provide evidence indicating that mitochondrial dysfunction-associated OPA1 cleavage may contribute to muscle degeneration, and olive oil compounds could be effective nutrients for preventing the development of muscle disorders.}, }
@article {pmid25393016, year = {2014}, author = {Li, L and Guo, Y and Zhai, H and Yin, Y and Zhang, J and Chen, H and Wang, L and Li, N and Liu, R and Xia, Y}, title = {Aging increases the susceptivity of MSCs to reactive oxygen species and impairs their therapeutic potency for myocardial infarction.}, journal = {PloS one}, volume = {9}, number = {11}, pages = {e111850}, pmid = {25393016}, issn = {1932-6203}, mesh = {Acetylcysteine/therapeutic use ; Aging/*physiology ; Animals ; Apoptosis ; Cell Adhesion ; Free Radical Scavengers/therapeutic use ; Heart/drug effects/physiopathology ; Hydrogen Peroxide/toxicity ; Integrins/metabolism ; Male ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/drug effects/physiology ; Myocardial Infarction/physiopathology/*therapy ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*toxicity ; }, abstract = {Myocardial infarction (MI) is one of the leading causes of death worldwide and Mesenchymal Stem Cells (MSCs) transplantation has been considered a promising therapy. Recently, it was reported that the therapeutic effectiveness of MSCs is dependent on the age of the donor, yet the underlying mechanism has not been thoroughly investigated. This study was designed to investigate whether this impaired therapeutic potency is caused by an increased susceptivity of MSCs from old donors to reactive oxygen species (ROS). The MSCs were isolated from the subcutaneous inguinal region of young (8-10 weeks) and old (18 months) Sprague-Dawley (SD) rats. By exposing these MSCs to H2O2, we found that the adhesion of MSCs from old donors was damaged more severely. Specifically, decreased expression of integrin and reduced phosphorylation of focal adhesion kinase Src and FAK were observed. Furthemore, H2O2 triggered an increased apoptosis of MSCs from old donors. To study the viability and therapeutic potency of MSCs from young and old donors in vivo, these MSCs were transplanted into acute MI model rats. We observed a more rapidly decreased survival rate of the old MSCs in the infarct region, which may be caused by their increased susceptivity to the micro-environmental ROS, as transplantation of the old MSCs with N-acetyl-L-cysteine (NAC), a ROS scavenger, protected them. The low viability of engrafted old MSCs consequently impaired their therapeutic effectiveness, judging by the histology and function of heart. Our study may help to understand the mechanism of MSCs-host interaction during MI, as well as shed light on the design of therapeutic strategy in clinic.}, }
@article {pmid25391429, year = {2015}, author = {You, BR and Shin, HR and Han, BR and Park, WH}, title = {PX-12 induces apoptosis in Calu-6 cells in an oxidative stress-dependent manner.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {36}, number = {3}, pages = {2087-2095}, pmid = {25391429}, issn = {1423-0380}, mesh = {Acetylcysteine/metabolism ; Annexin A5/metabolism ; Antineoplastic Agents/pharmacology ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Cell Death/drug effects ; Cell Line, Tumor ; Disulfides/*pharmacology ; Epithelial Cells/drug effects/metabolism ; Fluorescein-5-isothiocyanate/analogs &amp; derivatives/metabolism ; G2 Phase Cell Cycle Checkpoints/drug effects ; Glutathione/metabolism/pharmacology ; Humans ; Imidazoles/*pharmacology ; M Phase Cell Cycle Checkpoints/drug effects ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {PX-12 (1-methylpropyl 2-imidazolyl disulfide) as a thioredoxin (Trx) inhibitor has an anti-tumor effect. However, there is no report about the toxicological effect of PX-12 on lung cancer cells. Here, we investigated the anti-growth effects of PX-12 on Calu-6 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. PX-12 induced the growth inhibition of Calu-6 cells with IC50 of nearly 3 μM at 72 h. In contrast, PX-12 did not affect the growth of human small airway epithelial cells (HSAECs). Cell cycle distribution analysis indicated that PX-12 significantly induced a G2/M phase arrest in Calu-6 cells. PX-12 also increased the number of annexin V-FITC-positive cells in Calu-6 cells. All the tested caspase inhibitors markedly prevented Calu-6 cell death induced by PX-12. With regard to ROS and GSH levels, PX-12 increased ROS levels containing O2(·-) in Calu-6 cells and induced the depletion of GSH. N-acetyl cysteine (NAC), which is a well-known antioxidant, significantly reduced O2(·-) level in PX-12-treated Calu-6 cells and prevented apoptosis and GSH depletion in these cells. In conclusion, it is the first report that PX-12 inhibited the growth of Calu-6 cells via a G2/M phase arrest as well as apoptosis, which effect was related to the intracellular increases in ROS levels.}, }
@article {pmid25386077, year = {2014}, author = {Sun, Y and Pu, LY and Lu, L and Wang, XH and Zhang, F and Rao, JH}, title = {N-acetylcysteine attenuates reactive-oxygen-species-mediated endoplasmic reticulum stress during liver ischemia-reperfusion injury.}, journal = {World journal of gastroenterology}, volume = {20}, number = {41}, pages = {15289-15298}, pmid = {25386077}, issn = {2219-2840}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cells, Cultured ; Cytoprotection ; Disease Models, Animal ; Endoplasmic Reticulum/*drug effects/metabolism/pathology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Liver/*blood supply/*drug effects/metabolism/pathology ; Liver Diseases/*drug therapy/metabolism/pathology ; Male ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/*drug therapy/metabolism/pathology ; Signal Transduction/drug effects ; }, abstract = {AIM: To investigate the effects of N-acetylcysteine (NAC) on endoplasmic reticulum (ER) stress and tissue injury during liver ischemia reperfusion injury (IRI).<br><br>METHODS: Mice were injected with NAC (300 mg/kg) intraperitoneally 2 h before ischemia. Real-time polymerase chain reaction and western blotting determined ER stress molecules (GRP78, ATF4 and CHOP). To analyze the role of NAC in reactive oxygen species (ROS)-mediated ER stress and apoptosis, lactate dehydrogenase (LDH) was examined in cultured hepatocytes treated by H2O2 or thapsigargin (TG).<br><br>RESULTS: NAC treatment significantly reduced the level of ROS and attenuated ROS-induced liver injury after IRI, based on glutathione, malondialdehyde, serum alanine aminotransferase levels, and histopathology. ROS-mediated ER stress was significantly inhibited in NAC-treated mice. In addition, NAC treatment significantly reduced caspase-3 activity and apoptosis after reperfusion, which correlated with the protein expression of Bcl-2 and Bcl-xl. Similarly, NAC treatment significantly inhibited LDH release from hepatocytes treated by H2O2 or TG.<br><br>CONCLUSION: This study provides new evidence for the protective effects of NAC treatment on hepatocytes during IRI. Through inhibition of ROS-mediated ER stress, NAC may be critical to inhibit the ER-stress-related apoptosis pathway.}, }
@article {pmid25384603, year = {2015}, author = {Song, JW and Shim, JK and Soh, S and Jang, J and Kwak, YL}, title = {Double-blinded, randomized controlled trial of N-acetylcysteine for prevention of acute kidney injury in high risk patients undergoing off-pump coronary artery bypass.}, journal = {Nephrology (Carlton, Vic.)}, volume = {20}, number = {2}, pages = {96-102}, doi = {10.1111/nep.12361}, pmid = {25384603}, issn = {1440-1797}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/diagnosis/etiology/*prevention &amp; control ; Aged ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Coronary Artery Bypass, Off-Pump/*adverse effects ; Creatinine/blood ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Perioperative Care ; Republic of Korea ; Risk Assessment ; Risk Factors ; Time Factors ; Treatment Outcome ; Water-Electrolyte Balance ; }, abstract = {AIM: The aim of this study was to investigate the influence of perioperative N-acetylcysteine (NAC) administration, a known antioxidant, on the incidence of acute kidney injury (AKI) after off-pump coronary bypass surgery (OPCAB) in patients with known risk factors of AKI.<br><br>METHODS: One hundred and seventeen patients with &#x2265;1 of the following risk factors of AKI were randomized into either the control (n&#x2009;=&#x2009;57) or the NAC (n&#x2009;=&#x2009;60) group; (i) preoperative serum creatinine >1.4&#x2009;mg/dL; (ii) left ventricular ejection fraction <35% or congestive heart failure (iii) age >70 years (iv) diabetes or (v) re-operation. Patients in the NAC group received 150&#x2009;mg/kg of NAC IV bolus at anaesthetic induction followed by a continuous infusion at 150&#x2009;mg/kg per day for 24&#x2009;h. AKI was diagnosed based on Acute Kidney Injury Network criteria during 48&#x2009;h postoperatively.<br><br>RESULTS: The incidence of AKI was 32% (19/60) and 35% (20/57) in the control and the NAC group, respectively (P&#x2009;=&#x2009;0.695). The serum concentrations of creatinine and cystatin C were similar between the groups throughout the study period. Fluid balance including the amount of blood loss and transfusion requirement were similar between the groups except the amount of postoperative urine output, which was higher in the control group compared with the NAC group (5528&#x2009;&#xb1;&#x2009;1247&#x2009;mL vs. 4982&#x2009;&#xb1;&#x2009;1185&#x2009;mL, control vs. NAC, P&#x2009;=&#x2009;0.017).<br><br>CONCLUSION: Perioperative administration of NAC did not prevent the development of postoperative AKI after OPCAB in highly susceptible patients to AKI.}, }
@article {pmid25382668, year = {2015}, author = {Nie, X and Liang, L and Xi, H and Jiang, S and Jiang, J and Tang, C and Liu, X and Liu, S and Wan, C and Zhao, J and Yang, J}, title = {2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin induces premature senescence of astrocytes via WNT/β-catenin signaling and ROS production.}, journal = {Journal of applied toxicology : JAT}, volume = {35}, number = {7}, pages = {851-860}, doi = {10.1002/jat.3084}, pmid = {25382668}, issn = {1099-1263}, mesh = {Animals ; Astrocytes/*drug effects ; Blotting, Western ; Cell Cycle/drug effects ; Cellular Senescence/*drug effects ; DNA Damage/drug effects ; Dioxins/*pharmacology/toxicity ; Fluorescent Antibody Technique ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Wnt Signaling Pathway/*drug effects ; }, abstract = {2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous environmental contaminant that could exert significant neurotoxicity in the human nervous system. Nevertheless, the molecular mechanism underlying TCDD-mediated neurotoxicity has not been clarified clearly. Herein, we investigated the potential role of TCDD in facilitating premature senescence in astrocytes and the underlying molecular mechanisms. Using the senescence-associated β-galactosidase (SA-β-Gal) assay, we demonstrated that TCDD exposure triggered significant premature senescence of astrocyte cells, which was accompanied by a marked activation of the Wingless and int (WNT)/β-catenin signaling pathway. In addition, TCDD altered the expression of senescence marker proteins, such as p16, p21 and GFAP, which together have been reported to be upregulated in aging astrocytes, in both dose- and time-dependent manners. Further, TCDD led to cell-cycle arrest, F-actin reorganization and the accumulation of cellular reactive oxygen species (ROS). Moreover, the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and astrocyte senescence. Notably, the application of XAV939, an inhibitor of WNT/β-catenin signaling pathway, ameliorated the effect of TCDD on cellular β-catenin level, ROS production, cellular oxidative damage and premature senescence in astrocytes. In summary, our findings indicated that TCDD might induce astrocyte senescence via WNT/β-catenin and ROS-dependent mechanisms.}, }
@article {pmid25380745, year = {2015}, author = {da Rosa, DP and Forgiarini, LF and e Silva, MB and Fiori, CZ and Andrade, CF and Martinez, D and Marroni, NP}, title = {Antioxidants inhibit the inflammatory and apoptotic processes in an intermittent hypoxia model of sleep apnea.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {64}, number = {1}, pages = {21-29}, pmid = {25380745}, issn = {1420-908X}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/*therapeutic use ; Apoptosis/*drug effects ; Caspases/metabolism ; Disease Models, Animal ; Hypoxia/etiology/*metabolism/*pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Inflammation/metabolism/pathology/*prevention &amp; control ; Liver/drug effects/metabolism/pathology ; Male ; Melatonin/pharmacology/therapeutic use ; Mice ; Mice, Inbred BALB C ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress/drug effects ; Sleep Apnea Syndromes/*complications ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {BACKGROUND: Sleep apnea causes intermittent hypoxia (IH). We aimed to investigate the proteins related to oxidative stress, inflammation and apoptosis in liver tissue subjected to IH as a simulation of sleep apnea in conjunction with the administration of either melatonin (MEL, 200 μL/kg) or N-acetylcysteine (NAC, 10 mg/kg).<br><br>METHODS: Seventy-two adult male Balb-C mice were divided: simulation of IH (SIH), SIH&#xa0;+&#xa0;MEL, SIH&#xa0;+&#xa0;NAC, IH, IH&#xa0;+&#xa0;MEL and IH&#xa0;+&#xa0;NAC. The animals were subjected to simulations of sleep apnea for 8&#xa0;h a day for 35&#xa0;days. The data were analyzed with ANOVA and Tukey tests with the significance set at p&#xa0;<&#xa0;0.05.<br><br>RESULTS: In IH, there was a significant increase in oxidative stress and expression of HIF-1a. In addition, we observed increase in the activation levels of NF-kB. This increase may be responsible for the increased expression of TNF-alpha and iNOS as well as the significant increase of VEGF signaling and expression of caspase-3 and caspase-6, which suggests an increase in apoptosis. In the groups treated with antioxidants, the analysis showed that the enzyme activity and protein levels were similar to those of the non-simulated group.<br><br>CONCLUSIONS: Thus, we show that IH causes liver inflammation and apoptosis, which may be protected with either MEL or NAC.}, }
@article {pmid25380471, year = {2015}, author = {Wang, Q and Guerrero, F and Mazur, A and Lambrechts, K and Buzzacott, P and Belhomme, M and Theron, M}, title = {Reactive Oxygen Species, Mitochondria, and Endothelial Cell Death during In Vitro Simulated Dives.}, journal = {Medicine and science in sports and exercise}, volume = {47}, number = {7}, pages = {1362-1371}, doi = {10.1249/MSS.0000000000000563}, pmid = {25380471}, issn = {1530-0315}, mesh = {Acetylcysteine/pharmacology ; Air ; Animals ; Cattle ; Cell Death/drug effects ; Cells, Cultured ; *Diving ; Endothelial Cells/*pathology ; Endothelium, Vascular/*metabolism ; Free Radical Scavengers/pharmacology ; Hyperoxia/metabolism ; Membrane Potential, Mitochondrial ; Mitochondria/*metabolism/*pathology ; Models, Animal ; Nitrogen ; Oxygen ; Reactive Oxygen Species/*metabolism ; }, abstract = {PURPOSE: Excessive reactive oxygen species (ROS) is considered a consequence of hyperoxia and a major contributor to diving-derived vascular endothelial damage and decompression sickness. The aims of this work were: 1) to directly observe endothelial ROS production during simulated air dives as well as its relation with both mitochondrial activity and cell survival; and 2) to determine which ambient factor during air diving (hydrostatic pressure or oxygen and/or nitrogen partial pressure) is responsible for the observed modifications.<br><br>METHODS: In vitro diving simulation was performed with bovine arterial endothelial cells under real-time observation. The effects of air diving, hydrostatic, oxygen and nitrogen pressures, and N-acetylcysteine (NAC) treatment on mitochondrial ROS generation, mitochondrial membrane potential and cellular survival during simulation were investigated.<br><br>RESULTS: Vascular endothelial cells performing air diving simulation suffered excessive mitochondrial ROS, mitochondrial depolarization, and cell death. These effects were prevented by NAC: after NAC treatment, the cells presented no difference in damage from nondiving cells. Oxygen diving showed a higher effect on ROS generation but lower impacts on mitochondrial depolarization and cell death than hydrostatic or nitrogen diving. Nitrogen diving had no effect on the inductions of ROS, mito-depolarization, or cell death.<br><br>CONCLUSION: This study is the first direct observation of mitochondrial ROS production, mitochondrial membrane potential and cell survival during diving. Simulated air SCUBA diving induces excessive ROS production, which leads to mitochondrial depolarization and endothelial cell death. Oxygen partial pressure plays a crucial role in the production of ROS. Deleterious effects of hyperoxia-induced ROS are potentiated by hydrostatic pressure. These findings hold new implications for the pathogenesis of diving-derived endothelial dysfunction.}, }
@article {pmid25376115, year = {2015}, author = {Balliu, M and Guandalini, L and Romanelli, MN and D'Amico, M and Paoletti, F}, title = {HDAC-inhibitor (S)-8 disrupts HDAC6-PP1 complex prompting A375 melanoma cell growth arrest and apoptosis.}, journal = {Journal of cellular and molecular medicine}, volume = {19}, number = {1}, pages = {143-154}, pmid = {25376115}, issn = {1582-4934}, mesh = {Animals ; Apoptosis/*drug effects ; Benzodiazepinones/chemistry/*pharmacology ; Caspases/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Dibenzazepines/chemistry/*pharmacology ; Female ; Histone Deacetylase 6 ; Histone Deacetylase Inhibitors/chemistry/*pharmacology ; Histone Deacetylases/*metabolism ; Humans ; Male ; Melanocytes/drug effects/pathology ; Melanoma/*pathology ; Mice ; Neovascularization, Physiologic/drug effects ; Protein Phosphatase 1/*metabolism ; Signal Transduction/drug effects ; Stereoisomerism ; }, abstract = {Histone deacetylase inhibitors (HDACi) are agents capable of inducing growth arrest and apoptosis in different tumour cell types. Previously, we reported a series of novel HDACi obtained by hybridizing SAHA or oxamflatin with 1,4-benzodiazepines. Some of these hybrids proved effective against haematological and solid cancer cells and, above all, compound (S)-8 has emerged for its activities in various biological systems. Here, we describe the effectiveness of (S)-8 against highly metastatic human A375 melanoma cells by using normal PIG1 melanocytes as control. (S)-8 prompted: acetylation of histones H3/H4 and α-tubulin; G0 /G1 and G2 /M cell cycle arrest by rising p21 and hypophos-phorylated RB levels; apoptosis involving the cleavage of PARP and caspase 9, BAD protein augmentation and cytochrome c release; decrease in cell motility, invasiveness and pro-angiogenic potential as shown by results of wound-healing assay, down-regulation of MMP-2 and VEGF-A/VEGF-R2, besides TIMP-1/TIMP-2 up-regulation; and also intracellular accumulation of melanin and neutral lipids. The pan-caspase inhibitor Z-VAD-fmk, but not the antioxidant N-acetyl-cysteine, contrasted these events. Mechanistically, (S)-8 allows the disruption of cytoplasmic HDAC6-protein phosphatase 1 (PP1) complex in A375 cells thus releasing the active PP1 that dephosphorylates AKT and blocks its downstream pro-survival signalling. This view is consistent with results obtained by: inhibiting PP1 with Calyculin A; using PPP1R2-transfected cells with impaired PP1 activity; monitoring drug-induced HDAC6-PP1 complex re-shuffling; and, abrogating HDAC6 expression with specific siRNA. Altogether, (S)-8 proved very effective against melanoma A375 cells, but not normal melanocytes, and safe to normal mice thus offering attractive clinical prospects for treating this aggressive malignancy.}, }
@article {pmid25371760, year = {2014}, author = {Wang, F and Liu, S and Shen, Y and Zhuang, R and Xi, J and Fang, H and Pan, X and Sun, J and Cai, Z}, title = {Protective effects of N-acetylcysteine on cisplatin-induced oxidative stress and DNA damage in HepG2 cells.}, journal = {Experimental and therapeutic medicine}, volume = {8}, number = {6}, pages = {1939-1945}, pmid = {25371760}, issn = {1792-0981}, abstract = {Hepatocyte injury is a common pathological effect of cisplatin (CDDP) in various solid tumor therapies. Thus, strategies for minimizing CDDP toxicity are of great clinical interest. N-acetylcysteine (NAC), a known antioxidant, is often used as an antidote for acetaminophen overdose in the clinic due to its ability to increase the levels of glutathione (GSH). In the present study, the aim was to investigate the protective effects of NAC against CDDP-induced apoptosis in human-derived HepG2 cells. The results showed that upon exposure of the cells to CDDP, oxidative stress was significantly induced. DNA damage caused by CDDP was associated with cell apoptosis. NAC pre-treatment significantly reduced the malondialdehyde (MDA) levels and ameliorated the GSH modulation induced by CDDP. NAC also protected against DNA damage and cell apoptosis. These data suggest the protective role of NAC against hepatocyte apoptosis induced by CDDP was achieved through the inhibition of DNA damage and alterations of the redox status in human derived HepG2 cells. These results indicate that NAC administration may protect against CDDP-induced damage.}, }
@article {pmid25370167, year = {2015}, author = {You, BR and Shin, HR and Han, BR and Kim, SH and Park, WH}, title = {Auranofin induces apoptosis and necrosis in HeLa cells via oxidative stress and glutathione depletion.}, journal = {Molecular medicine reports}, volume = {11}, number = {2}, pages = {1428-1434}, doi = {10.3892/mmr.2014.2830}, pmid = {25370167}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Auranofin/*pharmacology ; Buthionine Sulfoximine/pharmacology ; Caspase Inhibitors/pharmacology ; Cell Proliferation/drug effects ; Glutathione/analysis/deficiency/*metabolism ; HeLa Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Necrosis ; Oligopeptides/pharmacology ; Oxidative Stress/*drug effects ; Singlet Oxygen/analysis/metabolism ; }, abstract = {Auranofin (Au), an inhibitor of thioredoxin reductase, is a known anti‑cancer drug. In the present study, the anti‑growth effect of Au on HeLa cervical cancer cells was examined in association with levels of reactive oxygen species (ROS) and glutathione (GSH). Au inhibited the growth of HeLa cells with an IC50 of ~2 µM at 24 h. This agent induced apoptosis and necrosis, accompanied by the cleavage of poly (ADP‑ribose) polymerase and loss of mitochondrial membrane potential. The pan‑caspase inhibitor, benzyloxycarbonyl‑Val‑Ala‑Asp‑fluoromethylketone, prevented apoptotic cell death and each of the assessed caspase inhibitors inhibited necrotic cell death induced by Au. With respect to the levels of ROS and GSH, Au increased intracellular O2•- in the HeLa cells and induced GSH depletion. The pan‑caspase inhibitor reduced the levels of O2•- and GSH depletion in Au‑treated HeLa cells. The antioxidant, N‑acetyl cysteine, not only attenuated apoptosis and necrosis in the Au‑treated HeLa cells, but also decreased the levels of O2•- and GSH depletion in the cells. By contrast, L‑buthionine sulfoximine, a GSH synthesis inhibitor, intensified cell death O2•- and GSH depletion in the Au‑treated HeLa cells. In conclusion, Au induced apoptosis and necrosis in HeLa cells via the induction of oxidative stress and the depletion of GSH.}, }
@article {pmid25368550, year = {2014}, author = {Arredondo Zamarripa, D and Díaz-Lezama, N and Meléndez García, R and Chávez Balderas, J and Adán, N and Ledesma-Colunga, MG and Arnold, E and Clapp, C and Thebault, S}, title = {Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress.}, journal = {Frontiers in cellular neuroscience}, volume = {8}, number = {}, pages = {333}, pmid = {25368550}, issn = {1662-5102}, abstract = {Vasoinhibins are prolactin fragments present in the retina, where they have been shown to prevent the hypervasopermeability associated with diabetes. Enhanced bradykinin (BK) production contributes to the increased transport through the blood-retina barrier (BRB) in diabetes. Here, we studied if vasoinhibins regulate BRB permeability by targeting the vascular endothelium and retinal pigment epithelium (RPE) components of this barrier. Intravitreal injection of BK in male rats increased BRB permeability. Vasoinhibins prevented this effect, as did the B2 receptor antagonist Hoe-140. BK induced a transient decrease in mouse retinal and brain capillary endothelial monolayer resistance that was blocked by vasoinhibins. Both vasoinhibins and the nitric oxide (NO) synthase inhibitor L-NAME, but not the antioxidant N-acetyl cysteine (NAC), blocked the transient decrease in bovine umbilical vein endothelial cell (BUVEC) monolayer resistance induced by BK; this block was reversed by the NO donor DETANONOate. Vasoinhibins also prevented the BK-induced actin cytoskeleton redistribution, as did L-NAME. BK transiently decreased human RPE (ARPE-19) cell monolayer resistance, and this effect was blocked by vasoinhibins, L-NAME, and NAC. DETANONOate reverted the blocking effect of vasoinhibins. Similar to BK, the radical initiator Luperox induced a reduction in ARPE-19 cell monolayer resistance, which was prevented by vasoinhibins. These effects on RPE resistance coincided with actin cytoskeleton redistribution. Intravitreal injection of vasoinhibins reduced the levels of reactive oxygen species (ROS) in retinas of streptozotocin-induced diabetic rats, particularly in the RPE and capillary-containing layers. Thus, vasoinhibins reduce BRB permeability by targeting both its main inner and outer components through NO- and ROS-dependent pathways, offering potential treatment strategies against diabetic retinopathies.}, }
@article {pmid25367877, year = {2015}, author = {Kumar, V and Tripathi, VK and Jahan, S and Agrawal, M and Pandey, A and Khanna, VK and Pant, AB}, title = {Lead Intoxication Synergies of the Ethanol-Induced Toxic Responses in Neuronal Cells--PC12.}, journal = {Molecular neurobiology}, volume = {52}, number = {3}, pages = {1504-1520}, pmid = {25367877}, issn = {1559-1182}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Calcium Signaling/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Ethanol/*toxicity ; Gene Expression Regulation/drug effects ; Glutathione/metabolism ; Lead/*toxicity ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Nerve Tissue Proteins/genetics/metabolism ; Oxidation-Reduction ; Oxidative Stress/drug effects ; PC12 Cells/*drug effects/metabolism ; Protein Transport/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Lead (Pb)-induced neurodegeneration and its link with widespread neurobehavioral changes are well documented. Experimental evidences suggest that ethanol could enhance the absorption of metals in the body, and alcohol consumption may increase the susceptibility to metal intoxication in the brain. However, the underlying mechanism of ethanol action in affecting metal toxicity in brain cells is poorly understood. Thus, an attempt was made to investigate the modulatory effect of ethanol on Pb intoxication in PC12 cells, a rat pheochromocytoma. Cells were co-exposed to biological safe doses of Pb (10 μM) and ethanol (200 mM), and data were compared to the response of cells which received independent exposure to these chemicals at similar doses. Ethanol (200 mM) exposure significantly aggravated the Pb-induced alterations in the end points associated with oxidative stress and apoptosis. The finding confirms the involvement of reactive oxygen species (ROS)-mediated oxidative stress, and impairment of mitochondrial membrane potential, which subsequently facilitate the translocation of triggering proteins between cytoplasm and mitochondria. We further confirmed the apoptotic changes due to induction of mitochondria-mediated caspase cascade. These cellular changes were found to recover significantly, if the cells are exposed to N-acetyl cysteine (NAC), a known antioxidant. Our data suggest that ethanol may potentiate Pb-induced cellular damage in brain cells, but such damaging effects could be recovered by inhibition of ROS generation. These results open up further possibilities for the design of new therapeutics based on antioxidants to prevent neurodegeneration and associated health problems.}, }
@article {pmid25363473, year = {2014}, author = {Feng, X and Zhang, Y and Wang, P and Liu, Q and Wang, X}, title = {Energy metabolism targeted drugs synergize with photodynamic therapy to potentiate breast cancer cell death.}, journal = {Photochemical &amp; photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology}, volume = {13}, number = {12}, pages = {1793-1803}, doi = {10.1039/c4pp00288a}, pmid = {25363473}, issn = {1474-9092}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis/drug effects/physiology/radiation effects ; Breast Neoplasms/pathology/physiopathology/*therapy ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/physiology/radiation effects ; Deoxyglucose/*pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Human Umbilical Vein Endothelial Cells ; Humans ; MAP Kinase Kinase 4/metabolism ; Mitochondrial Membranes/drug effects/physiology/radiation effects ; Photochemotherapy/*methods ; Photosensitizing Agents/pharmacology ; Pyruvates/*pharmacology ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Malignant cells are highly dependent on aerobic glycolysis, which differs significantly from normal cells (the Warburg effect). Interference of this metabolic process has been considered as an innovative method for developing selective cancer therapy. A recent study demonstrated that the glycolysis inhibitor 2-deoxyglucose (2-DG) can potentiate PDT efficacy, whereas the possible mechanisms have not been carefully investigated. This study firstly proved the general potentiation of PDT efficacy by 2-DG and 3-bromopyruvate (3-BP) in human breast cancer MDA-MB-231 cells, and carefully elucidated the underlying mechanism in the process. Our results showed that both 2-DG and 3-BP could significantly promote a PDT-induced cell cytotoxic effect when compared with either monotherapy. Synergistic potentiation of mitochondria- and caspase-dependent cell apoptosis was observed, including a mitochondrial membrane potential (MMP) drop, Bax translocation, and caspase-3 activation. Besides, ROS generation and the expression of oxidative stress related proteins such as P38 MAPK phosphorylation and JNK phosphorylation were notably increased after the combined treatments. Moreover, when pretreated with the ROS scavenger N-acetylcysteine (NAC), the ROS generation, the MMP drop, cell apoptosis and cytotoxicity were differently inhibited, suggesting that ROS was vertical in the pro-apoptotic process induced by 2-DG/3-BP combined with PDT treatment. These results indicate that the combination of glycolytic antagonists and PDT may be a promising therapeutic strategy to effectively kill cancer cells.}, }
@article {pmid25361473, year = {2015}, author = {Moraes, LH and Bollineli, RC and Mizobuti, DS and Silveira, Ldos R and Marques, MJ and Minatel, E}, title = {Effect of N-acetylcysteine plus deferoxamine on oxidative stress and inflammation in dystrophic muscle cells.}, journal = {Redox report : communications in free radical research}, volume = {20}, number = {3}, pages = {109-115}, pmid = {25361473}, issn = {1743-2928}, mesh = {Acetylcysteine/*pharmacology ; Aldehydes/metabolism ; Animals ; Cells, Cultured ; Deferoxamine/*pharmacology ; Hydrogen Peroxide/metabolism ; Inflammation/*drug therapy/pathology ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscle, Skeletal/*drug effects/metabolism/pathology ; Muscular Dystrophy, Duchenne/pathology ; NF-kappa B/metabolism ; Oxidative Stress/*drug effects ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVES: Oxidative stress and inflammatory process play an important role in the pathogenesis of Duchenne muscular dystrophy (DMD). We investigated whether deferoxamine (DFX) improves the antioxidant effects of N-acetylcysteine (NAC) on primary cultures of dystrophic muscle cells from mdx mice, the experimental model of DMD.<br><br>METHODS: Primary cultures of skeletal muscle cells from mdx mice were treated with either NAC (10 mM), DFX (5 mM), or NAC plus DFX for 24 hours. The muscle cells of C57BL/10 mice were used as controls.<br><br>RESULTS: Production of hydrogen peroxide (H2O2) and levels of 4-hydroxynonenal (4-HNE), tumor necrosis factor alpha (TNF-&#x3b1;), and nuclear factor kappa-B (NF-&#x3ba;B) were significantly higher in mdx muscle cells than in C57BL/10 muscle cells. Treatment with NAC, DFX, or NAC plus DFX significantly decreased H2O2 production (24, 58, and 72%, respectively), and levels of 4-HNE-protein adducts (62, 33, and 71%, respectively), TNF-&#x3b1; (32, 29, and 31%, respectively), and NF-&#x3ba;B (34, 38, and 52%, respectively) on dystrophic muscle cells.<br><br>DISCUSSION: This study demonstrates that mdx muscle cells are able to produce key oxidative stress and inflammatory markers, without the interference of inflammatory cells, and shows that NAC plus DFX reduced the inflammatory and oxidative stress indicators, mainly H2O2 production and NF-&#x3ba;B levels by dystrophic fibers.}, }
@article {pmid25359386, year = {2014}, author = {Yang, Y and Yang, D and Yang, D and Jia, R and Ding, G}, title = {Role of reactive oxygen species-mediated endoplasmic reticulum stress in contrast-induced renal tubular cell apoptosis.}, journal = {Nephron. Experimental nephrology}, volume = {128}, number = {1-2}, pages = {30-36}, doi = {10.1159/000366063}, pmid = {25359386}, issn = {1660-2129}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cell Line ; Cells, Cultured ; Contrast Media/*pharmacology ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/drug effects/*physiology ; Free Radical Scavengers/pharmacology ; Heat-Shock Proteins/metabolism ; Iohexol/*analogs &amp; derivatives/pharmacology ; Kidney Tubules, Proximal/*drug effects/metabolism/*pathology ; Models, Animal ; Rats ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/metabolism ; }, abstract = {BACKGROUND: Renal tubular cell apoptosis is a key mechanism of contrast-induced acute kidney injury. It has been reported that endoplasmic reticulum (ER) stress is the underlying mechanism of high osmolar contrast-induced renal tubular cell apoptosis. Whether ER stress is involved in low osmolar contrast-induced renal tubular cell injury remains unclear. In the present study, the roles of ER stress in iopromide-induced (a low osmolar contrast) renal tubular cell apoptosis and the effects of N-acetylcysteine (NAC) on ER stress were investigated.<br><br>METHODS: NRK-52E cells were exposed to different concentrations of iopromide [50, 100 and 150 mg iodine (I)/ml] for 4 h. In a separate experiment, NRK-52E cells were exposed to iopromide (100 mg I/ml, 4 h) with or without NAC (10 mmol/l). NAC was added 1 h before incubation with iopromide. Apoptosis was determined by Hoechst staining and flow cytometry. The intracellular formation of reactive oxygen species (ROS) was detected by confocal microscopy with fluorescent probe CM-H2DCFDA. The expression of glucose-regulated protein 78 (GRP78) and CAAT/enhancer-binding protein homologous protein (CHOP) was determined by Western blot.<br><br>RESULTS: Iopromide induced NRK-52E cell apoptosis in a concentration-dependent manner. The intracellular ROS production increased significantly following iopromide exposure in the NRK-52E cells. Significantly increased expressions of GRP78 and CHOP were observed in the NRK-52E cells exposed to iopromide for 4 h; NAC attenuated iopromide-induced NRK-52E cell apoptosis by inhibiting the overproduction of intracellular ROS and subsequently suppressing the overexpression of GRP78 and CHOP.<br><br>CONCLUSION: ROS-mediated ER stress is involved in contrast-induced renal tubular cell apoptosis.}, }
@article {pmid25356874, year = {2014}, author = {Rocha, CR and Garcia, CC and Vieira, DB and Quinet, A and de Andrade-Lima, LC and Munford, V and Belizário, JE and Menck, CF}, title = {Glutathione depletion sensitizes cisplatin- and temozolomide-resistant glioma cells in vitro and in vivo.}, journal = {Cell death &amp; disease}, volume = {5}, number = {10}, pages = {e1505}, pmid = {25356874}, issn = {2041-4889}, mesh = {Animals ; Apoptosis/drug effects ; Brain Neoplasms/*pathology ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/*pharmacology ; DNA Damage ; DNA Repair/drug effects ; Dacarbazine/*analogs &amp; derivatives/pharmacology ; Disease Progression ; Drug Resistance, Neoplasm/*drug effects ; Female ; Glioma/*pathology ; Glutathione/*deficiency ; Humans ; Mice, Nude ; Temozolomide ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Malignant glioma is a severe type of brain tumor with a poor prognosis and few options for therapy. The main chemotherapy protocol for this type of tumor is based on temozolomide (TMZ), albeit with limited success. Cisplatin is widely used to treat several types of tumor and, in association with TMZ, is also used to treat recurrent glioma. However, several mechanisms of cellular resistance to cisplatin restrict therapy efficiency. In that sense, enhanced DNA repair, high glutathione levels and functional p53 have a critical role on cisplatin resistance. In this work, we explored several mechanisms of cisplatin resistance in human glioma. We showed that cellular survival was independent of the p53 status of those cells. In addition, in a host-cell reactivation assay using cisplatin-treated plasmid, we did not detect any difference in DNA repair capacity. We demonstrated that cisplatin-treated U138MG cells suffered fewer DNA double-strand breaks and DNA platination. Interestingly, the resistant cells carried higher levels of intracellular glutathione. Thus, preincubation with the glutathione inhibitor buthionine sulfoximine (BSO) induced massive cell death, whereas N-acetyl cysteine, a precursor of glutathione synthesis, improved the resistance to cisplatin treatment. In addition, BSO sensitized glioma cells to TMZ alone or in combination with cisplatin. Furthermore, using an in vivo model the combination of BSO, cisplatin and TMZ activated the caspase 3-7 apoptotic pathway. Remarkably, the combined treatment did not lead to severe side effects, while causing a huge impact on tumor progression. In fact, we noted a remarkable threefold increase in survival rate compared with other treatment regimens. Thus, the intracellular glutathione concentration is a potential molecular marker for cisplatin resistance in glioma, and the use of glutathione inhibitors, such as BSO, in association with cisplatin and TMZ seems a promising approach for the therapy of such devastating tumors.}, }
@article {pmid25352760, year = {2014}, author = {Yoo, HJ and Im, CN and Youn, DY and Yun, HH and Lee, JH}, title = {Bis is Induced by Oxidative Stress via Activation of HSF1.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {18}, number = {5}, pages = {403-409}, pmid = {25352760}, issn = {1226-4512}, abstract = {The Bis protein is known to be involved in a variety of cellular processes including apoptosis, migration, autophagy as well as protein quality control. Bis expression is induced in response to a number of types of stress, such as heat shock or a proteasome inhibitor via the activation of heat shock factor (HSF)1. We report herein that Bis expression is increased at the transcriptional level in HK-2 kidney tubular cells and A172 glioma cells by exposure to oxidative stress such as H2O2 treatment and oxygen-glucose deprivation, respectively. The pretreatment of HK-2 cells with N-acetyl cysteine, suppressed Bis induction. Furthermore, HSF1 silencing attenuated Bis expression that was induced by H2O2, accompaniedby increase in reactive oxygen species (ROS) accumulation. Using a series of deletion constructs of the bis gene promoter, two putative heat shock elements located in the proximal region of the bis gene promoter were found to be essential for the constitutive expression is as well as the inducible expression of Bis. Taken together, our results indicate that oxidative stress induces Bis expression at the transcriptional levels via activation of HSF1, which might confer an expansion of antioxidant capacity against pro-oxidant milieu. However, the possible role of the other cis-element in the induction of Bis remains to be determined.}, }
@article {pmid25351153, year = {2014}, author = {Risso, PS and Koike, MK and Abrahão, Mde S and Ferreira, NC and Montero, EF}, title = {The effect of n-acetylcysteine on hepatic histomorphology during hypothermic preservation.}, journal = {Acta cirurgica brasileira}, volume = {29 Suppl 3}, number = {}, pages = {28-32}, doi = {10.1590/s0102-86502014001700006}, pmid = {25351153}, issn = {1678-2674}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Cryopreservation/*methods ; Free Radical Scavengers/*pharmacology ; Liver/anatomy &amp; histology/*drug effects ; Male ; Models, Animal ; Organ Preservation/adverse effects/*methods ; Random Allocation ; Rats, Wistar ; Reperfusion Injury/prevention &amp; control ; Time Factors ; }, abstract = {PURPOSE: To evaluate the NAC effects on liver hypothermic preservation at different time intervals.<br><br>METHODS: For this, we used livers of male Wistar rats weighing between 250 and 300 g, undergoing preservation in Ringer solution at 4&#xb0;C for up to 24 hours. Tissue samples were obtained at four moments of preservation for histological examination by hematoxylin and eosin staining: T0 = beginning of preservation, T12 = 12 hours, T18 = 18 hours and T24 = 24 hours. Will be analyzed vacuolation, hepatic apoptosis by optical microscopy and parenchymal.<br><br>RESULTS: The results showed a progressive increase in hepatic injury in both groups and showed that NAC was effective at T0. The parenchyma preservation was better in the NAC group and no difference when vacuolization of the cells.<br><br>CONCLUSION: Hypothermic preservation, over time, causes changes in the hepatic parenchyma with increased apoptosis, loss of architecture, vacuolization, culminating in severe injury. The administration of N-acetylcysteine protects against preservation liver injury.}, }
@article {pmid25351152, year = {2014}, author = {Amorim, EM and Damous, LL and Durando, MC and Saraiva, MV and Koike, MK and Montero, EF}, title = {N-acetylcysteine improves morphologic and functional aspects of ovarian grafts in rats.}, journal = {Acta cirurgica brasileira}, volume = {29 Suppl 3}, number = {}, pages = {22-27}, doi = {10.1590/s0102-86502014001700005}, pmid = {25351152}, issn = {1678-2674}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Estradiol/blood ; Estrous Cycle/drug effects ; Female ; Models, Animal ; Ovarian Follicle/drug effects ; Ovary/anatomy &amp; histology/drug effects/*transplantation ; Random Allocation ; Rats, Wistar ; Time Factors ; Transplants/*drug effects/physiology ; }, abstract = {PURPOSE: To evaluate morphological and functional aspects of the ovarian graft in transplanted rats treated with NAC.<br><br>METHODS: Female Wistar rats, virgin, 3 to 4 months old, weighing 200-250 grams were used in experiments. The rats have been kept in proper sanitary conditions, receiving food and water ad libitum. Five groups (n=10, each) were constituted: 4 groups treated subcutaneously with NAC, at doses of 150, 300, 600 and 1200 mg/kg (NAC150, NAC300, NAC600 and NAC1200, respectively), one hour of before the ovarian transplantation and control group (GTx) - treated with physiological solution and submitted to ovarian transplantation. The rats were anesthetized and submitted to autologous left ovarian transplantation, without anastomosis in retroperitoneum, and contralateral oophorectomy. During follow-up of 4 or 15 days, the estrous cycle was evaluated by vaginal smears to determine cycle regularity. At the end of 4th or 15th days, rats were re-anesthetized and blood and graft were obtained to estradiol analysis and morphological assessment. Data were analysed by One Way Analysis of Variance (ANOVA) or ANOVA on ranks complemented by Student-Newman-Keuls test.<br><br>RESULTS: At 4th day, viable follicles in the graft did not altered by NAC treatments. The NAC300 and NAC600 groups showed increasing in follicle atresia (p=0.012) compared to GTx and NAC1200 group. At 15th day, 50% of GTx, NAC150, and NAC300 rats showed regular oestrous cycle; 83% of NAC600 and 100% of NAC1200 rats returned to regular cycle. NAC1200 group showed increasing in primordial follicle compared to GTx, NAC150 or NAC300 (p=0.011). NAC did not interfere in estradiol levels after 4 or 15 days of transplantation.<br><br>CONCLUSION: In autologous ovarian transplantation, high dose of NAC promotes graft viability with recovery of estrous cycle.}, }
@article {pmid25351115, year = {2015}, author = {Park, JW and Min, KJ and Kim, DE and Kwon, TK}, title = {Withaferin A induces apoptosis through the generation of thiol oxidation in human head and neck cancer cells.}, journal = {International journal of molecular medicine}, volume = {35}, number = {1}, pages = {247-252}, doi = {10.3892/ijmm.2014.1983}, pmid = {25351115}, issn = {1791-244X}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cyclooxygenase 2/genetics/metabolism ; Gene Expression ; Head and Neck Neoplasms/genetics/*metabolism ; Humans ; Oxidation-Reduction/*drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sulfhydryl Compounds/*metabolism ; Withanolides/*pharmacology ; }, abstract = {Withaferin A is a steroidal lactone purified from the Indian medicinal plant, Withania somnifera. Withaferin A has been shown to inhibit the proliferation, metastasis, invasion and angiogenesis of cancer cells. In the present study, we investigated whether withaferin A induces apoptosis in the human head and neck cancer cells, AMC-HN4. Withaferin A markedly increased the sub-G1 cell population and the cleavage of poly(ADP-ribose) polymerase (PARP), which are markers of apoptosis. Pan-caspase inhibitor, z-VAD-fmk (z-VAD), markedly inhibited the withaferin A-induced apoptosis. However, the withaferin A-induced increase in the expression of COX-2 was not affected by treatment with z-VAD. Furthermore, withaferin A upregulated cyclooxygenase-2 (COX-2) expression. The COX-2 inhibitor, NS-398, reduced the withaferin A-induced production of prostaglandin E2. However, treatment with NS-398 did not affect the sub-G1 population and the cleavage of PARP. In addition, the withaferin A-induced apoptosis was independent of reactive oxygen species production. Thiol donors [N-acetylcysteine (NAC) and dithiothreitol (DTT)] reversed withaferin A-induced apoptosis. Therefore, our data suggest that withaferin A induces apoptosis through the mechanism of thiol oxidation in head and neck carcinoma cells.}, }
@article {pmid25350110, year = {2014}, author = {Choi, BY and Kim, JH and Kim, HJ and Lee, BE and Kim, IY and Sohn, M and Suh, SW}, title = {EAAC1 gene deletion increases neuronal death and blood brain barrier disruption after transient cerebral ischemia in female mice.}, journal = {International journal of molecular sciences}, volume = {15}, number = {11}, pages = {19444-19457}, pmid = {25350110}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood-Brain Barrier/drug effects/*metabolism/pathology ; Cell Death/drug effects/genetics ; Cysteine/metabolism ; Disease Models, Animal ; Excitatory Amino Acid Transporter 3/*genetics/metabolism ; Female ; *Gene Deletion ; Glutathione/metabolism ; Ischemic Attack, Transient/*genetics/*metabolism ; Mice ; Mice, Knockout ; Neurons/drug effects/*metabolism/pathology ; }, abstract = {EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1-/- female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood-brain barrier (BBB) disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1-/- female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under ischemic conditions.}, }
@article {pmid25349781, year = {2014}, author = {Thayyullathil, F and Rahman, A and Pallichankandy, S and Patel, M and Galadari, S}, title = {ROS-dependent prostate apoptosis response-4 (Par-4) up-regulation and ceramide generation are the prime signaling events associated with curcumin-induced autophagic cell death in human malignant glioma.}, journal = {FEBS open bio}, volume = {4}, number = {}, pages = {763-776}, pmid = {25349781}, issn = {2211-5463}, abstract = {Malignant gliomas are extremely resistant to therapies that induce apoptosis, but are less resistant to therapies that induce autophagy. Therefore, drugs targeting autophagy are promising in the management of malignant gliomas. In this study, we investigated the anti-glioma potential of curcumin in vitro, and further examined the molecular mechanisms of curcumin-induced cell death in human malignant glioma. Here, we provide evidence that curcumin is cytotoxic against human malignant glioma cell lines, and the mechanism of cell death caused by curcumin is associated with features of autophagy. Curcumin suppresses the growth of human malignant glioma cells via ROS-dependent prostate apoptosis response-4 (Par-4) induction and ceramide generation. Extracellular supplementation of antioxidants such as glutathione and N-acetylcysteine to glioma cells abrogated the Par-4 induction, ceramide generation, and in turn, prevented curcumin-induced autophagic cell death. Moreover, tumor cells transfected with Par-4 gene sensitized the curcumin-induced autophagic cell death. Overall, this study describes a novel signaling pathway by which curcumin induces ROS-dependent Par-4 activation and ceramide generation, leading to autophagic cell death in human malignant glioma cells.}, }
@article {pmid25348332, year = {2014}, author = {Topal, AE and Akkoc, H and Kelle, I and Yilmaz, S and Topal, D and Akkus, M}, title = {Impact of N-acetylcysteine and etodolac treatment on systolic and diastolic function in a rat model of myocardial steatosis induced by high-fat-diet.}, journal = {Endocrine, metabolic &amp; immune disorders drug targets}, volume = {14}, number = {4}, pages = {313-319}, doi = {10.2174/1871530314666141028144702}, pmid = {25348332}, issn = {2212-3873}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cardiomyopathies/*physiopathology ; Diastole/*drug effects/physiology ; Diet, High-Fat ; Disease Models, Animal ; Etodolac/*pharmacology ; Lipid Metabolism Disorders/*physiopathology ; Male ; Rats ; Rats, Sprague-Dawley ; Systole/*drug effects/physiology ; }, abstract = {OBJECTIVES: Obesity is a worldwide problem, leading to cardiomyopathy. Oxidative stress and inflammation have been reported to play significant roles in developing obesity cardiomyopathy. N-acetylcysteine is a glutathione prodrug that preserves liver against steatosis via constraining the production of reactive oxygen species. Etodolac is a nonsteroidal anti-inflammatory drug which has been demonstrated to protect liver against fibrosis. The aim of the present study was to evaluate and compare the effects of N-acetylcysteine and etodolac on impaired cardiac functions due to high-fat-diet (HFD) induced myocardial steatosis in rats.<br><br>MATERIAL AND METHODS: Thirty-two male Sprague-Dawley rats were randomly divided into four groups. Control group was maintained on standard-rat-basic-diet (SD) for 20 weeks, while HFD was given to three study groups for 20 weeks. Then N-acetylcysteine was given to one of the study groups (HFD+NAC), and etodolac to another group (HFD+ETD) as a supplement for 4 weeks while all groups were continued on SD. At the end of the study periods, hearts were examined by Langendorff technique and rat livers were evaluated histologically.<br><br>RESULTS: HFD and HFD+ETD groups presented with significantly higher steatosis and fibrosis in liver compared to other groups. HFD+NAC preserved diastolic functions. Also HFD+NAC and HFD+ETD groups had significantly better systolic funtions than HFD group.<br><br>CONCLUSIONS: Obesity is associated with diastolic dysfunction rather than systolic dysfunction. NAC may protect the heart against diastolic dysfunction due to obesity. NAC and etodolac treatment improve systolic function, even in the absence of systolic dysfunction.}, }
@article {pmid25348324, year = {2014}, author = {Korou, LM and Agrogiannis, G and Koros, C and Kitraki, E and Vlachos, IS and Tzanetakou, I and Karatzas, T and Pergialiotis, V and Dimitroulis, D and Perrea, DN}, title = {Impact of N-acetylcysteine and sesame oil on lipid metabolism and hypothalamic-pituitary-adrenal axis homeostasis in middle-aged hypercholesterolemic mice.}, journal = {Scientific reports}, volume = {4}, number = {}, pages = {6806}, pmid = {25348324}, issn = {2045-2322}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/administration &amp; dosage ; Cardiovascular System/drug effects/*metabolism/pathology ; Diet, High-Fat ; Homeostasis/drug effects ; Hyperlipidemias/*drug therapy/*metabolism/pathology ; Hypothalamo-Hypophyseal System/drug effects/metabolism/pathology ; Lipid Metabolism/drug effects ; Mice ; Receptors, Glucocorticoid/*metabolism ; Sesame Oil/administration &amp; dosage ; }, abstract = {Hyperlipidemia and stress are important factors affecting cardiovascular health in middle-aged individuals. We investigated the effects of N-acetylcysteine (NAC) and sesame oil on the lipidemic status, liver architecture and the hypothalamic-pituitary-adrenal (HPA) axis of middle-aged mice fed a cholesterol-enriched diet. We randomized 36 middle-aged C57bl/6 mice into 6 groups: a control group, a cholesterol/cholic acid diet group, a cholesterol/cholic acid diet group with NAC supplementation, a cholesterol/cholic acid diet enriched with 10% sesame oil and two groups receiving a control diet enriched with NAC or sesame oil. NAC administration prevented the onset of the disturbed lipid profile, exhibiting decreased lipid peroxidation and alkaline phosphatase (ALP) levels, restored nitric oxide bioavailability and reduced hepatic damage, compared to non-supplemented groups. High-cholesterol feeding resulted in increased hypothalamic glucocorticoid receptors (GR) levels, while NAC supplementation prevented this effect. NAC supplementation presented significant antioxidant capacity by means of preventing serum lipid status alterations, hepatic damage, and HPA axis disturbance due to high-cholesterol feeding in middle-aged mice. These findings suggest a beneficial preventive action of plant-derived antioxidants, such as NAC, on lipid metabolism and on the HPA axis.}, }
@article {pmid25344109, year = {2014}, author = {Xin, F and Jiang, L and Liu, X and Geng, C and Wang, W and Zhong, L and Yang, G and Chen, M}, title = {Bisphenol A induces oxidative stress-associated DNA damage in INS-1 cells.}, journal = {Mutation research. Genetic toxicology and environmental mutagenesis}, volume = {769}, number = {}, pages = {29-33}, doi = {10.1016/j.mrgentox.2014.04.019}, pmid = {25344109}, issn = {1879-3592}, mesh = {Animals ; Benzhydryl Compounds/*toxicity ; Blotting, Western ; Comet Assay ; DNA Damage/*drug effects ; Free Radical Scavengers/*toxicity ; Glutathione/metabolism ; Insulinoma/drug therapy/genetics/*pathology ; Oxidative Stress/*drug effects ; Pancreatic Neoplasms/drug therapy/genetics/*pathology ; Phenols/*toxicity ; Rats ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, abstract = {Bisphenol A (BPA), an endocrine disruptor, is widely used to manufacture polycarbonate plastic and epoxy resins. Many studies have demonstrated that BPA can play a role in reproductive toxicity and affect the normal metabolic function. Recent research has shown that BPA can influence the function of pancreatic islets. In this study, our aim is to assess the DNA damage induced by BPA and to clarify the mechanism, by use of rat insulinoma INS-1 cells. INS-1 cells were exposed to different doses of BPA (0, 25, 50, 100 μM). We conducted the single-cell gel electrophoresis (SCGE) assay to measure DNA damage, and studied proteins such as p53 and p-Chk2 (T68) by Western blotting, in order to verify the (geno)toxicity of BPA. Moreover, we examined intracellular reactive oxygen species (ROS) and glutathione (GSH) to discuss the possible mechanism of DNA damage. The results show that BPA caused an increased in DNA strand-breaks along with greater DNA migration from the nucleus into the comet tail. The expression of DNA damage-associated proteins (p53 and p-Chk2 (T68)) was significantly increased. The exposure to various doses of BPA caused a significant increase in intracellular ROS and a significant reduction in the level of GSH. N-Acetyl cysteine, an inhibitor of intracellular ROS formation, can significantly reduce the generation of intracellular reactive oxygen.}, }
@article {pmid25339490, year = {2014}, author = {Dinicola, S and De Grazia, S and Carlomagno, G and Pintucci, JP}, title = {N-acetylcysteine as powerful molecule to destroy bacterial biofilms. A systematic review.}, journal = {European review for medical and pharmacological sciences}, volume = {18}, number = {19}, pages = {2942-2948}, pmid = {25339490}, issn = {2284-0729}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Bacterial Infections/diagnosis/drug therapy ; Biofilms/*drug effects/*growth &amp; development ; Clinical Trials as Topic/methods ; Humans ; }, abstract = {OBJECTIVE: Biofilms are microbial communities consisting of bacteria, extremely capable to self-reproduce on biological surfaces, causing infections. Frequently, these biofilms are resistant to classical antibacterial treatments and host immune response. Thus, new adjuvant molecules are mandatory in clinical practice. N-acetylcysteine (NAC), a precursor to the antioxidant glutathione, has been investigated for its effectiveness both in inhibiting biofilm formation and in destroying developed biofilms. The aim of our study was to conduct a systematic literature review of clinical trials involving NAC as adjuvant treatment to eradicate pre-formed mature biofilms and to inhibit new biofilm production.<br><br>MATERIALS AND METHODS: A careful analysis of the Medline was conducted and eight studies were selected according to the following criteria: site of infection, kind of bacteria, design of the research, dose of the treatment, administration, biological effects and results. We fixed an arbitrary scale of scores from 0 (lowest score) to 5 (highest score) for each criterion and a threshold value of 3.<br><br>RESULTS: The studies analyzed, with score over 3, suggested a potential role for NAC as adjuvant molecule in the treatment of bacterial biofilms, with an excellent safety and efficacy profile. NAC, in combination with different antibiotics, significantly promoted their permeability to the deepest layers of the biofilm, overcoming the problem of the resistance to the classic antibacterial therapeutic approach.<br><br>CONCLUSIONS: Overall, these results are encouraging to a more widespread clinical use of NAC, as adjuvant therapy for microbial infections followed by biofilm settle, which may occur in several body districts, such as the vaginal cavity.}, }
@article {pmid25337555, year = {2013}, author = {Bae, M and Lim, JW and Kim, H}, title = {Oxidative DNA Damage Response in Helicobacter pylori-Infected Mongolian Gerbils.}, journal = {Journal of cancer prevention}, volume = {18}, number = {3}, pages = {271-275}, pmid = {25337555}, issn = {2288-3649}, abstract = {Helicobacter pylori (H. pylori) induced DNA damage which may be related to gastric cancer development. The DNA damage response coordinates DNA repair, cell-cycle transition, and apoptosis through activation of DNA damage response molecules. The damaged DNA is repaired through non-homologous end joining (NHEJ) or homologous recombination (HR). In the present study, we investigated the changes of HR DNA repair proteins (ataxia-telangiectasia-mutated; ATM, ATM and Rad3-related; ATR), NHEJ repair proteins (Ku70/80), cell cycle regulators (Chk1, Chk2), and apoptosis marker (p53/p-p53) were determined in H. pylori-infected Mongolian gerbils. In addition, the effect of an antioxidant N-acetylcysteine (NAC) on H. pylori-induced DNA damage response was determined to assess the involvement of oxidative stress on DNA damage of the animals infected with H. pylori. One week after intragastric inoculation with H. pylori, Mongolian gerbils were fed with basal diet with or without 3% NAC for 6 weeks. After 6 week, the expression levels of DNA repair proteins (Ku70/80, ATM, ATR), cell cycle regulators (Chk1, Chk2) and apoptosis marker (p-p53/p53) were increased in gastric mucosa of Mongolian gerbils, which was suppressed by NAC treatment. In conclusion, oxidative stress mediates H. pylori-induced DNA damage response including NHEJ and HR repairing processes, cell cycle arrest and apoptosis in gastric mucosa of Mongolian gerbils.}, }
@article {pmid25336009, year = {2014}, author = {Yavuz, H and Emiroglu, M}, title = {Toxic epidermal necrolysis treated with N-acetylcysteine.}, journal = {Pediatrics international : official journal of the Japan Pediatric Society}, volume = {56}, number = {5}, pages = {e52-4}, doi = {10.1111/ped.12410}, pmid = {25336009}, issn = {1442-200X}, mesh = {Acetylcysteine/*therapeutic use ; Child ; Female ; Humans ; Stevens-Johnson Syndrome/*drug therapy ; Treatment Outcome ; }, abstract = {Adverse drug reactions are the major cause of morbidity and mortality worldwide. Cutaneous drug reaction is the most common type of adverse reaction. Toxic epidermal necrolysis (TEN) is a rare, life-threatening mucocutaneous disease, usually attributable to drugs. There is no proven therapy for TEN. The mainstay of therapy is immediate withdrawal of the culprit drug, using disease-modifying agents, and meticulous supportive care. Several disease-modifying agents have been used such as steroid, i.v. human immunoglobulin (IVIg), plasmapheresis. A 10-year-old epileptic girl was admitted with lamotrigine-induced TEN. She was unresponsive to steroid. Her condition deteriorated despite IVIg treatment. She was treated with N-acetylcysteine (NAC). To our knowledge this is the first report of a child with TEN, a potentially lethal disorder, treated with NAC. NAC may be effective for children with TEN.}, }
@article {pmid25333278, year = {2014}, author = {Liu, C and Wan, X and Ye, T and Fang, F and Chen, X and Chen, Y and Dong, Y}, title = {Matrix metalloproteinase 2 contributes to pancreatic Beta cell injury induced by oxidative stress.}, journal = {PloS one}, volume = {9}, number = {10}, pages = {e110227}, pmid = {25333278}, issn = {1932-6203}, mesh = {Animals ; Apoptosis/drug effects/genetics ; Cell Line ; Gene Expression ; Insulin/biosynthesis ; Insulin-Secreting Cells/drug effects/*metabolism ; Matrix Metalloproteinase 2/genetics/*metabolism ; Matrix Metalloproteinase Inhibitors/pharmacology ; *Oxidative Stress/genetics ; Rats ; Reactive Oxygen Species/metabolism ; Transfection ; }, abstract = {OBJECTIVE: To investigate the role of matrix metalloproteinase 2 (MMP2) in pancreatic beta cell injury induced by oxidative stress.<br><br>METHODS: Rat pancreatic beta cell line INS-1 cells were treated with advanced glycation end-products (AGE) to induce intracellular oxidative stress. Intracellular MMP2 expression and activity were determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and zymography, respectively. MMP2 expression and activity were manipulated by over-expression with recombinant MMP2 plasmids or knockdown with either MMP2 specific siRNA or inhibitors, and effects on apoptosis and insulin-secretion were measured by flow cytometry and ELISA.<br><br>RESULTS: AGE treatment induced intracellular oxidative stress in INS-1 cells, as indicated by elevated ROS levels, apoptotic cell death, and suppressed insulin secretion. This was accompanied by increased MMP2 expression and activity. However, Antioxidant N-acetylcysteine (NAC) treatment inhibited MMP2 expression and activity, and partially reversed cell apoptosis and insulin secretion dysfunction induced by AGE. Forced expression of MMP2 mimicked the effects of AGE treatment while inhibition of MMP2 either by a specific MMP2 inhibitor or MMP2 siRNA protected oxidative stress induced by AGE.<br><br>CONCLUSION: MMP2 expression and intracellular activity are increased by oxidative stress, contributing to cellular dysfunction and apoptosis in INS-1 cells after AGE challenge.}, }
@article {pmid25331497, year = {2015}, author = {Li, J and Cai, X and Xia, Q and Yao, K and Chen, J and Zhang, Y and Naranmandura, H and Liu, X and Wu, Y}, title = {Involvement of endoplasmic reticulum stress in all-trans-retinal-induced retinal pigment epithelium degeneration.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {143}, number = {1}, pages = {196-208}, doi = {10.1093/toxsci/kfu223}, pmid = {25331497}, issn = {1096-0929}, mesh = {Antioxidants/pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/genetics/metabolism ; Cell Line ; Cytoprotection ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/*drug effects/metabolism/pathology ; Endoplasmic Reticulum Stress/*drug effects/genetics ; Gene Expression Regulation ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/*drug effects/metabolism/pathology ; Signal Transduction/drug effects ; Tretinoin/*toxicity ; }, abstract = {Excess accumulation of endogenous all-trans-retinal (atRAL) contributes to degeneration of the retinal pigment epithelium (RPE) and photoreceptor cells, and plays a role in the etiologies of age-related macular degeneration (AMD) and Stargardt's disease. In this study, we reveal that human RPE cells tolerate exposure of up to 5 µM atRAL without deleterious effects, but higher concentrations are detrimental and induce cell apoptosis. atRAL treatment significantly increased production of intracellular reactive oxygen species (ROS) and up-regulated mRNA expression of Nrf2, HO-1, and γ-GCSh within RPE cells, thereby causing oxidative stress. ROS localized to mitochondria and endoplasmic reticulum (ER). ER-resident molecular chaperone BiP, a marker of ER stress, was up-regulated at the translational level, and meanwhile, the PERK-eIF2α-ATF4 signaling pathway was activated. Expression levels of ATF4, CHOP, and GADD34 in RPE cells increased in a concentration-dependent manner after incubation with atRAL. Salubrinal, a selective inhibitor of ER stress, alleviated atRAL-induced cell death. The antioxidant N-acetylcysteine (NAC) effectively blocked RPE cell loss and ER stress activation, suggesting that atRAL-induced ROS generation is responsible for RPE degeneration and is an early trigger of ER stress. Furthermore, the mitochondrial transmembrane potential was lost after atRAL exposure, and was followed by caspase-3 activation and poly (ADP-ribose) polymerase cleavage. The results demonstrate that atRAL-driven ROS overproduction-induced ER stress is involved in cellular mitochondrial dysfunction and apoptosis of RPE cells.}, }
@article {pmid25326454, year = {2014}, author = {Petrov, AM and Yakovleva, AA and Zefirov, AL}, title = {Role of membrane cholesterol in spontaneous exocytosis at frog neuromuscular synapses: reactive oxygen species-calcium interplay.}, journal = {The Journal of physiology}, volume = {592}, number = {22}, pages = {4995-5009}, pmid = {25326454}, issn = {1469-7793}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Calcium/*metabolism ; Calcium Signaling ; Capsaicin/analogs &amp; derivatives/pharmacology ; Cholesterol/*metabolism ; Cyclosporine/pharmacology ; *Exocytosis ; Neuromuscular Junction/drug effects/*metabolism/physiology ; Okadaic Acid/pharmacology ; Ranidae ; Reactive Oxygen Species/*metabolism ; Ruthenium Red/pharmacology ; Synaptic Membranes/metabolism ; TRPV Cation Channels/antagonists &amp; inhibitors ; beta-Cyclodextrins/pharmacology ; }, abstract = {Using electrophysiological and optical techniques, we studied the mechanisms by which cholesterol depletion stimulates spontaneous transmitter release by exocytosis at the frog neuromuscular junction. We found that methyl-β-cyclodextrin (MCD, 10 mM)-mediated exhaustion of cholesterol resulted in the enhancement of reactive oxygen species (ROS) production, which was prevented by the antioxidant N-acetyl cysteine (NAC) and the NADPH oxidase inhibitor apocynin. An increase in ROS levels occurred both extra- and intracellularly, and it was associated with lipid peroxidation in synaptic regions. Cholesterol depletion provoked a rise in the intracellular Ca(2+) concentration, which was diminished by NAC and transient receptor potential vanilloid (TRPV) channel blockers (ruthenium red and capsazepine). By contrast, the MCD-induced rise in [Ca(2+)]i remained unaffected if Ca(2+) release from endoplasmic stores was blocked by TMB8 (8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride). The effects of cholesterol depletion on spontaneous release and exocytosis were significantly reduced by the antioxidant, intracellular Ca(2+) chelation with BAPTA-AM and blockers of TRPV channels. Bath application of the calcineurin antagonist cyclosporine A blocked MCD-induced enhancement of spontaneous release/exocytosis, whereas okadaic acid, an inhibitor of phosphatases PP1 and PP2A, had no effect. Thus, our findings indicate that enhancement of spontaneous exocytosis induced by cholesterol depletion may depend on ROS generation, leading to an influx of Ca(2+) via TRPV channels and, subsequently, activation of calcineurin.}, }
@article {pmid25323509, year = {2015}, author = {Khan, MI and Iqbal, Z and Khan, A}, title = {Simultaneous determination of ascorbic acid, aminothiols, and methionine in biological matrices using ion-pairing RP-HPLC coupled with electrochemical detector.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {1208}, number = {}, pages = {201-220}, doi = {10.1007/978-1-4939-1441-8_15}, pmid = {25323509}, issn = {1940-6029}, mesh = {Ascorbic Acid/*blood ; Calibration ; Chromatography, High Pressure Liquid/*methods ; Chromatography, Reverse-Phase/*methods ; Electrochemical Techniques/*instrumentation ; Humans ; Methionine/*blood ; Reference Standards ; Reproducibility of Results ; Solutions ; Sulfhydryl Compounds/*blood ; }, abstract = {A novel highly sensitive ion-pairing reversed-phase high performance liquid-chromatography/electrochemical detection method for simultaneous determination of L -ascorbic acid, aminothiols, and methionine in biological matrices is presented. Reduced forms of the analytes are extracted from sample matrices with 10% m-phosphoric acid solution(aqueous). To determine the total vitamin C, the total aminothiols, and the total methionine, samples are treated with tris(2-carboxyethyl)phosphine solution in 0.05% trifluoroacetic acid solution(aqueous) subsequent to deproteination to reduce the oxidized forms of these compounds. Various analytes are separated on a C18 (250 × 4.6 mm, 5 μm) analytical column using methanol-0.05% trifluoroacetic acid solution(aqueous) (05:95 v/v, containing 0.1 mM 1-octane sulfonic acid as the ion-pairing agent) as the isocratic mobile phase that is pumped at a flow rate of 1.5 ml/min at room temperature. The column eluents are monitored at a voltage of 0.85 V. These analytes are efficiently resolved in less than 20 min using n-acetyl cysteine as the internal standard.}, }
@article {pmid25322552, year = {2014}, author = {Meng, C and Yuan, CH and Zhang, CC and Wen, MD and Gao, YH and Ding, XY and Zhang, YY and Zhang, Z}, title = {[Ophiopogonin D protects cardiomyocytes against doxorubicin-induced injury through suppressing endoplasmic reticulum stress].}, journal = {Yao xue xue bao = Acta pharmaceutica Sinica}, volume = {49}, number = {8}, pages = {1117-1123}, pmid = {25322552}, issn = {0513-4870}, mesh = {Acetylcysteine ; Activating Transcription Factor 6/metabolism ; Animals ; Antioxidants ; Cell Line ; Cell Survival ; Doxorubicin/*adverse effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Heat-Shock Proteins/metabolism ; Mice ; Mitochondria/metabolism ; Myocytes, Cardiac/*drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Saponins/*pharmacology ; Spirostans/*pharmacology ; Transcription Factor CHOP/metabolism ; Up-Regulation ; }, abstract = {This study aimed to examine whether ophiopogonin D (OP-D) is capable of protecting cardiomyocytes against DOX-induced injury and the mechanisms involved. H9c2 cells were cultured. MTT assay was used to evaluate cell viability and toxicity. Mito-tracker as fluorescence probe was used to measure ROS content raised from mitochondria. The mRNA and protein expression of ATF6alpha, GRP78 and CHOP were analyzed using real-time PCR and Western blotting, respectively. The results showed that a significant endoplasmic reticulum stress (ERS) was induced upon exposure of H9c2 cells to DOX as indicated by the increase in the expression of ERS related proteins, which was paralleled with the accumulation of reactive oxygen species (ROS) and decrease in the viability of H9c2 cells. Whereas, DOX-induced ROS accumulation and up-regulation of ERS related proteins were partially abolished by pretreatment with OP-D. Consequently, a DOX-induced ERS was mitigated by application of OP-D. Similarly, DOX-induced decrease in cell viability was partially attenuated by either inhibiting CHOP or pretreatment with N-acetylcysteine (NAC), an antioxidant. Moreover, cardiac ultrastructural abnormalities seen in mouse receiving DOX injections were obviously ameliorated by pretreatment of OP-D. Taken together, the present study proved that OP-D protects cardiomyocytes against DOX-induced injury, at least in part, through reducing ROS accumulation and alleviating ERS.}, }
@article {pmid25316977, year = {2014}, author = {Agarwal, A and Robo, R and Jain, N and Gutch, M and Consil, S and Kumar, S}, title = {Oxidative stress determined through the levels of antioxidant enzymes and the effect of N-acetylcysteine in aluminum phosphide poisoning.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {18}, number = {10}, pages = {666-671}, pmid = {25316977}, issn = {0972-5229}, abstract = {INTRODUCTION: The primary objective of this study was to determine the serum level of antioxidant enzymes and to correlate them with outcome in patients of aluminum phosphide (ALP) poisoning and, secondly, to evaluate the effect of N-acetylcysteine (NAC) given along with supportive treatment of ALP poisoning.<br><br>DESIGN: We conducted a cohort study in patients of ALP poisoning hospitalized at a tertiary care center of North India. The treatment group and control group were enrolled during the study period of 1 year from May 2011 to April 2012.<br><br>INTERVENTIONS: Oxidative stress was evaluated in each subject by estimating the serum levels of the enzymes, viz. catalase, superoxide dismutase (SOD) and glutathione reductase (GR). The treatment group comprised of patients who were given NAC in addition to supportive treatment (magnesium sulfate and vasopressors, if required), while in the control group, only supportive treatment was instituted. The primary endpoint of the study was the survival of the patients.<br><br>MEASUREMENTS AND RESULTS: The baseline catalase (P = 0.008) and SOD (P < 0.01) levels were higher among survivors than non-survivors. Of the total patients in the study, 31 (67.4%) expired and 15 (32.6%) survived. Among those who expired, the mean duration of survival was 2.92 &#xb1; 0.40 days in the test group and 1.82 &#xb1; 0.33 days in the control group (P = 0.043).<br><br>CONCLUSIONS: This study suggests that the baseline level of catalase and SOD have reduced in ALP poisoning, but baseline GR level has not suppressed but is rather increasing with due time, and more so in the treatment group. NAC along with supportive treatment may have improved survival in ALP poisoning.}, }
@article {pmid25316973, year = {2014}, author = {Chaudhry, D and Rai, AS}, title = {N-acetyl cysteine in aluminum phosphide poisoning: Myth or hope.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {18}, number = {10}, pages = {646-647}, pmid = {25316973}, issn = {0972-5229}, }
@article {pmid25316328, year = {2015}, author = {Owens, KH and Medlicott, NJ and Zacharias, M and Whyte, IM and Buckley, NA and Reith, DM}, title = {Population pharmacokinetic-pharmacodynamic modelling to describe the effects of paracetamol and N-acetylcysteine on the international normalized ratio.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {42}, number = {1}, pages = {102-108}, doi = {10.1111/1440-1681.12327}, pmid = {25316328}, issn = {1440-1681}, mesh = {Acetaminophen/blood/*pharmacokinetics ; Acetylcysteine/blood/*pharmacokinetics ; Adolescent ; Adult ; Aged ; Analgesics, Non-Narcotic/blood/*pharmacokinetics ; Cohort Studies ; Cross-Over Studies ; Double-Blind Method ; Female ; Humans ; International Normalized Ratio/*methods ; Male ; Middle Aged ; *Models, Biological ; Prospective Studies ; Retrospective Studies ; Young Adult ; }, abstract = {Paracetamol is one of the most common pharmaceutical agents taken in self-poisonings, and can increase the prothrombin time (PT) through liver injury, and in overdose without hepatic injury by reducing functional factor VII. PT is a measure of hepatic injury used to predict and monitor hepatotoxicity, reported as the international normalized ratio (INR). The antidote for paracetamol poisoning, N-acetylcysteine (NAC), has been reported to have an effect on the PT. This analysis included patients from a retrospective case series, a prospective inception cohort of paracetamol and psychotropic (control) overdoses, and a cross-over clinical trial. A population pharmacokinetic-pharmacodynamic model describing the pharmacodynamic effects of paracetamol and NAC on the INR was developed in Phoenix NLME. The dataset included 172 patients; the median age was 22 years (range 13-71 years). A one-compartment model with first-order input and linear disposition best described paracetamol pharmacokinetics. The population mean estimate of the concentration that induced a response halfway between the baseline and maximal pharmacological effect of paracetamol was 1302 μmol/L (242), the maximum effect of paracetamol was 0.534 (202; from baseline) and the maximum effect of NAC was 0.325 (9.03; from baseline). Both paracetamol and NAC contributed a pharmacological effect to the elevation of INR. The estimated paracetamol concentration that induced a response halfway between the baseline and maximal pharmacological effect was within the range of plasma paracetamol values studied, fivefold greater than the maximum therapeutic concentration, suggesting that an elevated INR would not be expected within the therapeutic range. Simulated 24 and 48 g paracetamol overdoses with NAC administration produced INR values (50th percentile) that reached the upper limit of, or exceeded, the reference range.}, }
@article {pmid25315856, year = {2015}, author = {Rapado-Castro, M and Berk, M and Venugopal, K and Bush, AI and Dodd, S and Dean, OM}, title = {Towards stage specific treatments: effects of duration of illness on therapeutic response to adjunctive treatment with N-acetyl cysteine in schizophrenia.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {57}, number = {}, pages = {69-75}, doi = {10.1016/j.pnpbp.2014.10.002}, pmid = {25315856}, issn = {1878-4216}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Antipsychotic Agents/administration &amp; dosage/*therapeutic use ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Male ; Schizophrenia/*drug therapy ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {Schizophrenia is a chronic and often debilitating disorder in which stage of illness appears to influence course, outcome, prognosis and treatment response. Current evidence suggests roles for oxidative, neuroinflammatory, neurotrophic, apoptotic, mitochondrial and glutamatergic systems in the disorder; all targets of N-acetyl cysteine (NAC). A double blind, placebo controlled trial suggested NAC to be beneficial to those diagnosed with schizophrenia. The current manuscript aims to investigate duration of the illness as a key factor that may be modulating the response to NAC in the participants who took part in the study. A sample of 121 participants were randomised in a double fashion to 24 weeks (placebo=62; NAC=59). Clinical and functional variables were collected over the treatment period. Duration of the illness at baseline was grouped into <10 years, 10-<20 years and >20 years. Mixed Model Repeated Measures Analysis was used to explore the effect of illness duration on response to treatment with NAC. A significant interaction between duration of the illness and response to treatment with NAC was consistently found for positive symptoms and functional variables, but not for negative or general symptoms or for side effect related outcomes. The pattern of changes suggests that this mediator effect of duration of illness in response to treatment is more evident in those participants with 20 years or more of illness duration. Our results suggest a potential advantage of adjunctive NAC over placebo on functioning and positive symptoms reduction in those patients with chronic schizophrenia. This has potential for suggesting stage specific treatments.}, }
@article {pmid25310891, year = {2014}, author = {Sappal, R and MacDonald, N and Fast, M and Stevens, D and Kibenge, F and Siah, A and Kamunde, C}, title = {Interactions of copper and thermal stress on mitochondrial bioenergetics in rainbow trout, Oncorhynchus mykiss.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {157}, number = {}, pages = {10-20}, doi = {10.1016/j.aquatox.2014.09.007}, pmid = {25310891}, issn = {1879-1514}, mesh = {Animals ; Calcium/metabolism ; Cell Respiration/drug effects/physiology ; Copper/*toxicity ; Energy Metabolism/*drug effects/physiology ; *Hot Temperature ; Mitochondria/*drug effects/*physiology ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Oncorhynchus mykiss/*metabolism ; Reactive Oxygen Species ; Water Pollutants, Chemical/*toxicity ; }, abstract = {Thermal stress may influence how organisms respond to concurrent or subsequent chemical, physical and biotic stressors. To unveil the potential mechanisms via which thermal stress modulates metals-induced bioenergetic disturbances, the interacting effects of temperature and copper (Cu) were investigated in vitro. Mitochondria isolated from rainbow trout livers were exposed to a range of Cu concentrations at three temperatures (5, 15 and 25 °C) with measurement of mitochondrial complex I (mtCI)-driven respiratory flux indices and uncoupler-stimulated respiration. Additional studies assessed effects of temperature and Cu on mtCI enzyme activity, induction of mitochondrial permeability transition pore (MPTP), swelling kinetics and mitochondrial membrane potential (MMP). Maximal and basal respiration rates, as well as the proton leak, increased with temperature with the Q10 effects being higher at lower temperatures. The effect of Cu depended on the mitochondrial functional state in that the maximal respiration was monotonically inhibited by Cu exposure while low and high Cu concentrations stimulated and inhibited the basal respiration/proton leak, respectively. Importantly, temperature exacerbated the effects of Cu by lowering the concentration of the metal required for toxicity and causing loss of thermal dependence of mitochondrial respiration. Mitochondrial complex I activity was inhibited by Cu but was not affected by incubation temperature. Compared with the calcium (Ca) positive control, Cu-imposed mitochondrial swelling exhibited variable kinetics depending on the inducing conditions, and was highly temperature-sensitive. A partial reversal of the Cu-induced swelling by cyclosporine A was observed suggesting that it is in part mediated by MPTP. Interestingly, the combination of high Cu and high temperature not only completely inhibited mitochondrial swelling but also greatly increased the respiratory control ratio (RCR) relative to the controls. Copper exposure also caused marked MMP dissipation which was reversed by N-acetyl cysteine and vitamin E suggesting a role of reactive oxygen species (ROS) in this response. Taken together, Cu impairs oxidative phosphorylation in part by inhibiting the electron transport chain (ETC), stimulating proton leak, inducing MPTP and dissipating MMP, with high temperature exacerbating these effects. Thus environmental temperature rise due to natural phenomenon or global climate change may sensitize fish to Cu toxicity by exacerbating mitochondrial dysfunction.}, }
@article {pmid25310083, year = {2014}, author = {Ghani, S and Khan, N and Koriyama, C and Akiba, S and Yamamoto, M}, title = {N‑acetyl‑L‑cysteine reduces arsenite‑induced cytotoxicity through chelation in U937 monocytes and macrophages.}, journal = {Molecular medicine reports}, volume = {10}, number = {6}, pages = {2961-2966}, doi = {10.3892/mmr.2014.2612}, pmid = {25310083}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Arsenites/*pharmacology ; Humans ; Macrophages/*drug effects ; Monocytes/*drug effects ; Proto-Oncogene Proteins c-bcl-2 ; U937 Cells ; }, abstract = {In the present study, in order to clarify the preventive mechanism of N‑acetyl‑L‑cysteine (NAC) on arsenite‑induced apoptosis in U937 cells, which lack functional p53, the cytotoxicity among U937 cells [monocytes and 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑treated macrophages] receiving NAC treatment at different times post arsenite treatment was examined. TPA‑treated macrophages were more resistant to arsenite‑induced apoptosis than monocytes, which may be associated with the induction of Bcl‑2 expression. Pretreatment with 20 mM NAC prior to arsenite exposure suppressed apoptosis up to 75% in the monocytes and 100% in the macrophages. However, 6‑h NAC pretreatment and subsequent washing out of NAC from the culture medium prior to arsenite treatment did not inhibit the arsenite‑induced apoptosis. Post‑treatment by NAC up to 1 h following arsenite exposure almost completely inhibited the cytotoxic effects of arsenite in U937 monocytes and macrophages. The results of the current study indicate that the preventive mechanism of NAC on arsenite‑induced apoptosis in U937 monocytes and macrophages mainly involves chelation of arsenite in culture medium.}, }
@article {pmid25308836, year = {2014}, author = {Ganguli, A and Choudhury, D and Datta, S and Bhattacharya, S and Chakrabarti, G}, title = {Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis.}, journal = {Biochimie}, volume = {107 Pt B}, number = {}, pages = {338-349}, doi = {10.1016/j.biochi.2014.10.001}, pmid = {25308836}, issn = {1638-6183}, mesh = {Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/drug effects/physiology ; Artemisinins/administration &amp; dosage/*pharmacology ; Autophagy/*drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor/drug effects ; Cell Survival/drug effects ; Chloroquine/administration &amp; dosage/*pharmacology ; Drug Synergism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Artemisinin (ART) is a well-known anti-malarial drug, and recently it is shown prospective to selectively kill cancer cells. But low potency makes it inappropriate for use as an anticancer drug. In this study, we modulated the ART-induced autophagy to increase Potency of ART as an anticancer agent. ART reduced the cell viability and colony forming ability of non-small lung carcinoma (A549) cells and it was non-toxic against normal lung (WI38) cells. ART induced autophagy at the early stage of treatment. Pre-treatment with chloroquine (CQ) and followed by ART treatment had synergistic combination index (CI) for cell death. Inhibition of autophagy by CQ pre-treatment led to accumulation of acidic vacuoles (AVOs) which acquainted with unprocessed damage mitochondria that subsequently promoted ROS generation, and resulted releases of Cyt C in cytosol that caused caspase-3 dependent apoptosis cell death in ART-treated A549 cells. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) inhibited caspase-3 activity and rescued the cells from apoptosis. Similar effects were observed in other cancer cells SCC25 and MDA-MB-231. The appropriate manipulation of autophagy by using CQ provides a powerful strategy to increase the Potency of selective anticancer property of ART.}, }
@article {pmid25308201, year = {2015}, author = {Hodge, S and Hodge, G and Holmes, M and Jersmann, H and Reynolds, PN}, title = {Increased CD8 T-cell granzyme B in COPD is suppressed by treatment with low-dose azithromycin.}, journal = {Respirology (Carlton, Vic.)}, volume = {20}, number = {1}, pages = {95-100}, doi = {10.1111/resp.12415}, pmid = {25308201}, issn = {1440-1843}, mesh = {Adult ; Aged ; Anti-Bacterial Agents/administration &amp; dosage/pharmacokinetics ; Apoptosis/drug effects/immunology ; *Azithromycin/administration &amp; dosage/pharmacokinetics ; Biological Availability ; Bronchoalveolar Lavage/methods ; Bronchoalveolar Lavage Fluid/*immunology ; CD4-Positive T-Lymphocytes/drug effects/immunology/pathology ; *CD8-Positive T-Lymphocytes/drug effects/immunology/pathology ; Granzymes/*metabolism ; Humans ; Male ; Middle Aged ; *Pulmonary Disease, Chronic Obstructive/drug therapy/immunology/pathology ; Respiratory System/drug effects/immunology ; *T-Lymphocyte Subsets/drug effects/immunology/pathology ; Treatment Outcome ; }, abstract = {BACKGROUND AND OBJECTIVE: Corticosteroid resistance in chronic obstructive pulmonary disease (COPD) is a major challenge. We have reported increased bronchial epithelial cell apoptosis and increased airway CD8 T-cell numbers in COPD. Apoptosis can be induced via the serine protease, granzyme B. However, glucocorticosteroids fail to adequately suppress granzyme B production by CD8 T cells. We previously showed that low-dose azithromycin reduced airways inflammation in COPD subjects and we hypothesized that it would also reduce granzyme B production by CD8 T cells.<br><br>METHODS: We administered 250&#x2009;mg azithromycin daily for 5 days then twice weekly (total 12 weeks) to 11 COPD subjects (five current smokers; six ex-smokers) and assessed granzyme B in the airway (bronchoalveolar lavage), intra-epithelial compartment and peripheral blood, collected before and following administration of azithromycin. To then dissect the effects of on CD4 and CD8 T-cell subsets, we applied an in vitro assay and physiologically relevant concentrations of azithromycin (and, for comparison, n-acetyl cysteine) and stimulation of peripheral blood mononuclear cells from five healthy subjects with CD3/CD28 T-cell expander.<br><br>RESULTS: T-cell granzyme B production in both airway and intra-epithelial compartments was reduced in COPD patients following 12 weeks of azithromycin treatment, with no significant effect in blood. Both azithromycin and n-acetyl cysteine suppressed CD4 T-cell granzyme B production, but only azithromycin was effective at reducing CD8+ T-cell granzyme B production in vitro.<br><br>CONCLUSIONS: We provide further evidence for the application of low-dose azithromycin as an attractive adjunct treatment option for controlling epithelial cell apoptosis, abnormal airway repair and chronic inflammation in COPD.}, }
@article {pmid25305742, year = {2014}, author = {Torres, ME and dos Santos, AP and Gonçalves, LL and Andrade, V and Batoréu, MC and Mateus, ML}, title = {Role of N-acetylcysteine in protecting against 2,5-hexanedione neurotoxicity in a rat model: changes in urinary pyrroles levels and motor activity performance.}, journal = {Environmental toxicology and pharmacology}, volume = {38}, number = {3}, pages = {807-813}, doi = {10.1016/j.etap.2014.09.008}, pmid = {25305742}, issn = {1872-7077}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Chromatography, Liquid ; Hexanones/*administration &amp; dosage/toxicity/urine ; Male ; Motor Activity/*drug effects ; Neuroprotective Agents/*administration &amp; dosage/pharmacology ; Neurotoxins/*administration &amp; dosage/toxicity/urine ; Norleucine/urine ; Pyrroles/*urine ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry ; }, abstract = {The interference of N-acetylcysteine (NAC) on 2,5-hexanedione (2,5-HD) neurotoxicity was evaluated through behavioral assays and the analysis of urinary 2,5-HD, dimethylpyrrole norleucine (DMPN), and cysteine-pyrrole conjugate (DMPN NAC), by ESI-LC-MS/MS, in rats exposed to 2,5-HD and co-exposed to 2,5-HD and NAC. Wistar rats were treated with 4 doses of: 400mg 2,5-HD/kg bw (group I), 400mg 2,5-HD/kg bw+200mg NAC/kg bw (group II), 200mg NAC/kg bw (group III) and with saline (group IV). The results show a significant decrease (p<0.01) in urinary DMPN and free 2,5-HD, a significant increase (p<0.01) in DMPN NAC excretion, and a significant recovery (p<0.01) on motor activity in rats co-exposed to 2,5-HD+NAC, as compared with rats exposed to 2,5-HD alone. Taken together, our findings suggest that at the studied conditions NAC protects against 2,5-HD neurotoxicity and DMPN may be proposed as a new sensitive and specific biomarker of 2,5-HD neurotoxicity in animals treated with a toxic amount of 2,5-hexanedione.}, }
@article {pmid25305669, year = {2014}, author = {Machado, JT and Iborra, RT and Fusco, FB and Castilho, G and Pinto, RS and Machado-Lima, A and Nakandakare, ER and Seguro, AC and Shimizu, MH and Catanozi, S and Passarelli, M}, title = {N-acetylcysteine prevents endoplasmic reticulum stress elicited in macrophages by serum albumin drawn from chronic kidney disease rats and selectively affects lipid transporters, ABCA-1 and ABCG-1.}, journal = {Atherosclerosis}, volume = {237}, number = {1}, pages = {343-352}, doi = {10.1016/j.atherosclerosis.2014.09.020}, pmid = {25305669}, issn = {1879-1484}, mesh = {ATP Binding Cassette Transporter 1/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 1 ; ATP-Binding Cassette Transporters/metabolism ; Acetylcysteine/*metabolism ; Albumins/metabolism ; Animals ; Apolipoprotein A-I/*metabolism ; Biological Transport ; Body Weight ; Cholesterol/metabolism ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress ; Kidney Failure, Chronic/*metabolism ; Lipid Peroxidation ; Lipids/*chemistry ; Lipoproteins/metabolism ; Macrophages/*drug effects/metabolism ; Male ; Mice ; Nephrectomy ; Oxygen/chemistry ; Rats ; Rats, Wistar ; Serum Albumin/metabolism ; }, abstract = {In chronic kidney disease (CKD) nontraditional risk factors, such as oxidative stress and advanced glycation end products (AGE) contribute to cardiovascular disease. Particularly, disturbances in reverse cholesterol transport favor the development of atherosclerosis. We analyzed the influence of N-acetylcysteine (NAC) in CKD rats on plasma concentration of lipid peroxides (TBARS) and AGE and on the impact of serum albumin in the development of macrophage endoplasmic reticulum stress (ERS) and cholesterol efflux, namely apo A-I and HDL2-mediated cholesterol removal and ABCA-1 and ABCG-1 protein level. CKD was induced by 5/6 nephrectomy in 2-month old male Wistar rats. Controls (Sham) were false operated. Animals were treated or not with NAC (600 mg/L of water). After 60 days serum albumin was isolated by FPLC and purified by alcoholic extraction. J774 macrophages were incubated with serum albumin (1 mg/mL; 18 h) from all groups, and the expression of ERS markers (protein disulfide isomerase - PDI, Grp78 and Grp94), ABCA-1 and ABCG-1 determined by immunoblot. HDL2 or apo A-I were used for cholesterol efflux assays. Protein and lipid composition of total HDL from Sham and CKD was determined and these particles tested on their abilities to accept cell cholesterol. Comparisons were done by one-way ANOVA and Newman Keuls post test. After 60 days of CKD, body weight was 10% lower in CKD compared to Sham (p < 0.01). This was prevented by NAC. Urea, creatinine, total cholesterol (TC), triglycerides (TG) (mg/dL), proteinuria (mg/24 h) (Sham, n = 31; Sham + NAC, n = 20; CKD, n = 74; CKD + NAC, n = 32), total AGE and pentosidine (n = 8; fluorescence arbitrary unit) and TBARS (n = 7; nmoL/mL) were higher in CKD (122 ± 8; 0.9 ± 0.07; 151 ± 6; 83 ± 4; 46 ± 2.5; 32,620 ± 673; 16,700 ± 1,370; 6.6 ± 0.5, respectively) and in CKD + NAC (91.4 ± 5; 0.6 ± 0.02; 126 ± 7.5; 73 ± 6; 51 ± 3.5; 24,720 ± 1,114; 10,080 ± 748; 4.5 ± 0.5, respectively) in comparison to Sham (41 ± 0.9; 0.4 ± 0.03; 76 ± 2.7; 51.5 ± 3; 14 ± 0.9; 21,750 ± 960; 5,314 ± 129; 2.0 ± 0.2, respectively; p < 0.001) and Sham + NAC (40 ± 0.9; 0.3 ± 0.02; 76 ± 2.6; 68 ± 4; 18.4 ± 1.5; 20,040 ± 700; 5,050 ± 267; 1.8 ± 0.2, respectively; p < 0.001). TC, urea, creatinine, total AGE, pentosidine and TBARS were respectively, 17%, 25%, 33%, 24%, 40% and 28% (p < 0.01) lower in CKD + NAC, than in CKD. Glycemia was higher in Sham + NAC (107 ± 4.6) and CKD + NAC (107 ± 2.6) than in Sham (96 ± 1.8; p < 0.05) and CKD (98 ± 1.6; p < 0.01), respectively. In macrophages (n = 6), CKD albumin increased PDI (3 and 6 times, p < 0.01) and Grp94 (66% and 80%, p < 0.01) in comparison to Sham and CKD + NAC-albumin treated cells, respectively. ABCA-1 expression was lower (87% and 70%, p < 0.001) in macrophage treated with Sham + NAC and CKD albumin respectively in comparison to Sham albumin; ABCG-1 was higher (4 and 7 times, p < 0.001) in macrophages treated with Sham + NAC and CKD + NAC albumin, respectively in comparison to Sham and CKD albumin. Apo A-I mediated cholesterol efflux was lower (59% and 70%, p < 0.0001) in macrophage treated with Sham + NAC and CKD albumin respectively in comparison to Sham albumin, however, the HDL2 mediated cholesterol efflux was higher (54% and 25%, p < 0.0001) in macrophage treated with Sham + NAC albumin, in comparison to Sham and CKD + NAC albumin, respectively. CKD-HDL was enriched in total protein and lipids compared to Sham-HDL but preserved its capacity to remove cholesterol from macrophages. NAC reduces plasma lipid peroxidation and AGE and abrogates ERS induced by CKD-albumin. Despite diminishing ABCA-1, NAC increases ABCG-1 that counteracts the reduction in apo A-I-mediated cholesterol efflux. NAC may contribute to attenuate the deleterious effects of CKD-albumin on lipid accumulation in macrophages helping to prevent atherogenesis in CKD.}, }
@article {pmid25302047, year = {2014}, author = {Xu, B and Wang, W and Guo, H and Sun, Z and Wei, Z and Zhang, X and Liu, Z and Tischfield, JA and Gong, Y and Shao, C}, title = {Oxidative stress preferentially induces a subtype of micronuclei and mediates the genomic instability caused by p53 dysfunction.}, journal = {Mutation research}, volume = {770}, number = {}, pages = {1-8}, pmid = {25302047}, issn = {1873-135X}, support = {R01 ES011633/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; DNA Damage/drug effects ; Genomic Instability/drug effects/*genetics ; HEK293 Cells ; Histones/genetics/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; *Micronuclei, Chromosome-Defective/drug effects ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/*physiology ; }, abstract = {Reactive oxygen species (ROS) are known to cause many types of DNA lesions that could be converted into cancer-promoting genetic alterations. Evidence showed that tumor suppressor p53 plays an important role in regulating the generation of cellular ROS, either by reducing oxidative stress under physiological and mildly stressed conditions, or by promoting oxidative stress under highly stressed conditions. In this report we characterized the effect of oxidative stress on the induction of micronuclei, especially the subclass marked by pan-staining of γ-H2AX or MN-γ-H2AX (+). We found that MN-γ-H2AX (+) were more responsive to hydrogen peroxide (H2O2) than the MN-γ-H2AX (−). In human and mouse cells that are deficient in p53, the frequency of MN-γ-H2AX (+) is significantly elevated, but can be attenuated by antioxidant N-acetylcysteine (NAC). Depletion of p53-regulated antioxidant gene SESN1 by RNA interference also resulted in an elevation of MN-γ-H2AX (+). Furthermore, we found that in cells that were depleted of p400 by RNAi, and therefore were experiencing increased ROS, the frequency of MN-γ-H2AX (+), but not that of MN-γ-H2AX (−), was significantly induced. We further demonstrated that the induction of MN-γ-H2AX (+) by replication stress can also be attenuated by NAC, and that H2O2 also leads to increased phosphorylation of Chk1 and Rad17 that mimics replication stress, suggesting that replication stress and oxidative stress are intertwined and may reinforce each other in driving genomic instability. Our findings illustrate the importance of p53-regulated redox level in the maintenance of genomic stability.}, }
@article {pmid25299479, year = {2014}, author = {Fuccelli, R and Sepporta, MV and Rosignoli, P and Morozzi, G and Servili, M and Fabiani, R}, title = {Preventive activity of olive oil phenolic compounds on alkene epoxides induced oxidative DNA damage on human peripheral blood mononuclear cells.}, journal = {Nutrition and cancer}, volume = {66}, number = {8}, pages = {1322-1330}, doi = {10.1080/01635581.2014.956251}, pmid = {25299479}, issn = {1532-7914}, mesh = {Acetylcysteine/metabolism ; Butadienes/toxicity ; Catalase/metabolism ; Comet Assay ; DNA Damage/*drug effects ; DNA-Formamidopyrimidine Glycosylase/metabolism ; Epoxy Compounds/toxicity ; Humans ; Leukocytes, Mononuclear/*drug effects ; Olive Oil ; Oxidative Stress/drug effects ; Phenols/analysis/*pharmacology ; Plant Oils/*chemistry ; }, abstract = {The aim of this study was to investigate the ability of epoxides of styrene (styrene-7,8-oxide; SO) and 1,3-butadiene (3,4-epoxy-1-butene; 1,2:3,4:-diepoxybutane) to cause oxidative stress and oxidative DNA damage on human peripheral blood mononuclear cells (PBMCs) and whether a complex mixture of olive oil phenols (OOPE) could prevent these effects. The DNA damage was measured by the single-cell gel electrophoresis (SCGE; comet assay). We found that the DNA damage induced by alkene epoxides could be prevented by N-acetyl-cysteine (10 mM) and catalase (100 U/ml). Alkene epoxides caused a significant (P < 0.05) increase of both peroxide concentration in extra- and intracellular environment and formamidopyrimidine DNA glycosylase (FPG)- and Endonuclease III (ENDO III)-sensitive sites in PBMCs, demonstrating the presence of oxidized bases. OOPE (1 μg of total phenols/ml) was able to prevent the alkene epoxide induced DNA damage both after 2 and 24 h of incubation. In addition, OOPE completely inhibited the SO-induced intracellular peroxide accumulation in PBMCs and prevented the oxidative DNA damage induced by SO, as evidenced by the disappearance of both FPG- and ENDO III-sensitive sites. This is the first study demonstrating the ability of OOPE to prevent the DNA damage induced by alkene epoxides providing additional information about the chemopreventive properties of olive oil.}, }
@article {pmid25298958, year = {2014}, author = {Emami, MH and Zobeiri, M and Rahimi, H and Arjomandi, F and Daghagzadeh, H and Adibi, P and Hashemi, J}, title = {N-acetyl cysteine as an adjunct to standard anti-Helicobacter pylori eradication regimen in patients with dyspepsia: A prospective randomized, open-label trial.}, journal = {Advanced biomedical research}, volume = {3}, number = {}, pages = {189}, pmid = {25298958}, issn = {2277-9175}, abstract = {BACKGROUND: Increasing antibiotic resistance of Helicobacter pylori (H. pylori) which is associated with diseases of the upper gastrointestinal tract, has made alternative treatments necessary. This study compares the efficacy of adding N-acetyl cysteine (NAC) to standard regimen for H. pylori eradication.<br><br>MATERIALS AND METHODS: We conducted a randomized, open-label trial, comparing the efficacy of 14 days of quadruple therapy with Amoxicillin, Bismuth citrate, Omeprazole, Clarithromycin (group A) versus 14 days of above regimen plus NAC (group B) in adult patients with dyspepsia. Primary objective was H. pylori eradication. Compliance and side effects were determined by questionnaires. Our analysis was by intention-to-treat (ITT) and per-protocol. This study is registered with www.IRCT.ir, number: IRCT201201078634N1.<br><br>RESULT: A total of 121 participants aged 21-76 years with a mean age of 44.5 &#xb1; 14.1, and 52.9% female, were randomly allocated a treatment: 60 with 14-day standard therapy and 61 with 14-day standard therapy with NAC. The eradication rate in groups A and B with ITT analyses was 49/60 (81.7%; 95% [confidence intervals] CI = 71.6-91.8%) and 50/61 (82%; 95% CI = 72-91.9%), respectively (P = 0.96). In per-protocol analysis, the rate of H. pylori eradication in groups A and B was 45/54 (83.3%; 95% CI = 73.1-93.6%) and 45/53 (84.9%; 95% CI = 74.9-94.9%), respectively (P = 0.82). Minor well tolerated side effects were reported in 15 (34.9%) and 21 (35.6%) patients of groups A and B, respectively, and only one therapy cessation in group A was created.<br><br>CONCLUSION: Standard 14-day triple-drug therapy with NAC is not preferable to standard drug regimens for H. pylori infection.}, }
@article {pmid25295681, year = {2015}, author = {Dean, OM and Turner, A and Malhi, GS and Ng, C and Cotton, SM and Dodd, S and Sarris, J and Samuni, Y and Tanious, M and Dowling, N and Waterdrinker, A and Smith, D and Berk, M}, title = {Design and rationale of a 16-week adjunctive randomized placebo-controlled trial of mitochondrial agents for the treatment of bipolar depression.}, journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)}, volume = {37}, number = {1}, pages = {3-12}, doi = {10.1590/1516-4446-2013-1341}, pmid = {25295681}, issn = {1809-452X}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antidepressive Agents/therapeutic use ; Antioxidants/therapeutic use ; Bipolar Disorder/*therapy ; Combined Modality Therapy/methods ; Depressive Disorder/*therapy ; *Dietary Supplements ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Mitochondria/drug effects ; Mitochondrial Diseases/*therapy ; Placebos/therapeutic use ; Psychiatric Status Rating Scales ; Statistics, Nonparametric ; Time Factors ; Treatment Outcome ; Ubiquinone/analogs &amp; derivatives/therapeutic use ; Vitamin K 3/therapeutic use ; Vitamins/therapeutic use ; }, abstract = {OBJECTIVE: Bipolar disorder places a significant burden on individuals, caregivers and family, and the broader community. Current treatments are believed to be more effective against manic symptoms, leaving a shortfall in recovery during the depressive phase of the illness. The current study draws on recent evidence suggesting that, in addition to increased oxidative load, alterations in mitochondrial function occur in bipolar disorder.<br><br>METHODS: This 16-week study aims to explore the potential benefits of N-acetylcysteine (NAC) alone or in combination (CT) with selected nutraceuticals believed to enhance mitochondrial function. The study includes adults diagnosed with bipolar disorder currently experiencing an episode of depression. Participants are asked to take NAC, CT, or placebo in addition to any usual treatments. A post-discontinuation visit is conducted 4 weeks following the treatment phase.<br><br>RESULTS: The primary outcome of the study will be mean change on the Montgomery-Asberg Depression Rating Scale. Secondary outcomes include functioning, substance use, mania ratings, and quality of life. Blood samples will be collected at baseline and week 16 to explore biochemical alterations following treatment.<br><br>CONCLUSION: This study may provide a novel adjunctive treatment for bipolar depression. Analysis of biological samples may assist in understanding the therapeutic benefits and the underlying etiology of bipolar depression.<br><br>TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12612000830897.}, }
@article {pmid25289774, year = {2014}, author = {Duan, Y and Ke, J and Zhang, H and He, Y and Sun, G and Sun, X}, title = {Autophagic cell death of human hepatoma G2 cells mediated by procyanidins from Castanea mollissima Bl. Shell-induced reactive oxygen species generation.}, journal = {Chemico-biological interactions}, volume = {224}, number = {}, pages = {13-23}, doi = {10.1016/j.cbi.2014.09.021}, pmid = {25289774}, issn = {1872-7786}, mesh = {Aesculus/*chemistry ; Antineoplastic Agents, Phytogenic/chemistry/isolation &amp; purification/*pharmacology ; Autophagy/*drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Hep G2 Cells/*metabolism/*pathology ; Humans ; Proanthocyanidins/chemistry/isolation &amp; purification/*pharmacology ; Reactive Oxygen Species/*metabolism ; Structure-Activity Relationship ; }, abstract = {The autophagy of human hepatoma G2 (HepG2) cells induced by procyanidins from chestnut (Castanea mollissima Bl.) shell (CSPCs) was investigated, and the inherent relationship between autophagic levels and reactive oxygen species (ROS) generation was studied. The results showed that CSPCs induced HepG2 cell death in a time- and concentration-dependent manner, increased the accumulation of autophagolysosomes and microtubule-associated proteins light chain 3-II (LC3-II, a marker of autophagy). However, these phenomena were not observed in the group pretreated with the autophagy inhibitor 3-MA, suggesting that CSPCs induced HepG2 cell autophagy. Furthermore, we found that CSPCs triggered ROS generation in cells, while the levels of ROS decreased in the N-acetylcysteine (Nac) co-treatment, revealing that CSPCs-mediated autophagy was partly blocked by Nac. In addition, treatment with CSPCs decreased the mitochondrial membrane potential of HepG2 cells. These results suggested CSPCs could trigger autophagy via ROS generation, which may be associated with the mitochondria-dependent signaling way.}, }
@article {pmid25287706, year = {2014}, author = {Hu, L and Cheng, H and Gao, Y and Shi, M and Liu, Y and Hu, Z and Xu, J and Qiu, L and Yuan, W and Leung, AY and Yang, YG and Cheng, T}, title = {Antioxidant N-acetyl-L-cysteine increases engraftment of human hematopoietic stem cells in immune-deficient mice.}, journal = {Blood}, volume = {124}, number = {20}, pages = {e45-8}, pmid = {25287706}, issn = {1528-0020}, support = {P01 AI045897/AI/NIAID NIH HHS/United States ; R01 AI064569/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Bone Marrow/*drug effects/metabolism ; Female ; Hematopoiesis/drug effects ; *Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells/cytology/*drug effects ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, SCID ; Reactive Oxygen Species/*metabolism ; Transplantation, Heterologous ; }, abstract = {Immunocompromised mice, such as the nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, have been widely used to examine the self-renewal and differentiation potential of human hematopoietic stem cells (HSCs) in vivo. However, the efficiency of human HSC engraftment remains very low. Here, we report that NOD/SCID mice had higher levels of reactive oxygen species (ROS) in their bone marrow (BM) than other commonly used mouse strains (C57BL/6 and BALB/C). Treatment with the antioxidant N-acetyl-l-cysteine (NAC) decreased ROS levels in the BM of NOD/SCID mice. Furthermore, the NAC-treated mice displayed a significant increase in human HSC engraftment and multilineage hematopoietic differentiation in the mice. In comparison with the control mice, NAC-treated recipients displayed a 10.8-fold increase in hematopoietic engraftment in the injected tibiae. A beneficial effect of NAC for human hematopoietic engraftment was also observed in an additional immunodeficient mouse strain, namely NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NOD/SCID/γc(-/-) or NSG). Thus, this study uncovers a previously unappreciated negative effect of ROS on human stem cell engraftment in immunodeficient mice.}, }
@article {pmid25286681, year = {2014}, author = {Liu, ZP and Li, YY and Gao, B and Li, J and Gao, JP and Lin, P}, title = {[Feverfew lactone induces autophagic death of hepatocellular carcinoma SMMC 7721 cells].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {45}, number = {4}, pages = {587-590}, pmid = {25286681}, issn = {1672-173X}, mesh = {Acetylcysteine ; *Autophagy ; Carcinoma, Hepatocellular/*pathology ; Cell Line, Tumor ; Humans ; Lactones/*pharmacology ; Liver Neoplasms/*pathology ; Tanacetum parthenium/*chemistry ; }, abstract = {OBJECTIVE: To explore the effect and mechanism of feverfew lactone on inducing autophagic death of hepatocellular carcinoma.<br><br>METHODS: The proliferation of hepatocellular carcinoma SMMC 7721 cells treated with feverfew lactone was measured by MTT assay. The autophagy of SMMC 7721 induced with feverfew lactone was assessed by acridine orange staining, autophagic marker LC3 and p62 detecting and autophagic flows analyzing. In addition, a role of ROS in this process was stated by treatment with antioxidant agent N-acetyl-L-cysteine (NAC).<br><br>RESULTS: The proliferation of SMMC 7721 cells were inhibited by feverfew lactone in a concentration dependence manner. The expression of LC3 and autophagic flows of SMMC 7721 cells were increased by feverfew lactone, while p62 was decreased, which implied that feverfew lactone could induce the autophagy of SMMC 7721 cells. Further more, the autophagy effect induced by feverfew lactone was declined obviously when treated with NAC suggested that ROS played an important role in this effect.<br><br>CONCLUSION: Feverfew lactone induces autophagic death of SMMC 7721 cells by stimulating cells to produce ROS. The study will be helpful for the treatment of hepatocellular carcinoma and to provide theoretical basis for the clinical application of feverfew lactone.}, }
@article {pmid25286136, year = {2015}, author = {Pilz, LK and Trojan, Y and Quiles, CL and Benvenutti, R and Melo, G and Levandovski, R and Hidalgo, MP and Elisabetsky, E}, title = {Effects of N-acetylcysteine and imipramine in a model of acute rhythm disruption in BALB/c mice.}, journal = {Chronobiology international}, volume = {32}, number = {2}, pages = {248-254}, doi = {10.3109/07420528.2014.965315}, pmid = {25286136}, issn = {1525-6073}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Antidepressive Agents, Tricyclic/*pharmacology ; Behavior, Animal/drug effects ; Circadian Rhythm/*drug effects ; Corticosterone/blood ; Depression/physiopathology ; Disease Models, Animal ; Imipramine/*pharmacology ; Interleukin-6/blood ; Light ; Male ; Mice ; Mice, Inbred BALB C ; Motor Activity/drug effects ; Photoperiod ; Rest ; Social Behavior ; Temperature ; Time Factors ; }, abstract = {Circadian rhythm disturbances are among the risk factors for depression, but specific animal models are lacking. This study aimed to characterize the effects of acute rhythm disruption in mice and investigate the effects of imipramine and N-acetylcysteine (NAC) on rhythm disruption-induced changes. Mice were exposed to 12:12-hour followed by 10:10-hour light:dark cycles (LD); under the latter, mice were treated with saline, imipramine or NAC. Rhythms of rest/activity and temperature were assessed with actigraphs and iButtons, respectively. Hole-board and social preference tests were performed at the beginning of the experiment and again at the 8th 10:10 LD, when plasma corticosterone and IL-6 levels were also assessed. Actograms showed that the 10:10 LD schedule prevents the entrainment of temperature and activity rhythms for at least 13 cycles. Subsequent light regimen change activity and temperature amplitudes showed similar patterns of decline followed by recovery attempts. During the 10:10 LD schedule, activity and temperature amplitudes were significantly decreased (paired t test), an effect exacerbated by imipramine (ANOVA/SNK). The 10:10 LD schedule increased anxiety (paired t test), an effect prevented by NAC (30 mg/kg). This study identified mild but significant behavioral changes at specific time points after light regimen change. We suggest that if repeated overtime, these subtle changes may contribute to lasting behavioral disturbancess relevant to anxiety and mood disorders. Data suggest that imipramine may contribute to sustained rhythm disturbances, while NAC appears to prevent rhythm disruption-induced anxiety. Associations between sleep/circadian disturbances and the recurrence of depressive episodes underscore the relevance of potential drug-induced maintenance of disturbed rhythms.}, }
@article {pmid25284589, year = {2015}, author = {Cetinbas, N and Daugaard, M and Mullen, AR and Hajee, S and Rotblat, B and Lopez, A and Li, A and DeBerardinis, RJ and Sorensen, PH}, title = {Loss of the tumor suppressor Hace1 leads to ROS-dependent glutamine addiction.}, journal = {Oncogene}, volume = {34}, number = {30}, pages = {4005-4010}, pmid = {25284589}, issn = {1476-5594}, support = {R01 CA157996/CA/NCI NIH HHS/United States ; MOP-123416/CAPMC/CIHR/Canada ; }, mesh = {Animals ; Apoptosis ; Cells, Cultured ; Glutamine/*physiology ; Mice, Knockout ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Proteins/*genetics/metabolism ; Ubiquitin-Protein Ligases/*genetics/metabolism ; }, abstract = {Cellular transformation is associated with altered glutamine (Gln) metabolism. Tumor cells utilize Gln in the tricarboxylic acid (TCA) cycle to maintain sufficient pools of biosynthetic precursors to support rapid growth and proliferation. However, Gln metabolism also generates NADPH, and Gln-derived glutamate is used for synthesis of glutathione (GSH). As both NADPH and GSH are antioxidants, Gln may also contribute to redox balance in transformed cells. The Hace1 E3 ligase is a tumor suppressor inactivated in diverse human cancers. Hace1 targets the Rac1 GTPase for degradation at Rac1-dependent NADPH oxidase complexes, blocking superoxide generation by the latter. Consequently, loss of Hace1 increases reactive oxygen species (ROS) levels in vitro and in vivo. Given the link between Hace1 loss and increased ROS, we investigated whether genetic inactivation of Hace1 alters Gln metabolism. We demonstrate that mouse embryonic fibroblasts (MEFs) derived from Hace1(-/-) mice are highly sensitive to Gln withdrawal, leading to enhanced cell death compared with wild-type (wt) MEFs, and Gln depletion or chemical inhibition of Gln uptake blocks soft agar colony formation by Hace1(-/-) MEFs. Hace1(-/-) MEFs exhibit increased Gln uptake and ammonia secretion, and metabolic labeling using (13)C-Gln revealed that Hace1 loss increases incorporation of Gln carbons into the TCA cycle intermediates. Gln starvation markedly increases ROS levels in Hace1(-/-) but not in wt MEFs, and treatment with the antioxidant N-acetyl cysteine or the TCA cycle intermediate oxaloacetate efficiently rescues Gln starvation-induced ROS elevation and cell death in Hace1(-/-) MEFs. Finally, Gln starvation increases superoxide levels in Hace1(-/-) MEFs, and NADPH oxidase inhibitors block the induction of superoxide and cell death by Gln starvation. Together, these results suggest that increased ROS production due to Hace1 loss leads to Gln addiction as a mechanism to cope with increased ROS-induced oxidative stress.}, }
@article {pmid25264893, year = {2014}, author = {Wang, C and Chen, K and Xia, Y and Dai, W and Wang, F and Shen, M and Cheng, P and Wang, J and Lu, J and Zhang, Y and Yang, J and Zhu, R and Zhang, H and Li, J and Zheng, Y and Zhou, Y and Guo, C}, title = {N-acetylcysteine attenuates ischemia-reperfusion-induced apoptosis and autophagy in mouse liver via regulation of the ROS/JNK/Bcl-2 pathway.}, journal = {PloS one}, volume = {9}, number = {9}, pages = {e108855}, pmid = {25264893}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cytokines/metabolism ; Intracellular Space/metabolism ; Liver/*blood supply/drug effects/enzymology/*pathology ; MAP Kinase Signaling System/*drug effects ; Male ; Mice, Inbred BALB C ; Protective Agents/pharmacology/therapeutic use ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/drug therapy/enzymology/pathology/prevention &amp; control ; }, abstract = {BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) remains a pivotal clinical problem after hemorrhagic shock, transplantation, and some types of toxic hepatic injury. Apoptosis and autophagy play important roles in cell death during HIRI. It is also known that N-acetylcysteine (NAC) has significant pharmacologic effects on HIRI including elimination of reactive oxygen species (ROS) and attenuation of hepatic apoptosis. However, the effects of NAC on HIRI-induced autophagy have not been reported. In this study, we evaluated the effects of NAC on autophagy and apoptosis in HIRI, and explored the possible mechanism involved.<br><br>METHODS: A mouse model of segmental (70%) hepatic warm ischemia was adopted to determine hepatic injury. NAC (150 mg/kg), a hepatoprotection agent, was administered before surgery. We hypothesized that the mechanism of NAC may involve the ROS/JNK/Bcl-2 pathway. We evaluated the expression of JNK, P-JNK, Bcl-2, Beclin 1 and LC3 by western blotting and immunohistochemical staining. Autophagosomes were evaluated by transmission electron microscopy (TEM).<br><br>RESULTS: We found that ALT, AST and pathological changes were significantly improved in the NAC group. Western blotting analysis showed that the expression levels of Beclin 1 and LC3 were significantly decreased in NAC-treated mice. In addition, JNK, p-JNK, Bax, TNF-&#x3b1;, NF-&#x3ba;B, IL2, IL6 and levels were also decreased in NAC-treated mice.<br><br>CONCLUSION: NAC can prevent HIRI-induced autophagy and apoptosis by influencing the JNK signal pathway. The mechanism is likely to involve attenuation of JNK and p-JNK via scavenged ROS, an indirect increase in Bcl-2 level, and finally an alteration in the balance of Beclin 1 and Bcl-2.}, }
@article {pmid25263567, year = {2014}, author = {Ourique, AF and Chaves, Pdos S and Souto, GD and Pohlmann, AR and Guterres, SS and Beck, RC}, title = {Redispersible liposomal-N-acetylcysteine powder for pulmonary administration: development, in vitro characterization and antioxidant activity.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {65}, number = {}, pages = {174-182}, doi = {10.1016/j.ejps.2014.09.017}, pmid = {25263567}, issn = {1879-0720}, mesh = {Acetylcysteine/*pharmacology ; Administration, Inhalation ; Aerosols/pharmacology ; Animals ; Antioxidants/*pharmacology ; Chemistry, Pharmaceutical/methods ; Drug Compounding/methods ; Dry Powder Inhalers/methods ; Liposomes/*pharmacology ; Lung/*drug effects ; Male ; Oxidative Stress/drug effects ; Particle Size ; Powders/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {Liposomal dry powders of N-acetylcysteine (SD-NAC-Lip) were developed for pulmonary administration. Liposomes were prepared by reverse phase evaporation and spray dried using lactose (10%, w/w) as drying adjuvant. The powders were characterized according to process yield, drug content, residual water content, particle size distribution, morphology and redispersion behavior. In vitro aerosol performance was evaluated using an eight-stage Andersen Cascade Impactor. Moreover, in vitro antioxidant activity was determined by measuring thiobarbituric acid reactive species (TBARS) present in the lungs of healthy Wistar rats after induction of oxidation by iron/EDTA. The spray-drying process had a high yield (71%±2), drug content (mg/g) according to the expected value, moisture content below 9%, geometric mean diameter under 3μm with span value lower than 1. Spherical particles were observed by scanning electron microscopy. Liposomal dry-powders were able to recover the nanometric size of the original dispersion after their redispersion in aqueous medium, as shown by laser diffraction and transmission electron microscopy. Furthermore, the powders presented aerodynamic diameter of about 7μm and respirable fraction above 30%, indicating suitable properties for pulmonary use. The encapsulation of N-acetylcysteine in liposomes was essential to maintain its in vitro antioxidant activity after the drying process. In addition, the powder containing the encapsulated drug had better in vitro antioxidant activity than the liquid and solid formulations containing the non-encapsulated drug, which makes it a good candidate for the treatment of pulmonary diseases associated with oxidative stress.}, }
@article {pmid25260543, year = {2016}, author = {Ye, CL and Lai, YF}, title = {2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone, from buds of Cleistocalyx operculatus, induces apoptosis in human hepatoma SMMC-7721 cells through a reactive oxygen species-dependent mechanism.}, journal = {Cytotechnology}, volume = {68}, number = {2}, pages = {331-341}, pmid = {25260543}, issn = {0920-9069}, abstract = {Nowadays, much effort is being devoted to detect new substances that not only significantly induce the death of tumor cells, but also have little side effect on normal cells. Our previous study showed that 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) exhibited significant cytotoxic potential with an IC50 value of 32.3 ± 1.13 μM against SMMC-7721 cells and could induce SMMC-7721 cells apoptosis. In the present study, we found that DMC was almost nontoxic to human normal liver L-02 and human normal fetal lung fibroblast HFL-1 cells as their IC50 values (111.0 ± 4.57 and 152.0 ± 4.83 µM for L-02 and HFL-1 cells, respectively) were much higher. To further explore the apoptotic mechanism of DMC, we investigated the role of the reactive oxygen species (ROS) in the apoptosis induced by DMC in SMMC-7721 cells. Our results suggested that the cytotoxicity and the generation of intracellular ROS were inhibited by N-acetylcysteine (NAC). Reversal of apoptosis in NAC pretreated cells indicated the involvement of ROS in DMC-induced apoptosis. The loss of mitochondrial membrane potential (ΔΨm) induced by DMC was significantly blocked by NAC. NAC also prevented the decrease of Caspase-3 and -9 activities, the increase of Bcl-2 protein expression and the decrease of p53 and PUMA protein expressions. Together, these results indicated that ROS played a key role in the apoptosis induced by DMC in human hepatoma SMMC-7721 cells.}, }
@article {pmid25260493, year = {2014}, author = {Choi, J and Ravipati, A and Nimmagadda, V and Schubert, M and Castellani, RJ and Russell, JW}, title = {Potential roles of PINK1 for increased PGC-1α-mediated mitochondrial fatty acid oxidation and their associations with Alzheimer disease and diabetes.}, journal = {Mitochondrion}, volume = {18}, number = {}, pages = {41-48}, pmid = {25260493}, issn = {1872-8278}, support = {I01 RX001030/RX/RRD VA/United States ; R21 RR024888/RR/NCRR NIH HHS/United States ; P30 DK072488/DK/NIDDK NIH HHS/United States ; ZIA NS002997-12//Intramural NIH HHS/United States ; RR024888/RR/NCRR NIH HHS/United States ; ZIA NS002997-13//Intramural NIH HHS/United States ; }, mesh = {Alzheimer Disease/*genetics/physiopathology ; Animals ; Diabetes Mellitus/*genetics/physiopathology ; Fatty Acids/*metabolism ; *Gene Expression Profiling ; Humans ; Mice ; Mitochondria/*enzymology/metabolism ; Oxidation-Reduction ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Protein Kinases/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; }, abstract = {Down-regulation of PINK1 and PGC-1α proteins is implicated in both mitochondrial dysfunction and oxidative stress potentially linking metabolic abnormality and neurodegeneration. Here, we report that PGC-1α and PINK1 expression is markedly decreased in Alzheimer disease (AD) and diabetic brains. We observed a significant down-regulation of PGC-1α and PINK1 protein expression in H2O2-treated cells but not in those cells treated with N-acetyl cysteine. The protein levels of two key enzymes of the mitochondrial β-oxidation machinery, acyl-coenzyme A dehydrogenase, very long chain (ACADVL) and mitochondrial trifunctional enzyme subunit α are significantly decreased in AD and diabetic brains. Moreover, we observed a positive relationship between ACADVL and 64 kDa PINK1 protein levels in AD and diabetic brains. Overexpression of PGC-1α decreases lipid-droplet accumulation and increases mitochondrial fatty acid oxidation; down-regulation of PINK1 abolishes these effects. Together, these results provide new insights into potential cooperative roles of PINK1 and PGC-1α in mitochondrial fatty acid oxidation, suggesting possible regulatory roles for mitochondrial function in the pathogenesis of AD and diabetes.}, }
@article {pmid25257100, year = {2014}, author = {Qanungo, S and Uys, JD and Manevich, Y and Distler, AM and Shaner, B and Hill, EG and Mieyal, JJ and Lemasters, JJ and Townsend, DM and Nieminen, AL}, title = {N-acetyl-L-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {68}, number = {7}, pages = {855-864}, pmid = {25257100}, issn = {1950-6007}, support = {UL1TR000062/TR/NCATS NIH HHS/United States ; R01 CA119079/CA/NCI NIH HHS/United States ; R56 DK037034/DK/NIDDK NIH HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; R01 DK073336/DK/NIDDK NIH HHS/United States ; P20 RR024485/RR/NCRR NIH HHS/United States ; R56 ES017453/ES/NIEHS NIH HHS/United States ; P20RR024485/RR/NCRR NIH HHS/United States ; P20 GM103542/GM/NIGMS NIH HHS/United States ; I01 BX000290/BX/BLRD VA/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; Apoptosis/drug effects ; Cell Line, Tumor ; Cysteine/metabolism ; Deoxycytidine/*analogs &amp; derivatives/pharmacology ; Glutathione/metabolism ; Humans ; Male ; Mice ; Mice, Nude ; NF-kappa B/*metabolism ; Oxidative Stress/drug effects ; Pancreatic Neoplasms/*drug therapy/metabolism ; Signal Transduction/*drug effects ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; Gemcitabine ; }, abstract = {First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy.}, }
@article {pmid25256574, year = {2015}, author = {Mansour, MR and Reed, C and Eisenberg, AR and Tseng, JC and Twizere, JC and Daakour, S and Yoda, A and Rodig, SJ and Tal, N and Shochat, C and Berezovskaya, A and DeAngelo, DJ and Sallan, SE and Weinstock, DM and Izraeli, S and Kung, AL and Kentsis, A and Look, AT}, title = {Targeting oncogenic interleukin-7 receptor signalling with N-acetylcysteine in T cell acute lymphoblastic leukaemia.}, journal = {British journal of haematology}, volume = {168}, number = {2}, pages = {230-238}, pmid = {25256574}, issn = {1365-2141}, support = {K08 CA160660/CA/NCI NIH HHS/United States ; P01 CA109901/CA/NCI NIH HHS/United States ; R01 CA176746/CA/NCI NIH HHS/United States ; 5P01CA109901/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; P01 CA068484/CA/NCI NIH HHS/United States ; 5P01CA68484/CA/NCI NIH HHS/United States ; R01 CA151898/CA/NCI NIH HHS/United States ; 5K08CA160660/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/physiology ; Female ; Heterografts ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mutation ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/genetics/*metabolism/pathology ; Receptors, Laminin/genetics/*metabolism ; Ribosomal Proteins/genetics/*metabolism ; Signal Transduction ; }, abstract = {Activating mutations of the interleukin-7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T-ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand-independent activation of STAT5. We hypothesized that the reducing agent N-acetylcysteine (NAC), a well-tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R-mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R-mutant DND-41 cells as assessed by non-reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND-41 cells, and Ba/F3 cells transformed by an IL7R-mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND-41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T-ALL.}, }
@article {pmid25254489, year = {2014}, author = {Inda-Filho, AJ and Caixeta, A and Manggini, M and Schor, N}, title = {Do intravenous N-acetylcysteine and sodium bicarbonate prevent high osmolal contrast-induced acute kidney injury? A randomized controlled trial.}, journal = {PloS one}, volume = {9}, number = {9}, pages = {e107602}, pmid = {25254489}, issn = {1932-6203}, mesh = {Acetylcysteine/*administration &amp; dosage/*pharmacology ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Administration, Intravenous ; Contrast Media/*adverse effects/chemistry ; Coronary Angiography/adverse effects ; Female ; Humans ; Iothalamic Acid/adverse effects/analogs &amp; derivatives/chemistry ; Male ; Middle Aged ; Osmolar Concentration ; Sodium Bicarbonate/*administration &amp; dosage/*pharmacology ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) or sodium bicarbonate (NaHCO3), singly or combined, inconsistently prevent patients exposed to radiographic contrast media from developing contrast-induced acute kidney injury (CI-AKI).<br><br>OBJECTIVE: We asked whether intravenous isotonic saline and either NaHCO3 in 5% dextrose or else a high dose of NAC in 5% dextrose prevent CI-AKI in outpatients exposed to high-osmolal iodinated contrast medium more than does saline alone.<br><br>METHODS: This completed prospective, parallel, superiority, open-label, controlled, computer-randomized, single-center, Brazilian trial (NCT01612013) hydrated 500 adult outpatients (214 at high risk of developing CI-AKI) exposed to ioxitalamate during elective coronary angiography and ventriculography. From 1 hour before through 6 hours after exposure, 126 patients (group 1) received a high dose of NAC and saline, 125 (group 2) received NaHCO3 and saline, 124 (group 3) received both treatments, and 125 (group 4) received only saline.<br><br>RESULTS: Groups were similar with respect to age, gender, weight, pre-existing renal dysfunction, hypertension, medication, and baseline serum creatinine and serum cystatin C, but diabetes mellitus was significantly less prevalent in group 1. CI-AKI incidence 72 hours after exposure to contrast medium was 51.4% (257/500), measured as serum creatinine > (baseline+0.3 mg/dL) and/or serum cystatin C > (1.1 &#xb7; baseline), and 7.6% (38/500), measured as both serum creatinine and serum cystatin C > (baseline+0.3 mg/dL) or > (1.25 &#xb7; baseline). CI-AKI incidence measured less sensitively was similar among groups. Measured more sensitively, incidence in group 1 was significantly (p<0.05) lower than in groups 2 and 3 but not group 4; adjustment for confounding by infused volume equalized incidence in groups 1 and 3.<br><br>CONCLUSION: We found no evidence that intravenous isotonic saline and either NaHCO3 or else a high dose of NAC prevent CI-AKI in outpatients exposed to high osmolal iodinated contrast medium more than does saline alone.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT01612013.}, }
@article {pmid25251886, year = {2014}, author = {Guerrero, CA and Torres, DP and García, LL and Guerrero, RA and Acosta, O}, title = {N-Acetylcysteine treatment of rotavirus-associated diarrhea in children.}, journal = {Pharmacotherapy}, volume = {34}, number = {11}, pages = {e333-40}, doi = {10.1002/phar.1489}, pmid = {25251886}, issn = {1875-9114}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Antiviral Agents/administration &amp; dosage/*therapeutic use ; Child, Preschool ; Colombia ; Dehydration/etiology/prevention &amp; control ; Diarrhea/etiology/physiopathology/*prevention &amp; control ; Diarrhea, Infantile/etiology/physiopathology/*prevention &amp; control ; Female ; Gastroenteritis/*drug therapy/physiopathology/virology ; Humans ; Infant ; Male ; Recurrence ; Rotavirus Infections/*drug therapy/physiopathology/virology ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {Rotaviruses are the leading cause of severe, acute, and dehydrating diarrhea affecting children under 5 years of age worldwide. Despite an important reduction in rotavirus-caused deaths as a consequence of the rotavirus vaccine, alternative or complementary strategies for preventing or treating rotavirus-associated diarrhea are needed mainly in the poorest countries. We describe the cases of four rotavirus-unvaccinated 12-13-month-old girls and a 5-year-old boy who developed rotavirus-associated diarrhea confirmed by enzyme-linked immunosorbent assay, Western blotting, and immunochemistry analyses. After the first day of diarrheal episodes, three of the five patients were immediately administered oral N-acetylcysteine (NAC) 60 mg/kg daily, divided into three equal doses every 8 hours. The other two patients did not receive NAC and served as controls. Administration of NAC resulted in a decreased number of diarrheal episodes, excretion of fecal rotavirus antigen, and resolution of symptoms after 2 days of treatment. Our results suggest that NAC treatment after the first diarrheal episode could be an efficient strategy for treating rotavirus-affected children and preventing the associated severe life-threatening accompanying dehydration.}, }
@article {pmid25250647, year = {2015}, author = {Orban, JC and Quintard, H and Cassuto, E and Jambou, P and Samat-Long, C and Ichai, C}, title = {Effect of N-acetylcysteine pretreatment of deceased organ donors on renal allograft function: a randomized controlled trial.}, journal = {Transplantation}, volume = {99}, number = {4}, pages = {746-753}, pmid = {25250647}, issn = {1534-6080}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Intravenous ; Adult ; Allografts ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; Brain Death/diagnosis ; Cerebral Angiography ; Creatinine/blood ; Delayed Graft Function/diagnosis/etiology/mortality/physiopathology/*prevention &amp; control ; Drug Administration Schedule ; Female ; France ; Glomerular Filtration Rate/drug effects ; Graft Survival/drug effects ; Humans ; Kidney Transplantation/adverse effects/*methods/mortality ; Male ; Middle Aged ; Prospective Studies ; Renal Dialysis ; Single-Blind Method ; Time Factors ; *Tissue Donors ; Treatment Outcome ; Up-Regulation ; Urination/drug effects ; }, abstract = {BACKGROUND: Antioxidant donor pretreatment is one of the pharmacologic strategy proposed to prevent renal ischemia-reperfusion injuries and delayed graft function (DGF). The aim of the study was to investigate whether a donor pretreatment with N-acetylcysteine (NAC) reduces the incidence of DGF in adult human kidney transplant recipients.<br><br>METHODS: In this randomized, open-label, monocenter trial, 160 deceased heart-beating donors were allowed to perform 236 renal transplantations from September 2005 to December 2010. Donors were randomized to receive, in a single-blind controlled fashion, 600 mg of intravenous NAC 1 hr before and 2 hr after cerebral angiography performed to confirm brain death. Primary endpoint was DGF defined by the need for at least one dialysis session within the first week or a serum creatinine level greater than 200 &#x3bc;mol/L at day 7 after kidney transplantation.<br><br>RESULTS: The incidence of DGF was similar between donors pretreated with or without NAC (39/118; 33% vs. 30/118; 25.4%; P = 0.19). Requirement for at least one dialysis session was not different between the NAC and No NAC groups (17/118; 14.4% vs. 14/118; 11.8%, P = 0.56). The two groups had comparable serum creatinine levels, estimated glomerular filtration rates, and daily urine output at days 1, 7, 15, and 30 after kidney transplantation as well as at hospital discharge. No difference in recipient mortality nor in 1-year kidney graft survival was observed.<br><br>CONCLUSION: Donor pretreatment with NAC does not improve delayed graft function after kidney transplantation.}, }
@article {pmid25250213, year = {2014}, author = {Hao, W and Zhang, X and Zhao, W and Chen, X}, title = {Psoralidin induces autophagy through ROS generation which inhibits the proliferation of human lung cancer A549 cells.}, journal = {PeerJ}, volume = {2}, number = {}, pages = {e555}, pmid = {25250213}, issn = {2167-8359}, abstract = {Psoralidin (PSO), a natural furanocoumarin, is isolated from Psoralea corylifolia L. possessing anti-cancer properties. However, the mechanisms of its effects remain unclear. Herein, we investigated its anti-proliferative effect and potential approaches of action on human lung cancer A549 cells. Cell proliferation and death were measured by MTT and LDH assay respectively. Apoptosis was detected with Hoechst 33342 staining by fluorescence microscopy, Annexin V-FITC by flow cytometry and Western blot analysis for apoptosis-related proteins. The autophagy was evaluated using MDC staining, immunofluorescence assay and Western blot analyses for LC3-I and LC3-II. In addition, the reactive oxygen species (ROS) generation was measured by DCFH2-DA with flow cytometry. PSO dramatically decreased the cell viabilities in dose- and time-dependent manner. However, no significant change was observed between the control group and the PSO-treated groups in Hoechst 33342 and Annexin V-FITC staining. The expression of apoptosis-related proteins was not altered significantly either. While the MDC-fluorescence intensity and the expression ratio of LC3-II/LC3-I was remarkably increased after PSO treatment. Autophagy inhibitor 3-MA blocked the production of LC3-II and reduced the cytotoxicity in response to PSO. Furthermore, PSO increased intracellular ROS level which was correlated to the elevation of LC3-II. ROS scavenger N-acetyl cysteine pretreatment not only decreased the ROS level, reduced the expression of LC3-II but also reversed PSO induced cytotoxicity. PSO inhibited the proliferation of A549 cells through autophagy but not apoptosis, which was mediated by inducing ROS production.}, }
@article {pmid25249571, year = {2014}, author = {Pak, EJ and Son, GD and Yoo, BS}, title = {Cadmium inhibits neurite outgrowth in differentiating human SH-SY5Y neuroblastoma cells.}, journal = {International journal of toxicology}, volume = {33}, number = {5}, pages = {412-418}, doi = {10.1177/1091581814550338}, pmid = {25249571}, issn = {1092-874X}, mesh = {Acetylcysteine/pharmacology ; Blotting, Western ; Cadmium/*toxicity ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Free Radical Scavengers/pharmacology ; GAP-43 Protein/metabolism ; Humans ; Neurites/*drug effects/metabolism/ultrastructure ; Reactive Oxygen Species/metabolism ; }, abstract = {Cadmium, a highly ubiquitous heavy metal, is well known to induce neurotoxicity. However, the underlying mechanism of cadmium-mediated neurotoxicity remains unclear. We have studied cadmium inhibition of neurite outgrowth using human SH-SY5Y neuroblastoma cells induced to differentiate by all-trans-retinoic acid (RA). Cadmium, at a concentration of 3 μmol/L, had no significant effect on the viability of differentiating SH-SY5Y cells. However, the neurite outgrowth of the differentiating SH-SY5Y cells 48 hours after cadmium treatment (1-3 μmol/L cadmium) was significantly inhibited in a dose-dependent manner. Treatment of RA-stimulated differentiating SH-SY5Y cells with 1 to 3 μmol/L cadmium resulted in decreased level of cross-reactivities with 43-kDa growth-associated protein (GAP-43) in a dose-dependent manner. The reactive oxygen species (ROS) scavenger, NAC (N-acetyl-l-cysteine), recovered the expression of GAP-43 in cadmium-treated cells. The results indicate that cadmium is able to inhibit neurite outgrowth of differentiating SH-SY5Y cells and that this effect might result from ROS generation by cadmium.}, }
@article {pmid25249432, year = {2015}, author = {Ozgur, E and Sahin, D and Tomruk, A and Guler, G and Sepici Dinçel, A and Altan, N and Seyhan, N}, title = {The effects of N-acetylcysteine and epigallocatechin-3-gallate on liver tissue protein oxidation and antioxidant enzyme levels after the exposure to radiofrequency radiation.}, journal = {International journal of radiation biology}, volume = {91}, number = {2}, pages = {187-193}, doi = {10.3109/09553002.2015.966210}, pmid = {25249432}, issn = {1362-3095}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Phone ; Guinea Pigs ; Liver/*drug effects/enzymology/metabolism/*radiation effects ; Male ; Oxidation-Reduction/drug effects/radiation effects ; Protein Carbonylation/drug effects/radiation effects ; Proteins/*metabolism ; Radiation-Protective Agents/pharmacology ; Radio Waves/*adverse effects ; Superoxide Dismutase/metabolism ; }, abstract = {PURPOSE: The widespread and sustained use of mobile and cordless phones causes unprecedented increase of radiofrequency radiation (RFR). The aim of this experimental study was to investigate the effect of 900 MHz Global System for Mobile Communications (GSM)-modulated RFR (average whole body Specific Absorption Rate (SAR) of 0.4 W/kg, 10 or 20 min daily for consecutive 7 days) to the liver tissue of guinea pigs and the protective effects of antioxidant treatments.<br><br>MATERIALS AND METHODS: Adult male guinea pigs were randomly divided into nine groups as: Group I (sham/saline), Group II (sham/EGCG), Group III (sham/NAC), Group IV (10-min RF-exposure/saline), Group V (20-min RF-exposure/saline), Group VI (10-min RF-exposure/EGCG), Group VII (20-min RF-exposure/EGCG), Group VIII (10-min RF-exposure/NAC), and Group IX (20-min RF-exposure/NAC). Protein oxidation (PCO), advanced oxidation protein products (AOPP) and antioxidant enzyme activities of superoxide dismutase (SOD) were evaluated after the exposure and the treatments with N-acetylcysteine (NAC) and (-)-epigallocatechin-3-gallate (EGCG).<br><br>RESULTS AND CONCLUSIONS: Significant decreases in the activities of SOD were observed in the liver of guinea pigs after RFR exposure. Protein damage did not change due to RFR exposure. On the other hand, only NAC treatment induced increased PCO levels, whereas EGCG treatment alone elevated the level of AOPP. Due to antioxidants having pro-oxidant behavior, the well decided doses and treatment timetables of NAC and ECGC are needed.}, }
@article {pmid25248126, year = {2014}, author = {Lee, YH and Su, SB and Huang, CC and Sheu, HM and Tsai, JC and Lin, CH and Wang, YJ and Wang, BJ}, title = {N-acetylcysteine attenuates hexavalent chromium-induced hypersensitivity through inhibition of cell death, ROS-related signaling and cytokine expression.}, journal = {PloS one}, volume = {9}, number = {9}, pages = {e108317}, pmid = {25248126}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cells, Cultured ; Chromium/*toxicity ; Dermatitis, Allergic Contact/*drug therapy/etiology/pathology/prevention &amp; control ; Drug Evaluation, Preclinical ; Female ; Gene Expression Regulation/drug effects ; Guinea Pigs ; Interleukin-1alpha/*biosynthesis/genetics ; Keratinocytes/drug effects/metabolism ; MAP Kinase Signaling System/drug effects ; NF-kappa B/physiology ; Oncogene Protein v-akt/physiology ; RNA, Messenger/biosynthesis/genetics ; Reactive Oxygen Species/*antagonists &amp; inhibitors ; Signal Transduction/*drug effects ; Tumor Necrosis Factor-alpha/*biosynthesis/genetics ; }, abstract = {Chromium hypersensitivity (chromium-induced allergic contact dermatitis) is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI)) can activate the Akt, Nuclear factor κB (NF-κB), and Mitogen-activated protein kinase (MAPK) pathways and induce cell death, via the effects of reactive oxygen species (ROS). Recently, cell death stimuli have been proposed to regulate the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in Cr(VI)-induced hypersensitivity have not yet been fully demonstrated. N-acetylcysteine (NAC) could increase glutathione levels in the skin and act as an antioxidant. In this study, we investigated the effects of NAC on attenuating the Cr(VI)-triggered ROS signaling in both normal keratinocyte cells (HaCaT cells) and a guinea pig (GP) model. The results showed the induction of apoptosis, autophagy and ROS were observed after different concentrations of Cr(VI) treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr (VI) activated the Akt, NF-κB and MAPK pathways thereby increasing IL-1α and TNF-α production. However, all of these stimulation phenomena could be inhibited by NAC in both of in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting of ROS-induced cell death and cytokine expression.}, }
@article {pmid25245075, year = {2015}, author = {Tobwala, S and Khayyat, A and Fan, W and Ercal, N}, title = {Comparative evaluation of N-acetylcysteine and N-acetylcysteineamide in acetaminophen-induced hepatotoxicity in human hepatoma HepaRG cells.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {240}, number = {2}, pages = {261-272}, pmid = {25245075}, issn = {1535-3699}, mesh = {Acetaminophen/*adverse effects/pharmacology ; Acetylcysteine/*analogs &amp; derivatives/*pharmacology ; Analgesics, Non-Narcotic/*adverse effects/pharmacology ; Antidotes/*pharmacology ; Carcinoma, Hepatocellular/*metabolism/pathology ; Cell Line, Tumor ; Drug Overdose/*drug therapy/metabolism/pathology ; Free Radical Scavengers/*pharmacology ; Humans ; Lipid Peroxidation/drug effects ; Liver Neoplasms/*metabolism/pathology ; Mitochondria, Liver/metabolism/pathology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over-the-counter antipyretic analgesic medications. Despite being safe at therapeutic doses, an accidental or intentional overdose can result in severe hepatotoxicity; a leading cause of drug-induced liver failure in the U.S. Depletion of glutathione (GSH) is implicated as an initiating event in APAP-induced toxicity. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an APAP overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and intravenous administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteineamide (NACA), a novel antioxidant, with higher bioavailability and compared it with NAC in APAP-induced hepatotoxicity in a human-relevant in vitro system, HepaRG. Our results indicated that exposure of HepaRG cells to APAP resulted in GSH depletion, reactive oxygen species (ROS) formation, increased lipid peroxidation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase release. Both NAC and NACA protected against APAP-induced hepatotoxicity by restoring GSH levels, scavenging ROS, inhibiting lipid peroxidation, and preserving mitochondrial membrane potential. However, NACA was better than NAC at combating oxidative stress and protecting against APAP-induced damage. The higher efficiency of NACA in protecting cells against APAP-induced toxicity suggests that NACA can be developed into a promising therapeutic option for treatment of an APAP overdose.}, }
@article {pmid25243875, year = {2015}, author = {El Morsy, EM and Kamel, R}, title = {Protective effect of artichoke leaf extract against paracetamol-induced hepatotoxicity in rats.}, journal = {Pharmaceutical biology}, volume = {53}, number = {2}, pages = {167-173}, doi = {10.3109/13880209.2014.913066}, pmid = {25243875}, issn = {1744-5116}, mesh = {Acetaminophen/*toxicity ; Animals ; Antioxidants/isolation &amp; purification/*therapeutic use ; Apoptosis/drug effects ; Biomarkers/metabolism ; Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology/*prevention &amp; control ; Comet Assay ; Cynara scolymus/*chemistry ; DNA Damage/drug effects ; Liver Function Tests ; Male ; Necrosis ; Oxidative Stress/drug effects ; Plant Extracts/isolation &amp; purification/*therapeutic use ; Plant Leaves/chemistry ; Rats, Sprague-Dawley ; }, abstract = {CONTEXT: Paracetamol overdose is a predominant cause of hepatotoxicity in both humans and experimental animals.<br><br>OBJECTIVE: In this study, we investigated the protective effect of aqueous artichoke leaf extract (ALE) against paracetamol-induced liver injury in rats using N-acetylcysteine (NAC) as a reference drug.<br><br>MATERIALS AND METHODS: Rats were divided into five groups: negative control, paracetamol (2&#x2009;g/kg, single oral dose), ALE (1.5&#x2009;g/kg, orally for 14&#x2009;d), ALE&#x2009;+&#x2009;paracetamol, and NAC (100&#x2009;mg/kg)&#x2009;+&#x2009;paracetamol. Indices of liver damage (serum alanine aminotransferase and aspartate aminotransferase) were measured. Liver homogenates were analyzed for oxidative stress biomarkers (MDA, malondialdehyde; SOD activity, superoxide dismutase activity; NO, nitric oxide; GSH content, reduced glutathione), glutathione cycling (GR, glutathione reductase), and utilization (GST, glutathione-S-transferase). Apoptosis was assessed using the comet assay.<br><br>RESULTS: Paracetamol caused marked liver damage as noted by significant increased activities of serum aminotransferases (p&#x2009;<&#x2009;0.05) as well as a significant increase in hepatic MDA and NO levels (p&#x2009;<&#x2009;0.001) compared with the negative control group. GSH content, GR, GST, and SOD activities were decreased significantly (p&#x2009;<&#x2009;0.001). Comet assay parameters (tail length, percentage of tailed cells, percentage of migrated DNA, and tail moment) were increased (p&#x2009;<&#x2009;0.05), indicating apoptosis. Histopathological examination showed necrotic areas. Pre-treatment with ALE replenished hepatic GSH, reversed oxidative stress parameters, DNA damage, and necrosis induced by paracetamol.<br><br>DISCUSSION AND CONCLUSION: These results suggest that ALE may protect from paracetamol-induced liver toxicity via its antioxidant and anti-apoptotic properties.}, }
@article {pmid25241892, year = {2015}, author = {Song, JH and An, N and Chatterjee, S and Kistner-Griffin, E and Mahajan, S and Mehrotra, S and Kraft, AS}, title = {Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing.}, journal = {Oncogene}, volume = {34}, number = {28}, pages = {3728-3736}, pmid = {25241892}, issn = {1476-5594}, support = {P30 CA138313/CA/NCI NIH HHS/United States ; R01 CA173200/CA/NCI NIH HHS/United States ; R01 CA1732000/CA/NCI NIH HHS/United States ; P30-CA138313/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Cell Proliferation ; Cells, Cultured ; Fibroblasts/*cytology/metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Mice ; Mitochondria/metabolism ; Pentose Phosphate Pathway ; Proto-Oncogene Proteins c-pim-1/*genetics/*metabolism ; Proto-Oncogene Proteins p21(ras)/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {The Pim protein kinases contribute to transformation by enhancing the activity of oncogenic Myc and Ras, which drives significant metabolic changes during tumorigenesis. In this report, we demonstrate that mouse embryo fibroblasts (MEFs) lacking all three isoforms of Pim protein kinases, triple knockout (TKO), cannot tolerate the expression of activated K-Ras (K-Ras(G12V)) and undergo cell death. Transduction of K-Ras(G12V) into these cells markedly increased the level of cellular reactive oxygen species (ROS). The addition of N-acetyl cysteine attenuated ROS production and reversed the cytotoxic effects of K-Ras(G12V) in the TKO MEFs. The altered cellular redox state caused by the loss of Pim occurred as a result of lower levels of metabolic intermediates in the glycolytic and pentose phosphate pathways as well as abnormal mitochondrial oxidative phosphorylation. TKO MEFs exhibit reduced levels of superoxide dismutase (Sod), glutathione peroxidase 4 (Gpx4) and peroxiredoxin 3 (Prdx3) that render them susceptible to killing by K-Ras(G12V)-mediated ROS production. In contrast, the transduction of c-Myc into TKO cells can overcome the lack of Pim protein kinases by regulating cellular metabolism and Sod2. In the absence of the Pim kinases, c-Myc transduction permitted K-Ras(G12V)-induced cell growth by decreasing Ras-induced cellular ROS levels. These results demonstrate that the Pim protein kinases have an important role in regulating cellular redox, metabolism and K-Ras-stimulated cell growth.}, }
@article {pmid25239279, year = {2014}, author = {Shi, D and Li, X and Chen, H and Che, N and Zhou, S and Lu, Z and Shi, S and Sun, L}, title = {High level of reactive oxygen species impaired mesenchymal stem cell migration via overpolymerization of F-actin cytoskeleton in systemic lupus erythematosus.}, journal = {Pathologie-biologie}, volume = {62}, number = {6}, pages = {382-390}, doi = {10.1016/j.patbio.2014.07.009}, pmid = {25239279}, issn = {1768-3114}, support = {R01DE017449/DE/NIDCR NIH HHS/United States ; //Intramural NIH HHS/United States ; }, mesh = {Actin Cytoskeleton/*drug effects/metabolism ; Actins/*metabolism ; Adolescent ; Adult ; Animals ; Case-Control Studies ; Cell Movement/*drug effects ; Cells, Cultured ; Female ; Humans ; *Lupus Erythematosus, Systemic/metabolism/pathology/physiopathology ; Mesenchymal Stem Cells/*drug effects/pathology/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Middle Aged ; Protein Multimerization/drug effects ; Reactive Oxygen Species/*pharmacology ; Young Adult ; }, abstract = {Some lines of evidence have demonstrated abnormalities of bone marrow mesenchymal stem cells (MSCs) in systemic lupus erythematosus (SLE) patients, characterized by defective phenotype of MSCs and slower growth with enhanced apoptosis and senescence. However, whether SLE MSCs demonstrate aberrant migration capacity or abnormalities in cytoskeleton are issues that remain poorly understood. In this study, we found that MSCs from SLE patients did show impairment in migration capacity as well as abnormalities in F-actin cytoskeleton, accompanied by a high level of intracellular reactive oxygen species (ROS). When normal MSCs were treated in vitro with H2O2, which increases intracellular ROS level as an oxidant, both reorganization of F-actin cytoskeleton and impairment of migration capability were observed. On the other hand, treatment with N-acetylcysteine (NAC), as an exogenous antioxidant, made F-actin more orderly and increased migration ratio in SLE MSCs. In addition, oral administration of NAC markedly reduced serum autoantibody levels and ameliorated lupus nephritis (LN) in MRL/lpr mice, partially reversing the abnormalities of MSCs. These results indicate that overpolymerization of F-actin cytoskeleton, which may be associated with high levels of ROS, causes impairment in the migration capacity of SLE MSCs and that oral administration of NAC may have potential therapeutic effects on MRL/lpr mice.}, }
@article {pmid25237784, year = {2014}, author = {Hanff, E and Böhmer, A and Jordan, J and Tsikas, D}, title = {Stable-isotope dilution LC-MS/MS measurement of nitrite in human plasma after its conversion to S-nitrosoglutathione.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {970}, number = {}, pages = {44-52}, doi = {10.1016/j.jchromb.2014.08.041}, pmid = {25237784}, issn = {1873-376X}, mesh = {Adult ; Chromatography, Liquid/*methods ; Humans ; Isotope Labeling ; Limit of Detection ; Linear Models ; Male ; Middle Aged ; Nitrites/*blood/chemistry/*metabolism ; Reproducibility of Results ; S-Nitrosoglutathione/analysis/chemistry/*metabolism ; Tandem Mass Spectrometry/*methods ; Young Adult ; }, abstract = {A specific, sensitive and fast LC-MS/MS method with positive electrospray ionization for the quantitative determination of nitrite in human plasma is reported. Added [(15)N]nitrite served as the internal standard (IS). Endogenous nitrite and IS were converted to their S-nitrosoglutathione (GSNO) derivatives, i.e., GS(14)NO and GS(15)NO, respectively, by using excess glutathione (GSH) and HCl. For plasmatic nitrite, fresh plasma (0.5 mL) was spiked with the IS (1000 nM) and ultrafiltered (cut-off 10 kDa). Ultrafiltrate aliquots (100 μL) were treated with aqueous GSH at a final concentration of 1 mM and 1 μL of 5M HCl for 5 min. After final sample dilution (1:1, v/v) with acetonitrile-water (70:30, v/v), 2 μL aliquots were injected via a thermostated (4 °C) autosampler. The mobile phase was acetonitrile-water (70:30, v/v), contained 20mM ammonium formate, had a pH value of 7, and was pumped isocratically at 0.5 mL/min. A Nucleoshell column was used for LC separation. The retention time of GSNO was about 0.8 min and the total analysis time 5 min. Quantification was performed by selected-reaction monitoring the specific mass transition m/z337([M+H](+))→m/z 307([M+H-(14)NO](+·)) for GS(14)NO (i.e., for endogenous nitrite) and m/z338([M+H](+))→m/z307([M+H-(15)NO](+·)) for GS(15)NO (i.e., for the IS). The method was thoroughly validated in human plasma (range, 0-2000 nM). The LOD and LOQ values of the LC-MS/MS method were determined to be 1 fmol and 5 nM [(15)N]nitrite, respectively. The relative matrix-effect of about 21% was outweighed entirely by the IS. In freshly prepared plasma samples from heparinized blood donated by three healthy subjects, nitrite concentration was determined by LC-MS/MS to be 516, 199 and 369 nM. These concentrations were confirmed by using a previously reported GC-MS method and agree with those measured previously by HPLC-UV (334 nm) after nitrite conversion to S-nitroso-N-acetylcysteine (SNAC) by N-acetylcysteine (NAC). Measurement of nitrite by LC-MS/MS as GSNO is about 1000 times more sensitive than by HPLC-UV as SNAC. The applicability of the method to microdialysate, urine, and saliva samples from humans was demonstrated. The agreement of two orthogonal MS-based methods indicates that the concentration of nitrite in freshly prepared, non-frozen plasma from heparinized blood of fasted healthy humans is of the order of 400 nM.}, }
@article {pmid25234327, year = {2014}, author = {Wang, J and Zhu, H and Liu, X and Liu, Z}, title = {N-acetylcysteine protects against cadmium-induced oxidative stress in rat hepatocytes.}, journal = {Journal of veterinary science}, volume = {15}, number = {4}, pages = {485-493}, pmid = {25234327}, issn = {1976-555X}, mesh = {Acetylcysteine/*metabolism ; Animals ; Antioxidants/*metabolism ; Cadmium/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Environmental Pollutants/*toxicity ; Hepatocytes/drug effects/metabolism ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cadmium (Cd) is a well-known hepatotoxic environmental pollutant. We used rat hepatocytes as a model to study oxidative damage induced by Cd, effects on the antioxidant systems, and the role of N-acetylcysteine (NAC) in protecting cells against Cd toxicity. Hepatocytes were incubated for 12 and 24 h with Cd (2.5, 5, 10 µM). Results showed that Cd can induce cytotoxicity: 10 µM resulted in 36.2% mortality after 12 h and 47.8% after 24 h. Lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase activities increased. Additionally, reactive oxygen species (ROS) generation increased in Cd-treated hepatocytes along with malondialdehyde levels. Glutathione concentrations significantly decreased after treatment with Cd for 12 h but increased after 24 h of Cd exposure. In contrast, glutathione peroxidase activity significantly increased after treatment with Cd for 12 h but decreased after 24 h. superoxide dismutase and catalase activities increased at 12 h and 24 h. glutathione S-transferase and glutathione reductase activities decreased, but not significantly. Rat hepatocytes incubated with NAC and Cd simultaneously had significantly increased viability and decreased Cd-induced ROS generation. Our results suggested that Cd induces ROS generation that leads to oxidative stress. Moreover, NAC protects rat hepatocytes from cytotoxicity associated with Cd.}, }
@article {pmid25231285, year = {2014}, author = {Kang, MJ and Song, EJ and Kim, BY and Kim, DJ and Park, JH}, title = {Helicobacter pylori induces vascular endothelial growth factor production in gastric epithelial cells through hypoxia-inducible factor-1α-dependent pathway.}, journal = {Helicobacter}, volume = {19}, number = {6}, pages = {476-483}, doi = {10.1111/hel.12169}, pmid = {25231285}, issn = {1523-5378}, mesh = {Bacterial Proteins/genetics/metabolism ; Bacterial Secretion Systems ; Epithelial Cells/*metabolism/microbiology ; Gastric Mucosa/metabolism ; Helicobacter Infections/genetics/*metabolism/microbiology ; Helicobacter pylori/genetics/*physiology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; NF-kappa B/metabolism ; Signal Transduction ; Stomach/cytology/microbiology ; Vascular Endothelial Growth Factor A/genetics/*metabolism ; }, abstract = {BACKGROUND: Although Helicobacter pylori have been known to induce vascular endothelial growth factor (VEGF) production in gastric epithelial cells, the precise mechanism for cellular signaling is incompletely understood. In this study, we investigated the role of bacterial virulence factor and host cellular signaling in VEGF production of H. pylori-infected gastric epithelial cells.<br><br>MATERIALS AND METHODS: We evaluated production of VEGF, activation of nuclear factor nuclear factor-kappaB (NF-&#x3ba;B) and mitogen-activated protein kinases (MAPKs) and hypoxia-inducible factor-1&#x3b1; (HIF-1&#x3b1;) stabilization in gastric epithelial cells infected with H. pylori WT or isogenic mutants deficient in type IV secretion system (T4SS).<br><br>RESULTS: H. pylori induced VEGF production in gastric epithelial cells via both T4SS-dependent and T4SS-independent pathways, although T4SS-independent pathway seems to be the dominant signaling. The inhibitor assay implicated that activation of NF-&#x3ba;B and MAPKs is dispensable for H. pylori-induced VEGF production in gastric epithelial cells. H. pylori led to HIF-1&#x3b1; stabilization in gastric epithelial cells independently of T4SS, NF-&#x3ba;B, and MAPKs, which was essential for VEGF production in these cells. N-acetyl-cysteine (NAC), a reactive oxygen species (ROS) inhibitor, treatment impaired H. pylori-induced HIF-1&#x3b1; stabilization and VEGF production in gastric epithelial cells.<br><br>CONCLUSION: We defined the important role of ROS-HIF-1&#x3b1; axis in VEGF production of H. pylori-infected gastric epithelial cells, and bacterial T4SS has a minor role in H. pylori-induced VEGF production of gastric epithelial cells.}, }
@article {pmid25231009, year = {2015}, author = {Oh, DH and Kim, MJ and Jeon, SO and Seo, JE and Jeong, SH and Kang, JW and Choi, YW and Lee, S}, title = {Strategic approaches for enhancement of in vivo transbuccal peptide drug delivery in rabbits using iontophoresis and chemical enhancers.}, journal = {Pharmaceutical research}, volume = {32}, number = {3}, pages = {929-940}, pmid = {25231009}, issn = {1573-904X}, mesh = {Acetylcysteine/administration &amp; dosage ; Administration, Buccal ; Animals ; Biomarkers/blood ; Calcitonin/*administration &amp; dosage/chemistry/pharmacokinetics/toxicity ; Calcium/blood ; Chemistry, Pharmaceutical ; Down-Regulation ; Ethanol/administration &amp; dosage ; Excipients/*administration &amp; dosage/chemistry/toxicity ; Feasibility Studies ; Hydrogels ; Injections, Intravenous ; *Iontophoresis ; Male ; Mouth Mucosa/*drug effects/metabolism/pathology ; Oral Mucosal Absorption/*drug effects ; Permeability ; Rabbits ; Spectroscopy, Fourier Transform Infrared ; Technology, Pharmaceutical/methods ; }, abstract = {PURPOSE: To evaluate the feasibility of iontophoresis and the combination effects with chemical enhancers on in vivo hypocalcemic effect of transbuccally delivered salmon calcitonin (sCT).<br><br>METHODS: N-acetyl-L-cysteine (NAC), sodium deoxyglycocholate (SDGC), and ethanol were used as chemical enhancers; and 0.5 mA/cm(2) fixed electric current was employed as a physical enhancer. sCT hydrogel was applied to rabbit buccal mucosa, and blood samples were obtained via the central auricular artery. Blood calcium level was measured by calcium kit and the conformational changes of buccal mucosa were investigated with FT-IR spectroscopy. Hematoxylin/eosin staining was used for the histological evaluation of buccal mucosa.<br><br>RESULTS: Iontophoresis groups except iontophoresis-NAC group showed significant hypocalcemic effect compared to negative control, in particular iontophoresis-SDGC combination group showed fast onset of action as well as sustained hypocalcemic effect (p < 0.05). FT-IR result demonstrated the reduction of buccal barrier function, and the histological study showed a decrease in buccal thickness as well as minor damage to the dermal-epidermal junctions in the enhancing method groups; however, the damaged tissues virtually recovered within 24 h after the removal of electrodes.<br><br>CONCLUSIONS: Iontophoresis and combination with SDGC were found to be safe and potential strategies for transbuccal peptide delivery in vivo.}, }
@article {pmid25228446, year = {2015}, author = {Conrad, C and Lymp, J and Thompson, V and Dunn, C and Davies, Z and Chatfield, B and Nichols, D and Clancy, J and Vender, R and Egan, ME and Quittell, L and Michelson, P and Antony, V and Spahr, J and Rubenstein, RC and Moss, RB and Herzenberg, LA and Goss, CH and Tirouvanziam, R}, title = {Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.}, journal = {Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society}, volume = {14}, number = {2}, pages = {219-227}, doi = {10.1016/j.jcf.2014.08.008}, pmid = {25228446}, issn = {1873-5010}, mesh = {*Acetylcysteine/administration &amp; dosage/adverse effects ; Administration, Oral ; Adolescent ; Adult ; Antioxidants/administration &amp; dosage/adverse effects ; Child ; *Cystic Fibrosis/complications/drug therapy/metabolism/physiopathology ; Double-Blind Method ; Drug Monitoring ; Female ; Humans ; *Inflammation/drug therapy/metabolism ; Leukocyte Elastase/metabolism ; *Lung/drug effects/metabolism/physiopathology ; Male ; Oxidative Stress/*drug effects ; Respiratory Function Tests/methods ; Sputum/drug effects/metabolism ; Time ; Treatment Outcome ; }, abstract = {PURPOSE: To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways.<br><br>METHODS: A multicenter, randomized, double-blind proof of concept study in which 70 CF subjects received NAC or placebo orally thrice daily for 24 weeks.<br><br>ENDPOINTS: primary, change in sputum human neutrophil elastase (HNE) activity; secondary, FEV(1) and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF.<br><br>RESULTS: Lung function (FEV(1) and FEF(25-75%)) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log(10) HNE activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14).<br><br>CONCLUSIONS: NAC recipients maintained their lung function while placebo recipients declined (24 week FEV1 treatment effect=150 mL, p<0.02). However no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. Further studies on mechanism and clinical outcomes are warranted.}, }
@article {pmid25227831, year = {2014}, author = {Park, KW and Kundu, J and Chae, IG and Bachar, SC and Bae, JW and Chun, KS}, title = {Methanol extract of Flacourtia indica aerial parts induces apoptosis via generation of ROS and activation of caspases in human colon cancer HCT116 cells.}, journal = {Asian Pacific journal of cancer prevention : APJCP}, volume = {15}, number = {17}, pages = {7291-7296}, doi = {10.7314/apjcp.2014.15.17.7291}, pmid = {25227831}, issn = {2476-762X}, mesh = {Apoptosis/*drug effects ; *Carcinoma ; Caspase 3/drug effects/metabolism ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; *Colonic Neoplasms ; Cytochromes c/drug effects/metabolism ; Drug Screening Assays, Antitumor ; HCT116 Cells ; Humans ; Inhibitor of Apoptosis Proteins/drug effects/metabolism ; Methanol ; Plant Components, Aerial ; Plant Extracts/*pharmacology ; Poly(ADP-ribose) Polymerases/drug effects/metabolism ; Proto-Oncogene Proteins c-bcl-2/drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; *Salicaceae ; Survivin ; bcl-X Protein/drug effects/metabolism ; }, abstract = {Different plant parts of Flacourtia indica have long been used in Ayurvedic medicine. Previous studies have demonstrated that the methanolic extract of F. indica possess anti-inflammatory properties. The present study was aimed at investigating the anticancer effects of methanol extract of Flacourtia indica (FIM) aerial parts in human colon cancer (HCT116) cells. Treatment of cells with FIM at a concentration of 500 μg/ml for 24 hours significantly reduced cell viability and induced apoptosis, which was associated with the increased cytoplasmic expression of cytochrome c, activation of caspase-3, and the cleavage of poly-(ADP-ribose) polymerase. Incubation with FIM also inhibited the levels of Bcl-2, Bcl-xl and survivin, which are the markers of cell proliferation, whereas the expression of Bax remained unchanged. Treatment with FIM led to the generation of reactive oxygen species (ROS) in a concentration-dependent manner. Pharmacological inhibition of ROS generation by pretreatment of cells with N-acetyl cysteine abrogated FIM-induced apoptosis in HCT116 cells. Thus, these results demonstrate that FIM has anti-proliferative and pro-apoptotic effects in HCT116 cells and the effects are, at least in part, due to the ROS dependent activation of caspases.}, }
@article {pmid25227113, year = {2014}, author = {Harashima, N and Minami, T and Uemura, H and Harada, M}, title = {Transfection of poly(I:C) can induce reactive oxygen species-triggered apoptosis and interferon-β-mediated growth arrest in human renal cell carcinoma cells via innate adjuvant receptors and the 2-5A system.}, journal = {Molecular cancer}, volume = {13}, number = {}, pages = {217}, pmid = {25227113}, issn = {1476-4598}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Renal Cell/*drug therapy/*pathology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Endoribonucleases/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Interferon-beta/metabolism ; Kidney Neoplasms/*drug therapy/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Poly I-C/*pharmacology ; Reactive Oxygen Species/metabolism ; Transfection ; }, abstract = {BACKGROUND: Synthetic double-stranded RNA poly(I:C) is a useful immune adjuvant and exhibits direct antitumor effects against several types of cancers. In this study, we elucidated the mechanisms underlying the effects induced in poly(I:C)-transfected human renal cell carcinoma (RCC) cells.<br><br>RESULTS: In contrast to the lack of an effect of adding poly(I:C), poly(I:C) transfection drastically decreased RCC cell viability. Poly(I:C) transfection induced reactive oxygen species (ROS)-dependent apoptosis in RCC cells and decreased the mitochondrial membrane potential (&#x394;&#x3a8;m). Treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, suppressed apoptosis and restored the &#x394;&#x3a8;m. Although the levels of phosphorylated &#x3b3;H2A.X, an indicator of DNA damage, increased in poly(I:C)-transfected RCC cells, NAC treatment decreased their levels, suggesting ROS-mediated DNA damage. Furthermore, poly(I:C) transfection increased the levels of phosphorylated p53, NOXA, and tBid. Immunoblots and assays with a panel of caspase inhibitors revealed that poly(I:C) transfection-induced apoptosis was dependent on caspase-8 and -9, as well as caspase-2. Alternatively, poly(I:C) transfection increased mRNA expression of interferon (IFN)-&#x3b2;, and treatment with IFN-&#x3b2; suppressed growth of RCC cells without apoptosis. In addition, cyclinD1 and c-Myc expression decreased in poly(I:C)-transfected RCC cells. Moreover, RNA interference experiments revealed that poly(I:C) transfection exerted apoptotic effects on RCC cells through innate adjuvant receptors and the 2-5A system, the latter of which induces apoptosis in virus-infected cells.<br><br>CONCLUSIONS: These results suggest that poly(I:C) transfection induced two types of effects against RCC cells such as apoptosis, as a result of ROS-mediated DNA damage, and IFN-&#x3b2;-mediated growth arrest, both of which were exerted via innate adjuvant receptors and the 2-5A system.}, }
@article {pmid25226206, year = {2015}, author = {Pimton, P and Lecht, S and Stabler, CT and Johannes, G and Schulman, ES and Lelkes, PI}, title = {Hypoxia enhances differentiation of mouse embryonic stem cells into definitive endoderm and distal lung cells.}, journal = {Stem cells and development}, volume = {24}, number = {5}, pages = {663-676}, pmid = {25226206}, issn = {1557-8534}, support = {5R01 HL-104258-02/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Cell Differentiation ; Cell Hypoxia ; Cells, Cultured ; Endoderm/*cytology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lung/*cytology/embryology ; Mice ; Mouse Embryonic Stem Cells/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {We investigated the effects of hypoxia on spontaneous (SP)- and activin A (AA)-induced definitive endoderm (DE) differentiation of mouse embryonic stem cells (mESCs) and their subsequent differentiation into distal pulmonary epithelial cells. SP differentiation for 6 days of mESCs toward endoderm at hypoxia of 1% O2, but not at 3% or 21% (normoxia), increased the expression of Sox17 and Foxa2 by 31- and 63-fold above maintenance culture, respectively. Treatment of mESCs with 20 ng/mL AA for 6 days under hypoxia further increased the expression of DE marker genes Sox17, Foxa2, and Cxcr4 by 501-, 1,483-, and 126-fold above maintenance cultures, respectively. Transient exposure to hypoxia, as short as 24 h, was sufficient to enhance AA-induced endoderm formation. The involvement of hypoxia-inducible factor (HIF)-1α and reactive oxygen species (ROS) in the AA-induced endoderm enrichment was assessed using HIF-1α(-/-) mESCs and the ROS scavenger N-acetylcysteine (NAC). Under SP conditions, HIF-1α(-/-) mESCs failed to increase the expression of endodermal marker genes but rather shifted toward ectoderm. Hypoxia induced only a marginal potentiation of AA-induced endoderm differentiation in HIF-1α(-/-) mESCs. Treatment of mESCs with AA and NAC led to a dose-dependent decrease in Sox17 and Foxa2 expression. In addition, the duration of exposure to hypoxia in the course of a recently reported lung differentiation protocol resulted in differentially enhanced expression of distal lung epithelial cell marker genes aquaporin 5 (Aqp5), surfactant protein C (Sftpc), and secretoglobin 1a1 (Scgb1a1) for alveolar epithelium type I, type II, and club cells, respectively. Our study is the first to show the effects of in vitro hypoxia on efficient formation of DE and lung lineages. We suggest that the extent of hypoxia and careful timing may be important components of in vitro differentiation bioprocesses for the differential generation of distal lung epithelial cells from pluripotent progenitors.}, }
@article {pmid25224287, year = {2015}, author = {Karimi Zarchi, AA and Abbasi, S and Faramarzi, MA and Gilani, K and Ghazi-Khansari, M and Amani, A}, title = {Development and optimization of N-Acetylcysteine-loaded poly (lactic-co-glycolic acid) nanoparticles by electrospray.}, journal = {International journal of biological macromolecules}, volume = {72}, number = {}, pages = {764-770}, doi = {10.1016/j.ijbiomac.2014.09.004}, pmid = {25224287}, issn = {1879-0003}, mesh = {Acetylcysteine/*chemistry ; Chemistry, Pharmaceutical ; Drug Carriers ; Drug Stability ; Humans ; Lactic Acid/*chemistry ; Nanoparticles/*chemistry ; Particle Size ; Polyglycolic Acid/*chemistry ; Polylactic Acid-Polyglycolic Acid Copolymer ; Polymers/chemistry ; }, abstract = {N-Acetylcysteine (NAC) loaded PLGA nanoparticles were prepared by electrospray method. The influence of independent parameters such as concentration, flow rate and nozzle to collector distance was studied on particle size and size distribution of generated nanoparticles using a Box-Behnken experimental design. Smallest size was found to be obtained at minimum value for both flow rate and concentration of polymer, regardless of collecting distance value in the ranges studied. Additionally, the minimum value of size distribution was observed at lowest values of both concentration of polymer and collecting distance, regardless of flow rate value. In total, a sample with minimum size and polydispersity was predicted to have flow rate, polymer concentration and collecting distance values of 0.06(ml/h), 0.5(%w/w) and 9.28(cm), respectively. The experimentally prepared nanoparticles with lowest size and size distribution values, had a size of 122(nm) and size distribution of 24. Zeta potential, drug loading and encapsulation efficiency of optimized nanoparticles were -6.58, 5% and 54.5%, respectively.}, }
@article {pmid25222041, year = {2014}, author = {Ozdemir, ZC and Koc, A and Aycicek, A and Kocyigit, A}, title = {N-Acetylcysteine supplementation reduces oxidative stress and DNA damage in children with β-thalassemia.}, journal = {Hemoglobin}, volume = {38}, number = {5}, pages = {359-364}, doi = {10.3109/03630269.2014.951890}, pmid = {25222041}, issn = {1532-432X}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Antioxidants/adverse effects/*therapeutic use ; Chelation Therapy/adverse effects ; Child, Preschool ; Combined Modality Therapy/adverse effects ; Comet Assay ; *DNA Damage ; *Dietary Supplements/adverse effects ; Hemoglobins/analysis ; Humans ; Infant ; Iron Chelating Agents/adverse effects/therapeutic use ; Iron Overload/etiology/*prevention &amp; control ; Leukocytes, Mononuclear/drug effects/metabolism ; *Oxidative Stress ; Transfusion Reaction ; Turkey ; Vitamin E/adverse effects/therapeutic use ; beta-Thalassemia/blood/*diet therapy/drug therapy/therapy ; }, abstract = {There are several reports that increased oxidative stress and DNA damage were found in β-thalassemia major (β-TM) patients. In this study, we aimed to evaluate the effects of N-acetylcysteine (NAC) and vitamin E on total oxidative stress and DNA damage in children with β-TM. Seventy-five children with transfusion-dependent β-thalassemia (β-thal) were randomly chosen to receive 10 mg/kg/day of NAC or 10 IU/kg/day of vitamin E or no supplementation; 28 healthy controls were also included in the study. Serum total oxidant status (TOS) and total antioxidant capacity (TAC) were measured, oxidative stress index (OSI) was calculated, and mononuclear DNA damage was assessed by alkaline comet assay; they were determined before treatment and after 3 months of treatment. Total oxydent status, OSI, and DNA damage levels were significantly higher and TAC levels were significantly lower in the thalassemic children than in the healthy controls (p < 0.001). In both supplemented groups, mean TOS and OSI levels were decreased; TAC and pre transfusion hemoglobin (Hb) levels were significantly increased after 3 months (p ≤ 0.002). In the NAC group, DNA damage score decreased (p = 0.001). N-Acetylcysteine and vitamin E may be effective in reducing serum oxidative stress and increase pre transfusion Hb levels in children with β-thal. N-Acetylcysteine also can reduce DNA damage.}, }
@article {pmid25220073, year = {2014}, author = {Ye, J and Han, Y and Chen, X and Xie, J and Liu, X and Qiao, S and Wang, C}, title = {L-carnitine attenuates H2O2-induced neuron apoptosis via inhibition of endoplasmic reticulum stress.}, journal = {Neurochemistry international}, volume = {78}, number = {}, pages = {86-95}, doi = {10.1016/j.neuint.2014.08.009}, pmid = {25220073}, issn = {1872-9754}, mesh = {Apoptosis/*drug effects/physiology ; Carnitine/*pharmacology ; Cell Line, Tumor ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects/physiology ; Humans ; Hydrogen Peroxide/*toxicity ; Neurons/*drug effects/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {Both oxidative stress and endoplasmic reticulum stress (ER stress) have been linked to pathogenesis of neurodegenerative diseases. Our previous study has shown that L-carnitine may function as an antioxidant to inhibit H2O2-induced oxidative stress in neuroblastoma SH-SY5Y cells. To further explore the neuroprotection of L-carnitine, here we study the effects of L-carnitine on the ER stress response in H2O2-induced SH-SY5Y cell injury. Our results showed that L-carnitine pretreatment could increase cell viability; inhibit apoptosis and ROS accumulation caused by H2O2 or tunicamycin (TM). L-carnitine suppress the endoplasmic reticulum dilation and activation of ER stress-associated proteins including glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), JNK, Bax and Bim induced by H2O2 or TM. In addition, H2O2-induced cell apoptosis and activation of ER stress can also be attenuated by antioxidant N-acetylcysteine (NAC), CHOP siRNA and the inhibitor of ER stress 4-phenylbutyric acid (4-PBA). Taken together, our results demonstrated that H2O2 could trigger both oxidative stress and ER stress in SH-SY5Y cells, and ER stress participated in SH-SY5Y apoptosis mediated by H2O2-induced oxidative stress. CHOP/Bim or JNK/Bim-dependent ER stress signaling pathways maybe related to the neuroprotective effects of L-carnitine against H2O2-induced apoptosis and oxidative injury.}, }
@article {pmid25218171, year = {2014}, author = {Ko, JW and Lim, SY and Chung, KC and Lim, JW and Kim, H}, title = {Reactive oxygen species mediate IL-8 expression in Down syndrome candidate region-1-overexpressed cells.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {55}, number = {}, pages = {164-170}, doi = {10.1016/j.biocel.2014.08.017}, pmid = {25218171}, issn = {1878-5875}, mesh = {Acetylcysteine/pharmacology ; Blotting, Western ; Calcium/metabolism ; Chelating Agents/pharmacology ; DNA-Binding Proteins ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; HEK293 Cells ; Humans ; Interleukin-1beta/pharmacology ; Interleukin-8/genetics/*metabolism ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Intracellular Space/drug effects/*metabolism ; Microscopy, Confocal ; Mitochondria/drug effects/*metabolism ; Muscle Proteins/genetics/*metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Transfection ; }, abstract = {Reactive oxygen species (ROS) have been considered to mediate inflammation in Down syndrome (DS). The present study is purposed to examine the mechanism of increased ROS levels and inflammatory cytokine IL-8 expression in Down syndrome candidate region-1 (DSCR1)-transfected cells, by determining ROS levels, IL-8 expression, NF-κB activation, and SOD1 levels in human embryonic kidney (HEK) 293 cells. The cells were treated with an antioxidant N-acetyl cysteine (NAC) or a calcium chelator BAPTA and stimulated with or without IL-1β. As a result, basal levels of ROS, IL-8, and NF-κB-DNA binding activity were higher, and basal SOD1 levels were higher in DSCR1-transfected cells than pcDNA-transfected cells. BAPTA and NAC inhibited increase in ROS (intracellular and mitochondrial levels) in DSCR-1-transfected cells without treatment of IL-1β. DSCR1 transfection-induced changes were increased by treatment with IL-1β, which was suppressed by NAC and BAPTA. Transfection of SOD1 inhibited ROS levels in DSCR1-transfected cells. In conclusion, ROS activate NF-κB and IL-8 induction in DSCR1-transfected cells in a calcium-dependent manner, which is augmented by IL-1β since IL-1β increases calcium and ROS levels in the cells. Reducing ROS levels by treatment of antioxidants may be beneficial for preventing DS-associated inflammation by suppressing cytokine expression.}, }
@article {pmid25209888, year = {2014}, author = {Choi, H and Hwang, JS and Lee, DG}, title = {Identification of a novel antimicrobial peptide, scolopendin 1, derived from centipede Scolopendra subspinipes mutilans and its antifungal mechanism.}, journal = {Insect molecular biology}, volume = {23}, number = {6}, pages = {788-799}, doi = {10.1111/imb.12124}, pmid = {25209888}, issn = {1365-2583}, mesh = {Amino Acid Sequence ; Animals ; Antifungal Agents/chemical synthesis/chemistry/*pharmacology ; Antimicrobial Cationic Peptides/chemical synthesis/chemistry/*genetics/isolation &amp; purification/*pharmacology ; Apoptosis/drug effects ; Arthropod Proteins/genetics/*pharmacology ; Arthropods/*genetics/immunology/microbiology ; Candida albicans/drug effects/growth &amp; development ; Caspases ; Erythrocytes/drug effects ; Escherichia coli ; Hemolysis/drug effects ; Humans ; Microbial Sensitivity Tests ; Mitochondria/drug effects ; Molecular Sequence Data ; Reactive Oxygen Species/metabolism ; }, abstract = {In this study, a novel antimicrobial peptide, scolopendin 1, was identified from adult centipedes, Scolopendra subspinipes mutilans using RNA sequencing. Scolopendin 1 exerted an antimicrobial activity without inducing haemolysis of human erythrocytes. In order to understand the antifungal mechanism, a reactive oxygen species (ROS) assay was performed, which indicated that scolopendin 1 induced ROS accumulation in Candida albicans. Evaluation of fungal viability using N-acetyl cysteine, a ROS scavenger, suggested that ROS are a major factor in scolopendin 1-induced fungal cell death. Co-staining of annexin V-fluorescein isothiocyanate (FITC) and propidium iodide, and TUNEL and 4',6-diamidino-2-phenylindole (DAPI) assays confirmed that ROS-induced fungal cell death is associated with apoptosis. To further investigate the mechanism that facilitates the progression of apoptosis, changes in intracellular Ca(2+) concentration and mitochondrial dysfunction were examined. Ca(2+) , a signalling molecule in the apoptotic pathway, was increased in the cytosol and mitochondria, and ROS accumulation triggered mitochondrial depolarization and the release of cytochrome c, a pro-apoptotic factor, from the mitochondria to the cytosol. Finally, the released cytochrome c activated intracellular caspase. The present study suggests that scolopendin 1 could emerge as a model molecule that targets the apoptotic pathway and provides a novel remedy.}, }
@article {pmid25204891, year = {2015}, author = {Palit, S and Kar, S and Sharma, G and Das, PK}, title = {Hesperetin Induces Apoptosis in Breast Carcinoma by Triggering Accumulation of ROS and Activation of ASK1/JNK Pathway.}, journal = {Journal of cellular physiology}, volume = {230}, number = {8}, pages = {1729-1739}, doi = {10.1002/jcp.24818}, pmid = {25204891}, issn = {1097-4652}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms/*metabolism ; Enzyme Activation/drug effects ; Flow Cytometry ; Hesperidin/*pharmacology ; Humans ; Immunoblotting ; Immunoprecipitation ; In Situ Nick-End Labeling ; MAP Kinase Kinase Kinase 5/metabolism ; MAP Kinase Signaling System/*drug effects ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Transfection ; }, abstract = {Hesperetin, a flavanone glycoside predominantly found in citrus fruits, exhibits a wide array of biological properties. In the present study hesperetin exhibited a significant cytotoxic effect in human breast carcinoma MCF-7 cells in a concentration- and time-dependent manner without affecting normal (HMEC) as well as immortalized normal mammary epithelial cells (MCF-10A). The cytotoxic effect of hesperetin was due to the induction of apoptosis as evident from the phosphatidyl-serine externalization, DNA fragmentation, caspase-7 activation, and PARP cleavage. Apoptosis was associated with caspase-9 activation, mitochondrial membrane potential loss, release of cytochrome c, and increase in Bax:Bcl-2 ratio. Pre-treatment with caspase-9 specific inhibitor (Z-LEHD-fmk) markedly attenuated apoptosis suggesting an involvement of intrinsic mitochondrial apoptotic cascade. Further, DCFDA flow-cytometric analysis revealed triggering of ROS in a time-dependent manner. Pre-treatment with ROS scavenger N-acetylcysteine (NAC) and glutathione markedly abrogated hesperetin-mediated apoptosis whereas carbonyl cyanide m-chlorophenylhydrazone (CCCP) pretreatment along with DHR123-based flow-cytometry indicated the generation of cytosolic ROS. Profiling of MAPKs revealed activation of JNK upon hesperetin treatment which was abrogated upon NAC pre-treatment. Additionally, inhibition of JNK by SP600125 significantly reversed hesperetin-mediated apoptosis. The activation of JNK was associated with the activation of ASK1. Silencing of ASK1 resulted in significant attenuation of JNK activation as well as reversed the hesperetin-mediated apoptosis suggesting that hesperetin-mediated apoptosis of MCF-7 cells involves accumulation of ROS and activation of ASK1/JNK pathway. In addition, hesperetin also induced apoptosis in triple negative breast cancer MDA-MB-231 cells via intrinsic pathway via activation of caspase -9 and -3 and increase in Bax:Bcl-2 ratio.}, }
@article {pmid25202950, year = {2014}, author = {Fu, L and Zhou, F and Wang, X and Lu, F}, title = {[Effect of free fatty acid on NALP3 inflammasome signaling pathway in THP-1 macrophages].}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {39}, number = {8}, pages = {811-817}, doi = {10.3969/j.issn.1672-7347.2014.08.010}, pmid = {25202950}, issn = {1672-7347}, mesh = {Carrier Proteins/metabolism ; Caspase 1/metabolism ; Cell Line ; Fatty Acids, Nonesterified/*chemistry ; Humans ; Inflammasomes/*metabolism ; Interleukin-1beta/metabolism ; Macrophages/*cytology ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; *Signal Transduction ; }, abstract = {OBJECTIVE: To investigate the potential effect of NALP3 inflammasome on the occurrence and development of nonalcoholic steatohepatitis (NASH).<br><br>METHODS: THP-1 macrophages were cultured for 24 h by palmitic acid at various concentrations. The THP-1 macrophages were pretreated with N-acetyl-cysteine at different doses for 24 h before the palmitic acid cultivation. ROS production was determined by flow cytometry. The expression of IL- 1&#x3b2; was detected by ELISA; the expressions of NALP3 protein and caspase-1 protein were detected by immunofluorescence; NALP3, ASC, and caspase-1 mRNA were measured by real-time PCR.<br><br>RESULTS: Compared with the THP-1 macrophages without palmitic acid, the level of ROS, NALP3 protein and caspase-1 protein, and the expression of IL-1&#x3b2; were increased after palmitic acid treatment in a dose dependent manner (P<0.05). Compared with the THP-1 macrophages with palmitic acid (400 &#x3bc;mol/L), the level of NALP3 mRNA (P<0.05), the level of NALP3 protein and caspase-1 protein (P<0.05), the expression of IL-1&#x3b2; (P<0.05) were decreased after preadministration of N-acetyl-cysteine in a dose dependent manner.<br><br>CONCLUSION: ROS induced by free fatty acid can regulate the activation of NALP3 inflammasome signaling pathway leading to the release of inflammatory cytokines. This pathway may be the possible mechanism of NASH.}, }
@article {pmid25202034, year = {2014}, author = {Covvey, JR and Mancl, EE}, title = {Recent evidence for pharmacological treatment of idiopathic pulmonary fibrosis.}, journal = {The Annals of pharmacotherapy}, volume = {48}, number = {12}, pages = {1611-1619}, doi = {10.1177/1060028014551015}, pmid = {25202034}, issn = {1542-6270}, mesh = {Acetylcysteine/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Azathioprine/therapeutic use ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy ; Indoles/therapeutic use ; Prednisone/therapeutic use ; Pyridones/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {OBJECTIVE: To describe emerging evidence for the pharmacological treatment of idiopathic pulmonary fibrosis (IPF).<br><br>DATA SOURCES: A search of PubMed (1966 to July 2014) was performed using the terms idiopathic pulmonary fibrosis and treatment.<br><br>Review of articles was restricted to articles in English and relating to placebo-controlled or comparative clinical trial data of recent significance. Evidence statements from the most recent international guidelines and some historical trial data were also included for context.<br><br>DATA SYNTHESIS: Numerous treatment options have been evaluated for IPF. Therapies evaluated in large trials have either resulted in increased mortality (anticoagulation, triple-therapy with N-acetylcysteine [NAC], azathioprine, and prednisone) or demonstrated a lack of efficacy (endothelin receptor antagonists, single-agent NAC). Pirfenidone, a novel antifibrotic and anti-inflammatory agent, has demonstrated efficacy in several recent analyses and is the only approved medication for the treatment of IPF in more than 30 countries outside of the United States, with resubmission to the Food and Drug Administration (FDA) recently made. Nintedanib, a tyrosine kinase inhibitor, has demonstrated encouraging results in phase III studies and has also recently been submitted for FDA approval.<br><br>CONCLUSIONS: Limited options have existed for the treatment of IPF. New evidence suggests that safe and efficacious treatment options for IPF are on the horizon in the form of pirfenidone and nintedanib, although both agents await FDA decisions.}, }
@article {pmid25182817, year = {2014}, author = {Song, J and Lu, X and Li, Q and Liu, C and Liu, Y}, title = {[Role of oxidative stress in endoplasmic reticulum stress? induced apoptosis of alveolar macrophages triggered by quartz dust].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {32}, number = {7}, pages = {500-503}, pmid = {25182817}, issn = {1001-9391}, mesh = {Animals ; Caspase 12/metabolism ; Dust ; Endoplasmic Reticulum Stress/*drug effects ; Macrophages, Alveolar/drug effects/*pathology ; Male ; Oxidative Stress/*drug effects ; Protein Carbonylation ; Quartz/*toxicity ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: To investigate the role of oxidative stress in the endoplasmic reticulum stress-induced apoptosis of alveolar macrophages triggered by quartz dust.<br><br>METHODS: Seventy-two healthy adult Wistar rats were randomly divided into control group, quartz dust group, quartz dust plus N-acetyl cysteine (NAC) group, and NAC group, with 18 rats in each group. One milliliter of sterile saline (for the control and NAC groups) or 1 ml of saline with 5%ultrafine quartz dust (for dust group and dust plus NAC group) was given to each rat by non-exposed endotracheal infusion. From the second day after dust infusion, rats in dust plus NAC group and NAC group received intragastric administration of NAC (100 mg/kg). In each week, the treatment with NAC lasted for 5 consecutive days, followed by 2 days' interval. For each group, 6 rats were randomly selected on the 14th, 28th, or 56th day after dust exposure; they were sacrificed by bloodletting from the femoral artery, and the lungs were collected. Bronchoalveolar lavage fluid was collected to separate macrophages. The protein expression of caspase-12 in alveolar macrophages, the apoptosis rate and reactive oxygen species (ROS) content of alveolar macrophages, and the protein carbonyl content of alveolar macrophages were determined by Western blot, flow cytometry, and colorimetry, respectively.<br><br>RESULTS: Increased protein expression of caspase-12, apoptosis rate, and content of ROS and protein carbonyl were discovered on the 14th day in the dust group, in comparison with the control group (P < 0.05), and the increase lasted till the 28th and 56th days. (P < 0.05). Compared with the dust group, the dust plus NAC group showed significant decreases in the content of ROS on the 14th, 28th, and 56th days (P < 0.05), significant decreases in the content of protein carbonyl on the 28th and 56th days (P < 0.05), and significant decreases in the protein expression of caspase-12 and apoptosis rate (P < 0.05).<br><br>CONCLUSION: Oxidative stress is potentially involved in the endoplasmic reticulum stress-induced apoptosis of alveolar macrophages triggered by quartz dust. Oxidative damage of protein in the endoplasmic reticulum may play an important role in the process.}, }
@article {pmid25179587, year = {2014}, author = {McClure, EA and Sonne, SC and Winhusen, T and Carroll, KM and Ghitza, UE and McRae-Clark, AL and Matthews, AG and Sharma, G and Van Veldhuisen, P and Vandrey, RG and Levin, FR and Weiss, RD and Lindblad, R and Allen, C and Mooney, LJ and Haynes, L and Brigham, GS and Sparenborg, S and Hasson, AL and Gray, KM}, title = {Achieving cannabis cessation -- evaluating N-acetylcysteine treatment (ACCENT): design and implementation of a multi-site, randomized controlled study in the National Institute on Drug Abuse Clinical Trials Network.}, journal = {Contemporary clinical trials}, volume = {39}, number = {2}, pages = {211-223}, pmid = {25179587}, issn = {1559-2030}, support = {K01 DA036739/DA/NIDA NIH HHS/United States ; U10 DA015831/DA/NIDA NIH HHS/United States ; U10 DA013714/DA/NIDA NIH HHS/United States ; U10DA15831/DA/NIDA NIH HHS/United States ; K24 DA022288/DA/NIDA NIH HHS/United States ; U10 DA013732/DA/NIDA NIH HHS/United States ; N01DA102221/DA/NIDA NIH HHS/United States ; U10 DA013038/DA/NIDA NIH HHS/United States ; U10DA013045/DA/NIDA NIH HHS/United States ; K24DA022288/DA/NIDA NIH HHS/United States ; UG1 DA015815/DA/NIDA NIH HHS/United States ; N01DA92217/DA/NIDA NIH HHS/United States ; U10 DA013045/DA/NIDA NIH HHS/United States ; U10DA013034/DA/NIDA NIH HHS/United States ; U10 DA013034/DA/NIDA NIH HHS/United States ; U01 DA031779/DA/NIDA NIH HHS/United States ; U10DA013727/DA/NIDA NIH HHS/United States ; U10DA013714/DA/NIDA NIH HHS/United States ; U10 DA013727/DA/NIDA NIH HHS/United States ; K24 DA029647/DA/NIDA NIH HHS/United States ; U10 DA015815/DA/NIDA NIH HHS/United States ; U10DA013732/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Adolescent ; Adult ; Double-Blind Method ; Female ; Genetic Testing ; Humans ; Male ; Marijuana Abuse/*drug therapy/epidemiology/genetics ; Middle Aged ; National Institute on Drug Abuse (U.S.) ; *Research Design ; Smoking/epidemiology ; United States ; Young Adult ; }, abstract = {Despite recent advances in behavioral interventions for cannabis use disorders, effect sizes remain modest, and few individuals achieve long-term abstinence. One strategy to enhance outcomes is the addition of pharmacotherapy to complement behavioral treatment, but to date no efficacious medications targeting cannabis use disorders in adults through large, randomized controlled trials have been identified. The National Institute on Drug Abuse Clinical Trials Network (NIDA CTN) is currently conducting a study to test the efficacy of N-acetylcysteine (NAC) versus placebo (PBO), added to contingency management, for cannabis cessation in adults (ages 18-50). This study was designed to replicate positive findings from a study in cannabis-dependent adolescents that found greater odds of abstinence with NAC compared to PBO. This paper describes the design and implementation of an ongoing 12-week, intent-to-treat, double-blind, randomized, placebo-controlled study with one follow-up visit four weeks post-treatment. Approximately 300 treatment-seeking cannabis-dependent adults will be randomized to NAC or PBO across six study sites in the United States. The primary objective of this 12-week study is to evaluate the efficacy of twice-daily orally-administered NAC (1200 mg) versus matched PBO, added to contingency management, on cannabis abstinence. NAC is among the first medications to demonstrate increased odds of abstinence in a randomized controlled study among cannabis users in any age group. The current study will assess the cannabis cessation efficacy of NAC combined with a behavioral intervention in adults, providing a novel and timely contribution to the evidence base for the treatment of cannabis use disorders.}, }
@article {pmid25177911, year = {2014}, author = {Fang, Y and Zhang, Q and Tan, J and Li, L and An, X and Lei, P}, title = {Intermittent hypoxia-induced rat pancreatic β-cell apoptosis and protective effects of antioxidant intervention.}, journal = {Nutrition &amp; diabetes}, volume = {4}, number = {9}, pages = {e131}, pmid = {25177911}, issn = {2044-4052}, abstract = {PURPOSE: Obstructive sleep apnea hypopnea syndrome (OSAHS), a common sleep and breathing disorder, is independently associated with metabolic dysfunction, including impaired glucose tolerance and insulin resistance. Intermittent hypoxia (IH), a pathological component of OSAHS, increases oxidative stress damage to pancreatic β-cells in animal models resembling patients with OSAHS. However, the precise mechanisms of IH-induced pancreatic β-cell dysfunction are not fully understood. In the present study, we established a mice model to investigate the underlying mechanisms of oxidative stress in IH-induced pancreatic β-cell apoptosis through antioxidant N-acetylcysteine (NAC) pretreatment.<br><br>METHODS: Twenty-four Wistar rats were randomly divided into four experimental groups: normal control group, intermittent normoxia group, IH group and antioxidant intervention group. Pancreatic &#x3b2;-cell apoptosis rates were detected by terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling; Bcl-2 and Bax protein expressions were detected by immunohistochemistry staining and western blotting.<br><br>RESULTS: In our study, we demonstrated that IH exposure causes an increased activation of pancreatic &#x3b2;-cell apoptosis compared with that in the normal control group and intermittent normoxia group, accompanied by the downregulation of Bcl-2 and upregulation of Bax (P<0.05). Furthermore, compared with the IH group, antioxidant (NAC) pretreatment significantly decreased IH-mediated &#x3b2;-cell apoptosis and reversed the ratio of Bcl-2/Bax expression (P<0.05).<br><br>CONCLUSION: Taken together, these results demonstrate a critical role of oxidative stress in the regulation of apoptosis through Bcl-2 and Bax signaling. The antioxidant NAC has a protective effect against IH-induced pancreatic &#x3b2;-cell apoptosis.Nutrition &amp; Diabetes advance online publication, __PUBDATE__; doi:10.1038/nutd.2014.28.}, }
@article {pmid25176089, year = {2014}, author = {Xu, Z and Jiang, G and Lin, S and Guan, J and Chen, G and Chen, G}, title = {[Effect of N-acetylcysteine on intestinal injury induced by cardiopulmonary bypass in rats].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {34}, number = {8}, pages = {1171-1175}, pmid = {25176089}, issn = {1673-4254}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cardiopulmonary Bypass/*adverse effects ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Inflammation/drug therapy ; Interleukin-6/metabolism ; Intestines/*drug effects/physiopathology ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Rats ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha ; }, abstract = {OBJECTIVE: To observe the effect of N-acetylcysteine (NAC) on intestine injury induced by cardiopulmonary bypass (CPB) in rats.<br><br>METHODS: Thirty-two rats were randomly divided into sham-operated group, NAC control group, CPB model group, and CPB plus NAC treatment group (n=8). In the latter two groups, the rats were subjected to CPB for 1 h. The rats received intraperitoneal injections of normal saline or NAC (0.5 g/kg) as appropriate for 3 successive days prior to CPB, and those in CPB plus NAC group were given NAC (100 mg/kg) in CPB prime followed by infusion at 20 mgsol;(kg&#xb7;h) until the cessation of CPB. Intestinal and blood samples were collected 2 h after CPB for pathological analysis and measurement of intestinal concentrations of malondialdehyde (MDA), tumor necrosis factor (TNF)-&#x3b1;, interlukin (IL)-6 and activity of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-Px) and serum levels of diamine oxidase (DAO).<br><br>RESULTS: Evident oxidative stress and pathological damages of the intestines were observed in rats after CPB. NAC treatment obviously alleviated intestinal damages induced by CPB, decreased the levels of intestinal MDA, TNF-&#x3b1;, IL-6 and serum DAO and increased activity of SOD, GSH, and GSH-Px in the intestines.<br><br>CONCLUSION: Perioperative NAC treatment can alleviate intestinal injury induced by CPB in rats by suppressing oxidative stress and inflammatory response.}, }
@article {pmid25170865, year = {2014}, author = {Ping, M and Xiao, W and Mo, L and Xiao, X and Song, S and Tang, W and Yang, X}, title = {Paeonol attenuates advanced oxidation protein product-induced oxidative stress injury in THP-1 macrophages.}, journal = {Pharmacology}, volume = {93}, number = {5-6}, pages = {286-295}, doi = {10.1159/000363577}, pmid = {25170865}, issn = {1423-0313}, mesh = {Acetophenones/*pharmacology ; Advanced Oxidation Protein Products ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; CD36 Antigens/genetics ; Cell Line ; Cell Survival/drug effects ; Cytokines/genetics ; Humans ; Macrophages/*drug effects/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/genetics ; Oxidative Stress/drug effects ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic/genetics ; Scavenger Receptors, Class A/genetics ; Scavenger Receptors, Class B/genetics ; }, abstract = {BACKGROUND: Paeonol (2'-hydroxy-4'-methoxyacetophenone) is thought to possess a broad range of clinically curative effects that are likely mediated by its anti-inflammatory and antioxidant activities.<br><br>AIMS: To elucidate the efficacy of paeonol's anti-inflammatory and antioxidant activities and the underlying mechanism of paeonol in advanced oxidation protein product (AOPP) stimulation of THP-1 macrophages.<br><br>MATERIALS AND METHODS: After incubating cells with AOPP plus paeonol, nitric oxide (NO) production and the levels of inducible NO synthase (iNOS), receptor for advanced glycation end products (RAGE), CD36, scavenger receptor (SR)-A, and SR-B1 were calculated. Moreover, THP-1 macrophages were preincubated with paeonol, the free radical scavenger N-acetylcysteine (NAC), NADPH oxidase inhibitors [apocynin, diphenylene iodonium (DPI)], and the specific inhibitor of nuclear factor-&#x3ba;B pyrrolidine dithiocarbamate (PDTC) prior to incubation with AOPP, and the levels of intracellular reactive oxygen species (ROS) production and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;), interleukin (IL)-1&#x3b2;, IL-6, and monocyte chemotactic protein 1 (MCP-1) were determined.<br><br>RESULTS: Paeonol increased NO production and the mRNA level of iNOS, whereas it decreased ROS production. ROS production was also effectively attenuated by apocynin, DPI, NAC, and PDTC. Furthermore, these inhibitors and paeonol could downregulate the mRNA and protein levels of proinflammatory cytokines (TNF-&#x3b1;, IL-1&#x3b2;, IL-6, and MCP-1). Paeonol significantly reduced the expression levels of RAGE and CD36 but increased the expression levels of SR-A and SR-B1.<br><br>CONCLUSIONS: These results indicate that paeonol can decrease proinflammatory cytokines in THP-1 macrophages, likely through RAGE-, CD36-, SR-A-, and SR-B1-mediated signals involving NADPH oxidase-dependent ROS generation. This suggests that paeonol can be used as a therapeutic agent for diseases contributing to oxidative stress injury.}, }
@article {pmid25164590, year = {2015}, author = {Schiffl, H}, title = {Sodium bicarbonate infusion for prevention of acute kidney injury: no evidence for superior benefit, but risk for harm?.}, journal = {International urology and nephrology}, volume = {47}, number = {2}, pages = {321-326}, pmid = {25164590}, issn = {1573-2584}, mesh = {Acute Kidney Injury/etiology/*prevention &amp; control ; Cardiac Surgical Procedures/adverse effects ; Contrast Media/adverse effects ; Hemoglobinuria/complications ; Humans ; Hyperbilirubinemia/complications ; Infusions, Intravenous ; Myoglobin/metabolism ; Sepsis/complications ; Sodium Bicarbonate/adverse effects/*therapeutic use ; }, abstract = {The best "treatment" of acute kidney injury (AKI) is prevention. Patients who are at high risk of AKI should have an assessment of their volume status and receive appropriate volume expansion. The most effective type of intravenous fluid remains unclear. Innumerable studies have compared sodium bicarbonate and isotonic saline and have combined fluid hydration with pharmacological interventions, particularly N-acetyl-cysteine. However, abundant systematic reviews and meta-analyses have provided conflicting conclusions and have recognized a significant degree of heterogeneity between studies and publication bias. Most studies comparing intravenous sodium bicarbonate and saline were small. They often enrolled patients with a low risk for AKI, yielding low serious events (renal replacement therapy), and used different protocols for administration of fluids. Based on current literature, intravenous sodium bicarbonate does not seem to be more efficient than saline for the prevention of contrast-media-induced AKI, cardiac surgery-associated AKI, pigment nephropathy or septic AKI. However, some cohort studies or prospective randomized trials did track and report serious adverse events, such as higher rates of AKI or higher in-hospital mortality. At present, it should be concluded that the use of intravenous sodium bicarbonate administration to prevent AKI should be evaluated further in multicenter randomized double-blind trials rather than adopted into routine clinical practice.}, }
@article {pmid25164014, year = {2014}, author = {Kesarwani, P and Al-Khami, AA and Scurti, G and Thyagarajan, K and Kaur, N and Husain, S and Fang, Q and Naga, OS and Simms, P and Beeson, G and Voelkel-Johnson, C and Garrett-Mayer, E and Beeson, CC and Nishimura, MI and Mehrotra, S}, title = {Promoting thiol expression increases the durability of antitumor T-cell functions.}, journal = {Cancer research}, volume = {74}, number = {21}, pages = {6036-6047}, pmid = {25164014}, issn = {1538-7445}, support = {R01AR057643/AR/NIAMS NIH HHS/United States ; R01 AR057643/AR/NIAMS NIH HHS/United States ; R01 CA104947/CA/NCI NIH HHS/United States ; R01CA104947/CA/NCI NIH HHS/United States ; P01CA154778/CA/NCI NIH HHS/United States ; P20GM10354202/GM/NIGMS NIH HHS/United States ; R21 CA137725/CA/NCI NIH HHS/United States ; R21CA137725/CA/NCI NIH HHS/United States ; R01 CA138930/CA/NCI NIH HHS/United States ; U54 GM104940/GM/NIGMS NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; P01 CA154778/CA/NCI NIH HHS/United States ; R01CA138930/CA/NCI NIH HHS/United States ; }, mesh = {CD8-Positive T-Lymphocytes/immunology/*metabolism ; Cell- and Tissue-Based Therapy ; Humans ; Immunologic Memory/immunology ; *Immunotherapy, Adoptive ; Lymphocyte Activation ; Neoplasms/*immunology/therapy ; Receptors, Antigen, T-Cell/immunology ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Ex vivo-expanded CD8(+) T cells used for adoptive immunotherapy generally acquire an effector memory-like phenotype (TEM cells). With regard to therapeutic applications, two undesired features of this phenotype in vivo are limited persistence and reduced antitumor efficacy, relative to CD8(+) T cells with a central memory-like phenotype (TCM cells). Furthermore, there is incomplete knowledge about all the differences between TEM and TCM cells that may influence tumor treatment outcomes. Given that TCM cells survive relatively longer in oxidative tumor microenvironments, we investigated the hypothesis that TCM cells possess relatively greater antioxidative capacity than TEM cells. Here, we report that TCM cells exhibit a relative increase compared with TEM cells in the expression of cell surface thiols, a key target of cellular redox controls, along with other antioxidant molecules. Increased expression of redox regulators in TCM cells inversely correlated with the generation of reactive oxygen and nitrogen species, proliferative capacity, and glycolytic enzyme levels. Notably, T-cell receptor-transduced T cells pretreated with thiol donors, such as N-acetyl cysteine or rapamycin, upregulated thiol levels and antioxidant genes. A comparison of antitumor CD8(+) T-cell populations on the basis of surface thiol expression showed that thiol-high cells persisted longer in vivo and exerted superior tumor control. Our results suggest that higher levels of reduced cell surface thiols are a key characteristic of T cells that can control tumor growth and that profiling this biomarker may have benefits to adoptive T-cell immunotherapy protocols.}, }
@article {pmid25161103, year = {2015}, author = {Ravera, S and Capanni, C and Tognotti, D and Bottega, R and Columbaro, M and Dufour, C and Cappelli, E and Degan, P}, title = {Inhibition of metalloproteinase activity in FANCA is linked to altered oxygen metabolism.}, journal = {Journal of cellular physiology}, volume = {230}, number = {3}, pages = {603-609}, doi = {10.1002/jcp.24778}, pmid = {25161103}, issn = {1097-4652}, support = {GTB12001/TI_/Telethon/Italy ; }, mesh = {Antioxidants/administration &amp; dosage ; Bone Marrow/metabolism/pathology ; Chromosomal Instability/genetics ; DNA Repair/genetics ; DNA-Binding Proteins ; Fanconi Anemia/drug therapy/*metabolism/pathology ; Female ; Humans ; Metalloproteases/antagonists &amp; inhibitors/*metabolism ; Mitochondrial Proteins/metabolism ; Muscle Proteins/metabolism ; Muscle, Skeletal/*growth &amp; development/metabolism/pathology ; Oxygen/*metabolism ; Vimentin/metabolism ; }, abstract = {Bone marrow (BM) failure, increased risk of myelodysplastic syndrome, acute leukaemia and solid tumors, endocrinopathies and congenital abnormalities are the major clinical problems in Fanconi anemia patients (FA). Chromosome instability and DNA repair defects are the cellular characteristics used for the clinical diagnosis. However, these biological defects are not sufficient to explain all the clinical phenotype of FA patients. The known defects are structural alteration in cell cytoskeleton, altered structural organization for intermediate filaments, nuclear lamina, and mitochondria. These are associated with different expression and/or maturation of the structural proteins vimentin, mitofilin, and lamin A/C suggesting the involvement of metalloproteinases (MPs). Matrix metalloproteinases (MMP) are involved in normal physiological processes such as human skeletal tissue development, maturation, and hematopoietic reconstitution after bone marrow suppression. Current observations upon the eventual role of MPs in FA cells are largely inconclusive. We evaluated the overall MPs activity in FA complementation group A (FANCA) cells by exposing them to the antioxidants N-acetyl cysteine (NAC) and resveratrol (RV). This work supports the hypothesis that treatment of Fanconi patients with antioxidants may be important in FA therapy.}, }
@article {pmid25156898, year = {2014}, author = {Forgiarini, LF and Forgiarini, LA and da Rosa, DP and Silva, MB and Mariano, R and Paludo, Ade O and Andrade, CF}, title = {N-acetylcysteine administration confers lung protection in different phases of lung ischaemia-reperfusion injury.}, journal = {Interactive cardiovascular and thoracic surgery}, volume = {19}, number = {6}, pages = {894-899}, doi = {10.1093/icvts/ivu258}, pmid = {25156898}, issn = {1569-9285}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Intravenous ; Animals ; Anti-Inflammatory Agents/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Caspase 3/metabolism ; Cytoprotection ; Disease Models, Animal ; Hemodynamics/drug effects ; I-kappa B Kinase/metabolism ; Inflammation Mediators/metabolism ; Interleukin-1beta/metabolism ; Lipid Peroxidation/drug effects ; Lung/*blood supply/*drug effects/metabolism/pathology ; Lung Injury/metabolism/pathology/physiopathology/*prevention &amp; control ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress/drug effects ; Peroxidase/metabolism ; Rats, Wistar ; Reperfusion Injury/metabolism/pathology/physiopathology/*prevention &amp; control ; Superoxide Dismutase/metabolism ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {OBJECTIVES: To verify the effects of N-acetylcysteine (NAC) administered before and after ischaemia in an animal model of lung ischaemia-reperfusion (IR) injury.<br><br>METHODS: Twenty-four Wistar rats were subjected to an experimental model of selective left pulmonary hilar clamping for 45 min followed by 2 h of reperfusion. The animals were divided into four groups: control group (SHAM), ischaemia-reperfusion, N-acetylcysteine-preischaemia (NAC-Pre) and NAC-postischaemia (NAC-Post). We recorded the haemodynamic parameters, blood gas analysis and histology. We measured the thiobarbituric acid reactive substances concentration; the expression of superoxide dismutase (SOD), inducible nitric oxide synthase (iNOS), nitrotyrosine, cleaved caspase 3, nuclear factor &#x3ba;B (NF-&#x3ba;B), NF-kappa-B inhibitor alpha (I&#x3ba;B-&#x3b1;), tumour necrosis factor alpha (TNF-&#x3b1;) and interleukin-1 beta (IL-1&#x3b2;); myeloperoxidase activity (MPO).<br><br>RESULTS: No significant differences were observed in the haemodynamic parameters, blood gas analysis and SOD activity among the groups. Lipid peroxidation was significantly higher in the IR and NAC-Pre groups (P < 0.01). The expression of nitrotyrosine, cleaved caspase 3, NF-&#x3ba;B, I&#x3ba;B-&#x3b1;, TNF-&#x3b1; and IL-1&#x3b2; were significantly higher in the IR group when compared with the SHAM and NAC groups (P < 0.01). The NAC-Pre group showed a significantly higher expression of these proteins when compared with the SHAM and NAC-Post groups (P < 0.05). After reperfusion, the expression of iNOS increased almost uniformly in all groups when compared with the SHAM group (P < 0.01). The histological analysis showed fewer inflammatory cells in the NAC groups.<br><br>CONCLUSIONS: The intravenous administration of NAC demonstrated protective properties against lung IR injury. The use of NAC immediately after reperfusion potentiates its protective effects.}, }
@article {pmid25156619, year = {2014}, author = {Sen, H and Deniz, S and Yedekci, AE and Inangil, G and Muftuoglu, T and Haholu, A and Ozkan, S}, title = {Effects of dexpanthenol and N-acetylcysteine pretreatment in rats before renal ischemia/reperfusion injury.}, journal = {Renal failure}, volume = {36}, number = {10}, pages = {1570-1574}, doi = {10.3109/0886022X.2014.949768}, pmid = {25156619}, issn = {1525-6049}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/pathology/*prevention &amp; control ; Animals ; Drug Evaluation, Preclinical ; Free Radical Scavengers/*therapeutic use ; Kidney/pathology ; Male ; Pantothenic Acid/*analogs &amp; derivatives/therapeutic use ; Random Allocation ; Rats, Wistar ; Reperfusion Injury/pathology/*prevention &amp; control ; }, abstract = {BACKGROUND: We investigated the anti-inflammatory and protective effects of concomitant use of dexpanthenol (DXP) and N-acetylcysteine (NAC) induced ischemia/reperfusion (I/R) injury of kidney.<br><br>METHODS: Forty rats were randomly divided into 5 groups. In all groups except for Group 1(Sham), renal arteries bilaterally occluded with vascular clamp for IR injury. Group 1(Sham), received a single dose of 10&#x2009;mL/kg isotonic saline daily by intraperitoneal (IP) injection for three days. Group 2(IR), received a single dose of 10&#x2009;mL/kg isotonic saline daily by IP injection for three days. Group 3(IR&#x2009;+&#x2009;NAC), received 300&#x2009;mg/kg NAC daily by IP injection for three days. Group 4(IR&#x2009;+&#x2009;DXP), received 500&#x2009;mg/kg DXP daily by IP injection for three days. Group 5(IR&#x2009;+&#x2009;NAC&#x2009;+&#x2009;DXP), received 500&#x2009;mg/kg DXP and 300&#x2009;mg/kg NAC daily by IP injection for three days. Serum urea (BUN), creatinine (Cr) and neutrophil gelatinase-associated lipocalin (NGAL, lipocalin 2, siderocalin) levels were measured as kidney function tests. TNF-&#x3b1; levels were measured as inflammatory marker. Tissue sections were evaluated histopathologically under light microscopy.<br><br>RESULTS: IR&#x2009;+&#x2009;NAC&#x2009;+&#x2009;DXP group received both NAC and DXP before induction of renal I/R and as the biochemical and histopathological data revealed the results of the IR&#x2009;+&#x2009;NAC&#x2009;+&#x2009;DXP group and sham group were similar. Biochemically and histopathologically, combined use of NAC and DXP has better results when each of them used alone.<br><br>CONCLUSION: We concluded that concomitant use of DXP and NAC plays a major role against I/R injury and may be useful in acute treatment of I/R induced renal failure.}, }
@article {pmid25155888, year = {2015}, author = {Jeon, YJ and Kim, HS and Song, KS and Han, HJ and Park, SH and Chang, W and Lee, MY}, title = {Protective effect of dieckol against chemical hypoxia-induced cytotoxicity in primary cultured mouse hepatocytes.}, journal = {Drug and chemical toxicology}, volume = {38}, number = {2}, pages = {180-187}, doi = {10.3109/01480545.2014.928719}, pmid = {25155888}, issn = {1525-6014}, mesh = {Animals ; Benzofurans/*pharmacology ; Cell Hypoxia/*drug effects ; Cell Survival/*drug effects ; Cells, Cultured ; Cobalt/administration &amp; dosage/toxicity ; Cyclooxygenase 2/metabolism ; Dose-Response Relationship, Drug ; Hepatocytes/*drug effects/pathology ; Imidazoles/pharmacology ; Male ; Mice ; Mice, Inbred ICR ; Nitrobenzenes/pharmacology ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Sulfonamides/pharmacology ; Time Factors ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Hepatic ischemic injury is a major complication arising from liver surgery, transplantation, or other ischemic diseases, and both reactive oxygen species (ROS) and pro-inflammatory mediators play the role of key mediators in hepatic ischemic injury. In this study, we examined the effect of dieckol in chemical hypoxia-induced injury in mouse hepatocytes. Cell viability was significantly decreased after treatment with cobalt chloride (CoCl2), a well-known hypoxia mimetic agent in a time- and dose-dependent manner. Pretreatment with dieckol before exposure to CoCl2 significantly attenuated the CoCl2-induced decrease of cell viability. Additionally, pretreatment with dieckol potentiated the CoCl2-induced decrease of Bcl-2 expression and attenuated the CoCl2-induced increase in the expression of Bax and caspase-3. Treatment with CoCl2 resulted in an increased intracellular ROS generation, which is inhibited by dieckol or N-acetyl cysteine (NAC, a ROS scavenger), and p38 MAPK phosphorylation, which is also blocked by dieckol or NAC. In addition, dieckol and SB203580 (p38 MAPK inhibitor) increased the CoCl2-induced decrease of Bcl-2 expression and decreased the CoCl2-induced increase of Bax and caspase-3 expressions. CoCl2-induced decrease of cell viability was attenuated by pretreatment with dieckol, NAC, and SB203580. Furthermore, dieckol attenuated CoCl2-induced COX-2 expression. Similar to the effect of dieckol, NAC also blocked CoCl2-induced COX-2 expression. Additionally, CoCl2-induced decrease of cell viability was attenuated not only by dieckol and NAC but also by NS-398 (a selective COX-2 inhibitor). In conclusion, dieckol protects primary cultured mouse hepatocytes against CoCl2-induced cell injury through inhibition of ROS-activated p38 MAPK and COX-2 pathway.}, }
@article {pmid25148872, year = {2014}, author = {González-Flores, D and De Nicola, M and Bruni, E and Caputo, F and Rodríguez, AB and Pariente, JA and Ghibelli, L}, title = {Nanoceria protects from alterations in oxidative metabolism and calcium overloads induced by TNFα and cycloheximide in U937 cells: pharmacological potential of nanoparticles.}, journal = {Molecular and cellular biochemistry}, volume = {397}, number = {1-2}, pages = {245-253}, pmid = {25148872}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Antifungal Agents/*pharmacology ; Apoptosis/drug effects ; Calcium/*metabolism ; Cerium/*pharmacology ; Chromans/pharmacology ; Cycloheximide/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; *Nanoparticles ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/*pharmacology ; U937 Cells ; }, abstract = {The present study is aimed to determine the protective effect of a novel nanoparticle with antioxidant properties, nanoceria, on reactive oxygen species (ROS) production, and calcium signaling evoked by the tumor necrosis factor-alpha (TNFα) in combination with cycloheximide (CHX) on apoptosis in the human histiocytic lymphoma cell line U937. Our results show that treatment of U937 cells with 10 ng/mL TNFα in combination with 1 μg/mL CHX led to several Ca(2+) alterations. These stimulatory effects on calcium signals were followed by intracellular ROS production and mitochondria membrane depolarization, as well as a time-dependent increase in caspase-8 and -9 activities. Our results show that the pretreatment with well known antioxidants such as trolox and N-acetyl cysteine (NAC) partially reduced the apoptotic effects due to the administration of TNFα plus cycloheximide. Furthermore, nanoceria had a stronger protective effect than trolox or NAC. Our findings also suggest that TNFα plus cycloheximide-induced apoptosis is dependent on alterations in cytosolic concentration of calcium [Ca(2+)]c and ROS generation in human histiocytic U937 cells.}, }
@article {pmid25148231, year = {2014}, author = {Vidart, J and Wajner, SM and Leite, RS and Manica, A and Schaan, BD and Larsen, PR and Maia, AL}, title = {N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {99}, number = {12}, pages = {4537-4545}, pmid = {25148231}, issn = {1945-7197}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Acute Disease ; Acute-Phase Reaction ; Adult ; Aged ; Antioxidants/adverse effects/*therapeutic use ; Female ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Myocardial Infarction/*complications ; Pituitary Gland/drug effects ; Prospective Studies ; Thyroid Gland/drug effects ; Thyroid Hormones/blood ; Treatment Outcome ; }, abstract = {CONTEXT: The acute phase of the nonthyroidal illness syndrome (NTIS) is characterized by low T3 and high rT3 levels, affecting up to 75% of critically ill patients. Oxidative stress has been implicated as a causative factor of the disturbed peripheral thyroid hormone metabolism.<br><br>OBJECTIVE: The objective of the study was to investigate whether N-acetylcysteine (NAC), a potent intracellular antioxidant, can prevent NTIS in patients with acute myocardial infarction.<br><br>DESIGN: This was a randomized, multicenter clinical trial.<br><br>SETTINGS: Consecutive patients admitted to the emergency and intensive care units of two tertiary hospitals in southern Brazil were recruited. Patients and intervention included 67 patients were randomized to receive NAC or placebo during 48 hours. Baseline characteristics and blood samples for thyroid hormones and oxidative parameters were collected.<br><br>MAIN OUTCOME: Variation of serum T3 and rT3 levels was measured.<br><br>RESULTS: Baseline characteristics were similar between groups (all P > .05). T3 levels decreased in the placebo group at 12 hours of follow-up (P = .002) but not in NAC-treated patients (P = .10). Baseline rT3 levels were elevated in both groups and decreased over the initial 48 hours in the NAC-treated patients (P = .003) but not in the control group (P = .75). The free T4 and TSH levels were virtually identical between the groups throughout the study period (P > .05). Measurement of total antioxidant status and total carbonyl content demonstrated that oxidative balance was deranged in acute myocardial infarction patients, whereas NAC corrected these alterations (P < .001).<br><br>CONCLUSIONS: NAC administration prevents the derangement in thyroid hormone concentrations commonly occurring in the acute phase of acute myocardial infarction, indicating that oxidative stress is involved in the NTIS pathophysiology.}, }
@article {pmid25147347, year = {2015}, author = {Shimada, K and Uzui, H and Ueda, T and Lee, JD and Kishimoto, C}, title = {N-Acetylcysteine Ameliorates Experimental Autoimmune Myocarditis in Rats via Nitric Oxide.}, journal = {Journal of cardiovascular pharmacology and therapeutics}, volume = {20}, number = {2}, pages = {203-210}, doi = {10.1177/1074248414547574}, pmid = {25147347}, issn = {1940-4034}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Autoimmune Diseases/*drug therapy/physiopathology ; Disease Models, Animal ; Intercellular Adhesion Molecule-1/physiology ; Myocarditis/*drug therapy/physiopathology ; Nitric Oxide/*physiology ; Rats ; Rats, Inbred Lew ; Superoxides/metabolism ; }, abstract = {BACKGROUND: Oxidative stress may play an important role in the development of myocarditis. We investigated the effects of N-acetylcysteine (NAC), a potent antioxidant, on experimental autoimmune myocarditis (EAM) in rats.<br><br>METHODS AND RESULTS: A rat model of porcine myosin-induced EAM was used. After the immunization with myosin, NAC (20 mg/kg/d) or saline was injected intraperitoneally on days 1 to 21. Additional myosin-immunized rats treated with NAC were orally given 25 mg/kg/d of N(G)-nitro-l-arginine methylester (l-NAME), an inhibitor of nitric oxide (NO) synthase, and N(G)-nitro-d-arginine methylester (d-NAME), an inactive enantiomer. The NAC treatment improved cardiac pathology associated with reduced superoxide production. In the EAM rats treated with NAC associated with oral l-NAME, but not with oral d-NAME, the severity of myocarditis was not reduced. Expression of intercellular adhesion molecule 1 was reduced by NAC treatment. Myocardial c-kit(+) cells were demonstrated only in the NAC-treated group. Hemodynamic study showed that the increased left ventricular mass produced by myocardial inflammation tended to be reduced by NAC treatment.<br><br>CONCLUSION: Treatment with NAC ameliorated myocardial injury via NO system in a rat model of myocarditis.}, }
@article {pmid25147340, year = {2014}, author = {Vikram, A and Kim, YR and Kumar, S and Naqvi, A and Hoffman, TA and Kumar, A and Miller, FJ and Kim, CS and Irani, K}, title = {Canonical Wnt signaling induces vascular endothelial dysfunction via p66Shc-regulated reactive oxygen species.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {34}, number = {10}, pages = {2301-2309}, pmid = {25147340}, issn = {1524-4636}, support = {R01 HL070929/HL/NHLBI NIH HHS/United States ; R01 HL094959/HL/NHLBI NIH HHS/United States ; R21 HL098892/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Aorta/drug effects/enzymology ; Cattle ; Coculture Techniques ; Diet, High-Fat ; Disease Models, Animal ; Endothelial Cells/drug effects/*enzymology ; HEK293 Cells ; Human Umbilical Vein Endothelial Cells/enzymology ; Humans ; Hyperlipidemias/enzymology/physiopathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; NADPH Oxidases/genetics/metabolism ; *Oxidative Stress ; Phosphorylation ; RNA Interference ; Reactive Oxygen Species/*metabolism ; Shc Signaling Adaptor Proteins/genetics/*metabolism ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; Transfection ; U937 Cells ; Vasodilation ; Vasodilator Agents/pharmacology ; *Wnt Signaling Pathway ; Wnt3A Protein/genetics/*metabolism ; beta Catenin/metabolism ; }, abstract = {OBJECTIVE: Reactive oxygen species regulate canonical Wnt signaling. However, the role of the redox regulatory protein p66(Shc) in the canonical Wnt pathway is not known. We investigated whether p66(Shc) is essential for canonical Wnt signaling in the endothelium and determined whether the canonical Wnt pathway induces vascular endothelial dysfunction via p66(Shc)-mediated oxidative stress.<br><br>APPROACH AND RESULTS: The canonical Wnt ligand Wnt3a induced phosphorylation (activation) of p66(Shc) in endothelial cells. Wnt3a-stimulated dephosphorylation of &#x3b2;-catenin, and &#x3b2;-catenin-dependent transcription, was inhibited by knockdown of p66(Shc). Exogenous H2O2-induced &#x3b2;-catenin dephosphorylation was also mediated by p66(Shc). Moreover, p66(Shc) overexpression dephosphorylated &#x3b2;-catenin and increased &#x3b2;-catenin-dependent transcription, independent of Wnt3a ligand. P66(Shc)-induced &#x3b2;-catenin dephosphorylation was inhibited by antioxidants N-acetyl cysteine and catalase. Wnt3a upregulated endothelial NADPH oxidase-4, and &#x3b2;-catenin dephosphorylation was suppressed by knocking down NADPH oxidase-4 and by antioxidants. Wnt3a increased H2O2 levels in endothelial cells and impaired endothelium-dependent vasorelaxation in mouse aortas, both of which were rescued by p66(Shc) knockdown. P66(Shc) knockdown also inhibited adhesion of monocytes to Wnt3a-stimulated endothelial cells. Furthermore, constitutively active &#x3b2;-catenin expression in the endothelium increased vascular reactive oxygen species and impaired endothelium-dependent vasorelaxation. In vivo, high-fat diet feeding-induced endothelial dysfunction in mice was associated with increased endothelial Wnt3a, dephosphorylated &#x3b2;-catenin, and phosphorylated p66(Shc). High-fat diet-induced dephosphorylation of endothelial &#x3b2;-catenin was diminished in mice in which p66(Shc) was knocked down.<br><br>CONCLUSIONS: p66(Shc) plays a vital part in canonical Wnt signaling in the endothelium and mediates Wnt3a-stimulated endothelial oxidative stress and dysfunction.}, }
@article {pmid25147052, year = {2015}, author = {Liu, JW and Montero, M and Bu, L and De Leon, M}, title = {Epidermal fatty acid-binding protein protects nerve growth factor-differentiated PC12 cells from lipotoxic injury.}, journal = {Journal of neurochemistry}, volume = {132}, number = {1}, pages = {85-98}, pmid = {25147052}, issn = {1471-4159}, support = {P20 MD006988/MD/NIMHD NIH HHS/United States ; R25 GM060507/GM/NIGMS NIH HHS/United States ; 5R25GM060507/GM/NIGMS NIH HHS/United States ; 5P2MD006988/MD/NIMHD NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Eye Proteins/genetics/*physiology ; Fatty Acid-Binding Proteins/genetics/*physiology ; Lipids/*antagonists &amp; inhibitors/*toxicity ; Nerve Growth Factor/*pharmacology ; Nerve Tissue Proteins/genetics/*physiology ; PC12 Cells ; Palmitic Acid/antagonists &amp; inhibitors/toxicity ; RNA, Small Interfering/genetics ; Rats ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/pharmacology ; Transfection ; }, abstract = {Epidermal fatty acid-binding protein (E-FABP/FABP5/DA11) binds and transport long-chain fatty acids in the cytoplasm and may play a protecting role during neuronal injury. We examined whether E-FABP protects nerve growth factor-differentiated PC12 cells (NGFDPC12 cells) from lipotoxic injury observed after palmitic acid (C16:0; PAM) overload. NGFDPC12 cells cultures treated with PAM/bovine serum albumin at 0.3 mM/0.15 mM show PAM-induced lipotoxicity (PAM-LTx) and apoptosis. The apoptosis was preceded by a cellular accumulation of reactive oxygen species (ROS) and higher levels of E-FABP. Antioxidants MCI-186 and N-acetyl cysteine prevented E-FABP's induction in expression by PAM-LTx, while tert-butyl hydroperoxide increased ROS and E-FABP expression. Non-metabolized methyl ester of PAM, methyl palmitic acid (mPAM), failed to increase cellular ROS, E-FABP gene expression, or trigger apoptosis. Treatment of NGFDPC12 cultures with siE-FABP showed reduced E-FABP levels correlating with higher accumulation of ROS and cell death after exposure to PAM. In contrast, increasing E-FABP cellular levels by pre-loading the cells with recombinant E-FABP diminished the PAM-induced ROS and cell death. Finally, agonists for PPARβ (GW0742) or PPARγ (GW1929) increased E-FABP expression and enhanced the resistance of NGFDPC12 cells to PAM-LTx. We conclude that E-FABP protects NGFDPC12 cells from lipotoxic injury through mechanisms that involve reduction of ROS. Epidermal fatty acid-binding protein (E-FABP) may protect nerve cells from the damaging exposure to high levels of free fatty acids (FA). We show that E-FABP can neutralize the effects of reactive oxygen species (ROS) generated by the high levels of FA in the cell and protect PC12 cells from lipotoxic injuries common in Type 2 diabetes neuropathy. Potentially, E-FABP gene up-regulation may be mediated through the NFkB pathway and future studies are needed to further evaluate this proposition.}, }
@article {pmid25139326, year = {2014}, author = {Mattiolo, P and Barbero-Farran, A and Yuste, VJ and Boix, J and Ribas, J}, title = {2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53.}, journal = {Biochemical pharmacology}, volume = {91}, number = {3}, pages = {301-311}, doi = {10.1016/j.bcp.2014.08.005}, pmid = {25139326}, issn = {1873-2968}, mesh = {Antineoplastic Agents/*pharmacology ; Buthionine Sulfoximine/pharmacology ; Caspases/metabolism ; Cell Death/drug effects ; Chromatin/genetics ; Gene Expression Regulation/drug effects ; *Genes, p53 ; HCT116 Cells/drug effects ; Humans ; Necrosis/chemically induced ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Sulfonamides/*pharmacology ; }, abstract = {2-Phenylethynesulfonamide (PES) or pifithrin-μ is a promising anticancer agent with preferential toxicity for cancer cells. The type of cell death and the molecular cascades activated by this compound are controversial. Here, we demonstrate PES elicits a caspase- and BAX/BAK-independent non-necroptotic necrotic cell death, since it is not inhibited by necrostatin-1. This process is characterized by an early generation of reactive oxygen species (ROS) resulting in p53 up-regulation. Accordingly, thiolic antioxidants protect cells from PES-induced death. Furthermore, inhibiting the natural sources of glutathione with l-buthionine-sulfoximine (BSO) strongly cooperates with PES in triggering cytotoxicity. Genetically modified p53-null or p53 knocked-down cells show resistance to PES-driven necrosis. The predominant localization of p53 in chromatin-enriched fractions added to the up-regulation of the p53-responsive gene p21, strongly suggest the involvement of a transcription-dependent p53 program. On the other hand, we report an augmented production of ROS in p53-positive cells that, added to the increased p53 content in response to PES-elicited ROS, suggests that p53 and ROS are mutually regulated in response to PES. In sum, p53 up-regulation by ROS triggers a positive feedback loop responsible of further increasing ROS production and reinforcing PES-driven non-necroptotic necrosis.}, }
@article {pmid25139304, year = {2014}, author = {Steinebrunner, N and Mogler, C and Vittas, S and Hoyler, B and Sandig, C and Stremmel, W and Eisenbach, C}, title = {Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse.}, journal = {BMC gastroenterology}, volume = {14}, number = {}, pages = {148}, pmid = {25139304}, issn = {1471-230X}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/blood/drug effects ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/etiology/immunology/*mortality ; Cholinesterase Inhibitors/*pharmacology ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Interleukin-1beta/drug effects/immunology ; Lactate Dehydrogenases/blood/drug effects ; Liver/*drug effects/immunology ; Liver Failure, Acute/chemically induced/immunology/*mortality ; Mice ; Mice, Inbred BALB C ; Neostigmine/*pharmacology ; Tumor Necrosis Factor-alpha/drug effects/immunology ; }, abstract = {BACKGROUND: Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic pharmaceutical substances in the world and accounts for most cases of drug induced liver injury resulting in acute liver failure. Acute liver failure initiates a sterile inflammatory response with release of cytokines and innate immune cell infiltration in the liver. This study investigates, whether pharmacologic acetylcholinesterase inhibition with neostigmine diminishes liver damage in acute liver failure via the cholinergic anti-inflammatory pathway.<br><br>METHODS: Acute liver failure was induced in BALB/c mice by a toxic dose of acetaminophen (APAP). Neostigmine and/or N-acetyl-cysteine (NAC) were applied therapeutically at set time points and the survival was investigated. Liver damage was assessed by serum parameters, histopathology and serum cytokine assays 12 h after initiation of acute liver failure.<br><br>RESULTS: Serum parameters, histopathology and serum cytokine assays showed pronounced features of acute liver failure 12 h after application of acetaminophen (APAP). Neostigmine treatment led to significant reduction of serum liver enzymes (LDH (47,147 &#xb1; 12,726 IU/l vs. 15,822 &#xb1; 10,629 IU/l, p = 0.0014) and ALT (18,048 &#xb1; 4,287 IU/l vs. 7,585 &#xb1; 5,336 IU/l, p = 0.0013), APAP-alone-treated mice vs. APAP + neostigmine-treated mice), inflammatory cytokine levels (IL-1&#x3b2; (147 &#xb1; 19 vs. 110 &#xb1; 25, p = 0.0138) and TNF-&#x3b1; (184 &#xb1; 23 vs. 130 &#xb1; 33, p = 0.0086), APAP-alone-treated mice vs. APAP + neostigmine-treated mice) and histopathological signs of damage.Animals treated with NAC in combination with the peripheral cholinesterase inhibitor neostigmine showed prolonged survival and improved outcome.<br><br>CONCLUSIONS: Neostigmine is an acetylcholinesterase inhibitor that ameliorates the effects of APAP-induced acute liver failure in the mouse and therefore may provide new treatment options for affected patients.}, }
@article {pmid25135879, year = {2014}, author = {Liu, L and Li, T and Tan, J and Fu, J and Guo, Q and Ji, H and Zhang, Y}, title = {NG as a novel nitric oxide donor induces apoptosis by increasing reactive oxygen species and inhibiting mitochondrial function in MGC803 cells.}, journal = {International immunopharmacology}, volume = {23}, number = {1}, pages = {27-36}, doi = {10.1016/j.intimp.2014.08.005}, pmid = {25135879}, issn = {1878-1705}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Azo Compounds/*pharmacology ; Caspase 9/metabolism ; Cell Proliferation/drug effects ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Humans ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Mitochondria/*drug effects/physiology ; Nitric Oxide/metabolism ; Nitric Oxide Donors/*pharmacology ; Oxidative Stress/drug effects ; Prodrugs/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Saponins/*pharmacology ; Stomach Neoplasms/*metabolism/pathology ; Superoxide Dismutase/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {NG, O(2)-(2,4-dinitro-5-{[2-(12-en-28-β-D-galactopyranosyl-oleanolate-3-yl)-oxy-2-oxoethyl] amino} phenyl) 1-(N-hydroxyethylmethylamino) diazen-1-ium-1,2-diolate, was identified in our laboratory as a novel nitric oxide-releasing prodrug with antitumor effects. A previous study showed that NG inhibited cell growth, and induced apoptosis in HepG2 cells. In this study, the inhibitory effects of NG on the viability of MGC803 cells were examined using methylthiazolyl tetrazolium biomide (MTT) assay, neutral red assay and trypan blue exclusion test. The results showed that NG had strong cytotoxicity to induce apoptosis, which was characterized by a significant externalization of phosphatidylserine, nuclear morphological changes and enhanced Bax-to-Bcl-2 ratio. Moreover, the release of cytochrome c (Cyt c) from mitochondria and the activation of caspase-9/3 were also detected, indicating that NG may induce apoptosis through a mitochondrial-mediated pathway. NG induced mitochondrial dysfunction in MGC803 cells by altering membrane potential (△Ψm), the inhibition of complexes I, II and IV consequently decreasing ATP level. Furthermore, the treatment of MGC803 cells with NG caused a marked rise in oxidative stress as characterized by accumulation of reactive oxygen species (ROS), excessive malondialdehyde (MDA) production and a reduction in glutathione hormone (GSH) level and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. In addition, pretreatment with N-acetylcysteine (NAC), a GSH synthesis precursor, was partially protective against the NG-induced ROS generation and cell apoptosis. In contrast, pretreatment of MGC803 cells with L-buthionine-S, R-sulfoximine (BSO), a GSH synthesis inhibitor, increased the ROS levels, and aggravated cell apoptosis by NG. These results suggest that NG-induced apoptosis in MGC803 cells is mediated, at least in part, by the increase in ROS production, oxidative stress and mitochondrial dysfunction.}, }
@article {pmid25133498, year = {2014}, author = {Gosselin, S and Juurlink, DN and Kielstein, JT and Ghannoum, M and Lavergne, V and Nolin, TD and Hoffman, RS and , }, title = {Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {52}, number = {8}, pages = {856-867}, doi = {10.3109/15563650.2014.946994}, pmid = {25133498}, issn = {1556-9519}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy ; Drug Overdose/*drug therapy ; Humans ; Observational Studies as Topic ; Randomized Controlled Trials as Topic ; Renal Dialysis/*standards ; }, abstract = {BACKGROUND: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTR) in poisoning and the results are presented here for acetaminophen (APAP).<br><br>METHODS: After a systematic review of the literature, a subgroup selected and reviewed the articles and summarized clinical and toxicokinetic data in order to propose structured voting statements following a pre-determined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Following discussion, a second vote determined the final recommendations.<br><br>RESULTS: Twenty-four articles (1 randomized controlled trial, 1 observational study, 2 pharmacokinetic studies, and 20 case reports or case series) were identified, yielding an overall very low quality of evidence for all recommendations. Clinical data on 135 patients and toxicokinetic data on 54 patients were analyzed. Twenty-three fatalities were reviewed. The workgroup agreed that N-acetylcysteine (NAC) is the mainstay of treatment, and that ECTR is not warranted in most cases of APAP poisoning. However, given that APAP is dialyzable, the workgroup agreed that ECTR is suggested in patients with excessively large overdoses who display features of mitochondrial dysfunction. This is reflected by early development of altered mental status and severe metabolic acidosis prior to the onset of hepatic failure. Specific recommendations for ECTR include an APAP concentration over 1000 mg/L if NAC is not administered (1D), signs of mitochondrial dysfunction and an APAP concentration over 700 mg/L (4630 mmol/L) if NAC is not administered (1D) and signs of mitochondrial dysfunction and an APAP concentration over 900 mg/L (5960 mmol/L) if NAC is administered (1D). Intermittent hemodialysis (HD) is the preferred ECTR modality in APAP poisoning (1D).<br><br>CONCLUSION: APAP is amenable to extracorporeal removal. Due to the efficacy of NAC, ECTR is reserved for rare situations when the efficacy of NAC has not been definitively demonstrated.}, }
@article {pmid25132466, year = {2014}, author = {Cabungcal, JH and Counotte, DS and Lewis, E and Tejeda, HA and Piantadosi, P and Pollock, C and Calhoon, GG and Sullivan, E and Presgraves, E and Kil, J and Hong, LE and Cuenod, M and Do, KQ and O'Donnell, P}, title = {Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia.}, journal = {Neuron}, volume = {83}, number = {5}, pages = {1073-1084}, pmid = {25132466}, issn = {1097-4199}, support = {R01 MH057683/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Animals, Newborn ; Antioxidants/*administration &amp; dosage ; Disease Models, Animal ; Dopamine Agonists/pharmacology ; Drug Administration Schedule ; Excitatory Amino Acid Agonists/toxicity ; Excitatory Postsynaptic Potentials/drug effects ; Female ; Gene Expression Regulation, Developmental/drug effects/*physiology ; Hippocampus/cytology/growth &amp; development/injuries ; Ibotenic Acid/toxicity ; In Vitro Techniques ; Neurons/drug effects/physiology ; Pregnancy ; Quinpirole/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reflex, Startle/drug effects/physiology ; Schizophrenia/etiology/*physiopathology/*prevention &amp; control ; }, abstract = {Abnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention.}, }
@article {pmid25128739, year = {2014}, author = {Yang, LY and Shen, SC and Cheng, KT and Subbaraju, GV and Chien, CC and Chen, YC}, title = {Hispolon inhibition of inflammatory apoptosis through reduction of iNOS/NO production via HO-1 induction in macrophages.}, journal = {Journal of ethnopharmacology}, volume = {156}, number = {}, pages = {61-72}, doi = {10.1016/j.jep.2014.07.054}, pmid = {25128739}, issn = {1872-7573}, mesh = {Anthracenes/pharmacology ; Apoptosis/*drug effects ; Catechols/*pharmacology ; Dose-Response Relationship, Drug ; Heme Oxygenase-1 ; Inflammation/*metabolism ; Lipopolysaccharides/antagonists &amp; inhibitors ; *Macrophages ; NF-kappa B/biosynthesis ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors ; Nitriles/pharmacology ; RNA, Small Interfering ; Reactive Oxygen Species ; Structure-Activity Relationship ; Sulfones/pharmacology ; Teichoic Acids/antagonists &amp; inhibitors ; Transcription Factor AP-1/biosynthesis ; }, abstract = {Phellinus linteus (Berkeley &amp; Curtis), a well-known medical fungus, has long been used as a traditional medicine in Oriental countries to treat various diseases, and hispolon (HIS) is one of its bioactive components. HIS is known to possess potent antineoplastic and antiviral properties; however, its effect on inflammatory apoptosis is still undefined.<br><br>MATERIALS AND METHODS: RAW264.7 macrophages were incubated with HIS for 30 min followed by LPS, LTA, or PGN stimulation for 12h. The expression of indicated proteins AP-1 and NF-&#x3ba;B transcriptional activities was examined by Western blotting using specific antibodies. Levels of NO and ROS were examined by Griess reaction, and DCHF-DA staining via flow cytometric analysis, respectively. AP-1 and NF-&#x3ba;B transcriptional activities were detected by luciferase reporter assay. Knockdown of HO-1 protein expression was performed by transfection of macrophages with HO-1 siRNA. Pharmacological inhibitors including ROS scavenger NAC, JNK inhibitor SP600125, NF-&#x3ba;B inhibitor BAY117082 were applied for mechanism study.<br><br>RESULTS: HIS showed concentration-dependent inhibition of LPS, LTA, and PGN-induced iNOS protein expressions and NO production by RAW264.7 macrophages. Accordingly, HIS protected RAW264.7 cells from LPS-, LTA-, and PGN-induced apoptosis. Increased HO-1 by HIS was detected at both protein and mRNA levels along with an increase in intracellular peroxide, and this was inhibited by the translational inhibitor, cycloheximide (CHX), the transcriptional inhibitor, actinomycin D (Act D), and the reactive oxygen species scavenger, N-acetylcysteine (NAC). A mechanistic study indicated that inhibition of c-Jun N-terminal kinase (JNK) protein phosphorylation, and activator protein (AP)-1 and nuclear factor (NF)-&#x3ba;B activation were involved in the anti-inflammatory actions of HIS in macrophages. A structure-activity relationship analysis showed that HIS expressed the most potent effect of inhibiting iNOS and apoptosis elicited by LPS, LTA, and PGN with a significant increase in HO-1 protein in macrophages.<br><br>CONCLUSIONS: Evidence supporting HIS prevention of inflammatory apoptosis via blocking NO production and inducing HO-1 protein expression in macrophages is provided, and the hydroxyl at position C3 is a critical substitution for the anti-inflammatory actions of HIS.}, }
@article {pmid25126945, year = {2014}, author = {Columbaro, M and Ravera, S and Capanni, C and Panfoli, I and Cuccarolo, P and Stroppiana, G and Degan, P and Cappelli, E}, title = {Treatment of FANCA cells with resveratrol and N-acetylcysteine: a comparative study.}, journal = {PloS one}, volume = {9}, number = {7}, pages = {e104857}, pmid = {25126945}, issn = {1932-6203}, support = {GTB12001/TI_/Telethon/Italy ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Cells, Cultured ; Drug Evaluation, Preclinical ; Fanconi Anemia/*drug therapy/pathology ; Humans ; Mitochondria/pathology ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/*pharmacology ; }, abstract = {Fanconi anemia (FA) is a genetic disorder characterised by chromosome instability, cytokine ipersensibility, bone marrow failure and abnormal haematopoiesis associated with acute myelogenous leukemia. Recent reports are contributing to characterize the peculiar FA metabolism. Central to these considerations appears that cells from complementation group A (FANCA) display an altered red-ox metabolism. Consequently the possibility to improve FA phenotypical conditions with antioxidants is considered. We have characterized from the structural and biochemical point of view the response of FANCA lymphocytes to N-acetyl-cysteine (NAC) and resveratrol (RV). Surprisingly both NAC and RV failed to revert all the characteristic of FA phenotype and moreover their effects are not super imposable. Our data suggest that we must be aware of the biological effects coming from antioxidant treatment.}, }
@article {pmid25126895, year = {2014}, author = {Srivastava, A and Ramachandran, S and Hameed, SP and Ahuja, V and Hosagrahara, VP}, title = {Identification and mitigation of a reactive metabolite liability associated with aminoimidazoles.}, journal = {Chemical research in toxicology}, volume = {27}, number = {9}, pages = {1586-1597}, doi = {10.1021/tx500212c}, pmid = {25126895}, issn = {1520-5010}, mesh = {Animals ; Aza Compounds/chemistry ; Benzimidazoles/analysis/*metabolism ; Chromatography, High Pressure Liquid ; Imines/chemistry ; Quinones/chemistry ; Rats ; Tandem Mass Spectrometry ; }, abstract = {Reactive metabolites (RMs) have been implicated as causal factors in many drug-associated idiosyncratic toxicities. This study aims at identification and mitigation of an RM liability associated with aminoimidazole and amino(aza)benzimidazole structural motifs from an antimalarial project. Nineteen compounds with different structural modifications were studied in rat and human liver microsomes using glutathione (GSH) and N-acetyl cysteine (NAC) as trapping agents for RM. Metabolite profiling of aminoimidazole compounds in initial studies revealed the presence of dihydrodiol metabolites suggestive of reactive epoxide precursors, confirmed by the identification of a dihydrohydroxy GSH conjugate in GSH supplemented incubations. Substitution of methyl group at a potential site of metabolism blocked the epoxidation; however, formation of an imine-methide RM was suspected. Masking the site of metabolism via benzimidazole and 4/7-azabenzimidazole resulted in the possible formation of quinone-imine intermediates as a product of bioactivation. Further, substitutions with electron withdrawing groups and steric crowding did not address this liability. Mitigation of bioactivation was achieved with 5/6-azabenzimidazole and with CF3 substitution at the 6-position of the 7-azabenzimidazole ring. Moreover, compounds devoid of imidazole -NH2 do not undergo bioactivation. This study, therefore, establishes aminoimidazole and amino(aza)benzimidazoles as potential toxicophores and describes ways to mitigate this bioactivation liability by chemical modification.}, }
@article {pmid25125976, year = {2014}, author = {Tse, HN and Tseng, CZ}, title = {Update on the pathological processes, molecular biology, and clinical utility of N-acetylcysteine in chronic obstructive pulmonary disease.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {9}, number = {}, pages = {825-836}, pmid = {25125976}, issn = {1178-2005}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Animals ; Anti-Inflammatory Agents/adverse effects/*therapeutic use ; Antioxidants/adverse effects/*therapeutic use ; Disease Progression ; Dose-Response Relationship, Drug ; Humans ; Lung/*drug effects/metabolism/pathology/physiopathology ; Oxidative Stress/*drug effects ; Pulmonary Disease, Chronic Obstructive/diagnosis/*drug therapy/metabolism/physiopathology ; Quality of Life ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a common and morbid disease characterized by high oxidative stress. Its pathogenesis is complex, and involves excessive oxidative stress (redox imbalance), protease/antiprotease imbalance, inflammation, apoptosis, and autoimmunity. Among these, oxidative stress has a pivotal role in the pathogenesis of COPD by initiating and mediating various redox-sensitive signal transduction pathways and gene expression. The protective physiological mechanisms of the redox balance in the human body, their role in the pathogenesis of COPD, and the clinical correlation between oxidative stress and COPD are reviewed in this paper. N-acetylcysteine (NAC) is a mucolytic agent with both antioxidant and anti-inflammatory properties. This paper also reviews the use of NAC in patients with COPD, especially the dose-dependent properties of NAC, eg, its effects on lung function and the exacerbation rate in patients with the disease. Earlier data from BRONCUS (the Bronchitis Randomized on NAC Cost-Utility Study) did not suggest that NAC was beneficial in patients with COPD, only indicating that it reduced exacerbation in an "inhaled steroid-naïve" subgroup. With regard to the dose-dependent properties of NAC, two recent randomized controlled Chinese trials suggested that high-dose NAC (1,200 mg daily) can reduce exacerbations in patients with COPD, especially in those with an earlier (moderately severe) stage of disease, and also in those who are at high risk of exacerbations. However, there was no significant effect on symptoms or quality of life in patients receiving NAC. Further studies are warranted to investigate the effect of NAC at higher doses in non-Chinese patients with COPD.}, }
@article {pmid25125946, year = {2014}, author = {Tascilar, O and Cakmak, G and Emre, A and Bakkal, H and Kandemir, N and Turkcu, U and Demir, E}, title = {N-acetylcycsteine attenuates the deleterious effects of radiation therapy on inci-sional wound healing in rats.}, journal = {Hippokratia}, volume = {18}, number = {1}, pages = {17-23}, pmid = {25125946}, issn = {1108-4189}, abstract = {BACKGROUND: During preoperative radiotherapy, effective doses of ionizing radiation occasionally cause wound complications after subsequent surgery. This study was designed to determine the effects of intraperitoneally or orally administered N-acetylcysteine (NAC) on anastomotic healing of irradiated rats.<br><br>MATERIAL &amp; METHODS: Forty Wistar albino rats were randomized into four groups containing 10 rats each. A 3 cm long surgical full-thickness midline laparotomy was performed to all groups (Groups 1-4). Group 1 was designed as a control group without radiation therapy and NAC treatment. Groups 2, 3 and 4 received a single abdominal dose of 10 Gy irradiation before laparotomy and groups 3 and 4 received oral and intraperitoneal NAC, respectively.<br><br>RESULTS: Group comparisons demonstrated that breaking strength was significantly higher in NAC treated rats. A statistically significant difference was determined in terms of superoxide dismutase (SOD), malondealdehyde (MDA) and glutation (GSH) values between groups (p<0.001). Nevertheless, advanced oxidation protein products (AOPP) levels were found to be similar between groups (p=0.163). Serum GSH and SOD levels were significantly higher in groups 3 and 4 when compared to group 2 (p < 0.05). Similarly, there was a significant increase in serum MDA concentration, predicting lipid peroxidation, in group 2 when compared to groups 1, 3 and 4 (p < 0.05). There was not a significant difference between Groups 3 and 4 regarding GSH, MDA, SOD, and AOPP levels. Histopathological analysis revealed that NAC administration, either orally or intraperitoneally, leads to a better incisional healing in terms of inflammation, granulation, collagen deposition, reepithelization and neovascularization.<br><br>CONCLUSION: The present study supports the hypothesis that NAC administration alleviates the negative effects of radiotherapy on incisional wound healing by means of reducing oxidative stress markers and improving histologic parameters independent of the route of administration.}, }
@article {pmid25124169, year = {2014}, author = {Galvão, AM and Wanderley, MS and Silva, RA and Filho, CA and Melo-Junior, MR and Silva, LA and Streck, EL and Dornelas de Andrade, AF and Souza Maia, MB and Barbosa de Castro, CM}, title = {Intratracheal co-administration of antioxidants and ceftriaxone reduces pulmonary injury and mortality rate in an experimental model of sepsis.}, journal = {Respirology (Carlton, Vic.)}, volume = {19}, number = {7}, pages = {1080-1087}, doi = {10.1111/resp.12363}, pmid = {25124169}, issn = {1440-1843}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Anti-Bacterial Agents/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Ascorbic Acid/administration &amp; dosage ; Ceftriaxone/*administration &amp; dosage ; Disease Models, Animal ; Drug Administration Routes ; Drug Therapy, Combination ; Lung Injury/etiology/*prevention &amp; control ; Male ; Rats ; Rats, Wistar ; Sepsis/complications/*drug therapy ; Trachea ; Vitamin E/administration &amp; dosage ; }, abstract = {BACKGROUND AND OBJECTIVE: Recent studies showed that both sepsis and antibiotic therapy are associated with cell death and linked to reactive oxygen species generation. This study investigated the effects of intratracheal administration of combinations of antioxidants (n-acetyl cysteine (NAC), vitamins C and E) in the treatment of sepsis-induced lung injury.<br><br>METHODS: Ninety-six male Wistar rats subjected to sepsis were treated with ceftriaxone plus NAC with or without vitamins C and E and compared to appropriate controls. As an index of oxidative damage protein carbonyls, sulfhydryl groups, lipid peroxidation and superoxide anion were measured, as well as superoxide dismutase and catalase. Histopathological alterations and mortality rate were also analyzed.<br><br>RESULTS: Twenty-four hours after sepsis induction, markers of oxidative stress increased in all lungs examined. Ceftriaxone plus intratracheal combination of NAC, vitamins C and E decreased lung injury in infected animals by reducing superoxide anion production (54%), lipid peroxidation (53%) and protein carbonyl (58%) and restored the redox status (7.5 times). This therapy also reduced the imbalance of antioxidant enzymes activities and attenuated the alveolar architectural disorganization, inflammatory cell infiltration and pulmonary oedema. Survival increased from 66.6% with ceftriaxone to 83.2% with ceftriaxone plus antioxidants.<br><br>CONCLUSIONS: Ceftriaxone plus intratracheal co-administration of antioxidants provides better protection, by decreasing pulmonary oxidative stress, limiting histophatological alterations and improving survival. Antioxidants should be explored as a co-adjuvant in the treatment of severe lung injury.}, }
@article {pmid25123250, year = {2014}, author = {Tsou, PS and Balogh, B and Pinney, AJ and Zakhem, G and Lozier, A and Amin, MA and Stinson, WA and Schiopu, E and Khanna, D and Fox, DA and Koch, AE}, title = {Lipoic acid plays a role in scleroderma: insights obtained from scleroderma dermal fibroblasts.}, journal = {Arthritis research &amp; therapy}, volume = {16}, number = {5}, pages = {411}, pmid = {25123250}, issn = {1478-6362}, support = {K24 AR063120/AR/NIAMS NIH HHS/United States ; T32 AR007080/AR/NIAMS NIH HHS/United States ; K24 AR063120-02/AR/NIAMS NIH HHS/United States ; CA46952/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Blotting, Western ; Cells, Cultured ; Collagen Type I/genetics/metabolism ; Dermis/*metabolism/pathology ; Female ; Fibroblasts/*metabolism ; Gene Expression ; Humans ; Male ; Matrix Metalloproteinases/metabolism ; Middle Aged ; Oxidative Stress ; Phosphorylation ; Plasminogen Activator Inhibitor 1/metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/metabolism ; Receptor-Like Protein Tyrosine Phosphatases, Class 3/genetics/metabolism ; Receptors, Platelet-Derived Growth Factor/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Scleroderma, Diffuse/genetics/*metabolism/pathology ; Sulfurtransferases/blood/metabolism ; Thioctic Acid/analogs &amp; derivatives/*metabolism ; Tissue Inhibitor of Metalloproteinases/metabolism ; }, abstract = {INTRODUCTION: Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and organs. Increase in oxidative stress and platelet-derived growth factor receptor (PDGFR) activation promote collagen I (Col I) production, leading to fibrosis in SSc. Lipoic acid (LA) and its active metabolite dihydrolipoic acid (DHLA) are naturally occurring thiols that act as cofactors and antioxidants, and are produced by lipoic acid synthetase (LIAS). The goal of this study was to examine whether LA and LIAS was deficient in SSc patients and determine the effect of DHLA on the phenotype of SSc dermal fibroblasts. N-acetylcysteine (NAC), a commonly used thiol antioxidant, was included as a comparison.<br><br>METHODS: Dermal fibroblasts were isolated from healthy subjects and patients with diffuse cutaneous SSc. Matrix metalloproteinase (MMPs), tissue inhibitors of MMPs (TIMP), plasminogen activator inhibitor-1 (PAI-1) and LIAS were measured by ELISA. The expression of Col I was measured by immunofluorescence, hydroxyproline assay, and quantitative PCR. PDGFR phosphorylation and &#x3b1;-smooth muscle actin (&#x3b1;-SMA) was measured by Western blotting. Student's t-tests were performed for statistical analysis and p-values of less than 0.05 with two-tailed analysis were considered statistically significant.<br><br>RESULTS: The expression of LA and LIAS in SSc dermal fibroblasts was lower than normal fibroblasts, however LIAS was significantly higher in SSc plasma and appeared to be released from monocytes. DHLA lowered cellular oxidative stress, and decreased PDGFR phosphorylation, Col I, PAI-1, and &#x3b1;-SMA expression in SSc dermal fibroblasts. It also restored the activities of phosphatases that inactivated the PDGFR. SSc fibroblasts produced lower levels of MMP-1 and 3, and DHLA increased them. In contrast, TIMP-1 levels were higher in SSc but DHLA had minimal effect. Both DHLA and NAC increased MMP-1 activity when SSc cells were stimulated with PDGF. In general, DHLA showed better efficacy than NAC in most cases.<br><br>CONCLUSIONS: DHLA not only acts as an antioxidant but also an antifibrotic since it has the ability to reverse the profibrotic phenotype of SSc dermal fibroblasts. Our study suggests that thiol antioxidants, including NAC and LA/DHLA, could be beneficial for patients with SSc.}, }
@article {pmid25122679, year = {2014}, author = {Changou, CA and Chen, YR and Xing, L and Yen, Y and Chuang, FY and Cheng, RH and Bold, RJ and Ann, DK and Kung, HJ}, title = {Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {111}, number = {39}, pages = {14147-14152}, pmid = {25122679}, issn = {1091-6490}, support = {R01 DE014183/DE/NIDCR NIH HHS/United States ; R56 AI095382/AI/NIAID NIH HHS/United States ; R01 CA150197/CA/NCI NIH HHS/United States ; DE10742/DE/NIDCR NIH HHS/United States ; DE14183/DE/NIDCR NIH HHS/United States ; R01 DE010742/DE/NIDCR NIH HHS/United States ; CA150197S1/CA/NCI NIH HHS/United States ; R01 CA165263/CA/NCI NIH HHS/United States ; AI095382/AI/NIAID NIH HHS/United States ; P30 CA093373/CA/NCI NIH HHS/United States ; CA150197/CA/NCI NIH HHS/United States ; CA165263/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/pharmacology ; Arginine/deficiency/*metabolism ; Argininosuccinate Synthase/metabolism ; Autophagy/drug effects/physiology ; Cell Death/drug effects/*physiology ; Cell Line, Tumor ; Chromatin/drug effects/metabolism ; DNA, Neoplasm/*metabolism ; Humans ; Hydrolases/pharmacology ; Male ; Membrane Potential, Mitochondrial ; Microscopy, Electron, Transmission ; Mitochondria/drug effects/metabolism ; Nuclear Envelope/drug effects/ultrastructure ; Polyethylene Glycols/pharmacology ; Prostatic Neoplasms/drug therapy/*metabolism/*pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Autophagy is the principal catabolic prosurvival pathway during nutritional starvation. However, excessive autophagy could be cytotoxic, contributing to cell death, but its mechanism remains elusive. Arginine starvation has emerged as a potential therapy for several types of cancers, owing to their tumor-selective deficiency of the arginine metabolism. We demonstrated here that arginine depletion by arginine deiminase induces a cytotoxic autophagy in argininosuccinate synthetase (ASS1)-deficient prostate cancer cells. Advanced microscopic analyses of arginine-deprived dying cells revealed a novel phenotype with giant autophagosome formation, nucleus membrane rupture, and histone-associated DNA leakage encaptured by autophagosomes, which we shall refer to as chromatin autophagy, or chromatophagy. In addition, nuclear inner membrane (lamin A/C) underwent localized rearrangement and outer membrane (NUP98) partially fused with autophagosome membrane. Further analysis showed that prolonged arginine depletion impaired mitochondrial oxidative phosphorylation function and depolarized mitochondrial membrane potential. Thus, reactive oxygen species (ROS) production significantly increased in both cytosolic and mitochondrial fractions, presumably leading to DNA damage accumulation. Addition of ROS scavenger N-acetyl cysteine or knockdown of ATG5 or BECLIN1 attenuated the chromatophagy phenotype. Our data uncover an atypical autophagy-related death pathway and suggest that mitochondrial damage is central to linking arginine starvation and chromatophagy in two distinct cellular compartments.}, }
@article {pmid25122644, year = {2014}, author = {Katayama, IA and Pereira, RC and Dopona, EP and Shimizu, MH and Furukawa, LN and Oliveira, IB and Heimann, JC}, title = {High-salt intake induces cardiomyocyte hypertrophy in rats in response to local angiotensin II type 1 receptor activation.}, journal = {The Journal of nutrition}, volume = {144}, number = {10}, pages = {1571-1578}, doi = {10.3945/jn.114.192054}, pmid = {25122644}, issn = {1541-6100}, mesh = {Acetylcysteine/pharmacology ; Aldosterone/blood ; Angiotensin II/metabolism ; Animals ; Antihypertensive Agents/pharmacology ; Blood Pressure/drug effects ; Body Weight ; Cardiomegaly/chemically induced/genetics/*pathology ; Heart Rate ; Hematocrit ; Hydralazine/pharmacology ; Losartan/pharmacology ; Male ; Myocytes, Cardiac/*drug effects/metabolism ; Potassium/blood/urine ; Rats ; Rats, Wistar ; Receptor, Angiotensin, Type 1/genetics/*metabolism ; Receptor, Angiotensin, Type 2/genetics/metabolism ; Renin-Angiotensin System/drug effects ; Sodium/blood/urine ; Sodium Chloride, Dietary/administration &amp; dosage/*adverse effects ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Many studies have shown that risk factors that are independent of blood pressure (BP) can contribute to the development of cardiac hypertrophy (CH). Among these factors, high-salt (HS) intake was prominent. Although some studies have attempted to elucidate the role of salt in the development of this disease, the mechanisms by which salt acts are not yet fully understood. Thus, the aim of this study was to better understand the mechanisms of CH and interstitial fibrosis (IF) caused by HS intake. Male Wistar rats were divided into 5 groups according to diet [normal salt (NS; 1.27% NaCl) or HS (8% NaCl)] and treatment [losartan (LOS) (HS+LOS group), hydralazine (HZ) (HS+HZ group), or N-acetylcysteine (NAC) (HS+NAC group)], which was given in the drinking water. Tail-cuff BP, transverse diameter of the cardiomyocyte, IF, angiotensin II type 1 receptor (AT1) gene and protein expression, serum aldosterone, cardiac angiotensin II, cardiac thiobarbituric acid-reactive substances, and binding of conformation-specific anti-AT1 and anti-angiotensin II type 2 receptor (AT2) antibodies in the 2 ventricles were measured. Based on the left ventricle transverse diameter data, the primary finding was the occurrence of significant BP-independent CH in the HS+HZ group (96% of the HS group) and a partial or total prevention of such hypertrophy via treatment with NAC or LOS (81% and 67% of the HS group, respectively). The significant total or partial prevention of IF using all 3 treatments (HS+HZ, 27%; HS+LOS, 27%; and HS+NAC, 58% of the HS group, respectively), and an increase in the AT1 gene and protein expression and activity in groups that developed CH, confirmed that CH occurred via the AT1 in this experimental model. Thus, this study unveiled some relevant previously unknown mechanisms of CH induced by chronic HS intake in Wistar rats. The link of oxidative stress with CH in our experimental model is very interesting and stimulates further evaluation for its full comprehension.}, }
@article {pmid25119736, year = {2014}, author = {Kim, JS and Yu, IJ}, title = {Single-wall carbon nanotubes (SWCNT) induce cytotoxicity and genotoxicity produced by reactive oxygen species (ROS) generation in phytohemagglutinin (PHA)-stimulated male human peripheral blood lymphocytes.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {77}, number = {19}, pages = {1141-1153}, doi = {10.1080/15287394.2014.917062}, pmid = {25119736}, issn = {1528-7394}, mesh = {Acetylcysteine/metabolism ; Adult ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Comet Assay ; DNA Damage/*drug effects ; Humans ; Interleukin-6/genetics/metabolism ; Lymphocytes/*drug effects/metabolism ; Male ; Nanotubes, Carbon/*toxicity ; Oxidative Stress/drug effects ; Phytohemagglutinins/*adverse effects ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism ; }, abstract = {Single-wall carbon nanotubes (SWCNT) possess a small size, large surface area, and high reactivity, which enable them to permeate the cytoplasmic or nuclear membrane and attach to biological molecules. During medical applications, SWNCT are usually administered intravenously, which enhances interaction with blood components. Yet despite this exposure potential, safety evaluation studies of SWCNTs focused on human blood cells are still lacking. Therefore, this study was undertaken to examine cytotoxicity, genotoxicity, and proinflammatory responses following SWCNT treatment of phytohemagglutinin (PHA)-stimulated male human peripheral blood lymphocytes (PBL). SWCNT were found to inhibit cell growth, as well as to induce DNA breakage, and micronuclei (MN) formation via reactive oxygen species (ROS) generation. The addition of N-acetylcysteine (NAC) a cell-permeable antioxidant, decreased ROS generation, cytotoxicity, and genotoxicity produced by SWCNT treatment. In addition, SWCNT induced tumor necrosis factor (TNF)-α release after 24 h, yet this phenomenon was not related to ROS generation, as antioxidant NAC treatment did not affect increased proinflammatory cytokine levels in the phytohemagglutinin (PHA)-stimulated male human PBL.}, }
@article {pmid25119188, year = {2015}, author = {Park, S and Park, JA and Kim, YE and Song, S and Kwon, HJ and Lee, Y}, title = {Suberoylanilide hydroxamic acid induces ROS-mediated cleavage of HSP90 in leukemia cells.}, journal = {Cell stress &amp; chaperones}, volume = {20}, number = {1}, pages = {149-157}, pmid = {25119188}, issn = {1466-1268}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Caspase 10/metabolism ; Caspase Inhibitors/pharmacology ; Caspases/chemistry/metabolism ; HSP90 Heat-Shock Proteins/*metabolism ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Hydroxamic Acids/*pharmacology ; K562 Cells ; Leukemia ; Proteolysis/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Vorinostat ; fas Receptor/immunology/metabolism ; }, abstract = {Heat shock protein 90 (HSP90) is a molecular chaperone that supports stability of client proteins. We found that HSP90 was cleaved to 55 kDa protein after treatment with histone deacetylase (HDAC) inhibitors including suberoylanilide hydroxamic acid (SAHA) in several leukemia cell lines. We further analyzed molecular changes induced by SAHA in K562 cells. The SAHA-induced cleavage of HSP90 was blocked by a pan-caspase inhibitor, z-VAD-fmk, implying that the process is dependent on caspase activity. However, the experiments using antagonistic and agonistic Fas antibodies revealed that the cleavage of HSP90 was not dependent on Fas signaling. SAHA induced generation of reactive oxygen species (ROS), and the cleavage of HSP90 was blocked by a ROS scavenger N-acetylcystein (NAC). We also confirmed that hydrogen peroxide (H2O2) induced cleavage of HSP90 in a similar manner. Caspase 2, 3, 4, 6, 8, and 10 were activated by treatment with SAHA, and the activities were reduced by the pretreatment of NAC. Treatment of the cells with caspase 10 inhihitor, but not other inhibitors of caspases activated by SAHA, prevented cleavage of HSP90 by SAHA. SAHA-induced ROS generation and HSP90 cleavage were dependent on newly synthesized unknown proteins. Taken together, our results suggest that the cleavage of HSP90 by SAHA is mediated by ROS generation and caspase 10 activation. HSP90 cleavage may provide an additional mechanism involved in anti-cancer effects of HDAC inhibitors.}, }
@article {pmid25115833, year = {2014}, author = {Oltmanns, U and Kahn, N and Palmowski, K and Träger, A and Wenz, H and Heussel, CP and Schnabel, PA and Puderbach, M and Wiebel, M and Ehlers-Tenenbaum, S and Warth, A and Herth, FJ and Kreuter, M}, title = {Pirfenidone in idiopathic pulmonary fibrosis: real-life experience from a German tertiary referral center for interstitial lung diseases.}, journal = {Respiration; international review of thoracic diseases}, volume = {88}, number = {3}, pages = {199-207}, doi = {10.1159/000363064}, pmid = {25115833}, issn = {1423-0356}, mesh = {Acetylcysteine/therapeutic use ; Adrenal Cortex Hormones/therapeutic use ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Cohort Studies ; Disease Progression ; Drug Eruptions/etiology ; Drug Therapy, Combination ; Expectorants/therapeutic use ; Fatigue/chemically induced ; Female ; Gastrointestinal Diseases/chemically induced ; Germany ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy ; Male ; Medication Adherence ; Middle Aged ; Pyridones/*therapeutic use ; Retrospective Studies ; Tertiary Care Centers ; Treatment Outcome ; Vital Capacity ; Weight Loss ; }, abstract = {BACKGROUND: Pirfenidone is a novel antifibrotic drug for the treatment of mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, adverse events may offset treatment benefits and compliance.<br><br>OBJECTIVES: To assess recent course of disease, adverse events and compliance in patients who started pirfenidone.<br><br>METHODS: In an observational cohort study, 63 patients with mild-to-moderate IPF who started pirfenidone between May 2011 and June 2013 were reviewed. Pulmonary function, adverse events and treatment compliance were recorded at each clinic visit. Disease progression was defined as a reduction of vital capacity &#x2265;10% and/or diffusion capacity (DLCO) &#x2265;15%.<br><br>RESULTS: Follow-up time on pirfenidone treatment was 11 (&#xb1;7) months. Sixty-six percent of the patients continued with pirfenidone monotherapy and 34% of the patients received pirfenidone combined with corticosteroids (CCS) and/or N-acetylcysteine (NAC). There was a nonsignificant reduction in mean decline of percent predicted forced vital capacity after treatment start (0.7 &#xb1; 10.9%) compared to the pretreatment period (6.6 &#xb1; 6.7%, p = 0.098). Sixty-two percent of the patients had stable disease on pirfenidone treatment. Adverse events affected 85% of the patients, leading to discontinuation of pirfenidone in 20%. Adverse events and treatment discontinuation were seen more frequently in patients with concomitant CCS and/or NAC treatment.<br><br>CONCLUSIONS: Adverse events affect the majority of patients treated with pirfenidone, but are mostly manageable with supportive measures. In this heterogeneous patient group, a nonsignificant effect of pirfenidone treatment on pulmonary function was seen, underlining the need for more data on patient selection criteria and efficacy of pirfenidone, particularly in patients with coexistent emphysema and concomitant NAC/CCS treatment.}, }
@article {pmid25110444, year = {2014}, author = {Akbulut, S and Elbe, H and Eris, C and Dogan, Z and Toprak, G and Otan, E and Erdemli, E and Turkoz, Y}, title = {Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats.}, journal = {World journal of gastroenterology}, volume = {20}, number = {29}, pages = {10158-10165}, pmid = {25110444}, issn = {2219-2840}, mesh = {Acetylcysteine/*pharmacology ; Amifostine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Biomarkers/metabolism ; Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology/*prevention &amp; control ; Cytoprotection ; Disease Models, Animal ; Liver/*drug effects/metabolism/pathology ; Male ; *Methotrexate ; Oxidative Stress/*drug effects ; Rats, Sprague-Dawley ; Time Factors ; }, abstract = {AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity.<br><br>METHODS: An MTX-induced hepatotoxicity model was established in 44 male Sprague Dawley rats by administration of a single intraperitoneal injection of 20 mg/kg MTX. Eleven of the rats were left untreated (Model group; n = 11), and the remaining rats were treated with a 7-d course of 50 mg/kg per day NAC (MTX + NAC group; n = 11), 50 mg/kg per single dose AMF (MTX + AMF group; n = 11), or 10 mg/kg per day ASC (MTX + ASC group; n = 11). Eleven rats that received no MTX and no treatments served as the negative control group. Structural and functional changes related to MTX- and the various treatments were assessed by histopathological analysis of liver tissues and biochemical assays of malondialdehyde (MDA), superoxide dismutase (SOD), catalase, glutathione (GSH) and xanthine oxidase activities and of serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin.<br><br>RESULTS: Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by significantly worse histopathological scores [median (range) injury score: control group: 1 (0-3) vs 7 (6-9), P = 0.001] and significantly higher MDA activity [409 (352-466) nmol/g vs 455.5 (419-516) nmol/g, P < 0.05]. The extent of MTX-induced perturbation of both parameters was reduced by all three cytoprotective agents, but only the reduction in hepatotoxicity scores reached statistical significance [4 (3-6) for NAC, 4.5 (3-5) for AMF and 6 (5-6) for ASC; P = 0.001, P = 0.001 and P < 0.005 vs model group respectively]. Exposure to MTX also caused a significant reduction in the activities of GSH and SOD antioxidants in liver tissues [control group: 3.02 (2.85-3.43) &#x3bc;mol/g and 71.78 (61.88-97.81) U/g vs model group: 2.52 (2.07-3.34) &#x3bc;mol/g and 61.46 (58.27-67.75) U/g, P < 0.05]; however, only the NAC treatment provided significant increases in these antioxidant enzyme activities [3.22 (2.54-3.62) &#x3bc;mol/g and 69.22 (61.13-100.88) U/g, P < 0.05 and P < 0.01 vs model group respectively].<br><br>CONCLUSION: MTX-induced structural and functional damage to hepatic tissues in rats may involve oxidative stress, and cytoprotective agents (NAC > AMF > ASC) may alleviate MTX hepatotoxicity.}, }
@article {pmid25109871, year = {2014}, author = {Di, W and Khan, M and Rasul, A and Sun, M and Sui, Y and Zhong, L and Yang, L and Zhu, Q and Feng, L and Ma, T}, title = {Isoalantolactone inhibits constitutive NF-κB activation and induces reactive oxygen species-mediated apoptosis in osteosarcoma U2OS cells through mitochondrial dysfunction.}, journal = {Oncology reports}, volume = {32}, number = {4}, pages = {1585-1593}, doi = {10.3892/or.2014.3368}, pmid = {25109871}, issn = {1791-2431}, mesh = {Apoptosis/*drug effects ; *Bone Neoplasms ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Membrane Potential, Mitochondrial/*drug effects ; Mitochondria/*drug effects/metabolism ; NF-kappa B/*drug effects/metabolism ; *Osteosarcoma ; Reactive Oxygen Species ; Sesquiterpenes/*pharmacology ; }, abstract = {Human osteosarcoma is an aggressive tumor which frequently resists chemotherapy; therefore, the search for new agents for its treatment is of great importance. Isoalantolactone, isolated from Inula spp., has been reported to inhibit the growth of several types of cancer cells. However, no prior research has been conducted to demonstrate the antiproliferative potential of isoalantolactone on osteosarcoma. The present study is the first to investigate the effects of isoalantolactone on cell viability in human osteosarcoma U2OS, MG-63 and Saos-2 cells, and its mechanism of action in U2OS cells. Our results demonstrated that isoalantolactone triggered S and mainly G2/M cell cycle phase arrest, accompanied by the downregulation of the expression of cyclin B1 at the protein and mRNA levels. Moreover, isoalantolactone induced apoptosis that was associated with reactive oxygen species (ROS) generation and the dissipation of mitochondrial membrane potential (MMP). Furthermore, our results indicated that this compound upregulated DR5, FADD and cleaved caspase-8, increased the interation between DR5 and FADD, and inhibited the expression of nuclear NF-κBp65. We also found that isoalantolactone-induced apoptosis was associated with the downregulation of Bcl-2 and upregulation of Bax, which finally led to the activation of caspase-3 and its downstream substrate, PARP, in osteosarcoma U2OS cells. Isoalantolactone-induced apoptosis was markedly abrogated when the cells were pretreated with N-acetylcysteine (NAC), a specific ROS inhibitor, suggesting that the apoptosis-inducing effect of isoalantolactone in osteosarcoma cells was mediated by reactive oxygen species. Taken together, our data demonstrated that isoalantolactone induces ROS-dependent apoptosis in U2OS cells via a novel mechanism involving inhibition of NF-κBp65 and provide the rationale for further in vivo and preclinical investigation of isoalantolactone against osteosarcoma.}, }
@article {pmid25106704, year = {2014}, author = {Bianchi, A and Moulin, D and Hupont, S and Koufany, M and Netter, P and Reboul, P and Jouzeau, JY}, title = {Oxidative stress-induced expression of HSP70 contributes to the inhibitory effect of 15d-PGJ2 on inducible prostaglandin pathway in chondrocytes.}, journal = {Free radical biology &amp; medicine}, volume = {76}, number = {}, pages = {114-126}, doi = {10.1016/j.freeradbiomed.2014.07.028}, pmid = {25106704}, issn = {1873-4596}, mesh = {Animals ; Blotting, Western ; Cells, Cultured ; Chondrocytes/drug effects/metabolism/*pathology ; Cyclooxygenase 2/genetics/metabolism ; Female ; Gene Expression Regulation/*drug effects ; HSP70 Heat-Shock Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Interleukin-1/pharmacology ; NF-kappa B/genetics/metabolism ; Oligonucleotides, Antisense/pharmacology ; Oxidative Stress/*drug effects ; PPAR gamma/genetics/metabolism ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology ; Prostaglandins/*metabolism ; RNA, Messenger/genetics ; Rats ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*drug effects ; }, abstract = {The inhibitory effect of 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) on proinflammatory gene expression has been extensively documented and frequently ascribed to its ability to prevent NF-κB pathway activation. We and others have previously demonstrated that it was frequently independent of the peroxisome proliferator activated receptor (PPAR)γ activation. Here, we provide evidence that induction of intracellular heat shock protein (HSP)70 by oxidative stress is an additional regulatory loop supporting the anti-inflammatory effect of 15d-PGJ2 in chondrocytes. Using real-time quantitative PCR and Western blotting, we showed that 15d-PGJ2 stimulated HSP70, but not HSP27 expression while increasing oxidative stress as measured by spectrofluorimetry and confocal spectral imaging. Using N-acetylcysteine (NAC) as an antioxidant, we demonstrated further that oxidative stress was thoroughly responsible for the increased expression of HSP70. Finally, using an HSP70 antisense strategy, we showed that the inhibitory effect of 15d-PGJ2 on IL-1-induced activation of the NF-κB pathway, COX-2 and mPGES-1 expression, and PGE2 synthesis was partly supported by HSP70. These data provide a new anti-inflammatory mechanism to support the PPARγ-independent effect of 15d-PGJ2 in chondrocyte and suggest a possible feedback regulatory loop between oxidative stress and inflammation via intracellular HSP70 up-regulation. This cross talk is consistent with 15d-PGJ2 as a putative negative regulator of the inflammatory reaction.}, }
@article {pmid25105339, year = {2014}, author = {Yu, J and Deng, P and Zhong, D and Chen, X}, title = {Identification of amino acid and glutathione N-conjugates of toosendanin: bioactivation of the furan ring mediated by CYP3A4.}, journal = {Chemical research in toxicology}, volume = {27}, number = {9}, pages = {1598-1609}, doi = {10.1021/tx5002145}, pmid = {25105339}, issn = {1520-5010}, mesh = {Amino Acids/*chemistry ; Animals ; Chromatography, High Pressure Liquid ; Cytochrome P-450 CYP3A/genetics/*metabolism ; Drugs, Chinese Herbal/*analysis/metabolism ; Furans/chemistry/*metabolism ; Glutathione/*chemistry ; Humans ; Mass Spectrometry ; Melia/chemistry/metabolism ; Microsomes, Liver/metabolism ; Nitrogen/chemistry ; Rats ; Rats, Wistar ; Recombinant Proteins/biosynthesis/genetics ; Taurine/chemistry ; }, abstract = {Toosendanin (TSN) is a hepatotoxic triterpenoid extracted from Melia toosendan Sieb et Zucc. Considering that TSN contains the structural alert of the furan ring, it is believed that bioactivation of TSN may be responsible for its toxicity. Herein, the bioactivation potential and metabolism profiles of TSN were investigated. After an oral administration of 10 mg/kg TSN to rats, esterolysis and conjugation with amino acids were identified as the main metabolic pathways. The same types of conjugates were detected in liver microsomes in an NADPH-dependent manner. According to the remaining amount of the parent drug, the reactivity of trapping reagents with TSN reactive metabolites was sorted in a decreasing order of N(α)-(tert-butoxycarbonyl)-l-lysine (Boc-Lys) > alanine, lysine, taurine, phenylalanine, serine, glutamic acid, glycine, and glutathione (GSH) > cysteine. No conjugates were observed in NADPH and N-acetyl cysteine (NAC)-supplemented human liver microsomal incubations. Further phenotyping studies and the chemical synthesis of the major conjugated standards proved that TSN was bioactivated by CYP3A4 and yielded a cis-butene-1,4-dial intermediate, which was prone to undergo 1,2-addition with the amino group of amino acids and GSH to form 3-pyrroline-2-one adducts. The sulfydryl group of GSH also attacked the intermediate and yielded S-conjugates by 1,4- or 1,2-addition, which would form pyrrole conjugates by further reacting with the amino group. Compared to the well-recognized S-conjugation of the furan ring, N-conjugation with multiple amino acids and GSH played a more important part in the elimination of reactive metabolites of TSN. The significance of these conjugates requires further investigation.}, }
@article {pmid25104294, year = {2014}, author = {Jana, K and Dutta, A and Chakraborty, P and Manna, I and Firdaus, SB and Bandyopadhyay, D and Chattopadhyay, R and Chakravarty, B}, title = {Alpha-lipoic acid and N-acetylcysteine protects intensive swimming exercise-mediated germ-cell depletion, pro-oxidant generation, and alteration of steroidogenesis in rat testis.}, journal = {Molecular reproduction and development}, volume = {81}, number = {9}, pages = {833-850}, doi = {10.1002/mrd.22354}, pmid = {25104294}, issn = {1098-2795}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biomarkers/metabolism ; Body Weight/drug effects ; Corticosterone/blood ; Eating/drug effects ; Exercise Test ; Lipid Peroxidation/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Organ Size/drug effects ; Oxidative Stress/*drug effects ; Phosphoproteins/metabolism ; Rats ; Rats, Wistar ; Spermatozoa/drug effects ; Stress, Physiological ; Swimming ; Testis/cytology/*drug effects/pathology ; Testosterone/blood ; Thioctic Acid/*pharmacology ; }, abstract = {Prolonged and strenuous exercise has been proposed as a possible source of male-factor infertility. Forced intensive swimming has also been identified as one source of a dysfunctional male reproduction system. The present study evaluated the possible protective role of α-lipoic acid and N-acetylcysteine (NAC) on intensive swimming-induced germ-cell depletion in adult male rats. Forced exhaustive swimming of 1 hr/day, 6 days/week for 8 consecutive weeks resulted in a significant (P < 0.05) reduction in epididymal sperm; testicular androgenic enzyme activities; and plasma and intra-testicular testosterone; and produced different types of germ cells in the seminiferous epithelium cycle. Conversely, plasma corticosterone levels and sperm-head abnormalities increased. Western-blot analysis showed a considerable decrease in testicular StAR protein expression whereas reverse-transcriptase PCR analysis showed no significant change in cytochrome P450scc (Cyp11a1) gene expression. Significant (P < 0.05) elevation in testicular reactive oxygen species (ROS), lipid peroxidation, protein carbonyl content versus reduction in glucose-6-phosphate dehydrogenase, glutathione peroxidase, glutathione S-transferase, and caspase-3 activities along with a depletion in the glutathione pool, mitochondrial membrane potential (▵ψm), and intracellular ATP generation. A considerable level of DNA damage in testicular spermatogenic cells were also noted following forced extensive swimming. Alpha-lipoic acid and NAC supplementation prevented the swimming-induced testicular spermatogenic and steroidogenic disorders by lowering ROS generation. We therefore conclude that intensive forced swimming causes germ-cell depletion through the generation of ROS and depletion of steroidogenesis in the testis, which can be protected by the co-administration of α-lipoic acid and NAC.}, }
@article {pmid25101674, year = {2014}, author = {Liu, Y and Zhao, L and Ju, Y and Li, W and Zhang, M and Jiao, Y and Zhang, J and Wang, S and Wang, Y and Zhao, M and Zhang, B and Zhao, Y}, title = {A novel androstenedione derivative induces ROS-mediated autophagy and attenuates drug resistance in osteosarcoma by inhibiting macrophage migration inhibitory factor (MIF).}, journal = {Cell death &amp; disease}, volume = {5}, number = {8}, pages = {e1361}, pmid = {25101674}, issn = {2041-4889}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Androstenedione/analogs &amp; derivatives/chemical synthesis/*toxicity ; Autophagy/*drug effects ; Bone Neoplasms/metabolism/pathology ; Cell Line, Tumor ; Down-Regulation/drug effects ; Drug Resistance, Neoplasm/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; HMGB1 Protein/metabolism ; Humans ; Macrophage Migration-Inhibitory Factors/antagonists &amp; inhibitors/genetics/*metabolism ; Osteosarcoma/metabolism/pathology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Secosteroids/chemical synthesis/chemistry/*toxicity ; Translocation, Genetic ; }, abstract = {Osteosarcoma is a common primary bone tumor in children and adolescents. The drug resistance of osteosarcoma leads to high lethality. Macrophage migration inhibitory factor (MIF) is an inflammation-related cytokine implicated in the chemoresistance of breast cancer. In this study, we isolated a novel androstenedione derivative identified as 3,4-dihydroxy-9,10-secoandrosta-1,3,5,7-tetraene-9,17-dione (DSTD). DSTD could inhibit MIF expression in MG-63 and U2OS cells. The inhibition of MIF by DSTD promoted autophagy by inducing Bcl-2 downregulation and the translocation of HMGB1. N-acetyl-L-cysteine (NAC) and 3-methyladenine (3-MA) attenuated DSTD-induced autophagy but promoted cell death, suggesting that DSTD induced ROS-mediated autophagy to rescue cell death. However, in the presence of chemotherapy drugs, DSTD enhanced the chemosensitivity by decreasing the HMGB1 level. Our data suggest MIF inhibition as a therapeutic strategy for overcoming drug resistance in osteosarcoma.}, }
@article {pmid25096993, year = {2014}, author = {Hwang, KE and Kim, YS and Hwang, YR and Kwon, SJ and Park, DS and Cha, BK and Kim, BR and Yoon, KH and Jeong, ET and Kim, HR}, title = {Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction.}, journal = {International journal of oncology}, volume = {45}, number = {4}, pages = {1769-1777}, doi = {10.3892/ijo.2014.2584}, pmid = {25096993}, issn = {1791-2423}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Bcl-2-Like Protein 11 ; Cell Line, Tumor ; Drug Synergism ; Gene Expression Regulation, Neoplastic/drug effects ; Glutamates/*pharmacology ; Guanine/*analogs &amp; derivatives/pharmacology ; Humans ; Lung Neoplasms/drug therapy/metabolism/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Membrane Proteins/metabolism ; Mesothelioma/drug therapy/metabolism/*pathology ; Mesothelioma, Malignant ; Pemetrexed ; Proto-Oncogene Proteins/metabolism ; Reactive Oxygen Species/metabolism ; Simvastatin/*pharmacology ; }, abstract = {Pemetrexed is a multitarget antifolate currently used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used primarily for hyperlidpidemia, have been studied for their antiproliferative and pro-apoptotic effects. However, the effects of simvastatin on pemetrexed-induced apoptosis have not been investigated. In this study, we investigated whether combination treatment with pemetrexed and simvastatin potentiates the apoptotic activity above that is seen with either drug alone in malignant mesothelioma and NSCLC cells. We found that the combination of pemetrexed and simvastatin induced more extensive caspase-dependent apoptosis than either drug alone in malignant mesothelioma cells (MSTO-211) or NSCLC cells (A549). In addition, reactive oxygen species (ROS) generation in cells treated with both pemetrexed and simvastatin was markedly increased compared to cells treated with either pemetrexed or simvastatin alone. Combination treatment also increased the loss of mitochondrial membrane potential, increased cytosolic release of cytochrome c, and altered expression of inhibitor of apoptosis proteins (IAP) and B-cell lymphoma-2 (Bcl-2) families of apoptosis related proteins. On the other hand, pretreatment with N-acetylcysteine (NAC) prevented apoptosis and mitochondrial dysfunction by pemetrexed and simvastatin. In addition, Bim siRNA conferred protection against apoptosis induced by pemetrexed and simvastatin. These results suggest that combination of pemetrexed and simvastatin potentiates their apoptotic activity beyond that of either drug alone in malignant mesothelioma and lung cancer cells. This activity is mediated through ROS-dependent mitochondrial dysfunction and Bim induction.}, }
@article {pmid25096910, year = {2014}, author = {Chae, IG and Kim, DH and Kundu, J and Jeong, CH and Kundu, JK and Chun, KS}, title = {Generation of ROS by CAY10598 leads to inactivation of STAT3 signaling and induction of apoptosis in human colon cancer HCT116 cells.}, journal = {Free radical research}, volume = {48}, number = {11}, pages = {1311-1321}, doi = {10.3109/10715762.2014.951838}, pmid = {25096910}, issn = {1029-2470}, mesh = {Apoptosis/*drug effects ; Blotting, Western ; Cell Proliferation/drug effects ; Colonic Neoplasms/drug therapy/metabolism/*pathology ; Dinoprostone/*analogs &amp; derivatives/genetics/metabolism/pharmacology ; Humans ; Phosphorylation/drug effects ; Pyrrolidinones/*pharmacology ; RNA, Messenger/genetics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Receptors, Prostaglandin E, EP4 Subtype/*agonists ; Reverse Transcriptase Polymerase Chain Reaction ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/genetics/metabolism ; Signal Transduction/drug effects ; Tetrazoles/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {Prostaglandin E2 (PGE2) has been reported to play critical roles in cell fate decision by interacting with four types of prostanoid receptors such as EP1, EP2, EP3 and EP4. The present study was aimed at investigating the effect of the EP4-specific agonist CAY10598 in human colon cancer HCT116 cells. Our study revealed that treatment with CAY10598 significantly reduced the cell viability and induced apoptosis in HCT116 cells, as evidenced by the induction of p53 and Bax, release of cytochrome c, cleavage of caspase-9, -7, and -3, and PARP, and the inhibition of Bcl-2, Bcl-xL and survivin expression. Moreover, treatment with CAY10598 diminished the phosphorylation of JAK2, leading to the attenuation of STAT3 activation in HCT116 cells. CAY10598-induced apoptosis in cells which were transiently transfected with EP4 siRNA or treated with an EP4 antagonist prior to incubation with the compound remained unaffected, suggesting an EP4-independent mechanism of apoptosis induction by CAY10598. We found that treatment with CAY10598 generated reactive oxygen species (ROS) and pretreatment of cells with N-acetyl cysteine rescued cells from apoptosis by abrogating the inhibitory effect of CAY10598 on the activation of JAK2/STAT3 signaling. In conclusion, CAY10598 induced apoptosis in HCT116 cells in an EP4-independent manner, but through the generation of ROS and inactivation of JAK2/STAT3 signaling.}, }
@article {pmid25096201, year = {2015}, author = {Soleimani Asl, S and Saifi, B and Sakhaie, A and Zargooshnia, S and Mehdizadeh, M}, title = {Attenuation of ecstasy-induced neurotoxicity by N-acetylcysteine.}, journal = {Metabolic brain disease}, volume = {30}, number = {1}, pages = {171-181}, pmid = {25096201}, issn = {1573-7365}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Apoptosis/drug effects ; CA1 Region, Hippocampal/drug effects/pathology ; Drug Evaluation, Preclinical ; Learning Disabilities/chemically induced/*prevention &amp; control ; Male ; Maze Learning/drug effects ; N-Methyl-3,4-methylenedioxyamphetamine/*toxicity ; Nerve Tissue Proteins/biosynthesis/genetics ; Proto-Oncogene Proteins c-bcl-2/biosynthesis/genetics ; Rats ; Rats, Sprague-Dawley ; Spatial Memory/drug effects ; bcl-2-Associated X Protein/biosynthesis/genetics ; }, abstract = {UNLABELLED: Exposure to 3, 4-methylenedioxymethamphetamine (MDMA) can lead to spatial memory impairments and hippocampal cell death. Numerous evidence indicates that the antioxidant N-acetylcysteine (NAC) exerts protective effects in the brain. The present study evaluates the effects of NAC on MDMA-induced neurotoxicity.<br><br>METHODS: We intraperitoneally injected 28 adult male Sprague-Dawley rats (200-250 g) with either 0, 10 mg/kg of MDMA, or 10 mg/kg of MDMA plus 100 mg/kg of NAC. Spatial memory was assessed with a Morris Water Maze (MWM). At the end of the study, rats' brains were removed to study the structure and ultrastructure of CA1, and measure Bcl-2 and Bax expressions in the hippocampus. In the MWM, NAC treatment significantly attenuated the MDMA-induced increase in distance traveled (p < 0.05) and escape latency (p < 0.001). The decreased time spent in the target quadrant in MDMA-treated animals was attenuated by NAC (p < 0.01). NAC significantly protected against MDMA-induced apoptosis and the up- and down-regulation of Bax and Bcl-2, respectively. These data have suggested that NAC could protect against behavioral changes and apoptosis in the hippocampus following administration of MDMA. NAC might be useful for the treatment of neurotoxicity in MDMA users.}, }
@article {pmid25092309, year = {2014}, author = {Ward, J and Kanchagar, C and Veksler-Lublinsky, I and Lee, RC and McGill, MR and Jaeschke, H and Curry, SC and Ambros, VR}, title = {Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {111}, number = {33}, pages = {12169-12174}, pmid = {25092309}, issn = {1091-6490}, support = {P20 GM103549/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Hepatitis/*blood/complications ; Humans ; Ischemia/*blood ; MicroRNAs/*blood ; Poisoning/blood/drug therapy ; Real-Time Polymerase Chain Reaction ; }, abstract = {We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.}, }
@article {pmid25092119, year = {2015}, author = {Wu, CY and Lee, HJ and Liu, CF and Korivi, M and Chen, HH and Chan, MH}, title = {Protective role of L-ascorbic acid, N-acetylcysteine and apocynin on neomycin-induced hair cell loss in zebrafish.}, journal = {Journal of applied toxicology : JAT}, volume = {35}, number = {3}, pages = {273-279}, doi = {10.1002/jat.3043}, pmid = {25092119}, issn = {1099-1263}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animal Use Alternatives ; Animals ; Anti-Bacterial Agents/*toxicity ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Cell Survival/drug effects ; Embryo, Nonmammalian/*drug effects/metabolism/pathology ; Hair Cells, Auditory, Inner/*drug effects/metabolism/pathology ; Mechanoreceptors/drug effects/metabolism/pathology ; Microscopy, Confocal ; Neomycin/*toxicity ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; *Zebrafish/embryology ; }, abstract = {Hair cells are highly sensitive to environmental insults and other therapeutic drugs. The adverse effects of drugs such as aminoglycosides can cause hair cell death and lead to hearing loss and imbalance. The objective of the present study was to evaluate the protective activity of L-ascorbic acid, N-acetylcysteine (NAC) and apocynin on neomycin-induced hair cell damage in zebrafish (Danio rerio) larvae at 5 days post fertilization (dpf). Results showed that the loss of hair cells within the neuromasts of the lateral lines after neomycin exposure was evidenced by a significantly lower number of neuromasts labeled with fluorescent dye FM1-43FX observed under a microscope. Co-administration with L-ascorbic acid, NAC and apocynin protected neomycin-induced hair cell loss within the neuromasts. Moreover, these three compounds reduced the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin, indicating that their antioxidant action is involved. In contrast, the neuromasts were labeled with specific fluorescent dye Texas-red conjugated with neomycin to detect neomycin uptake. Interestingly, the uptake of neomycin into hair cells was not influenced by these three antioxidant compounds. These data imply that prevention of hair cell damage against neomycin by L-ascorbic acid, NAC and apocynin might be associated with inhibition of excessive ROS production, but not related to modulating neomycin uptake. Our findings conclude that L-ascorbic acid, NAC and apocynin could be used as therapeutic drugs to protect aminoglycoside-induced listening impairment after further confirmatory studies.}, }
@article {pmid25090113, year = {2014}, author = {Sue, YM and Chou, HC and Chang, CC and Yang, NJ and Chou, Y and Juan, SH}, title = {L-carnitine protects against carboplatin-mediated renal injury: AMPK- and PPARα-dependent inactivation of NFAT3.}, journal = {PloS one}, volume = {9}, number = {8}, pages = {e104079}, pmid = {25090113}, issn = {1932-6203}, mesh = {AMP-Activated Protein Kinases/*genetics ; Acute Kidney Injury/chemically induced/drug therapy/*genetics/pathology ; Animals ; Apoptosis/drug effects ; Carboplatin/adverse effects ; Carnitine/*administration &amp; dosage ; Cyclooxygenase 2/biosynthesis ; Gene Expression Regulation/drug effects ; Gene Knockdown Techniques ; Humans ; Inflammation/chemically induced/genetics/pathology ; Kidney/drug effects/injuries/pathology ; Mice ; NFATC Transcription Factors/*biosynthesis/genetics ; PPAR alpha/*biosynthesis/genetics ; Protective Agents/administration &amp; dosage ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {We have previously shown that carboplatin induces inflammation and apoptosis in renal tubular cells (RTCs) through the activation of the nuclear factor of activated T cells-3 (NFAT3) protein by reactive oxygen species (ROS), and that the ROS-mediated activation of NFAT3 is prevented by N-acetyl cysteine and heme oxygenase-1 treatment. In the current study, we investigated the underlying molecular mechanisms of the protective effect of L-carnitine on carboplatin-mediated renal injury. Balb/c mice and RTCs were used as model systems. Carboplatin-induced apoptosis in RTCs was examined using terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling. We evaluated the effects of the overexpression of the peroxisome-proliferator-activated receptor alpha (PPARα) protein, the knockdown of PPARα gene, and the blockade of AMPK activation and PPARα to investigate the underlying mechanisms of the protective effect of L-carnitine on carboplatin-mediated renal injury. Carboplatin reduced the nuclear translocation, phosphorylation, and peroxisome proliferator responsive element transactivational activity of PPARα. These carboplatin-mediated effects were prevented by L-carnitine through a mechanism dependent on AMPK phosphorylation and subsequent PPARα activation. The activation of PPARα induced cyclooxygenase 2 (COX-2) and prostacyclin (PGI2) synthase expression that formed a positive feedback loop to further activate PPARα. The coimmunoprecipitation of the nuclear factor (NF) κB proteins increased following the induction of PPARα by L-carnitine, which reduced NFκB transactivational activity and cytokine expression. The in vivo study showed that the inactivation of AMPK suppressed the protective effect of L-carnitine in carboplatin-treated mice, indicating that AMPK phosphorylation is required for PPARα activation in the L-carnitine-mediated protection of RTC apoptosis caused by carboplatin. The results of our study provide molecular evidence that L-carnitine prevents carboplatin-mediated apoptosis through AMPK-mediated PPARα activation.}, }
@article {pmid25089563, year = {2015}, author = {Meng, Y and Li, T and Zhou, GS and Chen, Y and Yu, CH and Pang, MX and Li, W and Li, Y and Zhang, WY and Li, X}, title = {The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway.}, journal = {Antioxidants &amp; redox signaling}, volume = {22}, number = {3}, pages = {241-258}, pmid = {25089563}, issn = {1557-7716}, mesh = {Angiotensin I/physiology ; Angiotensin-Converting Enzyme 2 ; Animals ; *Cell Movement ; Cells, Cultured ; Collagen Type I/metabolism ; Collagen Type I, alpha 1 Chain ; Fibroblasts/*physiology ; Male ; NADPH Oxidase 4 ; NADPH Oxidases/metabolism ; Peptide Fragments/physiology ; Peptidyl-Dipeptidase A/physiology ; Proto-Oncogene Mas ; Proto-Oncogene Proteins/metabolism ; Pulmonary Fibrosis/*enzymology/pathology ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Receptors, G-Protein-Coupled/metabolism ; rho-Associated Kinases/metabolism ; rhoA GTP-Binding Protein/*metabolism ; }, abstract = {UNLABELLED: Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear.<br><br>AIMS: To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway.<br><br>RESULTS: In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and &#x3b1;-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1-7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and &#x3b1;-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1-7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1-7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS.<br><br>INNOVATION: This study suggests that the ACE2/Ang(1-7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS.<br><br>CONCLUSION: The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway.}, }
@article {pmid25088507, year = {2014}, author = {Gamage, AM and Lee, KO and Gan, YH}, title = {Effect of oral N-acetyl cysteine supplementation in type 2 diabetic patients on intracellular glutathione content and innate immune responses to Burkholderia pseudomallei.}, journal = {Microbes and infection}, volume = {16}, number = {8}, pages = {661-671}, doi = {10.1016/j.micinf.2014.07.007}, pmid = {25088507}, issn = {1769-714X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Aged ; Burkholderia pseudomallei/*immunology ; Cells, Cultured ; Diabetes Mellitus, Type 2/*drug therapy ; Female ; Glutathione/*metabolism ; Humans ; *Immunity, Innate ; Interferon-gamma/metabolism ; Interleukin-12/metabolism ; Male ; Middle Aged ; }, abstract = {Type 2 diabetic patients have increased susceptibility to melioidosis, an infectious disease caused by Burkholderia pseudomallei. We had previously shown that peripheral blood mononuclear cells (PBMCs) from diabetic patients with poor glycemic control had a defective IL-12 and IFNγ response to B. pseudomallei infection, resulting in poor intracellular bacterial control. The impaired IL-12 response was due to glutathione (GSH) deficiency characterized by a low reduced to oxidized glutathione ratio (GSH ratio) and could be restored by the addition of reduced GSH to the infected cells. Our goal is to determine whether N-acetyl cysteine (NAC, a GSH pro-drug) supplementation in diabetic patients could improve their immune control of B. pseudomallei. Type 2 diabetic patients with poor glycemic control were given oral supplementation of NAC for six weeks at 1200 mg daily. Their PBMCs and subsets of immune cells showed a significant increase in free GSH concentration. However, the GSH ratio, IL-12 and IFNγ production, and intracellular bacterial killing upon ex-vivo infection did not improve. Thus, oral NAC supplementation in diabetic patients is sufficient to increase intracellular GSH content in blood cells. However, modulating the free GSH content is not sufficient to improve infection outcome as it is the GSH ratio that regulates the IL-12 response in monocytes.}, }
@article {pmid25085248, year = {2014}, author = {Xie, JM and Li, B and Yu, HP and Gao, QG and Li, W and Wu, HR and Qin, ZH}, title = {TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy.}, journal = {Cancer research}, volume = {74}, number = {18}, pages = {5127-5138}, doi = {10.1158/0008-5472.CAN-13-3517}, pmid = {25085248}, issn = {1538-7445}, mesh = {Animals ; Antibiotics, Antineoplastic/pharmacology ; Apoptosis/drug effects/physiology ; Apoptosis Regulatory Proteins ; Autophagy/drug effects/physiology ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Epirubicin/pharmacology ; Female ; Gene Knockdown Techniques ; Hep G2 Cells ; Heterografts ; Humans ; Intracellular Signaling Peptides and Proteins/*physiology ; Liver Neoplasms/drug therapy/*pathology ; Lung Neoplasms/drug therapy/*pathology ; Mice ; Mice, Nude ; Phosphoric Monoester Hydrolases ; Transfection ; }, abstract = {The p53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis, resulting in higher intracellular NADPH, lower reactive oxygen species (ROS) and autophagy activity. In this study, we investigated whether TIGAR might exert dual impacts on cancer cell survival based on its ability to inhibit both apoptosis and autophagy. In liver or lung cancer cells treated with the anticancer drug epirubicin, TIGAR levels increased in a dose- and time-dependent manner. TIGAR silencing enhanced epirubicin-induced elevations in ROS levels and apoptosis rates, in a manner that was blocked by ectopic addition of NADPH or N-acetyl cysteine. These findings were correlated with reduced tumorigenicity and increased chemosensitivity in mouse xenograft tumor assays. In parallel, TIGAR silencing also enhanced the epirubicin-induced activation of autophagy, in a manner that was also blocked by ectopic addition of NADPH. Notably, TIGAR silencing also licensed epirubicin-mediated inactivation of the mTOR pathway, suggesting TIGAR also exerted a negative impact on autophagy. However, genetic or pharmacologic inhibition of autophagy increased epirubicin-induced apoptosis in TIGAR-silenced cells. Overall, our results revealed that TIGAR inhibits both apoptosis and autophagy, resulting in a dual impact on tumor cell survival in response to tumor chemotherapy. Cancer Res; 74(18); 5127-38. ©2014 AACR.}, }
@article {pmid25083175, year = {2014}, author = {Cheraghi, E and Soleimani Mehranjani, M and Shariatzadeh, MA and Nasr Esfahani, MH and Ebrahimi, Z}, title = {Co-Administration of Metformin and N-Acetyl Cysteine Fails to Improve Clinical Manifestations in PCOS Individual Undergoing ICSI.}, journal = {International journal of fertility &amp; sterility}, volume = {8}, number = {2}, pages = {119-128}, pmid = {25083175}, issn = {2008-076X}, abstract = {BACKGROUND: Studies have demonstrated the efficacy of metformin (MTF) in reducing insulin resistance and N-acetyl cysteine (NAC) in inhibiting oxidative stress which are involved in the pathogenesis of polycystic ovarian syndrome (PCOS). We aimed to compare the effects of MTF and NAC combination on serum metabolite and hormonal levels during the course of ovulation induction in PCOS individual candidates of intracytoplasmic sperm injection (ICSI).<br><br>MATERIALS AND METHODS: In this prospective randomized clinical trial, placebo con- trolled pilot study, 80 patients of polycystic ovarian syndrome at the age of 25-35 years were divided into 4 groups (n=20): i. NAC=treated with N-acetyl cysteine (600 mg three times daily), ii. MTF=treated with metformin (500 mg three times daily), iii. MTF+NAC=treated with N-acetyl cysteine plus metformin (the offered doses) and iv. placebo (PLA). A total number of 20 patients (6 from MTF group, 4 from NAC group, 6 from MTF+NAC group and 4 from PLA group) were dropped of the study. The drugs were administrated from day 3 of menses of previous cycle until ovum pick-up.<br><br>RESULTS: Serum levels of luteinizing hormone (LH), total testosterone, cholester- ol and triglyceride, insulin and leptin significantly reduced in the MTF and NAC groups compared to the placebo (p<0.01). But levels of LH, total testosterone, cholesterol and triglyceride had no significant reduction in the MTF+NAC groups compared to the placebo. The serum levels of malonyldialdehyde (MDA), insulin and leptin reduced significantly after treatment in the MTF+NAC group compared to the placebo (p<0.05).<br><br>CONCLUSION: CONSIDERING THE ADVERSE EFFECT OF COMBINATION THERAPY, WE PROPOSED THE CONADMINISTRATION MIGHT HAVE NO BENEFICIAL EFFECT FOR PCOS PATIENT DURING COURSE OF OVULATION INDUCTION OF ICSI (REGISTRATION NUMBER: IRCT201204159476N1).}, }
@article {pmid25080489, year = {2014}, author = {Cozzoli, A and Liantonio, A and Conte, E and Cannone, M and Massari, AM and Giustino, A and Scaramuzzi, A and Pierno, S and Mantuano, P and Capogrosso, RF and Camerino, GM and De Luca, A}, title = {Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase.}, journal = {American journal of physiology. Cell physiology}, volume = {307}, number = {7}, pages = {C634-47}, pmid = {25080489}, issn = {1522-1563}, mesh = {Angiotensin II/*pharmacology ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Calcium/*metabolism ; Calcium Signaling/drug effects ; Chlorides/*metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Excitation Contraction Coupling/drug effects ; Free Radical Scavengers/pharmacology ; Homeostasis ; Male ; Membrane Potentials ; Mice, Inbred C57BL ; Muscle Fibers, Skeletal/*drug effects/enzymology ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; Oxidative Stress/drug effects ; Potassium/*metabolism ; Reactive Oxygen Species/metabolism ; Receptor, Angiotensin, Type 1/*agonists/metabolism ; Time Factors ; }, abstract = {Angiotensin II (ANG II) plays a role in muscle wasting and remodeling; however, little evidence shows its direct effects on specific muscle functions. We presently investigated the acute in vitro effects of ANG II on resting ionic conductance and calcium homeostasis of mouse extensor digitorum longus (EDL) muscle fibers, based on previous findings that in vivo inhibition of ANG II counteracts the impairment of macroscopic ClC-1 chloride channel conductance (gCl) in the mdx mouse model of muscular dystrophy. By means of intracellular microelectrode recordings we found that ANG II reduced gCl in the nanomolar range and in a concentration-dependent manner (EC50 = 0.06 μM) meanwhile increasing potassium conductance (gK). Both effects were inhibited by the ANG II receptors type 1 (AT1)-receptor antagonist losartan and the protein kinase C inhibitor chelerythrine; no antagonism was observed with the AT2 antagonist PD123,319. The scavenger of reactive oxygen species (ROS) N-acetyl cysteine and the NADPH-oxidase (NOX) inhibitor apocynin also antagonized ANG II effects on resting ionic conductances; the ANG II-dependent gK increase was blocked by iberiotoxin, an inhibitor of calcium-activated potassium channels. ANG II also lowered the threshold for myofiber and muscle contraction. Both ANG II and the AT1 agonist L162,313 increased the intracellular calcium transients, measured by fura-2, with a two-step pattern. These latter effects were not observed in the presence of losartan and of the phospholipase C inhibitor U73122 and the in absence of extracellular calcium, disclosing a Gq-mediated calcium entry mechanism. The data show for the first time that the AT1-mediated ANG II pathway, also involving NOX and ROS, directly modulates ion channels and calcium homeostasis in adult myofibers.}, }
@article {pmid25075522, year = {2014}, author = {Raza, H and John, A and Shafarin, J}, title = {NAC attenuates LPS-induced toxicity in aspirin-sensitized mouse macrophages via suppression of oxidative stress and mitochondrial dysfunction.}, journal = {PloS one}, volume = {9}, number = {7}, pages = {e103379}, pmid = {25075522}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Aspirin/*pharmacology ; Cell Line ; Cytochrome P-450 Enzyme System/metabolism ; Cytokines/biosynthesis ; Glutathione/metabolism ; Lipopolysaccharides/*immunology ; Macrophages/drug effects/*immunology/*metabolism ; Mice ; Mitochondria/*drug effects/*metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Bacterial endotoxin lipopolysaccharide (LPS) induces the production of inflammatory cytokines and reactive oxygen species (ROS) under in vivo and in vitro conditions. Acetylsalicylic acid (ASA, aspirin) is a commonly used anti-inflammatory drug. Our aim was to study the effects of N-acetyl cysteine (NAC), an antioxidant precursor of GSH synthesis, on aspirin-sensitized macrophages treated with LPS. We investigated the effects of LPS alone and in conjunction with a sub-toxic concentration of ASA, on metabolic and oxidative stress, apoptosis, and mitochondrial function using J774.2 mouse macrophage cell line. Protection from LPS-induced toxicity by NAC was also studied. LPS alone markedly induced ROS production and oxidative stress in macrophage cells. When ASA was added to LPS-treated macrophages, the increase in oxidative stress was significantly higher than that with LPS alone. Similarly, alteration in glutathione-dependent redox metabolism was also observed in macrophages after treatment with LPS and ASA. The combination of LPS and ASA selectively altered the CYP 3A4, CYP 2E1 and CYP 1A1 catalytic activities. Mitochondrial respiratory complexes and ATP production were also inhibited by LPS-ASA treatment. Furthermore a higher apoptotic cell death was also observed in LPS-ASA treated macrophages. NAC pre-treatment showed protection against oxidative stress induced apoptosis and mitochondrial dysfunction. These effects are presumed, at least in part, to be associated with alterations in NF-κB/Nrf-2 mediated cell signaling. These results suggest that macrophages are more sensitive to LPS when challenged with ASA and that NAC pre-treatment protects the macrophages from these deleterious effects.}, }
@article {pmid25073983, year = {2014}, author = {Dattilo, M and Cornet, D and Amar, E and Cohen, M and Menezo, Y}, title = {The importance of the one carbon cycle nutritional support in human male fertility: a preliminary clinical report.}, journal = {Reproductive biology and endocrinology : RB&amp;E}, volume = {12}, number = {}, pages = {71}, pmid = {25073983}, issn = {1477-7827}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Adult ; Birth Rate ; *Dietary Supplements ; Embryo Implantation ; Family Characteristics ; Female ; Fertilization in Vitro ; Fruit/chemistry ; Homocysteine/*metabolism ; Humans ; Infertility, Male/*diet therapy/metabolism ; Insemination, Artificial, Homologous ; Male ; Middle Aged ; Opuntia/chemistry ; Plant Extracts/administration &amp; dosage/therapeutic use ; Pregnancy ; Pregnancy Rate ; Switzerland/epidemiology ; Vitamin B Complex/administration &amp; dosage/therapeutic use ; Vitamin E/administration &amp; dosage/therapeutic use ; Zinc/administration &amp; dosage/therapeutic use ; }, abstract = {BACKGROUND: Sperm chromatin structure is often impaired; mainly due to oxidative damage. Antioxidant treatments do not consistently produce fertility improvements and, when given at high doses, they might block essential oxidative processes such as chromatin compaction. This study was intended to assess the effect on male sub-fertility of a pure one carbon cycle nutritional support without strong antioxidants.<br><br>METHODS: Male partners of couples resistant to at least 2 assisted reproductive technology (ART) attempts, with no evidence of organic causes of infertility and with either DNA fragmentation index (DFI) measured by Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) or nuclear decondensation index (SDI) measured by aniline blue staining exceeding 20%, were invited to take part in a trial of a nutritional support in preparation for a further ART attempt. The treatment consisted of a combination of B vitamins, zinc, a proprietary opuntia fig extract and small amounts of N-acetyl-cysteine and Vitamin E (Condensyl&#x2122;), all effectors of the one carbon cycle.<br><br>RESULTS: 84 patients were enrolled, they took 1 or 2 Condensyl&#x2122; tablets per day for 2 to 12 months. Positive response rates were 64.3% for SDI, 71.4% for DFI and 47.6% for both SDI and DFI. Eighteen couples (21%) experienced a spontaneous pregnancy before the planned ART cycle, all ended with a live birth. The remaining 66 couples underwent a new ART attempt (4 IUI; 18 IVF; 44 ICSI) resulting in 22 further clinical pregnancies and 15 live births. The clinical pregnancy rate (CPR) and the live birth rate (LBR) were 47.6% and 39.3% respectively. The full responders, i.e. the 40 patients achieving an improvement of both SDI and DFI, reported a CPR of 70% and a LBR of 57.5% (p<0.001).<br><br>CONCLUSIONS: Nutritional support of the one carbon cycle without strong antioxidants improves both the SDI and the DFI in ART resistant male partners and results in high pregnancy rates suggesting a positive effect on their fertility potential.}, }
@article {pmid25073872, year = {2015}, author = {Kocyigit, I and Vural, A and Unal, A and Sipahioglu, MH and Yucel, HE and Aydemir, S and Yazici, C and İlhan Sahin, M and Oymak, O and Tokgoz, B}, title = {Preventing amikacin related ototoxicity with N-acetylcysteine in patients undergoing peritoneal dialysis.}, journal = {European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery}, volume = {272}, number = {10}, pages = {2611-2620}, pmid = {25073872}, issn = {1434-4726}, mesh = {Acetylcysteine/*therapeutic use ; Amikacin/*adverse effects ; Anti-Bacterial Agents/adverse effects ; Ear Diseases/chemically induced/*prevention &amp; control ; Female ; Free Radical Scavengers/therapeutic use ; Humans ; Kidney Failure, Chronic/therapy ; Male ; Middle Aged ; Otoacoustic Emissions, Spontaneous/drug effects ; *Peritoneal Dialysis ; Peritonitis/drug therapy ; Prospective Studies ; }, abstract = {Amikacin is a frequently used antibiotic in the treatment of peritoneal dialysis (PD)-related peritonitis. Ototoxicity is a well-known complication of amikacin for which increased oxidative stress and free oxygen radicals are thought to be responsible. In this study, the effect of N-acetyl-cysteine (NAC) on cochlear function and oxidant situation in the amikacin related ototoxicity in PD-related peritonitis patients are investigated. Forty-six patients who had their first PD-related peritonitis attacks receiving empirical amikacin treatment were enrolled in the study. The patients were randomized into two groups; the first group (n = 23) as NAC receiving and the second group (n = 23) as a placebo receiving, control group. Otoacoustic emissions were measured before, 1 week after and 4 weeks after the treatment. Oxidative stress measurements were performed concurrently in order to evaluate the effectiveness of NAC. The results of screening with otoacoustic emission testing after amikacin treatment showed that cochlear function is protected especially in higher frequencies in NAC group when compared with the control group. Evaluation of the antioxidant status of the two groups showed no differences in the basal values, but at the first week there was an increase in the NAC group compared with the control group, and this increase became significant at the fourth week. NAC is found to be safe and effective in amikacin-related ototoxicity in patients with PD-related peritonitis. We suggest a close monitoring of the patients receiving amikacin containing treatment protocols and if amikacin is administrated supplementing the treatment with NAC.}, }
@article {pmid25070112, year = {2014}, author = {Kathuria, M and Bhattacharjee, A and Sashidhara, KV and Singh, SP and Mitra, K}, title = {Induction of mitochondrial dysfunction and oxidative stress in Leishmania donovani by orally active clerodane diterpene.}, journal = {Antimicrobial agents and chemotherapy}, volume = {58}, number = {10}, pages = {5916-5928}, pmid = {25070112}, issn = {1098-6596}, mesh = {Adenosine Triphosphate/metabolism ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cytochromes c/metabolism ; Diterpenes, Clerodane/*pharmacology ; Glutathione/metabolism ; Leishmania donovani/*drug effects/*metabolism/ultrastructure ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Confocal ; Microscopy, Electron, Transmission ; Mitochondria/drug effects/metabolism/ultrastructure ; Oxidative Stress/drug effects ; }, abstract = {This study was performed to investigate the mechanistic aspects of cell death induced by a clerodane diterpene (K-09) in Leishmania donovani promastigotes that was previously demonstrated to be safe and orally active against visceral leishmaniasis (VL). K-09 caused depolarization of the mitochondrion and the generation of reactive oxygen species, triggering an apoptotic response in L. donovani promastigotes. Mitochondrial dysfunction subsequently resulted in the release of cytochrome c into the cytosol, impairing ATP production. Oxidative stress caused the depletion of reduced glutathione, while pretreatment with antioxidant N-acetyl cysteine (NAC) was able to abrogate oxidative stress. However, NAC failed to restore the mitochondrial membrane potential or intracellular calcium homeostasis after K-09 treatment, suggesting that the generation of oxidative stress is a downstream event relative to the other events. Caspase-3/-7-like protease activity and genomic DNA fragmentation were observed. Electron microscopy studies revealed gross morphological alterations typical of apoptosis, including severe mitochondrial damage, pyknosis of the nucleus, structural disruption of the mitochondrion-kinetoplast complex, flagellar pocket alterations, and the displacement of organelles. Moreover, an increased number of lipid droplets was detected after K-09 treatment, which is suggestive of altered lipid metabolism. Our results indicate that K-09 induces mitochondrial dysfunction and oxidative stress-mediated apoptotic cell death in L. donovani promastigotes, sharing many features with metazoan apoptosis. These mechanistic insights provide a basis for further investigation toward the development of K-09 as a potential drug candidate for VL.}, }
@article {pmid25070093, year = {2014}, author = {Wang, JH and Singh, R and Benoit, M and Keyhan, M and Sylvester, M and Hsieh, M and Thathireddy, A and Hsieh, YJ and Matin, AC}, title = {Sigma S-dependent antioxidant defense protects stationary-phase Escherichia coli against the bactericidal antibiotic gentamicin.}, journal = {Antimicrobial agents and chemotherapy}, volume = {58}, number = {10}, pages = {5964-5975}, pmid = {25070093}, issn = {1098-6596}, support = {K08 DK087895/DK/NIDDK NIH HHS/United States ; DK087895/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology ; Antioxidants/*metabolism ; Escherichia coli/*drug effects/*metabolism ; Female ; Gene Expression Regulation, Bacterial/drug effects ; Gentamicins/*pharmacology ; Mice ; Sigma Factor/*metabolism ; }, abstract = {Stationary-phase bacteria are important in disease. The σ(s)-regulated general stress response helps them become resistant to disinfectants, but the role of σ(s) in bacterial antibiotic resistance has not been elucidated. Loss of σ(s) rendered stationary-phase Escherichia coli more sensitive to the bactericidal antibiotic gentamicin (Gm), and proteomic analysis suggested involvement of a weakened antioxidant defense. Use of the psfiA genetic reporter, 3'-(p-hydroxyphenyl) fluorescein (HPF) dye, and Amplex Red showed that Gm generated more reactive oxygen species (ROS) in the mutant. HPF measurements can be distorted by cell elongation, but Gm did not affect stationary-phase cell dimensions. Coadministration of the antioxidant N-acetyl cysteine (NAC) decreased drug lethality particularly in the mutant, as did Gm treatment under anaerobic conditions that prevent ROS formation. Greater oxidative stress, due to insufficient quenching of endogenous ROS and/or respiration-linked electron leakage, therefore contributed to the greater sensitivity of the mutant; infection by a uropathogenic strain in mice showed this to be the case also in vivo. Disruption of antioxidant defense by eliminating the quencher proteins, SodA/SodB and KatE/SodA, or the pentose phosphate pathway proteins, Zwf/Gnd and TalA, which provide NADPH for ROS decomposition, also generated greater oxidative stress and killing by Gm. Thus, besides its established mode of action, Gm also kills stationary-phase bacteria by generating oxidative stress, and targeting the antioxidant defense of E. coli can enhance its efficacy. Relevant aspects of the current controversy on the role of ROS in killing by bactericidal drugs of exponential-phase bacteria, which represent a different physiological state, are discussed.}, }
@article {pmid25064824, year = {2014}, author = {Panda, PK and Mukhopadhyay, S and Behera, B and Bhol, CS and Dey, S and Das, DN and Sinha, N and Bissoyi, A and Pramanik, K and Maiti, TK and Bhutia, SK}, title = {Antitumor effect of soybean lectin mediated through reactive oxygen species-dependent pathway.}, journal = {Life sciences}, volume = {111}, number = {1-2}, pages = {27-35}, doi = {10.1016/j.lfs.2014.07.004}, pmid = {25064824}, issn = {1879-0631}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; Autophagy/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; HeLa Cells/drug effects ; Hep G2 Cells/drug effects ; Humans ; In Vitro Techniques ; Lymphoma/drug therapy ; Mice ; Neoplasms/*drug therapy ; Neoplasms, Experimental/drug therapy ; Plant Lectins/*pharmacology ; Reactive Oxygen Species/*metabolism ; Soybean Proteins/*pharmacology ; }, abstract = {AIMS: The present study evaluated the potential role of soybean lectin's (SBL) anticancer effect in vitro in different cancer cell lines and the therapeutic effectiveness in vivo in Dalton's lymphoma (DL) bearing mice model.<br><br>MAIN METHODS: The effect of SBL on cell growth and viability was measured using MTT assay in different cancer cells in vitro. Apoptosis, autophagic cell death, DNA-damaging potential and reactive oxygen species (ROS) were analyzed in HeLa cells. The in vivo efficacy of SBL was demonstrated in Dalton's lymphoma (DL) bearing mice.<br><br>KEY FINDINGS: SBL demonstrated clear, strong antiproliferative activity without affecting normal cells; however, heat denaturation of SBL diminished the antiproliferative efficacy of molecule as demonstrated by MTT assay. A sharp 74.51 &#xb1; 3.5% and 82.95 &#xb1; 5.8% inhibition of tumor cell proliferation in DL mice occurred when SBL was administered at a dosage of 1 and 2mg/kg body weight (i.p.), respectively, for ten days with the induction of autophagic and apoptotic cell death. An in vitro investigation revealed that SBL-mediated autophagy, apoptosis and DNA damage in HeLa cells were inflicted through the generation of ROS in a dose-dependent manner. Interestingly, pre-treating HeLa cells with N-acetylcysteine (NAC), a typical ROS scavenger, led to a noticeable reduction in SBL-induced autophagy, apoptosis and DNA-damaging activities, suggesting that SBL's antitumor potential was governed by ROS activation.<br><br>SIGNIFICANCE: In this study, we evaluated the apoptotic, autophagic death, and DNA-damaging effects of SBL in cancer cells, which may have the potential to be used as a phyto-derived protein for cancer therapy.}, }
@article {pmid25064604, year = {2014}, author = {Cicek, FA and Toy, A and Tuncay, E and Can, B and Turan, B}, title = {Beta-blocker timolol alleviates hyperglycemia-induced cardiac damage via inhibition of endoplasmic reticulum stress.}, journal = {Journal of bioenergetics and biomembranes}, volume = {46}, number = {5}, pages = {377-387}, pmid = {25064604}, issn = {1573-6881}, mesh = {Adrenergic beta-Antagonists/*pharmacology ; Animals ; Apoptosis/drug effects ; Disease Models, Animal ; Endoplasmic Reticulum Stress/*drug effects ; Heart Diseases/*blood/*drug therapy/physiopathology ; Hyperglycemia/*drug therapy/metabolism/physiopathology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Timolol/*pharmacology ; }, abstract = {Current data support that pharmacological modulators of endoplasmic reticulum stress (ERS) have therapeutic potential for diabetic individuals. Therefore, we aimed to examine whether timolol, having free radical-scavenger action, besides being a β-blocker, exerts a cardioprotective effect via inhibition of ERS response in diabetic rats in a comparison with an antioxidant N-acetylcysteine (NAC). Histopathological data showed that either timolol- or NAC-treatment of diabetic rats prevented the changes in mitochondria and nucleus of the cardiac tissue while they enhanced the cellular redox-state in heart as well. The levels of ER-targeted cytoprotective chaperones GRP78 and calnexin, unfolded protein response signaling protein CHO/Gadd153 besides the levels of calpain, BCL-2, phospho-Akt, PUMA, and PML in the hearts from diabetic rats, treated with either timolol or NAC, are found to be similar among these groups, although all these parameters were markedly preserved in the untreated diabetics compared to those of the controls. Taken into consideration how important a balanced-ratio between anti-apoptotic and pro-apoptotic proteins for the maintenance mitochondria/ER function, our results suggest that ERS in diabetic rat heart is mediated by increased oxidative damage, which in turn triggers cardiac dysfunction. Moreover, we also demonstrated that timolol treatment of diabetic rats, similar to NAC treatment, induced a well-controlled redox-state and apoptosis in cardiac myocardium. We, thus for the first time, report that cardioprotective effect of timolol seems to be associated with normalization of ER function due to its antioxidant action in cardiomyocytes even under hyperglycemia.}, }
@article {pmid25064164, year = {2014}, author = {Wiest, DB and Chang, E and Fanning, D and Garner, S and Cox, T and Jenkins, DD}, title = {Antenatal pharmacokinetics and placental transfer of N-acetylcysteine in chorioamnionitis for fetal neuroprotection.}, journal = {The Journal of pediatrics}, volume = {165}, number = {4}, pages = {672-7.e2}, pmid = {25064164}, issn = {1097-6833}, support = {R01 NS052448/NS/NINDS NIH HHS/United States ; R01NSO52448//PHS HHS/United States ; }, mesh = {Acetylcysteine/*pharmacokinetics ; Chorioamnionitis/*drug therapy ; Double-Blind Method ; Female ; Fetal Blood/drug effects ; Free Radical Scavengers/pharmacokinetics ; Humans ; Inflammation/drug therapy ; Infusions, Intravenous ; Male ; Maternal-Fetal Exchange ; Mothers ; Neuroprotective Agents/*pharmacokinetics ; Pilot Projects ; Placenta/*drug effects ; Pregnancy ; Prospective Studies ; Time Factors ; }, abstract = {OBJECTIVE: To determine the pharmacokinetics (PK) and placental transfer of intravenous (i.v.) N-acetylcysteine (NAC) in mothers with a clinical diagnosis of chorioamnionitis (CA) and determine the PK of i.v. NAC in their infants.<br><br>STUDY DESIGN: In this prospective, double-blind study i.v. NAC 100 mg/kg/dose or saline was administered within 4 hours of CA diagnosis to pregnant women &#x2265;24 weeks' gestation and then every 6 hours until delivery. Maternal PK and placental transfer were determined with maternal blood and matched maternal and cord venous blood. Neonatal PK estimates were determined from i.v. NAC (12.5-25 mg/kg/dose) administered every 12 hours for 5 doses. Noncompartmental analyses were performed for maternal and neonatal PK estimates.<br><br>RESULTS: Eleven mothers (5 preterm, 6 near-term) and 12 infants (1 set of twins) received NAC. Maternal clearance (CL) of NAC was faster than in nonpregnant adults, with a terminal elimination half-life of 1.2 &#xb1; 0.2 hours. The NAC cord to maternal ratio was 1.4 &#xb1; 0.8, suggesting rapid placental transfer and slower rate of fetal CL. Neonatal PK estimates for near-term compared with preterm infants showed a significantly shorter terminal elimination half-life (5.1 vs 7.5 hours, respectively) and greater CL (53.7 vs 45.0 mL/h/kg, respectively).<br><br>CONCLUSIONS: Maternal CL and placental transfer of NAC was rapid, with umbilical cord concentrations frequently exceeding maternal concentrations. The administration of NAC to mothers with CA achieves predictable NAC plasma concentrations in the fetus, indicating that antenatal neuroprotection may be possible for these newborns at high risk for neuroinflammation.}, }
@article {pmid25063855, year = {2014}, author = {Dukoff, DJ and Hogg, DW and Hawrysh, PJ and Buck, LT}, title = {Scavenging ROS dramatically increase NMDA receptor whole-cell currents in painted turtle cortical neurons.}, journal = {The Journal of experimental biology}, volume = {217}, number = {Pt 18}, pages = {3346-3355}, doi = {10.1242/jeb.105825}, pmid = {25063855}, issn = {1477-9145}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Animals ; Calcium/metabolism ; Cerebral Cortex/*cytology/physiology ; Female ; Free Radical Scavengers ; Hydrogen Peroxide ; Membrane Potentials/physiology ; Mitochondria/drug effects/metabolism ; Neurons/cytology/*drug effects/physiology ; Oxygen ; Patch-Clamp Techniques ; Reactive Oxygen Species/*metabolism ; Receptors, N-Methyl-D-Aspartate/*physiology ; Rotenone ; Tiopronin/pharmacology ; Turtles/*physiology ; }, abstract = {Oxygen deprivation triggers excitotoxic cell death in mammal neurons through excessive calcium loading via over-activation of N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This does not occur in the western painted turtle, which overwinters for months without oxygen. Neurological damage is avoided through anoxia-mediated decreases in NMDA and AMPA receptor currents that are dependent upon a modest rise in intracellular Ca(2+) concentrations ([Ca(2+)]i) originating from mitochondria. Anoxia also blocks mitochondrial reactive oxygen species (ROS) generation, which is another potential signaling mechanism to regulate glutamate receptors. To assess the effects of decreased intracellular [ROS] on NMDA and AMPA receptor currents, we scavenged ROS with N-2-mercaptopropionylglycine (MPG) or N-acetylcysteine (NAC). Unlike anoxia, ROS scavengers increased NMDA receptor whole-cell currents by 100%, while hydrogen peroxide decreased currents. AMPA receptor currents and [Ca(2+)]i concentrations were unaffected by ROS manipulation. Because decreases in [ROS] increased NMDA receptor currents, we next asked whether mitochondrial Ca(2+) release prevents receptor potentiation during anoxia. Normoxic activation of mitochondrial ATP-sensitive potassium (mKATP) channels with diazoxide decreased NMDA receptor currents and was unaffected by subsequent ROS scavenging. Diazoxide application following ROS scavenging did not rescue scavenger-mediated increases in NMDA receptor currents. Fluorescent measurement of [Ca(2+)]i and ROS levels demonstrated that [Ca(2+)]i increases before ROS decreases. We conclude that decreases in ROS concentration are not linked to anoxia-mediated decreases in NMDA/AMPA receptor currents but are rather associated with an increase in NMDA receptor currents that is prevented during anoxia by mitochondrial Ca(2+) release.}, }
@article {pmid25063220, year = {2014}, author = {Zhang, Y and Zhang, Y and Kou, J and Wang, C and Wang, K}, title = {Role of reactive oxygen species in angiotensin II: induced receptor activator of nuclear factor-κB ligand expression in mouse osteoblastic cells.}, journal = {Molecular and cellular biochemistry}, volume = {396}, number = {1-2}, pages = {249-255}, pmid = {25063220}, issn = {1573-4919}, mesh = {Angiotensin II/*pharmacology ; Angiotensin II Type 2 Receptor Blockers/pharmacology ; Animals ; Cell Line/drug effects ; Cytochrome b Group/metabolism ; Dose-Response Relationship, Drug ; Imidazoles/pharmacology ; Mice ; Mitogen-Activated Protein Kinase 3/metabolism ; NADPH Oxidases/metabolism ; Osteoblasts/drug effects/*metabolism ; Phosphoproteins/metabolism ; Pyridines/pharmacology ; RANK Ligand/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptor, Angiotensin, Type 1/metabolism ; Up-Regulation/drug effects ; }, abstract = {Angiotensin II (Ang II) has been shown to induce receptor activator of nuclear factor-κB ligand (RANKL) expression in osteoblasts associated with its effect on reactive oxygen species (ROS) production. The objective of the present study was to investigate the potential pathways by which Ang II induces RANKL expression and the role of ROS in Ang II-induced RANKL expression in mouse osteoblastic MC3T3-E1 cells. Treatment with Ang IIinduced RANKL expression in a dose- and time-dependent manner in osteoblasts, which was attenuated by pre-treatment with an AT1 receptor antagonist (olmesartan), ROS scavenger (N-acetylcysteine, NAC), or the ERK inhibitor (U0126), but not with AT2R antagonist (PD123319). Furthermore, Ang II enhanced AT1R and NAD(P)H oxidase (NOX) p22(phox) and p67(phox) expression and activity in osteoblasts. In addition, Ang II promoted ROS production, which was mitigated by pre-treatment with olmesartan or a NOX inhibitor (diphenyleneiodonium, DPI), but not with PD1123319 or U0126, in osteoblasts. Moreover, Ang II enhanced the ERK1/2 phosphorylation, which was abrogated by pre-treatment with olmesartan, NAC, DPI, or U0126 in osteoblasts. These results suggest that Ang II, through its AT1R, enhanced NOX activity and ROS production, and activated the ERK pathway to up-regulate RANKL expression in osteoblasts in vitro.}, }
@article {pmid25062287, year = {2015}, author = {McClure, EA and Baker, NL and Gipson, CD and Carpenter, MJ and Roper, AP and Froeliger, BE and Kalivas, PW and Gray, KM}, title = {An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers.}, journal = {The American journal of drug and alcohol abuse}, volume = {41}, number = {1}, pages = {52-56}, pmid = {25062287}, issn = {1097-9891}, support = {UL1 TR000062/TR/NCATS NIH HHS/United States ; R25 DA020537/DA/NIDA NIH HHS/United States ; U01 DA031779/DA/NIDA NIH HHS/United States ; U01DA031779/DA/NIDA NIH HHS/United States ; P50DA015369/DA/NIDA NIH HHS/United States ; UL1TR000062/TR/NCATS NIH HHS/United States ; P50 DA015369/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Administration, Oral ; Adolescent ; Adult ; Aged ; Benzazepines/*administration &amp; dosage/adverse effects ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Nicotinic Agonists/*administration &amp; dosage/adverse effects ; Pilot Projects ; Quinoxalines/*administration &amp; dosage/adverse effects ; Smoking/*drug therapy ; Smoking Cessation ; Treatment Outcome ; Varenicline ; }, abstract = {BACKGROUND: Varenicline (VAR) has demonstrated superior efficacy over other smoking cessation pharmacotherapies, though 50-60% of those treated do maintain abstinence. Some preclinical findings suggest that new nicotine dependence pharmacotherapies should target the glutamatergic system, given its demonstrated role in addiction. Attention has been given to N-acetylcysteine (NAC), which appears to restore normal glutamate signaling in animal models. It is possible that NAC and VAR may work in concert to promote abstinence at higher rates than with either medication alone.<br><br>OBJECTIVE: To demonstrate the feasibility and safety of co-administering NAC and VAR in nicotine-dependent participants.<br><br>METHODS: Participants (n&#x2009;=&#x2009;19) were daily cigarette smokers, and did not need to be seeking treatment. They received 4 weeks of open-label treatment with NAC (1200&#x2009;mg twice daily) and VAR (1&#x2009;mg twice daily, following titration) and were assessed weekly for adverse events (AEs), smoking, craving and withdrawal.<br><br>RESULTS: Sixteen participants reported a total of 40 AEs, and most were mild (88%). The most commonly reported AE was nausea (15%). Medication adherence, assessed via self-reports and pill counts, was excellent (98%). Exploratory analyses showed reductions in cigarettes per day, though point prevalence abstinence at the end of the study was low.<br><br>CONCLUSIONS: These preliminary data provide the first demonstration of safety and feasibility of the co-administration of NAC and VAR in cigarette smokers. AEs were consistent with those typically reported for VAR and NAC. These data support future efficacy research on NAC and VAR for smoking cessation.}, }
@article {pmid25058920, year = {2014}, author = {Xiao, Y and Li, X and Cui, Y and Zhang, J and Liu, L and Xie, X and Hao, H and He, G and Kander, MC and Chen, M and Liu, Z and Verfaillie, CM and Zhu, H and Lei, M and Liu, Z}, title = {Hydrogen peroxide inhibits proliferation and endothelial differentiation of bone marrow stem cells partially via reactive oxygen species generation.}, journal = {Life sciences}, volume = {112}, number = {1-2}, pages = {33-40}, doi = {10.1016/j.lfs.2014.07.016}, pmid = {25058920}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Bone Marrow Cells/cytology/*drug effects/metabolism ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/cytology/*drug effects/metabolism ; Gene Expression/drug effects ; Hydrogen Peroxide/*pharmacology ; Multipotent Stem Cells/cytology/*drug effects/metabolism ; Octamer Transcription Factor-3/genetics/metabolism ; Platelet Endothelial Cell Adhesion Molecule-1/genetics/metabolism ; Rats ; Reactive Oxygen Species/*agonists/antagonists &amp; inhibitors/metabolism ; Vascular Endothelial Growth Factor Receptor-2/genetics/metabolism ; }, abstract = {AIMS: The present study was to investigate the effect of hydrogen peroxide (H2O2) on bone marrow stem cells and their endothelial differentiation and the underlying mechanisms in vitro.<br><br>MAIN METHODS: Rat bone marrow multipotent adult progenitor cells (MAPCs) were used as the source of bone marrow stem cells, and treated with H2O2 (with the final concentration from 0 to 50 &#x3bc;M) with or without N-acetylcysteine (NAC, 0.1 mM). Reactive oxygen species (ROS) was measured by electron paramagnetic resonance (EPR) and fluorescent microscope. Flow cytometry and immunoblotting were used to determine apoptosis and differentiation of MAPCs.<br><br>KEY FINDINGS: H2O2 generated a significant amount of intracellular and extracellular ROS in the culture system, substantially inhibited the proliferation of MAPCs and Oct-4 expression, and induced their apoptosis in a dose-dependent manner. Exposure to H2O2 also significantly attenuated the endothelial differentiation of MAPCs with reduced expression of endothelial markers CD31 and FLK-1 as well as impaired in vitro vascular structure formation. Both intracellular and extracellular ROS production from H2O2 were blocked by NAC. NAC treatment effectively prevented H2O2-induced reduction of Oct-4 expression in the cells. However, NAC treatment only partially prevented H2O2-induced apoptosis, and inhibition of cell proliferation and endothelial differentiation of MAPCs.<br><br>SIGNIFICANCE: H2O2 exposure suppressed Oct-4 expression in MAPCs through ROS-dependent mechanism, while increasing the apoptosis of MAPCs and inhibiting their proliferation and endothelial differentiation with a mechanism partially due to ROS generation in vitro.}, }
@article {pmid25058850, year = {2015}, author = {Hussain, S and Varelogianni, G and Särndahl, E and Roomans, GM}, title = {N-acetylcysteine and azithromycin affect the innate immune response in cystic fibrosis bronchial epithelial cells in vitro.}, journal = {Experimental lung research}, volume = {41}, number = {5}, pages = {251-260}, doi = {10.3109/01902148.2014.934411}, pmid = {25058850}, issn = {1521-0499}, mesh = {Acetylcysteine/*pharmacology ; Azithromycin/*pharmacology ; Bronchi/drug effects/immunology ; Cell Line ; Cystic Fibrosis/*immunology ; Epithelial Cells/*drug effects/*immunology ; Humans ; Immunity, Innate/*drug effects/immunology ; Interleukin-6/immunology ; Nod1 Signaling Adaptor Protein/immunology ; Nod2 Signaling Adaptor Protein/immunology ; Up-Regulation/drug effects/immunology ; }, abstract = {BACKGROUND AND OBJECTIVE: We have previously reported that N-acetylcysteine (NAC), ambroxol and azithromycin (AZM) (partially) correct the chloride efflux dysfunction in cystic fibrosis bronchial epithelial (CFBE) cells with the ΔF508 homozygous mutation in vitro.<br><br>METHODS: In the present paper, we further investigated possible immunomodulatory effects of these drugs on the regulation of the innate immune system by studying the expression of the cytosolic NOD-like receptors NLRC1 and NLRC2, and interleukin (IL)-6 production in CFBE cells.<br><br>RESULTS: Under basal conditions, PCR and Western Blot data indicate that the NLRC2 receptor has a reduced expression in CF cells as compared to non-CF (16HBE) cells, but that the NLRC1 expression is the same in both cell lines. AZM significantly upregulated NLRC1 and NLRC2 while NAC upregulated only NLRC2 receptor expression in CF cells. Reduced basal IL-6 production was found in CF cells as compared to non-CF cells. MDP (an NLRC2 agonist), NAC and AZM, but not Tri-DAP (an NLRC1 agonist), increased IL-6 production in CF cells, indicating that in CF cells IL-6 upregulation is independent of NLRC1, but involves the activation of NLRC2.<br><br>CONCLUSION: Overall, the results indicate that NAC and AZM not only can correct the chloride efflux dysfunction but also have a weakly strengthening effect on the innate immune system.}, }
@article {pmid25058312, year = {2014}, author = {Giunta, S and Andriolo, V and Castorina, A}, title = {Dual blockade of the A1 and A2A adenosine receptor prevents amyloid beta toxicity in neuroblastoma cells exposed to aluminum chloride.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {54}, number = {}, pages = {122-136}, doi = {10.1016/j.biocel.2014.07.009}, pmid = {25058312}, issn = {1878-5875}, mesh = {Adenosine A1 Receptor Antagonists/pharmacology ; Adenosine A2 Receptor Antagonists/pharmacology ; Aluminum Chloride ; Aluminum Compounds/*adverse effects ; Amyloid beta-Peptides/*adverse effects ; Apoptosis/drug effects ; Astringents/adverse effects ; Blotting, Western ; Caffeine/pharmacology ; Cell Proliferation/drug effects ; Cells, Cultured ; Chlorides/*adverse effects ; Humans ; Lipid Peroxidation/drug effects ; Neuroblastoma/etiology/metabolism/pathology/*prevention &amp; control ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Purinergic P1 Receptor Antagonists/pharmacology ; Pyrimidines/pharmacology ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Receptor, Adenosine A1/*chemistry/genetics/metabolism ; Receptor, Adenosine A2A/*chemistry/genetics/metabolism ; Triazoles/pharmacology ; Xanthines/pharmacology ; }, abstract = {In a previous work we have shown that exposure to aluminum (Al) chloride (AlCl3) enhanced the neurotoxicity of the amyloid beta(25-35) fragment (Abeta(25-35)) in neuroblastoma cells and affected the expression of Alzheimer's disease (AD)-related genes. Caffein, a compound endowed with beneficial effects against AD, exerts neuroprotection primarily through its antagonist activity on A2A adenosine receptors (A2AR), although it also inhibits A1Rs with similar potency. Still, studies on the specific involvement of these receptors in neuroprotection in a model of combined neurotoxicity (Abeta(25-35)+AlCl3) are missing. To address this issue, cultured SH-SY5Y cells exposed to Abeta(25-35)+AlCl3 were assessed for cell viability, morphology, intracellular ROS activity and expression of apoptosis-, stress- and AD-related proteins. To define the role of A1R and A2ARs, pretreatment with caffein, specific receptor antagonists (DPCPX or SCH58261) or siRNA-mediated gene knockdown were delivered. Results indicate that AlCl3 treatment exacerbated Abeta(25-35) toxicity, increased ROS production, lipid peroxidation, β-secretase-1 (BACE1) and amyloid precursor protein (APP). Interestingly, SCH58261 successfully prevented toxicity associated to Abeta(25-35) only, whereas pretreatment with both DPCPX and SCH58261 was required to fully avert Abeta(25-35)+AlCl3-induced damage, suggesting that A1Rs might also be critically involved in protection during combined toxicity. The effects of caffein were mimicked by both N-acetyl cysteine, an antioxidant, and desferrioxamine, likely acting through distinct mechanisms. Altogether, our data establish a novel protective function associated with A1R inhibition in the setting of combined Abeta(25-35)+AlCl3 neurotoxicity, and expand our current knowledge on the potential beneficial role of caffein to prevent AD progression in subjects environmentally exposed to aluminum.}, }
@article {pmid25055840, year = {2014}, author = {Shohrati, M and Karimzadeh, I and Saburi, A and Khalili, H and Ghanei, M}, title = {The role of N-acetylcysteine in the management of acute and chronic pulmonary complications of sulfur mustard: a literature review.}, journal = {Inhalation toxicology}, volume = {26}, number = {9}, pages = {507-523}, doi = {10.3109/08958378.2014.920439}, pmid = {25055840}, issn = {1091-7691}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Bronchiolitis Obliterans/chemically induced/*drug therapy ; Chemical Warfare Agents/toxicity ; Disease Models, Animal ; Humans ; Lung/drug effects ; Mustard Gas/*toxicity ; Oxidative Stress/drug effects ; Randomized Controlled Trials as Topic ; }, abstract = {CONTEXT: Sulfur mustard exposure, as the most widely used chemical weapon, can lead to acute and long-term pulmonary complications via various pathways, such as triggering an imbalance between the oxidant and antioxidant system. Currently, there is no validated antidote, chemoprophylaxis and curative modality for pulmonary toxicities secondary to sulfur mustard exposure.<br><br>OBJECTIVE: The aim of this literature review is to collect available experimental and clinical data on the efficacy of N-acetylcysteine (NAC), as a prominent antioxidant agent, in the prevention and/or treatment of sulfur mustard-induced acute and chronic pulmonary toxicities.<br><br>METHODS: A literature search was performed by the relevant keywords like "N-acetyl cysteine", "Sulfur mustard" and "Lung injury" in databases such as Scopus, Medline, Embase and ISI Web of Knowledge. No time limitation was considered. Nineteen articles were selected for review.<br><br>RESULTS: A number of in vitro and experimental studies concluded that oral, intravenous, intraperitoneal and intra-tracheal administration of NAC is effective in the management of sulfur mustard-induced acute lung injury, in a time-dependent manner, via direct scavenging, inhibition of oxidative stress, inflammatory responses and apoptosis. In addition, oral NAC alone (1200 or 1800&#x2009;mg/day for 4 months) or at a dose 600&#x2009;mg/day for 6 months in combination with clarithromycin (500&#x2009;mg/day) have led to improvements of clinical and paraclinical pulmonary parameters of patients with bronchiolitis obliterans due to sulfur mustard, through undetermined mechanisms.<br><br>CONCLUSION: Despite limitations of relevant experimental and clinical studies, NAC can be considered as a candidate agent for prevention and/or treatment of sulfur mustard-induced acute lung injuries, as well as its long-term pulmonary toxicities, especially bronchiolitis obliterans.}, }
@article {pmid25048265, year = {2014}, author = {Yamanashi, H and Hashizume, O and Yonekawa, H and Nakada, K and Hayashi, J}, title = {Administration of an antioxidant prevents lymphoma development in transmitochondrial mice overproducing reactive oxygen species.}, journal = {Experimental animals}, volume = {63}, number = {4}, pages = {459-466}, pmid = {25048265}, issn = {1881-7122}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Antioxidants/*administration &amp; dosage/pharmacology ; Apoptosis ; Bone Marrow Cells/metabolism ; DNA, Mitochondrial/*genetics ; Dinucleoside Phosphates ; Fas Ligand Protein/genetics ; Female ; Free Radical Scavengers/*administration &amp; dosage/pharmacology ; Gene Expression/drug effects ; Gene Expression Regulation, Neoplastic/drug effects/genetics ; Humans ; Killer Cells, Natural/physiology ; Lymphoma/*etiology/genetics/pathology/*prevention &amp; control ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Reactive Oxygen Species/*metabolism ; }, abstract = {Because of the difficulty to exclude possible involvement of nuclear DNA mutations, it has been a controversial issue whether pathogenic mutations in mitochondrial DNA (mtDNA) and the resultant respiration defects are involved in tumor development. To address this issue, our previous study generated transmitochondrial mice (mito-mice-ND6(13997)), which possess the nuclear and mtDNA backgrounds derived from C57BL/6J (B6) strain mice except that they carry B6 mtDNA with a G13997A mutation in the mt-Nd6 gene. Because aged mito-mice-ND6(13997) simultaneously showed overproduction of reactive oxygen species (ROS) in bone marrow cells and high frequency of lymphoma development, current study examined the effects of administrating a ROS scavenger on the frequency of lymphoma development. We used N-acetylcysteine (NAC) as a ROS scavenger, and showed that NAC administration prevented lymphoma development. Moreover, its administration induced longevity in mito-mice-ND6(13997). The gene expression profiles in bone marrow cells indicated the upregulation of the Fasl gene, which can be suppressed by NAC administration. Given that natural-killer (NK) cells mediate the apoptosis of various tumor cells via enhanced expression of genes encoding apoptotic ligands including Fasl gene, its overexpression would reflect the frequent lymphoma development in bone marrow cells. These observations suggest that continuous administration of an antioxidant would be an effective therapeutics to prevent lymphoma development enhanced by ROS overproduction.}, }
@article {pmid25039544, year = {2014}, author = {Kama, A and Yılmaz, S and Yaka, E and Dervişoğlu, E and Doğan, N&#xd6; and Erimşah, E and Pekdemir, M}, title = {Comparison of short-term infusion regimens of N-acetylcysteine plus intravenous fluids, sodium bicarbonate plus intravenous fluids, and intravenous fluids alone for prevention of contrast-induced nephropathy in the emergency department.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {21}, number = {6}, pages = {615-622}, doi = {10.1111/acem.12400}, pmid = {25039544}, issn = {1553-2712}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Contrast Media/administration &amp; dosage/*adverse effects ; Drug Administration Schedule ; Drug Therapy, Combination ; Emergency Service, Hospital ; Female ; Humans ; Infusions, Intravenous ; Iohexol/administration &amp; dosage/*adverse effects ; Kidney Diseases/chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Prospective Studies ; Protective Agents/*therapeutic use ; Sodium Bicarbonate/*therapeutic use ; Sodium Chloride/*therapeutic use ; Tomography, X-Ray Computed/methods ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND: There is no evidence regarding the several short-term prophylaxis protocols for contrast-induced nephropathy (CIN) that may be most feasibly convenient in emergency settings.<br><br>OBJECTIVES: The purpose of this study was to compare the efficacies of short-term CIN prophylaxis protocols of normal saline, N-acetylcysteine (NAC) plus saline, and sodium bicarbonate plus saline in emergency department (ED) patients at moderate or high risk of CIN after receiving intravenous (IV) contrast agent.<br><br>METHODS: This single-center, randomized, nonblinded clinical trial was conducted in the ED with adult patients requiring contrast-enhanced computed tomography (CT). Patients with moderate to high risk of CIN according to the Mehran risk score, who consented to participate, were eligible. Patients with continuous renal replacement therapy or who reported contrast allergy were excluded. Enrolled patients were randomly assigned to receive 150 mg/kg NAC in 1000 mL of 0.9% sodium chloride (NaCl), 150 mEq of sodium bicarbonate in 1000 mL of 0.9% NaCl, or 1000 mL of IV saline infusion, all given at 350 mL/hr for 3 hours. All of the patients were administered less than 100 mL of nonionic, low-osmolality contrast agent. The primary outcome of CIN was defined as a 25% increase or a greater than 0.5 mg/dL increase in the serum creatinine level 48 to 72 hours later compared with the baseline measurement.<br><br>RESULTS: A total of 107 patients were randomized to NAC (n = 36), sodium bicarbonate (n = 36), and saline prophylaxis (n = 35). The mean age of the patients was 71 years (95% confidence interval [CI] = 65 to 77 years), and 58 (54.2%) were male. The groups were similar regarding baseline characteristics and nephropathy risks. Of the 16 (14.9%) patients who eventually developed CIN, seven (19.4%) were in the NAC plus saline group, four (11.1%) were in the sodium bicarbonate plus saline group, and five (14.2%) were in the saline group. There were no significant differences between the groups in terms of the prevention of CIN (p = 0.60).<br><br>CONCLUSIONS: None of the short-term protocols with normal saline, NAC, or sodium bicarbonate was superior in ED patients requiring contrast-enhanced CT who had a moderate or high risk of CIN.}, }
@article {pmid25033789, year = {2014}, author = {Doosti, A and Lotfi, Y and Moossavi, A and Bakhshi, E and Talasaz, AH and Hoorzad, A}, title = {Comparison of the effects of N-acetyl-cysteine and ginseng in prevention of noise induced hearing loss in male textile workers.}, journal = {Noise &amp; health}, volume = {16}, number = {71}, pages = {223-227}, doi = {10.4103/1463-1741.137057}, pmid = {25033789}, issn = {1463-1741}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Audiometry, Pure-Tone ; Auditory Threshold ; Hearing Loss, Noise-Induced/*prevention &amp; control ; Humans ; Linear Models ; Male ; Middle Aged ; *Noise, Occupational ; Occupational Diseases/*prevention &amp; control ; *Panax ; Plant Preparations/*therapeutic use ; *Textile Industry ; Treatment Outcome ; }, abstract = {Previous studies revealed the role of antioxidant agents in prevention of noise induced hearing loss (NIHL). The aim of this study was to compare the protective effect of N-acetyl-cysteine (NAC) and ginseng on protection of NIHL in textile workers exposed to continuous noise in daily working. In this study, 48 participants were randomly allocated to three groups; Group I received NAC 1200 mg/day, Group II received ginseng 200 mg/day, and Group III (control group) received no supplement. Pure tone audiometry and high frequency audiometry were performed preshift before and after 14 days (on day 15). Linear regression analysis results showed reduced noise-induced temporary threshold shift (TTS) for NAC and ginseng groups at 4, 6 and 16 kHz (P < 0.001) in both ears. Furthermore, the protective effects were more prominent in NAC than ginseng. Our results show that NAC and ginseng can reduce noise induced TTS in workers exposed to occupational noise. Further studies are needed to prove antioxidants benefits in hearing conservation programs.}, }
@article {pmid25032123, year = {2014}, author = {Doosti, A and Lotfi, Y and Moosavi, A and Bakhshi, E and Talasaz, AH}, title = {Distortion Product Otoacoustic Emission (DPOAE) as an Appropriate Tool in Assessment of Otoprotective Effects of Antioxidants in Noise-Induced Hearing Loss (NIHL).}, journal = {Indian journal of otolaryngology and head and neck surgery : official publication of the Association of Otolaryngologists of India}, volume = {66}, number = {3}, pages = {325-329}, pmid = {25032123}, issn = {2231-3796}, abstract = {Distortion product otoacoustic emission (DPOAE) appears to be an objective sensitive test of cochlear function. The aim of this study was to investigate whether DPOAE is an appropriate tool for assessment of minute changes in cochlea due to usage of antioxidant material. 48 workers exposed to continuous noise in a textile factory were randomly assigned into three groups: (1) The Control group (n = 16) received no antioxidant drugs, (2) The N-acetyl-cysteine (NAC) group (n = 16) received oral antioxidant NAC (1200 mg/day), (3) The Ginseng group (n = 16) received oral antioxidant Ginseng (200 mg/day). All three groups had a follow-up period of 2 weeks. The cochlear changes were assessed using DPOAE test before starting the daily work shift on first and 15th day. The associations between groups and DPOAE amplitudes after 2 weeks were analyzed using linear regression analysis. Four separate models were fitted by side of ears and frequency. All models were adjusted for baseline amplitude. Reduced (better) amplitude at DPOAE test was found for NAC and Ginseng groups at high frequencies (4 and 6 kHz) in both ears after 2 weeks compared to control group. Moreover, NAC group showed better DPOAE amplitude than Ginseng group. In conclusion, DPOAE seems to be an appropriate tool in assessing minute changes in the cochlea after antioxidant drugs administration.}, }
@article {pmid25028602, year = {2014}, author = {Qi, Z and He, Q and Ji, L and Ding, S}, title = {Antioxidant supplement inhibits skeletal muscle constitutive autophagy rather than fasting-induced autophagy in mice.}, journal = {Oxidative medicine and cellular longevity}, volume = {2014}, number = {}, pages = {315896}, pmid = {25028602}, issn = {1942-0994}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis Regulatory Proteins ; Autophagy/*drug effects/genetics ; Biomarkers/metabolism ; *Dietary Supplements ; Down-Regulation/drug effects/genetics ; Fasting/*physiology ; Glycogen/metabolism ; Lipid Peroxidation/drug effects ; Male ; Mice, Inbred ICR ; Microtubule-Associated Proteins/metabolism ; Mitochondria/drug effects/metabolism ; Muscle, Skeletal/*cytology ; Organ Size/drug effects ; Oxidative Stress/drug effects ; Phosphoric Monoester Hydrolases ; Proteins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Up-Regulation/drug effects/genetics ; }, abstract = {In this study, we tested the hypothesis that NAC administration leads to reduced oxidative stress and thus to decreased expression of autophagy markers in young mice. Our results reveal that NAC administration results in reduced muscle mRNA levels of several autophagy markers, including Beclin-1, Atg7, LC3, Atg9, and LAMP2. However, NAC supplement fails to block the activation of skeletal muscle autophagy in response to fasting, because fasting significantly increases the mRNA level of several autophagy markers and LC3 lipidation. We further examined the effects of NAC administration on mitochondrial antioxidant capacity in fed and 24-hour fasted mice. Our results clearly show that NAC administration depresses the expression of manganese superoxide dismutase (MnSOD) and TP53-induced glycolysis and apoptosis regulator (TIGAR), both of which play a predominant antioxidant role in mitochondria by reducing ROS level. In addition, we found no beneficial effect of NAC supplement on muscle mass but it can protect from muscle loss in response to fasting. Collectively, our findings indicate that ROS is required for skeletal muscle constitutive autophagy, rather than starvation-induced autophagy, and that antioxidant NAC inhibits constitutive autophagy by the regulation of mitochondrial ROS production and antioxidant capacity.}, }
@article {pmid25028117, year = {2014}, author = {Avantaggiato, A and Bertuzzi, G and Vitiello, U and Iannucci, G and Pasin, M and Pascali, M and Cervelli, V and Carinci, F}, title = {Role of antioxidants in dermal aging: an in vitro study by q-RT-PCR.}, journal = {Aesthetic plastic surgery}, volume = {38}, number = {5}, pages = {1011-1016}, doi = {10.1007/s00266-014-0380-9}, pmid = {25028117}, issn = {1432-5241}, mesh = {Acetylcysteine/*pharmacology ; Amino Acids/administration &amp; dosage ; Antioxidants/*physiology ; Electrolytes/administration &amp; dosage ; Extracellular Matrix Proteins/genetics ; Fibroblasts/*drug effects ; Free Radical Scavengers/*pharmacology ; Gene Expression/drug effects ; Glucose/administration &amp; dosage ; Humans ; In Vitro Techniques ; Injections, Intradermal ; Parenteral Nutrition Solutions/administration &amp; dosage ; Reverse Transcriptase Polymerase Chain Reaction ; Skin Aging/*physiology ; Solutions/administration &amp; dosage ; }, abstract = {BACKGROUND: Reactive oxygen species production is the final step in skin aging. These unstable molecules can damage and destroy DNA, proteins, and membrane phospholipids. The aim of this study was to test the in vitro effect of an antioxidant precursor, N-acetylcysteine (NAC), on human dermal fibroblasts. NAC alone and a solution of NAC and amino acids together, used in aesthetic medicine as intradermal injection treatment, were tested.<br><br>METHODS: The expression levels of some connective related genes (HAS1, HYAL1, ELN, ELANE, DSP, GDF6, and IGF1) were analyzed on cultures of dermal fibroblasts using real-time reverse-transcription polymerase chain reaction (real time RT-PCR).<br><br>RESULTS: All genes were upregulated after 24 h of treatment.<br><br>CONCLUSIONS: An interesting effect of gene induction by administration of NAC and amino acids in vitro was demonstrated. Upregulation of elastin-, hyaluronic acid-, and GDF6-encoding genes supports the evidence of clinical improvement induced by NAC biostimulation in the prevention and correction of skin aging.}, }
@article {pmid25027749, year = {2014}, author = {Najafi, A and Mojtahedzadeh, M and Ahmadi, KH and Abdollahi, M and Mousavi, M and Chelkeba, L and Najmeddin, F and Ahmadi, A}, title = {The immunological benefit of higher dose N-acetyl cysteine following mechanical ventilation in critically ill patients.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {22}, number = {1}, pages = {57}, pmid = {25027749}, issn = {2008-2231}, mesh = {APACHE ; Acetylcysteine/*administration &amp; dosage ; Adult ; Antioxidants/administration &amp; dosage ; Creatinine/blood ; Critical Illness ; Female ; Glutathione/blood ; Humans ; Immunoglobulin M/blood ; Intensive Care Units ; Leukocyte Count ; Male ; Middle Aged ; Multiple Trauma/blood/*drug therapy ; Organ Dysfunction Scores ; Respiration, Artificial ; Sepsis/blood/*drug therapy ; Young Adult ; beta-Defensins/blood ; }, abstract = {BACKGROUND: Sepsis complication is a major cause of death in multiple trauma critically ill patients. Defensin (cysteine rich anti-microbial peptides), as an important component of immune system, might play an important role in this process. There is also rising data on immunological effects of N-acetyl-cysteine (NAC), a commonly used anti-oxidant in oxidative stress conditions and glutathione (GSH) deficiencies. The aim of the present study was to evaluate the potential beneficial effects of NAC administration on multiple trauma patients with sepsis.<br><br>METHODS: In a prospective, randomized controlled study, 44 multiple trauma critically ill patients who were mechanically ventilated and met the criteria of sepsis and admitted to the intensive care unit (ICU) were randomized into two groups . Control group received all standard ICU therapies and NAC group received intravenous NAC 3 gr every 6 hours for 72 hours in addition to standard therapies. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality were recorded. Levels of serum Immunoglobulin M (IgM), Human &#x3b2;-Defensin 2 (H&#x3b2;D2) and GSH were assessed at baseline and 24, 72, 120 hours after intervention.<br><br>RESULTS: During a period of 13-month screening, 44 patients underwent randomization but 5 patients had to be excluded. 21 patients in NAC group and 18 patients in control group completed the study. For both groups the length of ICU stay, SOFA score and systemic oxygenation were similar. Mortality rate (40% vs. 22% respectively, p&#x2009;=&#x2009;0.209) and ventilator days (Mean&#x2009;&#xb1;&#x2009;SD 19.82&#x2009;&#xb1;&#x2009;19.55 days vs. 13.82&#x2009;&#xb1;&#x2009;11.89 days respectively, p&#x2009;=&#x2009;0.266) were slightly higher for NAC group. IgM and GSH levels were similar between two groups (p&#x2009;=&#x2009;0.325, 0.125 respectively), H&#x3b2;D2 levels were higher for NAC group (at day 3).<br><br>CONCLUSION: High dose of NAC administration not only did not improve patients' outcome, but also raised the risk of inflammation and was associated with increased serum creatinine.}, }
@article {pmid25024403, year = {2014}, author = {Lin, D and Li, C and Peng, Y and Gao, H and Zheng, J}, title = {Cytochrome p450-mediated metabolic activation of diosbulbin B.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {42}, number = {10}, pages = {1727-1736}, doi = {10.1124/dmd.114.059261}, pmid = {25024403}, issn = {1521-009X}, mesh = {Acetylcysteine/metabolism ; Activation, Metabolic/drug effects ; Animals ; Bile/metabolism ; Cytochrome P-450 CYP3A/*metabolism ; Glutathione/metabolism ; Heterocyclic Compounds, 4 or More Rings/*metabolism/urine ; Humans ; Ketoconazole/pharmacology ; Lysine/metabolism ; Male ; Microsomes, Liver/metabolism ; Rats ; Urine ; }, abstract = {Diosbulbin B (DIOB), a furan-containing diterpenoid lactone, is the most abundant component of Dioscorea bulbifera L. (DB), a traditional Chinese medicine herb. Administration of purified DIOB or DB extracts has been reported to cause liver injury in animals. The mechanisms of DIOB-induced hepatotoxicity remain unknown. The major objective of this study was to identify reactive metabolites of DIOB. A DIOB-derived cis-enedial was trapped by N-acetyl lysine (NAL) and glutathione (GSH) or N-acetyl cysteine (NAC) in rat and human liver microsomal incubation systems after exposure to DIOB. Four metabolites (M1-M4) associated with GSH were detected by liquid chromatography coupled to tandem mass spectrometry. Apparently, M1 was derived from both NAL and GSH. M2 and M3 resulted from the reaction of GSH without the involvement of NAL. Two molecules of GSH participated in the formation of M4. M2 and M3 were also detected in bile and urine of rats given DIOB. M5, a DIOB-derived NAC/NAL conjugate, was detected in microsomal incubations with DIOB fortified with NAC and NAL as trapping agents. Biomimetic M1-M5 were prepared by oxidation of DIOB with Oxone for metabolite identification. Microsomal incubation study demonstrated that ketoconazole inhibited the production of the enedial in a concentration-dependent manner, and CYP3A4 was found to be the enzyme responsible for the metabolic activation of DIOB. The metabolism study facilitates the understanding of the role of bioactivation of DIOB in its hepatotoxicity.}, }
@article {pmid25023940, year = {2014}, author = {Jin, HO and Lee, YH and Park, JA and Lee, HN and Kim, JH and Kim, JY and Kim, B and Hong, SE and Kim, HA and Kim, EK and Noh, WC and Kim, JI and Chang, YH and Hong, SI and Hong, YJ and Park, IC and Lee, JK}, title = {Piperlongumine induces cell death through ROS-mediated CHOP activation and potentiates TRAIL-induced cell death in breast cancer cells.}, journal = {Journal of cancer research and clinical oncology}, volume = {140}, number = {12}, pages = {2039-2046}, pmid = {25023940}, issn = {1432-1335}, mesh = {Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/physiology ; Bcl-2-Like Protein 11 ; Breast Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Dioxolanes/*pharmacology ; Female ; Humans ; Membrane Proteins/physiology ; Proto-Oncogene Proteins/physiology ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/physiology ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; Transcription Factor CHOP/*metabolism ; }, abstract = {PURPOSE: Piperlongumine (PL) has been shown to selectively induce apoptotic cell death in cancer cells via reactive oxygen species (ROS) accumulation. In this study, we characterized a molecular mechanism for PL-induced cell death.<br><br>METHODS: Cell viability and cell death were assessed by MTT assay and Annexin V-FITC/PI staining, respectively. ROS generation was measured using the H2DCFDA. Small interfering RNA (siRNA) was used for suppressing gene expression. The mRNA and protein expression were analyzed by RT-PCR and Western blot analysis, respectively.<br><br>RESULTS: We found that PL promotes C/EBP homologous protein (CHOP) induction, which leads to the up-regulation of its targets Bim and DR5. Pretreatment with the ROS scavenger N-acetyl-cysteine abolishes the PL-induced up-regulation of CHOP and its target genes, suggesting an essential role for ROS in PL-induced CHOP activation. The down-regulation of CHOP or Bim with siRNA efficiently attenuates PL-induced cell death, suggesting a critical role for CHOP in this cell death. Furthermore, PL potentiates TRAIL-induced cytotoxicity in breast cancer cells by upregulating DR5, as DR5 knockdown abolished the sensitizing effect of PL on TRAIL responses.<br><br>CONCLUSIONS: Overall, our data suggest a new mechanism for the PL-induced cell death in which ROS mediates CHOP activation, and combination treatment with PL and TRAIL could be a potential strategy for breast cancer therapy.}, }
@article {pmid25023204, year = {2015}, author = {Ware, KM and Vance, JC and Muni, N and Hebert, LA and Satoskar, AA and Nadasdy, G and Ivanov, I and Nadasdy, T and Rovin, BH and Brodsky, SV}, title = {Oral warfarin and the thrombin inhibitor dabigatran increase blood pressure in rats: hidden danger of anticoagulants?.}, journal = {American journal of hypertension}, volume = {28}, number = {2}, pages = {182-189}, doi = {10.1093/ajh/hpu129}, pmid = {25023204}, issn = {1941-7225}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anticoagulants/pharmacology ; Antifibrinolytic Agents/pharmacology ; Antithrombins/*pharmacology ; Benzimidazoles/*pharmacology ; Blood Pressure/*drug effects ; Dabigatran ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Nephrectomy ; Pyrroles/pharmacology ; Quinazolines/pharmacology ; Rats ; Receptor, PAR-1/antagonists &amp; inhibitors ; *Renal Insufficiency, Chronic ; Vitamin K/pharmacology ; Warfarin/*pharmacology ; beta-Alanine/*analogs &amp; derivatives/pharmacology ; }, abstract = {BACKGROUND: Hypertension is a common comorbidity in patients with chronic kidney disease (CKD). We reported earlier that oral anticoagulants, including warfarin and dabigatran, may induce acute kidney injury. No effects of oral anticoagulants on blood pressure (BP) have been previously reported. The aim of this study was to examine in detail the relationship of anticoagulant therapy and BP in rats.<br><br>METHODS: Sham-operated and 5/6 nephrectomy rats were treated with different doses of oral anticoagulants (warfarin and dabigatran), superoxide scavenger N-acetylcysteine (NAC), vitamin K, and protease activated receptor 1 (PAR-1) inhibitor SCH79797. BP was measured by a tail cuff daily.<br><br>RESULTS: Warfarin and dabigatran both increased systolic BP in sham-operated and 5/6 nephrectomy rats in a dose-dependent manner. SCH79797 also increased systolic BP in a dose-dependent manner. Vitamin K prevented warfarin-induced increase in BP but did not affect BP when administered alone. NAC delayed the warfarin-associated increase in BP. Warfarin effects on BP were similar in 5/6 nephrectomy rats with different CKD stages.<br><br>CONCLUSIONS: Both warfarin and dabigatran increase systolic BP in rats. The mechanism of this effect is not clear, but our data suggest that it is related to decreased thrombin activity associated with anticoagulant treatment. The superoxide scavenger NAC delayed, but did not prevent, warfarin-induced hypertension.}, }
@article {pmid25019514, year = {2014}, author = {Attucks, OC and Jasmer, KJ and Hannink, M and Kassis, J and Zhong, Z and Gupta, S and Victory, SF and Guzel, M and Polisetti, DR and Andrews, R and Mjalli, AM and Kostura, MJ}, title = {Induction of heme oxygenase I (HMOX1) by HPP-4382: a novel modulator of Bach1 activity.}, journal = {PloS one}, volume = {9}, number = {7}, pages = {e101044}, pmid = {25019514}, issn = {1932-6203}, mesh = {*Antioxidant Response Elements ; Basic-Leucine Zipper Transcription Factors/*antagonists &amp; inhibitors/*metabolism ; Chromatin Immunoprecipitation ; Fanconi Anemia Complementation Group Proteins/*antagonists &amp; inhibitors/*metabolism ; Fibroblasts/drug effects ; Heme/metabolism ; Heme Oxygenase-1/*genetics/metabolism ; Humans ; Oxidative Stress ; *Transcriptional Activation ; }, abstract = {Oxidative stress is generated by reactive oxygen species (ROS) produced in response to metabolic activity and environmental factors. Increased oxidative stress is associated with the pathophysiology of a broad spectrum of inflammatory diseases. Cellular response to excess ROS involves the induction of antioxidant response element (ARE) genes under control of the transcriptional activator Nrf2 and the transcriptional repressor Bach1. The development of synthetic small molecules that activate the protective anti-oxidant response network is of major therapeutic interest. Traditional small molecules targeting ARE-regulated gene activation (e.g., bardoxolone, dimethyl fumarate) function by alkylating numerous proteins including Keap1, the controlling protein of Nrf2. An alternative is to target the repressor Bach1. Bach1 has an endogenous ligand, heme, that inhibits Bach1 binding to ARE, thus allowing Nrf2-mediated gene expression including that of heme-oxygenase-1 (HMOX1), a well described target of Bach1 repression. In this report, normal human lung fibroblasts were used to screen a collection of synthetic small molecules for their ability to induce HMOX1. A class of HMOX1-inducing compounds, represented by HPP-4382, was discovered. These compounds are not reactive electrophiles, are not suppressed by N-acetyl cysteine, and do not perturb either ROS or cellular glutathione. Using RNAi, we further demonstrate that HPP-4382 induces HMOX1 in an Nrf2-dependent manner. Chromatin immunoprecipitation verified that HPP-4382 treatment of NHLF cells reciprocally coordinated a decrease in binding of Bach1 and an increase of Nrf2 binding to the HMOX1 E2 enhancer. Finally we show that HPP-4382 can inhibit Bach1 activity in a reporter assay that measures transcription driven by the human HMOX1 E2 enhancer. Our results suggest that HPP-4382 is a novel activator of the antioxidant response through the modulation of Bach1 binding to the ARE binding site of target genes.}, }
@article {pmid25017974, year = {2014}, author = {Liu, YJ and Lin, YC and Lee, JC and Kuo, SC and Ho, CT and Huang, LJ and Kuo, DH and Way, TD}, title = {CCT327 enhances TRAIL-induced apoptosis through the induction of death receptors and downregulation of cell survival proteins in TRAIL-resistant human leukemia cells.}, journal = {Oncology reports}, volume = {32}, number = {3}, pages = {1257-1264}, doi = {10.3892/or.2014.3317}, pmid = {25017974}, issn = {1791-2431}, mesh = {Acetylcysteine/metabolism ; Antineoplastic Agents/chemical synthesis/*pharmacology ; Apoptosis ; CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/*drug effects ; HL-60 Cells ; Humans ; Leukemia/drug therapy/genetics/*metabolism ; Organoselenium Compounds/*chemical synthesis/*pharmacology ; Quinolines/*chemical synthesis/pharmacology ; Quinolones/*chemical synthesis/*pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Death Domain/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Up-Regulation ; }, abstract = {Tumor necrosis factor-related apoptosis‑inducing ligand (TRAIL) has potential application in cancer therapy and it has the ability to selectively kill cancer cells without affecting normal cells. However, the development of resistance to TRAIL in cancer cells cannot be avoided. This study investigated the effects of 2-(5-methylselenophen‑2‑yl)‑6,7‑methylenedioxyquinolin‑4-one (CCT327), an analogue of quinolin-4-one, on the sensitization of cancer cells to TRAIL and on TRAIL‑induced apoptosis in TRAIL‑resistance human leukemia cells (HL60‑TR). We found that CCT327 enhanced TRAIL‑induced apoptosis through upregulation of death receptors DR4 and DR5. In addition to upregulating DRs (death receptors), CCT327 suppressed the expression of decoy receptor DcR1 and DcR2. CCT327 significantly downregulated the expression of FLICE inhibitory protein (cFLIP) and other antiapoptotic proteins. We also demonstrated that CCT327 could activate p38 and JNK. Moreover, CCT327-induced induction of DR5 and DR4 was mediated by reactive oxygen species (ROS), and N-acetylcysteine (NAC) blocked the induction of DRs by CCT327. Taken together, these results showed that CCT327 combined with TRAIL treatment may provide an effective therapeutic strategy for cancer.}, }
@article {pmid25016575, year = {2014}, author = {Bonnaure, G and Néron, S}, title = {N-acetyl cysteine regulates the phosphorylation of JAK proteins following CD40-activation of human memory B cells.}, journal = {Molecular immunology}, volume = {62}, number = {1}, pages = {209-218}, doi = {10.1016/j.molimm.2014.06.027}, pmid = {25016575}, issn = {1872-9142}, mesh = {Acetylcysteine/*pharmacology ; B-Lymphocytes/drug effects/*immunology/metabolism ; CD40 Antigens/*metabolism ; Cell Differentiation/drug effects/immunology ; Cells, Cultured ; Humans ; Immunologic Memory/drug effects ; Janus Kinases/antagonists &amp; inhibitors/*metabolism ; Lymphocyte Activation/drug effects ; Phosphorylation/drug effects ; STAT3 Transcription Factor/metabolism ; Suppressor of Cytokine Signaling Proteins/metabolism ; Tyrosine/metabolism ; }, abstract = {During their development, human B lymphocytes migrate into various environments, each presenting important variations in their redox balance depending on oxygen availability. The modulation of the cells surroundings redox balance leads to the regulation of reactive oxygen species produced by the cell. These molecules are involved in the state of oxidation of the cytosol and affect many pathways involved in cell development, differentiation and protein secretion. B lymphocytes cultured in presence of interleukin (IL)-2, IL-4, IL-10 and under CD154 stimulation, present increases in their intracellular levels of ROS. However, when N-acetyl cysteine (NAC), an antioxidant, is added, STAT3 phosphorylation is decreased. In this study, we show that in activated human memory B cells, NAC inhibited STAT3 phosphorylation on tyrosine 705 but not on Serine 727. Moreover, higher concentrations of NAC decreased STAT3 synthesis. Two other antioxidants, α-tocopherol and Trolox, did not affect STAT3 phosphorylation. Furthermore, two kinases involved in STAT3 activation, known as JAK2 and JAK3, appeared down-regulated in presence of NAC. In parallel, 3h after antioxidants incubation, we have observed a decrease in SOCS1 and SOCS3 protein levels, which seems time-related to antioxidant treatment. The decrease in the phosphorylation of JAK2 and JAK3, earlier in the process, could explain the downregulation of STAT3 and offer a hypothesis on the mechanism of action of NAC antioxidant properties which were confirmed by a decrease in the level of S-glutathionylation of proteins. The reduced expression of SOCS1 and SOCS3 appears directly linked to the inhibition of this STAT3-regulated pathway. In summary, NAC appears as a potential regulator of the STAT3 pathway.}, }
@article {pmid25013451, year = {2014}, author = {Prottengeier, J and Koutsilieri, E and Scheller, C}, title = {The effects of opioids on HIV reactivation in latently-infected T-lymphoblasts.}, journal = {AIDS research and therapy}, volume = {11}, number = {}, pages = {17}, pmid = {25013451}, issn = {1742-6405}, abstract = {BACKGROUND: Opioids may have effects on susceptibility to HIV-infection, viral replication and disease progression. Injecting drug users (IDU), as well as anyone receiving opioids for anesthesia and analgesia may suffer the clinical consequences of such interactions. There is conflicting data between in vitro experiments showing an enhancing effect of opioids on HIV replication and clinical data, mostly showing no such effect. For clarification we studied the effects of the opioids heroin and morphine on HIV replication in cultured CD4-positive T cells at several concentrations and we related the observed effects with the relevant reached plasma concentrations found in IDUs.<br><br>METHODS: Latently-infected ACH-2&#xa0;T lymphoblasts were incubated with different concentrations of morphine and heroine. Reactivation of HIV was assessed by intracellular staining of viral Gag p24 protein and subsequent flow cytometric quantification of p24-positive cells. The influence of the opioid antagonist naloxone and the antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH) on HIV reactivation was determined. Cell viability was investigated by 7-AAD staining and flow cytometric quantification.<br><br>RESULTS: Morphine and heroine triggered reactivation of HIV replication in ACH-2 cells in a dose-dependent manner at concentrations above 1&#xa0;mM (EC50 morphine 2.82&#xa0;mM; EC50 morphine 1.96&#xa0;mM). Naloxone did not interfere with heroine-mediated HIV reactivation, even at high concentrations (1&#xa0;mM). Opioids also triggered necrotic cell death at similar concentrations at which HIV reactivation was observed. Both opioid-mediated reactivation of HIV and opioid-triggered cell death could be inhibited by the antioxidants GSH and NAC.<br><br>CONCLUSIONS: Opioids reactivate HIV in vitro but at concentrations that are far above the plasma levels of analgesic regimes or drug concentrations found in IDUs. HIV reactivation was mediated by effects unrelated to opioid-receptor activation and was tightly linked to the cytotoxic activity of the substances at millimolar concentrations, suggesting that opioid-mediated reactivation of HIV was due to accompanying effects of cellular necrosis such as activation of reactive oxygen species and NF-&#x3ba;B.}, }
@article {pmid25010594, year = {2014}, author = {Tzeng, TJ and Cao, L and Fu, Y and Zeng, H and Cheng, WH}, title = {Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin.}, journal = {PloS one}, volume = {9}, number = {7}, pages = {e101664}, pmid = {25010594}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Ataxia Telangiectasia Mutated Proteins/chemistry/metabolism ; Carboplatin/*pharmacology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Chromones/pharmacology ; DNA-Binding Proteins/metabolism ; Drug Synergism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Histones/metabolism ; Humans ; Morpholines/pharmacology ; Organoselenium Compounds/*pharmacology ; Ovarian Neoplasms/*pathology ; Phosphorylation/drug effects ; RNA, Messenger/genetics/metabolism ; Receptor, Notch3 ; Receptors, Notch/*metabolism ; Thioxanthenes/pharmacology ; }, abstract = {Ovarian cancer, the deadliest of gynecologic cancers, is usually not diagnosed until advanced stages. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-containing drug. Expression of neurogenic locus notch homolog 3 (Notch3) is associated with chemoresistance and poor overall survival in ovarian cancer patients. Overexpression of NICD3 (the constitutively active form of Notch3) in OVCA429 ovarian cancer cells (OVCA429/NICD3) renders them resistance to carboplatin treatment compared to OVCA429/pCEG cells expressing an empty vector. We have previously shown that methylseleninic acid (MSeA) induces oxidative stress and activates ataxia-telangiectasia mutated and DNA-dependent protein kinase in cancer cells. Here we tested the hypothesis that MSeA and carboplatin exerted a synthetic lethal effect on OVCA429/NICD3 cells. Co-treatment with MSeA synergistically sensitized OVCA429/NICD3 but not OVCA429/pCEG cells to the killing by carboplatin. This synergism was associated with a cell cycle exit at the G2/M phase and the induction of NICD3 target gene HES1. Treatment of N-acetyl cysteine or inhibitors of the above two kinases did not directly impact on the synergism in OVCA429/NICD3 cells. Taken together, these results suggest that the efficacy of carboplatin in the treatment of high grade ovarian carcinoma can be enhanced by a combinational therapy with MSeA.}, }
@article {pmid25008790, year = {2014}, author = {Su, YC and Chiu, HW and Hung, JC and Hong, JR}, title = {Beta-nodavirus B2 protein induces hydrogen peroxide production, leading to Drp1-recruited mitochondrial fragmentation and cell death via mitochondrial targeting.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {19}, number = {10}, pages = {1457-1470}, pmid = {25008790}, issn = {1573-675X}, mesh = {Animals ; *Apoptosis ; Cell Line ; Dynamins ; Fish Diseases/*metabolism/physiopathology/virology ; Fish Proteins/genetics/*metabolism ; Humans ; Hydrogen Peroxide/*metabolism ; Mitochondria/*metabolism ; Nodaviridae/genetics/*metabolism ; Oxidative Stress ; RNA Virus Infections/metabolism/physiopathology/*veterinary/virology ; Viral Nonstructural Proteins/genetics/*metabolism ; Zebrafish ; }, abstract = {Because the role of the viral B2 protein in the pathogenesis of nervous necrosis virus infection remains unknown, the aim of the present study was to determine the effects of B2 protein on hydrogen peroxide (H2O2)-mediated cell death via mitochondrial targeting. Using a B2 deletion mutant, the B2 mitochondrial targeting signal sequence ((41)RTFVISAHAA(50)) correlated with mitochondrial free radical production and cell death in fish cells, embryonic zebrafish, and human cancer cells. After treatment of grouper fin cells (GF-1) overexpressing B2 protein with the anti-oxidant drug, N-acetylcysteine (NAC), and overexpression of the antioxidant enzymes, zfCu/Zn superoxide dismutase (SOD) and zfCatalase, decreased H2O2 production and cell death were observed. To investigate the correlation between B2 cytotoxicity and H2O2 production in vivo, B2 was injected into zebrafish embryos. Cell damage, as assessed by the acridine orange assay, gradually increased over 24 h post-fertilization, and was accompanied by marked increases in H2O2 production and embryonic death. Increased oxidative stress, as evidenced by the up-regulation of Mn SOD, catalase, and Nrf2, was also observed during this period. Finally, B2-induced dynamin-related protein 1 (Drp1)-mediated mitochondrial fragmentation and cell death could be reversed by NAC and inhibitors of Drp1 and Mdivi in GF-1 cells. Taken together, betanodavirus B2 induces H2O2 production via targeting the mitochondria, where it inhibits complex II function. H2O2 activates Drp1, resulting in its association with the mitochondria, mitochondrial fission and cell death in vitro and in vivo.}, }
@article {pmid25004186, year = {2014}, author = {Berk, M and Dean, OM and Cotton, SM and Jeavons, S and Tanious, M and Kohlmann, K and Hewitt, K and Moss, K and Allwang, C and Schapkaitz, I and Robbins, J and Cobb, H and Ng, F and Dodd, S and Bush, AI and Malhi, GS}, title = {The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial.}, journal = {The Journal of clinical psychiatry}, volume = {75}, number = {6}, pages = {628-636}, doi = {10.4088/JCP.13m08454}, pmid = {25004186}, issn = {1555-2101}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Antidepressive Agents/adverse effects/*therapeutic use ; Depressive Disorder, Major/diagnosis/*drug therapy/psychology ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Patient Satisfaction ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: Major depressive disorder (MDD) is one of the most common psychiatric disorders, conferring considerable individual, family, and community burden. To date, treatments for MDD have been derived from the monoamine hypothesis, and there is a paucity of emerging antidepressants, especially with novel mechanisms of action and treatment targets. N-acetylcysteine (NAC) is a redox-active glutathione precursor that decreases inflammatory cytokines, modulates glutamate, promotes neurogenesis, and decreases apoptosis, all of which contribute to the neurobiology of depression.<br><br>METHOD: Participants with a current episode of MDD diagnosed according to DSM-IV-TR criteria (N = 252) were treated with NAC or placebo in addition to treatment as usual for 12 weeks and were followed to 16 weeks. Data were collected between 2007 and 2011.<br><br>RESULTS: The omnibus interaction between group and visit for the Montgomery-Asberg Depression Rating Scale (MADRS), the primary outcome measure, was not significant (F&#x2081;,&#x2085;&#x2082;&#x2080;.&#x2089; = 1.98, P = .067), and the groups did not separate at week 12 (t&#x2083;&#x2086;&#x2080;.&#x2083; = -1.12, P = .265). However, at week 12, the scores on the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) differed from placebo (P = .03). Among participants with a MADRS score &#x2265; 25, NAC separated from placebo at weeks 6, 8, 12, and 16 (P < .05). Additionally, the rate of change between baseline and week 16 was significant (t&#x2082;&#x2082;&#x2081;.&#x2080;&#x2083; = -2.11, P = .036). NAC treatment was superior to placebo at week 16 for secondary readouts of function and clinical impression. Remission and response were greater in the NAC group at week 16, but not at week 12. The NAC group had a greater rate of gastrointestinal and musculoskeletal adverse events.<br><br>CONCLUSIONS: Being negative at the week 12 end point, and with some positive secondary signals, the study provides only limited support for the role of NAC as a novel adjunctive therapy for MDD. These data implicate the pathways influenced by NAC in depression pathogenesis, principally oxidative and inflammatory stress and glutamate, although definitive confirmation remains necessary.<br><br>TRIAL REGISTRATION: www.anzctr.org.au Identifier: ACTRN12607000134426.}, }
@article {pmid25001062, year = {2014}, author = {Lea, J and Conlin, AE and Sekirov, I and Restelli, V and Ayakar, KG and Turnbull, L and Doyle, P and Noble, M and Rennie, R and Schreiber, WE and Westerberg, BD}, title = {In vitro efficacy of N-acetylcysteine on bacteria associated with chronic suppurative otitis media.}, journal = {Journal of otolaryngology - head &amp; neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale}, volume = {43}, number = {1}, pages = {20}, pmid = {25001062}, issn = {1916-0216}, mesh = {Acetylcysteine/*pharmacology ; Anti-Inflammatory Agents/*administration &amp; dosage ; Antineoplastic Combined Chemotherapy Protocols/*administration &amp; dosage ; Chronic Disease ; Ciprofloxacin/*administration &amp; dosage ; Dexamethasone/*administration &amp; dosage ; Drug Combinations ; Drug Resistance, Microbial ; Free Radical Scavengers ; Humans ; In Vitro Techniques ; Otitis Media, Suppurative/microbiology ; Pseudomonas aeruginosa/*drug effects ; Staphylococcus aureus/*drug effects ; }, abstract = {BACKGROUND: The safety and efficacy of Ciprodex® has been demonstrated for treatment of chronic suppurative otitis media (CSOM). However, symptoms fail to resolve in 9-15% of patients. The objective of this study is to evaluate the efficacy of N-acetylcysteine (NAC) on S. aureus, and planktonic and sessile (biofilm forming) P. aeruginosa in vitro using clinical isolates from patients with CSOM.<br><br>METHODS: 1) Stability was assessed using liquid chromatography-mass spectrometry for each component in a prepared mixture of Ciprodex&#xae; and NAC over 15&#xa0;days. Sterility was assessed by measuring bacterial growth on a blood agar plate. Efficacy was assessed using a disc diffusion method by inoculating plates with S. aureus ATCC 29513 and P. aeruginosa ATCC 27853, and measuring the clearance zone.2) Fifteen P. aeruginosa strains were isolated from patients with CSOM and tested in vitro using the bioFILM PA&#x2122; antimicrobial susceptibility assay. Treatment solutions included Ciprodex&#xae; &amp; ciprofloxacin +/- NAC, and NAC alone (0.25%, 0.5% &amp; 1.25%).<br><br>RESULTS: 1) NAC combined with Ciprodex&#xae; demonstrated stability, sterility, and efficacy over a two-week period2) P. aeruginosa strains in the sessile (33%-40%) and planktonic (13%) state demonstrated resistance to Ciprodex&#xae; and ciprofloxacin. When NAC &#x2265;0.5% was used in isolation or as an adjunct to either of these medications, no resistance was found in the sessile or planktonic state among all 15 strains.<br><br>CONCLUSION: 1) Ciprodex&#xae; combined with NAC has a shelf life of at least two weeks given the documented preservation of stability, sterility, and clinical efficacy of the mixed compounds.2) P. aeruginosa strains demonstrated resistance to both Ciprodex&#xae; and ciprofloxacin. NAC &#x2265;0.5% overcomes issues with resistance and shows promise in the treatment of CSOM.}, }
@article {pmid24999113, year = {2014}, author = {Mohanraj, B and Meloni, GR and Mauck, RL and Dodge, GR}, title = {A high-throughput model of post-traumatic osteoarthritis using engineered cartilage tissue analogs.}, journal = {Osteoarthritis and cartilage}, volume = {22}, number = {9}, pages = {1282-1290}, pmid = {24999113}, issn = {1522-9653}, support = {I01 RX001213/RX/RRD VA/United States ; P30 AR050950/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Cartilage, Articular/drug effects/*injuries/pathology/physiopathology ; Caspase Inhibitors/pharmacology ; Cattle ; Cell Death/drug effects ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Glycosaminoglycans/metabolism ; High-Throughput Screening Assays/methods ; Materials Testing/methods ; Osteoarthritis/*etiology ; Pilot Projects ; Poloxamer/pharmacology ; Stress, Mechanical ; Tissue Engineering/*methods ; }, abstract = {OBJECTIVE: A number of in vitro models of post-traumatic osteoarthritis (PTOA) have been developed to study the effect of mechanical overload on the processes that regulate cartilage degeneration. While such frameworks are critical for the identification therapeutic targets, existing technologies are limited in their throughput capacity. Here, we validate a test platform for high-throughput mechanical injury incorporating engineered cartilage.<br><br>METHOD: We utilized a high-throughput mechanical testing platform to apply injurious compression to engineered cartilage and determined their strain and strain rate dependent responses to injury. Next, we validated this response by applying the same injury conditions to cartilage explants. Finally, we conducted a pilot screen of putative PTOA therapeutic compounds.<br><br>RESULTS: Engineered cartilage response to injury was strain dependent, with a 2-fold increase in glycosaminoglycan (GAG) loss at 75% compared to 50% strain. Extensive cell death was observed adjacent to fissures, with membrane rupture corroborated by marked increases in lactate dehydrogenase (LDH) release. Testing of established PTOA therapeutics showed that pan-caspase inhibitor [Z-VAD-FMK (ZVF)] was effective at reducing cell death, while the amphiphilic polymer [Poloxamer 188 (P188)] and the free-radical scavenger [N-Acetyl-L-cysteine (NAC)] reduced GAG loss as compared to injury alone.<br><br>CONCLUSIONS: The injury response in this engineered cartilage model replicated key features of the response of cartilage explants, validating this system for application of physiologically relevant injurious compression. This study establishes a novel tool for the discovery of mechanisms governing cartilage injury, as well as a screening platform for the identification of new molecules for the treatment of PTOA.}, }
@article {pmid24998639, year = {2014}, author = {Mlejnek, P and Dolezel, P}, title = {N-acetylcysteine prevents the geldanamycin cytotoxicity by forming geldanamycin-N-acetylcysteine adduct.}, journal = {Chemico-biological interactions}, volume = {220}, number = {}, pages = {248-254}, doi = {10.1016/j.cbi.2014.06.025}, pmid = {24998639}, issn = {1872-7786}, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemistry/metabolism/*pharmacology ; Antibiotics, Antineoplastic/chemistry/toxicity ; Apoptosis/*drug effects ; Benzoquinones/*chemistry/metabolism/pharmacology/*toxicity ; Cell Cycle ; Glutathione/chemistry/metabolism ; Humans ; K562 Cells ; Lactams, Macrocyclic/*chemistry/metabolism/pharmacology/*toxicity ; Molecular Structure ; }, abstract = {Geldanamycin (GDN) is a benzoquinone ansamycin antibiotic with anti-proliferative activity on tumor cells. GDN cytotoxicity has been attributed to the disruption of heat shock protein 90 (Hsp90) binding and stabilizing client proteins, and by the induction of oxidative stress with concomitant glutathione (GSH) depletion. The later mechanism of cytotoxicity can be abrogated by N-acetylcysteine (NAC). It was suggested that NAC prevents GDN cytotoxicity mainly by the restoring of glutathione (GSH) level (Clark et al., 2009). Here we argue that NAC does not protect cells from the GDN cytotoxicity by restoring the level of GSH. A detailed LC/MS/MS analysis of cell extracts indicated formation of GDN adducts with GSH. The amount of the GDN-GSH adduct is proportional to the GDN concentration and increases with incubation time. While nanomolar and low micromolar GDN concentrations induce cell death without an apparent GSH decrease, only much higher micromolar GDN concentrations cause a significant GSH decrease. Therefore, only high micromolar GDN concentrations can cause cell death which might be related to GSH depletion. Addition of NAC leads to the formation of adducts with GDN which diminish formation of GDN adducts with GSH. NAC also forms stable adducts with GDN extracellularly. Although NAC induces an increase in the GSH pool, this effect is not crucial for abrogation of GDN cytotoxicity. Indeed, the presence of NAC in the growth medium causes a rapid conversion of GDN into the GDN-NAC adduct, which is the real cause of the abrogated GDN cytotoxicity.}, }
@article {pmid24997570, year = {2015}, author = {Torii, K and Yamada, S and Nakamura, K and Tanaka, H and Kajiyama, H and Tanahashi, K and Iwata, N and Kanda, M and Kobayashi, D and Tanaka, C and Fujii, T and Nakayama, G and Koike, M and Sugimoto, H and Nomoto, S and Natsume, A and Fujiwara, M and Mizuno, M and Hori, M and Saya, H and Kodera, Y}, title = {Effectiveness of plasma treatment on gastric cancer cells.}, journal = {Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association}, volume = {18}, number = {3}, pages = {635-643}, pmid = {24997570}, issn = {1436-3305}, mesh = {Acetylcysteine/pharmacology ; Aged ; Aged, 80 and over ; Apoptosis/drug effects ; Atmospheric Pressure ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Hyaluronan Receptors/genetics ; Middle Aged ; Plasma Gases/*therapeutic use ; Reactive Oxygen Species/metabolism ; Stomach Neoplasms/metabolism/*pathology/*therapy ; }, abstract = {BACKGROUND: Treatment of peritoneal carcinomatosis arising from gastric cancer remains a considerable challenge. In recent years, the anticancer effect of nonequilibrium atmospheric pressure plasma (NEAPP) has been reported in several cancer cell lines. Use of NEAPP may develop into a new class of anticancer therapy that augments surgery, chemotherapy, and radiotherapy.<br><br>METHOD: Gastric cancer cells were assessed for changes in cell morphology and rate of proliferation after treatment with NEAPP-exposed medium (PAM). To explore the functional mechanism, caspase&#xa0;3/7, annexin V, and uptake of reactive oxygen species (ROS) were evaluated, along with the effect of the ROS scavenger N-acetylcysteine (NAC).<br><br>RESULTS: PAM treatment for 24&#xa0;h affected cell morphology, suggestive of induction of apoptosis. PAM cytotoxicity was influenced by the time of exposure to PAM, the type of cell line, and the number of cells seeded. Cells treated with PAM for 2&#xa0;h demonstrated activated caspase&#xa0;3/7 and an increased proportion of annexin&#xa0;V-positive cells compared with untreated cells. Additionally, ROS uptake was observed in PAM-treated cells, whereas NAC reduced the cytotoxicity induced by PAM presumably through reduction of ROS uptake. Furthermore, CD44 variant 9, which reportedly leads to glutathione synthesis and suppresses stress signaling of ROS, was overexpressed in PAM-resistant cells.<br><br>CONCLUSIONS: PAM treatment induced apoptosis of gastric cancer cells through generation and uptake of ROS. Local administration of PAM could develop into an option to treat peritoneal carcinomatosis.}, }
@article {pmid24996181, year = {2014}, author = {Li, ZJ and Li, XM and Piao, YJ and Choi, DK and Kim, SJ and Kim, JW and Sohn, KC and Kim, CD and Lee, JH}, title = {Genkwadaphnin induces reactive oxygen species (ROS)-mediated apoptosis of squamous cell carcinoma (SCC) cells.}, journal = {Biochemical and biophysical research communications}, volume = {450}, number = {2}, pages = {1115-1119}, doi = {10.1016/j.bbrc.2014.06.118}, pmid = {24996181}, issn = {1090-2104}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Squamous Cell/*metabolism/pathology ; Cell Line, Tumor ; Diterpenes/*pharmacology ; Enzyme Activation ; Gene Knockdown Techniques ; Humans ; JNK Mitogen-Activated Protein Kinases/genetics/metabolism ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Skin Neoplasms/*metabolism/pathology ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Genkwadaphnin is a daphnane diterpene ester molecule isolated from the flower buds of Daphne genkwa. In the present study, we investigated the apoptosis-inducing effect of genkwadaphnin in squamous cell carcinoma (SCC) cells. Apoptosis was triggered in SCC12 cells following genkwadaphnin treatment in a time- and concentration-dependent manner. Genkwadaphnin treatment increased phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Knockdown of JNK and p38 MAPK by recombinant adenovirus expressing microRNA (miR) resulted in significant inhibition of genkwadaphnin-induced apoptosis in SCC12 cells. Finally, pretreatment with the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) markedly reduced SCC12 cell apoptosis, concomitant with significant inhibition of MAPK activation. These results indicate that genkwadaphnin has the potential to induce apoptosis in SCC cells, providing information on which to base further research with the aim of developing a cure for SCC.}, }
@article {pmid24995992, year = {2014}, author = {Selvaganapathy, M and Pravin, N and Pothiraj, K and Raman, N}, title = {Photo biological activation of NSO donor mixed-ligand complexes: in vivo and preclinical perspectives.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {138}, number = {}, pages = {256-272}, doi = {10.1016/j.jphotobiol.2014.06.003}, pmid = {24995992}, issn = {1873-2682}, mesh = {Animals ; Anti-Infective Agents/chemistry/pharmacology ; Anticonvulsants/chemistry/pharmacology/therapeutic use ; Antineoplastic Agents/chemistry/pharmacology ; Bacteria/drug effects ; Behavior, Animal/drug effects ; Cell Line ; Cell Survival/drug effects/radiation effects ; Coordination Complexes/*chemistry/pharmacology/therapeutic use ; DNA Cleavage/drug effects/radiation effects ; Edema/chemically induced/drug therapy ; Fungi/drug effects ; Humans ; *Ligands ; Light ; Lymphocytes/drug effects/radiation effects ; Microbial Sensitivity Tests ; Rats ; Seizures/chemically induced/drug therapy ; Ultraviolet Rays ; }, abstract = {Pyrazolone incorporating N-acetylcysteine (NAC) mixed-ligand complexes are described as promising anti-inflammatory, anticonvulsant, SODs mimetic and cytotoxic compounds possibly due to its antioxidant profile. In this study, we have evaluated the pharmacologic activity, antioxidant and toxicological profiles of compounds (1-6). Among them, compounds 1 and 4 were haemobiocompatible than the others. Both complexes 1 and 4 display efficient photo-nuclease activity upon irradiation with UV-A light of 365 nm and red light of 647 nm as compared with others. Mechanistic studies reveal that the DNA cleavage oxidative pathway involves H2O2 and singlet oxygen as the reactive oxygen species. Interestingly, both compounds 1 and 4, show non-toxic effects in vitro to human normal lymphocyte cells, revealing that they are selective in killing only the cancer cells as expected for a better drug. In addition, considering the safety profile, these compounds are promising as preventive and/or therapeutic agents against oxidative damage.}, }
@article {pmid24993441, year = {2014}, author = {Jang, JH and Cho, YC and Kim, KH and Lee, KS and Lee, J and Kim, DE and Park, JS and Jang, BC and Kim, S and Kwon, TK and Park, JW}, title = {BAI, a novel Cdk inhibitor, enhances farnesyltransferase inhibitor LB42708-mediated apoptosis in renal carcinoma cells through the downregulation of Bcl-2 and c-FLIP (L).}, journal = {International journal of oncology}, volume = {45}, number = {4}, pages = {1680-1690}, doi = {10.3892/ijo.2014.2534}, pmid = {24993441}, issn = {1791-2423}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis ; CASP8 and FADD-Like Apoptosis Regulating Protein/genetics/*metabolism ; Carcinoma, Renal Cell/genetics/metabolism/*pathology ; Cell Line, Tumor ; Drug Synergism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Imidazoles/*pharmacology ; Indazoles/*pharmacology ; Kidney Neoplasms/genetics/metabolism/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism ; Pyrroles/*pharmacology ; Thiazolidines/*pharmacology ; }, abstract = {Previously, we reported the potential of a novel Cdk inhibitor, 2-[1,1'-biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide (BAI) as a cancer chemotherapeutic agent. In this study, we investigated mechanisms by which BAI modulates FTI-mediated apoptosis in human renal carcinoma Caki cells. BAI synergizes with FTI to activate DEVDase, cleavage of poly ADP-ribose polymerase (PARP), and degradation of various anti-apoptotic proteins in Caki cells. BAI plus LB42708-induced apoptosis was inhibited by pretreatment with pan-caspase inhibitor, z-VAD-fmk, but not by overexpression of CrmA. The ROS scavenger, N-acetylcysteine (NAC) did not reduce BAI plus LB4270-induced apoptosis. Co-treatment of BAI and LB42708 reduced the mitochondrial membrane potential (MMP, ∆Ψm) in a time-dependent manner, and induced release of AIF and cytochrome c from mitochondria in Caki cells. Furthermore, BAL plus LB42708 induced downregulation of anti-apoptotic proteins [c-FLIP (L), c-FLIP (s), Bcl-2, XIAP, and Mcl-1 (L)]. Especially, we found that BAI plus LB42708-induced apoptosis was significantly attenuated by overexpression of Bcl-2 and partially blocked by overexpression of c-FLIP (L). Taken together, our results show that the activity of BAI plus LB42708 modulate multiple components in apoptotic response of human renal Caki cells, and indicate a potential as combinational therapeutic agents for preventing cancer such as renal carcinoma.}, }
@article {pmid24992193, year = {2014}, author = {Wang, Y and Cheng, X and Wang, P and Wang, L and Fan, J and Wang, X and Liu, Q}, title = {Investigating migration inhibition and apoptotic effects of Fomitopsis pinicola chloroform extract on human colorectal cancer SW-480 cells.}, journal = {PloS one}, volume = {9}, number = {7}, pages = {e101303}, pmid = {24992193}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Caco-2 Cells ; Caspase 3/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Chloroform/chemistry ; Coriolaceae/*chemistry/metabolism ; DNA Fragmentation/drug effects ; Ergosterol/analysis/chemistry ; Glutathione/metabolism ; HEK293 Cells ; Humans ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Plant Extracts/chemistry/*pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Fomitopsis pinicola (Sw. Ex Fr.m) Karst (FPK) which belongs to the Basidiomycota fungal class is one of the most popular medical fungi in China. It has been used for many diseases: cancer, heart diseases, diabetes and so on. However, little study on the pro-apoptotic effect and migration inhibition of FPK chloroform extract (FPKc) has been reported and the possible involved mechanism has not been illuminated.<br><br>Chemical analysis was performed by HPLC which showed ergosterol (ES) concentration was 105 &#xb5;g/mg. MTT assay revealed that FPKc could selectively inhibit SW-480 cells viability with the IC50 of 190.28 &#xb5;g/ml. Wound healing and transwell assay indicated that FPKc could inhibit the migration of SW-480 cells obviously, FPKc could also dramatically decreased the matrix metalloproteinases-2, 9 (MMP-2 and MMP-9) expression. Annexin V-FITC/PI staining, nuclear Hoechst 33342 staining and DNA fragmentation analysis revealed that FPKc and ES could induce SW-480 cells apoptosis. The apoptosis process closely involved in ROS accumulation and depletion of GSH, activation of caspase 3, poly (ADP-ribose) polymerase (PARP) degradation. FPKc could also up-regulate P53 expression and thus lead to G1 phase arrest. When SW-480 cells were pretreated with N-acetylcysteine (NAC), the ROS generation, cell viability and apoptotic ratio were partially declined, which indicated that ROS was vertical in the pro-apoptosis process induced by FPKc. Moreover, in the whole process, ES which has been previously found in FPKc had the similar effect to FPKc. Thus we could conclude that ES, as one of the highest abundant components in FPKc, might also be one of the active constituents.<br><br>CONCLUSION/SIGNIFICANCE: FPKc could inhibit the migration of SW-480 cells, induce SW-480 cells G1 phase arrest and cause ROS-mediated apoptosis effect. And ES might be one of the effective constituents in the whole process.}, }
@article {pmid24987704, year = {2014}, author = {Mittal, S and Pandey, AK}, title = {Cerium oxide nanoparticles induced toxicity in human lung cells: role of ROS mediated DNA damage and apoptosis.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {891934}, pmid = {24987704}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; *Cerium/adverse effects/chemistry/pharmacology ; *DNA Damage ; Free Radical Scavengers/pharmacology ; Humans ; Lung/*metabolism/pathology ; *Nanoparticles/adverse effects/chemistry ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cerium oxide nanoparticles (CeO2 NPs) have promising industrial and biomedical applications. In spite of their applications, the toxicity of these NPs in biological/physiological environment is a major concern. Present study aimed to understand the molecular mechanism underlying the toxicity of CeO2 NPs on lung adenocarcinoma (A549) cells. After internalization, CeO2 NPs caused significant cytotoxicity and morphological changes in A549 cells. Further, the cell death was found to be apoptotic as shown by loss in mitochondrial membrane potential and increase in annexin-V positive cells and confirmed by immunoblot analysis of BAX, BCl-2, Cyt C, AIF, caspase-3, and caspase-9. A significant increase in oxidative DNA damage was found which was confirmed by phosphorylation of p53 gene and presence of cleaved poly ADP ribose polymerase (PARP). This damage could be attributed to increased production of reactive oxygen species (ROS) with concomitant decrease in antioxidant "glutathione (GSH)" level. DNA damage and cell death were attenuated by the application of ROS and apoptosis inhibitors N-acetyl-L-cysteine (NAC) and Z-DEVD-fmk, respectively. Our study concludes that ROS mediated DNA damage and cell cycle arrest play a major role in CeO2 NPs induced apoptotic cell death in A549 cells. Apart from beneficial applications, these NPs also impart potential harmful effects which should be properly evaluated prior to their use.}, }
@article {pmid24987341, year = {2014}, author = {Chen, YW and Lin, HC and Ng, MC and Hsiao, YH and Wang, CC and Gean, PW and Chen, PS}, title = {Activation of mGluR2/3 underlies the effects of N-acetylcystein on amygdala-associated autism-like phenotypes in a valproate-induced rat model of autism.}, journal = {Frontiers in behavioral neuroscience}, volume = {8}, number = {}, pages = {219}, pmid = {24987341}, issn = {1662-5153}, abstract = {Autism-like phenotypes in male valproate (VPA)-exposed offspring have been linked to high glutamatergic neurotransmission in the thalamic-amygdala pathway. Glial cystine/glutamate exchange (system Xc(-)), which exchanges extracellular cystine for intracellular glutamate, plays a significant role in the maintenance of extracellular glutamate. N-acetylcysteine (NAC) is a cystine prodrug that restores extracellular glutamate by stimulating system Xc(-). In this study, we examined the effects of NAC on autism-like phenotypes and neurotransmission in the thalamic-amygdala synapses, as well as the involvement of metabotropic glutamate receptors 2/3 (mGluR2/3). Valproate-treated rats received a single intraperitoneal injection of 500 mg/kg NaVPA on E12.5. On postnatal day 21 (P21), NAC or saline was administered once daily for 10 days. From day 8 to 10, NAC was given 1/2 h prior to behavioral testing. Chronic administration of NAC restored the duration and frequency of social interaction and ameliorated anxiety-like behaviors in VPA-exposed offspring. In amygdala slices, NAC treatment normalized the increased frequency of mEPSCs and decreased the paired pulse facilitation (PPF) induced by VPA exposure. The effects of NAC on social interaction and anxiety-like behavior in the VPA-exposed offspring were blocked after intra-amygdala infusion of mGluR2/3 antagonist LY341495. The expressions of mGluR2/3 protein and mGluR2 mRNA were significantly lower in the VPA-exposed offspring. In contrast, the mGluR3 mRNA level did not differ between the saline- and VPA-exposed offspring. These results provide the first evidence that the disruption of social interaction and enhanced presynaptic excitatory transmission in VPA-exposed offspring could be rescued by NAC, which depends on the activation of mGluR2/3.}, }
@article {pmid24986373, year = {2014}, author = {Arbel, Y and Ben-Assa, E and Halkin, A and Keren, G and Schwartz, AL and Havakuk, O and Leshem-Rubinow, E and Konigstein, M and Steinvil, A and Abramowitz, Y and Finkelstein, A and Banai, S}, title = {Forced diuresis with matched hydration in reducing acute kidney injury during transcatheter aortic valve implantation (Reduce-AKI): study protocol for a randomized sham-controlled trial.}, journal = {Trials}, volume = {15}, number = {}, pages = {262}, pmid = {24986373}, issn = {1745-6215}, mesh = {Acetylcysteine/administration &amp; dosage ; Acute Kidney Injury/chemically induced/diagnosis/*prevention &amp; control ; Antioxidants/administration &amp; dosage ; Cardiac Catheterization/*adverse effects/methods ; Clinical Protocols ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Diuresis/drug effects ; Diuretics/*administration &amp; dosage ; Double-Blind Method ; Drug Administration Schedule ; *Fluid Therapy ; Furosemide/*administration &amp; dosage ; Heart Valve Prosthesis Implantation/*adverse effects/methods ; Humans ; Infusions, Intravenous ; Israel ; *Research Design ; Sodium Chloride/administration &amp; dosage ; Time Factors ; Treatment Outcome ; Urinary Catheterization ; }, abstract = {BACKGROUND: Acute kidney injury (AKI) is observed in up to 41% of patients undergoing transcatheter aortic valve implantation (TAVI) and is associated with increased risk for mortality. The aim of the present study is to evaluate whether furosemide-induced diuresis with matched isotonic intravenous hydration using the RenalGuard system reduces AKI in patients undergoing TAVI.<br><br>METHODS/DESIGN: Reduce-AKI is a randomized sham-controlled study designed to examine the effect of an automated matched hydration system in the prevention of AKI in patients undergoing TAVI. Patients will be randomized in a 1:1 fashion to the RenalGuard system (active group) versus non-matched saline infusion (sham-controlled group). Both arms receive standard overnight saline infusion and N-acetyl cysteine before the procedure.<br><br>DISCUSSION: The Reduce-AKI trial will investigate whether the use of automated forced diuresis with matched saline infusion is an effective therapeutic tool to reduce the occurrence of AKI in patients undergoing TAVI.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov: NCT01866800, 30 April 30 2013.}, }
@article {pmid24985174, year = {2014}, author = {Wang, X and Zhang, P and Zhao, L and Tu, Y and Dai, K}, title = {[Study of reactive oxygen species on the regulation of platelet apoptosis].}, journal = {Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi}, volume = {35}, number = {6}, pages = {511-514}, doi = {10.3760/cma.j.issn.0253-2727.2014.06.008}, pmid = {24985174}, issn = {0253-2727}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects/*physiology ; Blood Platelets/drug effects/metabolism/*physiology ; Caspase 3/metabolism ; Dibucaine/pharmacology ; Humans ; Membrane Potential, Mitochondrial/physiology ; Reactive Oxygen Species/*metabolism ; Thrombin/pharmacology ; bcl-X Protein/metabolism ; }, abstract = {OBJECTIVE: To study the effect of reactive oxygen species (ROS) on the regulation of platelet apoptosis.<br><br>METHODS: Washed healthy human platelets were pre-incubated with N-caetyl-Lcysteine (NAC), and then stimulated with dibucaine or thrombin. The production of ROS and depolarization of mitochondrial membrane potential (&#x2206; &#x3c8;m) were detected by flow cytometry. The activation of caspase-3 and expression of Bcl-xL were analyzed by Western blot.<br><br>RESULTS: (1)The average ROS fluorescence value of NAC+dibucaine group was lower than that of dibucaine group(0.66 &#xb1; 0.11 vs 1.06 &#xb1; 0.08, P<0.01), while that of NAC+thrombin group was also lower than that of thrombin group(0.45 &#xb1; 0.05 vs 0.71 &#xb1; 0.11, P=0.001). (2)The percentage of platelets with normal &#x2206;&#x3c8;m in NAC+Dibucaine group was higher than that of dibucaine group[(86.30 &#xb1; 9.37)% vs (13.52 &#xb1; 3.01)%, P=0.000], while that of NAC+thrombin group was also higher than that of thrombin group[(93.00 &#xb1; 3.03)% vs (76.58 &#xb1; 5.28)%, P=0.000]. (3)Fragmentation generated by caspase-3 activation in dibucaine group was much more than that in DMSO control group, while the fragmentation in NAC+dibucaine group was significantly decreased. (4)The expression of anti-apoptosis protein Bcl-xL of NAC+dibucaine group was significantly higher than that of the dibucaine group, while that of NAC+thrombin group was also higher than that of thrombin group.<br><br>CONCLUSION: Through the regulation of ROS, NAC could inhibit the platelet apoptosis induced by dibucaine or thrombin.}, }
@article {pmid24979751, year = {2014}, author = {Jasna, JM and Anandbabu, K and Bharathi, SR and Angayarkanni, N}, title = {Paraoxonase enzyme protects retinal pigment epithelium from chlorpyrifos insult.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e101380}, pmid = {24979751}, issn = {1932-6203}, mesh = {Aryldialkylphosphatase/genetics/*metabolism ; Cell Line ; Chlorpyrifos/*toxicity ; Glutathione/metabolism ; Humans ; Insecticides/*toxicity ; Organophosphate Poisoning/*metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/drug effects/*enzymology ; Sp1 Transcription Factor/genetics/metabolism ; }, abstract = {Retinal pigment epithelium (RPE) provides nourishment and protection to the eye. RPE dysfunction due to oxidative stress and inflammation is one of the major reason for many of the retinal disorders. Organophosphorus pesticides are widely used in the agricultural, industrial and household activities in India. However, their effects on the eye in the context of RPE has not been studied. In this study the defense of the ARPE19 cells exposed to Chlorpyrifos (1 nM to 100 µM) in terms of the enzyme paraoxonase (PON) was studied at 24 hr and 9 days of treatment. Chlorpyrifos was found to induce oxidative stress in the ARPE19 cells as seen by significant increase in ROS and decrease in glutathione (GSH) levels without causing cell death. Tissue resident Paraoxonase 2 (PON2) mRNA expression was elevated with chlorpyrifos exposure. The three enzymatic activities of PON namely, paraoxonase (PONase), arylesterase (PON AREase) and thiolactonase (PON HCTLase) were also found to be significantly altered to detoxify and as an antioxidant defense. Among the transcription factors regulating PON2 expression, SP1 was significantly increased with chlorpyrifos exposure. PON2 expression was found to be crucial as ARPE19 cells showed a significant loss in their ability to withstand oxidative stress when the cells were subjected to chlorpyrifos after silencing PON2 expression. Treatment with N-acetyl cysteine positively regulated the PON 2 expression, thus promoting the antioxidant defense put up by the cells in response to chlorpyrifos.}, }
@article {pmid24973647, year = {2014}, author = {Barajas-Espinosa, A and Basye, A and Jesse, E and Yan, H and Quan, D and Chen, CA}, title = {Redox activation of DUSP4 by N-acetylcysteine protects endothelial cells from Cd[2+]-induced apoptosis.}, journal = {Free radical biology &amp; medicine}, volume = {74}, number = {}, pages = {188-199}, pmid = {24973647}, issn = {1873-4596}, support = {K99 HL103846/HL/NHLBI NIH HHS/United States ; R00 HL103846/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects/genetics ; Cadmium/toxicity ; Cattle ; Cell Growth Processes ; Cell Line ; Cell Survival/drug effects/genetics ; Cytoprotection/drug effects ; Dual-Specificity Phosphatases/genetics/*metabolism ; Endothelial Cells/drug effects/*enzymology/pathology ; Glutathione/metabolism ; MAP Kinase Signaling System/drug effects/genetics ; Mitogen-Activated Protein Kinase Phosphatases/genetics/*metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/genetics/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects/*genetics ; RNA, Small Interfering/genetics ; Rats ; Up-Regulation ; }, abstract = {Redox imbalance is a primary cause of endothelial dysfunction (ED). Under oxidant stress, many critical proteins regulating endothelial function undergo oxidative modifications that lead to ED. Cellular levels of glutathione (GSH), the primary reducing source in cells, can significantly regulate cell function via reversible protein thiol modification. N-acetylcysteine (NAC), a precursor for GSH biosynthesis, is beneficial for many vascular diseases; however, the detailed mechanism of these benefits is still not clear. From HPLC analysis, NAC significantly increases both cellular GSH and tetrahydrobiopterin levels. Immunoblotting of endothelial NO synthase (eNOS) and DUSP4, a dual-specificity phosphatase with a cysteine as its active residue, revealed that both enzymes are upregulated by NAC. EPR spin trapping further demonstrated that NAC enhances NO generation from cells. Long-term exposure to Cd(2+) contributes to DUSP4 degradation and the uncontrolled activation of p38 and ERK1/2, leading to apoptosis. Treatment with NAC prevents DUSP4 degradation and protects cells against Cd(2+)-induced apoptosis. Moreover, the increased DUSP4 expression can redox-regulate the p38 and ERK1/2 pathways from hyperactivation, providing a survival mechanism against the toxicity of Cd(2+). DUSP4 gene knockdown further supports the hypothesis that DUSP4 is an antioxidant gene, critical in the modulation of eNOS expression, and thus protects against Cd(2+)-induced stress. Depletion of intracellular GSH by buthionine sulfoximine makes cells more susceptible to Cd(2+)-induced apoptosis. Pretreatment with NAC prevents p38 overactivation and thus protects the endothelium from this oxidative stress. Therefore, the identification of DUSP4 activation by NAC provides a novel target for future drug design.}, }
@article {pmid24968347, year = {2014}, author = {Zhang, RH and Li, CH and Wang, CL and Xu, MJ and Xu, T and Wei, D and Liu, BJ and Wang, GH and Tian, SF}, title = {N-acetyl-l-cystine (NAC) protects against H9N2 swine influenza virus-induced acute lung injury.}, journal = {International immunopharmacology}, volume = {22}, number = {1}, pages = {1-8}, pmid = {24968347}, issn = {1878-1705}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Lung Injury/etiology/*immunology/prevention &amp; control ; Animals ; Antioxidants/*administration &amp; dosage ; Cytokines/metabolism ; Disease Models, Animal ; Humans ; Inflammation Mediators/metabolism ; Influenza A Virus, H9N2 Subtype/drug effects/*physiology ; Influenza, Human/drug therapy/*immunology ; Lipid A/administration &amp; dosage/analogs &amp; derivatives/pharmacology ; Lung/drug effects/*immunology/virology ; Male ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections/complications/drug therapy/*immunology ; Peroxidase/metabolism ; Swine ; Toll-Like Receptor 4/antagonists &amp; inhibitors/genetics/metabolism ; Virus Replication/drug effects ; }, abstract = {The antioxidant N-acetyl-l-cysteine (NAC) had been shown to inhibit replication of seasonal human influenza A viruses. Here, the effects of NAC on H9N2 swine influenza virus-induced acute lung injury (ALI) were investigated in mice. BALB/c mice were inoculated intranasally with 10(7) 50% tissue culture infective doses (TCID(50)) of A/swine/HeBei/012/2008/(H9N2) viruses with or without NAC treatments to induce ALI model. The result showed that pulmonary inflammation, pulmonary edema, MPO activity, total cells, neutrophils, macrophages, TNF-α, IL-6, IL-1β and CXCL-10 in BALF were attenuated by NAC. Moreover, our data showed that NAC significantly inhibited the levels of TLR4 protein and TLR4 mRNA in the lungs. Pharmacological inhibitors of TLR4 (E5564) exerted similar effects like those determined for NAC in H9N2 swine influenza virus-infected mice. These results suggest that antioxidants like NAC represent a potential additional treatment option that could be considered in the case of an influenza A virus pandemic.}, }
@article {pmid24966097, year = {2014}, author = {Yang, K and Liu, W and Ren, W and Lv, S}, title = {Different interventions in preventing contrast-induced nephropathy after percutaneous coronary intervention.}, journal = {International urology and nephrology}, volume = {46}, number = {9}, pages = {1801-1807}, pmid = {24966097}, issn = {1573-2584}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Contrast Media/*adverse effects ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Middle Aged ; *Percutaneous Coronary Intervention ; Prospective Studies ; Single-Blind Method ; Sodium Bicarbonate/*therapeutic use ; Sodium Chloride/*therapeutic use ; }, abstract = {BACKGROUND: This study aimed to observe the preventive potential of different hydration solutions on contrast-induced nephropathy (CIN) after percutaneous coronary intervention.<br><br>METHODS: We initially screened 627 patients who were admitted to the Division of Cardiology, Beijing Anzhen Hospital between October 2010 and October 2011. The research subjects were randomly divided into four groups and were given: normal physiological saline (PS), sodium bicarbonate (SB), oral administration of PS + N-acetylcysteine (NAC) (PS + NAC), or oral administration of SB + NAC (SB + NAC). These patients were administered a hypotonic nonionic contrast agent, and the incidence of CIN in each group was observed.<br><br>RESULTS: The total incidence rate of CIN was 4.47 %, while the CIN incidence rates in the PS group, the SB group, the PS + NAC group and the SB + NAC group were 3.11, 5.03, 4.46 and 5.33 %, respectively. The differences between these groups were not statistically significant (P = 0.238), and for patients with diabetes and/or renal dysfunction, the incidence rates of CIN among the four groups did not show statistically significant differences (P = 0.238, 0.156, 0.287).<br><br>CONCLUSION: Use of PS, SB, and NAC caused no significant reduction in the incidence of CIN, but in high-risk patients with diabetes and/or renal dysfunction, SB + NAC might be superior to the application of isotonic crystalloid solution.}, }
@article {pmid24965576, year = {2014}, author = {Hashimoto, K}, title = {Targeting of NMDA receptors in new treatments for schizophrenia.}, journal = {Expert opinion on therapeutic targets}, volume = {18}, number = {9}, pages = {1049-1063}, doi = {10.1517/14728222.2014.934225}, pmid = {24965576}, issn = {1744-7631}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/pharmacology ; Antipsychotic Agents/*pharmacology/therapeutic use ; Drug Design ; Glutathione/metabolism ; Humans ; Molecular Targeted Therapy ; Oxidative Stress ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Schizophrenia/*drug therapy/physiopathology ; }, abstract = {INTRODUCTION: Abnormalities in glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) are implicated in the pathophysiology of schizophrenia, although the precise mechanisms are unknown.<br><br>AREAS COVERED: The author examines the role of the NMDA receptor in schizophrenia, focusing on results from preclinical and clinical studies that support the NMDA receptor hypothesis of schizophrenia. The author first reviewed papers detailing alterations in the levels of endogenous substances such as glutamine, glutamate, d-serine, l-serine, kynurenic acid and glutathione (GSH), all of which can affect NMDA receptor function. Next, the author reviewed clinical findings for glycine, d-serine, d-cycloserine, d-amino acid oxidase inhibitors (e.g., sodium benzoate) and glycine transporter-1 inhibitors (e.g., sarcosine, bitopertin), as potential therapeutic drugs. In addition, the author outlined how oxidative stress associated with decreased levels of the endogenous antioxidant GSH may play a role in the pathophysiology of schizophrenia. Finally, the author reviewed N-acetylcysteine (NAC), a precursor of GSH and an activator of the cystine-glutamate antiporter, as a potential therapeutic drug.<br><br>EXPERT OPINION: Given the NMDA receptor hypothesis of schizophrenia, the glycine modulatory site on NMDA receptors is the most attractive therapeutic target for this disease. In addition, both the kynurenine pathway and cystine-glutamate antiporter represent credible potential therapeutic targets for schizophrenia.}, }
@article {pmid24964211, year = {2014}, author = {Rossato, FA and Zecchin, KG and La Guardia, PG and Ortega, RM and Alberici, LC and Costa, RA and Catharino, RR and Graner, E and Castilho, RF and Vercesi, AE}, title = {Fatty acid synthase inhibitors induce apoptosis in non-tumorigenic melan-a cells associated with inhibition of mitochondrial respiration.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e101060}, pmid = {24964211}, issn = {1932-6203}, mesh = {Animals ; Apoptosis/*drug effects ; Blotting, Western ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cell Respiration/drug effects ; Cells, Cultured ; Cerulenin/*pharmacology ; Citrate (si)-Synthase/antagonists &amp; inhibitors ; Cytochromes c/metabolism ; Fatty Acid Synthases/*antagonists &amp; inhibitors ; Fatty Acid Synthesis Inhibitors/*pharmacology ; Humans ; Keratinocytes/drug effects/enzymology/*pathology ; Melanocytes/drug effects/enzymology/*pathology ; Melanoma/drug therapy/enzymology/pathology ; Membrane Potential, Mitochondrial/*drug effects ; Mice ; RNA, Messenger/genetics ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {The metabolic enzyme fatty acid synthase (FASN) is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm) and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD). The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin and orlistat induce apoptosis in non-tumorigenic cells via mitochondrial dysfunction, independent of FASN inhibition.}, }
@article {pmid24963595, year = {2014}, author = {Palanivel, K and Kanimozhi, V and Kadalmani, B and Akbarsha, MA}, title = {Verrucarin A induces apoptosis through ROS-mediated EGFR/MAPK/Akt signaling pathways in MDA-MB-231 breast cancer cells.}, journal = {Journal of cellular biochemistry}, volume = {115}, number = {11}, pages = {2022-2032}, doi = {10.1002/jcb.24874}, pmid = {24963595}, issn = {1097-4644}, mesh = {Antibiotics, Antineoplastic/*pharmacology ; Apoptosis ; Breast Neoplasms/*metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; Trichothecenes/*pharmacology ; }, abstract = {The present study was carried out to elucidate the mechanisms underlying Verrucarin A (VA)-induced cytotoxicity in human breast cancer cell line MDA-MB-231. VA inhibited the growth of MDA-MB-231 cells by induction of reactive oxygen species (ROS)-dependent mitochondrial apoptosis. Elevation of ROS production, associated with changes in Bax/Bcl-2 ratio, led to loss of mitochondrial membrane potential (Δψm) and cytochrome c release in VA-treated cells. Release of cytochrome c from mitochondria to cytosol triggered activation of caspase-3, PARP cleavage, DNA fragmentation, and finally apoptotic cell death. Furthermore, VA-induced apoptosis was accompanied by the activation of p38MAPK and inhibition of phosphorylation of EGFR as well as of Akt and ERK1/2. However, pre-treatment with n-acetyl cysteine, an ROS scavenger, and SB202190, a p38MAPK inhibitor, significantly inhibited VA-induced ROS generation, EGFR inhibition, p38MAPK activation and apoptosis. Moreover, pharmacological inhibition of EGFR and ERK1/2 significantly accelerated the VA-induced apoptosis in MDA-MB-231 cells. Collectively, these results indicate that VA-induces ROS elevation in cancer cells, which results in the activation of p38MAPK and inhibition of EGFR/Akt/ERK signaling cascade and, ultimately, cancer cell death.}, }
@article {pmid24962868, year = {2015}, author = {Kim, SM and Kim, C and Bae, H and Lee, JH and Baek, SH and Nam, D and Chung, WS and Shim, BS and Lee, SG and Kim, SH and Sethi, G and Ahn, KS}, title = {6-Shogaol exerts anti-proliferative and pro-apoptotic effects through the modulation of STAT3 and MAPKs signaling pathways.}, journal = {Molecular carcinogenesis}, volume = {54}, number = {10}, pages = {1132-1146}, doi = {10.1002/mc.22184}, pmid = {24962868}, issn = {1098-2744}, mesh = {Apoptosis/*drug effects ; CSK Tyrosine-Protein Kinase ; Caspases/metabolism ; Catechols/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Down-Regulation/drug effects ; G1 Phase/drug effects ; Hep G2 Cells ; Humans ; Inhibitor of Apoptosis Proteins/metabolism ; Janus Kinase 2/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; STAT3 Transcription Factor/*metabolism ; Signal Transduction/*drug effects ; Survivin ; bcl-X Protein/metabolism ; src-Family Kinases/metabolism ; }, abstract = {6-shogaol (6SG), one of active ingredients in ginger (Zingiber officinale), is known to exhibit anti-proliferative, anti-metastatic, and pro-apoptotic activities through a mechanism that is not fully elucidated. Because the aberrant activation of STAT3 and MAPKs have been associated with regulation of proliferation, invasion, and metastasis of tumors, we hypothesized that 6SG modulates the activation of STAT3 and MAPKs activation in tumor cells. We found that 6SG strongly inhibited constitutive phosphorylation of STAT3 through inhibition of the activation of upstream JAK2 and c-Src kinases and nuclear translocation of STAT3 on both MDA-MB231 and DU145 cells. Also, 6SG caused the activation of JNK, p38 MAPK, and ERK. Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented 6SG-induced apoptosis. 6SG induced apoptosis as characterized by cleavage of PARP, accumulation of cells in subG1 phase, positive Annexin V binding, down-regulation of STAT3-regulated proteins, and activation of caspase-8, -9, -3 in both MDA-MB231 cells. Compared with other analogues of 6SG, such as 6-gingerol (6G), 8-gingerol (8G), and 10-gingerol (10G), 6SG was found to be the most potent blocker of STAT3 activation. We observed that the administration of 6SG alone significantly suppressed the growth of the tumor. As compared to the vehicle control, 6SG also suppressed the expression of STAT3-regulated gene products such as Bcl-2, Bcl-xL, and Survivin in tumor tissues. Overall, these findings suggest that 6SG can interfere with multiple signaling cascades involved in tumorigenesis and can be used as a potential therapeutic candidate for both the prevention and treatment of cancer.}, }
@article {pmid24962643, year = {2015}, author = {Li, G and Fu, J and Zhao, Y and Ji, K and Luan, T and Zang, B}, title = {Alpha-lipoic acid exerts anti-inflammatory effects on lipopolysaccharide-stimulated rat mesangial cells via inhibition of nuclear factor kappa B (NF-κB) signaling pathway.}, journal = {Inflammation}, volume = {38}, number = {2}, pages = {510-519}, pmid = {24962643}, issn = {1573-2576}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/drug therapy/pathology/prevention &amp; control ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/pharmacology ; Cell Line ; Cell Survival/drug effects ; Cyclooxygenase 2/biosynthesis ; Dinoprostone/metabolism ; I-kappa B Kinase/metabolism ; I-kappa B Proteins/metabolism ; Inflammation/chemically induced/drug therapy/immunology ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Lipopolysaccharides ; Mesangial Cells/drug effects/*immunology ; NF-KappaB Inhibitor alpha ; NF-kappa B/*antagonists &amp; inhibitors ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/biosynthesis ; Phosphorylation ; Rats ; Sepsis/immunology/pathology ; Signal Transduction ; Thioctic Acid/*pharmacology ; Transcription Factor RelA/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Sepsis is often initiated by invasive infection, characterized by overwhelming induction of pro-inflammatory cytokines. The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, and lines of research into potential treatments are needed. This study was conducted to investigate effects of alpha-lipoic acid (ALA) on septic AKI in vitro. ALA of 200 or 400 μM was used to pretreat rat HBZY-1 mesangial cells before commencement of 1 μg/mL lipopolysaccharide (LPS). Our data indicated that ALA pretreatment reduced LPS-stimulated release of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1 beta (IL-1β), as well as IL-6, in HBZY-1 cell supernatant. Moreover, LPS-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) was inhibited by ALA pretreatment, and consequently, the secretion levels of their respective enzymatic products prostaglandin E2 (PGE2) and nitric oxide (NO) were significantly decreased. LPS-enhanced phosphorylation of nuclear factor kappa B (NF-κB) inhibitor alpha (IκBα) and IκB kinase alpha/beta (IKKα/β) and nuclear translocation of NF-κB subunit p65 in HBZY-1 cells were inhibited by ALA pretreatment. Additionally, the NF-κB inhibitor N-acetylcysteine (NAC) exerted similar inhibitory effects as ALA on COX-2 and iNOS expression. In summary, our study demonstrates that ALA mitigates LPS-induced inflammatory responses in rat mesangial cells probably via inhibition of NF-κB signaling pathway, suggesting a therapeutic potential of ALA in AKI related to sepsis.}, }
@article {pmid24959775, year = {2014}, author = {Kasperczyk, S and Dobrakowski, M and Kasperczyk, A and Zalejska-Fiolka, J and Pawlas, N and Kapka-Skrzypczak, L and Birkner, E}, title = {Effect of treatment with N-acetylcysteine on non-enzymatic antioxidant reserves and lipid peroxidation in workers exposed to lead.}, journal = {Annals of agricultural and environmental medicine : AAEM}, volume = {21}, number = {2}, pages = {272-277}, doi = {10.5604/1232-1966.1108590}, pmid = {24959775}, issn = {1898-2263}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/*metabolism ; Environmental Pollutants/toxicity ; Free Radical Scavengers/*pharmacology ; Humans ; Lead/toxicity ; Lipid Peroxidation/*drug effects ; Male ; Middle Aged ; *Occupational Exposure ; Oxidative Stress/*drug effects ; Poland ; }, abstract = {There are no published studies examining the effects of N-acetylcysteine (NAC) administration on the non-enzymatic defence systems in humans exposed to lead. In view of this, it was decided to measure the levels of uric acid (UA), albumin, bilirubin and alpha-tocopherol before and after treatment with NAC. An estimation was also made of the degree of oxidative stress by measuring the ferric reducing ability of plasma (FRAP), the levels of conjugated dienes (CD) and lipid hydroperoxides (LHP). Male employees who worked with lead were randomized into two groups. The first group included workers who were not administered any drugs (n=49), while the second group (n=122) consisted of workers who were treated with NAC at three different doses (200 mg, 400 mg and 800 mg) for 12 weeks. The administration of NAC (400 mg, 800 mg) resulted in significant decreases in the LHP levels. Similarly, a strong tendency toward lower levels of CD was observed in the same groups. The UA levels were significantly lower only in the group receiving the 200 mg dose of NAC. However, the alpha-tocopherol levels were significantly elevated after treatment with NAC (400 mg, 800 mg). NAC administration did not significantly affect the levels of bilirubin and albumin, but a tendency toward higher values was observed for FRAP. NAC reduced the extent of lipid peroxidation in a dose-dependent manner. Elevated concentrations of alpha-tocopherol may have enhanced the beneficial effects of NAC. Treatment with NAC may contribute to the restoration of non-enzymatic antioxidant reserves when administered to lead-exposed workers.}, }
@article {pmid24955304, year = {2014}, author = {Balter, RE and Cooper, ZD and Haney, M}, title = {Novel Pharmacologic Approaches to Treating Cannabis Use Disorder.}, journal = {Current addiction reports}, volume = {1}, number = {2}, pages = {137-143}, pmid = {24955304}, issn = {2196-2952}, support = {P50 DA009236/DA/NIDA NIH HHS/United States ; R01 DA019239/DA/NIDA NIH HHS/United States ; T32 DA007294/DA/NIDA NIH HHS/United States ; }, abstract = {With large and increasing numbers of people using cannabis, the development of cannabis use disorder (CUD) is a growing public health concern. Despite the success of evidence-based psychosocial therapies, low rates of initial abstinence and high rates of relapse during and following treatment for CUD suggest a need for adjunct pharmacotherapies. Here we review the literature on medication development for the treatment of CUD, with a particular focus on studies published within the last three years (2010-2013). Studies in both the human laboratory and in the clinic have tested medications with a wide variety of mechanisms. In the laboratory, the following medication strategies have been shown to decrease cannabis withdrawal and self-administration following a period of abstinence (a model of relapse): the cannabinoid receptor agonist, nabilone, and the adrenergic agonist, lofexidine, alone and in combination with dronabinol (synthetic THC), supporting clinical testing of these medication strategies. Antidepressant, anxiolytic and antipsychotic drugs targeting monoamines (norepinephrine, dopamine, and serotonin) have generally failed to decrease withdrawal symptoms or laboratory measures of relapse. In terms of clinical trials, dronabinol and multiple antidepressants (fluoxetine, venlafaxine and buspirone) have failed to decrease cannabis use. Preliminary results from controlled clinical trials with gabapentin and N-acetylcysteine (NAC) support further research on these medication strategies. Data from open label and laboratory studies suggest lithium and oxytocin also warrant further testing. Overall, it is likely that different medications will be needed to target distinct aspects of problematic cannabis use: craving, ongoing use, withdrawal and relapse. Continued research is needed in preclinical, laboratory and clinical settings.}, }
@article {pmid24954831, year = {2014}, author = {Jhang, KA and Lee, EO and Kim, HS and Chong, YH}, title = {Norepinephrine provides short-term neuroprotection against Aβ1-42 by reducing oxidative stress independent of Nrf2 activation.}, journal = {Neurobiology of aging}, volume = {35}, number = {11}, pages = {2465-2473}, doi = {10.1016/j.neurobiolaging.2014.05.020}, pmid = {24954831}, issn = {1558-1497}, mesh = {Alzheimer Disease/*drug therapy/metabolism/pathology ; Amyloid beta-Peptides/*metabolism/*toxicity ; *Antioxidants ; Cells, Cultured ; Humans ; NF-E2-Related Factor 2/*metabolism ; Neurons/*metabolism ; *Neuroprotective Agents ; Norepinephrine/*pharmacology ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Peptide Fragments/*metabolism/*toxicity ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Pathophysiological evidence correlating locus ceruleus neuron loss with increased Alzheimer's disease pathology suggests that norepinephrine (NE) is neuroprotective. Here, we evaluated the effects of NE on amyloid-β (Aβ)1-42-induced neurotoxicity and determined how NE exerts its actions in human SK-N-SH neurons. NE protected SK-N-SH cells against Aβ1-42-induced neurotoxicity only after a 4-hour treatment. The ability of NE to reduce Aβ1-42-induced neurotoxicity was independent of the adrenoceptor signaling pathway. Notably, NE downregulated Aβ1-42-mediated increases in intracellular reactive oxygen species (ROS) production. However, NE did not affect Aβ1-42-induced activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) redox signaling pathway, known to be involved in oxidative stress. Among the antioxidants tested, N-acetyl cysteine and glutathione, which are not only ROS scavengers but also thiol-reducing agents, mimicked the protective effects of NE. Consistently, Kelch-like ECH-associating protein 1 inhibitors, which activated the Nrf2 pathway, failed to decrease Aβ1-42-induced ROS generation and elicited no protection against Aβ1-42. Taken together, these findings suggest that NE could exert neuroprotective function against Aβ1-42 via redox cycling and reduction of intracellular oxidative stress regardless of downstream activation of the Nrf2 pathway.}, }
@article {pmid24952277, year = {2014}, author = {Kim, EC and Meng, H and Jun, AS}, title = {N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy.}, journal = {Experimental eye research}, volume = {127}, number = {}, pages = {20-25}, pmid = {24952277}, issn = {1096-0007}, support = {P30 NS050274/NS/NINDS NIH HHS/United States ; R01 EY019874/EY/NEI NIH HHS/United States ; EY019874/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blotting, Western ; Cell Count ; Cell Survival/drug effects ; Cells, Cultured ; *Disease Models, Animal ; Endoplasmic Reticulum Chaperone BiP ; Endothelium, Corneal/*drug effects/metabolism/pathology ; Free Radical Scavengers/*pharmacology ; Fuchs' Endothelial Dystrophy/metabolism/pathology/*prevention &amp; control ; Heat-Shock Proteins/genetics ; Hydrogen Peroxide/toxicity ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Confocal ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress ; Polymerase Chain Reaction ; RNA, Messenger/metabolism ; Thapsigargin/toxicity ; Transcription Factor CHOP/genetics ; }, abstract = {The present study evaluated survival effects of N-acetylcysteine (NAC) on cultured corneal endothelial cells exposed to oxidative and endoplasmic reticulum (ER) stress and in a mouse model of early-onset Fuchs endothelial corneal dystrophy (FECD). Cultured bovine corneal endothelial cell viability against oxidative and ER stress was determined by CellTiter-Glo(®) luminescent reagent. Two-month-old homozygous knock-in Col8a2(L450W/L450W) mutant (L450W) and C57/Bl6 wild-type (WT) animals were divided into two groups of 15 mice. Group I received 7 mg/mL NAC in drinking water and Group II received control water for 7 months. Endothelial cell density and morphology were evaluated with confocal microscopy. Antioxidant gene (iNos) and ER stress/unfolded protein response gene (Grp78 and Chop) mRNA levels and protein expression were measured in corneal endothelium by real time PCR and Western blotting. Cell viability of H2O2 and thapsigargin exposed cells pre-treated with NAC was significantly increased compared to untreated controls (p < 0.01). Corneal endothelial cell density (CD) was higher (p = 0.001) and percent polymegathism was lower (p = 0.04) in NAC treated L450W mice than in untreated L450W mice. NAC treated L450W endothelium showed significant upregulation of iNos, whereas Grp78 and Chop were downregulated compared to untreated L450W endothelium by real time PCR and Western blotting. NAC increases survival in cultured corneal endothelial cells exposed against ER and oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant and decreased ER stress markers in a mouse model of early-onset FECD. Our study presents in vivo evidence of a novel potential medical treatment for FECD.}, }
@article {pmid24946211, year = {2014}, author = {Zhang, LY and Wu, YL and Gao, XH and Guo, F}, title = {Mitochondrial protein cyclophilin-D-mediated programmed necrosis attributes to berberine-induced cytotoxicity in cultured prostate cancer cells.}, journal = {Biochemical and biophysical research communications}, volume = {450}, number = {1}, pages = {697-703}, doi = {10.1016/j.bbrc.2014.06.039}, pmid = {24946211}, issn = {1090-2104}, mesh = {Berberine/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclophilins/*metabolism ; Humans ; Male ; Mitochondrial Proteins/*metabolism ; Necrosis/chemically induced/metabolism/pathology ; Prostatic Neoplasms/*metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {The prostate cancer is one of the leading causes of men's cancer mortality. The development of alternative chemotherapeutic strategies is urgent. Berberine has displayed significant anti-prostate cancer activities. The underlying mechanisms are not fully understood. In the current study, we found that berberine induced apoptosis and programmed necrosis in cultured prostate cancer cells (LNCaP and PC-82 lines), and necrosis weighted more than apoptosis in contributing berberine's cytotoxicity. We demonstrated that mitochondrial protein cyclophilin-D (Cyp-D) is required for berberine-induced programmed necrosis. Inhibition of Cyp-D by its inhibitors cyclosporin A (CSA) or sanglifehrin A (SFA), and by Cyp-D shRNA depletion alleviated berberine-induced prostate cancer cell necrosis (but not apoptosis). Our data found that in prostate cancer cells, berberine induced reactive oxygen species (ROS) production, which dictated P53 translocation to mitochondria, where it physically interacted with Cyp-D to open mitochondrial permeability transition pore (mPTP). The anti-oxidant N-acetylcysteine (NAC), the P53 inhibitor pifithrin-α (PFTα) as well as P53 siRNA knockdown suppressed berberine-induced P53 mitochondrial translocation and Cyp-D association, thus inhibiting mitochondrial membrane potential (MMP) decrease and prostate cancer cell necrosis. In summary, the results of the present study provide mechanistic evidence that both apoptosis and programmed necrosis attribute to berberine's cytotoxicity in prostate cancer cells.}, }
@article {pmid24946209, year = {2014}, author = {Pyo, CW and Shin, N and Jung, KI and Choi, JH and Choi, SY}, title = {Alteration of copper-zinc superoxide dismutase 1 expression by influenza A virus is correlated with virus replication.}, journal = {Biochemical and biophysical research communications}, volume = {450}, number = {1}, pages = {711-716}, doi = {10.1016/j.bbrc.2014.06.037}, pmid = {24946209}, issn = {1090-2104}, mesh = {Cell Line ; Gene Expression Regulation, Viral/physiology ; Humans ; Influenza A virus/*physiology ; Lung/cytology/*enzymology/*virology ; Statistics as Topic ; Superoxide Dismutase/*metabolism ; Superoxide Dismutase-1 ; Virus Replication/*physiology ; }, abstract = {Viruses have evolved mechanisms designated to potentiate virus replication by modulating the physiological condition of host cells. The generation of reactive oxygen species (ROS) during infection with influenza virus A (IAV) is a well-established mechanism in animals, but little is known about the generation of ROS in in vitro cell culture models and about its role in virus replication. We show here that IAV H1N1 infected human alveolar cells increased superoxide anion level mainly by suppressing the copper-zinc superoxide dismutase 1 (SOD1) gene, and that the SOD1-controlled generation of ROS was tightly correlated with virus replication. The transcription factor Sp1, which is a major element of the proximal region of the sod1 promoter, was slightly downregulated at the transcriptional level during IAV infection, and subsequently modulated by post-translational control. A gradual reduction of whole Sp1 was largely responsible for the repression of sod1 transcription with increasing time post-infection, and their rescue by the proteasome inhibitor, MG132, proved the involvement of proteasomal degradation in Sp1 regulation during IAV infection. Furthermore, we observed that expression of viral polymerase PB1 was inversely proportional to SOD1 level. The antioxidant N-acetyl-cysteine (NAC) neutralized IAV-mediated oxidative stress, and either NAC treatment or sod1 transfection considerably diminished viral polymerase activity. These data indicate that IAV-induced SOD1 repression, which may cause impaired redox balance in host cells, can be attributed, at least in part, to enhance viral replication.}, }
@article {pmid24946181, year = {2014}, author = {Ju, TC and Chen, HM and Chen, YC and Chang, CP and Chang, C and Chern, Y}, title = {AMPK-α1 functions downstream of oxidative stress to mediate neuronal atrophy in Huntington's disease.}, journal = {Biochimica et biophysica acta}, volume = {1842}, number = {9}, pages = {1668-1680}, doi = {10.1016/j.bbadis.2014.06.012}, pmid = {24946181}, issn = {0006-3002}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Apoptosis ; Atrophy/metabolism/*pathology ; Blotting, Western ; Cell Proliferation ; Cells, Cultured ; Corpus Striatum/metabolism/*pathology ; *Disease Models, Animal ; Humans ; Huntingtin Protein ; Huntington Disease/metabolism/*pathology ; Immunoenzyme Techniques ; Mice ; Mice, Transgenic ; Nerve Degeneration ; Nerve Tissue Proteins/*physiology ; Neurons/metabolism/*pathology ; *Oxidative Stress ; }, abstract = {Huntington's disease (HD) is an autosomal dominant neurological disorder that is induced by a CAG trinucleotide expansion in exon 1 of the Huntingtin (HTT) gene. We previously reported that the abnormal activation of an important energy sensor, AMP-activated protein kinase α1 (AMPK-α1), occurs in the brains of mice and patients with HD, which suggests that this abnormal activation may contribute to neuronal degeneration in HD. In the present study, we demonstrated that the elevated oxidative stress that was evoked by a polyQ-expanded mutant HTT (mHTT) caused the abnormal activation of AMPK-α1 and, subsequently, resulted in neurotoxicity in a striatal progenitor cell line (STHdh(Q109)) and in the striatum of a transgenic mouse model of HD (R6/2). The systematic administration of an antioxidant (N-acetyl-cysteine, NAC) to R6/2 mice suppressed the activation of AMPK-α1, reduced neuronal toxicity, which was assessed by the activation of caspases, increased neuronal density, ameliorated ventricle enlargement, and improved motor dysfunction. This beneficial effect of NAC in vivo appears to be direct because NAC also reduced the activation of AMPK-α1 and the death of STHdh(Q109) cells upon elevated oxidative stress. Moreover, the activation of AMPK enhanced the level of oxidative stress in STHdh(Q109) cells, in primary neurons of R6/2 mice, and in the striatum of two different HD mouse models (R6/2 and Hdh(150Q/+)), whereas the inhibition of AMPK reduced the level of oxidative stress. Collectively, our findings suggest that positive feedback regulation between the elevated oxidative stress and the activation of AMPK-α1 contributes to the progression of HD.}, }
@article {pmid24941299, year = {2014}, author = {Joshi, D and Kumar, MD and Kumar, SA and Sangeeta, S}, title = {Reversal of methylmercury-induced oxidative stress, lipid peroxidation, and DNA damage by the treatment of N-acetyl cysteine: a protective approach.}, journal = {Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer}, volume = {33}, number = {2}, pages = {167-182}, doi = {10.1615/jenvironpatholtoxicoloncol.2014010291}, pmid = {24941299}, issn = {2162-6537}, mesh = {Acetylcysteine/*pharmacology ; Animals ; DNA Damage/*drug effects ; Humans ; Kidney/drug effects/physiopathology ; Lipid Peroxidation/*drug effects ; Liver/drug effects/physiopathology ; Male ; Methylmercury Compounds/*toxicity ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {This study was designed to evaluate the protective effect of N-acetyl cysteine in reducing methylmercury (MeHg)-induced oxidative stress, lipid peroxidation, DNA damage in liver, kidney, and brain, and their ability to restore altered hepatic, renal, and other biochemical variables. Male Sprague-Dawley rats (150±10 g) were randomly divided into three groups. Group 1 served as the control. Groups 2 and 3 were administered methylmercury (1 mg kg[-1] orally, 5 days/week) for 12 weeks, and group 2 served as the experimental control. Group 3 received N-acetyl cysteine (0.6 mg kg[-1] intraperitoneally, two days/week) for 12 weeks after methylmercury exposure. Methylmercury exposure caused a significant rise in bilirubin, gamma-glutamyl transpeptidase, protein, triglycerides, cholesterol, urea, creatinine, uric acid, and blood urea nitrogen, with a concomitant decrease in albumin content, reduced glutathione level and acetyl cholinesterase activity, antioxidant enzymes such as glutathione reductase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, and adenosine triphosphatase. However, lipid peroxidation level, metallothionein expression, and DNA damage with increment of tail length were observed after methylmercury intoxication. N-acetyl cysteine, a widely available, nontoxic amino acid derivative, is a promising antioxidant with a wide spectrum of biological functions. The ability of N-acetyl cysteine to enhance mercury excretion and its wide availability in clinical use indicate that it may be an ideal therapeutic agent against methylmercury poisoning.}, }
@article {pmid24935782, year = {2014}, author = {Li, X and Zhao, K and Guo, W and Liu, X and Liu, J and Gao, J and Chen, Q and Bai, Y}, title = {A novel manganese complex LMnAc selectively kills cancer cells by induction of ROS-triggered and mitochondrial-mediated cell death.}, journal = {Science China. Life sciences}, volume = {57}, number = {10}, pages = {998-1010}, doi = {10.1007/s11427-014-4682-6}, pmid = {24935782}, issn = {1869-1889}, mesh = {Acetylcysteine/chemistry ; Adenosine Triphosphate/chemistry ; Antineoplastic Agents/*chemistry ; Antioxidants/chemistry ; Apoptosis ; Autophagy ; Calcium/chemistry ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Coordination Complexes/*chemistry ; Drug Screening Assays, Antitumor ; Green Fluorescent Proteins/chemistry ; HeLa Cells ; Hep G2 Cells ; Humans ; Manganese Compounds/*chemistry ; Membrane Potential, Mitochondrial ; Mitochondria/*metabolism ; Propionates/*chemistry ; *Reactive Oxygen Species ; Receptors, Transferrin/chemistry ; Transferrin/chemistry ; }, abstract = {We previously identified a novel synthesized metal compound, LMnAc ([L2Mn2(Ac)(H2O)2](Ac) (L=bis(2-pyridylmethyl) amino-2-propionic acid)). This compound exhibited significant inhibition on cancer cell proliferation and was more selective against cancer cells than was the popular chemotherapeutic reagent cisplatin. In this study, we further investigated the underlying molecular mechanisms of LMnAc-induced cancer cell death. We found that LMnAc achieved its selectivity against cancer cells through the transferrin-transferrin receptor system, which is highly expressed in tumor cells. LMnAc triggered cancer cells to commit autophagy and apoptosis, which was mediated by the mitochondrial pathway. Moreover, LMnAc disrupted mitochondrial function, resulting in mitochondrial membrane potential collapse and ATP reduction. In addition, LMnAc induced intracellular Ca(2+) overload and reactive oxygen species generation. Interestingly, its anticancer effect was significantly reduced following pretreatment with the antioxidant N-acetyl cysteine, indicating that reactive oxygen species triggered cell death. Altogether, our data suggest that LMnAc appears to be a selectively promising anticancer drug candidate.}, }
@article {pmid24934700, year = {2014}, author = {Graudins, A}, title = {Overdose with modified-release paracetamol (Panadol Osteo®) presenting to a metropolitan emergency medicine network: a case series.}, journal = {Emergency medicine Australasia : EMA}, volume = {26}, number = {4}, pages = {398-402}, doi = {10.1111/1742-6723.12249}, pmid = {24934700}, issn = {1742-6723}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Clinical Audit ; Delivery of Health Care/*standards ; Drug Overdose/diagnosis/etiology/*therapy ; *Emergency Medical Services ; Female ; Guideline Adherence/standards ; Humans ; Male ; Middle Aged ; Practice Guidelines as Topic ; Retrospective Studies ; Time Factors ; Young Adult ; }, abstract = {BACKGROUND: There are currently no large cases series documenting poisoning with paracetamol modified-release (Panadol Osteo®, GlaxoSmithKline, Sydney, NSW, Australia). Management guidelines recommend at least two serum paracetamol concentrations 4 h apart and initiating treatment with N-acetylcysteine (NAC) if more than 10 g is ingested.<br><br>OBJECTIVE: To describe a cohort of Panadol Osteo&#xae; poisoning and determine if the management of identified cases was consistent with existing guidelines.<br><br>METHOD: Descriptive retrospective case series presenting to a metropolitan hospital network with paracetamol poisoning from October 2009 to September 2013.<br><br>RESULTS: There were 42 cases of Panadol Osteo&#xae; poisoning identified. Twenty-nine patients (median ingested dose 19&#x2009;950&#x2009;mg) were treated with NAC, of which 27 were acute single ingestions. Of NAC-treated patients, 85% (23/27) had an initial serum paracetamol concentration that was above the nomogram line. However, 15% (4/27) had an initial non-toxic concentration that later increased above the line. In 14 untreated patients (median ingested dose 7980&#x2009;mg), one was an unrecognised late line-crosser with initial non-toxic serum paracetamol concentration. Only 43% (6/14) had a repeat paracetamol concentration measured. Three patients had a 4&#x2009;h paracetamol >500&#x2009;&#x3bc;mol/L. Late line-crossing was seen in the NAC-treated group at this level. In two untreated patients, NAC should have been commenced on the reported dose.<br><br>CONCLUSION: Most patients presenting with Panadol Osteo&#xae; poisoning requiring NAC treatment had an initial serum paracetamol concentration indicating need for treatment. A small number of late treatment nomogram line-crossers was seen on repeat paracetamol estimation. The current guideline for Panadol Osteo&#xae; poisoning would have detected all cases requiring NAC treatment.}, }
@article {pmid24932583, year = {2014}, author = {Thakur, P and Lamoke, F and Chaffin, JM and Bartoli, M and Lee, JR and Duncan, MB}, title = {Dysplastic hepatocytes develop nuclear inclusions in a mouse model of viral hepatitis.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e99872}, pmid = {24932583}, issn = {1932-6203}, mesh = {Aldehydes/metabolism ; Animals ; Biomarkers/metabolism ; Cell Death ; Cell Nucleus/metabolism ; Cell Nucleus Size ; Cellular Senescence ; Disease Models, Animal ; Endoplasmic Reticulum/metabolism ; Glycogen/metabolism ; Hepatitis/immunology/*pathology/*virology ; Hepatitis B Surface Antigens/immunology ; Hepatocytes/metabolism/*pathology/*virology ; Intranuclear Inclusion Bodies/*pathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidative Stress ; Proliferating Cell Nuclear Antigen/metabolism ; Vacuoles/metabolism ; }, abstract = {Viral hepatitis resulting in chronic liver disease is an important clinical challenge and insight into the cellular processes that drive pathogenesis will be critical in order to develop new diagnostic and therapeutic options. Nuclear inclusions in viral and non-viral hepatitis are well documented and have diagnostic significance in some disease contexts. However, the origins and functional consequences of these nuclear inclusions remain elusive. To date the clinical observation of nuclear inclusions in viral and non-viral hepatitis has not been explored at depth in murine models of liver disease. Herein, we report that in a transgenic model of hepatitis B surface antigen mediated hepatitis, murine hepatocytes exhibit nuclear inclusions. Cells bearing nuclear inclusions were more likely to express markers of cell proliferation. We also established a correlation between these inclusions and oxidative stress. N-acetyl cysteine treatment effectively reduced oxidative stress levels, relieved endoplasmic reticulum (ER) stress, and the number of nuclear inclusions we observed in the transgenic mice. Our results suggest that the presence of nuclear inclusions in hepatocytes correlates with oxidative stress and cellular proliferation in a model of antigen mediated hepatitis.}, }
@article {pmid24930874, year = {2014}, author = {Umata, T}, title = {Involvement of reactive oxygen species in stimuli-induced shedding of heparin-binding epidermal growth factor-like growth factor.}, journal = {Journal of UOEH}, volume = {36}, number = {2}, pages = {105-114}, doi = {10.7888/juoeh.36.105}, pmid = {24930874}, issn = {0387-821X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blotting, Western ; Chlorocebus aethiops ; Diphtheria Toxin/metabolism ; Heparin-binding EGF-like Growth Factor ; Intercellular Signaling Peptides and Proteins/*physiology/radiation effects ; Ligands ; Lysophospholipids/pharmacology ; Mitogen-Activated Protein Kinases/analysis ; Protein Kinase C/analysis ; Reactive Oxygen Species/*pharmacology ; Receptors, G-Protein-Coupled/drug effects ; Sorbitol/pharmacology ; Tetradecanoylphorbol Acetate/pharmacology ; Vero Cells ; p38 Mitogen-Activated Protein Kinases/analysis ; }, abstract = {Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a critical growth factor for a number of physiological and pathological processes, such as wound healing, atherosclerosis and cancer proliferation. HB-EGF is synthesized as a membrane form (proHB-EGF), and is shedded at the cell surface to yield soluble HB-EGF, resulting in making it active. In this study, the involvement of reactive oxygen species (ROS) in stimuli-induced shedding of HB-EGF was investigated using monkey kidney Vero cells overexpressing HB-EGF (Vero-H cells). 12-O-tetradecanoylphorbol-13-acetate (TPA), lysophosphatidic acid (LPA) as a ligand for seventransmembrane G protein coupled receptors (GPCR) and sorbitol as stress induced shedding of HB-EGF mediated protein kinase C (PKC)-δ, mitogen-activated protein kinase (MAPK) and p38MAPK, respectively. These stimuli-induced sheddings of HB-EGF were inhibited by N-acetyl-L-cysteine (NAC), suggesting the involvement of ROS. As specific inhibitors of these protein kinases inhibited the shedding of HB-EGF, these signaling pathways seem to be independent, respectively. In contrast, γ-ray irradiation did not induce shedding although it did increase intracellular ROS levels. Taken together, these results suggest that the synergistic generation of ROS and the activation of protein kinase are required to promote stimuli-induced shedding of HB-EGF.}, }
@article {pmid24929652, year = {2014}, author = {Chaumais, MC and Ranchoux, B and Montani, D and Dorfmüller, P and Tu, L and Lecerf, F and Raymond, N and Guignabert, C and Price, L and Simonneau, G and Cohen-Kaminsky, S and Humbert, M and Perros, F}, title = {N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats.}, journal = {Respiratory research}, volume = {15}, number = {1}, pages = {65}, pmid = {24929652}, issn = {1465-993X}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Cells, Cultured ; Hypertension, Pulmonary/*chemically induced/*drug therapy/pathology ; Male ; Monocrotaline/*toxicity ; Myocytes, Cardiac/drug effects/pathology ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome ; }, abstract = {BACKGROUND: The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function.<br><br>METHODS: Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14-28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis.<br><br>RESULTS: The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71&#x2009;&#xb1;&#x2009;0.05 for MCT group to 0.50&#x2009;&#xb1;&#x2009;0.06 for MCT&#x2009;+&#x2009;NAC group, p&#x2009;<&#x2009;0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625&#x2009;&#xb1;&#x2009;69 vs. 439&#x2009;&#xb1;&#x2009;21&#xa0;&#x3bc;m2 for MCT and MCT&#x2009;+&#x2009;NAC group respectively, p&#x2009;<&#x2009;0.001) and heart fibrosis (14.1&#x2009;&#xb1;&#x2009;0.8 vs. 8.8&#x2009;&#xb1;&#x2009;0.1% for MCT and MCT&#x2009;+&#x2009;NAC group respectively, p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH.}, }
@article {pmid24928737, year = {2014}, author = {Gouix, E and Buisson, A and Nieoullon, A and Kerkerian-Le Goff, L and Tauskela, JS and Blondeau, N and Had-Aissouni, L}, title = {Oxygen glucose deprivation-induced astrocyte dysfunction provokes neuronal death through oxidative stress.}, journal = {Pharmacological research}, volume = {87}, number = {}, pages = {8-17}, doi = {10.1016/j.phrs.2014.06.002}, pmid = {24928737}, issn = {1096-1186}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Astrocytes/drug effects/*metabolism ; Benzoquinones/pharmacology ; Carboxylic Acids/pharmacology ; Caspase 3/metabolism ; Coculture Techniques ; Excitatory Amino Acid Antagonists/pharmacology ; Female ; Glucose/*metabolism ; Lipoxygenase Inhibitors/pharmacology ; Mice ; Neurons/drug effects/*metabolism ; Oxidative Stress ; Oxygen/*metabolism ; Pyridines/pharmacology ; }, abstract = {Understanding the role of astrocytes in stroke is assuming increasing prominence, not only as an important component on its own within the neurovascular unit, but also because astrocytes can influence neuronal outcome. Ischemia may induce astrogliosis and other phenotypic changes, but these remain poorly understood, in part due to limitations in reproducing these changes in vitro. Dibutyryl cyclic AMP-differentiated cultured astrocytes are more representative of the in vivo astroglial cell phenotype, and were much more susceptible than undifferentiated astrocytes to an ischemic-like stress, oxygen-glucose deprivation (OGD). OGD altered the expression/distribution and activity of glial glutamate transporters, impaired cellular glutamate uptake and decreased intracellular levels of glutathione preferentially in differentiated astrocytes. Resistance to OGD was conferred by inhibiting caspase-3 with DEVD-CHO and oxidative stress by the antioxidant N-acetylcysteine (NAC). The resistance of undifferentiated astrocytes to OGD may result from a transient but selective morphological transformation into Alzheimer type II astrocytes, an intermediary stage prior to transforming into reactive astrocytes. Co-culture of neurons with OGD-exposed astrocytes resulted in neurotoxicity, but at surprisingly lower levels with dying differentiated astrocytes. The antioxidant NAC or the 5-LOX inhibitor AA861 added upon co-culture delayed (day 1) but did not prevent neurotoxicity (day 3). Astrocytes undergoing apoptosis as a result of ischemia may represent a transient neuroprotective mechanism via ischemia-induced release of glutathione, but oxidative stress was responsible for neuronal demise when ischemia compromised astrocyte supportive functions.}, }
@article {pmid24923719, year = {2014}, author = {Soeda, J and Mouralidarane, A and Ray, S and Novelli, M and Thomas, S and Roskams, T and Diehl, AM and Oben, JA}, title = {The β-adrenoceptor agonist isoproterenol rescues acetaminophen-injured livers through increasing progenitor numbers by Wnt in mice.}, journal = {Hepatology (Baltimore, Md.)}, volume = {60}, number = {3}, pages = {1023-1034}, doi = {10.1002/hep.27266}, pmid = {24923719}, issn = {1527-3350}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetaminophen/poisoning ; Adrenergic beta-Agonists/pharmacology/*therapeutic use ; Analgesics, Non-Narcotic/poisoning ; Animals ; Cell Line ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology ; Drug Evaluation, Preclinical ; Isoproterenol/pharmacology/*therapeutic use ; Liver/*drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Stem Cells/metabolism/pathology ; Sympathetic Nervous System/drug effects ; Wnt Proteins/*metabolism ; }, abstract = {UNLABELLED: Acetaminophen (APAP)-induced acute liver injury (AILI) is a major health problem. Accumulating evidence suggests that the sympathetic nervous system (SNS) regulates neuronal and hematopoietic progenitors. SNS signaling affects hepatic progenitor/oval cells (HPCs) and β-adrenoceptor agonism will expand HPCs to reduce AILI. Dopamine β-hydroxylase-deficient mice (Dbh-/-), lacking catecholamine SNS neurotransmitters, isolated HPCs, and immature ductular 603B cells were initially used to investigate SNS involvement in HPC physiology. Subsequently, control mice were treated with APAP (350 mg/kg) followed by the β-adrenoceptor agonist, isoproterenol (ISO), or the β-adrenoceptor antagonist, propranolol. Mechanistic studies examined effects of non-SNS HPC expansion on AILI, involvement of the canonical Wnt/β-catenin pathway (CWP) in the action of ISO on HPC expansion and comparison of ISO with the current standard of care, N-acetylcysteine (NAC). Dbh-/- mice lacking catecholamines had low HPC numbers, reconstituted by ISO. In vitro, ISO-induced proliferation of 603B cells was CWP dependent. In control mice, AILI raised HPC numbers, further increased by ISO, with attenuation of liver injury. Delayed administration of NAC did not, but delayed ISO did, reverse AILI. Propranolol worsened AILI. AILI activated the CWP, and ISO enhanced Wnt-ligand production. HPCs were the major source of Wnt ligands. Recombinant Wnt3a and ISO-603B-conditioned media, but not ISO alone, protected isolated hepatocytes from death, reversed by DKK1-a Wnt antagonist. Additionally, tumor-associated weak inducer of apoptosis expanded HPCs and protected against AILI. Furthermore, allotransplantation of HPCs from APAP+ISO-treated mice to other APAP-injured mice improved AILI, an effect antagonized by DKK1.<br><br>CONCLUSION: SNS catecholamines expand HPCs, which are both targets and sources of Wnt ligands. Hepatoprotection by ISO is mediated by para- and autocrine effects of Wnt signaling. ISO represents novel pharmacotherapy for AILI.}, }
@article {pmid24923653, year = {2014}, author = {Wang, H and Yang, Y and Chen, H and Dan, J and Cheng, J and Guo, S and Sun, X and Wang, W and Ai, Y and Li, S and Li, Z and Peng, L and Tian, Z and Yang, L and Wu, J and Zhong, X and Zhou, Q and Wang, P and Zhang, Z and Cao, W and Tian, Y}, title = {The predominant pathway of apoptosis in THP-1 macrophage-derived foam cells induced by 5-aminolevulinic acid-mediated sonodynamic therapy is the mitochondria-caspase pathway despite the participation of endoplasmic reticulum stress.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {33}, number = {6}, pages = {1789-1801}, doi = {10.1159/000362958}, pmid = {24923653}, issn = {1421-9778}, mesh = {Aminolevulinic Acid/*pharmacology ; Apoptosis/*drug effects ; Caspases/*metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Cytosol/drug effects/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Foam Cells/*drug effects/metabolism ; Humans ; Immunoblotting ; Macrophages/drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Confocal ; Mitochondria/*drug effects/metabolism/physiology ; Protein Transport/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sonication/instrumentation ; Ultrasonic Therapy/instrumentation ; bcl-2-Associated X Protein/metabolism ; }, abstract = {BACKGROUND: In advanced atherosclerosis, chronic endoplasmic reticulum (ER) stress induces foam cells apoptosis and generates inflammatory reactions.<br><br>METHODS: THP-1 macrophage-derived foam cells (FC) were incubated with 1 mM 5-aminolevulinic acid (ALA). After ALA mediated sonodynamic therapy (ALA-SDT), apoptosis of FC was assayed by Annexin V-PI staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were detected by staining with CellROX&#xae; Green Reagent and jc-1. Pretreatment of FC with N-acetylcysteine (NAC), Z-VAD-FMK or 4-phenylbutyrate (4-PBA), mitochondria apoptotic pathway associated proteins and C/EBP-homologous (CHOP) expressions were assayed by wertern blotting.<br><br>RESULTS: Burst of apoptosis of FC was observed at 5-hour after ALA-SDT with 6-hour incubation of ALA and 0.4 W/cm(2) ultrasound. After ALA-SDT, intracellular ROS level increased and mitochondrial membrane potential collapsed. Translocations of cytochrome c from mitochondria into cytosol and Bax from cytosol into mitochondria, cleaved caspase 9, cleaved caspase 3, upregulation of CHOP, as well as downregulation of Bcl-2 after ALA-SDT were detected, which could be suppressed by NAC. Activation of mitochondria-caspase pathway could not be inhibited by 4-PBA. Cleaved caspase 9 and caspase 3 as well as apoptosis induced by ALA-SDT could be inhibited by Z-VAD-FMK.<br><br>CONCLUSION: The mitochondria-caspase pathway is predominant in the apoptosis of FC induced by ALA-SDT though ER stress participates in.}, }
@article {pmid24921657, year = {2014}, author = {Shieh, JM and Shen, CJ and Chang, WC and Cheng, HC and Chan, YY and Huang, WC and Chang, WC and Chen, BK}, title = {An increase in reactive oxygen species by deregulation of ARNT enhances chemotherapeutic drug-induced cancer cell death.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e99242}, pmid = {24921657}, issn = {1932-6203}, mesh = {Antineoplastic Agents/*pharmacology ; Aryl Hydrocarbon Receptor Nuclear Translocator/*metabolism ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/pathology ; Cisplatin/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Enzyme Activation/drug effects ; Gene Knockdown Techniques ; Humans ; Neoplasm Invasiveness ; Neoplasms/*metabolism/*pathology ; Proteolysis/drug effects ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Unique characteristics of tumor microenvironments can be used as targets of cancer therapy. The aryl hydrocarbon receptor nuclear translocator (ARNT) is an important mediator of tumor progression. However, the functional role of ARNT in chemotherapeutic drug-treated cancer remains unclear.<br><br>Here, we found that knockdown of ARNT in cancer cells reduced the proliferation rate and the transformation ability of those cells. Moreover, cisplatin-induced cell apoptosis was enhanced in ARNT-deficient cells. Expression of ARNT also decreased in the presence of cisplatin through proteasomal degradation pathway. However, ARNT level was maintained in cisplatin-treated drug-resistant cells, which prevented cell from apoptosis. Interestingly, reactive oxygen species (ROS) dramatically increased when ARNT was knocked down in cancer cells, enhancing cisplatin-induced apoptosis. ROS promoted cell death was inhibited in cells treated with the ROS scavenger, N-acetyl-cysteine (NAC).<br><br>CONCLUSIONS/SIGNIFICANCE: These results suggested that the anticancer activity of cisplatin is attributable to its induction of the production of ROS by ARNT degradation. Targeting ARNT could be a potential strategy to eliminate drug resistance in cancer cells.}, }
@article {pmid24918938, year = {2014}, author = {Buccigrossi, V and Laudiero, G and Russo, C and Miele, E and Sofia, M and Monini, M and Ruggeri, FM and Guarino, A}, title = {Chloride secretion induced by rotavirus is oxidative stress-dependent and inhibited by Saccharomyces boulardii in human enterocytes.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e99830}, pmid = {24918938}, issn = {1932-6203}, mesh = {Acetylcysteine/metabolism ; Antioxidants/metabolism ; Caco-2 Cells ; Cell Line, Tumor ; Chlorides/*metabolism ; Enterocytes/*metabolism/microbiology/virology ; Glutathione/metabolism ; Glycoproteins/metabolism ; Humans ; Intestinal Mucosa/metabolism ; Intestines/microbiology/virology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; Rotavirus/*metabolism ; Rotavirus Infections/metabolism/*microbiology/virology ; Saccharomyces/*metabolism ; Toxins, Biological/metabolism ; Viral Nonstructural Proteins/metabolism ; }, abstract = {Rotavirus (RV) infection causes watery diarrhea via multiple mechanisms, primarily chloride secretion in intestinal epithelial cell. The chloride secretion largely depends on non-structural protein 4 (NSP4) enterotoxic activity in human enterocytes through mechanisms that have not been defined. Redox imbalance is a common event in cells infected by viruses, but the role of oxidative stress in RV infection is unknown. RV SA11 induced chloride secretion in association with an increase in reactive oxygen species (ROS) in Caco-2 cells. The ratio between reduced (GSH) and oxidized (GSSG) glutathione was decreased by RV. The same effects were observed when purified NSP4 was added to Caco-2 cells. N-acetylcysteine (NAC), a potent antioxidant, strongly inhibited the increase in ROS and GSH imbalance. These results suggest a link between oxidative stress and RV-induced diarrhea. Because Saccharomyces boulardii (Sb) has been effectively used to treat RV diarrhea, we tested its effects on RV-infected cells. Sb supernatant prevented RV-induced oxidative stress and strongly inhibited chloride secretion in Caco-2 cells. These results were confirmed in an organ culture model using human intestinal biopsies, demonstrating that chloride secretion induced by RV-NSP4 is oxidative stress-dependent and is inhibited by Sb, which produces soluble metabolites that prevent oxidative stress. The results of this study provide novel insights into RV-induced diarrhea and the efficacy of probiotics.}, }
@article {pmid24916794, year = {2014}, author = {Dhouib, IB and Lasram, MM and Abdeladhim, M and Gharbi, N and Ahmed, MB and El-Fazaa, S}, title = {Immunosuppression and oxidative stress induced by subchronic exposure to carbosulfan in rat spleen: immunomodulatory and antioxidant role of N-acetylcysteine.}, journal = {Toxicology mechanisms and methods}, volume = {24}, number = {6}, pages = {417-427}, doi = {10.3109/15376516.2014.928764}, pmid = {24916794}, issn = {1537-6524}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Carbamates/*administration &amp; dosage/*toxicity ; Drug Administration Schedule ; Immunomodulation/*drug effects ; Lipid Peroxidation ; Male ; Oxidative Stress/*drug effects ; Pesticides/toxicity ; Random Allocation ; Rats ; Rats, Wistar ; Spleen/*drug effects ; }, abstract = {The present study was designed to determine the immunosuppressive effects of carbosulfan (CB) and their relationship with an increased formation of reactive oxygen species in rat. Further, we aimed to evaluate the protective effects of N-acetyl-cysteine (NAC) against immunopathological changes induced by CB. Carbosulfan (25 mg/kg) and NAC (2 g/l) were given daily to rats during 30 days, via oral gavage and drinking water, respectively. Cell-mediated immune function, cytokines production, biomarkers of cell redox state maintenance, lipid peroxidation and the activities of antioxidant enzymes were measured in the spleen. Our data showed an increase in WBC percent (28.42%), a reduction in spleen CD8 T-lymphocytes (-85.63%) and a decrease in immunosuppressive cytokines production such as INF-gamma and IL-4. There was a switch from Th1-type to Th2-type cytokines with an unbalance toward anti-inflammatory cytokines. Moreover, a significant decrease in reduced glutathione (-71.68%) and total thiols (-39.81%) levels were observed in treated rats. Conversely, malondialdehyde level in spleen was increased (-42.3%), while glutathione-S-transferase, glutathione peroxidase, superoxide dismutase and catalase activities were depleted. Our results suggest that subchronic CB administration affects cellular enzyme and non-enzyme-mediated antioxidant defense systems and promotes immunotoxicity in rat. On the other hand, our data showed protective effects of NAC. Indeed, there was a recovery of oxidative stress markers and cytokines production. The use of NAC, in our study, as a therapeutic agent showed interesting results against CB toxicity.}, }
@article {pmid24915841, year = {2014}, author = {Jin, J and Lv, X and Chen, L and Zhang, W and Li, J and Wang, Q and Wang, R and Lu, X and Miao, D}, title = {Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance.}, journal = {Aging cell}, volume = {13}, number = {5}, pages = {797-809}, pmid = {24915841}, issn = {1474-9726}, mesh = {Animals ; Cell Line, Tumor ; DNA Damage ; Epithelial-Mesenchymal Transition ; Genotyping Techniques ; Humans ; Kidney/metabolism/*pathology ; Kidney Diseases/*genetics/metabolism/*prevention &amp; control ; Mitogen-Activated Protein Kinase 7/*deficiency/*genetics/metabolism ; Nephritis, Interstitial ; Oxidation-Reduction ; Oxidative Stress/physiology ; }, abstract = {To determine whether Bmi-1 deficiency could lead to renal tubulointerstitial injury by mitochondrial dysfunction and increased oxidative stress in the kidney, 3-week-old Bmi-1(-/-) mice were treated with the antioxidant N-acetylcysteine (NAC, 1 mg mL(-1)) in their drinking water, or pyrro-quinoline quinone (PQQ, 4 mg kg(-1) diet) in their diet for 2 weeks, and their renal phenotypes were compared with vehicle-treated Bmi1(-/-) and wild-type mice. Bmi-1 was knocked down in human renal proximal tubular epithelial (HK2) cells which were treated with 1 mm NAC for 72 or 96 h, and their phenotypes were compared with control cells. Five-week-old vehicle-treated Bmi-1(-/-) mice displayed renal interstitial fibrosis, tubular atrophy, and severe renal function impairment with decreased renal cell proliferation, increased renal cell apoptosis and senescence, and inflammatory cell infiltration. Impaired mitochondrial structure, decreased mitochondrial numbers, and increased oxidative stress occurred in Bmi-1(-/-) mice; subsequently, this caused DNA damage, the activation of TGF-β1/Smad signaling, and the imbalance between extracellular matrix synthesis and degradation. Oxidative stress-induced epithelial-to-mesenchymal transition of renal tubular epithelial cells was enhanced in Bmi-1 knocked down HK2 cells. All phenotypic alterations caused by Bmi-1 deficiency were ameliorated by antioxidant treatment. These findings indicate that Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance and will be a novel therapeutic target for preventing renal tubulointerstitial injury.}, }
@article {pmid24914322, year = {2014}, author = {García, A and Salas-Jara, MJ and Herrera, C and González, C}, title = {Biofilm and Helicobacter pylori: from environment to human host.}, journal = {World journal of gastroenterology}, volume = {20}, number = {19}, pages = {5632-5638}, pmid = {24914322}, issn = {2219-2840}, mesh = {Acetylcysteine/chemistry ; Anti-Bacterial Agents/therapeutic use ; *Biofilms ; Curcumin/chemistry ; Environment ; Environmental Microbiology ; Gastric Mucosa/microbiology ; Helicobacter Infections/*microbiology/physiopathology ; Helicobacter pylori/*physiology ; Humans ; Water Microbiology ; }, abstract = {Helicobacter pylori (H. pylori) is a Gram negative pathogen that selectively colonizes the human gastric epithelium. Over 50% of the world population is infected with H. pylori reaching up to 90% of infected individuals in developing countries. Nonetheless the increased impact upon public health care, its reservoir and the transmission pathway of the species has not been clearly established yet. Molecular studies allowed the detection of H. pylori in various aquatic environments, even forming biofilm in tap water distribution systems in several countries, suggesting a role of water as a possible reservoir of the pathogen. The persistence of human infection with H. pylori and the resistance of clinical isolates to commonly used antibiotics in eradication therapy have been related to the genetic variability of the species and its ability to develop biofilm, demonstrated both in vivo and in vitro experiments. Thus, during the last years, experimental work with this pathogen has been focused in the search for biofilm inhibitors and biofilm destabilizing agents. However, only two anti- H. pylori biofilm disrupting agents have been successfully used: Curcumin - a natural dye - and N-acetyl cysteine - a mucolytic agent used in respiratory diseases. The main goal of this review was to discuss the evidences available in the literature supporting the ability of H. pylori to form biofilm upon various surfaces in aquatic environments, both in vivo and in vitro. The results published and our own observations suggest that the ability of H. pylori to form biofilm may be important for surviving under stress conditions or in the spread of the infection among humans, mainly through natural water sources and water distribution systems.}, }
@article {pmid24909514, year = {2014}, author = {Lu, C and Zhou, LY and Xu, HJ and Chen, XY and Tong, ZS and Liu, XD and Jia, YS and Chen, Y}, title = {RIP3 overexpression sensitizes human breast cancer cells to parthenolide in vitro via intracellular ROS accumulation.}, journal = {Acta pharmacologica Sinica}, volume = {35}, number = {7}, pages = {929-936}, pmid = {24909514}, issn = {1745-7254}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Breast/drug effects/metabolism/pathology ; Breast Neoplasms/*drug therapy/*genetics/metabolism/pathology ; Cell Line, Tumor ; Female ; Gene Deletion ; *Gene Expression Regulation, Neoplastic ; Humans ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases/*genetics/metabolism ; Sesquiterpenes/*pharmacology ; Up-Regulation ; }, abstract = {AIM: Receptor-interacting protein 3 (RIP3) is involved in tumor necrosis factor receptor signaling, and results in NF-κB-mediated prosurvival signaling and programmed cell death. The aim of this study was to determine whether overexpression of the RIP3 gene could sensitize human breast cancer cells to parthenolide in vitro.<br><br>METHODS: The expression of RIP3 mRNA in human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435 and T47D) was detected using RT-PCR. Both MDA-MB-231 and MCF-7 cells were transfected with RIP3 expression or blank vectors via lentivirus. Cell viability was measured with MTT assay; intracellular ROS level and cell apoptosis were analyzed using flow cytometry.<br><br>RESULTS: RIP3 mRNA expression was not detected in the four human breast cancer cell lines tested. However, the transfection induced higher levels of RIP3 protein in MCF-7 and MDA-MB-231 cells. Furthermore, overexpression of RIP3 decreased the IC50 values of parthenolide from 17.6 to 12.6 &#x3bc;mol/L in MCF-7 cells, and from 16.6 to 9.9 &#x3bc;mol/L in MDA-MB-231 cells. Moreover, overexpression of RIP3 significantly increased parthenolide-induced apoptosis and ROS accumulation in MCF-7 and MDA-MB-231 cells. Pretreatment with N-acetyl-cysteine abrogated the increased sensitivity of RIP3-transfected MCF-7 and MDA-MB-231 cells to parthenolide.<br><br>CONCLUSION: Overexpression of RIP3 sensitizes MCF-7 and MDA-MB-231 breast cancer cells to parthenolide in vitro via intracellular ROS accumulation.}, }
@article {pmid24909301, year = {2014}, author = {Kuse, Y and Ogawa, K and Tsuruma, K and Shimazawa, M and Hara, H}, title = {Damage of photoreceptor-derived cells in culture induced by light emitting diode-derived blue light.}, journal = {Scientific reports}, volume = {4}, number = {}, pages = {5223}, pmid = {24909301}, issn = {2045-2322}, mesh = {Animals ; Antioxidants/metabolism ; Apoptosis/*physiology ; Cells, Cultured ; Light/*adverse effects ; Mice ; Photoreceptor Cells, Vertebrate/metabolism/*pathology ; Reactive Oxygen Species/metabolism ; Retina/metabolism/pathology ; Rod Opsins/metabolism ; }, abstract = {Our eyes are increasingly exposed to light from the emitting diode (LED) light of video display terminals (VDT) which contain much blue light. VDTs are equipped with televisions, personal computers, and smart phones. The present study aims to clarify the mechanism underlying blue LED light-induced photoreceptor cell damage. Murine cone photoreceptor-derived cells (661 W) were exposed to blue, white, or green LED light (0.38 mW/cm(2)). In the present study, blue LED light increased reactive oxygen species (ROS) production, altered the protein expression level, induced the aggregation of short-wavelength opsins (S-opsin), resulting in severe cell damage. While, blue LED light damaged the primary retinal cells and the damage was photoreceptor specific. N-Acetylcysteine (NAC), an antioxidant, protected against the cellular damage induced by blue LED light. Overall, the LED light induced cell damage was wavelength-, but not energy-dependent and may cause more severe retinal photoreceptor cell damage than the other LED light.}, }
@article {pmid24908156, year = {2014}, author = {Schwingel, TE and Klein, CP and Nicoletti, NF and Dora, CL and Hadrich, G and Bica, CG and Lopes, TG and da Silva, VD and Morrone, FB}, title = {Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {387}, number = {9}, pages = {837-848}, pmid = {24908156}, issn = {1432-1912}, mesh = {Alanine Transaminase/blood ; Animals ; Antineoplastic Agents ; Aspartate Aminotransferases/blood ; Caspase 3/metabolism ; Emulsions ; Fatty Liver/chemically induced/*drug therapy/metabolism/pathology ; Hyperalgesia/drug therapy ; Lumbar Vertebrae ; Male ; Mice, Inbred BALB C ; Neurotoxicity Syndromes/*drug therapy/metabolism ; *Organoplatinum Compounds ; Oxaliplatin ; Peroxidase/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Quercetin/pharmacology/*therapeutic use ; Resveratrol ; Rutin/pharmacology/*therapeutic use ; Spinal Cord/metabolism ; Stilbenes/pharmacology/*therapeutic use ; }, abstract = {Oxaliplatin (OXA) is a platinum compound widely used in the treatment of some solid tumors, especially colorectal cancer. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug, and until now, there is no suitable treatment. Chemotherapy with oxaliplatin also increases the rate of developing hepatic damages with inflammatory activity, termed chemotherapy-associated steatohepatitis (CASH). In the present study, we aimed to compare the effects of a series of antioxidant compounds on simultaneous development of oxaliplatin-induced hepato- and neurotoxicity in mice. Mice BALB/c were treated with oxaliplatin for 6 weeks, 10 mg/kg, intraperitoneally, resulting in mechanical allodynia and hepatic steatosis. We administered the following antioxidant compounds--rutin (RT) (20 mg/kg), resveratrol (RVS) (100 mg/kg), quercetin (QT) (20 mg/kg), and quercetin nanoemulsion (NQT) (20 mg/kg)--daily by gavage to BALB/c, and N-acetylcysteine (NAC) was used as positive control. Treatments with RSV, RUT, or NQT were able to prevent mechanical allodynia when compared to the OXA group, and this effect was associated with decreased c-Fos immunopositivity in the lumbar spinal cord. Regarding the effects on steatohepatitis, RVS, QT, and NQT almost completely reversed the mean liver weight increase induced by OXA. In accordance with these previous data, histological evaluation indicated attenuation of all features of hepatic steatosis evaluated in RSV, RUT, QT, and NQT groups. These compounds were able to reduce the immunopositivity for the apoptosis marker caspase-3. On the other hand, only QT and NQT treatments were able to reduce neutrophil migration measured by myeloperoxidase (MPO) activity. These results suggest that the compounds tested, RSV, RUT, QT, and NQT, would be useful for the clinical treatment of neuro- and hepatoxicity induced by oxaliplatin.}, }
@article {pmid24907397, year = {2014}, author = {Kumar, P and Rao, GN and Pal, BB and Pal, A}, title = {Hyperglycemia-induced oxidative stress induces apoptosis by inhibiting PI3-kinase/Akt and ERK1/2 MAPK mediated signaling pathway causing downregulation of 8-oxoG-DNA glycosylase levels in glial cells.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {53}, number = {}, pages = {302-319}, doi = {10.1016/j.biocel.2014.05.038}, pmid = {24907397}, issn = {1878-5875}, mesh = {Animals ; Apoptosis/drug effects/*genetics ; Cysteine/metabolism ; DNA Glycosylases/*biosynthesis ; Diabetic Neuropathies/etiology/*genetics/pathology ; Glucose/administration &amp; dosage ; Humans ; Hyperglycemia/chemically induced/metabolism/pathology ; Lipid Peroxidation/genetics ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Neuroglia/*drug effects/metabolism/pathology ; Oncogene Protein v-akt/metabolism ; *Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Rats ; Signal Transduction/drug effects ; }, abstract = {Glial cells are very important for normal brain function and alterations in their activity due to hyperglycemia, could contribute to diabetes-related cognitive dysfunction. Oxidative insults often cause rapid changes in almost all cells including glial cells. However, pathophysiologic mechanisms that lead to diabetic complications are not completely elucidated. Therefore, we examined whether elevated glucose levels directly or indirectly disrupt antioxidant defense mechanisms causing alterations in signaling pathways, cell cycle dysregulation, and reactive oxygen/nitrogen species-mediated apoptosis in glial cells. Findings of this study demonstrated that exposure of glial cells to high glucose markedly induces cellular and molecular injuries, as evidenced by elevated levels of reactive oxygen/nitrogen species, biomolecules damage, cell cycle dysregulation, decrease in antioxidant enzymes, and decrease in cell viability. Pretreatment of cells with N-acetyl-L-cysteine reduced high glucose-induced cytotoxicity by increasing the levels of antioxidant enzymes, and decreasing the number of apoptotic cells. Further, at molecular level high glucose treatment resulted in a significant increase in phosphorylation of Akt, MAPKs, tuberin, down regulation of 8-oxoG-DNA glycosylase and increase in 8-hydroxydeoxyguanosine accumulations. Pretreatment of cells with N-acetyl-L-cysteine, phosphatidylinositol3-kinase/Akt and ERK1/2 inhibitors completely abolished the apoptotic effects of high glucose. Moreover, N-acetyl-L-cysteine significantly inhibited reactive oxygen/nitrogen species generation, elevated antioxidants levels, inhibited Akt, ERK1/2, tuberin phosphorylation, decreased 8-hydroxydeoxyguanosine accumulation and upregulated 8-oxoG-DNA glycosylase expression. Our results demonstrate that high glucose induces apoptosis and inhibits proliferation of glial cells, which may be mediated by the phosphorylation of tuberin, down regulation of 8-oxoG-DNA glycosylase and 8-hydroxydeoxyguanosine accumulation via activation of Akt and ERK1/2MAPK pathways.}, }
@article {pmid24905050, year = {2014}, author = {Kim, KA and Kook, SH and Song, JH and Lee, JC}, title = {A phenolic acid phenethyl urea derivative protects against irradiation-induced osteoblast damage by modulating intracellular redox state.}, journal = {Journal of cellular biochemistry}, volume = {115}, number = {11}, pages = {1877-1887}, doi = {10.1002/jcb.24857}, pmid = {24905050}, issn = {1097-4644}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Line ; Cell Proliferation/drug effects/radiation effects ; Gene Expression Regulation/drug effects/radiation effects ; Humans ; Lipid Peroxidation/drug effects/radiation effects ; Mice ; Osteoblasts/cytology/*drug effects/*radiation effects ; Radiation-Protective Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; Styrenes/pharmacology ; Urea/*analogs &amp; derivatives/pharmacology ; }, abstract = {Because irradiation may cause osteoradionecrosis, antioxidant supplementation is often used to suppress irradiation-mediated injury. This study examined whether a synthetic phenethyl urea compound, (E)-1-(3,4-dihydroxyphenethyl)-3-(3,4-dihydroxystyryl)urea (DPDS-U), prevents irradiation-mediated cellular damage in MC3T3-E1 osteoblastic cells. A relatively high dose of irradiation (>4 Gy) decreased cell viability and proliferation and induced DNA damage and cell cycle arrest at the G(2)/M phase with the attendant increase of cyclin B1. Irradiation with 8 Gy induced intracellular reactive oxygen species (ROS) production and lipid peroxidation, and reduced glutathione content and superoxide dismutase activity in the cells. These events were significantly suppressed by treatment with 200 µM DPDS-U or 5 mM N-acetyl cysteine (NAC). DPDS-U or irradiation alone significantly increased heme oxygenase-1 (HO-1) expression and nuclear factor E2 p45-related factor-2 (Nrf2) nuclear translocation. Interestingly, pretreatment with DPDS-U facilitated irradiation-induced activation of the Nrf2/HO-1 pathway. The potential of DPDS-U to mediate HO-1 induction and protect against irradiation-mediated cellular damage was almost completely attenuated by transient transfection with Nrf2-specific siRNA or treatment with a pharmacological HO-1 inhibitor, zinc protoporphyrin IX. Additional experiments revealed that DPDS-U induced a radioprotective mechanism that differs from that induced by NAC through activation of Nrf2/HO-1 signaling. Collectively, our data suggest that DPDS-U-induced radioprotection is due to its dual function as an antioxidant to remove directly excessive intracellular ROS and as a prooxidant to stimulate intracellular redox-sensitive survival signal.}, }
@article {pmid24904757, year = {2014}, author = {Yip, SW and Potenza, MN}, title = {Treatment of Gambling Disorders.}, journal = {Current treatment options in psychiatry}, volume = {1}, number = {2}, pages = {189-203}, pmid = {24904757}, issn = {2196-3061}, support = {RC1 DA028279/DA/NIDA NIH HHS/United States ; RL1 AA017539/AA/NIAAA NIH HHS/United States ; T32 DA007238/DA/NIDA NIH HHS/United States ; UL1 TR000142/TR/NCATS NIH HHS/United States ; }, abstract = {Preclinical and clinical research implicate several neurotransmitter systems in the pathophysiology of gambling disorder (GD). In particular, neurobiological research suggests alterations in serotonergic, dopaminergic, glutamatergic and opioidergic functioning. The relative efficacy of medications targeting these systems remains a topic of ongoing research, and there is currently no Food and Drug Administration (FDA) approved medication with an indication for GD. Considering co-occurring disorders may be particularly important when devising a treatment plan for GD: extant data suggest that the opioid antagonist naltrexone may by the most effective form of current pharmacotherapy for GD, particularly for individuals with a co-occurring substance-use disorder (SUD) or with a family history of alcoholism. In contrast, lithium or other mood stabilizers may be most effective for GD for patients presenting with a co-occurring bipolar-spectrum disorder (BSD). Further, serotonin reuptake inhibitors (SRIs) may be efficacious in reducing GD symptoms for individuals also presenting with a (non-BSD) mood or anxiety disorder. Finally, elevated rates of GD (and other Impulse Control Disorders; ICDs) have been noted among individuals with Parkinson's Disease (PD), and clinicians should assess for vulnerability to GD when considering treatment options for PD. Reducing levodopa or dopamine agonist (DA) dosages may partially reduce GD symptoms among patients with co-occurring PD. For GD patients not willing to consider drug treatment, n-acetyl cysteine or behavioral therapies may be effective. Ongoing research into the effectiveness of combined behavioral and pharmacotherapies is being conducted; thus combined treatments should also be considered.}, }
@article {pmid24901993, year = {2014}, author = {Zelnikar, M and Benčina, M and Jerala, R and Manček-Keber, M}, title = {Vanadate from air pollutant inhibits hrs-dependent endosome fusion and augments responsiveness to toll-like receptors.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e99287}, pmid = {24901993}, issn = {1932-6203}, mesh = {Air Pollutants/*chemistry ; Animals ; Cell Line, Tumor ; Endosomal Sorting Complexes Required for Transport/genetics/*metabolism ; Endosomes/*drug effects/metabolism ; HEK293 Cells ; Humans ; Lipopolysaccharides/pharmacology ; Lymphocyte Antigen 96/genetics/metabolism ; Mice ; Phosphoproteins/genetics/*metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 4/genetics/*metabolism ; Vanadates/chemistry/*toxicity ; }, abstract = {There is a well-established association between exposure to air pollutants and pulmonary injuries. For example, metals found in ROFA (residual oil fly ash) increase susceptibility of mice as well as humans to microbial infections. In our research, we have found that vanadate substantially increased the response of several Toll-like receptors (TLRs) to stimulation with their ligands. Although vanadate caused generation of reactive oxygen species (ROS), the addition of ROS scavenger N-acetyl cysteine (NAC) had no effect on augmented lipopolysaccharide (LPS) stimulation. We further showed that vanadate inhibits endosome fusion. This effect was determined by measuring the size of endosomes, NF-κB activity and TLR4 degradation in Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) overexpressed cells. Moreover, we identified the role of Hrs phosphorylation in these processes. Based on our findings, we can conclude that vanadate potentiates TLR4 activity by increasing Hrs phosphorylation status, reducing the size of Hrs/TLR4-positive endosomes and impacting TLR4 degradation, thus contributing to the detrimental effects of air pollutants on human health.}, }
@article {pmid24898644, year = {2014}, author = {Bueche, CZ and Garz, C and Stanaszek, L and Niklass, S and Kropf, S and Bittner, D and Härtig, W and Reymann, KG and Heinze, HJ and Carare, RO and Schreiber, S}, title = {Impact of N-Acetylcysteine on cerebral amyloid-β plaques and kidney damage in spontaneously hypertensive stroke-prone rats.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {42 Suppl 3}, number = {}, pages = {S305-13}, doi = {10.3233/JAD-132615}, pmid = {24898644}, issn = {1875-8908}, mesh = {Acetylcysteine/*therapeutic use ; Amyloid beta-Peptides/*metabolism ; Analysis of Variance ; Animals ; Blood-Brain Barrier/drug effects/physiopathology ; Cerebral Cortex/*drug effects/metabolism ; Cerebral Small Vessel Diseases/*complications/etiology ; Disease Models, Animal ; Fibronectins/metabolism ; Free Radical Scavengers/*therapeutic use ; *Kidney Diseases/drug therapy/etiology/pathology ; Lectins ; Male ; Plaque, Amyloid/prevention &amp; control ; Platelet Membrane Glycoproteins/metabolism ; Rats ; Rats, Inbred SHR ; }, abstract = {BACKGROUND: Cerebral small vessel disease (CSVD) in spontaneously hypertensive stroke prone rats (SHRSP) is accompanied by parenchymal amyloid-β (Aβ) deposition in the brain and by hypertensive nephropathy with tubulointerstitial damage. N-acetylcysteine (NAC) promotes blood-brain barrier (BBB) breakdown in SHRSP and may thus accelerate the failure of vascular and perivascular clearance of Aβ.<br><br>OBJECTIVE: In this study, we test the hypothesis that treatment with NAC increases the cerebral A&#x3b2; load and improves renal damage in the SHRSP model.<br><br>METHODS: A total of 46 SHRSP (ages 18-44 weeks) were treated daily with NAC (12 mg/kg body weight) and 74 no-treated age-matched SHRSP served as controls. The prevalence of parenchymal A&#x3b2; load, IgG positive small vessels, and small perivascular bleeds was assessed in different brain regions. Tubulointerstitial kidney damage was assessed through a) the presence of erythrocytes in peritubular capillaries and b) tubular protein cylinders.<br><br>RESULTS: SHRSP treated with NAC had an age-dependent increase of BBB breakdown (assessed by the presence of IgG positive small vessels) and small perivascular bleeds, mainly in the cortex. NAC significantly increased the A&#x3b2; plaque load in the cortex while the number of parenchymal amyloid deposits in the remaining brain areas including basal ganglia, hippocampus, thalamus, and corpus callosum were unchanged. There were no significant treatment effects on tubulointerstitial kidney damage.<br><br>CONCLUSION: The impact of NAC on cerebral cortical plaque load increase may result from the vascular pathology of SHRSP that accompanies BBB breakdown, leading to the failure of amyloid clearance mechanisms. It remains to be seen whether in humans chronic NAC intake may increase amyloid load in the aging human brain and dementia.}, }
@article {pmid24894173, year = {2014}, author = {Li, L and Yue, GG and Pu, JX and Sun, HD and Fung, KP and Leung, PC and Han, QB and Lau, CB and Leung, PS}, title = {Eriocalyxin B-induced apoptosis in pancreatic adenocarcinoma cells through thiol-containing antioxidant systems and downstream signalling pathways.}, journal = {Current molecular medicine}, volume = {14}, number = {5}, pages = {673-689}, doi = {10.2174/1566524014666140603102459}, pmid = {24894173}, issn = {1875-5666}, mesh = {Animals ; Antioxidants/*metabolism ; Apoptosis/*drug effects ; Cell Line, Tumor ; Diterpenes/*pharmacology/*therapeutic use ; Glutathione/metabolism ; Humans ; Male ; Mice ; Mice, Nude ; Pancreatic Neoplasms/*drug therapy/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {Thiol-containing antioxidant systems play an important role in regulating cellular redox homeostasis. Several anti-cancer agents act by targeting these systems by inducing the production of reactive oxygen species (ROS). Our earlier studies have shown that Eriocalyxin B (EriB), a diterpenoid isolated from Isodon eriocalyx, possesses anti-pancreatic tumour activities in vitro and in vivo. The present study further demonstrated that only thiol-containing antioxidants, N-acetylcysteine (NAC) or dithiothreitol (DTT), inhibited EriB-induced cytotoxicity and apoptosis. EriB suppressed the glutathione and thioredoxin antioxidant systems, thus increasing the intracellular ROS levels and regulating the MAPK, NFκB pathways. Treatment with EriB depleted the intracellular thiol-containing proteins in CAPAN-2 cells. In vivo studies also showed that EriB treatment (2.5 mg/kg) reduced the pancreatic tumour weights significantly in nude mice with increased superoxide levels. Taken together, our results shed important new light on the molecular mechanisms of EriB acting as an apoptogenic agent and its therapeutic potential for pancreatic cancer.}, }
@article {pmid24892995, year = {2014}, author = {Wang, G and Wang, J and Luo, X and Ansari, GA and Khan, MF}, title = {Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity.}, journal = {PloS one}, volume = {9}, number = {6}, pages = {e98660}, pmid = {24892995}, issn = {1932-6203}, support = {P30 ES006676/ES/NIEHS NIH HHS/United States ; R01 ES016302/ES/NIEHS NIH HHS/United States ; ES016302/ES/NIEHS NIH HHS/United States ; P30ES06676/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Autoantibodies/blood/immunology ; Autoimmunity/*drug effects ; Female ; Glutathione/blood/metabolism ; Liver/drug effects/metabolism ; Mice ; Mice, Mutant Strains ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Trichloroethylene/*pharmacology ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, has been linked to a variety of autoimmune diseases (ADs) including SLE, scleroderma and hepatitis. Mechanisms involved in the pathogenesis of ADs are largely unknown. Earlier studies from our laboratory in MRL+/+ mice suggested the contribution of oxidative/nitrosative stress in TCE-induced autoimmunity, and N-acetylcysteine (NAC) supplementation provided protection by attenuating oxidative stress. This study was undertaken to further evaluate the contribution of nitrosative stress in TCE-mediated autoimmunity and to identify proteins susceptible to nitrosative stress. Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, ∼ 250 mg/kg/day via drinking water). TCE exposure led to significant increases in serum anti-nuclear and anti-histone antibodies together with significant induction of iNOS and increased formation of nitrotyrosine (NT) in sera and livers. Proteomic analysis identified 14 additional nitrated proteins in the livers of TCE-treated mice. Furthermore, TCE exposure led to decreased GSH levels and increased activation of NF-κB. Remarkably, NAC supplementation not only ameliorated TCE-induced nitrosative stress as evident from decreased iNOS, NT, nitrated proteins, NF-κB p65 activation and increased GSH levels, but also the markers of autoimmunity, as evident from decreased levels of autoantibodies in the sera. These findings provide support to the role of nitrosative stress in TCE-mediated autoimmune response and identify specific nitrated proteins which could have autoimmune potential. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for designing therapeutic strategies.}, }
@article {pmid24892517, year = {2014}, author = {Steinritz, D and Schmidt, A and Simons, T and Ibrahim, M and Morguet, C and Balszuweit, F and Thiermann, H and Kehe, K and Bloch, W and Bölck, B}, title = {Chlorambucil (nitrogen mustard) induced impairment of early vascular endothelial cell migration - effects of α-linolenic acid and N-acetylcysteine.}, journal = {Chemico-biological interactions}, volume = {219}, number = {}, pages = {143-150}, doi = {10.1016/j.cbi.2014.05.015}, pmid = {24892517}, issn = {1872-7786}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents, Alkylating/*metabolism/toxicity ; Cell Movement/drug effects/*physiology ; Cell Polarity/physiology ; Chlorambucil/*metabolism/toxicity ; Endothelial Cells ; Endothelium, Vascular/cytology/*metabolism ; Free Radical Scavengers/pharmacology ; Immunohistochemistry ; Membrane Potential, Mitochondrial ; Mice ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; alpha-Linolenic Acid/*pharmacology ; }, abstract = {Alkylating agents (e.g. sulfur and nitrogen mustards) cause a variety of cell and tissue damage including wound healing disorder. Migration of endothelial cells is of utmost importance for effective wound healing. In this study we investigated the effects of chlorambucil (a nitrogen mustard) on early endothelial cells (EEC) with special focus on cell migration. Chlorambucil significantly inhibited migration of EEC in Boyden chamber and wound healing experiments. Cell migration is linked to cytoskeletal organization. We therefore investigated the distribution pattern of the Golgi apparatus as a marker of cell polarity. Cells are polarized under control conditions, whereas chlorambucil caused an encircling perinuclear position of the Golgi apparatus, indicating non-polarized cells. ROS are discussed to be involved in the pathophysiology of alkylating substances and are linked to cell migration and cell polarity. Therefore we investigated the influence of ROS-scavengers (α-linolenic acid (ALA) and N-acetylcysteine (NAC)) on the impaired EEC migration. Both substances, in particular ALA, improved EEC migration. Notably ALA restored cell polarity. Remarkably, investigations of ROS and RNS biomarkers (8-isoprostane and nitrotyrosine) did not reveal a significant increase after chlorambucil exposure when assessed 24h post exposure. A distinct breakdown of mitochondrial membrane potential (measured by TMRM) that recovered under ALA treatment was observed. In conclusion our results provide compelling evidence that the alkylating agent chlorambucil dramatically impairs directed cellular migration, which is accompanied by perturbations of cell polarity and mitochondrial membrane potential. ALA treatment was able to reconstitute cell polarity and to stabilize mitochondrial potential resulting in improved cell migration.}, }
@article {pmid24891925, year = {2014}, author = {Hung, KY and Liu, SY and Yang, TC and Liao, TL and Kao, SH}, title = {High-dialysate-glucose-induced oxidative stress and mitochondrial-mediated apoptosis in human peritoneal mesothelial cells.}, journal = {Oxidative medicine and cellular longevity}, volume = {2014}, number = {}, pages = {642793}, pmid = {24891925}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cells, Cultured ; Cytochromes c/metabolism ; DNA Damage/drug effects ; Dialysis Solutions/pharmacology ; Epithelial Cells/cytology/drug effects/*metabolism ; Glucose/*pharmacology ; Humans ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*metabolism ; Oxidative Stress/*drug effects ; Peritoneum/cytology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Human peritoneal mesothelial cells (HPMCs) are a critical component of the peritoneal membrane and play a pivotal role in dialysis adequacy. Loss of HPMCs can contribute to complications in peritoneal dialysis. Compelling evidence has shown that high-dialysate glucose is a key factor causing functional changes and cell death in HPMCs. We investigated the mechanism of HPMC apoptosis induced by high-dialysate glucose, particularly the role of mitochondria in the maintenance of HPMCs. HPMCs were incubated at glucose concentrations of 5 mM, 84 mM, 138 mM, and 236 mM. Additionally, N-acetylcysteine (NAC) was used as an antioxidant to clarify the mechanism of high-dialysate-glucose-induced apoptosis. Exposing HPMCs to high-dialysate glucose resulted in substantial apoptosis with cytochrome c release, followed by caspase activation and poly(ADP-ribose) polymerase cleavage. High-dialysate glucose induced excessive reactive oxygen species production and lipid peroxidation as well as oxidative damage to DNA. Mitochondrial fragmentation, multiple mitochondrial DNA deletions, and dissipation of the mitochondrial membrane potential were also observed. The mitochondrial dysfunction and cell death were suppressed using NAC. These results indicated that mitochondrial dysfunction is one of the main causes of high-dialysate-glucose-induced HPMC apoptosis.}, }
@article {pmid24889421, year = {2014}, author = {Wu, XY and Luo, AY and Zhou, YR and Ren, JH}, title = {N-acetylcysteine reduces oxidative stress, nuclear factor‑κB activity and cardiomyocyte apoptosis in heart failure.}, journal = {Molecular medicine reports}, volume = {10}, number = {2}, pages = {615-624}, pmid = {24889421}, issn = {1791-3004}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Dinoprost/analogs &amp; derivatives/analysis/blood ; Disease Models, Animal ; Glutathione/analysis ; Heart Failure/metabolism/pathology ; Hemodynamics ; I-kappa B Proteins/metabolism ; Myocardium/metabolism ; Myocytes, Cardiac/cytology/drug effects ; NF-KappaB Inhibitor alpha ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rabbits ; Transcription Factor RelA/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {The roles of oxidative stress on nuclear factor (NF)‑κB activity and cardiomyocyte apoptosis during heart failure were examined using the antioxidant N‑acetylcysteine (NAC). Heart failure was established in Japanese white rabbits with intravenous injections of doxorubicin, with ten rabbits serving as a control group. Of the rabbits with heart failure, 12 were not treated (HF group) and 13 received NAC (NAC group). Cardiac function was assessed using echocardiography and hemodynamic analysis. Myocardial cell apoptosis, apoptosis‑related protein expression, NF‑κBp65 expression and activity, total anti‑oxidative capacity (tAOC), 8‑iso‑prostaglandin F2α (8‑iso‑PGF2α) expression and glutathione (GSH) expression levels were determined. In the HF group, reduced tAOC, GSH levels and Bcl‑2/Bax ratios as well as increased 8‑iso‑PGF2α levels and apoptosis were observed (all P<0.05), which were effects that were attenuated by the treatment with NAC. NF‑κBp65 and iNOS levels were significantly higher and the P‑IκB‑α levels were significantly lower in the HF group; expression of all three proteins returned to pre‑HF levels following treatment with NAC. Myocardial cell apoptosis was positively correlated with left ventricular end-diastolic pressure (LVEDP), NF‑κBp65 expression and 8‑iso‑PGF2α levels, but negatively correlated with the maximal and minimal rates of increase in left ventricular pressure (+dp/dtmax and ‑dp/dtmin, respectively) and the Bcl‑2/Bax ratio (all P<0.001). The 8‑iso‑PGF2α levels were positively correlated with LVEDP and negatively correlated with +dp/dtmax and ‑dp/dtmin (all P<0.001). The present study demonstrated that NAC increased the antioxidant capacity, decreased the NF‑κB activation and reduced myocardial cell apoptosis in an in vivo heart failure model.}, }
@article {pmid26816073, year = {2014}, author = {Çavuş, UY and Yılmaz, A and Aytekin, MN and Taburcu, G and Albayrak, A and Yıldırım, S and Ağır, I}, title = {Efficacy of N-acetylcysteine on neuroclinical, biochemical, and histopathological parameters in experimental spinal cord trauma: comparison with methylprednisolone.}, journal = {European journal of trauma and emergency surgery : official publication of the European Trauma Society}, volume = {40}, number = {3}, pages = {363-371}, pmid = {26816073}, issn = {1863-9941}, abstract = {BACKGROUND: N-acetylcysteine (NAC) is an antioxidant agent that has been shown to have beneficial effects when treating various diseases. The aim of this study was to investigate the effects of NAC on spinal cord injury in an experimental rat model.<br><br>METHODS: A total of 48 adult male wistar albino rats were divided into six groups. Group C included the control rats, group L included the rats that underwent laminectomy, and group T included the rats in which spinal cord trauma was induced by the weight-drop method after laminectomy. Groups M (the methylprednisolone group), N (the NAC group), and MN (the methylprednisolone&#xa0;+&#xa0;NAC group) were the treatment groups. In the fourth group (group M), 30&#xa0;mg/kg methylprednisolone (MP) was administered as a bolus intraperitoneally (IP), and a standard MP treatmentat a dose of 5.4&#xa0;mg/kg was applied for 24&#xa0;h. In the fifth group (group N), only 300&#xa0;mg/kg NAC was administered as a bolus IP. In the sixth group (group MN), the standard MP treatment and a single 300&#xa0;mg/kg dose of NAC were administered as a bolus IP. The motor functions of the rats were evaluated on the 1st, 7th, and 14th days using the inclined plane test defined by Rivlin and Tator and the motor scale defined by Gale et al. Spinal cord samples were obtained on the 14th day. The samples were evaluated using pathological and biochemical analysis.<br><br>RESULTS: In the neuroclinical assessment, no differences were observed between groups T and M in terms of motor improvement. However, statistically significant differences were observed between group T and groups N and MN (p&#xa0;<&#xa0;0.001, p&#xa0;=&#xa0;0.01, respectively). Statistically significant differences were also seen between group M and groups N and MN on the 1st and 7th days (p&#xa0;<&#xa0;0.017, p&#xa0;<&#xa0;0.01, respectively). Additionally, when groups N and MN were compared with groups T and M,the pathological and biochemical analyses were found to be statistically different (p&#xa0;<&#xa0;0.05, p&#xa0;<&#xa0;0.001, respectively).<br><br>CONCLUSION: It was concluded that NAC treatment and the combined NAC&#xa0;+&#xa0;MP treatment may be more useful for healing in rats with experimental spinal cord injury in terms of neuroclinical, pathological, and biochemical results than MP-only therapy.}, }
@article {pmid26273528, year = {2014}, author = {Kim, JH and Singhal, V and Biswal, S and Thimmulappa, RK and DiGirolamo, DJ}, title = {Nrf2 is required for normal postnatal bone acquisition in mice.}, journal = {Bone research}, volume = {2}, number = {}, pages = {14033}, pmid = {26273528}, issn = {2095-4700}, support = {R01 AR062074/AR/NIAMS NIH HHS/United States ; }, abstract = {A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction. One of the body's front lines in defense against such damage is the transcription factor, Nrf2. This transcription factor regulates a plethora of antioxidant and cellular defense pathways to protect cells from such damage. Despite the breadth of knowledge of both the function of Nrf2 and the effects of reactive species in bone metabolism, the direct role of Nrf2 in skeletal biology has yet to be thoroughly examined. Thus, in the current study, we have examined the role of Nrf2 in postnatal bone metabolism in mice. Mice lacking Nrf2 (Nrf2(-/-)) exhibited a marked deficit in postnatal bone acquisition, which was most severe at 3 weeks of age when osteoblast numbers were 12-fold less than observed in control animals. While primary osteoblasts from Nrf2(-/-) mice functioned normally in vitro, the colony forming capacity of bone marrow stromal cells (BMSCs) from these mice was significantly reduced compared to controls. This defect could be rescued through treatment with the radical scavenger N-acetyl cysteine (NAC), suggesting that increased reactive species stress might impair early osteoblastogenesis in BMSCs and lead to the failure of bone acquisition observed in Nrf2(-/-) animals. Taken together, these studies suggest Nrf2 represents a key pathway in regulating bone metabolism, which may provide future therapeutic targets to treat osteoporosis.}, }
@article {pmid25960933, year = {2014}, author = {Gruenbacher, G and Nussbaumer, O and Gander, H and Steiner, B and Leonhartsberger, N and Thurnher, M}, title = {Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism.}, journal = {Oncoimmunology}, volume = {3}, number = {8}, pages = {e953410}, pmid = {25960933}, issn = {2162-4011}, abstract = {The potentially oncogenic mevalonate pathway provides building blocks for protein prenylation and induces cell proliferation and as such is an important therapeutic target. Among mevalonate metabolites, only isopentenyl pyrophosphate (IPP) has been considered to be an immunologically relevant antigen for primate-specific, innate-like Vγ9Vδ2 T cells with antitumor potential. We show here that Vγ9Vδ2 T cells pretreated with the stress-related, inflammasome-dependent cytokine interleukin 18 (IL-18) were potently activated not only by IPP but also by all downstream isoprenoid pyrophosphates that exhibit combined features of antigens and cell-extrinsic metabolic cues. Vγ9Vδ2 T cells induced this way effectively proliferated even under severe lymphopenic conditions and the antioxidant N-acetylcysteine significantly improved reconstitution of γδ T cells predominantly with a central memory phenotype. The homeostatic cytokine IL-15 induced the differentiation of effector cells in an antigen-independent fashion, which rapidly produced abundant interferon γ (IFNγ) upon antigen re-encounter. IL-15 induced effector γδ T cells displayed increased levels of the cytotoxic lymphocyte-associated proteins CD56, CD96, CD161 and perforin. In response to stimulation with isoprenoid pyrophosphates, these effector cells upregulated surface expression of CD107a and exhibited strong cytotoxicity against tumor cells in vitro. Our data clarify understanding of innate immunosurveillance mechanisms and will facilitate the controlled generation of robust Vγ9Vδ2 T cell subsets for effective cancer immunotherapy.}, }
@article {pmid25743345, year = {2014}, author = {Arai, T and Koyama, R and Yuasa, M and Kitamura, D and Mizuta, R}, title = {Acrolein, a highly toxic aldehyde generated under oxidative stress in vivo, aggravates the mouse liver damage after acetaminophen overdose.}, journal = {Biomedical research (Tokyo, Japan)}, volume = {35}, number = {6}, pages = {389-395}, doi = {10.2220/biomedres.35.389}, pmid = {25743345}, issn = {1880-313X}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/pharmacology ; Acrolein/*toxicity ; Animals ; Blotting, Western ; Cell Culture Techniques ; Chemical and Drug Induced Liver Injury/etiology/metabolism/*physiopathology ; Drug Overdose ; Liver/*drug effects/pathology ; Mesna/pharmacology ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Although acetaminophen-induced liver injury in mice has been extensively studied as a model of human acute drug-induced hepatitis, the mechanism of liver injury remains unclear. Liver injury is believed to be initiated by metabolic conversion of acetaminophen to the highly reactive intermediate N-acetyl p-benzoquinoneimine, and is aggravated by subsequent oxidative stress via reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and the hydroxyl radical (•OH). In this study, we found that a highly toxic unsaturated aldehyde acrolein, a byproduct of oxidative stress, has a major role in acetaminophen-induced liver injury. Acetaminophen administration in mice resulted in liver damage and increased acrolein-protein adduct formation. However, both of them were decreased by treatment with N-acetyl-L-cysteine (NAC) or sodium 2-mercaptoethanesulfonate (MESNA), two known acrolein scavengers. The specificity of NAC and MESNA was confirmed in cell culture, because acrolein toxicity, but not H2O2 or •OH toxicity, was inhibited by NAC and MESNA. These results suggest that acrolein may be more strongly correlated with acetaminophen-induced liver injury than ROS, and that acrolein produced by acetaminophen-induced oxidative stress can spread from dying cells at the primary injury site, causing damage to the adjacent cells and aggravating liver injury.}, }
@article {pmid25610275, year = {2013}, author = {Demiralay, R and Gürsan, N and Erdem, H}, title = {The effects of erdosteine and N-acetylcysteine on apoptotic and antiapoptotic markers in pulmonary epithelial cells in sepsis.}, journal = {The Eurasian journal of medicine}, volume = {45}, number = {3}, pages = {167-175}, pmid = {25610275}, issn = {1308-8734}, abstract = {OBJECTIVE: This study investigated the frequency of apoptosis in rat pulmonary epithelial cells after the injection of an intraperitoneal endotoxin lipopolysaccharide (LPS), the effects of LPS on apoptotic (bax, caspase-3) and antiapoptotic (bcl-2) markers during lung damage, and the protective effects of two known antioxidant agents, erdosteine and N-acetylcysteine (NAC).<br><br>MATERIALS AND METHODS: Male Wistar rats were divided into the following six groups, which included nine rats each: two control groups, two LPS-treated groups, one erdosteine-treated group (150 mg/kg), and one NAC-treated group (150 mg/kg). LPS was injected intraperitoneally at a dosage of 20 mg/kg. Following LPS injection, the antioxidants were orally administered. The rats were sacrificed at 24 h after LPS administration. The levels of apoptosis in bronchiolar and alveolar cells were determined using the TUNEL-staining method. Immunohistochemical staining of cytoplasmic bax, caspase-3, and bcl-2 in the epithelial cells was performed.<br><br>RESULTS: Erdosteine and NAC significantly reduced the rate of LPS-induced pulmonary epithelial cell apoptosis. The effect of NAC on regulating apoptosis was weaker than that of erdosteine. Erdosteine and NAC significantly reduced the local induction of bax and caspase 3 and significantly increased the reduced local production of bcl-2.<br><br>CONCLUSION: These findings suggest that erdosteine and N&#x391;C can effectively protect the lungs from the damaging effects of LPS.}, }
@article {pmid25867938, year = {2013}, author = {Akgül, GG and Yenidogan, E and Gülçelik, MA and Sahin, D and Çolakoglu, MK and Alagöl, H}, title = {[Not Available].}, journal = {Wounds : a compendium of clinical research and practice}, volume = {25}, number = {3}, pages = {68-74}, pmid = {25867938}, issn = {1044-7946}, abstract = {OBJECTIVE: The purpose of this study was to reveal the effect of N-acetylcysteine (NAC) on random-skin flaps in rats.<br><br>INTRODUCTION: N-acetylcysteine is an agent among free radical scavengers which is used primarily as a mucolitic agent. Experimental studies have demonstrated protective effects of NAC on hepatic, renal, lung, and intestinal injuries.<br><br>METHODS: Wistar female rats were divided into 2 groups (control and NAC group), and the NAC group received intramuscular injections for 7 days. Flaps were raised on day 2 and rats were sacrified on day 7. Skin samples from the second cm and fifth cm of the skin flap were collected for biochemical and histopathological examinations.<br><br>RESULTS: The mean necrotic area ratios in the control and NAC group were 38% and 12%, respectively (P <0.001). Malondialdehyde (MDA) levels were significantly lower in skin samples collected from the control group as compared to samples obtained from the NAC group (P = 0.002). Superoxide dismustase (SOD) activity was significantly higher in the NAC group (P < 0.0001). Histopathologically, a significant increase in macrophage and fibroblast activity was observed in the NAC group. Mononuclear cell infiltration and fibroblast activity had increased, especially in samples from the fifth cm of the skin flap in the NAC group. The histopathological evaluation in the NAC group revealed protective effects of NAC.<br><br>CONCLUSIONS: Treatment of rats with NAC significantly reduced flap necrosis and MDA levels while increasing SOD levels. These data suggest that NAC has a protective role in flap survival and demonstrates preventive effects against flap necrosis. &#xfeff;.}, }
@article {pmid25755470, year = {2013}, author = {Ramappa, V and Aithal, GP}, title = {Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management.}, journal = {Journal of clinical and experimental hepatology}, volume = {3}, number = {1}, pages = {37-49}, pmid = {25755470}, issn = {0973-6883}, abstract = {Development of idiosyncratic hepatotoxicity is an intricate process involving both concurrent as well as sequential events determining the direction of the pathways, degree of liver injury and its outcome. Decades of clinical observation have identified a number of drug and host related factors that are associated with an increased risk of antituberculous drug-induced hepatotoxicity, although majority of the studies are retrospective with varied case definitions and sample sizes. Investigations on genetic susceptibility to hepatotoxicity have so far focused on formation and accumulation reactive metabolite as well as factors that contribute to cellular antioxidant defense mechanisms and the environment which can modulate the threshold for hepatocyte death secondary to oxidative stress. Recent advances in pharmacogenetics have promised the development of refined algorithms including drug, host and environmental risk factors that allow better tailoring of medications based on accurate estimates of risk-benefit ratio. Future investigations exploring the pathogenesis of hepatotoxicity should be performed using human tissue and samples whenever possible, so that the novel findings can be translated readily into clinical applications.}, }
@article {pmid25207078, year = {2013}, author = {Kahraman, H and Kurutaş, E and Tokur, M and Bozkurt, S and Cıralık, H and Kabakcı, B and Köksal, N and Balkan, V}, title = {Protective effects of erythropoietin and N-acetylcysteine on methotrexate-induced lung injury in rats.}, journal = {Balkan medical journal}, volume = {30}, number = {1}, pages = {99-104}, pmid = {25207078}, issn = {2146-3123}, abstract = {OBJECTIVE: Methotrexate (MTX) is known to have deleterious side effects on lung tissue. We aimed to investigate the effects of erythropoietin (EPO) and N-acetyl-cysteine (NAC) on MTX-induced lung injury in rats.<br><br>STUDY DESIGN: Animal experiment.<br><br>MATERIAL AND METHODS: Twenty-six female Sprague-Dawley rats were divided into 4 groups. Sham group, 0.3 mL saline; MTX group, 5 mg/kg MTX; EPO group, 5mg/kg MTX and 2000 IU/kg EPO; NAC group, 5 mg/kg MTX and 200 mg/kg NAC were administered once daily for 4 consecutive days. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and inflammation and congestion scores in lung tissues were evaluated.<br><br>RESULTS: In MTX group MDA were significantly higher, CAT and SOD were significantly lower than in sham, EPO and NAC groups (p<0.005). In EPO group MDA, CAT, and SOD were higher, but not significant than those in group NAC (p>0.005). In group MTX both scores were significantly higher than in sham (p<0.005). The congestion score of group MTX was significantly higher than those of group EPO and NAC (p<0.005).<br><br>CONCLUSION: EPO and NAC have significant preventive effects on MTX-induced lung injury in rats. Decreased antioxidant capacity and increased MDA level may cause the oxidative damage in MTX group. Also, higher antioxidant capacity and lower MDA level may be a response to oxidative stress in EPO and NAC groups.}, }
@article {pmid26417226, year = {2013}, author = {Eftekhari, P and Hajizadeh, S and Raoufy, MR and Masjedi, MR and Yang, M and Hansbro, N and Li, JJ and Foster, PS}, title = {Preventive effect of N-acetylcysteine in a mouse model of steroid resistant acute exacerbation of asthma.}, journal = {EXCLI journal}, volume = {12}, number = {}, pages = {184-192}, pmid = {26417226}, issn = {1611-2156}, abstract = {Oxidative stress appears to have an important role in glucocorticoid insensitivity, as a crucial problem in asthma therapy. We studied the preventive effect of antioxidant N-acetylcysteine (NAC) on the airway hyper-responsiveness (AHR) and the accumulation of inflammatory cells in the airways in an animal model of steroid resistant acute exacerbation of asthma. Systemically sensitized Balb/C mice were exposed to Ovalbumin aerosol on days 13, 14, 15 and 16, followed by intratracheal lipopolysaccharide (LPS) to induce acute exacerbation. NAC (intraperitoneal, 320 mg/kg 30 min before and 12 hours after each challenge) reduced hyper-responsiveness with/out dexamethasone. LPS application caused neutrophilia in bronchoalveolar lavage fluid (BALF) and eosinophil count was higher than respective control in BALF as well as neutrophils after dexamethasone treatment. NAC significantly decreased neutrophil and eosinophil count in BALF as well as inflammatory cytokines (IL-13 and IL-5).We concluded that addition of NAC to asthma therapy has beneficial preventive effects in an animal model of steroid resistant acute exacerbation of asthma.}, }
@article {pmid25509127, year = {2013}, author = {Liublinskaia, OG and Kirpichnikova, KM and Gamaleĭ, IA}, title = {[Comparative antioxidant action on the level of reactive oxygen species in normal and transformed fibroblasts].}, journal = {Tsitologiia}, volume = {55}, number = {10}, pages = {732-736}, pmid = {25509127}, issn = {0041-3771}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Line, Transformed ; Fluoresceins ; Fluorescent Dyes ; Hydrogen Peroxide/pharmacology ; Mice ; NIH 3T3 Cells ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/*metabolism ; Thioctic Acid/analogs &amp; derivatives/pharmacology ; }, abstract = {We studied the changes in the level of reactive oxygen species (ROS) in normal (3T3) and transformed (3T3-SV40) murine fibroblasts under the antioxidant action for 15 min using fluorescent probe carbo- xy-H2DCFDA. We have shown that N-acetylcysteine (NAC) decreased ROS level in both cellular types. Another antioxidant, alpha-lipoic acid (ALA), and its reduced form, dihydrolipoic acid (DHLA), caused the prooxidant effects. Both ALA and DHLA in the concentration range of 0.1-1.25 mM increased ROS level in dose dependent manner in both cellular types. The ability of ALA and DHLA to activate hydrogen peroxide production is discussed.}, }
@article {pmid25383193, year = {2013}, author = {Click, RE}, title = {Anticancer activity and chemoprevention of xenobiotic organosulfurs in preclinical model systems.}, journal = {Oncology discovery}, volume = {1}, number = {4}, pages = {}, pmid = {25383193}, issn = {2052-6199}, support = {R01 AI027331/AI/NIAID NIH HHS/United States ; R01 CA023678/CA/NCI NIH HHS/United States ; }, abstract = {There seems to be little doubt that xenobiotic and plant derived organosulfur compounds have enormous benefits for in vitro cellular functions and for a multitude of diseases, including cancer. Since there are numerous reviews on anticancer activities of plant organosulfurs, the focus herein will be on alterations associated with xenobiotic organosulfurs. Benefits of 2-mercaptoethanol (2-Me), N-Acetyl-cysteine, cysteamine, thioproline, piroxicam, disulfiram, amifostine, sulindac, celecoxib, oltipraz and their derivates on transplanted homologous tumors and on autochthonous cancers with a viral-, radiation-, chemical carcinogen-, and undefined-etiology are assessed. Because all organosulfurs were not tested for activity in each of the etiology categories, comparative evaluations are restricted. In general, all 'appeared' to lower the incidence of cancer irrespective of etiology; however, since most of these values were determined at ages much younger than at a natural-end-of-life-age, differences most likely, instead, reflect a delayed initiation and/or a slowed progression of tumorigenesis. The poorest, long-term benefits of early intervention protocols occurred for viral- and chemical carcinogen-induced cancers. In addition, once tumorigenesis was beyond the initiation stage, outcomes of organosulfur therapies were extremely poor, indicating that they will not be of significant value as stand alone treatments. More importantly, except for the lifetime prevention of spontaneous and radiation-induced mammary tumors by daily dietary 2-Me, similar life long prevention of tumorigenesis was not achieved with other xenobiotics or any of nature's plant organosulfurs. These results raise an interesting question: Is the variability in incidence found for different organosulfurs associated with (a) their structure, (b) the length of the untreated latency period, (c) treatment duration/dose, and/or (d) the etiology-inducing agent?}, }
@article {pmid24967237, year = {2013}, author = {Nematbakhsh, M and Pezeshki, Z}, title = {Sex-Related Difference in Nitric Oxide Metabolites Levels after Nephroprotectant Supplementation Administration against Cisplatin-Induced Nephrotoxicity in Wistar Rat Model: The Role of Vitamin E, Erythropoietin, or N-Acetylcysteine.}, journal = {ISRN nephrology}, volume = {2013}, number = {}, pages = {612675}, pmid = {24967237}, issn = {2314-405X}, abstract = {Background. Nitric oxide (NO) concentration in serum is altered by cisplatin (CP), and NO influences CP-induced nephrotoxicity. The effect of nephroprotectant agent supplementation (vitamin E, human recombinant erythropoietin (EPO), or n-acetylcysteine (NAC)) on the NO metabolites levels after CP administration in the two genders was determined. Methods. Sixty-four adult Wistar rats were randomly divided into 10 groups. Male and female rats in different groups received vehicle (saline), CP (7 mg/kg) alone, CP plus EPO (100 IU/kg), CP plus vitamin E (250 mg/kg), and CP plus NAC (600 mg/kg). CP was administrated as a single dose, but the supplementations were given for a period of 7 days. Results. In male rats, the serum levels of total NO metabolites (NO x) and nitrite were increased significantly (P < 0.05) by CP. However, vitamin E significantly reduced the serum levels of these metabolites, which was increased by administration of CP (P < 0.05), and such findings were not observed for female rats. The EPO or NAC did not influence NO metabolites neither in male rats nor in female rats. Conclusion. Although vitamin E, EPO, and NAC are reported to be nephroprotectant agents against CP-induced nephrotoxicity, only vitamin E could reduce the level of all NO metabolites only in male rats.}, }
@article {pmid25755441, year = {2012}, author = {Devarbhavi, H}, title = {An Update on Drug-induced Liver Injury.}, journal = {Journal of clinical and experimental hepatology}, volume = {2}, number = {3}, pages = {247-259}, pmid = {25755441}, issn = {0973-6883}, abstract = {Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of hepatotoxicity, the pathogenesis and associated risk factors besides its clinical management.}, }
@article {pmid25755319, year = {2011}, author = {Atluri, DK and Prakash, R and Mullen, KD}, title = {Pathogenesis, diagnosis, and treatment of hepatic encephalopathy.}, journal = {Journal of clinical and experimental hepatology}, volume = {1}, number = {2}, pages = {77-86}, pmid = {25755319}, issn = {0973-6883}, abstract = {Hepatic encephalopathy (HE) is a neuropsychiatric disorder seen in patients with advanced liver disease or porto-systemic shunts. Based on etiology and severity of HE, the World Congress of Gastroenterology has divided HE into categories and sub-categories. Many user-friendly computer-based neuropsychiatric tests are being validated for diagnosing covert HE. Currently, emphasis is being given to view HE deficits as a continuous spectrum rather than distinct stages. Ammonia is believed to play crucial role in pathogenesis of HE via astrocyte swelling and cerebral edema. However, evidence has been building up which supports the synergistic role of oxidative stress, inflammation and neurosteroids in pathogenesis of HE. At present, treatment of HE aims at decreasing the production and intestinal absorption of ammonia. But as the role of new pathogenetic mechanisms becomes clear, many potential new treatment strategies may become available for clinician.}, }
@article {pmid25384734, year = {2009}, author = {Bernardo, M and Dodd, S and Gama, CS and Copolov, DL and Dean, O and Kohlmann, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Bush, AI and Berk, M}, title = {Effects of N-acetylcysteine on substance use in bipolar disorder: A randomised placebo-controlled clinical trial.}, journal = {Acta neuropsychiatrica}, volume = {21}, number = {6}, pages = {285-291}, doi = {10.1111/j.1601-5215.2009.00397.x}, pmid = {25384734}, issn = {0924-2708}, abstract = {OBJECTIVE: To evaluate the effect of N-acetylcysteine (NAC) on substance use in a double-blind, placebo-controlled trial of NAC in bipolar disorder. It is hypothesised that NAC will be superior to placebo for reducing scores on the Clinical Global Impressions scale for Substance Use (CGI-SU).<br><br>METHODS: Participants were randomised to a 6-months of treatment with 2 g/day NAC (n = 38) or placebo (n = 37). Substance use was assessed at baseline using a Habits instrument. Change in substance use was assessed at regular study visits using the CGI-SU.<br><br>RESULTS: Among the 75 participants 78.7% drank alcohol (any frequency), 45.3% smoked tobacco and 92% consumed caffeine. Other substances were used by fewer than six participants. Caffeine use was significantly lower for NAC-treated participants compared to placebo at week 2 of treatment but not at other study visits.<br><br>CONCLUSIONS: NAC appeared to have little effect on the participants who were using substances. A larger study on a substance-using population will be necessary to determine if NAC may be a useful treatment for substance use.}, }
@article {pmid25949275, year = {2009}, author = {Lameire, N and van Biesen, W and Hoste, E and Vanholder, R}, title = {The prevention of acute kidney injury an in-depth narrative review: Part 2: Drugs in the prevention of acute kidney injury.}, journal = {NDT plus}, volume = {2}, number = {1}, pages = {1-10}, pmid = {25949275}, issn = {1753-0784}, abstract = {The second part of this in-depth clinical review focuses on drugs used in the prevention of AKI in the patient at risk and/or in the management of the patient with incipient AKI. Among the drugs used to maintain a normal renal perfusion pressure, norepinephrine and vasopressin are most commonly used in hypotensive critically ill patients. The most recent RCT did not find a difference between low-dose vasopressin plus norepinephrine and norepinephrine alone in patients with septic shock, suggesting that either approach is reasonable. However, vasopressin may be beneficial in the less severe septic shock subgroup. Loop diuretics may convert an oliguric into a non-oliguric form of AKI that may allow easier fluid and/or nutritional support of the patient. Volume overload in AKI patients is common and diuretics may provide symptomatic benefit in that situation. However, loop diuretics are neither associated with improved survival, nor with better recovery of renal function in AKI. Among the renal vasodilating drugs, the routine administration of dopamine to patients for the prevention of AKI or incipient AKI is no longer justified. On the other hand, although additional studies may be warranted, fenoldopam may appear to be a likely candidate for the prevention of AKI, particularly in critically ill patients, if the positive results obtained in some recent studies are confirmed. Trials with natriuretic peptides were in general inconclusive but despite the fact that nesiritide is currently approved by the FDA only for the treatment of heart failure, this vasodilator may in the future play a role in the prevention of AKI, particularly in association with heart failure and cardiac surgery. The most recent trials seem to confirm a potential positive preventive effect of N-acetylcysteine (NAC), particularly in contrast-induced nephropathy (CIN), NAC alone should never take the place of IV hydration in patients at risk for CIN; fluids likely have a more substantiated benefit. At present, initiation of statin therapy for the prevention of CIN cannot be recommended, but these drugs should not be stopped before a radiological intervention in patients on chronic statin therapy. Rasburicase is very effective in the prevention of acute tumour lysis syndrome. Erythropoietin (EPO) has tissue-protective effects and prevents tissue damage during ischaemia and inflammation, and currently trials are performed with EPO in the prevention of AKI post-cardiac surgery, CIN and post-kidney transplantation. From this review it becomes clear that single-drug therapy will probably never be effective in the prevention of AKI and that multiple agents may be needed to improve outcomes. In addition, drugs should be administered early during the course of the disease.}, }
@article {pmid26549975, year = {2008}, author = {Yedjou, CG and Waters, D and Tchounwou, PB}, title = {N-Acetyl-cysteine Protection Against Lead-Induced Oxidative Stress and Genotoxicity in Human Liver Carcinoma (HepG2) Cells.}, journal = {Metal ions in biology and medicine : proceedings of the ... International Symposium on Metal Ions in Biology and Medicine held ... = Les ions metalliques en biologie et en medecine : ... Symposium international sur les ions metalliques ...}, volume = {10}, number = {}, pages = {419-424}, pmid = {26549975}, issn = {1257-2535}, support = {G12 RR013459/RR/NCRR NIH HHS/United States ; G12 RR013459-010007/RR/NCRR NIH HHS/United States ; G12 RR013459-10/RR/NCRR NIH HHS/United States ; R25 MH057113/MH/NIMH NIH HHS/United States ; }, abstract = {The human liver carcinoma (HepG2) cells as well as other cell lines are particularly susceptible to oxidative damage, and it is therefore important to find agents that protect against this process. N-acetyl-cysteine (NAC) is the acetylated form of L-cysteine. It has an impressive list of protective effects including: antioxidant activity, decrease of the biologically effective dose of carcinogens, anti-inflammatory activity, immunological effects, inhibition of progression to malignancy and metastasis, and protection from the adverse effects of chemopreventive and chemotherapeutic agents. Previous studies in our laboratory have shown that lead nitrate induces cytotoxicity and oxidative stress to HepG2 cells in a dose-dependent manner. In this research, we hypothesized that the antioxidant, n-acetyl-l-cysteine attenuates oxidative stress and genotoxicity, and thereby provides cellular protection against lead toxicity. To this hypothesis, we performed the thiobarbituric acid test for lipid peroxidation and the microgel electrophoresis (comet) assay for genotoxicity. The results generated from the thiobarbituric acid test showed a significant reduction of lipid peroxidation by-product (malondialdehyde) in HepG2 cells co-exposed to NAC and lead nitrate compared to lead nitrate alone. Incubation of HepG2 cells with increasing concentrations of NAC decreased the amount of MDA formation progressively in lead nitrate-treated HepG2 cells. Data obtained from the comet assay indicated a strong dose-response relationship with regard to lead nitrate-induced genotoxic damage in HepG2 cells. However, the addition of NAC in vitro showed a significant reduction (p < 0.05) in the comet tail length, percentage of DNA cleavage, comet tail moment, as well as comet tail arm respectively in cells co-treated with NAC and lead nitrate. Findings from these studies demonstrated that NAC inhibits malondialdehyde (MDA) production and genotoxicity in lead nitrate-treated HepG2 cells in a dose-dependent manner. Under this in vitro condition, NAC was found to be effective in reducing MDA formation, cellular injury, and genotoxic damage in HepG2 cells exposed to lead nitrate.}, }
@article {pmid26368632, year = {2000}, author = {Faux, SP and Houghton, CE}, title = {Cell Signaling in Mesothelial Cells by Asbestos: Evidence for the Involvement of Oxidative Stress in the Regulation of the Epidermal Growth Factor Receptor.}, journal = {Inhalation toxicology}, volume = {12 Suppl 3}, number = {}, pages = {327-336}, doi = {10.1080/08958378.2000.11463242}, pmid = {26368632}, issn = {0895-8378}, abstract = {Asbestos has been shown to stimulate the mitogen-activated protein kinase signaling cascade after autophosphoryiation of the epidermal growth factor recptor (EGF-R), an event important in regulating the response of cells to extracellular signals. In studies reported here, we have examined whether mineral fibers with known carcinogenicity can be discriminated from nonpathogenic fibers by their ability to upregulate expression of EGF-R protein in mesothelial cells. Crocidolite and erionite, two fibrous preparations known to induce mesothelioma, increased expression of EGF-R protein in a time- and dose-dependent manner, whereas milled (nonfibrous) crocidolite and chrysotile asbestos, two preparations with much less or no ability to induce mesothelioma, did not. Intense patterns of EGF-R protein expression were linked to mesothelial cells phagocytosing long fibers as observed by phase-contrast microscopy. To determine the importance of EGF-R expression in these cells, we assessed downstream signaling events in rat pleural mesothelial (RPM) cells by looking at the induction of activator protein-1 (AP-I), a transcription factor that controls the transition to S phase in the cell cycle, leading to cell proliferation. Crocidolite induced AP-I in RPM cells in a dose-dependent manner, and this induction of AP-I in RPM cells was inhibited by coincubation with tyrphostin AG 1478, a potent inhibitor of the EGF-R. To examine the mechanism of induction of EGF-R in RPM cells by asbestos, RPM cells were treated with crocidolite in the presence and absence of the antioxidant N-acetylcysteine (NAC). Reduced glutathione (GSH) was examined as a marker of oxidative stress and the expression of EGF-R protein was measured. Crocidolite asbestos caused a dose-dependent depletion of GSH in RPM cells, and the presence of NAC ameliorated the expression of EGF-R protein by crocidolite. Our data suggest that carcinogenic fibers induce EGF-R via a mechanism involving oxidative stress initiating cell signaling cascades in mesothelial cells leading to cell proliferation and carcinogenesis.}, }
@article {pmid24888787, year = {2014}, author = {Srinivasan, PK and Yagi, S and Nagai, K and Afify, M and Hata, K and Uemoto, S and Tolba, RH}, title = {Impact of oxygen free radicals in rat partial liver transplantation.}, journal = {The Journal of surgical research}, volume = {191}, number = {2}, pages = {469-475}, doi = {10.1016/j.jss.2014.05.002}, pmid = {24888787}, issn = {1095-8673}, mesh = {Acetylcysteine/pharmacology ; Animals ; Free Radicals/metabolism ; Lipid Peroxidation ; *Liver Transplantation ; Male ; Microcirculation ; Organ Preservation ; Oxygen/*metabolism ; Rats ; Rats, Inbred Lew ; }, abstract = {BACKGROUND: Due to the shortage of suitable organs, the demand for partial liver transplantation from living donors has increased worldwide. N-acetylcysteine (NAC) has shown protective effects as a free radical scavenger during hypothermic preservation and warm ischemia-reperfusion liver injury; however, no study has reported the effects in partial liver transplantation. The aim of this study was to analyze the impact of NAC on liver graft microcirculation and graft function after partial liver transplantation in rats.<br><br>METHODS: Orthotopic partial liver transplantations were performed in 40 rats following cold storage in histidine-tryptophan-ketoglutarate solution for 3 h with 20 mM NAC (NAC group, n = 20) or without (control group, n = 20). We assessed portal circulation, graft microcirculation, and biochemical analyses of plasma at 1, 3, 24, and 168 h after portal reperfusion.<br><br>RESULTS: (Control versus NAC, median and range): Portal venous pressure was significantly lower with NAC (P = 0.03). Microcirculation measured by laser Doppler was significantly improved with NAC throughout the time course (P = 0.003). Alanine aminotransferase levels were significantly lower in the NAC group (P < 0.05). Total antioxidative capacity was significantly higher in the NAC group at 1 h after reperfusion (Trolox equivalents: median, 3 &#x3bc;M; range, 2.9-6.7 versus median, 16.45 &#x3bc;M; range, 10.4-18.8). Lipid peroxidation was significantly abrogated in the NAC group (median, 177.6 nmol/mL; range, 75.9-398.1 versus median, 71.5 nmol/mL; range, 58.5-79 at 3 h).<br><br>CONCLUSIONS: This study showed that NAC treatment during cold storage resulted in improved microcirculation and preservation quality of partial liver graft likely because of enhanced antioxidant capacity and reduced lipid peroxidation.}, }
@article {pmid24885281, year = {2014}, author = {Lu, X and Kim-Han, JS and Harmon, S and Sakiyama-Elbert, SE and O'Malley, KL}, title = {The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons.}, journal = {Molecular neurodegeneration}, volume = {9}, number = {}, pages = {17}, pmid = {24885281}, issn = {1750-1326}, support = {R21 NS067561/NS/NINDS NIH HHS/United States ; }, mesh = {Adrenergic Agents/*toxicity ; Animals ; Axonal Transport/*drug effects/physiology ; Disease Models, Animal ; Dopaminergic Neurons/*drug effects/metabolism ; Mice ; Mice, Transgenic ; Microscopy, Confocal ; Mitochondria/*drug effects/metabolism ; Nerve Degeneration/chemically induced/metabolism/pathology ; Oxidopamine/*toxicity ; Parkinson Disease/metabolism/pathology ; }, abstract = {6-hydroxydopamine (6-OHDA) is one of the most commonly used toxins for modeling degeneration of dopaminergic (DA) neurons in Parkinson's disease. 6-OHDA also causes axonal degeneration, a process that appears to precede the death of DA neurons. To understand the processes involved in 6-OHDA-mediated axonal degeneration, a microdevice designed to isolate axons fluidically from cell bodies was used in conjunction with green fluorescent protein (GFP)-labeled DA neurons. Results showed that 6-OHDA quickly induced mitochondrial transport dysfunction in both DA and non-DA axons. This appeared to be a general effect on transport function since 6-OHDA also disrupted transport of synaptophysin-tagged vesicles. The effects of 6-OHDA on mitochondrial transport were blocked by the addition of the SOD1-mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), as well as the anti-oxidant N-acetyl-cysteine (NAC) suggesting that free radical species played a role in this process. Temporally, microtubule disruption and autophagy occurred after transport dysfunction yet before DA cell death following 6-OHDA treatment. The results from the study suggest that ROS-mediated transport dysfunction occurs early and plays a significant role in inducing axonal degeneration in response to 6-OHDA treatment.}, }
@article {pmid24880785, year = {2014}, author = {Peña-Llopis, S and Serrano, R and Pitarch, E and Beltrán, E and Ibáñez, M and Hernández, F and Peña, JB}, title = {N-Acetylcysteine boosts xenobiotic detoxification in shellfish.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {154}, number = {}, pages = {131-140}, doi = {10.1016/j.aquatox.2014.05.006}, pmid = {24880785}, issn = {1879-1514}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Enzyme Activation/drug effects ; Fenitrothion/analysis/metabolism/toxicity ; Free Radical Scavengers/pharmacology ; Glutathione/analysis/metabolism ; Glutathione Reductase/metabolism ; Glutathione Transferase/metabolism ; Humans ; Inactivation, Metabolic ; Mytilus/chemistry/drug effects/metabolism ; Pecten/*drug effects/metabolism ; Shellfish Poisoning/prevention &amp; control ; Water Pollutants, Chemical/analysis/metabolism/toxicity ; Xenobiotics/analysis/*metabolism/toxicity ; }, abstract = {Water pollution represents a threat of increasing importance to human health. Bivalve mollusks are filter-feeding organisms that can accumulate chemical and microbiological contaminants in their tissues from very low concentrations in the water or sediments. Consumption of contaminated shellfish is one of the main causes of seafood poisoning. Thus, marine bivalves are normally depurated in sterilized seawater for 48 h to allow the removal of bacteria. However, this depuration time might be insufficient to eliminate chemical contaminants from their tissues. We have developed a novel technology that accelerates up to fourfold the excretion rate of xenobiotics in bivalves by treatment with the antioxidant and glutathione (GSH) pro-drug N-acetylcysteine (NAC) during the depuration period. NAC improved dose-dependently the detoxification of the organophosphate (OP) pesticide fenitrothion in the mussel Mytilus galloprovincialis, diminishing its levels up to nearly a hundred fold compared to conventional depuration, by enhancing the glutathione S-transferase (GST) activity and inducing the GSH anabolism (GSH synthesis and reduction by glutathione reductase). Notably, this induction in GSH anabolism and GST activity was also observed in uncontaminated bivalves treated with NAC. As the GSH pathway is involved in the detoxification of many pollutants and biotoxins from harmful algal blooms, we validated this proof of principle in king scallops (Pecten maximus) that naturally accumulated the amnesic shellfish poisoning (ASP) toxin domoic acid. We illustrate here a method that enhances the elimination of organic contaminants in shellfish, opening new avenues of depuration of marine organisms.}, }
@article {pmid24877026, year = {2013}, author = {Liu, YB and Gao, X and Deeb, D and Arbab, AS and Gautam, SC}, title = {Pristimerin Induces Apoptosis in Prostate Cancer Cells by Down-regulating Bcl-2 through ROS-dependent Ubiquitin-proteasomal Degradation Pathway.}, journal = {Journal of carcinogenesis &amp; mutagenesis}, volume = {Suppl 6}, number = {}, pages = {005}, pmid = {24877026}, issn = {2157-2518}, support = {R01 CA130948/CA/NCI NIH HHS/United States ; }, abstract = {Pristimerin is a quinonemethide triterpenoid with the potential of a promising anticancer agent. Pristimerin (PM) has shown anticancer activity against a range of cancer cell lines, but its activity for prostate cancer has not been adequately investigated. In the present study we have examined the underlying mechanisms of the apoptotic response of the hormone-sensitive (LNCaP) and hormone-refractory (PC-3) prostate cancer cell lines to PM. Treatment with PM induced apoptosis in both cell lines as characterized by increased annexin V-binding and cleavage of PARP-1 and procaspases-3 and -9. It also induced mitochondrial depolarization, cytochrome c release from mitochondria and generation of reactive oxygen species (ROS). Response to PM is regulated by Bcl-2 since it down-regulated Bcl-2 expression and overexpression of Bcl-2 rendered prostate cancer cells resistant to PM. ROS plays a role in down-regulation of Bcl-2, since treatment with PM in the presence of various ROS modulators, e.g., n-acetylcysteine (NAC), a general purpose antioxidant; diphenylene iodonium (DPI), a NADPH inhibitor; rotenone (ROT), a mitochondrial electron transport chain interrupter rotenone or MnTBAP, a O2 scavenger, attenuated the down-regulation of Bcl-2. Furthermore, ROS is also involved in the ubiquitination and proteasomal degradation of Bcl-2 as both of these events were blocked by O 2[-] scavenger MnTBAP. Thus, pristimerin induces apoptosis in prostate cancer cells predominately through the mitochondrial apoptotic pathway by inhibiting antiapoptic Bcl-2 through a ROS-dependent ubiquitin-proteasomal degradation pathway.}, }
@article {pmid24876842, year = {2014}, author = {Sacchinelli, A and Venturella, R and Lico, D and Di Cello, A and Lucia, A and Rania, E and Cirillo, R and Zullo, F}, title = {The Efficacy of Inositol and N-Acetyl Cysteine Administration (Ovaric HP) in Improving the Ovarian Function in Infertile Women with PCOS with or without Insulin Resistance.}, journal = {Obstetrics and gynecology international}, volume = {2014}, number = {}, pages = {141020}, pmid = {24876842}, issn = {1687-9589}, abstract = {Objective. Substances such as inositol and N-acetylcysteine (NAC) have been recently shown to be effective in treatment of PCOS patients. The aim of this prospective trial is to evaluate the efficacy of NAC + Inositol + folic acid on ovulation rate and menstrual regularity in PCOS patients with and without insulin resistance. Methods. Among the 91 PCOS patients treated with NAC + Inositol + folic, insulin resistance was present in 44 subjects (A) and absent in 47 (B). The primary endpoint was the ovulation rate/year, determined by menstrual diary, serum progesterone performed between 21° and 24° days, ultrasound findings of growth follicular or luteal cysts, and luteal ratio. HOMA-index assessment after 6 and 12 months of treatment was evaluated as secondary endpoint. Results. In both groups there was a significant increase in ovulation rate and no significant differences were found in the primary outcome between two groups. In group A, a significant reduction of HOMA-index was observed. Conclusions. The association NAC + Inositol + folic, regardless of insulin-resistance state, seems to improve ovarian function in PCOS patients. Therefore, inositol and NAC may have additional noninsulin-related mechanisms of action that allow achieving benefits also in those patients with negative HOMA-index.}, }
@article {pmid24872935, year = {2014}, author = {Hsieh, CC and Hsieh, SC and Chiu, JH and Wu, YL}, title = {Protective Effects of N-acetylcysteine and a Prostaglandin E1 Analog, Alprostadil, Against Hepatic Ischemia: Reperfusion Injury in Rats.}, journal = {Journal of traditional and complementary medicine}, volume = {4}, number = {1}, pages = {64-71}, pmid = {24872935}, issn = {2225-4110}, abstract = {Ischemia-reperfusion (I/R) injury has a complex pathophysiology resulting from a number of contributing factors. Therefore, it is difficult to achieve effective treatment or protection by individually targeting the mediators or mechanisms. Our aim was to analyze the individual and combined effects of N-acetylcysteine (NAC) and the prostaglandin E1 (PGE1) analog alprostadil on hepatic I/R injury in rats. Thirty male Sprague-Dawley rats were randomly divided into five groups (six rats per group) as follows: Control group, I/R group, I/R + NAC group, I/R + alprostadil group, and I/R + NAC + alprostadil group. The rats received injections of NAC (150 mg/kg) and/or alprostadil (0.05 μg/kg) over a period of 30 min prior to ischemia. These rats were then subjected to 60 min of hepatic ischemia followed by a 60-min reperfusion period. Hepatic superoxide dismutase (SOD), catalase, and glutathione levels were significantly decreased as a result of I/R injury, but they were increased in groups treated with NAC. Hepatic malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) activities were significantly increased after I/R injury, but they were decreased in the groups with NAC treatment. Alprostadil decreased NO production, but had no effect on MDA and MPO. Histological results showed that both NAC and alprostadil were effective in improving liver tissue morphology during I/R injury. Although NAC and alprostadil did not have a synergistic effect, our findings suggest that treatment with either NAC or alprostadil has benefits for ameliorating hepatic I/R injury.}, }
@article {pmid24872003, year = {2014}, author = {Li, LP and Thacker, J and Lu, J and Franklin, T and Zhou, Y and Papadopoulou, MV and Solomon, R and Prasad, PV}, title = {Efficacy of preventive interventions for iodinated contrast-induced acute kidney injury evaluated by intrarenal oxygenation as an early marker.}, journal = {Investigative radiology}, volume = {49}, number = {10}, pages = {647-652}, pmid = {24872003}, issn = {1536-0210}, support = {R01 DK053221/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/blood/*diagnosis/etiology/*prevention &amp; control ; Acute-Phase Proteins/urine ; Animals ; Biomarkers/blood/urine ; Contrast Media/administration &amp; dosage/*adverse effects ; Disease Models, Animal ; Diuretics/pharmacology ; Free Radical Scavengers/pharmacology ; Furosemide/*pharmacology ; Iohexol/administration &amp; dosage ; Ioxaglic Acid/administration &amp; dosage ; Kidney/drug effects/pathology ; Lipocalin-2 ; Lipocalins/urine ; Magnetic Resonance Imaging/*methods ; Male ; Oxygen/*blood ; Proto-Oncogene Proteins/urine ; Rats ; Rats, Sprague-Dawley ; Triiodobenzoic Acids/administration &amp; dosage ; }, abstract = {OBJECTIVE: The objective of this study was to evaluate the effects of potential renoprotective interventions such as the administration of N-acetylcysteine (NAC; antioxidant) and furosemide (diuretic) on intrarenal oxygenation as evaluated by blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in combination with urinary neutrophil gelatinase-associated lipocalin (NGAL) measurements.<br><br>MATERIALS AND METHODS: Rats received nitric oxide synthase inhibitor L-NAME (10 mg/kg) and cyclooxygenase inhibitor indomethacin (10 mg/kg) to induce the risk for developing iodinated contrast-induced acute kidney injury before receiving one of the interventions: NAC, furosemide, or placebo. One of the 3 iodinated contrast agents (iohexol, ioxaglate, or iodixanol) was then administered (1600-mg organic iodine per kilogram body weight). Fifty-four Sprague-Dawley rats were allocated in a random order into 9 groups on the basis of the intervention and the contrast agent received.Blood-oxygen-level-dependent MRI-weighted images were acquired on a Siemens 3.0-T scanner using a multiple gradient recalled echo sequence at baseline, after L-NAME, indomethacin, interventions or placebo, and iodinated contrast agents. Data acquisition and analysis were performed in a blind fashion. R2* (=1/T2*) maps were generated inline on the scanner. A mixed-effects growth curve model with first-order autoregressive variance-covariance was used to analyze the temporal data. Urinary NGAL, a marker of acute kidney injury, was measured at baseline, 2 and 4 hours after the contrast injection.<br><br>RESULTS: Compared with the placebo-treated rats, those treated with furosemide showed a significantly lower rate of increase in R2* (P < 0.05) in the renal inner stripe of the outer medulla. The rats treated with NAC showed a lower rate of increase in R2* compared with the controls, but the difference did not reach statistical significance. Urinary NGAL showed little to no increase in R2* after administration of iodixanol in the rats pretreated with furosemide but demonstrated significant increase in the rats pretreated with NAC or placebo (P < 0.05).<br><br>CONCLUSIONS: This is the first study to evaluate the effects of interventions to mitigate the deleterious effects of contrast media using BOLD MRI. The rate of increase in R2* after administration of iodinated contrast is associated with acute renal injury as evaluated by NGAL. Further studies are warranted to determine the optimum dose of furosemide and NAC for mitigating the ill effects of contrast media. Because NGAL has been shown to be useful in humans to document iodinated contrast-induced acute kidney injury, the method presented in this study using BOLD MRI and NGAL measurements can be translated to humans.}, }
@article {pmid24870979, year = {2014}, author = {Rehman, K and Fu, YJ and Zhang, YF and Wang, QQ and Wu, B and Wu, Y and Zhou, XY and Sun, WH and Sun, TF and Naranmandura, H}, title = {Trivalent methylated arsenic metabolites induce apoptosis in human myeloid leukemic HL-60 cells through generation of reactive oxygen species.}, journal = {Metallomics : integrated biometal science}, volume = {6}, number = {8}, pages = {1502-1512}, doi = {10.1039/c4mt00119b}, pmid = {24870979}, issn = {1756-591X}, mesh = {Apoptosis/drug effects ; Arsenic/*pharmacology ; Arsenic Trioxide ; Arsenicals/pharmacology ; Arsenites/pharmacology ; Cacodylic Acid/analogs &amp; derivatives/pharmacology ; HL-60 Cells ; Humans ; Oxides/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Arsenic trioxide (As2O3) has remarkable therapeutic efficacy against leukemia. However, after As2O3 biotransformation, the role of arsenic metabolites in the clinical efficacy against leukemia still needs to be elucidated. Therefore, to explore the contribution of trivalent methylated arsenicals in the therapeutic effects, we investigated and compared the effects of arsenite (iAs(III)), monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) on HL-60 cells. Methylated arsenic species MMA(III) and DMA(III) showed potentially reduced cell survival with IC50 values of 3 and 2 μM, respectively. We found that methylated metabolites caused apoptosis through oxidative stress and loss of mitochondrial membrane potential. Furthermore, we found that the caspase-9 and -3 were markedly activated by exposure to methylated metabolites, with cleavage of poly-ADP ribose polymerase (PARP). Conversely, cellular apoptosis, generation of ROS, activation of caspase-3, -9 as well as PARP cleavage were significantly attenuated by pretreatment with an antioxidant, N-acetylcysteine (NAC). DNA damage was also markedly observed in HL-60 cells exposed to either MMA(III) or DMA(III), while iAs(III) did not show any relevant effects in HL-60 cells. Likewise, phosphorylation of the histone H2A variant (γ-H2AX), a biomarker of DNA damage, significantly occurred in cellular nuclei following exposure to two methylated species, which was reduced in the presence of NAC, suggesting that the induction of DNA damage was predominantly caused by the two metabolites via oxidative stress. In conclusion, we suggest that arsenic intermediate metabolites; MMA(III) and DMA(III) might prove to be of clinical relevance in future as such approaches may help in the treatment of leukemia and other types of cancers.}, }
@article {pmid24868543, year = {2014}, author = {Mahmood, ND and Mamat, SS and Kamisan, FH and Yahya, F and Kamarolzaman, MF and Nasir, N and Mohtarrudin, N and Tohid, SF and Zakaria, ZA}, title = {Amelioration of paracetamol-induced hepatotoxicity in rat by the administration of methanol extract of Muntingia calabura L. leaves.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {695678}, pmid = {24868543}, issn = {2314-6141}, mesh = {AMP-Activated Protein Kinases/metabolism ; Acetaminophen/*toxicity ; Active Transport, Cell Nucleus ; Animals ; Cell Nucleus/metabolism ; Dinoprostone/metabolism ; Down-Regulation ; Humans ; Immunohistochemistry ; Inflammation ; Interleukin-6/metabolism ; Lipopolysaccharides/metabolism ; Liver/*drug effects ; Liver Failure/chemically induced/*drug therapy ; Methanol ; Mice ; Microglia/metabolism ; NF-kappa B/metabolism ; Nitric Oxide/metabolism ; Plant Extracts/*therapeutic use ; Plant Leaves/chemistry ; Rats ; Sasa/*chemistry ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Muntingia calabura L. is a tropical plant species that belongs to the Elaeocarpaceae family. The present study is aimed at determining the hepatoprotective activity of methanol extract of M. calabura leaves (MEMC) using two models of liver injury in rats. Rats were divided into five groups (n=6) and received 10% DMSO (negative control), 50 mg/kg N-acetylcysteine (NAC; positive control), or MEMC (50, 250, and 500 mg/kg) orally once daily for 7 days and on the 8th day were subjected to the hepatotoxic induction using paracetamol (PCM). The blood and liver tissues were collected and subjected to biochemical and microscopical analysis. The extract was also subjected to antioxidant study using the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) and superoxide anion-radical scavenging assays. At the same time, oxygen radical antioxidant capacity (ORAC) and total phenolic content were also determined. From the histological observation, lymphocyte infiltration and marked necrosis were observed in PCM-treated groups (negative control), whereas maintenance of hepatic structure was observed in group pretreated with N-acetylcysteine and MEMC. Hepatotoxic rats pretreated with NAC or MEMC exhibited significant decrease (P<0.05) in ALT and AST enzymes level. Moreover, the extract also exhibited good antioxidant activity. In conclusion, MEMC exerts potential hepatoprotective activity that could be partly attributed to its antioxidant activity and, thus warrants further investigations.}, }
@article {pmid24866137, year = {2014}, author = {Zhu, R and Huang, X and Hu, XQ and Xiao, D and Zhang, L}, title = {Gestational hypoxia increases reactive oxygen species and inhibits steroid hormone-mediated upregulation of Ca(2+)-activated K(+) channel function in uterine arteries.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {64}, number = {2}, pages = {415-422}, pmid = {24866137}, issn = {1524-4563}, support = {R01 HL110125/HL/NHLBI NIH HHS/United States ; HD031226/HD/NICHD NIH HHS/United States ; R03 DA032510/DA/NIDA NIH HHS/United States ; DA032510/DA/NIDA NIH HHS/United States ; R01 HL089012/HL/NHLBI NIH HHS/United States ; HL110125/HL/NHLBI NIH HHS/United States ; P01 HD031226/HD/NICHD NIH HHS/United States ; HL089012/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Estradiol/pharmacology ; Female ; Hypoxia/*metabolism ; Potassium Channels, Calcium-Activated/*metabolism ; Pregnancy ; Progesterone/pharmacology ; Reactive Oxygen Species/*metabolism ; Sheep ; Up-Regulation/*drug effects ; Uterine Artery/drug effects/*metabolism ; }, abstract = {Gestational hypoxia inhibits steroid hormone-induced upregulation of Ca(2+)-activated K(+) (KCa) channel activities in uterine arteries. We tested the hypothesis that increased reactive oxygen species play an important role in hypoxia-mediated inhibition of KCa channel activities. Uterine arteries were isolated from nonpregnant (nonpregnant uterine artery) and near-term (≈142-145 day) pregnant (pregnant uterine artery) sheep maintained at either sea level or high altitude (3820 m, Pao2: 60 mm Hg) for 110 days. In pregnant uterine arteries, hypoxia significantly decreased large conductance channel opener NS1619- and small conductance channel opener NS309-induced relaxations, which were partially restored by reactive oxygen species inhibitor N-acetylcysteine (NAC). NAC significantly increased large conductance KCa but not small conductance KCa current densities in uterine arterial smooth muscle cells in pregnant animals acclimatized to high altitude. The NAC-sensitive component of small conductance KCa-induced relaxations was diminished in endothelium-denuded arteries. In nonpregnant uterine arteries, NS1619- and NS309-induced relaxations were diminished compared with those in pregnant uterine arteries. Treatment of nonpregnant uterine arteries with 17β-estradiol and progesterone for 48 hours increased small conductance KCa type 3 protein abundance and NS1619- and NS309-induced relaxations, which were inhibited by hypoxia. This hypoxia-mediated inhibition was reversed by NAC. Consistently, steroid hormone treatment had no significant effects on large conductance KCa current density in nonpregnant uterine arteries of hypoxic animals in the absence of NAC but significantly increased it in the presence of NAC. These results suggest an important role of hypoxia-mediated reactive oxygen species in negatively regulating steroid hormone-mediated upregulation of KCa channel activity and adaptation of uterine vascular reactivity in pregnancy, which may contribute to the increased incidence of preeclampsia and fetal intrauterine growth restriction associated with gestational hypoxia.}, }
@article {pmid24863792, year = {2014}, author = {Kunz, S and Maturi, MM and Schrader, I and Backenköhler, J and Tschurl, M and Heiz, U}, title = {Same ligand--different binding: a way to control the binding of N-acetyl-cysteine (NAC) to Pt clusters.}, journal = {Journal of colloid and interface science}, volume = {426}, number = {}, pages = {264-269}, doi = {10.1016/j.jcis.2014.04.017}, pmid = {24863792}, issn = {1095-7103}, mesh = {Acetylcysteine/*chemistry ; Catalysis ; Ligands ; Magnetic Resonance Spectroscopy ; Platinum/*chemistry ; Spectrophotometry, Infrared ; }, abstract = {The functionalization of "unprotected" Pt clusters with N-acetyl-cysteine (NAC) at different pH-values is presented that allows for binding NAC either via the thiol or the amide group to the particle. NMR-spectroscopy was used to study the chemical nature of NAC at weakly acidic and alkaline conditions. The formation of a cyclic isomer of NAC was found at high pH-values which occurs through an intramolecular reaction between the thiol and the amide group delivering a cyclic thioether. The absence of the bare thiol groups in aqueous alkaline solutions leads to binding of the cyclic isomer of NAC to the Pt clusters via its nitrogen atom. IR spectroscopy was applied, which confirmed that the cyclic isomer is, however, not stable upon drying, but undergoes ring-opening yielding the "normal" non-cyclic form. This distinctive property of NAC in combination with the use of "unprotected" clusters allows for binding the same ligand to clusters from the same batch, but with different binding modes, while the particle size is preserved. As a consequence, differences in the cluster properties can be related exclusively to the influence of the binding properties of the ligand. Finally, the catalytic hydrogenation of 2-butanone was used as a probe reaction and the resulting differences in the enantioselectivity can thus be related to this particular change in the binding mode.}, }
@article {pmid24861666, year = {2014}, author = {Comparsi, B and Meinerz, DF and Dalla Corte, CL and Prestes, AS and Stefanello, ST and Santos, DB and De Souza, D and Farina, M and Dafre, AL and Posser, T and Franco, JL and Rocha, JB}, title = {N-Acetylcysteine does not protect behavioral and biochemical toxicological effect after acute exposure of diphenyl ditelluride.}, journal = {Toxicology mechanisms and methods}, volume = {24}, number = {8}, pages = {529-535}, doi = {10.3109/15376516.2014.920449}, pmid = {24861666}, issn = {1537-6524}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/therapeutic use ; Behavior, Animal/drug effects ; Benzene Derivatives/administration &amp; dosage/antagonists &amp; inhibitors/*toxicity ; Brain/drug effects/enzymology ; Dose-Response Relationship, Drug ; Environmental Pollutants/administration &amp; dosage/antagonists &amp; inhibitors/*toxicity ; Glutathione Peroxidase/*antagonists &amp; inhibitors/metabolism ; Injections, Intraperitoneal ; Injections, Subcutaneous ; Male ; Mice ; Motor Activity/drug effects ; Nerve Tissue Proteins/*antagonists &amp; inhibitors/metabolism ; Neurons/drug effects/enzymology ; Neurotoxicity Syndromes/*enzymology/prevention &amp; control ; Organometallic Compounds/administration &amp; dosage/antagonists &amp; inhibitors/*toxicity ; Oxidative Stress/*drug effects ; Thioredoxin-Disulfide Reductase/*antagonists &amp; inhibitors/metabolism ; Toxicity Tests, Acute ; }, abstract = {Diphenyl ditelluride (PhTe)2 is a versatile molecule used in the organic synthesis and it is a potential prototype for the development of novel biologically active molecules. The mechanism(s) involved in (PhTe)2 toxicity is(are) elusive, but thiol oxidation of critical proteins are important targets. Consequently, the possible remedy of its toxicity by thiol-containing compounds is of experimental and clinical interest. The present study aimed to investigate putative mechanisms underlying the toxicity of (PhTe)2 in vivo. We assessed behavioral and oxidative stress parameters in mice, including the modulation of antioxidant enzymatic defense systems. In order to mitigate such toxicity, N-acetylcysteine (NAC) was administered before (3 d) and simultaneously with (PhTe)2 (7 d). Mice were separated into six groups receiving daily injections of (1) TFK (2.5 ml/kg, intraperitonealy (i.p.)) plus canola oil (10 ml/kg, subcutaneously (s.c.)), (2) NAC (100 mg/kg, i.p.) plus canola oil s.c., (3) TFK i.p. plus (PhTe)2 (10 µmol/kg, s.c.), (4) TFK i.p. plus (PhTe)2 (50 µmol/kg, s.c.), (5) NAC plus (PhTe)2 (10 µmol/kg, s.c.), and (6) NAC plus (PhTe)2 (50 µmol/kg, s.c.). (PhTe)2 treatment started on the fourth day of treatment with NAC. Results demonstrated that (PhTe)2 induced behavioral alterations and inhibited important selenoenzymes (thioredoxin reductase and glutathione peroxidase). Treatments produced no or minor effects on the activities of antioxidant enzymes catalase and glutathione reductase. Contrary to expected, NAC co-administration did not protect against the deleterious effects of (PhTe)2. Other low-molecular-thiol containing molecules should be investigated to determine whether or not they can be effective against ditellurides.}, }
@article {pmid24854598, year = {2014}, author = {Tarazi, FI and Sahli, ZT and Wolny, M and Mousa, SA}, title = {Emerging therapies for Parkinson's disease: from bench to bedside.}, journal = {Pharmacology &amp; therapeutics}, volume = {144}, number = {2}, pages = {123-133}, doi = {10.1016/j.pharmthera.2014.05.010}, pmid = {24854598}, issn = {1879-016X}, mesh = {Adenosine A2 Receptor Antagonists/pharmacology ; Apoptosis Regulatory Proteins/pharmacology ; Deep Brain Stimulation/methods ; Genetic Therapy/methods ; Glial Cell Line-Derived Neurotrophic Factor/pharmacology ; Humans ; MAP Kinase Kinase Kinases/antagonists &amp; inhibitors ; Pallidotomy/methods ; Parkinson Disease/*therapy ; Radiosurgery ; Stem Cell Transplantation ; Transcription Factors/antagonists &amp; inhibitors ; Transglutaminases/antagonists &amp; inhibitors ; }, abstract = {The prevalence of Parkinson's disease (PD) increases with age and is projected to increase in parallel to the rising average age of the population. The disease can have significant health-related, social, and financial implications not only for the patient and the caregiver, but for the health care system as well. While the neuropathology of this neurodegenerative disorder is fairly well understood, its etiology remains a mystery, making it difficult to target therapy. The currently available drugs for treatment provide only symptomatic relief and do not control or prevent disease progression, and as a result patient compliance and satisfaction are low. Several emerging pharmacotherapies for PD are in different stages of clinical development. These therapies include adenosine A2A receptor antagonists, glutamate receptor antagonists, monoamine oxidase inhibitors, anti-apoptotic agents, and antioxidants such as coenzyme Q10, N-acetyl cysteine, and edaravone. Other emerging non-pharmacotherapies include viral vector gene therapy, microRNAs, transglutaminases, RTP801, stem cells and glial derived neurotrophic factor (GDNF). In addition, surgical procedures including deep brain stimulation, pallidotomy, thalamotomy and gamma knife surgery have emerged as alternative interventions for advanced PD patients who have completely utilized standard treatments and still suffer from persistent motor fluctuations. While several of these therapies hold much promise in delaying the onset of the disease and slowing its progression, more pharmacotherapies and surgical interventions need to be investigated in different stages of PD. It is hoped that these emerging therapies and surgical procedures will strengthen our clinical armamentarium for improved treatment of PD.}, }
@article {pmid24854122, year = {2014}, author = {Nomura, S and Shimakawa, S and Miyamoto, R and Fukui, M and Tamai, H}, title = {3-Methyl-1-phenyl-2-pyrazolin-5-one or N-acetylcysteine prevents hippocampal mossy fiber sprouting and rectifies subsequent convulsive susceptibility in a rat model of kainic acid-induced seizure ceased by pentobarbital.}, journal = {Brain research}, volume = {1590}, number = {}, pages = {65-74}, doi = {10.1016/j.brainres.2014.05.017}, pmid = {24854122}, issn = {1872-6240}, mesh = {Acetylcysteine/*pharmacology ; Aldehydes/pharmacology ; Animals ; Anticonvulsants/pharmacology ; Antipyrine/*analogs &amp; derivatives/pharmacology ; Cell Survival/drug effects ; Edaravone ; Excitatory Amino Acid Antagonists/*toxicity ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Kainic Acid/*toxicity ; Male ; Mossy Fibers, Hippocampal/*drug effects ; Pentobarbital/pharmacology ; Rats ; Rats, Sprague-Dawley ; Seizures/*chemically induced/*prevention &amp; control ; }, abstract = {There is accumulating evidence that reactive oxygen species are involved in the development of seizures under pathological conditions, and antioxidant treatments are a novel therapeutic approach for epilepsy. The kainic acid (KA) model of induced seizures has been widely used to study temporal lobe epilepsy. However, research on the use of free radical scavengers following KA-induced status epilepticus (SE) is limited. We examined whether antioxidants already used in humans could reduce hippocampal neuronal cell loss, mossy fiber sprouting and the acquisition of hyperexcitability when administered as a single dose after SE. The antioxidant 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) (30mg/kg) or N-acetylcysteine (NAC) (30mg/kg) was administered after KA-induced SE ceased by pentobarbital. We evaluated neuronal cell viability 1 week after SE, determined the threshold for seizures induced by inhalation of flurothyl ether 12 weeks after SE, and examined the extent of mossy fiber sprouting 12 weeks after SE. We found that edaravone or NAC prevented neuronal cell loss and mossy fiber sprouting, and increased the threshold for seizures induced by flurothyl ether, even when administered after KA-induced SE. These results demonstrate that a single dose of edaravone or NAC can protect against neuronal cell loss and epileptogenesis when administered after SE ceased by pentobarbital.}, }
@article {pmid24852506, year = {2014}, author = {Behera, M and Dandapat, J and Rath, CC}, title = {Effect of heavy metals on growth response and antioxidant defense protection in Bacillus cereus.}, journal = {Journal of basic microbiology}, volume = {54}, number = {11}, pages = {1201-1209}, doi = {10.1002/jobm.201300805}, pmid = {24852506}, issn = {1521-4028}, mesh = {Antioxidants/*toxicity ; Bacillus cereus/chemistry/*drug effects/growth &amp; development/*physiology ; Cadmium/toxicity ; Catalase/analysis ; Copper/toxicity ; Glutathione/analysis ; Hydrogen Peroxide/analysis ; Metals, Heavy/*toxicity ; Oxidative Stress ; *Stress, Physiological ; Superoxide Dismutase/analysis ; }, abstract = {Bacterial cells in aerobic environment generate reactive oxygen species which may lead to oxidative stress, induced by a wide range of environmental factors including heavy metals. In the present context an attempt has been made to determine the toxic impact of cadmium and copper on growth performance, oxidative stress, and relative level of antioxidant protection in Bacillus cereus. Outcome of this study suggests that both the metal ions depleted the growth rate in this organism with respect to time and concentration of the metal ions. CdCl2 exposure induced extracellular glutathione (GSH) production, whereas, its level was declined in response to CuSO4. Superoxide dismutase (SOD) activity and hydrogen peroxide (H2 O2) content was elevated under CdCl2 stress but the activity of catalase (CAT) was inhibited. In contrast, incubation of bacteria with CuSO4 exhibited decreased SOD activity with concomitant rise in CAT activity and H2 O2 content. We also observed elevation of intracellular GSH level in this bacteria following supplementation of N-acetyl cysteine (NAC) in the medium. Overall findings of this study indicated differential toxicity of CdCl2 and CuSO4 in inducing oxidative stress, depleting growth rate and the possible involvement of GSH and CAT in adaptive antioxidant response.}, }
@article {pmid24846680, year = {2014}, author = {Smith, JR and Ade, CJ and Broxterman, RM and Skutnik, BC and Barstow, TJ and Wong, BJ and Harms, CA}, title = {Influence of exercise intensity on respiratory muscle fatigue and brachial artery blood flow during cycling exercise.}, journal = {European journal of applied physiology}, volume = {114}, number = {8}, pages = {1767-1777}, pmid = {24846680}, issn = {1439-6327}, mesh = {Adult ; Brachial Artery/*physiology ; *Exercise ; Hemodynamics ; Humans ; Male ; *Muscle Fatigue ; *Regional Blood Flow ; Respiratory Muscles/*physiology ; Skin/blood supply ; Upper Extremity/blood supply ; }, abstract = {PURPOSE: During high intensity exercise, both respiratory muscle fatigue and cardiovascular reflexes occur; however, it is not known how inactive limb blood flow is influenced. The purpose of this study was to determine the influence of moderate and high exercise intensity on respiratory muscle fatigue and inactive limb muscle and cutaneous blood flow during exercise.<br><br>METHODS: Twelve men cycled at 70 and 85 % [Formula: see text] for 20 min. Subjects also performed a second 85 % [Formula: see text] test after ingesting 1,800 mg of N-acetylcysteine (NAC), which has been shown to reduce respiratory muscle fatigue (RMF). Maximum inspiratory pressures (P Imax), brachial artery blood flow (BABF), cutaneous vascular conductance (CVC), and mean arterial pressure were measured at rest and during exercise.<br><br>RESULTS: Significant RMF occurred with 85 % [Formula: see text] (P Imax, -12.8 &#xb1; 9.8 %), but not with 70 % [Formula: see text] (P Imax, -5.0 &#xb1; 5.9 %). BABF and BA vascular conductance were significantly lower at end exercise of the 85 % [Formula: see text] test compared to the 70 % [Formula: see text] test. CVC during exercise was not different (p > 0.05) between trials. With NAC, RMF was reduced (p < 0.05) and BABF was significantly higher (~30 %) compared to 85 % [Formula: see text] (p < 0.05).<br><br>CONCLUSIONS: These data suggest that heavy whole-body exercise at 85 % [Formula: see text] leads to RMF, decreases in inactive arm blood flow, and vascular conductance, but not cutaneous blood flow.}, }
@article {pmid24845567, year = {2014}, author = {Seo, SK and Kim, JH and Choi, HN and Choe, TB and Hong, SI and Yi, JY and Hwang, SG and Lee, HG and Lee, YH and Park, IC}, title = {Knockdown of TWIST1 enhances arsenic trioxide- and ionizing radiation-induced cell death in lung cancer cells by promoting mitochondrial dysfunction.}, journal = {Biochemical and biophysical research communications}, volume = {449}, number = {4}, pages = {490-495}, doi = {10.1016/j.bbrc.2014.05.030}, pmid = {24845567}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Arsenic Trioxide ; Arsenicals ; Carcinoma, Non-Small-Cell Lung/metabolism/pathology/radiotherapy ; Cell Death/drug effects/radiation effects ; Gene Knockdown Techniques ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Nuclear Proteins/biosynthesis/*genetics ; Oxides ; RNA, Small Interfering/pharmacology ; Radiation, Ionizing ; Reactive Oxygen Species/metabolism ; Twist-Related Protein 1/biosynthesis/*genetics ; }, abstract = {TWIST1 is implicated in the process of epithelial mesenchymal transition, metastasis, stemness, and drug resistance in cancer cells, and therefore is a potential target for cancer therapy. In the present study, we found that knockdown of TWIST1 by small interfering RNA (siRNA) enhanced arsenic trioxide (ATO)- and ionizing radiation (IR)-induced cell death in non-small-cell lung cancer cells. Interestingly, intracellular reactive oxygen species levels were increased in cells treated with TWIST1 siRNA and further increased by co-treatment with ATO or IR. Pretreatment of lung cancer cells with the antioxidant N-acetyl-cysteine markedly suppressed the cell death induced by combined treatment with TWIST1 siRNA and ATO or IR. Moreover, treatment of cells with TWIST1 siRNA induced mitochondrial membrane depolarization and significantly increased mitochondrial fragmentation (fission) and upregulated the fission-related proteins FIS1 and DRP1. Collectively, our results demonstrate that siRNA-mediated TWIST1 knockdown induces mitochondrial dysfunction and enhances IR- and ATO-induced cell death in lung cancer cells.}, }
@article {pmid24844577, year = {2014}, author = {Chomchai, S and Chomchai, C}, title = {Predicting acute acetaminophen hepatotoxicity with acetaminophen-aminotransferase multiplication product and the Psi parameter.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {52}, number = {5}, pages = {506-511}, doi = {10.3109/15563650.2014.917180}, pmid = {24844577}, issn = {1556-9519}, mesh = {Acetaminophen/administration &amp; dosage/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Alanine Transaminase/*blood ; Antidotes/administration &amp; dosage/therapeutic use ; Aspartate Aminotransferases/*blood ; Chemical and Drug Induced Liver Injury/drug therapy/*etiology ; Drug Overdose ; Female ; Humans ; Likelihood Functions ; Male ; ROC Curve ; Retrospective Studies ; Sensitivity and Specificity ; Thailand ; Time Factors ; Young Adult ; }, abstract = {CONTEXT: Prediction of potential hepatotoxicity is important for individualizing therapy with N-acetylcysteine (NAC) in patients with acute acetaminophen overdose. Acetaminophen-aminotransferase multiplication product (APAP × AT) and the Psi Parameter (Psi) have been reported to be the predictors of acetaminophen hepatotoxicity.<br><br>OBJECTIVE: To determine the validity of APAP &#xd7; AT and Psi in predicting hepatotoxicity secondary to acute acetaminophen overdose.<br><br>MATERIALS AND METHODS: We retrospectively reviewed acute acetaminophen overdose cases who were treated with NAC at Siriraj Hospital, Thailand during January 2004-June 2012. The patients' ages were 12 years or more. Initial acetaminophen concentration (mg/L) and aminotransferase (IU/L) were multiplied to obtain APAP &#xd7; AT. Psi were derived from initial acetaminophen concentrations (mg/L) and lag time (hours) to NAC therapy. The cut-off values for APAP &#xd7; AT and Psi were 1500 mg&#x2219;IU/L(2) and 5 mM&#x2219;h, respectively. Hepatotoxicity (defined as aspartate or alanine aminotransferase (ALT) greater than 1000 IU/L) was the outcome of interest.<br><br>RESULTS: A total of 255 patients were included, 32 of whom developed hepatotoxicity. APAP &#xd7; AT had sensitivity, specificity, and negative likelihood ratio of 90.6%, 62.8%, and 0.2, respectively. The sensitivity of Psi, specificity, and negative likelihood ratio were 96.9%, 91.5%, and 0.0, respectively. The areas under the curve of the receiver operating characteristic (ROC) curve for APAP &#xd7; AT and Psi were 0.82 and 0.96, respectively, with a statistically significant difference between the two methods (p = 0.002). APAP &#xd7; AT showed higher specificity (92.5%) in patients who presented 8-24 h after the overdose.<br><br>DISCUSSION AND CONCLUSION: Psi and APAP &#xd7; AT are valid clinical tools in predicting hepatotoxicity secondary to acute acetaminophen overdose in adults. APAP &#xd7; AT is useful in predicting a low likelihood of hepatotoxicity after standard NAC therapy among late-presenting patients.}, }
@article {pmid24842665, year = {2014}, author = {Nazıroğlu, M and Senol, N and Ghazizadeh, V and Yürüker, V}, title = {Neuroprotection induced by N-acetylcysteine and selenium against traumatic brain injury-induced apoptosis and calcium entry in hippocampus of rat.}, journal = {Cellular and molecular neurobiology}, volume = {34}, number = {6}, pages = {895-903}, pmid = {24842665}, issn = {1573-6830}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Brain Injuries/*drug therapy/metabolism ; Calcium/*metabolism ; Caspase 3/metabolism ; Hippocampus/*drug effects/metabolism ; Male ; Neurons/drug effects/metabolism ; Rats, Sprague-Dawley ; Selenium/*pharmacology ; }, abstract = {Neurodegeneration associated with acute central nervous system injuries and diseases such as spinal cord injury and traumatic brain injury (TBI) are reported to be mediated by the regulation of apoptosis and oxidative stress through Ca(2+) influx. The thiol redox system antioxidants, such as N-acetylcysteine (NAC) and selenium (Se), display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties. However, there are no reports on hippocampal apoptosis, cytosolic reactive oxygen species (ROS), or Ca(2+) values in rats with an induced TBI. Therefore, we tested the effects of Se and NAC administration on apoptosis, oxidative stress, and Ca(2+) influx through TRPV1 channel activations in the hippocampus of TBI-induced rats. The 32 rats were divided into four groups: control, TBI, TBI + NAC, and TBI + Se groups. Intraperitoneal administrations of NAC and Se were performed at 1, 24, 48, and 72 h after TBI induction. After 3 days, the hippocampal neurons were freshly isolated from the rats. In cytosolic-free Ca(2+) analyses, the neurons were stimulated with the TRPV1 channel agonist capsaicin, a pungent compound found in hot chili peppers. Cytosolic-free Ca(2+), apoptosis, cytosolic ROS levels, and caspase-3 and -9 activities were higher in the TBI group than control. The values in the hippocampus were decreased by Se and NAC administrations. In conclusion, we observed that NAC and Se have protective effects on oxidative stress, apoptosis, and Ca(2+) entry via TRPV1 channel activation in the hippocampus of this TBI model, but the effect of NAC appears to be much greater than that of Se. They are both interesting candidates for studying the amelioration of TBIs.}, }
@article {pmid24842330, year = {2014}, author = {Panjehpour, M and Alaie, SH}, title = {N-acetylcysteine prevents cadmium-induced apoptosis in human breast cancer MDA-MB468 cell line.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {60}, number = {1}, pages = {33-38}, pmid = {24842330}, issn = {1165-158X}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms ; Cadmium/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Fragmentation ; Female ; Humans ; Oxidative Stress ; Protective Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Cadmium is a heavy metal posing severe risks and destructive effects on human health. Although cadmium was classified as a human carcinogen, it has been also shown to be a cytotoxic agent that induces cell death either by necrosis or apoptosis. In this study, we investigated the protective role of N-acetylcysteine, a free radical scavenger, on cadmium induced apoptosis in MDA-MB468 cells. The breast cancer cells were exposed to increasing concentrations of CdCl2 in the presence and absence of NAC and the cell viability was assessed using MTT assay. The microscopic studies of apoptosis were carried out with fluorescent staining. To investigate the induction of apoptosis, cellular DNA was isolated using DNA kit extraction and analyzed electrophoretically. The results showed significant decrease in cellular viability upon 48 hours exposure to CdCl2 in a dose-dependent manner (p < 0.05). Pretreatment of MDA-MB468 cells with N-acetylcysteine (1mM) reversed the cadmium cytotoxicity effects and protected cells from apoptotic death. DNA Hoechst staining showed the apoptotic bodies. The electrophoresis of extracted DNA identified a fragmentation pattern consistent with apoptosis mechanism. The results suggest that cytotoxic effects and induction of apoptosis caused by CdCl2 are mediated, by oxidative stress.}, }
@article {pmid24836981, year = {2014}, author = {Zheng, Q and Ren, Y and Reinach, PS and She, Y and Xiao, B and Hua, S and Qu, J and Chen, W}, title = {Reactive oxygen species activated NLRP3 inflammasomes prime environment-induced murine dry eye.}, journal = {Experimental eye research}, volume = {125}, number = {}, pages = {1-8}, doi = {10.1016/j.exer.2014.05.001}, pmid = {24836981}, issn = {1096-0007}, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Carrier Proteins/*metabolism ; Caspase 1/metabolism ; Conjunctiva/metabolism ; Cornea/metabolism ; Disease Models, Animal ; Disease Progression ; Dry Eye Syndromes/etiology/*metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Free Radical Scavengers/pharmacology ; Inflammasomes/*metabolism ; Interleukin-1beta/metabolism ; Mice ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction/physiology ; }, abstract = {Tear film hyperosmolarity along with exposure to oxidant stress are factors that can induce chronic ocular surface inflammation and pain. However, there is limited information on how increases in reactive oxygen species (ROS) generated by oxidant exposure can induce inflammation. There is emerging evidence in other tissues that innate immune responses to a variety of environmental stresses stem from ROS-induced cytosolic NLRP3 inflammasome activation. Once this occurs, pro-caspase-1 is converted into its catalytic active form, which in turn cleaves pro-IL-1β thereby generating its bioactive form. We determined the role of ROS generation in mediating increases in IL-1β secretion through caspase-1 activation caused by NLRP3 inflammasome activation in an environment-induced murine dry eye (DE) model. An intelligently controlled environmental system (ICES) induced evaporative DE in female 4-6 week old C57BL/6J mice. Increases in ROS production preceded rises in corneal and conjunctival gene expression of NLRP3 inflammasome components and IL-1β that were identified using real-time PCR. Confocal microscopy evaluated concomitant increases in NLPR3, caspase-1 and IL-1β immunostaining. Increases in caspase-1 activity were used as an indicator of inflammasome activation. Rises in ROS generation occurred after 1 week of ICES exposure, which preceded increases in gene expression of three NLRP3 inflammasome components (i.e. NLRP3, ASC and caspase-1) leading to rises in bioactive IL-1β release. Increases in caspase-1 activity occurred after 2 weeks of ICES exposure. Eyedrops containing 0.3% N-acetyl-l-cysteine (NAC) were applied to quench ROS generation by mice kept in the ICES for 2 weeks. This scavenger reduced corneal fluorescein staining and decreased ROS production. NAC also down-regulated both increases in NLRP3, ASC, caspase-1 and IL-1β mRNA levels, along with their immunostaining. It robustly attenuated rises in inflammasome mediated increases in caspase-1 catalytic activity. We show in a dessicating DE disease murine model that rises in ROS generation trigger NLRP3 inflammasome complexation and activation leading to increases in bioactive IL-1β secretion. These results prompt us to suggest that the ROS-NLRP3-IL-1β signaling pathway might play a priming role in environment-induced DE progression. Finally, our findings provide a basis for developing novel strategies that may improve the management of patients requiring treatment for environment-induced dry eye disease.}, }
@article {pmid24836433, year = {2014}, author = {Huang, ST and Bi, KW and Kuo, HM and Lin, TK and Liao, PL and Wang, PW and Chuang, JH and Liou, CW}, title = {Phyllanthus urinaria induces mitochondrial dysfunction in human osteosarcoma 143B cells associated with modulation of mitochondrial fission/fusion proteins.}, journal = {Mitochondrion}, volume = {17}, number = {}, pages = {22-33}, doi = {10.1016/j.mito.2014.05.002}, pmid = {24836433}, issn = {1872-8278}, mesh = {Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Mitochondria/chemistry/*drug effects ; Mitochondrial Dynamics/*drug effects ; Mitochondrial Proteins/*analysis ; Phyllanthus/*chemistry ; Plant Extracts/isolation &amp; purification/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Phyllanthus urinaria (P. urinaria), a widely used herbal medicine, has been reported to possess various biological characteristics including anti-inflammation, anti-virus, anti-bacteria, anti-hepatotoxicity and anti-cancer. This study provides molecular evidence associated with the dynamics and organization of mitochondria in osteosarcoma 143B cells resulted from P urinaria. Herein, P. urinaria-induced cytotoxicity and ROS associated with the inhibition of mitochondrial membrane potential were reversed by N-acetylcysteine (NAC). The endogenous antioxidant enzymes such as manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPX1) were activated by P. urinaria, but not correlated to catalase. P. urinaria decreased mitochondrial respiration activity as well as respiratory chain enzymes and HIF-1α in osteosarcoma 143B cells. Additionally, both adenosine triphosphate (ATP) synthase activation and ATP production were suppressed by P. urinaria. We further investigated changes of mitochondrial dynamic in osteosarcoma 143B cells. P. urinaria indeed fragmented the mitochondrial network of osteosarcoma 143B cells. We found a significant decrease in optic atrophy type 1 (Opa1) and mitofusin 1 (Mfn1) related to fusion proteins as well as increase mitochondrial fission 1 protein (Fis1) related to fission protein. It indicated that P. urinaria modulated the mitochondrial dynamics via fusion and fission machinery. Altogether, this study offers the evidence that mitochondrial dysfunction with dynamic change is essential components for the anti-cancer mechanism elicited by P. urinaria.}, }
@article {pmid24833327, year = {2014}, author = {Tse, HN and Raiteri, L and Wong, KY and Ng, LY and Yee, KS and Tseng, CZS}, title = {Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD.}, journal = {Chest}, volume = {146}, number = {3}, pages = {611-623}, doi = {10.1378/chest.13-2784}, pmid = {24833327}, issn = {1931-3543}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Forced Expiratory Volume/physiology ; Free Radical Scavengers/*therapeutic use ; Hong Kong ; Humans ; Male ; Physical Endurance/physiology ; Pulmonary Disease, Chronic Obstructive/*drug therapy/*epidemiology/physiopathology ; Risk Factors ; *Severity of Illness Index ; Surveys and Questionnaires ; Treatment Outcome ; }, abstract = {BACKGROUND: Although high-dose N-acetylcysteine (NAC) has been suggested to reduce COPD exacerbations, it is unclear which category of patients with COPD would benefit most from NAC treatment. The objective of this study was to compare the effect of high-dose NAC (600 mg bid) between high-risk and low-risk Chinese patients with COPD.<br><br>METHODS: Patients with spirometry-confirmed stable COPD were randomized to treatment with either NAC 600 mg bid or placebo in addition to their usual treatments. Patients were followed up every 16 weeks for a total of 1 year. Further analysis was performed according to each patient's exacerbation risk at baseline as defined by the current GOLD (Global Initiative for Chronic Obstructive Lung Disease) strategy to analyze the effect of high-dose NAC in high-risk and low-risk patients.<br><br>RESULTS: Of the 120 patients with COPD randomized (men, 93.2%; mean age, 70.8 &#xb1; 0.74 years; prebronchodilator FEV&#x2081;, 53.9 &#xb1; 2.0%; baseline characteristics comparable between treatment groups), 108 (NAC, 52; placebo, 56) completed the 1-year study. For high-risk patients (n = 89), high-dose NAC compared with placebo significantly reduced exacerbation frequency (0.85 vs 1.59 [P = .019] and 1.08 vs 2.22 [P = .04] at 8 and 12 months, respectively), prolonged time to first exacerbation (P = .02), and increased the probability of being exacerbation free at 1 year (51.3% vs 24.4%, P = .013). This beneficial effect of high-dose NAC vs placebo was not significant in low-risk patients.<br><br>CONCLUSIONS: High-dose NAC (600 mg bid) for 1 year reduces exacerbations and prolongs time to first exacerbation in high-risk but not in low-risk Chinese patients with COPD.<br><br>TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov.}, }
@article {pmid24831807, year = {2014}, author = {Dutta, S and Warshall, C and Bandyopadhyay, C and Dutta, D and Chandran, B}, title = {Interactions between exosomes from breast cancer cells and primary mammary epithelial cells leads to generation of reactive oxygen species which induce DNA damage response, stabilization of p53 and autophagy in epithelial cells.}, journal = {PloS one}, volume = {9}, number = {5}, pages = {e97580}, pmid = {24831807}, issn = {1932-6203}, mesh = {Acetylcysteine/chemistry ; *Autophagy ; Breast/pathology ; Breast Neoplasms/*metabolism ; Cell Line, Tumor ; Culture Media, Conditioned/chemistry ; DNA/chemistry ; *DNA Damage ; DNA Repair ; Epithelial Cells/*cytology ; Exosomes/*metabolism ; Female ; Humans ; MCF-7 Cells ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Exosomes are nanovesicles originating from multivesicular bodies and are released by all cell types. They contain proteins, lipids, microRNAs, mRNAs and DNA fragments, which act as mediators of intercellular communications by inducing phenotypic changes in recipient cells. Tumor-derived exosomes have been shown to play critical roles in different stages of tumor development and metastasis of almost all types of cancer. One of the ways by which exosomes affect tumorigenesis is to manipulate the tumor microenvironments to create tumor permissive "niches". Whether breast cancer cell secreted exosomes manipulate epithelial cells of the mammary duct to facilitate tumor development is not known. To address whether and how breast cancer cell secreted exosomes manipulate ductal epithelial cells we studied the interactions between exosomes isolated from conditioned media of 3 different breast cancer cell lines (MDA-MB-231, T47DA18 and MCF7), representing three different types of breast carcinomas, and normal human primary mammary epithelial cells (HMECs). Our studies show that exosomes released by breast cancer cell lines are taken up by HMECs, resulting in the induction of reactive oxygen species (ROS) and autophagy. Inhibition of ROS by N-acetyl-L-cysteine (NAC) led to abrogation of autophagy. HMEC-exosome interactions also induced the phosphorylation of ATM, H2AX and Chk1 indicating the induction of DNA damage repair (DDR) responses. Under these conditions, phosphorylation of p53 at serine 15 was also observed. Both DDR responses and phosphorylation of p53 induced by HMEC-exosome interactions were also inhibited by NAC. Furthermore, exosome induced autophagic HMECs were found to release breast cancer cell growth promoting factors. Taken together, our results suggest novel mechanisms by which breast cancer cell secreted exosomes manipulate HMECs to create a tumor permissive microenvironment.}, }
@article {pmid24819310, year = {2014}, author = {Aksit, H and Bildik, A}, title = {Determination of DNA damage in experimental liver intoxication and role of N-acetyl cysteine.}, journal = {Cell biochemistry and biophysics}, volume = {70}, number = {2}, pages = {1119-1125}, doi = {10.1007/s12013-014-0031-4}, pmid = {24819310}, issn = {1559-0283}, mesh = {Acetylation/drug effects ; Acetylcysteine/*metabolism ; Animals ; Apoptosis/drug effects ; Carbon Tetrachloride/*toxicity ; Chemical and Drug Induced Liver Injury/enzymology/*metabolism/pathology ; *DNA Damage ; Disease Models, Animal ; Histone Acetyltransferases/metabolism ; Histone Deacetylases/metabolism ; Histones/metabolism ; Liver/drug effects/metabolism/pathology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The present study aimed at detecting DNA damage and fragmentation as well as histone acetylation depending on oxidative stress caused by CCl4 intoxication. Also, the protective role of N-acetyl cysteine, a precursor for GSH, in DNA damage is investigated. Sixty rats were used in this study. In order to induce liver toxicity, CCl4 in was dissolved in olive oil (1/1) and injected intraperitoneally as a single dose (2 ml/kg). N-acetyl cysteine application (intraperitoneal, 50 mg/kg/day) was started 3 days prior to CCl4 injection and continued during the experimental period. Control groups were given olive oil and N-acetyl cysteine. After 6 and 72 h of CCl4 injection, blood and liver tissue were taken under ether anesthesia. Nuclear extracts were prepared from liver. Changes in serum AST and ALT activities as well as MDA, TAS, and TOS levels showed that CCl4 caused lipid peroxidation and liver damage. However, lipid peroxidation and liver damage were reduced in the N-acetyl cysteine group. Increased levels in 8-hydroxy-2-deoxy guanosine and histone acetyltransferase activities, decreased histone deacetylase activities, and DNA breakage detected in nuclear extracts showed that CCl4 intoxication induces oxidative stress and apoptosis in rat liver. The results of the present study indicate that N-acetyl cysteine has a protective effect on CCl4-induced DNA damage.}, }
@article {pmid24817286, year = {2014}, author = {Ju, SM and Pae, HO and Kim, WS and Kang, DG and Lee, HS and Jeon, BH}, title = {Role of reactive oxygen species in p53 activation during cisplatin-induced apoptosis of rat mesangial cells.}, journal = {European review for medical and pharmacological sciences}, volume = {18}, number = {8}, pages = {1135-1141}, pmid = {24817286}, issn = {2284-0729}, mesh = {Animals ; Antineoplastic Agents/*toxicity ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line ; Cell Survival/drug effects ; Cisplatin/*toxicity ; Dose-Response Relationship, Drug ; Mesangial Cells/*drug effects/metabolism/pathology ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Time Factors ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {BACKGROUND AND OBJECTIVES: Nephrotoxicity is one of the main side effects of the anticancer drug cisplatin, and one of its main therapeutic limitations. It has been suggested that p53 activation plays important roles in renal cell injury by cisplatin. However, the mechanism of p53 activation by cisplatin is unclear. This study examined whether reactive oxygen species (ROS) production by cisplatin would be linked to p53 activation in rat mesangial cells.<br><br>MATERIALS AND METHODS: Renal cells were incubated with cisplatin in the absence or presence of pifithrin-a (PFT), N-acetyl-cysteine (NAC), or dimethylthiourea (DMT). Cell viability was evaluated by 3-(4,5-dimethyl-2-thiazol yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis was evaluated by caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP). The relative levels of ROS and p53 phosphorylation were determined by fluorometric assay and Western blot analysis, respectively.<br><br>RESULTS: Cisplatin induced apoptotic cell death via caspase-3 activation and PARP cleavage, and also increased p53 activation and ROS production. The p53 inhibitor PFT inhibited cisplatin-induced apoptosis. NAC and DMT, two antioxidants, also inhibited cisplatin-induced apoptosis. Interestingly, NAC and DMT reduced ROS production and suppressed p53 activation in renal cells exposed to cisplatin.<br><br>CONCLUSIONS: Our results suggest that the ability of cisplatin to induce apoptosis of rat mesangial cells requires ROS-dependent p53 activation, thus, supporting the potential therapeutic role of antioxidants in preventing the cisplatin nephrotoxicity.}, }
@article {pmid24810974, year = {2014}, author = {Lasram, MM and Lamine, AJ and Dhouib, IB and Bouzid, K and Annabi, A and Belhadjhmida, N and Ahmed, MB and El Fazaa, S and Abdelmoula, J and Gharbi, N}, title = {Antioxidant and anti-inflammatory effects of N-acetylcysteine against malathion-induced liver damages and immunotoxicity in rats.}, journal = {Life sciences}, volume = {107}, number = {1-2}, pages = {50-58}, doi = {10.1016/j.lfs.2014.04.033}, pmid = {24810974}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Biomarkers/analysis ; Blotting, Western ; Cell Proliferation/drug effects ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology ; Cytokines/metabolism ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Inflammation/chemically induced/*drug therapy/immunology ; Insecticides/*toxicity ; Leukocytes/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism ; Lymphocytes/drug effects/metabolism ; Malathion/*toxicity ; Male ; Oxidative Stress/drug effects ; Peroxidase/metabolism ; RNA, Messenger/genetics ; Rats ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {AIMS: Occupational exposure to organophosphate pesticides is becoming a common and increasingly alarming world-wide phenomenon. The present study is designed to investigate the preventive effect of N-acetylcysteine on malathion-induced hepatic injury and inflammation in rats.<br><br>MAIN METHODS: Adult male Wistar rats of body weight 200-230 g were used for the study. Malathion (200mg/kg b.w./day) was administered to rats by oral intubation and N-acetylcysteine (2g/l) in drinking water for 28 days. Rats were sacrificed on the 28th day, 2h after the last administration. Markers of liver injury (aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate desyhdogenase), inflammation (leukocyte counts, myeloperoxidase, immunophenotyping of CD4(+) and CD8(+), interleukin-1&#x3b2;, interleukin-6 and interferon-&#x3b3; expression) and oxidative stress (lipid peroxidation, reduced glutathione and antioxidant status) were assessed.<br><br>KEY FINDINGS: Malathion induced an increase in activities of hepatocellular enzymes in plasma, lipid peroxidation index, CD3(+)/CD4(+) and CD3(+)/CD4(+) percent and pro-inflammatory cytokines, when decreased antioxidant status in liver was noted. When malathion-treated rats were compared to NAC supplemented rats, leukocytosis, T cell count and IL-1&#x3b2;, IL-6, INF-&#x3b3; expression were reduced. Furthermore, NAC restored liver enzyme activities and oxidative stress markers.<br><br>SIGNIFICANCE: Malathion induces hepatotoxicity, oxidative stress and liver inflammation. N-acetylcysteine showed therapeutic effects against malathion toxicity.}, }
@article {pmid24804146, year = {2014}, author = {Banerjee, K and Munshi, S and Sen, O and Pramanik, V and Roy Mukherjee, T and Chakrabarti, S}, title = {Dopamine Cytotoxicity Involves Both Oxidative and Nonoxidative Pathways in SH-SY5Y Cells: Potential Role of Alpha-Synuclein Overexpression and Proteasomal Inhibition in the Etiopathogenesis of Parkinson's Disease.}, journal = {Parkinson's disease}, volume = {2014}, number = {}, pages = {878935}, pmid = {24804146}, issn = {2090-8083}, abstract = {Background. The cytotoxic effects of dopamine (DA) on several catecholaminergic cell lines involve DA oxidation products like reactive oxygen species (ROS) and toxic quinones and have implications in the pathogenesis of sporadic Parkinson's disease (PD). However, many molecular details are yet to be elucidated, and the possible nonoxidative mechanism of dopamine cytotoxicity has not been studied in great detail. Results. Cultured SH-SY5Y cells treated with DA (up to 400 μM) or lactacystin (5 μM) or DA (400 μM) plus N-acetylcysteine (NAC, 2.5 mM) for 24 h are processed accordingly to observe the cell viability, mitochondrial dysfunctions, oxidative stress parameters, proteasomal activity, expression of alpha-synuclein gene, and intracellular accumulation of the protein. DA causes mitochondrial dysfunction and extensive loss of cell viability partially inhibited by NAC, potent inhibition of proteasomal activity marginally prevented by NAC, and overexpression with accumulation of intracellular alpha-synuclein partially preventable by NAC. Under similar conditions of incubation, NAC completely prevents enhanced production of ROS and increased formation of quinoprotein adducts in DA-treated SH-SY5Y cells. Separately, proteasomal inhibitor lactacystin causes accumulation of alpha-synuclein as well as mitochondrial dysfunction and cell death. Conclusions. DA cytotoxicity includes both oxidative and nonoxidative modes and may involve overexpression and accumulation of alpha-synuclein as well as proteasomal inhibition.}, }
@article {pmid24801128, year = {2014}, author = {Gao, M and Gao, L and Tao, Y and Hou, J and Yang, G and Wu, X and Xu, H and Tompkins, VS and Han, Y and Wu, H and Zhan, F and Shi, J}, title = {Proteasome inhibitor carfilzomib interacts synergistically with histone deacetylase inhibitor vorinostat in Jurkat T-leukemia cells.}, journal = {Acta biochimica et biophysica Sinica}, volume = {46}, number = {6}, pages = {484-491}, doi = {10.1093/abbs/gmu030}, pmid = {24801128}, issn = {1745-7270}, mesh = {Apoptosis/drug effects ; Drug Synergism ; Histone Deacetylase Inhibitors/*pharmacology ; Humans ; Hydroxamic Acids/*pharmacology ; Jurkat Cells ; Membrane Potential, Mitochondrial/drug effects ; Oligopeptides/*pharmacology ; Proteasome Endopeptidase Complex/*drug effects ; Reactive Oxygen Species/metabolism ; Vorinostat ; }, abstract = {In the present study, we investigated the interactions between proteasome inhibitor carfilzomib (CFZ) and histone deacetylase inhibitor vorinostat in Jurkat T-leukemia cells. Coexposure of cells to minimally lethal concentrations of CFZ with very low concentration of vorinostat resulted in synergistic antiproliferative effects and enhanced apoptosis in Jurkat T-leukemia cells, accompanied with the sharply increased reactive oxygen species (ROS), the striking decrease in the mitochondrial membrane potential (MMP), the increased release of cytochrome c, the enhanced activation of caspase-9 and -3, and the cleavage of PARP. The combined treatment of Jurkat cells pre-treated with ROS scavengers N-acetylcysteine (NAC) significantly blocked the loss of mitochondrial membrane potential, suggesting that ROS generation was a former event of the loss of mitochondrial membrane potential. Furthermore, NAC also resulted in a marked reduction in apoptotic cells, indicating a critical role for increased ROS generation by combined treatment. In addition, combined treatment arrested the cell cycle in G2-M phase. These results imply that CFZ interacted synergistically with vorinostat in Jurkat T-leukemia cells, which raised the possibility that the combination of carfilzomib with vorinostat may represent a novel strategy in treating T-cell Leukemia.}, }
@article {pmid24800642, year = {2014}, author = {Halladin, NL and Zahle, FV and Rosenberg, J and Gögenur, I}, title = {Interventions to reduce tourniquet-related ischaemic damage in orthopaedic surgery: a qualitative systematic review of randomised trials.}, journal = {Anaesthesia}, volume = {69}, number = {9}, pages = {1033-1050}, doi = {10.1111/anae.12664}, pmid = {24800642}, issn = {1365-2044}, mesh = {Adolescent ; Adult ; Aged ; Anesthesia ; Antioxidants/therapeutic use ; Female ; Humans ; Ischemia/*etiology/*prevention &amp; control ; Ischemic Preconditioning ; Male ; Middle Aged ; Orthopedic Procedures/*adverse effects ; Oxidative Stress/physiology ; Randomized Controlled Trials as Topic ; Research Design ; Tourniquets/*adverse effects ; Treatment Outcome ; Young Adult ; }, abstract = {Ischaemia of the extremity from the use of a tourniquet and the subsequent reperfusion contribute to the release of reactive oxygen species. This release may result in injury to remote organs. We performed a qualitative systematic review exploring the interventions used to prevent tourniquet-related oxidative damage in adults undergoing orthopaedic surgery, and the possible relationship between biochemical oxidative stress markers and postoperative clinical outcomes. Seventeen randomised controlled studies were included in the qualitative synthesis. Most trials were of low methodological quality and only two studies reported postoperative clinical outcomes. Nine studies tested anaesthetics (propofol, dexmedetomidine, ketamine, and spinal anaesthesia); four studies tested antioxidants (N-acetyl-cysteine, vitamin C, and mannitol); and four studies tested ischaemic pre-conditioning. Fifteen studies showed a significant reduction in biochemical oxidative stress markers. We conclude that propofol and ischaemic pre-conditioning, in particular, appear to show some benefit at reducing oxidative stress following operations under tourniquet; the correlation between a reduction in oxidative stress and postoperative clinical outcomes should be further investigated in the future.}, }
@article {pmid24799199, year = {2014}, author = {Yang, Q and Shi, L and Huang, K and Xu, W}, title = {Protective effect of N-acetylcysteine against DNA damage and S-phase arrest induced by ochratoxin A in human embryonic kidney cells (HEK-293).}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {70}, number = {}, pages = {40-47}, doi = {10.1016/j.fct.2014.04.039}, pmid = {24799199}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Cell Cycle Checkpoints/drug effects ; Cell Survival/drug effects ; Comet Assay ; Cyclin A2/genetics/metabolism ; Cyclin E/genetics/metabolism ; Cyclin-Dependent Kinase 2/genetics/metabolism ; DNA Damage/*drug effects ; Down-Regulation ; HEK293 Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Ochratoxins/*toxicity ; Oncogene Proteins/genetics/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {N-acetylcysteine (NAC) has recently gained particular interest as a beneficial antioxidant. This study investigated the protective effects of NAC against ochratoxin A (OTA)-induced DNA damage and S-phase arrest in human embryonic kidney cells (HEK-293). OTA exposure results in nephrotoxicity, hepatotoxicity as well as immunotoxicity; and, in the present study, the toxicity of OTA toward HEK-293 cells was explored by analyzing the involvement of the oxidative pathway. It was found that OTA treatment led to oxidative damage; meanwhile, OTA treatment induced significant DNA damage and S-phase arrest by down-regulating cyclin A2, cyclin E1, and CDK2 expression. However, NAC pretreatment alleviated OTA-induced ROS overproduction, the loss of mitochondrial membrane potential (ΔΨm), and the decrease in superoxide dismutase (SOD) activity. NAC pretreatment was also discovered to attenuate OTA-induced DNA damage using the comet assay and by determining the expression of γ-H2AX. In addition, NAC pretreatment partly ameliorated OTA-induced S-phase arrest by preventing the down-regulation of cyclin A2, cyclin E1 and CDK2 expression in HEK-293 cells. All of these results demonstrated that oxidative damage was involved in OTA-induced DNA damage and cell cycle arrest in HEK-293 cells. Therefore, NAC has the potential to reverse the DNA damage and S-phase arrest induced by OTA.}, }
@article {pmid24798751, year = {2014}, author = {Tsai, ML and Huang, HP and Hsu, JD and Lai, YR and Hsiao, YP and Lu, FJ and Chang, HR}, title = {Topical N-acetylcysteine accelerates wound healing in vitro and in vivo via the PKC/Stat3 pathway.}, journal = {International journal of molecular sciences}, volume = {15}, number = {5}, pages = {7563-7578}, pmid = {24798751}, issn = {1422-0067}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Topical ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Burns/*drug therapy/metabolism/pathology ; Cell Line ; Cell Proliferation/drug effects ; Humans ; Male ; Mitogen-Activated Protein Kinase 1/metabolism ; Protein Kinase C/*metabolism ; Rats ; Rats, Wistar ; STAT3 Transcription Factor/*metabolism ; Signal Transduction/drug effects ; Skin/drug effects/metabolism/pathology ; Wound Healing/*drug effects ; }, abstract = {N-Acetylcysteine (Nac) is an antioxidant administered in both oral and injectable forms. In this study, we used Nac topically to treat burn wounds in vitro and in vivo to investigate mechanisms of action. In vitro, we monitored glutathione levels, cell proliferation, migration, scratch-wound healing activities and the epithelialization-related proteins, matrixmetalloproteinase-1 (MMP-1) and proteins involved in regulating the expression of MMP-1 in CCD-966SK cells treated with Nac. Various Nac concentrations (0.1, 0.5, and 1.0 mM) increased glutathione levels, cell viability, scratch-wound healing activities and migration abilities of CCD-966SK cells in a dose-dependent manner. The MMP-1 expression of CCD-966SK cells treated with 1.0 mM Nac for 24 h was significantly increased. Levels of phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), janus kinase 1 (Jak1), signal transducer and activator of transcription 3 (Stat3), c-Fos and Jun, but not extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), were also significantly increased in a dose-dependent manner compared to the controls. In addition, Nac induced collagenous expression of MMP-1 via the PKC/Stat3 signaling pathway. In vivo, a burn wound healing rat model was applied to assess the stimulation activity and histopathological effects of Nac, with 3.0% Nac-treated wounds being found to show better characteristics on re-epithelialization. Our results demonstrated that Nac can potentially promote wound healing activity, and may be a promising drug to accelerate burn wound healing.}, }
@article {pmid24798519, year = {2015}, author = {Al-Halabi, R and Abou Merhi, R and Chakilam, S and El-Baba, C and Hamade, E and Di Fazio, P and Ocker, M and Schneider-Stock, R and Gali-Muhtasib, H}, title = {Gallotannin is a DNA damaging compound that induces senescence independently of p53 and p21 in human colon cancer cells.}, journal = {Molecular carcinogenesis}, volume = {54}, number = {10}, pages = {1037-1050}, doi = {10.1002/mc.22172}, pmid = {24798519}, issn = {1098-2744}, mesh = {Antioxidants/metabolism ; Catalase/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cellular Senescence/*drug effects ; Colonic Neoplasms/*drug therapy/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/*metabolism ; DNA Damage/*drug effects ; Dithiothreitol/metabolism ; HCT116 Cells ; Humans ; Hydrolyzable Tannins/*pharmacology ; Reactive Oxygen Species/metabolism ; S Phase/drug effects ; Superoxide Dismutase/metabolism ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {The plant secondary metabolite gallotannin (GT) is the simplest hydrolyzable tannin shown to have anti-carcinogenic properties in several cell lines and to inhibit tumor development in different animal models. Here, we determined if GT induces senescence and DNA damage and investigated the involvement of p53 and p21 in this response. Using HCT116 human colon cancer cells wildtype for p53(+/+) /p21(+/+) and null for p53(+/+) /p21(-/-) or p53(-/-) /p21(+/+) , we found that GT induces senescence independently of p21 and p53. GT was found to increase the production of reactive oxygen species (ROS) by altering the redox balance in the cell, mainly by reducing the levels of glutathione and superoxide dismutase (SOD). Using the key antioxidants N-acetyl cysteine, dithiothreitol, SOD, and catalase, we showed that ROS were partially involved in the senescence response. Furthermore, GT-induced cell cycle arrest in S-phase in all HCT116 cell lines. At later time points, we noticed that p53 and p21 null cells escaped complete arrest and re-entered cell cycle provoking higher rates of multinucleation. The senescence induction by GT was irreversible and was accompanied by significant DNA damage as evidenced by p-H2AX staining. Our findings indicate that GT is an interesting anti colon cancer agent which warrants further study.}, }
@article {pmid24796672, year = {2014}, author = {Yang, KM and Kim, BM and Park, JB}, title = {ω-Hydroxyundec-9-enoic acid induces apoptosis through ROS-mediated endoplasmic reticulum stress in non-small cell lung cancer cells.}, journal = {Biochemical and biophysical research communications}, volume = {448}, number = {3}, pages = {267-273}, doi = {10.1016/j.bbrc.2014.04.111}, pmid = {24796672}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology ; Caspase 6/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Endoplasmic Reticulum Stress/drug effects ; Free Radical Scavengers/pharmacology ; Gene Knockdown Techniques ; Humans ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; Transcription Factor CHOP/antagonists &amp; inhibitors/genetics/metabolism ; Undecylenic Acids/*pharmacology ; }, abstract = {ω-Hydroxyundec-9-enoic acid (ω-HUA), a hydroxyl unsaturated fatty acid derivative, is involved in the antifungal activity of wild rice (Oryza officinalis). Here, we investigated the anti-cancer activity of ω-HUA on a non-small cell lung cancer (NSCLC) cell line. ω-HUA increased apoptosis and induced cleavages of caspase-6, caspase-9, and poly (ADP-ribose) polymerase (PARP). ω-HUA treatment significantly induced endoplasmic reticulum (ER) stress response. Suppression of CHOP expression and inhibiting ER stress by 4-phenylbutyrate (4-PBA) significantly attenuated the ω-HUA treatment-induced activation of caspase-6, caspase-9, and PARP, and subsequent apoptotic cell death, indicating a role for ER stress in ω-HUA-induced apoptosis. In addition, cells subjected to ω-HUA exhibited significantly increased quantity of reactive oxygen species (ROS), and the ROS scavenger N-acetyl-L-cysteine (NAC) inhibited ω-HUA-induced apoptotic cell death and ER stress signals, indicating a role for ROS in ER stress-mediated apoptosis in ω-HUA-treated cells. Taken together, these results suggest that sequential ROS generation and ER stress activation are critical in ω-HUA treatment-induced apoptosis and that ω-HUA represents a promising candidate for NSCLC treatment.}, }
@article {pmid24795232, year = {2014}, author = {Itoh, T and Koketsu, M and Yokota, N and Touho, S and Ando, M and Tsukamasa, Y}, title = {Reduced scytonemin isolated from Nostoc commune suppresses LPS/IFNγ-induced NO production in murine macrophage RAW264 cells by inducing hemeoxygenase-1 expression via the Nrf2/ARE pathway.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {69}, number = {}, pages = {330-338}, doi = {10.1016/j.fct.2014.04.019}, pmid = {24795232}, issn = {1873-6351}, mesh = {Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Antioxidant Response Elements/*drug effects ; Cell Line/drug effects ; Cytoskeletal Proteins/metabolism ; Heme Oxygenase-1/*metabolism ; Indoles/*isolation &amp; purification/*pharmacology ; Interferon-gamma/metabolism/pharmacology ; Kelch-Like ECH-Associated Protein 1 ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects/metabolism ; Mice ; NF-E2-Related Factor 2/metabolism ; Nitric Oxide/*metabolism ; Nostoc commune/*chemistry ; Phenols/*isolation &amp; purification/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Reduced scytonemin (R-scy) and scytonemin (Scy) isolated from Nostoc commune exhibit anti-tumor and ultraviolet-absorbing properties. In this study, we examined the effects of R-scy and Scy on the induction of nitric oxide (NO) production by lipopolysaccharide (LPS) and interferon-γ (IFNγ) in murine macrophage RAW264 cells. While both R-scy and Scy suppressed LPS/IFNγ-induced NO production, R-scy exhibited a stronger inhibitory effect compared with Scy. To further elucidate the mechanisms underlying the anti-inflammatory effects of R-scy, we examined the changes in the intracellular signaling cascade after LPS/IFNγ stimulation in cells. In addition to the attenuation of LPS/IFNγ-induced upregulation of the inducible isoform of NO synthase, R-scy decreased the activity of nuclear factor-κB, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) after LPS/IFNγ stimulation. R-scy treatment increased heme oxygenase-1 (HO-1) expression by increasing the intracellular levels of reactive oxygen species and thereby activating nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element signaling. The induction of HO-1 by R-scy was inhibited by pretreatment with an antioxidant, N-acetyl-cysteine (NAC), as well as SB203580 and LY294002, inhibitors for p38 MAPK and PI3K/Akt, respectively. Our findings suggest that the anti-inflammatory effects of R-scy could involve both the ROS/PI3K/Akt and the p38 MAPK/Nrf2 signaling pathways.}, }
@article {pmid24794623, year = {2014}, author = {Dündar, R and İnan, S and Muluk, NB and Cingi, C and İlknur, AE and Katılmış, H}, title = {Inhibitory effect of N-acetyl cysteine and ascorbic acid on the development of myringosclerosis: an experimental study.}, journal = {International journal of pediatric otorhinolaryngology}, volume = {78}, number = {7}, pages = {1019-1025}, doi = {10.1016/j.ijporl.2014.03.029}, pmid = {24794623}, issn = {1872-8464}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Ascorbic Acid/*pharmacology ; Disease Models, Animal ; Female ; Fibrin Foam ; Fibroblasts/metabolism ; Free Radical Scavengers/pharmacology ; Guinea Pigs ; Hemostatics ; Immunohistochemistry ; Inflammation/pathology ; Leukocytes/metabolism ; Microscopy ; Mucous Membrane/pathology ; Myringosclerosis/pathology/*prevention &amp; control ; Nitric Oxide Synthase/metabolism ; Random Allocation ; Transforming Growth Factor beta/metabolism ; Tympanic Membrane/*metabolism/*pathology ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {OBJECTIVES: This study investigated the effects of ascorbic acid and N-acetyl cysteine (NAC) antioxidants on the development of myringosclerosis (MS) in an experimental model.<br><br>METHODS: Myringotomies were performed in the ears of 15 guinea pigs, and Spongostan pieces were placed on the perforated regions of the tympanic membrane. The subjects were divided randomly into three groups and treated with three different solutions on the Spongostan-group 1: (control, 0.9% saline), group 2 (ascorbic acid), and group 3 (NAC). On day 15 after treatment, specimens from the tympanic membranes were obtained and examined via light microscopy. Sclerosis and inflammation scores and the tympanic membrane thicknesses were evaluated. Immunohistochemical methods were used to evaluate the expression of VEGF, TGF-&#x3b2;, iNOS, and IL1-&#x3b2; in all groups.<br><br>RESULTS: Lower sclerosis and inflammation scores and reduced tympanic membrane thicknesses were observed in groups treated with NAC or ascorbic acid compared with the control group. Immunohistochemical studies revealed significantly less expression of VEGF, TGF-&#x3b2;, and iNOS in groups 2 and 3 compared with group 1. Additionally, IL1-&#x3b2; expression was significantly less in group 3 than in group 1. Compared with group 1, group 2 animals exhibited reduced inflammation in the lamina propria, fewer active fibroblasts, less leukocyte infiltration, and decreased thickness of the vessels; group 3 animals exhibited decreased numbers of active fibroblasts and collagen fibers in the lamina propria.<br><br>CONCLUSIONS: Inflammation scores, cellular infiltration, and expression of VEGF, TGF-&#x3b2;, and iNOS were reduced by ascorbic acid and/or NAC treatments, thereby decreasing MS development. Decreased expression of IL1-&#x3b2; was observed only in animals treated with NAC.}, }
@article {pmid24793375, year = {2014}, author = {Ma, WD and Zou, YP and Wang, P and Yao, XH and Sun, Y and Duan, MH and Fu, YJ and Yu, B}, title = {Chimaphilin induces apoptosis in human breast cancer MCF-7 cells through a ROS-mediated mitochondrial pathway.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {70}, number = {}, pages = {1-8}, doi = {10.1016/j.fct.2014.04.014}, pmid = {24793375}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Annexin A5/metabolism ; Apoptosis/*drug effects ; Caspase 3/genetics/metabolism ; Caspase 9/genetics/metabolism ; Cell Proliferation/drug effects ; DNA Fragmentation/drug effects ; Fluorescein-5-isothiocyanate/analogs &amp; derivatives/metabolism ; Humans ; Inhibitory Concentration 50 ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Naphthoquinones/*pharmacology ; Passiflora/chemistry ; Propidium/metabolism ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; bcl-Associated Death Protein/genetics/metabolism ; }, abstract = {Chimaphilin, 2,7-dimethyl-1,4-naphthoquinone, is extracted from pyrola [Passiflora incarnata Fisch.]. In this study, the anticancer activity and underlying mechanisms of chimaphilin toward human breast cancer MCF-7 cells are firstly investigated. Chimaphilin could inhibit the viability of MCF-7 cells in a concentration-dependent manner, and the IC50 value was 43.30μM for 24h. Chimaphilin markedly induced apoptosis through the investigation of characteristic apoptotic morphological changes, nuclear DNA fragmentation, annexin V-FITC/propidium iodide (PI) double staining. Flow cytometry assay revealed that chimaphilin triggered a significant generation of ROS and disruption of mitochondrial membrane potential. Additionally, western blotting assay showed that chimaphilin suppressed Bcl-2 level and enhanced Bad level, then activated caspase-9 and caspase-3, and further activated the poly ADP-ribose polymerase (PARP), finally induced cell apoptosis involving the mitochondrial pathway. Furthermore, free radical scavengers N-acetyl-L-cysteine (NAC) pretreatment test testified that chimaphilin could increase the generation of ROS, then induce cell apoptosis. In general, the present results demonstrated that chimaphilin induced apoptosis in human breast cancer MCF-7 cells via a ROS-mediated mitochondrial pathway.}, }
@article {pmid24792639, year = {2014}, author = {Pandya, JD and Readnower, RD and Patel, SP and Yonutas, HM and Pauly, JR and Goldstein, GA and Rabchevsky, AG and Sullivan, PG}, title = {N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI.}, journal = {Experimental neurology}, volume = {257}, number = {}, pages = {106-113}, pmid = {24792639}, issn = {1090-2430}, support = {R01NS069633/NS/NINDS NIH HHS/United States ; R01 NS069633/NS/NINDS NIH HHS/United States ; P30 NS051220/NS/NINDS NIH HHS/United States ; P30NS051220/NS/NINDS NIH HHS/United States ; R01 NS062993/NS/NINDS NIH HHS/United States ; F31 NS086395/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/therapeutic use ; Aldehydes/metabolism ; Animals ; Brain Injuries/*complications/*drug therapy ; Cerebral Cortex/drug effects/pathology/ultrastructure ; Disease Models, Animal ; Double-Blind Method ; Energy Metabolism/*drug effects ; Glutathione/metabolism ; Male ; Maze Learning/*drug effects ; Mitochondria/drug effects ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/drug effects ; Oxygen Consumption/drug effects ; Rats ; Rats, Sprague-Dawley ; Time Factors ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Traumatic brain injury (TBI) has become a growing epidemic but no approved pharmacological treatment has been identified. Our previous work indicates that mitochondrial oxidative stress/damage and loss of bioenergetics play a pivotal role in neuronal cell death and behavioral outcome following experimental TBI. One tactic that has had some experimental success is to target glutathione using its precursor N-acetylcysteine (NAC). However, this approach has been hindered by the low CNS bioavailability of NAC. The current study evaluated a novel, cell permeant amide form of N-acetylcysteine (NACA), which has high permeability through cellular and mitochondrial membranes resulting in increased CNS bioavailability. Cortical tissue sparing, cognitive function and oxidative stress markers were assessed in rats treated with NACA, NAC, or vehicle following a TBI. At 15days post-injury, animals treated with NACA demonstrated significant improvements in cognitive function and cortical tissue sparing compared to NAC or vehicle treated animals. NACA treatment also was shown to reduce oxidative damage (HNE levels) at 7days post-injury. Mechanistically, post-injury NACA administration was demonstrated to maintain levels of mitochondrial glutathione and mitochondrial bioenergetics comparable to sham animals. Collectively these data provide a basic platform to consider NACA as a novel therapeutic agent for treatment of TBI.}, }
@article {pmid24792472, year = {2014}, author = {Song, J and Wei, Y and Chen, Q and Xing, D}, title = {Cyclooxygenase 2-mediated apoptotic and inflammatory responses in photodynamic therapy treated breast adenocarcinoma cells and xenografts.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {134}, number = {}, pages = {27-36}, doi = {10.1016/j.jphotobiol.2014.03.015}, pmid = {24792472}, issn = {1873-2682}, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/drug therapy/metabolism/pathology ; Animals ; Apoptosis/*drug effects ; Breast Neoplasms/drug therapy/metabolism/pathology ; Cyclooxygenase 2/chemistry/genetics/*metabolism ; Dinoprostone/metabolism ; Female ; Humans ; Imidazoles/pharmacology ; Interleukin-1beta/metabolism ; Light ; MCF-7 Cells ; Mice ; Mice, Inbred BALB C ; Photosensitizing Agents/*pharmacology/therapeutic use ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/radiation effects ; Transplantation, Heterologous ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Cyclooxygenase 2 (COX-2) is an inducible enzyme that contributes to the generation of chronic inflammation and the development of cancer, and promotes neoplastic transformation, in response to chemical carcinogens and environmental stresses. In this study, we demonstrated that a sublethal dose photodynamic therapy (PDT) led to inflammatory response mediated by the induction of COX-2 and release of Prostaglandin E2 (PGE2). Pretreatment with N-acetylcysteine (NAC) reduced COX-2 expression and PGE2 release induced by PDT. The elevated COX-2 level and PGE2 release following PDT were inhibited by NADPH oxidase inhibitor and NF-κB inhibitor. Inhibition of COX-2 attenuated the levels of PGE2 and vascular endothelial growth factor (VEGF) following PDT in treated tumors, and also decreased the expression of proinflammatory mediators interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). In addition, PDT led to an appreciable accumulation of pSer15-p53/COX-2 complexes, and this association of complexes was partially inhibited by SB203580, an inhibitor of p38. Blockage of COX-2 expression by siRNA enhanced the transcriptional activity of p53, and facilitated PDT-induced loss of mitochondrial membrane potential and cleavage of caspase 3, probably due to the elevated Noxa expression disrupting the interaction of Mcl-1/Bax. Together, this study highlights the important roles of COX-2 in PDT-induced apoptosis and inflammation and the specific COX-2-mediated responses to PDT initiated by reactive oxygen species (ROS) involving the regulation of the multiple signaling pathways. These results indicate the inflammatory mediator COX-2 as a potential therapeutic target for improving PDT efficacy.}, }
@article {pmid24791566, year = {2014}, author = {Shiyovich, A and Rosman, Y and Krivoy, A and Statlender, L and Kassirer, M and Shrot, S}, title = {[Long-term complications of sulfur mustard exposure: a therapeutic update].}, journal = {Harefuah}, volume = {153}, number = {3-4}, pages = {199-205, 237}, pmid = {24791566}, issn = {0017-7768}, mesh = {*Chemical Warfare ; Chemical Warfare Agents/*toxicity ; Clinical Trials as Topic ; Eye Diseases/chemically induced/physiopathology/therapy ; Humans ; Iran ; Iraq ; Mustard Gas/*toxicity ; Respiratory Tract Diseases/chemically induced/physiopathology/therapy ; Skin Diseases/chemically induced/pathology ; Time Factors ; Warfare ; }, abstract = {Sulfur mustard (SM) is an alkylating chemical warfare agent with high military significance due to its high toxicity, resistance and availability. SM was widely used in military conflicts, the last being the Iran-Iraq war with more than 100,000 Iranians exposed, one-third of whom are still suffering from late effects. The intensity of the delayed complications correlates to the extent, the area and the route of exposure. The clinical manifestations most commonly involve respiratory, ocular and dermal effects. Respiratory complications include dyspnea, cough and expectorations and various obstructive and restrictive lung diseases. Dermal complications are itching, burning sensation, blisters, dry skin, dermatitis and pigmentary changes. Ocular complications include photophobia, red eye, tearing, corneal ulcers and blindness. Although the picture remains incomplete the major mechanisms responsible for the clinical and pathological effects of SM are: DNA alkylation and cross-linking, protein modification and membrane damage in addition to induction of inflammatory mediators in the target tissues causing extensive necrosis, apoptosis and loss of tissue structure. The current report reviews long-term complications of SM exposure, focusing on new treatments tested in clinical trials conducted on humans. Such treatments include: N-acetyl cysteine, bronchodilators, corticosteroids, Interferon-gamma, furosemide and morphine for the respiratory complications. Ocular complications may entail: Invasive procedures treating corneal complication, limbal ischemia and stem cell deficiency. Treatment for dermatological complications include: anti-depressants, pimercrolimus, Unna's boot, capsaicin, phenol and menthol, Aloe vera and olive oil, curcumin and Interferon-gamma.}, }
@article {pmid24791272, year = {2014}, author = {Bischel, LL and Casavant, BP and Young, PA and Eliceiri, KW and Basu, HS and Beebe, DJ}, title = {A microfluidic coculture and multiphoton FAD analysis assay provides insight into the influence of the bone microenvironment on prostate cancer cells.}, journal = {Integrative biology : quantitative biosciences from nano to macro}, volume = {6}, number = {6}, pages = {627-635}, pmid = {24791272}, issn = {1757-9708}, support = {R33CA160244/CA/NCI NIH HHS/United States ; T32HL007889/HL/NHLBI NIH HHS/United States ; R01 CA136590/CA/NCI NIH HHS/United States ; R21 CA176218/CA/NCI NIH HHS/United States ; T32 HL007899/HL/NHLBI NIH HHS/United States ; T32 HL007889/HL/NHLBI NIH HHS/United States ; R21CA176218-01/CA/NCI NIH HHS/United States ; R33 CA137673/CA/NCI NIH HHS/United States ; R01 CA185251/CA/NCI NIH HHS/United States ; R01EB10039/EB/NIBIB NIH HHS/United States ; R01 EB010039/EB/NIBIB NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Coculture Techniques ; Flavin-Adenine Dinucleotide/*metabolism ; Humans ; Male ; Mesenchymal Stem Cells/cytology/*metabolism ; Microfluidics ; Microscopy, Fluorescence, Multiphoton ; Prostatic Neoplasms/*metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; }, abstract = {In prostate cancer, bone is a frequent site of metastasis; however, the molecular mechanisms of this tumor tropism remain unclear. Here, we integrate a microfluidic coculture platform with multi-photon imaging based techniques to assess both phenotypic cell behavior and FAD fluorescence intensity and fluorescence lifetime in the same cell. This platform combines two independent assays normally performed with two different cell populations into a single device, allowing us to simultaneously assess both phenotypic cell behavior and enzyme activity. We observed that the osteotropic prostate cancer cell line (C4-2B), when in a coculture with bone marrow stromal cells (MC3T3-E1), has increased protrusive phenotype and increased total and protein-bound FAD compared to its parent cell line (LNCaP). We hypothesized that an increase in ROS-generating APAO activity may be responsible for these effects, and found that the effects were decreased in the presence of the antioxidant N-Acetyl Cysteine (NAC). This suggests that an ROS-related signaling mechanism at the bone metastatic site may be correlated with and play a role in increased invasion of metastasizing prostate cancer cells. The studies performed using this combined platform will lead to new insights into the mechanisms that drive prostate cancer metastasis.}, }
@article {pmid24787454, year = {2014}, author = {Santus, P and Corsico, A and Solidoro, P and Braido, F and Di Marco, F and Scichilone, N}, title = {Oxidative stress and respiratory system: pharmacological and clinical reappraisal of N-acetylcysteine.}, journal = {COPD}, volume = {11}, number = {6}, pages = {705-717}, pmid = {24787454}, issn = {1541-2563}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Bronchitis, Chronic/drug therapy ; Disease Progression ; Expectorants/pharmacology/*therapeutic use ; Forced Expiratory Volume/drug effects ; Hospitalization ; Humans ; Macrophages ; Neutrophils ; *Oxidative Stress ; Pulmonary Disease, Chronic Obstructive/*drug therapy/*etiology/physiopathology ; Reactive Oxygen Species/metabolism ; Respiratory Physiological Phenomena ; }, abstract = {The large surface area for gas exchange makes the respiratory system particularly susceptible to oxidative stress-mediated injury. Both endogenous and exogenous pro-oxidants (e.g. cigarette smoke) trigger activation of leukocytes and host defenses. These mechanisms interact in a "multilevel cycle" responsible for the control of the oxidant/antioxidant homeostasis. Several studies have demonstrated the presence of increased oxidative stress and decreased antioxidants (e.g. reduced glutathione [GSH]) in subjects with chronic obstructive pulmonary disease (COPD), but the contribution of oxidative stress to the pathophysiology of COPD is generally only minimally discussed. The aim of this review was to provide a comprehensive overview of the role of oxidative stress in the pathogenesis of respiratory diseases, particularly COPD, and to examine the available clinical and experimental evidence on the use of the antioxidant N-acetylcysteine (NAC), a precursor of GSH, as an adjunct to standard therapy for the treatment of COPD. The proposed concept of "multilevel cycle" helps understand the relationship between respiratory diseases and oxidative stress, thus clarifying the rationale for using NAC in COPD. Until recently, antioxidant drugs such as NAC have been regarded only as mucolytic agents. Nevertheless, several clinical trials indicate that NAC may reduce the rate of COPD exacerbations and improve small airways function. The most plausible explanation for the beneficial effects observed in patients with COPD treated with NAC lies in the mucolytic and antioxidant effects of this drug. Modulation of bronchial inflammation by NAC may further account for these favorable clinical results.}, }
@article {pmid24785381, year = {2014}, author = {Lasram, MM and Bini Douib, I and Bouzid, K and Annabi, A and El Elj, N and Dhouib, H and El Fazaa, S and Abdelmoula, J and Gharbi, N}, title = {Effects of N-acetyl-l-cysteine, in vivo, against pathological changes induced by malathion.}, journal = {Toxicology mechanisms and methods}, volume = {24}, number = {4}, pages = {294-306}, doi = {10.3109/15376516.2014.886003}, pmid = {24785381}, issn = {1537-6524}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/metabolism ; Alkaline Phosphatase/metabolism ; Animals ; Aspartate Aminotransferases/metabolism ; Cholinesterases/metabolism ; Creatine Kinase/metabolism ; Insecticides/*toxicity ; Kidney Function Tests ; L-Lactate Dehydrogenase/metabolism ; Liver/drug effects/enzymology ; Malathion/*toxicity ; Male ; Rats ; Rats, Wistar ; }, abstract = {Malathion toxicity has been related to the inhibition of acetylcholinesterase, induction of oxidative stress, liver damage and impairment of kidney function as well as hematotoxicity. N-acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the protective effect of NAC against toxic consequences of malathion exposure in Wistar rats. Malathion was given daily to rats via oral gavage and NAC in drinking water during seven days. When malathion-treated rats were compared with control, a leukocytosis and reduced hemoglobin (HGB) content were detected. Furthermore, malathion produced a significant increase in liver enzymes such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase and creatinine kinase. In addition, a decrease in acid phosphatase activity, protein and globulin levels were observed in malathion-treated rats compared with control. Moreover, analyses of the mineral status showed a disturbance in calcium, magnesium, phosphore and iron contents of the malathion-treated rats. Interestingly, NAC showed therapeutic effects against malathion toxicity. Indeed, HGB content and all liver enzymes were restored to normal values. Finally, the use of NAC as therapeutic agent for only seven days during malathion exposure showed interesting results on tissues damages.}, }
@article {pmid24778352, year = {2014}, author = {Lim, TY and Stafford, RJ and Kudchadker, RJ and Sankaranarayanapillai, M and Ibbott, G and Rao, A and Martirosyan, KS and Frank, SJ}, title = {MRI characterization of cobalt dichloride-N-acetyl cysteine (C4) contrast agent marker for prostate brachytherapy.}, journal = {Physics in medicine and biology}, volume = {59}, number = {10}, pages = {2505-2516}, pmid = {24778352}, issn = {1361-6560}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R43 CA150320/CA/NCI NIH HHS/United States ; 1R43CA150320-01A1/CA/NCI NIH HHS/United States ; }, mesh = {*Acetylcysteine ; Brachytherapy/*standards ; *Contrast Media ; *Fiducial Markers ; Humans ; *Magnetic Resonance Imaging ; Male ; Prostatic Neoplasms/*diagnosis/*radiotherapy ; Temperature ; Time Factors ; }, abstract = {Brachytherapy, a radiotherapy technique for treating prostate cancer, involves the implantation of numerous radioactive seeds into the prostate. While the implanted seeds can be easily identified on a computed tomography image, distinguishing the prostate and surrounding soft tissues is not as straightforward. Magnetic resonance imaging (MRI) offers superior anatomical delineation, but the seeds appear as dark voids and are difficult to identify, thus creating a conundrum. Cobalt dichloride-N-acetyl-cysteine (C4) has previously been shown to be promising as an encapsulated contrast agent marker. We performed spin-lattice relaxation time (T1) and spin-spin relaxation time (T2) measurements of C4 solutions with varying cobalt dichloride concentrations to determine the corresponding relaxivities, r1 and r2. These relaxation parameters were investigated at different field strengths, temperatures and orientations. T1 measurements obtained at 1.5 and 3.0 T, as well as at room and body temperature, showed that r1 is field-independent and temperature-independent. Conversely, the T2 values at 3.0 T were shorter than at 1.5 T, while the T2 values at body temperature were slightly higher than at room temperature. By examining the relaxivities with the C4 vials aligned in three different planes, we found no orientation-dependence. With these relaxation characteristics, we aim to develop pulse sequences that will enhance the C4 signal against prostatic stroma. Ultimately, the use of C4 as a positive contrast agent marker will encourage the use of MRI to obtain an accurate representation of the radiation dose delivered to the prostate and surrounding normal anatomical structures.}, }
@article {pmid24777714, year = {2014}, author = {Shen, SC and Wu, MS and Lin, HY and Yang, LY and Chen, YH and Chen, YC}, title = {Reactive oxygen species-dependent nitric oxide production in reciprocal interactions of glioma and microglial cells.}, journal = {Journal of cellular physiology}, volume = {229}, number = {12}, pages = {2015-2026}, doi = {10.1002/jcp.24659}, pmid = {24777714}, issn = {1097-4652}, mesh = {Anthracenes/administration &amp; dosage ; Butadienes/administration &amp; dosage ; Cell Line, Tumor ; Cell Survival/drug effects ; Chemokine CCL2/metabolism ; Coculture Techniques ; Culture Media, Conditioned ; Gene Expression Regulation, Neoplastic/drug effects ; Glioma/*metabolism/pathology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Microglia/*metabolism/pathology ; NF-kappa B/biosynthesis/metabolism ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitriles/administration &amp; dosage ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {Conditioned mediums (CMs) from glioma cells U87, GBM-8401, and C6 significantly induced iNOS protein and NO production by microglial cells BV-2 but without altering the cell viability or cell-cycle progression of BV2 microglia. Significant increases in intracellular peroxide by U87-CM and C6-CM were detected by a DCHF-DA assay, and vitamin (Vit) C and N-acetyl cysteine (NAC)-reduced intracellular peroxide levels elicited by CMs lead to inhibition of iNOS/NO production The extracellular signal-regulated kinase (ERK) inhibitor, U0126, and c-Jun N-terminal kinase (JNK) inhibitor, SP600125, suppressed U87-CM- and C6-CM-induced iNOS/NO production by respectively blocking phosphorylated ERK (pERK) and JNK (pJNK) protein expressions stimulated by U87-CM and C6-CM. Increased migration of U87 and C6 glioma cells by a co-culture with BV-2 microglial cells or adding the nitric oxide (NO) donor, sodium nitroprusside (SNP) was observed, and that was blocked by adding an NO synthase (NOS) inhibitor, N-nitro L-arginine methyl ester (NAME). Contributions of ROS, pERK, and pJNK to the migration of glioma cells was further demonstrated in a transwell coculture system of U87 and C6 gliomas with BV-2 microglial cells. Furthermore, expressions of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1 messenger (m)RNA in U87 and C6 cells were detected by an RT-PCR, and TNF-α and MCP-1 induced iNOS protein expression in time- and concentration-dependent manners. Neutralization of TNF-α or MCP-1 in U87-CM and C6-CM using a TNF-α or MCP-1 antibody inhibited iNOS protein expression, and increased intracellular peroxide by TNF-α or MCP-1 was identified in BV-2 cells. The reciprocal activation of glioma cells and microglia via ROS-dependent iNOS/NO elevation at least partially mediated by TNF-α and MCP-1 is elucidated.}, }
@article {pmid24769205, year = {2014}, author = {Zhu, Y and Hu, Y and Huang, T and Zhang, Y and Li, Z and Luo, C and Luo, Y and Yuan, H and Hisatome, I and Yamamoto, T and Cheng, J}, title = {High uric acid directly inhibits insulin signalling and induces insulin resistance.}, journal = {Biochemical and biophysical research communications}, volume = {447}, number = {4}, pages = {707-714}, doi = {10.1016/j.bbrc.2014.04.080}, pmid = {24769205}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Disease Models, Animal ; Glucose Intolerance/etiology/metabolism ; Hep G2 Cells ; Humans ; Hyperuricemia/complications/metabolism ; Insulin/*metabolism ; Insulin Receptor Substrate Proteins/antagonists &amp; inhibitors/chemistry/metabolism ; Insulin Resistance/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Phosphorylation ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/chemistry/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Uric Acid/*metabolism ; }, abstract = {BACKGROUND AND AIM: Accumulating clinical evidence suggests that hyperuricemia is strongly associated with abnormal glucose metabolism and insulin resistance. However, how high uric acid (HUA) level causes insulin resistance remains unclear. We aimed to determine the direct role of HUA in insulin resistance in vitro and in vivo in mice.<br><br>METHODS: An acute hyperuricemia mouse model was created by potassium oxonate treatment, and the impact of HUA level on insulin resistance was investigated by glucose tolerance test, insulin tolerance test and insulin signalling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt. HepG2 cells were exposed to HUA treatment and N-acetylcysteine (NAC), reactive oxygen species scavenger; IRS1 and Akt phosphorylation was detected by Western blot analysis after insulin treatment.<br><br>RESULTS: Hyperuricemic mice showed impaired glucose tolerance with insulin resistance. Hyperuricemia inhibited phospho-Akt (Ser473) response to insulin and increased phosphor-IRS1 (Ser307) in liver, muscle and fat tissues. HUA induced oxidative stress, and the antioxidant NAC blocked HUA-induced IRS1 activation and Akt inhibition in HepG2 cells.<br><br>CONCLUSION: This study supplies the first evidence of HUA directly inducing insulin resistance in vivo and in vitro. Increased uric acid level may inhibit IRS1 and Akt insulin signalling and induce insulin resistance. The reactive oxygen species pathway plays a key role in HUA-induced insulin resistance.}, }
@article {pmid24768707, year = {2014}, author = {Rajah, T and Chow, SC}, title = {The inhibition of human T cell proliferation by the caspase inhibitor z-VAD-FMK is mediated through oxidative stress.}, journal = {Toxicology and applied pharmacology}, volume = {278}, number = {2}, pages = {100-106}, doi = {10.1016/j.taap.2014.04.014}, pmid = {24768707}, issn = {1096-0333}, mesh = {Amino Acid Chloromethyl Ketones/*pharmacology ; Caspase Inhibitors/*pharmacology ; *Cell Proliferation/drug effects ; Cells, Cultured ; Dose-Response Relationship, Immunologic ; Glutathione/metabolism ; Growth Inhibitors/*pharmacology ; Humans ; Leukocytes, Mononuclear/drug effects/immunology/metabolism ; Lymphocyte Activation/*drug effects/immunology/physiology ; Oxidative Stress/*drug effects/immunology ; Reactive Oxygen Species/metabolism ; T-Lymphocyte Subsets/drug effects/immunology/*metabolism ; }, abstract = {The caspase inhibitor benzyloxycarbony (Cbz)-l-Val-Ala-Asp (OMe)-fluoromethylketone (z-VAD-FMK) has recently been shown to inhibit T cell proliferation without blocking caspase-8 and caspase-3 activation in primary T cells. We showed in this study that z-VAD-FMK treatment leads to a decrease in intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) levels in activated T cells. The inhibition of anti-CD3-mediated T cell proliferation induced by z-VAD-FMK was abolished by the presence of low molecular weight thiols such as GSH, N-acetylcysteine (NAC) and l-cysteine, whereas d-cysteine which cannot be metabolised to GSH has no effect. These results suggest that the depletion of intracellular GSH is the underlying cause of z-VAD-FMK-mediated inhibition of T cell activation and proliferation. The presence of exogenous GSH also attenuated the inhibition of anti-CD3-induced CD25 and CD69 expression mediated by z-VAD-FMK. However, none of the low molecular weight thiols were able to restore the caspase-inhibitory properties of z-VAD-FMK in activated T cells where caspase-8 and caspase-3 remain activated and processed into their respective subunits in the presence of the caspase inhibitor. This suggests that the inhibition of T cell proliferation can be uncoupled from the caspase-inhibitory properties of z-VAD-FMK. Taken together, the immunosuppressive effects in primary T cells mediated by z-VAD-FMK are due to oxidative stress via the depletion of GSH.}, }
@article {pmid24765894, year = {2014}, author = {Chomchai, S and Lawattanatrakul, N and Chomchai, C}, title = {Acetaminophen Psi Nomogram: a sensitive and specific clinical tool to predict hepatotoxicity secondary to acute acetaminophen overdose.}, journal = {Journal of the Medical Association of Thailand = Chotmaihet thangphaet}, volume = {97}, number = {2}, pages = {165-172}, pmid = {24765894}, issn = {0125-2208}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/therapeutic use ; Chemical and Drug Induced Liver Injury/*etiology ; Drug Overdose ; Humans ; *Nomograms ; Predictive Value of Tests ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Sensitivity and Specificity ; Thailand ; }, abstract = {BACKGROUND: Acetaminophen Psi Parameter (APP) is a composite of acetaminophen (paracetamol) level and lag time before N-acetylcysteine (NAC) therapy. The APP is a significant predictor of hepatotoxicity secondary to acute acetaminophen overdose. Acetaminophen Psi Nomogram (APN) was invented as a graphic analog of the APP for use in predicting individual patient's risk of hepatotoxicity. Clinical accuracy of the APN has never been validated<br><br>OBJECTIVE: The authors are reporting the validity of APN in predicting hepatotoxicity secondary to acute acetaminophen overdose at Siriraj Hospital.<br><br>MATERIAL AND METHOD: This present study is a retrospective review of medical records of patients with acute acetaminophen overdose at Siriraj Hospital between January 2004 and June 2009. Each case was classified by APN into an appropriate risk group. The outcome of interest was hepatotoxicity. The validity of the APN is reported as sensitivity and specificity. Secondary outcomes include serum acetaminophen concentrations, delay to NAC therapy, and APP for each APN's risk group.<br><br>RESULTS: One hundred and sixty-one patients were enrolled Higher APN risk classifications are associated with a trend towards higher acetaminophen levels, longer delayed to NAC initiation, and larger APP. Twenty five patients (15.5%) developed hepatotoxicity. The number of patients who were above the APN's risk lines, 1% and 50% were 88 (54.7%) and 17 (10.6%), respectively, with corresponding sensitivities of 100.0% (95% CI 186.6, 100.0) and 40.0% (95% C121.2, 61.3). APN's risk lines 50% had specificity of 94.9% (95% CI 89.7, 97.9).<br><br>CONCLUSION: Acetaminophen Psi Nomogram is a sensitive and specific tool for prediction of hepatotoxicity secondary to acute acetaminophen overdose. By application of the APN, a significant proportion of patients may not require either further follow-up after the completion of NAC therapy or prolongation of NAC therapy. Patients in high APN's risk ranges may be treated and monitored more intensively with confidence.}, }
@article {pmid24756473, year = {2015}, author = {Kumar, SM and Swaminathan, K and Clemens, DL and Dey, A}, title = {GSH protects against oxidative stress and toxicity in VL-17A cells exposed to high glucose.}, journal = {European journal of nutrition}, volume = {54}, number = {2}, pages = {223-234}, pmid = {24756473}, issn = {1436-6215}, mesh = {Acetylcysteine/metabolism ; Alcohol Dehydrogenase/genetics/metabolism ; Antimetabolites/pharmacology ; Antioxidants/pharmacology ; *Apoptosis/drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Survival/drug effects ; Clone Cells ; Cytochrome P-450 CYP2E1/genetics/metabolism ; Glucose/adverse effects ; Glutathione/antagonists &amp; inhibitors/*metabolism ; Hep G2 Cells ; Hepatocytes/drug effects/*metabolism ; Humans ; Hyperglycemia/*metabolism ; Lactoylglutathione Lyase/metabolism ; Maleates/pharmacology ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Recombinant Proteins/metabolism ; Ursodeoxycholic Acid/pharmacology ; }, abstract = {PURPOSE: The deficiency of glutathione (GSH) has been linked to several diseases. The study investigated the role of GSH as a protective factor against hyperglycemia-mediated injury in VL-17A cells treated with 50 mM glucose.<br><br>METHODS: The cell viability and different oxidative stress parameters including glyoxalase I activity were measured.<br><br>RESULTS: GSH supplementation with 2 mM N-acetyl cysteine (NAC) or 0.1 mM ursodeoxycholic acid (UDCA) increased the viability, GSH level and the GSH-dependent glyoxalase I activity in 50 mM glucose-treated VL-17A cells. Further, pretreatment of 50 mM glucose-treated VL-17A cells with NAC or UDCA decreased oxidative stress (levels of reactive oxygen species and protein carbonylation), apoptosis (caspase 3 activity and annexin V-propidium iodide positive cells) and glutathionylated protein formation, a measure of oxidative stress. GSH depletion with 0.4 mM buthionine sulfoximine (BSO) or 1 mM diethyl maleate (DEM) potentiated the decrease in viability, glyoxalase I activity and increase in oxidative stress and apoptosis, with decreased GSH levels in 50 mM glucose-treated VL-17A cells.<br><br>CONCLUSION: Thus, changes in GSH levels with exogenous agents such as NAC, UDCA, BSO or DEM modulate hyperglycemia-mediated injury in a cell model of VL-17A liver cells.}, }
@article {pmid24756058, year = {2015}, author = {Prakash, A and Kalra, JK and Kumar, A}, title = {Neuroprotective effect of N-acetyl cysteine against streptozotocin-induced memory dysfunction and oxidative damage in rats.}, journal = {Journal of basic and clinical physiology and pharmacology}, volume = {26}, number = {1}, pages = {13-23}, doi = {10.1515/jbcpp-2013-0150}, pmid = {24756058}, issn = {2191-0286}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Cognition Disorders/*prevention &amp; control ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Male ; Maze Learning/drug effects ; Memory Disorders/*prevention &amp; control ; Mitochondria/drug effects/pathology ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Streptozocin/toxicity ; }, abstract = {BACKGROUND: Growing evidences indicate that endogenous oxidants and antioxidant defense interact in a vicious cycle, which plays a critical role in the pathogenesis of cognitive dysfunction. In this study, we examined the effect of N-acetyl cysteine (NAC) against the intracerebroventricular infusion of streptozotocin (ICV STZ)-induced cognitive impairment and mitochondrial oxidative damage in rats.<br><br>METHODS: Male adult Wistar rats were injected with STZ (3 mg/kg) bilaterally through ICV. NAC (50 and 100 mg/kg) was administered for 3 weeks post-surgery. The rats were sacrificed on the 21st day following the last behavioral test, and cytoplasmic fractions of the hippocampus and cortex were prepared for the quantification of acetylcholinesterase, oxidative stress parameter, mitochondrial enzymes, inflammatory mediators and caspase-3 activity.<br><br>RESULTS: ICV STZ resulted in poor retention of memory in Morris water maze. It also increased the mito-oxidative damage and tumor necrosis factor-&#x3b1;, interleukin 6 and caspase-3 levels in the hippocampus and cortex compared to sham animals. NAC significantly improved memory retention and attenuated oxidative damage parameters, inflammatory markers in STZ-treated rats.<br><br>CONCLUSIONS: The results of the present study strongly indicate the effectiveness of NAC in preventing cognitive impairment as well as mito-oxidative stress and may be considered as a potential agent in the management of cognitive-related disorders.}, }
@article {pmid24756013, year = {2014}, author = {Licks, F and Marques, C and Zetler, C and Martins, MI and Marroni, CA and Marroni, NP}, title = {Antioxidant effect of N-acetylcysteine on prehepatic portal hypertensive gastropathy in rats.}, journal = {Annals of hepatology}, volume = {13}, number = {3}, pages = {370-377}, pmid = {24756013}, issn = {1665-2681}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; *Esophageal and Gastric Varices ; Gastric Mucosa/blood supply/*drug effects/pathology ; Glutathione Peroxidase/drug effects ; *Hypertension, Portal ; Lipid Peroxidation/*drug effects ; Male ; Nitrates/metabolism ; Nitrites/metabolism ; Oxidative Stress/drug effects ; Portal Pressure/*drug effects ; Rats, Wistar ; Stomach/drug effects ; Superoxide Dismutase/drug effects ; Thiobarbituric Acid Reactive Substances/*metabolism ; }, abstract = {BACKGROUND: Portal hypertension is a clinical syndrome associated with the development of a hyperdynamic circulation and gastroesophageal varices. Aim. To evaluate the antioxidant effect of N-acetylcysteine on portal hypertensive rats.<br><br>MATERIAL AND METHODS: Portal hypertension was induced by partial portal vein ligation (PPVL). Oxidative damage in the stomach was measured by lipoperoxidation trough thiobarbituric acid reactive substances (TBARS) and antioxidant enzyme activity; we also evaluated nitrates and nitrites level and histology stained by hematoxylin-eosin. We performed evaluation of portal pressure and measurement of vessels diameter. Liver damage was evaluated by measuring hepatic enzymes. The animals were divided in four experimental groups (n = 6): Sham-operated (SO), SO + NAC, Partial portal vein ligation (PPVL) and PPVL + NAC. N-acetylcysteine (10 mg/kg ip) was administered daily for 7 days and started 8 days after surgery.<br><br>RESULTS: The portal hypertensive group showed an increase in portal pressure, vessels diameter, levels of TBARS and nitrates and nitrites when compared to SO group. These values were accompanied by a decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant enzyme activity. Histology showed dilated vessels in the gastric mucosa in the PPVL group. NAC was able to decrease portal pressure values, vessels diameter, TBARS and also nitrates and nitrites levels when compared to PPVL group. Furthermore, PPVL+NAC group presented an increase in SOD and GPx activity. N-acetylcysteine attenuated damage in gastric mucosa.<br><br>CONCLUSION: Oxidative stress is associated with portal hypertension and that antioxidant NAC is able to minimize damages of PPVL in rats.}, }
@article {pmid24754562, year = {2014}, author = {Miller, RC and Murley, JS and Grdina, DJ}, title = {Metformin exhibits radiation countermeasures efficacy when used alone or in combination with sulfhydryl containing drugs.}, journal = {Radiation research}, volume = {181}, number = {5}, pages = {464-470}, pmid = {24754562}, issn = {1938-5404}, support = {R01 CA132998/CA/NCI NIH HHS/United States ; R01-CA132998/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Acute Radiation Syndrome/pathology/*prevention &amp; control ; Amifostine/administration &amp; dosage/pharmacology/therapeutic use ; Animals ; Captopril/administration &amp; dosage/pharmacology/therapeutic use ; Cell Line, Transformed ; Cell Line, Tumor ; Cells, Cultured ; Colony-Forming Units Assay ; Drug Evaluation, Preclinical ; Drug Synergism ; Endothelial Cells/drug effects/radiation effects ; Fibroblasts/drug effects/radiation effects ; Free Radical Scavengers/administration &amp; dosage/pharmacology/therapeutic use ; Humans ; Mesna/administration &amp; dosage/pharmacology/therapeutic use ; Metformin/administration &amp; dosage/pharmacology/*therapeutic use ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Radiation Injuries, Experimental/pathology/*prevention &amp; control ; Radiation-Protective Agents/administration &amp; dosage/pharmacology/*therapeutic use ; Sarcoma/pathology ; Sulfhydryl Compounds/administration &amp; dosage/pharmacology/*therapeutic use ; }, abstract = {Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl-cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, administered 30 min prior to irradiation, were used as positive controls. Treatment of MEF, HMEC and SA-NH cells with metformin elevated survival levels by 1.4-, 1.5- and 1.3-fold compared to 1.9-, 1.8- and 1.6-fold for these same cells treated with WR1065, respectively. Metformin (250 mg/kg) was effective in protecting splenic cells from a 7 Gy dose in vivo (protection factor = 1.8). Amifostine (400 mg/kg), administered 30 min prior to irradiation resulted in a 2.6-fold survival elevation, while metformin administered 24 h after irradiation in combination with NAC (400 mg/kg), MESNA (300 mg/kg) or captopril (200 mg/kg) enhanced survival by 2.6-, 2.8- and 2.4-fold, respectively. Each of these agents has been approved by the FDA for human use and each has a well characterized human safety profile. Metformin alone or in combination with selected sulfhydryl agents possesses radioprotective properties when administered 24 h after radiation exposure comparable to that observed for amifostine administered 30 min prior to irradiation making it a potentially useful agent for radiation countermeasures use.}, }
@article {pmid24754008, year = {2014}, author = {Abdoli, N and Azarmi, Y and Eghbal, MA}, title = {Protective Effects of N-acetylcysteine Against the Statins Cytotoxicity in Freshly Isolated Rat Hepatocytes.}, journal = {Advanced pharmaceutical bulletin}, volume = {4}, number = {3}, pages = {249-254}, pmid = {24754008}, issn = {2228-5881}, abstract = {PURPOSE: Hepatotoxicity is one of the most important side effects of the statins therapy as lipid-lowering agents. However, the mechanism(s) of hepatotoxicity induced by these drugs is not clearly understood yet, and no hepatoprotective agent has been developed against this complication.<br><br>METHODS: The protective effect of N-acetylcysteine (NAC) against statins-induced cytotoxicity was evaluated by using freshly isolated rat hepatocytes. Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. This technique is based on liver perfusion with collagenase after removal of calcium ion (Ca2+) with a chelator (ethylene glycol tetra acetic acid (EGTA) 0.5 mM). The level of parameters such as cell death, ROS formation, lipid peroxidation, mitochondrial membrane potential (MMP) in the statins-treated hepatocytes were determined. Additionally, the mentioned markers were assessed in the presence of NAC.<br><br>RESULTS: Incubation of hepatocytes with the statins resulted in cytotoxicity characterized by an elevation in cell death, increasing ROS generation and consequently lipid peroxidation and impairment of mitochondrial function. Administration of NAC caused reduction in amount of ROS formation, lipid peroxidation and finally, cell viability and mitochondrial membrane potential (MMP) were improved.<br><br>CONCLUSION: This study confirms that oxidative stress and consequently mitochondrial dysfunction is one of the mechanisms underlying the statins-induced liver injury and treating hepatocytes by NAC (200 &#x3bc;M) attenuates this cytotoxicity.}, }
@article {pmid24752591, year = {2014}, author = {Morris, G and Anderson, G and Dean, O and Berk, M and Galecki, P and Martin-Subero, M and Maes, M}, title = {The glutathione system: a new drug target in neuroimmune disorders.}, journal = {Molecular neurobiology}, volume = {50}, number = {3}, pages = {1059-1084}, pmid = {24752591}, issn = {1559-1182}, mesh = {Antioxidants/metabolism ; Brain Diseases/drug therapy/immunology/*metabolism ; Glutathione/*metabolism ; Humans ; Mitochondria/metabolism ; Neuroimmunomodulation/*physiology ; Oxidative Stress/*physiology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Glutathione (GSH) has a crucial role in cellular signaling and antioxidant defenses either by reacting directly with reactive oxygen or nitrogen species or by acting as an essential cofactor for GSH S-transferases and glutathione peroxidases. GSH acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS) and electrophiles produced by xenobiotics. Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. GSH is a ubiquitous regulator of the cell cycle per se. GSH also has crucial functions in the brain as an antioxidant, neuromodulator, neurotransmitter, and enabler of neuron survival. Depletion of GSH leads to exacerbation of damage by oxidative and nitrosative stress; hypernitrosylation; increased levels of proinflammatory mediators and inflammatory potential; dysfunctions of intracellular signaling networks, e.g., p53, nuclear factor-κB, and Janus kinases; decreased cell proliferation and DNA synthesis; inactivation of complex I of the electron transport chain; activation of cytochrome c and the apoptotic machinery; blockade of the methionine cycle; and compromised epigenetic regulation of gene expression. As such, GSH depletion has marked consequences for the homeostatic control of the immune system, oxidative and nitrosative stress (O&amp;NS) pathways, regulation of energy production, and mitochondrial survival as well. GSH depletion and concomitant increase in O&amp;NS and mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson's disease, suggesting that depleted GSH is an integral part of these diseases. Therapeutical interventions that aim to increase GSH concentrations in vivo include N-acetyl cysteine; Nrf-2 activation via hyperbaric oxygen therapy; dimethyl fumarate; phytochemicals, including curcumin, resveratrol, and cinnamon; and folate supplementation.}, }
@article {pmid24752472, year = {2014}, author = {Xu, G and Yan, W and Li, J}, title = {An update for the controversies and hypotheses of regulating nonthyroidal illness syndrome in chronic kidney diseases.}, journal = {Clinical and experimental nephrology}, volume = {18}, number = {6}, pages = {837-843}, pmid = {24752472}, issn = {1437-7799}, mesh = {Acetylcysteine/therapeutic use ; Comorbidity ; Cytokines/*physiology ; Disease Progression ; Euthyroid Sick Syndromes/drug therapy/epidemiology/*physiopathology ; Hormone Replacement Therapy ; Humans ; Oxidative Stress/*physiology ; Renal Insufficiency, Chronic/drug therapy/epidemiology/*physiopathology ; Sodium Bicarbonate/therapeutic use ; Thyroid Hormones/*physiology ; }, abstract = {Nonthyroidal illness syndrome (NTIS) is widely found in the patients with chronic kidney disease (CKD) or critical illness. However, the exact pathogenesis and reasonable treatment remain unclear. To identify suitable studies for inclusion in present review, a search for articles using PubMed search engine with combined terms: (thyroid OR hypothyroidism OR hyperthyroidism OR triiodothyronine) AND (glomerulonephritis OR chronic kidney disease OR chronic renal failure OR end stage renal disease OR hemodialysis OR peritoneal dialysis OR kidney transplantation OR renal transplantation) was performed. The bibliographies of relevant articles were also hand searched. The search was updated on November 8, 2013. Mechanisms for the alternations of thyroid hormone concentrations in NTIS are complicated. Inflammatory cytokines and oxidative stress may play pivotal roles in the pathogenesis of NTIS in patients with CKD. It was controversial whether CKD patients with NTIS should be treated with thyroid hormone replacement. N-Acetyl cysteine or sodium bicarbonate may negatively regulate the progress of micro-inflammation in CKD. Large-scale, multi-centered randomized controlled trials should be conducted to verify the NTIS hypothesis in CKD patients.}, }
@article {pmid24752286, year = {2014}, author = {Yan, H and Wang, X and Niu, J and Wang, Y and Wang, P and Liu, Q}, title = {Anti-cancer effect and the underlying mechanisms of gypenosides on human colorectal cancer SW-480 cells.}, journal = {PloS one}, volume = {9}, number = {4}, pages = {e95609}, pmid = {24752286}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Actin Cytoskeleton/drug effects/metabolism ; Antineoplastic Agents/chemistry/*pharmacology/*therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Membrane/drug effects/metabolism ; Cell Movement/drug effects ; Cell Nucleus/drug effects/metabolism ; Cell Shape/drug effects ; Cell Survival/drug effects ; Colorectal Neoplasms/*drug therapy/*pathology/ultrastructure ; DNA Fragmentation/drug effects ; Drug Screening Assays, Antitumor ; Flow Cytometry ; Gynostemma/chemistry ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Plant Extracts/chemistry/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Gypenosides (Gyp), the main components from Gynostemma pentaphyllum Makino, are widely used in traditional Chinese medicine. The present study aimed to investigate the anti-cancer effect and the underlying mechanisms of Gyp on human colorectal cancer cells SW-480.<br><br>MATERIALS AND METHODS: The inhibitory effect of Gyp on SW-480 cells was evaluated by MTT assay. Apoptotic cell death was detected by nuclear Hoechst 33342 staining and DNA fragmentation analysis. Apoptosis was analyzed using Annexin V-PE/7-amino-actinomycin D staining. Cell membrane integrity was evaluated with flow cytometry following PI staining. Changes of mitochondrial membrane potential (&#x394;&#x3c8;m) were detected through flow cytometry analysis of rhodamine 123 (Rh123). The role of reactive oxygen species (ROS) in Gyp induced cell death was investigated by intracellular ROS generation and general ROS scavenger. Wound-healing assay was carried out to investigate Gyp-inhibited migration of SW-480 cells in vitro. Additionally, the alterations in F-actin microfilaments were analyzed by FITC-labeled phalloidin toxin staining and the morphological changes were evaluated under scanning electron microscope (SEM).<br><br>RESULTS: After the Gyp treatment, the plasma membrane permeability of SW-480 cell was increased, &#x394;&#x3c8;m was decreased significantly, the level of intracellular ROS level was increased, DNA fragmentation and apoptotic morphology were observed. Cells treated with Gyp exert serious microfilament network collapse as well as the significant decrease in the number of microvilli. Gyp induced the changes of cell viability, cell migration, intracellular ROS generation and nuclear morphology were alleviated obviously by NAC.<br><br>CONCLUSION: The results in this study implied that ROS play an important role in Gyp induced cell toxicity and apoptosis, and the mitochondria damage may be upstream of ROS generation post Gyp treatment. The findings of the present study provide new evidences for anti-tumor mechanisms by which Gyp induces apoptosis in vitro.}, }
@article {pmid24752227, year = {2014}, author = {Tao, L and Fu, R and Wang, X and Yao, J and Zhou, Y and Dai, Q and Li, Z and Lu, N and Wang, W}, title = {LL-202, a newly synthesized flavonoid, inhibits tumor growth via inducing G(2)/M phase arrest and cell apoptosis in MCF-7 human breast cancer cells in vitro and in vivo.}, journal = {Toxicology letters}, volume = {228}, number = {1}, pages = {1-12}, doi = {10.1016/j.toxlet.2014.04.002}, pmid = {24752227}, issn = {1879-3169}, mesh = {Animals ; Annexin A5 ; *Antineoplastic Agents ; Apoptosis/*drug effects ; Blotting, Western ; Cell Cycle/*drug effects ; Cell Division/*drug effects ; Cell Line, Tumor ; Coloring Agents ; Flavonoids/*pharmacology ; Free Radical Scavengers/*pharmacology ; G2 Phase/*drug effects ; Humans ; Immunohistochemistry ; Membrane Potential, Mitochondrial/drug effects ; Mice, Inbred BALB C ; Mitochondria/drug effects ; Reactive Oxygen Species ; Signal Transduction/drug effects ; Subcellular Fractions/drug effects/metabolism ; Tetrazolium Salts ; Thiazoles ; }, abstract = {We recently established that LL-202, a newly synthesized flavonoid, exhibited obvious anticancer effects against human breast cells in vivo and in vitro. The underlying mechanism of its anticancer activity remains to be elucidated. In this study, we demonstrated that LL-202 inhibited the growth and proliferation of human breast cancer MCF-7 cells in a concentration and time-dependent manner. We reported that LL-202 induced both mitochondrial- and death-receptor-mediated apoptosis, which were characterized by the dissipation of mitochondrial membrane potential (ΔΨm), cytochrome c (Cyt c) release from mitochondria to cytosol, the activation of several caspases and induction of poly (ADP-ribose) polymerase (PARP) and Bid cleavage. N-acetylcysteine (NAC), a general ROS scavenger, partly blocked the LL-202-induced ROS levels and apoptosis. In addition, LL-202 induced arrest in cell cycle progression at G2/M phase in MCF-7 cells. After the treatment with LL-202, the expression of cell cycle-related proteins, such as cyclin B1, cyclin A, and p-CDK1 (Thr161) were down-regulated, whereas the expression of p21(WAF1/Cip1) and p-CDK1 (Thr14/Tyr15) were up-regulated. Finally, in vivo studies, LL-202 significantly suppressed the growth of MCF-7 breast cancer xenograft tumors in a dose-dependent manner with low systemic toxicity. In conclusion, the results showed that LL-202 had significant anticancer effects against human breast cells via the induction of apoptosis and G2/M phase arrest and it may be a novel anticancer agent for treatment of breast cancer.}, }
@article {pmid24743300, year = {2014}, author = {Kim, HR and Lee, A and Choi, EJ and Kie, JH and Lim, W and Lee, HK and Moon, BI and Seoh, JY}, title = {Attenuation of experimental colitis in glutathione peroxidase 1 and catalase double knockout mice through enhancing regulatory T cell function.}, journal = {PloS one}, volume = {9}, number = {4}, pages = {e95332}, pmid = {24743300}, issn = {1932-6203}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Catalase/genetics/*metabolism ; Colitis/chemically induced/drug therapy/*enzymology/genetics ; Dextran Sulfate/toxicity ; Glutathione Peroxidase/genetics/*metabolism ; Male ; Mice ; Mice, Knockout ; T-Lymphocytes, Regulatory/*metabolism ; Glutathione Peroxidase GPX1 ; }, abstract = {Reactive oxygen species (ROS) have been implicated in the progression of inflammatory diseases including inflammatory bowel diseases (IBD). Meanwhile, several studies suggested the protective role of ROS in immune-mediated inflammatory diseases, and it was recently reported that dextran sodium sulfate (DSS)-induced colitis was attenuated in mice with an elevated level of ROS due to deficiency of peroxiredoxin II. Regulatory T cells (Tregs) are critical in the prevention of IBD and Treg function was reported to be closely associated with ROS level, but it has been investigated only in lowered levels of ROS so far. In the present study, in order to clarify the relationship between ROS level and Treg function, and their role in the pathogenesis of IBD, we investigated mice with an elevated level of ROS due to deficiency of both glutathione peroxidase (GPx)-1 and catalase (Cat) for the susceptibility of DSS-induced colitis in association with Treg function. The results showed that DSS-induced colitis was attenuated and Tregs were hyperfunctional in GPx1-/- × Cat-/- mice. In vivo administration of N-acetylcysteine (NAC) aggravated DSS-induced colitis and decreased Treg function to the level comparable to WT mice. Attenuated Th17 cell differentiation from naïve CD4+ cells as well as impaired production of IL-6 and IL-17A by splenocytes upon stimulation suggested anti-inflammatory tendency of GPx1-/- × Cat-/- mice. Suppression of Stat3 activation in association with enhancement of indoleamine 2,3-dioxygenase and FoxP3 expression might be involved in the immunosuppressive mechanism of GPx1-/- × Cat-/- mice. Taken together, it is implied that ROS level is critical in the regulation of Treg function, and IBD may be attenuated in appropriately elevated levels of ROS.}, }
@article {pmid24742380, year = {2014}, author = {Nadeem, A and Siddiqui, N and Alharbi, NO and Alharbi, MM and Imam, F and Sayed-Ahmed, MM}, title = {Glutathione modulation during sensitization as well as challenge phase regulates airway reactivity and inflammation in mouse model of allergic asthma.}, journal = {Biochimie}, volume = {103}, number = {}, pages = {61-70}, doi = {10.1016/j.biochi.2014.04.001}, pmid = {24742380}, issn = {1638-6183}, mesh = {Animals ; Antioxidants/metabolism ; Asthma/complications/*immunology/*metabolism ; Buthionine Sulfoximine/pharmacology ; Disease Models, Animal ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione/*metabolism ; Hypersensitivity/*complications ; Inflammation/immunology/metabolism ; Lipid Peroxidation/drug effects ; Lung/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred BALB C ; NADPH Oxidases/genetics ; Oxidants/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Glutathione, being a major intracellular redox regulator has been shown to be implicated in regulation of airway reactivity and inflammation. However, no study so far has investigated the effect of glutathione depletion/repletion during sensitization and challenge phases separately, which could provide an important insight into the pathophysiology of allergic asthma. The aim of the present study was to evaluate the role of glutathione depletion/repletion during sensitization and challenge phases separately in a mouse model of allergic asthma. Buthionine sulphoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase or N-acetyl cysteine (NAC), a thiol donor were used for depletion or repletion of glutathione levels respectively during both sensitization and challenge phases separately followed by assessment of airway reactivity, inflammation and oxidant-antioxidant balance in allergic mice. Depletion of glutathione with BSO during sensitization as well as challenge phase worsened allergen induced airway reactivity/inflammation and caused greater oxidant-antioxidant imbalance as reflected by increased NADPH oxidase expression/reactive oxygen species (ROS) generation/lipid peroxides formation and decreased total antioxidant capacity. On the other hand, repletion of glutathione pool by NAC during sensitization and challenge phases counteracted allergen induced airway reactivity/inflammation and restored oxidant-antioxidant balance through a decrease in NADPH oxidase expression/ROS generation/lipid peroxides formation and increase in total antioxidant capacity. Taken together, these findings suggest that depletion or repletion of glutathione exacerbates or ameliorates allergic asthma respectively by regulation of airway oxidant-antioxidant balance. This might have implications towards increased predisposition to allergy by glutathione depleting environmental pollutants.}, }
@article {pmid24741196, year = {2014}, author = {Maheswari, E and Saraswathy, GR and Santhranii, T}, title = {Hepatoprotective and antioxidant activity of N-acetyl cysteine in carbamazepine-administered rats.}, journal = {Indian journal of pharmacology}, volume = {46}, number = {2}, pages = {211-215}, pmid = {24741196}, issn = {1998-3751}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Anticonvulsants/*toxicity ; Antioxidants/administration &amp; dosage/*therapeutic use ; Body Weight/drug effects ; Carbamazepine/*toxicity ; Chemical and Drug Induced Liver Injury/etiology/metabolism/pathology/*prevention &amp; control ; Dose-Response Relationship, Drug ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism/pathology ; Liver Function Tests ; Male ; Organ Size/drug effects ; Rats, Wistar ; }, abstract = {OBJECTIVES: The present study evaluates the hepatoprotective activity of N-acetyl cysteine (NAC) against carbamazepine (CBZ)-induced hepatotoxicity.<br><br>MATERIALS AND METHODS: Rats were treated with CBZ (50 mg/kg p.o.) and CBZ supplemented with NAC 50, 100 and 200 mg/kg for 45 days, after which blood samples were collected and subjected to liver function tests. Animals were killed, liver was separated, weighed and the levels of antioxidants and liver enzymes were estimated. In addition, histopathological investigation was also performed.<br><br>RESULTS: Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate (SGOT) transaminase, alkaline phosphatase (ALP), bilirubin, lipid peroxidation, absolute and relative liver weights were significantly (P < 0.05) elevated, whereas serum levels of albumin, total protein and body weight were decreased in the CBZ-treated animals. CBZ also produced vacuolar degeneration, centrilobular congestion and hepatic necrosis as evidenced from histopathological report. NAC significantly reduced the levels of serum transaminase, ALP, bilirubin and liver weight and increased the levels of total protein, albumin and body weight.<br><br>CONCLUSION: It was observed that NAC increased the glutathione (GSH) content, reduced lipid peroxidation and reversed the CBZ-induced histopathological abnormalities. CBZ-induced hepatotoxicity may be due its toxic epoxide metabolite-induced oxidative stress.}, }
@article {pmid24740427, year = {2014}, author = {Eakin, K and Baratz-Goldstein, R and Pick, CG and Zindel, O and Balaban, CD and Hoffer, ME and Lockwood, M and Miller, J and Hoffer, BJ}, title = {Efficacy of N-acetyl cysteine in traumatic brain injury.}, journal = {PloS one}, volume = {9}, number = {4}, pages = {e90617}, pmid = {24740427}, issn = {1932-6203}, support = {R01 NS070825/NS/NINDS NIH HHS/United States ; NS070825/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*therapeutic use ; Animals ; Antioxidants/chemistry/*therapeutic use ; Brain Injuries/*drug therapy ; Drug Evaluation, Preclinical ; Male ; Maze Learning ; Mice ; Mice, Inbred ICR ; Rats, Sprague-Dawley ; Recognition, Psychology ; }, abstract = {In this study, using two different injury models in two different species, we found that early post-injury treatment with N-Acetyl Cysteine (NAC) reversed the behavioral deficits associated with the TBI. These data suggest generalization of a protocol similar to our recent clinical trial with NAC in blast-induced mTBI in a battlefield setting, to mild concussion from blunt trauma. This study used both weight drop in mice and fluid percussion injury in rats. These were chosen to simulate either mild or moderate traumatic brain injury (TBI). For mice, we used novel object recognition and the Y maze. For rats, we used the Morris water maze. NAC was administered beginning 30-60 minutes after injury. Behavioral deficits due to injury in both species were significantly reversed by NAC treatment. We thus conclude NAC produces significant behavioral recovery after injury. Future preclinical studies are needed to define the mechanism of action, perhaps leading to more effective therapies in man.}, }
@article {pmid24739515, year = {2014}, author = {Liu, XH and Xu, CY and Fan, GH}, title = {Efficacy of N-acetylcysteine in preventing atrial fibrillation after cardiac surgery: a meta-analysis of published randomized controlled trials.}, journal = {BMC cardiovascular disorders}, volume = {14}, number = {}, pages = {52}, pmid = {24739515}, issn = {1471-2261}, mesh = {Acetylcysteine/*therapeutic use ; Anti-Arrhythmia Agents/*therapeutic use ; Atrial Fibrillation/etiology/mortality/*prevention &amp; control ; Cardiac Surgical Procedures/*adverse effects/mortality ; Chi-Square Distribution ; Humans ; Incidence ; Intensive Care Units ; Length of Stay ; Odds Ratio ; Randomized Controlled Trials as Topic ; Risk Factors ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Atrial fibrillation is a common complication after cardiac surgery. The aim of this study is to evaluate whether N-acetylcysteine (NAC) could prevent postoperative atrial fibrillation (POAF).<br><br>METHODS: PubMed, Embase and Cochrane Center Register of Controlled Trials were searched from the date of their inception to 1 July 2013 for relevant randomized controlled trials (RCTs), in which NAC was compared with controls for adult patients undergoing cardiac surgery. Outcome measures comprised the incidence of POAF, all-cause mortality, length of intensive care unit (ICU) stay, hospital length of stay, and the incidence of cerebrovascular events. The meta-analysis was performed with the fixed-effect model or random-effect model according to the heterogeneity.<br><br>RESULTS: We retrieved ten studies enrolling a total of 1026 patients. Prophylactic NAC reduced the incidence of POAF (OR 0.56; 95% CI 0.40 to 0.77; P&#x2009;<&#x2009;0.001) and all-cause mortality (OR 0.40; 95% CI 0.17 to 0.93; P&#x2009;=&#x2009;0.03) compared with controls, but failed to reduce the stay in ICU and overall stay in hospital. No difference in the incidence of cerebrovascular events was observed.<br><br>CONCLUSIONS: Prophylactic use of NAC could reduce the incidence of POAF and all-cause mortality in adult patients undergoing cardiac surgery. However, larger RCTs evaluating these and other postoperative complication endpoints are needed.}, }
@article {pmid24737302, year = {2015}, author = {Allaveisi, F and Hashemi, B and Mortazavi, SM}, title = {Radioprotective effect of N-acetyl-L-cysteine free radical scavenger on compressive mechanical properties of the gamma sterilized cortical bone of bovine femur.}, journal = {Cell and tissue banking}, volume = {16}, number = {1}, pages = {97-108}, doi = {10.1007/s10561-014-9446-9}, pmid = {24737302}, issn = {1573-6814}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cattle ; Femur/drug effects/*radiation effects ; Free Radical Scavengers/*pharmacology ; *Gamma Rays ; Radiation-Protective Agents/*pharmacology ; }, abstract = {Gamma sterilization of bone allografts is used as a gold standard method to provide safety against disease transmission. However, it is well documented that high dose levels of ionizing radiation can degrade bone mechanical properties. This effect, which is attributed to the formation of free radicals through radiolysis of the water content of collagen, can lead to post-implantation difficulties such as pre-failure and/or secondary fractures of bone allografts. Recently, treatment of irradiated allografts with free radical scavengers is used to protect them against radiation-induced damages. This study aimed to investigate the radioprotective role of N-acetyl-L-cysteine (NAC) during the gamma sterilization of the cortical bone of bovine femurs using the compressive test. Totally, 195 cubic specimens with a dimension of 5 × 5 × 3 cubic mm were divided into 13 groups including a control and 12 experimental groups exposed to 18, 36, and 70 kGy at three different NAC concentrations (1.25, 12.5, and 25 mM for 18 kGy; 5, 50, and 100 mM for 36 kGy; 10, 100, and 200 mM for 70 kGy). The mechanical behavior of the sterilized specimens was studied using the uniaxial compressive test. The results indicated a concentration-dependent radioprotection effect of NAC on the plastic properties of the cortical bones. The concentration dependency of NAC was in turn related to radiation dose levels. In conclusion, treatment of bone specimens with a characteristic concentration of NAC during exposure to specific radiation dose levels can provide an efficient radioprotection window for preserving the mechanical stability of gamma sterilized allografts.}, }
@article {pmid24734887, year = {2014}, author = {Zhang, L and Zhu, Z and Liu, J and Zhu, Z and Hu, Z}, title = {Protective effect of N-acetylcysteine (NAC) on renal ischemia/reperfusion injury through Nrf2 signaling pathway.}, journal = {Journal of receptor and signal transduction research}, volume = {34}, number = {5}, pages = {396-400}, doi = {10.3109/10799893.2014.908916}, pmid = {24734887}, issn = {1532-4281}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*physiopathology/*prevention &amp; control ; Animals ; Free Radical Scavengers/administration &amp; dosage ; Male ; NF-E2-Related Factor 2/drug effects/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*drug therapy/*physiopathology ; Signal Transduction/*drug effects ; Treatment Outcome ; }, abstract = {The aim of this study was to investigate whether N-acetylcysteine (NAC), a known antioxidant, can protect kidney against ischemic injury through regulating Nrf2 signaling pathway. The expression of Nrf2, HO-1 and cleaved caspase 3 were analyzed by Western blot analysis. Apoptosis of renal tubular epithelial cells was assessed by the TUNEL method. Malondialdehyde (MDA) levels were measured by the thiobarbituric acid reaction. Blood serum creatinine and blood urea nitrogen levels were measured with an Olympus automatic multi-analyzer. We found that NAC significantly increased Nrf2 and downstream HO-1 expression. Furthermore, NAC significantly decreased cleaved caspase 3, p53 and renal epithelial tubular cell apoptosis. In addition, NAC reduced the MDA level. These findings suggest that the protective action of NAC on ischemia renal injury is associated closely with Nrf2 signaling pathway.}, }
@article {pmid24732633, year = {2014}, author = {Chen, SH and Li, DL and Yang, F and Wu, Z and Zhao, YY and Jiang, Y}, title = {Gemcitabine-induced pancreatic cancer cell death is associated with MST1/cyclophilin D mitochondrial complexation.}, journal = {Biochimie}, volume = {103}, number = {}, pages = {71-79}, doi = {10.1016/j.biochi.2014.04.004}, pmid = {24732633}, issn = {1638-6183}, mesh = {Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Peptidyl-Prolyl Isomerase F ; Cyclophilins/genetics/*metabolism ; Cyclosporine/pharmacology ; Deoxycytidine/*analogs &amp; derivatives/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Intracellular Signaling Peptides and Proteins ; Mitochondria/*drug effects/*metabolism ; Mitochondrial Membrane Transport Proteins/chemistry/metabolism ; Mitochondrial Permeability Transition Pore ; Pancreatic Neoplasms/*pathology ; Protein Conformation/drug effects ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Protein Transport/drug effects ; Reactive Oxygen Species/metabolism ; Gemcitabine ; }, abstract = {The pancreatic adenocarcinoma remains the most aggressive human malignancy with an extremely low 5-year overall survival. Postoperative gemcitabine could significantly delay recurrence after complete resection of pancreatic cancer. However, the underlying mechanisms are not fully understood. The chemo-resistance factors against gemcitabine still need further characterizations. Here we studied the mechanism of gemcitabine-induced pancreatic cancer cell death by focusing on mammalian sterile 20-like kinase 1 (MST1) and cyclophilin D (Cyp-D). We found that MST1 and Cyp-D expressions were significantly lower in gemcitabine-resistant pancreatic cancer tissues and cell lines. In vitro, gemcitabine activated MST1 through reactive oxygen species (ROS) production, which was prevented by antioxidant n-acetyl-cysteine (NAC). We found that gemcitabine-activated MST1 translocated to mitochondria and formed a complex with the local protein Cyp-D. Gemcitabine-induced cell death was alleviated by MST1 or Cyp-D shRNA silencing, but was aggravated by MST1 or Cyp-D over-expression. Further, cyclosporin A (CsA), the Cyp-D inhibitor, prevented gemcitabine-induced MST1/Cyp-D mitochondrial complexation and cancer cell death. We suggest that gemcitabine-induced death of pancreatic cancer cells requires MST1/Cyp-D mitochondrial complexation.}, }
@article {pmid24728083, year = {2014}, author = {Dai, Y and Xiong, X and Huang, G and Liu, J and Sheng, S and Wang, H and Qin, W}, title = {Dichloroacetate enhances adriamycin-induced hepatoma cell toxicity in vitro and in vivo by increasing reactive oxygen species levels.}, journal = {PloS one}, volume = {9}, number = {4}, pages = {e92962}, pmid = {24728083}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Apoptosis/drug effects ; Carcinoma, Hepatocellular/*metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Dichloroacetic Acid/*pharmacology/therapeutic use ; Doxorubicin/*pharmacology/therapeutic use ; Humans ; Liver Neoplasms/*metabolism ; Male ; Mice ; Reactive Oxygen Species/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {A unique bioenergetic feature of cancer, aerobic glycolysis is considered an attractive therapeutic target for cancer therapy. Recently, dichloroacetate (DCA), a small-molecule metabolic modulator, was shown to reverse the glycolytic phenotype, induce reactive oxygen species (ROS) generation, and trigger apoptosis in various tumor cells. In this work, the capacity of DCA to enhance Adriamycin (ADM) efficacy in hepatoma cells by modulating glucose metabolism and redox status was evaluated. Two human hepatoma (HCC-LM3 and SMMC-7721) and a normal liver (LO2) cell lines were treated with DCA or ADM alone, or in combination. Exposure of hepatoma cells to DCA/ADM combination resulted in significantly decreased cell viability and increased percentage of apoptotic cells as well as intracellular ROS levels, in comparison with treatment with DCA or ADM alone. However, simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC, 10 mmol/L) reduced the elevated ROS levels and protected hepatoma cells from the cytotoxic effects of DCA/ADM combination. L-buthionine-[S,R]-sulfoximine, an inhibitor of glutathione synthesis, enhanced hepatoma cell sensitivity to DCA/ADM combination. Interestingly, treatment with DCA/ADM combination did not significantly increase cytotoxicity in normal hepatocytes in comparison with the drugs administered individually. Finally, DCA reduced tumor growth and enhanced ADM efficacy on HCC-LM3 hepatoma in mice. Overall, our data suggest that DCA enhances ADM cytotoxicity in hepatoma cells by increasing intracellular ROS levels and provide a strong biochemical rationale for the use of DCA in combination with ADM for treatment of hepatoma.}, }
@article {pmid24727577, year = {2014}, author = {Lee, JE and Lim, MS and Park, JH and Park, CH and Koh, HC}, title = {Nuclear NF-κB contributes to chlorpyrifos-induced apoptosis through p53 signaling in human neural precursor cells.}, journal = {Neurotoxicology}, volume = {42}, number = {}, pages = {58-70}, doi = {10.1016/j.neuro.2014.04.001}, pmid = {24727577}, issn = {1872-9711}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cells, Cultured ; Chlorpyrifos/antagonists &amp; inhibitors/*toxicity ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Humans ; Insecticides/antagonists &amp; inhibitors/toxicity ; L-Lactate Dehydrogenase/metabolism ; Malondialdehyde/metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Neural Stem Cells/*drug effects/*metabolism/pathology ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Chlorpyrifos (CPF) is one of the most widely used organophosphate insecticides with several harmful effects, including neurotoxicity. Although many studies have addressed the neurotoxicity induced by CPF, most data on neurodevelopmental damage was obtained from animal models. We are the first group to use human neural precursor cells (hNPCs) derived from human embryonic stem cells (hESCs) as a developing neuron model to evaluate the mechanisms involved in CPF-induced neurotoxicity. CPF was cytotoxic to these cells in a concentration-dependent manner, as shown by decreased cell viability and increased lactate dehydrogenase release. Furthermore, CPF reduced the expression of AKT and ERK proteins which are involved in intracellular survival pathways. Exposure of hNPCs to CPF led to the production of reactive oxygen species (ROS), and the antioxidant N-acetyl-cystein (NAC) attenuated ROS production induced by CPF. In addition, CPF increased cytochrome c release into the cytosol and activated caspase-9 and -3, indicating that cell death induced by CPF was due to apoptosis in hNPCs. Consistent with these findings, CPF treatment reduced the level of Bcl-2 protein and increased the level of Bax protein. Especially, CPF increased the translocation of BAX into the mitochondria. CPF also induced nuclear accumulation of NF-κB and p53 proteins in a concentration-dependent manner, and their inhibitors attenuated CPF-induced cytotoxicity. In addition, an inhibitor of NF-κB nuclear translocation blocked the increase of p53 in CPF-treated hNPCs. These findings show that CPF induced hNPCs death in part through NF-κB activation via ROS generation, enabling the interaction of p53 with Bcl-2 and Bax and subsequent release of cytochrome c. Collectively, these results represent a unique molecular characterization of CPF-induced cytotoxicity in hNPCs. These data suggest that CPF may affect neurodevelopment in a manner similar to that of several known and suspected neurotoxicants.}, }
@article {pmid24727104, year = {2014}, author = {Ulusoy, S and Ozkan, G and Mungan, S and Orem, A and Yulug, E and Alkanat, M and Yucesan, FB}, title = {GSPE is superior to NAC in the prevention of contrast-induced nephropathy: might this superiority be related to caspase 1 and calpain 1?.}, journal = {Life sciences}, volume = {103}, number = {2}, pages = {101-110}, doi = {10.1016/j.lfs.2014.03.030}, pmid = {24727104}, issn = {1879-0631}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Calpain/*metabolism ; Caspase 1/*metabolism ; Contrast Media/*toxicity ; Grape Seed Extract/*therapeutic use ; Kidney Diseases/chemically induced/*metabolism/prevention &amp; control ; Male ; Proanthocyanidins/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIMS: Our study was intended to evaluate the role of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), caspases 1 and 3 and calpain 1 in the pathogenesis of contrast-induced nephropathy (CIN) and to compare the protective effects of N acetyl cysteine (NAC) and grape seed proanthocyanidin extract (GSPE) against the development of CIN.<br><br>MAIN METHODS: 32 rats were divided into four groups; control, contrast media (CM), CM+NAC and CM+GSPE. CIN was induced by administration of 7 ml/kg diatrizoate. The experiment was discontinued on the ninth day. Blood was collected for blood urea nitrogen (BUN) and creatinine measurement. Rat kidney tissues were removed for histopathological evaluation and the investigation of caspases 1 and 3, iNOS, eNOS, TUNEL and calpain 1.<br><br>KEY FINDINGS: A significant increase in BUN, creatinine, renal histopathological injury, TUNEL, caspases 1, 3, calpain 1, iNOS and eNOS was observed in the CM group compared to the control group. There was amelioration in all these parameters in the CM+GSPE group, while there was no significant amelioration in BUN, creatinine and renal histopathological injury in the CM+NAC group. In addition, calpain 1 staining and creatinine were significantly lower in the CM+GSPE group compared to the CM+NAC group.<br><br>SIGNIFICANCE: Our study showed, for the first time in the literature, that GSPE has a greater renoprotective effect compared with NAC and that this effective protection may be related to decrease in calpain 1 levels.}, }
@article {pmid24726884, year = {2014}, author = {Ma, Z and Wei, Q and Dong, G and Huo, Y and Dong, Z}, title = {DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells.}, journal = {Biochimica et biophysica acta}, volume = {1842}, number = {7}, pages = {1088-1096}, pmid = {24726884}, issn = {0006-3002}, support = {R21 HL108922/HL/NHLBI NIH HHS/United States ; I01 BX000319/BX/BLRD VA/United States ; R01 HL095556/HL/NHLBI NIH HHS/United States ; R01 DK087843/DK/NIDDK NIH HHS/United States ; R01 DK058831/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Acute Kidney Injury/*genetics/metabolism ; Adenosine Triphosphate/*metabolism ; Animals ; Apoptosis/genetics ; Ataxia Telangiectasia Mutated Proteins/genetics/metabolism ; Checkpoint Kinase 2/genetics/metabolism ; *DNA Damage ; Glucose/metabolism ; Histones/genetics/metabolism ; Kidney/*blood supply/metabolism ; Kidney Tubules/blood supply/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reperfusion ; Reperfusion Injury/*genetics/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {Renal ischemia-reperfusion leads to acute kidney injury (AKI) that is characterized pathologically by tubular damage and cell death, followed by tubular repair, atrophy and interstitial fibrosis. Recent work suggested the possible presence of DNA damage response (DDR) in AKI. However, the evidence is sketchy and the role and regulation of DDR in ischemic AKI remain elusive. In this study, we demonstrated the induction of phosphorylation of ATM, H2AX, Chk2 and p53 during renal ischemia-reperfusion in mice, suggesting DDR in kidney tissues. DDR was also induced in vitro during the recovery or "reperfusion" of renal proximal tubular cells (RPTCs) after ATP depletion. DDR in RPTCs was abrogated by supplying glucose to maintain ATP via glycolysis, indicating that the DDR depends on ATP depletion. The DDR was also suppressed by the general caspase inhibitor z-VAD and the overexpression of Bcl-2, supporting a role of apoptosis-associated DNA damage in the DDR. N-acetylcysteine (NAC), an antioxidant, suppressed the phosphorylation of ATM and p53 and, to a less extent, Chk2, but NAC increased the phosphorylation and nuclear foci formation of H2AX. Interestingly, NAC increased apoptosis, which may account for the observed H2AX activation. Ku55933, an ATM inhibitor, blocked ATM phosphorylation and ameliorated the phosphorylation of Chk2 and p53, but it increased H2AX phosphorylation and nuclear foci formation. Ku55933 also increased apoptosis in RPTCs following ATP depletion. The results suggest that DDR occurs during renal ischemia-reperfusion in vivo and ATP-depletion injury in vitro. The DDR is partially induced by apoptosis and oxidative stress-related DNA damage. ATM, as a sensor in the DDR, may play a cytoprotective role against tubular cell injury and death.}, }
@article {pmid24726524, year = {2014}, author = {Zhou, CF and Zhou, DC and Zhang, JX and Wang, F and Cha, WS and Wu, CH and Zhu, QX}, title = {Bleomycin-induced epithelial-mesenchymal transition in sclerotic skin of mice: possible role of oxidative stress in the pathogenesis.}, journal = {Toxicology and applied pharmacology}, volume = {277}, number = {3}, pages = {250-258}, doi = {10.1016/j.taap.2014.03.024}, pmid = {24726524}, issn = {1096-0333}, support = {BB/G015554/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Antibiotics, Antineoplastic/*toxicity ; Bleomycin/*toxicity ; Epithelial-Mesenchymal Transition/*drug effects ; Fibrosis ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/*drug effects ; Sclerosis ; Skin Diseases/*chemically induced/pathology ; Specific Pathogen-Free Organisms ; }, abstract = {Epithelial-mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100mg/kg body weight/day) injected daily for 3weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice.}, }
@article {pmid24726294, year = {2014}, author = {Paquet, P and Jennes, S and Rousseau, AF and Libon, F and Delvenne, P and Piérard, GE}, title = {Effect of N-acetylcysteine combined with infliximab on toxic epidermal necrolysis. A proof-of-concept study.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {40}, number = {8}, pages = {1707-1712}, doi = {10.1016/j.burns.2014.01.027}, pmid = {24726294}, issn = {1879-1409}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/*therapeutic use ; Antigens, CD/analysis ; Burns/*complications ; Dermatologic Agents/*therapeutic use ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Immunohistochemistry ; Infliximab ; Macrophages/immunology ; Male ; Middle Aged ; Stevens-Johnson Syndrome/*drug therapy/immunology/pathology ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors ; Young Adult ; }, abstract = {INTRODUCTION: The pathophysiology of toxic epidermal necrolysis (TEN) is thought to be related to a drug-induced oxidative stress combined with TNFα overexpression by keratinocytes. None of the current treatments for TEN including systemic corticosteroids, cyclosporine and intravenous administration of immunoglobulins has proven superior over supportive care only.<br><br>METHODS: A total of 10 TEN patients were enrolled to be treated at admission in burn units with the antioxidant N-acetylcysteine [NAC, 150mg/kg in a 20-h intravenous (IV) administration], or the combination of the same IV NAC perfusion with the anti-TNF&#x3b1; antibody infliximab (Remicade(&#xae;)), administered at a 5mg/kg dosage as a single 2-h IV administration. TEN was confirmed by a skin biopsy taken from a bullous lesion. At entry in the trial and 48h later, the illness auxiliary score (IAS) of clinical severity was determined and the extent in altered skin area (erythema and blisters) was assessed as a relative body area. Skin biopsies of both clinically uninvolved and erythematous areas were collected and immunohistochemistry was performed for assessing the density of inflammatory cells (CD8+ T cells, CD68+ macrophages) and keratinocytes enriched in intracellular calcium (Ca(++)) identified by the Mac387 anti-calprotectin antibody.<br><br>RESULTS: No unexpected drug-induced adverse event was noticed. After 48h of both treatment modalities, improvements were not observed in the extent of skin involvement and in IAS. Immunohistopathology showed the absence of reduction in the amount of intraepidermal inflammatory cells. An increased intracellular Ca(++) load in clinically uninvolved keratinocytes and in erythematous epidermis was noticed. This latter finding suggested the progression in the way of the apoptotic process. On burn unit discharge, the survival in each modality of treatment was not improved compared to the expected outcomes determined from the IAS at admission.<br><br>CONCLUSIONS: In this proof-to-concept attempt, NAC treatment or its combination with infliximab did not appear to reverse the evolving TEN process.}, }
@article {pmid24725851, year = {2014}, author = {Herrmann, AP and Benvenutti, R and Pilz, LK and Elisabetsky, E}, title = {N-acetylcysteine prevents increased amphetamine sensitivity in social isolation-reared mice.}, journal = {Schizophrenia research}, volume = {155}, number = {1-3}, pages = {109-111}, doi = {10.1016/j.schres.2014.03.012}, pmid = {24725851}, issn = {1573-2509}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Amphetamine/*adverse effects ; Analysis of Variance ; Animals ; Central Nervous System/drug effects ; Central Nervous System Stimulants/*adverse effects ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology/*therapeutic use ; Hyperkinesis/*chemically induced/*prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Social Isolation/*psychology ; }, abstract = {Treating individuals at risk to develop schizophrenia may be strategic to delay or prevent transition to psychosis. We verified the effects of N-acetylcysteine (NAC) in a neurodevelopmental model of schizophrenia. C57 mice were reared in isolation or social groups and treated with NAC from postnatal day 42-70; the locomotor response to amphetamine was assessed at postnatal day 81. NAC treatment in isolated mice prevented the hypersensitivity to amphetamine, suggesting neuroprotection relevant to striatal dopamine. Considering its safety and tolerability profile, complementary studies are warranted to further evaluate the usefulness of NAC to prevent conversion to schizophrenia in at-risk individuals.}, }
@article {pmid24725344, year = {2014}, author = {van de Schootbrugge, C and Schults, EM and Bussink, J and Span, PN and Grénman, R and Pruijn, GJ and Kaanders, JH and Boelens, WC}, title = {Effect of hypoxia on the expression of αB-crystallin in head and neck squamous cell carcinoma.}, journal = {BMC cancer}, volume = {14}, number = {}, pages = {252}, pmid = {24725344}, issn = {1471-2407}, mesh = {Carcinoma, Squamous Cell/*genetics/pathology ; Cell Hypoxia/*genetics ; Cell Line, Tumor ; Cell Survival/genetics ; Gene Expression Regulation, Neoplastic ; Head and Neck Neoplasms/*genetics/pathology ; Humans ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/metabolism ; alpha-Crystallin B Chain/*biosynthesis/genetics ; }, abstract = {BACKGROUND: The presence of hypoxia in head and neck squamous cell carcinoma (HNSCC) is associated with therapeutic resistance and increased risk of metastasis formation. αB-crystallin (HspB5) is a small heat shock protein, which is also associated with metastasis formation in HNSCC. In this study, we investigated whether αB-crystallin protein expression is increased in hypoxic areas of HNSCC biopsies and analyzed whether hypoxia induces αB-crystallin expression in vitro and in this way may confer hypoxic cell survival.<br><br>METHODS: In 38 HNSCC biopsies, the overlap between immunohistochemically stained &#x3b1;B-crystallin and pimonidazole-adducts (hypoxiamarker) was determined. Moreover, expression levels of &#x3b1;B-crystallin were analyzed in HNSCC cell lines under hypoxia and reoxygenation conditions and after exposure to reactive oxygen species (ROS) and the ROS scavenger N-acetylcysteine (NAC). siRNA-mediated knockdown was used to determine the influence of &#x3b1;B-crystallin on cell survival under hypoxic conditions.<br><br>RESULTS: In all biopsies &#x3b1;B-crystallin was more abundantly present in hypoxic areas than in normoxic areas. Remarkably, hypoxia decreased &#x3b1;B-crystallin mRNA expression in the HNSCC cell lines. Only after reoxygenation, a condition that stimulates ROS formation, &#x3b1;B-crystallin expression was increased. &#x3b1;B-crystallin mRNA levels were also increased by extracellular ROS, and NAC abolished the reoxygenation-induced &#x3b1;B-crystallin upregulation. Moreover, it was found that decreased &#x3b1;B-crystallin levels reduced cell survival under hypoxic conditions.<br><br>CONCLUSIONS: We provide the first evidence that hypoxia stimulates upregulation of &#x3b1;B-crystallin in HNSCC. This upregulation was not caused by the low oxygen pressure, but more likely by ROS formation. The higher expression of &#x3b1;B-crystallin may lead to prolonged survival of these cells under hypoxic conditions.}, }
@article {pmid24720376, year = {2014}, author = {McClure, EA and Baker, NL and Gray, KM}, title = {Cigarette smoking during an N-acetylcysteine-assisted cannabis cessation trial in adolescents.}, journal = {The American journal of drug and alcohol abuse}, volume = {40}, number = {4}, pages = {285-291}, pmid = {24720376}, issn = {1097-9891}, support = {U01DA031779/DA/NIDA NIH HHS/United States ; R01 DA026777/DA/NIDA NIH HHS/United States ; UL1TR000062/TR/NCATS NIH HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; U10 DA013727/DA/NIDA NIH HHS/United States ; R01DA026777/DA/NIDA NIH HHS/United States ; U01 DA031779/DA/NIDA NIH HHS/United States ; U10DA013727/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Female ; Humans ; Male ; Marijuana Abuse/*drug therapy ; Marijuana Smoking/*drug therapy ; *Smoking ; Surveys and Questionnaires ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVES: Tobacco and cannabis use are both highly prevalent worldwide. Their co-use is also common in adults and adolescents. Despite this frequent co-occurrence, cessation from both substances is rarely addressed in randomized clinical trials. Given evidence that tobacco use may increase during cannabis cessation attempts, and additionally that tobacco users have poorer cannabis cessation outcomes, we explored tobacco outcomes, specifically cigarette smoking, from an adolescent cannabis cessation trial that tested the efficacy of N-acetylesteine (NAC).<br><br>METHODS: Cannabis-dependent adolescents (ages 15-21; n&#x2009;=&#x2009;116) interested in cannabis treatment were randomized to NAC (1200&#x2009;mg bid) or matched placebo for 8 weeks. Participants did not need to be cigarette smokers or be interested in smoking cessation to qualify for inclusion.<br><br>RESULTS: Approximately 59% of enrolled participants were daily and non-daily cigarette smokers, and only differed from non-smoking participants on the compulsion sub-scale of the Marijuana Craving Questionnaire. Among cigarette smokers who were retained in the study, there was no change in cigarettes per day for either NAC or placebo groups during the eight-week treatment phase. Being a cigarette smoker did not appear to influence the effects of NAC on cannabis abstinence, though there was a trend in the placebo group of poorer cannabis outcomes for cigarette smokers vs. non-smokers.<br><br>CONCLUSIONS: No evidence was found of compensatory cigarette smoking during this cannabis cessation trial in adolescents. Further work assessing interventions to reduce both cannabis and tobacco use in this population is greatly needed.}, }
@article {pmid24717091, year = {2014}, author = {Bissinger, R and Malik, A and Jilani, K and Lang, F}, title = {Triggering of erythrocyte cell membrane scrambling by salinomycin.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {115}, number = {5}, pages = {396-402}, doi = {10.1111/bcpt.12250}, pmid = {24717091}, issn = {1742-7843}, mesh = {Annexin A5/metabolism ; Anti-Bacterial Agents/administration &amp; dosage/pharmacology ; Calcium/metabolism ; Dose-Response Relationship, Drug ; Erythrocyte Membrane/*drug effects/metabolism ; Erythrocytes/*drug effects/metabolism ; Hemolysis/drug effects ; Humans ; Oxidative Stress/drug effects ; Phosphatidylserines/*metabolism ; Pyrans/administration &amp; dosage/*pharmacology ; }, abstract = {Salinomycin, a polyether ionophore antibiotic effective against a variety of pathogens, has been shown to trigger apoptosis of cancer cells and cancer stem cells. The substance is thus considered for the treatment of malignancy. Salinomycin compromises tumour cell survival at least in part by interference with mitochondrial function. Erythrocytes lack mitochondria but may undergo apoptosis-like suicidal cell death or eryptosis, which is characterized by scrambling of the cell membrane with phosphatidylserine exposure at the erythrocyte surface. Signalling involved in the triggering of eryptosis includes activation of oxidant-sensitive Ca(2+) permeable cation channels with subsequent increase in cytosolic Ca(2+) activity ([Ca(2+)]i). This study explored whether salinomycin stimulates eryptosis. Phosphatidylserine-exposing erythrocytes were identified by measurement of annexin-V binding, cell volume was estimated from forward scatter, haemolysis determined from haemoglobin release, [Ca(2+)]i quantified utilizing Fluo3-fluorescence and oxidative stress from 2',7' dichlorodihydrofluorescein diacetate (DCFDA) fluorescence in flow cytometry. A 48-hr exposure to salinomycin (5-100 nM) was followed by a significant increase in Fluo3-fluorescence, DCFDA fluorescence and annexin-V binding, as well as a significant decrease in forward scatter (at 5-10 nM, but not at 50 and 100 nM). The annexin-V binding after salinomycin treatment was significantly blunted but not abrogated in the nominal absence of extracellular Ca(2+) or in the presence of antioxidant n-acetyl cysteine (1 mM). Salinomycin triggers cell membrane scrambling, an effect at least partially due to oxidative stress and entry of extracellular Ca(2+).}, }
@article {pmid24714489, year = {2014}, author = {Thayssen, P and Lassen, JF and Jensen, SE and Hansen, KN and Hansen, HS and Christiansen, EH and Junker, A and Ravkilde, J and Thuesen, L and Veien, KT and Jensen, LO}, title = {Prevention of contrast-induced nephropathy with N-acetylcysteine or sodium bicarbonate in patients with ST-segment-myocardial infarction: a prospective, randomized, open-labeled trial.}, journal = {Circulation. Cardiovascular interventions}, volume = {7}, number = {2}, pages = {216-224}, doi = {10.1161/CIRCINTERVENTIONS.113.000653}, pmid = {24714489}, issn = {1941-7632}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aged ; Contrast Media/*adverse effects ; Creatinine/blood ; Drug Therapy, Combination ; Electrocardiography ; Female ; Humans ; Incidence ; Infusions, Intravenous ; Kidney Diseases/*chemically induced/epidemiology/*prevention &amp; control ; Male ; Middle Aged ; Myocardial Infarction/physiopathology/*therapy ; *Percutaneous Coronary Intervention/adverse effects/methods ; Prospective Studies ; Sodium Bicarbonate/administration &amp; dosage/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) is a serious condition in patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention. We compared the risk of acute CIN and the influence of preventive strategies in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention.<br><br>METHODS AND RESULTS: A total of 720 patients were randomized in the Prevention of Contrast-induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention (CINSTEMI) trial. Patients were randomly assigned in a 1:1:1:1 ratio to receive hydration with sodium chloride together with 1 of 4 prophylactic regimes (1) N-acetylcysteine (NAC), (2) sodium bicarbonate (NaHCO3) infusion, (3) NAC in combination with NaHCO3, or (4) hydration with sodium chloride infusion alone. Patients in cardiogenic shock were excluded. Acute CIN was defined as an increase in serum creatinine concentration >25% from the baseline value within a 3-day period. Overall, CIN occurred in 141 (21.9%) patients. The prevention treatment with NAC, NaHCO3, or the combined NAC and NaHCO3 did not reduce the rate of CIN significantly compared with hydration with intravenous sodium chloride infusion alone (20.1% versus 20.1% versus 20.8% versus 26.5%; P=NS). However, an increase in serum creatinine >25% from the baseline value to 30 day was significantly lower in patients treated with combined NAC and NaHCO3 (18.7% versus 19.1% versus 9.2% versus 21.3%; P=0.033).<br><br>CONCLUSIONS: Treatment with NAC or NaHCO3 did not reduce the rate of acute CIN significantly. Combined treatment with NAC and NaHCO3 may reduce the risk of renal dysfunction after 30 days.<br><br>http://www.clinicaltrials.gov. Unique identifier: NCT01160627.}, }
@article {pmid24714014, year = {2014}, author = {Sit, M and Yilmaz, EE and Tosun, M and Aktas, G}, title = {Effects of N-acetyl cysteine on lipid levels and on leukocyte and platelet count in rats after splenectomy.}, journal = {Nigerian journal of clinical practice}, volume = {17}, number = {3}, pages = {343-345}, doi = {10.4103/1119-3077.130237}, pmid = {24714014}, issn = {1119-3077}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Platelets/*drug effects ; Free Radical Scavengers/pharmacology ; Leukocytes/*drug effects ; Lipid Metabolism/*drug effects ; Lipids/*blood ; Rats ; Rats, Sprague-Dawley ; *Splenectomy ; }, abstract = {INTRODUCTION: Many of studies have shown that increased lipid levels play a significant role in the pathogenesis of atherosclerosis after splenectomy. We investigated the effects of N-acetyl cysteine (NAC) on lipid parameters and leukocyte and platelet (PLT) levels following splenectomy.<br><br>MATERIALS AND METHODS: 32 Sprague-Dawley rats weighing from 200 to 250 g were placed into four experimental groups. For 42 days post-operatively, all rats were fed standard rat food and water and the rats in the first group (n = 8) received no intraperitoneal infusion. Rats in the second group (n = 6) were given a 50 mg/kg saline solution (SF); those in the third group (n = 8) received 50 mg/kg NAC and the rats in the fourth group (n = 8) were administered a 100 mg/kg NAC infusion intraperitoneally.<br><br>RESULTS: All parameters other than white blood cell count were significantly different between the four groups. There were no significant differences between the control and SF groups in terms of total cholesterol and PLT levels. Triglyceride (TG), very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) levels were significantly elevated in the SF group compared with the control rats. There was no statistically significant difference between the SF and NAC 50/100 groups in terms of low-density lipoprotein levels. Total cholesterol, TG, HDL and VLDL levels were significantly reduced and the PLT level was significantly elevated in the NAC 50 and NAC 100 groups compared with the SF group.<br><br>CONCLUSION: Serum VLDL and TG levels should be monitored in patients after splenectomy. For reduction in these lipid parameters, early NAC treatment should be initiated. More prospective larger studies are needed to confirm our results.}, }
@article {pmid24713665, year = {2014}, author = {Shi, X and Li, X and Li, D and Li, Y and Song, Y and Deng, Q and Wang, J and Zhang, Y and Ding, H and Yin, L and Zhang, Y and Wang, Z and Li, X and Liu, G}, title = {β-Hydroxybutyrate activates the NF-κB signaling pathway to promote the expression of pro-inflammatory factors in calf hepatocytes.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {33}, number = {4}, pages = {920-932}, doi = {10.1159/000358664}, pmid = {24713665}, issn = {1421-9778}, mesh = {3-Hydroxybutyric Acid/*pharmacology ; Acetylcysteine/pharmacology ; Animals ; Cattle ; Cells, Cultured ; Glutathione Peroxidase/metabolism ; Hepatocytes/cytology/*drug effects/metabolism ; I-kappa B Kinase/metabolism ; I-kappa B Proteins/metabolism ; Interleukin-1beta/metabolism ; Interleukin-6/metabolism ; Malondialdehyde/metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Nitric Oxide/metabolism ; Phosphorylation/drug effects ; Pyrrolidines/pharmacology ; Signal Transduction/*drug effects ; Superoxide Dismutase/metabolism ; Thiocarbamates/pharmacology ; Transcription Factor RelA/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND/AIMS: β-hydroxybutyrate (BHBA) is the major component of ketone bodies in ketosis. Dairy cows with ketosis often undergo oxidative stress. BHBA is related to the inflammation involved in other diseases of dairy cattle. However, whether BHBA can induce inflammatory injury in dairy cow hepatocytes and the potential mechanism of this induction are not clear. The NF-κB pathway plays a vital role in the inflammatory response.<br><br>METHODS: Therefore, this study evaluated the oxidative stress, pro-inflammatory factors and NF-&#x3ba;B pathway in cultured calf hepatocytes treated with different concentrations of BHBA, pyrrolidine dithiocarbamate (PDTC, an NF-&#x3ba;B pathway inhibitor) and N-acetylcysteine (NAC, antioxidant).<br><br>RESULTS: The results showed that BHBA could significantly increase the levels of oxidation indicators (MDA, NO and iNOS), whereas the levels of antioxidation indicators (GSH-Px, CAT and SOD) were markedly decreased in hepatocytes. The IKK&#x3b2; activity and phospho-I&#x3ba;B&#x3b1; (p-I&#x3ba;B&#x3b1;) contents were increased in BHBA-treated hepatocytes. This increase was accompanied by the increased expression level and transcription activity of p65. The expression levels of NF-&#x3ba;B-regulated inflammatory cytokines, namely TNF-&#x3b1;, IL-6 and IL-1&#x3b2;, were markedly increased after BHBA treatment, while significantly decreased after NAC treatment. However, the p-I&#x3ba;B&#x3b1; level and the expression and activity of p65 and its target genes were markedly decreased in the PDTC + BHBA group compared with the BHBA (1.8 mM) group. Moreover, immunocytofluorescence of p65 showed a similar trend.<br><br>CONCLUSION: The present data indicate that higher concentrations of BHBA can induce cattle hepatocyte inflammatory injury through the NF-&#x3ba;B signaling pathway, which may be activated by oxidative stress.}, }
@article {pmid24711000, year = {2015}, author = {Ataei, S and Hadjibabaie, M and Moslehi, A and Taghizadeh-Ghehi, M and Ashouri, A and Amini, E and Gholami, K and Hayatshahi, A and Vaezi, M and Ghavamzadeh, A}, title = {A double-blind, randomized, controlled trial on N-acetylcysteine for the prevention of acute kidney injury in patients undergoing allogeneic hematopoietic stem cell transplantation.}, journal = {Hematological oncology}, volume = {33}, number = {2}, pages = {67-74}, doi = {10.1002/hon.2141}, pmid = {24711000}, issn = {1099-1069}, mesh = {Abdominal Pain/chemically induced ; Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Acute Kidney Injury/etiology/*prevention &amp; control ; Adult ; Allografts ; Antioxidants/administration &amp; dosage/adverse effects/*therapeutic use ; Double-Blind Method ; Drug Eruptions/etiology ; Dyspnea/chemically induced ; Female ; Graft Survival ; Graft vs Host Disease/prevention &amp; control ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Immunosuppression Therapy ; Infusions, Intravenous ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Pruritus/chemically induced ; Transplantation Conditioning ; Vasodilator Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Young Adult ; }, abstract = {Acute kidney injury (AKI) is one of the complications of hematopoietic stem cell transplantation and is associated with increased mortality. N-acetylcysteine (NAC) is a thiol compound with antioxidant and vasodilatory properties that has been investigated for the prevention of AKI in several clinical settings. In the present study, we evaluated the effects of intravenous NAC on the prevention of AKI in allogeneic hematopoietic stem cell transplantation patients. A double-blind randomized placebo-controlled trial was conducted, and 80 patients were recruited to receive 100 mg/kg/day NAC or placebo as intermittent intravenous infusion from day -6 to day +15. AKI was determined on the basis of the Risk-Injury-Failure-Loss-End-stage renal disease and AKI Network criteria as the primary outcome. We assessed urine neutrophil gelatinase-associated lipocalin (uNGAL) on days -6, -3, +3, +9 and +15 as the secondary outcome. Moreover, transplant-related outcomes and NAC adverse reactions were evaluated during the study period. Statistical analysis was performed using appropriate parametric and non-parametric methods including Kaplan-Meier for AKI and generalized estimating equation for uNGAL. At the end of the trial, data from 72 patients were analysed (NAC: 33 patients and placebo: 39 patients). Participants of each group were not different considering baseline characteristics. AKI was observed in 18% of NAC recipients and 15% of placebo group patients, and the occurrence pattern was not significantly different (p = 0.73). Moreover, no significant difference was observed between groups for uNGAL measures (p = 0.10). Transplant-related outcomes were similar for both groups, and all patients had successful engraftment. Three patients did not tolerate NAC because of abdominal pain, shortness of breath and rash with pruritus and were dropped from the intervention group before transplantation. However, the frequency of adverse reactions was not significantly different between groups. In conclusion, our findings could not show any clinical benefits from high-dose NAC particularly for AKI prevention in allogeneic hematopoietic stem cell transplantation patients.}, }
@article {pmid24708009, year = {2014}, author = {Wong, A and Graudins, A and Kerr, F and Greene, SL}, title = {Paracetamol toxicity: what would be the implications of a change in Australian treatment guidelines?.}, journal = {Emergency medicine Australasia : EMA}, volume = {26}, number = {2}, pages = {183-187}, doi = {10.1111/1742-6723.12200}, pmid = {24708009}, issn = {1742-6723}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/economics/*therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/economics/*therapeutic use ; Costs and Cost Analysis ; Drug Overdose/*drug therapy/economics/etiology ; Emergency Service, Hospital/economics/statistics &amp; numerical data ; Free Radical Scavengers/economics/*therapeutic use ; Health Care Costs ; Hospitalization/statistics &amp; numerical data ; Humans ; *Practice Guidelines as Topic ; Retrospective Studies ; Victoria ; }, abstract = {OBJECTIVES: The present study aims to study the implications for resource utilisation if Australia adopted recent revised UK treatment guidelines for paracetamol poisoning.<br><br>METHODS: Retrospective database review of paracetamol toxicity presentations and calls from the Victorian Poisons Information Centre (VPIC) and Austin Hospital, Victoria, Australia, from 1 January 2010 to 31 December 2011. There were 200 presentations at the Austin Hospital, and the VPIC received 4272 calls regarding paracetamol toxicity. An analytical model was designed to estimate the cost of this additional treatment and referral to hospital. The main outcome measures were the potential increase in number of admissions requiring treatment with N-acetylcysteine (NAC), costs involved and increased number of referrals to hospitals by the VPIC.<br><br>RESULTS: Twenty-five (12.5%, 95% confidence interval 8.4-17.6%, P < 0.01) patients in our study who did not qualify for NAC therapy based upon the current Australasian paracetamol treatment guideline would have received it if the revised UK guideline was followed. Eighteen (72%) of these presented with acute single ingestions of paracetamol. No patients re-presented to our hospital with acute liver injury or required admission to the liver transplant unit.<br><br>CONCLUSIONS: Alignment of current Australian paracetamol treatment guidelines with those in the UK would result in an increase in ED attendances as directed by Poisons Information Centres and hospital admissions for antidotal treatment. This would be associated with increased health expenditure and inpatient bed utilisation. The present study does not support the clinical need for adoption of UK paracetamol treatment guidelines in Australia.}, }
@article {pmid24706421, year = {2014}, author = {Nafisi, S and Heidari, R and Ghaffarzadeh, M and Ziaee, M and Hamzeiy, H and Garjani, A and Eghbal, MA}, title = {Cytoprotective effects of silafibrate, a newly-synthesised siliconated derivative of clofibrate, against acetaminophen-induced toxicity in isolated rat hepatocytes.}, journal = {Arhiv za higijenu rada i toksikologiju}, volume = {65}, number = {2}, pages = {169-178}, doi = {10.2478/10004-1254-65-2014-2434}, pmid = {24706421}, issn = {1848-6312}, mesh = {Acetaminophen/*adverse effects/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Chemical and Drug Induced Liver Injury/*physiopathology ; Clofibrate/*analogs &amp; derivatives/*pharmacology ; *Cytoprotection ; Hepatocytes/*drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Acetaminophen (N-acetyl para amino phenol, APAP) is a widely used antipyretic and analgesic drug responsible for various drug-induced liver injuries. This study evaluated APAP-induced toxicity in isolated rat hepatocytes alongside the protective effects of silafibrate and N-acetyl cysteine (NAC). Hepatocytes were isolated from male Sprague-Dawley rats by collagenase enzyme perfusion via the portal vein. This technique is based on liver perfusion with collagenase after removing calcium ions (Ca2+) with a chelator. Cells were treated with different concentrations of APAP, silafibrate, and NAC. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation, and mitochondrial depolarisation were measured as toxicity markers. ROS formation and lipid peroxidation occurred after APAP administration to rat hepatocytes. APAP caused mitochondrial depolarisation in isolated cells. Administration of silafibrate (200 μmol L-1) and/or NAC (200 μmol L-1) reduced the ROS formation, lipid peroxidation, and mitochondrial depolarisation caused by APAP. Cytotoxicity induced by APAP in rat hepatocytes was mediated by oxidative stress. In addition, APAP seemed to target cellular mitochondria during hepatocyte damage. The protective properties of silafibrate and/or NAC against APAP‑induced hepatic injury may have involved the induction of antioxidant enzymes, protection against oxidative stress and inflammatory responses, and alteration in cellular glutathione content.}, }
@article {pmid24704379, year = {2014}, author = {Horst, A and Kolberg, C and Moraes, MS and Riffel, AP and Finamor, IA and Belló-Klein, A and Pavanato, MA and Partata, WA}, title = {Effect of N-acetylcysteine on the spinal-cord glutathione system and nitric-oxide metabolites in rats with neuropathic pain.}, journal = {Neuroscience letters}, volume = {569}, number = {}, pages = {163-168}, doi = {10.1016/j.neulet.2014.03.063}, pmid = {24704379}, issn = {1872-7972}, mesh = {Acetylcysteine/*pharmacology ; Analgesics/*pharmacology ; Animals ; Constriction, Pathologic ; Glutathione/*metabolism ; Glutathione Peroxidase/*metabolism ; Glutathione Transferase/*metabolism ; Hot Temperature ; Hydrogen Peroxide/metabolism ; Hyperalgesia/physiopathology ; Lumbosacral Region ; Male ; Neuralgia/*metabolism/physiopathology ; Nitric Oxide/metabolism ; Physical Stimulation ; Rats, Wistar ; Sciatic Nerve/injuries ; Spinal Cord/*drug effects/metabolism ; Touch ; }, abstract = {Since N-acetylcysteine (NAC) is a donor of cysteine, we studied the relationship between NAC and concentration of oxidized and reduced glutathione (GSH/GSSG ratio), and glutathione peroxidase (GPx) and glutathione-S-transferase (GST) activities in the lumbosacral spinal cord of rats with chronic constriction injury (CCI) of the sciatic nerve that received NAC (150mg/kg/day, i.p.) or 0.9% saline solution for 3 or 10 days. Hydrogen peroxide (H2O2) and nitric-oxide (NO) metabolites were also measured. Von Frey hair and hot-plate tests showed hyperalgesia at day 1 in CCI rats. Hyperalgesia persisted at all other times in saline-treated CCI rats, but returned to pre-injury values in NAC-treated CCI rats after 3 postoperative days. GST activity and the GSH/GSSG ratio increased in saline-treated CCI rats, while the NAC treatment increased GST and GPx activities at day 10, with no significant change in the GSH/GSSG ratio. NAC treatment did not affect H2O2 levels, but it reduced NO metabolites in CCI rats 3 days after the surgery. Thus, the anti-hyperalgesic effect of NAC appears not to involve its action as a cysteine precursor for GSH synthesis, but involves a decrease in NO.}, }
@article {pmid24702479, year = {2014}, author = {Youl, E and Magous, R and Cros, G and Oiry, C}, title = {MAP Kinase cross talks in oxidative stress-induced impairment of insulin secretion. Involvement in the protective activity of quercetin.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {28}, number = {6}, pages = {608-615}, doi = {10.1111/fcp.12078}, pmid = {24702479}, issn = {1472-8206}, mesh = {Animals ; Calcium Channels, L-Type/metabolism ; Cell Line ; Hydrogen Peroxide/pharmacology ; Insulin/*metabolism ; Insulin Secretion ; Insulin-Secreting Cells/drug effects/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Oxidative Stress/*drug effects ; Phosphorylation/drug effects ; Quercetin/*pharmacology ; Rats ; Resveratrol ; Stilbenes/pharmacology ; }, abstract = {Insulin secretion preservation is a major issue for the prevention or treatment of type 2 diabetes. We previously showed on β-cells that quercetin (Q), but not resveratrol (R) or N-acetyl cysteine (NAC), amplified glucose-induced insulin secretion in a calcium- and ERK1/2-dependent manner. Quercetin, but not resveratrol or NAC, also protected β-cell function and hyperamplified ERK1/2 phosphorylation in oxidative stress conditions. As quercetin may interfere with other stress-activated protein kinases (JNK and p38 MAPK), we further explored MAPK cross talks and their relationships with the mechanism of the protective effect of quercetin against oxidative stress. In INS-1 insulin-secreting β-cells, using pharmacological inhibitors of MAPK pathways, we found that under oxidative stress (50 μm H2O2) and glucose-stimulating insulin secretion conditions: (i) p38 MAPK phosphorylation was increased and regulated by ERK1/2 (positively) and JNK (negatively), although p38 MAPK activation did not seem to play any significant role in oxidative stress-induced insulin secretion impairment; (ii) the JNK pathway appeared to inhibit both ERK1/2 activation and insulin secretion, although JNK phosphorylation was not significantly changed in our experimental conditions; (iii) the functionality of β-cell in the presence of oxidative stress was closely linked to the level of ERK1/2 activation, (iv) quercetin, resveratrol, or NAC inhibited H2O2 -induced p38 MAPK phosphorylation. The preservation of β-cell function against oxidative stress appears dependent on the balance between ERK1/2 and JNK activation. The protecting effect of quercetin appears due to ERK1/2 hyperactivation, possibly induced by L-type calcium channel opening as we recently showed.}, }
@article {pmid24701072, year = {2014}, author = {Habaragamuwa, BW and Dissanayaka, P}, title = {N-acetylcystein in dengue associated severe hepatitis.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {18}, number = {3}, pages = {181-182}, pmid = {24701072}, issn = {0972-5229}, abstract = {Although, N-acetylcystein (NAC) has shown benefit in non-acetaminophen related liver failure, it was not well studies in dengue associated severe hepatitis. We report a case of dengue hemorrhagic fever associated severe hepatitis (encephalopathy grade 2-drowsy and intermittent disorientation) treated with NAC resulted in good outcome without hepatic transplantation.}, }
@article {pmid24700345, year = {2014}, author = {Zhao, B and Li, X}, title = {Altholactone induces reactive oxygen species-mediated apoptosis in bladder cancer T24 cells through mitochondrial dysfunction, MAPK-p38 activation and Akt suppression.}, journal = {Oncology reports}, volume = {31}, number = {6}, pages = {2769-2775}, doi = {10.3892/or.2014.3126}, pmid = {24700345}, issn = {1791-2431}, mesh = {Acetylcysteine/administration &amp; dosage ; Apoptosis/drug effects ; Caspase 3/biosynthesis ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Furans/administration &amp; dosage ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mitochondria/*drug effects/pathology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*metabolism ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Pyrones/administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Urinary Bladder Neoplasms/*genetics/metabolism/pathology ; p38 Mitogen-Activated Protein Kinases/*biosynthesis ; }, abstract = {Human bladder cancer is an aggressive tumor which frequently resists chemotherapy. Therefore, the search for new therapeutic agents is of great importance. Altholactone, isolated from Goniothalamus sp., has been reported to inhibit the growth of various types of cancer cells. However, no prior research has been conducted to demonstrate the antiproliferative potential of altholactone on bladder cancer. In the present study, we characterized the effect of altholactone on cell growth and apoptosis in bladder cancer T24 cells. Treatment with altholactone resulted in a significant reduction in cell viability, induction of apoptosis and generation of reactive oxygen species (ROS) in T24 cells. Furthermore, our results revealed that altholactone-induced apoptosis was associated with decreased expression of Akt phosphorylation and activation of MAPK‑p38. Altholactone treatment was also found to result in a significant loss of mitochondrial membrane potential, Bcl-2 downregulation and caspase-3 activation. Pretreatment of T24 cells with the antioxidant N-acetylcysteine (NAC) significantly inhibited activation of caspase-3 and MAPK-p38 and prevented inactivation of Akt and Bcl-2. Taken together, our data demonstrate that altholactone induces ROS-dependent apoptosis in T24 cells via a novel mechanism involving inhibition of Akt and provide the rationale for further in vivo and preclinical investigation of altholactone against bladder cancer.}, }
@article {pmid24699798, year = {2014}, author = {Song, Y and Li, X and Li, Y and Li, N and Shi, X and Ding, H and Zhang, Y and Li, X and Liu, G and Wang, Z}, title = {Non-esterified fatty acids activate the ROS-p38-p53/Nrf2 signaling pathway to induce bovine hepatocyte apoptosis in vitro.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {19}, number = {6}, pages = {984-997}, doi = {10.1007/s10495-014-0982-3}, pmid = {24699798}, issn = {1573-675X}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Cattle ; Cells, Cultured ; Fatty Acids/*metabolism/toxicity ; Female ; Free Radical Scavengers/pharmacology ; Glucose/pharmacology ; Hepatocytes/*cytology/drug effects/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {A high plasma concentration of non-esterified fatty acids (NEFAs) is an important pathogenic factor that leads to ketosis and fatty liver in dairy cows. NEFAs may be associated with oxidative stress in dairy cows with ketosis or fatty liver and the subsequent induction of hepatocyte damage. However, the molecular mechanism of NEFAs-induced oxidative stress and whether NEFAs cause apoptosis of hepatocytes are unclear. Therefore, the aim of this study was to investigate the molecular mechanism of NEFAs-induced oxidative liver damage in bovine hepatocytes. The results showed that NEFAs increased oxidative stress, resulting in p38 phosphorylation. High activated p38 increased the expression, nuclear localization and transcriptional activity of p53 and decreased the nuclear localization and transcriptional activity of Nrf2 in bovine hepatocytes treated with high concentrations of NEFAs. High concentrations of NEFAs also promoted the apoptosis of bovine hepatocytes. Both N-acetyl-L-cysteine (NAC) and glucose (GLU) could attenuate the NEFA-induced apoptotic damage. These results indicate that NEFAs activate the ROS-p38-p53/Nrf2 signaling pathway to induce apoptotic damage in bovine hepatocytes.}, }
@article {pmid24695480, year = {2014}, author = {Gourishankar, A and Navarro, F and Debroy, AN and Smith, KC}, title = {Isoniazid hepatotoxicity with clinical and histopathology correlate.}, journal = {Annals of clinical and laboratory science}, volume = {44}, number = {1}, pages = {87-90}, pmid = {24695480}, issn = {1550-8080}, mesh = {Adolescent ; Biopsy ; Female ; Fibrosis ; Humans ; Inflammation/pathology ; Isoniazid/*adverse effects ; Liver/*drug effects/*pathology ; Lymphocytes/drug effects/pathology ; }, abstract = {A fifteen-year-old girl was treated with isoniazid (INH) for latent tuberculosis infection (LTBI), and subsequently developed epigastric pain, vomiting, and jaundice after three months of treatment. Acute fulminant hepatic failure was diagnosed. INH was stopped, and she received N-acetyl cysteine and Vitamin K. Liver biopsy showed moderate to severe lymphocytic and plasmacytic portal and lobular inflammation, prominent ductal proliferation, moderate cholestasis (predominantly hepatocellular and canalicular), hepatocellular damage, and stage 3 bridging fibrosis. She was treated with steroids and azathioprine for probable autoimmune hepatitis (AIH). She received six months of rifampicin treatment for LTBI. Liver biopsy two years later showed mild portal inflammation, predominantly lymphocytitic, mild portal fibrosis without bridging, irregular bile ducts without cholestasis, and no significant hepatocellular damage; overall the later biopsy demonstrated significant improvement. This case illustrates overlapping morphologic presentation in INH hepatotoxicity with hepatocellular injury and plasma cell infiltrate (due to probable AIH), as well as cholestatic features. Although her follow-up liver biopsy indicated lymphocytic inflammation, she is now asymptomatic with normal hepatic transaminases.}, }
@article {pmid24693334, year = {2014}, author = {Tuncay, E and Okatan, EN and Toy, A and Turan, B}, title = {Enhancement of cellular antioxidant-defence preserves diastolic dysfunction via regulation of both diastolic Zn2+ and Ca2+ and prevention of RyR2-leak in hyperglycemic cardiomyocytes.}, journal = {Oxidative medicine and cellular longevity}, volume = {2014}, number = {}, pages = {290381}, pmid = {24693334}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/*metabolism ; Blood Glucose/metabolism ; Body Weight/drug effects ; Calcium/*metabolism ; Diabetes Mellitus, Experimental/complications/metabolism/pathology/physiopathology ; *Diastole/drug effects ; Heart Ventricles/drug effects/pathology/physiopathology ; Hyperglycemia/complications/metabolism/pathology/physiopathology ; In Vitro Techniques ; Intracellular Space/drug effects/metabolism ; Male ; Myocardium/*metabolism/pathology/ultrastructure ; Myocytes, Cardiac/drug effects/*metabolism/pathology/ultrastructure ; NF-kappa B/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Ryanodine Receptor Calcium Release Channel/*metabolism ; Tacrolimus Binding Proteins/metabolism ; Zinc/*metabolism ; }, abstract = {We examined whether cellular antioxidant-defence enhancement preserves diastolic dysfunction via regulation of both diastolic intracellular free Zn(2+) and Ca(2+) levels ([Zn(2+)]i and [Ca(2+)]i) levels N-acetyl cysteine (NAC) treatment (4 weeks) of diabetic rats preserved altered cellular redox state and also prevented diabetes-induced tissue damage and diastolic dysfunction with marked normalizations in the resting [Zn(2+)]i and [Ca(2+)]i. The kinetic parameters of transient changes in Zn(2+) and Ca(2+) under electrical stimulation and the spatiotemporal properties of Zn(2+) and Ca(2+) sparks in resting cells are found to be normal in the treated diabetic group. Biochemical analysis demonstrated that the NAC treatment also antagonized hyperphosphorylation of cardiac ryanodine receptors (RyR2) and significantly restored depleted protein levels of both RyR2 and calstabin2. Incubation of cardiomyocytes with 10 µM ZnCl2 exerted hyperphosphorylation in RyR2 as well as higher phosphorphorylations in both PKA and CaMKII in a concentration-dependent manner, similar to hyperglycemia. Our present data also showed that a subcellular oxidative stress marker, NF-κB, can be activated if the cells are exposed directly to Zn(2+). We thus for the first time report that an enhancement of antioxidant defence in diabetics via directly targeting heart seems to prevent diastolic dysfunction due to modulation of RyR2 macromolecular-complex thereby leading to normalized [Ca(2+)]i and [Zn(2+)]i in cardiomyocytes.}, }
@article {pmid24690178, year = {2014}, author = {Chen, J and Solomides, C and Simpkins, H}, title = {Sensitization of mesothelioma cells to platinum-based chemotherapy by GSTπ knockdown.}, journal = {Biochemical and biophysical research communications}, volume = {447}, number = {1}, pages = {77-82}, doi = {10.1016/j.bbrc.2014.03.100}, pmid = {24690178}, issn = {1090-2104}, support = {R01-CA098804/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Activating Transcription Factor 2/metabolism ; Cell Line, Tumor ; Cisplatin/*therapeutic use ; Drug Resistance, Neoplasm ; Gene Knockdown Techniques ; Glutathione S-Transferase pi/*genetics/metabolism ; Glutathione Transferase/drug effects ; Humans ; MAP Kinase Kinase 4/drug effects ; MAP Kinase Signaling System/drug effects ; Mesothelioma/*drug therapy ; Organoplatinum Compounds/*therapeutic use ; Oxaliplatin ; Reactive Oxygen Species/metabolism ; }, abstract = {It is predicted that the incidence of mesothelioma will increase and thus it is important to find new ways to treat this chemoresistant tumor. Glutathione-S-Transferase π (GSTπ) is found at significant levels in mesotheliomas and thus attenuating its intracellular levels may provide a means of sensitizing mesothelioma cells to chemotherapy. GSTπ knockdowns were therefore prepared with shRNA (less off-target effects) employing two cell lines (211H, H2452) that were typed by immunohistochemistry to be of mesothelial origin. The knockdowns exhibited a decrease in both total GST enzyme activity and GSTπ protein levels as well as an increase in both glutathione levels and sensitivity to cis and oxaliplatin. Cisplatin treatment of the knockdowns increased ROS levels significantly (as compared to the parental cells) and produced activation of the JNK/p38 pathways and activating transcription factor (ATF2). The degree of activation and increase in ROS appeared to correlate with the cell line's sensitivity to cisplatin. Treatment with N-Acetyl Cysteine decreased ROS production and JNK/p38 phosphorylation but had minimal affect on ATF2 suggesting a direct interaction of GTPπ with this transcription factor. Oxaliplatin treatment produced only minimal changes in ROS levels and activation of the JNK/p38 pathway. Recently, new methods of siRNA delivery (nanoparticles) have been shown to be effective in decreasing the levels of target proteins in humans including candidate genes involved in drug resistance - thus this approach may have promise in sensitizing cisplatin-resistant tumors to chemotherapy.}, }
@article {pmid24687974, year = {2014}, author = {Maccallini, C and Di Matteo, M and Ammazzalorso, A and D'Angelo, A and De Filippis, B and Di Silvestre, S and Fantacuzzi, M and Giampietro, L and Pandolfi, A and Amoroso, R}, title = {Reversed-phase high-performance liquid chromatography method with fluorescence detection to screen nitric oxide synthases inhibitors.}, journal = {Journal of separation science}, volume = {37}, number = {12}, pages = {1380-1385}, doi = {10.1002/jssc.201400059}, pmid = {24687974}, issn = {1615-9314}, mesh = {Chromatography, High Pressure Liquid/*methods ; Chromatography, Reverse-Phase/*methods ; Enzyme Inhibitors/*chemistry ; Humans ; Kinetics ; Nitric Oxide Synthase Type II/*antagonists &amp; inhibitors/chemistry ; }, abstract = {Nitric oxide synthase (NOS) inhibitors are potential drug candidates due to the critical role of an excessive production of nitric oxide in a range of diseases. At present, the radiometric detection of L-[(3)H]-citrulline produced from L-[(3)H]-arginine during the enzymatic reaction is one of the most accepted methods to assess the in vitro activity of NOS inhibitors. Here we report a fast, easy, and cheap reversed-phase high-performance liquid chromatography method with fluorescence detection, based on the precolumn derivatization of L-citrulline with o-phthaldialdehyde/N-acetyl cysteine, for the in vitro screening of NOS inhibitors. To evaluate enzyme inhibition by the developed method, N-[3-(aminomethyl)benzyl]acetamidine, a potent and selective inhibitor of inducible NOS, was used as a test compound. The half maximal inhibitory concentration obtained was comparable to that derived by the well-established radiometric assay.}, }
@article {pmid24687190, year = {2014}, author = {Albers, JW and Chaudhry, V and Cavaletti, G and Donehower, RC}, title = {Interventions for preventing neuropathy caused by cisplatin and related compounds.}, journal = {The Cochrane database of systematic reviews}, volume = {2014}, number = {3}, pages = {CD005228}, pmid = {24687190}, issn = {1469-493X}, mesh = {Antineoplastic Agents/*adverse effects ; Cisplatin/*adverse effects/analogs &amp; derivatives ; Humans ; Neuroprotective Agents/*therapeutic use ; Peptide Fragments/therapeutic use ; Peripheral Nervous System Diseases/chemically induced/*prevention &amp; control ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Cisplatin and several related antineoplastic drugs used to treat many types of solid tumours are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought.<br><br>OBJECTIVES: To examine the efficacy and safety of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related drugs.<br><br>SEARCH METHODS: On 4 March 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and CINAHL Plus for randomised trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related drugs among human patients.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs in which the participants received chemotherapy with cisplatin or related compounds, with a potential chemoprotectant (acetylcysteine, amifostine, adrenocorticotrophic hormone (ACTH), BNP7787, calcium and magnesium (Ca/Mg), diethyldithiocarbamate (DDTC), glutathione, Org 2766, oxcarbazepine, or vitamin E) compared to placebo, no treatment, or other treatments. We considered trials in which participants underwent evaluation zero to six months after completing chemotherapy using quantitative sensory testing (the primary outcome) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary outcomes).<br><br>DATA COLLECTION AND ANALYSIS: Two review authors assessed each study, extracted the data and reached consensus, according to standard Cochrane methodology.<br><br>MAIN RESULTS: As of 2013, the review includes 29 studies describing nine possible chemoprotective agents, as well as description of two published meta-analyses. Among these trials, there were sufficient data in some instances to combine the results from different studies, most often using data from secondary non-quantitative measures. Nine of the studies were newly included at this update. Few of the included studies were at a high risk of bias overall, although often there was too little information to make an assessment. At least two review authors performed a formal review of an additional 44 articles but we did not include them in the final review for a variety of reasons.Of seven eligible amifostine trials (743 participants in total), one used quantitative sensory testing (vibration perception threshold) and demonstrated a favourable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Furthermore the change measured was subclinical. None of the three eligible Ca/Mg trials (or four trials if a single retrospective study was included) described our primary outcome measures. The four Ca/Mg trials included a total of 886 participants. Of the seven eligible glutathione trials (387 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing but reported disparate results; meta-analyses of three of these trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. Similarly, none of the three eligible vitamin E trials (246 participants) reported quantitative sensory testing. The eligible single trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), oxcarbazepine (32 participants), and retinoic acid (92 participants) did not perform quantitative sensory testing. In all, this review includes data from 2906 participants. However, only seven trials reported data for the primary outcome measure of this review, (quantitative sensory testing) and only nine trials reported our objective secondary measure, nerve conduction test results. Additionally, methodological heterogeneity precluded pooling of the results in most cases. Nonetheless, a larger number of trials reported the results of secondary (non-quantitative and subjective) measures such as the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for neuropathy (15 trials), and these results we pooled and reported as meta-analysis. Amifostine showed a significantly reduced risk of developing neurotoxicity NCI-CTC (or equivalent) &#x2265; 2 compared to placebo (RR 0.26, 95% CI 0.11 to 0.61). Glutathione was also efficacious with an RR of 0.29 (95% CI 0.10 to 0.85). In three vitamin E studies subjective measures not suitable for combination in meta analysis each favoured vitamin E. For other interventions the qualitative toxicity measures were either negative (N-acetyl cysteine, Ca/Mg, DDTC and retinoic acid) or not evaluated (oxcarbazepine and Org 2766).Adverse events were infrequent or not reported for most interventions. Amifostine was associated with transient hypotension in 8% to 62% of participants, retinoic acid with hypocalcaemia in 11%, and approximately 20% of participantss withdrew from treatment with DDTC because of toxicity.<br><br>AUTHORS' CONCLUSIONS: At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients, as determined using quantitative, objective measures of neuropathy. Amifostine, calcium and magnesium, glutathione, and vitamin E showed modest but promising (borderline statistically significant) results favouring their ability to reduce the neurotoxicity of cisplatin and related chemotherapies, as measured using secondary, non-quantitative and subjective measures such as the NCI-CTC neuropathy grading scale. Among these interventions, the efficacy of only vitamin E was evaluated using quantitative nerve conduction studies; the results were negative and did not support the positive findings based on the qualitative measures. In summary, the present studies are limited by the small number of participants receiving any particular agent, a lack of objective measures of neuropathy, and differing results among similar trials, which make it impossible to conclude that any of the neuroprotective agents tested prevent or limit the neurotoxicity of platinum drugs.}, }
@article {pmid24686235, year = {2014}, author = {Morris, TT and Keir, JL and Boshart, SJ and Lobanov, VP and Ruhland, AM and Bahl, N and Gailer, J}, title = {Mobilization of Cd from human serum albumin by small molecular weight thiols.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {958}, number = {}, pages = {16-21}, doi = {10.1016/j.jchromb.2014.03.012}, pmid = {24686235}, issn = {1873-376X}, mesh = {Acetylcysteine/metabolism ; Cadmium/*metabolism ; Chromatography, Gel/methods ; Chromatography, High Pressure Liquid/methods ; Cysteine/metabolism ; Glutathione/metabolism ; Humans ; Protein Binding ; Serum Albumin/*metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {Although the toxic metal Cd is an established human nephrotoxin, little is known about the role that interactions with plasma constitutents play in determining its mammalian target organs. To gain insight, a Cd-human serum albumin (HSA) complex was analyzed on a system consisting of size exclusion chromatography (SEC) coupled on-line to a flame atomic absorption spectrometer (FAAS). Using phosphate buffered saline (pH 7.4) as the mobile phase, we investigated the effect of 1-10mM oxidized glutathione (GSSG), l-cysteine (Cys), l-glutathione (GSH), or N-acetyl-l-cysteine (NAC) on the elution of Cd. As expected, GSSG did not mobilize Cd from the Cd-HSA complex up to a concentration of 4mM. With 1.0mM NAC, ∼30% of the injected Cd-HSA complex eluted as such, while the mobilized Cd was lost on the column. With 1.0mM of Cys or GSH, no parent Cd-HSA complex was detected and 88% and 82% of the protein bound Cd eluted close to the elution volume, likely in form of Cd(Cys)2 and a Cd-GSH 1:1 complex. Interestingly, with GSH and NAC concentrations >4.0mM, a Cd double peak was detected, which was rationalized in terms of the elution of a polynuclear Cd complex baseline-separated from a mononuclear Cd complex. In contrast, mobile phases which contained Cys concentrations ≥2mM resulted in the detection of only a single Cd peak, probably Cd(Cys)4. Our results establish SEC-FAAS as a viable tool to probe the mobilization of Cd from binding sites on plasma proteins at near physiological conditions. The detected complexes between Cd and Cys or GSH may be involved in the translocation of Cd to mammalian target organs.}, }
@article {pmid24685079, year = {2014}, author = {Zhao, X and Ren, H and Gao, S and Hao, J}, title = {[Effects of dioscin on apoptosis in pancreatic cancer MiaPaCa-2 cells and its mechanism].}, journal = {Zhonghua zhong liu za zhi [Chinese journal of oncology]}, volume = {36}, number = {1}, pages = {5-10}, pmid = {24685079}, issn = {0253-3766}, mesh = {Apoptosis/*drug effects ; Diosgenin/*analogs &amp; derivatives/pharmacology ; Humans ; Pancreatic Neoplasms/*pathology ; Peroxiredoxins/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: The aim of this study was to observe the effects of dioscin on apoptosis and on expression of PRDX1 in pancreatic cancer MiaPaCa-2 cells in vitro.<br><br>METHODS: MTT assay was used to detect the growth rate among the medication groups treated with different concentrations of dioscin. The apoptosis rate was determined by annexin V-fluorescein isothiocyanate/propidium iodide double staining and flow cytometry. Western blot analysis was used to assay the expression of PRDX1 and apoptotic proteins in the cells. Reactive oxygen species (ROS) formation was measured by 2'7'-dichlorofluorescein diacetate (DCFH-DA).<br><br>RESULTS: Dioscin considerably inhibited the proliferation of MiaPaCa-2 cells in vitro. The inhibitory action was enhanced in a dose-dependent manner. The levels of intracellular ROS detected with DCFH-DA were highly increased after dioscin treatment. The flow cytometry analysis using annexin V-PI staining showed that compared with the apoptotic rate of control group [(3.5 &#xb1; 0.7)%], 2.5 &#xb5;mol/L and 5 &#xb5;mol/L dioscin induced apoptosis in (28.4 &#xb1; 0.9)% and (49.6 &#xb1; 2.7)% MiaPaCa-2 cells, and Western blot analysis showed that apoptotic proteins Bax and cleaved caspase-3 expressions were increased and antiapoptotic protein Bcl-2 expression was decreased. In addition, these effects could be blocked by antioxidant N-acetylcysteine (NAC) administration, and the apoptotic rates decreased to (10.8 &#xb1; 2.3)% and (18.8 &#xb1; 3.0)%, respectively. We further observed the decrease of PRDX1 expression after dioscin treatment. Moreover, after PRDX1 overexpression, dioscin treatment no longer induced high levels of ROS and apoptosis, and the apoptotic rate was decreased to (21.3 &#xb1; 5.9)%.<br><br>CONCLUSION: Dioscin can down-regulate the PRDX1 expression, and then induces ROS-mediated apoptosis in cancer cells.}, }
@article {pmid24683506, year = {2014}, author = {Bavarsad Shahripour, R and Harrigan, MR and Alexandrov, AV}, title = {N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities.}, journal = {Brain and behavior}, volume = {4}, number = {2}, pages = {108-122}, pmid = {24683506}, issn = {2162-3279}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/*pharmacology ; Humans ; Nervous System Diseases/*drug therapy ; }, abstract = {BACKGROUND: There is an expanding field of research investigating the benefits of medicines with multiple mechanisms of action across neurological disorders. N-acetylcysteine (NAC), widely known as an antidote to acetaminophen overdose, is now emerging as treatment of vascular and nonvascular neurological disorders. NAC as a precursor to the antioxidant glutathione modulates glutamatergic, neurotrophic, and inflammatory pathways.<br><br>AIM AND DISCUSSION: Most NAC studies up to date have been carried out in animal models of various neurological disorders with only a few studies completed in humans. In psychiatry, NAC has been tested in over 20 clinical trials as an adjunctive treatment; however, this topic is beyond the scope of this review. Herein, we discuss NAC molecular, intracellular, and systemic effects, focusing on its potential applications in neurodegenerative diseases including spinocerebellar ataxia, Parkinson's disease, tardive dyskinesia, myoclonus epilepsy of the Unverricht-Lundbor type as well as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease.<br><br>CONCLUSION: Finally, we review the potential applications of NAC to facilitate recovery after traumatic brain injury, cerebral ischemia, and in treatment of cerebrovascular vasospasm after subarachnoid hemorrhage.}, }
@article {pmid24681787, year = {2014}, author = {Xie, J and Zhou, X and Hu, X and Jiang, H}, title = {H2O2 evokes injury of cardiomyocytes through upregulating HMGB1.}, journal = {Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese}, volume = {55}, number = {2}, pages = {101-106}, pmid = {24681787}, issn = {2241-5955}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies, Neutralizing/pharmacology ; Antioxidants/pharmacology ; *Apoptosis/drug effects/physiology ; Cardiotonic Agents/metabolism/pharmacology ; Cell Survival/drug effects/physiology ; HMGB1 Protein/*metabolism ; Hydrogen Peroxide/*pharmacology ; L-Lactate Dehydrogenase/metabolism ; *Myocytes, Cardiac/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/pharmacology ; Superoxide Dismutase/metabolism ; Up-Regulation ; }, abstract = {INTRODUCTION: Reactive oxygen species (ROS) have been shown to induce cell apoptosis in cardiomyocytes. However, the underlying mechanism remains unclear. This study aimed to investigate the role of high-mobility group box 1 protein (HMGB1) in cardiomyocytes undergoing H2O2 treatment.<br><br>METHODS: Neonatal rat cardiomyocytes were treated with H2O2 (100, 200, 500 &#xb5;M) or pre-treated with antioxidant N-acetylcysteine (NAC 200 &#xb5;M) or HMGB1 neutralizing antibody (20 &#xb5;g/ml) in an appropriate concentration of H2O2 (200 &#xb5;M). The cell viability, apoptosis rate, lactate dehydrogenase (LDH), and the activity of superoxide dismutase were measured. HMGB1 expression was assessed by immunoblotting.<br><br>RESULTS: H2O2-induced ROS significantly decreased cell viability, promoted the apoptosis of neonatal myocytes, and upregulated the expression of HMGB1 in a dose-dependent manner. However, NAC or HMGB1 neutralizing antibody suppressed the loss of cell viability and the rate of cell apoptosis induced by H2O2. NAC or HMGB1 neutralizing antibody also significantly suppressed the release of LDH and the expression of HMGB1.<br><br>CONCLUSION: The present study suggests that H2O2-induced ROS evoke injury to cardiomyocytes that may be associated with upregulating HMGB1.}, }
@article {pmid24681574, year = {2014}, author = {Wang, S and Zhou, M and Lin, F and Liu, D and Hong, W and Lu, L and Zhu, Y and Xu, A}, title = {Interferon-γ induces senescence in normal human melanocytes.}, journal = {PloS one}, volume = {9}, number = {3}, pages = {e93232}, pmid = {24681574}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Aging/drug effects/*metabolism/*physiology ; Apoptosis/drug effects/physiology ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; Cells, Cultured ; Cellular Senescence/drug effects/*physiology ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Humans ; Interferon-gamma/*metabolism ; Interleukin-6/metabolism ; Iron-Binding Proteins/metabolism ; Janus Kinase 1/metabolism ; Janus Kinase 2/metabolism ; Melanocytes/drug effects/*metabolism/*physiology ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; STAT1 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/metabolism ; beta-Galactosidase/metabolism ; }, abstract = {BACKGROUND: Interferon-γ (IFN-γ) plays an important role in the proceedings of vitiligo through recruiting lymphocytes to the lesional skin. However, the potential effects of IFN-γ on skin melanocytes and the subsequent contribution to the vitiligo pathogenesis are still unclear.<br><br>OBJECTIVE: To investigate the effects of IFN-&#x3b3; on viability and cellular functions of melanocytes.<br><br>METHODS: Primary human melanocytes were treated with IFN-&#x3b3;. Cell viability, apoptosis, cell cycle melanin content and intracellular reactive oxygen species (ROS) level were measured. mRNA expression was examined by real-time PCR. The release of interleukin 6 (IL-6) and heat shock protein 70 (HSP-70) was monitored by ELISA. &#x3b2;-galactosidase staining was utilized to evaluate melanocyte senescence.<br><br>RESULTS: Persistent IFN-&#x3b3; treatment induced viability loss, apoptosis, cell cycle arrest and senescence in melanocytes. Melanocyte senescence was characterized as the changes in pigmentation and morphology, as well as the increase of &#x3b2;-galactosidase activity. Increase of p21Cip1/Waf1 protein was evident in melanocytes after IFN-&#x3b3; treatment. IFN-&#x3b3; induction of senescence was attenuated by siRNAs against p21, Janus kinase 2 (JAK2) or signal transducer and activator of transcription 1 (STAT1), but not by JAK1 siRNA nor by p53 inhibitor pifithrin-&#x3b1;. IFN-&#x3b3; treatment increased the accumulation of intracellular ROS in melanocytes, while ROS scavenger N-acetyl cysteine (NAC) effectively inhibited IFN-&#x3b3; induced p21 expression and melanocyte senescence. IL-6 and HSP-70 release was significantly induced by IFN-&#x3b3; treatment, which was largely inhibited by NAC. The increase of IL-6 and HSP-70 release could also be observed in senescent melanocytes.<br><br>CONCLUSION: IFN-&#x3b3; can induce senescence in melanocytes and consequently enhance their immuno-competency, leading to a vitiligo-prone milieu.}, }
@article {pmid24680856, year = {2014}, author = {Karalija, A and Novikova, LN and Kingham, PJ and Wiberg, M and Novikov, LN}, title = {The effects of N-acetyl-cysteine and acetyl-L-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury.}, journal = {Neuroscience}, volume = {269}, number = {}, pages = {143-151}, doi = {10.1016/j.neuroscience.2014.03.042}, pmid = {24680856}, issn = {1873-7544}, mesh = {Acetylcarnitine/*pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/physiology ; Axons/drug effects/physiology ; Cell Survival/drug effects/physiology ; Cervical Vertebrae ; Disease Models, Animal ; Female ; Microglia/drug effects/physiology ; Motor Neurons/drug effects/physiology ; Nerve Regeneration/drug effects/physiology ; Neuroimmunomodulation/drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Random Allocation ; Rats, Sprague-Dawley ; Spinal Cord/drug effects/physiopathology ; Spinal Cord Injuries/*drug therapy/*physiopathology ; }, abstract = {Traumatic spinal cord injury induces a long-standing inflammatory response in the spinal cord tissue, leading to a progressive apoptotic death of spinal cord neurons and glial cells. We have recently demonstrated that immediate treatment with the antioxidants N-acetyl-cysteine (NAC) and acetyl-l-carnitine (ALC) attenuates neuroinflammation, induces axonal sprouting, and reduces the death of motoneurons in the vicinity of the trauma zone 4weeks after initial trauma. The objective of the current study was to investigate the effects of long-term antioxidant treatment on the survival of descending rubrospinal neurons after spinal cord injury in rats. It also examines the short- and long-term effects of treatment on apoptosis, inflammation, and regeneration in the spinal cord trauma zone. Spinal cord hemisection performed at the level C3 induced a significant loss of rubrospinal neurons 8 weeks after injury. At 2 weeks, an increase in the expression of the apoptosis-associated markers BCL-2-associated X protein (BAX) and caspase 3, as well as the microglial cell markers OX42 and ectodermal dysplasia 1 (ED1), was seen in the trauma zone. After 8 weeks, an increase in immunostaining for OX42 and the serotonin marker 5HT was detected in the same area. Antioxidant therapy reduced the loss of rubrospinal neurons by approximately 50%. Treatment also decreased the expression of BAX, caspase 3, OX42 and ED1 after 2 weeks. After 8 weeks, treatment decreased immunoreactivity for OX42, whereas it was increased for 5HT. In conclusion, this study provides further insight in the effects of treatment with NAC and ALC on descending pathways, as well as short- and long-term effects on the spinal cord trauma zone.}, }
@article {pmid24677730, year = {2015}, author = {Liu, X and Nie, S and Huang, D and Xie, M}, title = {Nonylphenol regulates cyclooxygenase-2 expression via Ros-activated NF-κB pathway in sertoli TM4 cells.}, journal = {Environmental toxicology}, volume = {30}, number = {10}, pages = {1144-1152}, doi = {10.1002/tox.21987}, pmid = {24677730}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cyclooxygenase 2/*metabolism ; Dinoprostone/analysis ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation/*drug effects ; Interleukin-6/analysis ; Male ; Mice ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Phenols/*toxicity ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/*metabolism ; Sertoli Cells/cytology/drug effects/metabolism ; Signal Transduction/drug effects ; Thiocarbamates/pharmacology ; Up-Regulation/drug effects ; }, abstract = {The aim of this study was to investigate the signaling pathways involved in the cyclooxygenase (COX)-2 regulation induced by nonylphenol (NP) in mouse testis Sertoli TM4 cells. Our results showed that treatment of TM4 cells with NP increased COX-2 protein expression and interleukin-6 (IL)-6 and prostaglandin E2 (PGE2) secretion in a dose-dependent manner. Pretreatment with reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC), attenuated NP-induced ROS production, COX-2 expression, and IL-6 and PGE2 release in TM4 cells. Exposure to NP stimulated activation of NF-κB, whereas the NF-κB inhibitor, pyrrolidine dithiocarbamate, attenuated NP-enhanced COX-2 expression and IL-6 and PGE2 release in TM4 cells in a dose-dependent manner. Furthermore, NAC blocked NP-induced activation of NF-κB. In addition, inhibition of COX-2 mitigated NP-induced IL-6 release. In conclusion, NP induced ROS generation, activation of NF-κB pathway, COX-2 upregulation, and IL-6 and PGE2 secretion in TM4 cells. NP may regulate COX-2 expression via ROS-activated NF-κB pathway in Sertoli TM4 cells.}, }
@article {pmid24676101, year = {2014}, author = {Zheng, L and Sun, X and Zhu, X and Lv, F and Zhong, Z and Zhang, F and Guo, W and Cao, W and Yang, L and Tian, Y}, title = {Apoptosis of THP-1 derived macrophages induced by sonodynamic therapy using a new sonosensitizer hydroxyl acetylated curcumin.}, journal = {PloS one}, volume = {9}, number = {3}, pages = {e93133}, pmid = {24676101}, issn = {1932-6203}, mesh = {Apoptosis/*drug effects ; Cell Line ; Cell Survival/drug effects ; Curcumin/chemistry/metabolism/*pharmacology ; Humans ; Macrophages/*drug effects/*metabolism/radiation effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Ultrasonic Waves ; }, abstract = {Curcumin is extracted from the rhizomes of the traditional Chinese herb Curcuma longa. Our previous study indicated curcumin was able to function as a sonosensitizer. Hydroxyl acylated curcumin was synthesized from curcumin to eliminate the unstable hydroxy perssad in our group. The potential use of Hydroxyl acylated curcumin as a sonosensitizer for sonodynamic therapy (SDT) requires further exploration. This study investigated the sonodynamic effect of Hydroxyl acylated curcumin on THP-1 macrophage. THP-1 macrophages were cultured with Hydroxyl acylated curcumin at a concentration of 5.0 μg/mL for 4 hours and then exposed to pulse ultrasound irradiation (0.5 W/cm2 with 1.0 MHz) for 5 min, 10 min and 15 min. Six hours later, cell viability decreased significantly by CCK-8 assay. After ultrasound irradiation, the ratio of apoptosis and necrosis in SDT group was higher than that in control, Hydroxyl acylated curcumin alone and ultrasound alone. Moreover, the apoptotic rate was higher than necrotic rate with the flow cytometry analysis. Furthermore, Hydroxyl acylated curcumin-SDT induced reactive oxygen species (ROS) generation in THP-1 macrophages immediately after the ultrasound treatment while ROS generation was reduced significantly with the scavenger of singlet oxygen Sodium azide (NaN3). Hydroxyl acylated curcumin-SDT led to a conspicuous loss of mitochondrial membrane potential (MMP) compared with other groups, while MMP was increased significantly with the scavenger of singlet oxygen Sodium azide (NaN3), ROS inhibitor N-acetyl cysteine (NAC) and Mitochondrial Permeability Transition Pore (MPTP) inhibitor Cyclosporin A (CsA). The cytochrome C, cleaved-Caspase-9, cleaved-Caspase-3 and cleaved-PARP upregulated after SDT through Western blotting. These findings suggested that Hydroxyl acylated curcumin under low-intensity ultrasound had sonodynamic effect on THP-1 macrophages via generation of intracellular singlet oxygen and mitochondria-caspase signaling pathway, indicating that Hydroxyl acylated curcumin could be used as a novel sonosensitizer in SDT for atherosclerosis.}, }
@article {pmid24676047, year = {2014}, author = {Asevedo, E and Mendes, AC and Berk, M and Brietzke, E}, title = {Systematic review of N-acetylcysteine in the treatment of addictions.}, journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)}, volume = {36}, number = {2}, pages = {168-175}, doi = {10.1590/1516-4446-2013-1244}, pmid = {24676047}, issn = {1809-452X}, mesh = {Acetylcysteine/*therapeutic use ; Behavior, Addictive/*drug therapy ; Clinical Trials as Topic ; Female ; Glutamic Acid/metabolism ; Humans ; Male ; Substance-Related Disorders/*drug therapy ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVE: To conduct the first systematic literature review of clinical trials of N-acetylcysteine (NAC) for the treatment of substance abuse disorders and addictive behaviors.<br><br>METHODS: A search of the MEDLINE, Embase and PsycINFO databases was conducted. The inclusion criteria for the review were clinical trials that used NAC in the treatment of a disorder related to substance use and/or addictive behaviors, limited to texts in English, Spanish, or French. The selected studies were evaluated with respect to type of trial, sample size, diagnostic input, intervention, length of follow-up, outcome variables, and results.<br><br>RESULTS: Nine studies analyzing a total of 165 patients met the eligibility criteria and were included in qualitative analysis. These studies evaluated the role of NAC in cocaine dependence (three studies), cannabis dependence (two studies), nicotine dependence (two studies), methamphetamine addiction (one study), and pathological gambling (one study). Five of these trials were double-blind, randomized, and placebo-controlled.<br><br>CONCLUSIONS: The studies analyzed suggest a potential role for NAC in the treatment of addiction, especially of cocaine and cannabis dependence. These results are concordant with the hypothesis of the involvement of glutamatergic pathways in the pathophysiology of addiction.}, }
@article {pmid24674838, year = {2014}, author = {Su, MW and Chang, SS and Chen, CH and Huang, CC and Chang, SW and Tsai, YC and Lam, CF}, title = {Preconditioning renoprotective effect of isoflurane in a rat model of virtual renal transplant.}, journal = {The Journal of surgical research}, volume = {189}, number = {1}, pages = {135-142}, doi = {10.1016/j.jss.2014.02.035}, pmid = {24674838}, issn = {1095-8673}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Acute Kidney Injury/etiology/*prevention &amp; control ; Anesthetics, Inhalation/pharmacology/*therapeutic use ; Animals ; Free Radical Scavengers/pharmacology/therapeutic use ; Ischemic Preconditioning/*methods ; Isoflurane/pharmacology/*therapeutic use ; Kidney/*blood supply/drug effects ; Kidney Transplantation/adverse effects ; Models, Animal ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/etiology/*prevention &amp; control ; }, abstract = {BACKGROUND: The development of warm-cold ischemia-reperfusion (IR) injury of the kidney grafts is inevitable during renal transplantation. However, there is currently no definite renoprotective strategy available in the protection of the graft tissue. In the present study, we compared the renal protection of preconditioning isoflurane with N-acetylcysteine (NAC) in a novel rat model of warm-cold renal IR injury.<br><br>MATERIALS AND METHODS: Adult Sprague-Dawley rats were randomly assigned to receive inhaled isoflurane (1.5% for 2 h), NAC (1 g/kg, intra-arterial injection) or placebo before the induction of brief warm ischemia (10 min) followed by cold ischemia (45 min) periods. Plasma levels of creatinine and tissue inflammatory reaction in the kidney were analyzed 72 h after reperfusion.<br><br>RESULTS: Elevated plasma level of creatinine and urea indicated the development of acute renal injury secondary to IR injury. The creatinine levels were reduced in animals pretreated with inhaled isoflurane and NAC, and the level was more significantly decreased in the isoflurane-treated group. Preconditioning with volatile isoflurane also significantly suppressed the tissue myeloperoxidase activity and expression of the inducible nitric oxide synthase. Immunostaining confirmed that myeloperoxidase expression was most significantly attenuated in the glomerulus and peritubular capillaries of rats pre-exposed to isoflurane.<br><br>CONCLUSIONS: We present the first study demonstrating that the administration of volatile isoflurane before induction of experimental warm-cold renal IR injury provides preconditioning renoprotective effect, which is superior to the treatment with NAC. The beneficial renoprotective effect of isoflurane is most likely mediated by attenuation of proinflammatory reaction in the injured kidney.}, }
@article {pmid24673154, year = {2014}, author = {Doherty, E and Oaks, Z and Perl, A}, title = {Increased mitochondrial electron transport chain activity at complex I is regulated by N-acetylcysteine in lymphocytes of patients with systemic lupus erythematosus.}, journal = {Antioxidants &amp; redox signaling}, volume = {21}, number = {1}, pages = {56-65}, pmid = {24673154}, issn = {1557-7716}, support = {R01 AI072648/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Cells, Cultured ; Electron Transport Complex I/*metabolism ; Female ; Humans ; Hydrogen Peroxide/metabolism ; Lupus Erythematosus, Systemic/*metabolism ; Lymphocytes/drug effects/*metabolism ; Middle Aged ; Oxygen Consumption/drug effects/physiology ; Young Adult ; }, abstract = {AIMS: Systemic lupus erythematosus (SLE) patients' peripheral blood lymphocytes (PBL) show mitochondrial dysfunction and oxidative stress. To determine the electrochemical bases of mitochondrial dysfunction, we measured electron transport chain (ETC) activity and its regulation by N-acetylcysteine (NAC) that reversed glutathione depletion and improved disease activity in SLE. ETC activity was assessed in PBL of 69 SLE patients and 37 healthy donors. Negatively isolated T cells were examined in 7 SLE patients, 11 healthy donors, and 10 nonlupus inflammatory arthritis (IA) donors.<br><br>RESULTS: O&#x2082; consumption (in nmol/ml/min) by lupus PBL was increased at baseline (SLE: 2.492&#xb1;0.196, control: 2.137&#xb1;0.153; p=0.027) and with complex IV substrates (SLE: 7.722&#xb1;0.419, control: 7.006&#xb1;0.505; p=0.028). SLE PBL consumed more O&#x2082; upon in-chamber T-cell activation (p=0.012). After overnight T-cell stimulation, ETC activity of SLE PBL was 2.27-fold increased through complex I (SLE: 1.606&#xb1;0.273, control: 0.709&#xb1;0.169; p=0.001) and, to a lesser extent, through complex IV. Likewise, complex I activity was elevated in negatively isolated "untouched" T cells of SLE patients (1.816&#xb1;0.180) relative to healthy controls (0.917&#xb1;0.094; p=0.0003) and IA disease controls studied in parallel (1.057&#xb1;0.199; p=0.0308). NAC diminished O&#x2082; consumption through complex I and H&#x2082;O&#x2082; levels both in SLE and in control PBL.<br><br>INNOVATION: O&#x2082; consumption was found to be increased in SLE patients' PBL relative to control subjects evaluated in parallel. ETC complex I is identified as the main source of oxidative stress in SLE.<br><br>CONCLUSIONS: Lupus PBL exhibit increased O&#x2082; consumption through mitochondrial ETC complex I that is inhibited by NAC, which may have therapeutic efficacy through reducing oxidative stress in SLE.}, }
@article {pmid24672814, year = {2014}, author = {Ozaydin, M and Peker, T and Akcay, S and Uysal, BA and Yucel, H and Icli, A and Erdogan, D and Varol, E and Dogan, A and Okutan, H}, title = {Addition of N-acetyl cysteine to carvedilol decreases the incidence of acute renal injury after cardiac surgery.}, journal = {Clinical cardiology}, volume = {37}, number = {2}, pages = {108-114}, pmid = {24672814}, issn = {1932-8737}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/blood/diagnosis/epidemiology/*prevention &amp; control ; Adrenergic beta-1 Receptor Antagonists/*therapeutic use ; Aged ; Anti-Inflammatory Agents/*therapeutic use ; Antioxidants/*therapeutic use ; Biomarkers/blood ; Carbazoles/*therapeutic use ; Cardiac Surgical Procedures/*adverse effects ; Carvedilol ; Creatinine/blood ; Double-Blind Method ; Female ; Humans ; Incidence ; Male ; Metoprolol/therapeutic use ; Middle Aged ; Propanolamines/*therapeutic use ; Prospective Studies ; Time Factors ; Treatment Outcome ; Turkey/epidemiology ; }, abstract = {BACKGROUND: Oxidative stress and inflammation during cardiac surgery may be associated with acute renal injury (ARI). N-acetyl cysteine (NAC) and carvedilol have antioxidant and anti-inflammatory properties.<br><br>HYPOTHESIS: A combination of carvedilol and NAC should decrease the incidence of ARI more than metoprolol or carvedilol.<br><br>METHODS: Patients undergoing cardiac surgery were randomized to metoprolol, carvedilol, or carvedilol plus NAC. End points were occurrence of ARI and change in preoperative to postoperative peak creatinine levels.<br><br>RESULTS: ARI incidence was lower in the carvedilol plus NAC group compared with the metoprolol (21.0% vs 42.1%; P = 0.002) or carvedilol (21.0% vs 38.6%; P = 0.006) groups, but was similar between the metoprolol and carvedilol groups (P = 0.62). Preoperative and postoperative day 1 creatinine levels were similar among the metoprolol (1.02 [0.9-1.2] and 1.2 [0.92-1.45]) the carvedilol (1.0 [0.88-1.08] and 1.2 [0.9-1.5]) and the carvedilol plus NAC groups (1.06 [0.9-1.18] and 1.1 [1.0-1.21] mg/dL; all P values >0.05). Postoperative day 3, day 5, and peak creatinine levels were lower in the carvedilol plus NAC group (1.11 [1.0-1.23], 1.14 [1.0-1.25] and 1.15 [1.0-1.25]) as compared with the metoprolol (1.4 [1.3-1.49], 1.3 [1.0-1.54] and 1.3 [1.0-1.54]) or carvedilol groups (1.2 [1.0-1.52], 1.25 [1.0-1.52] and 1.25 [1.0-1.55] mg/dL; all P values <0.05), but were similar between the metoprolol and carvedilol groups (all P values >0.05).<br><br>CONCLUSIONS: Combined carvedilol and NAC decreased ARI incidence as compared with carvedilol or metoprolol. No difference was detected between carvedilol and metoprolol.}, }
@article {pmid24672637, year = {2014}, author = {Khurana, S and Hollingsworth, A and Piche, M and Venkataraman, K and Kumar, A and Ross, GM and Tai, TC}, title = {Antiapoptotic actions of methyl gallate on neonatal rat cardiac myocytes exposed to H2O2.}, journal = {Oxidative medicine and cellular longevity}, volume = {2014}, number = {}, pages = {657512}, pmid = {24672637}, issn = {1942-0994}, mesh = {Animals ; Animals, Newborn ; Apoptosis/*drug effects ; Caspase 9/metabolism ; Cell Shape/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; DNA Damage ; Enzyme Activation/drug effects ; Gallic Acid/*analogs &amp; derivatives/pharmacology ; Glutathione/metabolism ; Hydrogen Peroxide/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; Myocytes, Cardiac/*cytology/drug effects/enzymology ; Oxidative Stress/drug effects ; Rats ; }, abstract = {Reactive oxygen species trigger cardiomyocyte cell death via increased oxidative stress and have been implicated in the pathogenesis of cardiovascular diseases. The prevention of cardiomyocyte apoptosis is a putative therapeutic target in cardioprotection. Polyphenol intake has been associated with reduced incidences of cardiovascular disease and better overall health. Polyphenols like epigallocatechin gallate (EGCG) can reduce apoptosis of cardiomyocytes, resulting in better health outcomes in animal models of cardiac disorders. Here, we analyzed whether the antioxidant N-acetyl cysteine (NAC) or polyphenols EGCG, gallic acid (GA) or methyl gallate (MG) can protect cardiomyocytes from cobalt or H2O2-induced stress. We demonstrate that MG can uphold viability of neonatal rat cardiomyocytes exposed to H2O2 by diminishing intracellular ROS, maintaining mitochondrial membrane potential, augmenting endogenous glutathione, and reducing apoptosis as evidenced by impaired Annexin V/PI staining, prevention of DNA fragmentation, and cleaved caspase-9 accumulation. These findings suggest a therapeutic value for MG in cardioprotection.}, }
@article {pmid24669777, year = {2014}, author = {Sheng, C and Chen, H and Wang, B and Wang, C and Lin, L and Li, Y and Ying, W}, title = {Poly(ADP-ribose) polymerase activation mediates synchrotron radiation X-ray-induced damage of rodent testes by exacerbating DNA damage and apoptotic changes.}, journal = {International journal of radiation biology}, volume = {90}, number = {7}, pages = {580-586}, doi = {10.3109/09553002.2014.908263}, pmid = {24669777}, issn = {1362-3095}, mesh = {Animals ; Apoptosis/*radiation effects ; Caspase 3/metabolism ; DNA Breaks, Double-Stranded/radiation effects ; *DNA Damage ; Enzyme Activation/radiation effects ; Male ; Oxidative Stress/radiation effects ; Poly(ADP-ribose) Polymerases/*metabolism ; Rats ; Rats, Sprague-Dawley ; *Synchrotrons ; Testis/cytology/metabolism/*radiation effects ; X-Rays/adverse effects ; }, abstract = {PURPOSES: Synchrotron radiation (SR) X-ray has great potential for cancer treatment and medical imaging. It is of significance to investigate the mechanisms underlying the effects of SR X-ray irradiation on biological tissues, and search for the strategies for preventing the damaging effects of SR X-ray irradiation on normal tissues. The major aim of our current study is to test our hypothesis that poly(ADP-ribose) polymerase (PARP) plays a significant role in SR X-ray-induced tissue damage.<br><br>METHODS AND MATERIALS: The testes of rodents were pre-treated with PARP inhibitor 3-aminobenzamide (3-AB) or antioxidant N-acetyl-acetylcysteine (NAC), followed by SR X-ray irradiation. PARP activation, double-strand DNA breaks (DSB), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) signals, caspase-3 activity and weight of the testes were determined.<br><br>RESULTS: SR X-ray irradiation produced dose-dependent increases in poly(ADP-ribose) (PAR) formation - an index of PARP activation, which can be prevented by NAC administration. Administration of 10 or 20 mg/kg 3-AB attenuated a variety of tissue injury induced by SR X-ray, including caspase-3 activation, increases in TUNEL signals and loss of testical weight. The PARP inhibitor also significantly decreased SR X-ray-induced &#x3b3;-H2AX signal - a marker of DSB.<br><br>CONCLUSIONS: Our study has provided the first evidence suggesting that SR X-ray can induce PARP activation by generating oxidative stress, which leads to various tissue injuries at least partially by exacerbating DNA damage and apoptotic changes.}, }
@article {pmid24669263, year = {2014}, author = {Roomi, MW and Roomi, NW and Kalinovsky, T and Rath, M and Niedzwiecki, A}, title = {Prevention of amiodarone-induced cardiac toxicity in male BALB/c mice by a nutrient mixture.}, journal = {Experimental and therapeutic medicine}, volume = {7}, number = {4}, pages = {987-989}, pmid = {24669263}, issn = {1792-0981}, abstract = {Amiodarone (Amio), a potent anti-arrhythmic drug, is associated with life-threatening pulmonary toxicity involving fibroses and inflammation. A unique nutrient mixture (NM) consisting of lysine, proline, ascorbic acid, N-acetyl cysteine and green tea extract has previously been shown to exhibit a broad spectrum of pharmacological, therapeutic, cardiovascular and chemopreventive properties. The present study was undertaken to determine whether the NM exhibits preventive effects on Amio-induced cardiac toxicity. Six-week-old male BALB/c mice were divided into four groups (A-D) of six animals per group. Mice in groups A and C were fed a regular diet for three weeks, while the diets of the mice in groups B and D were supplemented with 1% NM during that period. After three weeks, the mice in groups C and D received daily Amio injections of 50 mg/kg body weight intraperitoneally for 4 days, whilst those in groups A and B received saline alone. At 24 h after the final dose, mice were sacrificed, blood was withdrawn and serum was collected for clinical chemistry of the heart enzymes creatine phosphokinase (CPK) and aspartate aminotransferase (AST). In addition, livers, kidneys, hearts and lungs were excised and weighed. No significant differences in weight gain were identified among the groups and liver, kidney, heart and lung weights were comparable in all four groups. Administration of Amio to group C resulted in a significant increase in serum CPK levels, whereas in NM-fed group D, the CPK levels were comparable to those in the saline injection groups, A and B. Amio administration also resulted in a significant increase in serum AST levels in group C, but not in the group D animals which exhibited similar levels to those of groups A and B. Therefore, the results indicate that NM has the potential to protect against Amio-induced cardiac toxicity.}, }
@article {pmid24666324, year = {2014}, author = {Bateman, DN and Carroll, R and Pettie, J and Yamamoto, T and Elamin, ME and Peart, L and Dow, M and Coyle, J and Cranfield, KR and Hook, C and Sandilands, EA and Veiraiah, A and Webb, D and Gray, A and Dargan, PI and Wood, DM and Thomas, SH and Dear, JW and Eddleston, M}, title = {Effect of the UK's revised paracetamol poisoning management guidelines on admissions, adverse reactions and costs of treatment.}, journal = {British journal of clinical pharmacology}, volume = {78}, number = {3}, pages = {610-618}, pmid = {24666324}, issn = {1365-2125}, support = {DRF-2012-05-189/DH_/Department of Health/United Kingdom ; }, mesh = {Acetaminophen/economics/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antidotes/administration &amp; dosage/*therapeutic use ; Child ; Child, Preschool ; Female ; Health Care Costs ; Hospitalization/statistics &amp; numerical data ; Humans ; Infant ; Male ; Middle Aged ; *Practice Guidelines as Topic ; Prospective Studies ; Risk Assessment ; United Kingdom ; Young Adult ; }, abstract = {AIMS: In September 2012 the UK's Commission on Human Medicines (CHM) recommended changes in the management of paracetamol poisoning: use of a single '100 mg l(-1) ' nomogram treatment line, ceasing risk assessment, treating all staggered/uncertain ingestions and increasing the duration of the initial acetylcysteine (NAC) infusion from 15 to 60 min. We evaluated the effect of this on presentation, admission, treatment, adverse reactions and costs of paracetamol poisoning.<br><br>METHODS: Data were prospectively collected from adult patients presenting to three large UK hospitals from 3 September 2011 to 3 September 2013 (year before and after change). Infusion duration effect on vomiting and anaphylactoid reactions was examined in one centre. A cost analysis from an NHS perspective was performed for 90&#x2009;000 patients/annum with paracetamol overdose.<br><br>RESULTS: There were increases in the numbers presenting to hospital (before 1703, after 1854; increase 8.9% [95% CI 1.9, 16.2], P = 0.011); admitted (1060/1703 [62.2%] vs. 1285/1854 [69.3%]; increase 7.1% [4.0, 10.2], P < 0.001) and proportion treated (626/1703 [36.8%] vs. 926/1854 [50.0%]; increase: 13.2% [95% CI 10.0, 16.4], P < 0.001). Increasing initial NAC infusion did not change the proportion of treated patients developing adverse reactions (15&#x2009;min 87/323 [26.9%], 60&#x2009;min 145/514 [28.2%]; increase: 1.3% [95% CI -4.9, 7.5], P = 0.682). Across the UK the estimated cost impact is &#xa3;8.3 million (6.4 million-10.2 million) annually, with a cost-per-life saved of &#xa3;17.4 million (13.4 million-21.5 million).<br><br>CONCLUSIONS: The changes introduced by the CHM in September 2012 have increased the numbers of patients admitted to hospital and treated with acetylcysteine without reducing adverse reactions. A safety and cost-benefit review of the CHM guidance is warranted, including novel treatment protocols and biomarkers in the assessment of poisoning.}, }
@article {pmid24662196, year = {2014}, author = {Narimatsu, T and Ozawa, Y and Miyake, S and Nagai, N and Tsubota, K}, title = {Angiotensin II type 1 receptor blockade suppresses light-induced neural damage in the mouse retina.}, journal = {Free radical biology &amp; medicine}, volume = {71}, number = {}, pages = {176-185}, doi = {10.1016/j.freeradbiomed.2014.03.020}, pmid = {24662196}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II Type 1 Receptor Blockers/*pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/radiation effects ; Benzimidazoles/*pharmacology ; Biphenyl Compounds ; Dose-Response Relationship, Drug ; Fas Ligand Protein/agonists/genetics/metabolism ; Gene Expression Regulation ; Light ; Losartan/*pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Proto-Oncogene Proteins c-fos/antagonists &amp; inhibitors/genetics/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Receptor, Angiotensin, Type 1/genetics/metabolism ; Renin-Angiotensin System/drug effects ; Retinal Degeneration/*drug therapy/metabolism/pathology ; Retinal Photoreceptor Cell Outer Segment/*drug effects/metabolism/pathology/radiation effects ; Signal Transduction ; Tetrazoles/*pharmacology ; Valine/*analogs &amp; derivatives/pharmacology ; Valsartan ; }, abstract = {Exposure to light contributes to the development and progression of retinal degenerative diseases. However, the mechanisms underlying light-induced tissue damage are not fully understood. Here, we examined the role of angiotensin II type 1 receptor (AT1R) signaling, which is part of the renin-angiotensin system, in light-induced retinal damage. Light-exposed Balb/c mice that were treated with the AT1R blockers (angiotensin II receptor blockers; ARBs) valsartan, losartan, and candesartan before and after the light exposure exhibited attenuated visual function impairment, compared to vehicle-treated mice. This effect was dose-dependent and observed across the ARB class of inhibitors. Further evaluation of valsartan showed that it suppressed a number of light-induced retinal effects, including thinning of the photoreceptor cell layer caused by apoptosis, shortening of the photoreceptor cell outer segment, and increased levels of reactive oxygen species (ROS). The role of ROS in retinal pathogenesis was investigated further using the antioxidant N-acetyl-l-cysteine (NAC). Treatment of light-exposed mice with NAC before the light exposure suppressed the visual function impairment and photoreceptor cell histological changes due to apoptosis. Moreover, treatment with valsartan or NAC suppressed the induction of c-fos (a component of the AP-1 transcription factor) and the upregulation of fasl (a proapoptotic molecule whose transcript is regulated downstream of AP-1). Our results suggest that AT1R signaling mediates light-induced apoptosis, by increasing the levels of ROS and proapoptotic molecules in the retina. Thus, AT1R blockade may represent a new therapeutic approach for preventing light-induced retinal neural tissue damage.}, }
@article {pmid24661543, year = {2014}, author = {Gagnon, A and Langille, ML and Chaker, S and Antunes, TT and Durand, J and Sorisky, A}, title = {TSH signaling pathways that regulate MCP-1 in human differentiated adipocytes.}, journal = {Metabolism: clinical and experimental}, volume = {63}, number = {6}, pages = {812-821}, doi = {10.1016/j.metabol.2014.02.015}, pmid = {24661543}, issn = {1532-8600}, support = {MOP-102585//Canadian Institutes of Health Research/Canada ; }, mesh = {Adipocytes/*metabolism ; Adult ; Animals ; CHO Cells ; Cell Differentiation ; Chemokine CCL2/genetics/*metabolism ; Cricetinae ; Cricetulus ; Cyclic AMP-Dependent Protein Kinases/drug effects/*metabolism ; Female ; Gene Expression Regulation ; Humans ; I-kappa B Kinase/antagonists &amp; inhibitors/*metabolism ; Interleukin-6/*metabolism ; Lipolysis/drug effects ; Male ; Middle Aged ; Phosphorylation ; RNA, Messenger/metabolism ; Signal Transduction/drug effects ; Subcutaneous Fat, Abdominal/*cytology ; Thyrotropin/*metabolism/pharmacology ; }, abstract = {OBJECTIVE: Adipose tissue is an extra-thyroidal thyroid-stimulating hormone (TSH) target. Increases in lipolysis and in expression and release of interleukin-6 (IL-6) occur in TSH-stimulated adipocytes, and levels of circulating free fatty acids and IL-6 rise following TSH administration to patients with previous thyroidectomy and radioablation for thyroid cancer. Our first objective was to compare how TSH stimulates protein kinase A (PKA) and inhibitor of κB (IκB) kinase (IKK)-β. Our second objective was to investigate whether TSH induces other cytokines besides IL-6.<br><br>METHODS: TSH stimulation of either CHO cells expressing human TSH receptor or human abdominal subcutaneous differentiated adipocytes.<br><br>RESULTS: Signaling studies showed TSH increased NADPH oxidase activity, and either diphenyleneiodonium (oxidase inhibitor) or N-acetyl cysteine (scavenger of reactive oxygen species) reduced IKK&#x3b2; phosphorylation. Phosphorylation of protein kinase C-&#x3b4;, an upstream regulator of NADPH oxidase, was increased by TSH, and rottlerin (PKC&#x3b4; inhibitor) reduced TSH-stimulated IKK&#x3b2; phosphorylation. TSH upregulated monocyte chemoattractant protein-1 (MCP-1) mRNA expression and the release of MCP-1 protein in human abdominal differentiated adipocytes. H89 (PKA inhibitor) and sc-514 (IKK&#x3b2; inhibitor) each blocked TSH-stimulated MCP-1 mRNA expression and protein release, suggesting PKA and IKK&#x3b2; participate in this pathway.<br><br>CONCLUSIONS: These data provide new information about TSH signaling in human differentiated adipocytes, and add to the evidence that TSH is a pro-inflammatory stimulus of adipocytes.}, }
@article {pmid24659045, year = {2014}, author = {Ban, DK and Paul, S}, title = {Zinc oxide nanoparticles modulates the production of β-glucosidase and protects its functional state under alcoholic condition in Saccharomyces cerevisiae.}, journal = {Applied biochemistry and biotechnology}, volume = {173}, number = {1}, pages = {155-166}, doi = {10.1007/s12010-014-0825-2}, pmid = {24659045}, issn = {1559-0291}, mesh = {Ethanol/*metabolism ; Fermentation ; Nanoparticles/chemistry ; Saccharomyces cerevisiae/drug effects/*enzymology/growth &amp; development ; Saccharomyces cerevisiae Proteins/*biosynthesis ; Zinc Oxide/chemical synthesis/*pharmacology ; beta-Glucosidase/*biosynthesis ; }, abstract = {In the present investigation, we have investigated the effect of zinc oxide nanoparticles (ZnONP) on the production of β-glucosidase (BGL) in Saccharomyces cerevisiae under various conditions. ZnONP was synthesized chemically and characterized using various standard techniques. The results revealed that yeast culture administered with 5 mM ZnONP enhanced the intracellular BGL activity up to 28 % compared to control with simultaneous growth of cells. However, at a higher dose of ZnONP (10 and 15 mM), both the activity of the enzyme and yeast growth was dropped. When yeast cells were grown in alcoholic medium (2, 5, and 10 % ethanol), the growth was found inhibited with substantial reduction of intracellular BGL activity. Interestingly, the administration of ZnONP further inhibited the cell growth, however, suppressed the alcoholic effect on enzyme activity. Moreover, under the same condition, ZnONP enhanced the biological activity of the enzyme in cells, indicated a higher yield of BGL production. When the mechanism of ZnONP-mediated cell growth inhibition was investigated, N-acetylcysteine (NAC)-based cell growth study proved that reactive oxygen species (ROS) was not the sole cell death mechanism induced by ZnONP, indicating a second mechanism of cell death. Our findings provide a new insight on the potential application of ZnONP as an external supplement to enhance the active production of BGL like important industrial enzyme in S. cerevisiae in both normal and alcohol stressed condition as well as to produce baker’s yeast in higher amount.}, }
@article {pmid24655916, year = {2014}, author = {Large, M and Reichert, S and Hehlgans, S and Fournier, C and Rödel, C and Rödel, F}, title = {A non-linear detection of phospho-histone H2AX in EA.hy926 endothelial cells following low-dose X-irradiation is modulated by reactive oxygen species.}, journal = {Radiation oncology (London, England)}, volume = {9}, number = {}, pages = {80}, pmid = {24655916}, issn = {1748-717X}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Dose-Response Relationship, Radiation ; Endothelial Cells/*metabolism/pathology/*radiation effects ; Free Radical Scavengers/pharmacology ; Histones/*metabolism ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism/radiation effects ; Humans ; Nonlinear Dynamics ; Phosphorylation/drug effects/radiation effects ; Radiation Dosage ; Reactive Oxygen Species/metabolism/*pharmacology ; X-Rays ; }, abstract = {BACKGROUND: A discontinuous dose response relationship is a major characteristic of the anti-inflammatory effects of low-dose X-irradiation therapy. Although recent data indicate an involvement of a variety of molecular mechanisms in these characteristics, the impact of reactive oxygen species (ROS) production to give rise or contribute to these phenomena in endothelial cells (EC) remains elusive.<br><br>MATERIAL AND METHODS: HUVEC derived immortalized EA.hy926 cells were stimulated by tumor necrosis factor-&#x3b1; (TNF-&#x3b1;, 20 ng/ml) 4 h before irradiation with doses ranging from 0.3 to 1 Gy. To analyse DNA repair capacity, phospho-histone H2AX foci were assayed at 1 h, 4 h and 24 h after irradiation. ROS production and superoxide dismutase (SOD) activity were analysed by fluorometric 2',7'-dichlorodihydrofluorescein-diacetate (H2DCFDA) and colorimetric assays. A functional impact of ROS on &#x3b3;H2AX production was analysed by treatment with the scavenger N-acetyl-L-cysteine (NAC).<br><br>RESULTS: Irrespective of stimulation by TNF-&#x3b1;, EA.hy926 cells revealed a linear dose response characteristic of &#x3b3;H2AX foci detection at 1 h and 4 h after irradiation. By contrast, we observed a discontinuity in residual &#x3b3;H2AX foci detection at 24 h after irradiation with locally elevated values following a 0.5 Gy exposure that was abolished by inhibition of ROS by NAC. Moreover, SOD protein expression was significantly decreased at doses of 0.5 Gy and 0.7 Gy concomitant with a reduced SOD activity.<br><br>CONCLUSION: These data implicate a non-linear regulation of ROS production and SOD activity in EA.hy926 EC following irradiation with doses&#x2009;<&#x2009;1 Gy that may contribute to a discontinuous dose-response relationship of residual &#x3b3;H2AX foci detection.}, }
@article {pmid24652522, year = {2014}, author = {Smaga, I and Bystrowska, B and Gawliński, D and Pomierny, B and Stankowicz, P and Filip, M}, title = {Antidepressants and changes in concentration of endocannabinoids and N-acylethanolamines in rat brain structures.}, journal = {Neurotoxicity research}, volume = {26}, number = {2}, pages = {190-206}, pmid = {24652522}, issn = {1476-3524}, mesh = {Acetylcysteine/pharmacology ; Amides ; Amidohydrolases/antagonists &amp; inhibitors/metabolism ; Animals ; Antidepressive Agents/*pharmacology ; Arachidonic Acids/*metabolism ; Benzamides/pharmacology ; Brain/*drug effects/metabolism ; Carbamates/pharmacology ; Citalopram/pharmacology ; Endocannabinoids/*metabolism ; Enzyme Inhibitors/pharmacology ; Ethanolamines/*metabolism ; Expectorants/pharmacology ; Glycerides/*metabolism ; Imipramine/pharmacology ; Male ; Oleic Acids/*metabolism ; Palmitic Acids/*metabolism ; Polyunsaturated Alkamides/*metabolism ; Rats, Wistar ; Thiazepines/pharmacology ; }, abstract = {The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery.}, }
@article {pmid24647034, year = {2014}, author = {Kuo, LM and Kuo, CY and Lin, CY and Hung, MF and Shen, JJ and Hwang, TL}, title = {Intracellular glutathione depletion by oridonin leads to apoptosis in hepatic stellate cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {19}, number = {3}, pages = {3327-3344}, pmid = {24647034}, issn = {1420-3049}, mesh = {Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line ; Cell Survival/drug effects ; Diterpenes, Kaurane/*pharmacology ; Enzyme Activation/drug effects ; Glutathione/*metabolism ; Hepatic Stellate Cells/*drug effects/*metabolism ; Inhibitory Concentration 50 ; Intracellular Space/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinases/metabolism ; Oxidative Stress ; Phosphorylation ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Proliferation of hepatic stellate cells (HSCs) plays a key role in the pathogenesis of liver fibrosis. Induction of HSC apoptosis by natural products is considered an effective strategy for treating liver fibrosis. Herein, the apoptotic effects of 7,20-epoxy-ent-kaurane (oridonin), a diterpenoid isolated from Rabdosia rubescens, and its underlying mechanisms were investigated in rat HSC cell line, HSC-T6. We found that oridonin inhibited cell viability of HSC-T6 in a concentration-dependent manner. Oridonin induced a reduction in mitochondrial membrane potential and increases in caspase 3 activation, subG1 phase, and DNA fragmentation. These apoptotic effects of oridonin were completely reversed by thiol antioxidants, N-acetylcysteine (NAC) and glutathione monoethyl ester. Moreover, oridonin increased production of reactive oxygen species (ROS), which was also inhibited by NAC. Significantly, oridonin reduced intracellular glutathione (GSH) level in a concentration- and time-dependent fashion. Additionally, oridonin induced phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). NAC prevented the activation of MAPKs in oridonin-induced cells. However, selective inhibitors of MAPKs failed to alter oridonin-induced cell death. In summary, these results demonstrate that induction of apoptosis in HSC-T6 by oridonin is associated with a decrease in cellular GSH level and increase in ROS production.}, }
@article {pmid24642932, year = {2014}, author = {Xu, C and Ding, W and Yang, L and Yang, M and Zhang, M and Gu, Y}, title = {Contributions of endoplasmic reticulum stress and reactive oxygen species to renal injury in aldosterone/salt-induced rats.}, journal = {Nephron. Experimental nephrology}, volume = {126}, number = {1}, pages = {25-32}, doi = {10.1159/000357777}, pmid = {24642932}, issn = {1660-2129}, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 4/metabolism ; Aldosterone ; Animals ; Blotting, Western ; *Endoplasmic Reticulum Stress ; Free Radical Scavengers/pharmacology ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/metabolism ; Immunohistochemistry ; Kidney/drug effects/*metabolism/pathology ; Kidney Diseases/chemically induced/*metabolism/prevention &amp; control ; Male ; Membrane Proteins/metabolism ; NADPH Oxidases/metabolism ; Phosphoproteins/metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sodium Chloride ; Transcription Factor CHOP/metabolism ; }, abstract = {BACKGROUND: Recent studies have suggested that aldosterone (Aldo) plays a key role in the pathogenesis of renal injury; however, the molecular mechanisms of Aldo-induced renal injury have not been characterized. This study was performed to test the hypothesis that reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress contribute to the pathogenesis of Aldo- and salt-induced renal injury.<br><br>METHODS: Rats were uninephrectomized and treated with one of the following for 4 weeks: (1) vehicle, (2) vehicle + NaCl, (3) Aldo + NaCl or (4) Aldo + NaCl + N-acetyl-L-cysteine (NAC). Following this treatment period, the extent of renal injury was assessed by periodic acid-Schiff staining and immunohistochemistry, and the expression levels of proteins related to ER stress, as well as p47phox and p67phox in the kidney, were measured by Western blot. Intracellular ROS generation was evaluated by 2'7'-dichlorofluorescin diacetate fluorescence and ELISA kits.<br><br>RESULTS: Rats that received Aldo + 1% NaCl exhibited severe renal injury. ROS levels were higher in Aldo-infused rats and were inhibited by NAC. Renal cortical protein levels of GRP78, GRP94, CHOP, ATF-4, p47phox and p67phox were significantly upregulated in rats that received Aldo + 1% NaCl. Treatment with NAC significantly ameliorated the increase in the expression of these proteins.<br><br>CONCLUSION: These data suggest that ROS and ER stress play a role in the progression of Aldo- and salt-induced renal injury.}, }
@article {pmid24642019, year = {2014}, author = {Bartlett, DC and Hodson, J and Bhogal, RH and Youster, J and Newsome, PN}, title = {Combined use of N-acetylcysteine and Liberase improves the viability and metabolic function of human hepatocytes isolated from human liver.}, journal = {Cytotherapy}, volume = {16}, number = {6}, pages = {800-809}, pmid = {24642019}, issn = {1477-2566}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Cell Survival/*drug effects ; Collagenases/*pharmacology ; Hepatocytes/*drug effects/metabolism ; Humans ; Islets of Langerhans/drug effects/pathology ; Liver/drug effects/metabolism ; Thermolysin/*pharmacology ; Transplantation/methods ; }, abstract = {BACKGROUND AIMS: Successful hepatocyte isolation is critical for continued development of cellular transplantation. However, most tissue available for research is from diseased liver, and the results of hepatocyte isolation from such tissue are inferior compared with normal tissue. Liberase and N-acetylcysteine (NAC) have been shown separately to improve viability of isolated hepatocytes. This study aims to determine the effect of Liberase and NAC in combination on human hepatocyte isolation from normal and diseased liver tissues.<br><br>METHODS: Hepatocytes were isolated from 30 liver specimens through the use of a standard collagenase digestion technique (original protocol) and another 30 with the addition of NAC and standard collagenase substituted by Liberase (new protocol). Viability and success, defined as maintenance of cell adhesion and morphology for 48 hours, were assessed. Metabolic function was assessed by means of albumin and urea synthesis.<br><br>RESULTS: Baseline factors were similar for both groups. The delay to tissue processing was slightly shorter in the new protocol group (median, 2 versus 4 hours; P&#xa0;= 0.007). The success rate improved from 12 of 30 (40.0%) to 21 of 30 (70.0%) with the use of the new protocol (P&#xa0;= 0.037), and median viable cell yield increased from 7.3&#xa0;&#xd7; 10(4) to 28.3&#xa0;&#xd7; 10(4) cells/g tissue (P&#xa0;= 0.003). After adjusting for delay, success rate (P&#xa0;= 0.014) and viable cell yield/g tissue (P&#xa0;= 0.001) remained significantly improved. Albumin and urea synthesis were similar or superior in the new protocol group.<br><br>CONCLUSIONS: NAC and Liberase improve the success of hepatocyte isolation, with a significantly higher yield of viable cells. The use of these agents may improve the availability of hepatocytes for transplantation and laboratory research.}, }
@article {pmid24641112, year = {2014}, author = {Tuzcu, EA and Tuzcu, K and Basarslan, F and Motor, S and Coskun, M and Keskin, U and Ayintap, E and Ilhan, O and Oksuz, H}, title = {Protective effects of N-acetylcysteine on triamcinolone acetonide-induced lens damage in rats.}, journal = {Cutaneous and ocular toxicology}, volume = {33}, number = {4}, pages = {294-298}, doi = {10.3109/15569527.2013.857679}, pmid = {24641112}, issn = {1556-9535}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents/*toxicity ; Cataract/chemically induced/pathology/*prevention &amp; control ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Lens, Crystalline/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Oxidative Stress ; Protein Carbonylation/drug effects ; Rats ; Rats, Wistar ; Triamcinolone Acetonide/*toxicity ; }, abstract = {OBJECTIVE: To examine the relationship of cataract forming effect of intravitreal triamcinolone acetonide (IVTA) injection with oxidative status and the effect of N-acetylcysteine (NAC) on these alterations.<br><br>MATERIALS AND METHODS: Twenty-six Wistar-Albino rats were included in the study. Rats were assigned into four groups as follows: intravitreal saline injection group (controls); IVTA injection group; IVTA&#x2009;+ intraperitoneal NAC injection group (IVTA&#x2009;+ NAC); and intraperitoneal NAC injection group (NAC). Triamcinolone acetonide was intravitreally injected at a dose of 1 mg. NAC was intraperitoneally injected at a dose of 150 &#xb5;g/g body weight. Animals were sacrificed and lens specimens were analyzed for levels of malondialdehyde (MDA) and protein carbonyl (PC) and activities of glutathione (GSH) and glutathione peroxidase (GSH-Px).<br><br>RESULTS: We found that the MDA and PC levels of lenses were increased in the IVTA group (p < 0.01). It was seen that GSH and GSH-Px in lenses were decreased in the IVTA group (p < 0.01). NAC administration significantly ameliorated these changes in the IVTA&#x2009;+ NAC group (p < 0.05).<br><br>CONCLUSION: These results indicate that the NAC produces a protective mechanism against IVTA-induced cataract and suggest a role of oxidative stress in pathogenesis.}, }
@article {pmid24634593, year = {2014}, author = {Park, MY and Jeong, YJ and Kang, GC and Kim, MH and Kim, SH and Chung, HJ and Jung, JY and Kim, WJ}, title = {Nitric oxide-induced apoptosis of human dental pulp cells is mediated by the mitochondria-dependent pathway.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {18}, number = {1}, pages = {25-32}, pmid = {24634593}, issn = {1226-4512}, abstract = {Nitric oxide (NO) is recognized as a mediator and regulator of inflammatory responses. NO is produced by nitric oxide synthase (NOS), and NOS is abundantly expressed in the human dental pulp cells (HDPCs). NO produced by NOS can be cytotoxic at higher concentrations to HDPCs. However, the mechanism by which this cytotoxic pathway is activated in cells exposed to NO is not known. The purpose of this study was to elucidate the NO-induced cytotoxic mechanism in HDPCs. Sodium nitroprusside (SNP), a NO donor, reduced the viability of HDPCs in a dose- and time-dependent manner. We investigated the in vitro effects of nitric oxide on apoptosis of cultured HDPCs. Cells showed typical apoptotic morphology after exposure to SNP. Besides, the number of Annexin V positive cells was increased among the SNP-treated HDPCs. SNP enhanced the production of reactive oxygen species (ROS), and N-acetylcysteine (NAC) ameliorated the decrement of cell viability induced by SNP. However, a soluble guanylate cyclase inhibitor (ODQ) did not inhibited the decrement of cell viability induced by SNP. SNP increased cytochrome c release from the mitochondria to the cytosol and the ratio of Bax/Bcl-2 expression levels. Moreover, SNP-treated HDPCs elevated activities of caspase-3 and caspase-9. While pretreatment with inhibitors of caspase (z-VAD-fmk, z-DEVD-fmk) reversed the NO-induced apoptosis of HDPCs. From these results, it can be suggested that NO induces apoptosis of HDPCs through the mitochondria-dependent pathway mediated by ROS and Bcl-2 family, but not by the cyclic GMP pathway.}, }
@article {pmid24631677, year = {2014}, author = {Ouazia, D and Levros, LC and Rassart, E and Desrosiers, RR}, title = {Dopamine down-regulation of protein L-isoaspartyl methyltransferase is dependent on reactive oxygen species in SH-SY5Y cells.}, journal = {Neuroscience}, volume = {267}, number = {}, pages = {263-276}, doi = {10.1016/j.neuroscience.2014.03.001}, pmid = {24631677}, issn = {1873-7544}, mesh = {Antioxidants/pharmacology ; Catalase/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Dopamine/*pharmacology ; Dose-Response Relationship, Drug ; Down-Regulation/*drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Insecticides/pharmacology ; Mutation/genetics ; Neuroblastoma/pathology ; Promoter Regions, Genetic/drug effects/genetics ; Protein D-Aspartate-L-Isoaspartate Methyltransferase/genetics/*metabolism ; RNA, Messenger/genetics ; Reactive Oxygen Species/*metabolism ; Receptors, Aryl Hydrocarbon/metabolism ; Rotenone/pharmacology ; Transfection ; }, abstract = {Parkinson's disease (PD) is a chronic and progressive neurological disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra. Dopamine, via the oxidative stress that it generates in the cytosol, could contribute to the selective loss of neurons observed in PD. Protein L-isoaspartyl methyltransferase (PIMT) is an enzyme that repairs L-isoaspartyl-containing proteins and possesses anti-apoptotic properties. PIMT expression has been shown to decrease with age. Together, these observations prompted us to investigate whether dopamine can regulate PIMT expression in SH-SY5Y neuroblastoma cells. Here, we report that dopamine down-regulated PIMT at both gene and protein levels. The same inhibition of PIMT protein level was caused by the electron transport chain inhibitor, rotenone, which was accompanied, in both cases, by an increase in cell death and reactive oxygen species (ROS) production. In fact, pre-treatment with the antioxidant N-acetyl cysteine blocked PIMT dopamine-associated down-regulation. PCMT1 promoter mapping experiments allowed the identification of two regions that showed different sensitivity to DA action. A first region localized between 61 and 94bp upstream of transcription start site was very sensitive to dopamine inhibition while a second region between 41 and 61bp appeared more resistant to dopamine inhibitory effect. The inhibition of PCMT1 promoter activity was mediated by dopamine-induced ROS since it was prevented by the hydroxyl radical scavenger N,N'-dimethylthiourea. Conversely, H2O2 inhibited in a dose-dependent manner the transcriptional activity of PCMT1 promoter. Therefore, our findings identified new molecular mechanisms, cytosolic dopamine and its resulting ROS, as inhibitors of PIMT expression. This suggests that ROS generated from cytosolic dopamine could reduce both the PCMT1 gene promoter activity and the PIMT protein level thus decreasing its capacity to repair proteins involved in apoptosis and could contribute to neuronal cell death observed in PD.}, }
@article {pmid24627081, year = {2014}, author = {Wang, H and Ye, Y and Yu, ZL}, title = {Proteomic and functional analyses demonstrate the involvement of oxidative stress in the anticancer activities of oridonin in HepG2 cells.}, journal = {Oncology reports}, volume = {31}, number = {5}, pages = {2165-2172}, doi = {10.3892/or.2014.3081}, pmid = {24627081}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Caspase 3/biosynthesis ; Caspase 9/biosynthesis ; Cell Line, Tumor ; Cell Survival/drug effects ; Diterpenes, Kaurane/*pharmacology ; HSP70 Heat-Shock Proteins/*biosynthesis/genetics ; Hep G2 Cells ; Homeodomain Proteins/biosynthesis ; Humans ; JNK Mitogen-Activated Protein Kinases/biosynthesis ; Liver Neoplasms/*drug therapy ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Peroxiredoxins/biosynthesis ; Proteomics ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; RNA Interference ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/biosynthesis ; Tumor Suppressor Proteins/biosynthesis ; p38 Mitogen-Activated Protein Kinases/biosynthesis ; }, abstract = {Oridonin exhibits a curative effect on liver carcinoma in patients and experimental animals. In the present study, we performed proteomic and functional analyses to explore the mechanism involved in the anticancer activity of oridonin. Oridonin treatment for 24 h resulted in a dose-dependent decrease in cell viability with an IC50 value of 37.90 µM. Treatment with 40 µM oridonin for 24 h induced apoptosis as typical apoptotic nuclear alterations were observed following DAPI staining. Using a 2-DE-based proteomic approach, 3 upregulated oxidative stress markers, Hsp70-1, Hop and Prdx2, were identified in the HepG2 cells treated with 40 µM oridonin for 24 h. A pattern of alteration in Hsp70-1 was verified by western blotting. The mRNA expression patterns of Hsp70-1 and Hop as determined by qPCR were comparable to their protein expression patterns. Further investigations showed that oridonin treatment for 24 h resulted in reactive oxygen species (ROS) generation, and ROS scavenger N-acetylcysteine (NAC) completely inhibited ROS production and restored cell viability, suggesting that oxidative stress contributed to oridonin-induced HepG2 cell death. Western blot analysis of oxidative stress pathway-related proteins demonstrated that oridonin treatment increased p-JNK, p-p38 and p-p53, and decreased Bcl-2 protein expression levels, promoted cytochrome c release, decreased mitochondrial membrane potential, and activated caspase-9 and caspase-3. Furthermore, knockdown of Hsp70-1 expression with specific shRNA significantly decreased the viability of the cells treated with oridonin, suggesting a protective role of Hsp70-1 in oridonin-mediated oxidative stress. The results of the present study provide evidence for a link between oxidative stress and oridonin-induced apoptosis in HepG2 cells.}, }
@article {pmid24626405, year = {2014}, author = {You, BR and Park, WH}, title = {Suberoylanilide hydroxamic acid-induced HeLa cell death is closely correlated with oxidative stress and thioredoxin 1 levels.}, journal = {International journal of oncology}, volume = {44}, number = {5}, pages = {1745-1755}, doi = {10.3892/ijo.2014.2337}, pmid = {24626405}, issn = {1791-2423}, mesh = {Adenocarcinoma/metabolism/*pathology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase Inhibitors/pharmacology ; Caspases/metabolism ; Cell Cycle/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; HeLa Cells ; Humans ; Hydroxamic Acids/*pharmacology ; In Vitro Techniques ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; Thioredoxins/*metabolism ; Uterine Cervical Neoplasms/metabolism/*pathology ; Vorinostat ; }, abstract = {Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase (HDAC) inhibitor which has anticancer effects. We evaluated the growth inhibitory effects of SAHA on HeLa cervical cancer cells in relation to reactive oxygen species (ROS) levels. SAHA inhibited the growth of HeLa cells with an IC(50) of approximately 10 µM at 24 h, and induced apoptosis which was accompanied by the cleavage of PARP, caspase-3 activation and loss of mitochondrial membrane potential (MMP; ∆ψ(m)). All the tested caspase inhibitors prevented HeLa cell death induced by SAHA whereas TNF-α intensified apoptotic cell death in SAHA-treated HeLa cells. With respect to ROS and glutathione (GSH) levels, SAHA increased ROS levels, especially mitochondrial O(2)•- in HeLa cells and also induced GSH depletion. Caspase inhibitors reduced the levels of ROS and GSH depletion in SAHA-treated HeLa cells whereas TNF-α enhanced the levels in these cells. The well-known antioxidant N-acetyl cysteine (NAC) attenuated cell death and an increase in ROS levels was caused by SAHA. Moreover, SAHA decreased the levels of thioredoxin 1 (Trx1) in HeLa cells. While the downregulation of Trx1 enhanced cell death and ROS levels in SAHA-treated HeLa cells, the overexpression of Trx1 attenuated the levels in these cells. In conclusion, SAHA inhibited the growth of HeLa cell via caspase-dependent apoptosis, which was influenced by the mitochondrial O(2)•- and Trx1 levels.}, }
@article {pmid24626188, year = {2014}, author = {Sun, S and Han, Y and Liu, J and Fang, Y and Tian, Y and Zhou, J and Ma, D and Wu, P}, title = {Trichostatin A targets the mitochondrial respiratory chain, increasing mitochondrial reactive oxygen species production to trigger apoptosis in human breast cancer cells.}, journal = {PloS one}, volume = {9}, number = {3}, pages = {e91610}, pmid = {24626188}, issn = {1932-6203}, mesh = {Antineoplastic Agents/*pharmacology ; *Apoptosis ; Breast Neoplasms/*pathology ; Cell Differentiation ; Cell Division ; Cell Proliferation ; Cytochromes c/metabolism ; Electron Transport ; Female ; G2 Phase ; Histone Deacetylase Inhibitors/therapeutic use ; Humans ; Hydroxamic Acids/*pharmacology ; MCF-7 Cells/drug effects ; Membrane Potential, Mitochondrial ; Mitochondria/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {AIM: Histone deacetylase inhibitors (HDACIs)-based therapies have stimulated interest via their anti-tumor activities, including apoptosis induction, cell cycle arrest, cell differentiation, and autophagy. However, the mechanisms of HDACI-associated anti-tumor activity are not yet clearly defined. The aim of this study was to explore the key events of Trichostatin A (TSA), a classic HDACI agent, against breast cancer cells.<br><br>METHODS: The MCF-7, MDA-MB-231 and MCF-10A cell lines were evaluated with colony-forming and cell viability assays. Apoptosis and cell cycle distribution were detected by flow cytometry. Mitochondrial function was measured with biochemical assays, flow cytometry and transmission electron microscopy.<br><br>RESULTS: TSA inhibited breast cancer cell viability and proliferation, without affecting MCF-10A cell. TSA-induced breast cancer cell apoptosis was initiated by G2-M arrest and depended on mitochondrial reactive oxygen species (ROS) produced subsequent to reduced mitochondrial respiratory chain activity. The enhanced mitochondrial ROS production and apoptosis in cancer cells were markedly attenuated by antioxidants, such as N-acetyl cysteine (NAC), reduced glutathione (GSH) and Vitamin C.<br><br>CONCLUSION: The present study demonstrated that TSA-induced cell death by arresting cell cycle in G2-M phase and was dependent on production of mitochondria-derived ROS, which was derived from impaired mitochondrial respiratory chain.}, }
@article {pmid24625983, year = {2014}, author = {Wali, JA and Rondas, D and McKenzie, MD and Zhao, Y and Elkerbout, L and Fynch, S and Gurzov, EN and Akira, S and Mathieu, C and Kay, TW and Overbergh, L and Strasser, A and Thomas, HE}, title = {The proapoptotic BH3-only proteins Bim and Puma are downstream of endoplasmic reticulum and mitochondrial oxidative stress in pancreatic islets in response to glucotoxicity.}, journal = {Cell death &amp; disease}, volume = {5}, number = {3}, pages = {e1124}, pmid = {24625983}, issn = {2041-4889}, mesh = {Animals ; Antioxidants/pharmacology ; *Apoptosis/drug effects ; Apoptosis Regulatory Proteins/deficiency/genetics/*metabolism ; Bcl-2-Like Protein 11 ; Cell Line ; Diabetes Mellitus, Type 2/metabolism/pathology ; Endoplasmic Reticulum/drug effects/*metabolism/pathology ; *Endoplasmic Reticulum Stress/drug effects ; Glucose/*metabolism ; Humans ; Insulin-Secreting Cells/metabolism/pathology ; Islets of Langerhans/drug effects/*metabolism/pathology ; Membrane Proteins/deficiency/genetics/*metabolism ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/drug effects/*metabolism/pathology ; Oxidants/pharmacology ; *Oxidative Stress/drug effects ; Proto-Oncogene Proteins/deficiency/genetics/*metabolism ; RNA, Messenger/metabolism ; Ribose/metabolism ; Tissue Culture Techniques ; Transcription Factor CHOP/deficiency/genetics ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism ; }, abstract = {Apoptosis of pancreatic beta cells is a feature of type 2 diabetes and its prevention may have therapeutic benefit. High glucose concentrations induce apoptosis of islet cells, and this requires the proapoptotic Bcl-2 homology domain 3 (BH3)-only proteins Bim and Puma. We studied the stress pathways induced by glucotoxicity in beta cells that result in apoptosis. High concentrations of glucose or ribose increased expression of the transcription factor CHOP (C/EBP homologous protein) but not endoplasmic reticulum (ER) chaperones, indicating activation of proapoptotic ER stress signaling. Inhibition of ER stress prevented ribose-induced upregulation of Chop and Puma mRNA, and partially protected islets from glucotoxicity. Loss of Bim or Puma partially protected islets from the canonical ER stressor thapsigargin. The antioxidant N-acetyl-cysteine also partially protected islets from glucotoxicity. Islets deficient in both Bim and Puma, but not Bim or Puma alone, were significantly protected from killing induced by the mitochondrial reactive oxygen species donor rotenone. Our data demonstrate that high concentrations of glucose induce ER and oxidative stress, which causes cell death mediated by Bim and Puma. We observed significantly higher Bim and Puma mRNA in islets of human donors with type 2 diabetes. This indicates that inhibition of Bim and Puma, or their inducers, may prevent beta-cell destruction in type 2 diabetes.}, }
@article {pmid24624334, year = {2014}, author = {Cohen-Kutner, M and Khomsky, L and Trus, M and Ben-Yehuda, H and Lenhard, JM and Liang, Y and Martin, T and Atlas, D}, title = {Thioredoxin-mimetic peptide CB3 lowers MAPKinase activity in the Zucker rat brain.}, journal = {Redox biology}, volume = {2}, number = {}, pages = {447-456}, pmid = {24624334}, issn = {2213-2317}, mesh = {Animals ; Blood Glucose/metabolism ; Brain/*metabolism ; Cell Line, Tumor ; Diabetes Mellitus, Type 2/*drug therapy/metabolism ; Disease Models, Animal ; Humans ; Insulin/blood ; MAP Kinase Signaling System/*drug effects ; Male ; Obesity/*drug therapy/metabolism ; Oligopeptides/*administration &amp; dosage/pharmacology ; Oxidative Stress/drug effects ; Peptidomimetics/*administration &amp; dosage/pharmacology ; Phosphorylation ; Rats ; Rats, Zucker ; Sulfhydryl Compounds/*administration &amp; dosage/pharmacology ; }, abstract = {Diabetes is a high risk factor for dementia. High glucose may be a risk factor for dementia even among persons without diabetes, and in transgenic animals it has been shown to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the activation of mitogen-activated kinsase (MAPKs), c-jun NH2-terminal kinase (JNK), p38 MAP kinases (p38(MAPK)), and extracellular activating kinsae1/2 (ERK1/2) and the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats and human neuroblastoma SH-SY5Y cells. Daily i.p. injection of CB3 to ZDF rats inhibited the phosphorylation of JNK and p38(MAPK), and prevented the expression of thioredoxin-interacting-protein (TXNIP/TBP-2) in ZDF rat brain. Although plasma glucose/insulin remained high, CB3 also increased the phosphorylation of AMP-ribose activating kinase (AMPK) and inhibited p70(S6K) kinase in the brain. Both CB3 and CB4 reversed apoptosis induced by inhibiting thioredoxin reductase as monitored by decreasing caspase 3 cleavage and PARP dissociation in SH-SY5Y cells. The decrease in JNK and p38(MAPK) activity in the absence of a change in plasma glucose implies a decrease in oxidative or neuroinflammatory stress in the ZDF rat brain. CB3 not only attenuated MAPK phosphorylation and activated AMPK in the brain, but it also diminished apoptotic markers, most likely acting via the MAPK-AMPK-mTOR pathway. These results were correlated with CB3 and CB4 inhibiting inflammation progression and protection from oxidative stress induced apoptosis in human neuronal cells. We suggest that by attenuating neuro-inflammatory processes in the brain Trx1 mimetic peptides could become beneficial for preventing neurological disorders associated with diabetes.}, }
@article {pmid24615591, year = {2014}, author = {Hortigón-Vinagre, MP and Henao, F}, title = {Apoptotic cell death in cultured cardiomyocytes following exposure to low concentrations of 4-hydroxy-2-nonenal.}, journal = {Cardiovascular toxicology}, volume = {14}, number = {3}, pages = {275-287}, doi = {10.1007/s12012-014-9251-5}, pmid = {24615591}, issn = {1559-0259}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/*toxicity ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Apoptosis/*drug effects/physiology ; Calcium/metabolism ; Cardiotoxicity/pathology ; Cells, Cultured ; Chromans/pharmacology ; Cysteine Proteinase Inhibitors/*toxicity ; Cytoskeleton/pathology ; Flow Cytometry ; Lipid Peroxidation ; Membrane Potential, Mitochondrial/drug effects ; Myocytes, Cardiac/*pathology ; Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {Lipid peroxidation (LP), induced by oxidative stress, is associated with degenerative processes. 4-Hydroxy-2-nonenal (HNE), a highly reactive diffusible product of LP, is considered by-product and mediator of oxidative stress. Its level increases under pathological conditions such as cardiovascular diseases. In this study, we partially characterized the mechanisms of HNE-mediated cytotoxicity in cardiomyocytes. After establishing that pathophysiological doses of HNE trigger cell death dependent on the incubation time and dose of HNE (LD50 = 4.4 μM), we tackled the mechanisms that underlie the cell death induced by HNE. Our results indicate that HNE rapidly increases intracellular Ca(2+); it also increases the rate of reactive oxygen species generation and causes a loss of mitochondrial membrane potential (ΔΨm) as well as a decrease in the ATP and GSH levels. Such alterations result in the activation of caspase-3 and DNA breakdown, both characteristic features of apoptotic cell death, as well as disruption of the cytoskeleton. Moreover, the nucleophilic compounds N-acetyl-cysteine and β-mercapto-propionyl-glycine, and the synthetic antioxidant Trolox exert a potent antioxidant action against HNE damage; this suggests its use as effective compounds in order to reduce the damage occurred as consequence of cardiovascular disorders in which oxidative stress and hence LP take place.}, }
@article {pmid24614837, year = {2014}, author = {Moslehi, A and Taghizadeh-Ghehi, M and Gholami, K and Hadjibabaie, M and Jahangard-Rafsanjani, Z and Sarayani, A and Javadi, M and Esfandbod, M and Ghavamzadeh, A}, title = {N-acetyl cysteine for prevention of oral mucositis in hematopoietic SCT: a double-blind, randomized, placebo-controlled trial.}, journal = {Bone marrow transplantation}, volume = {49}, number = {6}, pages = {818-823}, pmid = {24614837}, issn = {1476-5365}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Allografts ; Antioxidants/adverse effects/therapeutic use ; Double-Blind Method ; Female ; Glutathione Peroxidase/blood ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Male ; Middle Aged ; Stomatitis/etiology/*prevention &amp; control ; Young Adult ; Glutathione Peroxidase GPX1 ; }, abstract = {Oral mucositis (OM) is a complication of high-dose chemotherapy (HDC) which is frequently observed in hematopoietic SCT settings. Antioxidant agents have been proposed to prevent OM and therefore N-acetyl cysteine (NAC) could have an important role. In the present study, we conducted a double-blind, randomized, placebo-controlled study to evaluate the NAC effect on OM incidence and severity, and also glutathione peroxidase-1 activity. Leukemia patients undergoing allogeneic hematopoietic SCT preceded by HDC were recruited into the study and received either NAC (100 mg/kg/day) (n=38) or placebo (n=42) from the starting day of HDC until day +15 after transplantation. OM was evaluated daily for 21 days after transplantation according to World Health Organization oral toxicity scale. The incidence of severe OM (grades 3-4) was significantly lower in the NAC group (23.7% vs 45.3%, P=0.04). Moreover, the mean duration of OM was significantly shorter in the intervention group (6.24(2.96) vs 8.12(3.97) days, P=0.02). The glutathione peroxidase-1 activity was also significantly higher in the NAC group seven days after transplantation (3.38(2.19) vs 2.41(1.70) ng/mL, P=0.003). It is concluded that parenteral NAC is effective in reducing the incidence of severe cases and the total duration of OM.}, }
@article {pmid24614525, year = {2014}, author = {Roy, R and Singh, SK and Chauhan, LK and Das, M and Tripathi, A and Dwivedi, PD}, title = {Zinc oxide nanoparticles induce apoptosis by enhancement of autophagy via PI3K/Akt/mTOR inhibition.}, journal = {Toxicology letters}, volume = {227}, number = {1}, pages = {29-40}, doi = {10.1016/j.toxlet.2014.02.024}, pmid = {24614525}, issn = {1879-3169}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cells, Cultured ; Female ; Gene Silencing ; Macrophages, Peritoneal/cytology/*drug effects/metabolism ; Metal Nanoparticles/chemistry/*toxicity/ultrastructure ; Mice ; Mice, Inbred BALB C ; Microscopy, Electron, Transmission ; Microtubule-Associated Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Oxidative Stress/drug effects ; Particle Size ; Phosphatidylinositol 3-Kinases/metabolism ; *Phosphoinositide-3 Kinase Inhibitors ; RNA, Small Interfering ; Reactive Oxygen Species ; Signal Transduction/*drug effects ; Surface Properties ; Zinc Oxide/antagonists &amp; inhibitors/chemistry/*toxicity ; }, abstract = {Zinc oxide nanoparticles (ZnO NPs) induced macrophage cell death and its mechanism remains to be solved. Herein, we report that ZnO NPs induced ROS generation by depleting antioxidant enzymes, increasing lipid peroxidation and protein carbonyl contents in macrophages. The oxidative stress was induced by the inhibition of Nrf2 transcription factor release. ZnO NPs also activated the cleavage of apoptosis markers like caspases 3, 8 and 9. γH2Ax activation and cleavage of poly (ADP-ribose) polymerase (PARP) that are known indicators of genotoxicity were found to be activated by following p53, p21/waf1 signaling. ZnO NPs increased the number of autophagosomes and autophagy marker proteins such as microtubule-associated protein 1 light chain 3-isoform II (MAP-LC3-II) and Beclin 1 after 0.5-24h of treatment. Phosphorylated Akt, PI3K and mTOR were significantly decreased on ZnO NPs exposure. Moreover, the apoptotic and autophagic cell death could be inhibited on blocking of ROS generation by N-acetylcysteine (NAC) which demonstrated the critical role of ROS in both types of cell death. In addition, inhibition of LC3-II by siRNA-dependent knockdown attenuated the cleavage of caspase 3. This study demonstrates autophagy supports apoptosis on ZnO NPs exposure.}, }
@article {pmid24613870, year = {2014}, author = {Mallebrera, B and Font, G and Ruiz, MJ}, title = {Disturbance of antioxidant capacity produced by beauvericin in CHO-K1 cells.}, journal = {Toxicology letters}, volume = {226}, number = {3}, pages = {337-342}, doi = {10.1016/j.toxlet.2014.02.023}, pmid = {24613870}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*metabolism ; CHO Cells ; Cell Proliferation/drug effects ; Cricetulus ; Depsipeptides/*toxicity ; Glutathione/analysis ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; }, abstract = {Glutathione (GSH) levels, glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) as antioxidant defense system were evaluated in CHO-K1 cells after beauvericin (BEA) exposure. The effect of N-acetyl-cysteine (NAC) pre-treatment was assessed. GSH levels significantly decrease 18% and 29% after 5 μM of BEA in fresh medium and NAC pre-treatment, respectively compared to their controls. The GPx activity increased significantly from 35% to 66% in fresh medium and 20% in NAC pre-treatment. GR activity decreased after 5 μM of BEA up to 43% and 53% in fresh medium and NAC pre-treatment, respectively. The GST activity increased in fresh medium (from 61% to 89%) and decreased (from 22% to 35%) after NAC pre-treatment. Comparing BEA exposure in fresh medium and NAC pre-treatment, GSH levels, GPx activity and GST activity increased 716%, 458% and 206%, respectively respect to fresh medium; conversely no changes were observed in GR activity. In addition, NAC is an effective scavenger of BEA. GSH and related enzymes play an antioxidant role in the defense system of CHO-K1 cells exposed to BEA.}, }
@article {pmid24613855, year = {2014}, author = {Sachdeva, S and Flora, SJS}, title = {Efficacy of some antioxidants supplementation in reducing oxidative stress post sodium tungstate exposure in male wistar rats.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {28}, number = {2}, pages = {233-239}, doi = {10.1016/j.jtemb.2014.01.004}, pmid = {24613855}, issn = {1878-3252}, mesh = {Animals ; Antioxidants/*pharmacology ; Body Weight/drug effects ; *Dietary Supplements ; Liver/drug effects/pathology ; Male ; Oxidative Stress/*drug effects ; Porphobilinogen Synthase/blood ; Rats, Wistar ; Spleen/drug effects/pathology ; Tungsten Compounds/*toxicity ; }, abstract = {This study aimed to evaluate the protective efficacy of some antioxidants against sodium tungstate induced oxidative stress in male wistar rats. Animals were sub-chronically exposed to sodium tungstate (100ppm in drinking water) for three months except for control group. In the same time, many rats were supplemented orally with different antioxidants (alpha-lipoic acid (ALA), n-acetylcysteine (NAC), quercetin or naringenin (0.30mM)) for five consecutive days a week for the same mentioned period before. Exposure to sodium tungstate significantly (P<0.05) inhibit blood δ-aminolevulinic acid dehydratase (ALAD) activity, liver and blood reduced glutathione (GSH) levels and an increase in oxidized glutathione (GSSG) and thiobarbituric acid reactive species (TBARS) levels in tissues. ALA acid and NAC supplementation post sodium tungstate exposure increased GSH and also, was beneficial in the recovery of altered superoxide dismutase and catalase activity, besides, significantly reducing blood and tissue reactive oxygen species and TBARS levels. The results suggest a more pronounced efficacy of ALA acid and NAC supplementation than quercetin or naringenin supplementation post sodium tungstate exposure in preventing induced oxidative stress in rats.}, }
@article {pmid24613240, year = {2014}, author = {Frankowska, M and Jastrzębska, J and Nowak, E and Białko, M and Przegaliński, E and Filip, M}, title = {The effects of N-acetylcysteine on cocaine reward and seeking behaviors in a rat model of depression.}, journal = {Behavioural brain research}, volume = {266}, number = {}, pages = {108-118}, doi = {10.1016/j.bbr.2014.02.044}, pmid = {24613240}, issn = {1872-7549}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Cocaine/*administration &amp; dosage ; Conditioning, Operant/drug effects ; Depression/*drug therapy/physiopathology/psychology ; Disease Models, Animal ; Dopamine Uptake Inhibitors/*administration &amp; dosage ; Drug-Seeking Behavior/*drug effects ; Extinction, Psychological/drug effects ; Free Radical Scavengers/pharmacology/*therapeutic use ; Male ; Motor Activity/drug effects ; Olfactory Bulb/surgery ; Rats ; Rats, Wistar ; *Reward ; Self Administration ; }, abstract = {Depression and substance-abuse (e.g., cocaine) disorders are common concurrent diagnoses. In the present study, we combined bilateral olfactory bulbectomy (OBX) with a variety of procedures of intravenous cocaine self-administration and extinction/reinstatement in rats. We also investigated the effects of N-acetylcysteine (NAC) on rewarding and seeking behaviors for cocaine in OBX rats and compared the drug's effects in sham-operated control animals (SHAM). The occurrence of depressive symptoms before introduction to cocaine self-administration enhanced subsequent cocaine-seeking behaviors but did not significantly influence cocaine's rewarding properties or extinction training. NAC (25-100mg/kg) given acutely or repeatedly did not alter the co-occurrence of cocaine reward and depression but effectively reduced the cocaine-seeking behavior observed in both phenotypes. Our results indicate that depression behavior is linked to more pronounced drug craving and a higher propensity to relapse in rats. We also show the lack of efficacy of repeated NAC treatment on SHAM or OBX animals in terms of cocaine self-administration, while the drug was an effective blocker of cocaine-seeking behavior in both studied phenotypes, with a more pronounced drug effect observed in OBX animals. The last finding demonstrates the potential clinical utility of NAC to reduce cocaine seeking enhanced by co-existing depression.}, }
@article {pmid24613086, year = {2014}, author = {Wang, S and Hannafon, BN and Wolf, RF and Zhou, J and Avery, JE and Wu, J and Lind, SE and Ding, WQ}, title = {Characterization of docosahexaenoic acid (DHA)-induced heme oxygenase-1 (HO-1) expression in human cancer cells: the importance of enhanced BTB and CNC homology 1 (Bach1) degradation.}, journal = {The Journal of nutritional biochemistry}, volume = {25}, number = {5}, pages = {515-525}, pmid = {24613086}, issn = {1873-4847}, support = {P20 RR016478/RR/NCRR NIH HHS/United States ; U54 GM104938/GM/NIGMS NIH HHS/United States ; 3P20RR016478-09S2/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Antioxidant Response Elements/drug effects ; Basic-Leucine Zipper Transcription Factors/*metabolism ; Cell Line, Tumor/drug effects ; Docosahexaenoic Acids/*pharmacology ; Fanconi Anemia Complementation Group Proteins/*metabolism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Heme Oxygenase-1/genetics/*metabolism ; Humans ; Lipid Peroxidation/drug effects ; Mice, Nude ; NF-E2-Related Factor 2/genetics/metabolism ; Promoter Regions, Genetic/drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {The effect of docosahexaenoic acid (DHA) on heme oxygenase-1 (HO-1) expression in cancer cells has never been characterized. This study examines DHA-induced HO-1 expression in human cancer cell model systems. DHA enhanced HO-1 gene expression in a time- and concentration-dependent manner, with maximal induction at 21 h of treatment. This induction of HO-1 expression was confirmed in vivo using a xenograft nude mouse model fed a fish-oil-enriched diet. The increase in HO-1 gene transcription induced by DHA was significantly attenuated by the antioxidant N-acetyl cysteine, suggesting the involvement of oxidative stress. This was supported by direct measurement of lipid peroxide levels after DHA treatment. Using a human HO-1 gene promoter reporter construct, we identified two antioxidant response elements (AREs) that mediate the DHA-induced increase in HO-1 gene transcription. Knockdown of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression compromised the DHA-induced increase in HO-1 gene transcription, indicating the importance of the Nrf2 pathway in this event. However, the nuclear protein levels of Nrf2 remained unchanged upon DHA treatment. Further studies demonstrated that DHA reduces nuclear Bach1 protein expression by promoting its degradation and attenuates Bach1 binding to the AREs in the HO-1 gene promoter. In contrast, DHA enhanced Nrf2 binding to the AREs without affecting nuclear Nrf2 expression levels, indicating a new cellular mechanism that mediates DHA's induction of HO-1 gene transcription. To our knowledge, this is the first characterization of DHA-induced HO-1 expression in human malignant cells.}, }
@article {pmid24612076, year = {2015}, author = {Reissner, KJ and Gipson, CD and Tran, PK and Knackstedt, LA and Scofield, MD and Kalivas, PW}, title = {Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement.}, journal = {Addiction biology}, volume = {20}, number = {2}, pages = {316-323}, pmid = {24612076}, issn = {1369-1600}, support = {F32 DA026254/DA/NIDA NIH HHS/United States ; K99-DA026254/DA/NIDA NIH HHS/United States ; R01 DA033436/DA/NIDA NIH HHS/United States ; P50 DA015369/DA/NIDA NIH HHS/United States ; K99 DA031790/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; R37 DA003906/DA/NIDA NIH HHS/United States ; T32 DA007288/DA/NIDA NIH HHS/United States ; R01-DA015369/DA/NIDA NIH HHS/United States ; DA003906/DA/NIDA NIH HHS/United States ; R00 DA031790/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Amino Acid Transport Systems, Acidic/*drug effects/metabolism ; Animals ; Cocaine/*administration &amp; dosage ; Cocaine-Related Disorders/*metabolism ; Dopamine Uptake Inhibitors/*administration &amp; dosage ; Drug-Seeking Behavior/*drug effects ; Excitatory Amino Acid Transporter 2/*drug effects/metabolism ; Free Radical Scavengers/*pharmacology ; *Inhibition, Psychological ; Rats ; *Reinforcement, Psychology ; Self Administration ; }, abstract = {Both pre-clinical and clinical studies indicate that N-acetylcysteine (NAC) may be useful in treating relapse to addictive drug use. Cocaine self-administration in rats reduces both cystine-glutamate exchange and glutamate transport via GLT-1 in the nucleus accumbens, and NAC treatment normalizes these two glial processes critical for maintaining glutamate homeostasis. However, it is not known if one or both of these actions by NAC is needed to inhibit relapse to cocaine seeking. To determine whether the restoration of GLT-1 and/or cystine-glutamate exchange is required for NAC to inhibit cue-induced reinstatement of cocaine seeking, we utilized the rat self-administration/extinction/reinstatement model of cocaine relapse. Rats were pre-treated in the nucleus accumbens with vivo-morpholino antisense oligomers targeting either GLT-1 or xCT (catalytic subunit of the cystine-glutamate exchanger) overlapping with daily NAC administration during extinction (100 mg/kg, i.p. for the last 5 days). Rats then underwent cue-induced reinstatement of active lever pressing in the absence of NAC, to determine if preventing NAC-induced restoration of one or the other protein was sufficient to block the capacity of chronic NAC to inhibit reinstatement. The vivo-morpholino suppression of xCT reduced cystine-glutamate exchange but did not affect NAC-induced reduction of reinstated cocaine seeking. In contrast, suppressing NAC-induced restoration of GLT-1 not only prevented NAC from inhibiting reinstatement, but augmented the capacity of cues to reinstate cocaine seeking. We hypothesized that the increased reinstatement after inhibiting NAC induction of GLT-1 resulted from increased extracellular glutamate, and show that augmented reinstatement is prevented by blocking mGluR5. Restoring GLT-1, not cystine-glutamate exchange, is a key mechanism whereby daily NAC reduces cue-induced cocaine reinstatement.}, }
@article {pmid24612036, year = {2014}, author = {Gamba, P and Guglielmotto, M and Testa, G and Monteleone, D and Zerbinati, C and Gargiulo, S and Biasi, F and Iuliano, L and Giaccone, G and Mauro, A and Poli, G and Tamagno, E and Leonarduzzi, G}, title = {Up-regulation of β-amyloidogenesis in neuron-like human cells by both 24- and 27-hydroxycholesterol: protective effect of N-acetyl-cysteine.}, journal = {Aging cell}, volume = {13}, number = {3}, pages = {561-572}, pmid = {24612036}, issn = {1474-9726}, mesh = {Acetylcysteine/*metabolism/*pharmacology ; Alzheimer Disease/*metabolism ; Amyloid beta-Peptides/*metabolism ; Cell Line, Tumor ; Disease Progression ; Humans ; Hydroxycholesterols/metabolism/*pharmacology ; Neurons/*drug effects/metabolism ; Oxidative Stress ; Up-Regulation/drug effects ; }, abstract = {An abnormal accumulation of cholesterol oxidation products in the brain of patients with Alzheimer's disease (AD) would further link an impaired cholesterol metabolism in the pathogenesis of the disease. The first evidence stemming from the content of oxysterols in autopsy samples from AD and normal brains points to an increase in both 27-hydroxycholesterol (27-OH) and 24-hydroxycholesterol (24-OH) in the frontal cortex of AD brains, with a trend that appears related to the disease severity. The challenge of differentiated SK-N-BE human neuroblastoma cells with patho-physiologically relevant amounts of 27-OH and 24-OH showed that both oxysterols induce a net synthesis of Aβ1-42 by up-regulating expression levels of amyloid precursor protein and β-secretase, as well as the β-secretase activity. Interestingly, cell pretreatment with N-acetyl-cysteine (NAC) fully prevented the enhancement of β-amyloidogenesis induced by the two oxysterols. The reported findings link an impaired cholesterol oxidative metabolism to an excessive β-amyloidogenesis and point to NAC as an efficient inhibitor of oxysterols-induced Aβ toxic peptide accumulation in the brain.}, }
@article {pmid24607408, year = {2014}, author = {Liu, FL and Hsu, JL and Lee, YJ and Dong, YS and Kung, FL and Chen, CS and Guh, JH}, title = {Calanquinone A induces anti-glioblastoma activity through glutathione-involved DNA damage and AMPK activation.}, journal = {European journal of pharmacology}, volume = {730}, number = {}, pages = {90-101}, pmid = {24607408}, issn = {1879-0712}, support = {P30 CA016058/CA/NCI NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases/*metabolism ; Antineoplastic Agents/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; *DNA Damage ; Enzyme Activation/drug effects ; Glioblastoma/*pathology ; Glutathione/*metabolism ; Humans ; Intracellular Space/drug effects/metabolism ; Quinones/*pharmacology ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; S Phase Cell Cycle Checkpoints/drug effects ; }, abstract = {Glioblastoma, a highly malignant glioma, is resistant to both radiation and chemotherapy and is an intractable problem in clinical treatment. New therapeutic approaches are in urgent need. Calanquinone A, an herbal constituent, displayed anti-proliferative activity against glioblastoma cells, including A172, T98 and U87. Flow cytometric analysis showed an S phase arrest and a subsequent apoptosis to calanquinone A action. Further identification demonstrated a rapid increase of γH2A.X formation at S phase. The data together with comet tail formation and Chk1 activation indicated DNA damage response. N-acetyl cysteine (an antioxidant and a glutathione precursor) and exogenously applied glutathione, but not trolox (an antioxidant), completely abolished calanquinone A-induced effects. Immunofluorescence assay revealed that calanquinone A decreased the intracellular glutathione levels in both A172 and T98 cells. However, calanquinone A, by itself, did not conjugate glutathione. The data suggested that the decrease of cellular glutathione predominantly contributed to the anticancer mechanism. Furthermore, calanquinone A induced the activation of AMP-activated protein kinase (AMPK) and the inhibition of p70S6K activity. Rhodamine efflux assay showed that calanquinone A did not block efflux activity, indicating that calanquinone A was not a P-glycoprotein substrate. In summary, the data suggest that calanquinone A displays anti-glioblastoma activity through a decrease of cellular glutathione levels that subsequently induces DNA damage stress and AMPK activation, leading to cell cycle arrest at S-phase and apoptotic cell death. Furthermore, calanquinone A does not serve as a P-glycoprotein substrate, suggesting a potential for further development in anti-glioblastoma therapy.}, }
@article {pmid24606795, year = {2014}, author = {Valero, T}, title = {Mitochondrial biogenesis: pharmacological approaches.}, journal = {Current pharmaceutical design}, volume = {20}, number = {35}, pages = {5507-5509}, doi = {10.2174/138161282035140911142118}, pmid = {24606795}, issn = {1873-4286}, mesh = {Animals ; DNA, Mitochondrial/metabolism ; Humans ; Metformin/pharmacology/therapeutic use ; Mitochondria/*drug effects/*metabolism ; Mitochondrial Diseases/*drug therapy/*metabolism ; Resveratrol ; Stilbenes/pharmacology/therapeutic use ; }, abstract = {Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber's hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh's syndrome. Likewise, other diseases in which mitochondrial dysfunction plays a very important role include neurodegenerative diseases, diabetes or cancer. Generally, in mitochondrial diseases a mutation in the mitochondrial DNA leads to a loss of functionality of the OXPHOS system and thus to a depletion of ATP and overproduction of ROS, which can, in turn, induce further mtDNA mutations. The work by Yu-Ting Wu, Shi-Bei Wu, and Yau-Huei Wei (Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taiwan) [4] focuses on the aforementioned mitochondrial diseases with special attention to the compensatory mechanisms that prompt mitochondria to produce more energy even under mitochondrial defect-conditions. These compensatory mechanisms include the overexpression of antioxidant enzymes, mitochondrial biogenesis and overexpression of respiratory complex subunits, as well as metabolic shift to glycolysis. The pathways observed to be related to mitochondrial biogenesis as a compensatory adaptation to the energetic deficits in mitochondrial diseases are described (PGC- 1, Sirtuins, AMPK). Several pharmacological strategies to trigger these signaling cascades, according to these authors, are the use of bezafibrate to activate the PPAR-PGC-1α axis, the activation of AMPK by resveratrol and the use of Sirt1 agonists such as quercetin or resveratrol. Other strategies currently used include the addition of antioxidant supplements to the diet (dietary supplementation with antioxidants) such as L-carnitine, coenzyme Q10,MitoQ10 and other mitochondria-targeted antioxidants,N-acetylcysteine (NAC), vitamin C, vitamin E vitamin K1, vitamin B, sodium pyruvate or -lipoic acid. As aforementioned, other diseases do not have exclusively a mitochondrial origin but they might have an important mitochondrial component both on their onset and on their development. This is the case of type 2 diabetes or neurodegenerative diseases. Type 2 diabetes is characterized by a peripheral insulin resistance accompanied by an increased secretion of insulin as a compensatory system. Among the explanations about the origin of insulin resistance Mónica Zamora and Josep A. Villena (Department of Experimental and Health Sciences, Universitat Pompeu Fabra / Laboratory of Metabolism and Obesity, Universitat Autònoma de Barcelona, Spain) [5] consider the hypothesis that mitochondrial dysfunction, e.g. impaired (mitochondrial) oxidative capacity of the cell or tissue, is one of the main underlying causes of insulin resistance and type 2 diabetes. Although this hypothesis is not free of controversy due to the uncertainty on the sequence of events during type 2 diabetes onset, e.g. whether mitochondrial dysfunction is the cause or the consequence of insulin resistance, it has been widely observed that improving mitochondrial function also improves insulin sensitivity and prevents type 2 diabetes. Thus restoring oxidative capacity by increasing mitochondrial mass appears as a suitable strategy to treat insulin resistance. The effort made by researchers trying to understand the signaling pathways mediating mitochondrial biogenesis has uncovered new potential pharmacological targets and opens the perspectives for the design of suitable treatments for insulin resistance. In addition some of the current used strategies could be used to treat insulin resistance such as lifestyle interventions (caloric restriction and endurance exercise) and pharmacological interventions (thiazolidinediones and other PPAR agonists, resveratrol and other calorie restriction mimetics, AMPK activators, ERR activators). Mitochondrial biogenesis is of special importance in modern neurochemistry because of the broad spectrum of human diseases arising from defects in mitochondrial ion and ROS homeostasis, energy production and morphology [1]. Parkinson´s Disease (PD) is a very good example of this important mitochondrial component on neurodegenerative diseases. Anuradha Yadav, Swati Agrawal, Shashi Kant Tiwari, and Rajnish K. Chaturvedi (CSIR-Indian Institute of Toxicology Research / Academy of Scientific and Innovative Research, India) [6] remark in their review the role of mitochondrial dysfunction in PD with special focus on the role of oxidative stress and bioenergetic deficits. These alterations may have their origin on pathogenic gene mutations in important genes such as DJ-1, -syn, parkin, PINK1 or LRRK2. These mutations, in turn, may cause defects in mitochondrial dynamics (key events like fission/fusion, biogenesis, trafficking in retrograde and anterograde directions, and mitophagy). This work reviews different strategies to enhance mitochondrial bioenergetics in order to ameliorate the neurodegenerative process, with an emphasis on clinical trials reports that indicate their potential. Among them creatine, Coenzyme Q10 and mitochondrial targeted antioxidants/peptides are reported to have the most remarkable effects in clinical trials. They highlight a dual effect of PGC-1α expression on PD prognosis. Whereas a modest expression of this transcriptional co-activator results in positive effects, a moderate to substantial overexpession may have deleterious consequences. As strategies to induce PGC-1α activation, these authors remark the possibility to activate Sirt1 with resveratrol, to use PPAR agonists such as pioglitazone, rosiglitazone, fenofibrate and bezafibrate. Other strategies include the triggering of Nrf2/antioxidant response element (ARE) pathway by triterpenoids (derivatives of oleanolic acid) or by Bacopa monniera, the enhancement of ATP production by carnitine and -lipoic acid. Mitochondrial dysfunctions are the prime source of neurodegenerative diseases and neurodevelopmental disorders. In the context of neural differentiation, Martine Uittenbogaard and Anne Chiaramello (Department of Anatomy and Regenerative Biology, George Washington University School of Medicine and Health Sciences, USA) [7] thoroughly describe the implication of mitochondrial biogenesis on neuronal differentiation, its timing, its regulation by specific signaling pathways and new potential therapeutic strategies. The maintenance of mitochondrial homeostasis is crucial for neuronal development. A mitochondrial dynamic balance is necessary between mitochondrial fusion, fission and quality control systems and mitochondrial biogenesis. Concerning the signaling pathways leading to mitochondrial biogenesis this review highlights the implication of different regulators such as AMPK, SIRT1, PGC-1α, NRF1, NRF2, Tfam, etc. on the specific case of neuronal development, providing examples of diseases in which these pathways are altered and transgenic mouse models lacking these regulators. A common hallmark of several neurodegenerative diseases (Huntington´s Disease, Alzheimer´s Disease and Parkinson´s Disease) is the impaired function or expression of PGC-1α, the master regulator of mitochondrial biogenesis. Among the promising strategies to ameliorate mitochondrial-based diseases these authors highlight the induction of PGC-1α via activation of PPAR receptors (rosiglitazone, bezafibrate) or modulating its activity by AMPK (AICAR, metformin, resveratrol) or SIRT1 (SRT1720 and several isoflavone-derived compounds). This article also presents a review of the current animal and cellular models useful to study mitochondriogenesis. Although it is known that many neurodegenerative and neurodevelopmental diseases are originated in mitochondria, the regulation of mitochondrial biogenesis has never been extensively studied. (ABSTRACT TRUNCATED)}, }
@article {pmid24604666, year = {2014}, author = {Posa, JK and Selvaraj, S and Sangeetha, KN and Baskaran, SK and Lakshmi, BS}, title = {p53 mediates impaired insulin signaling in 3T3-L1 adipocytes during hyperinsulinemia.}, journal = {Cell biology international}, volume = {38}, number = {7}, pages = {818-824}, doi = {10.1002/cbin.10275}, pmid = {24604666}, issn = {1095-8355}, mesh = {3T3-L1 Cells ; Acetylcysteine/pharmacology ; Adipocytes/cytology/metabolism ; Animals ; Cell Differentiation/drug effects ; Free Radical Scavengers/pharmacology ; Glucose/metabolism ; Hyperinsulinism/metabolism/pathology ; Insulin/*metabolism ; Insulin Resistance ; Mice ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/genetics/*metabolism ; }, abstract = {Hyperinsulinemia is being implicated in the development of insulin resistance but remains poorly understood. The present study focuses on p53-mediated impaired insulin signaling by hyperinsulinemia in 3T3-L1 adipocytes. Hyperinsulinemia impairs insulin-stimulated glucose uptake and its cellular signaling in a dose- and time-dependent manner. An increased level of reactive oxygen species (ROS) and stress response signals were observed, and quenching of the ROS by an antioxidant N-acetylcysteine (NAC) did not revert impaired insulin sensitivity. The tumor suppressor p53 has emerged as a crucial factor in the metabolic adaptation of cancer cells under nutritional starvation and is being studied in the development of insulin resistance in adipocytes at physiological level. Interestingly, we observed hyperinsulinemia-enhanced p53 level in a time-dependent manner without exhibiting cytotoxicity. Transient knockdown of p53 partially improved insulin sensitivity revealing a novel link between p53 and insulin signaling in adipocytes. The findings suggest that hyperinsulinemia-induced p53 impairs insulin sensitivity in 3T3-L1 adipocytes.}, }
@article {pmid24593692, year = {2014}, author = {Nocchi, L and Daly, DM and Chapple, C and Grundy, D}, title = {Induction of oxidative stress causes functional alterations in mouse urothelium via a TRPM8-mediated mechanism: implications for aging.}, journal = {Aging cell}, volume = {13}, number = {3}, pages = {540-550}, pmid = {24593692}, issn = {1474-9726}, support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Aging/*physiology ; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; TRPM Cation Channels/*metabolism ; Up-Regulation ; Urothelium/cytology/metabolism/pathology/*physiology ; }, abstract = {The incidence of bladder conditions such as overactive bladder syndrome and its associated urinary incontinence is highly prevalent in the elderly. However, the mechanisms underlying these disorders are unclear. Studies suggest that the urothelium forms a 'sensory network' with the underlying innervation, alterations in which, could compromise bladder function. As the accumulation of reactive oxygen species can cause functional alterations with age, the aim of this study was to investigate whether oxidative stress alters urothelial sensory signalling and whether the mechanism underlying the effect of oxidative stress on the urothelium plays a role in aging. Five-month-old(young) and 24-month-old (aged) mice were used. H2O2 , used to induce oxidative stress, resulted in an increase in bladder afferent nerve activity and urothelial intracellular calcium in preparations from young mice. These functional changes were concurrent with upregulation of TRPM8 in the urothelium. Moreover, application of a TRPM8 antagonist significantly attenuated the H2O2 -induced calcium responses. Interestingly, an upregulation of TRPM8 was also found in the urothelium from aged mice, where high oxidative stress levels were observed, together with a greater calcium response to the TRPM8 agonist WS12. Furthermore, these calcium responses were attenuated by pretreatment with the antioxidant N-acetyl-cysteine. This study shows that oxidative stress affects urothelial function involving a TRPM8-mediated mechanism and these effects may have important implications for aging. These data provide an insight into the possible mechanisms by which oxidative stress causes physiological alterations in the bladder, which may also occur in other organs susceptible to aging.}, }
@article {pmid24592864, year = {2014}, author = {Xu, C and Zhou, R and He, W and Wu, L and Wu, P and Hou, X}, title = {Fast imaging of eccrine latent fingerprints with nontoxic Mn-doped ZnS QDs.}, journal = {Analytical chemistry}, volume = {86}, number = {7}, pages = {3279-3283}, doi = {10.1021/ac404244v}, pmid = {24592864}, issn = {1520-6882}, mesh = {*Dermatoglyphics ; Eccrine Glands/*metabolism ; Humans ; Manganese/*chemistry ; *Quantum Dots ; Sulfides/*chemistry ; Zinc Compounds/*chemistry ; }, abstract = {Fingerprints are unique characteristics of an individual, and their imaging and recognition is a top-priority task in forensic science. Fast LFP (latent fingerprint) acquirement can greatly help policemen in screening the potential criminal scenes and capturing fingerprint clues. Of the two major latent fingerprints (LFP), eccrine is expected to be more representative than sebaceous in LFP identification. Here we explored the heavy metal-free Mn-doped ZnS quantum dots (QDs) as a new imaging moiety for eccrine LFPs. To study the effects of different ligands on the LFP image quality, we prepared Mn-doped ZnS QDs with various surface-capping ligands using QDs synthesized in high-temperature organic media as starting material. The orange fluorescence emission from Mn-doped ZnS QDs clearly revealed the optical images of eccrine LFPs. Interestingly, N-acetyl-cysteine-capped Mn-doped ZnS QDs could stain the eccrine LFPs in as fast as 5 s. Meanwhile, the levels 2 and 3 substructures of the fingerprints could also be simultaneously and clearly identified. While in the absence of QDs or without rubbing and stamping the finger onto foil, no fluorescent fingerprint images could be visualized. Besides fresh fingerprint, aged (5, 10, and 50 days), incomplete eccrine LFPs could also be successfully stained with N-acetyl-cysteine-capped Mn-doped ZnS QDs, demonstrating the analytical potential of this method in real world applications. The method was also robust for imaging of eccrine LFPs on a series of nonporous surfaces, such as aluminum foil, compact discs, glass, and black plastic bags.}, }
@article {pmid24588654, year = {2014}, author = {Wu, Z and Uchi, H and Morino-Koga, S and Nakamura-Satomura, A and Kita, K and Shi, W and Furue, M}, title = {Z-Ligustilide inhibits benzo(a)pyrene-induced CYP1A1 upregulation in cultured human keratinocytes via ROS-dependent Nrf2 activation.}, journal = {Experimental dermatology}, volume = {23}, number = {4}, pages = {260-265}, doi = {10.1111/exd.12360}, pmid = {24588654}, issn = {1600-0625}, mesh = {4-Butyrolactone/*analogs &amp; derivatives/pharmacology/therapeutic use ; Angelica ; Benzo(a)pyrene/toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Cnidium ; Cytochrome P-450 CYP1A1/*metabolism ; Dermatitis/etiology/*prevention &amp; control ; Drug Evaluation, Preclinical ; Environmental Pollutants/toxicity ; Humans ; Keratinocytes/*drug effects/metabolism ; NF-E2-Related Factor 2/*metabolism ; Phytotherapy ; Plant Extracts/therapeutic use ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/metabolism ; Up-Regulation/drug effects ; }, abstract = {UNLABELLED: Benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is an environmental contaminant that can induce cytochrome P4501A1 (CYP1A1) upregulation via aryl hydrocarbon receptor (AhR) activation and provoke inflammation. Here, we investigated the effect of Z-Ligustilide, an active ingredient isolated from the medicinal plants Cnidium officinale and Angelica acutiloba, on BaP-induced CYP1A1 upregulation in normal human epidermal keratinocytes (NHEKs) as well as its underlying mechanisms. Z-Ligustilide significantly inhibited BaP-induced CYP1A1 upregulation in NHEKs. Treatment of NHEKs with Z-Ligustilide induced Nuclear factor-E2-related factor 2 (Nrf2) nuclear translocation and expression of the Nrf2-regulated genes for haeme oxygenase-1 (HO-1) and<br><br>NAD(P)H: quinine oxidoreductase-1 (NQO1). AhR silencing, SB203580 (a p38 inhibitor), SP600125 (a JNK inhibitor), U0126 (a MEK inhibitor) and LY294002 (a PI3K inhibitor) did not suppress Z-Ligustilide-induced Nrf2 activation. Moreover, treatment of NHEKs with Z-Ligustilide increased reactive oxygen species (ROS) and L-N-acetylcysteine (L-NAC, an antioxidant) attenuated Z-ligustilide-induced Nrf2 nuclear translocation and HO-1 expression. L-NAC or knock-down of Nrf2 significantly attenuated the inhibitory effects of Z-Ligustilide on BaP-induced CYP1A1 upregulation in NHEKs. Taken together, these findings suggest that Z-Ligustilide can suppress BaP-induced CYP1A1 upregulation through ROS-dependent Nrf2 pathway activation and may be beneficial in preventing or treating BaP-induced skin damage.}, }
@article {pmid24587987, year = {2014}, author = {Zhang, L and Zhou, L and Du, J and Li, M and Qian, C and Cheng, Y and Peng, Y and Xie, J and Wang, D}, title = {Induction of apoptosis in human multiple myeloma cell lines by ebselen via enhancing the endogenous reactive oxygen species production.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {696107}, pmid = {24587987}, issn = {2314-6141}, mesh = {Apoptosis/*drug effects ; Azoles/*administration &amp; dosage ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Isoindoles ; Membrane Potential, Mitochondrial/drug effects ; Multiple Myeloma/*genetics/metabolism/pathology ; Organoselenium Compounds/*administration &amp; dosage ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; bcl-2-Associated X Protein/biosynthesis ; }, abstract = {Ebselen a selenoorganic compound showing glutathione peroxidase like activity is an anti-inflammatory and antioxidative agent. Its cytoprotective activity has been investigated in recent years. However, experimental evidence also shows that ebselen causes cell death in several cancer cell types whose mechanism has not yet been elucidated. In this study, we examined the effect of ebselen on multiple myeloma (MM) cell lines in vitro. The results showed that ebselen significantly enhanced the production of reactive oxygen species (ROS) accompanied by cell viability decrease and apoptosis rate increase. Further studies revealed that ebselen can induce Bax redistribution from the cytosol to mitochondria leading to mitochondrial membrane potential ΔΨm changes and cytochrome C release from the mitochondria to cytosol. Furtherly, we found that exogenous addition of N-acetyl cysteine (NAC) completely diminished the cell damage induced by ebselen. This result suggests that relatively high concentration of ebselen can induce MM cells apoptosis in culture by enhancing the production of endogenous ROS and triggering mitochondria mediated apoptotic pathway.}, }
@article {pmid24587218, year = {2014}, author = {Monticone, M and Taherian, R and Stigliani, S and Carra, E and Monteghirfo, S and Longo, L and Daga, A and Dono, M and Zupo, S and Giaretti, W and Castagnola, P}, title = {NAC, tiron and trolox impair survival of cell cultures containing glioblastoma tumorigenic initiating cells by inhibition of cell cycle progression.}, journal = {PloS one}, volume = {9}, number = {2}, pages = {e90085}, pmid = {24587218}, issn = {1932-6203}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/*pharmacology ; Acetylcysteine/*pharmacology ; Astrocytes/cytology/drug effects/metabolism ; Cell Cycle/*drug effects/genetics ; Cell Cycle Proteins/*genetics/metabolism ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chromans/*pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/*drug effects ; Glioblastoma/genetics/metabolism/pathology ; Humans ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Tumor Cells, Cultured ; }, abstract = {Reactive oxygen species (ROS) are metabolism by-products that may act as signaling molecules to sustain tumor growth. Antioxidants have been used to impair cancer cell survival. Our goal was to determine the mechanisms involved in the response to antioxidants of a human cell culture (PT4) containing glioblastoma (GBM) tumorigenic initiating cells (TICs). ROS production in the absence or presence of N-acetyl-L-cysteine (NAC), tiron, and trolox was evaluated by flow cytometry (FCM). The effects of these antioxidants on cell survival and apoptosis were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) and FCM. The biological processes modulated by these drugs were determined by oligonucleotide microarray gene expression profiling. Our results showed that NAC, tiron and trolox impaired PT4 cell survival, had minor effects on ROS levels and caused wide deregulation of cell cycle genes. Furthermore, tiron and trolox caused inhibition of cell survival in two additional cell cultures containing TICs, FO-1 and MM1, established from a melanoma and a mesothelioma patient, respectively. NAC, instead, impaired survival of the MM1 cells but not of the FO-1 cells. However, when used in combination, NAC enhanced the inhibitory effect of PLX4032 (BRAF V600E inhibitor) and Gefitinib (EGFR inhibitor), on FO-1 and PT4 cell survival. Collectively, NAC, tiron and trolox modulated gene expression and impaired the growth of cultures containing TICs primarily by inhibiting cell cycle progression.}, }
@article {pmid24587053, year = {2014}, author = {Wan, C and Liu, J and Nie, X and Zhao, J and Zhou, S and Duan, Z and Tang, C and Liang, L and Xu, G}, title = {2, 3, 7, 8-Tetrachlorodibenzo-P-dioxin (TCDD) induces premature senescence in human and rodent neuronal cells via ROS-dependent mechanisms.}, journal = {PloS one}, volume = {9}, number = {2}, pages = {e89811}, pmid = {24587053}, issn = {1932-6203}, mesh = {Actins/metabolism ; Analysis of Variance ; Animals ; Biomarkers/metabolism ; Blotting, Western ; Cellular Senescence/*drug effects ; DNA Damage/drug effects ; DNA Primers/genetics ; Dose-Response Relationship, Drug ; Environmental Pollutants/metabolism/*toxicity ; Fluorescence ; Histones/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Nerve Tissue/cytology/*drug effects ; PC12 Cells ; Phosphoproteins/metabolism ; Polychlorinated Dibenzodioxins/metabolism/*toxicity ; Rats ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Time Factors ; beta-Galactosidase/metabolism ; }, abstract = {The widespread environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent toxicant that causes significant neurotoxicity. However, the biological events that participate in this process remain largely elusive. In the present study, we demonstrated that TCDD exposure triggered apparent premature senescence in rat pheochromocytoma (PC12) and human neuroblastoma SH-SY5Y cells. Senescence-associated β-galactosidase (SA-β-Gal) assay revealed that TCDD induced senescence in PC12 neuronal cells at doses as low as 10 nM. TCDD led to F-actin reorganization and the appearance of an alternative senescence marker, γ-H2AX foci, both of which are important features of cellular senescence. In addition, TCDD exposure altered the expression of senescence marker proteins, such as p16, p21 and p-Rb, in both dose- and time-dependent manners. Furthermore, we demonstrated that TCDD promotes mitochondrial dysfunction and the accumulation of cellular reactive oxygen species (ROS) in PC12 cells, leading to the activation of signaling pathways that are involved in ROS metabolism and senescence. TCDD-induced ROS generation promoted significant oxidative DNA damage and lipid peroxidation. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) markedly attenuated TCDD-induced ROS production, cellular oxidative damage and neuronal senescence. Moreover, we found that TCDD induced a similar ROS-mediated senescence response in human neuroblastoma SH-SY5Y cells. In sum, these results demonstrate for the first time that TCDD induces premature senescence in neuronal cells by promoting intracellular ROS production, supporting the idea that accelerating the onset of neuronal senescence may be an important mechanism underlying TCDD-induced neurotoxic effects.}, }
@article {pmid24586814, year = {2014}, author = {Chen, HM and Zhu, BZ and Chen, RJ and Wang, BJ and Wang, YJ}, title = {The pentachlorophenol metabolite tetrachlorohydroquinone induces massive ROS and prolonged p-ERK expression in splenocytes, leading to inhibition of apoptosis and necrotic cell death.}, journal = {PloS one}, volume = {9}, number = {2}, pages = {e89483}, pmid = {24586814}, issn = {1932-6203}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Death/*drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Flow Cytometry ; Hydroquinones/*pharmacology ; Male ; Mice ; Mice, Inbred ICR ; Necrosis ; Pentachlorophenol/*metabolism ; Reactive Oxygen Species/*metabolism ; Spleen/cytology/*drug effects/enzymology/metabolism ; }, abstract = {Pentachlorophenol (PCP) has been used extensively as a biocide and a wood preservative and has been reported to be immunosuppressive in rodents and humans. Tetrachlorohydroquinone (TCHQ) is a major metabolite of PCP. TCHQ has been identified as the main cause of PCP-induced genotoxicity due to reactive oxidant stress (ROS). However, the precise mechanisms associated with the immunotoxic effects of PCP and TCHQ remain unclear. The aim of this study was to examine the effects of PCP and TCHQ on the induction of ROS and injury to primary mouse splenocytes. Our results shown that TCHQ was more toxic than PCP and that a high dose of TCHQ led to necrotic cell death of the splenocytes through induction of massive and sudden ROS and prolonged ROS-triggered ERK activation. Inhibition of ROS production by N-acetyl-cysteine (NAC) partially restored the mitochondrial membrane potential, inhibited ERK activity, elevated caspase-3 activity and PARP cleavage, and, eventually, switched the TCHQ-induced necrosis to apoptosis. We suggest that prolonged ERK activation is essential for TCHQ-induced necrosis, and that ROS play a pivotal role in the different TCHQ-induced cell death mechanisms.}, }
@article {pmid24586617, year = {2014}, author = {Domenis, R and Bergamin, N and Gianfranceschi, G and Vascotto, C and Romanello, M and Rigo, S and Vagnarelli, G and Faggiani, M and Parodi, P and Kelley, MR and Beltrami, CA and Cesselli, D and Tell, G and Beltrami, AP}, title = {The redox function of APE1 is involved in the differentiation process of stem cells toward a neuronal cell fate.}, journal = {PloS one}, volume = {9}, number = {2}, pages = {e89232}, pmid = {24586617}, issn = {1932-6203}, support = {R01 CA167291/CA/NCI NIH HHS/United States ; CA121168/CA/NCI NIH HHS/United States ; CA167291/CA/NCI NIH HHS/United States ; }, mesh = {Adipose Tissue/*cytology ; Adult ; Adult Stem Cells/metabolism/*physiology ; Benzoquinones ; Blotting, Western ; Cell Differentiation/*physiology ; Chromatin/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/*metabolism ; Flow Cytometry ; Humans ; Microscopy, Fluorescence ; Multipotent Stem Cells/metabolism/*physiology ; NF-kappa B/metabolism ; Neurogenesis/*physiology ; Oxidation-Reduction ; Propionates ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Statistics, Nonparametric ; }, abstract = {UNLABELLED: Low-to-moderate levels of reactive oxygen species (ROS) govern different steps of neurogenesis via molecular pathways that have been decrypted only partially. Although it has been postulated that redox-sensitive molecules are involved in neuronal differentiation, the molecular bases for this process have not been elucidated yet. The aim of this work was therefore to study the role played by the redox-sensitive, multifunctional protein APE1/Ref-1 (APE1) in the differentiation process of human adipose tissue-derived multipotent adult stem cells (hAT-MASC) and embryonic carcinoma stem cells (EC) towards a neuronal phenotype.<br><br>METHODS AND RESULTS: Applying a definite protocol, hAT-MASC can adopt a neural fate. During this maturation process, differentiating cells significantly increase their intracellular Reactive Oxygen Species (ROS) levels and increase the APE1 nuclear fraction bound to chromatin. This latter event is paralleled by the increase of nuclear NF-&#x3ba;B, a transcription factor regulated by APE1 in a redox-dependent fashion. Importantly, the addition of the antioxidant N-acetyl cysteine (NAC) to the differentiation medium partially prevents the nuclear accumulation of APE1, increasing the neuronal differentiation of hAT-MASC. To investigate the involvement of APE1 in the differentiation process, we employed E3330, a specific inhibitor of the APE1 redox function. The addition of E3330, either to the neurogenic embryonic carcinoma cell line NT2-D1or to hAT-MASC, increases the differentiation of stem cells towards a neural phenotype, biasing the differentiation towards specific subtypes, such as dopaminergic cells. In conclusion, during the differentiation process of stem cells towards a neuroectodermic phenotype, APE1 is recruited, in a ROS-dependent manner, to the chromatin. This event is associated with an inhibitory effect of APE1 on neurogenesis that may be reversed by E3330. Therefore, E3330 may be employed both to boost neural differentiation and to bias the differentiation potential of stem cells towards specific neuronal subtypes. These findings provide a molecular basis for the redox-mediated hypothesis of neuronal differentiation program.}, }
@article {pmid24583398, year = {2014}, author = {Fontani, F and Marcucci, T and Picariello, L and Tonelli, F and Vincenzini, MT and Iantomasi, T}, title = {Redox regulation of MMP-3/TIMP-1 ratio in intestinal myofibroblasts: effect of N-acetylcysteine and curcumin.}, journal = {Experimental cell research}, volume = {323}, number = {1}, pages = {77-86}, doi = {10.1016/j.yexcr.2014.02.019}, pmid = {24583398}, issn = {1090-2422}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Colon/cytology/metabolism ; Crohn Disease/drug therapy/*enzymology ; Curcumin/*pharmacology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/biosynthesis ; Humans ; Hydrogen Peroxide/metabolism ; Intestinal Mucosa/drug effects/metabolism/pathology ; Matrix Metalloproteinase 3/biosynthesis/*metabolism ; Middle Aged ; Myofibroblasts/cytology/*metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Tissue Inhibitor of Metalloproteinase-1/biosynthesis/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation ; Young Adult ; }, abstract = {Matrix metalloproteinases (MMPs) play a critical role in inflammation and ulcerations in gut of Crohn׳s disease (CD) patients. Intestinal subepithelial myofibroblasts (ISEMFs) secrete MMPs in response to inflammatory stimuli. Previous data showed in CD-ISEMFs increased oxidative status. The aim of this study was to investigate the role of ISEMFs in modulating the production of MMP-3 and TIMP-1, an inhibitor of MMPs activity. A relationship among oxidative stress, activity of antioxidants and MMP-3/TIMP-1 was also studied. ISEMFs isolated from CD patient colon and human colonic cell line of myofibroblasts (18Co) were used. Oxidative state was modulated by buthionine sulfoximine, an inhibitor of glutathione (GSH) synthesis, and N-acetylcysteine (NAC), GSH precursor. An up-regulation of MMP-3 due to increased oxidative state was found in CD-ISEMFs. Stimulation by tumor necrosis factor (TNF)α increased further MMP-3 levels. On the contrary, no change in TIMP-1 production was determined. NAC treatment decreased MMP-3 production in CD-ISMEFs and removed the enhancement due to TNFα. Similar effects were observed in 18Co cells treated with curcumin, antioxidant with anti-inflammatory properties. The involvement of MAPKs on MMP-3 redox regulation was also shown. This study demonstrates the involvement of ISEMFs and high oxidative state in the increased MMP-3 production found in intestinal mucosa of CD patients. NAC and curcumin normalize MMP-3 levels mainly in TNFα stimulated cells. A modulation of MMP-3 production by NAC and curcumin due to their direct action on transcriptional factors has been also suggested. Therefore, they could have a therapeutic use for the prevention and treatment of fistulaes in CD.}, }
@article {pmid24583029, year = {2014}, author = {Wang, L and Xiao, S and Gao, J and Liu, M and Zhang, X and Li, M and Zhao, G and Mo, D and Liu, X and Chen, Y}, title = {Inhibition of replication of porcine reproductive and respiratory syndrome virus by hemin is highly dependent on heme oxygenase-1, but independent of iron in MARC-145 cells.}, journal = {Antiviral research}, volume = {105}, number = {}, pages = {39-46}, doi = {10.1016/j.antiviral.2014.02.010}, pmid = {24583029}, issn = {1872-9096}, mesh = {Animals ; Antiviral Agents/*metabolism ; Cell Line ; Heme Oxygenase-1/*metabolism ; Hemin/*metabolism ; Inhibitory Concentration 50 ; Iron/*metabolism ; Microbial Sensitivity Tests ; Porcine respiratory and reproductive syndrome virus/*drug effects/*physiology ; Reactive Oxygen Species/analysis ; Swine ; Viral Load ; Virus Replication/*drug effects ; }, abstract = {Current vaccines against porcine reproductive and respiratory syndrome virus (PRRSV) have failed to provide sustainable disease control, and development of new antiviral strategies is of great importance. The present study investigated the mechanism of the antiviral effect of hemin during PRRSV infection in MARC-145 cells. Hemin, a commercial preparation of heme, is used as an iron donor or heme oxygenase 1 (HO-1) inducer, and has been shown to provide antiviral activity in many studies. In the current study, the anti-PRRSV activity of hemin was identified through suppressing PRRSV propagation. The 50% inhibitory concentration (IC50) of hemin antiviral activity was estimated to be 32μM, and the 50% cytotoxic concentration (CC50) of hemin was found to be higher than 125μM. Further study showed that the antiviral activity of hemin is independent of iron. In addition, after treatment with Protoporphyrin IX zinc (II) (ZnPP) or Sn (IV) Protoporphyrin IX dichloride (SnPP), inhibitors of HO-1, the inhibition of viral replication by hemin was partially reversed. Additionally, it was confirmed that hemin and N-acetyl cysteine were able to significantly reduce reactive oxygen species (ROS) in MARC-145 cells infected with virus. N-acetyl-L-cysteine (NAC), however, did not produce a reduction in viral load or promote expression of HO-1. Taken together, these data indicate that the effect of hemin on the inhibition of PRRSV propagation via HO-1 induction, as well as the antiviral mechanism of HO-1, is not dependent on decreased levels of ROS. In conclusion, these data demonstrate that hemin had antiviral activity against PRRSV and may serve as a useful antiviral agent inhibiting PRRSV replication.}, }
@article {pmid24581747, year = {2014}, author = {León-Gonzalez, AJ and Acero, N and Muñoz-Mingarro, D and López-Lázaro, M and Martín-Cordero, C}, title = {Cytotoxic activity of hirsutanone, a diarylheptanoid isolated from Alnus glutinosa leaves.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {21}, number = {6}, pages = {866-870}, doi = {10.1016/j.phymed.2014.01.008}, pmid = {24581747}, issn = {1618-095X}, mesh = {Adenocarcinoma/*drug therapy ; Alnus/*chemistry ; Antineoplastic Agents, Phytogenic/isolation &amp; purification/pharmacology/*therapeutic use ; Cell Death ; Colonic Neoplasms/*drug therapy/metabolism ; DNA/drug effects ; DNA Topoisomerases, Type II/metabolism ; Diarylheptanoids/isolation &amp; purification/pharmacology/*therapeutic use ; HT29 Cells ; Humans ; *Phytotherapy ; Plant Extracts/chemistry/pharmacology/*therapeutic use ; Plant Leaves ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: The low efficacy of cancer therapy for the treatment of patients with advanced disease makes the development of new anticancer agents necessary. Because natural products are a significant source of anticancer drugs, it is important to explore cytotoxic activity of novel compounds from natural origin.<br><br>PURPOSE: The aim of this work is to evaluate the cytotoxic capacity of hirsutanone, a diarylheptanoid isolated from Alnus glutinosa leaves. Hirsutanone cytotoxic way of action was also studied.<br><br>MATERIAL AND METHODS: The cytotoxic ability of Alnus glutinosa leaves ethyl acetate extract was studied over HeLa and PC-3 cell lines, with the MTT colorimetric assay. Hirsutanone was isolated from this extract using chromatographic methods, and its structure elucidated by spectroscopic analysis. HT-29 cell viability after hirsutanone treatment was determined using SRB assay. In order to understand hirsutanone way of action, cytotoxicity was evaluated adding the diarylheptanoid and antioxidants. DNA topoisomerase II (topo II) poison activity, was also evaluated using purified topo II and a supercoiled form of DNA that bears specific topo II recognition and binding region; topo II poisons stabilize normally transient DNA-topo II cleavage complexes, and lead an increased yield of linear form as a consequence of a lack of double-strand breaks rejoining.<br><br>RESULTS: The diarylheptanoid hirsutanone was isolated from Alnus glutinosa (L.) Gaertn. (Betulaceae) leaves extract that showed cytotoxic activity against PC-3 and HeLa cell lines. Hirsutanone showed cytotoxic activity against HT-29 human colon carcinoma cells. Pre-treatment with the antioxidants NAC (N-acetylcysteine) and MnTMPyP (Mn(III)tetrakis-(1-methyl-4-pyridyl)porthyrin) reduced this activity, suggesting that reactive oxygen species (ROS) participate in hirsutanone-induced cancer cell death. Using human topo II and a DNA supercoiled form, hirsutanone was found to stabilize topo II-DNA cleavage complexes, acting as a topo II poison.<br><br>CONCLUSION: Our data suggest that, like curcumin, an induction of oxidative stress and topo II-mediated DNA damage may play a role in hirsutanone-induced cancer cell death. Since both compounds share similar structure and cytotoxic profile, and curcumin is in clinical trials for the treatment of cancer, our results warrant further studies to evaluate the anticancer potential of hirsutanone.}, }
@article {pmid24581674, year = {2014}, author = {Strickland, AD}, title = {Prevention of cerebral palsy, autism spectrum disorder, and attention deficit-hyperactivity disorder.}, journal = {Medical hypotheses}, volume = {82}, number = {5}, pages = {522-528}, doi = {10.1016/j.mehy.2014.02.003}, pmid = {24581674}, issn = {1532-2777}, mesh = {Attention Deficit Disorder with Hyperactivity/*prevention &amp; control ; Cerebral Palsy/*prevention &amp; control ; Child Development Disorders, Pervasive/*prevention &amp; control ; Humans ; Models, Theoretical ; }, abstract = {This hypothesis states that cerebral palsy (CP), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) are all caused by an exaggerated central nervous system inflammatory response to a prenatal insult. This prenatal insult may be one or more episodes of ischemia-reperfusion, an infectious disease of the mother or the fetus, or other causes of maternal inflammation such as allergy or autoimmune disease. The resultant fetal inflammatory hyper-response injures susceptible neurons in the developing white matter of the brain in specific areas at specific gestational ages. The exaggerated neuroinflammatory response is theorized to occur between about 19 and 34 post-conception weeks for CP, about 32 and 40 weeks for ADHD, and about 36 and 48 weeks (i.e. 2 months after delivery) for ASD. The exaggerated inflammatory response is hypothesized to occur because present diets limit intake of effective antioxidants and omega-3 polyunsaturated fatty acids while increasing intake of omega-6 polyunsaturated fatty acids. Oxidation products of the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) limit neuroinflammation while oxidation products of the omega-6 fatty acid arachidonic acid exacerbate inflammation. Preventative treatment should begin in all pregnant women during the first trimester and should include both DHA and an effective antioxidant for prevention of neuroinflammation. The suggested antioxidant would be N-acetylcysteine, though melatonin could be chosen instead. Combined DHA and NAC therapy is theorized to decrease the incidence of the three disorders by more than 75%.}, }
@article {pmid24579807, year = {2014}, author = {Sharma, S and Raghuvanshi, BP and Shukla, S}, title = {Toxic effects of lead exposure in rats: involvement of oxidative stress, genotoxic effect, and the beneficial role of N-acetylcysteine supplemented with selenium.}, journal = {Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer}, volume = {33}, number = {1}, pages = {19-32}, doi = {10.1615/jenvironpatholtoxicoloncol.2014009712}, pmid = {24579807}, issn = {2162-6537}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Administration, Oral ; Animals ; Antioxidants/administration &amp; dosage/pharmacology/*therapeutic use ; DNA Damage/*drug effects ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Injections, Intraperitoneal ; Lead/administration &amp; dosage/pharmacology/*toxicity ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Models, Animal ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Selenium/administration &amp; dosage/pharmacology/*therapeutic use ; }, abstract = {This study was carried out to investigate the in vivo protective role of N-acetylcysteine (NAC) per se, along with selenium (Se), against lead-induced hepatic, nephritic-oxidative, and neuronal-oxidative damage in rats. Lead acetate at a dose of 50 mg/kg body weight administered intraperitoneally for 3 days was preferred as the source of lead. Various oxidative stress markers such as reduced glutathione content, lipid peroxidation, superoxide dismutase, and catalase were measured to determine the degree of oxidative damage and healing due to NAC (50 mg/kg body weight administered orally) and Se (0.5 mg/kg body weight administered orally) and were studied along with the activities of enzymes such as transaminases (aspartate aminotransferase/alanine aminotransferase), δ-aminolevulinic acid dehydratase, δ-aminolevulinic acid synthase, and acetyl cholinesterase activity. The genotoxic effect of lead also was studied in terms of DNA damage using comet assay. The effect of lead was studied in blood biochemical variables such as cholesterol, triglycerides, urea, uric acid, and creatinine. Our data suggest that supplementation of Se with NAC can improve the lead-induced biochemical oxidative stress in blood and tissue, the burden of lead on the body, and molecular alterations by recoupment in mean DNA damage.}, }
@article {pmid24577230, year = {2014}, author = {Kasperczyk, S and Dobrakowski, M and Kasperczyk, A and Machnik, G and Birkner, E}, title = {Effect of N-acetylcysteine administration on the expression and activities of antioxidant enzymes and the malondialdehyde level in the blood of lead-exposed workers.}, journal = {Environmental toxicology and pharmacology}, volume = {37}, number = {2}, pages = {638-647}, doi = {10.1016/j.etap.2014.01.024}, pmid = {24577230}, issn = {1872-7077}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Air Pollutants, Occupational/*toxicity ; Antioxidants/*pharmacology ; Catalase/blood ; Glutathione Peroxidase/blood ; Humans ; Lead/*toxicity ; Leukocytes/enzymology ; Male ; Malondialdehyde/blood ; Middle Aged ; Occupational Exposure/adverse effects ; Superoxide Dismutase/blood ; }, abstract = {We investigated whether treatment with N-acetylcysteine (NAC) reduces oxidative stress intensity and restores the expression and activities of superoxide dismutase (Sod1, SOD), catalase (Cat, CAT) and glutathione peroxidase (Gpx1, GPx) in lead-exposed workers. The exposed population was divided randomly into two groups. Workers in the first group (reference group, n=49) were not administered any drugs, while workers in the second group (n=122) were treated with NAC at three doses for 12 weeks (200 mg, 400 mg, 800 mg/day). NAC administered orally to lead-exposed workers normalized antioxidant enzyme activities in blood cells. Oxidative stress intensity measured as malondialdehyde (MDA) levels in serum, leukocytes and erythrocytes significantly decreased after NAC administration. NAC may be an alternative therapy for chronic lead intoxication.}, }
@article {pmid24576857, year = {2014}, author = {Slattery, KM and Dascombe, B and Wallace, LK and Bentley, DJ and Coutts, AJ}, title = {Effect of N-acetylcysteine on cycling performance after intensified training.}, journal = {Medicine and science in sports and exercise}, volume = {46}, number = {6}, pages = {1114-1123}, doi = {10.1249/MSS.0000000000000222}, pmid = {24576857}, issn = {1530-0315}, mesh = {Acetylcysteine/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Bicycling/*physiology ; Cross-Over Studies ; *Dietary Supplements ; Double-Blind Method ; Humans ; Inflammation/metabolism ; Oxidation-Reduction ; Oxidative Stress ; *Physical Education and Training ; Physical Endurance/*physiology ; }, abstract = {PURPOSE: This investigation examined the ergogenic effect of short-term oral N-acetylcysteine (NAC) supplementation and the associated changes in redox balance and inflammation during intense training.<br><br>METHODS: A double-blind randomized placebo-controlled crossover design was used to assess 9 d of oral NAC supplementation (1200 mg&#xb7;d) in 10 well-trained triathletes. For each supplement trial (NAC and placebo), baseline venous blood and urine samples were taken, and a presupplementation cycle ergometer race simulation was performed. After the loading period, further samples were collected preexercise, postexercise, and 2 and 24 h after the postsupplementation cycle ergometer race simulation. Changes in total antioxidant capacity, ferric reducing ability of plasma, reduced glutathione, oxidized glutathione, thiobarbituric acid-reactive substances, interleukin 6, xanthine oxidase, hypoxanthine, monocyte chemotactic protein 1, nuclear factor &#x3ba;B, and urinary 15-isoprostane F2t concentration were assessed. The experimental procedure was repeated with the remaining supplement after a 3-wk washout. Eight participants completed both supplementation trials.<br><br>RESULTS: NAC improved sprint performance during the cycle ergometer race simulation (P < 0.001, &#x3b7;p = 0.03). Supplementation with NAC also augmented postexercise plasma total antioxidant capacity (P = 0.005, &#x3b7;p = 0.19), reduced exercise-induced oxidative damage (plasma thiobarbituric acid-reactive substances, P = 0.002, &#x3b7;p = 0.22; urinary 15-isoprostane F2t concentration, P = 0.010, &#x3b7;p = 0.431), attenuated inflammation (plasma interleukin 6, P = 0.002, &#x3b7;p = 0.22; monocyte chemotactic protein 1, P = 0.012, &#x3b7;p = 0.17), and increased postexercise nuclear factor &#x3ba;B activity (P < 0.001, &#x3b7;p = 0.21).<br><br>CONCLUSION: Oral NAC supplementation improved cycling performance via an improved redox balance and promoted adaptive processes in well-trained athletes undergoing strenuous physical training.}, }
@article {pmid24576220, year = {2015}, author = {Anand, H and Misro, MM and Sharma, SB and Prakash, S}, title = {Protective effects of Eugenia jambolana extract versus N-acetyl cysteine against cisplatin-induced damage in rat testis.}, journal = {Andrologia}, volume = {47}, number = {2}, pages = {194-208}, doi = {10.1111/and.12247}, pmid = {24576220}, issn = {1439-0272}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antineoplastic Agents/adverse effects/pharmacology ; Antioxidants/pharmacology/therapeutic use ; Apoptosis/*drug effects ; Cisplatin/*adverse effects/pharmacology ; Leydig Cells/drug effects/metabolism/pathology ; Male ; Models, Animal ; Oxidative Stress/drug effects ; Plant Extracts/pharmacology/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Spermatozoa/drug effects/metabolism/pathology ; *Syzygium ; Testis/drug effects/metabolism/*pathology ; Testosterone/metabolism ; }, abstract = {To assess the protective effects of Eugenia jambolana extract (EJE) or N-acetyl cysteine (NAC) on testis, cisplatin (CIS, 5 mg kg(-1) bw, single dose) was administered either alone or along with EJE (25 mg kg(-1) bw, alternate day) or NAC (150 mg kg(-1) bw, Day 1 and 4) for 7 days. Significant alterations in serum LH, FSH and testosterone were observed in CIS group which were effectively modulated by EJE or NAC supplementation. Upregulation of 3β-HSD gene indicated the rise in functional Leydig cells. This was further confirmed from the identical improvement in hCG-stimulated testosterone production in isolated Leydig cells. Reduction in oxidative stress was associated with restoration of total antioxidant capacity and glutathione levels, and activation of antioxidant enzymes, SOD, catalase, glutathione s-transferase (GST) and glutathione reductase (GR). CIS-induced apoptosis of germ and Leydig cells was contained by both NAC and EJE intervention by effective modulation of apoptotic markers in the extrinsic, intrinsic and other pathways of metazoan apoptosis. Taken together, the study findings establish the potential of EJE as a therapeutically better antioxidant than NAC for use in curtailing the adverse effects of anticancer drugs on testicular function.}, }
@article {pmid24576052, year = {2014}, author = {Tanaka, R and Ishima, Y and Maeda, H and Kodama, A and Nagao, S and Watanabe, H and Chuang, VT and Otagiri, M and Maruyama, T}, title = {Albumin fusion prolongs the antioxidant and anti-inflammatory activities of thioredoxin in mice with acetaminophen-induced hepatitis.}, journal = {Molecular pharmaceutics}, volume = {11}, number = {4}, pages = {1228-1238}, doi = {10.1021/mp400690v}, pmid = {24576052}, issn = {1543-8392}, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/blood ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism ; Cytokines/blood ; Hep G2 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Serum Albumin/*pharmacology ; }, abstract = {Overdoses of acetaminophen (APAP) are a major cause of acute liver failure. N-Acetylcysteine (NAC) is the standard therapy for patients with such an overdose because oxidative stress plays an important role in the pathogenesis of APAP-induced hepatitis. However, NAC is not sufficiently efficacious. We previously developed a recombinant human serum albumin (HSA)-thioredoxin 1 (Trx) fusion protein (HSA-Trx), designed to overcome the unfavorable pharmacokinetic and short pharmacological properties of Trx, an endogenous protein with antioxidative and anti-inflammatory properties. In this study, we investigated the therapeutic impact of HSA-Trx in mice with APAP-induced hepatitis. The systemic administration of HSA-Trx significantly improved the survival rate of mice treated with a lethal dose of APAP compared with saline. HSA-Trx strongly attenuated plasma transaminases in APAP-induced hepatitis mice compared with HSA or Trx, components of the fusion protein. HSA-Trx also markedly caused a diminution in the histopathological features of hepatic injuries and the number of apoptosis-positive hepatic cells. In addition, an evaluation of oxidative stress markers and plasma cytokine and chemokine levels clearly showed that HSA-Trx significantly improved the breakdown of hepatic redox conditions and inflammation caused by the APAP treatment. HSA-Trx also significantly decreased oxidative and nitrosative/nitrative stress induced by SIN-1 in vitro. Finally, HSA-Trx, but not the NAC treatment at 4 h after APAP injection, significantly inhibited the elevation in plasma transaminase levels. In conclusion, the findings suggest that HSA-Trx has considerable potential for use as a novel therapeutic agent for APAP-induced hepatitis, due to its long-lasting antioxidative and anti-inflammatory effects.}, }
@article {pmid24573805, year = {2014}, author = {Wu, H and Song, W and Gao, X and Liu, N and Wang, P and Chen, H and Cai, Z}, title = {Proteomics study of N-acetylcysteine response in H1N1-infected cells by using mass spectrometry.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {28}, number = {7}, pages = {741-749}, doi = {10.1002/rcm.6840}, pmid = {24573805}, issn = {1097-0231}, mesh = {Acetylcysteine/*pharmacology ; Amino Acid Sequence ; Apoptosis/drug effects ; Cell Line, Tumor ; Electrophoresis, Gel, Two-Dimensional ; Humans ; *Influenza A Virus, H1N1 Subtype ; Influenza, Human/*metabolism ; Molecular Sequence Data ; Proteins/analysis/chemistry/metabolism ; *Proteome/analysis/chemistry/drug effects ; Proteomics/*methods ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/*methods ; }, abstract = {RATIONALE: The pathology of A/Puerto Rico/8/1934 (H1N1) infection associated with the interaction of virus and its host cells is not clear. N-Acetylcysteine (NAC) is an antioxidant as well as a premier antitoxin and immune support substance. A high dose of NAC was recently reported for a therapy of H1N1 (2009) influenza pneumonia.<br><br>METHODS: NAC was used as a small-molecule organic probe to investigate the protein expression of human lung carcinoma cell line (A549) infected by influenza virus A/Puerto Rico/8/1934 (H1N1). Differential proteins were identified from MALDI-TOF MS and Q-TOF MS/MS analyses.<br><br>RESULTS: The obtained results showed that NAC kept cells away from apoptosis. Virus-infected cells were arrested in G0/G1 phase. The lowest cell population of G0/G1 phase was detected when the cells were treated by 10&#x2009;mM NAC for one day. Application of MS-based proteomics allowed the identification of the differential proteins. Software analysis showed that four proteins had close relationship.<br><br>CONCLUSIONS: The results indicated that NAC as a small-molecule probe might effect the protein expression of A549 cells infected by the H1N1 virus.}, }
@article {pmid24573671, year = {2014}, author = {Sharma, N and Kumar, A}, title = {Mechanism of immunotoxicological effects of tributyltin chloride on murine thymocytes.}, journal = {Cell biology and toxicology}, volume = {30}, number = {2}, pages = {101-112}, doi = {10.1007/s10565-014-9272-7}, pmid = {24573671}, issn = {1573-6822}, mesh = {Animals ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Calcium/analysis ; Caspase 3/*biosynthesis ; Caspase Inhibitors/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Cysteine/analogs &amp; derivatives/pharmacology ; DNA Damage/drug effects ; Male ; Membrane Potential, Mitochondrial/*drug effects ; Mice ; Mice, Inbred BALB C ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Thymocytes/*pathology ; Thymus Gland/drug effects ; Trialkyltin Compounds/*pharmacology/toxicity ; }, abstract = {Tributyltin-chloride, a well-known organotin compound, is a widespread environmental toxicant. The immunotoxic effects of tributyltin-chloride on mammalian system and its mechanism is still unclear. This study is designed to explore the mode of action of tributyltin-induced apoptosis and other parallel apoptotic pathways in murine thymocytes. The earliest response in oxidative stress followed by mitochondrial membrane depolarization and caspase-3 activation has been observed. Pre-treatment with N-acetyl cysteine and buthionine sulfoximine effectively inhibited the tributyltin-induced apoptotic DNA and elevated the sub G1 population, respectively. Caspase inhibitors pretreatment prevent tributyltin-induced apoptosis. Western blot and flow cytometry indicate no translocation of apoptosis-inducing factor and endonuclease G in the nuclear fraction from mitochondria. Intracellular Ca(2+) levels are significantly raised by tributyltin chloride. These results clearly demonstrate caspase-dependent apoptotic pathway and support the role of oxidative stress, mitochondrial membrane depolarization, caspase-3 activation, and calcium during tributyltin-chloride (TBTC)-induced thymic apoptosis.}, }
@article {pmid24564180, year = {2014}, author = {Decroos, C and Boucher, JL and Mansuy, D and Xu-Li, Y}, title = {Reactions of amino acids, peptides, and proteins with oxidized metabolites of tris(p-carboxyltetrathiaaryl)methyl radical EPR probes.}, journal = {Chemical research in toxicology}, volume = {27}, number = {4}, pages = {627-636}, doi = {10.1021/tx400467p}, pmid = {24564180}, issn = {1520-5010}, mesh = {Amino Acids/chemistry ; Animals ; Electron Spin Resonance Spectroscopy ; Glutathione/chemistry ; Heterocyclic Compounds, 3-Ring/*chemistry ; Male ; Microsomes, Liver/metabolism ; *Molecular Probes ; Oxidants/chemistry ; Oxidation-Reduction ; Peptides/*chemistry ; Proteins/*chemistry ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Oxidation of the tris(p-carboxyltetrathiaaryl)methyl (TAM) EPR radical probe, TAMa(•), by rat liver microsomes (RLM) + NADPH, or horseradish peroxidase (HRP) + H2O2, or K2IrCl6, led to an intermediate cation, TAMa(+), which was treated with glutathione (GSH), with formation of an adduct, TAMa-SG(•), resulting from the substitution of a TAMa(•) carboxylate group with the SG group. L-α-Amino acids containing a strong nucleophilic residue (NuH), such as L-cysteine or L-histidine, also reacted with TAMa(+), with formation of radical adducts TAMa-Nu(•) in which a carboxylate group of TAMa(•) was replaced with Nu. Other less nucleophilic L-α-amino acids, such as L-arginine, L-serine, L-threonine, L-tyrosine, or L-aspartate, as well as the tetrapeptide H-(Gly)4-OH, reacted with TAMa(+) via their α-NH2 group, with formation of an iminoquinone methide, IQMa, deriving from an oxidative decarboxylation and amination of TAMa(•). Upon reaction of TAMa(+) with L-proline and L-lysine, N-substituted iminoquinone methide adducts, IQMa-Pro and IQMa-Lys, were formed. Finally, preliminary results showed that oxidation of TAMa(•) in the presence of bovine serum albumin (BSA), led to the covalent binding of TAMa-derived metabolites to BSA. Oxidation of another frequently used TAM probe, TAMb(•) (Oxo63), in the presence of GSH, N-acetyl-cysteine methyl ester, or histidine also led to TAMb-Nu(•) adducts equivalent to the corresponding TAMa-Nu(•) adducts, suggesting that the oxidative metabolism of such TAM(•) probes could lead to protein covalent binding. Moreover, the above data describe an easy access to new TAM radical EPR probes coupled to amino acids, peptides or proteins that could be useful for addressing various biological targets.}, }
@article {pmid24556569, year = {2014}, author = {Park, E and Yu, KH and Kim, DK and Kim, S and Sapkota, K and Kim, SJ and Kim, CS and Chun, HS}, title = {Protective effects of N-acetylcysteine against monosodium glutamate-induced astrocytic cell death.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {67}, number = {}, pages = {1-9}, doi = {10.1016/j.fct.2014.02.015}, pmid = {24556569}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Astrocytes/cytology/*drug effects/metabolism ; Base Sequence ; Cell Death/*drug effects ; Cell Line ; DNA Primers ; Endoplasmic Reticulum Chaperone BiP ; Membrane Potential, Mitochondrial/drug effects ; Polymerase Chain Reaction ; Reactive Oxygen Species/metabolism ; Sodium Glutamate/*pharmacology ; }, abstract = {Monosodium glutamate (MSG) is a flavor enhancer, largely used in the food industry and it was reported to have excitotoxic effects. Higher amounts of MSG consumption have been related with increased risk of many diseases, including Chinese restaurant syndrome and metabolic syndromes in human. This study investigated the protective effects of N-acetylcysteine (NAC) on MSG-induced cytotoxicity in C6 astrocytic cells. MSG (20 mM)-induced reactive oxygen species (ROS) generation and apoptotic cell death were significantly attenuated by NAC (500 μM) pretreatment. NAC effectively inhibited the MSG-induced mitochondrial membrane potential (MMP) loss and intracellular reduced glutathione (GSH) depletion. In addition, NAC significantly attenuated MSG-induced endoplasmic reticulum (ER) stress markers, such as XBP1 splicing and CHOP, PERK, and GRP78 up-regulation. Furthermore, NAC prevented the changes of MSG-induced Bcl-2 expression level. These results suggest that NAC can protect C6 astrocytic cells against MSG-induced oxidative stress, mitochondrial dysfunction, and ER stress.}, }
@article {pmid24556447, year = {2014}, author = {Ali-Hassan-Sayegh, S and Mirhosseini, SJ and Rezaeisadrabadi, M and Dehghan, HR and Sedaghat-Hamedani, F and Kayvanpour, E and Popov, AF and Liakopoulos, OJ}, title = {Antioxidant supplementations for prevention of atrial fibrillation after cardiac surgery: an updated comprehensive systematic review and meta-analysis of 23 randomized controlled trials.}, journal = {Interactive cardiovascular and thoracic surgery}, volume = {18}, number = {5}, pages = {646-654}, doi = {10.1093/icvts/ivu020}, pmid = {24556447}, issn = {1569-9285}, mesh = {Acetylcysteine/administration &amp; dosage ; Anti-Arrhythmia Agents/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Ascorbic Acid/administration &amp; dosage ; Atrial Fibrillation/diagnosis/etiology/*prevention &amp; control ; Cardiac Surgical Procedures/*adverse effects ; *Dietary Supplements ; Fatty Acids, Unsaturated/administration &amp; dosage ; Humans ; Length of Stay ; Odds Ratio ; Randomized Controlled Trials as Topic ; Risk Factors ; Time Factors ; Treatment Outcome ; }, abstract = {This systematic review with meta-analysis sought to determine the impact of antioxidants (N-acetylcysteine [NAC], polyunsaturated fatty acids [PUFAs] and vitamins) on incidence of postoperative atrial fibrillation (POAF) and duration of length of hospital stay. Medline, Embase, Elsevier, Sciences online database and Google Scholar literature search was made for studies in randomized controlled trials. The effect sizes measured were odds ratio (OR) for categorical variable and standard mean difference (SMD) with 95% confidence interval (CI) for calculating differences between mean values of duration of hospitalization in intervention and control groups. A value of P < 0.1 for Q-test or I(2) > 50% indicated significant heterogeneity between the studies. Literature search of all major databases retrieved 355 studies. After screening, a total of 23 trials were identified that reported outcomes of 4278 patients undergoing cardiac surgery. Pooled effects estimates on POAF showed a significant reduction after NAC (OR: 0.56, 95% CI: 0.40-0.77, P < 0.001), PUFA (OR: 0.84, 95% CI: 0.71-0.99, P = 0.03) and vitamin C treatment (OR: 0.50, 95% CI: 0.27-0.91, P = 0.02). Hospital length of stay was not reduced after NAC therapy (SMD: 0.082, 95% CI -0.09 to 0.25, P = 0.3), but could be decreased with PUFA (SMD: -0.185, 95% CI: -0.35 to -0.018, P = 0.03) and vitamin C (SMD: -0.325, 95% CI -0.50 to -0.14, P < 0.01). In conclusion, perioperative antioxidant supplementations with NAC, PUFA and vitamin C prevent atrial fibrillation after cardiac surgery. Moreover, PUFA and vitamin C are capable to reduce hospital stay, whereas NAC lacks this capacity.}, }
@article {pmid24553147, year = {2014}, author = {Lee, JO and Moon, JW and Lee, SK and Kim, SM and Kim, N and Ko, SG and Kim, HS and Park, SH}, title = {Rhus verniciflua extract modulates survival of MCF-7 breast cancer cells through the modulation of AMPK-pathway.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {37}, number = {5}, pages = {794-801}, doi = {10.1248/bpb.b13-00893}, pmid = {24553147}, issn = {1347-5215}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Acetyl-CoA Carboxylase/*metabolism ; Acetylcysteine/pharmacology ; Annexin A5/biosynthesis ; Antineoplastic Agents/chemistry/pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/*metabolism/*pathology ; Cell Survival/drug effects ; Humans ; MCF-7 Cells ; Phosphorylation/drug effects ; Plant Bark/*chemistry ; Plant Extracts/antagonists &amp; inhibitors/*pharmacology ; Reactive Oxygen Species/metabolism ; Rhus/*chemistry ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/metabolism ; bcl-2-Associated X Protein/biosynthesis ; }, abstract = {Rhus verniciflua STOKES (RVS) is used as an anti-cancer agent in traditional herbal medicine. However, the underlying molecular mechanism of its action is poorly understood. Here, we elucidated the mechanism of the anti-cancer mechanism of RVS in MCF-7 human breast cancer cells. We found that RVS increased the phosphorylation of AMP-activated protein kinase (AMPK) and downstream acetyl-CoA carboxylase (ACC) and suppressed cell viability in an AMPK-dependent fashion. RVS also induced an increase in reactive oxygen species (ROS) levels. RVS-induced AMPK phosphorylation was not observed in the presence of N-acetyl-cysteine (NAC), which indicated that ROS is associated with RVS-induced AMPK phosphorylation. In addition, fluorescent staining (Annexin V/propidium iodide) revealed that RVS increased the expression of Annexin V, which indicates that RVS leads to cancer-induced apoptosis. Moreover, RVS increased the phosphorylation of p53 and the expression of Bax. The inhibition of AMPK blocked RVS-induced p53 phosphorylation and Bax expression, which suggests that AMPK is involved in RVS-induced cancer apoptosis. Taken together, these results demonstrate that RVS has anti-tumor effects on MCF-7 cells through an AMPK-signaling pathway.}, }
@article {pmid24552822, year = {2014}, author = {Kenneth, NS and Hucks, GE and Kocab, AJ and McCollom, AL and Duckett, CS}, title = {Copper is a potent inhibitor of both the canonical and non-canonical NFκB pathways.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {13}, number = {6}, pages = {1006-1014}, pmid = {24552822}, issn = {1551-4005}, support = {R01 CA142809/CA/NCI NIH HHS/United States ; T32 HL007622/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cell Line, Tumor ; Clioquinol/pharmacology ; Copper/*metabolism ; Free Radical Scavengers/pharmacology ; Humans ; I-kappa B Proteins/metabolism ; Ionophores/pharmacology ; Mice ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Oxidative Stress/drug effects ; Phosphorylation ; Signal Transduction ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; }, abstract = {Copper is an essential trace element that plays key roles in many metabolic processes. Homeostatic regulation of intracellular copper is normally tightly controlled, but deregulated copper levels are found in numerous metabolic and neurodegenerative diseases, as well as in a range of neoplasms. There are conflicting reports regarding the exact role of copper in the regulation of NFκB-responsive genes, specifically whether copper leads to increased activation of the NFκB pathways, or downregulation. Here we show that increased intracellular levels of copper, using the ionophore clioquinol, leads to a potent inhibition of NFκB pathways, induced by multiple distinct stimuli. Addition of copper to cells inhibits ubiquitin-mediated degradation of IκBα by preventing its phoshorylation by the upstream IKK complex. Intriguingly, copper-dependent inhibition of NFκB can be reversed by the addition of the reducing agent, N-acetylcysteine (NAC). These results suggest that the oxidative properties of excess copper prevent NFκB activation by blocking IκBα destruction, and that NFκB activity should be assessed in diseases associated with copper excess.}, }
@article {pmid24551210, year = {2014}, author = {Zhou, Y and Shu, F and Liang, X and Chang, H and Shi, L and Peng, X and Zhu, J and Mi, M}, title = {Ampelopsin induces cell growth inhibition and apoptosis in breast cancer cells through ROS generation and endoplasmic reticulum stress pathway.}, journal = {PloS one}, volume = {9}, number = {2}, pages = {e89021}, pmid = {24551210}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 6/genetics/metabolism ; Ampelopsis/chemistry ; Antineoplastic Agents, Phytogenic/isolation &amp; purification/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects/genetics ; Female ; Flavonoids/isolation &amp; purification/*pharmacology ; *Gene Expression Regulation, Neoplastic ; Heat-Shock Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Humans ; Phenylbutyrates/pharmacology ; RNA, Small Interfering/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Thapsigargin/pharmacology ; Transcription Factor CHOP/genetics/metabolism ; Transcription Factors/genetics/metabolism ; eIF-2 Kinase/genetics/metabolism ; }, abstract = {Ampelopsin (AMP), a major bioactive constituent of Ampelopsis grossedentata, exerts a number of biological effects. In this study, we investigated its anti-cancer activity in human breast cancer cell lines, and explored the underlying mechanism of this action. Our results showed that treatment with AMP dose-dependently inhibited cell viability and induced apoptosis in MCF-7 and MDA-MB-231 breast cancer cells without cytotoxicity in human normal breast epithelial cells MCF-10A. Meanwhile, AMP dose- dependently triggered reactive oxygen species (ROS) generation in both breast cancer cells. The ROS scavenger N-acetyl-L-cysteine (NAC) strongly attenuated AMP-induced ROS production, along with cell growth inhibition and apoptosis. Furthermore, AMP was observed to activate endoplasmic reticulum (ER) stress, as evidenced by the up-regulation of ER stress-related proteins, including GRP78, p-PERK, p-elF2α, cleaved ATF6α and CHOP, while knockdown of ATF6α or PERK markedly down-regulated AMP-induced CHOP expression. Blocking ER stress using 4-phenylbutyric acid not only down-regulated AMP-induced GRP78 and CHOP expression, but also significantly decreased AMP-induced cell growth inhibition and apoptosis, whereas ER stress inducer thapsigargin played opposing effects. Additionally, NAC inhibited AMP-induced ER stress by down-regulating GRP78 and CHOP expression. Conversely, blocking ER stress using CHOP siRNA decreased AMP-induced ROS production and cell apoptosis. Taken together, these results demonstrate that AMP has anti-tumor effects against breast cancer cells through ROS generation and ER stress pathway, which therefore provide experimental evidences for developing AMP as a new therapeutic drug for breast cancer.}, }
@article {pmid24549171, year = {2014}, author = {Hamada, M and Wakabayashi, K and Masui, A and Iwai, S and Imai, T and Yura, Y}, title = {Involvement of hydrogen peroxide in safingol-induced endonuclease G-mediated apoptosis of squamous cell carcinoma cells.}, journal = {International journal of molecular sciences}, volume = {15}, number = {2}, pages = {2660-2671}, pmid = {24549171}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Carcinoma, Squamous Cell/metabolism/pathology ; Cell Line, Tumor ; Endodeoxyribonucleases/antagonists &amp; inhibitors/genetics/*metabolism ; Humans ; Hydrogen Peroxide/*toxicity ; Mouth Neoplasms/metabolism/pathology ; RNA Interference ; RNA, Small Interfering/metabolism ; Sphingosine/*analogs &amp; derivatives/toxicity ; }, abstract = {Safingol, a L-threo-dihydrosphingosine, induced the nuclear translocation of a mitochondrial apoptogenic mediator--endonuclease G (endo G)--and apoptosis of human oral squamous cell carcinoma (SCC) cells. Upstream mediators remain largely unknown. The levels of hydrogen peroxide (H2O2) in cultured oral SCC cells were measured. Treatment with safingol increased intracellular H2O2 levels but not extracellular H2O2 levels, indicating the production of H2O2. The cell killing effect of safingol and H2O2 was diminished in the presence of reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC). Dual staining of cells with annexin V and propidium iodide (PI) revealed that apoptotic cell death occurred by treatment with H2O2 and safingol. The number of apoptotic cells was reduced in the presence of NAC. In untreated cells, endo G distributed in the cytoplasm and an association of endo G with mitochondria was observed. After treatment with H2O2 and safingol, endo G was distributed to the nucleus and cytoplasm, indicating the nuclear translocation of the mitochondrial factor. NAC prevented the increase of apoptotic cells and the translocation of endo G. Knock down of endo G diminished the cell killing effect of H2O2 and safingol. These results suggest that H2O2 is involved in the endo G-mediated apoptosis of oral SCC cells by safingol.}, }
@article {pmid24548678, year = {2014}, author = {Pesonen, M and Häkkinen, M and Rilla, K and Juvonen, R and Kuitunen, T and Pasanen, M and Vähäkangas, K}, title = {Chloropicrin-induced toxic responses in human lung epithelial cells.}, journal = {Toxicology letters}, volume = {226}, number = {2}, pages = {236-244}, doi = {10.1016/j.toxlet.2014.02.006}, pmid = {24548678}, issn = {1879-3169}, mesh = {Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Cytoprotection ; Deoxyguanosine/metabolism ; Disulfides/metabolism ; Dose-Response Relationship, Drug ; Epithelial Cells/*drug effects/metabolism/pathology ; Glutathione/metabolism ; Humans ; Hydrocarbons, Chlorinated/*toxicity ; Irritants/*toxicity ; Lung/*drug effects/metabolism/pathology ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Oxidative Stress/*drug effects ; Phosphorylation ; Protein Multimerization ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Time Factors ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Chloropicrin is a slowly evaporating toxic irritant that is known to cause damage in the respiratory system. Here we used a lung epithelial cell line (A549) to study the molecular responses underlying chloropicrin toxicity. Glutathione (GSH), synthetic peptide and 2'-deoxyguanosine were used as in vitro trapping agents to identify early markers of chloropicrin toxicity. Microscopy of the cells revealed massive vacuolization by chloropicrin exposure (80-100μM). The number of apoptotic cells increased with the chloropicrin concentration as assessed by flow cytometry. Immunoblotting analysis revealed increases in the amount of four proteins (p53, p21, p27 and phospho-Erk1/2) that are involved in DNA-damage, cell cycle regulation and apoptosis. Chloropicrin evoked a dose-dependent increase in levels of reactive oxygen species within one hour of exposure. The treatment triggered also the formation of disulphide bonds between the model thiol-containing peptides as analysed by LC/MS. Chloropicrin did not form stable adducts with the model peptides or 2'-deoxyguanosine. N-acetyl-cysteine (1mM NAC) fully prevented the vacuoles and chloropicrin-induced cytotoxicity. The results suggest that an oxidative insult, particularly modification of free sulfhydryl groups in proteins is involved in the acute toxicity evoked by chloropicrin in airway epithelial cells. The protective effect of NAC as a potential antidote in chloropicrin intoxication will require further investigation.}, }
@article {pmid24548611, year = {2014}, author = {Hsieh, YC and Lin, PL and Gu, SH}, title = {Signaling of reactive oxygen species in PTTH-stimulated ecdysteroidogenesis in prothoracic glands of the silkworm, Bombyx mori.}, journal = {Journal of insect physiology}, volume = {63}, number = {}, pages = {32-39}, doi = {10.1016/j.jinsphys.2014.02.004}, pmid = {24548611}, issn = {1879-1611}, mesh = {AMP-Activated Protein Kinases/metabolism ; Animals ; Bombyx/growth &amp; development/*physiology ; Calcium/*metabolism ; Ecdysteroids/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Insect Hormones/*metabolism ; Insect Proteins/*metabolism ; Larva/physiology ; Oxidation-Reduction ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; Type C Phospholipases/*metabolism ; }, abstract = {Our previous study demonstrated that mitochondria-derived reactive oxygen species (ROS) generation is involved in prothoracicotropic hormone (PTTH)-stimulated ecdysteroidogenesis in Bombyx mori prothoracic glands (PGs). In the present study, we further investigated the mechanism of ROS production and the signaling pathway mediated by ROS. PTTH-stimulated ROS production was markedly attenuated in a Ca(2+)-free medium. The phospholipase C (PLC) inhibitor, U73122, greatly inhibited PTTH-stimulated ROS production, indicating the involvement of Ca(2+) and PLC. When the PGs were treated with agents that directly elevate the intracellular Ca(2+) concentration (either A23187, or the protein kinase C (PKC) activator, phorbol 12-myristate acetate (PMA)), a great increase in ROS production was observed. We further investigated the action mechanism of PTTH-stimulated ROS signaling. Results showed that in the presence of either an antioxidant (N-acetylcysteine, NAC), or the mitochondrial oxidative phosphorylation inhibitors (rotenone, antimycin A, the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), and diphenyleneiodonium (DPI)), PTTH-regulated phosphorylation of ERK, 4E-BP, and AMPK was blocked. Treatment with 1mM of H2O2 alone activated the phosphorylation of ERK and 4E-BP, and inhibited AMPK phosphorylation. From these results, we conclude that PTTH-stimulated ROS signaling is Ca(2+)- and PLC-dependent and that ROS signaling appears to lie upstream of the phosphorylation of ERK, 4E-BP, and AMPK.}, }
@article {pmid24534200, year = {2014}, author = {Lee, YJ and Choi, SY and Yang, JH}, title = {NMDA receptor-mediated ERK 1/2 pathway is involved in PFHxS-induced apoptosis of PC12 cells.}, journal = {The Science of the total environment}, volume = {491-492}, number = {}, pages = {227-234}, doi = {10.1016/j.scitotenv.2014.01.114}, pmid = {24534200}, issn = {1879-1026}, mesh = {Animals ; Apoptosis ; Fluorocarbons ; Hazardous Substances/*toxicity ; MAP Kinase Signaling System/*physiology ; PC12 Cells ; Rats ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Signal Transduction/drug effects ; Sulfonic Acids/*toxicity ; }, abstract = {Perfluorohexanesulfonate (PFHxS) is one of the major perfluoroalkyl compounds (PFCs) found in human blood and its possible neurotoxicity has been suggested. However, the neuronal responses to PFHxS are not much known. Many studies have demonstrated that the early exposure to environmental chemicals increases the risk of neurodegenerative diseases such as Parkinson's disease in later life. In this study, the effects of PFHxS on the neuronal cell death and the underlying mechanisms were examined using PC12 cells as a model of dopaminergic neuron. The treatment with PFHxS reduced cell viability in a dose-dependent manner. PFHxS increased cell apoptosis which was measured by caspase-3 activity and TUNEL staining. MK801, a NMDA receptor antagonist reduced PFHxS-induced apoptosis. PFHxS increased the activations of ERK1/2, JNK and p38 MAPK with different temporal activations. The treatment with PD98059, an ERK inhibitor, significantly reduced apoptosis, whereas SB203580, a p38 MAPK inhibitor, had no effect. JNK inhibition by SP600125 significantly increased apoptosis. PFHxS exposure also increased ROS formation, which was completely blocked by antioxidants, Trolox or N-acetylcysteine (NAC). However, neither Trolox nor NAC reduced PFHxS-increased apoptosis, suggesting that ROS may not be a critical mediator for PFHxS-induced apoptosis of cells. Moreover, ERK activation induced by PFHxS was blocked by MK801 but not antioxidants. Taken together, these results have demonstrated that PFHxS induces the apoptosis of dopaminergic neuronal cells, where NMDA receptor-mediated ERK pathway plays a pro-apoptotic role and JNK plays an anti-apoptotic role. Our results may contribute to understanding cellular mechanisms for PFHxS-induced neurotoxicity.}, }
@article {pmid24534112, year = {2014}, author = {Lee, MY and Chiang, CC and Chiu, HY and Chan, MH and Chen, HH}, title = {N-acetylcysteine modulates hallucinogenic 5-HT(2A) receptor agonist-mediated responses: behavioral, molecular, and electrophysiological studies.}, journal = {Neuropharmacology}, volume = {81}, number = {}, pages = {215-223}, doi = {10.1016/j.neuropharm.2014.02.006}, pmid = {24534112}, issn = {1873-7064}, mesh = {Acetylcysteine/*therapeutic use ; Action Potentials/*drug effects ; Amino Acids/pharmacology ; Amphetamines/toxicity ; Animals ; Benzoates/pharmacology ; Bicuculline/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Interactions ; Early Growth Response Protein 2/metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Free Radical Scavengers/*therapeutic use ; GABA-A Receptor Antagonists/pharmacology ; Glycine/analogs &amp; derivatives/pharmacology ; Hallucinations/chemically induced/*drug therapy ; Hallucinogens/toxicity ; Male ; Mice ; Proto-Oncogene Proteins c-fos/metabolism ; Receptors, Metabotropic Glutamate/*metabolism ; Xanthenes/pharmacology ; }, abstract = {N-acetylcysteine (NAC) has been reported to reverse the psychotomimetic effects in the rodent phencyclidine model of psychosis and shown beneficial effects in treating patients with schizophrenia. The effect of NAC has been associated with facilitating the activity of cystine-glutamate antiporters on glial cells concomitant with the release of non-vesicular glutamate, which mainly stimulates the presynaptic metabotropic glutamate receptor subtype 2 receptors (mGluR2). Recent evidence demonstrated that functional interactions between serotonin 5-HT2A receptor (5-HT(2A)R) and mGluR2 are responsible to unique cellular responses when targeted by hallucinogenic drugs. The present study determined the effects of NAC on hallucinogenic 5-HT(2A)R agonist (±)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-elicited behavioral and molecular responses in mice and DOI-evoked field potentials in the mouse cortical slices. NAC significantly attenuated DOI-induced head twitch response and expression of c-Fos and Egr-2 in the infralimbic and motor cortex and suppressed the increase in the frequency of excitatory field potentials elicited by DOI in the medial prefrontal cortex. In addition, the cystine-glutamate antiporter inhibitor (S)-4-carboxyphenylglycine (CPG) and the mGluR2 antagonist LY341495 reversed the suppressing effects of NAC on DOI-induced head twitch and molecular responses and increased frequency of excitatory field potentials, supporting that NAC attenuates the 5-HT(2A)R-mediated hallucinogenic effects via increased activity of cystine-glutamate antiporter followed by activation of mGluR2 receptors. These findings implicate NAC as a potential therapeutic agent for hallucinations and psychosis associated with hallucinogen use and schizophrenia.}, }
@article {pmid24533448, year = {2014}, author = {Moazzen, H and Lu, X and Ma, NL and Velenosi, TJ and Urquhart, BL and Wisse, LJ and Gittenberger-de Groot, AC and Feng, Q}, title = {N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes.}, journal = {Cardiovascular diabetology}, volume = {13}, number = {}, pages = {46}, pmid = {24533448}, issn = {1475-2840}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Blood Glucose/drug effects/metabolism ; Cardiotonic Agents/*administration &amp; dosage ; Diabetes Mellitus, Experimental/blood/*drug therapy/pathology ; Female ; Heart Defects, Congenital/blood/pathology/*prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Pregnancy ; Pregnancy in Diabetics/blood/drug therapy/pathology ; }, abstract = {BACKGROUND: Pregestational diabetes is a major risk factor of congenital heart defects (CHDs). Glutathione is depleted and reactive oxygen species (ROS) production is elevated in diabetes. In the present study, we aimed to examine whether treatment with N-acetylcysteine (NAC), which increases glutathione synthesis and inhibits ROS production, prevents CHDs induced by pregestational diabetes.<br><br>METHODS: Female mice were treated with streptozotocin (STZ) to induce pregestational diabetes prior to breeding with normal males to produce offspring. Some diabetic mice were treated with N-acetylcysteine (NAC) in drinking water from E0.5 to the end of gestation or harvesting of the embryos. CHDs were identified by histology. ROS levels, cell proliferation and gene expression in the fetal heart were analyzed.<br><br>RESULTS: Our data show that pregestational diabetes resulted in CHDs in 58% of the offspring, including ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defects (AVSD), transposition of great arteries (TGA), double outlet right ventricle (DORV) and tetralogy of Fallot (TOF). Treatment with NAC in drinking water in pregestational diabetic mice completely eliminated the incidence of AVSD, TGA, TOF and significantly diminished the incidence of ASD and VSD. Furthermore, pregestational diabetes increased ROS, impaired cell proliferation, and altered Gata4, Gata5 and Vegf-a expression in the fetal heart of diabetic offspring, which were all prevented by NAC treatment.<br><br>CONCLUSIONS: Treatment with NAC increases GSH levels, decreases ROS levels in the fetal heart and prevents the development of CHDs in the offspring of pregestational diabetes. Our study suggests that NAC may have therapeutic potential in the prevention of CHDs induced by pregestational diabetes.}, }
@article {pmid24531690, year = {2014}, author = {Onami, K and Kimura, Y and Ito, Y and Yamauchi, T and Yamasaki, K and Aiba, S}, title = {Nonmetal haptens induce ATP release from keratinocytes through opening of pannexin hemichannels by reactive oxygen species.}, journal = {The Journal of investigative dermatology}, volume = {134}, number = {7}, pages = {1951-1960}, pmid = {24531690}, issn = {1523-1747}, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Antioxidants/pharmacology ; Benzopyrans/pharmacology ; Cell Death/drug effects/physiology ; Cells, Cultured ; Connexins/chemistry/genetics/*metabolism ; Cystine/analogs &amp; derivatives/pharmacology ; Dermatitis, Contact/*metabolism/pathology ; Dinitrochlorobenzene/pharmacology ; Disease Models, Animal ; Female ; Haptens/*metabolism ; Humans ; Irritants/pharmacology ; Keratinocytes/cytology/*metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/chemistry/genetics/*metabolism ; Nickel/pharmacology ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Pyrimidinones/pharmacology ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; }, abstract = {Although extracellular adenosine 5'-triphosphate (eATP) has a crucial role in the sensitization phase of contact hypersensitivity (CHS), the mechanism by which hapten causes keratinocyte cell death and ATP release is unknown. We examined the time course of cell death, reactive oxygen species (ROS) production, and ATP release in HaCaT cells and in normal human keratinocytes after exposure to nonmetal haptens, NiCl2, or irritants. Both haptens and irritants caused cell death of keratinocytes but with different time courses. N-acetylcysteine (NAC) significantly reduced only nonmetal hapten-induced cell death as assessed by propidium iodide exclusion. We examined the effects of antioxidants and pannexin (Panx) inhibitors on cell death, ROS production, and ATP release by chemical-treated HaCaT cells. Nonmetal hapten-induced cell death, but not NiCl2- or irritant-related cell death, was dependent on reactivity to thiol residues in the cells. NAC reduced cell death and ATP release, whereas antioxidants and Panx inhibitors did not inhibit cell death but significantly attenuated ATP release. Panx1 small interfering RNA (siRNA) also suppressed ATP release from hapten-exposed HaCaT cells. Intraperitoneal injection of a Panx1 inhibitor attenuated murine CHS. These findings suggest that nonmetal hapten reactivity to thiol residues causes membrane disruption of keratinocytes and ROS production that leads to ATP release through opening of Panx hemichannels.}, }
@article {pmid24531561, year = {2014}, author = {Corbit, LH and Chieng, BC and Balleine, BW}, title = {Effects of repeated cocaine exposure on habit learning and reversal by N-acetylcysteine.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {39}, number = {8}, pages = {1893-1901}, pmid = {24531561}, issn = {1740-634X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cocaine/*pharmacology ; Conditioning, Operant/*drug effects ; Glutamic Acid/*metabolism ; *Habits ; Male ; Membrane Potentials/drug effects ; Neostriatum/drug effects ; Neuronal Plasticity/drug effects ; Rats ; Rats, Long-Evans ; }, abstract = {Exposure to drugs of abuse can result in a loss of control over both drug- and nondrug-related actions by accelerating the transition from goal-directed to habitual control, an effect argued to reflect changes in glutamate homeostasis. Here we examined whether exposure to cocaine accelerates habit learning and used in vitro electrophysiology to investigate its effects on measures of synaptic plasticity in the dorsomedial (DMS) and dorsolateral (DLS) striatum, areas critical for actions and habits, respectively. We then administered N-acetylcysteine (NAC) in an attempt to normalize glutamate homeostasis and hence reverse the cellular and behavioral effects of cocaine exposure. Rats received daily injections of cocaine (30 mg/kg) for 6 days and were then trained to lever press for a food reward. We used outcome devaluation and whole-cell patch-clamp electrophysiology to assess the behavioral and cellular effects of cocaine exposure. We then examined the ability of NAC to reverse the effects of cocaine exposure on these measures. Cocaine treatment produced a deficit in goal-directed action, as assessed by outcome devaluation, and increased the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) in the DMS but not in the DLS. Importantly, NAC treatment both normalized EPSC frequency and promoted goal-directed control in cocaine-treated rats. The promotion of goal-directed control has the potential to improve treatment outcomes in human cocaine addicts.}, }
@article {pmid24530511, year = {2014}, author = {Hu, Z and Yu, F and Gong, P and Qiu, Y and Zhou, W and Cui, Y and Li, J and Chen, H}, title = {Subneurotoxic copper(II)-induced NF-κB-dependent microglial activation is associated with mitochondrial ROS.}, journal = {Toxicology and applied pharmacology}, volume = {276}, number = {2}, pages = {95-103}, doi = {10.1016/j.taap.2014.01.020}, pmid = {24530511}, issn = {1096-0333}, mesh = {Animals ; Cells, Cultured ; Copper/*toxicity ; Humans ; Mice ; Microglia/*drug effects/metabolism ; Mitochondria/*drug effects/metabolism ; NADPH Oxidases/physiology ; NF-kappa B/*physiology ; Nitric Oxide/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Superoxides/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {Microglia-mediated neuroinflammation and the associated neuronal damage play critical roles in the pathogenesis of neurodegenerative disorders. Evidence shows an elevated concentration of extracellular copper(II) in the brains of these disorders, which may contribute to neuronal death through direct neurotoxicity. Here we explored whether extracellular copper(II) triggers microglial activation. Primary rat microglia and murine microglial cell line BV-2 cells were cultured and treated with copper(II). The content of tumor necrosis factor-α (TNF-α) and nitric oxide in the medium was determined. Extracellular hydrogen peroxide was quantified by a fluorometric assay with Amplex Red. Mitochondrial superoxide was measured by MitoSOX oxidation. At subneurotoxic concentrations, copper(II) treatment induced a dose- and time-dependent release of TNF-α and nitric oxide from microglial cells, and caused an indirect, microglia-mediated neurotoxicity that was blocked by inhibition of TNF-α and nitric oxide production. Copper(II)-initiated microglial activation was accompanied with reduced IкB-α expression as well as phosphorylation and translocation of nuclear factor-κB (NF-κB) p65 and was blocked by NF-κB inhibitors (BAY11-7082 and SC-514). Moreover, copper(II) treatment evoked a rapid release of hydrogen peroxide from microglial cells, an effect that was not affected by NADPH oxidase inhibitors. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), abrogated copper(II)-elicited microglial release of TNF-α and nitric oxide and subsequent neurotoxicity. Importantly, mitochondrial production of superoxide, paralleled to extracellular release of hydrogen peroxide, was induced after copper(II) stimulation. Our findings suggest that extracellular copper(II) at subneurotoxic concentrations could trigger NF-κB-dependent microglial activation and subsequent neurotoxicity. NADPH oxidase-independent, mitochondria-derived ROS may be involved in this activation.}, }
@article {pmid24523759, year = {2013}, author = {Tayarani-Najaran, Z and Asili, J and Aioubi, E and Emami, SA}, title = {Growth Inhibition and Apoptosis Induction of Salvia chloroleuca on MCF-7 Breast Cancer Cell Line.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {12}, number = {4}, pages = {789-799}, pmid = {24523759}, issn = {1735-0328}, abstract = {Fragrant species of the genus Salvia have been attributed many medicinal properties, which include anticancer activity. In the present study, cytotoxic properties of total methanol extract of Salvia chloroleuca Rech. f. &amp; Aellen and its fractions were investigated on MCF- 7, a breast carcinoma cell line. Malignant and non-malignant cells were cultured in RPMI medium and incubated with different concentrations of plant extracts. Cell viability was quantitated by 3-(4,5-dimethylthiazol-2-yl) -5-(3-carboxymethoxyphenyl) -2-(4-sulphophenyl) -2H-tetrazolium (MTS) assay. Apoptotic cells were determined using propidium iodide (PI) staining of DNA fragmentation by flow cytometry (sub-G1 peak). S. chloroleuca inhibited the growth of malignant cells in a dose-dependent manner. Among solvent fractions of S. chloroleuca, the n-hexane and methylene chloride fractions were found to be more toxic compared to other fractions. S. chloroleuca-induced a sub-G1 peak in flow cytometry histogram of treated cells compared to control and DNA fragmentation suggested the induction of apoptosis. Administration of N-acetyl cysteine and vitamin C two ROS scavengers also resulted in significant inhibition of cytotoxicity induced by S. chloroleuca. These results support a mechanism whereby S. chloroleuca induces apoptosis of MCF-7 human breast cells through a ROS-mediated pathway.}, }
@article {pmid24521900, year = {2013}, author = {Yu, HZ and Wu, Q and Du, ZZ and Sun, X and Wang, CZ and Li, L}, title = {[High-fat diet induces pulmonary fibrosis in rats and inhibitory effects of N-acetylcysteine].}, journal = {Zhonghua yi xue za zhi}, volume = {93}, number = {44}, pages = {3547-3550}, pmid = {24521900}, issn = {0376-2491}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Diet, High-Fat/*adverse effects ; Disease Models, Animal ; Lung/drug effects/metabolism/pathology ; Male ; Pulmonary Fibrosis/*etiology/metabolism/pathology ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/metabolism ; }, abstract = {OBJECTIVE: To explore the relation between high-fat diet and pulmonary fibrosis and the inhibition of N-acetylcysteine (NAC) on lung tissue in rats.<br><br>METHODS: Thirty Sprague Dawley (SD) male rats were randomly divided into control group (n = 10) on a quantitative control Lieber-DeCarli liquid diet, a high-fat diet group (n = 10) on a high fat-diet Lieber-DeCarli liquid diet and NAC group (n = 10) on NAC 300 mg&#xd7;kg(-1)&#xd7;d(-1). All rats were sacrificed 8 weeks later. The morphological changes and collagen deposition in lung tissue were observed by hematoxylin &amp; eosin and Masson staining while the contents of glutathione (GSH) and hyaluronic acid (HA) measured through colorimetry and enzyme-linked immunosorbent assay. And the expression of transforming growth factor-&#x3b2;1 (TGF-&#x3b2;1) expression in lung tissue was detected through immunohistochemistry.<br><br>RESULTS: There were variable degree of alveolar and alveolar septal infiltration of inflammatory cells. And more deposition of collagen fibers appeared at intervals of alveolar in high fat group. Similar pathological changes were found in NAC group, but the degree was lower than that of high-fat group. Compared to the control and NAC groups, the lung tissue content of GSH decreased (GSH: 0.11 &#xb1; 0.05 vs 0.19 &#xb1; 0.11, 0.22 &#xb1; 0.14 mg/g, both P < 0.05) while HA and TGF-&#x3b2;1 increased in high-fat diet group (HA: 0.57 &#xb1; 0.06 vs 0.46 &#xb1; 0.04, 0.41 &#xb1; 0.04 mg/g; TGF-&#x3b2;1: 24.6 &#xb1; 3.4 vs 16.8 &#xb1; 2.6, 11.7 &#xb1; 1.5, all P < 0.05).<br><br>CONCLUSION: High-fat diet may induce pulmonary fibrosis in rats and NAC has inhibitory effects.}, }
@article {pmid24521312, year = {2015}, author = {Yang, Y and Huang, H and Ba, Y and Cheng, XM and Cui, LX}, title = {Effect of oxidative stress on fluoride-induced apoptosis in primary cultured Sertoli cells of rats.}, journal = {International journal of environmental health research}, volume = {25}, number = {1}, pages = {1-9}, doi = {10.1080/09603123.2014.883595}, pmid = {24521312}, issn = {1369-1619}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cells, Cultured ; Male ; Oxidative Stress/*drug effects ; Rats ; Sertoli Cells/*drug effects ; Sodium Fluoride/*toxicity ; }, abstract = {This study examined the effect of oxidative stress on the apoptosis of Sertoli cells induced by sodium fluoride (NaF). Cell viability, reactive oxygen species, malondialdehyde content, superoxide dismutase activity, mitochondrial membrane potential, and apoptosis were measured after the rat Sertoli cells were exposed to various concentrations of (0, 6, 12, and 24 μg/ml) sodium fluoride in the presence and absence of 2 mM N-acetylcysteine (NAC) for 24 h. The present study showed that decrease in cell viability and excessive oxidative stress were observed in NaF-treated cells. The treatment with NAC restored the decreased cell viability and excessive oxidative stress. Moreover, fluoride exposure decreased mitochondrial membrane potential and increased apoptosis in Sertoli cells. NAC was also found to suppress a loss of mitochondrial membrane potential and the percentage of apoptosis in NaF-treated Sertoli cells. This study proved that oxidative stress probably play a major role in NaF-induced apoptosis of Sertoli cells.}, }
@article {pmid24521085, year = {2014}, author = {Trapani, A and Palazzo, C and Contino, M and Perrone, MG and Cioffi, N and Ditaranto, N and Colabufo, NA and Conese, M and Trapani, G and Puglisi, G}, title = {Mucoadhesive properties and interaction with P-glycoprotein (P-gp) of thiolated-chitosans and -glycol chitosans and corresponding parent polymers: a comparative study.}, journal = {Biomacromolecules}, volume = {15}, number = {3}, pages = {882-893}, doi = {10.1021/bm401733p}, pmid = {24521085}, issn = {1526-4602}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*chemistry ; Caco-2 Cells ; Chitosan/*chemistry ; *Drug Delivery Systems ; Glycols/chemistry ; Humans ; Polymers/*chemistry ; Sulfhydryl Compounds/chemistry ; }, abstract = {The aim of the present work was to compare the mucoadhesive and efflux pump P-glycoprotein (P-gp) interacting properties of chitosan (CS)- and glycolchitosan (GCS)-based thiomers and corresponding unmodified parent polymers. For this purpose, the glycol chitosan-N-acetyl-cysteine (GCS-NAC) and glycol chitosan-glutathione (GCS-GSH) thiomers were prepared under simple and mild conditions. Their mucoadhesive characteristics were studied by turbidimetric and zeta potential measurements. The P-gp interacting properties were evaluated measuring the effects of thiolated- and unmodified-polymers on the bidirectional transport (BA/AB) of rhodamine-123 across Caco-2 cells as well as in the calcein-AM and ATPase activity assays. Although all the thiomers and unmodified polymers showed optimal-excellent mucoadhesive properties, the best mucoadhesive performances have been obtained by CS and CS-based thiomers. Moreover, it was found that the pretreatment of Caco-2 cell monolayer with GCS-NAC or GCS restores Rho-123 cell entrance by inhibiting P-gp activity. Hence, GCS-NAC and GCS may constitute new biomaterials useful for improving the bioavailability of P-gp substrates.}, }
@article {pmid24519543, year = {2014}, author = {Senol, N and Nazıroğlu, M and Yürüker, V}, title = {N-acetylcysteine and selenium modulate oxidative stress, antioxidant vitamin and cytokine values in traumatic brain injury-induced rats.}, journal = {Neurochemical research}, volume = {39}, number = {4}, pages = {685-692}, pmid = {24519543}, issn = {1573-6903}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism ; Brain Injuries/drug therapy/*metabolism ; Cytokines/*metabolism ; Male ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects/*physiology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Selenium/pharmacology/*therapeutic use ; Vitamin A/*metabolism ; }, abstract = {It has been suggested that oxidative stress plays an important role in the pathophysiology of traumatic brain injury (TBI). N-acetylcysteine (NAC) and selenium (Se) display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties although there is no report on oxidative stress, antioxidant vitamin, interleukin-1 beta (IL)-1β and IL-4 levels in brain and blood of TBI-induced rats. We investigated effects of NAC and Se administration on physical injury-induced brain toxicity in rats. Thirty-six male Sprague-Dawley rats were equally divided into four groups. First and second groups were used as control and TBI groups, respectively. NAC and Se were administrated to rats constituting third and forth groups at 1, 24, 48 and 72 h after TBI induction, respectively. At the end of 72 h, plasma, erythrocytes and brain cortex samples were taken. TBI resulted in significant increase in brain cortex, erythrocytes and plasma lipid peroxidation, total oxidant status (TOS) in brain cortex, and plasma IL-1β values although brain cortex vitamin A, β-carotene, vitamin C, vitamin E, reduced glutathione (GSH) and total antioxidant status (TAS) values, and plasma vitamin E concentrations, plasma IL-4 level and brain cortex and erythrocyte glutathione peroxidase (GSH-Px) activities decreased by TBI. The lipid peroxidation and IL-1β values were decreased by NAC and Se treatments. Plasma IL-4, brain cortex GSH, TAS, vitamin C and vitamin E values were increased by NAC and Se treatments although the brain cortex vitamin A and erythrocyte GSH-Px values were increased through NAC only. In conclusion, NAC and Se caused protective effects on the TBI-induced oxidative brain injury and interleukin production by inhibiting free radical production, regulation of cytokine-dependent processes and supporting antioxidant redox system.}, }
@article {pmid24515807, year = {2014}, author = {Carocci, A and Rovito, N and Sinicropi, MS and Genchi, G}, title = {Mercury toxicity and neurodegenerative effects.}, journal = {Reviews of environmental contamination and toxicology}, volume = {229}, number = {}, pages = {1-18}, doi = {10.1007/978-3-319-03777-6_1}, pmid = {24515807}, issn = {0179-5953}, mesh = {Animals ; Glutathione/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Mercury/pharmacokinetics/*toxicity ; Mitochondria/drug effects ; Neurodegenerative Diseases/*chemically induced/metabolism ; }, abstract = {Mercury is among the most toxic heavy metals and has no known physiological role in humans. Three forms of mercury exist: elemental, inorganic and organic. Mercury has been used by man since ancient times. Among the earliest were the Chinese and Romans, who employed cinnabar (mercury sulfide) as a red dye in ink (Clarkson et al. 2007). Mercury has also been used to purify gold and silver minerals by forming amalgams. This is a hazardous practice, but is still widespread in Brazil's Amazon basin, in Laos and in Venezuela, where tens of thousands of miners are engaged in local mining activities to find and purify gold or silver. Mercury compounds were long used to treat syphilis and the element is still used as an antiseptic,as a medicinal preservative and as a fungicide. Dental amalgams, which contain about 50% mercury, have been used to repair dental caries in the U.S. since 1856.Mercury still exists in many common household products around the world.Examples are: thermometers, barometers, batteries, and light bulbs (Swain et al.2007). In small amounts, some organo mercury-compounds (e.g., ethylmercury tiosalicylate(thimerosal) and phenylmercury nitrate) are used as preservatives in some medicines and vaccines (Ballet al. 2001).Each mercury form has its own toxicity profile. Exposure to Hg0 vapor and MeHg produce symptoms in CNS, whereas, the kidney is the target organ when exposures to the mono- and di-valent salts of mercury (Hg+ and Hg++, respectively)occur. Chronic exposure to inorganic mercury produces stomatitis, erethism and tremors. Chronic MeHg exposure induced symptoms similar to those observed in ALS, such as the early onset of hind limb weakness (Johnson and Atchison 2009).Among the organic mercury compounds, MeHg is the most biologically available and toxic (Scheuhammer et a!. 2007). MeHg is neurotoxic, reaching high levels of accumulation in the CNS; it can impair physiological function by disrupting endocrine glands (Tan et a!. 2009).The most important mechanism by which mercury causes toxicity appears to bemitochondrial damage via depletion of GSH (Nicole et a!. 1998), coupled with binding to thiol groups (-SH), which generates free radicals. Mercury has a high affinity for thiol groups (-SH) and seleno groups (-SeH) that are present in amino acids as cysteine and N-acetyl cysteine, lipoic acid, proteins, and enzymes. N-acetylcysteine and cysteine are precursors for the biosynthesis of GSH, which is among the most powerful intracellular antioxidants available to protect against oxidative stress and inflammation.Mercury and methylmercury induce mitochondrial dysfunction, which reduces ATP synthesis and increases lipid, protein and DNA peroxidation. The content of metallothioneines, GSH, selenium and fish high in omega-3 fatty acids appear to be strongly related with degree of inorganic and organic mercury toxicity, and with the protective detoxifying mechanisms in humans. In conclusion, depletion of GSH,breakage of mitochondria, increased lipid peroxidation, and oxidation of proteins and DNA in the brain, induced by mercury and his salts, appear to be important factors in conditions such as ALS and AD (Bains and Shaw 1997; Nicole eta!. 1998;Spencer eta!. 1998; Alberti et a!. 1999).}, }
@article {pmid24511549, year = {2014}, author = {Uysal, AI and Ocmen, E and Akan, M and Ozkardesler, S and Ergur, BU and Guneli, E and Kume, T and Koca, U and Unal Togrul, B}, title = {The effects of remote ischemic preconditioning and N-acetylcysteine with remote ischemic preconditioning in rat hepatic ischemia reperfusion injury model.}, journal = {BioMed research international}, volume = {2014}, number = {}, pages = {892704}, pmid = {24511549}, issn = {2314-6141}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Animals ; Disease Models, Animal ; Ischemic Preconditioning/*methods ; Liver/enzymology/metabolism/pathology ; Male ; Rats ; Rats, Wistar ; Reperfusion Injury/*therapy ; }, abstract = {BACKGROUND: Remote ischemic preconditioning (RIP) and pharmacological preconditioning are the effective methods that can be used to prevent ischemia reperfusion (IR) injury. The aim of this study was to evaluate the effects of RIP and N-Acetylcysteine (NAC) with RIP in the rat hepatic IR injury model.<br><br>MATERIALS AND METHODS: 28 rats were divided into 4 groups. Group I (sham): only laparotomy was performed. Group II (IR): following 30 minutes of hepatic pedicle occlusion, 4 hours of reperfusion was performed. Group III (RIP + IR): following 3 cycles of RIP, hepatic IR was performed. Group IV (RIP + NAC + IR): following RIP and intraperitoneal administration of NAC (150 mg/kg), hepatic IR was performed. All the rats were sacrificed after blood samples were taken for the measurements of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver was processed for conventional histopathology.<br><br>RESULTS: The hepatic histopathological injury scores of RIP + IR and RIP + NAC + IR groups were significantly lower than IR group (P = 0.006, P = 0.003, resp.). There were no significant differences in AST and ALT values between the IR, RIP + IR, and RIP + NAC + IR groups.<br><br>CONCLUSIONS: In the present study, it was demonstrated histopathologically that RIP and RIP + NAC decreased hepatic IR injury significantly.}, }
@article {pmid24507776, year = {2014}, author = {Tummala, H and Kirwan, M and Walne, AJ and Hossain, U and Jackson, N and Pondarre, C and Plagnol, V and Vulliamy, T and Dokal, I}, title = {ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function.}, journal = {American journal of human genetics}, volume = {94}, number = {2}, pages = {246-256}, pmid = {24507776}, issn = {1537-6605}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/metabolism ; Anemia, Aplastic ; Bone Marrow Diseases ; Bone Marrow Failure Disorders ; Cell Line, Tumor ; Cell Nucleus/genetics/metabolism ; Cell Survival/drug effects ; DNA Damage/drug effects ; DNA Helicases/*genetics ; DNA Repair/*genetics ; Female ; Gene Knockdown Techniques ; HEK293 Cells ; HeLa Cells ; Hemoglobinuria, Paroxysmal/*genetics ; Histones/genetics/metabolism ; Humans ; Male ; Mitochondria/drug effects/*genetics ; Mitomycin/toxicity ; Mutation ; Pedigree ; Phosphorylation ; Reactive Oxygen Species ; Sesquiterpenes/toxicity ; }, abstract = {Exome sequencing was performed in three index cases with bone marrow failure and neurological dysfunction and whose parents are first-degree cousins. Homozygous truncating mutations were identified in ERCC6L2 in two of the individuals. Both of these mutations affect the subcellular localization and stability of ERCC6L2. We show here that knockdown of ERCC6L2 in human A549 cells significantly reduced their viability upon exposure to the DNA-damaging agents mitomycin C and Irofulven, but not etoposide and camptothecin, suggesting a role in nucleotide excision repair. ERCC6L2-knockdown cells also displayed H2AX phosphorylation, which significantly increased upon genotoxic stress, suggesting an early DNA-damage response. Intriguingly, ERCC6L2 was seen to translocate to the mitochondria and the nucleus in response to DNA damage, and ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger N-acetyl cysteine attenuated the Irofulven-induced cytotoxicity in ERCC6L2-knockdown cells and abolished ERCCGL2 traffic to the mitochondria and nucleus in response to this DNA-damaging agent. Collectively, these observations identify a distinct bone-marrow-failure syndrome due to mutations in ERCC6L2, a gene implicated in DNA repair and mitochondrial function.}, }
@article {pmid24506481, year = {2014}, author = {Hagihara, K and Mizukura, A and Kitai, Y and Yao, M and Ishida, K and Kita, A and Kunoh, T and Masuko, T and Matzno, S and Chiba, K and Sugiura, R}, title = {FTY720 stimulated ROS generation and the Sty1/Atf1 signaling pathway in the fission yeast Schizosaccharomyces pombe.}, journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms}, volume = {19}, number = {4}, pages = {325-337}, doi = {10.1111/gtc.12134}, pmid = {24506481}, issn = {1365-2443}, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 1/genetics/*metabolism ; Calcium/metabolism ; Cell Proliferation ; Fingolimod Hydrochloride ; Free Radical Scavengers/pharmacology ; Immunosuppressive Agents/*pharmacology ; Mitogen-Activated Protein Kinases/genetics/*metabolism ; Oxidative Stress ; Phosphoproteins/genetics/*metabolism ; Propylene Glycols/*pharmacology ; Reactive Oxygen Species/*metabolism ; Schizosaccharomyces/*drug effects/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Signal Transduction ; Sphingosine/*analogs &amp; derivatives/pharmacology ; }, abstract = {Fingolimod hydrochloride (FTY720) is the first-in-class immune modulator known as sphingosine 1-phosphate (S1P) receptor agonists. FTY720 has also been reported to exert a variety of physiological functions such as antitumor effect, angiogenesis inhibition, and Ca2+ mobilization. Here, we show that FTY720 treatment induced reactive oxygen species (ROS) accumulation, and investigated the effect of FTY720 on the stress-activated MAP kinase Spc1/Sty1, a functional homologue of p38 MAPK, using a Renilla luciferase reporter construct fused to the CRE, which gives an accurate measure of the transcriptional activity of Atf1 and thus serves as a faithful readout of the Spc1/Sty1 MAPK signaling in response to oxidative stresses. FTY720 stimulated the CRE responses in a concentration-dependent manner, which was markedly reduced by deletion of the components of the Spc1/Sty1 MAPK pathway. The blockade of ROS production by NAC (N-acetyl-L-cysteine) significantly reversed the FTY720-induced ROS accumulation, subsequent activation of the Spc1/Sty1 MAPK pathway, and inhibition of cell proliferation. Cells lacking the components of the Spc1/Sty1 MAPK exhibited higher sensitivity to FTY720 and higher ROS levels upon FTY720 treatment than in wild-type cells. Thus, our results demonstrate the usefulness of fission yeast for elucidating the FTY720-mediated signaling pathways involving ROS.}, }
@article {pmid24499315, year = {2014}, author = {Mishra, MK and Beaty, CA and Lesniak, WG and Kambhampati, SP and Zhang, F and Wilson, MA and Blue, ME and Troncoso, JC and Kannan, S and Johnston, MV and Baumgartner, WA and Kannan, RM}, title = {Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.}, journal = {ACS nano}, volume = {8}, number = {3}, pages = {2134-2147}, pmid = {24499315}, issn = {1936-086X}, support = {R01 HL091541/HL/NHLBI NIH HHS/United States ; S10 RR027445/RR/NCRR NIH HHS/United States ; U54 HD079123/HD/NICHD NIH HHS/United States ; R01 HL091541-18/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/chemistry/pharmacology/therapeutic use ; Animals ; Biological Transport ; Brain/drug effects/*metabolism/pathology/physiopathology ; Brain Injuries/*drug therapy/*metabolism/pathology/physiopathology ; Circulatory Arrest, Deep Hypothermia Induced/*adverse effects ; Dendrimers/chemistry/*metabolism ; Disease Models, Animal ; Dogs ; Drug Carriers/chemistry/*metabolism ; Male ; Microglia/drug effects/metabolism ; Nanomedicine ; Neurons/drug effects/metabolism ; Rabbits ; Treatment Outcome ; Valproic Acid/adverse effects/chemistry/pharmacology/therapeutic use ; }, abstract = {Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer-drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.}, }
@article {pmid24499192, year = {2014}, author = {Chai, W and Zhang, J and Duan, Y and Pan, D and Liu, W and Li, Y and Yan, X and Chen, B}, title = {Pseudomonas pyocyanin stimulates IL-8 expression through MAPK and NF-κB pathways in differentiated U937 cells.}, journal = {BMC microbiology}, volume = {14}, number = {}, pages = {26}, pmid = {24499192}, issn = {1471-2180}, mesh = {Gene Expression Profiling ; Humans ; Interleukin-8/biosynthesis/*immunology ; *MAP Kinase Signaling System ; Macrophages/*immunology/*microbiology ; NF-kappa B/*metabolism ; Pseudomonas aeruginosa/*immunology ; Pyocyanine/*immunology/metabolism ; U937 Cells ; }, abstract = {BACKGROUND: Pyocyanin (PCN), an extracellular product of Pseudomonas aeruginosa and a blue redox active secondary metabolite, plays an important role in invasive pulmonary infection. However, the detailed inflammatory response triggered by PCN infection in inflammatory cells (particularly macrophages), if present, remains to be clarified. To investigate the effects of PCN on macrophages, the ability of PCN to induce inflammation reaction and the signaling pathway for IL-8 release in PCN-induced differentiated U937 cells were examined.<br><br>RESULTS: It was found that PCN increased IL-8 release and mRNA expression in Phorbol 12-myristate 13-acetate (PMA) differentiated U937 cells in both a concentration- and time-dependent manner by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). P38 and ERK MAPKs were activated after 10 min of induction with PCN and their levels returned to baselines after 30 min by Western blotting. It was also found that within 10 min of PCN incubation, the level of p-I-&#x3ba;B&#x3b1; in the cytosol was increased, which returned to baseline level after 60 min. Meanwhile, the level of p-p65 was increased in the nuclear extract and cytosol, and maintained high in total cell lysates. The results were further confirmed by the observation that p38, ERK1/2 and NF-&#x3ba;B inhibitors inhibited PCN-induced NF-&#x3ba;B activation and attenuated PCN-induced IL-8 expression in U937 cells as a function of their concentrations. Moreover, it was shown that PCN induced oxidative stress in U937 cells and N-acetyl cysteine, an antioxidant, was able to inhibit PCN-induced IL-8 protein expression.<br><br>CONCLUSIONS: It is concluded that PCN induces IL-8 secretion and mRNA expression in PMA-differentiated U937 cells in a concentration- and time- dependent manner. Furthermore, p38 and ERK MAPKs and NF-&#x3ba;&#x392; signaling pathways may be involved in the expression of IL-8 in PCN-incubated PMA-differentiated U937 cells.}, }
@article {pmid24497307, year = {2014}, author = {Lu, J and Li, W and Du, X and Ewert, DL and West, MB and Stewart, C and Floyd, RA and Kopke, RD}, title = {Antioxidants reduce cellular and functional changes induced by intense noise in the inner ear and cochlear nucleus.}, journal = {Journal of the Association for Research in Otolaryngology : JARO}, volume = {15}, number = {3}, pages = {353-372}, pmid = {24497307}, issn = {1438-7573}, mesh = {Acetylcysteine/pharmacokinetics/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Benzenesulfonates/pharmacokinetics/*pharmacology ; Cochlear Nucleus/*drug effects/pathology/physiology ; Ear, Inner/*drug effects/pathology/physiology ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Hair Cells, Auditory/drug effects ; Hearing Loss, Noise-Induced/*drug therapy ; Male ; Neuroprotective Agents/*pharmacology ; Noise/*adverse effects ; Otoacoustic Emissions, Spontaneous/drug effects ; Proto-Oncogene Proteins c-fos/analysis ; Rats ; Rats, Long-Evans ; Spin Trapping ; Spiral Ganglion/pathology ; }, abstract = {The present study marks the first evaluation of combined application of the antioxidant N-acetylcysteine (NAC) and the free radical spin trap reagent, disodium 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07), as a therapeutic approach for noise-induced hearing loss (NIHL). Pharmacokinetic studies and C-14 tracer experiments demonstrated that both compounds achieve high blood levels within 30 min after i.p injection, with sustained levels of radiolabeled cysteine (released from NAC) in the cochlea, brainstem, and auditory cortex for up to 48 h. Rats exposed to 115 dB octave-band noise (10-20 kHz) for 1 h were treated with combined NAC/HPN-07 beginning 1 h after noise exposure and for two consecutive days. Auditory brainstem responses (ABR) showed that treatment substantially reduced the degree of threshold shift across all test frequencies (2-16 kHz), beginning at 24 h after noise exposure and continuing for up to 21 days. Reduced distortion product otoacoustic emission (DPOAE) level shifts were also detected at 7 and 21 days following noise exposure in treated animals. Noise-induced hair cell (HC) loss, which was localized to the basal half of the cochlea, was reduced in treated animals by 85 and 64% in the outer and inner HC regions, respectively. Treatment also significantly reduced an increase in c-fos-positive neuronal cells in the cochlear nucleus following noise exposure. However, no detectable spiral ganglion neuron loss was observed after noise exposure. The results reported herein demonstrate that the NAC/HPN-07 combination is a promising pharmacological treatment of NIHL that reduces both temporary and permanent threshold shifts after intense noise exposure and acts to protect cochlear sensory cells, and potentially afferent neurites, from the damaging effects of acoustic trauma. In addition, the drugs were shown to reduce aberrant activation of neurons in the central auditory regions of the brain following noise exposure. It is likely that the protective mechanisms are related to preservation of structural components of the cochlea and blocking the activation of immediate early genes in the auditory centers of the brain.}, }
@article {pmid24496840, year = {2014}, author = {Xu, CC and Yang, SF and Zhu, LH and Cai, X and Sheng, YS and Zhu, SW and Xu, JX}, title = {Regulation of N-acetyl cysteine on gut redox status and major microbiota in weaned piglets.}, journal = {Journal of animal science}, volume = {92}, number = {4}, pages = {1504-1511}, doi = {10.2527/jas.2013-6755}, pmid = {24496840}, issn = {1525-3163}, mesh = {Acetylcysteine/*metabolism ; Animals ; Antioxidants/metabolism ; Intestines/*enzymology/microbiology ; Oxidation-Reduction ; *Swine ; Weaning ; }, abstract = {This study was conducted to explore the regulation of N-acetyl cysteine (NAC) on gut redox status and proliferation of selected microbiota in weaned piglets. A total of 150 newborn piglets from 15 litters were randomly divided by litter to the control group (normally suckling), the weaning group (fed the basal diet), and the NAC group (basal + NAC diet) with 5 litters per group. Activities of total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and inhibition capacity of hydroxyl radical (IHR), and contents of malondialdehyde (MDA), H2O2, and NO in the ileum, colon, and cecum were analyzed to profile oxidative stress states. The real-time absolute quantitative PCR reaction was employed to quantify the amounts of total bacteria, Lactobacillus, Bifidobacterium, and Escherichia coli. The N-acetyl cysteine, as a universal antioxidant, was used to improve the redox status. Results showed that weaning stress resulted in the occurrence of gut oxidative stress and changes of gut microbiota (P < 0.05). Compared with the weaned piglets, the activities of ileal, colonic, and cecal T-AOC; ileal and colonic GSH-Px; cecal SOD; and colonic and cecal IHR were enhanced (P < 0.05), and the concentrations of ileal and cecal H2O2, ileal and colonic NO, and colonic MDA were reduced (P < 0.05) in the NAC-treated piglets. An increase (P < 0.05) in gut Lactobacillus and Bifidobacterium, accompanied with a decrease (P < 0.05) in Escherichia coli counts, was also observed in the NAC group. Bivariate correlation indicated that Lactobacillus and Bifidobacterium were positively correlated (P < 0.05) with the activities of T-AOC, GSH-Px, and SOD and inversely related (P < 0.05) to increased levels of H2O2, NO, OH, and MDA, and Escherichia coli showed a strong positive association (P < 0.05) with increased levels of free radicals and MDA and a negative association (P < 0.05) with the activities of antioxidant enzymes in intestines of weaned piglets. We concluded that NAC constructively regulated on the changes of the gut redox status and microbiota in piglets in response to weaning stress. The observed correlations implied that the NAC effects on the gut microbiota were confirmed, partly through an effect on oxidative stress in piglets, providing evidence that gut microbiota may be potentially improved by the modulation of the redox status by an antioxidant, which has relevance for gut health and function.}, }
@article {pmid24493151, year = {2014}, author = {Stinson, LF and Ireland, DJ and Kemp, MW and Payne, MS and Stock, SJ and Newnham, JP and Keelan, JA}, title = {Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes.}, journal = {Reproduction (Cambridge, England)}, volume = {147}, number = {3}, pages = {313-320}, doi = {10.1530/REP-13-0576}, pmid = {24493151}, issn = {1741-7899}, mesh = {Acetylcysteine/pharmacology ; Amides/pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Cell-Penetrating Peptides/pharmacology ; Cells, Cultured ; Cytokines/antagonists &amp; inhibitors/metabolism ; Dinoprostone/metabolism ; Extraembryonic Membranes/*drug effects/immunology/metabolism ; Female ; Humans ; Imidazoles/pharmacology ; Inflammation/immunology/*metabolism ; Pregnancy ; Pyrimidines/pharmacology ; Sheep ; Thiophenes/pharmacology ; }, abstract = {Intrauterine infection and inflammation are responsible for the majority of early (<32 weeks) spontaneous preterm births (PTBs). Anti-inflammatory agents, delivered intra-amniotically together with antibiotics, may be an effective strategy for preventing PTB. In this study, the effects of four cytokine-suppressive anti-inflammatory drugs (CSAIDs: N-acetyl cysteine (NAC), SB239063, TPCA-1 and NEMO binding domain inhibitor (NBDI)) were assessed on human and ovine gestational membrane inflammation. Full-thickness membranes were collected from healthy, term, human placentas delivered by Caesarean section (n=5). Using a Transwell model, they were stimulated ex vivo with γ-irradiation-killed Escherichia coli applied to the amniotic face. Membranes from near-term, ovine placentas were stimulated in utero with lipopolysaccharide, Ureaplasma parvum or saline control and subjected to explant culture. The effects of treatment with CSAIDs or vehicle (1% DMSO) on accumulation of PGE2 and cytokines (human interleukin 6 (IL6), IL10 and TNFα; ovine IL8 (oIL8)) were assessed in conditioned media at various time points (3-20 h). In human membranes, the IKKβ inhibitor TPCA-1 (7 μM) and p38 MAPK inhibitor SB239063 (20 μM) administered to the amniotic compartment were the most effective in inhibiting accumulation of cytokines and PGE2 in the fetal compartment. NAC (10 mM) inhibited accumulation of PGE2 and IL10 only; NBDI (10 μM) had no significant effect. In addition to the fetal compartment, SB239063 also exerted consistent and significant inhibitory effects in the maternal compartment. TPCA-1 and SB239063 suppressed oIL8 production, while all CSAIDs tested suppressed ovine PGE2 production. These results support the further investigation of intra-amniotically delivered CSAIDs for the prevention of inflammation-mediated PTB.}, }
@article {pmid24490082, year = {2013}, author = {Ishitsuka, Y and Fukumoto, Y and Kondo, Y and Irikura, M and Kadowaki, D and Narita, Y and Hirata, S and Moriuchi, H and Maruyama, T and Hamasaki, N and Irie, T}, title = {Comparative Effects of Phosphoenolpyruvate, a Glycolytic Intermediate, as an Organ Preservation Agent with Glucose and N-Acetylcysteine against Organ Damage during Cold Storage of Mouse Liver and Kidney.}, journal = {ISRN pharmacology}, volume = {2013}, number = {}, pages = {375825}, pmid = {24490082}, issn = {2090-5165}, abstract = {We evaluated the usefulness of phosphoenolpyruvate (PEP), a glycolytic intermediate with antioxidative and energy supplementation potentials, as an organ preservation agent. Using ex vivo mouse liver and kidney of a static cold storage model, we compared the effects of PEP against organ damage and oxidative stress during cold preservation with those of glucose or N-acetylcysteine (NAC). Lactate dehydrogenase (LDH) leakage, histological changes, and oxidative stress parameters (measured as thiobarbituric acid reactive substance and glutathione content) were determined. PEP (100 mM) significantly prevented an increase in LDH leakage, histological changes, such as tubulonecrosis and vacuolization, and changes in oxidative stress parameters during 72 h of cold preservation in mouse liver. Although glucose (100 mM) partly prevented LDH leakage and histological changes, no effects against oxidative stress were observed. By contrast, NAC inhibited oxidative stress in the liver and did not prevent LDH leakage or histological changes. PEP also significantly prevented kidney damage during cold preservation in a dose-dependent manner, and the protective effects were superior to those of glucose and NAC. We suggest that PEP, a functional carbohydrate with organ protective and antioxidative activities, may be useful as an organ preservation agent in clinical transplantation.}, }
@article {pmid24488173, year = {2014}, author = {González-Flores, D and Rodríguez, AB and Pariente, JA}, title = {TNFα-induced apoptosis in human myeloid cell lines HL-60 and K562 is dependent of intracellular ROS generation.}, journal = {Molecular and cellular biochemistry}, volume = {390}, number = {1-2}, pages = {281-287}, pmid = {24488173}, issn = {1573-4919}, mesh = {Apoptosis/drug effects/*genetics ; Caspase Inhibitors/administration &amp; dosage ; Caspases/*biosynthesis ; Chromans/administration &amp; dosage ; Gene Expression Regulation, Neoplastic/drug effects ; HL-60 Cells ; Humans ; K562 Cells ; Leukemia/*genetics/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/*administration &amp; dosage/metabolism ; }, abstract = {The present study determines the role of reactive oxygen species (ROS) production and calcium signaling evoked by the tumor necrosis factor-alpha (TNFα) on apoptosis in the human leukemia HL-60 and K562 cell lines. The results show that treatment of both cell lines cells with 10 ng/mL TNFα resulted in a rise in the percentage of apoptotic cells after 6 h of treatment. It was also observed that the administration of 10 ng/mL TNFα increased intracellular ROS production, as well as a time-dependent increase in caspase-8, -3, and -9 activities. The present results also show that the pretreatment with well-known antioxidants such as trolox and N-acetyl cysteine partially reduced the caspase activation caused by the administration of TNFα. The findings suggest that TNFα-induced apoptosis is dependent on alterations in intracellular ROS generation in human leukemia HL-60 and K562 cells.}, }
@article {pmid24486703, year = {2014}, author = {Xiao, GF and Xu, SH and Chao, Y and Xie, LD and Xu, CS and Wang, HJ}, title = {PPARδ activation inhibits homocysteine-induced p22(phox) expression in EA.hy926 cells through reactive oxygen species/p38MAPK pathway.}, journal = {European journal of pharmacology}, volume = {727}, number = {}, pages = {29-34}, doi = {10.1016/j.ejphar.2014.01.051}, pmid = {24486703}, issn = {1879-0712}, mesh = {Antioxidants/pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Endothelial Cells/*drug effects/enzymology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Homocysteine/*pharmacology ; Humans ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/*metabolism ; PPAR gamma/*agonists/metabolism ; Phosphorylation ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Thiazoles/*pharmacology ; Time Factors ; Up-Regulation ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Increased expression of the p22(phox) subunit of the NADPH oxidase complex may possibly contribute to both the enzyme׳s increased activation and the occurrence of oxidative stress during hyperhomocysteinaemia. However, the activation of peroxisome proliferator-activated receptor (PPAR) δ has been shown to inhibit p22(phox) expression. The purpose of this study was to elucidate the signaling pathway by which PPARδ activation regulated homocysteine-induced expression of p22(phox). EA.hy926 cells were stimulated with homocysteine (Hcy) in the presence or absence of the PPARδ-specific agonist, GW0742, or of various signaling inhibitors, including the antioxidants N-acetylcysteine (NAC), NADPH oxidase inhibitor, diphenyleneiodonium (DPI), and the p38MAPK inhibitor, SB203580. Expression of p22(phox) mRNA and phospho-p38MAPK protein were measured by real-time PCR and western blot analysis, respectively, and reactive oxygen species were measured by fluorescence microscopy. Our data indicate that Hcy increased both the expression of p22(phox) in a concentration-dependent manner and also increased phosphoryation of p38 MAPK and reactive oxygen species production in a time-dependent manner. However, activation of the PPARδ signaling pathway by the agonist GW0742 reversed all these changes induced by Hcy. Furthermore, SB203580 prevented the increase in p22(phox) expression, and NAC and DPI not only inhibited Hcy-induced phosphorylation of p38MAPK, but also prevented expression of p22(phox). These findings indicate that Hcy-induced expression of p22(phox) is regulated by the reactive oxygen species/p38MAPK pathway and that PPARδ activation is capable of attenuating this pathway by eliminating Hcy-induced reactive oxygen species production.}, }
@article {pmid24486459, year = {2014}, author = {Dilshara, MG and Lee, KT and Choi, YH and Moon, DO and Lee, HJ and Yun, SG and Kim, GY}, title = {Potential chemoprevention of LPS-stimulated nitric oxide and prostaglandin E2 production by α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranosyl-3-indolecarbonate in BV2 microglial cells through suppression of the ROS/PI3K/Akt/NF-κB pathway.}, journal = {Neurochemistry international}, volume = {67}, number = {}, pages = {39-45}, doi = {10.1016/j.neuint.2014.01.010}, pmid = {24486459}, issn = {1872-9754}, mesh = {Animals ; Anticarcinogenic Agents/*pharmacology ; Cell Line ; Chromatography, Ion Exchange ; Dinoprostone/*biosynthesis ; Disaccharides/*pharmacology ; Indoles/*pharmacology ; Lipopolysaccharides/*pharmacology ; Magnetic Resonance Spectroscopy ; Mice ; Microglia/*drug effects/enzymology/metabolism ; NF-kappa B/metabolism ; Nitric Oxide/*biosynthesis ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {α-l-Rhamnopyranosyl-(1→6)-β-d-glucopyranosyl-3-indolecarbonate (RG3I) is a chemical constituent isolated from the commonly used Asian traditional medicinal plant, Clematis mandshurica; however, no studies have been reported on its anti-inflammatory properties. In the present study, we found that RG3I attenuates the lipopolysaccharide (LPS)-induced DNA-binding activity of nuclear factor-κB (NF-κB) via the dephosphorylation of PI3K/Akt in BV2 microglial cells, leading to a suppression of nitric oxide (NO) and prostaglandin E2 (PGE2) production, along with that of their regulatory genes, inducible NO synthase (iNOS) and cyclooxygenase-2 (Cox-2). Further, the PI3K/Akt inhibitor, LY294002 diminished the expression of LPS-stimulated iNOS and COX-2 genes by suppressing NF-κB activity. Moreover, RG3I significantly inhibited LPS-induced reactive oxygen species (ROS) generation similar to the ROS inhibitors, N-acetylcysteine (NAC) and glutathione (GSH). Notably, NAC and GSH abolished the LPS-induced expression of iNOS and Cox-2 in BV2 microglial cells by inhibiting NF-κB activity. Taken together, our data indicate that RG3I suppresses the production of proinflammatory mediators such as NO and PGE2 as well as their regulatory genes in LPS-stimulated BV2 microglial cells by inhibiting the PI3K/Akt- and ROS-dependent NF-κB signaling pathway, suggesting that RG3I may be a good candidate to regulate LPS-induced inflammatory response.}, }
@article {pmid24486394, year = {2014}, author = {Elshazly, SM and El-Moselhy, MA and Barakat, W}, title = {Insights in the mechanism underlying the protective effect of α-lipoic acid against acetaminophen-hepatotoxicity.}, journal = {European journal of pharmacology}, volume = {726}, number = {}, pages = {116-123}, doi = {10.1016/j.ejphar.2014.01.042}, pmid = {24486394}, issn = {1879-0712}, mesh = {Acetaminophen/*adverse effects ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/blood/metabolism/pathology/*prevention &amp; control ; Cytoprotection/*drug effects ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione/metabolism ; Liver/*drug effects/enzymology/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Thioctic Acid/*pharmacology ; }, abstract = {Acetaminophen (APAP) is one of the most widely used analgesic antipyretic drugs and is a major cause of acute liver failure at overdose. The aim of this study is to investigate the possible protective effect of α-lipoic acid (α-LA, 20 or 100 mg/kg administered simultaneously or after 1.5 h) against APAP-induced hepatotoxicity in rats. Administration of APAP (1.5 g/kg i.p.) resulted in elevation of serum ALT and hepatic malondialdehyde (MDA) content, as well as decrease in hepatic glutathione (GSH) content. In addition, elevation in hepatic hemeoxygenase-1 (HO-1) and NADPH oxidase expression was observed accompanied with a significant reduction in glutathione synthase and cystathionine-beta-synthase (CβS) expression. Furthermore, nuclear factor kappa-B (NF-κB) activity was enhanced in APAP-treated rats. Administration of the standard APAP antidote; N-acetylcysteine (NAC, 1200 mg/kg) or α-LA (20 mg/kg), simultaneously or 1.5 h after APAP, ameliorated APAP-induced alterations in liver function, oxidant and inflammatory markers. Importantly, simultaneous administration of NAC or α-LA (20 mg/kg) was more protective than their later administration. However, the beneficial effect of α-LA was lost at higher dose level (100 mg/kg). Taken together, the beneficial effects of α-lipoic acid (20 mg/kg) were comparable to those of NAC which provides a new possible treatment for APAP-induced hepatotoxicity in patients who cannot tolerate NAC. However, careful dose selection is warranted since the beneficial effects of α-LA were lost at higher doses.}, }
@article {pmid24485406, year = {2014}, author = {Joshi, D and Mittal, DK and Shukla, S and Srivastav, AK and Srivastav, SK}, title = {N-acetyl cysteine and selenium protects mercuric chloride-induced oxidative stress and antioxidant defense system in liver and kidney of rats: a histopathological approach.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {28}, number = {2}, pages = {218-226}, doi = {10.1016/j.jtemb.2013.12.006}, pmid = {24485406}, issn = {1878-3252}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism ; Biomarkers/metabolism ; Catalase/metabolism ; Glutathione/metabolism ; Kidney/drug effects/metabolism/*pathology ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism/*pathology ; Male ; Mercuric Chloride/*toxicity ; Oxidative Stress/*drug effects ; Protective Agents/pharmacology ; Rats, Sprague-Dawley ; Selenium/*pharmacology ; Superoxide Dismutase/metabolism ; }, abstract = {Mercury exposure is second-most common cause of metal poisoning which is quite stable and biotransformed to highly toxic metabolites thus eliciting biochemical alterations and oxidative stress. The aim of present study describes the protective effect of selenium either alone or in combination with N-acetyl cysteine (NAC) against acute mercuric chloride poisoning. The experiment was carried out in male albino Sprague Dawley rats (n=30) which was divided into five groups. Group 1 served as control. Groups 2-5 were administered mercuric chloride (HgCl2: 12mol/kg, i.p.) once only, group 2 served as experimental control. Animals of groups 3, 4 and 5 were received N-acetyl cysteine (NAC: 0.6mg/kg, i.p.) and selenium (Se: 0.5mg/kg, p.o.) and NAC with Se in combination. Acute HgCl2 toxicity caused significant rise in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, albumin, bilirubin, γ-glutamyl transpeptidase, cholesterol, triglycerides, protein, urea, creatinine, uric acid and blood urea nitrogen content. Animals also showed significantly higher mercury content in liver and kidney, significant rise in lipid peroxidation level with concomitant decrease in reduced glutathione content and the antioxidant enzyme activities of superoxide dismutase and catalase after HgCl2 exposure. Results of the present investigation clearly showed that combination therapy with NAC+Se provide maximum protection against mercury toxicity than monotherapy (alone treated groups) by preventing oxidative degradation of biological membrane from metal mediated free radical attacks.}, }
@article {pmid24481553, year = {2014}, author = {Park, KW and Kundu, J and Chae, IG and Kim, DH and Yu, MH and Kundu, JK and Chun, KS}, title = {Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells.}, journal = {International journal of oncology}, volume = {44}, number = {4}, pages = {1309-1315}, doi = {10.3892/ijo.2014.2281}, pmid = {24481553}, issn = {1791-2423}, mesh = {Abietanes/*pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Caspase 3/biosynthesis ; Caspase 9/biosynthesis ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Colonic Neoplasms/*drug therapy ; Cyclin D1/biosynthesis ; Cyclin D2/biosynthesis ; Cyclin D3/biosynthesis ; DNA-Binding Proteins ; HCT116 Cells ; Humans ; Inhibitor of Apoptosis Proteins/biosynthesis ; Janus Kinase 2/antagonists &amp; inhibitors/metabolism ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-mdm2/biosynthesis ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors ; Signal Transduction/drug effects ; Survivin ; Tumor Suppressor Protein p53/biosynthesis ; bcl-2-Associated X Protein/biosynthesis ; bcl-X Protein/biosynthesis ; src-Family Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Carnosol, an active constituent of rosemary, has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of carnosol remain poorly understood. In the present study, we found that carnosol significantly reduced the viability of human colon cancer (HCT116) cells in a concentration- and time-dependent manner. Treatment of cells with carnosol induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of poly-(ADP-ribose) polymerase (PARP). Incubation with carnosol elevated the expression of Bax and inhibited the levels of Bcl-2 and Bcl-xl. Carnosol induced expression of p53 and inhibited that of murine-double minute-2 (Mdm2). Moreover, carnosol generated reactive oxygen species (ROS), and pretreatment with N-acetyl cysteine abrogated carnosol-induced cleavage of caspase-3 and PARP. The constitutive phosphorylation, the DNA binding and reporter gene activity of signal transducer and activator of transcription-3 (STAT3) was diminished by treatment with carnosol. To further elucidate the molecular mechanisms of STAT3 inactivation, we found that carnosol attenuated the phosphorylation of Janus-activated kinase-2 (Jak2) and Src kinase. Pharmacological inhibition of Jak2 and Src inhibited STAT3 phosphorylation. Furthermore, carnosol attenuated the expression of STAT3 target gene products, such as survivin, cyclin-D1, -D2, and -D3. Taken together, our study provides the first report that carnosol induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway.}, }
@article {pmid24480427, year = {2014}, author = {Shang, Y and Zhang, L and Jiang, Y and Li, Y and Lu, P}, title = {Airborne quinones induce cytotoxicity and DNA damage in human lung epithelial A549 cells: the role of reactive oxygen species.}, journal = {Chemosphere}, volume = {100}, number = {}, pages = {42-49}, doi = {10.1016/j.chemosphere.2013.12.079}, pmid = {24480427}, issn = {1879-1298}, mesh = {Acetylcysteine/pharmacology ; Calcium/metabolism ; Cell Line ; Cell Membrane/drug effects ; Cell Survival/drug effects ; *DNA Damage ; Epithelial Cells/cytology/*drug effects/metabolism ; Humans ; Intracellular Space/drug effects/metabolism ; Lung/*cytology ; Particulate Matter/*toxicity ; Quinones/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Ambient particulate matter (PM) is associated with adverse health effects. Quinones present in PM are hypothesized to contribute to these harmful effects through the generation of reactive oxygen species (ROS). However, whether the ROS induced by quinones is involved in mediating DNA damage as well as other biological responses in pulmonary cells is less well known. In this study, the toxic effects of five typical airborne quinones, including 1,2-naphthoquinone, 2-methylanthraquinone, 9,10-phenanthrenequinone, 2-methyl-1,4-naphthoquinone, and acenaphthenequinone, on cytotoxicity, DNA damage, intracellular calcium homeostasis, and ROS generation, were studied in human lung epithelial A549 cells. An antioxidant N-acetylcysteine (NAC) was used to examine the involvement of ROS in adverse biological responses induced by quinones. The quinones caused a concentration-dependent viability decrease, cellular LDH release, DNA damage, and ROS production in A549 cells. 1,2-Naphthoquinone, but not the other four quinones, increased intracellular calcium (Ca(2+)) levels in a dose-dependent manner. These toxic effects were abolished by administration of NAC, suggesting that ROS played a key role in the observed toxic effects of quinones in A549 cells. These results emphasize the importance of quinones in PM on the adverse health effects of PMs, which has been underestimated in the past few years, and highlight the need, when evaluating the effects on health and exposure management, to always consider their qualitative chemical compositions in addition to the size and concentration of PMs.}, }
@article {pmid24477817, year = {2014}, author = {Ozaydin, M and Peker, O and Erdogan, D and Akcay, S and Yucel, H and Icli, A and Ceyhan, BM and Sutcu, R and Uysal, BA and Varol, E and Dogan, A and Okutan, H}, title = {Oxidative status, inflammation, and postoperative atrial fibrillation with metoprolol vs carvedilol or carvedilol plus N-acetyl cysteine treatment.}, journal = {Clinical cardiology}, volume = {37}, number = {5}, pages = {300-306}, pmid = {24477817}, issn = {1932-8737}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Aged ; Antihypertensive Agents/adverse effects/*therapeutic use ; Atrial Fibrillation/*drug therapy/physiopathology ; Carbazoles/adverse effects/*therapeutic use ; Cardiac Surgical Procedures ; Carvedilol ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/adverse effects/*therapeutic use ; Humans ; Inflammation/*drug therapy ; Leukocyte Count ; Male ; Metoprolol/administration &amp; dosage/*therapeutic use ; Middle Aged ; Oxidative Stress/*drug effects ; Postoperative Period ; Propanolamines/adverse effects/*therapeutic use ; Prospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: Atrial fibrillation is associated with inflammation and oxidative stress.<br><br>HYPOTHESIS: Carvedilol and N-acetyl cysteine (NAC) combination decreases inflammation, oxidative stress, and postoperative atrial fibrillation (POAF) rates more than metoprolol or carvedilol.<br><br>METHODS: Preoperative and postoperative total oxidative stress (TOS), total antioxidant capacity (TAC), and white blood cells (WBC) were measured in metoprolol, carvedilol, or carvedilol plus NAC groups, and association with POAF was evaluated.<br><br>RESULTS: Preoperative TAC, TOS, and WBC levels were similar among the groups. Postoperative TAC levels were lower in the metoprolol group compared with the carvedilol group (1.0 vs 1.4) or the carvedilol plus NAC group (1.0 vs 1.9) and were also lower in the carvedilol group compared with the carvedilol plus NAC group (all P < 0.0001). Postoperative TOS levels were higher in the metoprolol group as compared with the carvedilol (29.6 vs 24.2; P < 0.0001) or the carvedilol plus NAC groups (P < 0.0001), and were also higher in the carvedilol group as compared with the carvedilol plus NAC group (24.2 vs 19.3; P < 0.0001). Postoperative WBC counts were lower in the carvedilol plus NAC group compared with the metoprolol group (12.9 vs 14.8; P = 0.004), were similar between the carvedilol and the metoprolol groups (13 vs 14.8) and between the carvedilol plus NAC group and the carvedilol group (both P > 0.05). Postoperative TAC, TOS, and WBC were associated with POAF.<br><br>CONCLUSIONS: Carvedilol plus NAC reduced oxidative stress and inflammation compared with metoprolol and decreased oxidative stress compared with carvedilol. Postoperative TAC, TOS, and WBC were associated with POAF.}, }
@article {pmid24477002, year = {2014}, author = {Sayin, VI and Ibrahim, MX and Larsson, E and Nilsson, JA and Lindahl, P and Bergo, MO}, title = {Antioxidants accelerate lung cancer progression in mice.}, journal = {Science translational medicine}, volume = {6}, number = {221}, pages = {221ra15}, doi = {10.1126/scitranslmed.3007653}, pmid = {24477002}, issn = {1946-6242}, mesh = {Acetylcysteine/adverse effects ; Animals ; Antioxidants/*adverse effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage ; Disease Models, Animal ; *Disease Progression ; Fibroblasts/drug effects/metabolism ; Humans ; Lung Neoplasms/*pathology ; Mice ; Reactive Oxygen Species/metabolism ; Solubility ; Tumor Suppressor Protein p53/metabolism ; Vitamin E/adverse effects/analogs &amp; derivatives ; }, abstract = {Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.}, }
@article {pmid24475426, year = {2013}, author = {Rouhi, H and Ganji, F}, title = {Effects of N-acetyl cysteine on serum lipoprotein (a) and proteinuria in type 2 diabetic patients.}, journal = {Journal of nephropathology}, volume = {2}, number = {1}, pages = {61-66}, pmid = {24475426}, issn = {2251-8363}, abstract = {BACKGROUND: About 30-40% of diabetic patients who developed nephropathy have lipoprotein disorders, especially lipoprotein a [Lp(a)], which is related to atherosclerosis.<br><br>OBJECTIVES: The aim of this study was to investigate the effect of N-acetyl cysteine (NAC) on the serum levels of Lp(a) and amount of proteinuria in a group of type 2 diabetic patients with diabetic nephropathy.<br><br>PATIENTS AND METHODS: A total of 40, type 2 diabetic (T2D) patients, patients with proteinuria, were randomly divided into two groups. The experimental group was treated by NAC (1200 mg/day) for two months in conjunction with conventional treatment for diabetes and hypertension. Control group received routine medications.<br><br>RESULTS: No significant change was identified in serum Lp(a) during treatment with NAC (P >0.05). However, NAC decreased the amount of proteinuria, serum triglyceride (TG) level and systolic blood pressure in experimental group compared to the control group (P <0.05).<br><br>CONCLUSIONS: These findings suggest that treatment with NAC has no significant effect on the serum level of Lp (a). However, it has beneficial effects on the reduction of proteinuria, serum TG level and systolic blood pressure in T2D patients with nephropathy. Further prospective studies are needed to determine its full role.}, }
@article {pmid24472723, year = {2014}, author = {Kim, TH and Woo, JS and Kim, YK and Kim, KH}, title = {Silibinin induces cell death through reactive oxygen species-dependent downregulation of notch-1/ERK/Akt signaling in human breast cancer cells.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {349}, number = {2}, pages = {268-278}, doi = {10.1124/jpet.113.207563}, pmid = {24472723}, issn = {1521-0103}, mesh = {Active Transport, Cell Nucleus ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis Inducing Factor/metabolism ; Breast Neoplasms ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Down-Regulation ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/genetics/*metabolism ; Female ; Humans ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptor, Notch1/genetics/*metabolism ; Signal Transduction ; Silybin ; Silymarin/*pharmacology ; }, abstract = {The present study was undertaken to determine the underlying mechanism of silibinin-induced cell death in human breast cancer cell lines MCF7 and MDA-MB-231. Silibinin-induced cell death was attenuated by antioxidants, N-acetylcysteine (NAC) and 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, suggesting that the effect of silibinin was dependent on generation of reactive oxygen species (ROS). Western blot analysis showed that silibinin induced downregulation of extracellular signal-regulated kinase (ERK) and Akt. When cells were transiently transfected with constitutively active (ca) mitogen-activated protein kinase (MEK), an upstream kinase of ERK and caAkt, they showed resistance to silibinin-induced cell death. Silibinin decreased the cleavage of Notch-1 mRNA and protein levels. Notch-1-overexpressed cells were resistant to the silibinin-induced cell death. Inhibition of Notch-1 signaling was dependent on ROSgeneration. Overexpression of Notch-1 prevented silibinin-induced inhibition of ERK and Akt phosphorylation. Silibinin-induced cell death was accompanied by increased cleavage of caspase-3 and was prevented by caspase-3 inhibitor in MDA-MB-231 cells but not in MCF7 cells. Silibinin induced translocation of apoptosis-inducing factor (AIF), which was blocked by NAC, and transfection of caMEK and caAkt. Silibinin-induced cell death was prevented by silencing of AIF expression using small interfering AIF RNA in MCF7 cells but not in MDA-MB-231 cells. In conclusion, silibinin induces cell death through an AIF-dependent mechanism in MCF7 cells and a caspase-3-dependent mechanism in MDA-MB-231 cells, and ROS generation and Notch-1 signaling act upstream of the ERK and Akt pathway. These data suggest that silibinin may serve as a potential agent for induction of apoptosis in human breast cancer cells.}, }
@article {pmid24469461, year = {2014}, author = {Vasudevarao, MD and Mizar, P and Kumari, S and Mandal, S and Siddhanta, S and Swamy, MM and Kaypee, S and Kodihalli, RC and Banerjee, A and Naryana, C and Dasgupta, D and Kundu, TK}, title = {Naphthoquinone-mediated inhibition of lysine acetyltransferase KAT3B/p300, basis for non-toxic inhibitor synthesis.}, journal = {The Journal of biological chemistry}, volume = {289}, number = {11}, pages = {7702-7717}, pmid = {24469461}, issn = {1083-351X}, mesh = {Binding Sites ; Cell Line, Tumor ; Cell Survival ; E1A-Associated p300 Protein/*antagonists &amp; inhibitors/chemistry ; Enzyme Inhibitors/*chemistry ; HEK293 Cells ; HeLa Cells ; Humans ; Kinetics ; Lysine/chemistry ; Naphthoquinones/*chemistry ; Oxidation-Reduction ; Protein Structure, Tertiary ; Reactive Oxygen Species ; Structure-Activity Relationship ; Sulfhydryl Compounds/chemistry ; }, abstract = {Hydroxynaphthoquinone-based inhibitors of the lysine acetyltransferase KAT3B (p300), such as plumbagin, are relatively toxic. Here, we report that free thiol reactivity and redox cycling properties greatly contribute to the toxicity of plumbagin. A reactive 3rd position in the naphthoquinone derivatives is essential for thiol reactivity and enhances redox cycling. Using this clue, we synthesized PTK1, harboring a methyl substitution at the 3rd position of plumbagin. This molecule loses its thiol reactivity completely and its redox cycling ability to a lesser extent. Mechanistically, non-competitive, reversible binding of the inhibitor to the lysine acetyltransferase (KAT) domain of p300 is largely responsible for the acetyltransferase inhibition. Remarkably, the modified inhibitor PTK1 was a nearly non-toxic inhibitor of p300. The present report elucidates the mechanism of acetyltransferase activity inhibition by 1,4-naphthoquinones, which involves redox cycling and nucleophilic adduct formation, and it suggests possible routes of synthesis of the non-toxic inhibitor.}, }
@article {pmid24466751, year = {2013}, author = {Noh, YH and Kim, JY and Kim, DH and Kim, OH and Park, J and Kee, BS and Sohn, DS and Kim, D and Chung, YH and Kim, KY and Lee, WB and Kim, SS}, title = {[Recovery from parkinsonism with N-acetylcysteine-differentiated neurons].}, journal = {Molekuliarnaia biologiia}, volume = {47}, number = {4}, pages = {618-624}, doi = {10.7868/s0026898413040186}, pmid = {24466751}, issn = {0026-8984}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/pathology ; Cell Differentiation/*drug effects ; Cells, Cultured ; Disease Models, Animal ; Dopamine/metabolism ; Embryonic Stem Cells/*drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/*drug effects ; Parkinsonian Disorders/*pathology/*therapy ; Stem Cell Transplantation ; Tretinoin/pharmacology ; }, abstract = {The upregulation of dopaminergic neuronal differentiation is necessary for stem cell therapy in Parkinson's disease (PD). In this study, neuronal differentiation efficiency increased by more than 2 times in P19 embryonic stem cells (ESCs) induced by N-acetylcysteine (NAC) and retinoic acid (RA) as compared to RA alone, with suppressed glial differentiation. The majority of NAC-treated stem cells grafted into brains of PD mice differentiated into dopaminergic neurons and persisted well for 6 weeks. Parkinsonism was also greatly improved after grafting NAC-treated cells in comparison to cells treated with only RA. Our results strongly suggest that NAC treatment may be an effective strategy for generating stem cells fated to become dopaminergic neurons for PD clinical therapy.}, }
@article {pmid24461528, year = {2014}, author = {Chen, F and Zhou, YJ}, title = {Hepatic effect of NAC on sevear acute pancteatise of rats.}, journal = {Asian Pacific journal of tropical medicine}, volume = {7}, number = {2}, pages = {141-143}, doi = {10.1016/S1995-7645(14)60010-9}, pmid = {24461528}, issn = {2352-4146}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Enzymes/blood ; Female ; Liver/*drug effects/pathology ; Male ; Pancreatitis/*drug therapy/pathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: To analyze the hepatic protection of n-acetyl cysteine (NAC) on severe acute pancreatitis (SAP).<br><br>METHODS: SD rats were randomly divided into control group, SAP group and NAC group. SAP AHO method was adopted to establish the model, 2 h after modeling, rats in NAC group had intraperitoneal injection of NAC (200 mg/kg). Ten rats from each group were sacrificed in every 6 and 12 h at different time points respectively. Liver damage, liver function and serum amylase, AST, ALT and malondialdehyde (MDA) were determined.<br><br>RESULTS: Serum amylase, AST, ALT and MDA content in SAP, NAC group at each time point were significantly higher in the control group (P<0.05), serum amylase, AST, ALT and MDA content in NAC group rats were lower in the SAP group significantly (P<0.05); Microscopic examination showed that the liver injury in rats and the NAC group significantly reduced in the SAP group.<br><br>CONCLUSIONS: NAC provides effective protection against liver damage to SAP, protective from SAP liver injury.}, }
@article {pmid24455716, year = {2013}, author = {Fan, NC and Tsai, CM and Hsu, CN and Huang, LT and Tain, YL}, title = {N-acetylcysteine prevents hypertension via regulation of the ADMA-DDAH pathway in young spontaneously hypertensive rats.}, journal = {BioMed research international}, volume = {2013}, number = {}, pages = {696317}, pmid = {24455716}, issn = {2314-6141}, mesh = {Acetylcysteine/*administration &amp; dosage ; Amidohydrolases/*metabolism ; Animals ; Arginine/analogs &amp; derivatives/metabolism ; Blood Pressure/drug effects ; Glutathione/biosynthesis ; Humans ; Hypertension/etiology/*metabolism/*physiopathology ; Metabolic Networks and Pathways ; Nitric Oxide/metabolism ; Oxidative Stress ; Rats ; Superoxides/metabolism ; }, abstract = {Asymmetric dimethylarginine (ADMA) reduces nitric oxide (NO), thus causing hypertension. ADMA is metabolized by dimethylarginine dimethylaminohydrolase (DDAH), which can be inhibited by oxidative stress. N-Acetylcysteine (NAC), an antioxidant, can facilitate glutathione (GSH) synthesis. We aimed to determine whether NAC can prevent hypertension by regulating the ADMA-DDAH pathway in spontaneously hypertensive rats (SHR). Rats aged 4 weeks were assigned into 3 groups (n = 8/group): control Wistar Kyoto rats (WKY), SHR, and SHR receiving 2% NAC in drinking water. All rats were sacrificed at 12 weeks of age. SHR had higher blood pressure than WKY, whereas NAC-treated animals did not. SHR had elevated plasma ADMA levels, which was prevented by NAC therapy. SHR had lower renal DDAH activity than WKY, whereas NAC-treated animals did not. Renal superoxide production was higher in SHR than in WKY, whereas NAC therapy prevented it. NAC therapy was also associated with higher GSH-to-oxidized GSH ratio in SHR kidneys. Moreover, NAC reduced oxidative stress damage in SHR. The observed antihypertensive effects of NAC in young SHR might be due to restoration of DDAH activity to reduce ADMA, leading to attenuation of oxidative stress. Our findings highlight the impact of NAC on the development of hypertension by regulating ADMA-DDAH pathway.}, }
@article {pmid24451478, year = {2014}, author = {Klarer, AC and O'Neal, J and Imbert-Fernandez, Y and Clem, A and Ellis, SR and Clark, J and Clem, B and Chesney, J and Telang, S}, title = {Inhibition of 6-phosphofructo-2-kinase (PFKFB3) induces autophagy as a survival mechanism.}, journal = {Cancer &amp; metabolism}, volume = {2}, number = {1}, pages = {2}, pmid = {24451478}, issn = {2049-3002}, support = {P30 GM106396/GM/NIGMS NIH HHS/United States ; R01 CA140991/CA/NCI NIH HHS/United States ; R01 CA149438/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Unlike glycolytic enzymes that directly catabolize glucose to pyruvate, the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFBs) control the conversion of fructose-6-phosphate to and from fructose-2,6-bisphosphate, a key regulator of the glycolytic enzyme phosphofructokinase-1 (PFK-1). One family member, PFKFB3, has been shown to be highly expressed and activated in human cancer cells, and derivatives of a PFKFB3 inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), are currently being developed in clinical trials. However, the effectiveness of drugs such as 3PO that target energetic pathways is limited by survival pathways that can be activated by reduced ATP and nutrient uptake. One such pathway is the process of cellular self-catabolism termed autophagy. We hypothesized that the functional glucose starvation induced by inhibition of PFKFB3 in tumor cells would induce autophagy as a pro-survival mechanism and that inhibitors of autophagy could increase the anti-tumor effects of PFKFB3 inhibitors.<br><br>RESULTS: We found that selective inhibition of PFKFB3 with either siRNA transfection or 3PO in HCT-116 colon adenocarcinoma cells caused a marked decrease in glucose uptake simultaneously with an increase in autophagy based on LC3-II and p62 protein expression, acridine orange fluorescence of acidic vacuoles and electron microscopic detection of autophagosomes. The induction of autophagy caused by PFKFB3 inhibition required an increase in reactive oxygen species since N-acetyl-cysteine blocked both the conversion of LC3-I to LC3-II and the increase in acridine orange fluorescence in acidic vesicles after exposure of HCT-116 cells to 3PO. We speculated that the induction of autophagy might protect cells from the pro-apoptotic effects of 3PO and found that agents that disrupt autophagy, including chloroquine, increased 3PO-induced apoptosis as measured by double staining with Annexin V and propidium iodide in both HCT-116 cells and Lewis lung carcinoma (LLC) cells. Chloroquine also increased the anti-growth effect of 3PO against LLCs in vivo and resulted in an increase in apoptotic cells within the tumors.<br><br>CONCLUSIONS: We conclude that PFKFB3 inhibitors suppress glucose uptake, which in turn causes an increase in autophagy. The addition of selective inhibitors of autophagy to 3PO and its more potent derivatives may prove useful as rational combinations for the treatment of cancer.}, }
@article {pmid24450481, year = {2014}, author = {Dear, JW and Antoine, DJ}, title = {Stratification of paracetamol overdose patients using new toxicity biomarkers: current candidates and future challenges.}, journal = {Expert review of clinical pharmacology}, volume = {7}, number = {2}, pages = {181-189}, doi = {10.1586/17512433.2014.880650}, pmid = {24450481}, issn = {1751-2441}, mesh = {Acetaminophen/administration &amp; dosage/*adverse effects ; Acetylcysteine/therapeutic use ; Analgesics, Non-Narcotic/administration &amp; dosage/*adverse effects ; Animals ; Antidotes/therapeutic use ; Biomarkers/metabolism ; Chemical and Drug Induced Liver Injury/*etiology/physiopathology ; Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Drug Overdose ; Humans ; }, abstract = {One of the most common causes of acute liver failure in the Western world is paracetamol (acetaminophen) overdose. Specific and sensitive detection of liver injury is important for the prompt and safe treatment of patients with the antidote N-acetylcysteine (NAC) and for the determination of NAC efficacy. Despite many years of intense research, the precise mechanisms of paracetamol-induced liver injury in humans are still not defined, and few studies have examined the optimal dosing regimen for clinical NAC use. It has been widely acknowledged that circulating biomarkers such as microRNA-122, keratin-18 and high mobility group box-1 hold potential to inform on the mechanistic-basis of human drug-induced liver injury. Here, we provide a perspective on the application of these mechanistic biomarkers to the deeper understanding of paracetamol hepatotoxicity in clinical and preclinical studies. Also, we discuss current barriers to using these experimental biomarkers to stratify patients presenting to hospital with this common medical emergency.}, }
@article {pmid24445685, year = {2014}, author = {Karimzadeh, I and Khalili, H and Dashti-Khavidaki, S and Sharifian, R and Abdollahi, A and Hasibi, M and Khazaeipour, Z and Farsaei, S}, title = {N-acetyl cysteine in prevention of amphotericin- induced electrolytes imbalances: a randomized, double-blinded, placebo-controlled, clinical trial.}, journal = {European journal of clinical pharmacology}, volume = {70}, number = {4}, pages = {399-408}, pmid = {24445685}, issn = {1432-1041}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Amphotericin B/*adverse effects ; Double-Blind Method ; Female ; Glomerular Filtration Rate/drug effects ; Humans ; Male ; Water-Electrolyte Imbalance/*chemically induced/*drug therapy ; Young Adult ; }, abstract = {PURPOSE: The aim of this study was to evaluate the effectiveness of oral n-acetyl cysteine, as a potential nephroprotective agent, in preventing and/or attenuating amphotericin B-induced electrolytes imbalances.<br><br>METHODS: During a one year period, patients were to receive conventional amphotericin b for any indication for at least one week and were randomly allocated to receive either placebo or 600 mg oral n-acetyl cysteine twice daily during the treatment course of amphotericin b. Demographic and clinical data of the study population were gathered. Different aspects of amphotericin b nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, renal magnesium and potassium wasting were assessed. Each patient was monitored for any adverse reaction to n-acetyl cysteine. Sixteen and 14 patients in the n-acetyl cysteine and placebo groups completed the study, 3incidences of hypokalemia (75 % versus 70 %; P&#x2009;=&#x2009;0.724) and hypomagnesemia (30 % versus 20 %; P&#x2009;=&#x2009;0.468) did not differ significantly between placebo and NAC groups, respectively. Although the rate of AmB nephrotoxicity was higher in the placebo than in the NAC group (60 % versus 40 %), this difference was not statistically significant (P&#x2009;=&#x2009;0.209) even after adjusting for probable associated factors of amphotericin b nephrotoxicity (P&#x2009;=&#x2009;0.206). The incidence as well as time of onset of electrolyte abnormalities also did not differ significantly between placebo and n-acetyl cysteine groups. About 44 % of n-acetyl cysteine recipients experienced new onset nausea and a mild unpleasant taste during the study.<br><br>CONCLUSION: Oral n-acetyl cysteine during the amphotericin B treatment course was not significantly effective in preventing or mitigating different features of its nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, and renal potassium as well as magnesium wasting.}, }
@article {pmid24443349, year = {2014}, author = {Shortt, CM and Fredsted, A and Chow, HB and Williams, R and Skelly, JR and Edge, D and Bradford, A and O'Halloran, KD}, title = {Reactive oxygen species mediated diaphragm fatigue in a rat model of chronic intermittent hypoxia.}, journal = {Experimental physiology}, volume = {99}, number = {4}, pages = {688-700}, doi = {10.1113/expphysiol.2013.076828}, pmid = {24443349}, issn = {1469-445X}, mesh = {Animals ; Antioxidants/pharmacology ; Chronic Disease ; Diaphragm/drug effects/*metabolism/physiopathology ; Disease Models, Animal ; Glutathione/metabolism ; Glycerolphosphate Dehydrogenase/metabolism ; Hypoxia/*metabolism/physiopathology ; Male ; *Muscle Contraction/drug effects ; *Muscle Fatigue/drug effects ; Myosin Heavy Chains/metabolism ; *Oxidative Stress/drug effects ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; Succinate Dehydrogenase/metabolism ; Time Factors ; }, abstract = {Respiratory muscle dysfunction documented in sleep apnoea patients is perhaps due to oxidative stress secondary to chronic intermittent hypoxia (CIH). We sought to explore the effects of different CIH protocols on respiratory muscle form and function in a rodent model. Adult male Wistar rats were exposed to CIH (n = 32) consisting of 90 s normoxia-90 s hypoxia (either 10 or 5% oxygen at the nadir; arterial O2 saturation ∼ 90 or 80%, respectively] for 8 h per day or to sham treatment (air-air, n = 32) for 1 or 2 weeks. Three additional groups of CIH-treated rats (5% O2 for 2 weeks) had free access to water containing N-acetyl cysteine (1% NAC, n = 8), tempol (1 mM, n = 8) or apocynin (2 mM, n = 8). Functional properties of the diaphragm muscle were examined ex vivo at 35 °C. The myosin heavy chain and sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform distribution, succinate dehydrogenase and glyercol phosphate dehydrogenase enzyme activities, Na(+)-K(+)-ATPase pump content, concentration of thiobarbituric acid reactive substances, DNA oxidation and antioxidant capacity were determined. Chronic intermittent hypoxia (5% oxygen at the nadir; 2 weeks) decreased diaphragm muscle force and endurance. All three drugs reversed the deleterious effects of CIH on diaphragm endurance, but only NAC prevented CIH-induced diaphragm weakness. Chronic intermittent hypoxia increased diaphragm muscle myosin heavy chain 2B areal density and oxidized glutathione/reduced glutathione (GSSG/GSH) ratio. We conclude that CIH-induced diaphragm dysfunction is reactive oxygen species dependent. N-Acetyl cysteine was most effective in reversing CIH-induced effects on diaphragm. Our results suggest that respiratory muscle dysfunction in sleep apnoea may be the result of oxidative stress and, as such, antioxidant treatment could prove a useful adjunctive therapy for the disorder.}, }
@article {pmid24442756, year = {2014}, author = {McClure, EA and Gipson, CD and Malcolm, RJ and Kalivas, PW and Gray, KM}, title = {Potential role of N-acetylcysteine in the management of substance use disorders.}, journal = {CNS drugs}, volume = {28}, number = {2}, pages = {95-106}, pmid = {24442756}, issn = {1179-1934}, support = {DA012513/DA/NIDA NIH HHS/United States ; P50 DA015369/DA/NIDA NIH HHS/United States ; DA031779/DA/NIDA NIH HHS/United States ; DA033690/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; UG1 DA013727/DA/NIDA NIH HHS/United States ; U01 DA031779/DA/NIDA NIH HHS/United States ; DA013727/DA/NIDA NIH HHS/United States ; R01 DA012513/DA/NIDA NIH HHS/United States ; F32 DA033690/DA/NIDA NIH HHS/United States ; DA003906,/DA/NIDA NIH HHS/United States ; K99 DA036569/DA/NIDA NIH HHS/United States ; R37 DA003906/DA/NIDA NIH HHS/United States ; DA015369/DA/NIDA NIH HHS/United States ; U10 DA013727/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/pharmacokinetics/*therapeutic use ; Animals ; Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Humans ; Molecular Structure ; Substance Withdrawal Syndrome/prevention &amp; control ; Substance-Related Disorders/*drug therapy/metabolism/psychology ; Treatment Outcome ; }, abstract = {There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs.}, }
@article {pmid24442604, year = {2014}, author = {Topcu-Tarladacalisir, Y and Tarladacalisir, T and Sapmaz-Metin, M and Karamustafaoglu, A and Uz, YH and Akpolat, M and Cerkezkayabekir, A and Turan, FN}, title = {N-Acetylcysteine counteracts oxidative stress and protects alveolar epithelial cells from lung contusion-induced apoptosis in rats with blunt chest trauma.}, journal = {Journal of molecular histology}, volume = {45}, number = {4}, pages = {463-471}, pmid = {24442604}, issn = {1567-2387}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Apoptosis/drug effects ; Contusions/*drug therapy ; Epithelial Cells/*cytology/*drug effects ; Female ; Lung Injury/*drug therapy ; Oxidative Stress/*drug effects ; Pulmonary Alveoli/*cytology ; Rats ; Rats, Sprague-Dawley ; Thoracic Injuries/*drug therapy ; }, abstract = {The aim of this study was to investigate the protective effects of N-acetylcysteine (NAC) on peroxidative and apoptotic changes in the contused lungs of rats following blunt chest trauma. The rats were randomly divided into three groups: control, contusion, and contusion + NAC. All the rats, apart from those in the control group, performed moderate lung contusion. A daily intramuscular NAC injection (150 mg/kg) was given immediately following the blunt chest trauma and was continued for two additional days following cessation of the trauma. Samples of lung tissue were taken in order to evaluate the tissue malondialdehyde (MDA) level, histopathology, and epithelial cell apoptosis using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and active caspase-3 immunostaining. In addition, we immunohistochemically evaluated the expression of surfactant protein D (SP-D) in the lung tissue. The blunt chest trauma-induced lung contusion resulted in severe histopathological injury, as well as an increase in the MDA level and in the number of cells identified on TUNEL assay together with active caspase-3 positive epithelial cells, but a decrease in the number of SP-D positive alveolar type 2 (AT-2) cells. NAC treatment effectively attenuated histopathologic, peroxidative, and apoptotic changes, as well as reducing alterations in SP-D expression in the lung tissue. These findings indicate that the beneficial effects of NAC administrated following blunt chest trauma is related to the regulation of oxidative stress and apoptosis.}, }
@article {pmid24439723, year = {2014}, author = {Babenko, NA and Shakhova, EG}, title = {Long-term food restriction prevents aging-associated sphingolipid turnover dysregulation in the brain.}, journal = {Archives of gerontology and geriatrics}, volume = {58}, number = {3}, pages = {420-426}, doi = {10.1016/j.archger.2013.12.005}, pmid = {24439723}, issn = {1872-6976}, mesh = {Acetylcysteine ; Aging/drug effects/physiology ; Animals ; Brain/*metabolism ; *Caloric Restriction ; Ceramides/*metabolism ; Hippocampus/*metabolism ; Male ; Oxidation-Reduction ; Rats ; Rats, Wistar ; Sphingolipids/*metabolism ; Sphingomyelin Phosphodiesterase ; Sphingomyelins/*metabolism ; alpha-Tocopherol/pharmacology ; }, abstract = {Abnormalities of sphingolipid turnover in the brain during normal aging and age-related neurological disorders were associated with the neurons loss and cognitive malfunction. Calorie restriction (CR) prevented age-related deficits in hippocampal long-term potentiation and improved cognitive function at old age. In the paper we investigated the ceramide and sphingomyelin (SM) levels in the brain regions, which are critical for learning and memory of 3- and 24-month-old rats, as well as the correction of sphingolipid turnover in the brain of old rats, by means of the CR diet and modulators of SM turnover. Using the [methyl-(14)C-choline]SM, the neutral, but not the acid SMase activity has been observed to increase in both the hippocampus and brain cortex of 24-month-old rats with respect to 3-month-old animals. Age-dependent changes of neutral SMase activities were associated with ceramide accumulation and SM level drop in the brain structures studied. Treatment of the rats with the CR diet or N-acetylcysteine (NAC) or α-tocopherol acetate, but not an inhibitor of acid SMase imipramine, reduced the ceramide content and neutral SMase activity in the hippocampus of 24-month-old animals with respect to control rats of the same age. These results suggest that redox-sensitive neutral SMase plays important role in SM turnover dysregulation in both the hippocampus and neocortex at old age and that the CR diet can prevent the age-dependent accumulation of ceramide mainly via neutral SMase targeting.}, }
@article {pmid24438160, year = {2014}, author = {Avantaggiato, A and Palmieri, A and Bertuzzi, G and Carinci, F}, title = {Fibroblasts behavior after N-acetylcysteine and amino acids exposure: extracellular matrix gene expression.}, journal = {Rejuvenation research}, volume = {17}, number = {3}, pages = {285-290}, doi = {10.1089/rej.2013.1511}, pmid = {24438160}, issn = {1557-8577}, mesh = {Acetylcysteine/*pharmacology ; Amino Acids/*pharmacology ; Base Sequence ; DNA Primers ; Extracellular Matrix Proteins/*genetics ; Female ; Fibroblasts/cytology/drug effects ; Gene Expression/*drug effects ; Humans ; Middle Aged ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Reactive oxygen species (ROS) are chemically reactive molecules with impaired electrons that make them unstable and able to react easily with a great variety of molecules. The main targets of ROS are DNA, proteins, and membrane phospholipids. In the skin, ROS are able to affect the production of collagen and elastin, the main components of the extracellular matrix (ECM). This action contributes to the skin's aging. N-Acetylcysteine (NAC) is an acetylated cysteine residue with excellent anti-oxidant activity that boosts glutathione (GSH) levels. This study evaluates the effect of a solution of NAC and amino acids, which is used in aesthetic medicine as an intra-dermal injective treatment, on fibroblast behavior. To this aim, the expression levels of some ECM-related genes (HAS1, HYAL1 ELN, ELANE, MMP2, MMP3, MMP13, COL1A1, COL3A1) were analyzed on cultured dermal fibroblasts using real-time reverse transcription polymerase chain reaction (RT-PCR). All but two collagen genes were up-regulated after 24 hr of treatment.}, }
@article {pmid24435707, year = {2014}, author = {Cho, KH and Choi, MJ and Jeong, KJ and Kim, JJ and Hwang, MH and Shin, SC and Park, CG and Lee, HY}, title = {A ROS/STAT3/HIF-1α signaling cascade mediates EGF-induced TWIST1 expression and prostate cancer cell invasion.}, journal = {The Prostate}, volume = {74}, number = {5}, pages = {528-536}, doi = {10.1002/pros.22776}, pmid = {24435707}, issn = {1097-0045}, mesh = {Acetylcysteine/pharmacology ; Cadherins/genetics/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects/physiology ; Disease Progression ; Epidermal Growth Factor/*pharmacology ; Epithelial-Mesenchymal Transition ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism ; Male ; Neoplasm Invasiveness/*pathology ; Nuclear Proteins/genetics/*metabolism ; Phosphorylation/drug effects/physiology ; Prostatic Neoplasms/metabolism/*pathology ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/genetics/*metabolism ; Signal Transduction/drug effects/*physiology ; Twist-Related Protein 1/genetics/*metabolism ; }, abstract = {BACKGROUND: Epidermal growth factor (EGF) has been known to induce epithelial-mesenchymal transition (EMT) and prostate cancer cell progression. However, a detailed underlying mechanism by which EGF induces EMT and prostate cancer cell progression remained to be answered. Hypoxia-inducible factor (HIF)-1α and TWIST1 are transcription factors implicated in EMT and cancer metastasis. The purpose of this study is to determine the underlying mechanism of EGF-induced TWIST1 expression and prostate cancer invasion.<br><br>METHODS: siRNAs were used to silence genes. Immunoblotting, quantitative RT-PCR and immunofluorescence analysis were used to examine protein or mRNA expression. Modified Boyden chamber and invasion assay kit with Matrigel-coated inserts were used to determine prostate cancer cell migration and invasion, respectively.<br><br>RESULTS: We observed that EGF induced HIF-1&#x3b1; expression and morphological change of prostate cancer epithelial cells to mesenchymal cells. Silencing HIF-1&#x3b1; expression dramatically reduced EGF-induced TWIST1 expression and prostate cancer cell EMT. Conversely, transfection of the cells with HIF-1&#x3b1; siRNA reversed the reduced E-cadherin expression by EGF. Pretreatment of the cells with pharmacological inhibitors of reactive oxygen species [ROS, N-acetylcysteine (NAC)] and STAT3 (WP1066) but not p38 MAPK (SB203580) significantly reduced EGF-induced HIF-1&#x3b1; mRNA and protein expression. Further, pretreatment of the cells with NAC attenuated EGF-induced STAT3 phosphorylation. In addition, we showed that TWIST1 mediated EGF-induced N-cadherin expression, leading to prostate cancer invasion.<br><br>CONCLUSIONS: We demonstrate a mechanism by which EGF promotes prostate cancer cell progression through a ROS/STAT3/HIF-1&#x3b1;/TWIST1/N-cadherin signaling cascade, providing novel biomarkers and promising therapeutic targets for prostate cancer cell progression.}, }
@article {pmid24434384, year = {2014}, author = {Saddadi, F and Alatab, S and Pasha, F and Ganji, MR and Soleimanian, T}, title = {The effect of treatment with N-acetylcysteine on the serum levels of C-reactive protein and interleukin-6 in patients on hemodialysis.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {25}, number = {1}, pages = {66-72}, doi = {10.4103/1319-2442.124489}, pmid = {24434384}, issn = {1319-2442}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Adult ; Aged ; Anti-Inflammatory Agents/administration &amp; dosage/*therapeutic use ; Biomarkers/blood ; C-Reactive Protein/*metabolism ; Down-Regulation ; Female ; Humans ; Inflammation Mediators/*blood ; Interleukin-6/*blood ; Iran ; Kidney Failure, Chronic/blood/immunology/*therapy ; Male ; Middle Aged ; *Renal Dialysis ; Time Factors ; Treatment Outcome ; }, abstract = {Patients with end-stage renal disease (ESRD) are at an increased risk of cardiovascular disease due to many factors including inflammation and oxidative stress. N-acetylcysteine (NAC) is a thiol-containing anti-oxidant with anti-inflammatory properties. We aimed to assess the effect of three months treatment with oral NAC on the plasma levels of inflammatory mediators like interleukin-6 (IL-6) and C-reactive protein (hs-CRP) in patients on hemodialysis (HD). Twenty-four patients (nine males and 15 females) on maintenance HD were recruited in the study. Their mean age was 55.3 years. All the patients received oral NAC (600 mg twice a day) for a period of three months. The serum levels of biomedical parameters and IL-6 and hs-CRP were measured at baseline and three months after initiation of treatment. A significant decrease in serum levels of hs-CRP (22.4 vs. 5.2), IL-6 (8.1 vs. 3.6), parathyroid hormone (iPTH) (257.2 vs. 158.8), ferritin (632.0 vs. 515.1) and erythrocyte sedimentation rate (ESR) (54.2 vs. 38.3) was observed following NAC treatment. Female subjects presented with a significantly higher change in serum levels of hs-CRP compared with males (23 vs. 5.4). In three subjects who were less than 40 years old, the hs-CRP and IL-6 levels showed an increase following NAC treatment. Our study found that short-term oral NAC treatment might result in the reduction of IL-6 and hs-CRP in patients who are on regular HD. This suggests that patients with ESRD may benefit from the anti-inflammatory effects of NAC.}, }
@article {pmid24434148, year = {2014}, author = {Yan, X and Lee, S and Gugiu, BG and Koroniak, L and Jung, ME and Berliner, J and Cheng, J and Li, R}, title = {Fatty acid epoxyisoprostane E2 stimulates an oxidative stress response in endothelial cells.}, journal = {Biochemical and biophysical research communications}, volume = {444}, number = {1}, pages = {69-74}, pmid = {24434148}, issn = {1090-2104}, support = {R00 HL105577/HL/NHLBI NIH HHS/United States ; HL064731/HL/NHLBI NIH HHS/United States ; HL30568/HL/NHLBI NIH HHS/United States ; R01 HL064731/HL/NHLBI NIH HHS/United States ; P01 HL030568/HL/NHLBI NIH HHS/United States ; }, mesh = {Apoptosis Regulatory Proteins ; Atherosclerosis/etiology/metabolism ; Cells, Cultured ; Endothelial Cells/*drug effects/*metabolism ; Heme Oxygenase-1/genetics ; Humans ; Isoprostanes/metabolism/*pharmacology ; NF-E2-Related Factor 2/antagonists &amp; inhibitors/genetics/metabolism ; Oxidative Stress/drug effects/genetics ; Phosphatidylcholines/metabolism/pharmacology ; Proteins/genetics ; RNA Interference ; RNA, Small Interfering/genetics ; Signal Transduction/drug effects ; Up-Regulation/drug effects ; }, abstract = {Atherosclerosis is the main underlying cause of major cardiovascular diseases such as stroke and heart attack. Oxidized phospholipids such as oxidized 1-palmitoyl-2-arachidonoyl-sn-Glycero-3-phosphorylcholine (OxPAPC) accumulate in lesions of and promote atherosclerosis. OxPAPC activates endothelial cells, a critical early event of atherogenesis. Epoxyisoprostane E2 (EI) is an oxidized fatty acid contained at the sn-2 position of 1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine (PEIPC), the most active component of OxPAPC in regulating inflammation. OxPAPC and its components including PEIPC activate endothelial cells to express an array of genes in different categories including oxidative stress response genes such as tumor suppressor gene OKL38 and Heme oxygenase-1 (HO-1). EI can be released by lipase from PEIPC. In this study, we examined the ability of EI to stimulate oxidative stress response in endothelial cells. EI released from OxPAPC and synthetic EI stimulated the expression of oxidative stress response gene OKL38 and antioxidant gene HO-1. Treatment of endothelial cells with EI increased the production of superoxide. NADPH oxidase inhibitor Apocynin and superoxide scavenger N-acetyl-cysteine (NAC) significantly attenuated EI-stimulated expression of OKL38 and HO-1. We further demonstrated that EI activated oxidative stress-sensitive transcription factor Nrf2. Silencing of Nrf2 with siRNA significantly reduced EI stimulated expression of OKL38 and HO-1. Thus, we demonstrated that EI induced oxidative stress in endothelial cells leading to increased expression of oxidative stress response gene OKL38 and HO-1 via Nrf2 signaling pathway relevant to atherosclerosis.}, }
@article {pmid24434067, year = {2014}, author = {Gonzales, CB and Kirma, NB and De La Chapa, JJ and Chen, R and Henry, MA and Luo, S and Hargreaves, KM}, title = {Vanilloids induce oral cancer apoptosis independent of TRPV1.}, journal = {Oral oncology}, volume = {50}, number = {5}, pages = {437-447}, pmid = {24434067}, issn = {1879-0593}, support = {CA054174/CA/NCI NIH HHS/United States ; UL1 TR000149/TR/NCATS NIH HHS/United States ; UL1TR000149/TR/NCATS NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; UL1 TR001120/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Capsaicin/pharmacology ; Carcinoma, Squamous Cell/metabolism/*pathology ; Diterpenes/*pharmacology ; Humans ; Mice ; Mouth Neoplasms/metabolism/*pathology ; Polymerase Chain Reaction ; TRPV Cation Channels/*physiology ; Xenograft Model Antitumor Assays ; }, abstract = {OBJECTIVE: To investigate the mechanisms of vanilloid cytotoxicity and anti-tumor effects in oral squamous cell carcinoma (OSCC).<br><br>MATERIALS AND METHODS: Immunohistochemistry and qPCR analyses demonstrated expression of the TRP vanilloid type 1 (TRPV1) receptor in OSCC. Using cell proliferation assays, calcium imaging, and three mouse xenograft models, prototypical vanilloid agonist (capsaicin) and antagonist (capsazepine) were evaluated for cytotoxic and anti-tumor effects in OSCC.<br><br>RESULTS: OSCC cell lines treated with capsaicin displayed significantly reduced cell viability. Pre-treatment with capsazepine failed to reverse these effects. Moreover, capsazepine alone was significantly cytotoxic to tumor cells, suggesting the mechanism-of-action is independent of TRPV1 activation. This was further confirmed by calcium imaging indicating that TRPV1 channels are not functional in the cell lines tested. We then examined whether the observed vanilloid cytotoxicity was due to the generation of reactive oxygen species (ROS) and subsequent apoptosis. Induction of ROS was confirmed by flow cytometry and reversed by co-treatment with the antioxidant N-acetyl-cysteine (NAC). NAC also significantly reversed vanilloid cytotoxicity in cell proliferation assays. Dose-dependent induction of apoptosis with capsazepine treatment was demonstrated by FACS analyses and c-PARP expression in treated cells. Our in vivo xenograft studies showed that intra-tumoral injections of capsazepine exhibited high effectiveness in suppressing tumor growth with no identifiable toxicities.<br><br>CONCLUSIONS: These findings confirm TRPV1 channel expression in OSCC. However anti-tumor effects of vanilloids are independent of TRPV1 activation and are most likely due to ROS induction and subsequent apoptosis. Importantly, these studies demonstrate capsazepine is a potential therapeutic candidate for OSCC.}, }
@article {pmid24425984, year = {2013}, author = {Kumar, D and Mishra, DS and Chakraborty, B and Kumar, P}, title = {Pericarp browning and quality management of litchi fruit by antioxidants and salicylic acid during ambient storage.}, journal = {Journal of food science and technology}, volume = {50}, number = {4}, pages = {797-802}, pmid = {24425984}, issn = {0022-1155}, abstract = {Different antioxidants and salicylic acid were tested to overcome pericarp browning and to maintain the postharvest quality of the litchi fruits at ambient storage. It was found that 0.5% salicylic acid, 1% isoascorbic acid and 1% N-acetyl cysteine performed better over sulphur dioxide (SO2) fumigation for most of the parameters under study. Application of 0.5% salicylic acid found superior to reduce the pericarp browning, relative leakage rate, and decay percentage. It was effective in reduction of polyphenol oxidase activity and improvement of anthocyanin pigments of the fruit pericarp over other treatments. Total soluble solid, titratable acidity and ascorbic acid of the litchi fruits were recorded highest with the application of 1% isoascorbic acid followed by 0.5% salicylic acid treatment. Therefore, 0.5% salicylic acid and 1% isoascorbic could be used as an alternative of SO2 fumigation for quality retention of litchi fruits.}, }
@article {pmid24424259, year = {2014}, author = {Chen, TH and Lin, CC and Meng, PJ}, title = {Zinc oxide nanoparticles alter hatching and larval locomotor activity in zebrafish (Danio rerio).}, journal = {Journal of hazardous materials}, volume = {277}, number = {}, pages = {134-140}, doi = {10.1016/j.jhazmat.2013.12.030}, pmid = {24424259}, issn = {1873-3336}, mesh = {Animals ; Antioxidants/pharmacology ; Dose-Response Relationship, Drug ; Embryo, Nonmammalian/*drug effects/metabolism ; Larva ; Locomotion/*drug effects ; *Nanoparticles ; Oxidative Stress/drug effects ; Swimming ; Water Pollutants, Chemical/chemistry/*toxicity ; *Zebrafish/growth &amp; development ; Zinc Oxide/chemistry/*toxicity ; }, abstract = {Zinc oxide nanoparticles (ZnO NP) are extensively used in various consumer products such as sunscreens and cosmetics, with high potential of being released into aquatic environments. In this study, fertilized zebrafish (Danio rerio) eggs were exposed to various concentrations of ZnO NP suspensions (control, 0.1, 0.5, 1, 5, and 10mg/L) or their respective centrifuged supernatants (0.03, 0.01, 0.08, 0.17, 0.75, and 1.21mg/L dissolved Zn ions measured) until reaching free swimming stage. Exposure to ZnO NP suspensions and their respective centrifuged supernatants caused similar hatching delay, but did not cause larval mortality or malformation. Larval activity level, mean velocity, and maximum velocity were altered in the groups exposed to high concentrations of ZnO NP (5-10mg/L) but not in the larvae exposed to the supernatants. To evaluate possible mechanism of observed effects caused by ZnO NP, we also manipulated the antioxidant environment by co-exposure to an antioxidant compound (N-acetylcysteine, NAC) or an antioxidant molecule suppressor (buthionine sulfoximine, BSO) with 5mg/L ZnO NP. Co-exposure to NAC did not alter the effects of ZnO NP on hatchability, but co-exposure to BSO caused further hatching delay. For larval locomotor activity, co-exposure to NAC rescued the behavioral effect caused by ZnO NP, but co-exposure to BSO did not exacerbate the effect. Our data indicated that toxicity of ZnO NP cannot be solely explained by dissolved Zn ions, and oxidative stress may involve in ZnO NP toxicity.}, }
@article {pmid24424051, year = {2014}, author = {Serrano-Nascimento, C and da Silva Teixeira, S and Nicola, JP and Nachbar, RT and Masini-Repiso, AM and Nunes, MT}, title = {The acute inhibitory effect of iodide excess on sodium/iodide symporter expression and activity involves the PI3K/Akt signaling pathway.}, journal = {Endocrinology}, volume = {155}, number = {3}, pages = {1145-1156}, doi = {10.1210/en.2013-1665}, pmid = {24424051}, issn = {1945-7170}, mesh = {Animals ; Anions ; Biotinylation ; Cell Line ; Enzyme Inhibitors/pharmacology ; *Gene Expression Regulation ; Insulin/metabolism ; Iodides/*chemistry ; Mitochondria/metabolism ; Oxygen/chemistry ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Reactive Oxygen Species ; *Signal Transduction ; Superoxides/metabolism ; Symporters/*metabolism ; Thyroid Gland/*metabolism ; }, abstract = {Iodide (I(-)) is an irreplaceable constituent of thyroid hormones and an important regulator of thyroid function, because high concentrations of I(-) down-regulate sodium/iodide symporter (NIS) expression and function. In thyrocytes, activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) cascade also inhibits NIS expression and function. Because I(-) excess and PI3K/Akt signaling pathway induce similar inhibitory effects on NIS expression, we aimed to study whether the PI3K/Akt cascade mediates the acute and rapid inhibitory effect of I(-) excess on NIS expression/activity. Here, we reported that the treatment of PCCl3 cells with I(-) excess increased Akt phosphorylation under normal or TSH/insulin-starving conditions. I(-) stimulated Akt phosphorylation in a PI3K-dependent manner, because the use of PI3K inhibitors (wortmannin or 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) abrogated the induction of I(-) effect. Moreover, I(-) inhibitory effect on NIS expression and function were abolished when the cells were previously treated with specific inhibitors of PI3K or Akt (Akt1/2 kinase inhibitor). Importantly, we also found that the effect of I(-) on NIS expression involved the generation of reactive oxygen species (ROS). Using the fluorogenic probes dihydroethidium and mitochondrial superoxide indicator (MitoSOX Red), we observed that I(-) excess increased ROS production in thyrocytes and determined that mitochondria were the source of anion superoxide. Furthermore, the ROS scavengers N-acetyl cysteine and 2-phenyl-1,2-benzisoselenazol-3-(2H)-one blocked the effect of I(-) on Akt phosphorylation. Overall, our data demonstrated the involvement of the PI3K/Akt signaling pathway as a novel mediator of the I(-)-induced thyroid autoregulation, linking the role of thyroid oxidative state to the Wolff-Chaikoff effect.}, }
@article {pmid24421152, year = {2014}, author = {Joshi, D and Mittal, DK and Shukla, S and Srivastav, AK and Srivastav, SK}, title = {Methylmercury toxicity: amelioration by selenium and water-soluble chelators as N-acetyl cysteine and dithiothreitol.}, journal = {Cell biochemistry and function}, volume = {32}, number = {4}, pages = {351-360}, doi = {10.1002/cbf.3023}, pmid = {24421152}, issn = {1099-0844}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/drug effects/metabolism ; Chelating Agents/*pharmacology ; Dithiothreitol/*pharmacology ; Environmental Pollutants/*toxicity ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Male ; Methylmercury Compounds/*toxicity ; Oxidative Stress/drug effects ; Rats, Sprague-Dawley ; Selenium Compounds/*pharmacology ; Solubility ; Water ; }, abstract = {The protective potential of chelators, i.e. N-acetyl cysteine (0.6 mg /kg, intraperitoneally) and dithiothreitol (15.4 mg kg(-1) , intraperitoneally) with selenium (0.5 mg kg(-1) , pre-oral) were evaluated individually and in combination against methylmercury-induced biochemical alterations and oxidative stress consequences. Forty-two male Sprague-Dawley rats were exposed with methylmercury (1.5 mg kg(-1) , pre-oral) daily for 21 days followed by different treatments for five consecutive days. Administration of methylmercury caused significant enhancement in the release of transaminases, alkaline phosphatases and lactate dehydrogenases in serum. A significant increased was observed in lipid peroxidation level with a concomitant decreased in glutathione content after methylmercury exposure in liver, kidney and brain. Hepatic microsomal drug metabolizing enzymes (aniline hydroxylase and amidopyrine N-demethylase) of cytochrome p4502E1 showed sharp depletion after methylmercury exposure. Alterations in histological changes in liver, kidney and brain were also noted in methylmercury administered group. All treated groups showed recovery pattern, but the combined treatments with N-acetyl cysteine and dithiothreitol in combination with selenium were more effective than that with either alone treatments in recovering blood biochemical changes after methylmercury toxicity. In conclusion, the results demonstrated that combination therapy may recover all blood biochemical alterations and offer maximum protection against methylmercury-induced toxicity.}, }
@article {pmid24412706, year = {2014}, author = {Venkataramana, M and Chandra Nayaka, S and Anand, T and Rajesh, R and Aiyaz, M and Divakara, ST and Murali, HS and Prakash, HS and Lakshmana Rao, PV}, title = {Zearalenone induced toxicity in SHSY-5Y cells: The role of oxidative stress evidenced by N-acetyl cysteine.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {65}, number = {}, pages = {335-342}, doi = {10.1016/j.fct.2013.12.042}, pmid = {24412706}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Base Sequence ; Cell Line, Tumor ; DNA Primers ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Zearalenone/*toxicity ; }, abstract = {Zearalenone (ZEN) is a mycotoxin from Fusarium species commonly found in many food commodities and are known to cause reproductive disorders, genotoxic and immunosuppressive effects. Although many studies have demonstrated the cytotoxic effects of ZEN, the mechanisms by which ZEN mediates its cytotoxic effects appear to differ according to cell type and route of exposure. Meantime, the available information on the neurotoxic effects of ZEN is very much limited. In the present study we evaluated the role of oxidative stress in ZEN mediated neurotoxicity in SH-SY5Y cells and investigated the possible underlying mechanism. ZEN induced ROS formation and elevated levels of MDA, loss of mitochondrial membrane potential (MMP) and increase in DNA damage in a dose dependent manner as assessed by COMET assay and agarose gel electrophoresis. However, there was no DNA damage by plasmid breakage assay at 6, 12 and 24h time points. DAPI staining showed apoptotic nuclei at 12 and 24h. Further, ZEN treated SH-SY5Y cells showed a marked suppressive effect on the neuronal gene expression. Use of an antioxidant N-acetylcysteine (NAC) reversed the toxin-induced generation of ROS and also attenuated loss of MMP. Collectively, these results suggest that ROS is the main upstream signal leading to increased ZEN mediated neurotoxicity in SH-SY5Y cells.}, }
@article {pmid24412461, year = {2014}, author = {Barone, JM and Frezzatti, R and Silveira, PF}, title = {Effects of N-acetyl-L-cysteine on redox status and markers of renal function in mice inoculated with Bothrops jararaca and Crotalus durissus terrificus venoms.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {79}, number = {}, pages = {1-10}, doi = {10.1016/j.toxicon.2013.12.010}, pmid = {24412461}, issn = {1879-3150}, mesh = {Acetylcysteine/*blood/*pharmacology ; Aminopeptidases/metabolism ; Animals ; Antioxidants/pharmacology ; Biomarkers/*blood/urine ; Bothrops ; Crotalid Venoms/*metabolism ; Crotalus ; Hyaluronoglucosaminidase/antagonists &amp; inhibitors/metabolism ; Kidney/*drug effects/metabolism ; Male ; Mice ; Oxidation-Reduction ; Snake Bites/drug therapy ; }, abstract = {Renal dysfunction is an important aggravating factor in accidents caused by Crotalus durissus terrificus (Cdt) and Bothrops jararaca (Bj) bites. N-acetyl-l-cysteine (NAC) is well known as a nephroprotective antioxidant with low toxicity. The present study investigated the effects of NAC on redox status and markers of renal function in mice that received vehicle (controls) or venoms (v) of Cdt and Bj. In controls NAC promoted hypercreatinemia, hypouremia, hyperosmolality with decreased urea in urine, hyperproteinuria, decreased protein and increased dipeptidyl peptidase IV (DPPIV) in membrane-bound fraction (MF) from renal cortex (RC) and medulla (RM). NAC ameliorated or normalized altered creatinuria, proteinemia and aminopeptidase (AP) acid in MF, AP basic (APB) in soluble fraction (SF), and neutral AP in SF and MF from RC and RM in vBj envenomation. NAC ameliorated or normalized altered neutral AP in SF from RC and RM, and DPPIV and protein in MF from RC in vCdt envenomation. NAC ameliorated or restored renal redox status respectively in vCdt and vBj, and normalized uricemia in both envenomations. These data are promising perspectives that recommend the clinical evaluation of NAC as potential coadjuvant in the anti venom serotherapy for accidents with these snake's genera.}, }
@article {pmid24409405, year = {2014}, author = {Heidari, R and Babaei, H and Roshangar, L and Eghbal, MA}, title = {Effects of Enzyme Induction and/or Glutathione Depletion on Methimazole-Induced Hepatotoxicity in Mice and the Protective Role of N-Acetylcysteine.}, journal = {Advanced pharmaceutical bulletin}, volume = {4}, number = {1}, pages = {21-28}, pmid = {24409405}, issn = {2228-5881}, abstract = {PURPOSE: Methimazole is the most convenient drug used in the management of hyperthyroid patients. However, associated with its clinical use is hepatotoxicity as a life threatening adverse effect. The exact mechanism of methimazole-induced hepatotoxicity is still far from clear and no protective agent has been developed for this toxicity.<br><br>METHODS: This study attempts to evaluate the hepatotoxicity induced by methimazole at different experimental conditions in a mice model. Methimazole-induced hepatotoxicity was investigated in different situations such as enzyme induced and/or glutathione depleted animals.<br><br>RESULTS: Methimazole (100 mg/kg, i.p) administration caused hepatotoxicity as revealed by increase in serum alanine aminotransferase (ALT) activity as well as pathological changes of the liver. Furthermore, a significant reduction in hepatic glutathione content and an elevation in lipid peroxidation were observed in methimazole-treated mice. Combined administration of L-buthionine sulfoximine (BSO), as a glutathione depletory agent, caused a dramatic change in methimazole-induced hepatotoxicity characterized by hepatic necrosis and a severe elevation of serum ALT activity. Enzyme induction using phenobarbital and/or &#x3b2;-naphtoflavone beforehand, deteriorated methimazole-induced hepatotoxicity in mice. N-acetyl cysteine (300 mg/kg, i.p) administration effectively alleviated hepatotoxic effects of methimazole in both glutathione-depleted and/or enzyme induced animals.<br><br>CONCLUSION: The severe hepatotoxic effects of methimazole in glutathione-depleted animals, reveals the crucial role of glutathione as a cellular defense mechanism against methimazole-induced hepatotoxicity. Furthermore, the more hepatotoxic properties of methimazole in enzyme-induced mice, indicates the role of reactive intermediates in the hepatotoxicity induced by this drug. The protective effects of N-acetylcysteine could be attributed to its radical/reactive metabolite scavenging, and/or antioxidant properties as well as glutathione replenishment activities.}, }
@article {pmid24401635, year = {2014}, author = {Hidalgo, M and Marchant, D and Quidu, P and Youcef-Ali, K and Richalet, JP and Beaudry, M and Besse, S and Launay, T}, title = {Oxygen modulates the glutathione peroxidase activity during the L6 myoblast early differentiation process.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {33}, number = {1}, pages = {67-77}, doi = {10.1159/000356650}, pmid = {24401635}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Differentiation/*drug effects ; Cell Lineage/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Culture Media/pharmacology ; Glutathione Peroxidase/*metabolism ; Myoblasts/*cytology/drug effects/*metabolism ; Oxidation-Reduction/drug effects ; Oxygen/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {AIM: This work aims to study the regulation of the glutathione peroxidase and catalase activities in myoblasts from the L6 line exposed to 21%, 5% and 1% O2 during the cell differentiation.<br><br>MATERIAL AND METHODS: Rat L6 myoblasts were grown in 1%, 5% or 21% O2 in the presence or absence of N-acetyl cysteine. The cell proliferation was evaluated by determining the doubling time and kinetics of cultures by counting cells. The cell differentiation was analyzed by determining the myogenic fusion index using antibodies against the myosin heavy chain. The glutathione peroxidase and catalase activities were assayed. The p110-PI3K/Thr308-Akt pathway was studied using western blotting. The oxidative status of the cells was carried out by determining TBARS.<br><br>RESULTS: 5% O2 improves the glutathione peroxidase activity, p110-PI3K/Thr308-Akt pathway and differentiation while 1% O2 alters all these parameters compared to 21% O2. NAC (0.5 mM) can prevent the deleterious effects of hypoxia (1% O2) on the L6 myoblast proliferation and enhances the myoblast differentiation when exposed to 21% O2. TBARS are reduced in 5% O2 compared to both 21% and 1% O2.<br><br>CONCLUSION: The glutathione peroxidase activity and p110-PI3K/Thr308-Akt are both modulated in the same way by oxygen.}, }
@article {pmid24400127, year = {2014}, author = {Sripetchwandee, J and Pipatpiboon, N and Chattipakorn, N and Chattipakorn, S}, title = {Combined therapy of iron chelator and antioxidant completely restores brain dysfunction induced by iron toxicity.}, journal = {PloS one}, volume = {9}, number = {1}, pages = {e85115}, pmid = {24400127}, issn = {1932-6203}, mesh = {Animals ; Antioxidants/*administration &amp; dosage ; Apoptosis ; Blood-Brain Barrier/metabolism ; Brain/drug effects/metabolism/pathology/physiopathology ; Brain Diseases/drug therapy/*etiology/*physiopathology ; Cognition ; Diet/adverse effects ; Disease Models, Animal ; Drug Therapy, Combination ; Iron/metabolism ; Iron Chelating Agents/*administration &amp; dosage ; Iron Overload/*complications/*drug therapy ; Male ; Maze Learning ; Mitochondria/drug effects/metabolism/pathology ; Oxidative Stress ; Rats ; Treatment Outcome ; }, abstract = {BACKGROUND: Excessive iron accumulation leads to iron toxicity in the brain; however the underlying mechanism is unclear. We investigated the effects of iron overload induced by high iron-diet consumption on brain mitochondrial function, brain synaptic plasticity and learning and memory. Iron chelator (deferiprone) and antioxidant (n-acetyl cysteine) effects on iron-overload brains were also studied.<br><br>METHODOLOGY: Male Wistar rats were fed either normal diet or high iron-diet consumption for 12 weeks, after which rats in each diet group were treated with vehicle or deferiprone (50 mg/kg) or n-acetyl cysteine (100 mg/kg) or both for another 4 weeks. High iron-diet consumption caused brain iron accumulation, brain mitochondrial dysfunction, impaired brain synaptic plasticity and cognition, blood-brain-barrier breakdown, and brain apoptosis. Although both iron chelator and antioxidant attenuated these deleterious effects, combined therapy provided more robust results.<br><br>CONCLUSION: In conclusion, this is the first study demonstrating that combined iron chelator and anti-oxidant therapy completely restored brain function impaired by iron overload.}, }
@article {pmid24398995, year = {2013}, author = {Hsieh, CL and Chen, KC and Ding, CY and Tsai, WJ and Wu, JF and Peng, CC}, title = {Valproic acid substantially downregulated genes folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3, N-acetylcysteine alleviated most of the induced gene alterations in chicken embryo model.}, journal = {Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie}, volume = {54}, number = {4}, pages = {993-1004}, pmid = {24398995}, issn = {2066-8279}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Avian Proteins/*genetics/metabolism ; Chick Embryo ; Chromatography, High Pressure Liquid ; Collagen Type VI/genetics/metabolism ; Dose-Response Relationship, Drug ; Down-Regulation/*drug effects/genetics ; Folate Receptor 1/genetics/metabolism ; Folic Acid/blood ; Gene Expression Regulation, Developmental/*drug effects ; Histone Deacetylases/metabolism ; Kruppel-Like Transcription Factors/genetics/metabolism ; *Models, Biological ; Neovascularization, Pathologic/embryology/genetics/pathology/physiopathology ; Neural Tube Defects/embryology/genetics ; Oligonucleotide Array Sequence Analysis ; Paired Box Transcription Factors/genetics/metabolism ; RGS Proteins/genetics/metabolism ; Receptor, IGF Type 2/genetics/metabolism ; Receptors, Endothelin/genetics/metabolism ; Valproic Acid/*pharmacology ; }, abstract = {Valproic acid induced teratogenicity at genetic and somatic levels, the action mechanism is still unclear. We hypothesized that folate receptor gene (folr1) and others may be interacting to elicit neural tube defect (NTD), while N-acetylcysteine (NAC) may be beneficial for protection. In chicken embryo model, the experiment was conducted in two parts. The first part was carried out to test the optimum dose of VPA. The second part was conducted to test the protective effect of NAC at doses 10 and 20 mM. VPA induced dysvascularization, incomplete somite enclosure, histone deacetylase (HDAC) inhibition, folate deficiency, homocysteine accumulation, SOD inhibition, glutathione depletion, elevated MDA and hydrogen peroxide. NAC alleviated most of these adverse effects. The microarray analysis revealed 17 genes downregulated and four upregulated. The relevancy covered translation (23%), signal transduction (23%), transcription (16%), cell adhesion (16%), neural cell migration (8%), transport (7%), and organismal development (7%). The genes insulin-like growth factor 2 receptor gene (IGF2R), regulator of G-protein signaling 4 gene (RGS4), alpha 3 (VI) collagen gene (COL6A3), endothelin receptor type b gene (EDNRB), and Krüppel-like factor 6 gene (KLF6) substantially downregulated in reality were directly intermodulating and associated with NTD. VPA downregulated folr1 gene in a dose responsive manner without affecting pax-3 gene, which was ascribed to the metahypoxic state. Conclusively, VPA affects 21 genes: 17 downregulated and four upregulated. VPA dose responsively downregulates gene folr1 without affecting pax-3 gene. These adverse effects can be partially alleviated by N-acetylcysteine.}, }
@article {pmid24397138, year = {2013}, author = {Yi, X and Cui, X and Wu, P and Wang, S and Wang, G and Yang, X and Yang, F and Zheng, S and Li, Z}, title = {[Effects of N-acetylcysteine on apoptosis induced by myocardial ischemia reperfusion injury in rats' heart transplantation].}, journal = {Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery}, volume = {27}, number = {10}, pages = {1234-1239}, pmid = {24397138}, issn = {1002-1892}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Disease Models, Animal ; Graft Survival ; Heart Transplantation/adverse effects/*methods ; Immunohistochemistry ; Injections, Intravenous ; Ischemic Preconditioning/*methods ; Male ; Myocardium/metabolism/pathology ; Protective Agents/*pharmacology ; Random Allocation ; Rats ; Rats, Inbred Lew ; Reperfusion Injury/etiology/pathology/*prevention &amp; control ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: To investigate the effect of N-acetylcysteine (NAC) on the apoptosis during myocardial ischemia reperfusion injury in rats' heart transplantation, and to explore the possible role of NAC in myocardial apoptosis.<br><br>METHODS: Sixty healthy male Lewis rats (weighing, 200-220 g) were randomly divided into 3 groups, 20 rats each group (10 donors and 10 recipients). In control group, 1 mL normal saline was infused via inferior vena cava at 30 minutes before donor harvesting; in donor preconditioning group, NAC (300 mg/kg) was infused via inferior vena cava at 30 minutes before donor harvesting, but no treatment in recipients; and in recipient preconditioning group, NAC (300 mg/kg) was infused via inferior vena cava at 30 minutes before recipient transplantation, but no treatment in donors. Heart transplantation was established in each group. Blood was drawn at 6 and 24 hours after reperfusion for analysis of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) as markers of graft injury; myocardial tissue was harvested to determine the superoxide dismutase (SOD) and lipid hydroperoxide (LPO) activity at 24 hours after reperfusion and to observe the histology and ultrastructural changes. Graft active Caspase-3 protein expression was measured by immunohistochemistry staining, and apoptosis index (AI) was calculated by TUNEL.<br><br>RESULTS: The heart transplantation operation was successfully completed in all groups, and the rats survived to the end of the experiment. The serum levels of AST, ALT, and LDH in donor and recipient preconditioning groups were significantly lower than those in control group at 6 hours after reperfusion (P < 0.05); the levels of AST and ALT in donor preconditioning group and the levels of AST and LDH in recipient preconditioning group were significantly lower than those in control group at 24 hours (P < 0.05); and no significant difference was found between donor and recipient perconditioning groups (P > 0.05). The levels of AST, ALT, and LDH at 24 hours were significantly lower than those at 6 hours in each group (P < 0.05) except the level of ALT in recipient preconditioning group (P > 0.05). SOD activity and SOD/LPO in donor and recipient preconditioning groups were significantly higher than those in control group (P < 0.05), but no significant difference between donor and recipient preconditioning groups (P > 0.05); there was no significant difference in LPO activity among 3 groups (P > 0.05). Histological staining and transmission electron microscope showed that myocardial injury in recipient preconditioning group was obviously lighter than that in donor preconditioning group and control group. Active Caspase-3 in recipient pretreatment group was significantly higher than that in donor preconditioning group and control group (P < 0.05). AI of donor and recipient preconditioning groups was significantly lower than that of control group (P < 0.05), but no significant difference was found between donor and recipient preconditioning groups (P > 0.05).<br><br>CONCLUSION: NAC can relieve ischemia reperfusion injury in rats' heart transplantation by improving myocardial SOD content, and reducing active Caspase-3 activity and AI, which has a protective effect on myocardial cell of donor heart.}, }
@article {pmid24396768, year = {2013}, author = {Motalebi Kashani, M and Saberi, H and Hannani, M}, title = {Prevention of Acoustic Trauma-Induced Hearing Loss by N-acetylcysteine Administration in Rabbits.}, journal = {Archives of trauma research}, volume = {1}, number = {4}, pages = {145-150}, pmid = {24396768}, issn = {2251-953X}, abstract = {BACKGROUND: Acoustic trauma is an injury to the hearing mechanisms in the inner ear due to excessive noise. This injury is the most prevalent cause of sensorineural hearing loss in humans, especially from occupational exposure. Previous studies have shown the essential role of free radical formation in the inner ear hearing loss caused by acoustic trauma.<br><br>OBJECTIVES: This study was performed to determine the effect of N-acetylcysteine (NAC) administration for reducing acute acoustic trauma in rabbits.<br><br>MATERIALS AND METHODS: TWENTY FOUR RABBITS WERE ASSIGNED TO FOUR GROUPS INCLUDING: control, noise plus saline, noise plus NAC administration (325 mg/kg body weight by intraperitoneal injection (IP), three days before exposure to noise and three days after noise exposure), and NAC alone. Auditory brain stem response (ABR) threshold was measured before exposure and one hour and 14 days after exposure.<br><br>RESULTS: The saline plus noise group had on average a 49 decibel (dB) temporary threshold shift (TTS) and 23.9 dB permanent threshold shift (PTS) at the studied frequencies, while rabbits in the NAC administration plus noise group had a 31.5 dB TTS and 10.7 dB PTS averaged across the frequencies.<br><br>CONCLUSIONS: Administration of NAC can provide appropriate protection against acoustic trauma-induced hearing loss in rabbits at all studied frequencies.}, }
@article {pmid24393850, year = {2014}, author = {Zaman, K and Bennett, D and Fraser-Butler, M and Greenberg, Z and Getsy, P and Sattar, A and Smith, L and Corey, D and Sun, F and Hunt, J and Lewis, SJ and Gaston, B}, title = {S-Nitrosothiols increases cystic fibrosis transmembrane regulator expression and maturation in the cell surface.}, journal = {Biochemical and biophysical research communications}, volume = {443}, number = {4}, pages = {1257-1262}, pmid = {24393850}, issn = {1090-2104}, support = {P30 DK027651/DK/NIDDK NIH HHS/United States ; HL096800/HL/NHLBI NIH HHS/United States ; U10 HL109250/HL/NHLBI NIH HHS/United States ; R01 HL096800/HL/NHLBI NIH HHS/United States ; 1P01HL 101871-01A1/HL/NHLBI NIH HHS/United States ; P01 HL101871/HL/NHLBI NIH HHS/United States ; }, mesh = {Bronchi/drug effects/metabolism ; Cell Membrane/drug effects/metabolism ; Cells, Cultured ; Cystic Fibrosis/genetics/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/*genetics/*metabolism ; Epithelial Cells/drug effects/metabolism ; Half-Life ; Humans ; Mutant Proteins/genetics/metabolism ; Protein Stability/drug effects ; S-Nitrosothiols/metabolism/*pharmacology ; Sequence Deletion ; Signal Transduction ; }, abstract = {S-nitrosothiols (SNOs) are endogenous signaling molecules with a broad spectrum of beneficial airway effects. SNOs are normally present in the airway, but levels tend to be low in cystic fibrosis (CF) patients. We and others have demonstrated that S-nitrosoglutathione (GSNO) increases the expression, maturation, and function of wild-type and mutant F508del cystic fibrosis transmembrane conductance regulator (CFTR) in human bronchial airway epithelial (HBAE) cells. We hypothesized that membrane permeable SNOs, such as S-nitrosoglutathione diethyl ester (GNODE) and S-nitroso-N-acetyl cysteine (SNOAC) may be more efficient in increasing the maturation of CFTR. HBAE cells expressing F508del CFTR were exposed to GNODE and SNOAC. The effects of these SNOs on the expression and maturation of F508del CFTR were determined by cell surface biotinylation and Western blot analysis. We also found for the first time that GNODE and SNOAC were effective at increasing CFTR maturation at the cell surface. Furthermore, we found that cells maintained at low temperature increased cell surface stability of F508del CFTR whereas the combination of low temperature and SNO treatment significantly extended the half-life of CFTR. Finally, we showed that SNO decreased the internalization rate of F508del CFTR in HBAE cells. We anticipate identifying the novel mechanisms, optimal SNOs, and lowest effective doses which could benefit cystic fibrosis patients.}, }
@article {pmid24392833, year = {2014}, author = {Zhang, L and He, YL and Li, QZ and Hao, XH and Zhang, ZF and Yuan, JX and Bai, YP and Jin, YL and Liu, N and Chen, G and Yun, X and Yao, SQ}, title = {N-acetylcysteine alleviated silica-induced lung fibrosis in rats by down-regulation of ROS and mitochondrial apoptosis signaling.}, journal = {Toxicology mechanisms and methods}, volume = {24}, number = {3}, pages = {212-219}, doi = {10.3109/15376516.2013.879974}, pmid = {24392833}, issn = {1537-6524}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Down-Regulation ; Lung/drug effects/pathology ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/physiology ; Procollagen/genetics ; Pulmonary Fibrosis/chemically induced/*prevention &amp; control ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Silicon Dioxide/*toxicity ; }, abstract = {Reactive oxygen species (ROS) is a normal metabolic product of cellular respiration, but too much ROS can induce cell apoptosis. Here, we used N-acetylcysteine (NAC) to inhibit ROS activity to explore the effects of NAC on silica-induced pulmonary fibrosis in rats and provide evidence for study on the mechanism of silicosis. 24 adult male Sprague-Dawley rats weighing 180-220 g were randomly divided into three groups with eight rats in each group. Silicosis model group and NAC group were adopted non-tracheal exposure method of disposable intrapulmonary injection of 50 g/L, silica suspension 1 mL to establish animal silicosis model, NAC group treated with 600 mg/kg NAC by gavage from the right day of modeling, all animals were sacrificed after 28 days. The level of ROS contents and mitochondrial transmembrane potential changes of AM, the mRNA expression level of type I and type III procollagen, cytochrome C, cysteinyl aspartate specific protease-9 and caspase-3 were detected. The severity of pathological changes and pulmonary fibrosis were observed by pathologic specimens. It was showed that ROS contents and MTP changes were lower in the NAC group compared with the silicosis model group, other indexes were lower in the NAC group than the model group, but higher than those of the control group, the degree of lung fibrotic lesions observed from the pathological slices showed the same trend. These data indicated that NAC can reduce ROS content of AM in silica exposure rats, the mitochondrial apoptosis pathway can also be inhibited, the severity of pulmonary fibrosis alleviated as a result.}, }
@article {pmid24390944, year = {2013}, author = {Dabirmoghaddam, P and Amali, A and Motiee Langroudi, M and Samavati Fard, MR and Hejazi, M and Sharifian Razavi, M}, title = {The effect of N-acetyl cysteine on laryngopharyngeal reflux.}, journal = {Acta medica Iranica}, volume = {51}, number = {11}, pages = {757-764}, pmid = {24390944}, issn = {1735-9694}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Female ; Humans ; Laryngopharyngeal Reflux/*drug therapy ; Male ; Middle Aged ; Omeprazole/administration &amp; dosage/*therapeutic use ; Placebos ; Proton Pump Inhibitors/administration &amp; dosage/*therapeutic use ; }, abstract = {Laryngopharyngeal reflux (LPR) is a variant of gastroesophageal reflux disease (GERD) in which the stomach contents go up into the pharynx and then down into the larynx. LPR causes a wide spectrum of manifestations mainly related to the upper and the lower respiratory system such as laryngitis, asthma, chronic obstructive pulmonary disease, cough, hoarseness, postnasal drip disease, sinusitis, otitis media, recurrent pneumonia, laryngeal cancer and etc. The object of this study was to examine the effect of N-acetyl Cysteine (NAC) with and without Omeprazole on laryngitis and LPR. Ninety patients with laryngitis or its symptoms were referred and randomly assigned into three groups. The first group was treated by Omeprazole and NAC. The second group was treated by Omeprazole and placebo and the last group was treated by NAC and placebo. Duration of treatment was 3 months and all patients were evaluated at the beginning of study, one month and three month after treatment of sign and symptoms, based on reflux symptom index (RSI) and reflex finding score (RFS). Based on the results of this study, despite therapeutic efficacy of all treatment protocols, the RSI before and after 3 months treatment had significant difference in (NAS+ Omeprazole) and (Omeprazole+ placebo) group (P<0.001 in the first group, P<0.001 in the second group and P=0.35 in the third group). Whereas RFS before and after 3 month treatment had significant difference in all groups. (P<0.001 in each group in comparison with itself) but this results had not significant difference after 1 month treatment. Our results showed that the combination therapy with Omeprazole and NAC treatment had the most effect on both subjective and objective questionnaire at least after 3 months treatment. Based on the results of the present study, it seems that the use objective tools are more accurate than subjective tools in evaluation of therapeutic effects in patients with GERD-related laryngitis.}, }
@article {pmid24389479, year = {2014}, author = {Zhu, CX and Yan, L and Wang, XJ and Miao, Q and Li, XX and Yang, F and Cao, YB and Gao, PH and Bi, XL and Jiang, YY}, title = {Transposition of the Zorro2 retrotransposon is activated by miconazole in Candida albicans.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {37}, number = {1}, pages = {37-43}, doi = {10.1248/bpb.b13-00508}, pmid = {24389479}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Antifungal Agents/*pharmacology ; Antioxidants/pharmacology ; Candida albicans/*drug effects/genetics ; DNA Repair ; Genome, Fungal ; Miconazole/*pharmacology ; *Open Reading Frames ; Reactive Oxygen Species/*metabolism ; *Retroelements ; *Transcription, Genetic ; }, abstract = {Zorro2 is a member of a non-long terminal repeat (LTR) retrotransposon family in Candida albicans, but as yet no clear evidence has been provided to establish either transcription or transposition activity for Zorro2. In this study, the relative expression changes of two open reading frames in Zorro2, ORF19.7274 and ORF19.7275, were examined in response to miconazole (MCZ), and were found to be increased by this treatment. As well, the copy number and the transcripts of Zorro2 in MCZ-induced resistant daughter strains were increased compared to the parental strain, indicating that transposition of Zorro2 occurred during long-term MCZ treatment. Intriguingly, the transcription activity of Zorro2 retrotransposons was significantly inhibited when the cells were treated with MCZ together with antioxidant N-acetyl-L-cysteine (NAC). As both the level of intracellular reactive oxygen species (ROS) and the expression of genes involving DNA repair activated by MCZ were reduced when combined with the treatment of NAC, we propose that the damage caused by accumulation of ROS under MCZ stress is a major reason for the transcription and transposition activation of the Zorro2 retrotransposon.}, }
@article {pmid24388697, year = {2015}, author = {Roseguini, BT and Silva, LM and Polotow, TG and Barros, MP and Souccar, C and Han, SW}, title = {Effects of N-acetylcysteine on skeletal muscle structure and function in a mouse model of peripheral arterial insufficiency.}, journal = {Journal of vascular surgery}, volume = {61}, number = {3}, pages = {777-786}, doi = {10.1016/j.jvs.2013.10.098}, pmid = {24388697}, issn = {1097-6809}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biomarkers/metabolism ; Collagen/metabolism ; Exercise Tolerance/drug effects ; Femoral Artery/surgery ; Ligation ; Lipid Peroxidation/drug effects ; Male ; Mice, Inbred BALB C ; Muscle Contraction/drug effects ; Muscle Fatigue/*drug effects ; Muscle, Skeletal/*blood supply/*drug effects/metabolism/pathology/physiopathology ; Oxidative Stress/drug effects ; Peripheral Arterial Disease/*drug therapy/metabolism/pathology/physiopathology ; Protein Carbonylation/drug effects ; Recovery of Function ; Time Factors ; }, abstract = {OBJECTIVE: Abnormalities in skeletal muscle structure and function are important contributors to exercise intolerance and functional decline in peripheral arterial disease. In this study, we tested the hypothesis that administration of N-acetylcysteine (NAC) would improve fatigue resistance and ameliorate the histopathological changes in skeletal muscle in a mouse model of peripheral arterial disease. We also anticipated that NAC treatment would lower the levels of biomarkers of oxidative damage in the ischemic muscle.<br><br>METHODS: Male Balb/c mice were subjected to bilateral ligation of the femoral artery and, after 2 weeks of recovery, received daily intraperitoneal injections of either NAC (150 mg/kg) or saline for 15 days. At the end of the treatment, the extensor digitorium longus (EDL) and soleus muscles were excised for assessment of contractile function in vitro and histological analysis. Free malondialdehyde and protein carbonyl levels were measured in the gastrocnemius muscle.<br><br>RESULTS: In the soleus muscle, force after 10 minutes of submaximal tetanic stimulation (60 Hz, 300 ms trains, 0.3 trains/s) was higher (P < .05) in NAC-treated animals (45% &#xb1; 3% of the initial value; n = 7) when compared with controls (30.3% &#xb1; 3%; n = 8). No differences were found in fatigue development between groups in the EDL muscle (ligated NAC, 35.7% &#xb1; 1.9%; ligated saline, 37.5% &#xb1; 1.1%). In addition, there was a tendency for lower levels of connective tissue deposition in the soleus of animals treated with NAC (n = 6) when compared with those that received only saline (n = 9) (ligated NAC, 16% &#xb1; 2% vs ligated saline, 24% &#xb1; 2%; P = .057). No differences were found in lipid peroxidation or protein carbonyl levels between ligated saline and ligated NAC groups.<br><br>CONCLUSIONS: Taken together, these results indicate that treatment with NAC improves fatigue resistance in the soleus but not the EDL muscle in a model of peripheral arterial insufficiency.<br><br>CLINICAL RELEVANCE: Despite the increasing burden of peripheral arterial disease (PAD) and its detrimental consequences on the quality of life of the patients, few pharmacological therapies have shown to evoke meaningful effects on functional performance in these individuals. N-acetylcysteine is approved for clinical use, has minimal side effects and most important, has shown to consistently improve exercise performance in animals and humans. In this study, we showed, for the first time, that treatment with this drug at a dose amenable for clinical application evoked marked effects on fatigue resistance in the soleus muscle in a mouse model of PAD. These encouraging findings set the stage for translational studies to determine the acute and long-term impact of this drug on walking capacity in patients with PAD.}, }
@article {pmid24388027, year = {2014}, author = {Leise, MD and Poterucha, JJ and Talwalkar, JA}, title = {Drug-induced liver injury.}, journal = {Mayo Clinic proceedings}, volume = {89}, number = {1}, pages = {95-106}, doi = {10.1016/j.mayocp.2013.09.016}, pmid = {24388027}, issn = {1942-5546}, mesh = {Adult ; Amoxicillin/*adverse effects ; Anti-Inflammatory Agents, Non-Steroidal/*adverse effects ; Causality ; Chemical and Drug Induced Liver Injury/*epidemiology ; China/epidemiology ; Clavulanic Acid/*adverse effects ; Comorbidity ; Democratic People's Republic of Korea/epidemiology ; Dietary Supplements/adverse effects ; Enzyme Inhibitors/adverse effects ; Female ; Fluoroquinolones/adverse effects ; France/epidemiology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects ; Iceland/epidemiology ; Isoniazid/*adverse effects ; Liver Diseases/*epidemiology ; Male ; Protein-Tyrosine Kinases/metabolism ; Republic of Korea/epidemiology ; Spain/epidemiology ; Tumor Necrosis Factor-alpha/adverse effects ; United States/epidemiology ; }, abstract = {Drug hepatoxicity can be nonidiosyncratic (predictable), as in the case of acetaminophen, or idiosyncratic (unpredictable). This review article focuses primarily on idiosyncratic drug-induced liver injury (DILI). New epidemiologic data suggest that approximately 20 new cases of DILI per 100,000 persons occur each year. Idiosyncratic DILI accounts for 11% of the cases of acute liver failure in the United States. Risk factors for DILI include medication dose, drug lipophilicity, and extent of hepatic metabolism. There is mixed evidence to support the role of host factors such as age, sex, and chronic liver disease in the development of DILI. For specific drugs, a genetic predisposition appears to be a risk factor for DILI. Suspected cases of idiosyncratic DILI should be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase and alkaline phosphatase. A careful evaluation for other causes of liver disease should be performed, though a liver biopsy is rarely needed. There is evidence that some patients with DILI may actually have hepatitis E and this diagnosis should be considered. Amoxicillin/clavulanate isoniazid, and nonsteroidal anti-inflammatory drugs are among the most common causes of DILI. Drug discontinuation or dechallenge should lead to an improvement in liver biochemistries in most patients, though a bilirubin value of more than 3 g/dL is associated with mortality of at least 10%. New biomarkers for DILI using proteomics and micro RNA appear promising but require further study. New studies on drugs with potential for causing DILI are reviewed herein, including tumor necrosis factor-alpha antagonists, fluoroquinolones, tyrosine kinase inhibitors, statins, and supplements. PubMed was used with search terms of drug induced liver injury OR DILI with filter settings of "English language" and "humans" and custom date range of "January 1, 2000." The authors also manually searched bibliographies from key references and included seminal references before the year 2000.}, }
@article {pmid24386346, year = {2013}, author = {Li, KR and Zhang, ZQ and Yao, J and Zhao, YX and Duan, J and Cao, C and Jiang, Q}, title = {Ginsenoside Rg-1 protects retinal pigment epithelium (RPE) cells from cobalt chloride (CoCl2) and hypoxia assaults.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e84171}, pmid = {24386346}, issn = {1932-6203}, mesh = {Apoptosis/drug effects ; Cell Hypoxia/drug effects ; Cell Line ; Cell Survival/drug effects ; Cobalt/*toxicity ; Cytoprotection/*drug effects ; Enzyme Activation/drug effects ; Ginsenosides/*pharmacology ; Humans ; Mechanistic Target of Rapamycin Complex 1 ; Mitogen-Activated Protein Kinases/metabolism ; Multiprotein Complexes/metabolism ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/*cytology/metabolism ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Severe retinal ischemia causes persistent visual impairments in eye diseases. Retinal pigment epithelium (RPE) cells are located near the choroidal capillaries, and are easily affected by ischemic or hypoxia. Ginsenoside Rg-1 has shown significant neuroprotective effects. This study was performed to test the cytoprotective effect of ginsenoside Rg-1 in RPE cells against hypoxia and cobalt chloride (CoCl2) assaults, and to understand the underlying mechanisms. We found that Rg-1 pre-administration significantly inhibited CoCl2- and hypoxia-induced RPE cell death and apoptosis. Reactive oxygen specisis (ROS)-dependent p38 and c-Jun NH(2)-terminal kinases (JNK) MAPK activation was required for CoCl2-induced RPE cell death, and Rg-1 pre-treatment significantly inhibited ROS production and following p38/JNK activation. Further, CoCl2 suppressed pro-survival mTOR complex 1 (mTORC1) activation in RPE cells through activating of AMP-activated protein kinase (AMPK), while Rg-1 restored mTORC1 activity through inhibiting AMPK activation. CoCl2-induced AMPK activation was also dependent on ROS production, and anti-oxidant N-acetylcysteine (NAC) prevented AMPK activation and RPE cell death by CoCl2. Our results indicated that Rg-1 could be further investigated as a novel cell-protective agent for retinal ischemia.}, }
@article {pmid24383086, year = {2013}, author = {Shen, S and Zhang, Y and Zhang, R and Gong, X}, title = {Sarsasapogenin induces apoptosis via the reactive oxygen species-mediated mitochondrial pathway and ER stress pathway in HeLa cells.}, journal = {Biochemical and biophysical research communications}, volume = {441}, number = {2}, pages = {519-524}, pmid = {24383086}, issn = {1090-2104}, mesh = {Anemarrhena/chemistry ; Antineoplastic Agents/*pharmacology ; Cell Cycle Checkpoints ; Cinnamates/pharmacology ; Cytochromes c/biosynthesis ; Drugs, Chinese Herbal/*pharmacology ; Endoplasmic Reticulum Stress/drug effects/*physiology ; Female ; G1 Phase Cell Cycle Checkpoints/drug effects/physiology ; HeLa Cells ; Humans ; M Phase Cell Cycle Checkpoints/drug effects ; Mitochondria/*drug effects ; Mitochondrial Membranes/drug effects ; Reactive Oxygen Species/*metabolism ; Spirostans/*pharmacology ; Thiourea/analogs &amp; derivatives/pharmacology ; Transcription Factor CHOP/biosynthesis ; Unfolded Protein Response ; Uterine Cervical Neoplasms/*metabolism/pathology ; bcl-2-Associated X Protein/biosynthesis ; }, abstract = {Sarsasapogenin is a sapogenin from the Chinese medical herb Anemarrhena asphodeloides Bunge. In the present study, we revealed that sarsasapogenin exhibited antitumor activity by inducing apoptosis in vitro as determined by Hoechst staining analysis and double staining of Annexin V-FITC/PI. In addition, cell cycle arrest in G2/M phase was observed in sarsasapogenin-treated HeLa cells. Moreover, the results revealed that perturbations in the mitochondrial membrane were associated with the deregulation of the Bax/Bcl-2 ratio which led to the upregulation of cytochrome c, followed by activation of caspases. Meanwhile, treatment of sarsasapogenin also activated Unfolded Protein Response (UPR) signaling pathways and these changes were accompanied by increased expression of CHOP. Salubrinal (Sal), a selective inhibitor of endoplasmic reticulum (ER) stress, partially abrogated the sarsasapogenin-related cell death. Furthermore, sarsasapogenin provoked the generation of reactive oxygen species, while the antioxidant N-acetyl cysteine (NAC) effectively blocked the activation of ER stress and apoptosis, suggesting that sarsasapogenin-induced reactive oxygen species is an early event that triggers ER stress mitochondrial apoptotic pathways. Taken together, the results demonstrate that sarsasapogenin exerts its antitumor activity through both reactive oxygen species (ROS)-mediate mitochondrial dysfunction and ER stress cell death.}, }
@article {pmid24381219, year = {2014}, author = {Cao, JJ and Picklo, MJ}, title = {N-acetylcysteine supplementation decreases osteoclast differentiation and increases bone mass in mice fed a high-fat diet.}, journal = {The Journal of nutrition}, volume = {144}, number = {3}, pages = {289-296}, doi = {10.3945/jn.113.185397}, pmid = {24381219}, issn = {1541-6100}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Body Weight ; Bone Density/*drug effects ; Bone Resorption/drug therapy/pathology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; *Diet, High-Fat ; Dietary Fats/administration &amp; dosage ; *Dietary Supplements ; Disease Models, Animal ; Glutathione/blood ; Leptin/blood ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity/blood/pathology ; Osteoclasts/*drug effects/metabolism ; }, abstract = {Obesity induced by high-fat (HF) diets increases bone resorption, decreases trabecular bone mass, and reduces bone strength in various animal models. This study investigated whether N-acetylcysteine (NAC), an antioxidant and a glutathione precursor, alters glutathione status and mitigates bone microstructure deterioration in mice fed an HF diet. Forty-eight 6-wk-old male C57BL/6 mice were randomly assigned to 4 treatment groups (n = 12 per group) and fed either a normal-fat [NF (10% energy as fat)] or an HF (45% energy as fat) diet ad libitum with or without NAC supplementation at 1 g/kg diet for 17 wk. Compared with the NF groups, mice in the HF groups had higher body weight, greater serum leptin concentrations and osteoclast differentiation, and lower trabecular bone volume, trabecular number, and connectivity density (P < 0.05). NAC supplementation increased the serum-reduced glutathione concentration and bone volume and decreased osteoclast differentiation in HF-fed mice (P < 0.05). We further demonstrated that osteoclast differentiation was directly regulated by glutathione status. NAC treatment of murine macrophage RAW 264.7 cells in vitro increased glutathione status and decreased osteoclast formation. These results show that NAC supplementation increases the bone mass of obese mice induced by an HF diet through elevating glutathione status and decreasing bone resorption.}, }
@article {pmid24380754, year = {2014}, author = {Kwon, SJ and Lee, JH and Moon, KD and Jeong, IY and Ahn, DU and Lee, MK and Seo, KI}, title = {Induction of apoptosis by isoegomaketone from Perilla frutescens L. in B16 melanoma cells is mediated through ROS generation and mitochondrial-dependent, -independent pathway.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {65}, number = {}, pages = {97-104}, doi = {10.1016/j.fct.2013.12.031}, pmid = {24380754}, issn = {1873-6351}, mesh = {Animals ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Line, Tumor ; Enzyme Activation ; Furans/*pharmacology ; Ketones/*pharmacology ; Melanoma, Experimental/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Perilla frutescens/*chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {We have demonstrated for the first time the mechanism underlying ROS-mediated mitochondria-dependent apoptotic cell death triggered by isoegomaketone (IK) treatment in melanoma cells. We showed that IK induced apoptotic cell death and tumor growth inhibition using tissue culture and in vivo models of B16 melanoma. Furthermore, we observed that IK effectively induced apoptotic cell death, including sub-G1 contents up-regulation, nuclei condensation, DNA fragmentation, and caspase activation in B16 melanoma cells. Pretreatment with caspase inhibitor increased the survival rate of IK-treated B16 cells, implying that caspases play a role in IK-induced apoptosis. Furthermore, IK treatment generated ROS in melanoma cells. We also determined whether or not IK-induced cell death is due to ROS production in B16 cells. N-acetyl cysteine (NAC) inhibitedIK-induced Bcl-2 family-mediated apoptosis. This result indicates that IK-induced apoptosis involves ROS generation as well as up-regulation of Bax and Bcl-2 expression, leading to release of cytochrome c and AIF. Our data suggest that IK inhibits growth and induces apoptosis in melanoma cells via activation of ROS-mediated caspase-dependent and -independent pathways.}, }
@article {pmid24380396, year = {2014}, author = {van Haandel, L and Goldman, JL and Pearce, RE and Leeder, JS}, title = {Urinary biomarkers of trimethoprim bioactivation in vivo following therapeutic dosing in children.}, journal = {Chemical research in toxicology}, volume = {27}, number = {2}, pages = {211-218}, doi = {10.1021/tx4003325}, pmid = {24380396}, issn = {1520-5010}, mesh = {Acetylcysteine/metabolism ; Anti-Infective Agents/*pharmacokinetics/pharmacology/urine ; Biomarkers/urine ; Biotransformation ; Child ; Child, Preschool ; Chromatography, Liquid ; Humans ; Microsomes, Liver/metabolism ; Tandem Mass Spectrometry ; Trimethoprim/*pharmacokinetics/pharmacology/urine ; Trimethoprim, Sulfamethoxazole Drug Combination/*pharmacokinetics/urine ; }, abstract = {The antimicrobial trimethoprim-sulfamethoxazole (TMP-SMX) is widely used for the treatment of skin and soft-tissue infections in the outpatient setting. Despite its therapeutic benefits, TMP-SMX has been associated with a number of adverse drug reactions, which have been primarily attributed to the formation of reactive metabolites from SMX. Recently, in vitro experiments have demonstrated that TMP may form reactive intermediates as well. However, evidence of TMP bioactivation in patients has not yet been demonstrated. In this study, we performed in vitro trapping experiments with N-acetyl-l-cysteine (NAC) to determine stable markers of reactive TMP intermediates, focusing on eight potential markers (NAC-TMP adducts), some of which were previously identified in vitro. We developed a specific and sensitive assay involving liquid chromatography followed by tandem mass spectrometry for measurement of these adducts in human liver microsomal samples and expanded the methodology toward the detection of these analytes in human urine. Urine samples from four patients receiving TMP-SMX treatment were analyzed, and all samples demonstrated the presence of six NAC-TMP adducts, which were also detected in vitro. These adducts are consistent with the formation of imino-quinone-methide and para-quinone-methide reactive intermediates in vivo. As a result, the TMP component of TMP-SMX should be considered as well when evaluating adverse drug reactions to TMP-SMX.}, }
@article {pmid24378334, year = {2014}, author = {Gao, K and Chi, Y and Sun, W and Takeda, M and Yao, J}, title = {5'-AMP-activated protein kinase attenuates adriamycin-induced oxidative podocyte injury through thioredoxin-mediated suppression of the apoptosis signal-regulating kinase 1-P38 signaling pathway.}, journal = {Molecular pharmacology}, volume = {85}, number = {3}, pages = {460-471}, doi = {10.1124/mol.113.089458}, pmid = {24378334}, issn = {1521-0111}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Adrenergic Agents/pharmacology ; Animals ; Apoptosis/drug effects ; Calcium/metabolism ; Cell Line ; Cyclic AMP/metabolism ; Doxorubicin/pharmacology ; Endocytosis/drug effects ; MAP Kinase Kinase Kinase 5/*metabolism ; MAP Kinase Signaling System/drug effects ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Podocytes/*drug effects/metabolism ; Receptors, Adrenergic, beta-2/metabolism ; Signal Transduction/*drug effects ; Thioredoxins/*pharmacology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Oxidative stress-induced podocyte injury is one of the major mechanisms underlying the initiation and progression of glomerulosclerosis. 5'-AMP-activated protein kinase (AMPK), a serine/threonine kinase that senses intracellular energy status and maintains energy homeostasis, is reported to have antioxidative effects. However, little is known about its application and mechanism. In this study, we investigated whether and how AMPK affected oxidative podocyte injury induced by Adriamycin (ADR; Wako Pure Chemical, Osaka, Japan). Exposure of podocytes to ADR resulted in cell injury, which was preceded by increased reactive oxygen species (ROS) generation and P38 activation. Prevention of oxidative stress with the antioxidant N-acetyl-cysteine and glutathione or inhibition of P38 with SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] attenuated cell injury. Activation of AMPK with three structurally different AMPK activators also protected podocytes from ADR-elicited cell injury. This effect was associated with strong suppression of oxidative stress-sensitive kinase apoptosis signal-regulating kinase 1 (ASK1) and P38 without obvious influence on ROS level. Further analyses revealed that AMPK promoted thioredoxin (Trx) binding to ASK1. Consistently, AMPK potently suppressed the expression of thioredoxin-interacting protein (TXNIP), a negative regulator of Trx, whereas it significantly enhanced the activity of Trx reductases that convert oxidized Trx to reduced form. In further support of a key role of Trx, downregulation or inhibition of Trx exaggerated but downregulation of TXNIP attenuated the cell injury. These results indicate that AMPK prevents oxidative cell injury through Trx-mediated suppression of ASK1-P38 signaling pathway. Our findings thus provide novel mechanistic insights into the antioxidative actions of AMPK. AMPK could be developed as a novel therapeutic target for treatment of oxidative cell injury.}, }
@article {pmid24378052, year = {2014}, author = {Shen, Y and Cai, W and Lei, S and Zhang, Z}, title = {Effect of high/low dose N-acetylcysteine on chronic obstructive pulmonary disease: a systematic review and meta-analysis.}, journal = {COPD}, volume = {11}, number = {3}, pages = {351-358}, doi = {10.3109/15412555.2013.858315}, pmid = {24378052}, issn = {1541-2563}, mesh = {Acetylcysteine/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Disease Progression ; Forced Expiratory Volume/drug effects ; Humans ; Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity worldwide, characterised by persistent airflow limitation, mucus hypersecretion, oxidative stress and airway inflammation. N-acetylcysteine (NAC) have anti-oxidant and anti-inflammatory properties, which have been shown an uncertain benefit in COPD patients.<br><br>METHOD: Systematic searches were conducted in Cochrane, Medline and Embase electronic databases. A meta-analysis was performed to evaluate the different effect between high and low-dose NAC treatment on COPD exacerbation.<br><br>RESULTS: This review yielded 11 studies. The methodological quality of included studies were scored using the Jadad score, with a scale of 1 to 5 (score of 5 being the highest). Data showed high-dose NAC can reduce both the total number of exacerbations (RR = 0.59, 0.47 to 0.74, 95%CI, p < 0.001) and the proportion of patients with at least one exacerbation (RR = 0.76, 0.59 to 0.98, 95%CI, p = 0.03). In the low-dose group, subgroup with jadad &#x2264; 3 showed a significant decrease (RR = 0.69, 0.61 to 0.77, 95%CI, p < 0.001) in the proportion of patients with exacerbation, the other subgroup with Jadad score > 3 showed no significant decrease (RR = 0.98, 0.90 to 1.06, 95%CI, p = 0.59). And low-dose NAC showed no benefit in the total number of exacerbations (RR = 0.97, 0.68 to 1.37, 95%CI, p = 0.85). Neither high nor low-dose NAC treatment showed benefit in forced expiratory volume in one second(FEV1)(WMD = 1.08, -9.97 to 12.13, 95%CI, p = 0.85).<br><br>CONCLUSION: Long-term high-dose NAC treatment may lead to a lower rate of exacerbations. But the effect of low-dose NAC treatment remains uncertain. Further researches are needed to confirm this outcome and to clarify its mechanisms.}, }
@article {pmid24376853, year = {2013}, author = {Huang, SY and Fang, CY and Wu, CC and Tsai, CH and Lin, SF and Chen, JY}, title = {Reactive oxygen species mediate Epstein-Barr virus reactivation by N-methyl-N'-nitro-N-nitrosoguanidine.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e84919}, pmid = {24376853}, issn = {1932-6203}, mesh = {Acetylcysteine ; Blotting, Western ; Catalase ; Chromatin Immunoprecipitation ; DNA Primers/genetics ; Fluorescent Antibody Technique ; Herpesvirus 4, Human/metabolism/*physiology ; Immediate-Early Proteins/metabolism ; Methylnitronitrosoguanidine/*metabolism ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Trans-Activators/metabolism ; Tumor Suppressor Protein p53/metabolism ; Virus Activation/*physiology ; }, abstract = {N-nitroso compounds (NOCs) and Epstein-Barr virus (EBV) reactivation have been suggested to play a role in the development of nasopharyngeal carcinoma (NPC). Although chemicals have been shown to be a risk factor contributing to the carcinogenesis of NPC, the underlying mechanism is not fully understood. We demonstrated recently that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) enhances the genomic instability and tumorigenicity of NPC cells via induction of EBV reactivation. However, the mechanisms that trigger EBV reactivation from latency remain unclear. Here, we address the role of ROS in induction of EBV reactivation under MNNG treatment. EBV reactivation was induced in over 70% of EBV-positive NA cells and the promoter of Rta (Rp) was activated after MNNG treatment. Inhibitor experiments revealed ATM, p38 MAPK and JNK were activated by ROS and involved in MNNG-induced EBV reactivation. Significantly, ROS scavengers N-acetyl-L-cysteine (NAC), catalase and reduced glutathione inhibited EBV reactivation under MNNG and H2O2 treatment, suggesting ROS mediate EBV reactivation. The p53 was essential for EBV reactivation and the Rp activation by MNNG. Moreover, the p53 was phosphorylated, translocated into nucleus, and bound to Rp following ROS stimulation. The results suggest ROS play an important role in initiation of EBV reactivation by MNNG through a p53-dependent mechanism. Our findings demonstrate novel signaling mechanisms used by NOCs to induce EBV reactivation and provide a novel insight into NOCs link the EBV reactivation in the contribution to the development of NPC. Notably, this study indicates that antioxidants might be effective for inhibiting N-nitroso compound-induced EBV reactivation and therefore could be promising preventive and therapeutic agents for EBV reactivation-associated malignancies.}, }
@article {pmid24376844, year = {2013}, author = {Jiang, J and Shan, Z and Xu, W and Wang, X and Zhou, J and Kong, D and Xu, J}, title = {Microcystin-LR induced reactive oxygen species mediate cytoskeletal disruption and apoptosis of hepatocytes in Cyprinus carpio L.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e84768}, pmid = {24376844}, issn = {1932-6203}, mesh = {Analysis of Variance ; Animals ; Apoptosis/drug effects/*physiology ; Buthionine Sulfoximine/toxicity ; Carps/*metabolism/physiology ; Cytoskeleton/drug effects/*pathology ; DNA Primers/genetics ; Flow Cytometry ; Hepatocytes/*metabolism/physiology ; Immunohistochemistry ; Marine Toxins ; Microcystins/metabolism/*toxicity ; Microscopy, Confocal ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Time Factors ; }, abstract = {Microcystins (MCs) are a group of cyclic hepatotoxic peptides produced by cyanobacteria. Microcystin-LR (MC-LR) contains Leucine (L) and Arginine (R) in the variable positions, and is one of the most common and potently toxic peptides. MC-LR can inhibit protein phosphatase type 1 and type 2A (PP1 and PP2A) activities and induce excessive production of reactive oxygen species (ROS). The underlying mechanism of the inhibition of PP1 and PP2A has been extensively studied. The over-production of ROS is considered to be another main mechanism behind MC-LR toxicity; however, the detailed toxicological mechanism involved in over-production of ROS in carp (Cyprinus carpio L.) remains largely unclear. In our present study, the hydroxyl radical (•OH) was significantly induced in the liver of carp after a relatively short-term exposure to MC-LR. The elevated reactive oxygen species (ROS) production may play an important role in the disruption of microtubule structure. Pre-injection of the antioxidant N-acetyl-cysteine (NAC) provided significant protection to the cytoskeleton, however buthionine sulfoximine (BSO) exacerbated cytoskeletal destruction. In addition, the elevated ROS formation induced the expression of apoptosis-related genes, including p38, JNKa, and bcl-2. A significant increase in apoptotic cells was observed at 12-48 hours. Our study further supports evidence that ROS are involved in MC-LR induced damage to liver cells in carp, and indicates the need for further study of the molecular mechanisms behind MC-LR toxicity.}, }
@article {pmid24373880, year = {2014}, author = {Liu, N and Huang, H and Liu, S and Li, X and Yang, C and Dou, QP and Liu, J}, title = {Calcium channel blocker verapamil accelerates gambogic acid-induced cytotoxicity via enhancing proteasome inhibition and ROS generation.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {28}, number = {3}, pages = {419-425}, doi = {10.1016/j.tiv.2013.12.008}, pmid = {24373880}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Calcium Channel Blockers/pharmacology ; Caspases/metabolism ; Cell Death/drug effects ; Drug Synergism ; Endoplasmic Reticulum Stress/drug effects ; Hep G2 Cells ; Humans ; K562 Cells ; Proteasome Inhibitors/administration &amp; dosage/*pharmacology ; Reactive Oxygen Species/*metabolism ; Verapamil/administration &amp; dosage/*pharmacology ; Xanthones/administration &amp; dosage/*pharmacology ; }, abstract = {Verapamil (Ver), an inhibitor of the multidrug resistance gene product, has been proved to be a promising combination partner with other anti-cancer agents including proteasome inhibitor bortezomib. Gambogic acid (GA) has been approved for Phase II clinical trials in cancer therapy in China. We have most recently reported that GA is a potent proteasome inhibitor, with anticancer efficiency comparable to bortezomib but much less toxicity. In the current study we investigated whether Ver can enhance the cytotoxicity of GA. We report that (i) the combination of Ver and GA results in synergistic cytotoxic effect and cell death induction in HepG2 and K562 cancer cell lines; (ii) a combinational treatment with Ver and GA induces caspase activation, endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production; (iii) caspase inhibitor z-VAD blocks GA+Ver-induced apoptosis but not proteasome inhibition; (iv) cysteine-containing compound N-acetylcysteine (NAC) prevents GA+Ver-induced poly(ADP-ribose) polymerase cleavage and proteasome inhibition. These results demonstrate that Ver accelerates GA-induced cytotoxicity via enhancing proteasome inhibition and ROS production. These findings indicate that the natural product GA is a valuable candidate that can be used in combination with Ver, thus representing a compelling anticancer strategy.}, }
@article {pmid24373863, year = {2014}, author = {Domínguez-Álvarez, M and Sabaté-Brescó, M and Vilà-Ubach, M and Gáldiz, JB and Alvarez, FJ and Casadevall, C and Gea, J and Barreiro, E}, title = {Molecular and physiological events in respiratory muscles and blood of rats exposed to inspiratory threshold loading.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {163}, number = {5}, pages = {478-493}, doi = {10.1016/j.trsl.2013.12.004}, pmid = {24373863}, issn = {1878-1810}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies, Monoclonal/pharmacology ; Antioxidants ; Biomechanical Phenomena ; Inflammation ; Infliximab ; Male ; Muscle Contraction/*physiology ; Muscle, Skeletal/*physiology ; Oxidative Stress ; Random Allocation ; Rats ; Rats, Wistar ; Regeneration/physiology ; Respiratory Muscles/*metabolism ; Specific Pathogen-Free Organisms ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/metabolism ; }, abstract = {High-intensity exercise induces oxidative stress and inflammatory events in muscles. Tumor necrosis factor (TNF)-α may alter muscle protein metabolism or promote muscle regeneration. We hypothesized that a program of noninvasive chronic inspiratory loading of different intensities induces a differential pattern of physiological, molecular, and cellular events within rat diaphragms. Antioxidants and TNF-α blockade may influence those events. In the diaphragm, gastrocnemius, and blood of rats exposed to high-intensity inspiratory threshold loads (2 hour every 24 hours for 14 days), with and without treatment with N-acetyl cysteine or infliximab (anti-TNF-α antibody), inflammatory cells and cytokines, superoxide anion production, myogenesis markers, and muscle structure were explored. In all animals, maximum inspiratory pressure (MIP) and body weight were determined. High-intensity inspiratory loading for 2 weeks caused a decline in MIP and body weight, and in the diaphragm induced a reduction in fast-twitch fiber proportions and sizes, whereas inflammatory cells and cytokine levels, including TNF-α immunohistochemical expression, superoxide anion, internal nuclei counts, and markers of myogenesis were increased. Blockade of TNF-α improved respiratory muscle function and structure, and animal weight, and, in the diaphragm, reduced inflammatory cell numbers and superoxide anion production drastically while inducing larger increases in protein and messenger RNA levels and immunohistochemical expression of TNF-α, internal nuclei, and markers of muscle regeneration. Blunting of TNF-α also induced a reduction in blood inflammatory cytokines and superoxide anion production. We conclude that TNF-α synthesized by inflammatory cells or myofibers could have differential effects on muscle structure and function in response to chronic, noninvasive, high-intensity inspiratory threshold loading.}, }
@article {pmid24367486, year = {2013}, author = {Utsumi, F and Kajiyama, H and Nakamura, K and Tanaka, H and Mizuno, M and Ishikawa, K and Kondo, H and Kano, H and Hori, M and Kikkawa, F}, title = {Effect of indirect nonequilibrium atmospheric pressure plasma on anti-proliferative activity against chronic chemo-resistant ovarian cancer cells in vitro and in vivo.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e81576}, pmid = {24367486}, issn = {1932-6203}, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Apoptosis/drug effects ; *Atmospheric Pressure ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/therapeutic use ; Drug Resistance, Neoplasm ; Female ; Humans ; Mice ; Mice, Nude ; Ovarian Neoplasms/*drug therapy ; Paclitaxel ; Plasma Gases/*therapeutic use ; Taxoids/therapeutic use ; Xenograft Model Antitumor Assays ; }, abstract = {PURPOSE: Nonequilibrium atmospheric pressure plasma (NEAPP) therapy has recently been focused on as a novel medical practice. Using cells with acquired paclitaxel/cisplatin resistance, we elucidated effects of indirect NEAPP-activated medium (NEAPP-AM) exposure on cell viability and tumor growth in vitro and in vivo.<br><br>METHODS: Using chronic paclitaxel/cisplatin-resistant ovarian cancer cells, we applied indirect NEAPP-exposed medium to cells and xenografted tumors in a mouse model. Furthermore, we examined the role of reactive oxygen species (ROS) or their scavengers in the above-mentioned EOC cells.<br><br>RESULTS: We assessed the viability of NOS2 and NOS3 cells exposed to NEAPP-AM, which was prepared beforehand by irradiation with NEAPP for the indicated time. In NOS2 cells, viability decreased by approximately 30% after NEAPP-AM 120-sec treatment (P<0.01). The growth-inhibitory effects of NEAPP-AM were completely inhibited by N-acetyl cysteine treatment, while L-buthionine-[S, R]-sulfoximine, an inhibitor of the ROS scavenger used with NEAPP-AM, decreased cell viability by 85% after NEAPP-AM 60-sec treatment(P<0.05) and by 52% after 120 sec, compared to the control (P<0.01). In the murine subcutaneous tumor-formation model, NEAPP-AM injection resulted in an average inhibition of the NOS2 cell-inoculated tumor by 66% (P<0.05) and NOS2TR cell-inoculated tumor by 52% (P<0.05), as compared with the control.<br><br>CONCLUSION: We demonstrated that plasma-activated medium also had an anti-tumor effect on chemo-resistant cells in vitro and in vivo. Indirect plasma therapy is a promising treatment option for EOC and may contribute to a better patient prognosis in the future.}, }
@article {pmid24365793, year = {2014}, author = {Erturk, M and Uslu, N and Gorgulu, S and Akbay, E and Kurtulus, G and Akturk, IF and Akgul, O and Surgit, O and Uzun, F and Gul, M and Isiksacan, N and Yildirim, A}, title = {Does intravenous or oral high-dose N-acetylcysteine in addition to saline prevent contrast-induced nephropathy assessed by cystatin C?.}, journal = {Coronary artery disease}, volume = {25}, number = {2}, pages = {111-117}, doi = {10.1097/MCA.0000000000000073}, pmid = {24365793}, issn = {1473-5830}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Biomarkers/blood ; Contrast Media/*administration &amp; dosage ; Creatinine/blood ; Cystatin C/*blood ; *Endovascular Procedures ; Female ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; *Radiology, Interventional ; Renal Insufficiency/blood/*complications/diagnosis ; Severity of Illness Index ; Single-Blind Method ; Sodium Chloride/adverse effects ; Time Factors ; Treatment Outcome ; Turkey ; Up-Regulation ; }, abstract = {AIMS: The objective of this study is to determine the effect of intravenous (i.v.) or oral N-acetylcysteine (NAC) in preventing contrast-induced nephropathy (CIN) in patients with moderate-to-severe renal insufficiency undergoing intra-arterial interventions.<br><br>MATERIALS AND METHODS: We studied 307 patients with estimated glomerular filtration rate of less than 60 ml/min/1.73 m undergoing an elective intra-arterial procedure. Patients were assigned randomly to three groups according to the prophylactic regimen used. In group 1, patients were administered an i.v. infusion of 0.9% saline (n=103); in group 2, patients were administered oral NAC in addition to an i.v. saline infusion (n=102); and in group 3, patients were administered i.v. NAC in addition to an i.v. saline infusion (n=102). Serum creatinine (SCr) and cystatin C levels were measured at baseline and 4, 24, and 48 h after the application of contrast media. The primary endpoint was defined as an increase in the SCr or cystatin C concentration of at least 0.5 mg/dl and/or of at least 25% from the baseline value at 48 h after administration of the contrast dye.<br><br>RESULTS: The overall incidence of SCr-based CIN was 11.1%: 6.8% in the saline group, 13.7% in the oral NAC group, and 12.7% in the i.v. NAC group (P=0.231). That of cystatin C-based CIN was 8.1%: 6.8% in the saline group, 6.9% in the oral NAC group, and 10.8% in the i.v. NAC group (P=0.491).<br><br>CONCLUSION: In this study, there was no detectable benefit of either high-dose oral or i.v. NAC over an aggressive hydration protocol in patients with moderate-to-severe renal insufficiency.}, }
@article {pmid24363250, year = {2014}, author = {Rivabene, R and Visentin, S and Piscopo, P and De Nuccio, C and Crestini, A and Svetoni, F and Rosa, P and Confaloni, A}, title = {Thapsigargin affects presenilin-2 but not presenilin-1 regulation in SK-N-BE cells.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {239}, number = {2}, pages = {213-224}, doi = {10.1177/1535370213514317}, pmid = {24363250}, issn = {1535-3699}, mesh = {Alzheimer Disease/genetics ; Apoptosis/drug effects ; Biological Transport/drug effects ; Brefeldin A/pharmacology ; Calcium/metabolism ; Cell Line ; Cytosol/metabolism ; Down-Regulation/drug effects ; Endoplasmic Reticulum/metabolism ; Enzyme Inhibitors/*pharmacology ; Homeostasis ; Humans ; Oxidative Stress ; Presenilin-1/genetics/*metabolism ; Presenilin-2/genetics/*metabolism ; Protein Synthesis Inhibitors/pharmacology ; Superoxide Dismutase/metabolism ; Thapsigargin/*pharmacology ; }, abstract = {Presenilin-1 (PS1) and presenilin-2 (PS2) are transmembrane proteins widely expressed in the central nervous system, which function as the catalytic subunits of γ-secretase, the enzyme that releases amyloid-β protein (Aβ) from ectodomain cleaved amyloid precursor protein (APP) by intramembrane proteolysis. Mutations in PS1, PS2, and Aβ protein precursor are involved in the etiology of familial Alzheimer's disease (FAD), while the cause of the sporadic form of AD (SAD) is still not known. However, since similar neuropathological changes have been observed in both FAD and SAD, a common pathway in the etiology of the disease has been suggested. Given that age-related deranged Ca(2+) regulation has been hypothesized to play a role in SAD pathogenesis via PS gene regulation and γ-secretase activity, we studied the in vitro regulation of PS1 and PS2 in the human neuron-like SK-N-BE cell line treated with the specific endoplasmic reticulum (ER) calcium ATPase inhibitor Thapsigargin (THG), to introduce intracellular Ca(2+) perturbations and mimic the altered Ca(2+) homeostasis observed in AD. Our results showed a consistent and significant down-regulation of PS2, while PS1 appeared to be unmodulated. These events were accompanied by oxidative stress and a number of morphological alterations suggestive of the induction of apoptotic machinery. The administration of the antioxidant N-acetylcysteine (NAC) did not revert the THG-induced effects reported, while treatment with the Ca(2+)-independent ER stressor Brefeldin A did not modulate basal PS1 and PS2 expression. Collectively, these results suggest that Ca(2+) fluctuation rather than ER stress and/or oxidative imbalance seems to play an essential role in PS2 regulation and confirm that, despite their strong homology, PS1 and PS2 could play different roles in AD.}, }
@article {pmid24362245, year = {2014}, author = {Li, W and Chen, J and Xie, P and He, J and Guo, X and Tuo, X and Zhang, W and Wu, L}, title = {Rapid conversion and reversible conjugation of glutathione detoxification of microcystins in bighead carp (Aristichthys nobilis).}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {147}, number = {}, pages = {18-25}, doi = {10.1016/j.aquatox.2013.12.001}, pmid = {24362245}, issn = {1879-1514}, mesh = {Animals ; Carps/*metabolism ; Glutathione/*metabolism ; Inactivation, Metabolic ; Microcystins/*metabolism ; Water Pollutants, Chemical/*metabolism ; }, abstract = {The glutathione and cysteine conjugates of microcystin (MC-GSH and MC-Cys, respectively) are two important metabolites in the detoxification of microcystins (MCs). Although studies have quantitated both conjugates, the reason why the amounts of MC-GSH are much lower than those of MC-Cys in various animal organs remains unknown. In this study, MC-RR-GSH and MC-RR-Cys were respectively i.p. injected into the cyanobacteria-eating bighead carp (Aristichthys nobilis), to explore the biotransformation and detoxification mechanisms of the two conjugates. The contents of MC-RR, MC-RR-GSH, MC-RR-Cys and MC-RR-N-acetyl-cysteine (MC-RR-Nac, the acetylation product of MC-RR-Cys) in the liver, kidney, intestine and blood of bighead carp in both groups were quantified via liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS). In the MC-RR-GSH-treated group, the MC-RR-Cys content in the kidney increased 96.7-fold from 0.25 to 0.5h post-injection, demonstrating that MC-RR-GSH acts as a highly reactive intermediate and is rapidly converted to MC-RR-Cys. The presence of MC-RR in both MC-RR-GSH- and MC-RR-Cys-treated groups indicates, for the first time, that MC conjugation with the thiol of GSH/Cys is a reversible process in vivo. Total MC-RR concentrations dissociated from MC-RR-Cys were lower than those from MC-RR-GSH, suggesting that MC-RR-Cys is more capable of detoxifying MC-RR. MC-RR-Cys was the most effectively excreted form in both the kidney and intestine, as the ratios of MC-RR-Cys to MC-RR reached as high as 15.2, 2.9 in the MC-RR-GSH-treated group and 63.4, 19.1 in the MC-RR-Cys-treated group. Whereas MC-RR-Nac could not be found in all of the samples of the present study. Our results indicate that MC-RR-GSH was rapidly converted to MC-RR-Cys and then excreted, and that both glutathione and cysteine conjugates could release MC-RR. This study quantitatively proves the importance of the GSH detoxification pathway and furthers our understanding of the biochemical mechanism by which bighead carp are resistant to toxic cyanobacteria.}, }
@article {pmid24361774, year = {2014}, author = {Unnithan, AS and Jiang, Y and Rumble, JL and Pulugulla, SH and Posimo, JM and Gleixner, AM and Leak, RK}, title = {N-acetyl cysteine prevents synergistic, severe toxicity from two hits of oxidative stress.}, journal = {Neuroscience letters}, volume = {560}, number = {}, pages = {71-76}, doi = {10.1016/j.neulet.2013.12.023}, pmid = {24361774}, issn = {1872-7972}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Catalase/metabolism ; Cell Count ; Cell Death/drug effects ; Cell Line, Tumor ; Drug Synergism ; Glutathione/metabolism ; Hydrogen Peroxide/toxicity ; Mice ; Neurons/cytology/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Paraquat/toxicity ; }, abstract = {The two hit hypothesis of neurodegeneration states that cells that have been severely stressed once are more vulnerable to the negative impact of a second hit. In other words, the toxicity of two hits of severe stress may be synergistic in neurons. We previously developed a two hit model of proteotoxic neurodegeneration using the proteasome inhibitor MG132. In that study, we found that the potent antioxidant N-acetyl cysteine was able to protect against the toxicity associated with dual MG132 hits. N-acetyl cysteine has been shown to ameliorate cognitive deficits in Alzheimer's patients and to reduce the symptoms of blast injury in soldiers. These studies and many others in experimental models of neurodegeneration suggest that N-acetyl cysteine can protect neurons even when they are severely injured. In the present study, we tested the hypotheses that dual hits of hydrogen peroxide and paraquat would elicit synergistic neurodegeneration and that this extreme toxicity would be prevented by N-acetyl cysteine. The findings reveal for the first time that neuronal N2a cells are much more sensitive to oxidative stress from hydrogen peroxide treatment when they have been exposed previously to the same toxin. Two hits of hydrogen peroxide also caused severe loss of glutathione. N-acetyl cysteine attenuated the loss of glutathione and reduced the near-complete loss of cells after exposure to dual hydrogen peroxide hits. The present study supports the notion that N-acetyl cysteine can robustly protect against severe, unremitting oxidative stress in a glutathione-dependent manner.}, }
@article {pmid24361401, year = {2014}, author = {Dang, B and Yang, Y and Zhang, E and Li, W and Mi, X and Meng, Y and Yan, S and Wang, Z and Wei, W and Shao, C and Xing, R and Lin, C}, title = {Simulated microgravity increases heavy ion radiation-induced apoptosis in human B lymphoblasts.}, journal = {Life sciences}, volume = {97}, number = {2}, pages = {123-128}, doi = {10.1016/j.lfs.2013.12.008}, pmid = {24361401}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*radiation effects ; B-Lymphocytes/*radiation effects ; Caspase 3/metabolism ; Cell Survival/radiation effects ; Cells, Cultured ; *Cosmic Radiation ; Dual Specificity Phosphatase 1/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Heavy Ions ; Humans ; Linear Energy Transfer ; Quercetin/pharmacology ; Reactive Oxygen Species/*radiation effects ; *Weightlessness Simulation ; }, abstract = {AIMS: Microgravity and radiation, common in space, are the main factors influencing astronauts' health in space flight, but their combined effects on immune cells are extremely limited. Therefore, the effect of simulated microgravity on heavy ion radiation-induced apoptosis, and reactive oxygen species (ROS)-sensitive apoptosis signaling were investigated in human B lymphoblast HMy2.CIR cells.<br><br>MAIN METHODS: Simulated microgravity was achieved using a Rotating Wall Vessel Bioreactor at 37&#xb0;C for 30 min. Heavy carbon-ion irradiation was carried out at 300 MeV/u, with a linear energy transfer (LET) value of 30 keV/&#x3bc;m and a dose rate of 1Gy/min. Cell survival was evaluated using the Trypan blue exclusion assay. Apoptosis was indicated by Annexin V/propidium iodide staining. ROS production was assessed by cytometry with a fluorescent probe dichlorofluorescein. Malondialdehyde was detected using a kit. Extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase phosphatase-1 (MKP-1) and caspase-3 activation were measured by immunoblotting.<br><br>KEY FINDINGS: Simulated microgravity decreased heavy ion radiation-induced cell survival and increased apoptosis in HMy2.CIR cells. It also amplified heavy ion radiation-elicited intracellular ROS generation, which induced ROS-sensitive ERK/MKP-1/caspase-3 activation in HMy2.CIR cells. The above phenomena could be reversed by the antioxidants N-acetyl cysteine (NAC) and quercetin.<br><br>SIGNIFICANCE: These results illustrated that simulated microgravity increased heavy ion radiation-induced cell apoptosis, mediated by a ROS-sensitive signal pathway in human B lymphoblasts. Further, the antioxidants NAC and quercetin, especially NAC, might be good candidate drugs for protecting astronauts' and space travelers' health and safety.}, }
@article {pmid24358342, year = {2013}, author = {Zhu, LQ and Zhen, YF and Zhang, Y and Guo, ZX and Dai, J and Wang, XD}, title = {Salinomycin activates AMP-activated protein kinase-dependent autophagy in cultured osteoblastoma cells: a negative regulator against cell apoptosis.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e84175}, pmid = {24358342}, issn = {1932-6203}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Apoptosis/drug effects ; Autophagy/*drug effects ; Enzyme Activation/drug effects ; Humans ; Osteoblastoma/*metabolism ; Pyrans/*pharmacology/toxicity ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND: The malignant osteoblastoma has poor prognosis, thus the search for novel and more efficient chemo-agents against this disease is urgent. Salinomycin induces broad anti-cancer effects both in vivo and in vitro, however, its role in osteoblastoma is still not clear.<br><br>KEY FINDINGS: Salinomycin induced both apoptosis and autophagy in cultured U2OS and MG-63 osteoblastoma cells. Inhibition of autophagy by 3-methyladenine (3-MA), or by RNA interference (RNAi) of light chain 3B (LC3B), enhanced salinomycin-induced cytotoxicity and apoptosis. Salinomycin induced a profound AMP-activated protein kinase (AMPK) activation, which was required for autophagy induction. AMPK inhibition by compound C, or by AMPK&#x3b1; RNAi prevented salinomycin-induced autophagy activation, while facilitating cancer cell death and apoptosis. On the other hand, the AMPK agonist AICAR promoted autophagy activation in U2OS cells. Salinomycin-induced AMPK activation was dependent on reactive oxygen species (ROS) production in osteoblastoma cells. Antioxidant n-acetyl cysteine (NAC) significantly inhibited salinomycin-induced AMPK activation and autophagy induction.<br><br>CONCLUSIONS: Salinomycin activates AMPK-dependent autophagy in osteoblastoma cells, which serves as a negative regulator against cell apoptosis. AMPK-autophagy inhibition might be a novel strategy to sensitize salinomycin's effect in cancer cells.}, }
@article {pmid24356372, year = {2013}, author = {Guo, R and Wu, K and Chen, J and Mo, L and Hua, X and Zheng, D and Chen, P and Chen, G and Xu, W and Feng, J}, title = {Exogenous hydrogen sulfide protects against doxorubicin-induced inflammation and cytotoxicity by inhibiting p38MAPK/NFκB pathway in H9c2 cardiac cells.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {32}, number = {6}, pages = {1668-1680}, doi = {10.1159/000356602}, pmid = {24356372}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/*toxicity ; Cell Line ; Cell Survival/drug effects ; Doxorubicin/*toxicity ; Inflammation/*chemically induced/pathology ; Interleukin-1beta/analysis ; Interleukin-6/analysis ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors/metabolism ; Phosphorylation/drug effects ; Proline/analogs &amp; derivatives/pharmacology ; RNA, Small Interfering/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Sulfites/*pharmacology ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/analysis ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {BACKGROUND/AIM: We have demonstrated that exogenous hydrogen sulfide (H2S) protects H9c2 cardiac cells against the doxorubicin (DOX)-induced injuries by inhibiting p38 mitogen-activated protein kinase (MAPK) pathway and that the p38 MAPK/nuclear factor-κB (NF-κB) pathway is involved in the DOX-induced inflammatory response and cytotoxicity. The present study attempts to test the hypothesis that exogenous H2S might protect cardiomyocytes against the DOX-induced inflammation and cytotoxicity through inhibiting p38 MAPK/NF-κB pathway.<br><br>METHODS: H9c2 cardiac cells were exposed to 5&#x3bc;M DOX for 24 h to establish a model of DOX cardiotoxicity. The cells were pretreated with NaHS(a donor of H2S) or other drugs before exposure to DOX. Cell viability was analyzed by cell counter kit 8 (CCK-8), The expression of NF-&#x3ba;B p65 and inducible nitric oxide synthase (iNOS) was detected by Western blot assay. The levels of interleukin-1&#x3b2; (IL-1&#x3b2;), IL-6 and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;) were tested by enzyme-linked immunosorbent assay (ELISA).<br><br>RESULTS: Our findings demonstrated that pretreatment of H9c2 cardiac cells with NaHS for 30 min before exposure to DOX markedly ameliorated the DOX-induced phosphorylation and nuclear translocation of NF-&#x3ba;B p65 subunit. Importantly, the pretreatment with NaHS significantly attenuated the p38 MAPK/NF-&#x3ba;B pathway-mediated inflammatory responses induced by DOX, as evidenced by decreases in the levels of IL-1&#x3b2;, IL-6 and TNF-&#x3b1;. In addition, application of NaHS or IL-1&#x3b2; receptor antagonist (IL-1Ra) or PDTC (an inhibitor of NF-&#x3ba;B) attenuated the DOX-induced expression of iNOS and production of nitric oxide (NO), respectively. Furthermore, IL-1Ra also dramatically reduced the DOX-induced cytotoxicity and phosphorylation of NF-&#x3ba;B p65. The pretreatment of H9c2 cells with N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS) prior to exposure to DOX depressed the phosphorylation of NF-&#x3ba;B p65 induced by DOX.<br><br>CONCLUSION: The present study has demonstrated the new mechanistic evidence that exogenous H2S attenuates the DOX-induced inflammation and cytotoxicity by inhibiting p38 MAPK/NF-&#x3ba;B pathway in H9c2 cardiac cells. We also provide novel data that the interaction between NF-&#x3ba;B pathway and IL-1&#x3b2; is important in the induction of DOX-induced inflammation and cytotoxicity in H9c2 cardiac cells.}, }
@article {pmid24355171, year = {2014}, author = {Kundu, J and Kim, DH and Kundu, JK and Chun, KS}, title = {Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKα as upstream targets.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {65}, number = {}, pages = {18-26}, doi = {10.1016/j.fct.2013.12.015}, pmid = {24355171}, issn = {1873-6351}, mesh = {Adenylate Kinase/*metabolism ; Base Sequence ; Benzoquinones/*pharmacology ; Cell Line ; DNA Primers ; Enzyme Activation ; Heme Oxygenase-1/*metabolism ; Humans ; NF-E2-Related Factor 2/*metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; }, abstract = {Thymoquinone (TQ), an active constituent of Nigella sativa, possesses anti-inflammatory and anticancer properties. Multiple lines of evidence suggest that the induction of heme oxygenase-1 (HO-1) suppresses inflammation and carcinogenesis. In the present study, we examined the effect of TQ on HO-1 expression in human keratinocytes (HaCaT) and elucidated its underlying molecular mechanisms. TQ induced the expression of HO-1 in HaCaT cells in a concentration- and time-dependent manner. Treatment with TQ increased the localization of nuclear factor (NF)-erythroid2-(E2)-related factor-2 (Nrf2) in the nucleus and elevated the antioxidant response element (ARE)-reporter gene activity. Knockdown of Nrf2 abrogated TQ-induced HO-1 expression and the ARE luciferase activity. TQ induced the phosphorylation of extracellular signal-regulated kinase (ERK), Akt and cyclic AMP-activated protein kinase-α (AMPKα). Pharmacological inhibition of Akt or AMPKα, but not that of ERK, abrogated TQ-induced nuclear localization of Nrf2, the ARE-luciferase activity and the expression of HO-1. TQ also generated reactive oxygen species (ROS) and pretreatment with N-acetyl cysteine (NAC) abrogated TQ-induced ROS accumulation, Akt and AMPKα activation, Nrf2 nuclear localization, the ARE-luciferase activity, and HO-1 expression in HaCaT cells. Taken together, TQ induces HO-1 expression in HaCaT cells by activating Nrf2 through ROS-mediated phosphorylation of Akt and AMPKα.}, }
@article {pmid24355064, year = {2014}, author = {Gallorini, M and Cataldi, A and di Giacomo, V}, title = {HEMA-induced cytotoxicity: oxidative stress, genotoxicity and apoptosis.}, journal = {International endodontic journal}, volume = {47}, number = {9}, pages = {813-818}, doi = {10.1111/iej.12232}, pmid = {24355064}, issn = {1365-2591}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Coculture Techniques ; DNA Damage ; Gingiva/cytology ; Humans ; Methacrylates/*toxicity ; *Mutagenicity Tests ; Oxidative Stress/*drug effects ; Streptococcus mitis/cytology ; }, abstract = {Dental resin composites consist of organic polymers with inorganic fillers used as bonding resins and direct filling materials in dentine adhesives and as sealing agents for inlays, crowns and orthodontic brackets. Despite various modifications in the formulation, the chemical composition of composite resins includes inorganic filler particles and additives, which are incorporated into a mixture of an organic resin matrix. Among them, 2-hydroxyethylmethacrylate (HEMA) is one of the most frequently used. Several studies have attempted to clarify the mechanisms underlying HEMA cytotoxicity. Most of them support the hypothesis that this compound, once released in the oral environment, increases reactive oxygen species (ROS) production and oxidative DNA damage through double-strand breaks evidenced by in vitro presence of micronuclei. As a consequence, the glutathione detoxifying intracellular pool forms adducts with HEMA through its cysteine motif and inflammation begins to occur: transcription of early genes of inflammation such as tumour necrosis factor α or inducible cyclooxygenase up to the secretion of prostaglandins 2. These phenomena are counteracted by N-acetylcysteine (NAC), a nonenzymatic antioxidant, but not by vitamin E or other antioxidant. Consequently, NAC prevents HEMA-induced apoptosis acting as a direct ROS scavenger. This minireview collects the most significant papers on HEMA and tries to make an overview of its cytotoxicity on different cell types and experimental models.}, }
@article {pmid24352527, year = {2014}, author = {Kumar, SM and Swaminathan, K and Clemens, DL and Dey, A}, title = {Modulation of GSH with exogenous agents leads to changes in glyoxalase 1 enzyme activity in VL-17A cells exposed to chronic alcohol plus high glucose.}, journal = {Food &amp; function}, volume = {5}, number = {2}, pages = {345-358}, doi = {10.1039/c3fo60354g}, pmid = {24352527}, issn = {2042-650X}, mesh = {Cell Line ; Cell Survival/drug effects ; Cells/drug effects/*enzymology/metabolism ; Ethanol/*adverse effects ; Glucose/adverse effects/analysis ; Glutathione/*metabolism ; Humans ; Lactoylglutathione Lyase/*metabolism ; Oxidative Stress/drug effects ; }, abstract = {Gluthathione (GSH) is a major cellular antioxidant. The present study utilizing VL-17A cells exposed to chronic alcohol plus high glucose investigated the changes in oxidative stress, toxicity, and glyoxalase 1 activity as a detoxification pathway due to changes in GSH level through GSH supplementation with N-acetyl cysteine (NAC) or ursodeoxycholic acid (UDCA) and its depletion through buthionine sulfoximine (BSO) or diethyl maleate (DEM). Glyoxalase 1 plays an important role in detoxification of methylglyoxal which is formed as a precursor of advanced glycated end products formed due to high glucose mediated oxidative stress. Significant changes in glyoxalase 1 activity utilizing methylglyoxal or glyoxal as substrates occurred with NAC or UDCA or BSO or DEM supplementation in chronic alcohol plus high glucose treated VL-17A cells. NAC or UDCA administration in chronic alcohol plus high glucose treated VL-17A cells increased viability and decreased ROS levels, lipid peroxidation and 3-nitrotyrosine adduct formation. Similarly, GSH depletion with BSO or DEM had an opposite effect on the parameters in chronic alcohol plus high glucose treated VL-17A cells. In conclusion, modulation of GSH with NAC or UDCA or BSO or DEM leads to significant changes in oxidative stress, glyoxalase 1 enzyme activity and toxicity in chronic alcohol plus high glucose treated VL-17A cells.}, }
@article {pmid24350947, year = {2014}, author = {Jones, GR}, title = {The Alzheimer pandemic: is paracetamol to blame?.}, journal = {Inflammation &amp; allergy drug targets}, volume = {13}, number = {1}, pages = {2-14}, pmid = {24350947}, issn = {2212-4055}, mesh = {Acetaminophen/adverse effects/metabolism/*therapeutic use ; Alzheimer Disease/*drug therapy/etiology/history ; Amyloid beta-Protein Precursor/immunology/metabolism ; Analgesics, Non-Narcotic/adverse effects/*therapeutic use ; Animals ; Autoantigens/immunology/metabolism ; Brain/*drug effects ; History, 19th Century ; History, 20th Century ; History, 21st Century ; Humans ; Metabolic Detoxication, Phase I/physiology ; Microglia/drug effects/*physiology ; Pandemics ; Peroxynitrous Acid/metabolism ; }, abstract = {HISTORICAL BACKGROUND: The clinical recognition of a form of dementia closely resembling Alzheimer's disease dates from around 1800. The role of analgesics derived from coal-tar in the spread of the pandemic is traced in terms of the introduction of phenacetin (PN) in 1887; its nephrotoxicity; the observation of lesions characteristic of the disease by Fischer and Alzheimer; the discovery of paracetamol (PA) as the major metabolite of PN; the linking of kidney injury and dementia with high PN usage; and the failure of PN replacement by PA to halt and reverse the exponential, inexorable rise in the incidence of Alzheimer-type dementia. Fischer observed his first case before Alzheimer; it is proposed to rename the syndrome Fischer-Alzheimer disease (F-AD). Disease development: PA-metabolising enzymes are localised in the synaptic areas of the frontal cortex and hippocampus, where F-AD lesions arise. The initiating chemical lesions in liver poisoning comprise covalent binding of a highly reactive product of PA metabolism to proteins; similar events are believed to occur in brain, where alterations in the antigenic profiles of cerebral proteins activate the microglia. β-Amyloid forms, and, like PA itself, induces nitric oxide synthase. Peroxynitrite modifies cerebral proteins by nitrating tyrosine residues, further challenging the microglia and exacerbating the amyloid cascade. Spontaneous reinnervation, N-acetyl cysteine administration and tyrosine supplementation may attenuate the early stages of F-AD development.<br><br>CONCLUSION: F-AD is primarily a man-made condition with PA as its principal risk factor.}, }
@article {pmid24349491, year = {2013}, author = {Yuzefovych, LV and LeDoux, SP and Wilson, GL and Rachek, LI}, title = {Mitochondrial DNA damage via augmented oxidative stress regulates endoplasmic reticulum stress and autophagy: crosstalk, links and signaling.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e83349}, pmid = {24349491}, issn = {1932-6203}, support = {R01 DK073808/DK/NIDDK NIH HHS/United States ; DK073808/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Autophagy ; Cell Line ; *DNA Damage ; DNA, Mitochondrial/*metabolism ; *Endoplasmic Reticulum Stress ; Humans ; Mitochondria, Muscle/*metabolism/pathology ; Muscle, Skeletal/*metabolism/pathology ; *Oxidative Stress ; Rats ; *Signal Transduction ; }, abstract = {Saturated free fatty acids (FFAs) have been implicated in the increase of oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, autophagy, and insulin resistance (IR) observed in skeletal muscle. Previously, we have shown that palmitate-induced mitochondrial DNA (mtDNA) damage triggers mitochondrial dysfunction, mitochondrial reactive oxygen species (mtROS) production, apoptosis and IR in L6 myotubes. The present study showed that mitochondrial overexpression of human 8-oxoguanine DNA glycosylase/AP lyase (hOGG1) decreased palmitate-induced carbonylation of proteins in mitochondria. Additionally, we found that protection of mtDNA from palmitate-induced damage significantly diminished markers of both ER stress and autophagy in L6 myotubes. Moreover, we observed that the addition of ROS scavenger, N-acetylcystein (NAC), to palmitate diminished both ER stress and autophagy markers mimicking the effect of mitochondrial overexpression of hOGG1. This is the first study to show that mtDNA damage is upstream of palmitate-induced ER stress and autophagy in skeletal muscle cells.}, }
@article {pmid24349162, year = {2013}, author = {Carvalho, NR and da Rosa, EF and da Silva, MH and Tassi, CC and Dalla Corte, CL and Carbajo-Pescador, S and Mauriz, JL and González-Gallego, J and Soares, FA}, title = {New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e81961}, pmid = {24349162}, issn = {1932-6203}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/pharmacology ; Alanine Transaminase/metabolism ; Animals ; Antioxidants/*pharmacology ; Aspartate Aminotransferases/metabolism ; Benzene Derivatives/*pharmacology ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology ; Lipid Peroxidation ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/*drug effects/metabolism ; Organoselenium Compounds/*pharmacology ; Oxidative Stress ; Protein Carbonylation ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {The acute liver failure (ALF) induced by acetaminophen (APAP) is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe)2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe)2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe)2 to the N-acetylcysteine (NAC) during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg), (PhSe)2 (15.6 mg/kg), NAC (1200 mg/kg), APAP+(PhSe)2 or APAP+NAC, where the (PhSe)2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation) and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe)2. The effectiveness of (PhSe)2 was similar at a lower dose than NAC. In summary, (PhSe)2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.}, }
@article {pmid24349127, year = {2013}, author = {Obeid, S and Alen, J and Nguyen, VH and Pham, VC and Meuleman, P and Pannecouque, C and Le, TN and Neyts, J and Dehaen, W and Paeshuyse, J}, title = {Artemisinin analogues as potent inhibitors of in vitro hepatitis C virus replication.}, journal = {PloS one}, volume = {8}, number = {12}, pages = {e81783}, pmid = {24349127}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Antimalarials/pharmacology ; Antioxidants/pharmacology ; Antiviral Agents/*pharmacology ; Artemisinins/antagonists &amp; inhibitors/*pharmacology ; Cell Line, Tumor ; Cyclic N-Oxides/pharmacology ; Drug Repositioning ; Hemin/pharmacology ; Hepacivirus/*drug effects/growth &amp; development/metabolism ; Hepatocytes/drug effects/virology ; Humans ; RNA, Viral/*antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Structure-Activity Relationship ; Virus Replication/*drug effects ; }, abstract = {We reported previously that Artemisinin (ART), a widely used anti-malarial drug, is an inhibitor of in vitro HCV subgenomic replicon replication. We here demonstrate that ART exerts its antiviral activity also in hepatoma cells infected with full length infectious HCV JFH-1. We identified a number of ART analogues that are up to 10-fold more potent and selective as in vitro inhibitors of HCV replication than ART. The iron donor Hemin only marginally potentiates the anti-HCV activity of ART in HCV-infected cultures. Carbon-centered radicals have been shown to be critical for the anti-malarial activity of ART. We demonstrate that carbon-centered radicals-trapping (the so-called TEMPO) compounds only marginally affect the anti-HCV activity of ART. This provides evidence that carbon-centered radicals are not the main effectors of the anti-HCV activity of the Artemisinin. ART and analogues may possibly exert their anti-HCV activity by the induction of reactive oxygen species (ROS). The combined anti-HCV activity of ART or its analogues with L-N-Acetylcysteine (L-NAC) [a molecule that inhibits ROS generation] was studied. L-NAC significantly reduced the in vitro anti-HCV activity of ART and derivatives. Taken together, the in vitro anti-HCV activity of ART and analogues can, at least in part, be explained by the induction of ROS; carbon-centered radicals may not be important in the anti-HCV effect of these molecules.}, }
@article {pmid24348678, year = {2013}, author = {Mburu, S and Marnewick, JL and Abayomi, A and Ipp, H}, title = {Modulation of LPS-induced CD4+ T-cell activation and apoptosis by antioxidants in untreated asymptomatic HIV infected participants: an in vitro study.}, journal = {Clinical &amp; developmental immunology}, volume = {2013}, number = {}, pages = {631063}, pmid = {24348678}, issn = {1740-2530}, mesh = {Adult ; Annexin A5/metabolism ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/*immunology ; Asymptomatic Diseases ; Biomarkers/metabolism ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/*drug effects/*immunology/metabolism/virology ; Case-Control Studies ; Cells, Cultured ; Cross-Sectional Studies ; Female ; HIV Infections/*immunology/virology ; HIV-1/*immunology ; Humans ; Interleukin-2 Receptor alpha Subunit/metabolism ; Lipopolysaccharides/immunology ; Lymphocyte Activation/drug effects/immunology ; Male ; Viral Load ; Young Adult ; }, abstract = {Persistent immune activation characterises HIV infection and is associated with depletion of CD4+ T-cells and increased risk of disease progression. Early loss of gut mucosal integrity results in the translocation of microbial products such as lipopolysaccharide (LPS) into the systemic circulation. This is an important source of on-going immune stimulation. The purpose of this study was to determine levels of CD4+ T-cell activation (%CD25 expression) and apoptosis (% annexin V/7-AAD) in asymptomatic, untreated HIV infection at baseline and after stimulation with LPS and incubation with or without vitamin C and N-acetylcysteine. LPS induced a significant (P < 0.03) increase in %CD25 expression, annexin V, and 7-AAD in HIV positive individuals. NAC in combination with vitamin C, significantly (P = 0.0018) reduced activation and early apoptosis of CD4+ T-cells to a greater degree than with either antioxidant alone. Certain combinations of antioxidants could be important in reducing the harmful effects of chronic immune activation and thereby limit CD4+ T-cell depletion. Importantly, we showed that CD4+ T-cells of the HIV positive group responded better to a combination of the antioxidants at this stage than those of the controls. Therefore, appropriate intervention at this asymptomatic stage could rescue the cells before repetitive activation results in the death of CD4+ T-cells.}, }
@article {pmid24344357, year = {2014}, author = {Huang, X and Zhang, F and Sun, X and Choi, KY and Niu, G and Zhang, G and Guo, J and Lee, S and Chen, X}, title = {The genotype-dependent influence of functionalized multiwalled carbon nanotubes on fetal development.}, journal = {Biomaterials}, volume = {35}, number = {2}, pages = {856-865}, pmid = {24344357}, issn = {1878-5905}, support = {Z99 EB999999//Intramural NIH HHS/United States ; ZIA EB000073-03//Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Brain/drug effects/embryology ; DNA Damage/drug effects ; Embryonic Development/drug effects ; Female ; Fetal Development/*drug effects/*genetics ; Fibroblasts/cytology/drug effects/metabolism ; *Genotype ; Image Processing, Computer-Assisted ; Mice ; Nanomedicine/methods ; Nanoparticles/adverse effects/chemistry ; Nanotubes, Carbon/*toxicity ; Placenta/drug effects/metabolism ; Pregnancy ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {In many cases cancer is caused by gene deficiency that is being passed along from generation to generation. Soluble carbon nanotubes (CNTs) have shown promising applications in the diagnosis and therapy of cancer, however, the potential relationship between cancer-prone individuals and response to CNT exposure as a prerequisite for development of personalized nanomedicine, is still poorly understood. Here we report that intravenous injections of multi-walled carbon nanotubes into p53 (a well-known cancer-susceptible gene) heterozygous pregnant mice can induce p53- dependent responses in fetal development. Larger sized multi-walled carbon nanotubes moved across the blood-placenta barrier (BPB), restricted the development of fetuses, and induced brain deformity, whereas single-walled and smaller sized multi-walled carbon nanotubes showed no or less fetotoxicity. A molecular mechanism study found that multi-walled carbon nanotubes directly triggered p53-dependent apoptosis and cell cycle arrest in response to DNA damage. Based on the molecular mechanism, we also incorporated N-acetylcysteine (NAC), an FDA approved antioxidant, to prevent CNTs induced nuclear DNA damage and reduce brain development abnormalities. Our findings suggest that CNTs might have genetic background-dependent toxic effect on the normal development of the embryo, and provide new insights into protection against nanoparticle-induced toxicity in potential clinical applications.}, }
@article {pmid24343415, year = {2014}, author = {Farshid, AA and Tamaddonfard, E and Simaee, N and Mansouri, S and Najafi, S and Asri-Rezaee, S and Alavi, H}, title = {Effects of histidine and N-acetylcysteine on doxorubicin-induced cardiomyopathy in rats.}, journal = {Cardiovascular toxicology}, volume = {14}, number = {2}, pages = {153-161}, doi = {10.1007/s12012-013-9239-6}, pmid = {24343415}, issn = {1559-0259}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers/blood ; Cardiomyopathies/chemically induced/metabolism/pathology/physiopathology/*prevention &amp; control ; Creatine Kinase/blood ; Cytoprotection ; Disease Models, Animal ; Dose-Response Relationship, Drug ; *Doxorubicin ; Drug Therapy, Combination ; Electrocardiography ; Free Radical Scavengers/*pharmacology ; Heart Rate/drug effects ; Histidine/*pharmacology ; L-Lactate Dehydrogenase/blood ; Male ; Malondialdehyde/metabolism ; Myocardium/metabolism/pathology ; Rats, Wistar ; Recovery of Function ; }, abstract = {The amino acids histidine and n-acetylcysteine have many biological activities such as antioxidant effect. The present study investigated the effects of histidine and n-acetylcysteine on the heart lesions induced by doxorubicin (DOX) in rats. Forty-eight male Wistar rats were divided into two major groups treated intraperitoneally (i.p.) with normal saline and 4 mg/kg of DOX, respectively. Each group was further divided into four subgroups that were treated with separate and combined i.p. injections of histidine and n-acetylcysteine (NAC) at a same dose of 40 mg/kg. Electrocardiography (ECG) was recorded using lead II. The heart lesions were evaluated by light microscopy. Serum levels of creatine phosphokinase and lactate dehydrogenase and heart tissue malondialdehyde levels were measured. Histidine and especially NAC at a same dose of 40 mg/kg recovered ECG changes, improved heart lesions and prevented biochemical changes induced by DOX. Co-administration of histidine and NAC showed better responses when compared with them used alone. The results of the present study showed protective effects for histidine and NAC on the heart. Reduction in free radical-induced toxic effects may be involved in cardioprotective properties of histidine and NAC.}, }
@article {pmid24339660, year = {2013}, author = {Vaish, AK and Consul, S and Agrawal, A and Chaudhary, SC and Gutch, M and Jain, N and Singh, MM}, title = {Accidental phosgene gas exposure: A review with background study of 10 cases.}, journal = {Journal of emergencies, trauma, and shock}, volume = {6}, number = {4}, pages = {271-275}, pmid = {24339660}, issn = {0974-2700}, abstract = {Here, authors present a review on clinical presentation and management of exposure of phosgene gas after reviewing the literature by searching with keywords phosgene exposure on Google, Cochrane, Embase and PubMed with a background of experience gained from 10 patients who were admitted to our institute after an accidental phosgene exposure in February 2011 nearby a city in India. Phosgene is a highly toxic gas, occupational workers may have accidental exposure. The gas can also be generated inadvertently during fire involving plastics and other chemicals and solvents containing chlorine, which is of concern to emergency responders. Phosgene inhalation may cause initially symptoms of respiratory tract irritation, patients feel fine thereafter, and then die of choking a day later because of build up of fluid in the lungs (delayed onset non-cardiogenic pulmonary edema). Phosgene exposure is associated with significant morbidity and mortality. Patients with a history of exposure should be admitted to the hospital for a minimum of 24 h for observation because of the potential for delayed onset respiratory failure and acute respiratory distress syndrome.}, }
@article {pmid24337227, year = {2014}, author = {Li, Y and Liu, G and Cai, D and Pan, B and Lin, Y and Li, X and Li, S and Zhu, L and Liao, X and Wang, H}, title = {H2S inhibition of chemical hypoxia-induced proliferation of HPASMCs is mediated by the upregulation of COX-2/PGI2.}, journal = {International journal of molecular medicine}, volume = {33}, number = {2}, pages = {359-366}, doi = {10.3892/ijmm.2013.1579}, pmid = {24337227}, issn = {1791-244X}, mesh = {Acetylcysteine/pharmacology ; Cell Hypoxia/drug effects ; Cell Line ; Cell Proliferation/*drug effects ; Cobalt/pharmacology ; Cyclooxygenase 2/genetics/*metabolism ; Down-Regulation ; Epoprostenol/metabolism ; Familial Primary Pulmonary Hypertension ; Humans ; Hydrogen Peroxide/adverse effects ; Hydrogen Sulfide/*pharmacology ; Hypertension, Pulmonary/*drug therapy ; Myocytes, Smooth Muscle/*cytology/drug effects/*metabolism ; Oxidative Stress/drug effects ; Pulmonary Artery/cytology ; Reactive Oxygen Species/metabolism ; Sulfides/metabolism ; }, abstract = {The hypoxia-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main cause of pulmonary arterial hypertension (PAH), in which oxidative stress, cyclooxygenase (COX)-2 and hydrogen sulfide (H(2)S) all play an important role. In the present study, we aimed to examine the effects of H(2)S on the hypoxia-induced proliferation of human PASMCs (HPASMCs) and to elucidate the underlying mechanisms. The HPASMCs were treated with cobalt chloride (CoCl(2)), a hypoxia-mimicking agent, to establish a cellular model of hypoxic PAH. Prior to treatment with CoCl(2), the cells were pre-conditioned with sodium hydrosulfide (NaHS), a donor of H(2)S. Cell proliferation, reactive oxygen species (ROS) production, COX-2 expression, prostacyclin (also known as prostaglandin I2 or PGI(2)) secretion and H(2)S levels were detected in the cells. The exposure of the HPASMCs to CoCl(2) markedly increased cell proliferation, accompanied by a decrease in COX-2 expression, PGI(2) secretion and H(2)S levels; however, the levels of ROS were not altered. Although the exogenous ROS donor, H(2)O(2), triggered similar degrees of proliferation to CoCl(2), the ROS scavenger, N-acetyl-L-cysteine (NAC), markedly abolished the H(2)O(2)‑induced cell proliferation, as opposed to the CoCl(2)-induced proliferation. The CoCl(2)-induced proliferation of HPASMCs was suppressed by exogenously applied PGI(2). The addition of H(2)S (NaHS) attenuated the CoCl(2)-induced cell proliferation through the increase in the intercellular content of H(2)S. Importantly, the exposure of the cells to H(2)S suppressed the CoCl(2)-induced downregulation in COX-2 expression and PGI(2) secretion from the HPASMCs. In conclusion, the results from the current study suggest that H(2)S enhances hypoxia-induced cell proliferation through the upregulation of COX-2/PGI(2), as opposed to ROS.}, }
@article {pmid24333024, year = {2014}, author = {Mukhopadhyay, S and Panda, PK and Behera, B and Das, CK and Hassan, MK and Das, DN and Sinha, N and Bissoyi, A and Pramanik, K and Maiti, TK and Bhutia, SK}, title = {In vitro and in vivo antitumor effects of Peanut agglutinin through induction of apoptotic and autophagic cell death.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {64}, number = {}, pages = {369-377}, doi = {10.1016/j.fct.2013.11.046}, pmid = {24333024}, issn = {1873-6351}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; HeLa Cells ; Humans ; Peanut Agglutinin/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {In this study we unravel the mechanism underlying the antitumorigenic effects of Peanut agglutinin (PNA) isolated from Arachis hypogea in Dalton's lymphoma (DL) bearing mice and elucidated the mechanism in vitro in HeLa cells. In vivo PNA administration at 1 and 2 mg/kg body weight reduced DL proliferation with increase in autophagic and apoptotic characteristics. In vitro data showed that PNA at 0.1-100 μg/ml dose exhibit selective antiproliferative activity on various cancer cell lines without displaying cytotoxic effect on normal cells. However, heat denatured PNA failed to show any antiproliferative activity. Moreover, PNA was found to induce autophagic and apoptotic cell death in HeLa cells. Exponential increase in reactive oxygen species (ROS) was proved to be the master signal for promoting PNA induced cell death in HeLa cells. Interestingly, when HeLa cells were pre-exposed with N-acetylcysteine (NAC) and followed to PNA treatment, there was sharp decline in autophagy, apoptosis and a concomitant abrogation of antiproliferative potential. PNA at lower doses was also seen to inflict senescence. Hence, this common culinary item derived molecule whose discovery dates back to late 1970s was for the first time evaluated mechanistically in vivo and in vitro as a novel naturally occurring therapeutic agent against cancer.}, }
@article {pmid24332653, year = {2014}, author = {Májer, F and Sharma, R and Mullins, C and Keogh, L and Phipps, S and Duggan, S and Kelleher, D and Keely, S and Long, A and Radics, G and Wang, J and Gilmer, JF}, title = {New highly toxic bile acids derived from deoxycholic acid, chenodeoxycholic acid and lithocholic acid.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {22}, number = {1}, pages = {256-268}, doi = {10.1016/j.bmc.2013.11.029}, pmid = {24332653}, issn = {1464-3391}, mesh = {Apoptosis ; Bile Acids and Salts/*metabolism/pharmacology ; Caco-2 Cells ; Cell Survival ; Chenodeoxycholic Acid/*metabolism/pharmacology ; Deoxycholic Acid/*metabolism/pharmacology ; Humans ; Lithocholic Acid/*metabolism/pharmacology ; Ursodeoxycholic Acid/*metabolism/pharmacology ; }, abstract = {We have prepared a new panel of 23 BA derivatives of DCA, chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) in order to study the effect of dual substitution with 3-azido and 24-amidation, features individually associated with cytotoxicity in our previous work. The effect of the compounds on cell viability of HT-1080 and Caco-2 was studied using the 3-[4,5-dimethylthizol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Compounds with high potency towards reduction of cell viability were further studied using flow cytometry in order to understand the mechanism of cell death. Several compounds were identified with low micromolar IC50 values for reducing cell viability in the Caco-2 and HT1080 cell lines, making them among the most potent BA apoptotic agents reported to date. There was no evidence of relationship between overall hydrophobicity and cytotoxicity supporting the idea that cell death induction by BAs may be structure-specific. Compounds derived from DCA caused cell death through apoptosis. There was some evidence of selectivity between the two cell lines studied which may be due to differing expression of CD95/FAS. The more toxic compounds increased ROS production in Caco-2 cells, and co-incubation with the antioxidant N-acetyl cysteine blunted pro-apoptotic effects. The properties these compounds suggest that there may be specific mechanism(s) mediating BA induced cell death. Compound 8 could be useful for investigating this phenomenon.}, }
@article {pmid24330764, year = {2014}, author = {Yeh, CF and Lee, TL}, title = {Critical airway induced by formalin injection: case report.}, journal = {The Journal of laryngology and otology}, volume = {128}, number = {1}, pages = {107-109}, doi = {10.1017/S0022215113003186}, pmid = {24330764}, issn = {1748-5460}, mesh = {Adult ; Airway Obstruction/diagnostic imaging/etiology/*therapy ; Edema/diagnostic imaging/etiology/*therapy ; Formaldehyde/*adverse effects ; Humans ; Injections/*adverse effects ; Intubation, Intratracheal ; Laryngeal Diseases/diagnostic imaging/etiology/*therapy ; Laryngoscopy ; Male ; Neck ; Pharyngeal Diseases/diagnostic imaging/etiology/*therapy ; *Suicide, Attempted ; Tomography, X-Ray Computed ; Tracheostomy ; }, abstract = {BACKGROUND: Formalin is a saturated aqueous solution comprising 37-40 per cent formaldehyde. It is often used in histopathology laboratories as a tissue preservative. The ingestion or injection of formalin has an immediate, powerful and destructive impact on humans. This paper reports a case of formalin injection and reviews the relevant world literature.<br><br>CASE REPORT: A 36-year-old male attempted suicide by injecting formalin into the right side of his neck, resulting in a critical airway situation. An endotracheal tube was inserted and a tracheostomy was then performed to secure his airway. After receiving medical treatment, including antibiotics and N-acetyl cysteine, the status of the patient's airway improved.<br><br>CONCLUSION: When examining patients who have injected substances into their neck, the possibility of deep neck inflammation with airway compromise should be considered. Immediate management, which should include establishment of a definitive airway and prophylactic infection control, is crucial.}, }
@article {pmid24329505, year = {2013}, author = {Cetinkaya, A and Kantarceken, B and Bulbuloglu, E and Kurutas, EB and Ciralik, H and Atli, Y}, title = {The effects of L-carnitine and N-acetylcysteine on carbontetrachloride induced acute liver damage in rats.}, journal = {Bratislavske lekarske listy}, volume = {114}, number = {12}, pages = {682-688}, doi = {10.4149/bll_2013_145}, pmid = {24329505}, issn = {0006-9248}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Carbon Tetrachloride/toxicity ; Carnitine/*pharmacology ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Liver/drug effects/*metabolism/pathology ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Vitamin B Complex/pharmacology ; }, abstract = {AIM: To investigate the effects of L-carnitine (LCAR) and N-acetylcysteine (NAC) on carbon tetrachloride (CCl4)-induced acute liver damage in rats.<br><br>MATERIAL AND METHODS: Totally, 40 rats in 5 groups were included in the study. The first group was the control group. Group 2 received CCl4 (2 ml/kg). Group 3 was given CCl4 + NAC (150 mg/kg). The rats in the Group 4 were administered CCl4 + LCAR (100 mg/kg), and the rats in the Group 5 were given CCl4 + NAC + LCAR. Both CCl4 and the treatment protocols were administered via intraperitoneal route for 10 days. Tissue oxidative stress and antioxidant markers were investigated in liver tissue and serum liver enzymes were measured.<br><br>RESULTS: The levels of blood liver enzymes (ALT and AST) increased significantly in the Group 2. However, they decreased markedly in all treatment groups. While malondialdehyde and myeloperoxidase levels in the liver tissue samples increased significantly in the 2nd group, those levels were determined to be decreased significantly in all treatment groups. When the liver tissue antioxidant levels were evaluated; reduced glutathione and catalase decreased markedly in the 2nd group, but increased following the administration of NAC and LCAR. The activities of liver tissue superoxide dismutase did not differ significantly among the groups. In the histopathologic evaluation of liver tissues, on the other hand, diffuse hepatosteatosis was observed in all groups except the control group and there was no significant difference among the groups from the point of steatosis.<br><br>CONCLUSION: LCAR and NAC were concluded to have beneficial effects on the acute liver damage induced by CCl4 administration (Tab. 1, Fig. 5, Ref. 52). Text in PDF www.elis.sk.}, }
@article {pmid24329483, year = {2014}, author = {Steckert, AV and de Castro, AA and Quevedo, J and Dal-Pizzol, F}, title = {Sepsis in the central nervous system and antioxidant strategies with N-acetylcysteine, vitamins and statins.}, journal = {Current neurovascular research}, volume = {11}, number = {1}, pages = {83-90}, doi = {10.2174/1567202610666131211111012}, pmid = {24329483}, issn = {1875-5739}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Central Nervous System/drug effects/*pathology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Sepsis/*drug therapy/*pathology ; Vitamins/therapeutic use ; }, abstract = {Sepsis is the complex syndrome characterized by an imbalance between proinflammatory and antiinflammatory response to infection. The brain may be affected during the sepsis, and acute and long-term brain dysfunctions have been observed in both animal models and septic patients. Oxidative stress and antioxidant systems may prove the basis underling brain dysfunction in sepsis. The antioxidant therapy may be theoretically achieved by the following strategies: restoring endogenous antioxidants and nutrients and supplementation with exogenous trace elements, vitamins, and nutrients with antioxidant proprieties; or administering drugs that reduce oxidative stress, such as N-acetylcysteine (NAC), vitamins and statins. In the review, we described below the involvement of oxidative stress and antioxidants defenses and potential utility of these strategies and present data regarding their use in sepsis.}, }
@article {pmid24326786, year = {2014}, author = {Pache de Faria Guimaraes, L and Seguro, AC and Shimizu, MH and Lopes Neri, LA and Sumita, NM and de Bragança, AC and Aparecido Volpini, R and Cunha Sanches, TR and Macaferri da Fonseca, FA and Moreira Filho, CA and Vaisbich, MH}, title = {N-acetyl-cysteine is associated to renal function improvement in patients with nephropathic cystinosis.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {29}, number = {6}, pages = {1097-1102}, pmid = {24326786}, issn = {1432-198X}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/*therapeutic use ; Child ; Cysteamine/therapeutic use ; Cystine Depleting Agents/therapeutic use ; Cystinosis/*drug therapy ; Female ; Humans ; Kidney Function Tests ; Male ; Oxidative Stress/*drug effects ; }, abstract = {BACKGROUND: Nephropathic cystinosis is an autosomal recessive systemic severe disease characterized by intralysosomal cystine storage. Cysteamine is an essential component of treatment. There is solid evidence that cystine accumulation itself is not responsible for all abnormalities in cystinosis; there is also a deficiency of glutathione in the cytosol. Patients with cystinosis can be more susceptible to oxidative stress.<br><br>CASE-DIAGNOSIS/TREATMENT: The patient cohort comprised 23 cystinosis patients (16 males) aged <18&#xa0;years (mean age 8.0&#x2009;&#xb1;&#x2009;3.6&#xa0;years) with chronic kidney disease class I-IV with good adherence to treatment, including cysteamine. Oxidative stress was evaluated based on the levels of serum thiobarbituric acid-reactive substances (TBARS), and renal function was evaluated based on serum creatinine and cystatin C levels and creatinine clearance (Schwartz formula). N-Acetylcysteine (NAC), an antioxidant drug was given to all patients for 3 months (T1) at 25&#xa0;mg/kg/day divided in three doses per day. The measured values at just before the initiation of NAC treatment (T0) served as the control for each patient.<br><br>RESULTS: Median serum TBARS levels at T0 and T1 were 6.92 (range 3.3-29.0) and 1.7 (0.6-7.2) &#xa0;nmol/mL, respectively (p&#x2009;<&#x2009;0.0001). In terms of renal function at T0 and T1, serum creatinine levels (1.1&#x2009;&#xb1;&#x2009;0.5 vs. 0.9&#x2009;&#xb1;&#x2009;0.5&#xa0;mg/dL, respectively; p&#x2009;<&#x2009;0.0001), creatinine clearance (69.7&#x2009;&#xb1;&#x2009;32.2 vs. T1 = 78.5&#x2009;&#xb1;&#x2009;33.9&#xa0;mL/min/1.73 m(2), respectively; p&#x2009;=&#x2009;0.006), and cystatin c level (1.33&#x2009;&#xb1;&#x2009;0.53 vs. 1.15&#x2009;&#xb1;&#x2009;0.54&#xa0;mg/l, respectively; p&#x2009;=&#x2009;0.0057) were all significantly different at these two time points. Serum creatinine measurements at 6 (T -6) and 3&#xa0;months (T -3) before NAC initiation and at 3 (T +3) and 6&#xa0;months (T +6) after NAC had been withdrawn were also evaluated.<br><br>CONCLUSION: During the 3-month period that our 23 cystinosis patients were treated with NAC, oxidative stress was reduced and renal function significantly improved. No side-effects were detected. Larger and controlled studies are needed to confirm these findings.}, }
@article {pmid24325217, year = {2014}, author = {Sankavaram, K and Chong, L and Bruno, RS and Freake, HC}, title = {Zinc status alters growth and oxidative stress responses in rat hepatoma cells.}, journal = {Nutrition and cancer}, volume = {66}, number = {1}, pages = {104-116}, doi = {10.1080/01635581.2014.851713}, pmid = {24325217}, issn = {1532-7914}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/metabolism ; Caspase 3/genetics/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Liver Neoplasms/metabolism ; Mitochondria/drug effects/metabolism ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-mdm2/genetics/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; Zinc/*deficiency/*pharmacology ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Zinc deficiency and excess influence cellular homeostasis and are believed to modulate apoptosis. Zinc also regulates cell growth and proliferation. Understanding of the role of zinc in the mechanisms associated with these changes is limited because of its diverse, complex, and cell-specific effects. Therefore, we investigated the oxidative stress responses and the underlying molecular mechanisms associated with the disruption of intracellular zinc homeostasis in H4IIE rat hepatoma cells. We found that zinc excess (100 μM) and DTPA (diethylenetriaminepentaacetic acid; 50-100 μM) induced zinc deficiency both generate reactive oxygen species (ROS) and decrease viability in H4IIE cells. However, cotreatment with the antioxidant, N-acetyl-L-cysteine (NAC) both reduced ROS production and protected cells from death. We additionally observed an increase in Bax mRNA and cytochrome c release from the mitochondria in DTPA-treated cells and an elevated expression of Fas/Fas ligand mRNA with zinc treatment. Both treatments increased p53 and MdM2 protein concentrations along with caspase 3/7 activity. These results suggest that zinc deficiency stimulates mitochondrial-dependent apoptosis whereas zinc activates the extrinsic-apoptotic pathway. Both decreasing and increasing cellular zinc concentrations modulate ROS mediated apoptosis and warrant further research on zinc mediated cancer chemoprevention in this and other cancer cell lines.}, }
@article {pmid24325097, year = {2013}, author = {Du, LJ and Zhou, JG and Ren, XJ and Yi, TT and Jiang, XL}, title = {[Oxidative mechanism of uric acid induced CRP expression in human umbilical vein endothelial cells].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {44}, number = {5}, pages = {717-21, 726}, pmid = {24325097}, issn = {1672-173X}, mesh = {C-Reactive Protein/genetics/*metabolism ; Cells, Cultured ; Human Umbilical Vein Endothelial Cells/cytology/*metabolism ; Humans ; *Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Uric Acid/*pharmacology ; }, abstract = {OBJECTIVE: To explore the oxidative mechanism of uric acid (UA) induced CRP expression in human umbilical vein endothelial cells.<br><br>METHODS: Different concentrations of UA (0 mg/dL, 4 mg/dL, 8 mg/dL, 12 mg/dL, 16 mg/dl) were incubated 12 h with HUVECs, and HUVECs were stimulated with 12 mg/dl. UA for different times (6 h, 12 h, 24 h, 48 h). CRP mRNA and protein expression were determined by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively; the effects of uric acid on the intracellular reactive oxygen species (ROS) production in HUVECs were measured by fluorescence microscope and flow cytometric analysis using a 2', 7'-Dichlorofluorescin diacetate (DCF-DA) fluorescence probe. The effects of N-acetyl cysteine (NAC) on UA-induced levels of ROS, mRNA and protein of CRP in HUVECs were also observed.<br><br>RESULTS: The results demonstrated that UA could significantly increase the mRNA and protein expression of CRP in HUVECs in time- and concentration-dependent manners. HUVECs were stimulated with 12 mg/dL UA at 6 h, mRNA and protein levels of CRP significantly higher than that of control level (P<0.05), reached a peak at 12 h (P<0. 01). NAC reduced UA-induced levels of ROS, mRNA and protein of CRP in HUVECs compared with those of 12 mg/dL UA induced group(P<0. 05).<br><br>CONCLUSION: Uric acid significantly increased mRNA and protein expression of CRP in HUVECs in time- and concentration-dependent manners. Its mechanism may be associated with uric acid induced increasing of ROS levels in endothelial cells, which suggested that the uric acid mediated oxidative stress and inflammation may be involved in the injury of endothelial cells.}, }
@article {pmid24319553, year = {2013}, author = {Azarkish, F and Nematbakhsh, M and Fazilati, M and Talebi, A and Pilehvarian, AA and Pezeshki, Z and Moeini, M and Mansouri, A and Safari, T}, title = {N-acetylcysteine Prevents Kidney and Lung Disturbances in Renal Ischemia/Reperfusion Injury in Rat.}, journal = {International journal of preventive medicine}, volume = {4}, number = {10}, pages = {1139-1146}, pmid = {24319553}, issn = {2008-7802}, abstract = {BACKGROUND: One of the most common causes of acute kidney injury (AKI) is kidney ischemia/reperfusion injury (IRI). The distant organ injury such as acute lung injury is one of the side effects of AKI or kidney IRI. In this study, we performed bilateral renal IRI in rats and the protective role of N-acetylcysteine (NAC) in kidney and lung was investigated.<br><br>METHODS: Rats (n = 30) were randomly assigned to four experiment groups. The group 1 was assigned as sham-operated group. Before kidney IRI performance, the others groups were treated with saline (group 2), 150 mg/kg (group 3) or 500 mg/kg (group 4) of NAC, and the treatment were continued daily after IRI for next 3 days. At day 3, the all groups' animals were subjected for the measurements.<br><br>RESULTS: The serum level of blood urea nitrogen (BUN) and creatinine (Cr) in the control group increased significantly (P < 0.05), and administration of NAC (150 mg/kg) decreased the serum levels of Cr and BUN. However, only the serum level of Cr decreased significantly (P < 0.05). NAC did not improve kidney weight and damage; however, its low dose (150 mg/kg) attenuated the lung injury score (P < 0.05) when compared with the control group. No significant differences were observed in lung water content and endothelial permeability, serum levels of malondialdehyde and nitrite between the groups.<br><br>CONCLUSIONS: Low dose of NAC as a protectant agent may protect the kidney function and lung tissue damage after kidney IRI.}, }
@article {pmid24318808, year = {2015}, author = {Bai, Y and Jiang, LP and Liu, XF and Wang, D and Yang, G and Geng, CY and Li, Q and Zhong, LF and Sun, Q and Chen, M}, title = {The role of oxidative stress in citreoviridin-induced DNA damage in human liver-derived HepG2 cells.}, journal = {Environmental toxicology}, volume = {30}, number = {5}, pages = {530-537}, doi = {10.1002/tox.21929}, pmid = {24318808}, issn = {1522-7278}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Aurovertins/*toxicity ; *DNA Damage ; Deoxyguanosine/analogs &amp; derivatives ; Glutathione/metabolism ; Hep G2 Cells ; Humans ; Lysosomes/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mycotoxins/*toxicity ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {We hypothesize that citreoviridin (CIT) induces DNA damage in human liver-derived HepG2 cells through an oxidative stress mechanism and that N-acetyl-l-cysteine (NAC) protects against CIT-induced DNA damage in HepG2 cells. CIT-induced DNA damage in HepG2 cells was evaluated by alkaline single-cell gel electrophoresis assay. To elucidate the genotoxicity mechanisms, the level of oxidative DNA damage was tested by immunoperoxidase staining for 8-hydroxydeoxyguanosine (8-OHdG); the intracellular generation of reactive oxygen species (ROS) and reduced glutathione (GSH) were examined; mitochondrial membrane potential and lysosomal membranes' permeability were detected; furthermore, protective effects of NAC on CIT-induced ROS formation and CIT-induced DNA damage were evaluated in HepG2 cells. A significant dose-dependent increment in DNA migration was observed at tested concentrations (2.50-10.00 µM) of CIT. The levels of ROS, 8-OHdG formation were increased by CIT, and significant depletion of GSH in HepG2 cells was induced by CIT. Destabilization of lysosome and mitochondria was also observed in cells treated with CIT. In addition, NAC significantly decreased CIT-induced ROS formation and CIT-induced DNA damage in HepG2 cells. The data indicate that CIT induces DNA damage in HepG2 cells, most likely through oxidative stress mechanisms; that NAC protects against DNA damage induced by CIT in HepG2 cells; and that depolarization of mitochondria and lysosomal protease leakage may play a role in CIT-induced DNA damage in HepG2 cells.}, }
@article {pmid24316526, year = {2014}, author = {Turell, L and Botti, H and Bonilla, L and Torres, MJ and Schopfer, F and Freeman, BA and Armas, L and Ricciardi, A and Alvarez, B and Radi, R}, title = {HPLC separation of human serum albumin isoforms based on their isoelectric points.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {944}, number = {}, pages = {144-151}, pmid = {24316526}, issn = {1873-376X}, support = {R01 HL058115/HL/NHLBI NIH HHS/United States ; R01 HL064937/HL/NHLBI NIH HHS/United States ; R37 HL058115/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Chromatography, High Pressure Liquid/*methods ; Humans ; Hydrogen-Ion Concentration ; Isoelectric Point ; Male ; Middle Aged ; Protein Isoforms/analysis/chemistry/isolation &amp; purification ; Serum Albumin/analysis/*chemistry/*isolation &amp; purification ; }, abstract = {Human serum albumin (HSA) is the most abundant protein in plasma. Cys34, the only free Cys residue, is the predominant plasma thiol and a relevant sacrificial antioxidant. Both in vivo circulating HSA and pharmaceutical preparations are heterogeneous with respect to the oxidation state of Cys34. In this work, we developed an external pH gradient chromatofocusing procedure that allows the analysis of the oxidation status of HSA in human plasma and biopharmaceutical products based on the different apparent isoelectric points and chemical properties of the redox isoforms. Specifically, reduced-mercury blocked HSA (HSA-SHg(+)), HSA with Cys34 oxidized to sulfenic acid (HSA-SOH) and HSA oxidized to sulfinate anion (HSA-SO2(-)) can be separated with resolutions of 1.4 and 3.1 (first and last pair) and hence quantified and purified. In addition, an N-terminally degraded isoform (HSA3-585) in different redox states can be resolved as well. Confirmation of the identity of the chromatofocusing isolated isoforms was achieved by high resolution whole protein MS. It is proposed that the chromatofocusing procedure can be used to produce more exact and complete descriptions of the redox status of HSA in vivo and in vitro. Finally, the scalability capabilities of the chromatofocusing procedure allow for the preparation of highly pure standards of several redox isoforms of HSA.}, }
@article {pmid24316344, year = {2014}, author = {Nassar, M and Hiraishi, N and Shimokawa, H and Tamura, Y and Otsuki, M and Kasugai, S and Ohya, K and Tagami, J}, title = {The inhibition effect of non-protein thiols on dentinal matrix metalloproteinase activity and HEMA cytotoxicity.}, journal = {Journal of dentistry}, volume = {42}, number = {3}, pages = {312-318}, doi = {10.1016/j.jdent.2013.11.023}, pmid = {24316344}, issn = {1879-176X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Infective Agents, Local/pharmacology ; Cell Line ; Cell Survival/drug effects ; Chlorhexidine/pharmacology ; Coloring Agents ; Dental Materials/*toxicity ; Dental Pulp/cytology/*drug effects ; Dentin/*enzymology ; Glutathione/*pharmacology ; Humans ; Materials Testing ; Matrix Metalloproteinase 2/drug effects ; Matrix Metalloproteinase Inhibitors/*pharmacology ; Matrix Metalloproteinases/*drug effects ; Methacrylates/*toxicity ; Phosphoric Acids/chemistry ; Rats ; Tetrazolium Salts ; Thiazoles ; }, abstract = {OBJECTIVES: Phosphoric acid (PA) etching used in etch-and-rinse adhesives is known to activate host-derived dentinal matrix-metalloproteinases (MMPs) and increase dentinal permeability. These two phenomena will result, respectively; in degradation of dentine-adhesive bond and leaching of some monomers especially 2-hydroxyethyl methacrylate (HEMA) into the pulp that would negatively affect the viability of pulpal cells. This study is the first to investigate the inhibitory effect of non-protein thiols (NPSH); namely reduced glutathione (GSH) and N-acetylcysteine (NAC) on dentinal MMPs and compare their effects on HEMA cytotoxicity.<br><br>METHODS: Dentine powder was prepared from human teeth, demineralized with 1% PA and then treated with 2% GSH, 2% NAC or 2% chlorhexidine (CHX). Zymographic analysis of extracted proteins was performed. To evaluate the effect of GSH, NAC and CHX on HEMA cytotoxicity, solutions of these compounds were prepared with or without HEMA and rat pulpal cells were treated with the tested solutions for (6 and 24h). Cells viability was measured by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cytotoxicity data were analysed by one-way ANOVA and Tukey post hoc tests (p<0.05).<br><br>RESULTS: The inhibitory effect of GSH and NAC on dentinal MMPs was confirmed. GSH showed similar effectiveness to NAC regarding HEMA cytotoxicity inhibition.<br><br>CONCLUSION: NPSH were effective to inhibit dentinal MMPs and HEMA cytotoxicity.<br><br>CLINICAL SIGNIFICANCE: The tested properties of NPSH provide promising clinical use of these agents which would enhance dentine-bond durability and decrease post-operative sensitivity.}, }
@article {pmid24316229, year = {2014}, author = {Kastl, L and Sauer, SW and Ruppert, T and Beissbarth, T and Becker, MS and Süss, D and Krammer, PH and Gülow, K}, title = {TNF-α mediates mitochondrial uncoupling and enhances ROS-dependent cell migration via NF-κB activation in liver cells.}, journal = {FEBS letters}, volume = {588}, number = {1}, pages = {175-183}, doi = {10.1016/j.febslet.2013.11.033}, pmid = {24316229}, issn = {1873-3468}, mesh = {ATPases Associated with Diverse Cellular Activities ; Animals ; Antimycin A/pharmacology ; Blotting, Western ; Carcinoma, Hepatocellular/genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Movement/*drug effects ; Cells, Cultured ; Electron Transport Complex III/genetics/metabolism ; Gene Expression/drug effects ; Hepatocytes/drug effects/metabolism ; Humans ; Liver Neoplasms/genetics/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/*drug effects/metabolism/physiology ; NADH Dehydrogenase/genetics/metabolism ; NF-kappa B/genetics/*metabolism ; Polymerase Chain Reaction ; RNA Interference ; RNA-Directed DNA Polymerase ; Reactive Oxygen Species/*metabolism ; Rotenone/pharmacology ; Tumor Necrosis Factor-alpha/*pharmacology ; Uncoupling Agents/pharmacology ; }, abstract = {Development of hepatocellular carcinoma (HCC) is accompanied by a continuous increase in reactive oxygen species (ROS) levels. To investigate the primary source of ROS in liver cells, we used tumor necrosis factor-alpha (TNF-α) as stimulus. Applying inhibitors against the respiratory chain complexes, we identified mitochondria as primary source of ROS production. TNF-α altered mitochondrial integrity by mimicking a mild uncoupling effect in liver cells, as indicated by a 40% reduction in membrane potential and ATP depletion (35%). TNF-α-induced ROS production activated NF-κB 3.5-fold and subsequently enhanced migration up to 12.7-fold. This study identifies complex I and complex III of the mitochondrial respiratory chain as point of release of ROS upon TNF-α stimulation of liver cells, which enhances cell migration by activating NF-κB signalling.}, }
@article {pmid24314956, year = {2013}, author = {Wu, NC and Chen, TH and Yang, YC and Liao, FT and Wang, JC and Wang, JJ}, title = {N-acetylcysteine improves cardiac contractility and ameliorates myocardial injury in a rat model of lung ischemia and reperfusion injury.}, journal = {Transplantation proceedings}, volume = {45}, number = {10}, pages = {3550-3554}, doi = {10.1016/j.transproceed.2013.09.005}, pmid = {24314956}, issn = {1873-2623}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biomarkers/blood ; Bronchoalveolar Lavage Fluid/chemistry ; Creatine Kinase, MB Form/blood ; Cytoprotection ; Disease Models, Animal ; Hydroxyl Radical/metabolism ; Lipid Peroxidation/drug effects ; Lung/*blood supply ; Lung Injury/blood/*drug therapy/physiopathology ; Male ; Myocardial Contraction/*drug effects ; Myocardium/metabolism/pathology ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/blood/*drug therapy/physiopathology ; Time Factors ; Troponin I/blood ; Ventricular Dysfunction, Left/blood/pathology/physiopathology/*prevention &amp; control ; Ventricular Function, Left/*drug effects ; Ventricular Pressure/drug effects ; }, abstract = {OBJECTIVES: Lung ischemia and reperfusion (I/R) injury is the major complication subsequent to cardiopulmonary bypass surgery and lung transplantation. Lung I/R injury frequently induces cardiac dysfunction leading to significant mortality. So far, the literature on therapeutic interventions in cardiac dysfunction and myocardial injury is still scarce. In this study, we examined the efficacy of N-acetylcysteine (NAC) administration against lung I/R injury-induced cardiac dysfunction.<br><br>METHODS: Lung ischemia was established by occluding the left lung hilum for 60 minutes, followed by 2 hours of reperfusion. Studies were performed in 3 groups: sham-operated (same surgical procedure except vessel occlusion; N = 8), lung I/R injury (N = 12), and NAC-administered group (N = 12). The cardiac function was assessed using simultaneous left ventricular (LV) pressure and volume measured via a high-fidelity pressure-volume catheter. Myocardial injury was assessed based on serum creatine kinase muscle brain fraction (CK-MB) and troponin I (cTnI) level, and lung injury based on the degree of protein concentration in lung lavage. We also examined the degrees of myocardial lipid peroxidation and hydroxyl radical production with and without NAC.<br><br>RESULTS: During lung ischemia, LV stiffness increased with relative intact contractility. After 2 hours of reperfusion, LV contractility decreased with dilated and stiffened ventricle, along with apparent myocardial and lung injury. NAC administration effectively attenuated heart and lung injury, and ameliorated impaired LV contractility and stiffening resulting from lung I/R injury.<br><br>CONCLUSIONS: NAC administration reduced lung I/R-induced increases in myocardial hydroxyl radical production and lipid peroxidation, and ameliorated LV contractility and stiffening.}, }
@article {pmid24312826, year = {2013}, author = {Heidari, R and Babaei, H and Eghbal, MA}, title = {Cytoprotective Effects of Organosulfur Compounds against Methimazole Induced Toxicity in Isolated Rat Hepatocytes.}, journal = {Advanced pharmaceutical bulletin}, volume = {3}, number = {1}, pages = {135-142}, pmid = {24312826}, issn = {2228-5881}, abstract = {PURPOSE: Methimazole is a drug widely used in hyperthyroidism. However, life threatening hepatotoxicity has been associated with its clinical use. No protective agent has been found to be effective against methimazole induced hepatotoxicity yet. Hence, the capacity of organosulfur compounds to protect rat hepatocytes against cytotoxic effects of methimazole and its proposed toxic metabolite, N-methylthiourea was evaluated.<br><br>METHODS: Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. Cells were treated with different concentrations of methimazole, N methylthiourea, and organosulfur chemicals. Cell death, protein carbonylation, reactive oxygen species formation, lipid peroxidation, and mitochondrial depolarization were assessed as toxicity markers and the role of organosulfurs administration on them was investigated.<br><br>RESULTS: Methimazole caused a decrease in cellular glutathione content, mitochondrial membrane potential (&#x394;&#x3a8;m) collapse, and protein carbonylation. In addition, an increase in reactive oxygen species (ROS) formation and lipid peroxidation was observed. Treating hepatocytes with N methylthiourea caused a reduction in hepatocytes glutathione reservoirs and an elevation in carbonylated proteins, but no significant ROS formation, lipid peroxidation, or mitochondrial depolarization was observed. N-acetyl cysteine, allylmercaptan, and diallyldisulfide attenuated cell death and prevented ROS formation and lipid peroxidation caused by methimazole. Furthermore, organosulfur compounds diminished methimazole induced mitochondrial damage and reduced the carbonylated proteins. In addition, these chemicals showed protective effects against cell death and protein carbonylation induced by methimazole metabolite.<br><br>CONCLUSION: Organosulfur chemicals extend their protective effects against methimazole-induced toxicity by attenuating oxidative stress caused by this drug and preventing the adverse effects of methimazole and/or its metabolite (s) on subcellular components such as mitochondria.}, }
@article {pmid24311388, year = {2014}, author = {Miller, JL and Angulo, M}, title = {An open-label pilot study of N-acetylcysteine for skin-picking in Prader-Willi syndrome.}, journal = {American journal of medical genetics. Part A}, volume = {164A}, number = {2}, pages = {421-424}, doi = {10.1002/ajmg.a.36306}, pmid = {24311388}, issn = {1552-4833}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Male ; Pilot Projects ; Prader-Willi Syndrome/*complications/diagnosis/genetics ; Self Mutilation/*drug therapy/*etiology ; Treatment Outcome ; Young Adult ; }, abstract = {Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by an abnormality on the long arm of chromosome 15 (q11-q13) that results in a host of behavioral characteristics including excessive interest in food, skin picking, difficulty with a change in routine, and obsessive and compulsive behaviors. Skin-picking can result in serious and potentially life-threatening infections. Recent evidence suggests that the excitatory neurotransmitter glutamate is dysregulated in obsessive-compulsive behaviors, and modulation of the glutaminergic pathway may decrease compulsive behaviors, such as recurrent hair pulling or skin-picking behaviors. N-acetylcysteine (NAC), a derivative of the amino acid cysteine, is thought to act either via modulation of NMDA glutamate receptors or by increasing glutathione in pilot studies. Thirty-five individuals with confirmed PWS (ages 5-39 years, 23 females/12 males) and skin-picking behavior for more than 1 year were treated with N-acetylcysteine (Pharma-NAC®) at a dose of 450-1,200 mg/day. Skin-picking symptoms and open lesions were assessed after 12 weeks of treatment by counting and measuring lesions before and after the medication. All 35 individuals had improvement in skin-picking behaviors. Ten (29%) individuals (six males and four females) did not have complete resolution of skin-picking behavior, but had significant reduction in the number of active lesions. Longer-term, placebo-controlled trials are needed to further assess the potential benefit of this treatment.}, }
@article {pmid24309932, year = {2013}, author = {Wang, J and Lin, D and Peng, H and Huang, Y and Huang, J and Gu, J}, title = {Cancer-derived immunoglobulin G promotes tumor cell growth and proliferation through inducing production of reactive oxygen species.}, journal = {Cell death &amp; disease}, volume = {4}, number = {12}, pages = {e945}, pmid = {24309932}, issn = {2041-4889}, mesh = {Antioxidants/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cytoplasm/metabolism ; HeLa Cells ; Humans ; Hydrogen Peroxide/metabolism/pharmacology ; Immunoglobulin G/*metabolism ; Immunoprecipitation ; Peroxiredoxins/metabolism ; Protein Binding ; Reactive Oxygen Species/*metabolism ; ran GTP-Binding Protein/metabolism ; }, abstract = {Cancer cells have been found to express immunoglobulin G (IgG), but the exact functions and underlying mechanisms of cancer-derived IgG remain elusive. In this study, we first confirmed that downregulation of IgG restrained the growth and proliferation of cancer cells in vitro and in vivo. To elucidate its mechanism, we carried out a co-immunoprecipitation assay in HeLa cells and identified 27 potential IgG-interacting proteins. Among them, receptor of activated protein kinase C 1 (RACK1), ras-related nuclear protein (RAN) and peroxiredoxin 1 (PRDX1) are closely related to cell growth and oxidative stress, which prompted us to investigate the mechanism of action of IgG in the above phenomena. Upon confirmation of the interactions between IgG and the three proteins, further experiments revealed that downregulation of cancer-derived IgG lowered levels of intracellular reactive oxygen species (ROS) by enhancing cellular total antioxidant capacity. In addition, a few ROS scavengers, including catalase (CAT), dimethylsulfoxide (DMSO), n-acetylcysteine (NAC) and superoxide dismutase (SOD), further inhibited the growth of IgG-deficient cancer cells through suppressing mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) signaling pathway induced by a low level of intracellular ROS, whereas exogenous hydrogen peroxide (H2O2) at low concentration promoted their survival via increasing intracellular ROS levels. Similar results were obtained in an animal model and human tissues. Taken together, our results demonstrate that cancer-derived IgG can enhance the growth and proliferation of cancer cells via inducing the production of ROS at low level. These findings provide new clues for understanding tumor proliferation and designing cancer therapy.}, }
@article {pmid24309147, year = {2014}, author = {Dong, H and Xu, D and Hu, L and Li, L and Song, E and Song, Y}, title = {Evaluation of N-acetyl-cysteine against tetrachlorobenzoquinone-induced genotoxicity and oxidative stress in HepG2 cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {64}, number = {}, pages = {291-297}, doi = {10.1016/j.fct.2013.11.036}, pmid = {24309147}, issn = {1873-6351}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*pharmacology ; Benzoquinones/*toxicity ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Enzyme-Linked Immunosorbent Assay ; Hep G2 Cells ; Histones/metabolism ; Humans ; Hydrocarbons, Chlorinated/*toxicity ; Micronucleus Tests ; Mutagens/*toxicity ; Oxidative Stress/*drug effects ; Phosphorylation ; Reactive Oxygen Species/metabolism ; }, abstract = {Tetrachlorobenzoquinone (TCBQ) is an active metabolite of pentachlorophenol (PCP). Although the genotoxic effect of PCP has been comprehensively investigated, there is little known about TCBQ's genotoxic effects. In the current study, TCBQ was tested for its genotoxicity using HepG2 cells as experimental model. To select the exposure concentration of interest, cell viability was measured and three concentrations were used for further investigation. In single cell gel electrophoresis (SCGE) assay, concentration-dependent increase in tail length, tail DNA percentage and tail moment were detected following TCBQ exposure. Micronucleus (MN) assay indicated TCBQ gradually increased MN frequency and decreased nuclear division index (NDI). Enzyme-linked immunosorbent assay (ELISA) and western blotting analyses both showed TCBQ caused histone H2AX phosphorylation (γ-H2AX). Furthermore, the elevation of 8-hydroxydeoxyguanosine (8-OHdG) and reactive oxygen species (ROS) level indicated TCBQ-induced genotoxicity is associated with oxidative stress. On the other hand, N-acetyl-cysteine (NAC) administration significantly protected cells from the genotoxic effect of TCBQ. Overall, our data suggested TCBQ exerted genotoxic effect possibly via an oxidative damage mechanism in HepG2 cells and this toxicity is prevented by pretreatment with NAC.}, }
@article {pmid24308969, year = {2014}, author = {Qaisiya, M and Coda Zabetta, CD and Bellarosa, C and Tiribelli, C}, title = {Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway.}, journal = {Cellular signalling}, volume = {26}, number = {3}, pages = {512-520}, doi = {10.1016/j.cellsig.2013.11.029}, pmid = {24308969}, issn = {1873-3913}, support = {GGP10051/TI_/Telethon/Italy ; }, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 3/biosynthesis ; Antioxidant Response Elements/*genetics ; Antioxidants/*pharmacology ; Apoferritins/biosynthesis ; Bilirubin/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects/genetics ; Free Radical Scavengers/pharmacology ; Heme Oxygenase-1/biosynthesis ; Hep G2 Cells ; Humans ; MAP Kinase Kinase 1/antagonists &amp; inhibitors ; MAP Kinase Kinase 2/antagonists &amp; inhibitors ; Mitogen-Activated Protein Kinase 14/antagonists &amp; inhibitors ; NAD(P)H Dehydrogenase (Quinone)/biosynthesis ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidative Stress/*drug effects ; Protein Kinase C/antagonists &amp; inhibitors ; RNA Interference ; RNA, Messenger/biosynthesis ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Transcription, Genetic/drug effects/genetics ; Transcriptional Activation/drug effects/genetics ; }, abstract = {Unconjugated bilirubin (UCB) is responsible for neonatal jaundice and high level of free bilirubin (Bf) can lead to kernicterus. Previous studies suggest that oxidative stress is a critical component of UCB-induced neurotoxicity. The Nrf2 pathway is a powerful sensor for cellular redox state and is activated directly by oxidative stress and/or indirectly by stress response protein kinases. Activated Nrf2 translocates to nucleus, binds to Antioxidant Response Element (ARE), and enhances the up-regulation of cytoprotective genes that mediate cell survival. The aim of the present study was to investigate the role of Nrf2 pathway in cell response to bilirubin mediated oxidative stress in the neuroblastoma SH-SY5Y cell line. Cells exposed to a toxic concentration of UCB (140 nM Bf) showed an increased intracellular ROS levels and enhanced nuclear accumulation of Nrf2 protein. UCB stimulated transcriptional induction of ARE-GFP reporter gene and induced mRNA expression of multiple antioxidant response genes as: xCT, Gly1, γGCL-m, γGCL-c, HO-1, NQO1, FTH, ME1, and ATF3. Nrf2 siRNA decreased UCB induced mRNA expression of HO1 (75%), NQO1 (54%), and FTH (40%). The Nrf2-related HO-1 induction was reduced to 60% in cells pre-treated with antioxidant (NAC) or specific signaling pathway inhibitors for PKC, P38α and MEK1/2 (80, 40 and 25%, respectively). In conclusion, we demonstrated that SH-SY5Y cells undergo an adaptive response against UCB-mediated oxidative stress by activation of multiple antioxidant response, in part through Nrf2 pathway.}, }
@article {pmid24307203, year = {2014}, author = {Alarifi, S and Ali, D and Alakhtani, S and Al Suhaibani, ES and Al-Qahtani, AA}, title = {Reactive oxygen species-mediated DNA damage and apoptosis in human skin epidermal cells after exposure to nickel nanoparticles.}, journal = {Biological trace element research}, volume = {157}, number = {1}, pages = {84-93}, doi = {10.1007/s12011-013-9871-9}, pmid = {24307203}, issn = {1559-0720}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Cell Line ; *DNA Damage ; Humans ; *Metal Nanoparticles ; Microscopy, Electron, Transmission ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {Nickel nanoparticles (NiNPs) are increasingly used in various applications due to their unique properties. However, there is little information concerning the toxicity of NiNPs in the human skin cell (A431). The present study was designed to investigate the cytotoxicity, apoptosis, and DNA damage due to NiNPs in A431 cells. A cellular proliferative capacity test showed that NiNPs induce significant cytotoxicity in a dose- and time-dependent manner. NiNPs were also found to induce oxidative stress evidenced by the generation of reactive oxygen species (ROS) and depletion of glutathione (GSH). Further, co-treatment with the antioxidant N-acetylcysteine (NAC) mitigated the ROS generation due to NiNPs, suggesting the potential mechanism of oxidative stress. NiNPs also induced significant elevation of lipid peroxidation, catalase, and superoxide dismutase and caspase-3 activity in A431 cells. In addition, NAC suppressed NiNP-induced caspase-3 activity. DNA fragmentation analysis using the comet assay showed that the NiNPs cause genotoxicity in a dose- and time-dependent manner. Therefore, the study points out the capability of the NiNPs to induce oxidative stress resulting in apoptosis and genotoxicity. This study warrants more careful assessment of NiNPs before their industrial applications.}, }
@article {pmid24304591, year = {2013}, author = {Tusskorn, O and Senggunprai, L and Prawan, A and Kukongviriyapan, U and Kukongviriyapan, V}, title = {Phenethyl isothiocyanate induces calcium mobilization and mitochondrial cell death pathway in cholangiocarcinoma KKU-M214 cells.}, journal = {BMC cancer}, volume = {13}, number = {}, pages = {571}, pmid = {24304591}, issn = {1471-2407}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Calcium Signaling/*drug effects ; Caspases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cholangiocarcinoma ; Drug Screening Assays, Antitumor ; Enzyme Activation ; Glutathione/metabolism ; Humans ; Inhibitory Concentration 50 ; Isothiocyanates/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Phenethyl isothiocyanate (PEITC) is a cancer chemopreventive agent from cruciferous vegetables. Cholangiocarcinoma (CCA) is a chemo-resistant cancer with very poor prognosis. We evaluated the effects of PEITC on induction of apoptotic cell death in relation to cellular glutathione (GSH) and mitochondrial function of a CCA cell line, KKU-M214.<br><br>METHODS: Cytotoxic effects of PEITC on a CCA cell line, KKU-M214, and a reference cell line, Chang cells were evaluated. To delineate mechanisms of cell death, the following parameters were measured; GSH and superoxide levels as the oxidative status parameters, apoptosis related proteins levels using Western blotting. Cellular free calcium level and mitochondrial transmembrane potential were also measured.<br><br>RESULTS: PEITC induced apoptotic cell death of both KKU-M214 and Chang cells. After PEITC treatment, both cells showed decrease of Bcl-xl and increase of Bax levels. While KKU-M214 cells released AIF, Chang cells released cytochrome c, with subsequent activation of caspase 3 and 9, upon PEITC treatment. PEITC induced superoxide formation in both cells, although it seemed not play a role in cell death. PEITC caused GSH redox stress in different ways in two cell types, because N-acetylcysteine (NAC) prevented redox stress in Chang but not in KKU-M214 cells. The loss of mitochondrial transmembrane potential was induced by PEITC concurrent with GSH stress, but was not a primary cause of cell death. The rapid increase of free calcium level in cytosol was associated with cell death in both cell lines. These events were prevented by NAC in Chang cells, but not in KKU-M214 cells.<br><br>CONCLUSION: PEITC induced cell death KKU-M214 cells and Chang cells via increase of cellular calcium mobilization and activation of mitochondrial cell death pathway. The effects of PEITC on the redox stress was mediated via different ways in CCA and Chang cells because NAC could prevent redox stress in Chang cells, but not in KKU-M214 cells. The multiple effects of PEITC may be useful for the development of novel chemotherapy for CCA.}, }
@article {pmid24299490, year = {2014}, author = {Chen, S and Ren, Q and Zhang, J and Ye, Y and Zhang, Z and Xu, Y and Guo, M and Ji, H and Xu, C and Gu, C and Gao, W and Huang, S and Chen, L}, title = {N-acetyl-L-cysteine protects against cadmium-induced neuronal apoptosis by inhibiting ROS-dependent activation of Akt/mTOR pathway in mouse brain.}, journal = {Neuropathology and applied neurobiology}, volume = {40}, number = {6}, pages = {759-777}, pmid = {24299490}, issn = {1365-2990}, support = {R01 CA115414/CA/NCI NIH HHS/United States ; CA115414/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Brain/*drug effects/metabolism/ultrastructure ; Cadmium/blood/*toxicity ; Male ; Mice ; Mice, Inbred ICR ; Neurons/*drug effects/metabolism/ultrastructure ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {AIMS: This study explores the neuroprotective effects and mechanisms of N-acetyl-L-cysteine (NAC) in mice exposed to cadmium (Cd).<br><br>METHODS: NAC (150 mg/kg) was intraperitoneally administered to mice exposed to Cd (10-50 mg/L) in drinking water for 6 weeks. The changes of cell damage and death, reactive oxygen species (ROS), antioxidant enzymes, as well as Akt/mammalian target of rapamycin (mTOR) signalling pathway in brain neurones were assessed. To verify the role of mTOR activation in Cd-induced neurotoxicity, mice also received a subacute regimen of intraperitoneally administered Cd (1 mg/kg) with/without rapamycin (7.5 mg/kg) for 11 days.<br><br>RESULTS: Chronic exposure of mice to Cd induced brain damage or neuronal cell death, due to ROS induction. Co-administration of NAC significantly reduced Cd levels in the plasma and brain of the animals. NAC prevented Cd-induced ROS and significantly attenuated Cd-induced brain damage or neuronal cell death. The protective effect of NAC was mediated, at least partially, by elevating the activities of Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, as well as the level of glutathione in the brain. Furthermore, Cd-induced activation of Akt/mTOR pathway in the brain was also inhibited by NAC. Rapamycin in vitro and in vivo protected against Cd-induced neurotoxicity.<br><br>CONCLUSIONS: NAC protects against Cd-induced neuronal apoptosis in mouse brain partially by inhibiting ROS-dependent activation of Akt/mTOR pathway. The findings highlight that NAC may be exploited for prevention and treatment of Cd-induced neurodegenerative diseases.}, }
@article {pmid24296245, year = {2014}, author = {Zhang, Z and Yan, J and Taheri, S and Liu, KJ and Shi, H}, title = {Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke.}, journal = {Free radical biology &amp; medicine}, volume = {68}, number = {}, pages = {8-21}, pmid = {24296245}, issn = {1873-4596}, support = {P30 GM103400/GM/NIGMS NIH HHS/United States ; R01 NS058807/NS/NINDS NIH HHS/United States ; R01NS058807/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/metabolism ; Animals ; Brain Ischemia/metabolism/pathology ; Disease Models, Animal ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Infarction, Middle Cerebral Artery/metabolism/*pathology ; Neuroprotective Agents/administration &amp; dosage/metabolism ; Rats ; Reperfusion Injury/metabolism/pathology ; Signal Transduction ; Stroke/*metabolism/pathology ; }, abstract = {Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90min middle cerebral artery occlusion (MCAO) and 24h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC's neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC's neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant's neuroprotection in ischemic stroke.}, }
@article {pmid24293993, year = {2013}, author = {De Backer, J and Vos, W and Van Holsbeke, C and Vinchurkar, S and Claes, R and Parizel, PM and De Backer, W}, title = {Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {8}, number = {}, pages = {569-579}, pmid = {24293993}, issn = {1178-2005}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Airway Resistance/*drug effects ; Antioxidants/*therapeutic use ; Computer Simulation ; Cross-Over Studies ; Female ; Forced Expiratory Volume ; Functional Residual Capacity ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Humans ; Lung/*drug effects/immunology/metabolism/physiopathology ; Male ; Middle Aged ; Models, Biological ; Multidetector Computed Tomography ; Oxidative Stress/*drug effects ; Phenotype ; Pilot Projects ; Pulmonary Disease, Chronic Obstructive/diagnosis/*drug therapy/immunology/metabolism/physiopathology ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Previous studies have demonstrated the potential beneficial effect of N-acetylcysteine (NAC) in chronic obstructive pulmonary disease (COPD). However, the required dose and responder phenotype remain unclear. The current study investigated the effect of high-dose NAC on airway geometry, inflammation, and oxidative stress in COPD patients. Novel functional respiratory imaging methods combining multislice computed tomography images and computer-based flow simulations were used with high sensitivity for detecting changes induced by the therapy.<br><br>METHODS: Twelve patients with Global Initiative for Chronic Obstructive Lung Disease stage II COPD were randomized to receive NAC 1800 mg or placebo daily for 3 months and were then crossed over to the alternative treatment for a further 3 months.<br><br>RESULTS: Significant correlations were found between image-based resistance values and glutathione levels after treatment with NAC (P = 0.011) and glutathione peroxidase at baseline (P = 0.036). Image-based resistance values appeared to be a good predictor for glutathione peroxidase levels after NAC (P = 0.02), changes in glutathione peroxidase levels (P = 0.035), and reduction in lobar functional residual capacity levels (P = 0.00084). In the limited set of responders to NAC therapy, the changes in airway resistance were in the same order as changes induced by budesonide/formoterol.<br><br>CONCLUSION: A combination of glutathione, glutathione peroxidase, and imaging parameters could potentially be used to phenotype COPD patients who would benefit from addition of NAC to their current therapy. The findings of this small pilot study need to be confirmed in a larger pivotal trial.}, }
@article {pmid24291634, year = {2014}, author = {Gutiérrez-Praena, D and Risalde, MA and Pichardo, S and Jos, A and Moyano, R and Blanco, A and Vasconcelos, V and Cameán, AM}, title = {Histopathological and immunohistochemical analysis of Tilapia (Oreochromis niloticus) exposed to cylindrospermopsin and the effectiveness of N-Acetylcysteine to prevent its toxic effects.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {78}, number = {}, pages = {18-34}, doi = {10.1016/j.toxicon.2013.11.014}, pmid = {24291634}, issn = {1879-3150}, mesh = {Acetylcysteine/*pharmacology ; Alkaloids ; Animals ; Aphanizomenon/*chemistry ; Bacterial Toxins ; Cichlids/*metabolism ; Cyanobacteria Toxins ; Dose-Response Relationship, Drug ; Gastrointestinal Tract/drug effects ; Immunohistochemistry/veterinary ; Kidney/drug effects ; Liver/drug effects ; Oxidative Stress/*drug effects ; Uracil/*analogs &amp; derivatives/toxicity ; }, abstract = {Cylindrospermopsin (CYN) is a cytotoxic cyanotoxin produced by several cyanobacteria species. It has been demonstrated that CYN is a potent protein and glutathione synthesis inhibitor, and induces genotoxicity and oxidative stress. The present study investigated the protective role of two different doses of N-Acetylcysteine (NAC) (22 and 45 mg/fish/day) against the pathological changes induced in tilapia (Oreochromis niloticus) orally exposed to a single dose of pure CYN or CYN from an Aphanizomenon ovalisporum CYN-producer strain (200 μg/kg of CYN in both cases). Moreover, an immunohistochemical (IHC) analysis was carried out in order to elucidate the CYN distribution in exposed fish. The histological findings were more pronounced when fish were intoxicated with CYN from the cyanobacterial strain, being liver and kidney the main targets for CYN toxicity. NAC pre-treatment was effective reducing the damage induced by CYN, especially at the highest dose employed (45 mg/fish/day), with a total prevention in all organs. The IHC analysis showed that CYN-antigen appeared mainly in the liver and gastrointestinal tract, although it was also present in kidney and gills. In this case, the immunopositive results were more abundant in those fish exposed to pure CYN. NAC reduced the number of immunopositive cases in a dose-dependent way. Therefore, NAC can be considered a useful chemoprotectant in the prophylaxis and treatment of CYN-related intoxications in fish.}, }
@article {pmid24289554, year = {2013}, author = {Tan, PX and Du, SS and Ren, C and Yao, QW and Yuan, YW}, title = {Radiation-induced Cochlea hair cell death: mechanisms and protection.}, journal = {Asian Pacific journal of cancer prevention : APJCP}, volume = {14}, number = {10}, pages = {5631-5635}, doi = {10.7314/apjcp.2013.14.10.5631}, pmid = {24289554}, issn = {2476-762X}, mesh = {Animals ; Cell Death/drug effects/genetics/*radiation effects ; Cochlea/drug effects/metabolism/*radiation effects ; Hair Cells, Auditory/drug effects/metabolism/*radiation effects ; Humans ; Radiation-Protective Agents/pharmacology/therapeutic use ; Radiotherapy/*adverse effects ; }, abstract = {Cochlea hair cell death is regarded to be responsible for the radiation-induced sensorineural hearing loss (SNHL), which is one of the principal complications of radiotherapy (RT) for head and neck cancers. In this mini- review, we focus on the current progresses trying to unravel mechanisms of radiation-induced hair cell death and find out possible protection. P53, reactive oxygen species (ROS) and c-Jun N-terminal kinase (JNK) pathways have been proposed as pivotal in the processes leading to radiation hair cell death. Potential protectants, such as amifostine, N-acetylcysteine (NAC) and epicatechin (EC) , are claimed to be effective at reducing radiation- inducedhair cell death. The RT dosage, selection and application of concurrent chemotherapy should be pre- examined in order to minimize the damage to cochlea hair cells.}, }
@article {pmid24288495, year = {2013}, author = {Fernández, V and Vargas, R and Castillo, V and Cádiz, N and Bastías, D and Román, S and Tapia, G and Videla, LA}, title = {Reestablishment of ischemia-reperfusion liver injury by N-acetylcysteine administration prior to a preconditioning iron protocol.}, journal = {TheScientificWorldJournal}, volume = {2013}, number = {}, pages = {607285}, pmid = {24288495}, issn = {1537-744X}, mesh = {Acetylcysteine/*adverse effects/pharmacology ; Animals ; Antioxidants/*adverse effects/pharmacology ; Iron/pharmacology/*therapeutic use ; *Ischemic Preconditioning ; Liver/blood supply/*drug effects/metabolism ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/metabolism/*prevention &amp; control ; }, abstract = {The role of iron (Fe)-induced prooxidant status in Fe preconditioning against ischemia (1 h)-reperfusion (20 h) induced liver injury was assessed using N-acetylcysteine (NAC) (1 g/kg) before Fe (50 mg/kg), given to male Sprague Dawley rats on alternate days during 10 days. IR significantly increased serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, with drastic changes in liver histology, hepatic glutathione depletion, and nuclear factor-κB (NF-κB) p65 diminution (P < 0.05) (ELISA). Fe-induced liver oxidative stress, as evidenced by higher protein carbonyl/glutathione content ratios (P < 0.05) at days 11 and 12 after treatment, was abolished by NAC. Under these conditions, short-term Fe administration exerted significant protection against IR liver injury, as shown by 85% and 60% decreases in IR-induced serum AST and ALT (P < 0.05), respectively, and normalization of hepatic histology, glutathione levels, and NF-κB activation, changes that were suppressed by NAC administration prior to Fe. Results of this study indicate that NAC administration prior to an iron protocol reestablishes IR liver injury, supporting the role of Fe-induced transient oxidative stress in hepatoprotection and its potential clinical application.}, }
@article {pmid24287800, year = {2014}, author = {Imai, T and Kosuge, Y and Endo-Umeda, K and Miyagishi, H and Ishige, K and Makishima, M and Ito, Y}, title = {Protective effect of S-allyl-L-cysteine against endoplasmic reticulum stress-induced neuronal death is mediated by inhibition of calpain.}, journal = {Amino acids}, volume = {46}, number = {2}, pages = {385-393}, doi = {10.1007/s00726-013-1628-4}, pmid = {24287800}, issn = {1438-2199}, mesh = {Animals ; Apoptosis/*drug effects ; Calcium-Binding Proteins/pharmacology ; Calpain/antagonists &amp; inhibitors/*metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cysteine/*analogs &amp; derivatives/pharmacology ; Dipeptides/pharmacology ; Endoplasmic Reticulum Stress/*drug effects ; Hippocampus/cytology ; Leupeptins/pharmacology ; Neurons/drug effects/*physiology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress ; Rats ; Rats, Wistar ; Spectrin/metabolism ; }, abstract = {Endoplasmic reticulum (ER) stress, implicated in various neurodegenerative processes, increases the level of intracellular Ca(2+) and leads to activation of calpain, a Ca(2+)-dependent cysteine protease. We have shown previously that S-allyl-L-cysteine (SAC) in aged garlic extracts significantly protects cultured rat hippocampal neurons (HPNs) against ER stress-induced neurotoxicity. The neuroprotective effect of SAC was compared with those of the related antioxidant compounds, L-cysteine (CYS) and N-acetylcysteine (NAC), on calpain activity in HPNs and also in vitro. SAC, but not CYS or NAC, reversibly restored the survival of HPNs and increased the degradation of α-spectrin, a substrate for calpain, induced by tunicamycin, a typical ER stress inducer. Activities of μ- and m-calpains in vitro were also concentration dependently suppressed by SAC, but not by CYS or NAC. At submaximal concentration, although ALLN (5 pM), which blocks the active site of calpain, and calpastatin (100 pM), an endogenous calpain-inhibitor protein, additively inhibited μ-calpain activity in vitro in combination with SAC, the effect of PD150606 (25 μM), which prevents interaction of Ca(2+) with the Ca(2+)-binding site of calpain, was unaffected by SAC. In contrast, SAC (1 mM) significantly reversed the effect of PD150606 at a concentration that elicited supramaximal inhibition (100 μM), but did not affect ALLN (1 nM)- and calpastatin (100 nM)-induced inhibition of μ-calpain activity. These results suggest that the protective effects of SAC against ER stress-induced neuronal cell death are not attributable to antioxidant activity, but to suppression of calpain through interaction with its Ca(2+)-binding site.}, }
@article {pmid24286856, year = {2014}, author = {Egnatchik, RA and Leamy, AK and Noguchi, Y and Shiota, M and Young, JD}, title = {Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes.}, journal = {Metabolism: clinical and experimental}, volume = {63}, number = {2}, pages = {283-295}, pmid = {24286856}, issn = {1532-8600}, support = {P30 DK020593/DK/NIDDK NIH HHS/United States ; P60 DK020593/DK/NIDDK NIH HHS/United States ; DK020593/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; *Apoptosis/drug effects ; Carbon Isotopes ; Carcinoma, Hepatocellular/*metabolism ; Caspases, Effector/drug effects/metabolism ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Hepatocytes/drug effects/*metabolism ; Liver Neoplasms/*metabolism ; Metabolic Flux Analysis/methods ; Mitochondria, Liver/*metabolism ; *Oxidative Stress/drug effects ; Palmitates/metabolism/*pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {OBJECTIVE: Hepatic lipotoxicity is characterized by reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and excessive apoptosis, but the precise sequence of biochemical events leading to oxidative damage and cell death remains unclear. The goal of this study was to delineate the role of mitochondrial metabolism in mediating hepatocyte lipotoxicity.<br><br>MATERIALS/METHODS: We treated H4IIEC3 rat hepatoma cells with free fatty acids in combination with antioxidants and mitochondrial inhibitors designed to block key events in the progression toward apoptosis. We then applied (13)C metabolic flux analysis (MFA) to quantify mitochondrial pathway alterations associated with these treatments.<br><br>RESULTS: Treatment with palmitate alone led to a doubling in oxygen uptake rate and in most mitochondrial fluxes. Supplementing culture media with the antioxidant N-acetyl-cysteine (NAC) reduced ROS accumulation and caspase activation and partially restored cell viability. However, (13)C MFA revealed that treatment with NAC did not normalize palmitate-induced metabolic alterations, indicating that neither elevated ROS nor downstream apoptotic events contributed to mitochondrial activation. To directly limit mitochondrial metabolism, the complex I inhibitor phenformin was added to cells treated with palmitate. Phenformin addition eliminated abnormal ROS accumulation, prevented the appearance of apoptotic markers, and normalized mitochondrial carbon flow. Further studies revealed that glutamine provided the primary fuel for elevated mitochondrial metabolism in the presence of palmitate, rather than fatty acid beta-oxidation, and that glutamine consumption could be reduced through co-treatment with phenformin but not NAC.<br><br>CONCLUSION: Our results indicate that ROS accumulation in palmitate-treated H4IIEC3 cells occurs downstream of altered mitochondrial oxidative metabolism, which is independent of beta-oxidation and precedes apoptosis initiation.}, }
@article {pmid24284796, year = {2014}, author = {Zhang, J and Li, Y and Jiang, S and Yu, H and An, W}, title = {Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis.}, journal = {American journal of physiology. Cell physiology}, volume = {306}, number = {3}, pages = {C279-90}, doi = {10.1152/ajpcell.00117.2013}, pmid = {24284796}, issn = {1522-1563}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Calcium/metabolism ; Cell Line, Tumor ; Cell Survival ; Down-Regulation ; Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Chaperone BiP ; *Endoplasmic Reticulum Stress ; Eukaryotic Initiation Factor-2 ; Fatty Acids, Nonesterified/metabolism ; Fatty Liver/*metabolism ; Heat-Shock Proteins/biosynthesis ; Hepatocytes/metabolism ; Humans ; Intercellular Signaling Peptides and Proteins ; Liver/metabolism ; Non-alcoholic Fatty Liver Disease ; Peptides/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/*metabolism ; Signal Transduction ; Sterol Regulatory Element Binding Proteins/biosynthesis ; Transcription Factor CHOP ; Transfection ; eIF-2 Kinase/biosynthesis ; }, abstract = {Although the potential pathogenesis of nonalcoholic fatty liver disease (NAFLD) is unclear, increasing evidence indicates that endoplasmic reticulum (ER) stress may link free fatty acids to NAFLD. Since we previously reported that hepatic stimulator substance (HSS) could protect the liver from steatosis, this study is aimed to investigate whether HSS protection could be related with its inhibition on ER stress. The HSS gene was stably transfected into BEL-7402 hepatoma cells and effectively expressed in ER. The palmitic acid (PA)-induced heptocyte lipotoxicity was reproduced in the HSS-transfected cells, and HSS alleviation of the ER stress and apoptosis were subsequently examined. The results showed that PA treatment led to a heavy accumulation of fatty acids within the cells and a remarkable increase in reactive oxygen species (ROS). However, in the HSS-expressing cells, production of ROS was inhibited and ER stress-related marker glucose-regulated protein 78 (GRP-78), sterol regulatory element-binding protein (SREBP), anti-phospho-PRK-1ike ER kinase (p-PERK), anti-phospho-eukaryotic initiation factor 2α (p-eIF2α), and anti-C/EBP homologous protein (CHOP) were downregulated compared with the wild-type or mutant HSS-transfected cells. Furthermore, PA treatment severely impaired the activity of sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), leading to imbalanced calcium homeostasis during ER stress, which could be rescued in the HSS-trasfected cells. The protection provided by HSS to the SERCA is identical to that observed with N-acetyl-l-cysteine (NAC) and sodium dimercaptopropane sulfonate (Na-DMPS), which are two typical free radical scavengers. As a consequence, the rate of ER stress-mediated apoptosis in the HSS-expressing cells was significantly reduced. In conclusion, the protective effect of HSS against ER stress may be associated with the removal of ROS to restore the activity of the SERCA.}, }
@article {pmid24275574, year = {2014}, author = {Zhao, W and Gan, X and Su, G and Wanling, G and Li, S and Hei, Z and Yang, C and Wang, H}, title = {The interaction between oxidative stress and mast cell activation plays a role in acute lung injuries induced by intestinal ischemia-reperfusion.}, journal = {The Journal of surgical research}, volume = {187}, number = {2}, pages = {542-552}, doi = {10.1016/j.jss.2013.10.033}, pmid = {24275574}, issn = {1095-8673}, mesh = {Acetylcysteine/metabolism ; Acute Lung Injury/*immunology/pathology ; Age Factors ; Animals ; Cell Degranulation/immunology ; Hydrogen Peroxide/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Interleukin-6/metabolism ; Intestinal Diseases/*immunology ; Intestines/blood supply ; Lung/metabolism/pathology ; Mast Cells/*immunology ; Membrane Glycoproteins/metabolism ; NADPH Oxidase 2 ; NADPH Oxidases/metabolism ; Oxidative Stress/*immunology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*immunology ; Tryptases/metabolism ; beta-N-Acetylhexosaminidases/blood ; }, abstract = {BACKGROUND: Both oxidative stress and mast cells are involved in acute lung injuries (ALIs) that are induced by intestinal ischemia-reperfusion (IIR). The aim of this study was to further investigate the interaction between oxidative stress and mast cells during the process of IIR-induced ALI.<br><br>MATERIALS AND METHODS: Thirty adult Sprague-Dawley rats were randomly divided into five groups: sham, IIR, IIR + compound 48/80 (CP), N-acetylcysteine (NAC) + IIR, and NAC + IIR + CP. All rats except those in the sham group were subjected to 75&#xa0;min of superior mesenteric artery occlusion, followed by 2&#xa0;h of reperfusion. The rats in the NAC + IIR and NAC + IIR + CP groups were injected intraperitoneally with NAC (0.5&#xa0;g/kg) for three successive days before undergoing IIR. The rats in the IIR + CP and NAC + IIR + CP groups were treated with CP (0.75&#xa0;mg/kg), which was administered intravenously 5&#xa0;min before the reperfusion. At the end of the experiment, lung tissue was obtained for pathologic and biochemical assays.<br><br>RESULTS: IIR resulted in ALI, which was detected by elevated pathology scores, a higher lung wet-to-dry ratio, and decreased expression of prosurfactant protein C (P&#xa0;<&#xa0;0.05). Concomitant elevations were observed in the expression levels of the nicotinamide adenine dinucleotide phosphate oxidase subunits p47(phox) and gp91(phox) and the levels of hydrogen peroxide and malondialdehyde. However, superoxide dismutase activity in the lung was reduced (P&#xa0;<&#xa0;0.05). The level of interleukin 6, the activity of myeloperoxidase, and the expression of intercellular adhesion molecule 1 were also increased in the lung. IIR led to pulmonary mast cell degranulation and increases in the plasma and pulmonary &#x3b2;-hexosaminidase levels, mast cell counts, and tryptase expression in lung tissue. CP aggravated these conditions, altering the measurements further, whereas NAC attenuated the IIR-induced ALI and all biochemical changes (P&#xa0;<&#xa0;0.05). However, CP abolished some of the protective effects of NAC.<br><br>CONCLUSIONS: Oxidative stress and mast cells interact with each other and promote IIR-induced ALI.}, }
@article {pmid24274460, year = {2014}, author = {Mateo, D and Morales, P and Ávalos, A and Haza, AI}, title = {Oxidative stress contributes to gold nanoparticle-induced cytotoxicity in human tumor cells.}, journal = {Toxicology mechanisms and methods}, volume = {24}, number = {3}, pages = {161-172}, doi = {10.3109/15376516.2013.869783}, pmid = {24274460}, issn = {1537-6524}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Glutathione/analysis ; Gold/*pharmacology ; Humans ; Metal Nanoparticles/*administration &amp; dosage ; *Oxidative Stress ; Particle Size ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Due to their exceptional properties, gold nanoparticles (AuNPs) have shown promising medical and technological applications in the treatment of cancer and the development of antimicrobial packaging and time-temperature indicators in the food sector. However, little is known about their cytotoxicity when they come into contact with biological systems. The aim of this work was to compare the effects of three commercially available AuNPs of different sizes (30, 50 and 90 nm) on human leukemia (HL-60) and hepatoma (HepG2) cell lines. AuNP-induced cytotoxicity was dose and time-dependent, with IC50 values higher than 15 μg/mL. Nanoparticle (NP) size and cell line slightly influenced on the cytotoxicity of AuNPs, although HL-60 cells proved to be more sensitive to the cytotoxic response than HepG2. N-Acetyl-L-cysteine (NAC) protected HL-60 and HepG2 cells only against treatment with 30 nm AuNPs. In both cell types, glutathione (GSH) content was drastically depleted after 72 h of incubation with the three AuNPs (less than 30% in all cases), while the reduction of superoxide dismutase activity (SOD) activity depended on cell line. HepG2, but not HL-60 cells, exhibited a decrease of SOD activity (∼ 45% of activity). The three AuNPs also caused a two-fold elevation of reactive oxygen species (ROS) production in both cell lines. Thus, protective effect of NAC, depletion of GSH and increase of ROS appear to be determined by NP size and indicate that oxidative stress contributes to cytotoxicity of AuNPs.}, }
@article {pmid24273860, year = {2013}, author = {León-González, AJ and López-Lázaro, M and Espartero, JL and Martín-Cordero, C}, title = {Cytotoxic activity of dihydrochalcones isolated from Corema album leaves against HT-29 colon cancer cells.}, journal = {Natural product communications}, volume = {8}, number = {9}, pages = {1255-1256}, pmid = {24273860}, issn = {1934-578X}, mesh = {Antineoplastic Agents, Phytogenic/*isolation &amp; purification ; Chalcones/*isolation &amp; purification ; Drug Screening Assays, Antitumor ; Ericaceae/*chemistry ; HT29 Cells ; Humans ; Plant Leaves/chemistry ; }, abstract = {During our search for cytotoxic compounds from Andalusian vascular plants, the ethyl acetate extract from the leaves of Corema album (L.) D. Don (Ericaceae) was selected for its cytotoxic activity against the HT-29 human colon adenocarcinoma cell line. Two dihydrochalcones, 2',4'-dihydroxydihydrochalcone (1) and 2'-methoxy-4'-hydroxydihydrochalcone (2), have been isolated from the leaves of C. album. Their structural identification was based on 1H NMR and 13C NMR data, including 2D NMR, and mass spectrometry. These compounds were subjected to the sulfhorhodamine B (SRB) cytotoxic assay against human colon adenocarcinoma cells (HT-29). Compounds 1 and 2 showed higher cytotoxicity than the positive control 5-fluorouracil (5-FU); the IC50 values (microM +/- SEM) were 1.8 +/- 0.4 for compound 1, 8.5 +/- 2.1 microM for compound 2, and 8.7 +/- 4.0 for 5-FU. The cytotoxic activity of 1 and 2 was reduced in the presence of the antioxidants N-acetylcysteine (NAC) and Mn(III) Tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), therefore suggesting that reactive oxygen species generation participates in the cytotoxic activity of these dihydrochalcones.}, }
@article {pmid24273738, year = {2013}, author = {Wu, D and Cederbaum, AI}, title = {Inhibition of autophagy promotes CYP2E1-dependent toxicity in HepG2 cells via elevated oxidative stress, mitochondria dysfunction and activation of p38 and JNK MAPK.}, journal = {Redox biology}, volume = {1}, number = {1}, pages = {552-565}, pmid = {24273738}, issn = {2213-2317}, support = {R01 AA018790/AA/NIAAA NIH HHS/United States ; R21 AA021362/AA/NIAAA NIH HHS/United States ; R01AA018790/AA/NIAAA NIH HHS/United States ; R21AA021362/AA/NIAAA NIH HHS/United States ; }, mesh = {Adenine/*analogs &amp; derivatives/pharmacology ; Arachidonic Acid/pharmacology ; Autophagy/drug effects ; Autophagy-Related Protein 7 ; Buthionine Sulfoximine/pharmacology ; Carbon Tetrachloride/pharmacology ; Cytochrome P-450 CYP2E1/*metabolism ; Hep G2 Cells ; Humans ; MAP Kinase Signaling System/drug effects ; Mitochondria ; Oxidative Stress ; Sirolimus/*pharmacology ; Ubiquitin-Activating Enzymes/*genetics/metabolism ; }, abstract = {Autophagy has been shown to be protective against drug and alcohol-induced liver injury. CYP2E1 plays a role in the toxicity of ethanol, carcinogens and certain drugs. Inhibition of autophagy increased ethanol-toxicity and accumulation of fat in wild type and CYP2E1 knockin mice but not in CYP2E1 knockout mice as well as in HepG2 cells expressing CYP2E1 (E47 cells) but not HepG2 cells lacking CYP2E1 (C34 cells). The goal of the current study was to evaluate whether modulation of autophagy can affect CYP2E1-dependent cytotoxicity in the E47 cells. The agents used to promote CYP2E1 -dependent toxicity were a polyunsaturated fatty acid, arachidonic acid (AA), buthionine sulfoximine (BSO), which depletes GSH, and CCl4, which is metabolized to the CCl3 radical. These three agents produced a decrease in E47 cell viability which was enhanced upon inhibition of autophagy by 3-methyladenine (3-MA) or Atg 7 siRNA. Toxicity was lowered by rapamycin which increased autophagy and was much lower to the C34 cells which do not express CYP2E1. Toxicity was mainly necrotic and was associated with an increase in reactive oxygen production and oxidative stress; 3-MA increased while rapamycin blunted the oxidative stress. The enhanced toxicity and ROS formation produced when autophagy was inhibited was prevented by the antioxidant N-Acetyl cysteine. AA, BSO and CCl4 produced mitochondrial dysfunction, lowered cellular ATP levels and elevated mitochondrial production of ROS. This mitochondrial dysfunction was enhanced by inhibition of autophagy with 3-MA but decreased when autophagy was increased by rapamycin. The mitogen activated protein kinases p38 MAPK and JNK were activated by AA especially when autophagy was inhibited and chemical inhibitors of p38 MAPK and JNK lowered the elevated toxicity of AA produced by 3-MA. These results show that autophagy was protective against the toxicity produced by several agents known to be activated by CYP2E1. Since CYP2E1 plays an important role in the toxicity of ethanol, drugs and carcinogens and is activated under various pathophysiological conditions such as diabetes, NASH and obesity, attempts to stimulate autophagy may be beneficial in preventing/lowering CYP2E1/ethanol liver injury.}, }
@article {pmid24270669, year = {2014}, author = {Zeng, F and Tee, C and Liu, M and Sherry, JP and Dixon, B and Duncker, BP and Bols, NC}, title = {The p53/HSP70 inhibitor, 2-phenylethynesulfonamide, causes oxidative stress, unfolded protein response and apoptosis in rainbow trout cells.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {146}, number = {}, pages = {45-51}, doi = {10.1016/j.aquatox.2013.10.026}, pmid = {24270669}, issn = {1879-1514}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cell Line ; HSP70 Heat-Shock Proteins/metabolism ; Oncorhynchus mykiss/*physiology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Sulfonamides/*toxicity ; Tumor Suppressor Protein p53/metabolism ; Unfolded Protein Response/*drug effects ; Water Pollutants, Chemical/*toxicity ; }, abstract = {The effect of 2-phenylethynesulfonamide (PES), which is a p53 and HSP70 inhibitor in mammalian cells, was studied on the rainbow trout (Oncorhynchus mykiss) gill epithelial cell line, RTgill-W1, in order to evaluate PES as a tool for understanding the cellular survival pathways operating in fish. As judged by three viability assays, fish cells were killed by 24h exposures to PES, but cell death was blocked by the anti-oxidant N-acetylcysteine (NAC). Cell death had several hallmarks of apoptosis: DNA laddering, nuclear fragmentation, Annexin V staining, mitochondrial membrane potential decline, and caspases activation. Reactive oxygen species (ROS) production peaked in several hours after the addition of PES and before cell death. HSP70 and BiP levels were higher in cultures treated with PES for 24h, but this was blocked by NAC. As well, PES treatment caused HSP70, BiP and p53 to accumulate in the detergent-insoluble fraction, and this too was prevented by NAC. Of several possible scenarios to explain the results, the following one is the simplest. PES enhances the generation of ROS, possibly by inhibiting the anti-oxidant actions of p53 and HSP70. ER stress arises from the ROS and from PES inhibiting the chaperone activities of HSP70. The ER stress in turn initiates the unfolded protein response (UPR), but this fails to restore ER homeostasis so proteins aggregate and cells die. Despite these multiple actions, PES should be useful for studying fish cellular survival pathways.}, }
@article {pmid24268738, year = {2014}, author = {Dludla, PV and Muller, CJ and Louw, J and Joubert, E and Salie, R and Opoku, AR and Johnson, R}, title = {The cardioprotective effect of an aqueous extract of fermented rooibos (Aspalathus linearis) on cultured cardiomyocytes derived from diabetic rats.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {21}, number = {5}, pages = {595-601}, doi = {10.1016/j.phymed.2013.10.029}, pmid = {24268738}, issn = {1618-095X}, mesh = {Animals ; Apoptosis/drug effects ; *Aspalathus ; Cells, Cultured ; Diabetic Cardiomyopathies/*drug therapy ; Drug Evaluation, Preclinical ; Fermentation ; Glutathione/metabolism ; Male ; Myocardial Ischemia/drug therapy ; Myocytes, Cardiac/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Phytotherapy ; Plant Extracts/pharmacology/*therapeutic use ; Rats ; Rats, Wistar ; Reactive Oxygen Species/analysis ; }, abstract = {Diabetic cardiomyopathy (DCM) is a disorder of the heart muscle that contributes to cardiovascular deaths in the diabetic population. Excessive generation of free radicals has been directly implicated in the pathogenesis of DCM. The use of antioxidants, through dietary supplementation, to combat increased cellular oxidative stress has gained popularity worldwide. Aspalathus linearis (rooibos) is a popular herbal tea that contains a novel antioxidant, aspalathin. Literature has reported on the antidiabetic, anti-inflammatory and free radical scavenging effects of rooibos. However, its protective effect against DCM has not been established. Therefore, this study investigated whether chronic exposure to an aqueous extract of fermented rooibos (FRE) has an ex vivo cardioprotective effect on hearts obtained from streptozotocin (STZ) induced diabetic rats. Adult Wistar rats were injected with 40 mg/kg of STZ. Two weeks after STZ injection, cardiomyocytes were isolated and cultured. Cultured cardiomyocytes were treated with FRE (1 and 10 μg/ml), vitamin E (50 μg/ml), and n-acetyl cysteine (1mM) for 6h, before exposure to either hydrogen peroxide (H2O2) or an ischemic solution. Cardiomyocytes exposed to H2O2 or an ischemic solution showed a decrease in metabolic activity and glutathione content with a concomitant increase in apoptosis and intracellular reactive oxygen species. Pretreatment with FRE was able to combat these effects and the observed amelioration was better than the known antioxidant vitamin E. This study provides evidence that an aqueous extract of fermented rooibos protects cardiomyocytes, derived from diabetic rats, against experimentally induced oxidative stress and ischemia.}, }
@article {pmid24267093, year = {2013}, author = {Gatti, R and Vitellaro, V}, title = {High performance liquid chromatography analysis of aliphatic thiols in alimentary supplements and pharmaceuticals using menadione as a new useful derivatization reagent.}, journal = {Analytica chimica acta}, volume = {804}, number = {}, pages = {273-279}, doi = {10.1016/j.aca.2013.09.059}, pmid = {24267093}, issn = {1873-4324}, mesh = {Chromatography, High Pressure Liquid/*methods ; *Dietary Supplements ; Magnetic Resonance Spectroscopy ; Pharmaceutical Preparations/administration &amp; dosage/*analysis ; Sulfhydryl Compounds/administration &amp; dosage/*analysis ; Vitamin K 3/administration &amp; dosage/*analysis ; }, abstract = {The use of menadione (MD) as a pre-column reagent for high performance liquid chromatography (HPLC) analysis of aliphatic thiols is proposed. The reaction was carried out for 5 min at room temperature and pH 8.5. The developed method was applied to the N-acetylcysteine (NAC) analysis of alimentary supplements and pharmaceutical formulations. The effect of the complex matrix was evaluated by the study of the thiol derivatization reaction both in standard and in placebo solutions. The yield of NAC-MD adduct was found to be quantitative at a reagent to thiol molar ratio of about 4 in comparison with an authentic specimen of synthesized NAC adduct, which was characterized by (1)H NMR, IR and UV. The routine chromatographic separations were performed on a Synergi MAX-RP column using a mobile phase consisting of methanol/triethylammonium (TEA) phosphate buffer (pH 3; 0.05 mol L(-1)) 70:30 (v/v) at a flow-rate of 0.4 mL min(-1). UV-diode array detection was used setting the wavelength at λ=260 nm. The validation parameters such as linearity, sensitivity, accuracy, precision, selectivity and ruggedness were found to be highly satisfactory. Similar linear responses were observed by standard and placebo solutions (determination coefficient: 0.9996). Limit of detection was about 0.019 μg g(-1). Intra-day precision (relative standard deviation, R.S.D.) was ≤0.81% for NAC to internal standard (IS) peak area ratio, ≤0.28% and ≤0.32%, respectively, for NAC and IS retention times (tR), without significant differences between intra- and inter-day data. NAC recovery studies gave good results (100.12%) with R.S.D.=1.05%.}, }
@article {pmid24263163, year = {2016}, author = {Radosevich, JJ and Patanwala, AE and Erstad, BL}, title = {Hepatotoxicity in Obese Versus Nonobese Patients With Acetaminophen Poisoning Who Are Treated With Intravenous N-Acetylcysteine.}, journal = {American journal of therapeutics}, volume = {23}, number = {3}, pages = {e714-9}, doi = {10.1097/01.mjt.0000434043.62372.00}, pmid = {24263163}, issn = {1536-3686}, mesh = {Acetaminophen/administration &amp; dosage/*adverse effects ; Acetylcysteine/*therapeutic use ; Administration, Intravenous ; Adult ; Alanine Transaminase/blood ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/*adverse effects ; Antidotes/*therapeutic use ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/blood/*epidemiology/etiology ; Drug Overdose/drug therapy ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Obesity/blood/*metabolism ; Retrospective Studies ; United States/epidemiology ; }, abstract = {There is limited information regarding the outcomes associated with acetaminophen (APAP) poisoning in obese individuals. It is possible that patients who are obese are more susceptible to APAP-induced liver injury, thereby diminishing the efficacy of antidotes such as N-acetylcysteine (NAC). We evaluated the outcomes associated with APAP poisoning in obese versus nonobese adults who are treated with intravenous (IV) NAC. This was a retrospective cohort study conducted in a tertiary care, academic medical center. Adult patients with APAP toxicity, who were treated with IV NAC between June 2005 and August 2012, were included. The patients were categorized into 2 groups based on their body mass index (BMI): (1) obese (BMI ≥ 30.0 kg/m) versus (2) nonobese (BMI 18.5-24.9 kg/m). The primary outcome measure was the proportion of patients who developed hepatotoxicity (aspartate aminotransferase or alanine aminotransferase >1000 IU/L). A total of 80 patients were included in the final cohort (40 in each group). The median BMI for the obese and nonobese groups was 34.5 kg/m [interquartile range (IQR) 31.4-40.2] and 22.4 kg/m (IQR 21.2-23.9), respectively (P < 0.001). Other than more white patients being present in the nonobese group, there were no other baseline differences between groups with regard to demographics, liver function tests, or coagulation studies. Obese patients received a median IV NAC dose of 291.5 mg/kg (IQR 270.8-300.7) compared with 300 mg/kg (IQR 287.8-301.9) in the nonobese group (P = 0.07). Hepatotoxicity occurred in 27.5% of the obese patients and 37.5% of the nonobese patients (P = 0.34). No adverse drug effects were noted in either group. Obese and nonobese patients being treated with IV NAC for APAP toxicity experienced similar rates of hepatotoxicity.}, }
@article {pmid24260479, year = {2013}, author = {Li, F and Wiegman, C and Seiffert, JM and Zhu, J and Clarke, C and Chang, Y and Bhavsar, P and Adcock, I and Zhang, J and Zhou, X and Chung, KF}, title = {Effects of N-acetylcysteine in ozone-induced chronic obstructive pulmonary disease model.}, journal = {PloS one}, volume = {8}, number = {11}, pages = {e80782}, pmid = {24260479}, issn = {1932-6203}, support = {//Wellcome Trust/United Kingdom ; 083905/WT_/Wellcome Trust/United Kingdom ; }, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Apoptosis ; Bronchial Hyperreactivity/chemically induced ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Deoxyguanosine/analogs &amp; derivatives/blood ; Disease Models, Animal ; Emphysema/pathology ; Expectorants/administration &amp; dosage/*pharmacology ; Gene Expression ; Lung/drug effects/metabolism/pathology/physiopathology ; Malondialdehyde/metabolism ; Mice ; Ozone/*adverse effects ; Pulmonary Disease, Chronic Obstructive/*chemically induced/pathology/*prevention &amp; control ; Respiratory Function Tests ; }, abstract = {INTRODUCTION: Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. We determined the recovery from ozone-induced injury and whether an antioxidant, N-acetylcysteine (NAC), could prevent or reverse the lung damage.<br><br>METHODS: Mice were exposed to ozone (2.5 ppm, 3 hours/12 exposures, over 6 weeks) and studied 24 hours (24h) or 6 weeks (6W) later. Nac (100 mg/kg, intraperitoneally) was administered either before each exposure (preventive) or after completion of exposure (therapeutic) for 6 weeks.<br><br>RESULTS: After ozone exposure, there was an increase in functional residual capacity, total lung volume, and lung compliance, and a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV25/FVC, FEV50/FVC). Mean linear intercept (Lm) and airway hyperresponsiveness (AHR) to acetylcholine increased, and remained unchanged at 6W after cessation of exposure. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells.<br><br>CONCLUSION: Emphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The beneficial effects of therapeutic NAC may be restricted to the ASM.}, }
@article {pmid24260080, year = {2013}, author = {Shin, HR and You, BR and Park, WH}, title = {PX-12-induced HeLa cell death is associated with oxidative stress and GSH depletion.}, journal = {Oncology letters}, volume = {6}, number = {6}, pages = {1804-1810}, pmid = {24260080}, issn = {1792-1074}, abstract = {PX-12, as an inhibitor of thioredoxin (Trx), has antitumor activity. However, little is known about the toxicological effect of PX-12 on cervical cancer cells. In the present study, the growth inhibitory effects of PX-12 on HeLa cervical cancer cells in association with reactive oxygen species (ROS) and glutathione (GSH) levels were investigated. Based on MTT assays, PX-12 inhibited the growth of HeLa cells with an IC50 value of ~7 μM at 72 h. DNA flow cytometry analysis indicated that 5 and 10 μM PX-12 significantly induced a G2/M phase arrest of the cell cycle. PX-12 also increased the number of dead cells and annexin V-fluorescein isothiocyanate-positive cells, which was accompanied by the loss of mitochondrial membrane potential. All the investigated caspase inhibitors significantly rescued certain cells from PX-12-induced HeLa cell death. With respect to ROS and GSH levels, PX-12 increased ROS levels (including O2[•-]) in HeLa cells and induced GSH depletion. N-acetyl cysteine markedly reduced the levels of O2[•-] in PX-12-treated HeLa cells, and prevented apoptotic cell death and GSH depletion in these cells. By contrast, L-buthionine sulfoximine intensified cell death and GSH depletion in PX-12-treated HeLa cells. To conclude, this is the first study to demonstrate that PX-12 inhibits the growth of HeLa cells via G2/M phase arrest, as well as inhibiting apoptosis; the effect was associated with intracellular increases in ROS levels and GSH depletion.}, }
@article {pmid24258150, year = {2014}, author = {Aoi, J and Endo, M and Kadomatsu, T and Miyata, K and Ogata, A and Horiguchi, H and Odagiri, H and Masuda, T and Fukushima, S and Jinnin, M and Hirakawa, S and Sawa, T and Akaike, T and Ihn, H and Oike, Y}, title = {Angiopoietin-like protein 2 accelerates carcinogenesis by activating chronic inflammation and oxidative stress.}, journal = {Molecular cancer research : MCR}, volume = {12}, number = {2}, pages = {239-249}, doi = {10.1158/1541-7786.MCR-13-0336}, pmid = {24258150}, issn = {1557-3125}, mesh = {Acetylcysteine/pharmacology ; Angiopoietins/*metabolism ; Animals ; Carcinoma, Squamous Cell/*chemically induced/*genetics/metabolism ; DNA Methylation ; Gene Expression Regulation, Neoplastic ; Inflammation/genetics/*metabolism ; Male ; Mice ; Mice, Knockout ; MutS Homolog 2 Protein/*genetics/metabolism ; Neoplasms, Experimental ; Oxidative Stress/*drug effects ; Promoter Regions, Genetic ; Skin Neoplasms/*chemically induced/genetics/metabolism ; }, abstract = {UNLABELLED: Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue.<br><br>IMPLICATIONS: Angptl2-induced inflammation increases susceptibility to microenvironmental changes, allowing increased oxidative stress and decreased Msh2 expression; therefore, Angptl2 might be a target to develop new strategies to antagonize these activities in premalignant tissue.}, }
@article {pmid24256565, year = {2014}, author = {Murphy, A and Testa, K and Berkelhammer, J and Hopkins, S and Loo, G}, title = {Impact of antioxidants on the ability of phenolic phytochemicals to kill HCT116 colon cancer cells.}, journal = {Free radical research}, volume = {48}, number = {3}, pages = {313-321}, doi = {10.3109/10715762.2013.867958}, pmid = {24256565}, issn = {1029-2470}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Ascorbic Acid/*pharmacology ; Catechin/*analogs &amp; derivatives/antagonists &amp; inhibitors/pharmacology ; Cell Line, Tumor ; Colonic Neoplasms/*drug therapy/genetics/pathology ; Curcumin/*pharmacology ; DNA Damage ; Drug Interactions ; Gene Expression/drug effects ; HCT116 Cells ; HT29 Cells ; Heme Oxygenase-1/biosynthesis ; Humans ; Iron Chelating Agents/pharmacology ; }, abstract = {Certain phenolic phytochemicals can kill cancer cells. Possible interference from antioxidants is a concern, and this issue has not been studied appreciably. Therefore, the effect of ascorbate and N-acetylcysteine on the ability of epigallocatechin gallate (EGCG) and curcumin to kill HCT116 colon cancer cells was examined. EGCG and curcumin each caused DNA damage in the cells. The DNA-damaging ability of EGCG, but not curcumin, was hindered by either ascorbate or NAC, which was also shown in HT29 and SW480 colon cancer cells. Also, iron chelators (deferoxamine and 2,2'-dipyridyl) inhibited the ability of EGCG, but not curcumin, to cause damage to the DNA in HCT116 cells. Interestingly, curcumin, but not EGCG, increased the expression of growth arrest and DNA damage-inducible gene 153 and also heme oxygenase-1, and this stress gene upregulation by curcumin was antioxidant-insensitive. With prolonged incubation of HCT116 cells with either EGCG or curcumin, cell shrinkage, membrane blebbing, apoptotic bodies, and chromatin condensation/fragmentation were observed. These morphological changes were not apparent in EGCG-treated cells that had been pretreated with either ascorbate or NAC. However, the ascorbate and NAC pretreatments did not prevent the occurrence of the morphological changes in curcumin-treated cells. Thus, these findings suggest that ascorbate and NAC interfere with the ability of EGCG, but not curcumin, to kill HCT116 cells. This basic knowledge may help to better plan and optimize strategies for chemoprevention or chemotherapy.}, }
@article {pmid24251357, year = {2014}, author = {Xu, R and Wang, Q and Zhang, J and Zang, M and Liu, X and Yang, J}, title = {Changes in pharmacokinetic profiles of acetaminophen and its glucuronide after pretreatment with combinations of N-acetylcysteine and either glycyrrhizin, silibinin or spironolactone in rat.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {44}, number = {6}, pages = {541-546}, doi = {10.3109/00498254.2013.858849}, pmid = {24251357}, issn = {1366-5928}, mesh = {Acetaminophen/*analogs &amp; derivatives/blood/pharmacokinetics/urine ; Acetylcysteine/*pharmacology ; Animals ; Glycyrrhizic Acid/*pharmacology ; Hepatobiliary Elimination/drug effects ; Injections, Intraperitoneal ; Liver/metabolism ; Male ; Rats, Sprague-Dawley ; Silybin ; Silymarin/*pharmacology ; Spironolactone/*pharmacology ; Time Factors ; }, abstract = {1. The present study was to investigate the effects of giving N-acetylcysteine (NAC) alone and in combination with either glycyrrhizin (GL), silibinin (SIB) or spironolactone (SL) on the plasma pharmacokinetic (PK) profiles, hepatic exposure, biliary excretion and urinary excretion of acetaminophen (APAP) and its major metabolite, acetaminophen glucuronide (AG). 2. Groups of rats (n = 5) were pretreated with oral doses of either NAC, NAC + GL, NAC + SIB or NAC + SL on five occasions every 12 h. At 1 h, after the last dose, they received APAP (200 mg/kg) by intraperitoneal injection. Blood, bile, liver and urine samples were collected at various times after APAP injection and analyzed for APAP and AG by HPLC. NAC alone and NAC + SIB did not significantly change the PK profiles of APAP and AG. In contrast, NAC + GL decreased the biliary excretion of APAP and AG leading to accumulation of APAP in the liver and systemic circulation whereas NAC + SL [multidrug resistance associated 2 (Mrp2) inducer] increased the biliary excretion of AG and decreased the hepatic exposure to APAP and AG. 3. Our results suggest that Mrp2 inhibitor GL should be discouraged with NAC to treat APAP hepatotoxicity. Such PK drug-drug interactions should be considered in the treatment of APAP-induced liver injury.}, }
@article {pmid24250582, year = {2013}, author = {Vahdati-Mashhadian, N and Jafari, MR and Sharghi, N and Sanati, T}, title = {Protective Effects of Vitamin C and NAC on the Toxicity of Rifampin on Hepg2 Cells.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {12}, number = {1}, pages = {141-146}, pmid = {24250582}, issn = {1735-0328}, abstract = {Rifampin, an antibiotic widely used for the treatment of mycobacterial infections, produces hepatic, renal and bone marrow toxicity in human and animals. In this study, the protective effects of vitamin C and n-acetylcysteine (NAC) on the toxicity of rifampin on HepG2 cells were investigated. Human hepatoma cells (HepG2) were cultured in 96-well M of rifampin in the presence of microplate and exposed to 10, 20, 50 and 100 vitamin C (0.1 mg/mL) and NAC (0.2 mg/mL). Protective effect of the two drugs against rifampin toxicity was assessed by MTT assay. Results show that both vitamin C and NAC significantly inhibited HepG2 cellular damage due to rifampin, and vitamin C was relatively more potent than NAC. Rifampin is metabolized by the liver and its toxic metabolites are responsible for the drug›s hepatic toxicity. Based on our results, it seems that reactive metabolites are the main agents responsible for rifampin hepatotoxicity. The importance of this finding is that if vitamin C or NAC do not affect the antibacterial activity of rifampin, they could be used as preventive agents in rifampin users.}, }
@article {pmid24248151, year = {2014}, author = {Sun, X and Sun, M and Xie, Y and Zhai, W and Zhu, W and Ma, R and Lu, R and Xu, W}, title = {Cytotoxic effects of acrylonitrile on human umbilical cord mesenchymal stem cells in vitro.}, journal = {Molecular medicine reports}, volume = {9}, number = {1}, pages = {97-102}, doi = {10.3892/mmr.2013.1802}, pmid = {24248151}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Acrylonitrile/*toxicity ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Differentiation/drug effects ; Cells, Cultured ; Humans ; Mesenchymal Stem Cells/cytology/*drug effects ; Osteogenesis/drug effects ; Umbilical Cord/*cytology ; }, abstract = {The effects of acrylonitrile (ACN) on human umbilical cord mesenchymal stem cells (hUC‑MSCs) remain unknown. The proliferation, differentiation, clonogenicity and apoptosis effects of ACN and/or N‑acetyl‑L‑cysteine (NAC) on hUC‑MSCs were investigated. The results showed that although ACN at a concentration of 0.1 µg/ml did not affect proliferation or the morphology of hUC‑MSCs compared with the control, osteogenic differentiation and the positive rate of alkaline phosphatase staining in the experimental group were significantly lower compared with the control (P<0.01). All of the effects of ACN were counteracted using NAC, a typical antioxidant. Using a flow cytometry assay, it was observed that ACN induced apoptosis in hUC‑MSCs. The results indicated that the toxic effect produced by ACN on hUC‑MSCs is based on a redox mechanism.}, }
@article {pmid24244749, year = {2013}, author = {Seo, JB and Gowda, GA and Koh, DS}, title = {Apoptotic damage of pancreatic ductal epithelia by alcohol and its rescue by an antioxidant.}, journal = {PloS one}, volume = {8}, number = {11}, pages = {e81893}, pmid = {24244749}, issn = {1932-6203}, support = {R01 DK080840/DK/NIDDK NIH HHS/United States ; R01-DK080840/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaldehyde/pharmacology ; Acetylcysteine/metabolism ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cells, Cultured ; Epithelial Cells/*cytology/drug effects/*metabolism ; Ethanol/*pharmacology ; Humans ; Pancreatic Ducts/*cytology ; Reactive Oxygen Species/metabolism ; }, abstract = {Alcohol abuse is a major cause of pancreatitis. However alcohol toxicity has not been fully elucidated in the pancreas and little is known about the effect of alcohol on pancreatic ducts. We report the molecular mechanisms of ethanol-induced damage of pancreatic duct epithelial cells (PDEC). Ethanol treatment for 1, 4, and 24 h resulted in cell death in a dose-dependent manner. The ethanol-induced cell damage was mainly apoptosis due to generation of reactive oxygen species (ROS), depolarization of mitochondrial membrane potential (MMP), and activation of caspase-3 enzyme. The antioxidant N-acetylcysteine (NAC) attenuated these cellular responses and reduced cell death significantly, suggesting a critical role for ROS. Acetaldehyde, a metabolic product of alcohol dehydrogenase, induced significant cell death, depolarization of MMP, and caspase-3 activation as ethanol and this damage was also averted by NAC. Reverse transcription-polymerase chain reaction revealed the expression of several subtypes of alcohol dehydrogenase and acetaldehyde dehydrogenase. Nuclear magnetic resonance spectroscopy data confirmed the accumulation of acetaldehyde in ethanol-treated cells, suggesting that acetaldehyde formation can contribute to alcohol toxicity in PDEC. Finally, ethanol increased the leakage of PDEC monolayer which was again attenuated by NAC. In conclusion, ethanol induces apoptosis of PDEC and thereby may contribute to the development of alcohol-induced pancreatitis.}, }
@article {pmid24243578, year = {2014}, author = {Avalos, A and Haza, AI and Mateo, D and Morales, P}, title = {Cytotoxicity and ROS production of manufactured silver nanoparticles of different sizes in hepatoma and leukemia cells.}, journal = {Journal of applied toxicology : JAT}, volume = {34}, number = {4}, pages = {413-423}, doi = {10.1002/jat.2957}, pmid = {24243578}, issn = {1099-1263}, mesh = {Acetylcysteine/pharmacology ; Cell Culture Techniques ; Cell Survival/drug effects ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; HL-60 Cells ; Hep G2 Cells ; Humans ; Metal Nanoparticles/chemistry/*toxicity ; Microscopy, Electron, Transmission ; Particle Size ; Reactive Oxygen Species/*metabolism ; Silver/chemistry/*toxicity ; Superoxide Dismutase/metabolism ; Surface Properties ; }, abstract = {Silver nanoparticles (AgNPs), which have well-known antimicrobial properties, are extensively used in various medical and general applications. In spite of the widespread use of AgNPs, relatively few studies have been undertaken to determine the cytotoxic effects of AgNPs. The aim of this study was investigate how AgNPs of different sizes (4.7 and 42 nm) interact with two different tumoral human cell lines (hepatoma [HepG2] and leukemia [HL-60]). In addition, glutathione depletion, inhibition of superoxide dismutase (SOD) and reactive oxygen species (ROS) generation were used to evaluate feasible mechanisms by which AgNPs exerted its toxicity. AgNPs of 4.7 nm and 42 nm exhibited a dramatic difference in cytotoxicity. Small AgNPs were much more cytotoxic than large AgNPs. A difference in the cellular response to AgNPs was found. HepG2 cells showed a higher sensitivity to the AgNPs than HL-60. However, the cytotoxicity induced by AgNPs was efficiently prevented by NAC treatment, which suggests that oxidative stress is primarily responsible for the cytotoxicity of AgNPs. Furthermore, cellular antioxidant status was disturbed: AgNPs exposure caused ROS production, glutathione depletion and slight, but not statistically significant inactivation of SOD.}, }
@article {pmid24240787, year = {2013}, author = {Sakamoto, S and Itoh, T and Muramatsu, Y and Satoh, K and Ishida, F and Sugino, K and Isobe, K and Homma, S}, title = {Efficacy of pirfenidone in patients with advanced-stage idiopathic pulmonary fibrosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {52}, number = {22}, pages = {2495-2501}, doi = {10.2169/internalmedicine.52.8498}, pmid = {24240787}, issn = {1349-7235}, mesh = {Acetylcysteine/administration &amp; dosage ; Administration, Inhalation ; Aged ; Aged, 80 and over ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/therapeutic use ; Antioxidants/administration &amp; dosage/therapeutic use ; Disease Progression ; Drug Therapy, Combination ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/physiopathology ; Male ; Middle Aged ; Pyridones/administration &amp; dosage/*therapeutic use ; Retrospective Studies ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {OBJECTIVE: To assess the efficacy of pirfenidone in patients with advanced-stage idiopathic pulmonary fibrosis (IPF), we conducted a retrospective study of patients who received pirfenidone therapy. In addition, the combined effects of inhaled N-acetylcysteine (NAC) and pirfenidone were evaluated.<br><br>METHODS: Eligible patients had a clinical and radiologic diagnosis of advanced-stage IPF (stages of severity III&amp;IV). Patients who exhibited a relative decline in forced vital capacity (FVC) of 10% or more within the preceding six (&#xb1;2) months were enrolled. The outcome was evaluated from the date of the 6-month follow-up PFT. Relative declines in FVC of more than 10% were defined as progressive disease (ineffective group), while those less than 10% were defined as stable disease (effective group). The clinical features were compared between the two groups. We also compared the efficacy of the combined therapy with inhaled NAC and pirfenidone (n=11) with that of pirfenidone alone (n=7).<br><br>RESULTS: Eighteen patients 59-82 years of age with IPF who received pirfenidone therapy were reviewed. Pirfenidone stabilized declines in FVC by 10% at six months in eight of the 18 cases (44%). The median changes in FVC at six months were +120 mL in the effective group and -590 mL in the ineffective group. The number of NAC users was significantly higher in the effective group (7/8=87.5%) than in the ineffective group (3/10=30%) (p=0.02). Furthermore, the use of combined NAC therapy was correlated with a favorable outcome. The median change in FVC at six months was 0 mL in the NAC group and -290 mL in the non-NAC group. The median survival period was 557 &#xb1; 66 days in the NAC group and 196 &#xb1; 57 days in the non-NAC group (p=0.03).<br><br>CONCLUSION: Among the advanced-stage IPF patients with a more progressive status, pirfenidone decreased the rate of decline in FVC. In addition, patients treated with pirfenidone combined with NAC therapy exhibited favorable outcomes. Additional studies are needed to confirm the efficacy of this combined therapy for IPF.}, }
@article {pmid24239970, year = {2014}, author = {Feng, YL and Tang, XL}, title = {Effect of glucocorticoid-induced oxidative stress on the expression of Cbfa1.}, journal = {Chemico-biological interactions}, volume = {207}, number = {}, pages = {26-31}, doi = {10.1016/j.cbi.2013.11.004}, pmid = {24239970}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Calcification, Physiologic/drug effects/genetics ; Cell Proliferation/drug effects ; Core Binding Factor Alpha 1 Subunit/*genetics/metabolism ; Dexamethasone/pharmacology ; Gene Expression Regulation/drug effects ; Glucocorticoids/*pharmacology ; Osteoblasts/cytology/drug effects/enzymology ; Osteocalcin/metabolism ; Oxidative Stress/*drug effects/genetics ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Staining and Labeling ; }, abstract = {Glucocorticoids therapy is strongly limited since extended glucocorticoids can cause serious side effects, including increased susceptibility to develop the bone disease osteoporosis. Despite its side effects recognized importance to clinicians, seldom is known about how glucocorticoids directly impact bone-forming osteoblasts. Previous studies showed that dexamethasone (DEX) induces excessive production of reactive oxygen species (ROS), and causes oxidative stress in rat hippocampal slice cultures. To assess the implications and investigate the mechanisms of glucocorticoid-elicited osteoporosis, we hypothesize that DEX exposure induces oxidative stress which leads to decreased Cbfa1 mRNA expression, and predict that the antioxidant N-acetylcysteine (NAC) mitigates the damaging effects of DEX. Oxidative stress is implicated in osteoporosis. Furthermore, the osteoblast transcriptional factor Cbfa1 is reported to play a protective role against osteoporosis in postmenopausal women. Cells treated with (0.1, 1, 10μM) DEX exhibited signs of oxidative damages including depletion in total antioxidant capacity (T-AOC), increased ROS formation, and enhanced lipid peroxidation. Cbfa1 mRNA expression, by RT-PCR, was significantly reduced after exposure to (0.1, 1, 10μM) DEX. Pretreatment with the antioxidant NAC (2mM) prevented DEX-induced decrease in Cbfa1 mRNA. This study provides insight into the underlying mechanisms of high dose DEX-induced osteotoxicity. DEX (0.1, 1, 10μM) decreases the expression of Cbfa1 mRNA and inhibits differentiation and function of osteoblasts by inducing oxidative stress. The antioxidant NAC can mitigate the oxidative stress damaging effects of DEX. In addition, this study distinguishes itself by identifying Cbfa1 as a target for high dose DEX-induced osteotoxicity.}, }
@article {pmid24239965, year = {2014}, author = {Basu, S}, title = {A complex interplay between PGC-1 co-activators and mTORC1 regulates hematopoietic recovery following 5-fluorouracil treatment.}, journal = {Stem cell research}, volume = {12}, number = {1}, pages = {178-193}, doi = {10.1016/j.scr.2013.10.006}, pmid = {24239965}, issn = {1876-7753}, mesh = {Animals ; Antimetabolites, Antineoplastic/*pharmacology ; Cell Proliferation/drug effects ; Fluorouracil/*pharmacology ; Hematopoietic Stem Cells/cytology/*drug effects/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism ; Multiprotein Complexes/*metabolism ; Reactive Oxygen Species/metabolism ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/*metabolism ; Transcription Factors/deficiency/genetics/*metabolism ; }, abstract = {In vitro stimulation of HSCs with growth factors generally leads to their depletion. Understanding the molecular mechanisms underlying expansion of HSCs in vivo following myeloablation could lead to successful expansion of HSCs ex vivo for therapeutic purposes. Current findings show that mTORC1 is activated in HSPCs following 5-fluorouracil treatment and that mTORC1 activation is dependent on mitochondrial ETC capacity of HSPCs. Moreover, expression of PGC-1 family members, proteins that regulate mitochondrial biogenesis, in HSPCs following 5-fluorouracil treatment changes; also, these proteins play a stage specific role in hematopoietic recovery. While PRC regulates HSCs' expansion during early recovery phase, PGC-1α regulates progenitor cell proliferation and recovery of hematopoiesis during later phase. During early recovery phase, PRC expression, mitochondrial activity and mTORC1 activation are relatively higher in PGC-1α(-/-) HSCs compared to WT HSCs, and PGC-1α(-/-) HSCs show greater expansion. Administration of rapamycin, but not NAC, during early recovery phase improves WT HSC numbers but decreases PGC-1α(-/-) HSC numbers. The current findings demonstrate that mTOR activation can increase HSC numbers provided that the energy demand created by mTOR activation is successfully met. Thus, critical tuning between mTORC1 activation and mitochondrial ETC capacity is crucial for HSC maintenance/expansion in response to mitogenic stimulation.}, }
@article {pmid24236859, year = {2014}, author = {Sadat, U}, title = {N-acetylcysteine in contrast-induced acute kidney injury: clinical use against principles of evidence-based clinical medicine!.}, journal = {Expert review of cardiovascular therapy}, volume = {12}, number = {1}, pages = {1-3}, doi = {10.1586/14779072.2014.852066}, pmid = {24236859}, issn = {1744-8344}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/chemically induced/diagnosis/*drug therapy ; Contrast Media/*adverse effects ; Evidence-Based Medicine ; Humans ; Kidney/drug effects ; Treatment Outcome ; }, abstract = {Contrast-induced acute kidney injury (CI-AKI) is one of the most widely discussed and debated topic in cardiovascular medicine and N-acetylcysteine (NAC) is the most widely used pharmacological agent assessed in clinical trials for offering renal protection against CI-AKI. Results of these clinical trials are though split between those that favor its use and vice versa. In this brief communication we discuss the latest research advances regarding the use of NAC against CI-AKI. Recent clinical evidence and overview of in-depth statistical analyses of relevant clinical trials and their meta-analyses do not support the use of NAC in prophylaxis against CI-AKI. Adequate hydration before and after contrast media exposure, along with avoidance of nephrotoxic drugs, remains the recommended prophylaxis against CI-AKI.}, }
@article {pmid24235282, year = {2014}, author = {Emmett, M}, title = {Acetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting futile cycle and the other a useful cycle.}, journal = {Clinical journal of the American Society of Nephrology : CJASN}, volume = {9}, number = {1}, pages = {191-200}, pmid = {24235282}, issn = {1555-905X}, mesh = {Acetaminophen/metabolism/*poisoning ; Acid-Base Equilibrium/drug effects ; Acidosis/*chemically induced/metabolism/therapy ; Adenosine Triphosphate/*metabolism ; Analgesics, Non-Narcotic/metabolism/*poisoning ; Animals ; Cysteine/deficiency ; Energy Metabolism/*drug effects ; Glutathione/deficiency ; Humans ; Poisoning/etiology/metabolism ; Prognosis ; Pyrrolidonecarboxylic Acid/*metabolism ; Substrate Cycling ; }, abstract = {The acquired form of 5-oxoproline (pyroglutamic acid) metabolic acidosis was first described in 1989 and its relationship to chronic acetaminophen ingestion was proposed the next year. Since then, this cause of chronic anion gap metabolic acidosis has been increasingly recognized. Many cases go unrecognized because an assay for 5-oxoproline is not widely available. Most cases occur in malnourished, chronically ill women with a history of chronic acetaminophen ingestion. Acetaminophen levels are very rarely in the toxic range; rather, they are usually therapeutic or low. The disorder generally resolves with cessation of acetaminophen and administration of intravenous fluids. Methionine or N-acetyl cysteine may accelerate resolution and methionine is protective in a rodent model. The disorder has been attributed to glutathione depletion and activation of a key enzyme in the γ-glutamyl cycle. However, the specific metabolic derangements that cause the 5-oxoproline accumulation remain unclear. An ATP-depleting futile 5-oxoproline cycle can explain the accumulation of 5-oxoproline after chronic acetaminophen ingestion. This cycle is activated by the depletion of both glutathione and cysteine. This explanation contributes to our understanding of acetaminophen-induced 5-oxoproline metabolic acidosis and the beneficial role of N-acetyl cysteine therapy. The ATP-depleting futile 5-oxoproline cycle may also play a role in the energy depletions that occur in other acetaminophen-related toxic syndromes.}, }
@article {pmid24225120, year = {2013}, author = {Ding, L and Zhao, X and Huang, Y and Du, Q and Dong, F and Zhang, H and Song, X and Zhang, W and Tong, D}, title = {Regulation of ROS in transmissible gastroenteritis virus-activated apoptotic signaling.}, journal = {Biochemical and biophysical research communications}, volume = {442}, number = {1-2}, pages = {33-37}, pmid = {24225120}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Cell Line ; Free Radical Scavengers/pharmacology ; Gastroenteritis, Transmissible, of Swine/*metabolism/*pathology/virology ; Membrane Potential, Mitochondrial ; Oxidative Stress ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Swine ; Thiocarbamates/pharmacology ; Transmissible gastroenteritis virus/*metabolism ; Tumor Suppressor Protein p53/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Transmissible gastroenteritis virus (TGEV), an enteropathogenic coronavirus, causes severe lethal watery diarrhea and dehydration in piglets. Previous studies indicate that TGEV infection induces cell apoptosis in host cells. In this study, we investigated the roles and regulation of reactive oxygen species (ROS) in TGEV-activated apoptotic signaling. The results showed that TGEV infection induced ROS accumulation, whereas UV-irradiated TGEV did not promote ROS accumulation. In addition, TGEV infection lowered mitochondrial transmembrane potential in PK-15 cell line, which could be inhibited by ROS scavengers, pyrrolidinedithiocarbamic (PDTC) and N-acetyl-l-cysteine (NAC). Furthermore, the two scavengers significantly inhibited the activation of p38 MAPK and p53 and further blocked apoptosis occurrence through suppressing the TGEV-induced Bcl-2 reduction, Bax redistribution, cytochrome c release and caspase-3 activation. These results suggest that oxidative stress pathway might be a key element in TGEV-induced apoptosis and TGEV pathogenesis.}, }
@article {pmid24223941, year = {2013}, author = {Liu, D and Zhang, H and Gu, W and Liu, Y and Zhang, M}, title = {Neuroprotective effects of ginsenoside Rb1 on high glucose-induced neurotoxicity in primary cultured rat hippocampal neurons.}, journal = {PloS one}, volume = {8}, number = {11}, pages = {e79399}, pmid = {24223941}, issn = {1932-6203}, mesh = {Animals ; Apoptosis/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/drug effects ; Ginsenosides/*pharmacology ; Glucose/*toxicity ; Hippocampus/*cytology ; Mitochondria/drug effects ; Neurons/cytology/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Ginsenoside Rb1 is one of the main active principles in traditional herb ginseng and has been reported to have a wide variety of neuroprotective effects. Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, so the present study aimed to observe the effects of ginsenoside Rb1 on ER stress signaling pathways in high glucose-treated hippocampal neurons. The results from MTT, TUNEL labeling and Annexin V-FITC/PI/Hoechst assays showed that incubating neurons with 50 mM high glucose for 72 h decreased cell viability and increased the number of apoptotic cells whereas treating neurons with 1 μM Rb1 for 72 h protected the neurons against high glucose-induced cell damage. Further molecular mechanism study demonstrated that Rb1 suppressed the activation of ER stress-associated proteins including protein kinase RNA (PKR)-like ER kinase (PERK) and C/EBP homology protein (CHOP) and downregulation of Bcl-2 induced by high glucose. Moreover, Rb1 inhibited both the elevation of intracellular reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential induced by high glucose. In addition, the high glucose-induced cell apoptosis, activation of ER stress, ROS accumulation and mitochondrial dysfunction can also be attenuated by the inhibitor of ER stress 4-phenylbutyric acid (4-PBA) and anti-oxidant N-acetylcysteine(NAC). In conclusion, these results suggest that Rb1 may protect neurons against high glucose-induced cell injury through inhibiting CHOP signaling pathway as well as oxidative stress and mitochondrial dysfunction.}, }
@article {pmid24222291, year = {2013}, author = {Sharma, M and Verma, N}, title = {N-acetyl cysteine in non-acetaminophen pediatric acute liver failure: recent evidence!.}, journal = {Indian pediatrics}, volume = {50}, number = {10}, pages = {972}, doi = {10.1007/s13312-013-0246-2}, pmid = {24222291}, issn = {0974-7559}, mesh = {Humans ; Liver Failure, Acute/*diagnosis/*therapy ; Liver Transplantation/*standards ; }, }
@article {pmid24221993, year = {2013}, author = {Jung, KH and Lee, JH and Thien Quach, CH and Paik, JY and Oh, H and Park, JW and Lee, EJ and Moon, SH and Lee, KH}, title = {Resveratrol suppresses cancer cell glucose uptake by targeting reactive oxygen species-mediated hypoxia-inducible factor-1α activation.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {54}, number = {12}, pages = {2161-2167}, doi = {10.2967/jnumed.112.115436}, pmid = {24221993}, issn = {1535-5667}, mesh = {Animals ; Biological Transport/drug effects ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Fluorodeoxyglucose F18/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Glucose/*metabolism ; Glucose Transporter Type 1/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Lactic Acid/biosynthesis ; Mice ; Reactive Oxygen Species/*metabolism ; Resveratrol ; Signal Transduction/drug effects ; Stilbenes/*pharmacology ; }, abstract = {UNLABELLED: Resveratrol is gaining attention for its anticancer effects and is also recognized for its antioxidant properties and influence on glucose metabolism. Augmented reactive oxygen species (ROS) and high glycolytic flux are common characteristics of malignant cells. We thus evaluated the effect of resveratrol on cancer cell glucose metabolism and investigated the role of ROS in the response.<br><br>METHODS: Cancer cells were measured for cell content and (18)F-FDG uptake. Assays were performed for lactate production; hexokinase activity and intracellular ROS; and immunoblotting for hypoxia-inducible factor-1&#x3b1; (HIF-1&#x3b1;), Akt, mammalian target of rapamycin, and glucose transporter type 1 (Glut-1). Animal studies were performed with small-animal PET imaging of Lewis lung carcinoma tumor-bearing mice.<br><br>RESULTS: Resveratrol mildly decreased cell content and more pronouncedly suppressed (18)F-FDG uptake in Lewis lung carcinoma, HT-29 colon, and T47D breast cancer cells. Hence, (18)F-FDG uptake normalized to cell content was reduced to less than half of controls by 24-h exposure to resveratrol. This reduction was attributed to reduced glycolytic flux and Glut-1 expression. Resveratrol also decreased intracellular ROS in patterns that closely paralleled (18)F-FDG uptake. Scavenging of ROS with N-acetyl cysteine, but not inhibition of nicotinamide adenine dinucleotide phosphate oxidase, was sufficient to suppress (18)F-FDG uptake. Conversely, ROS inducers effectively reversed the metabolic response of resveratrol. HIF-1&#x3b1; protein was markedly reduced by resveratrol, and inhibiting HIF-1&#x3b1; expression with cycloheximide or specific small interfering RNAs suppressed (18)F-FDG uptake. The proteosomal inhibitor MG132 partly restored HIF-1&#x3b1; level and (18)F-FDG uptake in resveratrol-treated cells. Resveratrol also inhibited Akt activation; in addition, inhibitors and small interfering RNAs against phosphoinositide 3-kinase decreased (18)F-FDG uptake. Finally, small-animal PET results showed resveratrol treatment to suppress tumor (18)F-FDG uptake in vivo.<br><br>CONCLUSION: Resveratrol suppresses cancer cell (18)F-FDG uptake and glycolytic metabolism in a manner that depends on the capacity of resveratrol to inhibit intracellular ROS, which downregulates HIF-1&#x3b1; accumulation.}, }
@article {pmid24217988, year = {2014}, author = {Papiris, SA and Kagouridis, K and Papadaki, G and Kolilekas, L and Manali, ED}, title = {Treating CTDs related fibrotic ILDs by immunosuppressants: "facts and faults".}, journal = {Lung}, volume = {192}, number = {2}, pages = {221-223}, pmid = {24217988}, issn = {1432-1750}, mesh = {Anti-Inflammatory Agents/*therapeutic use ; Cyclophosphamide/*therapeutic use ; Female ; Humans ; Lung Diseases, Interstitial/*drug therapy/*etiology ; Male ; Mycophenolic Acid/*analogs &amp; derivatives ; Scleroderma, Systemic/*complications ; }, abstract = {Fibrotic interstitial lung diseases (ILDs) are commonly encountered in scleroderma where they significantly influence prognosis. The mainstay of treatment in idiopathic fibrotic ILDs for the past 30 years was based on the combined administration of prednisone and cyclophosphamide (CYC) or prednisone, azathioprine plus N-acetyl cysteine, recently proved ineffective and harmful. Rheumatologists also despite "facts" showing that CYC treatment has no beneficial impact on fibrotic ILDs in scleroderma continue to commit the same, in a manner of speaking, "faults" by "treating their fibrotic ILDs by immunosuppressants." In this issue of the journal, Panopoulos et al. (Lung, 191, 483-489, 2013) recognizing the minimal effect of CYC on fibrotic ILDs in scleroderma patients and the increased use in clinical practice of mycophenolate mofetil (MMF) as an alternative, report that MMF use to replace CYC in this setting is not supported, confirming that restoration of purely fibrotic damage in the lungs remains one of the most challenging fields in medicine.}, }
@article {pmid24217896, year = {2014}, author = {Kumar, A and Sasmal, D and Sharma, N}, title = {Deltamethrin induced an apoptogenic signalling pathway in murine thymocytes : exploring the molecular mechanism.}, journal = {Journal of applied toxicology : JAT}, volume = {34}, number = {12}, pages = {1303-1310}, doi = {10.1002/jat.2948}, pmid = {24217896}, issn = {1099-1263}, mesh = {Animals ; Apoptosis/*drug effects/immunology ; CD4 Antigens/metabolism ; Cell Cycle/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Flow Cytometry ; Glutathione/metabolism ; Insecticides/*toxicity ; Male ; Mice, Inbred BALB C ; Molecular Docking Simulation ; Nitriles/*toxicity ; Protein Binding ; Pyrethrins/*toxicity ; Reactive Oxygen Species/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction/*drug effects/immunology ; Thymocytes/*drug effects/immunology/pathology ; }, abstract = {Deltamethrin (DLM) is a well-known pyrethroid insecticide; however, the immunotoxic effects of DLM on the mammalian system and its mechanism is still unclear. This study has been designed to first observe the binding affinity of DLM to immune cell receptors and its effects on the immune system. The docking score revealed that DLM has a strong binding affinity towards the CD4 and CD8 receptors. DLM induces apoptosis in murine thymocytes in a concentration-dependent manner. The ear\ly markers of apoptosis such as enhanced reactive oxygen species (ROS) and caspase-3 activation are evident as early as 1 h by 25 and 50 μM DLM. Glutathione (GSH) depletion has also been observed at 1 h by 50 μM DLM concentration. In cell-cycle studies using flow cytometry, the fraction of hypodiploid cells has gradually increased with all the concentrations of DLM at 18 h. The Annexin V binding assay measures the effect of DLM on apoptotic and necrotic cells. The apoptotic cells raised from 18.6% to 35.21% (10-50 μM DLM) at 18 h. N-acetyl cysteine (NAC) effectively reduced the percentage of apoptotic cells which is increased by DLM. In contrast, buthionine sulfoximine (BSO) caused an elevation in the percentage of apoptotic cells. These results demonstrate that caspase activation, ROS activation and GSH act as critical mediators in a DLM-induced apoptogenic signalling pathway in murine thymocytes. In the presence of caspase inhibitor, the percentage of apoptotic cells is partially decreased. Thus, there may be the possibility of some other caspase-independent pathways in DLM-induced apoptosis.}, }
@article {pmid24214724, year = {2014}, author = {Scaini, G and Jeremias, GC and Furlanetto, CB and Dominguini, D and Comim, CM and Quevedo, J and Schuck, PF and Ferreira, GC and Streck, EL}, title = {Behavioral responses in rats submitted to chronic administration of branched-chain amino acids.}, journal = {JIMD reports}, volume = {13}, number = {}, pages = {159-167}, pmid = {24214724}, issn = {2192-8304}, abstract = {Maple syrup urine disease (MSUD) is an inborn metabolism error caused by a deficiency of branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to an accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their corresponding α-keto and α-hydroxy acids. Previous reports suggest that MSUD patients are at high risk for chronic neuropsychiatric problems. Therefore, in this study, we assessed variables that suggest depressive-like symptoms (anhedonia as measured by sucrose intake, immobility during the forced swimming test and body and adrenal gland weight) in rats submitted to chronic administration of BCAA during development. Furthermore, we determined if these parameters were sensitive to imipramine and N-acetylcysteine/deferoxamine (NAC/DFX). Our results demonstrated that animals subjected to chronic administration of branched-chain amino acids showed a decrease in sucrose intake without significant changes in body weight. We also observed an increase in adrenal gland weight and immobility time during the forced swimming test. However, treatment with imipramine and NAC/DFX reversed these changes in the behavioral tasks. In conclusion, this study demonstrates a link between MSUD and depression in rats. Moreover, this investigation reveals that the antidepressant action of NAC/DFX and imipramine might be associated with their capability to maintain pro-/anti-oxidative homeostasis.}, }
@article {pmid24214100, year = {2013}, author = {Rothbart, R and Amos, T and Siegfried, N and Ipser, JC and Fineberg, N and Chamberlain, SR and Stein, DJ}, title = {Pharmacotherapy for trichotillomania.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {11}, pages = {CD007662}, doi = {10.1002/14651858.CD007662.pub2}, pmid = {24214100}, issn = {1469-493X}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Benzodiazepines/therapeutic use ; Clomipramine/therapeutic use ; Humans ; Naltrexone/therapeutic use ; Olanzapine ; Randomized Controlled Trials as Topic ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Trichotillomania/*drug therapy ; }, abstract = {BACKGROUND: Trichotillomania (TTM) (hair-pulling disorder) is a prevalent and disabling disorder characterised by recurrent hair-pulling. The effect of medication on trichotillomania has not been systematically evaluated.<br><br>OBJECTIVES: To assess the effects of medication for trichotillomania in adults compared with placebo or other active agents.<br><br>SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (to 31 July 2013), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years); EMBASE (1974 to date); MEDLINE (1950 to date) and PsycINFO (1967 to date). Two review authors identified relevant trials by assessing the abstracts of all possible studies.<br><br>SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of a medication versus placebo or active agent for TTM in adults.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently performed the data extraction and 'Risk of bias' assessments, and disagreements were resolved through discussion with a third review author. Primary outcomes included the mean difference (MD) in reduction of trichotillomania symptoms on a continuous measure of trichotillomania symptom severity, and the risk ratio (RR) of the clinical response based on a dichotomous measure, with 95% confidence intervals (CIs).<br><br>MAIN RESULTS: We identified eight studies with a total of 204 participants and a mean sample size of 25. All trials were single-centre trials, and participants seen on an outpatient basis. Seven studies compared medication and placebo (n = 184); one study compared medication and another active agent (n = 13). Duration of the studies was six to twelve weeks. Meta-analysis was not undertaken because of the methodological heterogeneity of the trials. The studies did not employ intention-to-treat analyses and were at a high risk of attrition bias. Adverse events were not well-documented in the studies.None of the three studies of selective serotonin reuptake inhibitors (SSRIs) demonstrated strong evidence of a treatment effect on any of the outcomes of interest. The unpublished naltrexone study did not provide strong evidence of a treatment effect. Two studies, an olanzapine study and a N-acetylcysteine (NAC) study, reported statistically significant treatment effects. One study of clomipramine demonstrated a treatment effect on two out of three measures of response to treatment.<br><br>AUTHORS' CONCLUSIONS: No particular medication class definitively demonstrates efficacy in the treatment of trichotillomania. Preliminary evidence suggests treatment effects of clomipramine, NAC and olanzapine based on three individual trials, albeit with very small sample sizes.}, }
@article {pmid24211992, year = {2014}, author = {Jiang, J and Yuan, X and Zhao, H and Yan, X and Sun, X and Zheng, Q}, title = {Licochalcone A inhibiting proliferation of bladder cancer T24 cells by inducing reactive oxygen species production.}, journal = {Bio-medical materials and engineering}, volume = {24}, number = {1}, pages = {1019-1025}, doi = {10.3233/BME-130899}, pmid = {24211992}, issn = {1878-3619}, mesh = {Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Chalcones/*pharmacology ; Dose-Response Relationship, Drug ; Fluoresceins/chemistry ; Glutathione/metabolism ; Glycyrrhiza/chemistry ; Humans ; Oxidative Stress ; Plant Extracts/chemistry ; Reactive Oxygen Species/*metabolism ; Rhodamines/chemistry ; Urinary Bladder Neoplasms/*pathology ; }, abstract = {The aim of this study was to determine the relationship between proliferation inhibition and the production of reactive oxygen species (ROS) induced by Licochalcone A (LCA). Cell viability was evaluated using sulforhodamine B (SRB) assay. Intracellular ROS level was assessed using the 2, 7-dichlorofluorescein diacetate (H2DCFDA) probe and dihydroethidium (DHE) probe assay. The results indicate that LCA inhibits human bladder cancer T24 proliferation in a concentration-dependent manner, with an IC50 value of approximately 55 μM. The LCA-induced ROS production is inhibited by the co-treatment of LCA and free radical scavenger N-acetyl-cysteine (NAC), on the contrary, the proliferation rate and ROS production increase when treated by the combination of LCA and L-buthionine-(S,R)-sulfoximine (BSO). The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) decreases in a concentration-dependent manner. The results suggest that LCA inhibits proliferation by increasing intracellular ROS levels resulted in an oxidative stress status in T24 cells.}, }
@article {pmid24211866, year = {2014}, author = {Zhang, Z and Zhang, C and Ding, Y and Zhao, Q and Yang, L and Ling, J and Liu, L and Ji, H and Zhang, Y}, title = {The activation of p38 and JNK by ROS, contribute to OLO-2-mediated intrinsic apoptosis in human hepatocellular carcinoma cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {63}, number = {}, pages = {38-47}, doi = {10.1016/j.fct.2013.10.043}, pmid = {24211866}, issn = {1873-6351}, mesh = {Apoptosis/*drug effects ; Blotting, Western ; Carcinoma, Hepatocellular/enzymology/metabolism/*pathology ; Cell Line, Tumor ; Enzyme Activation ; Enzyme Activators/*pharmacology ; Humans ; Liver Neoplasms/enzymology/metabolism/*pathology ; MAP Kinase Kinase 4/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Oleanolic Acid/*analogs &amp; derivatives/*pharmacology ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {In this study, we describe that a novel synthesized compound, olean-28,13β-olide 2 (OLO-2), exhibits selective cytotoxic activity via inducing apoptosis in human hepatocellular carcinoma (HCC) cell lines but not normal human hepatic cells in vitro. Exposure of human HCC HepG2 cells to OLO-2 results in significant loss of mitochondrial transmembrane potential (ΔΨm), the release of cytochrome c, the recruitment of B-cell lymphoma 2 (Bcl-2) assaciated X protein (Bax) and the downregulation of Bcl-2. The apoptosis induced by OLO-2 is associated with the activation of caspase-3/9 and the nuclear translocation of apoptosis inducing factor (AIF). Moreover, the increase of phosphorylated p38 and c-Jun N-terminal kinase (JNK) is observed. OLO-2-induced the externalization of phosphatidyl-serine (PS) and the loss of ΔΨm are blocked by p38 inhibitor SB203580 or JNK inhibitor SP600125. In addition, OLO-2 provokes the generation of reactive oxygen species (ROS) in HepG2 cells, while the antioxidant N-acetyl cysteine (NAC) almost completely blocks OLO-2-induced apoptosis and the activation of p38 and JNK. Taken together, the present study demonstrates that OLO-2 exhibits its cytotoxic activity through intrinsic apoptosis via ROS generation and the activation of p38 and JNK. Its potential to be a candidate of anti-cancer agent is worth being further investigated.}, }
@article {pmid24211779, year = {2013}, author = {Haidari, M and Zhang, W and Wakame, K}, title = {Disruption of endothelial adherens junction by invasive breast cancer cells is mediated by reactive oxygen species and is attenuated by AHCC.}, journal = {Life sciences}, volume = {93}, number = {25-26}, pages = {994-1003}, doi = {10.1016/j.lfs.2013.10.027}, pmid = {24211779}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Adherens Junctions/*drug effects ; Antigens, CD/metabolism ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/pharmacology ; Breast Neoplasms/*drug therapy/*metabolism/*pathology ; Cadherins/metabolism ; Cell Movement/*drug effects ; Endothelial Cells/drug effects ; Endothelium, Vascular/drug effects/metabolism ; Female ; Human Umbilical Vein Endothelial Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Male ; Ovarian Neoplasms/drug therapy/metabolism/pathology ; Plant Extracts/*pharmacology ; Prostatic Neoplasms/drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Cells, Cultured ; Tyrosine/metabolism ; beta Catenin/metabolism ; }, abstract = {AIMS: The effect of antioxidants on treatment of cancer is still controversial. Previously, we demonstrated that interaction of breast cancer cells with endothelial cells leads to tyrosine phosphorylation of VE-cadherin and disruption of endothelial adherens junction (EAJ). The molecular mechanism underlying the anti-metastatic effects of mushroom-derived active hexode correlated compound (AHCC) remains elusive.<br><br>MAIN METHODS: Several cellular and biochemical techniques were used to determine the contribution of oxidative stress in the disruption of EAJ and to test this hypothesis that AHCC inhibits the breast cancer cell-induced disruption of EAJ.<br><br>KEY FINDINGS: Interaction of breast cancer cells (MDA-MB-231 cells) with human umbilical vein endothelial cells (HUVECs) leads to an increase in generation of reactive oxygen species (ROS). Treatment of HUVECs with H2O2 or phorbol myristate acetate (PMA) led to tyrosine phosphorylation of VE-cadherin, dissociation of &#x3b2;-catenin from VE-cadherin complex and increased transendothelial migration (TEM) of MDA-MB-231 cells. Induction of VE-cadherin tyrosine phosphorylation by PMA or by interaction of MDA-MB-231 cells with HUVECs was mediated by HRas and protein kinase C-&#x3b1; signaling pathways. Disruption of EAJ and phosphorylation of VE-cadherin induced by interaction of MDA-MB-231 cells with HUVECs were attenuated when HUVECs were pretreated with an antioxidant, N-acetylcysteine (NAC) or AHCC. AHCC inhibited TEM of MDA-MB-231 cells and generation of ROS induced by interaction of MDA-MB-231 cells with HUVECs.<br><br>SIGNIFICANCE: Our studies suggest that ROS contributes to disruption of EAJ induced by interaction of MDA-MB-231 cells with HUVECs and AHCC attenuates this alteration.}, }
@article {pmid24211316, year = {2014}, author = {Sinojia, R and Shaikh, M and Kodgule, R and Bhosale, S and Madas, S and Vaidya, A and Salvi, S and Brashier, B}, title = {Priming of beta-2 agonist and antimuscarinic induced physiological responses induced by 1200mg/day NAC in moderate to severe COPD patients: A pilot study.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {191}, number = {}, pages = {52-59}, doi = {10.1016/j.resp.2013.10.010}, pmid = {24211316}, issn = {1878-1519}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Albuterol/therapeutic use ; Antioxidants/*therapeutic use ; Bronchodilator Agents/*therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Ipratropium/therapeutic use ; Male ; Middle Aged ; Muscarinic Antagonists/*therapeutic use ; Pilot Projects ; Plethysmography ; Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology ; Spirometry ; Statistics, Nonparametric ; Total Lung Capacity/drug effects ; }, abstract = {UNLABELLED: This study evaluated antioxidant modulations of lung physiological-responses to beta-2-agonist and antimuscarinic bronchodilators with 1200mg/day n-acetyl-cysteine (NAC) in a placebo-controlled, randomised, double-blind, parallel-group study, in moderate-very severe COPD patients.<br><br>METHODS: 15 COPD patients received NAC treatment, while 9 COPD patients received placebo treatment, for 15 days. Pre-and-post salbutamol and ipratopium-bromide lung-physiology responses were measured using body-plethysmography, impulse-oscillometry (IOS) and spirometry before-and-after study treatments.<br><br>RESULTS: Compared to pre-treatment, the NAC-treatment significantly enhanced the potential of ipratopium-bromide to reduce functional-residual-capacity (FRC) by nearly 3-folds (mean% FRC-response: pre-NAC: -5.51%&#xb1;10.42% versus post-NAC: -17.89%&#xb1;12.94%, p=0.02; mean-absolute FRC-response: pre-NAC: -300ml&#xb1;450ml versus post-NAC: -770ml&#xb1;550ml, p=0.02), which was superior to placebo-treatment. The increase in total-lung-capacity response to ipratopium-bromide, although insignificant, was superior with post-NAC treatment versus post-placebo treatment (p=0.049). The salbutamol-response remained unaltered with either treatment.<br><br>CONCLUSION: The treatment with 1200mg/day NAC has potential to enhance the bronchodilator ability of antimuscarinic-agents but not beta-2-agonist. However, its clinical application has to be established in large sample-size studies for longer-duration.}, }
@article {pmid24211203, year = {2013}, author = {Wang, Y and Tang, Q and Jiang, S and Li, M and Wang, X}, title = {Anti-colorectal cancer activity of macrostemonoside A mediated by reactive oxygen species.}, journal = {Biochemical and biophysical research communications}, volume = {441}, number = {4}, pages = {825-830}, doi = {10.1016/j.bbrc.2013.10.148}, pmid = {24211203}, issn = {1090-2104}, mesh = {Animals ; Antineoplastic Agents/chemistry/*therapeutic use ; Apoptosis/drug effects ; Caco-2 Cells ; Carcinogenesis/drug effects ; Cell Proliferation/drug effects ; Colorectal Neoplasms/*drug therapy ; Drugs, Chinese Herbal/chemistry/*therapeutic use ; Humans ; Mice ; Mice, Nude ; Reactive Oxygen Species/*metabolism ; Saponins/chemistry/*therapeutic use ; Steroids/chemistry/*therapeutic use ; Xenograft Model Antitumor Assays ; }, abstract = {Macrostemonoside A (MSS.A), an active steroidal saponin from Allium macrostemon Bung has been shown to possess anti-coagulation and anti-obesity effects. However, the functional role of MSS.A on tumor growth has not been elucidated. We found that MSS.A significantly inhibited human colorectal cancer cell growth in Caco2 and SW480 cells. Incubation of SW480 cells with MSS.A for 48 h resulted in cell cycle arrest. Moreover, MSS.A dose-dependently induced apoptosis in SW480 cells as shown by increased AnnexinV positively stained cell population, caspase activation, increased pro-apoptotic and reduced anti-apoptotic Bcl-2 family protein levels. Treatment of SW480 cells with MSS.A resulted in increased reactive oxygen species (ROS) generation. However, pre-incubation of SW480 cells with antioxidant N-acetylcysteine (NAC) attenuated the ROS generation and anti-colorectal cancer activities of MSS.A. Lastly, intra-peritoneal injections of MSS.A significantly inhibited tumor formation in BALB/c nude mice carcinogenesis xenograft model by reduced tumor volume and tumor weight when treated at dosages of 10, 50 or 100mg/kg daily for 35 days compared with PBS control. Taken together, our results indicate that MSS.A suppressed colorectal cancer growth and induced cell apoptosis by inducing ROS production, and that MSS.A may have therapeutic relevance in the treatment of human colorectal cancer.}, }
@article {pmid24206124, year = {2013}, author = {Flora, SJ and Shrivastava, R and Mittal, M}, title = {Chemistry and pharmacological properties of some natural and synthetic antioxidants for heavy metal toxicity.}, journal = {Current medicinal chemistry}, volume = {20}, number = {36}, pages = {4540-4574}, doi = {10.2174/09298673113209990146}, pmid = {24206124}, issn = {1875-533X}, mesh = {Animals ; Antioxidants/*chemistry/*pharmacology ; Chelating Agents/*chemistry/*pharmacology ; Chelation Therapy/*methods ; Free Radicals/chemistry ; *Heavy Metal Poisoning ; Humans ; Oxidative Stress/drug effects ; Poisoning/*drug therapy ; }, abstract = {Heavy metals are known to cause oxidative deterioration of bio-molecules by initiating free radical mediated chain reaction resulting in lipid per-oxidation, protein oxidation and oxidation of nucleic acid like DNA and RNA. The development of effective dual functioning antioxidants, possessing both metal-chelating and free radical-scavenging properties should bring into play. Administration of natural and synthetic antioxidants like, quercetin, catechin, taurine, captopril, gallic acid, melatonin, N-acetyl cysteine, α- lipoic acid and others have been recognized in the disease prevention and clinical recovery against heavy metal intoxication. These antioxidants affect biological systems not only through direct quenching of free radicals but also via chelation of toxic metal(s). These antioxidants also, have the capacity to enhance cellular antioxidant defense mechanism by regenerating endogenous antioxidants, such as glutathione and vitamin C and E. They also influence cellular signaling and trigger redox sensitive regulatory pathways. The reactivity of antioxidants in protecting against heavy metal induced oxidative stress depends upon their structural properties, their partitioning abilities between hydrophilic and lipophilic environment and their hydrogen donation antioxidant properties. Herein, we review the structural, biochemical and pharmacological properties of selected antioxidants with particular reference to their ability to (i) chelate heavy metals from its complex (ii) ameliorate free radical (iii) terminate heavy metal induced free radical chain reaction (iv) regenerate endogenous antioxidants and, (v) excretion of metal without its redistribution.}, }
@article {pmid24205200, year = {2013}, author = {Rodrigues, FS and Souza, MA and Magni, DV and Ferreira, AP and Mota, BC and Cardoso, AM and Paim, M and Xavier, LL and Ferreira, J and Schetinger, MR and Da Costa, JC and Royes, LF and Fighera, MR}, title = {N-acetylcysteine prevents spatial memory impairment induced by chronic early postnatal glutaric acid and lipopolysaccharide in rat pups.}, journal = {PloS one}, volume = {8}, number = {10}, pages = {e78332}, pmid = {24205200}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn/*metabolism ; Antioxidants/metabolism ; Glutarates/*adverse effects/*metabolism ; Hippocampus/drug effects/metabolism ; Interleukin-1beta/metabolism ; Lipopolysaccharides/*adverse effects ; Male ; Memory Disorders/*drug therapy/metabolism ; Rats ; Rats, Wistar ; Sodium-Potassium-Exchanging ATPase/metabolism ; Spatial Memory/*drug effects ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND AND AIMS: Glutaric aciduria type I (GA-I) is characterized by accumulation of glutaric acid (GA) and neurological symptoms, such as cognitive impairment. Although this disease is related to oxidative stress and inflammation, it is not known whether these processes facilitate the memory impairment. Our objective was to investigate the performance of rat pups chronically injected with GA and lipopolysaccharide (LPS) in spatial memory test, antioxidant defenses, cytokines levels, Na+, K+-ATPase activity, and hippocampal volume. We also evaluated the effect of N-acetylcysteine (NAC) on theses markers.<br><br>METHODS: Rat pups were injected with GA (5 umol g of body weight-1, subcutaneously; twice per day; from 5th to 28th day of life), and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). LPS (2 mg/kg; E.coli 055 B5) or vehicle (saline 0.9%) was injected intraperitoneally, once per day, from 25th to 28th day of life. Oxidative stress and inflammatory biomarkers as well as hippocampal volume were assessed.<br><br>RESULTS: GA caused spatial learning deficit in the Barnes maze and LPS potentiated this effect. GA and LPS increased TNF-&#x3b1; and IL-1&#x3b2; levels. The co-administration of these compounds potentiated the increase of IL-1&#x3b2; levels but not TNF-&#x3b1; levels in the hippocampus. GA and LPS increased TBARS (thiobarbituric acid-reactive substance) content, reduced antioxidant defenses and inhibited Na+, K+-ATPase activity. GA and LPS co-administration did not have additive effect on oxidative stress markers and Na+, K+ pump. The hippocampal volume did not change after GA or LPS administration. NAC protected against impairment of spatial learning and increase of cytokines levels. NAC Also protected against inhibition of Na+,K+-ATPase activity and oxidative markers.<br><br>CONCLUSIONS: These results suggest that inflammatory and oxidative markers may underlie at least in part of the neuropathology of GA-I in this model. Thus, NAC could represent a possible adjuvant therapy in treatment of children with GA-I.}, }
@article {pmid24205081, year = {2013}, author = {Rana, T and Chakrabarti, A and Freeman, M and Biswas, S}, title = {Doxorubicin-mediated bone loss in breast cancer bone metastases is driven by an interplay between oxidative stress and induction of TGFβ.}, journal = {PloS one}, volume = {8}, number = {10}, pages = {e78043}, pmid = {24205081}, issn = {1932-6203}, mesh = {Animals ; Antibodies/therapeutic use ; Bone Neoplasms/*metabolism/secondary ; Breast Neoplasms/*complications/*metabolism ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; Doxorubicin/*adverse effects/*therapeutic use ; Female ; Mice ; Osteoblasts/cytology/drug effects ; Oxidative Stress/*drug effects ; Transforming Growth Factor beta/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Breast cancer patients, who are already at increased risk of developing bone metastases and osteolytic bone damage, are often treated with doxorubicin. Unfortunately, doxorubicin has been reported to induce damage to bone. Moreover, we have previously reported that doxorubicin treatment increases circulating levels of TGFβ in murine pre-clinical models. TGFβ has been implicated in promoting osteolytic bone damage, a consequence of increased osteoclast-mediated resorption and suppression of osteoblast differentiation. Therefore, we hypothesized that in a preclinical breast cancer bone metastasis model, administration of doxorubicin would accelerate bone loss in a TGFβ-mediated manner. Administration of doxorubicin to 4T1 tumor-bearing mice produced an eightfold increase in osteolytic lesion areas compared untreated tumor-bearing mice (P = 0.002) and an almost 50% decrease in trabecular bone volume expressed in BV/TV (P = 0.0005), both of which were rescued by anti-TGFβ antibody (1D11). Doxorubicin, which is a known inducer of oxidative stress, decreased osteoblast survival and differentiation, which was rescued by N-acetyl cysteine (NAC). Furthermore, doxorubicin treatment decreased Cu-ZnSOD (SOD1) expression and enzyme activity in vitro, and treatment with anti-TGFβ antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFβ antibody might be beneficial for preventing therapy-related bone loss in cancer patients.}, }
@article {pmid24201812, year = {2013}, author = {Gong, F and Peng, X and Sang, Y and Qiu, M and Luo, C and He, Z and Zhao, X and Tong, A}, title = {Dichloroacetate induces protective autophagy in LoVo cells: involvement of cathepsin D/thioredoxin-like protein 1 and Akt-mTOR-mediated signaling.}, journal = {Cell death &amp; disease}, volume = {4}, number = {11}, pages = {e913}, pmid = {24201812}, issn = {2041-4889}, mesh = {Autophagy/*drug effects/genetics ; Cathepsin D/genetics/*metabolism ; Cell Line, Tumor ; Cell Proliferation ; Dichloroacetic Acid/*pharmacology ; HCT116 Cells ; Humans ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/genetics/physiology ; TOR Serine-Threonine Kinases/genetics/*metabolism ; Thioredoxins/genetics/*metabolism ; }, abstract = {Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase (PDK), and recently it has been shown as a promising nontoxic antineoplastic agent. In this study, we demonstrated that DCA could induce autophagy in LoVo cells, which were confirmed by the formation of autophagosomes, appearance of punctate patterns of LC3 immunoreactivity and activation of autophagy associated proteins. Moreover, autophagy inhibition by 3-methyladenine (3-MA) or Atg7 siRNA treatment can significantly enhance DCA-induced apoptosis. To determine the underlying mechanism of DCA-induced autophagy, target identification using drug affinity responsive target stability (DARTS) coupled with ESI-Q-TOF MS/MS analysis were utilized to profile differentially expressed proteins between control and DCA-treated LoVo cells. As a result, Cathepsin D (CTSD) and thioredoxin-like protein 1 (TXNL1) were identified with significant alterations compared with control. Further study indicated that DCA treatment significantly promoted abnormal reactive oxygen species (ROS) production. On the other hand, DCA-triggered autophagy could be attenuated by N-acetyl cysteine (NAC), a ROS inhibitor. Finally, we demonstrated that the Akt-mTOR signaling pathway, a major negative regulator of autophagy, was suppressed by DCA treatment. To our knowledge, it was the first study to show that DCA induced protective autophagy in LoVo cells, and the potential mechanisms were involved in ROS imbalance and Akt-mTOR signaling pathway suppression.}, }
@article {pmid24201233, year = {2013}, author = {Farokhnia, M and Azarkolah, A and Adinehfar, F and Khodaie-Ardakani, MR and Hosseini, SM and Yekehtaz, H and Tabrizi, M and Rezaei, F and Salehi, B and Sadeghi, SM and Moghadam, M and Gharibi, F and Mirshafiee, O and Akhondzadeh, S}, title = {N-acetylcysteine as an adjunct to risperidone for treatment of negative symptoms in patients with chronic schizophrenia: a randomized, double-blind, placebo-controlled study.}, journal = {Clinical neuropharmacology}, volume = {36}, number = {6}, pages = {185-192}, doi = {10.1097/WNF.0000000000000001}, pmid = {24201233}, issn = {1537-162X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Antipsychotic Agents/*administration &amp; dosage ; Chronic Disease ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Male ; Risperidone/*administration &amp; dosage ; Schizophrenia/diagnosis/*drug therapy ; *Schizophrenic Psychology ; Treatment Outcome ; }, abstract = {OBJECTIVES: Despite the burden of negative symptoms on quality of life in schizophrenic patients, no completely effective treatment has been developed to address such symptoms yet. Abnormalities in oxidative stress pathways have been recently demonstrated to be involved in the pathophysiology of schizophrenia, and a growing interest in antioxidant agents is emerging for targeting negative symptoms of schizophrenia. N-Acetylcysteine (NAC) is a potent antioxidant with neuroprotective properties. This study aimed to evaluate the possible effects of NAC as an adjunct to risperidone in treating negative symptoms of schizophrenia.<br><br>MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, 42 patients with chronic schizophrenia and a score of 20 or greater on the negative subscale of positive and negative syndrome scale (PANSS) were enrolled in the active phase of their illness. The participants were equally randomized to receive NAC (up to 2 g/d) or placebo, in addition to risperidone (up to 6 mg/d) for 8 weeks. The participants were rated using PANSS every 2 weeks, and the decrease of PANSS negative subscale score was considered as our primary outcome.<br><br>RESULTS: By the study end point, NAC-treated patients showed significantly greater improvement in the PANSS total (P = 0.006) and negative subscale (P < 0.001) scores than that in the placebo group, but this difference was not significant for positive and general psychopathology subscales. There was no significant difference between the 2 groups in the frequency of adverse effects.<br><br>CONCLUSIONS: NAC add-on therapy showed to be a safe and effective augmentative strategy for alleviating negative symptoms of schizophrenia.}, }
@article {pmid24195622, year = {2013}, author = {Trewin, AJ and Petersen, AC and Billaut, F and McQuade, LR and McInerney, BV and Stepto, NK}, title = {N-acetylcysteine alters substrate metabolism during high-intensity cycle exercise in well-trained humans.}, journal = {Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme}, volume = {38}, number = {12}, pages = {1217-1227}, doi = {10.1139/apnm-2012-0482}, pmid = {24195622}, issn = {1715-5320}, mesh = {*Acetylcysteine ; Blood Glucose ; *Double-Blind Method ; Exercise ; Exercise Test ; Humans ; Lactic Acid/blood ; }, abstract = {We investigated the effects of N-acetylcysteine (NAC) on metabolism during fixed work rate high-intensity interval exercise (HIIE) and self-paced 10-min time-trial (TT10) performance. Nine well-trained male cyclists (V̇O2peak, 69.4 ± 5.8 mL · kg(-1) · min(-1); peak power output (PPO), 385 ± 43 W; mean ± SD) participated in a double-blind, repeated-measures, randomised crossover trial. Two trials (NAC supplementation and placebo) were performed 7 days apart consisting of 6 × 5 min HIIE bouts at 82% PPO (316 ± 40 W) separated by 1 min at 100 W, and then after 2 min of recovery at 100 W, TT10 was performed. Expired gases, venous blood, and electromyographic (EMG) data were collected. NAC did not influence blood glutathione but decreased lipid peroxidation compared with the placebo (P < 0.05). Fat oxidation was elevated with NAC compared with the placebo during HIIE bouts 5 and 6 (9.9 ± 8.9 vs. 3.9 ± 4.8 μmol · kg(-1) · min(-1); P < 0.05), as was blood glucose throughout HIIE (4.3 ± 0.6 vs. 3.8 ± 0.6 mmol · L(-1); P < 0.05). Blood lactate was lower with NAC after TT10 (3.3 ± 1.3 vs. 4.2 ± 1.3 mmol · L(-1); P < 0.05). Median EMG frequency of the vastus lateralis was lower with NAC during HIIE (79 ± 10 vs. 85 ± 10 Hz; P < 0.05), but not TT10 (82 ± 11 Hz). Finally, NAC decreased mean power output 4.9% ± 6.6% (effect size = -0.3 ± 0.4, mean ± 90% CI) during TT10 (305 ± 57 W vs. 319 ± 45 W). These data suggest that NAC alters substrate metabolism and muscle fibre type recruitment during HIIE, which is detrimental to time-trial performance.}, }
@article {pmid24193368, year = {2014}, author = {Bochi, GV and Torbitz, VD and Cargnin, LP and de Carvalho, JA and Gomes, P and Moresco, RN}, title = {An alternative pathway through the Fenton reaction for the formation of advanced oxidation protein products, a new class of inflammatory mediators.}, journal = {Inflammation}, volume = {37}, number = {2}, pages = {512-521}, pmid = {24193368}, issn = {1573-2576}, mesh = {Acetylcysteine/pharmacology ; Advanced Oxidation Protein Products/*blood ; Antioxidants/pharmacology ; Case-Control Studies ; Diabetes Mellitus, Type 2/*blood/immunology ; Dose-Response Relationship, Drug ; Fructosediphosphates/pharmacology ; Humans ; Hydrogen Peroxide/*chemistry ; Inflammation Mediators/*blood ; Iron/*chemistry ; Oxidation-Reduction ; *Oxidative Stress/drug effects ; Reactive Oxygen Species/*blood ; }, abstract = {The accumulation of advanced oxidation protein products (AOPPs) has been linked to several pathological conditions, and their levels are formed during oxidative stress as a result of reactions between plasma proteins and chlorinated oxidants produced by myeloperoxidase (MPO). However, it was suggested that the generation of this mediator of inflammation may also occur via an MPO-independent pathway. The aim of this study was to induce the formation of AOPPs in vitro through Fenton reaction and to investigate whether this generation could be counteracted by N-acetylcysteine (NAC) and fructose-1,6-bisphosphate (FBP). The complete Fenton system increased the AOPPs levels and both NAC and FBP were capable of inhibiting the formation of Fenton reaction-induced AOPPs. These data provide a new hypothesis about another pathway of AOPPs formation, as well as report that NAC and FBP may be good candidates to neutralize pro-inflammatory and pro-oxidant effects of AOPPs in several diseases.}, }
@article {pmid24179013, year = {2013}, author = {Li, M and Qureshi, AR and Ellis, E and Axelsson, J}, title = {Impaired postprandial fibroblast growth factor (FGF)-19 response in patients with stage 5 chronic kidney diseases is ameliorated following antioxidative therapy.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {28 Suppl 4}, number = {}, pages = {iv212-9}, doi = {10.1093/ndt/gft337}, pmid = {24179013}, issn = {1460-2385}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Antioxidants/*therapeutic use ; Biomarkers/blood ; Blood Glucose/metabolism ; *Blueberry Plants ; Case-Control Studies ; Double-Blind Method ; Enzyme-Linked Immunosorbent Assay ; Female ; Fibroblast Growth Factors/*blood ; Humans ; Insulin/blood ; Male ; Middle Aged ; *Phytotherapy ; Postprandial Period ; Prognosis ; *Renal Dialysis ; Renal Insufficiency, Chronic/blood/*therapy ; Triglycerides/blood ; Young Adult ; }, abstract = {BACKGROUND: While dysmetabolism is common in patients with chronic kidney disease (CKD) and associated with mortality, the mechanisms mediating these changes are unclear. New data implicate fibroblast growth factor (FGF)-19 as a possible entero-hepatic modulator of lipid metabolism.<br><br>METHODS: Using samples previously gathered as part of a randomized placebo-controlled study of antioxidative therapy for postprandial dysmetabolism, we investigated short-term (4 h) postprandial changes in circulating FGF-19 (ELISA) and the relationship to metabolic markers in six haemodialysis (HD) patients and nine matched healthy subjects (HS), with each participant assessed on four separate occasions.<br><br>RESULTS: The postprandial FGF-19 response was blunted in patients [maximum change +34.63 (0.24-186) pg/mL] versus controls [maximum change +150.3 (31.2-378.7) pg/mL; P < 0.0001], and the area under the curve (AUC; pg &#xd7; min &#xd7; mL(-1)) was also significantly lower 18 019 (12 513-44 387) versus 38 517 (19 775-72 816; P < 0.01). In patients, we found univariate correlations between AUC FGF-19 with AUC C-peptide (rho = 0.71; P = 0.001), AUC insulin (rho = 0.63; P = 0.001), but not with AUCs for triglycerides (TG) or glucose. Finally, treatment with the antioxidative compounds N-acetyl cysteine or MP865, but not with placebo, was associated with higher plasma FGF-19 (NAC and MP865 coefficients -0.28 and -0.23, P < 0.05, respectively).<br><br>CONCLUSION: In advanced CKD, the postprandial FGF-19 response appears to be blunted, with partial normalization following antioxidative treatments. A blunted FGF-19 response was associated with impaired insulin and C-peptide signalling.}, }
@article {pmid24185179, year = {2014}, author = {Sato, A and Okada, M and Shibuya, K and Watanabe, E and Seino, S and Narita, Y and Shibui, S and Kayama, T and Kitanaka, C}, title = {Pivotal role for ROS activation of p38 MAPK in the control of differentiation and tumor-initiating capacity of glioma-initiating cells.}, journal = {Stem cell research}, volume = {12}, number = {1}, pages = {119-131}, doi = {10.1016/j.scr.2013.09.012}, pmid = {24185179}, issn = {1876-7753}, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain Neoplasms/metabolism/mortality/pathology ; Buthionine Sulfoximine/pharmacology ; *Cell Differentiation/drug effects ; Down-Regulation/drug effects ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/genetics/metabolism ; Glioma/metabolism/mortality/pathology ; Humans ; Hydrogen Peroxide/pharmacology ; Imidazoles/pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitogen-Activated Protein Kinase 7/genetics/metabolism ; Neoplastic Stem Cells/drug effects/metabolism/transplantation ; Pyridines/pharmacology ; RNA Interference ; Reactive Oxygen Species/*metabolism ; Transplantation, Heterologous ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/*metabolism ; }, abstract = {Reactive oxygen species (ROS) are involved in various aspects of cancer cell biology, yet their role in cancer stem cells (CSCs) has been poorly understood. In particular, it still remains unclear whether and how ROS control the self-renewal/differentiation process and the tumor-initiating capacity of CSCs. Here we show that ROS-mediated activation of p38 MAPK plays a pivotal role in the control of differentiation and tumor-initiating capacity of glioma-initiating cells (GICs) derived from human glioblastomas. Mechanistically, ROS triggered p38-dependent Bmi1 protein degradation and FoxO3 activation in GICs, which were shown to be responsible for the loss of their self-renewal capacity and differentiation, respectively. Thus, the results suggest that Bmi1 and FoxO3 govern distinct phases of transition from undifferentiated to fully differentiated cells. Furthermore, we also demonstrate in this study that oxidative stress deprives GICs of their tumor-initiating capacity through the activation of the ROS-p38 axis. As such, this is the first study to the best of our knowledge to delineate how ROS control self-renewal/differentiation and the tumor-initiating capacity of stem-like cancer cells. This study also suggests that targeting of the ROS-p38 axis could be a novel approach in the development of therapeutic strategies against gliomas, represented by glioblastoma.}, }
@article {pmid24184570, year = {2013}, author = {Ji, YY and Zhu, YM and Wang, JW}, title = {GS-2, a pyrazolo[1,5-a]indole derivative with inhibitory activity of topoisomerases, exerts its potent cytotoxic activity by ROS generation.}, journal = {Environmental toxicology and pharmacology}, volume = {36}, number = {3}, pages = {1186-1196}, doi = {10.1016/j.etap.2013.09.019}, pmid = {24184570}, issn = {1872-7077}, mesh = {Acetylcysteine/pharmacology ; *Antineoplastic Agents ; Antioxidants/metabolism/pharmacology ; Apoptosis/drug effects ; Caspases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Comet Assay ; DNA Damage/drug effects ; DNA Topoisomerases/biosynthesis/genetics ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione/metabolism ; Humans ; Indicators and Reagents ; Indoles/*chemical synthesis/*pharmacology ; L-Lactate Dehydrogenase/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Pyrazoles/*chemical synthesis/*pharmacology ; RNA/biosynthesis/isolation &amp; purification ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Topoisomerase Inhibitors/chemical synthesis/*pharmacology ; }, abstract = {Pyrazolo[1,5-a]indole derivatives, a new type of topoisomerase (topo) inhibitor, demonstrate a broad spectrum of antitumor activities. However, the mechanism underlying the induced cytotoxicity remains unclear. In this study, we investigated whether GS-2, one of the derivatives, altered the levels of ROS in breast cancer MDA-231 cells and whether these ROS contributed to the observed antitumoral activity. Our data revealed that GS-2 caused a time- and dose-dependent elevation of intracellular ROS level in MDA-231 cells. GS-2 subsequently elicited notable inhibition on the expression of topos, DNA damage, activation of caspase-3, -9. The loss of mitochondrial membrane potential (MMP) was observed during the induction. The addition of N-acetyl cysteine (NAC, a well-known antioxidant) could effectively attenuate the GS-2-induced ROS enhancement and subsequent apoptosis. NAC attenuated the induced inhibition on expression of topos, indicating that topos might be the target of GS-2-induced ROS. The finding of the induced ROS provides new evidence for the molecular mechanisms of antitumor activity of pyrazolo[1,5-a]indole derivatives.}, }
@article {pmid24184207, year = {2014}, author = {Terrazzano, G and Rubino, V and Damiano, S and Sasso, A and Petrozziello, T and Ucci, V and Palatucci, AT and Giovazzino, A and Santillo, M and De Felice, B and Garbi, C and Mondola, P and Ruggiero, G}, title = {T cell activation induces CuZn superoxide dismutase (SOD)-1 intracellular re-localization, production and secretion.}, journal = {Biochimica et biophysica acta}, volume = {1843}, number = {2}, pages = {265-274}, doi = {10.1016/j.bbamcr.2013.10.020}, pmid = {24184207}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Brefeldin A/pharmacology ; CD3 Complex/metabolism ; Cell Aggregation/drug effects ; Cluster Analysis ; Cytoplasmic Vesicles/drug effects/metabolism ; Enzyme Induction/drug effects ; Humans ; Intracellular Space/drug effects/*enzymology ; *Lymphocyte Activation/drug effects ; Protein Transport/drug effects ; Reactive Oxygen Species/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Superoxide Dismutase/*biosynthesis/*metabolism ; Superoxide Dismutase-1 ; T-Lymphocytes/cytology/drug effects/*enzymology/*immunology ; }, abstract = {Reactive oxygen species (ROS) behave as second messengers in signal transduction for a series of receptor/ligand interactions. A major regulatory role is played by hydrogen peroxide (H2O2), more stable and able to freely diffuse through cell membranes. Copper-zinc superoxide dismutase (CuZn-SOD)-1 is a cytosolic enzyme involved in scavenging oxygen radicals to H2O2 and molecular oxygen, thus representing a major cytosolic source of peroxides. Previous studies suggested that superoxide anion and H2O2 generation are involved in T cell receptor (TCR)-dependent signaling. Here, we describe that antigen-dependent activation of human T lymphocytes significantly increased extracellular SOD-1 levels in lymphocyte cultures. This effect was accompanied by the synthesis of SOD-1-specific mRNA and by the induction of microvesicle SOD-1 secretion. It is of note that SOD-1 increased its concentration specifically in T cell population, while no significant changes were observed in the "non-T" cell counterpart. Moreover, confocal microscopy showed that antigen-dependent activation was able to modify SOD-1 intracellular localization in T cells. Indeed, was observed a clear SOD-1 recruitment by TCR clusters. The ROS scavenger N-acetylcysteine (NAC) inhibited this phenomenon. Further studies are needed to define whether SOD-1-dependent superoxide/peroxide balance is relevant for regulation of T cell activation, as well as in the functional cross talk between immune effectors.}, }
@article {pmid24184196, year = {2014}, author = {Hsu, PY and Yang, YW}, title = {Gene delivery via the hybrid vector of recombinant adeno-associated virus and polyethylenimine.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {52}, number = {}, pages = {62-68}, doi = {10.1016/j.ejps.2013.10.009}, pmid = {24184196}, issn = {1879-0720}, mesh = {Acetylcysteine/pharmacology ; Androstadienes/pharmacology ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Cell Line, Tumor ; Cytochalasin B/pharmacology ; Dependovirus/*chemistry/*genetics ; *Gene Transfer Techniques ; *Genetic Vectors ; Humans ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Polyethyleneimine/*chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Vitamin E/analogs &amp; derivatives/pharmacology ; Wortmannin ; }, abstract = {The aim of this study was to investigate the cellular delivery mechanism of the hybrid vector comprising the recombinant adeno-associated virus (rAAV) and polyethylenimine (PEI). The rAAV vector, rAAV-rIns1-hInsM2-ΔEGFP, was fluorescently labeled with Cy3, a cyanine dye, and complexed with PEI. The interaction of the hybrid vector with the Huh7 hepatoma cells was monitored by confocal microscopy. Complexation of rAAV with PEI enhanced the transduction efficiency, which was decreased by pretreatment of the cells with sodium chlorate, an inhibitor of glycosaminoglycan sulfation, suggesting the roles of heparan sulfate proteoglycans (HSPG) in the uptake of the hybrid vector by the cells. Examination by flow cytometry and confocal microscopy demonstrated an enhanced interaction between the cells and the virus when complexed with PEI. Pretreatment with wortmannin or cytochalasin B significantly reduced the virus uptake by the cells, suggesting the involvement of phosphatidylinositol 3-kinase (PI3K) signaling and phagocytosis in the interaction between the cells and the hybrid vectors. Treatment of cells with the antioxidants, including l-ascorbic acid, δ-tocotrienol, or N-acetylcysteine (NAC), impaired the rAAV-PEI-mediated transduction. Results obtained in this study illustrated the involvement of PI3K/Akt signaling and the ROS production in gene delivery via the rAAV-PEI hybrid vector.}, }
@article {pmid24184051, year = {2013}, author = {Garrido-Gil, P and Rodriguez-Pallares, J and Dominguez-Meijide, A and Guerra, MJ and Labandeira-Garcia, JL}, title = {Brain angiotensin regulates iron homeostasis in dopaminergic neurons and microglial cells.}, journal = {Experimental neurology}, volume = {250}, number = {}, pages = {384-396}, doi = {10.1016/j.expneurol.2013.10.013}, pmid = {24184051}, issn = {1090-2430}, mesh = {Angiotensin II/*metabolism/pharmacology ; Animals ; Blotting, Western ; Brain/metabolism ; Cells, Cultured ; Dopaminergic Neurons/*metabolism ; Fluorescent Antibody Technique ; Homeostasis/*physiology ; Iron/*metabolism ; Male ; Microglia/*metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Angiotensin/metabolism ; }, abstract = {Dysfunction of iron homeostasis has been shown to be involved in ageing, Parkinson's disease and other neurodegenerative diseases. Increased levels of labile iron result in increased reactive oxygen species and oxidative stress. Angiotensin II, via type-1 receptors, exacerbates oxidative stress, the microglial inflammatory response and progression of dopaminergic degeneration. Angiotensin activates the NADPH-oxidase complex, which produces superoxide. However, it is not known whether angiotensin affects iron homeostasis. In the present study, administration of angiotensin to primary mesencephalic cultures, the dopaminergic cell line MES23.5 and to young adult rats, significantly increased levels of transferrin receptors, divalent metal transporter-1 and ferroportin, which suggests an increase in iron uptake and export. In primary neuron-glia cultures and young rats, angiotensin did not induce significant changes in levels of ferritin or labile iron, both of which increased in neurons in the absence of glia (neuron-enriched cultures, dopaminergic cell line) and in the N9 microglial cell line. In aged rats, which are known to display high levels of angiotensin activity, ferritin levels and iron deposits in microglial cells were enhanced. Angiotensin-induced changes were inhibited by angiotensin type-1 receptor antagonists, NADPH-oxidase inhibitors, antioxidants and NF-kB inhibitors. The results demonstrate that angiotensin, via type-1 receptors, modulates iron homeostasis in dopaminergic neurons and microglial cells, and that glial cells play a major role in efficient regulation of iron homeostasis in dopaminergic neurons.}, }
@article {pmid24182331, year = {2014}, author = {Choi, CH and Du, X and Floyd, RA and Kopke, RD}, title = {Therapeutic effects of orally administrated antioxidant drugs on acute noise-induced hearing loss.}, journal = {Free radical research}, volume = {48}, number = {3}, pages = {264-272}, doi = {10.3109/10715762.2013.861599}, pmid = {24182331}, issn = {1029-2470}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Chinchilla ; Dose-Response Relationship, Drug ; Female ; Hearing Loss, Noise-Induced/*drug therapy/etiology/pathology ; Imines/*pharmacology ; Phenols/*pharmacology ; Random Allocation ; }, abstract = {OBJECTIVE: The objective of this study was to investigate the dose-dependent therapeutic effect of the orally administrated antioxidant drugs [4-hydroxy alpha-phenyl-tert-butylnitrone (4-OHPBN) and N-acetyl-L-cysteine (NAC)] on acute noise-induced hearing loss because oral administration is the most commonly used method of drug administration due to its convenience, safety, and economical efficiency.<br><br>METHODS: Thirty chinchilla were exposed to a 105 dB octave band noise centered at 4 kHz for 6 h and randomly assigned to a control group (saline only) and three experimental groups [4-OHPBN (10 mg/kg) plus NAC (20 mg/kg), 4-OHPBN (20 mg/kg) plus NAC (50 mg/kg), and 4-OHPBN (50 mg/kg) plus NAC (100 mg/kg)]. The drugs were orally administrated beginning 4 h after noise exposure and then administered twice daily for the next 2 days. Permanent auditory brainstem response threshold shifts, distortion product otoacoustic emission threshold shifts, and the percentage of missing outer hair cell were determined.<br><br>RESULTS: The oral administration significantly reduced permanent hearing threshold shift, distortion product otoacoustic emission threshold shift, and the percentage of missing outer hair cell in a dose-dependent manner.<br><br>DISCUSSION: This result demonstrates that orally administered drugs can treat acute noise-induced hearing loss in a dose-dependent manner. This suggests that oral administration was effective in treating acute noise-induced hearing loss as in intraperitoneal administration.}, }
@article {pmid24180497, year = {2014}, author = {Rahman, M and Mofarrahi, M and Kristof, AS and Nkengfac, B and Harel, S and Hussain, SN}, title = {Reactive oxygen species regulation of autophagy in skeletal muscles.}, journal = {Antioxidants &amp; redox signaling}, volume = {20}, number = {3}, pages = {443-459}, doi = {10.1089/ars.2013.5410}, pmid = {24180497}, issn = {1557-7716}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {AMP-Activated Protein Kinases ; Animals ; Antioxidants/pharmacology ; Autophagy/drug effects/*genetics ; Cell Line ; Cyclic N-Oxides/pharmacology ; Food ; Mice ; Mitochondria/*drug effects/metabolism/pathology ; Muscle Fibers, Skeletal/cytology/drug effects/metabolism ; Muscle, Skeletal/drug effects/*metabolism ; Phosphorylation/drug effects ; Proteolysis/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Sirolimus/pharmacology ; Spin Labels ; }, abstract = {OBJECTIVE: To evaluate the effects of physiological levels of mitochondrial-derived reactive oxygen species (ROS) on skeletal muscle autophagy, a proteolytic pathway designed to regulate contractile and myofilament homeostasis and to recycle long-lived proteins and damaged organelles.<br><br>RESULTS: Basal levels of autophagy and autophagy triggered by 1.5 to 4&#x2009;h of acute nutrient deprivation, rapamycin treatment, or leucine deprivation were measured in differentiated C2C12 myotubes using long-lived protein degradation assays, LC3B lipidation, autophagy-related gene expression, and electron microscopy. Preincubation with the general antioxidants tempol (superoxide dismutase mimic) and N-acetyl cysteine (NAC) or the mitochondria-specific antioxidants mito-tempol and SS31 significantly decreased the rates of long-lived protein degradation and LC3B flux and blocked the induction of autophagy-related gene expression. Mitochondrial ROS levels significantly increased in response to acute nutrient deprivation and rapamycin treatment. Mito-tempol and tempol blocked this response. Antioxidants decreased AMP-activated protein kinase (AMPK) phosphorylation by 40% and significantly increased protein kinase B (AKT) phosphorylation, but exerted no effects on mTORC1-dependent ULK1 phosphorylation on Ser(555). NAC significantly decreased basal LC3B autophagic flux in skeletal muscles of mice.<br><br>INNOVATION: We report for the first time that endogenous ROS promote skeletal muscle autophagy at the basal level and in response to acute nutrient starvation and mTORC1 inhibition. We also report for the first time that mitochondrial-derived ROS promote skeletal muscle autophagy and that this effect is mediated, in part, through regulation of autophagosome initiation and AKT inhibition.<br><br>CONCLUSION: Mitochondrial-derived ROS promote skeletal muscle autophagy and this effect is mediated, in part, through activation of AMPK and inhibition of AKT.}, }
@article {pmid24178902, year = {2013}, author = {Wiegand, T and Wax, P and Smith, E and Hart, K and Brent, J}, title = {The Toxicology Investigators Consortium Case Registry--the 2012 experience.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {9}, number = {4}, pages = {380-404}, pmid = {24178902}, issn = {1937-6995}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Australia/epidemiology ; Canada/epidemiology ; Child ; Child, Preschool ; Cooperative Behavior ; Data Mining ; Female ; Humans ; Infant ; International Cooperation ; Israel/epidemiology ; Male ; Middle Aged ; *Poisoning/diagnosis/mortality/therapy ; *Registries ; Risk Factors ; Societies, Medical ; Time Factors ; Toxicology/*trends ; Treatment Outcome ; United States ; Young Adult ; }, abstract = {In 2010, the American College of Medical Toxicology (ACMT) established its Case Registry, the Toxicology Investigators Consortium (ToxIC). All cases are entered prospectively and include only suspected and confirmed toxic exposures cared for at the bedside by board-certified or board-eligible medical toxicologists at its participating sites. The primary aims of establishing this Registry include the development of a realtime toxico-surveillance system in order to identify and describe current or evolving trends in poisoning and to develop a research tool in toxicology. ToxIC allows for extraction of data from medical records from multiple sites across a national and international network. All cases seen by medical toxicologists at participating institutions were entered into the database. Information characterizing patients entered in 2012 was tabulated and data from the previous years including 2010 and 2011 were included so that cumulative numbers and trends could be described as well. The current report includes data through December 31st, 2012. During 2012, 38 sites with 68 specific institutions contributed a total of 7,269 cases to the Registry. The total number of cases entered into the Registry at the end of 2012 was 17,681. Emergency departments remained the most common source of consultation in 2012, accounting for 61 % of cases. The most common reason for consultation was for pharmaceutical overdose, which occurred in 52 % of patients including intentional (41 %) and unintentional (11 %) exposures. The most common classes of agents were sedative-hypnotics (1,422 entries in 13 % of cases) non-opioid analgesics (1,295 entries in 12 % of cases), opioids (1,086 entries in 10 % of cases) and antidepressants (1,039 entries in 10 % of cases). N-acetylcysteine (NAC) was the most common antidote administered in 2012, as it was in previous years, followed by the opioid antagonist naloxone, sodium bicarbonate, physostigmine and flumazenil. Anti-crotalid Fab fragments were administered in 109 cases or 82 % of cases in which a snake envenomation occurred. There were 57 deaths reported in the Registry in 2012. The most common associated agent alone or in combination was the non-opioid analgesic acetaminophen, being reported in 10 different cases. Other common agents and agent classes involved in death cases included ethanol, opioids, the anti-diabetic agent metformin, sedatives-hypnotics and cardiovascular agents, in particular amlodipine. There were significant trends identified during 2012. Abuse of over-the-counter medications such as dextromethorphan remains prevalent. Cases involving dextromethorphan continued to be reported at frequencies higher than other commonly abused drugs including many stimulants, phencyclidine, synthetic cannabinoids and designer amphetamines such as bath salts. And, while cases involving synthetic cannabinoids and psychoactive bath salts remained relatively constant from 2011 to 2012 several designer amphetamines and novel psychoactive substances were first reported in the Registry in 2012 including the NBOME compounds or "N-bomb" agents. LSD cases also spiked dramatically in 2012 with an 18-fold increase from 2011 although many of these cases are thought to be ultra-potent designer amphetamines misrepresented as "synthetic" LSD. The 2012 Registry included over 400 Adverse Drug Reactions (ADRs) involving 4 % of all Registry cases with 106 agents causing at least 2 ADRs. Additional data including supportive cares, decontamination, and chelating agent use are also included in the 2012 annual report. The Registry remains a valuable toxico-surveillance and research tool. The ToxIC Registry is a unique tool for identifying and characterizing confirmed cases of significant or potential toxicity or complexity to require bedside care by a medical toxicologist.}, }
@article {pmid24177245, year = {2014}, author = {Barbosa, DJ and Capela, JP and Silva, R and Ferreira, LM and Branco, PS and Fernandes, E and Bastos, ML and Carvalho, F}, title = {"Ecstasy"-induced toxicity in SH-SY5Y differentiated cells: role of hyperthermia and metabolites.}, journal = {Archives of toxicology}, volume = {88}, number = {2}, pages = {515-531}, doi = {10.1007/s00204-013-1147-9}, pmid = {24177245}, issn = {1432-0738}, mesh = {3,4-Methylenedioxyamphetamine/metabolism/toxicity ; Acetylcysteine/metabolism/pharmacology ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Differentiation/*drug effects ; Cell Line/drug effects ; Deoxyepinephrine/analogs &amp; derivatives/metabolism/toxicity ; Fever/*chemically induced/metabolism ; Glutathione/metabolism ; Humans ; Mitochondria/drug effects/metabolism ; N-Methyl-3,4-methylenedioxyamphetamine/*metabolism/pharmacokinetics/*toxicity ; Neurons/*drug effects/metabolism ; Neurotoxicity Syndromes/metabolism/pathology ; Temperature ; }, abstract = {3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a recreational hallucinogenic drug of abuse known to elicit neurotoxic properties. Hepatic formation of neurotoxic metabolites is thought to play a major role in MDMA-related neurotoxicity, though the mechanisms involved are still unclear. Here, we studied the neurotoxicity mechanisms and stability of MDMA and 6 of its major human metabolites, namely α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) and their correspondent glutathione (GSH) and N-acetyl-cysteine (NAC) conjugates, under normothermic (37 °C) or hyperthermic conditions (40 °C), using cultured SH-SY5Y differentiated cells. We showed that MDMA metabolites exhibited toxicity to SH-SY5Y differentiated cells, being the GSH and NAC conjugates more toxic than their catecholic precursors and MDMA. Furthermore, whereas the toxicity of the catechol metabolites was potentiated by hyperthermia, NAC-conjugated metabolites revealed higher toxicity under normothermia and GSH-conjugated metabolites-induced toxicity was temperature-independent. Moreover, a time-dependent decrease in extracellular concentration of MDMA metabolites was observed, which was potentiated by hyperthermia. The antioxidant NAC significantly protected against the neurotoxic effects of MDMA metabolites. MDMA metabolites increased intracellular glutathione levels, though depletion in thiol content was observed in MDMA-exposed cells. Finally, the neurotoxic effects induced by the MDMA metabolite N-Me-α-MeDA involved caspase 3 activation. In conclusion, this study evaluated the stability of MDMA metabolites in vitro, and demonstrated that the catechol MDMA metabolites and their GSH and NAC conjugates, rather than MDMA itself, exhibited neurotoxic actions in SH-SY5Y differentiated cells, which were differently affected by hyperthermia, thus highlighting a major role for reactive metabolites and hyperthermia in MDMA's neurotoxicity.}, }
@article {pmid24172913, year = {2014}, author = {You, BR and Shin, HR and Park, WH}, title = {PX-12 inhibits the growth of A549 lung cancer cells via G2/M phase arrest and ROS-dependent apoptosis.}, journal = {International journal of oncology}, volume = {44}, number = {1}, pages = {301-308}, doi = {10.3892/ijo.2013.2152}, pmid = {24172913}, issn = {1791-2423}, mesh = {Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Disulfides/*administration &amp; dosage ; G2 Phase Cell Cycle Checkpoints/drug effects ; Glutathione/metabolism ; Humans ; Imidazoles/*administration &amp; dosage ; Lung Neoplasms/*drug therapy/pathology ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {PX-12 (1-methylpropyl 2-imidazolyl disulfide) is an inhibitor of thioredoxin (Trx-1), which has antitumor effects. However, little is known about the toxicological effect of PX-12 on cancer cells. We investigated the anti-growth effects of PX-12 on A549 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Based on MTT assays, PX-12 inhibited the growth of A549 cells with an IC50 of approximately 20 µM at 72 h. DNA flow cytometric analysis indicated that PX-12 significantly induced the G2/M phase arrest of the cell cycle in A549 cells. This agent also induced apoptotic cell death, as demonstrated by Annexin V-FITC staining cells and the loss of mitochondrial membrane potential MMP (∆ψm). In addition, the administration of Bax siRNA attenuated PX-12-induced A549 cell death. All the tested caspase inhibitors, especially Z-VAD significantly prevented apoptosis induced by PX-12. With respect to ROS and GSH levels, PX-12 increased ROS levels including O2(•)- in A549 cells and induced GSH depletion. N-acetyl cysteine (NAC) markedly reduced ROS levels in PX-12-treated A549 cells. NAC also prevented apoptotic cell death and GSH depletion induced by PX-12. This is the first report to show that PX-12 inhibits the growth of A549 cells via G2/M phase arrest, and Bax-mediated and ROS-dependent apoptosis.}, }
@article {pmid24169090, year = {2013}, author = {Simet, SM and Pavlik, JA and Sisson, JH}, title = {Dietary antioxidants prevent alcohol-induced ciliary dysfunction.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {47}, number = {8}, pages = {629-635}, pmid = {24169090}, issn = {1873-6823}, support = {F32 AA019859/AA/NIAAA NIH HHS/United States ; R01 AA008769/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/analysis/*therapeutic use ; Adrenergic beta-2 Receptor Agonists/pharmacology ; Animals ; Antioxidants/*therapeutic use ; Bronchoalveolar Lavage Fluid/chemistry ; Cilia/drug effects/physiology ; Ciliary Motility Disorders/*chemically induced/diet therapy/physiopathology/*prevention &amp; control ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic GMP-Dependent Protein Kinases/metabolism ; *Dietary Supplements ; Ethanol/*toxicity ; Female ; Mice ; Procaterol/pharmacology ; Pyrrolidonecarboxylic Acid/administration &amp; dosage/*therapeutic use ; Reactive Nitrogen Species/analysis ; Thiazolidines/administration &amp; dosage/*therapeutic use ; Trachea/metabolism ; }, abstract = {Previously we have shown that chronic alcohol intake causes alcohol-induced ciliary dysfunction (AICD), leading to non-responsive airway cilia. AICD likely occurs through the downregulation of nitric oxide (NO) and cyclic nucleotide-dependent kinases, protein kinase G (PKG) and protein kinase A (PKA). Studies by others have shown that dietary supplementation with the antioxidants N-acetylcysteine (NAC) and procysteine prevent other alcohol-induced lung complications. This led us to hypothesize that dietary supplementation with NAC or procysteine prevents AICD. To test this hypothesis, C57BL/6 mice drank an alcohol/water solution (20% w/v) ad libitum for 6 weeks and were concurrently fed dietary supplements of either NAC or procysteine. Ciliary beat frequency (CBF) was measured in mice tracheas, and PKG/PKA responsiveness to β-agonists and NOx levels were measured from bronchoalveolar lavage (BAL) fluid. Long-term alcohol drinking reduced CBF, PKG and PKA responsiveness to β-agonists, and lung NOx levels in BAL fluid. In contrast, alcohol-drinking mice fed NAC or procysteine sustained ciliary function and PKG and PKA responsiveness to β-agonists. However, BAL NO levels remained low despite antioxidant supplementation. We also determined that removal of alcohol from the drinking water for as little as 1 week restored ciliary function, but not PKG and PKA responsiveness to β-agonists. We conclude that dietary supplementation with NAC or procysteine protects against AICD. In addition, alcohol removal for 1 week restores cilia function independent of PKG and PKA activity. Our findings provide a rationale for the use of antioxidants to prevent damage to airway mucociliary functions in chronic alcohol-drinking individuals.}, }
@article {pmid24167244, year = {2013}, author = {Farrow, MA and Chumbler, NM and Lapierre, LA and Franklin, JL and Rutherford, SA and Goldenring, JR and Lacy, DB}, title = {Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {110}, number = {46}, pages = {18674-18679}, pmid = {24167244}, issn = {1091-6490}, support = {P30 DK058404/DK/NIDDK NIH HHS/United States ; T32 GM065086/GM/NIGMS NIH HHS/United States ; R01 AI095755/AI/NIAID NIH HHS/United States ; P30DK058404/DK/NIDDK NIH HHS/United States ; R37 AI095755/AI/NIAID NIH HHS/United States ; }, mesh = {Bacterial Proteins/*toxicity ; Bacterial Toxins/metabolism/*toxicity ; Blotting, Western ; Caco-2 Cells ; Enterotoxins/metabolism ; HeLa Cells ; Humans ; Microscopy, Confocal ; Multiprotein Complexes/*metabolism ; NADPH Oxidases/*metabolism ; Necrosis/*metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Transfection ; Virulence Factors/metabolism ; }, abstract = {Clostridium difficile infection (CDI) is a leading cause of health care-associated diarrhea and has increased in incidence and severity over the last decade. Pathogenesis is mediated by two toxins, TcdA and TcdB, which cause fluid secretion, inflammation, and necrosis of the colonic mucosa. TcdB is a potent cytotoxin capable of inducing enzyme-independent necrosis in both cells and tissue. In this study, we show that TcdB-induced cell death depends on assembly of the host epithelial cell NADPH oxidase (NOX) complex and the production of reactive oxygen species (ROS). Treating cells with siRNAs directed against key components of the NOX complex, chemical inhibitors of NOX function, or molecules that scavenge superoxide or ROS confers protection against toxin challenge. To test the hypothesis that chemical inhibition of TcdB-induced cytotoxicity can protect against TcdB-induced tissue damage, we treated colonic explants with diphenyleneiodonium (DPI), a flavoenzyme inhibitor, or N-acetylcysteine (NAC), an antioxidant. TcdB-induced ROS production in colonic tissue was inhibited with DPI, and both DPI and NAC conferred protection against TcdB-induced tissue damage. The efficacy of DPI and NAC provides proof of concept that chemical attenuation of ROS could serve as a viable strategy for protecting the colonic mucosa of patients with CDI.}, }
@article {pmid24167127, year = {2013}, author = {Zhang, DY and Lin, YQ and He, F and Fang, J and Zhang, C and Wang, BM and Pan, JP}, title = {[TcpC induces apoptosis of macrophages through promoting ROS production].}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {42}, number = {5}, pages = {486-491}, pmid = {24167127}, issn = {1008-9292}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Escherichia coli/metabolism ; Escherichia coli Proteins/*pharmacology ; Macrophages/*drug effects/metabolism ; Mice ; Reactive Oxygen Species/*metabolism ; Virulence Factors/*pharmacology ; }, abstract = {OBJECTIVE: To investigate the effects of Toll/interleukin 1 receptor domain-containing protein(TcpC)on macrophages and its mechanisms.<br><br>METHODS: Murine macrophage J774A cells were co-cultured with TcpC producing wild type E. coli strain CFT073 (TcpC(wt)) or tcpc gene-deleted CFT073 mutant (TcpC(mut)) in Transwell system, respectively. Apoptosis of J774A cells co-cultured with TcpC(wt) or TcpC(mut) was analyzed by Annexin/PI double staining. The levels of reactive oxygen species (ROS) in J774A cells were determined by DCFH-DA staining after treatment with TcpC(wt) or TcpC(mut) at 6 h, 12 h,24 h or 36 h. After the ROS was scavenged by N-acetylcysteine (NAC), the changes of J774A cell apoptosis were also examined. The expression of caspase-3 in J774A cells co-cultured with TcpC(wt) or TcpC(mut) in the presence or absence of 0.1 mmol NAC was detected by Western blot.<br><br>RESULTS: J774A cells co-cultured with TcpC(wt) for 24 h or 36 h showed significantly increased apoptosis (27.39% &#xb1; 4.05% and 28.45% &#xb1; 4.55%,respectively) when compared to control group (7.96% &#xb1; 1.63% and 10.55% &#xb1; 1.44%,P<0.01) or TcpC(mut) group (11.45% &#xb1; 2.77% and 19.26%&#xb1; 2.89%,P<0.01). Levels of ROS in J774A cells treated with TcpC(wt) for 24 h (108.8 &#xb1; 9.73) or 36 h (100.3 &#xb1; 10.11) were significantly higher than those in control group (56.8 &#xb1; 4.11 and 52.8 &#xb1; 4.42,P<0.01) or TcpC(mut) (69.7 &#xb1; 5.66 and 62.6 &#xb1; 4.56, P < 0.01). The pro-apoptotic effects of TcpC(wt) on J774A cells were reversed by 0.1 or 1 mMol NAC treatment. Expression of caspase-3 in J774A cells co-cultured with TcpC(wt) (0.43 &#xb1; 0.04) decreased significantly when compared to control group (0.75 &#xb1; 0.08,P<0.05) or TcpC(mut) group (0.80 &#xb1; 0.12,P<0.05). However,total caspase-3 expression was restored in J774A cells co-cultured with TcpC(wt) in the presence of 0.1 mmol NAC (0.80 &#xb1; 0.09).<br><br>CONCLUSION: TcpC can promote ROS production in macrophages,hereby inducing macrophage apoptosis.}, }
@article {pmid24161787, year = {2014}, author = {Liu, SH and Lin, CH and Liang, FP and Chen, PF and Kuo, CD and Alam, MM and Maiti, B and Hung, SK and Chi, CW and Sun, CM and Fu, SL}, title = {Andrographolide downregulates the v-Src and Bcr-Abl oncoproteins and induces Hsp90 cleavage in the ROS-dependent suppression of cancer malignancy.}, journal = {Biochemical pharmacology}, volume = {87}, number = {2}, pages = {229-242}, doi = {10.1016/j.bcp.2013.10.014}, pmid = {24161787}, issn = {1873-2968}, mesh = {Amino Acid Sequence ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Diterpenes/*pharmacology/therapeutic use ; Down-Regulation/drug effects/physiology ; Genes, abl/drug effects/*physiology ; Genes, src/drug effects/*physiology ; HSP90 Heat-Shock Proteins/genetics/*metabolism ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/metabolism ; Molecular Sequence Data ; Reactive Oxygen Species/*metabolism ; }, abstract = {Andrographolide is a diterpenoid compound isolated from Andrographis paniculata that exhibits anticancer activity. We previously reported that andrographolide suppressed v-Src-mediated cellular transformation by promoting the degradation of Src. In the present study, we demonstrated the involvement of Hsp90 in the andrographolide-mediated inhibition of Src oncogenic activity. Using a proteomics approach, a cleavage fragment of Hsp90α was identified in andrographolide-treated cells. The concentration- and time-dependent induction of Hsp90 cleavage that accompanied the reduction in Src was validated in RK3E cells transformed with either v-Src or a human truncated c-Src variant and treated with andrographolide. In cancer cells, the induction of Hsp90 cleavage by andrographolide and its structural derivatives correlated well with decreased Src levels, the suppression of transformation, and the induction of apoptosis. Moreover, the andrographolide-induced Hsp90 cleavage, Src degradation, inhibition of transformation, and induction of apoptosis were abolished by a ROS inhibitor, N-acetyl-cysteine. Notably, Hsp90 cleavage, decreased levels of Bcr-Abl (another known Hsp90 client protein), and the induction of apoptosis were also observed in human K562 leukemia cells treated with andrographolide or its active derivatives. Together, we demonstrated a novel mechanism by which andrographolide suppressed cancer malignancy that involved inhibiting Hsp90 function and reducing the levels of Hsp90 client proteins. Our results broaden the molecular basis of andrographolide-mediated anticancer activity.}, }
@article {pmid24157994, year = {2013}, author = {Manchanda, A and Cameron, C and Robinson, G}, title = {Beware of paracetamol use in alcohol abusers: a potential cause of acute liver injury.}, journal = {The New Zealand medical journal}, volume = {126}, number = {1383}, pages = {80-84}, pmid = {24157994}, issn = {1175-8716}, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/blood ; Alcoholism/*complications ; Analgesics, Non-Narcotic/*toxicity ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/*complications/diagnosis/etiology ; Female ; Humans ; Liver/drug effects ; Middle Aged ; }, abstract = {There may be under-recognition of acute liver injury following reported therapeutic use of paracetamol in alcoholics. We present the case of an alcoholic patient who developed acute liver injury suspicious for chronic paracetamol toxicity on two occasions. The likely contribution of chronic paracetamol was not recognised at her second presentation, reflecting a need for increased awareness of this potential cause of acute liver injury. The biochemical hallmark of the syndrome is the 'towering' aspartate-aminotransferase (AST), often in the thousands; transaminases above 500 U/L should never be dismissed as secondary to alcoholic liver disease alone. Whether alcoholics are at increased risk of toxicity from therapeutic doses of paracetamol remains controversial, although many cases have been described for over 30 years. Randomised controlled trials to date have failed to show significant hepatic derangement in newly abstinent alcoholics exposed to short courses of paracetamol. We argue that these studies do not reflect the realities of paracetamol use in this population. In addition, alcoholics are at risk of accidental 'staggered overdoses', or repeated supra-therapeutic ingestions. In cases of suspected paracetamol toxicity, administration of the antidote n-acetyl cysteine (NAC) should be considered, even when the patient's serum paracetamol level is normal.}, }
@article {pmid24157519, year = {2013}, author = {Addae, C and Cheng, H and Martinez-Ceballos, E}, title = {Effect of the environmental pollutant hexachlorobenzene (HCB) on the neuronal differentiation of mouse embryonic stem cells.}, journal = {International journal of environmental research and public health}, volume = {10}, number = {10}, pages = {5244-5256}, pmid = {24157519}, issn = {1660-4601}, support = {P20 GM103424/GM/NIGMS NIH HHS/United States ; P20GM103424/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine ; Animals ; Biomarkers ; Cell Differentiation/*drug effects ; Cell Line ; Dose-Response Relationship, Drug ; Embryonic Stem Cells/*cytology/*drug effects ; Environmental Pollutants/administration &amp; dosage/*toxicity ; GABAergic Neurons/drug effects ; Gene Expression Regulation ; Hexachlorobenzene/administration &amp; dosage/*toxicity ; Mice ; Neurons/*cytology/drug effects/physiology ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Exposure to persistent environmental pollutants may constitute an important factor on the onset of a number of neurological disorders such as autism, Parkinson's disease, and Attention Deficit Disorder (ADD), which have also been linked to reduced GABAergic neuronal function. GABAergic neurons produce γ-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the brain. However, the lack of appropriate models has hindered the study of suspected environmental pollutants on GABAergic function. In this work, we have examined the effect of hexachlorobenzene (HCB), a persistent and bioaccumulative environmental pollutant, on the function and morphology of GABAergic neurons generated in vitro from mouse embryonic stem (ES) cells. We observed that: (1) treatment with 0.5 nM HCB did not affect cell viability, but affected the neuronal differentiation of ES cells; (2) HCB induced the production of reactive oxygen species (ROS); and (3) HCB repressed neurite outgrowth in GABAergic neurons, but this effect was reversed by the ROS scavenger N-acetylcysteine (NAC). Our study also revealed that HCB did not significantly interfere with the function of K+ ion channels in the neuronal soma, which indicates that this pollutant does not affect the maturation of the GABAergic neuronal soma. Our results suggest a mechanism by which environmental pollutants interfere with normal GABAergic neuronal function and may promote the onset of a number of neurological disorders such as autism and ADD.}, }
@article {pmid24157283, year = {2014}, author = {Lu, TH and Tseng, TJ and Su, CC and Tang, FC and Yen, CC and Liu, YY and Yang, CY and Wu, CC and Chen, KL and Hung, DZ and Chen, YW}, title = {Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways.}, journal = {Toxicology letters}, volume = {224}, number = {1}, pages = {130-140}, doi = {10.1016/j.toxlet.2013.10.013}, pmid = {24157283}, issn = {1879-3169}, mesh = {Animals ; Apoptosis/*drug effects ; Arsenic/*toxicity ; Endoplasmic Reticulum Chaperone BiP ; Extracellular Signal-Regulated MAP Kinases/*physiology ; Heat-Shock Proteins/*physiology ; JNK Mitogen-Activated Protein Kinases/*physiology ; MAP Kinase Signaling System/drug effects ; Mice ; Mitochondria/*physiology ; Neurons/*drug effects ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/*physiology ; }, abstract = {Arsenic (As), a well-known high toxic metal, is an important environmental and industrial contaminant, and it induces oxidative stress, which causes many adverse health effects and diseases in humans, particularly in inorganic As (iAs) more harmful than organic As. Recently, epidemiological studies have suggested a possible relationship between iAs exposure and neurodegenerative disease development. However, the toxicological effects and underlying mechanisms of iAs-induced neuronal cell injuries are mostly unknown. The present study demonstrated that iAs significantly decreased cell viability and induced apoptosis in Neuro-2a cells. iAs also increased oxidative stress damage (production of malondialdehyde (MDA) and ROS, and reduction of Nrf2 and thioredoxin protein expression) and induced several features of mitochondria-dependent apoptotic signals, including: mitochondrial dysfunction, the activations of PARP and caspase cascades, and the increase in caspase-3 activity. Pretreatment with the antioxidant N-acetylcysteine (NAC) effectively reversed these iAs-induced responses. iAs also increased the phosphorylation of JNK and ERK1/2, but did not that p38-MAPK, in treated Neuro-2a cells. NAC and the specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) abrogated iAs-induced cell cytotoxicity, caspase-3/-7 activity, and JNK and ERK1/2 activation. Additionally, exposure of Neuro-2a cells to iAs triggered endoplasmic reticulum (ER) stress identified through several key molecules (GRP 78, CHOP, XBP-1, and caspase-12), which was prevented by NAC. Transfection with GRP 78- and CHOP-specific si-RNA dramatically suppressed GRP 78 and CHOP expression, respectively, and attenuated the activations of caspase-12, -7, and -3 in iAs-exposed cells. Therefore, these results indicate that iAs induces ROS causing neuronal cell death via both JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-triggered apoptosis pathways.}, }
@article {pmid24149112, year = {2013}, author = {Chung, TW and Choi, HJ and Kim, CH and Jeong, HS and Ha, KT}, title = {Lipocalin-2 elicited by advanced glycation end-products promotes the migration of vascular smooth muscle cells.}, journal = {Biochimica et biophysica acta}, volume = {1833}, number = {12}, pages = {3386-3395}, doi = {10.1016/j.bbamcr.2013.10.011}, pmid = {24149112}, issn = {0006-3002}, mesh = {Acute-Phase Proteins/genetics/*metabolism ; Base Sequence ; CCAAT-Enhancer-Binding Protein-beta/metabolism ; Cell Movement/*drug effects ; Cell Proliferation/drug effects ; Chromatin Immunoprecipitation ; Gene Knockdown Techniques ; Glycation End Products, Advanced/*pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lipocalin-2 ; Lipocalins/genetics/*metabolism ; Models, Biological ; Molecular Sequence Data ; Muscle, Smooth, Vascular/*cytology ; Myocytes, Smooth Muscle/*cytology/drug effects/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Promoter Regions, Genetic/genetics ; Proto-Oncogene Proteins/genetics/*metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic/metabolism ; Signal Transduction/drug effects ; Transcriptional Activation/drug effects ; }, abstract = {Advanced glycation end-products (AGEs) play key roles in the development of diabetic vascular complications by activating the proliferation and migration of vascular smooth muscle cells. Here, we identified an increase of the migratory properties of human aortic smooth muscle cells (HASMC) through AGE-induced expression of lipocalin-2 (LCN2). Because the AGE-elicited expression of LCN2 was diminished by an antibody against the AGE receptor (RAGE), diphenylene iodonium (DPI), N-acetyl cysteine, LY294002, and SP600125, we suggest that AGEs enhance the expression of LCN2 via a RAGE-NADPH oxidase-reactive oxygen species pathway, leading to the phosphorylation of PI3K-Akt and JNK in HASMCs. In addition, a chromatin immunoprecipitation assay and promoter assay revealed that CCAAT/enhancer binding protein β is crucial for AGE-induced expression of LCN2. However, any other AGE-related signaling pathway, including ERK1/2, p38, NF-κB, and AP-1, did not affect the AGE- induced expression of LCN2. Knockdown of LCN2 expression by shRNA showed that AGE-elicited LCN2 expression enhanced the invasive and migratory properties of HASMCs, but showed no effect on cell proliferation. Considering the importance of HASMC migration in the development of atherosclerosis, our study provides a novel insight into diabetic vascular complications.}, }
@article {pmid24148476, year = {2013}, author = {Bian, W and Ma, J and Guo, W and Lu, D and Fan, M and Wei, Y and Li, Y and Shuang, S and Choi, MM}, title = {Phosphorescence detection of L-ascorbic acid with surface-attached N-acetyl-L-cysteine and L-cysteine Mn doped ZnS quantum dots.}, journal = {Talanta}, volume = {116}, number = {}, pages = {794-800}, doi = {10.1016/j.talanta.2013.07.076}, pmid = {24148476}, issn = {1873-3573}, mesh = {Acetylcysteine/*chemistry ; Ascorbic Acid/*urine ; Cysteine/*chemistry ; Humans ; Hydrogen-Ion Concentration ; Kinetics ; Limit of Detection ; Luminescent Measurements ; Manganese/chemistry ; Molecular Probes/*chemistry ; Quantum Dots/*chemistry ; Sulfides/chemistry ; Temperature ; Zinc Compounds/chemistry ; }, abstract = {N-Acetyl-L-cysteine (NAC) and L-cysteine (Cys) capped Mn doped ZnS quantum dots (NAC-Mn/ZnS QDs and Cys-Mn/ZnS QDs) are firstly prepared by hydrothermal methods. These QDs display strong phosphorescence emission peaks at 583 and 580 nm upon excitation at 315 and 306 nm, respectively. Since their room-temperature phosphorescence is efficiently quenched by L-ascorbic acid (AA), they have been employed as phosphorescence probes for detecting AA. The linear working ranges are 2.5-37.5 and 2.5-47.5 µM and the limits of detection are 0.72 and 1.38 µM for NAC-Mn/ZnS QDs and Cys-Mn/ZnS QDs, respectively. The possible quenching mechanisms have been discussed in detail. The QDs probes are highly selective to AA over other common ions, amino acids, glucose and bovine serum album. Finally, they have been applied successfully for detection of AA in human urine samples with satisfactory results. The recoveries are 98-104%. Our work provides a simple and convenient phosphorescence method to determine AA in real samples.}, }
@article {pmid24145059, year = {2013}, author = {Hossain, E and Ota, A and Karnan, S and Damdindorj, L and Takahashi, M and Konishi, Y and Konishi, H and Hosokawa, Y}, title = {Arsenic augments the uptake of oxidized LDL by upregulating the expression of lectin-like oxidized LDL receptor in mouse aortic endothelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {273}, number = {3}, pages = {651-658}, doi = {10.1016/j.taap.2013.10.012}, pmid = {24145059}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aorta/*cytology/drug effects ; Arsenites/*toxicity ; Atherosclerosis/chemically induced/pathology ; Caffeic Acids/pharmacology ; Cell Line ; Endothelial Cells/*drug effects/metabolism ; Lipoproteins, LDL/*pharmacokinetics ; Mice ; NF-kappa B/antagonists &amp; inhibitors/genetics/metabolism ; Phenylethyl Alcohol/analogs &amp; derivatives/pharmacology ; Phosphorylation ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Scavenger Receptors, Class E/genetics/*metabolism ; Signal Transduction ; Sodium Compounds/*toxicity ; Up-Regulation ; }, abstract = {Although chronic arsenic exposure is a well-known risk factor for cardiovascular diseases, including atherosclerosis, the molecular mechanism underlying arsenic-induced atherosclerosis remains obscure. Therefore, this study aimed to elucidate this molecular mechanism. We examined changes in the mRNA level of the lectin-like oxidized LDL (oxLDL) receptor (LOX-1) in a mouse aortic endothelial cell line, END-D, after sodium arsenite (SA) treatment. SA treatment significantly upregulated LOX-1 mRNA expression; this finding was also verified at the protein expression level. Flow cytometry and fluorescence microscopy analyses showed that the cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with SA treatment. In addition, an anti-LOX-1 antibody completely abrogated the augmented uptake of Dil-oxLDL. We observed that SA increased the levels of the phosphorylated forms of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB)/p65. SA-induced upregulation of LOX-1 protein expression was clearly prevented by treatment with an antioxidant, N-acetylcysteine (NAC), or an NF-κB inhibitor, caffeic acid phenethylester (CAPE). Furthermore, SA-augmented uptake of Dil-oxLDL was also prevented by treatment with NAC or CAPE. Taken together, our results indicate that arsenic upregulates LOX-1 expression through the reactive oxygen species-mediated NF-κB signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of the aberrant LOX-1 signaling pathway in the pathogenesis of arsenic-induced atherosclerosis.}, }
@article {pmid24142350, year = {2013}, author = {Condello, S and Currò, M and Ferlazzo, N and Costa, G and Visalli, G and Caccamo, D and Pisani, LR and Costa, C and Calabresi, P and Ientile, R and Pisani, F}, title = {Protective effects of zonisamide against rotenone-induced neurotoxicity.}, journal = {Neurochemical research}, volume = {38}, number = {12}, pages = {2631-2639}, pmid = {24142350}, issn = {1573-6903}, mesh = {Apoptosis/drug effects ; Cell Line, Tumor ; Humans ; Isoxazoles/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Nervous System/*drug effects ; Reactive Oxygen Species/metabolism ; Rotenone/*toxicity ; Zonisamide ; }, abstract = {Zonisamide (ZNS), an antiepileptic drug having beneficial effects also against Parkinson's disease symptoms, has proven to display an antioxidant effects in different experimental models. In the present study, the effects of ZNS on rotenone-induced cell injury were investigated in human neuroblastoma SH-SY5Y cells differentiated towards a neuronal phenotype. Cell cultures were exposed for 24 h to 500 nM rotenone with or without pre-treatment with 10-100 μM ZNS. Then, the following parameters were analyzed: (a) cell viability; (b) intracellular reactive oxygen species production; (c) mitochondrial transmembrane potential; (d) cell necrosis and apoptosis; (e) caspase-3 activity. ZNS dose-dependently suppressed rotenone-induced cell damage through a decrease in intracellular ROS production, and restoring mitochondrial membrane potential. Similarly to ZNS effects, the treatment with N-acetyl-cysteine (100 μM) displayed significant protective effects against rotenone-induced ROS production and Δψm at 4 and 12 h respectively, reaching the maximal extent at 24 h. Additionally, ZNS displayed antiapoptotic effects, as demonstrated by flow cytometric analysis of annexin V/propidium iodide double staining, and significant attenuated rotenone-increased caspase 3 activity. On the whole, these findings suggest that ZNS preserves mitochondrial functions and counteracts apoptotic signalling mechanisms mainly by an antioxidant action. Thus, ZNS might have beneficial effect against neuronal cell degeneration in different experimental models involving mitochondrial dysfunction.}, }
@article {pmid24141489, year = {2013}, author = {Luo, H and Wang, L and Schulte, BA and Yang, A and Tang, S and Wang, GY}, title = {Resveratrol enhances ionizing radiation-induced premature senescence in lung cancer cells.}, journal = {International journal of oncology}, volume = {43}, number = {6}, pages = {1999-2006}, pmid = {24141489}, issn = {1791-2423}, support = {UL1TR000062/TR/NCATS NIH HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; R21 HL106451/HL/NHLBI NIH HHS/United States ; HL106451/HL/NHLBI NIH HHS/United States ; CA138313/CA/NCI NIH HHS/United States ; P30 CA138313/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/radiation effects ; Carcinoma, Non-Small-Cell Lung/drug therapy/radiotherapy ; Cell Cycle Checkpoints/drug effects/radiation effects ; Cell Line, Tumor ; Cellular Senescence/*drug effects/*radiation effects ; DNA Breaks, Double-Stranded/drug effects/radiation effects ; Humans ; Lung Neoplasms/drug therapy/radiotherapy ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Radiation Tolerance/drug effects ; Radiation-Sensitizing Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; Resveratrol ; Ribonucleotide Reductases/antagonists &amp; inhibitors ; Stilbenes/*pharmacology ; TOR Serine-Threonine Kinases/metabolism ; beta-Galactosidase/metabolism ; }, abstract = {Radiotherapy is used in >50% of patients during the course of cancer treatment both as a curative modality and for palliation. However, radioresistance is a major obstacle to the success of radiation therapy and contributes significantly to tumor recurrence and treatment failure, highlighting the need for the development of novel radiosensitizers that can be used to overcome tumor radioresistance and, thus, improve the efficacy of radiotherapy. Previous studies indicated that resveratrol (RV) may sensitize tumor cells to chemotherapy and ionizing radiation (IR). However, the mechanisms by which RV increases the radiation sensitivity of cancer cells have not been well characterized. Here, we show that RV treatment enhances IR-induced cell killing in non-small cell lung cancer (NSCLC) cells through an apoptosis-independent mechanism. Further studies revealed that the percentage of senescence-associated β-galactosidase (SA-β-gal)-positive senescent cells was markedly higher in cells treated with IR in combination with RV compared with cells treated either with IR or RV alone, suggesting that RV treatment enhances IR-induced premature senescence in lung cancer cells. Comet assays demonstrate that RV and IR combined treatment causes more DNA double-strand breaks (DSBs) than IR or RV treatment alone. DCF-DA staining and flow cytometric analyses demonstrate that RV and IR combined treatment leads to a significant increase in ROS production in irradiated NSCLC cells. Furthermore, our investigation show that inhibition of ROS production by N-acetyl-cysteine attenuates RV-induced radiosensitization in lung cancer cells. Collectively, these results demonstrate that RV-induced radiosensitization is associated with significant increase of ROS production, DNA-DSBs and senescence induction in irradiated NSCLC cells, suggesting that RV treatment may sensitize lung cancer cells to radiotherapy via enhancing IR-induced premature senescence.}, }
@article {pmid24141202, year = {2013}, author = {Chen, Y and Qin, MY and Wu, JH and Wang, L and Chao, H and Ji, LN and Xu, AL}, title = {Synthesis, characterization, and anticancer activity of ruthenium(II)-β-carboline complex.}, journal = {European journal of medicinal chemistry}, volume = {70}, number = {}, pages = {120-129}, doi = {10.1016/j.ejmech.2013.09.051}, pmid = {24141202}, issn = {1768-3254}, mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Apoptosis/drug effects ; Carbolines/*chemistry ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; HCT116 Cells ; HeLa Cells ; Hep G2 Cells ; Humans ; MCF-7 Cells ; Molecular Structure ; Organometallic Compounds/chemical synthesis/chemistry/*pharmacology ; Reactive Oxygen Species/metabolism ; Ruthenium/*chemistry ; Structure-Activity Relationship ; Tumor Cells, Cultured ; }, abstract = {Four [Ru(tpy)(N-N)(L)] type complexes: [Ru(tpy)(bpy)(Nh)](2+) (Ru1, tpy = 2,2';6',2″-terpyridine, bpy = 2'2-bipyridine, Nh = Norharman), [Ru(tpy)(phen)(Nh)](2+) (Ru2, phen = 1,10-phenanthroline), [Ru(tpy)(dpa)(Nh)](2+) (Ru3, dpa = 2,2'-dipyridylamine) and [Ru(tpy)(dip)(Nh)](2+) (Ru4, dip = 4,7-diphenyl-1,10-phenanthroline) were presented as anticancer drugs. In vitro cytotoxicity assays indicated that these complexes showed anticancer activity against various cancer cells. Flow cytometry and signaling pathways analysis demonstrated that these complexes induced apoptosis via the mitochondrial pathway, as evidenced by the loss of mitochondrial membrane potential and the release of cytochrome c. The resulting accumulation of p53 proteins from phosphorylation at serine-15 and serine-392 was correlated with an increase in p21 and caspase activation. Taken together, these findings suggested that Ru1-Ru4 may contribute to the future development of improved chemotherapeutics against human cancers.}, }
@article {pmid24134853, year = {2013}, author = {Champelovier, P and Chauchet, X and Hazane-Puch, F and Vergnaud, S and Garrel, C and Laporte, F and Boutonnat, J and Boumendjel, A}, title = {Cellular and molecular mechanisms activating the cell death processes by chalcones: Critical structural effects.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {27}, number = {8}, pages = {2305-2315}, doi = {10.1016/j.tiv.2013.09.021}, pmid = {24134853}, issn = {1879-3177}, mesh = {Antineoplastic Agents/*pharmacology ; Catalase/genetics ; Cell Cycle/drug effects ; Cell Death/drug effects/physiology ; Cell Line, Tumor ; Chalcones/*pharmacology ; Glutathione Peroxidase/genetics ; Humans ; Malondialdehyde/metabolism ; Mitotic Index ; Reactive Oxygen Species/metabolism ; Glutathione Peroxidase GPX1 ; }, abstract = {Chalcones are naturally occurring compounds with diverse pharmacological activities. Chalcones derive from the common structure: 1,3-diphenylpropenone. The present study aims to better understand the mechanistic pathways triggering chalcones anticancer effects and providing evidences that minor structural difference could lead to important difference in mechanistic effect. We selected two recently investigated chalcones (A and B) and investigated them on glioblastoma cell lines. It was found that chalcone A induced an apoptotic process (type I PCD), via the activation of caspase-3, -8 and -9. Chalcone A also increased CDK1/cyclin B ratios and decreased the mitochondrial transmembrane potential (ΔΨm). Chalcone B induced an autophagic cell death process (type II PCD), ROS-related but independent of both caspases and protein synthesis. Both chalcones increased Bax/Bcl2 ratios and decreased Ki67 and CD71 antigen expressions. The present investigation reveals that despite the close structure of chalcones A and B, significant differences in mechanism of effect were found.}, }
@article {pmid24134840, year = {2013}, author = {Yu, T and Ji, J and Guo, YL}, title = {MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells.}, journal = {Biochemical and biophysical research communications}, volume = {441}, number = {1}, pages = {53-58}, doi = {10.1016/j.bbrc.2013.10.008}, pmid = {24134840}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Nucleus/drug effects/*metabolism ; Curcumin/*pharmacology ; Enzyme Activation/drug effects ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/*metabolism ; Hepatocyte Growth Factor/*metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Melanoma/*enzymology/pathology ; Melanoma, Experimental/enzymology/pathology ; Mice ; Protein Transport/drug effects ; Proto-Oncogene Proteins/*metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Different groups including ours have shown that curcumin induces melanoma cell apoptosis, here we focused the role of mammalian Sterile 20-like kinase 1 (MST1) in it. We observed that curcumin activated MST1-dependent apoptosis in cultured melanoma cells. MST1 silencing by RNA interference (RNAi) suppressed curcumin-induced cell apoptosis, while MST1 over-expressing increased curcumin sensitivity. Meanwhile, curcumin induced reactive oxygen species (ROS) production in melanoma cells, and the ROS scavenger, N-acetyl-cysteine (NAC), almost blocked MST1 activation to suggest that ROS might be required for MST1 activation by curcumin. c-Jun N-terminal protein kinase (JNK) activation by curcumin was dependent on MST1, since MST1 inhibition by RNAi or NAC largely inhibited curcumin-induced JNK activation. Further, curcumin induced Foxo3 nuclear translocation and Bim-1 (Foxo3 target gene) expression in melanoma cells, such an effect by curcumin was inhibited by MST1 RNAi. In conclusion, we suggested that MST1 activation by curcumin mediates JNK activation, Foxo3a nuclear translocation and apoptosis in melanoma cells.}, }
@article {pmid24128853, year = {2013}, author = {Yang, CR and Liao, WS and Wu, YH and Murugan, K and Chen, C and Chao, JI}, title = {CR108, a novel vitamin K3 derivative induces apoptosis and breast tumor inhibition by reactive oxygen species and mitochondrial dysfunction.}, journal = {Toxicology and applied pharmacology}, volume = {273}, number = {3}, pages = {611-622}, doi = {10.1016/j.taap.2013.10.007}, pmid = {24128853}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Aged ; Animals ; Apoptosis/*drug effects ; Cell Survival ; Cytochromes c/metabolism ; Female ; Humans ; Imidazoles/pharmacology ; Inhibitor of Apoptosis Proteins/antagonists &amp; inhibitors/metabolism ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Nude ; Mitochondria/*drug effects/metabolism ; Naphthoquinones/*pharmacology ; Phosphorylation ; Pyridines/pharmacology ; Reactive Oxygen Species/*metabolism ; Survivin ; Vitamin K 3/*analogs &amp; derivatives/*pharmacology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Vitamin K3 derivatives have been shown to exert anticancer activities. Here we show a novel vitamin K3 derivative (S)-2-(2-hydroxy-3-methylbutylthio)naphthalene-1,4-dione, which is named as CR108 that induces apoptosis and tumor inhibition through reactive oxygen species (ROS) and mitochondrial dysfunction in human breast cancer. CR108 is more effective on the breast cancer cell death than other vitamin K3 derivatives. Moreover, CR108 induced apoptosis in both the non-HER-2-overexpressed MCF-7 and HER-2-overexpressed BT-474 breast cancer cells. CR108 caused the loss of mitochondrial membrane potential, cytochrome c released from mitochondria to cytosol, and cleaved PARP proteins for apoptosis induction. CR108 markedly increased ROS levels in breast cancer cells. N-acetylcysteine (NAC), a general ROS scavenger, completely blocked the CR108-induced ROS levels, mitochondrial dysfunction and apoptosis. Interestingly, CR108 increased the phosphorylation of p38 MAP kinase but conversely inhibited the survivin protein expression. NAC treatment prevented the activation of p38 MAP kinase and rescued the survivin protein levels. SB202190, a specific p38 MAP kinase inhibitor, recovered the survivin protein levels and attenuated the cytotoxicity of CR108-treated cells. Furthermore, CR108 inhibited the xenografted human breast tumor growth in nude mice. Together, we demonstrate that CR108 is a novel vitamin K3 derivative that induces apoptosis and tumor inhibition by ROS production and mitochondrial dysfunction and associates with the phosphorylation of p38 MAP kinase and the inhibition of survivin in the human breast cancer.}, }
@article {pmid24126683, year = {2013}, author = {D'Anneo, A and Carlisi, D and Emanuele, S and Buttitta, G and Di Fiore, R and Vento, R and Tesoriere, G and Lauricella, M}, title = {Parthenolide induces superoxide anion production by stimulating EGF receptor in MDA-MB-231 breast cancer cells.}, journal = {International journal of oncology}, volume = {43}, number = {6}, pages = {1895-1900}, doi = {10.3892/ijo.2013.2137}, pmid = {24126683}, issn = {1791-2423}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/metabolism ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antioxidants/pharmacology ; Breast Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/antagonists &amp; inhibitors/*metabolism ; Female ; Humans ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; NF-kappa B/antagonists &amp; inhibitors ; Phosphorylation/drug effects ; Protein Tyrosine Phosphatases/antagonists &amp; inhibitors ; Quinazolines/pharmacology ; Sesquiterpenes/*pharmacology ; Superoxides/*metabolism ; Tyrphostins/pharmacology ; }, abstract = {The sesquiterpene lactone parthenolide (PN) has recently attracted considerable attention because of its anti-microbial, anti-inflammatory and anticancer effects. However, the mechanism of its cytotoxic action on tumor cells remains scarcely defined. We recently provided evidence that the effect exerted by PN in MDA-MB-231 breast cancer cells was mediated by the production of reactive oxygen species (ROS). The present study shows that PN promoted the phosphorylation of EGF receptor (phospho-EGFR) at Tyr1173, an event which was observed already at 1 h of incubation with 25 µM PN and reached a peak at 8-16 h. This effect seemed to be a consequence of ROS production, because N-acetylcysteine (NAC), a powerful ROS scavenger, prevented the increment of phospho-EGFR levels. In addition fluorescence analyses performed using dihydroethidium demonstrated that PN stimulated the production of superoxide anion already at 2-3 h of incubation and the effect further increased prolonging the time of treatment, reaching a peak at 8-16 h. Superoxide anion production was markedly hampered by apocynin, a well known NADPH oxidase (NOX) inhibitor, suggesting that the effect was dependent on NOX activity. The finding that AG1478, an EGFR kinase inhibitor, substantially blocked both EGFR phosphorylation and superoxide anion production strongly suggested that phosphorylation of EGFR can be responsible for the activation of NOX with the consequent production of superoxide anion. Therefore, EGFR phosphorylation can exert a key role in the production of superoxide anion and ROS induced by PN in MDA-MB-231 cells.}, }
@article {pmid24126434, year = {2013}, author = {Dinnen, RD and Mao, Y and Qiu, W and Cassai, N and Slavkovich, VN and Nichols, G and Su, GH and Brandt-Rauf, P and Fine, RL}, title = {Redirecting apoptosis to aponecrosis induces selective cytotoxicity to pancreatic cancer cells through increased ROS, decline in ATP levels, and VDAC.}, journal = {Molecular cancer therapeutics}, volume = {12}, number = {12}, pages = {2792-2803}, pmid = {24126434}, issn = {1538-8514}, support = {R01 CA082528/CA/NCI NIH HHS/United States ; R01 82528//PHS HHS/United States ; R56 CA109525/CA/NCI NIH HHS/United States ; P42 ES010349/ES/NIEHS NIH HHS/United States ; R01CA109525/CA/NCI NIH HHS/United States ; P30-ES09089/ES/NIEHS NIH HHS/United States ; R01 CA109525/CA/NCI NIH HHS/United States ; RC2 CA148346/CA/NCI NIH HHS/United States ; P30 ES009089/ES/NIEHS NIH HHS/United States ; P42-ES10349/ES/NIEHS NIH HHS/United States ; NCI-RC2-CA-148346/CA/NCI NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/*metabolism ; Animals ; Antineoplastic Agents/administration &amp; dosage/pharmacology ; *Apoptosis/drug effects ; Arsenic Trioxide ; Arsenicals/administration &amp; dosage/pharmacology ; Ascorbic Acid/administration &amp; dosage/pharmacology ; Cell Line, Tumor ; Disease Models, Animal ; Disulfiram/administration &amp; dosage/pharmacology ; Dose-Response Relationship, Drug ; Heterografts ; Humans ; Male ; Mice ; Necrosis/*metabolism ; Oxides/administration &amp; dosage/pharmacology ; Pancreatic Neoplasms/drug therapy/*metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Tumor Stem Cell Assay ; Voltage-Dependent Anion Channels/*metabolism ; }, abstract = {Pancreatic cancer cell lines with mutated ras underwent an alternative form of cell death (aponecrosis) when treated concomitantly with clinically achievable concentrations of arsenic trioxide, ascorbic acid, and disulfiram (Antabuse; AAA). AAA's major effects are mediated through generation of intracellular reactive oxygen species (ROS) and more than 50% decline in intracellular ATP. N-acetyl cysteine and a superoxide dismutase mimetic prevented aponecrosis and restored intracellular ATP levels. DIDS (4,4'-diisothiocyanatostilbene-2, 2' disulfonic acid), the pan- Voltage-Dependent Anion Channel (VDAC), -1, 2, 3 inhibitor and short hairpin RNA (shRNA) to VDAC-1 blocked cell death and ROS accumulation. In vivo exposure of AAA led to a 62% reduction in mean tumor size and eliminated tumors in 30% of nude mice with PANC-1 xenografts. We concluded that early caspase-independent apoptosis was shifted to VDAC-mediated "targeted" aponecrosis by the addition of disulfiram to arsenic trioxide and ascorbic acid. Conceptually, this work represents a paradigm shift where switching from apoptosis to aponecrosis death pathways, also known as targeted aponecrosis, could be utilized to selectively kill pancreatic cancer cells resistant to apoptosis.}, }
@article {pmid24126012, year = {2014}, author = {Aueviriyavit, S and Phummiratch, D and Maniratanachote, R}, title = {Mechanistic study on the biological effects of silver and gold nanoparticles in Caco-2 cells--induction of the Nrf2/HO-1 pathway by high concentrations of silver nanoparticles.}, journal = {Toxicology letters}, volume = {224}, number = {1}, pages = {73-83}, doi = {10.1016/j.toxlet.2013.09.020}, pmid = {24126012}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Caco-2 Cells ; Gene Expression Regulation/drug effects ; Gold/*toxicity ; Heme Oxygenase-1/*physiology ; Humans ; Metal Nanoparticles/*toxicity ; NF-E2-Related Factor 2/*physiology ; Oxidative Stress/drug effects ; Signal Transduction/*drug effects ; Silver/*toxicity ; }, abstract = {The most commonly used metal nanoparticles (NPs) across diverse applications, including in agro-food applications, include silver (AgNPs) and gold (AuNPs). In the present study, we aimed to investigate the biological responses and possible toxicological effects of AgNPs and AuNPs in the Caco-2 cells as an in vitro human GI tract model. Both AgNPs and AuNPs were internalized into the cytoplasm of Caco-2 cells, but not within the nucleus and only exposure to high concentrations of AgNPs, but not AuNPs, caused acute cytotoxicity and depolarization of the mitochondrial membrane potential. In addition, only AgNPs significantly depleted the total intracellular glutathione level, induced the activation of the stress-responsive gene, Nrf2, and dramatically increased the expression of heme oxygenase-1 (HO-1). Furthermore, siRNA silencing of Nrf2 transcripts significantly reduced the AgNP-induced HO-1 mRNA induction, suggesting a key role for Nrf2 in the control of HO-1 expression. Taken together, AgNPs but not AuNPs induced acute cytotoxicity and cellular responses via the oxidative stress-related activation of Nrf2/HO-1 signaling pathway in Caco-2 cells. The expression of HO-1 transcripts may be useful as a sensitive marker for safety evaluation of AgNPs in the GI tract of humans.}, }
@article {pmid24125707, year = {2014}, author = {Lee, YJ and Choi, SY and Yang, JH}, title = {PFHxS induces apoptosis of neuronal cells via ERK1/2-mediated pathway.}, journal = {Chemosphere}, volume = {94}, number = {}, pages = {121-127}, doi = {10.1016/j.chemosphere.2013.09.059}, pmid = {24125707}, issn = {1879-1298}, mesh = {Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Fluorocarbons ; Hazardous Substances/*toxicity ; MAP Kinase Signaling System/*physiology ; Neurons/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sulfonic Acids/*toxicity ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Perfluorohexanesulfonate (PFHxS) is one of the most widely distributed perfluoroalkyl compounds (PFCs) and its possible neurotoxicity has been suggested. However, the effects of PFHxS on neuronal function remain to be elucidated. In this study, the effects of PFHxS on neuronal cell death and the underlying mechanisms were examined. Cerebellar granule cells (CGCs) were isolated from 7-day old rat pups and maintained in culture for additional 7d. The apoptotic effects of PFHxS were determined by caspase-3 activity and TUNEL staining. PFHxS increased the apoptotic death of CGC in concentration-dependent manner. It also increased the activation of ERK1/2, JNK and p38 MAPK with different temporal activation. PD98059, an inhibitor of ERK1/2 pathway, completely blocked PFHxS-induced apoptosis whereas SP600125, a JNK inhibitor, significantly increased the apoptosis, showing their opposite roles in the apoptosis of CGCs. Treatment of antioxidants, Trolox or N-acetylcysteine (NAC), completely blocked ROS generation by PFHxS but neither of these antioxidants prevented PFHxS-induced apoptosis, suggesting that ROS may not play a key role in the process of apoptosis. PD98059 prevented ROS accumulation by PFHxS but the ERK1/2 activation was not affected by Trolox or NAC. These results indicate that ROS is one of downstream targets of ERK1/2, not vice versa. Taken together, PFHxS increased apoptosis of CGC in ERK1/2-dependent manner, where downstream pathway other than ROS may play a major role. This is a first report that PFHxS induces apoptosis of CGC isolated from the developing brain and its possible mode of action is associated with ERK1/2 pathway.}, }
@article {pmid24124652, year = {2014}, author = {Delgado, M and Garrido, F and Pérez-Miguelsanz, J and Pacheco, M and Partearroyo, T and Pérez-Sala, D and Pajares, MA}, title = {Acute liver injury induces nucleocytoplasmic redistribution of hepatic methionine metabolism enzymes.}, journal = {Antioxidants &amp; redox signaling}, volume = {20}, number = {16}, pages = {2541-2554}, pmid = {24124652}, issn = {1557-7716}, mesh = {Acetaminophen/pharmacology ; Acute Disease ; Adenosylhomocysteinase/*metabolism ; Animals ; Chemical and Drug Induced Liver Injury/*metabolism ; Cytoplasm/drug effects/*metabolism ; Galactosamine/pharmacology ; Liver/drug effects/*enzymology/metabolism ; Male ; Methionine/*metabolism ; Methionine Adenosyltransferase/*metabolism ; Rats ; Rats, Wistar ; Tumor Cells, Cultured ; }, abstract = {AIMS: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease.<br><br>RESULTS: Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) &#x3b1;1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MAT&#x3b1;1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MAT&#x3b1;1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MAT&#x3b1;1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MAT&#x3b1;1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells.<br><br>INNOVATION: Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker.<br><br>CONCLUSION: Altogether these results demonstrate galactosamine- and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of redox-dependent mechanisms in the control of MAT&#x3b1;1 subcellular distribution.}, }
@article {pmid24124565, year = {2013}, author = {Pereboeva, L and Westin, E and Patel, T and Flaniken, I and Lamb, L and Klingelhutz, A and Goldman, F}, title = {DNA damage responses and oxidative stress in dyskeratosis congenita.}, journal = {PloS one}, volume = {8}, number = {10}, pages = {e76473}, pmid = {24124565}, issn = {1932-6203}, support = {T35 HL007473/HL/NHLBI NIH HHS/United States ; AG0227388/AG/NIA NIH HHS/United States ; }, mesh = {Antineoplastic Agents/toxicity ; Apoptosis/drug effects/genetics/radiation effects ; Biomarkers ; *DNA Damage ; Dyskeratosis Congenita/*genetics/*metabolism ; Gene Expression Regulation/drug effects/radiation effects ; Humans ; *Oxidative Stress ; Radiation ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/drug effects/metabolism/radiation effects ; Tumor Suppressor Protein p53/genetics ; }, abstract = {Dyskeratosis congenita (DC) is an inherited multisystem disorder of premature aging, cancer predisposition, and bone marrow failure caused by selective exhaustion of highly proliferative cell pools. DC patients also have a poor tolerance to chemo/radiotherapy and bone marrow transplantation. Although critically shortened telomeres and defective telomere maintenance contribute to DC pathology, other mechanisms likely exist. We investigate the link between telomere dysfunction and oxidative and DNA damage response pathways and assess the effects of antioxidants. In vitro studies employed T lymphocytes from DC subjects with a hTERC mutation and age-matched controls. Cells were treated with cytotoxic agents, including Paclitaxel, Etoposide, or ionizing radiation. Apoptosis and reactive oxygen species (ROS) were assessed by flow cytometry, and Western blotting was used to measure expression of DNA damage response (DDR) proteins, including total p53, p53S15, and p21(WAF). N-acetyl-cysteine (NAC), an antioxidant, was used to modulate cell growth and ROS. In stimulated culture, DC lymphocytes displayed a stressed phenotype, characterized by elevated levels of ROS, DDR and apoptotic markers as well as a proliferative defect that was more pronounced after exposure to cytotoxic agents. NAC partially ameliorated the growth disadvantage of DC cells and decreased radiation-induced apoptosis and oxidative stress. These findings suggest that oxidative stress may play a role in the pathogenesis of DC and that pharmacologic intervention to correct this pro-oxidant imbalance may prove useful in the clinical setting, potentially alleviating untoward toxicities associated with current cytotoxic treatments.}, }
@article {pmid24122013, year = {2013}, author = {Gao, J and Ding, XS and Zhang, YM and Dai, DZ and Liu, M and Zhang, C and Dai, Y}, title = {Hypoxia/oxidative stress alters the pharmacokinetics of CPU86017-RS through mitochondrial dysfunction and NADPH oxidase activation.}, journal = {Acta pharmacologica Sinica}, volume = {34}, number = {12}, pages = {1575-1584}, pmid = {24122013}, issn = {1745-7254}, mesh = {Animals ; Anti-Arrhythmia Agents/*pharmacokinetics ; Area Under Curve ; Chromatography, High Pressure Liquid ; Dose-Response Relationship, Drug ; Enzyme Activation ; Half-Life ; Heterocyclic Compounds, 4 or More Rings/*pharmacokinetics ; Male ; Microsomes, Liver/enzymology ; NADPH Oxidases/*metabolism ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIM: Hypoxia/oxidative stress can alter the pharmacokinetics (PK) of CPU86017-RS, a novel antiarrhythmic agent. The aim of this study was to investigate the mechanisms underlying the alteration of PK of CPU86017-RS by hypoxia/oxidative stress.<br><br>METHODS: Male SD rats exposed to normal or intermittent hypoxia (10% O2) were administered CPU86017-RS (20, 40 or 80 mg/kg, ig) for 8 consecutive days. The PK parameters of CPU86017-RS were examined on d 8. In a separate set of experiments, female SD rats were injected with isoproterenol (ISO) for 5 consecutive days to induce a stress-related status, then CPU86017-RS (80 mg/kg, ig) was administered, and the tissue distributions were examined. The levels of Mn-SOD (manganese containing superoxide dismutase), endoplasmic reticulum (ER) stress sensor proteins (ATF-6, activating transcription factor 6 and PERK, PRK-like ER kinase) and activation of NADPH oxidase (NOX) were detected with Western blotting. Rat liver microsomes were incubated under N2 for in vitro study.<br><br>RESULTS: The Cmax, t1/2, MRT (mean residence time) and AUC (area under the curve) of CPU86017-RS were significantly increased in the hypoxic rats receiving the 3 different doses of CPU86017-RS. The hypoxia-induced alteration of PK was associated with significantly reduced Mn-SOD level, and increased ATF-6, PERK and NOX levels. In ISO-treated rats, the distributions of CPU86017-RS in plasma, heart, kidney, and liver were markedly increased, and NOX levels in heart, kidney, and liver were significantly upregulated. Co-administration of the NOX blocker apocynin eliminated the abnormalities in the PK and tissue distributions of CPU86017-RS induced by hypoxia/oxidative stress. The metabolism of CPU86017-RS in the N2-treated liver microsomes was significantly reduced, addition of N-acetylcysteine (NAC), but not vitamin C, effectively reversed this change.<br><br>CONCLUSION: The altered PK and metabolism of CPU86017-RS induced by hypoxia/oxidative stress are produced by mitochondrial abnormalities, NOX activation and ER stress; these abnormalities are significantly alleviated by apocynin or NAC.}, }
@article {pmid24120238, year = {2013}, author = {Zhang, P and Du, J and Zhao, L and Wang, X and Zhang, Y and Yan, R and Dai, J and Liu, G and Zhang, F and Dai, K}, title = {The role of intraplatelet reactive oxygen species in the regulation of platelet glycoprotein Ibα ectodomain shedding.}, journal = {Thrombosis research}, volume = {132}, number = {6}, pages = {696-701}, doi = {10.1016/j.thromres.2013.09.034}, pmid = {24120238}, issn = {1879-2472}, mesh = {Acetylcysteine/pharmacology ; Blood Platelets/drug effects/*metabolism ; Calcimycin/pharmacology ; Calpain/antagonists &amp; inhibitors/blood ; Collagen/pharmacology ; Dithiothreitol/pharmacology ; Flow Cytometry ; Humans ; Platelet Glycoprotein GPIb-IX Complex/*metabolism ; Reactive Oxygen Species/*metabolism ; Thrombin/pharmacology ; }, abstract = {Glycoprotein (GP) Ibα ectodomain shedding has become a generally accepted negative regulatory mechanism of platelet function. Stimulation of platelet with either physiological or chemical compound results in GPIbα ectodomain shedding in vitro and in vivo, the mechanism, however, is not totally understood. Here we show, collagen, thrombin, and calcium ionophore A23187 induce reactive oxygen species (ROS) generation, and simultaneously incur GPIbα ectodomain shedding. ROS scavengers N-acetylcysteine (NAC) and dithiothreitol (DTT) abolish not only collagen, thrombin, and A23187 induced ROS production, but also GPIbα ectodomain shedding. Interestingly, a recognized calpain activator, dibucaine, induces both ROS production and GPIbα shedding, which are also obviously reduced by NAC and DTT. Furthermore, calpain inhibitors calpain inhibitor I and carbobenzoxy-valinyl-phenylalaninal, obviously reduce dibucaine, thrombin, and A23187-induced ROS generation. These data indicate that ROS plays a key role in collagen, thrombin, and A23187-induced GPIbα ectodomain shedding. Calpain is an up-stream regulator that regulates ROS-mediated GPIbα shedding.}, }
@article {pmid24119926, year = {2014}, author = {Allaveisi, F and Hashemi, B and Mortazavi, SM}, title = {Effect of gamma sterilization on microhardness of the cortical bone tissue of bovine femur in presence of N-Acetyl-L-Cysteine free radical scavenger.}, journal = {Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB)}, volume = {30}, number = {3}, pages = {314-319}, doi = {10.1016/j.ejmp.2013.09.004}, pmid = {24119926}, issn = {1724-191X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cattle ; Dose-Response Relationship, Radiation ; Femur/*drug effects/*radiation effects ; Free Radical Scavengers/*pharmacology ; Gamma Rays/*adverse effects ; Hardness/drug effects/radiation effects ; Materials Testing ; Radiation-Protective Agents/*pharmacology ; Sterilization/*methods ; }, abstract = {Gamma sterilization is usually used to minimize the risk of infection transmission through bone allografts. However, it is believed that gamma irradiation affects the mechanical properties of allografts and free radical scavengers can be used to alleviate the radiation-induced degradation of these properties. The aim of this study was to investigate the radioprotective effects of N-Acetyl-L-Cysteine (NAC) free radical scavenger on the material properties of sterilized bovine cortical bone at microstructure level. Forty-two cortical tissue specimens were excised from three bovine femurs and irradiated to 35 and 70 kGy gamma rays in the presence of 5, 50, and 100 mM concentrations of NAC. The localized variations in microhardness were evaluated via indentation in the radial and longitudinal directions to examine different regions of the microstructures of the specimens, including the osteonal and interstitial tissues. A significant increase was observed in the hardness of osteonal, interstitial, and longitudinal combined microstructures exposed to 35 and 70 kGy radiations (P < 0.05), whereas a relative reduction of the hardness was observed in the radial direction. Furthermore, it was found that the application of 50 and 100 mM NAC during gamma irradiation significantly subsided the hardening in longitudinal combined microstructure. Moreover, the reduction of hardness in radial direction was suppressed in the presence of 100 mM of NAC. In conclusion, the results indicated that NAC free radical scavenger can protect the cortical bone against deteriorative effects of ionizing radiation and can be used to improve the material properties of sterilized allografts.}, }
@article {pmid24119918, year = {2013}, author = {Ma, S and Imazato, S and Takahashi, Y and Kiba, W and Takeda, K and Izutani, N and Kitagawa, H and Chen, J}, title = {Mechanism of detoxification of the cationic antibacterial monomer 12-methacryloyloxydodecylpyridiniumbromide (MDPB) by N-acetyl cysteine.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {29}, number = {12}, pages = {1219-1227}, doi = {10.1016/j.dental.2013.09.008}, pmid = {24119918}, issn = {1879-0097}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; Anti-Bacterial Agents/*pharmacology ; Cations ; Chromatography, Liquid ; Mass Spectrometry ; Mice ; Pyridinium Compounds ; }, abstract = {OBJECTIVES: The protective effects of N-acetyl cysteine (NAC) against cytotoxicity induced by conventional dental resin monomers have been widely documented. However, its effectiveness to detoxify cationic antibacterial monomers has not yet been elucidated. The aim of the present study was to investigate the possible protective effects of NAC against the cytotoxicity of 12-methacryloyloxydodecylpyridiniumbromide (MDPB) and explore the role of adduct formation in NAC-directed detoxification.<br><br>METHODS: The influences of NAC on the cytotoxicity of MDPB were studied in mouse osteoblast-like MC3T3-E1 cells using the MTT assay. Ultra-performance liquid chromatography (UPLC) and liquid chromatography-mass spectrometry (LC-MS) analysis were performed to investigate the possible chemical reaction between NAC and MDPB.<br><br>RESULTS: While only slight reduction in the cytotoxicity of MDPB by NAC was observed immediately after mixing with MDPB, remarkable protection against MDPB-induced cell death was detected when the mixture was tested after 24h of pre-incubation. UPLC and LC-MS analysis revealed that chemical binding of MDPB and NAC occurred under neutral conditions after 24h of pre-incubation.<br><br>SIGNIFICANCE: Our findings suggest that NAC reduces the toxicity of the cationic antibacterial monomer MDPB, and adduct formation is partially responsible for the detoxification ability of NAC against MDPB-induced cell damage.}, }
@article {pmid24118820, year = {2014}, author = {Chen, J and Guo, R and Yan, H and Tian, L and You, Q and Li, S and Huang, R and Wu, K}, title = {Naringin inhibits ROS-activated MAPK pathway in high glucose-induced injuries in H9c2 cardiac cells.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {114}, number = {4}, pages = {293-304}, doi = {10.1111/bcpt.12153}, pmid = {24118820}, issn = {1742-7843}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Apoptosis/drug effects ; Butadienes/pharmacology ; Cell Line ; Cell Survival/drug effects ; Enzyme Inhibitors/pharmacology ; Flavanones/*pharmacology ; Fruit/chemistry ; Glucose/*adverse effects ; Hyperglycemia/drug therapy ; Imidazoles/pharmacology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; *MAP Kinase Signaling System ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; Myocytes, Cardiac/drug effects/metabolism ; Nitriles/pharmacology ; Oxidative Stress/drug effects ; Phosphorylation ; Plant Extracts/pharmacology ; Pyridines/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Naringin, an active flavonoid isolated from citrus fruit extracts, exhibits biological and pharmacological properties, such as antioxidant activity and antidiabetic effect. Mitogen-activated protein kinase (MAPK) signalling pathway has been shown to participate in hyperglycaemia-induced injury. The present study tested the hypothesis that naringin protects against high glucose (HG)-induced injuries by inhibiting MAPK pathway in H9c2 cardiac cells. To examine this, the cells were treated with 35 mM glucose (HG) for 24 hr to establish a HG-induced cardiomyocyte injury model. The cells were pre-treated with 80 μM naringin for 2 hr before exposure to HG. The findings of this study showed that exposure of H9c2 cells to HG for 24 hr markedly induced injuries, as evidenced by a decrease in cell viability, increases in apoptotic cells and reactive oxygen species (ROS) production, as well as dissipation of mitochondrial membrance potential (MMP). These injuries were significantly attenuated by the pre-treatment of cells with either naringin or SB203580 (a selective inhibitor of p38 MAPK) or U0126 (a selective inhibitor of extracellular signal regulated kinase 1/2, ERK1/2) or SP600125 (a selective inhibitor of c-jun N-termanal kinase, JNK) before exposure to HG, respectively. Furthermore, exposure of cells to HG increased the phosphorylation of p38 MAPK, ERK1/2 and JNK. The increased activation of MAPK pathway was ameliorated by pre-treatment with either naringin or N-acetyl-L-cysteine (NAC), a ROS scavenger, which also reduced HG-induced cytotoxicity and apoptosis, leading to increase in cell viability and decrease in apoptotic cells. In conclusion, our findings provide new evidence for the first time that naringin protects against HG-induced injuries by inhibiting the activation of MAPK (p38 MAPK, ERK1/2 and JNK) and oxidative stress in H9c2 cells.}, }
@article {pmid24117464, year = {2014}, author = {Li, GW and Rambally, S and Kamboj, J and Reilly, S and Moake, JL and Udden, MM and Mims, MP}, title = {Treatment of refractory thrombotic thrombocytopenic purpura with N-acetylcysteine: a case report.}, journal = {Transfusion}, volume = {54}, number = {5}, pages = {1221-1224}, doi = {10.1111/trf.12440}, pmid = {24117464}, issn = {1537-2995}, mesh = {ADAM Proteins/blood ; ADAMTS13 Protein ; Acetylcysteine/*therapeutic use ; Adult ; Female ; Humans ; Platelet Count ; Purpura, Thrombotic Thrombocytopenic/blood/*drug therapy ; }, abstract = {BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease resulting in systemic microvascular thrombosis. The disease is caused by excessive platelet (PLT) adhesion to ultra-large (UL) von Willebrand factor (VWF) multimers inadequately cleaved by the processing enzyme ADAMTS-13. While many cases respond to plasma exchange performed with or without concurrent corticosteroids, treatment of the 10% to 20% of patients with refractory disease is difficult. Experimental studies demonstrating that N-acetylcysteine (NAC) inhibits PLT binding to endothelial cell-secreted and anchored UL VWF multimers suggest that NAC may be useful in the treatment of TTP.<br><br>CASE REPORT: A 44-year-old woman presented with malaise, confusion, chest and abdominal pain, and transient visual loss. Laboratory results and peripheral blood smear were consistent with TTP. The patient was begun on plasma exchange and corticosteroid treatment, but after 10 days the PLT count was still less than 10.0&#x2009;&#xd7;&#x2009;10(9) /L and she developed a fever. Rituximab was initiated, but the patient's condition worsened and she became comatose. Antibiotics were initiated, but cultures remained sterile. After 3&#x2009;days of coma and further clinical deterioration, treatment with NAC was begun. The patient received a loading dose of 150&#x2009;mg/kg NAC intravenously (IV) over 1 hour. Within 18&#x2009;hours the patient awakened abruptly and began communicating with medical personnel. Plasma exchange, corticosteroids, rituximab, and NAC infusion (150&#x2009;mg/kg IV over 17&#x2009;hr daily&#x2009;&#xd7;&#x2009;10 days) were continued and by Day 17 the PLT count was more than 50&#x2009;&#xd7;&#x2009;10(9) /L. The patient fully recovered and was discharged on Day 31.<br><br>CONCLUSION: This is the first complete report of a TTP patient treated with NAC. NAC was a safe and effective supplementary treatment for refractory TTP in this patient.}, }
@article {pmid24115584, year = {2014}, author = {Zhang, QS and Marquez-Loza, L and Sheehan, AM and Watanabe-Smith, K and Eaton, L and Benedetti, E and Major, A and Schubert, K and Deater, M and Joseph, E and Grompe, M}, title = {Evaluation of resveratrol and N-acetylcysteine for cancer chemoprevention in a Fanconi anemia murine model.}, journal = {Pediatric blood &amp; cancer}, volume = {61}, number = {4}, pages = {740-742}, pmid = {24115584}, issn = {1545-5017}, support = {P01 HL048546/HL/NHLBI NIH HHS/United States ; T32 GM071338/GM/NIGMS NIH HHS/United States ; 2 P01 HL048546-16A1/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Fanconi Anemia/genetics/pathology/*prevention &amp; control ; Fanconi Anemia Complementation Group D2 Protein/*physiology ; Flow Cytometry ; Free Radical Scavengers/*therapeutic use ; Mice ; Mice, Knockout ; Resveratrol ; Stilbenes/*therapeutic use ; Tumor Suppressor Protein p53/*physiology ; }, abstract = {Fanconi anemia (FA) patients suffer from progressive bone marrow failure and often develop cancers. Previous studies showed that antioxidants tempol and resveratrol (RV) delayed tumor onset and reduced hematologic defects in FA murine models, respectively. Here we tested whether antioxidants N-acetylcysteine (NAC) or RV could delay cancer in tumor prone Fancd2(-/-) /Trp53(+/-) mice. Unlike tempol, neither compound had any significant chemopreventive effect in this model. We conclude that not all anti-oxidants are chemopreventive in FA. In addition, when given to Fancd2(-/-) mice, NAC helped maintain Fancd2(-/-) KSL cells in quiescence while tempol did not. The mechanisms behind the different actions of these antioxidants await further investigation.}, }
@article {pmid24114663, year = {2014}, author = {Yuan, L and Wu, Y and Ren, X and Liu, Q and Wang, J and Liu, X}, title = {Isoorientin attenuates lipopolysaccharide-induced pro-inflammatory responses through down-regulation of ROS-related MAPK/NF-κB signaling pathway in BV-2 microglia.}, journal = {Molecular and cellular biochemistry}, volume = {386}, number = {1-2}, pages = {153-165}, pmid = {24114663}, issn = {1573-4919}, mesh = {Animals ; Blotting, Western ; Cell Line ; Cytokines/biosynthesis ; Down-Regulation/*drug effects ; Electrophoresis, Polyacrylamide Gel ; Inflammation/*chemically induced ; Inflammation Mediators/metabolism ; Lipopolysaccharides/*pharmacology ; Luteolin/*pharmacology ; MAP Kinase Signaling System/*drug effects ; Mice ; Microglia/*drug effects/metabolism ; NF-kappa B/*metabolism ; Nitric Oxide/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {Isoorientin (ISO) is a flavonoid compound in the human diet, and has been known to possess various bioactivities. However, the effects of ISO on microglia inflammation have not been investigated. The current study investigates the neuroprotective effect of ISO in LPS-activated mouse microglial (BV-2) cells. ISO significantly increased the BV-2 cells viability, blocked the protein expression of inducible nitric oxide synthase and cyclooxygenase-2, and decreased the production of nitric oxide, pro-inflammatory cytokines including tumor necrosis factor-α and interleukin-1β. The activation of mitogen-activated protein kinases (MAPKs) was blocked by ISO, and NF-κB nuclear translocation was decreased by ISO both alone and together with NF-κB inhibitor (PDTC) and MAPKs inhibitors (U0126, SP 600125, and SB 203580). Furthermore, ISO strongly quenched intracellular reactive oxygen species (ROS) generation. ROS inhibitor (N-acetyl cysteine, NAC) significantly inhibited pro-inflammatory cytokines release and NF-κB and MAPKs activation, indicating that ISO attenuated neuroinflammation by inhibiting the ROS-related MAPK/NF-κB signaling pathway.}, }
@article {pmid24113576, year = {2013}, author = {Kunz, S and Schreiber, P and Ludwig, M and Maturi, MM and Ackermann, O and Tschurl, M and Heiz, U}, title = {Rational design, characterization and catalytic application of metal clusters functionalized with hydrophilic, chiral ligands: a proof of principle study.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {15}, number = {44}, pages = {19253-19261}, doi = {10.1039/c3cp53626b}, pmid = {24113576}, issn = {1463-9084}, mesh = {Acetylcysteine/chemistry ; Butanones/chemistry ; Catalysis ; Cysteine/chemistry ; Glutathione/chemistry ; Hydrogenation ; Hydrophobic and Hydrophilic Interactions ; *Ligands ; Metals/*chemistry ; Platinum/chemistry ; Stereoisomerism ; }, abstract = {A proof of principle is presented for the rational design of metal clusters functionalized with hydrophilic, chiral ligands. A colloidal method is used to prepare "unprotected" metal clusters of well-defined size that are subsequently functionalized in a separate step with hydrophilic, chiral ligands. As clusters from the same batch are functionalized with different organic molecules while the cluster size is maintained, the approach allows for systematic investigations and the differences in the observed properties to be related to the influence of the functionalizing ligand. Within this work cysteine and two cysteine derivatives (glutathione and N-acetyl-cysteine) are used as functionalizing ligands for Pt clusters. The materials are characterized using various methods allowing for the determination of ligand coverage, binding mode and chiro-optical properties. Finally, 2-butanone hydrogenation is used as a simple model reaction to demonstrate that these systems exhibit the potential to be used as asymmetric, heterogeneous catalysts. The observed differences in selectivity and reactivity are discussed based on the knowledge gained from the characterization.}, }
@article {pmid24113378, year = {2013}, author = {Kim, SS and Seong, S and Lim, SH and Kim, SY}, title = {Biliverdin reductase plays a crucial role in hypoxia-induced chemoresistance in human glioblastoma.}, journal = {Biochemical and biophysical research communications}, volume = {440}, number = {4}, pages = {658-663}, doi = {10.1016/j.bbrc.2013.09.120}, pmid = {24113378}, issn = {1090-2104}, mesh = {Antineoplastic Agents, Alkylating/pharmacology ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Brain Neoplasms/*enzymology ; Cell Hypoxia ; Cell Line, Tumor ; Dacarbazine/analogs &amp; derivatives/pharmacology ; *Drug Resistance, Neoplasm ; Glioblastoma/*enzymology ; Humans ; Oxidation-Reduction ; Oxidoreductases Acting on CH-CH Group Donors/antagonists &amp; inhibitors/genetics/*physiology ; Paclitaxel/pharmacology ; Reactive Oxygen Species/metabolism ; Temozolomide ; }, abstract = {Hypoxia-induced alterations in the cellular redox status play a critical role in the development of hypoxia-induced chemoresistance in cancer cells. Human biliverdin reductase (hBVR), an enzyme involved in the conversion of biliverdin into bilirubin in heme metabolism, was recently identified as an important cytoprotectant against oxidative stress and hypoxia. However, the role of hBVR on hypoxia-induced drug resistance has not been previously investigated. Using human glioblastoma cell lines, we evaluated the potential role of hBVR in hypoxia-induced drug resistance. We found that hypoxia caused a significant increase in hBVR expression in glioblastoma cells that was accompanied by chemoresistance. We also observed that siRNA-based targeting of hBVR genes attenuated the hypoxia-induced chemoresistance. Furthermore, knocking down hBVR induced a marked increase in the levels of intracellular reactive oxygen species under hypoxic conditions, and the chemosensitizing effect of hBVR depletion was reversed by pretreatment with the antioxidant N-acetylcysteine. These findings suggest that hBVR significantly contributes to the modulation of hypoxia-induced chemoresistance of glioblastoma cells by adjusting their cellular redox status.}, }
@article {pmid24112955, year = {2013}, author = {Calzadilla, P and Gómez-Serrano, M and García-Santos, E and Schiappacasse, A and Abalde, Y and Calvo, JC and Peral, B and Guerra, LN}, title = {N-Acetylcysteine affects obesity-related protein expression in 3T3-L1 adipocytes.}, journal = {Redox report : communications in free radical research}, volume = {18}, number = {6}, pages = {210-218}, pmid = {24112955}, issn = {1743-2928}, mesh = {3T3-L1 Cells ; Acetylcysteine/*pharmacology ; Adipocytes/drug effects/*metabolism ; Adipogenesis/*drug effects ; Amidohydrolases/biosynthesis ; Animals ; Cell Differentiation/physiology ; Fatty Acid-Binding Proteins/biosynthesis ; HSP72 Heat-Shock Proteins/biosynthesis ; Mice ; Monoamine Oxidase/biosynthesis ; Oxidative Stress/drug effects ; Transketolase/biosynthesis ; Triglycerides/metabolism ; }, abstract = {OBJECTIVES: Oxidative stress plays critical roles in the pathogeneses of diabetes, hypertension, and atherosclerosis, but its effect on fat accumulation is still unclear. In this study, we analyzed the role of the well-known antioxidant and a glutathione (GSH) precursor N-acetylcysteine (NAC) in fat accumulation and the expression of obesity-associated proteins.<br><br>METHODS: We studied the effects of 10 &#xb5;M NAC on obesity-related protein expression in cultured 3T3-L1 preadipocytes, which are able to differentiate into mature adipocytes and accumulate lipids.<br><br>RESULTS: NAC treatment inhibited fat accumulation and reduced the expression of obesity-related proteins, including monoamine oxidase A, heat shock protein 70 (HSP70), aminoacylase -1 (ACY-1), and transketolase.<br><br>DISCUSSION: Our results suggest that the effects of NAC on triglycerides (Tgs) and protein expression are correlated. In support of this, we showed that NAC treatment affected both the Tg synthesis pathway and the expression levels of proteins implicated in human obesity.}, }
@article {pmid24109187, year = {2013}, author = {Quintero, GC}, title = {Role of nucleus accumbens glutamatergic plasticity in drug addiction.}, journal = {Neuropsychiatric disease and treatment}, volume = {9}, number = {}, pages = {1499-1512}, pmid = {24109187}, issn = {1176-6328}, abstract = {Substance dependence is characterized by a group of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR). These symptoms include tolerance, withdrawal, drug consumption for alleviating withdrawal, exaggerated consumption beyond original intention, failure to reduce drug consumption, expending a considerable amount of time obtaining or recovering from the substance's effects, disregard of basic aspects of life (for example, family), and maintenance of drug consumption, despite facing adverse consequences. The nucleus accumbens (NAc) is a brain structure located in the basal forebrain of vertebrates, and it has been the target of addictive drugs. Different neurotransmitter systems at the level of the NAc circuitry have been linked to the different problems of drug addiction, like compulsive use and relapse. The glutamate system has been linked mainly to relapse after drug-seeking extinction. The dopamine system has been linked mainly to compulsive drug use. The glutamate homeostasis hypothesis centers around the dynamics of synaptic and extrasynaptic levels of glutamate, and their impact on circuitry from the prefrontal cortex (PFC) to the NAc. After repetitive drug use, deregulation of this homeostasis increases the release of glutamate from the PFC to the NAc during drug relapse. Glial cells also play a fundamental role in this hypothesis; glial cells shape the interactions between the PFC and the NAc by means of altering glutamate levels in synaptic and extrasynaptic spaces. On the other hand, cocaine self-administration and withdrawal increases the surface expression of subunit glutamate receptor 1 (GluA1) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors at the level of the NAc. Also, cocaine self-administration and withdrawal induce the formation of subunit glutamate receptor 2 (GluA2), lacking the Ca(2+)-permeable AMPA receptors (CP-AMPARs) at the level of the NAc. Antagonism of the CP-AMPARs reduces cravings. It is necessary to pursue further exploration of the AMPA receptor subunit composition and variations at the level of the NAc for a better understanding of glutamatergic plastic changes. It is known that cocaine and morphine are able to induce changes in dendritic spine morphology by modifying actin cycling. These changes include an initial increase in spine head diameter and increases in AMPA receptor expression, followed by a second stage of spine head diameter retraction and reduction of the AMPA receptors' expression in spines. Besides glutamate and dopamine, other factors, like brain-derived neurotrophic factor (BDNF), can influence NAc activity and induce changes in dendritic spine density. BDNF also induces drug-related behaviors like self-administration and relapse. Neither apoptosis nor neurogenesis plays a relevant role in the neurobiological processes subjacent to cocaine addiction in adults (rodent or human). Different therapeutic drugs like N-acetylcysteine (NAC), modafinil, acamprosate, and topiramate have been tested in preclinical and/or clinical models for alleviating drug relapse. Moreover, these therapeutic drugs target the glutamatergic circuitry between the PFC and the NAc. NAC and acamprosate have shown inconsistent results in clinical trials. Modafinil and topiramate have shown some success, but more clinical trials are necessary. Based on the current review findings, it could be recommendable to explore therapeutic approaches that include synergism between different drugs and neurotransmitter systems. The discrepancy in the results of some therapeutic drugs between preclinical versus clinical trials for alleviating relapse or drug dependence could be linked to the scarce exploration of preclinical models that mimic polydrug abuse patterns, for example, cocaine plus alcohol. At the clinical level, the pattern of polydrug consumption is a phenomenon of considerable frequency. Finally, as a complement at the end, an updated summary is included about the role of glutamate in other neuropsychiatric disorders (for example, mood disorders, schizophrenia, and others).}, }
@article {pmid24107363, year = {2013}, author = {Zheng, S and Zhong, ZM and Qin, S and Chen, GX and Wu, Q and Zeng, JH and Ye, WB and Li, W and Yuan, K and Yao, L and Chen, JT}, title = {Advanced oxidation protein products induce inflammatory response in fibroblast-like synoviocytes through NADPH oxidase -dependent activation of NF-κB.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {32}, number = {4}, pages = {972-985}, doi = {10.1159/000354500}, pmid = {24107363}, issn = {1421-9778}, mesh = {Acetylcysteine/metabolism ; Advanced Oxidation Protein Products/*pharmacology ; Animals ; Enzyme-Linked Immunosorbent Assay ; Female ; Inflammation/*chemically induced/genetics/*metabolism ; NADPH Oxidases/genetics/*metabolism ; NF-kappa B/genetics/*metabolism ; Protein Binding ; Rats ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; Synovial Membrane/*cytology ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND: Advanced oxidation protein products (AOPPs), a marker of oxidative stress, are prevalent in many kinds of disorders. Rheumatoid arthritis (RA), mainly resulting from the dysfunction of fibroblast-like synoviocytes (FLSs), is related to oxidative stress. Although the increased levels of AOPPs in RA patients were reported, the effect of AOPPs on FLSs function still remains unclear. Therefore, our study aims to investigate whether AOPPs have an effect on the inflammatory response of FLSs in vitro.<br><br>METHODS: FLSs obtained from both knees of rats were treated with or without AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. The mRNA and protein expression of tumor necrosis factor (TNF)-&#x3b1;, interleukin(IL)-1&#x3b2;, matrix metalloproteinases(MMP)-3, MMP-13 and vascular endothelial growth factor (VEGF) were measured by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. Reactive oxygen species (ROS) generation was detected by fluorescent microscope and fluorescence microplate reader. Immunoprecipitation, Co-Immunoprecipitation and western blot were performed to examine the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nuclear factor kappa B (NF-&#x3ba;B).<br><br>RESULTS: Exposure of FLSs to AOPPs upregulated the mRNA and protein expression of TNF-&#x3b1;, IL-1&#x3b2;, MMP-3, MMP-13 and VEGF in a concentration dependent manner. AOPPs treatment triggered ROS production in FLSs, which was significantly abolished by ROS scavenger N-acetyl-L-cysteine (NAC), superoxide dismutase (SOD), NADPH oxidase inhibitors diphenyleneiodonium (DPI) and apocynin. Challenged AOPPs induced phosphorylation of p47(phox), triggered an interaction between p47(phox), p22(phox) and gp91(phox), and significantly upregulated expression of NADPH oxidase subunits p47(phox), p22(phox) and gp91(phox). I&#x3ba;B degradation and nuclear translocation of NF-&#x3ba;B p65 induced by AOPPs were significantly blocked by SOD, NAC, DPI and apocynin.<br><br>CONCLUSIONS: These data indicate that AOPPs induce inflammatory response in FLSs is medicated through NADPH oxidase-dependent activation of NF-&#x3ba;B.}, }
@article {pmid24106335, year = {2014}, author = {Sommer, IE and van Westrhenen, R and Begemann, MJ and de Witte, LD and Leucht, S and Kahn, RS}, title = {Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update.}, journal = {Schizophrenia bulletin}, volume = {40}, number = {1}, pages = {181-191}, pmid = {24106335}, issn = {1745-1701}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Humans ; Schizophrenia/*drug therapy/*immunology ; }, abstract = {BACKGROUND: The inflammatory hypothesis of schizophrenia is not new, but recently it has regained interest because more data suggest a role of the immune system in the pathogenesis of schizophrenia. If increased inflammation of the brain contributes to the symptoms of schizophrenia, reduction of the inflammatory status could improve the clinical picture. Lately, several trials have been conducted investigating the potential of anti-inflammatory agents to improve symptoms of schizophrenia. This study provides an update regarding the efficacy of anti-inflammatory agents on schizophrenic symptoms in clinical studies performed so far.<br><br>METHODS: An electronic search was performed using PubMed, Embase, the National Institutes of Health web site http://www.clinicaltrials.gov, Cochrane Schizophrenia Group entries in PsiTri, and the Cochrane Database of Systematic Reviews. Only randomized, double-blind, placebo-controlled studies that investigated clinical outcome were included.<br><br>RESULTS: Our search yielded 26 double-blind randomized controlled trials that provided information on the efficacy on symptom severity of the following components: aspirin, celecoxib, davunetide, fatty acids such as eicosapentaenoic acids and docosahexaenoic acids, estrogens, minocycline, and N-acetylcysteine (NAC). Of these components, aspirin (mean weighted effect size [ES]: 0.3, n = 270, 95% CI: 0.06-0.537, I(2) = 0), estrogens (ES: 0.51, n = 262, 95% CI: 0.043-0.972, I(2) = 69%), and NAC (ES: 0.45, n = 140, 95% CI: 0.112-0.779) showed significant effects. Celecoxib, minocycline, davunetide, and fatty acids showed no significant effect.<br><br>CONCLUSION: The results of aspirin addition to antipsychotic treatment seem promising, as does the addition of NAC and estrogens. These 3 agents are all very broadly active substances, and it has to be investigated if the beneficial effects on symptom severity are indeed mediated by their anti-inflammatory aspects.}, }
@article {pmid24105017, year = {2014}, author = {Talasaz, AH and Khalili, H and Fahimi, F and Jenab, Y and Broumand, MA and Salarifar, M and Darabi, F}, title = {Effects of N-acetylcysteine on the cardiac remodeling biomarkers and major adverse events following acute myocardial infarction: a randomized clinical trial.}, journal = {American journal of cardiovascular drugs : drugs, devices, and other interventions}, volume = {14}, number = {1}, pages = {51-61}, doi = {10.1007/s40256-013-0048-x}, pmid = {24105017}, issn = {1179-187X}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Antioxidants/adverse effects/*therapeutic use ; Biomarkers/metabolism ; Double-Blind Method ; Female ; Follow-Up Studies ; Hospitalization/statistics &amp; numerical data ; Humans ; Length of Stay ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Middle Aged ; Myocardial Infarction/*drug therapy ; Prospective Studies ; Secondary Prevention ; Treatment Outcome ; Ventricular Remodeling/*drug effects ; }, abstract = {AIMS: The aims of this study were to evaluate the effects of N-acetylcysteine (NAC) on cardiac remodeling and major adverse events following acute myocardial infarction (AMI).<br><br>METHODS: In a prospective, double-blind, randomized clinical trial, the effect of NAC on the serum levels of cardiac biomarkers was compared with that of placebo in 98 patients with AMI. Also, the patients were followed up for a 1-year period for major adverse cardiac events (MACE), including the occurrence of recurrent myocardial infarction, death, and need for target vessel revascularization.<br><br>RESULTS: In patients who received NAC, the serum levels of matrix metalloproteinase (MMP)-9 and MMP-2 after 72 h were significantly lower than those in the placebo group (p = 0.014 and p = 0.045, respectively). The length of hospitalization in patients who received NAC was significantly shorter than that in the placebo group (p = 0.024). With respect to MACE, there was a significant difference between those who received NAC (14 %) and those patients on placebo (25 %) (p = 0.024). Re-infarction took place in 4 % of patients in the NAC group as compared with 16.7 % in patients who received placebo (p = 0.007).<br><br>CONCLUSION: NAC can be beneficial in preventing early remodeling by reducing the level of MMP-2 and MMP-9. Moreover, NAC decreased the length of hospital stays in patients after AMI. By decreasing MACE, NAC could possibly be introduced as a 'magic bullet' in the pharmacotherapy of patients with AMI. Further studies are needed to elucidate NAC's role in this population.}, }
@article {pmid24099431, year = {2013}, author = {Sharma, S and Shrivastava, S and Shukla, S}, title = {Reversal of lead-induced toxicity due to the effect of antioxidants.}, journal = {Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer}, volume = {32}, number = {2}, pages = {177-187}, doi = {10.1615/jenvironpatholtoxicoloncol.2013006923}, pmid = {24099431}, issn = {2162-6537}, mesh = {Acetylcysteine/pharmacology ; Alanine Transaminase/metabolism ; Animals ; Antioxidants/*pharmacology ; Brain/drug effects/metabolism ; Cholesterol/metabolism ; Glutathione/pharmacology ; Injections, Intraperitoneal ; Kidney/drug effects/metabolism ; Lead/pharmacokinetics/*toxicity ; Lead Poisoning/*drug therapy ; Liver/drug effects/metabolism ; Male ; Organometallic Compounds/blood/pharmacokinetics ; Oxidative Stress/drug effects ; Porphobilinogen Synthase/metabolism ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; Uric Acid/metabolism ; }, abstract = {This study was designated to evaluate the protective effect of glutathione (GSH) and N-acetyl cysteine (NAC) in reducing the concentration of lead acetate in blood and soft tissues (liver, kidney, and brain) and their ability to restore altered hematopoietic, hepatic, renal, and other biochemical variables that are indicative of tissue oxidative stress in male rats. Male Wistar rats (150 ± 10 g) were randomly divided into 6 groups. Group 1 served as control. Group 2 served as experimental control was administered lead acetate (50 mg/kg intraperitoneally) for 3 days. Group 3 and 4 served as therapeutic controls. Animals in groups 5 and 6 received reduced GSH (1 mg/kg intraperitoneally) and NAC (50 mg/kg orally) for 3 days after the administration of lead acetate, as in group 2. The levels of hepatic and renal markers such as alanine aminotransferase, aspartate aminotransferase, triglycerides, cholesterol, urea, and uric acid were significantly increased (P ≤ 0.05) following administration of lead acetate. Administration of GSH and NAC provided significant protection to thiobarbituric acid reactive substances levels and reduced GSH content in tissues. On the other hand, significant recovery in lead-sensitive biochemical indices, like δ-aminolevulinic acid dehydratase, δ-aminolevulinic acid, and lead concentration in blood and soft tissues also were observed. It was concluded that NAC provided maximum protection compared with reduced GSH.}, }
@article {pmid24098573, year = {2013}, author = {Barbu, EM and Shirazi, F and McGrath, DM and Albert, N and Sidman, RL and Pasqualini, R and Arap, W and Kontoyiannis, DP}, title = {An antimicrobial peptidomimetic induces Mucorales cell death through mitochondria-mediated apoptosis.}, journal = {PloS one}, volume = {8}, number = {10}, pages = {e76981}, pmid = {24098573}, issn = {1932-6203}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R21 AI089812/AI/NIAID NIH HHS/United States ; U54 CA151668/CA/NCI NIH HHS/United States ; AI089812/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amino Acid Motifs ; Antimicrobial Cationic Peptides/chemical synthesis/*pharmacology ; Apoptosis/drug effects ; Humans ; Membrane Potential, Mitochondrial/*drug effects ; Microbial Sensitivity Tests ; Microbial Viability/drug effects ; Mitochondria/*drug effects/metabolism ; Mucorales/*drug effects/isolation &amp; purification/metabolism ; Mucormycosis/microbiology ; Peptidomimetics/chemical synthesis/*pharmacology ; Reactive Oxygen Species/agonists/antagonists &amp; inhibitors/metabolism ; Spores, Fungal/*drug effects/growth &amp; development/metabolism ; }, abstract = {The incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in fungi. Our group has previously designed and developed a proteolytically-resistant peptidomimetic motif D(KLAKLAK)2 with pleiotropic action ranging from targeted (i.e., ligand-directed) activity against cancer and obesity to non-targeted activity against antibiotic resistant gram-negative rods. Here we evaluated whether this non-targeted peptidomimetic motif is active against Mucorales. We show that D(KLAKLAK)2 has marked fungicidal action, inhibits germination, and reduces hyphal viability. We have also observed cellular changes characteristic of apoptosis in D(KLAKLAK)2-treated Mucorales cells. Moreover, the fungicidal activity was directly correlated with vacuolar injury, mitochondrial swelling and mitochondrial membrane depolarization, intracellular reactive oxygen species accumulation (ROS), and increased caspase-like enzymatic activity. Finally, these apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine indicating mechanistic pathway specificity. Together, these findings indicate that D(KLAKLAK)2 makes Mucorales exquisitely susceptible via mitochondrial injury-induced apoptosis. This prototype may serve as a candidate drug for the development of translational applications against mucormycosis and perhaps other fungal infections.}, }
@article {pmid24098333, year = {2013}, author = {Lin, H and Liu, XB and Yu, JJ and Hua, F and Hu, ZW}, title = {Antioxidant N-acetylcysteine attenuates hepatocarcinogenesis by inhibiting ROS/ER stress in TLR2 deficient mouse.}, journal = {PloS one}, volume = {8}, number = {10}, pages = {e74130}, pmid = {24098333}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Carcinogenesis/*drug effects ; Carcinoma, Hepatocellular/metabolism/pathology ; Cell Line ; Diethylnitrosamine/adverse effects ; Disease Progression ; Endoplasmic Reticulum Stress/*drug effects ; Liver Neoplasms/metabolism/*pathology ; Male ; Mice ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 2/*deficiency ; }, abstract = {Hepatocellular carcinoma (HCC) remains one of the most deadly solid tumor malignancies worldwide. We recently find that the loss of toll-like receptor 2 (TLR2) activities promotes the diethylnitrosamine (DEN) induced hepatocellular carcinogenesis and tumor progression, which associates with an abundant accumulation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. This finding suggests that the ROS/ER stress plays a role in TLR2 modulated carcinogenesis of HCC. To investigate the mechanism of TLR2 activity defending against hepatocarcinogenesis, the TLR2-deficient mice were treated with or without antioxidant N-acetylcysteine (NAC) before DEN administration. We found that pretreatment of these animals with NAC attenuated carcinogenesis and progression of HCC in the TLR2-deficient mice, declined ROS/ER stress, and alleviated the unfold protein response and inflammatory response in TLR2-deficient liver tissue. Moreover, the NAC treatment significantly reduced the enhanced aggregation of p62 and Mallory-Denk bodies in the DEN-induced HCC liver tissue, suggesting that NAC treatment improves the suppressive autophagic flux in the TLR2-deficient liver. These findings indicate that TLR2 activity defends against hepatocarcinogenesis through diminishing the accumulation of ROS and alleviating ER stress and unfold protein response mediated inflammatory response in the liver.}, }
@article {pmid24096876, year = {2014}, author = {Zhang, R and Yin, X and Shi, H and Wu, J and Shakya, P and Liu, D and Zhang, J}, title = {Adiponectin modulates DCA-induced inflammation via the ROS/NF-κ B signaling pathway in esophageal adenocarcinoma cells.}, journal = {Digestive diseases and sciences}, volume = {59}, number = {1}, pages = {89-97}, pmid = {24096876}, issn = {1573-2568}, mesh = {Adenocarcinoma/chemistry/drug therapy/*prevention &amp; control ; Adiponectin/*physiology/therapeutic use ; Cell Line, Tumor ; Deoxycholic Acid ; Disease Progression ; Drug Evaluation, Preclinical ; Esophageal Neoplasms/chemistry/drug therapy/*prevention &amp; control ; Humans ; Inflammation/metabolism/prevention &amp; control ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*physiology ; Transcription Factor RelA/*physiology ; }, abstract = {BACKGROUND: Deoxycholic acid (DCA) promotes the development and progression of esophageal adenocarcinoma (EAC) by inducing inflammation. Adiponectin is reported to have anti-inflammatory and anti-tumor effects.<br><br>PURPOSE: This study investigated the effects of two types of adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on DCA-induced inflammation, and investigated the involvement of the reactive oxygen species (ROS)/NF-&#x3ba;B signaling pathway in inflammation in EAC.<br><br>METHODS: OE19 cells were treated with DCA (50-300 &#x3bc;M) and/or f-Ad/g-Ad (10.0 &#x3bc;g/ml) or N-acetylcysteine (NAC). The viability of cells exposed to DCA was measured by use of the MTT assay. mRNA and protein levels of the inflammatory factors were examined by real-time PCR and ELISA. Intra-cellular ROS levels were determined by use of flow cytometry. Protein levels of total and p-NF-&#x3ba;B p65 were measured by western blot.<br><br>RESULTS: DCA induced dose and time-dependent cytotoxicity. mRNA and protein expression of TNF-&#x3b1;, IL-8, and IL-6 in cells treated with DCA alone were up-regulated, and intra-cellular ROS and p-NF-&#x3ba;B p65 protein levels were also increased. g-Ad promoted inflammatory factor production, ROS levels, and p-NF-&#x3ba;B p65 protein expression whereas f-Ad had a suppressive effect. When combined with DCA, g-Ad enhanced the pro-inflammatory effect of DCA whereas f-Ad, similar to NAC, suppressed the effect.<br><br>CONCLUSION: DCA has a pro-inflammatory effect in EAC. f-Ad has an anti-inflammatory effect whereas g-Ad seems to have a pro-inflammatory effect in an ROS/NF-&#x3ba;B p65-dependent manner. This indicates that f-Ad could be a potential anti-inflammatory reagent for cancer therapy.}, }
@article {pmid24096134, year = {2013}, author = {Jiang, Y and Rumble, JL and Gleixner, AM and Unnithan, AS and Pulugulla, SH and Posimo, JM and Choi, HJ and Crum, TS and Pant, DB and Leak, RK}, title = {N-Acetyl cysteine blunts proteotoxicity in a heat shock protein-dependent manner.}, journal = {Neuroscience}, volume = {255}, number = {}, pages = {19-32}, doi = {10.1016/j.neuroscience.2013.09.049}, pmid = {24096134}, issn = {1873-7544}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blotting, Western ; Cell Line, Tumor ; Cell Survival/drug effects ; Cysteine Proteinase Inhibitors/toxicity ; Free Radical Scavengers/pharmacology ; HSP70 Heat-Shock Proteins/*metabolism ; High-Throughput Screening Assays ; Leupeptins/toxicity ; Mice ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Proteasome Endopeptidase Complex/drug effects ; Protein Folding/*drug effects ; }, abstract = {N-Acetyl cysteine, a glutathione precursor, has been shown to benefit patients with Alzheimer's disease and reduce the symptoms of traumatic brain injury in soldiers. Parkinson's and Alzheimer's disease are both characterized by stress from protein misfolding, or proteotoxicity. We have developed a high-throughput model of proteotoxicity by treating neuroblastoma N2a cells with the proteasome inhibitor MG132 and performing three independent assays for viability. Our previous study showed that N-acetyl cysteine protects N2a cells against two sequential treatments of MG132 and raises glutathione levels in a two-hit model of synergistic neurodegeneration. In the present study, however, N-acetyl cysteine was found to reduce the toxicity of a single hit of MG132 independent of its effect on glutathione. All three viability assays confirmed this protection. We measured heat shock protein 70 (Hsp70) levels because Hsp70 is a protective chaperone that helps refold proteins or guides ubiquitinated proteins toward degradation by the proteasome. Hsp70 levels were higher in MG132-treated cells when N-acetyl cysteine was applied. No parallel change in heat shock cognate 70 (Hsc70) was elicited. Inhibition of Hsp70/Hsc70 activity with VER 155008 attenuated the protection afforded by N-acetyl cysteine in a dose-responsive manner. MG132 induced a large rise in ubiquitinated proteins and N-acetyl cysteine reduced this effect. Consistent with the chaperone functions of Hsp70, VER 155008 also prevented the reduction in ubiquitin-conjugated proteins by N-acetyl cysteine. These data reveal a new role for N-acetyl cysteine: this compound may reduce misfolded protein levels and ameliorate proteotoxicity through heat shock proteins. These findings broaden the potential mechanisms of action for this dietary supplement in neurodegenerative proteinopathies.}, }
@article {pmid24095861, year = {2013}, author = {Pawłowska-Góral, K and Kurzeja, E and Stec, M}, title = {N-acetylcysteine protects against fluoride-induced oxidative damage in primary rat hepatocytes.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {27}, number = {8}, pages = {2279-2282}, doi = {10.1016/j.tiv.2013.09.019}, pmid = {24095861}, issn = {1879-3177}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cells, Cultured ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Hepatocytes/*drug effects/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Sodium Fluoride/*toxicity ; Superoxide Dismutase/metabolism ; }, abstract = {Fluoride induces the overproduction of free radicals, which might in turn affect various biochemical parameters. Therefore, the aim of this study was to elucidate the role of N-acetylcysteine (NAC) in decreasing fluoride-induced oxidative stress. The fluoride intoxicated (0.002; 0.082; 0.164mmol/l) rat hepatocytes was pre-treated (60min) and simultaneously treated with NAC (1mmol/l). The resulting levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and intracellular reduced glutathione (GSH) were measured along with the total antioxidant status (TAS) to determine whether NAC treatment reduced cell damage and/or the antioxidant state. These results suggest that NAC pre-treatment provides protection against fluoride-induced oxidative stress in hepatocytes.}, }
@article {pmid24094269, year = {2013}, author = {Persiyantseva, NA and Storozhevykh, TP and Senilova, YE and Gorbacheva, LR and Pinelis, VG and Pomytkin, IA}, title = {Mitochondrial H2O2 as an enable signal for triggering autophosphorylation of insulin receptor in neurons.}, journal = {Journal of molecular signaling}, volume = {8}, number = {1}, pages = {11}, pmid = {24094269}, issn = {1750-2187}, abstract = {BACKGROUND: Insulin receptors are widely distributed in the brain, where they play roles in synaptic function, memory formation, and neuroprotection. Autophosphorylation of the receptor in response to insulin stimulation is a critical step in receptor activation. In neurons, insulin stimulation leads to a rise in mitochondrial H2O2 production, which plays a role in receptor autophosphorylation. However, the kinetic characteristics of the H2O2 signal and its functional relationships with the insulin receptor during the autophosphorylation process in neurons remain unexplored to date.<br><br>RESULTS: Experiments were carried out in culture of rat cerebellar granule neurons. Kinetic study showed that the insulin-induced H2O2 signal precedes receptor autophosphorylation and represents a single spike with a peak at 5-10&#xa0;s and duration of less than 30&#xa0;s. Mitochondrial complexes II and, to a lesser extent, I are involved in generation of the H2O2 signal. The mechanism by which insulin triggers the H2O2 signal involves modulation of succinate dehydrogenase activity. Insulin dose-response for receptor autophosphorylation is well described by hyperbolic function (Hill coefficient, nH, of 1.1&#xb1;0.1; R2=0.99). N-acetylcysteine (NAC), a scavenger of H2O2, dose-dependently inhibited receptor autophosphorylation. The observed dose response is highly sigmoidal (Hill coefficient, nH, of 8.0&#xb1;2.3; R2=0.97), signifying that insulin receptor autophosphorylation is highly ultrasensitive to the H2O2 signal. These results suggest that autophosphorylation occurred as a gradual response to increasing insulin concentrations, only if the H2O2 signal exceeded a certain threshold. Both insulin-stimulated receptor autophosphorylation and H2O2 generation were inhibited by pertussis toxin, suggesting that a pertussis toxin-sensitive G protein may link the insulin receptor to the H2O2-generating system in neurons during the autophosphorylation process.<br><br>CONCLUSIONS: In this study, we demonstrated for the first time that the receptor autophosphorylation occurs only if mitochondrial H2O2 signal exceeds a certain threshold. This finding provides novel insights into the mechanisms underlying neuronal response to insulin. The neuronal insulin receptor is activated if two conditions are met: 1) insulin binds to the receptor, and 2) the H2O2 signal surpasses a certain threshold, thus, enabling receptor autophosphorylation in all-or-nothing manner. Although the physiological rationale for this control remains to be determined, we propose that malfunction of mitochondrial H2O2 signaling may lead to the development of cerebral insulin resistance.}, }
@article {pmid24093724, year = {2014}, author = {Gille, T and Randrianarison-Pellan, N and Goolaerts, A and Dard, N and Uzunhan, Y and Ferrary, E and Hummler, E and Clerici, C and Planès, C}, title = {Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway.}, journal = {American journal of respiratory cell and molecular biology}, volume = {50}, number = {3}, pages = {526-537}, doi = {10.1165/rcmb.2012-0518OC}, pmid = {24093724}, issn = {1535-4989}, mesh = {Animals ; Antioxidants/pharmacology ; Cell Hypoxia ; Cells, Cultured ; Disease Models, Animal ; Endocytosis ; Endosomal Sorting Complexes Required for Transport/*metabolism ; Epithelial Cells/drug effects/*enzymology ; Epithelial Sodium Channels/deficiency/drug effects/genetics/*metabolism ; Hypoxia/*enzymology/genetics ; Male ; Membrane Potentials ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mucociliary Clearance ; Nedd4 Ubiquitin Protein Ligases ; Proteasome Endopeptidase Complex/*metabolism ; Proteasome Inhibitors/pharmacology ; Pulmonary Alveoli/drug effects/*enzymology ; Rats ; Rats, Sprague-Dawley ; Sodium/*metabolism ; Sodium Channel Blockers/pharmacology ; Time Factors ; Ubiquitin/*metabolism ; Ubiquitin-Protein Ligases/*metabolism ; }, abstract = {Transepithelial sodium transport via alveolar epithelial Na(+) channels (ENaC) and Na(+),K(+)-ATPase constitutes the driving force for removal of alveolar edema fluid. Alveolar hypoxia associated with pulmonary edema may impair ENaC activity and alveolar Na(+) absorption through a decrease of ENaC subunit expression at the apical membrane of alveolar epithelial cells (AECs). Here, we investigated the mechanism(s) involved in this process in vivo in the β-Liddle mouse strain mice carrying a truncation of β-ENaC C-terminus abolishing the interaction between β-ENaC and the ubiquitin protein-ligase Nedd4-2 that targets the channel for endocytosis and degradation and in vitro in rat AECs. Hypoxia (8% O2 for 24 h) reduced amiloride-sensitive alveolar fluid clearance by 69% in wild-type mice but had no effect in homozygous mutated β-Liddle littermates. In vitro, acute exposure of AECs to hypoxia (0.5-3% O2 for 1-6 h) rapidly decreased transepithelial Na(+) transport as assessed by equivalent short-circuit current Ieq and the amiloride-sensitive component of Na(+) current across the apical membrane, reflecting ENaC activity. Hypoxia induced a decrease of ENaC subunit expression in the apical membrane of AECs with no change in intracellular expression and induced a 2-fold increase in α-ENaC polyubiquitination. Hypoxic inhibition of amiloride-sensitive Ieq was fully prevented by preincubation with the proteasome inhibitors MG132 and lactacystin or with the antioxidant N-acetyl-cysteine. Our data strongly suggest that Nedd4-2-mediated ubiquitination of ENaC leading to endocytosis and degradation of apical Na(+) channels is a key feature of hypoxia-induced inhibition of transepithelial alveolar Na(+) transport.}, }
@article {pmid24091667, year = {2013}, author = {Wang, Y and Wang, JW and Xiao, X and Shan, Y and Xue, B and Jiang, G and He, Q and Chen, J and Xu, HG and Zhao, RX and Werle, KD and Cui, R and Liang, J and Li, YL and Xu, ZX}, title = {Piperlongumine induces autophagy by targeting p38 signaling.}, journal = {Cell death &amp; disease}, volume = {4}, number = {10}, pages = {e824}, pmid = {24091667}, issn = {2041-4889}, support = {R01CA133053/CA/NCI NIH HHS/United States ; P50 CA098252/CA/NCI NIH HHS/United States ; P30 AR048311/AR/NIAMS NIH HHS/United States ; R01 CA133053/CA/NCI NIH HHS/United States ; P50CA098252/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Autophagy/*drug effects ; Cell Line ; Dioxolanes/*pharmacology ; Energy Metabolism/drug effects ; Homeostasis/drug effects ; Humans ; Intracellular Space/drug effects/metabolism ; MAP Kinase Signaling System/*drug effects ; Mice ; Necrosis ; Phagosomes/drug effects/metabolism/ultrastructure ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Piperlongumine (PL), a natural product isolated from the plant species Piper longum L., can selectively induce apoptotic cell death in cancer cells by targeting the stress response to reactive oxygen species (ROS). Here we show that PL induces cell death in the presence of benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl)-fluoro-methylketone (zVAD-fmk), a pan-apoptotic inhibitor, and in the presence of necrostatin-1, a necrotic inhibitor. Instead PL-induced cell death can be suppressed by 3-methyladenine, an autophagy inhibitor, and substantially attenuated in cells lacking the autophagy-related 5 (Atg5) gene. We further show that PL enhances autophagy activity without blocking autophagy flux. Application of N-acetyl-cysteine, an antioxidant, markedly reduces PL-induced autophagy and cell death, suggesting an essential role for intracellular ROS in PL-induced autophagy. Furthermore, PL stimulates the activation of p38 protein kinase through ROS-induced stress response and p38 signaling is necessary for the action of PL as SB203580, a p38 inhibitor, or dominant-negative p38 can effectively reduce PL-mediated autophagy. Thus, we have characterized a new mechanism for PL-induced cell death through the ROS-p38 pathway. Our findings support the therapeutic potential of PL by triggering autophagic cell death.}, }
@article {pmid24091661, year = {2013}, author = {Česen, MH and Repnik, U and Turk, V and Turk, B}, title = {Siramesine triggers cell death through destabilisation of mitochondria, but not lysosomes.}, journal = {Cell death &amp; disease}, volume = {4}, number = {10}, pages = {e818}, pmid = {24091661}, issn = {2041-4889}, mesh = {Cathepsin L/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Endoplasmic Reticulum/drug effects/metabolism/ultrastructure ; Humans ; Indoles/*pharmacology ; Intracellular Membranes/drug effects/metabolism/ultrastructure ; Lysosomes/drug effects/*metabolism/ultrastructure ; Membrane Fusion/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Microtubule-Associated Proteins/metabolism ; Mitochondria/drug effects/*metabolism/ultrastructure ; Permeability/drug effects ; Phagosomes/drug effects/metabolism/ultrastructure ; Reactive Oxygen Species/metabolism ; Spiro Compounds/*pharmacology ; }, abstract = {A sigma-2 receptor agonist siramesine has been shown to trigger cell death of cancer cells and to exhibit a potent anticancer activity in vivo. However, its mechanism of action is still poorly understood. We show that siramesine can induce rapid cell death in a number of cell lines at concentrations above 20 μM. In HaCaT cells, cell death was accompanied by caspase activation, rapid loss of mitochondrial membrane potential (MMP), cytochrome c release, cardiolipin peroxidation and typical apoptotic morphology, whereas in U-87MG cells most apoptotic hallmarks were not notable, although MMP was rapidly lost. In contrast to the rapid loss of MMP above 20 μM siramesine, a rapid increase in lysosomal pH was observed at all concentrations tested (5-40 μM); however, it was not accompanied by lysosomal membrane permeabilisation (LMP) and the release of lysosomal enzymes into the cytosol. Increased lysosomal pH reduced the lysosomal degradation potential as indicated by the accumulation of immature forms of cysteine cathepsins. The lipophilic antioxidant α-tocopherol, but not the hydrophilic antioxidant N-acetyl-cysteine, considerably reduced cell death and destabilisation of mitochondrial membranes, but did not prevent the increase in lysosomal pH. At concentrations below 15 μM, siramesine triggered cell death after 2 days or later, which seems to be associated with a general metabolic and energy imbalance due to defects in the endocytic pathway, intracellular trafficking and energy production, and not by a specific molecular event. Overall, we show that cell death in siramesine-treated cells is induced by destabilisation of mitochondria and is independent of LMP and the release of cathepsins into the cytosol. Moreover, it is unlikely that siramesine acts exclusively through sigma-2 receptors, but rather through multiple molecular targets inside the cell. Our findings are therefore of significant importance in designing the next generation of siramesine analogues with high anticancer potential.}, }
@article {pmid24090735, year = {2013}, author = {Shen, H and Liu, J and Wang, Y and Lian, H and Wang, J and Xing, L and Yan, X and Wang, J and Zhang, X}, title = {Aflatoxin G1-induced oxidative stress causes DNA damage and triggers apoptosis through MAPK signaling pathway in A549 cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {62}, number = {}, pages = {661-669}, doi = {10.1016/j.fct.2013.09.030}, pmid = {24090735}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Aflatoxins/*toxicity ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; DNA Damage/*drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System/*drug effects ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Our previous studies showed that Aflatoxin G1 (AFG1) could induce lung adenocarcinoma, and that the cancer cells originated from alveolar type II cells (AT-II cells). Recently, we found AFG1 induced structural impairment in rat AT-II cells, which may account for an early event in lung tumorigenesis. However, the mechanism of AFG1-induced AT-II cell damage remains unclear. DNA damage and apoptosis induced by oxidative stress are well accepted causes of cell damage. Thus, we explore whether AFG1 activates the reactive oxygen species (ROS)/MAPK/apoptosis pathway to cause cell damage in human AT-II cells like the cell line (A549). We found AFG1 induced oxidative stress by increasing ROS generation and caused DNA double-strand breaks (DSBs) by up-regulating γH2AX expression. AFG1 also triggered apoptosis in A549 cells by regulating Fas/FasL, caspase-8, Bax, Bcl-2, and activating caspase-3. Pre-treatment with antioxidant n-acetyl-l-cysteine (NAC) reduced ROS generation and DNA DSBs, inhibited apoptosis, and increased cell viability in AFG1-treated cells. Furthermore, we found AFG1 activated ROS-mediated JNK and p38 pathways to induce cell apoptosis in A549 cells. In conclusion, our results indicate that AFG1 induces oxidative DNA damage and triggers apoptosis through ROS-mediated JNK and p38 signaling pathways in A549 cells, which may contribute to AFG1-induced AT-II cell damage.}, }
@article {pmid24085626, year = {2014}, author = {Jeon, YJ and Song, KS and Han, HJ and Park, SH and Chang, W and Lee, MY}, title = {Rosmarinic acid inhibits chemical hypoxia-induced cytotoxicity in primary cultured rat hepatocytes.}, journal = {Archives of pharmacal research}, volume = {37}, number = {7}, pages = {907-915}, doi = {10.1007/s12272-013-0234-z}, pmid = {24085626}, issn = {1976-3786}, mesh = {Animals ; Antioxidants/isolation &amp; purification/*pharmacology ; Cell Hypoxia/drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cinnamates/isolation &amp; purification/*pharmacology ; Depsides/isolation &amp; purification/*pharmacology ; Hepatocytes/*drug effects/*metabolism ; Male ; Plant Leaves ; Rats ; Rats, Sprague-Dawley ; Rosmarinic Acid ; }, abstract = {We examine the effect of rosmarinic acid (RA) in chemical hypoxia-induced injury in rat hepatocytes. Cell viability was significantly decreased by cobalt chloride (CoCl2), a well-known hypoxia mimetic agent in a time- and dose- dependent manner. RA pretreatment before exposure to CoCl2 significantly attenuated the CoCl2-induced decrease of cell viability. Additionally, pretreatment with RA potentiated the decrease of Bcl-2 expression and attenuated the increase of Caspase-3 expression by CoCl2. CoCl2 treatment resulted in an increase of intracellular ROS generation, which is inhibited by RA or N-acetyl-cysteine (NAC, a ROS scavenger), and p38MAPK phosphorylation, which is also blocked by RA or NAC. CoCl2-induced increase of Bax/Bcl-2 ratio and Caspase-3 expression was attenuated by RA, NAC and SB203580 (p38MAPK inhibitor). CoCl2-induced decrease of cell viability was also attenuated by RA, NAC and SB203580 pretreatment. Additionally, RA inhibited CoCl2-induced COX-2 expression and prostaglandin E2 (PGE2) secretion. Similar to the effect of RA, both NAC and NS-398 (COX-2 inhibitor) blocked CoCl2-induced COX-2 expression and PGE2 secretion. NS-398 attenuated not only CoCl2-induced increase of Bax/Bcl-2 ratio and Caspase-3 expression, but decrease of cell viability. Taken together, RA protects primary cultured rat hepatocytes against CoCl2-induced cell injury through inhibition of ROS-activated p38MAPK and COX-2/PGE2 pathway.}, }
@article {pmid24082739, year = {2013}, author = {Hemalatha, P and Reddy, AG and Reddy, YR and Shivakumar, P}, title = {Evaluation of protective effect of N-acetyl cysteine on arsenic-induced hepatotoxicity.}, journal = {Journal of natural science, biology, and medicine}, volume = {4}, number = {2}, pages = {393-395}, pmid = {24082739}, issn = {0976-9668}, abstract = {OBJECTIVE: The present study was aimed to study protective role of N-acetyl cysteine (NAC) was assessed against arsenic (As)-induced hepatotoxicity in rats.<br><br>METHODS: Twenty four male Wistar rats were divided into 4 groups of 6 animals each and treated as follows: Group 1: sham control, 2: arsenic control (sodium arsenite @ 10 mg/kg b. wt orally for 4 wks), 3: Pre-treatment with NAC (@ 300 mg/kg orally for 2 wks) followed by sodium arsenite along with NAC (as per above doses) and 4: Sodium arsenite + NAC (as per above doses for 4 wks).<br><br>RESULTS: The concentration of thiobarbituric acid reacting substances (TBARS) and protein carbonyls was significantly (P<0.05) increased, while the concentration of reduced glutathione (GSH), and the activity of CYP450, Na+ - K+ ATPase and Mg2+ ATPase in liver were significantly (P<0.05) reduced in group 2 as compared to control. Groups 3 and 4 revealed improvement in the parameters in study.<br><br>CONCLUSION: The study revealed that arsenic induces hepatotoxicity by inducing oxidative stress and supplementation of NAC is beneficial in countering the adverse effects.}, }
@article {pmid24081674, year = {2014}, author = {Lu, YX and Yu, XC and Zhu, MY}, title = {Antitumor effect of fructose 1,6-bisphosphate and its mechanism in hepatocellular carcinoma cells.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {35}, number = {2}, pages = {1679-1685}, pmid = {24081674}, issn = {1423-0380}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/*drug therapy/genetics/pathology ; Catalase/metabolism ; Cell Proliferation ; Fructosediphosphates/*pharmacology ; Gene Expression Regulation, Neoplastic ; Hep G2 Cells ; Humans ; Hydrogen Peroxide/metabolism ; Liver Neoplasms/*drug therapy ; Reactive Oxygen Species/metabolism ; }, abstract = {We aimed to investigate the antitumor effect and mechanism of fructose 1,6-bisphosphate (F1,6BP) in a hepatocellular carcinoma cell line. HepG2 cells were treated with different concentrations of F1,6BP alone or in combination with antioxidant N-acetyl-L-cysteine (NAC) or catalase (CAT), and cell proliferation assays were performed. Nuclear morphology was observed by fluorescence microscopy after Hoechst staining, and apoptosis was measured with flow cytometry. Changes in reactive oxygen species (ROS) levels in HepG2 cells were detected by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. A colorimetric assay was adopted to determine the percentage of oxidized glutathione in these cells. CAT and glutathione peroxidase (GSH-Px) mRNA expression levels in HepG2 cells were measured by real-time fluorescence quantitative PCR. HepG2 cell proliferation was significantly inhibited by F1,6BP, accompanied by an increase in intracellular ROS levels and oxidized glutathione. Upregulated apoptosis and characteristic nuclear morphological changes were observed, and the expression of CAT and GSH-Px mRNA was increased after F1,6BP treatment. The antitumor effect of F1,6BP was significantly decreased after pretreatment with NAC and CAT in HepG2 cells. In conclusion, F1,6BP can induce the apoptosis of HepG2 cells. The mechanism involved may be associated with the generation of ROS, especially the production of H2O2.}, }
@article {pmid24080471, year = {2014}, author = {Rushworth, GF and Megson, IL}, title = {Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits.}, journal = {Pharmacology &amp; therapeutics}, volume = {141}, number = {2}, pages = {150-159}, doi = {10.1016/j.pharmthera.2013.09.006}, pmid = {24080471}, issn = {1879-016X}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Glutathione/*metabolism ; Humans ; Prodrugs/*pharmacology/therapeutic use ; }, abstract = {N-acetyl-l-cysteine (NAC) has long been used therapeutically for the treatment of acetaminophen (paracetamol) overdose, acting as a precursor for the substrate (l-cysteine) in synthesis of hepatic glutathione (GSH) depleted through drug conjugation. Other therapeutic uses of NAC have also emerged, including the alleviation of clinical symptoms of cystic fibrosis through cysteine-mediated disruption of disulfide cross-bridges in the glycoprotein matrix in mucus. More recently, however, a wide range of clinical studies have reported on the use of NAC as an antioxidant, most notably in the protection against contrast-induced nephropathy and thrombosis. The results from these studies are conflicting and a consensus is yet to be reached regarding the merits or otherwise of NAC in the antioxidant setting. This review seeks to re-evaluate the mechanism of action of NAC as a precursor for GSH synthesis in the context of its activity as an "antioxidant". Results from recent studies are examined to establish whether the pre-requisites for effective NAC-induced antioxidant activity (i.e. GSH depletion and the presence of functional metabolic pathways for conversion of NAC to GSH) have received adequate consideration in the interpretation of the data. A key conclusion is a reinforcement of the concept that NAC should not be considered to be a powerful antioxidant in its own right: its strength is the targeted replenishment of GSH in deficient cells and it is likely to be ineffective in cells replete in GSH.}, }
@article {pmid24078461, year = {2013}, author = {Jones, KJ and Chetram, MA and Bethea, DA and Bryant, LK and Odero-Marah, V and Hinton, CV}, title = {Cysteine (C)-X-C Receptor 4 Regulates NADPH Oxidase-2 During Oxidative Stress in Prostate Cancer Cells.}, journal = {Cancer microenvironment : official journal of the International Cancer Microenvironment Society}, volume = {6}, number = {3}, pages = {277-288}, pmid = {24078461}, issn = {1875-2292}, support = {F31 CA153908/CA/NCI NIH HHS/United States ; G12 MD007590/MD/NIMHD NIH HHS/United States ; P20 MD002285/MD/NIMHD NIH HHS/United States ; R25 GM060414/GM/NIGMS NIH HHS/United States ; }, abstract = {Reactive oxygen species (ROS) are implicated in many human diseases, including cancer. We have previously demonstrated that ROS increased the expression and activity of the chemokine receptor, CXCR4, which enhanced metastatic functions in prostate cancer cells. Studies have also revealed that CXCR4 and its ligand, SDF-1α, promoted ROS accumulation; however the source of ROS was not investigated. Recent evidence suggested that ROS accumulation in prostate cancer cell lines was contributed by the NADPH oxidase (NOX) family of enzymes. Herein, we sought to determine whether the CXCR4/SDF-1α signaling axis mediates ROS production through NOX in prostate cancer. We observed an increase in intracellular ROS generation in prostate cancer cells upon SDF-1α stimulation compared to untreated samples. Conversely, lower levels of ROS were detected in cells treated with AMD3100 (CXCR4 antagonist) or the ROS scavenger, N-acetyl-cysteine (NAC). Markedly reduced levels of ROS were observed in cells treated with apocynin (NOX inhibitor) compared to rotenone (mitochondrial complex I inhibitor)-treated cells. Specifically, we determined that NOX2 responded to, and was regulated by, the SDF-1α/CXCR4 signaling axis. Moreover, chemical inhibition of the ERK1/2 and PI3K pathways revealed that PI3K/AKT signaling participated in CXCR4-mediated NOX activity, and that these collective signaling events resulted in enhanced cell movement towards a chemoattractant. Finally, NOX2 may be a potential therapeutic target, as Oncomine microarray database analysis of normal prostate, benign prostatic hyperplasia (BPH) and prostatic intraepithelial neoplasia (PIN) tissue samples determined a correlation between NOX2 expression and prostate cancer. Taken together, these results suggest that CXCR4/SDF-1α-mediated ROS production through NOX2 enzymes may be an emerging concept by which chemokine signaling progresses tumorigenesis.}, }
@article {pmid24078104, year = {2013}, author = {Greco, CM and Nakajima, C and Manzi, S}, title = {Updated review of complementary and alternative medicine treatments for systemic lupus erythematosus.}, journal = {Current rheumatology reports}, volume = {15}, number = {11}, pages = {378}, pmid = {24078104}, issn = {1534-6307}, support = {R01 AR046588/AR/NIAMS NIH HHS/United States ; R01AR046588/AR/NIAMS NIH HHS/United States ; R01 AR057338/AR/NIAMS NIH HHS/United States ; K24 AR002213/AR/NIAMS NIH HHS/United States ; R01 AT006453/AT/NCCIH NIH HHS/United States ; K23 AR051314/AR/NIAMS NIH HHS/United States ; }, mesh = {Acupuncture Therapy/methods ; Complementary Therapies/*methods ; Dietary Supplements ; Humans ; Lupus Erythematosus, Systemic/*therapy ; Mind-Body Therapies/methods ; Vitamins/therapeutic use ; }, abstract = {It is estimated that over 50 % of patients with systemic lupus erythematosus (SLE) have utilized complementary and alternative medicine (CAM) treatments to reduce symptoms and manage their health. However, there are relatively few randomized controlled trials of CAM for SLE. This review describes recent studies of vitamins and supplements, acupuncture, and mind-body interventions in SLE patients. The recent trials of CAM treatments for SLE indicate that supplements such as vitamin D, omega 3 fatty acids, N-acetyl cysteine and turmeric show some promise for reducing SLE disease activity. In addition, mind-body methods such as cognitive-behavioral therapy and other counseling interventions may improve mood and quality of life in SLE.}, }
@article {pmid24077426, year = {2013}, author = {Kanji, HD and Mithani, S and Boucher, P and Dias, VC and Yarema, MC}, title = {Coma, metabolic acidosis, and methemoglobinemia in a patient with acetaminophen toxicity.}, journal = {Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharmacologie clinique}, volume = {20}, number = {3}, pages = {e207-11}, pmid = {24077426}, issn = {2561-8741}, mesh = {Acetaminophen/*adverse effects ; Acidosis/chemically induced/complications/*diagnosis ; Aged ; Analgesics, Non-Narcotic/*adverse effects ; Coma/chemically induced/complications/*diagnosis ; Female ; Humans ; Methemoglobinemia/chemically induced/complications/*diagnosis ; }, abstract = {We present a case of early coma, metabolic acidosis and methemoglobinemia after substantial acetaminophen toxicity in the absence of hepatic failure. A 77-year-old female presented to the emergency department with a decreased level of consciousness. She was found unresponsive by a family member in her bed, and was reported to be acting normally when she was last seen eight hours earlier. Laboratory results on arrival were: pH 7.19, sodium 139 mmol/L, chloride 106 mmol/L, potassium 3.3 mmol/L, CO2 8 mmol/L, and an anion gap of 25. Both venous lactate (10.2 mmol/L) and methemoglobin (9.4 %) were elevated. The patient's acetaminophen concentration was markedly elevated at 7138 µmol/L (1078 µg/ml). Hepatic enzymes and coagulation tests were normal [alanine transaminase (ALT) 8 U/L, international normalized ratio (INR) 1.0]. Intravenous N-acetylcysteine (NAC) was initiated at a dose of 150 mg/kg over 15 minutes, followed by 50 mg/kg over the next four hours, followed by 100 mg/kg over the next 16 hours. Twenty-four hours after admission, the anion gap metabolic acidosis had resolved, and the methemoglobin was 2.1%. Aminotransferases peaked at 44 U/L and INR peaked at 1.9. A urine 5-oxoproline assay performed five days after admission was negative, suggesting no evidence of a 5-oxoprolinase deficiency. We describe the pathophysiology and discuss the literature on acetaminophen-induced coma and metabolic acidosis in the absence of hepatic injury; and propose mechanisms for associated methemoglobinemia.}, }
@article {pmid24076283, year = {2014}, author = {Leoncini, M and Toso, A and Maioli, M and Tropeano, F and Villani, S and Bellandi, F}, title = {Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: Results from the PRATO-ACS Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome).}, journal = {Journal of the American College of Cardiology}, volume = {63}, number = {1}, pages = {71-79}, doi = {10.1016/j.jacc.2013.04.105}, pmid = {24076283}, issn = {1558-3597}, mesh = {Acute Coronary Syndrome/*diagnostic imaging/drug therapy ; Acute Kidney Injury/chemically induced/*prevention &amp; control ; Aged ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects/methods ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Female ; Fluorobenzenes/*administration &amp; dosage ; Follow-Up Studies ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration &amp; dosage ; Male ; Platelet Aggregation Inhibitors/*therapeutic use ; Prospective Studies ; Pyrimidines/*administration &amp; dosage ; Rosuvastatin Calcium ; Sulfonamides/*administration &amp; dosage ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVES: This study sought to determine if in addition to standard preventive measures on-admission, high-dose rosuvastatin exerts a protective effect against contrast-induced acute kidney injury (CI-AKI).<br><br>BACKGROUND: Patients with acute coronary syndrome (ACS) are at high risk for CI-AKI, and the role of statin pre-treatment in preventing renal damage remains uncertain.<br><br>METHODS: Consecutive statin-na&#xef;ve non-ST elevation ACS patients scheduled to undergo early invasive strategy were randomly assigned to receive rosuvastatin (40 mg on admission, followed by 20 mg/day; statin group n&#xa0;= 252) or no statin treatment (control group n&#xa0;= 252). CI-AKI was defined as an increase in creatinine concentration of&#xa0;&#x2265;0.5 mg/dl or&#xa0;&#x2265;25% above baseline within 72 h after contrast administration.<br><br>RESULTS: The incidence of CI-AKI was significantly lower in the statin group than in controls (6.7% vs. 15.1%; adjusted odds ratio: 0.38; 95% confidence interval [CI]: 0.20 to 0.71; p&#xa0;= 0.003). The benefits against CI-AKI were consistent, even applying different CI-AKI definition criteria and in all the pre-specified risk categories. The 30-day incidence of adverse cardiovascular and renal events (death, dialysis, myocardial infarction, stroke, or persistent renal damage) was significantly lower in the statin group (3.6% vs. 7.9%, respectively; p&#xa0;= 0.036). Moreover, statin treatment given on admission was associated with a lower rate of death or nonfatal myocardial infarction at 6 month follow-up (3.6%&#xa0;vs. 7.2%, respectively; p&#xa0;= 0.07).<br><br>CONCLUSIONS: High-dose rosuvastatin given on admission to statin-na&#xef;ve patients with ACS who are scheduled for an early invasive procedure can prevent CI-AKI and improve short-term clinical outcome. (Statin Contrast Induced Nephropathy Prevention [PRATO-ACS]; NCT01185938).}, }
@article {pmid24074305, year = {2013}, author = {Abutarboush, R and Scultetus, A and Pappas, G and Arnaud, F and Auker, C and McCarron, R and Moon-Massat, PF}, title = {Effects of N-acetyl-L-cysteine and hyaluronic acid on HBOC-201-induced systemic and cerebral vasoconstriction in the rat.}, journal = {Current drug discovery technologies}, volume = {10}, number = {4}, pages = {315-324}, doi = {10.2174/15701638113109990034}, pmid = {24074305}, issn = {1875-6220}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Blood Pressure ; Cerebral Arteries/*drug effects/physiology ; Hemoglobins/*administration &amp; dosage ; Hyaluronic Acid/*administration &amp; dosage ; Male ; Rats ; Rats, Sprague-Dawley ; Vasoconstriction/*drug effects ; }, abstract = {Hemoglobin-based oxygen carrier-201 (HBOC) was developed as a resuscitative fluid but concerns exist over potentially adverse vasoconstriction. This study evaluated whether concurrent IV (intra venous) N-acetyl-L-cysteine (NAC) or hyaluronic acid (HA) would attenuate HBOC-associated vasoconstriction, assessed by systemic blood pressures and cerebral pial microvasculature, when administered to healthy, anesthetized rats. Rats (8-9/group) received a 30 min infusion of 3 ml/kg HBOC, HBOC plus 600 mg/kg NAC (HBOC/NAC), HBOC plus 1.5 mg/kg HA (HBOC/HA) or 3 ml/kg Albumin. Mean (MAP) and systolic (SBP) blood pressures, blood chemistries and cerebral pial vessel diameters were measured at baseline, end of infusion, and intermittently for an additional 90 min. HBOC caused immediate and sustained increases in SBP and MAP (35.3 ± 3.6 and 29.1 ± 2.5 mm Hg peak increases above baseline, respectively; mean ± SEM) and immediate but progressive vasoconstriction (11 µm maximum reduction) in medium-sized (50-100 µm) pial arterioles. When NAC was co-administered, blood pressure changes were attenuated and vessel changes were abolished. Similar trends were noted with co-administration of HA but were not statistically different from HBOC-alone. Small-sized (< 50 µm) pial vessels and blood parameters showed no differences from baseline or among groups. No adverse clinical signs were observed. We demonstrated that it is possible for adjuvant drugs to reduce the vasoconstriction associated with HBOC-201. Coinfusion of the anti-oxidant NAC mitigated HBOC-201-associated increases in blood pressures and vasoconstriction in medium-sized cerebral pial vessels. The drag-reducing polymer HA may be more effective at a higher dose as a similar but non-significant trend was observed.}, }
@article {pmid24070586, year = {2013}, author = {Du, K and Williams, CD and McGill, MR and Xie, Y and Farhood, A and Vinken, M and Jaeschke, H}, title = {The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation.}, journal = {Toxicology and applied pharmacology}, volume = {273}, number = {3}, pages = {484-491}, pmid = {24070586}, issn = {1096-0333}, support = {R01 DK070195/DK/NIDDK NIH HHS/United States ; R01 AA12916/AA/NIAAA NIH HHS/United States ; 5P20RR021940-07/RR/NCRR NIH HHS/United States ; P20 RR021940/RR/NCRR NIH HHS/United States ; 8 P20 GM103549-07/GM/NIGMS NIH HHS/United States ; T32 ES007079-26A2/ES/NIEHS NIH HHS/United States ; P20 GM12345/GM/NIGMS NIH HHS/United States ; P20 GM103549/GM/NIGMS NIH HHS/United States ; T32 ES007079/ES/NIEHS NIH HHS/United States ; R01 AA012916/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/*adverse effects ; Animals ; Boron Compounds/*pharmacology ; Chemical and Drug Induced Liver Injury/*drug therapy/prevention &amp; control ; Connexins/antagonists &amp; inhibitors/metabolism ; *Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/metabolism ; Dimethyl Sulfoxide/metabolism ; Gap Junctions/*drug effects/metabolism ; Hepatocytes/drug effects/metabolism ; JNK Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Signal Transduction ; tert-Butylhydroperoxide/administration &amp; dosage/adverse effects ; Gap Junction beta-1 Protein ; }, abstract = {Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the US. Although many aspects of the mechanism are known, recent publications suggest that gap junctions composed of connexin32 function as critical intercellular communication channels which transfer cytotoxic mediators into neighboring hepatocytes and aggravate liver injury. However, these studies did not consider off-target effects of reagents used in these experiments, especially the gap junction inhibitor 2-aminoethoxy-diphenyl-borate (2-APB). In order to assess the mechanisms of protection of 2-APB in vivo, male C56Bl/6 mice were treated with 400 mg/kg APAP to cause extensive liver injury. This injury was prevented when animals were co-treated with 20 mg/kg 2-APB and was attenuated when 2-APB was administered 1.5 h after APAP. However, the protection was completely lost when 2-APB was given 4-6 h after APAP. Measurement of protein adducts and c-jun-N-terminal kinase (JNK) activation indicated that 2-APB reduced both protein binding and JNK activation, which correlated with hepatoprotection. Although some of the protection was due to the solvent dimethyl sulfoxide (DMSO), in vitro experiments clearly demonstrated that 2-APB directly inhibits cytochrome P450 activities. In addition, JNK activation induced by phorone and tert-butylhydroperoxide in vivo was inhibited by 2-APB. The effects against APAP toxicity in vivo were reproduced in primary cultured hepatocytes without use of DMSO and in the absence of functional gap junctions. We conclude that the protective effect of 2-APB was caused by inhibition of metabolic activation of APAP and inhibition of the JNK signaling pathway and not by blocking connexin32-based gap junctions.}, }
@article {pmid24068521, year = {2014}, author = {Gao, H and Wang, H and Peng, J}, title = {Hispidulin induces apoptosis through mitochondrial dysfunction and inhibition of P13k/Akt signalling pathway in HepG2 cancer cells.}, journal = {Cell biochemistry and biophysics}, volume = {69}, number = {1}, pages = {27-34}, doi = {10.1007/s12013-013-9762-x}, pmid = {24068521}, issn = {1559-0283}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/genetics/metabolism ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Flavones/*pharmacology ; Gene Expression Regulation ; Hep G2 Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; *Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-akt/*antagonists &amp; inhibitors/genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/agonists/metabolism/pharmacology ; Signal Transduction/drug effects ; Time Factors ; }, abstract = {Hispidulin is a flavonoid compound which is an active ingredient in a number of traditional Chinese medicinal herbs. However, it's therapeutic activity remains poorly understood. The present study investigated the pro-apoptotic effects and mechanism by which Hispidulin induces apoptosis in human hepatoblastoma cancer (HepG2) cells. The results showed that Hispidulin induced cell death in a dose- and time-dependent manner in HepG2 cells whereas no toxic reaction was observed in normal human liver cells at indicated concentration. This study also demonstrated that Hispidulin induces apoptosis through mitochondrial dysfunction, which is characterized by decreased Bcl-2/Bax ratio, disrupted mitochondrial membrane potential and increased release of cytochrome C and activated capase-3. Our results also showed that mitochondrial dysfunction was triggered by Hispidulin-induced excessive ROS generation. Hispidulin also significantly inhibited Akt activation. ROS inhibitor NAC abrogated the inhibitory effect of Hispidulin on P13k/Akt signalling pathway and the proapoptotic effect in HepG2 cells. Our results demonstrate for the first time that Hispidulin induces apoptosis in HepG2 cells and suggested that the pro-apoptotic effect of Hispidulin was mediated through mitochondrial dysfunction and inhibition of P13k/Akt signalling pathway. Since no toxic effect was observed when normal liver cells were treated with Hispidulin, Hispidulin may have the potential to be used as therapeutic for liver cancer.}, }
@article {pmid24065159, year = {2013}, author = {Su, JH and Chen, YC and El-Shazly, M and Du, YC and Su, CW and Tsao, CW and Liu, LL and Chou, Y and Chang, WB and Su, YD and Chiang, MY and Yeh, YT and Lu, MC}, title = {Towards the small and the beautiful: a small dibromotyrosine derivative from Pseudoceratina sp. sponge exhibits potent apoptotic effect through targeting IKK/NFκB signaling pathway.}, journal = {Marine drugs}, volume = {11}, number = {9}, pages = {3168-3185}, pmid = {24065159}, issn = {1660-3397}, mesh = {Animals ; Antineoplastic Agents/*chemistry/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; DNA Topoisomerases, Type II/metabolism ; HeLa Cells ; Humans ; K562 Cells ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; NF-kappa B/*metabolism ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Porifera/*chemistry ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {A dibromotyrosine derivative, (1'R,5'S,6'S)-2-(3',5'-dibromo-1',6'-dihydroxy-4'-oxocyclohex-2'-enyl) acetonitrile (DT), was isolated from the sponge Pseudoceratina sp., and was found to exhibit a significant cytotoxic activity against leukemia K562 cells. Despite the large number of the isolated bromotyrosine derivatives, studies focusing on their biological mechanism of action are scarce. In the current study we designed a set of experiments to reveal the underlying mechanism of DT cytotoxic activity against K562 cells. First, the results of MTT cytotoxic and the annexin V-FITC/PI apoptotic assays, indicated that the DT cytotoxic activity is mediated through induction of apoptosis. This effect was also supported by caspases-3 and -9 activation as well as PARP cleavage. DT induced generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP) as indicated by flow cytometric assay. The involvement of ROS generation in the apoptotic activity of DT was further corroborated by the pretreatment of K562 cells with N-acetyl-cysteine (NAC), a ROS scavenger, which prevented apoptosis and the disruption of MMP induced by DT. Results of cell-free system assay suggested that DT can act as a topoisomerase II catalytic inhibitor, unlike the clinical anticancer drug, etoposide, which acts as a topoisomerase poison. Additionally, we found that DT treatment can block IKK/NFκB pathway and activate PI3K/Akt pathway. These findings suggest that the cytotoxic effect of DT is associated with mitochondrial dysfunction-dependent apoptosis which is mediated through oxidative stress. Therefore, DT represents an interesting reference point for the development of new cytotoxic agent targeting IKK/NFκB pathway.}, }
@article {pmid24064712, year = {2013}, author = {Han, BR and You, BR and Park, WH}, title = {Valproic acid inhibits the growth of HeLa cervical cancer cells via caspase-dependent apoptosis.}, journal = {Oncology reports}, volume = {30}, number = {6}, pages = {2999-3005}, doi = {10.3892/or.2013.2747}, pmid = {24064712}, issn = {1791-2431}, mesh = {Apoptosis/*drug effects ; Caspase Inhibitors/administration &amp; dosage ; Caspases/metabolism ; Cell Proliferation/*drug effects ; Female ; Glutathione/metabolism ; HeLa Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; Uterine Cervical Neoplasms/*drug therapy/genetics/pathology ; Valproic Acid/*administration &amp; dosage ; }, abstract = {Valproic acid (VPA) as a histone deacetylase (HDAC) inhibitor has an anticancer effect. In the present study, we evaluated the effects of VPA on the growth and death of HeLa cervical cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH). Dose- and time-dependent growth inhibition was observed in HeLa cells with an IC50 of approximately 10 mM at 24 h. DNA flow cytometric analysis indicated that 10 mM VPA induced a G2/M phase arrest of the cell cycle. This agent also induced apoptosis, which was accompanied by the cleavage of PARP, the activation of caspase-3, -8 and -9, and the loss of mitochondrial membrane potential (MMP; ∆Ψm). All the tested caspase inhibitors significantly prevented HeLa apoptotic cell death induced by VPA, whereas TNF-α intensified the apoptotic cell death. With respect to ROS and GSH levels, VPA increased ROS levels and induced GSH depletion. However, N-acetyl cysteine (NAC; an antioxidant) and L-buthionine sulfoximine (BSO; a GSH synthesis inhibitor) did not significantly affect cell death in VPA-treated HeLa cells. In conclusion, VPA inhibits the growth of HeLa cervical cancer cells via caspase-dependent apoptosis and the growth inhibition is independent of ROS and GSH level changes.}, }
@article {pmid24064383, year = {2013}, author = {Abdelmegeed, MA and Banerjee, A and Jang, S and Yoo, SH and Yun, JW and Gonzalez, FJ and Keshavarzian, A and Song, BJ}, title = {CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis.}, journal = {Free radical biology &amp; medicine}, volume = {65}, number = {}, pages = {1238-1245}, pmid = {24064383}, issn = {1873-4596}, support = {Z99 AA999999//Intramural NIH HHS/United States ; ZIA AA000036-26//Intramural NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Binge Drinking/*genetics ; Cytochrome P-450 CYP2E1/genetics/*metabolism ; Cytokines/blood ; Endotoxemia ; Endotoxins/blood ; Enterobacteriaceae ; Ethanol/*pharmacology ; Fatty Liver/*pathology ; Female ; Intestines/microbiology/pathology ; Lipid Metabolism/physiology ; Liver/microbiology/pathology ; Male ; Mice ; Mice, Knockout ; Oxidative Stress/drug effects ; Signal Transduction ; }, abstract = {Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed at investigating the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria, and liver histology obtained at 6h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria, and triglycerides. All these changes, including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetylcysteine, both of which suppressed oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-α, hepatic cytokines, CYP2E1, and lipid peroxidation, with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of proapoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK, and peroxisome proliferator-activated receptor-α, all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seems critical in binge alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia; altered fat metabolism; and inflammation contributing to hepatic apoptosis and steatohepatitis.}, }
@article {pmid24064301, year = {2014}, author = {Völzke, A and Koch, A and Meyer Zu Heringdorf, D and Huwiler, A and Pfeilschifter, J}, title = {Sphingosine 1-phosphate (S1P) induces COX-2 expression and PGE2 formation via S1P receptor 2 in renal mesangial cells.}, journal = {Biochimica et biophysica acta}, volume = {1841}, number = {1}, pages = {11-21}, doi = {10.1016/j.bbalip.2013.09.009}, pmid = {24064301}, issn = {0006-3002}, mesh = {Angiotensin II/pharmacology ; Animals ; Celecoxib ; Cells, Cultured ; Cyclooxygenase 2/*biosynthesis ; Cyclooxygenase Inhibitors/pharmacology ; Dinoprostone/*biosynthesis ; Gene Expression Regulation, Enzymologic/drug effects/*physiology ; Humans ; Interleukin-1beta/pharmacology ; Lysophospholipids/*metabolism/pharmacology ; MAP Kinase Signaling System/drug effects/physiology ; Male ; Mesangial Cells/cytology/*metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Pyrazoles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Lysosphingolipid/*metabolism ; Sphingosine/*analogs &amp; derivatives/metabolism/pharmacology ; Sphingosine-1-Phosphate Receptors ; Sulfonamides/pharmacology ; Up-Regulation/drug effects/physiology ; Vasoconstrictor Agents/pharmacology ; }, abstract = {Understanding the mechanisms of sphingosine 1-phosphate (S1P)-induced cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) formation in renal mesangial cells may provide potential therapeutic targets to treat inflammatory glomerular diseases. Thus, we evaluated the S1P-dependent signaling mechanisms which are responsible for enhanced COX-2 expression and PGE2 formation in rat mesangial cells under basal conditions. Furthermore, we investigated whether these mechanisms are operative in the presence of angiotensin II (Ang II) and of the pro-inflammatory cytokine interleukin-1β (IL-1β). Treatment of rat and human mesangial cells with S1P led to concentration-dependent enhanced expression of COX-2. Pharmacological and molecular biology approaches revealed that the S1P-dependent increase of COX-2 mRNA and protein expression was mediated via activation of S1P receptor 2 (S1P2). Further, inhibition of Gi and p42/p44 MAPK signaling, both downstream of S1P2, abolished the S1P-induced COX-2 expression. In addition, S1P/S1P2-dependent upregulation of COX-2 led to significantly elevated PGE2 levels, which were further potentiated in the presence of Ang II and IL-1β. A functional consequence downstream of S1P/S1P2 signaling is mesangial cell migration that is stimulated by S1P. Interestingly, inhibition of COX-2 by celecoxib and SC-236 completely abolished the migratory response. Overall, our results demonstrate that extracellular S1P induces COX-2 expression via activation of S1P2 and subsequent Gi and p42/p44 MAPK-dependent signaling in renal mesangial cells leading to enhanced PGE2 formation and cell migration that essentially requires COX-2. Thus, targeting S1P/S1P2 signaling pathways might be a novel strategy to treat renal inflammatory diseases.}, }
@article {pmid24064061, year = {2013}, author = {Shin, H and Yoo, HG and Inui, S and Itami, S and Kim, IG and Cho, AR and Lee, DH and Park, WS and Kwon, O and Cho, KH and Won, CH}, title = {Induction of transforming growth factor-beta 1 by androgen is mediated by reactive oxygen species in hair follicle dermal papilla cells.}, journal = {BMB reports}, volume = {46}, number = {9}, pages = {460-464}, pmid = {24064061}, issn = {1976-670X}, mesh = {Acetylcysteine/pharmacology ; Androgens/*pharmacology ; Animals ; Cell Line ; Dermis/cytology/*drug effects/metabolism ; Hair Follicle ; Hydrogen Peroxide/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Receptors, Androgen/genetics/metabolism ; Transforming Growth Factor beta1/*metabolism ; }, abstract = {The progression of androgenetic alopecia is closely related to androgen-inducible transforming growth factor (TGF)-β1 secretion by hair follicle dermal papilla cells (DPCs) in bald scalp. Physiological levels of androgen exposure were reported to increase reactive oxygen species (ROS) generation. In this study, rat vibrissae dermal papilla cells (DP-6) transfected with androgen receptor showed increased ROS production following androgen treatment. We confirmed that TGF-β1 secretion is increased by androgen treatment in DP-6, whereas androgen-inducible TGF-β1 was significantly suppressed by the ROS-scavenger, N-acetyl cysteine. Therefore, we suggest that induction of TGF-β1 by androgen is mediated by ROS in hair follicle DPCs.}, }
@article {pmid24063596, year = {2014}, author = {Chiu, CZ and Wang, BW and Shyu, KG}, title = {Angiotensin II and the ERK pathway mediate the induction of leptin by mechanical cyclic stretch in cultured rat neonatal cardiomyocytes.}, journal = {Clinical science (London, England : 1979)}, volume = {126}, number = {7}, pages = {483-495}, doi = {10.1042/CS20130235}, pmid = {24063596}, issn = {1470-8736}, mesh = {Angiotensin II/*physiology ; Animals ; Animals, Newborn ; Base Sequence ; Cells, Cultured ; DNA Primers ; Leptin/*biosynthesis ; *MAP Kinase Signaling System ; Myocytes, Cardiac/cytology/*metabolism ; Myosin Heavy Chains/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; STAT3 Transcription Factor/metabolism ; *Stress, Mechanical ; Transcription, Genetic ; }, abstract = {Mechanical cyclic stretch of cardiomyocytes causes cardiac hypertrophy through cardiac-restricted gene expression. Leptin induces cardiomyocyte hypertrophy in response to myocardial stress. In the present study, we evaluated the expression of leptin under cyclic stretch and its role in regulating genetic transcription in cardiomyocytes. Cultured rat neonatal cardiomyocytes were subjected to cyclic stretch, and the expression levels of leptin, ROS (reactive oxygen species) and AngII (angiotensin II) were evaluated. Signal transduction inhibitors were used to identify the pathway of leptin expression. EMSAs were used to identify the binding of leptin/STAT3 (signal transducer and activator of transcription 3) and luciferase assays were used to identify the transcription of leptin in cardiomyocytes. The study also used an in vivo model of AV (aortocaval) shunt in rats to investigate leptin, ROS and AngII expression. Leptin and leptin receptor levels increased after cyclic stretch with the earlier expression of AngII and ROS. Leptin expression was suppressed by AngII receptor blockers, an ROS scavenger [NAC (N-acetylcysteine)], an ERK (extracellular-signal-regulated kinase) pathway inhibitor (PD98059) and ERK siRNA. Binding of leptin/STAT3 was identified by EMSAs, and luciferase assays confirmed the transcription of leptin in neonatal cardiomyocytes after cyclic stretch. Increased MHC (myosin heavy chain) expression and [3H]-proline incorporation in cardiomyocytes was detected after cyclic stretch, which were inhibited by leptin siRNA and NAC. The in vivo model of AV shunt also demonstrated increased levels of plasma and myocardial leptin, ROS and AngII expression after cyclic stretch. Mechanical cyclic stretch in cardiomyocytes increased leptin expression mediated by the induction of AngII, ROS and the ERK pathway to cause cardiomyocyte hypertrophy. Myocardial hypertrophy can be identified by increased transcriptional activity and an enhanced hypertrophic phenotype of cardiomyocytes.}, }
@article {pmid24062022, year = {2013}, author = {Umadevi, S and Gopi, V and Vellaichamy, E}, title = {Inhibitory effect of gallic acid on advanced glycation end products induced up-regulation of inflammatory cytokines and matrix proteins in H9C2 (2-1) cells.}, journal = {Cardiovascular toxicology}, volume = {13}, number = {4}, pages = {396-405}, doi = {10.1007/s12012-013-9222-2}, pmid = {24062022}, issn = {1559-0259}, mesh = {Animals ; Cell Line ; Cells, Cultured ; Cytokines/*biosynthesis/physiology ; Extracellular Matrix Proteins/*biosynthesis/*physiology ; Gallic Acid/*pharmacology ; Glycation End Products, Advanced/*antagonists &amp; inhibitors/*metabolism ; Inflammation Mediators/*physiology ; Rats ; Reactive Oxygen Species/metabolism ; Up-Regulation/drug effects/*physiology ; }, abstract = {Accumulating evidences have demonstrated that increased production of advanced glycation end products (AGEs) contributes to etiology of cardiac complications in diabetes. However, the underlying mechanism of AGE-induced effects is not well understood. Recent studies evince the beneficial role of phytochemicals in reducing the risk of cardiovascular morbidity and mortality in patients with cardiovascular diseases and diabetes mellitus. Hence, in the present study, the cardioprotective role of gallic acid (GA) against in vitro synthesized AGE in H9C2 (2-1) cells was elucidated. H9C2 (2-1) cells exposed to AGE (100 μg/ml) with/without GA pre-treatment (10 μM) and the release of reactive oxygen species (ROS), expression of oxidative stress markers, matrix proteins, and cytokines were analyzed. Cells exposed to AGE demonstrate a significant increase in ROS release with augmented expression (P < 0.01) of receptor for AGE (RAGE) and NOX-p47 phox (P < 0.001) proteins compared to untreated control cells. Moreover, an increased expression of matrix proteins and cytokines such as TNF-α (P < 0.01), TGF-β (P < 0.001), and iNOS (P < 0.001) was also found in AGE-treated cells, whereas, cells pre-treated with N-acetyl cysteine or RAGE neutralizing antibody notably (P < 0.01) impede the ROS release. Further, cells pre-treated with GA significantly attenuated the expression of NOX, RAGE, and other cytokines. In addition, the abnormal expressions of matrix proteins were also decreased especially in GA-treated cells. Thus, the results of the present study demonstrated the deleterious effect of AGEs that directly induce oxidative stress and matrix derangement and, on the other way, the "pleiotropic" activity of GA in reducing the risk of AGE-mediated cellular complications.}, }
@article {pmid24056253, year = {2013}, author = {Wong, DP and Chu, JM and Hung, VK and Lee, DK and Cheng, CH and Yung, KK and Yue, KK}, title = {Modulation of endoplasmic reticulum chaperone GRP78 by high glucose in hippocampus of streptozotocin-induced diabetic mice and C6 astrocytic cells.}, journal = {Neurochemistry international}, volume = {63}, number = {6}, pages = {551-560}, doi = {10.1016/j.neuint.2013.09.010}, pmid = {24056253}, issn = {1872-9754}, mesh = {Animals ; Astrocytes/drug effects/*metabolism ; Cells, Cultured ; Diabetes Mellitus, Experimental/*metabolism ; Endoplasmic Reticulum/drug effects/*metabolism ; Endoplasmic Reticulum Chaperone BiP ; Glial Fibrillary Acidic Protein/metabolism ; Heat-Shock Proteins/*metabolism ; Hippocampus/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurodegenerative Diseases/psychology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Diabetes mellitus is known to increase the risk of neurodegeneration, and both diseases are reported to be linked to dysfunction of endoplasmic reticulum (ER). Astrocytes are important in the defense mechanism of central nervous system (CNS), with great ability of tolerating accumulation of toxic substances and sensitivity in Ca(2+) homeostasis which are two key functions of ER. Here, we investigated the modulation of the glucose-regulated protein 78 (GRP78) in streptozotocin (STZ)-induced diabetic mice and C6 cells cultured in high glucose condition. Our results showed that more reactive astrocytes were presented in the hippocampus of STZ-induced diabetic mice. Simultaneously, decrease of GRP78 expression was found in the astrocytes of diabetic mice hippocampus. In in vitro study, C6 cells were treated with high glucose to investigate the role of high glucose in GRP78 modulation in astrocytic cells. GRP78 as well as other chaperones like GRP94, calreticulin and calnexin, transcription levels were down-regulated after high glucose treatment. Also C6 cells challenged with 48h high glucose were activated, as indicated by increased level of glial fibrillary acidic protein (GFAP). Activated C6 cells simultaneously exhibited significant decrease of GRP78 level and was followed by reduced phosphorylation of Akt. Moreover, unfolded protein response was induced as an early event, which was marked by the induction of CHOP with high glucose treatment, followed by the reduction of GRP78 after 48h. Finally, the upsurge of ROS production was found in high glucose treated C6 cells and chelation of ROS could partially restore the GRP78 expression. Taken together, these data provide evidences that high glucose induced astrocytic activation in both in vivo and in vitro diabetic models, in which modulation of GRP78 would be an important event in this activation.}, }
@article {pmid24054849, year = {2013}, author = {Lee, YH and Bhattarai, G and Park, IS and Kim, GR and Kim, GE and Lee, MH and Yi, HK}, title = {Bone regeneration around N-acetyl cysteine-loaded nanotube titanium dental implant in rat mandible.}, journal = {Biomaterials}, volume = {34}, number = {38}, pages = {10199-10208}, doi = {10.1016/j.biomaterials.2013.08.080}, pmid = {24054849}, issn = {1878-5905}, mesh = {Animals ; Blotting, Western ; Bone Regeneration/*physiology ; Cell Line ; Cell Survival/physiology ; Cysteine/*chemistry ; *Dental Implants ; Mandible/surgery ; Mice ; Nanotubes/*chemistry ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Titanium/*chemistry ; }, abstract = {New strategies involving drugs loading onto implant surfaces are required to enhance osseointegration and shorten healing time after implantation. In this study, we examined the feasibility of N-acetyl cysteine (NAC)-loaded nanotube titanium (NLN-Ti) implants as a potential drug delivery system. To determine the effect of NLN-Ti in in vitro and in vivo, viability and ROS formation was assessed and enzyme-linked immunosorbant assay (ELISA), Western blot, micro-computed tomography (μ-CT), hematoxylin and eoxin (H&amp;E) staining and immunohistochemical (IHC) analysis were done. In vitro, cell viability was increased and inflammatory responses and reduced oxidative stress-related defense were decreased with MC 3T3-E1 cells exposed to a sustained release of NAC from NLN-Ti implants. Following NLN-Ti implant installation, μ-CT revealed an increase of newly formed bone volume and bone mineral density in the mandibles of Sprague Dawley rats. Relatively well formed new bone was demonstrated in close contact to the NLN-Ti implant surface by H&amp;E staining. IHC revealed significantly higher expression of bone morphogenetic protein-2, -7 and heme oxygenase-1, and reduced expression of receptor activator of nuclear factor-kappa B ligand. The data indicate that NLN-Ti implants enhance osseointegration and highlight the value of the small animal model in assessing diverse biological responses to dental implants.}, }
@article {pmid24053379, year = {2014}, author = {Su, X and Guo, S and Huang, X and Wang, X and Qi, D and Yang, C}, title = {Control of oxidative reactions of hemoglobin in the design of blood substitutes: role of the Vc, NAC, TEMPO and their reductant system.}, journal = {Artificial cells, nanomedicine, and biotechnology}, volume = {42}, number = {4}, pages = {222-228}, doi = {10.3109/21691401.2013.834907}, pmid = {24053379}, issn = {2169-141X}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Blood Substitutes/*metabolism ; Cyclic N-Oxides/*pharmacology ; Female ; Hemoglobins/*metabolism ; Humans ; Oxidation-Reduction/drug effects ; Oxygen/metabolism ; Pregnancy ; }, abstract = {Oxidative reactions of hemoglobin (Hb) are still a serious problem for Hb-based blood substitute development. Although varieties of antioxidant strategies have been suggested, this in vitro study examined the ability of the ascorbate, N-Acetyl-L-Cysteine (NAC), 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-1-oxygen free radicals (TEMPO) and their reductant system in preventing Hb oxidation. The content of ferric Hb is monitored in the process of vitamin C (Vc), NAC, TEMPO and their reductant system. The results suggest that ascorbate is effective in reducing ferryl Hb, and TEMPO with Vc/NAC could obviously shorten the reaction time, but it does not play the role of Met-Hb reductases. It demonstrates that TEMPO did little to recover Hb under oxidative stress.}, }
@article {pmid24051561, year = {2013}, author = {Dean, OM and Jeavons, S and Malhi, GS and Cotton, SM and Tanious, M and Kohlmann, K and Hewitt, K and Moss, K and Allwang, C and Schapkaitz, I and Robbins, J and Cobb, H and Dodd, S and Bush, A and Berk, M}, title = {Deserves a hearing? A case report of remitting tinnitus with N-acetyl cysteine.}, journal = {African journal of psychiatry}, volume = {16}, number = {4}, pages = {238, 240}, doi = {10.4314/ajpsy.v16i4.31}, pmid = {24051561}, issn = {1994-8220}, mesh = {*Acetylcysteine/administration &amp; dosage/pharmacokinetics ; Depressive Disorder/complications/*drug therapy ; Drug Repositioning ; Female ; Free Radical Scavengers/administration &amp; dosage/pharmacokinetics ; Glutathione/metabolism ; Hearing/*drug effects ; Humans ; Middle Aged ; Oxidative Stress/drug effects ; Tinnitus/complications/*drug therapy/metabolism ; Treatment Outcome ; }, }
@article {pmid24051401, year = {2013}, author = {Sun, FC and Shyu, HY and Lee, MS and Lee, MS and Lai, YK}, title = {Involvement of calcium-mediated reactive oxygen species in inductive GRP78 expression by geldanamycin in 9L rat brain tumor cells.}, journal = {International journal of molecular sciences}, volume = {14}, number = {9}, pages = {19169-19185}, pmid = {24051401}, issn = {1422-0067}, mesh = {Animals ; Antibiotics, Antineoplastic/*toxicity ; Benzoquinones/*toxicity ; Brain Neoplasms/metabolism/pathology ; Calcium/*metabolism ; Cell Line, Tumor ; Chelating Agents/pharmacology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Estrenes/pharmacology ; Gene Expression/*drug effects ; Heat-Shock Proteins/genetics/*metabolism ; Indoles/pharmacology ; Lactams, Macrocyclic/*toxicity ; Maleimides/pharmacology ; Protein Kinase C/metabolism ; Pyrrolidinones/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Type C Phospholipases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Treatment with geldanamycin (GA) leads to an increase in [Ca2+]c and the production of reactive oxygen species (ROS) in rat brain tumor 9L RBT cells. GA-exerted calcium signaling was blocked by BAPTA/AM and EGTA. The effect of GA on [Ca2+]c was significantly reduced in the presence of thapsigargin (TG) and ruthenium red (RR). GA-induced GRP78 expression is significantly decreased in the presence of BAPTA/AM, EGTA and RR, suggesting that the calcium influx from the extracellular space and intracellular calcium store oscillations are contributed to by the calcium mobilization and GRP78 expression induced by GA. The induced GRP78 expression is sensitive to added U73122 and Ro-31-8425, pinpointing the involvement of phospholipase C (PLC) and protein kinase C (PKC) in GA-induced endoplasmic reticulum (ER) stress. The antioxidants N-acetylcysteine (NAC), BAPTA/AM, EGTA and H7 also have significant inhibitory effects on ROS generation. Finally, neither H7 nor NAC was able to affect the calcium response elicited by GA. Our results suggest that the causal signaling cascade during GA-inducted GRP78 expression occurs via a pathway that connects PLC to cytoplasmic calcium increase, PKC activation and, then, finally, ROS generation. Our data provides new insights into the influence of GA on ER stress response in 9L RBT cells.}, }
@article {pmid24050937, year = {2013}, author = {Wyckhuys, T and Verhaeghe, J and Wyffels, L and Langlois, X and Schmidt, M and Stroobants, S and Staelens, S}, title = {N-acetylcysteine- and MK-801-induced changes in glutamate levels do not affect in vivo binding of metabotropic glutamate 5 receptor radioligand 11C-ABP688 in rat brain.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {54}, number = {11}, pages = {1954-1961}, doi = {10.2967/jnumed.113.121608}, pmid = {24050937}, issn = {1535-5667}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/diagnostic imaging/*drug effects/*metabolism ; Carbon Radioisotopes ; Dizocilpine Maleate/*pharmacology ; Glutamic Acid/*metabolism ; Ligands ; Oximes/*metabolism ; Positron-Emission Tomography ; Protein Binding/drug effects ; Pyridines/*metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Metabotropic Glutamate 5/*metabolism ; }, abstract = {UNLABELLED: Abnormal glutamate transmission is involved in various neurologic disorders, such as epilepsy, schizophrenia, and Parkinson disease. At present, no imaging techniques are capable of measuring acute fluctuations in endogenous glutamate levels in vivo. We evaluated the potential of (11)C-ABP688, a PET ligand that binds to an allosteric site of the metabotropic glutamate 5 receptor, in rats by using small-animal PET and β-microprobes after pharmacologic challenges with N-acetylcysteine (NAc) and MK-801. Both compounds are known to induce increases in endogenous glutamate levels.<br><br>METHODS: Three experiments with (11)C-ABP688 were performed to validate our study setup: first, metabolite analyses during workup (n = 3) and after a selected treatment (n = 3); second, a test-retest (n = 12) small-animal PET experiment (1 h scan; 27.75 MBq of (11)C-ABP688 administered intravenously; <3 nmol/kg); and third, a small-animal PET and &#x3b2;-microprobe cold blocking study (n = 6/condition) with unlabeled ABP688. After this experimental validation, rats were pretreated with either NAc (intravenous infusion of 50 mg/kg/h) or MK-801 (0.16 mg/kg; given intraperitoneally); this step was followed by small-animal PET with (11)C-ABP688 (n = 12) or &#x3b2;-microprobe measurements (n = 10/condition) of (11)C-ABP688. Time-activity curves were extracted, and the nondisplaceable binding potential (BPND) was calculated by use of the simplified reference tissue model with the cerebellum as a reference region.<br><br>RESULTS: (11)C-ABP688 BPND measurements were highly reproducible (test-retest), and both small-animal PET and &#x3b2;-microprobes were able to discriminate changes in (11)C-ABP688 binding (cold blocking). The average small-animal PET BPND measurements in the test experiment for the caudate putamen, frontal cortex, cerebral cortex, hippocampus, and thalamus were 2.58, 1.40, 1.60, 1.86, and 1.09, respectively. However, no significant differences in BPND measurements were observed with small-animal PET in the test and retest conditions on the one hand and the NAc and MK-801 conditions on the other hand for any of these regions. When &#x3b2;-microprobes were used, the average BPND in the caudate putamen was 0.94, and no significant changes in the test and MK-801 conditions were observed.<br><br>CONCLUSION: Pharmacologic challenges with NAc and MK-801 did not affect the (11)C-ABP688 BPND in the rat brain. These data suggest that the in vivo affinity of (11)C-ABP688 for binding to an allosteric site of the metabotropic glutamate 5 receptor is not modulated by changes in glutamate levels and that (11)C-ABP688 is not capable of measuring acute fluctuations in endogenous levels of glutamate in vivo in the rat brain.}, }
@article {pmid24048773, year = {2013}, author = {Talasaz, AH and Khalili, H and Jenab, Y and Salarifar, M and Broumand, MA and Darabi, F}, title = {N-Acetylcysteine effects on transforming growth factor-β and tumor necrosis factor-α serum levels as pro-fibrotic and inflammatory biomarkers in patients following ST-segment elevation myocardial infarction.}, journal = {Drugs in R&amp;D}, volume = {13}, number = {3}, pages = {199-205}, pmid = {24048773}, issn = {1179-6901}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Biomarkers/blood ; Double-Blind Method ; Drug Therapy, Combination ; Echocardiography ; Electrocardiography ; Female ; Fibrosis ; Humans ; Male ; Middle Aged ; Myocardial Infarction/blood/diagnostic imaging/*drug therapy/pathology ; Prospective Studies ; Transforming Growth Factor beta/*blood/immunology ; Treatment Outcome ; Tumor Necrosis Factor-alpha/*blood/immunology ; }, abstract = {BACKGROUND AND AIMS: Ischemia following acute myocardial infarction (AMI) increases the level of pro-fibrotic and inflammatory cytokines, including transforming growth factor (TGF)-β and tumor necrosis factor (TNF)-α. N-acetylcysteine (NAC) has therapeutic benefits in the management of patients with AMI. To the best of our knowledge, this is the first study that has evaluated the effect of NAC on TNF-α and TGF-β levels in patients with AMI.<br><br>METHODS: Following confirmation of AMI, 88 patients were randomly administered NAC 600&#xa0;mg (Fluimucil(&#xae;), Zambon, Ticino, Switzerland) or placebo orally twice daily for 3&#xa0;days. For quantification of TGF-&#x3b2; and TNF-&#x3b1; serum levels after 24 and 72&#xa0;h of NAC or placebo administration, peripheral venous blood (10&#xa0;mL) samples were collected at these time points.<br><br>RESULTS: Comparisons between levels of TGF-&#x3b2; and TNF-&#x3b1; after 24 and 72&#xa0;h within the NAC or placebo groups revealed that there was not any significant difference except for TGF-&#x3b2; levels in the placebo group, which increased significantly over time (p&#xa0;=&#xa0;0.042). Significant relationships existed between patients' ejection fraction (p&#xa0;=&#xa0;0.005) and TGF-&#x3b2; levels.<br><br>CONCLUSIONS: Receiving NAC could prevent TGF-&#x3b2; levels from increasing after 72&#xa0;h as compared with not receiving NAC. As TGF-&#x3b2; had strong correlations with the ejection fraction, its antagonism seems to be important in the prevention of remodeling.}, }
@article {pmid24044986, year = {2013}, author = {Kotronoulas, A and Pizarro, N and Serra, A and Robledo, P and Joglar, J and Rubió, L and Hernaéz, A and Tormos, C and Motilva, MJ and Fitó, M and Covas, MI and Solà, R and Farré, M and Saez, G and de la Torre, R}, title = {Dose-dependent metabolic disposition of hydroxytyrosol and formation of mercapturates in rats.}, journal = {Pharmacological research}, volume = {77}, number = {}, pages = {47-56}, doi = {10.1016/j.phrs.2013.09.001}, pmid = {24044986}, issn = {1096-1186}, mesh = {Acetylcysteine/*metabolism/urine ; Animals ; Antioxidants/*metabolism/*pharmacokinetics/toxicity ; Dose-Response Relationship, Drug ; Female ; Glutathione/urine ; Glutathione Disulfide/urine ; Male ; Phenylethyl Alcohol/*analogs &amp; derivatives/metabolism/pharmacokinetics/toxicity/urine ; Polyphenols/chemical synthesis/*pharmacokinetics/toxicity/urine ; Rats ; }, abstract = {Hydroxytyrosol (HT), one of the major polyphenols present in olive oil, is known to possess a high antioxidant capacity. The aim of the present study was to investigate dose dependent (0, 1, 10 and 100 mg/kg) alterations in the metabolism of HT in rats since it has been reported that metabolites may contribute to biological effects. Special attention was paid to the activation of the semiquinone-quinone oxidative cycle and the formation of adducts with potential deleterious effects. Thus, we developed a novel analytical methodology to monitor the in vivo formation of the HT mercapturate, N-acetyl-5-S-cysteinyl-hydroxytyrosol in urine samples. Biomarkers of hepatic and renal toxicity were evaluated within the dose range tested. Following HT administration, dose-dependent effects were observed for the recovery of all the metabolites studied. At the lowest dose of 1 mg/kg, the glucuronidation pathway was the most relevant (25-30%), with lower recoveries for sulfation (14%), while at the highest dose of 100 mg/kg, sulfation was the most prevalent (75%). In addition, we report for the first time the formation of the mercapturate conjugate of HT in a dose-dependent manner. The biochemical data did not reveal significant toxic effects of HT at any of the doses studied. An increase in the GSH/GSSG ratio at the highest dose was observed indicating that the products of HT autoxidation are counteracted by glutathione, resulting in their detoxification. These results indicate that the metabolic disposition of HT is highly dependent on the dose ingested.}, }
@article {pmid24043929, year = {2013}, author = {Qiao, J and Yan, X}, title = {Emerging treatment options for meibomian gland dysfunction.}, journal = {Clinical ophthalmology (Auckland, N.Z.)}, volume = {7}, number = {}, pages = {1797-1803}, pmid = {24043929}, issn = {1177-5467}, abstract = {Meibomian gland dysfunction (MGD) is one of the most common diseases observed in clinics; it influences a great number of people, and is the leading cause of evaporative dry eye. Given the increased recognition of the importance of MGD, a great amount of attention has been paid to therapies targeting this condition. The traditional treatments of MGD consist of warm compresses and lid hygiene for removing an obstructed meibum, as well as antibiotics and anti-inflammatory agents to improve the quality of the meibum. However, each of these treatments has a different shortcoming and the treatment of MGD remains challenging. Despite the numerous possible treatment options for MGD, it is still difficult to obtain complete relief of signs and symptoms. This review focuses on current emerging treatment options for MGD including intraductal meibomian gland probing, emulsion eye drops containing lipids, the LipiFlow® thermal pulsation system, N-acetyl-cysteine, azithromycin, oral supplementation with omega-3 essential fatty acids, and cyclosporine A.}, }
@article {pmid24041652, year = {2013}, author = {Wei, J and Shi, Y and Hou, Y and Ren, Y and Du, C and Zhang, L and Li, Y and Duan, H}, title = {Knockdown of thioredoxin-interacting protein ameliorates high glucose-induced epithelial to mesenchymal transition in renal tubular epithelial cells.}, journal = {Cellular signalling}, volume = {25}, number = {12}, pages = {2788-2796}, doi = {10.1016/j.cellsig.2013.09.009}, pmid = {24041652}, issn = {1873-3913}, mesh = {Carrier Proteins/*genetics/metabolism ; Epithelial Cells/cytology/*metabolism ; *Epithelial-Mesenchymal Transition ; *Gene Knockdown Techniques ; Glucose/*metabolism ; Humans ; Kidney Tubules/*cytology ; MAP Kinase Signaling System ; Transforming Growth Factor beta/metabolism ; }, abstract = {Epithelial to mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both high glucose and transforming growth factor-β (TGF-β) are able to induce EMT in cell culture. In this study, we examined the role of the thioredoxin-interacting protein (TXNIP) on EMT induced by high glucose or TGF-β1 in HK-2 cells. EMT was assessed by the expression of α-smooth muscle actin (α-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. High glucose (30mM) was shown to induce EMT at 72h. This was blocked by knockdown of TXNIP or antioxidant NAC. Meanwhile, we also found that knockdown of TXNIP or antioxidant NAC inhibited high glucose-induced generation of reactive oxygen species (ROS), phosphorylation of p38 MAPK and ERK1/2 and expression of TGF-β1. HK-2 cells that were exposed to TGF-β1 (4ng/ml) also underwent EMT. The expression of TXNIP gene and protein was increased in HK-2 cells treated with TGF-β1. Transfection with TXNIP shRNA was able to attenuate TGF-β1 induced-EMT. These results suggested that knockdown of TXNIP antagonized high glucose-induced EMT by inhibiting ROS production, activation of p38 MAPK and ERK1/2, and expression of TGF-β1, highlighting TXNIP as a potential therapy target for diabetic nephropathy.}, }
@article {pmid24038178, year = {2014}, author = {Allameh, A and Ahmadi-Ashtiani, H and Emami Aleagha, MS and Rastegar, H}, title = {The metabolic function of hepatocytes differentiated from human mesenchymal stem cells is inversely related to cellular glutathione levels.}, journal = {Cell biochemistry and function}, volume = {32}, number = {2}, pages = {194-200}, doi = {10.1002/cbf.2994}, pmid = {24038178}, issn = {1099-0844}, mesh = {Acetylcysteine/pharmacology ; Cell Differentiation ; Cell Line ; Glutathione/*metabolism ; Hepatocytes/cytology/drug effects/*metabolism ; Humans ; Mesenchymal Stem Cells/cytology/*metabolism ; Methionine/analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species/metabolism ; Sulfoxides/pharmacology ; }, abstract = {Differentiation of mesenchymal stem cells (MSCs) to hepatocytes-like cells is associated with alteration in the level of reactive oxygen species (ROS) and antioxidant defense system. Here, we report the role of glutathione in the functions of hepatocytes derived from MSCs. The stem cells undergoing differentiation were treated with glutathione modifiers [buthionine sulfoxide (BSO) or N-acetyl cysteine (NAC)], and hepatocytes were collected on day 14 of differentiation and analysed for their biological and metabolic functions. Differentiation process has been performed in presence of glutathione modifiers viz. BSO and NAC. Depending on the level of cellular glutathione, the proliferation rate of MSCs was affected. Glutathione depletion by BSO resulted in increased levels of albumin and ROS in hepatocytes. Whereas, albumin and ROS were inhibited in cells treated with glutathione precursor (NAC). The metabolic function of hepatocytes was elevated in BSO-treated cells as judged by increased urea, transferrin, albumin, alanine transaminase and aspartate transaminase secretions in the media. However, the metabolic activity of the hepatocytes was inhibited when glutathione was increased by NAC. We conclude that the efficiency of metabolic function of hepatocytes is inversely related to the levels of cellular glutathione. These data may suggest a novel role of glutathione in regulation of metabolic function of hepatocytes.}, }
@article {pmid24037197, year = {2013}, author = {Guerrero, CA and Paula Pardo, VR and Rafael Guerrero, OA}, title = {Inhibition of rotavirus ECwt infection in ICR suckling mice by N-acetylcysteine, peroxisome proliferator-activated receptor gamma agonists and cyclooxygenase-2 inhibitors.}, journal = {Memorias do Instituto Oswaldo Cruz}, volume = {108}, number = {6}, pages = {741-754}, pmid = {24037197}, issn = {1678-8060}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/therapeutic use ; Cyclooxygenase 2 Inhibitors/*pharmacology ; Cyclooxygenase Inhibitors/therapeutic use ; Diarrhea/*drug therapy/virology ; HSC70 Heat-Shock Proteins/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Intestines/virology ; Mice ; Mice, Inbred ICR ; NF-kappa B/metabolism ; PPAR gamma/*agonists ; Protein Disulfide-Isomerases/metabolism ; *Rotavirus ; Rotavirus Infections/*drug therapy ; }, abstract = {Live attenuated vaccines have recently been introduced for preventing rotavirus disease in children. However, alternative strategies for prevention and treatment of rotavirus infection are needed mainly in developing countries where low vaccine coverage occurs. In the present work, N-acetylcysteine (NAC), ascorbic acid (AA), some nonsteroidal anti-inflammatory drugs (NSAIDs) and peroxisome proliferator-activated receptor gamma (PPARγ) agonists were tested for their ability to interfere with rotavirus ECwt infectivity as detected by the percentage of viral antigen-positive cells of small intestinal villi isolated from ECwt-infected ICR mice. Administration of 6 mg NAC/kg every 8 h for three days following the first diarrhoeal episode reduced viral infectivity by about 90%. Administration of AA, ibuprofen, diclofenac, pioglitazone or rosiglitazone decreased viral infectivity by about 55%, 90%, 35%, 32% and 25%, respectively. ECwt infection of mice increased expression of cyclooxygenase-2, ERp57, Hsc70, NF-κB, Hsp70, protein disulphide isomerase (PDI) and PPARγ in intestinal villus cells. NAC treatment of ECwt-infected mice reduced Hsc70 and PDI expression to levels similar to those observed in villi from uninfected control mice. The present results suggest that the drugs tested in the present work could be assayed in preventing or treating rotaviral diarrhoea in children and young animals.}, }
@article {pmid24036456, year = {2013}, author = {Tan, J and Lai, Z and Liu, L and Long, W and Chen, T and Zha, J and Wang, L and Chen, M and Ji, H and Lai, Y}, title = {ONTD induces apoptosis of human hepatoma Bel-7402 cells via a MAPK-dependent mitochondrial pathway and the depletion of intracellular glutathione.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {45}, number = {11}, pages = {2632-2642}, doi = {10.1016/j.biocel.2013.08.021}, pmid = {24036456}, issn = {1878-5875}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Body Weight/drug effects ; Carcinoma, Hepatocellular/*enzymology/pathology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Cell Survival/drug effects ; Glutathione/*metabolism ; Humans ; Intracellular Space/drug effects/metabolism ; Liver Neoplasms/*enzymology/pathology ; MAP Kinase Signaling System/*drug effects ; Male ; Mice ; Mice, Inbred ICR ; Mitochondria/drug effects/*metabolism ; Mitochondrial Membrane Transport Proteins/metabolism ; Mitochondrial Permeability Transition Pore ; Reactive Oxygen Species/metabolism ; Triterpenes/chemistry/*pharmacology ; }, abstract = {3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile (ONTD) is a novel synthetic derivative of glycyrrhetinic acid (GA), which has the ability to inhibit the proliferation of human hepatocellular carcinoma (HCC) cells. However, the mechanisms by which ONTD exerts its inhibitory effects remain elusive. The present study was conducted to investigate the cytotoxicity of ONTD in Bel-7402 cells and its molecular mechanisms. We found that ONTD depleted intracellular GSH, increased the level of ROS, and consequently induced mitochondrial permeability transition (MPT) leading to the release of apoptosis-inducing factor (AIF) and cytochrome c (Cyt c) to the cytosol. Mitochondrial alteration and subsequent apoptotic cell death in ONTD-treated Bel-7402 cells could be blocked by addition of exogenous antioxidants N-acetylcystein (NAC), GSH and the MTP inhibitor cyclosporin A (CsA). In addition, ONTD activated the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPK) but not extracellular signal-regulated protein kinases (ERK 1/2). When the cells were exposed to SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), the deregulation of the expression of apoptotic proteins was attenuated. Furthermore, 40 mg/kg ONTD significantly reduced tumor weight (-70.62%, p<0.01) in the H22 tumor-bearing mouse model in vivo. Taken together, these findings provide the first experimental evidence supporting that ONTD could induce apoptosis of Bel-7402 cells via MAPK-mediated mitochondrial pathway and ONTD has the potential to be developed as a therapeutic agent for the treatment of HCC.}, }
@article {pmid24036416, year = {2013}, author = {Haber, M and Abdel Baki, SG and Grin'kina, NM and Irizarry, R and Ershova, A and Orsi, S and Grill, RJ and Dash, P and Bergold, PJ}, title = {Minocycline plus N-acetylcysteine synergize to modulate inflammation and prevent cognitive and memory deficits in a rat model of mild traumatic brain injury.}, journal = {Experimental neurology}, volume = {249}, number = {}, pages = {169-177}, doi = {10.1016/j.expneurol.2013.09.002}, pmid = {24036416}, issn = {1090-2430}, support = {R01 NS076693/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Avoidance Learning/drug effects/physiology ; Brain Injuries/pathology/physiopathology/*prevention &amp; control ; Cognition Disorders/pathology/physiopathology/*prevention &amp; control ; *Disease Models, Animal ; Drug Synergism ; Drug Therapy, Combination ; Inflammation/pathology/prevention &amp; control ; Memory Disorders/pathology/physiopathology/*prevention &amp; control ; Minocycline/*administration &amp; dosage ; Neuroprotective Agents/administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Traumatic brain injury (TBI) differs in severity from severe to mild. This study examined whether a combination of the drugs minocycline (MINO) plus N-acetylcysteine (NAC) produces behavioral and histological improvements in a mild version of the controlled cortical impact model of TBI (mCCI). Following mCCI, rats acquired an active place avoidance task by learning the location of a stationary shock zone on a rotating arena. Rats acquired this task with a training protocol using a 10-minute intertrial interval. Mildly injured rats had an apparent deficit in long-term memory since they did not acquire the task when the intertrial interval was increased to 24 h. Mildly injured rats also had an apparent deficit in set shifting since, after successfully learning one shock zone location they did not learn the location of a second shock zone. MINO plus NAC synergistically limited these behavioral deficits in long-term memory and set shifting. mCCI also produced neuroinflammation at the impact site and at distal white matter tracts including the corpus callosum. At the impact site, MINO plus NAC attenuated CD68-expressing phagocytic microglia without altering neutrophil infiltration or astrocyte activation. The drugs had no effect on astrocyte activation in the corpus callosum or hippocampus. In the corpus callosum, MINO plus NAC decreased CD68 expression yet increased overall microglial activation as measured by Iba-1. MINO plus NAC acted synergistically to increase Iba-1 expression since MINO alone suppressed expression and NAC alone had no effect. Despite the known anti-inflammatory actions of the individual drugs, MINO plus NAC appeared to modulate, rather than suppress neuroinflammation. This modulation of neuroinflammation may underlie the synergistic improvement in memory and set-shifting by the drug combination after mCCI.}, }
@article {pmid24036216, year = {2013}, author = {von Knethen, A and Sha, LK and Kuchler, L and Heeg, AK and Fuhrmann, D and Heide, H and Wittig, I and Maier, TJ and Steinhilber, D and Brüne, B}, title = {5-Lipoxygenase contributes to PPARγ activation in macrophages in response to apoptotic cells.}, journal = {Cellular signalling}, volume = {25}, number = {12}, pages = {2762-2768}, doi = {10.1016/j.cellsig.2013.08.045}, pmid = {24036216}, issn = {1873-3913}, mesh = {Animals ; *Apoptosis ; Arachidonate 5-Lipoxygenase/*immunology/metabolism ; Cell Line ; Humans ; Jurkat Cells ; Macrophages/*immunology ; Membrane Microdomains/immunology ; Mice ; PPAR gamma/*immunology ; Protein Transport ; Reactive Oxygen Species/immunology ; }, abstract = {Macrophage polarization to an anti-inflammatory phenotype upon contact with apoptotic cells is a contributing hallmark to immune suppression during the late phase of sepsis. Although the peroxisome proliferator-activated receptor γ (PPARγ) supports this macrophage phenotype switch, it remains elusive how apoptotic cells activate PPARγ. Assuming that a molecule causing PPARγ activation in macrophages originates in the cell membrane of apoptotic cells we analyzed lipid rafts from apoptotic, necrotic, and living human Jurkat T cells which showed the presence of 5-lipoxygenase (5-LO) in lipid rafts of apoptotic cells only. Incubating macrophages with lipid rafts of apoptotic, but not necrotic or living cells, induced PPAR responsive element (PPRE)-driven mRuby reporter gene expression in RAW 264.7 macrophages stably transduced with a 4xPPRE containing vector. Experiments with lipid rafts of apoptotic murine EL4 T cells revealed similar results. To verify the involvement of 5-LO in activating PPARγ in macrophages, Jurkat T cells were incubated with the 5-LO inhibitor MK-866 prior to induction of apoptosis, which failed to induce mRuby expression. Similar results were obtained with lipid rafts of apoptotic EL4 T cells preexposed to the 5-LO inhibitors zileuton and CJ-13610. Interestingly, Jurkat T cells overexpressing 5-LO failed to activate PPARγ in macrophages, while their 5-LO overexpressing apoptotic counterparts did. Our results suggest that during apoptosis 5-LO gets associated with lipid rafts and synthesizes ligands that in turn stimulate PPARγ in macrophages.}, }
@article {pmid24035645, year = {2014}, author = {Sofuoglu, M and Rosenheck, R and Petrakis, I}, title = {Pharmacological treatment of comorbid PTSD and substance use disorder: recent progress.}, journal = {Addictive behaviors}, volume = {39}, number = {2}, pages = {428-433}, pmid = {24035645}, issn = {1873-6327}, support = {K02 DA021304/DA/NIDA NIH HHS/United States ; R01 DA029577/DA/NIDA NIH HHS/United States ; K02-DA021304/DA/NIDA NIH HHS/United States ; }, mesh = {Adrenergic Agents/therapeutic use ; Adrenergic Agonists/therapeutic use ; Antidepressive Agents/therapeutic use ; Comorbidity ; Diagnosis, Dual (Psychiatry) ; Drug Therapy, Combination ; GABA Agents/therapeutic use ; Humans ; Norepinephrine/therapeutic use ; Randomized Controlled Trials as Topic ; Stress Disorders, Post-Traumatic/*drug therapy/epidemiology ; Substance-Related Disorders/*drug therapy/epidemiology ; *Veterans/psychology ; }, abstract = {Previous research has identified a strong association between posttraumatic stress disorder (PTSD) and substance use disorder (SUD), necessitating the development of treatments that address both conditions. Some pharmacotherapies are effective for the treatment of PTSD and SUD alone, however; no medications have been proven to be effective for the combination of these conditions. We review the recent advances in pharmacological treatment of comorbid PTSD and SUD. A randomized clinical trial of sertraline, a serotonin reuptake inhibitor (SSRI), did not show overall efficacy for comorbid PTSD and alcohol dependence (AD), although it may have efficacy among light drinkers. Another clinical trial demonstrated the efficacy of both disulfiram and naltrexone for the treatment of AD in individuals with PTSD. A more recent clinical trial suggested that norepinephrine uptake inhibitors may also have efficacy for the treatment of comorbid PTSD and AD. In animal and preliminary human studies, brain norepinephrine and glutamate/GABA have emerged as potential treatment targets for comorbid PTSD and SUD. Noradrenergic medications that are promising for comorbid PTSD and SUD include prazosin, guanfacine, and atomoxetine. Promising glutamate/GABA medications include topiramate, memantine, acamprosate, N-acetylcysteine (NAC), and ketamine. The safety and efficacy of these medications for the treatment of PTSD and SUD need to be tested in controlled clinical trials.}, }
@article {pmid24035394, year = {2013}, author = {Mayes, DA and Rizvi, TA and Titus-Mitchell, H and Oberst, R and Ciraolo, GM and Vorhees, CV and Robinson, AP and Miller, SD and Cancelas, JA and Stemmer-Rachamimov, AO and Ratner, N}, title = {Nf1 loss and Ras hyperactivation in oligodendrocytes induce NOS-driven defects in myelin and vasculature.}, journal = {Cell reports}, volume = {4}, number = {6}, pages = {1197-1212}, pmid = {24035394}, issn = {2211-1247}, support = {P30 DK090971/DK/NIDDK NIH HHS/United States ; R01 NS026543/NS/NINDS NIH HHS/United States ; T32 CA117846/CA/NCI NIH HHS/United States ; T32CA117846/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Blood Vessels/cytology/enzymology/metabolism ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myelin Sheath/*metabolism ; Neurofibromin 1/*deficiency/genetics/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/*metabolism ; Oligodendroglia/cytology/enzymology/*metabolism ; ras Proteins/genetics/*metabolism ; }, abstract = {Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1-NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients.}, }
@article {pmid24035253, year = {2013}, author = {Soares, AS and Costa, VM and Diniz, C and Fresco, P}, title = {Potentiation of cytotoxicity of paclitaxel in combination with Cl-IB-MECA in human C32 metastatic melanoma cells: A new possible therapeutic strategy for melanoma.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {67}, number = {8}, pages = {777-789}, doi = {10.1016/j.biopha.2013.08.003}, pmid = {24035253}, issn = {1950-6007}, mesh = {Adenosine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/*pharmacology/therapeutic use ; Caspases/metabolism ; Cell Culture Techniques ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Synergism ; Enzyme Activation ; Humans ; Melanoma/*drug therapy/pathology ; Neoplasm Metastasis ; Paclitaxel/administration &amp; dosage/*pharmacology/therapeutic use ; }, abstract = {Metastatic melanoma monotherapies with drugs such as dacarbazine, cisplatin or paclitaxel (PXT) are associated with significant toxicity and low efficacy rates. These facts reinforce the need for development of novel agents or combinatory strategies. Cl-IB-MECA is a small molecule, orally bioavailable, well tolerated and currently under clinical trials as an anticancer agent. Our aim was to investigate a possible combinatory therapeutic strategy using PXT and Cl-IB-MECA on human C32 melanoma cells and its underlying mechanisms. Cytotoxicity was evaluated using MTT reduction, lactate dehydrogenase leakage and neutral red uptake assays, for different concentrations and combinations of both agents, at 24 and 48 h. Apoptosis was also assessed using fluorescence microscopy and through the evaluation of caspases 8, 9, and 3 activities. We demonstrated, for the first time, that combination of PXT and Cl-IB-MECA significantly increases cytotoxicity for clinically relevant concentrations. This combination seems to act synergistically in disrupting membrane integrity, but also causing lysosomal and mitochondrial dysfunction. When using the lowest PTX concentration (10 ng/mL), co-incubation with CI-IB-MECA (micromolar concentrations) potentiated overall cytotoxic effects and morphological signs of apoptosis. All combinations studied enhanced caspase 8, 9, and 3 activities, suggesting the involvement of both intrinsic and extrinsic apoptotic pathways. The possibility that cytotoxicity elicited by Cl-IB-MECA, alone or in combination with PXT, involves adenosine receptor activation was discarded and results confirmed that oxidative stress is only involved in cytotoxicity after treatment with PXT, alone. Being melanoma a very apoptosis-resistance cancer, this combination seems to hold promise as a new therapeutic strategy for melanoma.}, }
@article {pmid24035100, year = {2013}, author = {Li, Q and Wang, H and Ye, S and Xiao, S and Xie, Y and Liu, X and Wang, J}, title = {Induction of apoptosis and inhibition of invasion in choriocarcinoma JEG-3 cells by α-calendic acid and β-calendic acid.}, journal = {Prostaglandins, leukotrienes, and essential fatty acids}, volume = {89}, number = {5}, pages = {367-376}, doi = {10.1016/j.plefa.2013.06.007}, pmid = {24035100}, issn = {1532-2823}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Caspases/genetics/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Fatty Acids, Unsaturated/*pharmacology ; Female ; Gene Expression Regulation, Neoplastic/*drug effects ; Glutathione/metabolism ; Humans ; Imidazoles/pharmacology ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Oxidative Stress ; Pyridines/pharmacology ; Reactive Oxygen Species/*agonists/metabolism ; Signal Transduction ; Stereoisomerism ; alpha-Tocopherol/pharmacology ; bcl-2 Homologous Antagonist-Killer Protein/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Alfa-calendic acid and β-calendic acid, geometric and positional isomers of linolenic acid were previously shown to possess potent anticancer properties. In this study, we found that α-calendic acid and β-calendic acid could induce apoptosis and suppress invasion of human choriocarcinoma JEG-3 cells in vitro. Treatment with α-calendic acid and β-calendic acid significantly increased oxidative stress in human choriocarcinoma JEG-3 cells detected by the level of reactive oxygen species (ROS), lipid peroxidation production malondialdehyde (MDA), glutathione (GSH) and the effects of antioxidants NAC and α-tocopherol. Furthermore, oxidative stress activated the phosphorylation of p38MAPK. SB203580, a selective p38MAPK inhibitor, blocked the apoptosis induced by α-calendic acid and β-calendic acid by upregulating Bcl-2/Bax ratio and inhibition of the activation of Caspase-3 and Caspase-9. SB20350 also partially abrogated the cell invasion effects of α-calendic acid and β-calendic acid. These results suggested that α-calendic acid and β-calendic acid induced apoptosis and inhibited invasion in JEG-3 cells by activation of oxidative stress pathways and subsequent activation of P38MAPK.}, }
@article {pmid24027097, year = {2013}, author = {Zacharias, M and Mugawar, M and Herbison, GP and Walker, RJ and Hovhannisyan, K and Sivalingam, P and Conlon, NP}, title = {Interventions for protecting renal function in the perioperative period.}, journal = {The Cochrane database of systematic reviews}, volume = {2013}, number = {9}, pages = {CD003590}, pmid = {24027097}, issn = {1469-493X}, mesh = {Adult ; Creatinine/urine ; Humans ; Postoperative Complications/*prevention &amp; control ; Randomized Controlled Trials as Topic ; Renal Insufficiency/*prevention &amp; control ; Surgical Procedures, Operative/*adverse effects ; Urine ; }, abstract = {BACKGROUND: Various methods have been used to try to protect kidney function in patients undergoing surgery. These most often include pharmacological interventions such as dopamine and its analogues, diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, N-acetyl cysteine (NAC), atrial natriuretic peptide (ANP), sodium bicarbonate, antioxidants and erythropoietin (EPO).<br><br>OBJECTIVES: This review is aimed at determining the effectiveness of various measures advocated to protect patients' kidneys during the perioperative period.We considered the following questions: (1) Are any specific measures known to protect kidney function during the perioperative period? (2) Of measures used to protect the kidneys during the perioperative period, does any one method appear to be more effective than the others? (3) Of measures used to protect the kidneys during the perioperative period,does any one method appear to be safer than the others?<br><br>SEARCH METHODS: In this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2, 2012), MEDLINE (Ovid SP) (1966 to August 2012) and EMBASE (Ovid SP) (1988 to August 2012). We originally handsearched six journals (Anesthesia and Analgesia, Anesthesiology, Annals of Surgery, British Journal of Anaesthesia, Journal of Thoracic and Cardiovascular Surgery, and Journal of Vascular Surgery) (1985 to 2004). However, because these journals are properly indexed in MEDLINE, we decided to rely on electronic searches only without handsearching the journals from 2004 onwards.<br><br>SELECTION CRITERIA: We selected all randomized controlled trials in adults undergoing surgery for which a treatment measure was used for the purpose of providing renal protection during the perioperative period.<br><br>DATA COLLECTION AND ANALYSIS: We selected 72 studies for inclusion in this review. Two review authors extracted data from all selected studies and entered them into RevMan 5.1; then the data were appropriately analysed. We performed subgroup analyses for type of intervention, type of surgical procedure and pre-existing renal dysfunction. We undertook sensitivity analyses for studies with high and moderately good methodological quality.<br><br>MAIN RESULTS: The updated review included data from 72 studies, comprising a total of 4378 participants. Of these, 2291 received some form of treatment and 2087 acted as controls. The interventions consisted most often of different pharmaceutical agents, such as dopamine and its analogues, diuretics, calcium channel blockers, ACE inhibitors, NAC, ANP, sodium bicarbonate, antioxidants and EPO or selected hydration fluids. Some clinical heterogeneity and varying risk of bias were noted amongst the studies, although we were able to meaningfully interpret the data. Results showed significant heterogeneity and indicated that most interventions provided no benefit.Data on perioperative mortality were reported in 41 studies and data on acute renal injury in 44 studies (all interventions combined). Because of considerable clinical heterogeneity (different clinical scenarios, as well as considerable methodological variability amongst the studies), we did not perform a meta-analysis on the combined data.Subgroup analysis of major interventions and surgical procedures showed no significant influence of interventions on reported mortality and acute renal injury. For the subgroup of participants who had pre-existing renal damage, the risk of mortality from 10 trials (959 participants) was estimated as odds ratio (OR) 0.76, 95% confidence interval (CI) 0.38 to 1.52; the risk of acute renal injury (as reported in the trials) was estimated from 11 trials (979 participants) as OR 0.43, 95% CI 0.23 to 0.80. Subgroup analysis of studies that were rated as having low risk of bias revealed that 19 studies reported mortality numbers (1604 participants); OR was 1.01, 95% CI 0.54 to 1.90. Fifteen studies reported data on acute renal injury (criteria chosen by the individual studies; 1600 participants); OR was 1.03, 95% CI 0.54 to 1.97.<br><br>AUTHORS' CONCLUSIONS: No reliable evidence from the available literature suggests that interventions during surgery can protect the kidneys from damage. However, the criteria used to diagnose acute renal damage varied in many of the older studies selected for inclusion in this review, many of which suffered from poor methodological quality such as insufficient participant numbers and poor definitions of end points such as acute renal failure and acute renal injury. Recent methods of detecting renal damage such as the use of specific biomarkers and better defined criteria for identifying renal damage (RIFLE (risk, injury, failure, loss of kidney function and end-stage renal failure) or AKI (acute kidney injury)) may have to be explored further to determine any possible benefit derived from interventions used to protect the kidneys during the perioperative period.}, }
@article {pmid24025361, year = {2013}, author = {Yang, F and Nam, S and Zhao, R and Tian, Y and Liu, L and Horne, DA and Jove, R}, title = {A novel synthetic derivative of the natural product berbamine inhibits cell viability and induces apoptosis of human osteosarcoma cells, associated with activation of JNK/AP-1 signaling.}, journal = {Cancer biology &amp; therapy}, volume = {14}, number = {11}, pages = {1024-1031}, pmid = {24025361}, issn = {1555-8576}, support = {P30 CA033572/CA/NCI NIH HHS/United States ; CA1155674/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Benzylisoquinolines/*pharmacology ; Bone Neoplasms/drug therapy/metabolism/*pathology ; Caspase 3/metabolism ; Cell Line, Tumor/drug effects ; Cell Survival/drug effects ; Cyclin D1/metabolism ; Cyclin D2/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/*physiology ; Osteosarcoma/drug therapy/metabolism/*pathology ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Transcription Factor AP-1/*physiology ; }, abstract = {Osteosarcoma is the most common primary bone tumor in children and adolescents. There is a critical need to find more potent drugs for patients with metastatic or recurrent disease. Berbamine (BBM) is a natural compound derived from the Berberis amurensis plants. BBM and its derivatives have been shown to have antitumor effects in several cancers. Here, we report that a novel synthetic berbamine derivative, BBMD3, inhibits cell viability and induces apoptosis of G292, KHOS, and MG-63 human osteosarcoma cells. Induction of apoptosis in these tumor cells depends on activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). Since pan-caspase inhibitor (Z-VAD-FMK) and caspase-9 inhibitor (Z-LEHD-FMK) could block the cleavage of PARP, the apoptosis induced by BBMD3 is through intrinsic signaling pathway. BBMD3 increased phosphorylation of c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK), resulting in increase of phosphorylated c-Jun and total c-Fos, the major components of transcriptional factor AP-1. JNK inhibitor could partially suppress antitumor effect of BBMD3 on osteosarcoma cells. BBMD3 increased the production of reactive oxygen species (ROS) and ROS scavenger, N-acetylcysteine (NAC), could block the phosphorylation of JNK and c-Jun induced by BBMD3. BBMD3 increased the expression of the pro-apototic gene Bad, associated with apoptosis induction. Finally, BBMD3 also decreased the expression of cyclin D1 and D2, the positive cell cycle regulators, which is correlated with growth inhibition in osteosarcoma cells. Collectively, these findings indicate that BBMD3 is a potentially promising drug for the treatment of human osteosarcoma.}, }
@article {pmid24024167, year = {2013}, author = {Chapple, SJ and Cheng, X and Mann, GE}, title = {Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease.}, journal = {Redox biology}, volume = {1}, number = {1}, pages = {319-331}, pmid = {24024167}, issn = {2213-2317}, support = {PG/13/1/29801/BHF_/British Heart Foundation/United Kingdom ; }, mesh = {Aldehydes/*metabolism ; Endoplasmic Reticulum/metabolism ; Endothelium, Vascular/cytology/*metabolism/*pathology ; *Health ; Humans ; Mitochondria/metabolism ; Muscle, Smooth/cytology/*metabolism/*pathology ; Oxidation-Reduction ; *Signal Transduction ; }, abstract = {4-hydroxynonenal (HNE) is a lipid hydroperoxide end product formed from the oxidation of n-6 polyunsaturated fatty acids. The relative abundance of HNE within the vasculature is dependent not only on the rate of lipid peroxidation and HNE synthesis but also on the removal of HNE adducts by phase II metabolic pathways such as glutathione-S-transferases. Depending on its relative concentration, HNE can induce a range of hormetic effects in vascular endothelial and smooth muscle cells, including kinase activation, proliferation, induction of phase II enzymes and in high doses inactivation of enzymatic processes and apoptosis. HNE also plays an important role in the pathogenesis of vascular diseases such as atherosclerosis, diabetes, neurodegenerative disorders and in utero diseases such as pre-eclampsia. This review examines the known production, metabolism and consequences of HNE synthesis within vascular endothelial and smooth muscle cells, highlighting alterations in mitochondrial and endoplasmic reticulum function and their association with various vascular pathologies.}, }
@article {pmid24024148, year = {2013}, author = {Tseng, BP and Lan, ML and Tran, KK and Acharya, MM and Giedzinski, E and Limoli, CL}, title = {Characterizing low dose and dose rate effects in rodent and human neural stem cells exposed to proton and gamma irradiation.}, journal = {Redox biology}, volume = {1}, number = {1}, pages = {153-162}, pmid = {24024148}, issn = {2213-2317}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Survival/drug effects/radiation effects ; Cells, Cultured ; Dose-Response Relationship, Radiation ; *Gamma Rays ; Humans ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells/*radiation effects ; Nitric Oxide/metabolism ; Oxidative Stress/drug effects/*radiation effects ; *Photons ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; }, abstract = {Past work has shown that exposure to gamma rays and protons elicit a persistent oxidative stress in rodent and human neural stem cells (hNSCs). We have now adapted these studies to more realistic exposure scenarios in space, using lower doses and dose rates of these radiation modalities, to further elucidate the role of radiation-induced oxidative stress in these cells. Rodent neural stem and precursor cells grown as neurospheres and human neural stem cells grown as monolayers were subjected to acute and multi-dosing paradigms at differing dose rates and analyzed for changes in reactive oxygen species (ROS), reactive nitrogen species (RNS), nitric oxide and superoxide for 2 days after irradiation. While acute exposures led to significant changes in both cell types, hNSCs in particular, exhibited marked and significant elevations in radiation-induced oxidative stress. Elevated oxidative stress was more significant in hNSCs as opposed to their rodent counterparts, and hNSCs were significantly more sensitive to low dose exposures in terms of survival. Combinations of protons and γ-rays delivered as lower priming or higher challenge doses elicited radioadaptive changes that were associated with improved survival, but in general, only under conditions where the levels of reactive species were suppressed compared to cells irradiated acutely. Protective radioadaptive effects on survival were eliminated in the presence of the antioxidant N-acetylcysteine, suggesting further that radiation-induced oxidative stress could activate pro-survival signaling pathways that were sensitive to redox state. Data corroborates much of our past work and shows that low dose and dose rate exposures elicit significant changes in oxidative stress that have functional consequences on survival.}, }
@article {pmid24024144, year = {2013}, author = {Maciag, AE and Holland, RJ and Robert Cheng, YS and Rodriguez, LG and Saavedra, JE and Anderson, LM and Keefer, LK}, title = {Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance.}, journal = {Redox biology}, volume = {1}, number = {1}, pages = {115-124}, pmid = {24024144}, issn = {2213-2317}, support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Azo Compounds/chemical synthesis/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Glutathione/metabolism ; Humans ; Leukemia/*metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Nitric Oxide/metabolism ; Nitric Oxide Donors/chemical synthesis/*pharmacology ; Oxidation-Reduction/drug effects ; Piperazines/chemical synthesis/*pharmacology ; Prodrugs/*chemical synthesis/pharmacology ; Reactive Nitrogen Species/metabolism ; }, abstract = {JS-K is a nitric oxide (NO)-releasing prodrug of the O (2)-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion) spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action.}, }
@article {pmid24024132, year = {2013}, author = {Diers, AR and Broniowska, KA and Hogg, N}, title = {Nitrosative stress and redox-cycling agents synergize to cause mitochondrial dysfunction and cell death in endothelial cells.}, journal = {Redox biology}, volume = {1}, number = {1}, pages = {1-7}, pmid = {24024132}, issn = {2213-2317}, support = {R01-GM-55792/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Aorta/*cytology/drug effects ; Cattle ; *Cell Death ; Cells, Cultured ; Cysteine/*analogs &amp; derivatives/pharmacology ; Drug Synergism ; Endothelial Cells/*drug effects/pathology ; Mitochondria/*drug effects/physiology ; Naphthoquinones/*pharmacology ; Nitrosation ; Reactive Oxygen Species ; S-Nitrosothiols/*pharmacology ; }, abstract = {Nitric oxide production by the endothelium is required for normal vascular homeostasis; however, in conditions of oxidative stress, interactions of nitric oxide with reactive oxygen species (ROS) are thought to underlie endothelial dysfunction. Beyond canonical nitric oxide signaling pathways, nitric oxide production results in the post-translational modification of protein thiols, termed S-nitrosation. The potential interplay between S-nitrosation and ROS remains poorly understood and is the focus of the current study. The effects of the S-nitrosating agent S-nitrosocysteine (CysNO) in combination with redox-cycling agents was examined in bovine aortic endothelial cells (BAEC). CysNO significantly impairs mitochondrial function and depletes the NADH/NAD(+) pool; however, these changes do not result in cell death. When faced with the additional stressor of a redox-cycling agent used to generate ROS, further loss of NAD(+) occurs, and cellular ATP pools are depleted. Cellular S-nitrosothiols also accumulate, and cell death is triggered. These data demonstrate that CysNO sensitizes endothelial cells to redox-cycling agent-dependent mitochondrial dysfunction and cell death and identify attenuated degradation of S-nitrosothiols as one potential mechanism for the enhanced cytotoxicity.}, }
@article {pmid24021887, year = {2014}, author = {Wall, SB and Smith, MR and Ricart, K and Zhou, F and Vayalil, PK and Oh, JY and Landar, A}, title = {Detection of electrophile-sensitive proteins.}, journal = {Biochimica et biophysica acta}, volume = {1840}, number = {2}, pages = {913-922}, pmid = {24021887}, issn = {0006-3002}, support = {DK079337/DK/NIDDK NIH HHS/United States ; T32 HL007918/HL/NHLBI NIH HHS/United States ; P30 DK079337/DK/NIDDK NIH HHS/United States ; T32HL007918/HL/NHLBI NIH HHS/United States ; R01 HL096638/HL/NHLBI NIH HHS/United States ; HL096638/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Humans ; Oxidation-Reduction ; Proteins/*analysis/*chemistry ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Redox signaling is an important emerging mechanism of cellular function. Dysfunctional redox signaling is increasingly implicated in numerous pathologies, including atherosclerosis, diabetes, and cancer. The molecular messengers in this type of signaling are reactive species which can mediate the post-translational modification of specific groups of proteins, thereby effecting functional changes in the modified proteins. Electrophilic compounds comprise one class of reactive species which can participate in redox signaling. Electrophiles modulate cell function via formation of covalent adducts with proteins, particularly cysteine residues.<br><br>SCOPE OF REVIEW: This review will discuss the commonly used methods of detection for electrophile-sensitive proteins, and will highlight the importance of identifying these proteins for studying redox signaling and developing novel therapeutics.<br><br>MAJOR CONCLUSIONS: There are several methods which can be used to detect electrophile-sensitive proteins. These include the use of tagged model electrophiles, as well as derivatization of endogenous electrophile-protein adducts.<br><br>GENERAL SIGNIFICANCE: In order to understand the mechanisms by which electrophiles mediate redox signaling, it is necessary to identify electrophile-sensitive proteins and quantitatively assess adduct formation. Strengths and limitations of these methods will be discussed. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.}, }
@article {pmid24019108, year = {2014}, author = {Wu, MS and Lien, GS and Shen, SC and Yang, LY and Chen, YC}, title = {N-acetyl-L-cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells.}, journal = {Molecular carcinogenesis}, volume = {53 Suppl 1}, number = {}, pages = {E119-29}, doi = {10.1002/mc.22053}, pmid = {24019108}, issn = {1098-2744}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Caspases/metabolism ; Cell Proliferation/drug effects ; Colorectal Neoplasms/*drug therapy/metabolism/*pathology ; Drug Synergism ; Flavonoids/*pharmacology ; Flavonols ; Free Radical Scavengers/pharmacology ; Humans ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Oxidative stress or excessive antioxidant levels-caused redox imbalance can alter apoptotic responses, and N-acetyl-L-cysteine (NAC) was able to inhibit H2 O2 -mediated cell death, but unable to prevent apoptosis induced by other chemicals such as etoposide. We now demonstrate that 10 and 20 mM NAC, non-toxic concentrations, can enhance fisetin (FIS)-mediated apoptosis in colon cancer cells COLO205. Compared to treatment with FIS alone, combination treatment with NAC increased the expression of cleaved caspase-3 and PAPR protein, and produced greater density of DNA ladders. NAC reduced the mitochondrial membrane potential of FIS-treated COLO205 cells with induction of caspase 9 protein cleavage. DNA ladders induced by FIS + NAC were diminished by adding the caspase 3 inhibitor, DEVD-FMK, and the caspase 9 inhibitor, YVAD-FMK. Combinatorial treatment COLO205 cells with NAC and FIS showed potent inhibition on ERK protein phosphorylation, compared with those from FIS or NAC-treated groups by Western blotting using specific antibodies. Addition of the chemical ERK inhibitors, PD98059 and U0126, significantly inhibited ERK protein phosphorylation, accompanied by induced DNA ladder formation, cleavage of caspase 3 and PARP protein in COLO205 cells. Furthermore, NAC showed an enhancement on a FIS-related chemical chrysin-induced apoptosis of COLO205 cells, and NAC sensitization of colon cancer cells to FIS-induced apoptosis was also identify in colonic cancer cells HCT-116, HT-29, and HCT-15 cells. The evidence to support NAC sensitizing human colon cancer cells to FIS-induced apoptosis was provided, and application of NAC and FIS as a strategy to treat colonic cancer deserved for further in vivo study.}, }
@article {pmid24013954, year = {2013}, author = {Zhao, S and Xiong, Z and Mao, X and Meng, D and Lei, Q and Li, Y and Deng, P and Chen, M and Tu, M and Lu, X and Yang, G and He, G}, title = {Atmospheric pressure room temperature plasma jets facilitate oxidative and nitrative stress and lead to endoplasmic reticulum stress dependent apoptosis in HepG2 cells.}, journal = {PloS one}, volume = {8}, number = {8}, pages = {e73665}, pmid = {24013954}, issn = {1932-6203}, mesh = {Antioxidants/metabolism ; *Apoptosis ; Atmospheric Pressure ; Caspase 12/metabolism ; Catalase/metabolism ; Endoplasmic Reticulum Chaperone BiP ; *Endoplasmic Reticulum Stress ; Enzyme Precursors/metabolism ; Glutathione/metabolism ; Heat-Shock Proteins/metabolism ; Hep G2 Cells ; Humans ; *Oxidative Stress ; Reactive Nitrogen Species/*metabolism ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; Transcription Factor CHOP/metabolism ; }, abstract = {Atmospheric pressure room temperature plasma jets (APRTP-Js) that can emit a mixture of different active species have recently found entry in various medical applications. Apoptosis is a key event in APRTP-Js-induced cellular toxicity, but the exact biological mechanisms underlying remain elusive. Here, we explored the role of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in APRTP-Js-induced apoptosis using in vitro model of HepG2 cells. We found that APRTP-Js facilitated the accumulation of ROS and RNS in cells, which resulted in the compromised cellular antioxidant defense system, as evidenced by the inactivation of cellular antioxidants including glutathione (GSH), superoxide dismutase (SOD) and catalase. Nitrotyrosine and protein carbonyl content analysis indicated that APRTP-Js treatment caused nitrative and oxidative injury of cells. Meanwhile, intracellular calcium homeostasis was disturbed along with the alteration in the expressions of GRP78, CHOP and pro-caspase12. These effects accumulated and eventually culminated into the cellular dysfunction and endoplasmic reticulum stress (ER stress)-mediated apoptosis. The apoptosis could be markedly attenuated by N-acetylcysteine (NAC, a free radical scavenger), which confirmed the involvement of oxidative and nitrative stress in the process leading to HepG2 cell apoptosis by APRTP-Js treatment.}, }
@article {pmid24012549, year = {2014}, author = {Soiferman, D and Ayalon, O and Weissman, S and Saada, A}, title = {The effect of small molecules on nuclear-encoded translation diseases.}, journal = {Biochimie}, volume = {100}, number = {}, pages = {184-191}, doi = {10.1016/j.biochi.2013.08.024}, pmid = {24012549}, issn = {1638-6183}, mesh = {Acetylcysteine/pharmacology ; Aminoimidazole Carboxamide/analogs &amp; derivatives/pharmacology ; Bezafibrate/pharmacology ; Cytochrome-c Oxidase Deficiency/*genetics/metabolism/pathology ; DNA, Mitochondrial/genetics/metabolism ; Electron Transport/drug effects/genetics ; Electron Transport Complex IV/genetics/metabolism ; Fibroblasts/*drug effects/metabolism/pathology ; Gene Expression Regulation ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/genetics/metabolism/pathology ; Mitochondrial Myopathies/*genetics/metabolism/pathology ; Mitochondrial Proteins/genetics/metabolism ; Mutation ; Oxidative Phosphorylation/drug effects ; Peptide Elongation Factor G/genetics/metabolism ; Primary Cell Culture ; Protein Biosynthesis/*drug effects ; Reactive Oxygen Species/metabolism ; Ribonucleotides/pharmacology ; Ribosomal Proteins/genetics/metabolism ; Small Molecule Libraries/*pharmacology ; tRNA Methyltransferases/genetics/metabolism ; }, abstract = {The five complexes of the mitochondrial respiratory chain (MRC) supply most organs and tissues with ATP produced by oxidative phosphorylation (OXPHOS). Inherited mitochondrial diseases affecting OXPHOS dysfunction are heterogeneous; symptoms may present at any age and may affect a wide range of tissues, with many diseases giving rise to devastating multisystemic disorders resulting in neonatal death. Combined respiratory chain deficiency with normal complex II accounts for a third of all respiratory deficiencies; mutations in nuclear-encoded components of the mitochondrial translation machinery account for many cases. Although mutations have been identified in over 20 such genes and our understanding of the mitochondrial translation apparatus is increasing, to date no definitive cure for these disorders exists. We evaluated the effect of seven small molecules with reported therapeutic potential in fibroblasts of four patients with combined respiratory complex disorders, each harboring a known mutation in a different nuclear-encoded component of the mitochondrial translation machinery: EFTs, GFM1, MRPS22 and TRMU. Six mitochondrial parameters were screened as follows; growth in glucose-free medium, reactive oxygen species (ROS) production, ATP content, mitochondrial content, mitochondrial membrane potential and complex IV activity. It was clearly evident that each patient displayed an individual response and there was no universally beneficial compound. AICAR increased complex IV activity in GFM1 cells and increased ATP content in MRPS22 fibroblasts but was detrimental to TRMU, who benefitted from bezafibrate. Two antioxidants, ascorbate and N-acetylcysteine (NAC), significantly improved cell growth, ATP content and mitochondrial membrane potential and decreased levels of intracellular reactive oxygen species (ROS) in EFTs fibroblasts. This study presents an expanded repertoire of assays that can be performed using the microtiter screening system with a small number of patients' fibroblasts and highlights some therapeutic options while providing additional evidence for the importance of personalized medicine in mitochondrial disorders.}, }
@article {pmid24009716, year = {2013}, author = {Muranaka, LS and Giorgiano, TE and Takita, MA and Forim, MR and Silva, LF and Coletta-Filho, HD and Machado, MA and de Souza, AA}, title = {N-acetylcysteine in agriculture, a novel use for an old molecule: focus on controlling the plant-pathogen Xylella fastidiosa.}, journal = {PloS one}, volume = {8}, number = {8}, pages = {e72937}, pmid = {24009716}, issn = {1932-6203}, mesh = {Acetylcysteine/chemistry/*pharmacology ; *Agriculture ; Anti-Bacterial Agents/chemistry/*pharmacology ; Biofilms ; Hydroponics/methods ; Phenotype ; Plant Diseases/*microbiology ; Plant Leaves/microbiology ; Plant Roots/drug effects/microbiology ; Plants/drug effects/microbiology ; Polysaccharides, Bacterial/metabolism ; Xylella/*drug effects/physiology ; }, abstract = {Xylella fastidiosa is a plant pathogen bacterium that causes diseases in many different crops. In citrus, it causes Citrus Variegated Chlorosis (CVC). The mechanism of pathogenicity of this bacterium is associated with its capacity to colonize and form a biofilm in the xylem vessels of host plants, and there is not yet any method to directly reduce populations of this pathogen in the field. In this study, we investigated the inhibitory effect of N-Acetylcysteine (NAC), a cysteine analogue used mainly to treat human diseases, on X. fastidiosa in different experimental conditions. Concentrations of NAC over 1 mg/mL reduced bacterial adhesion to glass surfaces, biofilm formation and the amount of exopolysaccharides (EPS). The minimal inhibitory concentration of NAC was 6 mg/mL. NAC was supplied to X. fastidiosa-infected plants in hydroponics, fertigation, and adsorbed to organic fertilizer (NAC-Fertilizer). HPLC analysis indicated that plants absorbed NAC at concentrations of 0.48 and 2.4 mg/mL but not at 6 mg/mL. Sweet orange plants with CVC symptoms treated with NAC (0.48 and 2.4 mg/mL) in hydroponics showed clear symptom remission and reduction in bacterial population, as analyzed by quantitative PCR and bacterial isolation. Experiments using fertigation and NAC-Fertilizer were done to simulate a condition closer to that normally is used in the field. For both, significant symptom remission and a reduced bacterial growth rate were observed. Using NAC-Fertilizer the lag for resurgence of symptoms on leaves after interruption of the treatment increased to around eight months. This is the first report of the anti-bacterial effect of NAC against a phytopathogenic bacterium. The results obtained in this work together with the characteristics of this molecule indicate that the use of NAC in agriculture might be a new and sustainable strategy for controlling plant pathogenic bacteria.}, }
@article {pmid24008628, year = {2013}, author = {Park, GB and Kim, YS and Lee, HK and Cho, DH and Kim, D and Hur, DY}, title = {CD80 (B7.1) and CD86 (B7.2) induce EBV-transformed B cell apoptosis through the Fas/FasL pathway.}, journal = {International journal of oncology}, volume = {43}, number = {5}, pages = {1531-1540}, doi = {10.3892/ijo.2013.2091}, pmid = {24008628}, issn = {1791-2423}, mesh = {B-Lymphocytes/metabolism/*pathology/virology ; B7-1 Antigen/*metabolism ; B7-2 Antigen/*metabolism ; *Cell Transformation, Viral ; Cells, Cultured ; Epstein-Barr Virus Infections/metabolism/*pathology/virology ; Fas Ligand Protein/*metabolism ; Flow Cytometry ; Herpesvirus 4, Human/physiology ; Humans ; Signal Transduction ; fas Receptor/*metabolism ; }, abstract = {CD80 and CD86 expression is strongly regulated in B cells and is induced by various stimuli (e.g., cytokines, ligation of MHC class II and CD40 ligand). Epstein-Barr virus (EBV) infection activates B lymphocytes and transforms them into lymphoblastoid cells. However, the role of CD80 and CD86 in EBV infection of B cells remains unclear. Here, we observed that cross-linking of CD80 and CD86 in EBV-transformed B cells induced apoptosis through caspase-dependent release of apoptosis-related molecules, cytochrome c and apoptosis-inducing factor (AIF) from mitochondria, because Z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone) and N-acetylcysteine (NAC) blocked apoptosis and disruption of mitochondria. Stimulation of CD80 and CD86 induced expression of Fas ligand (FasL) on EBV-transformed B cells and upregulated Fas and FasL expression in IM-9 cells. Apoptosis through Fas-FasL interactions was blocked by treatment of cells with ZB4, an antagonistic anti-Fas antibody. These results suggest that the co-stimulatory molecules CD80 and CD86 induced by EBV infection stimulate apoptosis of EBV-transformed lymphoblastoid B cells via the Fas/FasL pathway.}, }
@article {pmid24008345, year = {2013}, author = {Jin, HM and Zhou, DC and Gu, HF and Qiao, QY and Fu, SK and Liu, XL and Pan, Y}, title = {Antioxidant N-acetylcysteine protects pancreatic β-cells against aldosterone-induced oxidative stress and apoptosis in female db/db mice and insulin-producing MIN6 cells.}, journal = {Endocrinology}, volume = {154}, number = {11}, pages = {4068-4077}, doi = {10.1210/en.2013-1115}, pmid = {24008345}, issn = {1945-7170}, mesh = {Acetylcysteine/*pharmacology ; Aldosterone/*toxicity ; Animals ; Apoptosis/*drug effects ; Blood Glucose/drug effects ; Body Weight ; Cell Line ; Female ; Insulin/*metabolism ; Insulin-Secreting Cells/*drug effects/metabolism ; Mice ; Mice, Inbred NOD ; NADPH Oxidases/genetics/metabolism ; Oxidative Stress/*drug effects ; Potassium/urine ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Sodium/urine ; }, abstract = {Previous studies have shown that primary aldosteronism is associated with glucose-related metabolic disorders. However, the mechanisms by which aldosterone (ALDO) triggers β-cell dysfunction remains unclear. This study aimed to investigate whether oxidative stress is involved in and whether the antioxidant N-acetylcysteine (NAC) or the mineralocorticoid receptor antagonist spironolactone (SPL) could prevent or delay β-cell damage in vivo and in vitro. As expected, 8 weeks after ALDO treatment, 12-week-old female diabetic db/db mice exhibited impaired oral glucose tolerance, decreased β-cell mass, and heightened levels of oxidative stress marker (urinary 8-hydroxy-2'-deoxyguanosine). NAC reversed these symptoms completely, whereas SPL treatment did so only partially. After exposure to ALDO, the mouse pancreatic β-cell line MIN6 exhibited decreased viability and increased caspase-3 activity, as well as reduced expression of Bcl-2/Bax and p-AKT, even if mineralocorticoid receptor was completely suppressed with small interfering RNA. NAC, but not SPL, suppressed oxidative stress in MIN6 cells, as revealed by the decrease in inducible NOS levels and expression of the proteins p22-phox and p67-phox. These findings suggest that oxidative stress may be involved in ALDO-induced β-cell dysfunction and that NAC, but not SPL, may protect pancreatic β-cells of mice from ALDO-induced oxidative stress and apoptosis in a manner independent of its receptor.}, }
@article {pmid24008047, year = {2013}, author = {Park, JH and Lee, JE and Lee, SJ and Park, SJ and Park, KH and Jeong, M and Koh, HC}, title = {Potential autophagy enhancers protect against fipronil-induced apoptosis in SH-SY5Y cells.}, journal = {Toxicology letters}, volume = {223}, number = {1}, pages = {25-34}, doi = {10.1016/j.toxlet.2013.08.015}, pmid = {24008047}, issn = {1879-3169}, mesh = {Apoptosis/*drug effects ; Autophagy/*drug effects ; Blotting, Western ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Interactions ; Humans ; Insecticides/toxicity ; L-Lactate Dehydrogenase/metabolism ; Oxidative Stress/*drug effects ; Pyrazoles/antagonists &amp; inhibitors/*toxicity ; Sirolimus/*pharmacology ; }, abstract = {Oxidative stress created by environmental toxicants activates several signaling pathways. Autophagy is one of the first lines of defense against oxidative stress damage. The autophagy pathway can be induced and up-regulated in response to intracellular reactive oxygen species (ROS). Recently, we reported that fipronil (FPN)-induced mitochondria-dependent apoptosis is mediated through ROS in human neuroblastoma SH-SY5Y cells. In this study, we explored the role of autophagy to prevent FPN neurotoxicity. We investigated the modulation of FPN-induced apoptosis according to autophagy regulation. FPN activated caspase-9 and caspase-3, and induced nuclear fragmentation and condensation, all of which indicate that FPN-induced cell death was due to apoptosis. In addition, we observed FPN-induced autophagic cell death by monitoring the expression of LC3-II and Beclin-1. Exposure to FPN in SH-SY5Y cells led to the production of ROS. Treatment with N-acetyl-cysteine (NAC) effectively blocked both apoptosis and autophagy. Interestingly, pretreatment with rapamycin, an autophagy inducer, significantly enhanced the viability of FPN-exposed cells; the enhancement of cell viability was partially due to alleviation of FPN-induced apoptosis via a decrease in levels of cleaved caspase-3. However, pretreatment with 3-methyladenine (3MA) a specific inhibitor for autophagy, remarkably strengthened FPN toxicity and further induced activation of caspase-3 in these cells. Our studies suggest that FPN-induced cytotoxicity is modified by autophagy regulation and that rapamycin is neuroprotective against FPN-induced apoptosis through enhancing autophagy.}, }
@article {pmid24005553, year = {2013}, author = {Krakauer, T and Buckley, M}, title = {Efficacy of two FDA-approved drug combination in a mouse model of staphylococcal enterotoxin B-induced shock.}, journal = {Military medicine}, volume = {178}, number = {9}, pages = {1024-1028}, doi = {10.7205/MILMED-D-13-00129}, pmid = {24005553}, issn = {1930-613X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Chemokine CCL2/metabolism ; Dexamethasone/*therapeutic use ; Disease Models, Animal ; Drug Therapy, Combination ; Enterotoxins ; Female ; Free Radical Scavengers/*therapeutic use ; Interferon-gamma/metabolism ; Interleukin-2/metabolism ; Interleukin-6/metabolism ; Lung/metabolism ; Male ; Mice ; Shock, Septic/blood/chemically induced/*drug therapy ; }, abstract = {Staphylococcal enterotoxin B (SEB) causes lethal shock by potently stimulating the host immune response. Dexamethasone and N-acetyl cysteine (NAC) are anti-inflammatory and antioxidative drugs, respectively, which can independently modulate immune function. Dexamethasone was previously shown to be effective in preventing SEB-induced shock models only if administered early and in multiple doses for a long duration. In this study, dexamethasone and NAC were used in tandem and protected mice (75%) against SEB-induced lethal shock. Hypothermia and weight loss elicited by SEB were also diminished by this novel combination treatment. The levels of monocyte chemoattractant protein-1, interleukin-2, interleukin-6, and mouse gamma interferon in lung tissue after intranasal exposure to SEB were also significantly reduced in mice given a combination of dexamethasone and NAC versus controls.}, }
@article {pmid24002022, year = {2013}, author = {Saudagar, P and Saha, P and Saikia, AK and Dubey, VK}, title = {Molecular mechanism underlying antileishmanial effect of oxabicyclo[3.3.1]nonanones: inhibition of key redox enzymes of the pathogen.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {85}, number = {3 Pt A}, pages = {569-577}, doi = {10.1016/j.ejpb.2013.08.014}, pmid = {24002022}, issn = {1873-3441}, mesh = {Amide Synthases/*antagonists &amp; inhibitors ; Antiprotozoal Agents/administration &amp; dosage/chemistry/*pharmacology ; Apoptosis/drug effects ; Bridged Bicyclo Compounds/administration &amp; dosage/chemistry/*pharmacology ; DNA Damage/drug effects ; Drug Design ; Inhibitory Concentration 50 ; Leishmania/drug effects/enzymology ; Mitochondrial Membranes/metabolism ; NADH, NADPH Oxidoreductases/*antagonists &amp; inhibitors ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {We report oxabicyclo[3.3.1]nonanones as inhibitors of key redox enzymes, trypanothione synthetase (TryS), and trypanothione reductase (TryR) of Leishmania. Further, detailed cellular effects of 4-(4,4,8-Trimethyl-7-oxo-3-oxabicyclo[3.3.1]non-2-yl)-benzoic acid methyl ester, a oxabicyclo[3.3.1]nonanones, on the parasite were investigated. As these compounds inhibit key redox enzymes (TryR amd TryS), treatment of these compounds resulted in increased reactive oxygen species (ROS), mitochondrial membrane damage, activation of caspase like proteases, and DNA damage that finally leads to apoptosis. Although the compound has modest IC50 value against parasite (4.9±0.4 μM), they identify a novel chemical space to design and develop drugs based on these compounds against the Leishmania parasite. This is first report of oxabicyclo[3.3.1]nonanones as antileishmanial.}, }
@article {pmid24001791, year = {2013}, author = {Lan, CC and Wu, CS and Yu, HS}, title = {Solar-simulated radiation and heat treatment induced metalloproteinase-1 expression in cultured dermal fibroblasts via distinct pathways: implications on reduction of sun-associated aging.}, journal = {Journal of dermatological science}, volume = {72}, number = {3}, pages = {290-295}, doi = {10.1016/j.jdermsci.2013.07.015}, pmid = {24001791}, issn = {1873-569X}, mesh = {Cells, Cultured ; Fibroblasts/enzymology/*radiation effects ; Hot Temperature/*adverse effects ; Humans ; Matrix Metalloproteinase 1/*metabolism ; Skin Aging/*radiation effects ; Sunlight/*adverse effects ; }, abstract = {BACKGROUND: Sun exposure is an important environmental factor affecting human beings. Most knowledge regarding solar aging focused on light radiation (photoaging), and little emphasis has been placed on heat, a factor that is also closely associated with sun exposure.<br><br>OBJECTIVE: This study was launched to evaluate the effects of simulated solar radiation (SSR) and environmental heat on skin fibroblasts in terms of dermal aging.<br><br>METHODS: Cultured human dermal fibroblasts were treated with moderate amount of SSR (200J/cm(2)) and heat (+2&#xb0;C). The metalloproteinase-1 (MMP-1) expression was used as a surrogate marker for dermal aging and the involved regulatory mechanisms were explored.<br><br>RESULTS: Both treatment conditions did not affect viability but significantly increased the expressions of MMP-1. In parallel, both treatments increased the intracellular levels of reactive oxygen species (ROS), but the increase induced by SSR is much greater than heat. In contrast, transient receptor potential vanilloid 1 (TRPV-1), the sensor of environmental heat, was upregulated by heat but not SSR treatment. Pretreating fibroblasts with antioxidant abrogated the SSR-induced MMP-1 but has limited effect on heat-induced MMP-1. On the other hand, TRPV-1 antagonist pretreatment reduced heat-induced MMP-1 in fibroblasts but not their SSR-treated counterparts.<br><br>CONCLUSION: Both SSR and heat induced MMP-1 expression in dermal fibroblasts but through different pathways. As current strategies for reducing sun-related aging focused on filtering of light and use of antioxidants, future strategies design to reduce solar aging should also incorporate heat-induced aging into consideration.}, }
@article {pmid24001789, year = {2013}, author = {Jeong, SH and Kim, HJ and Ryu, HJ and Ryu, WI and Park, YH and Bae, HC and Jang, YS and Son, SW}, title = {ZnO nanoparticles induce TNF-α expression via ROS-ERK-Egr-1 pathway in human keratinocytes.}, journal = {Journal of dermatological science}, volume = {72}, number = {3}, pages = {263-273}, doi = {10.1016/j.jdermsci.2013.08.002}, pmid = {24001789}, issn = {1873-569X}, mesh = {Cell Line ; Cell Survival ; Early Growth Response Protein 1/*metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Inflammation Mediators/physiology ; Keratinocytes/*drug effects/metabolism/pathology ; Microscopy, Electron, Transmission ; Nanoparticles/*toxicity ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Tumor Necrosis Factor-alpha/*biosynthesis/genetics/physiology ; Zinc Oxide/*toxicity ; }, abstract = {BACKGROUND: The area of nanotechnology continues to expand rapidly and zinc oxide (ZnO) nanoparticles (NPs) are widely being used in cosmetics and sunscreens. Although ZnO-NPs are considered materials that can potentially cause skin inflammation, the underlying mechanisms remain elusive.<br><br>OBJECTIVE: The aim of this study was to investigate the signaling pathways of a cutaneous inflammatory response induced by ZnO-NPs. ZnO-NPs increased the early growth response-1 (Egr-1) expression, promoter activity and its nuclear translocation in HaCaT cells.<br><br>METHODS: HaCaT cells and primary keratinocytes were exposed to ZnO NPs over a range of doses and time course. Protein levels and mRNA levels of Egr-1 and mitogen-activated protein kinase (MAPK) were measured by Western blot and ELISA, respectively. As an in vivo study, ZnO-NPs were applicated on mouse skin, and immunohistochemical stain with TNF-&#x3b1; and Egr-1 was done.<br><br>RESULTS: ZnO-NPs activated extracellular signal-regulated kinase (ERK) of MAPK pathways. The up-regulation of Egr-1 expression by ZnO-NPs stimulation was found to be inhibited by an ERK inhibitor, but by neither c-Jun-N-terminal kinase (JNK) nor p38 inhibitor. Antioxidative N-acetyl-cysteine (NAC) strongly inhibited the level of Egr-1 and phosphorylated ERK expression in ZnO-NPs treated cells. ZnO NPs also increased tumor necrosis factor (TNF)-&#x3b1; expression and secretion, which were inhibited by the blockade of Egr-1 expression.<br><br>CONCLUSIONS: The present study demonstrated that ZnO-NPs might induce inflammatory response via ROS-ERK-Egr-1 pathway in human keratinocytes.}, }
@article {pmid24001404, year = {2013}, author = {Wang, Q and Hou, Y and Yi, D and Wang, L and Ding, B and Chen, X and Long, M and Liu, Y and Wu, G}, title = {Protective effects of N-acetylcysteine on acetic acid-induced colitis in a porcine model.}, journal = {BMC gastroenterology}, volume = {13}, number = {}, pages = {133}, pmid = {24001404}, issn = {1471-230X}, mesh = {*Acetic Acid ; Acetylcysteine/*pharmacology/therapeutic use ; Amphiregulin ; Animals ; Apoptosis/drug effects ; Caspase 3/drug effects/metabolism ; Claudin-1/drug effects/metabolism ; Colitis/chemically induced/pathology/*prevention &amp; control ; *Colitis, Ulcerative ; Colon/drug effects/metabolism/pathology ; Dietary Supplements ; Dinoprostone/metabolism ; Disease Models, Animal ; EGF Family of Proteins ; Epidermal Growth Factor/blood/drug effects ; ErbB Receptors/drug effects/genetics ; Free Radical Scavengers/*pharmacology/therapeutic use ; Glycoproteins/drug effects/genetics ; Intercellular Signaling Peptides and Proteins/genetics ; Interleukin-6/metabolism ; Intestinal Mucosa/drug effects/metabolism/pathology ; Swine ; Toll-Like Receptor 4/drug effects/genetics ; Transforming Growth Factor alpha/drug effects/metabolism ; Tumor Necrosis Factor-alpha/drug effects/genetics/metabolism ; }, abstract = {BACKGROUND: Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model.<br><br>METHODS: Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-&#x3b1;), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR.<br><br>RESULTS: Compared with the control group, AA treatment increased (P&#x2009;<&#x2009;0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P&#x2009;<&#x2009;0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P&#x2009;<&#x2009;0.05) by dietary supplementation with NAC. In addition, NAC prevented the AA-induced increase in caspase-3 protein, while stimulating claudin-1 protein expression in the colonic mucosa. Moreover, NAC enhanced mRNA levels for epidermal growth factor and amphiregulin in the colonic mucosa.<br><br>CONCLUSION: Dietary supplementation with NAC can alleviate AA-induced colitis in a porcine model through regulating anti-oxidative responses, cell apoptosis, and EGF gene expression.}, }
@article {pmid24000098, year = {2014}, author = {Bylda, C and Thiele, R and Kobold, U and Volmer, DA}, title = {Simultaneous quantification of acetaminophen and structurally related compounds in human serum and plasma.}, journal = {Drug testing and analysis}, volume = {6}, number = {5}, pages = {451-460}, doi = {10.1002/dta.1527}, pmid = {24000098}, issn = {1942-7611}, mesh = {Acetaminophen/*analogs &amp; derivatives/*blood ; Amitriptyline/blood ; Calibration ; Chromatography, Liquid ; Humans ; Imipramine/blood ; Limit of Detection ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {The method described in this study allows the simultaneous quantification of acetaminophen (APAP) and nine structurally related compounds, namely acetaminophen metabolites and structurally similar analogs (acetaminophen-glucuronide [APG], -sulfate [APS], mercapturate [APM], -cysteine [APC], p-phenetidine, phenacetin), antidote (N-acetylcysteine, NAC), and two tricyclic antidepressants (imipramine and amitryptiline). Due to the relatively high serum concentration levels in the µg/ml range, matrix effects were simply minimized by dilution. The samples were diluted with water and disulfide bonds between serum proteins and analytes reduced using tris(2-carboxyethyl)phosphine. Chromatographic separation of the analytes was achieved by gradient elution using a pentafluorphenyl (PFP) column with subsequent detection by electrospray ionization (ESI) triple quadrupole mass spectrometry in positive and negative ionization multiple reaction monitoring (MRM) modes. Quantification was performed by means of deuterated analogues of the analytes as internal standards. Total run time of the assay was 19 min. The method was fully validated and allowed quantification of the analytes with lower limits of quantification between 50 and 0.5 ng/ml. The calibration curves were linear over the range 0.1-100 µg/ml for APAP, APG, NAC, p-phenetidine and phenacetin, 0.03-50 µg/ml for APS, and 0.01-10 µg/ml for APM, APC, imipramine and amitriptyline with correlation coefficients r(2) > 0.99. The intra-assay precision was ≤5% for all analytes except NAC (CV < 10%). The inter-day precision was ≤10% for all analytes except NAC (inter-assay precision <11%). This method was used to analyze 77 patient and spiked samples and results were consistent with expected values from a round robin test.}, }
@article {pmid24000072, year = {2013}, author = {Möller, M and Du Preez, JL and Viljoen, FP and Berk, M and Harvey, BH}, title = {N-Acetyl cysteine reverses social isolation rearing induced changes in cortico-striatal monoamines in rats.}, journal = {Metabolic brain disease}, volume = {28}, number = {4}, pages = {687-696}, pmid = {24000072}, issn = {1573-7365}, mesh = {3,4-Dihydroxyphenylacetic Acid/metabolism ; Acetylcysteine/*pharmacology ; Animals ; Cerebral Cortex/*drug effects/metabolism ; Corpus Striatum/*drug effects/metabolism ; Dopamine/metabolism ; Dose-Response Relationship, Drug ; Homovanillic Acid/metabolism ; Hydroxyindoleacetic Acid/metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Serotonin/metabolism ; *Social Isolation ; }, abstract = {Schizophrenia is causally associated with early-life environmental stress, implicating oxidative stress in its pathophysiology. N-acetyl cysteine (NAC), a glutathione precursor and antioxidant, is emerging as a useful agent in the adjunctive treatment of schizophrenia and other psychiatric illnesses. However, its actions on brain monoamine metabolism are unknown. Social isolation rearing (SIR) in rats presents with face, predictive and construct validity for schizophrenia. This study evaluated the dose-dependent effects of NAC (50, 150 and 250 mg/kg/day × 14 days) on SIR- vs. socially reared induced changes in cortico-striatal levels of dopamine (DA), serotonin (5-HT) noradrenaline (NA) and their associated metabolites. SIR induced significant deficits in frontal cortical DA and its metabolites, 3,4-dihydroxyphenylacetic acid (Dopac) and homovanillic acid (HVA), reduced 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and reduced levels of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). In addition, significant elevations in frontal cortical NA and striatal DA, Dopac, HVA, 5-HT, 5-HIAA, NA and MHPG were also observed in SIR rats. NAC at 150 and 250 mg/kg reversed all cortico-striatal DA, Dopac, HVA, 5-HT, 5-HIAA and striatal NA alterations in SIR animals, with 250 mg/kg of NAC also reversing alterations in cortico-striatal MHPG. In conclusion, SIR profoundly alters cortico-striatal DA, 5-HT and NA pathways that parallel observations in schizophrenia, while these changes are dose-dependently reversed or abrogated by sub-chronic NAC treatment. A modulatory action on cortico-striatal monoamines may explain NACs' therapeutic use in schizophrenia and possibly other psychiatric disorders, where redox dysfunction or oxidative stress is a causal factor.}, }
@article {pmid23996467, year = {2013}, author = {Patten, AR and Brocardo, PS and Sakiyama, C and Wortman, RC and Noonan, A and Gil-Mohapel, J and Christie, BR}, title = {Impairments in hippocampal synaptic plasticity following prenatal ethanol exposure are dependent on glutathione levels.}, journal = {Hippocampus}, volume = {23}, number = {12}, pages = {1463-1475}, doi = {10.1002/hipo.22199}, pmid = {23996467}, issn = {1098-1063}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Age Factors ; Animals ; Animals, Newborn ; Body Weight/drug effects ; Central Nervous System Depressants/*toxicity ; Electric Stimulation ; Ethanol/*toxicity ; Female ; Free Radical Scavengers/administration &amp; dosage ; Glutathione/*metabolism ; Hippocampus/growth &amp; development/*pathology ; Male ; Neuronal Plasticity/*drug effects ; Patch-Clamp Techniques ; Pregnancy ; Prenatal Exposure Delayed Effects/diet therapy/*pathology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Previous studies from our laboratory have shown that prenatal ethanol exposure (PNEE) causes a significant deficit in synaptic plasticity, namely long-term potentiation (LTP), in the dentate gyrus (DG) region of the hippocampus of male rats. PNEE has also been shown to induce an increase in oxidative stress and a reduction in antioxidant capacity in the brains of both male and female animals. In this study the interaction between LTP and the major antioxidant in the brain, glutathione (GSH), is examined. We show that depletion of the intracellular reserves of GSH with diethyl maleate (DEM) reduces LTP in control male, but not female animals, mirroring the effects of PNEE. Furthermore, treatment of PNEE animals with N-acetyl cysteine (NAC), a cysteine donor for the synthesis of GSH, increases GSH levels in the hippocampus and completely restores the deficits in LTP in PNEE males. These results indicate that in males GSH plays a major role in regulating LTP, and that PNEE may cause reductions in LTP by reducing the intracellular pool of this endogenous antioxidant.}, }
@article {pmid23993974, year = {2013}, author = {Wang, G and Wang, J and Ma, H and Ansari, GA and Khan, MF}, title = {N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress.}, journal = {Toxicology and applied pharmacology}, volume = {273}, number = {1}, pages = {189-195}, pmid = {23993974}, issn = {1096-0333}, support = {R01 ES016302/ES/NIEHS NIH HHS/United States ; ES016302/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibodies, Antinuclear/blood ; Autoantibodies/blood ; Autoimmune Diseases/chemically induced/*drug therapy ; Female ; Interleukin-17/genetics/metabolism ; Kidney/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism ; Mice ; Mice, Inbred MRL lpr ; Oxidative Stress/*drug effects ; Protein Carbonylation/drug effects ; RNA, Messenger/genetics/metabolism ; Spleen/cytology/drug effects/metabolism ; Trichloroethylene/*toxicity ; }, abstract = {Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, is known to induce autoimmunity both in humans and animal models. However, mechanisms underlying TCE-mediated autoimmunity remain largely unknown. Previous studies from our laboratory in MRL+/+ mice suggest that oxidative stress may contribute to TCE-induced autoimmune response. The current study was undertaken to further assess the role of oxidative stress in TCE-induced autoimmunity by supplementing with an antioxidant N-acetylcysteine (NAC). Groups of female MRL+/+ mice were given TCE, NAC or TCE+NAC for 6 weeks (TCE, 10mmol/kg, i.p., every 4th day; NAC, 250mg/kg/day through drinking water). TCE exposure led to significant increases in serum levels of anti-nuclear, anti-dsDNA and anti-Sm antibodies. TCE exposure also led to significant induction of anti-malondiadelhyde (MDA)- and anti-hydroxynonenal (HNE)-protein adduct antibodies which were associated with increased ANA in the sera along with increased MDA-/HNE-protein adducts in the livers and kidneys, and increases in protein oxidation (carbonylation) in the sera, livers and kidneys, suggesting an overall increase in oxidative stress. Moreover, TCE exposure also resulted in increased release of IL-17 from splenocytes and increases in IL-17 mRNA expression. Remarkably, NAC supplementation attenuated not only the TCE-induced oxidative stress, IL-17 release and mRNA expression, but also the markers of autoimmunity, as evident from decreased levels of ANA, anti-dsDNA and anti-Sm antibodies in the sera. These results provide further support to a role of oxidative stress in TCE-induced autoimmune response. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for preventive and/or therapeutic strategies.}, }
@article {pmid23988789, year = {2013}, author = {Wang, B and Van Veldhoven, PP and Brees, C and Rubio, N and Nordgren, M and Apanasets, O and Kunze, M and Baes, M and Agostinis, P and Fransen, M}, title = {Mitochondria are targets for peroxisome-derived oxidative stress in cultured mammalian cells.}, journal = {Free radical biology &amp; medicine}, volume = {65}, number = {}, pages = {882-894}, doi = {10.1016/j.freeradbiomed.2013.08.173}, pmid = {23988789}, issn = {1873-4596}, mesh = {Animals ; Apoptosis ; Caspases/metabolism ; Cell Line ; Cell Survival ; Humans ; Mice ; Mitochondria/*metabolism ; *Oxidative Stress ; Peroxisomes/*metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Many cellular processes are driven by spatially and temporally regulated redox-dependent signaling events. Although mounting evidence indicates that organelles such as the endoplasmic reticulum and mitochondria can function as signaling platforms for oxidative stress-regulated pathways, little is known about the role of peroxisomes in these processes. In this study, we employ targeted variants of the genetically encoded photosensitizer KillerRed to gain a better insight into the interplay between peroxisomes and cellular oxidative stress. We show that the phototoxic effects of peroxisomal KillerRed induce mitochondria-mediated cell death and that this process can be counteracted by targeted overexpression of a select set of antioxidant enzymes, including peroxisomal glutathione S-transferase kappa 1, superoxide dismutase 1, and mitochondrial catalase. We also present evidence that peroxisomal disease cell lines deficient in plasmalogen biosynthesis or peroxisome assembly are more sensitive to KillerRed-induced oxidative stress than control cells. Collectively, these findings confirm and extend previous observations suggesting that disturbances in peroxisomal redox control and metabolism can sensitize cells to oxidative stress. In addition, they lend strong support to the ideas that peroxisomes and mitochondria share a redox-sensitive relationship and that the redox communication between these organelles is not only mediated by diffusion of reactive oxygen species from one compartment to the other. Finally, these findings indicate that mitochondria may act as dynamic receivers, integrators, and transmitters of peroxisome-derived mediators of oxidative stress, and this may have profound implications for our views on cellular aging and age-related diseases.}, }
@article {pmid23988537, year = {2014}, author = {Wang, Q and Zhan, G and Li, C}, title = {Facile synthesis of N-acetyl-L-cysteine capped CdHgSe quantum dots and selective determination of hemoglobin.}, journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy}, volume = {117}, number = {}, pages = {198-203}, doi = {10.1016/j.saa.2013.08.001}, pmid = {23988537}, issn = {1873-3557}, mesh = {Acetylcysteine/*chemistry ; Cadmium Compounds/*chemistry ; Hemoglobins/*analysis ; Humans ; Mercury Compounds/*chemistry ; Microscopy, Electron, Transmission ; Photoelectron Spectroscopy ; Quantum Dots/*chemistry ; Selenium Compounds/*chemistry ; Spectroscopy, Fourier Transform Infrared ; }, abstract = {Using N-acetyl-L-cysteine (NAC) as a stabilizer, well water-dispersed, high-quality and stable CdHgSe quantum dots were facilely synthesized via a simple aqueous phase method. The as-prepared NAC capped CdHgSe quantum dots were thoroughly characterized by fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, energy dispersive X-ray spectroscopy and transmission electron microscopy. A novel method for the selective determination of hemoglobin (Hb) was developed based on fluorescence quenching of the NAC capped CdHgSe quantum dots. A number of key factors including pH value of phosphate buffer solution, quantum dots concentration, the adding sequence of reagents and reaction time that influence the analytical performance of the NAC capped CdHgSe quantum dots in Hb determination were investigated. Under the optimal experimental conditions, the change of fluorescence intensity (ΔI) was linearly proportional to the concentration of Hb in the range of 4.0×10(-9)-4.4×10(-7) mol L(-1) with a detection limit of 2.0×10(-9) mol L(-1). The developed method has been successfully employed to determine Hb in human urine samples.}, }
@article {pmid23986968, year = {2012}, author = {Kaushik, G and Kaushik, T and Yadav, SK and Sharma, SK and Ranawat, P and Khanduja, KL and Pathak, CM}, title = {Curcumin sensitizes lung adenocarcinoma cells to apoptosis via intracellular redox status mediated pathway.}, journal = {Indian journal of experimental biology}, volume = {50}, number = {12}, pages = {853-861}, pmid = {23986968}, issn = {0019-5189}, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/*pathology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Caspase 3/metabolism ; Cell Line, Tumor/drug effects/pathology ; Curcumin/*pharmacology ; Drug Screening Assays, Antitumor ; Enzyme Activation/drug effects ; Enzyme Induction/drug effects ; Glutamate-Cysteine Ligase/biosynthesis/genetics ; Glutathione/antagonists &amp; inhibitors/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Lung Neoplasms/*pathology ; MAP Kinase Signaling System/drug effects ; Oxidants/antagonists &amp; inhibitors/*pharmacology ; Oxidation-Reduction ; Phosphorylation/drug effects ; Protein Processing, Post-Translational/drug effects ; RNA, Messenger/biosynthesis ; RNA, Neoplasm/biosynthesis ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; }, abstract = {The present study demonstrates that curcumin acts as pro-oxidant and sensitizes human lung adenocarcinoma epithelial cells (A549) to apoptosis via intracellular redox status mediated pathway. Results indicated that curcumin induced cell toxicity (light microscopy and MTT assay) and apoptosis (AnnexinV-FITC/PI labeling and caspase-3 activity) in these cells. These events seem to be mediated through generation of reactive oxygen species (ROS) and superoxide radicals (SOR) and enhanced levels of lipid peroxidation. These changes were accompanied by increase in oxidized glutathione (GSSG), reduced glutathione (GSH) and gamma-glutamylcysteine synthetase (gamma-GCS) activity, but decrease in GSH/GSSG ratio. The induction of apoptosis and decrease in GSH/GSSG ratio was also accompanied by sustained phosphorylation and activation of p38 mitogen activated protein kinase (MAPK). On the other hand, addition of N-acetyl cysteine (NAC), an antioxidant, blocked the curcumin-induced ROS production and rescued malignant cells from curcumin-induced apoptosis through caspase-3 deactivation. However, L-buthionine sulfoximine (BSO), a GSH synthesis blocking agent, further enhanced curcumin-induced ROS production and apoptosis in A549 cells. Decreased GSH/GSSG ratio seems to be a crucial factor for the activation of MAPK signaling cascade by curcumin. The study therefore, provides an insight into the molecular mechanism involved in sensitization of lung adenocarcinoma cells to apoptosis by curcumin.}, }
@article {pmid23986393, year = {2013}, author = {Jalilehvand, F and Parmar, K and Zielke, S}, title = {Mercury(II) complex formation with N-acetylcysteine.}, journal = {Metallomics : integrated biometal science}, volume = {5}, number = {10}, pages = {1368-1376}, doi = {10.1039/c3mt00173c}, pmid = {23986393}, issn = {1756-591X}, mesh = {Acetylcysteine/*chemistry ; Fourier Analysis ; Least-Squares Analysis ; Magnetic Resonance Spectroscopy ; Mercury/*chemistry ; Solutions ; Spectrum Analysis, Raman ; X-Ray Absorption Spectroscopy ; }, abstract = {N-Acetylcysteine (H2NAC) is a potent antioxidant, a precursor for cysteine and glutathione, and a potential antidote against certain metal ions such as cadmium and mercury. Little is known about the structural aspects of complexes formed between Hg(II) and N-acetylcysteine, despite many biological tests on its ability to bind to organic and inorganic mercury, and a few reports on formation constants for Hg(NAC)n (n = 1-3) complexes. We have combined several techniques, including Hg L3-edge EXAFS (extended X-ray absorption fine structure), (199)Hg NMR and Raman spectroscopy, to investigate the nature and structure of Hg(II) N-acetylcysteine complexes formed in aqueous solution at pH 7.5 and 10.5. To allow measurements on the same samples, rather concentrated solutions containing CHg(II) = 0.1 M and variable H2NAC/Hg(II) mole ratios = 2.0-10.0 were used. At physiological pH, Hg(NAC)2(2-) and Hg(NAC)3(4-) complexes form, while in ligand excess and at alkaline pH (H2NAC/Hg(II) > 4), a novel tetra-thiolate species Hg(NAC)4(6-) dominates. Comparison between the Hg(II) complex formation with cysteine, penicillamine and N-acetylcysteine in alkaline aqueous solution has been made to elucidate the influence of the blocked amino group of N-acetylcysteine.}, }
@article {pmid23982694, year = {2016}, author = {Loomba, RS and Shah, PH and Aggarwal, S and Arora, RR}, title = {Role of N-Acetylcysteine to Prevent Contrast-Induced Nephropathy: A Meta-analysis.}, journal = {American journal of therapeutics}, volume = {23}, number = {1}, pages = {e172-83}, doi = {10.1097/MJT.0b013e31829dbc1c}, pmid = {23982694}, issn = {1536-3686}, mesh = {Acetylcysteine/*therapeutic use ; Contrast Media/*adverse effects ; Humans ; Kidney Diseases/*chemically induced/prevention &amp; control ; }, abstract = {It is unclear whether N-acetylcysteine is useful in preventing contrast-induced nephropathy in patients undergoing coronary angiography. Because of different inclusion and exclusion criteria and different definitions of studied parameters, various studies have reported different outcomes. A systematic search was done using PubMed, Ovid, and the Cochrane library, and studies were pooled after strict inclusion and exclusion criteria. Separate analysis was conducted for all endpoints including only studies that used an N-acetylcysteine (NAC) dose of 600 mg, and another separate analysis was conducted for all endpoints including only studies that used oral route NAC to study how the dose and route of administration of NAC affect the outcomes. The results of the pooled analysis significantly favored the use of NAC to prevent contrast-induced nephropathy in patients undergoing coronary angiography but failed to show any significant benefit in terms of creatinine levels preangiography and postangiography, need for dialysis, and all-cause mortality. The effects of route and dose of NAC did not show any significant difference except in respect to incidence of postcatheterization nephropathy. This study shows that NAC may not have any impact on clinical outcomes after peripheral or coronary artery catheterization and that dose and route do not seem to have any effect on these outcomes.}, }
@article {pmid23979599, year = {2013}, author = {Zhao, Y and Wang, S and Sorenson, CM and Teixeira, L and Dubielzig, RR and Peters, DM and Conway, SJ and Jefcoate, CR and Sheibani, N}, title = {Cyp1b1 mediates periostin regulation of trabecular meshwork development by suppression of oxidative stress.}, journal = {Molecular and cellular biology}, volume = {33}, number = {21}, pages = {4225-4240}, pmid = {23979599}, issn = {1098-5549}, support = {EY018179/EY/NEI NIH HHS/United States ; P30 CA014520/CA/NCI NIH HHS/United States ; RC4 EY021357/EY/NEI NIH HHS/United States ; P30 EY016665/EY/NEI NIH HHS/United States ; P30-EY016665/EY/NEI NIH HHS/United States ; R01 DK090249/DK/NIDDK NIH HHS/United States ; R01 EY018179/EY/NEI NIH HHS/United States ; EY021357/EY/NEI NIH HHS/United States ; EY16995/EY/NEI NIH HHS/United States ; DK090249/DK/NIDDK NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Animals ; Apoptosis ; Aryl Hydrocarbon Hydroxylases/genetics/*metabolism ; Case-Control Studies ; Cell Adhesion ; Cell Adhesion Molecules/genetics/*metabolism ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Cytochrome P-450 CYP1B1 ; Female ; Fibrillar Collagens/metabolism ; Gene Expression Regulation ; Glaucoma/metabolism ; Humans ; Intraocular Pressure ; Lipid Peroxidation ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Oxidative Stress ; Trabecular Meshwork/*growth &amp; development/metabolism/pathology ; }, abstract = {Mutation in CYP1B1 has been reported for patients with congenital glaucoma. However, the underlying mechanisms remain unknown. Here we show increased diurnal intraocular pressure (IOP) in Cyp1b1-deficient (Cyp1b1(-/-)) mice. Cyp1b1(-/-) mice presented ultrastructural irregular collagen distribution in their trabecular meshwork (TM) tissue along with increased oxidative stress and decreased levels of periostin (Postn). Increased levels of oxidative stress and decreased levels of Postn were also detected in human glaucomatous TM tissues. Furthermore, Postn-deficient mice exhibited TM tissue ultrastructural abnormalities similar to those of Cyp1b1(-/-) mice. Administration of the antioxidant N-acetylcysteine (NAC) restored structural abnormality of TM tissue in Cyp1b1(-/-) mice. In addition, TM cells prepared from Cyp1b1(-/-) mice exhibited increased oxidative stress, altered adhesion, and decreased levels of Postn. These aberrant cellular responses were reversed in the presence of NAC or by restoration of Cyp1b1 expression. Cyp1b1 knockdown or inhibition of CYP1B1 activity in Cyp1b1(+/+) TM cells resulted in a Cyp1b1(-/-) phenotype. Thus, metabolic activity of CYP1B1 contributes to oxidative homeostasis and ultrastructural organization and function of TM tissue through modulation of Postn expression.}, }
@article {pmid23978616, year = {2014}, author = {Su, X and Li, Y and Wang, P and Wang, X and Liu, Q}, title = {Protoporphyrin IX-mediated sonodynamic action induces apoptosis of K562 cells.}, journal = {Ultrasonics}, volume = {54}, number = {1}, pages = {275-284}, doi = {10.1016/j.ultras.2013.07.015}, pmid = {23978616}, issn = {1874-9968}, mesh = {Apoptosis/*drug effects/radiation effects ; Electrophoresis/*methods ; Humans ; K562 Cells ; Protoporphyrins/*administration &amp; dosage ; Radiation-Sensitizing Agents/administration &amp; dosage ; Sonication/*methods ; Ultrasonic Therapy/*methods ; }, abstract = {OBJECTIVES: The present study aims to investigate apoptosis of human leukemia K562 cells induced by protoporphyrin IX (PpIX)-mediated sonodynamic therapy (PpIX-SDT).<br><br>METHODS: The uptakes of intracellular PpIX in K562 cells were detected by flow cytometry. The sub-cellular localization of PpIX was imaged by confocal microscope. The cytotoxic effect of PpIX-SDT was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenylter-trazolium bromide tetrazolium) assay. Apoptosis was evaluated by chromatin condensation with DAPI (4'-6-diamidino-2-phenylindole) staining, decrease of mitochondria membrane potential (MMP), re-distribution of Bax, and the expression changes of the key apoptosis-associated protein (Caspase-3 and polypeptide poly (ADP-robose) polymerase). The possible mechanism of SDT-induced apoptosis was investigated by detecting by intracellular ROS (reactive oxygen species) generation and effect of ROS scavenger-NAC (N-acetylcysteine) on SDT induced apoptosis.<br><br>RESULTS: The intracellular PpIX increased quickly within 2 h after PpIX administration and PpIX mainly localized in the mitochondria. Compared with PpIX alone and ultrasound alone groups, the synergistic cytotoxicity of PpIX plus ultrasound was significantly boosted. In addition, the ultrasound induced some extent of chromatin condensation and MMP loss was greatly enhanced by the presence of 2 &#x3bc;g/ml PpIX, where PpIX alone treatment showed no or only slight effect. Time-dependent Bax translocation, caspase-3 activation and PARP cleavage were detected in SDT treatment groups. Besides, intracellular ROS production was significantly enhanced after SDT, and the general ROS scavenger NAC could obviously alleviate the SDT-caused cell viability loss, MMP loss, Bax redistribution and nuclear changes.<br><br>CONCLUSIONS: These results indicated that PpIX-mediated sonodynamic action could induce apoptosis on K562 cells, and the intracellular ROS was involved in the PpIX-SDT induced apoptosis.}, }
@article {pmid23978445, year = {2013}, author = {Kim, MJ and Nepal, S and Lee, ES and Jeong, TC and Kim, SH and Park, PH}, title = {Ethanol increases matrix metalloproteinase-12 expression via NADPH oxidase-dependent ROS production in macrophages.}, journal = {Toxicology and applied pharmacology}, volume = {273}, number = {1}, pages = {77-89}, doi = {10.1016/j.taap.2013.08.005}, pmid = {23978445}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line, Tumor ; Ethanol/*adverse effects ; Female ; I-kappa B Proteins/metabolism ; Macrophages/*drug effects/enzymology ; Matrix Metalloproteinase 12/genetics/*metabolism ; Membrane Glycoproteins/genetics/*metabolism ; Mice ; Mice, Inbred BALB C ; NADPH Oxidase 2 ; NADPH Oxidases/genetics/*metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B/genetics/metabolism ; Nitriles/pharmacology ; Onium Compounds/pharmacology ; Oxidative Stress/drug effects ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Sulfones/pharmacology ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Matrix metalloproteinase-12 (MMP-12), an enzyme responsible for degradation of extracellular matrix, plays an important role in the progression of various diseases, including inflammation and fibrosis. Although most of those are pathogenic conditions induced by ethanol ingestion, the effect of ethanol on MMP-12 has not been explored. In the present study, we investigated the effect of ethanol on MMP-12 expression and its potential mechanisms in macrophages. Here, we demonstrated that ethanol treatment increased MMP-12 expression in primary murine peritoneal macrophages and RAW 264.7 macrophages at both mRNA and protein levels. Ethanol treatment also significantly increased the activity of nicotinamide adenine dinucleotide (NADPH) oxidase and the expression of NADPH oxidase-2 (Nox2). Pretreatment with an anti-oxidant (N-acetyl cysteine) or a selective inhibitor of NADPH oxidase (diphenyleneiodonium chloride (DPI)) prevented ethanol-induced MMP-12 expression. Furthermore, knockdown of Nox2 by small interfering RNA (siRNA) prevented ethanol-induced ROS production and MMP-12 expression in RAW 264.7 macrophages, indicating a critical role for Nox2 in ethanol-induced intracellular ROS production and MMP-12 expression in macrophages. We also showed that ethanol-induced Nox2 expression was suppressed by transient transfection with dominant negative IκB-α plasmid or pretreatment with Bay 11-7082, a selective inhibitor of NF-κB, in RAW 264.7 macrophages. In addition, ethanol-induced Nox2 expression was also attenuated by treatment with a selective inhibitor of p38 MAPK, suggesting involvement of p38 MAPK/NF-κB pathway in ethanol-induced Nox2 expression. Taken together, these results demonstrate that ethanol treatment elicited increase in MMP-12 expression via increase in ROS production derived from Nox2 in macrophages.}, }
@article {pmid23975535, year = {2013}, author = {Soleimani Asl, S and Mousavizadeh, K and Pourheydar, B and Soleimani, M and Rahbar, E and Mehdizadeh, M}, title = {Protective effects of N-acetylcysteine on 3, 4-methylenedioxymethamphetamine-induced neurotoxicity in male Sprague-Dawley rats.}, journal = {Metabolic brain disease}, volume = {28}, number = {4}, pages = {677-686}, pmid = {23975535}, issn = {1573-7365}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Caspase 3/metabolism ; Cell Death/*drug effects ; Down-Regulation/drug effects ; Hippocampus/*drug effects/metabolism ; Male ; Maze Learning/drug effects ; N-Methyl-3,4-methylenedioxyamphetamine/*toxicity ; Neurotoxicity Syndromes/drug therapy/*prevention &amp; control ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Rats, Sprague-Dawley ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Exposure to 3, 4-methylenedioxymethamphetamine (MDMA) leads to spatial memory impairment and hippocampal cell death. In the present study we have examined the protective effects of N-acetyl-L-cysteine (NAC) on MDMA-induced neurotoxicity. A total of 56 male Sprague Dawley rats (200-250 g) received twice daily intraperitoneal (IP) injections of 5, 10 or 20 mg/kg MDMA plus NAC (100 mg/kg). Rectal temperatures were recorded before and after daily treatment. We used a Morris water maze (MWM) to assess spatial learning and memory. At the end of the study rats' brains were removed, cells were counted and the level of Bcl-2, Bax and caspase-3 expression in the hippocampi were measured. NAC pretreatment significantly reduced MDMA-induced hyperthermia. In the MWM, NAC significantly attenuated the MDMA-induced increase in distance traveled; however the observed increase in escape latency was not significant. The decrease in time spent in the target quadrant in MDMA animals was significantly attenuated (p < 0.001, all groups). NAC protected against MDMA-induced cell death and the up -regulation of Bax and Caspase-3, in addition to the down-regulation of Bcl-2. This data suggested a possible benefit of NAC in the treatment of neurotoxicity among those who use MDMA.}, }
@article {pmid23975029, year = {2013}, author = {Horng, H and Benet, LZ}, title = {The nonenzymatic reactivity of the acyl-linked metabolites of mefenamic acid toward amino and thiol functional group bionucleophiles.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {41}, number = {11}, pages = {1923-1933}, pmid = {23975029}, issn = {1521-009X}, support = {P30 DK026743/DK/NIDDK NIH HHS/United States ; GM36633/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Acyl Coenzyme A/metabolism ; Acylation/physiology ; Adenosine Monophosphate/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*metabolism ; Glucuronates/metabolism ; Glutathione/metabolism ; Male ; Mefenamic Acid/analogs &amp; derivatives/*metabolism ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Mefenamic acid (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug, is metabolized into the chemically-reactive MFA-1-O-acyl-glucuronide (MFA-1-O-G), MFA-acyl-adenylate (MFA-AMP), and the MFA-S-acyl-coenzyme A (MFA-CoA), all of which are electrophilic and capable of acylating nucleophilic sites on biomolecules. In this study, we investigate the nonenzymatic ability of each MFA acyl-linked metabolite to transacylate amino and thiol functional groups on the acceptor biomolecules Gly, Tau, l-glutathione (GSH), and N-acetylcysteine (NAC). In vitro incubations with each of the MFA acyl-linked metabolites (1 μM) in buffer under physiologic conditions with Gly, Tau, GSH, or NAC (10 mM) revealed that MFA-CoA was 11.5- and 19.5-fold more reactive than MFA-AMP toward the acylation of cysteine-sulfhydryl groups of GSH and NAC, respectively. However, MFA-AMP was more reactive toward both Gly and Tau, 17.5-fold more reactive toward the N-acyl-amidation of taurine than its corresponding CoA thioester, while MFA-CoA displayed little reactivity toward glycine. Additionally, mefenamic acid-S-acyl-glutathione (MFA-GSH) was 5.6- and 108-fold more reactive toward NAC than MFA-CoA and MFA-AMP, respectively. In comparison with MFA-AMP and MFA-CoA, MFA-1-O-G was not significantly reactive toward all four bionucleophiles. MFA-AMP, MFA-CoA, MFA-1-O-G, MFA-GSH, and mefenamic acid-taurine were also detected in rat in vitro hepatocyte MFA (100 μM) incubations, while mefenamic acid-glycine was not. These results demonstrate that MFA-AMP selectively reacts with the amino functional groups of glycine and lysine nonenzymatically, MFA-CoA selectively reacts nonenzymatically with the thiol functional groups of GSH and NAC, and MFA-GSH reacts with the thiol functional group of GSH nonenzymatically, all of which may potentially elicit an idiosyncratic toxicity in vivo.}, }
@article {pmid23973622, year = {2013}, author = {Liu, H and Li, W and Rose, ME and Pascoe, JL and Miller, TM and Ahmad, M and Poloyac, SM and Hickey, RW and Graham, SH}, title = {Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites.}, journal = {Neurotoxicology}, volume = {39}, number = {}, pages = {35-44}, pmid = {23973622}, issn = {1872-9711}, support = {R01 NS037459/NS/NINDS NIH HHS/United States ; R01NS37459/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Carbazoles/pharmacology ; Cells, Cultured ; Cerebral Cortex/cytology ; Cyclopentanes/*metabolism ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Hypoxia/prevention &amp; control ; Intramolecular Oxidoreductases/genetics/metabolism ; Lipocalins/genetics/metabolism ; Mice ; Mice, Knockout ; Neurons/*drug effects ; Prostaglandin D2/analogs &amp; derivatives/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Prostaglandin/metabolism ; Sulfonamides/pharmacology ; }, abstract = {Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, Δ(12)-PGJ2 and 15-deoxy-Δ(12,14)-PGJ2, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD2 on neuronal cell death and its underlying mechanisms. PGD2 dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥10μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD2-induced cell death. Conversion of PGD2 to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD2, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD2 elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture.}, }
@article {pmid23973528, year = {2013}, author = {Guo, WZ and Shiina, I and Wang, Y and Umeda, E and Watanabe, C and Uetake, S and Ohashi, Y and Yamori, T and Dan, S}, title = {Ridaifen-SB8, a novel tamoxifen derivative, induces apoptosis via reactive oxygen species-dependent signaling pathway.}, journal = {Biochemical pharmacology}, volume = {86}, number = {9}, pages = {1272-1284}, doi = {10.1016/j.bcp.2013.08.020}, pmid = {23973528}, issn = {1873-2968}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/chemical synthesis/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor/genetics/metabolism ; Caspases/metabolism ; Cell Line, Tumor/drug effects ; Estrogen Receptor alpha/genetics/metabolism ; Free Radical Scavengers/pharmacology ; Gene Knockdown Techniques ; Gliosarcoma/drug therapy/genetics/metabolism/pathology ; Humans ; MCF-7 Cells/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Protein Transport/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tamoxifen/*analogs &amp; derivatives/pharmacology ; }, abstract = {Tamoxifen is an anticancer agent widely used for treatment of estrogen receptor (ERα)-positive breast cancer. We previously developed a novel synthesis of tamoxifen and its derivatives, named Ridaifens (RIDs). Some of them, including RID-SB8, exhibited a stronger anticancer activity than tamoxifen in ERα-positive MCF-7 cells while having lost the affinity for ERα, suggesting an ERα-independent anticancer mode of action. In this study, we investigated the underlying mechanism by which RID-SB8 exerts anticancer activity. As expected, anticancer activity of RID-SB8 was not influenced upon knockdown of ERα expression in MCF-7 cells. RID-SB8 exerted similar anticancer effects on thirteen ERα-negative cancer cell lines including human gliosarcoma SF539 cells. In SF539 cells, RID-SB8 triggered loss of mitochondrial membrane potential (ΔΨ(m)) and progression of apoptosis accompanied by activation of caspases and translocation of apoptosis-inducing factor (AIF) to the nucleus. Furthermore, it induced reactive oxygen species (ROS), and a ROS scavenger, N-acetylcysteine (NAC), canceled loss of ΔΨ(m) and progression of apoptosis triggered by RID-SB8. Using fifteen human cancer cell lines, we demonstrated a significant correlation between RID-SB8 concentration required for ROS production and that required for cytotoxic effect across these cell lines, but such correlation was not observed for tamoxifen. Finally, the selective induction of ROS and cytotoxic effect on cancer cells by RID-SB8 were confirmed. From these results, we concluded that RID-SB8 exerts an anticancer effect via a mode of action distinct from tamoxifen, and that RID-SB8 could become a promising anticancer lead compound which selectively induces ROS formation and apoptosis in cancer cells.}, }
@article {pmid23970139, year = {2013}, author = {Silveira, LF and Baca, P and Arias-Moliz, MT and Rodríguez-Archilla, A and Ferrer-Luque, CM}, title = {Antimicrobial activity of alexidine alone and associated with N-acetylcysteine against Enterococcus faecalis biofilm.}, journal = {International journal of oral science}, volume = {5}, number = {3}, pages = {146-149}, pmid = {23970139}, issn = {1674-2818}, mesh = {Acetylcysteine/*pharmacology ; Anti-Infective Agents, Local/*pharmacology ; Biguanides/*pharmacology ; Biofilms/*drug effects ; Dental Pulp Cavity/microbiology ; Drug Combinations ; Enterococcus faecalis/*drug effects ; Humans ; }, abstract = {The purpose of this study was to assess the efficacy of alexidine (ALX), alone and combined with N-acetylcysteine (NAC), in eradicating two Enterococcus faecalis strain biofilms. The biofilms of E. faecalis ATCC 29212 and the clinical isolate E. faecalis D1 were grown in the MBEC-high-throughput device for 24 h and were exposed to five twofold dilutions of ALX (2%-0.007 8%) alone and combined with 100 mg⋅mL(-1) NAC, for 1 and 5 min. Eradication was defined as 100% kill of biofilm bacteria. The Student's t-test was used to compare the efficacy of the associations of the two irrigants. After 1-min contact time, ALX eradicated the biofilms at all concentrations except for 0.007 8% and 0.015 6%-0.007 8% with E. faecalis ATCC 29212 and E. faecalis D1, respectively. Similar results for eradication and concentration were obtained when it was combined with 100 mg⋅mL(-1) NAC. After 5 min of contact time, ALX alone and combined with NAC eradicated all enterococci biofilms. ALX showed antimicrobial properties against the two E. faecalis strain biofilms tested at very low concentrations, and its combined use with NAC was not seen to enhance its activity.}, }
@article {pmid23964853, year = {2013}, author = {Duffull, SB and Isbister, GK}, title = {Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {51}, number = {8}, pages = {772-776}, pmid = {23964853}, issn = {1556-9519}, mesh = {Acetaminophen/administration &amp; dosage/blood/*poisoning ; Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Non-Narcotic/administration &amp; dosage/blood/*poisoning ; Antidotes/*therapeutic use ; Charcoal/therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy/pathology ; Child ; Databases, Factual ; Dose-Response Relationship, Drug ; Drug Overdose ; Female ; Humans ; Logistic Models ; Male ; Middle Aged ; Nomograms ; Nonlinear Dynamics ; Prospective Studies ; Retrospective Studies ; Risk Assessment/methods ; Time Factors ; Treatment Outcome ; Young Adult ; }, abstract = {CONTEXT: There is contention over whether reported dose correlates with toxicity in paracetamol poisoning and risk assessment is currently based on serum paracetamol concentration compared to a nomogram, irrespective of reported dose. Objective. To determine if reported dose predicts the need for N-acetylcysteine (NAC).<br><br>METHODS: Data were taken from paracetamol overdoses presenting to a tertiary toxicology service. Age, sex, reported dose, ingestion time, timed paracetamol concentrations between 4 and 16 h, hepatotoxicity (peak alanine transaminase > 1000 U/L) and treatment (single dose-activated charcoal [SDAC] and NAC) were analysed. Data were analysed within a repeated measures logistic regression framework using NONMEM (ver 7.2). The primary outcome was administration of NAC, which was determined based on a serum paracetamol concentration greater than the nomogram line.<br><br>RESULT: There were 1571 admissions in 1303 patients, with a median age of 27 years (12-96 years) and 1140 (73%) were females. The median dose was 10 g (1-100 g). The paracetamol concentration was above the nomogram line in 337 of 1571 (22%) patients. Patients presenting later (first paracetamol concentration between 7 and 16 h post-overdose) compared to those presenting earlier (4-7 h post-overdose) were more likely to have hepatotoxicity (5.5% vs. 0.4%; p < 0.0001), have a toxic paracetamol concentration (34% vs. 18%; p < 0.0001) and receive NAC (48% vs. 23%; p < 0.0001). SDAC reduced the probability of the paracetamol concentration being above the nomogram. Based on SDAC not being administered there was a 5% probability of requiring NAC at a dose of 6-9 g, a 10% chance of requiring NAC at a dose of 13-16 g, a 50% chance of requiring NAC at a dose of 30-34 g and a 90% chance for needing NAC at 48-50 g.<br><br>CONCLUSION: Reported dose was a good predictor of a toxic paracetamol concentration and SDAC reduced the probability of the concentration being above the nomogram. These predictions may assist in determining which patients could be started on NAC immediately.}, }
@article {pmid23962629, year = {2014}, author = {Laha, D and Pramanik, A and Maity, J and Mukherjee, A and Pramanik, P and Laskar, A and Karmakar, P}, title = {Interplay between autophagy and apoptosis mediated by copper oxide nanoparticles in human breast cancer cells MCF7.}, journal = {Biochimica et biophysica acta}, volume = {1840}, number = {1}, pages = {1-9}, doi = {10.1016/j.bbagen.2013.08.011}, pmid = {23962629}, issn = {0006-3002}, mesh = {*Apoptosis ; Apoptosis Regulatory Proteins/antagonists &amp; inhibitors/genetics/metabolism ; *Autophagy ; Beclin-1 ; Blotting, Western ; Breast Neoplasms/drug therapy/metabolism/*pathology ; Cadaverine/analogs &amp; derivatives/metabolism ; Cell Cycle ; Cell Proliferation ; Copper/*administration &amp; dosage ; Female ; Green Fluorescent Proteins/genetics/metabolism ; Humans ; MCF-7 Cells ; Membrane Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Metal Nanoparticles/*administration &amp; dosage ; Microtubule-Associated Proteins/genetics/metabolism ; RNA, Small Interfering/genetics ; }, abstract = {BACKGROUND: Metal oxide nanoparticles are well known to generate oxidative stress and deregulate normal cellular activities. Among these, transition metals copper oxide nanoparticles (CuO NPs) are more compelling than others and able to modulate different cellular responses.<br><br>METHODS: In this work, we have synthesized and characterized CuO NPs by various biophysical methods. These CuO NPs (~30nm) induce autophagy in human breast cancer cell line, MCF7 in a time- and dose-dependent manner. Cellular autophagy was tested by MDC staining, induction of green fluorescent protein-light chain 3 (GFP-LC3B) foci by confocal microscopy, transfection of pBABE-puro mCherry-EGFP-LC3B plasmid and Western blotting of autophagy marker proteins LC3B, beclin1 and ATG5. Further, inhibition of autophagy by 3-MA decreased LD50 doses of CuO NPs. Such cell death was associated with the induction of apoptosis as revealed by FACS analysis, cleavage of PARP, de-phosphorylation of Bad and increased cleavage product of caspase 3. siRNA mediated inhibition of autophagy related gene beclin1 also demonstrated similar results. Finally induction of apoptosis by 3-MA in CuO NP treated cells was observed by TEM.<br><br>RESULTS: This study indicates that CuO NPs are a potent inducer of autophagy which may be a cellular defense against the CuO NP mediated toxicity and inhibition of autophagy switches the cellular response into apoptosis.<br><br>CONCLUSIONS: A combination of CuO NPs with the autophagy inhibitor is essential to induce apoptosis in breast cancer cells.<br><br>GENERAL SIGNIFICANCE: CuO NP induced autophagy is a survival strategy of MCF7 cells and inhibition of autophagy renders cellular fate to apoptosis.}, }
@article {pmid23960423, year = {2013}, author = {Saha, L and Kaur, S and Saha, PK}, title = {N-acetyl cysteine in clomiphene citrate resistant polycystic ovary syndrome: A review of reported outcomes.}, journal = {Journal of pharmacology &amp; pharmacotherapeutics}, volume = {4}, number = {3}, pages = {187-191}, pmid = {23960423}, issn = {0976-500X}, abstract = {Clomiphene citrate (CC) has been the gold-standard drug for ovulation induction in polycystic ovary syndrome (PCOS), but still CC resistance is seen in approximately 15-40% in women with PCOS. N-acetyl cysteine (NAC), a safe and cheap drug available in the market many years ago as mucolytic agent, was found to have a role in infertility management. Recently, some reports discussed the possible beneficial effects of NAC on ovulation. The biological properties of the NAC make this drug a potential candidate for its use in the infertility treatment, especially in the PCOS in inducing or augmenting ovulation. An updated electronic search was performed through PUBMED, MEDLINE, and COCHRANE and focused on peer-reviewed, full text, randomized controlled trials, and observational cohort or case-control studies for role of NAC in CC-resistant PCOS. Thorough search through all the clinical studies showed mixed results. Studies with positive results showed improvement in induction of ovulation as compared to negative studies showing contrary results. More randomized clinical trials are still needed to establish its definitive role in CC-resistant PCOS.}, }
@article {pmid23958999, year = {2013}, author = {Mejía-García, TA and Portugal, CC and Encarnação, TG and Prado, MA and Paes-de-Carvalho, R}, title = {Nitric oxide regulates AKT phosphorylation and nuclear translocation in cultured retinal cells.}, journal = {Cellular signalling}, volume = {25}, number = {12}, pages = {2424-2439}, doi = {10.1016/j.cellsig.2013.08.001}, pmid = {23958999}, issn = {1873-3913}, mesh = {Active Transport, Cell Nucleus/drug effects ; Animals ; Arginine/metabolism ; Cells, Cultured ; Chickens ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Nitric Oxide/*metabolism ; Nitric Oxide Donors/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Retinal Neurons/cytology/*drug effects/*metabolism ; S-Nitroso-N-Acetylpenicillamine/*pharmacology ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Previous studies have shown that nitric oxide (NO) inhibits apoptosis of retinal neurons in culture through the canonical cyclic GMP/protein kinase G (PKG)-dependent pathway, but also involving multiple kinase pathways, such as phosphatidylinositol 3' kinase (PI3k) and AKT. NO and AKT exhibit survival-promoting properties and display important roles in both CNS development and plasticity. The purpose of this study was to evaluate the effects of exogenous NO, derived from the NO donor S-nitroso-N-acetylpenicillamin (SNAP), or endogenous NO, produced from l-arginine, on AKT phosphorylation in cultured chick retinal neurons. Our results demonstrate that SNAP or l-arginine enhances AKT phosphorylation on both serine-473 and threonine-308 residues in a concentration and time-dependent manner. This effect was mediated by the activation of soluble guanylyl cyclase and PKG, since it was blocked by the respective enzyme inhibitors ODQ or LY83583 and KT5823, as well as by transduction with shRNA lentiviruses coding PKGII shRNA, and mimicked by the respective enzyme activators YC-1 and 8-Bromo cyclic GMP, and also by the cyclic GMP phosphodiesterase inhibitor zaprinast. In addition, LY294002 or wortmannin suppressed the SNAP effect, indicating the involvement of phosphoinositide 3' kinase. Moreover, the mTOR inhibitor KU0063794 blocked SNAP-induced AKT phosphorylation at both residues, suggesting the participation of the mTORC2 complex in the process. Glutamate and NMDA also promoted AKT phosphorylation and a nitric oxide synthase inhibitor abrogated these effects, revealing a mechanism involving the activation of NMDA receptors and NO production. We have also found that SNAP and l-arginine induced AKT translocation into the nucleus of retinal neurons as well as other neuronal cell lines. SNAP also protects retinal cells from death induced by hydrogen peroxide and this effect was blocked by the phosphoinositide 3' kinase inhibitor LY294002. We therefore conclude that NO produced from endogenous or exogenous sources promotes AKT activation and its shuttling to the nucleus, probably participating in neuronal survival pathways important during CNS development.}, }
@article {pmid23958494, year = {2013}, author = {Hernández-Breijo, B and Monserrat, J and Román, ID and González-Rodríguez, &#xc1; and Fernández-Moreno, MD and Lobo, MV and Valverde, &#xc1;M and Gisbert, JP and Guijarro, LG}, title = {Azathioprine desensitizes liver cancer cells to insulin-like growth factor 1 and causes apoptosis when it is combined with bafilomycin A1.}, journal = {Toxicology and applied pharmacology}, volume = {272}, number = {3}, pages = {568-578}, doi = {10.1016/j.taap.2013.07.024}, pmid = {23958494}, issn = {1096-0333}, mesh = {Antimetabolites, Antineoplastic/administration &amp; dosage ; Apoptosis/*drug effects/physiology ; Azathioprine/*administration &amp; dosage ; Cell Line, Tumor ; Drug Therapy, Combination ; Enzyme Inhibitors/administration &amp; dosage ; Hep G2 Cells ; Humans ; Insulin-Like Growth Factor I/*toxicity ; Liver Neoplasms/*chemically induced/drug therapy/*pathology ; Macrolides/*administration &amp; dosage ; }, abstract = {Hepatoblastoma is a primary liver cancer that affects children, due to the sensitivity of this tumor to insulin-like growth factor 1 (IGF-1). In this paper we show that azathioprine (AZA) is capable of inhibiting IGF1-mediated signaling cascade in HepG2 cells. The efficiency of AZA on inhibition of proliferation differs in the evaluated cell lines as follows: HepG2 (an experimental model of hepatoblastoma)>Hep3B (derived from a hepatocellular carcinoma)>HuH6 (derived from a hepatoblastoma)>>HuH7 (derived from a hepatocellular carcinoma)=Chang Liver cells (a non-malignant cellular model). The effect of AZA in HepG2 cells has been proven to derive from activation of Ras/ERK/TSC2, leading to activation of mTOR/p70S6K in a sustained manner. p70S6K phosphorylates IRS-1 in serine 307 which leads to the uncoupling between IRS-1 and p85 (the regulatory subunit of PI3K) and therefore causing the lack of response of HepG2 to IGF-1. As a consequence, proliferation induced by IGF-1 is inhibited by AZA and autophagy increases leading to senescence of HepG2 cells. Our results suggest that AZA induces the autophagic process in HepG2 activating senescence, and driving to deceleration of cell cycle but not to apoptosis. However, when simultaneous to AZA treatment the autophagy was inhibited by bafilomycin A1 and the degradation of regulatory proteins of cell cycle (e.g. Rb, E2F, and cyclin D1) provoked apoptosis. In conclusion, AZA induces resistance in hepatoblastoma cells to IGF-1, which leads to autophagy activation, and causes apoptosis when it is combined with bafilomycin A1. We are presenting here a novel mechanism of action of azathioprine, which could be useful in treatment of IGF-1 dependent tumors, especially in its combination with other drugs.}, }
@article {pmid23958426, year = {2013}, author = {Branco, AF and Sampaio, SF and Wieckowski, MR and Sardão, VA and Oliveira, PJ}, title = {Mitochondrial disruption occurs downstream from β-adrenergic overactivation by isoproterenol in differentiated, but not undifferentiated H9c2 cardiomyoblasts: differential activation of stress and survival pathways.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {45}, number = {11}, pages = {2379-2391}, doi = {10.1016/j.biocel.2013.08.006}, pmid = {23958426}, issn = {1878-5875}, mesh = {Animals ; Antioxidants/pharmacology ; Calcium/metabolism ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Differentiation/*drug effects ; Cell Line ; Cell Survival/drug effects ; Cyclic AMP/metabolism ; Cytosol/drug effects/metabolism ; Isoproterenol/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/*metabolism ; Models, Biological ; Myocytes, Cardiac/*cytology/drug effects/enzymology/*metabolism ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Receptors, Adrenergic, beta-2/*metabolism ; Signal Transduction/drug effects ; Stress, Physiological/*drug effects ; Superoxides/metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {β-Adrenergic receptor stimulation plays an important role in cardiomyocyte stress responses, which may result in apoptosis and cardiovascular degeneration. We previously demonstrated that toxicity of the β-adrenergic agonist isoproterenol on H9c2 cardiomyoblasts depends on the stage of cell differentiation. We now investigate β-adrenergic receptor downstream signaling pathways and stress responses that explain the impact of muscle cell differentiation on hyper-β-adrenergic stimulation-induced cytotoxicity. When incubated with isoproterenol, differentiated H9c2 muscle cells have increased cytosolic calcium, cyclic-adenosine monophosphate content and oxidative stress, as well as mitochondrial depolarization, increased superoxide anion, loss of subunits from the mitochondrial respiratory chain, decreased Bcl-xL content, increased p53 and phosphorylated-p66Shc as well as activated caspase-3. Undifferentiated H9c2 cells incubated with isoproterenol showed increased Bcl-xL protein and increased superoxide dismutase 2 which may act as protective mechanisms. We conclude that the differentiation of H9c2 is associated with differential regulation of stress responses, which impact the toxicity of several agents, namely those acting through β-adrenergic receptors and resulting in mitochondrial disruption in differentiated cells only.}, }
@article {pmid23956714, year = {2013}, author = {Mirhosseini, SJ and Forouzannia, SK and Nasirian, M and Ali-Hassan-Sayegh, S}, title = {N-acetylcysteine instead of theophylline in patients with COPD who are candidates for elective off-pump CABG surgery: Is it possible in cardiovascular surgery unit?.}, journal = {Saudi journal of anaesthesia}, volume = {7}, number = {2}, pages = {151-154}, pmid = {23956714}, issn = {1658-354X}, abstract = {BACKGROUND: Forced expiratory volume in one second (FEV1) is a good predictor of chronic obstructive pulmonary disease (COPD). COPD is characterized by a chronic limitation of airflow. This study was designed to compare the effects and complications of theophylline alone, N-acetylcysteine (NAC) alone, and a combination of the two drugs on the rates of FEV1 in patients with COPD who were candidates for off-pump coronary artery bypass graft (CABG) surgery.<br><br>METHODS: This clinical trial was performed on 100 patients who had a smoking history of 27 pack years with a range of 20 to 40 pack years but were not heavy smokers and were candidates for elective off-pump CABG surgery in Afshar Cardiovascular Hospital, Yazd, Iran. The patients with a history of asthma and bronchospasm and non-COPD respiratory disorders were excluded. There were three groups, that is, the theophylline group (n=33) that received theophylline 10 mg/kg TDS after consumption of food, NAC group (n=33) who received NAC 10-15 mg/kg BD after consumption of food, and the combined group (n=32) who received theophylline and NAC together. Data were analyzed by analysis of variance (ANOVA), Chi-square, and exact test for quantitative and qualitative variables.<br><br>RESULTS: One hundred patients with COPD enrolled in this study as possible candidates for CABG surgery. Average age of the patients was 60.36&#xb1;10.21 years. Of the participants, 83 (83.3%) were male and 17 (17%) were female. Rate of postoperative FEV1 to basal FEV1 was 0.76&#xb1;0.32, 0.66&#xb1;0.22, and 0.69&#xb1;0.24 in the treatments with theophylline, NAC, and the combination, respectively. Theophylline, NAC, and a combination of these drugs can decrease the rate of postoperative FEV1 compared to basal FEV1 significantly. (P=0.0001).<br><br>CONCLUSION: Theophylline alone, NAC alone, and a combination of these drugs improve pulmonary function, and there are no significant differences between these protocols. Stomach discomfort and cardiac complications in treatment with theophylline alone is significantly higher than NAC alone and the combination.}, }
@article {pmid23956023, year = {2014}, author = {Neuwelt, AJ and Nguyen, T and Wu, YJ and Donson, AM and Vibhakar, R and Venkatamaran, S and Amani, V and Neuwelt, EA and Rapkin, LB and Foreman, NK}, title = {Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors.}, journal = {Pediatric blood &amp; cancer}, volume = {61}, number = {1}, pages = {120-127}, pmid = {23956023}, issn = {1545-5017}, support = {R01 CA199111/CA/NCI NIH HHS/United States ; R01 NS044687/NS/NINDS NIH HHS/United States ; }, mesh = {Acetaminophen/*administration &amp; dosage ; Acetylcysteine/*administration &amp; dosage ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Cell Line, Tumor ; Cisplatin/*administration &amp; dosage ; Drug Evaluation, Preclinical ; Glutathione/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; *Rhabdoid Tumor/metabolism/pathology ; }, abstract = {BACKGROUND: Atypical teratoid rhabdoid tumors (AT-RT) are pediatric tumors of the central nervous system with limited treatment options and poor survival rate. We investigated whether enhancing chemotherapy toxicity by depleting intracellular glutathione (GSH; a key molecule in cisplatin resistance) with high dose acetaminophen (AAP), may improve therapeutic efficacy in AT-RT in vitro.<br><br>PROCEDURE: BT16 (cisplatin-resistant) and BT12 (cisplatin-sensitive) AT-RT cell lines were treated with combinations of AAP, cisplatin, and the anti-oxidant N-acetylcysteine (NAC). Cell viability, GSH and peroxide concentrations, mitochondrial damage, and apoptosis were evaluated in vitro.<br><br>RESULTS: AAP enhanced cisplatin cytotoxicity in cisplatin-resistant BT16 cells but not cisplatin-sensitive BT12 cells. Baseline GSH levels were elevated in BT16 cells compared to BT12 cells, and AAP decreased GSH to a greater magnitude in BT16 cells than BT12 cells. Unlike BT12 cells, BT16 cells did not have elevated peroxide levels upon treatment with cisplatin alone, but did have elevated levels when treated with AAP + cisplatin. Both cell lines had markedly increased mitochondrial injury when treated with AAP + cisplatin relative to either drug treatment alone. The enhanced toxic effects were partially reversed with concurrent administration of NAC.<br><br>CONCLUSIONS: Our results suggest that AAP could be used as a chemo-enhancement agent to potentiate cisplatin chemotherapeutic efficacy particularly in cisplatin-resistant AT-RT tumors with high GSH levels in clinical settings.}, }
@article {pmid23955437, year = {2013}, author = {Shi, L and Chen, H and Yu, X and Wu, X}, title = {Advanced glycation end products delay corneal epithelial wound healing through reactive oxygen species generation.}, journal = {Molecular and cellular biochemistry}, volume = {383}, number = {1-2}, pages = {253-259}, pmid = {23955437}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies/pharmacology ; Cattle ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/drug effects/enzymology/metabolism ; Epithelium, Corneal/drug effects/*metabolism/*pathology ; Glycation End Products, Advanced/*pharmacology ; Humans ; In Vitro Techniques ; Intracellular Space/drug effects/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic/immunology ; Serum Albumin, Bovine/*pharmacology ; Sus scrofa ; Telomerase/metabolism ; Wound Healing/*drug effects ; }, abstract = {Delayed healing of corneal epithelial wounds is a serious complication in diabetes. Advanced glycation end products (AGEs) are intimately associated with the diabetic complications and are deleterious to the wound healing process. However, the effect of AGEs on corneal epithelial wound healing has not yet been evaluated. In the present study, we investigated the effect of AGE-modified bovine serum albumin (BSA) on corneal epithelial wound healing and its underlying mechanisms. Our data showed that AGE-BSA significantly increased the generation of intracellular ROS in telomerase-immortalized human corneal epithelial cells. However, the generation of intracellular ROS was completely inhibited by antioxidant N-acetylcysteine (NAC), anti-receptor of AGEs (RAGE) antibodies, or the inhibitor of NADPH oxidase. Moreover, AGE-BSA increased NADPH oxidase activity and protein expression of NADPH oxidase subunits, p22phox and Nox4, but anti-RAGE antibodies eliminated these effects. Furthermore, prevention of intracellular ROS generation using NAC or anti-RAGE antibodies rescued AGE-BSA-delayed epithelial wound healing in porcine corneal organ culture. In conclusion, our results demonstrated that AGE-BSA impaired corneal epithelial wound healing ex vivo. AGE-BSA increased intracellular ROS generation through NADPH oxidase activation, which accounted for the delayed corneal epithelial wound healing. These results may provide better insights for understanding the mechanism of delayed healing of corneal epithelial wounds in diabetes.}, }
@article {pmid23954561, year = {2013}, author = {Srivastava, RK and Li, C and Chaudhary, SC and Ballestas, ME and Elmets, CA and Robbins, DJ and Matalon, S and Deshane, JS and Afaq, F and Bickers, DR and Athar, M}, title = {Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption.}, journal = {Toxicology and applied pharmacology}, volume = {272}, number = {3}, pages = {879-887}, pmid = {23954561}, issn = {1096-0333}, support = {P30 AR044535/AR/NIAMS NIH HHS/United States ; R01 ES020344/ES/NIEHS NIH HHS/United States ; R21ES017494/ES/NIEHS NIH HHS/United States ; R21 ES017494/ES/NIEHS NIH HHS/United States ; R21AR064595/AR/NIAMS NIH HHS/United States ; R21 AR064595/AR/NIAMS NIH HHS/United States ; }, mesh = {Animals ; Arsenic Trioxide ; Arsenicals ; Cell Line ; Endoplasmic Reticulum Chaperone BiP ; Immunity, Innate/*drug effects/immunology ; Macrophages/drug effects/*immunology ; Mice ; Oxides/*toxicity ; Reactive Oxygen Species/immunology/metabolism ; Signal Transduction/drug effects/*immunology ; Unfolded Protein Response/drug effects/*immunology ; }, abstract = {Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses.}, }
@article {pmid23954472, year = {2013}, author = {Hyeon, S and Lee, H and Yang, Y and Jeong, W}, title = {Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation.}, journal = {Free radical biology &amp; medicine}, volume = {65}, number = {}, pages = {789-799}, doi = {10.1016/j.freeradbiomed.2013.08.005}, pmid = {23954472}, issn = {1873-4596}, mesh = {Animals ; Bone Resorption ; *Cell Differentiation ; Enzyme Activation ; Glutathione/metabolism ; Humans ; MAP Kinase Signaling System ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; NF-E2-Related Factor 2/*deficiency/genetics ; NF-kappa B/metabolism ; NFATC Transcription Factors/metabolism ; Osteoclasts/*physiology ; *Oxidative Stress ; Peroxidases/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; RANK Ligand/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of a variety of antioxidant and detoxification genes through an antioxidant-response element. Nrf2 has been shown to protect several types of cells against the acute and chronic injury that accompanies oxidative stress, but its role in osteoclasts remains unclear. In this study, we investigated the role of Nrf2 in osteoclast (OC) differentiation, a process in which reactive oxygen species (ROS) are generated and then participate, using Nrf2-knockout mice. Receptor activator of nuclear factor κB ligand (RANKL)-induced OC differentiation, actin ring formation, and osteoclastic bone resorption were substantially promoted in Nrf2-deficient OC precursor cells compared to wild-type cells. Under both unstimulated and RANKL-stimulated conditions, Nrf2 loss led to an increase in the intracellular ROS level and the oxidized-to-reduced glutathione ratio and a defect in the production of numerous antioxidant enzymes and glutathione. Moreover, pretreatment with N-acetylcysteine or diphenyleneiodonium significantly reduced the OC differentiation and decreased the intracellular ROS level in both Nrf2-deficient and wild-type cells. Pretreatment with sulforaphane and curcumin also inhibited the OC differentiation by activating Nrf2 in part. Nrf2 deficiency promoted the RANKL-induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38; the induction of c-Fos; and the consequent induction of nuclear factor of activated T cells, cytoplasmic 1, a pivotal determinant of OC differentiation. Our results suggest that Nrf2 probably inhibits RANKL-induced OC differentiation by regulating the cellular redox status by controlling the expression of oxidative response genes, findings that might form the basis of a new strategy for treating inflammatory bone diseases.}, }
@article {pmid23954204, year = {2014}, author = {Pathania, D and Sechi, M and Palomba, M and Sanna, V and Berrettini, F and Sias, A and Taheri, L and Neamati, N}, title = {Design and discovery of novel quinazolinedione-based redox modulators as therapies for pancreatic cancer.}, journal = {Biochimica et biophysica acta}, volume = {1840}, number = {1}, pages = {332-343}, doi = {10.1016/j.bbagen.2013.08.005}, pmid = {23954204}, issn = {0006-3002}, mesh = {Apoptosis/*drug effects ; Blotting, Western ; Cell Proliferation/drug effects ; *Drug Design ; Energy Metabolism/*drug effects ; Humans ; Molecular Structure ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Oxygen Consumption/drug effects ; Pancreatic Neoplasms/*drug therapy/metabolism/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Quinazolinones/chemical synthesis/chemistry/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Tumor Cells, Cultured ; Tumor Stem Cell Assay ; }, abstract = {BACKGROUND: Altered cellular bioenergetics and oxidative stress are emerging hallmarks of most cancers including pancreatic cancer. Elevated levels of intrinsic reactive oxygen species (ROS) in tumors make them more susceptible to exogenously induced oxidative stress. Excessive oxidative insults overwhelm their adaptive antioxidant capacity and trigger ROS-mediated cell death. Recently, we have discovered a novel class of quinazolinediones that exert their cytotoxic effects by modulating ROS-mediated signaling.<br><br>METHODS: Cytotoxic potential was determined by colorimetric and colony formation assays. An XF24 Extracellular Flux Analyzer, and colorimetric and fluorescent techniques were used to assess the bioenergetics and oxidative stress effects, respectively. Mechanism was determined by Western blots.<br><br>RESULTS: Compound 3a (6-[(2-acetylphenyl)amino]quinazoline-5,8-dione) was identified through a medium throughput screen of ~1000 highly diverse in-house compounds and chemotherapeutic agents for their ability to alter cellular bioenergetics. Further structural optimizations led to the discovery of a more potent analog, 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) that displayed anti-proliferative activities in low micromolar range in both drug-sensitive and drug-resistant cancer cells. Treatment with 3b causes Akt activation resulting in increased cellular oxygen consumption and oxidative stress in pancreatic cancer cells. Moreover, oxidative stress induced by 3b promoted activation of stress kinases (p38/JNK) resulting in cancer cell death. Treatment with antioxidants was able to reduce cell death confirming ROS-mediated cytotoxicity.<br><br>CONCLUSION: In conclusion, our novel quinazolinediones are promising lead compounds that selectively induce ROS-mediated cell death in cancer cells and warrant further preclinical studies.<br><br>GENERAL SIGNIFICANCE: Since 3b (6-[(3-acetylphenyl)amino]quinazoline-5,8-dione) exerts Akt-dependent ROS-mediated cell death, it might provide potential therapeutic options for chemoresistant and Akt-overexpressing cancers.}, }
@article {pmid23953209, year = {2013}, author = {Wang, X and Lin, R and Xu, Z and Huang, H and Li, L and Liu, F and Li, N and Yang, X}, title = {N-acetylcysteine induced quenching of red fluorescent oligonucleotide-stabilized silver nanoclusters and the application in pharmaceutical detection.}, journal = {Analytica chimica acta}, volume = {793}, number = {}, pages = {79-85}, doi = {10.1016/j.aca.2013.07.037}, pmid = {23953209}, issn = {1873-4324}, mesh = {Acetylcysteine/*chemistry ; Fluorescent Dyes/*chemistry ; Nanostructures/*chemistry ; Oligonucleotides/*chemistry ; Pharmaceutical Preparations/*analysis ; Silver/*chemistry ; *Spectrometry, Fluorescence ; }, abstract = {In this work, we reported a new, simple and sensitive method for determination of N-acetylcysteine (NAC) based on quenching of the red fluorescence of oligonuleotide-protected silver nanoculsters (Ag NCs) with the quantum yield of 68.3±0.3%. This method was successfully used for the assay of NAC granules presenting a linear range from 100 nM to 1200 nM (LOD of 50 nM) with minimal interferences from potential coexisting substances. It is for the first time that quenching performance of the thiol-containing compound was found to follow a non-linear Stern-Volmer profile, indicative of a complicated quenching mechanism with static quenching dominating, in which DNA-template of Ag NCs was partly replaced by NAC, as elucidated by spectral investigations. This study extended the analytical application of silver nanoclusters as well as provided a more insightful understanding of the quenching mechanism of thiol-compounds on the fluorescence of Ag NCs.}, }
@article {pmid23953206, year = {2013}, author = {Xu, C and Liu, S and Liu, Z and Song, F and Liu, S}, title = {Superoxide generated by pyrogallol reduces highly water-soluble tetrazolium salt to produce a soluble formazan: a simple assay for measuring superoxide anion radical scavenging activities of biological and abiological samples.}, journal = {Analytica chimica acta}, volume = {793}, number = {}, pages = {53-60}, doi = {10.1016/j.aca.2013.07.027}, pmid = {23953206}, issn = {1873-4324}, mesh = {Acetylcysteine/chemistry ; Anions/chemistry ; Ascorbic Acid/chemistry ; *Chromatography, High Pressure Liquid ; Humans ; Hydrogen-Ion Concentration ; *Mass Spectrometry ; Pyrogallol/*chemistry ; Serum Albumin/chemistry ; *Spectrophotometry ; Superoxide Dismutase/metabolism ; Superoxides/*analysis ; Temperature ; Tetrazolium Salts/*chemistry ; Water/chemistry ; }, abstract = {Superoxide anion radical (O2(˙-)) plays an important role in several human diseases. The xanthine/xanthine oxidase system is frequently utilized to produce O2(˙-). However, false positive results are easily got by using this system. The common spectrophotometric probes for O2(˙-) are nitroblue tetrazolium (NBT) and cytochrome c. Nevertheless, the application of NBT method is limited because of the water-insolubility of NBT formazan and the assay using cytochrome c lacks sensitivity and is not suitable for microplate measurement. We overcome these problems by using 1,2,3-trihydroxybenzene (pyrogallol) as O2(˙-)-generating system and a highly water-soluble tetrazolium salt, 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium sodium salt (WST-1) which can be reduced by superoxide anion radical to a stable water-soluble formazan with a high absorbance at 450 nm. The method is simple, rapid and sensitive. Moreover, it can be adapted to microplate format. In this study, the O2(˙-) scavenging activities of superoxide dismutase (SOD), L-ascorbic acid, N-acetyl-L-cysteine (NAC), albumin from human serum, flavonoids and herbal extracts were assessed by using this method. Meanwhile, the activities of tissue homogenates and serum were determined by using this validated method. This method, applicable to tissue homogenates, serum and herbal extracts, proved to be efficient for measuring O2(˙-) scavenging activities of biological and abiological samples.}, }
@article {pmid23952889, year = {2013}, author = {LaRowe, SD and Kalivas, PW and Nicholas, JS and Randall, PK and Mardikian, PN and Malcolm, RJ}, title = {A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence.}, journal = {The American journal on addictions}, volume = {22}, number = {5}, pages = {443-452}, pmid = {23952889}, issn = {1521-0391}, support = {P50 DA015369/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; R01 DA012513/DA/NIDA NIH HHS/United States ; DA0199903/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Amino Acid Transport System y+/*drug effects ; Cocaine-Related Disorders/*drug therapy ; Double-Blind Method ; Female ; Humans ; Male ; Psychiatric Status Rating Scales ; Psychological Tests ; Secondary Prevention ; Treatment Outcome ; }, abstract = {BACKGROUND: There remains no FDA approved medication for the treatment of cocaine dependence. Preclinical studies and early pilot clinical investigations have suggested that N-acetylcysteine (NAC) may be useful in the treatment of the disorder.<br><br>OBJECTIVE: The present report assessed the efficacy of NAC in the treatment of cocaine dependence.<br><br>METHODS: Cocaine-dependent volunteers (n = 111) were randomized to receive daily doses of 1,200 mg of NAC, 2,400 mg of NAC, or placebo. Participants were followed for 8 weeks (up to three visits weekly). At each of these visits, urine samples were collected, along with self-reports of cocaine use. Urine samples were assessed for quantitative levels of benzoylecognine (ie, cocaine metabolite).<br><br>RESULTS: Overall, the primary results for the clinical trial were negative. However, when considering only subjects who entered the trial having already achieved abstinence, results favored the 2,400 mg NAC group relative to placebo, with the 2,400 mg group having longer times to relapse and lower craving ratings.<br><br>CONCLUSION: While the present trial failed to demonstrate that NAC reduces cocaine use in cocaine-dependent individuals actively using, there was some evidence it prevented return to cocaine use in individuals who had already achieved abstinence from cocaine.<br><br>SCIENTIFIC SIGNIFICANCE: N-acetylcysteine may be useful as a relapse prevention agent in abstinent cocaine-dependent individuals.}, }
@article {pmid23950953, year = {2013}, author = {Chu, CS and Wang, YC and Lu, LS and Walton, B and Yilmaz, HR and Huang, RY and Sawamura, T and Dixon, RA and Lai, WT and Chen, CH and Lu, J}, title = {Electronegative low-density lipoprotein increases C-reactive protein expression in vascular endothelial cells through the LOX-1 receptor.}, journal = {PloS one}, volume = {8}, number = {8}, pages = {e70533}, pmid = {23950953}, issn = {1932-6203}, support = {R01 HL063364/HL/NHLBI NIH HHS/United States ; HL-63364/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Anticholesteremic Agents/therapeutic use ; Atorvastatin ; C-Reactive Protein/analysis/*metabolism ; Cells, Cultured ; Endothelial Cells/*metabolism ; Female ; Heptanoic Acids/therapeutic use ; Humans ; Hypercholesterolemia/blood/drug therapy/metabolism ; Lipoproteins, LDL/blood/*metabolism ; Male ; Middle Aged ; Pyrroles/therapeutic use ; Reactive Oxygen Species/metabolism ; Scavenger Receptors, Class E/*metabolism ; }, abstract = {OBJECTIVES: Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1.<br><br>METHODS AND RESULTS: Plasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6&#xb1;20 mg/dL; n&#x200a;=&#x200a;7) patients and normocholesterolemic (LDL-C levels, 86.1&#xb1;21 mg/dL; P<0.001; n&#x200a;=&#x200a;7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5] &#x200a;=&#x200a; L5% &#xd7; LDL-C) in the patient and control groups were 8.1&#xb1;2% vs. 2.3&#xb1;1% (P<0.001) and 12.6&#xb1;4 mg/dL vs. 1.9&#xb1;1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6&#xb1;4 mg/dL to 4.5&#xb1;1.1 mg/dL (P&#x200a;=&#x200a;0.011; n&#x200a;=&#x200a;5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine.<br><br>CONCLUSIONS: Our results suggest that CRP, L5, and LOX-1 form a cyclic mechanism in atherogenesis and that reducing plasma L5 levels with atorvastatin disrupts the vascular toxicity of L5.}, }
@article {pmid23950593, year = {2013}, author = {Li, YB and Gao, JL and Zhong, ZF and Hoi, PM and Lee, SM and Wang, YT}, title = {Bisdemethoxycurcumin suppresses MCF-7 cells proliferation by inducing ROS accumulation and modulating senescence-related pathways.}, journal = {Pharmacological reports : PR}, volume = {65}, number = {3}, pages = {700-709}, doi = {10.1016/s1734-1140(13)71048-x}, pmid = {23950593}, issn = {2299-5684}, mesh = {Acetylcysteine/metabolism/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cellular Senescence/*drug effects ; Curcumin/*analogs &amp; derivatives/pharmacology ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Diarylheptanoids ; Humans ; MCF-7 Cells ; Membrane Potential, Mitochondrial/drug effects ; Nitrogen Oxides ; Reactive Oxygen Species/*metabolism ; Retinoblastoma Protein/metabolism ; Signal Transduction/*drug effects ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {BACKGROUND: Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin present in the phenolic components extracted from the dried rhizome of Curcuma longa L. BDMC demonstrated potential chemotherapeutic activities but the underlying mechanisms have not been fully clarified. In the present study, the role of reactive oxidative species (ROS) in the anti-cancer effects of BDMC was investigated.<br><br>METHODS: MCF-7 cells were exposed to BDMC, and then the cell proliferation, colony formation ability and cell cycle profile were analyzed. Cellular ROS level was determined by flow cytometry and fluorescent microscope observation using specific fluorescent probes. Mitochondrial membrane potential (&#x3c8;m) was assessed using JC-1. In addition, effects of BDMC on senescence-related molecules were analyzed by western blot assay.<br><br>RESULTS: BDMC significantly inhibited MCF-7 breast cancer cell proliferation, while a rapid rise of the intracellular ROS level accompanied with a reduction of Dym were observed. In addition, BDMC activated the pro-apoptotic protein p53 and its downstream effector p21 as well as the cell cycle regulatory proteins p16 and its downstream effector retinoblastoma protein (Rb). All of these BDMC-induced effects were counteracted with the pre-incubation of the antioxidant N-acetylcysteine (NAC).<br><br>CONCLUSIONS: These results suggested that BDMC-induced ROS accumulation may contribute to its inhibitory effect on MCF-7 cell viability through regulation of p53/p21 and p16/Rb pathways.}, }
@article {pmid23948867, year = {2013}, author = {Kundu, S and Sengupta, S and Bhattacharyya, A}, title = {NF-κB acts downstream of EGFR in regulating low dose cadmium induced primary lung cell proliferation.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {26}, number = {6}, pages = {897-911}, doi = {10.1007/s10534-013-9666-7}, pmid = {23948867}, issn = {1572-8773}, mesh = {Animals ; Cadmium Chloride/*pharmacology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Epithelial Cells/cytology/*drug effects/metabolism ; ErbB Receptors/antagonists &amp; inhibitors/*genetics/metabolism ; Gene Expression Regulation ; Lung/cytology/drug effects/metabolism ; Male ; Mice ; Primary Cell Culture ; RNA, Small Interfering/genetics/metabolism ; Respiratory Mucosa/cytology/drug effects/metabolism ; Signal Transduction ; Transcription Factor RelA/antagonists &amp; inhibitors/*genetics/metabolism ; }, abstract = {Apart from cytotoxicity cadmium has no special attributes towards cell's physiological function. The role of cadmium with respect to cell growth is still under debate. Mitogen activated protein kinase and Ca(2+)/calmodulin dependent protein kinase dependent pathways are the two elaborately studied concerning cadmium induced cell proliferation. Low concentration of cadmium chloride (2.5 μM) was applied to mice primary lung epithelial cells and cell proliferation was measured both by cell cycle analysis and Brdu incorporation assay. Effects of differential dose of cadmium chloride on lung epithelial cells were evaluated morphologically by atomic force microscopy. RT-PCR and western blot altogether corroborated the specific signalling pathways concerning cadmium induced lung cell proliferation. Cadmium induced lung epithelial cells which over-expressed EGFR, were transfected with siEGFR, revealed downstream molecules and RNAi induced EGFR silencing. Use of siEGFR effectively prevents expression of proinflammatory and cell proliferative markers. Moreover N-acetyl cysteine and ascorbic acid mediated inhibition of EGFR and downstream signalling molecules indicate the involvement of reactive oxygen species. Exposure to low concentration of cadmium promotes the growth of primary mice lung epithelial cell by EGFR signalling. We have also transfected the primary lung epithelial cell with siRNA against the regulatory subunit of nuclear factor-κB (NF-κB) and the data shows that cadmium induced lung cell proliferation is the effect of EGFR mediated NF-κB activation.}, }
@article {pmid23948373, year = {2013}, author = {Weng, SW and Kuo, HM and Chuang, JH and Lin, TK and Huang, HL and Lin, HY and Liou, CW and Wang, PW}, title = {Study of insulin resistance in cybrid cells harboring diabetes-susceptible and diabetes-protective mitochondrial haplogroups.}, journal = {Mitochondrion}, volume = {13}, number = {6}, pages = {888-897}, doi = {10.1016/j.mito.2013.08.001}, pmid = {23948373}, issn = {1872-8278}, mesh = {Blotting, Western ; Cell Line, Tumor ; Diabetes Mellitus/*genetics ; Flow Cytometry ; *Genetic Predisposition to Disease ; Glucose Transporter Type 1/metabolism ; Glucose Transporter Type 4/metabolism ; *Haplotypes ; Humans ; *Insulin Resistance ; MAP Kinase Signaling System ; Protein Transport ; Reactive Oxygen Species/metabolism ; }, abstract = {AIM: This study aims to elucidate the independent role of mitochondria in the pathogenesis of insulin resistance (IR).<br><br>METHODS: Cybrids derived from 143B osteosarcoma cell line and harboring the same nuclear DNA but different mitochondrial haplogroups were studied. Cybrid B4 (the major diabetes-susceptible haplogroup in Chinese population), cybrid D4 (the major diabetes-resistant haplogroup in Chinese population) and cybrid N9 (the diabetes-resistant haplogroup in Japanese population) were cultured in a medium containing 25 mM glucose and stimulated with 0 &#x3bc;M, 0.1 &#x3bc;M, and 1.0 &#x3bc;M insulin. We compared the insulin activation of PI3K-Akt (glucose uptake) and ERK-MAPK (pro-inflammation) signaling pathways, intracellular and mitochondrial oxidative stress (DCF and MitoSOX Red), and their responses to the antioxidant N-acetylcysteine (NAC).<br><br>RESULTS: Upon insulin treatment, the translocation of cytoplasmic GLUT1/GLUT4 to the cell membrane in cybrid D4 and N9 cells increased significantly, whereas the changes in B4 cells were not or less significant. On the contrary, the ratio of insulin-induced JNK and P38 to Akt phosphorylation was significantly greater in cybrid B4 cells than in cybrid D4 and N9 cells. The levels of DCF and MitoSOX Red, which are indicative of the oxidative stress, were significantly higher in the B4 cells in basal conditions and after insulin treatment. Following treatment with the antioxidant NAC, cybrid B4 cells showed significantly reduced insulin-induced phosphorylation of P38 and increased GLUT1/GLUT4 translocation to the cell membrane, suggesting that NAC may divert insulin signaling from pro-inflammation to glucose uptake.<br><br>CONCLUSIONS: Mitochondria play an independent role in the pathogenesis of IR, possibly through altered production of intracellular ROS.}, }
@article {pmid23946126, year = {2014}, author = {Yoo, J and Hamilton, SJ and Angel, D and Fung, K and Franklin, J and Parnes, LS and Lewis, D and Venkatesan, V and Winquist, E}, title = {Cisplatin otoprotection using transtympanic L-N-acetylcysteine: a pilot randomized study in head and neck cancer patients.}, journal = {The Laryngoscope}, volume = {124}, number = {3}, pages = {E87-94}, doi = {10.1002/lary.24360}, pmid = {23946126}, issn = {1531-4995}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Audiometry/methods ; Auditory Threshold/drug effects ; Cisplatin/*adverse effects/therapeutic use ; Feasibility Studies ; Female ; Follow-Up Studies ; Head and Neck Neoplasms/*drug therapy/pathology ; Hearing Loss, Sensorineural/*chemically induced/*prevention &amp; control ; Humans ; Injections, Intralesional ; Male ; Middle Aged ; Prospective Studies ; Reference Values ; Risk Assessment ; Treatment Outcome ; Tympanic Membrane/drug effects ; }, abstract = {OBJECTIVES/HYPOTHESIS: To evaluate the feasibility and efficacy of transtympanic L-N-Acetylcysteine (L-NAC) administration in patients receiving cisplatin chemotherapy for head and neck cancer.<br><br>STUDY DESIGN: Prospective randomized nonblinded open-label clinical trial.<br><br>METHODS: Transtympanic 2% L-NAC was administered to one randomly selected ear with the other ear as control in each patient. Primary outcome parameter was the difference in the loss of pure tone averages (PTA) at 2, 4, and 8 kHz between the L-NAC and control ear at 1 to 2 months following chemotherapy.<br><br>RESULTS: Eleven patients completed the study, with two patients demonstrating significantly better hearing in the L-NAC treated ear (18.2%). However, for the overall group, the difference in hearing preservation did not reach significance. Two percent L-NAC administration was well tolerated in this patient population. There were no adverse effects associated with L-NAC.<br><br>CONCLUSION: Although the study did not demonstrate a significant benefit overall, transtympanic L-NAC was associated with significantly better hearing in two patients. Better delivery methods may improve the efficacy of this treatment. L-NAC remains a promising drug in preventing cisplatin-induced ototoxicity.}, }
@article {pmid23945523, year = {2013}, author = {Atabek Yigit, E and Ercal, N}, title = {Release of N-acetylcysteine and N-acetylcysteine amide from contact lenses.}, journal = {Eye &amp; contact lens}, volume = {39}, number = {5}, pages = {335-340}, doi = {10.1097/ICL.0b013e3182a2f8bc}, pmid = {23945523}, issn = {1542-233X}, mesh = {Acetylcysteine/*administration &amp; dosage/analogs &amp; derivatives ; Antioxidants/*administration &amp; dosage ; Chromatography, High Pressure Liquid ; *Contact Lenses, Hydrophilic ; *Drug Delivery Systems ; Free Radical Scavengers/*administration &amp; dosage ; }, abstract = {OBJECTIVE: To investigate the use of contact lenses to release N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) that have frequently used for the treatment of some eye diseases.<br><br>METHODS: Three commercial contact lenses were used: Soflens Multi-Focal, 1-Day ACUVUE TruEye, and Frequency 55. All contact lenses were individually kept for 3 days in 10 mL of 3 mM NAC or NACA solutions in phosphate-buffered saline (PBS). After the loading period, the lenses were removed from the solution and put into 5 mL of PBS for 3 days (static mode). During this period, samples were taken at specified times and analyzed by high-pressure liquid chromatography.<br><br>RESULTS: From the release profiles of NAC and NACA, it was found that both NAC and NACA could be released from the lenses within 72 hours. Frequency 55 released 95.9%&#xb1;2.7% of loaded NAC and 60.0%&#xb1;2.1% of loaded NACA in 24 hours, whereas 1-Day ACUVUE TruEye released 80.9%&#xb1;1.2% of loaded NAC and 54.0%&#xb1;1.9% of loaded NACA and Soflens Multi-Focal released 72.8%&#xb1;2.8% of loaded NAC and 51.9%&#xb1;2.3% of loaded NACA during that same period.<br><br>CONCLUSIONS: The lenses could achieve the appropriate delivery of drugs during their intended time of wear. The amount of released NACA was less than that of NAC because of the more hydrophobic structure of NACA. According to the power law, the values of the exponential constant n were found to be below 0.5, indicating that the behavior observed was "less Fickian".}, }
@article {pmid23935350, year = {2013}, author = {Orün, E and Polat, A and Andan, H and Cizmeci, N and Tufan, N}, title = {Incorrect prescription of intravenous paracetamol in a pediatric patient.}, journal = {Hippokratia}, volume = {17}, number = {1}, pages = {77-78}, pmid = {23935350}, issn = {1108-4189}, abstract = {Intravenous (IV) paracetamol is widely used for the treatment of pain and fever, when there is a clinical indication for an IV route. A 16-month-old girl weighing 12 kg had undergone anterior open reduction for developmental dysplasia of the hip. Twenty-four hours after the operation, IV paracetamol (Perfalgan® 10 mg/ml) infusion was started for the postoperative pain management. After 12 hours' infusion, she has developed nausea, vomiting and agitation. The liver function tests were found to be more than 10-fold elevated on the laboratory results. When the medication order was checked, it was shown that she had been administered paracetamol 5 times at a dose of 42 mg/kg (total: 2.5 g/30 hours or 168 mg/kg/24 hours). The patient was started on N-acetyl cysteine (NAC) therapy immediately. She was asymptomatic at the 36th hour of the NAC treatment and the liver function tests completely recovered over 15 days. Since the errors in the calculation of the dosage of IV paracetamol may lead to serious complications or even death, physicians should be careful not to miscalculate when preferring the IV form of the drug.}, }
@article {pmid23933437, year = {2013}, author = {Di Rosso, ME and Barreiro Arcos, ML and Elingold, I and Sterle, H and Baptista Ferreira, S and Ferreira, VF and Galleano, M and Cremaschi, G and Dubin, M}, title = {Novel o-naphthoquinones induce apoptosis of EL-4 T lymphoma cells through the increase of reactive oxygen species.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {27}, number = {7}, pages = {2094-2104}, doi = {10.1016/j.tiv.2013.08.002}, pmid = {23933437}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/antagonists &amp; inhibitors/*pharmacology ; Apoptosis/*drug effects ; Benzopyrans/antagonists &amp; inhibitors/pharmacology ; Benzoquinones/metabolism ; Cell Line, Tumor ; Cell Nucleus Shape/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chromatin Assembly and Disassembly/drug effects ; Free Radical Scavengers/pharmacology ; Glutathione/antagonists &amp; inhibitors/metabolism ; Kinetics ; Lymphoma, T-Cell/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Naphthoquinones/antagonists &amp; inhibitors/*pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Trypanocidal Agents/antagonists &amp; inhibitors/pharmacology ; Up-Regulation/*drug effects ; }, abstract = {Novel β-lapachone analogs 2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ1), 2-p-tolyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ3) and 2-methyl-2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ7), which have trypanocidal activity, were assayed for cytotoxic effects on murine EL-4 T lymphoma cells. The NQs inhibited the proliferation of EL-4 cells at concentrations above 1μM. Nuclear staining of the EL-4 cells revealed chromatin condensation and a nuclear morphology compatible with the induction of apoptosis. Flow cytometry assays with annexin V-FITC and propidium iodide confirmed the cell death by apoptosis. Using electron paramagnetic resonance (EPR), a semiquinone radical was detected in EL-4 cells treated with NQs. In addition, a decrease in the GSH level in parallel with reactive oxygen species (ROS) production was observed. Preincubation with n-acetyl-l-cysteine (NAC) was able to reverse the inhibitory effects of the NQs on cell proliferation, indicating that ROS generation is involved in NQ-induced apoptosis. In addition, the NQs induced a decrease in the mitochondrial membrane potential and increased the proteolytic activation of caspases 9 and 3 and the cleavage of Poly (ADP-Ribose) Polymerase (PARP). In conclusion, these results indicate that redox cycling is induced by the NQs in the EL-4 cell line, with the generation of ROS and other free radicals that could inhibit cellular proliferation as a result of the induction of the intrinsic apoptosis pathway.}, }
@article {pmid23932324, year = {2014}, author = {Suzuki, Y and Mitsushima, S and Kato, A and Yamaguchi, T and Ichihara, S}, title = {High-phosphorus/zinc-free diet aggravates hypertension and cardiac dysfunction in a rat model of the metabolic syndrome.}, journal = {Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology}, volume = {23}, number = {1}, pages = {43-49}, doi = {10.1016/j.carpath.2013.06.004}, pmid = {23932324}, issn = {1879-1336}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Blood Pressure ; Collagen/metabolism ; Connective Tissue Growth Factor/metabolism ; Diastole ; Disease Models, Animal ; Fibrosis ; Hypertension/*etiology/metabolism/physiopathology ; Male ; Metabolic Syndrome/*complications/drug therapy/metabolism/physiopathology ; Metallothionein/metabolism ; Myocardium/pathology ; Phosphorus, Dietary/*adverse effects ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Systole ; Ventricular Dysfunction, Left/*etiology/metabolism/pathology/physiopathology/prevention &amp; control ; Ventricular Function, Left ; Zinc/*deficiency ; }, abstract = {BACKGROUND: Cardiac dysfunction is reported in patients with the metabolic syndrome. We assessed the effects of high-phosphorus and zinc-free diet on cardiovascular system in spontaneously hypertensive rats (SHR)/NDmcr-cp (SHR/cp), a rat model of the metabolic syndrome. We also investigated the effects of N-acetyl-L-cysteine (NAC), an antioxidant, on the development of cardiac dysfunction under such conditions.<br><br>METHODS: Male SHR/cp and control [Wistar Kyoto (WKY)] rats were divided into three groups and fed control diet (P 0.3% w/w, Zn 0.2% w/w) or high-phosphorus and zinc-free (P 1.2% w/w, Zn 0.0% w/w) diet. The latter group was treated with either NAC (1.5 mg/g per day) or vehicle from 6 to 18 weeks of age (n=6 or 8 for each group).<br><br>RESULTS: High-phosphate and zinc-free diet increased systolic blood pressure in both WKY and SHR/cp. Echocardiography showed that high-phosphate and zinc-free diet markedly reduced left ventricular systolic and diastolic function in SHR/cp. Histopathologically, the same diet induced severe myocardial fibrosis in SHR/cp, and this effect was prevented by NAC. Whereas treatment with NAC prevented diastolic dysfunction induced by the same diet in WKY, it only improved systolic function but not diastolic function in SHR/cp.<br><br>CONCLUSIONS: High-phosphate and zinc-free diet induced hypertension and cardiac dysfunction. These changes hamper the protective effects of NAC in the metabolic syndrome.<br><br>SUMMARY: The present study showed that consumption of high-phosphorus and zinc-free diet increased the myocardial expression of connective tissue growth factor and reduced the expression of metallothionein, which enhanced the development of severe cardiac dysfunction in rats with the metabolic syndrome. The results suggest that the metabolic syndrome seems to aggravate cardiac dysfunction and hamper the protective effects of antioxidant, NAC.}, }
@article {pmid23929884, year = {2013}, author = {Blasi, A and Caballo, C and Galán, AM and Taura, P and Beltran, J and Escolar, G and Lozano, M}, title = {The addition of MESNA in vitro prolongs prothrombin time similar to N-acetyl cysteine.}, journal = {Clinical chemistry and laboratory medicine}, volume = {51}, number = {12}, pages = {e297-9}, doi = {10.1515/cclm-2013-0344}, pmid = {23929884}, issn = {1437-4331}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Blood Coagulation/drug effects ; Humans ; Mesna/chemistry/*pharmacology ; *Prothrombin Time ; Time Factors ; }, }
@article {pmid23928261, year = {2013}, author = {Bai, F and Ni, B and Liu, M and Feng, Z and Xiong, Q and Xiao, S and Shao, G}, title = {Mycoplasma hyopneumoniae-derived lipid-associated membrane proteins induce apoptosis in porcine alveolar macrophage via increasing nitric oxide production, oxidative stress, and caspase-3 activation.}, journal = {Veterinary immunology and immunopathology}, volume = {155}, number = {3}, pages = {155-161}, doi = {10.1016/j.vetimm.2013.07.004}, pmid = {23928261}, issn = {1873-2534}, mesh = {Animals ; Apoptosis/*drug effects ; Bacterial Proteins/*pharmacology ; Caspase 3/*physiology ; Cells, Cultured ; Enzyme Activation ; Intercellular Signaling Peptides and Proteins ; Macrophages, Alveolar/*physiology ; Membrane Proteins/*pharmacology ; Mycoplasma hyopneumoniae/*pathogenicity ; Nitric Oxide/*biosynthesis ; *Oxidative Stress ; Peptides/*pharmacology ; Superoxides/metabolism ; Swine ; }, abstract = {Mycoplasma hyopneumoniae is the primary etiological agent of enzootic pneumonia in swine. Lipid-associated membrane proteins (LAMP) of mycoplasma are the main pathogenicity factors in mycoplasma diseases. In this study, we investigated the effects of M. hyopneumoniae LAMP on porcine alveolar macrophage (PAM) 3D4/21 cell line. Apoptotic features, such as chromatin condensation and apoptotic bodies, were observed in LAMP-treated PAM 3D4/21 cells. Moreover, LAMP significantly increased the number of TUNEL positive apoptotic cells in PAM 3D4/21 cells compared with the untreated control. In addition, flow cytometric analysis using dual staining with annexin-V-FITC and propidium iodide (PI) showed that LAMP of M. hyopneumoniae induced a time-dependent apoptosis in PAM 3D4/21 cells. Moreover, increased levels of superoxide anion production and activated caspase-3 in PAM 3D4/21 cells were observed after exposure to LAMP. Increased production of nitric oxide (NO) was also confirmed in the cell supernatants. Besides, apoptotic rates increase and caspase-3 activation were suppressed by NOS inhibitor or antioxidant. It is suggested that LAMP of M. hyopneumoniae induced apoptosis in porcine alveolar macrophage via NO production, superoxide anion production, and caspase-3 activation.}, }
@article {pmid23925941, year = {2013}, author = {Taslipinar, MY and Aydin, I and Kaldirim, U and Aydin, FN and Agilli, M and Eyi, YE and Tuncer, SK and Altayli, E and Ucar, F and Macit, E and Toygar, M and Yigit, N and Cayci, T}, title = {Hyperbaric oxygen treatment and N-acetylcysteine ameliorate acetaminophen-induced liver injury in a rat model.}, journal = {Human &amp; experimental toxicology}, volume = {32}, number = {10}, pages = {1107-1116}, doi = {10.1177/0960327113499167}, pmid = {23925941}, issn = {1477-0903}, mesh = {*Acetaminophen ; Acetylcysteine/pharmacology/*therapeutic use ; *Analgesics, Non-Narcotic ; Animals ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Chemical and Drug Induced Liver Injury/etiology/pathology/*therapy ; Disease Models, Animal ; *Hyperbaric Oxygenation ; Interleukin-6/metabolism ; Liver/drug effects/metabolism/pathology ; Male ; Neopterin/metabolism ; Protective Agents/pharmacology/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {An overdose of acetaminophen (APAP) produces centrilobular hepatocellular necrosis. We aimed to investigate the hepatoprotective effects of N-acetylcysteine (NAC) only and hyperbaric oxygen (O(2)) treatment (HBOT) combined with NAC, and their anti-inflammatory properties in liver tissue. In the current study, a total of 32 male Sprague Dawley rats were divided into 4 groups: sham, APAP, NAC, and NAC + HBOT. In the APAP, NAC, and NAC + HBOT groups, liver injury was induced by oral administration of 1 g/kg APAP. The NAC group received 100 mg/kg NAC per day. NAC + HBOT group received intraperitoneal injection of 100 mg/kg/day NAC and were given HBOT at 2.8 ATA pressure with 100% O(2) inhalation for 90 min every 12 h for 5 days. Rats in the sham group received distilled water only by gastric tube. All animals were killed on day 6 after APAP or distilled water administration. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, hepatic neopterin, tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) levels were measured. There was a significant increase in serum AST and ALT activities in the APAP group compared with the sham group (in both p = 0.001). NAC and NAC + HBOT groups had significant decreases in hepatic neopterin, TNF-α, and IL-6 levels compared with the APAP group. APAP administration caused extensive hepatic necrosis. NAC and NAC + HBO treatments significantly reduced APAP-induced liver injury. Our results showed that the liver damage in APAP toxicity was attenuated by NAC and NAC + HBO treatments. NAC + HBOT exhibit hepatoprotective activity against APAP-induced liver injury in rats.}, }
@article {pmid23922799, year = {2013}, author = {Lin, CY and Huang, CC and Wang, WD and Hsiao, CD and Cheng, CF and Wu, YT and Lu, YF and Hwang, SP}, title = {Low temperature mitigates cardia bifida in zebrafish embryos.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e69788}, pmid = {23922799}, issn = {1932-6203}, mesh = {Animals ; Cell Movement/genetics ; Chromosome Mapping ; *Cold Temperature ; Embryo, Nonmammalian/*abnormalities/*metabolism ; Extracellular Matrix/genetics ; Fibronectins/genetics/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Gene Ontology ; Heart Defects, Congenital/*embryology/*prevention &amp; control ; Mutation/genetics ; Myocardium/metabolism/pathology ; Phenotype ; Reactive Oxygen Species/metabolism ; Time Factors ; Zebrafish/*embryology/genetics ; Zebrafish Proteins/genetics/metabolism ; }, abstract = {The coordinated migration of bilateral cardiomyocytes and the formation of the cardiac cone are essential for heart tube formation. We investigated gene regulatory mechanisms involved in myocardial migration, and regulation of the timing of cardiac cone formation in zebrafish embryos. Through screening of zebrafish treated with ethylnitrosourea, we isolated a mutant with a hypomorphic allele of mil (s1pr2)/edg5, called s1pr2(as10) (as10). Mutant embryos with this allele expressed less mil/edg5 mRNA and exhibited cardia bifida prior to 28 hours post-fertilization. Although the bilateral hearts of the mutants gradually fused together, the resulting formation of two atria and one tightly-packed ventricle failed to support normal blood circulation. Interestingly, cardia bifida of s1pr2(as10) embryos could be rescued and normal circulation could be restored by incubating the embryos at low temperature (22.5°C). Rescue was also observed in gata5 and bon cardia bifida morphants raised at 22.5 °C. The use of DNA microarrays, digital gene expression analyses, loss-of-function, as well as mRNA and protein rescue experiments, revealed that low temperature mitigates cardia bifida by regulating the expression of genes encoding components of the extracellular matrix (fibronectin 1, tenascin-c, tenascin-w). Furthermore, the addition of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, significantly decreased the effect of low temperature on mitigating cardia bifida in s1pr2(as10) embryos. Our study reveals that temperature coordinates the development of the heart tube and somitogenesis, and that extracellular matrix genes (fibronectin 1, tenascin-c and tenascin-w) are involved.}, }
@article {pmid23922721, year = {2013}, author = {Ma, J and Zhang, Q and Chen, S and Fang, B and Yang, Q and Chen, C and Miele, L and Sarkar, FH and Xia, J and Wang, Z}, title = {Mitochondrial dysfunction promotes breast cancer cell migration and invasion through HIF1α accumulation via increased production of reactive oxygen species.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e69485}, pmid = {23922721}, issn = {1932-6203}, mesh = {Blotting, Western ; Breast Neoplasms/genetics/*metabolism ; Cell Line, Tumor ; Cell Movement/physiology ; Electrophoresis, Polyacrylamide Gel ; Female ; Humans ; Hydrogen Peroxide/*metabolism ; Mitochondria/*metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Wound Healing/*physiology ; }, abstract = {Although mitochondrial dysfunction has been observed in various types of human cancer cells, the molecular mechanism underlying mitochondrial dysfunction mediated tumorigenesis remains largely elusive. To further explore the function of mitochondria and their involvement in the pathogenic mechanisms of cancer development, mitochondrial dysfunction clones of breast cancer cells were generated by rotenone treatment, a specific inhibitor of mitochondrial electron transport complex I. These clones were verified by mitochondrial respiratory defect measurement. Moreover, those clones exhibited increased reactive oxygen species (ROS), and showed higher migration and invasive behaviors compared with their parental cells. Furthermore, antioxidant N-acetyl cysteine, PEG-catalase, and mito-TEMPO effectively inhibited cell migration and invasion in these clones. Notably, ROS regulated malignant cellular behavior was in part mediated through upregulation of hypoxia-inducible factor-1 α and vascular endothelial growth factor. Our results suggest that mitochondrial dysfunction promotes cancer cell motility partly through HIF1α accumulation mediated via increased production of reactive oxygen species.}, }
@article {pmid23921797, year = {2013}, author = {Rasul, A and Di, J and Millimouno, FM and Malhi, M and Tsuji, I and Ali, M and Li, J and Li, X}, title = {Reactive oxygen species mediate isoalantolactone-induced apoptosis in human prostate cancer cells.}, journal = {Molecules (Basel, Switzerland)}, volume = {18}, number = {8}, pages = {9382-9396}, pmid = {23921797}, issn = {1420-3049}, mesh = {Apoptosis/*drug effects ; Cell Line, Tumor ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; }, abstract = {Isoalantolactone, a medicinal plant-derived natural compound, is known to induce apoptosis in various cancer cell lines. However, its effect on apoptosis in prostate cancer cells has not been addressed. Thus, we examined the effects of isoalantolactone on prostate cancer cells. It was found that isoalantolactone inhibits growth of both androgen-sensitive (LNCaP) as well as androgen-independent (PC3 and DU-145) prostate cancer cells in a dose-dependent manner. Furthermore, our results indicate that isoalantolactone-induced apoptosis in prostate cancer PC3 cells is associated with the generation of ROS and dissipation of mitochondrial membrane potential (Δψm). In addition, isoalantolactone triggers apoptosis in prostate cancer cells via up-regulation of Bax, down-regulation of Bcl-2, survivin, and significant activation of caspase-3. Isoalantolactone-induced apoptosis is markedly abrogated when the cells were pretreated with N-acetylcysteine (NAC), a specific ROS inhibitor, suggesting that the apoptosis-inducing effect of isoalantolactone in prostate cancer cells is mediated by reactive oxygen species. These findings indicate that isoalantolactone induces reactive oxygen species-dependent apoptosis in prostate cancer cells via a novel mechanism involving inhibition of survivin and provide the rationale for further in vivo and preclinical investigation of isoalantolactone against human prostate cancer.}, }
@article {pmid23919090, year = {2013}, author = {Squires, S and Christians, E and Riedel, M and Timothy, D and Rodesch, CK and Marvin, J and Benjamin, I}, title = {Effects of redox state on the efficient uptake of cell permeable Peptide in Mammalian cells.}, journal = {The open biochemistry journal}, volume = {7}, number = {}, pages = {54-65}, pmid = {23919090}, issn = {1874-091X}, support = {DP1 OD006438/OD/NIH HHS/United States ; R01 HL074370/HL/NHLBI NIH HHS/United States ; T32 HL007576/HL/NHLBI NIH HHS/United States ; }, abstract = {We investigated whether a cell-penetrating peptide linked via a disulfide bond to a fluorophore-labeled cargo peptide can be used to interrogate changes in cellular redox state. A fluorescence resonance energy transfer (FRET) pair was constructed so that the cargo peptide was labeled with fluorescein amidite (FAM) and the cell-penetrating peptide was attached to a quencher. Incubation of cells in culture with the FRET construct was visualized using live-cell, time-lapse imaging, which demonstrated earlier cellular uptake of the construct when cells were treated with the reducing agent n-acetylcysteine (NAC). The FRET peptide construct was easily detected in cells cultured in 96-well plates using a plate-reader. Treatment of cells with various classes of reducing or oxidizing agents resulted in an increase or decrease in FAM fluorescence, respectively. Changes in FAM fluorescence correlated significantly with redox-sensitive green fluorescent protein ratios in cells treated with hydrogen peroxide but not NAC. Detection of relative changes in cellular redox state was enhanced by the fact that uptake of the cell-penetrating peptide occurred more quickly in relatively reduced compared with oxidized cells. We conclude that cell-penetrating peptides coupled via disulfide bonds to detectable cargo is a novel and specific approach for assessment of relative changes in cellular thiol redox state.}, }
@article {pmid23917396, year = {2013}, author = {Chang, PY and Peng, SF and Lee, CY and Lu, CC and Tsai, SC and Shieh, TM and Wu, TS and Tu, MG and Chen, MY and Yang, JS}, title = {Curcumin-loaded nanoparticles induce apoptotic cell death through regulation of the function of MDR1 and reactive oxygen species in cisplatin-resistant CAR human oral cancer cells.}, journal = {International journal of oncology}, volume = {43}, number = {4}, pages = {1141-1150}, doi = {10.3892/ijo.2013.2050}, pmid = {23917396}, issn = {1791-2423}, mesh = {ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1/*biosynthesis/genetics ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/therapeutic use ; Curcumin/*administration &amp; dosage/chemistry ; Drug Resistance, Neoplasm/*drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mouth Neoplasms/*drug therapy/genetics/pathology ; Nanoparticles/administration &amp; dosage/chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {Curcumin is a polyphenolic compound which possesses anticancer potential. It has been shown to induce cell death in a variety of cancer cells, however, its effect on CAL27‑cisplatin-resistant human oral cancer cells (CAR cells) has not been elucidated to date. The low water solubility of curcumin which leads to poor bioavailability, however, has been highlighted as a major limiting factor. In this study, we utilized water-soluble PLGA curcumin nanoparticles (Cur-NPs), and investigated the effects of Cur-NPs on CAR cells. The results showed Cur-NPs induced apoptosis in CAR cells but exhibited low cytotoxicity to normal human gingival fibroblasts (HGFs) and normal human oral keratinocytes (OKs). Cur-NPs triggered DNA concentration, fragmentation and subsequent apoptosis. Compared to untreated CAR cells, a more detectable amount of Calcein-AM accumulation was found inside the treated CAR cells. Cur-NPs suppressed the protein and mRNA expression levels of MDR1. Both the activity and the expression levels of caspase-3 and caspase-9 were elevated in the treated CAR cells. The Cur-NP-triggered apoptosis was blocked by specific inhibitors of pan-caspase (z-VAD-fmk), caspase-3 (z-DEVD-fmk), caspase-9 (z-LEHD-fmk) and antioxidant agent (N-acetylcysteine; NAC). Cur-NPs increased reactive oxygen species (ROS) production, upregulated the protein expression levels of cleaved caspase-3/caspase-9, cytochrome c, Apaf-1, AIF, Bax and downregulated the protein levels of Bcl-2. Our results suggest that Cur-NPs triggered the intrinsic apoptotic pathway through regulating the function of multiple drug resistance protein 1 (MDR1) and the production of reactive oxygen species (ROS) in CAR cells. Cur-NPs could be potentially efficacious in the treatment of cisplatin-resistant human oral cancer.}, }
@article {pmid23913583, year = {2013}, author = {Showell, MG and Brown, J and Clarke, J and Hart, RJ}, title = {Antioxidants for female subfertility.}, journal = {The Cochrane database of systematic reviews}, volume = {}, number = {8}, pages = {CD007807}, doi = {10.1002/14651858.CD007807.pub2}, pmid = {23913583}, issn = {1469-493X}, support = {095195/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Administration, Oral ; Antioxidants/*administration &amp; dosage ; Female ; Humans ; Infertility, Female/*drug therapy ; Live Birth/epidemiology ; Oxidative Stress ; Pregnancy ; Pregnancy Rate ; }, abstract = {BACKGROUND: A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This difficulty with conception may affect up to a quarter of all couples planning a child. The reported prevalence of subfertility has increased significantly over the past twenty years. It is estimated that for 40% to 50% of couples, subfertility may be a result of female problems, including ovulatory disorders, poor egg quality, fallopian tube damage and endometriosis. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assessed the evidence for the effectiveness of different antioxidants in female subfertility.<br><br>OBJECTIVES: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women.<br><br>SEARCH METHODS: We searched the following databases (from inception to April 2013) with no language restrictions applied: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS and OpenSIGLE. We also searched conference abstracts and citation lists in the ISI Web of Knowledge. Ongoing trials were searched in the Trials Registers. Reference lists were checked, and a search on Google was performed.<br><br>SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. Trials comparing antioxidants with fertility drugs alone and trials that exclusively included fertile women attending a fertility clinic because of male partner infertility were excluded.<br><br>DATA COLLECTION AND ANALYSIS: Three review authors independently screened 2127 titles and abstracts, and 67 of these potentially eligible trials were appraised for inclusion and quality through review of full texts and contact with authors. Three review authors were involved in data extraction and assessment of risk of bias. Review authors also collected data on adverse events as reported from the trials. Studies were pooled using fixed-effect models; however, if high heterogeneity was found, a random-effects model was used. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. Analyses were stratified by type of antioxidant, by indications for subfertility and by those women also undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection techniques (ICSIs). The overall quality of the evidence was assessed by applying GRADE criteria.<br><br>MAIN RESULTS: A total of 28 trials involving 3548 women were included in this review. Investigators compared oral antioxidants, including combinations of antioxidants, pentoxifylline, N-acetyl-cysteine, melatonin, L-arginine, vitamin E, myo-inositol, vitamin C, vitamin D+calcium and omega-3-polyunsaturated fatty acids with placebo, with no treatment/standard treatment or another antioxidant.Antioxidants were not associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 1.25, 95% CI 0.19 to 8.26, P = 0.82, 2 RCTs, 97 women, I(2) = 75%, very low-quality evidence). This suggests that among subfertile women with an expected live birth rate of 37%, the rate among women taking antioxidants would be between 10% and 83%.Antioxidants were not associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.30, 95% CI 0.92 to 1.85, P = 0.14, 13 RCTs, 2441 women, I(2)= 55%, very low-quality evidence). This suggests that among subfertile women with an expected clinical pregnancy rate of 23%, the rate among women taking antioxidants would be between 22% and 36%.Only one trial reported on live birth in the antioxidant versus antioxidant comparison, and two trials reported on clinical pregnancy in this comparison. Only subtotals were used in this analysis, and meta-analysis was not possible as each trial used a different antioxidant.Pentoxifylline was associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.03, 95% CI 1.19 to 3.44, P = 0.009, 3 RCTs, 276 women, I(2) = 0%).Adverse events were reported by 14 trials in the meta-analysis and included miscarriage, multiple pregnancy, ectopic pregnancy and gastrointestinal effects. No evidence revealed a difference in adverse effects between antioxidant groups and control groups, but these data were limited.The overall quality of evidence was 'very low' to 'low' because of poor reporting of outcomes, the number of small studies included, high risk of bias within studies and heterogeneity in the primary analysis.<br><br>AUTHORS' CONCLUSIONS: The quality of the evidence in the 'antioxidant versus placebo/no treatment' and in the 'antioxidant versus antioxidant' comparisons was assessed to be 'very low'. Antioxidants were not associated with an increased live birth rate or clinical pregnancy rate. There was some evidence of an association of pentoxifylline with an increased clinical pregnancy rate; however, there were only three trials included in this comparison. Future trials may change this result. Variation in the types of antioxidants given meant that we could not assess whether one antioxidant was better than another. There did not appear to be any association of antioxidants with adverse effects for women, but data for these outcomes were limited.}, }
@article {pmid23912895, year = {2014}, author = {Katz, A and Hernández, A and Caballero, DM and Briceno, JF and Amezquita, LV and Kosterina, N and Bruton, JD and Westerblad, H}, title = {Effects of N-acetylcysteine on isolated mouse skeletal muscle: contractile properties, temperature dependence, and metabolism.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {466}, number = {3}, pages = {577-585}, pmid = {23912895}, issn = {1432-2013}, support = {IF32AR057619/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Female ; *Hot Temperature ; *Isometric Contraction ; Lactic Acid/metabolism ; Malates/metabolism ; Mice ; Mice, Inbred C57BL ; Muscle Relaxation ; Muscle, Skeletal/*drug effects/metabolism/physiology ; Myosin Light Chains/metabolism ; Phosphates/metabolism ; Phosphorylation ; }, abstract = {The effects of the general antioxidant N-acetylcysteine (NAC) on muscle function and metabolism were examined. Isolated paired mouse extensor digitorum longus muscles were studied in the absence or presence of 20 mM NAC. Muscles were electrically stimulated to perform 100 isometric tetanic contractions (300 ms duration) at frequencies resulting in ∼85% of maximal force (70-150 Hz at 25-40 °C). NAC did not significantly affect peak force in the unfatigued state at any temperature but significantly slowed tetanic force development in a temperature-dependent fashion (e.g., time to 50% of peak tension averaged 35 ± 2 ms [control] and 37 ± 1 ms [NAC] at 25 °C vs. 21 ± 1 ms [control] and 52 ± 6 ms [NAC, P < 0.01] at 40 °C). During repeated contractions, NAC maximally enhanced peak force by the fifth tetanus at all temperatures (by ∼30%). Thereafter, the effect of NAC disappeared rapidly at high temperatures (35-40 °C) and more slowly at the lower temperatures (25-30 °C). At all temperatures, the enhancing effect of NAC on peak force was associated with a slowing of relaxation. NAC did not significantly affect myosin light chain phosphorylation at rest or after five contractions (∼50% increase vs. rest). After five tetani, lactate and inorganic phosphate increased about 20-fold and 2-fold, respectively, both in control and NAC-treated muscles. Interestingly, after five tetani, the increase in glucose 6-P was ∼2-fold greater, whereas the increase in malate was inhibited by ∼75% with NAC vs. control, illustrating the metabolic effects of NAC. NAC slightly decreased the maximum shortening velocity in early fatigue (five to seven repeated tetani). These data demonstrate that the antioxidant NAC transiently enhances muscle force generation by a mechanism that is independent of changes in myosin light chain phosphorylation and inorganic phosphate. The slowing of relaxation suggests that NAC enhances isometric force by facilitating fusion (i.e., delaying force decline between pulses). The initial slowing of tension development and subsequent slowing of relaxation suggest that NAC would result in impaired performance during a high-intensity dynamic exercise.}, }
@article {pmid23912471, year = {2014}, author = {Yamamoto, T and Spencer, T and Dargan, PI and Wood, DM}, title = {Incidence and management of N-acetylcysteine-related anaphylactoid reactions during the management of acute paracetamol overdose.}, journal = {European journal of emergency medicine : official journal of the European Society for Emergency Medicine}, volume = {21}, number = {1}, pages = {57-60}, doi = {10.1097/MEJ.0b013e328364eb22}, pmid = {23912471}, issn = {1473-5695}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*adverse effects ; Adult ; Analgesics, Non-Narcotic/*adverse effects ; Anaphylaxis/*chemically induced/*epidemiology/therapy ; Drug Overdose ; Female ; Humans ; Incidence ; Male ; Retrospective Studies ; }, abstract = {OBJECTIVE: Adverse drug reactions (ADRs) to N-acetylcysteine (NAC) treatment for paracetamol overdose are typically anaphylactoid in origin and occur in 2-48% of treated patients. We explored the incidence and management of NAC ADR in our unit.<br><br>PATIENTS AND METHODS: Case notes of patients who presented with paracetamol overdose and had ADR to NAC between February 2005 and June 2011 were reviewed. A total of 1648 patients presented with suspected paracetamol overdose and 660 received NAC treatment. Within this group, 82 patients had documented NAC-related ADR.<br><br>RESULTS: ADR developed in 12.4% (82/660) of patients receiving intravenous NAC and 59 had full documentation available and were included in this study (34 women, 25 men). ADR occurred in the 15-min (150 mg/kg) bag in 36 cases (61%), 22 in the 4-h (50 mg/kg) bag (37%) and one in the 16-h (100 mg/kg) bag (2%). Symptoms were classified as minimal (n=16, 27%), moderate (n=26, 44%) and severe (n=17, 29%). Asthma and female sex, which are reported risk factors for ADR, did not lead to the development of more severe ADR (P=0.771 and 0.330, respectively). Treatments administered included stopping the NAC infusion (n=32, 54%), administration of antiemetics (n=36, 61%), H1 antihistamines (n=26, 44%), steroids (n=16, 27%), inhaled B2 agonists (n=6, 10%) and adrenaline (n=3, 5%).<br><br>CONCLUSION: The incidence of ADR to NAC was comparable with published studies, although there was no association of severity with asthma or female sex. The management of ADRs is variable, with frequent, inappropriate use of steroids. Education about the pathophysiology of these ADRs may improve management.}, }
@article {pmid23911883, year = {2013}, author = {Peng, H and Yuan, X and Shi, R and Wei, X and Ren, S and Yan, C and Ding, Y and Lin, Y and Fan, D and Yang, M and Zhang, Y and Xiong, D}, title = {PHII-7 inhibits cell growth and induces apoptosis in leukemia cell line K562 as well as its MDR- counterpart K562/A02 through producing reactive oxygen species.}, journal = {European journal of pharmacology}, volume = {718}, number = {1-3}, pages = {459-468}, doi = {10.1016/j.ejphar.2013.07.038}, pmid = {23911883}, issn = {1879-0712}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Damage ; Down-Regulation/drug effects ; Drug Resistance, Multiple/*drug effects ; Humans ; Indoles/*pharmacology ; K562 Cells ; Leukemia/*pathology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Multidrug resistance (MDR) is a major obstacle that hinders the efficacy of chemotherapy in many human malignancies. PHII-7 is a derivative of indirubin, which was designed and synthesized by our laboratory. Our preliminary work indicated its potent antitumor activities in vitro and in vivo. Furthermore, based on the model of MDR cell line, we found its powerful effects in inhibiting the expression of P-glycoprotein (P-gp) and killing multidrug-resistant (MDR) cells with the detailed mechanism remained to be explored. Reactive oxygen species are known for high reactive activity as they possess unmatched electrons. In this study, we showed that PHII-7 generated equal reactive oxygen species in parental K562 and its counterpart MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine(NAC) almost abolished the cytotoxicity of PHII-7. Moreover, NAC abrogated DNA damage, cell cycle arrests and apoptosis induced by PHII-7. Our results collectively indicated that reactive oxygen species production induced by PHII-7 contributed to both apoptosis and cell cycle arrets in MDR K562/A02 cells, thus extending our prior related findings. Notably, JNK phosphorylation was also induced by PHII-7 and pre-incubated of K562/A02 cells with NAC or inhibitor of JNK(SP006125) eliminated P-gp downregulation. Taken together, our results may provide a detailed biochemical basis for further clinical application of PHII-7.}, }
@article {pmid23909663, year = {2013}, author = {Lian, H and Zhang, T and Sun, J and Liu, X and Ren, G and Kou, L and Zhang, Y and Han, X and Ding, W and Ai, X and Wu, C and Li, L and Wang, Y and Sun, Y and Wang, S and He, Z}, title = {Enhanced oral delivery of paclitaxel using acetylcysteine functionalized chitosan-vitamin E succinate nanomicelles based on a mucus bioadhesion and penetration mechanism.}, journal = {Molecular pharmaceutics}, volume = {10}, number = {9}, pages = {3447-3458}, doi = {10.1021/mp400282r}, pmid = {23909663}, issn = {1543-8392}, mesh = {Acetylcysteine/*chemistry ; Animals ; Chitosan/*chemistry ; Drug Carriers/chemistry ; *Micelles ; Mucus ; Paclitaxel/*administration &amp; dosage/*chemistry ; Rats ; Rats, Sprague-Dawley ; Spectrometry, X-Ray Emission ; Thermogravimetry ; Vitamin E/*chemistry ; }, abstract = {In addition to being a physiological protective barrier, the gastrointestinal mucosal membrane is also a primary obstacle that hinders the oral absorption of many therapeutic compounds, especially drugs with a poor permeability. In order to resolve this impasse, we have designed multifunctional nanomicelles based on the acetylcysteine functionalized chitosan-vitamin E succinate copolymer (CS-VES-NAC, CVN), which exhibit marked bioadhesion, possess the ability to penetrate mucus, and enhance the oral absorption of a hydrophobic drug with a poor penetrative profile, paclitaxel. The intestinal absorption (Ka = 0.38 ± 0.04 min(-1), Papp = 0.059 cm · min(-1)) of CVN nanomicelles was greatly improved (4.5-fold) in comparison with paclitaxel solution, and CLSM (confocal laser scanning microscope) pictures also showed not only enhanced adhesion to the intestinal surface but improved accumulation within intestinal villi. The in vivo pharmacokinetics indicated that the AUC0-t (586.37 ng/mL · h) of CVN nanomicelles was markedly enhanced compared with PTX solution. In summary, the novel multifunctional CVN nanomicelles appear to be a promising nanocarrier for insoluble and poorly permeable drugs due to their high bioadhesion and permeation-enhancing capability.}, }
@article {pmid23908077, year = {2013}, author = {Su, X and Peng, S and He, R and Hu, C and He, J and Pan, P}, title = {[Endarterium injury and the related pathway in chronic intermittent hypoxia rats].}, journal = {Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences}, volume = {38}, number = {7}, pages = {676-680}, doi = {10.3969/j.issn.1672-7347.2013.07.004}, pmid = {23908077}, issn = {1672-7347}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aorta, Thoracic/*pathology ; C-Reactive Protein/metabolism ; Endothelium, Vascular/*pathology ; Hypoxia/*pathology/*physiopathology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lipoproteins, LDL/metabolism ; Male ; Oxidative Stress/physiology ; Rats ; Rats, Sprague-Dawley ; Serum Amyloid P-Component/metabolism ; }, abstract = {OBJECTIVE: To examine the pathological change and intima thickness of thoracic aorta, detect the serum concentration of hypoxia-inducible factor-1α (HIF-1α), oxidized LDL (ox-LDL), and pentraxin 3 (PTX3) in the rat model of chronic intermittent hypoxia (CIH), and to determine the effect of CIH on endarterium injury and its possible pathway.<br><br>METHODS: Twenty-four male Sprague-Dawley (SD) rats were divided into 4 groups: a CIH+Nacetylcysteine (NAC) group, a CIH+normal saline (NS) group, a CIH control group and a control group. CIH rats were subjected to alternating cycles of hypoxia (6%-8% O2 in N2 for 20-25 s) and normoxia (21% O2 in N2 for 2 min) every 180 s for 7 h/d. Rats in the control group were not treated. Rats in the CIH+NAC group were treated with NAC [800 mL/(kg.d)] intraperitoneal injection, and rats in the CIH+NS group were treated with NS [5 mL/(kg.d)] intraperitoneal injection. After 42 day treatment, the rats were sacrificed, blood taken, and thoracic aorta cut off. The serum concentration of HIF-1&#x3b1;, ox-LDL, and PTX3 were detected by ELISA. The thickness of intima was taken by computer digital image analysis.<br><br>RESULTS: Vascular endothelial cell injury and detachment were found in the thoracic aorta in the CIH and the CIH+NS group. The intima in the CIH and the CIH+NS group was thicker than that in the control and the CIH+NAC group (P<0.001). The serum concentration of HIF-1&#x3b1;, ox-LDL, and PTX3 in the CIH and the CIH+NS group was higher than that in the control and the CIH+NAC group (P<0.001). The serum concentration of HIF-1&#x3b1;, ox-LDL, and PTX3 was pairwise positive correlation, and the serum concentration of ox-LDL and PTX3 was positively correlated with the thickness of intina (P<0.001).<br><br>CONCLUSION: The vascular endothelial cell injury and endarterium thickening can be induced by CIH. It is an important pathway that CIH activates oxidative stress and elevates the levels of HIF- 1&#x3b1;, ox-LDL, and PTX3.}, }
@article {pmid23906793, year = {2013}, author = {Guaragnella, N and Ždralević, M and Lattanzio, P and Marzulli, D and Pracheil, T and Liu, Z and Passarella, S and Marra, E and Giannattasio, S}, title = {Yeast growth in raffinose results in resistance to acetic-acid induced programmed cell death mostly due to the activation of the mitochondrial retrograde pathway.}, journal = {Biochimica et biophysica acta}, volume = {1833}, number = {12}, pages = {2765-2774}, doi = {10.1016/j.bbamcr.2013.07.017}, pmid = {23906793}, issn = {0006-3002}, mesh = {Acetic Acid/*pharmacology ; Apoptosis/*drug effects ; Cytochromes c/metabolism ; Gene Deletion ; Glucose/pharmacology ; Hydrogen-Ion Concentration/drug effects ; Immunoblotting ; Intracellular Space/drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/*metabolism ; Phosphorylation/drug effects ; Raffinose/*pharmacology ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae/cytology/drug effects/*growth &amp; development ; Saccharomyces cerevisiae Proteins/metabolism ; Signal Transduction/*drug effects ; }, abstract = {In order to investigate whether and how a modification of mitochondrial metabolism can affect yeast sensitivity to programmed cell death (PCD) induced by acetic acid (AA-PCD), yeast cells were grown on raffinose, as a sole carbon source, which, differently from glucose, favours mitochondrial respiration. We found that, differently from glucose-grown cells, raffinose-grown cells were mostly resistant to AA-PCD and that this was due to the activation of mitochondrial retrograde (RTG) response, which increased with time, as revealed by the up-regulation of the peroxisomal isoform of citrate synthase and isocitrate dehydrogenase isoform 1, RTG pathway target genes. Accordingly, the deletion of RTG2 and RTG3, a positive regulator and a transcription factor of the RTG pathway, resulted in AA-PCD, as shown by TUNEL assay. Neither deletion in raffinose-grown cells of HAP4, encoding the positive regulatory subunit of the Hap2,3,4,5 complex nor constitutive activation of the RTG pathway in glucose-grown cells due to deletion of MKS1, a negative regulator of RTG pathway, had effect on yeast AA-PCD. The RTG pathway was found to be activated in yeast cells containing mitochondria, in which membrane potential was measured, capable to consume oxygen in a manner stimulated by the uncoupler CCCP and inhibited by the respiratory chain inhibitor antimycin A. AA-PCD resistance in raffinose-grown cells occurs with a decrease in both ROS production and cytochrome c release as compared to glucose-grown cells en route to AA-PCD.}, }
@article {pmid23900960, year = {2015}, author = {Arafa, MH and Mohamed, DA and Atteia, HH}, title = {Ameliorative effect of N-acetyl cysteine on alpha-cypermethrin-induced pulmonary toxicity in male rats.}, journal = {Environmental toxicology}, volume = {30}, number = {1}, pages = {26-43}, doi = {10.1002/tox.21891}, pmid = {23900960}, issn = {1522-7278}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Catalase/metabolism ; Glutathione/metabolism ; Heme Oxygenase-1/metabolism ; Insecticides/*toxicity ; Interleukin-1beta/metabolism ; Lipid Peroxidation/drug effects/immunology ; Lung/*drug effects/enzymology/immunology/pathology ; Male ; Malondialdehyde/metabolism ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; Oxidative Stress/*drug effects/immunology ; Pyrethrins/*toxicity ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Alpha-cypermethrin (α-CYP) is one of the most widely used insecticides. It may become an air pollutant and adversely affect the health. The present study was designed to determine whether treatment with N-acetyl cysteine (NAC), a well-known antioxidant, can be useful for the management of the deleterious effects of α-CYP on lung tissues. For this purpose, thirty two male rats were divided into four different groups (eight rats for each). Group (I) gavaged with corn oil (control group), group (II) gavaged daily with NAC (150 mg kg(-1) body weight), group (III) gavaged with α-CYP (14.5 mg kg(-1) body weight/day, dissolved in corn oil), group (IV) gavaged with NAC then with α-CYP 2 h later for 12 weeks. α-CYP significantly increased serum lactate dehydrogenase (LDH) and pulmonary malondialdehyde (MDA) levels, while decreased the activities of catalase (CAT) and superoxide dismutase (SOD) as well as reduced glutathione (GSH) content in lung. It also provoked higher levels of serum nitric oxide (NO), lung interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), hydroxyproline (Hyp) as well as heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-К B) gene expression in lung tissues. Histopathological alterations in lung with congestion, cellular infiltration, necrotic changes and thickening of inter-alveolar septa were observed following α-CYP administration. NAC reduced the adverse effects of α-CYP on lung tissues and improved the histological architecture of lung since it showed antioxidant, anti-inflammatory and antifibrotic effects on lung tissues. Our results indicate that NAC exerts a potent protective effect against α-CYP-induced oxidative damage and inflammation in lung tissues.}, }
@article {pmid23900080, year = {2013}, author = {Kim, MJ and Yun, HS and Hong, EH and Lee, SJ and Baek, JH and Lee, CW and Yim, JH and Kim, JS and Park, JK and Um, HD and Hwang, SG}, title = {Depletion of end-binding protein 1 (EB1) promotes apoptosis of human non-small-cell lung cancer cells via reactive oxygen species and Bax-mediated mitochondrial dysfunction.}, journal = {Cancer letters}, volume = {339}, number = {1}, pages = {15-24}, doi = {10.1016/j.canlet.2013.07.027}, pmid = {23900080}, issn = {1872-7980}, mesh = {*Apoptosis/genetics/radiation effects ; Carcinoma, Non-Small-Cell Lung/genetics/*metabolism ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics/*metabolism ; Microtubule-Associated Proteins/genetics/*metabolism ; Mitochondria/*metabolism ; RNA Interference ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; bcl-2-Associated X Protein/*metabolism ; }, abstract = {Although end-binding protein 1 (EB1) is well known to regulate microtubule dynamics, the role of EB1 in apoptosis of non-small cell lung cancer (NSCLC) is poorly understood. Here, we investigated the molecular mechanism by which EB1 regulates apoptosis in H460, A549, and H1299 cells. Depletion of EB1 in A549 and H1299 cells, which express high levels of EB1, induced cell death in a p53-independent manner through over-production of reactive oxygen species (ROS) and Bax induction. This phenomenon was potentiated in radiation-treated EB1-knockdown cells and was largely blocked by N-acetyl-L-cysteine, a scavenger of ROS. ROS accelerated the activation of nuclear factor-kappa B (NF-κB) to promote transcriptional activity of Bax, an action that was accompanied by cytochrome c translocation and apoptosis-inducing factor (AIF) release. The NF-κB inhibitor, BAY 11-7082, potently inhibited the apoptosis induced by EB1 knockdown and radiation treatment, in association with diminished activity of the mitochondrial death pathway. Conversely, ectopic overexpression of EB1 in H460 cells, which express low levels of EB1, remarkably abrogated radiation-induced apoptosis and NF-κB-mediated mitochondrial dysfunction. Our data provide the first demonstration that down-regulation of EB1 promotes NSCLC cell death by inducing ROS-mediated, NF-κB-dependent Bax signaling cascades, a process in which cytochrome c and AIF play important roles, indicating a potential therapeutic benefit of EB1 in lung cancer.}, }
@article {pmid23897119, year = {2013}, author = {Shin, JE and Baek, KJ and Choi, YS and Choi, Y}, title = {A periodontal pathogen Treponema denticola hijacks the Fusobacterium nucleatum-driven host response.}, journal = {Immunology and cell biology}, volume = {91}, number = {8}, pages = {503-510}, doi = {10.1038/icb.2013.35}, pmid = {23897119}, issn = {1440-1711}, mesh = {Animals ; CHO Cells ; Coinfection/*immunology ; Cricetulus ; Endosomes/metabolism ; Epithelial Cells/*immunology ; Fusobacterium nucleatum/*immunology ; Gingiva/pathology ; Host-Pathogen Interactions ; Humans ; Membrane Fusion ; Microbiota ; Periodontitis/*immunology ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 2/genetics/metabolism ; Transgenes/genetics ; Treponema denticola/*immunology ; beta-Defensins/metabolism ; }, abstract = {Periodontitis is a polymicrobial disease that arises from the dysbiosis of the plaque biofilm. To study polymicrobial interactions with gingival epithelial cells, the oral commensal Fusobacterium nucleatum and the periodontal pathogen Treponema denticola were chosen due to their opposing effects on the expression of human beta-defensins (HBDs) and interleukin (IL)-8 in gingival epithelial cells. Immortalized gingival epithelial HOK-16B cells were infected with either F. nucleatum or T. denticola alone or together, and the expression of HBDs and IL-8 was investigated. Coinfection with F. nucleatum and T. denticola neutralized the stimulatory and suppressive effects on the expression of HBD-2 and -3, but the suppressive effect of T. denticola on IL-8 expression remained. In CHO/CD14/TLR2 reporter cells, T. denticola attenuated F. nucleatum-induced activation of TLR2, a receptor that mediates HBD induction. Although F. nucleatum facilitated the invasion of T. denticola into host cells, T. denticola interfered with the fusion of internalized F. nucleatum with lysosomes, which may avert TLR9-dependent IL-8 induction. Furthermore, T. denticola suppressed the F. nucleatum-stimulated accumulation of intracellular reactive oxygen species (ROS), a group of essential signaling molecules for the TLR2 and TLR9 pathways. The elimination of ROS using N-acetyl cysteine completely blocked the inductions of HBD-3 and IL-8 and significantly reduced HBD-2 induction by F. nucleatum, confirming the importance of ROS in the host response. In sum, T. denticola incapacitates the F. nucleatum-induced expression of HBDs and IL-8 in gingival epithelial cells by interrupting endo-lysosomal maturation and ROS-dependent TLR activation. These results may provide new insights into polymicrobial interactions in the gingival sulcus.}, }
@article {pmid23896433, year = {2013}, author = {Xie, X and Chang, X and Chen, L and Huang, K and Huang, J and Wang, S and Shen, X and Liu, P and Huang, H}, title = {Berberine ameliorates experimental diabetes-induced renal inflammation and fibronectin by inhibiting the activation of RhoA/ROCK signaling.}, journal = {Molecular and cellular endocrinology}, volume = {381}, number = {1-2}, pages = {56-65}, doi = {10.1016/j.mce.2013.07.019}, pmid = {23896433}, issn = {1872-8057}, mesh = {Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus/drug effects ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Berberine/*pharmacology ; Cells, Cultured ; Diabetes Mellitus, Experimental/*complications/metabolism ; Drug Evaluation, Preclinical ; Fibronectins/genetics/*metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Intercellular Adhesion Molecule-1/genetics/metabolism ; Kidney/drug effects/pathology ; Male ; Mesangial Cells/drug effects/metabolism ; NF-kappa B/metabolism ; Nephritis/*drug therapy/etiology/metabolism ; Oxidative Stress/drug effects ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/*drug effects ; Transforming Growth Factor beta1/genetics/metabolism ; rho-Associated Kinases/metabolism ; rhoA GTP-Binding Protein/metabolism ; }, abstract = {The accumulation of glomerular extracellular matrix proteins, especially fibronectin (FN), is a critical pathological characteristic of diabetic renal fibrosis. Inflammation mediated by nuclear factor-κB (NF-κB) plays a critical role in the pathogenesis of diabetic nephropathy (DN). RhoA/ROCK signaling is responsible for FN accumulation and NF-κB activation. Berberine (BBR) treatment significantly inhibited renal inflammation and thus improved renal damage in diabetes. Here, we study whether BBR inhibits FN accumulation and NF-κB activation by inhibiting RhoA/ROCK signaling and the underlying mechanisms involved. Results showed that BBR effectively inhibited RhoA/ROCK signaling activation in diabetic rat kidneys and high glucose-induced glomerular mesangial cells (GMCs) and simultaneously down-regulated NF-κB activity, which was accompanied by reduced intercellular adhesionmolecule-1, transforming growth factor-beta 1 and FN overproduction. Furthermore, we observed that BBR abrogated high glucose-mediated reactive oxygen species generation in GMCs. BBR and N-acetylcysteine inhibited RhoA/ROCK signaling activation in high glucose-exposed GMCs. Collectively, our data suggest that the renoprotective effect of BBR on DN partly depends on RhoA/ROCK inhibition. The anti-oxidative stress effect of BBR is responsible for RhoA/ROCK inhibition in DN.}, }
@article {pmid23894333, year = {2013}, author = {Fioramonti, X and Deak, A and Deshpande, S and Carneiro, L and Zhou, C and Sayed, N and Orban, B and Berlin, JR and Pénicaud, L and Leloup, C and Beuve, A and Routh, VH}, title = {Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e68709}, pmid = {23894333}, issn = {1932-6203}, support = {R01 GM067640/GM/NIGMS NIH HHS/United States ; 1R01DK64566/DK/NIDDK NIH HHS/United States ; F31 DK086681/DK/NIDDK NIH HHS/United States ; R01 DK081358/DK/NIDDK NIH HHS/United States ; 1F31DK86681/DK/NIDDK NIH HHS/United States ; R01 DK064566/DK/NIDDK NIH HHS/United States ; T32 HL098049/HL/NHLBI NIH HHS/United States ; 5R01-GM067640/GM/NIGMS NIH HHS/United States ; 1R01DK81358/DK/NIDDK NIH HHS/United States ; R01 DK081538/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Glucose/metabolism ; Hypoglycemia/chemically induced/*metabolism/*physiopathology ; Hypothalamus/drug effects/*metabolism/*physiopathology ; Insulin/adverse effects ; Male ; Neurons/drug effects/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {AIMS: Hypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. During hypoglycemia, ventromedial hypothalamus (VMH) production of nitric oxide (NO) and activation of its receptor soluble guanylyl cyclase (sGC) are critical for the CRR. Hypoglycemia also increases brain reactive oxygen species (ROS) production. NO production in the presence of ROS causes protein S-nitrosylation. S-nitrosylation of sGC impairs its function and induces desensitization to NO. We hypothesized that during hypoglycemia, the interaction between NO and ROS increases VMH sGC S-nitrosylation levels and impairs the CRR to subsequent episodes of hypoglycemia. VMH ROS production and S-nitrosylation were quantified following three consecutive daily episodes of insulin-hypoglycemia (RH model). The CRR was evaluated in rats in response to acute insulin-induced hypoglycemia or via hypoglycemic-hyperinsulinemic clamps. Pretreatment with the anti-oxidant N-acetyl-cysteine (NAC) was used to prevent increased VMH S-nitrosylation.<br><br>RESULTS: Acute insulin-hypoglycemia increased VMH ROS levels by 49&#xb1;6.3%. RH increased VMH sGC S-nitrosylation. Increasing VMH S-nitrosylation with intracerebroventricular injection of the nitrosylating agent S-nitroso-L-cysteine (CSNO) was associated with decreased glucagon secretion during hypoglycemic clamp. Finally, in RH rats pre-treated with NAC (0.5% in drinking water for 9 days) hypoglycemia-induced VMH ROS production was prevented and glucagon and epinephrine production was not blunted in response to subsequent insulin-hypoglycemia.<br><br>CONCLUSION: These data suggest that NAC may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.}, }
@article {pmid23892094, year = {2013}, author = {Terrill, JR and Boyatzis, A and Grounds, MD and Arthur, PG}, title = {Treatment with the cysteine precursor l-2-oxothiazolidine-4-carboxylate (OTC) implicates taurine deficiency in severity of dystropathology in mdx mice.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {45}, number = {9}, pages = {2097-2108}, doi = {10.1016/j.biocel.2013.07.009}, pmid = {23892094}, issn = {1878-5875}, mesh = {Acetylcysteine/pharmacology ; Animals ; Disease Models, Animal ; Male ; Mice ; Mice, Inbred C57BL ; Muscular Dystrophy, Duchenne/*drug therapy/*metabolism ; Oxidative Stress/drug effects ; Pyrrolidonecarboxylic Acid/*pharmacology ; Taurine/*deficiency/metabolism ; Thiazolidines/*pharmacology ; }, abstract = {Oxidative stress has been implicated in the pathology of the lethal skeletal muscle disease Duchenne muscular dystrophy (DMD), and various antioxidants have been investigated as a potential therapy. Recently, treatment of the mdx mouse model for DMD with the antioxidant and cysteine and glutathione (GSH) precursor n-acetylcysteine (NAC) was shown to decrease protein thiol oxidation and improve muscle pathology and ex vivo muscle strength. This study further investigates the mechanism for the benefits of NAC on dystrophic muscle by administering l-2-oxothiazolidine-4-carboxylate (OTC) which also upregulates intracellular cysteine and GSH, but does not directly function as an antioxidant. We observed that OTC, like NAC, decreases protein thiol oxidation, decreases pathology and increases strength, suggesting that the both NAC and OTC function via increasing cysteine and GSH content of dystrophic muscle. We demonstrate that mdx muscle is not deficient in either cysteine or GSH and that these are not increased by OTC treatment. However, we show that dystrophic muscle of 12 week old mdx mice is deficient in taurine, a by-product of disposal of excess cysteine, a deficiency that is ameliorated by OTC treatment. These data suggest that in dystrophic muscles, apart from the strong association of increased oxidative stress and protein thiol oxidation with dystropathology, another major issue is an insufficiency in taurine that can be corrected by increasing the availability of cysteine. This study provides new insight into the molecular mechanism underlying the benefits of NAC in muscular dystrophy and supports the use of OTC as an alternative drug for potential clinical applications to DMD.}, }
@article {pmid23887056, year = {2013}, author = {Minarini, A and Zini, M and Milelli, A and Tumiatti, V and Marchetti, C and Nicolini, B and Falconi, M and Farruggia, G and Cappadone, C and Stefanelli, C}, title = {Synthetic polyamines activating autophagy: effects on cancer cell death.}, journal = {European journal of medicinal chemistry}, volume = {67}, number = {}, pages = {359-366}, doi = {10.1016/j.ejmech.2013.06.044}, pmid = {23887056}, issn = {1768-3254}, mesh = {Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology ; Autophagy/*drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; HT29 Cells ; HeLa Cells ; Humans ; Molecular Structure ; Neoplasms/*pathology ; Polyamines/chemical synthesis/chemistry/*pharmacology ; Structure-Activity Relationship ; Tumor Cells, Cultured ; }, abstract = {The ability of symmetrically substituted long chain polymethylene tetramines, methoctramine (1) and its analogs 2-4 to kill cancer cells was studied. We found that an elevated cytotoxicity was correlated with a 12 methylene chain length separating the inner amine functions (6-12-6 carbon backbone), together with the introduction of diphenylethyl moieties on the terminal nitrogen atoms (compound 4) of a tetramine backbone. Compound 4 triggered dissipation of mitochondrial transmembrane potential and increased intracellular peroxide levels, leading to a caspase-independent HeLa cell death associated with a rapid activation of autophagy. The antioxidant N-acetylcysteine inhibited cell death and activation of autophagy, indicating a link between oxidative stress and autophagy. Autophagy was rapidly triggered even by tetramines 2 and 3, indicating that is related to their polyamine structure. Autophagy did not protect HeLa cells against cytotoxicity elicited by compound 4. The present study shows that, by modifications of the methoctramine structure, it is possible to design polyamine derivatives highly cytotoxic against tumor cells and that the appropriate design of molecules bearing polyamine-like structures leads to powerful inducers of autophagy.}, }
@article {pmid23886027, year = {2013}, author = {Ghanizadeh, A and Moghimi-Sarani, E}, title = {A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders.}, journal = {BMC psychiatry}, volume = {13}, number = {}, pages = {196}, pmid = {23886027}, issn = {1471-244X}, mesh = {Adolescent ; Antipsychotic Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Autistic Disorder/*drug therapy ; Child ; Child, Preschool ; Cystine/administration &amp; dosage/adverse effects/*analogs &amp; derivatives/therapeutic use ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Irritable Mood/*drug effects ; Male ; Risperidone/administration &amp; dosage/adverse effects/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: This study examined the efficacy and safety of N-acetylcysteine (NAC) augmentation for treating irritability in children and adolescents with autism spectrum disorders (ASD).<br><br>METHOD: Forty children and adolescents met diagnostic criteria for ASD according to DSM-IV. They were randomly allocated into one of the two groups of NAC (1200&#x2009;mg/day)+risperidone or placebo+risperidone. NAC and placebo were administered in the form of effervescent and in two divided doses for 8 weeks. Irritability subscale score of Aberrant Behavior Checklist (ABC) was considered as the main outcome measure. Adverse effects were also checked.<br><br>RESULTS: The mean score of irritability in the NAC+risperidone and placebo+risperidone groups at baseline was 13.2(5.3) and 16.7(7.8), respectively. The scores after 8 weeks were 9.7(4.1) and 15.1(7.8), respectively. Repeated measures of ANOVA showed that there was a significant difference between the two groups after 8 weeks. The most common adverse effects in the NAC+risperidone group were constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%). There was no fatal adverse effect.<br><br>CONCLUSIONS: Risperidone plus NAC more than risperidone plus placebo decreased irritability in children and adolescents with ASD. Meanwhile, it did not change the core symptoms of autism. Adverse effects were not common and NAC was generally tolerated well.<br><br>TRIAL REGISTRATION: This trial was registered at http://www.irct.ir. The registration number of this trial was IRCT201106103930N6.}, }
@article {pmid23880890, year = {2014}, author = {Onalan, G and Gulumser, C and Mulayim, B and Dagdeviren, A and Zeyneloglu, H}, title = {Effects of amifostine on endometriosis, comparison with N-acetyl cysteine, and leuprolide as a new treatment alternative: a randomized controlled trial.}, journal = {Archives of gynecology and obstetrics}, volume = {289}, number = {1}, pages = {193-200}, doi = {10.1007/s00404-013-2963-0}, pmid = {23880890}, issn = {1432-0711}, mesh = {Abdominal Wall ; Acetylcysteine/*therapeutic use ; Amifostine/*therapeutic use ; Animals ; Disease Models, Animal ; Endometriosis/*drug therapy ; Endometrium/drug effects ; Female ; Leuprolide/*therapeutic use ; Peritoneal Diseases/*drug therapy ; Peritoneum/*drug effects ; Random Allocation ; Rats ; Rats, Wistar ; Treatment Outcome ; }, abstract = {PURPOSE: To assess the effects of amifostine, N-acetyl cysteine (NAC), and leuprolide as a scavenger in a rat endometriosis model.<br><br>METHODS: This is a prospective randomized animal study. Setting The Animal Laboratory of Medical University. Animals 40 rats were used for transplantation of an autologous fragment of endometrial tissue onto the inner surface of the abdominal wall. After allowing 3 weeks for growth, laparotomies were performed to check the implants. Then animals were randomized into four groups: Group I amifostine (200 mg/day loading dose after 20 mg/kg/day, p.o.); Group II NAC (200 mg/day, p.o.); Group III leuprolide acetate 1 mg/kg single dose, sc; and Group IV (controls) no medication. Three weeks later, implants were evaluated morphologically. Serum and peritoneal TNF-alpha levels were evaluated. The transmission electron microscopic examination of the peritoneal samples and ovaries was also performed.<br><br>RESULTS: Leuprolide acetate, amifostine and NAC caused significant decreases in the mean implant areas and significant decreases in serum and peritoneal TNF-alpha levels. On comparing all groups, these reductions were higher in Group II. According to the transmission electron microscopic findings, leuprolide seems to be protecting normal structure of peritoneum best when compared to the other groups.<br><br>CONCLUSIONS: Amifostine, NAC and leuprolide caused regression of endometriosis in this experimental rat model by a yet unsettled mechanism.}, }
@article {pmid23878731, year = {2013}, author = {Di Pierro, F and Rossoni, G}, title = {An amino acids mixture improves the hepatotoxicity induced by acetaminophen in mice.}, journal = {Journal of amino acids}, volume = {2013}, number = {}, pages = {615754}, pmid = {23878731}, issn = {2090-0104}, abstract = {Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The aim of this study was to evaluate the protective role of DDM-GSH, a mixture of L-cysteine, L-methionine, and L-serine in a weight ratio of 2 : 1 : 1, in comparison to N-acetylcysteine (NAC), against acetaminophen- (APAP-) induced hepatotoxicity in mice. Toxicity was induced in mice by the intraperitoneal (ip) administration of low dose (2 mmol/kg) or high dose (8 mmol/kg) of APAP. DDM-GSH (0.4 to 1.6 mmol/kg) was given ip to mice 1 h before the APAP administration. The same was done with NAC (0.9 to 3.6 mmol/kg), the standard antidote of APAP toxicity. Mice were sacrificed 8 h after the APAP injection to determine liver weight, serum alanine aminotransferase (ALT), and total glutathione (GSH) depletion and malondialdehyde (MDA) accumulation in liver tissues. DDM-GSH improved mouse survival rates better than NAC against a high dose of APAP. Moreover, DDM-GSH significantly reduced in a dose-dependent manner not only APAP-induced increases of ALT but also APAP-induced hepatic GSH depletion and MDA accumulation. Our results suggest that DDM-GSH may be more potent than NAC in protecting the liver from APAP-induced liver injury.}, }
@article {pmid23877794, year = {2013}, author = {Huang, M and Thomas, D and Li, MX and Feng, W and Chan, SM and Majeti, R and Mitchell, BS}, title = {Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib.}, journal = {Leukemia}, volume = {27}, number = {10}, pages = {1970-1980}, doi = {10.1038/leu.2013.222}, pmid = {23877794}, issn = {1476-5551}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Boronic Acids/*pharmacology ; Bortezomib ; Cell Nucleolus/drug effects/metabolism/pathology ; Cell Proliferation ; Cysteine/genetics ; Cytosol/drug effects/metabolism ; Drug Resistance, Neoplasm/drug effects/*genetics ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Humans ; Leukemia, Myeloid, Acute/drug therapy/genetics/*pathology ; Mutation/*genetics ; Nuclear Proteins/*genetics ; Nucleophosmin ; Oxides/*pharmacology ; Pyrazines/*pharmacology ; Reactive Oxygen Species/metabolism ; Tryptophan/genetics ; Tumor Cells, Cultured ; }, abstract = {Mutations in exon 12 of the nucleophosmin (NPM1) gene (NPMc+ (NPM1 COOH terminal mutations)) define a distinct subset of acute myelogenous leukemias (AMLs), in which the NPMc+ protein localizes aberrantly to the leukemic cell cytoplasm. We have found that introduction of the most common NPMc+ variant into K562 and 32D cells sensitizes these cells to apoptosis induced by drugs such as bortezomib and arsenic trioxide (ATO) that induce reactive oxygen species (ROS) formation, and that cytotoxicity is prevented in the presence of N-acetyl-L-cysteine (NAC), an ROS scavenger. The substitution of tryptophan 288 (W288) by cysteine occurs in the great majority of NPM1c+ mutations. Mutagenesis of cysteine 288 to alanine re-localizes NPMc+ from the cytoplasm to the nucleolus and attenuates the sensitivity of cells expressing this mutation to bortezomib and ATO. Primary AML cells expressing NPMc+ are also significantly more sensitive than other AML cells to apoptosis induced by both drugs at pharmacologically achievable doses. We conclude that the presence of a cysteine moiety at position 288 results in the cytoplasmic localization of NPM1c+ and the increased sensitivity to bortezomib and ATO. These data suggest that bortezomib and ATO may have increased therapeutic efficacy in NPM1c+ leukemias.}, }
@article {pmid23877122, year = {2014}, author = {Nakagawa, Y and Suzuki, T and Nakajima, K and Inomata, A and Ogata, A and Nakae, D}, title = {Effects of N-acetyl-L-cysteine on target sites of hydroxylated fullerene-induced cytotoxicity in isolated rat hepatocytes.}, journal = {Archives of toxicology}, volume = {88}, number = {1}, pages = {115-126}, doi = {10.1007/s00204-013-1096-3}, pmid = {23877122}, issn = {1432-0738}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cells, Cultured ; Cysteine/metabolism ; Fullerenes/*toxicity ; Glutathione/metabolism ; Hepatocytes/*drug effects/*metabolism ; Hydroxylation ; Male ; Maleates/pharmacology ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Protective Agents/pharmacology ; Rats ; Rats, Inbred F344 ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {The effects of N-acetyl-L-cysteine (NAC) on cytotoxicity caused by a hydroxylated fullerene [C60(OH)24], which is known a nanomaterial and/or a water-soluble fullerene derivative, were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C60(OH)24 at a concentration of 0.1 mM caused time (0-3 h)-dependent cell death accompanied by the formation of cell blebs, loss of cellular ATP, and reduced glutathione (GSH) and protein thiol levels, as well as the accumulation of glutathione disulfide and malondialdehyde (MDA), indicating lipid peroxidation. Despite this, C60(OH)24-induced cytotoxicity was effectively prevented by NAC pretreatment ranging in concentrations from 1 to 5 mM. Further, the loss of mitochondrial membrane potential (MMP) and generation of oxygen radical species in hepatocytes incubated with C60(OH)24 were inhibited by pretreatment with NAC, which caused increases in cellular and/or mitochondrial levels of GSH, accompanied by increased levels of cysteine via enzymatic deacetylation of NAC. On the other hand, severe depletion of cellular GSH levels caused by diethyl maleate at a concentration of 1.25 mM led to the enhancement of C60(OH)24-induced cell death accompanied by a rapid loss of ATP. Taken collectively, these results indicate that pretreatment with NAC ameliorates (a) mitochondrial dysfunction linked to the depletion of ATP, MMP, and mitochondrial GSH level and (b) induction of oxidative stress assessed by reactive oxygen species generation, losses of intracellular GSH and protein thiol levels, and MDA formation caused by C60(OH)24, suggesting that the onset of toxic effects is at least partially attributable to a thiol redox-state imbalance as well as mitochondrial dysfunction related to oxidative phosphorylation.}, }
@article {pmid23876760, year = {2013}, author = {Guo, D and Zhu, L and Huang, Z and Zhou, H and Ge, Y and Ma, W and Wu, J and Zhang, X and Zhou, X and Zhang, Y and Zhao, Y and Gu, N}, title = {Anti-leukemia activity of PVP-coated silver nanoparticles via generation of reactive oxygen species and release of silver ions.}, journal = {Biomaterials}, volume = {34}, number = {32}, pages = {7884-7894}, doi = {10.1016/j.biomaterials.2013.07.015}, pmid = {23876760}, issn = {1878-5905}, mesh = {Acetylcysteine/pharmacology ; Adolescent ; Adult ; Aged ; Antineoplastic Agents/chemistry/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Ascorbic Acid/pharmacology ; Cell Line, Tumor ; DNA Damage/drug effects ; Female ; HL-60 Cells ; Humans ; Ions/pharmacology ; Leukemia/*drug therapy ; Male ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/*chemistry ; Middle Aged ; Reactive Oxygen Species/*metabolism ; Silver/chemistry/*pharmacology ; }, abstract = {Silver nanoparticles (AgNPs) have anti-cancer effect. However, whether and how these particles could inhibit the growth of acute myeloid leukemia (AML) cells is unclear. In the present study, we prepared AgNPs with various sizes and investigated their cytotoxic effect on AML cells. We found that AgNPs could inhibit the viability of AML cells including the isolates from AML patients. AgNPs caused the production of reactive oxygen species (ROS), losses of mitochondrial membrane potential (MMP), DNA damage and apoptosis. Both vitamin C (Vit C) and N-acetyl-L-cysteine (NAC) could completely reverse the generation of ROS upon AgNPs, however only NAC but not Vit C could protect the cells from losses of MMP, DNA damage and apoptosis thoroughly. Similar results were obtained when cells were treated with silver ions alone. As NAC was not only an antioxidant to scavenge ROS but also a silver ion chelator, these data supported the model that both generation of ROS and release of silver ions played critical roles in the AgNPs-induced cytotoxic effect against AML cells. Taken together, this work elucidated the cytotoxic effect of AgNPs on AML cells and their underlying mechanism and might have significant impact on AML treatment.}, }
@article {pmid23874823, year = {2013}, author = {Mao, X and Wang, T and Liu, Y and Irwin, MG and Ou, JS and Liao, XL and Gao, X and Xu, Y and Ng, KF and Vanhoutte, PM and Xia, Z}, title = {N-acetylcysteine and allopurinol confer synergy in attenuating myocardial ischemia injury via restoring HIF-1α/HO-1 signaling in diabetic rats.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e68949}, pmid = {23874823}, issn = {1932-6203}, mesh = {2-Methoxyestradiol ; Acetylcysteine ; Allopurinol ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/physiology ; Cardiotonic Agents/*pharmacology ; Diabetes Mellitus, Experimental/*metabolism ; Dinoprost/analogs &amp; derivatives ; Drug Synergism ; Echocardiography ; Estradiol/analogs &amp; derivatives ; Heme Oxygenase (Decyclizing)/antagonists &amp; inhibitors/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists &amp; inhibitors/metabolism ; In Situ Nick-End Labeling ; Isoprostanes/blood ; Male ; Membrane Potential, Mitochondrial/drug effects/physiology ; Metalloporphyrins ; Myocardial Reperfusion Injury/*prevention &amp; control ; Protoporphyrins ; RNA, Small Interfering/genetics ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/*drug effects ; Superoxide Dismutase/blood ; }, abstract = {OBJECTIVES: To determine whether or not the antioxidants N-acetylcysteine (NAC) and allopurinol (ALP) confer synergistic cardioprotection against myocardial ischemia/reperfusion (MI/R) injury by stabilizing hypoxia inducible factor 1α (HIF-1α)/heme oxygenase 1 (HO-1) signaling in diabetic myocardium.<br><br>METHODS: Control or diabetic [streptozotocin (STZ)-induced] Sprague Dawley rats received vehicle or NAC, ALP or their combination for four weeks starting one week after STZ injection. The animals were then subjected to thirty minutes of coronary artery occlusion followed by two hours reperfusion in the absence or presence of the selective HO-1 inhibitor, tin protoporphyrin-IX (SnPP-IX) or the HIF-1&#x3b1; inhibitor 2-Methoxyestradiol (2ME2). Cardiomyocytes exposed to high glucose were subjected to hypoxia/re-oxygenation in the presence or absence of HIF-1&#x3b1; and HO-1 achieved by gene knock-down with related siRNAs.<br><br>RESULTS: Myocardial and plasma levels of 15-F2t-isoprostane, an index of oxidative stress, were significantly increased in diabetic rats while cardiac HO-1 protein and activity were reduced; this was accompanied with reduced cardiac protein levels of HIF-1&#x3b1;, and increased post-ischemic myocardial infarct size and cellular injury. NAC and ALP given alone and in particular their combination normalized cardiac levels of HO-1 and HIF-1&#x3b1; protein expression and prevented the increase in 15-F2t-isoprostane, resulting in significantly attenuated post-ischemic myocardial infarction. NAC and ALP also attenuated high glucose-induced post-hypoxic cardiomyocyte death in vitro. However, all the above protective effects of NAC and ALP were cancelled either by inhibition of HO-1 or HIF-1&#x3b1; with SnPP-IX and 2ME2 in vivo or by HO-1 or HIF-1&#x3b1; gene knock-down in vitro.<br><br>CONCLUSION: NAC and ALP confer synergistic cardioprotection in diabetes via restoration of cardiac HIF-1&#x3b1; and HO-1 signaling.}, }
@article {pmid23874646, year = {2013}, author = {Adachi, T and Takahara, K and Taneo, J and Uchiyama, Y and Inaba, K}, title = {Particle size of latex beads dictates IL-1β production mechanism.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e68499}, pmid = {23874646}, issn = {1932-6203}, mesh = {Acetylcysteine ; Adenosine Triphosphate/metabolism ; Animals ; Cathepsin B/metabolism ; Interleukin-1beta/*biosynthesis ; Lipopolysaccharides ; Macrophages/cytology/*immunology/*metabolism ; Mice ; *Microspheres ; *Particle Size ; Phagosomes/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Purinergic P2X7/metabolism ; Signal Transduction ; }, abstract = {Macrophages (Mϕ) are well documented to produce IL-1β through various signaling pathways in response to small particles such as silica, asbestos and urea crystals, in the presence of lipopolysaccharide (LPS). However, it has not been clear to what extent particle size affects the response. To investigate this point, we stimulated bone marrow-derived macrophages (BMDM) with size-defined latex beads (LxB). Although both nano-sized (20 nm) and micro-sized (1,000 nm) LxB induced IL-1β production, only the nano-sized particles formed large intracellular vacuoles. In contrast, 100 nm LxB did not induce either of the responses. The same cellular responses were also observed in primary microglia cells. Although K(+) efflux and NLRP3 activation in BMDM were crucial in response to both 20 and 1,000 nm LxB, only IL-1β production by 20 nm LxB was sensitive to cathepsin B and P2X7, a receptor for ATP. The response by 1,000 nm LxB relied on a robust production of reactive oxygen species (ROS), since IL-1β production was remarkably reduced by ROS inhibitors such as diphenylene iodonium (DPI) and N-acetylcysteine (NAC). In contrast, IL-1β production by 20 nm LxB was augmented by NAC and in BMDM deficient in thioredoxin-binding protein-2 (TBP-2), a negative regulator of the ROS scavenger thioredoxin. These results suggest that the cells responded differently in their secretion of IL-1β depending on particle size, and that there is a range within which neither pathway works.}, }
@article {pmid23874548, year = {2013}, author = {Das, A and Bhattacharya, A and Chakrabarty, S and Ganguli, A and Chakrabarti, G}, title = {Smokeless tobacco extract (STE)-induced toxicity in mammalian cells is mediated by the disruption of cellular microtubule network: a key mechanism of cytotoxicity.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e68224}, pmid = {23874548}, issn = {1932-6203}, mesh = {Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Line ; Cell Survival/drug effects ; Cysteine/metabolism ; Epithelial Cells/drug effects/metabolism ; Hep G2 Cells ; Humans ; Leukocytes, Mononuclear/drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Microtubules/*drug effects/metabolism ; Plant Extracts/toxicity ; Polymerization/drug effects ; Tobacco, Smokeless/*toxicity ; Tubulin/metabolism ; }, abstract = {Smokeless tobacco usage is a growing public health problem worldwide. The molecular mechanism(s) underlying smokeless tobacco associated tissue damage remain largely unidentified. In the present study we have tried to explore the effects of aqueous extract of smokeless tobacco (STE) on tubulin-microtubule, the major cytoskeleton protein that maintains cells morphology and participates in cell division. Exposure to STE resulted in dose-dependent cytotoxicity in a variety of mammalian transformed cell lines such as human lung epithelial cells A549, human liver epithelial cells HepG2, and mouse squamous epithelial cells SCC7, [corrected] as well as non-tumorogenic human peripheral blood mononuclear cells PBMC. Cellular morphology of STE-treated cells was altered and the associated disruption of microtubule network indicates that STE targets tubulin-microtubule system in both cell lines. Furthermore it was also observed that STE-treatment resulted in the selective degradation of cellular tubulin, whereas actin remains unaltered. In vitro, polymerization of purified tubulin was inhibited by STE with the IC50 value∼150 µg/ml and this is associated with the loss of reactive cysteine residues of tubulin. Application of thiol-based antioxidant N-acetyl cysteine (NAC) significantly abrogates STE-mediated microtubule damage and associated cytotoxicity in both A549 and HepG2 cells. These results suggest that microtubule damage is one of the key mechanisms of STE-induced cytotoxity in mammalian cells.}, }
@article {pmid23872073, year = {2013}, author = {Samarakoon, R and Dobberfuhl, AD and Cooley, C and Overstreet, JM and Patel, S and Goldschmeding, R and Meldrum, KK and Higgins, PJ}, title = {Induction of renal fibrotic genes by TGF-β1 requires EGFR activation, p53 and reactive oxygen species.}, journal = {Cellular signalling}, volume = {25}, number = {11}, pages = {2198-2209}, doi = {10.1016/j.cellsig.2013.07.007}, pmid = {23872073}, issn = {1873-3913}, support = {GM052742/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Benzothiazoles/pharmacology ; Connective Tissue Growth Factor/genetics/metabolism ; Endothelium, Vascular/cytology/drug effects/metabolism ; ErbB Receptors/agonists/*genetics/metabolism ; Fibroblasts/cytology/drug effects/*metabolism ; Fibrosis ; Gene Expression Regulation ; Isoquinolines/pharmacology ; Mice ; Mink ; Myocytes, Smooth Muscle/cytology/drug effects/metabolism ; Pyridines/pharmacology ; Pyrroles/pharmacology ; Quinazolines/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Renal Insufficiency, Chronic/*genetics/metabolism/pathology ; Serpin E2/genetics/metabolism ; Signal Transduction ; Smad2 Protein/genetics/metabolism ; Smad3 Protein/genetics/metabolism ; Toluene/analogs &amp; derivatives/pharmacology ; Transforming Growth Factor beta1/*pharmacology ; Tumor Suppressor Protein p53/*genetics/metabolism ; Tyrphostins/pharmacology ; }, abstract = {While transforming growth factor-β (TGF-β1)-induced SMAD2/3 signaling is a critical event in the progression of chronic kidney disease, the role of non-SMAD mechanisms in the orchestration of fibrotic gene changes remains largely unexplored. TGF-β1/SMAD3 pathway activation in renal fibrosis (induced by ureteral ligation) correlated with epidermal growth factor receptor(Y845) (EGFR(Y845)) and p53(Ser15) phosphorylation and induction of disease causative target genes plasminogen activator inhibitor-1 (PAI-1) and connective tissue growth factor (CTGF) prompting an investigation of the mechanistic involvement of EGFR and tumor suppressor p53 in profibrotic signaling. TGF-β1, PAI-1, CTGF, p53 and EGFR were co-expressed in the obstructed kidney localizing predominantly to the tubular and interstitial compartments. Indeed, TGF-β1 activated EGFR and p53 as well as SMAD2/3. Genetic deficiency of either EGFR or p53 or functional blockade with AG1478 or Pifithrin-α, respectively, effectively inhibited PAI-1and CTGF induction and morphological transformation of renal fibroblasts as did SMAD3 knockdown or pretreatment with the SMAD3 inhibitor SIS3. Reactive oxygen species (ROS)-dependent mechanisms initiated by TGF-β1 were critical for EGFR(Y845) and p53(Ser15) phosphorylation and target gene expression. The p22(Phox) subunit of NADPH oxidase was also elevated in the fibrotic kidney with an expression pattern similar to p53 and EGFR. EGF stimulation alone initiated, albeit delayed, c-terminal SMAD3 phosphorylation (that required the TGF-β1 receptor) and rapid ERK2 activation both of which are necessary for PAI-1 and CTGF induction in renal fibroblasts. These data highlight the extensive cross-talk among SMAD2/3, EGFR and p53 pathways essential for expression of TGF-β1-induced fibrotic target genes.}, }
@article {pmid23871785, year = {2013}, author = {Grosicka-Maciąg, E and Szumiło, M and Czeczot, H and Kurpios-Piec, D and Skrzycki, M and Rahden-Staroń, I}, title = {Modulation of antioxidant defense system by the dithiocarbamate fungicides Maneb and Zineb in Chinese hamster V79 cells and the role of N-acetyl-L-cysteine.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {60}, number = {}, pages = {130-134}, doi = {10.1016/j.fct.2013.07.034}, pmid = {23871785}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism ; Catalase/metabolism ; Cell Line ; Cricetulus ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Maneb/*toxicity ; Oxidative Stress/drug effects ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Zineb/*toxicity ; }, abstract = {Oxidative stress is one of the major factors leading to Maneb- and Zineb-induced disorders. The aim of this in vitro study was to examine (i) the potency of Maneb and Zineb to induce changes in antioxidant enzyme activities in Chinese hamster fibroblasts V79 cells and (ii) the role of N-acetyl-L-cysteine (NAC) in the preventing their action. Maneb increased mitochondrial superoxide dismutase (SOD2) activity but failed to affect the activity of cytoplasmic superoxide dismutase (SOD1), whereas Zineb did not change the activity of any of superoxide dismutases. The activity of catalase (CAT) was reduced only by Zineb. The activity of both glutathione peroxidases (non-Se-GPx, Se-GPx) and glutathione reductase (GR) was decreased after exposure to these agents. After NAC pre-treatment Maneb increased the activity of GR, whereas the activity of non-Se-GPx was decreased as compared to that in NAC-treated cells. On the other hand, the activity of both SODs and CAT was decreased. Zineb decreased the activity of both GPxs and SOD2 with a concomitant increase in CAT activity comparing to NAC-treated cells. The results obtained thus suggest that Zineb acts by another mechanism, than Maneb does, and that one of the mechanisms of NAC protection against Maneb or Zineb-induced effects in V79 cells is its impact on enzymatic defense. Activity of GR, SOD2, and GPxs are the most affected enzymes.}, }
@article {pmid23867903, year = {2013}, author = {Lo, YL and Wang, W}, title = {Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro.}, journal = {Chemico-biological interactions}, volume = {205}, number = {3}, pages = {188-197}, doi = {10.1016/j.cbi.2013.07.003}, pmid = {23867903}, issn = {1872-7786}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics/metabolism ; Antibiotics, Antineoplastic/administration &amp; dosage/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Apoptosis/*drug effects ; Caspases/genetics/metabolism ; Cell Survival/drug effects ; Drug Synergism ; Epirubicin/administration &amp; dosage/*pharmacology ; Female ; Flow Cytometry ; HeLa Cells ; Humans ; Isoflavones/administration &amp; dosage/*pharmacology ; Membrane Potential, Mitochondrial ; Multidrug Resistance-Associated Protein 2 ; Multidrug Resistance-Associated Proteins/genetics/metabolism ; Phytoestrogens/administration &amp; dosage/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; RNA, Neoplasm/chemistry/genetics ; Real-Time Polymerase Chain Reaction ; Uterine Cervical Neoplasms/*drug therapy/genetics/metabolism/pathology ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {The frequent development of multidrug resistance (MDR) hampers the efficacy of available anticancer drugs in treating cervical cancer. In this study, we aimed to use formononetin (7-hydroxy-4'-methoxyisoflavone), a potential herbal isoflavone, to intensify the chemosensitivity of human cervical cancer HeLa cells to epirubicin, an anticancer drug. The reactive oxygen species (ROS) levels were correlated with MDR modulation mechanisms, including the transporter inhibition and apoptosis induction. Our results revealed that formononetin significantly enhanced the cytotoxicity of epirubicin. Co-incubation of epirubicin with formononetin increased the ROS levels, including hydrogen peroxide and superoxide free radicals. Epirubicin alone markedly increased the mRNA expression of MDR1, MDR-associated protein (MRP) 1, and MRP2. In contrast, formononetin alone or combined treatment decreased the mRNA expression of MRP1 and MRP2. This result indicates that efflux transporter-mediated epirubicin resistance is inhibited at different degrees by the addition of formononetin. This isoflavone significantly intensified epirubicin uptake into HeLa cells. Apoptosis was induced by formononetin and/or epirubicin, as signified by nuclear DNA fragmentation, chromatin condensation, increased sub-G1 and G2/M phases. The cotreatment triggered the mitochondrial apoptotic pathway indicated by increased Bax-to-Bcl-2 expression ratio, loss of mitochondrial membrane potential, and significant activation of caspase-9 and -3. In addition, extrinsic/caspases-8 apoptotic pathway was also induced by the cotreatment. N-acetyl cysteine abrogated these events induced by formononetin, supporting the involvement of ROS in the MDR reversal mechanism. This study pioneered in demonstrating that formononetin may potentiate the cytotoxicity of epirubicin in HeLa cells through the ROS-mediated MRP inhibition and concurrent activation of the mitochondrial and death receptor pathways of apoptosis. Hence, the circumvention of pump and non-pump resistance using formononetin and epirubicin may pave the way for a powerful chemotherapeutic regimen for treating human cervical cancer.}, }
@article {pmid23867894, year = {2014}, author = {Zhang, Q and Gould, LJ}, title = {Hyperbaric oxygen reduces matrix metalloproteinases in ischemic wounds through a redox-dependent mechanism.}, journal = {The Journal of investigative dermatology}, volume = {134}, number = {1}, pages = {237-246}, pmid = {23867894}, issn = {1523-1747}, mesh = {Animals ; Antioxidants/metabolism ; Catalase/metabolism ; Disease Models, Animal ; Hyperbaric Oxygenation/*methods ; Ischemia/metabolism/*therapy ; Male ; Matrix Metalloproteinases/*metabolism ; Nitric Oxide/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Skin/*injuries/metabolism ; Superoxide Dismutase/metabolism ; Wound Healing/*physiology ; }, abstract = {Little is known about the impact of hyperbaric oxygen treatment (HBOT) on matrix metalloproteinase (MMP) production in pre-existing high-oxidant wounds. This study aimed to investigate whether HBOT modulates reactive oxygen species (ROS) and MMP regulation in ischemic wound tissue. Using a validated ischemic wound model, Sprague-Dawley rats were divided into four groups for daily treatment: HBOT, N-acetylcysteine (NAC), HBO and NAC, and control (normoxia at sea level). High levels of inducible nitric oxide synthase (iNOS), gp91-phox, and 3-nitrotyrosine were detected in ischemic wounds, indicating high-oxidant stress. HBOT not only increased antioxidant enzyme expression, such as Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase, but also significantly decreased pro-oxidant enzyme levels, such as iNOS and gp91-phox, thereby decreasing net oxygen radical production by means of negative feedback. This effect was blocked by NAC treatment in ischemic wounds. HBO-treated ischemic wounds also manifested reduced phosphorylation of extracellular signal-regulated kinases 1/2, c-Jun N-terminal kinase, and c-Jun, indicating downregulation of mitogen-activated protein kinases (MAPKs). Furthermore, HBOT decreased the expression of several MMPs while simultaneously increasing tissue inhibitor of MMP (tissue inhibitor of metalloproteinase 2). These results indicate that HBOT acts via the ROS/MAPK/MMP signaling axis to reduce tissue degeneration and improve ischemic wound healing.}, }
@article {pmid23867003, year = {2013}, author = {Hann, SS and Zheng, F and Zhao, S}, title = {Targeting 3-phosphoinositide-dependent protein kinase 1 by N-acetyl-cysteine through activation of peroxisome proliferators activated receptor alpha in human lung cancer cells, the role of p53 and p65.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {32}, number = {1}, pages = {43}, pmid = {23867003}, issn = {1756-9966}, mesh = {3-Phosphoinositide-Dependent Protein Kinases/*antagonists &amp; inhibitors/metabolism ; Acetylcysteine/*pharmacology ; Carcinoma, Non-Small-Cell Lung/genetics/*metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Activation/drug effects ; Gene Silencing ; Humans ; Lung Neoplasms/genetics/*metabolism ; PPAR alpha/*metabolism ; Promoter Regions, Genetic ; Protein Serine-Threonine Kinases/genetics/metabolism ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase ; Transcription Factor RelA/genetics/*metabolism ; Transcriptional Activation ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {BACKGROUND: N-Acetyl-Cysteine (NAC), a natural sulfur-containing amino acid derivative, and peroxisome proliferators activated receptor alpha (PPARα) ligand have been shown to have anticancer properties. However, the mechanisms by which these agents inhibit human non-small cell lung carcinoma (NSCLC) cell growth have not been well elucidated.<br><br>METHODS: Small interfering RNAs (siRNAs) were used to knockdown 3-phosphoinositide-dependent protein kinase 1 (PDK1), PPAR&#x3b1;, p65 and p53 genes; Western Blot was performed to detect the protein expression of PDK1, PPAR&#x3b1;, p65 and p53; Cell viability and MTT assays were carried out to determine the cell proliferation; Transient transfection and Dual-Luciferase Reporter assays were used to transfect siRNAs or exogenous expression vectors, and to measure the gene promoter activity.<br><br>RESULTS: We showed that NAC inhibited NSCLC cell proliferation through reduction of PDK1 expression. NAC also induced the protein expression of PPAR&#x3b1;. While PPAR&#x3b1; ligand enhanced, PPAR&#x3b1; antagonist and siRNA abrogated the effect of NAC on PDK1 promoter activity, protein expression and cell growth. Overexpression of PDK1 diminished the inhibitory effect of NAC on cell proliferation. NAC induced p53 and reduced p65 protein expression through activation of PPAR&#x3b1;. Silencing of p53 and overexpression of p65 blocked the effect of NAC on PDK1 promoter activity and protein expression.<br><br>CONCLUSION: Our results show that NAC inhibits PDK1 expression through PPAR&#x3b1;-mediated induction of p53 and inhibition of p65 protein expression. PPAR&#x3b1; ligand enhances the effect of NAC. This ultimately inhibits NSCLC cell growth. This study unveils a novel mechanism by which NAC in combination with PPAR&#x3b1; ligand inhibits growth of human lung carcinoma cells.}, }
@article {pmid23866879, year = {2013}, author = {Schwartz, RA and McDonough, PH and Lee, BW}, title = {Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment.}, journal = {Journal of the American Academy of Dermatology}, volume = {69}, number = {2}, pages = {187.e1-16; quiz 203-4}, doi = {10.1016/j.jaad.2013.05.002}, pmid = {23866879}, issn = {1097-6787}, mesh = {Acute Generalized Exanthematous Pustulosis/diagnosis/mortality/therapy ; Biopsy, Needle ; Diagnosis, Differential ; Disease Progression ; Early Diagnosis ; Education, Medical, Continuing ; Erythema Multiforme/diagnosis/mortality/therapy ; Female ; Graft vs Host Disease/diagnosis/mortality/therapy ; Humans ; Immunohistochemistry ; Male ; Primary Prevention/methods ; Risk Assessment ; Severity of Illness Index ; Staphylococcal Skin Infections/diagnosis/mortality/therapy ; Stevens-Johnson Syndrome/*diagnosis/mortality/prevention &amp; control/*therapy ; Survival Analysis ; }, abstract = {Toxic epidermal necrolysis (TEN) is a life-threatening, typically drug-induced, mucocutaneous disease. TEN has a high mortality rate, making early diagnosis and treatment of paramount importance. New but experimental diagnostic tools that measure serum granulysin and high-mobility group protein B1 (HMGB1) offer the potential to differentiate early TEN from other, less serious drug reactions, but these tests have not been validated and are not readily available. The mainstay of treatment for TEN involves discontinuation of the offending drug, specialized care in an intensive care unit or burn center, and supportive therapy. Pharmacogenetic studies have clearly established a link between human leukocyte antigen allotype and TEN. Human leukocyte antigen testing should be performed on patients of East Asian descent before the initiation of carbamezapine and on all patients before the initiation of abacavir. The effectiveness of systemic steroids, intravenous immunoglobulins, plasmapheresis, cyclosporine, biologics, and other agents is uncertain.}, }
@article {pmid23861961, year = {2013}, author = {Redpath, CJ and Bou Khalil, M and Drozdzal, G and Radisic, M and McBride, HM}, title = {Mitochondrial hyperfusion during oxidative stress is coupled to a dysregulation in calcium handling within a C2C12 cell model.}, journal = {PloS one}, volume = {8}, number = {7}, pages = {e69165}, pmid = {23861961}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium/*metabolism ; Calcium Signaling/drug effects ; Cell Differentiation/drug effects ; Mice ; Mitochondria/drug effects/*metabolism/ultrastructure ; Mitochondrial Dynamics/drug effects ; Mitochondrial Membranes/drug effects/metabolism ; *Models, Biological ; Muscle Contraction/drug effects ; Muscle Fibers, Skeletal/cytology/*metabolism/ultrastructure ; Mutant Proteins/metabolism ; Oxidation-Reduction/drug effects ; *Oxidative Stress/drug effects ; Protein Transport/drug effects ; Reactive Oxygen Species/metabolism ; Sarcoplasmic Reticulum/drug effects/metabolism ; }, abstract = {Atrial Fibrillation is the most common sustained cardiac arrhythmia worldwide harming millions of people every year. Atrial Fibrillation (AF) abruptly induces rapid conduction between atrial myocytes which is associated with oxidative stress and abnormal calcium handling. Unfortunately this new equilibrium promotes perpetuation of the arrhythmia. Recently, in addition to being the major source of oxidative stress within cells, mitochondria have been observed to fuse, forming mitochondrial networks and attach to intracellular calcium stores in response to cellular stress. We sought to identify a potential role for rapid stimulation, oxidative stress and mitochondrial hyperfusion in acute changes to myocyte calcium handling. In addition we hoped to link altered calcium handling to increased sarcoplasmic reticulum (SR)-mitochondrial contacts, the so-called mitochondrial associated membrane (MAM). We selected the C2C12 murine myotube model as it has previously been successfully used to investigate mitochondrial dynamics and has a myofibrillar system similar to atrial myocytes. We observed that rapid stimulation of C2C12 cells resulted in mitochondrial hyperfusion and increased mitochondrial colocalisation with calcium stores. Inhibition of mitochondrial fission by transfection of mutant DRP1K38E resulted in similar effects on mitochondrial fusion, SR colocalisation and altered calcium handling. Interestingly the effects of 'forced fusion' were reversed by co-incubation with the reducing agent N-Acetyl cysteine (NAC). Subsequently we demonstrated that oxidative stress resulted in similar reversible increases in mitochondrial fusion, SR-colocalisation and altered calcium handling. Finally, we believe we have identified that myocyte calcium handling is reliant on baseline levels of reactive oxygen species as co-incubation with NAC both reversed and retarded myocyte response to caffeine induced calcium release and re-uptake. Based on these results we conclude that the coordinate regulation of mitochondrial fusion and MAM contacts may form a point source for stress-induced arrhythmogenesis. We believe that the MAM merits further investigation as a therapeutic target in AF-induced remodelling.}, }
@article {pmid23860378, year = {2013}, author = {Martinez-Outschoorn, UE and Curry, JM and Ko, YH and Lin, Z and Tuluc, M and Cognetti, D and Birbe, RC and Pribitkin, E and Bombonati, A and Pestell, RG and Howell, A and Sotgia, F and Lisanti, MP}, title = {Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {12}, number = {16}, pages = {2580-2597}, pmid = {23860378}, issn = {1551-4005}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Caveolin 1/metabolism ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Drug Discovery ; Energy Metabolism/*physiology ; Epithelial Cells ; Flow Cytometry ; Gene Expression Regulation, Neoplastic/*physiology ; Glucose/metabolism ; Humans ; Mitochondrial Turnover/drug effects ; *Models, Biological ; Monocarboxylic Acid Transporters/*metabolism ; Muscle Proteins/*metabolism ; Oncogene Proteins/metabolism ; Oncogenes/genetics/*physiology ; Reactive Oxygen Species/metabolism ; Stromal Cells ; Tumor Microenvironment/*physiology ; }, abstract = {Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish "metabolic parasites", like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted "antibiotics" to selectively starve cancer cells. Our results provide new support for the "seed and soil" hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget.}, }
@article {pmid23860343, year = {2013}, author = {Holmay, MJ and Terpstra, M and Coles, LD and Mishra, U and Ahlskog, M and Öz, G and Cloyd, JC and Tuite, PJ}, title = {N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases.}, journal = {Clinical neuropharmacology}, volume = {36}, number = {4}, pages = {103-106}, pmid = {23860343}, issn = {1537-162X}, support = {S10 RR026783/RR/NCRR NIH HHS/United States ; P41 EB015894/EB/NIBIB NIH HHS/United States ; P41 RR008079/RR/NCRR NIH HHS/United States ; U54 NS065768/NS/NINDS NIH HHS/United States ; P30 NS076408/NS/NINDS NIH HHS/United States ; U54NS065768/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adolescent ; Antioxidants/administration &amp; dosage/*therapeutic use ; Antiparkinson Agents/administration &amp; dosage/therapeutic use ; Brain/*drug effects/metabolism ; Female ; Gaucher Disease/blood/*drug therapy/metabolism ; Glutathione/blood/*metabolism ; Humans ; Infusions, Intravenous ; Kinetics ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Neurons/drug effects/metabolism ; Oxidation-Reduction ; Parkinson Disease/blood/*drug therapy/metabolism ; Up-Regulation/*drug effects ; }, abstract = {OBJECTIVE: This study aimed to determine if the antioxidant N-acetylcysteine (NAC) is able to alter peripheral and central redox capabilities in patients with Parkinson disease (PD) or Gaucher disease (GD).<br><br>METHODS: The study included nondemented adult subjects: 3 with PD, 3 with GD, and 3 healthy controls. Baseline brain glutathione (GSH) concentrations were measured using 7-T magnetic resonance spectroscopy (MRS). Baseline blood reduced-to-oxidized GSH ratios were determined for each subject. Brain GSH concentrations and blood redox ratios were then determined during and at specified time points after a single, 150-mg/kg NAC infusion.<br><br>RESULTS: N-acetylcysteine increased blood GSH redox ratios in those with PD and GD and healthy controls, which was followed by an increase in brain GSH concentrations in all subjects.<br><br>CONCLUSIONS: This is the first demonstration that with MRS, it is possible to directly measure and monitor increases in brain GSH levels in the human brain in response to a single, intravenous administration of NAC. This work shows the potential utility of MRS monitoring, which could assist in determining dosing regimens for clinical trials of this potentially useful antioxidant therapy for PD disease, GD, and other neurodegenerative disorders.}, }
@article {pmid23857552, year = {2014}, author = {Kato, K and Matsushita, M}, title = {Proton concentrations can be a major contributor to the modification of osteoclast and osteoblast differentiation, working independently of extracellular bicarbonate ions.}, journal = {Journal of bone and mineral metabolism}, volume = {32}, number = {1}, pages = {17-28}, pmid = {23857552}, issn = {1435-5604}, mesh = {Acetylcysteine/pharmacology ; Animals ; Bicarbonates/*pharmacology ; Bone and Bones/cytology/drug effects/metabolism ; Bucladesine/pharmacology ; Buffers ; Calcification, Physiologic/drug effects ; Cell Culture Techniques ; *Cell Differentiation/drug effects ; Cells, Cultured ; Culture Media/pharmacology ; Extracellular Space/drug effects/*metabolism ; Hydrogen-Ion Concentration/drug effects ; Ions ; Mice ; Osteoblasts/*cytology/drug effects/metabolism ; Osteoclasts/*cytology/drug effects/metabolism ; *Protons ; RNA, Messenger/genetics/metabolism ; TRPV Cation Channels/antagonists &amp; inhibitors/genetics/metabolism ; Time Factors ; }, abstract = {We established a system to separately analyze the role of protons and bicarbonate ions in vitro in which the pH of the medium was controlled by HEPES at various concentrations of sodium bicarbonate (NaHCO3) in the absence of carbon dioxide (CO2). Using this system, we demonstrated that acidosis promoted osteoclast formation independently of extracellular NaHCO3 in a short-term culture. Protons and bicarbonate ions acted on osteoclast differentiation with opposite effects, the former positively and the latter negatively. The HEPES-based system maintained pH in the absence of extracellular NaHCO3 without CO2. Therefore, we could demonstrate that osteoblast differentiation was promoted at higher pH in a long-term culture system without NaHCO3 in which ALP activity and nodule mineralization were enhanced. This finding indicates that protons negatively control osteoblast differentiation independently of extracellular bicarbonate ions. However, the difference in the concentration of NaHCO3 did not have any influence on nodule mineralization. The opposite effects of protons, the promotion of osteoclast formation and the inhibition of osteoblast differentiation, were suppressed in the presence of 5 mM N-acetyl cysteine, a reagent activating the scavenging of reactive oxygen species (ROS), implying that ROS act on both systems, the promotion of large osteoclast formation and the deterioration of osteoblast formation under acidosis.}, }
@article {pmid23855763, year = {2013}, author = {Yu, CH and Liu, ZY and Sun, LS and Li, YJ and Zhang, DS and Pan, RT and Sun, ZL}, title = {Effect of Danofloxacin on Reactive Oxygen Species Production, Lipid Peroxidation and Antioxidant Enzyme Activities in Kidney Tubular Epithelial Cell Line, LLC-PK1.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {113}, number = {6}, pages = {377-384}, doi = {10.1111/bcpt.12110}, pmid = {23855763}, issn = {1742-7843}, mesh = {Animals ; Anti-Infective Agents/adverse effects/*pharmacology ; Antioxidants ; Catalase/drug effects/metabolism ; Dose-Response Relationship, Drug ; Fluoroquinolones/adverse effects/*pharmacology ; Glutathione Peroxidase/drug effects/metabolism ; Kidney Tubules/drug effects ; LLC-PK1 Cells/*drug effects/metabolism ; Lipid Peroxidation/*drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/drug effects/metabolism ; Swine ; }, abstract = {The purpose of this study was to investigate the possibility that oxidative stress was involved in danofloxacin-induced toxicity in renal tubular cells epithelial cell line (LLC-PK1). Confluent LLC-PK1 cells were incubated with various concentrations of danofloxacin. The extent of oxidative damage was assessed by measuring the reactive oxygen species (ROS) level, lipid peroxidation, cell apoptosis and antioxidative enzyme activities. Danofloxacin induced a concentration-dependent increase in the ROS production, not even cytotoxic conditions. Similarly, danofloxacin caused an about 4 times increase in the level of thiobarbituric acid reactive substances at the concentration of 400 μM for 24 hr, but it did not induce cytotoxicity and apoptosis. Antioxidant enzymes activities, such as superoxide dismutase (SOD) and catalase (CAT), were increased after treatment with 100, 200 and 400 μM of danofloxacin for 24 hr. The activity of glutathione peroxidase (GPX) was significantly decreased in a concentration-dependent manner. In addition, ROS production, lipid peroxidation and GPX decline were inhibited by additional glutathione and N-acetyl cysteine. These data suggested that danofloxacin could not induce oxidative stress in LLC-PK1 cells at the concentration (≤400 μM) for 24 hr. The increase levels of ROS and lipid peroxidation could be partly abated by the increase activities of SOD and CAT.}, }
@article {pmid23855452, year = {2013}, author = {Duong, HQ and Hong, YB and Kim, JS and Lee, HS and Yi, YW and Kim, YJ and Wang, A and Zhao, W and Cho, CH and Seong, YS and Bae, I}, title = {Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine.}, journal = {Journal of cellular and molecular medicine}, volume = {17}, number = {10}, pages = {1261-1270}, pmid = {23855452}, issn = {1582-4934}, support = {P30 CA051008/CA/NCI NIH HHS/United States ; R03 CA152530/CA/NCI NIH HHS/United States ; P30-CA051008/CA/NCI NIH HHS/United States ; 1R03CA152530/CA/NCI NIH HHS/United States ; }, mesh = {Adenocarcinoma/*drug therapy/metabolism/pathology ; Antimetabolites, Antineoplastic/*therapeutic use ; Apoptosis ; Blotting, Western ; Cell Line, Tumor ; Checkpoint Kinase 2/*antagonists &amp; inhibitors ; Deoxycytidine/*analogs &amp; derivatives/therapeutic use ; Humans ; Pancreatic Neoplasms/*drug therapy/metabolism/pathology ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Gemcitabine ; }, abstract = {Checkpoint kinase 2 (CHK2) plays pivotal function as an effector of cell cycle checkpoint arrest following DNA damage. Recently, we found that co-treatment of NSC109555 (a potent and selective CHK2 inhibitor) potentiated the cytotoxic effect of gemcitabine (GEM) in pancreatic cancer MIA PaCa-2 cells. Here, we further examined whether NSC109555 could enhance the antitumour effect of GEM in pancreatic adenocarcinoma cell lines. In this study, the combination treatment of NSC109555 plus GEM demonstrated strong synergistic antitumour effect in four pancreatic cancer cells (MIA PaCa-2, CFPAC-1, Panc-1 and BxPC-3). In addition, the GEM/NSC109555 combination significantly increased the level of intracellular reactive oxygen species (ROS), accompanied by induction of apoptotic cell death. Inhibition of ROS generation by N-acetyl cysteine (NAC) significantly reversed the effect of GEM/NSC109555 in apoptosis and cytotoxicity. Furthermore, genetic knockdown of CHK2 by siRNA enhanced GEM-induced apoptotic cell death. These findings suggest that inhibition of CHK2 would be a beneficial therapeutic approach for pancreatic cancer therapy in clinical treatment.}, }
@article {pmid23853776, year = {2013}, author = {Xu, J and Lei, S and Liu, Y and Gao, X and Irwin, MG and Xia, ZY and Hei, Z and Gan, X and Wang, T and Xia, Z}, title = {Antioxidant N-acetylcysteine attenuates the reduction of Brg1 protein expression in the myocardium of type 1 diabetic rats.}, journal = {Journal of diabetes research}, volume = {2013}, number = {}, pages = {716219}, pmid = {23853776}, issn = {2314-6745}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; DNA Helicases/*metabolism ; Diabetes Mellitus, Experimental/drug therapy/*metabolism ; Diabetes Mellitus, Type 1/drug therapy/*metabolism ; Dinoprost/analogs &amp; derivatives ; Free Radical Scavengers/*pharmacology/therapeutic use ; Heart/*drug effects ; Heme Oxygenase-1/metabolism ; Interleukin-6/blood ; Isoprostanes/blood ; Myocardium/*metabolism ; Nuclear Proteins/*metabolism ; Phosphorylation/drug effects ; Rats ; STAT3 Transcription Factor/metabolism ; Transcription Factors/*metabolism ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {Brahma-related gene 1 (Brg1) is a key gene in inducing the expression of important endogenous antioxidant enzymes, including heme oxygenase-1 (HO-1) which is central to cardioprotection, while cardiac HO-1 expression is reduced in diabetes. It is unknown whether or not cardiac Brg1 expression is reduced in diabetes. We hypothesize that cardiac Brg1 expression is reduced in diabetes which can be restored by antioxidant treatment with N-acetylcysteine (NAC). Control (C) and streptozotocin-induced diabetic (D) rats were treated with NAC in drinking water or placebo for 4 weeks. Plasma and cardiac free15-F2t-isoprostane in diabetic rats were increased, accompanied with increased plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), while cardiac Brg1, p-STAT3 and HO-1 protein expression levels were significantly decreased. Left ventricle weight/body weight ratio was higher, while the peak velocities of early (E) and late (A) flow ratio was lower in diabetic than in C rats. NAC normalized tissue and plasma levels of 15-F2t-isoprostane, significantly increased cardiac Brg1, HO-1 and p-STAT3 protein expression levels and reduced TNF-alpha and IL-6, resulting in improved cardiac function. In conclusion, myocardial Brg1 is reduced in diabetes and enhancement of cardiac Brg1 expression may represent a novel mechanism whereby NAC confers cardioprotection.}, }
@article {pmid23852079, year = {2013}, author = {Platz, S and Kühn, C and Schiess, S and Schreiner, M and Mewis, I and Kemper, M and Pfeiffer, A and Rohn, S}, title = {Determination of benzyl isothiocyanate metabolites in human plasma and urine by LC-ESI-MS/MS after ingestion of nasturtium (Tropaeolum majus L.).}, journal = {Analytical and bioanalytical chemistry}, volume = {405}, number = {23}, pages = {7427-7436}, doi = {10.1007/s00216-013-7176-7}, pmid = {23852079}, issn = {1618-2650}, mesh = {Acetylcysteine/chemistry ; Adult ; Biotransformation ; Chromatography, Liquid ; Cysteine/chemistry ; Dipeptides/chemistry ; Eating/physiology ; Female ; Glutathione/chemistry ; Humans ; *Isothiocyanates/blood/urine ; Male ; Middle Aged ; Nasturtium/*chemistry ; Spectrometry, Mass, Electrospray Ionization ; Tandem Mass Spectrometry ; }, abstract = {A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine the concentration of benzyl isothiocyanate (BITC) metabolites in human plasma and urine. In this study, the following BITC metabolites have been considered: BITC-glutathione, BITC-cysteinylglycine, BITC-cysteine, and BITC-N-acetyl-L-cysteine. The assay development included: (1) synthesis of BITC conjugates acting as reference substances; (2) sample preparation based on protein precipitation and solid-phase extraction; (3) development of a quantitative LC-MS/MS method working in the multiple-reaction monitoring mode; (4) validation of the assay; (5) investigation of the stability and the reactivity of BITC conjugates in vitro; (6) application of the method to samples from a human intervention study. The lower limits of quantification were in the range of 21-183 nM depending on analyte and matrix, whereas the average recovery rates from spiked plasma and urine were approximately 85 and 75 %, respectively. BITC conjugates were found to be not stable in alkaline buffered solutions. After consumption of nasturtium, containing 1,000 μM glucotropaeolin, the primary source of BITC, quantifiable levels of BITC-NAC, BITC-Cys, and BITC-CysGly were found in human urine samples. Maximum levels in urine were determined 4 h after the ingestion of nasturtium. With regard to the human plasma samples, all metabolites were determined including individual distributions. The work presented provides a validated LC-MS/MS method for the determination of BITC metabolites and its successful application for the analysis of samples collected in a human intervention study.}, }
@article {pmid23851615, year = {2013}, author = {Xia, J and Zhou, XL and Zhao, Y and Zhu, YQ and Jiang, S and Ni, SZ}, title = {Roles of lipoxin A4 in preventing paracetamol-induced acute hepatic injury in a rabbit model.}, journal = {Inflammation}, volume = {36}, number = {6}, pages = {1431-1439}, pmid = {23851615}, issn = {1573-2576}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Apoptosis/drug effects ; Chemical and Drug Induced Liver Injury/*drug therapy/prevention &amp; control ; Hepatocytes/drug effects/enzymology/*metabolism ; Inflammation/chemically induced/drug therapy ; Interleukin-10/biosynthesis ; Lipoxins/*therapeutic use ; Liver/drug effects/enzymology/*metabolism ; Male ; Rabbits ; Transcription Factor RelA/biosynthesis ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {The objective of this research is to investigate the potential role of lipoxin A4 in preventing paracetamol (PCM)-induced hepatic injury. One hundred male New Zealand white rabbits were randomly divided into control group, PCM group, N-acetylcysteine (NAC) group, lipoxin A4 (LXA4) group, and LXA4 + NAC group. The rabbits were assigned to receive 300 mg/kg weight PCM in 0.9 % saline or equivalent volume of saline via gastric lavage. LXA4 (1.5 μg/kg) and equivalent volume of 2 % ethanol were separately given to the rabbits in LXA4-treated and PCM groups 24 h after PCM administration. Meanwhile, the rabbits in the NAC-treated groups received a loading dose of 140 mg/kg of N-acetylcysteine. The blood samples and liver tissue were collected for biochemical and histological evaluation 36 h after paracetamol administration. The administration of LXA4 24 h after paracetamol poisoning resulted in significant improvement in hepatic injury as represented by decrease of hepatocellular enzyme release and attenuation of hepatocyte apoptosis and necrosis. In LXA4-treated groups, the expression of TNF-α was significantly lower than those in PCM and NAC groups (p < 0.05). In contrast, the level of IL-10 was significantly higher than PCM and NAC groups (p < 0.05). Moreover, the expressions of NF-κB p65 in PCM and NAC groups were significantly increased compared with those of LXA4-treated groups and control group (respectively, p < 0.05 and p < 0.01). LXA4-treated groups also showed significantly higher survival rates. Lipoxin A4 significantly mitigates paracetamol-induced hepatic injury, in which anti-inflammation effect may play an important role, leading to hepatic apoptosis and necrosis.}, }
@article {pmid23851285, year = {2013}, author = {Hsieh, YC and Hsu, SL and Gu, SH}, title = {Involvement of reactive oxygen species in PTTH-stimulated ecdysteroidogenesis in prothoracic glands of the silkworm, Bombyx mori.}, journal = {Insect biochemistry and molecular biology}, volume = {43}, number = {9}, pages = {859-866}, doi = {10.1016/j.ibmb.2013.06.008}, pmid = {23851285}, issn = {1879-0240}, mesh = {Animals ; Bombyx/genetics/*metabolism ; Ecdysteroids/*metabolism ; Endocrine Glands/metabolism ; Insect Hormones/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {In the present study, the possible involvement of reactive oxygen species (ROS) in prothoracicotropic hormone (PTTH)-stimulated ecdysteroidogenesis of Bombyx mori prothoracic glands (PGs) was investigated. Results showed that PTTH treatment resulted in a rapidly transient increase in the intracellular ROS concentration, as measured using 2',7'-dichlorofluorescin diacetate (DCFDA), an oxidation-sensitive fluorescent probe. The antioxidant, N-acetylcysteine (NAC), abolished PTTH-induced increase in fluorescence. Furthermore, PTTH-induced ROS production was partially inhibited by the NAD(P)H oxidase inhibitor, apocynin, indicating that NAD(P)H oxidase is one of the sources for PTTH-stimulated ROS production. Four mitochondrial oxidative phosphorylation inhibitors (rotenone, antimycin A, the uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), and diphenylene iodonium (DPI)) significantly attenuated ROS production induced by PTTH. These data suggest that the activity of complexes I and III in the electron transport chain and the mitochondrial inner membrane potential (ΔΨ) contribute to PTTH-stimulated ROS production. In addition, PTTH-stimulated ecdysteroidogenesis was greatly inhibited by treatment with either NAC or mitochondrial inhibitors (rotenone, antimycin A, FCCP, and DPI), but not with apocynin. These results indicate that mitochondria-derived, but not membrane NAD(P)H oxidase-mediated ROS signaling, is involved in PTTH-stimulated ecdysteroidogenesis of PGs in B. mori.}, }
@article {pmid23850346, year = {2013}, author = {Zeng, SY and Chen, X and Chen, SR and Li, Q and Wang, YH and Zou, J and Cao, WW and Luo, JN and Gao, H and Liu, PQ}, title = {Upregulation of Nox4 promotes angiotensin II-induced epidermal growth factor receptor activation and subsequent cardiac hypertrophy by increasing ADAM17 expression.}, journal = {The Canadian journal of cardiology}, volume = {29}, number = {10}, pages = {1310-1319}, doi = {10.1016/j.cjca.2013.04.026}, pmid = {23850346}, issn = {1916-7075}, mesh = {ADAM Proteins/biosynthesis/*genetics ; ADAM17 Protein ; Angiotensin II/*pharmacology ; Animals ; Cardiomegaly/drug therapy/*genetics/metabolism ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; ErbB Receptors/drug effects/*metabolism ; Male ; Myocardium/metabolism/pathology ; NADPH Oxidase 4 ; NADPH Oxidases/biosynthesis/*genetics ; RNA/*genetics ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/genetics ; Transcriptional Activation/drug effects ; Tumor Necrosis Factor-alpha ; Up-Regulation/*drug effects ; }, abstract = {BACKGROUND: Activation of epidermal growth factor receptor (EGFR) plays an important role in angiotensin II (Ang II)-induced cardiac hypertrophy, but little is known about the underlying mechanism that results in EGFR activation. In this study, we aimed to confirm the important role of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) in Ang II-induced EGFR activation and subsequent cardiac hypertrophy by upregulating expression of a disintegrin and metalloproteinase (MMP)-17 (ADAM17).<br><br>METHODS: Small interference RNA (siRNA) was adopted to knock down ADAM17 or Nox4 expression. Nox4 plasmid was used to construct cardiomyocytes with Nox4 overexpression.<br><br>RESULTS: Nox4 and ADAM17 increased in an abdominal artery coarctation-induced model of myocardial hypertrophy. In&#xa0;vitro studies showed that Nox4 was required in Ang II-induced EGFR activation and subsequent myocardial hypertrophy. Nox4 siRNA and Nox4 overexpression demonstrated that Nox4 controlled the transcription and translation of ADAM17. Furthermore, we observed that the ratio of phosphor-EGFR (p-EGFR) to EGFR was significantly reduced by ADAM17 siRNA in hypertrophic cardiomyocytes. Enzyme-linked immunosorbent assay studies revealed that Nox4 and ADAM17 mediated the release of mature heparin-binding EGF-like growth factor (HB-EGF), which played a critical role in the Ang II-induced EGFR activation. Moreover, the results of reactive oxygen species (ROS) scavenging by N-acetyl cysteine (NAC) indicated that ROS were required in the Nox4-mediated upregulation of ADAM17 expression.<br><br>CONCLUSIONS: In summary, Nox4 is required in Ang II-induced EGFR activation and subsequent cardiac hypertrophy; it increased the expression of ADAM17, which induced the release of mature HB-EGF. ROS were also required in the Nox4-mediated upregulation of ADAM17 expression.}, }
@article {pmid23845486, year = {2013}, author = {Xie, C and Zhong, D and Chen, X}, title = {A fragmentation-based method for the differentiation of glutathione conjugates by high-resolution mass spectrometry with electrospray ionization.}, journal = {Analytica chimica acta}, volume = {788}, number = {}, pages = {89-98}, doi = {10.1016/j.aca.2013.06.022}, pmid = {23845486}, issn = {1873-4324}, mesh = {Chemical Fractionation/methods ; Chromatography, Liquid/methods ; Disulfides/chemistry ; Glutathione/*analysis/*chemistry ; Ions ; Spectrometry, Mass, Electrospray Ionization/methods ; Tandem Mass Spectrometry/methods ; }, abstract = {Idiosyncratic reactions are one of the major causes of drug treatment limitations or market withdrawals, and likely involve the formation of reactive metabolites. Because of their unstable nature, reactive species are usually discovered as stable conjugates by glutathione (GSH) trapping rather than by direct detection. The GSH conjugates are then detected by neutral loss scanning of 129 Da or precursor ion scanning at m/z 272, but the conjugation sites can only be identified by comparison with reference standards. In the present study, the fragmentation behaviors of 52 GSH conjugates belonging to five structural classes (aliphatic, aromatic, benzylic, disulfide, and thioester) were investigated in both positive and negative electrospray ionization modes by high-resolution mass spectrometry with suitable collision energies such that the relative abundance of the parent ion was approximately 50% of the most abundant product ion. Several structural-diagnostic fragmentations were identified: aliphatic conjugates gave i/j-type ions upon cleavage of the C-S bond between the drug and GSH, and d/k-type ions formed by the cleavage of the cysteinyl C-S bond, with approximately equal intensity, in both positive and negative modes, whereas aromatic conjugates only possessed d/k-type ions, and benzylic conjugates primarily yielded i/j-type ions. Disulfide conjugates typically produced dehydrogenated GS(-) fragment ions ([i-2H]-type) in negative mode, and thioester conjugates displayed sequential losses of pyroglutamic acid and water ([e-H2O]-type) in positive mode. A fragmentation-based method was thus established to facilitate the discrimination of these five classes of GSH conjugates, thereby providing insight into the bioactivation mechanisms and supporting lead optimization.}, }
@article {pmid23843173, year = {2014}, author = {Pillai, K and Akhter, J and Chua, TC and Morris, DL}, title = {A formulation for in situ lysis of mucin secreted in pseudomyxoma peritonei.}, journal = {International journal of cancer}, volume = {134}, number = {2}, pages = {478-486}, doi = {10.1002/ijc.28380}, pmid = {23843173}, issn = {1097-0215}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bromelains/*pharmacology ; Drug Combinations ; Expectorants/*pharmacology ; Male ; Mucins/*metabolism ; Mucus/drug effects/*metabolism ; Peritoneal Neoplasms/*drug therapy ; Pseudomyxoma Peritonei/*drug therapy ; Rats ; Rats, Nude ; }, abstract = {Although numerous clinical attempts have been made to disintegrate mucin secreted by pseudomyxoma peritonei (PMP), none are clinically recommended. Through examination of the pharmacologic characteristics of two novel agents, we titrated an optimized combination of bromelain and N-acetyl cysteine (NAC) that demonstrates in vitro and in vivo efficacy in the dissolution of mucinous ascites from PMP. In the in vitro experiments, 1 g of mucin was incubated in varying concentrations of bromelain (0-400 µg/ml) and NAC (0-5%) individually followed by a combination before arriving at a therapeutic combination dose of 300 µg/ml bromelain+4% NAC. This established an effective dose of bromelain 300 µg/ml+4% NAC at pH 7.0, when tested in a rat model implanted with 3 g of mucin intraperitoneally (IP). IP administration of the drug in a rat model of PMP was shown to result in mucin disintegration within 72 hr with no toxicity observed.}, }
@article {pmid23842934, year = {2013}, author = {Teixeira, RK and Yamaki, VN and Yasojima, EY and Brito, MV}, title = {Effect of copaiba oil in hepatic damage induced by acetaminophen in rats.}, journal = {Acta cirurgica brasileira}, volume = {28}, number = {7}, pages = {526-530}, doi = {10.1590/s0102-86502013000700008}, pmid = {23842934}, issn = {1678-2674}, mesh = {Acetaminophen/*adverse effects ; Analgesics, Non-Narcotic/*adverse effects ; Animals ; Bilirubin/blood ; Chemical and Drug Induced Liver Injury/*drug therapy/pathology ; Fabaceae/*chemistry ; Male ; Plant Oils/*therapeutic use ; Random Allocation ; Rats ; Rats, Wistar ; Reproducibility of Results ; Time Factors ; Treatment Outcome ; }, abstract = {PURPOSE: To investigate the effects of copaiba oil on the hepatic damage induced by paracetamol.<br><br>METHODS: Thirty six rats were distributed into six study groups (N=6): control group, that didn't receive the acetaminophen; Acetaminophen Group, that only received the acetaminophen; Prophylactic Copaiba Group 1, that received copaiba oil two hours before the acetaminophen; Prophylactic Copaiba Group 7, that received copaiba oil seven days, once by day, before the acetaminophen; Therapy Copaiba Group, that received the copaiba oil two hours afther the acetaminophen; and N-Acetyl-Cysteine Group, , that received the N-Acetyl-Cysteine two hours afther the acetaminophen. Euthanasia was performed after 24 hours. The serum levels of AST, ALT, alkaline phosphatase, [formula see text] GT, total bilirubin, direct bilirubin and indirect bilirubin and histological analisis were analized.<br><br>RESULTS: The prophylactic copaiba group 7, therapy copaiba group and N-Acetyl-Cysteine Group showed amounts of AST and ALT similar to the control group; and the prophylactic copaiba group 1 showed similar levels to the acetaminophen group. There was no significant difference between the groups regarding the amount of alkaline phosphatase and [formula see text] GT (p>0.05). The therapy copaiba group showed the highest levels of bilirubin and was statistically different from the other groups (p<0.01) and this increased the costs of direct bilirubin. Regarding histopathology, the oil of copaiba administered prophylactic or therapeutic form for 7 days could decrease the amount of necrosis and inflammatory infiltrate.<br><br>CONCLUSION: Copaiba oil administered prophylactically for seven days, and therapeutic could reduce liver damage caused by paracetamol similarly N-Acetyl-Cysteine, however, when treated with copaiba therapeutically showed increases in bilirubin, costs increasing fraction indirect.}, }
@article {pmid23841076, year = {2013}, author = {Shin, S and Jing, K and Jeong, S and Kim, N and Song, KS and Heo, JY and Park, JH and Seo, KS and Han, J and Park, JI and Kweon, GR and Park, SK and Wu, T and Hwang, BD and Lim, K}, title = {The omega-3 polyunsaturated fatty acid DHA induces simultaneous apoptosis and autophagy via mitochondrial ROS-mediated Akt-mTOR signaling in prostate cancer cells expressing mutant p53.}, journal = {BioMed research international}, volume = {2013}, number = {}, pages = {568671}, pmid = {23841076}, issn = {2314-6141}, mesh = {Apoptosis/drug effects ; Autophagy/drug effects ; Cell Line, Tumor ; Docosahexaenoic Acids ; Fatty Acids, Omega-3/*administration &amp; dosage/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; Mitochondria/drug effects/metabolism/pathology ; Mutation ; Oncogene Protein v-akt/*metabolism ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/*metabolism ; Tumor Suppressor Protein p53/*biosynthesis/genetics ; }, abstract = {Docosahexaenoic acid (DHA) induces autophagy-associated apoptotic cell death in wild-type p53 cancer cells via regulation of p53. The present study investigated the effects of DHA on PC3 and DU145 prostate cancer cell lines harboring mutant p53. Results show that, in addition to apoptosis, DHA increased the expression levels of lipidated form LC3B and potently stimulated the autophagic flux, suggesting that DHA induces both autophagy and apoptosis in cancer cells expressing mutant p53. DHA led to the generation of mitochondrial reactive oxygen species (ROS), as shown by the mitochondrial ROS-specific probe mitoSOX. Similarly, pretreatment with the antioxidant N-acetyl-cysteine (NAC) markedly inhibited both the autophagy and the apoptosis triggered by DHA, indicating that mitochondrial ROS mediate the cytotoxicity of DHA in mutant p53 cells. Further, DHA reduced the levels of phospho-Akt and phospho-mTOR in a concentration-dependent manner, while NAC almost completely blocked that effect. Collectively, these findings present a novel mechanism of ROS-regulated apoptosis and autophagy that involves Akt-mTOR signaling in prostate cancer cells with mutant p53 exposed to DHA.}, }
@article {pmid23840457, year = {2013}, author = {Sceneay, J and Liu, MC and Chen, A and Wong, CS and Bowtell, DD and Möller, A}, title = {The antioxidant N-acetylcysteine prevents HIF-1 stabilization under hypoxia in vitro but does not affect tumorigenesis in multiple breast cancer models in vivo.}, journal = {PloS one}, volume = {8}, number = {6}, pages = {e66388}, pmid = {23840457}, issn = {1932-6203}, support = {//Cancer Research UK/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Carcinogenesis ; Cell Hypoxia ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Epithelial-Mesenchymal Transition ; Female ; Glutathione/blood ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Lung Neoplasms/blood supply/*drug therapy/metabolism/secondary ; Mammary Neoplasms, Experimental/blood supply/*drug therapy/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Neovascularization, Pathologic/metabolism/pathology/prevention &amp; control ; Phenotype ; Protein Stability ; Tumor Burden/drug effects ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Intratumoral hypoxia is a poor prognostic factor associated with reduced disease-free survival in many cancer types, including breast cancer. Hypoxia encourages tumor cell proliferation, stimulates angiogenesis and lymphangiogenesis, and promotes epithelial-mesenchymal transition and metastasis. Tumor cells respond to a hypoxic state by stabilizing the Hif-1α subunit of the Hypoxia-Inducible Factor (HIF) transcription factor to promote expression of various tumor- and metastasis-promoting hypoxic response genes. The antioxidant N-acetylcysteine (NAC) was recently shown to prevent Hif-1α stabilization under hypoxia, and has been identified as a potential alternative method to target the hypoxic response in tumors. We utilized three orthotopic syngeneic murine models of breast cancer, the PyMT, EO771 and 4T1.2 models, to investigate the ability of NAC to modulate the hypoxic response in vitro and in vivo. While NAC prevented Hif-1α stabilization under hypoxia in vitro and increased levels of glutathione in the blood of mice in vivo, this did not translate to a difference in tumor growth or the hypoxic state of the tumor compared to untreated control mice. In addition, NAC treatment actually increased metastatic burden in an experimental metastasis model. This work raises questions regarding the validity of NAC as an anti-tumorigenic agent in breast cancer, and highlights the need to further investigate its properties in vivo in different cancer models.}, }
@article {pmid23831462, year = {2013}, author = {Capanni, C and Bruschi, M and Columbaro, M and Cuccarolo, P and Ravera, S and Dufour, C and Candiano, G and Petretto, A and Degan, P and Cappelli, E}, title = {Changes in vimentin, lamin A/C and mitofilin induce aberrant cell organization in fibroblasts from Fanconi anemia complementation group A (FA-A) patients.}, journal = {Biochimie}, volume = {95}, number = {10}, pages = {1838-1847}, doi = {10.1016/j.biochi.2013.06.024}, pmid = {23831462}, issn = {1638-6183}, support = {GTB12001/TI_/Telethon/Italy ; }, mesh = {Cell Nucleus/drug effects/metabolism/ultrastructure ; Cells, Cultured ; Cytoskeleton/drug effects/*metabolism/ultrastructure ; Fanconi Anemia/genetics/*metabolism/pathology ; Fanconi Anemia Complementation Group A Protein/genetics/metabolism ; Fibroblasts/drug effects/*metabolism/pathology ; Gene Expression ; Humans ; Hydrogen Peroxide/pharmacology ; Lamin Type A/genetics/*metabolism ; Microscopy, Electron ; Mitochondria/drug effects/metabolism/ultrastructure ; Mitochondrial Proteins/genetics/*metabolism ; Muscle Proteins/genetics/*metabolism ; Mutation ; Oxidation-Reduction ; Oxidative Stress ; Vimentin/genetics/*metabolism ; }, abstract = {Growing number of publication has proved an increasing of cellular function of the Fanconi anemia proteins. To chromosome stability and DNA repair new roles have been attributed to FA proteins in oxidative stress response and homeostasis, immune response and cytokines sensibility, gene expression. Our work shows a new role for FA-A protein: the organization of the cellular structure. By 2D-PAGE of FA-A and correct fibroblasts treated and untreated with H2O2 we identify different expression of protein involved in the structural organization of nucleus, intermediate filaments and mitochondria. Immunofluorescence and electronic microscopy analysis clearly show an already altered cellular structure in normal culture condition and this worsted after oxidative stress. FA-A cell appears structurally prone to physiologic stress and this could explain part of the phenotype of FA cells.}, }
@article {pmid23831192, year = {2013}, author = {Raina, K and Tyagi, A and Kumar, D and Agarwal, R and Agarwal, C}, title = {Role of oxidative stress in cytotoxicity of grape seed extract in human bladder cancer cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {61}, number = {}, pages = {187-195}, pmid = {23831192}, issn = {1873-6351}, support = {R01 CA091883/CA/NCI NIH HHS/United States ; P30 CA046934/CA/NCI NIH HHS/United States ; CA102514/CA/NCI NIH HHS/United States ; R01 AT003623/AT/NCCIH NIH HHS/United States ; AT003623/AT/NCCIH NIH HHS/United States ; CA91883/CA/NCI NIH HHS/United States ; R01 CA102514/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Autophagy/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Death/drug effects ; Cell Line, Tumor/drug effects ; Cytoplasm/drug effects ; Grape Seed Extract/*pharmacology ; Humans ; Microtubule-Associated Proteins/metabolism ; Oxidative Stress/*drug effects/physiology ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; Urinary Bladder Neoplasms/*drug therapy/*metabolism/pathology ; }, abstract = {In present study, we evaluated grape seed extract (GSE) efficacy against bladder cancer and associated mechanism in two different bladder cancer cell lines T24 and HTB9. A significant inhibitory effect of GSE on cancer cell viability was observed, which was due to apoptotic cell death. Cell death events were preceded by vacuolar appearance in cytoplasm, which under electron microscopy was confirmed as swollen mitochondrial organelle and autophagosomes. Through detailed in vitro studies, we established that GSE generated oxidative stress that initiated an apoptotic response as indicated by the reversal of GSE-mediated apoptosis when the cells were pre-treated with antioxidants prior to GSE. However, parallel to a strong apoptotic cell death event, GSE also caused a pro-survival autophagic event as evidenced by tracking the dynamics of LC3-II within the cells. Since the pro-death apoptotic response was stronger than the pro-survival autophagy induction within the cells, cell eventually succumbed to cellular death after GSE exposure. Together, the findings in the present study are both novel and highly significant in establishing, for the first time, that GSE-mediated oxidative stress causes a strong programmed cell death in human bladder cancer cells, suggesting and advocating the effectiveness of this non-toxic agent against this deadly malignancy.}, }
@article {pmid23829996, year = {2014}, author = {Yi, D and Hou, Y and Wang, L and Ding, B and Yang, Z and Li, J and Long, M and Liu, Y and Wu, G}, title = {Dietary N-acetylcysteine supplementation alleviates liver injury in lipopolysaccharide-challenged piglets.}, journal = {The British journal of nutrition}, volume = {111}, number = {1}, pages = {46-54}, doi = {10.1017/S0007114513002171}, pmid = {23829996}, issn = {1475-2662}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adenosine Monophosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/metabolism/pharmacology/*therapeutic use ; Chemical and Drug Induced Liver Injury/blood/metabolism/pathology/*prevention &amp; control ; Cytokines/blood/*metabolism ; *Dietary Supplements ; Disease Models, Animal ; Energy Metabolism/drug effects ; Female ; HSP70 Heat-Shock Proteins/metabolism ; Inflammation Mediators/*metabolism ; Lipopolysaccharides ; Liver/*drug effects/enzymology/metabolism/pathology ; NF-kappa B/metabolism ; Random Allocation ; Swine ; }, abstract = {The present study was carried out to determine whether N-acetylcysteine (NAC) could modulate liver injury in a lipopolysaccharide (LPS)-challenged piglet model. For this purpose, eighteen piglets were randomly assigned to the control, LPS or NAC group. Piglets in the control and LPS groups were fed a basal diet, whereas those in the NAC group were fed the basal diet supplemented with 500 mg/kg NAC. On days 10, 13 and 20 of the trial, the LPS- and NAC-treated piglets were intraperitoneally administered LPS (100 μg/kg body weight), while the control group was administered the same volume of saline. On day 20 of the trial, blood samples were obtained 3 h after LPS or saline injection. On day 21, the piglets were killed to collect liver samples. Dietary NAC supplementation attenuated LPS-induced liver histomorphological abnormalities. Compared with the control group, in the LPS-challenged piglets, the activities of alanine aminotransferase and aspartate aminotransferase and the concentrations of H2O2, TNF-α, IL-6 and PGE2 were dramatically increased in the plasma and the activity of superoxide dismutase in the plasma and that of glutathione peroxidase in the liver were significantly decreased. The LPS challenge also increased the concentration of AMP and the ratio of AMP:ATP, but decreased adenylate energy charges and the levels of ATP and ADP. These adverse effects of the LPS challenge were ameliorated by NAC supplementation. Moreover, NAC inhibited the LPS-induced increases in the abundance of liver heat shock protein 70 and NF-κB proteins. In conclusion, these results suggest that dietary NAC supplementation alleviates LPS-induced liver injury by reducing the secretion of pro-inflammatory cytokines, increasing the antioxidative capacity and improving energy metabolism.}, }
@article {pmid23828861, year = {2013}, author = {Chang, YC and Yu, YH and Shew, JY and Lee, WJ and Hwang, JJ and Chen, YH and Chen, YR and Wei, PC and Chuang, LM and Lee, WH}, title = {Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human.}, journal = {EMBO molecular medicine}, volume = {5}, number = {8}, pages = {1165-1179}, pmid = {23828861}, issn = {1757-4684}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 HL087679/HL/NHLBI NIH HHS/United States ; 068545/Z/02/WT_/Wellcome Trust/United Kingdom ; G0000934/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Adipocytes/cytology ; Animals ; Antioxidants/metabolism ; Body Mass Index ; CCAAT-Enhancer-Binding Protein-beta/metabolism ; Carrier Proteins/genetics/*physiology ; Female ; *Gene Expression Regulation ; Glutathione Peroxidase ; Humans ; Male ; Mice ; Mice, Knockout ; Obesity/*genetics/metabolism ; *Oxidative Stress ; Peroxidases/genetics/*physiology ; Phenotype ; Polymorphism, Single Nucleotide ; Reactive Oxygen Species/*metabolism ; }, abstract = {Elevated oxidative stress is closely associated with obesity. Emerging evidence shows that instead of being a consequence of obesity, oxidative stress may also contribute to fat formation. Nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) is a conserved oxidative stress sensor/transducer and deficiency of NPGPx causes accumulation of reactive oxygen species (ROS). In this communication, we show that NPGPx was highly expressed in preadipocytes of adipose tissue. Deficiency of NPGPx promoted preadipocytes to differentiate to adipocytes via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of CCAAT/enhancer-binding protein beta (C/EBPβ). This enhanced adipogenesis was alleviated by antioxidant N-acetylcysteine (NAC). Consistently, NPGPx-deficient mice exhibited markedly increased fat mass and adipocyte hypertrophy, while treatment with NAC ablated these phenotypes. Furthermore, single nucleotide polymorphisms (SNPs) in human NPGPx gene, which correlated with lower NPGPx expression level in adipose tissue, were associated with higher body mass index (BMI) in several independent human populations. These results indicate that NPGPx protects against fat accumulation in mice and human via modulating ROS, and highlight the importance of targeting redox homeostasis in obesity management.}, }
@article {pmid23828143, year = {2013}, author = {Martinez, CA and de Almeida, MG and da Silva, CM and Ribeiro, ML and da Cunha, FL and Rodrigues, MR and Sato, DT and Pereira, JA}, title = {Enemas with N-acetylcysteine can reduce the level of oxidative damage in cells of the colonic mucosa diverted from the faecal stream.}, journal = {Digestive diseases and sciences}, volume = {58}, number = {12}, pages = {3452-3459}, pmid = {23828143}, issn = {1573-2568}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Colectomy/adverse effects ; Colitis/*drug therapy/etiology/metabolism ; Colon/pathology ; DNA Damage/drug effects ; *Enema ; Free Radical Scavengers/*administration &amp; dosage ; Intestinal Mucosa/drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Pouchitis/*drug therapy ; Random Allocation ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Oxidative stress has been related to inflammation of the colonic mucosa in patients with diversion colitis (DC).<br><br>AIM: The purpose of this study was to evaluate the antioxidants effects of n-acetylcysteine (NAC) in colon segments without faecal stream.<br><br>METHODS: Thirty-six Wistar rats were subjected to diversion of the faecal stream by proximal colostomy and a distal mucosal colon fistula. They were distributed into three experimental groups of 12 animals each; the animals in each group underwent daily enemas containing saline solution (control group) or either a 25 or 100 mg/kg dose of NAC (treated groups). In each group, animals were sacrificed after 2 or 4 weeks. The degree of inflammation was determined by histopathological analysis and stratified by inflammatory grading scale. Oxidative DNA damage was measured by comet assay. The Mann-Whitney test and ANOVA were used for statistical analysis; p<0.05 was considered significant.<br><br>RESULTS: The oxidative DNA damage in colon segments without faecal stream was significantly lower in animals treated with either concentration of NAC than in control group, regardless of the duration of intervention (p<0.01).<br><br>CONCLUSIONS: Intrarectal application of NAC reduces the inflammation as well as DNA oxidative damage and could be beneficial as a complementary agent in the treatment of DC.}, }
@article {pmid23827545, year = {2013}, author = {Beitollahi, H and Taher, MA and Mirrahimi, F and Hosseinzadeh, R}, title = {Electrochemical sensor for selective determination of N-acetylcysteine in the presence of folic acid using a modified carbon nanotube paste electrode.}, journal = {Materials science &amp; engineering. C, Materials for biological applications}, volume = {33}, number = {3}, pages = {1078-1084}, doi = {10.1016/j.msec.2012.11.036}, pmid = {23827545}, issn = {1873-0191}, mesh = {Acetylcysteine/*analysis ; Calibration ; Catalysis ; Electricity ; Electrochemical Techniques/*instrumentation/*methods ; Electrodes ; Ferrous Compounds/chemistry ; Folic Acid/*analysis ; Hydrogen-Ion Concentration ; Limit of Detection ; Metallocenes ; Nanotubes, Carbon/*chemistry ; Oxidation-Reduction ; Tablets ; }, abstract = {In the present paper, a novel benzoylferrocene (BF) modified carbon nanotube paste electrode (BFCNPE) was prepared. The modified electrode was further used for the successful determination of N-acetylcysteine (NAC), and it showed an excellent electrocatalytic oxidation activity toward NAC with a lower overvoltage, pronounced current response, and good sensitivity. Under the optimized experimental conditions, the proposed electrochemical NAC sensor exhibited a linear calibration plot that ranged from 3.0×10(-7) to 7.0×10(-4) M with a detection limit of 9.0×10(-8) M. Also, Square wave voltammetry (SWV) was used for simultaneous determination of NAC and folic acid (FA) at the modified electrode. Finally, the proposed method was applied to the determination of NAC in NAC tablets.}, }
@article {pmid23826152, year = {2013}, author = {Massicot, F and Hache, G and David, L and Chen, D and Leuxe, C and Garnier-Legrand, L and Rat, P and Laprévote, O and Coudoré, F}, title = {P2X7 Cell Death Receptor Activation and Mitochondrial Impairment in Oxaliplatin-Induced Apoptosis and Neuronal Injury: Cellular Mechanisms and In Vivo Approach.}, journal = {PloS one}, volume = {8}, number = {6}, pages = {e66830}, pmid = {23826152}, issn = {1932-6203}, mesh = {Animals ; Apoptosis/*drug effects/physiology ; Brain/drug effects/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Humans ; Macrophages/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Mitochondria/*drug effects/metabolism ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/pharmacology ; Organoplatinum Compounds/*toxicity ; Oxaliplatin ; Oxidative Stress/drug effects/physiology ; Receptors, Purinergic P2X7/*metabolism ; }, abstract = {Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y) and macrophage (RAW 264.7) cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA) induces oxidative stress and apoptosis. Cultured cells were treated with 2-200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen) were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose) significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain.}, }
@article {pmid23824011, year = {2013}, author = {Takeda, S and Nishimura, H and Koyachi, K and Matsumoto, K and Yoshida, K and Okamoto, Y and Amamoto, T and Shindo, M and Aramaki, H}, title = {(-)-Xanthatin induces the prolonged expression of c-Fos through an N-acetyl-L-cysteine (NAC)-sensitive mechanism in human breast cancer MDA-MB-231 cells.}, journal = {The Journal of toxicological sciences}, volume = {38}, number = {4}, pages = {547-557}, doi = {10.2131/jts.38.547}, pmid = {23824011}, issn = {1880-3989}, mesh = {Acetylcysteine/*pharmacology ; Antigens, Neoplasm ; Antineoplastic Agents/*pharmacology ; Breast Neoplasms/*genetics/metabolism/*pathology ; Cell Division/*genetics ; DNA Topoisomerases, Type II ; DNA-Binding Proteins/antagonists &amp; inhibitors ; Etoposide/pharmacology ; Female ; Free Radical Scavengers/*pharmacology ; Furans/*pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Genes, Tumor Suppressor/*drug effects ; Humans ; Intracellular Signaling Peptides and Proteins/*metabolism ; Proto-Oncogene Proteins c-fos/*metabolism ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Tumor Cells, Cultured ; Up-Regulation ; GADD45 Proteins ; }, abstract = {We reported that (-)-xanthatin, a xanthanolide sesquiterpene lactone present in the Cocklebur plant, exhibited potent anti-proliferative effects on human breast cancer cells, in which GADD45γ, a novel tumor suppressor gene, was induced. Mechanistically, topoisomerase IIα (Topo IIα) inhibition by (-)-xanthatin was shown to be the upstream trigger that stimulated the expression of GADD45γ mRNA and concomitantly produced reactive oxygen species (ROS) to maintain this expression. Since the anti-cancer drug etoposide, a selective Topo IIα inhibitor, has also been shown to induce intracellular ROS, (-)-xanthatin may exert its anti-proliferative effects on cancer cells in a similar manner to those of etoposide. In the present study, to generalize its applicability to cancer therapy, we further investigated the biological activities of (-)-xanthatin by comparing its activities to those of the established anti-cancer drug etoposide. After the exposure of breast cancer cells to (-)-xanthatin or etoposide, a prolonged and marked up-regulation in the expression of c-fos, a proapoptotic molecule, was detected together with GADD45γ; and the expression of these molecules was stabilized by ROS and abrogated by the pretreatment with N-acetyl-L-cysteine (NAC), a potent ROS scavenger. (-)-Xanthatin in particular exhibited stronger anti-proliferative potential than that of etoposide, which underlies the marked induction of c-fos/GADD45γ and ROS production.}, }
@article {pmid23818365, year = {2013}, author = {Guo, Y and Zhang, W and Yan, YY and Ma, CG and Wang, X and Wang, C and Zhao, JL}, title = {Triterpenoid pristimerin induced HepG2 cells apoptosis through ROS-mediated mitochondrial dysfunction.}, journal = {Journal of B.U.ON. : official journal of the Balkan Union of Oncology}, volume = {18}, number = {2}, pages = {477-485}, pmid = {23818365}, issn = {1107-0625}, mesh = {Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Carcinoma, Hepatocellular/*metabolism/pathology ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; ErbB Receptors/metabolism ; Flow Cytometry ; Hep G2 Cells ; Humans ; Liver Neoplasms/*metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Fluorescence ; Mitochondria, Liver/*drug effects/metabolism/pathology ; Pentacyclic Triterpenes ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Triterpenes/*pharmacology ; bcl-2-Associated X Protein/metabolism ; }, abstract = {PURPOSE: To investigate the anticancer properties implicated in a natural triterpenoid (pristimerin)-induced apoptosis and inhibited proliferation in human hepatocellular carcinoma (HCC) HepG2 cell line.<br><br>METHODS: The cytotoxic activity of pristimerin in HepG2 cells was determined by MTT assay. Apoptotic morphology was observed by fluorescence microscope with Hoechst 33258 staining and percent apoptosis was measured by annexin V/PI double staining. DiOC6 for mitochondrial potential (&#x394;&#x3a8;m) and DCFH-DA for reactive oxygen species (ROS) were determined by flow cytometry. Changes of apoptotic- related proteins were analysed by Western blot.<br><br>RESULTS: Pristimerin exerted a potent cytotoxic effect on HepG2 cells. After HepG2 cells were treated with pristimerin, typical apoptotic bodies, increasing the proportion of apoptotic annexin V-positive cells and activation of caspase-3 were detected in a dose-dependent manner. It was intriguing that pristimerin increased the generation of ROS with a collapse of the mitochondrial membrane potential in the cells. In addition, there was significant change in other mitochondrial membrane proteins triggered by pristimerin, such as Bcl-2 and Bax. Pristimerin also effectively induced subsequent release of cytochrome C from mitochondria into the cytosol, downregulated EGFR protein expression and inhibited downstream signaling pathways in HepG2 cells. Pretreatment with N-acetylcysteine (NAC) blocked ROS generation and resulted in loss of mitochondrial membrane potential, release of cytochrome C and apoptosis induced by pristimerin.<br><br>CONCLUSION: These data indicate that ROS play an essential role in the induction of apoptosis by pristimerin in HepG2 cells.}, }
@article {pmid23817939, year = {2013}, author = {Senanayake, MP and Jayamanne, MD and Kankananarachchi, I}, title = {N-acetylcysteine in children with acute liver failure complicating dengue viral infection.}, journal = {The Ceylon medical journal}, volume = {58}, number = {2}, pages = {80-82}, doi = {10.4038/cmj.v58i2.5684}, pmid = {23817939}, issn = {0009-0875}, mesh = {*Acetylcysteine/therapeutic use ; Child ; Dengue ; Dengue Virus ; Humans ; *Liver Failure, Acute ; Retrospective Studies ; }, abstract = {OBJECTIVES: To describe the outcome after administration of N-acetylcysteine (NAC) to seven children with nonparacetamol induced acute liver failure (ALF) complicating dengue infection.<br><br>METHODS: Clinical records of children with non paracetamol induced acute liver failure complicating severe dengue viral infection, were retrospectively analysed for clinical and biochemical outcome following treatment with NAC.<br><br>RESULTS: Seven patients between ages six months to twelve years with plasma leakage and circulatory compromise complicating dengue infection developed ALF. Three were exposed to prolonged shock prior to hospitalisation. NAC infusion (100 mg/kg) was administered as soon as ALF was diagnosed, based on low GCS scores, raised transaminases and prolonged prothrombin/INR. Full clinical and biochemical recovery occurred in all patients.<br><br>CONCLUSIONS: A successful outcome followed early administration of NAC to children with ALF complicating severe dengue infection.}, }
@article {pmid23811825, year = {2013}, author = {Latronico, T and Branà, MT and Merra, E and Fasano, A and Di Bari, G and Casalino, E and Liuzzi, GM}, title = {Impact of manganese neurotoxicity on MMP-9 production and superoxide dismutase activity in rat primary astrocytes. Effect of resveratrol and therapeutical implications for the treatment of CNS diseases.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {135}, number = {1}, pages = {218-228}, doi = {10.1093/toxsci/kft146}, pmid = {23811825}, issn = {1096-0929}, mesh = {Acetylcysteine/pharmacology ; Animals ; Astrocytes/*drug effects/enzymology ; Cells, Cultured ; Central Nervous System Diseases/*drug therapy ; Extracellular Signal-Regulated MAP Kinases/metabolism ; MAP Kinase Signaling System/drug effects ; Manganese/*toxicity ; Matrix Metalloproteinase 9/analysis/*biosynthesis ; Quercetin/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/*pharmacology/therapeutic use ; Superoxide Dismutase/*metabolism ; }, abstract = {Manganese (Mn) is an environmental contaminant and its overexposure contributes to the pathophysiological processes of numerous disorders of the central nervous system in humans with mechanisms of action not completely understood. Activation of astrocytes and the subsequent release of neurotoxic factors have been implicated to contribute to neurodegeneration. Here, we assessed the molecular basis of the effects of Mn on modulation of matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) in rat astrocyte cultures. Primary cultures of rat astrocytes were exposed to different doses of MnCl2. Culture supernatants and cell lysates were used for the detection of MMP-2 and MMP-9 levels and mRNA expression, respectively. The exposure of astrocytes to MnCl2 induced the levels and expression of MMP-9 in a dose-dependent manner. The addition of resveratrol (RSV) inhibited both levels and expression of MMP-9 in astrocytes, whereas N-acetylcysteine (NAC) and quercetin (QRC) were ineffective in inhibiting MMP-9. As a possible mechanism of Mn-induced MMP-9, we determined intracellular redox state in Mn-treated astrocytes by assessing superoxide dismutase (SOD) activity and intracellular reactive oxygen species (ROS) and found a significant increase of ROS and a decrease of SOD activity. RSV, NAC, and QRC restored the redox state. The study of the mitogen-activated protein kinase signaling pathway demonstrated that MMP-9 transcription is mainly regulated by extracellular-regulated protein kinases (ERK). Pretreatment with RSV significantly reduced ERK activation suggesting that its ability to counteract MMP-9 overexpression is due not only to a general redox balance phenomenon but also to the modulation of ERK signaling pathway.}, }
@article {pmid23811723, year = {2013}, author = {Qu, K and Shen, NY and Xu, XS and Su, HB and Wei, JC and Tai, MH and Meng, FD and Zhou, L and Zhang, YL and Liu, C}, title = {Emodin induces human T cell apoptosis in vitro by ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction.}, journal = {Acta pharmacologica Sinica}, volume = {34}, number = {9}, pages = {1217-1228}, pmid = {23811723}, issn = {1745-7254}, mesh = {Apoptosis/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Emodin/*pharmacology ; Endoplasmic Reticulum Stress/*drug effects/physiology ; Humans ; Leukocytes, Mononuclear/drug effects/physiology ; Mitochondria/*drug effects/physiology ; Reactive Oxygen Species/*metabolism ; T-Lymphocytes/*drug effects/physiology ; }, abstract = {AIM: To elucidate the molecular mechanisms underlying the immunosuppressive effects of emodin isolated from Rheum palmatum L.<br><br>METHODS: Human T cells were isolated from the peripheral venous blood of 10 healthy adult donors. Cell viability was analyzed with MTT assay. AO/EB and Annexin V/PI staining and DNA damage assay were used to detect cell apoptosis. Fluorescence staining was used to detect the levels of ROS, the mitochondrial membrane potential and intracellular Ca(2+). Colorimetry was used to detect the levels of MDA and total SOD and GSH/GSSG ratio. The expression and activity of caspase-3, -4, and -9 were detected with Western blotting and a fluorometric assay. Western blotting was also used to detect the expression of Bcl-2, Bax, cytochrome C, and endoplasmic reticulum (ER) markers.<br><br>RESULTS: Emodin (1, 10, and 100 &#x3bc;mol/L) inhibited the growth of human T cells and induced apoptosis in dose- and time dependent manners. Emodin triggered ER stress and significantly elevated intracellular free Ca(2+) in human T cells. It also disrupted mitochondrial membrane potential, and increased cytosolic level of cytochrome C, and the levels of activated cleavage fragments of caspase-3, -4, and -9 in human T cells. Furthermore, emodin significantly increased the levels of ROS and MDA, inhibited both SOD level and GSH/GSSG ratio in human T cells, whereas co-incubation with the ROS scavenger N-acetylcysteine (NAC, 20 &#x3bc;mol/L) almost completely blocked emodin-induced ER stress and mitochondrial dysfunction in human T cells, and decreased the caspase cascade-mediated apoptosis.<br><br>CONCLUSION: Emodin exerts immunosuppressive actions at least partly by inducing apoptosis of human T cells, which is triggered by ROS-mediated ER stress and mitochondrial dysfunction.}, }
@article {pmid23811559, year = {2013}, author = {Majid, AS and Yin, ZQ and Ji, D}, title = {Sulphur antioxidants inhibit oxidative stress induced retinal ganglion cell death by scavenging reactive oxygen species but influence nuclear factor (erythroid-derived 2)-like 2 signalling pathway differently.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {36}, number = {7}, pages = {1095-1110}, doi = {10.1248/bpb.b13-00023}, pmid = {23811559}, issn = {1347-5215}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Blotting, Western ; Cell Culture Techniques ; Cell Line, Transformed ; Cell Survival/drug effects ; Free Radical Scavengers/*pharmacology ; Heme Oxygenase (Decyclizing)/metabolism ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress/*drug effects ; Rats ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Retinal Ganglion Cells/*drug effects/metabolism ; Signal Transduction/*drug effects ; Thiamine/*analogs &amp; derivatives/pharmacology ; }, abstract = {This study aimed to show if two different sulphur containing drugs sulbutiamine and acetylcysteine (NAC) could attenuate the effects of two different insults being serum deprivation and glutamate/buthionine sulfoximine (GB)-induced death to transformed retinal ganglion cell line (RGC-5) in culture. Cells were exposed to either 5 mM of GB for 24 h or serum deprivation for 48 h with inclusion of either NAC or sulbutiamine. Cell viability, microscopic evidence for apoptosis, caspase 3 activity, reactive oxygen species (ROS), glutathione (GSH), catalase and gluthathione-S-transferase (GST) were determined. The effects of NAC and sulbutiamine on the oxidative stress related transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) levels and its dependent phase II enzyme haemeoxygenase-1 (HO-1) were carried out using Western blot and quantitative-polymerase chain reaction (PCR). NAC and sulbutiamine dose-dependently attenuated serum deprivation-induced cell death. However NAC but not sulbutiamine attenuated GB-induced cell death. NAC and sulbutiamine both independently stimulated the GSH and GST production but scavenged different types of ROS with different efficacy. Moreover only sulbutiamine stimulated catalase and significantly increased Nrf-2 and HO-1 levels. In addition, the pan caspase inhibitor, benzoylcarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk) attenuated the negative effect of serum deprivation while the necroptosis inhibitor (necrostatin-1) counteracted solely an insult of GB. The neuroprotective actions of NAC and sulbutiamine in GB or serum-deprivation insult are therefore different.}, }
@article {pmid23811485, year = {2013}, author = {Hu, B and Hu, LL and Chen, ML and Wang, JH}, title = {A FRET ratiometric fluorescence sensing system for mercury detection and intracellular colorimetric imaging in live Hela cells.}, journal = {Biosensors &amp; bioelectronics}, volume = {49}, number = {}, pages = {499-505}, doi = {10.1016/j.bios.2013.06.004}, pmid = {23811485}, issn = {1873-4235}, mesh = {Acetylcysteine/*chemistry ; Colorimetry/methods ; Fluorescence Resonance Energy Transfer/*methods ; Fluorescent Dyes/*chemistry ; HeLa Cells ; Humans ; Limit of Detection ; Mercury/*analysis ; Optical Imaging/methods ; *Quantum Dots ; Rhodamines/*chemistry ; }, abstract = {The detection of mercury in biological systems and its imaging is of highly importance. In this work, a ratiometric fluorescence sensor is developed based on fluorescence resonance energy transfer (FRET) with N-acetyl-L-cysteine functionalized quantum dots (NAC-QDs) as donor and Rhodamine 6G derivative-mercury conjugate (R6G-D-Hg) as acceptor. Mercury annihilates the fluorescence of NAC-QDs at 508 nm and meanwhile interacts with R6G derivative to form a fluorescent conjugate giving rise to emission at 554 nm. Resonance energy transfer from NAC-QDs to R6G-D-Hg is triggered by mercury resulting in concentration-dependent variation of fluorescence ratio F508/F554. A linear calibration of F508/F554 versus mercury concentration is obtained within 5-250 μg L(-1), along with a detection limit of 0.75 μg L(-1) and a RSD of 3.2% (175 μg L(-1)). The sensor generates colorimetric images for mercury within 0-250 μg L(-1), facilitating visual detection of mercury with a distinguishing ability of 50 μg L(-1). This feature is further demonstrated by colorimetric imaging of intracellular mercury. On the other hand, the NAC-QDs/R6G-D FRET sensing system is characterized by a combination of high sensitivity and selectivity. The present study provides an approach for further development of ratiometric sensors dedicated to selective in vitro or in vivo sensing some species of biologically interest.}, }
@article {pmid23810784, year = {2013}, author = {Suzuki, Y and Ichihara, G and Sahabudeen, SM and Kato, A and Yamaguchi, T and Imanaka-Yoshida, K and Yoshida, T and Yamada, Y and Ichihara, S}, title = {Rats with metabolic syndrome resist the protective effects of N-acetyl l-cystein against impaired spermatogenesis induced by high-phosphorus/zinc-free diet.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {65}, number = {7-8}, pages = {1173-1182}, doi = {10.1016/j.etp.2013.05.009}, pmid = {23810784}, issn = {1618-1433}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Diet/*adverse effects ; In Situ Nick-End Labeling ; Male ; Metabolic Syndrome/complications/*metabolism ; Oxidative Stress/drug effects ; Phosphorus ; Rats ; Rats, Inbred SHR ; Sperm Count ; Spermatogenesis/*drug effects ; Testicular Diseases/complications/metabolism/prevention &amp; control ; Zinc/deficiency ; }, abstract = {Consumption of relatively high amounts of processed food can result in abnormal nutritional status, such as zinc deficiency or phosphorus excess. Moreover, hyperphosphatemia and hypozincemia are found in some patients with diabetic nephropathy and metabolic syndrome. The present study investigated the effects of high-phosphorus/zinc-free diet on the reproductive function of spontaneously hypertensive rats/NDmcr-cp (SHR/cp), a model of the metabolic syndrome. We also investigated the effects of antioxidant, N-acetyl-l-cysteine (NAC), on testicular dysfunction under such conditions. Male SHR/cp and control rats (Wistar Kyoto rats, WKY) were divided into three groups; rats fed control diet (P 0.3%, w/w; Zn 0.2%, w/w), high-phosphorus and zinc-deficient diet (P 1.2%, w/w; Zn 0.0%, w/w) with vehicle, or high-phosphorus and zinc-deficient diet with NAC (1.5mg/g/day) for 12 weeks (n=6 or 8 rats/group). The weights of testis and epididymis were significantly reduced by high-phosphate/zinc-free diet in both SHR/cp and WKY. The same diet significantly reduced caudal epididymal sperm count and motility and induced histopathological changes in the testis in both strains. Treatment with NAC provided significant protection against the toxic effects of the diet on testicular function in WKY, but not in SHR/cp. The lack of the protective effects of NAC on impaired spermatogenesis in SHR/cp could be due to the more pronounced state of oxidative stress observed in these rats compared with WKY.}, }
@article {pmid23806718, year = {2013}, author = {Tsentsevitsky, A and Kovyazina, I and Nikolsky, E and Bukharaeva, E and Giniatullin, R}, title = {Redox-sensitive synchronizing action of adenosine on transmitter release at the neuromuscular junction.}, journal = {Neuroscience}, volume = {248}, number = {}, pages = {699-707}, doi = {10.1016/j.neuroscience.2013.05.065}, pmid = {23806718}, issn = {1873-7544}, mesh = {Acetylcholine/*metabolism ; Adenosine/*pharmacology ; Animals ; Antioxidants/pharmacology ; In Vitro Techniques ; Motor Neurons/physiology ; Neuromuscular Junction/drug effects/*metabolism/physiology ; Oxidation-Reduction ; Rana ridibunda ; Reactive Oxygen Species/pharmacology ; Receptor, Adenosine A1/metabolism ; Synaptic Transmission/*physiology ; }, abstract = {The kinetics of neurotransmitter release was recognized recently as an important contributor to synaptic efficiency. Since adenosine is the ubiquitous modulator of presynaptic release in peripheral and central synapses, in the current project we studied the action of this purine on the timing of acetylcholine quantal release from motor nerve terminals in the skeletal muscle. Using extracellular recording from frog neuromuscular junction we tested the action of adenosine on the latencies of single quantal events in the pro-oxidant and antioxidant conditions. We found that adenosine, in addition to previously known inhibitory action on release probability, also synchronized release by removing quantal events with long latencies. This action of adenosine on release timing was abolished by oxidants whereas in the presence of the antioxidant the synchronizing action of adenosine was further enhanced. Interestingly, unlike the timing of release, the inhibitory action of adenosine on release probability was redox-independent. Modulation of release timing by adenosine was mediated by purinergic A1 receptors as it was eliminated by the specific A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and mimicked by the specific A1 agonist N(6)-cyclopentyl-adenosine. Consistent with data obtained from dispersion of single quantal events, adenosine also reduced the rise-time of multiquantal synaptic currents. The latter effect was reproduced in the model based on synchronizing effect of adenosine on release timing. Thus, adenosine which is generated at the neuromuscular junction from the breakdown of the co-transmitter ATP induces the synchronization of quantal events. The effect of adenosine on release timing should preserve the fidelity of synaptic transmission via "cost-effective" use of less transmitter quanta. Our findings also revealed important crosstalk between purinergic and redox modulation of synaptic processes which could take place in the elderly or in neuromuscular diseases associated with oxidative stress like lateral amyotrophic sclerosis.}, }
@article {pmid23803658, year = {2013}, author = {Lin, CH and Hung, PH and Chen, YJ}, title = {CD44 is associated with the aggressive phenotype of nasopharyngeal carcinoma through redox regulation.}, journal = {International journal of molecular sciences}, volume = {14}, number = {7}, pages = {13266-13281}, pmid = {23803658}, issn = {1422-0067}, mesh = {Carcinoma ; Cell Line, Tumor ; *Epithelial-Mesenchymal Transition ; *Gene Expression Regulation, Neoplastic ; Humans ; Hyaluronan Receptors/*biosynthesis ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms/*metabolism/pathology ; Neoplasm Metastasis ; Neoplasm Proteins/*biosynthesis ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; }, abstract = {Recent studies have shown that cancer stem-like cells (CSCs) within a tumor have the capacity for self-renewal and differentiation, and are associated with an aggressive phenotype and therapeutic resistance. Studies have also associated tumor progression with alterations in the levels of intracellular reactive oxygen species (ROS). In this study, we cultured nasopharyngeal carcinoma (NPC) CSCs in conditions that allowed sphere formation. The resulting sphere cells displayed stemness properties, characteristics of the epithelial-mesenchymal transition (EMT), and increased expression of the CSC surface marker CD44. We further evaluated the association between CD44 expression and EMT marker expression, and any correlation with redox status, in these CSCs. We showed that the EMT in sphere cells is associated with the upregulation of CD44 expression and increased ROS generation, which might promote NPC aggressiveness. We also identified the coexpression of CD44 with the EMT marker N-cadherin in sphere cells, and downregulated CD44 expression after the addition of the antioxidant N-acetyl cysteine. Our results indicate that CD44 plays a role in the EMT phenotype of CSCs in NPC, and suggest its involvement in EMT-associated ROS production. These findings might facilitate the development of a novel therapy for the prevention of NPC recurrence and metastasis.}, }
@article {pmid23802669, year = {2013}, author = {Dycus, DL and Au, AY and Grzanna, MW and Wardlaw, JL and Frondoza, CG}, title = {Modulation of inflammation and oxidative stress in canine chondrocytes.}, journal = {American journal of veterinary research}, volume = {74}, number = {7}, pages = {983-989}, doi = {10.2460/ajvr.74.7.983}, pmid = {23802669}, issn = {1943-5681}, mesh = {Animals ; Cells, Cultured ; Chondrocytes/*drug effects/metabolism ; *Dogs ; Glutathione ; Hydrogen Peroxide/*pharmacology ; Inflammation/metabolism/*veterinary ; Oxidative Stress/drug effects ; Superoxide Dismutase/*metabolism ; }, abstract = {OBJECTIVE: To determine whether oxidative stress could be induced in canine chondrocytes in vitro.<br><br>SAMPLE: Chondrocytes obtained from healthy adult mixed-breed dogs.<br><br>PROCEDURES: Harvested chondrocytes were maintained at 37&#xb0;C with 5% CO2 for 24 hours. To assess induction of oxidative stress, 2 stimuli were used: hydrogen peroxide and a combination of interleukin-1&#x3b2; (IL-1&#x3b2;) and tumor necrosis factor-&#x3b1; (TNF-&#x3b1;). To determine the effect of hydrogen peroxide, a set of chondrocyte-seeded plates was incubated with control medium alone or hydrogen peroxide (100, 200, or 300&#x3bc;M) for 24 hours. For inhibition of oxidative stress, cells were incubated for 24 hours with N-acetylcysteine (NAC; 10mM) before exposure to hydrogen peroxide. Another set of chondrocyte-seeded plates was incubated with control medium alone or with IL-1&#x3b2; (10 ng/mL) and TNF-&#x3b1; (1 ng/mL) for 24 hours. Supernatants were obtained for measurement of prostaglandin E2 production, and cell lysates were used for measurement of superoxide dismutase (SOD) activity and reduced-glutathione (GSH) concentration.<br><br>RESULTS: Chondrocytes responded to the oxidative stressor hydrogen peroxide with a decrease in SOD activity and GSH concentration. Exposure to the antioxidant NAC caused an increase in SOD activity in hydrogen peroxide-stressed chondrocytes to a degree comparable with that in chondrocytes not exposed to hydrogen peroxide. Similarly, NAC exposure induced significant increases in GSH concentration. Activation with IL-1&#x3b2; and TNF-&#x3b1; also led to a decrease in SOD activity and increase in prostaglandin E2 production.<br><br>Canine chondrocytes responded to the oxidative stress caused by exposure to hydrogen peroxide and cytokines. Exposure to oxidative stress inducers could result in perturbation of chondrocyte and cartilage homeostasis and could contribute to the pathophysiology of osteoarthritis. Use of antioxidants, on the other hand, may be helpful in the treatment of arthritic dogs.}, }
@article {pmid23799549, year = {2013}, author = {Park, WH}, title = {The effect of MAPK inhibitors and ROS modulators on cell growth and death of H2O2-treated HeLa cells.}, journal = {Molecular medicine reports}, volume = {8}, number = {2}, pages = {557-564}, doi = {10.3892/mmr.2013.1551}, pmid = {23799549}, issn = {1791-3004}, mesh = {Antioxidants/*pharmacology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Glutathione/metabolism ; HeLa Cells ; Humans ; Hydrogen Peroxide/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; Protein Kinase Inhibitors/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Reactive oxygen species (ROS) influence the signaling of mitogen‑activated protein kinases (MAPKs) involved in cell survival and death. In the present study, the toxicological effect of hydrogen peroxide (H2O2) on HeLa cervical cancer cells was evaluated following treatment with MAPK inhibitors [MAP kinase or ERK kinase (MEK), c‑Jun N‑terminal kinase (JNK) or p38], N‑acetyl cysteine (NAC) and propyl gallate (PG) (well‑known antioxidants), or L‑buthionine sulfoximine [BSO; an inhibitor of glutathione (GSH) synthesis]. Treatment with 100 µM H2O2 inhibited the growth of HeLa cells and induced cell death, which was accompanied by loss of the mitochondrial membrane potential (MMP; ΔΨm). H2O2 did not induce any specific phase arrests of the cell cycle. ROS levels increased, while GSH levels decreased in H2O2‑treated HeLa cells after 1 and 24 h of treatment. The MAPK inhibitors enhanced H2O2‑induced HeLa cell death, while only p38 inhibitor increased ROS levels. Both NAC and PG attenuated H2O2‑induced HeLa cell growth inhibition and death together with the suppression of ROS levels. BSO increased ROS levels in H2O2‑treated HeLa cells without increasing cell death. The levels of MMP (ΔΨm) loss and GSH depletion were not closely associated with the levels of apoptosis in HeLa cells treated with the MAPK inhibitors, NAC, PG or BSO, in the presence of H2O2. In conclusion, H2O2 induced HeLa cell growth inhibition and death. MAPK inhibitors generally enhanced H2O2‑induced HeLa cell death. In particular, p38 inhibitor increased ROS levels in H2O2‑treated HeLa cells, while NAC and PG attenuated H2O2‑induced HeLa cell death by suppressing ROS levels.}, }
@article {pmid23796398, year = {2013}, author = {Fishman, AI and Green, D and Lynch, A and Choudhury, M and Eshghi, M and Konno, S}, title = {Preventive effect of specific antioxidant on oxidative renal cell injury associated with renal crystal formation.}, journal = {Urology}, volume = {82}, number = {2}, pages = {489.e1-7}, doi = {10.1016/j.urology.2013.03.065}, pmid = {23796398}, issn = {1527-9995}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Calcium Oxalate/*pharmacology ; Cell Survival/drug effects ; Cholecalciferol/pharmacology ; Crystallization ; Dogs ; Ethylene Glycol/pharmacology ; Free Radical Scavengers/*pharmacology ; Kidney/enzymology/*pathology ; Lactoylglutathione Lyase/metabolism ; Madin Darby Canine Kidney Cells ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {OBJECTIVE: To investigate whether calcium oxalate monohydrate (COM), a key element of hyperoxaluria, would induce renal cell injury through oxidative stress and also whether certain antioxidants could prevent chemically induced renal crystal formation in rats.<br><br>MATERIALS AND METHODS: COM-exerted oxidative stress on the kidney epithelial Madin-Darby canine kidney cells was assessed using the lipid peroxidation assay. Glyoxalase I (Gly-I) activity was also determined. Two antioxidants, vitamin C and N-acetylcysteine (NAC), were then tested to determine whether they could abolish such oxidative stress in Madin-Darby canine kidney cells. Both antioxidants were also tested to determine whether they might prevent or reduce renal crystal formation induced with ethylene glycol (EG) and vitamin D3 (VD3) in Wistar rats.<br><br>RESULTS: COM (200 &#x3bc;g/mL) demonstrated &#x223c;1.3-fold greater oxidative stress with a significant reduction in cell viability and Gly-I activity compared with controls. However, such adverse events were almost completely prevented with NAC but not with vitamin C. In the animal study, no renal crystals were seen in the sham group. However, numerous crystals, with reduced Gly-I activity and elevated oxidative stress, were found in the EG-VD3 group. However, markedly (>70%) fewer crystals, with full Gly-I activity and diminished oxidative stress, were detected in the EG-VD3+NAC group.<br><br>CONCLUSION: COM exerted oxidative stress on Madin-Darby canine kidney cells, leading to cell viability reduction and Gly-I inactivation, with NAC fully preventing such adverse consequences. Similarly, numerous crystals with Gly-I inactivation and elevated oxidative stress seen in the rats (EG-VD3) were also significantly prevented with NAC supplement. Thus, NAC might have clinical implications in preventing oxidative renal cell injury and, ultimately, kidney stone formation.}, }
@article {pmid23796245, year = {2013}, author = {Yang, WH and Zhang, Z and Sima, YH and Zhang, J and Wang, JW}, title = {Glaucocalyxin A and B-induced cell death is related to GSH perturbation in human leukemia HL-60 cells.}, journal = {Anti-cancer agents in medicinal chemistry}, volume = {13}, number = {8}, pages = {1280-1290}, doi = {10.2174/18715206113139990200}, pmid = {23796245}, issn = {1875-5992}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Diterpenes, Kaurane/*pharmacology ; Glutathione/*metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; HL-60 Cells ; Humans ; Reactive Oxygen Species/metabolism ; }, abstract = {Glaucocalyxin (Gla) A-C are major ent-kauranoid diterpenoids isolated from Rabdosia japonica var. glaucocalyx, a plant used in Chinese traditional medicine as an antitumor and anti-inflammatory agent. The present investigation was carried out to observe whether cellular reduced glutathione (GSH) plays important roles in Gla -induced cytotoxicity. Among major ent-kauranoid diterpenoids isolated, Gla A and B dose-dependently decreased the growth of HL-60 cells with an IC50 of approximately 6.15 and 5.86 µM at 24 h, respectively. Both Gla A and B could induce apoptosis, G2/M-phase cycle arrest, DNA damage and the accumulation of reactive oxygen species (ROS) in HL-60 cells. Moreover, Gla A, B caused rapid decrease of the intracellular GSH content, while inhibition of cellular GSH synthesis by buthionine sulfoximine (BSO) augmented the induced cytotoxicity and apoptosis in HL-60 cells. On the other hand, the administration of GSH or GSH precursor N-acetyl-cysteine (NAC) could rescue Gla A, B-depleted cellular GSH, and abrogate the induced cytotoxicity, G2/M-phase cycle arrest, DNA damage and ROS accumulation in HL-60 cells. Furthermore, Gla A, B decreased the activity of the GSH-related enzymes including glutathione reductase (GR) and glutathione peroxidase (GPX). These data suggest that the intracellular GSH redox system plays important roles in regulating the Gla A, B-induced cytotoxicity on HL-60 cells.}, }
@article {pmid23790287, year = {2013}, author = {Sarakbi, A and Aydogmus, Z and Dago, A and Mertens, D and Dewert, JY and Kauffmann, JM}, title = {Determination of aminothiols by liquid chromatography with amperometric detection at a silver electrode: application to white wines.}, journal = {Analytica chimica acta}, volume = {786}, number = {}, pages = {22-28}, doi = {10.1016/j.aca.2013.04.070}, pmid = {23790287}, issn = {1873-4324}, mesh = {Amino Acids, Sulfur/*analysis ; Chromatography, Liquid/methods ; Electrochemistry/methods ; Glutathione/*analysis ; *Ion-Selective Electrodes ; Silver/*chemistry ; Sulfhydryl Compounds/*analysis ; Wine/*analysis ; }, abstract = {Liquid chromatography coupled to a silver electrode based flow-through amperometric detector (LC-EC-Ag) was developed for the determination of aminothiols in white wines. The C18 reversed phase LC system operated in the isocratic mode at 0.7 mL min(-1) and used an acidic mobile phase composed of formic acid, EDTA, sodium nitrate, sodium hydroxide, and methanol 1% (v/v) at pH 4.5. The working electrode operated at 0.08 V vs Ag/AgCl, 3M KCl and its manual cleaning was realized once a month by smoothing on a polishing cloth. The analyzed aminothiols were resolved and eluted within 4 min, and all standard curves were linear in the range 2×10(-7)-2×10(-5) M. The analyzed wine samples needed no preparation other than dilution with the mobile phase. The concentration of cysteine (CYS), homocysteine (HCYS), glutathione (GSH) and N-acetylcysteine (NAC) in bottled white wines, determined by the method of standard addition, was found to be in the low μM range (0.2-2 mg L(-1)) depending on the wine type and its age.}, }
@article {pmid23793935, year = {2013}, author = {Beauchamp, GA and Hart, KW and Lindsell, CJ and Lyons, MS and Otten, EJ and Smith, CL and Ward, MJ and Wright, SW}, title = {Performance of a multi-disciplinary emergency department observation protocol for acetaminophen overdose.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {9}, number = {3}, pages = {235-241}, pmid = {23793935}, issn = {1937-6995}, support = {K12 HL109019/HL/NHLBI NIH HHS/United States ; UL1 RR026314/RR/NCRR NIH HHS/United States ; UL1 TR000077/TR/NCATS NIH HHS/United States ; 5UL1RR026314-03/RR/NCRR NIH HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; *Ambulatory Care ; Cohort Studies ; Drug Overdose/*drug therapy/physiopathology/psychology/therapy ; *Emergency Service, Hospital ; *Emergency Services, Psychiatric ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Hospitals, University ; Humans ; Infusions, Intravenous ; Interdisciplinary Communication ; Length of Stay ; Male ; Middle Aged ; Retrospective Studies ; Severity of Illness Index ; Young Adult ; }, abstract = {The availability of 20-h N-acetylcysteine (NAC) infusion for low-risk acetaminophen (APAP) overdose enabled our center to implement an Emergency Department observation unit (OU) protocol as an alternative to hospitalization. Our objective was to evaluate our early experience with this protocol. This retrospective cohort study included all patients treated for low-risk APAP overdose in our academic hospital between 2006 and 2011. Cases were identified using OU and pharmacy records. Successful OU discharge was defined as disposition with no inpatient admission. Differences in medians with 95 % confidence intervals were used for comparisons. One hundred ninety-six patients received NAC for APAP overdose with a mean age of 35 years (SD 14); 73 % were white, and 43 % were male. Twenty (10 %) received care in the OU; 3/20(15 %) met criteria for inclusion in the OU protocol and 13/20(65 %) were discharged successfully. Out of the 196 patients, 10 met criteria for inclusion in the OU protocol but instead received care in the inpatient setting. The median total length of stay from presentation to ED discharge was 41 h for all patients treated in the OU, compared to 68 h for ten patients who met criteria for inclusion in the OU protocol but who were admitted (difference 27 h, 95 % CI 18-72 h). ED observation for APAP overdose can be a viable alternative to inpatient admission. Most patients were successfully discharged from the OU. This evaluation identified both over- and under-utilization of the OU. OU treatment resulted in shorter median length of stay than inpatient admission.}, }
@article {pmid23792775, year = {2013}, author = {Luczak, MW and Zhitkovich, A}, title = {Role of direct reactivity with metals in chemoprotection by N-acetylcysteine against chromium(VI), cadmium(II), and cobalt(II).}, journal = {Free radical biology &amp; medicine}, volume = {65}, number = {}, pages = {262-269}, pmid = {23792775}, issn = {1873-4596}, support = {P42 ES013660/ES/NIEHS NIH HHS/United States ; R01 ES008786/ES/NIEHS NIH HHS/United States ; ES013660/ES/NIEHS NIH HHS/United States ; ES008786/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Blotting, Western ; Cadmium/*toxicity ; Cell Line ; Chromium/*toxicity ; Cobalt/*toxicity ; *Cytoprotection ; Humans ; Oxidative Stress/drug effects ; }, abstract = {The antioxidant N-acetylcysteine (NAC) is widely used for the assessment of the role of reactive oxygen species (ROS) in various biological processes and adverse drug reactions. NAC has been found to effectively inhibit the toxicity of carcinogenic metals, which was attributed to its potent ROS-suppressive properties. However, the absence of redox activity among some metals and findings from genetic models suggested a more diverse, smaller role of oxidative stress in metal toxicity. Here, we examined mechanisms of chemoprotection by NAC against Cd(II), Co(II), and Cr(VI) in human cells. We found that NAC displayed a broad-spectrum chemoprotective activity against all three metals, including suppression of cytotoxicity, apoptosis, p53 activation, and HSP72 and HIF-1α upregulation. Cytoprotection by NAC was independent of cellular glutathione. NAC strongly inhibited the uptake of all three metals in histologically different types of human cells, explaining its high chemoprotective potential. A loss of Cr(VI) accumulation by cells was caused by NAC-mediated extracellular reduction of chromate to membrane-impermeative Cr(III). Suppression of Co(II) uptake resulted from a rapid formation of Co(II)-NAC conjugates that were unable to enter cells. Our results demonstrate that NAC acts through more than one mechanism in preventing metal toxicity and its chemoprotective activity can be completely ROS-independent. Good clinical safety and effectiveness in Co(II) sequestration suggest that NAC could be useful in the prevention of tissue accumulation and toxic effects of Co ions released by cobalt-chromium hip prostheses.}, }
@article {pmid23792774, year = {2013}, author = {Rom, O and Kaisari, S and Aizenbud, D and Reznick, AZ}, title = {The effects of acetaldehyde and acrolein on muscle catabolism in C2 myotubes.}, journal = {Free radical biology &amp; medicine}, volume = {65}, number = {}, pages = {190-200}, doi = {10.1016/j.freeradbiomed.2013.06.024}, pmid = {23792774}, issn = {1873-4596}, mesh = {Acetaldehyde/*toxicity ; Acrolein/*toxicity ; Animals ; Blotting, Western ; Cell Line ; Cell Survival/drug effects ; Mice ; Muscle Fibers, Skeletal/*drug effects/*metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction/*drug effects/physiology ; }, abstract = {The toxic aldehydes acetaldehyde and acrolein were previously suggested to damage skeletal muscle. Several conditions in which exposure to acetaldehyde and acrolein is increased were associated with muscle wasting and dysfunction. These include alcoholic myopathy, renal failure, oxidative stress, and inflammation. A main exogenous source of both acetaldehyde and acrolein is cigarette smoking, which was previously associated with increased muscle catabolism. Recently, we have shown that exposure of skeletal myotubes to cigarette smoke stimulated muscle catabolism via increased oxidative stress, activation of p38 MAPK, and upregulation of muscle-specific E3 ubiquitin ligases. In this study, we aimed to investigate the effects of acetaldehyde and acrolein on catabolism of skeletal muscle. Skeletal myotubes differentiated from the C2 myoblast cell line were exposed to acetaldehyde or acrolein and their effects on signaling pathways related to muscle catabolism were studied. Exposure of myotubes to acetaldehyde did not promote muscle catabolism. However, exposure to acrolein caused increased generation of free radicals, activation of p38 MAPK, upregulation of the muscle-specific E3 ligases atrogin-1 and MuRF1, degradation of myosin heavy chain, and atrophy of myotubes. Inhibition of p38 MAPK by SB203580 abolished acrolein-induced muscle catabolism. Our findings demonstrate that acrolein but not acetaldehyde activates a signaling cascade resulting in muscle catabolism in skeletal myotubes. Although within the limitations of an in vitro study, these findings indicate that acrolein may promote muscle wasting in conditions of increased exposure to this aldehyde.}, }
@article {pmid23792120, year = {2013}, author = {Wang, SF and Chou, YC and Mazumder, N and Kao, FJ and Nagy, LD and Guengerich, FP and Huang, C and Lee, HC and Lai, PS and Ueng, YF}, title = {7-Ketocholesterol induces P-glycoprotein through PI3K/mTOR signaling in hepatoma cells.}, journal = {Biochemical pharmacology}, volume = {86}, number = {4}, pages = {548-560}, pmid = {23792120}, issn = {1873-2968}, support = {R37 CA090426/CA/NCI NIH HHS/United States ; }, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*biosynthesis ; Acetylcysteine/pharmacology ; Antibiotics, Antineoplastic/metabolism/pharmacology ; Antioxidants/pharmacology ; Carcinoma, Hepatocellular ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Cholesterol/pharmacology ; Doxorubicin/metabolism/pharmacology ; Drug Resistance, Neoplasm ; Hepatocytes/metabolism ; Humans ; Hydroxycholesterols/pharmacology ; Ketocholesterols/metabolism/*pharmacology ; Lactic Acid/biosynthesis ; Oligomycins/pharmacology ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Signal Transduction ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/*metabolism ; Up-Regulation ; }, abstract = {7-Ketocholesterol (7-KC) is found at an elevated level in patients with cancer and chronic liver disease. The up-regulation of an efflux pump, P-glycoprotein (P-gp) leads to drug resistance. To elucidate the effect of 7-KC on P-gp, P-gp function and expression were investigated in hepatoma cell lines Huh-7 and HepG2 and in primary hepatocyte-derived HuS-E/2 cells. At a subtoxic concentration, 48-h exposure to 7-KC reduced the intracellular accumulation and cytotoxicity of P-gp substrate doxorubicin in hepatoma cells, but not in HuS-E/2 cells. In Huh-7 cells, 7-KC elevated efflux function through the activation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. 7-KC activated the downstream protein synthesis initiation factor 4E-BP1 and induced P-gp expression post-transcriptionally. The stimulation of efflux was reversible and could not be prevented by N-acetyl cysteine. Total cellular ATP content remained the same, whereas the lactate production was increased and fluorescence lifetime of protein-bound NADH was shortened. These changes suggested a metabolic shift to glycolysis, but glycolytic inhibitors did not eliminate 7-KC-mediated P-gp induction. These results demonstrate that 7-KC induces P-gp through PI3K/mTOR signaling and decreased the cell-killing efficacy of doxorubicin in hepatoma cells.}, }
@article {pmid23791750, year = {2013}, author = {Ravera, S and Vaccaro, D and Cuccarolo, P and Columbaro, M and Capanni, C and Bartolucci, M and Panfoli, I and Morelli, A and Dufour, C and Cappelli, E and Degan, P}, title = {Mitochondrial respiratory chain Complex I defects in Fanconi anemia complementation group A.}, journal = {Biochimie}, volume = {95}, number = {10}, pages = {1828-1837}, doi = {10.1016/j.biochi.2013.06.006}, pmid = {23791750}, issn = {1638-6183}, support = {GTB12001/TI_/Telethon/Italy ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Monophosphate/metabolism ; Adenosine Triphosphate/*metabolism ; Adenylate Kinase/metabolism ; Adolescent ; Case-Control Studies ; Cell Respiration/drug effects ; Cells, Cultured ; Child ; Child, Preschool ; Electron Transport Complex I/genetics/*metabolism ; Fanconi Anemia/genetics/*metabolism/pathology ; Fanconi Anemia Complementation Group A Protein/genetics/metabolism ; Fibroblasts/drug effects/*metabolism/pathology ; Humans ; Lymphocytes/drug effects/*metabolism/pathology ; Microscopy, Electron ; Mitochondria/genetics/*metabolism/ultrastructure ; Mutation ; Oxidation-Reduction ; Oxygen Consumption/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Fanconi anemia (FA) is a rare and complex inherited blood disorder of the child. At least 15 genes are associated with the disease. The highest frequency of mutations belongs to groups A, C and G. Genetic instability and cytokine hypersensitivity support the selection of leukemic over non-leukemic stem cells. FA cellular phenotype is characterized by alterations in red-ox state, mitochondrial functionality and energy metabolism as reported in the past however a clear picture of the altered biochemical phenotype in FA is still elusive and the final biochemical defect(s) still unknown. Here we report an analysis of the respiratory fluxes in FANCA primary fibroblasts, lymphocytes and lymphoblasts. FANCA mutants show defective respiration through Complex I, diminished ATP production and metabolic sufferance with an increased AMP/ATP ratio. Respiration in FANCC mutants is normal. Treatment with N-acetyl-cysteine (NAC) restores oxygen consumption to normal level. Defective respiration in FANCA mutants appear correlated with the FA pro-oxidative phenotype which is consistent with the altered morphology of FANCA mitochondria. Electron microscopy measures indeed show profound alterations in mitochondrial ultrastructure and shape.}, }
@article {pmid23788172, year = {2013}, author = {Yu, SM and Kim, SJ}, title = {Thymoquinone-induced reactive oxygen species causes apoptosis of chondrocytes via PI3K/Akt and p38kinase pathway.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {238}, number = {7}, pages = {811-820}, doi = {10.1177/1535370213492685}, pmid = {23788172}, issn = {1535-3699}, mesh = {4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Anions ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology ; Cartilage, Articular/pathology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chondrocytes/drug effects/*enzymology/pathology ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; Imidazoles/pharmacology ; Intracellular Space/drug effects/metabolism ; Ion Channels/antagonists &amp; inhibitors/metabolism ; Mitochondria/drug effects/metabolism ; Models, Biological ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*metabolism ; Pyridines/pharmacology ; Rabbits ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Thymoquinone (TQ), a bioactive ingredient of the volatile oil of black seed (Nigella sativa), has been shown to possess anti-neoplastic and anti-inflammatory effects on a variety of tumours. However, the precise mechanism of action is not clear in normal cells such as primary chondrocytes. So, we have investigated the effects of TQ on the apoptosis of chondrocytes with a focus on reactive oxygen species (ROS) production. In in vitro experiments, chondrocytes were cultured with increasing concentrations of TQ for 24 h or with 20 µmol/L TQ for the indicated time periods, and various experiments were performed to detect the apoptotic effects caused by TQ. The results showed that TQ significantly increases apoptosis. Apoptosis was dose- and time-dependently expressed, and the generation of ROS also dramatically increased in a dose-dependent manner. Pretreatment of N-acetyl-L-cysteine (NAC), an inhibitor of ROS, inhibited both TQ-induced apoptosis and ROS generation. Also, TQ up-regulated phosphorylation of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinases ([MAPKs] p38kinase, ERK-1/-2, and JNKinase), and these effects were prevented by pretreatment of NAC. However, pretreatment with inhibitors of PI3K/Akt and MAPKs did not inhibit TQ-caused ROS generation. Among the inhibitors of PI3K/Akt, p38kinase, ERK-1/-2, and JNKinase, pretreatment with LY294002 and SB203580 abolished TQ-induced apoptosis, but PD98059 and SP600125 did not have any effect on TQ-caused apoptosis. These findings suggest that TQ-induced ROS generation regulates apoptosis by modulating PI3K/Akt and p38kinase pathways.}, }
@article {pmid23786532, year = {2013}, author = {Su, X and Wang, P and Wang, X and Guo, L and Li, S and Liu, Q}, title = {Involvement of MAPK activation and ROS generation in human leukemia U937 cells undergoing apoptosis in response to sonodynamic therapy.}, journal = {International journal of radiation biology}, volume = {89}, number = {11}, pages = {915-927}, doi = {10.3109/09553002.2013.817700}, pmid = {23786532}, issn = {1362-3095}, mesh = {Apoptosis/*drug effects/*radiation effects ; Biological Transport ; Chlorophyllides ; Enzyme Activation/drug effects/radiation effects ; Humans ; Intracellular Space/drug effects/metabolism/radiation effects ; Mitogen-Activated Protein Kinases/*metabolism ; *Photochemotherapy ; Porphyrins/metabolism/pharmacology/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; U937 Cells ; *Ultrasonics ; }, abstract = {PURPOSE: To elucidate the underlying events in Chlorin e6 (Ce6)-mediated sonodynamic therapy (SDT) (Ce6-SDT)-induced apoptosis of human leukemia cell line U937.<br><br>MATERIALS AND METHODS: The viability of cells was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltertrazolium bromide tetrazolium (MTT) test. Apoptosis was analyzed using a &#xfb02;ow cytometer as well as &#xfb02;uorescence microscopy with 4'-6-Diamidino-2-Phenylindole (DAPI) staining. Western blotting was used to analyze the expression of caspase-3, poly ADP- ribose polymerase (PARP) and mitogen-activated protein kinase (MAPK).<br><br>RESULTS: Several distinct sonochemical effects were found after SDT treatment. The participation of MAPK signals in SDT which caused U937 cell damage was specifically examined and the inhibition of p38 MAPK and Jun-N-terminal kinase (JNK) both apparently exerted a negative effect on SDT-induced cell death, while extracellular signal-regulating kinase (ERK1/2) inhibition enhanced SDT-induced cell death. The intracellular reactive oxygen species (ROS) was significantly enhanced by SDT, and pre-treatment with ROS scavenger N-acetylcysteine (NAC) partially alleviated SDT-induced cell viability loss, DNA fragmentation, mitochondria membrane potential (MMP) dissipation, caspase-3 activation, but interestingly MAPK activation was not affected much by NAC.<br><br>CONCLUSIONS: In the present paper, cell apoptosis of U937 cells was markedly enhanced after Ce6-SDT. Meanwhile, p38 MAPK, JNK and ERK were all differently activated in this process. One possible explanation for the induced cell apoptosis could be the increased ROS generation in Ce6-SDT.}, }
@article {pmid23782750, year = {2013}, author = {Arakaki, N and Yamashita, A and Niimi, S and Yamazaki, T}, title = {Involvement of reactive oxygen species in osteoblastic differentiation of MC3T3-E1 cells accompanied by mitochondrial morphological dynamics.}, journal = {Biomedical research (Tokyo, Japan)}, volume = {34}, number = {3}, pages = {161-166}, doi = {10.2220/biomedres.34.161}, pmid = {23782750}, issn = {1880-313X}, mesh = {Acetylcysteine/pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Antioxidants/pharmacology ; Biomarkers/metabolism ; Calcification, Physiologic/physiology ; Cell Differentiation/drug effects ; Cell Line ; Mice ; Mitochondria/drug effects/enzymology/*ultrastructure ; Mitochondrial Dynamics/drug effects ; Osteoblasts/*cytology/drug effects/enzymology ; Osteogenesis/physiology ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Bone remodeling is regulated by local factors that regulate bone-forming osteoblasts and bone-resorbing osteoclasts, in addition to hormonal activity. Recent studies have shown that reactive oxygen species (ROS) act as an intracellular signal mediator for osteoclast differentiation. However the role of ROS on osteoblast differentiation is poorly understood. Here, we investigated the impact of ROS on osteoblastic differentiation of MC3T3-E1 cells. Osteogenic induction resulted in notable enhancement of mineralization and expression of osteogenic marker gene alkaline phosphatase, which were accompanied by an increase in ROS production. Additionally, we found that mitochondrial morphology dynamically changed from tubular reticulum to fragmented structures during the differentiation, suggesting that mitochondrial morphological transition is a novel osteoblast differentiation index. The antioxidant N-acetyl cysteine prevented not only ROS production but also mineralization and mitochondrial fragmentation. It is therefore suggested that the ROS-dependent signaling pathways play a role in osteoblast differentiation accompanied by mitochondrial morphological transition.}, }
@article {pmid23782641, year = {2013}, author = {Mo, S and Xiong, H and Shu, G and Yang, X and Wang, J and Zheng, C and Xiong, W and Mei, Z}, title = {Phaseoloideside E, a novel natural triterpenoid saponin identified from Entada phaseoloides, induces apoptosis in Ec-109 esophageal cancer cells through reactive oxygen species generation.}, journal = {Journal of pharmacological sciences}, volume = {122}, number = {3}, pages = {163-175}, doi = {10.1254/jphs.12193fp}, pmid = {23782641}, issn = {1347-8648}, mesh = {Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Esophageal Neoplasms/drug therapy/*metabolism/*pathology ; Fabaceae/*chemistry ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Mice ; Phytotherapy ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Saponins/*isolation &amp; purification/*pharmacology/therapeutic use ; Triterpenes/*isolation &amp; purification/*pharmacology/therapeutic use ; Tumor Cells, Cultured ; Up-Regulation/drug effects ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Phaseoloideside E (PE), a new oleanane-type triterpene saponin, was isolated from the seed kernels of Entada phaseoloides (Linn.) Merr. PE had strong cytotoxic activity against an array of malignant cells. Typical morphological and biochemical features of apoptosis were observed in PE-treated Ec-109 cells. PE induced a dose-dependent increase in the sub-G1 fraction of the cell cycle and DNA fragmentation. Decreases in the mitochondrial membrane potential, SOD activity, and GSH content were also observed. Further investigations revealed that PE reduced the ratio of Bcl-2 to Bax and increased the activities of caspase-3 and -9, but this was prevented by Z-VAD-fmk. PE also induced a decrease of the sub-G1 fraction. Furthermore, PE-induced apoptosis was mediated by up-regulating cellular ROS, which was suppressed by cotreating the cells with N-acetylcysteine (NAC). NAC also attenuated the ratio of sub-G1, the generation of DNA fragmentation and the expression of Bcl-2, Bax, caspase-3, and caspase-9. Interestingly, PE did not up-regulate ROS or induce cell death in untransformed cells. These data showed that PE induces cell death through up-regulation of cellular ROS production. Our investigation provides the scientific basis for the traditional application of this herb and suggests the possibility that PE may be used for a treatment of esophageal carcinoma. [Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.12193FP].}, }
@article {pmid23782487, year = {2013}, author = {Stravitz, RT and Sanyal, AJ and Reisch, J and Bajaj, JS and Mirshahi, F and Cheng, J and Lee, WM and , }, title = {Effects of N-acetylcysteine on cytokines in non-acetaminophen acute liver failure: potential mechanism of improvement in transplant-free survival.}, journal = {Liver international : official journal of the International Association for the Study of the Liver}, volume = {33}, number = {9}, pages = {1324-1331}, pmid = {23782487}, issn = {1478-3231}, support = {R01 DK058369/DK/NIDDK NIH HHS/United States ; U01 DK058369/DK/NIDDK NIH HHS/United States ; UL1 TR000058/TR/NCATS NIH HHS/United States ; U-01 DK58369/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Cytokines/*blood ; Enzyme-Linked Immunosorbent Assay ; Hepatic Encephalopathy/*drug therapy ; Humans ; Liver Failure, Acute/*drug therapy ; Logistic Models ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) improves transplant-free survival in patients with non-acetaminophen acute liver failure (ALF) when administered in early stages of hepatic encephalopathy. The mechanisms of this benefit are unknown.<br><br>AIM: To determine whether NAC improves transplant-free survival in ALF by ameliorating the surge of pro-inflammatory cytokines.<br><br>METHODS: Serum samples were obtained from 78 participants of the randomized, ALF Study Group NAC Trial with grade 1 or 2 hepatic encephalopathy on randomization. Concentrations of ten cytokines, chosen to represent a wide array of inflammatory responses, were determined by multiplex enzyme-linked immunosorbent assay ELISA.<br><br>RESULTS: In univariate analysis, predictors of transplant-free survival included NAC administration (P&#xa0;=&#xa0;0.012), admission bilirubin (P&#xa0;=&#xa0;0.003), international normalized ratio INR (P&#xa0;=&#xa0;0.0002), grade 1 vs. grade 2 encephalopathy (P&#xa0;=&#xa0;0.006) and lower admission interleukin (IL)-17 concentrations (P&#xa0;=&#xa0;0.011). IL-17 levels were higher in patients with grade 2 vs. grade 1 encephalopathy on randomization (P&#xa0;=&#xa0;0.007) and in those who progressed to grade 3 or grade 4 encephalopathy over the following 7&#xa0;days (P&#xa0;&#x2264;&#xa0;0.01). Stepwise multivariate logistic regression analysis identified only NAC administration and lower IL-17 concentrations as independent predictors of transplant-free survival. In patients with detectable IL-17 concentrations on admission, 78% of those who received NAC vs. 44% of those who received placebo had undetectable levels by day 3-5 (P&#xa0;=&#xa0;0.042), and the mean decrease in IL-17 concentrations between admission and late samples was significantly greater in patients who received NAC vs. placebo (P&#xa0;=&#xa0;0.045).<br><br>CONCLUSIONS: N-acetylcysteine (NAC) may improve transplant-free survival in patients with non-acetaminophen ALF by ameliorating the production of IL-17, which is associated with progression of hepatic encephalopathy and poor outcome.}, }
@article {pmid23778727, year = {2013}, author = {,  and Bhatia, V and Bavdekar, A and Yachha, SK and , }, title = {Management of acute liver failure in infants and children: consensus statement of the pediatric gastroenterology chapter, Indian academy of pediatrics.}, journal = {Indian pediatrics}, volume = {50}, number = {5}, pages = {477-482}, doi = {10.1007/s13312-013-0147-4}, pmid = {23778727}, issn = {0974-7559}, mesh = {Child ; Child, Preschool ; Consensus ; Humans ; India ; Infant ; Liver Failure, Acute/*diagnosis/*therapy ; Liver Transplantation/*standards ; }, abstract = {PROCESS: Selected members were requested to prepare guidelines on specific issues, which were reviewed by two other members. These guidelines were then incorporated into a draft statement, which was circulated to all members. On 17th December 2011, Kunwar Viren Oswal round table conference was organized by the Apollo Center for Advanced Pediatrics, Indraprastha Apollo Hospital, New Delhi and the Sub-specialty Chapter of Pediatric Gastroenterology, Indian Academy of Pediatrics. Presentations, ensuing discussions, and opinions expressed by the participants were incorporated into the final draft.<br><br>OBJECTIVES: To formulate comprehensive evidence based guidelines for management of acute liver failure in India.<br><br>RECOMMENDATIONS: Viral hepatitis is the leading cause of acute liver failure (ALF) in India. Search for metabolic etiology, particularly in infants and neonates, and in apparently idiopathic cases needs to be done. Planning for early transfer is important as the risks involved with patient transport may increase or even preclude transfer at later stages. Management should be in an intensive care setting in select situations. There is currently insufficient evidence to routinely prescribe branched-chain amino acids, non-absorbable antibiotics or lactulose. Group recommends use of N-acetyl cysteine routinely in patients with ALF. Administration of antibiotics is recommended where infection is present or the likelihood of impending sepsis is high. Enteral nutrition is preferred to parenteral nutrition. Protein restriction is not recommended. An international normalized ratio >4 or Factor V concentration of <25% are the best available criteria for listing for liver transplantation. Overall 40-50% of ALF patients survive without transplantation. Survival in patients fulfilling criteria for liver transplantation and not transplanted is 10-20%. Liver transplantation is a definite treatment for ALF with high one-and five-year survival rates.}, }
@article {pmid23776698, year = {2013}, author = {Shi, L and Yu, X and Yang, H and Wu, X}, title = {Advanced glycation end products induce human corneal epithelial cells apoptosis through generation of reactive oxygen species and activation of JNK and p38 MAPK pathways.}, journal = {PloS one}, volume = {8}, number = {6}, pages = {e66781}, pmid = {23776698}, issn = {1932-6203}, mesh = {Apoptosis/drug effects/*physiology ; Blotting, Western ; Corneal Diseases/*etiology ; Diabetes Complications/*pathology ; Epithelial Cells/drug effects/*physiology ; Epithelium, Corneal/cytology ; Fluorescein-5-isothiocyanate ; Glycation End Products, Advanced/*pharmacology ; Humans ; MAP Kinase Signaling System/drug effects ; Reactive Oxygen Species/*metabolism ; Serum Albumin, Bovine/*pharmacology ; Telomerase/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Advanced Glycation End Products (AGEs) has been implicated in the progression of diabetic keratopathy. However, details regarding their function are not well understood. In the present study, we investigated the effects of intracellular reactive oxygen species (ROS) and JNK, p38 MAPK on AGE-modified bovine serum albumin (BSA) induced Human telomerase-immortalized corneal epithelial cells (HUCLs) apoptosis. We found that AGE-BSA induced HUCLs apoptosis and increased Bax protein expression, decreased Bcl-2 protein expression. AGE-BSA also induced the expression of receptor for advanced glycation end product (RAGE). AGE-BSA-RAGE interaction induced intracellular ROS generation through activated NADPH oxidase and increased the phosphorylation of p47phox. AGE-BSA induced HUCLs apoptosis was inhibited by pretreatment with NADPH oxidase inhibitors, ROS quencher N-acetylcysteine (NAC) or neutralizing anti-RAGE antibodies. We also found that AGE-BSA induced JNK and p38 MAPK phosphorylation. JNK and p38 MAPK inhibitor effectively blocked AGE-BSA-induced HUCLs apoptosis. In addition, NAC completely blocked phosphorylation of JNK and p38 MAPK induced by AGE-BSA. Our results indicate that AGE-BSA induced HUCLs apoptosis through generation of intracellular ROS and activation of JNK and p38 MAPK pathways.}, }
@article {pmid23774252, year = {2013}, author = {Yang, CM and Lee, IT and Hsu, RC and Chi, PL and Hsiao, LD}, title = {NADPH oxidase/ROS-dependent PYK2 activation is involved in TNF-α-induced matrix metalloproteinase-9 expression in rat heart-derived H9c2 cells.}, journal = {Toxicology and applied pharmacology}, volume = {272}, number = {2}, pages = {431-442}, doi = {10.1016/j.taap.2013.05.036}, pmid = {23774252}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Line ; Focal Adhesion Kinase 2/*metabolism ; Matrix Metalloproteinase 9/*biosynthesis ; *Myocardium/enzymology/metabolism ; NADPH Oxidases/*metabolism ; NF-kappa B/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/*pharmacology ; Up-Regulation ; }, abstract = {TNF-α plays a mediator role in the pathogenesis of chronic heart failure contributing to cardiac remodeling and peripheral vascular disturbances. The implication of TNF-α in inflammatory responses has been shown to be mediated through up-regulation of matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of TNF-α-induced MMP-9 expression in rat embryonic-heart derived H9c2 cells are largely not defined. We demonstrated that in H9c2 cells, TNF-α induced MMP-9 mRNA and protein expression associated with an increase in the secretion of pro-MMP-9. TNF-α-mediated responses were attenuated by pretreatment with the inhibitor of ROS (N-acetyl-l-cysteine, NAC), NADPH oxidase [apocynin (APO) or diphenyleneiodonium chloride (DPI)], MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), NF-κB (Bay11-7082), or PYK2 (PF-431396) and transfection with siRNA of TNFR1, p47(phox), p42, p38, JNK1, p65, or PYK2. Moreover, TNF-α markedly induced NADPH oxidase-derived ROS generation in these cells. TNF-α-enhanced p42/p44 MAPK, p38 MAPK, JNK1/2, and NF-κB (p65) phosphorylation and in vivo binding of p65 to the MMP-9 promoter were inhibited by U0126, SB202190, SP600125, NAC, DPI, or APO. In addition, TNF-α-mediated PYK2 phosphorylation was inhibited by NAC, DPI, or APO. PYK2 inhibition could reduce TNF-α-stimulated MAPKs and NF-κB activation. Thus, in H9c2 cells, we are the first to show that TNF-α-induced MMP-9 expression is mediated through a TNFR1/NADPH oxidase/ROS/PYK2/MAPKs/NF-κB cascade. We demonstrated that NADPH oxidase-derived ROS generation is involved in TNF-α-induced PYK2 activation in these cells. Understanding the regulation of MMP-9 expression and NADPH oxidase activation by TNF-α on H9c2 cells may provide potential therapeutic targets of chronic heart failure.}, }
@article {pmid23772801, year = {2013}, author = {Halasi, M and Wang, M and Chavan, TS and Gaponenko, V and Hay, N and Gartel, AL}, title = {ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.}, journal = {The Biochemical journal}, volume = {454}, number = {2}, pages = {201-208}, pmid = {23772801}, issn = {1470-8728}, support = {CA090764/CA/NCI NIH HHS/United States ; I01 BX000733/BX/BLRD VA/United States ; R01 CA090764/CA/NCI NIH HHS/United States ; R01CA135341/CA/NCI NIH HHS/United States ; AG016927/AG/NIA NIH HHS/United States ; R01 CA129414/CA/NCI NIH HHS/United States ; R01 CA135341/CA/NCI NIH HHS/United States ; 1R01CA129414/CA/NCI NIH HHS/United States ; R01 AG016927/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antineoplastic Agents, Phytogenic/antagonists &amp; inhibitors/pharmacology ; Apoptosis/drug effects ; Catalase/genetics/metabolism ; Cell Line, Tumor ; Chromans/antagonists &amp; inhibitors/metabolism/pharmacology ; Cytomegalovirus/enzymology ; Dioxolanes/antagonists &amp; inhibitors/pharmacology ; Forkhead Box Protein M1 ; Forkhead Transcription Factors/antagonists &amp; inhibitors/genetics/metabolism ; Free Radical Scavengers/metabolism/*pharmacology ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors/pharmacology ; Oxidants/antagonists &amp; inhibitors/pharmacology ; Proteasome Endopeptidase Complex/*drug effects/metabolism ; Proteasome Inhibitors/chemistry/metabolism/*pharmacology ; Protein Stability/drug effects ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Recombinant Proteins/antagonists &amp; inhibitors/metabolism ; Ubiquitinated Proteins/metabolism ; Viral Proteins/genetics/metabolism ; }, abstract = {NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H2O2. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.}, }
@article {pmid23771710, year = {2013}, author = {Zhang, H and Yin, G and Jiang, H and Zhang, C}, title = {High-dose N-acetylcysteine decreases silica-induced lung fibrosis in the rat.}, journal = {The Journal of international medical research}, volume = {41}, number = {4}, pages = {1179-1186}, doi = {10.1177/0300060513488503}, pmid = {23771710}, issn = {1473-2300}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Bronchoalveolar Lavage Fluid/chemistry ; C-Reactive Protein/immunology/metabolism ; Hydroxyproline/metabolism ; Inflammation/chemically induced/drug therapy/immunology/pathology ; Interleukin-8/immunology/metabolism ; Lung/*drug effects/immunology/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Pulmonary Fibrosis/chemically induced/*drug therapy/immunology/pathology ; Rats ; Rats, Wistar ; Silicon Dioxide ; Tumor Necrosis Factor-alpha/immunology/metabolism ; }, abstract = {OBJECTIVE: To study the potential of high-dose N-acetylcysteine (NAC) to attenuate silica-induced pulmonary fibrosis in the rat.<br><br>METHODS: Rats exposed to intratracheal instillation of silica particles were treated with 500 mg/kg NAC orally every day for 7 days, before and up to 28 days after silica administration (n = 32), or received no treatment following silica exposure (n = 32); a third group received intratracheal saline (n = 32). Fibrosis score, and hydroxyproline (HYP) and malondialdehyde (MDA) content, were assessed in lung tissue. Bronchoalveolar lavage fluid (BALF) and serum levels of tumour necrosis factor (TNF)-&#x3b1;, interleukin (IL)-8 and high-sensitivity C-reactive protein (hsCRP) were assessed by enzyme-linked immunosorbent assay.<br><br>RESULTS: Histopathology revealed inflammation and fibrosis in lung tissue from rats exposed to silica, but not in saline controls. The fibrosis score was significantly lower in animals treated with NAC compared with silica-exposed untreated rats. HYP and MDA content were significantly lower at all timepoints, following NAC treatment versus no treatment, in silica-exposed rats. NAC attenuated silica-induced increases in TNF-&#x3b1;, IL-8 and hsCRP in BALF and serum.<br><br>CONCLUSIONS: Oral treatment with high-dose NAC during early silica exposure can ameliorate the activity of proinflammatory cytokines, thus attenuating subsequent lung fibrosis. These results suggest that NAC has potential as a treatment for silica-induced lung fibrosis.}, }
@article {pmid23770845, year = {2013}, author = {Wang, X and Sun, Y and Wong, J and Conklin, DS}, title = {PPARγ maintains ERBB2-positive breast cancer stem cells.}, journal = {Oncogene}, volume = {32}, number = {49}, pages = {5512-5521}, pmid = {23770845}, issn = {1476-5594}, support = {R01 CA136658/CA/NCI NIH HHS/United States ; 1R01CA136658/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aldehyde Dehydrogenase/*metabolism ; Anilides/pharmacology ; Animals ; Benzamides/pharmacology ; Breast Neoplasms/metabolism/*pathology ; Cell Line, Tumor ; Female ; Humans ; Kruppel-Like Factor 4 ; MCF-7 Cells ; Mediator Complex Subunit 1/metabolism ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Transplantation ; Neoplastic Stem Cells/metabolism/*pathology ; Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism ; PPAR gamma/antagonists &amp; inhibitors/*metabolism ; Pyridines/pharmacology ; Reactive Oxygen Species ; Receptor, ErbB-2/*metabolism ; }, abstract = {Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers and is associated with aggressive disease and poor outcomes. Our recent findings have shown that NR1D1 and the peroxisome proliferator-activated receptor-γ (PPARγ)-binding protein (PBP) act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. NR1D1 and PBP are functionally related to PPARγ, a well-established positive regulator of adipogenesis and lipid storage. Here, we report that inhibition of the PPARγ pathway reduces the aldehyde dehydrogenase (ALDH)-positive population in ERBB2-positive breast cancer cells. Results from in vitro tumorsphere formation assays demonstrate that the PPARγ antagonists GW9662 and T0070907 decrease tumorsphere formation in ERBB2-positive cells, but not other breast cells. We show that the mechanism by which GW9662 treatment causes a reduction in ALDH-positive population cells is partially due to ROS, as it can be rescued by treatment with N-acetyl-cysteine. Furthermore, global gene expression analyses show that GW9662 treatment suppresses the expression of several lipogenic genes, including ACLY, MIG12, FASN and NR1D1, and the stem-cell related genes KLF4 and ALDH in BT474 cells. Antagonist treatment also decreases the level of acetylation in histone 3 and histone 4 in BT474 cells, compared with MCF7 cells. In vivo, GW9662 pre-treatment inhibits the tumor-seeding ability of BT474 cells. Together, these results show that the PPARγ pathway is critical for the cancer stem cell properties of ERBB2-positive breast cancer cells.}, }
@article {pmid23770516, year = {2013}, author = {Partyka, A and Niżański, W and Bajzert, J and Łukaszewicz, E and Ochota, M}, title = {The effect of cysteine and superoxide dismutase on the quality of post-thawed chicken sperm.}, journal = {Cryobiology}, volume = {67}, number = {2}, pages = {132-136}, doi = {10.1016/j.cryobiol.2013.06.002}, pmid = {23770516}, issn = {1090-2392}, mesh = {Acetylcysteine/*metabolism ; Animals ; Antioxidants/*metabolism ; *Chickens/physiology ; Cryopreservation/methods/*veterinary ; Cryoprotective Agents/metabolism ; Lipid Peroxidation/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Semen Analysis ; Semen Preservation/methods/*veterinary ; Sperm Motility/drug effects ; Spermatozoa/cytology/drug effects/metabolism ; Superoxide Dismutase/*metabolism ; }, abstract = {The study was conducted to determine the influence of N-acetyl-l-cysteine (NAC) and superoxide dismutase (SOD) on chicken sperm motility, plasma membrane and acrosome integrity, mitochondrial activity, lipid peroxidation (LPO) and apoptotic changes after freezing-thawing process. Semen samples from fifteen Greenlegged Partridge roosters were pooled, diluted with EK extender without antioxidants (control), or supplemented with 5 mM NAC, or 200 U/mL SOD. Samples were subjected to cryopreservation. After thawing, sperm parameters evaluated by using CASA system and flow cytometry were assessed. The extender supplemented with NAC and SOD caused the increase (P < 0.01) in sperm motility and provided the higher percentage of rapid sperm (P < 0.01) compared to control. The addition of NAC increased the progressive motility of cells (P < 0.01). In NAC and SOD groups post-thaw plasma membrane integrity was higher (P < 0.05) and less spermatozoa showed apoptotic changes (P < 0.01, P < 0.05). Post-thaw percentage of sperm with high mitochondrial activity was the greatest (P < 0.05) with NAC addition. The SOD supplementation only reduced (P < 0.05) the percentage of sperm with LPO, following the cryopreservation. These results indicate that the addition of NAC (5 mM) and SOD (200 U/mL) is beneficial for the function of frozen-thawed chicken spermatozoa. The antioxidants prevented the reduction in motility, viability and mitochondrial membrane potential, as well as protected from apoptotic changes in sperm. Lipid peroxidation in sperm plasma membrane was decreased by SOD supplementation. Therefore, these antioxidants can be recommended as an additional component of chicken freezing extender.}, }
@article {pmid23765110, year = {2013}, author = {Piao, SG and Kang, SH and Lim, SW and Chung, BH and Doh, KC and Heo, SB and Jin, L and Li, C and Yang, CW}, title = {Influence of N-acetylcysteine on Klotho expression and its signaling pathway in experimental model of chronic cyclosporine nephropathy in mice.}, journal = {Transplantation}, volume = {96}, number = {2}, pages = {146-153}, doi = {10.1097/TP.0b013e318296c9a9}, pmid = {23765110}, issn = {1534-6080}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Apoptosis/drug effects ; Chronic Disease ; Cyclosporine/*adverse effects ; Deoxyguanosine/analogs &amp; derivatives/urine ; Disease Models, Animal ; Forkhead Box Protein O1 ; Forkhead Transcription Factors/metabolism ; Gene Expression/drug effects ; Glucuronidase/*genetics/*metabolism ; Immunosuppressive Agents/*adverse effects ; Kidney Diseases/chemically induced/metabolism/*prevention &amp; control ; Klotho Proteins ; Male ; Mice ; Mice, Inbred ICR ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND: Cyclosporine A (CsA)-associated oxidative stress has been proposed as an important mechanism of renal injury. This study was designed to examine whether N-acetylcysteine (NAC), a well-known antioxidant, affects Klotho, antiaging gene, expression and its signaling pathway in an experimental model of chronic CsA nephropathy.<br><br>METHODS: Mice maintained on a low-sodium diet were given vehicle (olive oil, 1 mL/kg/day), CsA (30 mg/kg/day), NAC (150 mg/kg/day), or a combination of CsA and NAC for 4 weeks. The effect of NAC on CsA-induced renal injury was evaluated with basic parameters, histopathology, and markers of oxidative stress [8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion and manganese superoxide dismutase (MnSOD) expression]. The influence of NAC on Klotho and its signal pathway (p-AKT and p-FoxO1) in CsA-treated mouse kidney was evaluated with immunohistochemistry and/or immunoblot.<br><br>RESULTS: Concomitant administration of CsA and NAC significantly improved renal function and attenuated tubulointerstitial fibrosis, and these changes were accompanied by decreased urinary 8-OHdG level and increased MnSOD expression. NAC treatment preserved Klotho gene expression compared with CsA treatment alone (P < 0.05), and this correlated with urinary 8-OHdG excretion (r = -0.934) and MnSOD expression (r = 0.873, P < 0.001 for both). Concomitant treatment of CsA and NAC translocated FoxO1 from the cytoplasm to the nucleus, implicating dephosphorylation of FoxO1 by NAC in p-AKT/p-FoxO1 pathway.<br><br>CONCLUSION: NAC treatment preserves Klotho expression and modifies p-AKT/p-FoxO1 pathway in chronic CsA nephropathy.}, }
@article {pmid23764026, year = {2013}, author = {Spagnuolo, G and Desiderio, C and Rivieccio, V and Amato, M and Rossetti, DV and D'Antò, V and Schweikl, H and Lupi, A and Rengo, S and Nocca, G}, title = {In vitro cellular detoxification of triethylene glycol dimethacrylate by adduct formation with N-acetylcysteine.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {29}, number = {8}, pages = {e153-60}, doi = {10.1016/j.dental.2013.04.023}, pmid = {23764026}, issn = {1879-0097}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Cell Culture Techniques ; Cell Survival/drug effects ; Chromatography, High Pressure Liquid/methods ; Coloring Agents ; Cytosol/chemistry ; Dose-Response Relationship, Drug ; Drug Interactions ; Electrophoresis, Capillary ; Extracellular Space/chemistry ; Fibroblasts/*drug effects ; Methacrylates/analysis ; Mice ; Polyethylene Glycols/analysis/chemistry/*toxicity ; Polymethacrylic Acids/analysis/chemistry/*toxicity ; Protective Agents/chemistry/*pharmacology ; Swiss 3T3 Cells ; Tandem Mass Spectrometry/methods ; Tetrazolium Salts ; Thiazoles ; Time Factors ; Ultraviolet Rays ; }, abstract = {OBJECTIVE: Various protective effects of N-acetylcysteine (NAC) against triethylene glycol dimethacrylate (TEGDMA)-induced cell damage have been demonstrated, but so far there is no evidence on NAC direct monomer detoxification mechanism. Here, we hypothesized that NAC might reduce TEGDMA cytotoxicity due to direct NAC adduct formation.<br><br>METHODS: We measured the cytotoxic effects of TEGDMA in presence and in absence of NAC by MTT test. Then we analyzed the presence of TEGDMA-NAC adduct formation in extracellular and intracellular compartments by capillary electrophoresis-UV detection (CE-UV) and capillary electrophoresis-mass spectrometry (CE-MS) analytical techniques. Moreover, we quantified the effective intracellular and extracellular TEGDMA concentrations through HPLC in the presence and absence of 10 mmol/L NAC.<br><br>RESULTS: TEGDMA reduced 3T3 cell vitality in a dose- and time-dependent manner, while NAC decreased monomer cytotoxicity and extracellular monomer concentrations by a direct reaction with TEGDMA. The adducts between the two molecules were detected both in the presence and absence of cell. Moreover a signal ascribed to the methacrylic acid was present in the CE-UV electropherogram of cellular lysates obtained after incubation with TEGDMA.<br><br>SIGNIFICANCE: Our results suggest that in vitro detoxification capability of NAC against TEGDMA-induced cell damage might occur also through the formation of NAC-TEGDMA adduct.}, }
@article {pmid23760725, year = {2013}, author = {Park, WH}, title = {Effects of antioxidants and MAPK inhibitors on cell death and reactive oxygen species levels in H2O2-treated human pulmonary fibroblasts.}, journal = {Oncology letters}, volume = {5}, number = {5}, pages = {1633-1638}, pmid = {23760725}, issn = {1792-1074}, abstract = {H2O2-induced cytotoxicity in normal human pulmonary fibroblasts (HPFs) is of interest in toxicological research since HPFs are involved in lung inflammation, fibrosis and cancer. The present study investigated the cytotoxic effects of H2O2 on normal HPFs in relation to reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) using the well-known antioxidants N-acetyl cysteine (NAC) and propyl gallate (PG), as well as MAPK inhibitors. Treatment with 50 μM H2O2 inhibited the growth of the HPFs by ∼45% in 24 h. H2O2 induced cell death via apoptosis and triggered the loss of mitochondrial membrane potential (MMP; Δψm) in the HPFs. H2O2 also increased the ROS levels, including O2[•-], in the HPFs and induced glutathione (GSH) depletion. NAC and PG attenuated the death of the HPFs and the loss of MMP (Δψm) through the use of H2O2. NAC decreased the ROS levels in the H2O2-treated HPFs and PG markedly prevented an increase in O2[•-] levels in these cells. However, PG alone induced cell death in the HPF control cells and increased the ROS levels in these cells. None of the MAPK (MEK, JNK and p38) inhibitors affected cell growth inhibition or cell death by H2O2. In addition, these inhibitors did not significantly affect the ROS levels and GSH depletion in the H2O2-treated HPFs. In conclusion, H2O2 induced growth inhibition and cell death in the HPFs via GSH depletion. NAC and PG attenuated H2O2-induced HPF cell death but each regulated the ROS levels in a different manner. Treatment with MAPK inhibitors did not affect cell death or the ROS levels in the H2O2-treated HPFs.}, }
@article {pmid23760395, year = {2013}, author = {Yan, KH and Yao, CJ and Hsiao, CH and Lin, KH and Lin, YW and Wen, YC and Liu, CC and Yan, MD and Chuang, SE and Lai, GM and Lee, LM}, title = {Mefloquine exerts anticancer activity in prostate cancer cells via ROS-mediated modulation of Akt, ERK, JNK and AMPK signaling.}, journal = {Oncology letters}, volume = {5}, number = {5}, pages = {1541-1545}, pmid = {23760395}, issn = {1792-1074}, abstract = {Mefloquine (MQ) is a prophylactic anti-malarial drug. Previous studies have shown that MQ induces oxidative stress in vitro. Evidence indicates that reactive oxygen species (ROS) may be used as a therapeutic modality to kill cancer cells. This study investigated whether MQ also inhibits prostate cancer (PCa) cell growth. We used sulforhodamine B (SRB) staining to determine cell viability. MQ has a highly selective cytotoxicity that inhibits PCa cell growth. The antitumor effect was most significant when examined using a colony formation assay. MQ also induces hyperpolarization of the mitochondrial membrane potential (MMP), as well as ROS generation. The blockade of MQ-induced anticancer effects by N-acetyl cysteine (NAC) pre-treatment confirmed the role of ROS. This indicates that the MQ-induced anticancer effects are caused primarily by increased ROS generation. Moreover, we observed that MQ-mediated ROS simultaneously downregulated Akt phosphorylation and activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and adenosine monophosphate-activated protein kinase (AMPK) signaling in PC3 cells. These findings provide insights for further anticancer therapeutic options.}, }
@article {pmid23759509, year = {2013}, author = {Zhang, L and Gavin, T and Geohagen, BC and Liu, Q and Downey, KJ and LoPachin, RM}, title = {Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {346}, number = {2}, pages = {259-269}, pmid = {23759509}, issn = {1521-0103}, support = {R01 ES003830/ES/NIEHS NIH HHS/United States ; R01 ES003830-25/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/*poisoning ; Acetylcysteine/pharmacology/therapeutic use ; Administration, Oral ; Animals ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/metabolism/pathology/*prevention &amp; control ; Hepatocytes/drug effects/metabolism ; Injections, Intraperitoneal ; Ketones/*pharmacology/therapeutic use ; Liver/drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Quantum Theory ; }, abstract = {Our previous research showed that enolates formed from 1,3-dicarbonyl compounds, such as 2-acetylcyclopentanone (2-ACP), could provide protection in cell culture models from electrophile- or oxidative stress-induced toxicity. In the present study, we evaluated the protective abilities of 2-ACP in a mouse model of acetaminophen (APAP) hepatotoxicity. Results show that oral APAP overdose (500 mg/kg) was nearly 90% lethal within 72 hours and that the resulting hepatotoxicity was associated with substantial changes in plasma liver enzyme activities, histopathological indices, and markers of hepatocyte oxidative stress. 2-ACP administered intraperitoneally 20 minutes before APAP completely prevented lethality over a 7-day observation period. This effect was dose-dependent (0.80-2.40 mmol/kg) and was correlated with normalization of measured parameters. Nearly complete protection was afforded when 2-ACP was administered 20 minutes post-APAP, but not 60 minutes after intoxication. Although intraperitoneal administration of N-acetylcysteine (NAC) was not effective over a broad dose range (2.40-7.20 mmol/kg), temporal studies indicated that intraperitoneal NAC was hepatoprotective when injected 60 minutes after APAP intoxication. Because of a loss of function in stomach acid, oral administration of 2-ACP was associated with modest APAP protection. In contrast, NAC administered orally provided dose-dependent (0.80-2.40 mmol/kg) protection against APAP hepatotoxicity. In chemico studies and quantum mechanical calculations indicated that 2-ACP acted as a surrogate nucleophilic target for the reactive electrophilic APAP metabolite N-acetyl-p-benzoquinone imine. Our findings suggest that 2-ACP or a derivative might be useful in treating acquired toxicities associated with electrophilic drugs and metabolites or environmental toxicants.}, }
@article {pmid23758132, year = {2013}, author = {Rider, DA and Bayley, R and Clay, E and Young, SP}, title = {Does oxidative inactivation of CD45 phosphatase in rheumatoid arthritis underlie immune hyporesponsiveness?.}, journal = {Antioxidants &amp; redox signaling}, volume = {19}, number = {18}, pages = {2280-2285}, pmid = {23758132}, issn = {1557-7716}, support = {19325/ARC_/Arthritis Research UK/United Kingdom ; 19325/VAC_/Versus Arthritis/United Kingdom ; 089384/Z/09/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Arthritis, Rheumatoid/*enzymology/*immunology ; CD4-Positive T-Lymphocytes/*immunology/metabolism ; Humans ; Leukocyte Common Antigens/*antagonists &amp; inhibitors/immunology/*metabolism ; Oxidation-Reduction ; Oxidative Stress/immunology ; }, abstract = {The protein tyrosine phosphatase (PTP) CD45 is critical in regulating the earliest steps in T-cell-receptor signaling but, similar to all PTPs, it is susceptible to oxidative inactivation. Given the widely reported effects of oxidant damage associated with rheumatoid arthritis (RA), we examined whether CD45 phosphatase activity was altered in CD4(+) T cells from RA patients and related this to CD4(+) T-cell function and redox status. CD45 phosphatase specific activity in T cells from RA peripheral blood (PB) and synovial fluid was 56% and 59% lower than in healthy control (HC) PB, respectively. In contrast, CD45 activity in T cells from disease controls (DSC) was not significantly different from HC. Both reduced glutathione (GSH) (p<0.001) and oxidized glutathione (GSSG) (p<0.05) were significantly lower in RA PB T cells compared with HC PB T cells. Treatment of RA PB T cells with the GSH precursor N-acetyl cysteine increased CD45 phosphatase activity and proliferation, while it decreased Lck kinase phosphorylation, which is regulated by CD45. Our observations lead to the hypothesis that the largely reversible oxidative inactivation of the CD45 phosphatase may underlie the decreased signaling efficiency and functional responsiveness which are characteristic of RA PB CD4(+) T cells.}, }
@article {pmid23734956, year = {2013}, author = {Albera, C and Ferrero, C and Rindone, E and Zanotto, S and Rizza, E}, title = {Where do we stand with IPF treatment?.}, journal = {Respiratory research}, volume = {14 Suppl 1}, number = {Suppl 1}, pages = {S7}, pmid = {23734956}, issn = {1465-993X}, mesh = {Adrenal Cortex Hormones/*therapeutic use ; Antibodies, Monoclonal/*therapeutic use ; Clinical Trials as Topic/*statistics &amp; numerical data ; Evidence-Based Medicine ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/*epidemiology ; Immunosuppressive Agents/*therapeutic use ; Prevalence ; Respiratory System Agents/*therapeutic use ; Treatment Outcome ; }, abstract = {Despite receiving 'weak no' recommendations in the updated guidelines on treating patients with Idiopathic Pulmonary Fibrosis (IPF), two key treatment options are pirfenidone and N-acetylcysteine (NAC), and both are used in clinical practice. The efficacy of pirfenidone is supported by a number of Phase III trials as well as a Cochrane meta-analysis. Tolerability data are also provided by clinical trials and a long-term extension phase of these studies. Pirfenidone is approved in Europe for the treatment of patients with mild-to-moderate IPF. NAC-based therapy has no such approval, but is commonly used to treat patients. A Phase III trial suggested some benefit of the NAC, prednisone and azathioprine regimen for IPF patients, but the study had many limitations. A further study to investigate this regimen, compared with a placebo alone arm, was recently stopped due to increased mortality in the triple-therapy arm. Discussion of these data and recent findings highlight the importance of a further update to the existing guidelines, so that IPF specialists can provide the most up-to-date advice and treatment to patients in clinical practice.}, }
@article {pmid23751346, year = {2013}, author = {Du, Y and Navab, M and Shen, M and Hill, J and Pakbin, P and Sioutas, C and Hsiai, TK and Li, R}, title = {Ambient ultrafine particles reduce endothelial nitric oxide production via S-glutathionylation of eNOS.}, journal = {Biochemical and biophysical research communications}, volume = {436}, number = {3}, pages = {462-466}, pmid = {23751346}, issn = {1090-2104}, support = {R01HL083015/HL/NHLBI NIH HHS/United States ; R01 HL118650/HL/NHLBI NIH HHS/United States ; R01 HL111437/HL/NHLBI NIH HHS/United States ; R01HL111437/HL/NHLBI NIH HHS/United States ; R01 HL083015/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Animals ; Anthracenes/pharmacology ; Aorta/cytology ; Biomimetics ; Cells, Cultured ; Cyclic N-Oxides/pharmacology ; Endothelial Cells/drug effects/*metabolism ; Endothelium, Vascular/cytology ; Enzyme Activation ; Glutathione/metabolism ; Humans ; Metalloporphyrins/pharmacology ; Mice ; NADPH Oxidases/antagonists &amp; inhibitors ; Nitric Oxide/*biosynthesis ; Nitric Oxide Synthase Type III/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; *Particle Size ; Particulate Matter/*metabolism ; Spin Labels ; Superoxide Dismutase/antagonists &amp; inhibitors ; Superoxide Dismutase-1 ; }, abstract = {Exposure to airborne particulate pollutants is intimately linked to vascular oxidative stress and inflammatory responses with clinical relevance to atherosclerosis. Particulate matter (PM) has been reported to induce endothelial dysfunction and atherosclerosis. Here, we tested whether ambient ultrafine particles (UFP, diameter <200 nm) modulate eNOS activity in terms of nitric oxide (NO) production via protein S-glutathionylation. Treatment of human aortic endothelial cells (HAEC) with UFP significantly reduced NO production. UFP-mediated reduction in NO production was restored in the presence of JNK inhibitor (SP600125), NADPH oxidase inhibitor (Apocynin), anti-oxidant (N-acetyl cysteine), and superoxide dismutase mimetics (Tempol and MnTMPyP). UFP exposure increased the GSSG/GSH ratio and eNOS S-glutathionylation, whereas over-expression of Glutaredoxin-1 (to inhibit S-glutathionylation) restored UFP-mediated reduction in NO production by nearly 80%. Thus, our findings suggest that eNOS S-glutathionylation is a potential mechanism underlying ambient UFP-induced reduction of NO production.}, }
@article {pmid23748041, year = {2013}, author = {Kwon, KJ and Cho, KS and Kim, JN and Kim, MK and Lee, EJ and Kim, SY and Jeon, SJ and Kim, KC and Han, JE and Kang, YS and Kim, S and Kim, HY and Han, SH and Bahn, G and Choi, Jw and Shin, CY}, title = {Proteinase 3 induces oxidative stress-mediated neuronal death in rat primary cortical neuron.}, journal = {Neuroscience letters}, volume = {548}, number = {}, pages = {67-72}, doi = {10.1016/j.neulet.2013.05.060}, pmid = {23748041}, issn = {1872-7972}, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Cells, Cultured ; Cerebral Cortex/drug effects/*embryology/*metabolism ; Female ; Male ; Myeloblastin/*pharmacology ; Neurons/cytology/drug effects/*physiology ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {The recruitment of neutrophils into the cerebral microcirculation occurs, especially, in acute brain diseases like a focal cerebral ischemia and plays important role in pathological processes. Proteinase 3 is one of the three major proteinases expressed in neutrophils but no reports are available whether proteinase 3 can modulate neuronal survival. In this study, treatment of cultured rat primary cortical neuron with proteinase 3 induced overt reactive oxygen species production and decreased total glutathione contents as well as disruption of mitochondrial transmembrane potential. Proteinase 3 induced neuronal cell death as evidenced by MTT analysis as well as propidium iodide staining, which was prevented by pretreatment with an antioxidant, N-acetyl cysteine. Proteinase 3 increased activation of procaspase-3 and altered expression level of apoptotic regulator proteins, such as Bcl-2, Bax, and Bcl-xL. Similar to in vitro data, a direct microinjection of proteinase 3 into striatum of rat brain induced neuronal death, which was mediated by reactive oxygen species. These results suggest that proteinase 3 is new essential regulator of neuronal cell death pathway in a condition of excess neutrophil encounter in neuroinflammatory conditions.}, }
@article {pmid23747931, year = {2013}, author = {Wang, T and Mao, X and Li, H and Qiao, S and Xu, A and Wang, J and Lei, S and Liu, Z and Ng, KF and Wong, GT and Vanhoutte, PM and Irwin, MG and Xia, Z}, title = {N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes.}, journal = {Free radical biology &amp; medicine}, volume = {63}, number = {}, pages = {291-303}, doi = {10.1016/j.freeradbiomed.2013.05.043}, pmid = {23747931}, issn = {1873-4596}, mesh = {Acetylcysteine/administration &amp; dosage ; Adiponectin/administration &amp; dosage ; Allopurinol/administration &amp; dosage ; Animals ; Diabetes Complications/*metabolism/pathology ; Diabetes Mellitus, Experimental/chemically induced/*metabolism ; Gene Expression Regulation/drug effects ; Humans ; Janus Kinases/*metabolism ; Male ; Myocardial Reperfusion Injury/*metabolism/pathology ; Myocytes, Cardiac/drug effects/metabolism ; Nitric Oxide/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Rats ; STAT3 Transcription Factor/*metabolism ; Signal Transduction/drug effects/genetics ; Up-Regulation/drug effects ; }, abstract = {N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up-regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process.}, }
@article {pmid23745587, year = {2013}, author = {Balaji, SN and Trivedi, V}, title = {Suicidal inactivation of methemoglobin by generation of thiyl radical: insight into NAC mediated protection in RBC.}, journal = {Current molecular medicine}, volume = {13}, number = {6}, pages = {1000-1009}, doi = {10.2174/15665240113139990054}, pmid = {23745587}, issn = {1875-5666}, mesh = {Acetylcysteine/chemistry/metabolism/*pharmacology ; *Cytoprotection/drug effects ; Erythrocytes/*cytology/drug effects/enzymology/*metabolism ; Free Radicals/*metabolism ; Heme/chemistry ; Hemolysis/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Kinetics ; Methemoglobin/*metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Peroxidase/metabolism ; Piperidines ; Protective Agents/chemistry/metabolism/pharmacology ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {N-acetyl-L-cysteine (NAC) improves antioxidant potentials of RBCs to provide protection against oxidative stress induced hemolysis. The antioxidant mechanism of NAC to reduce oxidative stress in RBC, studied through inactivation of pro-oxidant MetHb. NAC causes irreversible inactivation of the MetHb in an H2O2 dependent manner, and the inactivation follows the pseudo- first- order kinetics. The kinetic constants are ki = 8.5μM, kinact = 0.706 min(-1) and t1/2 = 0.9 min. Spectroscopic studies indicate that MetHb accepts NAC as a substrate and oxidizes through a single electron transfer mechanism to the NACox. The single e- oxidation product of NAC has been identified as the 5, 5'- dimethyl-1- pyrroline N- oxide (DMPO) adduct of the sulfur centered radical (a(N) = 15.2 G and a(H)=16.78 G). Binding studies indicate that NACox interacts at the heme moiety and NAC oxidation through MetHb is essential for NAC binding. Heme-NAC adduct dissociated from MetHb and identified (m/z 1011.19) as 2:1 ratio of NAC/heme in the adduct. TEMPO and PBN treatment reduces NAC binding to MetHb and protects against inactivation confirms the role of thiyl radical in the inactivation process. Furthermore, scavenging thiyl radicals by TEMPO abolish the protective effect of NAC in hemolysis. Current work highlights antioxidant mechanism of NAC through NAC thiyl radical generation, and MetHb inactivation to exhibit protection in RBC against oxidative stress induced hemolysis.}, }
@article {pmid23743293, year = {2013}, author = {Iverson, SV and Eriksson, S and Xu, J and Prigge, JR and Talago, EA and Meade, TA and Meade, ES and Capecchi, MR and Arnér, ES and Schmidt, EE}, title = {A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification.}, journal = {Free radical biology &amp; medicine}, volume = {63}, number = {}, pages = {369-380}, pmid = {23743293}, issn = {1873-4596}, support = {R01 AG040020/AG/NIA NIH HHS/United States ; R21 CA152559/CA/NCI NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage ; Animals ; Benzoquinones/administration &amp; dosage ; Chemical and Drug Induced Liver Injury/metabolism/pathology ; Gene Expression Regulation/drug effects ; Glutathione/*metabolism ; Glycogen/genetics/metabolism ; Hepatocytes/drug effects/metabolism ; Imines/administration &amp; dosage ; Inactivation, Metabolic/*genetics ; Lipogenesis/drug effects/genetics ; Liver/drug effects/metabolism ; Mice ; Thioredoxin Reductase 1/genetics/*metabolism ; Thioredoxins/genetics/*metabolism ; }, abstract = {Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage.}, }
@article {pmid23743198, year = {2013}, author = {Wang, B and Wang, XB and Chen, LY and Huang, L and Dong, RZ}, title = {Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis.}, journal = {Biochemical and biophysical research communications}, volume = {437}, number = {1}, pages = {1-6}, doi = {10.1016/j.bbrc.2013.05.090}, pmid = {23743198}, issn = {1090-2104}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Activation/drug effects ; Humans ; Hydroxamic Acids/*pharmacology/therapeutic use ; MAP Kinase Kinase Kinases/*metabolism ; Pancreatic Neoplasms/drug therapy/*enzymology/*pathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Sulfonamides/*pharmacology/therapeutic use ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells.}, }
@article {pmid23742196, year = {2014}, author = {Ruiz-Ramírez, A and Ortiz-Balderas, E and Cardozo-Saldaña, G and Diaz-Diaz, E and El-Hafidi, M}, title = {Glycine restores glutathione and protects against oxidative stress in vascular tissue from sucrose-fed rats.}, journal = {Clinical science (London, England : 1979)}, volume = {126}, number = {1}, pages = {19-29}, doi = {10.1042/CS20130164}, pmid = {23742196}, issn = {1470-8736}, mesh = {Abdominal Fat/drug effects/physiology ; Animals ; Antioxidants/metabolism ; Aorta, Thoracic/*drug effects/metabolism/physiology ; Biomarkers/blood ; Blood Glucose/metabolism ; Blood Pressure/drug effects/physiology ; Body Weight/drug effects ; Dietary Supplements ; Endothelium, Vascular/drug effects/physiology ; Glutathione/*biosynthesis/physiology ; Glycine/*pharmacology ; Lipids/blood ; Male ; NADP/pharmacology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Oxidative Stress/*drug effects/physiology ; Rats ; Rats, Wistar ; Sucrose/*pharmacology ; Tissue Culture Techniques ; Vasodilation/drug effects ; }, abstract = {The attenuation of oxidative stress could be an important mechanism whereby the incidence of vascular complications in the MS (metabolic syndrome) may be diminished. The present study was undertaken to investigate the mechanism by which glycine, supplemented to the diet of SF (sucrose-fed) rats, modulates glutathione biosynthesis and protects against oxidative stress and altered endothelium-dependent relaxation in isolated aorta. Glycine reduced O2•- (superoxide anion radical) release in the presence of NADPH, and decreased protein carbonyl and lipid peroxidation. This effect of glycine could be because of the increased amount of glutathione synthetase, which may be responsible for increased glutathione (GSH) content in vascular tissue from SF rats. Moreover, glycine increased the amount of Cu,Zn-SOD (copper/zinc superoxide dismutase) and eNOS (endothelial NO synthase) in aorta from SF animals. Finally, it improved the relaxation response to ACh (acetylcholine) found impaired in aortic rings from SF rats. In the presence of NAC (N-acetylcysteine), a precursor of GSH, an improved ACh-mediated aortic relaxation of aortic rings from SF rats was observed, whereas BSO (buthionine sulfoximine), an inhibitor of glutathione biosynthesis, inhibited the relaxing effect of NAC in aortas from both control and SF rats. This experiment emphasizes the role of GSH in endothelial function in SF rats. The present data suggest that glycine rectifies vascular reactivity by increasing the biosynthesis of glutathione. Glutathione protects vascular tissue against oxidative stress, and enhances the availability of NO, which exerts its relaxing effect, thus contributing to the reduction of high BP (blood pressure) in the SF rats.}, }
@article {pmid23737821, year = {2013}, author = {Porpora, MG and Brunelli, R and Costa, G and Imperiale, L and Krasnowska, EK and Lundeberg, T and Nofroni, I and Piccioni, MG and Pittaluga, E and Ticino, A and Parasassi, T}, title = {A promise in the treatment of endometriosis: an observational cohort study on ovarian endometrioma reduction by N-acetylcysteine.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2013}, number = {}, pages = {240702}, pmid = {23737821}, issn = {1741-427X}, abstract = {Urged by the unmet medical needs in endometriosis treatment, often with undesirable side effects, and encouraged by N-acetylcysteine (NAC) efficacy in an animal model of endometriosis and by the virtual absence of toxicity of this natural compound, we performed an observational cohort study on ovarian endometriosis. NAC treatment or no treatment was offered to 92 consecutive Italian women referred to our university hospital with ultrasound confirmed diagnosis of ovarian endometriosis and scheduled to undergo laparoscopy 3 months later. According to patients acceptance or refusal, NAC-treated and untreated groups finally comprised 73 and 72 endometriomas, respectively. After 3 months, within NAC-treated patients cyst mean diameter was slightly reduced (-1.5 mm) versus a significant increase (+6.6 mm) in untreated patients (P = 0.001). Particularly, during NAC treatment, more cysts reduced and fewer cysts increased their size. Our results are better than those reported after hormonal treatments. Twenty-four NAC-treated patients-versus 1 within controls-cancelled scheduled laparoscopy due to cysts decrease/disappearance and/or relevant pain reduction (21 cases) or pregnancy (1 case). Eight pregnancies occurred in NAC-treated patients and 6 in untreated patients. We can conclude that NAC actually represents a simple effective treatment for endometriosis, without side effects, and a suitable approach for women desiring a pregnancy.}, }
@article {pmid23735887, year = {2012}, author = {Small, DM and Bennett, NC and Roy, S and Gabrielli, BG and Johnson, DW and Gobe, GC}, title = {Oxidative stress and cell senescence combine to cause maximal renal tubular epithelial cell dysfunction and loss in an in vitro model of kidney disease.}, journal = {Nephron. Experimental nephrology}, volume = {122}, number = {3-4}, pages = {123-130}, doi = {10.1159/000350726}, pmid = {23735887}, issn = {1660-2129}, mesh = {Acetylcysteine/pharmacology ; Apigenin/pharmacology ; Apoptosis/drug effects ; Cell Line ; *Cellular Senescence/drug effects ; Epithelial Cells/*drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Kidney/physiopathology ; Kidney Tubules/cytology/*physiopathology ; Lipid Peroxidation/drug effects ; Mitochondria/drug effects ; Oxidative Stress/drug effects ; Regeneration ; Renal Insufficiency, Chronic/*physiopathology ; }, abstract = {BACKGROUND: The incidence and cost of chronic kidney disease (CKD) are increasing. Renal tubular epithelial cell dysfunction and attrition, involving increased apoptosis and cell senescence, are central to the pathogenesis of CKD. The aim here was to use an in vitro model to investigate the separate and cumulative effects of oxidative stress, mitochondrial dysfunction and cell senescence in promoting loss of renal mass.<br><br>METHODS: Human kidney tubular epithelial cells (HK2) were treated with moderate hydrogen peroxide (H2O2) for oxidative stress, with or without cell cycle inhibition (apigenin, API) for cell senescence. Adenosine triphosphate (ATP) and oxidative stress were measured by ATP assay, lipid peroxidation, total antioxidant capacity, mitochondrial function with confocal microscopy, MitoTracker Red CMXRos and live cell imaging with JC-1. In parallel, cell death and injury (i.e. apoptosis and Bax/Bcl-XL expression, lactate dehydrogenase), cell senescence (SA-&#x3b2;-galactosidase) and renal regenerative ability (cell proliferation), and their modulation with the anti-oxidant N-acetyl-cysteine (NAC) were investigated.<br><br>RESULTS: H2O2 and API, separately, increased oxidative stress and mitochondrial dysfunction, apoptosis and cell senescence. Although API caused cell senescence, it also induced oxidative stress at levels similar to H2O2 treatment alone, indicating that senescence and oxidative stress may be intrinsically linked. When H2O2 and API were delivered concurrently, their detrimental effects on renal cell loss were compounded. The antioxidant NAC attenuated apoptosis and senescence, and restored regenerative potential to the kidney.<br><br>CONCLUSION: Oxidative stress and cell senescence both cause mitochondrial destabilization and cell loss and contribute to the development of the cellular characteristics of CKD.}, }
@article {pmid23732519, year = {2013}, author = {Hao, T and Rockwell, P}, title = {Signaling through the vascular endothelial growth factor receptor VEGFR-2 protects hippocampal neurons from mitochondrial dysfunction and oxidative stress.}, journal = {Free radical biology &amp; medicine}, volume = {63}, number = {}, pages = {421-431}, pmid = {23732519}, issn = {1873-4596}, support = {G12 RR003037/RR/NCRR NIH HHS/United States ; SC1 NS066033/NS/NINDS NIH HHS/United States ; RR003037/RR/NCRR NIH HHS/United States ; SC1NS066033/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Gene Expression Regulation ; *Hippocampus/metabolism/pathology ; Mitochondria/metabolism/*pathology ; *Neurons/metabolism/pathology ; Neuroprotective Agents/metabolism ; *Oxidative Stress ; Phosphorylation ; RNA, Small Interfering ; Rats ; Signal Transduction ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor Receptor-1/metabolism ; Vascular Endothelial Growth Factor Receptor-2/antagonists &amp; inhibitors/genetics/*metabolism ; bcl-Associated Death Protein/metabolism ; bcl-X Protein/metabolism ; }, abstract = {Vascular endothelial growth factor VEGF (VEGF-A or VEGF165) is a potent angiogenic factor that also signals neuroprotection through activation of its cognate receptor VEGFR-2. In this capacity, VEGF signaling can rescue neurons from the damage induced by stressful stimuli many of which elicit oxidative stress. However, the regulatory role that VEGFR-2 plays in providing neuroprotection remains elusive. Therefore, we investigated the effects of VEGFR-2 inhibition on primary cultures of mature hippocampal neurons undergoing nutritional stress. We found that neurons cultured under nutritional stress had increased expression of VEGF and its receptors, VEGFR-1, VEGFR-2, and NP-1, as well as enhanced levels of VEGFR-2 phosphorylation. These neurons also showed increased activation of the prosurvival pathways for MEK/ERK1/2 and PI3K/Akt, enhanced phosphorylation (inactivation) of the proapoptotic BAD, and higher levels of the antiapoptotic protein Bcl-xL, all of which were augmented by treatments with exogenous VEGF and blocked by VEGFR-2 inhibition. The blockade of VEGFR-2 function also elicited a cytotoxicity that was accompanied by caspase-3 activation, induction of hemeoxygenase-1 (HO-1), oxidative stress, and a collapse in the mitochondrial membrane potential (ΔΨ(m)). Knockdown of VEGFR-2 by siRNA generated a similar pattern of redox change and mitochondrial impairment. Pretreatments with VEGF, VEGF-B, or the antioxidant N-acetylcysteine (NAC) rescued SU1498 or siRNA-treated neurons from the mitochondrial dysfunction and oxidative stress induced by VEGFR-2 inhibition in a timely fashion. These findings suggested that VEGF or VEGF-B can provide neuroprotection by signaling through an alternate VEGF receptor. Together, our findings suggest that VEGF signaling through VEGFR-2 plays a critical regulatory role in protecting stressed hippocampal neurons from the damaging effects of an oxidative insult. These findings also implicate VEGFR-1 or NP-1 as compensatory receptors that mediate neuroprotection when VEGFR-2 function is blocked.}, }
@article {pmid23731375, year = {2013}, author = {Kasperczyk, S and Dobrakowski, M and Kasperczyk, A and Ostałowska, A and Birkner, E}, title = {The administration of N-acetylcysteine reduces oxidative stress and regulates glutathione metabolism in the blood cells of workers exposed to lead.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {51}, number = {6}, pages = {480-486}, doi = {10.3109/15563650.2013.802797}, pmid = {23731375}, issn = {1556-9519}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Erythrocytes/*drug effects/metabolism ; Glucosephosphate Dehydrogenase/drug effects/metabolism ; Glutathione/*metabolism ; Glutathione Reductase/drug effects/metabolism ; Glutathione Transferase/drug effects/metabolism ; Humans ; Lead/blood ; Lead Poisoning/blood/*drug therapy/metabolism ; Male ; Middle Aged ; *Occupational Exposure ; Oxidative Stress/*drug effects ; Young Adult ; }, abstract = {CONTEXT AND OBJECTIVE: The aim of the study was to investigate whether treatment with N-acetylcysteine (NAC) is able to restore erythrocyte glutathione (GSH) content in workers exposed to lead. Additionally, we measured the leukocyte and erythrocyte activities of GSH-related enzymes, such as glutathione reductase (GR), glutathione-S-transferase (GST), and glucose-6-phosphate dehydrogenase (G6PD), and estimated the influence of NAC administration on oxidative stress intensity, which was measured as the lipofuscin (LPS) level in erythrocytes.<br><br>METHODS: The exposed population consisted of 171 healthy males randomly divided into four groups. Workers in the first group (n = 49) were not administered any antioxidants, drugs, vitamins, or dietary supplements, while workers in the remaining groups were treated with NAC at three doses for 12 weeks (1 &#xd7; 200 mg per day, 2 &#xd7; 200 mg per day, and 2 &#xd7; 400 mg per day). All workers continued to work during the study. The blood of all examined workers was drawn two times: at the beginning of the study and after 12 weeks of treatment.<br><br>RESULTS AND CONCLUSION: Blood lead levels decreased significantly in all groups receiving NAC compared to those in baseline. Erythrocyte GSH concentrations were significantly elevated in workers receiving 400 and 800 mg of NAC compared to those in baseline by 5% and 6%, respectively. Erythrocyte G6PD activity was significantly elevated in workers receiving 200, 400, and 800 mg of NAC compared to those in baseline by 24%, 14%, and 14%, respectively. By contrast, there were no significant differences in leukocyte G6PD or leukocyte and erythrocyte glutathione reductase (GR) activities before and after treatment. Leukocyte GST activities decreased significantly after treatment in workers receiving 200 mg of NAC by 34%, while LPS levels decreased significantly in workers receiving 200, 400, and 800 mg of NAC compared to those in baseline by 5%, 15%, and 13%, respectively. In conclusion, NAC decreases oxidative stress in workers exposed to lead via stimulating GSH synthesis.}, }
@article {pmid23731362, year = {2013}, author = {Kazemi, B and Akbarzadeh, F and Safaei, N and Yaghoubi, A and Shadvar, K and Ghasemi, K}, title = {Prophylactic high-dose oral-N-acetylcysteine does not prevent atrial fibrillation after heart surgery: a prospective double blind placebo-controlled randomized clinical trial.}, journal = {Pacing and clinical electrophysiology : PACE}, volume = {36}, number = {10}, pages = {1211-1219}, doi = {10.1111/pace.12190}, pmid = {23731362}, issn = {1540-8159}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Age Distribution ; Anti-Arrhythmia Agents/administration &amp; dosage ; Atrial Fibrillation/*mortality/*prevention &amp; control ; Cardiovascular Surgical Procedures/*mortality ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Placebo Effect ; Postoperative Complications/*mortality/*prevention &amp; control ; Premedication/*mortality ; Prevalence ; Prospective Studies ; Risk Factors ; Sex Distribution ; Survival Rate ; Treatment Outcome ; }, abstract = {AIMS: Postoperative atrial fibrillation (POAF) following cardiac surgery is a frequent complication with multifactorial etiologies. Recently inflammation due to enhanced oxidative stress has been implicated in its pathogenesis. N-acetylcysteine (NAC) is a promising and novel antioxidant agent. The purpose of this study was to evaluate the efficacy of high-dose oral-NAC for prevention of POAF.<br><br>METHODS: Two hundred and forty patients were randomized in this prospective, double blind placebo-controlled trial to either 1,200-mg oral-NAC two times a day (n = 120) or placebo (n = 120) starting 48 hours before and up to 72 hours after open heart surgery.<br><br>RESULTS: The mean age was about 60 years, and 75% were male. Patients in the NAC group were older, with higher percentage of acute coronary syndrome, hypercholesterolemia, and left internal mammary artery use. Coronary involvement and hypertension were more prevalent in the placebo group. All other baseline patient characteristics were similar between groups. Overall POAF developed in 13.8% of the patients. There was no difference in the incidence of POAF between the NAC vs placebo groups (11.7% vs 15.8%, respectively; P = 0.34). Postoperative hospital stay, morbidity, and mortality were similar in both groups.<br><br>CONCLUSIONS: Prophylactic high-dose oral-NAC begun 2 days before open heart surgery and continued for 5 days, and had no significant effect on the incidence of POAF, in-hospital stay, and postoperative morbidity or mortality.}, }
@article {pmid23731245, year = {2013}, author = {Hsu, WH and Lee, BH and Li, CH and Hsu, YW and Pan, TM}, title = {Monascin and AITC attenuate methylglyoxal-induced PPARγ phosphorylation and degradation through inhibition of the oxidative stress/PKC pathway depending on Nrf2 activation.}, journal = {Journal of agricultural and food chemistry}, volume = {61}, number = {25}, pages = {5996-6006}, doi = {10.1021/jf401197r}, pmid = {23731245}, issn = {1520-5118}, mesh = {Animals ; Heterocyclic Compounds, 3-Ring/*pharmacology ; Isothiocyanates/*pharmacology ; Mice ; Mice, Inbred BALB C ; NF-E2-Related Factor 2/*genetics/metabolism ; Oxidative Stress/*drug effects ; PPAR gamma/genetics/*metabolism ; Phosphorylation/drug effects ; Protein Kinase C/genetics/*metabolism ; Proteolysis/drug effects ; Pyruvaldehyde/*pharmacology ; }, abstract = {Abnormal cellular accumulation of the dicarbonyl metabolite methylglyoxal (MG) results in cell damage, inflammation, and oxidative stress. It is also associated with increased protein linkage to form advanced glycation end products (AGEs) or induce DNA strand breaks. The association between peroxisome proliferator-activated receptor-γ (PPARγ) and nuclear factor-erythroid 2-related factor 2 (Nrf2) is unclear. This study investigated Nrf2 activator protection against PPARγ phosphorylation and degradation to maintain pancreatic function. MG was used at a noncytotoxic concentration (200 μM) to induce protein kinase C (PKC) and PPARγ phosphorylation in pancreatic RINm5F cells. For in vivo studies, MG (60 mg/kg bw) was intraperitoneally (IP) injected into Balb/C mice for 28 d to induce pancreas damage, at which point we investigated the effect of monascin protection (PPARγ and Nrf2 activator), rosiglitazone (PPARγ activator), allyl isothiocyanate (AITC; Nrf2 activator), or N-acetylcysteine (NAC) on pancreatic function. The in vitro and in vivo results indicated that MG leads to marked PPARγ phosphorylation (serine 82); this effect led to reduction in pancreatic and duodenal homeobox-1 (PDX-1), glucokinase (GCK), and insulin expression. However, monascin and rosiglitazone may protect PPARγ degradation by elevating PDX-1, GCK, and as a result, insulin expression. Monascin and AITC can attenuate PKC activation to suppress PPARγ phosphorylation caused by oxidative stress through the Nrf2 pathway. Similarly, the N-acetylcysteine (NAC) antioxidant also improved oxidative stress and pancreatic function. This study examined whether MG caused impairment of PDX-1, GCK, and insulin through PPARγ phosphorylation and degradation. MG and AGE accumulation improved on Nrf2 activation, thereby protecting against pancreas damage. Taken together, PPARγ activation maintained pancreatic PDX-1, GCK, and insulin expression levels to regulate blood glucose levels.}, }
@article {pmid23727952, year = {2013}, author = {Wang, J and Yu, M and Xiao, L and Xu, S and Yi, Q and Jin, W}, title = {Radiosensitizing effect of oleanolic acid on tumor cells through the inhibition of GSH synthesis in vitro.}, journal = {Oncology reports}, volume = {30}, number = {2}, pages = {917-924}, doi = {10.3892/or.2013.2510}, pmid = {23727952}, issn = {1791-2431}, mesh = {Animals ; Cell Death/drug effects ; Cell Line, Tumor ; DNA Damage ; Dipeptides/genetics/metabolism ; Down-Regulation/drug effects ; Glioma/drug therapy/metabolism/*radiotherapy ; Glutathione/*antagonists &amp; inhibitors/*biosynthesis/metabolism ; Glutathione Synthase/metabolism ; Humans ; Lung Neoplasms/drug therapy/metabolism/*radiotherapy ; Oleanolic Acid/*pharmacology ; Radiation Tolerance/*drug effects ; Radiation-Sensitizing Agents/*pharmacology ; Rats ; }, abstract = {Oleanolic acid (OA) is a natural pentacyclic triterpenoid that has been used in traditional medicine as an anticancer and anti-inflammatory agent. The aim of our study was to investigate whether or not OA increases the radiosensivity of tumor cells, and the relative mechanism was also investigated. Clonogenic assay was used to observe the radiosensitivity of C6 and A549 cells following different treatments. The alteration of intracellular DNA damage was determined using a micronucleus (MN) assay. In order to identify the mechanism of OA-mediated radiosensitization of tumor cells, the levels of glutathione (GSH) in irradiated cells following various pretreatments were determined using glutathione reductase/5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) recycling assay. Under the same condition, the activities of γ-glutamylcysteine synthetase (γ-GCS) and GSH synthase (GSS), both key enzymes for GSH synthesis, were detected using appropriate methods. In order to confirm the radiosensitizing effect of OA on cancer cells by attenuating GSH, N-acetylcysteine (NAC) was added to cells in culture for 12 h before irradiation. The results showed that the combined treatment of radiation with OA significantly decreased the clonogenic growth of tumor cells and enhanced the numbers of intracellular MN compared to irradiation alone. Furthermore, it was found that the synthesis of cellular GSH was inhibited concomitantly with the downregulation of γ-GCS activity. Therefore, the utilization of OA as a radiosensitizing agent for irradiation-inducing cell death offers a potential therapeutic approach to treat cancer.}, }
@article {pmid23727371, year = {2013}, author = {Wadhwa, S and Mumper, RJ}, title = {D-penicillamine and other low molecular weight thiols: review of anticancer effects and related mechanisms.}, journal = {Cancer letters}, volume = {337}, number = {1}, pages = {8-21}, doi = {10.1016/j.canlet.2013.05.027}, pmid = {23727371}, issn = {1872-7980}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Free Radicals/metabolism ; Glutathione/metabolism ; Humans ; Molecular Weight ; Penicillamine/*pharmacology ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {Low molecular weight thiols (LMWTs) like N-acetyl cysteine, D-penicillamine, captopril, Disulfiram and Amifostine, etc. have been used as chemo-preventive agents. Recent studies have reported cell growth inhibition and cytotoxicity in several different types of cancer cells following treatment with several LMWTs. Cytotoxic and cytostatic effects of LMWTs may involve interaction of the thiol group with cellular lipids, proteins, intermediates or enzymes. Some of the mechanisms that have been proposed include a p53 mediated apoptosis, thiyl radical induced DNA damage, membrane damage through lipid peroxidation, anti-angiogenic effects induced by inhibition of matrix metalloproteinase enzymes and angiostatin generation. LMWTs are strong chelators of transition metals like copper, nickel, zinc, iron and cobalt and may cause metal co-factor depletion resulting in cytotoxicity. Oxidation of thiol group can also generate cytotoxic reactive oxygen species (ROS).}, }
@article {pmid23726389, year = {2013}, author = {Zhu, L and Cai, X and Guo, Q and Chen, X and Zhu, S and Xu, J}, title = {Effect of N-acetyl cysteine on enterocyte apoptosis and intracellular signalling pathways' response to oxidative stress in weaned piglets.}, journal = {The British journal of nutrition}, volume = {110}, number = {11}, pages = {1938-1947}, doi = {10.1017/S0007114513001608}, pmid = {23726389}, issn = {1475-2662}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; *Apoptosis ; Caspases/genetics/metabolism ; China ; Crosses, Genetic ; *Dietary Supplements ; Down-Regulation ; Enterocytes/enzymology/*metabolism/ultrastructure ; Free Radical Scavengers/*therapeutic use ; Humans ; Hydrocortisone/blood ; *Oxidative Stress ; Oxidoreductases/blood ; *Signal Transduction ; Stress, Physiological ; Stress, Psychological/blood/metabolism/pathology/prevention &amp; control ; Sus scrofa ; Swine ; Swine Diseases/blood/metabolism/pathology/prevention &amp; control ; Weaning ; fas Receptor/genetics/metabolism ; }, abstract = {N-Acetyl cysteine (NAC) has been widely used for preventing reactive oxygen species-induced damage. However, little is known as to whether dietary NAC supplementation would alleviate intestinal injury in weaned piglets. The present study evaluated the effect of NAC on enterocyte apoptosis and intracellular signalling pathways' response to weaning stress. The control piglets were normally suckling, and piglets in the weaning and NAC groups were fed the basal diet and basal+NAC diet from 14 to 25 d of age, respectively. Compared with the control piglets, weaning increased cortisol concentrations (P< 0·05), decreased superoxide dismutase and glutathione peroxidase activities (P< 0·05), increased malondialdehyde content (P< 0·05) in serum and enhanced enterocyte apoptosis index (AI) and concentrations of caspase-3, caspase-8 and caspase-9 (P< 0·05). Gene expression analyses indicated that weaning induced apoptosis via Fas signalling and mitochondrial pathways in weaned piglets. Dietary NAC supplementation decreased (P< 0·05) cortisol concentrations and the AI, increased (P< 0·05) antioxidant status in serum and alleviated histopathological changes in the intestine. It also inhibited Fas, caspase-3, caspase-8 and integrin αvβ6 (αvβ6) gene expressions in the NAC-treated piglets. However, no significant decrease (P>0·10) in caspase-3, caspase-8 and caspase-9 concentrations was observed in the NAC group compared with the weaning group. In conclusion, weaning may induce enterocyte apoptosis via the activation of Fas-dependent and mitochondria-dependent apoptosis. Although NAC had no effect on caspase concentrations, it was clearly beneficial for preserving morphological integrity in weaned piglets via the regulation of cell apoptosis and the inhibition of Fas-dependent apoptosis and αvβ6 expression.}, }
@article {pmid23724149, year = {2013}, author = {Cousin, M and Silva-Zacarin, E and Kretzschmar, A and El Maataoui, M and Brunet, JL and Belzunces, LP}, title = {Size changes in honey bee larvae oenocytes induced by exposure to Paraquat at very low concentrations.}, journal = {PloS one}, volume = {8}, number = {5}, pages = {e65693}, pmid = {23724149}, issn = {1932-6203}, mesh = {Animals ; Bees/*cytology ; Cell Compartmentation/drug effects ; Cell Nucleus/drug effects/metabolism ; Cell Shape/drug effects ; *Cell Size ; *Environmental Exposure ; Honey ; Larva/cytology/drug effects ; Paraquat/*toxicity ; }, abstract = {The effects of the herbicide Paraquat were investigated in honey bee larvae with attention focused on oenocytes. Honey bee larvae were exposed to Paraquat at different concentrations in the food: 0, 0.001, 0.01, 0.1 and 1 µg/kg. In controls, between 24 h and 48 h, oenocytes grew from 630.1 to 1643.8 µm(2) while nuclei changed in size from 124.9 to 245.6 µm(2). At 24 h, Paraquat induced a slight decrease in the size of oenocytes and nuclei. N-acetylcysteine (NAC), an antioxidant substance, slightly lowered the effects of Paraquat. At 48 h, Paraquat elicited a strong concentration-dependent decrease in the size of oenocytes, even at the lowest concentration. NAC reversed the effect of Paraquat at a concentration of ≥0.01 µg/kg. This reversion suggested different modes of action of Paraquat, with an oxidant action prevalent at concentrations ≥0.01 µg/kg. This study is the first which reports an effect of a pesticide at the very low concentration of 1 ng/kg, a concentration below the detection limits of the most efficient analytic methods. It shows that chemicals, including pesticides, are likely to have a potential impact at such exposure levels. We also suggest that Paraquat could be used as a suitable tool for investigating the functions of oenocytes.}, }
@article {pmid23723505, year = {2013}, author = {Vikramkumar, AG and Kuruvila, S and Ganguly, S}, title = {Monilethrix: a rare hereditary condition.}, journal = {Indian journal of dermatology}, volume = {58}, number = {3}, pages = {243}, pmid = {23723505}, issn = {1998-3611}, abstract = {Monilethrix is a rare hereditary condition generally considered to be an autosomal-dominant disorder with variable penetrance. Here, we report a case of monilethrix in a 13-year-old boy with an affected sibling. A therapeutic trial with oral N-acetyl cysteine was attempted. There was slight improvement after 2 months of therapy. The hair density, however, did not show any further improvement subsequently. Monilethrix remains as a therapeutic challenge for dermatologists.}, }
@article {pmid23723006, year = {2013}, author = {Yildirim, SS and Akman, D and Catalucci, D and Turan, B}, title = {Relationship between downregulation of miRNAs and increase of oxidative stress in the development of diabetic cardiac dysfunction: junctin as a target protein of miR-1.}, journal = {Cell biochemistry and biophysics}, volume = {67}, number = {3}, pages = {1397-1408}, doi = {10.1007/s12013-013-9672-y}, pmid = {23723006}, issn = {1559-0283}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carrier Proteins/metabolism ; Cells, Cultured ; Diabetes Mellitus, Experimental/complications/metabolism/pathology ; Diabetic Cardiomyopathies/etiology/*metabolism ; *Down-Regulation/drug effects ; Gene Expression Regulation/drug effects ; Male ; Mice ; MicroRNAs/*metabolism ; Muscle Proteins/*antagonists &amp; inhibitors/chemistry/metabolism ; Myocardium/metabolism/pathology/ultrastructure ; Myocytes, Cardiac/cytology/drug effects/metabolism ; Nitric Oxide/metabolism ; *Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; }, abstract = {Oxidative stress is involved in the etiology of diabetes-induced cardiac dysfunction while microRNAs (miRNAs) are known as regulators for genes involved in cardiac remodeling. However, a functional link between miRNAs and diabetes-induced cardiac dysfunction remains to be investigated. Here, we aimed to identify whether the expression levels of miRNAs are associated with oxidative stress/diabetic heart and if proteins responsible from contractile activity during diabetes might be directly modulated by miRNAs. Diabetic cardiomyopathy developed with streptozotocin, is characterized with marked changes in sarcomere and mitochondria, depressed left ventricular developed pressure, and a massive oxidative stress that is particularly evident in the heart. miRNA profiling was performed in freshly isolated left ventricular cells from diabetic rats. Using microarray analysis, we identified marked changes in the expression of 43 miRNAs (37 of them were downregulated while 6 miRNAs were upregulated) out of examined total of 351 miRNAs. Among them, 6 miRNAs were further validated by real-time PCR. The expression levels of miR-1, miR-499, miR-133a, and miR-133b were markedly depressed in the diabetic cardiomyocytes while miR-21 level increased and miR-16 level was unchanged. Notably, normalization of cardiac function and oxidant/antioxidant level after N-acetylcysteine (NAC)-treatment of diabetic rats resulted with a significant restoration in the expression levels of miR-499, miR-1, miR-133a, and miR-133b in the myocardium. Since changes in the level of muscle-specific miR-1 has been implicated in cardiac diseases and its specific molecular targets involved in its action, in part, associated with oxidative stress are limited, we first examined the protein levels of some SR-associated proteins such as junctin and triadin. Junctin but not triadin is markedly overexpressed in diabetic cardiomyocytes while its level was normalized in NAC-treated diabetics. Luciferase reporter assay showed that junctin is targetted by miR-1. Taken together, our data demonstrates that intervention with an antioxidant treatment for 4-week leads to significant cardioprotection against diabetes-induced injury, controlling oxidant/antioxidant level, which may directly control the levels of some miRNAs including miR-1 and its target protein junctin, which is involved in the development of diabetic cardiomyopathy.}, }
@article {pmid23722706, year = {2013}, author = {Chen, F and Hadfield, JM and Berzingi, C and Hollander, JM and Miller, DB and Nichols, CE and Finkel, MS}, title = {N-acetylcysteine reverses cardiac myocyte dysfunction in a rodent model of behavioral stress.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {115}, number = {4}, pages = {514-524}, pmid = {23722706}, issn = {1522-1601}, support = {R0-1 HL-70565/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Calcium/metabolism ; Calcium Signaling/drug effects ; Cardiomyopathies/blood/*drug therapy/metabolism ; Catalase/metabolism ; Disease Models, Animal ; Epinephrine/blood ; Female ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Glutathione Peroxidase/metabolism ; Isoproterenol/pharmacology ; Male ; Myocardium/metabolism ; Myocytes, Cardiac/*drug effects/metabolism ; Norepinephrine/blood ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Compelling clinical reports reveal that behavioral stress alone is sufficient to cause reversible myocardial dysfunction in selected individuals. We developed a rodent stress cardiomyopathy model by a combination of prenatal and postnatal behavioral stresses (Stress). We previously reported a decrease in percent fractional shortening by echo, both systolic and diastolic dysfunction by catheter-based hemodynamics, as well as attenuated hemodynamic and inotropic responses to the β-adrenergic agonist, isoproterenol (ISO) in Stress rats compared with matched controls (Kan H, Birkle D, Jain AC, Failinger C, Xie S, Finkel MS. J Appl Physiol 98: 77-82, 2005). We now report enhanced catecholamine responses to behavioral stress, as evidenced by increased circulating plasma levels of norepinephrine (P < 0.01) and epinephrine (P < 0.01) in Stress rats vs. controls. Cardiac myocytes isolated from Stress rats also reveal evidence of oxidative stress, as indicated by decreased ATP, increased GSSG, and decreased GSH-to-GSSG ratio in the presence of increased GSH peroxidase and catalase activities (P < 0.01, for each). We also report blunted inotropic and intracellular Ca(2+) concentration responses to extracellular Ca(2+) (P < 0.05), as well as altered inotropic responses to the intracellular calcium regulator, caffeine (20 mM; P < 0.01). Treatment of cardiac myocytes with N-acetylcysteine (NAC) (10(-3) M) normalized calcium handling in response to ISO and extracellular Ca(2+) concentration and inotropic response to caffeine (P < 0.01, for each). NAC also attenuated the blunted inotropic response to ISO and Ca(2+) (P < 0.01, for each). Surprisingly, NAC did not reverse the changes in GSH, GSSG, or GSH-to-GSSG ratio. These data support a GSH-independent salutary effect of NAC on intracellular calcium signaling in this rodent model of stress-induced cardiomyopathy.}, }
@article {pmid23721499, year = {2013}, author = {Grabhorn, E and Nielsen, D and Hillebrand, G and Brinkert, F and Herden, U and Fischer, L and Ganschow, R}, title = {Successful outcome of severe Amanita phalloides poisoning in children.}, journal = {Pediatric transplantation}, volume = {17}, number = {6}, pages = {550-555}, doi = {10.1111/petr.12108}, pmid = {23721499}, issn = {1399-3046}, mesh = {Acetylcysteine/therapeutic use ; *Amanita ; Antioxidants/therapeutic use ; Child ; Child, Preschool ; Critical Care ; Female ; Follow-Up Studies ; Humans ; Infant ; Liver Failure, Acute/*chemically induced/*therapy ; Liver Transplantation/*methods ; Male ; Mushroom Poisoning/*therapy ; Prognosis ; Retrospective Studies ; Silybin ; Silymarin/therapeutic use ; Treatment Outcome ; }, abstract = {Amanita phalloides intoxication can lead to FHF with high mortality, especially in children. There is still ongoing discussion about the optimal treatment and decision criteria for emergency liver transplantation (LTx). Here, we summarize our experience with outcomes in five children. Five children with severe A. phalloides intoxication were treated at our tertiary center from 1995 to 2010 and studied retrospectively with respect to clinical and laboratory aspects that might help to decide between LTx or conservative therapy only. The findings are discussed with regard to recommended treatment and transplantation criteria for adults. All patients survived, of whom two of five received emergency LTx. Three patients survived with conservative treatment consisting of intravenous silibinin, NAC, detoxification measures, and intensive care. Indications for LTx in two children were progressive brain edema and cardiovascular failure. Children with FHF due to A. phalloides intoxication should be considered early for emergency LTx but should be monitored closely for the necessity of definite LTx. Early detoxification with active charcoal as well as silibinin and NAC seems to improve the outcome. Late recovery of liver function after day 4 post-ingestion is possible.}, }
@article {pmid23719546, year = {2013}, author = {Michailidis, Y and Karagounis, LG and Terzis, G and Jamurtas, AZ and Spengos, K and Tsoukas, D and Chatzinikolaou, A and Mandalidis, D and Stefanetti, RJ and Papassotiriou, I and Athanasopoulos, S and Hawley, JA and Russell, AP and Fatouros, IG}, title = {Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise.}, journal = {The American journal of clinical nutrition}, volume = {98}, number = {1}, pages = {233-245}, doi = {10.3945/ajcn.112.049163}, pmid = {23719546}, issn = {1938-3207}, mesh = {Acetylcysteine/administration &amp; dosage ; Adaptation, Physiological/drug effects ; Adult ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Creatine Kinase/metabolism ; Cross-Over Studies ; Cytokines/metabolism ; Diet ; *Dietary Supplements ; Double-Blind Method ; Exercise/*physiology ; Glutathione/metabolism ; Humans ; Immunohistochemistry ; Inflammation/drug therapy ; Male ; Muscle Contraction/drug effects ; NF-kappa B/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Quadriceps Muscle/*drug effects/metabolism/physiology ; Ribosomal Protein S6/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction/drug effects ; Sulfhydryl Compounds/*administration &amp; dosage ; Tumor Necrosis Factor-alpha/metabolism ; Young Adult ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND: The major thiol-disulfide couple of reduced glutathione (GSH) and oxidized glutathione is a key regulator of major transcriptional pathways regulating aseptic inflammation and recovery of skeletal muscle after aseptic injury. Antioxidant supplementation may hamper exercise-induced cellular adaptations.<br><br>OBJECTIVE: The objective was to examine how thiol-based antioxidant supplementation affects skeletal muscle's performance and redox-sensitive signaling during the inflammatory and repair phases associated with exercise-induced microtrauma.<br><br>DESIGN: In a double-blind, crossover design, 10 men received placebo or N-acetylcysteine (NAC; 20 mg &#xb7; kg(-1) &#xb7; d(-1)) after muscle-damaging exercise (300 eccentric contractions). In each trial, muscle performance was measured at baseline, after exercise, 2 h after exercise, and daily for 8 consecutive days. Muscle biopsy samples from vastus lateralis and blood samples were collected before exercise and 2 h, 2 d, and 8 d after exercise.<br><br>RESULTS: NAC attenuated the elevation of inflammatory markers of muscle damage (creatine kinase activity, C-reactive protein, proinflammatory cytokines), nuclear factor &#x3ba;B phosphorylation, and the decrease in strength during the first 2 d of recovery. NAC also blunted the increase in phosphorylation of protein kinase B, mammalian target of rapamycin, p70 ribosomal S6 kinase, ribosomal protein S6, and mitogen activated protein kinase p38 at 2 and 8 d after exercise. NAC also abolished the increase in myogenic determination factor and reduced tumor necrosis factor-&#x3b1; 8 d after exercise. Performance was completely recovered only in the placebo group.<br><br>CONCLUSION: Although thiol-based antioxidant supplementation enhances GSH availability in skeletal muscle, it disrupts the skeletal muscle inflammatory response and repair capability, potentially because of a blunted activation of redox-sensitive signaling pathways. This trial was registered at clinicaltrials.gov as NCT01778309.}, }
@article {pmid23718729, year = {2013}, author = {Abdelsaid, MA and Matragoon, S and El-Remessy, AB}, title = {Thioredoxin-interacting protein expression is required for VEGF-mediated angiogenic signal in endothelial cells.}, journal = {Antioxidants &amp; redox signaling}, volume = {19}, number = {18}, pages = {2199-2212}, pmid = {23718729}, issn = {1557-7716}, support = {R01 EY022408/EY/NEI NIH HHS/United States ; R01-EY022408/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Carrier Proteins/genetics/*metabolism ; Cells, Cultured ; Endothelial Cells/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Neovascularization, Pathologic ; *Signal Transduction ; Thioredoxins/genetics/*metabolism ; Vascular Endothelial Growth Factors/*metabolism ; }, abstract = {AIMS: Thioredoxin-interacting protein (TXNIP) contributes to cellular redox-state homeostasis via binding and inhibiting thioredoxin (TRX). Increasing evidence suggests that cellular redox homeostasis regulates vascular endothelial growth factor (VEGF)-mediated signaling. This study aims to examine the redox-dependant role of TXNIP in regulating VEGF-mediated S-glutathionylation and angiogenic signaling. TXNIP-knockout mice (TKO) or wild-type (WT) treated with the reduced glutathione (GSH)-precursor, N-acetyl cysteine (WT-NAC, 500 mg/kg) were compared to WT using hypoxia-induced neovascularization model.<br><br>RESULTS: In response to hypoxia, retinas from TKO and WT-NAC mice showed significant decreases in reparative revascularization and pathological neovascularization with similar VEGF expression compared with WT. VEGF failed to stimulate vascular sprouting from aortic rings of TKO compared to WT mice. TKO mice or WT+NAC experienced reductive stress as indicated by twofold increase in TRX reductase activity and fourfold increase in reduced-GSH levels compared with WT. In human microvascular endothelial (HME) cells, VEGF stimulated co-precipitation between vascular endothelial growth factor receptor 2 (VEGFR2) with low molecular weight protein tyrosine phosphatase (LMW-PTP). Silencing TXNIP expression blunted VEGF-induced oxidation of GSH and S-glutathionylation of the LMW-PTP in HME cells. These effects were associated with impaired VEGFR2 phosphorylation that culminated in inhibiting cell migration and tube formation. Overexpression of TXNIP restored VEGFR2 phosphorylation and cell migration in TKO-endothelial cells.<br><br>INNOVATION: TXNIP expression is required for VEGF-mediated VEGFR2 activation and angiogenic response in vivo and in vitro. TXNIP expression regulates VEGFR-2 phosphorylation via S-glutathionylation of LMW-PTP in endothelial cells.<br><br>CONCLUSION: Our results provide novel mechanistic insight into modulating TXNIP expression as a potential therapeutic target in diseases characterized by aberrant angiogenesis.}, }
@article {pmid23718574, year = {2013}, author = {Lu, H and Yao, K and Huang, D and Sun, A and Zou, Y and Qian, J and Ge, J}, title = {High glucose induces upregulation of scavenger receptors and promotes maturation of dendritic cells.}, journal = {Cardiovascular diabetology}, volume = {12}, number = {}, pages = {80}, pmid = {23718574}, issn = {1475-2840}, mesh = {Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Atherosclerosis/*etiology/genetics/immunology/metabolism ; CD36 Antigens/metabolism ; Cell Differentiation/*drug effects ; Cells, Cultured ; Cytokines/metabolism ; Dendritic Cells/*drug effects/immunology/metabolism ; Dose-Response Relationship, Drug ; Glucose/*pharmacology ; Humans ; Hyperglycemia/*complications/genetics/immunology/metabolism ; Inflammation Mediators/metabolism ; Lipoproteins, LDL/metabolism ; Phenotype ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Scavenger/genetics/*metabolism ; Scavenger Receptors, Class A/metabolism ; Scavenger Receptors, Class E/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND: Both hyperglycaemia and dendritic cells (DCs) play causative roles in atherosclerosis. However, whether they interact in atherosclerosis remains uncertain. Therefore, we examined whether high glucose could regulate the expression of scavenger receptors responsible for oxidised low-density lipoprotein (oxLDL) uptake in DCs, a critical step in atherogenesis. In addition, we investigated the impact of glucose on DC maturation regarding changes in phenotype and cytokine secretion.<br><br>METHODS: Immature DCs were cultured with different concentrations of glucose (5.5 mmol/L, 15 mmol/L, 30 mmol/L) in the absence or presence of N-acetylcysteine (NAC), SB203580 or Bay11-7082 for 24 hours. We used 30 mmol/L mannitol as a high-osmolarity control treatment. The expression of the scavenger receptors SR-A, CD36 and LOX-1 was determined by real-time PCR and western blot analysis. Furthermore, DCs were incubated with DiI-labelled oxLDL. The DiI-oxLDL-incorporated fraction was investigated by flow cytometry analysis. The intracellular production of ROS in DCs was measured by dichlorodihydrofluorescein (DCF) fluorescence using confocal microscopy. Finally, flow cytometry analysis was used to investigate immunophenotypic protein expression (CD83 and CD86). Supernatant cytokine measurements were used for immune function assays.<br><br>RESULTS: The incubation of DCs with glucose enhanced, in a dose-dependent manner, the gene and protein expression of SR-A, CD36 and LOX-1. This effect was partially abolished by NAC, SB203580 and Bay11-7082. Incubation of DCs with mannitol (30 mmol/L) did not enhance these scavenger receptors' expression. High glucose upregulated the production of ROS and expression of p38 MAPK in DCs. NAC partially reversed p38 MAPK upregulation. High glucose increased the oxLDL-uptake capacity of DCs. Blockage of the scavenger receptors SR-A and CD36 reduced oxLDL uptake, but blockage of LOX-1 did not. Furthermore, high-glucose (15 mmol/L or 30 mmol/L) treatment increased CD86 and CD83 in DCs. High glucose also increased IL-6 and IL-12 secretion and decreased IL-10 secretion.<br><br>CONCLUSION: High glucose can increase the expression of the scavenger receptors SR-A, CD36 and LOX-1, which can increase the oxLDL-uptake capacity of DCs. High glucose induces a proinflammatory cytokine profile in human DCs, leading to DC maturation. These results support the hypothesis that atherosclerosis is aggravated by hyperglycaemia-induced DC activation and oxLDL uptake.}, }
@article {pmid23717422, year = {2013}, author = {Han, MH and Park, C and Jin, CY and Kim, GY and Chang, YC and Moon, SK and Kim, WJ and Choi, YH}, title = {Apoptosis induction of human bladder cancer cells by sanguinarine through reactive oxygen species-mediated up-regulation of early growth response gene-1.}, journal = {PloS one}, volume = {8}, number = {5}, pages = {e63425}, pmid = {23717422}, issn = {1932-6203}, mesh = {Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects/genetics ; BH3 Interacting Domain Death Agonist Protein/genetics/metabolism ; Benzophenanthridines/*pharmacology ; Caspases/genetics/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/genetics ; Down-Regulation/drug effects ; Early Growth Response Protein 1/*genetics/metabolism ; Humans ; Isoquinolines/*pharmacology ; JNK Mitogen-Activated Protein Kinases/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Up-Regulation/*drug effects/genetics ; Urinary Bladder Neoplasms/*drug therapy/genetics/metabolism ; X-Linked Inhibitor of Apoptosis Protein/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Although the effects of sanguinarine, a benzophenanthridine alkaloid, on the inhibition of some kinds of cancer cell growth have been established, the underlying mechanisms are not completely understood. This study investigated possible mechanisms by which sanguinarine exerts its anticancer action in cultured human bladder cancer cell lines (T24, EJ, and 5637). Sanguinarine treatment resulted in concentration-response growth inhibition of the bladder cancer cells by inducing apoptosis. Sanguinarine-induced apoptosis was correlated with the up-regulation of Bax, the down-regulation of Bid and XIAP, the activation of caspases (-3, -8, and -9), and the generation of increased reactive oxygen species (ROS). The ROS scavenger N-acetyl cysteine (NAC) completely reversed the sanguinarine-triggered apoptotic events. In addition, sanguinarine effectively increased the activation of the c-Jun N-terminal kinase (JNK) and the expression of the early growth response gene-1 (Egr-1), which was recovered by pretreatment with NAC. Furthermore, knockdown of Egr-1 expression by small interfering RNA attenuated sanguinarine-induced apoptosis, but not the JNK inhibitor, indicating that the interception of ROS generation blocked the sanguinarine-induced apoptotic effects via deregulation of the expression of Egr-1 proteins. Taken together, the data provide evidence that sanguinarine is a potent anticancer agent, which inhibits the growth of bladder cancer cells and induces their apoptosis through the generation of free radicals.}, }
@article {pmid23714372, year = {2013}, author = {Chung, HY and Chang, CT and Young, HW and Hu, SP and Tzou, WS and Hu, CH}, title = {Ethanol inhibits retinal and CNS differentiation due to failure of cell cycle exit via an apoptosis-independent pathway.}, journal = {Neurotoxicology and teratology}, volume = {38}, number = {}, pages = {92-103}, doi = {10.1016/j.ntt.2013.05.006}, pmid = {23714372}, issn = {1872-9738}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Cycle/*drug effects/physiology ; Cell Differentiation/*drug effects/physiology ; Central Nervous System/cytology/*drug effects/growth &amp; development ; Dose-Response Relationship, Drug ; Embryonic Development/*drug effects ; Ethanol/antagonists &amp; inhibitors/*toxicity ; Gene Expression Regulation, Developmental/drug effects ; Neural Stem Cells/drug effects/metabolism ; Neurogenesis/*drug effects ; Reactive Oxygen Species/metabolism ; Retina/*drug effects/growth &amp; development ; Stem Cells/drug effects/metabolism ; Tumor Suppressor Protein p53/biosynthesis ; Zebrafish ; }, abstract = {Alcohol exposure during embryogenesis results in a variety of developmental disorders. Here, we demonstrate that continuous exposure to 1.5% ethanol causes substantial apoptosis and abrogated retinal and CNS development in zebrafish embryos. Chronic exposure to ethanol for 24h before hatching also induces apoptosis and retinal disorder. After the 2-day post-fertilization (dpf) stage, chronic exposure to ethanol continued to induce apoptosis, but did not block retinal differentiation. Although continuous ethanol exposure induces substantial accumulation of reactive oxygen species (ROS) and increases p53 expression, depletion of p53 did not eliminate ethanol-induced apoptosis. On the other hand, sequestering ROS with the antioxidant reagent N-acetylcysteine (NAC) successfully inhibited ethanol-associated apoptosis, suggesting that the ethanol-induced cell death primarily results from ROS accumulation. Continuous ethanol treatment of embryos reduced expression of the mature neural and photoreceptor markers elavl3/huC, rho, and crx; in addition, expression of the neural and retinal progenitor markers ascl1b and pax6b was maintained at the undifferentiated stage, indicating that retinal and CNS neural progenitor cells failed to undergo further differentiation. Moreover, ethanol treatment enhanced BrdU incorporation, histone H3 phosphorylation, and pcna expression in neural progenitor cells, thereby maintaining a high rate of proliferation. Ethanol treatment also resulted in sustained transcription of ccnd1/cyclin D1 and ccne/cyclin E throughout development in neural progenitor cells, without an appropriate increase of cdkn1b/p27 and cdkn1c/p57 expression, suggesting that these cells failed to exit from the cell cycle. Although NAC was able to mitigate ethanol-mediated apoptosis, it was unable to ameliorate the defects in visual and CNS neural differentiation, suggesting that abrogated neural development in ethanol-exposed embryos is unlikely to arise from excessive apoptosis. In conclusion, we demonstrate that the pathological effect of ethanol on zebrafish embryos is partially attributable to cell death and inhibition of visual and CNS neuron differentiation. Excessive apoptosis largely results from the accumulation of ROS, whereas abrogated neural development is caused by failure of cell cycle arrest, which in turn prevents a successful transition from proliferation to differentiation.}, }
@article {pmid23713575, year = {2013}, author = {Hill, M and Mor, MK and Travis, L and Ward, T and Palevsky, PM and Ramkumar, M and Weisbord, SD}, title = {Renal function following fistulography in patients with advanced chronic kidney disease.}, journal = {Renal failure}, volume = {35}, number = {6}, pages = {791-795}, doi = {10.3109/0886022X.2013.794432}, pmid = {23713575}, issn = {1525-6049}, mesh = {Acute Kidney Injury/*chemically induced ; Aged ; Angiography/adverse effects ; Arteriovenous Shunt, Surgical/adverse effects ; Contrast Media/*adverse effects ; Glomerular Filtration Rate ; Humans ; Kidney Failure, Chronic/*chemically induced/therapy ; Male ; Middle Aged ; Renal Dialysis ; Retrospective Studies ; Triiodobenzoic Acids/*adverse effects ; }, abstract = {BACKGROUND/AIMS: Contrast-induced acute kidney injury (CIAKI) is associated with an accelerated progression of underlying chronic kidney disease (CKD). We sought to characterize the rate of loss of kidney function following fistulography in patients with advanced CKD.<br><br>MATERIALS/METHODS: We identified all patients with stage 4 or 5 non-dialysis-dependent CKD who underwent fistulography with iodinated contrast for non-maturing arteriovenous fistulae between 1 January 2010 and 30 November 2011. We recorded all eGFR values measured during the 6 months prior to and 6 months following the procedure, the volume and type of contrast, use of intravenous fluid and N-acetylcysteine (NAC), and timing of dialysis initiation following the procedure. We used mixed linear regression with random effects to compare the composite slope of decline in eGFR prior to and following fistulography.<br><br>RESULTS: Overall, 27 patients underwent a total of 44 fistulograms. The mean age of the patients was 66 years and mean baseline eGFR was 16.7&#x2009;&#xb1;&#x2009;5&#x2009;mL/min/1.73&#x2009;m(2). Patients received a median volume of contrast of 12&#x2009;mL [IQR 10-20]. None of the patients initiated acute dialysis within weeks following the procedure. In unadjusted analyses, there was no statistically significant change in the rate of decline in eGFR following fistulography compared to pre-procedure (0.14&#x2009;mL/min/month versus -0.14&#x2009;mL/min/month, p&#x2009;=&#x2009;0.11). In analyses that adjusted for procedural, demographic and clinical variables, the decline in eGFR following fistulography was not statistically different than before the procedure (0.15&#x2009;mL/min/month versus -0.14&#x2009;mL/min/month, p&#x2009;=&#x2009;0.11).<br><br>CONCLUSIONS: Fistulography with small volumes of iodinated contrast in patients with advanced CKD does not result in more rapid progression of underlying CKD.}, }
@article {pmid23712640, year = {2013}, author = {Takeo, S and Kawahara-Miki, R and Goto, H and Cao, F and Kimura, K and Monji, Y and Kuwayama, T and Iwata, H}, title = {Age-associated changes in gene expression and developmental competence of bovine oocytes, and a possible countermeasure against age-associated events.}, journal = {Molecular reproduction and development}, volume = {80}, number = {7}, pages = {508-521}, doi = {10.1002/mrd.22187}, pmid = {23712640}, issn = {1098-2795}, mesh = {Animals ; Carbazoles/pharmacology ; Cattle/genetics/*metabolism ; Embryo, Mammalian/*metabolism ; Female ; Fertilization/drug effects ; Fluorescence ; Gene Expression Profiling ; Gene Expression Regulation, Developmental/*genetics ; High-Throughput Nucleotide Sequencing ; Maternal Age ; Oocytes/*metabolism ; Pregnancy ; Pregnancy Outcome ; Reactive Oxygen Species/metabolism ; Resveratrol ; Sirtuin 1/antagonists &amp; inhibitors/metabolism ; Stilbenes/pharmacology ; }, abstract = {In general, maternal age affects the quality of oocytes and embryos. The present study aimed to examine the features and age-associated gene expression profiles of bovine oocytes and embryos as well as to discover possible countermeasures against age-associated events. Comprehensive gene expression assays of germinal vesicle and metaphase II (MII)-stage oocytes and 8- to 16-cell-stage embryos were conducted using next-generation sequencing technology. The gene expression profiles of aged cows showed high expression of genes related to oxidative phosphorylation, eIF4 and p70S6K signaling, and mitochondrial dysfunction in MII-stage oocytes. Oocytes derived from aged cows, compared with those derived from their younger counterparts, exhibited high levels of abnormal fertilization and blastocysts with low total cell numbers. Levels of reactive oxygen species (ROS) and SIRT1 were higher in in vitro-matured oocytes derived from aged cows than in those derived from their younger counterparts. Supplementation of maturation medium with N-acetyl-cysteine (NAC), but not resveratrol, reduced the levels of ROS in the oocytes derived from cows of both age groups; however, resveratrol, but not NAC, improved the fertilization ratio. Conversely, EX 527, an inhibitor of SIRT1, increased the ratio of abnormal fertilization. In conclusion, gene expression profiles of oocytes and embryos derived from aged cows differ from those of oocytes and embryos derived from young cows; in particular, oocytes derived from aged cows show protein and mitochondrial dysfunction. In addition, activation of SIRT1 in oocytes may be a potential countermeasure against age-associated events in oocytes derived from aged cows.}, }
@article {pmid23711675, year = {2013}, author = {Yamada, M and Tsukimura, N and Ikeda, T and Sugita, Y and Att, W and Kojima, N and Kubo, K and Ueno, T and Sakurai, K and Ogawa, T}, title = {N-acetyl cysteine as an osteogenesis-enhancing molecule for bone regeneration.}, journal = {Biomaterials}, volume = {34}, number = {26}, pages = {6147-6156}, doi = {10.1016/j.biomaterials.2013.04.064}, pmid = {23711675}, issn = {1878-5905}, support = {C06RR014529/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alkaline Phosphatase/metabolism ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology/*therapeutic use ; Bone Marrow Cells/cytology/drug effects/metabolism ; Bone Regeneration/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dexamethasone/pharmacology ; Femur/*drug effects/injuries/physiology ; Gene Expression Regulation, Developmental/drug effects ; Male ; Osteoblasts/cytology/drug effects/metabolism ; Osteogenesis/*drug effects ; Rats ; Rats, Sprague-Dawley ; Stromal Cells/cytology/drug effects/metabolism ; }, abstract = {Bone regeneration often requires cues from osteogenesis-inducing factors for successful outcome. N-acetyl cysteine (NAC), an anti-oxidant small molecule, possibly modulates osteoblastic differentiation. This study investigated the potential of NAC as an osteogenesis-enhancing molecule in vitro and in vivo. Various concentrations of NAC (0, 2.5, 5.0, and 10 mM) were added to rat bone marrow stromal cell or osteoblastic cell culture in media with or without dexamethasone. The results showed marked enhancement of alkaline phosphatase activity and mineralized matrix formation together with consistent upregulation of bone-related gene markers such as collagen I, osteopontin, and osteocalcin in the osteoblastic culture with addition of 2.5 or 5.0 mM NAC regardless of the presence of dexamethasone. Micro-CT-based analysis and histological observation revealed that addition of NAC to a collagenous sponge implanted in a critical size cortical bone defect (3.0 mm × 5.0 mm) in rat femur yielded acceleration and completion of defect closure, with thick, compact, and contiguous bone after 6 weeks of healing. In contrast, with sponge alone, only sparse and incomplete bone regeneration was observed during the matching healing period. These results indicate that NAC can function as an osteogenesis-enhancing molecule to accelerate bone regeneration by activating differentiation of osteogenic lineages.}, }
@article {pmid23710636, year = {2013}, author = {Lee, EK and Kim, JA and Park, SJ and Kim, JK and Heo, K and Yang, KM and Son, TG}, title = {Low-dose radiation activates Nrf1/2 through reactive species and the Ca(2+)/ERK1/2 signaling pathway in human skin fibroblast cells.}, journal = {BMB reports}, volume = {46}, number = {5}, pages = {258-263}, pmid = {23710636}, issn = {1976-670X}, mesh = {Calcium/*metabolism ; Cell Line ; Cell Proliferation/radiation effects ; Fibroblasts/metabolism/*radiation effects ; Humans ; Ions ; MAP Kinase Signaling System/*physiology ; NF-E2-Related Factor 2/genetics/*metabolism/*radiation effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*radiation effects ; Skin/cytology/radiation effects ; }, abstract = {In the current study, we explored the effect of LDR on the activation of Nrfs transcription factor involved in cellular redox events. Experiments were carried out utilizing 0.05 and 0.5 Gy X-ray irradiated normal human skin fibroblast HS27 cells. The results showed LDR induced Nrf1 and Nrf2 activation and expression of antioxidant genes HO-1, Mn-SOD, and NQO1. In particular, 0.05 Gy-irradiation increased only Nrf1 activation, but 0.5 Gy induced both Nrf1 and Nrf2 activation. LDR-mediated Nrf1/2 activation was accompanied by reactive species (RS) generation and Ca(2+) flux. This effect was abolished in the presence of N-acetyl-cysteine and BAPTA- AM. Furthermore, Nrf1/2 activation by LDR was suppressed by PD98059, an inhibitor of ERK1/2. In conclusion, LDR induces Nrf1 and Nrf2 activation and expression of Nrf-regulated antioxidant defense genes through RS and Ca(2+)/ERK1/2 pathways, suggesting new insights into the molecular mechanism underlying the beneficial role of LDR in HS27 cells.}, }
@article {pmid23710319, year = {2013}, author = {Du, BQ and Yang, YM and Chen, YH and Liu, XB and Mai, G}, title = {N-acetylcysteine improves pancreatic microcirculation and alleviates the severity of acute necrotizing pancreatitis.}, journal = {Gut and liver}, volume = {7}, number = {3}, pages = {357-362}, pmid = {23710319}, issn = {1976-2283}, abstract = {BACKGROUND/AIMS: To investigate the beneficial effect of N-Acetylcysteine (NAC) on pancreatic microvascular perfusion in acute necrotizing pancreatitis (ANP).<br><br>METHODS: Fifty-four rats were divided into a control group, an ANP group and an NAC-treated group. The ANP model was established by a retrograde injection of 3% sodium taurocholate into the pancreatic duct. The NAC-treated group received an intravenous infusion of NAC just 2 hours before and 30 minutes after the induction of ANP. The pancreatic microvascular perfusion was measured with laser Doppler flowmetry and pancreatic samples were collected for histological examination.<br><br>RESULTS: The microvascular perfusion in the NAC-treated group decreased slightly and exhibited a significant increase compared to the ANP group (p<0.01). A pathological examination revealed that edema and inflammatory infiltration decreased, and the hemorrhaging and necrosis of the pancreas were significantly reduced.<br><br>CONCLUSIONS: NAC could improve pancreatic microvascular perfusion and alleviate the severity of sodium taurocholate-induced ANP, possibly representing a new therapeutic approach to prevent the progression of ANP.}, }
@article {pmid23708970, year = {2013}, author = {Kim, GD and Oh, J and Park, HJ and Bae, K and Lee, SK}, title = {Magnolol inhibits angiogenesis by regulating ROS-mediated apoptosis and the PI3K/AKT/mTOR signaling pathway in mES/EB-derived endothelial-like cells.}, journal = {International journal of oncology}, volume = {43}, number = {2}, pages = {600-610}, doi = {10.3892/ijo.2013.1959}, pmid = {23708970}, issn = {1791-2423}, mesh = {Acetylcysteine/metabolism ; Angiogenesis Inhibitors/*pharmacology ; Animals ; Apoptosis/*drug effects ; Biphenyl Compounds/*pharmacology ; Caspase 3/biosynthesis/drug effects/metabolism ; Cell Differentiation ; Cell Line ; Embryonic Stem Cells/cytology/drug effects/metabolism ; Endothelial Cells/drug effects/metabolism ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/drug effects/metabolism ; JNK Mitogen-Activated Protein Kinases/drug effects/metabolism ; Lignans/*pharmacology ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/metabolism ; Neovascularization, Pathologic/*drug therapy ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Phosphatidylinositol 3-Kinases/drug effects/metabolism ; Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis/drug effects ; Proto-Oncogene Proteins c-akt/drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; TOR Serine-Threonine Kinases/drug effects/metabolism ; p38 Mitogen-Activated Protein Kinases/drug effects/metabolism ; }, abstract = {Magnolol, a neolignan from the traditional medicinal plant Magnolia obovata, has been shown to possess neuroprotective, anti-inflammatory, anticancer and anti-angiogenic activities. However, the precise mechanism of the anti-angiogenic activity of magnolol remains to be elucidated. In the present study, the anti-angiogenic effect of magnolol was evaluated in mouse embryonic stem (mES)/embryoid body (EB)-derived endothelial-like cells. The endothelial-like cells were obtained by differentiation from mES/EB cells. Magnolol (20 µM) significantly suppressed the transcriptional and translational expression of platelet endothelial cell adhesion molecule (PECAM), an endothelial biomarker, in mES/EB-derived endothelial-like cells. To further understand the molecular mechanism of the suppression of PECAM expression, signaling pathways were analyzed in the mES/EB-derived endothelial-like cells. Magnolol induced the generation of reactive oxygen species (ROS) by mitochondria, a process that was associated with the induction of apoptosis as determined by positive Annexin V staining and the activation of cleaved caspase-3. The involvement of ROS generation by magnolol was confirmed by treatment with an antioxidant, N-acetyl-cysteine (NAC). NAC inhibited the magnolol-mediated induction of ROS generation and suppression of PECAM expression. In addition, magnolol suppressed the activation of MAPKs (ERK, JNK and p38) and the PI3K/AKT/mTOR signaling pathway in mES/EB-derived endothelial-like cells. Taken together, these findings demonstrate for the first time that the anti-angiogenic activity of magnolol may be associated with ROS-mediated apoptosis and the suppression of the PI3K/AKT/mTOR signaling pathway in mES/EB-derived endothelial-like cells.}, }
@article {pmid23708443, year = {2013}, author = {Badisa, RB and Goodman, CB and Fitch-Pye, CA}, title = {Attenuating effect of N-acetyl-L-cysteine against acute cocaine toxicity in rat C6 astroglial cells.}, journal = {International journal of molecular medicine}, volume = {32}, number = {2}, pages = {497-502}, pmid = {23708443}, issn = {1791-244X}, support = {G12 RR003020/RR/NCRR NIH HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; G12 RR03020/RR/NCRR NIH HHS/United States ; G12 MD007582/MD/NIMHD NIH HHS/United States ; 8G12 MD 007582-28/MD/NIMHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Astrocytes/*drug effects/metabolism ; Cell Line ; Cell Survival/drug effects ; Cocaine/*toxicity ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Glutathione/biosynthesis ; Nitric Oxide/metabolism ; Oxidants/*toxicity ; Rats ; }, abstract = {Astroglial cells are one of the most abundant cell types in the mammalian brain functioning in neuronal survival and in maintenance of fundamental patterns of circuitry. To date, no study has been conducted regarding the short-term impact of cocaine on these cells in cultures. The present study aimed to investigate acute cocaine (1 h) treatment on cell viability in rat C6 astroglial cells. In addition, the potential effect of N-acetyl-L-cysteine (NAC) against cocaine-induced toxicity was studied. It was observed that 1 h of acute cocaine exposure at 2, 3 and 4 mM caused a dose-dependent decrease in cell viability with an LC50 of 2.857 mM. Furthermore, cocaine treatment caused a decrease in glutathione (GSH) levels in the cells. It was found that cocaine did not exhibit pro-oxidant activity during its exposure to cells. Acute cocaine exposure did not induce nitric oxide (NO) release in the cells. A 5-point (1-5 mM) dose-response curve of NAC clearly indicated no adverse effect on astroglial cell viability. Pretreatment of cells with 5 mM NAC for 30 min, followed by its discard, and exposure to cocaine (2-4 mM) for 1 h protected cells against cytotoxicity by 90%. Treatment of cells with NAC-cocaine mixture rendered 100% protection. Further investigations revealed that the protection by NAC was through the increased GSH levels in the cells. Our results indicate that decreased GSH levels may represent one of the underlying pathologies of cell death and that antioxidant compounds which increase the GSH production could protect against cocaine-induced toxicity by promoting a pro-survival role in astroglial cells.}, }
@article {pmid23708403, year = {2013}, author = {Markopoulos, G and Noutsopoulos, D and Mantziou, S and Vartholomatos, G and Monokrousos, N and Angelidis, C and Tzavaras, T}, title = {Arsenic induces VL30 retrotransposition: the involvement of oxidative stress and heat-shock protein 70.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {134}, number = {2}, pages = {312-322}, doi = {10.1093/toxsci/kft118}, pmid = {23708403}, issn = {1096-0929}, mesh = {Animals ; Arsenic/*toxicity ; Green Fluorescent Proteins/genetics ; HSP70 Heat-Shock Proteins/*metabolism ; Mice ; NIH 3T3 Cells ; *Oxidative Stress ; Polymerase Chain Reaction/methods ; *Retroelements ; Up-Regulation/drug effects ; }, abstract = {Arsenic is an environmental contaminant with known cytotoxic and carcinogenic properties, but the cellular mechanisms of its action are not fully known. As retrotransposition consists a potent mutagenic factor affecting genome stability, we investigated the effect of arsenic on retrotransposition of an enhanced green fluorescent protein (EGFP)-tagged nonautonomous long terminal repeat (LTR)-retrotransposon viral-like 30 (VL30) in a mouse NIH3T3 cell culture-retrotransposition assay. Flow cytometry analysis of assay cells treated with 2.5-20μM sodium arsenite revealed induction of retrotransposition events in a dose- and time-dependent manner, which was further confirmed as genomic integrations by PCR analysis and appearance of EGFP-positive cells by UV microscopy. Specifically, 20μM sodium arsenite strongly induced the VL30 retrotransposition frequency, which was ~90,000-fold higher than the natural one and also VL30 RNA expression was ~6.6-fold. Inhibition of the activity of endogenous reverse transcriptases by efavirenz at 15μM or nevirapine at 375μM suppressed the arsenite-induced VL30 retrotransposition by 71.16 or 79.88%, respectively. In addition, the antioxidant N-acetyl-cysteine reduced the level of arsenite-induced retrotransposition, which correlated with the rescue of arsenite-induced G2/M cell cycle arrest and cell toxicity. Treatment of assay cells ectopically overexpressing the human heat-shock protein 70 (Hsp70) with 15μM sodium arsenite resulted in an additional ~4.5-fold induction of retrotransposition compared with normal assay cells, whereas treatment with 20μM produced a massive cell death. Our results show for the first time that arsenic both as an oxidative and heat-shock mimicking agent is a potent inducer of VL30 retrotransposition in mouse cells. The impact of arsenic-induced retrotransposition, as a cellular response, on contribution to or explanation of the arsenic-associated toxicity and carcinogenicity is discussed.}, }
@article {pmid23708127, year = {2013}, author = {Lim, EJ and Oak, CH and Heo, J and Kim, YH}, title = {Methylene blue-mediated photodynamic therapy enhances apoptosis in lung cancer cells.}, journal = {Oncology reports}, volume = {30}, number = {2}, pages = {856-862}, doi = {10.3892/or.2013.2494}, pmid = {23708127}, issn = {1791-2431}, mesh = {Apoptosis/*drug effects/genetics ; Apoptosis Regulatory Proteins/genetics/metabolism ; Caspase 3/genetics/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Down-Regulation/drug effects ; Humans ; Lung Neoplasms/*drug therapy/genetics/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Methylene Blue/*pharmacology ; Mitogen-Activated Protein Kinases/genetics/metabolism ; Myeloid Cell Leukemia Sequence 1 Protein/genetics/metabolism ; Phosphorylation/drug effects ; Photochemotherapy/*methods ; Photosensitizing Agents/*pharmacology ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Combined treatment with a photosensitizer and iodide laser [photodynamic therapy (PDT)] has improved the outcome of various cancers. In this study, we investigated the effects of using the photosensitizer methylene blue (MB) in PDT in human lung adenocarcinoma cells. We found that MB enhances PDT-induced apoptosis in association with downregulation of anti-apoptotic proteins, reduced mitochondrial membrane potential (MMP), increased phosphorylation of the mitogen-activated protein kinase (MAPK) and the generation of reactive oxygen species (ROS). In MB-PDT-treated A549 cells, we observed PARP cleavage, procaspase-3 activation, downregulation of the anti-apoptotic proteins Bcl-2 and Mcl-1, and the reduction of mitochondrial membrane potential (MMP). Western blot data showed that phosphorylation of p38 was increased in MB-PDT-treated A549 cells, indicating that several signaling molecules participate in the apoptotic cascade. Our data also showed that apoptotic cell death in MB-PDT-treated cells occurred through a series of steps beginning with the photochemical generation of ROS. Demonstrating the role of ROS, pretreatment of A549 cells with the antioxidant N-acetylcysteine (NAC) followed by MB-PDT resulted in increased cell viability and reduced proteolytic cleavage of PARP.}, }
@article {pmid23707800, year = {2013}, author = {Nishio, N and Taniguchi, W and Sugimura, YK and Takiguchi, N and Yamanaka, M and Kiyoyuki, Y and Yamada, H and Miyazaki, N and Yoshida, M and Nakatsuka, T}, title = {Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels.}, journal = {Neuroscience}, volume = {247}, number = {}, pages = {201-212}, doi = {10.1016/j.neuroscience.2013.05.023}, pmid = {23707800}, issn = {1873-7544}, mesh = {Animals ; Excitatory Postsynaptic Potentials/*physiology ; Male ; Organ Culture Techniques ; Posterior Horn Cells/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Synaptic Transmission/*physiology ; TRPA1 Cation Channel ; TRPC Cation Channels/*metabolism ; TRPV Cation Channels/*metabolism ; }, abstract = {Central neuropathic pain (CNP) in the spinal cord, such as chronic pain after spinal cord injury (SCI), is an incurable ailment. However, little is known about the spinal cord mechanisms underlying CNP. Recently, reactive oxygen species (ROS) have been recognized to play an important role in CNP of the spinal cord. However, it is unclear how ROS affect synaptic transmission in the dorsal horn of the spinal cord. To clarify how ROS impact on synaptic transmission, we investigated the effects of ROS on synaptic transmission in rat spinal cord substantia gelatinosa (SG) neurons using whole-cell patch-clamp recordings. Administration of tert-butyl hydroperoxide (t-BOOH), an ROS donor, into the spinal cord markedly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in SG neurons. This t-BOOH-induced enhancement was not suppressed by the Na(+) channel blocker tetrodotoxin. However, in the presence of a non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, t-BOOH did not generate any sEPSCs. Furthermore, in the presence of a transient receptor potential ankyrin 1 (TRPA1) channel antagonist (HC-030031) or a transient receptor potential vanilloid 1 (TRPV1) channel antagonist (capsazepine or AMG9810), the t-BOOH-induced increase in the frequency of sEPSCs was inhibited. These results indicate that ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons through TRPA1 and TRPV1 channel activation. Excessive activation of these ion channels by ROS may induce central sensitization in the spinal cord and result in chronic pain such as that following SCI.}, }
@article {pmid23682786, year = {2013}, author = {Pal, A and Alam, S and Singhal, J and Kumar, R and Ansari, KM and Das, M}, title = {Protective effect of topical application of α-tocopherol and/or N-acetyl cysteine on argemone oil/alkaloid-induced skin tumorigenesis in mice.}, journal = {Nutrition and cancer}, volume = {65 Suppl 1}, number = {}, pages = {78-87}, doi = {10.1080/01635581.2013.785005}, pmid = {23682786}, issn = {1532-7914}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Benzophenanthridines/adverse effects ; Carcinogenesis/chemically induced/*drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Female ; Glutathione/analysis/metabolism ; Humans ; Isoquinolines/adverse effects ; Lipid Peroxidation/drug effects ; MAP Kinase Signaling System ; Mice ; Mustard Plant/*adverse effects ; NF-kappa B/genetics/metabolism ; Plant Oils/*adverse effects ; Skin/drug effects/pathology ; alpha-Tocopherol/*pharmacology ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Since bioantioxidants in plasma of Epidemic Dropsy patients [a condition caused by consumption of adulterated mustard oil with argemone oil (AO)] were found to be significantly decreased, the beneficial effect of N-acetyl cysteine (NAC) and α-tocopherol (TOCO) against AO- or sanguinarine (SANG)-induced tumorigenicity was undertaken in mice. Topical application of TOCO and NAC either alone or in combination showed significant protection against AO/TPA- and SANG/TPA-induced skin tumorigenicity. Histopathological findings suggest that papillomatous growth in AO/TPA- and SANG/TPA-treated animals were substantially protected following topical application of TOCO or NAC. Further, treatment of TOCO and NAC either alone or in combination to AO/TPA- or SANG/TPA-induced mice significantly decreased lipid peroxidation, along with significant revival in glutathione (GSH) content and activities of tyrosinase, histidase, catalase, SOD, GSH peroxidase, and GSH reductase in skin. In vitro studies showed that TOCO and/or NAC significantly decreased the AO and SANG induced cell proliferation and activation of ERK, p38, JNK MAPKs and NF-κB signaling in HaCaT cells. In summary, TOCO and NAC may be useful in preventing the tumorigenic response of AO and SANG probably by acting as scavenger of free radicals and inhibiting MAPKs and NF-κB signaling.}, }
@article {pmid23697458, year = {2013}, author = {Schmidt, LE}, title = {Identification of patients at risk of anaphylactoid reactions to N-acetylcysteine in the treatment of paracetamol overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {51}, number = {6}, pages = {467-472}, doi = {10.3109/15563650.2013.799677}, pmid = {23697458}, issn = {1556-9519}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*adverse effects/therapeutic use ; Adult ; Analgesics, Non-Narcotic/blood/*poisoning ; Anaphylaxis/*chemically induced ; Antidotes/*adverse effects/therapeutic use ; Drug Hypersensitivity/*etiology ; Ethnicity/statistics &amp; numerical data ; Female ; Humans ; Logistic Models ; Male ; Recurrence ; Risk Factors ; Young Adult ; }, abstract = {CONTEXT: N-acetylcysteine (NAC) is acknowledged as an effective antidote for paracetamol overdose. However, adverse effects to NAC are common and may be a point of concern for the patient and the treating physician.<br><br>OBJECTIVE: The aim of the present study was to further analyse possible risk factors of anaphylactoid adverse effects to intravenous NAC in order to identify individual patients or groups of patients at particular risk.<br><br>METHODS: This study is an observational case series of adverse effects to NAC administered according to the standard guidelines in patients who presented with paracetamol overdose between March 1999 and September 2011.<br><br>RESULTS: A total of 1218 admissions for paracetamol overdose receiving intravenous NAC were recorded in 950 patients. Anaphylactoid adverse effects occurred in 18.6%. The proportion of cases with adverse effects gradually declined from 25.9% in cases with undetectable p-paracetamol to 6.3% in cases with p-paracetamol above 1.5 mmol/L (226 &#x3bc;g/mL) (Spearman Rank R-test: p < 0.00001). The proportion of cases with adverse effects was significantly higher in cases of non-Danish origin than that of Danish origin (28.5% vs. 15.1%; Chi-square: p < 0.00001). In patients with repeated exposure to NAC, the rate of adverse effects on re-exposure was significantly higher in patients with a previous reaction to NAC compared to those without a previous reaction (Rate Ratio 6.2; 95% CI 2.9-17.1).<br><br>CONCLUSION: The development of anaphylactoid adverse effects to intravenous NAC was strongly associated with a low p-paracetamol, non-Danish origin and a history of previous reaction to NAC. These adverse effects are common, but usually mild and easily manageable. The incidence of adverse effects may be reduced by pre-treating selected patients with antihistamines, in particular those with a previous reaction to NAC.}, }
@article {pmid23696824, year = {2013}, author = {Shirazi, F and Kontoyiannis, DP}, title = {Mitochondrial respiratory pathways inhibition in Rhizopus oryzae potentiates activity of posaconazole and itraconazole via apoptosis.}, journal = {PloS one}, volume = {8}, number = {5}, pages = {e63393}, pmid = {23696824}, issn = {1932-6203}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Antifungal Agents/*pharmacology ; Antimycin A/*pharmacology ; Apoptosis ; Caspases/metabolism ; Cytochromes c/metabolism ; DNA Fragmentation ; DNA, Fungal/genetics ; Drug Synergism ; Electron Transport ; Fungal Proteins/metabolism ; Hydroxamic Acids/*pharmacology ; Itraconazole/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Microbial Sensitivity Tests ; Mitochondria/drug effects/*metabolism ; Reactive Oxygen Species/metabolism ; Rhizopus/*drug effects/metabolism ; Triazoles/*pharmacology ; }, abstract = {The incidence of mucormycosis has increased drastically in immunocompromised patients. Also the array of targets whose inhibition results in Mucorales death is limited. Recently, researchers identified mitochondria as important regulators of detoxification and virulence mechanisms in fungi. In this context, targeting the mitochondrial respiratory chain may provide a new platform for antifungal development. We hypothesized that targeting respiratory pathways potentiates triazoles activity via apoptosis. We found that simultaneous administration of antimycin A (AA) and benzohydroxamate (BHAM), inhibitors of classical and alternative mitochondrial pathways respectively, resulted in potent activity of posaconazole (PCZ) and itraconazole (ICZ) against Rhizopus oryzae. We observed cellular changes characteristic of apoptosis in R. oryzae cells treated with PCZ or ICZ in combination with AA and BHAM. The fungicidal activity of this combination against R. oryzae was correlated with intracellular reactive oxygen species accumulation (ROS), phosphatidylserine externalization, mitochondrial membrane depolarization, and increased caspase like activity. DNA fragmentation and condensation assays also revealed apoptosis of R. oryzae cells. These apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine. Taken together, these findings suggest that the use of PCZ or ICZ in combination with AA and BHAM makes R. oryzae exquisitely sensitive to treatment with triazoles via apoptosis. This strategy may serve as a new model for the development of improved or novel antifungal agents.}, }
@article {pmid23695982, year = {2013}, author = {Zhang, YT and Ouyang, DY and Xu, LH and Zha, QB and He, XH}, title = {Formation of cofilin-actin rods following cucurbitacin-B-induced actin aggregation depends on Slingshot homolog 1-mediated cofilin hyperactivation.}, journal = {Journal of cellular biochemistry}, volume = {114}, number = {10}, pages = {2415-2429}, doi = {10.1002/jcb.24587}, pmid = {23695982}, issn = {1097-4644}, mesh = {Actins/*metabolism ; Animals ; Cell Cycle/drug effects ; Cell Line ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cofilin 1/*metabolism ; Cucurbitacins/*pharmacology ; Humans ; Mice ; Microscopy, Fluorescence ; Phosphoprotein Phosphatases/*metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Accumulating evidence indicates that cucurbitacin B (CuB), as well as other cucurbitacins, damages the actin cytoskeleton in a variety of cell types. However, the underlying mechanism of such an effect is not well understood. In this study, we showed that CuB rapidly induced actin aggregation followed by actin rod formation in melanoma cells. Cofilin, a critical regulator of actin dynamics, was dramatically dephosphorylated (i.e., activated) upon CuB treatment. Notably, the activated cofilin subsequently formed rod-like aggregates, which were highly colocalized with actin rods, indicating the formation of cofilin-actin rods. Cofilin knockdown significantly suppressed rod formation but did not prevent actin aggregation. Furthermore, knockdown of the cofilin phosphatase Slingshot homolog 1 (SSH1), but not chronophin (CIN), alleviated CuB-induced cofilin hyperactivation and cofilin-actin rod formation. The activity of Rho kinase and LIM kinase, two upstream regulators of cofilin activation, was downregulated after cofilin hyperactivation. Pretreatment with a thiol-containing reactive oxygen species (ROS) scavenger N-acetyl cysteine, but not other ROS inhibitors without thiol groups, suppressed CuB-induced actin aggregation, cofilin hyperactivation and cofilin-actin rod formation, suggesting that thiol oxidation might be involved in these processes. Taken together, our results demonstrated that CuB-induced formation of cofilin-actin rods was mediated by SSH1-dependent but CIN-independent cofilin hyperactivation.}, }
@article {pmid23691187, year = {2013}, author = {Shi, X and Zhao, Y and Jiao, Y and Shi, T and Yang, X}, title = {ROS-dependent mitochondria molecular mechanisms underlying antitumor activity of Pleurotus abalonus acidic polysaccharides in human breast cancer MCF-7 cells.}, journal = {PloS one}, volume = {8}, number = {5}, pages = {e64266}, pmid = {23691187}, issn = {1932-6203}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/*pathology ; Cell Cycle Checkpoints/drug effects ; Fungal Polysaccharides/chemistry/*pharmacology ; Humans ; Hydrogen-Ion Concentration ; MCF-7 Cells ; Mitochondria/*drug effects/*metabolism ; Pancreatitis-Associated Proteins ; Pleurotus/*chemistry ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: A greater reduction in cancer risk associated with mushroom diet rich in fungus polysaccharides is generally accepted. Meanwhile, edible Pleurotus abalonus as a member of Abalone mushroom family is a popular nutritional supplement that purportedly prevents cancer occurrence. However, these anecdotal claims are supported by limited studies describing tumor-inhibitory responses to the promising polysaccharides, and the molecular mechanisms underlying these properties have not yet been elucidated.<br><br>We here fractionated the crude polysaccharide preparation from the fruiting bodies of P. abalonus into three fractions, namely PAP-1, PAP-2 and PAP-3, and tested these fractions for antiproliferative activity in human breast cancer MCF-7 cells. The largest PAP-3, an acidic polysaccharide fraction with a molecular mass of 3.68&#xd7;10(5) Da, was the most active in inhibiting MCF-7 cancer cells with an IC50 of 193 &#xb5;g/mL. The changes in cell normal morphology were observed by DAPI staining and the PAP-3-induced apoptosis was confirmed by annexin V/propidium iodide staining. The apoptosis was involved in mitochondria-mediated pathway including the loss of mitochondrial membrane potential (&#x394;&#x3c8;m), the increase of Bax/Bcl-2 ratio, caspase-9/3 activation, and poly(ADP-ribose) polymerase (PARP) degradation, as well as intracellular ROS production. PAP-3 also induced up-regulation of p53, and cell cycle arrest at the S phase. The incubation of MCF-7 cells with antioxidant superoxide dismutase (SOD) and N-acetylcysteine (NAC) significantly attenuated the ROS generation and apoptosis caused by PAP-3, indicating that intracellular ROS plays a pivotal role in cell death.<br><br>CONCLUSIONS/SIGNIFICANCE: These findings suggest that the polysaccharides, especially acidic PAP-3, are very important nutritional ingredients responsible for, at least in part, the anticancer health benefits of P. abalonus via ROS-mediated mitochondrial apoptotic pathway. It is a major breakthrough bringing new insight of the potential use of the polysaccharides as health-care food or medicine to provide significant natural defense against human cancer.}, }
@article {pmid23685237, year = {2013}, author = {Deng, X and Zhang, F and Rui, W and Long, F and Wang, L and Feng, Z and Chen, D and Ding, W}, title = {PM2.5-induced oxidative stress triggers autophagy in human lung epithelial A549 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {27}, number = {6}, pages = {1762-1770}, doi = {10.1016/j.tiv.2013.05.004}, pmid = {23685237}, issn = {1879-3177}, mesh = {Air Pollutants/*toxicity ; Autophagy ; Catalase/metabolism ; Cell Line, Tumor ; Epithelial Cells/drug effects/metabolism ; Humans ; L-Lactate Dehydrogenase/metabolism ; Lung/cytology ; Oxidative Stress ; Particulate Matter/*toxicity ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Exposure to higher levels of air pollution particulate matter (PM) with an aerodynamic diameter of less than 2.5 μm (PM2.5) links with an increased risk of cardiovascular and respiratory deaths and hospital admission as well as lung cancer. Although the mechanism underlying the correlation between PM2.5 exposure and adverse effects has not fully elucidated, PM2.5-induced oxidative stress has been considered as an important molecular mechanism of PM2.5-mediated toxicity. In this work, human lung epithelial A549 cells were used to further investigate the biological effects of PM2.5 on autophagy. The cell viability showed both time- and concentration-dependent decrease when exposure to PM2.5, which can be attributed to increase of the levels of extracellular lactate dehydrogenase (LDH) release and intracellular reactive oxygen species (ROS) generation in A549 cells. Moreover, PM2.5-induced oxidative damage in A549 cells was observed through the alteration of superoxide dismutase (SOD) and catalase (CAT) activities compared to the unexposed control cells. PM2.5-induced autophagy was indicated by an increase in microtubule-associated protein light chain-3 (LC3) puncta, and accumulation of LC3 in both time- and concentration-dependent manner. PM2.5-induced mRNA expression of autophagy-related protein Atg5 and Beclin1 was also observed compared with those of the unexposed control cells. These results suggest the possibility that PM2.5-induced oxidative stress probably plays a key role in autophagy in A549 cells, which may contribute to PM2.5-induced impairment of pulmonary function.}, }
@article {pmid23685081, year = {2013}, author = {Chuang, HC and Jones, T and Chen, TT and BéruBé, K}, title = {Cytotoxic effects of incense particles in relation to oxidative stress, the cell cycle and F-actin assembly.}, journal = {Toxicology letters}, volume = {220}, number = {3}, pages = {229-237}, doi = {10.1016/j.toxlet.2013.05.004}, pmid = {23685081}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Actin Cytoskeleton/*metabolism/ultrastructure ; Apoptosis/drug effects/physiology ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Cell Survival/physiology ; Epithelial Cells/drug effects/pathology ; Humans ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Oxidative Stress/*drug effects ; Particulate Matter/*toxicity ; Reactive Oxygen Species/metabolism ; Respiratory Tract Diseases/*chemically induced/metabolism ; }, abstract = {Epidemiological studies have suggested that combustion-derived smoke, such as that produced during incense burning, is a deleterious air pollutant. It is capable of initiating oxidative stress and mutation; however, the related apoptotic processes remain unclear. In order to elucidate the biological mechanisms of reactive oxygen species (ROS)-induced respiratory toxicology, alveolar epithelial A549 cells were exposed to incense particulate matter (PM), with and without antioxidant N-acetyl-l-cysteine (NAC). The cross-linking associations between oxidative capacity, cell cycle events, actin cytoskeletal dynamics and intracellular calcium signals were investigated. An incense PM suspension caused significant oxidative stress in A549 cells, as shown by inhibition of the cell cycle at G1 and G2/M check-points, and the induction of apoptosis at Sub-G1. At the same time, alterations in the F-actin filamentous assemblies were observed. The levels of intracellular Ca(2+) were increased after incense PM exposure. Antioxidant NAC treatment revealed that oxidative stress and F-actin remodelling was significantly mitigated. This suggests that ROS accumulation could alter cell cycle regulation and anomalous remodelling of the cortical cytoskeleton that allowed impaired cells to enter into apoptosis. This study has elucidated the integral patho-physiological interactions of incense PM and the potential mechanisms for the development of ROS-driven respiratory impairment.}, }
@article {pmid23683568, year = {2013}, author = {Chousterman, BG and Bouadma, L and Moutereau, S and Loric, S and Alvarez-Gonzalez, A and Mekontso-Dessap, A and Laissy, JP and Rahmouni, A and Katsahian, S and Brochard, L and Schortgen, F}, title = {Prevention of contrast-induced nephropathy by N-acetylcysteine in critically ill patients: different definitions, different results.}, journal = {Journal of critical care}, volume = {28}, number = {5}, pages = {701-709}, doi = {10.1016/j.jcrc.2013.03.007}, pmid = {23683568}, issn = {1557-8615}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Contrast Media/*adverse effects ; Creatinine/blood ; *Critical Illness ; Cystatin C/blood ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Iohexol/*adverse effects ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Kidney Function Tests ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; }, abstract = {PURPOSE: The use of N-acetylcysteine (NAC) for preventing contrast induced nephropathy (CIN) is debated in the intensive care unit. NAC may alter the concentration of serum creatinine and interfere with CIN diagnosis. The effectiveness of NAC was evaluated with a special attention on its specific effect on creatinine levels compared to cystatin C.<br><br>METHODS: In a first period, we prospectively enrolled patients receiving saline and low osmolality contrast media for 140 exams in 2 intensive care units with opposite policies regarding the use of NAC. Renal impairment was defined by both the classical CIN and the "sensitive" Acute Kidney Injury Network (AKIN) (taking creatinine and diuresis) definitions. In a second period, we compared the evolution of serum creatinine and cystatin C after 23 additional contrast examinations under NAC.<br><br>RESULTS: Seventy exams with and without NAC were compared in the first period. Risk factors for CIN were similar in the two intensive care unit populations. No difference in CIN incidence was found with and without NAC, using the CIN (10/70 vs 15/70) or the AKIN (24/70 vs 22/70) definition. Interestingly, NAC seemed to reduce renal impairment when the creatinine criterion of the AKIN definition was considered alone [9% vs 21%, P=.033]. Overall, the incidence of renal impairment was 18%, 33% and 15% using the CIN definition, the AKIN, or using AKIN with creatinine alone. Serum creatinine significantly decreased after exams with NAC while cystatin C remained stable.<br><br>CONCLUSION: The incidence of CIN does not seem to be influenced by NAC, except if small changes in creatinine only are considered.}, }
@article {pmid23670941, year = {2013}, author = {Takahashi, K and Miyokawa-Gorin, K and Handa, K and Kitahara, A and Moriya, R and Onuma, H and Sumitani, Y and Tanaka, T and Katsuta, H and Nishida, S and Yoshimoto, K and Ohno, H and Ishida, H}, title = {Endogenous oxidative stress, but not ER stress, induces hypoxia-independent VEGF120 release through PI3K-dependent pathways in 3T3-L1 adipocytes.}, journal = {Obesity (Silver Spring, Md.)}, volume = {21}, number = {8}, pages = {1625-1634}, doi = {10.1002/oby.20206}, pmid = {23670941}, issn = {1930-739X}, mesh = {3T3-L1 Cells ; Acetylcysteine/pharmacology ; Adipocytes/cytology/metabolism ; Animals ; Cell Hypoxia ; Chemokine CCL2/metabolism ; Chromones/pharmacology ; Endoplasmic Reticulum Stress/*physiology ; Imidazoles/pharmacology ; Mice ; Morpholines/pharmacology ; Oxidative Stress/*physiology ; Palmitates/metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Pyridines/pharmacology ; Signal Transduction ; Vascular Endothelial Growth Factor A/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {OBJECTIVE: Expressions of vascular endothelial growth factor (VEGF) are increased in obese adipocytes and is secreted from obese adipose tissue through hypoxia-independent pathways. Therefore, we investigated the hypoxia-independent mechanism underlying increased expression and release of VEGF in obese adipocytes.<br><br>DESIGN AND METHODS: We compared signal transduction pathways regulating VEGF with those regulating monocyte chemoattractant protein-1 (MCP-1), which is increased in obese adipocytes, in an in vitro model of artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate, without the influence of hypoxia.<br><br>RESULTS: Palmitate-preloaded cells exhibited significantly enhanced oxidative stress (P < 0.01) and showed increased VEGF120 and MCP-1 release (P < 0.01, respectively), while endoplasmic reticulum (ER) stress was not induced. Increased VEGF120 release was significantly decreased with PI3K inhibitor LY294002 (P < 0.01). In addition, antioxidant N-acetyl-cysteine (NAC) markedly diminished not only VEGF120 secretion (P < 0.01) but also augmented Akt phosphorylation on Ser473 (P < 0.01). In contrast, increased MCP-1 release was suppressed with JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580 (P < 0.01).<br><br>CONCLUSIONS: VEGF120 release from hypertrophied adipocytes can be enhanced through PI3K pathways activated by oxidative stress but not by ER stress, suggesting that VEGF120 secretion is regulated through oxidative stress-dependent pathways distinct from those involved in MCP-1 release through either JNK or p38 MAPK activation.}, }
@article {pmid23669236, year = {2013}, author = {Novaes, R and Freire-de-Lima, CG and de Albuquerque, RC and Affonso-Mitidieri, OR and Espindola, O and Lima, MA and de Andrada Serpa, MJ and Echevarria-Lima, J}, title = {Modulation of glutathione intracellular levels alters the spontaneous proliferation of lymphocyte from HTLV-1 infected patients.}, journal = {Immunobiology}, volume = {218}, number = {9}, pages = {1166-1174}, doi = {10.1016/j.imbio.2013.04.002}, pmid = {23669236}, issn = {1878-3279}, mesh = {Acetylcysteine/metabolism ; Adult ; Aged ; CD8-Positive T-Lymphocytes/*immunology/virology ; Carrier State/*immunology ; Cell Proliferation ; Cells, Cultured ; Female ; Gene Expression Regulation/immunology ; Glutathione/*metabolism ; HTLV-I Infections/*immunology ; Human T-lymphotropic virus 1/*immunology ; Humans ; Intracellular Space/metabolism ; Lymphocyte Activation ; Male ; Methionine Sulfoximine/analogs &amp; derivatives/metabolism ; Middle Aged ; Multidrug Resistance-Associated Proteins/metabolism ; Young Adult ; }, abstract = {The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus associated with neoplasias and inflammatory diseases, such as adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-infected individuals present a spontaneous T lymphocyte proliferation. This phenomenon is related to the HTLV-1-proviral load and the persistence of the infection. Viral proteins induce many cellular mediators, which can be associated with the abnormal cellular proliferation. The intracellular levels of glutathione (GSH) are important to modulate the cellular proliferation. The aim of this study was to investigate the correlation between the modulation of intracellular GSH levels and the spontaneous lymphocyte proliferation during the HTLV-1 infection. Intracellular GSH level can be modulated by using dl-buthionine-[S,R]-sulfoximine (BSO, GSH synthesis inhibitor) and N-acetylcysteine (NAC, peptide precursor). Our results demonstrated that BSO was capable of inducing a decrease in the spontaneous proliferation of PBMC derived from HTLV-1 carriers. On the other hand, the GSH precursor induces an increase in mitogen-stimulated cellular proliferation in infected and uninfected individuals. Similar results were observed by the inhibition of ABCC1/MRP1 protein, augmenting the mitogen-induced proliferation. This effect can be related with an increase in the GSH levels since ABCC1/MRP1 transports GSH to the extracellular medium. There was a significant difference on the expression of CD69 and CD25 molecules during the lymphocyte activation. We did not observe any alterations on CD25 expression induced by BSO or NAC. However, our results demonstrated that NAC treatment induced an increase in CD69 expression on unstimulated CD8(+) T lymphocytes obtained from HTLV-1 infected individuals, healthy donors and HTLV carriers. Therefore, our results suggest that the cellular proliferation promoted by the infection with HTLV-1 and the activation phenotype of CD8(+) T lymphocytes can be regulated by changing the intracellular GSH levels; suggesting the modulation of these intracellular levels as a new approach for the treatment of pathologies associated with the HTLV-1 infection.}, }
@article {pmid23666527, year = {2013}, author = {Fu, R and Wassif, CA and Yanjanin, NM and Watkins-Chow, DE and Baxter, LL and Incao, A and Liscum, L and Sidhu, R and Firnkes, S and Graham, M and Ory, DS and Porter, FD and Pavan, WJ}, title = {Efficacy of N-acetylcysteine in phenotypic suppression of mouse models of Niemann-Pick disease, type C1.}, journal = {Human molecular genetics}, volume = {22}, number = {17}, pages = {3508-3523}, pmid = {23666527}, issn = {1460-2083}, support = {//Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/*therapeutic use ; Adolescent ; Adult ; Animals ; Child ; Child, Preschool ; Cross-Over Studies ; Disease Models, Animal ; Double-Blind Method ; Female ; Gene Expression ; Humans ; Liver/metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Niemann-Pick Disease, Type C/*drug therapy/*genetics/metabolism/physiopathology ; Oxidative Stress/*drug effects/genetics ; Ubiquinone/analogs &amp; derivatives/metabolism ; Young Adult ; }, abstract = {Niemann-Pick disease, type C1 (NPC1), which arises from a mutation in the NPC1 gene, is characterized by abnormal cellular storage and transport of cholesterol and other lipids that leads to hepatic disease and progressive neurological impairment. Oxidative stress has been hypothesized to contribute to the NPC1 disease pathological cascade. To determine whether treatments reducing oxidative stress could alleviate NPC1 disease phenotypes, the in vivo effects of the antioxidant N-acetylcysteine (NAC) on two mouse models for NPC1 disease were studied. NAC was able to partially suppress phenotypes in both antisense-induced (NPC1ASO) and germline (Npc1-/-) knockout genetic mouse models, confirming the presence of an oxidative stress-related mechanism in progression of NPC1 phenotypes and suggesting NAC as a potential molecule for treatment. Gene expression analyses of NAC-treated NPC1ASO mice suggested NAC affects pathways distinct from those initially altered by Npc1 knockdown, data consistent with NAC achieving partial disease phenotype suppression. In a therapeutic trial of short-term NAC administration to NPC1 patients, no significant effects on oxidative stress in these patients were identified other than moderate improvement of the fraction of reduced CoQ10, suggesting limited efficacy of NAC monotherapy. However, the mouse model data suggest that the distinct antioxidant effects of NAC could provide potential treatment of NPC1 disease, possibly in concert with other therapeutic molecules at earlier stages of disease progression. These data also validated the NPC1ASO mouse as an efficient model for candidate NPC1 drug screening, and demonstrated similarities in hepatic phenotypes and genome-wide transcript expression patterns between the NPC1ASO and Npc1-/- models.}, }
@article {pmid23665428, year = {2013}, author = {Capone, C and Cervelli, M and Angelucci, E and Colasanti, M and Macone, A and Mariottini, P and Persichini, T}, title = {A role for spermine oxidase as a mediator of reactive oxygen species production in HIV-Tat-induced neuronal toxicity.}, journal = {Free radical biology &amp; medicine}, volume = {63}, number = {}, pages = {99-107}, doi = {10.1016/j.freeradbiomed.2013.05.007}, pmid = {23665428}, issn = {1873-4596}, mesh = {AIDS Dementia Complex/*metabolism/pathology/virology ; Cell Line ; HIV Infections/*metabolism/pathology/virology ; HIV-1/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism/pathology ; *Oxidative Stress ; Oxidoreductases Acting on CH-NH Group Donors/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Spermine/metabolism ; tat Gene Products, Human Immunodeficiency Virus/genetics/metabolism ; Polyamine Oxidase ; }, abstract = {Chronic oxidative stress, which occurs in brain tissues of HIV-infected patients, is involved in the pathogenesis of HIV-associated dementia. Oxidative stress can be induced by HIV-1-secreted proteins, either directly or indirectly through the release of cytotoxic factors. In particular, HIV-1 Tat is able to induce neuronal death by interacting with and activating the polyamine-sensitive subtype of the NMDA receptor (NMDAR). Here, we focused on the role of polyamine catabolism in Tat-induced oxidative stress in human neuroblastoma (SH-SY5Y) cells. First, Tat was found to induce reactive oxygen species production and to affect cell viability in SH-SY5Y cells, these effects being mediated by spermine oxidase (SMO). Second, Tat was observed to increase SMO activity as well as decreasing the intracellular spermine levels. Third, Tat-induced SMO activation was completely prevented by the NMDAR antagonist MK-801, clearly indicating an involvement of NMDAR stimulation. Finally, pretreatment of cells with N-acetylcysteine, a scavenger of H2O2, and with MK-801 was able to completely inhibit reactive oxygen species formation and to restore cell viability. Altogether, these data strongly suggest a role for polyamine catabolism-derived H2O2 in neurotoxicity as elicited by Tat-stimulated NMDAR.}, }
@article {pmid23665395, year = {2013}, author = {Smeyne, M and Smeyne, RJ}, title = {Glutathione metabolism and Parkinson's disease.}, journal = {Free radical biology &amp; medicine}, volume = {62}, number = {}, pages = {13-25}, pmid = {23665395}, issn = {1873-4596}, support = {R01 NS070825/NS/NINDS NIH HHS/United States ; }, mesh = {Antioxidants/metabolism ; Dopamine/*metabolism ; Dopaminergic Neurons ; Glutathione/*metabolism ; Humans ; Mitochondria/enzymology/metabolism ; *Oxidative Stress ; Parkinson Disease/enzymology/*metabolism/physiopathology ; Substantia Nigra/enzymology ; }, abstract = {It has been established that oxidative stress, defined as the condition in which the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson disease. Glutathione is a ubiquitous thiol tripeptide that acts alone or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals, and peroxynitrites. In this review, we examine the synthesis, metabolism, and functional interactions of glutathione and discuss how these relate to the protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson disease.}, }
@article {pmid23661569, year = {2014}, author = {You, BR and Park, WH}, title = {Zebularine inhibits the growth of A549 lung cancer cells via cell cycle arrest and apoptosis.}, journal = {Molecular carcinogenesis}, volume = {53}, number = {11}, pages = {847-857}, doi = {10.1002/mc.22042}, pmid = {23661569}, issn = {1098-2744}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/biosynthesis ; Caspase 8/biosynthesis ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytidine/*analogs &amp; derivatives/pharmacology ; DNA Modification Methylases/antagonists &amp; inhibitors ; Down-Regulation ; Fibroblasts/drug effects/metabolism ; G1 Phase Cell Cycle Checkpoints/drug effects ; Glutathione/analysis/metabolism ; Humans ; Lung Neoplasms/metabolism/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; RNA Interference ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; S Phase Cell Cycle Checkpoints/drug effects ; Thioredoxin Reductase 1/*biosynthesis/genetics ; Tumor Suppressor Protein p53/biosynthesis ; }, abstract = {Zebularine (Zeb) is a DNA methyltransferase (DNMT) inhibitor to that has an anti-tumor effect. Here, we evaluated the anti-growth effect of Zeb on A549 lung cancer cells in relation to reactive oxygen species (ROS) levels. Zeb inhibited the growth of A549 cells with an IC50 of approximately 70 µM at 72 h. Cell cycle analysis indicated that Zeb induced an S phase arrest in A549 cells. Zeb also induced A549 cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; ΔΨm), Bcl-2 decrease, Bax increase, p53 increase and activation of caspase-3 and -8. In contrast, Zeb mildly inhibited the growth of human pulmonary fibroblast (HPF) normal cells and lead to a G1 phase arrest. Zeb did not induce apoptosis in HPF cells. In relation to ROS level, Zeb increased ROS level in A549 cells and induced glutathione (GSH) depletion. The well-known antioxidant, N-acetyl cysteine (NAC) prevented the death of Zeb-treated A549 cells. Moreover, Zeb increased the level of thioredoxin reductase 1 (TrxR1) in A549 cells. While the overexpression of TrxR1 attenuated death and ROS level in Zeb-treated A549 cells, the downregulation of TrxR1 intensified death and ROS level in these cells. In conclusion, Zeb inhibited the growth of A549 lung cancer cells via cell cycle arrest and apoptosis. The inhibition was influenced by ROS and TrxR1 levels.}, }
@article {pmid23660531, year = {2013}, author = {Kolesnik, B and Palten, K and Schrammel, A and Stessel, H and Schmidt, K and Mayer, B and Gorren, AC}, title = {Efficient nitrosation of glutathione by nitric oxide.}, journal = {Free radical biology &amp; medicine}, volume = {63}, number = {}, pages = {51-64}, pmid = {23660531}, issn = {1873-4596}, support = {P 20669/FWF_/Austrian Science Fund FWF/Austria ; P 21693/FWF_/Austrian Science Fund FWF/Austria ; P 23135/FWF_/Austrian Science Fund FWF/Austria ; P 24005/FWF_/Austrian Science Fund FWF/Austria ; }, mesh = {Aerobiosis ; Glutathione/*metabolism ; Humans ; Nitric Oxide/*metabolism ; Nitric Oxide Donors/metabolism ; Nitrosation ; Nitroso Compounds/metabolism ; Oxygen/*metabolism ; S-Nitrosoglutathione/metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {Nitrosothiols are increasingly regarded as important participants in a range of physiological processes, yet little is known about their biological generation. Nitrosothiols can be formed from the corresponding thiols by nitric oxide in a reaction that requires the presence of oxygen and is mediated by reactive intermediates (NO2 or N2O3) formed in the course of NO autoxidation. Because the autoxidation of NO is second order in NO, it is extremely slow at submicromolar NO concentrations, casting doubt on its physiological relevance. In this paper we present evidence that at submicromolar NO concentrations the aerobic nitrosation of glutathione does not involve NO autoxidation but a reaction that is first order in NO. We show that this reaction produces nitrosoglutathione efficiently in a reaction that is strongly stimulated by physiological concentrations of Mg(2+). These observations suggest that direct aerobic nitrosation may represent a physiologically relevant pathway of nitrosothiol formation.}, }
@article {pmid23660503, year = {2013}, author = {Forsyth, CB and Voigt, RM and Shaikh, M and Tang, Y and Cederbaum, AI and Turek, FW and Keshavarzian, A}, title = {Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {305}, number = {2}, pages = {G185-95}, pmid = {23660503}, issn = {1522-1547}, support = {R01 AA020216/AA/NIAAA NIH HHS/United States ; R21 AA018729/AA/NIAAA NIH HHS/United States ; AA020216/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; CLOCK Proteins/genetics/*metabolism ; Caco-2 Cells ; Cytochrome P-450 CYP2E1/genetics/*metabolism ; Ethanol/*toxicity ; Gene Expression Regulation/drug effects ; Humans ; Intestinal Mucosa/metabolism ; Intestines/*drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Period Circadian Proteins/genetics/*metabolism ; Permeability ; RNA, Messenger/genetics/metabolism ; }, abstract = {We have shown that alcohol increases Caco-2 intestinal epithelial cell monolayer permeability in vitro by inducing the expression of redox-sensitive circadian clock proteins CLOCK and PER2 and that these proteins are necessary for alcohol-induced hyperpermeability. We hypothesized that alcohol metabolism by intestinal Cytochrome P450 isoform 2E1 (CYP2E1) could alter circadian gene expression (Clock and Per2), resulting in alcohol-induced hyperpermeability. In vitro Caco-2 intestinal epithelial cells were exposed to alcohol, and CYP2E1 protein, activity, and mRNA were measured. CYP2E1 expression was knocked down via siRNA and alcohol-induced hyperpermeability, and CLOCK and PER2 protein expression were measured. Caco-2 cells were also treated with alcohol or H2O2 with or without N-acetylcysteine (NAC) anti-oxidant, and CLOCK and PER2 proteins were measured at 4 or 2 h. In vivo Cyp2e1 protein and mRNA were also measured in colon tissue from alcohol-fed mice. Alcohol increased CYP2E1 protein by 93% and enzyme activity by 69% in intestinal cells in vitro. Alcohol feeding also increased mouse colonic Cyp2e1 protein by 73%. mRNA levels of Cyp2e1 were not changed by alcohol in vitro or in mouse intestine. siRNA knockdown of CYP2E1 in Caco-2 cells prevented alcohol-induced hyperpermeability and induction of CLOCK and PER2 proteins. Alcohol-induced and H2O2-induced increases in intestinal cell CLOCK and PER2 were significantly inhibited by treatment with NAC. We concluded that our data support a novel role for intestinal CYP2E1 in alcohol-induced intestinal hyperpermeability via a mechanism involving CYP2E1-dependent induction of oxidative stress and upregulation of circadian clock proteins CLOCK and PER2.}, }
@article {pmid23660180, year = {2013}, author = {Weisbord, SD and Gallagher, M and Kaufman, J and Cass, A and Parikh, CR and Chertow, GM and Shunk, KA and McCullough, PA and Fine, MJ and Mor, MK and Lew, RA and Huang, GD and Conner, TA and Brophy, MT and Lee, J and Soliva, S and Palevsky, PM}, title = {Prevention of contrast-induced AKI: a review of published trials and the design of the prevention of serious adverse events following angiography (PRESERVE) trial.}, journal = {Clinical journal of the American Society of Nephrology : CJASN}, volume = {8}, number = {9}, pages = {1618-1631}, pmid = {23660180}, issn = {1555-905X}, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Administration, Intravenous ; Angiography/adverse effects ; Contrast Media/*adverse effects ; Free Radical Scavengers/therapeutic use ; Humans ; Randomized Controlled Trials as Topic/*standards ; Research Design/*standards ; Sodium Bicarbonate/therapeutic use ; }, abstract = {Contrast-induced AKI (CI-AKI) is a common condition associated with serious, adverse outcomes. CI-AKI may be preventable because its risk factors are well characterized and the timing of renal insult is commonly known in advance. Intravenous (IV) fluids and N-acetylcysteine (NAC) are two of the most widely studied preventive measures for CI-AKI. Despite a multitude of clinical trials and meta-analyses, the most effective type of IV fluid (sodium bicarbonate versus sodium chloride) and the benefit of NAC remain unclear. Careful review of published trials of these interventions reveals design limitations that contributed to their inconclusive findings. Such design limitations include the enrollment of small numbers of patients, increasing the risk for type I and type II statistical errors; the use of surrogate primary endpoints defined by small increments in serum creatinine, which are associated with, but not necessarily causally related to serious, adverse, patient-centered outcomes; and the inclusion of low-risk patients with intact baseline kidney function, yielding low event rates and reduced generalizability to a higher-risk population. The Prevention of Serious Adverse Events following Angiography (PRESERVE) trial is a randomized, double-blind, multicenter trial that will enroll 8680 high-risk patients undergoing coronary or noncoronary angiography to compare the effectiveness of IV isotonic sodium bicarbonate versus IV isotonic sodium chloride and oral NAC versus oral placebo for the prevention of serious, adverse outcomes associated with CI-AKI. This article discusses key methodological issues of past trials investigating IV fluids and NAC and how they informed the design of the PRESERVE trial.}, }
@article {pmid23658858, year = {2013}, author = {Meinerz, DF and Comparsi, B and Allebrandt, J and Mariano, DO and Dos Santos, DB and Zemolin, AP and Farina, M and Dafre, LA and Rocha, JB and Posser, T and Franco, JL}, title = {Sub-acute administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate induces toxicity and oxidative stress in mice: unexpected effects of N-acetylcysteine.}, journal = {SpringerPlus}, volume = {2}, number = {1}, pages = {182}, pmid = {23658858}, issn = {2193-1801}, abstract = {The organic tellurium compound (S)-dimethyl 2-(3-(phenyltellanyl) propanamide) succinate (TeAsp) exhibits thiol-peroxidase activity that could potentially offer protection against oxidative stress. However, data from the literature show that tellurium is a toxic agent to rodents. In order to mitigate such toxicity, N-acetylcysteine (NAC) was administered in parallel with TeAsp during 10 days. Mice were separated into four groups receiving daily injections of (A) vehicle (PBS 2.5 ml/kg, i.p. and DMSO 1 ml/kg, s.c.), (B) NAC (100 mg/kg, i.p. and DMSO s.c.), (C) PBS i.p. and TeAsp (92.5 μmol/kg, s.c), or (D) NAC plus TeAsp. TeAsp treatment started on the fourth day. Vehicle or NAC-treated animals showed an increase in body weight whereas TeAsp caused a significant reduction. Contrary to expected, NAC co-administration potentiated the toxic effect of TeAsp, causing a decrease in body weight. Vehicle, NAC or TeAsp did not affect the exploratory and motor activity in the open-field test at the end of the treatment, while the combination of NAC and TeAsp produced a significant decrease in these parameters. No DNA damage or alterations in cell viability were observed in leukocytes of treated animals. Treatments produced no or minor effects on the activities of antioxidant enzymes catalase, glutathione peroxidase and glutathione reductase, whereas the activity of the thioredoxin reductase was decreased in the brain and increased the liver of the animals in the groups receiving TeAsp or TeAsp plus NAC. In conclusion, the toxicity of TeAsp was potentiated by NAC and oxidative stress appears to play a central role in this process.}, }
@article {pmid23651231, year = {2013}, author = {Ghanizadeh, A and Derakhshan, N and Berk, M}, title = {N-acetylcysteine versus placebo for treating nail biting, a double blind randomized placebo controlled clinical trial.}, journal = {Anti-inflammatory &amp; anti-allergy agents in medicinal chemistry}, volume = {12}, number = {3}, pages = {223-228}, doi = {10.2174/1871523011312030003}, pmid = {23651231}, issn = {1875-614X}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Adolescent ; Child ; Chronic Disease ; Comorbidity ; Double-Blind Method ; Female ; Humans ; Male ; Nail Biting/*therapy ; }, abstract = {Nail biting is a common behavioral problem. While there are established behavioral interventions for management, they are of modest efficacy, and there is minimal evidence for effective pharmacotherapy. This study investigated the role of N-acetylcysteine (NAC) a potent glutathione and glutamate modulator for the treatment of pathological nail biting in children and adolescents. This pilot randomized, double-blind, placebo-controlled clinical trial of NAC (800 mg/day) or placebo enrolled 42 children and adolescents with chronic nail biting. Nail length was the objective outcome. Evaluations were carried out three times; before treatment, one month after enrollment in the study, and two months after enrollment. The duration (chronicity) of nail biting in the NAC and placebo groups was 3.63(2.45) and 5.09(3.74) years (P=0.14). The mean nail length gradually increased in both the NAC and placebo groups during this trial. There was a statistically significant difference between the two groups regarding increased nail length after the first month of trial [(5.21(5.75) and 1.18(3.02) millimeters], however no difference after two months was observed. Two patients in the NAC group discontinued medication due to adverse events. One patient experienced headache, agitation, and social withdrawal, and another patient expressed severe aggression after taking medication and was withdrawn from the study. This study supports the hypothesis that NAC decreases nail biting behavior in children and adolescents over the short term. NAC is relatively well tolerated and severe adverse effects are rare. However, there was a high rate of dropout. Further studies with longer durations that build on these preliminary data are recommended. This study is registered at the Iranian Registry of Clinical Trials (Irct registration number: IRCT201103023930N3).}, }
@article {pmid23650193, year = {2013}, author = {Zacharis, CK and Tzanavaras, PD and Vlessidis, AG}, title = {Determination of rimantadine in human urine by HPLC using a monolithic stationary phase and on-line post-column derivatization.}, journal = {Journal of separation science}, volume = {36}, number = {11}, pages = {1720-1725}, doi = {10.1002/jssc.201300106}, pmid = {23650193}, issn = {1615-9314}, mesh = {Automation/instrumentation/*methods ; Chromatography, High Pressure Liquid/instrumentation/*methods ; Healthy Volunteers ; Humans ; Rimantadine/*urine ; Sensitivity and Specificity ; }, abstract = {In the present study, we propose the first HPLC method coupled to postcolumn derivatization for the determination of rimantadine in human urine samples. The analyte and amantadine (internal standard) were isocratically separated using an RP monolithic stationary phase (100 × 4.6 mm id) with a mobile phase consisting of CH3OH/phosphate buffer (25 mmol/L, pH 3.0) at a volume ratio of 50:50. Postcolumn derivatization involved on-line reaction with o-phthalaldehyde (20 mmol/L) and N-acetyl-cysteine (5 mmol/L) at alkaline medium (100 mmol/L borate pH 11.0). Spectrofluorimetric detection at λ(ex)/λ(em) = 340/455 nm enabled the selective and sensitive determination of rimantadine in urine samples at a range of 50-500 ng/mL with an LOD of 5 ng/mL. Human urine samples were analyzed successfully after SPE using hydrophilic-lipophilic balanced RP cartridges (30 mg/mL, Oasis HLB). Recoveries ranged between 89.7 and 102.7%.}, }
@article {pmid23649480, year = {2013}, author = {Xia, WF and Jung, JU and Shun, C and Xiong, S and Xiong, L and Shi, XM and Mei, L and Xiong, WC}, title = {Swedish mutant APP suppresses osteoblast differentiation and causes osteoporotic deficit, which are ameliorated by N-acetyl-L-cysteine.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {28}, number = {10}, pages = {2122-2135}, pmid = {23649480}, issn = {1523-4681}, support = {I01 BX000838/BX/BLRD VA/United States ; R01 AG051773/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Acid Phosphatase/metabolism ; Adipogenesis/drug effects ; Aging/pathology ; Amyloid beta-Peptides/*metabolism ; Animals ; Animals, Newborn ; Bone Resorption/complications/drug therapy/metabolism/pathology ; Bone and Bones/drug effects/metabolism/pathology ; *Cell Differentiation/drug effects ; Cell Lineage/drug effects ; Cells, Cultured ; Cricetinae ; Humans ; Isoenzymes/metabolism ; Mesenchymal Stem Cells/drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation/*genetics ; Organ Size/drug effects ; Osteoblasts/drug effects/metabolism/*pathology ; Osteogenesis/drug effects ; Osteoporosis/complications/*drug therapy/metabolism/*pathology ; Tartrate-Resistant Acid Phosphatase ; }, abstract = {Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer's disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein (APP) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the APP gene identified in early-onset AD patients are believed to cause AD. But little is known about APP's role in bone remodeling. Here, we present evidence for Swedish mutant APP (APPswe) in suppression of OB differentiation and function in culture and in mouse. APP expression in BMSCs increases during aging. Ubiquitous expression of APPswe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal "aging-like" deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of APPswe in mature OB-lineage cells in TgAPPswe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for APPswe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in TgAPPswe-Ocn mice, implying that APPswe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC), an antioxidant, suggesting that reactive oxygen species (ROS) may underlie APPswe-induced osteoporotic deficits. Taken together, these results demonstrate a role for APPswe in suppressing OB differentiation and bone formation, implicate APPswe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits. © 2013 American Society for Bone and Mineral Research.}, }
@article {pmid23648861, year = {2013}, author = {Chang, KH and Jeong, YT and Kwak, CY and Choi, O and Kim, JH}, title = {Effect of mild-thiol reducing agents and alpha2,3-sialyltransferase expression on secretion and sialylation of recombinant EPO in CHO cells.}, journal = {Journal of microbiology and biotechnology}, volume = {23}, number = {5}, pages = {699-706}, doi = {10.4014/jmb.1303.03046}, pmid = {23648861}, issn = {1738-8872}, mesh = {Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Erythropoietin/genetics/*metabolism ; *Gene Expression ; Glycolates/metabolism ; Humans ; Protein Transport ; Recombinant Proteins/genetics/metabolism ; Reducing Agents/*metabolism ; Secretory Pathway ; Sialyltransferases/*genetics/*metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {We have previously reported that N-acetylcysteine (NAC) not only delayed apoptosis but also enhanced the production of recombinant erythropoietin (EPO) in Chinese hamster ovary (CHO) cell culture. To investigate the production enhancement mechanism, the effects of similar thiolreducing agents were studied. Intriguingly, all mild reducing agents examined including mercaptoethanesulfonic acid (MESNA), thiolactic acid (TLA), and thioglycolate (TG) were shown to block apoptosis and increase EPO production. A pulse-chase study of EPO secretion revealed that all four thiol-reducing agents increased the EPO secretion rate; among them TLA showed the highest rate. In terms of product quality, the sialic acid content of the glycoprotein is one of the most important factors. It was reported that a number of glycoproteins produced by CHO cells often have incomplete sialylation, particularly under high-producing conditions. Human alpha2,3-sialyltransferase (alpha2,3-ST) was introduced into EPO-producing CHO cells in order to compensate for the reduced sialylation during supplementation with NAC. When alpha2,3-ST was expressed in the presence of NAC, reduced sialylation was restored and an even more sialylated EPO was produced. Thus, our study is significant in that it offers increased EPO production while still allowing the prevention of decreased sialylation of EPO.}, }
@article {pmid23647723, year = {2013}, author = {Schloss, JM and Colosimo, M and Airey, C and Masci, PP and Linnane, AW and Vitetta, L}, title = {Nutraceuticals and chemotherapy induced peripheral neuropathy (CIPN): a systematic review.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {32}, number = {6}, pages = {888-893}, doi = {10.1016/j.clnu.2013.04.007}, pmid = {23647723}, issn = {1532-1983}, mesh = {Acetylcarnitine/therapeutic use ; Acetylcysteine/therapeutic use ; Antineoplastic Agents/*adverse effects ; *Dietary Supplements ; Fatty Acids, Omega-3/therapeutic use ; Glutamine/therapeutic use ; Glutathione/therapeutic use ; Humans ; Peripheral Nervous System Diseases/chemically induced/*therapy ; Randomized Controlled Trials as Topic ; Thioctic Acid/therapeutic use ; Trace Elements/therapeutic use ; Vitamins/therapeutic use ; }, abstract = {Chemotherapy induced peripheral neuropathy [CIPN] is a common significant and debilitating side effect resulting from the administration of neurotoxic chemotherapeutic agents. These pharmaco-chemotherapeutics can include taxanes, vinca alkaloids and others. Moderate to severe CIPN significantly decreases the quality of life and physical abilities of cancer patients and current pharmacotherapy for CIPN e.g. Amifostine and antidepressants have had limited efficacy and may themselves induce adverse side effects. To determine the potential use of nutraceuticals i.e. vitamin E, acetyl-L-carnitine, glutamine, glutathione, vitamin B6, omega-3 fatty acids, magnesium, calcium, alpha lipoic acid and n-acetyl cysteine as adjuvants in cancer treatments a systematic literature review was conducted. Revised clinical studies comprised of randomized clinical trials that investigated the anti-CIPN effect of nutraceuticals as the adjuvant intervention in patients administered chemotherapy. Twenty-four studies were assessed on methodological quality and limitations identified. Studies were mixed in their recommendations for nutraceuticals. Currently no agent has shown solid beneficial evidence to be recommended for the treatment or prophylaxis of CIPN. The standard of care for CIPN includes dose reduction and/or discontinuation of chemotherapy treatment. The management of CIPN remains an important challenge and future studies are warranted before recommendations for the use of supplements can be made.}, }
@article {pmid23646509, year = {2013}, author = {Chang, S and Chen, D and Kang, B and Dai, Y}, title = {UV-enhanced cytotoxicity of CdTe quantum dots in PANC-1 cells depend on their size distribution and surface modification.}, journal = {Journal of nanoscience and nanotechnology}, volume = {13}, number = {2}, pages = {751-754}, doi = {10.1166/jnn.2013.6085}, pmid = {23646509}, issn = {1533-4880}, mesh = {Cadmium Compounds/*pharmacology ; Cell Line, Tumor ; Cell Survival/*drug effects/radiation effects ; Humans ; *Quantum Dots ; Tellurium/*pharmacology ; *Ultraviolet Rays ; }, abstract = {The cytotoxicity of quantum dots (QDs) under normal conditions has received more and more attention, but their cytotoxicity under light illumination has not been fully investigated. In this study, different sized CdTe QDs coated with mercaptopropionic acid (MPA) and N-acetylcysteine (NAC) were employed to investigate the influences of size distribution and surface modification on their UV-enhanced cytotoxicity and mechanism. The results indicated that different sized MPA-CdTe QDs exhibited distinct cytotoxicity under UV illumination and the smaller-sized QDs presented more obviously damages to cells than the larger-sized QDs. Comparing with MPA-CdTe QDs, NAC-CdTe QDs had better cellular metabolizability and lower cytotoxicity. The generation of reactive oxygen species (ROS) were also investigated. The results revealed that ROS in cells containing MPA-CdTe QD538 were about 1.7 times of NAC-CdTe QD538 under UV illumination. ROS might play an important role in the UV-enhanced cytotoxicity of QDs. By selecting appropriate surface modifications and particle sizes, the cytotoxicity of QDs under UV illumination could be controlled.}, }
@article {pmid23644946, year = {2014}, author = {Shen, H and Li, M and Wang, B and Lai, IK and Robertson, LW and Ludewig, G}, title = {Dietary antioxidants (selenium and N-acetylcysteine) modulate paraoxonase 1 (PON1) in PCB 126-exposed rats.}, journal = {Environmental science and pollution research international}, volume = {21}, number = {10}, pages = {6384-6399}, pmid = {23644946}, issn = {1614-7499}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; ES 013661/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; Antioxidants/metabolism ; Aryldialkylphosphatase/*metabolism ; Cytochrome P-450 CYP1A1/metabolism ; Diet/statistics &amp; numerical data ; Environmental Pollutants/*toxicity ; Glutathione/metabolism ; Liver/metabolism ; Male ; Oxidation-Reduction ; Oxidative Stress ; Polychlorinated Biphenyls/*toxicity ; Rats ; Rats, Sprague-Dawley ; Receptors, Aryl Hydrocarbon/metabolism ; Selenium/*metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Environmental pollutants polychlorinated biphenyls (PCBs), especially dioxin-like PCBs, cause oxidative stress and associated toxic effects, including cancer and possibly atherosclerosis. We previously reported that PCB 126, the most potent dioxin-like PCB congener, not only decreases antioxidants such as hepatic selenium (Se), Se-dependent glutathione peroxidase, and glutathione (GSH) but also increases levels of the antiatherosclerosis enzyme paraoxonase 1 (PON1) in liver and serum. To probe the interconnection of these three antioxidant systems, Se, GSH, and PON1, we examined the influence of varying levels of dietary Se and N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS) and precursor for GSH synthesis, on PON1 in the absence and presence of PCB 126 exposure. Male Sprague-Dawley rats, fed diets with differing Se levels (0.02, 0.2, or 2 ppm) or NAC (1%), were treated with a single intraperitoneal injection of corn oil or various doses of PCB 126 and euthanized 2 weeks later. PCB 126 significantly increased liver PON1 mRNA, protein level and activity, and serum PON1 activity in all dietary groups but did not consistently increase thiobarbituric acid levels (thiobarbituric acid reactive substances, TBARS), an indicator of lipid oxidation and oxidative stress, in liver or serum. Inadequate (high or low) dietary Se decreased baseline and PCB 126-induced aryl hydrocarbon receptor (AhR) expression but further increased PCB 126-induced cytochrome P450 1A1 (CYP1A1) expression, the enzyme believed to be the cause for PCB 126-induced oxidative stress. In addition, a significant inverse relationship was observed not only between dietary Se levels and PON1 mRNA and PON1 activity but also with TBARS levels in the liver, suggesting significant antioxidant protection from dietary Se. NAC lowered serum baseline TBARS levels in controls and increased serum PON1 activity but lowered liver PON1 activities in animals treated with 1 μmol/kg PCB 126, suggesting antioxidant activity by NAC primarily in serum. These results also show an unexpected predominantly inverse relationship between Se or NAC and PON1 during control and PCB 126 exposure conditions. These interactions should be further explored in the development of dietary protection regimens.}, }
@article {pmid23643711, year = {2013}, author = {Barbosa, MR and Sampaio, IH and Teodoro, BG and Sousa, TA and Zoppi, CC and Queiroz, AL and Passos, MA and Alberici, LC and Teixeira, FR and Manfiolli, AO and Batista, TM and Cappelli, AP and Reis, RI and Frasson, D and Kettelhut, IC and Parreiras-e-Silva, LT and Costa-Neto, CM and Carneiro, EM and Curi, R and Silveira, LR}, title = {Hydrogen peroxide production regulates the mitochondrial function in insulin resistant muscle cells: effect of catalase overexpression.}, journal = {Biochimica et biophysica acta}, volume = {1832}, number = {10}, pages = {1591-1604}, doi = {10.1016/j.bbadis.2013.04.029}, pmid = {23643711}, issn = {0006-3002}, mesh = {Animals ; Antioxidants/metabolism ; Catalase/*metabolism ; Cells, Cultured ; Hydrogen Peroxide/*metabolism ; *Insulin Resistance ; Male ; Mitochondria, Muscle/enzymology/*physiology ; Muscle, Skeletal/cytology/enzymology/metabolism ; Oxygen Consumption ; Palmitic Acid/pharmacology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Wistar ; }, abstract = {The mitochondrial redox state plays a central role in the link between mitochondrial overloading and insulin resistance. However, the mechanism by which the ROS induce insulin resistance in skeletal muscle cells is not completely understood. We examined the association between mitochondrial function and H2O2 production in insulin resistant cells. Our hypothesis is that the low mitochondrial oxygen consumption leads to elevated ROS production by a mechanism associated with reduced PGC1α transcription and low content of phosphorylated CREB. The cells were transfected with either the encoded sequence for catalase overexpression or the specific siRNA for catalase inhibition. After transfection, myotubes were incubated with palmitic acid (500μM) and the insulin response, as well as mitochondrial function and fatty acid metabolism, was determined. The low mitochondrial oxygen consumption led to elevated ROS production by a mechanism associated with β-oxidation of fatty acids. Rotenone was observed to reduce the ratio of ROS production. The elevated H2O2 production markedly decreased the PGC1α transcription, an effect that was accompanied by a reduced phosphorylation of Akt and CREB. The catalase transfection prevented the reduction in the phosphorylated level of Akt and upregulated the levels of phosphorylated CREB. The mitochondrial function was elevated and H2O2 production reduced, thus increasing the insulin sensitivity. The catalase overexpression improved mitochondrial respiration protecting the cells from fatty acid-induced, insulin resistance. This effect indicates that control of hydrogen peroxide production regulates the mitochondrial respiration preventing the insulin resistance in skeletal muscle cells by a mechanism associated with CREB phosphorylation and β-oxidation of fatty acids.}, }
@article {pmid23642281, year = {2013}, author = {Leite, B and Gomes, F and Teixeira, P and Souza, C and Pizzolitto, E and Oliveira, R}, title = {Combined effect of linezolid and N-acetylcysteine against Staphylococcus epidermidis biofilms.}, journal = {Enfermedades infecciosas y microbiologia clinica}, volume = {31}, number = {10}, pages = {655-659}, doi = {10.1016/j.eimc.2012.11.011}, pmid = {23642281}, issn = {1578-1852}, mesh = {Acetamides/*pharmacology ; Acetylcysteine/*pharmacology ; Anti-Infective Agents/*pharmacology ; Biofilms/*drug effects ; Drug Therapy, Combination ; Humans ; Linezolid ; Microbial Sensitivity Tests ; Oxazolidinones/*pharmacology ; Staphylococcus epidermidis/*drug effects ; }, abstract = {INTRODUCTION: Staphylococcus epidermidis is an organism commonly associated with infections caused by biofilms. Biofilms are less sensible to antibiotics and therefore are more difficult to eradicate. Linezolid and N-acetylcysteine (NAC), have demonstrated to be active against gram-positive microorganisms. Therefore and since linezolid and NAC have different modes of action, the main objective of this work was to investigate the single and synergistic effect of linezolid and NAC against S. epidermidis biofilms.<br><br>METHODS: This work reports the in vitro effect of linezolid and NAC against S. epidermidis biofilms, treated with MIC (4mgml(-1)) and 10&#xd7;MIC of NAC, and MIC (1&#x3bc;gml(-1)) and peak serum concentration (PS=18&#x3bc;gml(-1)) of linezolid alone and in combination. After exposure of S. epidermidis biofilms to linezolid and/or NAC for 24h, several biofilm parameters were evaluated, namely the number of cultivable cells [colony forming unit (CFU) enumeration], total biofilm biomass and cellular activity.<br><br>RESULTS: When tested alone, NAC at 10&#xd7;MIC was the most effective agent against S. epidermidis biofilms. However, the combination linezolid (MIC)+NAC (10&#xd7;MIC) showed a synergistic effect and was the most biocidal treatment tested, promoting a 5log reduction in the number of biofilm viable cells.<br><br>CONCLUSION: This combination seems to be a potential candidate to combat infections caused by S. epidermidis biofilms, namely as a catheter lock solution therapy.}, }
@article {pmid23640483, year = {2013}, author = {Vatsyayan, R and Kothari, H and Pendurthi, UR and Rao, LV}, title = {4-Hydroxy-2-nonenal enhances tissue factor activity in human monocytic cells via p38 mitogen-activated protein kinase activation-dependent phosphatidylserine exposure.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {33}, number = {7}, pages = {1601-1611}, pmid = {23640483}, issn = {1524-4636}, support = {R01 HL058869/HL/NHLBI NIH HHS/United States ; R01 HL107483/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aldehydes/*pharmacology ; Antioxidants/pharmacology ; Blood Coagulation/drug effects ; Cell Line, Tumor ; Cell-Derived Microparticles/drug effects/metabolism ; Cytokines/pharmacology ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects/metabolism ; Enzyme Activation ; Factor Xa/metabolism ; Fibroblasts/drug effects/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Lipopolysaccharides/pharmacology ; Monocytes/*drug effects/enzymology/immunology ; Oxidative Stress/drug effects ; Phosphatidylserines/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Thrombin/metabolism ; Thromboplastin/*metabolism ; Time Factors ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {OBJECTIVE: 4-hydroxy-2-nonenal (HNE) is one of the major aldehydes formed during lipid peroxidation and is believed to play a role in the pathogenesis of atherosclerosis. The objective of the present study is to investigate the effect of HNE on tissue factor (TF) procoagulant activity expressed on cell surfaces.<br><br>APPROACH AND RESULTS: TF activity and antigen levels on intact cells were measured using factor Xa generation and TF monoclonal antibody binding assays, respectively. Exposure of phosphatidylserine on the cell surface was analyzed using thrombin generation assay or by binding of a fluorescent dye-conjugated annexin V. 2',7'-dichlorodihydrofluorescein diacetate was used to detect the generation of reactive oxygen species. Our data showed that HNE increased the procoagulant activity of unperturbed THP-1 cells that express traces of TF antigen, but had no effect on unperturbed endothelial cells that express no measurable TF antigen. HNE increased TF procoagulant activity but not TF antigen of both activated monocytic and endothelial cells. HNE treatment generated reactive oxygen species, activated p38 mitogen-activated protein kinase, and increased the exposure of phosphatidylserine at the outer leaflet in THP-1 cells. Treatment of THP-1 cells with an antioxidant, N-acetyl cysteine, suppressed the above HNE-induced responses and negated the HNE-mediated increase in TF activity. Blockade of p38 mitogen-activated protein kinase activation inhibited HNE-induced phosphatidylserine exposure and increased TF activity.<br><br>CONCLUSIONS: HNE increases TF coagulant activity in monocytic cells through a novel mechanism involving p38 mitogen-activated protein kinase activation that leads to enhanced phosphatidylserine exposure at the cell surface.}, }
@article {pmid23640046, year = {2013}, author = {Pramanik, KC and Kudugunti, SK and Fofaria, NM and Moridani, MY and Srivastava, SK}, title = {Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway.}, journal = {Carcinogenesis}, volume = {34}, number = {9}, pages = {2061-2070}, pmid = {23640046}, issn = {1460-2180}, support = {R01 CA106953/CA/NCI NIH HHS/United States ; R01 CA129038/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Caffeic Acids/administration &amp; dosage ; Gene Expression Regulation, Neoplastic/drug effects ; Heterografts ; Humans ; Melanoma/*drug therapy/pathology ; Mice ; Oncogene Protein v-akt/antagonists &amp; inhibitors/*metabolism ; Phenylethyl Alcohol/administration &amp; dosage/analogs &amp; derivatives ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation/drug effects ; Signal Transduction/drug effects ; Skin Neoplasms/*drug therapy/pathology ; X-Linked Inhibitor of Apoptosis Protein/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE treatment decreased the interaction of AKT with XIAP. To establish the involvement of AKT in the apoptosis-inducing effects of CAPE, cells were transfected with AKT. Our results revealed that AKT overexpression attenuated the decrease in XIAP and significantly blocked CAPE-mediated apoptosis. Similarly, overexpression of XIAP further decreased CAPE-induced apoptosis. Taken together, our results suggest that CAPE suppresses phosphoinositide 3-kinase/AKT/XIAP pathway leading to apoptosis in melanoma tumor cells in vitro and in vivo.}, }
@article {pmid23630952, year = {2013}, author = {Zurita, E and Moreno, G and Errea, A and Ormazabal, M and Rumbo, M and Hozbor, D}, title = {The stimulated innate resistance event in Bordetella pertussis infection is dependent on reactive oxygen species production.}, journal = {Infection and immunity}, volume = {81}, number = {7}, pages = {2371-2378}, pmid = {23630952}, issn = {1098-5522}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Bacterial Load ; Bordetella Infections/*immunology/microbiology ; Bordetella pertussis/drug effects/immunology/*pathogenicity ; Guanidines/pharmacology ; *Immunity, Innate ; Lipopolysaccharides/immunology/pharmacology ; Lung/immunology/microbiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C3H ; Nitric Oxide Synthase/antagonists &amp; inhibitors/metabolism ; Nitrites/metabolism ; Reactive Oxygen Species/*immunology ; Time Factors ; Toll-Like Receptor 4/immunology ; }, abstract = {The exacerbated induction of innate immune responses in airways can abrogate diverse lung infections by a phenomenon known as stimulated innate resistance (StIR). We recently demonstrated that the enhancement of innate response activation can efficiently impair Bordetella pertussis colonization in a Toll-like receptor 4 (TLR4)-dependent manner. The aim of this work was to further characterize the effect of lipopolysaccharide (LPS) on StIR and to identify the mechanisms that mediate this process. Our results showed that bacterial infection was completely abrogated in treated mice when the LPS of B. pertussis (1 μg) was added before (48 h or 24 h), after (24 h), or simultaneously with the B. pertussis challenge (10(7) CFU). Moreover, we detected that LPS completely cleared bacterial infection as soon as 2 h posttreatment. This timing suggests that the observed StIR phenomenon should be mediated by fast-acting antimicrobial mechanisms. Although neutrophil recruitment was already evident at this time point, depletion assays using an anti-GR1 antibody showed that B. pertussis clearance was achieved even in the absence of neutrophils. To evaluate the possible role of free radicals in StIR, we performed animal assays using the antioxidant N-acetyl cysteine (NAC), which is known to inactivate oxidant species. NAC administration blocked the B. pertussis clearance induced by LPS. Nitrite concentrations were also increased in the LPS-treated mice; however, the inhibition of nitric oxide synthetases did not suppress the LPS-induced bacterial clearance. Taken together, our results show that reactive oxygen species (ROS) play an essential role in the TLR4-dependent innate clearance of B. pertussis.}, }
@article {pmid23627353, year = {2012}, author = {Xueqing, H and Chenqi, Z and Xijin, D and Huabing, C and Cui, H and Tay, F}, title = {Potential implication of N-acetylcysteine detoxification on adhesive endodontics.}, journal = {Compendium of continuing education in dentistry (Jamesburg, N.J. : 1995)}, volume = {33}, number = {4}, pages = {e55-61}, pmid = {23627353}, issn = {1548-8578}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Cell Cycle ; Cell Proliferation/drug effects ; Cell Survival ; Composite Resins/*toxicity ; Dental Cements/*toxicity ; Dentin-Bonding Agents/*toxicity ; Fibroblasts/*drug effects ; In Vitro Techniques ; Methacrylates/*toxicity ; Polymethacrylic Acids/*toxicity ; Polystyrenes ; }, abstract = {Methacrylate resin-based dentin adhesives and root canal sealers used for bonding of filling materials inside the root canal system are cytotoxic and result in reduction in cell proliferation to a variable extent. An in vitro study to examine the detoxifying effects of N-acetylcysteine (NAC) on four commercial adhesive systems on adhesive-induced cytotoxicity and cell survival was conducted so that the use of methacrylate resin-based materials for filling root canals could be optimized. The finding that NAC co-treatment protected the cells from adhesive-induced toxicity by increasing cellular proliferation, attenuating cell cycle arrest, and reducing cell death suggests the null hypothesis that NAC has no effect on dentin adhesive-induced cell death and cell cycle arrest should be rejected.}, }
@article {pmid23625176, year = {2013}, author = {Paszti-Gere, E and Jakus, J}, title = {Protein phosphatases but not reactive oxygen species play functional role in acute amphetamine-mediated dopamine release.}, journal = {Cell biochemistry and biophysics}, volume = {66}, number = {3}, pages = {831-841}, doi = {10.1007/s12013-013-9608-6}, pmid = {23625176}, issn = {1559-0283}, mesh = {Amphetamine/*pharmacology ; Animals ; Cantharidin/pharmacology ; Dopamine/*metabolism ; Fluorescent Dyes/chemistry ; Hydrogen Peroxide/metabolism ; Neostriatum/drug effects/metabolism ; Oxazines/chemistry ; Oxidative Stress/drug effects ; PC12 Cells ; Phosphoprotein Phosphatases/antagonists &amp; inhibitors/*metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {Drug abuse-induced neurodegeneration can be triggered by elevated production of reactive oxygen species (ROS). Involvement of oxidative stress in acute amphetamine (AMPH)-mediated dopamine (DA) release, however, has not been completely understood yet. In order to elucidate the dopaminergic response of PC12 cells to a single dose of 10 μM AMPH, ROS production was measured as related to the extracellular DA level. Due to the spontaneous oxidation of peroxide-sensitive fluorophore 2',7'-dichlorofluorescin diacetate (DCFH-DA) to 2',7'-dichlorofluorescein (DCF), the increase in fluorescence could not be unambiguously attributed to AMPH-triggered ROS production. Based on Amplex Red fluorescence, no ROS production was detected after acute AMPH application. Our data strongly suggest that ROS development was not the main triggering factor for immediate DA release after acute AMPH treatment. On the other hand, AMPH-induced elevation of DA levels in rat brain striatal slices was quenched by the water soluble antioxidant, N-acetylcysteine (NAC) at 10 mM. In this study, we also investigated the contribution of protein phosphatases to the AMPH-induced rat brain striatal dopaminergic response. The experimental protocol, double AMPH challenge was applied for screening the effect of NAC and cantharidin on AMPH-mediated DA release. Here we show that AMPH-mediated DA release increased nearly twofold in striatal rat brain slices pretreated for 30 min with 1000 μM cantharidin, a selective PP1 and PP2A inhibitor. These findings prove the lack of ROS inhibitory action on protein phosphatase activity in acute AMPH-mediated DA efflux.}, }
@article {pmid23624663, year = {2013}, author = {Cermik, H and Taslipinar, MY and Aydin, I and Agilli, M and Aydin, FN and Ucar, F and Alp, BF and Toygar, M and Ozkan, E and Altayli, E and Cayci, T}, title = {The relationship between N-acetylcysteine, hyperbaric oxygen, and inflammation in a rat model of acetaminophen-induced nephrotoxicity.}, journal = {Inflammation}, volume = {36}, number = {5}, pages = {1145-1152}, pmid = {23624663}, issn = {1573-2576}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*therapeutic use ; Acute Kidney Injury/chemically induced/*drug therapy/*therapy ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Creatinine/blood ; Free Radical Scavengers/therapeutic use ; *Hyperbaric Oxygenation ; Inflammation/drug therapy/therapy ; Interleukin-6/blood ; Male ; Neopterin/blood ; Oxygen/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/blood ; Urea/blood ; }, abstract = {An overdose of acetaminophen (APAP) produces acute tubular necrosis. The aim of this study was to observe the effects of hyperbaric oxygen (HBO) only and combined with N-acetylcysteine (NAC) on inflammatory cytokines in kidney. Thirty-two male Sprague-Dawley rats were divided into four groups: sham, control (APAP), NAC, and NAC + HBO. In the APAP, NAC, and NAC + HBO groups, renal injury was induced by oral administration of 1 g/kg APAP. The NAC group received NAC (100 mg/kg/day). NAC + HBO group received NAC (100 mg/kg/day) intraperitoneally and HBO underwent at 2.8 ATA pressure with 100 % oxygen inhalation for 90 min every 12 h for 5 days. Rats in the sham group received distilled water only by gastric tube. All animals were killed on 6 days after APAP or distilled water administration. Creatinine, urea, neopterin, tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 levels were measured in sera. There was a significant increase in serum creatinine and urea levels in the control group compared to the sham group (in both, p = 0.001). NAC and NAC + HBO significantly decreased serum neopterin, TNF-α, and IL-6 levels compared to control group. APAP administration caused tubular necrosis in the renal. NAC and NAC + HBO treatments significantly reduced APAP-induced renal damage. The results of this study showed that renal dysfunction in APAP toxicity was attenuated by the use of HBO and NAC treatments. The combination of NAC and HBO treatments might be recommended as an effective treatment modality for APAP-induced nephrotoxicity.}, }
@article {pmid23624261, year = {2013}, author = {Jesse, HE and Nye, TL and McLean, S and Green, J and Mann, BE and Poole, RK}, title = {Cytochrome bd-I in Escherichia coli is less sensitive than cytochromes bd-II or bo'' to inhibition by the carbon monoxide-releasing molecule, CORM-3: N-acetylcysteine reduces CO-RM uptake and inhibition of respiration.}, journal = {Biochimica et biophysica acta}, volume = {1834}, number = {9}, pages = {1693-1703}, pmid = {23624261}, issn = {0006-3002}, support = {BB/H016805/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/1004122/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/H016805/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Carbon Monoxide/*metabolism ; Cell Membrane/drug effects/metabolism ; Cell Respiration/*drug effects ; Cytochrome b Group ; Cytochromes/*antagonists &amp; inhibitors/metabolism ; Electron Transport Chain Complex Proteins/*antagonists &amp; inhibitors/metabolism ; Escherichia coli/*metabolism ; Escherichia coli Proteins/*antagonists &amp; inhibitors/metabolism ; Heme/metabolism ; Hyperbaric Oxygenation ; Leghemoglobin/metabolism ; Organometallic Compounds/*pharmacology ; Oxidoreductases/*antagonists &amp; inhibitors/metabolism ; Oxygen Consumption/*drug effects ; Ruthenium/pharmacology ; }, abstract = {BACKGROUND: CO-releasing molecules (CO-RMs) are potential therapeutic agents, able to deliver CO - a critical gasotransmitter - in biological environments. CO-RMs are also effective antimicrobial agents; although the mechanisms of action are poorly defined, haem-containing terminal oxidases are primary targets. Nevertheless, it is clear from several studies that the effects of CO-RMs on biological systems are frequently not adequately explained by the release of CO: CO-RMs are generally more potent inhibitors than is CO gas and other effects of the molecules are evident.<br><br>METHODS: Because sensitivity to CO-RMs cannot be predicted by sensitivity to CO gas, we assess the differential susceptibilities of strains, each expressing only one of the three terminal oxidases of E. coli - cytochrome bd-I, cytochrome bd-II and cytochrome bo', to inhibition by CORM-3. We present the first sensitive measurement of the oxygen affinity of cytochrome bd-II (Km 0.24&#x3bc;M) employing globin deoxygenation. Finally, we investigate the way(s) in which thiol compounds abolish the inhibitory effects of CORM-2 and CORM-3 on respiration, growth and viability, a phenomenon that is well documented, but poorly understood.<br><br>RESULTS: We show that a strain expressing cytochrome bd-I as the sole oxidase is least susceptible to inhibition by CORM-3 in its growth and respiration of both intact cells and membranes. Growth studies show that cytochrome bd-II has similar CORM-3 sensitivity to cytochrome bo'. Cytochromes bo' and bd-II also have considerably lower affinities for oxygen than bd-I. We show that the ability of N-acetylcysteine to abrogate the toxic effects of CO-RMs is not attributable to its antioxidant effects, or prevention of CO targeting to the oxidases, but may be largely due to the inhibition of CO-RM uptake by bacterial cells.<br><br>CONCLUSIONS: A strain expressing cytochrome bd-I as the sole terminal oxidase is least susceptible to inhibition by CORM-3. N-acetylcysteine is a potent inhibitor of CO-RM uptake by E. coli.<br><br>GENERAL SIGNIFICANCE: Rational design and exploitation of CO-RMs require a fundamental understanding of their activity. CO and CO-RMs have multifaceted effects on mammalian and microbial cells; here we show that the quinol oxidases of E. coli are differentially sensitive to CORM-3. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.}, }
@article {pmid23624001, year = {2013}, author = {Robinson, SM and Mann, J and Vasilaki, A and Mathers, J and Burt, AD and Oakley, F and White, SA and Mann, DA}, title = {Pathogenesis of FOLFOX induced sinusoidal obstruction syndrome in a murine chemotherapy model.}, journal = {Journal of hepatology}, volume = {59}, number = {2}, pages = {318-326}, pmid = {23624001}, issn = {1600-0641}, support = {NC/K000748/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; WT084961MA/WT_/Wellcome Trust/United Kingdom ; G0900535/MRC_/Medical Research Council/United Kingdom ; WT087961MA/WT_/Wellcome Trust/United Kingdom ; WT090974MA/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Antineoplastic Combined Chemotherapy Protocols/*toxicity ; Antioxidants/administration &amp; dosage ; Cell Cycle ; Colorectal Neoplasms/drug therapy ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; Cytokines/genetics/metabolism ; Disease Models, Animal ; Fluorouracil/toxicity ; Hepatic Veno-Occlusive Disease/*chemically induced/metabolism/pathology ; Humans ; Inflammation Mediators/metabolism ; Leucovorin/toxicity ; Liver Cirrhosis/chemically induced ; Liver Neoplasms/drug therapy/secondary/surgery ; Mice ; Mice, Inbred C57BL ; Neovascularization, Pathologic/chemically induced ; Organoplatinum Compounds/*toxicity ; Oxaliplatin ; Oxidative Stress ; Serpin E2/genetics/metabolism ; Thrombosis/chemically induced ; }, abstract = {BACKGROUND &amp; AIMS: Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy can have a significant impact on post-operative outcome following resection of colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described. The aim of this project was to establish a rodent model which could be utilised to investigate mechanisms underlying SOS to aid the development of therapeutic strategies.<br><br>METHODS: C57Bl/6 mice, maintained on a purified diet, were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Sections of the liver and spleen were fixed in formalin and paraffin embedded for histological analysis. The role of oxidative stress on experimental-induced SOS was determined by dietary supplementation with butylated hydroxyanisole and N-acetylcysteine.<br><br>RESULTS: FOLFOX treatment was associated with the development of sinusoidal dilatation and hepatocyte atrophy on H&amp;E stained sections of the liver in keeping with SOS. Immunohistochemistry for p21 demonstrated the presence of replicative senescence within the sinusoidal endothelium. FOLFOX induced endothelial damage leads to a pro-thrombotic state within the liver associated with upregulation of PAI-1 (p<0.001), vWF (p<0.01) and Factor X (p<0.001), which may contribute to the propagation of liver injury. Dietary supplementation with the antioxidant BHA prevented the development of significant SOS.<br><br>CONCLUSIONS: We have developed the first reproducible model of chemotherapy induced SOS that reflects the pathogenesis of this disease in patients. It appears that the use of antioxidants alongside oxaliplatin based chemotherapy may be of value in preventing the development of SOS in patients with colorectal liver metastases.}, }
@article {pmid23623839, year = {2013}, author = {Lee, YJ and Lee, DM and Lee, SH}, title = {Production of Cyr61 protein is modulated by extracellular acidification and PI3K/Akt signaling in prostate carcinoma PC-3 cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {58}, number = {}, pages = {169-176}, doi = {10.1016/j.fct.2013.04.035}, pmid = {23623839}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Acids/*metabolism ; Apoptosis ; Cell Line, Tumor ; Cysteine-Rich Protein 61/*biosynthesis/genetics ; Gene Silencing ; Humans ; Male ; Phosphatidylinositol 3-Kinases/*metabolism ; Prostatic Neoplasms/*metabolism/pathology ; Proto-Oncogene Proteins c-akt/*metabolism ; *Signal Transduction ; Up-Regulation ; }, abstract = {High expression of Cyr61, an extracellular cysteine-rich heparin-binding protein, has been associated with a malignant cell phenotype and poor outcome in prostate cancers. Although Cyr61 was found by us to be overproduced in androgen-independent PC-3 cells treated with N-acetylcysteine (NAC), its significance is still unclear. We therefore aimed to determine how and why Cyr61 protein is overexpressed in NAC-treated cells. Here, we found that Cyr61 protein level markedly increased in cells treated with NAC at high cell seeding density. Silencing of Cyr61 by siRNA induced enhanced activity of caspase-3/7, upregulation of the proapototic Bok, BimL and BimS, cleavage of apoptosis hallmarkers such as Bax, PARP and caspase-3, and downregulation of antiapoptotic Bcl2, Bcl-xL and Mcl-1 proteins. NAC treatment caused a reduction of extracellular medium pH to acidic and an increase in Akt phosphorylation, after which the replacement with NAC-free medium returned them to control levels within 24h. Acid stimulation increased the levels of Cyr61 and p-Akt proteins, whereas it suppressed the induction of proapoptotic and antiapoptotic proteins. Overall, our data indicate that PC-3 cells overproduce Cyr61 protein via activation of the PI3K/Akt signaling as a part of the survival mechanisms under the conditions causing extracellular acidity and further cytotoxicity.}, }
@article {pmid23623538, year = {2013}, author = {Kim, JK and Park, J and Ryu, TH and Nili, M}, title = {Effect of N-acetyl-l-cysteine on Saccharomyces cerevisiae irradiated with gamma-rays.}, journal = {Chemosphere}, volume = {92}, number = {5}, pages = {512-516}, doi = {10.1016/j.chemosphere.2013.02.035}, pmid = {23623538}, issn = {1879-1298}, mesh = {Acetylcysteine/*metabolism ; Antioxidants/metabolism ; Gamma Rays ; Gene Expression Regulation, Fungal/radiation effects ; Glutathione/metabolism ; Glutathione Peroxidase/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae/enzymology/genetics/*metabolism/*radiation effects ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {Ionizing radiation (IR) induces DNA strand breaks (DSBs), base damage, inhibition of protein activity, apoptosis by reactive oxygen species (ROS). Detoxification or removal of generated ROS can reduce oxidative damage. Antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase are immediately triggered for ROS scavenging. N-acetyl-l-cysteine (NAC) having a thiol, a precursor for reduced glutathione (GSH), is known as one of the antioxidants. In this study, the effect of NAC as an antioxidant and a radioprotector was investigated on survival rate, transcriptional level of antioxidant enzymes gene, and protein level including SOD activity and intracellular GSH in yeast Saccharomyces cerevisiae W303-1A strain mutated YBP1 gene irradiated with gamma-rays. NAC did not protect the gamma-ray-induced cell death. The gene expression of antioxidant enzymes including SOD1, SOD2, GPX1, and GPX2 was induced by gamma-rays. In contrast, the pretreatment of NAC reduced the expression of these genes. NAC reduced SOD activity and intracellular GSH level in yeast. These data suggest that NAC is able to reduce radiation-induced ROS levels in vivo but does not protect yeast cells against radiation-induced death.}, }
@article {pmid23623166, year = {2013}, author = {Gores-Lindholm, AR and LeBlanc, MM and Causey, R and Hitchborn, A and Fayrer-Hosken, RA and Kruger, M and Vandenplas, ML and Flores, P and Ahlschwede, S}, title = {Relationships between intrauterine infusion of N-acetylcysteine, equine endometrial pathology, neutrophil function, post-breeding therapy, and reproductive performance.}, journal = {Theriogenology}, volume = {80}, number = {3}, pages = {218-227}, doi = {10.1016/j.theriogenology.2013.03.026}, pmid = {23623166}, issn = {1879-3231}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Endometritis/drug therapy/pathology/*veterinary ; Endometrium/*drug effects/pathology ; Female ; Horse Diseases/*drug therapy ; Horses ; Neutrophils/*drug effects/physiology ; Pregnancy ; Reproduction/*drug effects ; }, abstract = {Persistent endometritis in the mare is associated with hypersecretion of mucus by endometrial epithelium and migration of neutrophils into the uterine lumen. This study examines the relationships between N-acetylcysteine (NAC), a mucolytic agent with anti-inflammatory properties, and endometrial architecture, serum neutrophil function, post-breeding therapy, and reproductive performance of NAC-treated mares in a clinical setting. In study 1, endometrial biopsies from mares receiving intrauterine saline (fertile-control, n = 6) or 3.3% NAC (fertile-treatment, n = 6; barren-treatment, n = 10) were evaluated by histology and image analysis. In study 2, phagocytic activity of serum-derived neutrophils was measured after adding 0.5% or 3% NAC. In study 3, pregnancy rates of repeat breeders (n = 44) receiving an intrauterine infusion of 3.3% NAC 24-36 hours before mating (group 1) was recorded, as was first cycle of the season pregnancy rates of reproductively normal mares (group 2, n = 85), and mares treated for bacterial endometritis the cycle before mating (group 3, n = 25). Intrauterine NAC did not adversely affect endometrial histology. Extracellular mucus thickness and staining intensity were reduced in fertile-treatment mares (P < 0.03). Neutrophil function was inhibited by 3% NAC solution, but not by 0.5% NAC (P < 0.05). In study 3, for groups 1, 2, and 3, respectively, the first-cycle pregnancy rates were 77%, 74%, and 56%, and early embryonic death rates were 15%, 13%, and 7%. In group 2 mares treated with uterine lavage and oxytocin post-mating, the pregnancy rate was 89% (39/44), whereas in mares treated with uterine lavage and 1 g ceftiofur, it was 60% (24/40). Of the oxytocin-treated mares, 18% (8/44) had ≥ 1 cm of intrauterine fluid or marked uterine edema, whereas 80% (32/40) of the antibiotic-treated mares did. In conclusion, intrauterine infusion of a 3.3% solution of NAC was not irritating and inhibited the oxidative burst of neutrophils. Repeat breeder mares, with evidence of mucus hypersecretion, but no uterine pathogens, when treated with NAC followed by post-mating uterine lavage and oxytocin (and in some cases intrauterine antibiotics), achieved a pregnancy rate of 77%.}, }
@article {pmid23619020, year = {2013}, author = {Yang, HL and Lin, KY and Juan, YC and Kumar, KJ and Way, TD and Shen, PC and Chen, SC and Hseu, YC}, title = {The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {148}, number = {1}, pages = {254-265}, doi = {10.1016/j.jep.2013.04.023}, pmid = {23619020}, issn = {1872-7573}, mesh = {Antineoplastic Agents/*pharmacology ; *Antrodia ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Complex Mixtures/*pharmacology ; Female ; Humans ; Ovarian Neoplasms ; Reactive Oxygen Species/metabolism ; Receptor, ErbB-2/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Antrodia camphorata (AC) is well known in Taiwan as a traditional Chinese medicinal fungus. However, the anticancer activity of AC against human HER-2/neu-overexpressing ovarian cancers is poorly understood.<br><br>MATERIALS AND METHODS: The aim of this study is to investigate whether a submerged fermentation culture of AC can inhibit human ovarian carcinoma cell (SKOV-3) proliferation by suppressing the HER-2/neu signaling pathway. Cell viability, colony formation, DCFH-DA fluorescence microscopy, western blotting, HER-2/neu immunofluorescence imaging, flow cytometry, and TUNEL assays were carried out to determine the anti-cancer effects of AC.<br><br>RESULTS: MTT and colony formation assays showed that AC induced a dose-dependent reduction in SKOV-3 cell growth. Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC. Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector &#x3b2;-catenin. We also observed that AC caused G2/M arrest mediated by down-regulation of cyclin D1, cyclin A, cyclin B1, and Cdk1 and increased p27 expression. Notably, AC induced apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-9/-3 activation, PARP degradation, and Bcl-2/Bax dysregulation. An increase in intracellular reactive oxygen species (ROS) was observed in AC-treated cells, whereas the antioxidant N-acetylcysteine (NAC) prevented AC-induced cell death, HER-2/neu depletion, PI3K/Akt inactivation, and Bcl-2/Bax dysregulation, indicating that AC-induced cell death was mediated by ROS generation.<br><br>CONCLUSIONS: These results suggest that AC may exert anti-tumor activity against human ovarian carcinoma by suppressing HER-2/neu signaling pathways.}, }
@article {pmid23618697, year = {2013}, author = {Samuni, Y and Goldstein, S and Dean, OM and Berk, M}, title = {The chemistry and biological activities of N-acetylcysteine.}, journal = {Biochimica et biophysica acta}, volume = {1830}, number = {8}, pages = {4117-4129}, doi = {10.1016/j.bbagen.2013.04.016}, pmid = {23618697}, issn = {0006-3002}, mesh = {Acetylcysteine/*chemistry/metabolism/*pharmacology ; Animals ; Apoptosis/drug effects ; Blood-Brain Barrier ; Cell Cycle/drug effects ; Cell Membrane/metabolism ; Humans ; Mental Disorders/drug therapy ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) has been in clinical practice for several decades. It has been used as a mucolytic agent and for the treatment of numerous disorders including paracetamol intoxication, doxorubicin cardiotoxicity, ischemia-reperfusion cardiac injury, acute respiratory distress syndrome, bronchitis, chemotherapy-induced toxicity, HIV/AIDS, heavy metal toxicity and psychiatric disorders.<br><br>SCOPE OF REVIEW: The mechanisms underlying the therapeutic and clinical applications of NAC are complex and still unclear. The present review is focused on the chemistry of NAC and its interactions and functions at the organ, tissue and cellular levels in an attempt to bridge the gap between its recognized biological activities and chemistry.<br><br>MAJOR CONCLUSIONS: The antioxidative activity of NAC as of other thiols can be attributed to its fast reactions with OH, NO2, CO3(-) and thiyl radicals as well as to restitution of impaired targets in vital cellular components. NAC reacts relatively slowly with superoxide, hydrogen-peroxide and peroxynitrite, which cast some doubt on the importance of these reactions under physiological conditions. The uniqueness of NAC is most probably due to efficient reduction of disulfide bonds in proteins thus altering their structures and disrupting their ligand bonding, competition with larger reducing molecules in sterically less accessible spaces, and serving as a precursor of cysteine for GSH synthesis.<br><br>GENERAL SIGNIFICANCE: The outlined reactions only partially explain the diverse biological effects of NAC, and further studies are required for determining its ability to cross the cell membrane and the blood-brain barrier as well as elucidating its reactions with components of cell signaling pathways.}, }
@article {pmid23615707, year = {2014}, author = {van Tonder, JJ and Gulumian, M and Cromarty, AD and Steenkamp, V}, title = {In vitro effect of N-acetylcysteine on hepatocyte injury caused by dichlorodiphenyltrichloroethane and its metabolites.}, journal = {Human &amp; experimental toxicology}, volume = {33}, number = {1}, pages = {41-53}, doi = {10.1177/0960327113482954}, pmid = {23615707}, issn = {1477-0903}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Cell Survival/drug effects ; DDT/agonists/*antagonists &amp; inhibitors/toxicity ; Dichlorodiphenyl Dichloroethylene/agonists/*antagonists &amp; inhibitors/toxicity ; Dichlorodiphenyldichloroethane/agonists/*antagonists &amp; inhibitors/toxicity ; Hep G2 Cells ; Hepatocytes/*drug effects/metabolism ; Humans ; Insecticides/agonists/*antagonists &amp; inhibitors/toxicity ; Kinetics ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Liver/drug effects ; Osmolar Concentration ; Protective Agents/*pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {The organochlorine pesticide, dichlorodiphenyltrichloroethane (DDT), is still used to combat the spread of malaria in several developing countries despite its accumulation and known hepatotoxic effects that have been demonstrated both in vitro and in vivo. N-Acetylcysteine (NAC) is a recognized hepatoprotective agent that has been reported to reduce hepatotoxicity initiated by many different compounds. The aim of this study was to determine whether NAC could counter in vitro hepatocyte injury induced by DDT or its two major metabolites, dichlorodiphenyldichloroethylene and dichlorodiphenyldichloroethane. HepG2 cell cultures were used to assess the following parameters of toxicity: cellular viability, intracellular levels of reactive oxygen species (ROS), mitochondrial membrane potential and initiation of apoptosis. None of the three test compounds induced ROS generation, yet exposure to any of the three compounds produced mitochondrial hyperpolarization, which was countered by NAC pretreatment. All three test compounds also induced apoptotic cell death, which was inhibited by NAC. Despite NAC counteracting some adverse intracellular changes due to organochlorine exposure, it appeared to aggravate the cytotoxic effects of the organochlorine compounds at low test concentrations. As the same outcome may also occur in vivo, results from the present study raise concern about the use of NAC as treatment for DDT-induced hepatotoxicity.}, }
@article {pmid23436661, year = {2013}, author = {Alessandri, N and Lanzi, L and Garante, CM and Tersigni, F and Sergiacomi, R and Petrassi, M and Di Matteo, A and Tufano, F}, title = {Prevention of acute renal failure post-contrast imaging in cardiology: a randomized study.}, journal = {European review for medical and pharmacological sciences}, volume = {17 Suppl 1}, number = {}, pages = {13-21}, pmid = {23436661}, issn = {1128-3602}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/blood/chemically induced/diagnosis/physiopathology/*prevention &amp; control ; Aged ; Biomarkers/blood ; *Cardiology ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Female ; *Fluid Therapy ; Glomerular Filtration Rate/drug effects ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; Retrospective Studies ; Sodium Bicarbonate/*administration &amp; dosage ; Sodium Chloride/*administration &amp; dosage ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: The contrast-induced nephropathy (CIN) is the third most common cause of acute renal failure (ARF) and the worsening in a pre-existing chronic renal failure (CRF), with a foreseeable increase of morbidity, mortality, length of the stay in hospital and, as a consequence, of the health costs. We studied the effectiveness of N-acetylcysteine (NAC) associated with sodium bicarbonate (Na2HCO3) infusion in order to prevent CIN in patients undergoing coronary angiography with administration of contrast medium.<br><br>MATERIALS AND METHODS: 296 patients with indication to perform coronary angiography were included in a randomized, observational study. All patients were randomly assigned to receive pre- and post-contrast hydration with 1500 ml of 0.9% saline solution infusion (Group A) or NAC (1200 mg &#xd7; 2 days) + Na2HCO3 (Group B). The primary end-point was to examine CIN appearance, defined as a raise in serum values of Cr (Creatinine) &#x2265; 0.5 mg/dl or &#x2265; 25% within 24-72 hours after the exposure to the contrast medium.<br><br>RESULTS: It has been observed a frequency of CIN of 9.4% in Gr. A compared to 7.2% in Gr. B. Nevertheless, when we put these results through a more accurate screening according to gender, degree of raise in creatinine levels and the extent of change in GFR (glomerular filtration rate), we observed a very different behaviour. In patients with normal Cr and CrCl (Clearance of Creatinine) the frequency of CIN was similar in both group A and B (approximately 5%). In patients with normal Cr but reduced ClCr the use of NAC was more effective than hydration in preventing CIN (0% vs 18% in prevalence respectively in B and A group). In patients with moderately reduced Cr and CrCl, hydration with saline solution was more effective than NAC + Na2HCO3 (8.6% vs 17.6%) while in patients with severe CRF the combined use of NAC + Na2HCO3 showed off to be very successful in preventing CIN compared to the merely hydration (0% vs 50%).<br><br>CONCLUSIONS: In patients affected by severe CRF who are undergoing investigations with contrast medium administration, such as coronary angiography, the combined use of NAC + Na2HCO3 infusion significantly reduces the risk of developing CIN. In other circumstances the final result is related to the degree of previous GFR or creatinine values alteration or to gender. In such situations the combined use of both substances is more questionable and sometimes ineffective.}, }
@article {pmid23613809, year = {2013}, author = {Li, F and Chen, T and Hu, S and Lin, J and Hu, R and Feng, H}, title = {Superoxide mediates direct current electric field-induced directional migration of glioma cells through the activation of AKT and ERK.}, journal = {PloS one}, volume = {8}, number = {4}, pages = {e61195}, pmid = {23613809}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects/*physiology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Superoxides/antagonists &amp; inhibitors/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Direct current electric fields (DCEFs) can induce directional migration for many cell types through activation of intracellular signaling pathways. However, the mechanisms that bridge extracellular electrical stimulation with intracellular signaling remain largely unknown. In the current study, we found that a DCEF can induce the directional migration of U87, C6 and U251 glioma cells to the cathode and stimulate the production of hydrogen peroxide and superoxide. Subsequent studies demonstrated that the electrotaxis of glioma cells were abolished by the superoxide inhibitor N-acetyl-l-cysteine (NAC) or overexpression of mitochondrial superoxide dismutase (MnSOD), but was not affected by inhibition of hydrogen peroxide through the overexpression of catalase. Furthermore, we found that the presence of NAC, as well as the overexpression of MnSOD, could almost completely abolish the activation of Akt, extracellular-signal-regulated kinase (Erk)1/2, c-Jun N-terminal kinase (JNK), and p38, although only JNK and p38 were affected by overexpression of catalase. The presenting of specific inhibitors can decrease the activation of Erk1/2 or Akt as well as the directional migration of glioma cells. Collectively, our data demonstrate that superoxide may play a critical role in DCEF-induced directional migration of glioma cells through the regulation of Akt and Erk1/2 activation. This study provides novel evidence that the superoxide is at least one of the "bridges" coupling the extracellular electric stimulation to the intracellular signals during DCEF-mediated cell directional migration.}, }
@article {pmid23613694, year = {2013}, author = {Jo, SH and Kim, LS and Kim, SA and Kim, HS and Han, SJ and Park, WJ and Choi, YJ}, title = {Evaluation of Short-Term Use of N-Acetylcysteine as a Strategy for Prevention of Anthracycline-Induced Cardiomyopathy: EPOCH Trial - A Prospective Randomized Study.}, journal = {Korean circulation journal}, volume = {43}, number = {3}, pages = {174-181}, pmid = {23613694}, issn = {1738-5520}, abstract = {BACKGROUND AND OBJECTIVES: We investigate to determine whether N-acetylcysteine (NAC) can prevent anthracycline-induced cardiotoxicity.<br><br>SUBJECTS AND METHODS: A total of 103 patients were enrolled in this prospective randomized open label controlled trial. They are patients first diagnosed with breast cancer or lymphoma, who require chemotherapy, including anthracycline like adriamycine or epirubicine. Patients were randomized to the NAC group {n=50; 1200 mg orally every 8 hours starting before and ending after the intravenous infusion of anthracycline in all chemotherapy cycles (3-6)} or the control group (n=53). Primary outcome was the decrease in left ventricular ejection fraction (LVEF) absolutely &#x2265;10% from the baseline and concomitantly <50% at 6-month. Composite of all-cause death, heart failure and readmission were compared.<br><br>RESULTS: The primary outcome was not significantly different in the NAC and control groups {3/47 (6.4%) vs. 1/52 (1.9%), p=0.343}. The mean LVEF significantly decreased in both the NAC (from 64.5 to 60.8%, p=0.001) and control groups (from 64.1 to 61.3%, p<0.001) after the completion of whole chemotherapy. The mean LVEF change did not differ between the two groups (-3.64% in NAC vs. -2.78% in control group, p=0.502). Left ventricular (LV) end systolic dimension increased with higher trend in NAC by 3.08&#xb1;4.56 mm as compared with 1.47&#xb1;1.83 mm in the control group (p=0.064). LV end diastolic dimension did not change in each group and change does not differ in both. Peak E, A and E/A ratio change and cardiac enzymes were comparable in two groups. Cumulative 12-month event rate was 6% and 3.8% in the NAC group and the control group, respectively, with no difference (p=0.672).<br><br>CONCLUSION: We cannot prove that NAC prevents anthracycline-induced cardiomyopathy.}, }
@article {pmid23607780, year = {2013}, author = {Qu, X and Li, Q and Wang, X and Yang, X and Wang, D}, title = {N-acetylcysteine attenuates cardiopulmonary bypass-induced lung injury in dogs.}, journal = {Journal of cardiothoracic surgery}, volume = {8}, number = {}, pages = {107}, pmid = {23607780}, issn = {1749-8090}, mesh = {Acetylcysteine/*pharmacology ; Acute Lung Injury/*drug therapy/etiology ; Animals ; Cardiopulmonary Bypass/*adverse effects/methods ; Dogs ; Immunohistochemistry ; Lung/metabolism/*pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Transforming Growth Factor beta1/drug effects/*metabolism ; }, abstract = {BACKGROUND: Cardiopulmonary bypass (CPB) is usually associated with inflammatory response that leads to various degrees of organ dysfunction in multiple systems, including lung injury. Our previous study showed that transforming growth factor beta1 (TGFβ1) was involved in CPB-induced lung injury. N-acetylcysteine (NAC) is an antioxidant and is able to prevent CPB-induced pneumocyte apoptosis through scavenging radical. Therefore, we investigated whether NAC may attenuate CPB-induced lung injury by inhibiting TGFβ1 expression.<br><br>METHODS: Fifty-four 18 to 24-month-old mongrel dogs (15-16 kg) were randomly divided into control group, CPB group and NAC group (n&#x2009;=&#x2009;18). Six dogs in each group were killed prior to, as well as 30 and 60 minutes after the operation (T0, T1 and T2). Lung injury was evaluated by hematoxylin and eosin (H&amp;E) staining. Respiratory index (RI), oxygenation index (OI), malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in the lung were determined at each time point. TGF&#x3b2;1 expression was determined using real time RT-PCR and immunohistochemistry.<br><br>RESULTS: A serious lung injury was observed after CPB in dogs. RI and MDA content were increased significantly after CPB, whereas OI and SOD activity were decreased. H&amp;E staining showed that NAC treatment obviously attenuated CPB-induced lung injury. NAC treatment upregulated OI and SOD activity and downregulated RI and MDA content in the lung tissues of dogs after CPB. Treatment with NAC significantly suppressed the TGF&#x3b2;1 expression in the lung tissues at both mRNA and protein levels.<br><br>CONCLUSION: Our results suggest that NAC is a potent agent against CPB-induced acute lung injury through inhibiting TGF&#x3b2;1 expression.}, }
@article {pmid23603059, year = {2013}, author = {Hossain, E and Ota, A and Takahashi, M and Karnan, S and Damdindorj, L and Konishi, Y and Konishi, H and Hosokawa, Y}, title = {Arsenic upregulates the expression of angiotensin II Type I receptor in mouse aortic endothelial cells.}, journal = {Toxicology letters}, volume = {220}, number = {1}, pages = {70-75}, doi = {10.1016/j.toxlet.2013.04.006}, pmid = {23603059}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Aorta/*drug effects/metabolism ; Arsenites/*toxicity ; Cardiovascular Diseases/chemically induced/genetics/metabolism ; Cell Line ; Cell Proliferation/drug effects ; Endothelium, Vascular/*drug effects/metabolism ; Environmental Pollutants/*toxicity ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Mice ; Reactive Oxygen Species/metabolism ; Receptor, Angiotensin, Type 1/*genetics/metabolism ; Sodium Compounds/*toxicity ; Up-Regulation/*drug effects ; }, abstract = {Although chronic arsenic exposure is a well-known risk for cardiovascular disease and has a strong correlation with hypertension, the molecular pathogenesis underlying arsenic exposure-induced hypertension remains poorly understood. To delineate the pathogenesis, we examined changes in the mRNA levels of 2 angiotensin II Type I receptor (AT1R) subtypes, AT1AR and AT1BR, in a mouse aortic endothelial cell line, END-D. Quantitative real-time PCR analysis revealed significant increases in the mRNA levels of 2 AT1R subtypes, AT1AR and AT1BR following sodium arsenite (SA) treatment. Flow cytometry analysis revealed that SA increases the generation of reactive oxygen species (ROS) in a dose-dependent manner. In addition, western blot analysis revealed that SA enhances the phosphorylations of c-Jun N-terminal kinases (JNK) and activated protein 1 (AP-1). These phosphorylations were inhibited by N-acetylcysteine (NAC), an anti-oxidant. Finally, SA-induced AT1R expression was found to be prevented both by NAC and specific JNK inhibitor, SP6001325, strongly indicating that AT1R upregulation is a result of the ROS-mediated activation of the JNK signaling pathway. Taken together, our results indicate that arsenic indeed upregulates the AT1R expression, thus highlighting a role of arsenic-induced aberrant AT1R signaling in the pathogenesis of hypertension.}, }
@article {pmid23603004, year = {2013}, author = {Chen, Y and Nie, YC and Luo, YL and Lin, F and Zheng, YF and Cheng, GH and Wu, H and Zhang, KJ and Su, WW and Shen, JG and Li, PB}, title = {Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {58}, number = {}, pages = {133-140}, doi = {10.1016/j.fct.2013.04.024}, pmid = {23603004}, issn = {1873-6351}, mesh = {Acute Lung Injury/*chemically induced/prevention &amp; control ; Animals ; Antioxidants/metabolism ; Base Sequence ; Cytokines/metabolism ; DNA Primers ; Dose-Response Relationship, Drug ; Female ; Flavanones/*pharmacology ; Heme Oxygenase-1/metabolism ; Herbicides/*toxicity ; Male ; Mice ; Oxidative Stress ; Paraquat/*toxicity ; Pulmonary Fibrosis/*prevention &amp; control ; Real-Time Polymerase Chain Reaction ; }, abstract = {The present study evaluates protective effects of naringin against paraquat (PQ)-induced acute lung injury (ALI) and pulmonary fibrosis in mice. Survival probability against PQ intoxication was tested by a single intraperitoneal injection of PQ. Results showed that survival rates of mice exposed to PQ only (50 mg/kg within 7 days) were much lower than that in mice daily treatment with NAC or naringin. Moreover, protection against PQ-induced ALI was tested by daily pretreatment mice with saline, NAC or naringin for 3 days before PQ (30 mg/kg, i.p.). Results showed that increase in leukocytes infiltration and overexpressions of TNF-α and TGF-β1 caused by 8h of PQ exposure were dose-dependently ameliorated by naringin. Furthermore, protection against PQ-induced pulmonary fibrosis was tested by pretreatment mice with PQ (20 mg/kg, i.p.), and then daily administration with saline, NAC or naringin for prolonged 21 days. Results showed that naringin of 60 and 120 mg/kg significantly reduced PQ-induced upregulations of TNF-α, TGF-β1, MMP-9 and TIMP-1, levels of pulmonary malonaldehyde and hydroxyproline, as well as pulmonary fibrosis deposition, while increased activities of SOD, GSH-Px and HO-1. These results indicated that naringin had effective protection against PQ-induced ALI and pulmonary fibrosis.}, }
@article {pmid23600745, year = {2013}, author = {Alipour, M and Buonocore, C and Omri, A and Szabo, M and Pucaj, K and Suntres, ZE}, title = {Therapeutic effect of liposomal-N-acetylcysteine against acetaminophen-induced hepatotoxicity.}, journal = {Journal of drug targeting}, volume = {21}, number = {5}, pages = {466-473}, doi = {10.3109/1061186X.2013.765443}, pmid = {23600745}, issn = {1029-2330}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/chemistry/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Body Weight/drug effects ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/metabolism/pathology ; Chemistry, Pharmaceutical/methods ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Lipid Peroxidation/drug effects ; Liposomes/*administration &amp; dosage/chemistry ; Liver/*drug effects/metabolism/pathology ; Male ; Peroxidase/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Acetaminophen (APAP) is an antipyretic analgesic drug that when taken in overdose causes depletion of glutathione (GSH) and hepatotoxicity. N-acetylcysteine (NAC) is the antidote of choice for the treatment of APAP toxicity; however, due to its short-half-life repeated dosing of NAC is required.<br><br>PURPOSE: To determine whether a NAC-loaded liposomal formulation (Lipo-NAC) is more effective than the conventional NAC in protecting against acute APAP-induced hepatotoxicity.<br><br>METHODS: Male Sprague-Dawley rats were challenged with an intragastric dose of APAP (850&#x2009;mg/kg b.wt.); 4&#x2009;h later, animals were administered saline, NAC, Lipo-NAC or empty liposomes and sacrificed 24&#x2009;h post-APAP treatment.<br><br>RESULTS: APAP administration resulted in hepatic injury as evidenced by increases in plasma bilirubin, alanine (AST) and aspartate (ALT) aminotransferase levels and tissue levels of lipid peroxidation and myeloperoxidase as well as decreases in hepatic levels of reduced GSH, GSH peroxidase and GSH reductase. Treatment of animals with Lipo-NAC was significantly more effective than free NAC in reducing APAP-induced hepatotoxicity. Histological evaluation showed that APAP caused periacinar hepatocellular apoptosis and/or necrosis of hepatocytes around the terminal hepatic venules which was reduced by NAC treatment, the degree of reduction being greater for Lipo-NAC.<br><br>CONCLUSION: These data suggest that administration of Lipo-NAC ameliorated the APAP-induced hepatotoxicity.}, }
@article {pmid23597449, year = {2013}, author = {Fragoso, MF and Romualdo, GR and Ribeiro, DA and Barbisan, LF}, title = {Açai (Euterpe oleracea Mart.) feeding attenuates dimethylhydrazine-induced rat colon carcinogenesis.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {58}, number = {}, pages = {68-76}, doi = {10.1016/j.fct.2013.04.011}, pmid = {23597449}, issn = {1873-6351}, mesh = {1,2-Dimethylhydrazine/*toxicity ; Animals ; Apoptosis ; *Arecaceae ; *Carcinogenesis ; Carcinogens/*toxicity ; Cell Proliferation ; Colonic Neoplasms/chemically induced/metabolism/pathology/*prevention &amp; control ; Connexin 43/metabolism ; Rats ; beta Catenin/metabolism ; }, abstract = {This study investigated the protective effect of spray-dried açaí powder (AP) intake on colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) in male Wistar rats. After 4 weeks of DMH administrations, the groups were fed with standard diet, a diet containing 2.5% or 5.0% AP or a diet containing 0.2% N-acetylcysteine (NAC) for 10 weeks, using aberrant crypt foci (ACF) as the endpoint. Additionally, two groups were fed with standard diet or a diet containing 5.0% AP for 20 weeks, using colon tumors as the endpoint. In ACF assay, a reduction in the number of aberrant crypts (ACs) and ACF (1-3 AC) were observed in the groups fed with 5.0% AP (37% AC and 47% ACF inhibition, p=0.036) and 0.2% NAC (39% AC and 41% ACF inhibition, p=0.042). In tumor assay, a reduction in the number of invasive tumors (p<0.005) and tumor multiplicity (p=0.001) was observed in the group fed with 5.0% AP. Also, a reduction in tumor Ki-67 cell proliferation (p=0.003) and net growth index (p=0.001) was observed in the group fed with 5.0% AP. Therefore the findings of this study indicate that AP feeding may reduce the development of chemically-induced rat colon carcinogenesis.}, }
@article {pmid23597197, year = {2013}, author = {Luo, C and Li, Y and Wang, H and Cui, Y and Feng, Z and Li, H and Li, Y and Wang, Y and Wurtz, K and Weber, P and Long, J and Liu, J}, title = {Hydroxytyrosol promotes superoxide production and defects in autophagy leading to anti-proliferation and apoptosis on human prostate cancer cells.}, journal = {Current cancer drug targets}, volume = {13}, number = {6}, pages = {625-639}, doi = {10.2174/15680096113139990035}, pmid = {23597197}, issn = {1873-5576}, mesh = {Antineoplastic Agents, Phytogenic/adverse effects/antagonists &amp; inhibitors/*pharmacology ; Antioxidants/adverse effects/chemistry/*pharmacology ; Apoptosis/*drug effects ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Free Radical Scavengers/pharmacology ; Fruit/chemistry ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Mitochondria/drug effects/metabolism/pathology ; Olea/chemistry ; Olive Oil ; Phenylethyl Alcohol/adverse effects/*analogs &amp; derivatives/antagonists &amp; inhibitors/pharmacology ; Plant Oils/chemistry ; Prostate/drug effects ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Protein Kinase Inhibitors/pharmacology ; Superoxides/antagonists &amp; inhibitors/*metabolism ; Up-Regulation/*drug effects ; }, abstract = {Hydroxytyrosol, an important polyphenolic compound found in olive oil, has shown anti-tumor activity both in vitro and in vivo. However, effects of hydroxytyrosol on prostate cancer are largely unkown. We found that hydroxytyrosol preferentially reduces the viability of human prostate cancer cells (PC-3, DU145) compared to an immortalized non-malignant prostate epithelial cell line (RWPE-1). Exposure of PC-3 cells to 80 µmol/L hydroxytyrosol resulted in significant increases in both superoxide production and activation of apoptosis. These increases were accompanied by mitochondrial dysfunction, defects in autophagy, and activation of MAP kinases. Moreover, N-acetylcysteine (NAC), an efficient reactive oxygen species (ROS) scavenger, was able to reverse the hydroxytyrosol-induced effects of cell viability loss, defects in autophagy, and activation of apoptosis. This evidence suggests that ROS play a vital role in the loss of PC-3 cell viability. However, MAPK inhibitors including U0126 (for Erk1/2), SB203580 (for p38MAPK) and SP600125 (for JNK) did not decrease hydroxytyrosol-induced growth inhibition, suggesting that these kinases may not be required for the growth inhibitory effect of hydroxytyrosol. Moreover, addition of ROS scavengers (i.e. NAC, catalase, pyruvate, SOD) in the growth media can prevent hydroxytyrosol induced cell viability loss, suggesting that extracellular ROS (superoxide and hydrogen peroxide) facilitate the anti-proliferation effect of hydroxytyrosol in prostate cancer cells. The present work firstly shows that hydroxytyrosol induces apoptotic cell death and mitochondrial dysfunction by generating superoxide in PC-3 cells. This research presents preliminary evidence on the in vitro chemopreventive effect of hydroxytyrosol, and will contribute to further investigation of hydroxytyrosol as an anti-cancer agent.}, }
@article {pmid23593476, year = {2013}, author = {Yano, M and Yamamoto, T and Nishimura, N and Gotoh, T and Watanabe, K and Ikeda, K and Garan, Y and Taguchi, R and Node, K and Okazaki, T and Oike, Y}, title = {Increased oxidative stress impairs adipose tissue function in sphingomyelin synthase 1 null mice.}, journal = {PloS one}, volume = {8}, number = {4}, pages = {e61380}, pmid = {23593476}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Adipose Tissue, White/drug effects/metabolism/*pathology/*physiopathology ; Animals ; Antioxidants/pharmacology/therapeutic use ; Fatty Acids/metabolism ; Hyperlipidemias/complications/drug therapy/metabolism/pathology ; Lipodystrophy/complications/drug therapy/enzymology/pathology ; Lipoprotein Lipase/metabolism ; Mice ; Mice, Knockout ; Mitochondria/drug effects/metabolism ; Mitochondrial Turnover/drug effects ; *Oxidative Stress/drug effects ; Phenotype ; Transferases (Other Substituted Phosphate Groups)/*deficiency/metabolism ; }, abstract = {Sphingomyelin synthase 1 (SMS1) catalyzes the conversion of ceramide to sphingomyelin. Here, we found that SMS1 null mice showed lipodystrophic phenotype. Mutant mice showed up-regulation of plasma triglyceride concentrations accompanied by reduction of white adipose tissue (WAT) as they aged. Lipoprotein lipase (LPL) activity was severely reduced in mutant mice. In vivo analysis indicated that fatty acid uptake in WAT but not in liver decreased in SMS1 null compared to wild-type mice. In vitro analysis using cultured cell revealed that SMS1 depletion reduced fatty acid uptake. Proteins extracted from WAT of mutant mice were severely modified by oxidative stress, and up-regulation of mRNAs related to apoptosis, redox adjustment, mitochondrial stress response and mitochondrial biogenesis was observed. ATP content of WAT was reduced in SMS1 null mice. Blue native gel analysis indicated that accumulation of mitochondrial respiratory chain complexes was reduced. These results suggest that WAT of SMS1 null mice is severely damaged by oxidative stress and barely functional. Indeed, mutant mice treated with the anti-oxidant N-acetyl cysteine (NAC) showed partial recovery of lipodystrophic phenotypes together with normalized plasma triglyceride concentrations. Altogether, our data suggest that SMS1 is crucial to control oxidative stress in order to maintain WAT function.}, }
@article {pmid23590859, year = {2013}, author = {Alboni, S and Gibellini, L and Montanari, C and Benatti, C and Benatti, S and Tascedda, F and Brunello, N and Cossarizza, A and Pariante, CM}, title = {N-acetyl-cysteine prevents toxic oxidative effects induced by IFN-α in human neurons.}, journal = {The international journal of neuropsychopharmacology}, volume = {16}, number = {8}, pages = {1849-1865}, doi = {10.1017/S1461145713000266}, pmid = {23590859}, issn = {1469-5111}, support = {G108/603/MRC_/Medical Research Council/United Kingdom ; MR/J002739/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Apoptosis/drug effects ; Brain-Derived Neurotrophic Factor/genetics/metabolism ; Bromodeoxyuridine/metabolism ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Flow Cytometry ; Gene Expression Regulation/drug effects ; Humans ; In Situ Nick-End Labeling ; Neuroblastoma/pathology ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Time Factors ; Tretinoin/pharmacology ; Tumor Necrosis Factor-alpha/*toxicity ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Currently IFN-α is widely used for effective treatment of viral infections and several malignancies. However, IFN-α can cause neuropsychiatric disturbances and mental impairments, including fatigue, insomnia, depression, irritability and cognitive deficits. Molecular and cellular mechanisms leading to such side-effects are still poorly understood. Neurons seem to be an important target in mediating cellular effects induced by exposure to this cytokine, but so far little is known about IFN-α-induced effects on these cells. We have investigated the ability of IFN-α (2-100 ng/ml) to induce damage and toxicity to the human neuroblastoma SH-SY5Y cell line, commonly used for studying such phenomena, and the mechanisms underlying these effects. After 24 h treatment, IFN-α increased mitochondrial activity, whereas cell density was reduced in a dose- and time-dependent manner. This effect did not depend on reduced cell proliferation, but rather the activation of apoptosis, as revealed by an increased Bax:Bcl-2 mRNA ratio after 72-h IFN-α exposure. At this time-point, IFN-α also reduced the expression of the brain-derived neurotrophic factor gene, and induced an increase in reactive oxygen species (ROS). A co-treatment with N-acetyl-cysteine (NAC; 5 mm), a potent antioxidant and mitochondrial modulator, was able to counteract all of these IFN-α-induced effects. These findings demonstrated that IFN-α induces neurotoxicity and apoptosis that is, in part, very likely due to mitochondrial damages and production of ROS. We suggest that NAC, already tested for the treatment of psychiatric disorders, may be useful to prevent IFN-α-induced central side-effects in a safe and effective way.}, }
@article {pmid23590160, year = {2013}, author = {Boengler, K and Ungefug, E and Heusch, G and Schulz, R}, title = {The STAT3 inhibitor stattic impairs cardiomyocyte mitochondrial function through increased reactive oxygen species formation.}, journal = {Current pharmaceutical design}, volume = {19}, number = {39}, pages = {6890-6895}, doi = {10.2174/138161281939131127115940}, pmid = {23590160}, issn = {1873-4286}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Cyclic S-Oxides/*pharmacology ; Mitochondria, Heart/*drug effects/physiology ; Myocytes, Cardiac/*drug effects/physiology ; Phosphorylation ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/metabolism ; }, abstract = {The signal transducer and activator of transcription 3 (STAT3) transduces stress signals from the plasma membrane to the nucleus but has recently also been identified in mitochondria. Inhibition of cardiomyocyte mitochondrial STAT3 with the STAT3-specific inhibitor Stattic decreases ADP-stimulated respiration and enhances calcium-induced mitochondrial permeability transition pore (MPTP) opening. The aim of the present study was to analyze whether or not these effects of STAT3 inhibition by Stattic are mediated by the formation of reactive oxygen species (ROS). The H2O2 formation from isolated rat left ventricular mitochondria was measured continuously in the presence of the complex 1 substrates glutamate and malate using the H2O2 indicator Amplex UltraRed. Stattic dose-dependently increased mitochondrial ROS formation (slope of Amplex UltraRed fluorescence/time; DMSO: 0.39±0.01; 1 µM Stattic: 0.40±0.03; 10 µM Stattic: 0.71±0.04; 25 µM Stattic: 1.43±0.05; 50 µM Stattic: 3.53±0.23; 100 µM Stattic: 9.23±0.69, n=5 mitochondrial preparations, p<0.05 for 10-100 µM Stattic). The increase in the ROS signal by 100 µM Stattic was abolished in the presence of the ROS scavenger N-acetylcysteine (Nac, 0.46±0.02, n=7, p<0.05). Mitochondria treated with 100 µM Stattic produced less ATP than control mitochondria (86±3 arbitrary units (a.u.) vs. 128±7 a.u., n=9, p<0.05). Again, in the presence of Nac ATP production was similar between Stattic-treated and control mitochondria (142±4 a.u. vs. 147±12 a.u., n=5, p=ns). MPTP opening was induced by lower amounts of calcium in Stattic-treated than in control mitochondria (in nmol CaCl2/mg protein, Stattic: 507±57, n=7; control: 857±70, n=7, p<0.05). There was no difference in calcium-induced MPTP opening between Stattic-treated (833±57, n=6) and control mitochondria (921±75, n=7, p=ns) in the presence of Nac. Taken together, our data show that inhibition of mitochondrial STAT3 by Stattic impacts on mitochondrial ATP production and MPTP opening through enhanced ROS formation.}, }
@article {pmid23589085, year = {2014}, author = {Shin, JH and Kim, GH and Song, KH and Na, YG and Sul, CK and Lim, JS}, title = {Protective effect of N-acetylcysteine against ischemia/reperfusion injury in rat urinary bladders.}, journal = {Cell biochemistry and function}, volume = {32}, number = {1}, pages = {24-30}, doi = {10.1002/cbf.2967}, pmid = {23589085}, issn = {1099-0844}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Male ; Muscle Contraction ; Muscle, Smooth/drug effects/metabolism/physiopathology ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*drug therapy/metabolism/physiopathology ; Urinary Bladder/*drug effects/physiopathology ; }, abstract = {Ischemia/reperfusion (I/R) injury represents an important cause of bladder contractile dysfunction. One of the major causes leading to this dysfunction is thought to be reactive oxygen species formation. In this study, we investigated the potential benefit of N-acetylcysteine (NAC), a potent antioxidant that neutralizes free radicals, in a rat model of urinary bladder injury. NAC treatment rescues the reduction of contractile response to I/R injury in a dose-dependent manner. In addition, all levels of reactive oxygen species, lipid peroxidation, and NADPH-stimulated superoxide production in the I/R operation+NAC (I/R+NAC) group also decreased compared with a marked increase in the I/R operation+saline (I/R+S) group. Moreover, an in situ fluorohistological approach also showed that NAC reduces the generation of intracellular superoxides enlarged by I/R injury. Together, our findings suggest that NAC has a protective effect against the I/R-induced bladder contractile dysfunction via radical scavenging property.}, }
@article {pmid23589029, year = {2013}, author = {Strianese, M and Basile, A and Mazzone, A and Morello, S and Turco, MC and Pellecchia, C}, title = {Therapeutic potential of a pyridoxal-based vanadium(IV) complex showing selective cytotoxicity for cancer versus healthy cells.}, journal = {Journal of cellular physiology}, volume = {228}, number = {11}, pages = {2202-2209}, doi = {10.1002/jcp.24385}, pmid = {23589029}, issn = {1097-4652}, mesh = {Acetylcysteine/pharmacology ; Caspases/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Inhibitory Concentration 50 ; Leukocytes, Mononuclear/drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Neoplasms/*drug therapy/*pathology ; Pyridoxal/chemistry/pharmacology/*therapeutic use ; Reactive Oxygen Species/metabolism ; Tumor Stem Cell Assay ; Vanadium/chemistry/pharmacology/*therapeutic use ; }, abstract = {Vanadium compounds can exert anticancer effects, partly due to inhibition of tyrosine phosphatases. Here, we report the effect of N,N'-ethylenebis (pyridoxylideneiminato) vanadium (IV) complex (Pyr2 enV(IV)), that induced 93% and 57% of cell mortality in A375 (human melanoma) and A549 (human lung carcinoma) cells, respectively; the mortality was <24% in other cancer cell lines and in human normal epidermal keratinocytes, lung cells and peripheral blood mononuclear cells. The mechanism of Pyr2 enV(IV) effect relied on apoptosis induction; this was triggered by ROS increase, followed by mitochondrial membrane depolarization. Indeed, the addition of N-acetyl cysteine to cell cultures abated Pyr2 enV(IV)-induced apoptosis. These results disclose the pro-apoptotic activity of Pyr2 enV(IV) and its mechanism, relying on intracellular ROS increase.}, }
@article {pmid23587908, year = {2013}, author = {Bardai, GK and Hales, BF and Sunahara, GI}, title = {Glyceryl trinitrate metabolism in the quail embryo by the glutathione S-transferases leads to a perturbation in redox status and embryotoxicity.}, journal = {Comparative biochemistry and physiology. Part B, Biochemistry &amp; molecular biology}, volume = {165}, number = {3}, pages = {153-164}, doi = {10.1016/j.cbpb.2013.04.001}, pmid = {23587908}, issn = {1879-1107}, mesh = {Animals ; Coturnix/abnormalities/*embryology/*metabolism ; Embryo, Nonmammalian/abnormalities/*drug effects ; Glutathione Transferase/*metabolism ; Nitroglycerin/*metabolism/*toxicity ; Oxidation-Reduction/drug effects ; }, abstract = {Exposure of stage 9 quail (Coturnix coturnix japonica) embryos to glyceryl trinitrate (GTN) induces malformations that were associated in previous studies with an increase in protein nitration. Increased nitration suggests metabolism of GTN by the embryo. The goals of this study were to characterize the enzymes and co-factors required for GTN metabolism by quail embryos, and to determine the effects of in ovo treatment with N-acetyl cysteine (NAC), a precursor of glutathione (GSH), on GTN embryotoxicity. GTN treatment of quail embryos resulted in an increase in nitrite, a decrease in total GSH, and an increase in the ratio of NADP(+)/NADPH, indicating that redox balance may be compromised in exposed embryos. Glutathione S-transferases (GSTs; EC 2.5.1.18) purified from the whole embryo (K(m) 0.84 mM; V(max) 36 μM/min) and the embryonic eye (K(m) 0.20 mM; V(max) 30 μM/min) had GTN-metabolizing activity (1436 and 34 nmol/min/mg, respectively); the addition of ethacrynic acid, an inhibitor of GST activity, decreased GTN metabolism. Peptide sequencing of the GST isozymes indicated that alpha- or mu-type GSTs in the embryo and embryonic eye had GTN metabolizing activity. NAC co-treatment partially protected against the effects of GTN exposure. Thus, GTN denitration by quail embryo GSTs may represent a key initial step in the developmental toxicity of GTN.}, }
@article {pmid23587288, year = {2013}, author = {Bueche, CZ and Garz, C and Kropf, S and Bittner, D and Li, W and Goertler, M and Heinze, HJ and Reymann, K and Braun, H and Schreiber, S}, title = {NAC changes the course of cerebral small vessel disease in SHRSP and reveals new insights for the meaning of stases - a randomized controlled study.}, journal = {Experimental &amp; translational stroke medicine}, volume = {5}, number = {}, pages = {5}, pmid = {23587288}, issn = {2040-7378}, abstract = {BACKGROUND: N-Acetylcystein (NAC) reduces the reperfusion injury and infarct size in experimental macroangiopathic stroke. Here we now investigate the impact of NAC on the development of the histopathology of microangiopathic cerebrovascular disease including initial intravasal erythrocyte accumulations, blood-brain-barrier (BBB)-disturbances, microbleeds and infarcts.<br><br>METHODS: Spontaneously Hypertensive Stroke-Prone Rats (SHRSP) were treated with NAC (12&#xa0;mg/kg body weight, daily oral application for three to 30&#xa0;weeks) and compared to untreated SHRSP. In all rats the number of microbleeds, thromboses, infarcts and stases were quantified by HE-staining. Exemplary brains were stained against von Willebrand factor (vWF), IgG, Glutathione and GFAP.<br><br>RESULTS: NAC animals exhibited significant more microbleeds, a greater number of vessels with BBB-disturbances, but also an elevation of Glutathione-levels in astrocytes surrounding small vessels. NAC-treatment reduced the numbers of thromboses, infarcts and arteriolar stases.<br><br>CONCLUSIONS: NAC reduces the frequency of thromboses and infarcts to the expense of an increase of small microbleeds in a rat model of microangiopathic cerebrovascular disease. We suppose that NAC acts via an at least partial inactivation of vWF resulting in an insufficient sealing of initial endothelial injury leading to more small microbleeds. By elevating Glutathione-levels NAC most likely exerts a radical scavenger function and protects small vessels against extended ruptures and subsequent infarcts. Finally, it reveals that stases are mainly caused by endothelial injuries and restricted thromboses.}, }
@article {pmid23584725, year = {2013}, author = {Seo, BN and Ryu, JM and Yun, SP and Jeon, JH and Park, SS and Oh, KB and Park, JK and Han, HJ}, title = {Delphinidin prevents hypoxia-induced mouse embryonic stem cell apoptosis through reduction of intracellular reactive oxygen species-mediated activation of JNK and NF-κB, and Akt inhibition.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {18}, number = {7}, pages = {811-824}, doi = {10.1007/s10495-013-0838-2}, pmid = {23584725}, issn = {1573-675X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthocyanins/*pharmacology ; Anthracenes/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Caspases/genetics/metabolism ; Cell Hypoxia ; Cell Line ; Embryonic Stem Cells/cytology/*drug effects/metabolism ; Gene Expression Regulation ; MAP Kinase Kinase 4/*genetics/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/metabolism ; NF-kappa B/agonists/*genetics/metabolism ; Oxygen/pharmacology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*genetics/metabolism ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Signal Transduction ; bcl-2-Associated X Protein/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {Delphinidin, gallic acid, betulinic acid, and ursolic acid, which are bio-active ingredients in a variety of fruits, vegetables, and herbs, have potent antioxidant activity and various biological activities. However, it is not clear whether these bio-active ingredients can significantly contribute to the protection of embryonic stem (ES) cells from hypoxia-induced apoptosis. In the present study, hypoxia-induced ES cells apoptosis with time, which were abrogated by pretreatment with all ingredients. Hypoxia-induced ROS generation was blocked by pretreatment with all ingredients in a dose-dependent manner, with the maximum ROS scavenging effect observed for delphinidin. Hypoxia increased phosphorylation of JNK and NF-κB were blocked by pretreatment of delphinidin as well as NAC. Hypoxia decreased phosphorylation of Akt(thr308) and (ser473); these decreases were reversed by pretreatment with delphinidin or NAC. However, Akt inhibition did not affect NF-κB phosphorylation. Delphinidin attenuated the hypoxia-induced increase in Bax, cleaved caspase-9, cleaved caspase-3, and decrease in Bcl-2, which were diminished by pretreatment of Akt inhibitor. Hypoxia induced Bax translocation from the cytosol to mitochondria. Furthermore, hypoxia induced mitochondria membrane potential loss and cytochrome c release in cytosol, which were blocked by delphinidin pretreatment. Hypoxia induced cleavage of procaspase-9 and procaspase-3 which were blocked by delphinidin or SP600125, but Akt inhibitor abolished the protection effect of delphinidin. Moreover, inhibition of JNK and NF-κB abolished hypoxia-induced ES cell apoptosis and inhibition of Akt attenuated delphinidin-induced blockage of apoptosis. The results indicate that delphinidin can prevent hypoxia-induced apoptosis of ES cells through the inhibition of JNK and NF-κB phosphorylation, and restoration of Akt phosphorylation.}, }
@article {pmid23584358, year = {2013}, author = {Karakus, E and Halici, Z and Albayrak, A and Polat, B and Bayir, Y and Kiki, I and Cadirci, E and Topcu, A and Aksak, S}, title = {Agomelatine: an antidepressant with new potent hepatoprotective effects on paracetamol-induced liver damage in rats.}, journal = {Human &amp; experimental toxicology}, volume = {32}, number = {8}, pages = {846-857}, doi = {10.1177/0960327112472994}, pmid = {23584358}, issn = {1477-0903}, mesh = {Acetamides/pharmacology/*therapeutic use ; Acetaminophen ; Alanine Transaminase/blood ; Animals ; Antidepressive Agents/pharmacology/*therapeutic use ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology ; Dinoprost/analogs &amp; derivatives/metabolism ; Glutathione/metabolism ; Interleukin-6/blood ; Liver/drug effects/metabolism/pathology ; Male ; Protective Agents/pharmacology/*therapeutic use ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {Paracetamol was shown to induce hepatotoxicity or more severe fatal acute hepatic damage. Agomelatine, commonly known as melatonin receptor agonist, is a new antidepressant, which resynchronizes circadian rhythms with subjective and objective improvements in sleep quality and architecture, as melatonin does. In the present study, it was aimed to evaluate the hepatoprotective activity of agomelatine on paracetamol-induced hepatotoxicity and to understand the relationship between the hepatoprotective mechanism of agomelatine and antioxidant system and proinflammatory cytokines. A total of 42 rats were divided into 7 groups as each composed of 6 rats: (1) intact, (2) 40 mg/kg agomelatine, (3) 140 mg/kg N-acetylcysteine (NAC), (4) 2 g/kg paracetamol, (5) 2 g/kg paracetamol + 140 mg/kg NAC, (6) 2 g/kg paracetamol + 20 mg/kg agomelatine, and (7) 2 g/kg paracetamol + 40 mg/kg agomelatine groups. Paracetamol-induced hepatotoxicity was applied and liver and blood samples were analyzed histopathologically and biochemically. There were statistically significant increases in the activities of aspartate aminotransferase, alanine aminotransferase, levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and 8-iso-prostane, and decreases in the activity of superoxide dismutase and level of glutathione in the group treated with paracetamol. Administration of agomelatine and NAC separately reversed these changes significantly. In conclusion, agomelatine administration protects liver cells from paracetamol-induced hepatotoxicity via antioxidant activity and reduced proinflammatory cytokines, such as TNF-α and IL-6.}, }
@article {pmid23583729, year = {2013}, author = {Zhang, LH and Jia, YL and Lin, XX and Zhang, HQ and Dong, XW and Zhao, JM and Shen, J and Shen, HJ and Li, FF and Yan, XF and Li, W and Zhao, YQ and Xie, QM}, title = {AD-1, a novel ginsenoside derivative, shows anti-lung cancer activity via activation of p38 MAPK pathway and generation of reactive oxygen species.}, journal = {Biochimica et biophysica acta}, volume = {1830}, number = {8}, pages = {4148-4159}, doi = {10.1016/j.bbagen.2013.04.008}, pmid = {23583729}, issn = {0006-3002}, mesh = {Angiogenesis Inhibitors/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Ginsenosides/*pharmacology ; Humans ; Lung Neoplasms/*drug therapy ; MAP Kinase Signaling System/*drug effects ; Male ; Mice ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {BACKGROUND: Ginseng is a traditional Chinese herb that has been used for thousands of years. In the present study, effects and mechanisms of AD-1 were evaluated for its development as a novel anti-lung cancer drug.<br><br>METHODS: The cytotoxic activity was evaluated by MTT assay. Flow cytometry was employed to detect cell cycle, apoptosis and ROS. Western blot and immunohistochemistry were used to analyze signaling pathways. Lung cancer xenograft models were established by subcutaneous implantation of A549 or H292 cells into nude mice.<br><br>RESULTS: AD-1 concentration-dependently reduces lung cancer cell viability without affecting normal human lung epithelial cell viability. In A549 and H292 lung cancer cells, AD-1 induces G0/G1 cell cycle arrest, apoptosis and ROS production. The apoptosis can be attenuated by a ROS scavenger - N-acetylcysteine (NAC). In addition, AD-1 up-regulates the expression of p38 and ERK phosphorylation. Addition of a p38 inhibitor SB203580, suppresses the AD-1-induced decrease in cell viability. Furthermore, genetic silencing of p38 attenuates the expression of p38 and decreases the AD-1-induced apoptosis. Treatment with NAC reduces AD-1-induced p38 phosphorylation, which indicates that ROS generation is involved in the AD-1-induced p38 activation. In mice, oral administration of AD-1 (10-40mg/kg) dose-dependently inhibited the growth of xenograft tumors without affecting body weight and decreases the expression of VEGF, MMP-9 and CD34 in tumor tissue. TUNEL staining confirms that the tumors from AD-1 treated mice exhibit a markedly higher apoptotic index.<br><br>These data support development of AD-1 as a potential agent for lung cancer therapy.}, }
@article {pmid23578993, year = {2013}, author = {Nissar, AU and Farrukh, MR and Kaiser, PJ and Rafiq, RA and Afnan, Q and Bhushan, S and Adil, HS and Subhash, BC and Tasduq, SA}, title = {Effect of N-acetyl cysteine (NAC), an organosulfur compound from Allium plants, on experimentally induced hepatic prefibrogenic events in Wistar rat.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {20}, number = {10}, pages = {828-833}, doi = {10.1016/j.phymed.2013.03.009}, pmid = {23578993}, issn = {1618-095X}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; *Allium ; Animals ; Carbon Tetrachloride/administration &amp; dosage ; Disease Models, Animal ; Liver Cirrhosis/chemically induced/pathology/*prevention &amp; control ; Male ; Oxidative Stress/*drug effects ; Phytotherapy ; Rats ; Rats, Wistar ; Sulfur/*administration &amp; dosage ; Thioacetamide/administration &amp; dosage ; }, abstract = {Aim of present study was to investigate the effect of NAC on experimental chronic hepatotoxicity models induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). CCl4 toxicity was induced by administering 200 μl CCl4 (diluted 2:3 in coconut oil)/100 g body weight, p.o., twice weekly for 8 weeks. TAA toxicity was induced by administering 150 mg/kg b. wt. of TAA i.p., twice weekly for 8 weeks. NAC treatment was started along with toxicants (CCl4 and TAA) for 8 weeks and continued for further 4 weeks. Self reversal group was kept without any treatment for 4 weeks after completion of toxicant treatments. Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Bilirubin were measured in serum. Hydroxyproline (HP), lipid peroxidation (LPO), catalase (CAT), Glutathione peroxidase (GPx) and Glutathione (GSH) were determined in liver samples by colorimetric methods. Cytochrome P450 2E1 (CYP 450 2E1), activity was determined as hydroxylation of aniline in liver microsomes. General examination and histological analysis were also performed. Serum markers of liver damage (AST, ALT, ALP and Bilirubin) were increased by CCl4 and TAA intoxication (p<0.001), whereas co-treatment with NAC reversed such changes (p<0.001). HP was enhanced in toxicant groups (p<0.001 in CCl4 and TAA), but inhibited by NAC (p<0.001). LPO was increased while as GSH, CAT and GPx decreased by the administration of CCl4 and TAA (p<0.001); co-administration of NAC restored these liver markers to normal levels (p<0.001). Biochemical determinations were corroborated by general and histological findings. Keeping in view the biochemical and histopathological studies, it was concluded that CCl4 and TAA are strong hepatotoxic agents that produce liver fibrosis with close proximity to human etiology (micronodular cirrhosis) and NAC has a significant protective activity against CCl4 and TAA. NAC has also been validated as a model against oxidative burden in chronic liver pathology.}, }
@article {pmid23578607, year = {2013}, author = {Zhang, G and Nitteranon, V and Chan, LY and Parkin, KL}, title = {Glutathione conjugation attenuates biological activities of 6-dehydroshogaol from ginger.}, journal = {Food chemistry}, volume = {140}, number = {1-2}, pages = {1-8}, doi = {10.1016/j.foodchem.2013.02.073}, pmid = {23578607}, issn = {1873-7072}, mesh = {Animals ; Anti-Inflammatory Agents/*metabolism ; Catechols/chemistry/*metabolism ; Cell Line ; Fatty Alcohols/chemistry/*metabolism ; Zingiber officinale/*chemistry ; Glutathione/*metabolism ; Glutathione Transferase/metabolism ; Mice ; Plant Extracts/*metabolism ; }, abstract = {6-Dehydroshogaol (6-DHSG) is a bioactive α,β-unsaturated carbonyl compound isolated from fresh ginger with anti-inflammatory and phase II enzyme inducing activities. Here we describe the glutathione (GSH)-dependent metabolism and the effect of this metabolic transformation on the biological activities of 6-DHSG. Compared with other ginger compounds, such as 6-gingerol and 6-shogaol, 6-DHSG showed the most potent anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The biological activities of 6-DHSG were attenuated by sulfhydryl antioxidants such as glutathione (GSH) or N-acetyl cysteine (NAC), but not ascorbic acid (ASC). 6-DHSG was metabolised by GSH to form a GSH conjugate (GS-6-DHSG) in RAW 264.7 cells, via a potential mechanism involving the catalytic activity of glutathione-S-transferase (GST). GS-6-DHSG showed reduced biological activities compared with 6-DHSG in multiple biological assays. Together, these results indicate that GSH conjugation attenuates the biological activities of 6-DHSG and other α,β-unsaturated carbonyl compounds.}, }
@article {pmid23577223, year = {2013}, author = {Yiran, Z and Chenyang, J and Jiajing, W and Yan, Y and Jianhong, G and Jianchun, B and Xuezhong, L and Zongping, L}, title = {Oxidative stress and mitogen-activated protein kinase pathways involved in cadmium-induced BRL 3A cell apoptosis.}, journal = {Oxidative medicine and cellular longevity}, volume = {2013}, number = {}, pages = {516051}, pmid = {23577223}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Butadienes/pharmacology ; Cadmium/*toxicity ; Cell Line ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/metabolism ; Glutathione Peroxidase/metabolism ; Imidazoles/pharmacology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Malondialdehyde/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Nitriles/pharmacology ; Oxidative Stress/*drug effects ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {In this study, BRL 3A cells were treated with different Cd concentrations (0, 10, 20, and 40 μmol/L) for 12 h and preincubated with or without N-acetyl-L-cysteine (NAC) (2 mmol/L) for 30 min, and cells were treated with Cd (0 and 20 μmol/L), pretreated with p38 inhibitor (SB203580), JNK (c-Jun NH2-terminal kinases) inhibitor (SP600125), and extracellular signal-regulated kinase (ERK) inhibitor (U0126) for 30 min, and then treated with 20 μmol/L Cd for 12 h. Cd decreased cell viability, SOD, and GSH-Px activity in a concentration-dependent manner. Increased MDA level, ROS generation, nuclear condensation, shrinkage, and fragmentation in cell morphology were inhibited by NAC. Cd-induced apoptosis was attenuated by pretreatment with SB203580, SP600125, and U0126. The results of western blot showed that NAC preincubation affected Cd-activated MAPK pathways, p38 and ERK phosphorylation. Cd treatment elevated the mRNA levels of Bax and decreased the mRNA levels of Bcl-2, respectively. The same effect was found in their protein expression levels. These results suggest that oxidative stress and MAPK pathways participate in Cd-induced apoptosis and that the balance between pro- and antiapoptotic genes (Bax and Bcl-2) is important in Cd-induced apoptosis.}, }
@article {pmid23576637, year = {2013}, author = {Ware, K and Qamri, Z and Ozcan, A and Satoskar, AA and Nadasdy, G and Rovin, BH and Hebert, LA and Nadasdy, T and Brodsky, SV}, title = {N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy.}, journal = {American journal of physiology. Renal physiology}, volume = {304}, number = {12}, pages = {F1421-7}, doi = {10.1152/ajprenal.00689.2012}, pmid = {23576637}, issn = {1522-1466}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*chemically induced/*prevention &amp; control/urine ; Animals ; Creatinine/blood ; Deferoxamine/therapeutic use ; Erythrocytes ; Male ; Nephrectomy ; *Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/drug therapy ; Urine/cytology ; Warfarin/*adverse effects ; }, abstract = {Warfarin-related nephropathy (WRN) occurs under conditions of overanticoagulation with warfarin. WRN is characterized by glomerular hemorrhage with occlusive tubular red blood cell (RBC) casts and acute kidney injury (AKI). Herein we test the hypothesis that oxidative stress plays a role in the AKI of WRN. 5/6 Nephrectomy rats were treated with either warfarin (0.04 mg·kg[-1]·day[-1]) alone or with four different doses of the antioxidant N-acetylcysteine (NAC). Also tested was the ability of our NAC regimen to mitigate AKI in a standard ischemia-reperfusion model in the rat. Warfarin resulted in a threefold or greater increase in prothrombin time in each experimental group. Serum creatinine (Scr) increased progressively in animals receiving only warfarin + vehicle. However, in animals receiving warfarin + NAC, the increase in Scr was lessened, starting at 40 mg·kg[-1]·day[-1] NAC, and completely prevented at 80 mg·kg[-1]·day[-1] NAC. NAC did not decrease hematuria or obstructive RBC casts, but mitigated acute tubular injury. Oxidative stress in the kidney was increased in animals with WRN and it was decreased by NAC. The NAC regimen used in the WRN model preserved kidney function in the ischemia-reperfusion model. Treatment with deferoxamine (iron chelator) did not affect WRN. No iron was detected in tubular epithelial cells. In conclusion, this work taken together with our previous works in WRN shows that glomerular hematuria is a necessary but not sufficient explanation for the AKI in WRN. The dominant mechanism of the AKI of WRN is tubular obstruction by RBC casts with increased oxidative stress in the kidney.}, }
@article {pmid23570653, year = {2013}, author = {Cho, HJ and Suh, DS and Moon, SH and Song, YJ and Yoon, MS and Park, DY and Choi, KU and Kim, YK and Kim, KH}, title = {Silibinin inhibits tumor growth through downregulation of extracellular signal-regulated kinase and Akt in vitro and in vivo in human ovarian cancer cells.}, journal = {Journal of agricultural and food chemistry}, volume = {61}, number = {17}, pages = {4089-4096}, doi = {10.1021/jf400192v}, pmid = {23570653}, issn = {1520-5118}, mesh = {Acetylcysteine/adverse effects ; Animals ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Caspase 3/genetics/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Down-Regulation/drug effects ; Extracellular Signal-Regulated MAP Kinases/genetics/metabolism ; Female ; Humans ; Ki-67 Antigen/genetics/metabolism ; Mice ; Mice, Inbred BALB C ; Ovarian Neoplasms/metabolism/*pathology ; Proto-Oncogene Proteins c-akt/*genetics/metabolism ; Reactive Oxygen Species/metabolism ; Silybin ; Silymarin/*pharmacology ; }, abstract = {Anticancer activity of silibinin, a flavonoid, has been demonstrated in various cancer cell types. However, the underlying mechanisms were not elucidated in human ovarian cancer cells. The present study was undertaken to examine the effect of silibinin in vitro and in vivo on tumor growth in human ovarian cancer cells. Silibinin decreased cell viability in a dose- and time-dependent manner. Silibinin caused an increase in reactive oxygen species (ROS) generation, and the silibinin-induced cell death was prevented by the antioxidant N-acetylcysteine (NAC). Western blot analysis showed silibinin-induced downregulation of extracellular signal-regulated kinase (ERK) and Akt. Transfection of constitutively active forms of MEK and Akt prevented the silibinin-induced cell death. Oral administration of silibinin in animals with subcutaneous A2780 cells reduced tumor volume. Subsequent tumor tissue analysis showed that silibinin treatment induced a decrease in Ki-67-positive cells, an increase in transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, activation of caspase-3, and inhibition of p-ERK and p-Akt. These results indicate that silibinin reduces tumor growth through inhibition of ERK and Akt in human ovarian cancer cells. These data suggest that silibinin may serve as a potential therapeutic agent for human ovarian cancers.}, }
@article {pmid23567873, year = {2013}, author = {Yamagata, K and Tanaka, N and Suzuki, K}, title = {Epigallocatechin 3-gallate inhibits 7-ketocholesterol-induced monocyte-endothelial cell adhesion.}, journal = {Microvascular research}, volume = {88}, number = {}, pages = {25-31}, doi = {10.1016/j.mvr.2013.03.006}, pmid = {23567873}, issn = {1095-9319}, mesh = {Acetylcysteine/metabolism ; Arteriosclerosis/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Kinase/antagonists &amp; inhibitors ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Adhesion/*drug effects ; Endothelial Cells/*cytology/drug effects ; Enzyme Inhibitors/pharmacology ; Humans ; Intercellular Adhesion Molecule-1/metabolism ; Ketocholesterols/*metabolism ; Lipoproteins, HDL/metabolism ; Monocytes/*cytology/drug effects ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Signal Transduction ; U937 Cells ; }, abstract = {7-Ketocholesterol (7KC) induces monocytic adhesion to endothelial cells, and induces arteriosclerosis while high-density lipoprotein (HDL) inhibits monocytic adhesion to the endothelium. Epigallocatechin 3-gallate (EGCG) was found to have a protective effect against arteriosclerosis. Therefore, the purpose of this study was to examine the possible HDL-like mechanisms of EGCG in endothelial cells by investigating whether EGCG inhibits 7KC-induced monocyte-endothelial cell adhesion by activating HDL-dependent signal transduction pathways. 7KC and/or EGCG were added to human endothelial cells (ISO-HAS), and the adhesion of pro-monocytic U937 cells was examined. The expression of genes associated with HDL effects such as Ca(2+)/calmodulin-dependent kinase II (CaMKKII), liver kinase B (LKD1), PSD-95/Dlg/ZO-1 kinase 1 (PDZK1), phosphatidylinositol 3-kinase (PI3K), intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MCP-1), and endothelial nitric oxide synthase (eNOS) was examined by RT-PCR, and ICAM-1 protein expression was evaluated by western blot (WB). Production of reactive oxygen species (ROS) was examined with H2DCFDA. 7KC significantly induced adhesion of U937 cells to human endothelial cells while significantly increasing gene expressions of ICAM-1 and MCP-1 and decreasing eNOS and CaMKKII gene expressions. EGCG inhibited 7KC-induced monocytic adhesion to endothelial cells, and induced expression of eNOS and several genes involved in the CaMKKII pathway. Stimulation of endothelial cells with EGCG produced intracellular ROS, whereas treatment with N-acetylcysteine (NAC) blocked EGCG-induced expression of eNOS and CaMKKII. These results suggest that inhibition of monocyte-endothelial cell adhesion by EGCG is associated with CaMKKII pathway activation by ROS. Inhibition of 7KC-induced monocyte-endothelial cell adhesion induced by EGCG may function similarly to HDL.}, }
@article {pmid23560513, year = {2013}, author = {Ucar, F and Taslipinar, MY and Alp, BF and Aydin, I and Aydin, FN and Agilli, M and Toygar, M and Ozkan, E and Macit, E and Oztosun, M and Cayci, T and Ozcan, A}, title = {The effects of N-acetylcysteine and ozone therapy on oxidative stress and inflammation in acetaminophen-induced nephrotoxicity model.}, journal = {Renal failure}, volume = {35}, number = {5}, pages = {640-647}, doi = {10.3109/0886022X.2013.780530}, pmid = {23560513}, issn = {1525-6049}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/pharmacology/*therapeutic use ; Acute Kidney Injury/chemically induced/pathology/*prevention &amp; control ; Analgesics, Non-Narcotic/*poisoning ; Animals ; Drug Evaluation, Preclinical ; Free Radical Scavengers/pharmacology/*therapeutic use ; Kidney/pathology ; Male ; Nephritis/chemically induced/pathology/prevention &amp; control ; Oxidative Stress/drug effects ; Ozone/pharmacology/*therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {INTRODUCTION: Acetaminophen (APAP) is an analgesic and antipyretic agent. In overdoses, it is associated with nephrotoxicity. We examined the potential protective effects of N-acetylcysteine (NAC) and NAC + ozone therapy (OT) combination against APAP-induced nephrotoxicity.<br><br>MATERIALS AND METHODS: Thirty-two male Sprague-Dawley rats were divided into four groups: sham, control (APAP), NAC, and NAC + OT. In the APAP, NAC, and NAC + OT groups, kidney injury was induced by oral administration of 1 g/kg APAP. The NAC group received NAC (100 mg/kg/day). NAC + OT group received NAC (100 mg/kg/day) and ozone/oxygen mixture (0.7 mg/kg/day) intraperitoneally for 5 days immediately after APAP administration. All animals were killed at 5 days after APAP administration. Renal tissues and blood samples were obtained for biochemical and histopathological analyses. Neopterin, tumor necrosis factor-&#x3b1; (TNF-&#x3b1;), interleukin (IL)-6 and IL-10 levels were measured in sera. Malondialdehyde (MDA) levels and glutathione peroxidase (GPx) activities were determined in renal homogenates.<br><br>RESULTS: NAC and NAC + OT significantly decreased MDA and TNF-&#x3b1; levels and increased IL-10 levels and GPx activities. Serum neopterin and IL-6 levels were not different among all groups. APAP administration caused tubular necrosis in the kidney. The degrees of renal necrosis of the APAP group were higher than the other groups. Renal injury in rats treated with combination of NAC and OT were found to be significantly less than the other groups.<br><br>CONCLUSIONS: Our results showed that NAC and OT prevented renal injury in rats and reduced inflammation. These findings suggest that combination of NAC and OT might improve renal damages because of both oxidative stress and inflammation.}, }
@article {pmid23558526, year = {2013}, author = {Marty, C and Lacout, C and Droin, N and Le Couédic, JP and Ribrag, V and Solary, E and Vainchenker, W and Villeval, JL and Plo, I}, title = {A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression.}, journal = {Leukemia}, volume = {27}, number = {11}, pages = {2187-2195}, doi = {10.1038/leu.2013.102}, pmid = {23558526}, issn = {1476-5551}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Bone Marrow Transplantation ; Case-Control Studies ; DNA Damage/drug effects ; Disease Progression ; Female ; Flow Cytometry ; Hematopoietic Stem Cells/cytology/drug effects/metabolism ; Humans ; Immunoenzyme Techniques ; Janus Kinase 2/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloproliferative Disorders/genetics/*metabolism/*pathology ; Point Mutation/*genetics ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; RNA, Messenger/genetics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Although other mutations may predate the acquisition of the JAK2(V617F) mutation, the latter is sufficient to drive the disease phenotype observed in BCR-ABL-negative myeloproliferative neoplasms (MPNs). One of the consequences of JAK2(V617F) is genetic instability that could explain JAK2(V617F)-mediated MPN progression and heterogeneity. Here, we show that JAK2(V617F) induces the accumulation of reactive oxygen species (ROS) in the hematopoietic stem cell compartment of a knock-in (KI) mouse model and in patients with JAK2(V617F) MPNs. JAK2(V617F)-dependent ROS elevation was partly mediated by an AKT-induced decrease in catalase expression and was accompanied by an increased number of 8-oxo-guanines and DNA double-strand breaks (DSBs). Moreover, there was evidence for a mitotic recombination event in mice resulting in loss of heterozygosity of Jak2(V617F). Mice engrafted with 30% of Jak2(V617F) KI bone marrow (BM) cells developed a polycythemia vera-like disorder. Treatment with the anti-oxidant N-acetylcysteine (NAC) substantially restored blood parameters and reduced damages to DNA. Furthermore, NAC induced a marked decrease in splenomegaly with reduction in the frequency of the Jak2(V617F)-positive hematopoietic progenitors in BM and spleen. Altogether, overproduction of ROS is a mediator of JAK2(V617F)-induced DNA damages that promote disease progression. Targeting ROS accumulation might prevent the development of JAK2(V617F) MPNs.}, }
@article {pmid23556549, year = {2013}, author = {Thanacoody, HK and Gray, A and Dear, JW and Coyle, J and Sandilands, EA and Webb, DJ and Lewis, S and Eddleston, M and Thomas, SH and Bateman, DN}, title = {Scottish and Newcastle antiemetic pre-treatment for paracetamol poisoning study (SNAP).}, journal = {BMC pharmacology &amp; toxicology}, volume = {14}, number = {}, pages = {20}, pmid = {23556549}, issn = {2050-6511}, support = {G0800803/MRC_/Medical Research Council/United Kingdom ; SCD/05/CSO_/Chief Scientist Office/United Kingdom ; CZB/4/722/CSO_/Chief Scientist Office/United Kingdom ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage ; Anti-Inflammatory Agents, Non-Steroidal/*poisoning ; Antiemetics/*administration &amp; dosage ; Double-Blind Method ; Humans ; Ondansetron/*administration &amp; dosage ; Scotland ; Vomiting/*prevention &amp; control ; }, abstract = {BACKGROUND: Paracetamol (acetaminophen) poisoning remains the commonest cause of acute liver injury in Europe and North America. The intravenous (IV) N-acetylcysteine (NAC) regimen introduced in the 1970s has continued effectively unchanged. This involves 3 different infusion regimens (dose and time) lasting over 20 hours. The same weight-related dose of NAC is used irrespective of paracetamol dose. Complications include frequent nausea and vomiting, anaphylactoid reactions and dosing errors. We designed a randomised controlled study investigating the efficacy of antiemetic pre-treatment (ondansetron) using standard NAC and a modified, shorter, regimen.<br><br>METHODS/DESIGN: We designed a double-blind trial using a 2 &#xd7; 2 factorial design involving four parallel groups. Pre-treatment with ondansetron 4&#x2009;mg IV was compared against placebo on nausea and vomiting following the standard (20.25&#x2009;h) regimen, or a novel 12&#x2009;h NAC regimen in paracetamol poisoning. Each delivered 300&#x2009;mg/kg bodyweight NAC. Randomisation was stratified on: paracetamol dose, perceived risk factors, and time to presentation. The primary outcome was the incidence of nausea and vomiting following NAC. In addition the frequency of anaphylactoid reactions and end of treatment liver function documented. Where clinically necessary further doses of NAC were administered as per standard UK protocols at the end of the first antidote course.<br><br>DISCUSSION: This study is primarily designed to test the efficacy of prophylactic anti-emetic therapy with ondansetron, but is the first attempt to formally examine new methods of administering IV NAC in paracetamol overdose. We anticipate, from volunteer studies, that nausea and vomiting will be less frequent with the new NAC regimen. In addition as anaphylactoid response appears related to plasma concentrations of both NAC and paracetamol anaphylactoid reactions should be less likely. This study is not powered to assess the relative efficacy of the two NAC regimens, however it will give useful information to power future studies. As the first formal randomised clinical trial in this patient group in over 30&#x2009;years this study will also provide information to support further studies in patients in paracetamol overdose, particularly, when linked with modern novel biomarkers of liver damage, patients at different toxicity risk.<br><br>TRIAL REGISTRATION: EudraCT number 2009-017800-10, ClinicalTrials.gov IdentifierNCT01050270.}, }
@article {pmid23555559, year = {2013}, author = {Owada, S and Shimoda, Y and Tsuchihara, K and Esumi, H}, title = {Critical role of H2O2 generated by NOX4 during cellular response under glucose deprivation.}, journal = {PloS one}, volume = {8}, number = {3}, pages = {e56628}, pmid = {23555559}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Antimetabolites/pharmacology ; Deoxyglucose/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Knockdown Techniques ; *Glucose ; Hep G2 Cells ; Humans ; Hydrogen Peroxide/*metabolism ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/*metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; RNA Interference ; }, abstract = {Glucose is the most efficient energy source, and various cancer cells depend on glycolysis for energy production. For maintenance of survival and proliferation, glucose sensing and adaptation to poor nutritional circumstances must be well organized in cancer cells. While the glucose sensing machinery has been well studied in yeasts, the molecular mechanism of glucose sensing in mammalian cells remains to be elucidated. We have reported glucose deprivation rapidly induces AKT phosphorylation through PI3K activation. We assumed that regulation of AKT is relevant to glucose sensing and further investigated the underlying mechanisms. In this study, AKT phosphorylation under glucose deprivation was inhibited by galactose and fructose, but induced by 2-deoxyglucose (2-DG). Both 2-DG treatment and glucose deprivation were found to induce AKT phosphorylation in HepG2 cells. These findings suggested that glucose transporter may not be involved in the sensing of glucose and induction of AKT phosphorylation, and that downstream metabolic events may have important roles. A variety of metabolic stresses reportedly induce the production of reactive oxygen species (ROS). In the present study, glucose deprivation was found to induce intracellular hydrogen peroxide (H2O2) production in HepG2 cells. N-acetylcysteine (NAC), an antioxidant reagent, reduced both the increase in cellular H2O2 levels and AKT phosphorylation induced by glucose deprivation. These results strongly suggest that the glucose deprivation-induced increase of H2O2 in the cells mediated the AKT phosphorylation. RNA interference of NOX4, but not of NOX5, completely suppressed the glucose deprivation-induced AKT phosphorylation as well as increase of the intracellular levels of ROS, whereas exogenous H2O2 could still induce AKT phosphorylation in the NOX4-knockdown cells. In this study, we demonstrated that the ROS generated by NOX4 are involved in the intracellular adaptive responses by recognizing metabolic flux.}, }
@article {pmid23553137, year = {2013}, author = {Ljubisavljevic, S and Stojanovic, I and Pavlovic, D and Milojkovic, M and Sokolovic, D and Stevanovic, I and Petrovic, A}, title = {Suppression of the lipid peroxidation process in the CNS reduces neurological expression of experimentally induced autoimmune encephalomyelitis.}, journal = {Folia neuropathologica}, volume = {51}, number = {1}, pages = {51-57}, doi = {10.5114/fn.2013.34196}, pmid = {23553137}, issn = {1509-572X}, mesh = {Animals ; Brain/metabolism/pathology ; Encephalomyelitis, Autoimmune, Experimental/*metabolism/*pathology ; Female ; Lipid Peroxidation/*physiology ; Malondialdehyde/analysis ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/chemistry/metabolism/pathology ; }, abstract = {OBJECTIVE: Here we report the influence of malondialdehyde (MDA) as a measure of the lipid peroxidation process (LP), on multiple sclerosis (MS) pathogenesis and its neurological signs, during the treatment with aminoguanidine (AG) - a selective inducible nitric oxide synthase inhibitor and N-Acetyl cysteine (NAC) - an oxidative scavenger, in the experimental autoimmune encephalomyelitis (EAE), an animal model for studying MS.<br><br>MATERIAL AND METHODS: Encephalomyelitis induction by the subcutaneous injection of myelin basic protein of bovine type, dissolved in phosphate buffered saline (PBS) emulsified in equal volume of the complete Freund's adjuvant (CFA), was described in detail in our earlier published papers. Each of animals was randomly assigned to seven groups - control (PBS), EAE, CFA, EAE + AG, AG, EAE + NAC and NAC group. In each animal, the development of neurological signs of EAE was scored, these results were published earlier. MDA was evaluated in the central nervous system (CNS) structure - cerebellums and spinal cords.<br><br>RESULTS: The obtained results show that the AG and NAC treatment significantly reduces the MDA level in both examined tissues (p < 0.05) ameliorating at the same time EAE clinical signs (p < 0.05).<br><br>CONCLUSIONS: Taking together our present and earlier findings we conclude that LP may provoke and promote MS, while blocking of this process results in amelioration of the clinical onset and disease activity. These results may be useful as a new insight into mechanisms and potential targets for therapeutic strategies in MS.}, }
@article {pmid23552724, year = {2013}, author = {Wang, X and Bu, HF and Zhong, W and Asai, A and Zhou, Z and Tan, XD}, title = {MFG-E8 and HMGB1 are involved in the mechanism underlying alcohol-induced impairment of macrophage efferocytosis.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {19}, number = {1}, pages = {170-182}, pmid = {23552724}, issn = {1528-3658}, support = {R21AA020494/AA/NIAAA NIH HHS/United States ; R01AA020212/AA/NIAAA NIH HHS/United States ; R21 AA020494/AA/NIAAA NIH HHS/United States ; R01DK064240/DK/NIDDK NIH HHS/United States ; R01 DK064240/DK/NIDDK NIH HHS/United States ; R01 AA020212/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Antigens, Surface/*physiology ; Cell Line ; Ethanol/*administration &amp; dosage ; HMGB1 Protein/*physiology ; Macrophages, Peritoneal/*drug effects/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Milk Proteins ; Phagocytosis/drug effects/*physiology ; Rats ; }, abstract = {Efferocytosis is a unique phagocytic process for macrophages to remove apoptotic cells in inflammatory loci. This event is maintained by milk fat globule-EGF factor 8 (MFG-E8), but attenuated by high mobility group box 1 (HMGB1). Alcohol abuse causes injury and inflammation in multiple tissues. It alters efferocytosis, but precise molecular mechanisms for this effect remain largely unknown. Here, we showed that acute exposure of macrophages to alcohol (25 mmol/L) inhibited MFG-E8 gene expression and impaired efferocytosis. The effect was mimicked by hydrogen peroxide. Moreover, N-acetylcysteine (NAC), a potent antioxidant, blocked acute alcohol effect on inhibition of macrophage MFG-E8 gene expression and efferocytosis. In addition, recombinant MFG-E8 rescued the activity of alcohol-treated macrophages in efferocytosis. Together, the data suggest that acute alcohol exposure impairs macrophage efferocytosis via inhibition of MFG-E8 gene expression through a reactive oxygen species dependent mechanism. Alcohol has been found to suppress or exacerbate immune cell activities depending on the length of alcohol exposure. Thus, we further examined the role of chronic alcohol exposure on macrophage efferocytosis. Interestingly, treatment of macrophages with alcohol for seven days in vitro enhanced MFG-E8 gene expression and efferocytosis. However, chronic feeding of mice with alcohol caused increase in HMGB1 levels in serum. Furthermore, HMGB1 diminished efferocytosis by macrophages that were treated chronically with alcohol, suggesting that HMGB1 might attenuate the direct effect of chronic alcohol on macrophage efferocytosis in vivo. Therefore, we speculated that the balance between MFG-E8 and HMGB1 levels determines pathophysiological effects of chronic alcohol exposure on macrophage efferocytosis in vivo.}, }
@article {pmid23547745, year = {2013}, author = {Jugg, B and Fairhall, S and Smith, A and Rutter, S and Mann, T and Perrott, R and Jenner, J and Salguero, J and Shute, J and Sciuto, AM}, title = {N-acetyl-L-cysteine protects against inhaled sulfur mustard poisoning in the large swine.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {51}, number = {4}, pages = {216-224}, doi = {10.3109/15563650.2013.780208}, pmid = {23547745}, issn = {1556-9519}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Administration, Inhalation ; Aerosols ; Animals ; Antidotes/administration &amp; dosage/adverse effects/therapeutic use ; Antioxidants/administration &amp; dosage/adverse effects/*therapeutic use ; Bronchoalveolar Lavage Fluid/chemistry/immunology ; Chemical Warfare Agents/analysis/pharmacokinetics/*toxicity ; *Disease Models, Animal ; Expectorants/administration &amp; dosage/adverse effects/therapeutic use ; Female ; Gas Poisoning/*drug therapy/immunology/pathology/physiopathology ; Lung/*drug effects/immunology/pathology/physiopathology ; Lung Diseases/etiology/prevention &amp; control ; Mustard Gas/administration &amp; dosage/analysis/pharmacokinetics/*toxicity ; Neutrophil Infiltration/drug effects ; Random Allocation ; Respiratory Insufficiency/etiology/prevention &amp; control ; Survival Analysis ; Sus scrofa ; }, abstract = {CONTEXT: Sulfur mustard is a blister agent that can cause death by pulmonary damage. There is currently no effective treatment. N-acetyl-L-cysteine (NAC) has mucolytic and antioxidant actions and is an important pre-cursor of cellular glutathione synthesis. These actions may have potential to reduce mustard-induced lung injury.<br><br>OBJECTIVE: Evaluate the effect of nebulised NAC as a post-exposure treatment for inhaled sulfur mustard in a large animal model.<br><br>MATERIALS AND METHODS: Fourteen anesthetized, surgically prepared pigs were exposed to sulfur mustard vapor (100 &#x3bc;g.kg&#x207b;&#xb9;), 10 min) and monitored, spontaneously breathing, to 12 h. Control animals had no further intervention (n = 6). Animals in the treatment group were administered multiple inhaled doses of NAC (1 ml of 200 mg.ml&#x207b;&#xb9; Mucomyst&#x2122; at + 30 min, 2, 4, 6, 8, and 10 h post-exposure, n = 8). Cardiovascular and respiratory parameters were recorded. Arterial blood was collected for blood gas analysis while blood and bronchoalveolar lavage fluid were collected for hematology and inflammatory cell analysis. Urine was collected to detect a sulfur mustard breakdown product. Lung tissue samples were taken for histopathological and post-experimental analyses.<br><br>RESULTS: Five of six sulfur mustard-exposed animals survived to 12 h. Arterial blood oxygenation (PaO&#x2082;) and saturation levels were significantly decreased at 12 h. Arterial blood carbon dioxide (PaCO&#x2082;) significantly increased, and arterial blood pH and bicarbonate (HCO&#x2083;&#x207b;) significantly decreased at 12 h. Shunt fraction was significantly increased at 12 h. In the NAC-treated group all animals survived to 12 h (n = 8). There was significantly improved arterial blood oxygen saturation, HCO&#x2083;&#x207b; levels, and shunt fraction compared to those of the sulfur mustard controls. There were significantly fewer neutrophils and lower concentrations of protein in lavage compared to sulfur mustard controls.<br><br>DISCUSSION: NAC's mucolytic and antioxidant properties may be responsible for the beneficial effects seen, improving clinically relevant physiological indices affected by sulfur mustard exposure.<br><br>CONCLUSION: Beneficial effects of nebulized NAC were apparent following inhaled sulfur mustard exposure. Further therapeutic benefit may result from a combination therapy approach.}, }
@article {pmid23547683, year = {2013}, author = {Manna, P and Das, J and Sil, PC}, title = {Role of sulfur containing amino acids as an adjuvant therapy in the prevention of diabetes and its associated complications.}, journal = {Current diabetes reviews}, volume = {9}, number = {3}, pages = {237-248}, doi = {10.2174/1573399811309030005}, pmid = {23547683}, issn = {1875-6417}, mesh = {3T3-L1 Cells/drug effects ; Amino Acids, Sulfur/*pharmacology ; Animals ; Blood Glucose/*drug effects/metabolism ; Cells, Cultured ; Cysteine/pharmacology ; Diabetes Mellitus, Experimental/blood/*drug therapy/prevention &amp; control ; Diabetes Mellitus, Type 1/blood/drug therapy/*prevention &amp; control ; Diabetes Mellitus, Type 2/blood/drug therapy/*prevention &amp; control ; Humans ; Hyperglycemia/blood/*drug therapy ; Inflammation ; Methionine/pharmacology ; Mice ; Oxidative Stress/*drug effects ; Rats ; Taurine/pharmacology ; }, abstract = {Amino acid supplementation is gaining acceptance as an important adjuvant therapy in the treatment of diabetes and its associated complications. Numerous studies in the literature report the impaired amino acid metabolism in diabetes and the beneficial effects of amino acids are positively correlated with the increase in plasma levels of those amino acids. Oxidative stress is known to play a major role in diabetic pathophysiology. Sulfur containing compounds are well known in the treatment of oxidative stress induced pathological disorders. Methionine, cysteine, and homocysteine are the three common sulfur containing amino acids. In addition, taurine, a sulfonic acid containing an amino group (amino sulfonic acid), is found in substantial amounts in mammalian tissues. Both experimental and clinical studies reported the modulatory effects of cysteine, N-acetyl cysteine, or compounds having cysteine moiety in the regulation of insulin secretion and plasma glucose levels. Taurine supplementation has been found to prevent the onset of diabetes mellitus in experimental models of both insulin dependent and insulin independent pathways. Recent reports suggest that the beneficial role of cysteine or taurine is mediated via their ability in reducing glycooxidation and preventing the generation of intracellular reactive intermediates. Studies with methionine or S-adinosyl methionine has been shown to increase mitochondrial DNA density in skeletal muscle, improve insulin sensitivity and prevent body weight gain. Homocysteine, on the other hand, is an emerging risk factor for cardiovascular disease and diabetic patients have higher levels of this sulfur containing amino acid. Supplementation with cysteine or taurine, however, was found to be effective in reducing plasma homocysteine levels. This review will discuss the role of sulfur containing amino acids in the regulation of hyperglycemia and in the development of its associated pathological dysfunctions.}, }
@article {pmid23546866, year = {2013}, author = {Ahn, J and Won, M and Choi, JH and Kim, YS and Jung, CR and Im, DS and Kyun, ML and Lee, K and Song, KB and Chung, KS}, title = {Reactive oxygen species-mediated activation of the Akt/ASK1/p38 signaling cascade and p21(Cip1) downregulation are required for shikonin-induced apoptosis.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {18}, number = {7}, pages = {870-881}, doi = {10.1007/s10495-013-0835-5}, pmid = {23546866}, issn = {1573-675X}, mesh = {Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/*genetics/metabolism ; Drugs, Chinese Herbal/*pharmacology ; *Gene Expression Regulation, Neoplastic ; Humans ; MAP Kinase Kinase Kinase 5/*genetics/metabolism ; Naphthoquinones/*pharmacology ; Proto-Oncogene Proteins c-akt/*genetics/metabolism ; RNA, Small Interfering/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/*genetics/metabolism ; }, abstract = {Shikonin derivatives exert powerful cytotoxic effects, induce apoptosis and escape multidrug resistance in cancer. However, the diverse mechanisms underlying their anticancer activities are not completely understood. Here, we demonstrated that shikonin-induced apoptosis is caused by reactive oxygen species (ROS)-mediated activation of Akt/ASK1/p38 mitogen-activated protein kinase (MAPK) and downregulation of p21(Cip1). In the presence of shikonin, inactivation of Akt caused apoptosis signal-regulating kinase 1 (ASK1) dephosphorylation at Ser83, which is associated with ASK1 activation. Shikonin-induced apoptosis was enhanced by inhibition of Akt, whereas overexpression of constitutively active Akt prevented apoptosis through modulating ASK1 phosphorylation. Silencing ASK1 and MKK3/6 by siRNA reduced the activation of MAPK kinases (MKK) 3/6 and p38 MAPK, and apoptosis, respectively. Antioxidant N-acetyl cysteine attenuated ASK1 dephosphorylation and p38 MAPK activation, indicating that shikonin-induced ROS is involved in the activation of Akt/ASK1/p38 pathway. Expression of p21(Cip1) was significantly induced in early response, but gradually decreased by prolonged exposure to shikonin. Overexpression of p21(Cip1) have kept cells longer in G1 phase and attenuated shikonin-induced apoptosis. Depletion of p21(Cip1) facilitated shikonin-induced apoptosis, implying that p21(Cip1) delayed shikonin-induced apoptosis via G1 arrest. Immunohistochemistry and in vitro binding assays showed transiently altered localization of p21(Cip1) to the cytoplasm by shikonin, which was blocked by Akt inhibition. The cytoplasmic p21(Cip1) actually binds to and inhibits the activity of ASK1, regulating the cell cycle progression at G1. These findings suggest that shikonin-induced ROS activated ASK1 by decreasing Ser83 phosphorylation and by dissociation of the negative regulator p21(Cip1), leading to p38 MAPK activation, and finally, promoting apoptosis.}, }
@article {pmid23545271, year = {2013}, author = {Nazıroğlu, M and Ciğ, B and Ozgül, C}, title = {Neuroprotection induced by N-acetylcysteine against cytosolic glutathione depletion-induced Ca2+ influx in dorsal root ganglion neurons of mice: role of TRPV1 channels.}, journal = {Neuroscience}, volume = {242}, number = {}, pages = {151-160}, doi = {10.1016/j.neuroscience.2013.03.032}, pmid = {23545271}, issn = {1873-7544}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Buthionine Sulfoximine/pharmacology ; Calcium/*metabolism ; Calcium Signaling ; Capsaicin/analogs &amp; derivatives/pharmacology ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cytosol/metabolism ; Drug Interactions ; Ganglia, Spinal/*cytology/drug effects/metabolism ; Glutathione/*deficiency ; Lipid Peroxidation/drug effects ; Male ; Membrane Potentials/drug effects/physiology ; Mice ; Neurons/drug effects/*metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Oxidative Stress/*drug effects/physiology ; Reactive Oxygen Species/metabolism ; TRPV Cation Channels/agonists/antagonists &amp; inhibitors/*physiology ; }, abstract = {Glutathione (GSH) and N-acetylcysteine (NAC) are thiol-containing antioxidants, and also act through a direct reaction with free radicals. Transient receptor potential vanilloid 1 (TRPV1) is the principal transduction channel serving as a polymodal detector. Despite the importance of oxidative stress in pain sensitivity, its role in TRPV1 modulation is poorly understood. NAC may also have a regulator role on TRPV1 channel activity in the dorsal root ganglion (DRG) neuron. Therefore, we tested the effects of GSH and NAC on TRPV1 channel current, Ca(2+) influx, oxidative stress and caspase activity in the DRG of mice. DRG neurons were freshly isolated from mice and the neurons were incubated for 6 and 24h with buthionine sulfoximine (BSO). Pretreatment of cultured DRG neurons with NAC, results in a protection against oxidative damages. This neuroprotection is associated with the attenuation of a Ca(2+) influx triggered by oxidative agents such as H2O2, 5,5'-dithiobis-(2-nitrobenzoic acid) and GSH depletion via BSO. Here, we demonstrate the contribution of cytosolic factors (related to thiol group depletion) on the activation of TRPV1 channels in this mechanism. TRPV1 channels are activated by various agents including capsaicin (CAP), the pungent component of hot chili peppers, and are blocked by capsazepine. An oxidative environment also increased CAP-evoked TRPV1 currents in the neurons. When NAC and GSH were included in the patch pipette as well as extracellularly in the chamber, TRPV1 channels were not activated by CAP and H2O2. TRPV1 inhibitors, 2-aminoethyl diphenylborinate and N-(p-amylcinnamoyl)anthranilic acid strongly reduced BSO-induced oxidative toxicity and Ca(2+) influx, in a manner similar to pretreatment with NAC and GSH. Caspase-3 and -9 activities of all groups were not changed by the agonists or antagonists. In conclusion, in our experimental model, TRPV1 channels are involved in the oxidative stress-induced neuronal death, and negative modulation of this channel activity by GSH and NAC pretreatment may account for their neuroprotective activity against oxidative stress.}, }
@article {pmid23543867, year = {2013}, author = {Hiremath, SB and Srinivas, LD}, title = {Survival benefits of terlipressin and non-responder state in hepatorenal syndrome: a meta-analysis.}, journal = {Indian journal of pharmacology}, volume = {45}, number = {1}, pages = {54-60}, pmid = {23543867}, issn = {1998-3751}, mesh = {Dose-Response Relationship, Drug ; Hepatorenal Syndrome/*drug therapy/mortality ; Humans ; Lypressin/administration &amp; dosage/*analogs &amp; derivatives ; Survival Rate ; Terlipressin ; Time Factors ; Treatment Outcome ; Vasoconstrictor Agents/*administration &amp; dosage ; }, abstract = {OBJECTIVES: Terlipressin improves renal function in hepatorenal syndrome (HRS) is a known fact. However the reason for lack of its long-term survival benefits despite improvement in renal function remains unclear. The aim of this study was to analyze the survival benefits of terlipressin in HRS and to address the issue of non-responder state to terlipressin.<br><br>MATERIALS AND METHODS: Electronic databases and relevant articles were searched for all types of studies related to HRS and use of terlipressin in HRS. Reduction in all-cause mortality rate was the primary outcome measure. Reduction in mortality rate due to HRS and other causes of death were also analyzed.<br><br>RESULTS: With total 377 patients analyzed from eight eligible studies; terlipressin reduced all-cause mortality rate by 15% (Risk Difference: -0.15%, 95% CI:-0.26 to -0.03). Reduction in the mortality rate due to HRS at three months was 9% (Risk Difference:-0.09%, 95% CI:-0.18 to 0.00).<br><br>CONCLUSION: Terlipressin has long term survival benefits perhaps at least up to three months but only with HRS as a cause of death not for other causes of death. Benefits and role of antioxidants like N- Acetylcysteine (NAC) in non-responder patients' needs to be studied further. Long-term use of low dose terlipressin (<4 mg/d) plus albumin and addition of antioxidant NAC to this regimen may help in improving both HRS reversal rate and survival rate in non-responders to terlipressin.}, }
@article {pmid23543627, year = {2012}, author = {Balaji, SN and Trivedi, V}, title = {Extracellular Methemoglobin Mediated Early ROS Spike Triggers Osmotic Fragility and RBC Destruction: An Insight into the Enhanced Hemolysis During Malaria.}, journal = {Indian journal of clinical biochemistry : IJCB}, volume = {27}, number = {2}, pages = {178-185}, pmid = {23543627}, issn = {0970-1915}, abstract = {Malaria infection is known to cause severe hemolysis due to production of abnormal RBCs and enhanced RBC destruction through apoptosis. Infected RBC lysis exposes uninfected RBC to the large amount of pro-oxidant molecules such as methemoglobin. Methemoglobin (MetHb) exposure dose dependently makes RBCs susceptible to osmotic stress and causes hemolysis. MetHb mediated oxidative stress in RBC correlated well with osmotic fragility and hemolysis. Interestingly, a reactive oxygen species (ROS) spike at 15 min was responsible for the observed effects on RBC cells. Two natural antioxidants N-acetyl cysteine and mannitol protected the RBC from MetHb-mediated defects, which clearly indicated involvement of oxidative stress in the process. MetHb due to its pseudo-peroxidase activity produces ROS in the external microenvironment. Therefore, classical peroxidase inhibitors were tested to probe peroxidase activity mediated ROS production with defects in RBCs. Clotrimazole (CLT), which irreversibly inactivates the MetHb (CLT-MetHb) and abolishes peroxidase activity, did not produce significant ROS outside RBC and was inefficient to cause osmotic fragility and hemolysis. Hence, initiating a chain reaction, MetHb released from ruptured RBC produces significant ROS in the external microenvironment to make RBC membrane leaky and enhanced hemolysis. Together data presented in the current work explored the role of MetHb in accelerated humorless during malaria which could be responsible for severe outcomes of pathological disorders.}, }
@article {pmid23537951, year = {2013}, author = {Soejima, Y and Hu, Q and Krafft, PR and Fujii, M and Tang, J and Zhang, JH}, title = {Hyperbaric oxygen preconditioning attenuates hyperglycemia-enhanced hemorrhagic transformation by inhibiting matrix metalloproteinases in focal cerebral ischemia in rats.}, journal = {Experimental neurology}, volume = {247}, number = {}, pages = {737-743}, pmid = {23537951}, issn = {1090-2430}, support = {R01 HD043120/HD/NICHD NIH HHS/United States ; R01 NS043338/NS/NINDS NIH HHS/United States ; NS043338/NS/NINDS NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Blood Glucose ; Cerebral Hemorrhage/*etiology/*prevention &amp; control ; Cerebral Infarction/etiology/prevention &amp; control ; Cobalt/pharmacology ; Disease Models, Animal ; Free Radical Scavengers/therapeutic use ; Gene Expression Regulation/drug effects/physiology ; Glucose/toxicity ; Hemoglobins/metabolism ; Hyperbaric Oxygenation/*methods ; Hyperglycemia/chemically induced/*complications ; Infarction, Middle Cerebral Artery/*complications ; Ischemic Preconditioning/*methods ; Male ; Metalloproteases/*metabolism ; Neurologic Examination ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Spectrophotometry ; Time Factors ; }, abstract = {Hyperglycemia dramatically aggravates brain infarct and hemorrhagic transformation (HT) after ischemic stroke. Oxidative stress and matrix metalloproteinases (MMPs) play an important role in the pathophysiology of HT. Hyperbaric oxygen preconditioning (HBO-PC) has been proved to decrease oxidative stress and has been demonstrated to be neuroprotective in experimental stroke models. The present study determined whether HBO-PC would ameliorate HT by a pre-ischemic increase of reactive oxygen species (ROS) generation, and a suppression of MMP-2 and MMP-9 in hyperglycemic middle cerebral artery occlusion (MCAO) rats. Rats were pretreated with HBO (100% O2, 2.5 atmosphere absolutes) 1 h daily for 5 days before MCAO. Acute hyperglycemia was induced by an injection of 50% dextrose. Neurological deficits, infarction volume and hemorrhagic volume were assessed 24 h and 7 days after ischemia. ROS scavenger n-acetyl cysteine (NAC), hypoxia-inducible factor-1α (HIF-1α), inhibitor 2-methoxyestradiol (2ME2) and activator cobalt chloride (CoCl2), and MMP inhibitor SB-3CT were administrated for mechanism study. The activity of MMP-2 and MMP-9, and the expression HIF-1α were measured. HBO-PC improved neurological deficits, and reduced hemorrhagic volume; the expression of HIF-1α was significantly decreased, and the activity of MMP-2 and MMP-9 was reduced by HBO-PC compared with vehicle group. Our results suggested that HBO-PC attenuated HT via decreasing HIF-1α and its downstream MMP-2 and MMP-9 in hyperglycemic MCAO rats.}, }
@article {pmid23537042, year = {2013}, author = {Aldbass, AM and Bhat, RS and El-Ansary, A}, title = {Protective and therapeutic potency of N-acetyl-cysteine on propionic acid-induced biochemical autistic features in rats.}, journal = {Journal of neuroinflammation}, volume = {10}, number = {}, pages = {42}, pmid = {23537042}, issn = {1742-2094}, mesh = {Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Autistic Disorder/*chemically induced/pathology/*prevention &amp; control ; Brain/drug effects/metabolism ; Comet Assay ; DNA/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Glutathione Transferase/metabolism ; Interferon-gamma/metabolism ; Male ; Neuroprotective Agents/*therapeutic use ; Propionates/*toxicity ; ROC Curve ; Rats ; Serotonin/metabolism ; }, abstract = {BACKGROUND: The investigation of the environmental contribution for developmental neurotoxicity is very critical. Many environmental chemical exposures are now thought to contribute to the development of neurological disorders, especially in children. Results from animal studies may guide investigations of human populations towards identifying either environmental toxicants that cause or drugs that protect from neurotoxicity and may help in treatment of neurodevelopmental disorders.<br><br>OBJECTIVE: To study both the protective and therapeutic effects of N-acetyl cysteine on brain intoxication induced by propionic acid (PPA) in rats.<br><br>METHODS: Twenty-eight young male Western Albino rats were enrolled in the present study. They were grouped into four equal groups, each of 7 animals. Group 1: control group, orally received only phosphate buffered saline; Group 2: PPA-treated group, received a neurotoxic dose of of PPA of 250&#xa0;mg/kg body weight/day for 3&#xa0;days; Group 3: protective group, received a dose of 50&#xa0;mg/kg body weight/day&#xa0;N-acetyl-cysteine for one week followed by a similar dose of PPA for 3&#xa0;days; and Group 4: therapeutic group, treated with the same dose of N-acetyl cysteine after being treated with the toxic dose of PPA. Serotonin, interferon gamma (IFN-&#x3b3;), and glutathione-s-transferase activity, together with Comet DNA were assayed in the brain tissue of rats in all different groups.<br><br>RESULTS: The obtained data showed that PPA caused multiple signs of brain toxicity as measured by depletion of serotonin (5HT), increase in IFN-&#x3b3; and inhibition of glutathione-s-transferase activity as three biomarkers of brain dysfunction. Additionally Comet DNA assay showed remarkably higher tail length, tail DNA % damage and tail moment. N-acetyl-cysteine was effective in counteracting the neurotoxic effects of PPA.<br><br>CONCLUSIONS: The low dose and the short duration of N-acetyl-cysteine treatment tested in the present study showed much more protective rather than therapeutic effects on PPA-induced neurotoxicity in rats, as there was a remarkable amelioration in the impaired biochemical parameters representing neurochemical, inflammatory, detoxification and DNA damage processes.}, }
@article {pmid23536801, year = {2013}, author = {Posimo, JM and Titler, AM and Choi, HJ and Unnithan, AS and Leak, RK}, title = {Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.}, journal = {PloS one}, volume = {8}, number = {3}, pages = {e58596}, pmid = {23536801}, issn = {1932-6203}, mesh = {Animals ; Autophagy ; Cell Survival/drug effects ; *Cellular Senescence ; Cerebral Cortex/drug effects/*metabolism ; Female ; Glutathione/metabolism ; Hydrogen Peroxide/toxicity ; Leupeptins/toxicity ; Microtubule-Associated Proteins/metabolism ; Neocortex/drug effects/*metabolism ; Neurons/drug effects/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Rats ; *Stress, Physiological ; Ubiquitin/metabolism ; }, abstract = {In Parkinson's and Alzheimer's diseases, the allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middle age. PA28 levels rose with age and were higher in allocortex in vivo, also paralleling in vitro data. These neo- and allocortical differences have implications for the many studies that treat the telencephalic mantle as a single unit. Our observations suggest that the topographic progression of protein aggregations through the cerebrum may reflect differential responses to low level protein-misfolding stress but also reveal impressive compensatory adaptations in allocortex.}, }
@article {pmid23536773, year = {2013}, author = {Fraternale, A and Crinelli, R and Casabianca, A and Paoletti, MF and Orlandi, C and Carloni, E and Smietana, M and Palamara, AT and Magnani, M}, title = {Molecules altering the intracellular thiol content modulate NF-kB and STAT-1/IRF-1 signalling pathways and IL-12 p40 and IL-27 p28 production in murine macrophages.}, journal = {PloS one}, volume = {8}, number = {3}, pages = {e57866}, pmid = {23536773}, issn = {1932-6203}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Animals ; Cell Line ; Cysteamine/analogs &amp; derivatives/pharmacology ; Enzyme Activation ; Female ; Glutathione/analogs &amp; derivatives/pharmacology ; Interferon Regulatory Factor-1/*metabolism ; Interleukin-12 Subunit p40/*biosynthesis/genetics ; Interleukin-27/*biosynthesis/genetics ; Macrophages/drug effects/immunology/*metabolism ; Mice ; NF-kappa B/*metabolism ; Phosphorylation ; STAT1 Transcription Factor/*metabolism ; *Signal Transduction/drug effects ; Sulfhydryl Compounds/analysis/chemistry ; }, abstract = {BACKGROUND: The aim of this study was to investigate the molecular mechanisms involved in the production of Th1 cytokines, namely IL-12 and IL-27, when the intra-macrophage redox state was altered by different chemical entities such as GSH-C4, which is reduced glutathione carrying an aliphatic chain, or I-152, a pro-drug of N-acetyl-cysteine (NAC) and beta-mercaptoethylamine. We had already demonstrated that GSH-C4 and I-152 could shift the immune response towards Th1 in Ovalbumin-immunized mice as well as enhance Th1 response in HIV-1 Tat-immunized mice.<br><br>By a new high performance liquid chromatography method, we found that 20 mM GSH-C4 provided a number of thiol species in the form of GSH, while 20 mM I-152 decreased GSH and increased the thiols in the form of NAC and I-152. Under these experimental conditions, GSH-C4 and I-152 enhanced and suppressed respectively the mRNA expression levels of IL-12 p40 induced by LPS/IFN-&#x3b3; as assessed by Real-Time PCR. The protein production of IL-12 p40 was increased by GSH-C4 and decreased by I-152 as determined by Enzyme-linked immunosorbent assay. Western immunoblot and electrophoretic mobility shift assays revealed that Nuclear Factor -kB (NF-kB) activation was inhibited by I-152 and prolonged by GSH-C4. Twenty mM I-152 stimulated IL-27 p28 gene expression and sustained Signal Transducer and Activator of Transcription (STAT)-mediated interferon regulator factor 1 (IRF-1) de novo synthesis. By contrast, 20 mM GSH-C4 did not exert any effect on IL-27 p28 gene expression.<br><br>CONCLUSIONS AND SIGNIFICANCE: an increase in the intra-macrophage redox state by GSH-C4 and I-152 enhances Th1 cytokine production although the chemical structure and the intra-cellular metabolism influence differently signalling pathways involved in IL-27 or IL-12 production. GSH-C4 and I-152 may be used as Th1 immunomodulators in some pathologies and in ageing where GSH depletion may contribute to the Th1/Th2 imbalance, and in new immunization strategies.}, }
@article {pmid23535373, year = {2013}, author = {Kwon, DH and Kim, BS and Chang, H and Kim, YI and Jo, SA and Leem, YH}, title = {Exercise ameliorates cognition impairment due to restraint stress-induced oxidative insult and reduced BDNF level.}, journal = {Biochemical and biophysical research communications}, volume = {434}, number = {2}, pages = {245-251}, doi = {10.1016/j.bbrc.2013.02.111}, pmid = {23535373}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/metabolism ; Animals ; Brain-Derived Neurotrophic Factor/*metabolism ; Cognition/drug effects/*physiology ; Cognition Disorders/metabolism/pathology/*prevention &amp; control ; Corticosterone/blood ; Dose-Response Relationship, Drug ; Exercise Test/methods ; Hippocampus/drug effects/metabolism/pathology ; Hydrogen Peroxide/pharmacology ; Immunohistochemistry ; Male ; Malondialdehyde/metabolism ; Maze Learning/drug effects/physiology ; Mice ; Mice, Inbred C57BL ; *Oxidative Stress ; Phosphorylation ; *Physical Conditioning, Animal ; Primary Cell Culture ; Reactive Oxygen Species/metabolism ; Restraint, Physical/methods ; Signal Transduction ; Stress, Psychological/metabolism/*pathology ; }, abstract = {We assessed whether chronic treadmill exercise attenuated restraint stress-induced cognition impairment. Although serum corticosterone was not significantly altered by exercise, the restraint-induced increases in hippocampal malondialdehyde (MDA) and 4-hydroxynonenal (HNE) were reduced by chronic exercise. The exercise paradigm also reversed stress-induced reductions in brain-derived neurotrophic factor (BDNF), which increased cAMP response element-binding protein (CREB) and AKT activation. We verified the relationship between oxidative stress and BDNF signaling by treating primary hippocampal cultures with hydrogen peroxide (H2O2), which reduced BDNF and phosphorylated CREB and AKT (p-CREB, p-AKT) in a dose-dependent manner. Notably, pretreatment with N-acetylcysteine (NAC) reversed these decreases in a dose-dependent manner. These findings suggest that chronic exercise can ameliorate repeated stress-induced cognitive impairment by detoxifying reactive oxygen species (ROS) in the hippocampus and activating BDNF signaling.}, }
@article {pmid23533997, year = {2013}, author = {Khan, M and Li, T and Ahmad Khan, MK and Rasul, A and Nawaz, F and Sun, M and Zheng, Y and Ma, T}, title = {Alantolactone induces apoptosis in HepG2 cells through GSH depletion, inhibition of STAT3 activation, and mitochondrial dysfunction.}, journal = {BioMed research international}, volume = {2013}, number = {}, pages = {719858}, pmid = {23533997}, issn = {2314-6141}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caspase 3/biosynthesis ; Glutathione/*metabolism ; Hep G2 Cells ; Humans ; Lactones/antagonists &amp; inhibitors/*pharmacology ; Liver Neoplasms/genetics/*metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/*biosynthesis ; Sesquiterpenes, Eudesmane/antagonists &amp; inhibitors/*pharmacology ; Signal Transduction ; Transcriptional Activation/drug effects ; bcl-2-Associated X Protein/biosynthesis ; }, abstract = {Signal transducer and activator of transcription 3 (STAT3) constitutively expresses in human liver cancer cells and has been implicated in apoptosis resistance and tumorigenesis. Alantolactone, a sesquiterpene lactone, has been shown to possess anticancer activities in various cancer cell lines. In our previous report, we showed that alantolactone induced apoptosis in U87 glioblastoma cells via GSH depletion and ROS generation. However, the molecular mechanism of GSH depletion remained unexplored. The present study was conducted to envisage the molecular mechanism of alantolactone-induced apoptosis in HepG2 cells by focusing on the molecular mechanism of GSH depletion and its effect on STAT3 activation. We found that alantolactone induced apoptosis in HepG2 cells in a dose-dependent manner. This alantolactone-induced apoptosis was found to be associated with GSH depletion, inhibition of STAT3 activation, ROS generation, mitochondrial transmembrane potential dissipation, and increased Bax/Bcl-2 ratio and caspase-3 activation. This alantolactone-induced apoptosis and GSH depletion were effectively inhibited or abrogated by a thiol antioxidant, N-acetyl-L-cysteine (NAC). The data demonstrate clearly that intracellular GSH plays a central role in alantolactone-induced apoptosis in HepG2 cells. Thus, alantolactone may become a lead chemotherapeutic candidate for the treatment of liver cancer.}, }
@article {pmid23533664, year = {2013}, author = {Luo, H and Yang, A and Schulte, BA and Wargovich, MJ and Wang, GY}, title = {Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage.}, journal = {PloS one}, volume = {8}, number = {3}, pages = {e60065}, pmid = {23533664}, issn = {1932-6203}, support = {P30 CA138313/CA/NCI NIH HHS/United States ; R21 HL106451/HL/NHLBI NIH HHS/United States ; CA138313/CA/NCI NIH HHS/United States ; HL106451/HL/NHLBI NIH HHS/United States ; }, mesh = {Blotting, Western ; Cell Line, Tumor ; Cellular Senescence/*drug effects ; DNA Damage/*drug effects ; Flow Cytometry ; Humans ; Lung Neoplasms/*genetics ; Reactive Oxygen Species/*metabolism ; Resveratrol ; Reverse Transcriptase Polymerase Chain Reaction ; Stilbenes/*pharmacology ; }, abstract = {Resveratrol (RV) is a natural component of red wine and grapes that has been shown to be a potential chemopreventive and anticancer agent. However, the molecular mechanisms underlying RV's anticancer and chemopreventive effects are incompletely understood. Here we show that RV treatment inhibits the clonogenic growth of non-small cell lung cancer (NSCLC) cells in a dose-dependent manner. Interestingly, the tumor-suppressive effect of low dose RV was not associated with any significant changes in the expression of cleaved PARP and activated caspase-3, suggesting that low dose RV treatment may suppress tumor cell growth via an apoptosis-independent mechanism. Subsequent studies reveal that low dose RV treatment induces a significant increase in senescence-associated β-galactosidase (SA-β-gal) staining and elevated expression of p53 and p21 in NSCLC cells. Furthermore, we show that RV-induced suppression of lung cancer cell growth is associated with a decrease in the expression of EF1A. These results suggest that RV may exert its anticancer and chemopreventive effects through the induction of premature senescence. Mechanistically, RV-induced premature senescence correlates with increased DNA double strand breaks (DSBs) and reactive oxygen species (ROS) production in lung cancer cells. Inhibition of ROS production by N-acetylcysteine (NAC) attenuates RV-induced DNA DSBs and premature senescence. Furthermore, we show that RV treatment markedly induces NAPDH oxidase-5 (Nox5) expression in both A549 and H460 cells, suggesting that RV may increase ROS generation in lung cancer cells through upregulating Nox5 expression. Together, these findings demonstrate that low dose RV treatment inhibits lung cancer cell growth via a previously unappreciated mechanism, namely the induction of premature senescence through ROS-mediated DNA damage.}, }
@article {pmid23533505, year = {2013}, author = {Chen, CY and Chen, KC and Yang, TY and Liu, HC and Hsu, SL}, title = {Gallic Acid Induces a Reactive Oxygen Species-Provoked c-Jun NH2-Terminal Kinase-Dependent Apoptosis in Lung Fibroblasts.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2013}, number = {}, pages = {613950}, pmid = {23533505}, issn = {1741-427X}, abstract = {Idiopathic pulmonary fibrosis is a chronic lung disorder characterized by fibroblasts proliferation and extracellular matrix accumulation. Induction of fibroblast apoptosis therefore plays a crucial role in the resolution of this disease. Gallic acid (3,4,5-trihydroxybenzoic acid), a common botanic phenolic compound, has been reported to induce apoptosis in tumor cell lines and renal fibroblasts. The present study was undertaken to examine the role of mitogen-activated protein kinases (MAPKs) in lung fibroblasts apoptosis induced by gallic acid. We found that treatment with gallic acid resulted in activation of c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and protein kinase B (PKB, Akt), but not p38MAPK, in mouse lung fibroblasts. Inhibition of JNK using pharmacologic inhibitor (SP600125) and genetic knockdown (JNK specific siRNA) significantly inhibited p53 accumulation, reduced PUMA and Fas expression, and abolished apoptosis induced by gallic acid. Moreover, treatment with antioxidants (vitamin C, N-acetyl cysteine, and catalase) effectively diminished gallic acid-induced hydrogen peroxide production, JNK and p53 activation, and cell death. These observations imply that gallic acid-mediated hydrogen peroxide formation acts as an initiator of JNK signaling pathways, leading to p53 activation and apoptosis in mouse lung fibroblasts.}, }
@article {pmid23528858, year = {2013}, author = {Friedman, E}, title = {Mirk/dyrk1B Kinase in Ovarian Cancer.}, journal = {International journal of molecular sciences}, volume = {14}, number = {3}, pages = {5560-5575}, pmid = {23528858}, issn = {1422-0067}, abstract = {Mirk/dyrk1B kinase is expressed in about 75% of resected human ovarian cancers and in most ovarian cancer cell lines with amplification in the OVCAR3 line. Mirk (minibrain-related kinase) is a member of the Minibrain/dyrk family of related serine/threonine kinases. Mirk maintains cells in a quiescent state by stabilizing the CDK inhibitor p27 and by inducing the breakdown of cyclin D isoforms. Mirk also stabilizes the DREAM complex, which maintains G0 quiescence by sequestering transcription factors needed to enter cycle. By entering a quiescent state, tumor cells can resist the nutrient deficiencies, hypoxic and acidic conditions within the tumor mass. Mirk maintains the viability of quiescent ovarian cancer cells by reducing intracellular levels of reactive oxygen species. CDKN2A-negative ovarian cancer cells treated with a Mirk kinase inhibitor escaped G0/G1 quiescence, entered cycle with high ROS levels and underwent apoptosis. The ROS scavenger N-acetyl cysteine reduced the extent of cancer cell loss. In contrast, the Mirk kinase inhibitor slightly reduced the fraction of G0 quiescent diploid epithelial cells and fibroblasts, and the majority of the cells pushed into cycle accumulated in G2 + M. Apoptotic sub-G0/G1 cells were not detected. Thus, normal cells were spared because of their expression of CDK inhibitors that blocked unregulated cycling and Mirk kinase inhibitor-treated normal diploid cells were about as viable as untreated controls.}, }
@article {pmid23526214, year = {2013}, author = {Mathew, B and Jacobson, JR and Siegler, JH and Moitra, J and Blasco, M and Xie, L and Unzueta, C and Zhou, T and Evenoski, C and Al-Sakka, M and Sharma, R and Huey, B and Bulent, A and Smith, B and Jayaraman, S and Reddy, NM and Reddy, SP and Fingerle-Rowson, G and Bucala, R and Dudek, SM and Natarajan, V and Weichselbaum, RR and Garcia, JG}, title = {Role of migratory inhibition factor in age-related susceptibility to radiation lung injury via NF-E2-related factor-2 and antioxidant regulation.}, journal = {American journal of respiratory cell and molecular biology}, volume = {49}, number = {2}, pages = {269-278}, pmid = {23526214}, issn = {1535-4989}, support = {AI 42310/AI/NIAID NIH HHS/United States ; R56 AI042310/AI/NIAID NIH HHS/United States ; HL 58094/HL/NHLBI NIH HHS/United States ; P01 HL098050/HL/NHLBI NIH HHS/United States ; R01 AI042310/AI/NIAID NIH HHS/United States ; P01 HL058064/HL/NHLBI NIH HHS/United States ; }, mesh = {Acute Lung Injury/genetics/*metabolism/pathology/prevention &amp; control ; Aging/drug effects/genetics/metabolism/pathology/radiation effects ; Animals ; Bronchoalveolar Lavage Fluid ; Cells, Cultured ; Gamma Rays/*adverse effects ; Heme Oxygenase-1/genetics/metabolism ; Humans ; Hydrogen Peroxide/adverse effects/pharmacology ; Intramolecular Oxidoreductases/genetics/*metabolism/pharmacology ; Macrophage Migration-Inhibitory Factors/genetics/*metabolism/pharmacology ; Membrane Proteins/genetics/metabolism ; Mice ; Mice, Knockout ; NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidants/adverse effects/pharmacology ; Radiation Injuries, Experimental/genetics/*metabolism/pathology/prevention &amp; control ; }, abstract = {Microvascular injury and increased vascular leakage are prominent features of radiation-induced lung injury (RILI), and often follow cancer-associated thoracic irradiation. Our previous studies demonstrated that polymorphisms in the gene (MIF) encoding macrophage migratory inhibition factor (MIF), a multifunctional pleiotropic cytokine, confer susceptibility to acute inflammatory lung injury and increased vascular permeability, particularly in senescent mice. In this study, we exposed wild-type and genetically engineered mif(-/-) mice to 20 Gy single-fraction thoracic radiation to investigate the age-related role of MIF in murine RILI (mice were aged 8 wk, 8 mo, or 16 mo). Relative to 8-week-old mice, decreased MIF was observed in bronchoalveolar lavage fluid and lung tissue of 8- to 16-month-old wild-type mice. In addition, radiated 8- to 16-month-old mif(-/-) mice exhibited significantly decreased bronchoalveolar lavage fluid total antioxidant concentrations with progressive age-related decreases in the nuclear expression of NF-E2-related factor-2 (Nrf2), a transcription factor involved in antioxidant gene up-regulation in response to reactive oxygen species. This was accompanied by decreases in both protein concentrations (NQO1, GCLC, and heme oxygenase-1) and mRNA concentrations (Gpx1, Prdx1, and Txn1) of Nrf2-influenced antioxidant gene targets. In addition, MIF-silenced (short, interfering RNA) human lung endothelial cells failed to express Nrf2 after oxidative (H2O2) challenge, an effect reversed by recombinant MIF administration. However, treatment with an antioxidant (glutathione reduced ester), but not an Nrf2 substrate (N-acetyl cysteine), protected aged mif(-/-) mice from RILI. These findings implicate an important role for MIF in radiation-induced changes in lung-cell antioxidant concentrations via Nrf2, and suggest that MIF may contribute to age-related susceptibility to thoracic radiation.}, }
@article {pmid23525857, year = {2013}, author = {Tada, F and Abe, M and Kawasaki, K and Miyake, T and Shiyi, C and Hiasa, Y and Matsuura, B and Onji, M}, title = {B cell activating factor in obesity is regulated by oxidative stress in adipocytes.}, journal = {Journal of clinical biochemistry and nutrition}, volume = {52}, number = {2}, pages = {120-127}, pmid = {23525857}, issn = {0912-0009}, abstract = {Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, and plays a key role in the integration of systemic metabolism. We have previously shown that B cell activating factor is produced mainly in visceral adipose tissue and affects insulin sensitivity in obese individuals. In this study, we identified the signals that lead to production of B cell activating factor in adipocytes. 3T3-L1 and C3H/10T 1/2-clone 8 cells showed increased B cell activating factor expression upon exposure to hydrogen peroxide, and these changes were inhibited by treatment with the antioxidant N-acetyl-cysteine. B cell activating factor levels in both serum and visceral adipose tissue were increased in high fat diet-fed mice, and these increases were correlated with oxidative stress. In addition, serum BAFF levels in high fat diet-fed mice were reduced by N-acetyl-cysteine treatment. We also found that oxidative stress-induced B cell activating factor expression in adipocytes was regulated by NF-κB activation. These data indicate that control of the redox state in visceral adipose tissue is a potentially useful target for treating metabolic syndromes through regulation of adipokine production.}, }
@article {pmid23523744, year = {2013}, author = {Zhang, XY and Yao, JK}, title = {Oxidative stress and therapeutic implications in psychiatric disorders.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {46}, number = {}, pages = {197-199}, doi = {10.1016/j.pnpbp.2013.03.003}, pmid = {23523744}, issn = {1878-4216}, mesh = {Antioxidants/pharmacology/therapeutic use ; Free Radical Scavengers/pharmacology/therapeutic use ; Humans ; Lipid Peroxidation/drug effects/physiology ; Mental Disorders/*drug therapy/*metabolism/psychology ; Oxidative Stress/*drug effects/*physiology ; }, abstract = {Increasing evidence indicates that disturbances of antioxidant defense system and presence of oxidative stress can play a part in a wide range of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and major depression, as well as antipsychotic-induced tardive dyskinesia (TD). Moreover, researchers have embarked on using antioxidant treatment as adjunct therapy for psychiatry disorders. Evidence from clinical, pre-clinical and epidemiological studies suggests that a benefit of using antioxidant compounds should be considered as an adjunctive therapy in these patients. These are some of the main perspectives that are reviewed by four articles in this special section. Overall, there has been growing recognition of the importance of oxidative stress in the pathophysiology of psychiatric disorders and the development of TD. The collection of articles in this special section will contribute to providing more efficacious treatments arising from a better appreciation of the roles of oxidative stress in these psychiatric disorders.}, }
@article {pmid23518073, year = {2013}, author = {Li, Q and Zhang, L and Zu, Y and Liu, T and Zhang, B and He, W}, title = {Generation of reactive oxygen species by a novel berberine-bile acid analog mediates apoptosis in hepatocarcinoma SMMC-7721 cells.}, journal = {Biochemical and biophysical research communications}, volume = {433}, number = {4}, pages = {432-437}, doi = {10.1016/j.bbrc.2013.02.104}, pmid = {23518073}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus ; Antineoplastic Agents/pharmacology ; *Apoptosis ; Apoptosis Inducing Factor/metabolism ; Berberine/*analogs &amp; derivatives/pharmacology ; Bile Acids and Salts/*pharmacology ; Calcium/metabolism ; Carcinoma, Hepatocellular/metabolism/*pathology ; Caspase 3/genetics/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytochromes c/metabolism ; Cytosol/metabolism ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism ; Mitochondrial Membranes/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {2,3-Methenedioxy-9-O-(3'α,7'α-dihydroxy-5'β-cholan-24'-propy-lester)berberine (B4) is a novel berberine-bile acid analog synthesized in our laboratory. Previously, we showed that B4 exerted greater cytotoxicity than berberine in several human cancer cell lines. Therefore, we further evaluated the mechanism governing its anticancer actions in hepatocellular carcinoma SMMC-7721 cells. B4 inhibited the proliferation of SMMC-7721 cells, and stimulated reactive oxygen species (ROS) production and mitochondrial membrane depolarization; anti-oxidant capacity was reduced. B4 also induced the release of cytochrome c from the mitochondria to the cytosol and an increase in poly ADP-ribose polymerase (PARP) cleavage products, reflective of caspase-3 activation. Moreover, B4 induced the nuclear translocation of apoptosis-inducing factor (AIF) and a rise in DNA fragmentation. Pretreatment with the anti-oxidant N-acetylcysteine (NAC) inhibited B4-mediated effects, including cytotoxicity, ROS production, mitochondrial membrane depolarization increase in intracellular Ca2+, cytochrome c release, PARP cleavage, and AIF translocation. Our data suggest that B4 induces ROS-triggered caspase-dependent and caspase-independent apoptosis pathways in SMMC-7721 cells and that ROS production may be a specific potential strategy for treating hepatic carcinoma.}, }
@article {pmid23517443, year = {2013}, author = {Zhou, CF and Yu, JF and Zhang, JX and Jiang, T and Xu, SH and Yu, QY and Zhu, QX}, title = {N-acetylcysteine attenuates subcutaneous administration of bleomycin-induced skin fibrosis and oxidative stress in a mouse model of scleroderma.}, journal = {Clinical and experimental dermatology}, volume = {38}, number = {4}, pages = {403-409}, doi = {10.1111/ced.12033}, pmid = {23517443}, issn = {1365-2230}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibiotics, Antineoplastic ; Bleomycin ; Catalase/metabolism ; Disease Models, Animal ; Female ; Fibrosis/chemically induced/*drug therapy/metabolism ; Free Radical Scavengers/*pharmacology ; Injections, Subcutaneous ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Scleroderma, Localized/*drug therapy/metabolism ; Skin/*pathology ; Superoxide Dismutase/metabolism ; Thiobarbiturates/metabolism ; }, abstract = {BACKGROUND: Several lines of evidence suggest that the generation of reactive oxygen species (ROS) is of major importance in the pathogenesis of scleroderma, and thus antioxidant therapy may be useful for patients with an impaired oxidative defence mechanism.<br><br>AIM: To examine the effect of N-acetylcysteine (NAC) on skin fibrosis and oxidative stress in a bleomycin (BLM)-induced mouse model of scleroderma.<br><br>METHODS: We used this mouse model to evaluate the effect of NAC on skin fibrosis and oxidative stress. Skin fibrosis was evaluated by histopathological examination and hydroxyproline content. To measure lipid peroxidation, we used a thiobarbituric acid-reactive species, malondialdehyde (MDA). Oxidative protein damage (carbonyl content) and the activities of catalase (CAT) and superoxide dismutase (SOD) were determined to evaluate oxidative stress in the skin tissue.<br><br>RESULTS: Treatment with NAC attenuated the skin fibrosis induced by BLM, significantly reducing the MDA and protein carbonyl content in these mice. SOD activity in BLM-only mice and BLM plus NAC-treated mice was increased compared with control mice. However, there was no significant difference in skin SOD activity of mice treated with both BLM and NAC compared with those treated with BLM only. In addition, CAT activity was not altered in the BLM plus NAC mice.<br><br>CONCLUSIONS: NAC treatment attenuates skin fibrosis in a BLM-induced mouse model of scleroderma, and this is associated with diminished oxidative stress. The results suggest that NAC may be a potential therapeutic agent for patients with scleroderma.}, }
@article {pmid23515941, year = {2013}, author = {Cui, J and Liu, J and Wu, S and Wang, Y and Shen, H and Xing, L and Wang, J and Yan, X and Zhang, X}, title = {Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro.}, journal = {Archives of toxicology}, volume = {87}, number = {10}, pages = {1829-1840}, doi = {10.1007/s00204-013-1043-3}, pmid = {23515941}, issn = {1432-0738}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Caffeine/pharmacology ; Cell Line ; DNA Breaks, Double-Stranded/drug effects ; DNA Damage/*drug effects ; G2 Phase Cell Cycle Checkpoints/drug effects ; Gastric Mucosa/*drug effects/metabolism/pathology ; Humans ; Ochratoxins/*toxicity ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; RNA, Small Interfering/administration &amp; dosage ; Reactive Oxygen Species/metabolism ; }, abstract = {Ochratoxin A (OTA), one of the most abundant mycotoxin food contaminants, is classified as "possibly carcinogenic to humans." Our previous study showed that OTA could induce a G2 arrest in immortalized human gastric epithelium cells (GES-1). To explore the putative roles of oxidative DNA damage and the ataxia telangiectasia-mutated (ATM) pathways on the OTA-induced G2 arrest, the current study systematically evaluated the roles of reactive oxygen species (ROS) production, DNA damage, and ATM-dependent pathway activation on the OTA-induced G2 phase arrest in GES-1 cells. The results showed that OTA exposure elevated intracellular ROS production, which directly induced DNA damage and increased the levels of 8-OHdG and DNA double-strand breaks (DSBs). In addition, it was found that OTA treatment induced the phosphorylation of the ATM protein, as well as its downstream molecules Chk2 and p53, in response to DNA DSBs. Inhibition of ATM by the pharmacological inhibitor caffeine or siRNA effectively prevented the activation of ATM-dependent pathways and rescued the G2 arrest elicited by OTA. Finally, pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) reduced the OTA-induced DNA DSBs, ATM phosphorylation, and G2 arrest. In conclusion, the results of this study suggested that OTA-induced oxidative DNA damage triggered the ATM-dependent pathways, which ultimately elicited a G2 arrest in GES-1 cells.}, }
@article {pmid23515442, year = {2013}, author = {Huang, J and Simcox, J and Mitchell, TC and Jones, D and Cox, J and Luo, B and Cooksey, RC and Boros, LG and McClain, DA}, title = {Iron regulates glucose homeostasis in liver and muscle via AMP-activated protein kinase in mice.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {27}, number = {7}, pages = {2845-2854}, pmid = {23515442}, issn = {1530-6860}, support = {R01DK081842/DK/NIDDK NIH HHS/United States ; R01 DK081842/DK/NIDDK NIH HHS/United States ; I01 BX001140/BX/BLRD VA/United States ; 1T32DK091317/DK/NIDDK NIH HHS/United States ; T32 DK091317/DK/NIDDK NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases/genetics/*metabolism ; Acetylation/drug effects ; Adenosine Monophosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Blotting, Western ; Cell Differentiation/drug effects ; Cell Line ; Diet ; Enzyme Activation/drug effects ; Gene Expression/drug effects ; Gluconeogenesis/genetics ; Glucose/*metabolism ; Homeostasis/*drug effects ; Iron/administration &amp; dosage/metabolism/*pharmacology ; Liver/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscle, Skeletal/*metabolism ; Myoblasts/cytology/drug effects/metabolism ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Excess iron is associated with hepatic damage and diabetes in humans, although the detailed molecular mechanisms are not known. To investigate how iron regulates glucose homeostasis, we fed C57BL/6J male mice with high-iron (HI) diets (2 or 20 g Fe/kg chow). Mice fed an HI diet exhibited elevated AMP-activated protein kinase (AMPK) activity and impaired insulin signaling in skeletal muscle and liver. Consistent with the increased AMPK activity, glucose uptake was enhanced in mice fed an HI diet. The effects of improved glucose tolerance induced by HI feeding were abolished in transgenic mice with expression of muscle specific dominant-negative AMPK. Glucose output was suppressed in the liver of wild-type mice fed an HI diet, due to decreased expression of gluconeogenic genes and decreased substrate (lactate) from peripheral glycolysis. Iron activated AMPK by increasing deacetylase and decreasing LKB1 acetylation, in turn stimulating the phosphorylation of LKB1 and AMPK. The effects of HI diet were abrogated by treatment of the mice with N-acetyl cysteine, suggesting a redox-dependent mechanism for increasing deacetylase activity. In addition, tissue from iron-fed mice exhibited an elevated AMP/ATP ratio, further contributing to AMPK activation. In summary, a diet high in iron improves glucose tolerance by activating AMPK through mechanisms that include deacetylation.}, }
@article {pmid23514070, year = {2013}, author = {Boccia, P and Meconi, C and Mecozzi, M and Sturchio, E}, title = {Molecular modifications induced by inorganic arsenic in Vicia faba investigated by FTIR, FTNIR spectroscopy and genotoxicity testing.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {76}, number = {4-5}, pages = {281-290}, doi = {10.1080/15287394.2013.757211}, pmid = {23514070}, issn = {1528-7394}, mesh = {Acetylcysteine/*metabolism ; Antioxidants/analysis ; Arsenic/*toxicity ; Comet Assay ; Micronucleus Tests ; Plant Roots/drug effects/metabolism ; Seedlings/drug effects/metabolism ; Spectroscopy, Fourier Transform Infrared ; Vicia faba/*drug effects/*metabolism ; }, abstract = {Exposure to inorganic arsenic (iAs) through drinking water is a major public health concern affecting most countries. Epidemiologic studies showed a significant association between consumption of iAs through drinking water and different types of cancer. However, the exact mechanisms underlying As-induced cancer and other diseases are not yet well understood. The aim of this study is to determine the effects of exposure iAs (20 or 30 mg/L) on Vicia faba seedlings in terms of phytotoxicity, genotoxicity, and spectroscopy by investigation of molecular modifications using infrared (FTIR) and near infrared (FTNIR) spectroscopy. Further, the mitigation effects of a precursor of glutathione (GSH), N-acetylcysteine (NAC), were also assessed. Spectroscopic and genotoxicity analysis demonstrated that specific molecular changes were directly correlated with iAs exposure. Comet assay in Vicia faba showed significant effects at concentrations of 20 and 30 mg/L, depending on the structural changes involving nucleic acids as identified by FTIR and FTNIR spectroscopy. Results of phytotoxicity and micronuclei tests were significant only at higher iAs concentrations (30 mg/L), where an antioxidant effect of NAC was noted. The two spectroscopic techniques demonstrated molecular modifications predominantly associated with chemical interactions of iAs with biomolecules such as nucleic acids, carbohydrates, lipids, and proteins in Vicia faba. Our findings suggest that further studies are required to better understand the mechanisms underlying toxicity produced by different As chemical forms in vegetal and agricultural species.}, }
@article {pmid23513466, year = {2012}, author = {Supabphol, A and Supabphol, R}, title = {Antimetastatic potential of N-acetylcysteine on human prostate cancer cells.}, journal = {Journal of the Medical Association of Thailand = Chotmaihet thangphaet}, volume = {95 Suppl 12}, number = {}, pages = {S56-62}, pmid = {23513466}, issn = {0125-2208}, mesh = {Acetylcysteine/*pharmacology ; Adenocarcinoma/*drug therapy ; Cell Adhesion/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Humans ; Male ; Neoplasm Invasiveness ; Prostatic Neoplasms/*drug therapy ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC), is one of the cheapest, safest and widely used over-the-counter-drugs in Thailand. Here the authors examine the antimetastatic potential of NAC on the metastasis of human prostate cancer cells.<br><br>MATERIAL AND METHOD: Cytotoxicity of NAC to human prostate cancer cells, DU145 and PC3, were determined by proliferation assay using the 3-(4, 5-dimethylthiazol, 2-yl)-2, 5-diphenyltetrazolium bromide (MTT) reagent. Cell migration and invasion were assessed by using a chemotaxis chamber containing membrane pre-coated with collagen IV and Matrigel, respectively. Cell attachment onto the surface of the membrane coated with collagen IV was tested for its adhesion potentiality.<br><br>RESULTS: NAC could inhibit the growth of DU145 and PC3 cells. Suppression of migration and invasion of both human prostrate cancer cells were observed. Cell attachment to the collagen IV-coated surface was obviously reduced. All inhibitions occurred in a dose-dependent fashion in both cell lines.<br><br>CONCLUSION: NAC could have a high potential in attenuating the migration of the human prostate cancer cells from their primary site and their adhesion and invasion to the remote locations. Hence, NAC might suppress the growth of the primary and the secondary tumors. Our findings suggest that NAC had a high possibility to become an antimetastatic agent for testing in clinical trials. Then, NAC might be used clinically as an optional adjuvant therapeutic drug in addition to the conventional standard treatment of human prostate cancer, obtaining a better outcome with the least toxic and affordable substance.}, }
@article {pmid23511429, year = {2013}, author = {Mezencev, R and Wang, L and Xu, W and Kim, B and Sulchek, TA and Daneker, GW and McDonald, JF}, title = {Molecular analysis of the inhibitory effect of N-acetyl-L-cysteine on the proliferation and invasiveness of pancreatic cancer cells.}, journal = {Anti-cancer drugs}, volume = {24}, number = {5}, pages = {504-518}, doi = {10.1097/CAD.0b013e32836009d7}, pmid = {23511429}, issn = {1473-5741}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cellular Senescence/drug effects ; Deoxycytidine/analogs &amp; derivatives/pharmacology ; Dose-Response Relationship, Drug ; Doxorubicin/pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, myc ; Humans ; Mitomycin/pharmacology ; Pancreatic Neoplasms/*drug therapy/genetics/metabolism/*pathology ; Reactive Oxygen Species/metabolism ; Gemcitabine ; }, abstract = {Preliminary studies have suggested that the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) may be effective in inhibiting the growth of pancreatic cancer cells. In-depth cellular and molecular analyses were carried out to determine NAC's mode of action in inhibiting the growth of a well-characterized pancreatic cancer cell line (AsPC-1). Standardized assays were used to monitor cellular growth, apoptosis, levels of ROS, cellular senescence, migration, and invasiveness. Cell stiffness was measured using atomic force microscopy. Gene expression was monitored by quantitative PCR. NAC significantly inhibits the growth and metastatic potential of AsPC-1 cells by inducing cell-cycle arrest in G1 and subsequent cellular senescence and decreased invasiveness. These anticancer properties are associated with an unexpected increase in the intracellular concentrations of ROS. NAC does not decrease the susceptibility of AsPC-1 cells to the anticancer drugs gemcitabine, mitomycin C, and doxorubicin. NAC-induced changes in gene expression are consistent with the onset of mesenchymal-to-epithelial transition. In conclusion, our findings indicate that NAC induces an integrated series of responses in AsPC-1 cells that make it a highly promising candidate for development as a pancreatic cancer therapeutic.}, }
@article {pmid23509102, year = {2013}, author = {Starenki, D and Park, JI}, title = {Mitochondria-targeted nitroxide, Mito-CP, suppresses medullary thyroid carcinoma cell survival in vitro and in vivo.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {98}, number = {4}, pages = {1529-1540}, pmid = {23509102}, issn = {1945-7197}, support = {R01 CA138441/CA/NCI NIH HHS/United States ; 1R01CA138441/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/pharmacology/therapeutic use ; Carcinoma, Neuroendocrine ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclic N-Oxides/*pharmacology/*therapeutic use ; Drug Delivery Systems ; Female ; Humans ; Mice ; Mice, Nude ; Mitochondria/drug effects ; Nitrogen Oxides/pharmacology/therapeutic use ; Organophosphorus Compounds/*pharmacology/*therapeutic use ; Piperidines/pharmacology/therapeutic use ; Proto-Oncogene Mas ; Quinazolines/pharmacology/therapeutic use ; Thyroid Neoplasms/*drug therapy/*pathology ; Xenograft Model Antitumor Assays ; }, abstract = {CONTEXT: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. For MTC therapy, the U.S. Food and Drug Administration recently approved vandetanib and cabozantinib, multikinase inhibitors targeting RET and other tyrosine kinase receptors of vascular endothelial growth factor, epidermal growth factor, or hepatocyte growth factor. Nevertheless, not all patients with the progressive MTC respond to these drugs, requiring the development of additional therapeutic modalities that have distinct activity.<br><br>OBJECTIVE: We aimed to evaluate mitochondria-targeted carboxy-proxyl (Mito-CP), a mitochondria-targeted redox-sensitive agent, for its tumor-suppressive efficacy against MTC.<br><br>DESIGN: In vitro cultures of 2 human MTC cell lines, TT and MZ-CRC-1, and TT xenografts in mice were treated with Mito-CP in comparison with vandetanib. The effects on cell survival/death, RET expression, mitochondrial integrity, and oxidative stress were determined.<br><br>RESULTS: Contrary to vandetanib, Mito-CP induced RET downregulation and strong cytotoxic effects in both cell lines in vitro, including caspase-dependent apoptosis. These effects were accompanied by mitochondrial membrane depolarization, decreased oxygen consumption, and increased oxidative stress in cells. Intriguingly, Mito-CP-induced cell death, but not RET downregulation, was partially inhibited by the reactive oxygen species scavenger, N-acetyl-cysteine, indicating that Mito-CP mediates tumor-suppressive effects via redox-dependent as well as redox-independent mechanisms. Orally administered Mito-CP effectively suppressed TT xenografts in mice, with an efficacy comparable to vandetanib and relatively low toxicity to animals.<br><br>CONCLUSION: Our results suggest that Mito-CP can effectively suppress MTC cell growth/survival via a mechanism distinct from vandetanib effects. Mitochondrial targeting may be a potential strategy for MTC therapy.}, }
@article {pmid23508666, year = {2013}, author = {Hosseinjani, H and Moghaddas, A and Khalili, H}, title = {N-acetylcysteine for the prevention of non-contrast media agent-induced kidney injury: from preclinical data to clinical evidence.}, journal = {European journal of clinical pharmacology}, volume = {69}, number = {7}, pages = {1375-1390}, pmid = {23508666}, issn = {1432-1041}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Infective Agents/adverse effects/antagonists &amp; inhibitors ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/antagonists &amp; inhibitors ; Antineoplastic Agents/adverse effects/antagonists &amp; inhibitors ; Antioxidants/therapeutic use ; *Evidence-Based Medicine ; Humans ; Kidney/*drug effects ; Protective Agents/*therapeutic use ; Renal Insufficiency/chemically induced/*prevention &amp; control ; }, abstract = {PURPOSE: To review available evidence on the effectiveness of N-acetylcysteine (NAC) as a prophylactic agent in the prevention of non-contrast media agent-induced kidney injury.<br><br>METHOD: Data were collected by searching Scopus, PubMed, Medline, Science direct and Cochrane database systematic reviews. A total of 26 relevant experimental studies up to the date of publication were included in the review.<br><br>RESULTS: Available evidence shows that NAC has the potential to exert significant protective or ameliorative effects against drug-induced kidney injury in experimental models. The possible suggested renoprotective mechanisms of NAC in different experimental settings were acting as an antioxidant by restoring the pool of intracellular reduced glutathione, scavenging of free radicals, and/or interacting with reactive oxygen species.<br><br>CONCLUSION: Whether the administration of NAC could be an effective protective clinical strategy to prevent drug-induced kidney injury or not is a question that remains to be answered in future clinical trials.}, }
@article {pmid23507776, year = {2013}, author = {Choi, J and Park, KH and Kim, SZ and Shin, JH and Jang, SI}, title = {The ameliorative effects of L-2-oxothiazolidine-4-carboxylate on acetaminophen-induced hepatotoxicity in mice.}, journal = {Molecules (Basel, Switzerland)}, volume = {18}, number = {3}, pages = {3467-3478}, pmid = {23507776}, issn = {1420-3049}, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/blood ; Aldehydes/metabolism ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Aspartate Aminotransferases/blood ; Caspase 3/metabolism ; Chemical and Drug Induced Liver Injury/blood/*prevention &amp; control ; DNA Fragmentation ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Liver/drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred BALB C ; Necrosis/chemically induced/prevention &amp; control ; Oxidative Stress/drug effects ; Pyrrolidonecarboxylic Acid/*pharmacology/therapeutic use ; Thiazolidines/*pharmacology/therapeutic use ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {The aim of the study was to investigate the ameliorative effects and the mechanism of action of L-2-oxothiazolidine-4-carboxylate (OTC) on acetaminophen (APAP)-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC) as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH) production and glutathione peroxidase (GSH-px) activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.}, }
@article {pmid23499690, year = {2013}, author = {Burgeiro, A and Bento, AC and Gajate, C and Oliveira, PJ and Mollinedo, F}, title = {Rapid human melanoma cell death induced by sanguinarine through oxidative stress.}, journal = {European journal of pharmacology}, volume = {705}, number = {1-3}, pages = {109-118}, doi = {10.1016/j.ejphar.2013.02.035}, pmid = {23499690}, issn = {1879-0712}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Benzophenanthridines/*pharmacology ; Calcium/metabolism ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Glutathione/pharmacology ; Humans ; Isoquinolines/*pharmacology ; Melanoma/*drug therapy/metabolism/physiopathology ; Membrane Potential, Mitochondrial/drug effects ; Membrane Proteins/metabolism ; Mitochondria/drug effects/physiology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; bcl-X Protein/metabolism ; }, abstract = {Sanguinarine is a natural isoquinoline alkaloid derived from the root of Sanguinaria canadensis and from other poppy fumaria species, and is known to have a broad spectrum of pharmacological properties. Here we have found that sanguinarine, at low micromolar concentrations, showed a remarkably rapid killing activity against human melanoma cells. Time-lapse videomicroscopy showed rapid morphological changes compatible with an apoptotic cell death, which was further supported by biochemical markers, including caspase activation, poly(ADP-ribose) polymerase (PARP) cleavage and DNA breakdown. Pan-caspase inhibition blocked sanguinarine-induced cell death. Sanguinarine treatment also induced an increase in intracellular calcium concentration, which was inhibited by dantrolene, and promoted cleavage of BAP-31, thus suggesting a putative role for Ca(2+) release from endoplasmic reticulum and a cross-talk between endoplasmic reticulum and mitochondria in the anti-melanoma action of sanguinarine. Sanguinarine disrupted the mitochondrial transmembrane potential (ΔΨm), released cytochrome c and Smac/DIABLO from mitochondria to cytosol, and induced oxidative stress. Overexpression of Bcl-XL by gene transfer did not prevent sanguinarine-mediated cell death, oxidative stress or release of mitochondrial apoptogenic proteins. However, preincubation with N-acetyl-l-cysteine (NAC) prevented sanguinarine-induced oxidative stress, PARP cleavage, release of apoptogenic mitochondrial proteins, and cell death. Pretreatment with glutathione (GSH) also inhibited the anti-melanoma activity of sanguinarine. Thus, pretreatment with the thiol antioxidants NAC and GSH abrogated the killing activity of sanguinarine. Taking together, our data indicate that sanguinarine is a very rapid inducer of human melanoma caspase-dependent cell death that is mediated by oxidative stress.}, }
@article {pmid23493756, year = {2013}, author = {Magalhães, PV and Dean, OM and Bush, AI and Copolov, DL and Malhi, GS and Kohlmann, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Berk, M}, title = {A preliminary investigation on the efficacy of N-acetyl cysteine for mania or hypomania.}, journal = {The Australian and New Zealand journal of psychiatry}, volume = {47}, number = {6}, pages = {564-568}, doi = {10.1177/0004867413481631}, pmid = {23493756}, issn = {1440-1614}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Bipolar Disorder/*drug therapy ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; }, abstract = {OBJECTIVE: Oxidative imbalance has emerged as a treatment target in bipolar disorder. As very limited data are available on the clinical use of antioxidants for mania, we report here results from a post hoc and exploratory subgroup analysis of a randomized, placebo-controlled trial of N-acetyl cysteine (NAC).<br><br>METHODS: This was a placebo-controlled, randomized, clinical trial assessing the effect of NAC over 24 weeks in mania or hypomania. Symptomatic and functional outcomes were collected over the study period.<br><br>RESULTS: Fifteen participants were available for this report; two participants in each group failed to complete all assessments. Within-group analyses pointed to an improvement in the NAC group on manic symptoms and worsening in the placebo group on depressive symptoms at endpoint.<br><br>CONCLUSIONS: Although the sample size was small, these results indicated within-group efficacy for this glutathione precursor as compared to placebo. Future trials specifically designed to demonstrate the efficacy of NAC in mania are needed.}, }
@article {pmid23492188, year = {2013}, author = {Messier, EM and Day, BJ and Bahmed, K and Kleeberger, SR and Tuder, RM and Bowler, RP and Chu, HW and Mason, RJ and Kosmider, B}, title = {N-acetylcysteine protects murine alveolar type II cells from cigarette smoke injury in a nuclear erythroid 2-related factor-2-independent manner.}, journal = {American journal of respiratory cell and molecular biology}, volume = {48}, number = {5}, pages = {559-567}, pmid = {23492188}, issn = {1535-4989}, support = {R01 CA164780/CA/NCI NIH HHS/United States ; R01 ES016285/ES/NIEHS NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Alveolar Epithelial Cells/*drug effects/metabolism/physiology ; Animals ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Cytoprotection ; Emphysema/drug therapy/etiology/pathology ; Free Radical Scavengers/*pharmacology ; Gene Expression ; Gene Expression Regulation ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress ; Smoke ; Smoking/*adverse effects ; Nicotiana/chemistry ; }, abstract = {Emphysema is caused by the cigarette smoke (CS)-induced destruction of alveolar wall septa, and CS is the main risk factor for chronic obstructive pulmonary disease (COPD). To study the mechanisms of response to this insult, we focused on oxidant-induced lung injury and the potential role of nuclear erythroid 2-related factor-2 (Nrf2), which is a key regulator of the antioxidant defense system. We studied the protective role of N-acetylcysteine (NAC) against the injury of alveolar type II (ATII) cells induced by CS in vivo and in vitro. ATII cells were isolated and purified using magnetic MicroBeads (Miltenyi Biotec, Auburn, CA) from Nrf2(-/-) mice and wild-type mice. We analyzed pulmonary injury, inflammation, glutathione (GSH) concentrations, the expression of glutathione cysteine ligase catalytic subunit mRNA, glutathione cysteine ligase modifier subunit mRNA, and glutathione reductase mRNA, and Nrf2, heme oxygenase-1, and nicotinamide adenine dinucleotide phosphate-reduced:quinone oxireductase levels by Western blotting, TUNEL assay, and immunocytofluorescence for 4-hydroxynonenal as a marker of oxidative stress. We found that CS induced greater injury in ATII cells obtained from Nrf2(-/-) mice than from wild-type mice. Furthermore, NAC attenuated the injuries by CS in ATII cells obtained from wild-type mice both in vivo and in vitro. Moreover, NAC decreased the injury of ATII cells obtained from Nrf2(-/-) mice. Our results suggest that Nrf2-GSH signaling is important for the protective activity of NAC. In addition, in ATII cells deficient in Nrf2, this compound can provide partial protection through its reactive oxygen species-scavenging activities. Targeting the antioxidant system regulated by Nrf2 may provide an effective strategy against lung injury in COPD.}, }
@article {pmid23490067, year = {2013}, author = {Chien, CC and Wu, MS and Shen, SC and Yang, LY and Wu, WS and Chen, YC}, title = {Arachidonic acid enhances TPA-induced differentiation in human leukemia HL-60 cells via reactive oxygen species-dependent ERK activation.}, journal = {Prostaglandins, leukotrienes, and essential fatty acids}, volume = {88}, number = {4}, pages = {289-298}, doi = {10.1016/j.plefa.2013.01.004}, pmid = {23490067}, issn = {1532-2823}, mesh = {Arachidonic Acid/*pharmacology ; Cell Differentiation/*drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; HL-60 Cells ; Humans ; Reactive Oxygen Species/*metabolism ; Tetradecanoylphorbol Acetate/*pharmacology ; }, abstract = {The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), is a potent stimulator of differentiation in human leukemia cells; however, the effects of arachidonic acid (AA) on TPA-induced differentiation are still unclear. In the present study, we investigated the contribution of AA to TPA-induced differentiation of human leukemia HL-60 cells. We found that treatment of HL-60 cells with TPA resulted in increases in cell attachment and nitroblue tetrazolium (NBT)-positive cells, which were significantly enhanced by the addition of AA. Stimulation of TPA-induced intracellular reactive oxygen species (ROS) production by AA was detected in HL-60 cells via a DCHF-DA analysis, and the addition of the antioxidant, N-acetyl-cysteine (NAC), was able to reduce TPA+AA-induced differentiation in accordance with suppression of intracellular peroxide elevation by TPA+AA. Furthermore, activation of extracellular-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by TPA+AA was identified in HL-60 cells, and the ERK inhibitor, PD98059, but not the JNK inhibitor, SP600125, inhibited TPA+AA-induced NBT-positive cells. Suppression of TPA+AA-induced ERK protein phosphorylation by PD98059 and NAC was detected, and AA enhanced ERK protein phosphorylation by TPA was in HL-60 cells. AA clearly increased TPA-induced HL-60 cell differentiation, as evidenced by a marked increase in CD11b expression, which was inhibited by NAC and PD98059 addition. Eicosapentaenoic acid (EPA) as well as AA showed increased intracellular peroxide production and differentiation of HL-60 cells elicited by TPA. Evidence of AA potentiation of differentiation by TPA in human leukemia cells HL-60 via activation of ROS-dependent ERK protein phosphorylation was first demonstrated herein.}, }
@article {pmid23490044, year = {2013}, author = {Colak, N and Nazli, Y and Alpay, MF and Aksoy, ON and Akkaya, IO and Bayrak, R and Cakir, O}, title = {Effect of topical N-acetylcysteine in the prevention of postoperative pericardial adhesion formation in a rabbit model.}, journal = {Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology}, volume = {22}, number = {5}, pages = {368-372}, doi = {10.1016/j.carpath.2013.02.001}, pmid = {23490044}, issn = {1879-1336}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Topical ; Animals ; Disease Models, Animal ; Fibrosis ; Pericardium/*drug effects/*pathology/surgery ; Postoperative Complications/pathology/*prevention &amp; control ; Rabbits ; Tissue Adhesions/pathology/*prevention &amp; control ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC), a precursor of reduced glutathione, has been in clinical use primarily as a mucolytic. In addition, NAC is well known for their free radical scavenging and antioxidant properties. Increasing of reactive oxygen products occurring during cardiac surgery can play an important role in postoperative adhesion formation. We investigated to the efficacy of the NAC for postoperative pericardial adhesions.<br><br>METHODS: Sixteen New Zealand white rabbits (2.5-3 kg) were used and categorized into two groups including study (use of NAC) and control groups. In both groups, the pericardium was opened longitudinally, and the exposed epicardial surfaces were abraded with dry gauze. The rabbits were divided into two groups: Group 1 was treated with the sponge, which impregnated with NAC solution, (10%, 300 mg/3 ml) and applied over the abraded epicardium for 5 min (n=8). Group 2 was the control, and the sponge, which was impregnated with 3-ml isotonic NaCl solution (0.9%), was applied onto the surface of the abraded epicardium for 5 min (n=8). After a period of 2 weeks, the animals were sacrificed. The scores of adhesion were graded by macroscopic examination, and the pericardial tissues were analyzed microscopically in point of inflammation and fibrosis.<br><br>RESULTS: In Group 1, the adhesion scores were significantly lower compared with the control group [Group 1 vs. 2; 1 (1-2) vs. 3 (2-3), P<.001]. No significant difference was found between the groups in terms of the severity of inflammation [Group 1 vs. 2; 1.5 (1-3) vs. 2.5 (1-3), P=.083]. There was a difference between groups in terms of the degree of fibrosis [Group 1 vs. 2; 2 (1-2) vs. 3 (2-3), P=.007].<br><br>CONCLUSIONS: The use of NAC for preventing postoperative pericardial adhesions was reduced to adhesion and fibrosis scores in an experimental rabbit model. There was no statistically significant difference between groups in terms of inflammatory scores. The NAC effectively prevented the formation of pericardial adhesion.}, }
@article {pmid23485709, year = {2013}, author = {Holm, JB and Grygorczyk, R and Lambert, IH}, title = {Volume-sensitive release of organic osmolytes in the human lung epithelial cell line A549: role of the 5-lipoxygenase.}, journal = {American journal of physiology. Cell physiology}, volume = {305}, number = {1}, pages = {C48-60}, doi = {10.1152/ajpcell.00412.2012}, pmid = {23485709}, issn = {1522-1563}, mesh = {4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology ; Adenocarcinoma ; Adenosine Triphosphate ; Amino Acids/*metabolism ; Anti-Asthmatic Agents/pharmacology ; Arachidonate 5-Lipoxygenase/genetics/*metabolism ; Calcium ; Cell Line, Tumor ; Cell Size/drug effects ; Cell Survival ; Dose-Response Relationship, Drug ; Electrolytes ; Epithelial Cells/*drug effects/*metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Indoles ; Leukotriene Antagonists/pharmacology ; Lipoxygenase Inhibitors/pharmacology ; Lung Neoplasms ; Osmolar Concentration ; Osmotic Pressure/physiology ; Phenylcarbamates ; Reactive Oxygen Species/metabolism ; Sulfonamides ; Taurine/metabolism ; Tosyl Compounds/pharmacology ; Water/metabolism ; }, abstract = {Pathophysiological conditions challenge cell volume homeostasis and perturb cell volume regulatory mechanisms leading to alterations of cell metabolism, active transepithelial transport, cell migration, and death. We report that inhibition of the 5-lipoxygenase (5-LO) with AA861 or ETH 615-139, the cysteinyl leukotriene 1 receptor (CysLT1) with the antiasthmatic drug Zafirlukast, or the volume-sensitive organic anion channel (VSOAC) with DIDS blocks the release of organic osmolytes (taurine, meAIB) and the concomitant cell volume restoration following hypoosmotic swelling of human type II-like lung epithelial cells (A549). Reactive oxygen species (ROS) are produced in A549 cells upon hypotonic cell swelling by a diphenylene iodonium-sensitive NADPH oxidase. The swelling-induced taurine release is suppressed by ROS scavenging (butylated hydroxytoluene, N-acetyl cysteine) and potentiated by H2O2. Ca[2+] mobilization with ionomycin or ATP stimulates the swelling-induced taurine release whereas calmodulin inhibition (W7) inhibits the release. Chelation of the extracellular Ca[2+] (EGTA) had no effect on swelling-induced taurine release but prevented ATP-induced stimulation. H2O2, ATP, and ionomycin were unable to stimulate the taurine release in the presence of AA861 or Zafirlukast, placing 5-LO and CysLT1 as essential elements in the swelling-induced activation of VSOAC with ROS and Ca[2+] as potent modulators. Inhibition of tyrosine kinases (genistein, cucurbitacin) reduces volume-sensitive taurine release, adding tyrosine kinases (Janus kinase) as regulators of VSOAC activity. Caspase-3 activity during hypoxia is unaffected by inhibition of 5-LO/CysLT1 but reduced when swelling-induced taurine loss via VSOAC is prevented by DIDS excess extracellular taurine, indicating a beneficial role of taurine under hypoxia.}, }
@article {pmid23481873, year = {2013}, author = {Kamioka, Y and Fujikawa, C and Ogai, K and Sugitani, K and Watanabe, S and Kato, S and Wakasugi, K}, title = {Functional characterization of fish neuroglobin: zebrafish neuroglobin is highly expressed in amacrine cells after optic nerve injury and can translocate into ZF4 cells.}, journal = {Biochimica et biophysica acta}, volume = {1834}, number = {9}, pages = {1779-1788}, doi = {10.1016/j.bbapap.2013.02.021}, pmid = {23481873}, issn = {0006-3002}, mesh = {Amacrine Cells/cytology/drug effects/*metabolism ; Animals ; Blotting, Western ; Cell Survival/drug effects ; Cells, Cultured ; Embryo, Nonmammalian/cytology/*metabolism ; Fibroblasts/cytology/*metabolism ; Globins/genetics/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Hydroxyl Radical/metabolism ; Immunoenzyme Techniques ; In Situ Hybridization ; Microscopy, Fluorescence ; Nerve Tissue Proteins/genetics/*metabolism ; Neuroglobin ; Optic Nerve Injuries/*metabolism/pathology ; Oxidants/pharmacology ; Oxidative Stress/*drug effects ; Protein Transport ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Recombinant Fusion Proteins/genetics/metabolism ; Retina/cytology/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Zebrafish ; }, abstract = {Neuroglobin (Ngb) is a recently discovered vertebrate heme protein that is expressed in the brain and can reversibly bind oxygen. Mammalian Ngb is involved in neuroprotection under conditions of oxidative stress, such as ischemia and reperfusion. We previously found that zebrafish Ngb can penetrate the mammalian cell membrane. In the present study, we investigated the functional characteristics of fish Ngb by using the zebrafish cell line ZF4 and zebrafish retina. We found that zebrafish Ngb translocates into ZF4 cells, but cannot protect ZF4 cells against cell death induced by hydrogen peroxide. Furthermore, we demonstrated that a chimeric ZHHH Ngb protein, in which module M1 of human Ngb is replaced by that of zebrafish, is a cell-membrane-penetrating protein that can protect ZF4 cells against hydrogen peroxide exposure. Moreover, we investigated the localization of Ngb mRNA and protein in zebrafish retina and found that Ngb mRNA is expressed in amacrine cells in the inner nuclear layer and is significantly increased in amacrine cells 3days after optic nerve injury. Immunohistochemical studies clarified that Ngb protein levels were increased in both amacrine cells and presynaptic regions in the inner plexiform layer after nerve injury. Taken together, we hypothesize that fish Ngb, whose expression is upregulated in amacrine cells after optic nerve injury, might be released from amacrine cells, translocate into neighboring ganglion cells, and function in the early stage of optic nerve regeneration. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.}, }
@article {pmid23478644, year = {2013}, author = {Rideau Batista Novais, A and Guiramand, J and Cohen-Solal, C and Crouzin, N and de Jesus Ferreira, MC and Vignes, M and Barbanel, G and Cambonie, G}, title = {N-acetyl-cysteine prevents pyramidal cell disarray and reelin-immunoreactive neuron deficiency in CA3 after prenatal immune challenge in rats.}, journal = {Pediatric research}, volume = {73}, number = {6}, pages = {750-755}, doi = {10.1038/pr.2013.40}, pmid = {23478644}, issn = {1530-0447}, mesh = {Acetylcysteine/*pharmacology ; Animals ; CA3 Region, Hippocampal/cytology/*drug effects ; Cell Adhesion Molecules, Neuronal/*metabolism ; Extracellular Matrix Proteins/*metabolism ; Female ; Male ; *Maternal Exposure ; Nerve Tissue Proteins/*metabolism ; Neurons/*metabolism ; Pregnancy ; Pyramidal Cells/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reelin Protein ; Serine Endopeptidases/*metabolism ; }, abstract = {BACKGROUND: Prenatal infection is a major risk factor for the occurrence of neuropsychiatric disorders. These have been associated with hippocampal neuroanatomical and functional abnormalities. In the present study, we evaluated the occurrence of pyramidal cell disarray and reelin neuronal deficit in the hippocampus, and the protective role of N-acetyl-cysteine (NAC) in a rodent experimental model of prenatal immune challenge.<br><br>METHODS: Sprague-Dawley rats received either 500 &#x3bc;g/kg of endotoxin (lipopolysaccharide, LPS) or 2&#x2009;ml/kg of isotonic saline by i.p. injection on day 19 of gestation. After LPS injection, rats were or were not maintained on a preventive treatment of NAC (5&#x2009;g/l in tap water), up to delivery. The pyramidal cell orientation and the number and type of reelin-expressing neurons were determined in male offspring.<br><br>RESULTS: Prenatal LPS challenge led to permanent pyramidal cell disarray and to an early and transient decreased density of reelin-immunoreactive neurons. These disorders, more pronounced in the CA3 area, were prevented by NAC.<br><br>CONCLUSION: Hippocampal cytoarchitectural alterations and reelin deficiency may be involved in the development of remote cognitive impairments in this model. The antioxidant NAC is an efficient neuroprotective drug that underlines the role of oxidative stress in prenatal infection and associated neurodevelopmental damage.}, }
@article {pmid23478248, year = {2013}, author = {Karbasi, A and Hossein Hosseini, S and Shohrati, M and Amini, M and Najafian, B}, title = {Effect of oral N-acetyl cysteine on eradication of Helicobacter pylori in patients with dyspepsia.}, journal = {Minerva gastroenterologica e dietologica}, volume = {59}, number = {1}, pages = {107-112}, pmid = {23478248}, issn = {1121-421X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adolescent ; Adult ; Aged ; Double-Blind Method ; Dyspepsia/*drug therapy/microbiology ; Female ; Helicobacter Infections/complications/*drug therapy ; *Helicobacter pylori ; Humans ; Male ; Middle Aged ; Remission Induction ; Young Adult ; }, abstract = {AIM: Using mucolytic agents that decrease viscosity of the gastric mucous and therefore, increase the permeability of antibiotics through gastric membrane has been offered as an additive treatment to achieve a higher rate of eradication of Helicobacter pylori (H. Pylori) infection. The aim of this study was to determine the efficacy of oral N-acetyl cysteine (NAC) on eradication of H. pylori infections in patients suffering from dyspepsia.<br><br>METHODS: In this randomized double-blinded clinical trial, 60 H. pylori positive patients who were suffering from dyspepsia were included. They were divided into two groups. Both groups received three-drug regimen including pantoprazole 40 mg BD, ciprofloxacin 500 mg BD and bismuth subcitrate 120 mg two tablets BD. Experimental group (30 cases) received 600 mg of NAC besides three-drug regimen. Control group received placebo. The results of therapy were tested by 14C-UBT and were compared with each other two months after the first visit.<br><br>RESULTS: H. pylori infection was eradicated in 21 (70%) and 17 (60.7%) patients in experimental and control groups, respectively (P=0.526). Regarding clinical and endoscopic variables, no significant difference was observed between the two groups except for erosive gastritis (0.041) and erosive esophagitis (0.031).<br><br>CONCLUSION: Our findings offer that NAC has an additive effect on H. pylori triple therapy with pantoprazole, ciprofloxacin and bismuth subcitrate. Although NAC does not have any known activity against H. pylori, it can reduce the thickness of the mucus layer and increase the permeability of antibiotics at the site of infection. To evaluate this effect, more studies with larger sample size should be performed.}, }
@article {pmid23475956, year = {2013}, author = {Hui, KF and Lam, BH and Ho, DN and Tsao, SW and Chiang, AK}, title = {Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus.}, journal = {Molecular cancer therapeutics}, volume = {12}, number = {5}, pages = {747-758}, doi = {10.1158/1535-7163.MCT-12-0811}, pmid = {23475956}, issn = {1538-8514}, mesh = {Animals ; Antineoplastic Agents/chemistry/pharmacology/toxicity ; Apoptosis/drug effects ; Boronic Acids/chemistry/*pharmacology/toxicity ; Bortezomib ; Carcinoma ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Synergism ; Female ; Herpesvirus 4, Human/*drug effects/*physiology ; Heterografts ; Histone Deacetylase Inhibitors/chemistry/pharmacology/toxicity ; Humans ; Hydroxamic Acids/chemistry/*pharmacology/toxicity ; Mice ; Mice, Nude ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms/*metabolism/pathology/*virology ; Pyrazines/chemistry/*pharmacology/toxicity ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tumor Burden/drug effects ; Virus Replication/*drug effects ; Vorinostat ; }, abstract = {A novel drug combination of a proteasome inhibitor, bortezomib, and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was tested in nasopharyngeal carcinoma (NPC), both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPC was determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein-Barr virus (EBV) were investigated. Combination of bortezomib and SAHA (bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G1, Annexin V-positive, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8, and -9, reactive oxygen species (ROS) generation, and caspase-8-dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA, whereas caspase inhibitor Z-VAD-FMK significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in patients with NPC.}, }
@article {pmid23475579, year = {2014}, author = {Das, TP and Suman, S and Damodaran, C}, title = {Induction of reactive oxygen species generation inhibits epithelial-mesenchymal transition and promotes growth arrest in prostate cancer cells.}, journal = {Molecular carcinogenesis}, volume = {53}, number = {7}, pages = {537-547}, pmid = {23475579}, issn = {1098-2744}, support = {R01 AT002890/AT/NCCIH NIH HHS/United States ; R01 CA138797/CA/NCI NIH HHS/United States ; 5R01AT002890-02/AT/NCCIH NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Benzofurans/*pharmacology ; Cadherins/biosynthesis ; Caspase 3/metabolism ; Caspase 9/metabolism ; Catalase/biosynthesis ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Coumarins/*pharmacology ; Cytochromes c/metabolism ; Enzyme Activation ; Epithelial-Mesenchymal Transition/*drug effects ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Neoplasm Invasiveness ; Oxidative Stress ; Poly(ADP-ribose) Polymerases/metabolism ; Prostatic Neoplasms/*drug therapy/pathology ; Reactive Oxygen Species/*metabolism ; Snail Family Transcription Factors ; Superoxide Dismutase/biosynthesis ; Superoxide Dismutase-1 ; Transcription Factors/genetics ; Transcription, Genetic/drug effects ; beta Catenin/genetics ; }, abstract = {Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro-oxidant property of 3,9-dihydroxy-2-prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC-3 and C4-2B) cells. Pso greatly induced ROS generation (more than 20-fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti-oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N-acetylcysteine (NAC) significantly attenuated both pso-mediated ROS generation and pso-mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β-catenin, and slug, which promote epithelial-mesenchymal transition (EMT), and by concurrently inducing E-cadherin expression in CaP cells. Pso-induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome-c release, and activation of caspase-3 and -9 and poly (ADP-ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti-oxidants rescued pso-mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis.}, }
@article {pmid23475548, year = {2013}, author = {Sahin, S and Alatas, O}, title = {The protective effects of n-acetylcysteine against acute hepatotoxicity.}, journal = {Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology}, volume = {32}, number = {5}, pages = {311-315}, pmid = {23475548}, issn = {0975-0711}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Carbon Tetrachloride ; Chemical and Drug Induced Liver Injury/*blood/pathology/*prevention &amp; control ; Malondialdehyde/blood/*metabolism ; Nitric Oxide/blood ; Oxidative Stress/drug effects ; Peroxidase/blood ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVES: N-acetylcysteine (NAC) increases tissue levels of glutathione and has been widely investigated as a protective and antioxidative agent. This study evaluated the protective effect of NAC on under carbon tetrachloride (CCl4)-induced acute liver injury in the rat.<br><br>METHODS: Three-month-old Sprague-Dawley rats were intraperitoneally administered 4 mL/kg CCl4 (1:1 dissolved in olive oil, group 1) or 4 mL/kg CCl4&#x2009;+&#x2009;NAC 150 mg/kg, 3 and 6 h after CCL4 (group 2) or 4 mL/kg olive oil (group 3, control). Twenty-four hours after administering CCl4, all of the rats were sacrificed. Biochemical assessment of serum transaminases and malonaldehyde (MDA) and tissue MDA, myeloperoxidase (MPO), and nitric oxide was done. Histopathological assessments were performed.<br><br>RESULTS: Serum transaminases and tissue and serum MDA and tissue MPO were all increased in group 1 compared to control and were significantly decreased in the group treated with NAC. Histopathological comparison of the groups showed a decrease in congestion, polymorphonuclear leukocytes, mononuclear leukocytes, vacuolar degeneration of hepatocyte, and hepatocellular necrosis in the group treated with NAC.<br><br>CONCLUSION: Our results suggest that NAC prevents experimental acute hepatic failure by preventing oxidative stress.}, }
@article {pmid23472882, year = {2013}, author = {Sunitha, K and Hemshekhar, M and Thushara, RM and Santhosh, MS and Yariswamy, M and Kemparaju, K and Girish, KS}, title = {N-Acetylcysteine amide: a derivative to fulfill the promises of N-Acetylcysteine.}, journal = {Free radical research}, volume = {47}, number = {5}, pages = {357-367}, doi = {10.3109/10715762.2013.781595}, pmid = {23472882}, issn = {1029-2470}, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives ; Antioxidants/*administration &amp; dosage ; Apoptosis/drug effects ; Cell Survival/drug effects ; Drug Therapy/*methods ; Glutathione/metabolism ; Humans ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {In the present human health scenario, implication of oxidative stress in numerous pathologies including neurodegenerative, cardiovascular, liver, renal, pulmonary disorders, and cancer has gained attention. N-Acetylcysteine (NAC), a popular thiol antioxidant, has been clinically used to treat various pathophysiological disorders. However, NAC therapy is routine only in paracetamol intoxication and as a mucolytic agent. Over six decades, numerous studies involving NAC therapy have yielded inconsistent results, and this could be due to low bioavailability. In order to overcome the limitations of NAC, an amide derivative N-Acetylcysteine amide (NACA) has been synthesized to improve the lipophilicity, membrane permeability, and antioxidant property. Recent studies have demonstrated the blood-brain barrier permeability and therapeutic potentials of NACA in neurological disorders including Parkinson's disease, Alzheimer's disease, Multiple sclerosis, Tardive dyskinesia, and HIV-associated neurological disorders. In addition, NACA displays protective effect against pulmonary inflammation and antibiotic-induced apoptosis. Forthcoming research on the possible therapeutic properties of NACA and its generics in the management of pathologies associated with extracellular matrix degradation and oxidative stress-related inflammation is highly exiting. Superior bioavailability of NACA is likely to fulfill the promises of NAC as well as a molecule to improve the endurance and resident time of bioscaffolds and biomaterials. Till date, more than 800 reviews on NAC have been published. However, no comprehensive review is available on the therapeutic applications of NACA. Therefore, the current review would be the first to emphasize the therapeutic potentials of NACA and its derivatives.}, }
@article {pmid23470675, year = {2013}, author = {Deffenbacher, B}, title = {Successful experimental treatment of congenital ichthyosis in an infant.}, journal = {BMJ case reports}, volume = {2013}, number = {}, pages = {}, pmid = {23470675}, issn = {1757-790X}, mesh = {Acetylcysteine/*therapeutic use ; Emollients/therapeutic use ; Humans ; Ichthyosis/*drug therapy ; Infant, Newborn ; Male ; }, abstract = {Ichthyosis is a rare genetic disease that causes defects in skin keratinisation. Infants born with this disease have tight shiny skin that inhibits limb and ear mobilities, eyelid and lip deformities and poor hair and nail growths. In addition, the barrier properties of the skin are disrupted, which leads to dehydration, body temperature regulation difficulties and increased susceptibility to infection. The treatments currently available include topical keratolytics, emollients, and for severe disease systemic retinoids. Given the increased permeability of the skin and increased body surface area infants are particularly susceptible to accidental overdose from the topical keratolytic treatments currently available. An experimental emollient of 10% N-acetylcysteine (NAC) and 5% urea was recently used with success in Argentina. A newborn with congenital ichthyosis cared for in our clinic failed his initial treatment of topical emollients. He was subsequently treated successfully with off-label use of a topical 5% NAC and 5% urea emollient.}, }
@article {pmid23469273, year = {2013}, author = {Laurenzana, A and Balliu, M and Cellai, C and Romanelli, MN and Paoletti, F}, title = {Effectiveness of the histone deacetylase inhibitor (S)-2 against LNCaP and PC3 human prostate cancer cells.}, journal = {PloS one}, volume = {8}, number = {3}, pages = {e58267}, pmid = {23469273}, issn = {1932-6203}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Caspases/genetics/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/antagonists &amp; inhibitors/genetics/metabolism ; Gene Expression Regulation, Neoplastic/*drug effects ; Histone Deacetylase Inhibitors/*pharmacology ; Histones/antagonists &amp; inhibitors/genetics/metabolism ; Humans ; Hydroxamic Acids/*pharmacology ; Male ; Mice ; Mice, Nude ; Prostatic Neoplasms/drug therapy/genetics/metabolism ; Tumor Burden/drug effects ; Vorinostat ; Xenograft Model Antitumor Assays ; }, abstract = {Histone deacetylase inhibitors (HDACi) represent a promising class of epigenetic agents with anticancer properties. Here, we report that (S)-2, a novel hydroxamate-based HDACi, shown previously to be effective against acute myeloid leukemia cells, was also a potent inducer of apoptosis/differentiation in human prostate LNCaP and PC3 cancer cells. In LNCaP cells (S)-2 was capable of triggering H3/H4 histone acetylation, H2AX phosphorylation as a marker of DNA damage and producing G0/G1 cell cycle arrest. Consistently, (S)-2 led to enhanced expression of both the protein and mRNA p21 levels in LNCaP cells but, contrary to SAHA, not in normal non-tumorigenic prostate PNT1A cells. Mechanistic studies demonstrated that (S)-2-induced apoptosis in LNCaP cells developed through the cleavage of pro-caspase 9 and 3 and of poly(ADP-ribose)-polymerase accompanied by the dose-dependent loss of mitochondrial membrane potential. Indeed, the addition of the pan-caspase inhibitor Z-VAD-fmk greatly reduced drug-mediated apoptosis while the antioxidant N-acetyl-cysteine was virtually ineffective. Importantly, preliminary data with nude mice xenografted with LNCaP cells showed that (S)-2 prompted a decrease in the tumor volume and an increase in H2AX phosphorylation within the cancer cells. Moreover, the highly metastatic prostate cancer PC3 cells were also sensitive to (S)-2 that: i) induced growth arrest and moderate apoptosis; ii) steered cells towards differentiation and neutral lipid accumulation; iii) reduced cell invasiveness potential by decreasing the amount of MMP-9 activity and up-regulating TIMP-1 expression; and iv) inhibited cell motility and migration through the Matrigel. Overall, (S)-2 has proven to be a powerful HDACi capable of inducing growth arrest, cell death and/or differentiation of LNCaP and PC3 prostate cancer cells and, due to its low toxicity and efficacy in vivo, might also be of clinical interest to support conventional prostate cancer therapy.}, }
@article {pmid23462569, year = {2013}, author = {Bu, Q and Lv, L and Yan, G and Deng, P and Wang, Y and Zhou, J and Yang, Y and Li, Y and Cen, X}, title = {NMR-based metabonomic in hippocampus, nucleus accumbens and prefrontal cortex of methamphetamine-sensitized rats.}, journal = {Neurotoxicology}, volume = {36}, number = {}, pages = {17-23}, doi = {10.1016/j.neuro.2013.02.007}, pmid = {23462569}, issn = {1872-9711}, mesh = {Animals ; Brain/*drug effects/*metabolism ; Central Nervous System Sensitization/*drug effects ; Central Nervous System Stimulants/*toxicity ; Discriminant Analysis ; Disease Models, Animal ; Hippocampus ; Magnetic Resonance Spectroscopy ; Male ; *Metabolomics ; Methamphetamine/*toxicity ; Motor Activity/drug effects ; Neurotransmitter Agents/metabolism ; Nucleus Accumbens ; Prefrontal Cortex ; Rats ; Rats, Wistar ; Tritium ; }, abstract = {(1)H NMR spectroscopy was applied to investigate the changes of cerebral metabolites in brain hippocampus, nucleus accumbens (NAC) and prefrontal cortex (PFC) of the rats subjected to subcutaneous twice-daily injections of 2.5mg/kg methamphetamine (MAP) for 7 days. The results indicated that MAP exposure induced significant behavioral sensitization and altered cerebral metabolites in rats. The neurotransmitters glutamate, glutamine and GABA significantly decreased in hippocampus, NAC and PFC. Specifically, increased succinic acid semialdehyde, a metabolism product of GABA, was observed in hippocampus. Additionally, decreased serotonin was observed in both NAC and PFC, whereas decreased dopamine was only observed in NAC after repeated MAP treatment. Glutathione obviously decreased in above brain regions, whereas acetylcysteine declined in hippocampus and NAC, and taurine declined in NAC and PFC. Homocysteic acid was elevated in hippocampus and NAC by repeated MAP administration. Membrane ingredients like phosphocholine elevated in response to MAP administration in NAC and PFC. N-Acetyl-aspartate, a marker of neuronal viability, decreased in the three regions; however, myo-inositol, a glial cell marker, increased in hippocampus and PFC. Tricarboxylic acid cycle intermediate products, such as α-ketoglutarate, succinate, citrate and the methionine significantly decreased in above three brain regions after MAP administration; however, ADP decreased in hippocampus. These results indicate that repeated MAP treatment causes neurotransmitters disturbance, imbalance between oxidative stress and antioxidants, and gliosis in hippocampus, NAC and PFC. Profound metabolic changes detected across brain regions provide the first evidence of metabonomic changes in MAP-induced sensitized rats.}, }
@article {pmid23458734, year = {2013}, author = {Viviano, KR and VanderWielen, B}, title = {Effect of N-acetylcysteine supplementation on intracellular glutathione, urine isoprostanes, clinical score, and survival in hospitalized ill dogs.}, journal = {Journal of veterinary internal medicine}, volume = {27}, number = {2}, pages = {250-258}, doi = {10.1111/jvim.12048}, pmid = {23458734}, issn = {1939-1676}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Case-Control Studies ; Dietary Supplements ; Dog Diseases/blood/*drug therapy/metabolism/urine ; Dogs ; Female ; Glutathione/blood/*metabolism ; Hospitals, Animal ; Isoprostanes/*metabolism/urine ; Male ; Oxidative Stress/*drug effects ; Prospective Studies ; Selenium/blood ; Statistics, Nonparametric ; Survival Analysis ; Vitamin E/blood ; }, abstract = {BACKGROUND: Antioxidant depletion and lipid peroxidation have been correlated with disease severity and associated with poor outcomes.<br><br>HYPOTHESIS/OBJECTIVES: Supplementing dogs with N-acetylcysteine (NAC) during the first 48&#xa0;hours of hospitalization will increase cysteine, normalize glutathione concentrations, and decrease the degree of lipid peroxidation associated with illness.<br><br>ANIMALS: Sixty systemically ill hospitalized client-owned dogs and 14 healthy control dogs.<br><br>METHODS: Randomized investigator-blinded, placebo-controlled prospective study. Dogs were randomized to treatment with NAC (n&#xa0;=&#xa0;30) versus placebo (n&#xa0;=&#xa0;30). Antioxidants, urine 8-isoprostane/creatinine (IP/Cr), and clinical score were determined before and after treatment with NAC. Glutathione, cysteine, and vitamin E concentrations were quantified using high-performance liquid chromatography. Atomic absorption spectroscopy and enzyme-linked immunosorbent assays were used to quantify selenium and isoprostane concentrations, respectively.<br><br>RESULTS: Ill dogs had significantly lower vitamin E concentrations (27 versus 55&#xa0;&#x3bc;g/mL; P&#xa0;=&#xa0;.0005) as well as elevated IP/Cr ratios (872 versus 399&#xa0;pg/mg; P&#xa0;=&#xa0;.0007) versus healthy dogs. NAC supplementation significantly increased plasma cysteine (8.67 versus 15.1&#xa0;&#x3bc;M; P&#xa0;<&#xa0;.0001) while maintaining glutathione concentrations. Dogs in the placebo group experienced a statistically significant decrease in glutathione concentrations (1.49 versus 1.44&#xa0;mM; P&#xa0;=&#xa0;.0463). Illness severity and survival were unchanged after short duration NAC supplementation.<br><br>CONCLUSIONS: Ill dogs experience systemic oxidative stress. Supplementation with NAC during the first 48&#xa0;hours of hospitalization stabilized erythrocyte glutathione concentrations. The clinical impact of this supplementation and glutathione concentration stabilization was undetermined.}, }
@article {pmid23458723, year = {2013}, author = {Robinson, SM and Saif, R and Sen, G and French, JJ and Jaques, BC and Charnley, RM and Manas, DM and White, SA}, title = {N-acetylcysteine administration does not improve patient outcome after liver resection.}, journal = {HPB : the official journal of the International Hepato Pancreato Biliary Association}, volume = {15}, number = {6}, pages = {457-462}, pmid = {23458723}, issn = {1477-2574}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Aged, 80 and over ; Analysis of Variance ; Antioxidants/*administration &amp; dosage ; Chi-Square Distribution ; Female ; Hepatectomy/*adverse effects/mortality ; Humans ; Liver Failure/etiology/metabolism/mortality/*prevention &amp; control ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Reperfusion Injury/etiology/metabolism/mortality/*prevention &amp; control ; Risk Factors ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Post-operative hepatic dysfunction is a major cause of concern when undertaking a liver resection. The generation of reactive oxygen species (ROS) as a result of hepatic ischaemia/reperfusion (I/R) injury can result in hepatocellular injury. Experimental evidence suggests that N-acetylcysteine may ameliorate ROS-mediated liver injury.<br><br>METHODS: A cohort of 44 patients who had undergone a liver resection and receiving peri-operative N-acetylcysteine (NAC) were compared with a further cohort of 44 patients who did not. Liver function tests were compared on post-operative days 1, 3 and 5. Peri-operative outcome data were retrieved from a prospectively maintained database within our unit.<br><br>RESULTS: Administration of NAC was associated with a prolonged prothrombin time on the third post-operative day (18.4 versus 16.4 s; P = 0.002). The incidence of grades B and C liver failure was lower in the NAC group although this difference did not reach statistical significance (6.9% versus 14%; P = 0.287). The overall complication rate was similar between groups (32% versus 25%; P = ns). There were two peri-operative deaths in the NAC group and one in the control group (P = NS).<br><br>CONCLUSION: In spite of promising experimental evidence, this study was not able to demonstrate any advantage in the routine administration of peri-operative NAC in patients undergoing a liver resection.}, }
@article {pmid23454527, year = {2013}, author = {Bayram, H and Fakili, F and Gögebakan, B and Bayraktar, R and Oztuzcu, S and Dikensoy, O and Chung, KF}, title = {Effect of serum on diesel exhaust particles (DEP)-induced apoptosis of airway epithelial cells in vitro.}, journal = {Toxicology letters}, volume = {218}, number = {3}, pages = {215-223}, doi = {10.1016/j.toxlet.2013.02.006}, pmid = {23454527}, issn = {1879-3169}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclin E/genetics/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism ; Dose-Response Relationship, Drug ; Epithelial Cells/*drug effects/immunology/metabolism/pathology ; Humans ; Inflammation Mediators/metabolism ; Interleukin-8/metabolism ; Mitogen-Activated Protein Kinase 9/antagonists &amp; inhibitors/genetics/metabolism ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Particulate Matter/*toxicity ; Protein Kinase Inhibitors/pharmacology ; RNA, Messenger/metabolism ; Respiratory Mucosa/*drug effects/immunology/metabolism/pathology ; Serum/*metabolism ; Time Factors ; Tumor Suppressor Protein p53/genetics/metabolism ; Vehicle Emissions/*toxicity ; }, abstract = {Patients with chronic airway diseases may be more susceptible to adverse effects of air pollutants including diesel exhaust particles (DEP). We investigated effects of foetal calf serum (FCS) on DEP-induced changes in airway epithelial cell apoptosis and inflammation. DEP (50-200 μg/ml) increased A549 cell viability in the absence of FCS. In the presence of 3.3%FCS, DEP (50-400 μg/ml) decreased A549 cell viability. N-acetylcysteine (NAC, 33 mM) and the c-jun N-terminal kinase (JNK) inhibitor (SP600125, 33 μM) further decreased the viability in the presence of DEP (200 μg/ml) and 3.3% FCS. Under serum-free (SF) condition, DEP (50 μg/ml) reduced apoptotic cells; however, when 3.3% FCS added to the culture medium, this effect was abolished. DEP (200 μg/ml) induced mRNA expression of p21(CIP1/WAF1) both in absence or presence of 3.3% FCS and enhanced JNK2 mRNA expression only in the presence of 3.3% FCS. Under SF condition, DEP (50 μg/ml) induced mRNA expression for p27 and p53, whereas cyclin E mRNA expression was inhibited by DEP (50 and 200 μg/ml). Furthermore, DEP (200 μg/ml) decreased the release of interleukin (IL)-8 in the absence of FCS. In conclusion, FCS modulates effects of DEP on cell death, cell cycle and apoptosis regulating proteins, and IL-8 release by activating oxidant stress pathways, JNK and NF-κB. Extravasation of serum, as occurs in the inflamed airways of patients with chronic airway diseases such as asthma and COPD, may render airway epithelial cells more susceptible to the deleterious effects of DEP.}, }
@article {pmid23454206, year = {2013}, author = {Nho, KJ and Chun, JM and Kim, HK}, title = {Corosolic acid induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {56}, number = {}, pages = {8-17}, doi = {10.1016/j.fct.2013.02.002}, pmid = {23454206}, issn = {1873-6351}, mesh = {Adenocarcinoma/*pathology ; Adenocarcinoma of Lung ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 7/metabolism ; Caspase 8/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Lung Neoplasms/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Oligopeptides/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Triterpenes/*pharmacology ; }, abstract = {Corosolic acid (CRA), a triterpenoid from medicinal herbs, has been shown to induce apoptosis in several cell lines, with the exception of A549 cells. In this report, we investigated the apoptotic effect and mechanism of CRA in A549 cells. The present study shows that CRA significantly inhibits cell viability in a concentration- and time-dependent manner. Exposure to CRA induces sub-G1 cell cycle arrest and causes apoptotic death in A549 cells. CRA also triggers the activation of caspases and poly(ADP-ribose) polymerase, an effect antagonized by z-vad-fmk. In addition, exposure to CRA leads to a significant increase in the levels of reactive oxygen species (ROS) in A549 cells. Furthermore, exposure to the ROS scavenger N acetylcysteine (NAC)prevents CRA-induced apoptosis, suggesting a role for ROS in CRA-induced apoptosis. ROS are critical regulators of caspase-mediated apoptosis in A549 cells. These results indicate that CRA induces mitochondria-mediated and caspase-dependent apoptosis in A549 cells by altering anti-apoptotic proteins in a ROS-dependent manner.}, }
@article {pmid23454065, year = {2013}, author = {Abdelmegeed, MA and Jang, S and Banerjee, A and Hardwick, JP and Song, BJ}, title = {Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury.}, journal = {Free radical biology &amp; medicine}, volume = {60}, number = {}, pages = {211-222}, pmid = {23454065}, issn = {1873-4596}, support = {Z99 AA999999/ImNIH/Intramural NIH HHS/United States ; ZIA AA000036-25/ImNIH/Intramural NIH HHS/United States ; ZIA AA000036-26/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetaminophen/*administration &amp; dosage/toxicity ; Acetanilides/administration &amp; dosage ; Acetylcysteine/*administration &amp; dosage/metabolism ; Animals ; Antioxidants ; Chemical and Drug Induced Liver Injury/*metabolism/pathology ; Mice ; Mitochondria, Liver/*drug effects/pathology ; Nitrates/*metabolism ; Oxidative Stress ; Proteins/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Acetaminophen (APAP), a widely used analgesic/antipyretic agent, can cause liver injury through increased nitrative stress, leading to protein nitration. However, the identities of nitrated proteins and their roles in hepatotoxicity are poorly understood. Thus, we aimed at studying the mechanism of APAP-induced hepatotoxicity by systematic identification and characterization of nitrated proteins in the absence or presence of an antioxidant, N-acetylcysteine (NAC). The levels of nitrated proteins markedly increased at 2h in mice exposed to a single APAP dose (350mg/kg ip), which caused severe liver necrosis at 24h. Protein nitration and liver necrosis were minimal in mice exposed to nontoxic 3-hydroxyacetanilide or animals co-treated with APAP and NAC. Mass-spectral analysis of the affinity-purified nitrated proteins identified numerous mitochondrial and cytosolic proteins, including mitochondrial aldehyde dehydrogenase, Mn-superoxide dismutase, glutathione peroxidase, ATP synthase, and 3-ketoacyl-CoA thiolase, involved in antioxidant defense, energy supply, or fatty acid metabolism. Immunoprecipitation followed by immunoblot with anti-3-nitrotyrosine antibody confirmed that the aforementioned proteins were nitrated in APAP-exposed mice but not in NAC-cotreated mice. Consistently, NAC cotreatment significantly restored the suppressed activity of these enzymes. Thus, we demonstrate a new mechanism by which many nitrated proteins with concomitantly suppressed activity promotes APAP-induced mitochondrial dysfunction and hepatotoxicity.}, }
@article {pmid23452680, year = {2013}, author = {Bloch, MH and Panza, KE and Grant, JE and Pittenger, C and Leckman, JF}, title = {N-Acetylcysteine in the treatment of pediatric trichotillomania: a randomized, double-blind, placebo-controlled add-on trial.}, journal = {Journal of the American Academy of Child and Adolescent Psychiatry}, volume = {52}, number = {3}, pages = {231-240}, pmid = {23452680}, issn = {1527-5418}, support = {UL1 RR024139/RR/NCRR NIH HHS/United States ; T32MH018268-26/MH/NIMH NIH HHS/United States ; K08 MH081190/MH/NIMH NIH HHS/United States ; R25 MH077823/MH/NIMH NIH HHS/United States ; T32 MH018268/MH/NIMH NIH HHS/United States ; UL1RR024139/RR/NCRR NIH HHS/United States ; K23MH091240/MH/NIMH NIH HHS/United States ; K08MH081190/MH/NIMH NIH HHS/United States ; K23 MH091240/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*pharmacology ; Adolescent ; Child ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage/adverse effects/*pharmacology ; Humans ; Male ; Placebos ; Psychiatric Status Rating Scales ; Severity of Illness Index ; Treatment Outcome ; Trichotillomania/*drug therapy ; }, abstract = {OBJECTIVE: To examine the efficacy of N-acetylcysteine (NAC) for the treatment of pediatric trichotillomania (TTM) in a double-blind, placebo-controlled, add-on study.<br><br>METHOD: A total of 39 children and adolescents aged 8 to 17 years with pediatric trichotillomania were randomly assigned to receive NAC or matching placebo for 12 weeks. Our primary outcome was change in severity of hairpulling as measured by the Massachusetts General Hospital-Hairpulling Scale (MGH-HPS). Secondary measures assessed hairpulling severity, automatic versus focused pulling, clinician-rated improvement, and comorbid anxiety and depression. Outcomes were examined using linear mixed models to test the treatment&#xd7;time interaction in an intention-to-treat population.<br><br>RESULTS: No significant difference between N-acetylcysteine and placebo was found on any of the primary or secondary outcome measures. On several measures of hairpulling, subjects significantly improved with time regardless of treatment assignment. In the NAC group, 25% of subjects were judged as treatment responders, compared to 21% in the placebo group.<br><br>CONCLUSIONS: We observed no benefit of NAC for the treatment of children with trichotillomania. Our findings stand in contrast to a previous, similarly designed trial in adults with TTM, which demonstrated a very large, statistically significant benefit of NAC. Based on the differing results of NAC in pediatric and adult TTM populations, the assumption that pharmacological interventions demonstrated to be effective in adults with TTM will be as effective in children, may be inaccurate. This trial highlights the importance of referring children with TTM to appropriate behavioral therapy before initiating pharmacological interventions, as behavioral therapy has demonstrated efficacy in both children and adults with trichotillomania.}, }
@article {pmid23450460, year = {2012}, author = {da Rocha, FP and Fagundes, DJ and Pires, JA and da Rocha, FS}, title = {Effects of hyperbaric oxygen and N-acetylcysteine in survival of random pattern skin flaps in rats.}, journal = {Indian journal of plastic surgery : official publication of the Association of Plastic Surgeons of India}, volume = {45}, number = {3}, pages = {453-458}, pmid = {23450460}, issn = {0970-0358}, abstract = {OBJECTIVE: Our aim is to investigate the role of HBO (hyperbaric oxygen), NAC (N-acetylcysteine), and HBO plus NAC on the necrosis area of random rat's skin flaps of a modified McFarlane flap design.<br><br>MATERIALS AND METHODS: Thirty-two male Wistar rats were randomly divided into four groups: G-S (sham: n = 8), G-NAC (NAC: n = 8), G-HBO (HBO: n = 8), and G-HN (HBO plus NAC: n = 8). A rectangular skin flap (2 &#xd7; 8 cm(2)) was dissected from the muscular dorsal layer, preserving the cranial pedicle. Polyethylene film was placed over the muscular layer and an interrupted 3.0 nylon suture was employed to fix the flap into the original place. On the eighth day, full-thickness biopsy samples (2 &#xd7; 1 cm(2)) were collected from the proximal, middle, and cranial areas of the skin flap, and in a site away from the flap labelled as the control area.<br><br>RESULTS: The measurements of necrotic areas in the groups were 18.3% in G-S, 24.3% in G-NAC, 12.6% in G-HBO, and 14.9% in G-HN. Significant difference was observed between the groups G-HBO and G-HN as well as G-NAC.<br><br>CONCLUSION: HBO is associated with reduced area of necrosis of skin flap. The G-NAC group was associated with poor results when examined in isolation. The association between HBO and NAC did not produce favourable results with respect to the use of HBO alone. These findings suggest that the diffusion of oxygen through the interstitial space was the determining factor of more favourable results of HBO.}, }
@article {pmid23443459, year = {2013}, author = {Arya, N and Arora, A and Vasu, KS and Sood, AK and Katti, DS}, title = {Combination of single walled carbon nanotubes/graphene oxide with paclitaxel: a reactive oxygen species mediated synergism for treatment of lung cancer.}, journal = {Nanoscale}, volume = {5}, number = {7}, pages = {2818-2829}, doi = {10.1039/c3nr33190c}, pmid = {23443459}, issn = {2040-3372}, mesh = {Antineoplastic Agents, Phytogenic/*administration &amp; dosage ; Antineoplastic Combined Chemotherapy Protocols/chemistry/therapeutic use ; Cell Line, Tumor ; Drug Carriers/administration &amp; dosage/*chemical synthesis/chemistry ; Drug Compounding/methods ; Drug Synergism ; Graphite/*chemistry ; Humans ; Lung Neoplasms/*drug therapy/pathology ; Nanotubes, Carbon/*chemistry ; Oxides/administration &amp; dosage/chemical synthesis/chemistry ; Paclitaxel/*administration &amp; dosage ; Reactive Oxygen Species/*metabolism ; }, abstract = {Heterogeneity in tumors has led to the development of combination therapies that enable enhanced cell death. Previously explored combination therapies mostly involved the use of bioactive molecules. In this work, we explored a non-conventional strategy of using carbon nanostructures (CNs) [single walled carbon nanotube (SWNT) and graphene oxide (GO)] for potentiating the efficacy of a bioactive molecule [paclitaxel (Tx)] for the treatment of lung cancer. The results demonstrated enhanced cell death following combination treatment of SWNT/GO and Tx indicating a synergistic effect. In addition, synergism was abrogated in the presence of an anti-oxidant, N-acetyl cysteine (NAC), and was therefore shown to be reactive oxygen species (ROS) dependent. It was further demonstrated using bromodeoxyuridine (BrdU) incorporation assay that treatment with CNs was associated with enhanced mitogen associated protein kinase (MAPK) activation that was ROS mediated. Hence, these results for the first time demonstrated the potential of SWNT/GO as co-therapeutic agents with Tx for the treatment of lung cancer.}, }
@article {pmid23443244, year = {2013}, author = {Sooriyaarachchi, M and Narendran, A and Gailer, J}, title = {N-acetyl-L-cysteine modulates the metabolism of cis-platin in human plasma in vitro.}, journal = {Metallomics : integrated biometal science}, volume = {5}, number = {3}, pages = {197-207}, doi = {10.1039/c3mt00012e}, pmid = {23443244}, issn = {1756-591X}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/*pharmacology ; Blood Proteins/*drug effects ; Chromatography, Gel ; Cisplatin/blood/*pharmacokinetics/*pharmacology ; Humans ; Metalloproteins/blood ; Spectrophotometry, Atomic ; Thiosulfates/pharmacology ; }, abstract = {Cis-Platin (CP) is a remarkably effective Pt-based anticancer drug, but it also exhibits severe toxic side-effects, including nephrotoxicity and ototoxicity. Previous studies conducted with mammalian model organisms have clearly demonstrated that the intravenous administration of N-acetyl-L-cysteine (NAC) or sodium thiosulfate (STS) along with CP can significantly reduce these toxic side effects. A molecular understanding of the biochemical events that unfold in the bloodstream when these 'ameliorating agents' and CP are co-administered, therefore, constitutes an important first step in devising novel strategies to ultimately improve the quality of life of patients undergoing treatment with CP. We have employed size exclusion chromatography (SEC) coupled on-line to an inductively coupled plasma atomic emission spectrometer (ICP-AES) to visualize how NAC affects the metabolism of CP in human plasma (obtained from healthy male volunteers) in vitro. Clinically relevant doses of CP and NAC were added to plasma at various NAC : CP molar ratios and the Pt-distribution was determined after 10 and 50 min. The results revealed that a putative Pt-NAC complex was formed in plasma with NAC : CP molar ratios ≥ 50 : 1 and that plasma protein binding of CP-derived Pt-species was marginally affected by NAC. In addition, the anti-tumor active CP remained in plasma for more than 50 min. Furthermore, NAC (but not CP) adversely affected the integrity of Fe and Zn plasma metalloproteins in a dose and a time dependent manner. Based on these in vitro data, NAC appears to be a less ideal ameliorating agent to mitigate CP toxicity compared to STS.}, }
@article {pmid23441133, year = {2013}, author = {Velpula, KK and Gogineni, VR and Nalla, AK and Dinh, DH and Rao, JS}, title = {Radiation-induced hypomethylation triggers urokinase plasminogen activator transcription in meningioma cells.}, journal = {Neoplasia (New York, N.Y.)}, volume = {15}, number = {2}, pages = {192-203}, pmid = {23441133}, issn = {1476-5586}, support = {R01 NS061835/NS/NINDS NIH HHS/United States ; NS061835/NS/NINDS NIH HHS/United States ; }, mesh = {Brain Neoplasms/*genetics/pathology ; Cell Line, Tumor ; Cell Proliferation/radiation effects ; CpG Islands/genetics ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/genetics/metabolism ; DNA Methylation/*genetics ; DNA-Binding Proteins/genetics/metabolism ; Gene Expression Regulation, Neoplastic/radiation effects ; Humans ; Immunoglobulins/metabolism ; Meningioma/*genetics/pathology ; Oxidative Stress/radiation effects ; Promoter Regions, Genetic/radiation effects ; Signal Transduction/radiation effects ; Transcription Factors/genetics/metabolism ; Transcriptional Activation/genetics/radiation effects ; Urokinase-Type Plasminogen Activator/*genetics/metabolism ; }, abstract = {Our previous studies have shown the role of radiation-induced urokinase plasminogen activator (uPA) expression in the progression of meningioma. In the present study, we investigated whether modulation of DNA methylation profiles could regulate uPA expression. Initially, radiation treatment was found to induce hypomethylation in meningioma cells with a decrease in DNA (cytosine-5)-methyltransferase 1 (DNMT1) and methyl-CpG binding domain protein (MBD) expression. However, oxidative damage by H(2)O(2) or pretreatment of irradiated cells with N-acetyl cysteine (NAC) did not show any influence on these proteins, thereby indicating a radiation-specific change in the methylation patterns among meningioma cells. Further, we identified that hypomethylation is coupled to an increase in uPA expression in these cells. Azacytidine treatment induced a dose-dependent surge of uPA expression, whereas pre-treatment with sodium butyrate inhibited radiation-induced uPA expression, which complemented our prior results. Methylation-specific polymerase chain reaction on bisulfite-treated genomic DNA revealed a diminished methylation of uPA promoter in irradiated cells. Transfection with small hairpin RNA (shRNA)-expressing plasmids targeting CpG islands of the uPA promoter showed a marked decline in uPA expression with subsequent decrease in invasion and proliferation of meningioma cells. Further, radiation treatment was found to recruit SP1 transcription factor, which was abrogated by shRNA treatment. Analysis on signaling events demonstrated the activation of MAP kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) in radiation-treated cells, while U0126 (MEK/ERK inhibitor) blocked hypomethylation, recruitment of SP1, and uPA expression. In agreement with our in vitro data, low DNMT1 levels and high uPA were found in intracranial tumors treated with radiation compared to untreated tumors. In conclusion, our data suggest that radiation-mediated hypomethylation triggers uPA expression in meningioma cells.}, }
@article {pmid23438298, year = {2013}, author = {Fleming, AM and Burrows, CJ}, title = {G-quadruplex folds of the human telomere sequence alter the site reactivity and reaction pathway of guanine oxidation compared to duplex DNA.}, journal = {Chemical research in toxicology}, volume = {26}, number = {4}, pages = {593-607}, pmid = {23438298}, issn = {1520-5010}, support = {R01 CA090689/CA/NCI NIH HHS/United States ; CA090689/CA/NCI NIH HHS/United States ; }, mesh = {DNA/chemistry/*metabolism ; *G-Quadruplexes ; Guanine/*metabolism ; Humans ; Oxidants/pharmacology ; Oxidation-Reduction ; Telomere/chemistry/*metabolism ; }, abstract = {Telomere shortening occurs during oxidative and inflammatory stress with guanine (G) as the major site of damage. In this work, a comprehensive profile of the sites of oxidation and structures of products observed from G-quadruplex and duplex structures of the human telomere sequence was studied in the G-quadruplex folds (hybrid (K(+)), basket (Na(+)), and propeller (K(+) + 50% CH3CN)) resulting from the sequence 5'-(TAGGGT)4T-3' and in an appropriate duplex containing one telomere repeat. Oxidations with four oxidant systems consisting of riboflavin photosensitization, carbonate radical generation, singlet oxygen, and the copper Fenton-like reaction were analyzed under conditions of low product conversion to determine relative reactivity. The one-electron oxidants damaged the 5'-G in G-quadruplexes leading to spiroiminodihydantoin (Sp) and 2,2,4-triamino-2H-oxazol-5-one (Z) as major products as well as 8-oxo-7,8-dihydroguanine (OG) and 5-guanidinohydantoin (Gh) in low relative yields, while oxidation in the duplex context produced damage at the 5'- and middle-Gs of GGG sequences and resulted in Gh being the major product. Addition of the reductant N-acetylcysteine (NAC) to the reaction did not alter the riboflavin-mediated damage sites but decreased Z by 2-fold and increased OG by 5-fold, while not altering the hydantoin ratio. However, NAC completely quenched the CO3(•-) reactions. Singlet oxygen oxidations of the G-quadruplex showed reactivity at all Gs on the exterior faces of G-quartets and furnished the product Sp, while no oxidation was observed in the duplex context under these conditions, and addition of NAC had no effect. Because a long telomere sequence would have higher-order structures of G-quadruplexes, studies were also conducted with 5'-(TAGGGT)8-T-3', and it provided oxidation profiles similar to those of the single G-quadruplex. Lastly, Cu(II)/H2O2-mediated oxidations were found to be indiscriminate in the damage patterns, and 5-carboxamido-5-formamido-2-iminohydantoin (2Ih) was found to be a major duplex product, while nearly equal yields of 2Ih and Sp were observed in G-quadruplex contexts. These findings indicate that the nature of the secondary structure of folded DNA greatly alters both the reactivity of G toward oxidative stress as well as the product outcome and suggest that recognition of damage in telomeric sequences by repair enzymes may be profoundly different from that of B-form duplex DNA.}, }
@article {pmid23434081, year = {2013}, author = {Qiu, Y and Zhang, J and Liu, Y and Ma, H and Cao, F and Xu, J and Hou, Y and Xu, L}, title = {The combination effects of acetaminophen and N-acetylcysteine on cytokines production and NF-κB activation of lipopolysaccharide-challenged piglet mononuclear phagocytes in vitro and in vivo.}, journal = {Veterinary immunology and immunopathology}, volume = {152}, number = {3-4}, pages = {381-388}, doi = {10.1016/j.vetimm.2013.01.013}, pmid = {23434081}, issn = {1873-2534}, mesh = {Acetaminophen/*administration &amp; dosage ; Acetylcysteine/*administration &amp; dosage ; Animals ; Cytokines/*blood ; Drug Synergism ; Female ; Inflammation Mediators/blood ; Interleukin-10/blood ; Lipopolysaccharides/pharmacology ; Male ; Monocytes/*drug effects/*immunology ; Sus scrofa/*immunology ; Transcription Factor RelA/*metabolism ; }, abstract = {Lipopolysaccharide (LPS) is a known activator of mononuclear phagocytes. LPS activates the pro-inflammatory gene expression and induces the release of mediators/cytokines by TLR4-NF-κB signaling pathway. The purpose of this study was to investigate the effects of acetaminophen (AAP) and N-acetylcysteine (NAC), individually as well as in combination on LPS-induced cytokines production and NF-κB activation in piglets. AAP (0.125-1.0mM) and NAC (0.0625-1.0mM) down-regulate the expression of cytokines and inhibit NF-κB p65 protein transfer from the cytoplasm to the nucleus in vitro. NAC enhances the inhibition action of AAP on cytokines expression in vitro. IL-6 in piglet plasma of the AAP group (mixed feed concentration of 600 mg/kg) was significantly reduced (P<0.05) at 3h after LPS-challenge as compared with the LPS control group. IL-10 also significantly reduced (P<0.05) at 24h after LPS injection. The levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10) in piglet plasma of the NAC group (mixed feeding concentration of 1200 mg/kg) were significantly lower at 3h after LPS stimulation (P<0.05). IL-10 was significantly decreased in the NAC group at 24h after LPS stimulation (P<0.05). AAP or NAC treated alone could reduce the NF-κB p65 concentration ratio. The levels of cytokines (TNF-α, IL-1β, IL-6, and IL-10) in the group with piglet plasma of AAP (mixed feed concentration of 600 mg/kg) plus NAC (mixed feeding concentration of 1200 mg/kg) group were significantly lower (P<0.05) at 3h after LPS activation. The level of IL-10 in the group with AAP plus NAC was significantly lower (P<0.05) at 24h after LPS stimulation, while the rest of the inflammatory cytokines were returned to the original levels. The NF-κB p65 concentration ratio had significantly reduced (P<0.05) when AAP and NAC were used in combination. In summary, NAC could enhance the anti-inflammatory effects of AAP both in vitro and in vivo.}, }
@article {pmid23433350, year = {2014}, author = {Piso, DY and Ribeiro, AP and Silva, ML and Guimarães, PJ and Morales, A and Martins, BC and Padua, IM and Renzo, R and Andrade, AL and Uscátegui, RR and Laus, JL}, title = {Effects of antiproteolytic agents on corneal epithelial viability and matrix metalloproteinase-2 and metalloproteinase-9 activity in alkali-burned corneas of rats.}, journal = {Veterinary ophthalmology}, volume = {17}, number = {1}, pages = {23-31}, doi = {10.1111/vop.12032}, pmid = {23433350}, issn = {1463-5224}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Caustics/toxicity ; Chondroitin Sulfates/*therapeutic use ; Corneal Diseases/*chemically induced/drug therapy ; Epithelium, Corneal/*drug effects/injuries ; Female ; Free Radical Scavengers/therapeutic use ; Gene Expression Regulation, Enzymologic/drug effects ; Matrix Metalloproteinase 2/genetics/*metabolism ; Matrix Metalloproteinase 9/genetics/*metabolism ; Proteolysis/drug effects ; Rats ; Rats, Wistar ; Sodium Hydroxide/toxicity ; }, abstract = {OBJECTIVE: To evaluate the effects of agents on corneal re-epithelization and metalloproteinase-2 and metalloproteinase-9 (MMP-2 and MMP-9) activities in corneas of rats submitted to ulceration.<br><br>ANIMALS STUDIED: Ninety eight healthy rats.<br><br>PROCEDURES: Corneal ulcers were created using 1N NaOH in their left eye. Eyes were treated every 6 h with 1% ethylenediaminetetraacetic acid (EDTA), 3% chondroitin sulfate (CS), 10% N-acetylcysteine NAc and saline (S) at 6-h intervals. Corneas were stained with fluorescein and photographed at the same time points. Following 20 h and 40-42 h of corneal injury, corneas were processed for scanning electron microscopy (SEM) to quantify microvilli density, and MMPs activities were analyzed using zymography.<br><br>RESULTS: The percentage of wound area and the time in hours for corneal re-epithelization did not differ significantly among treatment groups (P > 0.05). In first and the second moments, latent MMP-2 was significantly elevated in the eyes treated with NAC and CS (P < 0.001). Active MMP-2 did not change significantly among treatment groups in the first moment (P > 0.05); significantly higher activity was observed in the second moment in the eyes treated with CS (P <0.001). In the second moment, latent MMP-9 decreased significantly in eyes treated with EDTA and S (P < 0.01). Microvilli corneal density did not change significantly between healthy subjects and treatment groups (P > 0.05).<br><br>CONCLUSION: Any of the studied substances did not accelerate corneal re-epithelization and did not add protection to the corneal microvilli. Significant higher levels of active form of MMP-2 in 3% chondroitin sulfate-treated group may indicate that the agent acts as substrate for such enzyme. At the end of the experiment, 1% EDTA was the most efficient agent to inhibit significantly the latent form of MMP-9. However, any of the substances add benefit over saline on reducing the proteolytic activity in the cornea of rats after alkali injury.}, }
@article {pmid23433325, year = {2013}, author = {Beloosesky, R and Ginsberg, Y and Khatib, N and Maravi, N and Ross, MG and Itskovitz-Eldor, J and Weiner, Z}, title = {Prophylactic maternal N-acetylcysteine in rats prevents maternal inflammation-induced offspring cerebral injury shown on magnetic resonance imaging.}, journal = {American journal of obstetrics and gynecology}, volume = {208}, number = {3}, pages = {213.e1-6}, doi = {10.1016/j.ajog.2013.01.023}, pmid = {23433325}, issn = {1097-6868}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Animals, Newborn ; Brain/*drug effects/pathology ; Brain Injuries/chemically induced/pathology/*prevention &amp; control ; Female ; *Infectious Disease Transmission, Vertical ; Inflammation/chemically induced/pathology/*prevention &amp; control ; Lipopolysaccharides ; Magnetic Resonance Imaging ; Pregnancy ; *Pregnancy, Animal ; Prenatal Exposure Delayed Effects/pathology/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: Maternal infection or inflammation may induce fetal inflammatory responses associated with fetal injury and cerebral palsy. We sought to assess the inflammation-associated neuroprotective potential of prophylactic N-acetyl-cysteine (NAC). We examined the effect of NAC on prevention of maternal lipopolysaccharide (LPS)-induced neonatal brain injury using magnetic resonance imaging.<br><br>STUDY DESIGN: Pregnant Sprague Dawley dams (n = 5-8) at embryonic day 18 received intraperitoneal injection of LPS or saline at time 0. Animals were randomized to receive 2 intravenous injections of NAC or saline (time -30 and 120 minutes). Pups were delivered spontaneously and allowed to mature until postnatal day 25. Female offspring were examined by magnetic resonance brain imaging and analyzed using voxel-based analysis after spatial normalization. T2 relaxation time was used to assess white matter injury and diffusion tensor imaging for apparent diffusion coefficient (ADC) to assess white and gray matter injury.<br><br>RESULTS: Offspring of LPS-treated dams exhibited significantly increased T2 levels and increased ADC levels in white and gray matter (eg, hypothalamus, motor cortex, corpus callosum, thalamus, hippocampus), consistent with diffuse cerebral injury. In contrast, offspring of NAC-treated LPS dams demonstrated similar T2 and ADC levels as control in both white and gray matter.<br><br>CONCLUSION: Maternal NAC treatment significantly reduced evidence of neonatal brain injury associated with maternal LPS. These studies suggest that maternal NAC therapy may be effective in human deliveries associated with maternal/fetal inflammation.}, }
@article {pmid23433299, year = {2013}, author = {Dinicola, S and Mariggiò, MA and Morabito, C and Guarnieri, S and Cucina, A and Pasqualato, A and D'Anselmi, F and Proietti, S and Coluccia, P and Bizzarri, M}, title = {Grape seed extract triggers apoptosis in Caco-2 human colon cancer cells through reactive oxygen species and calcium increase: extracellular signal-regulated kinase involvement.}, journal = {The British journal of nutrition}, volume = {110}, number = {5}, pages = {797-809}, doi = {10.1017/S0007114512006095}, pmid = {23433299}, issn = {1475-2662}, mesh = {Apoptosis/*drug effects ; Caco-2 Cells ; Calcium/*metabolism ; Calcium Signaling/drug effects ; Colonic Neoplasms/metabolism ; Extracellular Signal-Regulated MAP Kinases/genetics/*metabolism ; Gene Expression Regulation, Enzymologic/*drug effects ; Grape Seed Extract/*pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinase Kinases/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Grape seed extract (GSE) from Italia, Palieri and Red Globe cultivars inhibits cell growth and induces apoptosis in Caco-2 human colon cancer cells in a dose-dependent manner. In order to investigate the mechanism(s) supporting the apoptotic process, we analysed reactive oxygen species (ROS) production, intracellular Ca2+ handling and extracellular signal-regulated kinase (ERK) activation. Upon exposure to GSE, ROS and intracellular Ca2+ levels increased in Caco-2 cells, concomitantly with ERK inactivation. As ERK activity is thought to be essential for promoting survival pathways, inhibition of this kinase is likely to play a relevant role in GSE-mediated anticancer effects. Indeed, pretreatment with N-acetyl cysteine, a ROS scavenger, reversed GSE-induced apoptosis, and promoted ERK phosphorylation. This effect was strengthened by ethylene glycol tetraacetic acid-mediated inhibition of extracellular Ca2+ influx. ROS and Ca2+ influx inhibition, in turn, increased ERK phosphorylation, and hence almost entirely suppressed GSE-mediated apoptosis. These data suggested that GSE triggers a previously unrecognised ERK-based mechanism, involving both ROS production and intracellular Ca2+ increase, eventually leading to apoptosis in cancer cells.}, }
@article {pmid23432994, year = {2013}, author = {Marthandan, S and Hyland, P and Pawelec, G and Barnett, Y}, title = {An investigation of the effects of the antioxidants, ebselen or N-acetyl cysteine on human peripheral blood mononuclear cells and T cells.}, journal = {Immunity &amp; ageing : I &amp; A}, volume = {10}, number = {1}, pages = {7}, pmid = {23432994}, issn = {1742-4933}, abstract = {BACKGROUND: The research literature has documented age-related increases in genetic damage, including oxidative DNA damage, in human T lymphocytes, in vitro and ex vivo. Such damage has the potential to interfere with the ability of the T cells to proliferate at times when they need to, such as when antigen challenged. The consequence of this could be a sub-optimal immune response in vivo.<br><br>CONTEXT AND PURPOSE: The purpose of the research reported in this paper was to investigate the impact of two antioxidants, which can be administered in vivo, Ebselen and N-acetyl L-cysteine, on the age-related increase in genetic damage, and on T cell proliferation and lifespan. In vitro human T cell clones, ex vivo peripheral blood mononuclear cells or T cells were supplemented with different concentrations of antioxidants, under standard conditions and for different periods of time. A range of assays were then applied in order to determine any impact of the antioxidants.<br><br>RESULTS: 30 &#x3bc;M ebselen or 7.5 mM N-acetyl L-cysteine supplementation resulted in a significantly higher intracellular GSH: GSSG ratio. This increased ratio was accompanied by reduced levels of oxidative DNA damage in established CD4+ human T cell clones, from a young or a middle-aged donor. Additionally, cultures of primary human peripheral blood mononuclear cells and CD4+ T cells from donors aged 25-30 or 55-60 years were also supplemented with these agents. Cells from all sources exhibited increased proliferation, and in the case of the T cell clones, an increase in cumulative population doublings. Neither ebselen nor N-acetyl L-cysteine had such effects on clones supplemented from the midpoint of their in vitro lifespan.<br><br>CONCLUSIONS: Ebselen and N-acetyl L-cysteine, under certain conditions, may have anti-immunosenescent potential in T cells in in vitro clonal and ex vivo polyclonal culture models.}, }
@article {pmid23429749, year = {2013}, author = {Lee, BS and Cha, HY and Shin, YS and Kim, YS and Kim, CH}, title = {AY4, an agonistic anti-death receptor 4 MAB, induces apoptotic cell death in anaplastic thyroid cancer cells via downregulation of Bcl-xL with reactive oxygen species generation.}, journal = {Endocrine-related cancer}, volume = {20}, number = {3}, pages = {283-291}, doi = {10.1530/ERC-12-0405}, pmid = {23429749}, issn = {1479-6821}, mesh = {Antibodies, Monoclonal/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Down-Regulation ; Humans ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology ; Thyroid Carcinoma, Anaplastic ; Thyroid Neoplasms/*metabolism ; bcl-X Protein/*metabolism ; }, abstract = {Anaplastic thyroid carcinoma (ATC) is an aggressive human tumor with a median survival of 6 months. We previously developed an agonistic anti-death receptor 4 MAB, AY4, and demonstrated the antitumor effects of AY4 in head and neck cancer cells. Presently, we show that ATC cells are sensitive to AY4 and that the sensitivity correlates with the reduced expression level of Bcl-xL and reactive oxygen species (ROS) generation. AY4 induced death of C-643, U-HTH 7, HTH83, and SW1736 cells. To elucidate the role of ROS generation in AY4-induced apoptosis of ATC cells, U-HTH 7 and SW1736 cells were pretreated with an antioxidant (N-acetyl cysteine, NAC) followed by AY4 treatment. The cell death was blocked by NAC. AY4-induced cell death was accompanied by the downregulation of the anti-apoptotic protein, Bcl-xL (BCL2L1). To examine the link between the apoptotic response and Bcl-xL protein expression, U-HTH 7 cells were transfected with Bcl-xL plasmid. The consequence of the overexpression of Bcl-xL appeared to decrease AY4-mediated cell death by blocking ROS generation in U-HTH 7 cells. By contrast, Bcl-xL knockdown using small interfering RNA of Bcl-xL enhanced AY4 sensitivity in HTH83 and C-643 cells and rendered the cells sensitive to AY4-induced cell death. The results support the conclusion that the expression level of Bcl-xL is important in the AY4-induced apoptosis of ATC cells through ROS generation. AY4 may be a promising tool for ATC therapy.}, }
@article {pmid23426507, year = {2013}, author = {Liu, YL and Liu, B and Qu, YY and Chai, HJ and Li, R and Zhang, L}, title = {[Oxidative stress and calcium/calmodulin-dependent protein kinase II contribute to the development of sustained β adrenergic receptor-stimulated cardiac hypertrophy in rats].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {65}, number = {1}, pages = {1-7}, pmid = {23426507}, issn = {0371-0874}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism ; Cardiomegaly/*physiopathology ; Isoproterenol/pharmacology ; Male ; Mitochondria, Heart/metabolism ; Myocardium/pathology ; NADPH Oxidase 4 ; NADPH Oxidases/metabolism ; *Oxidative Stress ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptors, Adrenergic, beta/*metabolism ; }, abstract = {Sustained activation of β adrenergic receptor (βAR) leads to pathologic cardiac hypertrophy. However, the related mechanisms still remain unclear. In this study, we observe how N-acetylcysteine (NAC) affects the oxidative stress and calcium/calmodulin-dependent protein kinase II (CaMKII) expression in heart of isoproterenol (ISO)-stimulated rats, and investigate whether oxidative stress and CaMKII contribute to the development of sustained βAR-stimulated cardiac hypertrophy. Healthy male Wistar rats were randomly separated into 4 groups: control (CTRL), ISO-treated (ISO), control with NAC supplement (CTRL+NAC) and ISO-treated with NAC supplement (ISO+NAC) groups (6 rats in each group). Systolic blood pressure (SBP) was measured in awake rats with the tail-cuff method every week for two weeks. Heart weight/body weight ratio (HW/BW) and HE staining were used for the detection of myocardial hypertrophy. Myocardial mitochondrial reactive oxygen species (ROS) levels were measured by DCF fluorometry. The expressions of activated-CaMKII (p-CaMKII/CaMKII) and NADPH oxidase 4 (NOX(4)) were determined by Western blot analysis. The results showed that ISO-treated (i.p., daily 3 mg/kg, 2 weeks) rats developed an obvious cardiac hypertrophy as expressed by increases of HW/BW and myocyte cross-section area. Cardiac mitochondrial ROS level was significantly enhanced in ISO group as compared to CTRL group (P < 0.05). The expressions of NOX(4) and p-CaMKII in ISO group were also up-regulated as compared to CTRL group (1.4 and 1.6 times of CTRL, respectively, P < 0.05). NAC supplement significantly suppressed the hypertrophic development of heart in ISO-stimulated rats. The cardiac mitochondrial ROS level showed a significant decrease in rats of ISO+NAC group (P < 0.05 vs ISO). In accordance with this, ISO+NAC group rats also showed marked reductions in the expressions of NOX(4) and p-CaMKII/CaMKII compared to ISO group rats (P < 0.05). There were no significant differences of the detected indices between the rats from CTRL+NAC and CTRL groups. SBP showed no differences among four groups. These results suggest that both oxidative stress and CaMKII play important roles in sustained βAR-stimulated cardiac hypertrophy. NAC may suppress ISO-induced cardiac hypertrophy by down-regulating the expression of activated-CaMKII, and by reducing the level of oxidative stress originated from mitochondria and NADPH oxidase pathways.}, }
@article {pmid23424206, year = {2013}, author = {Arica, V and Demir, &#x130;H and Tutanc, M and Basarslan, F and Arica, S and Karcoıglu, M and Öztürk, H and Nacar, A}, title = {N-acetylcysteine prevents doxorubucine-induced cardiotoxicity in rats.}, journal = {Human &amp; experimental toxicology}, volume = {32}, number = {6}, pages = {655-661}, doi = {10.1177/0960327112467043}, pmid = {23424206}, issn = {1477-0903}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Cardiomyopathies/*chemically induced/*prevention &amp; control ; Doxorubicin/*toxicity ; Free Radical Scavengers/*therapeutic use ; Nitric Oxide/metabolism ; Rats ; Thiobarbituric Acid Reactive Substances/metabolism ; Topoisomerase II Inhibitors/*toxicity ; }, abstract = {This study is designed to observe the effects of N-acetylcysteine (NAC) on doxorubucine-induced cardiac toxicity in rats both histologically and biochemically. Totally 32 rats divided equally into four groups were studied. The first group received only 200 mg/kg NAC intraperitoneal (i.p.) once every 24 h for 5 days (group 1); the second group received 20 mg/kg doxorubucine (DOX) i.p. single dose plus NAC 200 mg/kg i.p. once every 24 h for 5 days (group 2); the third group received DOX 20 mg/kg DOX i.p. single dose (group 3) and the fourth group, which is also the control group, received saline (group 4). Following 24 h of the final dose, blood samples were drawn from a portal vein and heart tissue were obtained. Tissue thiobarbituric acid reactive substance (TBARS) and nitric oxide (NO) levels were highest in the DOX group. In the DOX-treated rats, serum TBARS, NO, aspartate transaminase, lactate dehydrogenase and creatine kinase levels were highest when compared with other groups. Except for serum superoxide dismutase levels, all other parameters differed significantly between the DOX plus NAC group and the DOX group. In the DOX plus NAC group, general architecture was preserved better than the DOX group and myofibril loss was minimal compared with the DOX group. NAC demonstrated, both biochemically and histologically, to be effective in the prevention of DOX-induced cardiotoxicity in rat models. Evaluation of NAC's effect on DOX toxicity warrants further clinical trials on cancer patients.}, }
@article {pmid23424090, year = {2013}, author = {Sandiego, CM and Nabulsi, N and Lin, SF and Labaree, D and Najafzadeh, S and Huang, Y and Cosgrove, K and Carson, RE}, title = {Studies of the metabotropic glutamate receptor 5 radioligand [[11]C]ABP688 with N-acetylcysteine challenge in rhesus monkeys.}, journal = {Synapse (New York, N.Y.)}, volume = {67}, number = {8}, pages = {489-501}, pmid = {23424090}, issn = {1098-2396}, support = {T90 DK070068/DK/NIDDK NIH HHS/United States ; UL1 RR024139/RR/NCRR NIH HHS/United States ; 1T90DK070068/DK/NIDDK NIH HHS/United States ; UL1RR024139/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/diagnostic imaging/metabolism ; Carbon Radioisotopes/pharmacokinetics/pharmacology ; Female ; Macaca mulatta ; Male ; Oximes/pharmacokinetics/*pharmacology ; Positron-Emission Tomography ; Protein Binding/drug effects ; Pyridines/pharmacokinetics/*pharmacology ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/antagonists &amp; inhibitors/*metabolism ; Tissue Distribution/drug effects ; }, abstract = {Detecting changes in receptor binding at the metabotropic glutamate receptor 5 (mGluR5) with the PET allosteric antagonist, [[11]C]ABP688, may be valuable for studying dysfunctional glutamate transmission associated with psychiatric illnesses. This study was designed to validate the findings of a recent pilot study in baboons which reported a significant global decrease from baseline [[11]C]ABP688 binding after increasing endogenous glutamate with 50 mg/kg N-acetylcysteine (NAC), with no change from test to retest. In rhesus monkeys (n = 5), paired [[11]C]ABP688 scans were performed on the same day on the Focus-220 as follows (n = 3 per group): test-retest, baseline-NAC (50 mg/kg), and baseline-NAC (100 mg/kg). Multiple modeling methods were evaluated for kinetic analysis to estimate the total volume of distribution (VT) and non-displaceable binding potential (BP(ND)) in regions-of-interest (ROIs), with the cerebellum gray matter (CGM) as the reference region. There was an increasing trend from test to retest BP(ND) across ROIs (13%). NAC (50 mg/kg and 100 mg/kg) increased VT (5% and 19%) and decreased BP(ND) (3% and 10%), respectively, significant only for VT in ROIs at the 100 mg/kg dose. High intersubject variability in BP(ND) was comparable to that reported in the baboon study. However, interpretability of BP(ND) is difficult with increases in VT in the CGM reference region at the higher NAC dose. Additionally, the net reduction in BP(ND) from the baseline-NAC scans may be obscured due to observed increases in test-retest BP(ND). Thus, we did not strictly replicate the findings in the baboon study based on BP(ND).}, }
@article {pmid23423955, year = {2013}, author = {Bonella, F and Wessendorf, TE and Costabel, U}, title = {[Clinical experience with pirfenidone for the treatment of idiopathic pulmonary fibrosis].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {138}, number = {11}, pages = {518-523}, doi = {10.1055/s-0032-1332930}, pmid = {23423955}, issn = {1439-4413}, mesh = {Adrenal Cortex Hormones/*therapeutic use ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Drug Therapy, Combination/statistics &amp; numerical data ; Evidence-Based Medicine ; Female ; Germany/epidemiology ; Humans ; Idiopathic Pulmonary Fibrosis/diagnosis/*drug therapy/*epidemiology ; Male ; Prevalence ; Pyridones/*therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with an estimated median survival of only 3 years after diagnosis. Pirfenidone is the only medication approved in the European Union for the treatment of adults with mild to moderate lung fibrosis. We analyzed data on safety and efficacy of pirfenidone in the treatment of patients with IPF in our centre.<br><br>PATIENTS AND METHODS: From 2006 to 2012, 45 patients (28 inside clinical trials, 17 outside) with mild to moderate IPF were treated with pirfenidone. Clinical data, results of lung function tests, and radiological findings as well as data about side effects were collected routinely.<br><br>RESULTS: The mean duration of treatment per patient was 48 [range 3-321] weeks. 16 patients (35 %) received pirfenidone as monotherapy and 29 (65 %) in combination with corticosteroids and/or N-acetylcysteine (NAC). At the end of the follow-up period 28 of 40 patients (70 %) with treatment duration > 3 months were in a stable condition. 26 patients (58 %) suffered from side effects, mostly gastrointestinal (17 [38 %]). Pirfenidone was discontinued by six patients (13 %) because of side effects. The median survival after the start of pirfenidone was 3.8 years.<br><br>CONCLUSION: Pirfenidone alone or in combination with NAC and/or corticosteroids was generally well tolerated. Severe side effects were rare. The course of the disease was stable during treatment with pirfenidone in two out of three patients. Our results are in line with the previous published safety and efficacy data on pirfenidone as treatment for IPF.}, }
@article {pmid23423816, year = {2013}, author = {Meyer, M and Bell, SP and Chen, Z and Nyotowidjojo, I and Lachapelle, RR and Christian, TF and Gibson, PC and Keating, FF and Dauerman, HL and LeWinter, MM}, title = {High dose intracoronary N-acetylcysteine in a porcine model of ST-elevation myocardial infarction.}, journal = {Journal of thrombosis and thrombolysis}, volume = {36}, number = {4}, pages = {433-441}, pmid = {23423816}, issn = {1573-742X}, support = {R21 HL094807-01A1/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Contrast Media/*pharmacology ; *Coronary Angiography ; Disease Models, Animal ; Female ; Free Radical Scavengers/*pharmacology ; Iopamidol/*pharmacology ; *Myocardial Infarction/diagnostic imaging/drug therapy ; *Myocardial Reperfusion Injury/diagnostic imaging/drug therapy ; Swine ; }, abstract = {We sought to evaluate the safety and efficacy of N-acetylcysteine (NAC) on ischemia and reperfusion in a pig model focusing on cardio-renal protection. High doses of NAC may provide protection from contrast induced nephropathy (CIN). NAC has also been demonstrated to reduce myocardial infarction size and improve left ventricular function after ischemia in both humans and animals studies. In this study we tested the safety and cardiorenal protective efficacy of intracoronary NAC delivered in the radiographic contrast agent in a pig model that simulates the catheter based reperfusion therapy of ST elevation myocardial infarctions. 27 pigs underwent 45 min of ischemia after surgical ligation of distal left descending coronary artery. With coronary reperfusion the animals received at total of 200 mL of the contrast agent Iopamidol with and without NAC to mimic radiographic contrast use during invasive reperfusion therapy. At 24 h the following endpoints were compared: LV function (MRI, echocardiography), myocardial injury (infarct size, area-at-risk, troponin, creatinine kinase) and CIN (creatinine, BUN and renal histology). The effects of NAC on platelet reactivity were also evaluated. Intracoronary administration of NAC administered in the contrast agent is safe. NAC reduces platelet reactivity and there was a trend towards a better cardiac function at 24 h. There was no significant difference in the size of the myocardial infarction. In this model of ischemia-reperfusion high dose NAC did not protect from CIN. High dose intracoronary NAC administered with the radiographic contrast is safe but does not provide significant cardio-renal protection.}, }
@article {pmid23421903, year = {2013}, author = {Ritzenthaler, JD and Roser-Page, S and Guidot, DM and Roman, J}, title = {Nicotinic acetylcholine receptors are sensors for ethanol in lung fibroblasts.}, journal = {Alcoholism, clinical and experimental research}, volume = {37}, number = {6}, pages = {914-923}, pmid = {23421903}, issn = {1530-0277}, support = {I01 BX000745/BX/BLRD VA/United States ; P50 AA013757/AA/NIAAA NIH HHS/United States ; R01 AA019953/AA/NIAAA NIH HHS/United States ; AA013757/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcholine/pharmacology ; Animals ; Cells, Cultured ; Ethanol/*pharmacology ; Fibroblasts/drug effects/*metabolism/physiology ; Fibronectins/drug effects/*metabolism ; Lung/*cytology/drug effects/metabolism ; Mice ; Mice, Transgenic ; Oxidative Stress ; Receptors, Nicotinic/drug effects/*metabolism/physiology ; }, abstract = {BACKGROUND: Chronic ethanol (EtOH) abuse in humans is known to independently increase the incidence of and mortality due to acute lung injury in at-risk individuals. However, the mechanisms by which EtOH affects lung cells remain incompletely elucidated. In earlier work, we reported that EtOH increased the expression in lung fibroblasts of fibronectin, a matrix glycoprotein implicated in lung injury and repair. This effect was blocked by α-bungarotoxin, a neurotoxin that binds certain nicotinic acetylcholine receptors (nAChRs) thereby implicating nAChRs in this process. Here, we examine the identity of these receptors.<br><br>METHODS: Mouse lung fibroblasts were stimulated with EtOH (60&#xa0;mM) or acetylcholine (100 to 500&#xa0;&#x3bc;M) and evaluated for the expression of fibronectin and nAChRs. Inhibitors to nAChRs or the antioxidant N-acetyl cysteine (NAC) were used to assess changes in fibronectin expression. Animals exposed to EtOH for up to 6&#xa0;weeks were used to evaluate the expression of nAChRs in vivo.<br><br>RESULTS: First, in EtOH-treated fibroblasts, we observed increased expression of &#x3b1;4 and &#x3b1;9 nAChR subunits. Second, we found that acetylcholine, a natural ligand for nAChRs, mimicked the effects of EtOH. Dihydro-&#x3b2;-erythroidin hydrobromide, a competitive inhibitor of &#x3b1;4 nAChR, blocked the increase in fibronectin expression and cell proliferation. Furthermore, EtOH-induced fibronectin expression was inhibited in cells silenced for &#x3b1;4 nAChR. However, EtOH-treated cells showed increased &#x3b1;-bungarotoxin binding suggesting that &#x3b1;4 nAChR mediates the effects of EtOH via a ligand-independent pathway. Knowing there are several important cysteine residues near the ligand-binding site of &#x3b1;4 nAChRs, we tested the antioxidant NAC and found that it too blocked the induction of fibronectin expression by EtOH. Also, fibroblasts exposed to oxidant stress showed increased fibronectin expression that was blocked with &#x3b1;-bungarotoxin. Finally, we showed increased expression of &#x3b1;4 nAChRs in the lung tissue of mice and rats exposed to EtOH suggesting a role for these receptors in vivo.<br><br>CONCLUSIONS: Altogether, our observations suggest that &#x3b1;4 nAChRs serve as sensors for EtOH-induced oxidant stress in lung fibroblasts, thereby revealing a new mechanism by which EtOH may affect lung cells and tissue remodeling and pointing to nAChRs as potential targets for intervention.}, }
@article {pmid23419244, year = {2013}, author = {Costa-Campos, L and Herrmann, AP and Pilz, LK and Michels, M and Noetzold, G and Elisabetsky, E}, title = {Interactive effects of N-acetylcysteine and antidepressants.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {44}, number = {}, pages = {125-130}, doi = {10.1016/j.pnpbp.2013.02.008}, pmid = {23419244}, issn = {1878-4216}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Antidepressive Agents/*pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Hindlimb Suspension/*physiology ; Immobility Response, Tonic/drug effects ; Locomotion/*drug effects ; Male ; Mice ; }, abstract = {N-acetylcysteine (NAC), a glutathione precursor and glutamate modulator, has been shown to possess various clinically relevant psychopharmacological properties. Considering the role of glutamate and oxidative stress in depressive states, the poor effectiveness of antidepressant drugs (ADs) and the benefits of drug combination for treating depression, the aim of this study was to explore the possible benefit of NAC as an add on drug to treat major depression. For that matter we investigated the combination of subeffective and effective doses of NAC with subeffective and effective doses of several ADs in the mice tail suspension test. The key finding of this study is that a subeffective dose of NAC reduced the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion. Moreover, the same subeffective dose of NAC increased the minimum effective dose of fluoxetine in the same model. In view of the advantages associated with using the lowest effective dose of antidepressant, the results of this study suggest the potential of a clinically useful interaction of NAC with imipramine and escitalopram. Further studies are necessary to better characterize the molecular basis of such interactions, as well as to typify the particular drug combinations that would optimize NAC as an alternative for treating depression.}, }
@article {pmid23416263, year = {2013}, author = {Cheng, G and Guo, W and Han, L and Chen, E and Kong, L and Wang, L and Ai, W and Song, N and Li, H and Chen, H}, title = {Cerium oxide nanoparticles induce cytotoxicity in human hepatoma SMMC-7721 cells via oxidative stress and the activation of MAPK signaling pathways.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {27}, number = {3}, pages = {1082-1088}, doi = {10.1016/j.tiv.2013.02.005}, pmid = {23416263}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Carcinoma, Hepatocellular ; Catalase/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cerium/*toxicity ; Glutathione Peroxidase/metabolism ; Humans ; MAP Kinase Signaling System/drug effects ; Malondialdehyde/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Nanoparticles/*toxicity ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND: Lanthanide cerium oxide (CeO2) nanoparticles have extensive applications in industrial fields, and concerns regarding their potential toxicity in humans and their environmental impact have increased. We investigated the underlying molecular mechanisms by which CeO2 nanoparticles induce toxicity in human hepatoma SMMC-7721 cells.<br><br>RESULTS: Our results demonstrated that CeO2 nanoparticles reduced viability, caused dramatic morphological damage, and induced apoptosis in SMMC-7721 cells. CeO2 nanoparticles significantly increased the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and significantly reduced the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-px) and catalase (CAT). The phosphorylation levels of ERK1/2, JNK and p38 MAPK were significantly elevated after treatment with CeO2 nanoparticles. Pretreatment with the antioxidant N-acetyl-cysteine (NAC): reduced the induction of ROS and MDA by CeO2 nanoparticles; recovered the activity of SOD, GSH-px and CAT; reduced the phosphorylation levels of ERK1/2, JNK and p38; and attenuated CeO2 nanoparticles-induced damage and apoptosis in SMMC-7721 cells.<br><br>CONCLUSIONS: Our data demonstrated that CeO2 nanoparticles induced damage and apoptosis in human SMMC-7721 cells via oxidative stress and the activation of MAPK signaling pathways.}, }
@article {pmid23415145, year = {2013}, author = {Wang, P and Wang, X and Zhang, K and Gao, K and Song, M and Liu, Q}, title = {The spectroscopy analyses of PpIX by ultrasound irradiation and its sonotoxicity in vitro.}, journal = {Ultrasonics}, volume = {53}, number = {5}, pages = {935-942}, doi = {10.1016/j.ultras.2012.10.019}, pmid = {23415145}, issn = {1874-9968}, mesh = {Analysis of Variance ; Animals ; Apoptosis ; Cell Line, Tumor ; Cell Survival ; Flow Cytometry ; In Vitro Techniques ; Mice ; Microscopy, Confocal ; Photosensitizing Agents/analysis/*pharmacology ; Protoporphyrins/analysis/*pharmacology ; Reactive Oxygen Species/metabolism ; Sarcoma 180 ; Sonication ; Time Factors ; Ultrasonic Therapy/*methods ; }, abstract = {Protoporphyrin IX (PpIX) has been used as a sensitizer in photodynamic therapy (PDT) as well as in sonodynamic therapy (SDT). The photo-bleaching of PpIX has been well investigated in many experimental systems and some photo-products have also been identified in PDT. But until now, little information has been reported about the sono-damage of PpIX in SDT. So, the present study was to investigate changes of PpIX properties before and after different ultrasound treatment, and the potential interactions between PpIX, ultrasound and the irradiated cells. In cell-free system, the absorption and fluorescence spectra of PpIX in different solutions were measured by ultraviolet spectrometer and fluorescence spectrophotometer, respectively. The terephthalic acid dosimetry was applied to evaluate the efficiency of ultrasound cavitation by monitoring hydroxyl radical (OH) production on the thermolysis of H2O in the ultrasound field. In in vitro study, confocal microscopy was applied to detect the sub-cellular localization of PpIX in S180 cells before and after ultrasound exposure. Flow cytometry was used to detect the reactive oxygen species (ROS) generation during PpIX-SDT. MTT assay was performed to evaluate the cell viability of S180 cells after SDT treatment with or without ROS scavengers. The results show that PpIX displayed different spectral patterns in different solutions. PpIX was decomposed by ultrasound exposure as measured by the decreased absorption and fluorescence peak values in RPMI-1640 medium. In addition, the decomposition of PpIX was found to be simultaneously accompanied by OH production with increasing output power from ultrasound generator. PpIX at 1μg/ml significantly enhanced the ultrasound induced cavitation as measured by OH generation, and which was greatly eliminated by NaN3, histidine, mannitol, EDTA and catalase, but not by SOD. The in vitro study indicates more PpIX entered into S180 cells after ultrasound exposure. And, the extra-cellular PpIX play an important role in the enhanced cell killing of PpIX-SDT. SDT induced obvious ROS generation in S180 cells, which could be mostly inhibited by the general ROS scavenge NAC (N-acetylcysteine). Other scavengers such as NaN3, histidine, mannitol all partially prevented the SDT induced cell viability loss of S180 cells, suggesting OH, (1)O2 might be involved during the process.}, }
@article {pmid23409922, year = {2013}, author = {Morris, D and Guerra, C and Khurasany, M and Guilford, F and Saviola, B and Huang, Y and Venketaraman, V}, title = {Glutathione supplementation improves macrophage functions in HIV.}, journal = {Journal of interferon &amp; cytokine research : the official journal of the International Society for Interferon and Cytokine Research}, volume = {33}, number = {5}, pages = {270-279}, doi = {10.1089/jir.2012.0103}, pmid = {23409922}, issn = {1557-7465}, mesh = {Acetylcysteine/administration &amp; dosage ; Cell Growth Processes/drug effects ; Cells, Cultured ; Colony Count, Microbial ; Dietary Supplements ; Gene Expression Regulation, Enzymologic/drug effects ; Glutamate-Cysteine Ligase/genetics/metabolism ; Glutathione/*administration &amp; dosage ; HIV Infections/*immunology ; Humans ; Immunity, Innate/drug effects ; Immunosuppression Therapy ; Macrophages, Alveolar/*drug effects/immunology ; Mycobacterium tuberculosis/*immunology ; Tuberculosis/immunology/*prevention &amp; control ; }, abstract = {In this study, we determined the effects of glutathione (GSH)-enhancing agents in restoring the levels of GSH in isolated macrophages from individuals with HIV infection thereby resulting in improved control of Mycobacterium tuberculosis. Our results indicate that treatment with N-acetyl cysteine or a liposomal formulation of glutathione (lGSH) resulted in replenishment of reduced also known as free GSH (rGSH), and correlated with a decrease in the intracellular growth of M. tuberculosis. Finally, we observed differences in the amount of the catalytic subunit of glutamine-cysteine ligase (GCLC), glutathione synthase, and glutathione reductase present in macrophages derived from healthy and HIV-infected individuals. These changes correlated with changes in free radicals as well as rGSH levels. Our results indicate that HIV infection leads to increased production of free radicals and decreased production of GCLC resulting in depletion of rGSH and this may lead, in part, to the loss of innate immune function observed in HIV patients. These findings represent a novel mechanism for control of M. tuberculosis infection, and a possible supplement to current HIV treatments.}, }
@article {pmid23407882, year = {2013}, author = {Shimizu, H and Saito, S and Higashiyama, Y and Nishijima, F and Niwa, T}, title = {CREB, NF-κB, and NADPH oxidase coordinately upregulate indoxyl sulfate-induced angiotensinogen expression in proximal tubular cells.}, journal = {American journal of physiology. Cell physiology}, volume = {304}, number = {7}, pages = {C685-92}, doi = {10.1152/ajpcell.00236.2012}, pmid = {23407882}, issn = {1522-1563}, mesh = {Angiotensinogen/genetics/*metabolism ; Animals ; Cell Line ; Cyclic AMP Response Element-Binding Protein/genetics/*metabolism ; Gene Expression Regulation/physiology ; Humans ; Indican/*pharmacology ; Kidney Cortex/metabolism ; Kidney Tubules, Proximal/*cytology ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/*metabolism ; NF-kappa B/genetics/*metabolism ; Rats ; Reactive Oxygen Species ; Up-Regulation ; }, abstract = {In chronic kidney disease (CKD), indoxyl sulfate, a uremic toxin, accumulates in serum, and the expression of angiotensinogen (AGT) is upregulated in renal proximal tubular cells. The present study aimed to determine the relationship between indoxyl sulfate and the upregulation of AGT expression in proximal tubular cells. Indoxyl sulfate induced expression of AGT in rat renal cortex and in cultured human proximal tubular cells (HK-2). In proximal tubular cells, indoxyl sulfate induced phosphorylation of cAMP response element-binding protein (CREB) on Ser-133, and small interfering RNA (siRNA) specific to CREB inhibited indoxyl sulfate-induced AGT expression. Our previous study demonstrated that indoxyl sulfate activated nuclear factor-κB (NF-κB) through reactive oxygen species (ROS) production. NF-κB inhibitors (pyrrolidine dithiocarbamate and isohelenin), NF-κB p65 siRNA, an antioxidant [N-acetylcysteine (NAC)], and a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor [diphenyleneiodonium (DPI)] suppressed indoxyl sulfate-induced AGT expression. Both NAC and DPI suppressed indoxyl sulfate-induced expression of NF-κB p65 and CREB. CREB siRNA suppressed indoxyl sulfate-induced NF-κB p65 expression, whereas both NF-κB inhibitors and NF-κB p65 siRNA prevented indoxyl sulfate-induced CREB expression. Furthermore, we focused on the expression of NADPH oxidase 4 (NOX4), because indoxyl sulfate induced NOX4 expression in vascular smooth muscle cells and vascular endothelial cells. Indoxyl sulfate induced the expression of NOX4 in proximal tubular cells, which was suppressed by NAC, DPI, NF-κB inhibitors, NF-κB p65 siRNA, and CREB siRNA. Taken together, CREB, NF-κB, and NOX4 coordinately upregulate indoxyl sulfate-induced AGT expression in proximal tubular cells.}, }
@article {pmid23405080, year = {2013}, author = {Chang, KC and Hsu, CC and Liu, SH and Su, CC and Yen, CC and Lee, MJ and Chen, KL and Ho, TJ and Hung, DZ and Wu, CC and Lu, TH and Su, YC and Chen, YW and Huang, CF}, title = {Cadmium induces apoptosis in pancreatic β-cells through a mitochondria-dependent pathway: the role of oxidative stress-mediated c-Jun N-terminal kinase activation.}, journal = {PloS one}, volume = {8}, number = {2}, pages = {e54374}, pmid = {23405080}, issn = {1932-6203}, mesh = {Animals ; Apoptosis/*drug effects ; Cadmium/*pharmacology ; Caspases/metabolism ; Cell Line ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/cytology/*drug effects/metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; MAP Kinase Signaling System/*physiology ; Male ; Malondialdehyde/metabolism ; Mice, Inbred ICR ; Mitochondria/drug effects/*metabolism ; Oxidative Stress/*drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53 ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Cadmium (Cd), one of well-known highly toxic environmental and industrial pollutants, causes a number of adverse health effects and diseases in humans. The growing epidemiological studies have suggested a possible link between Cd exposure and diabetes mellitus (DM). However, the toxicological effects and underlying mechanisms of Cd-induced pancreatic β-cell injury are still unknown. In this study, we found that Cd significantly decreased cell viability, and increased sub-G1 hypodiploid cells and annexin V-Cy3 binding in pancreatic β-cell-derived RIN-m5F cells. Cd also increased intracellular reactive oxygen species (ROS) generation and malondialdehyde (MDA) production and induced mitochondrial dysfunction (the loss of mitochondrial membrane potential (MMP) and the increase of cytosolic cytochrome c release), the decreased Bcl-2 expression, increased p53 expression, poly (ADP-ribose) polymerase (PARP) cleavage, and caspase cascades, which accompanied with intracellular Cd accumulation. Pretreatment with the antioxidant N-acetylcysteine (NAC) effectively reversed these Cd-induced events. Furthermore, exposure to Cd induced the phosphorylations of c-jun N-terminal kinases (JNK), extracellular signal-regulated kinases (ERK)1/2, and p38-mitogen-activated protein kinase (MAPK), which was prevented by NAC. Additionally, the specific JNK inhibitor SP600125 or JNK-specific small interference RNA (si-RNA) transfection suppressed Cd-induced β-cell apoptosis and related signals, but not ERK1/2 and p38-MAPK inhibitors (PD98059 and SB203580) did not. However, the JNK inhibitor or JNK-specific si-RNA did not suppress ROS generation in Cd-treated cells. These results indicate that Cd induces pancreatic β-cell death via an oxidative stress downstream-mediated JNK activation-triggered mitochondria-regulated apoptotic pathway.}, }
@article {pmid23400548, year = {2013}, author = {Garcia, RJ and Francis, L and Dawood, M and Lai, ZW and Faraone, SV and Perl, A}, title = {Attention deficit and hyperactivity disorder scores are elevated and respond to N-acetylcysteine treatment in patients with systemic lupus erythematosus.}, journal = {Arthritis and rheumatism}, volume = {65}, number = {5}, pages = {1313-1318}, pmid = {23400548}, issn = {1529-0131}, support = {R01 AI072648/AI/NIAID NIH HHS/United States ; R01 AT004332/AT/NCCIH NIH HHS/United States ; U01 AR076092/AR/NIAMS NIH HHS/United States ; AT-004332/AT/NCCIH NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Attention Deficit Disorder with Hyperactivity/complications/*drug therapy/physiopathology ; Early Diagnosis ; Female ; Free Radical Scavengers/*therapeutic use ; Health Status ; Humans ; Lupus Erythematosus, Systemic/*drug therapy/physiopathology/psychology ; Male ; Middle Aged ; Neuropsychological Tests ; Self Report ; Severity of Illness Index ; Surveys and Questionnaires ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVE: To investigate whether attention deficit hyperactivity disorder (ADHD) may serve as a marker of neuropsychiatric disease and as a target for N-acetylcysteine (NAC) treatment in patients with systemic lupus erythematosus (SLE).<br><br>METHODS: The ADHD Self-Report Scale (ASRS) was used to assess 49 patients with SLE and 46 matched healthy control subjects. Twenty-four of the patients with SLE were randomized to receive either placebo, NAC at a dosage of 2.4 gm/day, or NAC at a dosage of 4.8 gm/day. Disease activity was evaluated monthly using the British Isles Lupus Assessment Group (BILAG) index, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Fatigue Assessment Scale (FAS), and the ASRS, before and during the 3-month treatment period and after a 1-month washout period.<br><br>RESULTS: The cognitive/inattentive (ASRS part A), hyperactivity/impulsive (ASRS part B), and combined (total) ASRS scores were increased in patients with SLE compared with control subjects (mean &#xb1; SEM 17.37 &#xb1; 1.03 [P = 3 &#xd7; 10(-7) ], 14.51 &#xb1; 0.89 [P = 2 &#xd7; 10(-4) ], and 31.92 &#xb1; 1.74 [P = 8 &#xd7; 10(-7) ], respectively, versus 10.41 &#xb1; 1.02, 9.61 &#xb1; 1.21, and 20.02 &#xb1; 1.98, respectively. ASRS part A scores correlated with SLEDAI (r = 0.53, P < 0.0001) and BILAG scores (r = 0.36, P = 0.011). ASRS total scores also correlated with SLEDAI (r = 0.45, P = 0.0009) and BILAG scores (r = 0.31, P = 0.025). ASRS part A (r = 0.73, P < 0.0001), ASRS part B (r = 0.47, P = 0.0006), and ASRS total scores (r = 0.67, P < 0.0001) correlated with the FAS score. Relative to the scores in placebo-treated patients, ASRS total scores were reduced in SLE patients treated with NAC dosages of 2.4 gm/day and 4.8 gm/day combined (P = 0.037). ASRS part A scores were reduced by NAC dosages of 2.4 gm/day (P = 0.001) and 4.8 gm/day (P < 0.0001) as well as by NAC at dosages of 2.4 gm/day and 4.8 gm/day combined (P = 0.001).<br><br>CONCLUSION: In patients with SLE, elevated ASRS scores reveal previously unrecognized and clinically significant symptoms of ADHD that respond to NAC treatment.}, }
@article {pmid23398207, year = {2013}, author = {Ni, Z and Dai, X and Wang, B and Ding, W and Cheng, P and Xu, L and Lian, J and He, F}, title = {Natural Bcl-2 inhibitor (-)- gossypol induces protective autophagy via reactive oxygen species-high mobility group box 1 pathway in Burkitt lymphoma.}, journal = {Leukemia &amp; lymphoma}, volume = {54}, number = {10}, pages = {2263-2268}, doi = {10.3109/10428194.2013.775437}, pmid = {23398207}, issn = {1029-2403}, mesh = {Antioxidants/pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Burkitt Lymphoma/*metabolism ; Cell Line, Tumor ; Cytosol/metabolism ; Gossypol/*pharmacology ; HMGB1 Protein/*metabolism ; Humans ; Protein Transport/drug effects ; Proto-Oncogene Proteins c-bcl-2/*antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {(-)- Gossypol, a natural inhibitor of anti-apoptotic Bcl-2 proteins, has presented an effective anti-tumor activity in numerous preclinical trials. More and more evidence in vivo and in vitro validates that (-)- gossypol can dramatically suppress cell proliferation and induce cell death in hematological malignancies. However, the detailed mechanisms are not well known. In the present study, we showed that treatment with (-)- gossypol stimulated reactive oxygen species (ROS) generation and induced autophagy in Burkitt lymphoma cells. Antioxidant N-acetyl-cysteine (NAC) pretreatment attenuated (-)- gossypol-induced autophagy. Furthermore, (-)- gossypol treatment increased the translocation of high mobility group box 1 (HMGB1) from nuclei to cytoplasm, which can be suppressed by NAC pretreatment. NAC pretreatment also dramatically enhanced (-)- gossypol-induced apoptosis and total cell death. These results indicate that (-)- gossypol induces a protective autophagy in Burkitt lymphoma cells, partly due to ROS induction and cytosolic translocation of HMGB1. Antioxidants may serve as potent chemosensitizers to enhance cell death through blocking (-)- gossypol-induced autophagy.}, }
@article {pmid23396447, year = {2013}, author = {Douarre, C and Mergui, X and Sidibe, A and Gomez, D and Alberti, P and Mailliet, P and Trentesaux, C and Riou, JF}, title = {DNA damage signaling induced by the G-quadruplex ligand 12459 is modulated by PPM1D/WIP1 phosphatase.}, journal = {Nucleic acids research}, volume = {41}, number = {6}, pages = {3588-3599}, pmid = {23396447}, issn = {1362-4962}, mesh = {Apoptosis ; Cell Line, Tumor ; Cell Nucleolus/metabolism ; Cellular Senescence ; Checkpoint Kinase 1 ; *DNA Damage ; G2 Phase Cell Cycle Checkpoints ; Humans ; Phosphoprotein Phosphatases/*metabolism ; Protein Kinases/metabolism ; Protein Phosphatase 2C ; Quinolinium Compounds/*pharmacology ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; Telomere/metabolism ; Triazines/*pharmacology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {The triazine derivative 12459 is a potent G-quadruplex ligand that triggers apoptosis or delayed growth arrest, telomere shortening and G-overhang degradation, as a function of its concentration and time exposure to the cells. We have investigated here the DNA damage response induced by 12459 in A549 cells. Submicromolar concentrations of 12459 triggers a delayed Chk1-ATR-mediated DNA damage response associated with a telomeric dysfunction and a G2/M arrest. Surprisingly, increasing concentrations of 12459 leading to cell apoptosis induced a mechanism that bypasses the DNA damage signaling and leads to the dephosphorylation of Chk1 and γ-H2AX. We identified the phosphatase Protein Phosphatase Magnesium dependent 1D/Wild-type P53-Induced Phosphatase (PPM1D/WIP1) as a factor responsible for this dephosphorylation. SiRNA-mediated depletion of PPM1D/WIP1 reactivates the DNA damage signaling by 12459. In addition, PPM1D/WIP1 is activated by reactive oxygen species (ROS) induced by 12459. ROS generated by 12459 are sufficient to trigger an early DNA damage in A549 cells when PPM1D/WIP1 is depleted. However, ROS inactivation by N-acetyl cysteine (NAC) treatment does not change the apoptotic response induced by 12459. Because PPM1D expression was recently reported to modulate the recruitment of DNA repair molecules, our data would suggest a cycle of futile protection against 12459, thus leading to a delayed mechanism of cell death.}, }
@article {pmid23396376, year = {2013}, author = {Duan, JL and Wang, JW and Guan, Y and Yin, Y and Wei, G and Cui, J and Zhou, D and Zhu, YR and Quan, W and Xi, MM and Wen, AD}, title = {Safflor yellow A protects neonatal rat cardiomyocytes against anoxia/reoxygenation injury in vitro.}, journal = {Acta pharmacologica Sinica}, volume = {34}, number = {4}, pages = {487-495}, pmid = {23396376}, issn = {1745-7254}, mesh = {Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Carthamus tinctorius/chemistry ; Caspase 3/metabolism ; Catalase/metabolism ; Cell Hypoxia/physiology ; Cell Survival/drug effects ; Chalcone/*analogs &amp; derivatives/pharmacology ; Flavonoids/pharmacology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Hypoxia/*drug therapy/metabolism ; L-Lactate Dehydrogenase/metabolism ; Myocardial Reperfusion Injury/*drug therapy/metabolism/prevention &amp; control ; Myocytes, Cardiac/*drug effects/metabolism ; Oxidative Stress/drug effects ; Plant Extracts/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {AIM: To investigate the effects of safflor yellow A (SYA), a flavonoid extracted from Carthamus tinctorius L, on cultured rat cardiomyocytes exposed to anoxia/reoxygenation (A/R).<br><br>METHODS: Primary cultured neonatal rat cardiomyocytes were exposed to anoxia for 3 h followed by reoxygenation for 6 h. The cell viability was measured using MTT assay. The releases of lactate dehydrogenase (LDH) and creatine kinase (CK), level of malondialdehyde (MDA), and activities of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were analyzed. Hoechst 33258 staining and changes in Bcl-2/Bax ratio and caspase 3 activity were used to examine A/R-induced apoptosis.<br><br>RESULTS: The A/R exposure markedly decreased the viability of cardiomyocytes, suppressed the activities of SOD, GSH, CAT and GSH-Px, and Bcl-2 protein expression. Meanwhile, the A/R exposure markedly increased the release of LDH and CK, and MDA production in the cardiomyocytes, and increased the rate of apoptosis, caspase 3 activity, Bax protein expression. Pretreatment with SYA (40, 60 and 80 nmol/L) concentration-dependently blocked the A/R-induced changes in the cardiomyocytes. Pretreatment of the cardiomyocytes with the antioxidant N-acetylcysteine (NAC, 200 &#x3bc;mol/L) produced protective effects that were comparable to those caused by SYA (80 nmol/L).<br><br>CONCLUSION: SYA protects cultured rat cardiomyocytes against A/R injury, maybe via inhibiting cellular oxidative stress and apoptosis.}, }
@article {pmid23396095, year = {2013}, author = {O'Leary, SJ and Monksfield, P and Kel, G and Connolly, T and Souter, MA and Chang, A and Marovic, P and O'Leary, JS and Richardson, R and Eastwood, H}, title = {Relations between cochlear histopathology and hearing loss in experimental cochlear implantation.}, journal = {Hearing research}, volume = {298}, number = {}, pages = {27-35}, doi = {10.1016/j.heares.2013.01.012}, pmid = {23396095}, issn = {1878-5891}, mesh = {Acetylcysteine/administration &amp; dosage ; Acoustic Stimulation ; Administration, Topical ; Animals ; Audiometry, Pure-Tone ; Auditory Threshold ; Cochlea/drug effects/injuries/*pathology/physiopathology ; Cochlear Implantation/*adverse effects/instrumentation ; Cochlear Implants/*adverse effects ; Dexamethasone/administration &amp; dosage ; Evoked Potentials, Auditory, Brain Stem ; Guinea Pigs ; Hair Cells, Auditory, Outer/pathology ; Hearing Loss/*etiology/pathology/physiopathology ; Hemocyanins/administration &amp; dosage ; Injections, Intravenous ; Injections, Subcutaneous ; Prosthesis Design ; Time Factors ; }, abstract = {This study reviews the cochlear histology from four hearing preservation cochlear implantation experiments conducted on 73 guinea pigs from our institution, and relates histopathological findings to residual hearing. All guinea pigs had normal hearing prior to surgery and underwent cochlear implantation via a cochleostomy with a silastic-platinum dummy electrode. Pure tone auditory brainstem response (ABR) thresholds from 2 to 32 kHz were recorded prior to surgery, and at one and four weeks postoperatively. The cochleae were then fixed in paraformaldehyde, decalcified, paraffin embedded, and mid-modiolar sections were prepared. The treatment groups were as follows: 1) Systemic dexamethasone, 0.2 mg/kg administered 1 h before implantation, 2) Local dexamethasone, 2% applied topically to the round window for 30 min prior to cochlear implantation, 3) Local n-acetyl cysteine, 200 μg applied topically to the round window for 30 min prior to implantation, 4) inoculation to keyhole-limpet hemocyanin (KLH) prior to implantation, and 5) untreated controls. There was a significant correlation between the extent of the tissue reaction in the cochlea and the presence of foreign body giant cells (FBGCs), new bone formation and injury to the osseous spiral lamina (OSL). The extent of the tissue response, as a percentage of the area of the scala tympani, limited the best hearing that was observed four weeks after cochlear implantation. Poorer hearing at four weeks correlated with a more extensive tissue response, lower outer hair cell (OHC) counts and OSL injury in the basal turn. Progressive hearing loss was also correlated with the extent of tissue response. Hearing at 2 kHz, which corresponds to the region of the second cochlear turn, did not correspond with loco-regional inner hair cell (IHC), OHC or SGC counts. We conclude that cochlear injury is associated with poorer hearing early after implantation. The tissue response is related to indices of cochlear inflammation and injury. An extensive tissue response limits hearing at four weeks, and correlates with progressive hearing loss. These latter effects may be due to inflammation, but would also be consistent with interference of cochlear mechanics.}, }
@article {pmid23392884, year = {2013}, author = {Acharya, M and Lau-Cam, CA}, title = {Comparative evaluation of the effects of taurine and thiotaurine on alterations of the cellular redox status and activities of antioxidant and glutathione-related enzymes by acetaminophen in the rat.}, journal = {Advances in experimental medicine and biology}, volume = {776}, number = {}, pages = {199-215}, doi = {10.1007/978-1-4614-6093-0_20}, pmid = {23392884}, issn = {0065-2598}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Animals ; Antioxidants/*metabolism ; Aspartate Aminotransferases/blood ; Catalase/blood ; Glutamate-Cysteine Ligase/blood ; Glutathione/blood/*metabolism ; Glutathione Disulfide/blood ; Glutathione Reductase/blood ; Glutathione Transferase/blood ; L-Lactate Dehydrogenase/blood ; Liver/drug effects/*enzymology/*pathology ; Male ; Malondialdehyde/blood ; Oxidation-Reduction/drug effects ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/blood ; Taurine/*analogs &amp; derivatives/*pharmacology ; }, abstract = {The present study was carried out to ascertain the impact of replacing the sulfonate group of TAU with thiosulfonate, as present in thiotaurine (TTAU), on the protective actions of TAU against hepatocellular damage and biochemical alterations related to oxidative stress and glutathione redox cycling, synthesis, and utilization caused by a high dose of acetaminophen (APAP). To this end, male Sprague-Dawley rats, 225-250 g, were intraperitoneally treated with a 2.4 mmol/kg dose of TAU (or TTAU), followed 30 min later by 800 mg/kg of APAP. A reference group received 2.4 mmol/kg of N-acetylcysteine (NAC) prior to APAP. Naive rats served as controls. The animals were sacrificed 6 h after receiving APAP and their blood and livers were collected. Plasma and liver homogenates were analyzed for indices of cell damage (plasma transaminases, plasma lactate dehydrogenase), -oxidative stress (malondialdehyde = MDA, reduced glutathione = GSH, glutathione disulfide = GSSG, catalase, glutathione peroxidase, superoxide dismutase), glutathione cycling (glutathione reductase), utilization (glutathione S-transferase), and synthesis (γ-glutamylcysteine synthetase) activities. APAP increased MDA formation and lowered the GSH/GSSG ratio and all enzyme activities, especially those of antioxidant enzymes. In general, TTAU was equipotent with NAC and more potent than TAU in protecting the liver. Taken into account the results of a previous study comparing the actions of TAU and hypotaurine (HTAU), the sulfinate analog of TAU, it appears that the sulfinate and thiosulfonate analogs are somewhat more effective than the parent sulfonate TAU in counteracting APAP-induced hepatic alterations in the liver and plasma.}, }
@article {pmid23392711, year = {2013}, author = {Xu, SQ and Zhu, HY and Lin, JG and Su, TF and Liu, Y and Luo, XP}, title = {Copper ions stimulate the proliferation of hepatic stellate cells via oxygen stress in vitro.}, journal = {Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban}, volume = {33}, number = {1}, pages = {75-80}, pmid = {23392711}, issn = {1672-0733}, mesh = {Cell Line ; Cell Proliferation/*drug effects ; Copper/*administration &amp; dosage ; Dose-Response Relationship, Drug ; Hepatic Stellate Cells/*cytology/drug effects/*physiology ; Humans ; Ions ; Liver Cirrhosis/metabolism ; Oxidative Stress/drug effects/*physiology ; Oxygen/*metabolism ; }, abstract = {This study examined the effect of copper ions on the proliferation of hepatic stellate cells (HSCs) and the role of oxidative stress in this process in order to gain insight into the mechanism of hepatic fibrosis in Wilson's disease. LX-2 cells, a cell line of human HSCs, were cultured in vitro and treated with different agents including copper sulfate, N-acetyl cysteine (NAC) and buthionine sulfoximine (BSO) for different time. The proliferation of LX-2 cells was measured by non-radioactive cell proliferation assay. Real-time PCR and Western blotting were used to detect the mRNA and protein expression of platelet-derived growth factor receptor β subunit (PDGFβR), ELISA to determine the level of glutathione (GSH) and oxidized glutathione (GSSG), dichlorofluorescein assay to measure the level of reactive oxygen species (ROS), and lipid hydroperoxide assay to quantify the level of lipid peroxide (LPO). The results showed that copper sulfate over a certain concentration range could promote the proliferation of LX-2 cells in a time- and dose-dependent manner. The effect was most manifest when LX-2 cells were treated with copper sulfate at a concentration of 100 μmol/L for 24 h. Additionally, copper sulfate could dose-dependently increase the levels of ROS and LPO, and decrease the ratio of GSH/GSSG in LX-2 cells. The copper-induced increase in mRNA and protein expression of PDGFβR was significantly inhibited in LX-2 cells pre-treated with NAC, a precursor of GSH, and this phenomenon could be reversed by the intervention of BSO, an inhibitor of NAC. It was concluded that copper ions may directly stimulate the proliferation of HSCs via oxidative stress. Anti-oxidative stress therapies may help suppress the copper-induced activation and proliferation of HSCs.}, }
@article {pmid23392177, year = {2013}, author = {Cheng, P and Ni, Z and Dai, X and Wang, B and Ding, W and Rae Smith, A and Xu, L and Wu, D and He, F and Lian, J}, title = {The novel BH-3 mimetic apogossypolone induces Beclin-1- and ROS-mediated autophagy in human hepatocellular carcinoma [corrected] cells.}, journal = {Cell death &amp; disease}, volume = {4}, number = {2}, pages = {e489}, pmid = {23392177}, issn = {2041-4889}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*toxicity ; Antioxidants/pharmacology ; Apoptosis Regulatory Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Autophagy/*drug effects ; Beclin-1 ; Carcinoma, Hepatocellular/metabolism/pathology ; Cell Line, Tumor ; Cyclin D1/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gossypol/*analogs &amp; derivatives/toxicity ; HMGB1 Protein/metabolism ; Hep G2 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Liver Neoplasms/metabolism/pathology ; Membrane Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; Microtubule-Associated Proteins/metabolism ; Phosphorylation ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; TOR Serine-Threonine Kinases/metabolism ; bcl-X Protein/metabolism ; }, abstract = {Apogossypolone (ApoG2), a novel derivative of gossypol, exhibits superior antitumor activity in Bcl-2 transgenic mice, and induces autophagy in several cancer cells. However, the detailed mechanisms are not well known. In the present study, we showed that ApoG2 induced autophagy through Beclin-1- and reactive oxygen species (ROS)-dependent manners in human hepatocellular carcinoma (HCC) cells. Incubating the HCC cell with ApoG2 abrogated the interaction of Beclin-1 and Bcl-2/xL, stimulated ROS generation, increased phosphorylation of ERK and JNK, and HMGB1 translocation from the nucleus to cytoplasm while suppressing mTOR. Moreover, inhibition of the ROS-mediated autophagy by antioxidant N-acetyl-cysteine (NAC) potentiates ApoG2-induced apoptosis and cell killing. Our results show that ApoG2 induced protective autophagy in HCC cells, partly due to ROS generation, suggesting that antioxidant may serve as a potential chemosensitizer to enhance cancer cell death through blocking ApoG2-stimulated autophagy. Our novel insights may facilitate the rational design of clinical trials for Bcl-2-targeted cancer therapy.}, }
@article {pmid23386420, year = {2013}, author = {Kucuksayan, E and Cort, A and Timur, M and Ozdemir, E and Yucel, SG and Ozben, T}, title = {N-acetyl-L-cysteine inhibits bleomycin induced apoptosis in malignant testicular germ cell tumors.}, journal = {Journal of cellular biochemistry}, volume = {114}, number = {7}, pages = {1685-1694}, doi = {10.1002/jcb.24510}, pmid = {23386420}, issn = {1097-4644}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Bleomycin/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Male ; Oxidative Stress/drug effects ; Testicular Neoplasms/metabolism ; }, abstract = {Antioxidants may prevent apoptosis of cancer cells via inhibiting reactive oxygen species (ROS). However, to date no study has been carried out to elucidate the effects of strong antioxidant N-acetylcysteine (NAC) on Bleomycin induced apoptosis in human testicular cancer (NTERA-2, NT2) cells. For this reason, we studied the effects of Bleomycin and NAC alone and in combination on apoptotic signaling pathways in NT2 cell line. We determined the cytotoxic effect of bleomycin on NT2 cells and measured apoptosis markers such as Caspase-3, -8, -9 activities and Bcl-2, Bax, Cyt-c, Annexin V-FTIC and PI levels in NT2 cells incubated with different agents for 24 h. Early apoptosis was determined using FACS assay. We found half of the lethal dose (LD50) of Bleomycin on NT2 cell viability as 400, 100, and 20 µg/ml after incubations for 24, 48, and 72 h, respectively. Incubation with bleomycin (LD50) and H2O2 for 24 h increased Caspase-3, -8, -9 activities, Cyt-c and Bax levels and decreased Bcl-2 levels. The concurrent incubation of NT2 cells with bleomycin/H2O2 and NAC (5 mM) for 24 h abolished bleomycin/H2O2-dependent increases in Caspase-3, -8, -9 activities, Bax and Cyt-c levels and bleomycin/H2O2-dependent decrease in Bcl-2 level. Our results indicate that bleomycin/H2O2 induce apoptosis in NT2 cells by activating mitochondrial pathway of apoptosis, while NAC diminishes bleomycin/H2O2 induced apoptosis. We conclude that NAC has antagonistic effects on Bleomycin-induced apoptosis in NT2 cells and causes resistance to apoptosis which is not a desired effect in eliminating cancer cells.}, }
@article {pmid23384600, year = {2013}, author = {Ma, T and Zhu, J and Chen, X and Zha, D and Singhal, PC and Ding, G}, title = {High glucose induces autophagy in podocytes.}, journal = {Experimental cell research}, volume = {319}, number = {6}, pages = {779-789}, pmid = {23384600}, issn = {1090-2422}, support = {R01 DK083931/DK/NIDDK NIH HHS/United States ; R01 DK084910/DK/NIDDK NIH HHS/United States ; R01DK083931/DK/NIDDK NIH HHS/United States ; R01DK084910/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis Regulatory Proteins/metabolism ; *Autophagy ; Beclin-1 ; Blood Glucose/drug effects/metabolism ; Catalase/metabolism ; Culture Media/metabolism ; Diabetes Mellitus, Experimental/metabolism/pathology ; Glucose/*metabolism/pharmacology ; Male ; Microscopy, Electron ; Microtubule-Associated Proteins/metabolism ; Podocytes/*drug effects/metabolism/ultrastructure ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sirolimus/pharmacology ; Streptozocin/adverse effects ; Superoxide Dismutase/metabolism ; Tumor Cells, Cultured ; }, abstract = {Autophagy is a cellular pathway involved in protein and organelle degradation. It is relevant to many types of cellular homeostasis and human diseases. High level of glucose is known to inflict podocyte injury, but little is reported about the relationship between high concentrations of glucose and autophagy in these cells. The present study demonstrates that high glucose promotes autophagy in podocytes. Rapamycin further enhances this effect, but 3-methyadenine inhibits it. The proautophagic effect of high glucose manifested in the form of enhanced podocyte expression of LC3-2 and beclin-1; interestingly, antioxidants such as NAC were found to inhibit high glucose-induced autophagy. High glucose induced the generation of ROS by podocytes in a time-dependent manner. High glucose also enhanced podocyte expression of MnSOD and catalase. These findings indicate that high glucose-induced autophagy is mediated through podocyte ROS generation.}, }
@article {pmid23384394, year = {2013}, author = {Alipour, M and Mitsopoulos, P and Smith, MG and Bolger, G and Pucaj, K and Suntres, ZE}, title = {Safety and pharmacokinetic studies of liposomal antioxidant formulations containing N-acetylcysteine, α-tocopherol or γ-tocopherol in beagle dogs.}, journal = {Toxicology mechanisms and methods}, volume = {23}, number = {6}, pages = {419-431}, doi = {10.3109/15376516.2013.774079}, pmid = {23384394}, issn = {1537-6524}, mesh = {1,2-Dipalmitoylphosphatidylcholine/chemistry ; *Acetylcysteine/administration &amp; dosage/pharmacokinetics/toxicity ; Animals ; *Antioxidants/administration &amp; dosage/pharmacokinetics/toxicity ; Chemistry, Pharmaceutical ; Dogs ; Dose-Response Relationship, Drug ; Drug Stability ; Female ; Injections, Intravenous ; Liposomes ; Male ; Metabolic Clearance Rate ; Toxicity Tests ; *alpha-Tocopherol/administration &amp; dosage/pharmacokinetics/toxicity ; *gamma-Tocopherol/administration &amp; dosage/pharmacokinetics/toxicity ; }, abstract = {The safety and pharmacokinetic profile of liposomal formulations containing combinations of the antioxidants α-tocopherol, γ-tocopherol or N-acetylcysteine in beagle dogs was examined. Each group consisted of beagle dogs of both genders with a control group receiving empty dipalmitoylphosphatidylcholine (DPPC) liposomes (330 mg/kg DPPC, EL), and test groups receiving liposomes prepared from DPPC lipids with (i) N-acetylcysteine (NAC) (60 mg/kg NAC [L-NAC]); (ii) NAC and α-tocopherol (αT) (60 mg/kg NAC and 25 mg/kg α-tocopherol [L-αT-NAC]) and (iii) NAC and γ-tocopherol (60 mg/kg NAC and 25 mg/kg γ-tocopherol (γT) [L-γT-NAC]). The dogs in the control group (EL) and three test groups exhibited no signs of toxicity during the dosing period or day 15 post treatment. Weight gain, feed consumption and clinical pathology findings (hematology, coagulation, clinical chemistry, urinalysis) were unremarkable in all dogs and in all groups. Results from the pharmacokinetic study revealed that the inclusion of tocopherols in the liposomal formulation significantly increased the area under the curve (AUC) and β-half life for NAC; the tocopherols had greater impact on the clearance of NAC, where reductions of central compartment clearance (CL) ranged from 56% to 60% and reductions of tissue clearance (CL2) ranged from 73% to 77%. In conclusion, there was no treatment-related toxicity in dogs at the maximum feasible dose level by a single bolus intravenous administration while the addition of tocopherols to the liposomal formulation prolonged the circulation of NAC in plasma largely due to a decreased clearance of NAC.}, }
@article {pmid23383076, year = {2013}, author = {Sun, Z and Fu, Q and Cao, L and Jin, W and Cheng, L and Li, Z}, title = {Intravenous N-acetylcysteine for prevention of contrast-induced nephropathy: a meta-analysis of randomized, controlled trials.}, journal = {PloS one}, volume = {8}, number = {1}, pages = {e55124}, pmid = {23383076}, issn = {1932-6203}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects/*pharmacology ; Administration, Intravenous ; Contrast Media/*adverse effects ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control/therapy ; *Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) is one of the common causes of acute renal insufficiency after contrast procedures. Whether intravenous N-acetylcysteine (NAC) is beneficial for the prevention of contrast-induced nephropathy is uncertain. In this meta-analysis of randomized controlled trials, we aimed to assess the efficacy of intravenous NAC for preventing CIN after administration of intravenous contrast media.<br><br>STUDY DESIGN: Relevant studies published up to September 2012 that investigated the efficacy of intravenous N-acetylcysteine for preventing CIN were collected from MEDLINE, OVID, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and the conference proceedings from major cardiology and nephrology meetings. The primary outcome was CIN. Secondary outcomes included renal failure requiring dialysis, mortality, and length of hospitalization. Data were combined using random-effects models with the performance of standard tests to assess for heterogeneity and publication bias. Meta-regression analyses were also performed.<br><br>RESULTS: Ten trials involving 1916 patients met our inclusion criteria. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The summary risk ratio for contrast-induced nephropathy was 0.68 (95% CI, 0.46 to 1.02), a nonsignificant trend towards benefit in patients treated with intravenous NAC. There was evidence of significant heterogeneity in NAC effect across studies (Q&#x200a;=&#x200a;17.42, P&#x200a;=&#x200a;0.04; I(2)&#x200a;=&#x200a;48%). Meta-regression revealed no significant relation between the relative risk of CIN and identified differences in participant or study characteristics.<br><br>CONCLUSION: This meta-analysis showed that research on intravenous N-acetylcysteine and the incidence of CIN is too inconsistent at present to warrant a conclusion on efficacy. A large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of CIN is required to more adequately assess the role for intravenous NAC in CIN prevention.}, }
@article {pmid23379731, year = {2013}, author = {Zhang, G and Parkin, KL}, title = {S-alk(en)ylmercaptocysteine: chemical synthesis, biological activities, and redox-related mechanism.}, journal = {Journal of agricultural and food chemistry}, volume = {61}, number = {8}, pages = {1896-1903}, doi = {10.1021/jf305486q}, pmid = {23379731}, issn = {1520-5118}, mesh = {Allium/*chemistry ; Animals ; Antioxidants/*chemical synthesis/chemistry/pharmacology ; Cell Line ; Cysteine/*analogs &amp; derivatives ; Humans ; Mice ; Oxidation-Reduction ; Plant Extracts/*chemical synthesis/chemistry/pharmacology ; Sulfinic Acids/*chemistry ; }, abstract = {S-Alk(en)ylmercaptocysteine (CySSR, R = methyl, ethyl, propyl, 1-propenyl, and allyl), which are the putative metabolites of Allium thiosulfinates, were chemically synthesized. CySSR, but not the corresponding monosulfide species S-alk(en)yl cysteine (CySR), were able to induce quinone reductase (QR, a representative phase II enzyme) in Hepa 1c1c7 cells and inhibit nitric oxide (NO, an inflammatory biomarker) formation in lipopolysaccharide (LPS)-activated RAW 264.7 cells. These results indicate the importance of the disulfide bond for the biological activities of CySSR. Glutathione (GSH) and N-acetylcysteine (NAC), but not other types of cellular antioxidants, suppressed multiple biological activities of CySSR in vitro. The inhibitory effects of GSH and NAC on the biological activities of CySSR were correlated with a glutaredoxin (Grx)-dependent intracellular reduction of CySSR to generate cysteine and RSH, which were secreted into the extracellular medium.}, }
@article {pmid23379449, year = {2013}, author = {McIntyre, S and McD Taylor, D and Greene, S}, title = {Introduction of an N-acetylcysteine weight-based dosing chart reduces prescription errors in the treatment of paracetamol poisoning.}, journal = {Emergency medicine Australasia : EMA}, volume = {25}, number = {1}, pages = {28-35}, doi = {10.1111/1742-6723.12020}, pmid = {23379449}, issn = {1742-6723}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Australia ; *Body Weight ; *Drug Dosage Calculations ; Emergency Service, Hospital/statistics &amp; numerical data ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Male ; Medication Errors/*prevention &amp; control/statistics &amp; numerical data ; Poisoning/drug therapy ; Retrospective Studies ; Young Adult ; }, abstract = {OBJECTIVE: Under- or overdosing of N-acetylcysteine (NAC), when used to treat paracetamol toxicity, is associated with significant morbidity and mortality. This study evaluated the effect of a weight-based dosing chart (WBDC) introduced to decrease NAC prescription errors.<br><br>METHODS: We undertook a pre- and post-intervention trial in a single ED. The intervention (the NAC WBDC) was introduced in January 2011 and publicised by posters and presentations at medical handovers and education sessions. ED staff were not aware that use of the WBDC was to be evaluated. Data were collected using a retrospective explicit medical record review by a single investigator. The study end-point was the proportion of NAC prescriptions with errors.<br><br>RESULTS: The 81 and 42 patients enrolled in the pre- and post-intervention periods, respectively, did not differ in age, sex or weight (P > 0.05). Post-intervention, there were significant reductions in prescription errors of fluid type/volume (50.6% vs 4.8%, P < 0.001), NAC dosage (13.6% vs 0.0%, P = 0.01) and infusion rate (11.1% vs 0.0%, P = 0.03). The proportion of prescriptions with any errors also decreased (56.8% vs 14.3%, P < 0.001). However, there were no improvements in the documentation of patient weight (65.4% vs 64.3%, respectively, P = 0.90) or the proportion of incomplete prescriptions (4.9% vs 11.9%, P = 0.16).<br><br>CONCLUSION: The introduction of a WBDC did not produce a clinically significant reduction in major NAC prescription error rates (as pre-defined in this study); however, there was a clear trend towards a reduction. The WBDC significantly reduced total and minor NAC prescription error rates.}, }
@article {pmid23376779, year = {2013}, author = {Kerksick, CM and Roberts, MD and Dalbo, VJ and Kreider, RB and Willoughby, DS}, title = {Changes in skeletal muscle proteolytic gene expression after prophylactic supplementation of EGCG and NAC and eccentric damage.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {61}, number = {}, pages = {47-52}, doi = {10.1016/j.fct.2013.01.026}, pmid = {23376779}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Calpain/genetics ; Catechin/*analogs &amp; derivatives/pharmacology ; Dietary Supplements ; Double-Blind Method ; Exercise ; Gene Expression/*drug effects ; Humans ; Male ; Muscle Contraction/drug effects/genetics ; Muscle Proteins/genetics ; Muscle, Skeletal/*drug effects/physiology ; Nontherapeutic Human Experimentation ; SKP Cullin F-Box Protein Ligases/genetics ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases/genetics ; Young Adult ; }, abstract = {PURPOSE: The impact of prophylactic supplementation of N-acetyl-cysteine (NAC) and epigallocatechin gallate (EGCG) on intramuscular expression of proteolytic genes after unaccustomed eccentric muscle contractions was investigated.<br><br>METHODS: Thirty apparently healthy males (mean &#xb1; SD: 20.0 &#xb1; 1.8 years, 175 &#xb1; 7.1cm, 76.1 &#xb1; 16.9 kg) ingested daily either 1,800 mg of NAC or 1,800 mg of EGCG (98% total polyphenols, 80% total catechins, and 50% EGCG), or 1,000 mg of a glucomannan placebo (PLA) in a double blind, prophylactic fashion for 14 days. Subjects then completed an unaccustomed eccentric exercise bout (100 repetitions at 30 &#xb0;s(-1)) using the dominant knee extensors. Skeletal muscle biopsies were collected from the vastus lateralis at baseline and both 6 and 24h after exercise. The expression of proteolytic genes [i.e., muscle ring-finger 1 (MuRF1), atrogin-1, &#x3b1;-type 20S subunit C2 (HC2), &#x3b1;-type 20S subunit C3 (HC3), ubiquitin protein ligase 3B (UBE3B), &#x3bc;-calpain, and m-calpain] was quantified using real-time RT-PCR. Separate 3 &#xd7; 3 (group &#xd7; time) repeated measures ANOVAs were used to analyze changes in gene expression over time between groups.<br><br>RESULTS: No significant group &#xd7; time interactions were detected between groups for the expression of any of the atrogenes or calpains (p>0.05). Significant main effects for time identified increases in MuRF1 (6h: 5.3 &#xb1; 10.8 fold; p=0.046), UBE3B (6h: 5.3 &#xb1; 7.7 fold; p=0.006; 24h: 3.3 &#xb1; 4.5 fold; p=0.005), and m-calpain expression (6h: 2.7 &#xb1; 4.4 fold; p=0.045) in all participants following exercise. Increases approached significance in HC2 (6h: 1.9 &#xb1; 2.4 fold; p=0.079; 24h: 1.6 &#xb1; 1.9 fold; p=0.084) and m-calpain expression (24h: 1.8 &#xb1; 2.3 fold; p=0.084) following exercise.<br><br>CONCLUSIONS: Prophylactic supplementation of NAC and EGCG did not impact acute changes in skeletal muscle proteolytic gene expression following eccentric exercise. Eccentric muscle contractions elevated MuRF1 and UBE3B, while m-calpain and HC2 mRNA tended to increase.}, }
@article {pmid23372680, year = {2013}, author = {Hoffer, ME and Balaban, C and Slade, MD and Tsao, JW and Hoffer, B}, title = {Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study.}, journal = {PloS one}, volume = {8}, number = {1}, pages = {e54163}, pmid = {23372680}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adolescent ; Adult ; Blast Injuries/*drug therapy/physiopathology ; Brain Injuries/*drug therapy/physiopathology ; Cognition Disorders/prevention &amp; control ; Double-Blind Method ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Humans ; *Iraq War, 2003-2011 ; Male ; Memory Disorders/prevention &amp; control ; *Military Personnel ; Neuropsychological Tests ; Placebos ; Severity of Illness Index ; Sleep Initiation and Maintenance Disorders/prevention &amp; control ; }, abstract = {BACKGROUND: Mild traumatic brain injury (mTBI) secondary to blast exposure is the most common battlefield injury in Southwest Asia. There has been little prospective work in the combat setting to test the efficacy of new countermeasures. The goal of this study was to compare the efficacy of N-acetyl cysteine (NAC) versus placebo on the symptoms associated with blast exposure mTBI in a combat setting.<br><br>METHODS: This study was a randomized double blind, placebo-controlled study that was conducted on active duty service members at a forward deployed field hospital in Iraq. All symptomatic U.S. service members who were exposed to significant ordnance blast and who met the criteria for mTBI were offered participation in the study and 81 individuals agreed to participate. Individuals underwent a baseline evaluation and then were randomly assigned to receive either N-acetyl cysteine (NAC) or placebo for seven days. Each subject was re-evaluated at 3 and 7 days. Outcome measures were the presence of the following sequelae of mTBI: dizziness, hearing loss, headache, memory loss, sleep disturbances, and neurocognitive dysfunction. The resolution of these symptoms seven days after the blast exposure was the main outcome measure in this study. Logistic regression on the outcome of 'no day 7 symptoms' indicated that NAC treatment was significantly better than placebo (OR&#x200a;=&#x200a;3.6, p&#x200a;=&#x200a;0.006). Secondary analysis revealed subjects receiving NAC within 24 hours of blast had an 86% chance of symptom resolution with no reported side effects versus 42% for those seen early who received placebo.<br><br>CONCLUSION: This study, conducted in an active theatre of war, demonstrates that NAC, a safe pharmaceutical countermeasure, has beneficial effects on the severity and resolution of sequelae of blast induced mTBI. This is the first demonstration of an effective short term countermeasure for mTBI. Further work on long term outcomes and the potential use of NAC in civilian mTBI is warranted.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT00822263.}, }
@article {pmid23371060, year = {2013}, author = {Allen-Gipson, DS and Zimmerman, MC and Zhang, H and Castellanos, G and O'Malley, JK and Alvarez-Ramirez, H and Kharbanda, K and Sisson, JH and Wyatt, TA}, title = {Smoke extract impairs adenosine wound healing: implications of smoke-generated reactive oxygen species.}, journal = {American journal of respiratory cell and molecular biology}, volume = {48}, number = {5}, pages = {665-673}, pmid = {23371060}, issn = {1535-4989}, support = {R37AA008769/AA/NIAAA NIH HHS/United States ; R01 AA008769/AA/NIAAA NIH HHS/United States ; R01 AA017993/AA/NIAAA NIH HHS/United States ; K01 HL084684/HL/NHLBI NIH HHS/United States ; R01AA017993/AA/NIAAA NIH HHS/United States ; K01HL084684/HL/NHLBI NIH HHS/United States ; I01 BX000728/BX/BLRD VA/United States ; VA101BX000728/BX/BLRD VA/United States ; R37 AA008769/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine/metabolism/*physiology ; Animals ; Bronchi/pathology ; Catalase/physiology ; Cattle ; Cells, Cultured ; Cyclic AMP/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Enzyme Activation ; Epithelial Cells/drug effects/*metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/*metabolism ; Primary Cell Culture ; Protein Kinase C/metabolism ; Reactive Oxygen Species/metabolism ; Receptor, Adenosine A2A/genetics/metabolism ; Second Messenger Systems ; *Smoke ; Nicotiana/chemistry ; *Wound Healing ; }, abstract = {Adenosine concentrations are elevated in the lungs of patients with asthma and chronic obstructive pulmonary disease, where it balances between tissue repair and excessive airway remodeling. We previously demonstrated that the activation of the adenosine A2A receptor promotes epithelial wound closure. However, the mechanism by which adenosine-mediated wound healing occurs after cigarette smoke exposure has not been investigated. The present study investigates whether cigarette smoke exposure alters adenosine-mediated reparative properties via its ability to induce a shift in the oxidant/antioxidant balance. Using an in vitro wounding model, bronchial epithelial cells were exposed to 5% cigarette smoke extract, were wounded, and were then stimulated with either 10 μM adenosine or the specific A2A receptor agonist, 5'-(N-cyclopropyl)-carboxamido-adenosine (CPCA; 10 μM), and assessed for wound closure. In a subset of experiments, bronchial epithelial cells were infected with adenovirus vectors encoding human superoxide dismutase and/or catalase or control vector. In the presence of 5% smoke extract, significant delay was evident in both adenosine-mediated and CPCA-mediated wound closure. However, cells pretreated with N-acetylcysteine (NAC), a nonspecific antioxidant, reversed smoke extract-mediated inhibition. We found that cells overexpressing mitochondrial catalase repealed the smoke extract inhibition of CPCA-stimulated wound closure, whereas superoxide dismutase overexpression exerted no effect. Kinase experiments revealed that smoke extract significantly reduced the A2A-mediated activation of cyclic adenosine monophosphate-dependent protein kinase. However, pretreatment with NAC reversed this effect. In conclusion, our data suggest that cigarette smoke exposure impairs A2A-stimulated wound repair via a reactive oxygen species-dependent mechanism, thereby providing a better understanding of adenosine signaling that may direct the development of pharmacological tools for the treatment of chronic inflammatory lung disorders.}, }
@article {pmid23369637, year = {2013}, author = {Berk, M and Malhi, GS and Gray, LJ and Dean, OM}, title = {The promise of N-acetylcysteine in neuropsychiatry.}, journal = {Trends in pharmacological sciences}, volume = {34}, number = {3}, pages = {167-177}, doi = {10.1016/j.tips.2013.01.001}, pmid = {23369637}, issn = {1873-3735}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Humans ; Mental Disorders/*drug therapy ; }, abstract = {N-Acetylcysteine (NAC) targets a diverse array of factors germane to the pathophysiology of multiple neuropsychiatric disorders including glutamatergic transmission, the antioxidant glutathione, neurotrophins, apoptosis, mitochondrial function, and inflammatory pathways. This review summarises the areas where the mechanisms of action of NAC overlap with known pathophysiological elements, and offers a précis of current literature regarding the use of NAC in disorders including cocaine, cannabis, and smoking addictions, Alzheimer's and Parkinson's diseases, autism, compulsive and grooming disorders, schizophrenia, depression, and bipolar disorder. There are positive trials of NAC in all these disorders, and although many of these require replication and are methodologically preliminary, this makes it one of the most promising drug candidates in neuropsychiatric disorders. The efficacy pattern of NAC interestingly shows little respect for the current diagnostic systems. Its benign tolerability profile, its action on multiple operative pathways, and the emergence of positive trial data make it an important target to investigate.}, }
@article {pmid23368424, year = {2013}, author = {Du, H and Li, J and Moe, B and McGuigan, CF and Shen, S and Li, XF}, title = {Cytotoxicity and oxidative damage induced by halobenzoquinones to T24 bladder cancer cells.}, journal = {Environmental science &amp; technology}, volume = {47}, number = {6}, pages = {2823-2830}, doi = {10.1021/es303762p}, pmid = {23368424}, issn = {1520-5851}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Benzoquinones/chemistry/*toxicity ; Cell Line, Tumor ; Deoxyguanosine/analogs &amp; derivatives/analysis ; Disinfectants/chemistry/*toxicity ; Drinking Water/adverse effects/analysis ; Halogenation ; Humans ; Lipid Peroxidation/drug effects ; Malondialdehyde/analysis ; Oxidative Stress/drug effects ; Protein Carbonylation/drug effects ; Urinary Bladder/cytology/drug effects/metabolism ; Urinary Bladder Neoplasms/*chemically induced/metabolism ; }, abstract = {Four halobenzoquinones (HBQs), 2,6-dichloro-1,4-benzoquinone (DCBQ), 2,6-dichloro-3-methyl-1,4-benzoquinone (DCMBQ), 2,3,6-trichloro-1,4-benzoquinone (TCBQ), and 2,6-dibromobenzoquinone (DBBQ), have been recently confirmed as disinfection byproducts (DBPs) in drinking water; however, their toxicological information is scarce. Here, we report that HBQs are cytotoxic to T24 bladder cancer cells and that the IC50 values are 95 μM for DCBQ, 110 μM for DCMBQ, 151 μM for TCBQ, and 142 μM for DBBQ, after a 24-h exposure. The antioxidant N-acetyl-l-cysteine (NAC) significantly reduces the cytotoxicity induced by the four HBQs, supporting the hypothesis that oxidative stress contributes to the cytotoxicity of HBQs. To further explore the oxidative mechanisms of cytotoxicity, we examined HBQ-induced production of reactive oxygen species (ROS) in T24 cells, and measured 8-hydroxydeoxyguanosine (8-OHdG), protein carbonyls, and malondialdehyde (MDA) adducts of proteins, markers of oxidative damage to DNA, proteins, and lipids, respectively. All four HBQs generated intracellular ROS in T24 cells in a concentration-dependent manner. HBQs also produced 8-OHdG in genomic DNA of T24 cells, with the highest levels of 8-OHdG induced by DCMBQ. Protein carbonylation was significantly increased in T24 cells that were incubated with each of the four HBQs for 24 h. However, MDA adduct formation, a marker of lipid peroxidation, was not affected by any of the four HBQs tested. These results suggest that the ROS-induced oxidative damage to DNA and protein carbonylation are involved in the observed toxicity of HBQs in T24 cells.}, }
@article {pmid23363356, year = {2013}, author = {Buur, JL and Diniz, PP and Roderick, KV and KuKanich, B and Tegzes, JH}, title = {Pharmacokinetics of N-acetylcysteine after oral and intravenous administration to healthy cats.}, journal = {American journal of veterinary research}, volume = {74}, number = {2}, pages = {290-293}, doi = {10.2460/ajvr.74.2.290}, pmid = {23363356}, issn = {1943-5681}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacokinetics ; Administration, Intravenous/veterinary ; Administration, Oral ; Animals ; Antiviral Agents/administration &amp; dosage/*pharmacokinetics ; Area Under Curve ; Biological Availability ; Cats/*physiology ; Chromatography, High Pressure Liquid/veterinary ; Cross-Over Studies ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacokinetics ; Half-Life ; Male ; Mass Spectrometry/veterinary ; }, abstract = {OBJECTIVE: To describe the pharmacokinetics of N-acetylcysteine (NAC) in healthy cats after oral and IV administration.<br><br>ANIMALS: 6 healthy cats.<br><br>PROCEDURES: In a crossover study, cats received NAC (100 mg/kg) via IV and oral routes of administration; there was a 4-week washout period between treatments. Plasma samples were obtained at 0, 5, 15, 30, and 45 minutes and 1, 2, 4, 8, 12, 24, 36, and 48 hours after administration, and NAC concentrations were quantified by use of a validated high-performance liquid chromatography-mass spectrometry protocol. Data were analyzed via compartmental and noncompartmental pharmacokinetic analysis.<br><br>RESULTS: Pharmacokinetics for both routes of administration were best described by a 2-compartment model. Mean &#xb1; SD elimination half-life was 0.78 &#xb1; 0.16 hours and 1.34 &#xb1; 0.24 hours for the IV and oral routes of administration, respectively. Mean bioavailability of NAC after oral administration was 19.3 &#xb1; 4.4%.<br><br>The pharmacokinetics of NAC for this small population of healthy cats differed from values reported for humans. Assuming there would be similar pharmacokinetics in diseased cats, dose extrapolations from human medicine may result in underdosing of NAC in cats with acute disease. Despite the low bioavailability, plasma concentrations of NAC after oral administration at 100 mg/kg may be effective in the treatment of chronic diseases.}, }
@article {pmid23363008, year = {2013}, author = {Xiao, H and Wang, J and Yuan, L and Xiao, C and Wang, Y and Liu, X}, title = {Chicoric acid induces apoptosis in 3T3-L1 preadipocytes through ROS-mediated PI3K/Akt and MAPK signaling pathways.}, journal = {Journal of agricultural and food chemistry}, volume = {61}, number = {7}, pages = {1509-1520}, doi = {10.1021/jf3050268}, pmid = {23363008}, issn = {1520-5118}, mesh = {3T3-L1 Cells ; Acetylcysteine/pharmacology ; Adipocytes/drug effects ; Animals ; Apoptosis/*drug effects ; Caffeic Acids/*pharmacology ; Caspase 3/genetics/metabolism ; Cell Survival/drug effects ; Cyclooxygenase 2/genetics/metabolism ; Cytochromes c/genetics/metabolism ; Down-Regulation ; Heme Oxygenase-1/genetics/metabolism ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Membrane Proteins/genetics/metabolism ; Mice ; Phosphatidylinositol 3-Kinases/*metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Succinates/*pharmacology ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Chicoric acid has been reported to possess various bioactivities. However, the antiobesity effects of chicoric acid remain poorly understood. In this study, we investigated the effects of chicoric acid on 3T3-L1 preadipocytes and its molecular mechanisms of apoptosis. Chicoric acid inhibited cell viability and induced apoptosis in 3T3-L1 preadipocytes which was characterized by chromatin condensation and poly ADP-ribose-polymerase (PARP) cleavage. Mitochondrial membrane potential (MMP) loss, Bax/Bcl-2 dysregulation, cytochrome c release, and caspase-3 activation were observed, indicating mitochondria-dependent apoptosis induced by chicoric acid. Furthermore, PI3K/Akt and MAPK (p38 MAPK, JNK, and ERK1/2) signaling pathways were involved in chicoric acid-induced apoptosis. The employment of protein kinase inhibitors LY294002, SB203580, SP600125, and U0126 revealed that PI3K/Akt signaling pathway interplayed with MAPK signaling pathways. Moreover, chicoric acid induced reactive oxygen species (ROS) generation. Pretreatment with the antioxidant N-acetylcysteine (NAC) significantly blocked cell death and changes of Akt and MAPK signalings induced by chicoric acid. In addition, chicoric acid down regulated HO-1 and COX-2 via the PI3K/Akt pathway.}, }
@article {pmid23357435, year = {2013}, author = {Goldstein, BI}, title = {In this issue/abstract thinking: NAC attack: is N-acetylcysteine ready for prime time in child and adolescent psychiatry?.}, journal = {Journal of the American Academy of Child and Adolescent Psychiatry}, volume = {52}, number = {2}, pages = {111-112}, doi = {10.1016/j.jaac.2012.11.010}, pmid = {23357435}, issn = {1527-5418}, mesh = {Acetylcysteine/metabolism ; Adolescent ; Adolescent Psychiatry/methods ; Child ; Child Psychiatry/methods ; Humans ; *Mental Disorders/metabolism/therapy ; Psychotherapy/methods ; Psychotropic Drugs/therapeutic use ; }, }
@article {pmid23353834, year = {2013}, author = {Devi, TS and Hosoya, K and Terasaki, T and Singh, LP}, title = {Critical role of TXNIP in oxidative stress, DNA damage and retinal pericyte apoptosis under high glucose: implications for diabetic retinopathy.}, journal = {Experimental cell research}, volume = {319}, number = {7}, pages = {1001-1012}, pmid = {23353834}, issn = {1090-2422}, support = {P30 EY004068/EY/NEI NIH HHS/United States ; P30EY04068/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Carrier Proteins/*metabolism ; Cell Cycle Proteins ; Cells, Cultured ; *DNA Damage/physiology ; Diabetic Retinopathy/*metabolism ; Glucose/*pharmacology ; Hyperglycemia/metabolism ; Oxidative Stress/*drug effects ; Pericytes/*drug effects/metabolism ; Rats ; Retina/cytology/*metabolism ; Thioredoxins/metabolism ; Up-Regulation/drug effects ; }, abstract = {Diabetic retinopathy (DR) is characterized by early loss of retinal capillary pericytes and microvascular dysfunction. We recently showed that pro-oxidative stress and pro-apoptotic thioredoxin interacting protein (TXNIP) is significantly up-regulated in rat retinas in experimental diabetes and mediates inflammation and apoptosis. Therefore, we hypothesize here that TXNIP up-regulation in pericyte plays a causative role in oxidative stress and apoptosis under sustained high glucose exposure in culture. We maintained a rat retinal capillary pericyte cell line (TR-rPCT1) for 5 days under low glucose (LG, 5.5mM) or high glucose (HG, 25 mM) with or without anti-oxidant N-acetylcysteine (5mM, NAC), Azaseine (2 μM, AzaS), an inhibitor of TXNIP, and TXNIP siRNA (siTXNIP3, 20 nM). The results show that HG increases TXNIP expression in TR-rPCT1, which correlates positively with ROS generation, protein S-nitrosylation, and pro-apoptotic caspase-3 activation. Furthermore, pericyte apoptosis is demonstrated by DNA fragmentation (alkaline comet assay) and a reduction in MTT survival assay. Treatment of TR-rPCT1 with NAC or an inhibition of TXNIP by AzaS or siTXNIP3 each reduces HG-induced ROS, caspase-3 activation and DNA damage demonstrating that TXNIP up-regulation under chronic hyperglycemia is critically involved in cellular oxidative stress, DNA damage and retinal pericyte apoptosis. Thus, TXNIP represents a novel gene and drug target to prevent pericyte loss and progression of DR.}, }
@article {pmid23353715, year = {2013}, author = {Ji, YL and Wang, H and Zhang, C and Zhang, Y and Zhao, M and Chen, YH and Xu, DX}, title = {N-acetylcysteine protects against cadmium-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in testes.}, journal = {Asian journal of andrology}, volume = {15}, number = {2}, pages = {290-296}, pmid = {23353715}, issn = {1745-7262}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cadmium/*toxicity ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/drug effects ; Glutathione/metabolism ; Heat-Shock Proteins/genetics/metabolism ; Heme Oxygenase-1/metabolism ; Male ; Membrane Proteins/metabolism ; Mice ; Models, Biological ; RNA, Messenger/genetics/metabolism ; Spermatozoa/drug effects/pathology ; Testis/*drug effects/metabolism/pathology ; Unfolded Protein Response/drug effects ; }, abstract = {Cadmium (Cd) is a reproductive toxicant that induces germ cell apoptosis in the testes. Previous studies have demonstrated that endoplasmic reticulum (ER) stress is involved in Cd-induced germ cell apoptosis. The aim of the present study was to investigate the effects of N-acetylcysteine (NAC), an antioxidant, on Cd-induced ER stress and germ cell apoptosis in the testes. Male CD-1 mice were intraperitoneally injected with CdCl2 (2.0 mg kg(-1)). As expected, acute Cd exposure induced germ cell apoptosis in the testes, as determined by terminal dUTP nick-end labelling (TUNEL). However, the administration of NAC alleviated Cd-induced germ cell apoptosis in the testes. Further analysis showed that NAC attenuated the Cd-induced upregulation of testicular glucose-regulated protein 78 (GRP78), an important ER molecular chaperone. Moreover, NAC inhibited the Cd-induced phosphorylation of testicular eukaryotic translation initiation factor 2α (eIF2α), a downstream target of the double-stranded RNA-activated kinase-like ER kinase (PERK) pathway. In addition, NAC blocked the Cd-induced activation of testicular X binding protein (XBP)-1, indicating that NAC attenuates the Cd-induced ER stress and the unfolded protein response (UPR). Interestingly, NAC almost completely prevented the Cd-induced elevation of C/EBP homologous protein (CHOP) and phosphorylation of c-Jun N-terminal kinase (JNK), two components of the ER stress-mediated apoptotic pathway. In conclusion, NAC protects against Cd-induced germ cell apoptosis by inhibiting endoplasmic reticulum stress in the testes.}, }
@article {pmid23352441, year = {2013}, author = {Zang, L and He, H and Xu, Q and Yu, Y and Zheng, N and Liu, W and Hayashi, T and Tashiro, S and Onodera, S and Ikejima, T}, title = {Reactive oxygen species H2O2 and •OH, but not O2•(-) promote oridonin-induced phagocytosis of apoptotic cells by human histocytic lymphoma U937 cells.}, journal = {International immunopharmacology}, volume = {15}, number = {2}, pages = {414-423}, doi = {10.1016/j.intimp.2013.01.004}, pmid = {23352441}, issn = {1878-1705}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Autophagy/drug effects ; Diterpenes, Kaurane/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Hydroxyl Radical/metabolism ; Lymphoma, Large B-Cell, Diffuse/*metabolism ; MAP Kinase Signaling System/drug effects ; Phagocytosis/*drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Phospholipase C gamma/metabolism ; Reactive Oxygen Species/*metabolism ; U937 Cells ; raf Kinases/metabolism ; ras Proteins/metabolism ; }, abstract = {We reported previously that phagocytosis of apoptotic cells by U937 cells was enhanced by the treatment with oridonin that showed high activity to induce the generation of reactive oxygen species (ROS) in many cells. ROS, important signaling molecules, are involved in the immune defenses, cell repair and proliferation. In this study, oridonin caused modest amount of ROS generation in U937 cells, with hydrogen peroxide (H2O2) and hydroxyl free radical (OH) as the major types. Meanwhile, H2O2 and OH were positive regulators involved in oridonin-enhanced engulfment of apoptotic cells through down-regulating mitochondrial membrane potential (MMP) and inducing autophagy. The ROS-mediated phagocytosis was independent of cellular adenosine triphosphate (ATP) levels. H2O2 and OH generation also activated phosphatidylinositol 3-kinases-Akt (PI3K-Akt) and phospholipase C γ-protein kinase C(PLC γ)-Ras-Raf-ERK signaling pathways, which were essential for oridonin-induced engulfment of apoptotic cells. Phagocytosis, the loss of MMP, autophagy and the activated signaling pathways were all suppressed by ROS scavenger N-acetyl-l-cysteine (NAC), H2O2 scavenger catalase or OH scavenger glutathione (GSH). However, superoxide anion (O2-) and its scavenger superoxide dismutase (SOD) did not significantly affect these oridonin-induced biological processes.}, }
@article {pmid23351387, year = {2012}, author = {Ehsani, M and Moghadamnia, AA and Zahedpasha, S and Maliji, G and Haghanifar, S and Mir, SM and Kani, NM}, title = {The role of prophylactic ibuprofen and N-acetylcysteine on the level of cytokines in periapical exudates and the post-treatment pain.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {20}, number = {1}, pages = {30}, pmid = {23351387}, issn = {1560-8115}, abstract = {BACKGROUND: Periapical lesions are inflammatory diseases that result in periapical bone destruction because of host defensive-microbial disturbances.<br><br>OBJECTIVE: To evaluate the role of prophylactic ibuprofen and N-acetylcysteine (NAC) on the levels of tumor necrosis factor alpha (TNF- &#x3b1;), interleukin- 6(IL-6) and IL-17 and post-treatment pain level in chronic periapical lesions.<br><br>MATERIALS AND METHODS: Eighty patients with chronic apical lesions less than 1&#x2009;cm were randomly assigned to receive NAC tablets (400&#x2009;mg), ibuprofen tablets (400&#x2009;mg), NAC (400&#x2009;mg)/ibuprofen (200&#x2009;mg) combination and placebo 90 minutes prior to sampling. Periapical exudates were collected from root canals. TNF- &#x3b1;, IL-6 and IL-17 levels were determined by ELISA and post-treatment pain was assessed using a visual analog scale (VAS).<br><br>RESULTS: There was a significant difference in IL-6 level between ibuprofen group and placebo (p&#x2009;=&#x2009;0.019). Significant difference in IL-17 level was observed between NAC/ibuprofen combination group and placebo (p&#x2009;=&#x2009;0.043). Four hours after treatment, a significant difference was observed in VAS pain score between ibuprofen group and placebo (p&#x2009;=&#x2009;0.017). Eight hours post-treatment, VAS pain score for NAC group was statistically lower than placebo group (p&#x2009;=&#x2009;0.033). After 12 hours VAS pain score showed a significant decrease in NAC group compared to placebo (p&#x2009;=&#x2009;0.049).<br><br>CONCLUSION: The prophylactic ibuprofen and NAC failed to clearly reflect their effect on cytokines levels in exudates of chronic periapical lesions. On the other hand it seems that NAC can be a substitute for ibuprofen in the management of post endodontic pain.}, }
@article {pmid23351386, year = {2013}, author = {Kim, NH and Park, HJ and Oh, MK and Kim, IS}, title = {Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells.}, journal = {BMB reports}, volume = {46}, number = {1}, pages = {59-64}, pmid = {23351386}, issn = {1976-670X}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*toxicity ; Auranofin/*toxicity ; Breast Neoplasms/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Down-Regulation ; Female ; Gold/chemistry ; Humans ; Phosphorylation/drug effects ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/metabolism ; Telomerase/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Signal transducer and activator of transcription 3 (STAT3) and telomerase are considered attractive targets for anticancer therapy. The in vitro anticancer activity of the gold(I) compound auranofin was investigated using MDA-MB 231 human breast cancer cells, in which STAT3 is constitutively active. In cell culture, auranofin inhibited growth in a dose-dependent manner, and N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS), markedly blocked the effect of auranofin. Incorporation of 5-bromo-2'-deoxyuridine into DNA and anchorage-independent cell growth on soft agar were decreased by auranofin treatment. STAT3 phosphorylation and telomerase activity were also attenuated in cells exposed to auranofin, but NAC pretreatment restored STAT3 phosphorylation and telomerase activity in these cells. These findings indicate that auranofin exerts in vitro antitumor effects in MDA-MB 231 cells and its activity involves inhibition of STAT3 and telomerase. Thus, auranofin shows potential as a novel anticancer drug that targets STAT3 and telomerase.}, }
@article {pmid23351193, year = {2012}, author = {Moghadamnia, AA}, title = {An update on toxicology of aluminum phosphide.}, journal = {Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences}, volume = {20}, number = {1}, pages = {25}, pmid = {23351193}, issn = {1560-8115}, abstract = {Aluminum phosphide (AlP) is a cheap solid fumigant and a highly toxic pesticide which is commonly used for grain preservation. In Iran it is known as the "rice tablet". AlP has currently aroused interest with increasing number of cases in the past four decades due to increased use in agricultural and non-agricultural purposesand also its easy availability in the markets has increased its misuse to commit suicide. Upon contact with moisture in the environment, AlP undergoes a chemical reaction yielding phosphine gas, which is the active pesticidal component. Phosphine inhibits cellular oxygen utilization and can induce lipid peroxidation. It was reported that AlP has a mortality rate more than 50% of intoxication cases. Poisoning with AlP has usually occurred in attempts to suicide. It is a more common case in adults rather than teen agers. In some eastern countries it is a very common agent with rapid action for suicide. Up to date, there is no effective antidote or treatment for its intoxication. Also, some experimental results suggest that magnesium sulfate, N-acetyl cysteine (NAC), glutathione, vitamin C and E, beta-carotenes, coconut oil and melatonin may play an important role in reducing the oxidative outcomes of phosphine. This article reviews the experimental and clinical features of AlP intoxication and tries to suggest a way to encounter its poisoning.}, }
@article {pmid23348995, year = {2013}, author = {Rasul, A and Bao, R and Malhi, M and Zhao, B and Tsuji, I and Li, J and Li, X}, title = {Induction of apoptosis by costunolide in bladder cancer cells is mediated through ROS generation and mitochondrial dysfunction.}, journal = {Molecules (Basel, Switzerland)}, volume = {18}, number = {2}, pages = {1418-1433}, pmid = {23348995}, issn = {1420-3049}, mesh = {Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Flow Cytometry ; G2 Phase/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism/*pathology ; Mitosis/drug effects ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/chemistry/*pharmacology ; Urinary Bladder Neoplasms/*metabolism/*pathology ; }, abstract = {Despite the availability of several therapeutic options, a safer and more effective modality is urgently needed for treatment of bladder cancer. Costunolide, a member of sesquiterpene lactone family, possesses potent anticancer properties. In this study, for the first time we investigated the effects of costunolide on the cell viability and apoptosis in human bladder cancer T24 cells. Treatment of T24 cells with costunolide resulted in a dose-dependent inhibition of cell viability and induction of apoptosis which was associated with the generation of ROS and disruption of mitochondrial membrane potential (Δψm). These effects were significantly blocked when the cells were pretreated with N-acetyl- cysteine (NAC), a specific ROS inhibitor. Exposure of T24 cells to costunolide was also associated with increased expression of Bax, down-regulation of Bcl-2, survivin and significant activation of caspase-3, and its downstream target PARP. These findings provide the rationale for further in vivo and clinical investigation of costunolide against human bladder cancer.}, }
@article {pmid23348146, year = {2013}, author = {Tse, HN and Raiteri, L and Wong, KY and Yee, KS and Ng, LY and Wai, KY and Loo, CK and Chan, MH}, title = {High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study.}, journal = {Chest}, volume = {144}, number = {1}, pages = {106-118}, doi = {10.1378/chest.12-2357}, pmid = {23348146}, issn = {1931-3543}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Aged ; Aged, 80 and over ; Antioxidants/adverse effects/*therapeutic use ; *Asian People ; Dose-Response Relationship, Drug ; Double-Blind Method ; Dyspnea/epidemiology/physiopathology ; Female ; Hong Kong ; Humans ; Incidence ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*drug therapy/*physiopathology ; Respiratory Function Tests ; Surveys and Questionnaires ; Treatment Outcome ; Walking/physiology ; }, abstract = {BACKGROUND: The mucolytic and antioxidant effects of N-acetylcysteine (NAC) may have great value in COPD treatment. However, beneficial effects have not been confirmed in clinical studies, possibly due to insufficient NAC doses and/or inadequate outcome parameters used. The objective of this study was to investigate high-dose NAC plus usual therapy in Chinese patients with stable COPD.<br><br>METHODS: The 1-year HIACE (The Effect of High Dose N-acetylcysteine on Air Trapping and Airway Resistance of Chronic Obstructive Pulmonary Disease-a Double-blinded, Randomized, Placebo-controlled Trial) double-blind trial conducted in Kwong Wah Hospital, Hong Kong, randomized eligible patients aged 50 to 80 years with stable COPD to NAC 600 mg bid or placebo after 4-week run-in. Lung function parameters, symptoms, modified Medical Research Council (mMRC) dyspnea and St. George's Respiratory Questionnaire (SGRQ) scores, 6-min walking distance (6MWD), and exacerbation and admission rates were measured at baseline and every 16 weeks for 1 year.<br><br>RESULTS: Of 133 patients screened, 120 were eligible (93.2% men; mean age, 70.8&#xb1;0.74 years; %FEV1 53.9&#xb1;2.0%). Baseline characteristics were similar in the two groups. At 1 year, there was a significant improvement in forced expiratory flow 25% to 75% (P=.037) and forced oscillation technique, a significant reduction in exacerbation frequency (0.96 times/y vs 1.71 times/y, P=.019), and a tendency toward reduction in admission rate (0.5 times/y vs 0.8 times/y, P=.196) with NAC vs placebo. There were no significant between-group differences in mMRC dypsnea score, SGRQ score, and 6MWD. No major adverse effects were reported.<br><br>CONCLUSION: In this study, 1-year treatment with high-dose NAC resulted in significantly improved small airways function and decreased exacerbation frequency in patients with stable COPD.<br><br>TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01136239; URL: www.clinicaltrials.gov.}, }
@article {pmid23341476, year = {2013}, author = {Das, P and Tanious, M and Fritz, K and Dodd, S and Dean, OM and Berk, M and Malhi, GS}, title = {Metabolite profiles in the anterior cingulate cortex of depressed patients differentiate those taking N-acetyl-cysteine versus placebo.}, journal = {The Australian and New Zealand journal of psychiatry}, volume = {47}, number = {4}, pages = {347-354}, doi = {10.1177/0004867412474074}, pmid = {23341476}, issn = {1440-1614}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Aspartic Acid/analogs &amp; derivatives/metabolism ; Depressive Disorder, Major/drug therapy/*metabolism ; Double-Blind Method ; Female ; Free Radical Scavengers/*pharmacology/therapeutic use ; Functional Neuroimaging/*psychology ; Glutamic Acid/metabolism ; Glutamine/metabolism ; Gyrus Cinguli/drug effects/*metabolism ; Humans ; Inositol/metabolism ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; }, abstract = {BACKGROUND: Increased oxidative stress is thought to contribute to the pathophysiology of major depressive disorder (MDD), which is in part due to diminished levels of glutathione, the primary anti-oxidant of the brain. Oral administration of N-acetyl-cysteine (NAC) replenishes glutathione and has therefore been shown to reduce depressive symptoms. Proton magnetic spectroscopy ((1)H-MRS) that allows quantification of brain metabolites pertinent to both MDD and oxidative biology may provide some novel insights into the neurobiological effects of NAC, and in particular metabolite concentrations within the anterior cingulate cortex (ACC) are likely to be important given the key role of this region in the regulation of affect.<br><br>OBJECTIVE: The aim of this study was to determine whether the metabolite profile of the ACC in MDD patients predicts treatment with adjunctive NAC versus placebo.<br><br>METHODS: This study was nested within a multicentre, randomized, double-blind, placebo-controlled study of MDD participants treated with adjunctive NAC. Participants (n = 76) from one site completed the spectroscopy component at the end of treatment (12 weeks). Spectra from a single-voxel in the ACC were acquired and absolute concentrations of glutamate (Glu), glutamate-glutamine (Glx), N-acetyl-aspartate (NAA) and myo-inositol (mI) were obtained. Binary logistic regression analysis was performed to determine whether metabolite profiles could predict NAC versus placebo group membership.<br><br>RESULTS: When predicting group outcome (NAC or placebo), Glx, NAA and mI were a significant model, and had 75% accuracy, while controlling for depression severity and sex. However, the Glu, NAA and mI profile was only predictive at a trend level, with 68.3% accuracy. For both models, the log of the odds of a participant being in the NAC group was positively related to NAA, Glx and Glu levels and negatively related to mI levels.<br><br>CONCLUSION: The finding of higher Glx and NAA levels being predictive of the NAC group provides preliminary support for the putative anti-oxidative role of NAC in MDD.}, }
@article {pmid23340170, year = {2013}, author = {Kausar, H and Munagala, R and Bansal, SS and Aqil, F and Vadhanam, MV and Gupta, RC}, title = {Cucurbitacin B potently suppresses non-small-cell lung cancer growth: identification of intracellular thiols as critical targets.}, journal = {Cancer letters}, volume = {332}, number = {1}, pages = {35-45}, doi = {10.1016/j.canlet.2013.01.008}, pmid = {23340170}, issn = {1872-7980}, mesh = {Acetylcysteine/pharmacology ; Actin Cytoskeleton/drug effects/metabolism ; Animals ; Antineoplastic Agents, Phytogenic/metabolism/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Shape/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Female ; G2 Phase Cell Cycle Checkpoints/drug effects ; Glutathione/metabolism ; HSP27 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins ; Humans ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Mass Spectrometry ; Mice ; Mice, Nude ; Mitochondria/drug effects/metabolism/pathology ; Molecular Chaperones ; Oxidation-Reduction ; Signal Transduction/drug effects ; Spectrophotometry, Ultraviolet ; Spectroscopy, Fourier Transform Infrared ; Sulfhydryl Compounds/*metabolism ; Time Factors ; Triterpenes/metabolism/*pharmacology ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Cucurbitacin B (CuB), has recently emerged as a potent anticancer agent; however, its efficacy in non-small-cell lung cancer (NSCLC) and the mechanism(s) initiating its biological effects remain largely unclear. In this study, CuB potently suppressed the growth of four NSCLC cells (H1299, A549, HCC-827 and H661) in vitro and the highly aggressive H1299 xenograft in vivo. CuB significantly altered the actin cytoskeletal assembly, induced G2/M cell-cycle arrest and mitochondrial apoptosis through the modulation of several key molecular targets mediating the aforementioned processes. Interestingly, all cellular effects of CuB were completely attenuated only by the thiol antioxidant N-acetylcysteine (NAC). Furthermore, pretreatment with glutathione synthesis inhibitor butithione-sulfoxime (BSO), significantly exacerbated CuB's cytotoxic effects. To this end, cells treated with CuB revealed a rapid and significant decrease in the levels of protein thiols and GSH/GSSG ratio, suggesting disruption of cellular redox balance as the primary event in CuB's cytotoxic arsenal. Using UV and FTICR mass spectrometry we also demonstrate for the first time a physical interaction of CuB with NAC and GSH in a cell-free system suggesting that CuB interacts with and modulates cellular thiols to mediate its anti-cancer effects. Collectively, our data sheds new light on the working mechanisms of CuB and demonstrate its therapeutic potential against NSCLC.}, }
@article {pmid23339468, year = {2013}, author = {Kim, S and Cheon, HS and Kim, SY and Juhnn, YS and Kim, YY}, title = {Cadmium induces neuronal cell death through reactive oxygen species activated by GADD153.}, journal = {BMC cell biology}, volume = {14}, number = {}, pages = {4}, pmid = {23339468}, issn = {1471-2121}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; CCAAT-Enhancer-Binding Proteins/metabolism ; Cadmium/chemistry/*toxicity ; Cell Line, Tumor ; Free Radical Scavengers/pharmacology ; Humans ; Neurons/drug effects/*metabolism ; Promoter Regions, Genetic ; Protein Binding/drug effects ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/antagonists &amp; inhibitors/genetics/*metabolism ; bcl-2 Homologous Antagonist-Killer Protein/genetics/metabolism ; }, abstract = {BACKGROUND: Cadmium(Cd), a heavy metal, which has a potent harmful effects, is a highly stress-inducible material that is robustly expressed following disruption of homeostasis in the endoplasmic reticulum (ER) (so-called ER stress). The mechanism Cd induced cell death of neuroblastoma cells complex, involving cellular signaling pathways as yet incompletely defined but, in part, involving the generation of reactive oxygen species (ROS). Several studies have correlated GADD153 expression with cell death, but a mechanistic link between GADD153 and apoptosis has never been demonstrated.<br><br>RESULTS: SH-SY5Y cells were treated Cd led to increase in intracellular ROS levels. ROS generation is not consistent with intracellular [Ca2+]. The exposure of neuroblastoma cells to Cd led to increase in intracellular GADD153 and Bak levels in a doses and time dependent manner. The induction of these genes by Cd was attenuated by NAC. Cd-induced apoptosis is decreased in GADD153 knockdown cells compared with normal cells. The effect of GADD153 on the binding of C/EBP to the Bak promoters were analyzed ChIP assay. Basal constitutive GADD153 recruitment to the -3,398/-3,380 region of the Bak promoter is observed in SH-SY5Y cells.<br><br>CONCLUSIONS: The exposure of SH-SY5Y cells to Cd led to increase in intracellular ROS levels in a doses and time dependent manner. The generation of ROS result in the induction of GADD153 is causative of cadmium-induced apoptosis. GADD153 regulates Bak expression by its binding to promoter region (between -3,398 and -3,380). Therefore, we conclude that GADD153 sensitizes cells to ROS through mechanisms that involve up-regulation of BAK and enhanced oxidant injury.}, }
@article {pmid23338126, year = {2013}, author = {Guo, R and Lin, J and Xu, W and Shen, N and Mo, L and Zhang, C and Feng, J}, title = {Hydrogen sulfide attenuates doxorubicin-induced cardiotoxicity by inhibition of the p38 MAPK pathway in H9c2 cells.}, journal = {International journal of molecular medicine}, volume = {31}, number = {3}, pages = {644-650}, doi = {10.3892/ijmm.2013.1246}, pmid = {23338126}, issn = {1791-244X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Cardiotoxins ; Cell Line ; Cell Survival/drug effects ; Doxorubicin/*adverse effects ; Hydrogen Sulfide/*pharmacology ; Imidazoles/pharmacology ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Myocytes, Cardiac/*drug effects ; Oxidative Stress/drug effects ; Phosphorylation ; Pyridines/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; *p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/biosynthesis/metabolism ; }, abstract = {We previously demonstrated the protective effect of hydrogen sulfide (H2S) against doxorubicin (DOX)-induced cardiotoxicity through inhibition of endoplasmic reticulum stress. The aim of the present study was to explore the role of p38 mitogen-activated protein kinase (MAPK) in DOX-induced cardiotoxicity and ascertain whether exogenous H2S protects DOX-induced injury by inhibiting p38 MAPK in cardiomyoblasts (H9c2). We observed that exposure of H9c2 cells to 5 µM DOX not only markedly induced injuries, including cytotoxicity, apoptosis, overproduction of reactive oxygen species (ROS) and dissipation of mitochondrial membrane potential (MMP), but also enhanced the expression level of phosphorylated (p)-p38 MAPK. The DOX-induced increase in expression of p-p38 MAPK was significantly attenuated by pretreatment of H9c2 cells with either 400 µM sodium hydrogen sulfide (NaHS) (a donor of H2S) or 1,000 µM N-acetyl-L-cysteine (NAC, an ROS scavenger) prior to exposure to DOX. Pretreatment with either 400 µM NaHS or 3 µM SB203580, a selective inhibitor of p38 MAPK, ameliorated DOX-induced cardiomyocyte injuries, as evidenced by an increase in cell viability, and decreases in the number of apoptotic cells, ROS generation as well as dissipation of MMP. In conclusion, the findings of the present study demonstrated that the activation of p38 MAPK contributes to DOX-induced injuries, including cytotoxicity, apoptosis, mitochondrial damage and oxidative stress in H9c2 cells. We also provide novel evidence that exogenous H2S protects H9c2 cells against DOX-induced cardiotoxicity by inhibition of the p38 MAPK pathway.}, }
@article {pmid23335484, year = {2013}, author = {Bozhokina, E and Vakhromova, E and Gamaley, I and Khaitlina, S}, title = {N-acetylcysteine increases susceptibility of HeLa cells to bacterial invasion.}, journal = {Journal of cellular biochemistry}, volume = {114}, number = {7}, pages = {1568-1574}, doi = {10.1002/jcb.24498}, pmid = {23335484}, issn = {1097-4644}, mesh = {Acetylcysteine/*pharmacology ; Bacteria/*metabolism ; Bacterial Proteins/metabolism ; Cytoskeleton/drug effects/metabolism ; Escherichia coli/metabolism/physiology ; HeLa Cells ; Humans ; Metalloproteases/metabolism ; Microscopy, Fluorescence ; Reverse Transcriptase Polymerase Chain Reaction ; Serratia/metabolism/physiology ; }, abstract = {Serratia grimesii are non-pathogenic bacteria capable, however, to invade eukaryotic cells provided that they synthesize intracellular metalloprotease grimelysin (Bozhokina et al. [2011] Cell. Biol. Int. 35: 111-118). To elucidate how invasion of grimelysin containing bacteria depends on physiological state of host cells, we studied the effect of N-acetylcysteine (NAC) on susceptibility of HeLa cells to invasion by the wild-type S. grimesii and recombinant E. coli expressing grimelysin gene. Incubation of HeLa cells with 10 mM NAC resulted in changes of cell morphology and disassembly of actin cytoskeleton that were reversed when NAC was removed from the culture medium. Both in the presence of NAC and upon its removal, the entry of grimelysin producing bacteria increased by a factor of 1.5-2 and 3-3.5 for wild-type S. grimesii and recombinant E. coli, respectively. This effect does not correlate with cytoskeleton rearrangements but may be due to the NAC-induced up-regulation of cell surface receptors playing a role in cell adhesion and cell-cell junctions. A twofold difference in the efficiency of S. grimesii and recombinant E. coli to enter the NAC-treated cells suggests that the entry of the wild-type and recombinant bacteria occurs via different receptors which activity is differently affected by NAC.}, }
@article {pmid23334036, year = {2012}, author = {Tozlovanu, M and Canadas, D and Pfohl-Leszkowicz, A and Frenette, C and Paugh, RJ and Manderville, RA}, title = {Glutathione conjugates of ochratoxin A as biomarkers of exposure.}, journal = {Arhiv za higijenu rada i toksikologiju}, volume = {63}, number = {4}, pages = {417-427}, doi = {10.2478/10004-1254-63-2012-2202}, pmid = {23334036}, issn = {1848-6312}, mesh = {Animals ; Biomarkers/metabolism ; Carcinogens/*metabolism ; DNA Adducts/chemistry/metabolism/toxicity ; Environmental Exposure/*analysis ; Environmental Monitoring/*methods ; Female ; Glutathione/chemistry/*metabolism ; Kidney/*metabolism ; Liver/*metabolism ; Lung/metabolism ; Male ; Mutagens/metabolism/toxicity ; Mycotoxins/chemistry/metabolism/toxicity ; Ochratoxins/chemistry/*metabolism/toxicity ; Rats ; Sex Characteristics ; Toxicity Tests, Chronic ; }, abstract = {In the present study the photoreactivity of the fungal carcinogen ochratoxin A (OTA) has been utilised to generate authentic samples of reduced glutathione (GSH) and N-acetylcysteine (NAC) conjugates of the parent toxin. These conjugates, along with the nontoxic OTα, which is generated through hydrolysis of the amide bond of OTA by carboxypeptidase A, were utilised as biomarkers to study the metabolism of OTA in the liver and kidney of male and female Dark Agouti rats. Male rats are more susceptible than female rats to OTA carcinogenesis with the kidney being the target organ. Our studies show that the distribution of OTA in male and female rat kidney is not significantly different. However, the extent of OTA metabolism was greater in male than female rats. Much higher levels of OTα were detected in the liver compared to the kidney, and formation of OTα is a detoxification pathway for OTA. These findings suggest that differences in metabolism between male and female rats could provide an explanation for the higher sensitivity of male rats to OTA toxicity.}, }
@article {pmid23333652, year = {2013}, author = {Pierre, AS and Minville-Walz, M and Fèvre, C and Hichami, A and Gresti, J and Pichon, L and Bellenger, S and Bellenger, J and Ghiringhelli, F and Narce, M and Rialland, M}, title = {Trans-10, cis-12 conjugated linoleic acid induced cell death in human colon cancer cells through reactive oxygen species-mediated ER stress.}, journal = {Biochimica et biophysica acta}, volume = {1831}, number = {4}, pages = {759-768}, doi = {10.1016/j.bbalip.2013.01.005}, pmid = {23333652}, issn = {0006-3002}, mesh = {Cell Death/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Humans ; Immunohistochemistry ; Linoleic Acids, Conjugated/*pharmacology ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Dietary conjugated linoleic acids (CLA) are fatty acid isomers with anticancer activities produced naturally in ruminants or from vegetable oil processing. The anticancer effects of CLA differ upon the cancer origin and the CLA isomers. In this study, we carried out to precise the effects of CLA isomers, c9,t11 and t10,c12 CLA, on mechanisms of cell death induction in colon cancer cells. We first showed that only t10,c12 CLA treatment (25 and 50μM) for 72h triggered apoptosis in colon cancer cells without affecting viability of normal-derived colon epithelial cells. Exposure of colon cancer cells to t10,c12 CLA activated ER stress characterized by induction of eIF2α phoshorylation, splicing of Xbp1 mRNA and CHOP expression. Furthermore, we evidenced that inhibition of CHOP expression and JNK signaling decreased t10,c12 CLA-mediated cancer cell death. Finally, we showed that CHOP induction by t10,c12 CLA was dependent on ROS production and that the anti-oxidant N-acetyl-cysteine reduced CHOP induction-dependent cell death. These results highlight that t10,c12 CLA exerts its cytotoxic effect through ROS generation and a subsequent ER stress-dependent apoptosis in colon cancer cells.}, }
@article {pmid23333634, year = {2013}, author = {Yao, HD and Wu, Q and Zhang, ZW and Li, S and Wang, XL and Lei, XG and Xu, SW}, title = {Selenoprotein W serves as an antioxidant in chicken myoblasts.}, journal = {Biochimica et biophysica acta}, volume = {1830}, number = {4}, pages = {3112-3120}, doi = {10.1016/j.bbagen.2013.01.007}, pmid = {23333634}, issn = {0006-3002}, support = {R01 DK053018/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cell Survival/drug effects ; Chickens ; Myoblasts/*drug effects/metabolism ; Selenoprotein W/*pharmacology ; }, abstract = {BACKGROUND: Selenoprotein W (SelW) was thought to play an antioxidant role in mammals. Because chicken SelW has no cysteine (Cys) at the residue 37 (Cys37) that is required for the presumed antioxidant function in mammals, this study was conducted to determine whether chicken SelW possessed the same function.<br><br>METHODS: Small interfering RNAs (siRNAs) technology was applied to suppress the SelW expression in chicken embryonic myoblasts. Thereafter, these myoblasts were treated with different concentrations of H2O2 and assayed for cell viability, apoptosis rate, reactive oxygen species (ROS) status, and expression levels of apoptosis-related genes and proteins (Bax, Bcl-2, and caspase-3).<br><br>RESULTS: Silencing of the myoblast SelW gene decreased their cell viability, and increased their apoptosis rate and susceptibility to H2O2. While the knockout down of SelW up-regulated Bax and caspase-3 and down-regulated Bcl-2, the induced oxidative injuries were alleviated by treatment with a ROS scavenger, N-acetyl-l-cysteine (NAC).<br><br>CONCLUSION: Chicken SelW protected embryonic myoblasts against cell apoptosis mediated by endogenous and exogenous H2O2.<br><br>GENERAL SIGNIFICANCE: Chicken SelW possesses antioxidant function similar to the mammalian homologues despite the lack of Cys37 in the peptide.}, }
@article {pmid23328668, year = {2013}, author = {Ahmad, T and Aggarwal, K and Pattnaik, B and Mukherjee, S and Sethi, T and Tiwari, BK and Kumar, M and Micheal, A and Mabalirajan, U and Ghosh, B and Sinha Roy, S and Agrawal, A}, title = {Computational classification of mitochondrial shapes reflects stress and redox state.}, journal = {Cell death &amp; disease}, volume = {4}, number = {1}, pages = {e461}, pmid = {23328668}, issn = {2041-4889}, mesh = {Acetylcysteine/pharmacology ; *Algorithms ; Anti-Bacterial Agents/pharmacology ; Antimycin A/analogs &amp; derivatives/pharmacology ; Antioxidants/pharmacology ; Calcium/metabolism ; Cell Line ; Flow Cytometry ; Humans ; Mitochondria/*classification/drug effects/metabolism ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Rotenone/pharmacology ; }, abstract = {Dynamic variations in mitochondrial shape have been related to function. However, tools to automatically classify and enumerate mitochondrial shapes are lacking, as are systematic studies exploring the relationship of such shapes to mitochondrial stress. Here we show that during increased generation of mitochondrial reactive oxygen species (mtROS), mitochondria change their shape from tubular to donut or blob forms, which can be computationally quantified. Imaging of cells treated with rotenone or antimycin, showed time and dose-dependent conversion of tubular forms to donut-shaped mitochondria followed by appearance of blob forms. Time-lapse images showed reversible transitions from tubular to donut shapes and unidirectional transitions between donut and blob shapes. Blobs were the predominant sources of mtROS and appeared to be related to mitochondrial-calcium influx. Mitochondrial shape change could be prevented by either pretreatment with antioxidants like N-acetyl cysteine or inhibition of the mitochondrial calcium uniporter. This work represents a novel approach towards relating mitochondrial shape to function, through integration of cellular markers and a novel shape classification algorithm.}, }
@article {pmid23325162, year = {2013}, author = {Singh, S and Hynan, LS and Lee, WM and , }, title = {Improvements in hepatic serological biomarkers are associated with clinical benefit of intravenous N-acetylcysteine in early stage non-acetaminophen acute liver failure.}, journal = {Digestive diseases and sciences}, volume = {58}, number = {5}, pages = {1397-1402}, pmid = {23325162}, issn = {1573-2568}, support = {R01 DK058369/DK/NIDDK NIH HHS/United States ; U01 DK058369/DK/NIDDK NIH HHS/United States ; DK-058369/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Biomarkers/*blood ; Coma/blood/etiology/mortality/therapy ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Infusions, Intravenous ; Liver Failure, Acute/*blood/complications/mortality/*therapy ; Liver Function Tests ; Liver Transplantation ; Male ; Prospective Studies ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) improves transplant-free survival in early coma grade (I-II) patients with non-acetaminophen induced acute liver failure (ALF). We determined whether the clinical benefit was associated with improvements in hepatic function.<br><br>METHODS: In a prospective, double blind trial, 173 ALF patients without evidence of acetaminophen overdose were stratified by coma grade (I-II vs. III-IV) and randomly assigned to receive either intravenous NAC or dextrose (placebo) for 72 h, resulting in four patient groups. INR, ALT, bilirubin, creatinine, and AST obtained on admission (day 1) and subsequent days (days 2-4) were used for secondary analysis performed by fitting longitudinal logistic regression models to predict death or transplantation or transplantation alone.<br><br>RESULTS: Treatment group and day of study in models including bilirubin or ALT were predictors of transplantation or death (maximum p < 0.03). Those patients with early coma grade who were treated with NAC showed significant improvement in bilirubin and ALT levels when compared to the other three groups (maximum p < 0.02 for NAC 1-2 vs. the 3 other treatments) when predicting death or transplantation. Treatment group, day of study, and bilirubin were predictors of transplantation (maximum p < 0.03) in ALF patients.<br><br>CONCLUSION: The decreased risk of transplantation or death or of transplantation alone with intravenous NAC in early coma grade patients with non-acetaminophen induced ALF was reflected in improvement in parameters related to hepatocyte necrosis and bile excretion including ALT and bilirubin, but not in INR, creatinine, or AST. Hepatic recovery appears hastened by NAC as measured by several important lab values.}, }
@article {pmid23322302, year = {2013}, author = {Nicolay, BN and Gameiro, PA and Tschöp, K and Korenjak, M and Heilmann, AM and Asara, JM and Stephanopoulos, G and Iliopoulos, O and Dyson, NJ}, title = {Loss of RBF1 changes glutamine catabolism.}, journal = {Genes &amp; development}, volume = {27}, number = {2}, pages = {182-196}, pmid = {23322302}, issn = {1549-5477}, support = {F32 CA165856/CA/NCI NIH HHS/United States ; R01 CA122591/CA/NCI NIH HHS/United States ; C06 CA059267/CA/NCI NIH HHS/United States ; R01 CA163698/CA/NCI NIH HHS/United States ; R01 CA160458/CA/NCI NIH HHS/United States ; F32CA165856/CA/NCI NIH HHS/United States ; R01 GM084947/GM/NIGMS NIH HHS/United States ; R01-GM084947/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis ; Cell Line, Tumor ; DNA Damage ; Drosophila Proteins/*genetics/*metabolism ; Drosophila melanogaster/*genetics/*metabolism ; Fasting/metabolism ; Glutamine/*biosynthesis ; Glutathione/biosynthesis ; Humans ; Larva ; Mutation ; Nucleotides/biosynthesis ; Oxidative Stress ; Retinoblastoma Protein ; Stress, Physiological ; Transcription Factors/*genetics/*metabolism ; }, abstract = {Inactivation of the retinoblastoma tumor suppressor (pRB) alters the expression of a myriad of genes. To understand the altered cellular environment that these changes create, we took advantage of the Drosophila model system and used targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) to profile the metabolic changes that occur when RBF1, the fly ortholog of pRB, is removed. We show that RBF1-depleted tissues and larvae are sensitive to fasting. Depletion of RBF1 causes major changes in nucleotide synthesis and glutathione metabolism. Under fasting conditions, these changes interconnect, and the increased replication demand of RBF1-depleted larvae is associated with the depletion of glutathione pools. In vivo (13)C isotopic tracer analysis shows that RBF1-depleted larvae increase the flux of glutamine toward glutathione synthesis, presumably to minimize oxidative stress. Concordantly, H(2)O(2) preferentially promoted apoptosis in RBF1-depleted tissues, and the sensitivity of RBF1-depleted animals to fasting was specifically suppressed by either a glutamine supplement or the antioxidant N-acetyl-cysteine. Effects of pRB activation/inactivation on glutamine catabolism were also detected in human cell lines. These results show that the inactivation of RB proteins causes metabolic reprogramming and that these consequences of RBF/RB function are present in both flies and human cell lines.}, }
@article {pmid23320127, year = {2012}, author = {Mendivil-Perez, M and Velez-Pardo, C and Jimenez-Del-Rio, M}, title = {TPEN induces apoptosis independently of zinc chelator activity in a model of acute lymphoblastic leukemia and ex vivo acute leukemia cells through oxidative stress and mitochondria caspase-3- and AIF-dependent pathways.}, journal = {Oxidative medicine and cellular longevity}, volume = {2012}, number = {}, pages = {313275}, pmid = {23320127}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor/*metabolism ; Caspase 3/*metabolism ; Cell Nucleus/drug effects/metabolism ; Chelating Agents/pharmacology ; Chromatin/metabolism ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Ethylenediamines/*pharmacology ; Female ; Glucose/pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Jurkat Cells ; Membrane Potential, Mitochondrial/drug effects ; Middle Aged ; Mitochondria/drug effects/enzymology ; Oxidative Stress/*drug effects ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology/*pathology ; Signal Transduction/drug effects ; Superoxides/metabolism ; Time Factors ; Transcription Factors/metabolism ; Zinc/*pharmacology ; }, abstract = {Acute lymphoblastic leukemia is still an incurable disease with resistance to therapy developing in the majority of patients. We investigated the effect of TPEN, an intracellular zinc chelator, in Jurkat and in ex vivo acute lymphoblastic leukemia (ALL) cells resistant to chemotherapy. Changes of nuclei morphology, reactive oxygen species generation, presence of hypodiploid cells, phosphatidylserine translocation, mitochondrial membrane depolarization, immunohistochemical identification of cell death signalling molecules, and pharmacological inhibition were assayed to detect the apoptotic cell death pathways. We found that TPEN induces apoptosis in both types of cells by a molecular oxidative stress pathway involving O(2)(•-) > H(2)O(2) >> NF-κB (JNK/c-Jun) >p53> loss ΔΨ(m)> caspase-3, AIF > chromatin condensation/DNA fragmentation. Interestingly, TPEN induced apoptosis independently of glucose; leukemic cells are therefore devoid of survival capacity by metabolic resistance to treatment. Most importantly, TPEN cytotoxic effect can eventually be regulated by the antioxidant N-acetyl-cysteine and zinc ions. Our data suggest that TPEN can be used as a potential therapeutic prooxidant agent against refractory leukemia. These data contribute to understanding the importance of oxidative stress in the treatment of ALL.}, }
@article {pmid23319348, year = {2012}, author = {Berniakovich, I and Laricchia-Robbio, L and Izpisua Belmonte, JC}, title = {N-acetylcysteine protects induced pluripotent stem cells from in vitro stress: impact on differentiation outcome.}, journal = {The International journal of developmental biology}, volume = {56}, number = {9}, pages = {729-735}, doi = {10.1387/ijdb.120070ji}, pmid = {23319348}, issn = {1696-3547}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Cell Differentiation/*drug effects ; Cellular Senescence/drug effects ; Free Radical Scavengers/*pharmacology ; Humans ; Induced Pluripotent Stem Cells/*drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Nitric Oxide/metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Induced pluripotent stem cells (iPSCs) have the ability to differentiate towards various cell types of the adult organism and are a potential source of transplantable material in regenerative medicine. The entire process of conversion of iPSCs into terminally differentiated cells takes place in vitro and requires long periods of time. During in vitro culture, cells are exposed to environmental factors, which are capable of decreasing cellular performance and viability. Oxidative stress is the major underlying mechanism of such negative impact of in vitro environmental factors. We aimed to study the alteration of cellular properties during in vitro hematopoietic differentiation of human iPSCs and the ability of N-acetylcysteine (NAC), a potent free radical scavenger, to prevent such alterations. IPSCs were differentiated towards hematopoietic cells in the presence of 1 mM NAC. Intracellular reactive oxygen species (ROS), nitric oxide (NO), senescence, apoptosis and mitochondrial membrane potential (MMP) were evaluated at 1 and 3 weeks of differentiation. In the course of hematopoietic differentiation of iPSCs, cells progressively accumulated intracellular ROS and NO, increased the levels of apoptosis and senescence, and showed a decrease in mitochondrial functionality. NAC supplementation reversed all these phenomena. NAC administration also improved hematopoietic differentiation of iPSCs in terms of production of CD34, CD45 and CD43 positive cells. In conclusion, when supplemented during hematopoietic differentiation of iPSCs, NAC decreased oxidative stress, rescued the decline in cellular properties induced by long-term in vitro culture and promoted hematopoietic differentiation of iPSCs.}, }
@article {pmid23319318, year = {2013}, author = {Koo, TY and Kim, YJ and Yang, WS and Park, JS and Han, NJ and Lee, JM and Park, SK}, title = {Mycophenolic acid regulates spleen tyrosine kinase to repress tumour necrosis factor-alpha-induced monocyte chemotatic protein-1 production in cultured human aortic endothelial cells.}, journal = {Cell biology international}, volume = {37}, number = {1}, pages = {19-28}, doi = {10.1002/cbin.10003}, pmid = {23319318}, issn = {1095-8355}, mesh = {Anti-Inflammatory Agents/*pharmacology ; Aorta/cytology/metabolism ; Chemokine CCL2/*biosynthesis ; Endothelial Cells/cytology/*drug effects/metabolism ; Endothelium, Vascular/cytology/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/*genetics/metabolism ; Mycophenolic Acid/*pharmacology ; NF-kappa B/metabolism ; Protein-Tyrosine Kinases/*genetics/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Syk Kinase ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*genetics/metabolism ; }, abstract = {Atherosclerosis develops from cascades of inflammatory processes. Spleen tyrosine kinase (Syk) and monocyte chemotatic protein-1 (MCP-1) play important roles in the pathogenesis of atherosclerosis. Mycophenolic acid (MPA) has an anti-inflammatory effect. We have investigated whether MPA regulates Syk to repress tumour necrosis factor-α (TNF-α)-induced MCP-1 production in cultured human aortic endothelial cells. Expression of MCP-1 mRNA and its protein were measured by real time RT-PCR and ELISA, respectively. Reactive oxygen species (ROS) production were measured using 2'7'-dichlorofluorescein diacetate. Activation of AP-1 and NF-κB were assessed by electrophoretic mobility shift assay. Tyrosine phosphorylation of Syk was examined by Western blot analysis. TNF-α increased MCP-1 at both mRNA and protein levels. TNF-α-induced MCP-1 mRNA expression was inhibited by N-acetylcysteine (NAC), Syk inhibitor, Syk-siRNA and MPA. TNF-α-induced MCP-1 protein production was also inhibited by Syk inhibitor and MPA. TNF-α increased DNA binding activity of AP-1 and NF-κB, whereas both AP-1 and NF-κB decoy oligodeoxynucleotides downregulated TNF-α-induced MCP-1 mRNA expression. TNF-α increased ROS generation, which was inhibited by NAC and MPA, but not by Syk inhibitor. TNF-α increased tyrosine phosphorylation of Syk, which was attenuated by NAC and MPA. MPA and Syk inhibitor attenuated TNF-α-induced DNA binding activity of NF-κB and AP-1. TNF-α induced MCP-1 expression via activation of AP-1 and NF-κB. AP-1 and NF-κB were mediated through ROS, followed by Syk. MPA exerts anti-inflammatory effect by inhibiting MCP-1 expression via suppression of ROS and Syk.}, }
@article {pmid23313471, year = {2013}, author = {Erne, BV and Jungraithmayr, W and Buschmann, J and Arni, S and Weder, W and Inci, I}, title = {Effect of N-acetylcysteine on acute allograft rejection after rat lung transplantation.}, journal = {The Annals of thoracic surgery}, volume = {95}, number = {3}, pages = {1021-1027}, doi = {10.1016/j.athoracsur.2012.11.008}, pmid = {23313471}, issn = {1552-6259}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Animals ; Antigens, CD/immunology/metabolism ; Antigens, Differentiation, Myelomonocytic/immunology/metabolism ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Graft Rejection/etiology/immunology/*prevention &amp; control ; Immunity, Innate/*drug effects ; Immunohistochemistry ; *Lung Transplantation ; Macrophages, Alveolar/immunology/metabolism ; Male ; Rats ; Rats, Inbred BN ; Rats, Inbred Lew ; Receptors, Cell Surface/immunology/metabolism ; Receptors, Scavenger ; Reperfusion Injury/complications/*drug therapy/pathology ; T-Lymphocytes/immunology/metabolism ; Transplantation, Homologous ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) attenuates ischemia-reperfusion injury after lung transplantation in animal models. The purpose of this study is to evaluate a protective effect of NAC against acute lung rejection.<br><br>METHODS: Rat single-lung transplantation was performed in four groups (n = 7 per group). In NAC groups, donors and recipients received NAC 150 mg/kg per day intraperitoneally before transplantation and recipients thereafter until euthanasia. Control groups (CON) received 0.5 mL of 0.9% saline solution intraperitoneally instead of NAC. Animals were euthanized on day 1 (CON1, NAC1) or day 5 (CON5, NAC5) after transplantation. Lung tissue was assessed by histology, immunohistochemistry for CD68+/CD163+ macrophages and CD3+ T cells, immunofluorescence for interleukin 4 and interleukin 12, concentration of reduced glutathione, and activated nuclear factor-kappa B.<br><br>RESULTS: CD68+ macrophages in CON5 accumulated significantly compared with NAC5 grafts (p < 0.001). No significant difference was observed for CD163+ macrophages on day 5. T cells were significantly more frequent in NAC1 (p < 0.001), but significantly less in NAC5 (p < 0.001) compared with control groups, respectively. Interleukin 4 and interleukin 12 expression did not differ between groups. Treatment with NAC significantly influenced glutathione levels (p = 0.019) and reduced nuclear factor-kappa B activation (p = 0.034) in transplanted lungs.<br><br>CONCLUSIONS: N-Acetylcysteine has the potential to attenuate acute pulmonary rejection by reduction of macrophage and T-cell infiltration, which is intimately linked to a reduced action of the nuclear factor-kappa B proinflammatory signaling pathway. In view of these observations, NAC should be considered a promising substance that could play a role in strategies for the prevention of acute rejection.}, }
@article {pmid23307413, year = {2013}, author = {Yang, CM and Hsieh, HL and Lin, CC and Shih, RH and Chi, PL and Cheng, SE and Hsiao, LD}, title = {Multiple factors from bradykinin-challenged astrocytes contribute to the neuronal apoptosis: involvement of astroglial ROS, MMP-9, and HO-1/CO system.}, journal = {Molecular neurobiology}, volume = {47}, number = {3}, pages = {1020-1033}, pmid = {23307413}, issn = {1559-1182}, mesh = {Animals ; Apoptosis/*drug effects ; Astrocytes/drug effects/*metabolism ; Bradykinin/*pharmacology ; Carbon Monoxide/metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; Culture Media, Conditioned/pharmacology ; Enzyme Induction/drug effects ; Heme Oxygenase-1/biosynthesis/*metabolism ; Humans ; Matrix Metalloproteinase 9/*metabolism ; Neurons/*cytology/drug effects/enzymology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Bradykinin (BK) has been shown to induce the expression of several inflammatory mediators, including reactive oxygen species (ROS) and matrix metalloproteinases (MMPs), in brain astrocytes. These mediators may contribute to neuronal dysfunction and death in various neurological disorders. However, the effects of multiple inflammatory mediators released from BK-challenged astrocytes on neuronal cells remain unclear. Here, we found that multiple factors were released from brain astrocytes (RBA-1) exposed to BK in the conditioned culture media (BK-CM), including ROS, MMP-9, and heme oxygenase-1 (HO-1)/carbon monoxide (CO), leading to neuronal cell (SK-N-SH) death. Exposure of SK-N-SH cells to BK-CM or H2O2 reduced cell viability and induced cell apoptosis which were attenuated by N-acetyl cysteine, indicating a role of ROS in these responses. The effect of BK-CM on cell viability and cell apoptosis was also reversed by immunoprecipitation of BK-CM with anti-MMP-9 antibody (MMP-9-IP-CM) or MMP2/9 inhibitor, suggesting the involvement of MMP-9 in BK-CM-mediated responses. Astroglial HO-1/CO in BK-CM induced cell apoptosis and reduced cell viability which was reversed by hemoglobin. Consistently, the involvement of CO in these cellular responses was revealed by incubation with a CO donor CO-RM2 which was reversed by hemoglobin. The role of HO-1 in BK-CM-induced responses was confirmed by overexpression of HO-1 in SK-N-SH infected with Adv-HO-1. BK-CM-induced cell apoptosis was due to the activation of caspase-3 and cleavage of PARP. Together, we demonstrate that BK-induced several neurotoxic factors, including ROS, MMP-9, and CO released from astrocytes, may induce neuronal death through a caspase-3-dependent apoptotic pathway.}, }
@article {pmid23307410, year = {2013}, author = {Guibas, GV and Spandou, E and Meditskou, S and Vyzantiadis, TA and Priftis, KN and Anogianakis, G}, title = {N-acetylcysteine exerts therapeutic action in a rat model of allergic rhinitis.}, journal = {International forum of allergy &amp; rhinology}, volume = {3}, number = {7}, pages = {543-549}, doi = {10.1002/alr.21145}, pmid = {23307410}, issn = {2042-6984}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Administration, Intranasal ; Allergens/administration &amp; dosage ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Cyclooxygenase 2/immunology ; Disease Models, Animal ; Male ; Nasal Mucosa/immunology/pathology ; Nitric Oxide Synthase Type II/immunology ; Ovalbumin/administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; Rhinitis, Allergic ; Rhinitis, Allergic, Perennial/*drug therapy/immunology/pathology ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: The pathophysiologic mechanism of allergy is dependent on the action of many redox-sensitive proinflammatory mediators. However, even though redox disturbances are believed to be a hallmark of inflammation, little is known of the effect of redox imbalance to the pathophysiology of allergic rhinitis. We thus opted to investigate the relation of oxidative stress and allergic rhinitis, through the utilization of a potent antioxidant substance (N-acetylcysteine [NAC]) in a rat model of allergic rhinitis and the evaluation of its action on specific markers of inflammation.<br><br>METHODS: NAC (50 mg/kg and 250 mg/kg) was intraperitoneally administered to ovalbumin (OVA)-sensitized rats prior to intranasal challenge with OVA. Mucosal congregation of inflammatory cells (eosinophils and mast cells), mucosal expression of redox-sensitive enzymes (inducible nitric oxide synthase [iNOS] and cyclooxygenase 2 [COX-2]), and the blood levels of a key proinflammatory mediator (tumor necrosis factor-&#x3b1; [TNF-&#x3b1;]) were evaluated.<br><br>RESULTS: Intranasal OVA challenges lead to mucosal inflammation, induction of the mucosal expression of iNOS and COX-2 and elevation of TNF-&#x3b1; blood levels. NAC significantly inhibited accumulation of inflammatory cells and downregulated iNOS expression and TNF-&#x3b1; serum levels. The role of COX-2 appeared to be 2-fold and its expression was divergently modulated by NAC.<br><br>CONCLUSION: Our findings suggest that redox balance is involved in the pathophysiology of allergic rhinitis in rats and that NAC can potentially suppress the allergen-induced nasal inflammatory cascade. The investigation of the role of oxidative stress in atopy could help in the evaluation of the therapeutic potential of antioxidant substances in allergic diseases.}, }
@article {pmid23307329, year = {2013}, author = {Çağlar, Y and Özgür, H and Matur, I and Yenilmez, ED and Tuli, A and Gönlüşen, G and Polat, S}, title = {Ultrastructural evaluation of the effect of N-acetylcysteine on methotrexate nephrotoxicity in rats.}, journal = {Histology and histopathology}, volume = {28}, number = {7}, pages = {865-874}, doi = {10.14670/HH-28.865}, pmid = {23307329}, issn = {1699-5848}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Urea Nitrogen ; Creatinine/blood ; Glutathione Peroxidase/metabolism ; Immunohistochemistry ; Ki-67 Antigen/metabolism ; Kidney/*drug effects/ultrastructure ; Kidney Glomerulus/drug effects ; Male ; Malondialdehyde/blood ; Methotrexate/*toxicity ; Rats ; Rats, Wistar ; Renal Insufficiency/*chemically induced ; Superoxide Dismutase/metabolism ; }, abstract = {The aim of this study is to investigate the possible protective effect of N-Acetylcysteine (NAC) against the likely methotrexate (MTX) toxicity on the kidney using ultrastructural together with biochemical data. Moreover, the immunohistochemical detection of Ki67 nuclear antigen is to be evaluated. Fifteen male Wistar albino rats, weighing 240-290 g, were divided into three equal groups: Rats receiving MTX alone, rats receiving MTX plus NAC treatment, and rats comprising the control group. MTX (18 mg/kg/day, body weight) in dissolved physiologic saline was administered intraperitoneally to rats during 3 days. For the MTX plus NAC group, N-Acetylcysteine (300 mg/kg/day, body weight) was administered together with MTX. At the end of the third day, all the rats were killed with cervical dislocation to obtain blood and tissue samples. Application of MTX principally induced prominent large vacuolization in the proximal convoluted tubule cells, and focal thickening in the glomerular basal lamina of some glomeruli. A decrease in tissue SOD (superoxide dismutase) and GSH-Px (glutathione peroxidase), and an increase in serum urea nitrogen and creatinine and in tissue MDA (malondialdehyde) levels were also seen in the MTX group. These changes were significantly reversed in the MTX-plus-NAC-treated group. Most of the vacuoles in the proximal convoluted tubule cells disappeared. Furthermore, an increase in antioxidant enzyme activities, a decrease in serum urea nitrogen and creatinine, and tissue MDA levels were all significant. Additionally, an increase in the number of Ki67 positive-stained cells in proximal tubules was also noted. In conclusion, NAC may be a promising substance against MTX-induced renal damage. It might be useful to use NAC supplementally to minimize MTX-induced nephrotoxicity.}, }
@article {pmid23305708, year = {2013}, author = {Birukova, AA and Starosta, V and Tian, X and Higginbotham, K and Koroniak, L and Berliner, JA and Birukov, KG}, title = {Fragmented oxidation products define barrier disruptive endothelial cell response to OxPAPC.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {161}, number = {6}, pages = {495-504}, pmid = {23305708}, issn = {1878-1810}, support = {R01 HL107920/HL/NHLBI NIH HHS/United States ; R01 HL076259/HL/NHLBI NIH HHS/United States ; HL064731/HL/NHLBI NIH HHS/United States ; HL087823/HL/NHLBI NIH HHS/United States ; HL076259/HL/NHLBI NIH HHS/United States ; R01 HL064731/HL/NHLBI NIH HHS/United States ; HL107920/HL/NHLBI NIH HHS/United States ; R56 HL107920/HL/NHLBI NIH HHS/United States ; R01 HL087823/HL/NHLBI NIH HHS/United States ; }, mesh = {Blood-Air Barrier/*drug effects/metabolism ; Capillary Permeability/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Electric Impedance ; Electrochemical Techniques ; Endothelium, Vascular/*drug effects/metabolism ; Humans ; Oxidation-Reduction ; Phosphatidylcholines/*pharmacology ; }, abstract = {Excessive concentrations of oxidized phospholipids (OxPL), the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (PAPC) oxidation have been detected in atherosclerosis, septic inflammation, and acute lung injury (ALI) and have been shown to induce vascular barrier dysfunction. In contrast, oxidized PAPC (OxPAPC) at low concentrations exhibit potent barrier protective effects. The nature of such biphasic effects remains unclear. We tested the hypothesis that barrier-disruptive effects of high OxPAPC doses on endothelial cell (EC) monolayer are defined by fragmented products of PAPC oxidation (lysophosphatidyl choline [lyso-PC], 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-phosphatidylcholine [POVPC], 1-palmitoyl-2-glutaroyl-sn-glycero-phosphatidylcholine [PGPC]), whereas barrier enhancing effects are mediated by full length oxidated PAPC products and may be reproduced by single compounds contained in the OxPAPC such as 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphatidyl choline (PEIPC). All 3 fragmented OxPAPC products increased EC permeability in a dose-dependent manner, whereas PEIPC decreased it and reversed barrier disruptive effects of lyso-PC, POVPC, and PGPC monitored by measurements of transendothelial electrical resistance. Immunofluorescence staining and western blot analysis showed that PGPC mimicked the cytoskeletal remodeling and tyrosine phosphorylation of adherens junction (AJ) protein vascular endothelial (VE)-cadherin leading to EC barrier dysfunction induced by high OxPAPC concentrations. Barrier-disruptive effects of PGPC were abrogated by reactive oxygen species (ROS) inhibitor, N-acetyl cysteine, or Src kinase inhibitor, PP-2. The results of this study show that barrier disruptive effects of fragmented OxPAPC constituents (lyso-PC, POVPC, PGPC) are balanced by barrier enhancing effects of full length oxygenated products (PEIPC). These data strongly suggest that barrier disruptive effects of OxPAPC at higher concentrations are dictated by predominant effects of fragmented phospholipids such as PGPC, which promote ROS-dependent activation of Src kinase and VE-cadherin phosphorylation at Tyr(658) and Tyr(731) leading to disruption of endothelial cell AJs.}, }
@article {pmid23305704, year = {2013}, author = {Sunitha, K and Suresh, P and Santhosh, MS and Hemshekhar, M and Thushara, RM and Marathe, GK and Thirunavukkarasu, C and Kemparaju, K and Kumar, MS and Girish, KS}, title = {Inhibition of hyaluronidase by N-acetyl cysteine and glutathione: role of thiol group in hyaluronan protection.}, journal = {International journal of biological macromolecules}, volume = {55}, number = {}, pages = {39-46}, doi = {10.1016/j.ijbiomac.2012.12.047}, pmid = {23305704}, issn = {1879-0003}, mesh = {Acetylcysteine/chemistry/metabolism/*pharmacology ; Animals ; Enzyme Inhibitors/chemistry/metabolism/pharmacology ; Glutathione/chemistry/metabolism/*pharmacology ; Hyaluronoglucosaminidase/*antagonists &amp; inhibitors/chemistry/metabolism ; Kinetics ; Molecular Conformation ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Binding ; }, abstract = {Hyaluronidase inhibitors have immense applications in pathophysiological conditions associated with hyaluronan-hyaluronidase system. The present study demonstrates the inhibitory efficacy of clinically accepted antioxidant N-acetyl cysteine (NAC) against hyaluronidase of serum, testis, and snake and bee venoms. The experimental and molecular dynamic simulation data suggest the non-competitive inhibition and involvement of thiol groups of both NAC and glutathione in exertion of inhibition. The bioavailability, less-toxic and antioxidant nature of NAC and glutathione could become valuable in the management of pathologies triggered by extracellular matrix degradation and to increase the endurance of hyaluronan based biomaterials/supplements, which are highly exciting aspects.}, }
@article {pmid23302579, year = {2013}, author = {Raverdy, V and Ampe, E and Hecq, JD and Tulkens, PM}, title = {Stability and compatibility of vancomycin for administration by continuous infusion.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {68}, number = {5}, pages = {1179-1182}, doi = {10.1093/jac/dks510}, pmid = {23302579}, issn = {1460-2091}, mesh = {Anti-Bacterial Agents/administration &amp; dosage/*chemistry/*pharmacokinetics ; Bacterial Infections/drug therapy ; Drug Stability ; Humans ; Infusions, Intravenous/methods ; Vancomycin/administration &amp; dosage/*chemistry/*pharmacokinetics ; }, abstract = {BACKGROUND: Vancomycin is increasingly used by continuous infusion, but few specific data are available about stability under practical conditions of preparation and use, and compatibility with other intravenous drugs commonly used in the routine hospital setting.<br><br>METHODS: Vancomycin stability [defined as recovery &#x2265;&#x200a;93% of the original content (validated HPLC assay)] was examined throughout the whole process of centralized preparation, storage and use in the ward by infusion for up to 48 h, with allowances for deviations from recommended practice [exposure to high temperature; use of concentrated solutions (up to 83 g/L)]. Compatibility was assessed by mimicking co-administration in a single line via Y-shaped connectors with contact of 1 h at 25&#xb0;C, followed by visual inspection (professional viewer), detection of particulate matter (particle analyser) and HPLC assay of vancomycin.<br><br>RESULTS: Vancomycin was stable during the whole process and also during 72 h exposure of concentrated solutions at temperatures up to 37&#xb0;C. Major incompatibilities were seen with &#x3b2;-lactams (temocillin, piperacillin/tazobactam, ceftazidime, imipenem, cefepime and flucloxacillin) and moxifloxacin, but not with ciprofloxacin, aminoglycosides and macrolides. Propofol, valproic acid, phenytoin, theophylline, methylprednisolone and furosemide were also incompatible, whereas ketamine, sufentanil, midazolam, morphine, piritramide, nicardipine, urapidil, dopamine, dobutamine and adrenaline were compatible. No effect or incompatibility with N-acetyl-cysteine or amino acid solutions was detected.<br><br>CONCLUSIONS: Centralized preparation of vancomycin and its use by continuous infusion in wards is safe concerning stability, but careful attention must be paid to incompatibilities. Several drugs (including all &#x3b2;-lactams) require distinct intravenous lines or appropriate procedures to avoid undue contact.}, }
@article {pmid23299316, year = {2013}, author = {Ryu, MJ and Kim, AD and Kang, KA and Chung, HS and Kim, HS and Suh, IS and Chang, WY and Hyun, JW}, title = {The green algae Ulva fasciata Delile extract induces apoptotic cell death in human colon cancer cells.}, journal = {In vitro cellular &amp; developmental biology. Animal}, volume = {49}, number = {1}, pages = {74-81}, pmid = {23299316}, issn = {1543-706X}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Colonic Neoplasms/*drug therapy ; DNA Fragmentation/drug effects ; HCT116 Cells ; Humans ; Mitochondrial Membranes/drug effects ; Plant Extracts/antagonists &amp; inhibitors/*pharmacology ; Reactive Oxygen Species/metabolism ; Ulva/*chemistry ; }, abstract = {This study investigated the mechanisms underlying the cytotoxicity of the green algae Ulva fasciata Delile. U. fasciata extract (UFE) inhibited the growth of HCT 116 human colon cancer cells by 50% at a concentration of 200 μg/ml. In addition, UFE stimulated the production of intracellular reactive oxygen species, an effect that was abolished by pretreatment with N-acetyl cysteine, which also inhibited the cytotoxic effects of UFE. UFE also induced morphological changes indicative of apoptosis, such as the formation of apoptotic bodies, DNA fragmentation, an increase in the population of apoptotic sub-G(1) phase cells, and mitochondrial membrane depolarization. Concomitant activation of the mitochondria-dependent apoptotic pathway occurred via modulation of Bax and Bcl-2 expression, resulting in disruption of the mitochondrial membrane potential and activation of caspase-9 and caspase-3. This is the first report to demonstrate the cytotoxic effect of U. fasciata on human colon cancer cells and to provide a possible mechanism for this activity.}, }
@article {pmid23299230, year = {2013}, author = {Williamson, K and Wahl, MS and Mycyk, MB}, title = {Direct comparison of 20-hour IV, 36-hour oral, and 72-hour oral acetylcysteine for treatment of acute acetaminophen poisoning.}, journal = {American journal of therapeutics}, volume = {20}, number = {1}, pages = {37-40}, doi = {10.1097/MJT.0b013e318250f829}, pmid = {23299230}, issn = {1536-3686}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/therapeutic use ; Acute Disease ; Administration, Oral ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*administration &amp; dosage/therapeutic use ; Child ; Drug Administration Schedule ; Drug Overdose/*drug therapy ; Female ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; Young Adult ; }, abstract = {There is no general consensus among clinicians on the superior route or duration of treatment with N-acetylcysteine (NAC) for acute acetaminophen (APAP) poisoning, and head-to-head studies comparing intravenous (IV) and oral NAC have not been done. Recent 20-hour IV NAC protocol failures in the United States prompted some to question its safety. Our objective was to determine if treatment with the 20-hour IV NAC protocol results in clinical outcomes different from the longer 36-hour oral or 72-hour oral NAC protocols in cases of acute APAP poisoning. We performed a retrospective analysis of all consecutive cases of acute APAP overdose where NAC treatment was initiated within 8 hours of ingestion between January 1, 2002, and December 31, 2007. Outcomes were survival, transplant, and death; secondary outcomes were based on King's College Criteria; interrater reliability was calculated with a kappa score. Out of 4642 cases of APAP overdose, 795 met study inclusion criteria: 213 were treated with 20-hour IV protocol, 213 with the 36-hour oral protocol, and 369 with the 72-hour oral protocol. The mean age in these groups was 25 years [95% confidence interval (CI): 22-26], 26 years (95%CI: 23-29), and 27 years (95%CI: 25-28), respectively. The mean 4-hour APAP concentration was 199 μg/mL (95%CI: 188-211), 174 μg/mL (95%CI: 164-184), and 205 μg/mL (95%CI: 195-216), respectively. No cases of transplant or death occurred, and secondary outcomes were rare. When administered within 8 hours of acute APAP poisoning, the 20-hour IV treatment protocol was as effective as the longer 36-hour oral and 72-hour oral treatment protocols. Further study is needed to determine outcome differences between IV and oral NAC when treatment is initiated >8 hours after overdose or in cases of coingestion with other drugs.}, }
@article {pmid23299189, year = {2015}, author = {El-Sisi, Ael-D and El-Syaad, ME and El-Desoky, KI and Moussa, EA}, title = {Protective effects of alpha lipoic acid versus N-acetylcysteine on ifosfamide-induced nephrotoxicity.}, journal = {Toxicology and industrial health}, volume = {31}, number = {2}, pages = {97-107}, doi = {10.1177/0748233712469649}, pmid = {23299189}, issn = {1477-0393}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Acute Kidney Injury/chemically induced/*drug therapy ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Glutathione/blood ; Ifosfamide/toxicity ; Kidney/*drug effects/pathology ; Lipid Peroxidation/drug effects ; Male ; Nitric Oxide/blood ; Oxidative Stress/*drug effects ; Rats ; Thioctic Acid/*pharmacology/therapeutic use ; }, abstract = {Ifosfamide (IFO) is a highly effective chemotherapeutic agent for treating a variety of pediatric solid tumors. However, its use is limited due to its serious side effect on kidneys. The side-chain oxidation of IFO in renal tubular cells produces a reactive toxic metabolite that is believed to be responsible for its nephrotoxic effect. Therefore, this study was carried out to investigate the possible underlying mechanisms that may be involved in IFO-induced nephrotoxicity, including free radical generation and the possible role of alpha lipoic acid (ALA) versus N-acetylcysteine (NAC) in protection against this toxicity. Male albino rats were injected intraperitoneally with saline, IFO (50 mg/kg daily for 5 days), IFO + ALA (100 mg/kg daily for 8 days) and IFO + NAC (200 mg/kg daily for 8 days). Kidney malondialdehyde, nitric oxide and glutathione contents and serum biochemical parameters and histopathological analysis were determined. Both ALA and NAC markedly reduced the severity of renal dysfunction induced by IFO. NAC was more nephroprotective than ALA. This study suggests that oxidative stress is possibly involved in the IFO-induced nephrotoxicity in rats. The study also suggests the potential therapeutic role for ALA and NAC against IFO-induced nephrotoxicity.}, }
@article {pmid23297317, year = {2013}, author = {Hirose, K and Monzen, S and Yoshino, H and Sato, H and Aoki, M and Hatayama, Y and Kawaguchi, H and Sato, M and Narita, Y and Takai, Y and Kashiwakura, I}, title = {Effects of radiation on the maturation of megakaryocytes.}, journal = {Journal of radiation research}, volume = {54}, number = {3}, pages = {447-452}, pmid = {23297317}, issn = {1349-9157}, mesh = {Cell Differentiation/drug effects/*radiation effects ; Humans ; K562 Cells ; MAP Kinase Signaling System/*drug effects/*radiation effects ; Megakaryocytes/*metabolism/*pathology/radiation effects ; Radiation Dosage ; Reactive Oxygen Species/*metabolism ; Tetradecanoylphorbol Acetate/*administration &amp; dosage ; }, abstract = {Megakaryocytes are generated by the differentiation of megakaryocytic progenitors; however, little information has been reported regarding how ionizing radiation affects the differentiation pathway and cellular responses. Human leukemia K562 cells have been used as a model to study megakaryocytic differentiation. In the present study, to investigate the effects of radiation on phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic differentiation of K562 cells, the cellular processes responsible for the expression of CD41 antigen (GPIIb/IIIa), which is reported to be expressed early in megakaryocyte maturation, were analyzed. The expression of CD41 antigens was significantly increased 72 h after treatment with both 4 Gy X-irradiation and PMA. In this fraction, two populations, CD41(low) and CD41(high) cells, were detected by flow cytometry. The CD41(high) cells sustained intracellular ROS at the initial level for up to 72 h, but CD41(low) cells had reduced ROS by 48 h. The maximum suppressive effect on CD41 expression was observed when N-acetyl cysteine, which is known to act as a ROS scavenger, was administered 48 h after PMA stimulation. When K562 cells were pretreated with mitogen-activated protein kinase (MAPK) pathway inhibitors, an ERK1/2 inhibitor and a p38 MAPK inhibitor, followed by X-irradiation and PMA stimulation, the reactivity profiles of both inhibitors showed the involvement of MAPK pathway. There is a possibility that the K562 cell population contains at least two types of radiosensitive megakaryocytic progenitors with respect to ROS production mechanisms, and intracellular ROS levels determine the extent of CD41 expression.}, }
@article {pmid23297002, year = {2013}, author = {Kim, N and Hwangbo, C and Lee, S and Lee, JH}, title = {Eupatolide inhibits PDGF-induced proliferation and migration of aortic smooth muscle cells through ROS-dependent heme oxygenase-1 induction.}, journal = {Phytotherapy research : PTR}, volume = {27}, number = {11}, pages = {1700-1707}, doi = {10.1002/ptr.4924}, pmid = {23297002}, issn = {1099-1573}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Aorta/cytology ; Butadienes/pharmacology ; Cell Movement/drug effects ; Cell Proliferation/*drug effects ; Cells, Cultured ; Chromones/pharmacology ; Enzyme Inhibitors/pharmacology ; Heme Oxygenase (Decyclizing)/genetics/*metabolism ; Imidazoles/pharmacology ; Inula/chemistry ; Male ; Morpholines/pharmacology ; Muscle, Smooth, Vascular/cytology/drug effects ; Myocytes, Smooth Muscle/*drug effects/metabolism ; NF-E2-Related Factor 2/metabolism ; Nitriles/pharmacology ; Platelet-Derived Growth Factor/*pharmacology ; Pyridines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; }, abstract = {The abnormal proliferation and migration of vascular smooth muscle cell (VSMC) contributes importantly to the pathogenesis of atherosclerosis and restenosis. Here, we investigated the effects of eupatolide (EuTL), a sesquiterpene lactone isolated from the medicinal plant Inula britannica, on platelet-derived growth factor (PDGF)-induced proliferation and migration of primary rat aortic smooth muscle cells (RASMCs), as well as its underlying mechanisms. EuTL remarkably inhibited PDGF-induced proliferation and migration of RASMCs. Treatment of RASMCs with EuTL induced both protein and mRNA expression of heme oxygenase-1 (HO-1). SB203580 (a p38 inhibitor), SP600125 (a JNK inhibitor), U0126 (a MEK inhibitor) and LY294002 (a PI3K inhibitor) did not suppress EuTL-induced HO-1 expression; however, N-acetylcysteine (NAC, an antioxidant) blocked EuTL-induced HO-1 expression. Moreover, treatment of RASMCs with EuTL increased reactive oxygen species (ROS) accumulation and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2); however, this translocation was also inhibited by NAC. NAC or inhibition of HO-1 significantly attenuated the inhibitory effects of EuTL on PDGF-induced proliferation and migration of RASMCs. Taken together, these findings suggest that EuTL could suppress PDGF-induced proliferation and migration of VSMCs through HO-1 induction via ROS-Nrf2 pathway and may be a potential HO-1 inducer for preventing or treating vascular diseases.}, }
@article {pmid23296100, year = {2013}, author = {Stephenson, AP and Schneider, JA and Nelson, BC and Atha, DH and Jain, A and Soliman, KF and Aschner, M and Mazzio, E and Renee Reams, R}, title = {Manganese-induced oxidative DNA damage in neuronal SH-SY5Y cells: attenuation of thymine base lesions by glutathione and N-acetylcysteine.}, journal = {Toxicology letters}, volume = {218}, number = {3}, pages = {299-307}, pmid = {23296100}, issn = {1879-3169}, support = {P30 ES000267/ES/NIEHS NIH HHS/United States ; G12 RR003020/RR/NCRR NIH HHS/United States ; 5S11ES01187-05/ES/NIEHS NIH HHS/United States ; U50 TS473408/TS/ATSDR CDC HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; G12 MD007582/MD/NIMHD NIH HHS/United States ; R01 ES10653/ES/NIEHS NIH HHS/United States ; 2G12RR03020-25/RR/NCRR NIH HHS/United States ; S11 ES011182/ES/NIEHS NIH HHS/United States ; S06 GM008111/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Chlorides/*toxicity ; Comet Assay ; *DNA Breaks, Single-Stranded ; Dose-Response Relationship, Drug ; Flow Cytometry ; Gas Chromatography-Mass Spectrometry ; Glutathione/*pharmacology ; Humans ; In Situ Nick-End Labeling ; Manganese Compounds ; Manganese Poisoning/*drug therapy/metabolism/pathology ; Neurons/*drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects ; Thymine ; }, abstract = {Manganese (Mn) is an essential trace element required for normal function and development. However, exposure to this metal at elevated levels may cause manganism, a progressive neurodegenerative disorder with neurological symptoms similar to idiopathic Parkinson's disease (IPD). Elevated body burdens of Mn from exposure to parental nutrition, vapors in mines and smelters and welding fumes have been associated with neurological health concerns. The underlying mechanism of Mn neurotoxicity remains unclear. Accordingly, the present study was designed to investigate the toxic effects of Mn(2+) in human neuroblastoma SH-SY5Y cells. Mn(2+) caused a concentration dependent decrease in SH-SY5Y cellular viability compared to controls. The LD50 value was 12.98 μM Mn(2+) (p<0.001 for control vs. 24h Mn treatment). Both TUNEL and annexin V/propidium iodide (PI) apoptosis assays confirmed the induction of apoptosis in the cells following exposure to Mn(2+) (2 μM, 62 μM or 125 μM). In addition, Mn(2+) induced both the formation and accumulation of DNA single strand breaks (via alkaline comet assay analysis) and oxidatively modified thymine bases (via gas chromatography/mass spectrometry analysis). Pre-incubation of the cells with characteristic antioxidants, either 1mM N-acetylcysteine (NAC) or 1mM glutathione (GSH) reduced the level of DNA strand breaks and the formation of thymine base lesions, suggesting protection against oxidative cellular damage. Our findings indicate that (1) exposure of SH-SY5Y cells to Mn promotes both the formation and accumulation of oxidative DNA damage, (2) SH-SY5Y cells with accumulated DNA damage are more likely to die via an apoptotic pathway and (3) the accumulated levels of DNA damage can be abrogated by the addition of exogenous chemical antioxidants. This is the first known report of Mn(2+)-induction and antioxidant protection of thymine lesions in this SH-SY5Y cell line and contributes new information to the potential use of antioxidants as a therapeutic strategy for protection against Mn(2+)-induced oxidative DNA damage.}, }
@article {pmid23287530, year = {2013}, author = {Galluzzi, L and Marsili, S and Vitale, I and Senovilla, L and Michels, J and Garcia, P and Vacchelli, E and Chatelut, E and Castedo, M and Kroemer, G}, title = {Vitamin B6 metabolism influences the intracellular accumulation of cisplatin.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {12}, number = {3}, pages = {417-421}, pmid = {23287530}, issn = {1551-4005}, mesh = {Adenosine Triphosphatases/metabolism ; Antineoplastic Agents/*metabolism/pharmacology ; Biological Transport ; Carcinoma, Non-Small-Cell Lung/metabolism ; Cation Transport Proteins/metabolism ; Cisplatin/*metabolism/pharmacology ; Copper Transporter 1 ; Copper-Transporting ATPases ; Drug Resistance, Neoplasm/drug effects ; Glutathione/*metabolism ; Humans ; Lung Neoplasms/metabolism ; Pyridoxal Kinase/biosynthesis/genetics/*metabolism ; RNA Interference ; RNA, Small Interfering ; Vitamin B 6/*metabolism ; }, abstract = {Vitamin B6 metabolism influences the adaptive response of non-small lung carcinoma (NSCLC) cells to distinct, potentially lethal perturbations in homeostasis, encompassing nutrient deprivation, hyperthermia, hypoxia, irradiation as well as the exposure to cytotoxic chemicals, including the DNA-damaging agent cisplatin (CDDP). Thus, the siRNA-mediated downregulation of pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6, protects NSCLC cells (as well as a large collection of human and murine malignant cells of distinct histological derivation) from the cytotoxic effects of CDDP. Accordingly, the administration of pyridoxine, one of the inactive precursors of vitamin B6, exacerbates cisplatin-induced cell death, in vitro and in vivo, but only when PDXK is expressed. Conversely, antioxidants such as non-oxidized glutathione (GSH) are known to protect cancer cells from CDDP toxicity. Pyridoxine increases the amount of CDDP-DNA adducts formed upon the exposure of NSCLC cells to CDDP and aggravates the consequent DNA damage response. On the contrary, in the presence of GSH, NSCLC cells exhibit near-to-undetectable levels of CDDP-DNA adducts and a small fraction of the cell population activates the DNA damage response. We therefore wondered whether vitamin B6 metabolism and GSH might interact with CDDP in a pharmacokinetic fashion. In this short communication, we demonstrate that GSH inhibits the intracellular accumulation of CDDP, while pyridoxine potentiates it in a PDXK-dependent fashion. Importantly, such pharmacokinetic effects do not involve plasma membrane transporters that mediate a prominent fraction of CDDP influx, i.e., solute carrier family 31, member 1 (SLC31A1, best known as copper transporter 1, CTR1) and efflux, i.e., ATPase, Cu (2+) transporting, β polypeptide (ATP7B).}, }
@article {pmid23284930, year = {2012}, author = {Ritchie, IR and Dyck, DJ}, title = {Rapid loss of adiponectin-stimulated fatty acid oxidation in skeletal muscle of rats fed a high fat diet is not due to altered muscle redox state.}, journal = {PloS one}, volume = {7}, number = {12}, pages = {e52193}, pmid = {23284930}, issn = {1932-6203}, mesh = {Adiponectin/*pharmacology ; Animals ; Blood Glucose/drug effects ; Body Weight/drug effects ; Diet, High-Fat/adverse effects ; Fatty Acids/*metabolism ; Female ; Glutathione/metabolism ; Lipid Metabolism/drug effects ; Muscle, Skeletal/*drug effects/*metabolism ; Oxidation-Reduction/drug effects ; Protein Carbonylation/drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {A high fat (HF) diet rapidly impairs the ability of adiponectin (Ad) to stimulate fatty acid (FA) oxidation in oxidative soleus muscle, but the underlying mechanism remains elusive. Mere days of HF feeding also increase the muscle's production and accumulation of reactive oxygen species (ROS) and shift cellular redox to a more oxidized state. It seems plausible that this shift towards a more oxidized state might act as negative feedback to suppress the ability of Ad to stimulate FA oxidation and generate more ROS. Therefore, we sought to determine whether i) a shift towards a more oxidized redox state (reduction in GSH/2GSSG) coincided with impaired Ad-stimulated palmitate oxidation in oxidative and glycolytic rodent muscle after 5 days of HF feeding (60% kCal), and ii) if supplementation with the antioxidant, N-acetylcysteine (NAC) could prevent the HF-diet induced impairment in Ad-response. Globular Ad (gAd) increased palmitate oxidation in isolated soleus and EDL muscles by 42% and 34%, respectively (p<0.05) but this was attenuated with HF feeding in both muscles. HF feeding decreased total GSH (-26%, p<0.05) and GSH/2GSSG (-49%, p<0.05) in soleus, but not EDL. Supplementation with NAC prevented the HF diet-induced reductions in GSH and GSH/2GSSG in soleus, but did not prevent the loss of Ad response in either muscle. Furthermore, direct incubations with H(2)O(2) did not impair Ad-stimulated FA oxidation in either muscle. In conclusion, our data indicates that skeletal muscle Ad resistance is rapidly induced in both oxidative and glycolytic muscle, independently of altered cellular redox state.}, }
@article {pmid23284002, year = {2013}, author = {Yang, L and Qu, M and Wang, Y and Duan, H and Chen, P and Wang, Y and Shi, W and Danielson, P and Zhou, Q}, title = {Trichostatin A inhibits transforming growth factor-β-induced reactive oxygen species accumulation and myofibroblast differentiation via enhanced NF-E2-related factor 2-antioxidant response element signaling.}, journal = {Molecular pharmacology}, volume = {83}, number = {3}, pages = {671-680}, doi = {10.1124/mol.112.081059}, pmid = {23284002}, issn = {1521-0111}, mesh = {Actins/metabolism ; Antioxidant Response Elements/drug effects ; Antioxidants/metabolism ; Cell Differentiation/drug effects ; Cell Line ; Collagen/metabolism ; Cornea/drug effects/metabolism ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/*antagonists &amp; inhibitors/metabolism ; Hydroxamic Acids/*pharmacology ; Isothiocyanates ; Myofibroblasts/*cytology/drug effects/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors ; NF-E2-Related Factor 2/*metabolism ; Onium Compounds/pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Signal Transduction/drug effects ; Sulfoxides ; Thiocyanates/pharmacology ; Transforming Growth Factor beta/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Trichostatin A (TSA) has been shown to prevent fibrosis in vitro and in vivo. The present study aimed at investigating the role of reactive oxygen species (ROS) scavenging by TSA on transforming growth factor-β (TGF-β)-induced myofibroblast differentiation of corneal fibroblasts in vitro. Human immortalized corneal fibroblasts were treated with TGF-β in the presence of TSA, the NAD(P)H oxidase inhibitor diphenyleneiodonium (DPI), the antioxidant N-acetyl-cysteine (NAC), the NF-E2-related factor 2-antioxidant response element (Nrf2-ARE) activator sulforaphane, or small interfering RNA. Myofibroblast differentiation was assessed by α-smooth muscle actin (α-SMA) expression, F-actin bundle formation, and collagen gel contraction. ROS, H(2)O(2), intracellular glutathione (GSH) level, cellular total antioxidant capacity, and the activation of Nrf2-ARE signaling were determined with various assays. Treatment with TSA and the Nrf2-ARE activator resulted in increased inhibition of the TGF-β-induced myofibroblast differentiation as compared with treatment with DPI or NAC. Furthermore, TSA also decreased cellular ROS and H(2)O(2) accumulation induced by TGF-β, whereas it elevated intracellular GSH level and cellular total antioxidant capacity. In addition, TSA induced Nrf2 nuclear translocation and up-regulated the expression of Nrf2-ARE downstream antioxidant genes, whereas Nrf2 knockdown by RNA interference blocked the inhibition of TSA on myofibroblast differentiation. In conclusion, this study provides the first evidence implicating that TSA inhibits TGF-β-induced ROS accumulation and myofibroblast differentiation via enhanced Nrf2-ARE signaling.}, }
@article {pmid23283594, year = {2013}, author = {Wu, MY and Hsiang, HF and Wong, CS and Yao, MS and Li, YW and Hsiang, CY and Bai, CH and Hsu, YH and Lin, YF and Tam, KW}, title = {The effectiveness of N-Acetylcysteine in preventing contrast-induced nephropathy in patients undergoing contrast-enhanced computed tomography: a meta-analysis of randomized controlled trials.}, journal = {International urology and nephrology}, volume = {45}, number = {5}, pages = {1309-1318}, pmid = {23283594}, issn = {1573-2584}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*chemically induced/physiopathology/*prevention &amp; control/therapy ; Contrast Media/*adverse effects ; Creatinine/blood ; Cystatin C/blood ; Fluid Therapy ; Free Radical Scavengers/*therapeutic use ; Glomerular Filtration Rate ; Humans ; Randomized Controlled Trials as Topic ; Renal Dialysis ; Tomography, X-Ray Computed ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) is reported to have potential for preventing of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography. However, the effectiveness of NAC in preventing CIN in patients undergoing contrast-enhanced computed tomography (CT) is still controversial. We conducted a meta-analysis of relevant randomized controlled trials (RCTs) to further examine this issue.<br><br>METHODS: RCTs were identified by computerized searching in PubMed, EMBASE, SCOPUS, and Cochrane databases. Two reviewers independently assessed the methodological quality of each study. A meta-analysis was performed to evaluate the effectiveness of NAC in preventing CIN in patients undergoing CT. The primary outcome was the incidence of contrast-induced nephropathy, and the requirement for dialysis. The secondary outcome was the change of serum creatinine.<br><br>RESULTS: Six randomized controlled trials were identified with a total of 496 patients meeting the criteria for this study. Prophylactic administration of NAC in patients with serum creatinine above 1.2 mg/dL undergoing contrast-enhanced CT, along with hydration, reduced the risk of CIN (relative risk 0.20; 95 % confidence interval: 0.07-0.57). Requirement for dialysis was not significantly different between the NAC group and the control group.<br><br>CONCLUSIONS: This review provides evidence of the efficacy of NAC in preventing the incidence of CIN and recommends that NAC be more widely used in high-risk patients undergoing contrast-enhanced CT. On the basis of the evidence reviewed, further research involving large RCTs may be warranted.}, }
@article {pmid23281030, year = {2013}, author = {Stachurska, A and Ciesla, M and Kozakowska, M and Wolffram, S and Boesch-Saadatmandi, C and Rimbach, G and Jozkowicz, A and Dulak, J and Loboda, A}, title = {Cross-talk between microRNAs, nuclear factor E2-related factor 2, and heme oxygenase-1 in ochratoxin A-induced toxic effects in renal proximal tubular epithelial cells.}, journal = {Molecular nutrition &amp; food research}, volume = {57}, number = {3}, pages = {504-515}, doi = {10.1002/mnfr.201200456}, pmid = {23281030}, issn = {1613-4133}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cells, Cultured ; Deferoxamine/pharmacology ; Epithelial Cells/*drug effects/metabolism ; Erythropoietin/genetics/metabolism ; Gene Expression Regulation/drug effects ; Heme Oxygenase-1/genetics/*metabolism ; Kidney Tubules, Proximal/*cytology/drug effects ; MicroRNAs/*metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Ochratoxins/*toxicity ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Swine ; Transforming Growth Factor beta/genetics/metabolism ; }, abstract = {SCOPE: Ochratoxin A (OTA) is a mycotoxin exhibiting nephrotoxic and potential carcinogenic activity. We investigated the cross-talk between microRNAs, nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in ochratoxin A-mediated effects.<br><br>METHODS AND RESULTS: In porcine renal proximal tubular cells, OTA increased expression of profibrotic transforming growth factors &#x3b2; (TGF&#x3b2;) while concomitantly decreasing expression of Nrf2, HO-1, and erythropoietin. Adenoviral overexpression of Nrf2 counteracted OTA-mediated reduction in HO-1 and erythropoietin expression and cell proliferation as well as increase in reactive oxygen species (ROS) generation and TGF&#x3b2; expression. Additionally, inhibition of HO activity enhanced whereas adenoviral overexpression of HO-1 reduced expression of TGF&#x3b2;. Moreover, antioxidants, N-acetyl-cysteine and desferioxamine, prevented OTA-mediated enhancement of ROS generation, and TGF&#x3b2; expression. Finally, OTA modulated microRNA processing by upregulating LINeage protein 28 and DiGeorge syndrome critical region-8, increasing the total pool of cellular microRNAs and elevating the expression of miR-132 and miR-200c. Inhibition of miR-132 by specific antagomir restored the OTA-driven reduction in Nrf2 expression. Moreover, anti-miR-132 and anti-miR-200c counteracted OTA-mediated decrease in HO-1 levels as well as increase in ROS production and TGF&#x3b2; expression.<br><br>CONCLUSION: We showed that attenuation of Nrf2 and HO-1 expression through induction of miR-132 and miR-200c by OTA elevates ROS levels and profibrotic TGF&#x3b2; expression.}, }
@article {pmid23278213, year = {2013}, author = {Ávalos Fúnez, A and Isabel Haza, A and Mateo, D and Morales, P}, title = {In vitro evaluation of silver nanoparticles on human tumoral and normal cells.}, journal = {Toxicology mechanisms and methods}, volume = {23}, number = {3}, pages = {153-160}, doi = {10.3109/15376516.2012.762081}, pmid = {23278213}, issn = {1537-6524}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology/toxicity ; Antioxidants/pharmacology ; Biomarkers/metabolism ; Cell Membrane/drug effects/metabolism ; Cell Survival/drug effects ; Cytoprotection ; Dose-Response Relationship, Drug ; Fibroblasts/*drug effects/metabolism/pathology ; HL-60 Cells ; Hep G2 Cells ; Humans ; L-Lactate Dehydrogenase/metabolism ; *Metal Nanoparticles/toxicity ; Mitochondria/drug effects/metabolism ; Neoplasms/*metabolism/pathology ; Oxidative Stress/*drug effects ; Silver Compounds/*pharmacology/toxicity ; Time Factors ; }, abstract = {Silver nanoparticles (AgNPs), which have well-known antimicrobial properties, are extensively used in various medical and general applications. Despite the widespread use of AgNPs, relatively few studies have been undertaken to determine the toxicity effects of AgNPs exposure. The aim of the present work was to study how AgNPs interact with four different human cell lines (hepatoma, leukemia, dermal and pulmonary fibroblast) in order to understand the impact of such nanomaterials on cellular biological functions. For toxicity evaluations, mitochondrial function (MTT assay) and membrane leakage of lactate dehydrogenase (LDH assay) were assessed under control and exposed conditions (24, 48 and 72 h of exposure). Furthermore, we evaluated the protective effect of N-acetyl-l-cysteine (NAC) against AgNP-induced cytotoxicity. Results showed that mitochondrial function decreased in all cell lines exposed to AgNPs at 6.72-13.45 µg/ml. LDH leakage also increased in all cell lines exposed to AgNPs (6.72-13.45 µg/ml). However, the cytotoxic effect of AgNPs (13.45 µg/ml) was prevented by pretreatment of different concentrations of NAC (1-20 mM). Our findings indicate that AgNPs are cytotoxic on human tumor and normal cells, the tumor cells being more sensitive to the cytotoxic effect of AgNPs. In addition, NAC protects human cells from cytotoxicity of AgNPs, suggesting that oxidative stress is in part responsible of this effect.}, }
@article {pmid23277025, year = {2013}, author = {Dergarabetian, EM and Ghattass, KI and El-Sitt, SB and Al-Mismar, RM and El-Baba, CO and Itani, WS and Melhem, NM and El-Hajj, HA and Bazarbachi, AA and Schneider-Stock, R and Gali-Muhtasib, HU}, title = {Thymoquinone induces apoptosis in malignant T-cells via generation of ROS.}, journal = {Frontiers in bioscience (Elite edition)}, volume = {5}, number = {2}, pages = {706-719}, doi = {10.2741/e651}, pmid = {23277025}, issn = {1945-0508}, mesh = {Amino Acid Chloromethyl Ketones ; Analysis of Variance ; Animals ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology ; Catalase ; Glutathione/metabolism ; Human T-lymphotropic virus 1/metabolism ; Humans ; Jurkat Cells ; Lymphoma, T-Cell/*drug therapy/immunology/metabolism/virology ; Membrane Potential, Mitochondrial/physiology ; Reactive Oxygen Species/*metabolism ; T-Lymphocytes/*drug effects/metabolism ; }, abstract = {We show that HTLV-1 negative leukemia cells are more sensitive to TQ due to higher levels of drug-induced reactive oxygen species (ROS). PreG1 population in HTLV-1 negative Jurkat and CEM was higher than HTLV-1 transformed HuT-102 and MT-2 cells. Peripheral blood mononuclear cells were more resistant. Hoechst staining indicated more features of apoptosis, namely nuclear blebs and shrunken nuclei in HuT-102 than Jurkat. A greater depletion of the antioxidant enzyme glutathione occurred in Jurkat, which consequently led to an increase in ROS, loss of mitochondrial membrane potential, cytochrome c release, activation of caspases 3 and 9, and cleavage of PARP. Treatment with z-VAD-fmk partially reversed TQ-induced apoptosis, suggesting a caspase-dependent mechanism. N-acetyl cysteine prevented apoptosis providing evidence that cell death is ROS-dependent. Catalase prevented apoptosis to a lesser extent than NAC. In summary, TQ induces apoptosis in adult T cell leukemia/lymphoma by decreasing glutathione and increasing ROS, and levels of ROS underlie the differential cellular response to TQ. Our data suggest a potential therapeutic role for TQ in sensitizing HTLV-I-negative T-cell lymphomas.}, }
@article {pmid24829665, year = {2013}, author = {Alavi Nejad, P and Hajiani, E and Hashemi, J and Masjedizadeh, AR and Shayesteh, AA and Sebghatollahi, V}, title = {Evaluation of N-acetyl Cysteine for the Prevention of Post-endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Prospective Double Blind Randomized Pilot Study.}, journal = {Middle East journal of digestive diseases}, volume = {5}, number = {1}, pages = {17-21}, pmid = {24829665}, issn = {2008-5230}, abstract = {BACKGROUND: Acute pancreatitis is the most common serious complication of endoscopic retrograde cholangiopancreatography (ERCP) that can occasionally be fatal. Multiple drugs have been examined for the prevention of this side effect, with generally uncertain results. This study is an effort to prevent this complication by the use of oral N-acetyl cysteine (NAC).<br><br>METHODS: A total of 100 patients who were candidates for ERCP were divided randomly into two groups. In the NAC (N) group, patients received 1200 mg NAC with 150 cc water orally 2 h before ERCP. In the placebo (P) group, 150 cc water was prescribed as a placebo. We measured serum amylase and lipase levels before and 24 h after ERCP. The prevalence of pancreatitis and duration of admission in each group were determined and compared.<br><br>RESULTS: In group N there were 5 (10%) cases of pancreatitis, whereas in group P there were 14 (28%) cases, which was significant (risk reduction ratio: 2.8; p=0.02).The average admission time was 1.16&#xb1;0.55 days in group N and 1.18&#xb1;0.44 days in group P, which was not significant.<br><br>CONCLUSION: There were significant differences in the prevalence of acute pancreatitis between the two groups. In addition, the number of need to treat (NNT) consisted of five cases for NAC. With regards to the above results and the safety profile of NAC, it could be used as a therapeutic agent for the prevention of post-ERCP pancreatitis. We recommend that the results of this study be verified by additional clinical trials.}, }
@article {pmid24081245, year = {2013}, author = {Valenzuela, C and Ancochea, J}, title = {Treatment switching in idiopathic pulmonary fibrosis: from triple therapy to enrollment into a clinical investigational drug trial.}, journal = {Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG}, volume = {30 Suppl 1}, number = {}, pages = {44-47}, pmid = {24081245}, issn = {2532-179X}, mesh = {Acetylcysteine ; Azathioprine ; Double-Blind Method ; *Drugs, Investigational ; Humans ; *Idiopathic Pulmonary Fibrosis ; Pulmonary Fibrosis ; Treatment Outcome ; }, abstract = {A number of pharmacological agents have been the focus of clinical trials over the past years. Although no single pharmacological agent is recommended by current guidelines, preliminary negative findings regarding the safety of a triple therapy regimen consisting of prednisone, azathioprine and N-acetylcysteine have raised the question of whether it is no longer a treatment option. More recent data have resulted in the approval of pirfenidone in Europe. Pirfenidone shows a favourable risk-benefit profile and a beneficial effect in reducing the decline in lung function in patients with IPF. This case study describes the diagnosis and initial treatment of a patient with IPF with triple therapy of prednisone, azathioprine and N-acetylcysteine (NAC) followed by inclusion into a double-blind, randomised, placebo-controlled study and subsequent open-label extension trial of pirfenidone in IPF.}, }
@article {pmid23275087, year = {2013}, author = {Zhang, H and Wang, ZW and Wu, HB and Li, Z and Li, LC and Hu, XP and Ren, ZL and Li, BJ and Hu, ZP}, title = {Transforming growth factor-β1 induces matrix metalloproteinase-9 expression in rat vascular smooth muscle cells via ROS-dependent ERK-NF-κB pathways.}, journal = {Molecular and cellular biochemistry}, volume = {375}, number = {1-2}, pages = {11-21}, pmid = {23275087}, issn = {1573-4919}, mesh = {Animals ; Cell Line ; Enzyme Induction ; Extracellular Signal-Regulated MAP Kinases/metabolism ; MAP Kinase Signaling System ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/*genetics/metabolism ; Muscle, Smooth, Vascular/cytology ; Myocytes, Smooth Muscle/*enzymology ; Rats ; Reactive Oxygen Species/metabolism ; Transcription Factor RelA/metabolism ; Transforming Growth Factor beta1/*physiology ; }, abstract = {Both matrix metalloproteinase-9 (MMP9) and transforming growth factors-β1 (TGF-β1) are the important factors in the pathogenesis of the aortic aneurysm (AA) and aortic dissection (AD). Recent studies have shown that inhibition of reactive oxygen species (ROS) production, extracellular signal-regulated kinase 1/2(ERK1/2) or NF-κB pathways is able to suppress aneurysm formation. The median layers of arterial walls are mainly the vascular smooth muscle cells (VSMCs), while the pathogenesis of AA and AD is closely related to the changes in the median layer structure. Thus, we investigated the molecular mechanisms underlying TGF-β1-induced MMP-9 expression in VSMC, the involvement of intracellular ROS and signaling molecules, including ERK1/2 and NF-κB. Rat vascular smooth muscle cells (A7r5) were used. MMP-9 expression was analyzed by gelatin zymography, western blot and RT-PCR. The involvement of intracellular ROS and signaling molecules including ERK1/2 and NF-κB in the responses was investigated using reactive oxygen scavenger N-acetylcysteine (NAC) and pharmacological inhibitors (U0126 and BAY11-7082), determined by ROS testing and western blot testing for their corresponding proteins. TGF-β1 induces MMP-9 expression via ROS-dependent signaling pathway. ROS production leads to activation of ERK1/2 and then activation of the NF-κB transcription factor. Activated NF-κB turns on transcription of the MMP-9 gene. The process in which TGF-β1 induces MMP9 expression involves the ROS-dependent ERK-NF-κB signal pathways in VSMC. This discovery raises a new regulation pathway in the VSMC, and it shows the potential to help to find a new solution to treating aortic aneurysm and aortic dissection.}, }
@article {pmid23274526, year = {2013}, author = {Tsai, CH and Chiang, YC and Chen, HT and Huang, PH and Hsu, HC and Tang, CH}, title = {High glucose induces vascular endothelial growth factor production in human synovial fibroblasts through reactive oxygen species generation.}, journal = {Biochimica et biophysica acta}, volume = {1830}, number = {3}, pages = {2649-2658}, doi = {10.1016/j.bbagen.2012.12.017}, pmid = {23274526}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Androstadienes/pharmacology ; Chromones/pharmacology ; Curcumin/pharmacology ; Dose-Response Relationship, Drug ; Fibroblasts/*drug effects/metabolism/pathology ; Gene Expression Regulation/drug effects ; Glucose/metabolism/*pharmacology ; Humans ; Joint Capsule/drug effects/metabolism/pathology ; Morpholines/pharmacology ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/metabolism ; Osteoarthritis/genetics/metabolism/pathology ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation ; Primary Cell Culture ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/genetics/metabolism ; Proto-Oncogene Proteins c-jun/agonists/genetics/metabolism ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/agonists/*metabolism ; Signal Transduction/drug effects ; Transcription Factor AP-1/antagonists &amp; inhibitors/genetics/metabolism ; Vascular Endothelial Growth Factor A/antagonists &amp; inhibitors/*genetics/metabolism ; Wortmannin ; }, abstract = {BACKGROUND: Diabetes is an independent risk factor of osteoarthritis (OA). Angiogenesis is essential for the progression of OA. Here, we investigated the intracellular signaling pathways involved in high glucose (HG)-induced vascular endothelial growth factor (VEGF) expression in human synovial fibroblast cells.<br><br>METHODS: HG-mediated VEGF expression was assessed with qPCR and ELISA. The mechanisms of action of HG in different signaling pathways were studied using Western blotting. Knockdown of proteins was achieved by transfection with siRNA. Chromatin immunoprecipitation assays were used to study in vivo binding of c-Jun to the VEGF promoter.<br><br>RESULTS: Stimulation of OA synovial fibroblasts (OASF) with HG induced concentration- and time-dependent increases in VEGF expression. Treatment of OASF with HG increased reactive oxygen species (ROS) generation. Pretreatment with NADPH oxidase inhibitor (APO or DPI), ROS scavenger (NAC), PI3K inhibitor (Ly294002 or wortmannin), Akt inhibitor, or AP-1 inhibitor (curcumin or tanshinone IIA) blocked the HG-induced VEGF production. HG also increased PI3K and Akt activation. Treatment of OASF with HG increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the VEGF promoter.<br><br>CONCLUSIONS: Our results suggest that the HG increases VEGF expression in human synovial fibroblasts via the ROS, PI3K, Akt, c-Jun and AP-1 signaling pathway.<br><br>GENERAL SIGNIFICANCE: We link high glucose on VEGF expression in osteoarthritis.}, }
@article {pmid23271497, year = {2013}, author = {Romagnoli, C and Marcucci, T and Picariello, L and Tonelli, F and Vincenzini, MT and Iantomasi, T}, title = {Role of N-acetylcysteine and GSH redox system on total and active MMP-2 in intestinal myofibroblasts of Crohn's disease patients.}, journal = {International journal of colorectal disease}, volume = {28}, number = {7}, pages = {915-924}, pmid = {23271497}, issn = {1432-1262}, mesh = {Acetylcysteine/*metabolism ; Adult ; Buthionine Sulfoximine/pharmacology ; Crohn Disease/*enzymology/*pathology ; Enzyme Activation/drug effects ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Humans ; Intestines/*pathology ; Intracellular Space/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Matrix Metalloproteinase 2/*metabolism ; Middle Aged ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Myofibroblasts/*enzymology/metabolism/pathology ; Oxidation-Reduction/drug effects ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; Young Adult ; }, abstract = {PURPOSE: Intestinal subepithelial myofibroblasts (ISEMFs)(1) are the predominant source of matrix metalloproteinase-2 (MMP-2) in gut, and a decrease in glutathione/oxidized glutathione (GSH/GSSG) ratio, intracellular redox state index, occurs in the ISEMFs of patients with Crohn's disease (CD). The aim of this study is to demonstrate a relationship between MMP-2 secretion and activation and changes of GSH/GSSG ratio in ISEMFs stimulated or not with tumor necrosis factor alpha (TNFα).<br><br>METHODS: ISEMFs were isolated from ill and healthy colon mucosa of patients with active CD. Buthionine sulfoximine, GSH synthesis inhibitor, and N-acetylcysteine (NAC), precursor of GSH synthesis, were used to modulate GSH/GSSG ratio. GSH and GSSG were measured by HPLC and MMP-2 by ELISA Kit.<br><br>RESULTS: In cells, stimulated or not with TNF&#x3b1;, a significant increase in MMP-2 secretion and activation, related to increased oxidative stress, due to low GSH/GSSG ratio, was detected. NAC treatment, increasing this ratio, reduced MMP-2 secretion and exhibited a direct effect on the secreted MMP-2 activity. In NAC-treated and TNF&#x3b1;-stimulated ISEMFs of CD patients' MMP-2 activity were restored to physiological value. The involvement of c-Jun N-terminal kinase pathway on redox regulation of MMP-2 secretion has been demonstrated.<br><br>CONCLUSION: For the first time, in CD patient ISEMFs, a redox regulation of MMP-2 secretion and activation related to GSH/GSSG ratio and inflammatory state have been demonstrated. This study suggests that compounds able to maintain GSH/GSSG ratio to physiological values can be useful to restore normal MMP-2 levels reducing in CD patient intestine the dysfunction of epithelial barrier.}, }
@article {pmid23271050, year = {2013}, author = {Fernandes, ES and Vong, CT and Quek, S and Cheong, J and Awal, S and Gentry, C and Aubdool, AA and Liang, L and Bodkin, JV and Bevan, S and Heads, R and Brain, SD}, title = {Superoxide generation and leukocyte accumulation: key elements in the mediation of leukotriene B4-induced itch by transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {27}, number = {4}, pages = {1664-1673}, doi = {10.1096/fj.12-221218}, pmid = {23271050}, issn = {1530-6860}, support = {19296/VAC_/Versus Arthritis/United Kingdom ; BB/E527098/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 19296/ARC_/Arthritis Research UK/United Kingdom ; }, mesh = {Animals ; Ankyrins/pharmacology ; Female ; Leukocytes/drug effects/*metabolism ; Leukotriene B4/*pharmacology ; Mice ; Mice, Knockout ; Pruritus/drug therapy/metabolism ; Receptors, Leukotriene B4/antagonists &amp; inhibitors ; Superoxides/*metabolism ; TRPV Cation Channels/metabolism ; Transient Receptor Potential Channels/*metabolism ; }, abstract = {The underlying mechanisms of itch are poorly understood. We have investigated a model involving the chemoattractant leukotriene B4 (LTB4) that is up-regulated in common skin diseases. Intradermal injection of LTB4 (0.1 nmol/site) into female CD1 mice induced significant scratching movements (used as an itch index) compared with vehicle-injected (0.1% bovine serum albumin-saline) mice. Intraperitoneal transient receptor potential (TRP) channel antagonist treatment significantly inhibited itch as follows: TRP vanilloid 1 (TRPV1) antagonist SB366791 (0.5 mg/kg, by 97%) and the TRP ankyrin 1 (TRPA1) antagonists TCS 5861528 (10 mg/kg; 82%) and HC-030031 (100 mg/kg; 76%). Leukotriene B4 receptor 2 antagonism by LY255283 (5 mg/kg i.p.; 62%) reduced itch. Neither TRPV1-knockout (TRPV1-KO) nor TRPA1-knockout (TRPA1-KO mice exhibited LTB4-induced itch compared with their wild-type counterparts. The reactive oxygen species scavengers N-acetylcysteine (NAC; 204 mg/kg i.p.; 86%) or superoxide dismutase (SOD; 10 mg/kg i.p.; 83%) also inhibited itch. LTB4-induced superoxide release was attenuated by TCS 5861528 (56%) and HC-030031 (66%), NAC (58%), SOD (50%), and LY255283 (59%) but not by the leukotriene B4 receptor 1 antagonist U-75302 (9 nmol/site) or SB366791. Itch, superoxide, and myeloperoxidase generation were inhibited by the leukocyte migration inhibitor fucoidan (10 mg/kg i.v.) by 80, 61, and 34%, respectively. Myeloperoxidase activity was also reduced by SB366791 (35%) and SOD (28%). TRPV1-KO mice showed impaired myeloperoxidase release, whereas TRPA1-KO mice exhibited diminished production of superoxide. This result provides novel evidence that TRPA1 and TRPV1 contribute to itch via distinct mechanisms.}, }
@article {pmid23270677, year = {2013}, author = {Möller, M and Du Preez, JL and Viljoen, FP and Berk, M and Emsley, R and Harvey, BH}, title = {Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine.}, journal = {Brain, behavior, and immunity}, volume = {30}, number = {}, pages = {156-167}, doi = {10.1016/j.bbi.2012.12.011}, pmid = {23270677}, issn = {1090-2139}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Antipsychotic Agents/pharmacology ; Behavior, Animal/drug effects/*physiology ; Brain/drug effects/*metabolism ; Clozapine/*pharmacology ; Dopamine/metabolism ; Free Radical Scavengers/pharmacology ; Kynurenine/metabolism ; Male ; Maternal Deprivation ; Memory/drug effects/physiology ; Mitochondria/drug effects/*metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Social Behavior ; *Social Isolation ; }, abstract = {Apart from altered dopamine (DA) function, schizophrenia displays mitochondrial and immune-inflammatory abnormalities, evidenced by oxidative stress, altered kynurenine metabolism and cytokine release. N-acetyl cysteine (NAC), an antioxidant and glutamate modulator, is effective in the adjunctive treatment of schizophrenia. Social isolation rearing (SIR) in rats is a valid neurodevelopmental animal model of schizophrenia. This study evaluated whether SIR-induced behavioural deficits may be explained by altered plasma pro- and anti-inflammatory cytokines, kynurenine metabolism, and cortico-striatal DA and mitochondrial function (via adenosine triphosphate (ATP) release), and if clozapine or NAC (alone and in combination) reverses these changes. SIR induced pronounced deficits in social interactive behaviours, object recognition memory, and prepulse inhibition (PPI), while simultaneously increasing striatal but reducing frontal cortical accumulation of ATP as well as DA. SIR increased pro- vs. anti-inflammatory cytokine balance and altered kynurenine metabolism with a decrease in neuroprotective ratio. Clozapine (5mg/kg/day×14days) as well as clozapine+NAC (5mg/kg/day and 150mg/kg/day×14days) reversed these changes, with NAC (150mg/kg/day) alone significantly but partially effective in some parameters. Clozapine+NAC was more effective than clozapine alone in reversing SIR-induced PPI, mitochondrial, immune and DA changes. In conclusion, SIR induces mitochondrial and immune-inflammatory changes that underlie cortico-striatal DA perturbations and subsequent behavioural deficits, and responds to treatment with clozapine or NAC, with an additive effect following combination treatment. The data provides insight into the mechanisms that might underlie the utility of NAC as an adjunctive treatment in schizophrenia.}, }
@article {pmid23269626, year = {2013}, author = {You, BR and Park, WH}, title = {Suberoyl bishydroxamic acid-induced apoptosis in HeLa cells via ROS-independent, GSH-dependent manner.}, journal = {Molecular biology reports}, volume = {40}, number = {5}, pages = {3807-3816}, pmid = {23269626}, issn = {1573-4978}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects/*physiology ; Ascorbic Acid/pharmacology ; Buthionine Sulfoximine/pharmacology ; Caspase Inhibitors/pharmacology ; Cell Proliferation/drug effects ; Glutathione/*metabolism ; HeLa Cells ; Histone Deacetylases/metabolism ; Humans ; Hydroxamic Acids/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Suberoyl bishydroxamic acid (SBHA) is a HDAC inhibitor that can regulate many biological functions including apoptosis and proliferation in various cancer cells. Here, we evaluated the effect of SBHA on the growth of HeLa cervical cancer cells in relation to apoptosis, reactive oxygen species (ROS) and glutathione (GSH) levels. Dose-dependent inhibition of cell growth was observed in HeLa cells with an IC50 of approximately 15 μM at 72 h. SBHA also induced apoptosis in HeLa cells, as evidenced by sub-G1 cells, annexin V-FITC staining cells, activations of caspase 3 and 8, and the loss of mitochondrial membrane potential (ΔΨm). In addition, all of the tested caspase inhibitors rescued some cells from SBHA-induced HeLa cell death. SBHA increased ROS levels including O2(•-) and induced GSH depletion in HeLa cells. Generally, caspase inhibitors did not affect ROS levels in SBHA-treated HeLa cells, but they significantly prevented GSH depletion in these cells. Furthermore, while the well-known antioxidants, N-acetyl cysteine and vitamin C, did not affect cell death, ROS level or GSH depletion in SBHA-treated HeLa cells, L-buthionine sulfoximine, a GSH synthesis inhibitor, enhanced cell death and GSH depletion in these cells. In conclusion, SBHA inhibits the growth of HeLa cervical cancer cells via caspase-dependent apoptosis, and the inhibition is independent of ROS level changes, but dependent on GSH level changes.}, }
@article {pmid23268593, year = {2013}, author = {Chen, MJ and Wang, HY and Chang, CW and Hu, KC and Hung, CY and Chen, CJ and Shih, SC}, title = {The add-on N-acetylcysteine is more effective than dimethicone alone to eliminate mucus during narrow-band imaging endoscopy: a double-blind, randomized controlled trial.}, journal = {Scandinavian journal of gastroenterology}, volume = {48}, number = {2}, pages = {241-245}, doi = {10.3109/00365521.2012.749509}, pmid = {23268593}, issn = {1502-7708}, mesh = {*Acetylcysteine/administration &amp; dosage ; Administration, Oral ; *Dimethylpolysiloxanes/administration &amp; dosage ; Double-Blind Method ; *Expectorants/administration &amp; dosage ; Female ; Gastroscopy/*methods ; Humans ; Male ; Middle Aged ; Narrow Band Imaging/*methods ; Outcome Assessment, Health Care ; Stomach Neoplasms/*diagnosis ; }, abstract = {OBJECTIVE: Recent studies have shown that pronase can improve mucosal visibility, but this agent is not uniformly available for human use worldwide. This study aimed to assess the efficacy of N-acetylcysteine (NAC), a mucolytic agent, in improving mucus elimination as measured by decreased endoscopic water flushes during narrow-band imaging (NBI) endoscopy.<br><br>MATERIAL AND METHODS: A consecutive series of patients scheduled for upper gastrointestinal endoscopy at outpatient clinics were enrolled in this double-blind, randomized controlled trial. The control group drank a preparation of 100 mg dimethicone (5 ml at 20 mg/ml) plus water up to 100 ml, and the NAC group drank 300 mg NAC plus 100 mg dimethicone and water up to 100 ml. During the endoscopy, the endoscopist used as many flushes of water as deemed necessary to produce a satisfactory NBI view of the entire gastric mucosa.<br><br>RESULTS: In all, 177 patients with a mean age of 51 years were evaluated in this study. Significantly lesser water was used for flushing during NBI endoscopy for the NAC group than the control group; 40 ml (30-70, 0-120) versus 50 ml (30-100, 0-150) (median (interquartile range, range), p = 0.0095).<br><br>CONCLUSIONS: Considering the safety profile of NAC, decreasing the number of water flushes for optimal vision and unavailability of pronase in some areas, the authors suggest the use of add-on NAC to eliminate mucus during NBI endoscopy.}, }
@article {pmid23267148, year = {2013}, author = {Gao, X and Liu, Y and Deeb, D and Liu, P and Liu, A and Arbab, AS and Gautam, SC}, title = {ROS mediate proapoptotic and antisurvival activity of oleanane triterpenoid CDDO-Me in ovarian cancer cells.}, journal = {Anticancer research}, volume = {33}, number = {1}, pages = {215-221}, pmid = {23267148}, issn = {1791-7530}, support = {R01 CA130948/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor/drug effects ; Cell Proliferation/drug effects ; Female ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors/metabolism/pharmacology ; Oleanolic Acid/*analogs &amp; derivatives/pharmacology ; *Ovarian Neoplasms/drug therapy/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism/pharmacology ; Signal Transduction/drug effects ; }, abstract = {Oleanane triterpenoids are broad-spectrum antiproliferative and proapoptotic agents. In this study, we investigated whether reactive oxygen species (ROS) play a role in the antitumor activity of methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) in OVCAR-5 and MDAH 2774 ovarian cancer cells. Treatment with CDDO-Me caused the generation of ROS (H(2)O(2)) and pre-treatment with N-acetylcysteine (NAC) prevented the generation of ROS. NAC also blocked the inhibition of cell proliferation by CDDO-Me. Likewise, NAC prevented the CDDO-Me-caused binding of fluorescein isothiocyanate (FITC)-tagged annexin V, cleavage of poly ADP-ribose polymerase-1 (PARP-1), procaspases-3, -8 and -9 and loss of mitochondrial membrane potential. CDDO-Me inhibited the expression of prosurvival phospho-AKT (p-AKT), phospho-mammalian target of rapamycin (p-mTOR) and nuclear factor-kappa B (NF-κB) (p65) signaling molecules and NF-κB-regulated antiapoptotic B-cell lymphoma-2 (BCL-2), B-cell lymphoma-extra large (BCL-xL), cellular inhibitor of apoptosis protein 1(c-IAP1) and survivin, but pre-treatment with NAC blocked the down-modulation of these signaling and antiapoptotic proteins by CDDO-Me. Together, these results indicate the pivotal role ROS play in the antiproliferative- and apoptosis-inducing activity of CDDO-Me in ovarian cancer cells; however, the role of ROS in the down-regulation of prosurvival AKT, mTOR, NF-κB and antiapoptotic BCL-2, BCL-xL, c-IAP1 and survivin warrants further investigation.}, }
@article {pmid23265409, year = {2013}, author = {Guerdjikova, AI and Blom, TJ and Mori, N and McElroy, SL}, title = {N-acetylcysteine in bulimia nervosa--open-label trial.}, journal = {Eating behaviors}, volume = {14}, number = {1}, pages = {87-89}, doi = {10.1016/j.eatbeh.2012.11.001}, pmid = {23265409}, issn = {1873-7358}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Binge-Eating Disorder/*drug therapy ; Bulimia Nervosa/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; Patient Dropouts ; Prospective Studies ; Psychiatric Status Rating Scales ; Severity of Illness Index ; Treatment Outcome ; Young Adult ; }, abstract = {The objective of this 12-week open-label flexible-dose study was to preliminarily assess the effectiveness of N-acetylcysteine (NAC) in bulimia nervosa (BN). The primary outcome was binge-purge episode frequency. Eight individuals with BN by DSM-IV criteria received NAC, but only two completed the study. NAC was not associated with significant reductions in frequency of binge-purge episodes or measures of clinical severity, eating, or mood pathology. In this trial, NAC was ineffective in BN and was associated with a high discontinuation rate.}, }
@article {pmid23261677, year = {2013}, author = {Park, S and Shin, H and Cho, Y}, title = {Shikonin induces programmed necrosis-like cell death through the formation of receptor interacting protein 1 and 3 complex.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {55}, number = {}, pages = {36-41}, doi = {10.1016/j.fct.2012.12.017}, pmid = {23261677}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Mice ; NIH 3T3 Cells ; Naphthoquinones/*pharmacology ; Protein Binding ; Reactive Oxygen Species/metabolism ; Receptor-Interacting Protein Serine-Threonine Kinases ; }, abstract = {An alternative cell demise programmed necrosis has also been proposed when apoptotic machinery is impaired or blocked during tumor necrosis factor alpha (TNFα) stimulation. Shikonin (SKN), an herbal extract from the Chinese plant, has been reported to induce either apoptosis or necrosis depending on cell types or its concentrations. In this presentation, SKN caused cell death of NIH3T3 in a dose-dependent manner. Intriguingly, SKN-mediated cell death was in part protected by necrostatin-1 (Nec-1), a specific inhibitor of programmed necrosis, but not zVAD a pan-caspase inhibitor. SKN directly mediated cell death via receptor interacting protein1 and 3 (RIP1-RIP3) complex formation, which is required for TNFα-mediated programmed necrosis. Additionally, SKN-caused cell death was reversed by a reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) whereas TNFα-mediated necrosis was successfully protected by butylated hydroxyanisole (BHA), implying that ROS may be differentially derived from death inducing agents. Concurrently with the protective effect of the ROS scavenger or Nec-1 on TNFα or SKN, the RIP1-RIP3 complex was significantly affected in the presence of those agents. Here, it is highlighted that SKN as well as TNFα can directly mediate cell death via a pronecrotic complex, but ROS were generated via different routes depending on cell death-inducing agents.}, }
@article {pmid23261493, year = {2013}, author = {Roten, AT and Baker, NL and Gray, KM}, title = {Marijuana craving trajectories in an adolescent marijuana cessation pharmacotherapy trial.}, journal = {Addictive behaviors}, volume = {38}, number = {3}, pages = {1788-1791}, pmid = {23261493}, issn = {1873-6327}, support = {R25DA020537-06/DA/NIDA NIH HHS/United States ; R01 DA026777/DA/NIDA NIH HHS/United States ; UL1 RR029882/RR/NCRR NIH HHS/United States ; R25 DA020537/DA/NIDA NIH HHS/United States ; UL1RR029882/RR/NCRR NIH HHS/United States ; R01DA026777/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Adolescent ; Combined Modality Therapy/methods ; Counseling ; Drug Administration Schedule ; Excitatory Amino Acid Agonists/*administration &amp; dosage ; Female ; Humans ; Male ; Marijuana Abuse/psychology/*rehabilitation ; Self Report ; Substance Withdrawal Syndrome/rehabilitation ; Young Adult ; }, abstract = {Marijuana is the most widely used illicit substance among youths and recent epidemiological data indicate that rates of marijuana use are on the rise. The purpose of this study was to examine marijuana craving trajectories among adolescents in an eight-week, placebo-controlled pharmacotherapy trial targeting marijuana cessation. All participants received contingency management and cessation counseling, and were randomized to either N-acetylcysteine (1200mg NAC twice daily; n=45) or placebo (n=44). Craving for marijuana was measured using the short-form of the Marijuana Craving Questionnaire (MCQ). Results demonstrated a significant decrease in MCQ scores over time for the total sample, but no significant differential change in scores between the NAC and placebo groups. This lack of significant difference is in the setting of NAC participants submitting significantly more negative urine cannabinoid tests as compared to placebo participants. This suggests that cessation effects associated with NAC may be mediated by effects other than marijuana craving.}, }
@article {pmid23257780, year = {2013}, author = {Sanchez-Alvarez, R and Martinez-Outschoorn, UE and Lin, Z and Lamb, R and Hulit, J and Howell, A and Sotgia, F and Rubin, E and Lisanti, MP}, title = {Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism: implications for breast cancer prevention.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {12}, number = {2}, pages = {289-301}, pmid = {23257780}, issn = {1551-4005}, support = {T32 AA007467/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohol Drinking/*adverse effects ; Biomarkers/metabolism ; Breast Neoplasms/*chemically induced/metabolism/prevention &amp; control ; Caveolin 1/metabolism ; Ethanol/*toxicity ; Female ; Fibroblasts/*drug effects/metabolism ; Flow Cytometry ; Fluorescent Antibody Technique ; Humans ; Immunoblotting ; Ketone Bodies/biosynthesis ; MCF-7 Cells ; Microscopy, Confocal ; Mitochondrial Turnover/drug effects ; Monocarboxylic Acid Transporters/metabolism ; Muscle Proteins/metabolism ; Myofibroblasts/cytology/drug effects ; Oxidative Stress/drug effects/physiology ; Reactive Oxygen Species/metabolism ; Tumor Microenvironment/*drug effects/physiology ; }, abstract = {Little is known about how alcohol consumption promotes the onset of human breast cancer(s). One hypothesis is that ethanol induces metabolic changes in the tumor microenvironment, which then enhances epithelial tumor growth. To experimentally test this hypothesis, we used a co-culture system consisting of human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts. Here, we show that ethanol treatment (100 mM) promotes ROS production and oxidative stress in cancer-associated fibroblasts, which is sufficient to induce myofibroblastic differentiation. Oxidative stress in stromal fibroblasts also results in the onset of autophagy/mitophagy, driving the induction of ketone body production in the tumor microenvironment. Interestingly, ethanol has just the opposite effect in epithelial cancer cells, where it confers autophagy resistance, elevates mitochondrial biogenesis and induces key enzymes associated with ketone re-utilization (ACAT1/OXCT1). During co-culture, ethanol treatment also converts MCF7 cells from an ER(+) to an ER(-) status, which is thought to be associated with "stemness," more aggressive behavior and a worse prognosis. Thus, ethanol treatment induces ketone production in cancer-associated fibroblasts and ketone re-utilization in epithelial cancer cells, fueling tumor cell growth via oxidative mitochondrial metabolism (OXPHOS). This "two-compartment" metabolic model is consistent with previous historical observations that ethanol is first converted to acetaldehyde (which induces oxidative stress) and then ultimately to acetyl-CoA (a high-energy mitochondrial fuel), or can be used to synthesize ketone bodies. As such, our results provide a novel mechanism by which alcohol consumption could metabolically convert "low-risk" breast cancer patients to "high-risk" status, explaining tumor recurrence or disease progression. Hence, our findings have clear implications for both breast cancer prevention and therapy. Remarkably, our results also show that antioxidants [such as N-acetyl cysteine (NAC)] can effectively reverse or prevent ethanol-induced oxidative stress in cancer-associated fibroblasts, suggesting a novel strategy for cancer prevention. We also show that caveolin-1 and MCT4 protein expression can be effectively used as new biomarkers to monitor oxidative stress induced by ethanol.}, }
@article {pmid23256569, year = {2013}, author = {Heidari, R and Babaei, H and Eghbal, M}, title = {Mechanisms of methimazole cytotoxicity in isolated rat hepatocytes.}, journal = {Drug and chemical toxicology}, volume = {36}, number = {4}, pages = {403-411}, doi = {10.3109/01480545.2012.749272}, pmid = {23256569}, issn = {1525-6014}, mesh = {Animals ; Cell Survival/drug effects ; Glutathione/metabolism ; Glyoxal/metabolism/toxicity ; Hepatocytes/*drug effects ; Lipid Peroxidation/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Methimazole/*metabolism/*toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Thiourea/analogs &amp; derivatives/metabolism/toxicity ; }, abstract = {Methimazole is an antithyroid drug widely used in the treatment of hyperthyroidism. Administration of this drug, often in a chronic manner, is associated with several adverse drug reactions in humans, including life-threatening hepatotoxicity. This study attempted to investigate the cytotoxic mechanism(s) of methimazole toward isolated rat hepatocytes. In addition, the role of proposed methimazole intermediary metabolites, such as N-methylthiourea and glyoxal, in the toxicity induced by this drug was evaluated. Isolated hepatocytes were prepared by the collagenase enzyme perfusion method. Cells were treated with methimazole, N-methylthiourea, and other chemicals and markers, such as cell viability, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) formation, lipid peroxidation (LPO), and cellular glutathione (GSH) content, were measured. Methimazole-induced cytotoxicity was accompanied by collapse in MMP, increase in ROS formation, and LPO. Further, methimazole caused reduction in GSH reservoirs, and the cytotoxic effect of the drug was much more severe in GSH-depleted cells. N-methylthiourea caused toxicity in lower concentrations than methimazole and reduced hepatocytes glutathione content. The specific flavin-containing monooxygenase inhibitor, N,N-dimethylaniline, attenuated toxicity induced by N-methylthiourea. Administration of glyoxal trapping agents, such as metformin, hydralazine, or N-acetyl cysteine, effectively prevented methimazole toxicity in intact or GSH-depleted rat hepatocytes. This study indicates that methimazole reactive metabolites are responsible for the cytotoxicity induced by this drug, but the role of glyoxal as a metabolite, which causes ROS formation, LPO, and mitochondrial injury, is predominant because the glyoxal-trapping agents diminished these adverse effects.}, }
@article {pmid23254439, year = {2013}, author = {Park, WH}, title = {The effects of exogenous H2O2 on cell death, reactive oxygen species and glutathione levels in calf pulmonary artery and human umbilical vein endothelial cells.}, journal = {International journal of molecular medicine}, volume = {31}, number = {2}, pages = {471-476}, doi = {10.3892/ijmm.2012.1215}, pmid = {23254439}, issn = {1791-244X}, mesh = {Animals ; Apoptosis ; Caspases/metabolism ; Cattle ; Cell Line ; Cell Proliferation ; Endothelial Cells/*cytology/metabolism ; Glutathione/*metabolism ; Human Umbilical Vein Endothelial Cells/cytology/metabolism ; Humans ; Hydrogen Peroxide/*metabolism ; Membrane Potential, Mitochondrial ; Pulmonary Artery/cytology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Enhanced oxidative stress contributes to endothelial dysfunction via the apoptotic induction of endothelial cells (ECs). However, the precise molecular mechanisms underlying its important effect remain unclear. Here, we evaluated the effects of exogenous hydrogen peroxide (H(2)O(2)) on cell growth and death in ECs such as calf pulmonary artery endothelial cells (CPAECs) and human umbilical vein endothelial cells (HUVECs) and investigated its mechanism of action in CPAECs. H(2)O(2) inhibited the growth of CPAECs and HUVECs at 24 h with IC50 of approximately 20 and 300 µM, respectively. H(2)O(2) induced cell death in both ECs, which was accompanied by the loss of mitochondrial membrane potential (MMP; ΔΨ(m)). H(2)O(2)-induced CPAEC death occurred via apoptosis, demonstrated by Annexin V-staining cells and Z-VAD (a pan-caspase inhibitor) treatment. H(2)O(2) increased superoxide anion levels in HUVECs but not in CPAECs. Treatment with 30 µM H(2)O(2) significantly decreased the activities of superoxide dismutases and catalase in CPAECs. H(2)O(2) induced glutathione (GSH) depletion in both ECs. Z-VAD and N-acetyl cysteine (NAC; a well-known antioxidant) attenuated apoptotic cell death and GSH depletion in H(2)O(2)-treated CPAECs. In conclusion, H(2)O(2) induced growth inhibition and death in ECs via GSH depletion. HUVECs were relatively resistant to H(2)O(2) compared with CPAECs. H(2)O(2)-induced CPAEC apoptosis required the activation of various caspases.}, }
@article {pmid23249634, year = {2012}, author = {Ben-Shachar, R and Chen, Y and Luo, S and Hartman, C and Reed, M and Nijhout, HF}, title = {The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model.}, journal = {Theoretical biology &amp; medical modelling}, volume = {9}, number = {}, pages = {55}, pmid = {23249634}, issn = {1742-4682}, support = {R01 ES019876/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/metabolism/*toxicity ; Allosteric Regulation ; Anti-Inflammatory Agents, Non-Steroidal/metabolism/*toxicity ; Glucuronides/metabolism ; Glutathione/metabolism ; Humans ; *Models, Statistical ; }, abstract = {BACKGROUND: Acetaminophen (N-acetyl-para-aminophenol) is the most widely used over-the-counter or prescription painkiller in the world. Acetaminophen is metabolized in the liver where a toxic byproduct is produced that can be removed by conjugation with glutathione. Acetaminophen overdoses, either accidental or intentional, are the leading cause of acute liver failure in the United States, accounting for 56,000 emergency room visits per year. The standard treatment for overdose is N-acetyl-cysteine (NAC), which is given to stimulate the production of glutathione.<br><br>METHODS: We have created a mathematical model for acetaminophen transport and metabolism including the following compartments: gut, plasma, liver, tissue, urine. In the liver compartment the metabolism of acetaminophen includes sulfation, glucoronidation, conjugation with glutathione, production of the toxic metabolite, and liver damage, taking biochemical parameters from the literature whenever possible. This model is then connected to a previously constructed model of glutathione metabolism.<br><br>RESULTS: We show that our model accurately reproduces published clinical and experimental data on the dose-dependent time course of acetaminophen in the plasma, the accumulation of acetaminophen and its metabolites in the urine, and the depletion of glutathione caused by conjugation with the toxic product. We use the model to study the extent of liver damage caused by overdoses or by chronic use of therapeutic doses, and the effects of polymorphisms in glucoronidation enzymes. We use the model to study the depletion of glutathione and the effect of the size and timing of N-acetyl-cysteine doses given as an antidote. Our model accurately predicts patient death or recovery depending on size of APAP overdose and time of treatment.<br><br>CONCLUSIONS: The mathematical model provides a new tool for studying the effects of various doses of acetaminophen on the liver metabolism of acetaminophen and glutathione. It can be used to study how the metabolism of acetaminophen depends on the expression level of liver enzymes. Finally, it can be used to predict patient metabolic and physiological responses to APAP doses and different NAC dosing strategies.}, }
@article {pmid23249342, year = {2013}, author = {Henze, A and Raila, J and Scholze, A and Zidek, W and Tepel, M and Schweigert, FJ}, title = {Does N-acetylcysteine modulate post-translational modifications of transthyretin in hemodialysis patients?.}, journal = {Antioxidants &amp; redox signaling}, volume = {19}, number = {11}, pages = {1166-1172}, doi = {10.1089/ars.2012.5125}, pmid = {23249342}, issn = {1557-7716}, mesh = {Acetylcysteine/chemistry/*metabolism/pharmacology ; Aged ; Case-Control Studies ; Female ; Humans ; Kidney Failure, Chronic/metabolism/therapy ; Male ; Middle Aged ; Prealbumin/chemistry/*metabolism ; Protein Binding ; *Protein Processing, Post-Translational/drug effects ; *Renal Dialysis ; }, abstract = {It is assumed that effects of the thiol antioxidant N-acetylcysteine (NAC) are mediated by interaction with protein-associated cysteine residues, however, information on protein level in vivo are missing. Therefore, we analyzed NAC-induced modifications of the protein transthyretin (TTR) in plasma of hemodialysis patients in a randomized, placebo-controlled study. TTR was selected due to its low molecular weight and the free cysteine residue in the polypeptide chain, which is known to be extensively modified by formation of mixed disulfides. The intravenous application of NAC during a hemodialysis session resulted in a substantial increase of native TTR from median 15% (range 8.8%-30%) to median 40% (37-50) and reduction of S-cysteinylated TTR [51% (44-60) vs. 6.6% (2.4-10)]. Additionally the pronounced formation of a TTR-NAC adduct was detected. However, all these modifications seemed to be reversible. Additionally, in vitro incubation of plasma with NAC confirmed the in vivo results and indicated that changes in post-translational modification pattern of TTR were a function of NAC concentration. Based on these observations and the essential metabolic and biochemical role of protein-associated cysteine residues we hypothesize that the interaction of NAC with proteins may explain altered protein functions due to modification of cysteine residues.}, }
@article {pmid23244588, year = {2013}, author = {Gao, X and Usas, A and Lu, A and Tang, Y and Wang, B and Chen, CW and Li, H and Tebbets, JC and Cummins, JH and Huard, J}, title = {BMP2 is superior to BMP4 for promoting human muscle-derived stem cell-mediated bone regeneration in a critical-sized calvarial defect model.}, journal = {Cell transplantation}, volume = {22}, number = {12}, pages = {2393-2408}, pmid = {23244588}, issn = {1555-3892}, support = {P30 AG024827/AG/NIA NIH HHS/United States ; R01 DE013420/DE/NIDCR NIH HHS/United States ; 5R01-DE13420-09/DE/NIDCR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adult ; Aged, 80 and over ; Animals ; Biomarkers/metabolism ; Bone Diseases/metabolism/pathology/*surgery ; Bone Morphogenetic Protein 4/*metabolism ; *Bone Regeneration ; Cell Survival/drug effects ; Cells, Cultured ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Nude ; Mice, SCID ; Muscle, Skeletal/*cytology/metabolism ; Osteogenesis ; Stem Cell Transplantation ; Stem Cells/*cytology/drug effects/metabolism ; Transplantation, Heterologous ; Young Adult ; }, abstract = {Muscle-derived cells have been successfully isolated using a variety of different methods and have been shown to possess multilineage differentiation capacities, including an ability to differentiate into articular cartilage and bone in vivo; however, the characterization of human muscle-derived stem cells (hMDSCs) and their bone regenerative capacities have not been fully investigated. Genetic modification of these cells may enhance their osteogenic capacity, which could potentially be applied to bone regenerative therapies. We found that hMDSCs, isolated by the preplate technique, consistently expressed the myogenic marker CD56, the pericyte/endothelial cell marker CD146, and the mesenchymal stem cell markers CD73, CD90, CD105, and CD44 but did not express the hematopoietic stem cell marker CD45, and they could undergo osteogenic, chondrogenic, adipogenic, and myogenic differentiation in vitro. In order to investigate the osteoinductive potential of hMDSCs, we constructed a retroviral vector expressing BMP4 and GFP and a lentiviral vector expressing BMP2. The BMP4-expressing hMDSCs were able to undergo osteogenic differentiation in vitro and exhibited enhanced mineralization compared to nontransduced cells; however, when transplanted into a calvarial defect, they failed to regenerate bone. Local administration of BMP4 protein and cell pretreatment with N-acetylcysteine (NAC), which improves cell survival, did not enhance the osteogenic capacity of the retro-BMP4-transduced cells. In contrast, lenti-BMP2-transduced hMDSCs not only exhibited enhanced in vitro osteogenic differentiation but also induced robust bone formation and nearly completely healed a critical-sized calvarial defect in CD-1 nude mice 6 weeks following transplantation. Herovici's staining of the regenerated bone demonstrated that the bone matrix contained a large amount of type I collagen. Our findings indicated that the hMDSCs are likely mesenchymal stem cells of muscle origin and that BMP2 is more efficient than BMP4 in promoting the bone regenerative capacity of the hMDSCs in vivo.}, }
@article {pmid23242830, year = {2013}, author = {Wang, HW and Yang, W and Lu, JY and Li, F and Sun, JZ and Zhang, W and Guo, NN and Gao, L and Kang, JR}, title = {N-acetylcysteine administration is associated with reduced activation of NF-kB and preserves lung dendritic cells function in a zymosan-induced generalized inflammation model.}, journal = {Journal of clinical immunology}, volume = {33}, number = {3}, pages = {649-660}, pmid = {23242830}, issn = {1573-2592}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Apoptosis/drug effects/immunology ; Cytokines/biosynthesis ; Dendritic Cells/drug effects/*immunology/ultrastructure ; Disease Models, Animal ; Enzyme Activation/drug effects ; Histocompatibility Antigens Class II/immunology ; Inflammation/chemically induced/*immunology/*metabolism/mortality ; Lung/drug effects/immunology/pathology ; Male ; Mice ; NF-kappa B/*metabolism ; RNA, Messenger/genetics ; Receptors, CCR5/genetics/metabolism ; Receptors, CCR7/genetics/metabolism ; Respiratory Function Tests ; Zymosan/adverse effects ; }, abstract = {PURPOSE: In severe sepsis, functional impairment and decreased numbers of dendritic cells (DCs) are essential reasons for immune function paralysis, secondary organ infection, and organ failure. We investigated the effects of N-acetylcysteine (NAC) administration on protecting lung DCs function in a zymosan-induced generalized inflammation (ZIGI) model.<br><br>METHODS: ZIGI was initiated in 80 Balb/c mice by intraperitoneal injection of zymosan (ZYM; 900&#xa0;mg/kg). Mice were divided into 4 groups: (1) SHAM+Vehicle; (2) SHAM+NAC; (3) ZYM+Vehicle; and (4) ZYM+NAC. NAC (100&#xa0;mg/kg) was administered at different time after ZYM injection. After 48&#xa0;h, we assessed: lung tissue pathological changes; arterial blood gas values; purified lung DCs surface expressions of MHC-II/I-A(d) and co-stimulatory molecules CD80, CD83, and CD86; lung DCs mRNA levels of chemokine receptors CCR5 and CCR7; lung DCs apoptosis; lung DCs ultrastructure by transmission electron microscopy; lung DCs NF-kB transcription factor activity; and LPS-stimulated lung DCs in vitro production of IL-12 and IL-10 were examined.<br><br>RESULTS: NAC treatment resulted in: significant improvements in ZYM-induced lung tissue damage and impaired lung function; inhibited lung DCs ZYM-induced increased expression of MHC-II/I-A(d), CD83, and CD86, but not CD80; reduced lung DCs ZYM-induced CCR5 and CCR7 mRNA levels; suppressed ZYM-induced lung DCs apoptosis; ameliorated ZYM-induced lung DCs ultrastructural abnormalities; inhibited ZYM-induced lung DCs NF-&#x3ba;B activity; and enhanced lung DCs production of IL-12 and inhibited their production of IL-10.<br><br>CONCLUSIONS: Repeated injections of NAC during the early stage of severe sepsis effectively inhibited lung DCs activation and their apoptosis, which could preserve DCs function.}, }
@article {pmid23232844, year = {2013}, author = {Ozaydin, M and Icli, A and Yucel, H and Akcay, S and Peker, O and Erdogan, D and Varol, E and Dogan, A and Okutan, H}, title = {Metoprolol vs. carvedilol or carvedilol plus N-acetyl cysteine on post-operative atrial fibrillation: a randomized, double-blind, placebo-controlled study.}, journal = {European heart journal}, volume = {34}, number = {8}, pages = {597-604}, doi = {10.1093/eurheartj/ehs423}, pmid = {23232844}, issn = {1522-9645}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Analysis of Variance ; Anti-Arrhythmia Agents/*therapeutic use ; Atrial Fibrillation/*drug therapy ; Carbazoles/*therapeutic use ; Carvedilol ; Coronary Artery Bypass ; Double-Blind Method ; Drug Therapy, Combination ; Humans ; Length of Stay ; Metoprolol/*therapeutic use ; Middle Aged ; Postoperative Complications/*drug therapy ; Propanolamines/*therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {AIMS: Carvedilol and N-acetyl cysteine (NAC) have antioxidant and anti-inflammatory properties. Aim was to evaluate the efficacy of metoprolol, carvedilol, and carvedilol plus NAC on the prevention of post-operative atrial fibrillation (POAF).<br><br>METHODS AND RESULTS: Patients undergoing cardiac surgery (n = 311) were randomized to metoprolol, carvedilol, or carvedilol plus NAC. Baseline characteristics were similar. The incidence of POAF was lower in the carvedilol plus NAC group compared with the metoprolol group (P < 0.0001) or the carvedilol group (P = 0.03). There was a borderline significance for lower POAF rates in the carvedilol group compared with the metoprolol group (P = 0.06). Duration of hospitalization was lower in the carvedilol plus NAC group compared to the metoprolol group (P = 0.004). Multivariate independent predictors of POAF included left-atrial diameter, hypertension, bypass duration, pre-randomization and pre-operative heart rates, carvedilol plus NAC group vs. metoprolol group, and carvedilol plus NAC group vs. carvedilol group.<br><br>CONCLUSION: Carvedilol plus NAC decreased POAF incidence and duration of hospitalization compared with metoprolol and decreased POAF incidence compared with carvedilol.}, }
@article {pmid23226323, year = {2012}, author = {Madureira, PA and Hill, R and Lee, PW and Waisman, DM}, title = {Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage.}, journal = {PloS one}, volume = {7}, number = {11}, pages = {e50591}, pmid = {23226323}, issn = {1932-6203}, mesh = {Active Transport, Cell Nucleus/drug effects ; Amino Acid Sequence ; Annexin A2/chemistry/*metabolism ; Cell Nucleus/*drug effects/genetics/*metabolism ; *DNA Damage ; HEK293 Cells ; Humans ; Hydrogen Peroxide/pharmacology ; MCF-7 Cells ; Mutagens/*toxicity ; Nuclear Export Signals ; Oxidative Stress/drug effects/genetics ; }, abstract = {Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H2O2), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2'-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.}, }
@article {pmid23222262, year = {2013}, author = {Perng, DW and Chang, TM and Wang, JY and Lee, CC and Lu, SH and Shyue, SK and Lee, TS and Kou, YR}, title = {Inflammatory role of AMP-activated protein kinase signaling in an experimental model of toxic smoke inhalation injury.}, journal = {Critical care medicine}, volume = {41}, number = {1}, pages = {120-132}, doi = {10.1097/CCM.0b013e318265f653}, pmid = {23222262}, issn = {1530-0293}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Cells, Cultured ; Humans ; Inflammation/enzymology/immunology/pathology ; Interleukin-8/*metabolism ; *MAP Kinase Signaling System ; Male ; Mice ; Mice, Inbred C57BL ; NADPH Oxidases/metabolism ; Random Allocation ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/immunology ; Smoke Inhalation Injury/*enzymology/*immunology/pathology ; }, abstract = {OBJECTIVE: The molecular mechanisms underlying lung inflammation in toxic smoke inhalation injury are unknown. We investigated the signaling pathway responsible for the induction of interleukin 8 by wood smoke extract in lung epithelial cells and lung inflammation induced by wood smoke exposure in mice.<br><br>DESIGN: A randomized, controlled study.<br><br>SETTING: A research laboratory.<br><br>Exposure of primary human bronchial epithelial cells to wood smoke extract sequentially activated NADPH oxidase and increased intracellular reactive oxygen species level; activated AMP-activated protein kinase, extracellular signal-regulated kinase and Jun N-terminal kinase (two mitogen-activated protein kinases), and nuclear factor-&#x3ba;B and signal transducer and activator of transcription protein 3 (two transcription factors); and induced interleukin-8. Inhibition of NADPH oxidase activation with apocynin or siRNA targeting p47(phox) (a subunit of NADPH oxidase) attenuated the increased intracellular reactive oxygen species level, AMP-activated protein kinase activation, and interleukin-8 induction. Removal of intracellular reactive oxygen species by N-acetyl-cysteine reduced the activation of AMP-activated protein kinase, extracellular signal-regulated kinase and Jun N-terminal kinase, and interleukin-8 induction. Prevention of AMP-activated protein kinase activation by Compound C or AMP-activated protein kinase siRNA lessened the activation of Jun N-terminal kinase, extracellular signal-regulated kinase, nuclear factor-&#x3ba;B, signal transducer and activator of transcription protein 3 and interleukin-8 induction. Inhibition of Jun N-terminal kinase and extracellular signal-regulated kinase activation by inhibitors reduced the activation of nuclear factor-&#x3ba;B and signal transducer and activator of transcription protein 3 and interleukin-8 induction. Abrogation of nuclear factor-&#x3ba;B and signal transducer and activator of transcription protein 3 activation by inhibitors attenuated the interleukin-8 induction. Additionally, acute exposure of mice to wood smoke promoted AMP-activated protein kinase phosphorylation and expression of macrophage inflammatory protein 2 (an interleukin-8 homolog) in lung epithelial cells and lungs and lung inflammation, all of which were reduced by Compound C treatment.<br><br>CONCLUSIONS: Interleukin-8 induction by wood smoke extract in lung epithelial cells is mediated by novel NADPH oxidase-dependent, reactive oxygen species-sensitive AMP-activated protein kinase signaling with Jun N-terminal kinase and extracellular signal-regulated kinase as the downstream kinases and nuclear factor-&#x3ba;B and signal transducer and activator of transcription protein 3 as the downstream transcription factors. This AMP-activated protein kinase signaling is likely important for inducing lung inflammation with toxic smoke exposure in mice.}, }
@article {pmid23219310, year = {2013}, author = {Camuglia, AC and Maeder, MT and Starr, J and Farrington, C and Kaye, DM}, title = {Impact of N-acetylcysteine on endothelial function, B-type natriuretic peptide and renal function in patients with the cardiorenal syndrome: a pilot cross over randomised controlled trial.}, journal = {Heart, lung &amp; circulation}, volume = {22}, number = {4}, pages = {256-259}, doi = {10.1016/j.hlc.2012.10.012}, pmid = {23219310}, issn = {1444-2892}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Aged ; *Cardio-Renal Syndrome/blood/drug therapy/physiopathology ; Cross-Over Studies ; Double-Blind Method ; *Endothelium, Vascular/metabolism/physiopathology ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; *Kidney/metabolism/physiopathology ; Kidney Function Tests ; Male ; Middle Aged ; Natriuretic Peptide, Brain/*blood ; Pilot Projects ; }, abstract = {BACKGROUND: Both heart and renal failure are characterised by increased systemic oxidative stress and endothelial dysfunction and occur in the cardiorenal syndrome (CRS). The aim of the present study was to assess the impact of N-acetylcysteine (NAC), a potent antioxidant, on endothelial function, B-type natriuretic peptide (BNP) and renal function in patients with CRS.<br><br>METHODS: In a double blind, placebo controlled manner, we randomised nine stable outpatients with both heart failure (LVEF<40% and NYHA class II or III) and renal failure (Cockroft Gault clearance of 20-60ml/min) to placebo or NAC (500mg orally twice daily) for 28 days followed by a wash out period (>7 days) and crossover to the other treatment.<br><br>RESULTS: Eight patients completed the study and all data (N=9) was used in the analysis. Mean forearm blood flow improved significantly with NAC with mean ratio of improvement of 1.99 (SEM: &#xb1;0.49) for NAC and 0.73 (SEM: &#xb1;0.23) for placebo with a p-value of 0.047. There was no significant difference in BNP (p=0.25), renal function (p=0.71) or NYHA class (p=0.5). No deaths occurred during the trial.<br><br>CONCLUSION: In this pilot trial of patients with CRS, NAC therapy was associated with improved forearm blood flow. This may represent a general improvement in endothelial function and warrants further investigation of antioxidant therapy in these patients.}, }
@article {pmid23218652, year = {2013}, author = {Sagredo, S and Brahm, J and Uribe, M and Codoceo, V and Smok, G}, title = {[Acute liver failure after bariatric surgery. A case report and literature review].}, journal = {Gastroenterologia y hepatologia}, volume = {36}, number = {2}, pages = {76-80}, doi = {10.1016/j.gastrohep.2012.06.004}, pmid = {23218652}, issn = {0210-5705}, mesh = {Adult ; Bariatric Surgery/*adverse effects ; Biopsy ; Female ; Humans ; Liver Failure, Acute/*etiology ; Obesity, Morbid/surgery ; }, abstract = {Non-alcoholic fatty liver disease is common among morbidly obese people. Bariatric surgery is increasingly used in this population to control weight but is not free of risks. We present the case of a 28-year-old morbidly obese woman who underwent gastroplasty with intestinal resection and a gastro-jejunal anastomosis. Eleven months later, and with a weight reduction of 35%, the patient developed acute liver failure. A biopsy showed severe steatohepatitis and fibrosis. After prolonged hospital stay and management that consisted of support measures, nutritional assistance, N-acetyl cysteine, zinc and vitamin E, liver function was restored. A follow-up biopsy showed marked regression of the initial findings. Bariatric surgery has many beneficial effects. However, even with the most up-to-date techniques, complications can occur. Familiarity with these complications is important for their prevention and treatment.}, }
@article {pmid23212479, year = {2013}, author = {Bémeur, C and Butterworth, RF}, title = {Liver-brain proinflammatory signalling in acute liver failure: role in the pathogenesis of hepatic encephalopathy and brain edema.}, journal = {Metabolic brain disease}, volume = {28}, number = {2}, pages = {145-150}, pmid = {23212479}, issn = {1573-7365}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Ammonia/metabolism ; Animals ; Blood-Brain Barrier/physiology ; Brain/*physiopathology ; Brain Edema/pathology/*physiopathology ; Cytokines/metabolism/physiology ; Hepatic Encephalopathy/pathology/*physiopathology/therapy ; Humans ; Inflammation/*physiopathology ; Lactates/metabolism ; Liver/*physiopathology ; Liver Failure, Acute/physiopathology ; Signal Transduction/physiology ; }, abstract = {A robust neuroinflammatory response characterized by microglial activation and increased brain production of pro-inflammatory cytokines is common in acute liver failure (ALF). Mechanisms proposed to explain the neuroinflammatory response in ALF include direct effects of systemically-derived proinflammatory cytokines and the effects of brain lactate accumulation on pro-inflammatory cytokine release from activated microglia. Cell culture studies reveal a positive synergistic effect of ammonia and pro-inflammatory cytokines on the expression of proteins involved in glutamate homeostasis and in oxidative/nitrosative stress. Proinflammatory cytokines have the capacity to alter blood-brain barrier (BBB) integrity and preliminary studies suggest that the presence of infection in ALF results in rupture of the BBB and vasogenic brain edema. Treatments currently under investigation that are effective in prevention of encephalopathy and brain edema in ALF which are aimed at reduction of neuroinflammation in ALF include mild hypothermia, albumin dialysis systems, N-acetyl cysteine and the antibiotic minocycline with potent anti-inflammatory actions that are distinct from its anti-microbial properties.}, }
@article {pmid23210443, year = {2012}, author = {Rains, JL and Kanikarla-Marie, P and Jain, SK}, title = {Hyperketonemia induces upregulation of LFA-1 in monocytes, which is mediated by ROS and P38 MAPK activation.}, journal = {Canadian journal of physiology and pharmacology}, volume = {90}, number = {12}, pages = {1642-1646}, doi = {10.1139/y2012-131}, pmid = {23210443}, issn = {1205-7541}, support = {R01 DK072433/DK/NIDDK NIH HHS/United States ; }, mesh = {3-Hydroxybutyric Acid/pharmacology ; Acetoacetates/pharmacology ; Acetylcysteine/pharmacology ; Cardiovascular Diseases/enzymology/genetics/metabolism ; Cell Adhesion Molecules/genetics/metabolism ; Cells, Cultured ; Humans ; Ketosis/enzymology/genetics/*metabolism ; Lymphocyte Function-Associated Antigen-1/genetics/*metabolism ; MAP Kinase Signaling System ; Monocytes/enzymology/*metabolism ; Oxidative Stress/drug effects/genetics ; Reactive Oxygen Species/*metabolism ; Up-Regulation ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Type 1 diabetic patients have hyperketonemia, elevated levels of pro-inflammatory and oxidative stress markers, and a higher incidence of vascular disease. This study examines the hypothesis that hyperketonemia increases reactive oxygen species (ROS) and is in part responsible for increased expression of adhesion molecules in monocytes. THP-1 monocytes were treated with acetoacetate (AA) or β-hydroxybutyrate (BHB) (0-10 mmol/L) for 24 h. Results show that AA, but not BHB, increases ROS production in monocytes. Pretreatment of monocytes with N-acetylcysteine (NAC) inhibited AA-induced ROS production. AA treatment induced upregulation of LFA-1 and pretreatment of monocytes with NAC or an inhibitor to p38 MAPK inhibited this upregulation in monocytes. This suggests that physiological concentrations of AA can contribute to increased ROS and activation of p38 MAPK, which may be responsible for AA-induced upregulation of LFA-1 in monocytes. Thus, hyperketonemia contributes to the risk for cardiovascular disease in type 1 diabetes.}, }
@article {pmid23210087, year = {2012}, author = {Momeni, A and Mirhoseini, M and Beigi, FM and Esfahani, MR and Kheiri, S and Amiri, M and Seidain, Z}, title = {Effect of N-acetyl cysteine in prevention of contrast nephropathy on patients under intravenous pyelography and contrast CT.}, journal = {Advanced biomedical research}, volume = {1}, number = {}, pages = {28}, pmid = {23210087}, issn = {2277-9175}, abstract = {BACKGROUND: Contrast nephropathy is a common and often reversible cause of acute renal failure (ARF). About 10% of ARF in admitted patients might be due to it and may also lead to dialysis. Some methods could prevent it such as fluid therapy with half or normal saline, Na bicarbonate, N-acetyl cysteine (NAC), and so on. The aim of this study was to evaluate the efficacy of NAC to prevent contrast nephropathy.<br><br>MATERIALS AND METHODS: In a cross-sectional study, 110 patients who were candidate for intravenous pyelography (IVP) or CT scan enrolled in two groups: Case and control. In patients of case group, meglumine compound and in control group, placebo was prescribed before procedure. Before study and after 48 h, blood urea nitrogen (BUN) and creatinine (Cr) was checked, and glomerular filtration rate (GFR) was measured with Cockcroft-Gault formula.<br><br>RESULTS: There were no difference between age and gender of two groups. There was also no significant difference between mean Cr before and after study; however, GFR of patients in case group was significantly higher than the control group after 48 h of procedure.<br><br>CONCLUSION: Because GFR was higher in case group and there were no drug side-effects in patients, we recommend the use of NAC before administration of intravenous contrast especially in high-risk population such as diabetic patients.}, }
@article {pmid23207767, year = {2012}, author = {Yu, Y and Fan, SM and Song, JK and Tashiro, S and Onodera, S and Ikejima, T}, title = {Hydroxyl radical (·OH) played a pivotal role in oridonin-induced apoptosis and autophagy in human epidermoid carcinoma A431 cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {35}, number = {12}, pages = {2148-2159}, doi = {10.1248/bpb.b12-00405}, pmid = {23207767}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Carcinoma, Squamous Cell/*drug therapy/metabolism/physiopathology ; Cell Line, Tumor ; Diterpenes, Kaurane/*pharmacology/therapeutic use ; Dose-Response Relationship, Drug ; Down-Regulation ; Free Radical Scavengers/pharmacology ; Glutathione/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Hydroxyl Radical/*metabolism ; Iron/pharmacology ; Isodon/*chemistry ; Membrane Potential, Mitochondrial/drug effects/physiology ; Oxidative Stress/drug effects ; Phytotherapy ; Plant Extracts/pharmacology/therapeutic use ; Protein-Tyrosine Kinases/metabolism ; Signal Transduction ; }, abstract = {Oridonin, a diterpenoid compound extracted and purified from Rabdosia rubescen, has been reported to induce tumor cell apoptosis through tyrosine kinase pathway. To further examine the mechanism of oridonin, we selected human epidermoid carcinoma A431 cell as a test object. Besides apoptosis, oridonin also induced A431 cell autophagy, and this autophagy antagonized apoptosis and played a protective role for A431 cells. Reactive oxygen species (ROS) played a pivotal role in induction of cytotoxicity. Therefore, a ROS scavenger, N-acetylcysteine (NAC) combined with oridonin was appiled. Results of morphologic observation, flow cytometric analysis and Western blot analysis showed that NAC could significantly reverse both ROS generation and down-regulation of mitochondrial membrane potential in oridonin treated cells. NAC inhibited oridonin induced apoptosis through both the intrinsic and extrinsic apoptotic pathways. NAC effectively inhibited both oridonin-induced apoptosis and autophagy by reducing intracellular oxidative stress. To further examine the mechanism of ROS, exogenous enzyme antioxidants (superoxide dismutase (SOD), catalase (CAT)) and non-enzyme antioxidants (glutathione (GSH)) were applied to detect the effect of oridonin on ROS generation. Only GSH exerted a similar role with NAC, suggesting that hydroxyl radical (·OH) played the major role in oridonin-induced cell death. Oridonin could decrease the GSH level in A431 cells in a dose-dependent manner. In addition, after treatment with ·OH donor, Fenton reagent, the changes in A431cells were similar to the results of oridonin treatment. All the results proved that ·OH played the pivotal role in oridonin induced apoptosis and autophagy in A431 cells.}, }
@article {pmid23206959, year = {2012}, author = {Kretzmann, NA and Chiela, E and Matte, U and Marroni, N and Marroni, CA}, title = {N-acetylcysteine improves antitumoural response of Interferon alpha by NF-kB downregulation in liver cancer cells.}, journal = {Comparative hepatology}, volume = {11}, number = {1}, pages = {4}, pmid = {23206959}, issn = {1476-5926}, abstract = {BACKGROUND: Liver cancer is one of the most common malignancies in the world and at the moment, there is no drug intervention effective for the treatment of liver tumours. Investigate the effect of N-acetylcysteine (NAC), which has been studied for its antitumoural properties, on the toxicity of hepatocarcinoma (HCC) cells in vitro when used with the drug interferon alpha-2A (IFN), which is used clinically to treat HCC.<br><br>RESULTS: NAC, IFN and NAC plus IFN reduced cell viability, as determined by MTT assay. More importantly, NAC potentiates the cytotoxic effect of IFN, with the best response achieved with 10 mM of NAC and 2.5 x 104 of IFN. These results were confirmed by Annexin/PI staining through flow cytometry and morphologic analyses. Co-treatment reduced the expression of the nuclear transcription factor kappa-B (NF-kB). In a similar way to NAC, RNAi against p65 potentiated the toxic effect of IFN, suggesting that, indeed, NAC may be enhancing the effect of IFN through inhibition of NF-kB.<br><br>CONCLUSIONS: Our results support the notion that NAC may be an important drug for the treatment of liver tumours as primary or adjuvant therapy. IFN has a limited clinical response, and therefore, the anti-proliferative properties of NAC in the liver should be explored further as an alternative for non-responders to IFN treatment.}, }
@article {pmid23201137, year = {2013}, author = {Odiatou, EM and Skaltsounis, AL and Constantinou, AI}, title = {Identification of the factors responsible for the in vitro pro-oxidant and cytotoxic activities of the olive polyphenols oleuropein and hydroxytyrosol.}, journal = {Cancer letters}, volume = {330}, number = {1}, pages = {113-121}, doi = {10.1016/j.canlet.2012.11.035}, pmid = {23201137}, issn = {1872-7980}, mesh = {Animals ; Breast Neoplasms/drug therapy/metabolism ; Cell Line, Tumor ; Culture Media ; Female ; Humans ; Hydrogen Peroxide/metabolism ; Iridoid Glucosides ; Iridoids ; Mice ; Olea/*chemistry ; Oxidants/*pharmacology ; Oxidative Stress/drug effects ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; Plant Extracts/pharmacology ; Plant Oils/pharmacology ; Pyrans/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {The olive polyphenols oleuropein and hydroxytyrosol were reported recently to produce extracellular hydrogen peroxide (H2O2) under standard culture conditions. The precise factors responsible for this production and the conditions promoting or retarding it are critical for the interpretation of the in vitro results. In this study, a systematic evaluation of the components of the most commonly used culture media revealed that sodium bicarbonate is the defining cause for the production of H2O2 by these polyphenols. The produced H2O2 caused extensive oxidative DNA damage and significant decrease in cell viability of cancer (MDA-MB-231) and normal (MCF-10A, STO) cells alike. Sodium pyruvate and the antioxidant N-acetyl cysteine (NAC) totally reversed these effects. Therefore, we conclusively identified the culture conditions that promote H2O2 production by these polyphenols, producing artifacts that may be misinterpreted as a specific anticancer activity. Our findings raise considerable questions regarding the use of culture media with sodium bicarbonate or sodium pyruvate as components, for the in vitro study of these and possibly other plant polyphenols.}, }
@article {pmid24653882, year = {2012}, author = {Choi, CH}, title = {Mechanisms and treatment of blast induced hearing loss.}, journal = {Korean journal of audiology}, volume = {16}, number = {3}, pages = {103-107}, pmid = {24653882}, issn = {2092-9862}, abstract = {The main objective of this study is to provide an overview of the basic mechanisms of blast induced hearing loss and review pharmacological treatments or interventions that can reduce or inhibit blast induced hearing loss. The mechanisms of blast induced hearing loss have been studied in experimental animal models mimicking features of damage or injury seen in human. Blast induced hearing loss is characterized by perforation and rupture of the tympanic membrane, ossicular damage, basilar membrane damage, inner and outer hair cell loss, rupture of round window, changes in chemical components of cochlear fluid, vasospasm, ischemia, oxidative stress, excitotoxicity, hematoma, and hemorrhage in both animals and humans. These histopathological consequences of blast exposure can induce hearing loss, tinnitus, dizziness, and headache. The pharmacological approaches to block or inhibit some of the auditory pathological consequences caused by blast exposure have been developed with antioxidant drugs such as 2,4-disulfonyl α-phenyl tertiary butyl nitrone (HXY-059, now called HPN-07) and N-acetylcysteine (NAC). A combination of antioxidant drugs (HPN-07 and NAC) was administered to reduce blast induced cochlear damage and hearing loss. The combination of the antioxidant drugs can prevent or treat blast induced hearing loss by reducing damage to the mechanical and neural component of the auditory system. Although information of the underlying mechanisms and treatment of blast induced hearing loss are provided, further and deep research should be achieved due to the limited and controversial knowledge.}, }
@article {pmid23194825, year = {2013}, author = {Ferreira, PS and Nogueira, TB and Costa, VM and Branco, PS and Ferreira, LM and Fernandes, E and Bastos, ML and Meisel, A and Carvalho, F and Capela, JP}, title = {Neurotoxicity of "ecstasy" and its metabolites in human dopaminergic differentiated SH-SY5Y cells.}, journal = {Toxicology letters}, volume = {216}, number = {2-3}, pages = {159-170}, doi = {10.1016/j.toxlet.2012.11.015}, pmid = {23194825}, issn = {1879-3169}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/*pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Death/drug effects ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Dipeptides/metabolism ; Dopaminergic Neurons/*drug effects/metabolism/pathology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Humans ; N-Methyl-3,4-methylenedioxyamphetamine/*toxicity ; Neurotoxicity Syndromes/*etiology/pathology ; Piperazines/pharmacology ; }, abstract = {"Ecstasy" (3,4-methylenedioxymethamphetamine or MDMA) is a widely abused recreational drug, reported to produce neurotoxic effects, both in laboratory animals and in humans. MDMA metabolites can be major contributors for MDMA neurotoxicity. This work studied the neurotoxicity of MDMA and its catechol metabolites, α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) in human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate. Differentiation led to SH-SY5Y neurons with higher ability to accumulate dopamine and higher resistance towards dopamine neurotoxicity. MDMA catechol metabolites were neurotoxic to SH-SY5Y neurons, leading to caspase 3-independent cell death in a concentration- and time-dependent manner. MDMA did not show a concentration- and time-dependent death. Pre-treatment with the antioxidant and glutathione precursor, N-acetylcysteine (NAC), resulted in strong protection against the MDMA metabolites' neurotoxicity. Neither the superoxide radical scavenger, tiron, nor the inhibitor of the dopamine (DA) transporter, GBR 12909, prevented the metabolites' toxicity. Cells exposed to α-MeDA showed an increase in intracellular glutathione (GSH) levels, which, at the 48 h time-point, was not dependent in the activity increase of γ-glutamylcysteine synthetase (γ-GCS), revealing a possible transient effect. Importantly, pre-treatment with buthionine sulfoximine (BSO), an inhibitor of γ-GCS, prevented α-MeDA induced increase in GSH levels, but did not augment this metabolite cytotoxicity. Even so, BSO pre-treatment abolished NAC protective effects against α-MeDA neurotoxicity, which were, at least partially, due to GSH de novo synthesis. Inversely, pre-treatment of cells with BSO augmented N-Me-α-MeDA-induced neurotoxicity, but only slightly affected NAC neuroprotection. In conclusion, MDMA catechol metabolites promote differential toxic effects to differentiated dopaminergic human SH-SY5Y cells.}, }
@article {pmid23194005, year = {2013}, author = {Rollstin, AD and Seifert, SA}, title = {Acetaminophen/diphenhydramine overdose in profound hypothermia.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {51}, number = {1}, pages = {50-53}, doi = {10.3109/15563650.2012.748195}, pmid = {23194005}, issn = {1556-9519}, mesh = {Acetaminophen/blood/pharmacokinetics/*poisoning ; Acetylcysteine/administration &amp; dosage/therapeutic use ; Adult ; Analgesics, Non-Narcotic/blood/pharmacokinetics/*poisoning ; Chemical and Drug Induced Liver Injury/prevention &amp; control ; Cholinergic Antagonists/blood/pharmacokinetics/*poisoning ; Diphenhydramine/blood/pharmacokinetics/*poisoning ; Drug Combinations ; Drug Overdose/*drug therapy/metabolism/physiopathology/therapy ; Female ; Humans ; Hypothermia/etiology/*therapy ; Infusions, Intravenous ; Nonprescription Drugs/analysis/pharmacokinetics/*poisoning ; Rewarming ; Treatment Outcome ; }, abstract = {BACKGROUND: There are few reports of acetaminophen overdose in hypothermic patients and even fewer reports describing profound hypothermia. The kinetics, risk of hepatotoxicity, and the possible dose adjustments to N-acetylcysteine (NAC) therapy are not known in this setting.<br><br>CASE REPORT: A 37-year-old female was found unconscious outside in December and was brought by ambulance to a tertiary care Emergency Department (ED) following a presumed overdose of acetaminophen and diphenhydramine. She later confirmed the ingestion and reported the ingestion had occurred approximately 18 hours prior to being found. On arrival, she was profoundly hypothermic, with a core rectal temperature of 17&#xb0;C. Her initial serum acetaminophen concentration was 232 mcg/mL 19 hours post ingestion of a reported dose of approximately 50 grams of acetaminophen and 2.5 grams of diphenhydramine. Active rewarming was started immediately and IV NAC was initiated using the standard treatment protocol. The patient did not develop serious signs of hepatic injury or NAC toxicity. The patient's AST and ALT peaked 12 hours after admission at 84 IU/L (ref 10-37 U/L) and 104 IU/L (ref 12-78 U/L), respectively. Her INR peaked 2 hours after admission at 1.46 (ref < 1.2).<br><br>DISCUSSION: Despite the significant ingestion of acetaminophen, delayed presentation, prolonged period of decreased responsiveness, and profound hypothermia, the patient did not develop any signs/symptoms of liver injury. NAC was administered in a standard dose during her rewarming period without apparent toxicity. The patient's absorption and/or metabolism of acetaminophen were likely slowed by her hypothermia and possibly by the anticholinergic coingestant. Initiation of IV NAC at a standard dose was apparently safe and effective in preventing hepatotoxicity as the patient was rewarmed.<br><br>CONCLUSIONS: Profound hypothermia may be protective of hepatic injury in acetaminophen overdose. Delayed absorption from the coingestant, diphenhydramine, may also have played a role. IV NAC was given in a standard dose without apparent toxicity in the setting of profound hypothermia. Lastly, IV NAC, in standard dosing, appeared to be effective in preventing hepatotoxicity during rewarming in a patient with a potentially hepatotoxic concentration of acetaminophen with a coingestion of the anticholinergic agent, diphenhydramine.}, }
@article {pmid23192945, year = {2013}, author = {Kim, KY and Cho, HJ and Yu, SN and Kim, SH and Yu, HS and Park, YM and Mirkheshti, N and Kim, SY and Song, CS and Chatterjee, B and Ahn, SC}, title = {Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin.}, journal = {Journal of cellular biochemistry}, volume = {114}, number = {5}, pages = {1124-1134}, doi = {10.1002/jcb.24455}, pmid = {23192945}, issn = {1097-4644}, support = {I01 BX000280/BX/BLRD VA/United States ; R01 AG010486/AG/NIA NIH HHS/United States ; R01 AG019660/AG/NIA NIH HHS/United States ; }, mesh = {Apoptosis/*drug effects ; Calcium/*metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Drug Screening Assays, Antitumor ; Drugs, Chinese Herbal ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Enzyme Activation/drug effects ; G2 Phase Cell Cycle Checkpoints/drug effects ; Homeostasis/*drug effects ; Humans ; Intracellular Space/drug effects/metabolism ; M Phase Cell Cycle Checkpoints/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/*metabolism ; Models, Biological ; Podophyllotoxin/*analogs &amp; derivatives/chemistry/pharmacology ; Prostatic Neoplasms/metabolism/*pathology ; Protein Transport/drug effects ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {The limited treatment option for recurrent prostate cancer and the eventual resistance to conventional chemotherapy drugs has fueled continued interest in finding new anti-neoplastic agents of natural product origin. We previously reported anti-proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC-3 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase-3-dependent pathway that is activated due to dysregulated mitochondrial function. DPT-treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Ca (i)(2+) surge, increased mitochondrial membrane potential (MMP, ΔΨ(m)), Bax protein translocation to mitochondria and cytochrome c release to the cytoplasm. This resulted in caspase-3 activation, which in turn induced apoptosis. The antioxidant N-acetylcysteine (NAC) reduced ROS accumulation, MMP and Ca (i)(2+) surge, on the other hand the Ca(2+) chelator BAPTA inhibited the Ca(i)(2+) overload and MMP without affecting the increase of ROS, indicating that the generation of ROS occurred prior to Ca(2+) flux. This suggested that both ROS and Ca(i)(2+) signaling play roles in the increased MMP via Ca (i)(2+)-dependent and/or -independent mechanisms, since ΔΨ(m) elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS- and Ca(i)(2+)-activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca(2+) flux homeostasis.}, }
@article {pmid23188834, year = {2013}, author = {O'Sullivan, S and Healy, DA and Moloney, MC and Grace, PA and Walsh, SR}, title = {The role of N--acetylcysteine in the prevention of contrast-induced nephropathy in patients undergoing peripheral angiography: a structured review and meta-analysis.}, journal = {Angiology}, volume = {64}, number = {8}, pages = {576-582}, doi = {10.1177/0003319712467223}, pmid = {23188834}, issn = {1940-1574}, mesh = {Acetylcysteine ; Acute Kidney Injury/chemically induced ; *Angiography ; Creatinine/blood ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Randomized Controlled Trials as Topic ; }, abstract = {Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI). N-acetylcysteine (NAC) was proposed as an effective preventative measure. As data in relation to the use of NAC for the prevention of CIN in peripheral angiography are lacking, a systematic review and meta-analysis were undertaken. A comprehensive search for the published and unpublished data was performed. Data were extracted from the eligible studies. Pooled odds ratios (ORs) were used to calculate the effect of NAC on CIN incidence. Pooled effect size estimates were used to calculate the effect of NAC on serum creatinine (SCr) postcontrast. Our results showed that NAC did not reduce CIN incidence (pooled OR 1.05; 95% confidence interval [CI] 0.38-2.88; P = .92) or the mean SCr levels (pooled weighted mean difference, 4.38; 95% CI 10.4-1.65; P = .15). In conclusion, insufficient evidence exists to recommend NAC for the prevention of CIN in patients undergoing peripheral angiography.}, }
@article {pmid23187459, year = {2013}, author = {Park, EJ and Choi, KS and Yoo, YH and Kwon, TK}, title = {Nutlin-3, a small-molecule MDM2 inhibitor, sensitizes Caki cells to TRAIL-induced apoptosis through p53-mediated PUMA upregulation and ROS-mediated DR5 upregulation.}, journal = {Anti-cancer drugs}, volume = {24}, number = {3}, pages = {260-269}, doi = {10.1097/CAD.0b013e32835c0311}, pmid = {23187459}, issn = {1473-5741}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects/physiology ; Apoptosis Regulatory Proteins/*metabolism ; Cell Line, Tumor ; Fibroblasts/drug effects/metabolism ; Genes, p53 ; HCT116 Cells/drug effects ; Humans ; Imidazoles/*pharmacology ; Kidney Neoplasms/drug therapy/metabolism/pathology ; Piperazines/*pharmacology ; Proto-Oncogene Proteins/*metabolism ; Proto-Oncogene Proteins c-mdm2/*antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/metabolism/pharmacology ; Up-Regulation/drug effects ; }, abstract = {Nutlin-3 is a novel small-molecule antagonist of the human homolog of mouse double minute (MDM2) that binds MDM2 in the p53-binding pocket and activates the p53 signaling pathway. In this study, we show that nutlin-3 sensitizes Caki human renal cancer cells, but not normal human skin fibroblast (HSF) cells or human mesangial cells, to TRAIL-mediated apoptosis. Combined treatment with nutlin-3 and TRAIL markedly induces apoptosis in HCT116 cells (p53 wild type), but not in HCT116 p53-/- cells, suggesting that p53 is critical for the sensitizing effect of nutlin-3 on TRAIL-induced apoptosis. Pretreatment with N-acetylcysteine (NAC) significantly inhibited nutlin-3-induced DR5 upregulation and cell death induced by the combined treatment with nutlin-3 and TRAIL, suggesting that reactive oxygen species (ROS) mediate nutlin-3-induced DR5 upregulation, which contributes toward TRAIL-mediated apoptosis. However, the upregulation of the p53-mediated protein p53 upregulated modulator of apoptosis (PUMA) by nutlin-3 is likely to be ROS independent because antioxidants failed to block PUMA upregulation. Interestingly, a combined treatment with NAC and PUMA small interfering RNAs significantly blocks nutlin-3-induced and TRAIL-induced apoptosis. Therefore, the present study shows that nutlin-3 enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated or p53-mediated DR5 upregulation and p53-induced PUMA upregulation. These results may offer a novel therapeutic approach to TRAIL-based cancer therapy.}, }
@article {pmid23186260, year = {2013}, author = {Melkus, E and Witte, T and Walter, I and Heuwieser, W and Aurich, C}, title = {Investigations on the endometrial response to intrauterine administration of N-acetylcysteine in oestrous mares.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {48}, number = {4}, pages = {591-597}, doi = {10.1111/rda.12131}, pmid = {23186260}, issn = {1439-0531}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Biopsy/veterinary ; Cyclooxygenase 2/analysis ; Endometrium/cytology/*drug effects/physiology ; Estrus/*physiology ; Female ; *Horses ; Immunohistochemistry/veterinary ; Ki-67 Antigen/analysis ; Leukocyte Count ; Neutrophils ; Periodic Acid-Schiff Reaction/veterinary ; Uterus/drug effects/microbiology ; }, abstract = {In mares, mating-induced persistent endometritis contributes to low fertility. The condition is in part related to delayed clearance of mucus accumulated within the uterine lumen. The objective of this study was to investigate the endometrial response of healthy mares to intrauterine (i.u.) treatment with N-acetylcysteine (NAC). Oestrous mares (n = 12) were randomly assigned to a treatment (TM) or control (C) group and received an i.u. infusion of 5% NAC and saline (total volume 140 ml), respectively. Endometrial biopsies were collected in five of the mares 24 h after treatment, in the remaining seven mares 72 h after treatment. Endometrial biopsies were evaluated for integrity of the luminal epithelium, number of polymorphonuclear neutrophils (PMN), staining for cyclooxygenase 2 (COX2), staining with Kiel 67 antigen (Ki-67), lectins and periodic acid-Schiff (PAS). The integrity of endometrial epithelial cells was not affected by treatment (no statistical differences between groups or times). At 24 h after treatment, the mean number of PMN in endometrial biopsies from NAC- and C-mares did not differ, but at 72 h after treatment, number of PMN was significantly higher (p < 0.05) in C (3.9 ± 0.6 PMN/field) compared with NAC-treated mares (2.3 ± 0.2 PMN/field). At 72 h after treatment, the intensity of staining for COX2 was significantly higher after saline than after NAC treatment (p < 0.05). In the epithelium, no differences in staining for the proliferation marker Ki-67 were seen with respect to time and treatment. Score for the lectin wheat germ agglutinin (WGA) was slightly higher in NAC-treated mares than in C-mares 72 h after treatment (p < 0.05). Score for PAS staining of mucus in deep uterine glands differed significantly between groups at 24 h after treatment (p < 0.05). The present study demonstrates that NAC does not adversely affect the endometrial function. Moreover, an anti-inflammatory effect on the equine endometrium was observed.}, }
@article {pmid23183129, year = {2013}, author = {Shimizu, MH and Volpini, RA and de Bragança, AC and Campos, R and Canale, D and Sanches, TR and Andrade, L and Seguro, AC}, title = {N-acetylcysteine attenuates renal alterations induced by senescence in the rat.}, journal = {Experimental gerontology}, volume = {48}, number = {2}, pages = {298-303}, doi = {10.1016/j.exger.2012.11.006}, pmid = {23183129}, issn = {1873-6815}, mesh = {Acetylcysteine/*pharmacology ; Age Factors ; Aging/*metabolism/pathology ; Animals ; Antioxidants/*pharmacology ; Aquaporin 2/metabolism ; Biomarkers/metabolism ; Blotting, Western ; *Cellular Senescence ; Cholesterol/blood ; Ectodysplasins/metabolism ; Glucuronidase/metabolism ; Immunohistochemistry ; Inulin/metabolism ; Kidney/*drug effects/metabolism/pathology/physiopathology ; Klotho Proteins ; Male ; Membrane Transport Proteins/metabolism ; Oxidative Stress/drug effects ; Phosphates/urine ; Rats ; Rats, Wistar ; Sodium-Potassium-Chloride Symporters/metabolism ; Solute Carrier Family 12, Member 1 ; Thiobarbituric Acid Reactive Substances/metabolism ; Tumor Suppressor Protein p53/metabolism ; Urea Transporters ; }, abstract = {The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) on renal function, as well as on sodium and water transporters, in the kidneys of aged rats. Normal, 8-month-old male Wistar rats were treated (n=6) or not (n=6) with NAC (600 mg/L in drinking water) and followed for 16 months. At the end of the follow-up period, we determined inulin clearance, serum thiobarbituric acid reactive substances (TBARS), serum cholesterol, and urinary phosphate excretion. In addition, we performed immunohistochemical staining for p53 and for ED-1-positive cells (macrophages/monocytes), together with Western blotting of kidney tissue for NKCC2, aquaporin 2 (AQP2), urea transporter A1 (UT-A1) and Klotho protein. At baseline, the two groups were similar in terms of creatinine clearance, proteinuria, cholesterol, and TBARS. At the end of the follow-up period, NAC-treated rats presented greater inulin clearance and reduced proteinuria, as well as lower serum cholesterol, serum TBARS, and urinary phosphate excretion, in comparison with untreated rats. In addition, NAC-treated rats showed upregulated expression of NKCC2, AQP2, and UT-A1; elevated Klotho protein expression, low p53 expression, and few ED-1 positive cells. In conclusion, we attribute these beneficial effects of NAC (the significant improvements in inulin clearance and in the expression of NKCC2, AQP2, and UT-A1) to its ability to decrease oxidative stress, inhibit p53 expression, minimize kidney inflammation, and stimulate Klotho expression.}, }
@article {pmid23181454, year = {2012}, author = {Sabbioni, G and Dongari, N and Schneider, S and Kumar, A}, title = {Synthetic approaches to obtain amino acid adducts of 4,4'-methylenediphenyl diisocyanate.}, journal = {Chemical research in toxicology}, volume = {25}, number = {12}, pages = {2704-2714}, doi = {10.1021/tx300347e}, pmid = {23181454}, issn = {1520-5010}, mesh = {Acetylcysteine/chemistry ; Albumins/*chemistry ; Allergens/*chemistry ; Amino Acids/*chemistry ; Isocyanates/*chemistry ; }, abstract = {4,4'-Methylenediphenyl diisocyanate (MDI) is the most important isocyanate used in the chemical industry. Lung sensitization and asthma are the main types of damage after exposure to MDI. Albumin adducts of MDI might be involved in the etiology of sensitization reactions. It is therefore necessary to have sensitive and specific biomarkers such as blood protein adducts to monitor people exposed to isocyanates. For the discovery of new isocyanate adducts with blood proteins present in vivo, new synthetic standards are needed. To achieve this, we developed five methods to obtain amino acid adducts of MDI. We synthesized and isolated MDI adducts of aspartic acid, glutamic acid, cysteine, and valine. The new adducts were characterized by LC-MS/MS and NMR. We synthesized the corresponding isotope-labeled MDI adducts to develop analytical methods using LC-MS/MS. Glutathione adducts of isocyanates are an important way of transportation of the reactive isocyanates to distant sites from the original site of exposure. Therefore, we used N-acetyl-cysteine adducts of MDI as reactants: N-acetyl-S-[[4-(4-aminobenzyl)phenyl]carbamoyl]-cysteine (MDI-AcCys) and N-acetyl-S-[[4-(4-acetylaminobenzyl)phenyl]carbamoyl]-cysteine (AcMDI-AcCys). MDI-AcCys or AcMDI-AcCys formed adducts with albumin, N(α)-acetyl lysine, and valine. Isotope-labeled albumin adducts (= d(4)-MDI-albumin) were synthesized from d(4)-MDI-AcCys and albumin. d(4)-MDI-albumin can be used as an internal standard to analyze biological samples. Such an internal standard will not correct only for the extraction recovery of the adducts but also for the potential variation of the enzymatic digestions used in the procedure to analyze albumin adducts of MDI. The synthetic procedures described in this manuscript will be applicable to the synthesis of amino acid adducts from other isocyanates.}, }
@article {pmid23179315, year = {2013}, author = {Smith, BA and Neal, CL and Chetram, M and Vo, B and Mezencev, R and Hinton, C and Odero-Marah, VA}, title = {The phytoalexin camalexin mediates cytotoxicity towards aggressive prostate cancer cells via reactive oxygen species.}, journal = {Journal of natural medicines}, volume = {67}, number = {3}, pages = {607-618}, pmid = {23179315}, issn = {1861-0293}, support = {5P20MD002285/MD/NIMHD NIH HHS/United States ; P20 MD002285/MD/NIMHD NIH HHS/United States ; G12 MD007590/MD/NIMHD NIH HHS/United States ; F31 CA153908/CA/NCI NIH HHS/United States ; G12 RR003062/RR/NCRR NIH HHS/United States ; 8G12MD007590-26/MD/NIMHD NIH HHS/United States ; }, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Epithelial-Mesenchymal Transition/drug effects ; Humans ; Indoles/*pharmacology ; Male ; Neoplasm Invasiveness ; Oxidative Stress/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Prostatic Neoplasms/*drug therapy/genetics/*metabolism ; RNA Interference ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; Snail Family Transcription Factors ; Thiazoles/*pharmacology ; Time Factors ; Transcription Factors/genetics/metabolism ; Transfection ; Phytoalexins ; }, abstract = {Camalexin is a phytoalexin that accumulates in various cruciferous plants upon exposure to environmental stress and plant pathogens. Besides moderate antibacterial and antifungal activity, camalexin was reported to also exhibit antiproliferative and cancer chemopreventive effects in breast cancer and leukemia. We studied the cytotoxic effects of camalexin treatment on prostate cancer cell lines and whether this was mediated by reactive oxygen species (ROS) generation. As models, we utilized LNCaP and its aggressive subline, C4-2, as well as ARCaP cells stably transfected with empty vector (Neo) control or constitutively active Snail cDNA that represents an epithelial to mesenchymal transition (EMT) model and displays increased cell migration and tumorigenicity. We confirmed previous studies showing that C4-2 and ARCaP-Snail cells express more ROS than LNCaP and ARCaP-Neo, respectively. Camalexin increased ROS, decreased cell proliferation, and increased apoptosis more significantly in C4-2 and ARCaP-Snail cells as compared to LNCaP and ARCaP-Neo cells, respectively, while normal prostate epithelial cells (PrEC) were unaffected. Increased caspase-3/7 activity and increased cleaved PARP protein shown by Western blot analysis was suggestive of increased apoptosis. The ROS scavenger N-acetyl cysteine (NAC) antagonized the effects of camalexin, whereas the addition of exogenous hydrogen peroxide potentiated the effects of camalexin, showing that camalexin is mediating its effects through ROS. In conclusion, camalexin is more potent in aggressive prostate cancer cells that express high ROS levels, and this phytoalexin has a strong potential as a novel therapeutic agent for the treatment of especially metastatic prostate cancer.}, }
@article {pmid23178030, year = {2013}, author = {Tsai, HH and Lee, WR and Wang, PH and Cheng, KT and Chen, YC and Shen, SC}, title = {Propionibacterium acnes-induced iNOS and COX-2 protein expression via ROS-dependent NF-κB and AP-1 activation in macrophages.}, journal = {Journal of dermatological science}, volume = {69}, number = {2}, pages = {122-131}, doi = {10.1016/j.jdermsci.2012.10.009}, pmid = {23178030}, issn = {1873-569X}, mesh = {Allopurinol/pharmacology ; Animals ; Cell Line ; Cyclooxygenase 2/*metabolism ; Dinoprostone/metabolism ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic/immunology ; Gram-Positive Bacterial Infections/immunology/*metabolism ; Imidazoles/pharmacology ; Luciferases/genetics ; MAP Kinase Signaling System/physiology ; Macrophages/*enzymology/immunology/microbiology ; Mice ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; NF-kappa B/genetics/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/*metabolism ; Propionibacterium acnes/immunology/*metabolism ; Pyrroles/pharmacology ; Reactive Oxygen Species/metabolism ; Transcription Factor AP-1/genetics/metabolism ; Xanthine Oxidase/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND: Propionibacterium acnes (P. acnes), a gram-positive anaerobic bacterium, plays a critical role in the development of inflammatory lesion as a result of cytokines production by keratinocytes and macrophages activation. However, effect of P. acnes on iNOS/NO and COX-2/PGE2 production in macrophages is still uninvestigated.<br><br>OBJECTIVE: This study aimed at determining the reactive oxygen species (ROS), inducible nitric oxide (NO) synthase (iNOS)/nitric oxide (NO), and cyclooxygenase (COX)-2/prostaglandin (PG)E2 produced by macrophages upon P. acnes infection, and dissecting the mechanism of P. acnes-stimulated multiplicity of infection (MOI)-dependent increases in iNOS and COX-2 protein expressions in accordance with the elevation of NO and PGE2 production by RAW264.7 macrophages.<br><br>METHODS: Using an in vitro cell culture system, the effects of P. acnes on iNOS/NO, COX-2/PGE2, ROS production, ERK/JNK, and AP-1/NF-&#x3ba;B activation were examined via Western blotting, a flow cytometric analysis, and luciferase assay. In pharmacological studies, the ROS scavenger, N-acetyl cysteine (NAC), the NADPH oxidase inhibitor, diphenylene iodide (DPI), and mitogen-activated protein kinase (MAPK) inhibitors (U0126 and SP600125) were applied to investigate the mechanism.<br><br>RESULTS: We found that P. acnes exposures increased iNOS/NO and COX-2/PGE2 expression in RAW264.7, J774A.1, and peritoneal macrophages via a MOI-dependent manner. Increased ROS production, ERK/JNK protein phosphorylation, and elevated AP-1/NF-&#x3ba;B luciferase activity are identified in P. acnes-induced iNOS/NO and COX-2/PGE2 production. Additionally, hispolon but not its analogs, hispolon methylether or dehydroxyhispolon, showed significant inhibition of P. acnes-induced iNOS/NO and COX-2/PGE2 production, indicating an important role of OH at C5 for hispolon's inhibition of P. acnes-induced inflammatory events in macrophages.<br><br>CONCLUSION: ROS-dependent stimulation of ERK, JNK, NF-&#x3ba;B, and AP-1 activation contributes to P. acnes-induced iNOS/NO and COX-2/PGE2 in macrophages, and chemicals such as hispolon possessing ability to block iNOS/NO and COX-2/PGE2 production reserve potential to be further developed for treatment of the early phase of inflammation elicited by P. acnes.}, }
@article {pmid23175375, year = {2013}, author = {Bottero, V and Chakraborty, S and Chandran, B}, title = {Reactive oxygen species are induced by Kaposi's sarcoma-associated herpesvirus early during primary infection of endothelial cells to promote virus entry.}, journal = {Journal of virology}, volume = {87}, number = {3}, pages = {1733-1749}, pmid = {23175375}, issn = {1098-5514}, support = {R01 CA168472/CA/NCI NIH HHS/United States ; AI097540/AI/NIAID NIH HHS/United States ; CA075911/CA/NCI NIH HHS/United States ; R21 AI097540/AI/NIAID NIH HHS/United States ; R01 CA075911/CA/NCI NIH HHS/United States ; CA168472/CA/NCI NIH HHS/United States ; }, mesh = {Cell Line ; Endothelial Cells/*metabolism/*virology ; Herpesvirus 8, Human/pathogenicity/*physiology ; *Host-Pathogen Interactions ; Humans ; Pinocytosis ; Reactive Oxygen Species/*metabolism ; *Virus Internalization ; }, abstract = {The entry of Kaposi's sarcoma-associated herpesvirus (KSHV) into human dermal microvascular endothelial cells (HMVEC-d), natural in vivo target cells, via macropinocytosis is initiated through a multistep process involving the binding of KSHV envelope glycoproteins with cell surface α3β1, αVβ3, and αVβ5 integrin molecules and tyrosine kinase ephrin-A2 receptor, followed by the activation of preexisting integrin-associated signaling molecules such as focal adhesion kinase (FAK), Src, c-Cbl, phosphoinositide 3-kinase (PI-3K), and Rho-GTPases. Many viruses, including KSHV, utilize cellular reactive oxygen species (ROS) for viral genomic replication and survival within host cells; however, the role of ROS in early events of viral entry and the induction of signaling has not been elucidated. Here we show that KSHV induced ROS production very early during the infection of HMVEC-d cells and that ROS production was sustained over the observation period (24 h postinfection). ROS induction was dependent on the binding of KSHV to the target cells, since pretreatment of the virus with heparin abolished ROS induction. Pretreatment of HMVEC-d cells with the antioxidant N-acetylcysteine (NAC) significantly inhibited KSHV entry, and consequently gene expression, without affecting virus binding. In contrast, H(2)O(2) treatment increased the levels of KSHV entry and infection. In addition, NAC inhibited KSHV infection-induced translocation of αVβ3 integrin into lipid rafts, actin-dependent membrane perturbations, such as blebs, observed during macropinocytosis, and activation of the signal molecules ephrin-A2 receptor, FAK, Src, and Rac1. In contrast, H(2)O(2) treatment increased the activation of ephrin-A2, FAK, Src, and Rac1. These studies demonstrate that KSHV infection induces ROS very early during infection to amplify the signaling pathways necessary for its efficient entry into HMVEC-d cells via macropinocytosis.}, }
@article {pmid23175273, year = {2013}, author = {Anthérieu, S and Bachour-El Azzi, P and Dumont, J and Abdel-Razzak, Z and Guguen-Guillouzo, C and Fromenty, B and Robin, MA and Guillouzo, A}, title = {Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells.}, journal = {Hepatology (Baltimore, Md.)}, volume = {57}, number = {4}, pages = {1518-1529}, doi = {10.1002/hep.26160}, pmid = {23175273}, issn = {1527-3350}, mesh = {ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 11 ; ATP-Binding Cassette Transporters/metabolism ; Actins/metabolism ; Carcinoma, Hepatocellular/metabolism/*pathology ; Cell Line, Tumor ; Chlorpromazine/*adverse effects/pharmacology ; Cholestasis/*chemically induced/metabolism/*physiopathology ; Humans ; In Vitro Techniques ; Liver Neoplasms/metabolism/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; Taurocholic Acid/metabolism ; }, abstract = {UNLABELLED: Drugs induce cholestasis by diverse and still poorly understood mechanisms in humans. Early hepatic effects of chlorpromazine (CPZ), a neuroleptic drug known for years to induce intrahepatic cholestasis, were investigated using the differentiated human hepatoma HepaRG cells. Generation of reactive oxygen species (ROS) was detected as early as 15 minutes after CPZ treatment and was associated with an altered mitochondrial membrane potential and disruption of the pericanalicular distribution of F-actin. Inhibition of [3H]-taurocholic acid efflux was observed after 30 minutes and was mostly prevented by N-acetyl cysteine (NAC) cotreatment, indicating a major role of oxidative stress in CPZ-induced bile acid (BA) accumulation. Moreover, 24-hour treatment with CPZ decreased messenger RNA (mRNA) expression of the two main canalicular bile transporters, bile salt export pump (BSEP) and multidrug resistance protein 3 (MDR3). Additional CPZ effects included inhibition of Na+ -dependent taurocholic cotransporting polypeptide (NTCP) expression and activity, multidrug resistance-associated protein 4 (MRP4) overexpression and CYP8B1 inhibition that are involved in BA uptake, basolateral transport, and BA synthesis, respectively. These latter events likely represent hepatoprotective responses which aim to reduce intrahepatic accumulation of toxic BA. Compared to CPZ effects, overloading of HepaRG cells with high concentrations of cholic and chenodeoxycholic acids induced a delayed oxidative stress and, similarly, after 24 hours it down-regulated BSEP and MDR3 in parallel to a decrease of NTCP and CYP8B1 and an increase of MRP4. By contrast, low BA concentrations up-regulated BSEP and MDR3 in the absence of oxidative stress.<br><br>CONCLUSION: These data provide evidence that, among other mechanisms, oxidative stress plays a major role as both a primary causal and an aggravating factor in the early CPZ-induced intrahepatic cholestasis in human hepatocytes.}, }
@article {pmid23173828, year = {2013}, author = {Lee, SS and Tsai, CH and Kuan, YH and Huang, FM and Chang, YC}, title = {The upregulation of transglutaminase-2 by cyclosporin a in human gingival fibroblasts is augmented by oxidative stress.}, journal = {Journal of periodontology}, volume = {84}, number = {10}, pages = {1469-1475}, doi = {10.1902/jop.2012.120554}, pmid = {23173828}, issn = {1943-3670}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants/pharmacology ; Catechin/analogs &amp; derivatives/pharmacology ; Cell Culture Techniques ; Cells, Cultured ; Chromones ; Curcumin/pharmacology ; Cyclosporine/*pharmacology/toxicity ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors ; Female ; Fibroblasts/*drug effects ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; GTP-Binding Proteins/antagonists &amp; inhibitors/*drug effects ; Gingiva/cytology/*drug effects ; Humans ; Imidazoles/pharmacology ; Immunosuppressive Agents/*pharmacology/toxicity ; Male ; Morpholines ; Oxidative Stress/*physiology ; Phosphoinositide-3 Kinase Inhibitors ; Protease Inhibitors/pharmacology ; Protein Glutamine gamma Glutamyltransferase 2 ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Transglutaminases/antagonists &amp; inhibitors/*drug effects ; Up-Regulation/drug effects ; }, abstract = {BACKGROUND: Transglutaminase-2 (TGM-2) has been implicated in several fibrotic disorders and can be induced by reactive oxygen species (ROS). Hence, the authors hypothesize that cyclosporin A (CsA) may regulate TGM-2 via ROS, and this regulation may have a role in the pathogenesis of CsA-induced gingival overgrowth.<br><br>METHODS: Cytotoxicity, 2',7'-dichlorodihydrofluorescein diacetate assay, and Western blot were used to investigate the effects of CsA in human gingival fibroblasts (HGFs). In addition, extracellular signal-regulated kinase (ERK) inhibitor PD98059, phosphatidylinositol 3-kinase inhibitor LY294002, glutathione precursor N-acetyl-L-cysteine (NAC), curcumin, epigallocatechin-3 gallate (EGCG), and p38 inhibitor SB203580 were added to find the possible regulatory mechanisms.<br><br>RESULTS: Concentrations of CsA >500 ng/mL demonstrated cytotoxicity to HGFs (P < 0.05). CsA enhanced the generation of intracellular ROS at concentrations >200 ng/mL (P <0.05). TGM-2 protein induced by CsA was found in HGFs in a dose- and time-dependent manner (P <0.05). The addition of PD98059, LY294002, NAC, curcumin, EGCG, and SB203580 markedly inhibited TGM-2 expression induced by CsA (P <0.05).<br><br>CONCLUSIONS: These results demonstrate that CsA significantly upregulates intracellular ROS generation and elevates TGM-2 expression in HGFs. In addition, TGM-2 induced by CsA is downregulated by PD98059, LY294002, NAC, curcumin, EGCG, and SB203580.}, }
@article {pmid23172921, year = {2013}, author = {Kennedy, DJ and Chen, Y and Huang, W and Viterna, J and Liu, J and Westfall, K and Tian, J and Bartlett, DJ and Tang, WH and Xie, Z and Shapiro, JI and Silverstein, RL}, title = {CD36 and Na/K-ATPase-α1 form a proinflammatory signaling loop in kidney.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {61}, number = {1}, pages = {216-224}, pmid = {23172921}, issn = {1524-4563}, support = {P01 HL087018/HL/NHLBI NIH HHS/United States ; P01 HL046403/HL/NHLBI NIH HHS/United States ; HL072942/HL/NHLBI NIH HHS/United States ; P01 HL072942/HL/NHLBI NIH HHS/United States ; R01 HL09015/HL/NHLBI NIH HHS/United States ; R01 HL111614/HL/NHLBI NIH HHS/United States ; P01 HL46403/HL/NHLBI NIH HHS/United States ; R01 HL109015/HL/NHLBI NIH HHS/United States ; UL1 TR000439/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; CD36 Antigens/*metabolism ; Cell Adhesion ; Cell Movement ; Diet, High-Fat/adverse effects ; Fibrosis ; Hyperlipidemias/metabolism ; Inflammation/*metabolism ; Kidney/*metabolism ; Macrophages/metabolism ; Mice ; Obesity/etiology/metabolism ; Oxidative Stress/physiology ; Renal Insufficiency, Chronic/metabolism ; Signal Transduction/*physiology ; Sodium-Potassium-Exchanging ATPase/*metabolism ; }, abstract = {Proatherogenic, hyperlipidemic states demonstrate increases in circulating ligands for scavenger receptor CD36 (eg, oxidized low-density lipoprotein [oxLDL]) and the Na/K-ATPase (eg, cardiotonic steroids). These factors increase inflammation, oxidative stress, and progression of chronic kidney disease. We hypothesized that diet-induced obesity and hyperlipidemia potentiate a CD36/Na/K-ATPase-dependent inflammatory paracrine loop between proximal tubule cells (PTCs) and their associated macrophages and thereby facilitate development of chronic inflammation and tubulointerstitial fibrosis. ApoE(-/-) and apoE(-/-)/cd36(-/-) mice were fed a high-fat diet for ≤32 weeks and examined for physiologic and histologic changes in renal function. Compared with apoE(-/-), apoE(-/-)/cd36(-/-) mice had improved creatinine clearance and blood pressure which corresponded histologically with less glomerular and tubulointerstitial macrophage accumulation, foam cell formation, oxidant stress, and interstitial fibrosis. Coimmunopreciptation and a cell surface fluorescence-based crosslinking assay showed that CD36 and Na/K-ATPase α-1 colocalized in PTCs and macrophages, and this association was increased by oxLDL or the cardiotonic steroid ouabain. OxLDL and ouabain also increased activation of Src and Lyn in PTCs. Cell-free conditioned medium from PTCs treated with oxLDL or ouabain increased macrophage migration. OxLDL, ouabain, or plasma isolated from high-fat diet-fed mice stimulated reactive oxygen species production in PTCs, which was inhibited by N-acetyl-cysteine, apocynin, or Na/K-ATPase α-1 knockdown. These data suggest that ligands generated in hyperlipidemic states activate CD36 and the Na/K-ATPase and potentiate an inflammatory signaling loop involving PTCs and their associated macrophages, which facilitates the development of chronic inflammation, oxidant stress, and fibrosis underlying the renal dysfunction common to proatherogenic, hyperlipidemic states.}, }
@article {pmid23172369, year = {2012}, author = {Martinez-Outschoorn, UE and Balliet, R and Lin, Z and Whitaker-Menezes, D and Birbe, RC and Bombonati, A and Pavlides, S and Lamb, R and Sneddon, S and Howell, A and Sotgia, F and Lisanti, MP}, title = {BRCA1 mutations drive oxidative stress and glycolysis in the tumor microenvironment: implications for breast cancer prevention with antioxidant therapies.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {11}, number = {23}, pages = {4402-4413}, pmid = {23172369}, issn = {1551-4005}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; BRCA1 Protein/genetics/*metabolism ; Breast Neoplasms/metabolism/pathology/prevention &amp; control ; Caveolin 1/metabolism ; Cell Line ; Coculture Techniques ; Cyclic N-Oxides/pharmacology ; Female ; *Glycolysis ; Humans ; Hydrogen Peroxide/metabolism ; Monocarboxylic Acid Transporters/metabolism ; Muscle Proteins/metabolism ; Mutation ; *Oxidative Stress ; Spin Labels ; Tumor Microenvironment/*drug effects ; Up-Regulation/drug effects ; }, abstract = {Mutations in the BRCA1 tumor suppressor gene are commonly found in hereditary breast cancer. Similarly, downregulation of BRCA1 protein expression is observed in the majority of basal-like breast cancers. Here, we set out to study the effects of BRCA1 mutations on oxidative stress in the tumor microenvironment. To mimic the breast tumor microenvironment, we utilized an in vitro co-culture model of human BRCA1-mutated HCC1937 breast cancer cells and hTERT-immortalized human fibroblasts. Notably, HCC1937 cells induce the generation of hydrogen peroxide in the fibroblast compartment during co-culture, which can be inhibited by genetic complementation with the wild-type BRCA1 gene. Importantly, treatment with powerful antioxidants, such as NAC and Tempol, induces apoptosis in HCC1937 cells, suggesting that microenvironmental oxidative stress supports cancer cell survival. In addition, Tempol treatment increases the apoptotic rates of MDA-MB-231 cells, which have wild-type BRCA1, but share a basal-like breast cancer phenotype with HCC1937 cells. MCT4 is the main exporter of L-lactate out of cells and is a marker for oxidative stress and glycolytic metabolism. Co-culture with HCC1937 cells dramatically induces MCT4 protein expression in fibroblasts, and this can be prevented by either BRCA1 overexpression or by pharmacological treatment with NAC. We next evaluated caveolin-1 (Cav-1) expression in stromal fibroblasts. Loss of Cav-1 is a marker of the cancer-associated fibroblast (CAF) phenotype, which is linked to high stromal glycolysis, and is associated with a poor prognosis in numerous types of human cancers, including breast cancers. Remarkably, HCC1937 cells induce a loss of Cav-1 in adjacent stromal cells during co-culture. Conversely, Cav-1 expression in fibroblasts can be rescued by administration of NAC or by overexpression of BRCA1 in HCC1937 cells. Notably, BRCA1-deficient human breast cancer samples (9 out of 10) also showed a glycolytic stromal phenotype, with intense mitochondrial staining specifically in BRCA1-deficient breast cancer cells. In summary, loss of BRCA1 function leads to hydrogen peroxide generation in both epithelial breast cancer cells and neighboring stromal fibroblasts, and promotes the onset of a reactive glycolytic stroma, with increased MCT4 and decreased Cav-1 expression. Importantly, these metabolic changes can be reversed by antioxidants, which potently induce cancer cell death. Thus, antioxidant therapy appears to be synthetically lethal with a BRCA1-deficiency in breast cancer cells and should be considered for future cancer prevention trials. In this regard, immunostaining with Cav-1 and MCT4 could be used as cost-effective biomarkers to monitor the response to antioxidant therapy.}, }
@article {pmid23171803, year = {2012}, author = {Leone, AM and De Caterina, AR and Sciahbasi, A and Aurelio, A and Basile, E and Porto, I and Trani, C and Burzotta, F and Niccoli, G and Mongiardo, R and Mazzari, MA and Buffon, A and Panocchia, N and Romagnoli, E and Lioy, E and Rebuzzi, AG and Crea, F}, title = {Sodium bicarbonate plus N-acetylcysteine to prevent contrast-induced nephropathy in primary and rescue percutaneous coronary interventions: the BINARIO (BIcarbonato e N-Acetil-cisteina nell'infaRto mIocardico acutO) study.}, journal = {EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology}, volume = {8}, number = {7}, pages = {839-847}, doi = {10.4244/EIJV8I7A127}, pmid = {23171803}, issn = {1969-6213}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Contrast Media/*adverse effects ; Female ; *Fluid Therapy ; Hospital Mortality ; Humans ; Italy/epidemiology ; Kidney Diseases/chemically induced/mortality/*prevention &amp; control ; Male ; Middle Aged ; Myocardial Infarction/mortality/*therapy ; Odds Ratio ; Percutaneous Coronary Intervention/*adverse effects/mortality ; Prospective Studies ; Registries ; Renal Dialysis ; Retrospective Studies ; Risk Factors ; Sodium Bicarbonate/*therapeutic use ; Time Factors ; Treatment Outcome ; }, abstract = {AIMS: Contrast-induced nephropathy (CIN) is a frequent and potentially harmful complication of percutaneous coronary interventions (PCI), especially in the setting of ST-elevation myocardial infarction (STEMI). We tested the efficacy of a sodium bicarbonate (SB)-based hydration in urgent PCI for STEMI.<br><br>METHODS AND RESULTS: From June 2009 to September 2010, 262 consecutive STEMI patients undergoing urgent PCI were prospectively enrolled and treated by SB-based hydration (154 mEq/L at 3 ml Kg-1 for one hour followed by 1 ml Kg-1 for six hours) (group A). As controls, 262 consecutive STEMI patients receiving 0.9% saline hydration (1 ml Kg-1 for 24 hours) before June 2009 were retrospectively enrolled (group B). Both groups received high-dose N-acetylcysteine (NAC). The primary endpoint was the composite of in-hospital death, need for dialysis and CIN (&#x2265;25% increase in serum creatinine at 48 hours). The two groups were comparable for baseline clinical and procedural characteristics, for Mehran risk score and baseline estimated glomerular filtration rate. The primary combined endpoint was significantly reduced in group A as compared to group B (9.2 vs. 18.7%, p=0.023) with a number needed to treat (NNT) of 11. Specifically, a significant reduction of both in-hospital death (2.3 vs. 6.1%, p=0.049, NNT 27) and CIN (8.0 vs. 14.1%, p=0.03, NNT 17) was observed, with no difference in the need for dialysis.<br><br>CONCLUSIONS: Our data indicate that hydration with sodium bicarbonate in addition to high-dose NAC in the setting of urgent PCI for STEMI is associated with a net clinical benefit.}, }
@article {pmid23165748, year = {2013}, author = {You, BR and Park, WH}, title = {Trichostatin A induces apoptotic cell death of HeLa cells in a Bcl-2 and oxidative stress-dependent manner.}, journal = {International journal of oncology}, volume = {42}, number = {1}, pages = {359-366}, doi = {10.3892/ijo.2012.1705}, pmid = {23165748}, issn = {1791-2423}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Flow Cytometry ; Glutathione/*metabolism ; HeLa Cells ; Histone Deacetylase Inhibitors/*pharmacology ; Histone Deacetylases/chemistry/metabolism ; Humans ; Hydroxamic Acids/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/antagonists &amp; inhibitors/genetics/*metabolism ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; }, abstract = {Trichostatin A (TSA) as a HDAC inhibitor can regulate many biological properties including apoptosis and cell proliferation in various cancer cells. Here, we evaluated the effect of TSA on the growth and death of HeLa cervical cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Dose- and time-dependent growth inhibition was observed in HeLa cells with an IC50 of approximately 20 nM at 72 h. This agent also induced apoptotic cell death, as evidenced by annexin V-FITC staining cells, caspase-3 activation and the loss of mitochondrial membrane potential (MMP; ∆ψm). In addition, the administration of Bcl-2 siRNA intensified TSA-induced HeLa cell death. All of the tested caspase inhibitors significantly rescued some cells from TSA-induced HeLa cell death. TSA increased O2•- level and induced GSH depletion in HeLa cells. Caspase inhibitors significantly attenuated O2•- level and GSH depletion in TSA-treated HeLa cells. In addition, N-acetyl cysteine (NAC; a well known antioxidant) significantly prevented cell death and GSH depletion in TSA-treated HeLa cells via decreasing O2•- level. In conclusion, TSA inhibited the growth of HeLa cells via Bcl-2-mediated apoptosis, which was closely related to O2•- and GSH content levels.}, }
@article {pmid23164665, year = {2013}, author = {Chuang, HC and Hsueh, TW and Chang, CC and Hwang, JS and Chuang, KJ and Yan, YH and Cheng, TJ}, title = {Nickel-regulated heart rate variability: the roles of oxidative stress and inflammation.}, journal = {Toxicology and applied pharmacology}, volume = {266}, number = {2}, pages = {298-306}, doi = {10.1016/j.taap.2012.11.006}, pmid = {23164665}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/*pharmacology ; Celecoxib ; Heart Rate/*drug effects ; Inflammation/*chemically induced ; Injections, Intraperitoneal ; Male ; Models, Theoretical ; Nickel/*toxicity ; Oxidative Stress/*drug effects ; Pyrazoles/pharmacology ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Sulfonamides/pharmacology ; }, abstract = {Heart rate variability (HRV) has been reported to be a putative marker of cardiac autonomic imbalance caused by exposure to ambient particulate matter (PM). Our objective in this study was to determine the effects on HRV from exposure to nickel, an important chemical component of ambient PM that results in oxidative stress and inflammation. HRV data were collected for 72 h before lung exposure (baseline) and 72 h after intratracheal exposure (response) to nickel sulphate (NiSO(4); 526 μg) in Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats. The antioxidant N-acetyl-L-cysteine (NAC) and the anti-inflammatory celecoxib were intraperitoneally injected to examine post-exposure oxidative and inflammatory responses. Self-controlled experiments examined the effects of NiSO(4) exposure on average normal-to-normal intervals (ANN), natural logarithm-transformed standard deviation of the normal-to-normal intervals (LnSDNN) and root mean square of successive differences of adjacent normal-to-normal intervals (LnRMSSD); the resulting data were sequentially analysed using the generalised estimating equation model. HRV effects on NiSO(4)-exposed SH rats were greater than those on NiSO(4)-exposed WKY rats. After adjusted the HRV responses in the WKY rats as control, ANN and LnRMSSD were found to be quadratically increased over 72 h after exposure to NiSO(4). Both NAC and celecoxib mitigated the NiSO(4)-induced alterations in HRV during the exposure period. The results suggest that concurrent Ni-induced oxidative stress and inflammatory responses play important roles in regulating HRV. These findings help bridge the gap between epidemiological and clinical studies on the plausible mechanisms of the cardiovascular consequences induced by chemical components in ambient PM.}, }
@article {pmid23159886, year = {2013}, author = {Ahmad, I and Shukla, S and Kumar, A and Singh, BK and Kumar, V and Chauhan, AK and Singh, D and Pandey, HP and Singh, C}, title = {Biochemical and molecular mechanisms of N-acetyl cysteine and silymarin-mediated protection against maneb- and paraquat-induced hepatotoxicity in rats.}, journal = {Chemico-biological interactions}, volume = {201}, number = {1-3}, pages = {9-18}, doi = {10.1016/j.cbi.2012.10.027}, pmid = {23159886}, issn = {1872-7786}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2E1/blood/metabolism ; Cytochromes/metabolism ; Drug Interactions ; Glutathione/metabolism ; Herbicides/*toxicity ; Histocytochemistry ; Interleukin-1beta/metabolism ; Liver/*drug effects/enzymology/metabolism ; Male ; Maneb/*toxicity ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress/*drug effects/physiology ; Paraquat/*toxicity ; Rats ; Rats, Wistar ; Silymarin/*pharmacology ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Oxidative stress is one of the major players in the pathogenesis of maneb (MB) and paraquat (PQ)-induced disorders. N-acetyl cysteine (NAC), a glutathione (GSH) precursor and silymarin (SIL), a naturally occurring antioxidant, encounter oxidative stress-mediated cellular damage. The present study was aimed to investigate the effects of NAC and SIL against MB and/or PQ-induced hepatotoxicity in rats. The levels of hepatotoxicity markers - alanine aminotransaminase (ALT), aspartate aminotransaminase (AST) and total bilirubin, histological changes, oxidative stress indices, phase I and phase II xenobiotic metabolizing enzymes - cytochrome P450 (CYP) and glutathione S-transferase (GST) and pro-inflammatory molecules - inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured in animals treated with MB and/or PQ in the presence or absence of NAC and SIL. MB and/or PQ augmented ALT, AST, total bilirubin, lipid peroxidation and nitrite contents and catalytic activities of superoxide dismutase and glutathione peroxidase however, the GSH content was attenuated. NAC and SIL restored the above-mentioned alterations towards basal levels but the restorations were more pronounced in SIL treated groups. Similarly, MB and/or PQ-mediated histopathological symptoms and changes in the catalytic activities/expressions of CYP1A2, CYP2E1, iNOS, TNF-α, and IL-1β were alleviated by NAC and SIL. Conversely, MB and/or PQ-induced GSTA4-4 expression/activity was further increased by NAC/SIL and glutathione reductase activity was also increased. The results obtained thus suggest that NAC and SIL protect MB and/or PQ-induced hepatotoxicity by reducing oxidative stress, inflammation and by modulating xenobitic metabolizing machinery and SIL seems to be more effective.}, }
@article {pmid23158927, year = {2013}, author = {Kuo, WW and Wang, WJ and Tsai, CY and Way, CL and Hsu, HH and Chen, LM}, title = {Diallyl trisufide (DATS) suppresses high glucose-induced cardiomyocyte apoptosis by inhibiting JNK/NFκB signaling via attenuating ROS generation.}, journal = {International journal of cardiology}, volume = {168}, number = {1}, pages = {270-280}, doi = {10.1016/j.ijcard.2012.09.080}, pmid = {23158927}, issn = {1874-1754}, mesh = {Allyl Compounds/*pharmacology ; Animals ; Apoptosis/drug effects/physiology ; Dose-Response Relationship, Drug ; Glucose/*toxicity ; JNK Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; Male ; Myocytes, Cardiac/*drug effects/metabolism ; NF-kappa B/*antagonists &amp; inhibitors/metabolism ; Phosphorylation/drug effects/physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects/physiology ; Sulfides/*pharmacology ; }, abstract = {BACKGROUND: Hyperglycemia is an important risk factor for cardiovascular diseases no matter if it resulted from type I or type II diabetes mellitus. High glucose-induced generation of reactive oxygen species (ROS) can lead to diabetic cardiomyopathy. In our previous study, we showed that NADPH oxidase-related ROS-induced apoptosis is mediated via the JNK-dependent activation of NF-κB in cardiomyocytes exposed to high glucose (HG).<br><br>OBJECTIVE: In this study, we investigated the mechanisms governing the anti-apoptotic effect of diallyl trisulfide (DATS) on HG-exposed cardiac cells both in vitro and in vivo.<br><br>METHODS: H9c2 cells were incubated with media containing 5.5 or 33 mM of glucose for 36 h in the presence or absence of DATS.<br><br>RESULTS: We found that DATS treatment led to a dose-dependent decrease in ROS levels as well as protein levels of p22phox, gp91phox, phosphorylated JNK, and phosphorylated c-Jun. In addition, DATS inhibited the HG-induced activation of caspase 3 as well as the nuclear translocation of NF-&#x3ba;B. Similar results were observed in HG-exposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats. Echocardiographic data showed that DATS administration led to a marked increase in fractional shortening and cardiac output.<br><br>CONCLUSION: DATS appears to suppress high glucose-induced cardiomyocyte apoptosis by inhibiting NADPH oxidase-related ROS and its downstream JNK/NF-&#x3ba;B signaling, and may possess the potential on the therapy of diabetic cardiomyopathy.}, }
@article {pmid23156673, year = {2012}, author = {Noh, YH and Chob, HS and Kim, DH and Kim, OH and Park, J and Lee, SA and Yang, HS and Sohn, DS and Kim, W and Kim, D and Chung, YH and Kim, KY and Kim, SS and Lee, WB}, title = {N-acetylcysteine enhances neuronal differentiation of P19 embryonic stem cells via Akt and N-cadherin activation.}, journal = {Molekuliarnaia biologiia}, volume = {46}, number = {5}, pages = {741-746}, pmid = {23156673}, issn = {0026-8984}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cadherins/genetics/*metabolism ; Cell Count ; Cell Differentiation/drug effects/genetics ; Cell Line ; Chromones/pharmacology ; Embryoid Bodies/cytology/*metabolism ; Embryonic Stem Cells/cytology/*drug effects/metabolism ; Mice ; Microtubule-Associated Proteins/genetics/metabolism ; Morpholines/pharmacology ; Neurons/cytology/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/genetics/*metabolism ; Signal Transduction/drug effects ; Transcriptional Activation/drug effects ; }, abstract = {We examined whether N-acetylcysteine (NAC) enhanced embryonic body (EB) formation and neuronal differentiation in terms of EB formation, neuronal marker (microtubule-associated protein 2; MAP-2) expression, and neuron maturation using P19 embryonic stem cells. The size and numbers of EBs were greatly increased, together with the up-regulated N-cadherin expression. Also, MAP-2 expression and neurite outgrowth were much increased with activation of serine/threonine protein kinase (Akt) and blocked by addition of an Akt inhibitor (LY294002). Our results suggested that NAC increased EB formation by up-regulating the N-cadherin expression. Furthermore, NAC-enhanced neuronal differentiation was mediated by activation of Akt.}, }
@article {pmid23154184, year = {2013}, author = {Elshorbagy, AK and Valdivia-Garcia, M and Mattocks, DA and Plummer, JD and Orentreich, DS and Orentreich, N and Refsum, H and Perrone, CE}, title = {Effect of taurine and N-acetylcysteine on methionine restriction-mediated adiposity resistance.}, journal = {Metabolism: clinical and experimental}, volume = {62}, number = {4}, pages = {509-517}, doi = {10.1016/j.metabol.2012.10.005}, pmid = {23154184}, issn = {1532-8600}, mesh = {Acetylcysteine/*pharmacology ; Adiposity/*drug effects ; Amino Acids/blood ; Amino Acids, Sulfur/metabolism ; Animals ; Cysteine/blood ; Diet ; Fatty Acids, Nonesterified/blood ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Lipids/blood ; Male ; Methionine/*deficiency ; Rats ; Rats, Inbred F344 ; Stearoyl-CoA Desaturase/biosynthesis/genetics/metabolism ; Taurine/*pharmacology ; Weight Gain/drug effects ; }, abstract = {OBJECTIVES: Methionine-restricted (MR) rats, which are lean and insulin sensitive, have low serum total cysteine (tCys) and taurine and decreased hepatic expression and activity indices of stearoyl-coenzyme A desaturase-1 (SCD1). These effects are partly or completely reversed by cysteine supplementation. We investigated whether reversal of MR phenotypes can be achieved by other sulfur compounds, namely taurine or N-acetylcysteine (NAC).<br><br>METHODS: MR and control-fed (CF) rats were supplemented with taurine (0.5%) or NAC (0.5%) for 12weeks. Adiposity, serum sulfur amino acids (SAA), Scd1 gene expression in liver and white adipose tissue, and SCD1 activity indices (calculated from serum fatty acid profile) were monitored.<br><br>RESULTS: Taurine supplementation of MR rats did not restore weight gain or hepatic Scd1 expression or indices to CF levels, but further decreased adiposity. Taurine supplementation of CF rats did not affect adiposity, but lowered triglyceridemia. NAC supplementation in MR rats raised tCys and partly or completely reversed MR effects on weight, fat %, Scd1 expression in liver and white adipose tissue, and estimated SCD1 activity. In CF rats, NAC decreased body fat % and lowered SCD1-18 activity index (P<0.001). Serum triglycerides and leptin were over 40% lower in CF+NAC relative to CF rats (P&#x2264;0.003 for both). In all groups, change in tCys correlated with change in SCD1-16 index (partial r=0.60, P<0.001) independent of other SAA.<br><br>CONCLUSION: The results rule out taurine as a mediator of increased adiposity produced by cysteine in MR, and show that NAC, similar to L-cysteine, blocks anti-obesity effects of MR. Our data show that dietary SAA can influence adiposity in part through mechanisms that converge on SCD1 function. This may have implications for understanding and preventing human obesity.}, }
@article {pmid23148565, year = {2013}, author = {Tehrani, H and Halvaie, Z and Shadnia, S and Soltaninejad, K and Abdollahi, M}, title = {Protective effects of N-acetylcysteine on aluminum phosphide-induced oxidative stress in acute human poisoning.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {51}, number = {1}, pages = {23-28}, doi = {10.3109/15563650.2012.743029}, pmid = {23148565}, issn = {1556-9519}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adolescent ; Adult ; Aluminum Compounds/administration &amp; dosage/*antagonists &amp; inhibitors/toxicity ; Antioxidants/administration &amp; dosage/analysis/*therapeutic use ; Biomarkers/blood ; Electron Transport Complex IV/*antagonists &amp; inhibitors ; Enzyme Inhibitors/administration &amp; dosage/*chemistry/toxicity ; Female ; Humans ; Infusions, Intravenous ; Iran ; Length of Stay ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/blood ; Oxidative Stress/*drug effects ; Pesticides/*antagonists &amp; inhibitors/toxicity ; Phosphines/administration &amp; dosage/*antagonists &amp; inhibitors/toxicity ; Suicide, Attempted ; Young Adult ; }, abstract = {OBJECTIVE: Aluminum phosphide is used as a fumigant. It produces phosphine gas (PH3). PH3 is a mitochondrial poison which inhibits cytochrome c oxidase, it leads to generation of reactive oxygen species; so one of the most important suggested mechanisms for its toxicity is induction of oxidative stress. In this regard, it could be proposed that a drug like N-acetylcysteine (NAC) as an antioxidant would improve the tolerance of aluminum phosphide-intoxicated cases. The objective of this study was to evaluate the protective effects of NAC on acute aluminum phosphide poisoning.<br><br>METHODS: This was a prospective, randomized, controlled open-label trial. All patients received the same supportive treatments. NAC treatment group also received NAC. The blood thiobarbituric acid reactive substances as a marker of lipid peroxidation and total antioxidant capacity of plasma were analyzed.<br><br>RESULTS: Mean ingested dose of aluminum phosphide in NAC treatment and control groups was 4.8 &#xb1; 0.9 g vs. 5.4 &#xb1; 3.3 g, respectively (p = 0.41). Significant increase in plasma malonyldialdehyde level in control group was observed (139 &#xb1; 28.2 vs. 149.6 &#xb1; 35.2 &#x3bc;mol/L, p = 0.02). NAC infusion in NAC treatment group significantly decreased malondialdehyde level (195.7 &#xb1; 67.4 vs. 174.6 &#xb1; 48.9 &#x3bc;mol/L, p = 0.03), duration of hospitalization (2.7 &#xb1; 1.8 days vs. 8.5 &#xb1; 8.2 days, p = 0.02), rate of intubation and ventilation (45.4% vs. 73.3%, p = 0.04). Mortality rate in NAC treatment and control groups were 36% and 60%, respectively with odds ratio 2.6 (0.7-10.1, 95% CI).<br><br>CONCLUSION: NAC may have a therapeutic effect in acute aluminum phosphide poisoning.}, }
@article {pmid23147562, year = {2013}, author = {Gonçalves, JF and Spanevello, RM and Fiorenza, AM and Mazzanti, CM and Bagatini, MD and da Rosa, CS and Becker, LV and da Costa, P and Abdalla, FH and Morsch, VM and Schetinger, MR}, title = {NTPDase and 5'-nucleotidase activities from synaptosomes and platelets of rats exposed to cadmium and treated with N-acetylcysteine.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {31}, number = {1}, pages = {69-74}, doi = {10.1016/j.ijdevneu.2012.11.001}, pmid = {23147562}, issn = {1873-474X}, mesh = {5'-Nucleotidase/*metabolism ; Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Blood Platelets/*drug effects ; Brain/ultrastructure ; Cadmium/*pharmacology ; Free Radical Scavengers/*pharmacology ; Male ; Pyrophosphatases/*metabolism ; Rats ; Rats, Wistar ; Synaptosomes/*drug effects ; }, abstract = {The purpose of the present investigation was to evaluate the hydrolysis of adenine nucleotides on synaptosomes and platelets obtained from rats exposed to cadmium (Cd) and treated with N-acetylcysteine (NAC). Rats received Cd (2 mg/kg) and NAC (150 mg/kg) by gavage every other day for 30 days. Animals were divided into four groups (n = 4-6): control/saline, NAC, Cd, and Cd/NAC. The results of this study demonstrated that NTPDase and 5'-nucleotidase activities were increased in the cerebral cortex synaptosomes of Cd-poisoned rats, and NAC co-treatment reversed these activities to the control levels. In relation to hippocampus synaptosomes, no differences on the NTPDase and 5'-nucleotidase activities of Cd-poisoned rats were observed and only the 5'-nucleotidase activity was increased by the administration of NAC per se. In platelets, Cd-intoxicated rats showed a decreased NTPDase activity and no difference in the 5'-nucleotidase activity; NAC co-treatment was inefficient in counteracting this undesirable effect. Our findings reveal that adenine nucleotide hydrolysis in synaptosomes and platelets of rats were altered after Cd exposure leading to a compensatory response in the central nervous system and acting as a modulator of the platelet activity. NAC was able to modulate the purinergic system which is interesting since the regulation of these enzymes could have potential therapeutic importance. Thus, our results reinforce the importance of the study of the ecto-nucleotidases pathway in poisoning conditions and highlight the possibility of using antioxidants such as NAC as adjuvant against toxicological conditions.}, }
@article {pmid23143036, year = {2013}, author = {Hsu, T and Huang, KM and Tsai, HT and Sung, ST and Ho, TN}, title = {Cadmium(Cd)-induced oxidative stress down-regulates the gene expression of DNA mismatch recognition proteins MutS homolog 2 (MSH2) and MSH6 in zebrafish (Danio rerio) embryos.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {126}, number = {}, pages = {9-16}, doi = {10.1016/j.aquatox.2012.09.020}, pmid = {23143036}, issn = {1879-1514}, mesh = {Animals ; Antioxidants/pharmacology ; Cadmium/*toxicity ; DNA-Binding Proteins/*genetics ; Down-Regulation/*drug effects ; Embryo, Nonmammalian/drug effects ; MutS Homolog 2 Protein/*genetics ; Oxidative Stress/*drug effects ; Protein Binding/drug effects ; Water Pollutants, Chemical/*toxicity ; Zebrafish/embryology/*physiology ; }, abstract = {DNA mismatch repair (MMR) of simple base mismatches and small insertion-deletion loops in eukaryotes is initiated by the binding of the MutS homolog 2 (MSH2)-MSH6 heterodimer to mismatched DNA. Cadmium (Cd) is a genotoxic heavy metal that has been recognized as a human carcinogen. Oxidant stress and inhibition of DNA repair have been proposed as major factors underlying Cd genotoxicity. Our previous studies indicated the ability of Cd to disturb the gene expression of MSH6 in zebrafish (Danio rerio) embryos. This study was undertaken to explore if Cd-induced oxidative stress down-regulated MSH gene activities. Following the exposure of zebrafish embryos at 1 h post fertilization (hpf) to sublethal concentrations of Cd at 3-5 μM for 4 or 9 h, a parallel down-regulation of MSH2, MSH6 and Cu/Zn superoxide dismutase (Cu/Zn-SOD) gene expression was detected by real-time RT-PCR and the expression levels were 40-50% of control after a 9-h exposure. Cd exposure also induced oxidative stress, yet no inhibition of catalase gene activity was observed. Whole mount in situ hybridization revealed a wide distribution of msh6 mRNA in the head regions of 10 hpf embryos and pretreatment of embryos with antioxidants butylhydroxytoluene (BHT), d-mannitol or N-acetylcysteine (NAC) at 1-10 μM restored Cd-suppressed msh6 expression. QPCR confirmed the protective effects of antioxidants on Cd-suppressed msh2/msh6 mRNA production. Down-regulated MSH gene activities reaching about 50% of control were also induced in embryos exposed to paraquat, a reactive oxygen species (ROS)-generating herbicide, or hydrogen peroxide at 200 μM. Hence, Cd at sublethal levels down-regulates msh2/msh6 expression primarily via ROS as signaling molecules. The transcriptional activation of human msh6 is known to be fully dependent on the specificity factor 1 (Sp1). Cd failed to inhibit the DNA binding activity of zebrafish Sp1 unless at lethal concentrations based on band shift assay, therefore excluding the involvement of Sp1 inactivation in Cd-induced MSH gene inhibition in zebrafish embryos.}, }
@article {pmid23138396, year = {2013}, author = {Heguilén, RM and Liste, AA and Payaslian, M and Ortemberg, MG and Albarracín, LM and Bernasconi, AR}, title = {N-acethyl-cysteine reduces the occurrence of contrast-induced acute kidney injury in patients with renal dysfunction: a single-center randomized controlled trial.}, journal = {Clinical and experimental nephrology}, volume = {17}, number = {3}, pages = {396-404}, pmid = {23138396}, issn = {1437-7799}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/chemically induced/*prevention &amp; control ; Adult ; Aged ; Contrast Media/*adverse effects ; Creatinine/blood ; Female ; Humans ; Male ; Middle Aged ; Plasma Substitutes/administration &amp; dosage ; Renal Insufficiency/diagnosis ; Sodium Bicarbonate/*administration &amp; dosage ; Sodium Chloride/administration &amp; dosage ; Triiodobenzoic Acids/adverse effects ; }, abstract = {BACKGROUND: The occurrence of contrast-induced acute kidney injury (CIAKI) has paralleled the increased number of diagnostic interventions requiring radiographic contrast media (CM). Several strategies aimed at preventing renal injury following iodine have been carried out over the last several years. The aim of this study was to evaluate the impact of three different strategies aimed at preventing CIAKI in patients with renal dysfunction (serum creatinine >1.25 mg/dl or estimated creatinine clearance <45 ml/min) receiving low osmolar CM for diagnostic-therapeutic procedures.<br><br>METHODS: Candidates received 154 mmol NaHCO3 solution (B0) at a rate of 3 ml/kg/h from at least 2 h before the procedure and at 1 ml/kg/h during and for the next 6-12 h; the same schedule plus N-acethyl-cysteine (NAC) 600 mg twice daily the day before and the day of the procedure (BN) or NAC as above plus 154 mmol NaCl solution at a rate of 3 ml/kg/h from at least 2 h before the procedure and at 1 ml/kg/h during and for the next 6-12 h (SN). Serum creatinine (SCr) was measured at baseline and on days 2 or occasionally 3 after CM. The main outcome measure was the occurrence of CIAKI, defined as a &#x2265;25% increase in SCr within 2-3 days of CM.<br><br>RESULTS: The three groups were similar with regard to age, gender distribution, weight, baseline serum levels of creatinine, sodium, potassium, urate and estimated creatinine clearance. A larger proportion of individuals received ACEIs/ARAs in the BN group (p < 0.05), but in the SN group, more patients declared a past history of acute myocardial infarction or had high blood pressure, and few displayed mild-moderate left ventricular dysfunction (p < 0.05). CIAKI occurred in 24/123 (19.5%) assessable patients (15/42 in the B0 group, 3/43 in the BN group and 6/38 in the SN group; p < 0.01). Thus, 15/42 patients who did not receive NAC developed CIAKI in contrast to 9/81 who did (p < 0.01). Multivariate logistic regression models showed that the use of NAC was the unique factor associated with a statistically significant influence for the occurrence of CIAKI (OR: 0.18; 95% CI: 0.04-0.72; p = 0.016).<br><br>CONCLUSIONS: The results from this study show that: (1) the occurrence of CIAKI after low-osmolar CM administration is similar to that reported worldwide. (2) NAC-based renoprotective measures are superior for the prevention of CIAKI in patients with previous renal dysfunction. (3) They also demonstrate that bicarbonate expansion alone has limited value in preventing CIAKI. For those individuals at risk, combination prophylaxis including volume expansion plus NAC should be recommended to reduce the chance of overt kidney injury following CM administration.}, }
@article {pmid23135377, year = {2012}, author = {Cacciapuoti, F}, title = {Lowering homocysteine levels may prevent cardiovascular impairments? Possible therapeutic behaviors.}, journal = {Blood coagulation &amp; fibrinolysis : an international journal in haemostasis and thrombosis}, volume = {23}, number = {8}, pages = {677-679}, doi = {10.1097/MBC.0b013e3283597586}, pmid = {23135377}, issn = {1473-5733}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aspirin/adverse effects ; Blood Vessels/drug effects/pathology ; Cardiovascular Diseases/blood/pathology/*prevention &amp; control ; Clopidogrel ; Diuretics/adverse effects ; Fatty Acids, Omega-3/*administration &amp; dosage ; Folic Acid/administration &amp; dosage ; Homocysteine/*blood ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects ; Hypoglycemic Agents/adverse effects ; Metformin/adverse effects ; Platelet Aggregation Inhibitors/adverse effects ; S-Adenosylmethionine/*administration &amp; dosage ; Ticlopidine/adverse effects/analogs &amp; derivatives ; Vitamin B 12/administration &amp; dosage ; Vitamin B 6/administration &amp; dosage ; }, abstract = {Homocysteine (Hcy) is metabolized through two pathways, requiring folates and B6-12 vitamins as cofactors. Increased Hcy concentration is responsible for early atherosclerosis with possible acute cardiovascular events. Ample evidence has demonstrated that Hcy lowering with folic acid and B vitamin supplementation, even if reduces Hcy serum levels, is unable to lower cardiovascular risk. On the contrary, omega-3 fatty acids and some nutraceuticals, such as N-acetyl cysteine, taurine, or S-adenosyl-methionine, reduce both Hcy serum concentration and cardiovascular risk. Instead, antiplatelet drugs, such as aspirin and clopidogrel or ticlopidine and statins only antagonize vascular derangements. Finally, metformin, some lipid-lowering drugs, and some diuretics should be avoided because they can increase Hcy levels.}, }
@article {pmid23132788, year = {2012}, author = {Hamdy, MA and El-Maraghy, SA and Kortam, MA}, title = {Modulatory effects of curcumin and green tea extract against experimentally induced pulmonary fibrosis: a comparison with N-acetyl cysteine.}, journal = {Journal of biochemical and molecular toxicology}, volume = {26}, number = {11}, pages = {461-468}, doi = {10.1002/jbt.21447}, pmid = {23132788}, issn = {1099-0461}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Biomarkers/analysis/blood/metabolism ; Bronchoalveolar Lavage Fluid/chemistry ; Camellia sinensis/*chemistry ; Curcumin/*therapeutic use ; Cyclophosphamide ; Dietary Supplements ; Disease Models, Animal ; Inflammation Mediators/analysis/blood/metabolism ; Lipid Peroxidation/drug effects ; Lung/immunology/metabolism/pathology ; Male ; Plant Extracts/*therapeutic use ; Plant Leaves/*chemistry ; Protective Agents/*therapeutic use ; Pulmonary Fibrosis/immunology/metabolism/pathology/*prevention &amp; control ; Rats ; Rats, Wistar ; Tea/chemistry ; }, abstract = {The study was aimed to investigate the protective effect of green tea extract (GTE), curcumin, and N-acetyl cysteine (NAC) on experimentally induced pulmonary fibrosis. Curcumin (200 mg/kg b.w), GTE (150 mg/kg b.w), and NAC (490 mg/kg b.w) were administered orally for 14 days with concomitant administration of cyclophosphamide (CP). Lung fibrosis was assessed by measuring hydroxyproline and elastin levels and confirmed by histopathological examination. Oxidative stress was also observed in the CP group. Lung myeloperoxidase activity was significantly decreased in animals of the CP group. N-acetyl-β-d-glucosaminidase, leukotriene C4, and protein were increased in bronchoalveolar lavage fluid (BALF). Transforming growth factor-β, interleukin -1β, and histamine were increased in both serum and BALF. All modulators markedly attenuated the altered biochemical parameters as compared to CP-treated rats. These results suggest the possibility of using these treatments as protective agents with chemotherapy and as protective agents for lung fibrosis.}, }
@article {pmid23128467, year = {2013}, author = {Brum, G and Carbone, T and Still, E and Correia, V and Szulak, K and Calianese, D and Best, C and Cammarata, G and Higgins, K and Ji, F and Di, W and Wan, Y}, title = {N-acetylcysteine potentiates doxorubicin-induced ATM and p53 activation in ovarian cancer cells.}, journal = {International journal of oncology}, volume = {42}, number = {1}, pages = {211-218}, pmid = {23128467}, issn = {1791-2423}, support = {P20 RR016457/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antibiotics, Antineoplastic/*pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cytoskeletal Proteins/metabolism ; DNA-Binding Proteins/*metabolism ; Doxorubicin/*pharmacology ; Drug Synergism ; Female ; Free Radical Scavengers/*pharmacology ; Histones/metabolism ; Humans ; Ovarian Neoplasms/drug therapy/*metabolism/pathology ; Protein Serine-Threonine Kinases/*metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/*metabolism ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {Doxorubicin has been used clinically to treat various types of cancer, and yet the molecular mode of actions of doxorubicin remains to be fully unraveled. In this study, we investigated the effect of doxorubicin on cultured ovarian cancer cells (CaOV3). MTT assay data showed that doxorubicin inhibits cell proliferation in a time- and dose-dependent manner. Phagokinetic cell motility assay data indicated that doxorubicin inhibits both basal level and EGF-induced cell migration in CaOV3 cells. Confocal microscopic data revealed that doxorubicin induces reorganization of cytoskeletal proteins including actin, tubulin and vimentin. Doxorubicin induces phosphorylation of p53 at Ser15 and 20, acetylation of p53 and ATM activation. Doxorubicin also induces phosphorylation of histone H2AX at Ser139. Interestingly, doxorubicin also inhibits mTOR activity, measured by phosphorylation of S6 ribosomal protein. Pretreatment of CaOV3 cells with antioxidant N-acetylcysteine (NAC), but not pyrrolidine dithiocarbamate (PDTC) potentiates doxorubicin-induced phosphorylation of p53 and ATM. Collectively, we conclude that doxorubicin induces ATM/p53 activation leading to reorganization of cytoskeletal networks, inhibition of mTOR activity, and inhibition of cell proliferation and migration. Our data also suggest that removal of oxidants by antioxidants such as NAC may enhance the efficacy of doxorubicin in vivo.}, }
@article {pmid23128413, year = {2013}, author = {Kim, HS and Suh, KS and Ko, A and Sul, D and Choi, D and Lee, SK and Jung, WW}, title = {The flavonoid glabridin attenuates 2-deoxy-D-ribose-induced oxidative damage and cellular dysfunction in MC3T3-E1 osteoblastic cells.}, journal = {International journal of molecular medicine}, volume = {31}, number = {1}, pages = {243-251}, doi = {10.3892/ijmm.2012.1172}, pmid = {23128413}, issn = {1791-244X}, mesh = {3T3 Cells ; Acetylcysteine/pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Bone Morphogenetic Protein 2/genetics/metabolism ; Bone Morphogenetic Protein 4/genetics/metabolism ; Bone Morphogenetic Protein 7/genetics/metabolism ; Cell Differentiation ; Cell Survival/drug effects ; Collagen/metabolism ; Deoxyribose/*adverse effects ; Glutathione Peroxidase/genetics/metabolism ; Isoflavones/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Osteoblasts/*cytology/drug effects/metabolism ; Osteocalcin/genetics/metabolism ; Osteopontin/genetics/metabolism ; Osteoprotegerin/genetics/metabolism ; Oxidative Stress/*drug effects ; Phenols/*pharmacology ; Phosphatidylinositol 3-Kinases/genetics/metabolism ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Superoxide Dismutase/genetics/metabolism ; Superoxide Dismutase-1 ; Up-Regulation ; }, abstract = {Reducing sugar 2-deoxy-D-ribose (dRib) produces reactive oxygen species (ROS) through autoxidation and protein glycosylation and causes dysfunction of osteoblasts. In the present study, glabridin, a natural flavonoid, was investigated to determine whether it could influence dRib-induced oxidative damage and cellular dysfunction in the MC3T3-E1 mouse osteoblastic cell line. Osteoblastic cells were treated with dRib in the presence or absence of glabridin. Cell viability, apoptosis, ROS production and mitochondrial membrane potential (ΔΨm) were subsequently examined. It was observed that dRib reduced cell survival and ΔΨm, while it markedly increased intracellular levels of ROS and apoptosis. However, pretreatment of cells with glabridin attenuated all the dRib-induced effects. The antioxidant N-acetyl-L-cysteine (NAC) also prevented dRib-induced oxidative cell damage. In addition, treatment with glabridin resulted in a significant elevation of alkaline phosphatase (ALP) activity, collagen contents and osteoblast differentiation genes [ALP, collagen, osteopontin (OPN), osteoprotegerin (OPG) and osteocalcin (OC)] and bone morphogenetic protein (BMP) genes (BMP2, BMP4 and BMP7). In mechanistic studies of the antioxidative potential of glabridin, we found that glabridin activated dRib-induced decreased expression of phosphatidylinositol 3'-kinase (PI3K) and protein kinase B 2 (AKT2) genes, which are master regulators of survival-related signaling pathways. Glabridin also upregulated the gene expression of antioxidant enzymes, superoxide dismutase 1 (SOD1) and glutathione peroxidase 4 (GPX4), which were inhibited by dRib. Taken together, these results suggest that glabridin attenuates dRib-induced cell damage in osteoblastic cells and may be useful for the treatment of diabetes-related bone disease.}, }
@article {pmid23127406, year = {2012}, author = {Liu, Y and Jiang, P and Xu, Y}, title = {[Role of Toll-like receptor 4 in hyperoxia-exposed microglia injury].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {28}, number = {11}, pages = {1162-1165}, pmid = {23127406}, issn = {1007-8738}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blotting, Western ; Hyperoxia/*metabolism ; Mice ; Mice, Inbred C3H ; Mice, Inbred ICR ; Microglia/*metabolism ; NF-kappa B/metabolism ; RNA, Messenger/analysis ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 4/genetics/*physiology ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {AIM: To explore the role of Toll-like receptor 4 (TLR4) in the injury of microglia exposed to hyperoxia.<br><br>METHODS: N9 microglia (TLR4 wild type) and EOC20 microglia (TLR4 knock-out type) were exposed to 950 mL/L high oxygen respectively for different time periods to establish the high oxygen cell injury model. Expression of TLR4 mRNA and protein levels were detected by RT-PCR and Western blotting, respectively. After intervention with the antioxidant NAC (N-acetyl-L-cysteine, N-acetyl half pathway of ammonia), we detected the activity of reactive oxygen species (ROS), NF-&#x3ba;B and the expression of TNF-&#x3b1; in cellular supernatant of N9 and EOC20 microglia exposed to hyperoxia for 2, 6 h.<br><br>RESULTS: Expression of TLR4 mRNA in N9 microglia exposed to hyperoxia increased in a time-dependent manner, meanwhile, activity of ROS, NF-&#x3ba;B and expression of TNF-&#x3b1; in microglia exposed to hyperoxia significantly increased (P<0.05), while decreased (P<0.05) after intervention with the antioxidant NAC. The activity of ROS, NF-&#x3ba;B and the expression of TNF-&#x3b1; were lower in EOC20 microglia than in N9 microglia after exposed to hyperoxia for different time periods (P<0.05).<br><br>CONCLUSION: TLR4 involves in the regulation of forming ROS and the release of inflammatory markers on microglia after exposed to hyperoxia.}, }
@article {pmid23124986, year = {2013}, author = {Jiang, L and Li, L and Geng, C and Gong, D and Jiang, L and Ishikawa, N and Kajima, K and Zhong, L}, title = {Monosodium iodoacetate induces apoptosis via the mitochondrial pathway involving ROS production and caspase activation in rat chondrocytes in vitro.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {31}, number = {3}, pages = {364-369}, doi = {10.1002/jor.22250}, pmid = {23124986}, issn = {1554-527X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects/physiology ; Cartilage, Articular/cytology ; Caspase 3/metabolism ; Cell Survival/drug effects ; Chondrocytes/cytology/*drug effects/metabolism ; Cytochromes c/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Inhibitors/toxicity ; Femur Head/cytology ; Iodoacetates/*toxicity ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*metabolism ; Osteoarthritis/*chemically induced/metabolism/pathology ; Primary Cell Culture ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Monosodium iodoacetate (MIA) is an inhibitor of glyceraldehyde-3-phosphate dehydrogenase activity, and causes dose-dependent cartilage degradation resembling the pathological changes of human osteoarthritis (OA). In this study, we assessed the apoptosis induced by MIA and clarified the underlying mechanisms using the primary rat chondrocytes. The apoptosis of primary rat chondrocytes was analyzed by flow cytometry. The levels of mitochondrial membrane potential (ΔΨm) were evaluated using fluorescence spectrophotometer. The production of reactive oxygen species (ROS) was determined by fluorescence spectrophotometer. Apoptosis-related protein cytochrome c and procaspase-3 expressions were examined by Western blotting. We found that MIA treatment induces apoptosis in chondrocytes, as confirmed by increases in the percent of apoptotic cells, up-regulation of cytochrome c and caspase-3 protein levels. Treatment with MIA increases ROS production and decreases the levels of ΔΨm. The antioxidant, N-acetylcysteine (NAC), significantly prevented the production of ROS, the reduction of ΔΨm, the release of cytochrome c and the activation of caspase-3. Further, NAC completely protected the cells from MIA-induced apoptosis. Together these observations suggest that the mechanisms of MIA-induced apoptosis are primarily via ROS production and mitochondria-mediated caspase-3 activation in primary rat chondrocytes.}, }
@article {pmid23123467, year = {2012}, author = {Miao, H and Zhao, L and Li, C and Shang, Q and Lu, H and Fu, Z and Wang, L and Jiang, Y and Cao, Y}, title = {Inhibitory effect of Shikonin on Candida albicans growth.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {35}, number = {11}, pages = {1956-1963}, doi = {10.1248/bpb.b12-00338}, pmid = {23123467}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Antifungal Agents/*pharmacology ; Candida albicans/*drug effects/growth &amp; development ; Gene Expression Regulation, Fungal/drug effects ; Genes, Fungal/genetics ; Glutathione/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Microbial Sensitivity Tests ; Naphthoquinones/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Our study showed that Shikonin (SK) could provide an action against almost all Candida albicans isolates tested. More importantly, to some Fluconazole (FCZ)-resistant Candida albicans, the action of SK (MIC(80) value 4 µg/mL) was shown to be >16 times higher than that of FCZ (MIC(80) >64 µg/mL). To clarify the mechanism underlying this action, we performed a comparative study in untreated control C. albicans and C. albicans treated with SK. In this study, we found that SK treatment increased generation of endogenous reactive oxygen species (ROS) and decreased mitochondrial membrane potential. Furthermore, anti-oxidants N-acetylcysteine (NAC) and glutathione (GSH) could reduce the antifungal activity of SK significantly in C. albicans. Our analyses also identified 9 differentially expressed genes, which were related to glycolysis-related genes (CDC19 and HXK2), fermentation-related genes (ALD5 and ADH1), antioxidant defense-related genes (SOD2 and SOD5), thioredoxin reductase-related gene (TRR1), mitochondrial respiratory electron transport chain-related gene (MRF1) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidoreductase-related gene (EBP1). These results suggest that mitochondrial aerobic respiration shift and endogenous ROS augmentation contribute to the action of SK against C. albicans.}, }
@article {pmid23123357, year = {2013}, author = {Pandya, CD and Howell, KR and Pillai, A}, title = {Antioxidants as potential therapeutics for neuropsychiatric disorders.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {46}, number = {}, pages = {214-223}, pmid = {23123357}, issn = {1878-4216}, support = {R03 MH083215/MH/NIMH NIH HHS/United States ; R21 MH087857/MH/NIMH NIH HHS/United States ; MH087857/MH/NIMH NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology/*therapeutic use ; Brain/drug effects/metabolism ; Free Radicals/metabolism ; Humans ; Mental Disorders/*drug therapy/*metabolism ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Oxidative stress has been implicated in the pathophysiology of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression etc. Both genetic and non-genetic factors have been found to cause increased cellular levels of reactive oxygen species beyond the capacity of antioxidant defense mechanism in patients of psychiatric disorders. These factors trigger oxidative cellular damage to lipids, proteins and DNA, leading to abnormal neural growth and differentiation. Therefore, novel therapeutic strategies such as supplementation with antioxidants can be effective for long-term treatment management of neuropsychiatric disorders. The use of antioxidants and PUFAs as supplements in the treatment of neuropsychiatric disorders has provided some promising results. At the same time, one should be cautious with the use of antioxidants since excessive antioxidants could dangerously interfere with some of the protective functions of reactive oxygen species. The present article will give an overview of the potential strategies and outcomes of using antioxidants as therapeutics in psychiatric disorders.}, }
@article {pmid23118923, year = {2012}, author = {Mata, M and Sarrion, I and Armengot, M and Carda, C and Martinez, I and Melero, JA and Cortijo, J}, title = {Respiratory syncytial virus inhibits ciliagenesis in differentiated normal human bronchial epithelial cells: effectiveness of N-acetylcysteine.}, journal = {PloS one}, volume = {7}, number = {10}, pages = {e48037}, pmid = {23118923}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Antiviral Agents/*pharmacology ; Axonemal Dyneins/genetics/metabolism ; Bronchi/*pathology ; Cell Differentiation ; Cells, Cultured ; Cilia/pathology/physiology/virology ; Epithelial Cells/drug effects/*pathology/virology ; Forkhead Transcription Factors/genetics/metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Humans ; Interleukin-13/genetics/metabolism ; Microscopy, Video ; Mucin 5AC/genetics/metabolism ; Pulmonary Disease, Chronic Obstructive/pathology/virology ; Respiratory Syncytial Virus Infections/complications/pathology/virology ; Respiratory Syncytial Virus, Human/drug effects/*physiology ; Tubulin/genetics/metabolism ; Virus Replication/drug effects ; }, abstract = {Persistent respiratory syncytial virus (RSV) infections have been associated with the exacerbation of chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). This virus infects the respiratory epithelium, leading to chronic inflammation, and induces the release of mucins and the loss of cilia activity, two factors that determine mucus clearance and the increase in sputum volume. These alterations involve reactive oxygen species-dependent mechanisms. The antioxidant N-acetylcysteine (NAC) has proven useful in the management of COPD, reducing symptoms, exacerbations, and accelerated lung function decline. NAC inhibits RSV infection and mucin release in human A549 cells. The main objective of this study was to analyze the effects of NAC in modulating ciliary activity, ciliagenesis, and metaplasia in primary normal human bronchial epithelial cell (NHBEC) cultures infected with RSV. Our results indicated that RSV induced ultrastructural abnormalities in axonemal basal bodies and decreased the expression of β-tubulin as well as two genes involved in ciliagenesis, FOXJ1 and DNAI2. These alterations led to a decrease in ciliary activity. Furthermore, RSV induced metaplastic changes to the epithelium and increased the number of goblet cells and the expression of MUC5AC and GOB5. NAC restored the normal functions of the epithelium, inhibiting ICAM1 expression, subsequent RSV infection through mechanisms involving nuclear receptor factor 2, and the expression of heme oxygenase 1, which correlated with the restoration of the antioxidant capacity, the intracellular H(2)O(2) levels and glutathione content of NHBECs. The results presented in this study support the therapeutic use of NAC for the management of chronic respiratory diseases, including COPD.}, }
@article {pmid23115158, year = {2013}, author = {Li, S and Chou, AP and Chen, W and Chen, R and Deng, Y and Phillips, HS and Selfridge, J and Zurayk, M and Lou, JJ and Everson, RG and Wu, KC and Faull, KF and Cloughesy, T and Liau, LM and Lai, A}, title = {Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation.}, journal = {Neuro-oncology}, volume = {15}, number = {1}, pages = {57-68}, pmid = {23115158}, issn = {1523-5866}, support = {R25 NS079198/NS/NINDS NIH HHS/United States ; K08CA124479/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents, Alkylating/pharmacology ; Apoptosis ; Blotting, Western ; Brain Neoplasms/drug therapy/metabolism/pathology/*radiotherapy ; Cell Adhesion ; Cell Movement ; Cell Proliferation ; Dacarbazine/analogs &amp; derivatives/pharmacology ; Electromagnetic Radiation ; Flow Cytometry ; Fluorescent Antibody Technique ; Gene Expression Regulation, Neoplastic/radiation effects ; Glioma/drug therapy/metabolism/pathology/*radiotherapy ; Humans ; Isocitrate Dehydrogenase/*genetics/metabolism ; Mutant Proteins/*genetics/metabolism ; Mutation/*genetics ; Radiation Tolerance/*genetics ; Reactive Oxygen Species/metabolism ; Temozolomide ; Tumor Cells, Cultured ; }, abstract = {Mutations in isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) are found in a subset of gliomas. Among the many phenotypic differences between mutant and wild-type IDH1/2 gliomas, the most salient is that IDH1/2 mutant glioma patients demonstrate markedly improved survival compared with IDH1/2 wild-type glioma patients. To address the mechanism underlying the superior clinical outcome of IDH1/2 mutant glioma patients, we investigated whether overexpression of the IDH1(R132H) protein could affect response to therapy in the context of an isogenic glioma cell background. Stable clonal U87MG and U373MG cell lines overexpressing IDH1(WT) and IDH1(R132H) were generated, as well as U87MG cell lines overexpressing IDH2(WT) and IDH2(R172K). In vitro experiments were conducted to characterize baseline growth and migration and response to radiation and temozolomide. In addition, reactive oxygen species (ROS) levels were measured under various conditions. U87MG-IDH1(R132H) cells, U373MG-IDH1(R132H) cells, and U87MG-IDH2(R172K) cells demonstrated increased sensitivity to radiation but not to temozolomide. Radiosensitization of U87MG-IDH1(R132H) cells was accompanied by increased apoptosis and accentuated ROS generation, and this effect was abrogated by the presence of the ROS scavenger N-acetyl-cysteine. Interestingly, U87MG-IDH1(R132H) cells also displayed decreased growth at higher cell density and in soft agar, as well as decreased migration. Overexpression of IDH1(R132H) and IDH2(R172K) mutant protein in glioblastoma cells resulted in increased radiation sensitivity and altered ROS metabolism and suppression of growth and migration in vitro. These findings provide insight into possible mechanisms contributing to the improved outcomes observed in patients with IDH1/2 mutant gliomas.}, }
@article {pmid23114871, year = {2013}, author = {Hu, J and Deng, H and Friedman, EA}, title = {Ovarian cancer cells, not normal cells, are damaged by Mirk/Dyrk1B kinase inhibition.}, journal = {International journal of cancer}, volume = {132}, number = {10}, pages = {2258-2269}, pmid = {23114871}, issn = {1097-0215}, support = {R21 CA135164/CA/NCI NIH HHS/United States ; 5R21CA135164/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Female ; Flow Cytometry ; Gene Expression Regulation, Enzymologic/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Ovarian Neoplasms/*drug therapy/*enzymology/metabolism ; Ovary/cytology/drug effects ; Protein Kinase Inhibitors/*pharmacology ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors/metabolism ; Protein-Tyrosine Kinases/*antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; Dyrk Kinases ; }, abstract = {Prior studies had shown that the Mirk/dyrk1B gene is amplified/upregulated in about 75% of ovarian cancers, that protein levels of this kinase are elevated in quiescent G0 cells and that Mirk maintains tumor cells in quiescence by initiating rapid degradation of cyclin D isoforms and by phosphorylation of a member of the DREAM complex. Depletion of Mirk/dyrk1B led to increased cyclin D levels, an elevated reactive oxygen species (ROS) content and loss of viability. However, many normal cells in vivo are quiescent, and therefore, targeting a kinase found in quiescent cells might be problematic. In our study, Mirk kinase activity was found to be higher in ovarian cancer cells than in normal cells. Pharmacological inhibition of Mirk/dyrk1B kinase increased cyclin D levels both in quiescent normal diploid cells and in quiescent CDKN2A-negative ovarian cancer cells, but led to more active CDK4/cyclin D complexes in quiescent ovarian cancer cells, allowing them to escape G0/G1 quiescence, enter cycle with high ROS levels and undergo apoptosis. The ROS scavenger N-acetyl cysteine reduced both the amount of cleaved poly(ADP-ribose) polymerase (PARP) and the extent of cancer cell loss. In contrast, normal cells were spared because of their expression of cyclin directed kinase (CDK) inhibitors that blocked unregulated cycling. Quiescent early passage normal ovarian epithelial cells and two strains of quiescent normal diploid fibroblasts remained viable after the inhibition of Mirk/dyrk1B kinase, and the few cells that left G0/G1 quiescence were accumulated in G2+M. Thus, inhibition of Mirk kinase targeted quiescent ovarian cancer cells.}, }
@article {pmid23114776, year = {2013}, author = {Mansouri, MD and Hull, RA and Stager, CE and Cadle, RM and Darouiche, RO}, title = {In vitro activity and durability of a combination of an antibiofilm and an antibiotic against vascular catheter colonization.}, journal = {Antimicrobial agents and chemotherapy}, volume = {57}, number = {1}, pages = {621-625}, pmid = {23114776}, issn = {1098-6596}, support = {R21 AI074010/AI/NIAID NIH HHS/United States ; R41 AI096702/AI/NIAID NIH HHS/United States ; AI074010/AI/NIAID NIH HHS/United States ; AI096702/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Anti-Infective Agents/*pharmacology ; Biofilms/drug effects/growth &amp; development ; Colony Count, Microbial ; Drug Combinations ; Equipment Contamination/prevention &amp; control ; Gram-Negative Bacteria/drug effects/growth &amp; development ; Gram-Positive Bacteria/drug effects/growth &amp; development ; *Levofloxacin ; Ofloxacin/*pharmacology ; Vascular Access Devices/*microbiology ; }, abstract = {Catheter-associated infections can cause severe complications and even death. Effective antimicrobial modification of catheters that can prevent device colonization has the potential of preventing clinical infection. We studied in vitro the antimicrobial activities of central venous catheters impregnated with N-acetylcysteine (NAC), an antibiofilm agent, and a broad-spectrum antibiotic against a range of important clinical pathogens. NAC-levofloxacin-impregnated (NACLEV) catheters were also evaluated for their antiadherence activity. NACLEV catheters produced the most active and durable antimicrobial effect against both Gram-positive and Gram-negative isolates and significantly reduced colonization (P < 0.0001) by all tested pathogens compared to control catheters. These in vitro results suggest that this antimicrobial combination can potentially be used to combat catheter colonization and catheter-associated infection.}, }
@article {pmid23113953, year = {2012}, author = {Seagrave, J and Albrecht, HH and Hill, DB and Rogers, DF and Solomon, G}, title = {Effects of guaifenesin, N-acetylcysteine, and ambroxol on MUC5AC and mucociliary transport in primary differentiated human tracheal-bronchial cells.}, journal = {Respiratory research}, volume = {13}, number = {1}, pages = {98}, pmid = {23113953}, issn = {1465-993X}, mesh = {Acetylcysteine/*pharmacology ; Ambroxol/*pharmacology ; Cells, Cultured ; Expectorants/pharmacology ; Guaifenesin/*pharmacology ; Humans ; Interleukin-13/*pharmacology ; Mucin 5AC/*metabolism ; Mucociliary Clearance/drug effects/*physiology ; Respiratory Mucosa/drug effects/*metabolism ; }, abstract = {BACKGROUND: Therapeutic intervention in the pathophysiology of airway mucus hypersecretion is clinically important. Several types of drugs are available with different possible modes of action. We examined the effects of guaifenesin (GGE), N-acetylcysteine (NAC) and ambroxol (Amb) on differentiated human airway epithelial cells stimulated with IL-13 to produce additional MUC5AC.<br><br>METHODS: After IL-13 pre-treatment (3 days), the cultures were treated with GGE, NAC or Amb (10-300 &#x3bc;M) in the continued presence of IL-13. Cellular and secreted MUC5AC, mucociliary transport rates (MTR), mucus rheology at several time points, and the antioxidant capacity of the drugs were assessed.<br><br>RESULTS: IL-13 increased MUC5AC content (~25%) and secretion (~2-fold) and decreased MTR, but only slightly affected the G' (elastic) or G" (viscous) moduli of the secretions. GGE significantly inhibited MUC5AC secretion and content in the IL-13-treated cells in a concentration-dependent manner (IC50s at 24 hr ~100 and 150 &#x3bc;M, respectively). NAC or Amb were less effective. All drugs increased MTR and decreased G' and G" relative to IL-13 alone. Cell viability was not affected and only NAC exhibited antioxidant capacity.<br><br>CONCLUSIONS: Thus, GGE effectively reduces cellular content and secretion of MUC5AC, increases MTR, and alters mucus rheology, and may therefore be useful in treating airway mucus hypersecretion and mucostasis in airway diseases.}, }
@article {pmid23229601, year = {2012}, author = {Guastoni, C and De Servi, S and Covella, P and Turri, C and Gidaro, B and Bellotti, N and Stasi, A}, title = {[Prevention of contrast-induced acute kidney injury].}, journal = {Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia}, volume = {29 Suppl 58}, number = {}, pages = {S33-45}, pmid = {23229601}, issn = {1724-5990}, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Algorithms ; Contrast Media/*adverse effects ; Fluid Therapy ; Humans ; Incidence ; Renal Dialysis ; Risk Factors ; }, abstract = {Contrast-induced nephropathy (CIN) is one of the most frequent causes of acute kidney injury in hospitalized patients. Its incidence depends on patient risk factors (chronic kidney disease, diabetes, cardiovascular diseases and older age) and procedure-related factors (high contrast dose, intraarterial administration). Chronic kidney disease, especially if associated with diabetes, is the main risk factor for CIN. Hydration before and after contrast administration is the only preventive therapy that is strongly recommended by guidelines in patients at risk. CIN prevention studies have focused mainly on cardiac patients with a moderate renal risk (GFR 60-40 mL/min) who underwent intraarterial contrast administration. Many clinical trials have evaluated the efficacy of hydration associated with sodium bicarbonate and of N-acetylcysteine (NAC) in CIN prevention. Sodium bicarbonate infusion has shown better efficacy than saline infusion, particularly when short infusion times are needed, such as in emergency procedures. NAC has not shown any clear effect, and some positive study results have not been confirmed in other trials. The discussion is still open on the efficacy of renal replacement therapies for the prevention of CIN in individuals at high renal risk (GFR <30 mL/min), in whom CIN could mark the entrance to chronic dialysis.}, }
@article {pmid23111737, year = {2012}, author = {Wang, R and Liang, S and Yue, H and Chen, L}, title = {Using a novel in vivo model to study the function of nuclear factor kappa B in cerebral ischemic injury.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {18}, number = {11}, pages = {BR461-7}, pmid = {23111737}, issn = {1643-3750}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Apoptosis/drug effects ; Brain Ischemia/drug therapy/*metabolism/pathology/prevention &amp; control ; Disease Models, Animal ; I-kappa B Proteins/metabolism ; Male ; Mutant Proteins/metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Rats ; Rats, Wistar ; Transcription Factor RelA/metabolism ; }, abstract = {BACKGROUND: Cerebral ischemia is a situation with a deficit blood supply to the brain, which eventually leads to cell death, inflammation, and tissue damage. Nuclear factor kappa B (NF-κB) plays an important role in inflammation and immune regulation. The aim of this study was to test the function of the activation of NF-κB in vivo in cerebral ischemic injury.<br><br>MATERIAL/METHODS: We generated an animal model that used the method of occlusion of the middle cerebral artery (MCAO). The 60 traits were equally divided into 5 groups to investigate the role of NAC pretreatment: (1) sham-operation (control), (2) ischemia for 6 hours, (3) ischemia for 6 hours and NAC pretreatment, (4) ischemia for 24 hours, (5) ischemia for 24 hours and NAC pretreatment. The 36 rats were divided randomly into 3 groups: (A) recombinant adenovirus expressing wild-type &#x3ba;B&#x3b1;(AdI&#x3ba;B&#x3b1;M) group, (B) recombinant adenovirus expressing wild-type IkappaBalpha (AdI&#x3ba;B&#x3b1;) group, and (C) simple ischemia group. Triphenyltetrazolium chloride (TTC) was used to measure infarct volume. Detection of expression of NF-&#x3ba;B was by Immunohistochemistry analysis.<br><br>RESULTS: The infarct size of the 24-hours ischemia groups were bigger than those of 6-hours ischemia groups (P<0.01). The infarct size of using NAC pretreatment groups was obviously reduced compared with saline control groups (P<0.01).The percentage of cortical p65-positive cells of the group of (A) were significantly less than the groups of (B) and (C).<br><br>CONCLUSIONS: Our data suggest that N-acetylcysteine (NAC) and Ad-I&#x3ba;B&#x3b1;-Mut can inhibit the activation of NF-&#x3ba;B in vivo, reduce the focal infarct size, and protect the brain tissue in ischemia.}, }
@article {pmid23111281, year = {2013}, author = {Bogdani, M and Henschel, AM and Kansra, S and Fuller, JM and Geoffrey, R and Jia, S and Kaldunski, ML and Pavletich, S and Prosser, S and Chen, YG and Lernmark, A and Hessner, MJ}, title = {Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes.}, journal = {The Journal of endocrinology}, volume = {216}, number = {2}, pages = {111-123}, pmid = {23111281}, issn = {1479-6805}, support = {P01AI42380/AI/NIAID NIH HHS/United States ; DK17047/DK/NIDDK NIH HHS/United States ; R01 AI078713/AI/NIAID NIH HHS/United States ; P01 AI042380/AI/NIAID NIH HHS/United States ; R01AI078713/AI/NIAID NIH HHS/United States ; P30 DK017047/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Animals, Genetically Modified ; Antioxidants/*metabolism ; Cell Line, Tumor ; Cysteine/*therapeutic use ; Diabetes Mellitus, Type 1/*drug therapy/*metabolism ; Flow Cytometry ; Gene Expression Profiling ; Glutathione Transferase/blood/metabolism ; Insulin-Secreting Cells/metabolism ; Islets of Langerhans/drug effects/metabolism ; Oxidoreductases/metabolism ; Peroxidases/genetics/metabolism ; Peroxiredoxins/metabolism ; Rats ; Rats, Inbred F344 ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Islet-level oxidative stress has been proposed as a trigger for type 1 diabetes (T1D), and release of cytokines by infiltrating immune cells further elevates reactive oxygen species (ROS), exacerbating β cell duress. To identify genes/mechanisms involved with diabetogenesis at the β cell level, gene expression profiling and targeted follow-up studies were used to investigate islet activity in the biobreeding (BB) rat. Forty-day-old spontaneously diabetic lymphopenic BB DRlyp/lyp rats (before T cell insulitis) as well as nondiabetic BB DR+/+ rats, nondiabetic but lymphopenic F344lyp/lyp rats, and healthy Fischer (F344) rats were examined. Gene expression profiles of BB rat islets were highly distinct from F344 islets and under-expressed numerous genes involved in ROS metabolism, including glutathione S-transferase (GST) family members (Gstm2, Gstm4, Gstm7, Gstt1, Gstp1, and Gstk1), superoxide dismutases (Sod2 and Sod3), peroxidases, and peroxiredoxins. This pattern of under-expression was not observed in brain, liver, or muscle. Compared with F344 rats, BB rat pancreata exhibited lower GST protein levels, while plasma GST activity was found significantly lower in BB rats. Systemic administration of the antioxidant N-acetyl cysteine to DRlyp/lyp rats altered abundances of peripheral eosinophils, reduced severity of insulitis, and significantly delayed but did not prevent diabetes onset. We find evidence of β cell dysfunction in BB rats independent of T1D progression, which includes lower expression of genes related to antioxidative defense mechanisms during the pre-onset period that may contribute to overall T1D susceptibility.}, }
@article {pmid23110331, year = {2013}, author = {Uraz, S and Tahan, G and Aytekin, H and Tahan, V}, title = {N-acetylcysteine expresses powerful anti-inflammatory and antioxidant activities resulting in complete improvement of acetic acid-induced colitis in rats.}, journal = {Scandinavian journal of clinical and laboratory investigation}, volume = {73}, number = {1}, pages = {61-66}, doi = {10.3109/00365513.2012.734859}, pmid = {23110331}, issn = {1502-7686}, mesh = {Acetic Acid/*toxicity ; Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Antioxidants/*therapeutic use ; Colitis, Ulcerative/chemically induced/*drug therapy/metabolism ; Colon/enzymology/metabolism ; Cytokines/metabolism ; Female ; Male ; Malondialdehyde/metabolism ; Organ Size ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; }, abstract = {High free radical production, low antioxidant capacity and excessive inflammation are well known features in the pathogenesis of inflammatory bowel disease. N-acetylcysteine (NAC) is a powerful antioxidant and a scavenger of hydroxyl radicals. Recently, NAC has also been shown to have anti-inflammatory activities in tissues. Our study objective was to investigate the effects of NAC on tissue inflammatory activities using an ulcerative colitis model induced by acetic acid (AA) in rats. Wistar rats (n = 32) were divided into four groups. AA-induced colitis was performed in two of the groups while the other two groups were injected with saline intrarectally. One of the AA-induced colitis groups and one of the control groups were administered NAC (500 mg/kg/day) intrarectally, and the other control groups were given saline. After 4 days, colonic changes were evaluated biochemically by measuring proinflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6], myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) levels in tissue homogenates and by histopathological examination. AA caused colonic mucosal injury, whereas NAC administration suppressed these changes in the AA-induced colitis group (p < 0.001). AA-administration resulted in increased TNF-α, IL-1β, IL-6, MPO and MDA levels, and decreased GSH and SOD levels, whereas NAC reversed these effects (all p < 0.001). In conclusion, the present study proposes that intrarectal NAC therapy has a dual action as an effective anti-inflammatory and an antioxidant, and may be a promising therapeutic option for ulcerative colitis.}, }
@article {pmid23109475, year = {2012}, author = {Saha, S and Hollands, W and Teucher, B and Needs, PW and Narbad, A and Ortori, CA and Barrett, DA and Rossiter, JT and Mithen, RF and Kroon, PA}, title = {Isothiocyanate concentrations and interconversion of sulforaphane to erucin in human subjects after consumption of commercial frozen broccoli compared to fresh broccoli.}, journal = {Molecular nutrition &amp; food research}, volume = {56}, number = {12}, pages = {1906-1916}, doi = {10.1002/mnfr.201200225}, pmid = {23109475}, issn = {1613-4133}, support = {BBS/E/F/00041700/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BBS/E/F/00044453/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 42/D1800/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 42/D 20475/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Adult ; Aged ; Anticarcinogenic Agents/pharmacokinetics ; Biological Availability ; Brassica/*chemistry ; Cross-Over Studies ; Female ; Food Handling ; Freezing ; Gastrointestinal Tract/drug effects/metabolism/microbiology ; Glucosinolates/pharmacokinetics ; Glycoside Hydrolases/metabolism ; Humans ; Imidoesters/pharmacokinetics ; Isothiocyanates/analysis/*pharmacokinetics ; Kinetics ; Male ; Metagenome ; Middle Aged ; Oximes ; Sulfides/*pharmacokinetics/urine ; Sulfoxides ; Thiocyanates/blood/*pharmacokinetics/urine ; Young Adult ; }, abstract = {SCOPE: Sulforaphane (a potent anticarcinogenic isothiocyanate derived from glucoraphanin) is widely considered responsible for the protective effects of broccoli consumption. Broccoli is typically purchased fresh or frozen and cooked before consumption. We compared the bioavailability and metabolism of sulforaphane from portions of lightly cooked fresh or frozen broccoli, and investigated the bioconversion of sulforaphane to erucin.<br><br>METHODS AND RESULTS: Eighteen healthy volunteers consumed broccoli soups produced from fresh or frozen broccoli florets that had been lightly cooked and sulforaphane thio-conjugates quantified in plasma and urine. Sulforaphane bioavailability was about tenfold higher for the soups made from fresh compared to frozen broccoli, and the reduction was shown to be due to destruction of myrosinase activity by the commercial blanching-freezing process. Sulforaphane appeared in plasma and urine in its free form and as several thio-conjugates forms. Erucin N-acetyl-cysteine conjugate was a significant urinary metabolite, and it was shown that human gut microflora can produce sulforaphane, erucin, and their nitriles from glucoraphanin.<br><br>CONCLUSION: The short period of blanching used to produce commercial frozen broccoli destroys myrosinase and substantially reduces sulforaphane bioavailability. Sulforaphane was converted to erucin and excreted in urine, and it was shown that human colonic flora were capable of this conversion.}, }
@article {pmid23108103, year = {2013}, author = {Li, W and Maloney, RE and Circu, ML and Alexander, JS and Aw, TY}, title = {Acute carbonyl stress induces occludin glycation and brain microvascular endothelial barrier dysfunction: role for glutathione-dependent metabolism of methylglyoxal.}, journal = {Free radical biology &amp; medicine}, volume = {54}, number = {}, pages = {51-61}, pmid = {23108103}, issn = {1873-4596}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; DK44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Blood-Brain Barrier/drug effects/pathology/*physiology ; Brain/blood supply/*drug effects/metabolism ; Cells, Cultured ; Diabetes Mellitus, Experimental/*metabolism ; Endothelium/*drug effects/pathology ; Glutathione/metabolism ; Glycation End Products, Advanced/chemistry ; Humans ; Male ; Microvessels/drug effects ; Occludin/chemistry/*metabolism ; Oxidative Stress ; Polymerization/drug effects ; Protein Carbonylation ; Pyruvaldehyde/*metabolism/pharmacology ; Rats ; Rats, Wistar ; Zonula Occludens-1 Protein/metabolism ; }, abstract = {We recently demonstrated that methylglyoxal (MG) induced apoptosis of brain microvascular endothelial cells (IHECs) that was preceded by glutathione (GSH) depletion. Here, we test the hypothesis that MG induces occludin glycation and disrupts IHEC barrier function, which is prevented by GSH-dependent MG metabolism. Exposure of IHECs to MG decreased transendothelial electrical resistance (TEER) in association with MG-adduct formation. A 65-kDa MG-glycated protein corresponded to occludin, which was confirmed by immunoprecipitation. Moreover, immunofluorescence staining showed that MG disrupted the architectural organization of ZO-1. Occludin glycation and ZO-1 disruption were prevented by N-acetylcysteine (NAC). Accordingly, TEER loss was abrogated by NAC (via GSH synthesis) and exacerbated by buthionine sulfoximine (BSO; GSH synthesis inhibitor). BSO treatment attenuated D-lactate production, consistent with a role for GSH in glyoxalase I-catalyzed MG elimination. Although MG increased reactive oxygen species (ROS) generation, the ROS scavengers tempol and tiron did not block barrier disruption. This suggests that endogenously generated ROS were unlikely to be a major cause of or did not reach a threshold to elicit barrier failure as elicited by exogenous hydrogen peroxide (300-400 μM). Immunohistochemistry revealed a lower percentage of microvessels stained with anti-occludin, but a higher percentage stained with anti-MG in diabetic rat brain compared to controls. Western analyses confirmed the decrease in diabetic brain occludin expression, but an increase in glycated occludin levels. These results provide novel evidence that reactive carbonyl species can mediate occludin glycation in cerebral microvessels and in microvascular endothelial cells that contribute to barrier dysfunction, a process that was prevented by GSH through enhanced MG catabolism.}, }
@article {pmid23104863, year = {2012}, author = {Kolosova, NG and Stefanova, NA and Muraleva, NA and Skulachev, VP}, title = {The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats.}, journal = {Aging}, volume = {4}, number = {10}, pages = {686-694}, pmid = {23104863}, issn = {1945-4589}, mesh = {Acetylcysteine ; Aging/blood/*drug effects ; Animals ; Antioxidants/*pharmacology ; Biomarkers/blood ; Body Weight ; Dehydroepiandrosterone/blood ; Growth Hormone/blood ; Insulin-Like Growth Factor I/metabolism ; Leukocyte Count ; Male ; Plastoquinone/*analogs &amp; derivatives/pharmacology ; Rats ; Rats, Wistar ; Testosterone/blood ; }, abstract = {Although antioxidants have been repeatedly tested in animal models and clinical studies, there is no evidence that antioxidants reduce already developed age-related decline. Recently we demonstrated that mitochondria targeted antioxidant 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) delayed some manifestations of aging.Here we compared effects of SkQ1 and N-acetyl-L-cysteine (NAC) on age-dependent decline in blood levels of leukocytes,growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, dehydroepiandrosterone (DHEA) in Wistar and senescence-accelerated OXYS rats. When started late in life, supplementation with SkQ1 not only prevented age-related decline but also significantly reversed it. With NAC, all the observed effects were of the lower magnitude compared with SkQ1 (in spite of that dose of NAC was 16000 times higher). We suggest that supplementation with low doses of SkQ1 is a promising intervention to achieve a healthy ageing.}, }
@article {pmid23104176, year = {2013}, author = {Miller, MS and Moore, JE and Walb, MC and Kock, ND and Attia, A and Isom, S and McBride, JE and Munley, MT}, title = {Chemoprevention by N-acetylcysteine of low-dose CT-induced murine lung tumorigenesis.}, journal = {Carcinogenesis}, volume = {34}, number = {2}, pages = {319-324}, pmid = {23104176}, issn = {1460-2180}, support = {P30 CA012197/CA/NCI NIH HHS/United States ; R01 CA136910/CA/NCI NIH HHS/United States ; P30-CA12197/CA/NCI NIH HHS/United States ; R01-CA136910/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Carcinogens/toxicity ; Cell Transformation, Neoplastic/*drug effects/radiation effects ; Female ; Free Radical Scavengers/*therapeutic use ; Lung Neoplasms/etiology/*prevention &amp; control ; Male ; Mice ; Mice, Inbred A ; Neoplasms, Radiation-Induced/etiology/*prevention &amp; control ; Nitrosamines/toxicity ; Tomography, X-Ray Computed/*adverse effects ; }, abstract = {Data from the National Lung Screening Trial suggested that annual computed tomography (CT) screening of at-risk patients decreases lung cancer mortality by 20%. We assessed the effects of low-dose CT radiation in mice exposed to 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) to mimic the effects of annual CT screening in heavy smokers and ex-smokers. A/J mice were treated at 8 weeks with NNK followed 1 week later by 4 weekly doses of 0, 10, 30 or 50 mGy of whole-body CT and euthanized 8 months later. Irradiated mice exhibited significant 1.8- to 2-fold increases in tumor multiplicity in males (16.1 ± 0.8 versus 9.1 ± 1.5 tumors per mouse; P < 0.0001) and females (21.6 ± 0.8 versus 10.5 ± 1.4 tumors per mouse; P < 0.0001), respectively, compared with unirradiated mice with no dose effect observed; female mice exhibited higher sensitivity to radiation exposure than did males (P < 0.0001). Similar results were obtained when tumor area was determined. To assess if the deleterious effects of radiation could be prevented by antioxidants, female mice were fed a diet containing 0.7% N-acetylcysteine (NAC) starting 3 days prior to the first CT exposure and continuing for a total of 5 weeks. NAC prevented CT induced increases in tumor multiplicity (10.5 ± 1.2 versus 20.7 ± 1.5 tumors per mouse; P < 0.0001) back to levels seen in NNK/unirradiated mice (10.5 ± 1.2). Our data suggest that exposure of sensitive populations to CT radiation increases the risk of tumorigenesis, and that antioxidants may prevent the long-term carcinogenic effects of low-dose radiation exposure. This would allow annual screening with CT while preventing the potential long-term toxicity of radiation exposure.}, }
@article {pmid23103613, year = {2013}, author = {Chen, CH and Chen, SJ and Su, CC and Yen, CC and Tseng, TJ and Jinn, TR and Tang, FC and Chen, KL and Su, YC and Lee, kI and Hung, DZ and Huang, CF}, title = {Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals.}, journal = {Toxicology}, volume = {303}, number = {}, pages = {72-82}, doi = {10.1016/j.tox.2012.10.008}, pmid = {23103613}, issn = {1879-3185}, mesh = {Acetates/administration &amp; dosage/*toxicity ; Animals ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Imidazoles/pharmacology ; Mice ; Mitochondria/drug effects/pathology ; Neuroblastoma/metabolism ; Neurons/*drug effects/pathology ; Neurotoxicity Syndromes/*etiology/pathology ; Oxidative Stress/drug effects ; Pyridines/pharmacology ; p38 Mitogen-Activated Protein Kinases/*drug effects/metabolism ; }, abstract = {Chloroacetic acid (CA), a toxic chlorinated analog of acetic acid, is widely used in chemical industries as an herbicide, detergent, and disinfectant, and chemical intermediates that are formed during the synthesis of various products. In addition, CA has been found as a by-product of chlorination disinfection of drinking water. However, there is little known about neurotoxic injuries of CA on the mammalian, the toxic effects and molecular mechanisms of CA-induced neuronal cell injury are mostly unknown. In this study, we examined the cytotoxicity of CA on cultured Neuro-2a cells and investigated the possible mechanisms of CA-induced neurotoxicity. Treatment of Neuro-2a cells with CA significantly reduced the number of viable cells (in a dose-dependent manner with a range from 0.1 to 3mM), increased the generation of ROS, and reduced the intracellular levels of glutathione depletion. CA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria-dependent apoptosis pathway. These CA-induced apoptosis-related signals were markedly prevented by the antioxidant N-acetylcysteine (NAC). Moreover, CA activated the JNK and p38-MAPK pathways, but did not that ERK1/2 pathway, in treated Neuro-2a cells. Pretreatment with NAC and specific p38-MAPK inhibitor (SB203580), but not JNK inhibitor (SP600125) effectively abrogated the phosphorylation of p38-MAPK and attenuated the apoptotic signals (including: decrease in cytotoxicity, caspase-3/-7 activation, the cytosolic cytochrome c release, and the reversed alteration of Bcl-2 and Bax mRNA) in CA-treated Neuro-2a cells. Taken together, these data suggest that oxidative stress-induced p38-MAPK activated pathway-regulated mitochondria-dependent apoptosis plays an important role in CA-caused neuronal cell death.}, }
@article {pmid23103569, year = {2013}, author = {Kashfi, K and Olson, KR}, title = {Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras.}, journal = {Biochemical pharmacology}, volume = {85}, number = {5}, pages = {689-703}, pmid = {23103569}, issn = {1873-2968}, support = {R24 DA018055/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/chemistry/pharmacology ; Chemoprevention ; Chimera/*metabolism ; Humans ; Hydrogen Sulfide/*chemistry/*pharmacology ; Neoplasms/prevention &amp; control ; }, abstract = {Hydrogen sulfide, H2S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance. However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H2S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology. In this review, we have provided an overview of the chemistry and biology of H2S and have summarized the chemistry and biological activity of some natural and synthetic H2S-donating compounds. The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin. The synthetic H2S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine. Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail. The newly reported NOSH-aspirin that releases both NO and H2S has also been discussed.}, }
@article {pmid23101021, year = {2012}, author = {Choi, JS and Lee, HS and Seo, KH and Na, JO and Kim, YH and Uh, ST and Park, CS and Oh, MH and Lee, SH and Kim, YT}, title = {The effect of post-treatment N-acetylcysteine in LPS-induced acute lung injury of rats.}, journal = {Tuberculosis and respiratory diseases}, volume = {73}, number = {1}, pages = {22-31}, pmid = {23101021}, issn = {2005-6184}, abstract = {BACKGROUND: Oxidation plays an important role in acute lung injury. This study was conducted in order to elucidate the effect of repetitive post-treatment of N-acetylcysteine (NAC) in lipopolysaccaride (LPS)-induced acute lung injury (ALI) of rats.<br><br>METHODS: Six-week-old male Sprague-Dawley rats were divided into 4 groups. LPS (Escherichia coli 5 mg/kg) was administered intravenously via the tail vein. NAC (20 mg/kg) was injected intraperitoneally 3, 6, and 12 hours after LPS injection. Broncho-alveolar lavage fluid (BALF) and lung tissues were obtained to evaluate the ALI at 24 hours after LPS injection. The concentration of tumor necrosis factor &#x3b1; (TNF-&#x3b1;) and interleukin 1&#x3b2; (IL-1&#x3b2;) were measured in BALF. Nuclear factor &#x3ba;B (NF-&#x3ba;B), lipid peroxidation (LPO), and myeloperoxidase (MPO) were measured using lung tissues. Micro-computed tomography (micro-CT) images were examined in each group at 72 hours apart from the main experiments in order to observe the delayed effects of NAC.<br><br>RESULTS: TNF-&#x3b1; and IL-1&#x3b2; concentration in BALF were not different between LPS and NAC treatment groups. The concentration of LPO in NAC treatment group was significantly lower than that of LPS group (5.5&#xb1;2.8 nmol/mL vs. 16.5&#xb1;1.6 nmol/mL) (p=0.001). The activity of MPO in NAC treatment group was significantly lower than that of LPS group (6.4&#xb1;1.8 unit/g vs. 11.2&#xb1;6.3 unit/g, tissue) (p<0.048). The concentration of NF-&#x3ba;B in NAC treatment group was significantly lower than that of LPS group (0.3&#xb1;0.1 ng/&#xb5;L vs. 0.4&#xb1;0.2 ng/&#xb5;L) (p=0.0001). Micro-CT showed less extent of lung injury in NAC treatment than LPS group.<br><br>CONCLUSION: After induction of ALI with lipopolysaccharide, the therapeutic administration of NAC partially attenuated the extent of ALI through the inhibition of NF-&#x3ba;B activation.}, }
@article {pmid23094217, year = {2012}, author = {Choi, BH and Choo, GY and Kang, JH and Lee, CY and Park, CS}, title = {Effect of anti-siglec-f antibody and reactive oxygen species blocking on histamine release in urinary bladder of ovalbumin-treated mice.}, journal = {International neurourology journal}, volume = {16}, number = {3}, pages = {122-125}, pmid = {23094217}, issn = {2093-6931}, abstract = {PURPOSE: Sialic acid-binding Ig-like lectin (Siglec) is an immune inhibitory receptor that plays a role in the negative regulation of the activation of immune cells. This study aimed to evaluate the effects of anti-Siglec-F on plasma and urinary histamine levels in ovalbumin (OVA)-challenged urinary bladder in mice.<br><br>METHODS: Thirty BALB/c mice were used. In group I (control group, n=5), mice were sensitized with OVA and challenged with saline. In group II (OVA challenge group, n=5), OVA was used for intraperitoneal sensitization and intravesical challenge. The challenged mice in group III (control immunoglobulin G [IgG] group, n=5) and those in group IV (anti-Siglec-F group, n=5) were intraperitoneally pretreated with rabbit control IgG or anti-Siglec-F antibody, respectively. In groups V (N-acetylcysteine [NAC] in OVA challenge group, n=5) and VI (control NAC only, n=5), mice were pretreated with NAC.<br><br>RESULTS: Urinary histamine concentrations were significantly higher 7 days after intravesical OVA challenge (P<0.01), whereas plasma histamine levels were not. Pretreatment with anti-Siglec-F antibody significantly prevented the increase in urinary histamine release (P<0.05), whereas pretreatment with the IgG antibody control did not. Also, pretreatment of the OVA challenge group with NAC did not affect the histamine concentration in either urine or plasma.<br><br>CONCLUSIONS: Systemic anti-Siglec-F treatment showed anti-allergic effects at least on local histamine release, particularly in the lower urinary bladder.}, }
@article {pmid23094067, year = {2012}, author = {Li, X and Cai, Y and Wang, YS and Shi, YY and Hou, W and Xu, CS and Wang, HY and Ye, Z and Yao, LB and Zhang, J}, title = {Hyperglycaemia exacerbates choroidal neovascularisation in mice via the oxidative stress-induced activation of STAT3 signalling in RPE cells.}, journal = {PloS one}, volume = {7}, number = {10}, pages = {e47600}, pmid = {23094067}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Choroid/*blood supply/drug effects/*metabolism ; Choroidal Neovascularization/drug therapy/etiology/*metabolism/pathology ; DNA Damage ; Diabetes Mellitus, Experimental ; Epithelial Cells/drug effects/metabolism/pathology ; Gene Expression/drug effects ; Hyperglycemia/chemically induced/drug therapy/metabolism/*pathology ; Light Coagulation/adverse effects ; Mice ; Oxidative Stress/drug effects ; Phosphorylation ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Retina/drug effects/metabolism/pathology ; Retinal Pigment Epithelium/drug effects/*metabolism/pathology ; STAT3 Transcription Factor/antagonists &amp; inhibitors/*genetics/metabolism ; Severity of Illness Index ; Signal Transduction/drug effects ; Streptozocin ; Tyrphostins/pharmacology ; Vascular Endothelial Growth Factor A/genetics/metabolism ; }, abstract = {Choroidal neovascularisation (CNV) that occurs as a result of age-related macular degeneration (AMD) causes severe vision loss among elderly patients. The relationship between diabetes and CNV remains controversial. However, oxidative stress plays a critical role in the pathogenesis of both AMD and diabetes. In the present study, we investigated the influence of diabetes on experimentally induced CNV and on the underlying molecular mechanisms of CNV. CNV was induced via photocoagulation in the ocular fundi of mice with streptozotocin-induced diabetes. The effect of diabetes on the severity of CNV was measured. An immunofluorescence technique was used to determine the levels of oxidative DNA damage by anti-8-hydroxy-2-deoxyguanosine (8-OHdG) antibody, the protein expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and vascular endothelial growth factor (VEGF), in mice with CNV. The production of reactive oxygen species (ROS) in retinal pigment epithelial (RPE) cells that had been cultured under high glucose was quantitated using the 2',7'-dichlorofluorescein diacetate (DCFH-DA) method. p-STAT3 expression was examined using Western blot analysis. RT-PCR and ELISA processes were used to detect VEGF expression. Hyperglycaemia exacerbated the development of CNV in mice. Oxidative stress levels and the expression of p-STAT3 and VEGF were highly elevated both in mice and in cultured RPE cells. Treatment with the antioxidant compound N-acetyl-cysteine (NAC) rescued the severity of CNV in diabetic mice. NAC also inhibited the overexpression of p-STAT3 and VEGF in CNV and in RPE cells. The JAK-2/STAT3 pathway inhibitor AG490 blocked VEGF expression but had no effect on the production of ROS in vitro. These results suggest that hyperglycaemia promotes the development of CNV by inducing oxidative stress, which in turn activates STAT3 signalling in RPE cells. Antioxidant supplementation helped attenuate the development of CNV. Thus, our results reveal a potential strategy for the treatment and prevention of diseases involving CNV.}, }
@article {pmid23092727, year = {2013}, author = {Frank, SJ and Johansen, MJ and Martirosyan, KS and Gagea, M and Van Pelt, CS and Borne, A and Carmazzi, Y and Madden, T}, title = {A biodistribution and toxicity study of cobalt dichloride-N-acetyl cysteine in an implantable MRI marker for prostate cancer treatment.}, journal = {International journal of radiation oncology, biology, physics}, volume = {85}, number = {4}, pages = {1024-1030}, pmid = {23092727}, issn = {1879-355X}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacokinetics/toxicity ; Animals ; Brachytherapy/methods ; Humans ; Kidney/metabolism ; Liver/metabolism ; Magnetic Resonance Imaging/*methods ; Male ; Prostate/*metabolism ; Prostatic Neoplasms/radiotherapy ; Rats ; Tissue Distribution ; }, abstract = {PURPOSE: C4, a cobalt dichloride-N-acetyl cysteine complex, is being developed as a positive-signal magnetic resonance imaging (MRI) marker to localize implanted radioactive seeds in prostate brachytherapy. We evaluated the toxicity and biodistribution of C4 in rats with the goal of simulating the systemic effects of potential leakage from C4 MRI markers within the prostate.<br><br>METHODS AND MATERIALS: 9-&#x3bc;L doses (equivalent to leakage from 120 markers in a human) of control solution (0.9% sodium chloride), 1% (proposed for clinical use), and 10% C4 solution were injected into the prostates of male Sprague-Dawley rats via laparotomy. Organ toxicity and cobalt disposition in plasma, tissues, feces, and urine were evaluated.<br><br>RESULTS: No C4-related morbidity or mortality was observed in the biodistribution arm (60 rats). Biodistribution was measurable after 10% C4 injection: cobalt was cleared rapidly from periprostatic tissue; mean concentrations in prostate were 163 &#x3bc;g/g and 268 &#x3bc;g/g at 5 and 30 minutes but were undetectable by 60 minutes. Expected dual renal-hepatic elimination was observed, with percentages of injected dose recovered in tissues of 39.0 &#xb1; 5.6% (liver), >11.8 &#xb1; 6.5% (prostate), and >5.3 &#xb1; 0.9% (kidney), with low plasma concentrations detected up to 1 hour (1.40 &#x3bc;g/mL at 5-60 minutes). Excretion in urine was 13.1 &#xb1; 4.6%, with 3.1 &#xb1; 0.54% recovered in feces by 24 hours. In the toxicity arm, 3 animals died in the control group and 1 each in the 1% and 10% groups from surgical or anesthesia-related complications; all others survived to scheduled termination at 14 days. No C4-related adverse clinical signs or organ toxicity were observed.<br><br>CONCLUSION: C4-related toxicity was not observed at exposures at least 10-fold the exposure proposed for use in humans. These data demonstrating lack of systemic toxicity with dual routes of elimination in the event of in situ rupture suggest that C4 warrants further investigation as an MRI marker for prostate brachytherapy.}, }
@article {pmid23091297, year = {2012}, author = {Unnisa, Z and Clark, JP and Roychoudhury, J and Thomas, E and Tessarollo, L and Copeland, NG and Jenkins, NA and Grimes, HL and Kumar, AR}, title = {Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress.}, journal = {Blood}, volume = {120}, number = {25}, pages = {4973-4981}, pmid = {23091297}, issn = {1528-0020}, support = {K08 CA122191/CA/NCI NIH HHS/United States ; R01 CA159845/CA/NCI NIH HHS/United States ; K08-CA122191/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Cell Cycle ; Cell Hypoxia ; Gene Deletion ; Gene Expression Regulation ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/*metabolism ; Homeodomain Proteins/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Ecotropic Viral Integration Site 1 Protein ; Neoplasm Proteins/genetics/*metabolism ; *Oxidative Stress ; Pre-B-Cell Leukemia Transcription Factor 1 ; Reactive Oxygen Species/metabolism ; Transcription Factors/metabolism ; }, abstract = {The transcription factor Meis1 is expressed preferentially in hematopoietic stem cells (HSCs) and overexpressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. In the present study, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over the long term, whereas steady-state hematopoiesis was sustained in the absence of Meis1 in inducible knock-out mice. BM cells of Meis1-deficient mice showed reduced colony formation and contained significantly fewer numbers of long-term HSCs, which exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species in HSCs and decreased expression of genes implicated in hypoxia response. Finally, reactive oxygen species scavenging by N-acetyl cysteine or stabilization of hypoxia signaling by knockdown of the von-Hippel-Lindau (VHL) protein led to reversal of the effects of Meis1 deletion. The results of the present study demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism.}, }
@article {pmid23088929, year = {2013}, author = {Shen, XL and Zhang, Y and Xu, W and Liang, R and Zheng, J and Luo, Y and Wang, Y and Huang, K}, title = {An iTRAQ-based mitoproteomics approach for profiling the nephrotoxicity mechanisms of ochratoxin A in HEK 293 cells.}, journal = {Journal of proteomics}, volume = {78}, number = {}, pages = {398-415}, doi = {10.1016/j.jprot.2012.10.010}, pmid = {23088929}, issn = {1876-7737}, mesh = {Acetylcysteine/pharmacology ; Calcium Channel Blockers/*adverse effects/pharmacology ; Electron Transport Chain Complex Proteins/metabolism ; Free Radical Scavengers/pharmacology ; HEK293 Cells ; Humans ; Kidney Diseases/chemically induced/*metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*metabolism/pathology ; Mitochondrial Proteins/*biosynthesis ; *Models, Biological ; Ochratoxins/*adverse effects/pharmacology ; }, abstract = {Nephrotoxicity is the most prominent of ochratoxin A (OTA) among the diverse range of toxicological effects. Previous work indicated that reactive oxygen species (ROS) play an important role in the pathogenesis of a variety of renal diseases, and its major endogenous source is mitochondria. No research has used global protein expression profiling to investigate potential toxicity mechanisms of OTA at the mitochondria level. An iTRAQ-based mitoproteomics approach was used to explore possible toxicity mechanisms of OTA and potential protective mechanisms of N-acetyl-L-cysteine (NAC) using the mitochondria of Human Embryonic Kidney 293 (HEK 293) cells. Our results showed that OTA induced a decrease in ΔΨm, and an increase in ROS and cell death. We identified a total of 1973 nonredundant proteins, among which 1398 proteins (70.86%) were overlapped. There were 66 significantly different proteins expressed in response to OTA, which were mainly involved in the perturbation of the mitochondrial electron transport chain (mETC), inhibition of protein synthesis, and induction of stress response and cell death. In addition, NAC could almost completely reverse the adverse effects of OTA at the protein level. Finally, a hypothetical model of OTA-induced mitochondria damage is proposed to provide a framework for the toxicity mechanism of OTA.}, }
@article {pmid23088864, year = {2012}, author = {Bernabucci, M and Notartomaso, S and Zappulla, C and Fazio, F and Cannella, M and Motolese, M and Battaglia, G and Bruno, V and Gradini, R and Nicoletti, F}, title = {N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors.}, journal = {Molecular pain}, volume = {8}, number = {}, pages = {77}, pmid = {23088864}, issn = {1744-8069}, mesh = {Acetylcysteine/*therapeutic use ; Amino Acid Transport System y+/genetics/metabolism ; Analgesics/*therapeutic use ; Animals ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pain/*drug therapy ; Receptors, Metabotropic Glutamate/genetics/*metabolism ; }, abstract = {BACKGROUND: Pharmacological activation of type-2 metabotropic glutamate receptors (mGlu2 receptors) causes analgesia in experimental models of inflammatory and neuropathic pain. Presynaptic mGlu2 receptors are activated by the glutamate released from astrocytes by means of the cystine/glutamate antiporter (System x(c)(-) or Sx(c)(-)). We examined the analgesic activity of the Sx(c)(-) activator, N-acetyl-cysteine (NAC), in mice developing inflammatory or neuropathic pain.<br><br>RESULTS: A single injection of NAC (100 mg/kg, i.p.) reduced nocifensive behavior in the second phase of the formalin test. NAC-induced analgesia was abrogated by the Sxc- inhibitor, sulphasalazine (8 mg/kg, i.p.) or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). NAC still caused analgesia in mGlu3(-/-) mice, but was inactive in mGlu2(-/-) mice. In wild-type mice, NAC retained the analgesic activity in the formalin test when injected daily for 7 days, indicating the lack of tolerance. Both single and repeated injections of NAC also caused analgesia in the complete Freund's adjuvant (CFA) model of chronic inflammatory pain, and, again, analgesia was abolished by LY341495. Data obtained in mice developing neuropathic pain in response to chronic constriction injury (CCI) of the sciatic nerve were divergent. In this model, a single injection of NAC caused analgesia that was reversed by LY341495, whereas repeated injections of NAC were ineffective. Thus, tolerance to NAC-induced analgesia developed in the CCI model, but not in models of inflammatory pain. The CFA and CCI models differed with respect to the expression levels of xCT (the catalytic subunit of Sx(c)(-)) and activator of G-protein signaling type-3 (AGS3) in the dorsal portion of the lumbar spinal cord. CFA-treated mice showed no change in either protein, whereas CCI mice showed an ipislateral reduction in xCT levels and a bilateral increase in AGS3 levels in the spinal cord.<br><br>CONCLUSIONS: These data demonstrate that pharmacological activation of Sxc- causes analgesia by reinforcing the endogenous activation of mGlu2 receptors. NAC has an excellent profile of safety and tolerability when clinically used as a mucolytic agent or in the management of acetaminophen overdose. Thus, our data encourage the use of NAC for the experimental treatment of inflammatory pain in humans.}, }
@article {pmid23088786, year = {2012}, author = {Lin, TY and Huang, CP and Au, LC and Chang, YW and Hu, CY and Lin, SB}, title = {A cysteine-reactive alkyl hydroquinone modifies topoisomerase IIα, enhances DNA breakage, and induces apoptosis in cancer cells.}, journal = {Chemical research in toxicology}, volume = {25}, number = {11}, pages = {2340-2351}, doi = {10.1021/tx3002302}, pmid = {23088786}, issn = {1520-5010}, mesh = {Antigens, Neoplasm/metabolism ; Antineoplastic Agents/chemistry/isolation &amp; purification/*pharmacology ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Cysteine/*chemistry ; DNA Breaks/*drug effects ; DNA Breaks, Double-Stranded/*drug effects ; DNA Topoisomerases, Type II/metabolism ; DNA-Binding Proteins/*antagonists &amp; inhibitors/metabolism ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/chemistry/isolation &amp; purification/*pharmacology ; Flow Cytometry ; Humans ; Hydroquinones/chemistry/isolation &amp; purification/*pharmacology ; Structure-Activity Relationship ; Tumor Cells, Cultured ; }, abstract = {We previously reported that the anticancer activity of a botanical compound 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)] was attributed to topoisomerase (Topo) IIα poisoning and the induction of oxidative damage. HQ17(3) irreversibly inhibits Topo IIα activity in vitro and is more cytotoxic in leukemia HL-60 cells than in Topo IIα-deficient variant HL-60/MX2 cells, which suggests that Topo IIα is a cellular target of HQ17(3). This study further characterizes the molecular mechanisms of the anticancer activity of HQ17(3). Proteomic analyses indicated that HQ17(3) reacted with Cys-427, Cys-733, and Cys-997 of recombinant Topo IIα in vitro, whereas it reacted with Cys-427 of cellular Topo IIα in Huh7 hepatoma cells. The modification of HQ17(3) inhibited Topo IIα catalytic activity, increased the Topo IIα-DNA cleavage complex, and caused the accumulation of DNA breakage. In Huh7 cells, HQ17(3) treatment caused prompt inhibition of DNA synthesis and consequently induced the expression of DNA damage-related genes DDIT3, GADD45A, and GADD45G. Topo IIα inhibition, apoptosis, and oxidative stress were found to account for cytotoxicity caused by HQ17(3). Pretreatment of Huh7 cells with N-acetylcysteine (NAC) partially attenuated mitochondrial membrane damage, DNA breakage, and caspase activation. However, NAC pretreatment did not diminish HQ17(3)-induced cell death. These results suggest that the anticancer activity of HQ17(3) is attributed significantly to Topo IIα poisoning. The structural feature of HQ17(3) can be used as a model for the design of Topo IIα inhibitors and anticancer drugs.}, }
@article {pmid23085672, year = {2013}, author = {Wang, Q and Zhu, H and Zhou, WG and Guo, XC and Wu, MJ and Xu, ZY and Jiang, JF and Shen, C and Liu, HQ}, title = {N-acetylcysteine-pretreated human embryonic mesenchymal stem cell administration protects against bleomycin-induced lung injury.}, journal = {The American journal of the medical sciences}, volume = {346}, number = {2}, pages = {113-122}, doi = {10.1097/MAJ.0b013e318266e8d8}, pmid = {23085672}, issn = {1538-2990}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibiotics, Antineoplastic/adverse effects ; Antioxidants/metabolism ; Bleomycin/*adverse effects ; Cell Survival ; Embryonic Stem Cells/*drug effects ; Humans ; Lung Diseases/*chemically induced/prevention &amp; control ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*drug effects ; Mice ; Mice, Nude ; Reactive Oxygen Species ; }, abstract = {INTRODUCTION: The transplantation of mesenchymal stem cells (MSCs) has been reported to be a promising approach in the treatment of acute lung injury. However, the poor efficacy of transplanted MSCs is one of the serious handicaps in the progress of MSC-based therapy. Therefore, the purpose of this study was to investigate whether the pretreatment of human embryonic MSCs (hMSCs) with an antioxidant, namely N-acetylcysteine (NAC), can improve the efficacy of hMSC transplantation in lung injury.<br><br>METHODS: In vitro, the antioxidant capacity of NAC-pretreated hMSCs was assessed using intracellular reactive oxygen species (ROS) and glutathione assays and cell adhesion and spreading assays. In vivo, the therapeutic potential of NAC-pretreated hMSCs was assessed in a bleomycin-induced model of lung injury in nude mice.<br><br>RESULTS: The pretreatment of hMSCs with NAC improved antioxidant capacity to defend against redox imbalances through the elimination of cellular ROS, increasing cellular glutathione levels, and the enhancement of cell adhesion and spreading when exposed to oxidative stresses in vitro. In addition, the administration of NAC-pretreated hMSCs to nude mice with bleomycin-induced lung injury decreased the pathological grade of lung inflammation and fibrosis, hydroxyproline content and numbers of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid and apoptotic cells, while enhancing the retention and proliferation of hMSCs in injured lung tissue and improving the survival rate of mice compared with results from untreated hMSCs.<br><br>CONCLUSIONS: The pretreatment of hMSCs with NAC could be a promising therapeutic approach to improving cell transplantation and, therefore, the treatment of lung injury.}, }
@article {pmid23085426, year = {2012}, author = {Rana, T and Schultz, MA and Freeman, ML and Biswas, S}, title = {Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL.}, journal = {Free radical biology &amp; medicine}, volume = {53}, number = {12}, pages = {2298-2307}, pmid = {23085426}, issn = {1873-4596}, support = {P30 CA068485/CA/NCI NIH HHS/United States ; T32 CA093240/CA/NCI NIH HHS/United States ; P30CA68485/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Bone Marrow Cells/physiology/radiation effects ; Cell Survival/radiation effects ; Mice ; Mice, Knockout ; NF-E2-Related Factor 2/deficiency/*genetics ; Osteoblasts/physiology/radiation effects ; Osteoclasts/physiology/radiation effects ; Osteoporosis/*genetics/metabolism ; Oxidative Stress ; RANK Ligand/genetics/*metabolism ; Radiation Injuries, Experimental/*genetics/metabolism ; Radiation Tolerance ; Skull/metabolism/pathology/radiation effects ; Tibia/metabolism/pathology/radiation effects ; Up-Regulation/radiation effects ; }, abstract = {Radiation therapy is an integral part of treatment for cancer patients; however, major side effects of this modality include aberrant bone remodeling and bone loss. Ionizing radiation (IR) is a major external factor that contributes to a significant increase in oxidative stress such as reactive oxygen species (ROS), has been implicated in osteoporotic phenotypes, and has been implicated in osteoporotic phenotypes, bone loss, and fracture risk. One of the major cellular defenses against heightened oxidative stress is mediated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that regulates induction of antioxidant gene expression and phase II antioxidant enzymes. Our objective was to test the hypothesis that loss of functional Nrf2 increases radiation-induced bone loss. We irradiated (single dose, 20Gy) the hindlegs of age- and sex-matched Nrf2(+/+) and Nrf2(-/-) mice. After 1 month, microCT analysis and histology revealed a drastic overall decrease in the bone volume after irradiation of mice lacking Nrf2. Although radiation exposure led to bone loss in mice with intact Nrf2, it was dramatically enhanced by loss of Nrf2. Furthermore, in the absence of Nrf2, a decrease in osteoblast mineralization was noted in calvarial osteoblasts compared with wild-type controls, and treatment with a common antioxidant, N-acetyl-l-cysteine (NAC), was able to rescue the mineralization. As expected, we observed a higher number of osteoclasts in Nrf2(-/-) mice compared to Nrf2(+/+) mice, and after irradiation, the trend remained the same. RT-PCR analysis of calvarial osteoblasts revealed that in the absence of Nrf2, the expression of RANKL was increased after irradiation. Interestingly, RANKL expression was suppressed when the calvarial osteoblasts were treated with NAC before IR exposure. Taken together, our data suggest that loss of Nrf2 leads to heightened oxidative stress and increased susceptibility to radiation-induced bone loss.}, }
@article {pmid23078777, year = {2012}, author = {Onishi, K and Douke, M and Nakamura, T and Ochiai, Y and Kakusawa, N and Yasuike, S and Kurita, J and Yamamoto, C and Kawahata, M and Yamaguchi, K and Yagura, T}, title = {A novel organobismuth compound, 1-[(2-di-p-tolylbismuthanophenyl)diazenyl]pyrrolidine, induces apoptosis in the human acute promyelocytic leukemia cell line NB4 via reactive oxygen species.}, journal = {Journal of inorganic biochemistry}, volume = {117}, number = {}, pages = {77-84}, doi = {10.1016/j.jinorgbio.2012.09.009}, pmid = {23078777}, issn = {1873-3344}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; *Apoptosis ; Cell Division ; Cell Line, Tumor ; HeLa Cells ; Humans ; Leukemia, Promyelocytic, Acute/*metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Organometallic Compounds/chemistry/*pharmacology ; Reactive Oxygen Species/*metabolism ; Tubulin/metabolism ; }, abstract = {A novel organobismuth compound, 1-[(2-di-p-tolylbismuthanophenyl)diazenyl]pyrrolidine (4), which has 1-(phenyldiazenyl)pyrrolidine (1) substituent in a benzene ring of tri(p-tolyl)bismuthane (2), was synthesized and tested for biological activity toward human tumor cell lines. 4 had a potent anti-proliferative effect on human cancer cell lines, although both 1 and 2 exhibited only weak activity. The sensitivity of leukemic cell lines to 4 was relatively high; IC(50) values for the human leukemia cell line NB4 and cervical cancer cell line HeLa were 0.88 μM and 5.36 μM, respectively. Treatment of NB4 cells with 4 induced apoptosis, loss of mitochondrial membrane potential (ΔΨ(mt)) and the generation of cellular reactive oxygen species (ROS). 1 and 2 did not induce apoptosis and had only a marginal effect on ΔΨ(mt) and the generation of ROS. N-acetyl cysteine (NAC) reduced the generation of ROS and conferred protection against 4-induced apoptosis, indicating a role for oxidative stress. 4 did not inhibit the polymerization of tubulin in vitro. 1-[2-(di-p-tolylstibanophenyl)diazenyl]pyrrolidine (3), which has the same chemical structure as 4 but contains antimony in place of bismuth, did not show any cytotoxic activity. The results suggest that the conjugated structure of the diazenylpyrrolidine moiety and bismuth center are key to the bioactivity of 4.}, }
@article {pmid23077524, year = {2012}, author = {Martinez, EE and Anderson, PD and Logan, M and Abdulkadir, SA}, title = {Antioxidant treatment promotes prostate epithelial proliferation in Nkx3.1 mutant mice.}, journal = {PloS one}, volume = {7}, number = {10}, pages = {e46792}, pmid = {23077524}, issn = {1932-6203}, support = {P30 CA068485/CA/NCI NIH HHS/United States ; R01 CA094858/CA/NCI NIH HHS/United States ; 2T32H007735-17//PHS HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Cell Proliferation/drug effects ; Gene Deletion ; Gene Expression Regulation/drug effects ; Homeodomain Proteins/*genetics/metabolism ; Male ; Mice ; Oxidative Stress/drug effects ; Prostate/cytology/*drug effects/metabolism/pathology ; Prostatic Hyperplasia/*drug therapy/*genetics/pathology ; Reactive Oxygen Species/metabolism ; Transcription Factors/*genetics/metabolism ; }, abstract = {Discordant results in preclinical and clinical trials have raised questions over the effectiveness of antioxidants in prostate cancer chemoprevention. Results from the large-scale Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that antioxidants failed to prevent, and in some cases promoted, prostate cancer formation in men without a history of the disease. One possible explanation for these alarming results is the notion that the effects of antioxidant treatment on the prostate are modified by specific, intrinsic genetic risk factors, causing some men to respond negatively to antioxidant treatment. Loss of expression of the homeobox transcription factor NKX3.1 in the prostate is frequently associated with human prostate cancer. Nkx3.1 mutant mice display prostatic hyperplasia and dysplasia and are used as a model of the early stages of prostate cancer initiation. While the mechanisms by which Nkx3.1 loss promotes prostate tumorigenicity are not completely understood, published data have suggested that elevated reactive oxygen species (ROS) associated with Nkx3.1 loss may be a causative factor. Here we have tested this hypothesis by treating Nkx3.1 mutant mice with the antioxidant N-acetylcysteine (NAC) for 13 weeks post-weaning. Surprisingly, while NAC treatment decreased ROS levels in Nkx3.1 mutant mouse prostates, it failed to reduce prostatic epithelial hyperplasia/dysplasia. Rather, NAC treatment increased epithelial cell proliferation and promoted the expression of a pro-proliferative gene signature. These results show that ROS do not promote proliferation in the Nkx3.1-null prostate, but instead inhibit proliferation, suggesting that antioxidant treatment may encourage prostate epithelial cell proliferation early in prostate tumorigenesis. Our findings provide new insight that may help explain the increased prostate cancer risk observed with vitamin E treatment in the SELECT trial and emphasize the need for preclinical studies using accurate models of cancer.}, }
@article {pmid23077170, year = {2012}, author = {Wang, W and Craig, ZR and Basavarajappa, MS and Hafner, KS and Flaws, JA}, title = {Mono-(2-ethylhexyl) phthalate induces oxidative stress and inhibits growth of mouse ovarian antral follicles.}, journal = {Biology of reproduction}, volume = {87}, number = {6}, pages = {152}, pmid = {23077170}, issn = {1529-7268}, support = {K99 ES021467/ES/NIEHS NIH HHS/United States ; R01 ES019178/ES/NIEHS NIH HHS/United States ; R01ES019178/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Apoptosis Regulatory Proteins/agonists/antagonists &amp; inhibitors/metabolism ; Cell Cycle Proteins/agonists/antagonists &amp; inhibitors/metabolism ; Diethylhexyl Phthalate/*analogs &amp; derivatives/antagonists &amp; inhibitors/toxicity ; Down-Regulation/drug effects ; Endocrine Disruptors/chemistry/*toxicity ; Female ; Free Radical Scavengers/therapeutic use ; Infertility, Female/chemically induced/metabolism/pathology/prevention &amp; control ; Mice ; Mice, Inbred Strains ; Ovarian Follicle/*drug effects/metabolism/*pathology ; Oxidative Stress/*drug effects ; Oxidoreductases/antagonists &amp; inhibitors/chemistry/metabolism ; Plasticizers/*toxicity ; RNA, Messenger/metabolism ; Random Allocation ; Reactive Oxygen Species/metabolism ; Up-Regulation/drug effects ; }, abstract = {Mono-(2-ethylhexyl) phthalate (MEHP) is the active metabolite of the most commonly used plasticizer, di-(2-ethylhexyl) phthalate, and is considered to be a reproductive toxicant. However, little is known about the effects of MEHP on ovarian antral follicles. Thus, the present study tested the hypothesis that MEHP inhibits follicle growth via oxidative stress pathways. The data indicate that MEHP increases reactive oxygen species (ROS) levels and inhibits follicle growth in antral follicles, whereas N-acetylcysteine (NAC; an antioxidant) restores ROS levels to control levels and rescues follicles from MEHP-induced inhibition of follicle growth. To further analyze the mechanism by which MEHP induces oxidative stress and inhibits follicle growth, the expression and activities of various key antioxidant enzymes (copper/zinc superoxide dismutase [SOD1], glutathione peroxidase [GPX], and catalase [CAT]) and the expression of key cell-cycle regulators (Ccnd2, Ccne1, and Cdk4) and apoptotic regulators (Bcl-2 and Bax) were compared in control and MEHP-treated follicles. The data indicate that MEHP inhibits the expression and activities of SOD1 and GPX; does not inhibit Cat expression; inhibits the expression of Ccnd2, Ccne1, Cdk4, and Bcl-2; but increases the expression of Bax compared to controls. Furthermore, NAC blocks these toxic effects of MEHP. Collectively, these data suggest that MEHP induces oxidative stress by disrupting the activities of antioxidant enzymes. This may lead to decreased expression of cell-cycle regulators and antiapoptotic regulators and increased expression of proapoptotic factors, which then may lead to inhibition of follicle growth.}, }
@article {pmid23076030, year = {2012}, author = {Duong, HQ and Hwang, JS and Kim, HJ and Seong, YS and Bae, I}, title = {BML-275, an AMPK inhibitor, induces DNA damage, G2/M arrest and apoptosis in human pancreatic cancer cells.}, journal = {International journal of oncology}, volume = {41}, number = {6}, pages = {2227-2236}, pmid = {23076030}, issn = {1791-2423}, support = {P30 CA051008/CA/NCI NIH HHS/United States ; R03 CA152530/CA/NCI NIH HHS/United States ; P30-CA051008/CA/NCI NIH HHS/United States ; 1R03CA152530/CA/NCI NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases/*antagonists &amp; inhibitors/genetics/metabolism ; Apoptosis/*drug effects/genetics ; Cell Line, Tumor ; DNA Damage/*drug effects ; Enzyme Activation/drug effects ; Epithelial Cells/metabolism ; G2 Phase Cell Cycle Checkpoints/*drug effects ; Gene Silencing ; Humans ; M Phase Cell Cycle Checkpoints/*drug effects ; Models, Biological ; Pancreatic Neoplasms/genetics/*metabolism ; Pyrazoles/*pharmacology ; Pyrimidines/*pharmacology ; RNA Interference ; Reactive Oxygen Species/metabolism ; }, abstract = {Adenosine monophosphate-activated protein kinase (AMPK) is a principal intracellular energy sensor which regulates energy producing pathways and energy requiring pathways when the cellular AMP/ATP ratio is altered. BML-275 (compound C), a well-known inhibitor of AMPK, has been found to induce apoptosis in myeloma, glioma and prostate cancer cells. However, the mechanisms responsible for the selective apoptotic effect(s) by BML-275 in cancer cells remain unknown. In the present study, BML-275 was investigated for its antitumor effect(s) in human pancreatic cancer cell lines. BML-275 inhibited the cell proliferation of 4 human pancreatic cancer cell lines (MIA PaCa-2, Panc-1, Colo-357 and AsPC-1). In addition, BML-275 significantly increased the generation of intracellular reactive oxygen species (ROS), followed by induction of DNA damage signaling and apoptosis. Furthermore, BML-275 induced cell cycle arrest in the G2/M phase. The inhibition of ROS generation by N-acetyl cysteine (NAC) significantly prevented the induction of DNA damage and apoptosis, but failed to prevent the induction of G2/M arrest by BML-275. Small interfering RNA (siRNA)-mediated knockdown of AMPKα increased the generation of intracellular ROS, DNA damage signaling and apoptosis without cell cycle arrest at the G2/M phase. These findings suggest that BML-275 exerts its antitumor effects by inducing ROS generation, DNA damage and apoptosis via inhibition of the AMPK pathway and by inducing G2/M arrest via a pathway independent of AMPK, implicating its potential application as an antitumor agent for pancreatic cancer.}, }
@article {pmid23072389, year = {2012}, author = {Antonacci, L and Guaragnella, N and Ždralevic, M and Passarella, S and Marra, E and Giannattasio, S}, title = {The N-acetylcysteine-insensitive acetic acid-induced yeast programmed cell death occurs without macroautophagy.}, journal = {Current pharmaceutical biotechnology}, volume = {13}, number = {15}, pages = {2705-2711}, doi = {10.2174/138920112804724819}, pmid = {23072389}, issn = {1873-4316}, mesh = {Acetic Acid/*pharmacology ; Acetylcysteine/pharmacology ; Alkaline Phosphatase/metabolism ; Antioxidants/pharmacology ; Caspases/genetics/*metabolism ; Cytochromes c/genetics/*metabolism ; In Situ Nick-End Labeling ; Saccharomyces cerevisiae/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; }, abstract = {Programmed cell death can occur through two separate pathways caused by treatment of Saccharomyces cerevisiae with acetic acid (AA-PCD), which differ from one another essentially with respect to their sensitivity to N-acetylcysteine (NAC) and to the role played by cytochrome c and metacaspase YCA1. Moreover, yeast can also undergo macroautophagy which occurs in NAC-insensitive manner. In order to gain some insight into the relationship between AA-PCD and macroautophagy use was made of WT and knock-out cells lacking YCA1 and/or cytochrome c. We show that i. macroautophagy is modulated by YCA1 and by cytochrome c in a negative and positive manner, respectively, ii. the NAC-insensitive AA-PCD and macroautophagy differ from one another and iii. NAC-insensitive AA-PCD pathway takes place essentially without macroautophagy, even if the shift of extracellular pH to acidic values required for AA-PCD to occur leads itself to increased or decreased macroautophagy in YCA1 or cytochrome c-lacking cells.}, }
@article {pmid23070635, year = {2014}, author = {Saritas, A and Kandis, H and Baltaci, D and Yildirim, U and Kaya, H and Karakus, A and Colakoglu, S and Memisogullari, R and Kara, IH}, title = {N-Acetyl cysteine and erdosteine treatment in acetaminophen-induced liver damage.}, journal = {Toxicology and industrial health}, volume = {30}, number = {7}, pages = {670-678}, doi = {10.1177/0748233712463780}, pmid = {23070635}, issn = {1477-0393}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Antidotes/*therapeutic use ; Antipyretics/*toxicity ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/*drug therapy/prevention &amp; control ; Female ; International Normalized Ratio ; Oxidants/blood ; Prothrombin Time ; Rats ; Rats, Wistar ; Thioglycolates/*therapeutic use ; Thiophenes/*therapeutic use ; }, abstract = {OBJECTIVE: This study is aimed to investigate the efficacy of erdosteine usage in acetaminophen-induced liver damage and to compare it with N-acetyl cysteine (NAC) in the treatment and prevention of liver toxicity due to overdose of acetaminophen.<br><br>METHODS: The rats were separated into the following six groups of seven rats each: control group; acetaminophen (1 g/kg, orally); acetaminophen (1 g/kg, orally) + erdosteine (150 mg/kg/day, orally); acetaminophen (1 g/kg, orally) + NAC (140 mg/kg loading dose, followed by 70 mg/kg, orally); NAC (140 mg/kg loading dose, followed by 70 mg/kg, orally); erdosteine (150 mg/kg/kg, orally), subsequently. In all the groups, potential liver injuries were evaluated using biochemical and hematological analyses, oxidant-antioxidant parameters and histopathological parameters.<br><br>RESULTS: In acetaminophen-treated group, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total oxidant status (TOS) in the blood, prothrombin time (PT) and international normalized ratio (INR) were significantly increased when compared with controls. However, total antioxidant capacity (TAC) and glutathione (GSH) levels were decreased in group treated with acetaminophen, when compared with control group. Levels of AST, ALT and TOS, PT and INR were decreased in groups treated with NAC and erdosteine after acetaminophen administration, but the levels of TAC and GSH were increased. Histopathological improvements were observed in the groups treated with NAC and erdosteine after acetaminophen administration.<br><br>CONCLUSION: The present study demonstrated that, in the prevention of liver damage induced by acetaminophen intoxication, an early treatment with a single dose of erdosteine was beneficial instead of NAC administration.}, }
@article {pmid23066769, year = {2012}, author = {Dean, OM and Bush, AI and Copolov, DL and Kohlmann, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Berk, M}, title = {Effects of N-acetyl cysteine on cognitive function in bipolar disorder.}, journal = {Psychiatry and clinical neurosciences}, volume = {66}, number = {6}, pages = {514-517}, doi = {10.1111/j.1440-1819.2012.02392.x}, pmid = {23066769}, issn = {1440-1819}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Analysis of Variance ; Bipolar Disorder/*drug therapy/*psychology ; Cognition/*drug effects ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Trail Making Test ; Treatment Outcome ; Verbal Behavior ; }, abstract = {AIMS: Bipolar disorder is characterized by progressive changes in cognition with declines in executive functioning, memory and sustained attention. Current pharmacotherapies for bipolar disorder target mood symptoms but have not addressed these cognitive changes resulting in euthymic individuals who still experience cognitive deficits. N-acetyl cysteine (NAC) has been shown to have effects on antioxidant status, glutamate transmission, inflammation and neurogenesis. Adjunctive treatment with NAC improves the symptoms experienced by those with bipolar disorder, particularly depression, and it was hypothesized that cognition may also be improved following NAC treatment.<br><br>METHODS: As part of a larger randomized, double-blind, placebo-controlled trial, participants in the current report were tested at baseline and 6 months to assess changes in cognitive function following either 2000 mg of NAC daily or placebo.<br><br>RESULTS: This study failed to find changes in cognitive function following treatment with NAC compared to placebo.<br><br>CONCLUSIONS: While an important pilot study, this study had a small sample size and included a limited battery of cognitive tests. Further investigations on the effects of NAC on cognitive performance in bipolar disorder are required.}, }
@article {pmid23065916, year = {2013}, author = {Amore, A and Formica, M and Giacchino, F and Gigliola, G and Bonello, F and Conti, G and Camilla, R and Coppo, R}, title = {N-Acetylcysteine in hemodialysis diabetic patients resets the activation of NF-kB in lymphomonocytes to normal values.}, journal = {Journal of nephrology}, volume = {26}, number = {4}, pages = {778-786}, doi = {10.5301/jn.5000167}, pmid = {23065916}, issn = {1724-6059}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Aged, 80 and over ; Cross-Over Studies ; Diabetic Nephropathies/*blood/*therapy ; Female ; Humans ; Leukocytes, Mononuclear/*drug effects ; Male ; Middle Aged ; NF-kappa B/*drug effects/*physiology ; Reference Values ; *Renal Dialysis ; }, abstract = {BACKGROUND: Oxidative stress pathways are activated in diabetes, particularly when dialysis is required (DD). NF-kB is activated in this clinical condition. Since N-Acetyl-cysteine (NAC) is an anti-oxidant, we aimed at investigating its effect in modulating NF-kB activation in lymphomonocytes (PBMC) of DD patients.<br><br>METHODS: Twenty-five DD patients were enrolled in a cross-over designed study. Tests were performed at T0 and after one month (T1) of treatment with NAC and three months after NAC withdrawal. We assessed NF-kB activation by EMSA, levels of advanced oxidation protein products (AOPP) by spectral analysis, total antioxidant capacity (TAC) by colorimetry, and apoptosis by FACS.<br><br>RESULTS: At T0 a statistically significant increased activation of the subunits of NF-kB, p50/p65, was detected in PBMC of DD patients in comparison to controls (both P<.0001). After one month of NAC both p50-p50/p50-p65 dimers were significantly reduced (P<.004 and .006). Three months after drug withdrawal NF-kB increased again to basal levels (P<.002 and P<.001 vs. end of treatment with NAC). AOPP and TAC levels and the percentage of apoptotic PBMC revealed modifications in accordance with NFkB activation. In a multivariate linear regression model using delta AOPP as the dependent variable and delta p50-p50, delta TAC, and delta APO as independent variables, we found that all three dependent parameters all retained an independent correlation with delta AOPP.<br><br>CONCLUSIONS: Our data indicate in vivo a modulation by NAC of parameters indicating a redox imbalance in DD patients on hemodialysis. The use of NAC might suggest a potential clinical benefit.}, }
@article {pmid23065881, year = {2012}, author = {Aslam, S and Jenne, K and Reed, S and Ghannoum, M and Mehta, R and Darouiche, R}, title = {N-acetylcysteine lock solution prevents catheter-associated bacteremia in rabbits.}, journal = {The International journal of artificial organs}, volume = {35}, number = {10}, pages = {893-897}, pmid = {23065881}, issn = {1724-6040}, support = {K23 DK078828/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Bacterial Agents/*pharmacology ; Bacteremia/microbiology/prevention &amp; control ; Catheter-Related Infections/microbiology/*prevention &amp; control ; Catheterization, Central Venous/*adverse effects/instrumentation ; Catheters, Indwelling/*adverse effects ; Central Venous Catheters/*adverse effects ; Colony Count, Microbial ; Disease Models, Animal ; Female ; Rabbits ; Staphylococcal Infections/microbiology/*prevention &amp; control ; Staphylococcus aureus/isolation &amp; purification ; Time Factors ; }, abstract = {PURPOSE: Indwelling vascular catheters are the most common cause of nosocomial bloodstream infections. One approach to infection prevention is the use of antimicrobial catheter lock solutions, although their widespread use is limited due to concern regarding the emergence of antimicrobial resistance. The primary purpose of this study was to determine the efficacy of N-acetylcysteine (NAC) lock solution in preventing peripheral bacteremia using an in vivo model of catheter-associated infection.<br><br>METHODS: Twenty-four hours after inoculating a clinical isolate of Staphylococcus aureus into the lumen of tunneled external jugular catheters in rabbits, a catheter lock solution that contained NAC vs. heparinized saline alone was allowed to dwell for two consecutive periods of 72 hours. Surveillance peripheral and centrally collected blood cultures were obtained. Distal intravascular segments of the catheters were removed at day 7 and cultured using a sonication method.<br><br>RESULTS: At 7 days after catheter insertion, none of the NAC-treated rabbits (0/8) developed peripheral bacteremia with S. aureus whereas 4/7 controls did (p=0.026). The bacterial yield from catheter tip cultures was not statistically different between the two arms.<br><br>CONCLUSIONS: These promising data encourage further clinical evaluation of an NAC lock solution for prevention of catheter-associated bacteremia in patients.}, }
@article {pmid23063593, year = {2013}, author = {Qiao, Y and Xiang, Q and Yuan, L and Xu, L and Liu, Z and Liu, X}, title = {Herbacetin induces apoptosis in HepG2 cells: Involvements of ROS and PI3K/Akt pathway.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {51}, number = {}, pages = {426-433}, doi = {10.1016/j.fct.2012.09.036}, pmid = {23063593}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Flavonoids/*pharmacology ; Heat-Shock Proteins/metabolism ; Hep G2 Cells/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Transcription Factors/metabolism ; }, abstract = {Herbacetin (HER) is a natural flavonoid compound that can be extracted from Ramose Scouring Rush Herb, and its biological and pharmacological activities lack of corresponding attention. In this study, the apoptotic effect of HER against the human hepatoma cell line (HepG2) was investigated. The results showed that HepG2 cells apoptosis occurred in a dose-dependent manner within 48h incubated with HER, which was confirmed by DNA fragmentation, nuclear shrinkage, and poly (ADP-ribose) polymerase (PARP) cleavage. HER at 25-100μM induced a mitochondria-dependent apoptotic pathway associated with Bcl-2/Bax ratio decrease, mitochondrial membrane potential (ΔΨ) collapse, cytochrome c release, and caspase-3 activation. Increasing expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) was also observed in HER-treated cells. Furthermore, the addition of a ROS inhibitor (N-Acetyl-l-cysteine, NAC) significantly attenuated the apoptosis induced by HER and also blocked the expression of PGC-1α protein. Additionally, HER effectively inhibited the phosphorylation of Akt and the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 increased the inhibition effect of HER on Akt phosphorylation. These findings provide evidences that HER induces HepG2 apoptosis in a ROS-mediated mitochondria-dependent manner that correlate with the inactivation of the PI3K/Akt pathway.}, }
@article {pmid23063000, year = {2013}, author = {Simard, B and Ratel, D and Dupré, I and Pautre, V and Berger, F}, title = {Shark cartilage extract induces cytokines expression and release in endothelial cells and induces E-selectin, plasminogen and t-PA genes expression through an antioxidant-sensitive mechanism.}, journal = {Cytokine}, volume = {61}, number = {1}, pages = {104-111}, doi = {10.1016/j.cyto.2012.08.035}, pmid = {23063000}, issn = {1096-0023}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cells, Cultured ; Cytokines/biosynthesis/*metabolism ; E-Selectin/*biosynthesis ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System/drug effects ; NF-kappa B/metabolism ; Neovascularization, Physiologic/drug effects ; Oligonucleotide Array Sequence Analysis ; Plasminogen/*biosynthesis ; Reactive Oxygen Species/metabolism ; Tissue Extracts/metabolism/*pharmacology ; Tissue Plasminogen Activator/*biosynthesis ; Tumor Necrosis Factor-alpha/metabolism/pharmacology ; }, abstract = {Neovastat® is a standardized extract of marine cartilage, an avascular tissue, which contains many biologically active molecules and has multiple antiangiogenic properties. In addition to VEGFR2 and MMPs inhibition, shark cartilage extract (SCE) has recently been shown to induce tissue plasminogen activator gene (PLAT) expression in bovine endothelial cells in a TNF like manner, by inducing the typical mediators NF-κB and JNK. There is now compelling evidences that the NF-κB and JNK pathways are activated by cytokines induced generation of reactive oxygen species (ROS). We used macroarray genes expression analysis on human umbilical vein endothelial cells, to investigate if that mechanism could mediate the effect of SCE. Transcriptomic results showed that SCE induced expression of several cytokines. Their impact must be important, given that treatment of endothelial cells with the cytokine TNF-α was able to reproduce most of the effects of cartilage extract on genes expression. In addition, most of the genes, known to be inducible by NF-κB or JNK following cytokines stimulation, were less induced by SCE when endothelial cells were pretreated with the antioxidant N-Acetylcysteine (NAC), suggesting a role of ROS in endothelial cell activation by SCE. Finally, the possible effects of PLAT, PLG, SELE, IL8 and PRDX2 (those validated by q-PCR) on angiogenesis, will also be discussed.}, }
@article {pmid23062438, year = {2012}, author = {Özyürek, M and Baki, S and Güngör, N and Çelik, SE and Güçlü, K and Apak, R}, title = {Determination of biothiols by a novel on-line HPLC-DTNB assay with post-column detection.}, journal = {Analytica chimica acta}, volume = {750}, number = {}, pages = {173-181}, doi = {10.1016/j.aca.2012.03.056}, pmid = {23062438}, issn = {1873-4324}, mesh = {*Chromatography, High Pressure Liquid ; Cysteine/analogs &amp; derivatives/analysis ; Dithioerythritol/analysis ; Dithionitrobenzoic Acid/*chemistry ; Glutathione/analysis ; Oligosaccharides/chemistry ; Pharmaceutical Preparations/chemistry ; Sulfhydryl Compounds/*analysis ; }, abstract = {A novel on-line HPLC-DTNB method was developed for the selective determination of biologically important thiols (biothiols) such as L-cysteine (Cys), glutathione (GSH), homocysteine (HCys), N-acetylcysteine (NAC), and 1,4-dithioerythritol (DTE) in pharmaceuticals and tissue homogenates. The biothiols were separated on C18 column using gradient elution, reacted with the postcolumn reagent, DTNB in 0.5% M-β-CD (w/v) solution at pH 8, to form yellow-colored 5-thio-2-nitrobenzoic acid (TNB), and monitored with a PDA detector (λ=410 nm). With the optimized conditions for chromatography and the post-column derivatization, 40 nM of NAC, 40 nM of Cys, and 50 nM of GSH can be determined. The relative standard deviations of the recommended method were in the range of 3.2-5.4% for 50 μM biothiols. The negative peaks of biothiol constituents were monitored by measuring the increase in absorbance due to TNB chromophore. The detection limits of biothiols at 410 nm (in the range of 0.04-0.58 μM) after post-column derivatization with DTNB+M-β-CD were much lower than those at 205 nm UV-detection without derivatization, and were distinctly lower than those with post-column DTNB alone. The method is rapid, inexpensive, versatile, nonlaborious, uses stable reagents, and enables the on-line qualitative and quantitative estimation of biothiol constituents of biological fluids and pharmaceuticals.}, }
@article {pmid23061828, year = {2013}, author = {Zheng, JP and Wen, FQ and Bai, CX and Wan, HY and Kang, J and Chen, P and Yao, WZ and Ma, LJ and Xia, QK and Gao, Y and Zhong, NS and , }, title = {High-dose N-acetylcysteine in the prevention of COPD exacerbations: rationale and design of the PANTHEON Study.}, journal = {COPD}, volume = {10}, number = {2}, pages = {164-171}, doi = {10.3109/15412555.2012.732628}, pmid = {23061828}, issn = {1541-2563}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Adult ; Aged ; Aged, 80 and over ; *Disease Progression ; Double-Blind Method ; Expectorants/*administration &amp; dosage/adverse effects ; Female ; Forced Expiratory Volume ; Humans ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/physiopathology/*prevention &amp; control ; Quality of Life ; Research Design ; Time Factors ; Vital Capacity ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation; from a pathophysiological point of view it involves many components, including mucus hypersecretion, oxidative stress and inflammation. N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. Long-term efficacy of NAC 600mg/d in COPD is controversial; a dose-effect relationship has been demonstrated, but at present it is not known whether a higher dose provides clinical benefits. The PANTHEON Study is a prospective, ICS stratified, randomized, double-blind, placebo-controlled, parallel-group, multi-center trial designed to assess the efficacy and safety of high-dose (1200 mg/daily) NAC treatment for one year in moderate-to-severe COPD patients. The primary endpoint is the annual exacerbation rate. Secondary endpoints include recurrent exacerbations hazard ratio, time to first exacerbation, as well as quality of life and pulmonary function. The hypothesis, design and methodology are described and baseline characteristics of recruited patients are presented. 1006 COPD patients (444 treated with maintenance ICS, 562 ICS naive, aged 66.27±8.76 yrs, average post-bronchodilator FEV1 48.95±11.80 of predicted) have been randomized at 34 hospitals in China. Final results of this study will provide objective data on the effects of high-dose (1200 mg/daily) long-term NAC treatment in the prevention of COPD exacerbations and other outcome variables.}, }
@article {pmid23056996, year = {2012}, author = {Chandramani Shivalingappa, P and Jin, H and Anantharam, V and Kanthasamy, A and Kanthasamy, A}, title = {N-Acetyl Cysteine Protects against Methamphetamine-Induced Dopaminergic Neurodegeneration via Modulation of Redox Status and Autophagy in Dopaminergic Cells.}, journal = {Parkinson's disease}, volume = {2012}, number = {}, pages = {424285}, pmid = {23056996}, issn = {2042-0080}, support = {R01 ES010586/ES/NIEHS NIH HHS/United States ; R01 NS065167/NS/NINDS NIH HHS/United States ; R01 NS074443/NS/NINDS NIH HHS/United States ; }, abstract = {Methamphetamine- (MA-) induced neurotoxicity is associated with mitochondrial dysfunction and enhanced oxidative stress. Our previous study demonstrated that MA induces autophagy in a dopaminergic neuronal cell model (N27 cells). The cellular mechanisms underlying MA-induced autophagy and apoptosis remain poorly characterized. In the present study we sought to investigate the importance of GSH redox status in MA-induced neurotoxicity using a thiol antioxidant, N-acetylcysteine (NAC). Morphological and biochemical analysis revealed that MA-induced autophagy in N27 dopaminergic cells was associated with pronounced depletion of GSH levels. Moreover, pretreatment with NAC reduced MA-induced GSH depletion and autophagy, while depletion of GSH using L-buthionine sulfoximine (L-BSO) enhanced autophagy. Furthermore, treatment with NAC significantly attenuated MA-induced apoptotic cell death as well as oxidative stress markers, namely, 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE). Together, these results suggest that NAC exhibits significant protective effects against MA-induced dopaminergic cell death, presumably via modulation of the GSH level and autophagy. Collectively, our data provide mechanistic insights into the role of cellular GSH redox status in MA-induced autophagy and apoptotic cell death, and additional studies are needed to determine the therapeutic effectiveness of cellular redox modifiers in attenuating dopaminergic neurodegeneration in vivo.}, }
@article {pmid23056433, year = {2012}, author = {Zhang, Y and Yang, ND and Zhou, F and Shen, T and Duan, T and Zhou, J and Shi, Y and Zhu, XQ and Shen, HM}, title = {(-)-Epigallocatechin-3-gallate induces non-apoptotic cell death in human cancer cells via ROS-mediated lysosomal membrane permeabilization.}, journal = {PloS one}, volume = {7}, number = {10}, pages = {e46749}, pmid = {23056433}, issn = {1932-6203}, mesh = {Apoptosis/*drug effects ; Blotting, Western ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Survival/drug effects ; Hep G2 Cells ; Humans ; Intracellular Membranes/*drug effects/*metabolism ; Lysosomes/*drug effects/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {(-)-Epigallocatechin-3-gallate (EGCG) is the most extensive studied tea polyphenol for its anti-cancer function. In this study, we report a novel mechanism of action for EGCG-mediated cell death by identifying the critical role of lysosomal membrane permeabilization (LMP). First, EGCG-induced cell death in human cancer cells (both HepG2 and HeLa) was found to be caspase-independent and accompanied by evident cytosolic vacuolization, only observable when cells were treated in serum-free medium. The cytosolic vacuolization observed in EGCG-treated cells was most probably caused by lysosomal dilation. Interestingly, EGCG was able to disrupt autophagic flux at the degradation stage by impairment of lysosomal function, and EGCG-induced cell death was independent of Atg5 or autophagy. The key finding of this study is that EGCG is able to trigger LMP, as evidenced by Lyso-Tracker Red staining, cathepsin D cytosolic translocation and cytosolic acidification. Consistently, a lysosomotropic agent, chloroquine, effectively rescues the cell death via suppressing LMP-caused cytosolic acidification. Lastly, we found that EGCG promotes production of intracellular ROS upstream of LMP and cell death, as evidenced by increased level of ROS in cells treated with EGCG and the protective effects of antioxidant N-acetylcysteine (NAC) against EGCG-mediated LMP and cell death. Taken together, data from our study reveal a novel mechanism underlying EGCG-induced cell death involving ROS and LMP. Therefore, understanding this lysosome-associated cell death pathway shed new lights on the anti-cancer effects of EGCG.}, }
@article {pmid23055666, year = {2012}, author = {Kagan, DB and Liu, H and Hutnik, CM}, title = {Efficacy of various antioxidants in the protection of the retinal pigment epithelium from oxidative stress.}, journal = {Clinical ophthalmology (Auckland, N.Z.)}, volume = {6}, number = {}, pages = {1471-1476}, pmid = {23055666}, issn = {1177-5483}, abstract = {BACKGROUND: Oxidative stress induced retinal pigment epithelium (RPE) dysfunction is hypothesized to be fundamental in the pathogenesis of age-related macular degeneration (AMD). This study investigated whether vitamin C, vitamin C phosphate, vitamin E, propofol, betaxolol, and N-acetyl cysteine (NAC) protect human RPE cells from oxidative stress.<br><br>METHODS: ARPE-19 cells were pretreated with the compounds under investigation. The chemical oxidant tert-butyl hydroperoxide (t-BOOH) was used to induce oxidative stress. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.<br><br>RESULTS: Exposure to t-BOOH resulted in a dose- and time-dependent reduction in ARPE-19 cell viability. Compared with cells given t-BOOH alone, vitamin E and NAC pretreated cells had significantly improved viability, propofol and betaxolol pretreated cells had no significant difference in viability, and vitamin C and vitamin C phosphate pretreated cells had significantly reduced viability.<br><br>CONCLUSION: Of the compounds studied, only vitamin E and NAC significantly mitigated the effects of oxidative stress on RPE cells. Because of their potential therapeutic value for AMD patients, these and other RPE protective compounds continue to merit further investigation.}, }
@article {pmid23054190, year = {2013}, author = {Radhika, A and Sudhakaran, PR}, title = {Upregulation of macrophage-specific functions by oxidized LDL: lysosomal degradation-dependent and -independent pathways.}, journal = {Molecular and cellular biochemistry}, volume = {372}, number = {1-2}, pages = {181-190}, pmid = {23054190}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Cell Differentiation/drug effects ; Cells, Cultured ; Chloroquine/pharmacology ; Chromones/pharmacology ; Copper Sulfate/pharmacology ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Humans ; Imidazoles/pharmacology ; Leukocytes, Mononuclear/drug effects/metabolism/physiology ; Lipoproteins, LDL/pharmacology/*physiology ; Lysosomes/drug effects/*metabolism ; Macrophages/drug effects/*metabolism/physiology ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Morpholines/pharmacology ; NF-kappa B/metabolism ; Naphthalenes/pharmacology ; Oxidation-Reduction ; PPAR gamma/genetics/metabolism ; Proteolysis ; Pyridines/pharmacology ; Signal Transduction/drug effects ; Transcription Factor AP-1/metabolism ; Transcriptional Activation/drug effects ; Up-Regulation ; }, abstract = {Formation of foam cells from macrophages, which are formed by the differentiation of blood-borne monocytes, is a critical early event in atherogenesis. To examine how pre-exposure of monocytes to modified proteins, such as oxLDL, influences their differentiation to macrophages, an in vitro model system using isolated PBMC maintained in culture in the presence of oxLDL was used. Pretreatment of monocytes with oxLDL caused a faster rate of expression of macrophage-specific functions and loss of monocyte-specific functions compared to unmodified LDL. The effect of oxidation of lipid component of LDL by CuSO(4) and its protein component by HOCl, on mo-mϕ differentiation was studied by monitoring the upregulation of macrophage-specific functions, particularly MMP-9. Chloroquine, a lysosomal degradation blocker, significantly reversed the effect mediated by CuSO(4) oxLDL, indicating the involvement of lysosomal degradation products, while no such effect was observed in HOCl oxLDL-treated cells, indicating the existence of a pathway independent of its lysosomal degradation products. Reversal of the effect of oxLDL by NAC and Calphostin C, an inhibitor of PKC, suggested the activation of RO-mediated signaling pathways. Use of inhibitors of signaling pathways showed that CuSO(4) oxLDL upregulated mϕ-specific MMP-9 through p38 MAPK and Akt-dependent pathways, while HOCl oxLDL utilized ERK ½ and Akt. Further analysis showed the activation of PPARγ and AP-1 in CuSO(4) oxLDL, while HOCl-oxLDL-mediated effect involved NFκB and AP-1. These results suggest that lipid oxLDL- and protein oxLDL-mediated upregulation of mo-mϕ-specific functions involve lysosomal degradation-dependent and -independent activation of intracellular signaling pathways.}, }
@article {pmid23052971, year = {2013}, author = {Grillo, MP and Lohr, MT and Khera, S}, title = {Interaction of γ-glutamyltranspeptidase with ibuprofen-S-acyl-glutathione in vitro and in vivo in human.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {41}, number = {1}, pages = {111-121}, doi = {10.1124/dmd.112.048645}, pmid = {23052971}, issn = {1521-009X}, mesh = {Animals ; Cattle ; Chromatography, Liquid ; Glutathione/*analogs &amp; derivatives/metabolism ; Humans ; Ibuprofen/*analogs &amp; derivatives/metabolism ; In Vitro Techniques ; Magnetic Resonance Spectroscopy ; Tandem Mass Spectrometry ; gamma-Glutamyltransferase/*metabolism ; }, abstract = {Ibuprofen is metabolized to chemically reactive acyl glucuronide and S-acyl-CoA metabolites that are proposed to transacylate glutathione (GSH) forming ibuprofen-S-acyl-GSH (I-SG) in vivo. Herein, we report the detection of novel metabolites of ibuprofen, namely ibuprofen-N-acyl-cysteinylglycine (I-N-CG), ibuprofen-N-acyl-cysteine (I-N-C), and the mercapturic acid conjugate, ibuprofen-S-acyl-N-acetylcysteine (I-S-NAC), in urine from an ibuprofen-dosed volunteer. Thus, analysis of ibuprofen-dosed (Advil, 800 mg, Pfizer, Madison, NJ) human urine extracts by sensitive liquid chromatography tandem mass spectrometric detection resulted in the identification of I-N-CG, I-N-C, and I-S-NAC derivatives as minor metabolites (6.0, 1.7, and 0.2 µg excreted 10-hours postadministration, respectively). I-N-CG is proposed to be formed from the degradation of I-SG by γ-glutamyltranspeptidase (γ-GT)-mediated cleavage of the γ-glutamyl group, leading to an unstable ibuprofen-S-acyl-cysteinylglycine (I-S-CG) intermediate that undergoes spontaneous S to N intramolecular rearrangement. Then, dipeptidase-mediated cleavage of glycine from I-N-CG leads to the formation of I-N-C. Treatment of racemic I-SG (100 µM) in vitro with commercially available bovine kidney γ-GT (0.1 units/ml) in buffer at pH 7.4 and 37°C resulted in its complete degradation, yielding (R)- and (S)-I-N-CG after 15 minutes of incubation. In vitro enzyme kinetic studies with bovine kidney γ-GT incubated separately with (R)- and (S)-I-SG isomers revealed no enantioselective degradation. Results from these studies provided evidence that ibuprofen is metabolized in human to reactive transacylating-type intermediates that react with GSH, forming I-SG thioester that, following degradation by γ-GT and dipeptidase enzymes and following S to N intramolecular rearrangement, leads to the urinary excretion of the I-N-CG and I-N-C amide-linked conjugates, respectively.}, }
@article {pmid23047606, year = {2012}, author = {Martinez-Outschoorn, UE and Balliet, RM and Lin, Z and Whitaker-Menezes, D and Howell, A and Sotgia, F and Lisanti, MP}, title = {Hereditary ovarian cancer and two-compartment tumor metabolism: epithelial loss of BRCA1 induces hydrogen peroxide production, driving oxidative stress and NFκB activation in the tumor stroma.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {11}, number = {22}, pages = {4152-4166}, pmid = {23047606}, issn = {1551-4005}, mesh = {Antioxidants/pharmacology ; Apoptosis/drug effects ; BRCA1 Protein/deficiency/genetics/*metabolism ; Caveolin 1/antagonists &amp; inhibitors/genetics/metabolism ; Cell Line, Tumor ; Coculture Techniques ; Female ; Humans ; Hydrogen Peroxide/*metabolism ; Monocarboxylic Acid Transporters/metabolism ; Muscle Proteins/metabolism ; Mutation ; NF-kappa B/genetics/*metabolism ; Ovarian Neoplasms/metabolism/pathology ; *Oxidative Stress ; RNA Interference ; RNA, Small Interfering/metabolism ; }, abstract = {Mutations in the BRCA1 tumor suppressor gene are commonly found in hereditary ovarian cancers. Here, we used a co-culture approach to study the metabolic effects of BRCA1-null ovarian cancer cells on adjacent tumor-associated stromal fibroblasts. Our results directly show that BRCA1-null ovarian cancer cells produce large amounts of hydrogen peroxide, which can be abolished either by administration of simple antioxidants (N-acetyl-cysteine; NAC) or by replacement of the BRCA1 gene. Thus, the BRCA1 gene normally suppresses tumor growth by functioning as an antioxidant. Importantly, hydrogen peroxide produced by BRCA1-null ovarian cancer cells induces oxidative stress and catabolic processes in adjacent stromal fibroblasts, such as autophagy, mitophagy and glycolysis, via stromal NFκB activation. Catabolism in stromal fibroblasts was also accompanied by the upregulation of MCT4 and a loss of Cav-1 expression, which are established markers of a lethal tumor microenvironment. In summary, loss of the BRCA1 tumor suppressor gene induces hydrogen peroxide production, which then leads to metabolic reprogramming of the tumor stroma, driving stromal-epithelial metabolic coupling. Our results suggest that new cancer prevention trials with antioxidants are clearly warranted in patients that harbor hereditary/familial BRCA1 mutations.}, }
@article {pmid23046028, year = {2012}, author = {Buggiani, G and Tsampau, D and Hercogovà, J and Rossi, R and Brazzini, B and Lotti, T}, title = {Clinical efficacy of a novel topical formulation for vitiligo: compared evaluation of different treatment modalities in 149 patients.}, journal = {Dermatologic therapy}, volume = {25}, number = {5}, pages = {472-476}, doi = {10.1111/j.1529-8019.2012.01484.x}, pmid = {23046028}, issn = {1529-8019}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/therapeutic use ; Administration, Cutaneous ; Adolescent ; Adult ; Aged ; Clobetasol/administration &amp; dosage/adverse effects/therapeutic use ; Combined Modality Therapy ; Cucumis melo/chemistry ; Dermatologic Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Female ; Gels ; Glucocorticoids/administration &amp; dosage/adverse effects/therapeutic use ; Humans ; Male ; Middle Aged ; Ointments ; Phenylalanine/administration &amp; dosage/adverse effects/therapeutic use ; Plant Extracts/administration &amp; dosage/adverse effects/therapeutic use ; Skin Pigmentation/drug effects ; Ultraviolet Therapy/*methods ; Vitiligo/pathology/*therapy ; Young Adult ; }, abstract = {Current vitiligo treatments are not always satisfactory for both patients and dermatologists. Recently, combination therapies have been introduced in order to obtain better results and reduce risks in the management of the disease. Novel efficacious products are needed to improve the therapeutic possibilities of dermatologists in the respect of safety for the patients. The objective of the present study was to evaluate the effects of a novel topical in a gel formulation containing phenylalanine, cucumis melo extract, and acetyl cysteine in vitiligo. The present study used an open observational study to evaluate the efficacy and safety of the investigated product, given alone or in combination with 311-nm narrow band microphototherapy. Results were compared with those obtained treating a matched patient population with microphototherapy alone and with clobetasol propionate 0.05% ointment alone. One hundred forty-nine patients suffering from symmetrical vitiligo affecting less than 10% of the skin surface were evaluated. Patients affected by acral vitiligo only were excluded from the analysis. Treatment duration was scheduled for 12 weeks. Excellent repigmentation (>75%) was achieved by 38-73% of patients, depending on the treatment regimen. Mild to moderate side effects were observed only in patients treated with clobetasol 0.05% ointment. The tested gel formulation showed a good efficacy in improving vitiligo repigmentation. No side effects were observed.}, }
@article {pmid23044269, year = {2013}, author = {Lai, L and Lin, C and Xiao, CQ and Xu, ZQ and Han, XL and Fu, L and Li, DW and Mei, P and Jiang, FL and Guo, QL and Liu, Y}, title = {Adhesion of quantum dots-induced membrane damage of Escherichia coli.}, journal = {Journal of colloid and interface science}, volume = {389}, number = {1}, pages = {61-70}, doi = {10.1016/j.jcis.2012.09.002}, pmid = {23044269}, issn = {1095-7103}, mesh = {Acetylcysteine/chemistry/*toxicity ; Cadmium Compounds/chemistry/*toxicity ; Escherichia coli/*drug effects ; Glutathione/chemistry/*toxicity ; Ligands ; Particle Size ; *Quantum Dots ; Sulfhydryl Compounds/chemistry/*toxicity ; Tellurium/chemistry/*toxicity ; Toxicity Tests ; }, abstract = {The toxicity of CdTe QDs modified with three different ligands, namely mercaptopropionic acid (MPA), N-acetyl-L-cysteine (NAC), and glutathione (GSH), were investigated via microcalorimetric, spectroscopic, and microscopic methods. The three ligand-modified QDs have nearly identical hydrodynamic size. The results of the calorimetric experiments and optical density measurements indicate that the QDs inhibited the growth of Gram-negative Escherichia coli. The toxicity order of the three QDs is MPA-CdTe QDs>GSH-CdTe QDs>NAC-CdTe QDs. The inhibitory effects of the QDs, cadmium chloride (CdCl(2)), MPA, and the CdCl(2) and MPA mixture on E. coli growth indicate that the toxicity mechanism of QDs may be related to their bacterial adhesion. When dispersed in the cell suspensions, QDs tend to have their high surface energy reduced through adsorption to the bacterial surface, as confirmed by transmission electron microscopy and inductively coupled plasma atomic emission spectroscopy results. Furthermore, the effect of QDs on the membrane fluidity and permeability was investigated. GSH-CdTe QDs have a greater effect on the membrane function of E. coli than those of MPA-CdTe and NAC-CdTe QDs. This result may be attributed to the stronger lipophilicity of GSH compared with those of MPA and NAC.}, }
@article {pmid23044263, year = {2013}, author = {Dhanda, S and Kaur, S and Sandhir, R}, title = {Preventive effect of N-acetyl-L-cysteine on oxidative stress and cognitive impairment in hepatic encephalopathy following bile duct ligation.}, journal = {Free radical biology &amp; medicine}, volume = {56}, number = {}, pages = {204-215}, doi = {10.1016/j.freeradbiomed.2012.09.017}, pmid = {23044263}, issn = {1873-4596}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bile Ducts/*surgery ; Cognition Disorders/*complications/*drug therapy ; Hepatic Encephalopathy/*complications/*drug therapy ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Oxidative stress caused by ammonia toxicity is known to play a key role in the pathogenesis of hepatic encephalopathy (HE). The present study was designed to evaluate the protective effect of N-acetyl-L-cysteine (NAC) supplementation in a bile duct ligation (BDL)-induced model of HE. Three weeks after BDL, rats developed biliary fibrosis which was supported by liver function tests, ammonia levels, and hydroxyproline content. Impaired cognitive and motor functions were observed along with decreased acetylcholinesterase activity in the brain of BDL rats. Cerebral cortex and cerebellum of BDL animals showed an increase in lipid peroxidation and reduction in total and nonprotein thiols along with reduction in antioxidant enzymes. Histopathological examination of cortex and cerebellum of BDL rats showed astrocytic swelling, inflammation, necrosis, and white matter edema. One week after BDL surgery, animals administered with NAC at a daily dose 100 mg/kg for 2 weeks showed significant improvement in the activity of liver marker enzymes and restored structural morphology of liver. NAC was able to ameliorate spatial memory and motor coordination deficits observed in BDL rats. NAC supplementation decreased lipid peroxidation and was also able to restore the activity of antioxidant enzymes as well as structural deficits observed in the cortex and cerebellum of BDL animals. The results clearly demonstrate that the protective effect of NAC in an experimental model of HE is mediated through attenuation of oxidative stress, suggesting a therapeutic role for NAC in individuals withHE.}, }
@article {pmid23043505, year = {2013}, author = {Sharifudin, SA and Fakurazi, S and Hidayat, MT and Hairuszah, I and Moklas, MA and Arulselvan, P}, title = {Therapeutic potential of Moringa oleifera extracts against acetaminophen-induced hepatotoxicity in rats.}, journal = {Pharmaceutical biology}, volume = {51}, number = {3}, pages = {279-288}, doi = {10.3109/13880209.2012.720993}, pmid = {23043505}, issn = {1744-5116}, mesh = {Acetaminophen/*poisoning ; Analgesics, Non-Narcotic/poisoning ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Antipyretics/poisoning ; Biomarkers/blood/metabolism ; Chemical and Drug Induced Liver Injury/metabolism/pathology/physiopathology/*prevention &amp; control ; Dose-Response Relationship, Drug ; Flowers/*chemistry ; Injections, Intraperitoneal ; Liver/drug effects/metabolism/pathology/physiopathology ; Male ; Moringa oleifera/*chemistry ; Oxidative Stress/drug effects ; Phytotherapy ; Plant Extracts/administration &amp; dosage/*therapeutic use ; Plant Leaves/*chemistry ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Severity of Illness Index ; }, abstract = {CONTEXT: Moringa oleifera Lam. (Moringaceae) is a rich source of essential minerals and antioxidants; it has been used in human and animal nutrition. The leaves and flowers are being used by the population with great dietary importance.<br><br>OBJECTIVE: The present study was to investigate the therapeutic effects of the hydroethanolic extract of Moringa oleifera (MO) leaves and flowers against hepatotoxicity induced by acetaminophen (APAP) in rats.<br><br>MATERIALS AND METHODS: In the hepatoprotective study, either flowers or leaves of hydroethanolic extract (200 or 400&#x2009;mg/kg bw through IP injection) were administered an hour after APAP administration. N-Acetylcysteine (NAC) was used as the positive control for this study. Liver and kidney function tests including lipid peroxidation levels were analyzed and histopathological changes of liver and kidney were also observed.<br><br>RESULTS: Acetaminophen-induced hepatotoxicity increased the activities of liver marker enzymes. Histologically, the liver was observed to have inflammation and bridging necrosis. Liver marker enzymes were significantly reduced when treated with flower and leaf extracts of MO in animals with APAP induced toxicity. In addition, there were no significant changes observed in clinical markers of kidney function. Histological observation on liver tissue from the rats treated with MO flower and leaf extract showed reduction in the severity of the liver damage.<br><br>DISCUSSION AND CONCLUSION: These results indicated the possible therapeutic action of flower and leaf extract from MO in protecting liver damage in rats given an over dosage of APAP.}, }
@article {pmid23042187, year = {2012}, author = {Chien, CC and Shen, SC and Yang, LY and Chen, YC}, title = {Prostaglandins as negative regulators against lipopolysaccharide, lipoteichoic acid, and peptidoglycan-induced inducible nitric oxide synthase/nitric oxide production through reactive oxygen species-dependent heme oxygenase 1 expression in macrophages.}, journal = {Shock (Augusta, Ga.)}, volume = {38}, number = {5}, pages = {549-558}, doi = {10.1097/SHK.0b013e31826b2826}, pmid = {23042187}, issn = {1540-0514}, mesh = {Animals ; Cell Line ; Gene Expression Regulation, Enzymologic/*drug effects/genetics ; Gene Knockdown Techniques ; Heme Oxygenase-1/*biosynthesis/genetics ; Lipopolysaccharides/*pharmacology ; Macrophages/cytology/*metabolism ; Membrane Proteins/*biosynthesis/genetics ; Mice ; Nitric Oxide/*biosynthesis/genetics ; Nitric Oxide Synthase Type II/*biosynthesis/genetics ; Peptidoglycan/*pharmacology ; Prostaglandins/*pharmacology ; Reactive Oxygen Species/*metabolism ; Teichoic Acids/*pharmacology ; }, abstract = {Although prostaglandins (PGs) were reported to exert proinflammatory and anti-inflammatory effects in macrophages, their action mechanisms remain unclear. The effects of PGs including PGJ2 (J2), Δ-PGJ2 (Δ), 15-deoxy-Δ PGJ2 (15d), PGE2 (E2), and PGF2α (F2α) on lipopolysaccharide (LPS)-, lipoteichoic acid (LTA)-, and peptidoglycan (PGN)-induced inducible nitric oxide (NO) synthase (iNOS)/NO production by RAW264.7 macrophages were investigated. First, we found that induction of cyclooxygenase 2 (COX-2) protein occurred at a time earlier than that of heme oxygenase 1 (HO-1) protein, and the addition of the COX-2 inhibitor NS398 reduced HO-1 protein expression in LPS-, LTA-, and PGN-treated RAW264.7 macrophages. Incubation of RAW264.7 macrophages with the indicated PGs showed that J2, Δ, and 15d significantly induced HO-1 protein expression; however, E2 and F2α did not. Heme oxygenase 1 protein induced by J2, Δ, and 15d was inhibited by the transcriptional inhibitor, actinomycin (Act) D; the translational inhibitor, cycloheximide; and the antioxidant, N-acetyl cysteine (NAC). Increases in intracellular peroxide levels by J2, Δ, and 15d were detected via a 2',7'™-dichlorofluorescein diacetate (DCFH-DA) analysis, and they were prevented by the addition of NAC. In addition, J2, Δ, and 15d produced significant inhibition of LPS-, LTA-, and PGN-induced iNOS protein and NO production by RAW264.7 cells, in accordance with increased HO-1 protein expression. Reductions of LPS-, LTA-, and PGN-induced phosphorylated c-Jun N-terminal kinase, c-Jun protein, and activator protein 1 luciferase activity by J2, Δ, and 15d were identified, and the addition of the HO-1 inhibitor, tin protoporphyrin, reversed the inhibitory effects of Δ and 15d on LPS- and LTA-induced iNOS/NO, phosphorylated c-Jun N-terminal kinase, and c-Jun protein expressions by macrophages. Knockdown of HO-1 protein expression by HO-1 small interfering RNA blocked Δ and 15d inhibition of LPS- and LTA-induced events. Moreover, the compound, cyclopentenone (CP), which mimics the CP moiety of 15d, and its analog cyclohexenone were used, and cyclohexenone showed more potent induction of the HO-1 protein with effective inhibition of LPS-, LTA-, and PGN-induced iNOS/NO production than CP in macrophages. Reactive oxygen species-dependent HO-1 protein expression by PGs, which inhibited LPS-, LTA-, and PGN-induced iNOS/NO production, was identified in macrophages.}, }
@article {pmid23041016, year = {2013}, author = {Ozaydin, M and Erdogan, D and Yucel, H and Peker, O and Icli, A and Akcay, S and Etli, M and Ceyhan, BM and Sutcu, R and Varol, E and Dogan, A and Yavuz, T}, title = {N-acetyl cysteine for the conversion of atrial fibrillation into sinus rhythm after cardiac surgery: a prospective, randomized, double-blind, placebo-controlled pilot study.}, journal = {International journal of cardiology}, volume = {165}, number = {3}, pages = {580-583}, doi = {10.1016/j.ijcard.2012.09.031}, pmid = {23041016}, issn = {1874-1754}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Aged ; Atrial Fibrillation/*drug therapy/epidemiology/physiopathology ; *Cardiac Surgical Procedures/adverse effects ; Double-Blind Method ; Female ; Follow-Up Studies ; Free Radical Scavengers/pharmacology/therapeutic use ; Heart Rate/*drug effects/*physiology ; Humans ; Male ; Middle Aged ; Pilot Projects ; Prospective Studies ; }, }
@article {pmid23038752, year = {2013}, author = {Murray, J and Auwerx, J and Huss, JM}, title = {Impaired myogenesis in estrogen-related receptor γ (ERRγ)-deficient skeletal myocytes due to oxidative stress.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {27}, number = {1}, pages = {135-150}, pmid = {23038752}, issn = {1530-6860}, support = {R01 DK074700/DK/NIDDK NIH HHS/United States ; R01DK074700/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Blotting, Western ; DNA Primers ; Mice ; *Muscle Development ; Muscle, Skeletal/cytology/metabolism/*physiology ; *Oxidative Stress ; Real-Time Polymerase Chain Reaction ; Receptors, Estrogen/genetics/*physiology ; }, abstract = {Specialized contractile function and increased mitochondrial number and oxidative capacity are hallmark features of myocyte differentiation. The estrogen-related receptors (ERRs) can regulate mitochondrial biogenesis or mitochondrial enzyme expression in skeletal muscle, suggesting that ERRs may have a role in promoting myogenesis. Therefore, we characterized myogenic programs in primary myocytes isolated from wild-type (M-ERRγWT) and muscle-specific ERRγ(-/-) (M-ERRγ(-/-)) mice. Myotube maturation and number were decreased throughout differentiation in M-ERRγ(-/-) primary myocytes, resulting in myotubes with reduced mitochondrial content and sarcomere assembly. Compared with M-ERRγWT myocytes at the same differentiation stage, the glucose oxidation rate was reduced by 30% in M-ERRγ(-/-) myotubes, while medium-chain fatty acid oxidation was increased by 34% in M-ERRγ(-/-) myoblasts and 36% in M-ERRγ(-/-) myotubes. Concomitant with increased reliance on mitochondrial β-oxidation, H(2)O(2) production was significantly increased by 40% in M-ERRγ(-/-) myoblasts and 70% in M-ERRγ(-/-) myotubes compared to M-ERRγWT myocytes. ROS activation of FoxO and NF-κB and their downstream targets, atrogin-1 and MuRF1, was observed in M-ERRγ(-/-) myocytes. The antioxidant N-acetyl cysteine rescued myotube formation and atrophy gene induction in M-ERRγ(-/-) myocytes. These results suggest that loss of ERRγ causes metabolic defects and oxidative stress that impair myotube formation through activation of skeletal muscle atrophy pathways.}, }
@article {pmid23038011, year = {2012}, author = {Yokomakura, A and Hong, J and Ohuchi, K and Oh, SE and Lee, JY and Mano, N and Takahashi, T and Hwang, GW and Naganuma, A}, title = {Increased production of reactive oxygen species by the vacuolar-type (H(+))-ATPase inhibitors bafilomycin A1 and concanamycin A in RAW 264 cells.}, journal = {The Journal of toxicological sciences}, volume = {37}, number = {5}, pages = {1045-1048}, doi = {10.2131/jts.37.1045}, pmid = {23038011}, issn = {1880-3989}, mesh = {Animals ; Cell Line ; Cell Survival/drug effects ; Enzyme Inhibitors/*toxicity ; Macrolides/*toxicity ; Mice ; Reactive Oxygen Species/*metabolism ; Vacuolar Proton-Translocating ATPases/*antagonists &amp; inhibitors ; }, abstract = {Treatment of the mouse leukemic cell line RAW 264 with bafilomycin A1 or concanamycin A, inhibitors of vacuolar-type (H(+))-ATPases (V-ATPases), significantly increased the production of reactive oxygen species (ROS) and decreased cell viability. These effects were significantly suppressed by the presence of N-acetyl cysteine (NAC), an ROS scavenger. si-RNA mediated knockdown of the gene for the c subunit of the V0 domain of V-ATPase also resulted in an increase in ROS production and a decrease in cell viability. These results suggest that decreased cellular V-ATPase activity decreases cell viability by increasing ROS production in RAW 264 cells.}, }
@article {pmid23037460, year = {2012}, author = {Hsu, TF and Huang, MK and Yu, SH and Yen, DH and Kao, WF and Chen, YC and Huang, MS}, title = {N-acetylcysteine for the prevention of contrast-induced nephropathy in the emergency department.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {51}, number = {19}, pages = {2709-2714}, doi = {10.2169/internalmedicine.51.7894}, pmid = {23037460}, issn = {1349-7235}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aged ; Aged, 80 and over ; Contrast Media/*adverse effects ; *Emergency Medical Services ; Emergency Service, Hospital ; Female ; Humans ; Iohexol/adverse effects/analogs &amp; derivatives ; Kidney Diseases/*chemically induced/*prevention &amp; control/therapy ; Male ; Prospective Studies ; Renal Dialysis ; Taiwan ; Tomography, X-Ray Computed/*adverse effects ; }, abstract = {OBJECTIVE: To evaluate the use of N-acetylcysteine (NAC), a potent antioxidant, to prevent contrast-induced nephropathy (CIN).<br><br>METHODS: We prospectively studied 209 patients (106 in the NAC group and 103 in the control group) who received contrast-enhanced computed tomography (CECT) in the emergency department (ED). The NAC group received intravenous NAC (600 mg) before CECT imaging to prevent CIN. Both the NAC and control groups were treated using a standardized hydration strategy, where clinically feasible.<br><br>RESULTS: The patients' mean age was 79.6&#xb1;9.8 years. The prevalence of hypertension, diabetes, and chronic kidney disease (CKD) were 63.2%, 27.3%, and 21.5%, respectively. The baseline clinical characteristics were similar between the two groups except for their body weight (p=0.011), amount of contrast material administered (p=0.049) and prevalence of CKD (p=0.002). The incidence of CIN was 7.5% in the NAC group and 14.6% in the control group. The adjusted odds ratio was 0.305 (95% confidence interval: 0.097 to 0.960, p=0.042). All-cause mortality was 7.5% in the NAC group and 12.6% in the control group, which was not significantly different. Temporary hemodialysis was required in 0% of subjects in the NAC group and 1.0% in the control group, which was not a statistically significant difference.<br><br>CONCLUSION: A single dose of NAC before CECT imaging can prevent CIN in an ED setting. However, it does not improve the mortality rate or the need for dialysis.}, }
@article {pmid23036870, year = {2012}, author = {Soares, CO and Colli, W and Bechara, EJ and Alves, MJ}, title = {1,4-Diamino-2-butanone, a putrescine analogue, promotes redox imbalance in Trypanosoma cruzi and mammalian cells.}, journal = {Archives of biochemistry and biophysics}, volume = {528}, number = {2}, pages = {103-110}, doi = {10.1016/j.abb.2012.09.005}, pmid = {23036870}, issn = {1096-0384}, mesh = {Animals ; Cell Line ; Models, Biological ; Oxidants/*pharmacology/toxicity ; Oxidation-Reduction ; Protozoan Proteins/metabolism ; Putrescine/*analogs &amp; derivatives/pharmacology/toxicity ; Sulfhydryl Compounds/metabolism ; Superoxide Dismutase/metabolism ; Trypanocidal Agents/pharmacology ; Trypanosoma cruzi/*drug effects/growth &amp; development/*metabolism/pathogenicity ; }, abstract = {The putrescine analogue 1,4-diamino-2-butanone (DAB) is highly toxic to various microorganisms, including Trypanosoma cruzi. Similar to other α-aminocarbonyl metabolites, DAB exhibits pro-oxidant properties. DAB undergoes metal-catalyzed oxidation yielding H(2)O(2), NH(4)(+) ion, and a highly toxic α-oxoaldehyde. In vitro, DAB decreases mammalian cell viability associated with changes in redox balance. Here, we aim to clarify the DAB pro-oxidant effects on trypomastigotes and on intracellular T. cruzi amastigotes. DAB (0.05-5 mM) exposure in trypomastigotes, the infective stage of T. cruzi, leads to a decline in parasite viability (IC(50)c.a. 0.2 mM DAB; 4 h incubation), changes in morphology, thiol redox imbalance, and increased TcSOD activity. Medium supplementation with catalase (2.5 μM) protects trypomastigotes against DAB toxicity, while host cell invasion by trypomastigotes is hampered by DAB. Additionally, intracellular amastigotes are susceptible to DAB toxicity. Furthermore, pre-treatment with 100-500 μM buthionine sulfoximine (BSO) of LLC-MK2 potentiates DAB cytotoxicity, whereas 5 mM N-acetyl-cysteine (NAC) protects cells from oxidative stress. Together, these data support the hypothesis that redox imbalance contributes to DAB cytotoxicity in both T. cruzi and mammalian host cells.}, }
@article {pmid23030646, year = {2012}, author = {Shao, ZR and Wang, Q and Xu, XF and Zhang, Z and Lu, YB and Shen, G and Wu, M}, title = {Phospholipase D participates in H(2)O(2)-induced A549 alveolar epithelial cell migration.}, journal = {Experimental lung research}, volume = {38}, number = {8}, pages = {427-433}, doi = {10.3109/01902148.2012.719282}, pmid = {23030646}, issn = {1521-0499}, mesh = {1-Butanol/pharmacology ; Alveolar Epithelial Cells/*drug effects/enzymology ; Antioxidants/pharmacology ; Cell Line, Tumor ; Cell Movement/*drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Coloring Agents/metabolism ; Dose-Response Relationship, Drug ; Drug Antagonism ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors/*toxicity ; Lung Neoplasms/*drug therapy/enzymology ; Oxidants/antagonists &amp; inhibitors/*toxicity ; Phosphatidic Acids/pharmacology ; Phospholipase D/*metabolism ; Reactive Oxygen Species/metabolism ; Tetrazolium Salts/metabolism ; Thiazoles/metabolism ; }, abstract = {To investigate the effects of phospholipase D (PLD) on low-concentration hydrogen peroxide (H(2)O(2))-induced growth and migration in alveolar epithelial A549 cells, the cells were exposed to H(2)O(2) (3-100 μM) for 12-48 hours, cell proliferation was determined by MTT assay and cell migration was tested by a modified epithelial wound healing assay. We found that one bolus of H(2)O(2) (10-100 μM) did not affect proliferation, but significantly stimulated migration (143-161% of control) after a 12-hour exposure. Pretreatment with the antioxidants catalase (1000 U/ml), N-acetyl-cysteine (2 mM), or edaravone (10 μM) abolished the migration induced by 30 μM H(2)O(2); the PLD inhibitor 1-butanol (0.5%) also attenuated H(2)O(2)-induced migration to the control level; while exogenous phosphatidic acid (PA) (10(-7)-10(-4) M) mimicked the effects of PLD activation and induced migration in a dose-dependent manner. We suggest that the alveolar epithelial cell migration induced by exposure to low concentrations of H(2)O(2) benefits tissue repair during acute lung injury (ALI) and PLD is involved in the underlying mechanism.}, }
@article {pmid23029446, year = {2012}, author = {Chen, LC and Hsu, C and Chiueh, CC and Lee, WS}, title = {Ferrous citrate up-regulates the NOS2 through nuclear translocation of NFκB induced by free radicals generation in mouse cerebral endothelial cells.}, journal = {PloS one}, volume = {7}, number = {9}, pages = {e46239}, pmid = {23029446}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Binding Sites ; Cell Nucleus/metabolism ; Cells, Cultured ; Cerebral Cortex/cytology/drug effects/metabolism ; Citric Acid ; Endothelial Cells/cytology/*drug effects/metabolism ; Endothelium, Vascular/cytology/drug effects/metabolism ; Ferrous Compounds/*pharmacology ; Free Radical Scavengers/pharmacology ; Free Radicals/agonists/antagonists &amp; inhibitors/*metabolism ; Male ; Mice ; NF-kappa B/genetics/*metabolism ; Nitric Oxide Synthase Type II/genetics/*metabolism ; *Promoter Regions, Genetic ; Protein Binding ; Protein Transport ; RNA, Messenger/biosynthesis ; Transcription, Genetic/drug effects ; Up-Regulation/drug effects ; }, abstract = {Previous studies indicate that the inducible nitric oxide synthase 2 (NOS2) of the brain vascular tissue in experimental subarachnoid hemorrhage (SAH) rats is a critical factor for inducing cerebral vasospasm. However, the underlying molecular mechanisms remain to be elucidated. Here, we applied ferrous citrate (FC) complexes to the primary cultured mouse cerebral endothelial cell (CEC) to mimic the SAH conditions and to address the issue how SAH-induced NOS2 up-regulation. Using immunocytochemical staining technique, we demonstrated that NOS2 was expressed in the cultured CEC. Treatment of the CEC with FC induced increases of the intracellular level of ROS, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) nuclear translocation as well as NFκB binding onto the NOS promoter, and the levels of NOS2 mRNA and protein. These effects were abolished by pre-treatment of the cell with N-Acetyl-Cysteine (NAC), a reactive oxygen species (ROS) scavenger. In the present study, two previously predicted NFκB binding sites were confirmed in the NOS2 promoter within the range of -1529 bp to -1516 bp and -1224 bp to -1210 bp. Interestingly, both NFκB binding sites are involved in the FC-activated NOS2 transcriptional activity; the binding site located at -1529 bp to -1516 bp played a greater role than the other binding site located at -1224 bp to -1210 bp in the mouse CEC. These findings highlight the molecular mechanism underlying FC-induced up-regulation of NOS2 in the mouse CEC.}, }
@article {pmid23029306, year = {2012}, author = {Njomnang Soh, P and Witkowski, B and Gales, A and Huyghe, E and Berry, A and Pipy, B and Benoit-Vical, F}, title = {Implication of glutathione in the in vitro antiplasmodial mechanism of action of ellagic acid.}, journal = {PloS one}, volume = {7}, number = {9}, pages = {e45906}, pmid = {23029306}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimalarials/*pharmacology ; Antioxidants/metabolism/*pharmacology/physiology ; Ascorbic Acid/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Deferoxamine/pharmacology ; Drug Synergism ; Ellagic Acid/*pharmacology ; Enzyme Inhibitors/pharmacology ; Erythrocytes/drug effects/metabolism/parasitology ; Glutathione/metabolism/pharmacology/*physiology ; Humans ; Inhibitory Concentration 50 ; Mice ; Oxidation-Reduction ; Plasmodium falciparum/*drug effects/growth &amp; development/metabolism ; Plasmodium yoelii/drug effects ; Reactive Oxygen Species ; Siderophores/pharmacology ; }, abstract = {The search for new antimalarial chemotherapy has become increasingly urgent due to parasite resistance to current drugs. Ellagic acid (EA) is a polyphenol, recently found in various plant products, that has effective antimalarial activity in vitro and in vivo without toxicity. To further understand the antimalarial mechanism of action of EA in vitro, we evaluated the effects of EA, ascorbic acid and N-acetyl-L-cysteine (NAC), alone and/or in combination on the production of reactive oxygen species (ROS) during the trophozoite and schizonte stages of the erythrocytic cycle of P. falciparum. The parasitized erythrocytes were pre-labelled with DCFDA (dichlorofluorescein diacetate). We showed that NAC had no effect on ROS production, contrary to ascorbic acid and EA, which considerably reduced ROS production. Surprisingly, EA reduced the production of the ROS with concentrations (6.6×10(-9) - 6.6×10(-6) M) ten-fold lower than ascorbic acid (113×10(-6) M). Additionally, the in vitro drug sensitivity of EA with antioxidants showed that antiplasmodial activity is independent of the ROS production inside parasites, which was confirmed by the additive activity of EA and desferrioxamine. Finally, EA could act by reducing the glutathione content inside the Plasmodium parasite. This was consolidated by the decrease in the antiplasmodial efficacy of EA in the murine model Plasmodium yoelii- high GSH strain, known for its high glutathione content. Given its low toxicity and now known mechanism of action, EA appears as a promising antiplasmodial compound.}, }
@article {pmid23028742, year = {2012}, author = {Lee, JH and Yeon, JH and Kim, H and Roh, W and Chae, J and Park, HO and Kim, DM}, title = {The natural anticancer agent plumbagin induces potent cytotoxicity in MCF-7 human breast cancer cells by inhibiting a PI-5 kinase for ROS generation.}, journal = {PloS one}, volume = {7}, number = {9}, pages = {e45023}, pmid = {23028742}, issn = {1932-6203}, mesh = {Antineoplastic Agents/chemistry/*pharmacology/therapeutic use ; Breast Neoplasms/drug therapy/*enzymology/*pathology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Down-Regulation/drug effects ; Drug Screening Assays, Antitumor ; Female ; Gene Knockdown Techniques ; Haploinsufficiency/genetics ; Heterozygote ; Humans ; MCF-7 Cells ; Models, Biological ; Mutation/genetics ; Naphthoquinones/chemistry/*pharmacology/therapeutic use ; Phosphotransferases (Alcohol Group Acceptor)/*antagonists &amp; inhibitors/genetics/metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Schizosaccharomyces/cytology/drug effects ; }, abstract = {Drug-induced haploinsufficiency (DIH) in yeast has been considered a valuable tool for drug target identification. A plant metabolite, plumbagin, has potent anticancer activity via reactive oxygen species (ROS) generation. However, the detailed molecular targets of plumbagin for ROS generation are not understood. Here, using DIH and heterozygous deletion mutants of the fission yeast Schizosaccharomyces pombe, we identified 1, 4-phopshatidylinositol 5-kinase (PI5K) its3 as a new molecular target of plumbagin for ROS generation. Plumbagin showed potent anti-proliferative activity (GI(50); 10 µM) and induced cell elongation and septum formation in wild-type S. pombe. Furthermore, plumbagin dramatically increased the intracellular ROS level, and pretreatment with the ROS scavenger, N-acetyl cysteine (NAC), protected against growth inhibition by plumbagin, suggesting that ROS play a crucial role in the anti-proliferative activity in S. pombe. Interestingly, significant DIH was observed in an its3-deleted heterozygous mutant, in which ROS generation by plumbagin was higher than that in wild-type cells, implying that its3 contributes to ROS generation by plumbagin in this yeast. In MCF7 human breast cancer cells, plumbagin significantly decreased the level of a human ortholog, 1, 4-phopshatidylinositol 5-kinase (PI5K)-1B, of yeast its3, and knockdown of PI5K-1B using siPI5K-1B increased the ROS level and decreased cell viability. Taken together, these results clearly show that PI5K-1B plays a crucial role in ROS generation as a new molecular target of plumbagin. Moreover, drug target screening using DIH in S. pombe deletion mutants is a valuable tool for identifying molecular targets of anticancer agents.}, }
@article {pmid23028492, year = {2012}, author = {Verdoodt, B and Vogt, M and Schmitz, I and Liffers, ST and Tannapfel, A and Mirmohammadsadegh, A}, title = {Salinomycin induces autophagy in colon and breast cancer cells with concomitant generation of reactive oxygen species.}, journal = {PloS one}, volume = {7}, number = {9}, pages = {e44132}, pmid = {23028492}, issn = {1932-6203}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Autophagy/*drug effects ; Breast Neoplasms/*metabolism ; Caspases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Colonic Neoplasms/*metabolism ; Female ; Humans ; MCF-7 Cells ; Pyrans/*pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tumor Stem Cell Assay ; }, abstract = {BACKGROUND: Salinomycin is a polyether ionophore antibiotic that has recently been shown to induce cell death in human cancer cells displaying multiple mechanisms of drug resistance. The underlying mechanisms leading to cell death after salinomycin treatment have not been well characterized. We therefore investigated the role of salinomycin in caspase dependent and independent cell death in colon cancer (SW480, SW620, RKO) and breast cancer cell lines (MCF-7, T47D, MDA-MB-453).<br><br>We detected features of apoptosis in all cell lines tested, but the executor caspases 3 and 7 were only strongly activated in RKO and MDA-MB-453 cells. MCF-7 and SW620 cells instead presented features of autophagy such as cytoplasmic vacuolization and LC3 processing. Caspase proficient cell lines activated autophagy at lower salinomycin concentrations and before the onset of caspase activation. Salinomycin also led to the formation of reactive oxygen species (ROS) eliciting JNK activation and induction of the transcription factor JUN. Salinomycin mediated cell death could be partially inhibited by the free radical scavenger N-acetyl-cysteine, implicating ROS formation in the mechanism of salinomycin toxicity.<br><br>CONCLUSIONS: Our data indicate that, in addition to its previously reported induction of caspase dependent apoptosis, the initiation of autophagy is an important and early effect of salinomycin in tumor cells.}, }
@article {pmid23027866, year = {2012}, author = {Prantner, D and Perkins, DJ and Lai, W and Williams, MS and Sharma, S and Fitzgerald, KA and Vogel, SN}, title = {5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential.}, journal = {The Journal of biological chemistry}, volume = {287}, number = {47}, pages = {39776-39788}, pmid = {23027866}, issn = {1083-351X}, support = {R37 AI067497/AI/NIAID NIH HHS/United States ; R01 AI067497/AI/NIAID NIH HHS/United States ; R56 AI067497/AI/NIAID NIH HHS/United States ; R01 AI070823/AI/NIAID NIH HHS/United States ; R37 AI018797/AI/NIAID NIH HHS/United States ; R01 AI018797/AI/NIAID NIH HHS/United States ; AI-070823/AI/NIAID NIH HHS/United States ; R56 AI018797/AI/NIAID NIH HHS/United States ; AI-18797/AI/NIAID NIH HHS/United States ; AI-067497/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Enzyme Inhibitors/pharmacology ; Immunity, Innate/*drug effects/genetics ; Interferon-beta/biosynthesis/genetics/immunology ; Interleukin-6/genetics/immunology/metabolism ; Macrophages, Peritoneal/cytology/immunology/metabolism ; Membrane Glycoproteins/genetics/metabolism ; Membrane Potential, Mitochondrial/*drug effects/genetics/immunology ; Membrane Proteins/genetics/immunology/*metabolism ; Mice ; Mice, Knockout ; NADPH Oxidase 2 ; NADPH Oxidases/genetics/metabolism ; Onium Compounds/pharmacology ; Oxidants/pharmacology ; Signal Transduction/*drug effects/genetics/immunology ; Tumor Necrosis Factor-alpha/genetics/immunology/metabolism ; Up-Regulation/drug effects/genetics/immunology ; Xanthones/*pharmacology ; }, abstract = {The chemotherapeutic agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a potent inducer of type I IFNs and other cytokines. This ability is essential for its chemotherapeutic benefit in a mouse cancer model and suggests that it might also be useful as an antiviral agent. However, the mechanism underlying DMXAA-induced type I IFNs, including the host proteins involved, remains unclear. Recently, it was reported that the antioxidant N-acetylcysteine (NAC) decreased DMXAA-induced TNF-α and IL-6, suggesting that oxidative stress may play a role. The goal of this study was to identify host proteins involved in DMXAA-dependent signaling and determine how antioxidants modulate this response. We found that expression of IFN-β in response to DMXAA in mouse macrophages requires the mitochondrial and endoplasmic reticulum resident protein STING. Addition of the antioxidant diphenylene iodonium (DPI) diminished DMXAA-induced IFN-β, but this decrease was independent of both the NADPH oxidase, Nox2, and de novo generation of reactive oxygen species. Additionally, IFN-β up-regulation by DMXAA was inhibited by agents that target the mitochondrial electron transport chain and, conversely, loss of mitochondrial membrane potential correlated with diminished innate immune signaling in response to DMXAA. Up-regulation of Ifnb1 gene expression mediated by cyclic dinucleotides was also impaired by DPI, whereas up-regulation of Ifnb1 mRNA due to cytosolic double-stranded DNA was not. Although both stimuli signal through STING, cyclic dinucleotides interact directly with STING, suggesting that recognition of DMXAA by STING may also be mediated by direct interaction.}, }
@article {pmid23026832, year = {2012}, author = {Yuan, L and Wang, J and Xiao, H and Xiao, C and Wang, Y and Liu, X}, title = {Isoorientin induces apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cancer cells.}, journal = {Toxicology and applied pharmacology}, volume = {265}, number = {1}, pages = {83-92}, doi = {10.1016/j.taap.2012.09.022}, pmid = {23026832}, issn = {1096-0333}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Chromones/pharmacology ; Cytochromes c/metabolism ; DNA Fragmentation/drug effects ; Humans ; Luteolin/*toxicity ; Membrane Potentials/drug effects ; Mitochondria, Liver/*drug effects ; Mitochondrial Membranes/drug effects ; Morpholines/pharmacology ; Nitric Oxide/biosynthesis/physiology ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors ; *Phosphoinositide-3 Kinase Inhibitors ; Poly(ADP-ribose) Polymerase Inhibitors ; Proto-Oncogene Proteins c-akt/*antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {Isoorientin (ISO) is a flavonoid compound that can be extracted from several plant species, such as Phyllostachys pubescens, Patrinia, and Drosophyllum lusitanicum; however, its biological activity remains poorly understood. The present study investigated the effects and putative mechanism of apoptosis induced by ISO in human hepatoblastoma cancer (HepG2) cells. The results showed that ISO induced cell death in a dose-dependent manner in HepG2 cells, but no toxicity in human liver cells (HL-7702) and buffalo rat liver cells (BRL-3A) treated with ISO at the indicated concentrations. ISO-induced cell death included apoptosis which characterized by the appearance of nuclear shrinkage, the cleavage of poly (ADP-ribose) polymerase (PARP) and DNA fragmentation. ISO significantly (p<0.01) increased the Bax/Bcl-2 ratio, disrupted the mitochondrial membrane potential (MMP), increased the release of cytochrome c, activated caspase-3, and enhanced intracellular levels of reactive oxygen species (ROS) and nitric oxide (NO). In addition, ISO effectively inhibited the phosphorylation of Akt and increased FoxO4 expression. The PI3K/Akt inhibitor LY294002 enhanced the apoptosis-inducing effect of ISO. However, LY294002 markedly quenched ROS and NO generation and diminished the protein expression of heme peroxidase enzyme (HO-1) and inducible nitric oxide synthase (iNOS). Furthermore, the addition of a ROS inhibitor (N-acetyl cysteine, NAC) or iNOS inhibitor (N-[3-(aminomethyl) benzyl] acetamidine, dihydrochloride, 1400W) significantly diminished the apoptosis induced by ISO and also blocked the phosphorylation of Akt. These results demonstrated for the first time that ISO induces apoptosis in HepG2 cells and indicate that this apoptosis might be mediated through mitochondrial dysfunction and PI3K/Akt signaling pathway, and has no toxicity in normal liver cells, suggesting that ISO may have good potential as a therapeutic and chemopreventive agent for liver cancer.}, }
@article {pmid23026831, year = {2012}, author = {Mohammad, MK and Avila, D and Zhang, J and Barve, S and Arteel, G and McClain, C and Joshi-Barve, S}, title = {Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress.}, journal = {Toxicology and applied pharmacology}, volume = {265}, number = {1}, pages = {73-82}, pmid = {23026831}, issn = {1096-0333}, support = {U01 AA021901/AA/NIAAA NIH HHS/United States ; K01 ES017105/ES/NIEHS NIH HHS/United States ; R01AA015970/AA/NIAAA NIH HHS/United States ; P01 AA017103/AA/NIAAA NIH HHS/United States ; R01DK071765/DK/NIDDK NIH HHS/United States ; RC2AA019385/AA/NIAAA NIH HHS/United States ; R01 AA018016/AA/NIAAA NIH HHS/United States ; P30AA019360/AA/NIAAA NIH HHS/United States ; P30 AA019360/AA/NIAAA NIH HHS/United States ; R37AA010762/AA/NIAAA NIH HHS/United States ; R01 AA015970/AA/NIAAA NIH HHS/United States ; K01ES017105/ES/NIEHS NIH HHS/United States ; R01AA018869/AA/NIAAA NIH HHS/United States ; P01AA017103/AA/NIAAA NIH HHS/United States ; R01 AA018869/AA/NIAAA NIH HHS/United States ; R01 DK071765/DK/NIDDK NIH HHS/United States ; RC2 AA019385/AA/NIAAA NIH HHS/United States ; R01AA018016/AA/NIAAA NIH HHS/United States ; R37 AA010762/AA/NIAAA NIH HHS/United States ; }, mesh = {Acrolein/antagonists &amp; inhibitors/*toxicity ; Adenosine Triphosphate/metabolism ; Antioxidants/metabolism ; Caspase Inhibitors/pharmacology ; Caspases/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Hepatocytes/*drug effects ; Humans ; Indicators and Reagents ; MAP Kinase Kinase 4/antagonists &amp; inhibitors ; Mitochondria, Liver/*drug effects/*metabolism ; Oxidative Stress/*drug effects ; Permeability/drug effects ; Phosphotransferases/metabolism ; }, abstract = {Acrolein is a common environmental, food and water pollutant and a major component of cigarette smoke. Also, it is produced endogenously via lipid peroxidation and cellular metabolism of certain amino acids and drugs. Acrolein is cytotoxic to many cell types including hepatocytes; however the mechanisms are not fully understood. We examined the molecular mechanisms underlying acrolein hepatotoxicity in primary human hepatocytes and hepatoma cells. Acrolein, at pathophysiological concentrations, caused a dose-dependent loss of viability of hepatocytes. The death was apoptotic at moderate and necrotic at high concentrations of acrolein. Acrolein exposure rapidly and dramatically decreased intracellular glutathione and overall antioxidant capacity, and activated the stress-signaling MAP-kinases JNK, p42/44 and p38. Our data demonstrate for the first time in human hepatocytes, that acrolein triggered endoplasmic reticulum (ER) stress and activated eIF2α, ATF-3 and -4, and Gadd153/CHOP, resulting in cell death. Notably, the protective/adaptive component of ER stress was not activated, and acrolein failed to up-regulate the protective ER-chaperones, GRP78 and GRP94. Additionally, exposure to acrolein disrupted mitochondrial integrity/function, and led to the release of pro-apoptotic proteins and ATP depletion. Acrolein-induced cell death was attenuated by N-acetyl cysteine, phenyl-butyric acid, and caspase and JNK inhibitors. Our data demonstrate that exposure to acrolein induces a variety of stress responses in hepatocytes, including GSH depletion, oxidative stress, mitochondrial dysfunction and ER stress (without ER-protective responses) which together contribute to acrolein toxicity. Our study defines basic mechanisms underlying liver injury caused by reactive aldehyde pollutants such as acrolein.}, }
@article {pmid23026584, year = {2012}, author = {Silva, SM and Carbonel, AA and Taha, MO and Simões, MJ and Montero, EF}, title = {Proliferative activity in ischemia/reperfusion injury in hepatectomized mice: effect of N-acetylcysteine.}, journal = {Transplantation proceedings}, volume = {44}, number = {8}, pages = {2321-2325}, doi = {10.1016/j.transproceed.2012.07.009}, pmid = {23026584}, issn = {1873-2623}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Biomarkers/blood/metabolism ; Cell Proliferation/*drug effects ; Cytoprotection ; Disease Models, Animal ; *Hepatectomy ; Immunohistochemistry ; Liver/blood supply/*drug effects/metabolism/pathology/*surgery ; Liver Regeneration/*drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Necrosis ; Proliferating Cell Nuclear Antigen/metabolism ; Reperfusion Injury/*drug therapy/metabolism/pathology ; Time Factors ; }, abstract = {BACKGROUND: Dysfunction of the liver after transplantation may be related to the graft size and ischemia/reperfusion (I/R) injury. N-Acetylcysteine (NAC) exerts beneficial effects on livers undergoing ischemia reperfusion. We sought to evaluate NAC modulation on reduced livers associated with I/R injury.<br><br>METHODS: Male C57BL/6 mice of 8 weeks of age were divided into groups: 50% hepatectomy (G-Hep); NAC (G-Hep + NAC [150 mg/kg]) via vena cava 15 minutes before hepatectomy; ischemia (G-Hep + IR); NAC with hepatectomy (G-IR + Hep + Nac); and IR using 30 minutes selective hepatic occlusion and reperfusion for 24 hours. After 24 hours, the remaining liver was removed, for staining with hematoxylin and eosin or labeling by proliferating cell nuclear antigen. Blood was collected for biochemical evaluations. Significance was considered for P &#x2264; .05.<br><br>RESULTS: Aspartate aminotransferase was high in all studied groups reflecting the hepatectomy and intervention. injuries. However, when assessing alanine aminotransferase, which depicts liver function, induction of IR promoted a greater increase than hepatectomy (P = .0003). NAC decreased ALT activity in all groups, even in association with I/R (P < .05), reflecting a modulation of the injury. Necrosis resulting from IR was mitigated by NAC. The experimental model of 50% reduced live promoted regeneration of the hepatic remnant, which was accentuated by NAC, according to the total number of hepatocytes and PCNA values.<br><br>CONCLUSION: NAC preserved the remnant liver in mice and stimulates regeneration even after IR injury.}, }
@article {pmid23023949, year = {2012}, author = {Selvaraj, V and Yeager-Armstead, M and Murray, E}, title = {Protective and antioxidant role of selenium on arsenic trioxide-induced oxidative stress and genotoxicity in the fish hepatoma cell line PLHC-1.}, journal = {Environmental toxicology and chemistry}, volume = {31}, number = {12}, pages = {2861-2869}, doi = {10.1002/etc.2022}, pmid = {23023949}, issn = {1552-8618}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Arsenic Trioxide ; Arsenicals ; Caspase 3/metabolism ; Cell Line, Tumor ; DNA Damage/drug effects ; Fishes/metabolism ; Free Radical Scavengers/metabolism ; Hazardous Substances/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; Mutagens/*toxicity ; Oxidative Stress/*drug effects ; Oxides/*toxicity ; Reactive Oxygen Species/metabolism ; Selenium/*pharmacology ; }, abstract = {In vitro models are useful tools for rapid screening for toxicity, elucidation of mechanisms of toxicity, and understanding complex interactions among environmental toxicants. These evaluations may provide useful information for ecological evaluations if the relationship between in vitro and in vivo effects is established. The present study was undertaken to evaluate the protective effect of selenium on arsenic trioxide (As(2) O(3))-induced cytotoxicity, DNA damage, and apoptosis. N-acetylcysteine (NAC), a free radical scavenger, was used to determine the involvement of reactive oxygen species (ROS) in As(2) O(3) -induced DNA damage and apoptosis. Poeciliopsis lucida hepatocellular carcinoma line 1 (PLHC-1) cells were pretreated with selenium (1, 5, and 10 µM) and NAC (50 and 100 µM) for 2 h. After pretreatment, cells were exposed to 100 µM of As(2) O(3) for 10-, 20-, and 40-h intervals. The As(2) O(3) exposure promoted extensive DNA damage and apoptosis compared to control, while selenium- and NAC-pretreated cells improved cell survival rate against As(2) O(3) -induced cell death. Improved survival likely resulted from increasing glutathione peroxidase activity and reduction of ROS formation, reduction of mitochondrial membrane potential damage, DNA damage, and caspase-3 activity. During As(2) O(3) exposure, selenium played the same role as NAC. The authors conclude that As(2) O(3) -induced DNA damage and apoptosis are mediated by oxidative stress and selenium and that, although toxic at higher concentrations, selenium provides significant protection against As(2) O(3) effects in PLHC-1 cells.}, }
@article {pmid23023382, year = {2012}, author = {Ahmadi-Ashtiani, HR and Allameh, A and Rastegar, H and Mortaz, E and Saraf, Z}, title = {Immunoregulatory effects of glutathione during mesenchymal stem cell differentiation to hepatocyte-like cells.}, journal = {Iranian journal of immunology : IJI}, volume = {9}, number = {3}, pages = {175-187}, pmid = {23023382}, issn = {1735-367X}, mesh = {Acetylcysteine/pharmacology ; Bone Marrow Cells/cytology ; Buthionine Sulfoximine/*pharmacology ; Cell Differentiation/*drug effects ; Cells, Cultured ; Cytokines/metabolism ; Glutathione/*pharmacology ; Guided Tissue Regeneration ; Hepatocytes/*cytology ; Humans ; Immunomodulation ; Inflammation Mediators/*pharmacology ; *Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: The role of mesenchymal stem cell in cellular therapy is the subject of interest for many researchers. The differentiation potential of MSCs and abilities in modulations of the recipient's immune system makes them important cells in tissue regenerative studies. MSCs by releasing the proinflammatory cytokines play important role in immunomodulatory systems; however the signaling pathways for releasing of these mediators are not well understood. Glutathione has been shown to play a role in modulation of cytokines in hepatogenic differentiation.<br><br>OBJECTIVE: In the current study we aimed to investigate the effects of buthionine sulfoximine (BSO, inhibitor for glutathione synthesis) and N-acetylecystin (NAC, an inhibitor for ROS generation) on proinflammatory cytokines production in a hepatogenic differentiation model.<br><br>RESULTS: BSO and NAC significantly decreased IL-6 and TNF-&#x3b1; levels at 14 days of differentiation, whereas, NAC decreased the levels of IL-8 at days 2 and 14 of differentiation. Moreover, intracellular glutathione level during the differentiation was depleted.<br><br>CONCLUSION: Our current study suggests a novel role of GSH as an immunopharmacological regulatory molecule during hepatogenic differentiation. Finally, this information may shed some light on the understanding of MSCs responses in transplantation and cell therapy in diseases such as chronic hepatic diseases.}, }
@article {pmid23022673, year = {2013}, author = {Lee, SY and Lee, SJ and Han, C and Patkar, AA and Masand, PS and Pae, CU}, title = {Oxidative/nitrosative stress and antidepressants: targets for novel antidepressants.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {46}, number = {}, pages = {224-235}, doi = {10.1016/j.pnpbp.2012.09.008}, pmid = {23022673}, issn = {1878-4216}, mesh = {Animals ; Antidepressive Agents/*administration &amp; dosage ; Brain/drug effects/metabolism ; Depressive Disorder/drug therapy/*metabolism ; Drug Delivery Systems/*trends ; Humans ; Oxidative Stress/drug effects/*physiology ; Reactive Nitrogen Species/antagonists &amp; inhibitors/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {The brain is an organ predisposed to oxidative/nitrosative stress. This is especially true in the case of aging as well as several neurodegenerative diseases. Under such circumstances, a decline in the normal antioxidant defense mechanisms leads to an increase in the vulnerability of the brain to the deleterious effects of oxidative damage. Highly reactive oxygen/nitrogen species damage lipids, proteins, and mitochondrial and neuronal genes. Unless antioxidant defenses react appropriately to damage inflicted by radicals, neurons may experience microalteration, microdysfunction, and degeneration. We reviewed how oxidative and nitrosative stresses contribute to the pathogenesis of depressive disorders and reviewed the clinical implications of various antioxidants as future targets for antidepressant treatment.}, }
@article {pmid23022272, year = {2012}, author = {Prigol, M and Nogueira, CW and Zeni, G and Bronze, MR and Constantino, L}, title = {In vitro metabolism of diphenyl diselenide in rat liver fractions. Conjugation with GSH and binding to thiol groups.}, journal = {Chemico-biological interactions}, volume = {200}, number = {2-3}, pages = {65-72}, doi = {10.1016/j.cbi.2012.09.007}, pmid = {23022272}, issn = {1872-7786}, mesh = {Animals ; Benzene Derivatives/metabolism/*pharmacokinetics ; Biotransformation ; Chromatography, High Pressure Liquid ; Cytochrome P-450 Enzyme System/metabolism ; Glutathione/metabolism ; Liver/enzymology/*metabolism ; Organoselenium Compounds/metabolism/*pharmacokinetics ; Rats ; Sulfhydryl Compounds/*metabolism ; Tandem Mass Spectrometry ; }, abstract = {In spite of an extensive literature reporting pharmacological properties of diphenyl diselenide, (PhSe)(2), little is known about its metabolism. The aim of this study was to identify possible metabolic pathways of (PhSe)(2) in vitro to get insights into the mechanism of its toxicity. Rat liver preparations, namely total homogenate, S9 fraction, cytosol and microsomes were used in the incubations. Samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), high-performance liquid chromatography (HPLC) or inductively coupled plasma (ICP). A reduced glutathione (GSH)-selenol adduct (m/z 462) was identified in all liver fraction incubations by LC-MS/MS, suggesting a reaction between (PhSe)(2) and GSH in tissues. Results from incubation of (PhSe)(2) with microsomal fraction showed that (PhSe)(2) disappears from the supernatant without formation of phase I metabolites. The addition of exogenous GSH maintained constant (PhSe)(2) levels in supernatant and significantly reduced the amount of selenium in the precipitate obtained when microsomal incubations were treated with methanol. Addition of N-acetylcysteine (NAC) had a similar effect; moreover, a NAC-selenol adduct similar to the GSH-selenol adduct was identified by LC-MS/MS (m/z 318) in the NAC incubations. The data indicates that (PhSe)(2) probably binds covalently to microsomal components and that GSH and NAC can prevent binding. The depletion of GSH levels in vitro may be related to (PhSe)(2) toxicity. The inhibition of cytochrome P450 (CYP) activity by carbon monoxide or proadifen did not change the amount of (PhSe)(2) in supernatant and selenium levels in the precipitate, neither did the inactivation of the microsomes by heat indicating that binding was not mediated by cytochrome P450 metabolism and was probably due to a direct reaction between (PhSe)(2) and microsomal components. Due to the covalent binding of (PhSe)(2) to microsomal components the potential of (PhSe)(2) to inhibit cytochrome P450 was examined. (PhSe)(2) at a concentration as low as 1 μM reduced monooxygenase activity with an IC(50) value of 78 μM.}, }
@article {pmid23018672, year = {2012}, author = {Radtke, KK and Coles, LD and Mishra, U and Orchard, PJ and Holmay, M and Cloyd, JC}, title = {Interaction of N-acetylcysteine and cysteine in human plasma.}, journal = {Journal of pharmaceutical sciences}, volume = {101}, number = {12}, pages = {4653-4659}, doi = {10.1002/jps.23325}, pmid = {23018672}, issn = {1520-6017}, mesh = {Acetylcysteine/blood/*pharmacology ; Antioxidants/*pharmacology ; Blood Proteins/*metabolism ; Chromatography, High Pressure Liquid ; Cysteine/blood/*metabolism ; Humans ; Mass Spectrometry ; Protein Binding/drug effects ; }, abstract = {N-acetyl-L-cysteine (NAC), a well-known antioxidant, has been successfully used as adjuvant therapy for late-stage childhood cerebral adrenoleukodystrophy (c-ALD); however, the mechanisms of NAC action are poorly understood. Previous research indicates that NAC serves as a precursor to L-cysteine (Cys), the rate-limiting substrate in the biosynthesis of glutathione (GSH), a potent, endogenous antioxidant. We hypothesized that NAC acts by liberating protein-bound Cys in plasma in an NAC concentration-dependent manner, which increases unbound Cys available for GSH biosynthesis. Human plasma was incubated for 1 h with varying, clinically relevant concentrations of NAC (0-1000 µg/mL). The effect of this interaction over time was evaluated by incubating plasma for 5-90 min with 100 µg/mL NAC. Unbound and bound Cys and NAC were separated by ultrafiltration, and concentrations were measured using high-performance liquid chromatography-mass spectrometry. Significant increases in unbound Cys were observed with increasing NAC concentrations. Also, Cys plasma protein binding decreased from 85% (10 µg/mL NAC) to approximately 0% (1000 µg/mL). Total endogenous Cys was 66% unbound at 5 min after incubation. These results demonstrate that NAC liberates endogenous, protein-bound Cys in human plasma at clinically relevant NAC concentrations. A greater understanding of NAC actions will aid in the optimization of NAC therapy including its use in c-ALD.}, }
@article {pmid23012616, year = {2012}, author = {Azzopardi, N and Chetcuti, S and Sant, J and Pocock, J}, title = {Acute Liver Impairment in a Young, Healthy Athlete: Hypoxic Hepatitis and Rhabdomyolysis following Heat Stroke.}, journal = {Case reports in gastroenterology}, volume = {6}, number = {2}, pages = {563-568}, pmid = {23012616}, issn = {1662-0631}, abstract = {Any process that substantially diminishes arterial blood flow or arterial oxygen content to the liver can result in hypoxic (ischaemic) hepatitis. 90% of hypoxic hepatitis occurs in unstable patients in intensive care units with haemodynamic failure secondary to heart failure, respiratory failure and toxic shock. The rate of in-hospital mortality in hypoxic hepatitis is very high with studies recording mortalities of 61.5%. It tends to be very uncommon in healthy, young patients with no underlying medical problems. We report here the case of a young healthy athlete who developed heat stroke associated with rhabdomyolysis and hypoxic hepatitis while he was running the final stages of a marathon. The patient required intensive care admission and inotropic support for a few hours after he was admitted with heat stroke. He underwent a rapid recovery after he was resuscitated with fluids. N-acetyl cysteine was also given during the acute stage of the hepatitis. This case highlights an uncommon case of hypoxic hepatitis in a young, healthy patient secondary to hypotension and heat stroke. Inotropic support might have precipitated the hypoxic hepatitis in this young patient.}, }
@article {pmid23012453, year = {2012}, author = {Gold, B and Pingle, M and Brickner, SJ and Shah, N and Roberts, J and Rundell, M and Bracken, WC and Warrier, T and Somersan, S and Venugopal, A and Darby, C and Jiang, X and Warren, JD and Fernandez, J and Ouerfelli, O and Nuermberger, EL and Cunningham-Bussel, A and Rath, P and Chidawanyika, T and Deng, H and Realubit, R and Glickman, JF and Nathan, CF}, title = {Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {109}, number = {40}, pages = {16004-16011}, pmid = {23012453}, issn = {1091-6490}, support = {T32 GM007739/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Chromatography, High Pressure Liquid ; Drug Resistance, Microbial/*drug effects/physiology ; Fatty Acids/metabolism ; Female ; High-Throughput Screening Assays/*methods ; Hydroxylation ; Magnetic Resonance Spectroscopy ; Mice ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/*drug effects/physiology ; Oxyphenbutazone/metabolism/pharmacokinetics/*pharmacology ; Reactive Nitrogen Species/metabolism ; }, abstract = {Existing drugs are slow to eradicate Mycobacterium tuberculosis (Mtb) in patients and have failed to control tuberculosis globally. One reason may be that host conditions impair Mtb's replication, reducing its sensitivity to most antiinfectives. We devised a high-throughput screen for compounds that kill Mtb when its replication has been halted by reactive nitrogen intermediates (RNIs), acid, hypoxia, and a fatty acid carbon source. At concentrations routinely achieved in human blood, oxyphenbutazone (OPB), an inexpensive anti-inflammatory drug, was selectively mycobactericidal to nonreplicating (NR) Mtb. Its cidal activity depended on mild acid and was augmented by RNIs and fatty acid. Acid and RNIs fostered OPB's 4-hydroxylation. The resultant 4-butyl-4-hydroxy-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione (4-OH-OPB) killed both replicating and NR Mtb, including Mtb resistant to standard drugs. 4-OH-OPB depleted flavins and formed covalent adducts with N-acetyl-cysteine and mycothiol. 4-OH-OPB killed Mtb synergistically with oxidants and several antituberculosis drugs. Thus, conditions that block Mtb's replication modify OPB and enhance its cidal action. Modified OPB kills both replicating and NR Mtb and sensitizes both to host-derived and medicinal antimycobacterial agents.}, }
@article {pmid23011167, year = {2014}, author = {Varney, SM and Buchanan, JA and Kokko, J and Heard, K}, title = {Acetylcysteine for acetaminophen overdose in patients who weigh &gt;100 kg.}, journal = {American journal of therapeutics}, volume = {21}, number = {3}, pages = {159-163}, doi = {10.1097/MJT.0b013e3182459c40}, pmid = {23011167}, issn = {1536-3686}, support = {DA020573/DA/NIDA NIH HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/adverse effects ; Administration, Intravenous ; Administration, Oral ; Adult ; Antidotes/*administration &amp; dosage/adverse effects ; Body Weight ; Chemical and Drug Induced Liver Injury/epidemiology/*etiology/prevention &amp; control ; Dose-Response Relationship, Drug ; Drug Overdose ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {N-Acetylcysteine (NAC) dosing for acetaminophen (APAP) overdose is weight based (150 mg/kg intravenous or 140-mg/kg oral loading dose) and, in the United States, the dosing protocol recommends using a maximum patient weight of 100 and 110 kg, respectively. Little clinical data describe the use of NAC for APAP poisoning in patients weighing >100 kg. The aim of this study was to describe the demographics, outcomes, and adverse event (AE) rates of patients weighing >100 kg treated with oral or IV NAC for APAP poisoning. Patients were identified from a multicenter retrospective NAC safety study for APAP overdose. We included patients with a recorded weight. Trained chart abstractors used a standardized form. Selected data included age, gender, weight, serum alanine transaminase, and aspartate transaminases, coingestants, NAC administration route, ingestion type, AEs, and outcome [hepatotoxicity (alanine transaminase > 1000 U/L), liver transplant, or death]. Descriptive statistics were used. Of 503 study patients, 37 (7.4%) had recorded weights >100 kg. The median (range) weight was 110 kg (101-160). The median (range) dosing for patients treated with oral NAC was 140 mg/kg (127-143 mg/kg) and 150 (108-168) mg/kg for IV NAC. Hepatotoxicity occurred in 12/36 (33.3%) patients. Death occurred in 4/36 (11.1%) patients. Thirteen NAC-related AEs occurred in 8 patients (1.6 per person). All AEs were related to NAC and were rated nonserious by the reviewer. Clinicians use an actual weight-based NAC dose rather than a maximum weight cutoff dose. Hepatotoxicity was common in our cohort. AEs were relatively common but not serious.}, }
@article {pmid23010122, year = {2013}, author = {Salmanipour, A and Taher, MA and Beitollahi, H and Hosseinzadeh, R}, title = {New voltammetric strategy for simultaneous determination of N-acetylcysteine and folic acid using a carbon nanotube modified glassy carbon electrode.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {102}, number = {}, pages = {385-390}, doi = {10.1016/j.colsurfb.2012.08.022}, pmid = {23010122}, issn = {1873-4367}, mesh = {Acetylcysteine/*analysis ; Carbon/*chemistry ; Electrochemistry/*methods ; *Electrodes ; Folic Acid/*analysis ; Nanotubes, Carbon/*chemistry ; }, abstract = {A novel 1-benzyl-4-ferrocenyl-1H-[1,2,3]-triazole (BFT)/carbon nanotube modified glassy carbon electrode (BFT-CNT-GCE) was prepared for the simultaneous determination of N-acetylcysteine (NAC) and folic acid (FA). Cyclic voltammetry (CV), chronoamperometry (CHA), and square wave voltammetry (SWV) methods were used to investigate the modified electrode for the electrocatalytic oxidation of NAC and FA in aqueous solutions. The separation of the oxidation peak potentials for NAC-FA was about 280 mV. The calibration curve obtained for NAC was in the range of 0.1-600.0 μM. The detection limit (S/N=3) was 62.0±2.0 nM for NAC. The diffusion coefficient and the catalytic rate constant for the oxidation of NAC at the modified electrode were calculated as (3.5±0.2)×10(-5) cm(2) s(-1) and (9.85±0.4)×10(-4) M(-1) s(-1), respectively. The method was employed for the determination of NAC and FA in some real samples.}, }
@article {pmid23009681, year = {2012}, author = {Kato, Y and Peskin, AV and Dickerhof, N and Harwood, DT and Kettle, AJ}, title = {Myeloperoxidase catalyzes the conjugation of serotonin to thiols via free radicals and tryptamine-4,5-dione.}, journal = {Chemical research in toxicology}, volume = {25}, number = {11}, pages = {2322-2332}, doi = {10.1021/tx300218f}, pmid = {23009681}, issn = {1520-5010}, mesh = {Biocatalysis ; Free Radicals/chemistry/metabolism ; Humans ; Indolequinones/chemistry/*metabolism ; Oxidation-Reduction ; Peroxidase/*metabolism ; Serotonin/chemistry/*metabolism ; Sulfhydryl Compounds/chemistry/*metabolism ; Time Factors ; Tryptamines/chemistry/*metabolism ; }, abstract = {Serotonin (5-hydroxytryptamine; 5HT) is a favorable substrate for myeloperoxidase and is likely to be oxidized by this heme enzyme during inflammation. In this study, we have investigated how serotonin becomes conjugated to amino acid residues and proteins when it is oxidized by myeloperoxidase. 5HT formed three adducts with N-acetylcysteine (NAC) when it was incubated with myeloperoxidase, xanthine oxidase, and acetaldehyde. One of the adducts was identified as 5HT-NAC, and the others were conjugates of NAC and tryptamine-4,5-dione (TD). There was no evidence for coupling of oxidized serotonin to amine residues. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was exposed to 5HT with the enzymatic system or synthetic TD. Both caused a loss of thiols on GAPDH and covalent attachment of quinones derived from TD to the protein. Biotin-labeled 5HT was used instead of 5HT to confirm the conjugation of 5HT to GAPDH. It was incorporated into the GAPDH when oxidized by myeloperoxidase. Analysis of tryptic peptides of human GAPDH by liquid chromatography with mass spectrometry revealed that an adduct of TD was formed with the peptide containing Cys(152) and Cys(156). Our results indicate that myeloperoxidase can oxidize serotonin to species that form adducts with low molecular weight thiols and cysteine residues in proteins. Low molecular weight conjugates will redox cycle and fuel oxidative stress. Conjugation of serotonin to proteins will affect their function and may provide useful biomarkers of serotonin oxidation during inflammatory events.}, }
@article {pmid23006535, year = {2012}, author = {Li, S and Yang, X and Li, W and Li, J and Su, X and Chen, L and Yan, G}, title = {N-acetylcysteine downregulation of lysyl oxidase activity alleviating bleomycin-induced pulmonary fibrosis in rats.}, journal = {Respiration; international review of thoracic diseases}, volume = {84}, number = {6}, pages = {509-517}, doi = {10.1159/000340041}, pmid = {23006535}, issn = {1423-0356}, mesh = {Acetylcysteine/*pharmacology ; Actins/drug effects/metabolism ; Animals ; Antibiotics, Antineoplastic/adverse effects ; Bleomycin/adverse effects ; Collagen/drug effects/metabolism ; Disease Models, Animal ; Down-Regulation ; Free Radical Scavengers/*pharmacology ; Glutathione/drug effects/metabolism ; Idiopathic Pulmonary Fibrosis/drug therapy/metabolism ; Lung/drug effects/pathology ; Male ; Protein-Lysine 6-Oxidase/drug effects/*metabolism ; Pulmonary Fibrosis/chemically induced/drug therapy/*metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1/drug effects/metabolism ; }, abstract = {BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease without beneficial therapy, except for lung transplantation. A high oral dose of N-acetylcysteine (NAC) added to prednisone and azathioprine has been found to improve lung function in IPF patients, though the mechanism of action remains poorly understood.<br><br>OBJECTIVE: Based on our previous findings showing elevation of glutathione (GSH) content associated with downregulation of lysyl oxidase (LOX) activity, which is essential for collagen deposition, the aim of the present study was to test the hypothesis that NAC alleviates IPF by regulating LOX function.<br><br>METHODS: We firstly analyzed the time course of collagen deposition in lung tissue, hydroxyproline content, LOX activity, GSH levels, and transforming growth factor-&#x3b2;(1) (TGF-&#x3b2;(1)) and &#x3b1;-smooth muscle actin (&#x3b1;-SMA) expression in bleomycin (BLM)-induced pulmonary fibrosis in a rat model. Then, we focused our studies on NAC modulation of LOX activity.<br><br>RESULTS: LOX activity was increased on day 9 and peaked 14 days after BLM administration, while TGF-&#x3b2;(1) protein peaked on day 9. Interestingly, NAC treatment for 14 days from day 0 reversed LOX activity to normal levels and increased GSH levels in the lung of BLM-dosed rats. Consistently, NAC partially attenuated pulmonary fibrosis and inhibited TGF-&#x3b2;(1) and &#x3b1;-SMA expression in this model.<br><br>CONCLUSIONS: Our study supports a novel mechanism of NAC alleviating IPF by inhibition of LOX activity via elevation of lung GSH in BLM-induced pulmonary fibrosis. The TGF-&#x3b2;(1)/&#x3b1;-SMA pathway may also play an important role in modulation of LOX activity.}, }
@article {pmid23002174, year = {2012}, author = {Garcia, LG and Lemaire, S and Kahl, BC and Becker, K and Proctor, RA and Tulkens, PM and Van Bambeke, F}, title = {Intracellular forms of menadione-dependent small-colony variants of methicillin-resistant Staphylococcus aureus are hypersusceptible to β-lactams in a THP-1 cell model due to cooperation between vacuolar acidic pH and oxidant species.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {67}, number = {12}, pages = {2873-2881}, doi = {10.1093/jac/dks325}, pmid = {23002174}, issn = {1460-2091}, mesh = {Anti-Bacterial Agents/pharmacology ; Carboxylic Acids/*pharmacology ; Cell Line ; Colony Count, Microbial ; Human Experimentation ; Humans ; Hydrogen-Ion Concentration ; Methicillin-Resistant Staphylococcus aureus/*drug effects/*growth &amp; development/metabolism ; Microbial Sensitivity Tests ; Microbial Viability/drug effects ; Monocytes/immunology/*microbiology ; Oxidants/*pharmacology ; Phagocytosis ; Vacuoles/chemistry/microbiology ; Vitamin K 3/*metabolism ; beta-Lactams/*pharmacology ; }, abstract = {OBJECTIVES: Phagocytosed methicillin-resistant Staphylococcus aureus (MRSA) are susceptible to β-lactams because of an acid-induced conformational change of penicillin-binding protein (PBP) 2a within phagolysosomes. We have examined whether this mechanism applies to menD and hemB small-colony variants (SCVs) of the COL MRSA strain, using cloxacillin, meropenem, doripenem, and vancomycin as comparator.<br><br>METHODS: Intracellularly, the change in cfu from post-phagocytosis inoculum was measured after 24 h of incubation with antibiotics combined or not with N-acetylcysteine (NAC; oxidant species scavenger); the relative potency (C(s)) was calculated from the Hill equation of concentration-response curves. Extracellularly, the effect of a pre-incubation with H(2)O(2) was determined on MICs and killing at pH 7.4 and 5.5.<br><br>RESULTS: Intracellularly, the &#x3b2;-lactam C(s) was similar for the COL strain and the hemB mutant and not modified or slightly decreased (2- to 16-fold) by NAC. In contrast, the C(s) was 100- to 900-fold lower for the menD mutant, but similar to that for the COL strain when NAC was present. Extracellularly, &#x3b2;-lactam MICs were markedly reduced at pH 5.5 for the parental strain and the haemin-supplemented hemB mutant, with limited additional effect of pre-incubation with H(2)O(2). In contrast, MICs remained elevated at pH 5.5 for the menD mutant (supplemented with menadione sodium bisulphite or not), but were 7-10 dilutions lower after pre-incubation with H(2)O(2). Vancomycin MICs were unaltered in all conditions, with no marked effect of NAC on C(s).<br><br>CONCLUSIONS: Cooperation between acidic pH and oxidant species confers high potency to &#x3b2;-lactams against intracellular forms of menD SCVs of MRSA.}, }
@article {pmid23000913, year = {2012}, author = {Giustarini, D and Milzani, A and Dalle-Donne, I and Tsikas, D and Rossi, R}, title = {N-Acetylcysteine ethyl ester (NACET): a novel lipophilic cell-permeable cysteine derivative with an unusual pharmacokinetic feature and remarkable antioxidant potential.}, journal = {Biochemical pharmacology}, volume = {84}, number = {11}, pages = {1522-1533}, doi = {10.1016/j.bcp.2012.09.010}, pmid = {23000913}, issn = {1873-2968}, mesh = {Acetylcysteine/*chemistry/pharmacology ; Animals ; Antioxidants/*pharmacology ; Permeability ; Rats ; }, abstract = {Recent large clinical trials failed to confirm the supposed beneficial effects of N-acetylcysteine (NAC) in preventing oxidative stress-related diseases. This may be due to its low bioavailability. We thought that esterification of the carboxyl group of NAC to produce N-acetylcysteine ethyl ester (NACET) would drastically increase the lipophilicity of NAC, thus greatly improving its pharmacokinetics. In the present work, we report on representative chemical, pharmacological and anti-oxidant properties of NACET, especially in direct comparison with its congener NAC. We found that NACET is rapidly absorbed in rats after oral administration but reaches very low concentrations in plasma. This is due to a unique feature of NACET: it rapidly enters the cells where it is trapped being transformed into NAC and cysteine. After oral treatment, NACET (but not NAC) was able to increase significantly the glutathione content of most tissues examined, brain included, and to protect from paracetamol intoxication in the rat. NACET has also the unique feature to accumulate in human erythrocytes where it behaves as a potent protector against hydroperoxide-induced oxidative damage. Our study shows that being able to enter cells and to produce NAC and cysteine, NACET increases circulating hydrogen sulfide (H(2)S), thus representing a good candidate for the oral use as an H(2)S producer, with clear advantages over NAC. NACET has the potential to substitute NAC as a mucolytic agent, as a paracetamol antidote and as a GSH-related antioxidant.}, }
@article {pmid23000343, year = {2013}, author = {Li, L and Chen, Y and Gibson, SB}, title = {Starvation-induced autophagy is regulated by mitochondrial reactive oxygen species leading to AMPK activation.}, journal = {Cellular signalling}, volume = {25}, number = {1}, pages = {50-65}, doi = {10.1016/j.cellsig.2012.09.020}, pmid = {23000343}, issn = {1873-3913}, mesh = {AMP-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/*metabolism ; Acetylcysteine/pharmacology ; Autophagy/*drug effects ; Cell Line, Tumor ; Culture Media/*pharmacology ; Electron Transport Chain Complex Proteins/deficiency/genetics/metabolism ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; HeLa Cells ; Humans ; Hydrogen Peroxide/metabolism ; Lysosomes/metabolism ; Mitochondria/*metabolism ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; RNA Interference ; RNA, Small Interfering/metabolism ; Superoxide Dismutase/genetics/metabolism ; Superoxides/*metabolism ; }, abstract = {Starvation is the most extensively studied condition that induces autophagy. Previous studies have demonstrated that starvation-induced autophagy is regulated by reactive oxygen species (ROS) such as superoxide (O(2)(·-)) but the source for ROS under starvation conditions and the downstream signaling pathways regulating autophagy are unclear. In this study, a cervical cancer HeLa cell line was generated that was deficient in mitochondrial electron transport chain (mETC) (HeLa ρ° cells). This resulted in endogenous levels of O(2)(·-) being significantly reduced and failed to be induced under starvation of glucose, L-glutamine, pyruvate, and serum (GP) or of amino acids and serum (AA) compared to wild type (wt) HeLa cells. In contrast, H(2)O(2) production failed to increase under GP starvation in both wild type and ρ° cells whereas it increased in wt cells but not in ρ° cells under AA starvation. GP or AA starvation induced autophagy was blocked in ρ° cells as determined by the amount of autophagosomes and autolysosomes. Autophagy is regulated by 5' adenosine monophosphate-activated protein kinase (AMPK) activation and AMPK is activated under starvation conditions. We demonstrate that ρ° cells and HeLa cells over expressing manganese-superoxide dismutase 2 (SOD2) cells fail to activate AMPK activation following starvation. This indicates that mitochondrial ROS might regulate AMPK activation. In addition, inhibiting AMPK activation either by siRNA or compound C resulted in reduced autophagy during starvation. Using a ROS scavenger NAC, AMPK activation is reduced under starvation condition and mTOR signaling is increased. Taken together, mitochondria-generated ROS induces autophagy mediated by the AMPK pathway under starvation conditions.}, }
@article {pmid23000131, year = {2012}, author = {Lijia, Z and Zhao, S and Wang, X and Wu, C and Yang, J}, title = {A self-propelling cycle mediated by reactive oxide species and nitric oxide exists in LPS-activated microglia.}, journal = {Neurochemistry international}, volume = {61}, number = {7}, pages = {1220-1230}, doi = {10.1016/j.neuint.2012.09.002}, pmid = {23000131}, issn = {1872-9754}, mesh = {Animals ; Base Sequence ; Blotting, Western ; Cell Line ; Culture Media, Conditioned ; DNA Primers ; Lipopolysaccharides/*pharmacology ; Membrane Glycoproteins/genetics ; Mice ; Microglia/*drug effects/metabolism ; NADPH Oxidase 2 ; NADPH Oxidases/genetics ; Nitric Oxide/biosynthesis/*metabolism ; Nitric Oxide Donors/pharmacology ; Nitroprusside/pharmacology ; Polymerase Chain Reaction ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; }, abstract = {It has been widely accepted that microglia, the innate immune cells in the brain, can be chronically activated in response to neuron death, fuelling a self-renewing cycle of microglial activation followed by further neuron damage (reactive microgliosis), which has been considered as the main reason responsible for the progressive nature of neurodegenerative diseases. In the present study, it was found that LPS (lipopolysaccharide) significantly induced the activation of N9 microglia, and the increase of NO level induced by pretreatment of LPS could last after the removal of LPS. The culture medium of activated microglia significantly decreased the viability of rat primary cortical neuron. These results can be blocked by the antioxidant N-acetylcysteine (NAC) and nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase inhibitor diphenyleneiodonium sulfate (DPI), suggesting that intracellular reactive oxide species (iROS) released from the activated microglial cells may continue to further activate microglia. Next, it was shown that the iROS level increased rapidly after the LPS treatment in microglia cells followed by the NO production through the regulation of iNOS (inducible nitric oxide synthase) expression. The increase of iROS could be reversed by gp91phox (the critical and catalytic subunit of NADPH oxidase) siRNA. Moreover, NO released from sodium nitroprusside (SNP) was able to increase the iROS production of N9 microglia by regulating of the activity and the expression of NADPH oxidase. In conclusion, our research suggests for the first time that there may exist a self-propelling cycle in microglial cells possibly mediated by iROS and NO when they become activated by LPS. It may be responsible partially for the ongoing microglial activation and the progressive nature of neurodegenerative diseases.}, }
@article {pmid23000044, year = {2012}, author = {Yang, B and Fu, J and Zheng, H and Xue, P and Yarborough, K and Woods, CG and Hou, Y and Zhang, Q and Andersen, ME and Pi, J}, title = {Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage.}, journal = {Toxicology and applied pharmacology}, volume = {264}, number = {3}, pages = {315-323}, pmid = {23000044}, issn = {1096-0333}, support = {K01 DK076788/DK/NIDDK NIH HHS/United States ; R01 ES016005/ES/NIEHS NIH HHS/United States ; ES016005/ES/NIEHS NIH HHS/United States ; DK76788/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antioxidants ; Arsenic/*toxicity ; Cell Line ; Environmental Pollutants/*toxicity ; Gene Knockdown Techniques ; Gene Silencing ; Insulin-Secreting Cells/*drug effects/pathology ; Mice ; NF-E2-Related Factor 2/genetics/*metabolism ; Reactive Oxygen Species ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of type 2 diabetes, where impairment of pancreatic β-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs[3+]) exposure, blunts glucose-triggered reactive oxygen species (ROS) signaling and impairs glucose-stimulated insulin secretion (GSIS). In the current study, we found that MIN6 pancreatic β-cells with stable knockdown of Nrf2 (Nrf2-KD) by lentiviral shRNA and pancreatic islets isolated from Nrf2-knockout (Nrf2[-]/[-]) mice exhibited reduced expression of several antioxidant and detoxification enzymes in response to acute iAs[3+] exposure. As a result, Nrf2-KD MIN6 cells and Nrf2[-]/[-] islets were more susceptible to iAs[3+] and monomethylarsonous acid (MMA[3+])-induced cell damage, as measured by decreased cell viability, augmented apoptosis and morphological change. Pretreatment of MIN6 cells with Nrf2 activator tert-butylhydroquinone protected the cells from iAs[3+]-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N-acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs[3+]. The present study demonstrates that Nrf2-mediated antioxidant response is critical in the pancreatic β-cell defense mechanism against acute cytotoxicity by arsenic. The findings here, combined with our previous results on the inhibitory effect of antioxidants on ROS signaling and GSIS, suggest that Nrf2 plays paradoxical roles in pancreatic β-cell dysfunction induced by environmental arsenic exposure.}, }
@article {pmid22995584, year = {2013}, author = {Rogalska, A and Marczak, A and Gajek, A and Szwed, M and Śliwińska, A and Drzewoski, J and Jóźwiak, Z}, title = {Induction of apoptosis in human ovarian cancer cells by new anticancer compounds, epothilone A and B.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {27}, number = {1}, pages = {239-249}, doi = {10.1016/j.tiv.2012.09.006}, pmid = {22995584}, issn = {1879-3177}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Epothilones/*pharmacology ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Ovarian Neoplasms ; Paclitaxel/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Epothilones are a new group of compounds with action mechanisms similar to taxanes. The aim of this study was to compare the effects of epothilone A (Epo A) and epothilone B (Epo B) on ovarian cancer cell line SKOV-3 with those of paclitaxel (PTX), a classic taxane. We evaluate glycoprotein P (P-gp) activity in the ovarian cancer cell line. Apoptotic and necrotic cell levels were measured by double staining with Hoechst 33258 and propidium iodide (PI) as well as Annexin V staining. The production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (ΔΨm) in cells exposed to Epo A, Epo B and PTX were studied using specific fluorescence probes, DCFH(2)-DA (2',7'-dichlorodihydrofluorescein diacetate) and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine). The cytotoxic activity of the drugs was determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) test. All probes were analyzed in both the presence and absence of the antioxidant N-acetylcysteine (NAC). The results obtained demonstrated that the antiproliferative capacity of Epo A and Epo B in SKOV-3 cell line (measured as IC(50) after 72 h continuous treatment) was six and five times greater than that of PTX's respectively. Epothilones induced timecourse-dependent apoptosis and necrosis. Apoptotic and necrotic events were partially blocked by NAC, indicating ROS played a substantial role in epothilone-induced apoptosis. Cell death was also associated with a decrease in mitochondrial membrane potential, which was more pronounced after treatment with epothilones as compared to paclitaxel.}, }
@article {pmid22994682, year = {2013}, author = {Albabtain, MA and Almasood, A and Alshurafah, H and Alamri, H and Tamim, H}, title = {Efficacy of ascorbic acid, N-acetylcysteine, or combination of both on top of saline hydration versus saline hydration alone on prevention of contrast-Induced nephropathy: a prospective randomized study.}, journal = {Journal of interventional cardiology}, volume = {26}, number = {1}, pages = {90-96}, doi = {10.1111/j.1540-8183.2012.00767.x}, pmid = {22994682}, issn = {1540-8183}, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/chemically induced/*prevention &amp; control ; Adult ; Aged ; Aged, 80 and over ; Antioxidants/therapeutic use ; Ascorbic Acid/therapeutic use ; Contrast Media/*adverse effects ; Creatinine/analysis ; Drug Therapy, Combination ; Female ; Fluid Therapy ; Free Radical Scavengers/therapeutic use ; Humans ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {BACKGROUND: Antioxidant drugs such as N-acetylcysteine (NAC) and ascorbic acid have been evaluated in interventional studies to prevent contrast-induced nephropathy (CIN), however, there are limited data on comparing either or both, with background of standard intravenous saline hydration versus the standard intravenous saline hydration alone in preventing CIN.<br><br>METHODS: We conducted a single-center randomized trial among patients undergoing coronary angiography or percutaneous coronary intervention who had serum creatinine &#x2265; 1.3 mg/dL or were on diabetes mellitus medication. Eligible patients were randomly assigned to one of the following 4 groups: (1) NAC, (2) ascorbic acid, (3) combination of both drugs, and (4) control group. Additionally, all the groups received the standard intravenous saline hydration. Creatinine was measured 4-5 days after procedure.<br><br>RESULTS: A total of 243 patients were randomized; 62 to NAC, 57 to ascorbic acid, 58 to both drugs, and 66 to placebo. The development of 0.5 mg/dL absolute increase of serum creatinine, 25% relative decrease of creatinine clearance, or either (CIN) were measured in the ascorbic acid group (3.6% for all), NAC group (6.8%, 3.4%, 8.5%, respectively), combined group (5.5%, 5.5%, 9.1%, respectively), and control group (6.2%, 6.2%, 7.7%, respectively). None of these differences were significant (P = 0.896 for serum creatinine, P = 0.863 for creatinine clearance, and P = 0.684 for CIN).<br><br>CONCLUSIONS: In a cohort of patients at risk of developing CIN, we could not detect any significant benefit of the use of ascorbic acid, NAC, or a combination of both drugs over the standard hydration regimen in preventing CIN.}, }
@article {pmid22993321, year = {2012}, author = {Hanly, L and Figueredo, R and Rieder, MJ and Koropatnick, J and Koren, G}, title = {The Effects of N-acetylcysteine on ifosfamide efficacy in a mouse xenograft model.}, journal = {Anticancer research}, volume = {32}, number = {9}, pages = {3791-3798}, pmid = {22993321}, issn = {1791-7530}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents, Alkylating/*pharmacology ; Bone Neoplasms/*drug therapy/pathology ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Drug Interactions ; Female ; Humans ; Ifosfamide/*pharmacology ; Mice ; Sarcoma, Ewing/*drug therapy/pathology ; Treatment Outcome ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND/AIM: Nephrotoxicity is observed in 30% of children treated with ifosfamide. We have shown that n-acetylcysteine (NAC) successfully mitigates nephrotoxicity of ifosfamide in cell and rodent models. However, before this treatment is evaluated clinically, it must be established that NAC does not interfere with the efficacy of ifosfamide.<br><br>MATERIALS AND METHODS: Mice implanted with Ewing's sarcoma tumours received the following treatments: saline, ifosfamide, ifosfamide + NAC concurrently, pre-treatment with NAC + ifosfamide, or NAC alone.<br><br>RESULTS: Median volumes of EW-7 tumour xenografts in mice treated with ifosfamide (n=8), ifosfamide with concurrent NAC therapy (n=7), and NAC pre-treatment (n=6) (p<0.05) were significantly reduced compared to median tumour volumes of control mice (n=6). None of the NAC treatments affected ifosfamide-mediated reduction in tumour volumes.<br><br>CONCLUSION: NAC does not interfere with the efficacy of ifosfamide in a EW-7 xenograft model. These results support the clinical evaluation of NAC as a strategy against ifosfamide-induced nephrotoxicity in children.}, }
@article {pmid22991071, year = {2012}, author = {Gonçalves, JF and Duarte, MM and Fiorenza, AM and Spanevello, RM and Mazzanti, CM and Schmatz, R and Bagatini, MD and Antes, FG and Costa, P and Abdalla, FH and Dressler, VL and Morsch, VM and Schetinger, MR}, title = {Hematological indices and activity of NTPDase and cholinesterase enzymes in rats exposed to cadmium and treated with N-acetylcysteine.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {25}, number = {6}, pages = {1195-1206}, doi = {10.1007/s10534-012-9582-2}, pmid = {22991071}, issn = {1572-8773}, mesh = {Acetylcholinesterase/blood/*metabolism ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antigens, CD/blood/*metabolism ; Apyrase/antagonists &amp; inhibitors/blood/*metabolism ; Butyrylcholinesterase/blood/*metabolism ; Cadmium/administration &amp; dosage/blood/*pharmacology ; Lymphocytes/drug effects/enzymology/metabolism ; Male ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; }, abstract = {The present study aimed to investigate the influence of N-acetylcysteine (NAC) on cadmium (Cd) poisoning by evaluating Cd concentration in tissues, hematological indices as well as the activity of NTPDase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes of rats exposed to Cd and co-treated with NAC. For this purpose, the rats received Cd (2 mg/kg) and NAC (150 mg/kg) by gavage every other day for 30 days. Animals were divided into four groups (n = 6-8): control/saline, NAC, Cd, and Cd/NAC. Cd exposure increased Cd concentration in plasma, spleen and thymus, and NAC co-treatment modulated this augment in both lymphoid organs. Cd exposure reduced red blood cell count, hemoglobin content and hematocrit value. Cd intoxication caused a decrease in total white blood cell count. NAC treatment per se caused an increase in lymphocyte and a decrease in neutrophil counts. On contrary, Cd exposure caused a decrease in lymphocyte and an increase in neutrophil and monocyte counts. NAC reversed or ameliorated the hematological impairments caused by Cd poisoning. There were no significant alterations in the NTPDase activity in lymphocytes of rats treated with Cd and/or NAC. Cd caused a decrease in the activities of lymphocyte AChE, whole blood AChE and serum BChE. However, NAC co-treatment was inefficient in counteracting the negative effect of Cd in the cholinesterase activities. The present investigation provides ex vivo evidence supporting the hypothesis that Cd induces immunotoxicity by interacting with the lymphoid organs, altering hematological parameters and inhibiting peripheral cholinesterase activity. Also, it highlights the possibility to use NAC as adjuvant against toxicological conditions.}, }
@article {pmid22990675, year = {2012}, author = {Porto, C and Ferrara, MC and Meli, M and Acampora, E and Avolio, V and Rosa, M and Cobucci-Ponzano, B and Colombo, G and Moracci, M and Andria, G and Parenti, G}, title = {Pharmacological enhancement of α-glucosidase by the allosteric chaperone N-acetylcysteine.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {20}, number = {12}, pages = {2201-2211}, pmid = {22990675}, issn = {1525-0024}, support = {TGM11MT4/TI_/Telethon/Italy ; }, mesh = {Acetylcysteine/pharmacokinetics/*therapeutic use ; Animals ; Blotting, Western ; COS Cells ; Chlorocebus aethiops ; Enzyme Stability/drug effects ; Fibroblasts/drug effects/enzymology/metabolism ; Fluorescent Antibody Technique ; Glycogen Storage Disease Type II/drug therapy ; Humans ; Mice ; Microscopy, Confocal ; Molecular Chaperones/pharmacology/therapeutic use ; alpha-Glucosidases/chemistry/*metabolism/*therapeutic use ; }, abstract = {Pompe disease (PD) is a metabolic myopathy due to the deficiency of the lysosomal enzyme α-glucosidase (GAA). The only approved treatment for this disorder, enzyme replacement with recombinant human GAA (rhGAA), has shown limited therapeutic efficacy in some PD patients. Pharmacological chaperone therapy (PCT), either alone or in combination with enzyme replacement, has been proposed as an alternative therapeutic strategy. However, the chaperones identified so far also are active site-directed molecules and potential inhibitors of target enzymes. We demonstrated that N-acetylcysteine (NAC) is a novel allosteric chaperone for GAA. NAC improved the stability of rhGAA as a function of pH and temperature without disrupting its catalytic activity. A computational analysis of NAC-GAA interactions confirmed that NAC does not interact with GAA catalytic domain. NAC enhanced the residual activity of mutated GAA in cultured PD fibroblasts and in COS7 cells overexpressing mutated GAA. NAC also enhanced rhGAA efficacy in PD fibroblasts. In cells incubated with NAC and rhGAA, GAA activities were 3.7-8.7-fold higher than those obtained in cells treated with rhGAA alone. In a PD mouse model the combination of NAC and rhGAA resulted in better correction of enzyme activity in liver, heart, diaphragm and gastrocnemia, compared to rhGAA alone.}, }
@article {pmid22989604, year = {2013}, author = {Barbosa, VA and Luciano, TF and Marques, SO and Vitto, MF and Souza, DR and Silva, LA and Santos, JP and Moreira, JC and Dal-Pizzol, F and Lira, FS and Pinho, RA and De Souza, CT}, title = {Acute exercise induce endothelial nitric oxide synthase phosphorylation via Akt and AMP-activated protein kinase in aorta of rats: Role of reactive oxygen species.}, journal = {International journal of cardiology}, volume = {167}, number = {6}, pages = {2983-2988}, doi = {10.1016/j.ijcard.2012.08.050}, pmid = {22989604}, issn = {1874-1754}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Animals ; Aorta, Thoracic/*enzymology ; Male ; Nitric Oxide Synthase Type III/*metabolism ; Phosphorylation/physiology ; Physical Conditioning, Animal/*physiology ; Proto-Oncogene Proteins c-akt/*metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {BACKGROUND: Acute exercise increases reactive oxygen species (ROS) levels, including hydrogen peroxide (H2O2). H2O2 promotes endothelial nitric oxide synthase (eNOS) activation and phosphorylation in endothelial cells. With this in mind, the present study was designed to evaluate ex vivo eNOS phosphorylation in rat aortas incubated with H2O2 and to test this hypothesis in vivo in the aortas of rats submitted to acute exercise.<br><br>METHODS: For ex vivo studies, six groups of aortic tissue were formed: control, H2O2, N-acetylcysteine (NAC), LY294002, compound C, and LY294002 plus compound C. While incubation with H2O2 increased Akt, AMPK and eNOS phosphorylation, pre-incubation with NAC strongly reduced the phosphorylation of these enzymes. For in vivo studies, male Wistar rats were divided into four groups: control, cont+NAC, exercise, and exer+NAC. After a 3h swimming session, animals were decapitated and aortas were excised for biochemical and immunoblotting analysis.<br><br>RESULTS: Acute exercise increased superoxide levels and dichlorofluorescein (DCF) concentrations, and this increase was related to phosphorylation of Akt, AMPK and eNOS. On the other hand, use of NAC reduced superoxide levels and DCF concentration. Reduced superoxide levels and DCF in the exer+NAC group were associated with decreased Akt, AMPK and eNOS phosphorylation. These results appear to be connected with vascular function because VASP phosphorylation increased in acute exercise and decreased in exer+NAC.<br><br>CONCLUSION: Our results indicate that ROS induced by acute exercise play the important role of activating eNOS, a process apparently mediated by Akt and AMPK.}, }
@article {pmid22986467, year = {2013}, author = {Liao, PC and Chao, LK and Chou, JC and Dong, WC and Lin, CN and Lin, CY and Chen, A and Ka, SM and Ho, CL and Hua, KF}, title = {Lipopolysaccharide/adenosine triphosphate-mediated signal transduction in the regulation of NLRP3 protein expression and caspase-1-mediated interleukin-1β secretion.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {62}, number = {1}, pages = {89-96}, pmid = {22986467}, issn = {1420-908X}, mesh = {Adenosine Triphosphate/*pharmacology ; Animals ; Carrier Proteins/*genetics ; Caspase 1/*physiology ; Cells, Cultured ; Interleukin-1beta/*metabolism ; Lipopolysaccharides/*pharmacology ; Mice ; NADPH Oxidases/physiology ; NF-kappa B/physiology ; NLR Family, Pyrin Domain-Containing 3 Protein ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {OBJECTIVE: Reactive oxygen species (ROS) plays a critical role in the regulation of NLRP3 inflammasome activation. However, the ROS-mediated signaling pathways controlling NLRP3 inflammasome activation are not well defined.<br><br>METHODS: Using lipopolysaccharide (LPS) and adenosine triphosphate (ATP) activated murine macrophages as the testing model, cytokine release and protein expression were quantified by enzyme-linked immunosorbent assay and Western blot, respectively. ROS was scavenged by N-acetyl cysteine; NADPH oxidase, the major source of ROS, was inhibited by diphenyliodonium, apocynin or gp91-phox siRNA transfection; and protein kinase was inhibited by its specific inhibitor.<br><br>RESULTS: LPS-induced NLRP3 protein expression was regulated through the NADPH oxidase/ROS/NF-&#x3ba;B-dependent, JAK2/PI3-kinase/AKT/NF-&#x3ba;B-dependent, and MAPK-dependent pathways, while ATP-induced caspase-1 activation was regulated through the NADPH oxidase/ROS-dependent pathway.<br><br>CONCLUSIONS: These results demonstrate that ROS regulates not only the priming stage, but also the activation stage, of NLRP3 inflammasome activation in LPS&#xa0;+&#xa0;ATP-activated macrophages.}, }
@article {pmid22986110, year = {2013}, author = {Yoshida, N and Ikeda, Y and Notomi, S and Ishikawa, K and Murakami, Y and Hisatomi, T and Enaida, H and Ishibashi, T}, title = {Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa.}, journal = {Ophthalmology}, volume = {120}, number = {1}, pages = {e5-12}, doi = {10.1016/j.ophtha.2012.07.008}, pmid = {22986110}, issn = {1549-4713}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/therapeutic use ; Apoptosis/drug effects ; Cell Count ; Cell Survival/drug effects ; Chemokine CCL2/*genetics/metabolism ; Chemokine CCL5/*genetics/metabolism ; *Disease Models, Animal ; Gene Expression Regulation/drug effects/*physiology ; Immunohistochemistry ; In Situ Nick-End Labeling ; Interleukin-1beta/*genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Microglia/drug effects/metabolism/pathology ; Photoreceptor Cells, Vertebrate/metabolism/pathology ; RNA, Messenger/metabolism ; Real-Time Polymerase Chain Reaction ; Retinitis Pigmentosa/*genetics/metabolism/prevention &amp; control ; Tumor Necrosis Factor-alpha/*genetics/metabolism ; }, abstract = {PURPOSE: To study the nature of retinal inflammatory response in rd10 mice, an animal model of retinitis pigmentosa (RP), and to investigate the effect of an antioxidant on retinal inflammation and photoreceptor apoptosis.<br><br>DESIGN: Experimental study.<br><br>PARTICIPANTS AND CONTROLS: This study included 42 untreated rd10 mice, 30 N-acetylcysteine (NAC)-treated rd10 mice, and 20 C57BL/6 mice as controls.<br><br>METHODS: Real-time polymerase chain reaction (PCR) was performed to evaluate the expression levels of inflammatory factors (proinflammatory cytokines and chemokines) in rd10 mouse retinas. Rd10 mice were treated with an antioxidant NAC, and its effect on retinal inflammation and photoreceptor apoptosis were examined by immunohistochemistry.<br><br>MAIN OUTCOME MEASURES: Real-time PCR and immunohistochemistry.<br><br>RESULTS: We demonstrated sequential events involving increased expression of proinflammatory cytokines and chemokines, activation of microglia, and photoreceptor apoptosis during retinal degeneration of rd10 mice. Furthermore, antioxidant treatment with NAC prevented the photoreceptor cell death along with suppression of inflammatory factors and microglial activation.<br><br>CONCLUSIONS: Sustained chronic inflammatory reaction may contribute to the pathogenesis of retinal degeneration in rd10 mice, suggesting interventions for ocular inflammatory reaction using antioxidants as a potential treatment for patients with RP.<br><br>FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.}, }
@article {pmid22978600, year = {2013}, author = {Andre, L and Fauconnier, J and Reboul, C and Feillet-Coudray, C and Meschin, P and Farah, C and Fouret, G and Richard, S and Lacampagne, A and Cazorla, O}, title = {Subendocardial increase in reactive oxygen species production affects regional contractile function in ischemic heart failure.}, journal = {Antioxidants &amp; redox signaling}, volume = {18}, number = {9}, pages = {1009-1020}, doi = {10.1089/ars.2012.4534}, pmid = {22978600}, issn = {1557-7716}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/therapeutic use ; Calcium/pharmacology ; Catalase/metabolism ; Cyclic AMP/physiology ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/pharmacology ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Heart Failure/etiology/metabolism/*physiopathology ; Lipid Peroxidation ; Male ; Mitochondria, Heart/metabolism ; *Myocardial Contraction/drug effects ; Myocardial Ischemia/complications/metabolism/*physiopathology ; Myocytes, Cardiac/metabolism ; Myofibrils/drug effects/physiology ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Protein Processing, Post-Translational/drug effects ; Random Allocation ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Recombinant Proteins/pharmacology ; Superoxide Dismutase/metabolism ; }, abstract = {AIMS: Heart failure (HF) is characterized by regionalized contractile alterations resulting in loss of the transmural contractile gradient across the left ventricular free wall. We tested whether a regional alteration in mitochondrial oxidative metabolism during HF could affect myofilament function through protein kinase A (PKA) signaling.<br><br>RESULTS: Twelve weeks after permanent left coronary artery ligation that induced myocardial infarction (MI), subendocardial (Endo) cardiomyocytes had decreased activity of complex I and IV of the mitochondrial electron transport chain and produced twice more superoxide anions than sham Endo and subepicardial cells. This effect was associated with a reduced antioxidant activity of superoxide dismutase and Catalase only in MI Endo cells. The myofilament contractile properties (Ca(2+) sensitivity and maximal tension), evaluated in skinned cardiomyocytes, were also reduced only in MI Endo myocytes. Conversely, in MI rats treated with the antioxidant N-acetylcysteine (NAC) for 4 weeks, the generation of superoxide anions in Endo cardiomyocytes was normalized and the contractile properties of skinned cardiomyocytes restored. This effect was accompanied by improved in vivo contractility. The beneficial effects of NAC were mediated, at least, in part, through reduction of the PKA activity, which was higher in MI myofilaments, particularly, the PKA-mediated hyperphosphorylation of cardiac Troponin I.<br><br>INNOVATION: The Transmural gradient in the mitochondrial content/activity is lost during HF and mediates reactive oxygen species-dependent contractile dysfunction.<br><br>CONCLUSIONS: Regionalized alterations in redox signaling affect the contractile machinery of sub-Endo myocytes through a PKA-dependent pathway that contributes to the loss of the transmural contractile gradient and impairs global contractility.}, }
@article {pmid22977060, year = {2012}, author = {Shi-wen, X and Thompson, K and Khan, K and Liu, S and Murphy-Marshman, H and Baron, M and Denton, CP and Leask, A and Abraham, DJ}, title = {Focal adhesion kinase and reactive oxygen species contribute to the persistent fibrotic phenotype of lesional scleroderma fibroblasts.}, journal = {Rheumatology (Oxford, England)}, volume = {51}, number = {12}, pages = {2146-2154}, doi = {10.1093/rheumatology/kes234}, pmid = {22977060}, issn = {1462-0332}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Cells, Cultured ; Female ; Focal Adhesion Protein-Tyrosine Kinases/*physiology ; Humans ; Male ; Mice ; Myofibroblasts/*physiology ; Phosphorylation/physiology ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Scleroderma, Systemic/*etiology/metabolism ; Signal Transduction ; }, abstract = {OBJECTIVE: Fibrotic diseases such as SSc (systemic sclerosis, scleroderma) are characterized by the abnormal presence of the myofibroblast, a specialized type of fibroblast that overexpresses the highly contractile protein α-smooth muscle actin. Myofibroblasts display excessive adhesive properties and hence exert a potent mechanical force. We aim to identify the precise contribution of adhesive signalling, which requires integrin-mediated activation of focal adhesion kinase (FAK)/src, to fibrogenic gene expression in normal and fibrotic SSc fibroblasts.<br><br>METHODS: We subject either FAK wild-type and knockout fibroblasts or normal and SSc fibroblasts treated with FAK/src inhibitors to real-time polymerase chain, western blot, cell migration and collagen gel contraction analyses.<br><br>RESULTS: FAK operates downstream of both integrin &#x3b2;1 and reactive oxygen species (ROS) to promote the expression of genes involved in matrix production and remodelling, including CCN2, &#x3b1;-smooth muscle actin and type I collagen. Blocking either FAK/src with PP2 or ROS with N-acetyl cysteine alleviates the elevated contractile and migratory capability of lesional SSc dermal fibroblasts.<br><br>CONCLUSIONS: Excessive adhesive signalling is intimately involved with the fibrotic phenotype of lesional SSc fibroblasts; blocking adhesive signalling or ROS generation may be beneficial in controlling the fibrosis observed in SSc.}, }
@article {pmid24250472, year = {2012}, author = {Daraie, B and Pourahmad, J and Hamidi-Pour, N and Hosseini, MJ and Shaki, F and Soleimani, M}, title = {Uranyl acetate induces oxidative stress and mitochondrial membrane potential collapse in the human dermal fibroblast primary cells.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {11}, number = {2}, pages = {495-501}, pmid = {24250472}, issn = {1735-0328}, abstract = {Cytotoxicity of depleted uranium, as a byproduct of military has been came to spotlight in recent decades. DU is known as a chemical rather than radioactive hazard and efforts to illustrating its mechanism is undergo, but the precise complete molecular mechanisms are still unclear. Recent studies showed that uranium induces biological changes in many different target tissues, such as the kidney, brain and skin. The aim of this study was to assess the impact of depleted uranium exposure at the cellular level in the human dermal fibroblast primary cells. The human dermal fibroblast primary cells incubated with different concentration (250-750 μM) of depleted uranium. Cytotoxicity and mitochondrial function in this cell lines were determined with the LDH leakage assay and the MTT test respectively. MDA levels were measured for determination of Lipid peroxidation in DU treated cells. Besides glutathione depletion and apoptosis phenotype detection were also assessed to complete the mechanistic screening. Results showed that the cell viability ameliorates in concentration and time dependent manners following in 24, 48 and 72 h incubation with DU. Moreover the significant increase in lipid peroxidation and significant decrease in cellular GSH recorded in DU treated human dermal fibroblast primary cells suggesting the preoxidant effect of uranyl ions. Cytoprotective effects of N-acetylcysteine (NAC) and dramatic decrease of cell viability in buthionin sulfoxamid (BSO) pretreated cells indicated the possibility of a critical role for glutathione system in DU detoxification. Death pattern, in fibroblast cells following DU treatment was varied from apoptosis to necrosis while the time and concentration increased. Since ROS formation is the initiation step for cell apoptosis, the present studies suggest Uranyl-induced toxicity in the human dermal fibroblast primary cells originated from oxidative stress and lead to occurrence of programmed cell death.}, }
@article {pmid24116290, year = {2012}, author = {Im, YS and Ryu, YK and Moon, EY}, title = {Mouse Melanoma Cell Migration is Dependent on Production of Reactive Oxygen Species under Normoxia Condition.}, journal = {Biomolecules &amp; therapeutics}, volume = {20}, number = {2}, pages = {165-170}, pmid = {24116290}, issn = {1976-9148}, abstract = {Cell migration plays a role in many physiological and pathological processes. Reactive oxygen species (ROS) produced in mammalian cells influence intracellular signaling processes which in turn regulate various biological activities. Here, we investigated whether melanoma cell migration could be controlled by ROS production under normoxia condition. Cell migration was measured by wound healing assay after scratching confluent monolayer of B16F10 mouse melanoma cells. Cell migration was enhanced over 12 h after scratching cells. In addition, we found that ROS production was increased by scratching cells. ERK phosphorylation was also increased by scratching cells but it was decreased by the treatment with ROS scavengers, N-acetylcysteine (NAC). Tumor cell migration was inhibited by the treatment with PD98059, ERK inhibitor, NAC or DPI, well-known ROS scavengers. Tumor cell growth as judged by succinate dehydrogenase activity was inhibited by NAC treatment. When mice were intraperitoneally administered with NAC, the intracellular ROS production was reduced in peripheral blood mononuclear cells. In addition, B16F10 tumor growth was significantly inhibited by in vivo treatment with NAC. Collectively, these findings suggest that tumor cell migration and growth could be controlled by ROS production and its downstream signaling pathways, in vitro and in vivo.}, }
@article {pmid24312774, year = {2012}, author = {Mostafalou, S and Abdollahi, M and Eghbal, MA and Saeedi Kouzehkonani, N}, title = {Protective effect of NAC against malathion-induced oxidative stress in freshly isolated rat hepatocytes.}, journal = {Advanced pharmaceutical bulletin}, volume = {2}, number = {1}, pages = {79-88}, pmid = {24312774}, issn = {2228-5881}, abstract = {PURPOSE: Induction of oxidative stress by Organophosphate compounds (OPs) has been previously reported. In the present work, the mechanism of protective effects of N-acetylcysteine as a glutathion (GSH) prodrug against malathion-induced cell toxicity was investigated. In this work, freshly isolated rat hepatocytes were used to determine the effect of NAC on malathion-induced cytotoxicity, formation of reactive oxygen species (ROS) and mitochondrial dysfunction.<br><br>METHODS: Rat hepatocytes were isolated using collagenase perfusion and then cell viability, mitchondrial membrane potential (MMP) and ROS formation were determined using trypan blue exclusion, Rhodamine 123 fluorescence and fluorogenic probe, 2', 7' -dichlorofluorescin diacetate (DCFH-DA), respectively.<br><br>RESULTS: Despite the protective effect of NAC on malathion-induced cell toxicity and MMP dysfunction, its efficacy against ROS formation was not adequate to completely protect the cells.<br><br>CONCLUSION: Cytotoxic effects of malathion regardless of its cholinergic feature, is started with gradual free radical production but, the main factor that causes cell death, is mitochondrial dysfunction, so that reduction of ROS formation alone is not sufficient for cell survival, and the maintenance of mitochondrial integrity through different mechanisms is the most ameliorative factor specially at high levels of cell damage, as NAC seemed to protect cells with various fashions apart from ROS scavenging in concentrations higher than malathion's LC50.}, }
@article {pmid24031823, year = {2012}, author = {Gomes, F and Leite, B and Teixeira, P and Azeredo, J and Oliveira, R}, title = {Farnesol in combination with N-acetylcysteine against Staphylococcus epidermidis planktonic and biofilm cells.}, journal = {Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology]}, volume = {43}, number = {1}, pages = {235-242}, pmid = {24031823}, issn = {1517-8382}, abstract = {Staphylococcus epidermidis is the most frequent cause of nosocomial sepsis and catheter-related infections, in which biofilm formation is considered to be the main virulence mechanism. In biofilm environment, microbes exhibit enhanced resistance to antimicrobial agents. This fact boosted the search of possible alternatives to antibiotics. Farnesol and N-acetylcysteine (NAC) are non-antibiotic drugs that have demonstrated antibacterial properties. In this study, the effect of farnesol and NAC isolated or in combination (farnesol+NAC) was evaluated. NAC at 10 × MIC caused a total cell death in planktonic cells. On the other hand, S. epidermidis biofilms exhibited 4 log reduction in viable cell number after a 24h treatment with NAC at the former concentration. Our results demonstrated that there was a higher CFU log reduction of S. epidermidis planktonic cells when farnesol was combined with NAC at 1 × MIC relatively to each agent alone. However, these results were not relevant because NAC alone at 10 × MIC was always the condition which gave the best results, having a very high killing effect on planktonic cells and a significant bactericidal effect on biofilm cells. This study demonstrated that no synergy was observed between farnesol and NAC. However, the pronounced antibacterial effect of NAC against S. epidermidis, on both lifestyles, indicates the use of NAC as a potential therapeutic agent in alternative to antibiotics.}, }
@article {pmid24822348, year = {2011}, author = {Fan, ZG and Li, KJ and Zhang, LM}, title = {[Effect of N-acetylcysteine on malondialdehyde and superoxide dismutase in hepatic tissue of mice with Schistosomiasis japonica].}, journal = {Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology &amp; parasitic diseases}, volume = {29}, number = {6}, pages = {457-460}, pmid = {24822348}, issn = {1000-7423}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Female ; Glutathione Peroxidase/metabolism ; Liver/*drug effects/enzymology ; Male ; Malondialdehyde/*metabolism ; Mice ; Mice, Inbred Strains ; Schistosoma japonicum ; Schistosomiasis japonica/*metabolism ; Superoxide Dismutase/*metabolism ; }, abstract = {90 mice were randomly divided into six groups: normal control, infected control, long-term drug use group 1 (L1), long-term drug use group 2 (L2), short-term drug use group 1 (S1) and short-term drug use group 2 (S2). Mice in all groups except those in the normal control group were infected with 30 cercariae of Schistosoma japonicum through abdominal skin. N-acetylcysteine (NAC) solution was orally given to mice in L1 and L2 groups, 200 mg/kg and 400 mg/kg, respectively, 2 times/d from the day of infection, while for S1 and S2 groups, 200 mg/kg and 400 mg/kg, respectively, 2 times/d from the 42th day after L2 infection. Mice in the groups of normal control, infected control, L1 and L2 were sacrificed either on day 42 or day 56 after infection, while those in S1 and S2 were sacrificed on day 56 after infection. Number and area of the single egg granuloma were measured with computer image analysis software. The concentration of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in serum and hepatic tissue were detected. The number of "+" single egg granulomas in the liver of mice in L1 was the fewest by 3.04, followed by those in S1, by 4.87. The results indicated that the level of MAD in hepatic tissue of L2 (9.2-9.3 nmol/mg)was markedly lower than that of L1 (P < 0.05), and the level of SOD in hepatic tissue of L1 was 170.00-190.00 U/(g x pro), similar to those of S1 and L2 at the 42th day (P > 0.05), but the level in L2 at the 56th day was close to that of S2 (P > 0.05). Hence, NAC may retard the formation of single egg granulomas in the liver of infected mice, and may regulate the concentration of MDA and the activity of SOD in the liver.}, }
@article {pmid24278567, year = {2011}, author = {Lee, JG and Noh, WJ and Kim, H and Lee, MY}, title = {Generation of reactive oxygen species contributes to the development of carbon black cytotoxicity to vascular cells.}, journal = {Toxicological research}, volume = {27}, number = {3}, pages = {161-166}, pmid = {24278567}, issn = {1976-8257}, abstract = {Carbon black, a particulate form of pure elemental carbon, is an industrial chemical with the high potential of occupational exposure. Although the relationship between exposure to particulate matters (PM) and cardiovascular diseases is well established, the cardiovascular risk of carbon black has not been characterized clearly. In this study, the cytotoxicity of carbon black to vascular smooth muscle and endothelial cells were examined to investigate the potential vascular toxicity of carbon black. Carbon black with distinct particle size, N330 (primary size, 28~36 nm) and N990 (250~350 nm) were treated to A-10, rat aortic smooth muscle cells and human umbilical vein endothelial cell line, ECV304, and cell viability was assessed by lactate dehydrogenase (LDH) leakage assay. Treatment of carbon black N990 resulted in the significant reduction of viability in A-10 cells at 100 μg/ml, the highest concentration tested, while N330 failed to cause cell death. Cytotoxicity to ECV304 cells was induced only by N330 at higher concentration, 200 μg/ml, suggesting that ECV304 cells were relatively resistant to carbon black. Treatment of 100 μg/ml N990 led to the elevation of reactive oxygen species (ROS) detected by dichlorodihydrofluorescein (DCF) in A-10 cells. Pretreatment of antioxidants, N-acetylcysteine (NAC) and sulforaphane restored decreased viability of N990-treated A-10 cells, and N-acetylcysteine, but not sulforaphane, attenuated N990-induced ROS generation in A-10 cells. Taken together, present study shows that carbon black is cytotoxic to vascular cells, and the generation of reactive oxygen contributes to the development of cytotoxicity. ROS scavenging antioxidant could be a potential strategy to attenuate the toxicity induced by carbon black exposure.}, }
@article {pmid23359750, year = {2011}, author = {Sarchahi, AA and Meimandi Parizi, A and Eghtedari, M and Keshavarz, S}, title = {Effect of different treatment regimen with dexamethasone and acetylcysteine on corneal wound healing in rabbits.}, journal = {Iranian journal of medical sciences}, volume = {36}, number = {3}, pages = {188-195}, pmid = {23359750}, issn = {0253-0716}, abstract = {BACKGROUND: The effect of corticosteroid therapy on corneal wound healing is controversial. The objective of this study was to evaluate the effects of combination therapy with dexamethasone and acetylcysteine at different times and durations on experimentally-induced corneal wounds and haze in rabbits.<br><br>METHODS: Eighteen adult New Zealand white rabbits were divided into three groups of six each. Under anesthesia corneal wounds were created surgically in the center of all eyes. The right eyes of rabbits in group 1 were treated topically with acetylcysteine and dexamethasone immediately after surgery, those in group 2 were treated with acetylcysteine from day 1 and with acetylcysteine and dexamethasone from day 8, and those in group 3 were treated with acetylcysteine from day 1 and with acetylcysteine and dexamethasone from day 15. The left eyes were assigned as controls and were treated with normal saline. All eyes were treated six times a day for 28 days. Corneal wounds were measured by fluorescein staining every day.<br><br>RESULTS: The combination of acetylcysteine and dexamethasone in group 1 significantly increased mean healing time, but did not change that in groups 2 and 3. Clinical and histopathologic examinations revealed that one month after the ulceration in groups 1 corneal haze was greater in treated than in the control eyes. Moreover, there was no significant difference between the control and treated eyes of group 1, 2, or 3 in terms of corneal haze at two or three months after the ulceration.<br><br>CONCLUSIONS: The findings of the present study show that the association of 3% concentration of NAC and 0.1% concentration of dexamethasone immediately after corneal ulceration can delay corneal wound healing, and consequently produce more corneal haze. Thus, the use of 0.1% concentration of dexamethasone should be delayed at least until the completion of the epithelial defects.}, }
@article {pmid23675187, year = {2010}, author = {Confalone, E and D'Alessio, G and Furia, A}, title = {IL-6 Induction by TNFα and IL-1β in an Osteoblast-Like Cell Line.}, journal = {International journal of biomedical science : IJBS}, volume = {6}, number = {2}, pages = {135-140}, pmid = {23675187}, issn = {1550-9702}, abstract = {Stress cytokines tumor necrosis factor α, interleukin-1 β and interleukin-6 modulate the activity of a variety of cell types including osteoblasts, and are involved in the pathogenesis of several rheumatic diseases associated with systemic bone loss. We have studied the expression of interleukin-6 induced by interleukin-1 β and tumor necrosis factor α in the osteoblast-like cell line MG-63, derived from a human osteosarcoma. We have observed marked differences in the regulation of interleukin-6 gene expression by tumor necrosis factor α or interleukin-1 β, at the level of mRNA steady state and stability and cytokine secretion. In addition, N-acetyl cysteine, a scavenger of reactive oxygen species, inhibits activation of NF-κB and induction of interleukin-6 by tumor necrosis factor α, being ineffective on interleukin-1 β activity. These data illustrate the action of stress cytokines on a cell line widely used in in vitro studies as a reliable model of osteoblast response to cytokines involved in bone resorbing diseases, an important issue for developing new strategies for treatments of bone diseases.}, }
@article {pmid24692817, year = {2008}, author = {Nikas, DN and Chatziathanasiou, G and Kotsia, A and Papamichael, N and Thomas, C and Papafaklis, M and Naka, KK and Kazakos, N and Milionis, HJ and Vakalis, K and Katsouras, CS and Mpoumpa, V and Vougiouklakis, T and Michalis, L}, title = {Effect of intravenous administration of antioxidants alone and in combination on myocardial reperfusion injury in an experimental pig model.}, journal = {Current therapeutic research, clinical and experimental}, volume = {69}, number = {5}, pages = {423-439}, pmid = {24692817}, issn = {0011-393X}, abstract = {BACKGROUND: Several antioxidants have been found to have conflicting results in attenuating myocardial reperfusion injury. These studies were done primarily in experimental protocols that did not approximate clinical situations.<br><br>OBJECTIVE: The aim of this study was to test the efficacy of 3 different antioxidants (ascorbic acid [AA], desferrioxamine, and N-acetylcysteine [NAC]) administered IV alone and in combination in a closed-chest pig model.<br><br>METHODS: Farm-raised domestic male pigs (aged 3-5 months, weight of 30-35 kg) were assigned to 1 of 5 groups to receive treatment as follows: group A, AA 100 mg/kg; group B, desferrioxamine 60 mg/kg; group C, a loading dose of NAC 100 mg/kg for 20 minutes and a 20-mg/kg maintenance dose; group D, all 3 drugs in combination; and group E, normal saline (control group). The infusion of all drugs was started 15 minutes before and completed 5 minutes after reperfusion, except for the administration of NAC, which was terminated 60 minutes postreperfusion. Myocardial ischemia (45 minutes) and reperfusion (210 minutes) were achieved percutaneously by circumflex artery balloon occlusion. Ejection fraction, left ventricular end-diastolic pressure (LVEDP), flow in the infarcted artery, and all ventricular arrhythmias were recorded. Oxidative stress was estimated by serial measurements of thiobarbituric acid reactive substance (TBARS) concentration in coronary sinus blood. Infarct size was assessed as a percentage of the area at risk (I/R ratio) using the tetrazolium red staining method.<br><br>RESULTS: The 25 pigs were divided into 5 groups of 5 pigs each. No significant between-group differences were found in I/R ratio or in oxidative stress (as measured by TBARS concentration). Group C developed significantly more ventricular atrhythmias than the control group (80% vs 0%, P = 0.02). No other differences among groups were found. LVEDP was significantly elevated in all treatment groups (mean LVEDP difference [SD] for group A, 6.0 [1.6] mm Hg; group B, 17.6 [1.9] mm Hg; group C, 3.6 [1.7] mm Hg; group D, 6.8 [3.2] and group E, 5.4 [3.4] mm Hg). LVEDP elevation was found to be significantly higher in group B compared with all the other groups (all, P < 0.001). No significant between-group differences were found in the other parameters measured.<br><br>CONCLUSION: In this experimental pig model, the antioxidants AA, desferrioxamine, and NAC administered alone or in combination did not reduce the deleterious effects of reperfusion injury and specifically the extent of myocardial necrosis.}, }
@article {pmid24573876, year = {2007}, author = {Zou, Y and Niu, P and Gong, Z and Yang, J and Yuan, J and Wu, T and Chen, X}, title = {Relationship between reactive oxygen species and sodium-selenite-induced DNA damage in HepG2 cells.}, journal = {Frontiers of medicine in China}, volume = {1}, number = {3}, pages = {327-332}, pmid = {24573876}, issn = {1673-7342}, abstract = {Selenium compounds, as an effective chemopreventive agent, can induce apoptosis in tumor cells. Reactive oxygen species (ROS) are important mediators in apoptosis induced by various stimuli, which include chemopreventive agents. In this study, we investigated the relationship between ROS and the levels of DNA damage induced by selenite in HepG2 cells. After HepG2 cells were treated with selenite, there was a dose-dependent decrease in cell viability. The levels of ROS induced by selenite were measured by 2', 7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence, which shos a dose-and time-dependent increase in HepG2 cells. The levels of DNA damage in HepG2 increased in all cells treated with an increasing dose of selenite at 0, 2.5, 5, 10, and 20 μmol/L. N-acetylcysteine (NAC), a known antioxidant, increased cell viability and decreased ROS generation. Moreover, NAC effectively blocked DNA damage induced by selenite. These results revealed that ROS might play an important role in selenite-induced DNA damage that can be reduced by NAC treatment.}, }
@article {pmid23675008, year = {2006}, author = {Suckow, BK and Suckow, MA}, title = {Lifespan extension by the antioxidant curcumin in Drosophila melanogaster.}, journal = {International journal of biomedical science : IJBS}, volume = {2}, number = {4}, pages = {402-405}, pmid = {23675008}, issn = {1550-9702}, abstract = {The interest in health benefits associated with consumption of anti-oxidants has led to investigations examining the possibility that diets rich in anti-oxidants promote lifespan extension. Studies using the standard fruit fly (Drosophila melanogaster) model of longevity have shown that the antioxidants vitamin E and N-acetyl cysteine prolong lifespan. Turmeric is a spice which has been consumed and used for medicinal purposes for many centuries in Asia. Interestingly, turmeric contains the powerful antioxidant, curcumin. To test the hypothesis that dietary curcumin prolongs lifespan, groups of 30 male D. melanogaster were cultured on media containing 1) no additive; 2) 0.5 mg of curcumin/gram of media; 3) 1.0 mg of curumin/gram of media; 4) 1.0μg of the superoxide dismutase inhibitor, disulfiram/gram of media; 5) 10 g of disulfiram/gram of media; 6) 0.5 mg curcumin and 1.0 g disulfiram/ gram of media; 7) 1.0 mg curcumin and 1.0 g disulfiram/ gram of media; 8) 0.5 mg curcumin and 10 g disulfiram/gram of media; or 9) 1.0 mg curcumin and 10 g disulfiram/gram of media. The number of live fruitflies was noted daily and mean lifespan determined for each treatment group. A significant (P≤0.05) increase in mean lifespan was noted only for the fruitflies maintained on 1.0 mg of curcumin/gram of media; this effect was reversed by addition of disulfiram. These results demonstrate that dietary curcumin prolongs lifespan and that this effect is associated with enhanced superoxide dismutase activity.}, }
@article {pmid24186123, year = {1994}, author = {Yao, WB and Zhao, YQ and Abe, T and Ohta, J and Ubuka, T}, title = {Effect ofN-acetylcysteine administration on cysteine and glutathione contents in liver and kidney and in perfused liver of intact and diethyl maleate-treated rats.}, journal = {Amino acids}, volume = {7}, number = {3}, pages = {255-266}, pmid = {24186123}, issn = {0939-4451}, abstract = {Effect ofN-acetyl-L-cysteine (NAC) administration on cysteine and glutathione (GSH) contents in rat liver and kidney was studied using intact and diethyl maleate (DEM)-treated rats and perfused rat liver. Cysteine contents increased rapidly, reaching peak at 10 min after intraperitoneal NAC administration. In liver mitochondria it increased slowly, reaching peak at 60 min. GSH content did not change significantly in these tissues. However, in liver and kidney depleted of GSH with DEM, NAC administration restored GSH contents in 60 and 120 min, respectively. Perfusion with 10 mM NAC resulted in 76% increase in liver cysteine content, but not in GSH content. Liver perfusion of DEM-injected rats with 10 mM NAC restored GSH content by 15%. Present findings indicate that NAC is an effective precursor of cysteine in the intact liver and kidney and in the perfused rat liver, and that NAC stimulated GSH synthesis in GSH-depleted tissues.}, }
@article {pmid24194103, year = {1991}, author = {Dröge, W and Eck, HP and Gmünder, H and Mihm, S}, title = {Dysregulation of plasma amino acid levels in HIV-infection and cancer and its relevance for the immune system.}, journal = {Amino acids}, volume = {1}, number = {2}, pages = {193-198}, pmid = {24194103}, issn = {0939-4451}, abstract = {T cells have a weak membrane transport actitivity for cystine but strong transport activity for cysteine. Even moderate variations of the cysteine concentration affect T cell functions in spite of the high concentration of cystine in cultures with physiological amino acid concentrations. The IL-2 dependent DNA synthesis and the activation of cytotoxic T cells are positively regulated by cysteine, while the activity of the transcription factor NFkB and the production of IL-2 are stimulated by active oxygen species and inhibited by cysteine or GSH. Macrophages, in contrast to T cells, take up more cystine than they need and release the excess after intracellular reduction as cysteine into the extracellular space. This "cysteine pumping activity" of macrophages raises intracellular GSH levels and DNA synthesis of T cells in the vicinity. The difference between the cystine transport activities of T cells and macrophages, therefore, enables T cells to switch between prooxidant and antioxidant states. The "cysteine pump" favors selectively the antigen-specific T cells that are about to be stimulated by antigen-presenting macrophages. The capacity of macrophages to take up cystine and to release cysteine is inhibited, however, by elevated extracellular glutamate concentrations. Elevated plasma glutamate levels have been found in several pathological conditions including cancer and HIV-infection. In HIV-infected patients, the hyperglutamataemia is aggravated by hypocystinaemia and hypocysteinaemia. Our studies, therefore, suggest that the cysteine supply is impaired in several pathological conditions with immunodeficiencies including AIDS. N-acetyl-cysteine (NAC) is a safe and well established drug that may be considered for the treatment of patients with HIV-infection.}, }
@article {pmid22974601, year = {2012}, author = {Ozdemir, R and Yurttutan, S and Sarı, FN and Uysal, B and Unverdi, HG and Canpolat, FE and Erdeve, O and Dilmen, U}, title = {Antioxidant effects of N-acetylcysteine in a neonatal rat model of necrotizing enterocolitis.}, journal = {Journal of pediatric surgery}, volume = {47}, number = {9}, pages = {1652-1657}, doi = {10.1016/j.jpedsurg.2012.02.016}, pmid = {22974601}, issn = {1531-5037}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Biomarkers/metabolism ; Disease Models, Animal ; Drug Administration Schedule ; Enterocolitis, Necrotizing/*drug therapy/metabolism/pathology ; Injections, Intraperitoneal ; Intestinal Mucosa/*drug effects/metabolism/pathology ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Random Allocation ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND/PURPOSE: Hypoxia and ischemia appear to play an important role in the pathogenesis of necrotizing enterocolitis (NEC), which may be related to oxygen-derived free radical formation. This study was designed to evaluate the role of oxidative stress and potentially beneficial effects of N-acetylcysteine (NAC) in a neonatal rat model of NEC.<br><br>METHODS: Thirty Wistar albino rat pups were randomly divided into 3 groups: group 1, control; group 2, NEC and saline; and group 3, NEC and NAC treatment. Necrotizing enterocolitis was induced by hyperosmolar enteral formula feeding and exposure to hypoxia after cold stress at 4&#xb0;C and oxygen. The pups were killed on the fourth day, and their intestinal tissues were harvested for biochemical and histopathologic analysis.<br><br>RESULTS: Mucosal injury scores and intestinal malondialdehyde levels in group 2 were found to be significantly higher than that in other groups (P &#x2264; .05). Intestinal superoxide dismutase activities in group 3 were significantly higher than that in group 2 (P = .018). Intestinal tissue tumor necrosis factor &#x3b1; levels were significantly reduced with NAC treatment in group 3 compared with group 2 (P < .003).<br><br>CONCLUSIONS: It is likely that oxidative stress and inflammatory mediators contribute to the pathogenesis of NEC and that NAC has a protective effect on intestinal injury through its antiinflammatory and antioxidant properties.}, }
@article {pmid22955351, year = {2012}, author = {Del Piano, M and Anderloni, A and Balzarini, M and Ballarè, M and Carmagnola, S and Montino, F and Orsello, M and Pagliarulo, M and Tari, R and Soattini, L and Sforza, F and Mogna, L and Mogna, G}, title = {The innovative potential of Lactobacillus rhamnosus LR06, Lactobacillus pentosus LPS01, Lactobacillus plantarum LP01, and Lactobacillus delbrueckii Subsp. delbrueckii LDD01 to restore the "gastric barrier effect" in patients chronically treated with PPI: a pilot study.}, journal = {Journal of clinical gastroenterology}, volume = {46 Suppl}, number = {}, pages = {S18-26}, doi = {10.1097/MCG.0b013e318267b55d}, pmid = {22955351}, issn = {1539-2031}, mesh = {Bacterial Load ; Duodenum/*microbiology ; Enterobacteriaceae/*growth &amp; development/isolation &amp; purification ; Enterococcus/*growth &amp; development/isolation &amp; purification ; Female ; Gastric Juice/microbiology ; Gastroesophageal Reflux/*drug therapy ; Humans ; Lactobacillus/*growth &amp; development ; Lactobacillus delbrueckii/growth &amp; development ; Lactobacillus plantarum/growth &amp; development ; Lacticaseibacillus rhamnosus/growth &amp; development ; Male ; Pilot Projects ; Probiotics/*administration &amp; dosage ; Proton Pump Inhibitors/*adverse effects/therapeutic use ; Time Factors ; Treatment Outcome ; Yeasts/growth &amp; development/isolation &amp; purification ; }, abstract = {BACKGROUND: Gastroesophageal reflux disease is a very widespread condition. In Europe, it is estimated that about 175 million people suffer from this disease and have to chronically take drugs to increase gastric pH. The proton pump inhibitors (PPIs) such as omeprazole, lansoprazole, and esomeprazole are the most widely used drug typology in this regard. However, the inhibition of normal gastric acid secretion has important side effects, the most important being bacterial overgrowth in the stomach and duodenum with a concentration of >10[5] viable cells/mL. As a major consequence of this, many harmful or even pathogenic bacteria contained in some foods could survive the gastric transit and colonize either the stomach itself, the duodenum, or the gut, where they could establish acute and even chronic infections with unavoidable consequences for the host's health. In other words, the "gastric barrier effect" is strongly reduced or even disrupted. To date, there are no real strategies to deal with this widespread, although still relatively little known, problem. The aim of this study was to confirm the gastric bacterial overgrowth in long-term PPI consumers and to assess the efficacy of some probiotic bacteria, belonging to both genera Lactobacillus and Bifidobacterium, in the reduction of gastric and duodenal bacterial overgrowth, therefore partially restoring the gastric barrier effect against foodborne pathogenic bacteria.<br><br>METHODS: For this purpose, probiotics with a strong demonstrated inhibitory activity on gram-negative bacteria, such as Escherichia coli, were tested in a human intervention trial involving a total of 30 subjects treated with PPIs for either 3 to 12 consecutive months (short-term) or >12 consecutive months (long-term). An additional 10 subjects not taking PPIs were enrolled and used as a control group representing the general population. Four selected probiotics Probiotical SpA (Novara, Italy), namely Lactobacillus rhamnosus LR06 (DSM 21981), Lactobacillus pentosus LPS01 (DSM 21980), Lactobacillus plantarum LP01 (LMG P-21021), and Lactobacillus delbrueckii subsp. delbrueckii LDD01 (DSM 22106) were administered for 10 days to 10 subjects treated with PPIs for >12 months (group B). In the 60 mg formulation, N-acetylcysteine was included as well in light of its well-known mechanical effects on bacterial biofilms. Gastroscopies were performed at the beginning of the study (d0) in all the groups (A, B, C, and D) and after 10 days (d10) in group B only; that is, at the end of probiotics intake. The total viable cells and total Lactobacillus were quantified in gastric juice and duodenal brushing material from all subjects. The results were compared among all the groups and with the control subjects (group D) to confirm the bacterial overgrowth. A comparison was made also between d0 and d10 in group B to quantify the efficacy of the 4 probiotics administered for 10 days. Fecal samples were collected from all groups at d0, including subjects not treated with PPIs, and in group B only at d10. Specific bacterial classes, namely enterococci, total coliforms, E. coli, molds, and yeasts were quantified in all fecal specimens.<br><br>RESULTS: The results collected confirmed the strong bacterial overgrowth in the stomach and duodenum of people treated with PPIs compared with subjects with a normal intragastric acidity. It is also worth noting that the bacterial cell counts in subjects who underwent a long-term treatment with a PPI were greater than the results from subjects taking these drugs for 3 to 12 months. The intake of 4 specific probiotic strains with a marked antagonistic activity towards 5 E. coli bacteria, including the enterohaemorrhagic O157:H7 strain, and an effective amount of N-acetylcysteine (NAC) was able to significantly reduce bacterial overgrowth in long-term PPI-treated subjects. Total lactobacilli represented the major percentage of bacterial counts, thus demonstrating the ability of such bacteria to colonize the stomach and the duodenum, at least temporarily, and to consequently restore the gastric barrier effect. A significant decrease in fecal enterococci, total coliforms, E. coli, molds, and yeasts in subjects treated with PPIs was recorded at the end of probiotics supplementation (d10) compared with baseline (d0) in group B. This is a further confirmation of the barrier effect also exerted at the stomach level.<br><br>CONCLUSIONS: PPIs are the most widely sold and used drugs in the world. However, the chronic use of these pharmacological molecules exposes the subject to the risk of foodborne infections as most pathogens are able to survive the gastric transit in a condition of significantly decreased acidity.}, }
@article {pmid22967661, year = {2012}, author = {Guo, XF and Chen, JB and Wang, H and Zhang, HS and Huang, WH and Guo, J}, title = {Real-time and in-situ cell imaging of thiol compounds in living cells using maleimide BODIPY labeling.}, journal = {Talanta}, volume = {99}, number = {}, pages = {1046-1050}, doi = {10.1016/j.talanta.2012.06.018}, pmid = {22967661}, issn = {1873-3573}, mesh = {Boron Compounds/*chemistry ; Cell Line, Tumor ; Cell Survival ; Feasibility Studies ; Heterocyclic Compounds, 3-Ring/*chemistry/*metabolism ; Humans ; Maleimides/*chemistry/*metabolism ; Molecular Imaging/*methods ; Staining and Labeling ; Sulfhydryl Compounds/*metabolism ; Time Factors ; }, abstract = {In this paper, a simple analytical method for the visualization of thiol compounds including glutathione (GSH), N-acetylcysteine (NAC), cysteine (Cys) and coenzyme A (CoA) in living cells is developed based on 1,3,5,7-tetramethyl-8-phenyl-(2-maleimide)-difluoroboradiaza-s-indacene (TMPAB-o-M) labeling. By using of this fluorogenic reagent, in-situ imaging of thiol compounds in cells could be achieved in only 90 s, which is much faster than that mentioned in other reports. The fluorescence of derivative products in living cells could be stable for atleast 15 min under irradiation, and can be quantified by HPLC easily in only 6 min.}, }
@article {pmid22965839, year = {2013}, author = {Tsai, CH and Lee, SS and Huang, FM and Chang, YC}, title = {Regulation of protease-activated receptor-1 expression in human buccal fibroblasts stimulated with arecoline.}, journal = {Head &amp; neck}, volume = {35}, number = {9}, pages = {1314-1318}, doi = {10.1002/hed.23130}, pmid = {22965839}, issn = {1097-0347}, mesh = {Acetylcysteine/pharmacology ; Arecoline/*pharmacology ; Blotting, Western ; Cell Culture Techniques ; Cholinergic Agonists/*pharmacology ; Chromones/pharmacology ; Enzyme Inhibitors/pharmacology ; Fibroblasts/drug effects/*enzymology ; Flavonoids/pharmacology ; Humans ; Immunohistochemistry ; Morpholines/pharmacology ; Mouth Mucosa/*cytology ; Nitrobenzenes/pharmacology ; Oral Submucous Fibrosis/*enzymology ; Receptor, PAR-1/*metabolism ; Rifabutin/analogs &amp; derivatives/pharmacology ; Sulfonamides/pharmacology ; }, abstract = {BACKGROUND: The purpose of this study was to compare the major thrombin receptor protease-activated receptor-1 (PAR-1) expression in normal human buccal mucosa and oral submucous fibrosis (OSF) specimens and further explore the potential mechanisms that may lead to induce PAR-1 expression.<br><br>METHODS: Thirty OSF and 10 normal buccal mucosa specimens were examined by immunohistochemistry. Buccal mucosal fibroblasts (BMFs) were challenged with arecoline by using Western blot analysis. N-acetyl-L-cysteine (NAC), LY294002, herbimycin A, NS-398, and PD98059 were added to find the possible regulatory mechanisms.<br><br>RESULTS: PAR-1 expression was significantly higher in OSF specimens (p < .05). Arecoline was found to elevate PAR-1 expression in a dose-dependent and time-dependent manner (p < .05). The addition of NAC, LY294002, herbimycin A, NS398, and PD98059 markedly inhibited the arecoline-induced PAR-1 expression (p < .05).<br><br>CONCLUSION: PAR-1 expression is significantly upregulated in areca quid chewing-associated OSF. Arecoline-induced PAR-1 expression was downregulated by NAC, LY294002, herbimycin A, NS398, and PD98059.}, }
@article {pmid22963691, year = {2013}, author = {Fröhlich, E and Meindl, C and Höfler, A and Leitinger, G and Roblegg, E}, title = {Combination of small size and carboxyl functionalisation causes cytotoxicity of short carbon nanotubes.}, journal = {Nanotoxicology}, volume = {7}, number = {7}, pages = {1211-1224}, pmid = {22963691}, issn = {1743-5404}, support = {P 22576/FWF_/Austrian Science Fund FWF/Austria ; }, mesh = {Animals ; Apoptosis/*drug effects ; Carbon Dioxide/*chemistry ; Cell Culture Techniques ; Cell Line ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Humans ; Microscopy, Electron, Scanning Transmission ; Nanotubes, Carbon/*chemistry/*toxicity ; Oxidative Stress/*drug effects ; Particle Size ; Phagocytes/drug effects/metabolism/pathology ; Surface Properties ; }, abstract = {The use of carbon nanotubes (CNTs) could improve medical diagnosis and treatment provided they show no adverse effects in the organism. In this study, short CNTs with different diameters with and without carboxyl surface functionalisation were assessed. After physicochemical characterisation, cytotoxicity in phagocytic and non-phagocytic cells was determined. The role of oxidative stress was evaluated according to the intracellular glutathione levels and protection by N-acetyl cysteine (NAC). In addition to this, the mode of cell death was also investigated. CNTs <8 nm acted more cytotoxic than CNTs ≥20 nm and carboxylated CNTs more than pristine CNTs. Protection by NAC was maximal for large diameter pristine CNTs and minimal for small diameter carboxylated CNTs. Thin (<8 nm) CNTs acted mainly by disruption of membrane integrity and CNTs with larger diameter induced mainly apoptotic changes. It is concluded that cytotoxicity of small carboxylated CNTs occurs by necrosis and cannot be prevented by antioxidants.}, }
@article {pmid22951071, year = {2012}, author = {Whitaker, BD and Casey, SJ and Taupier, R}, title = {The effects of N-acetyl-L-cysteine supplementation on in vitro porcine oocyte maturation and subsequent fertilisation and embryonic development.}, journal = {Reproduction, fertility, and development}, volume = {24}, number = {8}, pages = {1048-1054}, doi = {10.1071/RD12002}, pmid = {22951071}, issn = {1448-5990}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Blastocyst/drug effects/physiology ; DNA Fragmentation/drug effects ; Dietary Supplements ; Embryo Culture Techniques/veterinary ; Embryonic Development/*drug effects ; Female ; Fertilization in Vitro/drug effects/*veterinary ; Oocytes/chemistry/*drug effects/*physiology ; *Sus scrofa ; }, abstract = {The effects of supplementation with 1.5 mM n-acetyl-l-cysteine (NAC) during in vitro oocyte maturation were studied. Oocytes were supplemented with 1.5 mM NAC during maturation for 0 to 24 h, 24 to 48 h, or 0 to 48 h then subjected to IVF and embryo development. Oocytes were evaluated after maturation for intracellular glutathione concentration, superoxide dismutase and glutathione peroxidase activities and DNA fragmentation. Fertilisation and embryonic development success were also evaluated. There was no effect of treatment on intracellular glutathione concentrations, enzyme activities or fertilisation success rates. Supplementing NAC during maturation significantly decreased (P < 0.05) the percentage of oocytes with fragmented DNA compared with no NAC supplementation. Supplementing NAC from 24 to 48 h or 0 to 48 h resulted in a significantly higher (P < 0.05) percentage of oocytes with male pronuclei than for oocytes from the other treatment groups. There was no difference in the percentage of embryos cleaved by 48 h after IVF between treatment groups. Supplementing NAC from 24 to 48 h or 0 to 48 h resulted in a significantly higher (P < 0.05) percentage of embryos reaching the blastocyst stage by 144 h after IVF compared with the other treatment groups. These results indicate that supplementation of the oocyte maturation medium with 1.5 mM NAC, specifically during the last 24 h, improves male pronucleus formation and blastocyst development in pigs.}, }
@article {pmid22949836, year = {2012}, author = {Tsai, CF and Yeh, WL and Huang, SM and Tan, TW and Lu, DY}, title = {Wogonin induces reactive oxygen species production and cell apoptosis in human glioma cancer cells.}, journal = {International journal of molecular sciences}, volume = {13}, number = {8}, pages = {9877-9892}, pmid = {22949836}, issn = {1422-0067}, mesh = {Apoptosis/*drug effects ; Blotting, Western ; Caspases/metabolism ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Flavanones/*pharmacology ; Flow Cytometry ; Glioma/drug therapy/*metabolism/*pathology ; Humans ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tumor Cells, Cultured ; }, abstract = {Glioma is the most common primary adult brain tumor with poor prognosis because of the ease of spreading tumor cells to other regions of the brain. Cell apoptosis is frequently targeted for developing anti-cancer drugs. In the present study, we have assessed wogonin, a flavonoid compound isolated from Scutellaria baicalensis Georgi, induced ROS generation, endoplasmic reticulum (ER) stress and cell apoptosis. Wogonin induced cell death in two different human glioma cells, such as U251 and U87 cells but not in human primary astrocytes (IC 50 > 100 μM). Wogonin-induced apoptotic cell death in glioma cells was measured by propidine iodine (PI) analysis, Tunnel assay and Annexin V staining methods. Furthermore, wogonin also induced caspase-9 and caspase-3 activation as well as up-regulation of cleaved PARP expression. Moreover, treatment of wogonin also increased a number of signature ER stress markers glucose-regulated protein (GRP)-78, GRP-94, Calpain I, and phosphorylation of eukaryotic initiation factor-2α (eIF2α). Treatment of human glioma cells with wogonin was found to induce reactive oxygen species (ROS) generation. Wogonin induced ER stress-related protein expression and cell apoptosis was reduced by the ROS inhibitors apocynin and NAC (N-acetylcysteine). The present study provides evidence to support the fact that wogonin induces human glioma cell apoptosis mediated ROS generation, ER stress activation and cell apoptosis.}, }
@article {pmid22946344, year = {2012}, author = {Deeb, D and Gao, X and Liu, YB and Gautam, SC}, title = {Inhibition of cell proliferation and induction of apoptosis by CDDO-Me in pancreatic cancer cells is ROS-dependent.}, journal = {Journal of experimental therapeutics &amp; oncology}, volume = {10}, number = {1}, pages = {51-64}, pmid = {22946344}, issn = {1359-4117}, support = {R01 CA130948/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Glutathione Peroxidase/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Membrane Potential, Mitochondrial ; Oleanolic Acid/administration &amp; dosage/*analogs &amp; derivatives ; Pancreatic Neoplasms/*metabolism ; *Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; Superoxides/metabolism ; }, abstract = {Oleanolic acid-derived synthetic triterpenoids are broad spectrum antiproliferative and antitumorigenic agents. In this study, we investigated the role of reactive oxygen species (ROS) in induction of apoptosis and inhibition of prosurvival Akt, NF-kappaB and mTOR signaling pro-teins by methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) in pancreatic cancer cells. Micromolar concentrations of CDDO-Me inhibited proliferation and induced apoptosis in MiaPaCa-2 and Panc-1 pancreatic cancer cells. Treatment with CDDO-Me caused the generation of hydrogen peroxide and superoxide anion and pretreatment of cells with NADPH oxidase inhibitor diphylene iodonium (DPI) or respiratory chain complex 1 inhibitor rotenone prevented ROS generation. Pretreatment with N-acetylcysteine (NAC) or overexpression of glutathione peroxidase (GPx) or superoxide dismutase-1 (SOD-1) blocked the antiproliferative effects of CDDO-Me. Likewise, NAC prevented the induction of apoptosis (annexin V-FITC binding and cleavage of PARP-1 and procaspases-3,-8 and -9) and reversed the loss of mitochondrial membrane potential and release of cytochrome c from mitochondria by CDDO-Me. CDDO-Me down-regulated p-Akt, p-mTOR and NF-kappaB (p65) but increased the activation of Erk1/2 and NAC blocked the modulation of these cell signaling proteins by CDDO-Me. Thus, the results of this study indicate that the antiproliferative and apoptosis inducing effects of CDDO-Me are mediated through a ROS-dependent mechanism and the role of ROS in modulation of signaling proteins by CDDO-Me warrants further investigation.}, }
@article {pmid22944654, year = {2012}, author = {Asevedo, E and Cunha, GR and Zugman, A and Mansur, RB and Brietzke, E}, title = {N-acetylcysteine as a potentially useful medication to prevent conversion to schizophrenia in at-risk individuals.}, journal = {Reviews in the neurosciences}, volume = {23}, number = {4}, pages = {353-362}, doi = {10.1515/revneuro-2012-0039}, pmid = {22944654}, issn = {0334-1763}, mesh = {Acetylcysteine/metabolism/*therapeutic use ; Animals ; Disease Progression ; Free Radical Scavengers/metabolism/*therapeutic use ; Humans ; Risk ; Schizophrenia/diagnosis/*prevention &amp; control ; }, abstract = {Schizophrenia is a chronic and often severe psychotic disorder. Its causes include imbalances in mediators involved in neuroplasticity, apoptosis, cell resilience and dendritic arborization. Among these mediators, oxidative species are particularly relevant for the pathophysiology of the disease, and this is the rationale for experimental use of antioxidant medications, such as N-acetylcysteine (NAC). Onset of schizophrenia is usually preceded by a period of subtle and unspecific symptoms, the prodrome, in which preventive interventions could delay or even stop the progression to full-blown psychosis. In this article, we propose that NAC could be a useful medication to prevent evolution of schizophrenia in individuals at risk for psychosis.}, }
@article {pmid22944050, year = {2013}, author = {Lee, MF and Chan, CY and Hung, HC and Chou, IT and Yee, AS and Huang, CY}, title = {N-acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box-containing protein 1 (HBP1) signaling pathway in invasive oral cancer.}, journal = {Oral oncology}, volume = {49}, number = {2}, pages = {129-135}, doi = {10.1016/j.oraloncology.2012.08.003}, pmid = {22944050}, issn = {1879-0593}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Base Sequence ; Cell Cycle ; Cell Division/*drug effects ; DNA Primers ; ErbB Receptors/*metabolism ; Gene Knockdown Techniques ; High Mobility Group Proteins/genetics/*metabolism ; Humans ; Male ; Mice ; Mouth Neoplasms/metabolism/*pathology ; Neoplasm Invasiveness ; Proto-Oncogene Proteins c-akt/*metabolism ; Repressor Proteins/genetics/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*drug effects ; }, abstract = {OBJECTIVES: Overexpression of the epidermal growth factor (EGF) receptor (EGFR) gene in the squamous cell carcinomas of the head and neck (SCCHN) is often associated with inauspicious prognosis and poor survival. N-acetylcysteine (NAC), a compound from some vegetables and allium species, appears anti-tumorigenesis, but the underlying mechanism is unclear. The objective of this study is to investigate the role of NAC in EGFR-overexpressing oral cancer.<br><br>MATERIALS AND METHODS: Both HSC-3 and SCC-4 human tongue squamous carcinoma cell lines and an HSC-3 xenograft mouse model were used to test the anti-growth efficacy of NAC in vitro and in vivo, respectively.<br><br>RESULTS: NAC treatment suppressed cell growth, with concomitantly increased expression of HMG box-containing protein 1 (HBP1), a transcription suppressor, and decreased EGFR/Akt activation, in EGFR-overexpressing HSC-3 oral cancer cells. HBP1 knockdown attenuated the growth arrest and apoptosis induced by NAC. Lastly, NAC and AG1478, an EGFR inhibitor, additively suppressed colony formation in HSC-3 cells.<br><br>CONCLUSION: Taken together, our data indicate that NAC exerts its growth-inhibitory function through modulating EGFR/Akt signaling and HBP1 expression in EGFR-overexpressing oral cancer.}, }
@article {pmid22941945, year = {2013}, author = {Hadžić, N}, title = {Challenging the dogmas; the NAC tie.}, journal = {Hepatology (Baltimore, Md.)}, volume = {57}, number = {4}, pages = {1297-1300}, doi = {10.1002/hep.26044}, pmid = {22941945}, issn = {1527-3350}, mesh = {Acetylcysteine/*administration &amp; dosage/*therapeutic use ; Female ; Humans ; Liver Failure, Acute/*drug therapy/*mortality ; Male ; }, }
@article {pmid22940535, year = {2012}, author = {Cort, A and Ozdemir, E and Timur, M and Ozben, T}, title = {Effects of N-acetyl-L-cysteine on bleomycin induced oxidative stress in malignant testicular germ cell tumors.}, journal = {Biochimie}, volume = {94}, number = {12}, pages = {2734-2739}, doi = {10.1016/j.biochi.2012.08.015}, pmid = {22940535}, issn = {1638-6183}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/metabolism ; Bleomycin/*pharmacology ; Cell Line, Tumor ; Dinoprost/analogs &amp; derivatives/metabolism ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/*pharmacology ; Lipid Peroxides/metabolism ; Male ; Mutation ; Neoplasms, Germ Cell and Embryonal/genetics/metabolism/pathology ; Oxidants/pharmacology ; Oxidative Stress/*drug effects ; Protein Carbonylation/drug effects ; Testicular Neoplasms/genetics/metabolism/pathology ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Testicular cancer is a very common cancer in males aged 15-44 years. Bleomycin is used in chemotherapy regimens in the treatment of patients having testicular germ-cell tumor. Bleomycin generates oxygen radicals, induces oxidative cleavage of DNA strand and induces apoptosis in cancer cells. There is no study in the literature investigating effects of N-Acetyl-L-Cysteine (NAC) on bleomycin-induced oxidative stress in testicular germ cell tumors. For this reason, we studied effects of NAC on oxidative stress produced in wild-type NTera-2 and p53-mutant NCCIT testis cancer cells incubated with bleomycin and compared the results with H(2)O(2) which directly produces oxidative stress. We determined protein carbonyl content, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), 8-isoprostane, lipid hydroperoxide levels and total antioxidant capacity in both testicular cancer cells. Bleomycin and H(2)O(2) significantly increased 8-isoprostane, TBARS, protein carbonyl and lipid hydroperoxide levels in NTera-2 and NCCIT cells. Bleomycin and H(2)O(2) significantly decreased antioxidant capacity and GSH levels in both cell lines. Co-incubation with NAC significantly decreased lipid hydroperoxide, 8-isoprostane, protein carbonyl content and TBARS levels increased by bleomycin and H(2)O(2). NAC enhanced GSH levels and antioxidant capacity in the NTera-2 and NCCIT cells. It can be concluded that NAC diminishes oxidative stress in human testicular cancer cells induced by bleomycin and H(2)O(2).}, }
@article {pmid22940466, year = {2013}, author = {Chairuangkitti, P and Lawanprasert, S and Roytrakul, S and Aueviriyavit, S and Phummiratch, D and Kulthong, K and Chanvorachote, P and Maniratanachote, R}, title = {Silver nanoparticles induce toxicity in A549 cells via ROS-dependent and ROS-independent pathways.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {27}, number = {1}, pages = {330-338}, doi = {10.1016/j.tiv.2012.08.021}, pmid = {22940466}, issn = {1879-3177}, mesh = {Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/*toxicity ; Proliferating Cell Nuclear Antigen/metabolism ; Reactive Oxygen Species/metabolism ; Silver/*toxicity ; }, abstract = {Silver nanoparticles (AgNPs) are incorporated into a large number of consumer and medical products. Several experiments have demonstrated that AgNPs can be toxic to the vital organs of humans and especially to the lung. The present study evaluated the in vitro mechanisms of AgNP (<100 nm) toxicity in relationship to the generation of reactive oxygen species (ROS) in A549 cells. AgNPs caused ROS formation in the cells, a reduction in their cell viability and mitochondrial membrane potential (MMP), an increase in the proportion of cells in the sub-G1 (apoptosis) population, S phase arrest and down-regulation of the cell cycle associated proliferating cell nuclear antigen (PCNA) protein, in a concentration- and time-dependent manner. Pretreatment of the A549 cells with N-acetyl-cysteine (NAC), an antioxidant, decreased the effects of AgNPs on the reduced cell viability, change in the MMP and proportion of cells in the sub-G1population, but had no effect on the AgNP-mediated S phase arrest or down-regulation of PCNA. These observations allow us to propose that the in vitro toxic effects of AgNPs on A549 cells are mediated via both ROS-dependent (cytotoxicity) and ROS-independent (cell cycle arrest) pathways.}, }
@article {pmid22940465, year = {2013}, author = {Usta, J and Hachem, Y and El-Rifai, O and Bou-Moughlabey, Y and Echtay, K and Griffiths, D and Nakkash-Chmaisse, H and Makki, RF}, title = {Fragrance chemicals lyral and lilial decrease viability of HaCat cells' by increasing free radical production and lowering intracellular ATP level: protection by antioxidants.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {27}, number = {1}, pages = {339-348}, doi = {10.1016/j.tiv.2012.08.020}, pmid = {22940465}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Aldehydes/*toxicity ; Animals ; Antioxidants/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Chromans/pharmacology ; Cyclohexenes/*toxicity ; Electron Transport Chain Complex Proteins/metabolism ; Glutathione/metabolism ; Humans ; L-Lactate Dehydrogenase/metabolism ; Mice ; Mitochondrial Membranes/drug effects/metabolism ; NIH 3T3 Cells ; *Perfume ; Reactive Oxygen Species/metabolism ; Thioctic Acid/pharmacology ; }, abstract = {We investigate in this study the biochemical effects on cells in culture of two commonly used fragrance chemicals: lyral and lilial. Whereas both chemicals exerted a significant effect on primary keratinocyte(s), HaCat cells, no effect was obtained with any of HepG2, Hek293, Caco2, NIH3T3, and MCF7 cells. Lyral and lilial: (a) decreased the viability of HaCat cells with a 50% cell death at 100 and 60 nM respectively; (b) decreased significantly in a dose dependant manner the intracellular ATP level following 12-h of treatment; (c) inhibited complexes I and II of electron transport chain in liver sub-mitochondrial particles; and (d) increased reactive oxygen species generation that was reversed by N-acetyl cysteine and trolox and the natural antioxidant lipoic acid, without influencing the level of free and/or oxidized glutathione. Lipoic acid protected HaCat cells against the decrease in viability induced by either compound. Dehydrogenation of lyral and lilial produce α,β-unsaturated aldehydes, that reacts with lipoic acid requiring proteins resulting in their inhibition. We propose lyral and lilial as toxic to mitochondria that have a direct effect on electron transport chain, increase ROS production, derange mitochondrial membrane potential, and decrease cellular ATP level, leading thus to cell death.}, }
@article {pmid22939972, year = {2012}, author = {Kurdi, M and Sivakumaran, V and Duhé, RJ and Aon, MA and Paolocci, N and Booz, GW}, title = {Depletion of cellular glutathione modulates LIF-induced JAK1-STAT3 signaling in cardiac myocytes.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {44}, number = {12}, pages = {2106-2115}, pmid = {22939972}, issn = {1878-5875}, support = {R56 DK082781/DK/NIDDK NIH HHS/United States ; R01 HL091923/HL/NHLBI NIH HHS/United States ; T32HL007227/HL/NHLBI NIH HHS/United States ; 1R56DK082781-01/DK/NIDDK NIH HHS/United States ; R01 HL088101/HL/NHLBI NIH HHS/United States ; T32 HL007227/HL/NHLBI NIH HHS/United States ; R01HL091923-01/HL/NHLBI NIH HHS/United States ; R01HL088101-06/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism/physiology ; Janus Kinase 1/*metabolism ; Leukemia Inhibitory Factor/*metabolism/physiology ; MAP Kinase Signaling System ; Male ; Mice ; Mice, Inbred C57BL ; Myocytes, Cardiac/drug effects/*metabolism ; Oxidative Stress ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; STAT1 Transcription Factor/metabolism ; STAT3 Transcription Factor/*metabolism ; }, abstract = {Previously we reported that the sesquiterpene lactone parthenolide induces oxidative stress in cardiac myocytes, which blocks Janus kinase (JAK) activation by the interleukin 6 (IL-6)-type cytokines. One implication suggested by this finding is that IL-6 signaling is dependent upon cellular anti-oxidant defenses or redox status. Therefore, the present study was undertaken to directly test the hypothesis that JAK1 signaling by the IL-6-type cytokines in cardiac myocytes is impaired by glutathione (GSH) depletion, since this tripeptide is one of the major anti-oxidant molecules and redox-buffers in cells. Cardiac myocytes were pretreated for 6h with l-buthionine-sulfoximine (BSO) to inhibit GSH synthesis. After 24h, cells were dosed with the IL-6-like cytokine, leukemia inhibitory factor (LIF). BSO treatment decreased GSH levels and dose-dependently attenuated activation of JAK1, Signal Transducer and Activator of Transcription 3 (STAT3), and extracellular signal regulated kinases 1 and 2 (ERK1/2). Addition of glutathione monoethyl ester, which is cleaved intracellularly to GSH, prevented attenuation of LIF-induced JAK1 and STAT3 activation, as did the reductant N-acetyl-cysteine. Unexpectedly, LIF-induced STAT1 activation was unaffected by GSH depletion. Evidence was found that STAT3 is more resistant than STAT1 to intermolecular disulfide bond formation under oxidizing conditions and more likely to retain the monomeric form, suggesting that conformational differences explain the differential effect of GSH depletion on STAT1 and STAT3. Overall, our findings indicate that activation of both JAK1 and STAT3 is redox-sensitive and the character of IL-6 type cytokine signaling in cardiac myocytes is sensitive to changes in the cellular redox status. In cardiac myocytes, activation of STAT1 may be favored over STAT3 under oxidizing conditions due to GSH depletion and/or augmented reactive oxygen species production, such as in ischemia-reperfusion and heart failure.}, }
@article {pmid22939515, year = {2013}, author = {Ma, H and Zheng, L and Li, Y and Pan, S and Hu, J and Yu, Z and Zhang, G and Sheng, G and Fu, J}, title = {Triclosan reduces the levels of global DNA methylation in HepG2 cells.}, journal = {Chemosphere}, volume = {90}, number = {3}, pages = {1023-1029}, doi = {10.1016/j.chemosphere.2012.07.063}, pmid = {22939515}, issn = {1879-1298}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Anti-Infective Agents, Local/*pharmacology ; DNA/genetics/metabolism ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/antagonists &amp; inhibitors/metabolism ; DNA Methylation/*drug effects ; DNA-Binding Proteins/genetics ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Down-Regulation/drug effects ; Hep G2 Cells/*drug effects/metabolism ; Humans ; Methyl-CpG-Binding Protein 2/genetics ; Triclosan/*pharmacology ; }, abstract = {Triclosan (TCS), an antibacterial agent, is widely used in a variety of personal care and industrial products. TCS is associated with the development of liver tumors in rodents and has become a concern to environmental and human health. This study is aimed at investigating whether TCS could modulate the levels of global DNA methylation (GDM) in human hepatocytes. We found that treatment with different doses (1.25-10 μM) of TCS did not affect HepG2 cell viability, but significantly reduced the levels of GDM in HepG2 cells, and inhibited DNMT1 activity. Furthermore, treatment with TCS significantly inhibited the methylated DNA-binding domain 2 (MBD2), MBD3, and MeCP2 mRNA transcription. In addition, treatment with TCS promoted the accumulation of 8-hydroxy-2-deoxyguanosine (8-OHdG) in a dose-dependent manner, which was abrogated by treatment with an antioxidant, N-acetylcysteine (NAC). Collectively, our data indicated that TCS reduced the levels of GDM and down-regulated the MBD2, MBD3, and MeCP2 gene expression by increasing 8-OHdG levels and inhibiting the DNMT1 activity in HepG2 cells.}, }
@article {pmid22937109, year = {2012}, author = {Duguez, S and Duddy, WJ and Gnocchi, V and Bowe, J and Dadgar, S and Partridge, TA}, title = {Atmospheric oxygen tension slows myoblast proliferation via mitochondrial activation.}, journal = {PloS one}, volume = {7}, number = {8}, pages = {e43853}, pmid = {22937109}, issn = {1932-6203}, support = {U54 HD053177/HD/NICHD NIH HHS/United States ; U54HD053177/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; *Cell Proliferation ; Cells, Cultured ; Hyperoxia/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/*metabolism ; MyoD Protein/metabolism ; Myoblasts, Skeletal/cytology/*metabolism ; PAX7 Transcription Factor/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {BACKGROUND: Mitochondrial activity inhibits proliferation and is required for differentiation of myoblasts. Myoblast proliferation is also inhibited by the ~20% oxygen level used in standard tissue culture. We hypothesize that mitochondrial activity would be greater at hyperoxia (20% O(2)) relative to more physiological oxygen (5% O(2)).<br><br>Murine primary myoblasts from isolated myofibres and conditionally immortalized H-2K myoblasts were cultured at 5% and 20% oxygen. Proliferation, assayed by cell counts, EdU labeling, and CFSE dilution, was slower at 20% oxygen. Expression of MyoD in primary myoblasts was delayed at 20% oxygen, but myogenicity, as measured by fusion index, was slightly higher. FACS-based measurement of mitochondrial activity indicators and luminometric measurement of ATP levels revealed that mitochondria exhibited greater membrane potential and higher levels of Reactive Oxygen Species (ROS) at 20% oxygen with concomitant elevation of intracellular ATP. Mitochondrial mass was unaffected. Low concentrations of CCCP, a respiratory chain uncoupler, and Oligomycin A, an ATP synthase inhibitor, each increased the rate of myoblast proliferation. ROS were investigated as a potential mechanism of mitochondrial retrograde signaling, but scavenging of ROS levels by N-acetyl-cysteine (NAC) or &#x3b1;-Phenyl-N-tert-butylnitrone (PBN) did not rescue the suppressed rate of cell division in hyperoxic conditions, suggesting other pathways. Primary myoblasts from older mice showed a slower proliferation than those from younger adult mice at 20% oxygen but no difference at 5% oxygen.<br><br>CONCLUSIONS/SIGNIFICANCE: These results implicate mitochondrial regulation as a mechanistic explanation for myoblast response to oxygen tension. The rescue of proliferation rate in myoblasts of aged mice by 5% oxygen suggests a major artefactual component to age-related decline of satellite cell proliferation in standard tissue culture at 20% oxygen. It lends weight to the idea that these age-related changes result at least in part from environmental factors rather than characteristics intrinsic to the satellite cell.}, }
@article {pmid22936379, year = {2012}, author = {Xiong, L and Sun, J and Hirche, C and Yang, J and Yang, Y and Xia, Y and Lehnhardt, M and Wang, R and Fu, X}, title = {In vitro N-acetyl-L-cysteine promotes proliferation and suppresses interleukin-8 expression in adipose-derived stem cells.}, journal = {Aesthetic plastic surgery}, volume = {36}, number = {5}, pages = {1260-1265}, doi = {10.1007/s00266-012-9960-8}, pmid = {22936379}, issn = {1432-5241}, mesh = {Acetylcysteine/*pharmacology ; Adipose Tissue/*cytology ; Cell Proliferation/*drug effects ; Cells, Cultured ; Female ; Humans ; Interleukin-8/*antagonists &amp; inhibitors ; Stem Cells/*cytology/*drug effects ; }, abstract = {UNLABELLED: Adipose-derived stem cells (ADSCs) hold great promise for repair and regeneration of burn wounds by producing growth factors, but proinflammatory cytokines such as interleukin-8 (IL-8) released by ADSCs would potentially deepen the wound and inhibit healing. The reported research aimed to identify the effects of N-acetyl-L-cysteine (NAC) on the proliferation, death, and IL-8 production of ADSCs. In the presence or absence of NAC, ADSC proliferation was examined using a CCK-8 Kit, and cell death was evaluated by flow cytometry analysis. Subsequently, IL-8 mRNA expression was detected by reverse transcriptase-polymerase chain reaction and protein production by enzyme-linked immunoassay. Findings showed that cell proliferation in the NAC-treated group was a significant 1.53-fold greater than in the control group, that the apoptosis rate of ADSCs decreased by 55.4 % compared with the control group, and that the necrosis rate decreased by 48.8 %. Additionally, the IL-8 mRNA expression decreased to 46.2 ± 8.7 % that of the control group, and the IL-8 protein production decreased to 9.98 ± 0.57 %. The authors believe that NAC might be helpful in burn wound repair and regeneration by stimulating the proliferation of ADSCs, inhibiting cell death, and suppressing IL-8 production.<br><br>LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article.}, }
@article {pmid22935961, year = {2012}, author = {Fu, D and Wu, M and Zhang, J and Du, M and Yang, S and Hammad, SM and Wilson, K and Chen, J and Lyons, TJ}, title = {Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy.}, journal = {Diabetologia}, volume = {55}, number = {11}, pages = {3128-3140}, pmid = {22935961}, issn = {1432-0428}, support = {P20 GM104934/GM/NIGMS NIH HHS/United States ; P20 RR024215/RR/NCRR NIH HHS/United States ; P20 RR 024215/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacokinetics ; Activating Transcription Factor 6/metabolism ; Apolipoproteins B/metabolism ; Apoptosis/physiology ; Autophagy/physiology ; Butylamines/pharmacokinetics ; Cell Survival/physiology ; Cells, Cultured ; Cyclosporine/pharmacokinetics ; Diabetic Retinopathy/*metabolism/*pathology ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/physiology ; Enzyme Inhibitors/pharmacokinetics ; Glycosylation ; Heat-Shock Proteins/metabolism ; Humans ; Lipid Peroxidation/physiology ; Lipoproteins, LDL/*metabolism ; Mitochondria/metabolism/pathology ; Oxidative Stress/physiology ; Pericytes/metabolism/*pathology ; Poly I/pharmacokinetics ; Retina/metabolism/pathology ; Retinal Vessels/metabolism/*pathology ; }, abstract = {AIMS/HYPOTHESIS: In previous studies we have shown that extravasated, modified LDL is associated with pericyte loss, an early feature of diabetic retinopathy (DR). Here we sought to determine detailed mechanisms of this LDL-induced pericyte loss.<br><br>METHODS: Human retinal capillary pericytes (HRCP) were exposed to 'highly-oxidised glycated' LDL (HOG-LDL) (a model of extravasated and modified LDL) and to 4-hydroxynonenal or 7-ketocholesterol (components of oxidised LDL), or to native LDL for 1 to 24 h with or without 1 h of pretreatment with inhibitors of the following: (1) the scavenger receptor (polyinosinic acid); (2) oxidative stress (N-acetyl cysteine); (3) endoplasmic reticulum (ER) stress (4-phenyl butyric acid); and (4) mitochondrial dysfunction (cyclosporin A). Oxidative stress, ER stress, mitochondrial dysfunction, apoptosis and autophagy were assessed using techniques including western blotting, immunofluorescence, RT-PCR, flow cytometry and TUNEL assay. To assess the relevance of the results in vivo, immunohistochemistry was used to detect the ER stress chaperon, 78 kDa glucose-regulated protein, and the ER sensor, activating transcription factor 6, in retinas from a mouse model of DR that mimics exposure of the retina to elevated glucose and elevated LDL levels, and in retinas from human participants with and without diabetes and DR.<br><br>RESULTS: Compared with native LDL, HOG-LDL activated oxidative and ER stress in HRCP, resulting in mitochondrial dysfunction, apoptosis and autophagy. In a mouse model of diabetes and hyperlipidaemia (vs mouse models of either condition alone), retinal ER stress was enhanced. ER stress was also enhanced in diabetic human retina and correlated with the severity of DR.<br><br>CONCLUSIONS/INTERPRETATION: Cell culture, animal, and human data suggest that oxidative stress and ER stress are induced by modified LDL, and are implicated in pericyte loss in DR.}, }
@article {pmid22935960, year = {2012}, author = {Treweeke, AT and Winterburn, TJ and Mackenzie, I and Barrett, F and Barr, C and Rushworth, GF and Dransfield, I and MacRury, SM and Megson, IL}, title = {N-Acetylcysteine inhibits platelet-monocyte conjugation in patients with type 2 diabetes with depleted intraplatelet glutathione: a randomised controlled trial.}, journal = {Diabetologia}, volume = {55}, number = {11}, pages = {2920-2928}, pmid = {22935960}, issn = {1432-0428}, support = {G0901697/MRC_/Medical Research Council/United Kingdom ; CZB/4/622/CSO_/Chief Scientist Office/United Kingdom ; }, mesh = {Acetylcysteine/*administration &amp; dosage/blood ; Administration, Oral ; Aged ; Blood Platelets/cytology/*drug effects/immunology ; Cardiovascular Diseases/prevention &amp; control ; Cell Communication/*drug effects ; Cell-Derived Microparticles/drug effects ; Cross-Over Studies ; Diabetes Mellitus, Type 2/*drug therapy/immunology/metabolism ; Female ; Free Radical Scavengers/administration &amp; dosage/blood ; Glutathione/*metabolism ; Humans ; Hypoglycemic Agents/administration &amp; dosage ; Male ; Middle Aged ; Monocytes/cytology/*drug effects/immunology ; Placebos ; }, abstract = {AIMS/HYPOTHESIS: The aim of this study was to determine whether oral dosing with N-acetylcysteine (NAC) increases intraplatelet levels of the antioxidant, glutathione (GSH), and reduces platelet-monocyte conjugation in blood from patients with type 2 diabetes.<br><br>METHODS: In this placebo-controlled randomised crossover study, the effect of oral NAC dosing on platelet-monocyte conjugation and intraplatelet GSH was investigated in patients with type 2 diabetes (eligibility criteria: men or post-menopausal women with well-controlled diabetes (HbA(1c) < 10%), not on aspirin or statins). Patients (n = 14; age range 43-79 years, HbA(1c) = 6.9 &#xb1; 0.9% [52.3 &#xb1; 10.3 mmol/mol]) visited the Highland Clinical Research Facility, Inverness, UK on day 0 and day 7 for each arm of the study. Blood was sampled before and 2 h after oral administration of placebo or NAC (1,200 mg) on day 0 and day 7. Patients received placebo or NAC capsules for once-daily dosing on the intervening days. The order of administration of NAC and placebo was allocated by a central office and all patients and research staff involved in the study were blinded to the allocation until after the study was complete and the data fully analysed. The primary outcome for the study was platelet-monocyte conjugation.<br><br>RESULTS: Oral NAC reduced platelet-monocyte conjugation (from 53.1 &#xb1; 4.5% to 42.5 &#xb1; 3.9%) at 2 h after administration and the effect was maintained after 7 days of dosing. Intraplatelet GSH was raised in individuals with depleted GSH and there was a negative correlation between baseline intraplatelet GSH and platelet-monocyte conjugation. There were no adverse events.<br><br>CONCLUSIONS/INTERPRETATION: The NAC-induced normalisation of intraplatelet GSH, coupled with a reduction in platelet-monocyte conjugation, suggests that NAC might help to reduce atherothrombotic risk in type 2 diabetes.<br><br>FUNDING: Chief Scientist Office (CZB/4/622), Scottish Funding Council, Highlands &amp; Islands Enterprise and European Regional Development Fund.<br><br>TRIAL REGISTRATION: isrctn.org ISRCTN89304265.}, }
@article {pmid22932184, year = {2012}, author = {Yang, XH and Liu, HG and Liu, X and Chen, JN}, title = {Thioredoxin and impaired spatial learning and memory in the rats exposed to intermittent hypoxia.}, journal = {Chinese medical journal}, volume = {125}, number = {17}, pages = {3074-3080}, pmid = {22932184}, issn = {2542-5641}, mesh = {Animals ; Apoptosis ; Hippocampus/pathology ; Hypoxia/*complications ; Learning Disabilities/*etiology ; Male ; Maze Learning ; Memory Disorders/*etiology ; Rats ; Rats, Sprague-Dawley ; Sleep Apnea, Obstructive/*complications ; Thioredoxins/*physiology ; }, abstract = {BACKGROUND: Obstructive sleep apnea (OSA) can cause cognitive dysfunction and may be a reversible cause of cognitive loss in patients with Alzheimer's disease (AD). Chronic exposure to intermittent hypoxia (IH), such as encountered in OSA, is marked by neurodegenerative changes in rat brain. We investigated the change of thioredoxin (Trx), spatial learning and memory in rats exposed to chronic intermittent hypoxia (CIH).<br><br>METHODS: Forty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups of ten each: a CIH+normal saline (CIH+NS group), a N-acetylcystein-treated CIH (CIH+NAC) group, a sham CIH group (sham CIH+NS), and a sham NAC-treated sham CIH (CIH+NAC) group. Spatial learning and memory in each group was assessed with the Morris water maze. Real-time PCR and Western blotting were used to examine mRNA and protein expression of Trx in the hippocampus tissue. The terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling (TUNEL) method was used to detect the apoptotic cells of the hippocampus CA1 region.<br><br>RESULTS: CIH-rats showed impaired spatial learning and memory in the Morris water maze, including longer mean latencies for the target platform, reduced numbers of passes over the previous target platform and a smaller percentage of time spent in the target quadrant. Trx mRNA and protein levels were significantly decreased in the CIH-hippocampus, meanwhile, an elevated apoptotic index revealed apoptosis of hippocampal neurons of rats exposed to CIH. The rats, which acted better in the Morris water maze, showed higher levels of the Trx mRNA and protein in the hippocampus; apoptotic index of the neurons in the hippocampus of each group was negatively correlated with the Trx mRNA and protein levels.<br><br>CONCLUSION: The Trx deficit likely plays an important role in the impaired spatial learning and memory in the rats exposed to CIH and may work through the apoptosis of neurons in the hippocampus.}, }
@article {pmid22931549, year = {2012}, author = {Wang, T and Wang, L and Moreno-Vinasco, L and Lang, GD and Siegler, JH and Mathew, B and Usatyuk, PV and Samet, JM and Geyh, AS and Breysse, PN and Natarajan, V and Garcia, JG}, title = {Particulate matter air pollution disrupts endothelial cell barrier via calpain-mediated tight junction protein degradation.}, journal = {Particle and fibre toxicology}, volume = {9}, number = {}, pages = {35}, pmid = {22931549}, issn = {1743-8977}, support = {NIH HL058064/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/*toxicity ; Calcium/metabolism ; Calpain/*metabolism ; Cells, Cultured ; Electric Impedance ; Endothelium, Vascular/*drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Humans ; Lung/cytology ; Oxidative Stress/drug effects ; Particulate Matter/*toxicity ; Permeability ; Reactive Oxygen Species/metabolism ; TRPM Cation Channels/*metabolism ; Zonula Occludens-1 Protein/*metabolism ; }, abstract = {BACKGROUND: Exposure to particulate matter (PM) is a significant risk factor for increased cardiopulmonary morbidity and mortality. The mechanism of PM-mediated pathophysiology remains unknown. However, PM is proinflammatory to the endothelium and increases vascular permeability in vitro and in vivo via ROS generation.<br><br>OBJECTIVES: We explored the role of tight junction proteins as targets for PM-induced loss of lung endothelial cell (EC) barrier integrity and enhanced cardiopulmonary dysfunction.<br><br>METHODS: Changes in human lung EC monolayer permeability were assessed by Transendothelial Electrical Resistance (TER) in response to PM challenge (collected from Ft. McHenry Tunnel, Baltimore, MD, particle size >0.1 &#x3bc;m). Biochemical assessment of ROS generation and Ca2+ mobilization were also measured.<br><br>RESULTS: PM exposure induced tight junction protein Zona occludens-1 (ZO-1) relocation from the cell periphery, which was accompanied by significant reductions in ZO-1 protein levels but not in adherens junction proteins (VE-cadherin and &#x3b2;-catenin). N-acetyl-cysteine (NAC, 5 mM) reduced PM-induced ROS generation in ECs, which further prevented TER decreases and atteneuated ZO-1 degradation. PM also mediated intracellular calcium mobilization via the transient receptor potential cation channel M2 (TRPM2), in a ROS-dependent manner with subsequent activation of the Ca2+-dependent protease calpain. PM-activated calpain is responsible for ZO-1 degradation and EC barrier disruption. Overexpression of ZO-1 attenuated PM-induced endothelial barrier disruption and vascular hyperpermeability in vivo and in vitro.<br><br>CONCLUSIONS: These results demonstrate that PM induces marked increases in vascular permeability via ROS-mediated calcium leakage via activated TRPM2, and via ZO-1 degradation by activated calpain. These findings support a novel mechanism for PM-induced lung damage and adverse cardiovascular outcomes.}, }
@article {pmid22927544, year = {2012}, author = {Goehe, RW and Di, X and Sharma, K and Bristol, ML and Henderson, SC and Valerie, K and Rodier, F and Davalos, AR and Gewirtz, DA}, title = {The autophagy-senescence connection in chemotherapy: must tumor cells (self) eat before they sleep?.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {343}, number = {3}, pages = {763-778}, pmid = {22927544}, issn = {1521-0103}, support = {P30 NS047463/NS/NINDS NIH HHS/United States ; T32CA113277-04/CA/NCI NIH HHS/United States ; R01 NS064593/NS/NINDS NIH HHS/United States ; R21-CA156995/CA/NCI NIH HHS/United States ; R21 CA156995/CA/NCI NIH HHS/United States ; R01-NS064593/NS/NINDS NIH HHS/United States ; P30 CA016059/CA/NCI NIH HHS/United States ; 5P30NS047463/NS/NINDS NIH HHS/United States ; T32 CA113277/CA/NCI NIH HHS/United States ; P30CA16059/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Autophagy/*drug effects/genetics ; Blotting, Western ; Camptothecin/*pharmacology ; Cell Culture Techniques ; Cellular Senescence/*drug effects/genetics ; *DNA Damage ; Doxorubicin/*pharmacology ; Flow Cytometry ; HCT116 Cells ; Humans ; MCF-7 Cells ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Reactive Oxygen Species/metabolism ; }, abstract = {Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) or camptothecin results in both autophagy and senescence. To determine whether autophagy is required for chemotherapy-induced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ataxia telangiectasia mutated, p53, and p21 was modulated pharmacologically and/or genetically. In all cases, autophagy and senescence were collaterally suppressed. The close association between autophagy and senescence indicated by these experiments reflects their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further examined through pharmacologic inhibition of autophagy with chloroquine and 3-methyl-adenine and genetic ablation of the autophagy-related genes ATG5 and ATG7. However, inhibition of autophagy by pharmacological and genetic approaches could not entirely abrogate the senescence response, which was only reduced and/or delayed. Taken together, our findings suggest that autophagy and senescence tend to occur in parallel, and furthermore that autophagy accelerates the development of the senescent phenotype. However, these responses are not inexorably linked or interdependent, as senescence can occur when autophagy is abrogated.}, }
@article {pmid22926926, year = {2012}, author = {Choi, JH and Lee, JY and Choi, AY and Hwang, KY and Choe, W and Yoon, KS and Ha, J and Yeo, EJ and Kang, I}, title = {Apicidin induces endoplasmic reticulum stress- and mitochondrial dysfunction-associated apoptosis via phospholipase Cγ1- and Ca(2+)-dependent pathway in mouse Neuro-2a neuroblastoma cells.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {17}, number = {12}, pages = {1340-1358}, doi = {10.1007/s10495-012-0755-9}, pmid = {22926926}, issn = {1573-675X}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Calcium/*metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Mice ; Mitochondria/drug effects/*metabolism ; Neuroblastoma/drug therapy/*metabolism/physiopathology ; Peptides, Cyclic/*pharmacology ; Phospholipase C gamma/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Transcription Factor CHOP/genetics/metabolism ; }, abstract = {Apicidin, a fungal metabolite that functions as a histone deacetylase inhibitor, induces apoptosis in cancer cells. We investigated the molecular mechanisms of the anti-cancer effects of apicidin in mouse Neuro-2a neuroblastoma cells. Apicidin induced apoptotic cell death and activation of caspase-12, -9, and -3. Apicidin induced expression of endoplasmic reticulum (ER) stress-associated proteins, including CCAAT/enhancer binding protein homologous protein (CHOP), cleavage of activating transcription factor 6α, and phosphorylation of eukaryotic initiation factor 2α. Inhibition of ER stress by CHOP knockdown or using the ER stress inhibitors, salubrinal and 4-phenylbutyric acid, reduced apicidin-induced cell death. Apicidin induced reactive oxygen species accumulation and mitochondrial membrane potential loss. An antioxidant, N-acetyl cysteine, reduced apicidin-induced cell death, CHOP expression, and mitochondrial dysfunction. In addition, apicidin increased cytosolic Ca(2+), which was blocked by 2-aminoethoxydiphenyl borate, an antagonist of inositol 1,4,5-trisphosphate receptor, and BAPTA-AM, an intracellular Ca(2+) chelator. 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited apicidin-induced cell death and ER stress. Interestingly, apicidin induced phosphorylation of phospholipase Cγ1 (PLCγ1) and epidermal growth factor receptor (EGFR), and inhibition of PLCγ1 and EGFR reduced cell death and ER stress. Finally, apicidin-induced histone H3 hyperacetylation and reduction of histone deacetylase 2 mRNA expression were not affected by either a PLCγ1 inhibitor, U73122, or the antioxidant, N-acetyl cysteine. Taken together, the results suggest that apicidin induces apoptosis by ER stress and mitochondrial dysfunction via PLCγ1 activation, Ca(2+) release, and reactive oxygen species accumulation in Neuro-2a neuroblastoma cells.}, }
@article {pmid22925602, year = {2012}, author = {Toyooka, T and Shinmen, T and Aarts, JM and Ibuki, Y}, title = {Dual effects of N-acetyl-L-cysteine dependent on NQO1 activity: suppressive or promotive of 9,10-phenanthrenequinone-induced toxicity.}, journal = {Toxicology and applied pharmacology}, volume = {264}, number = {3}, pages = {404-412}, doi = {10.1016/j.taap.2012.08.017}, pmid = {22925602}, issn = {1096-0333}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Cricetinae ; Fibroblasts/*drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Gene Knockdown Techniques ; Humans ; Keratinocytes/*drug effects/metabolism ; NAD(P)H Dehydrogenase (Quinone)/*metabolism ; Phenanthrenes/*toxicity ; }, abstract = {A typical antioxidant, N-acetyl-L-cysteine (NAC) generally protects cells from oxidative damage induced by reactive oxygen species (ROS). 9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, produces ROS in redox cycling following two-electron reduction by NAD(P)H:quinone oxidoreductase 1 (NQO1), which has been considered as a cause of its cyto- and genotoxicity. In this study, we show that NAC unexpectedly augments the toxicity of 9,10-PQ in cells with low NQO1 activity. In four human skin cell lines, the expression and the activity of NQO1 were lower than in human adenocarcinoma cell lines, A549 and MCF7. In the skin cells, the cytotoxicity of 9,10-PQ was significantly enhanced by addition of NAC. The formation of DNA double strand breaks accompanying phosphorylation of histone H2AX, was also remarkably augmented. On the other hand, the cyto- and genotoxicity were suppressed by addition of NAC in the adenocarcinoma cells. Two contrasting experiments: overexpression of NQO1 in CHO-K1 cells which originally expressed low NQO1 levels, and knock-down of NQO1 in the adenocarcinoma cell line A549 by transfection of RNAi, also showed that NAC suppressed 9,10-PQ-induced toxicity in cell lines expressing high NQO1 activity and enhanced it in cell lines with low NQO1 activity. The results suggested that dual effects of NAC on the cyto- and genotoxicity of 9,10-PQ were dependent on tissue-specific NQO1 activity.}, }
@article {pmid22923417, year = {2013}, author = {Al-Hasan, YM and Evans, LC and Pinkas, GA and Dabkowski, ER and Stanley, WC and Thompson, LP}, title = {Chronic hypoxia impairs cytochrome oxidase activity via oxidative stress in selected fetal Guinea pig organs.}, journal = {Reproductive sciences (Thousand Oaks, Calif.)}, volume = {20}, number = {3}, pages = {299-307}, pmid = {22923417}, issn = {1933-7205}, support = {R01 HL049999/HL/NHLBI NIH HHS/United States ; T32 HL072757/HL/NHLBI NIH HHS/United States ; R01HL 49999/HL/NHLBI NIH HHS/United States ; T32-HL072757/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Chronic Disease ; Electron Transport Complex IV/*metabolism ; Enzyme Activation/physiology ; Female ; Fetal Heart/embryology/*enzymology ; Guinea Pigs ; Hypoxia/*enzymology ; Liver/embryology/*enzymology ; Lung/embryology/*enzymology ; Oxidative Stress/*physiology ; Pregnancy ; Saccharomyces cerevisiae Proteins/*metabolism ; }, abstract = {We hypothesized that chronic hypoxia disrupts mitochondrial function via oxidative stress in fetal organs. Pregnant guinea pig sows were exposed to either normoxia or hypoxia (10.5% O2, 14 days) in the presence or absence of the antioxidant, N-acetylcysteine (NAC). Near-term anesthetized fetuses were delivered via hysterotomy, and fetal livers, hearts, lungs, and forebrains harvested. We quantified the effects of chronic hypoxia on cytochrome oxidase (CCO) activity and 2 factors known to regulate CCO activity: malondialdehyde (MDA) and CCO subunit 4 (COX4). Hypoxia increased the MDA levels in fetal liver, heart, and lung with a corresponding reduction in CCO activity, prevented by prenatal NAC. The COX4 expression paralleled CCO activity in fetal liver and lung, but was unaltered in fetal hearts due to hypoxia. Hypoxia reduced the brain COX4 expression despite having no effect on CCO activity. This study identifies the mitochondrion as an important target site in tissue-specific oxidative stress for the induction of fetal hypoxic injury.}, }
@article {pmid22923157, year = {2012}, author = {Giampietri, C and Petrungaro, S and Padula, F and D'Alessio, A and Marini, ES and Facchiano, A and Filippini, A and Ziparo, E}, title = {Autophagy modulators sensitize prostate epithelial cancer cell lines to TNF-alpha-dependent apoptosis.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {17}, number = {11}, pages = {1210-1222}, doi = {10.1007/s10495-012-0752-z}, pmid = {22923157}, issn = {1573-675X}, mesh = {Adenine/analogs &amp; derivatives ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Blotting, Western ; CASP8 and FADD-Like Apoptosis Regulating Protein/genetics/metabolism ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Enzyme Activation/drug effects ; Epithelial Cells/drug effects/metabolism/*pathology ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/metabolism ; Humans ; Male ; Microtubule-Associated Proteins/metabolism ; Promoter Regions, Genetic/genetics ; Prostatic Neoplasms/enzymology/*pathology ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors/pharmacology ; Proteolysis/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Sirolimus/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {TNF-alpha levels in prostate cancer correlate with the extent of disease and are significantly elevated in the metastatic stage. TNF receptor superfamily controls two distinct signalling cascades, leading to opposite effects, i.e. apoptosis and survival; in prostate cancer TNF-alpha-mediated signalling induces cell survival and resistance to therapy. The apoptosis of prostate epithelial cancer cells LNCaP and PC3 was investigated upon treatment with the autophagy inhibitor 3-methyladenine and the autophagy inducer rapamycin, in combination with TNF-alpha. Cells were exposed to these molecules for 18, 24 and 48 h. Autophagy was assessed via LC3 Western blot analysis; propidium iodide and TUNEL stainings followed by flow cytometry or caspase-8 and caspase-3 activation assays were performed to evaluate apoptosis. TNF-alpha-induced apoptosis was potentiated by 3-methyladenine in the androgen-responsive LNCaP cells, whereas no effect was observed in the androgen-insensitive PC3 cells. Interestingly such pro-apoptosis effect in LNCaP cells was associated with reduced c-Flip levels through proteasomal degradation via increased reactive oxygen species production and p38 activation; such c-Flip reduction was reversed in the presence of either the proteasome inhibitor MG132 or the reactive oxygen species scavenger N-acetyl-cysteine. Conversely in PC3 but not in LNCaP cells, rapamycin stimulated TNF-alpha-dependent apoptosis; such effect was associated with reduced c-Flip promoter activity and FoxO3a activation. We conclude that TNF-alpha-induced apoptosis may be potentiated, in prostate cancer epithelial cells, through autophagy modulators. Increased sensitivity to TNF-alpha-dependent apoptosis correlates with reduced c-Flip levels which are consequent to a post-transcriptional and a transcriptional mechanism in LNCaP and PC3 cells respectively.}, }
@article {pmid22923154, year = {2012}, author = {Kim, HJ and Han, MH and Kim, GY and Choi, YW and Choi, YH}, title = {Hexane extracts of garlic cloves induce apoptosis through the generation of reactive oxygen species in Hep3B human hepatocarcinoma cells.}, journal = {Oncology reports}, volume = {28}, number = {5}, pages = {1757-1763}, doi = {10.3892/or.2012.1985}, pmid = {22923154}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis/*drug effects ; BH3 Interacting Domain Death Agonist Protein/biosynthesis ; Carcinoma, Hepatocellular/*metabolism/*pathology ; Caspase 3/metabolism ; Caspase 8/metabolism ; Caspase 9/metabolism ; Caspase Inhibitors/pharmacology ; Cell Line, Tumor ; Cysteine Proteinase Inhibitors ; Down-Regulation ; Enzyme Activation ; Free Radical Scavengers/pharmacology ; Garlic/*chemistry ; Humans ; Liver Neoplasms/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Plant Extracts/*pharmacology ; Reactive Oxygen Species/*metabolism ; bcl-2 Homologous Antagonist-Killer Protein/biosynthesis ; bcl-2-Associated X Protein/biosynthesis ; }, abstract = {Garlic (Allium sativum) compounds have recently received increasing attention due to their cancer chemopreventive properties, and their anticancer activities are extensively reported in many cancer cell lines. However, the anticancer activity and the signaling pathway associated with the induction of apoptosis by extracts of garlic cloves have not been elucidated. In this study, we examined the effects of hexane extracts of garlic cloves (HEGCs) on reactive oxygen species (ROS) production and the association of these effects with apoptotic cell death, using a Hep3B human hepatocarcinoma cell line in vitro. The results demonstrated that HEGCs mediate ROS production, and that this mediation is followed by a collapse of mitochondrial membrane potential (MMP, ΔΨm), the downregulation of anti-apoptotic Bcl-2 and Bcl-xL and the activation of caspase-9 and -3. HEGCs also promoted the activation of caspase-8 and the downregulation of Bid, a BH3-only pro-apoptotic member of the Bcl-2. However, the apoptotic phenomena displayed by HEGCs were significantly diminished by the presence of z-VAD-fmk (non-selective caspase inhibitor). Moreover, N-acetyl-L-cysteine (NAC), a widely used ROS scavenger, effectively blocked the HEGC-induced apoptotic effects via the inhibition of ROS production and MMP collapse. These observations clearly indicate that HEGC-induced ROS are key mediators of MMP collapse, which leads to the induction of apoptosis, followed by caspase activation.}, }
@article {pmid22922937, year = {2012}, author = {Doudican, NA and Wen, SY and Mazumder, A and Orlow, SJ}, title = {Sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide in multiple myeloma cells via stress-mediated pathways.}, journal = {Oncology reports}, volume = {28}, number = {5}, pages = {1851-1858}, pmid = {22922937}, issn = {1791-2431}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Caspase 3/metabolism ; Caspases, Initiator/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA-Binding Proteins/metabolism ; Drug Synergism ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Glutathione/metabolism ; HSP90 Heat-Shock Proteins/biosynthesis/metabolism ; Humans ; I-kappa B Kinase/metabolism ; Isothiocyanates ; Multiple Myeloma/*drug therapy/metabolism ; Oxides/*pharmacology ; Phosphorylation/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; Regulatory Factor X Transcription Factors ; Signal Transduction/drug effects ; Sulfoxides ; Thiocyanates/*pharmacology ; Transcription Factors/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Unfolded Protein Response/drug effects ; X-Box Binding Protein 1 ; eIF-2 Kinase/biosynthesis ; }, abstract = {Persistent paraprotein production in plasma cells necessitates a highly developed rough endoplasmic reticulum (ER) that is unusually susceptible to perturbations in protein synthesis. This biology is believed to account for the exquisite sensitivity of multiple myeloma (MM) to the proteasomal inhibitor bortezomib (BTZ). Despite remarkable response rates to BTZ in MM, BTZ carries the potential for serious side-effects and development of resistance. We, therefore, sought to identify therapeutic combinations that effectively disrupt proteostasis in order to provide new potential treatments for MM. We found that sulforaphane, a dietary isothiocyanate found in cruciferous vegetables, inhibits TNFα-induced Iκβ proteasomal degradation in a manner similar to BTZ. Like BTZ, sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide (ATO), an agent with clinical activity in MM. ATO and sulforaphane co-treatment augmented apoptotic induction as demonstrated by cleavage of caspase-3, -4 and PARP. The enhanced apoptotic response was dependent upon production of reactive oxygen species (ROS) as demonstrated by glutathione depletion and partial inhibition of the apoptotic cascade after pretreatment with the radical scavenger N-acetyl-cysteine (NAC). Combination treatment resulted in enhanced ER stress signaling and activation of the unfolded protein response (UPR), indicative of perturbation of proteostasis. Specifically, combination treatment caused elevated expression of the molecular chaperone HSP90 (heat shock protein 90) along with increased PERK (protein kinase RNA-like endoplasmic reticulum kinase) and eIF2α phosphorylation and XBP1 (X-box binding protein 1) splicing, key indicators of UPR activation. Moreover, increased splicing of XBP1 was apparent upon combination treatment compared to treatment with either agent alone. Sulforaphane in combination with ATO effectively disrupts protein homeostasis through ROS generation and induction of ER stress to culminate in inhibition of protein secretion and apoptotic induction in MM. Our results suggest that sulforaphane deserves further investigation in combination with ATO in the treatment of MM.}, }
@article {pmid22922739, year = {2012}, author = {Sin, S and Kim, SY and Kim, SS}, title = {Chronic treatment with ginsenoside Rg3 induces Akt-dependent senescence in human glioma cells.}, journal = {International journal of oncology}, volume = {41}, number = {5}, pages = {1669-1674}, doi = {10.3892/ijo.2012.1604}, pmid = {22922739}, issn = {1791-2423}, mesh = {Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cellular Senescence/*drug effects/genetics ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Enzyme Activation/drug effects ; Ginsenosides/administration &amp; dosage/*pharmacology ; Glioma/drug therapy/genetics/*metabolism ; Humans ; Mitochondria/drug effects/metabolism ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Therapy-induced senescence, an irreversible growth arrest, in cancer cells is regarded as a novel functional target that may improve cancer therapy. 20(S)-ginsenoside Rg3 [20(S)-Rg3], a chemical component extracted from Panax ginseng, has recently emerged as an effective anticancer medicine with evident antitumor effects and no observed toxic adverse reactions. We report here that chronic treatment with 20(S)-Rg3 in a sub-lethal concentration induced senescence-like growth arrest in human glioma cells. Glioma cells treated with 20(S)-Rg3 showed high expression of senescence-associated β-galactosidase, followed by upregulation of the CDK inhibitors p21 and p16. Moreover, reactive oxygen species (ROS) generation markedly increased in 20(S)-Rg3-treated cells compared with control cells. Consistently, co-incubation with the antioxidant N-acetyl cysteine interfered with 20(S)-Rg3-induced senescence in glioma cells. In addition, 20(S)-Rg3-induced-activation of Akt was associated with increased ROS levels, and depletion of Akt partially prevented 20(S)-Rg3-induced ROS generation and senescence induction in glioma cells. Furthermore, 20(S)-Rg3-induced senescence was partially rescued when the p53/p21 pathway was inactivated. Our data indicate that 20(S)-Rg3 induces senescence-like growth arrest in human glioma cancer through the Akt and p53/p21-dependent signaling pathways. This is the first report of a pro-senescent effect of 20(S)-Rg3 in cancer cells.}, }
@article {pmid22917661, year = {2012}, author = {Liu, Y and Wang, C and Wang, Y and Ma, Z and Xiao, J and McClain, C and Li, X and Feng, W}, title = {Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells.}, journal = {Toxicology and applied pharmacology}, volume = {264}, number = {2}, pages = {212-221}, pmid = {22917661}, issn = {1096-0333}, support = {U01 AA021901/AA/NIAAA NIH HHS/United States ; R01AA015970/AA/NIAAA NIH HHS/United States ; P01 AA017103/AA/NIAAA NIH HHS/United States ; R01DK071765/DK/NIDDK NIH HHS/United States ; RC2AA019385/AA/NIAAA NIH HHS/United States ; R01 AA018016/AA/NIAAA NIH HHS/United States ; P30AA019360/AA/NIAAA NIH HHS/United States ; P30 AA019360/AA/NIAAA NIH HHS/United States ; R37AA010762/AA/NIAAA NIH HHS/United States ; R01 AA015970/AA/NIAAA NIH HHS/United States ; R01AA018869/AA/NIAAA NIH HHS/United States ; R01 AA010496/AA/NIAAA NIH HHS/United States ; P01AA017103/AA/NIAAA NIH HHS/United States ; R01 AA018869/AA/NIAAA NIH HHS/United States ; R01 DK071765/DK/NIDDK NIH HHS/United States ; RC2 AA019385/AA/NIAAA NIH HHS/United States ; R01AA018016/AA/NIAAA NIH HHS/United States ; R37 AA010762/AA/NIAAA NIH HHS/United States ; }, mesh = {Aryl Hydrocarbon Receptor Nuclear Translocator/biosynthesis ; Azo Compounds ; Blotting, Western ; Caco-2 Cells ; Cell Nucleus/drug effects/metabolism ; Cobalt/*pharmacology ; Coloring Agents ; Fibroblast Growth Factors/*biosynthesis ; Humans ; Hypoxia-Inducible Factor 1/*physiology ; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis ; Oxidative Stress/*drug effects ; PPAR alpha/physiology ; PPAR gamma/physiology ; RNA Interference ; RNA, Messenger/biosynthesis ; Real-Time Polymerase Chain Reaction ; Superoxides/metabolism ; Triglycerides/metabolism ; }, abstract = {Fibroblast growth factor-21 (FGF21) is a potential metabolic regulator with multiple beneficial effects on metabolic diseases. FGF21 is mainly expressed in the liver, but is also found in other tissues including the intestine, which expresses β-klotho abundantly. The intestine is a unique organ that operates in a physiologically hypoxic environment, and is responsible for the fat absorption processes including triglyceride breakdown, re-synthesis and absorption into the portal circulation. In the present study, we investigated the effects of hypoxia and the chemical hypoxia inducer, cobalt chloride (CoCl(2)), on FGF21 expression in Caco-2 cells and the consequence of fat accumulation. Physical hypoxia (1% oxygen) and CoCl(2) treatment decreased both FGF21 mRNA and secreted protein levels. Gene silence and inhibition of hypoxia-inducible factor-α (HIFα) did not affect the reduction of FGF21 mRNA and protein levels by hypoxia. However, CoCl(2) administration caused a significant increase in oxidative stress. The addition of n-acetylcysteine (NAC) suppressed CoCl(2)-induced reactive oxygen species (ROS) formation and completely negated CoCl(2)-induced FGF21 loss. mRNA stability analysis demonstrated that the CoCl(2) administration caused a remarkable reduction in FGF21 mRNA stability. Furthermore, CoCl(2) increased intracellular triglyceride (TG) accumulation, along with a reduction in mRNA levels of lipid lipase, hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), and an increase of sterol regulatory element-binding protein-1c (SREBP1c) and stearoyl-coenzyme A (SCD1). Addition of both NAC and recombinant FGF21 significantly attenuated the CoCl(2)-induced TG accumulation. In conclusion, the decrease of FGF21 in Caco-2 cells by chemical hypoxia is independent of HIFα, but dependent on an oxidative stress-mediated mechanism. The regulation of FGF21 by hypoxia may contribute to intestinal lipid metabolism and absorption.}, }
@article {pmid22917563, year = {2012}, author = {Arsikin, K and Kravic-Stevovic, T and Jovanovic, M and Ristic, B and Tovilovic, G and Zogovic, N and Bumbasirevic, V and Trajkovic, V and Harhaji-Trajkovic, L}, title = {Autophagy-dependent and -independent involvement of AMP-activated protein kinase in 6-hydroxydopamine toxicity to SH-SY5Y neuroblastoma cells.}, journal = {Biochimica et biophysica acta}, volume = {1822}, number = {11}, pages = {1826-1836}, doi = {10.1016/j.bbadis.2012.08.006}, pmid = {22917563}, issn = {0006-3002}, mesh = {AMP-Activated Protein Kinases/genetics/*metabolism ; Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing ; Apoptosis/*drug effects ; Autophagy/*drug effects/genetics ; Cell Line ; Gene Expression Regulation/drug effects ; Humans ; Microscopy, Electron, Transmission ; Microtubule-Associated Proteins/genetics/metabolism ; Neuroblastoma/*metabolism ; Oxidopamine/*pharmacology ; Phosphorylation ; RNA, Small Interfering ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Sequestosome-1 Protein ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The role of the main intracellular energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK) in the induction of autophagic response and cell death was investigated in SH-SY5Y human neuroblastoma cells exposed to the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA). The induction of autophagy in SH-SY5Y cells was demonstrated by acridine orange staining of intracellular acidic vesicles, the presence of autophagosome- and autophagolysosome-like vesicles confirmed by transmission electron microscopy, as well as by microtubule-associated protein 1 light-chain 3 (LC3) conversion and p62 degradation detected by immunoblotting. 6-OHDA induced phosphorylation of AMPK and its target Raptor, followed by the dephosphorylation of the major autophagy inhibitor mammalian target of rapamycin (mTOR) and its substrate p70S6 kinase (S6K). 6-OHDA treatment failed to suppress mTOR/S6K phosphorylation and to increase LC3 conversion, p62 degradation and cytoplasmatic acidification in neuroblastoma cells in which AMPK expression was downregulated by RNA interference. Transfection of SH-SY5Y cells with AMPK or LC3β shRNA, as well as treatment with pharmacological autophagy inhibitors suppressed, while mTOR inhibitor rapamycin potentiated 6-OHDA-induced oxidative stress and apoptotic cell death. 6-OHDA induced phosphorylation of p38 mitogen-activated protein (MAP) kinase in an AMPK-dependent manner, and pharmacological inhibition of p38 MAP kinase reduced neurotoxicity, but not AMPK activation and autophagy triggered by 6-OHDA. Finally, the antioxidant N-acetyl cysteine antagonized 6-OHDA-induced activation of AMPK, p38 and autophagy. These data suggest that oxidative stress-mediated AMPK/mTOR-dependent autophagy and AMPK/p38-dependent apoptosis could be valid therapeutic targets for neuroprotection.}, }
@article {pmid22907277, year = {2012}, author = {Krishna, S}, title = {Adjunctive management of malaria.}, journal = {Current opinion in infectious diseases}, volume = {25}, number = {5}, pages = {484-488}, doi = {10.1097/QCO.0b013e3283567b20}, pmid = {22907277}, issn = {1473-6527}, mesh = {Antimalarials/*administration &amp; dosage ; Artemisinins/*administration &amp; dosage ; Artesunate ; Blood Transfusion/methods ; Fluid Therapy/methods ; Humans ; Malaria/*therapy ; Malaria, Cerebral/diagnosis/therapy ; Nitric Oxide/administration &amp; dosage ; }, abstract = {PURPOSE OF REVIEW: Artesunate treatment reduces mortality in severe malaria when compared with quinine. Nevertheless, severe malaria is associated with mortality rates between 1.4 and 9.5% after hospitalization. This review puts into context the recent developments in understanding the pathophysiology of malaria and how these may be reflected in renewed attempts at improving adjunct therapies. Identifying new adjunct approaches has been particularly difficult for severe malaria because most interventions have either caused harm or failed to confer benefit.<br><br>RECENT FINDINGS: Imaging and postmortem findings in children with severe and cerebral malaria have given impetus to study new interventions that could be added to antimalarial treatment. Some pilot studies have (re)tested different approaches to improve complications of cerebral malaria such as the use of N-acetyl cysteine or mannitol. Fluids administration, blood transfusions and red cell exchanges in severe malaria are controversial and important areas that are also reviewed with new evidence. Other interventions such as measures to increase nitric oxide, manage acute renal failure or optimize artesunate dosing are discussed.<br><br>SUMMARY: Outcomes with adjunct therapies for severe malaria have been poor, but as insights into pathophysiological processes are deepened it may be possible eventually to reduce mortality further.}, }
@article {pmid22906610, year = {2012}, author = {Jung, HS and Pradhan, T and Han, JH and Heo, KJ and Lee, JH and Kang, C and Kim, JS}, title = {Molecular modulated cysteine-selective fluorescent probe.}, journal = {Biomaterials}, volume = {33}, number = {33}, pages = {8495-8502}, doi = {10.1016/j.biomaterials.2012.08.009}, pmid = {22906610}, issn = {1878-5905}, mesh = {Buthionine Sulfoximine/pharmacology ; Coumarins/chemistry ; Cysteine/chemistry/*metabolism ; Fluorescence ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors ; Glutathione/chemistry/metabolism ; Hep G2 Cells ; Humans ; Microscopy, Confocal ; Molecular Probes ; Spectrometry, Fluorescence ; }, abstract = {We have synthesized a series of coumarins (1-3) that can emit fluorescence in a turn-on manner through a Michael-type reaction with thiol-containing compounds. The only difference among the coumarins is the position of a carboxyl group on its benzene ring moiety near the double-bond conjugated coumarin. Their selectivity for Cys, GSH, and Hcy as well as the associated fluorogenic mechanism were illustrated by fluorescence spectroscopy, DFT calculations, and kinetic studies. All isomers prefer Cys over GSH in the reaction from 48.6 (probe 3) to 111-fold (probe 1) as demonstrated in a second order kinetics. The high selectivity of probe 1 to Cys might be achieved since the ortho carboxyl group on its benzene ring prefers a less negatively charged nucleophile. During intracellular Cys detection using 1, a possible interference by a large amount of GSH in the HepG2 cells was evaluated. The cells were treated with l-buthionine sulfoximine (BSO), an inhibitor of γ-glutamylcysteine synthetase, providing an experimental condition where the cells could not synthesize GSH from Cys or other species. Then, the fluorescence intensity of 1 in HepG2 cells under BSO-H(2)O(2) treatment was strongly enhanced by N-acetylcysteine (NAC), a precursor of Cys, implicating that the fluorescence signal from the cells is mainly associated with changes in intracellular [Cys] rather than that in intracellular [GSH].}, }
@article {pmid22906494, year = {2012}, author = {Adnan, H and Antenos, M and Kirby, GM}, title = {The effect of menadione on glutathione S-transferase A1 (GSTA1): c-Jun N-terminal kinase (JNK) complex dissociation in human colonic adenocarcinoma Caco-2 cells.}, journal = {Toxicology letters}, volume = {214}, number = {1}, pages = {53-62}, doi = {10.1016/j.toxlet.2012.08.007}, pmid = {22906494}, issn = {1879-3169}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/*metabolism ; Aldehydes/metabolism ; Antifibrinolytic Agents/pharmacology ; Caco-2 Cells ; Colonic Neoplasms/*metabolism ; Dose-Response Relationship, Drug ; Down-Regulation ; Gene Expression Regulation, Enzymologic/*drug effects ; Glutathione/metabolism ; Glutathione Transferase/genetics/*metabolism ; Humans ; Lipid Peroxidation ; MAP Kinase Kinase 4/genetics/*metabolism ; Malondialdehyde/metabolism ; Oxidative Stress ; Time Factors ; Vitamin K 3/*toxicity ; }, abstract = {Glutathione S-transferases (GSTs) act as modulators of mitogen-activated protein kinase signal transduction pathways via a mechanism involving protein-protein interactions. We have demonstrated that GSTA1 forms complexes with JNK and modifies JNK activation during cellular stress, but the factors that influence complex association and dissociation are unknown. We hypothesized that menadione causes dissociation of GSTA1-JNK complexes, activates JNK, and the consequences of menadione exposure depend on GSTA1 expression. We demonstrate that menadione causes GSTA1-JNK dissociation and JNK activation in preconfluent Caco-2 cells, whereas postconfluent cells are resistant to this effect. Moreover, preconfluent cells are more sensitive than postconfluent cells to menadione-induced cytotoxicity. Activation of JNK is transient since removal of menadione causes GSTA1 to re-associate with JNK reducing cytotoxicity. Over-expression and knockdown of GSTA1 did not alter JNK activation by menadione or sensitivity to menadione-induced cytotoxicity. These results indicate that GSTA1-JNK complex integrity does not affect the ability of menadione to activate JNK. N-acetyl cysteine prevents GSH depletion and blocks menadione-induced complex dissociation, JNK activation and inhibits menadione-induced cytotoxicity. JNK activation and inhibits menadione-induced cytotoxicity. The data suggest that the mechanism of menadione-induced JNK activation involves the production of reactive oxygen species, likely superoxide anion, and intracellular GSH levels play an important role in preventing GSTA1-JNK complex dissociation, subsequent JNK activation and induction of cytotoxicity.}, }
@article {pmid22903390, year = {2013}, author = {Ramirez-Niño, AM and D'Souza, MS and Markou, A}, title = {N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking.}, journal = {Psychopharmacology}, volume = {225}, number = {2}, pages = {473-482}, pmid = {22903390}, issn = {1432-2072}, support = {R01 DA011946/DA/NIDA NIH HHS/United States ; R56 DA011946/DA/NIDA NIH HHS/United States ; DA11946/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Conditioning, Operant/drug effects ; Cues ; Dose-Response Relationship, Drug ; Eating/*drug effects ; Feeding Behavior/*drug effects ; Male ; Nicotine/*administration &amp; dosage ; Rats ; Rats, Wistar ; Reinforcement Schedule ; Self Administration ; }, abstract = {RATIONALE: Chronic nicotine administration decreases the functioning of the cystine-glutamate antiporter system x(c)- which is hypothesized to promote nicotine-taking and nicotine-seeking behaviors. N-acetylcysteine (NAC), a cystine pro-drug, increases the activity of the cystine-glutamate antiporter system x(c)-. Thus, NAC could potentially reverse nicotine-induced alterations in glutamatergic transmission and decrease nicotine taking and seeking.<br><br>OBJECTIVES AND METHODS: To test this hypothesis in the present study, the effects of acute NAC treatment (30, 60, and 90 mg/kg, i.p.) on nicotine (fixed- and progressive-ratio schedules) and food (fixed-ratio schedule) self-administration were assessed in rats. In addition, the effects of acute NAC treatment on cue-induced reinstatement of nicotine- and food-seeking behaviors were investigated. Finally, the effects of repeated daily NAC administration (60 mg/kg, i.p., 14 days) on nicotine and food self-administration were assessed.<br><br>RESULTS: Acute NAC administration decreased nicotine self-administration but not food responding under a fixed-ratio schedule of reinforcement. In addition, acute NAC administration showed a nonsignificant trend in attenuating nicotine self-administration under a progressive-ratio schedule that was similar to the dose-response function under the fixed-ratio schedule. Furthermore, repeated NAC administration decreased nicotine self-administration from day 6 to 14 compared with vehicle treatment, with no indication of tolerance development. By contrast, repeated NAC administration decreased food responding from day 6 to 8 compared with vehicle treatment and showed rapid development of tolerance. Finally, acute NAC administration attenuated cue-induced reinstatement of nicotine and food seeking.<br><br>CONCLUSIONS: Altogether, these findings suggest that NAC may be useful in promoting smoking cessation in humans.}, }
@article {pmid22902709, year = {2012}, author = {Faghihi, M and Alizadeh, AM and Khori, V and Latifpour, M and Khodayari, S}, title = {The role of nitric oxide, reactive oxygen species, and protein kinase C in oxytocin-induced cardioprotection in ischemic rat heart.}, journal = {Peptides}, volume = {37}, number = {2}, pages = {314-319}, doi = {10.1016/j.peptides.2012.08.001}, pmid = {22902709}, issn = {1873-5169}, mesh = {Animals ; Male ; Myocardial Ischemia/*metabolism/*prevention &amp; control ; Nitric Oxide/*metabolism ; Oxytocin/*pharmacology/*therapeutic use ; Protein Kinase C/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {Ischemia-reperfusion injury is a common complication of heart disease that is the leading cause of death worldwide. Here, we plan to elucidate oxytocin cardioprotection effects against ischemia-reperfusion via nitric oxide (NO), reactive oxygen species (ROS), and protein kinase C (PKC) in anesthetized rat preconditioned myocardium. Forty-eight Sprague-Dawley rats were equally divided into eight groups. All animals were subjected to 25 min ischemia and 120 min reperfusion. Oxytocin (OT), L-NAME (LNA, a nitric oxide synthase inhibitor), chelerythrine (CHE, a PKC enzyme inhibitor), and N-acetylcysteine (NAC, a ROS scavenger) were used prior to ischemia. Results showed that mean arterial pressure significantly reduced during the first 10 min of ischemia and reperfusion in IR, LNA, CHE, and NAC groups (p<0.05). OT prevented mean arterial pressure decline during early phase of ischemia and reperfusion. Cardioprotective effects of OT in infarct size, plasma levels of creatine kinase-MB and lactate dehydrogenase, severity and incidence of ventricular arrhythmias were abolished by L-NAME, chelerythrine, and N-acetylcysteine (p<0.05). The present study showed that OT pretreatment reduces myocardial infarct size and ventricular arrhythmias, and improves mean arterial pressure via NO production, PKC activation, and ROS balance. These findings provide new insight into therapeutic strategies for ischemic heart disease.}, }
@article {pmid22898295, year = {2012}, author = {Arent, CO and Réus, GZ and Abelaira, HM and Ribeiro, KF and Steckert, AV and Mina, F and Dal-Pizzol, F and Quevedo, J}, title = {Synergist effects of n-acetylcysteine and deferoxamine treatment on behavioral and oxidative parameters induced by chronic mild stress in rats.}, journal = {Neurochemistry international}, volume = {61}, number = {7}, pages = {1072-1080}, doi = {10.1016/j.neuint.2012.07.024}, pmid = {22898295}, issn = {1872-9754}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Behavior, Animal/*drug effects ; Deferoxamine/*pharmacology ; Drug Synergism ; Oxidative Stress/*drug effects ; Rats ; Stress, Psychological/metabolism/*psychology ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {A growing body of evidence has pointed to a relationship between oxidative stress and depression. Thus, the present study was aimed at evaluating the effects of the antioxidants n-acetylcysteine (NAC), deferoxamine (DFX) or their combination on sweet food consumption and oxidative stress parameters in rats submitted to 40days of exposure to chronic mild stress (CMS). Our results showed that in stressed rats treated with saline, there was a decrease in sweet food intake and treatment with NAC or NAC in combination with DFX reversed this effect. Treatment with NAC and DFX decreased the oxidative damage, which include superoxide and TBARS production in submitochondrial particles, and also thiobarbituric acid reactive substances (TBARS) levels and carbonyl proteins in the prefrontal cortex, amygdala and hippocampus. Treatment with NAC and DFX also increased the activity of the antioxidant enzymes, superoxide dismutase and catalase in the same brain areas. Even so, a combined treatment with NAC and DFX produced a stronger increase of antioxidant activities in the prefrontal cortex, amygdala and hippocampus. The results described here indicate that co-administration may induce a more pronounced antidepressant activity than each treatment alone. In conclusion, these results suggests that treatment with NAC or DFX alone or in combination on oxidative stress parameters could have positive effects against neuronal damage caused by oxidative stress in major depressive disorders.}, }
@article {pmid22895548, year = {2012}, author = {Yang, LH and Ho, YJ and Lin, JF and Yeh, CW and Kao, SH and Hsu, LS}, title = {Butein inhibits the proliferation of breast cancer cells through generation of reactive oxygen species and modulation of ERK and p38 activities.}, journal = {Molecular medicine reports}, volume = {6}, number = {5}, pages = {1126-1132}, doi = {10.3892/mmr.2012.1023}, pmid = {22895548}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Breast Neoplasms/metabolism/pathology ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Chalcones/*pharmacology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Female ; Humans ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Butein (3,4,2',4'-tetrahydroxychalcone) is a polyphenol derived from various natural plants and is capable of inducing several types of death in cancer cells. However, the molecular mechanisms underlying butein-induced breast cancer cell apoptosis remain unknown. The present study aimed to prove that butein inhibits the proliferation of MDA-MB‑231 human breast cancer cells in a dose- and time-dependent manner. Butein markedly induced the generation of reactive oxygen species (ROS), decreased the phosphorylation of extracellular signal-regulated kinase (ERK), increased p38 activity, diminished Bcl-2 expression, induced caspase 3 cleavage and was associated with poly(ADP-ribose) polymerase (PARP) cleavage. Our findings also indicate that ROS may play an important role in butein-induced apoptosis, as pre-treatment with the antioxidant, N-acetyl cysteine (NAC), prevented butein-induced apoptosis. In conclusion, our results demonstrate that butein inhibits the proliferation of breast cancer cells through the generation of ROS and the modulation of ERK and p38 activities. We also demonstrate that these effects may be abrogaged by pre-treatment with NAC. Our results suggest that butein may function as a potential therapeutic agent for the treatment of breast cancer.}, }
@article {pmid22892127, year = {2012}, author = {Ji, C and Yang, B and Yang, Z and Tu, Y and Yang, YL and He, L and Bi, ZG}, title = {Ultra-violet B (UVB)-induced skin cell death occurs through a cyclophilin D intrinsic signaling pathway.}, journal = {Biochemical and biophysical research communications}, volume = {425}, number = {4}, pages = {825-829}, doi = {10.1016/j.bbrc.2012.07.160}, pmid = {22892127}, issn = {1090-2104}, mesh = {Apoptosis/*radiation effects ; Cell Line ; Peptidyl-Prolyl Isomerase F ; Cyclophilins/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Keratinocytes/enzymology/radiation effects ; Signal Transduction ; Skin/enzymology/*radiation effects ; *Skin Aging ; Ultraviolet Rays/*adverse effects ; }, abstract = {UVB-induced skin cell damage involves the opening of mitochondrial permeability transition pore (mPTP), which leads to both apoptotic and necrotic cell death. Cyclophilin D (Cyp-D) translocation to the inner membrane of mitochondrion acts as a key component to open the mPTP. Our Western-Blot results in primary cultured human skin keratinocytes and in HaCaT cell line demonstrated that UVB radiation and hydrogen peroxide (H(2)O(2)) induced Cyp-D expression, which was inhibited by anti-oxidant N-acetyl cysteine (NAC). We created a stable Cyp-D deficiency skin keratinocytes by expressing Cyp-D-shRNA through lentiviral infection. Cyp-D-deficient cells were significantly less susceptible than their counterparts to UVB- or H(2)O(2)-induced cell death. Further, cyclosporine A (Cs-A), a Cyp-D inhibitor, inhibited UVB- or H(2)O(2)-induced keratinocytes cell death. Reversely, over-expression of Cyp-D in primary keratinocytes caused spontaneous keratinocytes cell death. These results suggest Cyp-D's critical role in UVB/oxidative stress-induced skin cell death.}, }
@article {pmid22891797, year = {2012}, author = {Berk, M and Dean, OM and Cotton, SM and Gama, CS and Kapczinski, F and Fernandes, B and Kohlmann, K and Jeavons, S and Hewitt, K and Moss, K and Allwang, C and Schapkaitz, I and Cobb, H and Bush, AI and Dodd, S and Malhi, GS}, title = {Maintenance N-acetyl cysteine treatment for bipolar disorder: a double-blind randomized placebo controlled trial.}, journal = {BMC medicine}, volume = {10}, number = {}, pages = {91}, pmid = {22891797}, issn = {1741-7015}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Antidepressive Agents/*administration &amp; dosage ; Bipolar Disorder/*drug therapy ; Female ; Humans ; Maintenance Chemotherapy/*methods ; Male ; Middle Aged ; New Zealand ; Placebos/administration &amp; dosage ; Quality of Life ; Secondary Prevention ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: N-acetyl cysteine (NAC) is a glutathione precursor that has been shown to have antidepressant efficacy in a placebo-controlled trial. The current study aimed to investigate the maintenance effects of NAC following eight weeks of open-label treatment for bipolar disorder.<br><br>METHOD: The efficacy of a double blind randomized placebo controlled trial of 2 g/day NAC as adjunct maintenance treatment for bipolar disorder was examined. Participants (n = 149) had a Montgomery Asberg Depression Rating Score of &#x2265;12 at trial entry and, after eight weeks of open-label NAC treatment, were randomized to adjunctive NAC or placebo, in addition to treatment as usual. Participants (primarily outpatients) were recruited through public and private services and through newspaper advertisements. Time to intervention for a mood episode was the primary endpoint of the study, and changes in mood symptoms, functionality and quality of life measures were secondary outcomes.<br><br>RESULTS: There was a substantial decrease in symptoms during the eight-week open-label NAC treatment phase. During the subsequent double-blind phase, there was minimal further change in outcome measures with scores remaining low. Consequently, from this low plateau, between-group differences did not emerge on recurrence, clinical functioning or quality of life measures.<br><br>CONCLUSIONS: There were no significant between-group differences in recurrence or symptomatic outcomes during the maintenance phase of the trial; however, these findings may be confounded by limitations.<br><br>TRIAL REGISTRATION: The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12607000074493).}, }
@article {pmid22890714, year = {2012}, author = {Nyberg, M and Blackwell, JR and Damsgaard, R and Jones, AM and Hellsten, Y and Mortensen, SP}, title = {Lifelong physical activity prevents an age-related reduction in arterial and skeletal muscle nitric oxide bioavailability in humans.}, journal = {The Journal of physiology}, volume = {590}, number = {21}, pages = {5361-5370}, pmid = {22890714}, issn = {1469-7793}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/pharmacology ; Adult ; Aged ; Aging/*physiology ; Antioxidants/pharmacology ; Femoral Artery/*physiology ; Humans ; Leg/blood supply ; Male ; Middle Aged ; Motor Activity/*physiology ; Muscle, Skeletal/*physiology ; Nitrates/metabolism ; Nitric Oxide/*physiology ; Nitric Oxide Synthase Type I/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Nitrites/metabolism ; Norepinephrine/metabolism ; Regional Blood Flow ; Young Adult ; }, abstract = {Ageing has been proposed to be associated with increased levels of reactive oxygen species (ROS) that scavenge nitric oxide (NO). In eight young sedentary (23 ± 1 years; Y), eight older lifelong sedentary (66 ± 2 years; OS) and eight older lifelong physically active subjects (62 ± 2 years; OA), we studied the effect of ROS on systemic and skeletal muscle NO bioavailability and leg blood flow by infusion of the antioxidant N-acetylcysteine (NAC). Infusion of NAC increased the bioavailability of NO in OS, as evidenced by an increased concentration of stable metabolites of NO (NOx) in the arterial and venous circulation and in the muscle interstitium. In OA, infusion of NAC only increased NOx concentrations in venous plasma whereas in Y, infusion of NAC did not affect NOx concentrations. Skeletal muscle protein levels of endothelial and neuronal NO synthase were 32% and 24% higher, respectively, in OA than in OS. Exercise at 12 W elicited a lower leg blood flow response that was associated with a lower leg oxygen uptake in OS than in Y. The improved bioavailability of NO in OS did not increase blood flow during exercise. These data demonstrate that NO bioavailability is compromised in the systemic circulation and in the musculature of sedentary ageing humans due to increased oxidative stress. Lifelong physical activity opposes this effect within the trained musculature and in the arterial circulation. The lower blood flow response to leg exercise in ageing humans is not associated with a reduced NO bioavailability.}, }
@article {pmid22886633, year = {2013}, author = {Squires, RH and Dhawan, A and Alonso, E and Narkewicz, MR and Shneider, BL and Rodriguez-Baez, N and Olio, DD and Karpen, S and Bucuvalas, J and Lobritto, S and Rand, E and Rosenthal, P and Horslen, S and Ng, V and Subbarao, G and Kerkar, N and Rudnick, D and Lopez, MJ and Schwarz, K and Romero, R and Elisofon, S and Doo, E and Robuck, PR and Lawlor, S and Belle, SH and , }, title = {Intravenous N-acetylcysteine in pediatric patients with nonacetaminophen acute liver failure: a placebo-controlled clinical trial.}, journal = {Hepatology (Baltimore, Md.)}, volume = {57}, number = {4}, pages = {1542-1549}, pmid = {22886633}, issn = {1527-3350}, support = {U01-DK58369/DK/NIDDK NIH HHS/United States ; UL1 TR000150/TR/NCATS NIH HHS/United States ; P30 DK026743/DK/NIDDK NIH HHS/United States ; M01 RR000069/RR/NCRR NIH HHS/United States ; M01 RR000037/RR/NCRR NIH HHS/United States ; M01 RR08084/RR/NCRR NIH HHS/United States ; U01 DK058369/DK/NIDDK NIH HHS/United States ; UL1 TR000077/TR/NCATS NIH HHS/United States ; U01 DK072146/DK/NIDDK NIH HHS/United States ; M01-RR00069/RR/NCRR NIH HHS/United States ; M01 RR008084/RR/NCRR NIH HHS/United States ; M01-RR00037/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/*therapeutic use ; Adolescent ; Child ; Child, Preschool ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Hepatic Encephalopathy/drug therapy/mortality ; Humans ; Infant ; Infant, Newborn ; Infusions, Intravenous ; Liver Failure, Acute/*drug therapy/*mortality ; Liver Transplantation ; Male ; Severity of Illness Index ; Survival Rate ; Treatment Outcome ; }, abstract = {UNLABELLED: N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with nonacetaminophen (non-APAP) acute liver failure (ALF) and grade 1-2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of intensive care unit (ICU) and hospital stays, organ system failure, and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (P = 0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (P = 0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0-1 (NAC 25%; placebo 60%; P = 0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE.<br><br>CONCLUSION: NAC did not improve 1-year survival in non-APAP PALF. One-year LTx-free survival was significantly lower with NAC, particularly among those <2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults.}, }
@article {pmid22886373, year = {2012}, author = {Xiao, F and Feng, X and Zeng, M and Guan, L and Hu, Q and Zhong, C}, title = {Hexavalent chromium induces energy metabolism disturbance and p53-dependent cell cycle arrest via reactive oxygen species in L-02 hepatocytes.}, journal = {Molecular and cellular biochemistry}, volume = {371}, number = {1-2}, pages = {65-76}, pmid = {22886373}, issn = {1573-4919}, mesh = {Acetylcysteine/metabolism ; Benzothiazoles/pharmacology ; Carcinogens, Environmental/*toxicity ; Cell Cycle Checkpoints ; Chromium/*toxicity ; Cyclin-Dependent Kinase 2/metabolism ; Dose-Response Relationship, Drug ; Energy Metabolism ; Environmental Pollutants/*toxicity ; Hepatocytes/*drug effects/metabolism ; Humans ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Hexavalent chromium [Cr(VI)] has become a non-negligible pollutant in the world. Cr(VI) exposure leads to severe damage to the liver, but the mechanisms involved in Cr(VI)-mediated toxicity in the liver are unclear. The present study aimed to explore whether Cr(VI) induces energy metabolism disturbance and cell cycle arrest in human L-02 hepatocytes. We showed that Cr(VI) inhibited state 3 respiration, respiratory control rate (RCR), and subsequently induced energy metabolism disturbance with decreased ATP production. Interestingly, cell cycle analysis by flow cytometry and protein expression analysis by western blotting revealed that low dose of Cr(VI) (4 uM) exposure induced S phase cell cycle arrest with decreased mediator of replication checkpoint 1 (Mrc1) and cyclin-dependent kinase 2 (CDK2), while higher doses of Cr(VI) (16, 32 uM) exposure resulted in G2/M phase arrest with decreased budding uninhibited by benzimidazoles-related 1 (BubR1) and cell division cycle 25 (CDC25). Mechanism study revealed that Cr(VI) decreased the activities of mitochondrial respiratory chain complex (MRCC) I and II, thus leading to ROS accumulation. Moreover, inhibiting ROS production by antioxidant N-acetyl-L-cysteine (NAC) rescued Cr(VI)-induced ATP depletion and cell cycle arrest. ROS-mediated p53 activation was found to involve in Cr(VI)-induced cell cycle arrest, and p53 inhibitor Pifithrin-α (PFT-α) rescued Cr(VI)-induced reduction of check point proteins Mrc1 and BubR1, thus inhibiting cell cycle arrest. In summary, the present study provides experimental evidence that Cr(VI) leads to energy metabolism disturbance and p53-dependent cell cycle arrest via ROS in L-02 hepatocytes.}, }
@article {pmid22886019, year = {2012}, author = {Head, E and Murphey, HL and Dowling, AL and McCarty, KL and Bethel, SR and Nitz, JA and Pleiss, M and Vanrooyen, J and Grossheim, M and Smiley, JR and Murphy, MP and Beckett, TL and Pagani, D and Bresch, F and Hendrix, C}, title = {A combination cocktail improves spatial attention in a canine model of human aging and Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {32}, number = {4}, pages = {1029-1042}, pmid = {22886019}, issn = {1875-8908}, support = {R44 AT003025/AT/NCCIH NIH HHS/United States ; R44AT003025/AT/NCCIH NIH HHS/United States ; }, mesh = {Aging/*drug effects/psychology ; Alzheimer Disease/*drug therapy/psychology ; Animals ; Antioxidants/*administration &amp; dosage ; Attention/*drug effects/physiology ; Camellia sinensis ; Curcuma ; *Disease Models, Animal ; Dogs ; Drug Therapy, Combination ; Humans ; Plant Extracts/administration &amp; dosage ; Spatial Behavior/*drug effects/physiology ; }, abstract = {Alzheimer's disease (AD) involves multiple pathological processes in the brain, including increased inflammation and oxidative damage, as well as the accumulation of amyloid-β (Aβ) plaques. We hypothesized that a combinatorial therapeutic approach to target these multiple pathways may provide cognitive and neuropathological benefits for AD patients. To test this hypothesis, we used a canine model of human aging and AD. Aged dogs naturally develop learning and memory impairments, human-type Aβ deposits, and oxidative damage in the brain. Thus, 9 aged beagles (98-115 months) were treated with a medical food cocktail containing (1) an extract of turmeric containing 95% curcuminoids; (2) an extract of green tea containing 50% epigallocatechingallate; (3) N-acetyl cysteine; (4) R-alpha lipoic acid; and (5) an extract of black pepper containing 95% piperine. Nine similarly aged dogs served as placebo-treated controls. After 3 months of treatment, 13 dogs completed a variable distance landmark task used as a measure of spatial attention. As compared to placebo-treated animals, dogs receiving the medical food cocktail had significantly lower error scores (t11 = 4.3, p = 0.001) and were more accurate across all distances (F(1,9) = 20.7, p = 0.001), suggesting an overall improvement in spatial attention. Measures of visual discrimination learning, executive function and spatial memory, and levels of brain and cerebrospinal fluid Aβ were unaffected by the cocktail. Our results indicate that this medical food cocktail may be beneficial for improving spatial attention and motivation deficits associated with impaired cognition in aging and AD.}, }
@article {pmid22883437, year = {2013}, author = {Saad, KR and Saad, PF and Dantas Filho, L and Brito, JM and Koike, MK and Zanoni, FL and Dolhnikoff, M and Montero, EF}, title = {Pulmonary impact of N-acetylcysteine in a controlled hemorrhagic shock model in rats.}, journal = {The Journal of surgical research}, volume = {182}, number = {1}, pages = {108-115}, doi = {10.1016/j.jss.2012.07.037}, pmid = {22883437}, issn = {1095-8673}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Acute Lung Injury/metabolism/pathology/*prevention &amp; control ; Animals ; Antioxidants/pharmacology/therapeutic use ; Disease Models, Animal ; Fluid Therapy ; Interleukin-10/metabolism ; Interleukin-6/metabolism ; Lung/*drug effects/metabolism/*pathology ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Reperfusion Injury/metabolism/pathology/*prevention &amp; control ; Resuscitation ; Shock, Hemorrhagic/*complications ; }, abstract = {BACKGROUND: Experimental hemorrhagic shock (HS) is based on controlling bleeding and the treatment of fluid resuscitation to restore tissue oxygenation and perfusion. The HS could promote ischemia/reperfusion injury, which induces a general exacerbation of the inflammatory process, initially compromising the lungs. N-acetylcysteine (NAC), an antioxidant, may attenuate ischemia/reperfusion injury. This study evaluated the effect of NAC in association with fluid resuscitation on pulmonary injury in a controlled HS model in rats.<br><br>METHODS: Male Wistar rats were submitted to controlled HS (mean arterial pressure of 35&#xa0;mm Hg for 60 min). Two groups were constituted according to resuscitation solution administered: RLG (Ringer's lactate solution) and RLG+NAC (Ringer's lactate in association with 150 mg/kg NAC. A control group was submitted to catheterization only. After 120 min of resuscitation, bronchoalveolar lavage was performed to assess intra-alveolar cell infiltration and pulmonary tissue was collected for assessment of malondialdehyde, interleukin 6, and interleukin 10 and histopathology.<br><br>RESULTS: Compared with the RLG group, the RLG+NAC group showed lower bronchoalveolar lavage inflammatory cell numbers, lower interstitial inflammatory infiltration in pulmonary parenchyma, and lower malondialdehyde concentration. However, tissue cytokine (interleukin 6 and interleukin 10) expression levels were similar.<br><br>CONCLUSION: N-acetylcysteine was associated with fluid resuscitation-attenuated oxidative stress and inflammatory cell infiltration in pulmonary parenchyma. N-acetylcysteine did not modify cytokine expression.}, }
@article {pmid22881126, year = {2012}, author = {Yu, Y and Fan, SM and Ye, YC and Tashiro, S and Onodera, S and Ikejima, T}, title = {The tyrphostin AG1478 augments oridonin-induced A431 cell apoptosis by blockage of JNK MAPK and enhancement of oxidative stress.}, journal = {Free radical research}, volume = {46}, number = {11}, pages = {1393-1405}, doi = {10.3109/10715762.2012.720017}, pmid = {22881126}, issn = {1029-2470}, mesh = {Apoptosis/*drug effects ; Cell Culture Techniques ; Cell Line, Tumor ; Diterpenes, Kaurane/*pharmacology ; Dose-Response Relationship, Drug ; Drug Synergism ; ErbB Receptors/antagonists &amp; inhibitors/metabolism ; Humans ; MAP Kinase Kinase 4/*antagonists &amp; inhibitors/metabolism ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Quinazolines/*pharmacology ; Tyrphostins/*pharmacology ; }, abstract = {Oridonin, a diterpenoid compound, extracted and purified from Rabdosia rubescen has been reported to have cytotoxic effect on tumour cells through apoptosis, and tyrosine kinase pathways are involved in these processes. A specific epidermal growth factor receptor (EGFR) inhibitor AG1478 was used to examine the relationship between EGFR signal pathways and oridonin-induced apoptosis and autophagy in EGFR abundant human epidermoid carcinoma A431 cells. Inhibition of EGFRaugmented oridonin-induced A431 cell apoptosis, while the changes of expression of downstream proteins, Bcl-2, Bcl-xL, Bax, cytochrome c, pro-caspase-3, Fas, FADD and pro-caspase-8 suggested that both the intrinsic and extrinsic apoptotic pathways are involved in these processes. Pretreatment with AG1478 aggravated oridonin-induced loss of mitochondrial membrane potential (MMP) and increased ROS generation in A431 cells, while a ROS scavenger, N-acetylcysteine (NAC) completely reversed oridonin- and AG1478-induced ROS generation and apoptosis. Therefore, AG1478 augmented oridonin-induced apoptosis by enhancing oxidative stress. Pretreatment with AG1478 decreased the expression of downstream MAPK proteins ERK, JNK and P38 and their phosphorylated forms to varying degrees compared with oridonin alone treatment. Then after administration of ERK, JNK and P38 inhibitors, only JNK inhibitor SP600125 effectively augmented oridonin-induced apoptosis and ROS generation. Therefore, in EGFR downstream pathways, JNK played a major role in preventing oridonin-induced apoptosis. Autophagy antagonised apoptosis and exerted a protective effect in A431 cells, and both AG1478 and SP600125 decreased oridonin-induced autophagy. Inhibition of EGFR augmented oridonin-induced apoptosis and this was caused by enhanced oxidative stress, and JNK played a major protective role by increasing autophagy, leading to antagonising apoptosis and ROS generation.}, }
@article {pmid22878643, year = {2012}, author = {Kim, TH and Kim, YK and Woo, JS}, title = {The adenosine A3 receptor agonist Cl-IB-MECA induces cell death through Ca[2+]/ROS-dependent down regulation of ERK and Akt in A172 human glioma cells.}, journal = {Neurochemical research}, volume = {37}, number = {12}, pages = {2667-2677}, pmid = {22878643}, issn = {1573-6903}, mesh = {Adenosine/*analogs &amp; derivatives/pharmacology ; Adenosine A3 Receptor Agonists/*pharmacology ; Base Sequence ; Blotting, Western ; Calcium/*metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Primers ; Down-Regulation/*drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Adenosine A(3) receptor (A3AR) is coupled to G proteins that are involved in a variety of intracellular signaling pathways and physiological functions. 2-Chloro-N(6)-(3-iodobenzyl) adenosine-5'-N-methylcarboxamide (Cl-IB-MECA), an agonist of A3AR, has been reported to induce cell death in various cancer cells. However, the effect of CI-IB-MECA on glioma cell growth is not clear. This study was undertaken to examine the effect of CI-IB-MECA on glioma cell viability and to determine its molecular mechanism. CI-IB-MECA inhibited cell proliferation and induced cell death in a dose- and time-dependent manner. Treatment of CI-IB-MECA resulted in an increase in intracellular Ca(2+) followed by enhanced reactive oxygen species (ROS) generation. EGTA and N-acetylcysteine (NAC) blocked the cell death induced by CI-IB-MECA, suggesting that Ca(2+) and ROS are involved in the Cl-IB-MECA-induced cell death. Western blot analysis showed that CI-IB-MECA induced the down-regulation of extracellular signal-regulated kinases (ERK) and Akt, which was prevented by EGTA, NAC, and the A3AR antagonist MRS1191. Transfection of constitutively active forms of MEK, the upstream kinase of ERK, and Akt prevented the cell death. CI-IB-MECA induced caspase-3 activation and the CI-IB-MECA-induced cell death was blocked by the caspase inhibitors DEVD-CHO and z-VAD-FMK. In addition, expression of XIAP and Survivin were decreased in cells treated with Cl-IB-MECA. Collectively, these findings demonstrate that CI-IB-MECA induce a caspase-dependent cell death through suppression of ERK and Akt mediated by an increase in intracellular Ca(2+) and ROS generation in human glioma cells. These suggest that A3AR agonists may be a potential therapeutic agent for induction of apoptosis in human glioma cells.}, }
@article {pmid22877754, year = {2012}, author = {Handayaningsih, AE and Takahashi, M and Fukuoka, H and Iguchi, G and Nishizawa, H and Yamamoto, M and Suda, K and Takahashi, Y}, title = {IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway.}, journal = {Biochemical and biophysical research communications}, volume = {425}, number = {2}, pages = {478-484}, doi = {10.1016/j.bbrc.2012.07.140}, pmid = {22877754}, issn = {1090-2104}, mesh = {Animals ; Cells, Cultured ; Cellular Senescence/drug effects/*physiology ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Histones/metabolism ; Humans ; Insulin-Like Growth Factor I/pharmacology/*physiology ; Mice ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Recombinant Proteins/pharmacology ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Cellular senescence is characterized by growth arrest, enlarged and flattened cell morphology, the expression of senescence-associated β-galactosidase (SA-β-gal), and by activation of tumor suppressor networks. Insulin-like growth factor-I (IGF-I) plays a critical role in cellular growth, proliferation, tumorigenesis, and regulation of aging. In the present study, we show that IGF-I enhances cellular senescence in mouse, rat, and human primary cells in the confluent state. IGF-I induced expression of a DNA damage marker, γH2AX, the increased levels of p53 and p21 proteins, and activated SA-β-gal. In the confluent state, an altered downstream signaling of IGF-I receptor was observed. Treatment with a reactive oxygen species (ROS) scavenger, N-acetylcystein (NAC) significantly suppressed induction of these markers, indicating that ROS are involved in the induction of cellular senescence by IGF-I. In p53-null mouse embryonic fibroblasts, the IGF-I-induced augmentation of SA-β-gal and p21 was inhibited, demonstrating that p53 is required for cellular senescence induced by IGF-I. Thus, these data reveal a novel pathway whereby IGF-I enhances cellular senescence in the ROS and p53-dependent manner and may explain the underlying mechanisms of IGF-I involvement in tumorigenesis and in regulation of aging.}, }
@article {pmid22867088, year = {2012}, author = {Wu, W and Peden, DB and McConnell, R and Fruin, S and Diaz-Sanchez, D}, title = {Glutathione-S-transferase M1 regulation of diesel exhaust particle-induced pro-inflammatory mediator expression in normal human bronchial epithelial cells.}, journal = {Particle and fibre toxicology}, volume = {9}, number = {}, pages = {31}, pmid = {22867088}, issn = {1743-8977}, support = {P30 ES010126/ES/NIEHS NIH HHS/United States ; R01ES016535/ES/NIEHS NIH HHS/United States ; U19AI077437/AI/NIAID NIH HHS/United States ; }, mesh = {Bronchi/*drug effects/metabolism ; Cells, Cultured ; Epithelial Cells/*drug effects/metabolism ; Gene Knockdown Techniques ; Glutathione Transferase/deficiency/*genetics ; Humans ; Inflammation Mediators/*metabolism ; Interleukins/metabolism ; MAP Kinase Signaling System/drug effects ; Particulate Matter/*toxicity ; Phosphorylation ; RNA, Small Interfering/genetics/pharmacology ; Vehicle Emissions/*toxicity ; }, abstract = {BACKGROUND: Diesel exhaust particles (DEP) contribute substantially to ambient particulate matter (PM) air pollution in urban areas. Inhalation of PM has been associated with increased incidence of lung disease in susceptible populations. We have demonstrated that the glutathione S-transferase M1 (GSTM1) null genotype could aggravate DEP-induced airway inflammation in human subjects. Given the critical role airway epithelial cells play in the pathogenesis of airway inflammation, we established the GSTM1 deficiency condition in primary bronchial epithelial cells from human volunteers with GSTM1 sufficient genotype (GSTM1+) using GSTM1 shRNA to determine whether GSTM1 deficiency could exaggerate DEP-induced expression of interleukin-8 (IL-8) and IL-1β proteins. Furthermore, the mechanisms underlying GSTM1 regulation of DEP-induced IL-8 and IL-1β expression were also investigated.<br><br>METHODS: IL-8 and IL-1&#x3b2; protein levels were measured using enzyme-linked immunosorbent assay. GSTM1 deficiency in primary human bronchial epithelial cells was achieved using lentiviral GSTM1 shRNA particles and verified using real-time polymerase chain reaction and immunoblotting. Intracellular reactive oxygen species (ROS) production was evaluated using flow cytometry. Phosphorylation of protein kinases was detected using immunoblotting.<br><br>RESULTS: Exposure of primary human bronchial epithelial cells (GSTM1+) to 25-100&#x2009;&#x3bc;g/ml DEP for 24&#x2009;h significantly increased IL-8 and IL-1&#x3b2; protein expression. Knockdown of GSTM1 in these cells further elevated DEP-induced IL-8 and IL-1&#x3b2; expression, implying that GSTM1 deficiency aggravated DEP-induced pro-inflammatory response. DEP stimulation induced the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, the downstream kinase of phosphoinositide 3-kinase (PI3K), in GSTM1+ bronchial epithelial cells. Pharmacological inhibition of ERK kinase and PI3K activity blocked DEP-induced IL-8 and IL-1&#x3b2; expression. DEP-induced ERK and Akt phosphorylation could be increased by GSTM1 knockdown. In addition, pretreatment of HBEC with the antioxidant N-acetyl cysteine significantly inhibited DEP-induced ERK and Akt phosphorylation, and subsequent IL-8 and IL-1&#x3b2; expression.<br><br>CONCLUSION: GSTM1 regulates DEP-induced IL-8 and IL-1&#x3b2; expression in primary human bronchial epithelial cells by modulation of ROS, ERK and Akt signaling.}, }
@article {pmid22865599, year = {2013}, author = {Meier, P and Renga, M and Hoppeler, H and Baum, O}, title = {The impact of antioxidant supplements and endurance exercise on genes of the carbohydrate and lipid metabolism in skeletal muscle of mice.}, journal = {Cell biochemistry and function}, volume = {31}, number = {1}, pages = {51-59}, doi = {10.1002/cbf.2859}, pmid = {22865599}, issn = {1099-0844}, mesh = {Acetylcysteine/*pharmacology ; Adaptation, Physiological/genetics/physiology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Carbohydrate Metabolism/*genetics ; Drug Evaluation, Preclinical ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation/*drug effects ; Lipid Metabolism/*genetics ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Proteins/*biosynthesis/genetics ; Muscle, Skeletal/*drug effects/metabolism ; Peroxiredoxin VI/biosynthesis/genetics ; Physical Conditioning, Animal/*physiology ; Physical Endurance/genetics/*physiology ; Random Allocation ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/biosynthesis/genetics ; Superoxide Dismutase-1 ; Ubiquinone/*analogs &amp; derivatives/pharmacology ; }, abstract = {To ascertain whether reactive oxygen species (ROS) contribute to training-induced adaptation of skeletal muscle, we administered ROS-scavenging antioxidants (AOX; 140 mg/l of ascorbic acid, 12 mg/l of coenzyme Q10 and 1% N-acetyl-cysteine) via drinking water to 16 C57BL/6 mice. Sixteen other mice received unadulterated tap water (CON). One cohort of both groups (CON(EXE) and AOX(EXE)) was subjected to treadmill exercise for 4 weeks (16-26 m/min, incline of 5°-10°). The other two cohorts (CON(SED) and AOX(SED)) remained sedentary. In skeletal muscles of the AOX(EXE) mice, GSSG and the expression levels of SOD-1 and PRDX-6 were significantly lower than those in the CON(EXE) mice after training, suggesting disturbance of ROS levels. The peak power related to the body weight and citrate synthase activity was not significantly influenced in mice receiving AOX. Supplementation with AOX significantly altered the mRNA levels of the exercise-sensitive genes HK-II, GLUT-4 and SREBF-1c and the regulator gene PGC-1alpha but not G6PDH, glycogenin, FABP-3, MCAD and CD36 in skeletal muscle. Although the administration of AOX during endurance exercise alters the expression of particular genes of the ROS metabolism, it does not influence peak power or generally shift the metabolism, but it modulates the expression of specific genes of the carbohydrate and lipid metabolism and PGC-1alpha within murine skeletal muscle.}, }
@article {pmid22859317, year = {2013}, author = {D'Amico, F and Vitale, A and Piovan, D and Bertacco, A and Ramirez Morales, R and Chiara Frigo, A and Bassi, D and Bonsignore, P and Gringeri, E and Valmasoni, M and Garbo, G and Lodo, E and D'Amico, FE and Scopelliti, M and Carraro, A and Gambato, M and Brolese, A and Zanus, G and Neri, D and Cillo, U}, title = {Use of N-acetylcysteine during liver procurement: a prospective randomized controlled study.}, journal = {Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society}, volume = {19}, number = {2}, pages = {135-144}, doi = {10.1002/lt.23527}, pmid = {22859317}, issn = {1527-6473}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Aged ; Antioxidants/*administration &amp; dosage ; Chi-Square Distribution ; Female ; Graft Survival/*drug effects ; Humans ; Infusions, Intravenous ; Italy ; Kaplan-Meier Estimate ; *Liver Transplantation/adverse effects/mortality ; Male ; Middle Aged ; Portal Vein ; Primary Graft Dysfunction/etiology/prevention &amp; control ; Proportional Hazards Models ; Prospective Studies ; Single-Blind Method ; Time Factors ; Tissue and Organ Harvesting/*methods ; Treatment Outcome ; Young Adult ; }, abstract = {Antioxidant agents have the potential to reduce ischemia/reperfusion damage to organs for liver transplantation (LT). In this prospective, randomized study, we tested the impact of an infusion of N-acetylcysteine (NAC) during liver procurement on post-LT outcomes. Between December 2006 and July 2009, 140 grafts were transplanted into adult candidates with chronic liver disease who were listed for first LT, and according to a sequential, closed-envelope, single-blinded procedure, these patients were randomly assigned in a 1/1 ratio to an NAC protocol (69 patients) or to the standard protocol without NAC [71 patients (the control group)]. The NAC protocol included a systemic NAC infusion (30 mg/kg) 1 hour before the beginning of liver procurement and a locoregional NAC infusion (300 mg through the portal vein) just before cross-clamping. The primary endpoint was graft survival. The graft survival rates at 3 and 12 months were 93% and 90%, respectively, in the NAC group and 82% and 70%, respectively, in the control group (P = 0.02). An adjusted Cox analysis showed a significant NAC effect on graft survival at both 3 months [hazard ratio = 1.65, 95% confidence interval (CI) = 1.01-2.93, P = 0.04] and 12 months (hazard ratio = 1.73, 95% CI = 1.14-2.76, P ≤ 0.01). The incidence of postoperative complications was lower in the NAC group (23%) versus the control group (51%, P < 0.01). In the subgroup of 61 patients (44%) receiving suboptimal grafts (donor risk index > 1.8), the incidence of primary dysfunction of the liver was lower (P = 0.09) for the NAC group (15%) versus the control group (32%). In conclusion, the NAC harvesting protocol significantly improves graft survival. The effect of NAC on early graft function and survival seems higher when suboptimal grafts are used.}, }
@article {pmid22858589, year = {2012}, author = {Yuan, Y and Ming, Z and Gong-Hua, H and Lan, G and Lu, D and Peng, L and Feng, J and Cai-Gao, Z}, title = {Cr(VI) induces the decrease of ATP level and the increase of apoptosis rate mediated by ROS or VDAC1 in L-02 hepatocytes.}, journal = {Environmental toxicology and pharmacology}, volume = {34}, number = {2}, pages = {579-587}, doi = {10.1016/j.etap.2012.06.016}, pmid = {22858589}, issn = {1872-7077}, mesh = {Adenosine Triphosphate/*metabolism ; Apoptosis/drug effects ; Carcinogens/*toxicity ; Cell Line ; Cell Survival/drug effects ; Chromium/*toxicity ; Environmental Pollutants/*toxicity ; Hepatocytes/drug effects/metabolism ; Humans ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Voltage-Dependent Anion Channel 1/*genetics ; }, abstract = {The present study explored the ability of the voltage-dependent anion channel 1 (VDAC1) mRNA and ROS levels to modulate the effects of hexavalent chromium Cr(VI) on the adenosine triphosphate (ATP) level and the rate of apoptotic cell death. Cultured L-02 cells were pretreated with 20mM N-acetyl-cysteine (NAC) for 24h or transiently transfected with small interfering RNAs targeting VDAC1 (siVDAC1) for 48h; cells that were not pretreated were used as the control. The cells were subsequently treated with 0, 2, 8, or 32μM Cr(VI) for 24h. Then, levels of VDAC1 mRNA, ROS, and ATP and the apoptosis rate were measured by reverse-transcription quantitative PCR, fluorometry, a bioluminescence assay, and flow cytometry, respectively. The results showed that Cr(VI) at 32μM led to increase in the ROS level, VDAC1 mRNA expression, and the apoptosis rate and a decrease in the ATP level; pretreatment with NAC led to the down-regulation in the levels of ROS, VDAC1 mRNA and apoptosis and the significant up-regulation in the ATP levels. Interestingly, after the pretreatment with siVDAC1 to inhibit VDAC1 mRNA expression, the increased apoptosis rates and decreased ATP levels were reversed as well. These results suggested that changes in the ROS or VDAC1 mRNA levels were associated with changes in the ATP level and apoptosis rate. Furthermore, correlation analysis confirmed the association between both the ROS and VDAC1 levels and both the ATP level and the apoptosis rate. In conclusion, Cr(VI) induced ROS- and VDAC1-mediated decreases in ATP levels and increases in the apoptosis rate.}, }
@article {pmid22855324, year = {2012}, author = {Foltz, WU and Wagner, M and Rudakova, E and Volk, T}, title = {N-acetylcysteine prevents electrical remodeling and attenuates cellular hypertrophy in epicardial myocytes of rats with ascending aortic stenosis.}, journal = {Basic research in cardiology}, volume = {107}, number = {5}, pages = {290}, doi = {10.1007/s00395-012-0290-4}, pmid = {22855324}, issn = {1435-1803}, mesh = {Acetylcysteine/*therapeutic use ; Action Potentials/drug effects ; Animals ; Antioxidants/*therapeutic use ; Aorta ; Aortic Valve Stenosis/complications/*drug therapy/pathology ; Calcium/metabolism ; Calcium Channels, L-Type/physiology ; Cardiomegaly/*drug therapy ; Endocardium/*pathology ; Female ; Hemodynamics/drug effects ; Myocytes, Cardiac/*pathology ; Rats ; Rats, Sprague-Dawley ; *Ventricular Remodeling ; }, abstract = {Pressure overload is associated with cardiac hypertrophy and electrical remodeling. Here, we investigate the effects of the antioxidant N-acetylcysteine (NAC) on the cellular cardiac electrophysiology of female Sprague-Dawley rats with ascending aortic stenosis (AS). Rats were treated with NAC (1 g/kg body weight) or control solution 1 week before the intervention and in the week following AS or sham operation. Seven days after the operation, blood pressure and left ventricular pressure were measured before the heart was excised. Single cells were isolated from epicardial and endocardial layers of the left ventricular free wall and investigated using the whole-cell patch-clamp technique. Systolic blood pressure and left ventricular peak pressure were not significantly altered in the NAC group. NAC reduced the increase (p < 0.001) in the relative left ventricular weight (p < 0.05) as well as the increase (p < 0.001) in cell capacitance in epicardial (p < 0.05), but not in endocardial myocytes of AS animals. The L-type Ca(2+) current (I (CaL)) was significantly increased by AS in epicardial (+19 % at 0 mV, p < 0.01) but not in endocardial myocytes. NAC completely prevented this increase in I (CaL) (p < 0.01). The current density of the transient outward K(+) current (I (to)) was not affected by AS or NAC. Action potential duration to 90 % repolarization was significantly prolonged in epicardial (p < 0.01) as well as in endocardial (p < 0.001) cells of AS animals. NAC prevented the AP prolongation in epicardial myocytes only (p < 0.05). We conclude that reducing oxidative stress in pressure overload can prevent electrical remodeling and ameliorate hypertrophy in epicardial but not in endocardial myocytes.}, }
@article {pmid22854047, year = {2012}, author = {Abdelsaid, MA and El-Remessy, AB}, title = {S-glutathionylation of LMW-PTP regulates VEGF-mediated FAK activation and endothelial cell migration.}, journal = {Journal of cell science}, volume = {125}, number = {Pt 20}, pages = {4751-4760}, doi = {10.1242/jcs.103481}, pmid = {22854047}, issn = {1477-9137}, mesh = {*Cell Movement/drug effects/genetics ; Cells, Cultured ; *Endothelial Cells/cytology/drug effects/metabolism ; Focal Adhesion Kinase 1/genetics/*metabolism ; Glutathione/metabolism ; Humans ; Molecular Weight ; Neovascularization, Physiologic/genetics ; Oxidation-Reduction/drug effects ; Oxidative Stress ; Peroxynitrous Acid/pharmacology ; Phosphorylation/drug effects ; *Protein Tyrosine Phosphatases/genetics/metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor A/genetics/*metabolism ; }, abstract = {Although promising, the ability to regulate angiogenesis through delivery of VEGF remains an unrealized goal. We have shown previously that physiological levels of peroxynitrite (1 µM) are required for a VEGF-mediated angiogenic response, yet the redox-regulated mechanisms that govern the VEGF signal remain unexplored. We assessed the impact of VEGF and peroxynitrite on modifying redox-state, the level of reduced-glutathione (GSH) and S-glutathionylation on regulation of the low molecular weight protein tyrosine phosphatase (LMW-PTP) and focal adhesion kinase (FAK), which are key mediators of VEGF-mediated cell migration. Stimulation of human microvascular endothelial (HME) cells with VEGF (20 ng/ml) or peroxynitrite (1 µM) caused an immediate and reversible negative-shift in the cellular redox-state and thiol oxidation of LMW-PTP, which culminated in cell migration. VEGF causes reversible S-glutathionylation of LMW-PTP, which inhibits its phosphorylation and activity, and causes the transient activation of FAK. Modulating the redox-state using decomposing peroxynitrite (FeTPPS, 2.5 µM) or the GSH-precursor [N-acetylcysteine (NAC), 1 mM] caused a positive-shift of the redox-state and prevented VEGF-mediated S-glutathionylation and oxidative inhibition of LMW-PTP. NAC and FeTPPS prevented the activation of FAK, its association with LMW-PTP and cell migration. Inhibiting LMW-PTP expression markedly enhanced FAK activation and cell migration. Although mild oxidative stress achieved by combining VEGF with 0.1-0.2 mM peroxynitrite augmented cell migration, an acute shift to oxidative stress achieved by combining VEGF with 0.5 mM peroxynitrite induced and sustained FAK activation, and LMW-PTP S-glutathionylation, resulting in LMW-PTP inactivation and inhibited cell migration. In conclusion, our findings demonstrate that a balanced redox-state is required for VEGF to facilitate reversible S-glutathionylation of LMW-PTP, FAK activation and endothelial cell migration. Shifting the redox-state to reductive stress or oxidative stress inhibited the VEGF-mediated angiogenic response.}, }
@article {pmid22851277, year = {2012}, author = {Thakurta, IG and Chattopadhyay, M and Ghosh, A and Chakrabarti, S}, title = {Dietary supplementation with N-acetyl cysteine, α-tocopherol and α-lipoic acid reduces the extent of oxidative stress and proinflammatory state in aged rat brain.}, journal = {Biogerontology}, volume = {13}, number = {5}, pages = {479-488}, doi = {10.1007/s10522-012-9392-5}, pmid = {22851277}, issn = {1573-6768}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Brain/*metabolism ; Cell Nucleus/metabolism ; Cytokines/metabolism ; *Dietary Supplements ; Enzyme-Linked Immunosorbent Assay ; Inflammation/*metabolism ; Mitochondria/metabolism ; NF-kappa B/metabolism ; *Oxidative Stress ; Rats ; Reactive Oxygen Species/metabolism ; Thioctic Acid/*administration &amp; dosage ; alpha-Tocopherol/*administration &amp; dosage ; }, abstract = {The present study has attempted to understand how oxidative stress contributes to the development of proinflammatory state in the brain during aging. Three groups of rats have been used in this study: young (4-6 months, Group I), aged (22-24 months, Group II) and aged with dietary antioxidant supplementation (Group III). The antioxidants were given daily from 18 months onwards in the form of a combination of N-acetyl cysteine (50 mg/100 g body weight), α-lipoic acid (3 mg/100 g body weight), and α-tocopherol (1.5 mg/100 g body weight) till the animals were used for the experiments between 22 and 24 months. Several measurements have been made to evaluate the ROS (reactive oxygen species) production rate, the levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and the activation status of NF-κβ (p65 subunit) in brain of the three groups of rats under the study. Our results reveal that brain aging is accompanied with a significant increase in NADPH oxidase activity and mitochondrial ROS production, a distinct elevation of IL-1β, IL-6 and TNF-α levels along with increased nuclear translocation of NF-κβ (p65 subunit) and all these phenomena are partially but significantly prevented by the long-term dietary antioxidant treatment. The results imply that chronic dietary antioxidants by preventing oxidative stress and proinflammatory state may produce beneficial effects against multiple age-related deficits of the brain.}, }
@article {pmid22850708, year = {2012}, author = {Saad, PF and Saad, KR and Oliveira Filho, LD and Ferreira, SG and Koike, MK and Montero, EF}, title = {Effect of N-acetylcysteine on pulmonary cell death in a controlled hemorrhagic shock model in rats.}, journal = {Acta cirurgica brasileira}, volume = {27}, number = {8}, pages = {561-565}, doi = {10.1590/s0102-86502012000800008}, pmid = {22850708}, issn = {1678-2674}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Caspase 3/metabolism ; Cell Death/*drug effects ; Disease Models, Animal ; Fluid Therapy ; In Situ Nick-End Labeling ; Lung/*cytology ; Lung Injury/prevention &amp; control ; Male ; Rats ; Resuscitation/*methods ; Shock, Hemorrhagic/*drug therapy/pathology ; Time Factors ; }, abstract = {PURPOSE: To evaluate the effect of N-acetylcysteine (NAC) combined with fluid resuscitation on pulmonary cell death in rats induced with controlled hemorrhagic shock (HS).<br><br>METHODS: Two arteries (MAP calculation and exsanguination) and one vein (treatments) were catheterized in 22 anesthetized rats. Two groups of male albino rats were induced with controlled HS at 35mmHg MAP for 60 min. After this period, the RL group was resuscitated with Ringer's lactate and the RL+NAC group was resuscitated with Ringer's lactate combined with 150mg/Kg NAC. The control group animals were cannulated only. The animals were euthanized after 120 min of fluid resuscitation. Lung tissue samples were collected to evaluate the following: histopathology, TUNEL and imunohistochemical expression of caspase 3.<br><br>RESULTS: RL showed a greater number of cells stained by TUNEL than RL + NAC, but there was no change in caspase 3 expression in any group.<br><br>CONCLUSION: N-acetylcysteine associate to fluid resuscitation, after hemorrhagic shock, decreased cell death attenuating lung injury.}, }
@article {pmid22849820, year = {2012}, author = {Hawkins-Salsbury, JA and Qin, EY and Reddy, AS and Vogler, CA and Sands, MS}, title = {Oxidative stress as a therapeutic target in globoid cell leukodystrophy.}, journal = {Experimental neurology}, volume = {237}, number = {2}, pages = {444-452}, pmid = {22849820}, issn = {1090-2430}, support = {R01 HD055461/HD/NICHD NIH HHS/United States ; R01 NS084861/NS/NINDS NIH HHS/United States ; HD055461/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; *Bone Marrow Transplantation ; Disease Models, Animal ; Immunohistochemistry ; Leukodystrophy, Globoid Cell/*drug therapy/*surgery ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; *Oxidative Stress/drug effects ; }, abstract = {Globoid cell leukodystrophy (GLD, Krabbe Disease) is a lysosomal storage disease, resulting from the genetic deficiency of galactosylceramidase (GALC). This disease is marked by accumulation of the cytotoxic lipid psychosine (Psy). Psychosine is known to induce oxidative stress in cultured cells, and this stress can be ameliorated through co-treatment with the antioxidant N-acetyl cysteine (NAC). Oxidative stress has also been observed in vivo in the mouse model of GLD, the Twitcher mouse (Twi). We hypothesized that treating oxidative stress with NAC; either alone or in combination with bone marrow transplant (BMT) would improve the course of disease. All breeding cages were maintained on water containing NAC. Once born, the pups received IP boluses of NAC three times per week, and were maintained on NAC-containing water. A separate cohort of animals received the same regimen of NAC in addition to a BMT on post-natal days 2-3. Although NAC lowers the level of oxidized proteins in the brains of Twi mice, and dramatically improves immunohistochemical markers of disease, neither treatment results in any clinical improvements in the Twi mouse. Our data suggest that oxidative stress may be sufficiently down-stream in the pathogenic cascade initiated by Psy accumulation as to be difficult or impossible to treat with standard pharmacologic agents. It is possible that NAC may synergize with other therapies or combinations of therapies. A better understanding of the initiating effects of Psy toxicity and oxidative damage may uncover treatable therapeutic targets.}, }
@article {pmid22842004, year = {2012}, author = {Guerrero, CA and Murillo, A and Acosta, O}, title = {Inhibition of rotavirus infection in cultured cells by N-acetyl-cysteine, PPARγ agonists and NSAIDs.}, journal = {Antiviral research}, volume = {96}, number = {1}, pages = {1-12}, doi = {10.1016/j.antiviral.2012.06.011}, pmid = {22842004}, issn = {1872-9096}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Cell Line ; Drug Evaluation, Preclinical/methods ; Haplorhini ; Microbial Sensitivity Tests ; PPAR gamma/*antagonists &amp; inhibitors ; Rotavirus/*drug effects/physiology ; Virus Replication/*drug effects ; }, abstract = {Although the current rotavirus vaccines have shown good tolerance and significant efficacy, it would be useful to develop alternative or complementary strategies aimed at preventing or treating acute diarrhoeal disease caused by this viral agent. A variety of antiviral strategies other than vaccines have been assayed for rotavirus infection management. The recently demonstrated sensitivity of rotavirus infectivity to thiol/disulfide reagents prompted assays for screening drugs that potentially affect cellular redox reactions. MA104 or Caco-2 cells were inoculated with the rotavirus strains RRV, Wa, Wi or M69 and then incubated with different concentrations of drugs belonging to a selected group of 60 drugs that are currently used in humans for purposes other than rotavirus infection treatment. Eighteen of these drugs were able to inhibit rotavirus infectivity to different extents. A more systematic evaluation was performed with drugs that could be used in children such as N-acetylcysteine and ascorbic acid, in addition to ibuprofen, pioglitazone and rosiglitazone, all of which affecting cellular pathways potentially needed by the rotavirus infection process. Evidence is provided here that rotavirus infectivity is significantly inhibited by NAC in different cell-culture systems. These findings suggest that NAC has the potential to be used as a therapeutic tool for treatment and prevention of rotavirus disease in children.}, }
@article {pmid22837810, year = {2012}, author = {Ma, Y and Nie, H and Sheng, C and Chen, H and Wang, B and Liu, T and Shao, J and He, X and Zhang, T and Zheng, C and Xia, W and Ying, W}, title = {Roles of oxidative stress in synchrotron radiation X-ray-induced testicular damage of rodents.}, journal = {International journal of physiology, pathophysiology and pharmacology}, volume = {4}, number = {2}, pages = {108-114}, pmid = {22837810}, issn = {1944-8171}, abstract = {Synchrotron radiation (SR) X-ray has characteristic properties such as coherence and high photon flux, which has excellent potential for its applications in medical imaging and cancer treatment. However, there is little information regarding the mechanisms underlying the damaging effects of SR X-ray on biological tissues. Oxidative stress plays an important role in the tissue damage induced by conventional X-ray, while the role of oxidative stress in the tissue injury induced by SR X-ray remains unknown. In this study we used the male gonads of rats as a model to study the roles of oxidative stress in SR X-ray-induced tissue damage. Exposures of the testes to SR X-ray at various radiation doses did not significantly increase the lipid peroxidation of the tissues, assessed at one day after the irradiation. No significant decreases in the levels of GSH or total antioxidation capacity were found in the SR X-ray-irradiated testes. However, the SR X-ray at 40 Gy induced a marked increase in phosphorylated H2AX - a marker of double-strand DNA damage, which was significantly decreased by the antioxidant N-acetyl cysteine (NAC). NAC also attenuated the SR X-ray-induced decreases in the cell layer number of seminiferous tubules. Collectively, our observations have provided the first characterization of SR X-ray-induced oxidative damage of biological tissues: SR X-ray at high doses can induce DNA damage and certain tissue damage during the acute phase of the irradiation, at least partially by generating oxidative stress. However, SR X-ray of various radiation doses did not increase lipid peroxidation.}, }
@article {pmid22834414, year = {2012}, author = {Zhang, S and Jiang, Y and Chen, CS and Spurgin, J and Schwehr, KA and Quigg, A and Chin, WC and Santschi, PH}, title = {Aggregation, dissolution, and stability of quantum dots in marine environments: importance of extracellular polymeric substances.}, journal = {Environmental science &amp; technology}, volume = {46}, number = {16}, pages = {8764-8772}, doi = {10.1021/es301000m}, pmid = {22834414}, issn = {1520-5851}, mesh = {Light ; Osmolar Concentration ; Oxidative Stress ; Phytoplankton/*chemistry ; Polymers/*chemistry ; *Quantum Dots ; *Seawater ; Solubility ; }, abstract = {There is an increasing concern that a considerable fraction of engineered nanoparticles (ENs), including quantum dots (QDs), will eventually find their way into the marine environment and have negative impacts on plankton. As ENs enter the ocean, they will encounter extracellular polymeric substances (EPS) from microbial sources before directly interacting with plankton cells. In this study, EPS harvested from four phytoplankton species, Amphora sp., Dunaliella tertiolecta, Phaeocystis globosa, and Thalassiosira pseudonana, were examined for potential interactions with CdSe nonfunctionalized and functionalized (carboxyl- and amine-) QDs in artificial seawater. Our results show that EPS do not reduce the solubility of QDs but rather decrease their stability. The degradation rate of QDs was positively correlated to the protein composition of EPS (defined by the ratio of protein/carbohydrate). Two approaches showed significant inhibition to the degradation of carboxyl-functionalized QDs: (1) the presence of an antioxidant, such as N-acetyl cysteine, and (2) absence of light. Owing to the complexity in evaluating integrated effects of QDs intrinsic properties and the external environmental factors that control the stability of QDs, conclusions must be based on a careful consideration of all these factors when attempting to evaluate the bioavailability of QDs and other ENs in the marine environments.}, }
@article {pmid22833345, year = {2013}, author = {Shimojo, Y and Akimoto, M and Hisanaga, T and Tanaka, T and Tajima, Y and Honma, Y and Takenaga, K}, title = {Attenuation of reactive oxygen species by antioxidants suppresses hypoxia-induced epithelial-mesenchymal transition and metastasis of pancreatic cancer cells.}, journal = {Clinical &amp; experimental metastasis}, volume = {30}, number = {2}, pages = {143-154}, pmid = {22833345}, issn = {1573-7276}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Apoptosis/drug effects ; Blotting, Western ; Cell Adhesion ; Cell Movement ; Cell Proliferation ; Epithelial-Mesenchymal Transition/*drug effects ; Female ; Fluorescent Antibody Technique ; Humans ; Hypoxia/*pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists &amp; inhibitors/genetics/metabolism ; Liver Neoplasms/metabolism/*prevention &amp; control/secondary ; Mice ; Mice, Nude ; NF-kappa B/antagonists &amp; inhibitors/genetics/metabolism ; Pancreatic Neoplasms/metabolism/pathology/*prevention &amp; control ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Snail Family Transcription Factors ; Transcription Factors/genetics/metabolism ; Tumor Cells, Cultured ; Twist-Related Protein 1/genetics/metabolism ; }, abstract = {Hypoxia has been shown to promote metastasis of cancer cells through induction of epithelial-mesenchymal transition (EMT). It is also known to cause generation of reactive oxygen species (ROS). We investigated here the role of ROS in hypoxia-induced EMT and whether attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastasis of human pancreatic cancer cells in a xenograft nude mouse model. PANC-1 and MiaPaCa-2 cells exposed to hypoxia (1 % O(2)) showed increased ROS generation and characteristic changes of EMT such as morphological changes, enhanced invasiveness, and upregulation of EMT regulators, SLUG, SNAI1 and TWIST. The antioxidants N-acetylcysteine (NAC) and ebselen significantly suppressed EMT and the expression of EMT regulators during hypoxia. NAC abrogated activation of HIF-1α and NF-κB, both of which were found to play an active role in hypoxia-induced EMT. Administration of NAC to nude mice with orthotopic tumors suppressed the expression of EMT regulators in hypoxic areas and significantly inhibited hepatic metastasis. Together, the present findings demonstrate that attenuation of ROS by antioxidants suppresses hypoxia-induced EMT and metastatic phenotype, suggesting that antioxidants may be of therapeutic value in treating pancreatic cancers.}, }
@article {pmid22825687, year = {2012}, author = {Tateda, K and Okazaki, S and Nagoya, S and Katada, R and Mizuo, K and Watanabe, S and Yamashita, T and Matsumoto, H}, title = {The suppression of TRIM21 and the accumulation of IFN-α play crucial roles in the pathogenesis of osteonecrosis of the femoral head.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {92}, number = {9}, pages = {1318-1329}, doi = {10.1038/labinvest.2012.89}, pmid = {22825687}, issn = {1530-0307}, mesh = {Animals ; Electrophoretic Mobility Shift Assay ; Femur Head Necrosis/metabolism/*physiopathology ; Immunohistochemistry ; Interferon-alpha/*metabolism ; Male ; Rats ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Tripartite Motif Proteins ; Ubiquitin-Protein Ligases/*physiology ; }, abstract = {Osteonecrosis of the femoral head (ONFH), the pathogenesis of which remains unclear, has been observed in autoimmune disease patients treated with corticosteroids. Recently, it has been shown that anti-tripartite motif-containing 21 (TRIM21) autoantibodies, which are often present in patients with systemic lupus erythematosis and Sjögren's syndrome, inhibit the E3 ligase activity of TRIM21. TRIM21 negatively regulates nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) 3 and 7, three downstream transcription factors, via toll-like receptor 4 signaling. The aim of this study was to clarify the role of TRIM21 in the pathogenesis of ONFH using an animal model. Male Wistar rats were injected with lipopolysaccharide (LPS) twice and with methylprednisolone (MPSL) or saline three times. N-acetyl cysteine (NAC) was administered either concurrently with MPSL or once daily for the 3 days following the last MPSL injection. The incidence of ONFH in the MPSL group was 23.5%. Co-treatment of NAC and MPSL increased the incidence of ONFH to 55.6%. MPSL treatment decreased the activity of NF-κB in the liver and significantly increased the activity of both IRF3 and IRF7. No significant differences were observed in the activity of any of these three transcription factors between the MPSL and the co-treatment groups. In the femoral head, co-treatment with NAC and MPSL significantly decreased the expression of TRIM21 at 3 h and significantly increased the expression of interferon (IFN)-α at 24 h when compared with the MPSL group. IFN-α is known to induce cell death. These findings suggest that the suppression of TRIM21 in the femoral head causes an accumulation of IFN-α, which in turn leads to the development of ONFH. In conclusion, the suppression of TRIM21 resulting from altered NF-κB and IRF homeostasis accelerates the ONFH in rats treated with corticosteroids following LPS administration.}, }
@article {pmid22825625, year = {2012}, author = {Kim, HJ and Kim, SR and Park, JK and Kim, DI and Jeong, JS and Lee, YC}, title = {PI3Kγ activation is required for LPS-induced reactive oxygen species generation in respiratory epithelial cells.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {61}, number = {11}, pages = {1265-1272}, pmid = {22825625}, issn = {1420-908X}, mesh = {Cell Line ; Cell Line, Tumor ; Class Ib Phosphatidylinositol 3-Kinase/genetics/*metabolism ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Lipopolysaccharides ; Lung/cytology ; NF-kappa B/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Quinoxalines/pharmacology ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Thiazolidinediones/pharmacology ; }, abstract = {OBJECTIVE: In this study, we investigated the molecular basis of reactive oxygen species (ROS) generation induced by lipopolysaccharide (LPS) in A549 cells--an alveolar epithelial cell line.<br><br>EXPERIMENTAL DESIGN: A549 cells or normal human bronchial epithelial (NHBE) cells were stimulated with LPS. ROS generation was measured in A549 cells or NHBE cells pre-treated with a selective inhibitor of phosphatidylinositol 3-kinase &#x3b3; (PI3K&#x3b3;), AS 605240, PI3K&#x3b3; siRNA, or a ROS scavenger, pyridoxamine (PM).<br><br>RESULTS: Treatment of A549 cells or NHBE cells with LPS caused a significant increase in intracellular ROS generation. Pretreatment with the PI3K&#x3b3; inhibitor, AS 605240 decreased the LPS-induced increase of ROS generation, phosphorylation of Akt, and production of phosphatidyl 3,4,5-trisphosphate in A549 cells. In addition, interference with siRNA for PI3K&#x3b3; significantly reduced LPS-induced ROS generation in A549 cells. Treatment of A549 cells with LPS or hydrogen peroxide increased the nuclear factor-&#x3ba;B (NF-&#x3ba;B) in the nucleus, accompanying an increase in phosphorylation of inhibitory &#x3ba;B-&#x3b1;, degradation of the protein, and reduction of cytosolic NF-&#x3ba;B. Pretreatment with AS 605240 reduced these LPS-induced changes. In addition, pretreatment with PM or N-acetyl cysteine resulted in inhibition of nuclear NF-&#x3ba;B activation.<br><br>CONCLUSION: These results suggest that PI3K&#x3b3; plays a key role in LPS-induced ROS generation in alveolar epithelial cells, thereby activating NF-&#x3ba;B.}, }
@article {pmid22825350, year = {2012}, author = {Cheng, YY and Yang, JS and Tsai, SC and Liaw, CC and Chung, JG and Huang, LJ and Lee, KH and Lu, CC and Chien, HC and Tsuzuki, M and Kuo, SC}, title = {The newly synthesized 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one triggers cell apoptosis through induction of oxidative stress and upregulation of the p38 MAPK signaling pathway in HL-60 human leukemia cells.}, journal = {Oncology reports}, volume = {28}, number = {4}, pages = {1482-1490}, doi = {10.3892/or.2012.1923}, pmid = {22825350}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects/physiology ; Benzodioxoles/*pharmacology ; Caspases/metabolism ; Cell Survival/drug effects ; Free Radical Scavengers/pharmacology ; HL-60 Cells/drug effects/pathology ; Humans ; Leukemia/drug therapy ; Oxidative Stress/*drug effects ; Quinolones/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Up-Regulation ; fas Receptor/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {The aim of the present study was to discover the signaling pathways associated with 2-(3-hydroxy-5-methoxy-phenyl)-6,7-methylenedioxyquinolin-4-one (YYK1)-induced apoptosis in HL-60 human leukemia cells. YYK1 induced cytotoxic effects, cell morphological changes, decreased the cell number and increased reactive oxygen species (ROS) production and loss of mitochondrial membrane potential (ΔΨm) in HL-60 cells. YYK1-induced apoptosis was confirmed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Results from colorimetric assays and western blot analysis indicated that activities of caspase-7/-3, caspase-8 and caspase-9 were increased in YYK1-treated HL-60 cells. Western blot analysis showed that the protein levels of extrinsic apoptotic proteins (Fas/CD95, FasL and FADD), intrinsic related proteins (cytochrome c, Apaf-1, AIF and Endo G), the ratio of Bax/Bcl-2 and phosphorylated p38 MAPK were increased in HL-60 cells after YYK1 treatment. Cell apoptosis was significantly reduced after pre-treatment with N-acetylcysteine (NAC; a ROS scavenger) or diphenyleneiodonium chloride (DPI; a NADPH oxidase inhibitor). Blockage of p38 MAPK signaling by SB202190 abolished YYK1-induced Fas/CD95 upregulation and apoptosis in HL-60 cells. We conclude that YYK1 induces both of extrinsic and intrinsic apoptotic pathways via ROS-mediated activation of p38 MAPK signaling in HL-60 human leukemia cells in vitro.}, }
@article {pmid22824464, year = {2012}, author = {Liu, L and Fu, J and Li, T and Cui, R and Ling, J and Yu, X and Ji, H and Zhang, Y}, title = {NG, a novel PABA/NO-based oleanolic acid derivative, induces human hepatoma cell apoptosis via a ROS/MAPK-dependent mitochondrial pathway.}, journal = {European journal of pharmacology}, volume = {691}, number = {1-3}, pages = {61-68}, doi = {10.1016/j.ejphar.2012.07.031}, pmid = {22824464}, issn = {1879-0712}, mesh = {4-Aminobenzoic Acid/*chemistry ; Animals ; Antineoplastic Agents/chemistry/pharmacology ; Apoptosis/*drug effects ; Azo Compounds/*pharmacology ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/pathology ; MAP Kinase Signaling System/*drug effects ; Male ; Mice ; Mitochondria/*drug effects/metabolism/pathology ; Nitric Oxide/*chemistry ; Oleanolic Acid/analogs &amp; derivatives/*pharmacology ; Reactive Oxygen Species/*metabolism ; Saponins/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {O(2)-(2,4-dinitro-5-{[2-(12-en-28-β-D- galactopyranosyl-oleanolate-3-yl) -oxy-2-oxoethyl]amino}phenyl)1-(N-hydroxyethylmethylamino)diazen-1-ium-1,2- diolate (NG), a novel PABA/NO-based derivative of oleanolic acid (OA), has been found to show potent antitumor activity both in vivo and in vitro. In the present study, NG could significantly reduce tumor volume and weight in the H22 solid tumor mouse model. Meanwhile, NG showed selective effects on the HepG2 cells including NO generation, cytotoxic effect and apoptosis, which were prevented by hemoglobin (NO scavenger). Moreover, NG-induced apoptosis of HepG2 cells was characteristic of intracellular reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (Δψm) and enhanced Bax-to-Bcl-2 ratio. The release of apoptotic inducing factor (AIF) and cytochrome c (Cyt c) from mitochondria and the activation of caspase-3, 9 were also detected, indicating that NG may induce apoptosis through a mitochondrial-mediated pathway. Simultaneously, NG treatment could lead to the activation of the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK but not ERK1/2. Treatment with SP600125 (an inhibitor of JNK) and SB203580 (an inhibitor of p38) prior to NG was found to reverse NG-induced apoptosis. Moreover, it was found that antioxidant N-acetylcysteine (NAC) blocked the induction of apoptosis and partly reversed the activation of JNK and p38, up-regulation of Bax, down-regulation of Bcl-2 and the activation of caspase-3 in NG-treated cells. Taking together, these findings suggest that NO can be released from NG, which induces apoptosis through a ROS/MAPK-mediated mitochondrial pathway.}, }
@article {pmid22824136, year = {2013}, author = {Di Maio, R and Mastroberardino, PG and Hu, X and Montero, LM and Greenamyre, JT}, title = {Thiol oxidation and altered NR2B/NMDA receptor functions in in vitro and in vivo pilocarpine models: implications for epileptogenesis.}, journal = {Neurobiology of disease}, volume = {49}, number = {}, pages = {87-98}, doi = {10.1016/j.nbd.2012.07.013}, pmid = {22824136}, issn = {1095-953X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/physiology ; Cells, Cultured ; Disease Models, Animal ; Dizocilpine Maleate/pharmacology ; Epilepsy, Temporal Lobe/drug therapy/*physiopathology ; Excitatory Amino Acid Antagonists/pharmacology ; Hippocampus/drug effects/*physiopathology ; MAP Kinase Signaling System/drug effects/physiology ; Male ; Neurons/drug effects/physiology ; Neuroprotective Agents/pharmacology ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects/physiology ; Pilocarpine ; Piperidines/pharmacology ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/*metabolism ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Hippocampal sclerosis, the main pathological sign of chronic temporal lobe epilepsy (TLE), is associated with oxidative injury, altered N-methyl d-aspartate receptor (NMDAR) stoichiometry, and loss of hippocampal neurons. However, the mechanisms that drive the chronic progression of TLE remain elusive. Our previous studies have shown that NADPH oxidase activation and ERK 1/2 phosphorylation are required for the up-regulation of the predominantly pre-synaptic NR2B subunit auto-receptor in both in vitro and in vivo pilocarpine (PILO) models of TLE. To provide further understanding of the cellular responses during the early-stages of hyper excitability, we investigated the role of oxidative damage and altered NR2B functions. In rat primary hippocampal cultures, we found that N-acetylcysteine (NAC) prevented PILO-mediated thiol oxidation, apoptosis, cell death and NR2B subunit over-expression. Interestingly, NAC did not block thiol oxidation when added to the neurons 6h after the PILO exposure, suggesting that disulfide formation could rapidly become an irreversible phenomenon. Moreover, NAC pre-treatment did not prevent PILO-induced NR2A subunit over-expression, a critical event in hippocampal sclerosis. Pre-treatment with the highly specific NR2B subunit inhibitor, ifenprodil, partially decreased PILO-mediated thiol oxidation and was not effective in preventing apoptosis and cell death. However, if acutely administered 48h after PILO exposure, ifenprodil blocked glutamate-induced aberrant calcium influx, suggesting the crucial role of NR2B over-expression in triggering neuronal hyper-excitability. Furthermore, ifenprodil treatment was able to prevent NR2A subunit over-expression by means of ERK1/2 phosphorylation. Our findings indicate oxidative stress and NR2B/NMDA signaling as promising therapeutic targets for co-treatments aimed to prevent chronic epilepsy following the seizure onset.}, }
@article {pmid22824115, year = {2012}, author = {Lai, IK and Dhakal, K and Gadupudi, GS and Li, M and Ludewig, G and Robertson, LW and Olivier, AK}, title = {N-acetylcysteine (NAC) diminishes the severity of PCB 126-induced fatty liver in male rodents.}, journal = {Toxicology}, volume = {302}, number = {1}, pages = {25-33}, pmid = {22824115}, issn = {1879-3185}, support = {ES 05605/ES/NIEHS NIH HHS/United States ; P30 CA 086862/CA/NCI NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; P42 ES 013661/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; ES 013661/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; CD36 Antigens/genetics ; Chemical and Drug Induced Liver Injury/etiology/pathology/*prevention &amp; control ; Fatty Liver/chemically induced/pathology/*prevention &amp; control ; Gene Expression Regulation/drug effects ; Glutathione/metabolism ; Injections, Intraperitoneal ; Male ; Organ Size/drug effects ; Polychlorinated Biphenyls/administration &amp; dosage/*toxicity ; Rats ; Rats, Sprague-Dawley ; Receptors, Aryl Hydrocarbon/agonists ; Severity of Illness Index ; }, abstract = {Potent aryl hydrocarbon receptor agonists like PCB 126 (3,3',4,4',5-pentachlorobiphenyl) cause oxidative stress and liver pathology, including fatty liver. Our question was whether dietary supplementation with N-acetylcysteine (NAC), an antioxidant, can prevent these adverse changes. Male Sprague-Dawley rats were fed a standard AIN-93G diet (sufficient in cysteine) or a modified diet supplemented with 1.0% NAC. After one week, rats on each diet were exposed to 0, 1, or 5μmol/kg body weight PCB 126 by i.p. injection (6 rats per group) and euthanized two weeks later. PCB-treatment caused a dose-dependent reduction in growth, feed consumption, relative thymus weight, total glutathione and glutathione disulfide (GSSG), while relative liver weight, glutathione transferase activity and hepatic lipid content were dose-dependently increased with PCB dose. Histologic examination of liver tissue showed PCB 126-induced hepatocellular steatosis with dose dependent increase in lipid deposition and distribution. Dietary NAC resulted in a reduction in hepatocellular lipid in both PCB groups. This effect was confirmed by gravimetric analysis of extracted lipids. Expression of CD36, a scavenger receptor involved in regulating hepatic fatty acid uptake, was reduced with high dose PCB treatment but unaltered in PCB-treated rats on NAC-supplemented diet. These results demonstrate that NAC has a protective effect against hepatic lipid accumulation in rats exposed to PCB 126. The mechanism of this protective effect appears to be independent of NAC as a source of cysteine/precursor of glutathione.}, }
@article {pmid22820949, year = {2013}, author = {Gatti, R and Andreatta, P and Boschetti, S}, title = {Study of 1,4-naphthoquinone as a new useful derivatization reagent for LC analysis of aliphatic thiols in dietary supplements and pharmaceuticals.}, journal = {Analytical and bioanalytical chemistry}, volume = {405}, number = {2-3}, pages = {817-825}, doi = {10.1007/s00216-012-6250-x}, pmid = {22820949}, issn = {1618-2650}, mesh = {Acetylcysteine/chemistry ; Chromatography, High Pressure Liquid/instrumentation/*methods ; Dietary Supplements/*analysis ; Naphthoquinones/*chemistry ; Pharmaceutical Preparations/*analysis ; Sulfhydryl Compounds/*analysis ; }, abstract = {The use of 1,4-naphthoquinone as an advantageous pre-column reagent for liquid chromatography analysis of aliphatic thiol compounds is proposed. The compound reacts selectively in mild conditions (5 min at room temperature; pH 7.5) with thiol function. The resulting adducts were separated under isocratic conditions by using a reversed-phase column (C-12n) with a mobile phase corresponding to methanol/triethylammonium phosphate buffer (pH 3; 0.05 mol L(-1)) 65:35, v/v, at a flow rate of 0.4 mL min(-1) in presence of quercetin as internal standard. Detection was set at a wavelength of 420 nm. The effect of the derivatization reaction conditions on the N-acetylcysteine (NAC) reaction yield was investigated by a series of experiments. The yield of NAC derivative was found to be quantitative at a reagent thiol molar ratio of about 3 by comparison with an authentic specimen of synthesized NAC adduct, which was characterized by (1) H NMR, IR, and UV. Similar linear responses were observed by standard and placebo solutions (determination coefficient, 0.9998). The within- and between-day standard deviations (RSD) were ≤0.47 %. Recovery studies showed good results (100.03 %) with RSD 0.76 %. The limit of detection was about 20 pmol. The utility of the validated method for the determination of NAC in a new dietary supplement and commercial formulations is demonstrated.}, }
@article {pmid22820874, year = {2012}, author = {Zeini Jahromi, E and Gailer, J}, title = {In vitro assessment of chelating agents with regard to their abstraction efficiency of Cd(2+) bound to plasma proteins.}, journal = {Metallomics : integrated biometal science}, volume = {4}, number = {9}, pages = {995-1003}, doi = {10.1039/c2mt20084h}, pmid = {22820874}, issn = {1756-591X}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/chemistry/metabolism ; Animals ; Blood Proteins/*metabolism ; Cadmium/*metabolism ; Calcium/metabolism ; Chelating Agents/chemistry/*metabolism ; Chromatography, Gel ; Humans ; Rabbits ; Spectrophotometry, Atomic ; Succimer/chemistry/metabolism ; Unithiol/chemistry/metabolism ; Zinc/metabolism ; }, abstract = {The exposure of various human populations to Cd(2+) is of increasing health concern. After its gastrointestinal absorption into the bloodstream, Cd(2+) binds to α(2)-macroglobulin and serum albumin. Although animal studies have demonstrated that meso-2,3-dimercaptosuccinic acid (DMSA) and diethylenetriamine pentaacetic acid (DTPA) can effectively mobilize Cd(2+) to urine and decrease the Cd concentrations of the kidneys, the liver and the brain, not much is known about the abstraction of Cd(2+) from blood plasma proteins. We prepared a stock of Cd(2+) spiked rabbit plasma (2.0 μg of Cd(2+)/mL) and analyzed aliquots by size exclusion chromatography coupled on-line to an inductively coupled plasma atomic emission spectrometer (SEC-ICP-AES) while simultaneously monitoring the emission lines of Ca, Cd, Cu, Fe, and Zn. After the addition of 0.33 mM, 0.66 mM or 0.99 mM of DMSA, DTPA, 2,3-dimercapto-1-propanesulfonic acid (DMPS) or N-acetyl-l-cysteine (NAC) to plasma aliquots, the obtained mixtures were analyzed by SEC-ICP-AES after 5 min and 30 min. None of the investigated compounds adversely affected the plasma distribution of Fe at all investigated doses. At 0.33 mM, DTPA was most effective at mobilizing plasma protein bound Cd(2+) to a ~5 kDa Cd-species (100% removal), followed by DMPS (94%), DMSA (83%) and NAC (3%). All investigated compounds also mobilized Zn(2+) from plasma proteins to ~5 kDa Zn-species (DTPA: 80% removal; DMPS: 63%; DMSA: 29% and NAC: 3%). The addition of DTPA resulted in the dose-dependent elution of a [Ca-DTPA](3-) complex. Based on these results, 0.33 mM DMSA represents the best compromise that can be achieved between maximizing the abstraction of Cd(2+) from plasma proteins (83%), while minimizing the mobilization of Zn(2+) from plasma proteins (29%), and avoiding the complexation of Ca(2+).}, }
@article {pmid22820675, year = {2012}, author = {Smaga, I and Pomierny, B and Krzyżanowska, W and Pomierny-Chamioło, L and Miszkiel, J and Niedzielska, E and Ogórka, A and Filip, M}, title = {N-acetylcysteine possesses antidepressant-like activity through reduction of oxidative stress: behavioral and biochemical analyses in rats.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {39}, number = {2}, pages = {280-287}, doi = {10.1016/j.pnpbp.2012.06.018}, pmid = {22820675}, issn = {1878-4216}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/therapeutic use ; Animals ; Antidepressive Agents/administration &amp; dosage/*pharmacology/therapeutic use ; Antioxidants/*pharmacology/therapeutic use ; Brain/drug effects/metabolism ; Depression/drug therapy ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Imipramine/pharmacology/therapeutic use ; Immobility Response, Tonic/drug effects ; Male ; Motor Activity/drug effects ; Olfactory Bulb/surgery ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {The growing body of evidence implicates the significance of oxidative stress in the pathophysiology of depression. The aim of this paper was to examine N-acetylcysteine (NAC) - a putative precursor of the most important tissue antioxidant glutathione - in an animal model of depression and in ex vivo assays to detect oxidative stress parameters. Imipramine (IMI), a classical and clinically-approved antidepressant drug was also under investigation. Male Wistar rats which underwent either bulbectomy (BULB; removal of the olfactory bulbs) or sham surgery (SHAM; olfactory bulbs were left undestroyed) were treated acutely or repeatedly with NAC (50-100mg/kg, ip) or IMI (10mg/kg, ip). Following 10-daily injections with NAC or IMI or their solvents, or 9-daily injections with a corresponding solvent plus acute NAC or acute IMI forced swimming test on day 10, and locomotor activity were performed; immediately after behavioral tests animals were decapitated. Biochemical tests (the total antioxidant capacity - TAC and the superoxide dismutase activity - SOD) were performed on homogenates in several brain structures. In behavioral studies, chronic (but not acute) administration of NAC resulted in a dose-dependent reduction in the immobility time seen only in BULB rats while chronic IMI produced a significant decrease in this parameter in both SHAM and BULB animals. On the other hand, chronic administration of NAC and IMI resulted in a significant increase in cellular antioxidant mechanisms (SOD activity) that reversed the effects of BULB in the frontal cortex, hippocampus and striatum. Our study further supports the antidepressant-like activity of NAC and links its effect as well as IMI actions with the enhancement of brain SOD activity.}, }
@article {pmid22819282, year = {2012}, author = {Witte, TS and Melkus, E and Walter, I and Senge, B and Schwab, S and Aurich, C and Heuwieser, W}, title = {Effects of oral treatment with N-acetylcysteine on the viscosity of intrauterine mucus and endometrial function in estrous mares.}, journal = {Theriogenology}, volume = {78}, number = {6}, pages = {1199-1208}, doi = {10.1016/j.theriogenology.2012.05.013}, pmid = {22819282}, issn = {1879-3231}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage ; Body Fluids/drug effects/physiology ; Breeding ; Endometritis/etiology/prevention &amp; control/veterinary ; Endometrium/chemistry/drug effects/*physiology ; Female ; Horse Diseases/etiology/prevention &amp; control ; Horses/*physiology ; Immunohistochemistry ; Ki-67 Antigen/analysis ; Lectins/metabolism ; Mucus/*drug effects/physiology ; Uterus ; Viscosity/drug effects ; }, abstract = {Persistent breeding-induced endometritis is ranked as the third most common medical problem in the adult mare and leads to enormous economic loss in horse breeding. In mares suffering from persistent breeding-induced endometritis, increased amounts of intrauterine (i.u.) fluid or viscous mucus in estrus or after breeding may act as a barrier for sperm and can contribute to low fertility. Current therapies of these mares aim to eliminate i.u. fluid and mucus by uterine lavage and/or administration of ecbolic drugs. Recently, i.u. administration of N-acetylcysteine (NAC) has been shown to support therapy in mares with endometritis. It was the objective of the present study to investigate effects of an oral administration of NAC on the viscosity of i.u. fluid in estrous mares. It was hypothesized that oral treatment with NAC reduces the viscosity of i.u. fluid and has a positive effect on the inflammatory response of the endometrium. Mares (n = 12) were included in the study as soon as estrus was detected (ovarian follicle >3.0 cm and endometrial edema), which was defined as Day 1. They were randomly assigned to a treatment (10 mg/kg NAC on Days 1-4) or a control group (no treatment). On days 1 and 5 i.u. mucus was collected and its rheologic properties were accessed. On Day 5, endometrial biopsies were obtained and evaluated for integrity of the luminal epithelium, number of polymorphonuclear neutrophils (PMN), staining for cyclooxygenase 2 (COX2), staining with Kiel 67 antigen (Ki-67), lectins and periodic acid Schiff (PAS). In the treatment group, viscosity of i.u. mucus increased significantly between Days 1 and 5 (P < 0.05), while no differences were found in control mares (n.s.). At no time were significant differences between treated and control mares seen. Integrity of epithelium was not affected. After NAC treatment the mean number of PMN in endometrial biopsies was significantly lower compared to mares of the control group (1.9 ± 0.3 vs. 4.8 ± 0.4; P < 0.05). Nuclear immunostaining for COX2 was significantly lower after NAC treatment compared to control mares (P < 0.05). Score for PAS and Alcain staining of mucus in deep uterine glands differed significantly between groups (both P < 0.05). We conclude that oral NAC treatment does not reduce viscosity of uterine mucus but has an antiinflammatory effect on the equine endometrium.}, }
@article {pmid22818091, year = {2012}, author = {Mata-Campuzano, M and Alvarez-Rodríguez, M and del Olmo, E and Fernández-Santos, MR and Garde, JJ and Martínez-Pastor, F}, title = {Quality, oxidative markers and DNA damage (DNA) fragmentation of red deer thawed spermatozoa after incubation at 37 °C in presence of several antioxidants.}, journal = {Theriogenology}, volume = {78}, number = {5}, pages = {1005-1019}, doi = {10.1016/j.theriogenology.2011.12.018}, pmid = {22818091}, issn = {1879-3231}, mesh = {Animals ; Antioxidants/pharmacology ; Biomarkers ; *DNA Fragmentation ; *Deer ; Freezing ; Lipid Peroxidation ; Male ; Malondialdehyde ; Oxidative Stress ; Reactive Oxygen Species ; Semen Preservation/*methods ; Spermatozoa/*physiology ; Temperature ; }, abstract = {Antioxidants may be useful for supplementing sperm extenders. We have tested dehydroascorbic acid (DHA), TEMPOL, N-acetyl-cysteine (NAC) and rutin on epididymal spermatozoa from red deer, during incubation at 37 °C. Cryopreserved spermatozoa were thawed, washed and incubated with 1 mM or 0.1 mM of each antioxidant, including oxidative stress (Fe(2+)/ascorbate). Motility (CASA and clustering of subpopulations), viability, mitochondrial membrane potential, and acrosomal status were assessed at 2 and 4 h. Lipoperoxidation, intracellular reactive oxygen species (ROS) and DNA damage (DNA) status (TUNEL) were checked at 4 h. Oxidative stress increased ROS, lipoperoxidation and DNA damage. Overall, antioxidants negatively affected motility and physiological parameters. Only DHA 1 mm protected motility, increasing the fast and progressive subpopulation. However, it had a detrimental effect on acrosomal and DNA status, in absence of oxidative stress. Tempol and rutin efficiently reduced lipoperoxidation, ROS, and DNA damage in presence of oxidative stress. NAC was not as efficient as TEMPOL or rutin reducing lipoperoxidation or protecting DNA, and did not reduce ROS, but its negative effects were lower than the other antioxidants when used at 1 mm, increasing the subpopulation of hyperactivated-like spermatozoa at 2 h. Our results show that these antioxidants have mixed effects when spermatozoa are incubated at physiological temperatures. DHA may not be suitable because of prooxidant effects, but TEMPOL, NAC and rutin may be considered for cryopreservation trials. In general, exposure of red deer spermatozoa to these antioxidants should be limited to low temperatures, when only protective effects may develop.}, }
@article {pmid22817928, year = {2012}, author = {Frigerio, C and Abreu, VL and Santos, JL}, title = {Evaluation of acetylcysteine promoting effect on CdTe nanocrystals photoluminescence by using a multipumping flow system.}, journal = {Talanta}, volume = {96}, number = {}, pages = {55-61}, doi = {10.1016/j.talanta.2012.02.002}, pmid = {22817928}, issn = {1873-3573}, mesh = {Acetylcysteine/*chemistry ; Buffers ; Cadmium Compounds/*chemistry ; Chemistry, Pharmaceutical ; Feasibility Studies ; Flow Injection Analysis/*methods ; Hydrogen-Ion Concentration ; Kinetics ; Nanoparticles/*chemistry ; Spectrometry, Fluorescence ; Surface Properties ; Tellurium/*chemistry ; Time Factors ; }, abstract = {A simple and straightforward quantification method integrated in a fully automated multi-pumping flow system (MPFS) using water-soluble mercaptopropionic acid (MPA)-capped CdTe quantum dots (QDs) was implemented for the fluorescence quantification of N-acetyl-L-cysteine (NAC) in pharmaceutical formulations. The developed approach was based on NAC ability to establish surface interactions that result in enhanced nanocrystals fluorescence intensity, proportional to analyte concentration. Size and concentration of QDs, ageing, composition, concentration and pH of the buffer solution revealed to have a noticeable effect on the enhancing efficiency affecting sensitivity and linear working range of the methodology. Under the optimal conditions, a linear working range was obtained for NAC concentrations ranging from 50 to 750μmolL(-1) (r=0.9978), with good precision (r.s.d.<1.6%; n=5) and a sampling rate of about 75hr(-1). The detection limit (LOD) was approximately 1.6μmolL(-1). The method was applied to pharmaceutical preparations and the results revealed good agreement with those obtained by the reference procedure with relative deviations between -2.1 and +4.2%. Advantages of the new procedure include speed, low consumption of reagents, minor waste generation, requiring also much less work than the recommended HPLC method. The mechanism for luminescence enhancement of CdTe QDs is discussed. FT-IR spectra revealed that sulphydryl groups of NAC have a high affinity with the nanocrystals.}, }
@article {pmid22815926, year = {2012}, author = {Karalija, A and Novikova, LN and Kingham, PJ and Wiberg, M and Novikov, LN}, title = {Neuroprotective effects of N-acetyl-cysteine and acetyl-L-carnitine after spinal cord injury in adult rats.}, journal = {PloS one}, volume = {7}, number = {7}, pages = {e41086}, pmid = {22815926}, issn = {1932-6203}, mesh = {Acetylcarnitine/*pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Astrocytes/cytology ; Female ; Inflammation ; Microglia/metabolism ; Microtubule-Associated Proteins/metabolism ; Models, Biological ; Motor Neurons/pathology ; Neuroglia/drug effects ; Neurons/drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Injuries/*drug therapy ; }, abstract = {Following the initial acute stage of spinal cord injury, a cascade of cellular and inflammatory responses will lead to progressive secondary damage of the nerve tissue surrounding the primary injury site. The degeneration is manifested by loss of neurons and glial cells, demyelination and cyst formation. Injury to the mammalian spinal cord results in nearly complete failure of the severed axons to regenerate. We have previously demonstrated that the antioxidants N-acetyl-cysteine (NAC) and acetyl-L-carnitine (ALC) can attenuate retrograde neuronal degeneration after peripheral nerve and ventral root injury. The present study evaluates the effects of NAC and ALC on neuronal survival, axonal sprouting and glial cell reactions after spinal cord injury in adult rats. Tibial motoneurons in the spinal cord were pre-labeled with fluorescent tracer Fast Blue one week before lumbar L5 hemisection. Continuous intrathecal infusion of NAC (2.4 mg/day) or ALC (0.9 mg/day) was initiated immediately after spinal injury using Alzet 2002 osmotic minipumps. Neuroprotective effects of treatment were assessed by counting surviving motoneurons and by using quantitative immunohistochemistry and Western blotting for neuronal and glial cell markers 4 weeks after hemisection. Spinal cord injury induced significant loss of tibial motoneurons in L4-L6 segments. Neuronal degeneration was associated with decreased immunostaining for microtubular-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker GFAP and microglial marker OX42 was increased. Treatment with NAC and ALC rescued approximately half of the motoneurons destined to die. In addition, antioxidants restored MAP2 and synaptophysin immunoreactivity. However, the perineuronal synaptophysin labeling was not recovered. Although both treatments promoted axonal sprouting, there was no effect on reactive astrocytes. In contrast, the microglial reaction was significantly attenuated. The results indicate a therapeutic potential for NAC and ALC in the early treatment of traumatic spinal cord injury.}, }
@article {pmid22815709, year = {2012}, author = {Pereira, LV and Shimizu, MH and Rodrigues, LP and Leite, CC and Andrade, L and Seguro, AC}, title = {N-acetylcysteine protects rats with chronic renal failure from gadolinium-chelate nephrotoxicity.}, journal = {PloS one}, volume = {7}, number = {7}, pages = {e39528}, pmid = {22815709}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chelating Agents/chemistry/*toxicity ; Gadolinium/*chemistry ; Glomerular Filtration Rate ; Inulin/pharmacokinetics ; Kidney/*drug effects/metabolism/physiopathology ; Kidney Failure, Chronic/*metabolism/*physiopathology ; Male ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC). Male Wistar rats were submitted to 5/6 nephrectomy (Nx) to induced CRF. An ionic-cyclic Gd (Gadoterate Meglumine) was administrated (1.5 mM/KgBW, intravenously) 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd- chelate administration: 1--Nx (n = 7); 2--Nx+NAC (n = 6); 3--Nx+Gd (n = 7); 4--Nx+NAC+Gd (4.8 g/L in drinking water), initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6). This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW), proteinuria (mg/24 hs), serum iron (µg/dL); serum ferritin (ng/mL); transferrin saturation (%), TIBC (µg/dL) and TBARS (nmles/ml). Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.}, }
@article {pmid22814705, year = {2012}, author = {Anderson, G and Maes, M and Berk, M}, title = {Inflammation-related disorders in the tryptophan catabolite pathway in depression and somatization.}, journal = {Advances in protein chemistry and structural biology}, volume = {88}, number = {}, pages = {27-48}, doi = {10.1016/B978-0-12-398314-5.00002-7}, pmid = {22814705}, issn = {1876-1631}, mesh = {Depression/*metabolism ; Humans ; Inflammation/metabolism/*pathology ; Tryptophan/*metabolism ; }, abstract = {A recent study--comparing those with depression, somatization, comorbid depression+somatization, and controls--showed specific changes in the tryptophan catabolite (TRYCAT) pathway in somatization, specifically lowered tryptophan and kynurenic acid, and increased kynurenine/kynurenic acid (KY/KA) and kynurenine/tryptophan ratios. These findings suggest that somatization and depression with somatization are characterized by increased activity of indoleamine 2,3-dioxygenase and disorders in kynurenine aminotransferase activity, which carry a neurotoxic potential. This chapter reviews the evidence that the TRYCAT pathway may play a pathophysiological role in the onset of somatization and depression with somatization and, furthermore, suggests treatment options based on identified pathophysiological processes. Lowered plasma tryptophan may be associated with enhanced pain, autonomic nervous system responses, gut motility, peripheral nerve function, ventilation, and cardiac dysfunctions. The imbalance in the KY/KA ratio may increase pain, intestinal hypermotility, and peripheral neuropathy through effects of KY and KA acid, both centrally and peripherally, at the N-methyl-d-aspartate receptor (NMDAR), G-protein-coupled receptor-35 (GPR35), and aryl hydrocarbon receptor (AHr). These alterations in the TRYCAT pathway in somatization and depression may interface with the role of the mu-opioid, serotonin, and oxytocin systems in the regulation of stress reactions and early attachment. It is hypothesized that irregular parenting and insecure attachment paralleled by chronic stress play a key role in the expression of variations in the TRYCAT pathway-both centrally and peripherally-driving the etiology of somatization through interactions with the mu-opioid receptors. Therefore, the TRYCAT pathway, NMDARs, GPR35, and AHrs may be new drug targets in somatization and depression with somatizing. We lastly review new pathophysiologically driven drug candidates for somatization, including St. John's wort, resveratrol, melatonin, agomelatine, Garcinia mangostana (γ-mangostin), N-acetyl cysteine, and pamoic acid.}, }
@article {pmid22809665, year = {2012}, author = {Erickson, MA and Hansen, K and Banks, WA}, title = {Inflammation-induced dysfunction of the low-density lipoprotein receptor-related protein-1 at the blood-brain barrier: protection by the antioxidant N-acetylcysteine.}, journal = {Brain, behavior, and immunity}, volume = {26}, number = {7}, pages = {1085-1094}, pmid = {22809665}, issn = {1090-2139}, support = {R01 AG029839/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/*pharmacology ; Algorithms ; Amyloid beta-Peptides/metabolism ; Animals ; Antioxidants/metabolism/*pharmacology ; Blood-Brain Barrier/*drug effects/*metabolism ; Calcium Channel Blockers/metabolism ; Cerebral Cortex/metabolism/pathology ; Chemokines/blood/metabolism ; Cytokines/blood/metabolism ; Glutathione/metabolism ; Hippocampus/metabolism/pathology ; Inflammation/chemically induced/metabolism/*physiopathology ; Lipopolysaccharides ; Low Density Lipoprotein Receptor-Related Protein-1 ; Male ; Mice ; Oxidative Stress/drug effects ; Protein Carbonylation/drug effects ; Receptors, LDL/*metabolism ; Serum Albumin/metabolism ; Tumor Suppressor Proteins/*metabolism ; Verapamil/metabolism ; alpha-Macroglobulins/metabolism ; }, abstract = {Impairment in two blood-brain barrier (BBB) efflux transporters, p-glycoprotein (Pgp) and low-density lipoprotein receptor-related protein-1 (LRP-1) are thought to contribute to the progression of Alzheimer's disease (AD) by resulting in the brain accumulation of their substrate amyloid beta peptide (Aβ). The initial cause of impaired efflux, however, is unknown. We have shown that induction of systemic inflammation by intraperitoneal administration of lipopolysaccharide impairs the efflux of Aβ from the brain, suggesting that systemic inflammation could be one such initiator. In this study, we determined whether pre-administration of the antioxidant N-aceytlcysteine (Nac) has a protective effect against LPS-induced Aβ transporter dysfunction. Our findings were that Nac protected against LPS-induced Aβ transport dysfunction at the BBB through an LRP-1-dependent and Pgp-independent mechanism. This was associated with Nac exerting antioxidant effects in the periphery but not the brain, despite an increased rate of entry of Nac into the brain following LPS. We also found that Nac pre-administration resulted in lower blood levels of the cytokines and chemokines interferon-γ, interleukin-10, CCL2, CCL4, and CCL5, but only lowered CCL4 in the cerebral cortex and hippocampus. Finally, we observed that hippocampal cytokine responses to LPS were decreased compared to cortex. These findings demonstrate a novel mechanism by which antioxidants prevent Aβ accumulation in the brain caused by inflammation, and therefore protect against AD.}, }
@article {pmid22808196, year = {2012}, author = {Niu, R and Yoshida, M and Ling, F}, title = {Increases in mitochondrial DNA content and 4977-bp deletion upon ATM/Chk2 checkpoint activation in HeLa cells.}, journal = {PloS one}, volume = {7}, number = {7}, pages = {e40572}, pmid = {22808196}, issn = {1932-6203}, mesh = {Ataxia Telangiectasia Mutated Proteins ; Base Pairing/*genetics ; Cell Cycle/genetics ; Cell Cycle Proteins/*metabolism ; Checkpoint Kinase 2 ; DNA Helicases/metabolism ; DNA, Mitochondrial/*genetics ; DNA-Binding Proteins/*metabolism ; Enzyme Activation ; Gene Dosage/genetics ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; Minichromosome Maintenance Complex Component 2 ; Minichromosome Maintenance Complex Component 3 ; Mitochondrial Proteins/metabolism ; Models, Biological ; Mutation Rate ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; Reactive Oxygen Species/metabolism ; Sequence Deletion/*genetics ; Signal Transduction/genetics ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/*metabolism ; Up-Regulation/genetics ; }, abstract = {Activation of the Mec1/Rad53 damage checkpoint pathway influences mitochondrial DNA (mtDNA) content and point mutagenesis in Saccharomyces cerevisiae. The effects of this conserved checkpoint pathway on mitochondrial genomes in human cells remain largely unknown. Here, we report that knockdown of the human DNA helicase RRM3 enhances phosphorylation of the cell cycle arrest kinase Chk2, indicating activation of the checkpoint via the ATM/Chk2 pathway, and increases mtDNA content independently of TFAM, a regulator of mtDNA copy number. Cell-cycle arrest did not have a consistent effect on mtDNA level: knockdown of cell cycle regulators PLK1 (polo-like kinase), MCM2, or MCM3 gave rise, respectively, to decreased, increased, or almost unchanged mtDNA levels. Therefore, we concluded that the mtDNA content increase upon RRM3 knockdown is not a response to delay of cell cycle progression. Also, we observed that RRM3 knockdown increased the levels of reactive oxygen species (ROS); two ROS scavengers, N-acetyl cysteine and vitamin C, suppressed the mtDNA content increase. On the other hand, in RRM3 knockdown cells, we detected an increase in the frequency of the common 4977-bp mtDNA deletion, a major mtDNA deletion that can be induced by abnormal ROS generation, and is associated with a decline in mitochondrial genome integrity, aging, and various mtDNA-related disorders in humans. These results suggest that increase of the mitochondrial genome by TFAM-independent mtDNA replication is connected, via oxidative stress, with the ATM/Chk2 checkpoint activation in response to DNA damage, and is accompanied by generation of the common 4977-bp deletion.}, }
@article {pmid22800651, year = {2012}, author = {Wang, Y and Zalups, RK and Barfuss, DW}, title = {Luminal transport of thiol S-conjugates of methylmercury in isolated perfused rabbit renal proximal tubules.}, journal = {Toxicology letters}, volume = {213}, number = {2}, pages = {203-210}, pmid = {22800651}, issn = {1879-3169}, support = {R01 ES005980/ES/NIEHS NIH HHS/United States ; ES05157/ES/NIEHS NIH HHS/United States ; ES05980/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/*pharmacokinetics ; Animals ; Biological Transport ; Cysteine/analogs &amp; derivatives/*pharmacokinetics ; Female ; Glutathione/analogs &amp; derivatives/*pharmacokinetics ; In Vitro Techniques ; Isoxazoles/pharmacology ; Kidney Tubules, Proximal/drug effects/*metabolism ; Methylmercury Compounds/*pharmacokinetics ; Rabbits ; Unithiol/pharmacology ; }, abstract = {Lumen-to-cell transport, cellular accumulation, and toxicity of L-cysteine (Cys), glutathione (GSH) and N-acetylcysteine (NAC) S-conjugates of methylmercury (CH(3)Hg(+)) were evaluated in isolated, perfused rabbit proximal tubular segments. When these conjugates were perfused individually through the lumen of S(2) segments of the proximal tubule it was found that Cys-S-CH(3)Hg and GSH-S-CH(3)Hg were transported avidly, while NAC-S-CH(3)Hg was transported minimally. In addition, 95% of the (203)Hg taken up by the tubular cells was associated with precipitable proteins of the tubule, while very little was found in the acid-soluble cytosol. No visual cellular pathological changes were observed during 30min of study. Luminal uptake of Cys-S-CH(3)Hg was temperature-dependent and inhibited significantly by the amino acids L-methionine and l-cystine. Rates of luminal uptake of GSH-S-CH(3)Hg were twice as great as that of Cys-S-CH(3)Hg and uptake was inhibited significantly (74%) by the presence of acivicin. When 2,3-bis(sulfanyl)propane-1-sulfonate (DMPS) was added to the bathing or luminal fluid, luminal uptake of Cys-S-CH(3)Hg was diminished significantly. Overall, our data indicate that Cys-S-CH(3)Hg is likely a transportable substrate of one or more amino acid transporters (such as system B(0,+) and system b(0,+)) involved in luminal absorption of L-methionine and L-cystine along the renal proximal tubule. In addition, GSH-S-CH(3)Hg appears to be degraded enzymatically to Cys-S-CH(3)Hg, which can then be taken up at the luminal membrane. By contrast NAC-S-CH(3)Hg and Cys-S-CH(3)Hg (in the presence of DMPS) are not taken up avidly at the luminal membrane of proximal tubular cells, thus promoting the excretion of CH(3)Hg(+) into the urine.}, }
@article {pmid22797560, year = {2012}, author = {Salie, R and Moolman, JA and Lochner, A}, title = {The mechanism of beta-adrenergic preconditioning: roles for adenosine and ROS during triggering and mediation.}, journal = {Basic research in cardiology}, volume = {107}, number = {5}, pages = {281}, doi = {10.1007/s00395-012-0281-5}, pmid = {22797560}, issn = {1435-1803}, mesh = {Adenosine/*physiology ; Animals ; Ethanolamines/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Formoterol Fumarate ; *Ischemic Preconditioning, Myocardial ; Isoproterenol/pharmacology ; Myocardial Infarction/pathology/physiopathology ; Phosphatidylinositol 3-Kinases/physiology ; Potassium Channels/physiology ; Protein Kinase C/physiology ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Receptors, Adrenergic, beta/*physiology ; Receptors, Purinergic P1/physiology ; Triazines/pharmacology ; Triazoles/pharmacology ; }, abstract = {The aim of this study was to investigate the mechanism of beta-adrenergic preconditioning (BPC). The roles of adenosine and its receptor subtypes, the generation of oxygen free radicals (ROS) and activation of the K(ATP) channels as well as the phosphoinositide-3-kinase (PI(3)K)/PKB/Akt and extracellular signal-regulated kinase (ERK) signal transduction pathways during the triggering and mediation phases were evaluated. Using the isolated working rat heart, BPC was elicited by administration of denopamine (beta1 adrenergic receptor agonist, 10(-7) M), isoproterenol (beta1/beta2 adrenergic receptor agonist, 10(-7) M) or formoterol (beta2 adrenergic receptor agonist, 10(-9) M) for 5 min followed by 5 min washout. Index ischaemia was 35 min regional ischaemia and infarct size determined using the tetrazolium method. The role of adenosine was studied using adenosine deaminase and selective antagonists as well as the PI(3)K and ERK inhibitors, wortmannin and PD98,059, bracketing the triggering and mediating phases. Involvement of ROS, PKC, the mitochondrial K(ATP) channels, release of endogenous opioids and bradykinin was studied by administration of N-acetyl cysteine (NAC), bisindolylmaleimide, the K(ATP) channel blocker 5-hydroxydecanoate (5-HD), naloxone or HOE140, respectively. Activation of PKB/Akt and ERKp44/p42 during triggering and reperfusion was determined by Western blot. Preconditioning with all three beta-adrenergic receptor agonists caused a reduction in infarct size and an improvement in postischaemic function. BPC preconditioning with isoproterenol, denopamine or formoterol was abolished by the adenosine A3 receptor antagonist MRS1191 during both the triggering and mediation phases. Isoproterenol-induced preconditioning (beta1/beta2 PC) was attenuated by MRS1754, an adenosine A(2B) receptor antagonist, during the triggering phase and abolished during reperfusion. The mediation phase of beta1/beta2 PC was also abolished by ZM241385, an adenosine A(2A) antagonist. The free radical scavenger NAC caused a significant attenuation of cardioprotection induced by isoproterenol when administered during both trigger and mediation phases, while being effective during the trigger phase with denopamine and during reperfusion in formoterol preconditioned hearts. The mitochondrial K(ATP) channel blocker, 5-HD, was without effect on beta1/beta2 PC during both triggering and mediation phases. BPC in rat hearts is dependent on activation of the A(3) adenosine receptors by endogenously produced adenosine and production of free radicals during the triggering and mediation phases while the A(2A) and A(2B) adenosine receptors participate mainly during reperfusion. The mitochondrial K(ATP) channels do not contribute to cardioprotection at any stage. Activation of ERK and PI3K/PKB/Akt during the triggering and reperfusion phases is associated with cardioprotection.}, }
@article {pmid22791152, year = {2012}, author = {Hong, JY and Boo, HJ and Kang, JI and Kim, MK and Yoo, ES and Hyun, JW and Koh, YS and Kim, GY and Maeng, YH and Hyun, CL and Chang, WY and Kim, YH and Kim, YR and Kang, HK}, title = {(1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-olide, a cembrenolide diterpene from soft coral Lobophytum sp., inhibits growth and induces apoptosis in human colon cancer cells through reactive oxygen species generation.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {35}, number = {7}, pages = {1054-1063}, doi = {10.1248/bpb.b11-00024}, pmid = {22791152}, issn = {1347-5215}, mesh = {Animals ; *Anthozoa ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Caspases/metabolism ; Catalase/metabolism ; Cell Proliferation/drug effects ; Colonic Neoplasms ; Diterpenes/*pharmacology ; Glutathione Peroxidase/metabolism ; HT29 Cells ; Heme Oxygenase-1/metabolism ; Humans ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Kinases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Superoxide Dismutase/metabolism ; Glutathione Peroxidase GPX1 ; }, abstract = {We observed that (1S,2S,3E,7E,11E)-3,7,11,15-Cembratetraen-17,2-olide (LS-1), marine cembrenolide diterpene, inhibited growth and induced apoptosis in colon cancer cells via a reactive oxygen species (ROS) dependent mechanism. Treatment of HT-29 cells with LS-1 resulted in ROS generation, which was accompanied by disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, sub-G1 peak accumulation, activation of Bid, caspase-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase (PARP) along with the suppressive expression of B cell lymphoma-2 (Bcl-2). All these effects were significantly blocked on pretreatment with the ROS inhibitor N-acetylcysteine (NAC), indicating the involvement of increased ROS in the proapoptotic activity of LS-1. Moreover, we showed that LS-1 induced the phosphorylation of c-Jun N-terminal kinase (JNK) and dephosphorylation of p38, extracellular signal-regulated kinase (ERK), Akt, Src and signal transducer and activator of transcription (STAT)3, which were effectively attenuated by NAC. In addition, the expressions of antioxidant catalase and glutathione peroxidase were abrogated by treatment using LS-1 with or without NAC. These findings reveal the novel anticancer efficacy of LS-1 mediated by the induction of apoptosis via ROS generation in human colon cancer cells.}, }
@article {pmid22781576, year = {2012}, author = {Xie, LH and Tang, AZ and Yin, SH and Tan, SH}, title = {[Protective effects of N-acetylcysteine on cochlear damage occur in guinea pigs exposed to irradiation].}, journal = {Zhonghua yi xue za zhi}, volume = {92}, number = {14}, pages = {989-992}, pmid = {22781576}, issn = {0376-2491}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cochlea/*drug effects/*metabolism/radiation effects ; Guinea Pigs ; Hair Cells, Auditory/cytology ; Malondialdehyde/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: To explore the protective effects of N-acetylcysteine (NAC) on cochlear damage occurring in irradiated guinea pigs.<br><br>METHODS: Seventy-two guinea pigs were randomly divided into 4 groups (n = 18 each). Control group received neither NAC nor irradiation, irradiation group received total cranium irradiation of 70 Gy, irradiation &amp; saline group cranium irradiation of 70 Gy and saline solution through a round window and NAC group cranium irradiation of 70 Gy and NAC through a round window. The right ear received radiation. The animals were sacrificed at Day 14 post-irradiation. The specimens were dehydrated, embeded in paraffin and serially cut into 5-&#xb5;m slices. Sections were stained with immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). The cochlear basal membranes were observed for malondialdehyde (MDA) and superoxide dismutase (SOD) with scanning electron microscope.<br><br>RESULTS: The cilium of hair cells had no clear loss and apoptotic number of spiral ganglion cells decreased in NAC group. The average optical density value of Caspase 3 in spiral ganglion in NAC group significantly decreased versus the irradiation group (0.08 &#xb1; 0.02 vs 0.10 &#xb1; 0.01, P < 0.01). The level of MDA of NAC group also decreased versus the irradiation group (0.33 &#xb1; 0.05 vs 0.84 &#xb1; 0.13, P < 0.05). The level of SOD in the NAC group increased versus the irradiation group (10.7 &#xb1; 3.0 vs 8.7 &#xb1; 1.3, P < 0.05). The ratio of apoptotic cell in SGC in the NAC group at Day 14 (7.8% &#xb1; 1.8%) decreased versus the irradiation group (32.0% &#xb1; 8.7%) at Day 14.<br><br>CONCLUSION: MDA and SOD may be involved in the pathogenesis of cochlear cell damage. And NAC protects the irradiated cochlear cell.}, }
@article {pmid22781119, year = {2012}, author = {Chan, DK and Miskimins, WK}, title = {Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures.}, journal = {Journal of ovarian research}, volume = {5}, number = {1}, pages = {19}, pmid = {22781119}, issn = {1757-2215}, support = {P20 RR017662/RR/NCRR NIH HHS/United States ; P20 RR024219/RR/NCRR NIH HHS/United States ; }, abstract = {BACKGROUND: High mortality rates in ovarian cancer are largely a result of resistance to currently used chemotherapies. Expanding therapies with a variety of drugs has the potential to reduce this high mortality rate. Metformin and phenethyl isothiocyanate (PEITC) are both potentially useful in ovarian cancer, and they are particularly attractive because of their safety.<br><br>METHODS: Cell proliferation of each drug and drug combination was evaluated by hemacytometry with Trypan blue exclusion or Sytox green staining for cell death. Levels of total and cleaved PARP were measured by Western blot. General cellular and mitochondrial reactive oxygen species were measured by flow cytometry and live cell confocal microscopy with the fluorescent dyes dihydroethidine and MitoSOX.<br><br>RESULTS: Individually, metformin and PEITC each show inhibition of cell growth in multiple ovarian cancer cell lines. Alone, PEITC was also able to induce apoptosis, whereas metformin was primarily growth inhibitory. Both total cellular and mitochondrial reactive oxygen species were increased when treated with either metformin or PEITC. The growth inhibitory effects of metformin were reversed by methyl succinate supplementation, suggesting complex I plays a role in metformin's anti-cancer mechanism. PEITC's anti-cancer effect was reversed by N-acetyl-cysteine supplementation, suggesting PEITC relies on reactive oxygen species generation to induce apoptosis. Metformin and PEITC together showed a synergistic effect on ovarian cancer cell lines, including the cisplatin resistant A2780cis.<br><br>CONCLUSIONS: Here we show that when used in combination, these drugs are effective in both slowing cancer cell growth and killing ovarian cancer cells in vitro. Furthermore, the combination of these drugs remains effective in cisplatin resistant cell lines. Novel combinations such as metformin and PEITC show promise in expanding ovarian cancer therapies and overcoming the high incidence of cisplatin resistant cancers.}, }
@article {pmid22777066, year = {2012}, author = {Bochi, GV and Torbitz, VD and Cargnin, LP and Sangoi, MB and Santos, RC and Gomes, P and Moresco, RN}, title = {Fructose-1,6-bisphosphate and N-acetylcysteine attenuate the formation of advanced oxidation protein products, a new class of inflammatory mediators, in vitro.}, journal = {Inflammation}, volume = {35}, number = {6}, pages = {1786-1792}, pmid = {22777066}, issn = {1573-2576}, mesh = {Acetylcysteine/chemistry/*metabolism ; Advanced Oxidation Protein Products/*metabolism ; Biomarkers/metabolism ; Fructosediphosphates/chemistry/*metabolism ; Humans ; Inflammation ; Inflammation Mediators/metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Serum Albumin/chemistry/metabolism ; }, abstract = {The accumulation of advanced oxidation protein products (AOPP) has been linked to several pathological conditions. Previous studies have identified AOPP as a novel biomarker of oxidative damage to proteins and a novel class of mediator of inflammation. The aim of this study was to determine the effects of fructose-1,6-bisphosphate (FBP) and N-acetylcysteine (NAC) as well as the synergistic effect of both treatments on the formation of AOPP in vitro. For this purpose, we incubated the human serum albumin (HSA) with various hypochlorous acid (HOCl) concentrations to produce albumin-advanced oxidation protein products (HSA-AOPP). Both FBP and NAC were capable of inhibiting the formation of HOCl-induced AOPP in a concentration-dependent manner. The synergistic effect promoted by the association of these drugs showed to be more effective than when tested alone. Thus, both FBP and NAC may be good candidates to mitigate and neutralize pro-inflammatory and pro-oxidant effects of AOPP in several diseases.}, }
@article {pmid22776360, year = {2012}, author = {Salis, C and Davio, C and Usach, V and Urtasun, N and Goitia, B and Martinez-Vivot, R and Pasquini, JM and Setton-Avruj, CP}, title = {Iron and holotransferrin induce cAMP-dependent differentiation of Schwann cells.}, journal = {Neurochemistry international}, volume = {61}, number = {5}, pages = {798-806}, doi = {10.1016/j.neuint.2012.06.023}, pmid = {22776360}, issn = {1872-9754}, mesh = {Animals ; Animals, Newborn ; Cell Differentiation/drug effects/*physiology ; Cells, Cultured ; Cyclic AMP/*physiology ; Ferric Compounds/*pharmacology ; Iron/physiology ; Quaternary Ammonium Compounds/*pharmacology ; Rats ; Rats, Wistar ; Schwann Cells/drug effects/*physiology ; Transferrin/*physiology ; }, abstract = {The differentiation of myelin-forming Schwann cells (SC) is completed with the appearance of myelin proteins MBP and P(0) and a concomitant downregulation of markers GFAP and p75NTR, which are expressed by immature and adult non-myelin-forming SC. We have previously demonstrated that holotransferrin (hTf) can prevent SC dedifferentiation in culture (Salis et al., 2002), while apotransferrin (aTf) cannot. As a consequence, we used pure cultured SC and submitted them to serum deprivation in order to promote dedifferentiation and evaluate the prodifferentiating ability of ferric ammonium citrate (FAC) through the expression of MBP, P(0), p75NTR and c-myc. The levels of cAMP, CREB and p-CREB were also measured. Results show that Fe(3+), either in its free form or as hTf, can prevent the dedifferentiation promoted by serum withdrawal. Both FAC and hTf were proven to promote differentiation, probably through the increase in cAMP levels and CREB phosphorylation, as well as levels of reactive oxygen species. This effect was inhibited by deferroxamine (Dfx, an iron chelator), H9 (a cAMP-PKA antagonist) and N-acetylcysteine (NAC, a powerful antioxidant).}, }
@article {pmid22773008, year = {2012}, author = {de Lima Aires, A and de Azevedo Albuquerque, MC and Silva, RA and Schirato, GV and de Pontes Filho, NT and de Araújo, SB and Souza, VM and Costa, VM and Malagueño, E}, title = {Immunohistopathological changes in murine Schistosomiasis mansoni under the influence of N-acetyl-L-cysteine.}, journal = {Parasitology research}, volume = {111}, number = {4}, pages = {1569-1578}, pmid = {22773008}, issn = {1432-1955}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Animals ; Anthelmintics/administration &amp; dosage ; Anti-Inflammatory Agents/*administration &amp; dosage ; Disease Models, Animal ; Female ; Granuloma/pathology ; Histocytochemistry ; Immunohistochemistry ; Liver/pathology ; Male ; Mice ; Praziquantel/administration &amp; dosage ; Schistosomiasis mansoni/*drug therapy/*pathology ; Treatment Outcome ; }, abstract = {The main pathology associated with Schistosomiasis mansoni is granulomatous inflammation that may develop into hepatosplenic disease with fibrosis and hepatoesplenomegaly. It is known that N-acetyl-L-cysteine (NAC) reduces tissue damage in chronic liver diseases owing to its anti-inflammatory, antioxidant, and detoxifying properties. In this study, we investigated the imunohistopathological changes in murine schistosomiasis mansoni under the influence of NAC, in combination with Praziquantel (PZQ) or not. Three groups of mice were formed to evaluate the effects of NAC during infection in the acute, intermediate, and chronic phases. Each group was further subdivided into four subgroups: NAC, PZQ, NAC + PZQ and control (without treatment). Oral administration of NAC (200 mg/kg/day) was carried out on the first day after infection for the acute phase and on the 45th for the intermediate and chronic phases for 59 and 45, 75 days, respectively. PZQ (100 mg/kg/day), was given orally by gavage from the 45th to 49th day after infection. Histopathological analysis of liver tissue provided evidence that combined NAC + PZQ treatment reduced the development of granulomas observed in the chronic phase. Animals treated with NAC and/or PZQ showed a reduction in the size of granulomas and all those treated with NAC exhibited a lower degree of fibrosis. In all groups, NAC decreased the synthesis of interferon-γ and nitric oxide, while increasing the levels of interleukin-10, but it did not influence the production of interleukin-4. On the whole, NAC treatment induced an immunomodulatory effect and reduced liver damage during the granulomatous inflammation in S. mansoni-infected mice.}, }
@article {pmid22766540, year = {2012}, author = {Ramaesh, T and Ramaesh, K and Riley, SC and West, JD and Dhillon, B}, title = {Effects of N-acetylcysteine on matrix metalloproteinase-9 secretion and cell migration of human corneal epithelial cells.}, journal = {Eye (London, England)}, volume = {26}, number = {8}, pages = {1138-1144}, pmid = {22766540}, issn = {1476-5454}, support = {G1002033/MRC_/Medical Research Council/United Kingdom ; }, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; Cell Movement/*drug effects ; Cells, Cultured ; Coculture Techniques ; Dose-Response Relationship, Drug ; Epithelium, Corneal/cytology/*drug effects/enzymology ; Fluorescent Antibody Technique, Indirect ; Free Radical Scavengers/*pharmacology ; Humans ; Matrix Metalloproteinase 9/*metabolism ; Mice ; Tissue Donors ; Wound Healing ; }, abstract = {BACKGROUND: Matrix metalloproteinase-9 (MMP-9) secreted by corneal epithelial cells has a role in the remodelling of extracellular matrix and migration of epithelial cells. Elevated levels of MMP-9 activity in the ocular surface may be involved in the pathogenesis of corneal diseases. N-acetylcysteine (NAC) has been used to treat corneal diseases, including recurrent epithelial erosions. In this study, its effects on the MMP-9 secretion and human corneal epithelial (HCE) cell migration were evaluated in vitro.<br><br>METHODS: Confluent HCE cell cultures were treated with 0-20 mM NAC, and tested for MMP-9 secretion and epithelial cell migration by gelatin zymography and scratch wound assay, respectively. Comparisons between different treatment groups were made using analysis of variance, followed by multiple pairwise comparisons.<br><br>RESULTS: Twenty mM NAC inhibited the secretion of MMP-9 significantly. Cell migration, assessed after 24 h of wounding, showed a highly significant dose-dependent inhibitory effect.<br><br>CONCLUSIONS: This study shows that NAC reduces MMP-9 production by HCE cells and inhibits cell migration in vitro. This information helps to elucidate the mechanisms by which NAC may be beneficial therapeutically and suggests that NAC may be useful for managing corneal erosions and related conditions.}, }
@article {pmid22759776, year = {2012}, author = {Steele, ML and Ooi, L and Münch, G}, title = {Development of a high-performance liquid chromatography method for the simultaneous quantitation of glutathione and related thiols.}, journal = {Analytical biochemistry}, volume = {429}, number = {1}, pages = {45-52}, doi = {10.1016/j.ab.2012.06.023}, pmid = {22759776}, issn = {1096-0309}, mesh = {Astrocytes/cytology ; Calibration ; Cell Line, Tumor ; Chromatography, High Pressure Liquid/*methods/standards ; Disulfides/chemistry ; Extracellular Space/chemistry ; Glutathione/*analysis/*chemistry/isolation &amp; purification ; Humans ; Limit of Detection ; Linear Models ; Oxidation-Reduction ; Reference Standards ; Reproducibility of Results ; Sulfhydryl Compounds/*analysis/*chemistry/isolation &amp; purification ; Time Factors ; }, abstract = {The development of drugs with the ability to increase the level of the antioxidant glutathione and related metabolites has become an important research area for many age-related diseases. Here we describe a high-performance liquid chromatography (HPLC) method that uses the thiol-specific, fluorogenic reagent 4-fluoro-7-aminosulfonylbenzofurazan (ABD-F) for the simultaneous determination of total glutathione (GSH), cysteine (Cys), cysteinylglycine (CysGly), and homocysteine (Hcys) in cell culture medium. ABD-F-labeled thiols were separated using an isocratic mobile phase consisting of 14% methanol and 86% 0.1M acetate buffer at pH4.0. The method was validated for linearity, accuracy, and intra- and interday precision, and the lower and upper limits of quantitation (LLOQ and ULOQ, respectively) were determined using a Dionex RF-2000 detector set to medium sensitivity. In addition, the suitability of N-acetylcysteine (NAC) as an internal standard was evaluated by external and internal standard calibration methods. Although both calibration methods showed acceptable linearity (correlation coefficients>0.99) and intra- and interday precision (relative standard deviations=10.2 and 6.6%, respectively), the external standard calibration method performed better in terms of accuracy (recovery=93.7-125%) and also had lower LLOQ values for all analytes (Cys=6.3μM, CysGly=0.8μM, Hcys=0.8μM, and GSH=1.6μM).}, }
@article {pmid22752270, year = {2012}, author = {Betto, MR and Lazarotto, LF and Watanabe, TT and Driemeier, D and Leite, CE and Campos, MM}, title = {Effects of treatment with enalapril on hepatotoxicity induced by acetaminophen in mice.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {385}, number = {9}, pages = {933-943}, pmid = {22752270}, issn = {1432-1912}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/toxicity ; Angiotensin-Converting Enzyme Inhibitors/*pharmacology ; Animals ; Aspartate Aminotransferases/blood ; Catalase/metabolism ; Chemical and Drug Induced Liver Injury/etiology/pathology/*prevention &amp; control ; Enalapril/*pharmacology ; Female ; Glutathione/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; }, abstract = {There is a current need for new therapeutic options for acetaminophen (APAP)-induced hepatotoxicity. Herein, we assessed the effects of prophylactic and therapeutic treatment with the angiotensin-converting enzyme (ACE) inhibitor, enalapril, on APAP-caused hepatotoxicity. Male and female C57BL/6 J mice were used, and hepatotoxicity was induced by a single application of APAP (400 mg/kg, i.p.). Macroscopic and histological liver alterations, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, liver catalase activity (CAT), reduced glutathione concentrations (GSH), hepatic measurement of neutrophil migration (myeloperoxidase, MPO activity), and caspase-3 liver expression were evaluated. The prophylactic and the therapeutic treatments with enalapril were able to markedly reduce the macroscopic and histological liver alterations as well as the caspase-3 immunopositivity. Both schedules of treatment were also effective in reducing GSH concentrations as well as neutrophil migration. Conversely, only the pre-treatment (but not the post-administration) with enalapril significantly reversed APAP-induced CAT decrease. Furthermore, the pre- or the post-treatment with enalapril largely reduced ALT and AST serum activity in APAP-intoxicated mice. The hepatoprotective effects of enalapril were comparable to those obtained with the clinically used compound N-acetylcysteine (NAC) when given in a therapeutic regimen. Data obtained with the prophylactic protocol of treatment might indicate that individuals under treatment with ACE inhibitors are less susceptible to the toxic effects of APAP. Additionally, the therapeutic approach allows us to suggest that enalapril might represent an innovative tool for treating APAP intoxication.}, }
@article {pmid22751949, year = {2012}, author = {Tabata, S and Ikeda, R and Yamamoto, M and Furukawa, T and Kuramoto, T and Takeda, Y and Yamada, K and Haraguchi, M and Nishioka, Y and Sone, S and Akiyama, S}, title = {Thymidine phosphorylase enhances reactive oxygen species generation and interleukin-8 expression in human cancer cells.}, journal = {Oncology reports}, volume = {28}, number = {3}, pages = {895-902}, doi = {10.3892/or.2012.1887}, pmid = {22751949}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Free Radical Scavengers/pharmacology ; *Gene Expression ; Gene Expression Regulation, Neoplastic ; Glutamate-Cysteine Ligase/genetics/metabolism ; Glutathione/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Humans ; Interleukin-8/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Thymidine Phosphorylase/*metabolism ; }, abstract = {Thymidine phosphorylase (TP) is an angiogenic factor that plays a pivotal role in tumor angiogenesis. Various kinds of solid tumors express TP and high TP activity is correlated with microvessel density. We have previously reported that TP enhances interleukin-8 (IL-8) expression in KB human epidermoid carcinoma cells. In this study, TP was shown to be involved in enhanced expression of IL-8 in EJ human bladder cancer cells and Yumoto human cervical cancer cells as well as KB human epidermoid carcinoma cells. The enzymatic activity of TP was required for the enhanced expression of IL-8. A degradation product of thymidine was implicated in the enhanced expression of IL-8. TP augmented reactive oxygen species (ROS) generation in KB and Yumoto cells, and the enzymatic activity of TP was again required for the generation of ROS. An antioxidant, N-acetylcysteine (NAC), attenuated the generation of ROS and IL-8 mRNA expression in KB and Yumoto cells, and H2O2 increased IL-8 mRNA expression in Yumoto cells, suggesting that ROS generated by TP caused the increased expression of IL-8 mRNA. Since TP also reduced cellular glutathione levels and transcription of γ-GCS in KB cells, the TP-induced augmentation of ROS may be partially attributed to the decreased glutathione. Our findings suggest that thymidine-derived sugars enhanced ROS generation and consequently increased IL-8 expression.}, }
@article {pmid22749861, year = {2012}, author = {Kaida, Y and Ueda, S and Yamagishi, S and Nakayama, Y and Ando, R and Iwatani, R and Fukami, K and Okuda, S}, title = {Proteinuria elevates asymmetric dimethylarginine levels via protein arginine methyltransferase-1 overexpression in a rat model of nephrotic syndrome.}, journal = {Life sciences}, volume = {91}, number = {9-10}, pages = {301-305}, doi = {10.1016/j.lfs.2012.06.015}, pmid = {22749861}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Arginine/*analogs &amp; derivatives/metabolism ; Cells, Cultured ; Disease Models, Animal ; Doxorubicin/toxicity ; Epithelial Cells/metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Kidney Tubules, Proximal/cytology/metabolism ; Male ; Nephrotic Syndrome/*physiopathology ; Oxidative Stress ; Protein-Arginine N-Methyltransferases/*genetics ; Proteinuria/*physiopathology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Serum Albumin/administration &amp; dosage ; Time Factors ; }, abstract = {AIMS: Proteinuria is an independent risk factor for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Asymmetric dimethylarginine (ADMA) is a mediator of endothelial dysfunction and is associated with proteinuria in CKD patients. Thus, ADMA can partially account for the increased risk of CVD in CKD patients presenting proteinuria. However, a causal relationship between proteinuria and ADMA remains to be demonstrated.<br><br>MAIN METHODS: We first investigated whether and how proteinuria might increase ADMA levels in adriamycin (ADR)-treated rats. Next, we examined the effects of human serum albumin (HSA) on ADMA production by human renal proximal tubular epithelial cells (RPTECs) cultured in vitro.<br><br>KEY FINDINGS: Proteinuria was associated with ADMA levels in ADR treated rats. Although ADR treatment did not affect the expression levels of the dimethylarginine dimethylaminohydrolase (DDAH)-1 or -2 enzymes that degrade ADMA, it significantly increased the expression levels of protein arginine methyltransferase-1 (PRMT-1) that facilitates the production of ADMA. HSA increased the generation of reactive oxygen species in RPTECs, which was blocked by the anti-oxidant N-acetylcysteine (NAC) or an inhibitor of NADPH oxidase. Furthermore, HSA increased ADMA generation by RPTECs in a dose- and time-dependent manner and induced gene expression of PRMT-1 but not DDAHs, which were also suppressed by NAC.<br><br>SIGNIFICANCE: Our data suggest that proteinuria might enhance ADMA generation in tubular cells, at least in part via the overexpression of PRMT-1 triggered by oxidative stress. Our findings thereby propose a mechanistic link between proteinuria and ADMA levels in CKD patients.}, }
@article {pmid22746102, year = {2013}, author = {Ma, Q and Cavallin, LE and Leung, HJ and Chiozzini, C and Goldschmidt-Clermont, PJ and Mesri, EA}, title = {A role for virally induced reactive oxygen species in Kaposi's sarcoma herpesvirus tumorigenesis.}, journal = {Antioxidants &amp; redox signaling}, volume = {18}, number = {1}, pages = {80-90}, pmid = {22746102}, issn = {1557-7716}, support = {R01 CA136387/CA/NCI NIH HHS/United States ; CA75918/CA/NCI NIH HHS/United States ; CA136387/CA/NCI NIH HHS/United States ; HL71536/HL/NHLBI NIH HHS/United States ; 5P30AI073961/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Angiogenesis Inhibitors/pharmacology ; Animals ; Antiviral Agents/pharmacology/therapeutic use ; Cell Proliferation ; Cell Transformation, Neoplastic/drug effects/*metabolism ; Free Radical Scavengers/pharmacology/therapeutic use ; Gene Expression/drug effects ; HEK293 Cells ; Herpesvirus 8, Human/drug effects/*genetics/physiology ; Humans ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neovascularization, Pathologic/prevention &amp; control ; Neuropeptides/metabolism ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Receptors, G-Protein-Coupled/genetics/metabolism ; STAT3 Transcription Factor/genetics/metabolism ; Sarcoma, Kaposi/pathology/prevention &amp; control/*virology ; Transcription, Genetic/drug effects ; Viral Proteins/genetics/metabolism ; rac GTP-Binding Proteins/metabolism ; rac1 GTP-Binding Protein ; }, abstract = {AIMS: Kaposi's sarcoma (KS), caused by the Kaposi's sarcoma herpesvirus (KSHV), is an AIDS-associated cancer characterized by angiogenesis and proliferation of spindle cells. Rac1-activated reactive oxygen species (ROS) production has been implicated in KS tumorigenesis. We used an animal model of KSHV-induced Kaposi's sarcomagenesis (mECK36) to study the role of ROS in KS and the efficacy of N-acetyl l-cysteine (NAC) in inhibiting or preventing KS.<br><br>RESULTS: Signaling by the KSHV early lytic gene viral G protein-coupled receptor (vGPCR) activated ROS production in mECK36 cells via a Rac1-NADPH oxidase pathway. Induction of the lytic cycle in KSHV-infected KS spindle cells upregulated ROS along with upregulation of vGPCR expression. We also found that expression of the major latent transcript in 293 cells increased ROS levels. ROS scavenging with NAC halted mECK36 tumor growth in a KSHV-specific manner. NAC inhibited KSHV latent gene expression as well as tumor angiogenesis and lymphangiogenesis. These effects correlated with the reduction of vascular endothelial growth factor (VEGF), c-myc, and cyclin D1, and could be explained on the basis of inhibition of STAT3 tyrosine phosphorylation. NAC prevented mECK36 de novo tumor formation. Molecular analysis of NAC-resistant tumors revealed a strong upregulation of Rac1 and p40(PHOX).<br><br>INNOVATION AND CONCLUSION: Our results demonstrate that ROS-induction by KSHV plays a causal role in KS oncogenesis by promoting proliferation and angiogenesis. Our results show that both ROS and their molecular sources can be targeted therapeutically using NAC or other Food and Drug Administration (FDA)-approved inhibitors for prevention and treatment of AIDS-KS.}, }
@article {pmid22745145, year = {2012}, author = {Purwanto, B and Prasetyo, DH}, title = {Effect of oral N-acetylcysteine treatment on immune system in continuous ambulatory peritoneal dialysis patients.}, journal = {Acta medica Indonesiana}, volume = {44}, number = {2}, pages = {140-144}, pmid = {22745145}, issn = {0125-9326}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/*pharmacology ; Biomarkers/blood ; C-Reactive Protein/drug effects/metabolism ; Calcitonin/blood/drug effects ; Calcitonin Gene-Related Peptide ; Complement C3/drug effects/metabolism ; Female ; Humans ; Inflammation/*blood/*drug therapy ; Interleukin-1/blood ; Interleukin-6/blood ; Kidney Failure, Chronic/immunology/therapy ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; *Peritoneal Dialysis, Continuous Ambulatory ; Protein Precursors/blood/drug effects ; Tumor Necrosis Factor-alpha/blood/drug effects ; }, abstract = {AIM: to determine the effect of oral N-acetylcysteine (NAC) on plasma levels of inflammatory markers in Continuous Ambulatory Peritoneal Dialysis (CAPD) patients.<br><br>METHODS: we performed a placebo-controlled study over 8 weeks in 32 patients on regular CAPD. The patients were divided into 2 groups of 16 patients matched for age and gender. The first group was given NAC 2x600 mg/day for 8 weeks and inflammatory parameter was compared with control group. The immune system is determined from the average levels of Procalcitonin, IL-6, IL-1, C3, SICAM, hsCRP, and TNF- before and after treatment with NAC. Student t-test was performed to compare the means between NAC receiving and control groups. All statistics were done using SPSS software (SPSS Ver 16.0).<br><br>RESULTS: administration of NAC, significantly diminished PCT (-0.38&#xb1;0.57 vs 0.09&#xb1;0.14; p=0.004), IL-6 (-1.94&#xb1;3.03 vs 1.19&#xb1;1.99; p=0.002), IL-1 (-0.14&#xb1;0.21 vs 0.01&#xb1;0.04; p=0.010), C3 (-7.40&#xb1;12.04 vs 4.60&#xb1;8.12; p=0.002), sICAM (-80.59&#xb1;29.18 vs -35.02&#xb1;46.99; p=0.007), hsCRP (-1.50&#xb1;1.32 vs 0.81&#xb1;1.17; p<0.001) and TNF- (-0.73&#xb1;0.47 vs 0.14&#xb1;0.74; p<0.001) levels compared control to group.<br><br>CONCLUSION: short-term oral NAC treatment resulted in reduction of circulating PCT, IL-6, IL-1, C3, sICAM, hsCRP, and TNF- in CAPD patients.}, }
@article {pmid22743636, year = {2012}, author = {Sonoki, K and Iwase, M and Ohdo, S and Ieiri, I and Matsuyama, N and Takata, Y and Kitazono, T}, title = {Telmisartan and N-acetylcysteine suppress group V secretory phospholipase A2 expression in TNFα-stimulated human endothelial cells and reduce associated atherogenicity.}, journal = {Journal of cardiovascular pharmacology}, volume = {60}, number = {4}, pages = {367-374}, doi = {10.1097/FJC.0b013e3182646ccc}, pmid = {22743636}, issn = {1533-4023}, mesh = {Acetylcysteine/*pharmacology ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Antioxidants/pharmacology ; Atherosclerosis/prevention &amp; control ; Benzimidazoles/*pharmacology ; Benzoates/*pharmacology ; Chemokine CCL2/genetics ; Diabetes Mellitus, Type 2/drug therapy/physiopathology ; Female ; Gene Expression Regulation/drug effects ; Group V Phospholipases A2/genetics ; Human Umbilical Vein Endothelial Cells/*drug effects/metabolism ; Humans ; Hypertension/*drug therapy/physiopathology ; Lipoproteins, LDL/drug effects/metabolism ; Lysophosphatidylcholines/metabolism ; Male ; Middle Aged ; RNA, Messenger/metabolism ; Telmisartan ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Group V secretory phospholipase A2 (sPLA2-V) hydrolyzes phosphatidylcholine in low-density lipoprotein (LDL) to increase lysophosphatidylcholine (LPC) content. Because in human umbilical vein endothelial cells (HUVEC), tumor necrosis factor alpha (TNFα)-induced sPLA2-V expression, and LPC content in LDL and monocyte chemoattractant protein-1 mRNA were enhanced by incubation of LDL with TNFα-stimulated HUVEC, we investigated whether an angiotensin II receptor type 1 blocker, telmisartan, or an antioxidant drug, N-acetylcysteine (NAC), suppressed TNFα-induced sPLA2-V expression. Telmisartan or NAC administered before and during TNFα stimulation diminished the increase of sPLA2-V mRNA in HUVEC and reduced TNFα-induced sPLA2-V protein at 3 days after TNFα stimulation. Angiotensin II did not induce sPLA2-V mRNA, and a peroxisome proliferator-activated receptor-γ antagonist, GW3335, did not influence the inhibitory effect of telmisartan on TNFα-induced sPLA2-V mRNA. At 3 days after TNFα stimulation, 30 μM telmisartan or 20 mM NAC administered before and during TNFα stimulation prevented the enhancement of LPC content in LDL and monocyte chemoattractant protein-1 mRNA by LDL incubation with TNFα-stimulated HUVEC. A 2-month treatment with telmisartan in 29 hypertensive type 2 diabetic patients significantly reduced LPC content in circulating LDL. Telmisartan's suppressive effect on TNFα-induced sPLA2-V expression may have beneficial effects in preventing proatherogenic changes of LDL.}, }
@article {pmid22742659, year = {2013}, author = {Oksay, T and Nazıroğlu, M and Ergün, O and Doğan, S and Özatik, O and Armağan, A and Özorak, A and Çelik, &#xd6;}, title = {N-acetyl cysteine attenuates diazinon exposure-induced oxidative stress in rat testis.}, journal = {Andrologia}, volume = {45}, number = {3}, pages = {171-177}, doi = {10.1111/j.1439-0272.2012.01329.x}, pmid = {22742659}, issn = {1439-0272}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Ascorbic Acid/metabolism ; Diazinon/*toxicity ; Drug Interactions ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Insecticides/*toxicity ; Lipid Peroxidation/drug effects ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Testis/*drug effects/metabolism ; Vitamin A/metabolism ; Vitamin E/metabolism ; Glutathione Peroxidase GPX1 ; }, abstract = {The aim of this study was to investigate the gonadotoxic effects of diazinon and its mechanism of action with special reference to its possible reactive oxygen species generating potential in rat testis and the protective effect of N-Acetyl Cysteine (NAC) on the exposure of diazinon. The vehicle was given orally to the control group and NAC, diazinon, combination of NAC and diazinon were given to three treatment groups for 4 weeks. Testis lipid peroxidation levels were higher in diazinon group than in control although lipid peroxidation levels were lower in diazinon + NAC group than in diazinon group. The reduced glutathione (GSH) levels were lower in diazinon group than in control and NAC group although its levels were higher in diazinon + NAC group than in diazinon group. Vitamin C, Vitamin E and β-carotene concentrations were also lower in diazinon group than in control and NAC groups. Vitamin E and β-carotene concentrations were higher in diazinon + NAC group than diazinon group. Glutathione peroxidase activity and vitamin A concentrations in the testis did not show any difference between the four groups. In conclusion, we observed that NAC treatment modulated diazinon-induced oxidative injury in the rat testis. These findings suggest that NAC supplementation can be useful in testis oxidative injury caused by the organophosphate insecticides.}, }
@article {pmid22742653, year = {2012}, author = {Tang, FR and Loke, WK}, title = {Sulfur mustard and respiratory diseases.}, journal = {Critical reviews in toxicology}, volume = {42}, number = {8}, pages = {688-702}, doi = {10.3109/10408444.2012.698405}, pmid = {22742653}, issn = {1547-6898}, mesh = {Animals ; Bronchiolitis Obliterans/etiology/*physiopathology ; Chemical Warfare Agents/*toxicity ; Disease Models, Animal ; E-Selectin/metabolism ; Glutathione/metabolism ; Humans ; Iran ; Iraq ; Lung Neoplasms/etiology/*physiopathology ; Mustard Gas/*toxicity ; Nitric Oxide Synthase/metabolism ; Peroxynitrous Acid/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Pulmonary Fibrosis/etiology/*physiopathology ; Respiratory System/*drug effects ; World War I ; }, abstract = {Victims exposed to sulfur mustard (HD) in World War I and Iran-Iraq war, and those suffered occupational or accidental exposure have endured discomfort in the respiratory system at early stages after exposure, and marked general physical deterioration at late stages due to pulmonary fibrosis, bronchiolitis obliterans or lung cancer. At molecule levels, significant changes of cytokines and chemokines in bronchoalveolar lavage and serum, and of selectins (in particular sE-selectin) and soluble Fas ligand in the serum have been reported in recent studies of patients exposed to HD in Iran-Iraq war, suggesting that these molecules may be associated with the pathophysiological development of pulmonary diseases. Experimental studies in rodents have revealed that reactive oxygen and nitrogen species, their product peroxynitrite (ONOO(-)), nitric oxide synthase, glutathione, poly (adenosine diphosphate-ribose) polymerase, activating protein-1 signaling pathway are promising drug targets for preventing HD-induced toxicity, whereas N-acetyl cysteine, tocopherols, melatonin, aprotinin and many other molecules have been proved to be effective in prevention of HD-induced damage to the respiratory system in different animal models. In this paper, we will systemically review clinical and pathophysiological changes of respiratory system in victims exposed to HD in the last century, update clinicians and researchers on the mechanism of HD-induced acute and chronic lung damages, and on the relevant drug targets for future development of antidotes for HD. Further research directions will also be proposed.}, }
@article {pmid22741616, year = {2012}, author = {Durukan, AB and Erdem, B and Durukan, E and Sevim, H and Karaduman, T and Gurbuz, HA and Gurpinar, A and Yorgancioglu, C}, title = {May toxicity of amiodarone be prevented by antioxidants? A cell-culture study.}, journal = {Journal of cardiothoracic surgery}, volume = {7}, number = {}, pages = {61}, pmid = {22741616}, issn = {1749-8090}, mesh = {Acetylcysteine/pharmacology ; Amiodarone/*toxicity ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Cell Line, Transformed ; Cell Survival/drug effects ; Drug Interactions ; Fibroblasts/cytology/drug effects ; Mice ; Oxidative Stress/drug effects ; }, abstract = {BACKGROUND: Atrial Fibrillation is the most common arrhythmia encountered following cardiac surgery. The most commonly administered drug used in treatment and prophylaxis is amiodarone which has several toxic effects on major organ functions. There are few clinical data concerning prevention of toxic effects and there is no routinely suggested agent. The aim of this study is to document the cytotoxic effects of amiodarone on cell culture media and compare the cytoprotective effects of commonly used antioxidant agents.<br><br>METHODS: L929 mouse fibroblast cell line was cultured and 100,000 cells/well-plate were obtained. First group of cells were treated with increasing concentrations of amiodarone (20 to 180 &#x3bc;M) alone. Second and third group of cells were incubated with one-fold equimolar dose of vitamin C and N-acetyl cysteine prior to amiodarone exposure. The viability of cells were measured by MTT assay and the cytoprotective effect of each agent was compared.<br><br>RESULTS: The cytotoxicity of amiodarone was significant with concentrations of 100 &#x3bc;M and more. The viabilities of both vitamin C and N-acetyl cysteine treated cells were higher compared to untreated cells.<br><br>CONCLUSIONS: Vitamin C and N-acetyl cysteine are commonly used in the clinical setting for different purposes in context of their known antioxidant actions. Their role in prevention of amiodarone induced cytotoxicity is not fully documented. The study fully demonstrates the cytoprotective role of both agents in amiodarone induced cytotoxicity on cell culture media; more pronounced with vitamin C in some concentrations. The findings may be projectile for further clinical studies.}, }
@article {pmid22739240, year = {2012}, author = {Park, SK and Dahmer, MK and Quasney, MW}, title = {MAPK and JAK-STAT signaling pathways are involved in the oxidative stress-induced decrease in expression of surfactant protein genes.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {30}, number = {2}, pages = {334-346}, doi = {10.1159/000339068}, pmid = {22739240}, issn = {1421-9778}, mesh = {ATP-Binding Cassette Transporters/genetics/metabolism ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Butadienes/pharmacology ; Cell Line, Tumor ; DNA-Binding Proteins/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Imidazoles/pharmacology ; Janus Kinases/antagonists &amp; inhibitors/*metabolism ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Nitriles/pharmacology ; *Oxidative Stress/drug effects ; Phosphorylation ; Promoter Regions, Genetic ; Protein Binding ; Pulmonary Surfactant-Associated Protein A/genetics/metabolism ; Pulmonary Surfactant-Associated Protein B/genetics/metabolism ; Pulmonary Surfactant-Associated Protein D/genetics/metabolism ; Pyridines/pharmacology ; RNA, Messenger/metabolism ; STAT3 Transcription Factor/antagonists &amp; inhibitors/*metabolism ; *Signal Transduction/drug effects ; Transcription Factors ; Tyrphostins/pharmacology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Oxidative stress is generated by reactive oxygen species (ROS) including hydrogen peroxide (H(2)O(2)), hydroxyl radical (•OH) and superoxide anion (O(2--)), which are produced as by-products of cellular metabolism. An imbalance in cellular redox status is a potent pathogenic factor that contributes to various chronic inflammatory diseases. In this study, we demonstrate that H(2)O(2)decreases surfactant protein A, B and ABCA3 mRNA level, and increases SP-D mRNA level in human pulmonary lung epithelial cells. The decreased mRNA level of SP-A and SP-B were significant with a maximum inhibition of 79 and 87%, respectively by 150 µM H(2)O(2)after 24 hrs of incubation. In addition, ABCA3 mRNA level was decreased with a maximum inhibition of 55% by 150 µM H(2)O(2)after 12 hrs of incubation. In contrast, 150 µM H(2)O(2)caused the SP-D mRNA level to increase to 200% of control after 8 hrs of incubation. The H(2)O(2)-induced gene repression or activation of SP-A, SP-B, SP-D and ABCA3 was blocked by pretreatment with the antioxidants N-acetyl-L-cysteine (NAC) and catalase. Furthermore, the inhibition of SP-A and SP-B was associated with reduced thyroid transcription factor -1 (TTF-1) DNA binding activity, and this reduced TTF-1 binding activity may be due to decreased TTF-1 protein expression level. The analyses of signal transduction pathways that may play a role in the regulation of gene expression by H(2)O(2)using several specific inhibitors showed that U0126, an inhibitor of ERK1/2 upstream kinase MEK1/2, blocked both H(2)O(2)-induced inhibition of SP-A and SP-B gene expression, whereas SB203580, an inhibitor of p38 MAPK, partially blocked H(2)O(2)-mediated inhibition of SP-A gene expression but not SP-B expression. In contrast, AG-490, a specific inhibitor of JAK-STAT pathway, blocked H(2)O(2)-mediated inhibition of SP-B gene expression but not SP-A expression. Immunoblot analyses using specific phosphor-antibodies demonstrated that ERK1/2, p38 MAPK and STAT3 are phosphorylated by oxidative stress suggesting that H(2)O(2)-induced inhibition of SP-A and SP-B gene expression is associated with MAPK and JAKSTAT signaling pathway. These data, therefore, suggest that H(2)O(2)affects SP-A and SP-B gene regulation by reducing TTF-1 DNA binding activity via MAPKs or STAT signaling pathways.}, }
@article {pmid22739213, year = {2012}, author = {Lv, Y and Fang, M and Zheng, J and Yang, B and Li, H and Xiuzigao, Z and Song, W and Chen, Y and Cao, W}, title = {Low-intensity ultrasound combined with 5-aminolevulinic acid administration in the treatment of human tongue squamous carcinoma.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {30}, number = {2}, pages = {321-333}, doi = {10.1159/000339067}, pmid = {22739213}, issn = {1421-9778}, mesh = {Aminolevulinic Acid/pharmacology/*therapeutic use ; Animals ; Apoptosis/drug effects ; Calcium/metabolism ; Carcinoma, Squamous Cell/metabolism/pathology/*therapy ; Caspase 3/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/metabolism ; Photosensitizing Agents/pharmacology/*therapeutic use ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Protoporphyrins/metabolism ; Reactive Oxygen Species/metabolism ; Tongue Neoplasms/metabolism/pathology/*therapy ; Transplantation, Heterologous ; *Ultrasonic Therapy ; bcl-2-Associated X Protein/metabolism ; }, abstract = {We investigated the anti-tumor efficiency of sonodynamic therapy (SDT) on human tongue squamous carcinoma SAS cell line using low intensity ultrasound (LIU) of 0.6 and 0.8 W/cm(2), plus 5-aminolevulinic acid (ALA). Xenograft in vivo experiments using Balb/ca nude mice and MTT assays in vitro showed that ALA-LIU therapy significantly suppressed the proliferation of SAS cells. ALA-LIU therapy markedly enhanced SAS cell apoptosis rate compared to LIU alone. Based on TEM and fluorescence microscopy observations, there are notably morphology changes and seriously swollen mitochondria in xenograft tissues, and ALA-induced PpIX bond strongly to mitochondria of SAS cells. Immunohistochemical staining and western blotting demonstrated upregulation of Bax, cytochrome c and caspase-3, and downregulation of Bcl-2 for both in vivo and in vitro cases after ALA-LIU treatment. Increase of reactive oxygen species (ROS) in the ALA-LIU treatment groups were found using 2, 7-dichlorofluorescin diacetate (DCFH-DA) staining. Administration of the ROS scavenger, N-acetylcysteine (NAC), suppressed ALA-LIU-induced apoptosis and the expression of mitochondria apoptosis-related proteins, which confirmed that the ALA-LIU induced SAS cell apoptosis is through the generation of ROS. The process initially damaged mitochondria, activated pro-apoptotic factors Bax and cytochrome c and suppressed the anti-apoptotic factor Bcl-2, activated caspase-3 to executed apoptosis through mitochondrial signaling pathway.}, }
@article {pmid22739166, year = {2012}, author = {Zhao, S and Pu, JX and Sun, HD and Wu, YL}, title = {[Longikaurin A induces apoptosis of multiple myeloma H929 cells].}, journal = {Zhongguo shi yan xue ye xue za zhi}, volume = {20}, number = {3}, pages = {611-615}, pmid = {22739166}, issn = {1009-2137}, mesh = {Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Diterpenes, Kaurane/*pharmacology ; Humans ; Multiple Myeloma/*pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {The aim of this study was to investigate the biological effect of longikaurin A on multiple myeloma H929 cells. Effects of oridonin and longikaurin A on proliferation of H929 cells were evaluated by CCK-8 assay. Cell morphological features of H929 cells were examined under inverted phase contrast microscope. Apoptosis was determined by Annexin V/PI staining. Expression of caspase-3, caspase-9, and PARP were detected by Western blot. Reactive oxygen species (ROS) level was determined by DCFDA assay. The results showed that longikaurin A (IC(50) 0.85 µmol/L) was more effective than oridonin ((IC(50) 10.66 µmol/L) to inhibit the proliferation of H929 cells. Treatment with longikaurin 2 µmol/L significantly increased the percentage of Annexin V positive cells. Caspase-3 and caspase-9 were activated and PARP, one substrate of caspase-3, was cleaved into 85 kDa fragments. The ROS scavenger N-acetyl-cysteine significantly blocked apoptosis induced by longikaurin A. However, longikaurin A did not increase the ROS level in H929 cells. It is concluded that longikaurin A is more effective than oridonin to induce apoptosis in multiple myeloma H929 cells without increasing the ROS level.}, }
@article {pmid22733602, year = {2013}, author = {Jang, DH and Weaver, MD and Pizon, AF}, title = {In vitro study of N-acetylcysteine on coagulation factors in plasma samples from healthy subjects.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {9}, number = {1}, pages = {49-53}, pmid = {22733602}, issn = {1937-6995}, support = {UL1 RR029893/RR/NCRR NIH HHS/United States ; 5UL1RR029893/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antidotes/*pharmacology ; Blood Coagulation Factors/*drug effects ; Cells, Cultured ; Female ; Free Radical Scavengers/*pharmacology ; Humans ; Male ; Prothrombin Time ; }, abstract = {INTRODUCTION: In the treatment of acetaminophen toxicity, clinicians believe that N-acetylcysteine (NAC) artificially elevates prothrombin time (PT). However, the effect of NAC on human blood coagulation remains unverified. In a previous study, we show that NAC had a dose-dependent effect on PT. To our knowledge, there are no studies that specifically examine the mechanism by which NAC affects PT. This study evaluates the effect from a therapeutic NAC dose on the activity of coagulation factors II, VII, IX, and X in human plasma.<br><br>METHOD: We obtained blood samples from ten volunteer subjects. After centrifugation of each volunteer's blood sample, the plasma was pipetted and divided into two 1-mL aliquots. We used the first-1 mL sample as a control. The second 1-mL plasma sample had 5 &#x3bc;L of 20 % NAC, added to make a final concentration of 1,000 mg of NAC per L of plasma. This concentration of NAC approximates the plasma levels achieved after a 150-mg/kg dose. We incubated the two samples for each subject (control and 1,000 mg/L) at 37&#xb0;C for 1 h and measured the activity of coagulation factors II, VII, IX, and X. We compared factor activity using the paired student t test.<br><br>RESULTS: Participants included ten healthy subjects; six males, four females, median age 31 years. Mean values of the control samples for factors II, VII, IX, and X were 134 (CI 119-149), 126 (CI 90-163), 137 (CI 117-157), and 170 (CI 144-196)&#x2009;%, respectively. Mean values of the NAC-containing samples for factors II, VII, IX, and X were 90 (CI 79-100), 66 (CI 51-80), 74 (CI 63-85), and 81 (CI 71-90) %, respectively. All samples containing NAC had significantly lower coagulation factor activity level than their controls with a p&#x2009;<&#x2009;0.001.<br><br>DISCUSSION: In a previous study, we were able to demonstrate that NAC had a dose-dependent effect on PT. In this study, we compared activity of factors II, VII, IX, and X at baseline and for samples that received NAC. All factor activity had a significant decrease with the addition of NAC. This fall in factor activity is not explained by the dilution of adding NAC to the test samples.<br><br>CONCLUSION: We are able to demonstrate a significant decrease in the activity of coagulation factors II, VII, IX, and X with the addition of NAC. This may be the mechanism by which PT increased in our previous study.}, }
@article {pmid22732651, year = {2012}, author = {Amrouche-Mekkioui, I and Djerdjouri, B}, title = {N-acetylcysteine improves redox status, mitochondrial dysfunction, mucin-depleted crypts and epithelial hyperplasia in dextran sulfate sodium-induced oxidative colitis in mice.}, journal = {European journal of pharmacology}, volume = {691}, number = {1-3}, pages = {209-217}, doi = {10.1016/j.ejphar.2012.06.014}, pmid = {22732651}, issn = {1879-0712}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/pharmacology/therapeutic use ; Apoptosis/drug effects ; Biomarkers/metabolism ; Colitis/chemically induced/*drug therapy/metabolism/pathology ; Colon/drug effects/metabolism/pathology ; Dextran Sulfate/*pharmacology ; Epithelial Cells/drug effects/*pathology ; Hyperplasia/drug therapy ; Intestinal Mucosa/*drug effects/metabolism/pathology ; Male ; Mice ; Mitochondria/*drug effects/metabolism/pathology ; Mucins/*deficiency ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; }, abstract = {The effect of N-acetylcysteine (NAC), a pharmacological antioxidant was investigated in a murine model of chronic colitis. Male NMRI mice were given 5% dextran sulfate sodium (DSS) in drinking water for 5 days followed by 10 days of water, three times. Compared to control mice given water, DSS-treated mice displayed severe imbalanced redox status with decreased glutathione and catalase, but increased malondialdehyde, protein carbonyls, nitric oxide and myeloperoxidase levels, at days 35th (active colitis) and 45th (recovery period). It also resulted in mitochondrial dysfunction, mucosal ulcers, mucin-depleted crypts and epithelial cell apoptosis. Crypt abscesses and glandular hyperplasia occurred selectively in distal colon. NAC (150 mg/kg) given in drinking water for 45 days along with 3 DSS cycles improved the hallmarks of DSS-colitis. Interestingly, the moderate impact of NAC on lipids and proteins oxidation correlated with myeloperoxidase and nitric oxide levels.NAC as a mucoregulator and a thiol restoring agent is protective on oxidative crypt alterations, mucin depletion, epithelial cell hyperplasia and apoptosis. Taken together, our results highlight the role of NAC as a scavenger of phagocytes-derived reactive oxygen species in mice DDS-colitis, suggesting that a long term NAC diet might be beneficial in inflammatory bowel diseases and colorectal cancer.}, }
@article {pmid22732503, year = {2012}, author = {Cao, L and Li, L and Zuo, Z}, title = {N-acetylcysteine reverses existing cognitive impairment and increased oxidative stress in glutamate transporter type 3 deficient mice.}, journal = {Neuroscience}, volume = {220}, number = {}, pages = {85-89}, pmid = {22732503}, issn = {1873-7544}, support = {R01 GM065211/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; *Aging ; Animals ; Antioxidants/*pharmacology ; Behavior, Animal/drug effects ; Brain/drug effects/metabolism ; Cognition Disorders/genetics/metabolism/*prevention &amp; control ; Enzyme-Linked Immunosorbent Assay ; Excitatory Amino Acid Transporter 3/deficiency/genetics ; Glutathione/biosynthesis ; Male ; Mice ; Mice, Knockout ; Oxidative Stress/*drug effects ; }, abstract = {Oxidative stress contributes significantly to brain aging. Animals lacking glutamate transporter type 3 (EAAT3) have a decreased level of glutathione, the major intracellular anti-oxidant, in neurons, and present with early onset of brain aging including brain atrophy and cognitive impairment at 11 months of age. Here, 12-month-old male EAAT3 knockout mice received intraperitoneal injection of N-acetylcysteine (NAC) at 150 mg/kg once every day for 4 weeks. NAC is a membrane permeable cysteine precursor that can work as a substrate for glutathione synthesis. EAAT3 knockout mice that received saline injection or did not receive any injection were also included in the study. EAAT3 knockout mice had significantly less freezing behavior than age- and gender-matched wild-type mice in context- and tone-related fear conditioning tests. The knockout mice also had decreased levels of glutathione and increased levels of 4-hydroxy-2-nonenal and proteins containing nitrotyrosine, indicators of oxidative stress, in the cerebral cortex and hippocampus. NAC but not saline injection attenuated these behavioral and biochemical changes in the EAAT3 knockout mice. These results suggest that improvement of anti-oxidative capacity in neurons reverses the existing cognitive impairment in aging brains, implying a potential role of glutathione replacement in cognitive improvement of aging population.}, }
@article {pmid22727548, year = {2013}, author = {de Senzi Moraes Pinto, R and Ferretti, R and Moraes, LH and Neto, HS and Marques, MJ and Minatel, E}, title = {N-acetylcysteine treatment reduces TNF-α levels and myonecrosis in diaphragm muscle of mdx mice.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {32}, number = {3}, pages = {472-475}, doi = {10.1016/j.clnu.2012.06.001}, pmid = {22727548}, issn = {1532-1983}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/therapeutic use ; Diaphragm/*drug effects/pathology ; Dystrophin/deficiency/genetics ; Inflammation/drug therapy/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscle, Skeletal/*drug effects/pathology ; Necrosis/*drug therapy/pathology ; Tumor Necrosis Factor-alpha/*blood ; }, abstract = {BACKGROUND &amp; AIMS: Duchenne muscular dystrophy (DMD) is a genetic muscle disease caused by the absence of dystrophin. An established animal model of DMD is the mdx mouse, which is unable to express dystrophin. Inflammation, particularly the proinflammatory cytokine tumor necrosis factor alpha (TNF-α), strongly contributes to necrosis in the dystrophin-deficient fibers of the mdx mice and in DMD. In this study we investigated whether the antioxidant N-acetylcysteine (NAC) decreases TNF-α levels and protects the diaphragm muscle of mdx mice against necrosis.<br><br>METHODS: Mdx mice (14 days old) received daily intraperitoneal injections of NAC for 14 days, followed by removal of the diaphragm muscle. Control mdx mice were injected with saline.<br><br>RESULTS: NAC reduced TNF-&#x3b1; and 4-HNE-protein adducts levels, inflammation, creatine kinase levels, and myonecrosis in diaphragm muscle.<br><br>CONCLUSIONS: NAC may be used as a complementary treatment for dystrophinopathies. However, clinical trials are needed to determine the appropriate dose for patients with Duchenne muscular dystrophy.}, }
@article {pmid22717346, year = {2012}, author = {Turkmen, S and Mentese, A and Karaguzel, E and Karaca, Y and Kucuk, A and Uzun, A and Yulug, E and Turedi, S}, title = {A comparison of the effects of N-acetylcysteine and ethyl pyruvate on experimental testicular ischemia-reperfusion injury.}, journal = {Fertility and sterility}, volume = {98}, number = {3}, pages = {626-631}, doi = {10.1016/j.fertnstert.2012.05.034}, pmid = {22717346}, issn = {1556-5653}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Male ; Malondialdehyde/analysis ; Peroxidase/metabolism ; Pyruvates/*therapeutic use ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/*drug therapy/metabolism/pathology ; Serum Albumin/analysis ; Testis/*blood supply ; }, abstract = {OBJECTIVE: To compare the effects of N-acetylcysteine (NAC) and ethyl pyruvate (EP) on experimental testicular ischemia-reperfusion (I/R) injury.<br><br>DESIGN: Randomized, controlled, experimental study.<br><br>SETTING: University hospital.<br><br>ANIMAL(S): Twenty-four mature male Wistar rats.<br><br>INTERVENTION(S): Rats were divided into four groups: control group, torsion-detorsion (T/D) group, EP group, and NAC group. In the pretreatment of the NAC and EP groups, 20 mg/kg NAC and 50 mg/kg EP were given intraperitoneally (IP) 30 minutes before detorsion.<br><br>MAIN OUTCOME MEASURE(S): Serum ischemia-modified albumin (IMA), tissue and serum malondialdehyde, and myeloperoxidase activity levels and histopathological damage scores were then compared.<br><br>RESULT(S): Ethyl pyruvate and N-acetylcysteine exhibited a protective effect against I/R injury. Of the biochemical parameters evaluated as a result of testicular I/R, only IMA levels were significantly elevated. There was a strong and significant correlation between serum IMA levels and histopathological injury scores, and the increase in serum IMA level exhibited a strong parallel with the increase in histopathological injury. In the EP group, although the histopathological injury score was similar to that of the control group, serum IMA levels were significantly elevated.<br><br>CONCLUSION(S): Both NAC and EP, the effects of which on I/R injury are evaluated in the present study, reduce such injury in testicular torsion-detorsion. Comparing their effects on IMA levels, NAC may be regarded as a relatively more effective treatment than EP.}, }
@article {pmid22714038, year = {2012}, author = {Lee, JE and Park, JH and Shin, IC and Koh, HC}, title = {Reactive oxygen species regulated mitochondria-mediated apoptosis in PC12 cells exposed to chlorpyrifos.}, journal = {Toxicology and applied pharmacology}, volume = {263}, number = {2}, pages = {148-162}, doi = {10.1016/j.taap.2012.06.005}, pmid = {22714038}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Chlorpyrifos/*toxicity ; Dopamine/metabolism ; Female ; Gene Expression Regulation/drug effects ; Heme Oxygenase-1/genetics ; Insecticides/*toxicity ; Mitochondria/*drug effects/metabolism/pathology ; Mitogen-Activated Protein Kinases/drug effects/metabolism ; Oxidative Stress/*drug effects ; PC12 Cells ; Phosphorylation/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Substantia Nigra/drug effects/metabolism ; Superoxide Dismutase/metabolism ; Time Factors ; }, abstract = {Reactive oxidative species (ROS) generated by environmental toxicants including pesticides could be one of the factors underlying the neuronal cell damage in neurodegenerative diseases. In this study we found that chlorpyrifos (CPF) induced apoptosis in dopaminergic neuronal components of PC12 cells as demonstrated by the activation of caspases and nuclear condensation. Furthermore, CPF also reduced the tyrosine hydroxylase-positive immunoreactivity in substantia nigra of the rat. In addition, CPF induced inhibition of mitochondrial complex I activity. Importantly, N-acetyl cysteine (NAC) treatment effectively blocked apoptosis via the caspase-9 and caspase-3 pathways while NAC attenuated the inhibition of mitochondrial complex I activity as well as the oxidative metabolism of dopamine (DA). These results demonstrated that CPF-induced apoptosis was involved in mitochondrial dysfunction through the production of ROS. In the response of cellular antioxidant systems to CPF, we found that CPF treatment increased HO-1 expression while the expression of CuZnSOD and MnSOD was reduced. In addition, we found that CPF treatment activated MAPK pathways, including ERK 1/2, the JNK, and the p38 MAP kinase in a time-dependent manner. NAC treatment abolished MAPK phosphorylation caused by CPF, indicating that ROS are upstream signals of MAPK. Interestingly, MAPK inhibitors abolished cytotoxicity and reduced ROS generation by CPF treatment. Our results demonstrate that CPF induced neuronal cell death in part through MAPK activation via ROS generation, suggesting its potential to generate oxidative stress via mitochondrial damage and its involvement in oxidative stress-related neurodegenerative disease.}, }
@article {pmid22713468, year = {2012}, author = {Phalitakul, S and Okada, M and Hara, Y and Yamawaki, H}, title = {A novel adipocytokine, vaspin inhibits platelet-derived growth factor-BB-induced migration of vascular smooth muscle cells.}, journal = {Biochemical and biophysical research communications}, volume = {423}, number = {4}, pages = {844-849}, doi = {10.1016/j.bbrc.2012.06.052}, pmid = {22713468}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Adipokines/*pharmacology ; Animals ; Antioxidants/pharmacology ; Becaplermin ; Cell Movement/*drug effects/physiology ; HSP27 Heat-Shock Proteins/metabolism ; Muscle, Smooth, Vascular/*drug effects/physiology ; Myocytes, Smooth Muscle/*drug effects/physiology ; Phosphorylation ; Proto-Oncogene Proteins c-sis/*antagonists &amp; inhibitors/pharmacology ; Rats ; Rats, Inbred OLETF ; Reactive Oxygen Species/metabolism ; Serpins/*pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Vaspin is a novel adipocytokine originally identified in visceral white adipose tissues of Otsuka Long-Evans Tokushima fatty rats, an animal model of type 2 diabetes. We have previously shown that vaspin has anti-inflammatory effects in vascular smooth muscle cells (SMCs). SMCs migration is an important process for development atherosclerosis. However, effects of vaspin on SMCs migration remain to be clarified. Rat mesenteric arterial SMCs were treated with platelet-derived growth factor (PDGF)-BB (10 ng/ml, 90 min) in the absence or presence of vaspin (0.01-10 ng/ml, pretreatment for 2h). SMCs migration was evaluated by a Boyden chamber assay. Western blotting was performed to analyze cellular signals. Reactive oxygen species (ROS) generation was fluorometrically measured using 2',7'-dichlorofluorescein diacetate. Vaspin significantly inhibited PDGF-BB-induced SMCs migration. Vaspin significantly inhibited PDGF-BB-induced phosphorylation of p38 and heat shock protein (HSP) 27 as well as ROS generation. SMCs migration was blocked by an inhibitor of p38 or an anti-oxidant drug, N-acetyl-l-cysteine (NAC). NAC significantly inhibited the PDGF-BB-induced phosphorylation of p38 and HSP27. In addition, vaspin inhibited PDGF-BB-induced actin cytoskeletal reorganization (lamellipodia formation) as revealed by a rhodamine phalloidin staining. The present study for the first time revealed that vaspin inhibits PDGF-BB-induced SMCs migration through inhibiting p38/HSP27 signals via preventing the ROS generation.}, }
@article {pmid22712627, year = {2012}, author = {Toker, H and Ozdemir, H and Balcı, H and Ozer, H}, title = {N-acetylcysteine decreases alveolar bone loss on experimental periodontitis in streptozotocin-induced diabetic rats.}, journal = {Journal of periodontal research}, volume = {47}, number = {6}, pages = {793-799}, doi = {10.1111/j.1600-0765.2012.01497.x}, pmid = {22712627}, issn = {1600-0765}, mesh = {Acetylcysteine/*therapeutic use ; Alveolar Bone Loss/etiology/*prevention &amp; control ; Animals ; Antioxidants/*therapeutic use ; Diabetes Mellitus, Experimental/chemically induced/*complications ; Osteoblasts/physiology ; Periodontitis/complications/*drug therapy ; Rats ; Rats, Wistar ; Streptozocin ; }, abstract = {BACKGROUND AND OBJECTIVE: The purpose of this study was to evaluate the morphometric and histopathological changes associated with experimental periodontitis in diabetic rats in response to systemic administration of N-acetylcysteine (NAC), a sulfhydryl-containing thiol antioxidant.<br><br>MATERIAL AND METHODS: &#x2002;Sixty Wistar rats were divided into six experimental groups: nonligated (NL) group; ligature-only (L) group; streptozotocin-only (STZ) group; STZ and ligature (STZ + L) group; and systemic administration of NAC and ligature (70 and 100 mg/kg body weight per day, respectively) (NAC70 and NAC100 groups). Diabetes mellitus was induced by 60 mg/kg of streptozotocin. Silk ligatures were placed at the gingival margin of the lower first molars of the mandibular quadrant. The study duration was 30 d and the animals were killed at the end of this period. Changes in alveolar bone levels were clinically measured and tissues were histopathologically examined to assess the differences among the study groups.<br><br>RESULTS: At the end of the 30-d study period, alveolar bone loss was significantly higher in the STZ + L group compared with the other groups (p < 0.05). Also, alveolar bone loss in all the NAC groups was significantly lower than in the STZ + L and L groups (p < 0.05). The osteoblastic activity in the NAC100 group was significantly higher than in the other groups (p < 0.05).<br><br>CONCLUSION: Within the limits of this study, it can be suggested that NAC, when administered systemically, prevents alveolar bone loss in the diabetic rat model.}, }
@article {pmid22711881, year = {2013}, author = {Nierenberg, AA and Kansky, C and Brennan, BP and Shelton, RC and Perlis, R and Iosifescu, DV}, title = {Mitochondrial modulators for bipolar disorder: a pathophysiologically informed paradigm for new drug development.}, journal = {The Australian and New Zealand journal of psychiatry}, volume = {47}, number = {1}, pages = {26-42}, doi = {10.1177/0004867412449303}, pmid = {22711881}, issn = {1440-1614}, mesh = {Bipolar Disorder/drug therapy/genetics/*metabolism ; Brain/*metabolism ; Down-Regulation ; Free Radical Scavengers/therapeutic use ; Genes, Mitochondrial/genetics ; Glycolysis ; Humans ; Mitochondria/*metabolism ; Neuroprotective Agents/therapeutic use ; Nootropic Agents/therapeutic use ; Oxidative Phosphorylation ; Oxidative Stress ; Up-Regulation ; }, abstract = {OBJECTIVES: Bipolar patients frequently relapse within 12 months of their previous mood episode, even in the context of adequate treatment, suggesting that better continuation and maintenance treatments are needed. Based on recent research of the pathophysiology of bipolar disorder, we review the evidence for mitochondrial dysregulation and selected mitochondrial modulators (MM) as potential treatments.<br><br>METHODS: We reviewed the literature about mitochondrial dysfunction and potential MMs worthy of study that could improve the course of bipolar disorder, reduce subsyndromal symptoms, and prevent subsequent mood episodes.<br><br>RESULTS: MM treatment targets mitochondrial dysfunction, oxidative stress, altered brain energy metabolism and the dysregulation of multiple mitochondrial genes in patients with bipolar disorder. Several tolerable and readily available candidates include N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q(10) (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin. The specific metabolic pathways by which these MMs may improve the symptoms of bipolar disorder are discussed and combinations of selected MMs could be of interest as well.<br><br>CONCLUSIONS: Convergent data implicate mitochondrial dysfunction as an important component of the pathophysiology of bipolar disorder. Clinical trials of individual MMs as well as combinations are warranted.}, }
@article {pmid22710416, year = {2012}, author = {Xiao, F and Li, Y and Dai, L and Deng, Y and Zou, Y and Li, P and Yang, Y and Zhong, C}, title = {Hexavalent chromium targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent caspase-3 activation in L-02 hepatocytes.}, journal = {International journal of molecular medicine}, volume = {30}, number = {3}, pages = {629-635}, doi = {10.3892/ijmm.2012.1031}, pmid = {22710416}, issn = {1791-244X}, mesh = {Caspase 3/*metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Chromium/*pharmacology ; Dose-Response Relationship, Drug ; Electron Transport Complex I/antagonists &amp; inhibitors/*metabolism ; Enzyme Activation/drug effects ; Hepatocytes/drug effects/metabolism ; Mitochondria/*drug effects/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Hexavalent chromium [Cr(VI)], which is used for various industrial applications, such as leather tanning and chroming, can cause a number of human diseases including inflammation and cancer. Cr(VI) exposure leads to severe damage to the liver, but the mechanisms involved in Cr(VI)-mediated toxicity in the liver are unclear. The present study provides evidence that Cr(VI) enhances reactive oxygen species (ROS) accumulation by inhibiting the mitochondrial respiratory chain complex (MRCC) I. Cr(VI) did not affect the expression levels of antioxidative proteins such as superoxide dismutase (SOD), catalase and thioredoxin (Trx), indicating that the antioxidative system was not involved in Cr(VI)-induced ROS accumulation. We found that ROS mediated caspase-3 activation partially depends on the downregulation of the heat shock protein (HSP) 70 and 90. In order to confirm our hypothesis that ROS plays a key role in Cr(VI)-mediated cytotoxicity, we used N-acetylcysteine (NAC) to inhibit the accumulation of ROS. NAC successfully blocked the inhibition of HSP70 and HSP90 as well as the activation of caspase-3, suggesting that ROS is essential in Cr(VI)-induced caspase-3 activation. By applying different MRCC substrates as electron donors, we also confirmed that Cr(VI) could accept the electrons leaked from MRCC I and the reduction occurs at MRCC I. In conclusion, the present study demonstrates that Cr(VI) induces ROS-dependent caspase-3 activation by inhibiting MRCC I activity, and MRCC I has been identified as a new target and a new mechanism for the apoptosis-inducing activity displayed by Cr(VI).}, }
@article {pmid22708712, year = {2012}, author = {Feldman, L and Sherman, RA and Weissgarten, J}, title = {N-acetylcysteine use for amelioration of aminoglycoside-induced ototoxicity in dialysis patients.}, journal = {Seminars in dialysis}, volume = {25}, number = {5}, pages = {491-494}, doi = {10.1111/j.1525-139X.2012.01090.x}, pmid = {22708712}, issn = {1525-139X}, mesh = {Acetylcysteine/*therapeutic use ; Aminoglycosides/*adverse effects ; Ear Diseases/*chemically induced/*drug therapy ; Free Radical Scavengers/*therapeutic use ; Humans ; Oxidative Stress/drug effects ; *Renal Dialysis ; Risk Factors ; }, abstract = {Use of aminoglycoside antibiotics is associated with significant ototoxicity, especially on patients with decreased renal function. The risk of aminoglycoside ototoxicity may approach 60%. Oxidative stress has been suggested as a general mechanism of aminoglycoside ototoxicity and is prevalent in dialysis population. N-acetylcysteine (NAC) is an effective antioxidant and has been safely used in dialysis patients. New experimental and clinical data, explored in this review, provide a good case to recommend NAC administration to all dialysis patients, receiving aminoglycosides.}, }
@article {pmid22706327, year = {2012}, author = {Gray, KM and Carpenter, MJ and Baker, NL and DeSantis, SM and Kryway, E and Hartwell, KJ and McRae-Clark, AL and Brady, KT}, title = {A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents.}, journal = {The American journal of psychiatry}, volume = {169}, number = {8}, pages = {805-812}, pmid = {22706327}, issn = {1535-7228}, support = {K23 DA020482/DA/NIDA NIH HHS/United States ; R01 DA026777/DA/NIDA NIH HHS/United States ; UL1 TR000062/TR/NCATS NIH HHS/United States ; UL1 RR029882/RR/NCRR NIH HHS/United States ; K23DA020482/DA/NIDA NIH HHS/United States ; UL1RR029882/RR/NCRR NIH HHS/United States ; R01DA026777/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Cannabinoids/urine ; Counseling ; Double-Blind Method ; Excitatory Amino Acid Antagonists/*therapeutic use ; Female ; Humans ; Male ; Marijuana Abuse/*drug therapy ; Treatment Outcome ; Young Adult ; }, abstract = {OBJECTIVE: Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy.<br><br>METHOD: In an 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group.<br><br>RESULTS: Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events.<br><br>CONCLUSIONS: This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.}, }
@article {pmid22705913, year = {2012}, author = {Nacharaju, P and Tuckman-Vernon, C and Maier, KE and Chouake, J and Friedman, A and Cabrales, P and Friedman, JM}, title = {A nanoparticle delivery vehicle for S-nitroso-N-acetyl cysteine: sustained vascular response.}, journal = {Nitric oxide : biology and chemistry}, volume = {27}, number = {3}, pages = {150-160}, pmid = {22705913}, issn = {1089-8611}, support = {P01 HL071064/HL/NHLBI NIH HHS/United States ; P01 HL110900/HL/NHLBI NIH HHS/United States ; R01 HL052684/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives/chemistry ; Animals ; Blood Pressure/drug effects ; Carbon Dioxide/blood ; Cricetinae ; Drug Carriers/administration &amp; dosage/chemistry ; Glutathione/metabolism ; Heart Rate/drug effects ; Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry ; Male ; Mesocricetus ; Nanoparticles/*administration &amp; dosage/*chemistry ; Oxygen/blood ; S-Nitrosoglutathione/metabolism ; S-Nitrosothiols/chemistry/pharmacology ; Vasodilation/*drug effects ; }, abstract = {Interest in the development of nitric oxide (NO) based therapeutics has grown exponentially due to its well elucidated and established biological functions. In line with this surge, S-nitroso thiol (RSNO) therapeutics are also receiving more attention in recent years both as potential stable sources of NO as well as for their ability to serve as S-nitrosating agents; S-nitrosation of protein thiols is implicated in many physiological processes. We describe two hydrogel based RSNO containing nanoparticle platforms. In one platform the SNO groups are covalently attached to the particles (SNO-np) and the other contains S-nitroso-N-acetyl cysteine encapsulated within the particles (NAC-SNO-np). Both platforms function as vehicles for sustained activity as trans-S-nitrosating agents. NAC-SNO-np exhibited higher efficiency for generating GSNO from GSH and maintained higher levels of GSNO concentration for longer time (24 h) as compared to SNO-np as well as a previously characterized nitric oxide releasing platform, NO-np (nitric oxide releasing nanoparticles). In vivo, intravenous infusion of the NAC-SNO-np and NO-np resulted in sustained decreases in mean arterial pressure, though NAC-SNO-np induced longer vasodilatory effects as compared to the NO-np. Serum chemistries following infusion demonstrated no toxicity in both treatment groups. Together, these data suggest that the NAC-SNO-np represents a novel means to both study the biologic effects of nitrosothiols and effectively capitalize on its therapeutic potential.}, }
@article {pmid22704995, year = {2012}, author = {Guo, J and Zhang, Y and Zhang, J and Liang, J and Zeng, L and Guo, G}, title = {Anticancer effect of tert-butyl-2(4,5-dihydrogen-4,4,5,5-tetramethyl-3-O-1H-imidazole-3-cationic-1-oxyl-2)-pyrrolidine-1-carboxylic ester on human hepatoma HepG2 cell line.}, journal = {Chemico-biological interactions}, volume = {199}, number = {1}, pages = {38-48}, doi = {10.1016/j.cbi.2012.06.001}, pmid = {22704995}, issn = {1872-7786}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Carcinoma, Hepatocellular/drug therapy/pathology ; Cell Line ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Glutathione/metabolism ; Hep G2 Cells/drug effects ; Humans ; Imidazoles/*pharmacology ; Male ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred BALB C ; Pyrrolidines/*pharmacology ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Tert-butyl-2(4,5-dihydrogen-4,4,5,5-tetramethyl-3-O-1H-imidazole-3-cationic-1-oxyl-2)-pyrrolidine-1-carboxylic ester (L-NNP) is a stable nitroxyl nitroxide radical, which have displayed cytotoxicity on human breast cancer MCF-7 and MDA-MB-231 cell lines. In the present study, we investigated the selective cytotoxicity of L-NNP on isogenetic human hepatoma HepG2 and normal L-02 cell lines. Cell growth inhibition, intracellular reactive oxygen species production, the mitochondrial membrane potential loss, malondialdehyde generation and glutathione levels were analyzed. The expression of Bax, Bcl-2 and NF-κBp65 proteins was also examined. The anticancer activity was evaluated in a HepG2 cell xenograft nude mice model. The results showed that 10, 20, 40 μg/ml L-NNP exposure for 48 h caused 52%, 82% and 91% cell growth inhibition of HepG2 cells, compared with 5%, 10% and 15% that of L-02 cells (p < 0.01). Concentrations of 10, 20, 40 μg/ml L-NNP induced cell death by increasing the generation of intracellular reactive oxygen species and MDA, by depolarizing the mitochondrial membrane potential, and by decreasing intracellular GSH levels in HepG2 cells. Western blot assay showed that Bax, Bcl-2 and NF-κBp65 might be implicated in L-NNP-induced selective HepG2 cell death. L-NNP was also found to inhibit HepG2 hepatoma growth and extend the life span of nude mice model (p < 0.01). The pretreatment and co-treatment of 10 mM N-acetyl-cysteine alleviated L-NNP exposure induced intracellular reactive oxygen species increase and cell growth inhibition demonstrated that L-NNP exhibited neoplasm-selective cytotoxicity and pro-apoptotic activities via reactive oxygen species mediated oxidative damage in HepG2 cells. It might be promising for developing a new class of anticancer agent for liver cancer.}, }
@article {pmid22701784, year = {2012}, author = {Javazon, EH and Radhi, M and Gangadharan, B and Perry, J and Archer, DR}, title = {Hematopoietic stem cell function in a murine model of sickle cell disease.}, journal = {Anemia}, volume = {2012}, number = {}, pages = {387385}, pmid = {22701784}, issn = {2090-1275}, support = {R01 HL073307/HL/NHLBI NIH HHS/United States ; }, abstract = {Previous studies have shown that the sickle environment is highly enriched for reactive oxygen species (ROS). We examined the oxidative effects of sickle cell disease on hematopoietic stem cell function in a sickle mouse model. In vitro colony-forming assays showed a significant decrease in progenitor colony formation derived from sickle compared to control bone marrow (BM). Sickle BM possessed a significant decrease in the KSL (c-kit(+), Sca-(1+), Lineage(-)) progenitor population, and cell cycle analysis showed that there were fewer KSL cells in the G(0) phase of the cell cycle compared to controls. We found a significant increase in both lipid peroxidation and ROS in sickle-derived KSL cells. In vivo analysis demonstrated that normal bone marrow cells engraft with increased frequency into sickle mice compared to control mice. Hematopoietic progenitor cells derived from sickle mice, however, demonstrated significant impairment in engraftment potential. We observed partial restoration of engraftment by n-acetyl cysteine (NAC) treatment of KSL cells prior to transplantation. Increased intracellular ROS and lipid peroxidation combined with improvement in engraftment following NAC treatment suggests that an altered redox environment in sickle mice affects hematopoietic progenitor and stem cell function.}, }
@article {pmid22701723, year = {2012}, author = {Østerholt, HC and Dannevig, I and Wyckoff, MH and Liao, J and Akgul, Y and Ramgopal, M and Mija, DS and Cheong, N and Longoria, C and Mahendroo, M and Nakstad, B and Saugstad, OD and Savani, RC}, title = {Antioxidant protects against increases in low molecular weight hyaluronan and inflammation in asphyxiated newborn pigs resuscitated with 100% oxygen.}, journal = {PloS one}, volume = {7}, number = {6}, pages = {e38839}, pmid = {22701723}, issn = {1932-6203}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Analysis of Variance ; Animals ; Animals, Newborn ; Antioxidants/metabolism/*pharmacology ; Asphyxia/*physiopathology/*therapy ; Bronchoalveolar Lavage ; DNA Primers/genetics ; Enzyme-Linked Immunosorbent Assay ; Hyaluronic Acid/*metabolism ; Interleukin-1beta/metabolism ; Lung/metabolism ; Oxidative Stress/drug effects/*physiology ; Oxygen Inhalation Therapy/*adverse effects ; Peroxynitrous Acid/metabolism ; Real-Time Polymerase Chain Reaction ; Sus scrofa ; Tumor Necrosis Factor-alpha/metabolism ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {BACKGROUND: Newborn resuscitation with 100% oxygen is associated with oxidative-nitrative stresses and inflammation. The mechanisms are unclear. Hyaluronan (HA) is fragmented to low molecular weight (LMW) by oxidative-nitrative stresses and can promote inflammation. We examined the effects of 100% oxygen resuscitation and treatment with the antioxidant, N-acetylcysteine (NAC), on lung 3-nitrotyrosine (3-NT), LMW HA, inflammation, TNFα and IL1ß in a newborn pig model of resuscitation.<br><br>Newborn pigs (n&#x200a;=&#x200a;40) were subjected to severe asphyxia, followed by 30 min ventilation with either 21% or 100% oxygen, and were observed for the subsequent 150 minutes in 21% oxygen. One 100% oxygen group was treated with NAC. Serum, bronchoalveolar lavage (BAL), lung sections, and lung tissue were obtained. Asphyxia resulted in profound hypoxia, hypercarbia and metabolic acidosis. In controls, HA staining was in airway subepithelial matrix and no 3-NT staining was seen. At the end of asphyxia, lavage HA decreased, whereas serum HA increased. At 150 minutes after resuscitation, exposure to 100% oxygen was associated with significantly higher BAL HA, increased 3NT staining, and increased fragmentation of lung HA. Lung neutrophil and macrophage contents, and serum TNF&#x3b1; and IL1&#xdf; were higher in animals with LMW than those with HMW HA in the lung. Treatment of 100% oxygen animals with NAC blocked nitrative stress, preserved HMW HA, and decreased inflammation. In vitro, peroxynitrite was able to fragment HA, and macrophages stimulated with LMW HA increased TNF&#x3b1; and IL1&#xdf; expression.<br><br>Compared to 21%, resuscitation with 100% oxygen resulted in increased peroxynitrite, fragmentation of HA, inflammation, as well as TNF&#x3b1; and IL1&#xdf; expression. Antioxidant treatment prevented the expression of peroxynitrite, the degradation of HA, and also blocked increases in inflammation and inflammatory cytokines. These findings provide insight into potential mechanisms by which exposure to hyperoxia results in systemic inflammation.}, }
@article {pmid22701695, year = {2012}, author = {Massaoka, MH and Matsuo, AL and Figueiredo, CR and Farias, CF and Girola, N and Arruda, DC and Scutti, JA and Romoff, P and Favero, OA and Ferreira, MJ and Lago, JH and Travassos, LR}, title = {Jacaranone induces apoptosis in melanoma cells via ROS-mediated downregulation of Akt and p38 MAPK activation and displays antitumor activity in vivo.}, journal = {PloS one}, volume = {7}, number = {6}, pages = {e38698}, pmid = {22701695}, issn = {1932-6203}, mesh = {Acetylcysteine ; Animals ; Annexin A5 ; Antineoplastic Agents/analysis/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Asteraceae/*chemistry ; Benzoquinones/analysis/*pharmacology/therapeutic use ; Blotting, Western ; Cell Line, Tumor ; Chromatin/metabolism ; Colorimetry ; Down-Regulation ; Humans ; In Situ Nick-End Labeling ; In Vitro Techniques ; Male ; Melanoma/*drug therapy ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Microscopy, Electron, Transmission ; Nuclear Magnetic Resonance, Biomolecular ; Phytotherapy/*methods ; Plant Extracts/*pharmacology ; Propidium ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Superoxides ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND: Malignant melanoma is a deadly type of metastatic skin cancer with increased incidence over the past 30 years. Despite the advanced knowledge on the biology, immunobiology and molecular genetics of melanoma, the alternatives of treatment are limited with poor prognosis. On clinical trials, natural products and among them redox-active quinones have been tested in the attempt to control the growth of cancer cells. Recently, we isolated jacaranone from Pentacalia desiderabilis, a benzoquinone derivative that showed a broad antitumor activity and protective anti-melanoma effect in a syngeneic model. The purified substance is active at micromolar concentrations, is not hemolytic, and is not toxic in naïve mice.<br><br>The jacaranone antitumor activity was shown against several human cancer cell lines in vitro. Moreover, the induction of apoptosis in murine melanoma cells and jacaranone antitumor activity in vivo, in a melanoma experimental model, were also shown. Jacaranone renders antiproliferative and proapoptotic responses in tumor cells, by acting on Akt and p38 MAPK signaling pathways through generation of reactive oxygen species (ROS). The free radical scavenger N-acetyl-cysteine (NAC) was able to completely suppress cell death induced by jacaranone as it blocked Akt downregulation, p38 MAPK activation as well as upregulation of proapoptotic Bax. Notably, treatment of melanoma growing subcutaneously in mice with jacaranone significantly extended the mean survival times in a dose-dependent manner.<br><br>CONCLUSIONS/SIGNIFICANCE: The results provide evidence for the mechanisms of action of jacaranone and emphasize the potential use of this quinone for the treatment of melanoma.}, }
@article {pmid22701598, year = {2012}, author = {Downs, I and Liu, J and Aw, TY and Adegboyega, PA and Ajuebor, MN}, title = {The ROS scavenger, NAC, regulates hepatic Vα14iNKT cells signaling during Fas mAb-dependent fulminant liver failure.}, journal = {PloS one}, volume = {7}, number = {6}, pages = {e38051}, pmid = {22701598}, issn = {1932-6203}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R56 AI085150/AI/NIAID NIH HHS/United States ; DK44510/DK/NIDDK NIH HHS/United States ; R56AI085150/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Analysis of Variance ; Animals ; Antibodies, Monoclonal/*adverse effects/immunology ; Apoptosis/physiology ; Blotting, Western ; Fas Ligand Protein/immunology ; Flow Cytometry ; Free Radical Scavengers/*pharmacology/therapeutic use ; Glutathione/metabolism ; In Situ Nick-End Labeling ; Interferon-gamma/genetics/metabolism ; Liver/metabolism ; Liver Failure, Acute/*chemically induced/*drug therapy/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Natural Killer T-Cells/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects/physiology ; }, abstract = {Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18(-/-) mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.}, }
@article {pmid22701509, year = {2012}, author = {Lee, CC and Yang, HL and Way, TD and Kumar, KJ and Juan, YC and Cho, HJ and Lin, KY and Hsu, LS and Chen, SC and Hseu, YC}, title = {Inhibition of Cell Growth and Induction of Apoptosis by Antrodia camphorata in HER-2/neu-Overexpressing Breast Cancer Cells through the Induction of ROS, Depletion of HER-2/neu, and Disruption of the PI3K/Akt Signaling Pathway.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2012}, number = {}, pages = {702857}, pmid = {22701509}, issn = {1741-4288}, abstract = {Previously, we demonstrated that a submerged fermentation culture of Antrodia camphorata (AC) promotes cell-cycle arrest and apoptosis in human estrogen receptor-positive/negative breast cancer cells. However, whether AC is effective against HER-2/neu-overexpressing breast cancers has not been thoroughly elucidated. In the present study, we showed that AC exhibited a significant cytotoxic effect against HER-2/neu-overexpressing MDA-MB-453 and BT-474 cells. Immunoblot analysis demonstrated that HER-2/neu and their tyrosine phosphorylation were inhibited by AC in a dose-dependent manner. An increase in intracellular reactive oxygen species (ROS) was observed in AC-treated cells, whereas antioxidant N-acetylcysteine (NAC) significantly prevented AC induced HER-2/neu depletion and cell death, which directly indicates that AC-induced HER-2/neu depletion and cell death was mediated by ROS generation. Also, AC significantly downregulated the expression of cyclin D1, cyclin E, and CDK4 followed by the suppression of PI3K/Akt, and their downstream effectors GSK-3β and β-catenin. Notably, AC-treatment induced apoptotic cell death, which was associated with sub-G1 accumulation, DNA fragmentation, mitochondrial dysfunction, cytochrome c release, caspase-3/-9 activation, PARP degradation, and Bcl-2/Bax dysregulation. Assays for colony formation also confirmed the growth-inhibitory effects of AC. This is the first report confirming the anticancer activity of this potentially beneficial mushroom against human HER-2/neu-overexpressing breast cancers.}, }
@article {pmid22700875, year = {2012}, author = {Roy, S and Short, MK and Stanley, ER and Jubinsky, PT}, title = {Essential role of Drosophila black-pearl is mediated by its effects on mitochondrial respiration.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {26}, number = {9}, pages = {3822-3833}, pmid = {22700875}, issn = {1530-6860}, support = {CA26504/CA/NCI NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; R01 CA026504/CA/NCI NIH HHS/United States ; 5P30-CA13330/CA/NCI NIH HHS/United States ; R37 CA026504/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Autophagy/physiology ; Base Sequence ; Blotting, Western ; DNA Primers ; Drosophila Proteins/*physiology ; Drosophila melanogaster/*physiology ; Electron Transport ; Electron Transport Complex IV/metabolism ; Flow Cytometry ; G1 Phase ; Microscopy, Electron, Scanning ; Mitochondria/metabolism/*physiology ; RNA Interference ; Reactive Oxygen Species/metabolism ; S Phase ; }, abstract = {Black-pearl (Blp) is a highly conserved, essential inner-mitochondrial membrane protein. The yeast Blp homologue, Magmas/Pam16, is required for mitochondrial protein transport, growth, and survival. Our purpose was to determine the role of Drosophila Blp in mitochondrial function, cell survival, and proliferation. To this end, we performed mitotic recombination in Drosophila melanogaster, RNAi-mediated knockdown, MitoTracker staining, measurement of reactive oxygen species (ROS), flow cytometry, electron transport chain complex assays, and hemocyte isolation from Drosophila larvae. Proliferation-defective, Blp-deficient Drosophila Schneider cells exhibited mitochondrial membrane depolarization, a 60% decrease in ATP levels, increased amounts of ROS (3.5-fold), cell cycle arrest, and activation of autophagy that were associated with a selective 65% reduction of cytochrome c oxidase activity. N-acetyl cysteine (NAC) rescued Blp-RNAi-treated cells from cell cycle arrest, indicating that increased production of ROS is the primary cause of the proliferation and survival defects in Blp-depleted cells. blp hypomorph larvae had a 35% decreased number of plasmatocytes with a 45% reduced active mitochondrial staining and their viability was increased 2-fold by administration of NAC, which blocked melanotic lesions. Loss of Blp decreases cytochrome c oxidase activity and uncouples oxidative phosphorylation, causing ROS production, which selectively affects mitochondria-rich plasmatocyte survival and function, leading to melanotic lesions in Blp-deficient flies.}, }
@article {pmid22700867, year = {2012}, author = {Glista-Baker, EE and Taylor, AJ and Sayers, BC and Thompson, EA and Bonner, JC}, title = {Nickel nanoparticles enhance platelet-derived growth factor-induced chemokine expression by mesothelial cells via prolonged mitogen-activated protein kinase activation.}, journal = {American journal of respiratory cell and molecular biology}, volume = {47}, number = {4}, pages = {552-561}, pmid = {22700867}, issn = {1535-4989}, support = {RC2 ES018772/ES/NIEHS NIH HHS/United States ; T32 ES007046/ES/NIEHS NIH HHS/United States ; RC2-ES018772/ES/NIEHS NIH HHS/United States ; T32-ES007046-31/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Antioxidants/pharmacology ; Cell Line ; Chemokine CCL2/genetics/*metabolism ; Chemokine CXCL10/genetics/*metabolism ; Enzyme Activation ; Epithelial Cells/drug effects/*enzymology/ultrastructure ; Gene Expression/drug effects ; Gene Expression Regulation/drug effects ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; MAP Kinase Signaling System ; *Metal Nanoparticles ; Mitogen-Activated Protein Kinases/*metabolism ; Nickel/metabolism/*pharmacology ; Phosphorylation ; Platelet-Derived Growth Factor/*physiology ; Pleura/cytology ; Protein Processing, Post-Translational ; Rats ; Receptors, Platelet-Derived Growth Factor/metabolism ; }, abstract = {Pleural diseases (fibrosis and mesothelioma) are a major concern for individuals exposed by inhalation to certain types of particles, metals, and fibers. Increasing attention has focused on the possibility that certain types of engineered nanoparticles (NPs), especially those containing nickel, might also pose a risk for pleural diseases. Platelet-derived growth factor (PDGF) is an important mediator of fibrosis and cancer that has been implicated in the pathogenesis of pleural diseases. In this study, we discovered that PDGF synergistically enhanced nickel NP (NiNP)-induced increases in mRNA and protein levels of the profibrogenic chemokine monocyte chemoattractant protein-1 (MCP-1 or CCL2), and the antifibrogenic IFN-inducible CXC chemokine (CXCL10) in normal rat pleural mesothelial 2 (NRM2) cells in vitro. Carbon black NPs (CBNPs), used as a negative control NP, did not cause a significant increase in CCL2 or CXCL10 in the absence or presence of PDGF. NiNPs prolonged PDGF-induced phosphorylation of the mitogen-activated protein kinase family termed extracellular signal-regulated kinases (ERK)-1 and -2 for up to 24 hours, and NiNPs also synergistically increased PDGF-induced hypoxia-inducible factor (HIF)-1α protein levels in NRM2 cells. Inhibition of ERK-1,2 phosphorylation with the mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, blocked the synergistic increase in CCL2, CXCL10, and HIF-1α levels induced by PDGF and NiNPs. Moreover, the antioxidant, N-acetyl-L-cysteine (NAC), significantly reduced HIF-1α, ERK-1,2 phosphorylation, and CCL2 protein levels that were synergistically increased by the combination of PDGF and NiNPs. These data indicate that NiNPs enhance the activity of PDGF in regulating chemokine production in NRM2 cells through a mechanism involving reactive oxygen species generation and prolonged activation of ERK-1,2.}, }
@article {pmid22696870, year = {2012}, author = {Koksal, M and Kurcer, Z and Erdogan, D and Iraz, M and Tas, M and Eren, MA and Aydogan, T and Ulas, T}, title = {Effect of melatonin and n-acetylcysteine on hepatic injury in rat induced by methanol intoxication: a comparative study.}, journal = {European review for medical and pharmacological sciences}, volume = {16}, number = {4}, pages = {437-444}, pmid = {22696870}, issn = {1128-3602}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chemical and Drug Induced Liver Injury/etiology/pathology/*prevention &amp; control ; Cytoprotection ; Disease Models, Animal ; Liver/*drug effects/ultrastructure ; Male ; Melatonin/*pharmacology ; Methanol ; Microscopy, Electron ; Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; Time Factors ; }, abstract = {BACKGROUND: Methanol intoxication leads liver injury; in contrast melatonin and n-acetyl cysteine (NAC) are known to have protective effects on liver.<br><br>AIM: We aimed to investigate the ultrastructural effects of melatonin and NAC on livers of methanol intoxicated rats and compare potential protective effects of melatonin and NAC on their liver ultrastructure.<br><br>MATERIALS AND METHODS: Fifty-six adult male Wistar rats were carried out and were randomized to eight groups that have seven rats each: Control groups (C 6h, C 24h), treated with intragastric (i.g.) 1.0 ml saline; Methanol groups (M 6h, M 24h), treated with a dose of 3 g/kg i.g. methanol; Melatonin plus methanol groups (MEL+M 6h, MEL+M 24h), treated with dose of 10 mg/kg i.p melatonin immediately, following with a dose of 3 g/kg i.g. methanol; NAC plus methanol groups (NAC+M 6h, NAC+M 24h), treated with dose of 150 mg/kg, following with a dose of 3 g/kg i.g. methanol. 24 h group rats were given the same dose of melatonin and NAC 12 h after intoxication. Electron microscopy was used to evaluate histological changes in liver tissue at both 6th and 24th hour.<br><br>RESULTS: Histopathological damage was found to be higher in methanol-induced intoxicated rats compared with the controls. Extensive tubules of smooth endoplasmic reticulum, increased mitochondria, increased primary lysosomes and some marked openings of bile canaliculus were distinguished. Melatonin administration prevents liver injury especially in early hours and although not as effective as melatonin, NAC also prevents liver injury.<br><br>CONCLUSIONS: Melatonin is much more efficient than NAC, as well as significantly greater hepatoprotective effect against the liver injury secondary to the methanol intoxication.}, }
@article {pmid22696312, year = {2012}, author = {Nagoor Meeran, MF and Stanely Mainzen Prince, P}, title = {Protective effects of N-acetyl cysteine on membrane-bound adenosine triphosphatases and minerals in isoproterenol-induced myocardial-infarcted rats: an in vivo and in vitro study.}, journal = {Journal of biochemical and molecular toxicology}, volume = {26}, number = {7}, pages = {276-281}, doi = {10.1002/jbt.21419}, pmid = {22696312}, issn = {1099-0461}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphatases/*blood ; Animals ; Cardiotonic Agents/*pharmacology ; Cell Membrane/enzymology ; Enzyme Activation/drug effects ; Isoproterenol/toxicity ; Lipid Peroxidation/drug effects ; Male ; Membrane Proteins/*blood ; Minerals/blood ; Molecular Targeted Therapy ; Myocardial Infarction/*blood/chemically induced/drug therapy ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The present study was aimed to evaluate the protective effects of N-acetyl cysteine (NAC) on changes in the activities/levels of adenosine triphosphatases and minerals in isoproterenol-induced myocardial-infarcted rats. Male albino Wistar rats were pretreated with NAC (10 mg/kg body weight) daily for a period of 14 days. After pretreatment period, rats were induced myocardial infarction (MI) by isoproterenol (100 mg/kg body weight). The activity of sodium/potassium-dependent adenosine triphosphatase was decreased, and the activities of calcium- and magnesium-dependent adenosine triphosphatases were increased in the heart of isoproterenol-induced myocardial-infarcted rats. Furthermore, the levels of potassium were lowered and the levels of sodium and calcium were increased in the heart of isoproterenol-induced rats. Increased plasma lipid peroxidation was observed in isoproterenol-induced rats. Pretreatment with NAC showed protective effects on adenosine triphosphatases, minerals, and lipid peroxidation. The in vitro study confirmed the reducing property of NAC. The observed effects are due to the membrane-stabilizing and antioxidant effects of NAC. The results of this study will be useful for the prevention of MI.}, }
@article {pmid22695865, year = {2012}, author = {Drago, L and Romanò, CL and Mattina, R and Signori, V and De Vecchi, E}, title = {Does dithiothreitol improve bacterial detection from infected prostheses? A pilot study.}, journal = {Clinical orthopaedics and related research}, volume = {470}, number = {10}, pages = {2915-2925}, pmid = {22695865}, issn = {1528-1132}, mesh = {*Acetylcysteine/administration &amp; dosage ; Bacteria/*isolation &amp; purification ; Bacteriological Techniques/methods ; *Biofilms ; *Dithiothreitol/administration &amp; dosage ; Joint Prosthesis/*microbiology ; Pilot Projects ; Sonication ; Time Factors ; }, abstract = {BACKGROUND: Sonication and scraping of infected prostheses usually are used to improve diagnosis of prosthetic infections, reducing false negatives. Chemical methods that reduce biofilms also may allow higher levels of detection.<br><br>QUESTIONS/PURPOSES: We therefore asked: (1) Do dithiothreitol (DTT) and N-acetylcysteine (NAC) remove bacteria from biofilm formed on prosthetic materials? (2) Is bacterial recovery affected by differing DTT and NAC concentrations and incubation times? (3) Do treatments with DTT and NAC detach the same amounts of bacteria from biofilm on prosthetic materials as sonication and scraping? (4) Are these methods reproducible?<br><br>METHODS: We treated polyethylene and titanium discs covered by biofilm formed by Pseudomonas aeruginosa and Staphylococcus aureus with DTT or NAC solutions at different concentrations for different times. We compared colony counts of S aureus, P aeruginosa, Staphylococcus epidermidis and Escherichia coli after treatment with NAC, DTT, sonication and scraping. We determined colony counts after treatment of biofilm formed by one strain of S aureus and one of P aeruginosa on five discs of each material analyzed on the same day and on five discs analyzed on five consecutive days.<br><br>RESULTS: Mean colony counts (LogCFU/mL) obtained after treatment with 1&#xa0;g/L DTT for 15 minutes (5.3) were similar to those after sonication (4.9) and greater than those obtaining by scraping (3.4) and treatment with 2&#xa0;g/L NAC for 30 minutes (1.9). DTT and sonication showed good reproducibility.<br><br>CLINICAL RELEVANCE: Our data suggest that treatment of prostheses with DTT may be a reasonable alternative to sonication to improve detection of biofilm-associated bacteria and supplement conventional laboratory culturing techniques for diagnosing periprosthetic infections.}, }
@article {pmid22694287, year = {2012}, author = {Yuan, X and Zhang, B and Chen, N and Chen, XY and Liu, LL and Zheng, QS and Wang, ZP}, title = {Isoliquiritigenin treatment induces apoptosis by increasing intracellular ROS levels in HeLa cells.}, journal = {Journal of Asian natural products research}, volume = {14}, number = {8}, pages = {789-798}, doi = {10.1080/10286020.2012.694873}, pmid = {22694287}, issn = {1477-2213}, mesh = {Apoptosis/drug effects ; Blotting, Western ; Buthionine Sulfoximine/pharmacology ; Cell Survival/drug effects ; Chalcones/chemistry/*pharmacology ; Free Radical Scavengers/pharmacology ; HeLa Cells ; Humans ; Molecular Structure ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/analysis/metabolism ; }, abstract = {This study focuses on the relationship between the apoptosis induced by isoliquiritigenin (ISL) and the production of reactive oxygen species (ROS). Cell viability was evaluated using sulforhodamine B assay. The apoptotic rate was determined via flow cytometry. Intracellular ROS level was assessed using the 2,7-dichlorofluorescein probe assay. Poly-ADP-ribose polymerase (PARP) protein expression was examined using Western blot analysis. The results showed that ISL treatment inhibited cell proliferation by inducing apoptosis. The increased apoptotic rate and ROS production induced by ISL were inhibited by the co-treatment of ISL and free radical scavenger N-acetyl-cysteine (NAC), catalase (CAT), and 4,5-dihydroxyl-1,3-benzededisulfonic acid (Tiron). On the contrary, the increased apoptotic rate and the ROS production were compensated by the co-treatment of ISL and l-buthionine-(S,R)-sulfoximine (BSO). ISL treatment increased the degradation of PARP, which was counteracted by antioxidants (NAC or CAT), whereas the combination treatment of ISL and pro-oxidant (BSO) enhanced the PARP degradation induced by ISL. Our findings suggested that ISL treatment induced apoptosis by increasing intracellular ROS levels in HeLa cells.}, }
@article {pmid22692827, year = {2012}, author = {Kim, JB and Lim, N and Kim, SJ and Heo, TH}, title = {N-acetylcysteine normalizes the urea cycle and DNA repair in cells from patients with Batten disease.}, journal = {Cell biochemistry and function}, volume = {30}, number = {8}, pages = {677-682}, doi = {10.1002/cbf.2849}, pmid = {22692827}, issn = {1099-0844}, mesh = {Acetylcysteine/*pharmacology ; Blotting, Western ; Carbamoyl-Phosphate Synthase (Ammonia)/genetics/*metabolism ; Cell Line ; DNA Glycosylases/genetics/*metabolism ; DNA Polymerase beta/genetics/*metabolism ; DNA Repair/*drug effects ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Neuronal Ceroid-Lipofuscinoses/genetics/metabolism/pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Up-Regulation/drug effects ; Urea/*metabolism ; }, abstract = {Batten disease is an inherited disorder characterized by early onset neurodegeneration due to the mutation of the CLN3 gene. The function of the CLN3 protein is not clear, but an association with oxidative stress has been proposed. Oxidative stress and DNA damage play critical roles in the pathogenesis of neurodegenerative diseases. Antioxidants are of interest because of their therapeutic potential for treating neurodegenerative diseases. We tested whether N-acetylcysteine (NAC), a well-known antioxidant, improves the pathology of cells from patients with Batten disease. At first, the expression levels of urea cycle components and DNA repair enzymes were compared between Batten disease cells and normal cells. We used both mRNA expression levels and Western blot analysis. We found that carbamoyl phosphate synthetase 1, an enzyme involved in the urea cycle, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta, enzymes involved in DNA repair, were expressed at higher levels in Batten disease cells than in normal cells. The treatment of Batten disease cells with NAC for 48 h attenuated activities of the urea cycle and of DNA repair, as indicated by the substantially decreased expression levels of carbamoyl phosphate synthetase 1, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta proteins compared with untreated Batten cells. NAC may serve in alleviating the burden of urea cycle and DNA repair processes in Batten disease cells. We propose that NAC may have beneficial effects in patients with Batten disease.}, }
@article {pmid22692000, year = {2012}, author = {Wang, J and Wang, Q and Li, J and Shen, Q and Wang, F and Wang, L}, title = {Cadmium induces hydrogen peroxide production and initiates hydrogen peroxide-dependent apoptosis in the gill of freshwater crab, Sinopotamon henanense.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {156}, number = {3-4}, pages = {195-201}, doi = {10.1016/j.cbpc.2012.05.006}, pmid = {22692000}, issn = {1532-0456}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Biomarkers/metabolism ; Brachyura/anatomy &amp; histology/*drug effects/metabolism ; Cadmium/*toxicity ; Caspase 3/metabolism ; Caspase 9/metabolism ; Caspase Inhibitors/pharmacology ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Enzyme Activation ; Gills/*drug effects/metabolism/ultrastructure ; Hydrogen Peroxide/*metabolism ; Male ; Microscopy, Electron, Transmission ; Reactive Oxygen Species/metabolism ; Thiourea/analogs &amp; derivatives/pharmacology ; Time Factors ; Toxicity Tests/methods ; }, abstract = {Cadmium (Cd) is a well-known toxic heavy metal that accumulates in the aquatic environment. Cd has been reported to induce oxidative damage and apoptosis. We investigated the regulation mechanism of hydrogen peroxide (H(2)O(2)) on Cd-induced apoptosis. We show that in the gills of the freshwater crab Sinopotamon henanense Cd induced apoptosis, in a time- and concentration-dependent manner, as confirmed by DNA fragmentation analysis and transmission electron microscopy. Additionally, Cd caused production of H(2)O(2) after 2 h of treatment at 58 mg L(-1) Cd, and significantly increased the caspase-3/8/9 activity in crabs relative to the control group. Pre-treatment with the scavenger for H(2)O(2), dimethylthiourea (DMTU) and antioxidant, N-acetyl cysteine (NAC), effectively inhibited the activities of caspase-3 and caspase-9, eventually blocked Cd-induced DNA fragmentation and the appearance of markers for apoptotic cell death. These results suggest that Cd might induce intracellular H(2)O(2) generation to trigger the crab apoptotic processes by regulating the activities of caspase enzymes.}, }
@article {pmid22691629, year = {2012}, author = {Unnithan, AS and Choi, HJ and Titler, AM and Posimo, JM and Leak, RK}, title = {Rescue from a two hit, high-throughput model of neurodegeneration with N-acetyl cysteine.}, journal = {Neurochemistry international}, volume = {61}, number = {3}, pages = {356-368}, doi = {10.1016/j.neuint.2012.06.001}, pmid = {22691629}, issn = {1872-9754}, mesh = {Acetylcysteine/*pharmacology ; Autophagy ; Blotting, Western ; Cell Line, Tumor ; Humans ; Immunohistochemistry ; Neurons/cytology/*drug effects ; }, abstract = {Postmortem tissue from patients with neurodegeneration exhibits protein-misfolding stress and reduced proteasome activity. This hallmark burden of proteotoxic stress has led to the term "proteinopathies" for neurodegenerative diseases. Proteinopathies may also be exacerbated by previous insults, according to the two hit hypothesis of accelerated neurodegeneration. In order to model the response to two successive insults in a high-throughput fashion, we exposed the neuronal cell line N2a to two hits of the proteasome inhibitor MG132 and performed three unbiased viability assays. MG132 toxicity was synergistically exacerbated following sequential hits provided the first hit was high enough to be toxic. This accelerated viability loss was apparent by (1) a nuclear and cytoplasmic stain (DRAQ5+Sapphire), (2) immunocytochemistry for a cytoskeletal marker (α-tubulin), and (3) ATP levels (Cell Titer Glo). Ubiquitin-conjugated proteins were raised by toxic, but not subtoxic MG132, and were thus correlated with toxicity exacerbation at higher doses. We hypothesized that levels of autophagic and antioxidant defenses would be reduced with toxic, but not subtoxic MG132, explaining their differential impact on a second hit. However, proteins involved in chaperone-mediated autophagy were raised by toxic MG132, not reduced. Furthermore, inhibiting autophagy enhanced the toxicity of both subtoxic and toxic MG132 as well as of dual hits, suggesting that autophagic removal of cellular debris protected against proteasome inhibition. Two toxic hits of MG132 synergistically decreased the antioxidant glutathione. The glutathione precursor N-acetyl cysteine reversed this glutathione loss and prevented the toxic response to dual hits by all three assays. Dietary supplementation with N-acetyl cysteine benefits Alzheimer's patients and is currently undergoing clinical trials in Parkinson's disease. The present report is the first demonstration that this versatile compound is protective against synergistic loss of viability as well as of glutathione following unrelenting, sequential hits of proteotoxic stress as may occur in the diseased brain.}, }
@article {pmid22691542, year = {2012}, author = {Ferrucci, A and Nonnemacher, MR and Cohen, EA and Wigdahl, B}, title = {Extracellular human immunodeficiency virus type 1 viral protein R causes reductions in astrocytic ATP and glutathione levels compromising the antioxidant reservoir.}, journal = {Virus research}, volume = {167}, number = {2}, pages = {358-369}, pmid = {22691542}, issn = {1872-7492}, support = {R01 DA019807/DA/NIDA NIH HHS/United States ; R01 NS032092/NS/NINDS NIH HHS/United States ; DA19807/DA/NIDA NIH HHS/United States ; NS32092/NS/NINDS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/*metabolism ; Antioxidants/*metabolism ; Astrocytes/*virology ; Cell Line ; Culture Media, Conditioned ; Cytoplasm/chemistry ; Gene Products, vpr/*metabolism ; Glutathione/*metabolism ; HIV-1/*pathogenicity ; Humans ; Virulence Factors/*metabolism ; }, abstract = {Patients infected with human immunodeficiency virus type 1 (HIV-1) often display neurological complications in late stage disease and increased viral loads directly correlated with higher concentrations of extracellular HIV-1 viral protein r (Vpr) in the blood serum and cerebrospinal fluid. Additionally, HIV-1-infected patients with a low CD4+ T-lymphocyte count displayed lower concentrations of reduced glutathione (GSH), the main intracellular antioxidant molecule, and lower level of survival. To establish a correlation between increased concentrations of extracellular Vpr and an oxidative stress-induced phenotype, the U-87 MG astroglioma cell line has been used to determine the downstream effects induced by Vpr. Conditioned media obtained from the human endothelial kidney (HEK) 293 T cell line transfected either in the absence or presence of HIV-1 Vpr contained free Vpr. Exposure of U-87 MG to this conditioned media decreased intracellular levels of both adenosine triphosphate (ATP) and GSH. These observations were recapitulated using purified recombinant HIV-1 Vpr both in U-87 MG and primary human fetal astrocytes in a dose- and time-dependent manner. Vpr-induced oxidative stress could be partly restored by co-treatment with the antioxidant molecule N-acetyl-cysteine (NAC). In addition, free Vpr augmented production of reactive oxygen species due to an increase in the level of oxidized glutathione (GSSG). This event was almost entirely suppressed by treatment with an anti-Vpr antibody or co-treatment with NAC. These studies confirm a role of extracellular Vpr in impairing astrocytic levels of intracellular ATP and GSH. Studies are underway to better understand the intricate correlation between reductions in ATP and GSH metabolites and how they affect neuronal survival in end-stage disease.}, }
@article {pmid22685948, year = {2012}, author = {Chaudhari, D and Sung, EC and Paranjpe, A and Jewett, A}, title = {Novel strategies to enhance survival and growth of pulp cells after dental restorations.}, journal = {Journal of the California Dental Association}, volume = {40}, number = {5}, pages = {409-417}, pmid = {22685948}, issn = {1043-2256}, support = {R01-10331//PHS HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aluminum Compounds/pharmacology ; Calcium Compounds/pharmacology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Composite Resins/pharmacology ; Dental Materials/*pharmacology ; Dental Pulp/cytology/*drug effects ; *Dental Restoration, Permanent ; Drug Combinations ; Drug Synergism ; Free Radical Scavengers/*pharmacology ; Glass Ionomer Cements/pharmacology ; Humans ; Lipopolysaccharides/pharmacology ; Methacrylates/pharmacology ; Oxides/pharmacology ; Protective Agents/pharmacology ; Silicates/pharmacology ; Stromal Cells/drug effects/physiology ; }, abstract = {Using ex vivo human tooth, the authors demonstrated that dental pulp stromal cells that survive after placement of composite, mineral trioxide aggregate, and glass ionomer are weaker since they undergo synergistic cell death when exposed to 2-hydroxyethylmethacrylate. DPSCs extracted from teeth that were restored with the combination of composite or MTA or GI with N-acetyl cysteine were protectedfrom cell death. Therefore, application of NAC may protect the DPSCs from adverse effects after tooth restoration.}, }
@article {pmid22684917, year = {2012}, author = {You, BR and Park, WH}, title = {Arsenic trioxide induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion.}, journal = {Oncology reports}, volume = {28}, number = {2}, pages = {749-757}, doi = {10.3892/or.2012.1852}, pmid = {22684917}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/metabolism ; Apoptosis/drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Ascorbic Acid/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Fibroblasts/cytology/*drug effects ; Glutathione/deficiency/*metabolism ; Humans ; Lung/cytology/*drug effects/metabolism ; Oxides/*pharmacology ; Reactive Oxygen Species/*metabolism ; Transfection ; }, abstract = {Arsenic trioxide (ATO; As2O3) induces apoptotic cell death in various cancer cells including lung cancer via the induction of reactive oxygen species (ROS). However, little is known about the toxicological effects of ATO on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well-known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on ATO-treated human pulmonary fibroblast (HPF) cells in relation to cell death, ROS and glutathione (GSH). ATO induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm). ATO increased ROS levels including O2•- and GSH depleted cell numbers. NAC attenuated the growth inhibition, death and MMP (∆ψm) loss in ATO-treated HPF cells and also decreased the ROS levels in these cells. However, vitamin C enhanced the growth inhibition, death, MMP (∆ψm) loss and GSH depletion by ATO and even strongly increased mitochondrial O2•- levels in ATO-treated HPF cells. BSO showed a strong increase in ROS levels in ATO-treated HPF cells and intensified the growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion. Moreover, superoxide dismutase (SOD2) or thioredoxin (TXN) siRNAs attenuated HPF cell death by ATO, which was not correlated with ROS and GSH level changes. In conclusion, ATO induced the growth inhibition and death of HPF cells, accompanied by increasing ROS levels and GSH depletion. NAC attenuated HPF cell death by ATO whereas vitamin C and BSO enhanced the death.}, }
@article {pmid22683606, year = {2012}, author = {Michael Brown, J and Ball, JG and Wright, MS and Van Meter, S and Valentovic, MA}, title = {Novel protective mechanisms for S-adenosyl-L-methionine against acetaminophen hepatotoxicity: improvement of key antioxidant enzymatic function.}, journal = {Toxicology letters}, volume = {212}, number = {3}, pages = {320-328}, pmid = {22683606}, issn = {1879-3169}, support = {P20 RR016477/RR/NCRR NIH HHS/United States ; 5P20RR016477/RR/NCRR NIH HHS/United States ; 2P20RR016477-09S4/RR/NCRR NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Chemical and Drug Induced Liver Injury/metabolism/*prevention &amp; control ; Cytochrome P-450 CYP2E1/metabolism ; Cytochrome P-450 CYP2E1 Inhibitors ; Drug Antagonism ; Liver/drug effects/enzymology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria, Liver/drug effects/metabolism ; Mitochondrial Swelling/drug effects ; Oxidative Stress/drug effects ; Oxidoreductases/*metabolism ; Protein Carbonylation/drug effects ; S-Adenosylmethionine/*pharmacology ; }, abstract = {Acetaminophen (APAP) overdose leads to severe hepatotoxicity, increased oxidative stress and mitochondrial dysfunction. S-adenosyl-L-methionine (SAMe) protects against APAP toxicity at a mmol/kg equivalent dose to N-acetylcysteine (NAC). SAMe acts as a principle biological methyl donor and participates in polyamine synthesis which increase cell growth and has a role in mitochondrial protection. The purpose of the current study tested the hypothesis that SAMe protects against APAP toxicity by maintaining critical antioxidant enzymes and markers of oxidative stress. Male C57Bl/6 mice were treated with vehicle (Veh; water 15 ml/kg, ip), SAMe (1.25 mmol/kg, ip), APAP (250 mg/kg, ip), and SAMe+APAP (SAMe given 1 h following APAP). Liver was collected 2 and 4 h following APAP administration; mitochondrial swelling as well as hepatic catalase, glutathione peroxidase (GPx), glutathione reductase, and both Mn- and Cu/Zn-superoxide dismutase (SOD) enzyme activity were evaluated. Mitochondrial protein carbonyl, 3-nitrotyrosine cytochrome c leakage were analyzed by Western blot. SAMe significantly increased SOD, GPx, and glutathione reductase activity at 4 h following APAP overdose. SAMe greatly reduced markers of oxidative stress and cytochrome C leakage following APAP overdose. Our studies also demonstrate that a 1.25 mmol/kg dose of SAMe does not inhibit CYP 2E1 enzyme activity. The current study identifies a plausible mechanism for the decreased oxidative stress observed when SAMe is given following APAP.}, }
@article {pmid22683510, year = {2012}, author = {Teng, CC and Kuo, HC and Cheng, HC and Wang, TC and Sze, CI}, title = {The inhibitory effect of CIL-102 on the growth of human astrocytoma cells is mediated by the generation of reactive oxygen species and induction of ERK1/2 MAPK.}, journal = {Toxicology and applied pharmacology}, volume = {263}, number = {1}, pages = {73-80}, doi = {10.1016/j.taap.2012.05.025}, pmid = {22683510}, issn = {1096-0333}, mesh = {Antineoplastic Agents/*pharmacology/therapeutic use ; Astrocytoma/*drug therapy ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Central Nervous System Neoplasms/*drug therapy ; Enzyme Induction/drug effects ; Glioblastoma/*drug therapy ; Humans ; Mitogen-Activated Protein Kinase Kinases/*biosynthesis ; Quinolines/*pharmacology/therapeutic use ; Reactive Oxygen Species/*metabolism ; Tetrazolium Salts ; Thiazoles ; }, abstract = {CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is the major active agent of the alkaloid derivative of Camptotheca acuminata, with multiple pharmacological activities, including anticancer effects and promotion of apoptosis. The mechanism by which CIL-102 inhibits growth remains poorly understood in human astrocytoma cells. Herein, we investigated the molecular mechanisms by which CIL-102 affects the generation of reactive oxygen species (ROS) and cell cycle G2/M arrest in glioma cells. Treatment of U87 cells with 1.0μM CIL-102 resulted in phosphorylation of extracellular signal-related kinase (ERK1/2), downregulation of cell cycle-related proteins (cyclin A, cyclin B, cyclin D1, and cdk1), and phosphorylation of cdk1Tyr(15) and Cdc25cSer(216). Furthermore, treatment with the ERK1/2 inhibitor PD98059 abolished CIL-102-induced Cdc25cSer(216) expression and reversed CIL-102-inhibited cdk1 activation. In addition, N-acetyl cysteine (NAC), an ROS scavenger, blocked cell cycle G2/M arrest and phosphorylation of ERK1/2 and Cdc25cSer(216) in U87 cells. CIL-102-mediated ERK1/2 and ROS production, and cell cycle arrest were blocked by treatment with specific inhibitors. In conclusion, we have identified a novel CIL-102-inhibited proliferation in U87 cells by activating the ERK1/2 and Cdc25cSer(216) cell cycle-related proteins and inducing ROS production; this might be a new mechanism in human astrocytoma cells.}, }
@article {pmid22679834, year = {2012}, author = {Tu, Y and Yang, X and Zhang, S and Zhu, Y}, title = {Determination of theanine and gamma-aminobutyric acid in tea by high performance- liquid chromatography with precolumn derivatization.}, journal = {Se pu = Chinese journal of chromatography}, volume = {30}, number = {2}, pages = {184-189}, doi = {10.3724/sp.j.1123.2011.10037}, pmid = {22679834}, issn = {1000-8713}, mesh = {Acetylcysteine/chemistry ; Chromatography, High Pressure Liquid/*methods ; Glutamates/*analysis ; Tea/*chemistry ; gamma-Aminobutyric Acid/*analysis ; o-Phthalaldehyde/chemistry ; }, abstract = {A method of precolumn derivatization-high performance liquid chromatography (HPLC) for the determination of theanine and gamma-aminobutyric acid (GABA) in tea was established. o-Phthalaldehyde (OPA) and N-acetyl-L-cysteine (NAC) were chosen as the derivatization reagents. The effects of teapolyphenol (Tp), proline (Pro) and Vitamin C (Vc) on derivatization yields were investigated. The results indicated that Vc not only stabilized the stock solution of OPA, but also enhanced the yield of GABA derivative. However, the yield of theanine derivative was less affected. The HPLC separation system was also optimized. The resolution of the derivatives was improved by adjusting the pH value and phosphate-citric buffer concentration of the mobile phase. The limits of detection (LODs) for GABA and theanine were 3.01 x 10(-5) mmol/L and 7.98 x 10(-5) mmol/L, and the limits of quantification (LOQs) were 9.99 x 10(-5) mmol/L and 2.658 x 10(-4) mmol/L, respectively. The linear ranges of GABA and theanine were 0.01 - 0.4 mmol/L with the correlation coefficient of 0.996 and 0.05 - 0.8 mmol/L with the correlation coefficient of 0.995, respectively. The main recoveries for GABA and theanine in green tea, Oolong tea, and black tea, ranged from 99.29% to 119.60% and from 62.88% to 141.06% respectively. The method with simple procedure and efficient separation was proved to be suitable for the determination of GABA and theanine in tea.}, }
@article {pmid22678775, year = {2012}, author = {Itharat, A and Hiransai, P}, title = {Dioscoreanone suppresses LPS-induced nitric oxide production and inflammatory cytokine expression in RAW 264.7 macrophages by NF-κB and ERK1/2 signaling transduction.}, journal = {Journal of cellular biochemistry}, volume = {113}, number = {11}, pages = {3427-3435}, doi = {10.1002/jcb.24219}, pmid = {22678775}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Genes, Reporter ; Inhibitory Concentration 50 ; Interleukin-1beta/genetics/metabolism ; Interleukin-6/genetics/metabolism ; Lipopolysaccharides/pharmacology ; Luciferases ; MAP Kinase Signaling System/drug effects ; Macrophages/cytology/*drug effects/metabolism ; Mice ; Mitogen-Activated Protein Kinase 1/genetics/*metabolism ; Mitogen-Activated Protein Kinase 3/genetics/*metabolism ; NF-kappa B/genetics/*metabolism ; Nitric Oxide/*antagonists &amp; inhibitors/biosynthesis ; Nitric Oxide Synthase Type II/genetics/metabolism ; Phenanthrenes/*pharmacology ; Quinones/*pharmacology ; }, abstract = {Dioscoreanone, a 1,4-phenanthraquinone isolated from an ethanolic extract of the rhizome of Dioscorea membranacea, Pierre ex Prain &amp; Burkill, a plant which has been used to treat inflammation and cancer in Thai Traditional Medicine. In this study, the mechanisms of dioscoreanone on LPS-induced NO production and cytokine expression through the activation of NF-κB and ERK1/2 are demonstrated in RAW 264.7 cells. Through measurement with Griess reagent, dioscoreanone was found to reduce NO levels with an IC(50) value of 2.50 ± 0.64 µM, due to the significant suppression of LPS-induced iNOS mRNA expression, as well as IL-1β and IL-6 levels at a concentration of 6 µM. At the signal transduction level, using the pNFκB-Luciferase reporter system, dioscoreanone significantly inhibited NF-κB transcriptional activity, which resulted from the prevention of IκBα degradation. In addition, dioscoreanone in the range of 1.2-5 µM significantly enhanced LPS-induced ERK1/2 activation and dioscoreanone alone induced the activation of ERK1/2 proteins in a concentration- and time-dependent response. The activation of ERK1/2 proteins by dioscoreanone was due to both an arylating reaction, which was suppressed by N-acetyl cysteine, and a redox cycling reaction of NQOR, which was inhibited by dicoumarol. In conclusion, the mechanisms of dioscoreanone on the inhibition of NO production and mRNA expression of iNOS, IL-1β, and IL-6 were due to both the inhibition of NF-κB activation and the activation of ERK1/2 proteins. The activation of dioscoreanone may in turn inhibit the binding of NF-κB to pro-inflammatory gene promoters in LPS-induced RAW264.7 macrophage cells.}, }
@article {pmid22678501, year = {2012}, author = {Wu, M and Yang, S and Elliott, MH and Fu, D and Wilson, K and Zhang, J and Du, M and Chen, J and Lyons, T}, title = {Oxidative and endoplasmic reticulum stresses mediate apoptosis induced by modified LDL in human retinal Müller cells.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {53}, number = {8}, pages = {4595-4604}, pmid = {22678501}, issn = {1552-5783}, support = {P20 RR024215/RR/NCRR NIH HHS/United States ; R01 EY019494/EY/NEI NIH HHS/United States ; EY019494/EY/NEI NIH HHS/United States ; 3P20 RR024215-03S109/RR/NCRR NIH HHS/United States ; }, mesh = {Adult ; Apoptosis/*drug effects ; Blotting, Western ; Cell Survival/drug effects ; Cells, Cultured ; Diabetic Retinopathy/metabolism/pathology ; Endoplasmic Reticulum/drug effects/metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Female ; Glycation End Products, Advanced ; Glycosylation ; Humans ; In Situ Nick-End Labeling ; Lipoproteins, LDL/*pharmacology ; Male ; Middle Aged ; Neuroglia/drug effects/metabolism/*pathology ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Retinal Ganglion Cells/drug effects/metabolism/*pathology ; Young Adult ; }, abstract = {PURPOSE: We previously showed that extravasated, modified LDL is implicated in pericyte loss in diabetic retinopathy (DR). Here, we investigate whether modified LDL induces apoptosis in retinal Müller glial cells.<br><br>METHODS: Cultured human retinal M&#xfc;ller cells (MIO-M1) were treated with highly oxidized glycated LDL (HOG-LDL, 200 mg protein/L) or native LDL (N-LDL, 200 mg protein/L) for up to 24 hours with or without pretreatment with N-acetyl-cysteine (NAC, a blocker of oxidative stress) and 4-phenylbutyrate (4-PBA, a blocker of endoplasmic reticulum [ER] stress). Effects of HOG-LDL on cell viability, apoptosis, oxidative stress, and ER stress were assessed by cell viability, TUNEL, and Western blot assays. In separate experiments, M&#xfc;ller cells were treated with 7-ketocholesterol (7-KC, 5-20 &#x3bc;M) or 4-hydroxynonenal (4-HNE, 5-40 &#x3bc;M) for up to 24 hours. The same markers were measured.<br><br>RESULTS: HOG-LDL induced apoptosis (decreased cell viability, increased TUNEL staining, increased expression of cleaved PARP, cleaved caspase-3, and BAX; decreased Bcl-2), oxidative stress (increased NOX4 and antioxidant enzymes, catalase, and superoxide dismutase 2), and ER stress (increased phospho-eIF2&#x3b1;, KDEL, ATF6, and CHOP). Pretreatment with NAC or 4-PBA partially attenuated apoptosis. In addition. NAC attenuated activation of ER stress. Similar to HOG-LDL, 7KC, and 4HNE also induced apoptosis, oxidative stress, and ER stress.<br><br>CONCLUSIONS: Our data suggest that extravasated, modified lipoproteins may be implicated in apoptotic M&#xfc;ller cell death, acting at least partially via enhanced levels of oxidative and ER stresses. They support our main hypothesis that, in addition to hyperglycemia, extravasated and oxidized LDL is an important insult to the diabetic retina.}, }
@article {pmid22676250, year = {2012}, author = {Chang, EY and Zhang, J and Sullivan, S and Newman, R and Singh, I}, title = {N-acetylcysteine prevents preterm birth by attenuating the LPS-induced expression of contractile associated proteins in an animal model.}, journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians}, volume = {25}, number = {11}, pages = {2395-2400}, doi = {10.3109/14767058.2012.697942}, pmid = {22676250}, issn = {1476-4954}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Connexin 43/genetics/metabolism ; Contractile Proteins/*genetics/metabolism ; Cyclooxygenase 2/genetics/metabolism ; Down-Regulation/drug effects/genetics ; Female ; Gene Expression Regulation/drug effects/immunology ; Lipopolysaccharides/*pharmacology ; Mice ; Models, Animal ; Models, Biological ; NF-kappa B/genetics/metabolism ; Pregnancy ; Premature Birth/genetics/metabolism/pathology/*prevention &amp; control ; Receptors, Oxytocin/genetics/metabolism ; Uterine Contraction/drug effects/genetics/immunology/metabolism ; Uterus/drug effects/immunology/metabolism ; }, abstract = {OBJECTIVE: Intrauterine infection is associated with maternal immune activation (MIA) leading to preterm birth through upregulation of contractile associated proteins (CAPs). We hypothesized that N-acetylcysteine would decrease NF-κB activation and CAP expression in a MIA model for preterm birth.<br><br>METHODS: Pregnant CD-1 mice were given intrauterine LPS or saline on day 15/20. They received NAC or saline prior to injection and were monitored until delivery. The rate of preterm birth in the control, LPS, and LPS + NAC animals was determined. In another group, animals were sacrificed 6 h after treatment and myometrium was collected. COX-2, connexin 43, and oxytocin receptor expression was determined.<br><br>RESULTS: LPS administration resulted in preterm birth and this effect was attenuated by NAC. LPS increased COX-2, connexin 43, and oxytocin receptor expression. NAC significantly decreased COX-2 expression. LPS increased NF-&#x3ba;B activation; this was attenuated by NAC.<br><br>CONCLUSION: NAC may be beneficial in prevention of MIA-related preterm birth through attenuation of NF-&#x3ba;B activation and COX-2 upregulation.}, }
@article {pmid22668245, year = {2012}, author = {Scapagnini, G and Davinelli, S and Drago, F and De Lorenzo, A and Oriani, G}, title = {Antioxidants as antidepressants: fact or fiction?.}, journal = {CNS drugs}, volume = {26}, number = {6}, pages = {477-490}, pmid = {22668245}, issn = {1179-1934}, mesh = {Animals ; Antidepressive Agents/administration &amp; dosage/*therapeutic use ; Antioxidants/administration &amp; dosage/*therapeutic use ; Depressive Disorder, Major/*drug therapy/metabolism ; Disease Models, Animal ; Drug Therapy, Combination/methods/*psychology ; Humans ; Models, Biological ; Oxidative Stress/drug effects ; }, abstract = {Depression is a medical condition with a complex biological pattern of aetiology, involving genetic and epigenetic factors, along with different environmental stressors. Recent evidence suggests that oxidative stress processes might play a relevant role in the pathogenic mechanism(s) underlying many major psychiatric disorders, including depression. Reactive oxygen and nitrogen species have been shown to modulate levels and activity of noradrenaline (norepinephrine), serotonin, dopamine and glutamate, the principal neurotransmitters involved in the neurobiology of depression. Major depression has been associated with lowered concentrations of several endogenous antioxidant compounds, such as vitamin E, zinc and coenzyme Q10, or enzymes, such as glutathione peroxidase, and with an impairment of the total antioxidant status. These observations introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the possible role of oxidative stress processes in the pathogenesis of depression. The therapeutic potential of antioxidant compounds as a co-adjuvant treatment to conventional antidepressants is discussed. For instance, N-acetyl-cysteine has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. Additionally, curcumin, the yellow pigment of curry, has been shown to strongly interfere with neuronal redox homeostasis in the CNS and to possess antidepressant activity in various animal models of depression, also thanks to its ability to inhibit monoamine oxidases. There is an urgent need to develop better tolerated and more effective treatments for depressive disorders and several antioxidant treatments appear promising and deserve further study.}, }
@article {pmid22666346, year = {2012}, author = {Kong, R and Jia, G and Cheng, ZX and Wang, YW and Mu, M and Wang, SJ and Pan, SH and Gao, Y and Jiang, HC and Dong, DL and Sun, B}, title = {Dihydroartemisinin enhances Apo2L/TRAIL-mediated apoptosis in pancreatic cancer cells via ROS-mediated up-regulation of death receptor 5.}, journal = {PloS one}, volume = {7}, number = {5}, pages = {e37222}, pmid = {22666346}, issn = {1932-6203}, mesh = {Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Artemisinins/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Pancreatic Neoplasms/*pathology ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Up-Regulation/*drug effects ; }, abstract = {BACKGROUND: Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown antitumor activity in various cancer cells. Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is regarded as a promising anticancer agent, but chemoresistance affects its efficacy as a treatment strategy. Apoptosis induced by the combination of DHA and Apo2L/TRAIL has not been well documented, and the mechanisms involved remain unclear.<br><br>Here, we report that DHA enhances the efficacy of Apo2L/TRAIL for the treatment of pancreatic cancer. We found that combined therapy using DHA and Apo2L/TRAIL significantly enhanced apoptosis in BxPC-3 and PANC-1 cells compared with single-agent treatment in vitro. The effect of DHA was mediated through the generation of reactive oxygen species, the induction of death receptor 5 (DR5) and the modulation of apoptosis-related proteins. However, N-acetyl cysteine significantly reduced the enhanced apoptosis observed with the combination of DHA and Apo2L/TRAIL. In addition, knockdown of DR5 by small interfering RNA also significantly reduced the amount of apoptosis induced by DHA and Apo2L/TRAIL.<br><br>CONCLUSIONS/SIGNIFICANCE: These results suggest that DHA enhances Apo2L/TRAIL-mediated apoptosis in human pancreatic cancer cells through reactive oxygen species-mediated up-regulation of DR5.}, }
@article {pmid22665164, year = {2012}, author = {Park, WH and Kim, SH}, title = {Involvement of reactive oxygen species and glutathione in gallic acid-induced human umbilical vein endothelial cell death.}, journal = {Oncology reports}, volume = {28}, number = {2}, pages = {695-700}, doi = {10.3892/or.2012.1842}, pmid = {22665164}, issn = {1791-2431}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Gallic Acid/*pharmacology ; Glutathione/*metabolism ; Human Umbilical Vein Endothelial Cells/cytology/*drug effects/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Gallic acid (GA) has various biological effects including apoptosis. In this study, we investigated the effects of GA on human primary umbilical vein endothelial cells (HUVECs) in relation to cell growth, cell death, reactive oxygen species (ROS) and glutathione (GSH). Treatment with 200 or 400 µM GA inhibited the growth of HUVECs at 24 h and induced cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; ∆Ψm). GA decreased or increased ROS levels including O2•-. It dose-dependently increased GSH depleted cell numbers. Pan-caspase inhibitor (Z-VAD) did not affect cell growth inhibition, cell death, ROS and GSH levels in GA-treated HUVECs. However, N-acetyl-cysteine (NAC; a well known antioxidant) and L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) enhanced cell growth inhibition, cell death and MMP (∆Ψm) loss in GA-treated HUVECs. NAC decreased general ROS levels in GA-treated HUVECs, but strongly increased O2•- levels in these cells. Both NAC and BSO intensified the GSH depletion of GA-treated HUVECs. In conclusion, GA treatment induced growth inhibition and death of HUVECs. The changes of ROS and GSH levels by NAC and BSO influenced cell growth and death in GA-treated HUVECs.}, }
@article {pmid22664789, year = {2012}, author = {Pires, KM and Lanzetti, M and Rueff-Barroso, CR and Castro, P and Abrahão, A and Koatz, VL and Valença, SS and Porto, LC}, title = {Oxidative damage in alveolar macrophages exposed to cigarette smoke extract and participation of nitric oxide in redox balance.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {26}, number = {6}, pages = {791-798}, doi = {10.1016/j.tiv.2012.05.011}, pmid = {22664789}, issn = {1879-3177}, mesh = {Animals ; Cell Line ; Cell Survival/drug effects ; Cells, Cultured ; Complex Mixtures/*toxicity ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation/drug effects ; Macrophages, Alveolar/*drug effects/metabolism ; Male ; Mice ; NF-kappa B/metabolism ; Nitrites/metabolism ; Oxidation-Reduction ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; *Smoke ; Superoxide Dismutase/metabolism ; *Nicotiana ; }, abstract = {Nitric oxide (NO) acts in both pathological and biological processes. We investigated the role of NO in the regulation of cigarette smoke-induced oxidative stress in rat alveolar macrophages (RAM). RAM collected from Wistar rats were cultured in 5% concentration cigarette smoke extract (CSE) for 1h. RAM exposed to CSE were then co-incubated with L-NAME (LN), L-arginine (LA), N-acetylcysteine (NAC) and both LN and NAC. RAM cultured only with medium was considered as control group. Biochemical analysis were performed to measure cellular metabolism (MTT), nitrite levels, superoxide dismutase (SOD) and glutathione peroxidase activities, reduced glutathione (GSH) and oxidized (GSSG), malondialdehyde and myeloperoxidase activity. During exposure to CSE, increased NO levels were not only associated with an increase of cell activation, but also affected MTT levels in RAM. CSE exposure resulted in significant redox imbalance in RAM. NAC administration affected SOD antioxidant profile regardless NO levels; however nitrite values were associated with GSH/GSSG ratio. In addition, lipid peroxidation appeared to be nitric-oxide dependent. Furthermore, the use of NAC significantly reduced the expression of NFkB normally observed in RAM exposed to CSE. The present results show that NO appeared to be involved in RAM activation, oxidative status maintenance and lipid peroxidation process during exposure to CSE.}, }
@article {pmid22664745, year = {2013}, author = {Lee, JH and Jo, YH and Kim, K and Lee, JH and Rim, KP and Kwon, WY and Suh, GJ and Rhee, JE}, title = {Effect of N-acetylcysteine (NAC) on acute lung injury and acute kidney injury in hemorrhagic shock.}, journal = {Resuscitation}, volume = {84}, number = {1}, pages = {121-127}, doi = {10.1016/j.resuscitation.2012.05.017}, pmid = {22664745}, issn = {1873-1570}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/*drug therapy/etiology ; Acute Lung Injury/*drug therapy/etiology ; Animals ; Arterial Pressure ; Glucose/pharmacology ; I-kappa B Proteins/metabolism ; Interleukin-6/blood ; Male ; Malondialdehyde/blood ; NF-KappaB Inhibitor alpha ; NF-kappa B/blood ; Nitrates/blood ; Nitrites/blood ; Oxidative Stress ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Shock, Hemorrhagic/complications/*drug therapy ; }, abstract = {AIM OF THE STUDY: N-acetylcysteine (NAC) has been investigated to attenuate organ injury in various experimental and clinical studies. However, results in hemorrhagic shock (HS) were controversial. We determined the effects of continuous administration of NAC on acute lung injury (ALI) and acute kidney injury (AKI) in HS model.<br><br>METHODS: Twenty male Sprague-Dawley rats were used. Pressure controlled HS model defined by mean arterial pressure (MAP) 40&#xb1;2 mmHg for 90 min followed by resuscitation and observation was used. Rats (n=10 per group) were randomized into 2 groups with NAC or dextrose. Intravenous NAC was given continuously from 15 min after induction of HS to the end of observation period (2 h). We measured serum IL-6, nitrite/nitrate concentration. NF-&#x3ba;B p65 DNA binding activity, expressions of cytoplasmic phosphorylated I&#x3ba;B-&#x3b1; (p-I&#x3ba;B-&#x3b1;) and I&#x3ba;B-&#x3b1;, malondialdehyde (MDA) and histopathological injury scores in lung and kidney were also evaluated.<br><br>RESULTS: MAP did not show any difference during the study period. NAC decreased histopathologic scores in both lung and kidney. Lung and kidney MDA levels were significantly lower in the NAC group compared to control group. Serum nitrite/nitrate and IL-6 were also significantly lower in the NAC group. The levels of lung cytoplasmic p-I&#x3ba;B-&#x3b1; expression was mitigated by NAC, and NF-&#x3ba;B p65 DNA binding activity was also significantly decreased in the NAC group.<br><br>CONCLUSIONS: Continuous infusion of NAC attenuated inflammatory response and acute lung and kidney injury after hemorrhagic shock in rats.}, }
@article {pmid22663304, year = {2012}, author = {Gérard, AC and Humblet, K and Wilvers, C and Poncin, S and Derradji, H and de Ville de Goyet, C and Abou-el-Ardat, K and Baatout, S and Sonveaux, P and Denef, JF and Colin, IM}, title = {Iodine-deficiency-induced long lasting angiogenic reaction in thyroid cancers occurs via a vascular endothelial growth factor-hypoxia inducible factor-1-dependent, but not a reactive oxygen species-dependent, pathway.}, journal = {Thyroid : official journal of the American Thyroid Association}, volume = {22}, number = {7}, pages = {699-708}, doi = {10.1089/thy.2011.0387}, pmid = {22663304}, issn = {1557-9077}, mesh = {Animals ; Carcinoma/blood supply/*metabolism ; Cell Line, Tumor ; Deficiency Diseases/complications/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Iodine/*deficiency ; Laser-Doppler Flowmetry ; Mice ; Mice, Transgenic ; Neovascularization, Pathologic/etiology/metabolism ; RNA, Messenger/analysis ; Reactive Oxygen Species/metabolism ; Symporters/metabolism ; Thyroid Gland/blood supply/diagnostic imaging ; Thyroid Neoplasms/blood supply/diagnostic imaging/*metabolism ; Ultrasonography ; Vascular Endothelial Growth Factor A/*metabolism ; }, abstract = {BACKGROUND: In the thyroid, iodine deficiency (ID) induces angiogenesis via a tightly controlled reactive oxygen species (ROS)-hypoxia inducible factor-1 (HIF-1)-vascular endothelial growth factor (VEGF) dependent pathway (ROS-HIF-VEGF). Deficient iodine intake may be associated with increased thyroid cancer incidence. The hypothesis of this work is to test whether ID affects the angiogenic processes in thyroid malignant cells by altering the ROS-HIF-VEGF pathway.<br><br>METHODS: Goiters were obtained in RET/PTC3 transgenic and wild-type (wt) mice and ID was induced in three thyroid carcinoma cell lines (TPC-1, 8305c, and R082-w1). Thyroid blood flow, VEGF mRNA and protein, and HIF-1&#x3b1; protein expression were measured. The role of HIF-1 and of ROS was assessed using echinomycin and N-acetylcysteine (NAC), respectively.<br><br>RESULTS: The goitrogen treatment increased the thyroid blood flow in wt and RET/PTC3 mice. Compared with wt mice, basal VEGF expression was higher in RET/PTC3 mice and increased with goitrogen treatment. In the three cell lines, ID induced marked increases in VEGF mRNA, and moderate increases in HIF-1&#x3b1; protein expression that were not transient as in normal cells. ID-induced VEGF mRNA expression was fully (8305c), partially (TPC-1), or not (R082-w1) blocked by echinomycin. NAC had no effect on ID-induced VEGF mRNA and HIF-1&#x3b1; protein expression in the three cell lines.<br><br>CONCLUSIONS: ID induces a long lasting angiogenic phenotype in thyroid cancer cells that occurs through VEGF induction via a pathway partially mediated by HIF-1, but not by ROS. These results suggest that, in contrast with normal cells, ID-induced angiogenesis in cancer cells occurs via alternative and likely less controlled routes, thereby leading to uncontrolled growth.}, }
@article {pmid22661398, year = {2014}, author = {Satpute, R and Lomash, V and Hariharakrishnan, J and Rao, P and Singh, P and Gujar, N and Bhattacharya, R}, title = {Oxidative stress and tissue pathology caused by subacute exposure to ammonium acetate in rats and their response to treatments with alpha-ketoglutarate and N-acetyl cysteine.}, journal = {Toxicology and industrial health}, volume = {30}, number = {1}, pages = {12-24}, doi = {10.1177/0748233712448117}, pmid = {22661398}, issn = {1477-0393}, mesh = {Acetates/*toxicity ; Acetylcysteine/*pharmacology ; Ammonia/blood ; Animals ; Brain/drug effects/metabolism/pathology ; Brain Chemistry/drug effects ; Ketoglutaric Acids/*pharmacology ; Liver/drug effects/metabolism/pathology ; Male ; Oxidative Stress/*drug effects ; Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; Statistics, Nonparametric ; Toxicity Tests, Subacute ; }, abstract = {Ammonia is a widely used industrial chemical that is recognized as a potent neurotoxin and environmental pollutant. The present study addresses the oxidative stress and tissue pathology caused by 4 weeks of exposure to ammonium acetate (AMA; 100 mg/kg daily; orally) in rats, and their response to oral treatments with alpha-ketoglutarate (A-KG; 1.0 g/kg), a potential cyanide antidote, and/or N-acetyl cysteine (NAC; 10 mg/kg), an antioxidant. The organ-body weight index of brain and liver was significantly increased by AMA but kidney was unaffected. Also, plasma ammonia levels were significantly elevated without any concomitant change in blood gas status and hematology but levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and reduced glutathione (GSH) in the brain and liver were diminished, accompanied by elevated levels of malondialdehyde. Levels of glutathione disulfide (GSSG) were unaffected, but the ratio of GSH:GSSG was reduced. Plasma alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and total bilirubin were raised but urea, uric acid and creatinine levels were not altered. AMA also caused temporal, hepatic and renal pathology. However, the renal pathology was not supported by any biochemical alterations. A-KG or NAC alone afforded less protection against AMA as compared to both given together. The protective efficacy of A-KG can be ascribed to its ability to detoxify ammonia and additionally both A-KG and NAC have antioxidant properties as well. The study suggests a new therapeutic regimen for ammonia poisoning.}, }
@article {pmid22653043, year = {2012}, author = {Briguori, C}, title = {Renalguard system in high-risk patients for contrast-induced acute kidney injury.}, journal = {Minerva cardioangiologica}, volume = {60}, number = {3}, pages = {291-297}, pmid = {22653043}, issn = {0026-4725}, mesh = {Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Contrast Media/*adverse effects ; Humans ; Primary Prevention/instrumentation/*methods ; Risk Factors ; }, abstract = {Contrast-induced acute kidney injury (CI-AKI) predicts unfavorable outcomes. The use of the RenalGuard™® system, to create high urine output and fluid balancing, may be beneficial in preventing CI-AKI. The REMEDIAL II trial is a randomized, multicenter, investigator-driven trial addressing the prevention of CI-AKI in high risk patients. Consecutive patients with an estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2 and/or a risk score ≥11 were randomly assigned to 1) sodium bicarbonate solution and N-acetylcysteine (NAC) (Control group) or 2) the RenalGuard therapy, that is, hydration with saline and NAC controlled by the RenalGuard System and furosemide (RenalGuard group). CI-AKI (defined as an increase of ≥0.3 mg/dL in the serum creatinine concentration at 48 hours after the procedure) occurred in 16/146 patients in the RenalGuard group (11%) and in 30/146 patients in the Control group (20.5%) (P=0.025; OR=0.47; 95% CI=0.24-0.92). Absolute changes in CyC at 24 hours (0.02±0.32 versus -0.08±0.26; P=0.002) and at 48 hours (0.12±0.42 versus -0.03±0.31; P=0.001), as well as the rate of in-hospital dialysis (4.1% versus 0.7%; P=0.056) were higher in the Control group. In conclusion, the RenalGuard therapy seems to be a promising new approach in preventing CI-AKI in high risk patients.}, }
@article {pmid22652647, year = {2012}, author = {Hardison, MT and Brown, MD and Snelgrove, RJ and Blalock, JE and Jackson, P}, title = {Cigarette smoke enhances chemotaxis via acetylation of proline-glycine-proline.}, journal = {Frontiers in bioscience (Elite edition)}, volume = {4}, number = {7}, pages = {2402-2409}, pmid = {22652647}, issn = {1945-0508}, support = {082727/Z/07/Z/WT_/Wellcome Trust/United Kingdom ; S10 RR019231/RR/NCRR NIH HHS/United States ; 095707/WT_/Wellcome Trust/United Kingdom ; P30 CA013148/CA/NCI NIH HHS/United States ; R01 HL087824/HL/NHLBI NIH HHS/United States ; P50 AT000477/AT/NCCIH NIH HHS/United States ; P30 DK079337/DK/NIDDK NIH HHS/United States ; HL087824/HL/NHLBI NIH HHS/United States ; P30 DK072482/DK/NIDDK NIH HHS/United States ; HL090999/HL/NHLBI NIH HHS/United States ; P30AR050948/AR/NIAMS NIH HHS/United States ; P30CA13148/CA/NCI NIH HHS/United States ; HL07783/HL/NHLBI NIH HHS/United States ; P50 AT00477/AT/NCCIH NIH HHS/United States ; P30 DKO72482//PHS HHS/ ; U54CA100949/CA/NCI NIH HHS/United States ; U54 CA100949/CA/NCI NIH HHS/United States ; P30 AR050948/AR/NIAMS NIH HHS/United States ; R01 HL090999/HL/NHLBI NIH HHS/United States ; RR19231/RR/NCRR NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Acetylation ; Acetylcysteine/pharmacology ; Carbocysteine/pharmacology ; *Chemotaxis, Leukocyte ; Humans ; Neutrophils/cytology ; Oligopeptides/*metabolism ; Proline/*analogs &amp; derivatives/metabolism ; *Smoke ; *Nicotiana ; }, abstract = {Several chronic lung diseases have been linked to cigarette smoking (Chronic Obstructive Pulmonary Disease (COPD), and cancer are associated with increased tobacco use). We recently described a collagen fragment, proline-glycine-proline (PGP), chemotactic for neutrophils, that appears to play a role in COPD, cystic fibrosis, and bronchiolitis obliterans syndrome. PGP can exist in either its native or acetylated form (NAcPGP), although the mechanism of N-terminal-acetylation remains unknown. This work investigates the possibility that cigarette smoke (CS) and its components acetylate PGP, describing a possible mechanism for some of the chronic inflammation seen in tobacco-associated disease. CSE and CSC (3.56 and 12.38 ng/ml NAcPGP respectively, p less than 0.01) and its components (acrolein, acetaldehyde, and methyl glyoxal) acetylated PGP (0.51, 1.03, and 0.23 ng/ml NAcPGP, p less than 0.01). Both N-acetyl-cysteine and carbocysteine (scavengers of reactive aldehydes) blocked chemical acetylation of PGP by CS (100 percent and 97 percent inhibition, respectively, p less than 0.01). NAcPGP is more chemoattractive to neutrophils, and less susceptible to degradation by Leukotriene-A4-Hydrolase (detected in the lung). These experiments propose a mechanism for the increased neutrophil recruitment seen in smoking-associated lung diseases.}, }
@article {pmid22652454, year = {2012}, author = {Byun, HO and Jung, HJ and Seo, YH and Lee, YK and Hwang, SC and Hwang, ES and Yoon, G}, title = {GSK3 inactivation is involved in mitochondrial complex IV defect in transforming growth factor (TGF) β1-induced senescence.}, journal = {Experimental cell research}, volume = {318}, number = {15}, pages = {1808-1819}, doi = {10.1016/j.yexcr.2012.04.012}, pmid = {22652454}, issn = {1090-2422}, mesh = {Animals ; Base Sequence ; Binding Sites ; Cell Line ; Cellular Senescence/*drug effects/*physiology ; DNA Primers/genetics ; Electron Transport Complex IV/chemistry/*metabolism ; Glycogen Synthase Kinase 3/*antagonists &amp; inhibitors/genetics/metabolism ; Mink ; Mitochondria/metabolism ; Models, Biological ; Phosphorylation ; Protein Subunits ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/*pharmacology ; }, abstract = {Transforming growth factor β1 (TGF β1) induces Mv1Lu cell senescence by persistently producing mitochondrial reactive oxygen species (ROS) through decreased complex IV activity. Here, we investigated the molecular mechanism underlying the effect of TGF β1 on mitochondrial complex IV activity. TGF β1 progressively phosphorylated the negative regulatory sites of both glycogen synthase kinase 3 (GSK3) α and β, corresponding well to the intracellular ROS generation profile. Pre-treatment of N-acetyl cysteine, an antioxidant, did not alter this GSK3 phosphorylation (inactivation), whereas pharmacological inhibition of GSK3 by SB415286 significantly increased mitochondrial ROS, implying that GSK3 phosphorylation is an upstream event of the ROS generation. GSK3 inhibition by SB415286 decreased complex IV activity and cellular O(2) consumption rate and eventually induced senescence of Mv1Lu cell. Similar results were obtained with siRNA-mediated knockdown of GSK3. Moreover, we found that GSK3 not only exists in cytosol but also in mitochondria of Mv1Lu cell and the mitochondrial GSK3 binds complex IV subunit 6b which has no electron carrier and is topologically located in the mitochondrial intermembrane space. Involvement of subunit 6b in controlling complex IV activity and overall respiration rate was proved with siRNA-mediated knockdown of subunit 6b. Finally, TGF β1 treatment decreased the binding of the subunit 6b to GSK3 and subunit 6b phosphorylation. Taken together, our results suggest that GSK3 inactivation is importantly involved in TGF β1-induced complex IV defects through decreasing phosphorylation of the subunit 6b, thereby contributing to senescence-associated mitochondrial ROS generation.}, }
@article {pmid22648949, year = {2012}, author = {Liu, Y and Hernández-Ochoa, EO and Randall, WR and Schneider, MF}, title = {NOX2-dependent ROS is required for HDAC5 nuclear efflux and contributes to HDAC4 nuclear efflux during intense repetitive activity of fast skeletal muscle fibers.}, journal = {American journal of physiology. Cell physiology}, volume = {303}, number = {3}, pages = {C334-47}, pmid = {22648949}, issn = {1522-1563}, support = {R01 AR055099/AR/NIAMS NIH HHS/United States ; R01 AR056477/AR/NIAMS NIH HHS/United States ; R01-AR056477/AR/NIAMS NIH HHS/United States ; }, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs &amp; derivatives/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Enzyme Inhibitors/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Histone Deacetylases/*metabolism ; Hydrogen Peroxide/metabolism/pharmacology ; Membrane Glycoproteins/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle Fibers, Fast-Twitch/drug effects/*metabolism ; NADPH Oxidase 2 ; NADPH Oxidases/*metabolism ; Protein Kinases/metabolism ; Reactive Oxygen Species/*metabolism ; Recombinant Fusion Proteins/metabolism ; }, abstract = {Reactive oxygen species (ROS) have been linked to oxidation and nuclear efflux of class IIa histone deacetylase 4 (HDAC4) in cardiac muscle. Here we use HDAC-GFP fusion proteins expressed in isolated adult mouse flexor digitorum brevis muscle fibers to study ROS mediation of HDAC localization in skeletal muscle. H(2)O(2) causes nuclear efflux of HDAC4-GFP or HDAC5-GFP, which is blocked by the ROS scavenger N-acetyl-l-cysteine (NAC). Repetitive stimulation with 100-ms trains at 50 Hz, 2/s ("50-Hz trains") increased ROS production and caused HDAC4-GFP or HDAC5-GFP nuclear efflux. During 50-Hz trains, HDAC5-GFP nuclear efflux was completely blocked by NAC, but HDAC4-GFP nuclear efflux was only partially blocked by NAC and partially blocked by the calcium-dependent protein kinase (CaMK) inhibitor KN-62. Thus, during intense activity both ROS and CaMK play roles in nuclear efflux of HDAC4, but only ROS mediates HDAC5 nuclear efflux. The 10-Hz continuous stimulation did not increase the rate of ROS production and did not cause HDAC5-GFP nuclear efflux but promoted HDAC4-GFP nuclear efflux that was sensitive to KN-62 but not NAC and thus mediated by CaMK but not by ROS. Fibers from NOX2 knockout mice lacked ROS production and ROS-dependent nuclear efflux of HDAC5-GFP or HDAC4-GFP during 50-Hz trains but had unmodified Ca(2+) transients. Our results demonstrate that ROS generated by NOX2 could play important roles in muscle remodeling due to intense muscle activity and that the nuclear effluxes of HDAC4 and HDAC5 are differentially regulated by Ca(2+) and ROS during muscle activity.}, }
@article {pmid22640979, year = {2012}, author = {Barret, M and Batteux, F and Beuvon, F and Mangialavori, L and Chryssostalis, A and Pratico, C and Chaussade, S and Prat, F}, title = {N-acetylcysteine for the prevention of stricture after circumferential endoscopic submucosal dissection of the esophagus: a randomized trial in a porcine model.}, journal = {Fibrogenesis &amp; tissue repair}, volume = {5}, number = {1}, pages = {8}, pmid = {22640979}, issn = {1755-1536}, abstract = {BACKGROUND: Circumferential endoscopic submucosal dissection (CESD) of the esophagus would allow for both the eradication of Barrett's esophagus and its related complications, such as advanced neoplasia. However, such procedures generally induce inflammatory repair resulting in a fibrotic stricture. N-acetylcysteine (NAC) is an antioxidant that has shown some efficacy against pulmonary and hepatic fibrosis. The aim of our study was to evaluate the benefit of NAC in the prevention of esophageal cicatricial stricture after CESD in a swine model.<br><br>ANIMALS AND METHODS: Two groups of six pigs each were subjected to general anesthesia and CESD: after randomization, a first group received an oral NAC treatment regimen of 100 mg/kg/day, initiated one week before the procedure, whereas a second group was followed without any prophylactic treatment. Follow-up endoscopies took place seven, fourteen, twenty-one, and twenty-eight days after CESD. Necropsy, histological assessment of esophageal inflammation, and fibrosis were performed on day 28.<br><br>RESULTS: The median esophageal lumen diameter on day 21 (main judgment criterion) was 4 mm (range 2 to 5) in group 1 and 3 mm (range 1 to 7) in group 2 (P&#x2009;=&#x2009;0.95). No significant difference was observed between the two groups regarding clinical evaluation (time before onset of clinically significant esophageal obstruction), number of dilations, esophageal inflammation and fibrosis, or oxidative stress damage on immunohistochemistry.<br><br>CONCLUSIONS: Despite its antioxidant effect, systemic administration of NAC did not show significant benefit on esophageal fibrosis in our animal model of esophageal wound healing within the experimental conditions of this study. Since the administered doses were relatively high, it seems unlikely that NAC might be a valuable option for the prevention of post-endoscopic esophageal stricture.}, }
@article {pmid22634311, year = {2012}, author = {Loo, AE and Halliwell, B}, title = {Effects of hydrogen peroxide in a keratinocyte-fibroblast co-culture model of wound healing.}, journal = {Biochemical and biophysical research communications}, volume = {423}, number = {2}, pages = {253-258}, doi = {10.1016/j.bbrc.2012.05.100}, pmid = {22634311}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cells, Cultured ; Coculture Techniques ; Fibroblasts/*drug effects/physiology ; Humans ; Hydrogen Peroxide/*pharmacology ; Keratinocytes/*drug effects/physiology ; Mitogens/*pharmacology ; Models, Biological ; Wound Healing/*drug effects/physiology ; }, abstract = {Recently, there has been renewed interest in the role of reactive oxygen species (ROS), especially H(2)O(2), in wound healing. We previously showed that H(2)O(2) stimulates healing in a keratinocyte scratch wound model. In this paper, we used a more complex and physiologically relevant model that involves co-culturing primary keratinocytes and fibroblasts. We found that the two main cell types within the skin have different sensitivities to H(2)O(2) and to the widely used "antioxidant"N-acetyl-l-cysteine (NAC). Keratinocytes were very resistant to the toxicity of H(2)O(2) (250 and 500 μM) or NAC (5 mM). However, the viability of fibroblasts was decreased by both compounds. Using the co-culture model, we also found that H(2)O(2) increases re-epithelialization while NAC retards it. Our data further illustrate the possible role of ROS in wound healing and the co-culture model should be useful for screening agents that may influence the wound healing process.}, }
@article {pmid22622864, year = {2012}, author = {Yen, YP and Tsai, KS and Chen, YW and Huang, CF and Yang, RS and Liu, SH}, title = {Arsenic induces apoptosis in myoblasts through a reactive oxygen species-induced endoplasmic reticulum stress and mitochondrial dysfunction pathway.}, journal = {Archives of toxicology}, volume = {86}, number = {6}, pages = {923-933}, doi = {10.1007/s00204-012-0864-9}, pmid = {22622864}, issn = {1432-0738}, mesh = {Apoptosis/*drug effects ; Arsenic/*toxicity ; Arsenic Trioxide ; Arsenicals ; Cell Line ; Cytotoxins/toxicity ; Endoplasmic Reticulum Stress/*drug effects ; Humans ; Mitochondria/*drug effects ; Myoblasts/*drug effects/metabolism ; Oxides/toxicity ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {A pool of myoblasts available for myogenesis is important for skeletal muscle size. The decreased number of skeletal muscle fibers could be due to the decreased myoblast proliferation or cytotoxicity. Identification of toxicants that regulate myoblast apoptosis is important in skeletal muscle development or regeneration. Here, we investigate the cytotoxic effect and its possible mechanisms of arsenic trioxide (As(2)O(3)) on myoblasts. C2C12 myoblasts underwent apoptosis in response to As(2)O(3) (1-10 μM), accompanied by increased Bax/Bcl-2 ratio, decreased mitochondria membrane potential, increased cytochrome c release, increased caspase-3/-9 activity, and increased poly (ADP-ribose) polymerase (PARP) cleavage. Moreover, As(2)O(3) triggered the endoplasmic reticulum (ER) stress indentified through several key molecules of the unfolded protein response, including glucose-regulated protein (GRP)-78, GRP-94, PERK, eIF2α, ATF6, and caspase-12. Pretreatment with antioxidant N-acetylcysteine (NAC, 0.5 mM) dramatically suppressed the increases in reactive oxygen species (ROS), lipid peroxidation, ER stress, caspase cascade activity, and apoptosis in As(2)O(3) (10 μM)-treated myoblasts. Furthermore, As(2)O(3) (10 μM) effectively decreased the phosphorylation of Akt, which could be reversed by NAC. Over-expression of constitutive activation of Akt (c.a. Akt) also significantly attenuated As(2)O(3)-induced myoblast apoptosis. Taken together, these results suggest that As(2)O(3) may exert its cytotoxicity on myoblasts by inducing apoptosis through a ROS-induced mitochondrial dysfunction, ER stress, and Akt inactivation signaling pathway.}, }
@article {pmid22618532, year = {2012}, author = {Yang, L and Tan, P and Zhou, W and Zhu, X and Cui, Y and Zhu, L and Feng, X and Qi, H and Zheng, J and Gu, P and Fan, X and Chen, H}, title = {N-acetylcysteine protects against hypoxia mimetic-induced autophagy by targeting the HIF-1α pathway in retinal ganglion cells.}, journal = {Cellular and molecular neurobiology}, volume = {32}, number = {8}, pages = {1275-1285}, pmid = {22618532}, issn = {1573-6830}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Animals, Newborn ; Autophagy/drug effects/*physiology ; Cell Hypoxia/drug effects/physiology ; Cell Line ; Cell Line, Transformed ; Cell Survival/drug effects/physiology ; Cobalt/toxicity ; Dose-Response Relationship, Drug ; *Drug Delivery Systems/methods ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists &amp; inhibitors/*biosynthesis ; Neuroprotective Agents/*administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Retinal Ganglion Cells/drug effects/*metabolism ; }, abstract = {Hypoxia-induced retinal ganglion cell (RGC) death has been proposed to be the critical event in the pathophysiology of glaucoma. Therefore, delaying or halting RGC degeneration, known as neuroprotection, is a novel and promising approach with potential clinical applications for treating glaucoma. In this study, we investigate hypoxia-induced cell death of RGCs and the underlying mechanisms of N-acetylcysteine (NAC) as a neuroprotectant. To establish a model for chemical hypoxia-induced cell death, RGC-5 cells were treated with the hypoxia mimetic cobalt chloride (CoCl2). Following CoCl2 exposure, significant levels of apoptotic and autophagic cell death were observed in RGC-5 cells, evidenced by lysosome dysfunction and autophagosome formation. Pretreating RGC-5 cells with NAC significantly counteracted the autophagic cell death. NAC-mediated neuroprotection was attributed to the direct scavenging of reactive oxygen species and was mediated by targeting the hypoxia-inducible factor-1α pathway via the BNIP3 and PI3K/Akt/mTOR pathways. These results provide insights into the degeneration of RGCs and present a potential clinical application for NAC as a neuroprotectant.}, }
@article {pmid22617349, year = {2012}, author = {Jayasooriya, RG and Kang, SH and Kang, CH and Choi, YH and Moon, DO and Hyun, JW and Chang, WY and Kim, GY}, title = {Apigenin decreases cell viability and telomerase activity in human leukemia cell lines.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {50}, number = {8}, pages = {2605-2611}, doi = {10.1016/j.fct.2012.05.024}, pmid = {22617349}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Apigenin/*pharmacology ; Apoptosis/drug effects ; Base Sequence ; Cell Line, Tumor ; Cell Survival/*drug effects ; DNA Primers ; Electrophoretic Mobility Shift Assay ; Flow Cytometry ; Glutathione/pharmacology ; Humans ; Leukemia/enzymology/*pathology ; Reactive Oxygen Species/metabolism ; Telomerase/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Recent studies have shown that apigenin (4',5,7-trihydroxyflavone inhibits human malignant cancer cell growth through cell cycle arrest and apoptosis. However, the underlying relationship between apoptosis and telomerase activity in response to apigenin exposure is not well understood. In this study, we found that apigenin significantly induces direct cytotoxicity in human leukemia cells (U937, THP-1 and HL60) through activation of the caspase pathway. As we presumed, treatment with apigenin was found to increase the level of intracellular reactive oxygen species (ROS), whereas pretreatment with antioxidants, N-acetyl-cysteine (NAC) or glutathione (GSH), completely attenuated ROS generation. Surprisingly, these antioxidants did not promote recuperation from apigenin-induced cell death. We further showed that apigenin downregulates telomerase activity in caspase-dependent apoptosis and observed that apigenin dosing results in downregulation of telomerase activity by suppression of c-Myc-mediated telomerase reverse transcriptase (hTERT) expression. In addition, treatment of apigenin-dosed cells with the two antioxidants did not restore telomerase activity. Taken together, this data suggests that ROS is not essential for suppression of apigenin-mediated apoptosis associated with the activation of caspases and regulation of telomerase activity via suppression of hTERT. We conclude that apigenin has a direct cytotoxic effect and the loss of telomerase activity in leukemia cells.}, }
@article {pmid22613333, year = {2012}, author = {Hu, Z and Huang, J and Li, Z and Li, X and Fu, Z and Liu, H and Guan, L}, title = {[Hypoxia upregulates the expression of annexin A1 in lung adenocarcinoma a549 cells].}, journal = {Zhongguo fei ai za zhi = Chinese journal of lung cancer}, volume = {15}, number = {5}, pages = {277-280}, pmid = {22613333}, issn = {1999-6187}, mesh = {Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus ; Adenocarcinoma/genetics/metabolism/pathology ; Annexin A1/*genetics/*metabolism ; Antioxidants/pharmacology ; Blotting, Western ; Cell Hypoxia ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Free Radical Scavengers/pharmacology ; *Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics/metabolism/pathology ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Thiocarbamates/pharmacology ; *Up-Regulation ; }, abstract = {BACKGROUND AND OBJECTIVE: The growth of tumor often faced up with lackness of blood and oxygen, and it has been reported that Annexin A1 may be involved in tumor. The aim of this investigation is to explore the characteristics of expression of Annexin A1 in lung adenocarcinoma A549 cells after hypoxia.<br><br>METHODS: A549 cells were exposured to either normoxia (21%O&#x2082;) or hypoxia (1%O&#x2082;) condition for 4 h, 12 h, 24 h. The expressions of Annexin A1 mRNA levels were measured by RT-PCR. The expressions of Annexin 1 protein were investigaged by Western blot. The relative content of reactive oxygen species (ROS) were assayed by special kit. The expressions of nuclear translocation of NF-&#x3ba;B was assayed by Western blot; After been treated with ROS scavenger NAC and PDTC, the levels of Annexin 1 protein of A549 cells were measured by Western blot.<br><br>RESULTS: Compared with normoxia group, the Annexin A1 mRNA in hypoxia group increased after 4 h, and then decreased gradually; Moreover, Annexin 1 protein levels of A549 cells were also increased when treated with hypoxia. An increaing of ROS production in cells exprosed to hypoxia was detected. NAC and PDTC inhibited hypoxia-induced Annexin A1 increase.<br><br>CONCLUSION: Hypoxia upregulates the expression of Annexin A1 in lung adenocarcinoma A549 cells, in which process ROS-NF-&#x3ba;B may paticipate in.}, }
@article {pmid22612071, year = {2012}, author = {Bilasy, ME and Oraby, MA and Ismail, HM and Maklady, FA}, title = {Effectiveness of theophylline in preventing contrast-induced nephropathy after coronary angiographic procedures.}, journal = {Journal of interventional cardiology}, volume = {25}, number = {4}, pages = {404-410}, doi = {10.1111/j.1540-8183.2012.00730.x}, pmid = {22612071}, issn = {1540-8183}, mesh = {Acetylcysteine/administration &amp; dosage ; Adult ; Aged ; Contrast Media/*adverse effects ; *Coronary Angiography ; Creatinine/blood ; Drug Therapy, Combination ; Female ; Glomerular Filtration Rate ; Humans ; Incidence ; Kidney Diseases/chemically induced/epidemiology/*prevention &amp; control ; Male ; Middle Aged ; Risk Assessment ; Single-Blind Method ; Sodium Chloride/administration &amp; dosage ; Theophylline/*administration &amp; dosage ; Treatment Outcome ; Vasodilator Agents/*administration &amp; dosage ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) is the third most common cause of hospital acquired acute renal failure and is associated with increased morbidity and mortality. The use of theophylline for prevention of CIN has yielded conflicting results. This study aimed at examining the effectiveness of theophylline in prevention of CIN when added to IV hydration and N-acetylcysteine (NAC).<br><br>METHODS: Patients with stable serum creatinine and at least moderate risk for CIN according to Mehran's risk score were included in this parallel group, 1:1, single-blind, randomized controlled trial. All patients received IV hydration (1 mL/kg per hour for 24 hours) and NAC (600 mg bid for 2 days). Patients were randomized to placebo (group P) or theophylline (200 mg in 100 mL 0.9% saline, as IV infusion 30 minutes before contrast medium (CM) administration; group T). Patients underwent standard coronary angiography &#xb1; angioplasty. Serum creatinine (SCr) was assessed just before and 72 hours after contrast administration and estimated glomerular filtration rate (eGFR) was calculated.<br><br>RESULTS: This study included 60 patients with mean SCr 1.44 &#xb1; 0.7 mg/dL and eGFR 60.2 &#xb1; 29.2 mL/min. Mean SCr among group T was 1.54 &#xb1; 0.7 mg/dL with eGFR 58.6 &#xb1; 28.6 mL/min, while group P showed mean SCr of 1.34 &#xb1; 0.7 mg/dL and eGFR of 61.8 &#xb1; 30.1 mL/min. Among group P, 6 (20%) patients developed CIN while none of the patients in group T developed CIN. In comparison to placebo, theophylline significantly decreased SCr (P = 0.0001) and increased eGFR (P = 0.001) at 72 hours. Multivariate regression analysis showed that receiving placebo instead of theophylline, anemia, congestive heart failure, chronic renal impairment, and high-contrast load are all independent predictors for deteriorating renal function after CM administration.<br><br>CONCLUSION: Theophylline seems to be an effective prophylaxis against CIN for moderate- and high-risk patients undergoing coronary angiography or angioplasty. It offers additive protection when added to IV hydration and NAC.}, }
@article {pmid22609960, year = {2012}, author = {Zhao, YF and Zhang, C and Suo, YR}, title = {MMPT as a reactive oxygen species generator induces apoptosis via the depletion of intracellular GSH contents in A549 cells.}, journal = {European journal of pharmacology}, volume = {688}, number = {1-3}, pages = {6-13}, doi = {10.1016/j.ejphar.2012.05.003}, pmid = {22609960}, issn = {1879-0712}, mesh = {Acetylcysteine/pharmacology ; Aniline Compounds/*pharmacology ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; G2 Phase Cell Cycle Checkpoints/drug effects ; Glutathione/*metabolism ; Humans ; Intracellular Space/*drug effects/*metabolism ; M Phase Cell Cycle Checkpoints/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; Thiazoles/*pharmacology ; }, abstract = {MMPT, (5-[(4-methylphenyl)methylene]-2-(phenylamino)-4(5H)-thiazolone), a thiazolidin compound, was identified in our laboratory as a novel antineoplastic agent with a broad spectrum of antitumor activity against many human cancer cells. A previous study showed that MMPT inhibited cell growth, and induced apoptosis in H1792 cells. In this study, the antiproliferative activity of MMPT was investigated. The results showed that MMPT was able to inhibit A549 cell growth in a time- and dose-dependent manner by blocking cell cycle progression in the G2 phase and inducing apoptosis. MMPT induced DNA fragmentation and caspase activation in A549 cells, both of which are hallmarks of apoptosis. The apoptotic process was accompanied by the generation of reactive oxygen species, depletion of glutathione (GSH), and reduction the GSH/GSSG ratio, suggesting that MMPT may induce apoptosis in A549 cells through a reactive oxygen species dependent pathway. Treatment with a thiol antioxidant, NAC, showed the recovery of GSH depletion and the reduction of reactive oxygen species levels in MMPT-treated cells, which were accompanied by the inhibition of apoptosis. In contrast, L-buthionine sulfoximine (BSO), a well-known inhibitor of GSH synthesis, aggravated GSH depletion and cell death in MMPT-treated cells. In conclusion, we have demonstrated that MMPT inhibits the growth of A549 cells by inducing a G2 arrest of the cell cycle and by triggering apoptosis accompanied with the depletion of GSH.}, }
@article {pmid22609276, year = {2012}, author = {Sun, Z and Wang, H and Ye, S and Xiao, S and Liu, J and Wang, W and Jiang, D and Liu, X and Wang, J}, title = {Beta-eleostearic acid induce apoptosis in T24 human bladder cancer cells through reactive oxygen species (ROS)-mediated pathway.}, journal = {Prostaglandins &amp; other lipid mediators}, volume = {99}, number = {1-2}, pages = {1-8}, doi = {10.1016/j.prostaglandins.2012.04.001}, pmid = {22609276}, issn = {1098-8823}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase Inhibitors/pharmacology ; Catalase/pharmacology ; Cell Survival/drug effects ; Down-Regulation ; Glutathione/metabolism ; Humans ; Linolenic Acids/*pharmacology ; PPAR gamma/antagonists &amp; inhibitors ; Polyethylene Glycols/pharmacology ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; Urinary Bladder Neoplasms/metabolism ; }, abstract = {Beta-eleostearic acid (β-ESA, 9E11E13E-18:3), a linolenic acid isomer with a conjugated triene system, is a natural and biologically active compound. Herein, we investigated effects of β-eleostearic acid on T24 human bladder cancer cells. In this study, results showed that β-eleostearic acid had strong cytotoxicity to induce cell apoptosis, which was mediated by reactive oxygen species (ROS) in T24 cells. The cell viability assay results showed that incubation with β-eleostearic acid concentrations of 10-80μmol/L caused a dose- and time-dependent decrease of T24 cell viability, and the IC(50) value was 21.2μmol/L at 24h and 13.1μmol/L at 48h. Annexin V/PI double staining was used to assess apoptosis with flow cytometry. Treatment with β-eleostearic acid caused massive ROS accumulation and GSH decrease, which lead to activation of caspase-3 and down-regulation of Bcl-2 indicating induction of apoptosis. Subsequently, N-acetyl-l-cysteine (NAC) and PEG-catalase effectively blocked the ROS elevated effect of β-eleostearic acid, which suggested that β-eleostearic acid-induced apoptosis involved ROS generated. Additionally, we found that treating T24 cells with β-eleostearic acid induced activation of PPARγ. A PPARγ-activated protein kinase inhibitor was able to partially abrogate the effects of β-eleostearic acid. These results suggested that β-eleostearic acid can induce T24 cells apoptosis via a ROS-mediated pathway which may be involved PPARγ activation.}, }
@article {pmid22607134, year = {2012}, author = {,  and Raghu, G and Anstrom, KJ and King, TE and Lasky, JA and Martinez, FJ}, title = {Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis.}, journal = {The New England journal of medicine}, volume = {366}, number = {21}, pages = {1968-1977}, pmid = {22607134}, issn = {1533-4406}, support = {K24 HL111316/HL/NHLBI NIH HHS/United States ; U10 HL080413/HL/NHLBI NIH HHS/United States ; U10 HL080513/HL/NHLBI NIH HHS/United States ; U10 HL080543/HL/NHLBI NIH HHS/United States ; U10HL080510/HL/NHLBI NIH HHS/United States ; U10 HL080685/HL/NHLBI NIH HHS/United States ; U10HL080413/HL/NHLBI NIH HHS/United States ; U10HL080383/HL/NHLBI NIH HHS/United States ; U10HL080371/HL/NHLBI NIH HHS/United States ; U10 HL080274/HL/NHLBI NIH HHS/United States ; U10HL080513/HL/NHLBI NIH HHS/United States ; U10HL080685/HL/NHLBI NIH HHS/United States ; R01 HL105479/HL/NHLBI NIH HHS/United States ; U10 HL080371/HL/NHLBI NIH HHS/United States ; U10HL080411/HL/NHLBI NIH HHS/United States ; U10 HL080383/HL/NHLBI NIH HHS/United States ; R01 HL089249/HL/NHLBI NIH HHS/United States ; U10HL080370/HL/NHLBI NIH HHS/United States ; U10 HL080370/HL/NHLBI NIH HHS/United States ; U10HL080571/HL/NHLBI NIH HHS/United States ; U10 HL080411/HL/NHLBI NIH HHS/United States ; U10HL080509/HL/NHLBI NIH HHS/United States ; U10HL080274/HL/NHLBI NIH HHS/United States ; U10 HL080509/HL/NHLBI NIH HHS/United States ; U10 HL080571/HL/NHLBI NIH HHS/United States ; U10 HL080510/HL/NHLBI NIH HHS/United States ; U10HL080543/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Aged ; Azathioprine/adverse effects/*therapeutic use ; Disease Progression ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Hospitalization ; Humans ; Kaplan-Meier Estimate ; Male ; Medication Adherence ; Middle Aged ; Prednisone/adverse effects/*therapeutic use ; Pulmonary Fibrosis/*drug therapy/mortality/physiopathology ; Treatment Outcome ; Vital Capacity ; }, abstract = {BACKGROUND: A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown.<br><br>METHODS: In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups -- receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo -- in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period.<br><br>RESULTS: When approximately 50% of data had been collected (with 77 patients in the combination-therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P=0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here.<br><br>CONCLUSIONS: Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; ClinicalTrials.gov number, NCT00650091.).}, }
@article {pmid22606295, year = {2012}, author = {Schmukler, E and Shai, B and Ehrlich, M and Pinkas-Kramarski, R}, title = {Neuregulin promotes incomplete autophagy of prostate cancer cells that is independent of mTOR pathway inhibition.}, journal = {PloS one}, volume = {7}, number = {5}, pages = {e36828}, pmid = {22606295}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Anthracenes/pharmacology ; Apoptosis Regulatory Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Autophagy/drug effects/physiology ; Beclin-1 ; Cell Death/drug effects/physiology ; Cell Line, Tumor ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Membrane Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Neoplasms, Hormone-Dependent/drug therapy/pathology/physiopathology ; Neuregulins/pharmacology/*physiology ; Prostatic Neoplasms/drug therapy/*pathology/*physiopathology ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/pharmacology ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/*antagonists &amp; inhibitors/physiology ; }, abstract = {BACKGROUND: Growth factors activating the ErbB receptors have been described in prostate tumors. The androgen dependent prostate cancer cell line, LNCaP, expresses the ErbB-1, ErbB-2 and ErbB-3 receptor tyrosine kinases. Previously, it was demonstrated that NRG activates ErbB-2/ErbB-3 heterodimers to induce LNCaP cell death, whereas, EGF activates ErbB-1/ErbB-1 or ErbB-1/ErbB-2 dimers to induce cell growth and survival. It was also demonstrated that PI3K inhibitors repressed this cell death suggesting that in androgen deprived LNCaP cells, NRG activates a PI3K-dependent pathway associated with cell death.<br><br>In the present study we demonstrate that NRG induces autophagy in LNCaP cells, using LC3 as a marker. However, the autophagy induced by NRG may be incomplete since p62 levels elevate. We also demonstrated that NRG- induced autophagy is independent of mammalian target of rapamycin (mTOR) inhibition since NRG induces Akt and S6K activation. Interestingly, inhibition of reactive oxygen species (ROS) by N-acetylcysteine (NAC), inhibited NRG-induced autophagy and cell death. Our study also identified JNK and Beclin 1 as important components in NRG-induced autophagy and cell death. NRG induced elevation in JNK phosphorylation that was inhibited by NAC. Moreover, inhibitor of JNK inhibited NRG-induced autophagy and cell death. Also, in cells overexpressing Bcl-2 or cells expressing sh-RNA against Beclin 1, the effects of NRG, namely induction of autophagy and cell death, were inhibited.<br><br>CONCLUSIONS/SIGNIFICANCE: Thus, in LNCaP cells, NRG-induces incomplete autophagy and cell death that depend on ROS levels. These effects of NRG are mediated by signaling pathway that activates JNK and Beclin 1, but is independent of mTOR inhibition.}, }
@article {pmid22594971, year = {2012}, author = {Singh, BR and Singh, BN and Khan, W and Singh, HB and Naqvi, AH}, title = {ROS-mediated apoptotic cell death in prostate cancer LNCaP cells induced by biosurfactant stabilized CdS quantum dots.}, journal = {Biomaterials}, volume = {33}, number = {23}, pages = {5753-5767}, doi = {10.1016/j.biomaterials.2012.04.045}, pmid = {22594971}, issn = {1878-5905}, mesh = {Achyranthes/microbiology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Cadmium Compounds/*pharmacology ; Caspases/metabolism ; Cell Line, Tumor ; Humans ; Male ; Prostatic Neoplasms/*drug therapy/metabolism ; *Quantum Dots ; Reactive Oxygen Species/*metabolism ; Sulfides/*pharmacology ; Surface-Active Agents/chemistry/isolation &amp; purification ; }, abstract = {Cadmium sulfide (CdS) quantum dots (QDs) have raised great attention because of their superior optical properties and wide utilization in biological and biomedical studies. However, little is known about the cell death mechanisms of CdS QDs in human cancer cells. This study was designed to investigate the possible mechanisms of apoptosis induced by biosurfactant stabilized CdS QDs (denoted as "bsCdS QDs") in human prostate cancer LNCaP cells. It was also noteworthy that apoptosis correlated with reactive oxygen species (ROS) production, mitochondrial damage, oxidative stress and chromatin condensation in a dose- and time-dependent manner. Results also showed involvement of caspases, Bcl-2 family proteins, heat shock protein 70, and a cell-cycle checkpoint protein p53 in apoptosis induction by bsCdS QDs in LNCaP cells. Moreover, pro-apoptotic protein Bax was upregulated and the anti-apoptotic proteins, survivin and NF-κB were downregulated in bsCdS QDs exposed cells. Protection of N-acetyl cysteine (NAC) against ROS clearly suggested the implication of ROS in hyper-activation of apoptosis and cell death. It is encouraging to conclude that biologically stabilized CdS QDs bear the potential of its applications in biomedicine, such as tumor therapy specifically by inducing caspase-dependent apoptotic cell death of human prostate cancer LNCaP cells.}, }
@article {pmid22593437, year = {2012}, author = {Russell, LH and Mazzio, E and Badisa, RB and Zhu, ZP and Agharahimi, M and Oriaku, ET and Goodman, CB}, title = {Autoxidation of gallic acid induces ROS-dependent death in human prostate cancer LNCaP cells.}, journal = {Anticancer research}, volume = {32}, number = {5}, pages = {1595-1602}, pmid = {22593437}, issn = {1791-7530}, support = {GM08111/GM/NIGMS NIH HHS/United States ; G12 RR003020/RR/NCRR NIH HHS/United States ; SD34HP0 4018//PHS HHS/United States ; G12 MD007582-28/MD/NIMHD NIH HHS/United States ; S06 GM008111/GM/NIGMS NIH HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; G12 RR03020/RR/NCRR NIH HHS/United States ; G12 MD007582/MD/NIMHD NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Gallic Acid/chemistry/*pharmacology ; Glutathione/pharmacology ; Humans ; Male ; Membrane Potential, Mitochondrial/drug effects ; Oxidation-Reduction ; Prostatic Neoplasms/*drug therapy/pathology ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Prostate cancer is the second most common cause of mortality. Gallic acid (GA) is a natural polyphenol, and we tested its in-vitro cytotoxicity after 24 h in prostate cancer LNCaP cells.<br><br>MATERIALS AND METHODS: GA autoxidation was measured fluorimetrically for H(2)O(2), and O(2)(&#x2022;-) radicals by chemiluminescence. Intracellular reactive oxygen species (ROS) levels were detected with 2',7'-dichlorodihydrofluorescein diacetate. Cytotoxicity was evaluated by crystal-violet, while apoptosis and mitochondrial membrane potential were determined by flow cytometry. Cytochrome c release was detected by enzyme-linked immunosorbent assay, and caspase-8, -9 and -3 activities were measured calorimetrically.<br><br>RESULTS: GA autoxidation produced significant levels of H(2)O(2) and O2.-. Increased intracellular ROS levels with GA were reduced by N-acetyl-L-cysteine (NAC) and L-glutathione (GSH). Cells were protected against GA cytotoxicity when pretreated with increasing levels of superoxide dismutase/catalase mixture, NAC, or GSH for 3 h. The number of apoptotic cells increased with GA dose. GA caused mitochondrial potential loss, cytochrome c release, and activation of caspases 3, 8 and 9.<br><br>CONCLUSION: The ROS-dependent apoptotic mechanism of GA kills malignant cells effectively; it is likely that GA could be a good anticancer agent.}, }
@article {pmid22593093, year = {2012}, author = {Woodhead, JL and Howell, BA and Yang, Y and Harrill, AH and Clewell, HJ and Andersen, ME and Siler, SQ and Watkins, PB}, title = {An analysis of N-acetylcysteine treatment for acetaminophen overdose using a systems model of drug-induced liver injury.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {342}, number = {2}, pages = {529-540}, doi = {10.1124/jpet.112.192930}, pmid = {22593093}, issn = {1521-0103}, mesh = {Acetaminophen/administration &amp; dosage/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Alanine Transaminase/metabolism ; Benzoquinones/metabolism ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism ; Cohort Studies ; Computer Simulation ; Hepatocytes/drug effects/metabolism ; Humans ; Imines/metabolism ; Infusions, Intravenous ; Liver/drug effects/metabolism ; Prescription Drug Misuse ; Risk Factors ; }, abstract = {N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n = 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. V(max) for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.}, }
@article {pmid22592920, year = {2012}, author = {Wang, T and Wang, L and Zaidi, SR and Sammani, S and Siegler, J and Moreno-Vinasco, L and Mathew, B and Natarajan, V and Garcia, JG}, title = {Hydrogen sulfide attenuates particulate matter-induced human lung endothelial barrier disruption via combined reactive oxygen species scavenging and Akt activation.}, journal = {American journal of respiratory cell and molecular biology}, volume = {47}, number = {4}, pages = {491-496}, pmid = {22592920}, issn = {1535-4989}, support = {P01 HL058064/HL/NHLBI NIH HHS/United States ; HL058064/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Capillary Permeability ; Cells, Cultured ; Electric Impedance ; Endothelial Cells/immunology/metabolism/physiology ; Enzyme Activation ; Free Radical Scavengers/*pharmacology ; Humans ; Hydrogen Sulfide/*pharmacology ; Lung/drug effects/pathology ; MAP Kinase Signaling System ; Male ; Mice ; Microvessels/enzymology/*metabolism/pathology ; Particulate Matter/*toxicity ; Phosphorylation ; Pneumonia/immunology/metabolism/pathology ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Exposure to particulate air pollution is associated with increased cardiopulmonary morbidity and mortality, although the pathogenic mechanisms are poorly understood. We previously demonstrated that particulate matter (PM) exposure triggers massive oxidative stress in vascular endothelial cells (ECs), resulting in the loss of EC integrity and lung vascular hyperpermeability. We investigated the protective role of hydrogen sulfide (H(2)S), an endogenous gaseous molecule present in the circulation, on PM-induced human lung EC barrier disruption and pulmonary inflammation. Alterations in EC monolayer permeability, as reflected by transendothelial electrical resistance (TER), the generation of reactive oxygen species (ROS), and murine pulmonary inflammatory responses, were studied after exposures to PM and NaSH, an H(2)S donor. Similar to N-acetyl cysteine (5 mM), NaSH (10 μM) significantly scavenged PM-induced EC ROS and inhibited the oxidative activation of p38 mitogen-activated protein kinase. Concurrent with these events, NaSH (10 μM) activated Akt, which helps maintain endothelial integrity. Both of these pathways contribute to the protective effect of H(2)S against PM-induced endothelial barrier dysfunction. Furthermore, NaSH (20 mg/kg) reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in bronchoalveolar lavage fluids in a murine model of PM-induced lung inflammation. These data suggest a potentially protective role for H(2)S in PM-induced inflammatory lung injury and vascular hyperpermeability.}, }
@article {pmid22592642, year = {2012}, author = {Chiou, SM and Chiu, CH and Yang, ST and Yang, JS and Huang, HY and Kuo, CL and Chen, PY and Chung, JG}, title = {Danthron triggers ROS and mitochondria-mediated apoptotic death in C6 rat glioma cells through caspase cascades, apoptosis-inducing factor and endonuclease G multiple signaling.}, journal = {Neurochemical research}, volume = {37}, number = {8}, pages = {1790-1800}, pmid = {22592642}, issn = {1573-6903}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthraquinones/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor/*physiology ; Caspases/*metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cytochromes c/metabolism ; Endodeoxyribonucleases/physiology ; Glioma/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction/physiology ; }, abstract = {This research focused on the induction of cytotoxic effects by danthron, a natural anthraquinone derivative on C6 rat glioma cells through exploring the means of cell death and the effects on mitochondrial function. We found that danthron decreased the percentage of viable C6 cells and induced cell morphological changes in a dose-and time-dependent manner. The morphological and nuclei changes (DAPI staining) in C6 cells were observed using a contrast-microscope and fluorescence microscopy, respectively. The results suggest that cell death of C6 cells which are induced by danthron is closely related to apoptotic death. Danthron decreased the level of mitochondrial membrane potential (ΔΨ(m)), stimulated the release of cytochrome c from mitochondria to cytosol and promoted the levels of caspase-9 and caspase-3, or induced the release of AIF and Endo G from mitochondria. Based on both observations, we suggest that the danthron-provoked apoptotic death of C6 cells is mediated through the mitochondria-dependent pathway. Furthermore, our results also indicated that danthron triggered apoptosis through reactive oxygen species (ROS) production which were increased after 1 h exposure of danthron, which was reversed by the ROS scavenger N-acetyl-L: -cysteine (NAC). As a consequence, danthron-mediated cell death of C6 cells via ROS production, mitochondrial transmembrane potential collapse and releases of cytochrome c, AIF and Endo G. Taken together, danthron was demonstrated to be effective in killing C6 rat glioma cells via the ROS-promoted and mitochondria-dependent apoptotic pathways.}, }
@article {pmid22591656, year = {2012}, author = {Ponte, F and Sousa, R and Fernandes, AP and Gonçalves, C and Barbot, J and Carvalho, F and Porto, B}, title = {Improvement of genetic stability in lymphocytes from Fanconi anemia patients through the combined effect of α-lipoic acid and N-acetylcysteine.}, journal = {Orphanet journal of rare diseases}, volume = {7}, number = {}, pages = {28}, pmid = {22591656}, issn = {1750-1172}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/metabolism ; Cells, Cultured ; Chromosomal Instability/drug effects/genetics ; Fanconi Anemia/genetics/*metabolism ; Female ; Humans ; Lymphocytes/drug effects/*metabolism ; Male ; Oxidative Stress/drug effects/genetics ; Thioctic Acid/*pharmacology ; Young Adult ; }, abstract = {Fanconi Anemia (FA) is a rare genetic disorder, characterized by progressive bone marrow failure and increased predisposition to cancer. Despite being highly heterogeneous, all FA patients are hypersensitive to alkylating agents, in particular to 1,2:3,4-diepoxybutane (DEB), and to oxidative damage. Recent studies point to defective mitochondria in FA cells, which is closely related with increased production of reactive oxygen species (ROS) and concomitant depletion of antioxidant defenses, of which glutathione is a well-known biomarker.The objective of the present work is to evaluate the putative protective effect of α-lipoic acid (α-LA), a mitochondrial protective agent, and N-acetylcysteine (NAC), a direct antioxidant and a known precursor for glutathione synthesis, in spontaneous and DEB-induced chromosome instability (CI) in lymphocyte cultures from FA patients.For that purpose, lymphocyte cultures from 15 FA patients and 24 healthy controls were pre-treated with 20 μM α-LA, 500 μM NAC and α-LA plus NAC at the same concentrations, and some of them were exposed to DEB (0.05 μg/ml). A hundred metaphases per treatment were scored to estimate the relative frequency of spontaneous and DEB-induced chromosome breakage.The obtained results revealed that a cocktail of α-LA and NAC can drastically improve the genetic stability in FA lymphocytes in vitro, decreasing CI by 60% and 80% in cultures from FA patients and FA mosaic/chimera patients, respectively. These results suggest that the studied cocktail can be used as a prophylactic approach to delay progressive clinical symptoms in FA patients caused by CI, which can culminate in the delay of the progressive bone marrow failure and early cancer development.}, }
@article {pmid22587339, year = {2012}, author = {Nagy, A and Steinbrück, A and Gao, J and Doggett, N and Hollingsworth, JA and Iyer, R}, title = {Comprehensive analysis of the effects of CdSe quantum dot size, surface charge, and functionalization on primary human lung cells.}, journal = {ACS nano}, volume = {6}, number = {6}, pages = {4748-4762}, doi = {10.1021/nn204886b}, pmid = {22587339}, issn = {1936-086X}, mesh = {Bronchi/*drug effects ; Cadmium Compounds/*toxicity ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Humans ; Materials Testing ; Particle Size ; *Quantum Dots ; Selenium Compounds/*toxicity ; Static Electricity ; Titanium/*chemistry ; }, abstract = {The growing potential of quantum dots (QDs) in applications as diverse as biomedicine and energy has provoked much dialogue about their conceivable impact on human health and the environment at large. Consequently, there has been an urgent need to understand their interaction with biological systems. Parameters such as size, composition, surface charge, and functionalization can be modified in ways to either enhance biocompatibility or reduce their deleterious effects. In the current study, we simultaneously compared the impact of size, charge, and functionalization alone or in combination on biological responses using primary normal human bronchial epithelial cells. Using a suite of cellular end points and gene expression analysis, we determined the biological impact of each of these properties. Our results suggest that positively charged QDs are significantly more cytotoxic compared to negative QDs. Furthermore, while QDs functionalized with long ligands were found to be more cytotoxic than those functionalized with short ligands, negative QDs functionalized with long ligands also demonstrated size-dependent cytotoxicity. We conclude that QD-elicited cytotoxicity is not a function of a single property but a combination of factors. The mechanism of toxicity was found to be independent of reactive oxygen species formation, as cellular viability could not be rescued in the presence of the antioxidant n-acetyl cysteine. Further exploring these responses at the molecular level, we found that the relatively benign negative QDs increased gene expression of proinflammatory cytokines and those associated with DNA damage, while the highly toxic positive QDs induced changes in genes associated with mitochondrial function. In an attempt to tentatively "rank" the contribution of each property in the observed QD-induced responses, we concluded that QD charge and ligand length, and to a lesser extent, size, are key factors that should be considered when engineering nanomaterials with minimal bioimpact (charge > functionalization > size).}, }
@article {pmid22584350, year = {2012}, author = {Chen, X and Qiao, H and Liu, T and Yang, Z and Xu, L and Xu, Y and Ge, HM and Tan, RX and Li, E}, title = {Inhibition of herpes simplex virus infection by oligomeric stilbenoids through ROS generation.}, journal = {Antiviral research}, volume = {95}, number = {1}, pages = {30-36}, doi = {10.1016/j.antiviral.2012.05.001}, pmid = {22584350}, issn = {1872-9096}, mesh = {Acetylcysteine/metabolism ; Animals ; Antiviral Agents/*pharmacology ; Cell Line ; Free Radical Scavengers/metabolism ; Herpesvirus 1, Human/*drug effects ; Herpesvirus 2, Human/*drug effects ; Humans ; Reactive Oxygen Species/*metabolism ; Stilbenes/*pharmacology ; }, abstract = {Stilbenoids including resveratrol contain the basic structural unit of 1,2-diphenylethylene. Naturally occurring stilbenoids have broad structural features due to oligomerization and modifications and some have demonstrated potent biological activities. In an effort to identify bioactive stilbenoids, we screened a group of dimeric and oligomeric stilbenoids against HSV-1 and HSV-2 infection. Several trimeric and tetrameric derivatives showed anti-herpetic activity at single digit micromolar concentrations. HSV-1 and HSV-2 replication requires for NF-κB and MAPK activation. The compounds showed no inhibitory activity against NF-κB and Erk/MAPK activation, instead those compounds promoted rapid and transient release of reactive oxygen species (ROS). Addition of N-acetylcysteine (NAC), a scavenger of ROS, reversed the inhibitory effect of those compounds against HSV replication. In addition to the identification of resveratrol derivatives with potent anti-HSV activity, our results uncover a mechanism of polyphenol-mediated anti-HSV response, linking anti-herpetic activity of oligomeric stilbenoids to innate immunity.}, }
@article {pmid22583868, year = {2012}, author = {Radnai, B and Antus, C and Racz, B and Engelmann, P and Priber, JK and Tucsek, Z and Veres, B and Turi, Z and Lorand, T and Sumegi, B and Gallyas, F}, title = {Protective effect of the poly(ADP-ribose) polymerase inhibitor PJ34 on mitochondrial depolarization-mediated cell death in hepatocellular carcinoma cells involves attenuation of c-Jun N-terminal kinase-2 and protein kinase B/Akt activation.}, journal = {Molecular cancer}, volume = {11}, number = {}, pages = {34}, pmid = {22583868}, issn = {1476-4598}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects/genetics ; Carcinoma, Hepatocellular/genetics/*metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/genetics/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/*metabolism ; Mitogen-Activated Protein Kinase 9/*metabolism ; Necrosis ; Phenanthrenes/*pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors ; Proto-Oncogene Proteins c-akt/*metabolism ; RNA Interference ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND: 2,4-Dimethoxyphenyl-E-4-arylidene-3-isochromanone (IK11) was previously described to induce apoptotic death of A431 tumor cells. In this report, we investigated the molecular action of IK11 in the HepG2 human hepatocellular carcinoma cell line to increase our knowledge of the role of poly (ADP-ribose)-polymerase (PARP), protein kinase B/Akt and mitogen activated protein kinase (MAPK) activation in the survival and death of tumor cells and to highlight the possible role of PARP-inhibitors in co-treatments with different cytotoxic agents in cancer therapy.<br><br>RESULTS: We found that sublethal concentrations of IK11 prevented proliferation, migration and entry of the cells into their G2 phase. At higher concentrations, IK11 induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, activation of c-Jun N-terminal kinase 2 (JNK2), and substantial loss of HepG2 cells. ROS production appeared marginal in mediating the cytotoxicity of IK11 since N-acetyl cysteine was unable to prevent it. However, the PARP inhibitor PJ34, although not a ROS scavenger, strongly inhibited both IK11-induced ROS production and cell death. JNK2 activation seemed to be a major mediator of the effect of IK11 since inhibition of JNK resulted in a substantial cytoprotection while inhibitors of the other kinases failed to do so. Inhibition of Akt slightly diminished the effect of IK11, while the JNK and Akt inhibitor and ROS scavenger trans-resveratrol completely protected against it.<br><br>CONCLUSIONS: These results indicate significant involvement of PARP, a marginal role of ROS and a pro-apoptotic role of Akt in this system, and raise attention to a novel mechanism that should be considered when cancer therapy is augmented with PARP-inhibition, namely the cytoprotection by inhibition of JNK2.}, }
@article {pmid22580211, year = {2012}, author = {Odziomek, M and Sosnowski, TR and Gradoń, L}, title = {Conception, preparation and properties of functional carrier particles for pulmonary drug delivery.}, journal = {International journal of pharmaceutics}, volume = {433}, number = {1-2}, pages = {51-59}, doi = {10.1016/j.ijpharm.2012.04.067}, pmid = {22580211}, issn = {1873-3476}, mesh = {Acetylcysteine/*administration &amp; dosage/chemistry/pharmacokinetics ; Administration, Inhalation ; Aerosols ; Dextrans/*chemistry ; Drug Carriers/chemistry ; *Drug Delivery Systems ; Drug Stability ; Drug Storage ; Dry Powder Inhalers ; Expectorants/administration &amp; dosage/chemistry/pharmacokinetics ; Humidity ; Mannitol/*chemistry ; Microscopy, Electron, Scanning ; Particle Size ; Phase Transition ; Powders ; Temperature ; Thermodynamics ; Tissue Distribution ; }, abstract = {BACKGROUND: The effectiveness of aerosol therapy is significantly reduced by the mucus layer covering the airways of the tracheobronchial tree. According to the present concept, drug particles are delivered to the lung together with the functional carrier particle that facilitates both the drug transport into the lungs and the penetration of deposited particles through the mucus. The approach of manufacturing multi-component powders with mucoactive compounds and anti-asthmatic medicines (DSCG) bound together in a single particle is additionally considered.<br><br>METHODS: Powders were produced with the spray-drying technique from aqueous precursor solutions containing pure low molecular weight dextran, pure mannitol and dextran/mannitol-N-acetyl cysteine (NAC) mixtures (4:1 and 1:1). NAC has been selected for this purpose as a compound, which is known to be mucolytic. Dextran and mannitol are potentially applicable in the field of inhalation drug delivery. They have been used as stabilizers of functional carrier particles. Powders were characterized for their yield and physicochemical properties including: morphology (SEM), moisture content and thermal properties (DSC). Aerosol performance was determined with NGI impactor after standardized aerosolization of the produced powders in a commercial DPI.<br><br>RESULTS: Particle size distributions of dextran-NAC powders were characterized by high fine particle fraction (45-62%), which assures good particle deposition in the lower airways. The thermodynamic properties of the powders based on the temperature of the glass transition T(g) (50-63 &#xb0;C) suggest the required stability during storage at moderate humidity.<br><br>CONCLUSIONS: Preliminary examination of the required properties of these particles confirms their potential as functional carriers for pulmonary drug delivery.}, }
@article {pmid22578287, year = {2012}, author = {Choi, YH and Park, HS}, title = {Apoptosis induction of U937 human leukemia cells by diallyl trisulfide induces through generation of reactive oxygen species.}, journal = {Journal of biomedical science}, volume = {19}, number = {1}, pages = {50}, pmid = {22578287}, issn = {1423-0127}, mesh = {Acetylcysteine/pharmacology ; Allyl Compounds/*pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Reactive Oxygen Species/*metabolism ; Sulfides/*pharmacology ; U937 Cells ; }, abstract = {BACKGROUND: Diallyl trisulfide (DATS) is one of the major constituents in garlic oil and has demonstrated various pharmacological activities, including antimicrobial, antihyperlipidemic, antithrombotic, and anticancer effects. However, the mechanisms of antiproliferative activity in leukemia cells are not fully understood. In this study, the apoptotic effects of DATS were investigated in human leukemia cells.<br><br>RESULTS: Results of this study indicated that treatment with DATS resulted in significantly inhibited leukemia cell growth in a concentration- and time-dependent manner by induction of apoptosis. In U937 cells, DATS-induced apoptosis was correlated with down-regulation of Bcl-2, XIAP, and cIAP-1 protein levels, cleavage of Bid proteins, activation of caspases, and collapse of mitochondrial membrane potential. The data further demonstrated that DATS increased intracellular reactive oxygen species (ROS) generation, which was attenuated by pretreatment with antioxidant N-acetyl-l-cysteine (NAC), a scavenger of ROS. In addition, administration of NAC resulted in significant inhibition of DATS-induced apoptosis by inhibiting activation of caspases.<br><br>CONCLUSIONS: The present study reveals that the cytotoxicity caused by DATS is mediated by generation of ROS and subsequent activation of the ROS-dependent caspase pathway in U937 leukemia cells.}, }
@article {pmid22570238, year = {2012}, author = {Jia, P and Xu, YJ and Zhang, ZL and Li, K and Li, B and Zhang, W and Yang, H}, title = {Ferric ion could facilitate osteoclast differentiation and bone resorption through the production of reactive oxygen species.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {30}, number = {11}, pages = {1843-1852}, doi = {10.1002/jor.22133}, pmid = {22570238}, issn = {1554-527X}, mesh = {Acetylcysteine ; Animals ; Bone Resorption/*metabolism ; *Cell Differentiation ; Cell Line ; Ferric Compounds ; Glutathione/metabolism ; Iron/*metabolism ; Male ; Mice ; Mice, Inbred ICR ; Osteoclasts/*cytology ; Oxidative Stress ; Quaternary Ammonium Compounds ; RANK Ligand/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Iron overload is widely regarded as a risk factor for osteoporosis. It has been demonstrated that iron can inhibit osteoblast differentiation. However, the effects of iron on osteoclast differentiation and bone resorption remain controversial. In this study, we found that ferric ion promoted Receptor Activator of Nuclear Factor κ B Ligand (RANKL)-induced osteoclast (OC) formation in both RAW264.7 cells and bone marrow-derived macrophages (BMMs), and this effect was accompanied by elevated levels of reactive oxygen species (ROS) and oxidative stress. Moreover, this effect was attenuated by the administration of antioxidant N-acetyl-L-cysteine (NAC). Therefore, we conclude that ferric ion can promote osteoclast differentiation and bone resorption through the production of ROS.}, }
@article {pmid22568348, year = {2012}, author = {Tominaga, A and Toyoguchi, T and Takahashi, N and Hosoya, J and Suzuki, T and Shiraishi, T and Iseki, K}, title = {[Study of the serum concentrations of acetaminophen overdose].}, journal = {Chudoku kenkyu : Chudoku Kenkyukai jun kikanshi = The Japanese journal of toxicology}, volume = {25}, number = {1}, pages = {59-64}, pmid = {22568348}, issn = {0914-3777}, mesh = {Acetaminophen/adverse effects/*blood/poisoning ; Acetylcysteine/administration &amp; dosage ; Adolescent ; Adult ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/*blood/poisoning ; Female ; Humans ; Liver Failure, Acute/chemically induced/prevention &amp; control ; Male ; Middle Aged ; *Prescription Drug Misuse ; Young Adult ; }, abstract = {Acetaminophen (APAP) is a commonly used nonsteroidal analgesic because it is considered safe. However, APAP is a major cause of acute poisoning because of its easy availability. APAP overdose causes hepatic failure. A previous study reported a case of death occurring 3-4 days after APAP overdose. Serum APAP level is an index for administration of N-acetyl-L-cysteine (NAC). We investigated cases of APAP overdose to determine the correlation between serum APAP level and estimated APAP dosage, NAC medication, hepatic failure, etc. In one case, we found that the use of estimated APAP dosage alone led to inappropriate NAC medication. Moreover, there were cases in which serum APAP level increased 4 hr after APAP overdose. Repeated cases of APAP overdose suggested that the presence of NAC medication caused a difference in liver function test values.}, }
@article {pmid22562160, year = {2012}, author = {Cort, A and Timur, M and Dursun, E and Kucuksayan, E and Aslan, M and Ozben, T}, title = {Effects of N-acetylcystein on bleomycin-induced apoptosis in malignant testicular germ cell tumors.}, journal = {Journal of physiology and biochemistry}, volume = {68}, number = {4}, pages = {555-562}, pmid = {22562160}, issn = {1877-8755}, mesh = {Acetylcysteine/*pharmacology ; Antibiotics, Antineoplastic/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Bleomycin/*pharmacology ; Caspases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Lethal Dose 50 ; Male ; Neoplasms, Germ Cell and Embryonal ; Oxidants/pharmacology ; Oxidative Stress ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Testicular Neoplasms ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Oxidative stress has been shown to induce apoptosis in cancer cells. Therefore, one might suspect that antioxidants may inhibit reactive oxygen species (ROS) and prevent apoptosis of cancer cells. No study has been carried out so far to elucidate the effects of N-acetylcysteine (NAC) on bleomycin-induced apoptosis in human testicular cancer (NCCIT) cells. We investigated the molecular mechanisms of apoptosis induced by bleomycin and the effect of NAC in NCCIT cells. We compared the effects of bleomycin on apoptosis with H(2)O(2) which directly produces ROS. Strong antioxidant NAC was evaluated alone and in combination with bleomycin or H(2)O(2) in germ cell tumor-derived NCCIT cell line (embryonal carcinoma, being the nonseminomatous stem cell component). We determined the cytotoxic effect of bleomycin and H(2)O(2) on NCCIT cells and measured apoptosis markers such as caspase-3, caspase-8, and caspase-9 activities and Bcl-2, Bax, and cytochrome c (Cyt-c) levels in NCCIT cells incubated with bleomycin, H(2)O(2), and/or NAC. We found half of the lethal dose (LD(50)) of bleomycin on NCCIT cell viability as 120 μg/ml after incubation for 72 h. Incubation with bleomycin (LD(50)) induced increases in caspase-3, caspase-8, and caspase-9 activities and Cyt-c and Bax protein levels and a decrease in Bcl-2 level. Co-incubation of NCCIT cells with bleomycin and 10 mM NAC abolished bleomycin-induced increases in caspase-3 and caspase-9 activities, Bax, and Cyt-c levels and bleomycin-induced decrease in Bcl-2 level. Our results indicate that bleomycin induces apoptosis in NICCT cells and that NAC diminishes bleomycin-induced apoptosis via inhibiting the mitochondrial pathway. We conclude that NAC has negative effects on bleomycin-induced apoptosis in NICCT cells and causes resistance to apoptosis, which is not a desirable effect in the fight against cancer.}, }
@article {pmid22561002, year = {2012}, author = {Hung, WY and Huang, KH and Wu, CW and Chi, CW and Kao, HL and Li, AF and Yin, PH and Lee, HC}, title = {Mitochondrial dysfunction promotes cell migration via reactive oxygen species-enhanced β5-integrin expression in human gastric cancer SC-M1 cells.}, journal = {Biochimica et biophysica acta}, volume = {1820}, number = {7}, pages = {1102-1110}, doi = {10.1016/j.bbagen.2012.04.016}, pmid = {22561002}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Anti-Bacterial Agents/pharmacology ; Antimycin A/pharmacology ; Blotting, Western ; Cell Adhesion/drug effects ; Cell Membrane/metabolism ; *Cell Movement ; Free Radical Scavengers/pharmacology ; Humans ; Immunoenzyme Techniques ; Integrin beta Chains/*metabolism ; Mitochondria/*metabolism/*pathology ; Neoplasm Invasiveness ; Oxygen Consumption/drug effects ; Reactive Oxygen Species/*metabolism ; Stomach Neoplasms/drug therapy/*metabolism/*pathology ; Tumor Cells, Cultured ; Vitronectin/pharmacology ; }, abstract = {BACKGROUND: Mitochondrial dysfunction has been shown to promote cancer cell migration. However, molecular mechanism by which mitochondrial dysfunction enhances gastric cancer (GC) cell migration remains unclear.<br><br>METHODS: Mitochondria specific inhibitors, oligomycin and antimycin A, were used to induce mitochondrial dysfunction and to enhance cell migration of human gastric cancer SC-M1 cells. Antioxidant N-acetylcysteine (NAC) was used for evaluating the effect of reactive oxygen species (ROS). Protein expressions of epithelial-to-mesenchymal transition (EMT) markers and the cell-extracellular matrix (ECM) adhesion molecules, the integrin family, were analyzed. A migratory subpopulation of SC-M1 cells (SC-M1-3rd) was selected using a transwell assay for examining the association of mitochondrial bioenergetic function, intracellular ROS content and &#x3b2;5-integrin expression. Clinicopathologic characteristics of &#x3b2;5-integrin expression were analyzed in GC specimens by immunohistochemical staining.<br><br>RESULTS: Treatments with mitochondrial inhibitors elevated mitochondria-generated ROS and cell migration of SC-M1 cells. The protein expression of &#x3b2;5-integrin and cell surface expression of &#x3b1;v&#x3b2;5-integrin were upregulated, and which were suppressed by NAC. Pretreatments with NAC and anti-&#x3b1;v&#x3b2;5-integrin neutralizing antibody respectively prevented the mitochondrial dysfunction-induced cell migration. The selected migratory SC-M1-3rd cells showed impaired mitochondrial function, higher mitochondria-generated ROS, and increased &#x3b2;5-integrin expression. The migration ability was also repressed by anti-&#x3b1;v&#x3b2;5-integrin neutralizing antibody. In clinical specimens, GCs with higher &#x3b2;5-integrin protein expression had more aggressive behavior. In conclusion, mitochondrial dysfunction may lead to GC progression by enhancing migration through mitochondria-generated ROS mediated &#x3b2;5-integrin expression.<br><br>GENERAL SIGNIFICANCE: These results support the role of mitochondrial dysfunction in GC progression.}, }
@article {pmid22559321, year = {2012}, author = {Wan, R and Mo, Y and Feng, L and Chien, S and Tollerud, DJ and Zhang, Q}, title = {DNA damage caused by metal nanoparticles: involvement of oxidative stress and activation of ATM.}, journal = {Chemical research in toxicology}, volume = {25}, number = {7}, pages = {1402-1411}, pmid = {22559321}, issn = {1520-5010}, support = {P30 ES014443/ES/NIEHS NIH HHS/United States ; T32 ES011564/ES/NIEHS NIH HHS/United States ; T32-ES011564/ES/NIEHS NIH HHS/United States ; ES01443/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Ataxia Telangiectasia Mutated Proteins ; Catalase/metabolism ; Cell Cycle Proteins/antagonists &amp; inhibitors/*metabolism ; Cell Line, Tumor ; Cobalt/chemistry ; DNA/*metabolism ; DNA Damage/*drug effects ; DNA-Binding Proteins/antagonists &amp; inhibitors/*metabolism ; Histones/metabolism ; Humans ; Metal Nanoparticles/chemistry/*toxicity ; Morpholines/pharmacology ; Oxidative Stress/*drug effects ; Phosphorylation ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/*metabolism ; Pyrones/pharmacology ; Rad51 Recombinase/metabolism ; Reactive Oxygen Species/metabolism ; Titanium/chemistry ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Nanotechnology is a fast growing emerging field, the benefits of which are widely publicized. Our current knowledge of the health effects of metal nanoparticles such as nanosized cobalt (Nano-Co) and titanium dioxide (Nano-TiO(2)) is limited but suggests that metal nanoparticles may exert more adverse pulmonary effects as compared with standard-sized particles. To investigate metal nanoparticle-induced genotoxic effects and the potential underlying mechanisms, human lung epithelial A549 cells were exposed to Nano-Co and Nano-TiO(2). Our results showed that exposure of A549 cells to Nano-Co caused reactive oxygen species (ROS) generation that was abolished by pretreatment of cells with ROS inhibitors or scavengers, such as catalase and N-acetyl-L(+)-cysteine (NAC). However, exposure of A549 cells to Nano-TiO(2) did not cause ROS generation. Nano-Co caused DNA damage in A549 cells, which was reflected by an increase in length, width, and DNA content of the comet tail by the Comet assay. Exposure of A549 cells to Nano-Co also caused a dose- and a time-response increased expression of phosphorylated histone H2AX (γ-H2AX), Rad51, and phosphorylated p53. These effects were significantly attenuated when A549 cells were pretreated with catalase or NAC. Nano-TiO(2) did not show these effects. These results suggest that oxidative stress may be involved in Nano-Co-induced DNA damage. To further investigate the pathways involved in the Nano-Co-induced DNA damage, we measured the phosphorylation of ataxia telangiectasia mutant (ATM). Our results showed that phosphorylation of ATM was increased when A549 cells were exposed to Nano-Co, and this effect was attenuated when cells were pretreated with catalase or NAC. Pretreatment of A549 cells with an ATM specific inhibitor, KU55933, significantly abolished Nano-Co-induced DNA damage. Furthermore, pretreatment of A549 cells with ROS scavengers, such as catalase and NAC, significantly abolished Nano-Co-induced increased expression of phosphorylated ATM. Taken together, oxidative stress and ATM activation are involved in Nano-Co-induced DNA damage. These findings have important implications for understanding the potential health effects of metal nanoparticle exposure.}, }
@article {pmid22558435, year = {2012}, author = {Raza, H and John, A}, title = {Implications of altered glutathione metabolism in aspirin-induced oxidative stress and mitochondrial dysfunction in HepG2 cells.}, journal = {PloS one}, volume = {7}, number = {4}, pages = {e36325}, pmid = {22558435}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Aconitate Hydratase/metabolism ; Adenosine Triphosphate/metabolism ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Apoptosis/drug effects ; Aspirin/*pharmacology ; Biomarkers/metabolism ; Buthionine Sulfoximine/pharmacology ; Caspase 3/metabolism ; Cell Respiration/drug effects ; DNA Fragmentation/drug effects ; Enzyme Activation/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione/*metabolism ; Glutathione Transferase/metabolism ; Hep G2 Cells ; Humans ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/*metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {We have previously reported that acetylsalicylic acid (aspirin, ASA) induces cell cycle arrest, oxidative stress and mitochondrial dysfunction in HepG2 cells. In the present study, we have further elucidated that altered glutathione (GSH)-redox metabolism in HepG2 cells play a critical role in ASA-induced cytotoxicity. Using selected doses and time point for ASA toxicity, we have demonstrated that when GSH synthesis is inhibited in HepG2 cells by buthionine sulfoximine (BSO), prior to ASA treatment, cytotoxicity of the drug is augmented. On the other hand, when GSH-depleted cells were treated with N-acetyl cysteine (NAC), cytotoxicity/apoptosis caused by ASA was attenuated with a significant recovery in oxidative stress, GSH homeostasis, DNA fragmentation and some of the mitochondrial functions. NAC treatment, however, had no significant effects on the drug-induced inhibition of mitochondrial aconitase activity and ATP synthesis in GSH-depleted cells. Our results have confirmed that aspirin increases apoptosis by increased reactive oxygen species production, loss of mitochondrial membrane potential and inhibition of mitochondrial respiratory functions. These effects were further amplified when GSH-depleted cells were treated with ASA. We have also shown that some of the effects of aspirin might be associated with reduced GSH homeostasis, as treatment of cells with NAC attenuated the effects of BSO and aspirin. Our results strongly suggest that GSH dependent redox homeostasis in HepG2 cells is critical in preserving mitochondrial functions and preventing oxidative stress associated complications caused by aspirin treatment.}, }
@article {pmid22556393, year = {2012}, author = {Chen, F and Lewis, W and Hollander, JM and Baseler, W and Finkel, MS}, title = {N-acetylcysteine reverses cardiac myocyte dysfunction in HIV-Tat proteinopathy.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {113}, number = {1}, pages = {105-113}, doi = {10.1152/japplphysiol.00068.2012}, pmid = {22556393}, issn = {1522-1601}, mesh = {Acetylcysteine/*therapeutic use ; Adenosine Triphosphate/analysis ; Animals ; Antiviral Agents/*therapeutic use ; Calcium/pharmacology ; Cardiomyopathies/*drug therapy/metabolism/*virology ; Catalase/analysis ; Female ; Gene Products, tat/*metabolism ; Glutathione/analysis ; Glutathione Peroxidase/analysis ; HIV Infections/*complications/metabolism ; Hydrogen Peroxide/analysis ; Male ; Mice ; Mice, Transgenic ; Myocardial Contraction/drug effects/physiology ; Myocytes, Cardiac/*drug effects/metabolism ; Oxidative Stress/drug effects ; Glutathione Peroxidase GPX1 ; }, abstract = {HIV cardiomyopathy remains highly prevalent among the estimated 33 million HIV-infected individuals worldwide. This is particularly true in developing countries. Potential mechanisms responsible for myocardial dysfunction following HIV infection include direct effects of HIV proteins. We have previously reported that cardiac myocyte-specific expression of HIV-Tat (Tat) results in a murine cardiomyopathy model. We now report that Tat exhibits decreased myocardial ATP [wild type (WT) vs. Tat transgenic (TG), P < 0.01] and myocyte GSH levels (WT vs. TG, P < 0.01), decreased GSH/GSSG ratio (WT vs. TG, P < 0.01), increased H(2)O(2) levels (WT vs. TG, P < 0.05), and increased catalase (TG vs. WT, P < 0.05) and GPX1 (glutathione peroxidase 1) activities (WT vs. TG, P < 0.05), blunted cardiac myocyte positive inotropy (% peak shortening, WT vs. TG, P < 0.01; +dl/dt, WT vs. TG, P < 0.01) and negative inotropy (-dl/dt, WT vs. TG, P < 0.01), and blunted inotropic responses to Ca(2+) (P < 0.01, for each) and shortened anatomical and functional survival in vitro (P < 0.01). The sulfhydryl donor, N-acetylcysteine (NAC; 10(-4) M), completely reversed both the positive and negative inotropic defects in Tat; increased GSH (P < 0.01) and GSH/GSSG (P < 0.01); reversed H(2)O(2) level (P < 0.05) and GPX1 activity (P < 0.05); and normalized the blunted inotropic response to Ca(2+) (P < 0.01). NAC (10(-7)) M normalized duration of contractile function from <40 min to >120 min (P < 0.01), with no effect on GSH and GSH/GSSG. NAC (10(-4) M) reverses cardiac myocyte dysfunction and markers of oxidative stress. NAC (10(-7) M) enhances myocyte function independent of changes in glutathione. Elucidating the molecular mechanisms involved in the GSH-dependent and GSH-independent salutary effects of NAC should identify novel therapeutic targets for myocardial proteinopathies recently appreciated in human cardiomyopathies.}, }
@article {pmid22554995, year = {2012}, author = {Kim, JY and Cho, TJ and Woo, BH and Choi, KU and Lee, CH and Ryu, MH and Park, HR}, title = {Curcumin-induced autophagy contributes to the decreased survival of oral cancer cells.}, journal = {Archives of oral biology}, volume = {57}, number = {8}, pages = {1018-1025}, doi = {10.1016/j.archoralbio.2012.04.005}, pmid = {22554995}, issn = {1879-1506}, mesh = {Acetylcysteine/pharmacology ; Acridine Orange ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Blotting, Western ; Cadaverine/analogs &amp; derivatives ; Carcinoma, Squamous Cell/*drug therapy/pathology ; Cell Proliferation/drug effects ; Curcumin/*pharmacology ; Flow Cytometry ; Humans ; Microtubule-Associated Proteins/metabolism ; Mouth Neoplasms/*drug therapy/pathology ; Reactive Oxygen Species/metabolism ; Staining and Labeling ; Tumor Cells, Cultured ; Vacuoles/drug effects ; }, abstract = {Curcumin, a major active component of turmeric Curcuma longa, has been shown to have inhibitory effects on cancers. In vitro studies suggest that curcumin inhibits cancer cell growth by activating apoptosis, but the mechanism underlying the anticancer effects of curcumin is unclear. Recently, it has been suggested that autophagy may play an important role in cancer therapy. However, little data are available regarding the role of autophagy in oral cancers. In this study, we have shown that curcumin has anticancer activity against oral squamous cell carcinoma (OSCC). Induction of autophagy, marked by autophagic vacuoles formation, was detected by acridine orange staining and monodansylcadaverine (MDC) dye after exposure to curcumin. Conversion of LC3-I to LC3-II, a marker of active autophagosome formation, was also detectable by Western blot following curcumin treatment. We have also observed that curcumin induced reactive oxygen species (ROS) production and autophagic vacuoles formation by curcumin was almost completely blocked in the presence of N-acetylcystein (NAC), an antioxidant. Rescue experiments using an autophagy inhibitor suppressed curcumin-induced cell death in OSCC, confirming that autophagy acts as a pro-death signal. Furthermore, curcumin shows anticancer activity against OSCC via both autophagy and apoptosis. These findings suggest that curcumin may potentially contribute to oral cancer treatment and provide useful information for the development of a new therapeutic agent.}, }
@article {pmid22552812, year = {2012}, author = {Gao, L and Williams, JL}, title = {Nitric oxide-donating aspirin induces G2/M phase cell cycle arrest in human cancer cells by regulating phase transition proteins.}, journal = {International journal of oncology}, volume = {41}, number = {1}, pages = {325-330}, pmid = {22552812}, issn = {1791-2423}, support = {K01 CA106604/CA/NCI NIH HHS/United States ; R01 CA140487/CA/NCI NIH HHS/United States ; K01CA106604/CA/NCI NIH HHS/United States ; R01CA140487/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Aspirin/*analogs &amp; derivatives/pharmacology ; Caspase 3/metabolism ; Cell Cycle Proteins/*metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; G2 Phase Cell Cycle Checkpoints/*drug effects ; Humans ; Inhibitory Concentration 50 ; Nitric Oxide Donors/*pharmacology ; Oxidative Stress/drug effects ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {NO-aspirin (NO-ASA), consisting of aspirin and a nitric oxide-releasing group, is safer than aspirin and effective in colon cancer prevention. Here, we examined the mechanism of action of NO-ASA by focusing primarily on its effects on the cell cycle. NO-ASA reduced the growth of several cell lines from colon, pancreas, skin, cervix and breast cancer much more potently than aspirin, with 24-h IC(50) values of 133-268 µM, while those of ASA were >1,000 µM. NO-ASA elevated the intracellular levels of reactive oxygen species, generating a state of oxidative stress. In all cell lines examined, NO-ASA induced cell cycle arrest in the G(2)/M phase transition accompanied by altered expression of G(2)/M transition-related proteins. In SW480 colon cancer cells NO-ASA modulated proteins controlling this transition. Thus, it markedly increased the levels of cyclin B1, decreased the expression of cyclin D1 and Cdc25C, and increased the Thr14/Tyr15-phosphorylation of Cdk1 while leaving unchanged its protein levels. These changes, including the G2/M arrest, were prevented by pretreating the cells with the anti-oxidant N-acetyl-cysteine, indicating that redox signaling is likely responsible for the cell cycle changes, a conclusion consistent with the known redox regulation of these proteins. Collectively, these results confirm the profound cytokinetic effect of NO-ASA and provide strong evidence that it regulates cell cycle transitions through its ability to induce oxidative stress, which activates redox signaling in the target cell.}, }
@article {pmid22552773, year = {2012}, author = {Lu, Y and Zhang, XH and Cederbaum, AI}, title = {Ethanol induction of CYP2A5: role of CYP2E1-ROS-Nrf2 pathway.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {128}, number = {2}, pages = {427-438}, pmid = {22552773}, issn = {1096-0929}, support = {R21 AA020877/AA/NIAAA NIH HHS/United States ; AA-018790/AA/NIAAA NIH HHS/United States ; R01 AA017425/AA/NIAAA NIH HHS/United States ; R01 AA018790/AA/NIAAA NIH HHS/United States ; R01 AA-017425/AA/NIAAA NIH HHS/United States ; P20-AA017067/AA/NIAAA NIH HHS/United States ; P20 AA017067/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Aryl Hydrocarbon Hydroxylases/*biosynthesis ; Cytochrome P-450 CYP2A6 ; Cytochrome P-450 CYP2E1/*metabolism ; Cytochrome P450 Family 2 ; Enzyme Induction/*drug effects ; Ethanol/*toxicity ; Mice ; Mice, Knockout ; Microsomes, Liver/drug effects/enzymology/metabolism ; NF-E2-Related Factor 2/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Chronic ethanol consumption was previously shown to induce CYP2A5 in mice, and this induction of CYP2A5 by ethanol was CYP2E1 dependent. In this study, the mechanisms of CYP2E1-dependent ethanol induction of CYP2A5 were investigated. CYP2E1 was induced by chronic ethanol consumption to the same degree in wild-type (WT) mice and CYP2A5 knockout (Cyp2a5 (-/-)) mice, suggesting that unlike the CYP2E1-dependent ethanol induction of CYP2A5, ethanol induction of CYP2E1 is not CYP2A5 dependent. Microsomal ethanol oxidation was about 25% lower in Cyp2a5 (-/-) mice compared with that in WT mice, suggesting that CYP2A5 can oxidize ethanol although to a lesser extent than CYP2E1 does. CYP2A5 was induced by short-term ethanol consumption in human CYP2E1 transgenic knockin (Cyp2e1 (-/-) KI) mice but not in CYP2E1 knockout (Cyp2e1 (-/-)) mice. The redox-sensitive transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) was also induced by acute ethanol in Cyp2e1 (-/-) KI mice but not in Cyp2e1 (-/-) mice. Ethanol induction of CYP2A5 in Nrf2 knockout (Nrf2 (-/-)) mice was lower compared with that in WT mice, whereas CYP2E1 induction by ethanol was comparable in WT and Nrf2 (-/-) mice. Antioxidants (N-acetyl-cysteine and vitamin C), which blocked oxidative stress induced by chronic ethanol in WT mice and acute ethanol in Cyp2e1 (-/-) KI mice, also blunted the induction of CYP2A5 and Nrf2 by ethanol but not the induction of CYP2E1 by ethanol. These results suggest that oxidative stress induced by ethanol via induction of CYP2E1 upregulates Nrf2 activity, which in turn regulates ethanol induction of CYP2A5. Results obtained from primary hepatocytes, mice gavaged with binge ethanol or fed chronic ethanol, show that Nrf2-regulated ethanol induction of CYP2A5 protects against ethanol-induced steatosis.}, }
@article {pmid22551149, year = {2012}, author = {Hornick, JR and Vangveravong, S and Spitzer, D and Abate, C and Berardi, F and Goedegebuure, P and Mach, RH and Hawkins, WG}, title = {Lysosomal membrane permeabilization is an early event in Sigma-2 receptor ligand mediated cell death in pancreatic cancer.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {31}, number = {1}, pages = {41}, pmid = {22551149}, issn = {1756-9966}, support = {UL1 TR000448/TR/NCATS NIH HHS/United States ; 5T32CA009621-22/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/pharmacokinetics/*pharmacology ; Apoptosis/drug effects/physiology ; Caspase 3/metabolism ; Cell Death/drug effects/physiology ; Cell Line, Tumor ; Cell Membrane Permeability ; Cell Survival/drug effects/physiology ; Female ; Humans ; Ligands ; Lysosomes/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Microscopy, Confocal ; Pancreatic Neoplasms/*drug therapy/*metabolism/pathology ; Reactive Oxygen Species/metabolism ; Receptors, sigma/genetics/*metabolism ; }, abstract = {BACKGROUND: Sigma-2 receptor ligands have been studied for treatment of pancreatic cancer because they are preferentially internalized by proliferating cells and induce apoptosis. This mechanism of apoptosis is poorly understood, with varying reports of caspase-3 dependence. We evaluated multiple sigma-2 receptor ligands in this study, each shown to decrease tumor burden in preclinical models of human pancreatic cancer.<br><br>RESULTS: Fluorescently labeled sigma-2 receptor ligands of two classes (derivatives of SW43 and PB282) localize to cell membrane components in Bxpc3 and Aspc1 pancreatic cancer cells and accumulate in lysosomes. We found that interactions in the lysosome are critical for cell death following sigma-2 ligand treatment because selective inhibition of a protective lysosomal membrane glycoprotein, LAMP1, with shRNA greatly reduced the viability of cells following treatment. Sigma-2 ligands induced lysosomal membrane permeabilization (LMP) and protease translocation triggering downstream effectors of apoptosis. Subsequently, cellular oxidative stress was greatly increased following treatment with SW43, and the hydrophilic antioxidant N-acetylcysteine (NAC) gave greater protection against this than a lipophilic antioxidant, &#x3b1;-tocopherol (&#x3b1;-toco). Conversely, PB282-mediated cytotoxicity relied less on cellular oxidation, even though &#x3b1;-toco did provide protection from this ligand. In addition, we found that caspase-3 induction was not as significantly inhibited by cathepsin inhibitors as by antioxidants. Both NAC and &#x3b1;-toco protected against caspase-3 induction following PB282 treatment, while only NAC offered protection following SW43 treatment. The caspase-3 inhibitor DEVD-FMK offered significant protection from PB282, but not SW43.<br><br>CONCLUSIONS: Sigma-2 ligand SW43 commits pancreatic cancer cells to death by a caspase-independent process involving LMP and oxidative stress which is protected from by NAC. PB282 however undergoes a caspase-dependent death following LMP protected by DEVD-FMK and &#x3b1;-toco, which is also known to stabilize the mitochondrial membrane during apoptotic stimuli. These differences in mechanism are likely dependent on the structural class of the compounds versus the inherent sigma-2 binding affinity. As resistance of pancreatic cancers to specific apoptotic stimuli from chemotherapy is better appreciated, and patient-tailored treatments become more available, ligands with high sigma-2 receptor affinity should be chosen based on sensitivities to apoptotic pathways.}, }
@article {pmid22549432, year = {2012}, author = {Lai, ZW and Hanczko, R and Bonilla, E and Caza, TN and Clair, B and Bartos, A and Miklossy, G and Jimah, J and Doherty, E and Tily, H and Francis, L and Garcia, R and Dawood, M and Yu, J and Ramos, I and Coman, I and Faraone, SV and Phillips, PE and Perl, A}, title = {N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial.}, journal = {Arthritis and rheumatism}, volume = {64}, number = {9}, pages = {2937-2946}, pmid = {22549432}, issn = {1529-0131}, support = {R01 AI072648-03/AI/NIAID NIH HHS/United States ; R01 AT004332/AT/NCCIH NIH HHS/United States ; R01 AT004332-03/AT/NCCIH NIH HHS/United States ; AT-004332/AT/NCCIH NIH HHS/United States ; R01 AT004332-02/AT/NCCIH NIH HHS/United States ; R01 AI072648-05/AI/NIAID NIH HHS/United States ; R01 AI072648-02/AI/NIAID NIH HHS/United States ; R01 AI072648/AI/NIAID NIH HHS/United States ; R01 AI072648-04/AI/NIAID NIH HHS/United States ; AI-072648/AI/NIAID NIH HHS/United States ; R01 AT004332-01A1/AT/NCCIH NIH HHS/United States ; U01 AR076092/AR/NIAMS NIH HHS/United States ; R01 AT004332-04/AT/NCCIH NIH HHS/United States ; R01 AI072648-01A2/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/pharmacology/*therapeutic use ; Adult ; Double-Blind Method ; Female ; Free Radical Scavengers/adverse effects/pharmacology/*therapeutic use ; Humans ; Lupus Erythematosus, Systemic/*drug therapy/metabolism ; Male ; Membrane Potential, Mitochondrial/drug effects ; Middle Aged ; Pilot Projects ; Placebos ; Severity of Illness Index ; T-Lymphocytes/*drug effects/metabolism ; TOR Serine-Threonine Kinases/*metabolism ; Treatment Outcome ; }, abstract = {OBJECTIVE: Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double-blind, placebo-controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N-acetylcysteine (NAC).<br><br>METHODS: A total of 36 SLE patients received either daily placebo or 1.2 gm, 2.4 gm, or 4.8 gm of NAC. Disease activity was evaluated monthly by the British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index (SLEDAI), and the Fatigue Assessment Scale (FAS) before, during, and after a 3-month treatment period. Mitochondrial transmembrane potential and mTOR were assessed by flow cytometry. Forty-two healthy subjects matched to patients for age, sex, and ethnicity were studied as controls.<br><br>RESULTS: NAC up to 2.4 gm/day was tolerated by all patients, while 33% of those receiving 4.8 gm/day had reversible nausea. Placebo or NAC 1.2 gm/day did not influence disease activity. Considered together, 2.4 gm and 4.8 gm NAC reduced the SLEDAI score after 1 month (P = 0.0007), 2 months (P = 0.0009), 3 months (P = 0.0030), and 4 months (P = 0.0046); the BILAG score after 1 month (P = 0.029) and 3 months (P = 0.009); and the FAS score after 2 months (P = 0.0006) and 3 months (P = 0.005). NAC increased &#x394;&#x3c8;m (P = 0.0001) in all T cells, profoundly reduced mTOR activity (P = 0.0009), enhanced apoptosis (P = 0.0004), reversed expansion of CD4-CD8- T cells (mean &#xb1; SEM 1.35 &#xb1; 0.12-fold change; P = 0.008), stimulated FoxP3 expression in CD4+CD25+ T cells (P = 0.045), and reduced anti-DNA production (P = 0.049).<br><br>CONCLUSION: This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.}, }
@article {pmid22549117, year = {2012}, author = {Schmaal, L and Veltman, DJ and Nederveen, A and van den Brink, W and Goudriaan, AE}, title = {N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {37}, number = {9}, pages = {2143-2152}, pmid = {22549117}, issn = {1740-634X}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Cocaine-Related Disorders/diagnosis/*drug therapy/*metabolism ; Cross-Over Studies ; Glutamic Acid/*metabolism ; Gyrus Cinguli/metabolism/pathology ; Humans ; *Magnetic Resonance Spectroscopy/methods ; Male ; Pilot Projects ; }, abstract = {Treatment with N-acetylcysteine (NAC) normalizes glutamate (Glu) homeostasis and prevents relapse in drug-dependent animals. However, the effect of NAC on brain Glu levels in substance-dependent humans has not yet been investigated. Proton magnetic resonance spectroscopy ((1)H MRS) was used to investigate Glu changes in the dorsal anterior cingulate cortex (dACC) after a single dose of NAC in cocaine-dependent patients and normal controls. In an open-label, randomized, crossover study, 8 cocaine-dependent patients and 14 healthy controls underwent two scan sessions: one group receiving no compound and the other following a single administration of 2400 mg NAC. The Barratt Impulsiveness Scale was administered to examine the relation between dACC Glu levels and impulsivity. In the medication-free condition, Glu levels in the dACC were significantly higher in cocaine-dependent patients compared with healthy controls. After administration of NAC, Glu levels were reduced in the cocaine-dependent group, whereas NAC had no effect in healthy controls. Higher baseline Glu levels were associated with higher impulsivity, and both were predictive of greater NAC-induced Glu reduction. The current findings indicate that NAC can normalize elevated Glu levels in cocaine-dependent patients. These findings may have important implications for treatment, because abnormal Glu levels are related to relapse, and treatment with NAC prevented relapse in animal studies. Furthermore, clinical studies have indicated beneficial effects of NAC in cocaine-dependent patients, and the current study suggests that these beneficial effects might in part be mediated by the ability of NAC to normalize glutamatergic abnormalities.}, }
@article {pmid22546753, year = {2012}, author = {Martínez-Banaclocha, MA}, title = {N-acetyl-cysteine in the treatment of Parkinson's disease. What are we waiting for?.}, journal = {Medical hypotheses}, volume = {79}, number = {1}, pages = {8-12}, doi = {10.1016/j.mehy.2012.03.021}, pmid = {22546753}, issn = {1532-2777}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Drug Therapy, Combination ; Glutathione/deficiency ; Humans ; Levodopa/administration &amp; dosage/therapeutic use ; Models, Theoretical ; Oxidative Stress ; Parkinson Disease/*drug therapy/etiology ; }, abstract = {Parkinson's disease is an age-related neurodegenerative disorder that is ameliorated with levodopa. However, long-term use of this drug is limited by motor complications, postural instability and dementia resulting in the progression of the disease. Insights into the organization of the basal ganglia and knowledge of the mechanisms responsible for cell death in Parkinson's disease has permitted the development of putative neuro-protective drugs that might slow the disease progression. Although no drug has yet been established to alter the rate of disease progression, recent publications have confirmed previous results and hypotheses about the probable role of thiolic antioxidants on Parkinson's disease, demonstrating a significant reduction of dopaminergic neuronal degeneration in α-synuclein over expressing mice treated with oral N-acetyl-cysteine. This thiolic antioxidant is a modified form of the natural amino acid cysteine, which is the precursor of the most potent intracellular antioxidant glutathione. Besides, increasing evidence has been accumulated in the last 10years about the beneficial effects of this thiolic antioxidant in experimental and pathologic states of the nervous system, including against neurotoxic substances. The present paper put forward the existing rationale evidence for the use of N-acetyl-cysteine alone or in combination with levodopa in the clinical management of this neurodegenerative disorder.}, }
@article {pmid22541137, year = {2012}, author = {Feldman, L and Shani, M and Sinuani, I and Beberashvili, I and Weissgarten, J}, title = {N-acetylcysteine may improve residual renal function in hemodialysis patients: a pilot study.}, journal = {Hemodialysis international. International Symposium on Home Hemodialysis}, volume = {16}, number = {4}, pages = {512-516}, doi = {10.1111/j.1542-4758.2012.00702.x}, pmid = {22541137}, issn = {1542-4758}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics ; Aged ; Female ; Humans ; Kidney/drug effects/metabolism/physiopathology ; Kidney Failure, Chronic/drug therapy/metabolism/physiopathology/*therapy ; Kidney Function Tests/methods ; Male ; Metabolic Clearance Rate ; Peritoneal Dialysis ; Pilot Projects ; Renal Dialysis/*methods ; }, abstract = {Clinical outcomes in chronic dialysis patients are highly dependent on preservation of residual renal function (RRF). N-acetylcysteine (NAC) may have a positive effect on renal function in the setting of nephrotoxic contrast media administration. In our recent study, we showed that NAC may improve RRF in peritoneal dialysis patients. The aim of the present study was to investigate the effect of NAC on RRF in patients treated with chronic hemodialysis. Prevalent chronic hemodialysis patients with a residual urine output of at least 100 mL/24 hours were included. The patients were administered oral NAC 1200 mg twice daily for 2 weeks. Residual renal function was assessed at baseline and at the end of treatment using a midweek interdialytic urine collection for measurement of urine output and calculation of residual renal Kt/V and glomerular filtration rate (GFR). Residual GFR was measured as the mean of urea and creatinine residual renal clearance. Each patient served as his own control. Twenty patients were prospectively enrolled in the study. Administration of NAC 1200 mg twice daily for 2 weeks resulted in significant improvement in RRF: urine volume increased from 320 ± 199 to 430 ± 232 mL/24 hours (P < 0.01), residual renal Kt/V increased from 0.19 ± 0.12 to 0.29 ± 0.14 (P < 0.01), and residual GFR increased from 1.6 ± 1.6 to 2.4 ± 2.3 mL/minute/1.73 m(2) (P < 0.01). N-acetylcysteine may improve RRF in patients treated with chronic hemodialysis.}, }
@article {pmid22540635, year = {2012}, author = {Salehpour, S and Sene, AA and Saharkhiz, N and Sohrabi, MR and Moghimian, F}, title = {N-Acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome.}, journal = {The journal of obstetrics and gynaecology research}, volume = {38}, number = {9}, pages = {1182-1186}, doi = {10.1111/j.1447-0756.2012.01844.x}, pmid = {22540635}, issn = {1447-0756}, mesh = {Acetylcysteine/*therapeutic use ; Adjuvants, Pharmaceutic ; Adult ; Clomiphene/therapeutic use ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Fertility Agents, Female/therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Infertility, Female/*drug therapy/etiology ; Ovulation Induction/*methods ; Polycystic Ovary Syndrome/*complications ; Pregnancy ; Young Adult ; }, abstract = {AIM: The aim of this study was to evaluate the effect of oral N-acetylcysteine (NAC) administration as an adjuvant to clomiphene citrate (CC) on induction of ovulation outcomes in patients with polycystic ovary syndrome (PCOS).<br><br>MATERIAL AND METHODS: In this placebo-controlled double-blind randomized clinical trial, 180 PCOS infertile patients were randomly divided into two groups for induction of ovulation. Patients in group 1 received CC 100 mg/d plus NAC 1.2 g/d and patients in group 2 received CC plus placebo for 5 days starting at day 3 of the cycle. On the 12th day of the menstrual cycle in the presence of at least one follicle with an 18-20-mm diameter in ultrasound evaluation, 10,000 U hCG was injected intramuscularly and timed intercourse was advised 36 h after hCG injection. Serum &#x3b2;-hCG level was measured on the 16th day after hCG injection.<br><br>RESULTS: The number of follicles >18 mm and the mean endometrial thickness on the day of hCG administration were significantly higher among the CC+NAC group (P-value = 0.001). The ovulation and pregnancy rates were also significantly higher in the CC+NAC group (P-value = 0.02 and 0.04, respectively). No adverse side-effects and no cases of ovarian hyperstimulation syndrome were observed in the group receiving NAC.<br><br>CONCLUSION: NAC as a safe and well-tolerated adjuvant to CC for induction of ovulation can improve the ovulation and pregnancy rates in PCOS patients. It may also have some beneficial impacts on endometrial thickness.}, }
@article {pmid22538170, year = {2012}, author = {Xue, T and Luo, P and Zhu, H and Zhao, Y and Wu, H and Gai, R and Wu, Y and Yang, B and Yang, X and He, Q}, title = {Oxidative stress is involved in Dasatinib-induced apoptosis in rat primary hepatocytes.}, journal = {Toxicology and applied pharmacology}, volume = {261}, number = {3}, pages = {280-291}, doi = {10.1016/j.taap.2012.04.010}, pmid = {22538170}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cell Separation ; DNA/chemistry ; Dasatinib ; Electrophoresis, Gel, Pulsed-Field ; Fluorescent Dyes ; Hepatocytes/*drug effects ; In Situ Nick-End Labeling ; Indoles ; L-Lactate Dehydrogenase/blood ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Liver/drug effects ; Mitochondrial Swelling/drug effects ; Oxidative Stress/*drug effects ; Protein Kinase Inhibitors/*toxicity ; Pyrimidines/*toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Thiazoles/*toxicity ; }, abstract = {Dasatinib, a multitargeted inhibitor of BCR-ABL and SRC kinases, exhibits antitumor activity and extends the survival of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). However, some patients suffer from hepatotoxicity, which occurs through an unknown mechanism. In the present study, we found that Dasatinib could induce hepatotoxicity both in vitro and in vivo. Dasatinib reduced the cell viability of rat primary hepatocytes, induced the release of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) in vitro, and triggered the ballooning degeneration of hepatocytes in Sprague-Dawley rats in vivo. Apoptotic markers (chromatin condensation, cleaved caspase-3 and cleaved PARP) were detected to indicate that the injury induced by Dasatinib in hepatocytes in vitro was mediated by apoptosis. This result was further validated in vivo using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays. Here we found that Dasatinib dramatically increased the level of reactive oxygen species (ROS) in hepatocytes, reduced the intracellular glutathione (GSH) content, attenuated the activity of superoxide dismutase (SOD), generated malondialdehyde (MDA), a product of lipid peroxidation, decreased the mitochondrial membrane potential, and activated nuclear factor erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinases (MAPK) related to oxidative stress and survival. These results confirm that oxidative stress plays a pivotal role in Dasatinib-mediated hepatotoxicity. N-acetylcysteine (NAC), a typical antioxidant, can scavenge free radicals, attenuate oxidative stress, and protect hepatocytes against Dasatinib-induced injury. Thus, relieving oxidative stress is a viable strategy for reducing Dasatinib-induced hepatotoxicity.}, }
@article {pmid22537850, year = {2012}, author = {Lee, GH and Lee, MH and Yoon, YD and Kang, JS and Pyo, S and Moon, EY}, title = {Protein kinase C stimulates human B cell activating factor gene expression through reactive oxygen species-dependent c-Fos in THP-1 pro-monocytic cells.}, journal = {Cytokine}, volume = {59}, number = {1}, pages = {115-123}, doi = {10.1016/j.cyto.2012.03.017}, pmid = {22537850}, issn = {1096-0023}, mesh = {Acetylcysteine/pharmacology ; Animals ; B-Cell Activating Factor/*genetics/metabolism ; Base Sequence ; COS Cells ; Cell Line ; Chlorocebus aethiops ; Enzyme Activation/drug effects ; *Gene Expression Regulation/drug effects ; Humans ; Ionomycin/pharmacology ; Mice ; Molecular Sequence Data ; Monocytes/drug effects/*enzymology ; Promoter Regions, Genetic/genetics ; Protein Binding/drug effects ; Protein Kinase C/*metabolism ; Proto-Oncogene Proteins c-fos/*metabolism ; Reactive Oxygen Species/*metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Transcription Factor AP-1/metabolism ; }, abstract = {BAFF is associated with various immunological diseases. Previously, we have reported that mouse B cell activating factor (mBAFF) expression was dependent on nuclear localization of co-activator, p300 and the activation of transcription factors including NF-κB and CREB. Here, we investigated whether transcription factor, c-Fos, regulates human (h) BAFF expression through promoter activation by PMA-induced reactive oxygen species (ROS) production. We cloned hBAFF promoter into luciferase-expressing pGL3-basic vector. The activity of 1.0 kb hBAFF promoter was higher than that in 0.75, 0.5 or 0.25 kb hBAFF promoter. The existence of three AP-1 binding motifs was computer-analyzed in hBAFF promoter. The stimulation with PMA and ionomycin (IOM) increased 1.0 kb hBAFF promoter activity, time-dependently. PMA/IOM-stimulation rapidly enhanced c-Fos expression in THP-1 human pro-monocytic cells. Binding of c-Fos to hBAFF promoter was detected by chromatin immunoprecipitation (ChIP) assay. hBAFF expression and its promoter activity were decreased by the transfection with small interference (si) RNA of c-Fos. ROS production in THP-1 cells was increased by PMA/IOM-stimulation. In addition, hBAFF activity stimulated by PMA/IOM was reduced by N-acetyl-cysteine (NAC), a well-known ROS scavenger. Serum starvation (0.5% FBS) producing ROS and the exogenous H(2)O(2) treatment also enhanced hBAFF promoter activity. c-Fos expression and AP-1 binding to oligonucleotide were reduced by the treatment with NAC. H(2)O(2) was not able to induce hBAFF expression in the presence of staurosporine, PKC inhibitor. Data suggest that hBAFF expression could be regulated by promoter activation through c-Fos association, which might be dependent on PMA-induced ROS production.}, }
@article {pmid22537319, year = {2012}, author = {Devi, PU and Saraogi, P and Manocha, A and Vohora, D}, title = {Pharmacological and biochemical analysis of interactions between N-acetylcysteine and some antiepileptic drugs on experimental seizures in mice.}, journal = {CNS neuroscience &amp; therapeutics}, volume = {18}, number = {5}, pages = {406-413}, pmid = {22537319}, issn = {1755-5949}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Animals ; Anticonvulsants/*therapeutic use ; Aspartate Aminotransferases/blood ; Calcium/blood ; Disease Models, Animal ; Drug Interactions ; Drug Therapy, Combination/methods ; Electroshock/adverse effects ; Exploratory Behavior/drug effects ; Female ; Glutathione/metabolism ; Hand Strength/physiology ; Male ; Malondialdehyde/metabolism ; Mice ; Seizures/*drug therapy/etiology/physiopathology ; }, abstract = {PURPOSE: In view of a putative role of oxidative stress in the pathophysiology of seizures, this study addressed the interactions between N-acetylcysteine (NAC), a potent antioxidant and two antiepileptic drugs sodium valproate (SVP) and phenytoin (PHT) on experimental seizures in mice.<br><br>METHODS: The interaction was studied at three fixed ratio combinations (i.e., 1:1, 1:3, and 3:1) in the mouse maximal electroshock (MES) test using isobolographic analysis. Markers of oxidative stress (reduced glutathione [GSH] and malondialdehyde [MDA]) were estimated in the cortex of mice pretreated with either of these drugs alone or their 3:1 ratio combinations at the experimentally determined ED(50) values (ED(50 exp) values). The grip strength and spontaneous alternation behavior (SAB) were also assessed. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and calcium levels were estimated.<br><br>RESULTS: We found an anticonvulsant action of NAC in the MES test. Further, the ED(50 exp) values for the combinations of PHT and NAC did not differ from the theoretically calculated ED(50) values indicating additive effects. In case of SVP and NAC, however, the ED(50 exp) values were lower than the theoretically calculated ED(50) values. The interaction of SVP with NAC at the fixed ratios of 1:3 and 3:1 was found to be synergistic. No significant changes were observed in the grip strength, SAB, cortical GSH and MDA levels, serum AST, ALT, ALP, or calcium levels.<br><br>CONCLUSION: Our results thus hold promise for the use of NAC as an adjunct to PHT and SVP therapy.}, }
@article {pmid22534811, year = {2012}, author = {Lee, EJ and Silva, SM and Simões, Mde J and Montero, EF}, title = {Effect of N-acetylcysteine in liver ischemia-reperfusion injury after 30% hepatectomy in mice.}, journal = {Acta cirurgica brasileira}, volume = {27}, number = {4}, pages = {346-349}, doi = {10.1590/s0102-86502012000400011}, pmid = {22534811}, issn = {1678-2674}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/*blood ; Animals ; Aspartate Aminotransferases/*blood ; Hepatectomy/adverse effects/methods ; Liver/*blood supply/drug effects/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Reperfusion Injury/blood/*prevention &amp; control ; }, abstract = {PURPOSE: Evaluate the effect of N-acetylcysteine in liver remnant after hepatectomy associated to ischemia-reperfusion injury in mice.<br><br>METHODS: Male adult BALB/c mice, weighing 20-22 g were used. Animals were anesthetized with ketamine (70 mg/kg) and xylazine (10 mg/kg); received N-acetylcysteine (150 mg/kg, H-IR-NAC group) or vehicle (H-IR group). Surgical procedures were performed under 10X magnification. Partial hepatectomy (30%) was followed by ischemia-reperfusion injury (30 minutes of ischemia and 60 minutes of reperfusion). Blood sample and liver tissue were removed before animal was euthanized. AST and ALT were evaluated in blood samples and histomorphological analyses were performed in remnant liver. Groups were compared by Mann-Whitney test, and it was considered significant when p<0.05.<br><br>RESULTS: Biochemical evaluations showed reduced levels of ALT in NAC group (H-IR-NAC=376 &#xb1; 127 U/l vs H-IR=636 &#xb1; 39 U/l, p=0.023). AST was similar (p=0.456). H-IR group showed hepatic tissue with preserved architecture, large area of steatosis, vascular congestion and rare mitogenic activity. NAC group showed hepatic tissue with small area of steatosis, vascular congestion and elevated mitogenic activity, evidenced by increased binuclear cells (H-IR-NAC=15.88 &#xb1; 0.52 vs H-IR=7.4 &#xb1; 0.37, p<0.001).<br><br>CONCLUSION: N-acetylcysteine promotes enzymatic and morphological protection against hepatectomy and ischemia-reperfusion injury.}, }
@article {pmid22534333, year = {2012}, author = {Hashimoto, K and Pinkas, G and Evans, L and Liu, H and Al-Hasan, Y and Thompson, LP}, title = {Protective effect of N-acetylcysteine on liver damage during chronic intrauterine hypoxia in fetal guinea pig.}, journal = {Reproductive sciences (Thousand Oaks, Calif.)}, volume = {19}, number = {9}, pages = {1001-1009}, pmid = {22534333}, issn = {1933-7205}, support = {R01 HL049999/HL/NHLBI NIH HHS/United States ; R01HL 49999/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/therapeutic use ; Female ; Fetal Hypoxia/*drug therapy/metabolism/pathology ; Guinea Pigs ; Liver Diseases/metabolism/pathology/*prevention &amp; control ; Organ Size ; Oxidative Stress/drug effects/physiology ; Pregnancy ; Protective Agents/pharmacology/therapeutic use ; }, abstract = {Chronic exposure to hypoxia during pregnancy generates a stressed intrauterine environment that may lead to fetal organ damage. The objectives of the study are (1) to quantify the effect of chronic hypoxia in the generation of oxidative stress in fetal guinea pig liver and (2) to test the protective effect of antioxidant treatment in hypoxic fetal liver injury. Pregnant guinea pigs were exposed to either normoxia (NMX) or 10.5% O(2) (HPX, 14 days) prior to term (65 days) and orally administered N-acetylcysteine ([NAC] 10 days). Near-term anesthetized fetuses were excised and livers examined by histology and assayed for malondialdehyde (MDA) and DNA fragmentation. Chronic HPX increased erythroid precursors, MDA (NMX vs HPX; 1.26 ± 0.07 vs 1.78 ± 0.07 nmol/mg protein; P < .001, mean ± standard error of the mean [SEM]) and DNA fragmentation levels in fetal livers (0.069 ± 0.01 vs 0.11 ± 0.005 OD/mg protein; P < .01). N-acetylcysteine inhibited erythroid aggregation and reduced (P < .05) both MDA and DNA fragmentation of fetal HPX livers. Thus, chronic intrauterine hypoxia generates cell and nuclear damage in the fetal guinea pig liver. Maternal NAC inhibited the adverse effects of fetal liver damage suggestive of oxidative stress. The suppressive effect of maternal NAC may implicate the protective role of antioxidants in the prevention of liver injury in the hypoxic fetus.}, }
@article {pmid22534037, year = {2012}, author = {Krifka, S and Hiller, KA and Spagnuolo, G and Jewett, A and Schmalz, G and Schweikl, H}, title = {The influence of glutathione on redox regulation by antioxidant proteins and apoptosis in macrophages exposed to 2-hydroxyethyl methacrylate (HEMA).}, journal = {Biomaterials}, volume = {33}, number = {21}, pages = {5177-5186}, doi = {10.1016/j.biomaterials.2012.04.013}, pmid = {22534037}, issn = {1878-5905}, mesh = {Animals ; Antioxidants/*metabolism ; Apoptosis/*drug effects ; Cells, Cultured ; Glutathione/*pharmacology ; Macrophages/*cytology/drug effects/enzymology/*metabolism ; Methacrylates/*pharmacology ; Mice ; Models, Biological ; Necrosis ; Oxidation-Reduction/drug effects ; Proteins/*metabolism ; Reactive Oxygen Species/metabolism ; Resins, Synthetic/pharmacology ; }, abstract = {Resin monomers like 2-hydroxyethyl methacrylate (HEMA) disturb cell functions including responses of the innate immune system, mineralization and differentiation, or induce cell death via apoptosis. These phenomena are associated with oxidative stress and a reduction in the concentration of the antioxidant glutathione (GSH), resulting in imbalanced redox homeostasis. Thus far, the precise mechanism of how resin monomers interfere with cellular redox regulation is unknown. The present study provides insight into the induction of apoptosis and the differential expression of antioxidant enzymes depending on the availability of GSH. Buthionine sulfoximine (BSO) was used to inhibit GSH synthesis, while 2-oxothiazolidine-4-carboxylate (OTC), and N-acetylcysteine (NAC) as prodrugs supported GSH synthesis in RAW264.7 mouse macrophages exposed to HEMA (0-8 mm) for 24 h. The level of GSH was significantly decreased after cells were preincubated with BSO, and the formation of reactive oxygen species (ROS) increased in cultures subsequently exposed to HEMA. Apoptosis was drastically increased by BSO in HEMA-exposed cell cultures as well, but OTC and NAC retracted HEMA-induced cell death. These results show that dental monomer-induced apoptosis is causally related to the availability of GSH. The hydrogen peroxide decomposing enzymes glutathione peroxidase (GPx1/2) and catalase were differentially regulated in HEMA-exposed cultures. Expression of GPx1/2 was inhibited by HEMA and further reduced in the presence of BSO. SOD1 (superoxide dismutase) expression was inhibited in the presence of HEMA, and was decreased to an even greater extent by BSO, possibly due to H(2)O(2)-feedback inhibition. The expression of catalase was considerably up-regulated in HEMA-exposed cultures, implying that H(2)O(2) is the type of ROS that is significantly increased in monomer-exposed cells. OTC and NAC counteracted the effect of HEMA on GPx1/2, SOD1, and catalase expression. HO-1 (heme oxygenase) expression was strongly enhanced by HEMA, suggesting the need for further antioxidants like bilirubin to support enzyme activities that directly regulate H(2)O(2) equilibrium. Expression of the oxidoreductase thioredoxin (TRX1), the second major thiol-dependent antioxidant system in eukaryotic cells, was slightly reduced, while the oxygen-sensing protein HIF-1α was downregulated in HEMA-exposed cell cultures. These results indicate that cells and tissues actively respond to monomer-induced oxidative stress by the differential expression of enzymatic antioxidants.}, }
@article {pmid22532787, year = {2012}, author = {Khan, M and Ding, C and Rasul, A and Yi, F and Li, T and Gao, H and Gao, R and Zhong, L and Zhang, K and Fang, X and Ma, T}, title = {Isoalantolactone induces reactive oxygen species mediated apoptosis in pancreatic carcinoma PANC-1 cells.}, journal = {International journal of biological sciences}, volume = {8}, number = {4}, pages = {533-547}, pmid = {22532787}, issn = {1449-2288}, mesh = {Apoptosis/*drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Humans ; Immunoblotting ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Pancreatic Neoplasms/*metabolism ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; }, abstract = {Isoalantolactone, a sesquiterpene lactone compound possesses antifungal, antibacteria, antihelminthic and antiproliferative activities. In the present study, we found that isoalantolactone inhibits growth and induces apoptosis in pancreatic cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of reactive oxygen species, cardiolipin oxidation, reduced mitochondrial membrane potential, release of cytochrome c and cell cycle arrest at S phase. N-Acetyl Cysteine (NAC), a specific ROS inhibitor restored cell viability and completely blocked isoalantolactone-mediated apoptosis in PANC-1 cells indicating that ROS are involved in isoalantolactone-mediated apoptosis. Western blot study showed that isoalantolactone increased the expression of phosphorylated p38 MAPK, Bax, and cleaved caspase-3 and decreased the expression of Bcl-2 in a dose-dependent manner. No change in expression of phosphorylated p38 MAPK and Bax was found when cells were treated with isoalantolactone in the presence of NAC, indicating that activation of these proteins is directly dependent on ROS generation. The present study provides evidence for the first time that isoalantolactone induces ROS-dependent apoptosis through intrinsic pathway. Furthermore, our in vivo toxicity study demonstrated that isoalantolactone did not induce any acute or chronic toxicity in liver and kidneys of CD1 mice at dose of 100 mg/kg body weight. Therefore, isoalantolactone may be a safe chemotherapeutic candidate for the treatment of human pancreatic carcinoma.}, }
@article {pmid22532030, year = {2013}, author = {Hou, Y and Wang, L and Yi, D and Ding, B and Yang, Z and Li, J and Chen, X and Qiu, Y and Wu, G}, title = {N-acetylcysteine reduces inflammation in the small intestine by regulating redox, EGF and TLR4 signaling.}, journal = {Amino acids}, volume = {45}, number = {3}, pages = {513-522}, doi = {10.1007/s00726-012-1295-x}, pmid = {22532030}, issn = {1438-2199}, mesh = {Acetylcysteine/administration &amp; dosage/metabolism/*pharmacology ; Animals ; *Dietary Supplements ; Epidermal Growth Factor/blood/*metabolism ; Female ; Inflammation/metabolism/*prevention &amp; control ; Intestine, Small/*drug effects/metabolism ; Lipopolysaccharides/administration &amp; dosage/antagonists &amp; inhibitors/pharmacology ; Oxidation-Reduction/drug effects ; RNA, Messenger/drug effects/genetics/metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction/*drug effects ; Swine ; Toll-Like Receptor 4/genetics/*metabolism ; }, abstract = {This study determined whether N-acetylcysteine (NAC) could affect intestinal redox status, proinflammatory cytokines, epidermal growth factor (EGF), EGF receptor (EGFR), Toll-like receptor-4 (TLR4), and aquaporin-8 in a lipopolysaccharide (LPS)-challenged piglet model. Eighteen piglets (35-day-old) were randomly allocated into one of the three treatments (control, LPS and NAC). The control and LPS groups were fed a basal diet, and the NAC group received the basal diet +500 mg/kg NAC. On days 10, 13, and 20 of the trial, the LPS- and NAC-treated piglets received intraperitoneal administration of LPS (100 μg/kg BW), whereas the control group received the same volume of saline. On days 10 and 20, venous blood samples were obtained at 3 h post LPS or saline injection. On day 21 of the trial, piglets were killed to obtain the intestinal mucosa for analysis. Compared with the control group, LPS challenge reduced (P < 0.05) the activities of superoxide dismutase, catalase, and glutathione peroxidase in jejunal mucosae, while increasing (P < 0.05) the concentrations of malondialdehyde, H2O2, O2 (·-) and the ratio of oxidized to reduced glutathione in jejunal mucosae, and concentrations of TNF-α, cortisol, interleukin-6, and prostaglandin E2 in both plasma and intestinal mucosae. These adverse effects of LPS were attenuated (P < 0.05) by NAC supplementation. Moreover, NAC prevented LPS-induced increases in abundances of intestinal HSP70 and NF-κB p65 proteins and TLR4 mRNA. NAC supplementation enhanced plasma EGF concentration and intestinal EGFR mRNA levels. Collectively, these results indicate that dietary NAC supplementation alleviates LPS-induced intestinal inflammation via regulating redox, EGF, and TLR4 signaling.}, }
@article {pmid22530011, year = {2012}, author = {Ren, F and Chen, X and Hesketh, J and Gan, F and Huang, K}, title = {Selenium promotes T-cell response to TCR-stimulation and ConA, but not PHA in primary porcine splenocytes.}, journal = {PloS one}, volume = {7}, number = {4}, pages = {e35375}, pmid = {22530011}, issn = {1932-6203}, mesh = {Animals ; Concanavalin A/*pharmacology ; Enzyme Activation/drug effects ; Glutathione/metabolism ; Glutathione Peroxidase/genetics/metabolism ; Interleukin-2/biosynthesis ; Lymphocyte Activation/drug effects/immunology ; Oxidation-Reduction ; Phytohemagglutinins/*pharmacology ; Receptors, Antigen, T-Cell/*immunology ; Selenium/*pharmacology ; Sodium Selenite/pharmacology ; Spleen/*immunology/metabolism ; Swine ; T-Lymphocytes/*drug effects/*immunology/metabolism ; Trace Elements/pharmacology ; Glutathione Peroxidase GPX1 ; }, abstract = {There is controversy in the literature over whether the selenium (Se) influences cellular immune responses, and the mechanisms possibly underlying these effects are unclear. In this study, the effects of Se on T-cell proliferation and IL-2 production were studied in primary porcine splenocytes. Splenocytes were treated with different mitogens in the presence of 0.5-4 µmol/L sodium selenite. Se significantly promoted T-cell receptor (TCR) or concanavalin A (ConA)-induced T-cell proliferation and IL-2 production but failed to regulate T-cell response to phytohemagglutinin (PHA). In addition, Se significantly increased the levels of cytosolic glutathione peroxidase (GPx1) and thioredoxin reductase 1 (TR1) mRNA, the activity of GPx1 and the concentration of reduced glutathione (GSH) in the unstimulated, or activated splenocytes. These results indicated that Se improved the redox status in all splenocytes, including unstimulated, TCR, ConA and PHA -stimulated, but only TCR and ConA-induced T-cell activation was affected by the redox status. N-acetylcysteine (NAC), a pharmacological antioxidant, increased T-cell proliferation and IL-2 production by TCR and ConA stimulated splenocytes but had no effect on the response to PHA in primary porcine splenocytes confirming that PHA-induced T-cell activation is insensitive to the redox status. We conclude that Se promotes GPx1 and TR1 expression and increases antioxidative capacity in porcine splenocytes, which enhances TCR or ConA -induced T-cell activation but not PHA-induced T-cell activation. The different susceptibilities to Se between the TCR, ConA and PHA -induced T-cell activation may help to explain the controversy in the literature over whether or not Se boosts immune responses.}, }
@article {pmid22527635, year = {2012}, author = {Tian, C and Sun, L and Jia, B and Ma, K and Curthoys, N and Ding, J and Zheng, J}, title = {Mitochondrial glutaminase release contributes to glutamate-mediated neurotoxicity during human immunodeficiency virus-1 infection.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {7}, number = {3}, pages = {619-628}, pmid = {22527635}, issn = {1557-1904}, support = {P01 NS043985/NS/NINDS NIH HHS/United States ; R01 NS061642/NS/NINDS NIH HHS/United States ; P20 RR15635-01/RR/NCRR NIH HHS/United States ; R01 NS 061642-01/NS/NINDS NIH HHS/United States ; 3R01NS61642-2S1/NS/NINDS NIH HHS/United States ; R21 MH 083525-01/MH/NIMH NIH HHS/United States ; R21 MH083525/MH/NIMH NIH HHS/United States ; R01 NS041858/NS/NINDS NIH HHS/United States ; P01NS043985/NS/NINDS NIH HHS/United States ; P20 RR015635/RR/NCRR NIH HHS/United States ; R01 NS 41858-01/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Cerebral Cortex/drug effects/metabolism ; Fetus ; Glutamic Acid/physiology/*toxicity ; Glutaminase/*metabolism ; HIV Infections/enzymology/*metabolism ; *HIV-1 ; Humans ; Mitochondria/drug effects/*metabolism ; Oxidative Stress/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Human immunodeficiency virus (HIV) induces a neurological disease culminating in frank dementia referred to as HIV-associated dementia (HAD). Neurotoxins from HIV-1-infected and activated mononuclear phagocytes contribute to the neuropathogenesis of HAD. Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS) and functions through activation of multiple receptors. Excessive glutamate production by HIV-infected macrophages in HAD may contribute to neuronal injury. Our previous studies have suggested that mitochondrial glutaminase is responsible for the excessive production of glutamate. However, how HIV-1 infection regulates glutamate over-production remains unclear. In this study, we propose that HIV infection-induced oxidative stress contributes to mitochondrial glutaminase release, which results in the excessive production of glutamate and subsequent neuronal injury. We collected conditioned media from HIV-1 infected macrophages and analyzed glutamate concentration in the media by RP-HPLC, and found that the cyclosporine A (CsA), an inhibitor of HIV-1 replication and mitochondrial permeability transition pore, and N-acetylcysteine (NAC), a remover of reactive oxygen species (ROS), not only blocked the excessive glutamate production, but also decreased the glutamate-mediated neurotoxicity. In addition, HIV-infection-induced ROS generation was accompanied with the excessive glutamate production, suggesting that oxidative stress was involved in glutamate regulation. Using the isolated rat brain mitochondria as an ex vivo model and over-expressing GFP-glutaminase fusion protein in mammalian cells as a cell model, we confirm oxidative stress-mediated mitochondrial glutaminase release during HIV-1 infection contributes to glutamate over-production and the subsequent neurotoxicity. These results may provide insight into HAD pathogenesis and a therapeutic strategy for HAD treatment.}, }
@article {pmid22527349, year = {2012}, author = {McQuade, DJ and Dargan, PI and Keep, J and Wood, DM}, title = {Paracetamol toxicity: What would be the implications of a change in UK treatment guidelines?.}, journal = {European journal of clinical pharmacology}, volume = {68}, number = {11}, pages = {1541-1547}, pmid = {22527349}, issn = {1432-1041}, mesh = {Acetaminophen/antagonists &amp; inhibitors/*blood/pharmacokinetics/*poisoning ; Acetylcysteine/economics/*therapeutic use ; Analgesics, Non-Narcotic/antagonists &amp; inhibitors/*blood/pharmacokinetics/*poisoning ; Chemical and Drug Induced Liver Injury/blood/economics/*prevention &amp; control/therapy ; Cohort Studies ; Drug Costs ; Drug Overdose ; Emergency Service, Hospital ; Free Radical Scavengers/economics/*therapeutic use ; Health Care Costs ; Hospitals, Urban ; Humans ; London ; Practice Guidelines as Topic ; Retrospective Studies ; Risk ; Risk Assessment ; United Kingdom ; }, abstract = {BACKGROUND: Treatment of single-time-point ingestion acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is guided by plotting a timed plasma paracetamol concentration on established nomograms. Guidelines in the UK differ from those in the U.S. and Australasia by having two treatment lines on the nomogram. Patients deemed to be at 'normal' risk of hepatotoxicity are treated using the treatment line starting at 200 mg/L at 4 h post-ingestion; those at higher risk are treated using the 'high risk' treatment line starting at 100 mg/L at 4 h post-ingestion.<br><br>AIM: To examine the effect on treatment numbers if UK guidelines were to adopt a single treatment line nomogram or lower, risk-stratified treatment lines.<br><br>METHODS: We undertook a retrospective analysis of a series of acute single-time-point paracetamol poisonings presenting to our inner city emergency department. Treatment numbers and effect on treatment costs were modelled for three alternative scenarios: a 150 line-a combined single treatment line starting at a 4 h concentration of 150 mg/L, a 100 line-a combined single treatment line starting at a 4 h concentration of 100 mg/L, and a 150/75 line-a double treatment line at the lower concentrations of 150 mg/L for normal risk and 75 mg/L for high risk patients.<br><br>RESULTS: A total of 1,214 cases were identified. Under current UK guidance, 133 (11.0%) high risk cases and 98 (8.1%) normal risk cases needed treatment (total 231, 19.0%). A 150 line would result in 87 (7.2%) high risk cases and 155 (12.8%) normal risk cases needing treatment (total 242, 19.9%). A 100 line would result in 133 (11.0%) high risk and 251 (20.7%) normal risk cases needing treatment (total 384, 31.6%). A 150/75 line would result in 153 (12.6%) high risk and 155 (12.8%) normal risk cases needing treatment (total 308, 25.4%).<br><br>CONCLUSIONS: Both a 100 line and a 150/75 line would result in a large increase in the number of patients being treated and an associated increase in the costs of treatment. A single 150 mg/L treatment line would simplify treatment algorithms and lead to a similar number of patients being treated with NAC overall. A potential concern however is whether any of the high risk cases that would no longer be treated might develop significant hepatotoxicity. After consideration of the evidence for dual treatment lines, we feel that these risks are small and that it is worth reconsidering a change of treatment recommendations to a single 150 line.}, }
@article {pmid22526333, year = {2012}, author = {Rodrigues, M and Turner, O and Stolz, D and Griffith, LG and Wells, A}, title = {Production of reactive oxygen species by multipotent stromal cells/mesenchymal stem cells upon exposure to fas ligand.}, journal = {Cell transplantation}, volume = {21}, number = {10}, pages = {2171-2187}, pmid = {22526333}, issn = {1555-3892}, support = {R01 GM069668/GM/NIGMS NIH HHS/United States ; R01 GM063569/GM/NIGMS NIH HHS/United States ; GM069668/GM/NIGMS NIH HHS/United States ; DE019523/DE/NIDCR NIH HHS/United States ; R01 DE019523/DE/NIDCR NIH HHS/United States ; }, mesh = {Apoptosis/drug effects/physiology ; Cell Culture Techniques ; Fas Ligand Protein/*pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mesenchymal Stem Cells/*drug effects/*metabolism ; Oxidative Stress/drug effects/physiology ; Reactive Oxygen Species/*metabolism ; Recombinant Proteins/pharmacology ; Signal Transduction ; Superoxides/metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Multipotent stromal cells (MSCs) can be differentiated into osteoblasts and chondrocytes, making these cells candidates to regenerate cranio-facial injuries and lesions in long bones. A major problem with cell replacement therapy, however, is the loss of transplanted MSCs at the site of graft. Reactive oxygen species (ROS) and nonspecific inflammation generated at the ischemic site have been hypothesized to lead to MSCs loss; studies in vitro show MSCs dying both in the presence of ROS or cytokines like FasL. We questioned whether MSCs themselves may be the source of these death inducers, specifically whether MSCs produce ROS under cytokine challenge. On treating MSCs with FasL, we observed increased ROS production within 2 h, leading to apoptotic death after 6 h of exposure to the cytokine. N-acetyl cysteine, an antioxidant, is able to protect MSCs from FasL-induced ROS production and subsequent ROS-dependent apoptosis, though the MSCs eventually succumb to ROS-independent death signaling. Epidermal growth factor (EGF), a cell survival factor, is able to protect cells from FasL-induced ROS production initially; however, the protective effect wanes with continued FasL exposure. In parallel, FasL induces upregulation of the uncoupling protein UCP2, the main uncoupling protein in MSCs, which is not abrogated by EGF; however, the production of ROS is followed by a delayed apoptotic cell death despite moderation by UCP2. FasL-induced ROS activates the stress-induced MAPK pathways JNK and p38MAPK as well as ERK, along with the activation of Bad, a proapoptotic protein, and suppression of survivin, an antiapoptotic protein; the latter two key modulators of the mitochondrial death pathway. FasL by itself also activates its canonical extrinsic death pathway noted by a time-dependent degradation of c-FLIP and activation of caspase 8. These data suggest that MSCs participate in their own demise due to nonspecific inflammation, holding implications for replacement therapies.}, }
@article {pmid22524730, year = {2012}, author = {More, VR and Wen, X and Thomas, PE and Aleksunes, LM and Slitt, AL}, title = {Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice.}, journal = {Comparative hepatology}, volume = {11}, number = {1}, pages = {1}, pmid = {22524730}, issn = {1476-5926}, support = {K22 ES013782/ES/NIEHS NIH HHS/United States ; R01 ES016042/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Type-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites.<br><br>RESULTS: Transporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice.<br><br>CONCLUSION: A severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels.}, }
@article {pmid22521432, year = {2012}, author = {Kim, DE and Min, KJ and Kim, JS and Kwon, TK}, title = {High-mobility group box-1 protein induces mucin 8 expression through the activation of the JNK and PI3K/Akt signal pathways in human airway epithelial cells.}, journal = {Biochemical and biophysical research communications}, volume = {421}, number = {3}, pages = {436-441}, doi = {10.1016/j.bbrc.2012.03.131}, pmid = {22521432}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Chromans/pharmacology ; Free Radical Scavengers/pharmacology ; HMGB1 Protein/genetics/*metabolism ; Humans ; MAP Kinase Kinase 4/biosynthesis ; Mucins/*biosynthesis/genetics ; Phosphatidylinositol 3-Kinases/biosynthesis ; Proto-Oncogene Proteins c-akt/biosynthesis ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/drug effects/*metabolism ; Signal Transduction ; }, abstract = {High-mobility group box-1 protein (HMGB1), which is produced by immune cells, was recently identified as a proinflammatory mediator in various inflammatory diseases. In this study, we investigated the effect of HMGB1 on the expression of mucin (MUC) genes in human airway epithelial cells. We showed that HMGB1 markedly increased MUC8 expression, and that the expression of other MUC genes was also regulated by HMGB1. HMGB1 activated the JNK and PI3K/Akt signaling pathways, and inhibitors of JNK and PI3K/Akt markedly inhibited HMGB1-induced MUC8 expression. Furthermore, HMGB1 increased the production of intracellular reactive oxygen species (ROS). However, the ROS scavengers Trolox and N-acetylcysteine (NAC) had no effect on MUC8 expression in HMGB1-treated NCI-H292 cells. Taken together, our results suggest that HMGB1 induces MUC8 expression in a JNK and PI3K/Akt signaling pathway-dependent manner but that HMGB1 acts in an ROS-independent manner.}, }
@article {pmid22520068, year = {2012}, author = {Onishi, H and Imura, Y and Uchida, M and Machida, Y}, title = {Enhancement potential of sucrose laurate (L-1695) on intestinal absorption of water-soluble high molecular weight compounds.}, journal = {Current drug delivery}, volume = {9}, number = {5}, pages = {487-494}, doi = {10.2174/156720112802650699}, pmid = {22520068}, issn = {1875-5704}, mesh = {Animals ; Dextrans/blood/chemistry/*pharmacokinetics ; Esters/*pharmacology ; Fatty Acids/*pharmacology ; Fluorescein-5-isothiocyanate/*analogs &amp; derivatives/chemistry/pharmacokinetics ; Intestinal Absorption/*drug effects ; Male ; Molecular Weight ; Rats ; Rats, Wistar ; Solubility ; Sucrose/*analogs &amp; derivatives/pharmacology ; Water/chemistry ; }, abstract = {PURPOSE: The potential of sucrose fatty acid esters (SEs) to enhance intestinal absorption was investigated in order to identify their utility for the intestinal absorption of water-soluble high molecular weight compounds.<br><br>METHODS: Fluorescein isothiocyanate-labeled dextran (FD) with a molecular weight (MW) of 4,000 (FD-4) was used as a model compound, and several SEs were tested as absorption enhancers. After FD-4 was administered intra-duodenally at 10 % (w/v) with the non-loop method in situ in rats in the absence or presence of SEs, the plasma concentration-time profiles of FD-4 were examined. As to sucrose laurate (L-1695), the relationship between concentration and enhancement effect was investigated. In addition, the enhancement effect after dosing into the different small intestinal regions, the effect on FDs with different MWs and the influence of N-acetyl-cysteine (NAC) co-existence were examined.<br><br>RESULTS: Low water-soluble SEs exhibited slight and/or slow absorption enhancement effects, while L-1695, being highly water-soluble, had good potential to enhance the absorption rate and extent. The enhancement effect became greater as the concentration of L1695 increased. L-1695 displayed high enhancement potential in wide intestinal areas. The enhancement effect of L-1695 (10 %, w/v) depended on MWs of FDs; the mean values of the area under the plasma concentration curve from 0-120 min (AUC0-120 mins) increased by 14 and 8 times for FD-4 and FD-10 (MW 10,000), while it was hardly changed as for FD-70 (MW 70,000). The enhancement effect of L-1695 (10 %, w/v) was similar to that of sodium caprate (10 %, w/v), and was influenced to some extent by the co-existence of NAC (5 %, w/v).<br><br>CONCLUSION: The absorption enhancement potential of SEs depended on their water-solubility. L-1695, being highly water-soluble, showed a good enhancement effect, and its absorption profiles were elucidated. This study proposes the possibility of SEs, in particular, L-1695, as intestinal absorption enhancers. As far as the present non-loop method is concerned, the intestinal damage was not observed macroscopically with the addition of L1695 at 2.5-20 % (w/v).}, }
@article {pmid22517883, year = {2012}, author = {Kannan, S and Dai, H and Navath, RS and Balakrishnan, B and Jyoti, A and Janisse, J and Romero, R and Kannan, RM}, title = {Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model.}, journal = {Science translational medicine}, volume = {4}, number = {130}, pages = {130ra46}, pmid = {22517883}, issn = {1946-6242}, support = {K08 HD050652/HD/NICHD NIH HHS/United States ; ZIA HD002400/ImNIH/Intramural NIH HHS/United States ; ZIA HD002400-18/ImNIH/Intramural NIH HHS/United States ; 5K08HD050652/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Blood-Brain Barrier/metabolism ; Brain/drug effects/metabolism ; Cerebral Palsy/*drug therapy ; Dendrimers/*chemistry ; Polyamines/chemistry ; Rabbits ; }, abstract = {Cerebral palsy (CP) is a chronic childhood disorder with no effective cure. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP and disorders such as Alzheimer's disease and multiple sclerosis. Targeting neuroinflammation can be a potent therapeutic strategy. However, delivering drugs across the blood-brain barrier to the target cells for treating diffuse brain injury is a major challenge. We show that systemically administered polyamidoamine dendrimers localize in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not healthy controls. We further demonstrate that dendrimer-based N-acetyl-l-cysteine (NAC) therapy for brain injury suppresses neuroinflammation and leads to a marked improvement in motor function in the CP kits. The well-known and safe clinical profile for NAC, when combined with dendrimer-based targeting, provides opportunities for clinical translation in the treatment of neuroinflammatory disorders in humans. The effectiveness of the dendrimer-NAC treatment, administered in the postnatal period for a prenatal insult, suggests a window of opportunity for treatment of CP in humans after birth.}, }
@article {pmid22517678, year = {2012}, author = {Wu, R and Wyatt, E and Chawla, K and Tran, M and Ghanefar, M and Laakso, M and Epting, CL and Ardehali, H}, title = {Hexokinase II knockdown results in exaggerated cardiac hypertrophy via increased ROS production.}, journal = {EMBO molecular medicine}, volume = {4}, number = {7}, pages = {633-646}, pmid = {22517678}, issn = {1757-4684}, support = {K02 HL107448/HL/NHLBI NIH HHS/United States ; R01 HL087149/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cardiomegaly/*metabolism/pathology ; Cells, Cultured ; Fibrosis ; Heterozygote ; Hexokinase/*antagonists &amp; inhibitors/genetics/metabolism ; Male ; Mice ; Mitochondria/metabolism ; Myocytes, Cardiac/drug effects/metabolism ; Oxidative Stress/drug effects ; Pressure ; Protein Binding ; RNA Interference ; RNA, Small Interfering/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {Hexokinase-II (HKII) is highly expressed in the heart and can bind to the mitochondrial outer membrane. Since cardiac hypertrophy is associated with a substrate switch from fatty acid to glucose, we hypothesized that a reduction in HKII would decrease cardiac hypertrophy after pressure overload. Contrary to our hypothesis, heterozygous HKII-deficient (HKII(+/-)) mice displayed increased hypertrophy and fibrosis in response to pressure overload. The mechanism behind this phenomenon involves increased levels of reactive oxygen species (ROS), as HKII knockdown increased ROS accumulation, and treatment with the antioxidant N-acetylcysteine (NAC) abrogated the exaggerated response. HKII mitochondrial binding is also important for the hypertrophic effects, as HKII dissociation from the mitochondria resulted in de novo hypertrophy, which was also attenuated by NAC. Further studies showed that the increase in ROS levels in response to HKII knockdown or mitochondrial dissociation is mediated through increased mitochondrial permeability and not by a significant change in antioxidant defenses. Overall, these data suggest that HKII and its mitochondrial binding negatively regulate cardiac hypertrophy by decreasing ROS production via mitochondrial permeability.}, }
@article {pmid22511847, year = {2012}, author = {Lee, JJ and Hsiao, CC and Yang, IH and Chou, MH and Wu, CL and Wei, YC and Chen, CH and Chuang, JH}, title = {High-mobility group box 1 protein is implicated in advanced glycation end products-induced vascular endothelial growth factor A production in the rat retinal ganglion cell line RGC-5.}, journal = {Molecular vision}, volume = {18}, number = {}, pages = {838-850}, pmid = {22511847}, issn = {1090-0535}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Cattle ; Cell Line ; Culture Media, Conditioned/pharmacology ; Dose-Response Relationship, Drug ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/metabolism ; Glycation End Products, Advanced/*pharmacology ; Glycyrrhizic Acid/pharmacology ; HMGB1 Protein/*biosynthesis/metabolism ; MAP Kinase Kinase 4/antagonists &amp; inhibitors/metabolism ; RNA, Messenger/*biosynthesis ; Rats ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Retinal Ganglion Cells/cytology/drug effects/*metabolism ; Serum Albumin, Bovine/pharmacology ; Signal Transduction/drug effects ; Vascular Endothelial Growth Factor A/*biosynthesis/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {PURPOSE: High-mobility group box 1 protein (HMGB1) has been reported to be a potent proangiogenic factor induced by inflammatory stress. In this study, we explore the role of HMGB1 in advanced glycation end products (AGEs)-induced vascular endothelial growth factor A (VEGF-A) production in rat retinal ganglion cell line 5 (RGC-5) cells.<br><br>METHODS: The VEGF-A protein and mRNA levels in conditioned medium of RGC-5 cells incubated with AGE-modified BSA (AGE-BSA) were examined with real-time PCR and enzyme-linked immunosorbent assay (ELISA), and BSA-treated cells were used as controls. The expression of HMGB1, c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (p38 MAPK) was assessed with immunofluorescence and western blot analysis. Reactive oxidative species (ROS) were detected with flow cytometry measurements of peroxide-dependent oxidation of 2'-7'-dichlorofluorescein-diacetate (DCFH-DA). N-Acetyl-L-cysteine (NAC), glycyrrhizin (GZ), and SP600125 were used to block ROS, HMGB1, and JNK, respectively.<br><br>RESULTS: Compared with the BSA controls, the RGC-5 cells incubated with AGE-BSA showed a dose- and time-dependent increase in VEGF-A mRNA and VEGF-A protein secretion in the supernatant, with the highest levels achieved at 24 h. AGE-BSA stimulated a significant release of HMGB1 in the supernatant and a significant increase of intracellular ROS production at 3 h. NAC blocked HMGB1 production in a dose-dependent manner. Blocking with GZ, NAC, and JNK significantly suppressed AGE-induced VEGF-A production.<br><br>CONCLUSIONS: HMGB1 is implicated in the production of VEGF-A in retinal ganglion cell line-5 (RGC-5). Blocking HMGB1, ROS, or the JNK pathway may attenuate VEGF-A production, suggesting HMGB1 and related signaling molecules play a role in diabetic retinopathy.}, }
@article {pmid22511839, year = {2012}, author = {Park, CH and Kim, JW}, title = {Effect of advanced glycation end products on oxidative stress and senescence of trabecular meshwork cells.}, journal = {Korean journal of ophthalmology : KJO}, volume = {26}, number = {2}, pages = {123-131}, pmid = {22511839}, issn = {2092-9382}, mesh = {Acetylcysteine/metabolism ; Apoptosis/drug effects/physiology ; Arginine/metabolism ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cellular Senescence/drug effects/*physiology ; Glycation End Products, Advanced/metabolism/*toxicity ; Humans ; Nitric Oxide/metabolism ; Oxidative Stress/*physiology ; Pterins/metabolism ; Reactive Oxygen Species/metabolism ; Serum Albumin, Bovine/metabolism/toxicity ; Trabecular Meshwork/drug effects/*metabolism/*pathology ; }, abstract = {PURPOSE: To investigate the effect of advanced glycation end products (AGE) on oxidative stress and cellular senescence in cultured human trabecular meshwork cells (HTMC).<br><br>METHODS: Primarily cultured HTMC were exposed to 0, 10, 50, 100, 200 &#xb5;g/mL of glycated bovine serum albumin (G-BSA) for 5 days. Also co-exposed were L-arginine, sepiapterin, and antioxidant N-acetylcysteine (NAC). Cellular survival and production of nitric oxide (NO), superoxide, and reactive oxygen species were assessed by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assay, Griess assay, cytochrome c assay, and dichlorofluorescin diacetate assay, respectively. Senescence-associated &#x3b2;-galactosidase staining was performed to quantify the degree of cellular senescence.<br><br>RESULTS: G-BSA decreased cellular survival, NO production, and increased superoxide production significantly in a dose-dependent manner. The effects of G-BSA were abolished with co-exposure of L-arginine, sepiapterin, and NAC. G-BSA enhanced cellular senescence accompanied by increased production of reactive oxygen species. G-BSA-induced cellular senescence was suppressed by application of L-arginine, sepiapterin, and NAC.<br><br>CONCLUSIONS: AGE enhances cellular senescence of HTMC accompanied with increased oxidative stress. AGE-induced oxidative stress and cellular senescence could be delayed by application of anti-oxidants.}, }
@article {pmid22511637, year = {2012}, author = {Mimche, PN and Thompson, E and Taramelli, D and Vivas, L}, title = {Curcumin enhances non-opsonic phagocytosis of Plasmodium falciparum through up-regulation of CD36 surface expression on monocytes/macrophages.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {67}, number = {8}, pages = {1895-1904}, doi = {10.1093/jac/dks132}, pmid = {22511637}, issn = {1460-2091}, mesh = {CD36 Antigens/*biosynthesis ; Curcumin/*pharmacology ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Gene Expression Profiling ; Humans ; Immunologic Factors/*pharmacology ; Macrophages/drug effects/*immunology ; Microscopy ; Monocytes/drug effects/*immunology ; NF-E2-Related Factor 2/biosynthesis ; PPAR gamma/biosynthesis ; Phagocytosis/*drug effects ; Plasmodium falciparum/*immunology ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Up-Regulation ; }, abstract = {OBJECTIVES: Curcumin is a natural plant product with antimalarial activity and immunomodulatory properties. In this study we aimed to investigate its effects on CD36 expression and CD36-mediated Plasmodium falciparum phagocytosis as well as the role played by reactive oxygen species (ROS) and the peroxisome proliferator-activated receptor γ retinoid X receptor (PPARγ-RXR) in these processes.<br><br>METHODS: In vitro antimalarial activity was evaluated by the [&#xb3;H]hypoxanthine assay. ROS production and surface CD36 in human monocyte/macrophages were measured by flow cytometry. PPAR&#x3b3; and CD36 mRNA expression was determined by the QuantiGene Plex&#xae; assay and RT-qPCR. Nuclear PPAR&#x3b3; activation was analysed by a DNA-binding ELISA while nuclear erythroid-related factor 2 (Nrf2) expression was analysed by western blotting. P. falciparum phagocytosis was assessed by light microscopy.<br><br>RESULTS: Curcumin's antimalarial activity was confirmed and did not differ between drug-susceptible and -resistant P. falciparum strains. Curcumin increased monocyte ROS production and expression of PPAR&#x3b3; and CD36 at the mRNA and protein levels. Although PPAR&#x3b3; activation was blocked by the PPAR&#x3b3; antagonist GW9662, CD36 expression and CD36-mediated P. falciparum phagocytosis were only inhibited by N-acetylcysteine (NAC), suggesting a PPAR&#x3b3;-independent CD36 expression pathway. We then identified seven putative Nrf2 antioxidant response elements on the CD36 gene promoter and showed that NAC inhibited curcumin-induced Nrf2 protein expression.<br><br>CONCLUSIONS: CD36 expression and CD36-mediated P. falciparum phagocytosis by curcumin are dependent on ROS production and probably involve the Nrf2 pathway. The dual immunomodulatory and antimalarial mechanisms of curcumin action may mean that curcumin has potential as an adjuvant treatment limiting the risk of recrudescence following standard antimalarial therapy.}, }
@article {pmid22511408, year = {2012}, author = {Gutiérrez-Praena, D and Puerto, M and Prieto, AI and Jos, &#xc1; and Pichardo, S and Vasconcelos, V and Cameán, AM}, title = {Protective role of dietary N-acetylcysteine on the oxidative stress induced by cylindrospermopsin in tilapia (Oreochromis niloticus).}, journal = {Environmental toxicology and chemistry}, volume = {31}, number = {7}, pages = {1548-1555}, doi = {10.1002/etc.1838}, pmid = {22511408}, issn = {1552-8618}, mesh = {Acetylcysteine/*pharmacology ; Alkaloids ; Animals ; Bacterial Toxins ; Cichlids/*metabolism ; Cyanobacteria/chemistry ; Cyanobacteria Toxins ; Diet ; Dietary Supplements ; Glutamate-Cysteine Ligase/metabolism ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Transferase/metabolism ; Kidney/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism ; Male ; Oxidative Stress/*drug effects ; Protein Carbonylation ; Uracil/*analogs &amp; derivatives/toxicity ; }, abstract = {Cylindrospermopsin (CYN) is a toxin produced by various cyanobacteria species. Fish can be exposed to this cyanotoxin in their natural environments and in aquaculture ponds, and toxic effects can be derived. The present study investigated the effects of dietary N-acetylcysteine (NAC) on the oxidative stress induced by pure CYN and CYN from lyophilized cells of Aphanizomenon ovalisporum in tilapia (Oreochromis niloticus). Fish were pretreated with 0, 22, and 45 mg NAC/fish/d for a week, and on day seven, they received a single dose of 200 µg/kg CYN and were killed after 24 h. Oxidative biomarkers evaluated included lipid peroxidation, protein oxidation, glutathione (GSH)/oxidized glutathione (GSSG) ratio, activity of the enzyme γ-glutamylcysteine synthetase, and activity and gene expression of glutathione-S-transferase and glutathione peroxidase. Results showed that CYN induced oxidative stress as evidenced by the increase of lipid peroxidation and protein oxidation, the decrease in GSH/GSSG, and the alteration of the enzymatic activities assayed. Moreover, exposure to cyanobacterial cells containing CYN induced higher toxic effects in comparison to pure CYN. N-acetylcysteine supplementation was effective at reducing the toxicity induced by CYN, particularly at the highest dose employed, with a recovery of some of the biomarkers assayed to basal levels. Therefore, NAC can be considered a useful chemoprotectant that reduces hepatic and renal oxidative stress in the prophylaxis and treatment of CYN-related intoxication in fish.}, }
@article {pmid22511379, year = {2012}, author = {Sergie, Z and Mehran, R}, title = {NAC and CIN prevention: mounting evidence of inefficacy.}, journal = {Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography &amp; Interventions}, volume = {79}, number = {6}, pages = {927-928}, doi = {10.1002/ccd.24424}, pmid = {22511379}, issn = {1522-726X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Coronary Syndrome/*diagnostic imaging ; *Angioplasty, Balloon, Coronary ; Antioxidants/*administration &amp; dosage ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Female ; Humans ; Kidney Diseases/*prevention &amp; control ; Male ; }, }
@article {pmid22511233, year = {2012}, author = {Lee, S and Seo, J and Ryoo, S and Cuong, TD and Min, BS and Lee, JH}, title = {Malabaricone C inhibits PDGF-induced proliferation and migration of aortic smooth muscle cells through induction of heme oxygenase-1.}, journal = {Journal of cellular biochemistry}, volume = {113}, number = {9}, pages = {2866-2876}, doi = {10.1002/jcb.24161}, pmid = {22511233}, issn = {1097-4644}, mesh = {Animals ; Aorta/*cytology ; Cell Movement/*drug effects ; Cell Proliferation/*drug effects ; Cells, Cultured ; Heme Oxygenase-1/genetics/*metabolism ; Male ; Myocytes, Smooth Muscle/cytology/*drug effects/metabolism ; Platelet-Derived Growth Factor/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Resorcinols/*pharmacology ; }, abstract = {Malabaricone C (Mal-C), isolated from nutmeg, is known to exert a variety of pharmacological activities. However, the effect of Mal-C on vascular smooth muscle cells (VSMCs) is unknown. This study examined the effect of Mal-C on proliferation and migration of primary rat aortic smooth muscle cells (RASMCs) as well as its underlying mechanisms. Treatment of RASMCs with Mal-C induced both protein and mRNA expression of heme oxygenase-1 (HO-1) in a dose- and time-dependent manner. Mal-C-mediated HO-1 induction was inhibited by treatment with actinomycin D or by cycloheximide. SB203580 (a p38 inhibitor), SP600125 (a JNK inhibitor), U0126 (a MEK inhibitor), and N-acetylcysteine (NAC, an antioxidant) did not suppress Mal-C-induced HO-1 expression. In contrast, LY294002 (a PI3K inhibitor) blocked Mal-C-induced HO-1 expression. Moreover, RASMCs treated with Mal-C exhibited activation of AKT in a dose- and time-dependent manner. Treatment of RASMCs with Mal-C increased nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2), which is a key regulator of HO-1 expression, and this translocation was also inhibited by LY294002. Consistent with the notion that HO-1 has protective effects against VSMCs, Mal-C remarkably inhibited platelet-derived growth factor (PDGF)-induced proliferation and migration of RASMCs. However, inhibition of HO-1 significantly attenuated the inhibitory effects of Mal-C on PDGF-induced proliferation and migration of RASMCs. Taken together, these findings suggest that Mal-C could suppress PDGF-induced proliferation and migration of RASMCs through Nrf2 activation and subsequent HO-1 induction via the PI3K/AKT pathway, and may be a potential HO-1 inducer for preventing or treating vascular diseases.}, }
@article {pmid22510519, year = {2012}, author = {Egashira, N and Shirakawa, A and Abe, M and Niki, T and Mishima, K and Iwasaki, K and Oishi, R and Fujiwara, M}, title = {N-acetyl-L-cysteine inhibits marble-burying behavior in mice.}, journal = {Journal of pharmacological sciences}, volume = {119}, number = {1}, pages = {97-101}, doi = {10.1254/jphs.11228sc}, pmid = {22510519}, issn = {1347-8648}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antipsychotic Agents/*pharmacology ; Anxiety Disorders/*drug therapy ; Behavior, Animal/*drug effects ; Fluvoxamine/pharmacology ; Male ; Mianserin/analogs &amp; derivatives/pharmacology ; Mice ; Mice, Inbred ICR ; Mirtazapine ; Motor Activity/*drug effects ; Obsessive-Compulsive Disorder/*drug therapy ; alpha-Tocopherol/pharmacology ; }, abstract = {In the present study, we examined the effect of N-acetyl-L-cysteine (NAC), a glutamate-modulating agent, on marble-burying behavior in mice. Fluvoxamine (30 mg/kg, p.o.) and mirtazapine (3 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. Similarity, NAC (150 mg/kg, i.p.) significantly inhibited marble-burying behavior without affecting locomotor activity. On the other hand, the antioxidant α-tocopherol (10, 30, and 100 mg/kg, p.o.) had no effect on the marble-burying behavior. These results suggest that the glutamatergic system is involved in the marble-burying behavior, and NAC may be useful for treatment of OCD.}, }
@article {pmid22509835, year = {2012}, author = {Shen, SC and Lee, WR and Yang, LY and Tsai, HH and Yang, LL and Chen, YC}, title = {Quercetin enhancement of arsenic-induced apoptosis via stimulating ROS-dependent p53 protein ubiquitination in human HaCaT keratinocytes.}, journal = {Experimental dermatology}, volume = {21}, number = {5}, pages = {370-375}, doi = {10.1111/j.1600-0625.2012.01479.x}, pmid = {22509835}, issn = {1600-0625}, mesh = {Animals ; Apoptosis/*drug effects ; Arsenic/*pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Cell Survival/drug effects ; Fibroblasts/cytology/drug effects/metabolism ; Humans ; Keratinocytes/cytology/drug effects/*metabolism ; Leupeptins/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Models, Animal ; NIH 3T3 Cells ; Peroxides/metabolism ; Quercetin/*pharmacology ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/*metabolism ; Ubiquitination/*drug effects ; }, abstract = {In this study, QUE, but not the structurally related chemical, rutin, enhanced the cytotoxicity of arsenic trioxide (As(+3)) against the viability of normal human HaCaT keratinocytes via induction of apoptosis. QUE enhancement of As(+3)-mediated apoptosis was accompanied by increased intracellular peroxide production according to a DCFH-DA analysis, and DNA ladders induced by QUE/As(+3) were inhibited by adding the antioxidative compound, N-acetyl cysteine (NAC). A loss of the mitochondrial membrane potential by QUE/As(+3) was observed according to DiOC(6) staining in concert with increased Bax protein and cytosolic cytochrome (Cyt) c protein expression in HaCaT cells, which was prevented by the addition of NAC. A decrease in the p53 protein with increased protein ubiquitination was detected in QUE/As(+3)-treated HaCaT cells, and this was prevented by the addition of NAC. The decrease in the p53 protein by QUE/As(+3) was reversed by adding the proteasome inhibitor, MG132. L-Buthionine sulphoximine (BSO) enhanced the cytotoxicity of As(+3) against the viability of HaCaT cells with reduced p53 protein through inducing protein ubiquitination and reactive oxygen species (ROS) production, and disrupting the mitochondrial membrane potential in HaCaT cells. Additionally, QUE and BSO enhanced the cytotoxic effects of monomethylarsonous acid (MMA(+3)) but not other arsenic compounds in accordance with increased p53 protein ubiquitination in HaCaT cells. QUE plus As(+3) stimulation of apoptosis in human HaCaT keratinocytes via activating ROS-dependent p53 protein ubiquitination may offer a rationale for the use of QUE to improve the clinical efficacy of arsenics in treating psoriasis.}, }
@article {pmid22508082, year = {2012}, author = {Ljubisavljevic, S and Stojanovic, I and Pavlovic, D and Milojkovic, M and Vojinovic, S and Sokolovic, D and Stevanovic, I}, title = {Correlation of nitric oxide levels in the cerebellum and spinal cord of experimental autoimmune encephalomyelitis rats with clinical symptoms.}, journal = {Acta neurobiologiae experimentalis}, volume = {72}, number = {1}, pages = {33-39}, doi = {10.55782/ane-2012-1878}, pmid = {22508082}, issn = {1689-0035}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cerebellum/drug effects/metabolism ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/immunology/*metabolism ; Female ; Freund's Adjuvant/pharmacology ; Myelin Basic Protein/immunology ; Nitric Oxide/*metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord/*metabolism ; }, abstract = {Experimental autoimmune encephalomyelitis (EAE) is a well-established cell-mediated autoimmune inflammatory disease of the CNS, which has been used as a model of the human demyelinating disease. EAE is characterized by infiltration of the CNS by lymphocytes and mononuclear cells, microglial and astrocytic hypertrophy, and demyelination which cumulatively contribute to clinical expression of the disease. EAE was induced in female Sprague-Dawley rats, 3 months old (300 g ± 20 g), by immunization with myelin basic protein (MBP) in combination with Complete Freund's adjuvant (CFA). The animals were divided into 7 groups: control, EAE, CFA, EAE + aminoguanidine (AG), AG, EAE + N-acetyl-L-cysteine (NAC) and NAC. The animals were sacrificed 15 days after EAE induction, and the level of nitric oxide (NO(·)) production was determined by measuring nitrite and nitrate concentrations in 10% homogenate of cerebellum and spinal cord. Obtained results showed that the level of NO(·) was significantly increased in all examined tissues of the EAE rats compared to the control and CFA groups. Also, AG and NAC treatment decreased the level of NO(·) in all tissues compared to the EAE group. The level of NO(·) is increased significantly in the spinal cord compared to the cerebellum. The clinical course of the EAE was significantly decreased in the EAE groups treated with AG and NAC during the development of the disease compared to EAE group and its correlates with the NO(·) level in cerebellum and spinal cord. The findings of our work suggest that NO(·) and its derivatives play an important role in multiple sclerosis (MS). It may be the best target for new therapies in human demyelinating disease and recommend the new therapeutic approaches based on a decreased level of NO(·) during the course of MS.}, }
@article {pmid22507072, year = {2012}, author = {Lee, TM and Chen, CC and Chang, NC}, title = {Cardiac sympathetic hyperinnervation in deoxycorticosterone acetate-salt hypertensive rats.}, journal = {Clinical science (London, England : 1979)}, volume = {123}, number = {7}, pages = {445-457}, doi = {10.1042/CS20120080}, pmid = {22507072}, issn = {1470-8736}, mesh = {Animals ; Autonomic Nervous System Diseases/*etiology/metabolism/physiopathology ; Blood Pressure/physiology ; Cardiac Pacing, Artificial ; Desoxycorticosterone/*pharmacology ; Glutathione/metabolism ; Hypertension/*chemically induced/*complications/physiopathology ; Hypertrophy, Left Ventricular/*etiology/metabolism/physiopathology ; Male ; Mineralocorticoids/pharmacology ; Myocardium/metabolism ; Nerve Growth Factor/genetics/metabolism ; Norepinephrine/metabolism ; Oxidative Stress/physiology ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Sodium Chloride, Dietary/pharmacology ; Superoxides/metabolism ; Tachycardia, Ventricular/etiology/metabolism/physiopathology ; }, abstract = {Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (deoxycorticosterone acetate)-salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC (N-acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT-PCR (reverse transcription-PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO (L-buthionine sulfoximine), an inhibitor of glutamate-cysteine ligase. In conclusion, DOCA-salt treatment contributes to up-regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation.}, }
@article {pmid22503982, year = {2012}, author = {Hino, S and Kito, A and Yokoshima, R and Sugino, R and Oshima, K and Morita, T and Okajima, T and Nadano, D and Uchida, K and Matsuda, T}, title = {Discharge of solubilized and Dectin-1-reactive β-glucan from macrophage cells phagocytizing insoluble β-glucan particles: involvement of reactive oxygen species (ROS)-driven degradation.}, journal = {Biochemical and biophysical research communications}, volume = {421}, number = {2}, pages = {329-334}, doi = {10.1016/j.bbrc.2012.04.009}, pmid = {22503982}, issn = {1090-2104}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Antipyrine/analogs &amp; derivatives/pharmacology ; Cell Line ; Edaravone ; Enzyme-Linked Immunosorbent Assay ; Humans ; Lectins, C-Type/*immunology ; Macrophages, Peritoneal/drug effects/*immunology ; Mice ; *Phagocytosis ; Reactive Oxygen Species/*metabolism ; Solubility ; beta-Glucans/analysis/*immunology ; }, abstract = {Phagocytes engulf pathogenic microbes, kill them and degrade their cellular macromolecules by hydrolytic enzymes in phagolysosomes. However, such enzymes are unable to degrade some microbial polysaccharides, and fate of such indigestible polysaccharides in phagocytes remains uncertain. Using the extracellular domain of Dectin-1 as β-glucan-specific probes, we succeeded in detection of soluble and Dectin-1-reactive β-glucan discharged from mouse RAW 264.7 and human THP-1 macrophage cell lines as well as mouse peritoneal macrophages, which had phagocytized insoluble β-glucan particles. The RAW 264.7 cell culture-supernatant containing the discharged β-glucan stimulated naïve RAW 264.7 cells, resulting in the induction of cytokine expression. Such discharge of Dectin-1-reactive β-glucan from macrophage cells was inhibited by either NADPH oxidase inhibitors (apocynin and diphenylene iodonium) or radical scavengers (N-acetyl cysteine and MCI-186). Moreover, reactive oxygen species (ROS) produced by a Cu(2+)/ascorbic acid system solubilized insoluble β-glucan particles in vitro, and a part of the solubilized β-glucan was Dectin-1 reactive and biologically active in macrophage activation. The soluble and biologically active β-glucan was degraded further during prolonged exposure to ROS. These results suggest that degraded but Dectin-1-reactive β-glucan is discharged from macrophage cells phagocytizing insoluble β-glucan particles and stimulates not only themselves again but also the other naïve phagocytes, leading to the effective elimination of infecting microbes and the ultimate breakdown and inactivation of metabolically resistant β-glucan.}, }
@article {pmid22498431, year = {2012}, author = {Liu, J and Wang, Y and Cui, J and Xing, L and Shen, H and Wu, S and Lian, H and Wang, J and Yan, X and Zhang, X}, title = {Ochratoxin A induces oxidative DNA damage and G1 phase arrest in human peripheral blood mononuclear cells in vitro.}, journal = {Toxicology letters}, volume = {211}, number = {2}, pages = {164-171}, doi = {10.1016/j.toxlet.2012.03.800}, pmid = {22498431}, issn = {1879-3169}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cyclin D1/metabolism ; Cyclin-Dependent Kinase 4/metabolism ; *DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; G1 Phase Cell Cycle Checkpoints/*drug effects ; Glutathione/metabolism ; Humans ; Leukocytes, Mononuclear/cytology/*drug effects/metabolism ; Ochratoxins/*toxicity ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Ochratoxin A is one of the most abundant food-contaminating mycotoxins worldwide, and its immunosuppressive effects in human caused more and more concern in biomedical field. In the present study, the toxicity of OTA on human peripheral blood mononuclear cells (hPBMC) was explored by analyzing the involvement of oxidative pathway. It was found that OTA treatment led to the release of reactive oxygen species (ROS) and the increase of 8-hydroxydeoxyguanosine (8-OHdG), an important biomarker of oxidative DNA stress. Moreover, we found that OTA treatment induced DNA strand breaks in hPBMC as evidenced by DNA comet tails formation and increased γ-H2AX expression. In addition, OTA could induce cell cycle arrest at G1 phase by down-regulating the expression of CDK4 and cyclinD1 protein, as well as apoptosis in hPBMC in vitro. Pre-treatment of hPBMC with antioxidant, N-acetyl-L-cysteine (NAC), could reduce OTA-induced ROS release and DNA damage, thus confirming the involvement of oxidative DNA damage in the OTA genotoxicity in hPBMC. NAC pre-treatment could also significantly prevent OTA-induced down-regulation of CDK4 and cyclinD1 expression in hPBMC. All the results demonstrated the involvement of oxidative pathway in OTA mediated cytotoxicity in human immune cells, which including the ROS accumulation-oxidative DNA damage-G1 arrest and apoptosis. Our results provide new insights into the molecular mechanisms by which OTA might promote immunotoxicity.}, }
@article {pmid22496405, year = {2012}, author = {Simone, S and Cosola, C and Loverre, A and Cariello, M and Sallustio, F and Rascio, F and Gesualdo, L and Schena, FP and Grandaliano, G and Pertosa, G}, title = {BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation.}, journal = {American journal of physiology. Renal physiology}, volume = {303}, number = {1}, pages = {F23-34}, doi = {10.1152/ajprenal.00328.2011}, pmid = {22496405}, issn = {1522-1466}, mesh = {Acute Kidney Injury/*metabolism/pathology ; Bone Morphogenetic Protein 2/genetics/*metabolism ; Carcinoma, Renal Cell/genetics/metabolism/pathology ; Cell Differentiation/*physiology ; Cells, Cultured ; Fibronectins/metabolism ; Fibrosis/metabolism/pathology ; Humans ; Kidney/*metabolism/pathology ; Kidney Neoplasms/genetics/metabolism/pathology ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Stem Cells/*metabolism/pathology ; Up-Regulation ; }, abstract = {Adult renal progenitor cells (ARPCs) isolated from the human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling, and regeneration processes in several tissues. The aim of this study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidneys, and it was upregulated in vivo after delayed graft function (DGF) of renal transplantation, a condition of AKI. ARPCs expressed BMP receptors, suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced reactive oxygen species (ROS) production, NADPH oxidase activity, and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2-expressing CD133+ cells at the tubular level after DGF. BMP-2 incubation induced α-smooth muscle actin (SMA), collagen I, and fibronectin protein expression in ARPCs. Moreover, α-SMA colocalized with CD133 in vivo after DGF. The oxidative stimulus (H(2)O(2)) induced α-SMA expression in ARPCs, while the antioxidant N-acetyl-cysteine inhibited BMP-2-induced α-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that 1) ARPCs express BMP-2, 2) this expression is increased in a model of AKI; 3) BMP-2 may induce the commitment of ARPCs toward a myofibroblastic phenotype in vitro and in vivo; and 4) this profibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage.}, }
@article {pmid22493722, year = {2012}, author = {Krawczyk, SA and Haller, JF and Ferrante, T and Zoeller, RA and Corkey, BE}, title = {Reactive oxygen species facilitate translocation of hormone sensitive lipase to the lipid droplet during lipolysis in human differentiated adipocytes.}, journal = {PloS one}, volume = {7}, number = {4}, pages = {e34904}, pmid = {22493722}, issn = {1932-6203}, support = {R01 DK035914/DK/NIDDK NIH HHS/United States ; R01 DK056690/DK/NIDDK NIH HHS/United States ; DK46200/DK/NIDDK NIH HHS/United States ; P30 DK046200/DK/NIDDK NIH HHS/United States ; DK056690/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adipocytes/*drug effects/metabolism/pathology ; Adipose Tissue/*drug effects/metabolism/pathology ; Adult ; Antioxidants/pharmacology ; Biphenyl Compounds/pharmacology ; Colforsin/adverse effects ; Female ; Humans ; Lipids/chemistry ; Lipolysis/drug effects ; Middle Aged ; Obesity/metabolism/pathology ; Onium Compounds/pharmacology ; Phosphorylation/drug effects ; Primary Cell Culture ; Protein Transport/drug effects ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Resveratrol ; Serine/metabolism ; *Signal Transduction ; Sterol Esterase/*metabolism ; Stilbenes/pharmacology ; }, abstract = {In obesity, there is an increase in reactive oxygen species (ROS) within adipose tissue caused by increases in inflammation and overnutrition. Hormone sensitive lipase (HSL) is part of the canonical lipolytic pathway and critical for complete lipolysis. This study hypothesizes that ROS is a signal that integrates regulation of lipolysis by targeting HSL. Experiments were performed with human differentiated adipocytes from the subcutaneous depot. Antioxidants were employed as a tool to decrease ROS, and it was found that scavenging ROS with diphenyliodonium, N-acetyl cysteine, or resveratrol decreased lipolysis in adipocytes. HSL phosphorylation of a key serine residue, Ser552, as well as translocation of this enzyme from the cytosol to the lipid droplet upon lipolytic stimulation were both abrogated by scavenging ROS. The phosphorylation status of other serine residues on HSL were not affected. These findings are significant because they document that ROS contributes to the physiological regulation of lipolysis via an effect on translocation. Such regulation could be useful in developing new obesity therapies.}, }
@article {pmid22490108, year = {2012}, author = {Lee, SS and Tsai, CH and Ho, YC and Yu, CC and Chang, YC}, title = {Heat shock protein 27 expression in areca quid chewing-associated oral squamous cell carcinomas.}, journal = {Oral diseases}, volume = {18}, number = {7}, pages = {713-719}, doi = {10.1111/j.1601-0825.2012.01933.x}, pmid = {22490108}, issn = {1601-0825}, mesh = {Acetylcysteine/pharmacology ; Areca/*adverse effects ; Arecoline/*adverse effects ; Carcinoma, Squamous Cell/etiology/*metabolism ; Case-Control Studies ; Catechin/analogs &amp; derivatives/pharmacology ; Cyclooxygenase 2 Inhibitors/pharmacology ; Down-Regulation ; Female ; Flavonoids/pharmacology ; Gene Expression/drug effects ; Gene Expression Regulation, Neoplastic ; HSP27 Heat-Shock Proteins/*biosynthesis/genetics ; Humans ; Imidazoles/pharmacology ; Male ; Middle Aged ; Mouth Neoplasms/etiology/*metabolism ; Nitrobenzenes/pharmacology ; Pyridines/pharmacology ; Quercetin/pharmacology ; Sulfonamides/pharmacology ; }, abstract = {OBJECTIVES: Heat shock protein (HSP) 27 is a low-molecular-weight protein that functions as a molecular chaperone and plays a cytoprotective role through its antioxidant activity during cell stress. Areca quid chewing is associated with the high incidence of oral squamous cell carcinomas (OSCCs) in Taiwan. The aim of this study was to compare heat shock protein 27 (HSP27) expression in OSCCs and the normal oral tissues.<br><br>METHODS: Forty-eight OSCCs from areca quid chewers and ten normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry for HSP27. The normal human oral keratinocytes (HOKs) were challenged with arecoline, the major alkaloid of areca nut, by Western blot for HSP27. Furthermore, epigallocatechin-3 gallate (EGCG), glutathione precursor N-acetyl-L-cysteine (NAC), cyclooxygenase-2 inhibitor NS-398, HSP inhibitor quercetin, extracellular signal-regulated protein kinase (ERK) inhibitor PD98059, and p38 inhibitor SB203580 were added to find the possible regulatory mechanisms.<br><br>RESULTS: Heat shock protein 27 exhibited higher expression in OSCCs than normal specimens (P < 0.05). Arecoline was found to elevate HSP27 expression in a dose- and time-dependent manner (P < 0.05). The additions of pharmacological agents were found to inhibit arecoline-induced HSP27 expression (P < 0.05).<br><br>CONCLUSIONS: Heat shock protein 27 expression is significantly elevated in areca quid chewing-associated OSCCs. Arecoline-induced HSP27 expression was downregulated by EGCG, NS398, NAC, quercetin, PD98059, and SB203580.}, }
@article {pmid22487454, year = {2012}, author = {Belrose, JC and Xie, YF and Gierszewski, LJ and MacDonald, JF and Jackson, MF}, title = {Loss of glutathione homeostasis associated with neuronal senescence facilitates TRPM2 channel activation in cultured hippocampal pyramidal neurons.}, journal = {Molecular brain}, volume = {5}, number = {}, pages = {11}, pmid = {22487454}, issn = {1756-6606}, support = {15514//Canadian Institutes of Health Research/Canada ; 44008//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Diphosphate Ribose/pharmacology ; Animals ; Cells, Cultured ; *Cellular Senescence/drug effects ; Gene Expression Regulation/drug effects ; Glutathione/*metabolism/pharmacology ; HEK293 Cells ; *Homeostasis/drug effects ; Humans ; *Ion Channel Gating/drug effects ; Mice ; Neurons/*cytology/drug effects/metabolism ; Pyramidal Cells/cytology/drug effects/*metabolism ; RNA, Messenger/genetics/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Sulfhydryl Compounds/metabolism ; TRPM Cation Channels/genetics/*metabolism ; Time Factors ; }, abstract = {BACKGROUND: Glutathione (GSH) plays an important role in neuronal oxidant defence. Depletion of cellular GSH is observed in neurodegenerative diseases and thereby contributes to the associated oxidative stress and Ca2+ dysregulation. Whether depletion of cellular GSH, associated with neuronal senescence, directly influences Ca2+ permeation pathways is not known. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+ permeable non-selective cation channel expressed in several cell types including hippocampal pyramidal neurons. Moreover, activation of TRPM2 during oxidative stress has been linked to cell death. Importantly, GSH has been reported to inhibit TRPM2 channels, suggesting they may directly contribute to Ca2+ dysregulation associated with neuronal senescence. Herein, we explore the relation between cellular GSH and TRPM2 channel activity in long-term cultures of hippocampal neurons.<br><br>RESULTS: In whole-cell voltage-clamp recordings, we observe that TRPM2 current density increases in cultured pyramidal neurons over time in vitro. The observed increase in current density was prevented by treatment with NAC, a precursor to GSH synthesis. Conversely, treatment of cultures maintained for 2 weeks in vitro with L-BSO, which depletes GSH by inhibiting its synthesis, augments TRPM2 currents. Additionally, we demonstrate that GSH inhibits TRPM2 currents through a thiol-independent mechanism, and produces a 3.5-fold shift in the dose-response curve generated by ADPR, the intracellular agonist for TRPM2.<br><br>CONCLUSION: These results indicate that GSH plays a physiologically relevant role in the regulation of TRPM2 currents in hippocampal pyramidal neurons. This interaction may play an important role in aging and neurological diseases associated with depletion of GSH.}, }
@article {pmid22482460, year = {2012}, author = {George, S and Lin, S and Ji, Z and Thomas, CR and Li, L and Mecklenburg, M and Meng, H and Wang, X and Zhang, H and Xia, T and Hohman, JN and Lin, S and Zink, JI and Weiss, PS and Nel, AE}, title = {Surface defects on plate-shaped silver nanoparticles contribute to its hazard potential in a fish gill cell line and zebrafish embryos.}, journal = {ACS nano}, volume = {6}, number = {5}, pages = {3745-3759}, pmid = {22482460}, issn = {1936-086X}, support = {R01 ES016746/ES/NIEHS NIH HHS/United States ; RC2 ES018766/ES/NIEHS NIH HHS/United States ; U19 ES019528/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; Gills/*cytology ; Mass Spectrometry ; *Metal Nanoparticles ; Microscopy, Electron, Transmission ; Silver/*chemistry ; Surface Properties ; Zebrafish/*embryology ; }, abstract = {We investigated and compared nanosize Ag spheres, plates, and wires in a fish gill epithelial cell line (RT-W1) and in zebrafish embryos to understand the mechanism of toxicity of an engineered nanomaterial raising considerable environmental concern. While most of the Ag nanoparticles induced N-acetyl cysteine sensitive oxidative stress effects in RT-W1, Ag nanoplates were considerably more toxic than other particle shapes. Interestingly, while Ag ion shedding and bioavailability failed to comprehensively explain the high toxicity of the nanoplates, cellular injury required direct particle contact, resulting in cell membrane lysis in RT-W1 as well as red blood cells (RBC). Ag nanoplates were also considerably more toxic in zebrafish embryos in spite of their lesser ability to shed Ag into the exposure medium. To elucidate the "surface reactivity" of Ag nanoplates, high-resolution transmission electron microscopy was performed and demonstrated a high level of crystal defects (stacking faults and point defects) on the nanoplate surfaces. Surface coating with cysteine was used to passivate the surface defects and demonstrated a reduction of toxicity in RT-W1 cells, RBC, and zebrafish embryos. This study demonstrates the important role of crystal defects in contributing to Ag nanoparticle toxicity in addition to the established roles of Ag ion shedding by Ag nanoparticles. The excellent correlation between the in vitro and in vivo toxicological assessment illustrates the utility of using a fish cell line in parallel with zebrafish embryos to perform a predictive environmental toxicological paradigm.}, }
@article {pmid22481525, year = {2012}, author = {Wu, JP and Chen, HC and Li, MH}, title = {Bioaccumulation and toxicodynamics of cadmium to freshwater planarian and the protective effect of N-acetylcysteine.}, journal = {Archives of environmental contamination and toxicology}, volume = {63}, number = {2}, pages = {220-229}, doi = {10.1007/s00244-012-9764-5}, pmid = {22481525}, issn = {1432-0703}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Cadmium/analysis/*toxicity ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; *Models, Animal ; Oxidative Stress/drug effects ; Planarians/chemistry/*drug effects/metabolism ; Random Allocation ; Toxicity Tests, Acute ; Water Pollutants, Chemical/analysis/*toxicity ; }, abstract = {Although toxic responses of freshwater planarians after exposure to environmental toxicants can be observed through external toxicological end points, physiological responses inside the bodies of treated planarians have rarely been investigated. The present study was designed, using cadmium (Cd) as a reference toxicant, to determine its bioaccumulation and toxicodynamics in the freshwater planarian, Dugesia japonica, after acute toxicity was obtained. Accumulated Cd concentrations, metallothionein levels, and the oxidative status in planarians were determined after exposure to Cd. Furthermore, we hypothesized that the acute death of Cd-treated planarians was associated with increased oxidative stress. After Cd-treated planarians were coexposed to antioxidant, N-acetylcysteine (NAC), we found that NAC protected planarians from Cd lethality by maintaining the oxidative status and decreasing the bioaccumulation of Cd. The results of the present study support planarians being used as a practical model for toxicological studies of environmental contaminants in the future.}, }
@article {pmid22477544, year = {2012}, author = {Begrow, F and Böckenholt, C and Ehmen, M and Wittig, T and Verspohl, EJ}, title = {Effect of myrtol standardized and other substances on the respiratory tract: ciliary beat frequency and mucociliary clearance as parameters.}, journal = {Advances in therapy}, volume = {29}, number = {4}, pages = {350-358}, doi = {10.1007/s12325-012-0014-z}, pmid = {22477544}, issn = {1865-8652}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Infective Agents/*pharmacology ; Cilia/drug effects/physiology ; Cyclohexanols/*pharmacology ; Dose-Response Relationship, Drug ; Drug Combinations ; Eucalyptol ; Expectorants/*pharmacology ; Female ; Mice ; Mice, Inbred C57BL ; Microdialysis ; Monoterpenes/*pharmacology ; Mucociliary Clearance/*drug effects ; Rats ; Rats, Wistar ; Trachea/*drug effects ; }, abstract = {INTRODUCTION: Myrtol standardized is a phytomedicine obtained by distillation, consisting of many constituents. In vitro and in vivo, the major monterpenes, d-limonene, 1,8-cineole, and alpha-pinene, are used as biological marker substances. Myrtol standardized has secretolytic, secretomotor, and mucolytic effects in addition to anti-inflammatory and antioxidative actions. The aim of the study was to investigate the effects of different concentrations of Myrtol standardized on in vivo mucociliary clearance in mice and the ciliary beat frequency (CBF) in rat tracheal rings.<br><br>METHODS: Data regarding the effects of 1,8-cineole and N-acetylcysteine (NAC) were compared. Salbutamol was used as a positive control. CBF was measured using rat tracheal explants and a high-speed video camera linked to a microscope with specific software equipment. Mucociliary clearance was determined using the microdialysis technique, which measured the acceleration of a fluorescent sample in the trachea in vivo.<br><br>RESULTS: Myrtol standardized accelerated both CBF and mucociliary transport in a concentration-dependent manner. Significant effects were seen at a concentration of 0.01% Myrtol regarding CBF (P<0.01) and 17.1 mg/kg body weight regarding mucociliary clearance experiments (P<0.05) according to doses relevant to humans. The 1,8-cineole dosage relative to humans only accelerated the mucociliary clearance in vivo without having an effect on the CBF. Extremely high doses of Myrtol were not able to additionally increase the CBF effect in comparison to salbutamol. Compared to NAC, also used in a dosage relative to humans, Myrtol standardized showed a tendency to be more effective.<br><br>CONCLUSION: In summary, the present data suggest that Myrtol standardized is a pharmacologically important drug which, when used at a dose relative to humans, shows positive effects on both measured parameters, CBF and mucociliary clearance, in vivo.}, }
@article {pmid22473610, year = {2012}, author = {Xu, X and Liu, T and Zhang, A and Huo, X and Luo, Q and Chen, Z and Yu, L and Li, Q and Liu, L and Lun, ZR and Shen, J}, title = {Reactive oxygen species-triggered trophoblast apoptosis is initiated by endoplasmic reticulum stress via activation of caspase-12, CHOP, and the JNK pathway in Toxoplasma gondii infection in mice.}, journal = {Infection and immunity}, volume = {80}, number = {6}, pages = {2121-2132}, pmid = {22473610}, issn = {1098-5522}, mesh = {Animals ; Apoptosis/*drug effects ; Caspase 12/genetics/metabolism ; DNA/metabolism ; Endoplasmic Reticulum/*metabolism ; Female ; Gene Expression Regulation/physiology ; Glutathione/metabolism ; Lipid Peroxidation ; MAP Kinase Kinase 4/genetics/metabolism ; MAP Kinase Kinase Kinase 5/genetics/metabolism ; MAP Kinase Signaling System/physiology ; Mice ; Mice, Inbred ICR ; NADH, NADPH Oxidoreductases/genetics/metabolism ; NADPH Oxidase 1 ; Oxidative Stress ; Placenta/metabolism/parasitology ; Pregnancy ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Stress, Physiological/*physiology ; Toxoplasmosis, Animal/*metabolism/pathology ; Transcription Factor CHOP/genetics/metabolism ; Trophoblasts/cytology/*drug effects ; }, abstract = {Toxoplasma gondii infection in pregnant women may result in abortion or in fetal teratogenesis; however, the underlying mechanisms are still unclear. In this paper, based on a murine model, we showed that maternal infection with RH strain T. gondii tachyzoites induced elevated production of reactive oxygen species (ROS), local oxidative stress, and subsequent apoptosis of placental trophoblasts. PCR array analysis of 84 oxidative stress-related genes demonstrated that 27 genes were upregulated at least 2-fold and that 9 genes were downregulated at least 2-fold in the T. gondii infection group compared with levels in the control group. The expression of NADPH oxidase 1 (Nox1) and glutathione peroxidase 6 (Gpx6) increased significantly, about 25-fold. The levels of malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) increased significantly with T. gondii infection, and levels of glutathione (GSH) decreased rapidly. T. gondii infection increased the early expression of endoplasmic reticulum stress (ERS) markers, followed by cleavage of caspase-12, activation of ASK1/JNK, and increased apoptosis of trophoblasts, both in vivo and in vitro. The apoptosis of trophoblasts, the activation of caspase-12 and the ASK1/JNK pathway, and the production of peroxides were dramatically inhibited by pretreatment with N-acetylcysteine (NAC). The upregulation of Nox1 was contact dependent and preceded the increase in levels of ERS markers and the activation of the proapoptosis cascade. Thus, we concluded that apoptosis in placental trophoblasts was initiated predominantly by ROS-mediated ERS via activation of caspase-12, CHOP, and the JNK pathway in acute T. gondii infection. Elevated ROS production is the central event in T. gondii-induced apoptosis of placental trophoblasts.}, }
@article {pmid22472608, year = {2012}, author = {Hota, KB and Hota, SK and Srivastava, RB and Singh, SB}, title = {Neuroglobin regulates hypoxic response of neuronal cells through Hif-1α- and Nrf2-mediated mechanism.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {32}, number = {6}, pages = {1046-1060}, pmid = {22472608}, issn = {1559-7016}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Hypoxia ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Free Radical Scavengers/pharmacology ; Globins/*metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Male ; NF-E2-Related Factor 2/*metabolism ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/metabolism ; Neuroglobin ; Neurons/*metabolism ; Oxidation-Reduction/drug effects ; *Proteolysis ; Rats, Sprague-Dawley ; }, abstract = {Oxygen sensing in hypoxic neurons has been classically attributed to cytochrome c oxidase and prolyl-4-hydroxylases and involves stabilization of transcription factors, hypoxia-inducible factor-1α (Hif-1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) that mediate survival responses. On the contrary, release of cytochrome c into the cytosol during hypoxic stress triggers apoptosis in neuronal cells. We, here advocate that the redox state of neuroglobin (Ngb) could regulate both Hif-1α and Nrf2 stabilization and cytochrome c release during hypoxia. The hippocampal regions showing higher expression of Ngb were less susceptible to global hypoxia-mediated neurodegeneration. During normoxia, Ngb maintained cytochrome c in the reduced state and prevented its release from mitochondria by using cellular antioxidants. Greater turnover of oxidized cytochrome c and increased utilization of cellular antioxidants during acute hypoxia altered cellular redox status and stabilized Hif-1α and Nrf2 through Ngb-mediated mechanism. Chronic hypoxia, however, resulted in oxidation and degradation of Ngb, accumulation of ferric ions and release of cytochrome c that triggered apoptosis. Administration of N-acetyl-cysteine during hypoxic conditions improved neuronal survival by preventing Ngb oxidation and degradation. Taken together, these results establish a role for Ngb in regulating both the survival and apoptotic mechanisms associated with hypoxia.}, }
@article {pmid22470450, year = {2012}, author = {Kang, X and Xie, Q and Zhou, X and Li, F and Huang, J and Liu, D and Huang, T}, title = {Effects of hepatitis B virus S protein exposure on sperm membrane integrity and functions.}, journal = {PloS one}, volume = {7}, number = {3}, pages = {e33471}, pmid = {22470450}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Annexin A5/metabolism ; Antibodies, Monoclonal/immunology/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 8/metabolism ; Caspase 9/metabolism ; Cell Membrane/drug effects ; Chromosomes/metabolism ; DNA Damage/drug effects ; Hepatitis B Surface Antigens/immunology/*pharmacology ; Hepatitis B virus/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Phosphatidylserines/metabolism ; Propidium/pharmacology ; Reactive Oxygen Species/metabolism ; Spermatozoa/*drug effects/metabolism ; }, abstract = {BACKGROUND: Hepatitis B is a public health problem worldwide. Viral infection can affect a man's fertility, but only scant information about the influence of hepatitis B virus (HBV) infection on sperm quality is available. The purpose of this study was to investigate the effect of hepatitis B virus S protein (HBs) on human sperm membrane integrity and functions.<br><br>METHODS/PRINCIPAL FINDINGS: Reactive oxygen species (ROS), lipid peroxidation (LP), total antioxidant capacity (TAC) and phosphatidylserine (PS) externalization were determined. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assays and flow cytometric analyses were performed. (1) After 3 h incubation with 25 &#xb5;g/ml of HBs, the average rates of ROS positive cells, annexin V-positive/propidium iodide (PI)-negative cells, Caspases-3,-8,-9 positive cells and TUNEL-positive cells were significantly increased in the test groups as compared to those in the control groups, while TAC level was decreased when compared with the control. The level of malondialdehyde (MDA) in the sperm cells exposed to 50 &#xb5;g/ml of HBs for 3 h was significantly higher than that in the control (P<0.05-0.01). (2) HBs increased the MDA levels and the numbers of ROS positive cells, annexin V-positive/PI-negative cells, caspases-3, -8, -9 positive cells and TUNEL-positive cells in a dose-dependent manner. (3) HBs monoclonal antibody (MAb) and N-Acetylcysteine (NAC) reduced the number of ROS-positive sperm cells. (4) HBs decreased the TAC levels in sperm cells in a dose-dependent manner.<br><br>CONCLUSION: HBs exposure could lead to ROS generation, lipid peroxidation, TAC reduction, PS externalization, activation of caspases, and DNA fragmentation, resulting in increased apoptosis of sperm cells and loss of sperm membrane integrity and causing sperm dysfunctions.}, }
@article {pmid22470108, year = {2012}, author = {Shang, F and Wang, J and Liu, X and Li, J and Zheng, Q and Xue, Y and Zhao, L}, title = {Involvement of reactive oxygen species and JNK in increased expression of MCP-1 and infiltration of inflammatory cells in pressure-overloaded rat hearts.}, journal = {Molecular medicine reports}, volume = {5}, number = {6}, pages = {1491-1496}, doi = {10.3892/mmr.2012.852}, pmid = {22470108}, issn = {1791-3004}, mesh = {Acetylcysteine/pharmacology ; Administration, Oral ; Animals ; Antibodies, Phospho-Specific/immunology ; Aortic Coarctation/physiopathology ; Chemokine CCL2/genetics/*metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation ; Heart/*physiopathology ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Male ; Myocardium/*metabolism ; Pressure ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Ventricular Remodeling/drug effects ; }, abstract = {Increasing evidence has shown that inflammation is involved in pressure overload-induced cardiac remodeling. Monocyte chemoattractant protein-1 (MCP-1) plays a pivotal role in the inflammatory process. However, the mechanisms underlying the upregulation of MCP-1 expression remain poorly understood. In the present study, we examined the hypothesis that an increased production of reactive oxygen species (ROS) mediates the upregulation of MCP-1. In a pressure-overloaded rat heart model with abdominal aortic coarctation (AC), superoxide dismutase-inhibitable cytochrome C reduction assay showed that ROS generation in the myocardium increased significantly at 1 week by 61% (n=8, P<0.01), peaked at 2 weeks and maintained these high levels for 4 weeks. The elevation of ROS was paralleled by the increased expression of MCP-1 and left ventricular remodeling (cardiac hypertrophy, perivascular and interstitial fibrosis). The oral administration of the antioxidant, N-acetylcysteine (NAC, 0.2 g/kg/day), for 2 or 4 weeks, significantly attenuated ROS production by 69 and 68%, respectively (n=8, P<0.01), as well as left ventricular remodeling. NAC treatment for 2 weeks also significantly reduced the MCP-1 mRNA and protein levels by 52 and 60%, respectively (n=4-8, both P<0.01), but had no effect on blood pressure. In the rats with AC at 2 weeks, when MCP-1 expression and inflammation changes were overt, immunoblotting with phospho-specific antibodies revealed that extracellular regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK), but not p38 mitogen-activated protein kinase, were activated. NAC administration attenuated JNK activation, but had no effect on ERK. Our results suggest that increased ROS production may play an important role in the increased expression of MCP-1 in pressure overload-induced cardiac remodeling. JNK is likely involved in the signaling pathway.}, }
@article {pmid22465686, year = {2012}, author = {Lee, JE and Kang, JS and Ki, YW and Park, JH and Shin, IC and Koh, HC}, title = {Fluazinam targets mitochondrial complex I to induce reactive oxygen species-dependent cytotoxicity in SH-SY5Y cells.}, journal = {Neurochemistry international}, volume = {60}, number = {8}, pages = {773-781}, doi = {10.1016/j.neuint.2012.03.007}, pmid = {22465686}, issn = {1872-9754}, mesh = {Aminopyridines/*pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Cell Line, Tumor ; Humans ; Mitochondria/*enzymology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Although the underlying cause of Parkinson's disease (PD) is not well characterized, epidemiological studies suggest that exposure to agricultural chemicals is a risk factor for PD. Fluazinam (FZN) is a new active ingredient for the control of grey mould, belonging to the novel broad spectrum phenylpyridinamine fungicides. We used human neuroblastoma SH-SY5Y cells to investigate mechanisms of dopaminergic cell death in response to FZN. FZN treatment produced dose-dependent cytotoxicity, and decreased the tyrosine hydroxylase (TH) expression in SH-SY5Y cells. We provided evidence for the occurrence of oxidative stress and oxidative damage during FZN exposure on dopaminergic cells through the measurement of reactive oxygen species (ROS) in cells with DCFH-DA. The cytotoxic effects of FZN appear to involve an increase in ROS generation since pretreatment with N-acetyl cysteine (NAC), an anti-oxidant, reduced cell death. After FZN treatment, dopamine (DA) levels decreased in both cell and culture media, and oxidative effects of FZN were blocked by NAC pretreatment. We show that cell death in response to FZN was due to apoptosis since FZN exposure results in an increased in cytochrome c release into the cytosol and activated caspase-3 through p38 and JNK signaling. Furthermore, the blocking of p38 or JNK signaling inhibits FZN-induced cell death. Phosphorylation of mitogen-activated protein kinases precedes cytochrome c release and caspase-3 activation. This cellular response is characteristic of mitochondrial dysfunction. Therefore, we also investigated the effect of FZN on mitochondrial complex I activity in FZN-treated cell. Interestingly, we show that FZN inhibited the complex I activity. Thus in this study, we report a new mode of action by which the fungicide FZN could triggers apoptosis.}, }
@article {pmid22459196, year = {2012}, author = {Lim, DH and Jang, J and Kim, S and Kang, T and Lee, K and Choi, IH}, title = {The effects of sub-lethal concentrations of silver nanoparticles on inflammatory and stress genes in human macrophages using cDNA microarray analysis.}, journal = {Biomaterials}, volume = {33}, number = {18}, pages = {4690-4699}, doi = {10.1016/j.biomaterials.2012.03.006}, pmid = {22459196}, issn = {1878-5905}, mesh = {Cell Line ; Cell Survival/drug effects ; HSP70 Heat-Shock Proteins/metabolism ; Heme Oxygenase-1/metabolism ; Humans ; Interleukin-8/metabolism ; Macrophages/*drug effects/*metabolism ; Metal Nanoparticles/adverse effects/chemistry/*therapeutic use/ultrastructure ; Microscopy, Electron, Transmission ; Oligonucleotide Array Sequence Analysis/*methods ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Silver/adverse effects/chemistry/*therapeutic use ; }, abstract = {Because of the limited information on size-dependent particle-mediated effects, the present study was conducted to determine if the changes in induced protein expression between 5 nm silver nanoparticles and 100 nm particles after exposure to sub-lethal concentrations. A total of 28,000 cDNA profiles were screened using 5 nm silver nanoparticles and 100 nm silver nanoparticles in a macrophage cell line. Based on results obtained from cDNA microarray we also assessed protein levels of hemeoxygenase-1 (HO-1), heat shock protein-70 (HSP-70) and interleukin-8 (IL-8), which were shown to significantly increase. Together with results obtained using N-acetylcystein (NAC), we were able to clearly show that low level and early stage exposure to 5 nm silver nanoparticles, but not 100 nm, induces expression of IL-8 as well as stress genes against reactive oxygen species (ROS). Therefore, we provide important data to understand and identify the early effects of silver nanoparticles on the immune system.}, }
@article {pmid22459046, year = {2012}, author = {Pamenter, ME and Ali, SS and Tang, Q and Finley, JC and Gu, XQ and Dugan, LL and Haddad, GG}, title = {An in vitro ischemic penumbral mimic perfusate increases NADPH oxidase-mediated superoxide production in cultured hippocampal neurons.}, journal = {Brain research}, volume = {1452}, number = {}, pages = {165-172}, pmid = {22459046}, issn = {1872-6240}, support = {5P01HD032573/HD/NICHD NIH HHS/United States ; K25 AG026379/AG/NIA NIH HHS/United States ; P01 HD032573/HD/NICHD NIH HHS/United States ; R01 AG033679/AG/NIA NIH HHS/United States ; P01 HD032573-15/HD/NICHD NIH HHS/United States ; 1K25AG026379/AG/NIA NIH HHS/United States ; K25 AG026379-05/AG/NIA NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cells, Cultured ; Hippocampus/drug effects/*metabolism ; Mice ; NADPH Oxidases/*metabolism ; Neurons/drug effects/*metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Superoxides/*metabolism ; }, abstract = {The currently accepted scheme for reactive oxygen species production during ischemia/reperfusion injury is characterized by a deleterious mitochondria-derived burst of radical generation during reperfusion; however, recent examination of the penumbra suggests a central role for NADPH-oxidase (Nox)-mediated radical generation during the ischemic period. Therefore, we utilized a novel in vitro model of the penumbra to examine the free radical profile of ischemic murine hippocampal neurons using electron paramagnetic resonance spectroscopy, and also the role of Nox in this generation and in cell fate. We report that free radical production increased ~75% at 2 h of ischemia, and this increase was abolished by: (1) scavenging of extracellular free radicals with superoxide dismutase (SOD), (2) a general anion channel antagonist, or (3) the Nox inhibitor apocynin. Similarly, at 24 h of ischemia, [ATP] decreased >95% and vital dye uptake increased 6-fold relative to controls; whereas apocynin, the Cl(-) channel antagonist 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), or the free radical scavenger N-acetyl cysteine (NAC) each provided moderate neuroprotection, ameliorating 13-32% of [ATP]-depletion and 19-56% of vital dye uptake at 24 h. Our results support a cytotoxic role for Nox-mediated free radical production from penumbral neurons during the ischemic period.}, }
@article {pmid22453841, year = {2012}, author = {Yubero, S and Ramudo, L and Manso, MA and Collía, F and De Dios, I}, title = {Evaluation of N-acetylcysteine treatment in acute pancreatitis-induced lung injury.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {61}, number = {7}, pages = {699-705}, pmid = {22453841}, issn = {1420-908X}, mesh = {Acetylcysteine/*therapeutic use ; Amylases/blood ; Animals ; Chemokine CCL2/genetics ; Chemokine CXCL1/genetics ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Lung/metabolism/pathology ; Lung Injury/*drug therapy/etiology/metabolism/pathology ; Male ; Pancreatitis/chemically induced/*complications/metabolism/pathology ; Peroxidase/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Taurocholic Acid ; }, abstract = {OBJECTIVE: Pulmonary complications are frequent during acute pancreatitis (AP). We investigate the effects of N-acetylcysteine (NAC) on lung injury in mild and severe AP. ANIMALS AND TREATMENT: Mild and severe AP was induced in rats by bile-pancreatic duct obstruction (BPDO) and infusion of 3.5 % sodium taurocholate (NaTc) into the bile-pancreatic duct, respectively. NAC (50 mg/kg) was given 1 h before and 1 h after AP.<br><br>METHODS: Amylase activity was measured in plasma. Lungs were harvested for mRNA expression analysis of monocyte chemoattractant protein-1 (MCP-1), cytokine-induced neutrophil chemoattractant (CINC), P-selectin and intercellular adhesion molecule-1 (ICAM-1), myeloperoxidase (MPO) activity and histological examination.<br><br>RESULTS: Hyperamylasemia was reduced by NAC in both AP models. NAC down-regulated MCP-1, CINC and P-selectin in BPDO- but not in NaTc-induced AP. Pulmonary insults did not vary in mild AP and were exacerbated in severe AP by NAC treatment. NAC reduced lung MPO activity in mild but not in severe AP.<br><br>CONCLUSIONS: Although NAC treatment down-regulated inflammatory mediators in lungs during AP it did not prevent leukocyte infiltration, which could be responsible for maintaining the lung injury. As a result, NAC aggravated the lung damage in severe AP and failed to exert beneficial effects in the mild disease model.}, }
@article {pmid22451225, year = {2012}, author = {Xue, B and Deng, DW and Cao, J and Liu, F and Li, X and Akers, W and Achilefu, S and Gu, YQ}, title = {Synthesis of NAC capped near infrared-emitting CdTeS alloyed quantum dots and application for in vivo early tumor imaging.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {41}, number = {16}, pages = {4935-4947}, doi = {10.1039/c2dt12436j}, pmid = {22451225}, issn = {1477-9234}, mesh = {Acetylcysteine/chemistry ; Animals ; Cadmium Compounds/*chemistry/pharmacokinetics/toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; Diagnostic Imaging/methods ; Female ; Human Umbilical Vein Endothelial Cells ; Humans ; Kidney/metabolism ; Liver/metabolism ; Lung/metabolism ; Mice ; Mice, Nude ; Microscopy, Fluorescence ; Neoplasm Transplantation ; Neoplasms/*diagnosis ; *Quantum Dots ; Sulfides/*chemistry/pharmacokinetics/toxicity ; Tellurium/*chemistry/pharmacokinetics/toxicity ; }, abstract = {The synthesis of water-soluble near-infrared (NIR)-emitting quantum dots (QDs) has recently received extensive attention for non-invasive detection of biological information in living subjects. Highly fluorescent CdTeS alloyed QDs for biological application are introduced in this paper. QDs were synthesized by a hydrothermal method and coated with N-acetyl-l-cysteine (NAC) as both bioactive ligand and sulfur source for biocompatibility and biological stability. The optical properties, morphology and structure of CdTeS alloyed QDs were characterized. The in vitro and in vivo toxicity was intensively investigated. Furthermore, the dynamics and bio-distribution of CdTeS alloyed QDs on living mice were studied. To explore biomedical application, folate-polyethylene glycol (FA-PEG) was used to decorate the CdTeS alloyed QDs (FP-CdTeS QDs) for targeted imaging of tumors over-expressing the folate receptor (FR). The tumor targeting capability of FP-CdTeS QDs on tumor bearing nude mice was demonstrated. The results showed that the prepared CdTeS QDs have excellent optical properties and low toxicity, which makes them an ideal inorganic material for biomedical imaging. In addition, the folate-PEG conjugated NIR-QDs displayed good biocompatibility as well as excellent sensitivity and specificity for optical imaging of tumors which can extend the application of CdTeS QDs.}, }
@article {pmid22450310, year = {2012}, author = {Nagasaki, H and Yoshimura, T and Aoki, N}, title = {Real-time monitoring of inflammation status in 3T3-L1 adipocytes possessing a secretory Gaussia luciferase gene under the control of nuclear factor-kappa B response element.}, journal = {Biochemical and biophysical research communications}, volume = {420}, number = {3}, pages = {623-627}, doi = {10.1016/j.bbrc.2012.03.049}, pmid = {22450310}, issn = {1090-2104}, mesh = {3T3-L1 Cells ; Adipocytes/drug effects/*metabolism ; Animals ; Antioxidants/pharmacology ; Cytokines/*genetics ; *Gene Expression Regulation ; *Genes, Reporter ; Inflammation/*genetics ; Luciferases/*genetics ; Mice ; Monitoring, Physiologic/*methods ; NF-kappa B/metabolism ; Response Elements ; Time Factors ; }, abstract = {We have established 3T3-L1 cells possessing a secretory Gaussia luciferase (GLuc) gene under the control of nuclear factor-kappa B (NF-κB) response element. The 3T3-L1 cells named 3T3-L1-NF-κB-RE-GLuc could differentiate into adipocyte as comparably as parental 3T3-L1 cells. Inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β induced GLuc secretion of 3T3-L1-NF-κB-RE-GLuc adipocytes in a concentration- and time-dependent manner. GLuc secretion of 3T3-L1-NF-κB-RE-GLuc adipocytes was also induced when cultured with RAW264.7 macrophages and was dramatically enhanced by lipopolysaccharide (LPS)-activated macrophages. An NF-κB activation inhibitor BAY-11-7085 and an antioxidant N-acetyl cysteine significantly suppressed GLuc secretion induced by macrophages. Finally, we found that rosemary-derived carnosic acid strongly suppressed GLuc secretion induced by macrophages and on the contrary up-regulated adiponectin secretion. Collectively, by using 3T3-L1-NF-κB-RE-GLuc adipocytes, inflammation status can be monitored in real time and inflammation-attenuating compounds can be screened more conveniently.}, }
@article {pmid22448774, year = {2012}, author = {Míčová, K and Linhart, I}, title = {Reactions of benzene oxide, a reactive metabolite of benzene, with model nucleophiles and DNA.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {42}, number = {10}, pages = {1028-1037}, doi = {10.3109/00498254.2012.669872}, pmid = {22448774}, issn = {1366-5928}, mesh = {Acetylcysteine/analogs &amp; derivatives/chemistry/*metabolism ; Adenosine Monophosphate/metabolism ; Animals ; Benzene/*metabolism ; Cattle ; Cyclohexanes/chemistry/*metabolism ; DNA/chemistry/*metabolism ; DNA Adducts/chemistry/metabolism ; Deoxyadenosines/metabolism ; Deoxyguanine Nucleotides/metabolism ; Deoxyguanosine/metabolism ; Solutions ; Spectrometry, Mass, Electrospray Ionization ; Temperature ; }, abstract = {1. Reactivity of benzene oxide (BO), a reactive metabolite of benzene, was studied in model reactions with biologically relevant S- and N-nucleophiles by LC-ESI-MS. 2. Reaction with N-acetylcysteine (NAC) in aqueous buffer solutions gave N-acetyl-S-(6-hydroxycyclohexa-2,4-dien-1-yl)cysteine (pre-phenylmercapturic acid, PPhMA), which was easily dehydrated in acidic solutions to phenylmercapturic acid (PhMA). The yield of PPhMA + PhMA increased exponentially with pH up to 11% in the pH range from 5.5 to 11.4. 3. Primary 6-hydroxycyclohexa-2,4-dien-1-yl (HC) adducts were detected also in reactions of purine nucleosides and nucleotides under physiological conditions. After a vigorous acidic hydrolysis, all HC adducts were converted to corresponding phenyl purines, which were identified as 7-phenylguanine (7-PhG), 3-phenyladenine (3-PhA) and N(6)-phenyladenine (6-PhA). The yield of 7-PhG amounted to 14 ± 5 and 16 ± 7 ppm for 2'-deoxyguanosine and 2'-deoxyguanosine-5'-monophosphate, respectively, that of 6-PhA was 500 ± 70 and 455 ± 75 ppm with 2'-deoxyadenosine and 2'-deoxyadenosine-5'-phosphate, respectively, with only traces of 3-PhA. 4. Reactions with the DNA followed by acidic hydrolysis yielded 26 ± 11 ppm (mean ± SD; n = 9) of 7-PhG as the sole adduct detected. 5. In contrast to the reactions with S-nucleophiles, the reactivity of BO with nucleophilic sites in the DNA is very low and can therefore hardly account for a significant DNA damage caused by benzene.}, }
@article {pmid22446899, year = {2012}, author = {Chen, CH and Lin, ML and Ong, PL and Yang, JT}, title = {Novel multiple apoptotic mechanism of shikonin in human glioma cells.}, journal = {Annals of surgical oncology}, volume = {19}, number = {9}, pages = {3097-3106}, doi = {10.1245/s10434-012-2324-4}, pmid = {22446899}, issn = {1534-4681}, mesh = {Acetylcysteine/pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Apoptosis/*drug effects ; Benzothiazoles/pharmacology ; Catalase/drug effects/metabolism ; Cell Line, Tumor ; Cyclosporine/pharmacology ; G1 Phase Cell Cycle Checkpoints/drug effects ; Glioma/*metabolism ; Glutathione/drug effects/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/physiology ; Naphthoquinones/*pharmacology ; Oxidative Stress/drug effects ; Poly(ADP-ribose) Polymerases/drug effects/metabolism ; Proto-Oncogene Proteins c-bcl-2/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/drug effects/metabolism ; Superoxide Dismutase-1 ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/drug effects/metabolism ; bcl-2-Associated X Protein/drug effects/metabolism ; }, abstract = {BACKGROUND: Shikonin is the main naphthoquinone compound of the root of Lithospermum erythrorhizon. Our previous study demonstrated that shikonin possesses anticancer activity in human hepatoma cells. However, the anticancer mechanism of shikonin in human glioma cells is unclear at present. In the present study, we demonstrated that shikonin induces apoptosis in three human glioma cell lines: U87MG, Hs683, and M059K cells.<br><br>METHODS: Cell cycle, generation of reactive oxygen species (ROS), depletion of glutathione (GSH), and disruption of mitochondrial transmembrane potential in shikonin-treated cells were determined by flow cytometry. Apoptosis-related proteins, catalase, and superoxide dismutase-1 (SOD-1) were determined by Western blot testing. N-acetylcysteine (NAC), pifithrin-&#x3b1; (PFT-&#x3b1;), or cyclosporin A were applied to evaluate the molecular mechanism of shikonin in apoptosis.<br><br>RESULTS: Shikonin induces the generation of ROS, depletion of GSH, disruption of mitochondrial transmembrane potential, upregulation of p53, and cleavage of PARP [poly(ADP-ribose) polymerase] in U87MG glioma cells. Moreover, shikonin causes catalase downregulation and SOD-1 upregulation as well as decreased Bcl-2 and increased Bax expression. Pretreatment with NAC, PFT-&#x3b1;, or cyclosporin A causes the recovery of shikonin-induced apoptosis. The ROS generation and GSH depletion induced by shikonin trigger mitochondrial transmembrane potential disruption. ROS production was partially dependent on the upregulation of p53 upon shikonin treatment.<br><br>CONCLUSIONS: These studies are the first to show that shikonin-induced apoptosis occurs through multiple pathways in human glioma cells. We conclude that shikonin may be used as a potential chemotherapeutic agent against human glioma.}, }
@article {pmid22445879, year = {2012}, author = {Morabito, R and Condello, S and Currò, M and Marino, A and Ientile, R and La Spada, G}, title = {Oxidative stress induced by crude venom from the jellyfish Pelagia noctiluca in neuronal-like differentiated SH-SY5Y cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {26}, number = {5}, pages = {694-699}, doi = {10.1016/j.tiv.2012.03.002}, pmid = {22445879}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Differentiation ; Cell Line, Tumor ; Cnidarian Venoms/*toxicity ; Free Radical Scavengers/pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Neurons ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Scyphozoa ; }, abstract = {Marine toxins are a suitable research model and their mechanism of action is intriguing and still under debate. Either a pore formation mechanism or oxidative stress phenomena may explain the damage induced by toxins. The effect of crude venom from isolated nematocysts of the jellyfish Pelagia noctiluca on neuronal-like cells derived from human neuroblastoma SH-SY5Y has been here studied. To prove the possible oxidative stress events, cell viability, assessed by MTT quantitative colorimetric assay, intracellular reactive oxygen species (ROS) quantified by the non-fluorescent probe H2DCF-DA and changes in mitochondrial transmembrane potential (ΔΨm) measured by the incorporation of a cationic fluorescent dye rhodamine-123 were verified on venom-treated cells (0.05-0.5μg/ml doses). A dose- and time-dependent reduction of all parameters was observed after venom treatment. NAC (N-acetyl-cysteine), antioxidant applied before crude venom application, significantly counteracted the decrease in cell viability and ROS production, while ΔΨm was only partially restored. The disruption of mitochondrial membrane by P. noctiluca crude venom may thus induce oxidative stress by inhibiting mitochondrial respiration and uncoupling oxidative phosphorylation, sensitizing mitochondria in SH-SY5H cells and facilitating membrane permeability. In sum, our findings suggest that P. noctiluca crude venom directly induces ΔΨm collapse with further generation of ROS and add novel information to the understanding of such toxins, still not completely clarified.}, }
@article {pmid22445861, year = {2012}, author = {Zhu, S and Wang, Y and Jin, J and Guan, C and Li, M and Xi, C and Ouyang, Z and Chen, M and Qiu, Y and Huang, M and Huang, Z}, title = {Endoplasmic reticulum stress mediates aristolochic acid I-induced apoptosis in human renal proximal tubular epithelial cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {26}, number = {5}, pages = {663-671}, doi = {10.1016/j.tiv.2012.03.005}, pmid = {22445861}, issn = {1879-3177}, mesh = {Activating Transcription Factor 3/genetics ; Apoptosis/*drug effects ; Aristolochic Acids/*toxicity ; Butylamines/pharmacology ; Caspase 3/metabolism ; Cell Line ; Cinnamates/pharmacology ; DNA Fragmentation ; Endoplasmic Reticulum Chaperone BiP ; Endoplasmic Reticulum Stress/*drug effects ; Epithelial Cells/*drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Heat-Shock Proteins/genetics ; Humans ; Kidney Tubules, Proximal/cytology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Thiourea/analogs &amp; derivatives/pharmacology ; Transcription Factor CHOP/genetics/metabolism ; }, abstract = {Aristolochic acid (AA), derived from the Aristolochia species, has been associated with aristolochic acid nephropathy (AAN), which has emerged as a worldwide disease. Aristolochic acid I (AAI) is the main ingredient of AA, and the underlying mechanisms for AAI-induced nephrotoxicity are still unclear. In this study, we investigated whether endoplasmic reticulum (ER) stress was involved in AAI-induced nephrotoxicity. The results showed that treatment of HK-2 cells (a human proximal tubular epithelial cell line) with AAI caused an increase in eukaryotic initiation factor-2α (eIF2α) phosphorylation, X-box binding protein 1 (XBP1) mRNA splicing and the expression of glucose-regulated protein (GRP) 78 and CAAT/enhancer-binding protein-homologous protein (CHOP). These events represent typical markers of the ER stress-related signaling pathway. Pretreatment with 4-phenylbutyrate (4-PBA) or salubrinal (Sal) significantly inhibited AAI-induced apoptosis, indicating the role of ER stress in AAI-induced apoptosis. In addition, AAI-induced cell death followed an increase of reactive oxygen species (ROS) formation in HK-2 cells. Pretreatment with N-acetyl cysteine (NAC) or glutathione (GSH) significantly inhibited AAI-induced ER stress proteins and cell death, suggesting that ROS mediate AAI-induced ER stress. Taken together, these results suggest that the ER stress response is involved in apoptosis induced by AAI in HK-2 cells, thus offering a new insight into the nephrotoxicity of AAI.}, }
@article {pmid22442667, year = {2012}, author = {Sun, L and Gu, L and Wang, S and Yuan, J and Yang, H and Zhu, J and Zhang, H}, title = {N-acetylcysteine protects against apoptosis through modulation of group I metabotropic glutamate receptor activity.}, journal = {PloS one}, volume = {7}, number = {3}, pages = {e32503}, pmid = {22442667}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cell Line ; Cell Survival ; Disease Models, Animal ; Enzyme Inhibitors/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Free Radical Scavengers/*pharmacology ; Methoxyhydroxyphenylglycol/analogs &amp; derivatives/pharmacology ; Oxidation-Reduction/drug effects ; Parkinson Disease/*drug therapy/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Receptors, Metabotropic Glutamate/agonists/antagonists &amp; inhibitors/*metabolism ; Staurosporine/pharmacology ; }, abstract = {The activation of group I metabotropic glutamate receptor (group I mGlus) has been shown to produce neuroprotective or neurotoxic effects. In this study, we investigated the effects of N-acetylcysteine (NAC), a precursor of the antioxidant glutathione, on group I mGlus activation in apoptosis of glial C6 and MN9D cell lines, and a rat model of Parkinson's disease (PD). We demonstrated that NAC protected against apoptosis through modulation of group I mGlus activity. In glial C6 cells, NAC promoted phosphorylation of ERK induced by (s)-3,5-dihydroxy-phenylglycine (DHPG), an agonist of group I mGlus. NAC enhanced the group I mGlus-mediated protection from staurosporine (STS)-induced apoptosis following DHPG treatment. Moreover, in rotenone-treated MN9D cells and PD rat model, NAC protected against group I mGlus-induced toxicity by compromising the decrease in phosphorylation of ERK, phosphorylation or expression level of TH. Furthermore, the results showed that NAC prohibited the level of ROS and oxidation of cellular GSH/GSSG (E(h)) accompanied by activated group I mGlus in the experimental models. Our results suggest that NAC might act as a regulator of group I mGlus-mediated activities in both neuroprotection and neurotoxicity via reducing the oxidative stress, eventually to protect cell survival. The study also suggests that NAC might be a potential therapeutics targeting for group I mGlus activation in the treatment of PD.}, }
@article {pmid22436589, year = {2012}, author = {Wang, G and Deng, S and Li, C and Liu, Y and Chen, L and Hu, C}, title = {Damage to DNA caused by UV-B radiation in the desert cyanobacterium Scytonema javanicum and the effects of exogenous chemicals on the process.}, journal = {Chemosphere}, volume = {88}, number = {4}, pages = {413-417}, doi = {10.1016/j.chemosphere.2012.02.056}, pmid = {22436589}, issn = {1879-1298}, mesh = {Antioxidants/*pharmacology ; Cyanobacteria/*drug effects/genetics/metabolism/*radiation effects ; *DNA Damage ; DNA, Bacterial/drug effects/genetics/radiation effects ; *Desert Climate ; Herbicides/*toxicity ; Photosynthesis/drug effects/radiation effects ; Reactive Oxygen Species/metabolism ; Soil Microbiology ; Superoxide Dismutase/metabolism ; Ultraviolet Rays/*adverse effects ; }, abstract = {Radiation with UV-B increased the damage to DNA in Scytonema javanicum, a desert-dwelling soil microorganism, and the level of damage varied with the intensity of UV-B radiation and duration of exposure. Production of reactive oxygen species (ROS) also increased because of the radiation. Different exogenous chemicals (ascorbate acid, ASC; N-acetylcysteine, NAC; glyphosate, GPS; and 2-methyl-4-chlorophenoxyacetic acid, MCPA-Na) differed in their effect on the extent of DNA damage and ROS production: whereas NAC and ASC protected the DNA from damage and resulted in reduced ROS production, the herbicides (GPS and MCPA-Na) increased the extent of damage, lowered the rate of photosynthesis, and differed in their effect on ROS production. The chemicals probably have different mechanisms to exercise their effects: NAC and ASC probably function as antioxidant agents or as precursors of other antioxidant molecules that protect the DNA and photosynthetic apparatus directly from the ROS produced as a result of UV-B radiation, and GPS and MCPA-Na probably disrupt the normal metabolism in S. javanicum to induce the leaking of ROS into the photosynthetic electron transfer pathway following UV-B radiation, and thereby damage the DNA. Such mechanisms have serious implications for the use of environment-friendly herbicides, which, because they can destroy DNA, may prove harmful to soil microorganisms.}, }
@article {pmid22433584, year = {2012}, author = {Scaini, G and Teodorak, BP and Jeremias, IC and Morais, MO and Mina, F and Dominguini, D and Pescador, B and Comim, CM and Schuck, PF and Ferreira, GC and Quevedo, J and Streck, EL}, title = {Antioxidant administration prevents memory impairment in an animal model of maple syrup urine disease.}, journal = {Behavioural brain research}, volume = {231}, number = {1}, pages = {92-96}, doi = {10.1016/j.bbr.2012.03.004}, pmid = {22433584}, issn = {1872-7549}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Amino Acids, Branched-Chain ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Deferoxamine/pharmacology/therapeutic use ; Disease Models, Animal ; Male ; Maple Syrup Urine Disease/chemically induced/*complications ; Memory/*drug effects ; Memory Disorders/*complications/drug therapy/*prevention &amp; control ; Rats ; Rats, Wistar ; }, abstract = {Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder resulting from deficiency of branched-chain α-keto acid dehydrogenase complex leading to branched chain amino acids (BCAA) leucine, isoleucine, and valine accumulation as well as their corresponding transaminated branched-chain α-keto acids. MSUD patients present neurological dysfunction and cognitive impairment. Here, we investigated whether acute and chronic administration of a BCAA pool causes impairment of acquisition and retention of avoidance memory in young rats. We have used two administration protocols. Acute administration consisted of three subcutaneous administrations of the BCAA pool (15.8 μL/g body weight at 1-h intervals) containing 190 mmol/L leucine, 59 mmol/L isoleucine, and 69 mmol/L valine or saline solution (0.85% NaCl; control group) in 30 days old Wistar rats. Chronic administration consisted of two subcutaneous administrations of BCAA pool for 21 days in 7 days old Wistar rats. N-acetylcysteine (NAC; 20 mg/kg) and deferoxamine (DFX; 20 mg/kg) co administration influence on behavioral parameters after chronic BCAA administration was also investigated. BCAA administration induced long-term memory impairment in the inhibitory avoidance and CMIA (continuous multiple-trials step-down inhibitory avoidance) tasks whereas with no alterations in CMIA retention memory. Inhibitory avoidance alterations were prevented by NAC and DFX. BCAA administration did not impair the neuropsychiatric state, muscle tone and strength, and autonomous function evaluated with the SHIRPA (SmithKline/Harwell/ImperialCollege/RoyalHospital/Phenotype Assessment) protocol. Taken together, our results indicate that alterations of motor activity or emotionality probably did not contribute to memory impairment after BCAA administration and NAC and DFX effects suggest that cognition impairment after BCAA administration may be caused by oxidative brain damage.}, }
@article {pmid22432090, year = {2012}, author = {Liu, AM and Qu, WW and Liu, X and Qu, CK}, title = {Chromosomal instability in in vitro cultured mouse hematopoietic cells associated with oxidative stress.}, journal = {American journal of blood research}, volume = {2}, number = {1}, pages = {71-76}, pmid = {22432090}, issn = {2160-1992}, support = {R01 DK092722/DK/NIDDK NIH HHS/United States ; R01 HL068212/HL/NHLBI NIH HHS/United States ; }, abstract = {Hematopoietic stem cells (HSCs) that give rise to all blood cell types are important vehicles for cell-based and gene therapies. After isolation from the bone marrow, HSCs are often cultured in laboratory settings for purposes of ex vivo expansion, gene transduction, and bone marrow transplantation for the treatment of various disorders of the blood and immune systems. Here we demonstrate that during in vitro culturing outside of hypoxic bone marrow niches, HSCs may genetically alter even after short durations of time. Lineage(-) Scal-1(+) c-Kit(+) (LSK) cells that are enriched with HSCs revealed significant levels of genomic instability following culture, as evidenced by the emergence of aneuploid cells. To further determine the effects of in vitro culturing conditions, whole bone marrow cells were cultured in a hypoxic environment of 3% oxygen, mimicking conditions within the body's bone marrow, following which, cells proved to undergo less genetic alterations. Proper dosages of the antioxidant N-Acetyl-Cysteine (NAC) similarly decreased occurrences of chromosomal change. Furthermore, analysis of aged hematopoietic cells revealed enhanced in vitro normoxic culture-induced chromosomal instability compared to that of young hematopoietic cells due to noted increased oxidative stress in aged cells. These results reveal that in vitro cell culturing does indeed cause genomic instability in hematopoietic cells. Reduced oxygen to physiological levels and additions of antioxidants can be employed as possible strategies to lower oxidative stress and decrease chances of chromosomal transformation. Because hematopoietic cells are commonly processed in laboratory settings before transplantation for patient treatment, our findings also raise a concern on the therapeutic use of cultured hematopoietic cells.}, }
@article {pmid22425133, year = {2012}, author = {Trabut, JB and Thépot, V and Sogni, P and Pol, S}, title = {[Alcoholic hepatitis].}, journal = {La Revue de medecine interne}, volume = {33}, number = {6}, pages = {311-317}, doi = {10.1016/j.revmed.2012.02.002}, pmid = {22425133}, issn = {1768-3122}, mesh = {Diagnosis, Differential ; Diagnostic Imaging/methods ; Disease Progression ; Hepatitis, Alcoholic/complications/diagnosis/etiology/*therapy ; Humans ; Infections/etiology/therapy ; Prognosis ; }, abstract = {Alcoholic hepatitis is one of the most severe presentations of alcoholic liver disease. It is usually revealed by the recent onset of jaundice in a patient with alcoholic cirrhosis. Maddrey's discriminant function can help to recognize patients with poor prognosis (the 6-month mortality is above 50% when it exceeds 32). Corticosteroids increase survival in those patients with high risk of death. Other treatments (pentoxifylline, N-acetyl-cysteine or enteral nutrition) need to be investigated further before to recommend their routine use instead of, or in association with, corticoids. Liver transplantation can be proposed to highly selected patients who do not respond to medical therapy. In any case, long-term prognosis will primarily depend on the maintenance of alcohol abstinence.}, }
@article {pmid22424351, year = {2012}, author = {Tayman, C and Tonbul, A and Kosus, A and Hirfanoglu, IM and Uysal, S and Haltas, H and Tatli, MM and Andiran, F}, title = {N-acetylcysteine may prevent severe intestinal damage in necrotizing enterocolitis.}, journal = {Journal of pediatric surgery}, volume = {47}, number = {3}, pages = {540-550}, doi = {10.1016/j.jpedsurg.2011.09.051}, pmid = {22424351}, issn = {1531-5037}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism ; Apoptosis/drug effects ; Biomarkers/metabolism ; Caspases/metabolism ; Colon/drug effects/metabolism/pathology ; Disease Models, Animal ; Drug Administration Schedule ; Enterocolitis, Necrotizing/mortality/*prevention &amp; control ; Free Radical Scavengers/pharmacology/*therapeutic use ; Ileum/drug effects/metabolism/pathology ; In Situ Nick-End Labeling ; Kaplan-Meier Estimate ; Lipid Peroxidation/drug effects ; Oxidants/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: The aim of this study was to evaluate the preventive effect of N-acetylcysteine (NAC) on the development of necrotizing enterocolitis (NEC) in an experimental rat model.<br><br>MATERIAL AND METHODS: Thirty newborn Sprague-Dawley rats were randomly divided into 3 groups: NEC, NEC + NAC, and control. Necrotizing enterocolitis was induced by enteral formula feeding, exposure to hypoxia-hyperoxia, and cold stress. Pups in the NEC + NAC group were administered NAC at a dose of 150 mg/kg daily by intraperitoneal route from the first day until the last day of the study. All pups were killed on the fifth day. Proximal colon and ileum were excised for histopathologic, immunohistochemical (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling and caspase-3, caspase-8, caspase-9), and biochemical evaluation, including xanthine oxidase, total antioxidant status, total oxidant status, malondialdehyde, and myeloperoxidase activities.<br><br>RESULTS: The pups in the NEC + NAC group had better clinical sickness scores compared with those in the NEC group (P < .05). In histopathologic and apoptosis evaluations (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling and immunohistochemical evaluation for caspase-3 and caspase-9), the severity of bowel damage was significantly less in the NEC + NAC group compared with the NEC group (P < .01). Tissue malondialdehyde, myeloperoxidase, xanthine oxidase levels, and total oxidant status were significantly decreased in the NEC + NAC group, whereas total antioxidant status (TAS) was significantly increased in the NEC + NAC group (P < .01).<br><br>CONCLUSION: N-acetylcysteine therapy significantly reduced the severity of intestinal damage in NEC.}, }
@article {pmid22421270, year = {2012}, author = {Ki, YW and Lee, JE and Park, JH and Shin, IC and Koh, HC}, title = {Reactive oxygen species and mitogen-activated protein kinase induce apoptotic death of SH-SY5Y cells in response to fipronil.}, journal = {Toxicology letters}, volume = {211}, number = {1}, pages = {18-28}, doi = {10.1016/j.toxlet.2012.02.022}, pmid = {22421270}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Humans ; Insecticides/*pharmacology ; Mitogen-Activated Protein Kinases/*metabolism ; Neuroblastoma/metabolism ; Oxidative Stress/drug effects ; Pyrazoles/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {There are multiple lines of evidence showing that environmental toxicants including pesticides may contribute to neuronal cell death. Fipronil (FPN) is a phenylpyrazole insecticide that acts on insect GABA receptors. Although the action of FPN is restricted to insect neuronal or muscular transmitter systems, a few studies have assessed the effects of this neurotoxicant on neuronal cell death distinct from an insect. To determine the mechanisms underlying FPN-induced neuronal cell death, we evaluated the ability of this chemical to induce oxidative stress and studied the involvement of mitogen activated protein kinases (MAPKs) in FPN-induced apoptosis stress in human neuroblastoma SH-SY5Y (SH-SY5Y) cells. Exposure of SH-SY5Y cells to FPN led to the production of reactive oxygen species (ROS) and apoptotic cell death via activation of caspase-9 and caspase-3. Interestingly, the antioxidant, N-acetyl-cysteine (NAC) attenuated apoptotic cell death and ROS production induced by FPN. These results indicated that oxidative stress plays a central role in FPN-induced cytotoxicity. Mitochondrial complex I activity was also inhibited by FPN treatment. These finding indicate that FPN triggers intrinsic apoptosis via the mitochondrial signaling pathway that is initiated by the generation of ROS. Furthermore, FPN treatment induced phosphorylation of MAPK members. Activation of these protein kinases by FPN was involved in the onset of apoptosis as inhibitors specific to these kinases protect against FPN-induced cell death as well as ROS generation. Our data indicate that FPN-induced apoptosis is mediated primarily by the generation of ROS and activation of MAPK members followed by activation of the intrinsic apoptotic pathway.}, }
@article {pmid22420031, year = {2012}, author = {Falluel-Morel, A and Lin, L and Sokolowski, K and McCandlish, E and Buckley, B and DiCicco-Bloom, E}, title = {N-acetyl cysteine treatment reduces mercury-induced neurotoxicity in the developing rat hippocampus.}, journal = {Journal of neuroscience research}, volume = {90}, number = {4}, pages = {743-750}, pmid = {22420031}, issn = {1097-4547}, support = {R21 ES019762/ES/NIEHS NIH HHS/United States ; F31 NS062591-02/NS/NINDS NIH HHS/United States ; P01 ES011256-01/ES/NIEHS NIH HHS/United States ; P30 ES005022/ES/NIEHS NIH HHS/United States ; NS062591/NS/NINDS NIH HHS/United States ; ES11256/ES/NIEHS NIH HHS/United States ; P01 ES011256/ES/NIEHS NIH HHS/United States ; P30 ES005022-12/ES/NIEHS NIH HHS/United States ; P30ES005022/ES/NIEHS NIH HHS/United States ; ES07148/ES/NIEHS NIH HHS/United States ; F31 NS062591/NS/NINDS NIH HHS/United States ; R21 ES019762-01/ES/NIEHS NIH HHS/United States ; T32 ES007148-12/ES/NIEHS NIH HHS/United States ; ES019762/ES/NIEHS NIH HHS/United States ; ES05022/ES/NIEHS NIH HHS/United States ; T32 ES007148/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Animals, Newborn ; Cell Death/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Female ; *Hippocampus/cytology/embryology/growth &amp; development ; Male ; Methylmercury Compounds/*toxicity ; Neurons/drug effects/physiology ; Neuroprotective Agents/*therapeutic use ; Neurotoxicity Syndromes/*drug therapy/*etiology ; Pregnancy ; Rats ; Spectrophotometry, Atomic/methods ; Thymidine/metabolism ; Tritium/metabolism ; }, abstract = {Mercury is an environmental toxicant that can disrupt brain development. However, although progress has been made in defining its neurotoxic effects, we know far less about available therapies that can effectively protect the brain in exposed individuals. We previously developed an animal model in which we defined the sequence of events underlying neurotoxicity: Methylmercury (MeHg) injection in postnatal rat acutely induced inhibition of mitosis and stimulated apoptosis in the hippocampus, which later resulted in intermediate-term deficits in structure size and cell number. N-acetyl cysteine (NAC) is the N-acetyl derivative of L-cysteine used clinically for treatment of drug intoxication. Here, based on its known efficacy in promoting MeHg urinary excretion, we evaluated NAC for protective effects in the developing brain. In immature neurons and precursors, MeHg (3 μM) induced a >50% decrease in DNA synthesis at 24 hr, an effect that was completely blocked by NAC coincubation. In vivo, injection of MeHg (5 μg/g bw) into 7-day-old rats induced a 22% decrease in DNA synthesis in whole hippocampus and a fourfold increase in activated caspase-3-immunoreactive cells at 24 hr and reduced total cell numbers by 13% at 3 weeks. Treatment of MeHg-exposed rats with repeated injections of NAC abolished MeHg toxicity. NAC prevented the reduction in DNA synthesis and the marked increase in caspase-3 immunoreactivity. Moreover, the intermediate-term decrease in hippocampal cell number provoked by MeHg was fully blocked by NAC. Altogether these results suggest that MeHg toxicity in the perinatal brain can be ameliorated by using NAC, opening potential avenues for therapeutic intervention.}, }
@article {pmid22415070, year = {2012}, author = {Li, DY and Xue, MY and Geng, ZR and Chen, PY}, title = {The suppressive effects of Bursopentine (BP5) on oxidative stress and NF-ĸB activation in lipopolysaccharide-activated murine peritoneal macrophages.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {29}, number = {1-2}, pages = {9-20}, doi = {10.1159/000337581}, pmid = {22415070}, issn = {1421-9778}, mesh = {Animals ; Catalase/metabolism ; Down-Regulation ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Lipid Peroxidation/drug effects ; Lipopolysaccharides/toxicity ; Macrophages, Peritoneal/drug effects/immunology/*metabolism ; Mice ; Mice, Inbred BALB C ; NF-kappa B/*metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Oligopeptides/*pharmacology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND/AIM: Bursopentine (BP5) is a novel thiol-containing pentapeptide isolated from chicken bursa of Fabricius, and is reported to exert immunomodulatory effects on B and T lymphocytes. It has been found that some thiol compounds, such as glutathione (GSH) and N-acetylcysteine (NAC) protect living cells from oxidative stress. This led us to investigate whether BP5 had any ability to protect macrophages from oxidative stress as well as any mechanism that might underlie this process.<br><br>METHODS: Murine peritoneal macrophages activated by lipopolysaccharide (LPS) (2 &#x3bc;g/ml) were treated with single bouts (0, 25, 50, and 100 &#x3bc;M) of BP5.<br><br>RESULTS: BP5 potently suppressed the markers for oxidative stress, including nitric oxide (NO), reactive oxygen species (ROS), lipid peroxidation, and protein oxidation. It also decreased the expression and activity of inducible nitric oxide synthase (iNOS) and promoted a protective antioxidant state by elevating GSH content and by activating the expression and activity of certain key antioxidant and redox enzymes, including glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT). This suppressive effect on oxidative stress was accompanied by down-regulated expression and activity of nuclear factor kappa B (NF-&#x3ba;B).<br><br>CONCLUSION: These findings demonstrate that BP5 can protect LPS-activated murine peritoneal macrophages from oxidative stress. BP5 may have applications as an anti-oxidative stress reagent.}, }
@article {pmid22409285, year = {2012}, author = {Patel, RB and Kotha, SR and Sauers, LA and Malireddy, S and Gurney, TO and Gupta, NN and Elton, TS and Magalang, UJ and Marsh, CB and Haley, BE and Parinandi, NL}, title = {Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant, N-acetyl-L-cysteine, and novel thiol antioxidant, N,N'-bis-2-mercaptoethyl isophthalamide.}, journal = {Toxicology mechanisms and methods}, volume = {22}, number = {5}, pages = {383-396}, pmid = {22409285}, issn = {1537-6524}, support = {R01 HL093463/HL/NHLBI NIH HHS/United States ; HL093463/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*pharmacology ; Actin Cytoskeleton/*drug effects/metabolism/pathology ; Animals ; Antioxidants/chemistry/*pharmacology ; Bleomycin/*pharmacology ; Cattle ; Cell Culture Techniques ; Cell Survival/drug effects ; Cells, Cultured ; Cysteamine/*analogs &amp; derivatives/chemistry/pharmacology ; Endothelial Cells/drug effects/metabolism/pathology ; Endothelium, Vascular/*drug effects/metabolism/pathology ; Glutathione/metabolism ; Idiopathic Pulmonary Fibrosis/metabolism/pathology/*prevention &amp; control ; Lung/blood supply/*drug effects/metabolism/pathology ; Microscopy, Fluorescence ; Molecular Structure ; Oxidation-Reduction ; Phthalic Acids/chemistry/*pharmacology ; Reactive Oxygen Species/metabolism ; Structure-Activity Relationship ; Sulfhydryl Compounds/chemistry/*pharmacology ; }, abstract = {Lung vascular alterations and pulmonary hypertension associated with oxidative stress have been reported to be involved in idiopathic lung fibrosis (ILF). Therefore, here, we hypothesize that the widely used lung fibrosis inducer, bleomycin, would cause cytoskeletal rearrangement through thiol-redox alterations in the cultured lung vascular endothelial cell (EC) monolayers. We exposed the monolayers of primary bovine pulmonary artery ECs to bleomycin (10 µg) and studied the cytotoxicity, cytoskeletal rearrangements, and the macromolecule (fluorescein isothiocyanate-dextran, 70,000 mol. wt.) paracellular transport in the absence and presence of two thiol-redox protectants, the classic water-soluble N-acetyl-L-cysteine (NAC) and the novel hydrophobic N,N'-bis-2-mercaptoethyl isophthalamide (NBMI). Our results revealed that bleomycin induced cytotoxicity (lactate dehydrogenase leak), morphological alterations (rounding of cells and filipodia formation), and cytoskeletal rearrangement (actin stress fiber formation and alterations of tight junction proteins, ZO-1 and occludin) in a dose-dependent fashion. Furthermore, our study demonstrated the formation of reactive oxygen species, loss of thiols (glutathione, GSH), EC barrier dysfunction (decrease of transendothelial electrical resistance), and enhanced paracellular transport (leak) of macromolecules. The observed bleomycin-induced EC alterations were attenuated by both NAC and NBMI, revealing that the novel hydrophobic thiol-protectant, NBMI, was more effective at µM concentrations as compared to the water-soluble NAC that was effective at mM concentrations in offering protection against the bleomycin-induced EC alterations. Overall, the results of the current study suggested the central role of thiol-redox in vascular EC dysfunction associated with ILF.}, }
@article {pmid22403609, year = {2012}, author = {Mirochnik, Y and Veliceasa, D and Williams, L and Maxwell, K and Yemelyanov, A and Budunova, I and Volpert, OV}, title = {Androgen receptor drives cellular senescence.}, journal = {PloS one}, volume = {7}, number = {3}, pages = {e31052}, pmid = {22403609}, issn = {1932-6203}, support = {R01 CA118890/CA/NCI NIH HHS/United States ; }, mesh = {Androgen Receptor Antagonists/pharmacology ; Cell Line, Tumor ; *Cellular Senescence/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cytokines/metabolism ; Flutamide/pharmacology ; Humans ; Membrane Proteins/metabolism ; Nuclear Proteins/metabolism ; Phosphorylation/drug effects ; Promyelocytic Leukemia Protein ; Reactive Oxygen Species/metabolism ; Receptors, Androgen/*metabolism ; Retinoblastoma Protein/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; Up-Regulation/drug effects ; }, abstract = {The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.}, }
@article {pmid22401703, year = {2012}, author = {Alipour, M and Smith, MG and Pucaj, K and Suntres, ZE}, title = {Acute toxicity study of liposomal antioxidant formulations containing N-acetylcysteine, α-tocopherol, and γ-tocopherol in rats.}, journal = {Journal of liposome research}, volume = {22}, number = {2}, pages = {158-167}, doi = {10.3109/08982104.2012.662654}, pmid = {22401703}, issn = {1532-2394}, mesh = {Acetylcysteine/*administration &amp; dosage/*toxicity ; Animals ; Antioxidants/administration &amp; dosage/*chemistry ; Chemistry, Pharmaceutical ; Female ; Injections, Intravenous ; Liposomes/administration &amp; dosage/*chemistry ; Male ; Rats ; Rats, Sprague-Dawley ; *Toxicity Tests, Acute ; alpha-Tocopherol/administration &amp; dosage/*toxicity ; gamma-Tocopherol/administration &amp; dosage/*toxicity ; }, abstract = {Liposomes have been used for the delivery of antioxidants to different tissues and organs for the treatment of oxidative stress-induced injuries. In this study, the acute toxicity of a single dose of intravenously (i.v.) administered liposomal antioxidant formulation, containing N-acetylcysteine (NAC) with or without α-tocopherol (α-T) or γ-tocopherol (γ-T), in rats was examined. Each group consisted of 5 male and 5 female Sprague-Dawley rats, with a control group receiving empty dipalmitoylphosphatidylcholine (DPPC) liposomes (660 mg/kg) and test groups receiving DPPC liposomes (660 mg/kg) entrapped with 1) NAC (200 mg/kg), 2) NAC (200 mg/kg) and α-T (83.3 mg/kg), and 3) NAC (200 mg/kg) and γ-T (71.4 mg/kg). These dose levels were determined from the dose-range-finding study and were considered to be the maximum feasible dose (MFD) levels, based on the volume of 10 mL/kg and physical properties and viscosity of the test articles that could be safely administered to rats by an i.v. injection. Two weeks after treatment (day 15), rats in the control group and three test groups exhibited no clinical signs of toxicity during the dosing period or during the 14-day post-treatment period. Weight gain and food consumption in all animals was appropriate for the age and sex of animals. Clinical pathology findings (e.g., hematology, coagulation, clinical chemistry, and urinalysis) were unremarkable in all rats and in all groups. In conclusion, the results of this study showed no treatment-related toxicity in rats at the MFD level by a single bolus i.v. administration.}, }
@article {pmid22396448, year = {2012}, author = {Pillon, NJ and Croze, ML and Vella, RE and Soulère, L and Lagarde, M and Soulage, CO}, title = {The lipid peroxidation by-product 4-hydroxy-2-nonenal (4-HNE) induces insulin resistance in skeletal muscle through both carbonyl and oxidative stress.}, journal = {Endocrinology}, volume = {153}, number = {5}, pages = {2099-2111}, doi = {10.1210/en.2011-1957}, pmid = {22396448}, issn = {1945-7170}, mesh = {Aldehydes/*pharmacology ; Animals ; Cell Line ; Cells, Cultured ; Glutathione/metabolism ; Insulin/metabolism ; Insulin Resistance/*physiology ; Lipid Peroxidation/*physiology ; Male ; Mice ; Muscle, Skeletal/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Numerous oxidants are produced as by-products of aerobic cell metabolism, and there is growing evidence that they play key roles in the pathogenesis of insulin resistance. Under conditions of oxidative stress, lipid peroxidation of ω6-polyunsaturated fatty acids leads to the production of 4-hydroxy-2-nonenal (4-HNE). Several lines of evidence suggest that 4-HNE could be involved in the pathophysiology of metabolic diseases; therefore, in this study we assessed the direct effects of 4-HNE on skeletal muscle insulin sensitivity. Gastrocnemius muscle and L6 muscle cells were treated with 4-HNE. Insulin signaling was measured by Western blotting and glucose uptake using 2-deoxy-d-[3H]glucose. Carbonyl stress, glutathione content, and oxidative stress were assessed as potential mechanisms leading to insulin resistance. Protection of cells was induced by pretreatment with 3H-1,2-dithiole-3-thione, N-acetyl-cysteine, aminoguanidine, or S-adenosyl-methionine. 4-HNE induced a time- and dose-dependent decrease in insulin signaling and insulin-induced glucose uptake in muscle. It induced a state of carbonyl stress through adduction of proteins as well as a depletion in reduced glutathione and production of radical oxygen species. A pharmacological increase in glutathione pools was achieved by 3H-1,2-dithiole-3-thione and protected the cells against all deleterious effects of 4-HNE; furthermore, N-acetylcysteine, aminoguanidine, and S-adenosylmethionine prevented 4-HNE noxious effects. 4-HNE can impair insulin action in muscle cells through oxidative stress and oxidative damage to proteins, eventually leading to insulin resistance. These deleterious effects can be prevented by pretreatment with antioxidants, scavengers, or an increase in intracellular glutathione pools. Use of such molecules could represent a novel strategy to combat insulin resistance and other oxidative stress-associated pathologies.}, }
@article {pmid22395404, year = {2012}, author = {Yu, M and Zheng, Y and Sun, HX and Yu, DJ}, title = {Inhibitory effects of enalaprilat on rat cardiac fibroblast proliferation via ROS/P38MAPK/TGF-β1 signaling pathway.}, journal = {Molecules (Basel, Switzerland)}, volume = {17}, number = {3}, pages = {2738-2751}, pmid = {22395404}, issn = {1420-3049}, mesh = {Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus/drug effects ; Angiotensin II/physiology ; Angiotensin-Converting Enzyme Inhibitors/*pharmacology ; Animals ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Enalaprilat/*pharmacology ; Fibroblasts/drug effects/*physiology ; Gene Expression/drug effects ; Imidazoles/pharmacology ; *MAP Kinase Signaling System ; Myocardium/*cytology ; Phenols/pharmacology ; Phosphorylation/drug effects ; Plant Extracts/pharmacology ; Pyridines/pharmacology ; Rats ; Rats, Inbred WKY ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Enalaprilat (Ena.), an angiotensin II (Ang II) converting enzyme inhibitor (ACEI), can produce some therapeutic effects on hypertension, ventricular hypertrophy and myocardial remodeling in clinic, but its precise mechanism, especially its signaling pathways remain elusive. In this study, cardiac fibroblasts (CFb) was isolated by the trypsin digestion method; a BrdU proliferation assay was adopted to determine cell proliferation; an immunofluorescence assay was used to measure intracellular reactive oxygen species (ROS); immunocytochemistry staining and Western blotting assay were used to detect phosphorylated p38 mitogen activated protein kinase (p-p38MAPK) and transforming growth factor-β(1) (TGF-β(1)) protein expression, respectively. The results showed that Ang II (10(-7) M) stimulated the cardiac fibroblast proliferation which was inhibited by NAC (an antioxidant), SB203580 (a p38MAPK inhibitor) or enalaprilat; Ang II caused an burst of intracellular ROS level within thirty minutes, an increase in p-p38MAPK (3.6-fold of that in the control group), as well as an elevation of TGF-β(1) meantime; NAC, an antioxidant, and enalaprilat treatment attenuated cardiac fibroblast proliferation induced by Ang II and decreased ROS and p-p38MAPK protein levels in rat cardiac fibroblast; SB203580 lowered TGF-β(1) protein expression in rats' CFb in a dose-dependent manner. It could be concluded that enalaprilat can inhibit the cardiac fibroblast proliferation induced by Ang II via blocking ROS/P38MAPK/TGF-β(1) signaling pathways and the study provides a theoretical proof for the application of ACEIs in treating myocardial fibrosis and discovering the primary mechanism through which ACEIs inhibit CFb proliferation.}, }
@article {pmid22389501, year = {2012}, author = {Islam, KN and Koch, WJ}, title = {Involvement of nuclear factor κB (NF-κB) signaling pathway in regulation of cardiac G protein-coupled receptor kinase 5 (GRK5) expression.}, journal = {The Journal of biological chemistry}, volume = {287}, number = {16}, pages = {12771-12778}, pmid = {22389501}, issn = {1083-351X}, support = {P01 HL075443/HL/NHLBI NIH HHS/United States ; P01 HL091799/HL/NHLBI NIH HHS/United States ; R01 HL085503/HL/NHLBI NIH HHS/United States ; R37 HL061690/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; G-Protein-Coupled Receptor Kinase 5/*genetics/metabolism ; Gene Expression Regulation, Enzymologic/drug effects/*physiology ; Heart Diseases/enzymology/genetics ; Myocytes, Cardiac/*enzymology ; NF-kappa B p50 Subunit/genetics/*metabolism ; Primary Cell Culture ; Promoter Regions, Genetic/physiology ; RNA, Small Interfering/genetics ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/*physiology ; Tetradecanoylphorbol Acetate/analogs &amp; derivatives/pharmacology ; Thiophenes/pharmacology ; Transcription Factor RelA/genetics/*metabolism ; }, abstract = {G protein-coupled receptor kinase 5 (GRK5) plays a key role in cardiac signaling regulation, and its expression is increased in heart failure. Recently, increased expression of GRK5 in the myocardium of mice has been shown to be detrimental in the setting of pressure-overload hypertrophy. The ubiquitous nuclear transcription factor κB (NF-κB) is involved in the regulation of numerous genes in various tissues, and activation of NF-κB has been shown to be associated with heart disease. Here, we investigated the role of NF-κB signaling in the regulation of the GRK5 gene and expression of this kinase in cardiomyocytes. First, in analyzing the 5'-flanking DNA of GRK5, the presence of a potential NF-κB binding site was observed in the promoter region. Phorbol myristate acetate, a known stimulator of NF-κB, increased the levels of GRK5 in myocytes whereas treatment of cells with N-acetyl cysteine, a known inhibitor of NF-κB, or with SC 514, an inhibitor of IκB kinase 2 decreased GRK5. Utilizing EMSA or ChIP assays, we found that both p50 and p65 NF-κB could interact with the promoter of GRK5 following myocytes NF-κB activation. Importantly, short interfering RNA (siRNA)-mediated loss of p65 in myocytes decreased the stimulated increased levels of GRK5 mRNA and protein. Finally, adenovirus-mediated overexpression of a dominant-negative IκBα in myocytes inhibited the levels of GRK5. Taken together, our study demonstrates that NF-κB plays a critical role in the regulation of GRK5 transcription in myocytes and that this may translate to the significant expression changes seen in heart disease.}, }
@article {pmid22389426, year = {2012}, author = {Moody, TW and Osefo, N and Nuche-Berenguer, B and Ridnour, L and Wink, D and Jensen, RT}, title = {Pituitary adenylate cyclase-activating polypeptide causes tyrosine phosphorylation of the epidermal growth factor receptor in lung cancer cells.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {341}, number = {3}, pages = {873-881}, pmid = {22389426}, issn = {1521-0103}, support = {//Intramural NIH HHS/United States ; }, mesh = {Blotting, Western ; Enzyme-Linked Immunosorbent Assay ; ErbB Receptors/*metabolism ; Humans ; Lung Neoplasms/*metabolism ; Phosphorylation ; Pituitary Adenylate Cyclase-Activating Polypeptide/*pharmacology ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/*metabolism ; Tumor Cells, Cultured/metabolism ; Tyrosine/*metabolism ; }, abstract = {Pituitary adenylate cyclase-activating polypeptide (PACAP) is an autocrine growth factor for some lung cancer cells. The activated PACAP receptor (PAC1) causes phosphatidylinositol turnover, elevates cAMP, and increases the proliferation of lung cancer cells. PAC1 and epidermal growth factor receptor (EGFR) are present in non-small-cell lung cancer (NSCLC) cells, and the growth of NSCLC cells is inhibited by the PAC1 antagonist PACAP(6-38) and the EGFR tyrosine kinase inhibitor gefitinib. Here, the ability of PACAP to transactivate the EGFR was investigated. Western blot analysis indicated that the addition of PACAP but not the structurally related vasoactive intestinal peptide increased EGFR tyrosine phosphorylation in NCI-H838 or H345 cells. PACAP-27, in a concentration-dependent manner, increased EGFR transactivation 4-fold 2 min after addition to NCI-H838 cells. The ability of 100 nM PACAP-27 to increase EGFR or extracellular signal-regulated kinase tyrosine phosphorylation in NCI-H838 cells was inhibited by PACAP(6-38), gefitinib, 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2; Src inhibitor), (R)-N4-hydroxy-N1-[(S)-2-(1H-indol-3-yl)-1-methylcarbamoyl-ethyl]-2-isobutyl-succinamide (GM6001; matrix metalloprotease inhibitor), or antibody to transforming growth factor α (TGFα). By enzyme-linked immunosorbent assay, PACAP addition to NCI-H838 cells increased TGFα secretion into conditioned media. EGFR transactivation caused by the addition of PACAP to NCI-H838 cells was inhibited by N-acetyl-cysteine (antioxidant), tiron (superoxide scavenger), diphenylene iodonium (NADPH oxidase inhibitor), or 1-[6-[[(17β)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122; phospholipase C inhibitor), but not N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide (H89; protein kinase A inhibitor). PACAP addition to NCI-H838 cells significantly increased reactive oxygen species, and the increase was inhibited by tiron. The results indicate that PACAP causes transactivation of the EGFR in NSCLC cells in an oxygen-dependent manner that involves phospholipase C but not protein kinase A.}, }
@article {pmid22385249, year = {2012}, author = {Guerra, C and Johal, K and Morris, D and Moreno, S and Alvarado, O and Gray, D and Tanzil, M and Pearce, D and Venketaraman, V}, title = {Control of Mycobacterium tuberculosis growth by activated natural killer cells.}, journal = {Clinical and experimental immunology}, volume = {168}, number = {1}, pages = {142-152}, pmid = {22385249}, issn = {1365-2249}, mesh = {Acetylcysteine/*pharmacology ; CD40 Ligand/antagonists &amp; inhibitors/biosynthesis ; Fas Ligand Protein/biosynthesis ; Female ; Glutathione/pharmacology ; HIV Infections/immunology ; Humans ; Immunity, Innate ; Interleukin-12/metabolism ; Interleukin-2/metabolism ; Killer Cells, Natural/drug effects/*immunology/metabolism ; Leukocytes, Mononuclear/immunology/microbiology ; Lymphocyte Activation ; Male ; Mycobacterium tuberculosis/growth &amp; development/*immunology/pathogenicity ; NK Cell Lectin-Like Receptor Subfamily K/analysis ; Tuberculosis/immunology ; }, abstract = {We characterized the underlying mechanisms by which glutathione (GSH)-enhanced natural killer (NK) cells inhibit the growth of Mycobacterium tuberculosis (M. tb) inside human monocytes. We observed that in healthy individuals, treatment of NK cells with N-acetyl cysteine (NAC), a GSH prodrug in conjunction with cytokines such as interleukin (IL)-2 + IL-12, resulted in enhanced expression of NK cytotoxic ligands (FasL and CD40L) with concomitant stasis in the intracellular growth of M. tb. Neutralization of FasL and CD40L in IL-2 + IL-12 + NAC-treated NK cells resulted in abrogation in the growth inhibition of M. tb inside monocytes. Importantly, we observed that the levels of GSH are decreased significantly in NK cells derived from individuals with HIV infection compared to healthy subjects, and this decrease correlated with a several-fold increase in the growth of M. tb inside monocytes. This study describes a novel innate defence mechanism adopted by NK cells to control M. tb infection.}, }
@article {pmid22383949, year = {2012}, author = {Carmeli, C and Knyazeva, MG and Cuénod, M and Do, KQ}, title = {Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial.}, journal = {PloS one}, volume = {7}, number = {2}, pages = {e29341}, pmid = {22383949}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Biomarkers ; Cross-Over Studies ; Double-Blind Method ; Electroencephalography/*methods ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/*metabolism ; Humans ; Male ; Models, Statistical ; Multivariate Analysis ; Oscillometry ; Oxidation-Reduction ; Placebos ; Schizophrenia/*drug therapy/physiopathology ; *Signal Processing, Computer-Assisted ; }, abstract = {UNLABELLED: Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT01506765.}, }
@article {pmid22375792, year = {2012}, author = {Zheng, F and Yang, WJ and Sun, KJ and Wan, XM and Man, N and Wen, LP}, title = {Hoechst 33342-induced autophagy protected HeLa cells from caspase-independent cell death with the participation of ROS.}, journal = {Free radical research}, volume = {46}, number = {6}, pages = {740-749}, doi = {10.3109/10715762.2012.670701}, pmid = {22375792}, issn = {1029-2470}, mesh = {Acetylcysteine/pharmacology ; Autophagy/*drug effects/physiology ; Benzimidazoles/*pharmacology ; Caspases/metabolism ; Cell Death/drug effects/physiology ; Cell Line, Tumor ; HeLa Cells ; Humans ; Microscopy, Electron ; Reactive Oxygen Species/*metabolism ; Transfection ; }, abstract = {Autophagy, an evolutionarily-conserved intracellular organelle and protein degradation process, may exhibit drastically different effects on cell survival depending on the particular environmental and culturing conditions. Hoechst 33342 (HO), a fluorescent dye widely used for staining DNA, has been reported to induce apoptosis in mammalian cells. Here we showed that, in addition to caspase-independent cell death, HO also induced autophagy in HeLa cells, as evidenced by the accumulation of autophagosomes, LC3 form conversion and LC3 puncta formation in a cell line stably expressing GFP-LC3. HO treatment led to generation of reactive oxygen species (ROS), and inhibition of ROS with N-acetyl-l-cysteine (NAC) abrogated both autophagy and caspase-independent cell death. Finally, autophagy played a protective role against caspase-independent cell death, as cell death induced by HO was enhanced under pharmacological and siRNA-mediated genetic inhibition of autophagy.}, }
@article {pmid22372742, year = {2012}, author = {Mata-Campuzano, M and Alvarez-Rodríguez, M and Alvarez, M and Anel, L and de Paz, P and Garde, JJ and Martínez-Pastor, F}, title = {Effect of several antioxidants on thawed ram spermatozoa submitted to 37°C up to four hours.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {47}, number = {6}, pages = {907-914}, doi = {10.1111/j.1439-0531.2012.01990.x}, pmid = {22372742}, issn = {1439-0531}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cyclic N-Oxides/administration &amp; dosage/pharmacology ; DNA Damage/drug effects ; Dehydroascorbic Acid/administration &amp; dosage/pharmacology ; Dose-Response Relationship, Drug ; Male ; Semen Preservation/methods/*veterinary ; Spermatozoa/*drug effects/*physiology ; Spin Labels ; Temperature ; Time Factors ; }, abstract = {Thawed ram spermatozoa were incubated at 37°C in the presence of dehydroascorbic acid (DHA), TEMPOL (TPL), N-acetyl-cysteine (NAC) and rutin (RUT), at 0.1 and 1 mm, in order to test their effects on sperm physiology. Cryopreserved spermatozoa from four rams were thawed, pooled, washed and incubated in TALP-Hepes with 1 mm or 0.1 mm of each antioxidant, performing a replicate with induced oxidative stress (Fe(2+) /ascorbate). Motility (CASA), viability and mitochondrial membrane potential (flow cytometry) were analysed at 2 and 4 h. Lipoperoxidation (MDA production), intracellular reactive oxygen species (ROS) and DNA status (TUNEL) were analysed at 4 h. Antioxidants, except DHA 0.1 mm, decreased motility and kinematic parameters, but had little effect on viability or mitochondrial activity. Except 1 mm DHA, the antioxidants reduced ROS at 4 h. Moreover, NAC 1 mm, rutin and TEMPOL reduced ROS and DNA damage in the presence of oxidative stress. N-acetyl-cysteine, rutin 1 mm and TEMPOL reduced lipoperoxidation in the presence of oxidative stress. However, DHA did not affect lipoperoxidation. At 1 mm, DHA increased DNA damage in the absence of oxidative stress. Dehydroascorbic acid effects could arise from spermatozoa having a low capacity for reducing it to ascorbic acid, and it may be tested in the presence of other antioxidants or reducing power. Future research should focus in testing whether the inhibition of motility observed for NAC, rutin and TEMPOL is reversible. These antioxidants might be useful at lower temperatures (refrigerated storage or cryopreservation) when their protective effects could be advantageous.}, }
@article {pmid22370236, year = {2012}, author = {Song, JJ and Lim, HW and Kim, K and Kim, KM and Cho, S and Chae, SW}, title = {Effect of caffeic acid phenethyl ester (CAPE) on H2O2 induced oxidative and inflammatory responses in human middle ear epithelial cells.}, journal = {International journal of pediatric otorhinolaryngology}, volume = {76}, number = {5}, pages = {675-679}, doi = {10.1016/j.ijporl.2012.01.041}, pmid = {22370236}, issn = {1872-8464}, mesh = {Antioxidants ; Blotting, Western ; Caffeic Acids/*pharmacology ; Cell Culture Techniques ; Cytokines ; Ear, Middle/cytology/*drug effects/pathology ; Epithelial Cells/*drug effects/metabolism ; Flow Cytometry ; Humans ; Hydrogen Peroxide/*pharmacology ; Inflammation/*drug therapy ; Oxidative Stress/*drug effects ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species ; Real-Time Polymerase Chain Reaction ; }, abstract = {OBJECTIVE: Acute otitis media (OM) is a common pediatric disease. Recent research into the pathogenesis of OM has focused on oxidative damage, induced by oxygen free radicals, to the middle ear mucosa along with inflammation. Caffeic acid phenethyl ester (CAPE) is a biologically active ingredient of propolis honey bees, with antioxidative and anti-inflammatory activities. The effect of CAPE on hydrogen peroxide (H(2)O(2))-induced inflammatory and oxidative reactions in the middle ear is still not known. The aim of this study was to evaluate the anti-inflammatory and antioxidative effects of CAPE on cultured human middle ear epithelial cells (HMEECs).<br><br>METHODS: The inflammatory injury of H(2)O(2) and the anti-inflammatory effect of CAPE were determined by measuring levels of pro-inflammatory cytokines (tumor necrosis factor (TNF)-&#x3b1; and COX-2) with real-time reverse transcription polymerase chain reaction and Western blot analysis. Oxidative stress induced by H(2)O(2) and antioxidative effects of CAPE were evaluated directly by reactive oxygen species (ROS) production using flow cytometric analysis of 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H(2)DCFDA), and indirectly by the expression of superoxide dismutase (SOD) using Western blot analysis. The effect of CAPE was compared with N-acetyl cysteine (NAC) which has well-known antioxidative and anti-inflammatory effects.<br><br>RESULTS: CAPE significantly inhibited H(2)O(2)-induced upregulation of TNF-&#x3b1; and COX-2 expression in a dose and time dependent manner. ROS accumulation induced by H(2)O(2) stimulation was decreased by CAPE pretreatment. Induced SOD expression after H(2)O(2) stimulation was diminished by CAPE pretreatment. The anti-inflammatory and antioxidative effects of CAPE were similar to those of NAC.<br><br>CONCLUSIONS: These findings suggest that inflammation induced by H(2)O(2) can be inhibited by CAPE via inhibition of the expression of pro-inflammatory cytokines such as TNF-&#x3b1; and COX-2. Furthermore, CAPE has antioxidative effects, which decreases the need for endogenous SOD expression.}, }
@article {pmid22367066, year = {2012}, author = {Park, SH and Chi, GY and Eom, HS and Kim, GY and Hyun, JW and Kim, WJ and Lee, SJ and Yoo, YH and Choi, YH}, title = {Role of autophagy in apoptosis induction by methylene chloride extracts of Mori cortex in NCI-H460 human lung carcinoma cells.}, journal = {International journal of oncology}, volume = {40}, number = {6}, pages = {1929-1940}, doi = {10.3892/ijo.2012.1386}, pmid = {22367066}, issn = {1791-2423}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Autophagy/*drug effects ; Carcinoma, Non-Small-Cell Lung/metabolism/pathology ; Caspases/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; G1 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Lung Neoplasms/metabolism/pathology ; Medicine, East Asian Traditional ; Membrane Potential, Mitochondrial ; Methylene Chloride/*chemistry ; Microtubule-Associated Proteins/genetics/metabolism ; Plant Extracts/*pharmacology ; Plant Roots/chemistry ; Plants, Medicinal/chemistry ; Reactive Oxygen Species/metabolism ; Solvents/*chemistry ; }, abstract = {The root of Mori cortex has traditionally been used in Korea for the treatment of cutaneous inflammation, pulmonary asthma, and congestion for thousands of years. The present study was designed to validate the anticancer effects of methylene chloride extracts of the M. cortex root (MEMC) in NCI-H460 human lung carcinoma cells. Exposure to MEMC was found to result in growth inhibition by the induction of caspase‑dependent apoptosis in NCI-H460 cells, which correlated with upregulated expression of death receptor (DR)4, DR5 and FasL, downregulation of anti-apoptotic Bcl-2 and Bcl-xL expression, cleavage of Bid, and loss of mitochondrial membrane potential. In addition, autophagosomes, a characteristic finding of autophagy, and markers of autophagy, conversion of microtubule-associated protein light chain-3 (LC3)-I to LC3-II and increased beclin-1 accumulation, were observed in MEMC-treated NCI-H460 cells. Inhibition of autophagy by 3-methyladenine or LC3B small interfering (siRNA) resulted in enhanced apoptotic cell death, suggesting that MEMC-induced autophagy functions as a suppressor of apoptosis. MEMC-induced autophagy was also blocked by N-acetyl-cysteine (NAC) and catalase, indicating that H2O2 can regulate autophagy. Our data demonstrate that MEMC triggers both ROS-mediated autophagy and caspase-dependent apoptosis, and that autophagy plays a protective role against apoptotic cell death.}, }
@article {pmid22364443, year = {2012}, author = {Seifi, B and Kadkhodaee, M and Delavari, F and Mikaeili, S and Shams, S and Ostad, SN}, title = {Pretreatment with pentoxifylline and N-acetylcysteine in liver ischemia reperfusion-induced renal injury.}, journal = {Renal failure}, volume = {34}, number = {5}, pages = {610-615}, doi = {10.3109/0886022X.2012.660827}, pmid = {22364443}, issn = {1525-6049}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/etiology/pathology/*prevention &amp; control ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Liver/*blood supply ; Male ; Pentoxifylline/administration &amp; dosage/*therapeutic use ; Phosphodiesterase Inhibitors/administration &amp; dosage/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*complications ; Treatment Outcome ; }, abstract = {BACKGROUND AND AIMS: Acute hepatic injury causes systematic inflammatory responses which may finally lead to functional disturbances in remote organs. In this study, the effects of an inhibitor of inflammatory cytokines (pentoxifylline, PTX) and a well-known antioxidant, N-acetylcysteine (NAC), were evaluated on renal damage and oxidative stress following liver ischemia reperfusion (IR).<br><br>METHOD: Five groups of six male rats were used. Group 1 was sham operated. In group 2, 90 min liver partial ischemia was induced by a clamp around both hepatic artery and portal vein and then followed by 4 h of reperfusion. In groups 3 and 4, PTX or NAC was injected intraperitoneally before the ischemia, while in group 5 both drugs were co-administered. The levels of alanine amino-transferase (ALT), aspartate amino-transferase (AST), blood urea nitrogen (BUN), and creatinine in serum as well as malonyldialdehyde (MDA) and glutathione (GSH) levels and morphological changes in renal tissues were assessed.<br><br>RESULTS: Significant increase in the serum levels of ALT and AST in IR group is indicative of liver functional damages. Elevated BUN and renal tissue MDA, decreased GSH levels, and morphological damages in IR group demonstrate a significant kidney injury and oxidative stress comparing to sham group. Administration of PTX alone and PTX + NAC prevented the IR-induced increase in renal MDA levels. Administration of both drugs and their co-administration prevented the reduction in renal GSH levels and morphological changes.<br><br>CONCLUSION: Pretreatment with PTX and NAC before liver IR may be useful to ameliorate renal oxidative damage by preservation of cellular GSH concentration and a reduction in MDA levels.}, }
@article {pmid22364379, year = {2012}, author = {Gu, WJ and Wu, ZJ and Wang, PF and Aung, LH and Yin, RX}, title = {N-Acetylcysteine supplementation for the prevention of atrial fibrillation after cardiac surgery: a meta-analysis of eight randomized controlled trials.}, journal = {BMC cardiovascular disorders}, volume = {12}, number = {}, pages = {10}, pmid = {22364379}, issn = {1471-2261}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Aged, 80 and over ; Atrial Fibrillation/etiology/*prevention &amp; control ; Cardiac Surgical Procedures ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Postoperative Complications/*prevention &amp; control ; Prospective Studies ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Atrial fibrillation is the most common type of arrhythmia after cardiac surgery. An increasing body of evidence demonstrates that oxidative stress plays a pivotal role in the pathophysiology of atrial fibrillation. N-acetylcysteine (NAC) is a free radical scavenger, and may attenuate this pathophysiologic response and reduce the incidence of postoperative AF (POAF). However, it is unclear whether NAC could effectively prevent POAF. Therefore, this meta-analysis aims to assess the efficacy of NAC supplementation on the prevention of POAF.<br><br>METHODS: Medline and Embase were systematically reviewed for studies published up to November 2011, in which NAC was compared with controls for adult patients undergoing cardiac surgery. Outcome measures comprised the incidence of POAF and hospital length of stay (LOS). The meta-analysis was performed with the fixed-effect model or random-effect model according to the heterogeneity.<br><br>RESULTS: Eight randomized trials incorporating 578 patients provided the best evidence and were included in this meta-analysis. NAC supplementation significantly reduced the incidence of POAF (OR 0.62, 95% CI 0.41 to 0.93; P = 0.021) compared with controls, but had no effect on LOS (WMD -0.07, 95% CI -0.42 to 0.28; P = 0.703).<br><br>CONCLUSIONS: The prophylactic NAC supplementation may effectively reduce the incidence of POAF. However, the overall quality of current studies is poor and further research should focus on adequately powered randomized controlled trials with POAF incidence as a primary outcome measure.}, }
@article {pmid22361928, year = {2012}, author = {Sadowska, AM}, title = {N-Acetylcysteine mucolysis in the management of chronic obstructive pulmonary disease.}, journal = {Therapeutic advances in respiratory disease}, volume = {6}, number = {3}, pages = {127-135}, doi = {10.1177/1753465812437563}, pmid = {22361928}, issn = {1753-4666}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Expectorants/pharmacology/*therapeutic use ; Gene Expression Regulation/drug effects ; Humans ; Inflammation/drug therapy/physiopathology ; Mucins/drug effects/genetics ; Mucus/metabolism ; Oxidative Stress/drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {To develop an efficient therapy for chronic obstructive pulmonary disease (COPD), N-acetylcysteine (NAC) has been tested as a medication that can suppress various pathogenic processes in this disease. NAC is a thiol compound, which provides sulfhydryl groups. NAC can act as a precursor of reduced glutathione and as a direct reactive oxygen species scavenger, hence regulating the redox status in the cells. In this way NAC can interfere with several signaling pathways that play a role in regulating apoptosis, angiogenesis, cell growth and inflammatory response. Mucus hypersecretion has been reported in COPD and in other respiratory conditions. Two pathological processes have been described to play an important role in COPD, namely oxidative stress and inflammation. Both of these processes can induce mucin gene expression leading to mucin production. NAC, therefore, may influence mucin expression by acting on oxidative stress and inflammation, and play a role as a mucolytic agent. In this review we focus on the mucolysis of NAC in the management of COPD.}, }
@article {pmid22357770, year = {2012}, author = {Liu, J and Liu, M and Ye, X and Liu, K and Huang, J and Wang, L and Ji, G and Liu, N and Tang, X and Baltz, JM and Keefe, DL and Liu, L}, title = {Delay in oocyte aging in mice by the antioxidant N-acetyl-L-cysteine (NAC).}, journal = {Human reproduction (Oxford, England)}, volume = {27}, number = {5}, pages = {1411-1420}, doi = {10.1093/humrep/des019}, pmid = {22357770}, issn = {1460-2350}, mesh = {Acetylcysteine/*pharmacology ; Age Factors ; Animals ; Antioxidants/*pharmacology ; Cellular Senescence/*drug effects ; Embryonic Development/drug effects ; Female ; Litter Size/drug effects ; Mice ; Mice, Inbred Strains ; Oocytes/cytology/*drug effects ; Proto-Oncogene Proteins c-myc/metabolism ; Sirtuins/metabolism ; Spindle Apparatus/metabolism/ultrastructure ; Telomerase/metabolism ; Telomere/chemistry/drug effects ; }, abstract = {BACKGROUND: Ovarian aging is associated with declining numbers and quality of oocytes and follicles. Oxidative stress by reactive oxygen species (ROS) contributes to somatic aging in general, and also has been implicated in reproductive aging. Telomere shortening is also involved in aging, and telomeres are particularly susceptible to ROS-induced damage. Previously, we have shown that antioxidant N-acetyl-L-cysteine (NAC) effectively rescues oocytes and embryos from ROS-induced telomere shortening and apoptosis in vitro. Using mice as models, we tested the hypothesis that reducing oxidative stress by NAC might prevent or delay ovarian aging in vivo.<br><br>METHODS: Initially, young females were treated with NAC in drinking water for 2 months and the quality of fertilized oocytes and early embryo development were evaluated. Next, young mice 1-1&#xbd; months old were treated for 1 year with NAC added in drinking water, and their fertility was analyzed starting at 6 months, as indicated by litter size, oocyte number and quality. The ovaries were also examined for telomere activity and length and the expression of selected genes related to aging and DNA damage.<br><br>RESULTS: Short-term treatment of mice for 2 months with NAC demonstrated that NAC improved the quality of fertilized oocytes and early embryo development. Mice treated with a long-term low concentration (0.1 mM) of NAC had increased litter sizes at the ages of 7-10 months compared with age-matched controls without NAC treatment. NAC also increased the quality of the oocytes from these older mice. Moreover, the expression of sirtuins was increased, telomerase activity was higher and telomere length was longer in the ovaries of mice treated with NAC compared with those of the control group.<br><br>CONCLUSIONS: These data suggest that appropriate treatment with the antioxidant NAC postpones the process of oocyte aging in mice.}, }
@article {pmid22354444, year = {2012}, author = {Maheshwari, A and Misro, MM and Aggarwal, A and Sharma, RK}, title = {N-acetyl-L-cysteine modulates multiple signaling pathways to rescue male germ cells from apoptosis induced by chronic hCG administration to rats.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {17}, number = {6}, pages = {551-565}, doi = {10.1007/s10495-012-0703-8}, pmid = {22354444}, issn = {1573-675X}, mesh = {Acetylcysteine/*metabolism ; Animals ; *Apoptosis ; Chorionic Gonadotropin/*metabolism ; Humans ; Male ; Rats ; *Signal Transduction ; Spermatogenesis ; Spermatozoa/*cytology/*metabolism ; Testis/*cytology/metabolism ; }, abstract = {The present study was aimed to investigate the beneficial effects of N-acetyl-L: -cysteine (NAC, 150 mg/kg bw twice/week) against testicular germ cell apoptosis in rats induced by chronic hCG administration (100 IU/rat/day for 30 days). NAC co-treatment improved serum testosterone, prevented rise in lipid peroxidation, intracellular H(2)O(2) and the activities of antioxidant enzymes in germ cells. Replenishment of intracellular GSH and total antioxidant capacity was seen. There was a marked reduction in TUNEL positive germ cells and expression of caspase-3 (p < 0.01) and PARP cleavage. Pro-apoptotic markers Fas, FasL, caspase-8 were also significantly downregulated. While Bcl-2 was fully restored, rise in Bax, caspase-9, phospho-JNK/JNK and phospho-c-Jun/c-Jun expression was significantly arrested. Anti-apoptotic phospho-Akt/Akt and NF-κB were otherwise found upregulated. Taken together, the above findings demonstrate that NAC intervention rescued the testicular germ cells from demise following chronic hCG treatment through regulation of multiple signaling mechanisms of metazoan apoptosis.}, }
@article {pmid22353688, year = {2012}, author = {Lee, BS and Kang, SU and Hwang, HS and Kim, YS and Sung, ES and Shin, YS and Lim, YC and Kim, CH}, title = {An agonistic antibody to human death receptor 4 induces apoptotic cell death in head and neck cancer cells through mitochondrial ROS generation.}, journal = {Cancer letters}, volume = {322}, number = {1}, pages = {45-57}, doi = {10.1016/j.canlet.2012.02.007}, pmid = {22353688}, issn = {1872-7980}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies, Monoclonal/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Head and Neck Neoplasms/*drug therapy/metabolism/pathology ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2/analysis ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/agonists/analysis/*physiology ; TNF-Related Apoptosis-Inducing Ligand/pharmacology ; X-Linked Inhibitor of Apoptosis Protein/analysis/antagonists &amp; inhibitors ; Zebrafish ; bcl-X Protein/analysis/antagonists &amp; inhibitors ; }, abstract = {The proapoptotic death receptor 4 (DR4), along with DR5, is currently regarded as a promising target for development of agonistic anti-cancer agents due to its tumor-selective apoptosis-inducing ability with no significant cytotoxicity to normal cells. In this study, we examine susceptibility of various head and neck cancer (HNC) cells and mechanism of cell death to an anti-DR4 agonistic monoclonal antibody (mAb), AY4. AY4 as a single agent induced caspase-dependent apoptotic cell death of KB and HN9, but not in SNU899 and FaDu cell lines. AY4 treatment resulted in accumulation of intracellular reactive oxygen species (ROS) generated from mitochondria in AY4-sensitive cells. Blockade of ROS production by N-acetyl-l-cysteine (NAC) resulted in protection of AY4-sensitive cells against AY4-induced apoptosis. ROS generation induced by AY4 treatment triggered down-regulation of anti-apoptotic molecules of Bcl-xL and X-linked inhibitor of apoptosis (XIAP) without affecting the expression levels of DR4, Mcl-1, and survivin. AY4 also inhibited growth of pre-established HN9 tumors in a nude mouse xenograft model and did not show noticeable cytotoxicity in a zebrafish model. Our results provide further insight into the mechanism of DR4-mediated cell death and potential use of AY4 mAb as an anti-cancer therapeutic agent in AY4-sensitive HNC types.}, }
@article {pmid22353463, year = {2012}, author = {Galea, E and Launay, N and Portero-Otin, M and Ruiz, M and Pamplona, R and Aubourg, P and Ferrer, I and Pujol, A}, title = {Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: a paradigm for multifactorial neurodegenerative diseases?.}, journal = {Biochimica et biophysica acta}, volume = {1822}, number = {9}, pages = {1475-1488}, doi = {10.1016/j.bbadis.2012.02.005}, pmid = {22353463}, issn = {0006-3002}, mesh = {Adrenoleukodystrophy/drug therapy/*metabolism/pathology ; Animals ; Antioxidants/therapeutic use ; Axons/*metabolism/pathology ; Cell Membrane/metabolism ; Humans ; Inflammation/metabolism ; Mitochondria/metabolism ; Neurodegenerative Diseases/*metabolism/pathology ; *Oxidative Stress ; Peroxisomes/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder expressed as four disease variants characterized by adrenal insufficiency and graded damage in the nervous system. X-ALD is caused by a loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation of very long chain fatty acids (VLCFA) in the organs and plasma, which have potentially toxic effects in CNS and adrenal glands. We have recently shown that treatment with a combination of antioxidants containing α-tocopherol, N-acetyl-cysteine and α-lipoic acid reversed oxidative damage and energetic failure, together with the axonal degeneration and locomotor impairment displayed by Abcd1 null mice, the animal model of X-ALD. This is the first direct demonstration that oxidative stress, which is a hallmark not only of X-ALD, but also of other neurodegenerative processes, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), contributes to axonal damage. The purpose of this review is, first, to discuss the molecular and cellular underpinnings of VLCFA-induced oxidative stress, and how it interacts with energy metabolism and/or inflammation to generate a complex syndrome wherein multiple factors are contributing. Particular attention will be paid to the dysregulation of redox homeostasis by the interplay between peroxisomes and mitochondria. Second, we will extend this analysis to the aforementioned neurodegenerative diseases with the aim of defining differences as well as the existence of a core pathogenic mechanism that would justify the exchange of therapeutic opportunities among these pathologies.}, }
@article {pmid22351438, year = {2012}, author = {Syed Alwi, SS and Cavell, BE and Donlevy, A and Packham, G}, title = {Differential induction of apoptosis in human breast cancer cell lines by phenethyl isothiocyanate, a glutathione depleting agent.}, journal = {Cell stress &amp; chaperones}, volume = {17}, number = {5}, pages = {529-538}, pmid = {22351438}, issn = {1466-1268}, support = {//Cancer Research UK/United Kingdom ; }, mesh = {Anticarcinogenic Agents/*pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms/metabolism/pathology ; Caspases/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Female ; Glutathione/*metabolism ; Humans ; Isothiocyanates/*pharmacology ; MCF-7 Cells ; NF-E2-Related Factor 2/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Phenethyl isothiocyanate (PEITC) is a naturally occurring electrophile which depletes intracellular glutathione (GSH) levels and triggers accumulation of reactive oxygen species (ROS). PEITC is of considerable interest as a potential chemopreventive/chemotherapeutic agent, and in this work, we have investigated the effects of PEITC on human breast cancer cell lines. Whereas PEITC readily induced apoptosis in MDA-MB-231 cells (associated with rapid activation of caspases 9 and 3, and decreased expression of BAX), MCF7 cells were relatively resistant to the apoptosis promoting effects of PEITC. The relative resistance of MCF7 cells was associated with high basal expression of NRF2, a transcription factor that coordinates cellular protective responses to oxidants and electrophiles and raised intracellular levels of GSH. This raised basal expression of NRF2 appeared to be a response to on-going production of ROS, since treatment with the antioxidant and GSH precursor N-acetylcysteine (NAC) reduced NRF2 expression. Moreover, pre-treatment of MDA-MB-231 cells with NAC rendered these cells relatively resistant to PEITC-induced apoptosis. In summary, our data confirm that PEITC may be an effective chemopreventive/therapeutic agents for breast cancer. However, differences in the basal expression of NRF2 and resultant changes in GSH levels may be an important determinant of sensitivity to PEITC-induced apoptosis.}, }
@article {pmid22350845, year = {2012}, author = {Narahara, S and Matsushima, H and Sakai, E and Fukuma, Y and Nishishita, K and Okamoto, K and Tsukuba, T}, title = {Genetic backgrounds and redox conditions influence morphological characteristics and cell differentiation of osteoclasts in mice.}, journal = {Cell and tissue research}, volume = {348}, number = {1}, pages = {81-94}, doi = {10.1007/s00441-012-1325-8}, pmid = {22350845}, issn = {1432-0878}, mesh = {Acetylcysteine/pharmacology ; Animals ; Biomarkers/metabolism ; Bone Marrow Cells/cytology/drug effects/metabolism ; Cell Count ; Cell Differentiation/drug effects/*genetics ; Cell Shape/drug effects/*genetics ; Cell Size/drug effects ; Gene Expression Regulation/drug effects ; Hydrogen Peroxide/pharmacology ; Intracellular Space/drug effects/metabolism ; Macrophages/cytology/drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Osteoclasts/*cytology/drug effects/*metabolism ; Osteogenesis/drug effects/genetics ; Oxidation-Reduction/drug effects ; RNA, Messenger/genetics/metabolism ; Signal Transduction/drug effects ; }, abstract = {Osteoclasts (OCLs) are multinucleated giant cells and are formed by the fusion of mononuclear progenitors of monocyte/macrophage lineage. It is known that macrophages derived from different genetic backgrounds exhibit quite distinct characteristics of immune responses. However, it is unknown whether OCLs from different genetic backgrounds show distinct characteristics. In this study, we showed that bone-marrow macrophages (BMMs) derived from C57BL/6, BALB/c and ddY mice exhibited considerably distinct morphological characteristics and cell differentiation into OCLs. The differentiation of BMMs into OCLs was comparatively quicker in the C57BL/6 and ddY mice, while that of BALB/c mice was rather slow. Morphologically, ddY OCLs showed a giant cell with a round shape, C57BL/6 OCLs were of a moderate size with many protrusions and BALB/c OCLs had the smallest size with fewer nuclei. The intracellular signaling of differentiation and expression levels of marker proteins of OCLs were different in the respective strains. Treatment of BMMs from the three different strains with the reducing agent N-acetylcysteine (NAC) or with the oxidation agent hydrogen peroxide (H(2)O(2)) induced changes in the shape and sizes of the cells and caused distinct patterns of cell differentiation and survival. Thus, genetic backgrounds and redox conditions regulate the morphological characteristics and cell differentiation of OCLs.}, }
@article {pmid22346036, year = {2011}, author = {Kumar, AS and Amalnath, D and Dutta, TK}, title = {Cartap poisoning: A rare case report.}, journal = {Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine}, volume = {15}, number = {4}, pages = {233-235}, pmid = {22346036}, issn = {1998-359X}, abstract = {Cartap is a pesticide commonly used to control weevil and caterpillars. It is an analogue of nereistoxin, a neurotoxic substance isolated from the marine annelid Lumbriconereis heteropoda. It causes neuromuscular blockade. Poisoning with cartap is very rare and not yet reported from India. We report a 35-year-old lady with cartap poisoning who presented with nausea, vomiting, and dyspnea. She improved with N-acetyl cysteine and symptomatic management.}, }
@article {pmid22344537, year = {2012}, author = {Furfaro, AL and Nitti, M and Marengo, B and Domenicotti, C and Cottalasso, D and Marinari, UM and Pronzato, MA and Traverso, N}, title = {Impaired synthesis contributes to diabetes-induced decrease in liver glutathione.}, journal = {International journal of molecular medicine}, volume = {29}, number = {5}, pages = {899-905}, doi = {10.3892/ijmm.2012.915}, pmid = {22344537}, issn = {1791-244X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Diabetes Mellitus, Experimental/chemically induced/*drug therapy/*metabolism ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Heme Oxygenase-1/metabolism ; Liver/drug effects/*metabolism ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Streptozocin ; Taurine/*therapeutic use ; }, abstract = {Diabetes-induced glutathione (GSH) decrease is usually ascribed to GSH oxidation. Here we investigate, in streptozotocin-treated rats, if impairment of GSH synthesis contributes to GSH decrease in diabetic liver, and if antioxidant treatments can provide protection. Diabetic rats were divided into 3 groups: untreated diabetic rats (UD); N-acetyl-cysteine (NAC)-treated diabetic rats; taurine (TAU)-treated diabetic rats; a group of non-streptozotocin-treated rats was used as control (CTR). All rats were sacrificed at 40 weeks of age. Diabetes induced hepatic glutathione decrease, but oxidized glutathione (GSSG) did not increase significantly. Accumulations of cysteine and cysteinyl-glycine in UD suggest respectively decreased glutathione synthesis and increased loss through the plasma membrane with subsequent degradation. Decreased expression of γ-glutamyl-cysteine synthetase in UD is consistent with repressed GSH synthesis. Moreover, diabetes caused increase of GSSG/GSH ratio and induction of heme oxygenase-1, both signs of oxidative stress. Supplementation with NAC or TAU resulted in amelioration of glutathione levels, probably depending on antioxidant activity, more efficient glutathione synthesis and decreased GSH loss and degradation. In conclusion, impaired synthesis and increased loss and degradation of GSH appear to contribute to a decrease in GSH levels in diabetic liver. NAC and TAU are able to partially protect from oxidative stress and GSH decrease, while enhancing GSH synthesis and restricting GSH loss.}, }
@article {pmid22343798, year = {2012}, author = {Aslanger, E and Uslu, B and Akdeniz, C and Polat, N and Cizgici, Y and Oflaz, H}, title = {Intrarenal application of N-acetylcysteine for the prevention of contrast medium-induced nephropathy in primary angioplasty.}, journal = {Coronary artery disease}, volume = {23}, number = {4}, pages = {265-270}, doi = {10.1097/MCA.0b013e328351aacc}, pmid = {22343798}, issn = {1473-5830}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; *Angioplasty, Balloon, Coronary ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Female ; Humans ; Injections, Intra-Arterial ; Injections, Intravenous ; Ioxaglic Acid/*adverse effects ; Kidney Diseases/chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Myocardial Infarction/*therapy ; Prospective Studies ; Renal Artery ; Treatment Outcome ; }, abstract = {OBJECTIVE: Contrast medium-induced nephropathy (CIN) is a well-known complication of coronary angiographic procedures, especially in patients treated with primary angioplasty. To prevent CIN, we examined using a local application of N-acetylcysteine (NAC) for the prevention of CIN during primary angioplasty. We hypothesized that a local application of NAC into the renal arteries would provide the benefit of a higher local concentration, lower first-pass metabolism, and faster efficacy. To evaluate the effects of NAC by the intrarenal route, we performed a prospective, randomized clinical study in patients with acute myocardial infarction treated with primary angioplasty.<br><br>METHODS: Participants were 312 patients with ST-segment elevation myocardial infarction undergoing primary angiography. Eligible patients were randomly assigned to receive intravenous NAC, intrarenal NAC, or placebo.<br><br>RESULTS: Overall, CIN occurred in 74 (23.7%) of the 312 patients. The rate of CIN was 25% in the intravenous NAC group, 22.9% in the intrarenal NAC group, and 23.2% in the placebo group, with no significant effect seen for either treatment (P=0.64). We did find a significant correlation between CIN and ejection fraction (P=0.05) and baseline renal function (P=0.01).<br><br>CONCLUSION: Both intrarenal and intravenous applications of NAC failed to show any benefit over placebo in the prevention of CIN. This result shows that NAC application does not have any prophylactic effect, dose dependent or otherwise, on CIN, as previously reported. Our results suggest that more attention should be paid to optimize hemodynamic variables for the prevention of CIN.}, }
@article {pmid22343223, year = {2012}, author = {Lampiasi, N and Azzolina, A and Umezawa, K and Montalto, G and McCubrey, JA and Cervello, M}, title = {The novel NF-κB inhibitor DHMEQ synergizes with celecoxib to exert antitumor effects on human liver cancer cells by a ROS-dependent mechanism.}, journal = {Cancer letters}, volume = {322}, number = {1}, pages = {35-44}, doi = {10.1016/j.canlet.2012.02.008}, pmid = {22343223}, issn = {1872-7980}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Benzamides/*pharmacology ; Carcinoma, Hepatocellular/*drug therapy/pathology ; Celecoxib ; Cell Cycle Proteins/antagonists &amp; inhibitors/physiology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclohexanones/*pharmacology ; Cyclooxygenase 2 Inhibitors/*pharmacology ; Drug Synergism ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Liver Neoplasms/*drug therapy/pathology ; NF-kappa B/*antagonists &amp; inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/physiology ; Pyrazoles/*pharmacology ; Reactive Oxygen Species/*metabolism ; Repressor Proteins/antagonists &amp; inhibitors/physiology ; Sulfonamides/*pharmacology ; fas Receptor/physiology ; }, abstract = {In a previous work of ours dehydroxymethyl-epoxyquinomicin (DHMEQ), an inhibitor of NF-κB, was shown to induce apoptosis through Reactive Oxygen Species (ROS) production in hepatoma cells. The present study demonstrated that DHMEQ cooperates with Celecoxib (CLX) to decrease NF-κB DNA binding and to inhibit cell growth and proliferation more effectively than treatment with these single agents alone in the hepatoma cell lines HA22T/VGH and Huh-6. ROS production induced by the DHMEQ-CLX combination in turn generated the expression of genes involved in endoplasmic reticulum (ER) stress and silencing TRB3 mRNA significantly decreased DHMEQ-CLX-induced cell growth inhibition. Moreover, the DHMEQ-CLX combination was associated with induction of PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2, Mcl-1 and survivin, as well as activated Akt. CD95 and CD95 ligand expression increased synergistically in the combination treatment, which was reversed in the presence of NAC. Knockdown of CD95 mRNA expression significantly decreased DHMEQ-CLX-induced cell growth inhibition in both cell lines. These data suggest that the DHMEQ-CLX combination kills hepatoma cells via ROS production, ER stress response and the activation of intrinsic and extrinsic apoptotic pathways.}, }
@article {pmid22342303, year = {2012}, author = {Zhang, H and Liu, H and Borok, Z and Davies, KJ and Ursini, F and Forman, HJ}, title = {Cigarette smoke extract stimulates epithelial-mesenchymal transition through Src activation.}, journal = {Free radical biology &amp; medicine}, volume = {52}, number = {8}, pages = {1437-1442}, pmid = {22342303}, issn = {1873-4596}, support = {R56 ES005511/ES/NIEHS NIH HHS/United States ; R01 ES003598/ES/NIEHS NIH HHS/United States ; R01 ES005511/ES/NIEHS NIH HHS/United States ; ES05511/ES/NIEHS NIH HHS/United States ; R01 ES005511-22/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Acrolein/administration &amp; dosage ; Catalase/administration &amp; dosage ; Cell Line, Tumor ; Enzyme Activation ; Epithelial-Mesenchymal Transition/*drug effects ; Humans ; Smoke/*analysis ; *Nicotiana ; src-Family Kinases/*metabolism ; }, abstract = {Epithelial-mesenchymal transition (EMT) is implicated in the pathogenesis of lung fibrosis and cancer metastasis, two conditions associated with cigarette smoke (CS). CS has been reported to promote the EMT process. CS is the major cause of lung cancer and nearly half of lung cancer patients are active smokers. Nonetheless, the mechanism whereby CS induces EMT remains largely unknown. In this study we investigated the induction of EMT by CS and explored the underlying mechanisms in the human non-small-cell lung carcinoma (H358) cell line. We demonstrate that exposure to an extract of CS (CSE) decreases E-cadherin and increases N-cadherin and vimentin, markers of EMT, in H358 cells cultured in RPMI 1640 medium with 1% fetal bovine serum. Pretreatment with N-acetylcysteine (NAC), a potent antioxidant and precursor of glutathione, abrogated changes in these EMT markers. In addition, CSE activated Src kinase (shown as increased phosphorylation of Src at Tyr418), and the Src kinase inhibitor PP2 inhibited CS-stimulated EMT changes, suggesting that Src is critical in CSE-stimulated EMT induction. Furthermore, NAC treatment abrogated CSE-stimulated Src activation. However, co-incubation with catalase had no effect on CSE-mediated Src activation. Finally, acrolein, an unsaturated aldehyde present in CSE, caused Src activation. Taken together, these data suggest that CSE initiates EMT through Src, which is activated by CS through redox modification.}, }
@article {pmid22342106, year = {2012}, author = {Hardan, AY and Fung, LK and Libove, RA and Obukhanych, TV and Nair, S and Herzenberg, LA and Frazier, TW and Tirouvanziam, R}, title = {A randomized controlled pilot trial of oral N-acetylcysteine in children with autism.}, journal = {Biological psychiatry}, volume = {71}, number = {11}, pages = {956-961}, pmid = {22342106}, issn = {1873-2402}, support = {KL2 RR024990/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Autistic Disorder/*drug therapy ; Child ; Child, Preschool ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Irritable Mood/drug effects ; Male ; Pilot Projects ; Stereotyped Behavior/drug effects ; Treatment Outcome ; }, abstract = {BACKGROUND: An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism.<br><br>METHODS: This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale.<br><br>RESULTS: Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96).<br><br>CONCLUSIONS: Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.}, }
@article {pmid22336129, year = {2012}, author = {Chiang, CH and Chuang, CH and Liu, SL and Chian, CF and Zhang, H and Ryu, JH}, title = {N-acetylcysteine attenuates ventilator-induced lung injury in an isolated and perfused rat lung model.}, journal = {Injury}, volume = {43}, number = {8}, pages = {1257-1263}, doi = {10.1016/j.injury.2011.12.026}, pmid = {22336129}, issn = {1879-0267}, support = {MOP69042//Canadian Institutes of Health Research/Canada ; MOP77818//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blotting, Western ; Bronchoalveolar Lavage Fluid/cytology ; Chemokine CXCL2/*metabolism ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Interleukin-1beta/*metabolism ; Male ; Organ Size ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tidal Volume/drug effects ; Tumor Necrosis Factor-alpha/*metabolism ; Ventilator-Induced Lung Injury/metabolism/*pathology ; }, abstract = {N-acetylcysteine (NAC) suppresses the generation of reactive oxygen species (ROS) that are implicated in ventilator-induced lung injury (VILI). We thus hypothesised that NAC attenuates VILI. VILI was induced by mechanical ventilation with a tidal volume (Vt) of 15mlkg(-1) in isolated and perfused rat lung. NAC was administered in the perfusate prior to the onset of mechanical ventilation. A group ventilated with low Vt of 5mlkg(-1) served as control. Haemodynamics, lung injury indices, inflammatory responses and activation of apoptotic pathways were determined upon completion of the mechanical ventilation. There was an increase in lung permeability and lung weight gain after mechanical ventilation with high Vt, compared to low Vt. The levels of inflammatory cytokines including interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and macrophage inflammatory protein-2 (MIP-2) increased in lung lavage fluids; the concentrations of H(2)O(2) were higher in lung lavage fluids, and the expression of myeloperoxidase (MPO), JNK, P38, pAKT and caspase-3 in lung tissue was greater in the high Vt than in the low Vt group. The concentrations of glutathione (GSH) in lung tissue were higher in low Vt than those in high Vt. The administration of NAC increased GSH, attenuated ROS, cytokines, MPO, JNK, pAKT and caspase-3 and lung permeability associated with decreased activation of nuclear factor-κB. VILI is associated with inflammatory responses including the generation of ROS, cytokines and the activation of mitogen-activated protein kinase cascade. The administration of NAC attenuates the inflammatory responses, apoptosis and VILI in the isolated, perfused rat lung model.}, }
@article {pmid22333152, year = {2011}, author = {Xie, F and Zhao, MF and Zhu, HB and Lu, WY and Xu, XN and Xiao, X and Mu, J and Liu, PJ and Li, YM}, title = {[Effects of oxidative stress on hematopoiesis of hematopoietic stem and progenitor cells with iron overload].}, journal = {Zhonghua yi xue za zhi}, volume = {91}, number = {46}, pages = {3284-3288}, pmid = {22333152}, issn = {0376-2491}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cells, Cultured ; Fetal Blood/cytology ; Glutathione/pharmacology ; *Hematopoiesis ; Hematopoietic Stem Cells/*metabolism/*physiology ; Humans ; *Iron Overload ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: To establish a model of hematopoietic stem and progenitor cells with iron overload derived from umbilical cord blood (UCB) cells and explore the effects of reactive oxygen species (ROS) on the hematopoiesis of hematopoietic stem and progenitor cells with iron overload.<br><br>METHODS: The model was established by adding different concentrations (50, 100, 200, 400 &#xb5;mol/L)of ferric citrate (FAC) into mononuclear cells from UCB and culturing for different times (6, 12, 24 h). The UCB cells were divided into 4 groups: control group, group FAC, group FAC+N-acetyl-L-cysteine (NAC) and group FAC+ L-Glutathione (GSH). Then the changes of ROS, labile iron pool (LIP), apoptosis, the capacity of hematopoietic colony forming (CFU-E, BFU-E, CFU-GM, CFU-mix) and the percentage and the numbers of CD34(+), CD33(+), GlyA(+) cells were detected. And the changes of these indices were tested after the treatment of iron overload UCB with antioxidants (NAC and GSH).<br><br>RESULTS: UCB cells were cultured with the addition of FAC at different concentrations for different times. The level of total ROS increased in time and concentration-dependent manners. The intracellular level of ROS peaked when cultured at 200 &#xb5;mol/L of FAC for 24 hours. Cells were treated with antioxidants NAC or GSH after cultured with 200 &#xb5;mol/L FAC for 24 hours. Then the ROS levels of total cells, myeloid cells and erythroid cells decreased markedly versus normal controls. The LIP of total cells, myeloid cells and erythroid cells increased markedly when cells were cultured at 200 &#xb5;mol/L of FAC for 24 hours versus normal controls (P < 0.05). NAC and GSH had no effect on the level of LIP. The apoptotic rates of FAC-treated cells [(20.90 &#xb1; 3.45)%] increased significantly versus normal controls [(9.20 &#xb1; 1.29)%] (P < 0.05). The capacity of hematopoietic colony forming in FAC treated cells decreased markedly versus normal controls. The percentage and numbers of CD34(+), CD33(+), GlyA(+) cells of FAC-treated cells also decreased significantly versus normal controls (P < 0.05). And these changes could be recovered by the addition of NAC or GSH.<br><br>CONCLUSION: Oxidative stress plays an important role in the injuries of hematopoiesis of hematopoietic stem and progenitor cells with iron overload by inducing the generation of ROS. These findings may help us find a specific target and improve the therapeutic efficacy of ineffective hematopoiesis in patients with iron overload.}, }
@article {pmid22331703, year = {2012}, author = {Remien, CH and Adler, FR and Waddoups, L and Box, TD and Sussman, NL}, title = {Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death.}, journal = {Hepatology (Baltimore, Md.)}, volume = {56}, number = {2}, pages = {727-734}, doi = {10.1002/hep.25656}, pmid = {22331703}, issn = {1527-3350}, mesh = {Acetaminophen/*poisoning ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/poisoning ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/blood/*mortality/*pathology ; Creatinine/blood ; Drug Overdose/blood/mortality/pathology ; Hepatocytes/drug effects/pathology ; Humans ; International Normalized Ratio ; *Models, Biological ; *Models, Statistical ; Predictive Value of Tests ; Sensitivity and Specificity ; }, abstract = {UNLABELLED: Acetaminophen (APAP) is the leading cause of acute liver injury in the developed world. Timely administration of N-acetylcysteine (N-Ac) prevents the progression of serious liver injury and disease, whereas failure to administer N-Ac within a critical time frame allows disease progression and in the most severe cases may result in liver failure or death. In this situation, liver transplantation may be the only life-saving measure. Thus, the outcome of an APAP overdose depends on the size of the overdose and the time to first administration of N-Ac. We developed a system of differential equations to describe acute liver injury due to APAP overdose. The Model for Acetaminophen-induced Liver Damage (MALD) uses a patient's aspartate aminotransferase (AST), alanine aminotransferase (ALT), and international normalized ratio (INR) measurements on admission to estimate overdose amount, time elapsed since overdose, and outcome. The mathematical model was then tested on 53 patients from the University of Utah. With the addition of serum creatinine, eventual death was predicted with 100% sensitivity, 91% specificity, 67% positive predictive value (PPV), and 100% negative predictive value (NPV) in this retrospective study. Using only initial AST, ALT, and INR measurements, the model accurately predicted subsequent laboratory values for the majority of individual patients. This is the first dynamical rather than statistical approach to determine poor prognosis in patients with life-threatening liver disease due to APAP overdose.<br><br>CONCLUSION: MALD provides a method to estimate overdose amount, time elapsed since overdose, and outcome from patient laboratory values commonly available on admission in cases of acute liver failure due to APAP overdose and should be validated in multicenter prospective evaluation.}, }
@article {pmid22330067, year = {2012}, author = {Yamada, T and Egashira, N and Bando, A and Nishime, Y and Tonogai, Y and Imuta, M and Yano, T and Oishi, R}, title = {Activation of p38 MAPK by oxidative stress underlying epirubicin-induced vascular endothelial cell injury.}, journal = {Free radical biology &amp; medicine}, volume = {52}, number = {8}, pages = {1285-1293}, doi = {10.1016/j.freeradbiomed.2012.02.003}, pmid = {22330067}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Cells, Cultured ; Enzyme Activation ; Epirubicin/*pharmacology ; Glutathione/pharmacology ; In Situ Nick-End Labeling ; Mitochondria/drug effects ; *Oxidative Stress ; Swine ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Epirubicin, an anthracycline antitumor drug, often causes vascular injury such as vascular pain, phlebitis, and necrotizing vasculitis. However, an effective prevention for the epirubicin-induced vascular injury has not been established. The purpose of this study is to identify the mechanisms of cell injury induced by epirubicin in porcine aorta endothelial cells (PAECs). PAECs were exposed to epirubicin for 10 min followed by further incubation without epirubicin. The exposure to epirubicin (3-30 μM) decreased the cell viability concentration and time dependently. Epirubicin increased the activity of caspase-3/7, apoptotic cells, and intracellular lipid peroxide levels, and also induced depolarization of mitochondrial membranes. These intracellular events were reversed by glutathione (GSH) and N-acetylcysteine (NAC), while epirubicin rather increased intracellular GSH slightly and L-buthionine-(S,R)-sulfoximine, a specific inhibitor of GSH synthesis, had no effect on the epirubicin-induced cell injury. The epirubicin-induced cell injury and increase of caspase-3/7 activity were also attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors, SB203580 and PD169316. Moreover, epirubicin significantly enhanced the phosphorylation of p38 MAPK, and these effects were attenuated by GSH and NAC. In contrast, a c-Jun N-terminal kinase inhibitor SP600125, an extracellular signal-regulated kinase inhibitor PD98059, and a p53 inhibitor pifithrin α did not affect the epirubicin-induced cell injury and increase of caspase-3/7 activity. These results indicate that an activation of p38 MAPK by oxidative stress is involved in the epirubicin-induced endothelial cell injury.}, }
@article {pmid22329198, year = {2011}, author = {Ren, L and Yang, HY and Choi, HI and Chung, KJ and Yang, U and Lee, IK and Kim, HJ and Lee, DS and Park, BJ and Lee, TH}, title = {The role of peroxiredoxin V in (-)-epigallocatechin 3-gallate-induced multiple myeloma cell death.}, journal = {Oncology research}, volume = {19}, number = {8-9}, pages = {391-398}, doi = {10.3727/096504011x13127606672922}, pmid = {22329198}, issn = {0965-0407}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Multiple Myeloma/*enzymology ; Peroxiredoxins/*drug effects/metabolism ; Phosphorylation/drug effects ; Plasma Cells/drug effects/immunology ; Reactive Oxygen Species ; Signal Transduction/*drug effects ; Syndecan-1 ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {(-)-Epigallocatechin 3-gallate (EGCG) is a potent antioxidant polyphenol in green tea that acts as an anticancer agent via both direct and indirect pathways. Although the relationship between EGCG's anticancer effects and its antioxidant activity is not fully understood, it is known that EGCG stimulates production of reactive oxygen species (ROS), which induce oxidative stress leading to cell death. In IM9 multiple myeloma cells, EGCG acted in a dose- and time-dependent manner to induce apoptotic cell death. Among the antioxidant enzymes expressed in IM9 cells, levels of peroxiredoxin V (PrdxV) were selectively and significantly reduced by EGCG. Moreover, the ROS scavenger NAC completely inhibited EGCG-induced apoptosis and PrdxV reduction, while overexpression of PrdxV, but not a Prdx(VC48S) mutant, protected IM9 cells from EGCG-induced apoptosis. EGCG-induced reductions in cell viability and PrdxV levels were also observed in primary CD138+ multiple myeloma cells from patients. These results suggest that PrdxV is a key target via which EGCG mediates its anticancer effects.}, }
@article {pmid22327485, year = {2012}, author = {Sandhir, R and Sood, A and Mehrotra, A and Kamboj, SS}, title = {N-Acetylcysteine reverses mitochondrial dysfunctions and behavioral abnormalities in 3-nitropropionic acid-induced Huntington's disease.}, journal = {Neuro-degenerative diseases}, volume = {9}, number = {3}, pages = {145-157}, doi = {10.1159/000334273}, pmid = {22327485}, issn = {1660-2862}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Behavior, Animal/*drug effects ; Caspase 3/metabolism ; Cognition/drug effects ; Corpus Striatum/drug effects/metabolism ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Huntington Disease/chemically induced/*drug therapy/metabolism/physiopathology ; Lipid Peroxidation/drug effects ; Mitochondria/*drug effects/metabolism ; Motor Skills/*drug effects ; Nitro Compounds/*poisoning ; Oxidative Stress/drug effects ; Propionates/*poisoning ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Mitochondrial dysfunction is a major event involved in the pathogenesis of Huntington's disease (HD). The present study evaluates the role of N-acetyl-L-cysteine (NAC) in preventing mitochondrial dysfunctions in a 3-nitropropionic acid (3-NP)-induced model of HD. Administration of 3-NP to rats (Wistar strain) resulted in significant inhibition of mitochondrial complexes II, IV and V in the striatum. However, no significant effect on complex I was observed. Increased generation of reactive oxygen species and lipid peroxidation was observed in mitochondria of 3-NP-treated animals. Endogenous antioxidants (thiols and manganese-superoxide dismutase) were lowered in mitochondria of 3-NP-treated animals. 3-NP-treated animals showed increased cytosolic cytochrome c levels and mitochondrial swelling. Increased expressions of caspase-3 and p53 were also observed in 3-NP-treated animals. Histopathological examination of the striata of 3-NP-treated animals revealed increased neural space, neurodegeneration and gliosis. This was accompanied by cognitive and motor deficits. NAC treatment, on the other hand, was found to be effective in reversing 3-NP-induced mitochondrial dysfunctions and neurobehavioral deficits. Our findings suggest a beneficial effect of NAC in HD.}, }
@article {pmid22327021, year = {2012}, author = {Linck, VM and Costa-Campos, L and Pilz, LK and Garcia, CR and Elisabetsky, E}, title = {AMPA glutamate receptors mediate the antidepressant-like effects of N-acetylcysteine in the mouse tail suspension test.}, journal = {Behavioural pharmacology}, volume = {23}, number = {2}, pages = {171-177}, doi = {10.1097/FBP.0b013e3283512c3a}, pmid = {22327021}, issn = {1473-5849}, mesh = {Acetylcysteine/antagonists &amp; inhibitors/*pharmacology ; Animals ; Antidepressive Agents/antagonists &amp; inhibitors/*pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions/physiology ; Enzyme Inhibitors/pharmacology ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Fenclonine/analogs &amp; derivatives/pharmacology ; Hindlimb Suspension/*physiology ; Locomotion/drug effects ; Male ; Mice ; Mice, Inbred Strains ; N-Methylaspartate/pharmacology ; Quinoxalines/pharmacology ; Receptors, AMPA/*agonists/antagonists &amp; inhibitors/physiology ; alpha-Methyltyrosine/pharmacology ; }, abstract = {The aim of this study was to investigate the involvement of noradrenaline, serotonin, and subtypes of glutamate receptors in the antidepressant-like effects of N-acetylcysteine (NAC). The tail suspension test was used with male CF1 albino mice. D,L-α-methyl-ρ-tyrosine and ρ-chlorophenylalanine methyl ester hydrochloride were used as synthesis inhibitors of noradrenaline and serotonin, respectively. N-methyl-D-aspartate (NMDA) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione were used as an NMDA receptor agonist and an α-amino acid-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA) receptor antagonist, respectively. NAC (10, 25, and 50 mg/kg intraperitoneally) significantly (P<0.05) decreased tail suspension test immobility time, whereas pretreatment with D,L-α-methyl-ρ-tyrosine, ρ-chlorophenylalanine methyl ester hydrochloride, and NMDA partially prevented (P<0.05) the effects of NAC (25 mg/kg), and pretreatment with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione completely abolished (P<0.01) this effect. The study corroborates the antidepressant-like effects of NAC in the TST, a model with a well-established predictive value. The results point to the key role of AMPA receptors in the mechanism of the antidepressant-like action of NAC. Like other AMPA potentiators, NAC indirectly modulates noradrenaline and serotonin pathways. It is suggested that the value of NAC as an antidepressant arises from combined and intertwined effects on a variety of pathways.}, }
@article {pmid22326494, year = {2012}, author = {Lee, HG and Lee, YJ and Yang, JH}, title = {Perfluorooctane sulfonate induces apoptosis of cerebellar granule cells via a ROS-dependent protein kinase C signaling pathway.}, journal = {Neurotoxicology}, volume = {33}, number = {3}, pages = {314-320}, doi = {10.1016/j.neuro.2012.01.017}, pmid = {22326494}, issn = {1872-9711}, mesh = {Alkanesulfonic Acids/*toxicity ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cerebellum/*drug effects/enzymology/pathology ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Enzyme Activation ; Fluorocarbons/*toxicity ; In Situ Nick-End Labeling ; Isoenzymes ; Neurons/*drug effects/enzymology/pathology ; Neurotoxicity Syndromes/enzymology/*etiology/genetics/pathology/prevention &amp; control ; Oxidative Stress/*drug effects ; Protein Kinase C/genetics/*metabolism ; Protein Transport ; RNA Interference ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Transfection ; }, abstract = {Perfluorinated chemicals (PFCs) have been widely used in a variety of industry and consumer products. Perfluorooctane sulfonate (PFOS), a prominent member of perfluoroalkyls, is known as a neurotoxicant in developing brain and affects behavior and motor activity. However, mechanism of neurotoxicity still remains unknown. In this study, we attempted to analyze apoptotic effects of PFOS on developing neuron. Cerebellar granule cells derived from 7-day old SD rats and grown in culture for additional 7 days were used to mimic postnatal day (PND)-14 conditions. PFOS exposure increased ROS production, which was blocked by ROS inhibitor, N-acetylcysteine (NAC). PFOS selectively induced dose-dependent translocations of PKC-α, -βII and -ɛ among PKC isozymes tested. The translocation of these specific PKC isozymes was blocked by NAC. A panel of different approaches was utilized to detect apoptotic effects. PFOS induced caspase-3 activity and nucleosomal DNA fragmentation in a dose-dependent manner, which were blocked by pretreatment of NAC. These apoptotic effects were further confirmed by TUNEL staining. Increases of caspase-3 activity and nucleosomal DNA fragmentation were dampened by the inhibition of PKC isozymes using siRNA technique. Taken together, our results suggest that PFOS may induce apoptosis of cerebellar granule cells via a ROS-mediated PKC signaling pathway. PKC signal transduction pathway is pivotal in learning and memory and apoptosis of neuronal cells is a critical event in neurotoxicity. Thus, this study may contribute to understand a new mechanistic aspect of PFOS-induced neurotoxicities.}, }
@article {pmid22326291, year = {2012}, author = {Ewert, DL and Lu, J and Li, W and Du, X and Floyd, R and Kopke, R}, title = {Antioxidant treatment reduces blast-induced cochlear damage and hearing loss.}, journal = {Hearing research}, volume = {285}, number = {1-2}, pages = {29-39}, doi = {10.1016/j.heares.2012.01.013}, pmid = {22326291}, issn = {1878-5891}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Auditory Threshold/drug effects ; Benzenesulfonates/administration &amp; dosage/therapeutic use ; Cochlea/*drug effects/*injuries/pathology/physiopathology ; Disease Models, Animal ; Drug Therapy, Combination ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Hair Cells, Auditory, Inner/drug effects/pathology/physiology ; Hair Cells, Auditory, Outer/drug effects/pathology/physiology ; Hearing Loss, Noise-Induced/*drug therapy/pathology/physiopathology ; Male ; Otoacoustic Emissions, Spontaneous/drug effects ; Rats ; Rats, Long-Evans ; Time Factors ; }, abstract = {Exposure to blast overpressure has become one of the hazards of both military and civilian life in many parts of the world due to war and terrorist activity. Auditory damage is one of the primary sequela of blast trauma, affecting immediate situational awareness and causing permanent hearing loss. Protecting against blast exposure is limited by the inability to anticipate the timing of these exposures, particularly those caused by terrorists. Therefore a therapeutic regimen is desirable that is able to ameliorate auditory damage when administered after a blast exposure has occurred. The purpose of this study was to determine if administration of a combination of antioxidants 2,4-disulfonyl α-phenyl tertiary butyl nitrone (HPN-07) and N-acetylcysteine (NAC) beginning 1 h after blast exposure could reduce both temporary and permanent hearing loss. To this end, a blast simulator was developed and the operational conditions established for exposing rats to blast overpressures comparable to those encountered in an open-field blast of 14 pounds per square inch (psi). This blast model produced reproducible blast overpressures that resulted in physiological and physical damage to the auditory system that was proportional to the number and amplitude of the blasts. After exposure to 3 consecutive 14 psi blasts 100% of anesthetized rats had permanent hearing loss as determined at 21 days post exposure by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) testing. Animals treated with HPN-07 and NAC after blast exposure showed a significant reduction in ABR threshold shifts and DPOAE level shifts at 2-16 kHz with significant reduction in inner hair cell (IHC) and outer hair cell (OHC) loss across the 5-36 kHz region of the cochlea compared with control animals. The time course of changes in the auditory system was documented at 3 h, 24 h, 7 day and 21 day after blast exposure. At 3 h after blast exposure the auditory brainstem response (ABR) threshold shifts were elevated by 60 dB in both treated and control groups. A partial recovery of to 35 dB was observed at 24 h in the controls, indicative of a temporary threshold shift (TTS) and there was essentially no further recovery by 21 days representing a permanent threshold shift (PTS) of about 30 dB. Antioxidant treatment increased the amount of both TTS and PTS recovery relative to controls by 10 and 20 dB respectively. Distortion product otoacoustic emission (DPOAE) reached a maximum level shift of 25-30 dB measured in both control and treated groups at 3 h after blast exposure. These levels did not change by day 21 in the control group but in the treatment group the level shifts began to decline at 24 h until by day 21 they were 10-20 dB below that of the controls. Loss of cochlear hair cells measured at 21 day after blast exposure was mostly in the outer hair cells (OHC) and broadly distributed across the basilar membrane, consistent with the distribution of loss of frequency responses as measured by ABR and DPOAE analysis and typical of blast-induced damage. OHC loss progressively increased after blast exposure reaching an average loss of 32% in the control group and 10% in the treated group at 21 days. These findings provide the first evidence that a combination of antioxidants, HPN-07 and NAC, can both enhance TTS recovery and prevent PTS by reducing damage to the mechanical and neural components of the auditory system when administered shortly after blast exposure.}, }
@article {pmid22324429, year = {2012}, author = {Hseu, YC and Lee, MS and Wu, CR and Cho, HJ and Lin, KY and Lai, GH and Wang, SY and Kuo, YH and Kumar, KJ and Yang, HL}, title = {The chalcone flavokawain B induces G2/M cell-cycle arrest and apoptosis in human oral carcinoma HSC-3 cells through the intracellular ROS generation and downregulation of the Akt/p38 MAPK signaling pathway.}, journal = {Journal of agricultural and food chemistry}, volume = {60}, number = {9}, pages = {2385-2397}, doi = {10.1021/jf205053r}, pmid = {22324429}, issn = {1520-5118}, mesh = {Anticarcinogenic Agents ; Apoptosis/*drug effects ; Cell Cycle Checkpoints/*drug effects ; Cell Line, Tumor ; Chalcones/pharmacology ; Down-Regulation ; Flavonoids/*pharmacology ; Humans ; MAP Kinase Signaling System/drug effects/*physiology ; Mouth Neoplasms/*pathology/prevention &amp; control ; Reactive Oxygen Species/*metabolism ; }, abstract = {Chalcones have been described to represent cancer chemopreventive food components that are rich in fruits and vegetables. In this study, we examined the anti-oral cancer effect of flavokawain B (FKB), a naturally occurring chalcone isolated from Alpinia pricei (shell gingers), and revealed its molecular mechanism of action. Treatment of human oral carcinoma (HSC-3) cells with FKB (1.25-10 μg/mL; 4.4-35.2 μM) inhibited cell viability and caused G(2)/M arrest through reductions in cyclin A/B1, Cdc2, and Cdc25C levels. Moreover, FKB treatment resulted in the induction of apoptosis, which was associated with DNA fragmentation, mitochondria dysfunction, cytochrome c and AIF release, caspase-3 and caspase-9 activation, and Bcl-2/Bax dysregulation. Furthermore, increased Fas activity and procaspase-8, procaspase-4, and procaspase-12 cleavages were accompanied by death receptor and ER-stress, indicating the involvement of mitochondria, death-receptor, and ER-stress signaling pathways. FKB induces apoptosis through ROS generation as evidenced by the upregulation of oxidative-stress markers HO-1/Nrf2. This mechanism was further confirmed by the finding that the antioxidant N-acetylcysteine (NAC) significantly blocked ROS generation and consequently inhibited FKB-induced apoptosis. Moreover, FKB downregulated the phosphorylation of Akt and p38 MAPK, while their inhibitors LY294002 and SB203580, respectively, induced G(2)/M arrest and apoptosis. The profound reduction in cell number was observed in combination treatment with FKB and Akt/p38 MAPK inhibitors, indicating that the disruption of Akt and p38 MAPK cascades plays a functional role in FKB-induced G(2)/M arrest and apoptosis in HSC-3 cells.}, }
@article {pmid22319213, year = {2012}, author = {Lange, SS and Wittschieben, JP and Wood, RD}, title = {DNA polymerase zeta is required for proliferation of normal mammalian cells.}, journal = {Nucleic acids research}, volume = {40}, number = {10}, pages = {4473-4482}, pmid = {22319213}, issn = {1362-4962}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; CA132840/CA/NCI NIH HHS/United States ; P30ES007784/ES/NIEHS NIH HHS/United States ; R01 CA132840/CA/NCI NIH HHS/United States ; P01 CA097175/CA/NCI NIH HHS/United States ; P30-CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antigens, Viral, Tumor/genetics ; Apoptosis ; Cell Division ; *Cell Proliferation ; Cells, Cultured ; Cellular Senescence ; Chromatids ; DNA Breaks, Double-Stranded ; DNA-Binding Proteins/genetics/*physiology ; DNA-Directed DNA Polymerase/genetics/*physiology ; Gene Deletion ; Mice ; Reactive Oxygen Species/metabolism ; }, abstract = {Unique among translesion synthesis (TLS) DNA polymerases, pol ζ is essential during embryogenesis. To determine whether pol ζ is necessary for proliferation of normal cells, primary mouse fibroblasts were established in which Rev3L could be conditionally inactivated by Cre recombinase. Cells were grown in 2% O(2) to prevent oxidative stress-induced senescence. Cells rapidly became senescent or apoptotic and ceased growth within 3-4 population doublings. Within one population doubling following Rev3L deletion, DNA double-strand breaks and chromatid aberrations were found in 30-50% of cells. These breaks were replication dependent, and found in G1 and G2 phase cells. Double-strand breaks were reduced when cells were treated with the reactive oxygen species scavenger N-acetyl-cysteine, but this did not rescue the cell proliferation defect, indicating that several classes of endogenously formed DNA lesions require Rev3L for tolerance or repair. T-antigen immortalization of cells allowed cell growth. In summary, even in the absence of external challenges to DNA, pol ζ is essential for preventing replication-dependent DNA breaks in every division of normal mammalian cells. Loss of pol ζ in slowly proliferating mouse cells in vivo may allow accumulation of chromosomal aberrations that could lead to tumorigenesis. Pol ζ is unique amongst TLS polymerases for its essential role in cell proliferation.}, }
@article {pmid22318816, year = {2012}, author = {Lei, S and Liu, Y and Liu, H and Yu, H and Wang, H and Xia, Z}, title = {Effects of N-acetylcysteine on nicotinamide dinucleotide phosphate oxidase activation and antioxidant status in heart, lung, liver and kidney in streptozotocin-induced diabetic rats.}, journal = {Yonsei medical journal}, volume = {53}, number = {2}, pages = {294-303}, pmid = {22318816}, issn = {1976-2437}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*metabolism ; Diabetes Mellitus, Experimental/*drug therapy/*metabolism ; Heart/drug effects ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Lung/drug effects/metabolism ; Male ; NADPH Oxidases/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {PURPOSE: Hyperglycemia increases reactive oxygen species (ROS) and the resulting oxidative stress plays a key role in the pathogenesis of diabetic complications. Nicotinamide dinucleotide phosphate (NADPH) oxidase is one of the major sources of ROS production in diabetes. We, therefore, examined the possibility that NADPH oxidase activation is increased in various tissues, and that the antioxidant N-acetylcysteine (NAC) may have tissue specific effects on NADPH oxidase and tissue antioxidant status in diabetes.<br><br>MATERIALS AND METHODS: Control (C) and streptozotocin-induced diabetic (D) rats were treated either with NAC (1.5 g/kg/day) orally or placebo for 4 weeks. The plasma, heart, lung, liver, kidney were harvested immediately and stored for biochemical or immunoblot analysis.<br><br>RESULTS: levels of free 15-F(2t)-isoprostane were increased in plasma, heart, lung, liver and kidney tissues in diabetic rats, accompanied with significantly increased membrane translocation of the NADPH oxidase subunit p67phox in all tissues and increased expression of the membrane-bound subunit p22phox in heart, lung and kidney. The tissue antioxidant activity in lung, liver and kidney was decreased in diabetic rats, while it was increased in heart tissue. NAC reduced the expression of p22phox and p67phox, suppressed p67phox membrane translocation, and reduced free 15-F(2t)-isoprostane levels in all tissues. NAC increased antioxidant activity in liver and lung, but did not significantly affect antioxidant activity in heart and kidney.<br><br>CONCLUSION: The current study shows that NAC inhibits NADPH oxidase activation in diabetes and attenuates tissue oxidative damage in all organs, even though its effects on antioxidant activity are tissue specific.}, }
@article {pmid22318468, year = {2012}, author = {Nur, E and Brandjes, DP and Teerlink, T and Otten, HM and Oude Elferink, RP and Muskiet, F and Evers, LM and ten Cate, H and Biemond, BJ and Duits, AJ and Schnog, JJ and , }, title = {N-acetylcysteine reduces oxidative stress in sickle cell patients.}, journal = {Annals of hematology}, volume = {91}, number = {7}, pages = {1097-1105}, pmid = {22318468}, issn = {1432-0584}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Adult ; Anemia, Sickle Cell/blood/drug therapy/*metabolism ; Biomarkers/blood/metabolism ; Down-Regulation/drug effects ; Female ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Glutathione/analysis/blood ; Hemolysis/drug effects ; Humans ; Male ; Middle Aged ; Oxidative Stress/*drug effects/physiology ; Phosphatidylserines/blood/metabolism ; Pilot Projects ; Young Adult ; }, abstract = {Oxidative stress is of importance in the pathophysiology of sickle cell disease (SCD). In this open label randomized pilot study the effects of oral N-acetylcysteine (NAC) on phosphatidylserine (PS) expression as marker of cellular oxidative damage (primary end point), and markers of hemolysis, coagulation and endothelial activation and NAC tolerability (secondary end points) were studied. Eleven consecutive patients (ten homozygous [HbSS] sickle cell patients, one HbSβ(0)-thalassemia patient) were randomly assigned to treatment with either 1,200 or 2,400 mg NAC daily during 6 weeks. The data indicate an increment in whole blood glutathione levels and a decrease in erythrocyte outer membrane phosphatidylserine exposure, plasma levels of advanced glycation end-products (AGEs) and cell-free hemoglobin after 6 weeks of NAC treatment in both dose groups. One patient did not tolerate the 2,400 mg dose and continued with the 1,200 mg dose. During the study period, none of the patients experienced painful crises or other significant SCD or NAC related complications. These data indicate that N-acetylcysteine treatment of sickle cell patients may reduce SCD related oxidative stress.}, }
@article {pmid22318155, year = {2012}, author = {Shi, RZ and Hu, CP and Luo, D and Li, D and Pan, W and Li, SX and Yang, TL and Li, YJ and Zhang, GG}, title = {Decreased anandamide transporter activity and calcitonin gene-related peptide production in spontaneously hypertensive rats: role of angiotensin II.}, journal = {European journal of pharmacology}, volume = {680}, number = {1-3}, pages = {81-87}, doi = {10.1016/j.ejphar.2012.01.028}, pmid = {22318155}, issn = {1879-0712}, mesh = {Angiotensin II/*blood/metabolism/pharmacology ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Antioxidants/pharmacology ; Arachidonic Acids/*blood/*metabolism/pharmacology ; Blood Pressure/drug effects ; Calcitonin Gene-Related Peptide/*blood/genetics/*metabolism ; Endocannabinoids ; Ganglia, Spinal/drug effects/metabolism ; Hypertension/blood/metabolism ; Losartan/pharmacology ; Lymphocytes/drug effects/metabolism ; Male ; Membrane Transport Proteins/*metabolism ; Polyunsaturated Alkamides/*blood/*metabolism/pharmacology ; RNA, Messenger/genetics ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Reactive Oxygen Species/metabolism ; Up-Regulation/drug effects ; }, abstract = {In the present study, we investigated the role of angiotensin II in regulating the anandamide transporter activity and resultant calcitonin gene-related peptide (CGRP) production in spontaneously hypertensive rats (SHRs). Systolic blood pressure, plasma levels of anandamide, angiotensin II and CGRP, CGRP mRNA expression in dorsal root ganglion and anandamide transporter activity in peripheral blood lymphocytes were measured in SHRs treated with selective angiotensin II type 1 receptor antagonist losartan. Rat peripheral blood lymphocytes were isolated to examine the effect of exogenous angiotensin II on anandamide-induced CGRP mRNA expression, anandamide transporter activity and intracellular reactive oxygen species production in presence or absence of losartan and antioxidant n-acetyl-cysteine. In SHRs, the plasma level of angiotensin II and anandamide was elevated, but the anandamide transporter activity was attenuated concomitantly with decreased CGRP production. Treatment with losartan for 2weeks produced depressor effect, restored the reduced anandamide transporter activity, decreased the plasma anandamide level and increased the plasma level and mRNA expression of CGRP in SHRs. In cultured lymphocytes, up-regulation of CGRP mRNA expression by exogenous administration of anandamide was inhibited by anandamide transporter blocker and angiotensin II. Angiotensin II also inhibited the anandamide transporter activity concentration-dependently while increased intracellular reactive oxygen species production, which was reversed by pretreatment with losartan or n-acetyl-cysteine. The present findings suggest that angiotensin II plays a critical role in mediating the decrease in anandamide transporter activity and CGRP production in SHRs, which is likely due to activation angiotensin II type 1 receptor and resultant reactive oxygen species production.}, }
@article {pmid22316545, year = {2012}, author = {Zhang, Z and Shen, H and Qin, HD and Xu, Y and Ma, MZ and Bao, L and Wang, H}, title = {[Protective effect of N-acetylcysteine against pneumocyte apoptosis during ischemia/reperfusion injury of lung in rats].}, journal = {Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue}, volume = {24}, number = {2}, pages = {111-115}, pmid = {22316545}, issn = {1003-0603}, mesh = {Acetylcysteine/*pharmacology ; Alveolar Epithelial Cells/*cytology ; Animals ; Apoptosis/*drug effects ; Caspase 3/*metabolism ; Lung/blood supply ; Male ; Malondialdehyde/analysis ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*metabolism/pathology ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: To investigate the effect of N-acetylcysteine (NAC) on apoptosis of pneumocytes and expression of caspase-3 during lung ischemia/reperfusion injury (LIRI) in rats, and to explore the possible role of NAC in pneumocyte apoptosis.<br><br>METHODS: Forty-two male Sprague-Dawley rats were randomly divided into three groups: sham operation group, LIRI group (LIRI was produced by 45 minutes of clamping of the pulmonary hilum followed by 3 hours or 6 hours of reperfusion), and NAC group (NAC 150 mg/kg was injected intraperitoneally before LIRI). Lung specimens were harvested 3 hours or 6 hours after LIRI. Apoptosis rate in lung tissue was determined with flow cytometer after Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) staining. Malondialdehyde (MDA, thiobarbituric acid) and superoxide dismutase (SOD, xanthine oxidase) of lung tissue were measured. Expression of caspase-3 in lung was determined by reverse transcription-polymerase chain reaction (RT-PCR), and the changes in ultrastructure of lung tissue were observed by electron microscope.<br><br>RESULTS: Compared with that of the sham operation group, apoptosis rate of pulmonary cells was significantly increased at 3 hours and 6 hours in LIRI group [(25.60 &#xb1; 3.22)% vs. (2.19 &#xb1; 0.48)% , (26.01 &#xb1; 4.50)% vs. (2.55 &#xb1; 0.36)%], the content of MDA (nmol/mg) was significantly increased (3.26 &#xb1; 0.32 vs. 0.73 &#xb1; 0.23, 3.53 &#xb1; 0.46 vs. 1.08 &#xb1; 0.42), and the activity of SOD (U/mg) was significantly lowered (32.80 &#xb1; 3.82 vs. 60.51 &#xb1; 6.81, 33.44 &#xb1; 3.24 vs. 64.19 &#xb1; 6.60), and the expression of caspase-3 mRNA in lung tissue was significantly up-regulated (0.717 &#xb1; 0.037 vs. 0.216 &#xb1; 0.046, 0.744 &#xb1; 0.046 vs. 0.227 &#xb1; 0.037, all P < 0.01). Compared with that of the LIRI group, apoptosis rate of pulmonary cell was significantly decreased [(14.42 &#xb1; 1.61)% vs. (25.60 &#xb1; 3.22)%, (10.02 &#xb1; 1.64)% vs. (26.01 &#xb1; 4.50)%], content of MDA (nmol/mg) was lowered significantly (1.75 &#xb1; 0.33 vs. 3.26 &#xb1; 0.32, 2.15 &#xb1; 0.25 vs. 3.53 &#xb1; 0.46), and activity of SOD (U/mg) was significantly elevated (42.76 &#xb1; 2.06 vs. 32.80 &#xb1; 3.82, 44.94 &#xb1; 3.11 vs. 33.44 &#xb1; 3.24, all P < 0.01) in NAC group. The expression of caspase-3 in lung tissue was remarkably down-regulated compared with that of LIRI group (0.441 &#xb1; 0.038 vs. 0.717 &#xb1; 0.037, 0.410 &#xb1; 0.037 vs. 0.744 &#xb1; 0.046, both P < 0.01). The ultrastructure changes in lung tissue were milder in NAC group than in LIRI group. Positive correlation was found between the expression of caspase-3 and apoptosis rate and the content of MDA (3 hours: r = 0.9036, 0.9216; 6 hours: r = 0.9655, 0.9650, all P < 0.01), but negative correlation was found between apoptosis rate and activity of SOD (3 hours: r = -0.9511, 6 hours: r = - 0.9574, both P < 0.01) after LIRI 3 hours and 6 hours.<br><br>CONCLUSION: During early period of LIRI, caspase-3 was significantly deregulated by NAC, therefore the cellular apoptosis was inhibited, thus protecting lung tissue from LIRI.}, }
@article {pmid22315655, year = {2012}, author = {Koh, G and Kim, MK and Yang, EJ and Lee, DH}, title = {Gliclazide does not fully prevent 2-deoxy-D-ribose-induced oxidative damage because it does not restore glutathione content in a pancreatic β-cell line.}, journal = {Oxidative medicine and cellular longevity}, volume = {2012}, number = {}, pages = {390678}, pmid = {22315655}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Cell Line ; Cell Survival/drug effects ; Cricetinae ; Deoxyribose/antagonists &amp; inhibitors/*pharmacology ; Drug Interactions ; Gliclazide/*pharmacology ; Glutathione/*metabolism ; Hydroxyl Radical/metabolism ; Hypoglycemic Agents/*pharmacology ; Insulin-Secreting Cells/*drug effects/*metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {We compared the effects of gliclazide, an antidiabetic agent with antioxidant properties, and N-acetyl-L-cysteine (NAC), a glutathione precursor, in protecting against 2-deoxy-D-ribose- (dRib-) induced oxidative damage in HIT-T15 cells. Using trypan blue staining and flow cytometry with annexin V/PI staining, gliclazide treatment slightly reversed dRib-induced cell death and apoptosis, and NAC treatment markedly reduced both measures. Likewise, flow cytometry using DHR 123 staining showed that the levels of dRib-induced reactive oxygen species (ROS) were partially suppressed by gliclazide and completely inhibited by NAC. Using electron spin resonance spectrometry, gliclazide and NAC scavenged hydroxyl radicals generated by Fenton reaction to a similar degree in a cell-free system. NAC, but not gliclazide, completely restored the intracellular glutathione depleted by dRib using monochlorobimane fluorescence and glutathione assays. Thus, gliclazide treatment suppressed dRib-induced oxidative damage in HIT-T15 cells less than NAC did because gliclazide did not restore the intracellular glutathione content as effectively as NAC. In addition, the elevation of intracellular glutathione rather than free radical scavenging might be an important mechanism for protecting against dRib-induced oxidative damage in a β-cell line.}, }
@article {pmid22314570, year = {2011}, author = {Wrotek, S and Jedrzejewski, T and Potera-Kram, E and Kozak, W}, title = {Antipyretic activity of N-acetylcysteine.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {62}, number = {6}, pages = {669-675}, pmid = {22314570}, issn = {1899-1505}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antipyretics/pharmacology/*therapeutic use ; Circadian Rhythm/drug effects ; Fever/*drug therapy/physiopathology ; Male ; Motor Activity/drug effects ; Rats ; Rats, Wistar ; }, abstract = {N-acetylcysteine (NAC) has been used primarily as a mucolytic agent for the treatment of respiratory diseases. It has been recently suggested that NAC also possesses some anti-inflammatory properties. The aim of the present study is to investigate the effects of NAC on fever provoked either by bacterial lipopolysaccharide (LPS) or a turpentine-induced aseptic abscess in the rats. The body temperature (Tb) and the motor activity of the Wistar rats were measured using biotelemetry system. NAC (200 mg/kg) was injected intraperitoneally (i.p.) One hour prior to the injection of LPS (50 μg/kg; i.p.) or turpentine (100 μl/rat; subcutaneously) into separate groups of rats. The injection of NAC into normal non-febrile rats did not alter the animal circadian rhythm in Tb and activity. Pretreatment of rats with NAC resulted in the reduction of both infectious and aseptic fevers. Fever in rats was associated with inhibition of the motor activity and loss of body weight. Treatment with NAC diminished the decrease of motor activity and had no effect on the reduction of body weight in rats injected with LPS. It did, however, attenuate the drop of body mass in rats challenged with turpentine oil. Based on these data one may conclude that NAC, in addition to its mucolytic, antioxidant and anti-inflammatory properties, may be considered as a therapeutic fever-modulating agent under certain clinical circumstances.}, }
@article {pmid22310733, year = {2012}, author = {Piao, MS and Park, JJ and Choi, JY and Lee, DH and Yun, SJ and Lee, JB and Lee, SC}, title = {Nrf2-dependent and Nrf2-independent induction of phase 2 detoxifying and antioxidant enzymes during keratinocyte differentiation.}, journal = {Archives of dermatological research}, volume = {304}, number = {5}, pages = {387-395}, doi = {10.1007/s00403-012-1215-7}, pmid = {22310733}, issn = {1432-069X}, mesh = {Acetylcysteine/metabolism ; Antioxidants/*metabolism ; Cell Differentiation ; Down-Regulation ; Enzyme Induction ; Glutathione S-Transferase pi/metabolism ; Heme Oxygenase-1/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Keratinocytes/*cytology/*enzymology ; *Metabolic Detoxication, Phase II ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; NF-E2-Related Factor 2/*genetics/*metabolism ; RNA Interference ; RNA, Messenger/biosynthesis ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Transcriptional Activation ; Up-Regulation ; }, abstract = {As antioxidant enzymes can be actively modulated during keratinocyte (KC) differentiation, this study was aimed to evaluate the modulation of a group of phase 2 detoxifying and antioxidant enzymes (phase 2 enzymes) during KC differentiation. In postconfluence-induced differentiation model of KC, heme oxygenase-1 (HO-1), NADP(H):quinone oxidoreductase-1 (NQO-1), and glutathione S-transferase pi (GSTpi) were up-regulated at a transcriptional level. In Western blot analysis, the phase 2 enzymes were up-regulated by H(2)O(2), but down-regulated by N-acetyl cysteine, indicating the active role of reactive oxygen species for their expression during KC differentiation. When a redox-sensitive NF-E2 related factor-2 (Nrf2), a key transcriptional factor for phase 2 enzymes, was knocked down by small interfering RNA transfection in differentiated KCs, only NQO-1 was down-regulated in both mRNA and protein levels. In human skin, expression levels of the phase 2 enzymes were up-regulated in the differentiated KC in the normal epidermis and keratotic foci in squamous cell carcinoma, further supporting the differentiation-dependent expression of phase 2 enzymes in vivo. This study demonstrates that a group of phase 2 enzymes are modulated during KC differentiation via either Nrf2-dependent (NQO-1) or Nrf2-independent (HO-1 and GSTpi) ways.}, }
@article {pmid22306110, year = {2012}, author = {Fan, J and Cai, H and Li, Q and Du, Z and Tan, W}, title = {The effects of ROS-mediating oxygen tension on human CD34(+)CD38(-) cells induced into mature dendritic cells.}, journal = {Journal of biotechnology}, volume = {158}, number = {3}, pages = {104-111}, doi = {10.1016/j.jbiotec.2012.01.017}, pmid = {22306110}, issn = {1873-4863}, mesh = {ADP-ribosyl Cyclase 1 ; Acetylcysteine/pharmacology ; Antigens, CD34 ; Antigens, Differentiation/biosynthesis ; *Cell Differentiation ; Cell Hypoxia/drug effects ; Cells, Cultured ; Dendritic Cells/cytology/*metabolism ; Female ; Free Radical Scavengers/pharmacology ; Gene Expression Profiling ; Hematopoietic Stem Cells/cytology/*metabolism ; Humans ; Oxygen/*metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; *Transcription, Genetic ; }, abstract = {Oxygen tension regulates the biological characteristics of hematopoietic stem and progenitor cells (HSPCs) by modulating intracellular reactive oxygen species (ROS). To better understand oxygen tension mechanism on HSPCs culture, gene expression analysis of human CD34(+)CD38(-) HSPCs was performed using microarrays. The CD34(+)CD38(-) HSPCs cultured under normoxia, hypoxia, or with N-acetyl cysteine (NAC, an ROS scavenger) were isolated for transcriptional profilings. Compared to normoxia group, 1 gene was up-regulated and 22 genes were down-regulated in hypoxia group, while 1 gene was up-regulated and 29 genes were down-regulated in NAC group. These differently expressed genes were involved in cell surface markers, blood activation and differentiation. The common down-regulated genes related to dendritic cells (DCs) maturation (CD80, CD86, and JAG1) were confirmed by real-time RT-PCR. Furthermore, the analysis of the phenotypes of DCs, including the DC-characteristic surface molecule CD1a, the costimulatory molecules CD80 and CD86, and HLA-DR, associated with the capacity of DCs to stimulate allogeneic T cells, showed that hypoxia-mediating ROS inhibited the potential of CD34(+)CD38(-) HSPCs differentiating to mature DCs. All these results demonstrated that hypoxia-reducing ROS down-regulated the genes driving CD34(+)CD38(-) HSPCs differentiation, which provides an interesting molecular hint to direct their development to DCs during cultures.}, }
@article {pmid22303701, year = {2011}, author = {Ge, Z and Ma, S and Jia, X and Song, L}, title = {[Study of protective effects on noise-induced hearing loss using N-acetyl-cysteine].}, journal = {Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery}, volume = {25}, number = {22}, pages = {1040-1041}, pmid = {22303701}, issn = {2096-7993}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Hearing Loss, Noise-Induced/drug therapy/*prevention &amp; control ; Humans ; Male ; Military Personnel ; Young Adult ; }, abstract = {OBJECTIVE: To evaluate the protective effects of oral administration of N-acetyl-cysteine (NAC) on noise-induced hearing loss.<br><br>METHOD: Three hundred sixty three volunteers were recruited and randomly divided into two groups: experimental group (n=223) and control group (n=140). The subjects had received oral administration of NAC in the experimental group and placebo in the control group before noise exposure. The routine audiometric evaluation and ABR testing were performed and recorded pre- and post-noise exposure. The statistical analysis was carried out on the data obtained from two groups with SPSS 11.0.<br><br>RESULT: The hearings of all the participatory were changed after noise exposure, but there were statistically significant differences between two groups.<br><br>CONCLUSION: The protective effects of NAC were prominent on the noise-induced hearing loss.}, }
@article {pmid22300897, year = {2012}, author = {Özgül, C and Nazıroğlu, M}, title = {TRPM2 channel protective properties of N-acetylcysteine on cytosolic glutathione depletion dependent oxidative stress and Ca2+ influx in rat dorsal root ganglion.}, journal = {Physiology &amp; behavior}, volume = {106}, number = {2}, pages = {122-128}, doi = {10.1016/j.physbeh.2012.01.014}, pmid = {22300897}, issn = {1873-507X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Boron Compounds/pharmacology ; Buthionine Sulfoximine/pharmacology ; Calcium/*metabolism ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Ganglia, Spinal/metabolism/*physiology ; Glutathione/*adverse effects/metabolism ; Glutathione Peroxidase/metabolism ; Hydrogen Peroxide/pharmacology ; In Vitro Techniques ; Lipid Peroxidation/drug effects/physiology ; Male ; Membrane Potentials/drug effects/*physiology ; Neurons/metabolism/physiology ; Oxidants/pharmacology ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Wistar ; TRPM Cation Channels/antagonists &amp; inhibitors/metabolism/*physiology ; }, abstract = {N-acetylcysteine (NAC) is a thiol-containing (sulphydryl donor) antioxidant, which contributes to regeneration of glutathione (GSH) and also acts through a direct reaction with free radicals. Thiol depletion has been implicated in the neurobiology of sensory neurons and pain. We reported recently an activator role of intracellular GSH depletion on calcium influx through transient receptor potential melastatin-like 2 (TRPM2) channels in rat dorsal root ganglion (DRG). NAC may have a protective role on calcium influx through regulation of TRPM2 channels in the neurons. Therefore, we tested the effects of NAC on TRPM2 channel currents in cytosolic GSH depleted DRG in rats. DRG neurons were freshly isolated from rats and the neurons were incubated for 24 h with buthionine sulfoximine (BSO). In whole-cell patch clamp experiments, TRPM2 currents in the DRG incubated with BSO were gated by H(2)O(2). TRPM2 channels current densities, cytosolic free Ca(2+) content, and lipid peroxidation values in the neurons were higher in H(2)O(2) and BSO + H(2)O(2) group than in controls; however GSH and GSH peroxidase (GSH-Px) values were decreased. BSO + H(2)O(2)-induced TRPM2 channel gating was totally inhibited by extracellular NAC and partially inhibited by 2-aminoethyl diphenylborinate. GSH-Px activity, lipid peroxidation and GSH levels in the DRG neurons were also modulated by NAC. In conclusion, we observed a modulator role of NAC on Ca(2+) influx through a TRPM2 channel in intracellular GSH depleted DRG neurons. NAC incubation before BSO exposure appears to be more protective than NAC incubation after BSO exposure. Since cytosolic thiol group depletion is a common feature of neuropathic pain, our findings are relevant to the etiology and treatment of pain neuropathology in DRG neurons.}, }
@article {pmid22296293, year = {2012}, author = {Abe, N and Okuhira, M and Tsutsui, C and Murata, Y and Nakamura, Y}, title = {Cytotoxicity of benzyl isothiocyanate in normal renal proximal tubular cells and its modulation by glutathione.}, journal = {Journal of agricultural and food chemistry}, volume = {60}, number = {7}, pages = {1887-1892}, doi = {10.1021/jf2052042}, pmid = {22296293}, issn = {1520-5118}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Cell Line ; Cell Survival/*drug effects ; Glutathione/*pharmacology ; Isothiocyanates/*antagonists &amp; inhibitors/metabolism/*toxicity ; Kidney Tubules, Proximal/*cytology/*drug effects ; Necrosis ; Oxidative Stress ; Swine ; }, abstract = {In the present study, we examined the toxicity of benzyl ITC (BITC) and its urinary mercapturic acid metabolite (BITC-NAC), using a normal renal proximal tubular cell line, pig LLC-PK1. BITC increased cell death with an IC(50) value of about 7 μM, whereas the cytotoxic effect of BITC-NAC was five times weaker than that of BITC. We observed a significant necrosis of the compounds on LLC-PK1 cells with oxidative stress. In the presence of 5 mM glutathione (GSH), comparable to physiological levels, the cytotoxicity of BITC-NAC as well as BITC was significantly reduced. Furthermore, the increase in intracellular GSH levels by pretreatment with NAC before the BITC treatment resulted in inhibition of the BITC-induced necrotic events as well as intracellular oxidative stress. These results suggest that GSH is a determinant of cellular resistance against the BITC-mediated and oxidative stress-dependent cytotoxicity in renal proximal tubular cells.}, }
@article {pmid22295426, year = {2011}, author = {Brooks, CE and Middleton, A and Dhillon, R and Scott, D and Denton, M}, title = {Predictors of creatinine rise post-endovascular abdominal aortic aneurysm repair.}, journal = {ANZ journal of surgery}, volume = {81}, number = {11}, pages = {827-830}, doi = {10.1111/j.1445-2197.2011.05699.x}, pmid = {22295426}, issn = {1445-2197}, mesh = {Acute Kidney Injury/*diagnosis/etiology ; Aged ; Aged, 80 and over ; Aortic Aneurysm, Abdominal/diagnostic imaging/*surgery ; Aortography/methods ; Biomarkers/metabolism ; Blood Vessel Prosthesis Implantation/*adverse effects/methods ; Cohort Studies ; Contrast Media ; Creatinine/*metabolism ; Female ; Follow-Up Studies ; Humans ; Logistic Models ; Male ; Multivariate Analysis ; Postoperative Complications/diagnosis/*metabolism ; Postoperative Period ; Predictive Value of Tests ; Retrospective Studies ; Risk Assessment ; Severity of Illness Index ; Tomography, X-Ray Computed/methods ; Treatment Outcome ; }, abstract = {BACKGROUND: Endovascular abdominal aortic aneurysm repair involves manipulation of the aorta around the renal arteries. Fenestrated grafts involve the direct cannulation, stenting and injecting of contrast into the renal arteries. These procedures may be associated with an acute post-operative creatinine rise.<br><br>METHODS: We retrospectively examined data from all endovascular aortic repairs at our institution from 2005 to 2009, where contrast dosage had been recorded. Renal impairment was defined as a 25% increase in creatinine during the 5-day postoperative period. Univariable analysis was undertaken for a number of likely predictors, including: age, contrast dosage, preoperative creatinine, graft type (fenestrated or standard), diabetes mellitus, hypertension, hypercholesterolaemia, ischaemic heart disease, aspirin therapy, statins therapy, non-steroidal anti-inflammatory drug use, preoperative N-acetyl-cysteine and intravenous pre-hydration. Multivariable analysis was then applied to variables with a univariable P-value of < 0.05.<br><br>RESULTS: We identified 106 consecutive cases, with complete data for 102. Twenty per cent of patients developed renal impairment (22/102). Contrast dose (P = 0.043) and fenestrated grafts (P = 0.006) were identified as significant risk factors for post-operative creatinine increase (P = 0.043). Multivariable analysis demonstrated that fenestrated grafts were a risk factor independent of contrast dosage (P < 0.05).<br><br>CONCLUSIONS: Patients who received a fenestration graft (P < 0.01) and increased contrast dose (P < 0.05) were at a significant increased risk of a 25% post-operative creatinine rise. The risk of fenestration grafts persisted when multivariable regression was performed to control for contrast dosage (P < 0.05). Other variables investigated were not found to be significant in this study.}, }
@article {pmid22293418, year = {2012}, author = {Akhtar, MJ and Ahamed, M and Fareed, M and Alrokayan, SA and Kumar, S}, title = {Protective effect of sulphoraphane against oxidative stress mediated toxicity induced by CuO nanoparticles in mouse embryonic fibroblasts BALB 3T3.}, journal = {The Journal of toxicological sciences}, volume = {37}, number = {1}, pages = {139-148}, doi = {10.2131/jts.37.139}, pmid = {22293418}, issn = {1880-3989}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; BALB 3T3 Cells ; Cell Survival/drug effects ; Copper/*toxicity ; Glutathione/metabolism ; Glutathione Reductase/metabolism ; Isothiocyanates ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation ; Mice ; Microscopy, Electron, Transmission ; Nanoparticles/*toxicity/ultrastructure ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Sulfoxides ; Thiocyanates/*pharmacology ; }, abstract = {Despite the great interest in nanoparticles (NPs) safety, no comprehensive test paradigm has been developed. Oxidative stress has been implicated as an explanation behind the toxicity of NPs. It is reported that sulphoraphane (SFN) present in cruciferous vegetables like cauliflower and broccoli has potential to protect cells from oxidative damage and inflammation. However, protective role of SFN in nanotoxicity is not explored. We investigated the protective effect of SFN against the toxic response of copper oxide (CuO) NPs in mouse embryonic fibroblasts (BALB 3T3). Results showed that CuO NPs induced dose-dependent (5-15 µg/ml) cytotoxicity in BALB 3T3 cells demonstrated by MTT and lactate dehydrogenase (LDH) assays. CuO NPs were also found to induce oxidative stress in dose-dependent manner indicated by induction of reactive oxygen species (ROS) and lipid peroxidation (LPO) and depletion of glutathione and glutathione reductase. Co-treatment of BALB 3T3 cells with SFN (6 µM) significantly attenuated the cytotoxicity, ROS generation and oxidative stress caused by CuO NPs. Moreover, we found that co-treatment of another antioxidant N-acetyl-cysteine (NAC) (2 mM) also significantly attenuated glutathione depletion caused by CuO NPs but protection from the loss of cell viability due to CuO NPs exposure was not significant. We believe this is the first report showing that SFN significantly protected the BALB 3T3 cells from CuO NPs toxicity, which is mediated through generation of oxidants and depletion of antioxidants. Consequently, protective mechanism of SFN against CuO NPs toxicity was different from NAC that should be further investigated.}, }
@article {pmid22292182, year = {2011}, author = {Huang, D and Fang, F and Xu, F}, title = {[Hyperoxia-induced up-regulation of Toll-like receptors expression in alveolar epithelial cells].}, journal = {Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue}, volume = {23}, number = {11}, pages = {645-649}, pmid = {22292182}, issn = {1003-0603}, mesh = {Cell Line, Tumor ; Epithelial Cells/*metabolism ; Humans ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; *Oxidative Stress ; Oxygen/*metabolism ; Pulmonary Alveoli/*cytology/metabolism ; Signal Transduction ; Toll-Like Receptor 2/*metabolism ; Toll-Like Receptor 4/*metabolism ; }, abstract = {OBJECTIVE: To examine the correlation between the hyperoxia-induced reactive oxygen species (ROS) production and Toll-like receptors (TLRs) expression in cultured alveolar epithelial cells in order to understand the role of TLRs signaling in inflammatory response during acute lung injury.<br><br>METHODS: Three groups of cultured human lung adenocarcinoma cell line A549 were exposed to: ()air,)hyperoxia(95%O2 + 5%COz) and &#xae; N-acetylcysteine (NAC) pretreatment + hyperoxia. The level of intracellular ROS, TLR2/4 mRNA, TLR2/4 protein and cytokine interleukin-6/8 (IL-6/8) concentrations in the culture supernatant were measured by flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR)and enzyme linked immunosorbent assay (ELISA) in cells harvested at different time points into the treatment.<br><br>RESULTS: A549 cells were found to have a baseline (mainly intracellular) TLR2/4 expression.Continued exposure to hyperoxia caused () a progressive increase in intracellular ROS, which became significantly higher than the air treated cells after 2 hours of exposure (11. 820&#xb1;3. 123 vs. 7. 223 &#xb1; 1. 170,P < 0.01), and reached a peak after 48 hours of exposure (113. 837 &#xb1; 5. 247, P < 0. 01); &#xa9; an increase in intracellular TLR2/4 mRNA which peaked after 2 hours of exposure (TLR2 mRNA: 1. 820 &#xb1; 0. 056 vs.1. 263 &#xb1; 0. 023; TLR4 mRNA: 2. 080 &#xb1; 0. 220 vs. 1. 317 &#xb1; 0. 107, both P < 0.01); &#xa9; significant increase inTLR2/4 protein expression (mainly intracellular), both peaked after exposure for 6 hours (TLR2 protein:8. 370 &#xb1; 1. 548 vs. 3. 930 &#xb1; 0.277; TLR4 protein: 25. 803 &#xb1; 5. 783 vs. 8. 867+2. 230, both P < 0.01); a progressive increase in culture supernatant IL-6 (ng/L), IL-8 (ng/L) concentration, both peaked at 48 hours (IL-6: 2 213.41 69.99 vs. 9. 76 &#xb1; i1. 47; IL-8: 11 520. 38 &#xb1; 429. 93 vs. 159. 56 &#xb1; 20. 80, both P < 0.01). NAC pre-treatment significantly suppressed the hyperoxia induced intracellular ROS (14. 050 &#xb1; 1. 257 vs. 31.180+2.336, P < 0.01) production, the hyperoxia induced expression of TLR2/4 (TLR2 mRNA: 1. 270&#xb1;0. 061 vs. 1. 683+0. 025; TLR4 mRNA: 1. 5870. 058 vs. 1. 650 &#xb1; 0. 139; TLR2 protein: 3. 458 &#xb1; 0.258 vs. 8.371 + 1.548; TLR4 protein: 11.611 &#xb1; 3.403 vs. 25. 803 &#xb1; 5.783, all P < 0.05), and the hyperoxia induced increase in IL-6 and IL-8 in supernatant level (IL-6: 8.42+0.70 vs. 73.51+16.70; IL-8: 134.94 &#xb1; 5.19 vs. 772.82 &#xb1; 96.05, both P < 0.05), as seen in the hyperoxia treated groups.<br><br>CONCLUSION: Hyperoxia induced intracellular ROS production can up-regulate TLR2/4 expression in A549 cells, leading to the release pro-inflammatory cytokines IL-6 and IL-8 from these cells.}, }
@article {pmid22289847, year = {2012}, author = {Evans, LC and Liu, H and Pinkas, GA and Thompson, LP}, title = {Chronic hypoxia increases peroxynitrite, MMP9 expression, and collagen accumulation in fetal guinea pig hearts.}, journal = {Pediatric research}, volume = {71}, number = {1}, pages = {25-31}, doi = {10.1038/pr.2011.10}, pmid = {22289847}, issn = {1530-0447}, support = {R01 HL049999/HL/NHLBI NIH HHS/United States ; R01HL 49999/HL/NHLBI NIH HHS/United States ; F31HL 90044/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Body Weight ; Collagen/*metabolism ; Female ; Fetal Heart/*metabolism ; Guinea Pigs ; Hypoxia/*metabolism ; Lipid Peroxidation ; Matrix Metalloproteinase 9/*metabolism ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors ; Organ Size ; Peroxynitrous Acid/*metabolism ; Pregnancy ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {INTRODUCTION: Chronic hypoxia increases the expression of inducible nitric oxide synthase (iNOS) mRNA and protein levels in fetal guinea pig heart ventricles. Excessive generation of nitric oxide (NO) can induce nitrosative stress leading to the formation of peroxynitrite, which can upregulate the expression of matrix metalloproteinases (MMPs). This study tested the hypothesis that maternal hypoxia increases fetal cardiac MMP9 and collagen through peroxynitrite generation in fetal hearts.<br><br>RESULTS: In heart ventricles, levels of malondialdehyde, 3-nitrotyrosine (3-NT), MMP9, and collagen were increased in hypoxic (HPX) vs. normoxic (NMX) fetal guinea pigs.<br><br>DISCUSSION: Thus, maternal hypoxia induces oxidative-nitrosative stress and alters protein expression of the extracellular matrix (ECM) through upregulation of the iNOS pathway in fetal heart ventricles. This identifies iNOS-derived NO as an important stimulus for initiating the adverse effects of peroxynitrite in HPX fetal hearts.<br><br>METHODS: Pregnant guinea pigs were exposed to normoxia (room air) or hypoxia (10.5% O(2), 14 d) before term (term &#x2248; 65 d) and administered water, L-N6-(1-iminoethyl)-lysine (LNIL), an iNOS inhibitor, or N-acetylcysteine (NAC), an antioxidant.}, }
@article {pmid22289559, year = {2011}, author = {Demirel, C and Kilciksiz, S and Gurgul, S and Erdal, N and Yildiz, A}, title = {N-acetylcysteine ameliorates γ-radiation-induced deterioration of bone quality in the rat femur.}, journal = {The Journal of international medical research}, volume = {39}, number = {6}, pages = {2393-2401}, doi = {10.1177/147323001103900640}, pmid = {22289559}, issn = {1473-2300}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomechanical Phenomena/drug effects ; Bone Density/drug effects ; Diaphyses/drug effects/pathology/physiopathology/radiation effects ; Female ; Femur/*drug effects/pathology/physiopathology/*radiation effects ; *Gamma Rays ; Male ; Radiation-Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {This animal study evaluated the radioprotective effects of N-acetylcysteine (NAC) and amifostine on the biomechanical properties of bone in Wistar albino rats of both genders. The rats were randomly divided into four groups of eight: a control group (C); a group given a single dose of 40 Gy of γ-irradiation (R); a group given γ-irradiation plus 200 mg/kg amifostine (R + amifostine); and a group given γ-irradiation plus 1000 mg/kg NAC (R + NAC). Extrinsic and intrinsic properties of bone, bone mineral density (BMD) and the cross-sectional area of the femoral shaft were determined. The cross-sectional area was significantly higher in the R + NAC and R + amifostine groups compared with the R and C groups. The BMD, maximum load and stiffness were also significantly higher in the R + NAC and R + amifostine groups than in the R group, and energy absorption capacity was higher in the R + NAC group than in the R group. These findings indicate that NAC and amifostine preserve bone quality in rats exposed to γ-irradiation.}, }
@article {pmid22286146, year = {2012}, author = {Sanmartin, CD and Adasme, T and Hidalgo, C and Paula-Lima, AC}, title = {The antioxidant N-acetylcysteine prevents the mitochondrial fragmentation induced by soluble amyloid-β peptide oligomers.}, journal = {Neuro-degenerative diseases}, volume = {10}, number = {1-4}, pages = {34-37}, doi = {10.1159/000334901}, pmid = {22286146}, issn = {1660-2862}, mesh = {Acetylcysteine/*pharmacology ; Amyloid beta-Peptides/*pharmacology ; Animals ; Calcium/metabolism ; Cells, Cultured ; Cresols/pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; HSP70 Heat-Shock Proteins/metabolism ; Hippocampus/cytology ; Mitochondria/*drug effects/pathology ; Neurons/*drug effects/metabolism/ultrastructure ; Neuroprotective Agents/*pharmacology ; Rats ; Time Factors ; }, abstract = {BACKGROUND: Soluble amyloid-β peptide oligomers (AβOs), which are centrally involved in the pathogenesis of Alzheimer's disease, trigger Ca(2+) influx through N-methyl-D-aspartate receptors and stimulate reactive oxygen species generation in primary hippocampal neurons. We have previously reported that AβOs promote Ca(2+) release mediated by ryanodine receptors (RyR), which in turn triggers mitochondrial fragmentation. We have also reported that the antioxidant N-acetylcysteine (NAC) prevents AβOs-induced Ca(2+) signal generation.<br><br>OBJECTIVES: To determine if RyR-mediated Ca(2+) release activated by the specific agonist 4-chloro-m-cresol (4-CMC) induces fragmentation of the mitochondrial network, and to ascertain if NAC prevents the mitochondrial fragmentation induced by A&#x3b2;Os and/or 4-CMC.<br><br>METHODS: Mature primary rat hippocampal neurons were incubated for 24 h with sublethal concentrations of A&#x3b2;Os (500 nM) or for 1-3 h with 4-CMC (0.5-1 mM), &#xb1; 10 mM NAC. Mitochondrial morphology was assessed by confocal microscopy of fixed neurons stained with anti-mHsp70. Intracellular Ca(2+) levels were determined by time series microscopy of neurons preloaded with Fluo-4 AM.<br><br>RESULTS: Preincubation of neurons for 30 min with NAC prevented the mitochondrial fragmentation induced by A&#x3b2;Os or 4-CMC. In addition, we confirmed that preincubation with NAC abolished the stimulation of RyR-mediated Ca(2+) release induced by A&#x3b2;Os or 4-CMC.<br><br>CONCLUSION: The present results strongly suggest that the general antioxidant NAC prevents A&#x3b2;O-induced mitochondrial fragmentation by preventing RyR-mediated Ca(2+)-induced Ca(2+) release.}, }
@article {pmid22284448, year = {2012}, author = {Chen, W and Ercal, N and Huynh, T and Volkov, A and Chusuei, CC}, title = {Characterizing N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) binding for lead poisoning treatment.}, journal = {Journal of colloid and interface science}, volume = {371}, number = {1}, pages = {144-149}, pmid = {22284448}, issn = {1095-7103}, support = {R15 ES012167/ES/NIEHS NIH HHS/United States ; R15 ES012167-02A1/ES/NIEHS NIH HHS/United States ; (2R15ES012167-02A1/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemistry/*metabolism/pharmacology ; Chromatography, High Pressure Liquid ; Free Radical Scavengers/chemistry/*pharmacology ; Lead/chemistry/*metabolism ; Lead Poisoning/*drug therapy ; Photoelectron Spectroscopy ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {Using antioxidants is an important means of treating lead poisoning. Prior in vivo studies showed marked differences between various chelator antioxidants in their ability to decrease both blood Pb(II) levels and oxidative stress resulting from lead poisoning. The comparative abilities of NAC and NACA to Pb(II) were studied in vitro, for the first time, to examine the role of the -OH/-NH(2) functional group in antioxidant binding behavior. To assay the antioxidant-divalent metal interaction, the antioxidants were probed as solid surfaces, adsorbing Pb(II) onto them. Surface characterization was carried out using X-ray photoelectron spectroscopy (XPS) analysis to quantify Pb(II) in the resulting adducts. XPS of the Pb 4f orbitals showed that more Pb(II) was chemically bound to NACA than NAC. In addition, the antioxidant surfaces probed via point-of-zero charge (PZC) measurements of NAC and NACA were obtained to gain further insight into the Pb-NAC and Pb-NACA binding, showing that Coulombic interactions played a partial role in facilitating complex formation. The data correlated well with solution analysis of metal-ligand complexation. UV-vis spectroscopy was used to probe complexation behavior. NACA was found to have the higher binding affinity as shown by free Pb(II) available in the solution after complexation from HPLC data. Electrospray ionization mass spectrometry (ESI-MS) was applied to delineate the structures of Pb-antioxidant complexes. Experimental results were further supported by density functional theory (DFT) calculations of supermolecular interaction energies (E(inter)) showing a greater interaction of Pb(II) with NACA than NAC.}, }
@article {pmid22283740, year = {2012}, author = {Fan, S and Qi, M and Yu, Y and Li, L and Yao, G and Tashiro, S and Onodera, S and Ikejima, T}, title = {P53 activation plays a crucial role in silibinin induced ROS generation via PUMA and JNK.}, journal = {Free radical research}, volume = {46}, number = {3}, pages = {310-319}, doi = {10.3109/10715762.2012.655244}, pmid = {22283740}, issn = {1029-2470}, mesh = {Anthracenes/pharmacology ; Apoptosis/drug effects ; Apoptosis Regulatory Proteins/*physiology ; Benzothiazoles/pharmacology ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor/drug effects/metabolism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, p53 ; HeLa Cells/drug effects/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/*physiology ; MAP Kinase Signaling System ; Membrane Potential, Mitochondrial ; Oxidative Stress ; Phosphorylation ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins/*physiology ; Reactive Oxygen Species/*metabolism ; Silybin ; Silymarin/pharmacology ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/*physiology ; Vulvar Neoplasms/pathology ; }, abstract = {Silibinin is an active constituent extracted from blessed milk thistle (Silybum marianum). Our previous study demonstrated that silibinin induced autophagy and apoptosis via reactive oxygen species (ROS) generation in HeLa cells. In this study, we investigated whether the autophagy- and apoptosis-associated molecules also involved in ROS generation. Silibinin promoted the expression phosphorylated-p53 (p-p53) in a dose-dependent manner. Pifithrin-α (PFT-α), a specific inhibitor of p53, reduced ROS production and reversed silibinin's growth-inhibitory effect. The ROS scavenger N-acetyl cysteine (NAC) attenuated silibinin-induced up-regulation of p-p53 expression, suggesting that p53 might be regulated by ROS and forms a positive feedback loop with ROS. On the other hand, silibinin dose-dependently promoted the expression of phosphorylated-c-Jun N-terminal kinase (p-JNK). Inhibition of JNK by SP600125 decreased ROS generation. NAC down-regulated the expression of p-JNK, indicating that JNK could be activated by ROS. Activation of p53 was suppressed by SP600125 and expression of p-JNK was inhibited by PFT-α, therefore silibinin might activate a ROS-JNK-p53 cycle to induce cell death. Silibinin up-regulated the PUMA and Bax expressions and down-regulated the mitochondrial membrane potential (MMP) level. PFT-α reduced the expression of PUMA and Bax. These results showed that p53 could interfere with mitochondrial functions such as MMP via PUMA pathways, thus resulting in ROS generation. In order to elucidate the functions of p53 in silibinin induced ROS generation, we have chosen the A431 cells (human epithelial carcinoma) because they lack p53 activity (p53His273 mutation). Interestingly, silibinin did not up-regulate the ROS level in A431 cells but lower the ROS level. PFT-α had no influence on ROS level in A431 cells. p53 activation plays a crucial role in silibinin induced ROS generation.}, }
@article {pmid22281495, year = {2012}, author = {Ding, W and Yang, L and Zhang, M and Gu, Y}, title = {Reactive oxygen species-mediated endoplasmic reticulum stress contributes to aldosterone-induced apoptosis in tubular epithelial cells.}, journal = {Biochemical and biophysical research communications}, volume = {418}, number = {3}, pages = {451-456}, doi = {10.1016/j.bbrc.2012.01.037}, pmid = {22281495}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Aldosterone/pharmacology/*physiology ; Annexin A5/chemistry ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Cell Line ; Endoplasmic Reticulum Chaperone BiP ; *Endoplasmic Reticulum Stress ; Epithelial Cells/cytology/drug effects/physiology ; Fluoresceins/chemistry ; Heat-Shock Proteins/biosynthesis ; Humans ; Kidney Tubules/cytology/drug effects/*physiology ; Propidium/chemistry ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/biosynthesis/genetics ; }, abstract = {Apoptosis contributes to tubular epithelial cell death and atrophy in aldosterone (Aldo)-induced renal injury. This study aimed to determine mechanisms underlying Aldo-induced reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress in tubular epithelial cells. Intracellular ROS generation was evaluated by 2',7'-dichlorofluorescin diacetate fluorescence. Apoptosis was detected by annexin V/propidium iodide staining and flow cytometry. ER stress induced protein and mRNA were evaluated by Western blot and real-time PCR, respectively. Aldo promoted tubular epithelial cell apoptosis, increased intracellular ROS production and induced ER stress, as evidenced by increased expression of glucose-regulated protein 78 (GRP78) and CAAT/enhancer-binding protein homologous protein (CHOP) in a dose- and time-dependent manner. Additionally, siRNA knockdown of CHOP and antioxidant N-acetyl-l-cysteine (NAC) attenuated ER stress-mediated apoptosis. NAC also could inhibit Aldo-induced expression of GRP78 and CHOP. Altogether, these observations suggest that Aldo induces apoptosis via ROS-mediated, CHOP-dependent activation in renal tubular epithelial cells.}, }
@article {pmid22275514, year = {2012}, author = {Sheveleva, EV and Landowski, TH and Samulitis, BK and Bartholomeusz, G and Powis, G and Dorr, RT}, title = {Imexon induces an oxidative endoplasmic reticulum stress response in pancreatic cancer cells.}, journal = {Molecular cancer research : MCR}, volume = {10}, number = {3}, pages = {392-400}, pmid = {22275514}, issn = {1557-3125}, support = {P30 CA023074/CA/NCI NIH HHS/United States ; P01 CA017094-32/CA/NCI NIH HHS/United States ; CA017094/CA/NCI NIH HHS/United States ; P01 CA017094/CA/NCI NIH HHS/United States ; CA023074/CA/NCI NIH HHS/United States ; CA120613/CA/NCI NIH HHS/United States ; CA077204/CA/NCI NIH HHS/United States ; R01 CA077204/CA/NCI NIH HHS/United States ; }, mesh = {Cell Line, Tumor ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Eukaryotic Initiation Factor-2B/metabolism ; Gene Silencing/drug effects ; Hexanones/*pharmacology ; Humans ; Membrane Glycoproteins/metabolism ; Neoplasm Proteins/metabolism ; Oxidation-Reduction/drug effects ; Oxidoreductases/metabolism ; Pancreatic Neoplasms/metabolism/*pathology ; Protein Biosynthesis/drug effects ; }, abstract = {Oxidative protein folding in the endoplasmic reticulum (ER) requires strict regulation of redox homeostasis. Disruption of the lumenal redox balance induces an integrated ER stress response that is associated with reduced protein translation, increased chaperone activity, and ultimately cell death. Imexon is a small-molecule chemotherapeutic agent that has been shown to bind glutathione (GSH) and induce oxidative stress in tumor cells; however, the mechanism of cytotoxicity is not well understood. In this report, we investigate the effects of imexon on the integrated ER stress response in pancreatic carcinoma cells. Acute exposure to imexon induces an ER stress response characterized by accumulation of the oxidized form of the oxidoreductase Ero1α, phosphorylation of eIF2α, and inhibition of protein synthesis. An RNA interference chemosensitization screen identified the eukaryotic translation initiation factor eIF2B5 as a target that enhanced imexon-induced growth inhibition of MiaPaCa-2 pancreatic cancer cells, but did not significantly augment the effects of imexon on protein synthesis. Concurrent reduction of intracellular thiols with N-acetyl cysteine reversed imexon activity, however cotreatment with superoxide scavengers had no effect, suggesting thiol binding may be a primary component of the oxidative effects of imexon. Moreover, the data suggest that disruption of the redox balance in the ER is a potential therapeutic target.}, }
@article {pmid22274925, year = {2012}, author = {Kang, KA and Zhang, R and Kim, GY and Bae, SC and Hyun, JW}, title = {Epigenetic changes induced by oxidative stress in colorectal cancer cells: methylation of tumor suppressor RUNX3.}, journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine}, volume = {33}, number = {2}, pages = {403-412}, pmid = {22274925}, issn = {1423-0380}, mesh = {Caco-2 Cells ; Cell Line, Tumor ; Colorectal Neoplasms/*genetics/metabolism ; Core Binding Factor Alpha 3 Subunit/*genetics ; Cytosine/chemistry ; DNA (Cytosine-5-)-Methyltransferase 1 ; DNA (Cytosine-5-)-Methyltransferases/genetics ; *DNA Methylation ; *Epigenesis, Genetic ; Gene Silencing ; Genes, Tumor Suppressor ; Histone Deacetylase 1/genetics ; Humans ; Hydrogen Peroxide/chemistry/pharmacology ; *Oxidative Stress ; Reactive Oxygen Species ; Reverse Transcriptase Polymerase Chain Reaction/methods ; }, abstract = {Runt domain transcription factor 3 (RUNX3) is a tumor suppressor that is silenced in cancer via hypermethylation of its promoter. This study investigated the mechanisms involved in reactive oxygen species (ROS)-induced silencing of RUNX3 in terms of epigenetic alteration since the effects of oxidative stress in tumor suppressor gene transcription are largely unknown. RUNX3 mRNA and protein expressions were down-regulated in response to hydrogen peroxide (H(2)O(2)) in the human colorectal cancer cell line SNU-407. This down-regulation was abolished with pretreatment of the ROS scavenger, N-acetylcysteine (NAC). Moreover, methylation-specific PCR data revealed that H(2)O(2) treatment increased RUNX3 promoter methylation; however, NAC and the cytosine methylation inhibitor, 5-aza-2-deoxycytidine (5-Aza-dC), decreased it, suggesting that an epigenetic regulatory mechanism by ROS-induced methylation may be involved in RUNX3 silencing. H(2)O(2) treatment resulted in DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1) up-regulation with increased expression and activity, increased binding of DNMT1 to HADC1, and increased DNMT1 binding to the RUNX3 promoter. In addition, 5-Aza-dC treatment prevented the decrease in RUNX3 mRNA and protein levels by H(2)O(2) treatment. Additionally, H(2)O(2) treatment inhibited the nuclear localization and expression of RUNX3, which was abolished by NAC treatment. Furthermore, the down-regulation of RUNX3 expression by H(2)O(2) also influenced cell proliferation. Taken together, the data suggested that ROS silenced the tumor suppressor, RUNX3, by epigenetic regulation and may therefore be associated with the progression of colorectal cancer.}, }
@article {pmid22270622, year = {2012}, author = {Choi, SY and Lim, JW and Shimizu, T and Kuwano, K and Kim, JM and Kim, H}, title = {Reactive oxygen species mediate Jak2/Stat3 activation and IL-8 expression in pulmonary epithelial cells stimulated with lipid-associated membrane proteins from Mycoplasma pneumoniae.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {61}, number = {5}, pages = {493-501}, pmid = {22270622}, issn = {1420-908X}, mesh = {Acetylcysteine/pharmacology ; Bacterial Proteins/*pharmacology ; Cell Line ; DNA/metabolism ; Enzyme Activation ; Epithelial Cells/metabolism ; Humans ; Interleukin-8/*genetics ; Janus Kinase 2/*physiology ; Lung/*metabolism ; Membrane Proteins/*pharmacology ; Mycoplasma pneumoniae/*pathogenicity ; NF-kappa B/physiology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/*physiology ; Toll-Like Receptors/physiology ; }, abstract = {OBJECTIVE: To investigate the involvement of reactive oxygen species (ROS) in the activation of Janus kinase2 (Jak2)/signal transducers and activators of transcription3 (Stat3), and IL-8 expression in pulmonary epithelial cells stimulated with lipid-associated membrane proteins (LAMP) from Mycoplasma pneumoniae using a known antioxidant, N-acetylcysteine (NAC).<br><br>METHODS: Pulmonary epithelial A549 cells were treated with or without NAC in the presence or absence of LAMP. Intracellular ROS levels were detected by fluorescent analysis for fluorescent dichlorofluorescein. mRNA expression of IL-8 was analyzed by reverse transcription-polymerase chain reaction. IL-8 protein in the medium was determined by enzyme-linked immunosorbent assay. Activation of Jak2/Stat3 was determined by the increases in phospho-specific forms of Jak2/Stat3 compared to total forms of Jak2/Stat3 by western blotting. Stat3-DNA binding activity was assessed by electrophoretic mobility shift assay.<br><br>RESULTS: LAMP increased the level of ROS, phosphorylation of Jak2/Stat3, Stat3-DNA binding activity, and IL-8 expression in A549 cells, which were inhibited by NAC dose-dependently.<br><br>CONCLUSION: LAMP of M. pneumoniae induces the production of ROS, Jak2/Stat3 activation, and IL-8 induction in A549 cells. Antioxidants such as NAC may be beneficial for preventing pulmonary inflammation caused by M. pneumoniae.}, }
@article {pmid22270335, year = {2012}, author = {Snell, TW and Fields, AM and Johnston, RK}, title = {Antioxidants can extend lifespan of Brachionus manjavacas (Rotifera), but only in a few combinations.}, journal = {Biogerontology}, volume = {13}, number = {3}, pages = {261-275}, pmid = {22270335}, issn = {1573-6768}, support = {R01 AG037960/AG/NIA NIH HHS/United States ; R01 AG037960-02/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*pharmacology ; *Life Expectancy ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Rotifera/*drug effects/physiology ; Superoxides/metabolism ; Swimming ; }, abstract = {Animal cells are protected from oxidative damage by an antioxidant network operating as a coordinated system, with strong synergistic interactions. Lifespan studies with whole animals are expensive and laborious, so there has been little investigation of which antioxidant interactions might be useful for life extension. Animals in the phylum Rotifera are particularly promising models for aging studies because they are small (0.1-1 mm), have short, two-week lifespan, display typical patterns of animal aging, and have well characterized, easy to measure phenotypes of aging and senescence. One class of interventions that has consistently produced significant rotifer life extension is antioxidants. Although the mechanism of antioxidant effects on animal aging remains controversial, the ability of some antioxidant supplements to extend rotifer lifespan was unequivocal. We found that exposing rotifers to certain combinations of antioxidant supplements can produce up to about 20% longer lifespan, but that most antioxidants have no effect. We performed life table tests with 20 single antioxidants and none yielded significant rotifer life extension. We tested 60 two-way combinations of selected antioxidants and only seven (12%) produced significant rotifer life extension. None of the 20 three- and four-way antioxidant combinations tested yielded significant rotifer life extension. These observations suggest that dietary exposure of antioxidants can extend rotifer lifespan, but most antioxidants do not. We observed significant rotifer life extension only when antioxidants were paired with trolox, N-acetyl cysteine, L: -carnosine, or EUK-8. This illustrates that antioxidant treatments capable of rotifer life extension are patchily distributed in the parameter space, so large regions must be searched to find them. It furthermore underscores the value of the rotifer model to conduct rapid, facile life table experiments with many treatments, which makes such a search feasible. Although some antioxidants extended rotifer lifespan, they likely did so by another mechanism than direct antioxidation.}, }
@article {pmid22268121, year = {2012}, author = {Campos, R and Shimizu, MH and Volpini, RA and de Bragança, AC and Andrade, L and Lopes, FD and Olivo, C and Canale, D and Seguro, AC}, title = {N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {302}, number = {7}, pages = {L640-50}, doi = {10.1152/ajplung.00097.2011}, pmid = {22268121}, issn = {1522-1504}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/drug therapy/*prevention &amp; control ; Animals ; Antioxidants/pharmacology ; Cecum/injuries ; Disease Models, Animal ; Glomerular Filtration Rate/drug effects/physiology ; Kidney/pathology ; Lung/pathology ; Male ; Neutrophils/drug effects/physiology ; Oxidative Stress/drug effects ; Pulmonary Edema/drug therapy/*prevention &amp; control ; Rats ; Rats, Wistar ; *Respiration, Artificial ; Sepsis/*pathology/physiopathology ; Sodium Channels/metabolism ; Sodium-Potassium-Chloride Symporters/metabolism ; Solute Carrier Family 12, Member 2 ; }, abstract = {Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the α-subunit of the epithelial sodium channel (α-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, α-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis.}, }
@article {pmid22266922, year = {2012}, author = {Park, WH and Kim, SH}, title = {MG132, a proteasome inhibitor, induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion.}, journal = {Oncology reports}, volume = {27}, number = {4}, pages = {1284-1291}, pmid = {22266922}, issn = {1791-2431}, mesh = {Antioxidants/pharmacology ; Catalase/genetics/metabolism ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Down-Regulation ; Fibroblasts/*drug effects/enzymology/pathology ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors/metabolism ; Glutathione/*metabolism ; Glutathione Peroxidase/genetics/metabolism ; Humans ; Leupeptins/*pharmacology ; Lung/*drug effects/enzymology/pathology ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/*drug effects ; Protease Inhibitors/*pharmacology ; Proteasome Endopeptidase Complex/metabolism ; *Proteasome Inhibitors ; RNA Interference ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/genetics/metabolism ; Transfection ; Ubiquitination ; Up-Regulation ; }, abstract = {MG132 as a proteasome inhibitor can induce apoptotic cell death in lung cancer cells. However, little is known about the toxicological cellular effects of MG132 on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on MG132-treated human pulmonary fibroblast (HPF) cells in relation to cell death, reactive oxygen species (ROS) and glutathione (GSH). MG132 induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm). MG132 increased ROS levels and GSH-depleted cell numbers in HPF cells. Both antioxidants, NAC and vitamin C, prevented growth inhibition, death and MMP (∆ψm) loss in MG132-treated HPF cells and also attenuated ROS levels in these cells. BSO showed a strong increase in ROS levels in MG132-treated HPF cells and slightly enhanced the growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion. In addition, NAC decreased anonymous ubiquitinated protein levels in MG132-treated HPF cells. Furthermore, superoxide dismutase (SOD) 2, catalase (CTX) and GSH peroxidase (GPX) siRNAs enhanced HPF cell death by MG132, which was not correlated with ROS and GSH level changes. In conclusion, MG132 induced the growth inhibition and death of HPF cells, which were accompanied by increasing ROS levels and GSH depletion. Both NAC and vitamin C attenuated HPF cell death by MG132, whereas BSO slightly enhanced the death.}, }
@article {pmid22266044, year = {2012}, author = {Xu, HL and Yu, XF and Qu, SC and Qu, XR and Jiang, YF and Sui, da Y}, title = {Juglone, from Juglans mandshruica Maxim, inhibits growth and induces apoptosis in human leukemia cell HL-60 through a reactive oxygen species-dependent mechanism.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {50}, number = {3-4}, pages = {590-596}, doi = {10.1016/j.fct.2012.01.002}, pmid = {22266044}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Annexin A5/metabolism ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Division/*drug effects ; Cytochromes c/metabolism ; Enzyme Activation ; Glutathione/metabolism ; HL-60 Cells ; Humans ; Juglans/*chemistry ; Leukemia/*pathology ; Membrane Potentials/drug effects ; Naphthoquinones/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Juglone, a major chemical constituent of Juglans mandshruica Maxim, is a promising anticancer agent that has shown a strong activity against cancer cells in vitro. Our previous study showed that juglone inhibited the proliferation of HL-60 cells with an IC50 value ∼8 μM. To further explore the proapoptotic mechanism of juglone, we investigated the role of the reactive oxygen species (ROS) in the apoptosis induced by juglone in HL-60 cells. The generation of ROS was about 2 to 8-fold as compared to control cell after treatment with juglone (2, 4 and 8 μM) for 24 h. The glutathione (GSH) depletion was consistent with ROS generation after treatment with juglone. Reversal of apoptosis in antioxidants (NAC and catalase) pretreated cells indicated the involvement of ROS in juglone-induced apoptosis. The cleavage of PARP and procaspase-3 and -9, loss of mitochondrial membrane potential (△Ψm), and release of cytochrome c (Cyt c) and Smac induced by juglone were significantly blocked by NAC. NAC also prevented the inhibition the phosphorylation of Akt and mTOR proteins by juglone. Collectively, these results indicated that ROS played a significant role in the apoptosis induced by juglone in human leukemia cell HL-60.}, }
@article {pmid22264228, year = {2012}, author = {Talbot, S and Dias, JP and Lahjouji, K and Bogo, MR and Campos, MM and Gaudreau, P and Couture, R}, title = {Activation of TRPV1 by capsaicin induces functional kinin B(1) receptor in rat spinal cord microglia.}, journal = {Journal of neuroinflammation}, volume = {9}, number = {}, pages = {16}, pmid = {22264228}, issn = {1742-2094}, support = {MOP-79471//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Anilides/pharmacology ; Animals ; Antioxidants/pharmacology ; Autoradiography ; Bradykinin/analogs &amp; derivatives/pharmacokinetics/pharmacology ; Bradykinin B1 Receptor Antagonists ; Capsaicin/analogs &amp; derivatives/*pharmacology ; Cinnamates/pharmacology ; Dose-Response Relationship, Drug ; Gene Expression Regulation/drug effects ; Iodine Isotopes/pharmacokinetics ; Male ; Microglia/*drug effects ; Protein Binding ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Bradykinin B1/genetics/*metabolism ; Sensory System Agents/*pharmacology ; Spinal Cord/*cytology ; Superoxides/metabolism ; TRPV Cation Channels/antagonists &amp; inhibitors/*metabolism ; Tetrahydroisoquinolines/pharmacokinetics ; Time Factors ; }, abstract = {BACKGROUND: The kinin B(1) receptor (B(1)R) is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1) activation. To examine the link between TRPV1 and B(1)R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B(1)R expression in the spinal cord dorsal horn, and the underlying mechanism.<br><br>METHODS: B(1)R expression (mRNA, protein and binding sites) was measured in cervical, thoracic and lumbar spinal cord in response to TRPV1 activation by systemic capsaicin (1-50 mg/kg, s.c) in rats pre-treated with TRPV1 antagonists (capsazepine or SB-366791), the antioxidant N-acetyl-L-cysteine (NAC), or vehicle. B(1)R function was assessed using a tail-flick test after intrathecal (i.t.) injection of a selective B(1)R agonist (des-Arg(9)-BK), and its microglial localization was investigated by confocal microscopy with the selective fluorescent B(1)R agonist, [N&#x3b1;-bodipy]-des-Arg(9)-BK. The effect of i.t. capsaicin (1 &#x3bc;g/site) was also investigated.<br><br>RESULTS: Capsaicin (10 to 50 mg/kg, s.c.) enhanced time-dependently (0-24h) B(1)R mRNA levels in the lumbar spinal cord; this effect was prevented by capsazepine (10 mg/kg, i.p.; 10 &#x3bc;g/site, i.t.) and SB-366791 (1 mg/kg, i.p.; 30 &#x3bc;g/site, i.t.). Increases of B(1)R mRNA were correlated with IL-1&#x3b2; mRNA levels, and they were significantly less in cervical and thoracic spinal cord. Intrathecal capsaicin (1 &#x3bc;g/site) also enhanced B(1)R mRNA in lumbar spinal cord. NAC (1 g/kg/d &#xd7; 7 days) prevented B(1)R up-regulation, superoxide anion production and NF-kB activation induced by capsaicin (15 mg/kg). Des-Arg(9)-BK (9.6 nmol/site, i.t.) decreased by 25-30% the nociceptive threshold at 1 min post-injection in capsaicin-treated rats (10-50 mg/kg) while it was without effect in control rats. Des-Arg(9)-BK-induced thermal hyperalgesia was blocked by capsazepine, SB-366791 and by antagonists/inhibitors of B(1)R (SSR240612, 10 mg/kg, p.o.), glutamate NMDA receptor (DL-AP5, 10 &#x3bc;g/site, i.t.), substance P NK-1 receptor (RP-67580, 10 &#x3bc;g/site, i.t.) and nitric oxide synthase (L-NNA, 10 &#x3bc;g/site, i.t.). The B(1)R fluorescent agonist was co-localized with an immunomarker of microglia (Iba-1) in spinal cord dorsal horn of capsaicin-treated rats.<br><br>CONCLUSION: This study highlights a new mechanism for B(1)R induction via TRPV1 activation and establishes a link between these two pro-nociceptive receptors in inflammatory pain.}, }
@article {pmid22263782, year = {2012}, author = {Napierska, D and Rabolli, V and Thomassen, LC and Dinsdale, D and Princen, C and Gonzalez, L and Poels, KL and Kirsch-Volders, M and Lison, D and Martens, JA and Hoet, PH}, title = {Oxidative stress induced by pure and iron-doped amorphous silica nanoparticles in subtoxic conditions.}, journal = {Chemical research in toxicology}, volume = {25}, number = {4}, pages = {828-837}, doi = {10.1021/tx200361v}, pmid = {22263782}, issn = {1520-5010}, mesh = {Cell Line ; Cell Survival/drug effects ; Cell-Free System ; Gene Expression Regulation ; Glutathione/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Humans ; Hydroxyl Radical/metabolism ; Iron/*chemistry ; Lipid Peroxidation/drug effects ; Nanoparticles/chemistry/*toxicity ; Oxidative Stress/*drug effects ; Particle Size ; Silicon Dioxide/*chemistry ; }, abstract = {Amorphous silica nanoparticles (SiO2-NPs) have found broad applications in industry and are currently intensively studied for potential uses in medical and biomedical fields. Several studies have reported cytotoxic and inflammatory responses induced by SiO2-NPs in different cell types. The present study was designed to examine the association of oxidative stress markers with SiO2-NP induced cytotoxicity in human endothelial cells. We used pure monodisperse amorphous silica nanoparticles of two sizes (16 and 60 nm; S16 and S60) and a positive control, iron-doped nanosilica (16 nm; SFe), to study the generation of hydroxyl radicals (HO·) in cellular-free conditions and oxidative stress in cellular systems. We investigated whether SiO2-NPs could influence intracellular reduced glutathione (GSH) and oxidized glutathione (GSSG) levels, increase lipid peroxidation (malondialdehyde (MDA) and 4-hydroxyalkenal (HAE) concentrations), and up-regulate heme oxygenase-1 (HO-1) mRNA expression in the studied cells. None of the particles, except SFe, produced ROS in cell-free systems. We found significant modifications for all parameters in cells treated with SFe nanoparticles. At cytotoxic doses of S16 (40-50 μg/mL), we detected weak alterations of intracellular glutathione (4 h) and a marked induction of HO-1 mRNA (6 h). Cytotoxic doses of S60 elicited similar responses. Preincubation of cells being exposed to SiO2-NPs with an antioxidant (5 mM N-acetylcysteine, NAC) significantly reduced the cytotoxic activity of S16 and SFe (when exposed up to 25 and 50 μg/mL, respectively) but did not protect cells treated with S60. Preincubation with NAC significantly reduced HO-1 mRNA expression in cells treated with SFe but did not have any effect on HO-1 mRNA level in cell exposed to S16 and S60. Our study demonstrates that the chemical composition of the silica nanoparticles is a dominant factor in inducing oxidative stress.}, }
@article {pmid22262455, year = {2012}, author = {Tyra, HM and Spitz, DR and Rutkowski, DT}, title = {Inhibition of fatty acid oxidation enhances oxidative protein folding and protects hepatocytes from endoplasmic reticulum stress.}, journal = {Molecular biology of the cell}, volume = {23}, number = {5}, pages = {811-819}, pmid = {22262455}, issn = {1939-4586}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; R01 DK084058/DK/NIDDK NIH HHS/United States ; R01 DK084058-03/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Cell Line, Tumor ; Cells, Cultured ; *Endoplasmic Reticulum Stress ; Fatty Acids/*metabolism ; Glutathione/metabolism ; Hepatocytes/metabolism/*physiology ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction ; Protein Folding ; Rats ; *Unfolded Protein Response ; }, abstract = {The unfolded protein response (UPR) signals protein misfolding in the endoplasmic reticulum (ER) to effect gene expression changes and restore ER homeostasis. Although many UPR-regulated genes encode ER protein processing factors, others, such as those encoding lipid catabolism enzymes, seem unrelated to ER function. It is not known whether UPR-mediated inhibition of fatty acid oxidation influences ER function or, if so, by what mechanism. Here we demonstrate that pharmacological or genetic inhibition of fatty acid oxidation renders liver cells partially resistant to ER stress-induced UPR activation both in vitro and in vivo. Reduced stress sensitivity appeared to be a consequence of increased cellular redox potential as judged by an elevated ratio of oxidized to reduced glutathione and enhanced oxidative folding in the ER. Accordingly, the ER folding benefit of inhibiting fatty acid (FA) oxidation could be phenocopied by manipulating glutathione recycling during ER stress. Conversely, preventing cellular hyperoxidation with N-acetyl cysteine partially negated the stress resistance provided by blocking FA oxidation. Our results suggest that ER stress can be ameliorated through alteration of the oxidizing environment within the ER lumen, and they provide a potential logic for the transient regulation of metabolic pathways by the UPR during stress.}, }
@article {pmid22261571, year = {2012}, author = {Borges-Santos, MD and Moreto, F and Pereira, PC and Ming-Yu, Y and Burini, RC}, title = {Plasma glutathione of HIV[+] patients responded positively and differently to dietary supplementation with cysteine or glutamine.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {28}, number = {7-8}, pages = {753-756}, doi = {10.1016/j.nut.2011.10.014}, pmid = {22261571}, issn = {1873-1244}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Amino Acids, Sulfur/blood ; Antioxidants/*therapeutic use ; Cross-Over Studies ; *Dietary Supplements ; Female ; Glutamine/blood/*therapeutic use ; Glutathione/*blood ; HIV Seropositivity/*blood/immunology ; Humans ; Male ; Middle Aged ; Oxidation-Reduction ; *Oxidative Stress ; Young Adult ; }, abstract = {OBJECTIVE: Patients with positivity for the human immunodeficiency virus (HIV[+]) present low concentrations of antioxidant nutrients, including total glutathione (GSH) and its precursors. We investigated the responses of the sulfur-containing amino acid pathway to cysteine and glutamine (Gln) dietary supplements in patients with HIV[+] compared with healthy controls.<br><br>METHODS: Twelve treated patients (six men and six women, 22-45 y old) and 20 healthy controls (10 men and 10 women, 20-59 y old) were randomly assigned to 7-d dietary supplements containing N-acetylcysteine (NAC; 1 g/d) or Gln (20 g/d), with a 7-d washout period ingesting their usual diet. Blood samples were drawn after an overnight fast. High-performance liquid chromatographic plasma analysis of sulfur-containing amino acids (methionine, homocysteine, cysteine, and taurine), GSH, oxidized GSH, and serine, glycine, glutamic acid, and Gln was carried out moments before and after 7-d supplementations. Statistical comparisons were undertaken between groups and between dietary supplements (P < 0.05).<br><br>RESULTS: Patients with HIV&#x207a; showed higher oxidized GSH and lower concentrations of GSH and all amino acids except homocysteine. The HIV&#x207a; group responded to the NAC by increased levels of sulfur-containing amino acids and GSH and equalized taurine and GSH levels in the control group. The Gln supplements also equalized the levels of GSH, Gln, and glycine in the control group.<br><br>CONCLUSION: An increase in GSH may be attained by NAC or Gln supplementation, with NAC acting by increasing cysteine levels and Gln likely acting by replenishing the glycine pool (trial registered at http://www.clinicaltrials.gov, identifier NCT00910442).}, }
@article {pmid22261284, year = {2012}, author = {Pazdro, R and Burgess, JR}, title = {Differential effects of α-tocopherol and N-acetyl-cysteine on advanced glycation end product-induced oxidative damage and neurite degeneration in SH-SY5Y cells.}, journal = {Biochimica et biophysica acta}, volume = {1822}, number = {4}, pages = {550-556}, doi = {10.1016/j.bbadis.2012.01.003}, pmid = {22261284}, issn = {0006-3002}, mesh = {Acetylcysteine/*pharmacology ; Cell Line ; Glutathione/metabolism ; Glycation End Products, Advanced/*metabolism ; Humans ; Neurites/*pathology ; *Oxidative Stress ; Serum Albumin, Bovine/metabolism ; alpha-Tocopherol/*pharmacology ; }, abstract = {Advanced glycation end products (AGEs) result from non-enzymatic glycation of proteins and cause cellular oxidative stress in a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent manner. Due to these effects, AGEs are implicated as a causal factor in diabetic complications. Several antioxidants, including vitamin E, improve cell viability and diminish markers of oxidative damage in cells exposed to AGEs. However, vitamin E has been studied in cell culture systems with primary focus on apoptosis and lipid peroxidation, while its influences on AGE-induced protein and DNA oxidation, intracellular antioxidant status and cell morphology remain largely unknown. Here, we verify the suppression of AGE-induced cell death and lipid peroxidation by 200μM α-tocopherol in SH-SY5Y cells. We report the partial inhibition of DNA oxidation and a decrease in protein carbonyl formation by α-tocopherol with no effects on intracellular GSH concentrations. We observed that 2mM N-acetyl cysteine (NAC) also had a suppressive effect on DNA and protein oxidation, but unlike α-tocopherol, it caused a marked increase in intracellular GSH. Finally, we compared the ability of both antioxidants to maintain neurites in SH-SY5Y cells and found that α-tocopherol had no effect on neurite loss due to AGEs, while NAC fully maintained cell morphology. Thus, while α-tocopherol suppressed AGE-induced macromolecule damage, it was ineffective against neurite degeneration. These results may implicate thiol oxidation and maintenance as a major regulator of neurite degeneration in this model.}, }
@article {pmid22259598, year = {2011}, author = {Jo, SH}, title = {N-acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Narrative Review.}, journal = {Korean circulation journal}, volume = {41}, number = {12}, pages = {695-702}, pmid = {22259598}, issn = {1738-5555}, abstract = {Contrast-induced nephropathy (CIN) affects in-hospital, short- and long-term morbidity and mortality. It also leads to prolonged hospital stay and increased medical cost. Given the potential clinical severity of CIN, there has been considerable interest in the development of preventative strategies to reduce the risk of contrast-induced renal deterioration in at-risk populations. A number of pharmacologic and mechanical preventive measures have been attempted, but no method other than adequate periprocedural hydration has been conclusively successful. Since its introduction in 2000, N-acetylcysteine (NAC) has been widely investigated, albeit with conflicting findings for its nephroprotection capability in patients receiving contrast media procedures. However, there is still virtually no definitive evidence of effectiveness of NAC. Although the exact mechanism responsible for the protective action of NAC from renal function deterioration remains unclear, the antioxidant and vasodilatory properties of NAC have been suggested as the main mechanisms. This review summarizes the current status of NAC as a potential agent to prevent renal functional deterioration and its limitations.}, }
@article {pmid22257422, year = {2012}, author = {Homma, S and Azuma, A and Taniguchi, H and Ogura, T and Mochiduki, Y and Sugiyama, Y and Nakata, K and Yoshimura, K and Takeuchi, M and Kudoh, S and , }, title = {Efficacy of inhaled N-acetylcysteine monotherapy in patients with early stage idiopathic pulmonary fibrosis.}, journal = {Respirology (Carlton, Vic.)}, volume = {17}, number = {3}, pages = {467-477}, doi = {10.1111/j.1440-1843.2012.02132.x}, pmid = {22257422}, issn = {1440-1843}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Inhalation ; Aged ; Asian People/statistics &amp; numerical data ; Disease Progression ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy ; Male ; Middle Aged ; Severity of Illness Index ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a fatal disorder for which there are currently no specific or effective medical treatments. A multicentre, prospective, randomized, controlled clinical trial was conducted to assess the efficacy of inhaled N-acetylcysteine (NAC) monotherapy in Japanese patients with early stage IPF.<br><br>METHODS: Eligible patients had well-defined IPF of mild-to-moderate severity, with no desaturation on exercise. Of 100 patients screened, 76 were randomly assigned to an NAC treatment group (group A; n = 38) that received 352.4 mg of NAC by inhalation twice daily or to a control group (group B; n = 38) that received no therapy. The primary endpoint was the change from baseline in forced vital capacity (FVC) at 48 weeks.<br><br>RESULTS: There were no significant overall differences in the change in FVC between groups A and B. Post hoc exploratory analyses showed that NAC therapy was associated with stability of FVC in (i) a subset of patients with initial FVC <95% of predicted (n = 49; difference in FVC decline 0.12 L; P = 0.02) and (ii) in patients with initial diffusing capacity of carbon monoxide <55% of predicted (n = 21; difference in FVC decline 0.17 L; P = 0.009).<br><br>CONCLUSIONS: These findings indicate that NAC monotherapy may have some beneficial effect in patients with early stage IPF. Further trials in more select IPF populations with progressive disease are required to prove the efficacy of inhaled NAC.}, }
@article {pmid22253064, year = {2012}, author = {Chetboun, M and Abitbol, G and Rozenberg, K and Rozenfeld, H and Deutsch, A and Sampson, SR and Rosenzweig, T}, title = {Maintenance of redox state and pancreatic beta-cell function: role of leptin and adiponectin.}, journal = {Journal of cellular biochemistry}, volume = {113}, number = {6}, pages = {1966-1976}, doi = {10.1002/jcb.24065}, pmid = {22253064}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Adenylate Kinase/metabolism ; Adiponectin/metabolism/*pharmacology ; Animals ; Apoptosis/drug effects ; Catalase/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Glutathione Peroxidase/biosynthesis/genetics ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/*metabolism ; Leptin/metabolism/*pharmacology ; Mice ; NADPH Oxidases/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Phosphatidylinositol 3-Kinase/metabolism ; Polyethylene Glycols/pharmacology ; RNA, Messenger/genetics/metabolism ; Rats ; Reactive Oxygen Species ; Signal Transduction/drug effects ; Superoxide Dismutase/biosynthesis/genetics ; Superoxide Dismutase-1 ; }, abstract = {Whereas oxidative stress is linked to cellular damage, reactive oxygen species (ROS) are also believed to be involved in the propagation of signaling pathways. Studies on the role of ROS in pancreatic beta-cell physiology, in contrast to pathophysiology, have not yet been reported. In this study we investigate the importance of maintaining cellular redox state on pancreatic beta-cell function and viability, and the effects of leptin and adiponectin on this balance. Experiments were conducted on RINm and MIN6 pancreatic beta-cells. Leptin (1-100 ng/ml) and adiponectin (1-100 nM) increased ROS accumulation, as was determined by DCFDA fluorescence. Using specific inhibitors, we found that the increase in ROS levels was mediated by NADPH oxidase (Nox), but not by AMP kinase (AMPK) or phosphatidyl inositol 3 kinase (PI3K). Leptin and adiponectin increased beta-cell number as detected by the XTT method, but did not affect apoptosis, indicating that the increased cell number results from increased proliferation. The adipokines-induced increase in viability is ROS dependent as this effect was abolished by N-acetyl-L-cysteine (NAC) or PEG-catalase. In addition, insulin secretion was found to be regulated by alterations in redox state, but not by adipokines. Finally, the effects of the various treatments on activity and mRNA expression of several antioxidant enzymes were determined. Both leptin and adiponectin reduced mRNA levels of superoxide dismutase (SOD)1. Adiponectin also decreased SOD activity and increased catalase and glutathione peroxidase (GPx) activities in the presence of H2O2. The results of this study show that leptin and adiponectin, by inducing a physiological increase in ROS levels, may be positive regulators of beta-cell mass.}, }
@article {pmid22250825, year = {2012}, author = {Kawiak, A and Zawacka-Pankau, J and Wasilewska, A and Stasilojc, G and Bigda, J and Lojkowska, E}, title = {Induction of apoptosis in HL-60 cells through the ROS-mediated mitochondrial pathway by ramentaceone from Drosera aliciae.}, journal = {Journal of natural products}, volume = {75}, number = {1}, pages = {9-14}, doi = {10.1021/np200247g}, pmid = {22250825}, issn = {1520-6025}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/chemistry/*isolation &amp; purification/pharmacology ; Apoptosis/drug effects ; Drosera/*chemistry ; Drug Screening Assays, Antitumor ; Free Radical Scavengers/pharmacology ; HL-60 Cells ; Humans ; Mitochondria/*physiology ; Molecular Structure ; Naphthoquinones/chemistry/*isolation &amp; purification/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Ramentaceone (1) is a naphthoquinone constituent of Drosera aliciae that exhibits potent cytotoxic activity against various tumor cell lines. However, its molecular mechanism of cell death induction has still not been determined. The present study demonstrates that 1 induces apoptosis in human leukemia HL-60 cells. Typical morphological and biochemical features of apoptosis were observed in 1-treated cells. Compound 1 induced a concentration-dependent increase in the sub-G1 fraction of the cell cycle. A decrease in the mitochondrial transmembrane potential (ΔΨm) was also observed. Furthermore, 1 reduced the ratio of anti-apoptotic Bcl-2 to pro-apoptotic Bax and Bak, induced cytochrome c release, and increased the activity of caspase 3. The generation of reactive oxygen species (ROS) was detected in 1-treated HL-60 cells, which was attenuated by the pretreatment of cells with a free radical scavenger, N-acetylcysteine (NAC). NAC also prevented the increase of the sub-G1 fraction induced by 1. These results indicate that ramentaceone induces cell death through the ROS-mediated mitochondrial pathway.}, }
@article {pmid22248260, year = {2012}, author = {Monteiro, PF and Morganti, RP and Delbin, MA and Calixto, MC and Lopes-Pires, ME and Marcondes, S and Zanesco, A and Antunes, E}, title = {Platelet hyperaggregability in high-fat fed rats: a role for intraplatelet reactive-oxygen species production.}, journal = {Cardiovascular diabetology}, volume = {11}, number = {}, pages = {5}, pmid = {22248260}, issn = {1475-2840}, mesh = {Adenosine Diphosphate ; Animals ; Antioxidants/pharmacology ; Blood Platelets/drug effects/*metabolism ; Cyclic GMP/blood ; Diet, High-Fat/*adverse effects ; Enzyme Activation ; Enzyme Activators/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Glucose Intolerance/blood/etiology ; Glucose Tolerance Test ; Guanylate Cyclase/blood ; Insulin Resistance ; Male ; Nitric Oxide/blood ; Nitric Oxide Donors/pharmacology ; *Oxidative Stress/drug effects ; *Platelet Aggregation/drug effects ; Platelet Aggregation Inhibitors/pharmacology ; Platelet Function Tests ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*blood ; Receptors, Cytoplasmic and Nuclear/blood ; Signal Transduction ; Soluble Guanylyl Cyclase ; Thrombin ; Time Factors ; Weight Gain ; }, abstract = {BACKGROUND: Adiposity greatly increases the risk of atherothrombotic events, a pathological condition where a chronic state of oxidative stress is reported to play a major role. This study aimed to investigate the involvement of (NO)-soluble guanylyl cyclase (sGC) signaling pathway in the platelet dysfunction from high fat-fed (HFF) rats.<br><br>METHODS: Male Wistar rats were fed for 10 weeks with standard chow (SCD) or high-fat diet (HFD). ADP (10 &#x3bc;M)- and thrombin (100 mU/ml)-induced washed platelet aggregation were evaluated. Measurement of intracellular levels of ROS levels was carried out using flow cytometry. Cyclic GMP levels were evaluated using ELISA kits.<br><br>RESULTS: High-fat fed rats exhibited significant increases in body weight, epididymal fat, fasting glucose levels and glucose intolerance compared with SCD group. Platelet aggregation induced by ADP (n = 8) and thrombin from HFD rats (n = 8) were significantly greater (P < 0.05) compared with SCD group. Platelet activation with ADP increased by 54% the intraplatelet ROS production in HFD group, as measured by flow cytometry (n = 6). N-acetylcysteine (NAC; 1 mM) and PEG-catalase (1000 U/ml) fully prevented the increased ROS production and platelet hyperaggregability in HFD group. The NO donors sodium nitroprusside (SNP; 10 &#x3bc;M) and SNAP (10 &#x3bc;M), as well as the NO-independent soluble guanylyl cyclase stimulator BAY 41-2272 (10 &#x3bc;M) inhibited the platelet aggregation in HFD group with lower efficacy (P < 0.05) compared with SCD group. The cGMP levels in response to these agents were also markedly lower in HFD group (P < 0.05). The prostacyclin analogue iloprost (1 &#x3bc;M) reduced platelet aggregation in HFD and SCD rats in a similar fashion (n = 4).<br><br>CONCLUSIONS: Metabolic abnormalities as consequence of HFD cause platelet hyperaggregability involving enhanced intraplatelet ROS production and decreased NO bioavailability that appear to be accompanied by potential defects in the prosthetic haem group of soluble guanylyl cyclase.}, }
@article {pmid22245810, year = {2012}, author = {Chen, YH and Yeh, CW and Lo, HC and Su, SL and Hseu, YC and Hsu, LS}, title = {Generation of reactive oxygen species mediates butein-induced apoptosis in neuroblastoma cells.}, journal = {Oncology reports}, volume = {27}, number = {4}, pages = {1233-1237}, pmid = {22245810}, issn = {1791-2431}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Chalcones/*pharmacology ; Dose-Response Relationship, Drug ; G1 Phase Cell Cycle Checkpoints/drug effects ; Mice ; Neuroblastoma/*metabolism/pathology ; Oxidative Stress/*drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species/*metabolism ; Time Factors ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Flavonoids exhibit chemopreventive and chemotherapeutic effects. Butein, a bioactive flavonoid isolated from numerous native plants, has been shown to induce apoptosis in human cancer cells. In the current study, the molecular mechanisms of butein action on cell proliferation and apoptosis of neuroblastoma cells were evaluated. Treatment with butein decreased the viability of Neuro-2A neuroblastoma cells in a dose- and time-dependent manner. The dose-dependent nature of butein-induced apoptosis was characterized by an increase in the sub-G1 phase population. Treatment with butein significantly increased intracellular reactive oxygen species (ROS)levels and reduced the Bcl-2/Bax ratio, triggering the cleavage of pro-caspase 3 and poly-(ADP-ribose) polymerase (PARP). Pre-treatment with the antioxidant agent, N-acetyl cysteine (NAC), blocks butein-induced ROS generation and cell death. NAC also recovers butein-induced apoptosis-related protein alteration. In conclusion, butein-triggered neuroblastoma cells undergo apoptosis via generation of ROS, alteration of the Bcl‑2/Bax ratio, and cleavage of pro-caspase 3 and PARP. Our results suggest that butein may serve as a potential therapeutic agent for the treatment of neuroblastoma.}, }
@article {pmid22245600, year = {2012}, author = {Zhang, L and Pang, S and Deng, B and Qian, L and Chen, J and Zou, J and Zheng, J and Yang, L and Zhang, C and Chen, X and Liu, Z and Le, Y}, title = {High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {44}, number = {4}, pages = {629-638}, doi = {10.1016/j.biocel.2012.01.001}, pmid = {22245600}, issn = {1878-5875}, mesh = {Animals ; Cell Line ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Fibronectins/*metabolism ; Gene Expression Regulation/*drug effects ; Glucose/*antagonists &amp; inhibitors/*pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mesangial Cells/cytology/*drug effects/metabolism ; NADPH Oxidases/genetics/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Protein Subunits/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Resveratrol ; Signal Transduction/*drug effects ; Stilbenes/*pharmacology ; }, abstract = {Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. Hyperglycemia-induced oxidative stress is implicated in the etiology of diabetic nephropathy. Resveratrol has potent antioxidative and protective effects on diabetic nephropathy. We aimed to examine whether high glucose (HG)-induced NADPH oxidase activation and reactive oxygen species (ROS) production contribute to glomerular mesangial cell proliferation and fibronectin expression and the effect of resveratrol on HG action in mesangial cells. By using rat mesangial cell line and primary mesangial cells, we found that NADPH oxidase inhibitor (apocynin) and ROS inhibitor (N-acetyl cysteine) both inhibited HG-induced mesangial cell proliferation and fibronectin expression. HG-induced elevation of NADPH oxidase activity and production of ROS in mesangial cells was inhibited by apocynin. These results suggest that HG induces mesangial cell proliferation and fibronectin expression through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunits p22(phox) and p47(phox) expression through JNK/NF-κB pathway, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced mesangial cell proliferation and fibronectin expression through inhibiting HG-induced JNK and NF-κB activation, NADPH oxidase activity elevation and ROS production. These results demonstrate that HG enhances mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide novel therapeutic targets for diabetic nephropathy.}, }
@article {pmid22245127, year = {2012}, author = {Wang, YF and Shyu, HW and Chang, YC and Tseng, WC and Huang, YL and Lin, KH and Chou, MC and Liu, HL and Chen, CY}, title = {Nickel (II)-induced cytotoxicity and apoptosis in human proximal tubule cells through a ROS- and mitochondria-mediated pathway.}, journal = {Toxicology and applied pharmacology}, volume = {259}, number = {2}, pages = {177-186}, doi = {10.1016/j.taap.2011.12.022}, pmid = {22245127}, issn = {1096-0333}, mesh = {Acetates/antagonists &amp; inhibitors/*toxicity ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects/physiology ; Caspases/metabolism ; Cell Line ; Cell Survival/drug effects ; Comet Assay ; DNA Damage ; Flow Cytometry ; Humans ; Kidney Tubules, Proximal/*drug effects/metabolism ; Membrane Potential, Mitochondrial/physiology ; Mitochondria/*drug effects/metabolism ; Organometallic Compounds/antagonists &amp; inhibitors/*toxicity ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Nickel compounds are known to be toxic and carcinogenic in kidney and lung. In this present study, we investigated the roles of reactive oxygen species (ROS) and mitochondria in nickel (II) acetate-induced cytotoxicity and apoptosis in the HK-2 human renal cell line. The results showed that the cytotoxic effects of nickel (II) involved significant cell death and DNA damage. Nickel (II) increased the generation of ROS and induced a noticeable reduction of mitochondrial membrane potential (MMP). Analysis of the sub-G1 phase showed a significant increase in apoptosis in HK-2 cells after nickel (II) treatment. Pretreatment with N-acetylcysteine (NAC) not only inhibited nickel (II)-induced cell death and DNA damage, but also significantly prevented nickel (II)-induced loss of MMP and apoptosis. Cell apoptosis triggered by nickel (II) was characterized by the reduced protein expression of Bcl-2 and Bcl-xL and the induced the protein expression of Bad, Bcl-Xs, Bax, cytochrome c and caspases 9, 3 and 6. The regulation of the expression of Bcl-2-family proteins, the release of cytochrome c and the activation of caspases 9, 3 and 6 were inhibited in the presence of NAC. These results suggest that nickel (II) induces cytotoxicity and apoptosis in HK-2 cells via ROS generation and that the mitochondria-mediated apoptotic signaling pathway may be involved in the positive regulation of nickel (II)-induced renal cytotoxicity.}, }
@article {pmid22244881, year = {2012}, author = {Kumar, A and Singh, BK and Ahmad, I and Shukla, S and Patel, DK and Srivastava, G and Kumar, V and Pandey, HP and Singh, C}, title = {Involvement of NADPH oxidase and glutathione in zinc-induced dopaminergic neurodegeneration in rats: similarity with paraquat neurotoxicity.}, journal = {Brain research}, volume = {1438}, number = {}, pages = {48-64}, doi = {10.1016/j.brainres.2011.12.028}, pmid = {22244881}, issn = {1872-6240}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Apoptosis ; CD11b Antigen/metabolism ; Caspases/metabolism ; Corpus Striatum/metabolism ; Cytochromes c/metabolism ; Dopamine/metabolism ; Dopaminergic Neurons/drug effects/*metabolism ; Enzyme Inhibitors/pharmacology ; Glutathione/*metabolism ; Male ; Membrane Glycoproteins/genetics/*metabolism ; Mitochondria/metabolism ; Motor Activity/drug effects ; NADPH Oxidase 2 ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/*metabolism ; Oxidative Stress ; Paraquat/*toxicity ; Parkinsonian Disorders/*metabolism ; Phosphoproteins/metabolism ; Rats ; Rats, Wistar ; Serotonin/metabolism ; Substantia Nigra/metabolism ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {An association between excessive zinc (Zn) accumulation in brain and incidences of Parkinson's disease (PD) has been shown in several epidemiological and experimental investigations. The involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and glutathione (GSH) in the pathogenesis of PD has also been proposed in a few studies. Despite the implicated role of oxidative stress in PD, the entire mechanism of Zn-induced dopaminergic neurodegeneration has not yet been clearly understood. The present study aimed to investigate the involvement of NADPH oxidase and GSH in Zn-induced dopaminergic neurodegeneration and also to assess its similarity with paraquat (PQ)-induced rat model of PD. Male Wistar rats were treated either with Zn (20 mg/kg; i.p.) or PQ (5 mg/kg; i.p.) in the presence and absence of NADPH oxidase inhibitor, apocynin (10 mg/kg; i.p.) and a GSH precursor, N-acetyl cysteine (NAC; 200 mg/kg; i.p.) either alone or in combination along with the respective controls. Apocynin and/or NAC pre-treatment significantly alleviated Zn- and PQ-induced changes in neurobehavioral deficits, number of dopaminergic neurons and contents of the striatal dopamine and its metabolites. Apocynin and/or NAC also mitigated Zn- and PQ-induced alterations in oxidative stress, NADPH oxidase activation and cytochrome c release, caspases-9 and -3 activation and CD11b expression. The results obtained thus suggest that Zn induces oxidative stress via the activation of NADPH oxidase and depletion of GSH, which in turn activate the apoptotic machinery leading to dopaminergic neurodegeneration similar to PQ.}, }
@article {pmid22244740, year = {2012}, author = {Bauzo, RM and Kimmel, HL and Howell, LL}, title = {The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {101}, number = {2}, pages = {288-296}, pmid = {22244740}, issn = {1873-5177}, support = {K02 DA000517/DA/NIDA NIH HHS/United States ; Z01 DA000517//Intramural NIH HHS/United States ; K02 DA000517-05/DA/NIDA NIH HHS/United States ; F31 DA021476/DA/NIDA NIH HHS/United States ; P51 RR000165/RR/NCRR NIH HHS/United States ; P51 RR000165-50S1/RR/NCRR NIH HHS/United States ; K02 DA000517-07/DA/NIDA NIH HHS/United States ; R01 DA012514/DA/NIDA NIH HHS/United States ; R01 DA012514-10/DA/NIDA NIH HHS/United States ; RR00165/RR/NCRR NIH HHS/United States ; DA021476/DA/NIDA NIH HHS/United States ; P51 RR000165-50/RR/NCRR NIH HHS/United States ; DA12514/DA/NIDA NIH HHS/United States ; R01 DA012514-09/DA/NIDA NIH HHS/United States ; K02 DA000517-06/DA/NIDA NIH HHS/United States ; K05 DA031246/DA/NIDA NIH HHS/United States ; R01 DA012514-08/DA/NIDA NIH HHS/United States ; F31 DA021476-01A1/DA/NIDA NIH HHS/United States ; P51 RR000165-50S2/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Amino Acid Transport System y+/agonists/*metabolism ; Animals ; Behavior, Addictive/drug therapy/metabolism ; Cocaine/*administration &amp; dosage/antagonists &amp; inhibitors ; Corpus Striatum/*drug effects/*metabolism ; Dopamine/*metabolism ; Male ; Saimiri ; Self Administration ; }, abstract = {Extrasynaptic glutamate has been shown to regulate dopamine function in the mesocorticolimbic pathway, which plays an important role in the behavioral pharmacology of psychostimulants. Basal levels of glutamate are primarily regulated by the cystine-glutamate transporter and provide glutamatergic tone on extrasynaptic glutamate receptors. The present study examined the effects of a cystine-glutamate transporter enhancer on the neurochemical and behavioral effects of cocaine and amphetamine in nonhuman primates. It was hypothesized that augmenting extrasynaptic glutamate release with N-acetyl-L-cysteine (NAC), a cystine prodrug, would attenuate cocaine- or amphetamine-induced increases in extracellular dopamine and their corresponding behavioral-stimulant and reinforcing effects. In vivo microdialysis was used to evaluate cocaine-induced changes in extracellular dopamine (DA) in the caudate nucleus (n=3). NAC significantly attenuated cocaine-induced increases in dopamine but had inconsistent effects on amphetamine-induced increases in dopamine (n=4). Separate groups of subjects were either trained on a fixed-interval schedule of stimulus termination (n=6) or on a second-order schedule of self-administration (n=5) to characterize the behavioral-stimulant and reinforcing effects of psychostimulants, respectively. Systemic administration of NAC did not alter the behavioral-stimulant effects of either cocaine or amphetamine. Furthermore, cocaine self-administration and reinstatement of previously extinguished cocaine self-administration were not altered by pretreatment with NAC. Hence, drug interactions on caudate neurochemistry in vivo were not reflected in behavioral measures in squirrel monkeys. The present results in nonhuman primates do not support the use of NAC as a pharmacotherapy for cocaine abuse, although rodent and clinical studies suggest otherwise.}, }
@article {pmid22242616, year = {2012}, author = {Winbladh, A and Björnsson, B and Trulsson, L and Bojmar, L and Sundqvist, T and Gullstrand, P and Sandström, P}, title = {N-acetyl cysteine improves glycogenesis after segmental liver ischemia and reperfusion injury in pigs.}, journal = {Scandinavian journal of gastroenterology}, volume = {47}, number = {2}, pages = {225-236}, doi = {10.3109/00365521.2011.643480}, pmid = {22242616}, issn = {1502-7708}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Analysis of Variance ; Animals ; Apoptosis ; Aspartate Aminotransferases/blood ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Glycogen/*biosynthesis ; Lactic Acid/metabolism ; Leukocyte Count ; Liver/*metabolism/physiopathology ; Male ; Microdialysis ; Neutrophils ; Nitrates/metabolism ; Nitrites/metabolism ; Reperfusion Injury/*metabolism/pathology/physiopathology ; Swine ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC) is an antioxidative molecule known to protect liver tissue from oxygen radical species generated during ischemia and reperfusion (IR). Nutritional and toxicology studies have shown that NAC also improves glucose metabolism and glycogen stores. We hypothesized that NAC improves glycogenesis and that impaired glycogenesis is a key element in IR injury.<br><br>MATERIAL AND METHODS: In an experimental model, 80 min of segmental liver ischemia was induced in 16 pigs and the reperfusion was followed for 360 min. Eight animals received NAC 150 mg/kg as a bolus injection followed by an infusion of NAC 50 mg/kg/h intravenously.<br><br>RESULTS: AST and leukocyte density were lower in the NAC-treated animals, unrelated to the glutathione levels or apoptosis. Glycogen stores returned to a higher degree in the NAC-treated animals and microdialysis revealed lower levels of lactate during the reperfusion phase. Nitrite/Nitrate levels in the NAC group were lower in both serum and microdialysates, indicating that NAC scavenges radical nitrosative species.<br><br>CONCLUSIONS: NAC treatment improves glycogenesis after liver IR injury and reduces the level of intraparenchymal lactate during reperfusion, possibly due to the scavenging of radical nitrosative species.}, }
@article {pmid22242225, year = {2011}, author = {Li, XF and Ouyang, B and Wu, JF and Chen, J and Guan, XD}, title = {[N-acetylcysteine (NAC) inhibited pulmonary fibrosis in acute respiratory distress syndrome (ARDS)].}, journal = {Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue}, volume = {23}, number = {10}, pages = {599-601}, pmid = {22242225}, issn = {1003-0603}, mesh = {Acetylcysteine/*pharmacology ; Cells, Cultured ; Collagen/metabolism ; Fibroblasts/*drug effects ; Glutathione/analogs &amp; derivatives/metabolism ; Humans ; Lipopolysaccharides ; Lung/*cytology/drug effects ; Pulmonary Fibrosis/metabolism ; Respiratory Distress Syndrome/metabolism ; }, abstract = {OBJECTIVE: To investigate the effect of NAC treatment on lipopolysaccharide (LPS) treated human embryonic lung fibroblasts (HELF), in regard to oxidant injury and changes in indexes related to pulmonary fibrosis in ARDS.<br><br>METHODS: Four groups of cultured HELF were treated with: vehicle, LPS(1 pg/ml), NAC (1 mmol/L)+LPS (1 pg/ml) and dexamethasone (DEX, 1 pmol/L)+LPS (1 pg/ml) for 24 hours. The content of collagen and the &#x3b3;-glutamylcysteinylglycine (GSH) in the cells were determined.<br><br>RESULTS: As compared to the control group, the collagen content (pg/mg: 78.97+1.79 vs. 72.90+1.70)and GSH content (pg/mg: 23. 27 0. 92 vs. 26. 34+ 0. 83) in LPS group were significantly (P<0. 05) higher and lower, respectively; NAC and DEX both suppressed the effect of LPS on collagen content (72. 23 &#xb1; 1.35, 73.64 1.89 vs. 78.97 + 1.79); and GSH content (26.52 0.62, 25.85 &#xb1; 0.60 vs. 23.27+ 0.92)significantly (P < 0. 05 or P < 0. 01) in the treated cells. No significant difference was found between NAC+LPS and DEX+LPS group, either in the content of collagen or GSH.<br><br>CONCLUSION: NAC can inhibit oxidant injury and pulmonary fibrosis in ARDS.}, }
@article {pmid22241216, year = {2012}, author = {Galicia-Moreno, M and Favari, L and Muriel, P}, title = {Antifibrotic and antioxidant effects of N-acetylcysteine in an experimental cholestatic model.}, journal = {European journal of gastroenterology &amp; hepatology}, volume = {24}, number = {2}, pages = {179-185}, doi = {10.1097/MEG.0b013e32834f3123}, pmid = {22241216}, issn = {1473-5687}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Catalase/metabolism ; Cholestasis/etiology/metabolism/*prevention &amp; control ; Cytokines/metabolism ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Fibrosis/prevention &amp; control ; Glutathione/metabolism ; Inflammation Mediators/metabolism ; Lipid Peroxidation/drug effects ; Liver/metabolism/pathology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; }, abstract = {OBJECTIVES: Several studies have suggested that oxidative stress may play an important role in the pathogenesis of hepatic injury during cholestasis in rats and humans. The aim of this study was to evaluate the ability of N-acetylcysteine (NAC) to prevent the damage induced by bile duct ligation (BDL) for 28 days in male Wistar rats.<br><br>METHODS: NAC was administered daily (300 mg/kg, orally) for 28 days. Alanine aminotransferase was quantified in the serum; lipid peroxidation, glutathione, and catalase activity were measured in the liver. Fibrosis was assessed by measuring the liver hydroxyproline content; transforming growth factor-&#x3b2; (TGF-&#x3b2;), interleukin (IL)-6, and IL-10 were determined in the liver by a western blot and quantified densitometrically.<br><br>RESULTS: The induction of cholestatic damage by BDL was associated with an increase in alanine aminotransferase. Oxidative stress was also evaluated; lipid peroxidation increased, whereas the liver glutathione content and catalase activity decreased by BDL. NAC treatment prevented these alterations. Hydroxyproline was increased by chronic BDL, but NAC preserved the normal hydroxyproline levels. Cytokines TGF-&#x3b2;, IL-6, and IL-10 increased after 28 days of BDL. NAC was effectively significant in preventing TGF-&#x3b2; and IL-6 expression and further augmented the IL-10 expression.<br><br>CONCLUSION: Our data indicate that in the development to cholestatic liver damage, oxidative stress plays an important role and this in turn leads to fibrosis. This study shows that the beneficial effects of NAC are because of its antioxidant and immunomodulatory properties.}, }
@article {pmid22237206, year = {2012}, author = {Kang, MA and So, EY and Simons, AL and Spitz, DR and Ouchi, T}, title = {DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway.}, journal = {Cell death &amp; disease}, volume = {3}, number = {1}, pages = {e249}, pmid = {22237206}, issn = {2041-4889}, support = {R01CA133114/CA/NCI NIH HHS/United States ; K01 CA134941/CA/NCI NIH HHS/United States ; R01 CA133114/CA/NCI NIH HHS/United States ; R01 CA90631/CA/NCI NIH HHS/United States ; R01 CA090631/CA/NCI NIH HHS/United States ; R01CA79892/CA/NCI NIH HHS/United States ; T32 CA078586/CA/NCI NIH HHS/United States ; R01 CA079892/CA/NCI NIH HHS/United States ; K01CA134941/CA/NCI NIH HHS/United States ; }, mesh = {14-3-3 Proteins/genetics/metabolism ; Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport/antagonists &amp; inhibitors/genetics/metabolism ; Antioxidants/pharmacology ; Cell Death ; Cell Line, Tumor ; Cytotoxins/toxicity ; DNA Damage ; Flow Cytometry ; Gene Expression/*drug effects ; Histones/genetics/*metabolism ; Humans ; NADPH Oxidase 1 ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/metabolism ; Phosphorylation ; Plasmids ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/*genetics ; Transfection ; Zinostatin/*toxicity ; rac1 GTP-Binding Protein/genetics/*metabolism ; }, abstract = {The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells with neocarzinostatin (NCS), an ionizing radiation mimetic, is at least partly mediated by increasing histone H2AX. Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine (NAC), the NADP(H) oxidase (Nox) inhibitor DPI, expression of Rac1N17, and knockdown of Nox1, but not Nox4, indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase. H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta. These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage.}, }
@article {pmid22231145, year = {2012}, author = {Chi, PL and Chen, YW and Hsiao, LD and Chen, YL and Yang, CM}, title = {Heme oxygenase 1 attenuates interleukin-1β-induced cytosolic phospholipase A2 expression via a decrease in NADPH oxidase/reactive oxygen species/activator protein 1 activation in rheumatoid arthritis synovial fibroblasts.}, journal = {Arthritis and rheumatism}, volume = {64}, number = {7}, pages = {2114-2125}, doi = {10.1002/art.34371}, pmid = {22231145}, issn = {1529-0131}, mesh = {Animals ; Arthritis, Rheumatoid/*metabolism ; Fibroblasts/drug effects/metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Interleukin-1beta/*pharmacology ; Mice ; NADPH Oxidases/*metabolism ; Phospholipases A2, Cytosolic/*metabolism ; Phosphorylation/drug effects ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Synovial Membrane/drug effects/metabolism ; Transcription Factor AP-1/*metabolism ; }, abstract = {OBJECTIVE: Reactive oxygen species (ROS) produced by cytokines induce the expression of inflammatory mediators in rheumatoid arthritis (RA). Heme oxygenase 1 (HO-1) exerts an antiinflammatory effect. The aim of this study was to examine the mechanisms underlying interleukin-1β (IL-1β)-induced cytosolic phospholipase A2 (cPLA2) expression through ROS generation as modulated by HO-1 in RA synovial fibroblasts (RASFs).<br><br>METHODS: IL-1&#x3b2;-induced ROS generation was determined by flow cytometry. The involvement of MAPKs and NADPH oxidase (NOX)/ROS in IL-1&#x3b2;-induced cPLA2 expression was investigated using pharmacologic inhibitors and transfection with small interfering RNAs (siRNAs) and was analyzed by Western blotting and promoter assay. Overexpression of HO-1 was performed by transfection of RASFs with a recombinant adenovirus containing human HO-1 plasmid. SCID mice with inflammation caused by IL-1&#x3b2; were infected with adenovirus containing HO-1. Histologic characterization of joint inflammation and local expression of cPLA2 were evaluated after treatment.<br><br>RESULTS: IL-1&#x3b2;-induced cPLA2 expression was mediated through NOX activation/ROS production, which was attenuated by N-acetylcysteine (NAC; a scavenger of ROS), the inhibitors of NOX (diphenyleneiodonium chloride and apocynin), MEK-1/2 (U0126), and JNK-1/2 (SP600125), transfection with the respective siRNAs, and the overexpression of HO-1 in RASFs. IL-1&#x3b2;-induced cPLA2 expression was mediated through recruitment of activator protein 1 (AP-1) to the cPLA2 promoter region, which was attenuated by NAC and overexpression of HO-1. Furthermore, HO-1 overexpression inhibited IL-1&#x3b2;-mediated cPLA2 expression in SCID mice.<br><br>CONCLUSION: In RASFs, IL-1&#x3b2; induced cPLA2 expression via activation of p42/p44 MAPK and JNK-1/2, leading to p47phox phosphorylation, ROS production, and AP-1 activation. The induction of HO-1 exerted protective effects on the pathogenesis of RA.}, }
@article {pmid22230687, year = {2012}, author = {Kwon, O and Soung, NK and Thimmegowda, NR and Jeong, SJ and Jang, JH and Moon, DO and Chung, JK and Lee, KS and Kwon, YT and Erikson, RL and Ahn, JS and Kim, BY}, title = {Patulin induces colorectal cancer cells apoptosis through EGR-1 dependent ATF3 up-regulation.}, journal = {Cellular signalling}, volume = {24}, number = {4}, pages = {943-950}, pmid = {22230687}, issn = {1873-3913}, support = {R01 HL083365/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 3/*agonists/genetics/metabolism ; Antioxidants/pharmacology ; Apoptosis/*genetics ; Caco-2 Cells ; Caspase 3/genetics/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Proliferation/drug effects ; Colorectal Neoplasms/genetics/metabolism/*pathology ; Gene Expression Regulation, Neoplastic ; Glutathione/pharmacology ; HCT116 Cells ; Humans ; Mycotoxins/pharmacology ; Patulin/*pharmacology ; Phosphorylation ; Poly(ADP-ribose) Polymerases/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Receptor, IGF Type 1/genetics/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Patulin is a fungal mycotoxin of Aspergilus and Penicillium that is commonly found in rotting fruits and exerts its potential toxic effect mainly by reactive oxygen species (ROS) generation. However, the effect of patulin on cancer cells as well as its intracellular mechanism has been controversial and not clearly defined yet. In this study, patulin was found to induce G1/S accumulation and cell growth arrest accompanied by caspase-3 activation, PARP cleavage and ATF3 expression in human colon cancer cell line HCT116. Ser/Thr phosphorylation of a transcription factor, EGR-1, was increased while its expression did not change upon patulin treatment to the cells. Knockdown of ATF3 and EGR-1 using their respective siRNAs showed EGR-1 dependent ATF3 expression. Moreover, treatment of the cells with antioxidants N-acetylcysteine (NAC) and glutathione (GSH) revealed that patulin induced ATF3 expression and apoptosis were dependent on ROS generation. ATF3 expression was also increased by patulin in other colorectal cancer cell types, Caco2 and SW620. Collectively, our data present a new anti-cancer molecular mechanism of patulin, suggesting EGR-1 and ATF3 as critical targets for the development of anti-cancer chemotherapeutics. In this regard, patulin could be a candidate for the treatment of colorectal cancers.}, }
@article {pmid22230264, year = {2012}, author = {Haxaire, C and Turpin, FR and Potier, B and Kervern, M and Sinet, PM and Barbanel, G and Mothet, JP and Dutar, P and Billard, JM}, title = {Reversal of age-related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting D-serine-dependent NMDA receptor activation.}, journal = {Aging cell}, volume = {11}, number = {2}, pages = {336-344}, doi = {10.1111/j.1474-9726.2012.00792.x}, pmid = {22230264}, issn = {1474-9726}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; *Aging ; Animals ; Hippocampus/*metabolism ; Lysine/analogs &amp; derivatives/pharmacology ; Male ; *Neuronal Plasticity/drug effects ; *Oxidative Stress ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Serine/metabolism ; }, abstract = {Oxidative stress (OS) resulting from an imbalance between antioxidant defenses and the intracellular accumulation of reactive oxygen species (ROS) contributes to age-related memory deficits. While impaired synaptic plasticity in neuronal networks is thought to underlie cognitive deficits during aging, whether this process is targeted by OS and what the mechanisms involved are still remain open questions. In this study, we investigated the age-related effects of the reducing agent N-acetyl-L-cysteine (L-NAC) on the activation of the N-methyl-D-aspartate receptor (NMDA-R) by its co-agonist D-serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long-term dietary supplementation with L-NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA-R-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous D-serine. Chronic treatment with L-NAC, but not acute application of the reducing agent, restored potent D-serine-dependent NMDA-R activation and LTP induction in aged rats. In addition, it is also revealed that the age-related decrease in D-serine levels and in the expression of the synthesizing enzyme serine racemase, which underlies the decrease in NMDA-R activation by the amino acid, was rescued by long-term dietary treatment with L-NAC. Our results indicate that protecting redox status in aged animals could prevent injury to the cellular mechanisms underlying cognitive aging, in part by maintaining potent NMDA-R activation through the D-serine-dependent pathway.}, }
@article {pmid22230155, year = {2012}, author = {Gurm, HS and Smith, DE and Berwanger, O and Share, D and Schreiber, T and Moscucci, M and Nallamothu, BK and , }, title = {Contemporary use and effectiveness of N-acetylcysteine in preventing contrast-induced nephropathy among patients undergoing percutaneous coronary intervention.}, journal = {JACC. Cardiovascular interventions}, volume = {5}, number = {1}, pages = {98-104}, doi = {10.1016/j.jcin.2011.09.019}, pmid = {22230155}, issn = {1876-7605}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Aged, 80 and over ; Angioplasty, Balloon, Coronary/*adverse effects/statistics &amp; numerical data ; Contrast Media/*adverse effects ; Cooperative Behavior ; Coronary Artery Disease/prevention &amp; control ; Female ; Free Radical Scavengers/*therapeutic use ; Glomerular Filtration Rate ; Health Status Indicators ; Humans ; Male ; Michigan ; Middle Aged ; Practice Patterns, Physicians'/*statistics &amp; numerical data ; Propensity Score ; Prospective Studies ; Registries ; Statistics as Topic ; Treatment Outcome ; }, abstract = {OBJECTIVES: The aim of this study was to examine the use of and outcomes associated with use of N-acetylcysteine (NAC) in real-world practice.<br><br>BACKGROUND: The role of NAC in the prevention of contrast-induced nephropathy (CIN) is controversial, leading to widely varying recommendations for its use.<br><br>METHODS: Use of NAC was assessed in consecutive patients undergoing nonemergent percutaneous coronary intervention from 2006 to 2009 in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium, a large multicenter quality improvement collaborative. We examined the overall prevalence of NAC use in these patients and then used propensity matching to link its use with clinical outcomes, including CIN, nephropathy-requiring dialysis, and death.<br><br>RESULTS: Of the 90,578 percutaneous coronary interventions performed during the study period, NAC was used in 10,574 (11.6%) procedures, with its use steadily increasing over the study period. Patients treated with NAC were slightly older and more likely to have baseline renal insufficiency and other comorbidities. In propensity-matched, risk-adjusted models, we found no differences in outcomes between patients treated with NAC and those not receiving NAC for CIN (5.5% vs. 5.5%, p = 0.99), nephropathy-requiring dialysis (0.6% vs. 0.6%, p = 0.69), or death (0.6% vs. 0.8%, p = 0.15). These findings were consistent across many prespecified subgroups.<br><br>CONCLUSIONS: Use of NAC is common and has steadily increased over the study period but does not seem to be associated with improved clinical outcomes in real-world practice.}, }
@article {pmid22227002, year = {2012}, author = {Hsiao, YH and Kuo, JR and Chen, SH and Gean, PW}, title = {Amelioration of social isolation-triggered onset of early Alzheimer's disease-related cognitive deficit by N-acetylcysteine in a transgenic mouse model.}, journal = {Neurobiology of disease}, volume = {45}, number = {3}, pages = {1111-1120}, doi = {10.1016/j.nbd.2011.12.031}, pmid = {22227002}, issn = {1095-953X}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alzheimer Disease/*complications/genetics/pathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Analysis of Variance ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Biophysics ; Biotinylation ; Calpain/metabolism ; Cell Line, Transformed ; Cognition Disorders/*etiology/*prevention &amp; control ; Conditioning, Psychological/drug effects/physiology ; Cyclin-Dependent Kinase 5/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Electric Stimulation ; Enzyme-Linked Immunosorbent Assay ; Fear/psychology ; Hippocampus/drug effects/pathology ; Humans ; In Vitro Techniques ; Long-Term Potentiation/drug effects/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Patch-Clamp Techniques ; Peptide Fragments/metabolism ; Presenilin-1/genetics ; Protein Kinase C-delta/genetics/metabolism ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics/metabolism ; Receptors, Metabotropic Glutamate/metabolism ; Signal Transduction/drug effects/genetics ; Social Isolation/*psychology ; Time Factors ; Transfection ; }, abstract = {Epidemiological study reveals that socially isolated persons have increased risk of developing Alzheimer's disease (AD). Whether this risk arises from an oxidative stress is unclear. Here we show that N-acetylcysteine (NAC), an anti-oxidant, is capable of preventing social isolation-induced accelerated impairment of contextual fear memory and rundown of hippocampal LTP in 3-month old APP/PS1 mice. Increased hippocampal levels of γ-secretase activity, Aβ-40 and Aβ-42 seen in the isolated APP/PS1 mice were reduced by chronic treatment of NAC. In addition, social isolation-induced increase in calpain activity and p25/p35 ratio concomitant with decrease in membrane-associated p35 and p35/Cdk5 activity was normalized by NAC. NAC pretreatment also reversed isolation-induced decrease in GluR1 Ser831 phosphorylation, surface expression of AMPARs and p35-GluR1-CaMKII interactions. These results suggest that NAC decreases γ-secretase activity resulting in the attenuation of Aβ production, calpain activity and conversion of p35 to p25 which stabilized p35-GluR1-CaMKII interactions and restored GluR1 and GluR2 surface expression. Our results indicate that NAC is effective in mouse models of AD and has translation potential for the human disorder.}, }
@article {pmid22226754, year = {2012}, author = {Perna, AF and Violetti, E and Lanza, D and Sepe, I and Bellinghieri, G and Savica, V and Santoro, D and Satta, E and Cirillo, G and Lupo, A and Abaterusso, C and Raiola, I and Raiola, P and Coppola, S and Di Iorio, B and Tirino, G and Cirillo, M and Ingrosso, D and De Santo, NG}, title = {Therapy of hyperhomocysteinemia in hemodialysis patients: effects of folates and N-acetylcysteine.}, journal = {Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation}, volume = {22}, number = {5}, pages = {507-514.e1}, doi = {10.1053/j.jrn.2011.10.007}, pmid = {22226754}, issn = {1532-8503}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Drug Therapy, Combination ; Female ; Folic Acid/administration &amp; dosage/*analogs &amp; derivatives ; Homocysteine/blood ; Humans ; Hyperhomocysteinemia/*drug therapy/etiology ; Kidney Failure, Chronic/complications/therapy ; Male ; Middle Aged ; *Renal Dialysis ; }, abstract = {OBJECTIVE: Uremia represents a state where hyperhomocysteinemia is resistant to folate therapy, thus undermining intervention trials' efficacy. N-acetylcysteine (NAC), an antioxidant, in addition to folates (5-methyltetrahydrofolate, MTHF), was tested in a population of hemodialysis patients.<br><br>DESIGN: The study is an open, parallel, intervention study.<br><br>SETTING: Ambulatory chronic hemodialysis patients.<br><br>SUBJECTS: Clinically stable chronic hemodialysis patients, on hemodialysis since more than 3 months, undergoing a folate washout. Control group on standard therapy (n = 50).<br><br>INTERVENTION: One group was treated with intravenous MTHF (MTHF group, n = 48). A second group was represented by patients treated with MTHF, and, during the course of 10 hemodialysis sessions, NAC was administered intravenous (MTHF + NAC group, n = 47).<br><br>MAIN OUTCOME MEASURE: Plasma homocysteine measured before and after dialysis at the first and the last treatment.<br><br>RESULTS: At the end of the study, there was a significant decrease in predialysis plasma homocysteine levels in the MTHF group and MTHF + NAC group, compared with the control group, but no significant difference between the MTHF group and MTHF + NAC group. A significant decrease in postdialysis plasma homocysteine levels in MTHF + NAC group (10.27 &#xb1; 0.94 &#x3bc;mol/L, 95% confidence interval: 8.37-12.17) compared with the MTHF group (16.23 &#xb1; 0.83, 95% confidence interval: 14.55-17.90) was present. In the MTHF + NAC group, 64% of patients reached a postdialysis homocysteine level <12 &#x3bc;mol/L, compared with 19% in the MTHF group and 16% in the control group.<br><br>CONCLUSIONS: NAC therapy induces a significant additional decrease in homocysteine removal during dialysis. The advantage is limited to the time of administration.}, }
@article {pmid22223899, year = {2011}, author = {Beyaz, SG and Yelken, B and Kanbak, G}, title = {The effects of N-acetylcysteine on hepatic function during isoflurane anaesthesia for laparoscopic surgery patients.}, journal = {Indian journal of anaesthesia}, volume = {55}, number = {6}, pages = {567-572}, pmid = {22223899}, issn = {0976-2817}, abstract = {INTRODUCTION: Although most general anaesthesia procedures are performed without any complications, volatile agents may have adverse effects on various living systems. This study aims to compare the antioxidant effects of isoflurane and N-acetylcysteine (NAC) on liver function.<br><br>METHODS: Forty-one patients in the ASA I-II risk groups, who were scheduled to undergo gynaecologic laparoscopy, were randomly divided into two groups: The placebo (group P, n=21) and the NAC group (group N, n=20). In both groups, anaesthesia was maintained with 1-2% isoflurane in 50% Oxygen-50% N(2)O at 6&#x2005;l/min, also administered by inhalation. Venous blood samples were obtained before anaesthesia induction, and then in the postoperative 1(st) hour and at the 24(th) hour. The samples were centrifuged and serum levels of glutathione S-transferase (GST), malondialdehyde (MDA), aspartate amino transferase (AST), alanine amino transferase (ALT), lactate dehydrogenase (LDH), gamma glutamyltranspeptidase (GGT), prothrombin time (PT), activated partial thromboplastin time (aPTT) and international normalised ratio were determined.<br><br>RESULTS: GST levels were significantly higher in group N than in group P in the postoperative 1(st) hour. Postoperative values of GST in the two groups were higher when compared to preoperative values (P<0.05). When postoperative levels were compared with preoperative levels, the postoperative MDA levels of group N were significantly higher (P<0.05). Levels of AST, ALT, GGT and LDH in both groups revealed significant decreases at the postoperative 1(st) hour and postoperative 24(th) hour compared to preoperative values (P<0.05, P<0.001). PT values were significantly higher in both groups in the postoperative 1(st) hour and 24(th) hour (P<0.05, P<0.001), although there were no differences in aPTT levels.<br><br>CONCLUSION: Our results showed that liver functions were well preserved with administration of NAC during anaesthesia with isoflurane. Isoflurane with NAC has lesser effect on liver function tests compared to isoflurane alone.}, }
@article {pmid22222931, year = {2012}, author = {de Melo, FT and de Oliveira, IM and Greggio, S and Dacosta, JC and Guecheva, TN and Saffi, J and Henriques, JA and Rosa, RM}, title = {DNA damage in organs of mice treated acutely with patulin, a known mycotoxin.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {50}, number = {10}, pages = {3548-3555}, doi = {10.1016/j.fct.2011.12.022}, pmid = {22222931}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Animals ; Comet Assay ; DNA Damage/*drug effects ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Hippocampus/drug effects ; Kidney/drug effects ; Male ; Mice ; Molecular Structure ; Oxidative Stress ; Patulin/administration &amp; dosage/chemistry/*toxicity ; }, abstract = {Patulin, a known mycotoxin, is considered a significant contaminant in apples, apple-derived products and feeds. This study investigated the genotoxic effects of patulin in multiple organs (brain, kidney, liver and urinary bladder) of mice using an in vivo comet assay. We assessed the mechanism underlying this genotoxicity by measuring the GSH content and the thiobarbituric acid-reactive species (TBARS) level. Male CF-1 mice were given 1.0-3.75 mg/kg patulin intraperitoneally. The effect of patulin was dose-dependent and the highest patulin dose induced DNA strand breaks in the brain (damage index, DI, in hippocampus increased from 36.2 in control animals to 127.5), liver (44.3-138.4) and kidneys (31.5-99); decreased levels of GSH (hippocampus--from 46.9 to 18.4 nmol/mg protein); and an increase in lipid peroxidation (hippocampus--from 5.8 to 20.3 MDA equivalents/mg protein). This finding establishes an interrelationship between the pro-oxidant and genotoxic effects of patulin. Pre-treatment administration of N-acetyl-cysteine reduced patulin-induced DNA damage (hippocampus--DI from 127.5 to 39.8) and lipid peroxidation (hippocampus--20.3 to 12.8 MDA equivalents/mg protein) by restoring cellular GSH levels, reinforcing the positive relationship between patulin-induced GSH depletion and DNA damage caused by systemic administration of this mycotoxin.}, }
@article {pmid22218562, year = {2012}, author = {Miki, H and Uehara, N and Kimura, A and Sasaki, T and Yuri, T and Yoshizawa, K and Tsubura, A}, title = {Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells.}, journal = {International journal of oncology}, volume = {40}, number = {4}, pages = {1020-1028}, pmid = {22218562}, issn = {1791-2423}, mesh = {Anticarcinogenic Agents/pharmacology ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/*drug effects ; Autophagy/drug effects ; Caspase 3/metabolism ; Caspase 8/metabolism ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; HT29 Cells ; Humans ; Oligopeptides/pharmacology ; Reactive Oxygen Species/*metabolism ; Resveratrol ; Signal Transduction/drug effects ; Stilbenes/*pharmacology ; }, abstract = {Resveratrol (Res; 3,4',5-trihydroxy-trans-stilbene), which is a polyphenol found in grapes, can block cell proliferation and induce growth arrest and/or cell death in several types of cancer cells. However, the precise mechanisms by which Res exerts anticancer effects remain poorly understood. Res blocked both anchorage-dependent and -independent growth of HT-29 and COLO 201 human colon cancer cells in a dose- and time-dependent manner. Annexin V staining and Western blot analysis revealed that Res induced apoptosis accompanied by an increase in Caspase-8 and Caspase-3 cleavage. In HT-29 cells, Res caused autophagy as characterized by the appearance of autophagic vacuoles by electron microscopy and elevation of microtubule-associated protein 1 light chain 3 (LC3)-II by immunoblotting, which was associated with the punctuate pattern of LC3 detected by fluorescein microscopy. Inhibition of Res-induced autophagy by the autophagy inhibitor 3-methyladenine caused a significant decrease in apoptosis accompanied by decreased cleavage of Casapse-8 and Caspase-3, indicating that Res-induced autophagy was cytotoxic. However, inhibition of Res-induced apoptosis by the pan-caspase inhibitor Z-VAD(OMe)-FMK did not decrease autophagy but elevated LC3-II levels. Interestingly, Res increased the intracellular reactive oxygen species (ROS) level, which correlated to the induction of Casapse-8 and Caspase-3 cleavage and the elevation of LC3-II; treatment with ROS scavenger N-acetyl cysteine diminished this effect. Therefore, the effect of Res on the induction of apoptosis via autophagy is mediated through ROS in human colon cancer cells.}, }
@article {pmid22218118, year = {2012}, author = {Rasi Hashemi, S and Noshad, H and Tabrizi, A and Mobasseri, M and Tayebi Khosroshahi, H and Heydarnejad, M and Khalaj, MR and Aghamohammadzadeh, N}, title = {Angiotensin receptor blocker and N-acetyl cysteine for reduction of proteinuria in patients with type 2 diabetes mellitus.}, journal = {Iranian journal of kidney diseases}, volume = {6}, number = {1}, pages = {39-43}, pmid = {22218118}, issn = {1735-8604}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Angiotensin II Type 1 Receptor Blockers/*therapeutic use ; Diabetes Mellitus, Type 2/*complications/urine ; Diabetic Nephropathies/*drug therapy/urine ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Losartan/*therapeutic use ; Male ; Middle Aged ; Proteinuria/*drug therapy/etiology ; Statistics, Nonparametric ; }, abstract = {INTRODUCTION: Proteinuria and albuminuria are established risk factors for progressive renal damage. Albuminuria can be effectively controlled by antihypertensive drugs that interrupt the renin-angiotensin-aldosterone system. However, the efficiency of N-acetyl cysteine (NAC) in preventing diabetic nephropathy is uncertain. Renoprotective effects of angiotensin receptor blockers and NAC in preventing or reducing of proteinuria in patients with diabetic nephropathy was studied.<br><br>MATERIALS AND METHODS: In a randomized controlled trial, 70 patients with type 2 diabetic nephropathy (proteinuria and renal insufficiency) were studied. The patients were randomly divided into two groups and were treated with losartan, 25 mg, twice per day, with and without NAC, 600 mg twice daily (study and control groups, respectively; 35 patients in each group). Urine protein was checked before treatment and after 2 months of treatment.<br><br>RESULTS: The two groups were comparable regarding gender, age, serum creatinine, and urine protein excretion levels. Proteinuria improved in both groups. The mean proteinuria level decreased more in patients with losartan and NAC; however, comparison of proteinuria between the two groups showed no significant difference after 2 months.<br><br>CONCLUSIONS: Angiotensin receptor blockers reduced proteinuria due to diabetic nephropathy, and this study failed to detect additional effect when NAC was combined with these medications.}, }
@article {pmid22216281, year = {2011}, author = {Buccigrossi, V and Laudiero, G and Nicastro, E and Miele, E and Esposito, F and Guarino, A}, title = {The HIV-1 transactivator factor (Tat) induces enterocyte apoptosis through a redox-mediated mechanism.}, journal = {PloS one}, volume = {6}, number = {12}, pages = {e29436}, pmid = {22216281}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Cell Line ; Enterocytes/*cytology ; Gene Products, tat/*physiology ; HIV-1/*physiology ; Humans ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {The intestinal mucosa is an important target of human immunodeficiency virus (HIV) infection. HIV virus induces CD4+ T cell loss and epithelial damage which results in increased intestinal permeability. The mechanisms involved in nutrient malabsorption and alterations of intestinal mucosal architecture are unknown. We previously demonstrated that HIV-1 transactivator factor (Tat) induces an enterotoxic effect on intestinal epithelial cells that could be responsible for HIV-associated diarrhea. Since oxidative stress is implicated in the pathogenesis and morbidity of HIV infection, we evaluated whether Tat induces apoptosis of human enterocytes through oxidative stress, and whether the antioxidant N-acetylcysteine (NAC) could prevent it. Caco-2 and HT29 cells or human intestinal mucosa specimens were exposed to Tat alone or combined with NAC. In an in-vitro cell model, Tat increased the generation of reactive oxygen species and decreased antioxidant defenses as judged by a reduction in catalase activity and a reduced (GSH)/oxidized (GSSG) glutathione ratio. Tat also induced cytochrome c release from mitochondria to cytosol, and caspase-3 activation. Rectal dialysis samples from HIV-infected patients were positive for the oxidative stress marker 8-hydroxy-2'-deoxyguanosine. GSH/GSSG imbalance and apoptosis occurred in jejunal specimens from HIV-positive patients at baseline and from HIV-negative specimens exposed to Tat. Experiments with neutralizing anti-Tat antibodies showed that these effects were direct and specific. Pre-treatment with NAC prevented Tat-induced apoptosis and restored the glutathione balance in both the in-vitro and the ex-vivo model. These findings indicate that oxidative stress is one of the mechanism involved in HIV-intestinal disease.}, }
@article {pmid22212518, year = {2013}, author = {Alioglu, E and Saygi, S and Turk, U and Kirilmaz, B and Tuzun, N and Duman, C and Tengiz, I and Yildiz, S and Ercan, E}, title = {N-acetylcysteine in preventing contrast-induced nephropathy assessed by cystatin C.}, journal = {Cardiovascular therapeutics}, volume = {31}, number = {3}, pages = {168-173}, doi = {10.1111/j.1755-5922.2011.00309.x}, pmid = {22212518}, issn = {1755-5922}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Contrast Media/*adverse effects ; Cystatin C/*blood ; Female ; Glomerular Filtration Rate ; Humans ; Kidney Diseases/chemically induced/*prevention &amp; control ; Male ; Middle Aged ; }, abstract = {AIMS: Prophylactic oral N-acetylcysteine (NAC) has been widely used for prevention of contrast-induced nephropathy (CIN). However, clinical studies have not been demonstrating this effect consistently because of evidence that NAC can alter serum creatinine levels without affecting glomerular filtration rate (GFR). We investigated NAC for the prevention of CIN by monitoring creatinine and cystatin C.<br><br>METHODS: We enrolled 113 patients (49 patients in NAC group and 64 patients in control group) with normal to subnormal GFR who were scheduled for cardiovascular procedures. Patients in NAC group receive acetylcysteine 600 mg twice a day, on the day before and on the day of cardiovascular procedure. All patients received a periprocedural intravenous infusion ("volume expansion") of 1 ml/kg/h with 0.45% saline for 24 h (12 h before and 12 h after exposure to contrast medium). Serum cystatin C and creatinine levels were measured before and at 12, 24, and 48 h after procedure.<br><br>RESULTS: The incidence of cystatin C-based CIN was 28.5% (n = 14) in NAC and 23.4% (n = 15) in control group (p = 0.663) and serum creatinine-based CIN was 12.2% (n = 6) in NAC and 17.2% (n = 11) in control group (P= 0.468). In this study, oral NAC had no effect on the prevention of CIN in patients undergoing cardiovascular procedures.<br><br>CONCLUSION: In this study, oral NAC administration does not reduce neither the incidence of cystatin C-based CIN nor serum creatinine-based CIN in patients undergoing cardiovascular procedures.}, }
@article {pmid22212173, year = {2012}, author = {Magalhães, PV and Dean, OM and Bush, AI and Copolov, DL and Weisinger, D and Malhi, GS and Kohlmann, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Berk, M}, title = {Systemic illness moderates the impact of N-acetyl cysteine in bipolar disorder.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {37}, number = {1}, pages = {132-135}, doi = {10.1016/j.pnpbp.2011.11.011}, pmid = {22212173}, issn = {1878-4216}, mesh = {Acetylcysteine/metabolism/pharmacology/*therapeutic use ; Adult ; Bipolar Disorder/*drug therapy/*epidemiology/metabolism ; Cardiovascular Diseases/drug therapy/epidemiology/metabolism ; Double-Blind Method ; Endocrine System Diseases/drug therapy/epidemiology/metabolism ; Female ; Free Radical Scavengers/metabolism/pharmacology/*therapeutic use ; Humans ; Inflammation/drug therapy/epidemiology/metabolism ; Male ; Middle Aged ; Oxidative Stress/drug effects/physiology ; }, abstract = {OBJECTIVES: Bipolar disorder (BD) is intricately associated with chronic clinical conditions. Medical comorbidity is not only more prevalent in mood disorders, but is associated with increased costs, cognitive impairment and, ultimately, premature mortality. Oxidative stress and inflammation may mediate part of this association. To further investigate the association between medical comorbidity status and clinical improvement with adjuvant N acetyl cysteine (NAC) in the context of a placebo-controlled trial.<br><br>METHODS: Placebo-controlled randomized clinical trial assessing the effect of NAC over 24 weeks. Symptomatic and functional outcomes were collected over the study period. Medical comorbidities were self-reported, and we took special interest in cardiovascular and endocrine conditions. We evaluated change from baseline to endpoint and the interaction between change and reported medical comorbidities.<br><br>RESULTS: Fifty-one percent of patients reported have a cardiovascular or endocrine comorbidity. Although not found for depressive symptoms or quality of life, a significant interaction between medical comorbidity and change scores was consistently found for all functional outcomes. This indicated an advantage of NAC over placebo in those with a clinical comorbidity.<br><br>CONCLUSION: Systemic illness moderated only the effect of NAC on functioning, not on depression. Demonstrating an improvement in functional outcomes with an agent that modulates redox and inflammatory pathways, this study lends empirical support to the idea that medical and psychiatric comorbidity are additive in contributing to allostatic states. One intriguing possibility is that comorbid clinical illness could be a marker for more severe oxidative stress states--and thus guide antioxidant use--in BD.}, }
@article {pmid22206641, year = {2012}, author = {Terrill, JR and Radley-Crabb, HG and Grounds, MD and Arthur, PG}, title = {N-Acetylcysteine treatment of dystrophic mdx mice results in protein thiol modifications and inhibition of exercise induced myofibre necrosis.}, journal = {Neuromuscular disorders : NMD}, volume = {22}, number = {5}, pages = {427-434}, doi = {10.1016/j.nmd.2011.11.007}, pmid = {22206641}, issn = {1873-2364}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Glutathione/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscle, Skeletal/*metabolism/pathology ; Muscular Dystrophy, Animal/*therapy ; Necrosis/prevention &amp; control ; Oxidative Stress ; Physical Conditioning, Animal ; Protein Carbonylation ; Proteins/chemistry/*metabolism ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Oxidative stress is implicated as a factor that increases necrosis of skeletal muscles in Duchenne Muscular Dystrophy (DMD) and the dystrophic mdx mouse. Consequently, drugs that minimize oxidative stress are potential treatments for muscular dystrophy. This study examined the in vivo benefits to mdx mice of an antioxidant treatment with the cysteine precursor N-acetylcysteine (NAC), administered in drinking water. NAC was completely effective in preventing treadmill exercise-induced myofibre necrosis (assessed histologically) and the increased blood creatine kinase levels (a measure of sarcolemma leakiness) following exercise were significantly lower in the NAC treated mice. While NAC had no effect on malondialdehyde level or protein carbonylation (two indicators of irreversible oxidative damage), treatment with NAC for one week significantly decreased the oxidation of glutathione and protein thiols, and enhanced muscle protein thiol content. These data provide in vivo evidence for protective benefits of NAC treatment on dystropathology, potentially via protein thiol modifications.}, }
@article {pmid22203419, year = {2012}, author = {Wang, XY and Yang, CT and Zheng, DD and Mo, LQ and Lan, AP and Yang, ZL and Hu, F and Chen, PX and Liao, XX and Feng, JQ}, title = {Hydrogen sulfide protects H9c2 cells against doxorubicin-induced cardiotoxicity through inhibition of endoplasmic reticulum stress.}, journal = {Molecular and cellular biochemistry}, volume = {363}, number = {1-2}, pages = {419-426}, pmid = {22203419}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/*toxicity ; Antioxidants/metabolism/*pharmacology ; Cell Line ; Cell Survival/drug effects ; Cystathionine gamma-Lyase/metabolism ; Cytoprotection ; Dose-Response Relationship, Drug ; Doxorubicin/*toxicity ; Endoplasmic Reticulum Stress/*drug effects ; Free Radical Scavengers/pharmacology ; Heat-Shock Proteins/metabolism ; Hydrogen Peroxide/toxicity ; Hydrogen Sulfide/*metabolism ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; Oxidants/toxicity ; Rats ; Reactive Oxygen Species/metabolism ; Sulfides/metabolism/*pharmacology ; Time Factors ; Transcription Factor CHOP/metabolism ; }, abstract = {The roles of hydrogen sulfide (H(2)S) and endoplasmic reticulum (ER) stress in doxorubicin (DOX)-induced cardiotoxicity are still unclear. This study aimed to dissect the hypothesis that H(2)S could protect H9c2 cells against DOX-induced cardiotoxicity by inhibiting ER stress. Our results showed that exposure of H9c2 cells to DOX significantly inhibited the expression and activity of cystathionine-γ-lyase (CSE), a synthetase of H(2)S, accompanied by the decreased cell viability and the increased reactive oxygen species (ROS) accumulation. In addition, exposure of cells to H(2)O(2) (an exogenous ROS) mimicked the inhibitory effect of DOX on the expression and activity of CSE. Pretreatment with N-acetyl-L: -cysteine (NAC) (a ROS scavenger) attenuated intracellular ROS accumulation, cytotoxicity, and the inhibition of expression and activity of CSE induced by DOX. Notably, the ER stress-related proteins, including glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) were obviously upregulated in DOX-treated H9c2 cells. Pretreatment with sodium hydrosulfide (NaHS, a H(2)S donor) before DOX exposure markedly suppressed DOX-induced overexpressions of GRP78 and CHOP, cytotoxicity and oxidative stress. In conclusion, we have demonstrated that ROS-mediated inhibition of CSE is involved in DOX-induced cytotoxicity in H9c2 cells, and that exogenous H(2)S can confer protection against DOX-induced cardiotoxicity partly through inhibition of ER stress.}, }
@article {pmid22202674, year = {2012}, author = {Zhang, H and Limphong, P and Pieper, J and Liu, Q and Rodesch, CK and Christians, E and Benjamin, IJ}, title = {Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {26}, number = {4}, pages = {1442-1451}, pmid = {22202674}, issn = {1530-6860}, support = {5R01HL074370-03/HL/NHLBI NIH HHS/United States ; R01 HL074370/HL/NHLBI NIH HHS/United States ; DP1 HL117650/HL/NHLBI NIH HHS/United States ; 2 R01 HL063834-06/HL/NHLBI NIH HHS/United States ; 1R01HL66701/HL/NHLBI NIH HHS/United States ; R01 HL063834/HL/NHLBI NIH HHS/United States ; DP1 OD006438/OD/NIH HHS/United States ; 5DP1OD006438-02/OD/NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cytosol/metabolism ; Dinitrochlorobenzene/pharmacology ; Free Radical Scavengers/pharmacology ; Glutamate-Cysteine Ligase/metabolism ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Green Fluorescent Proteins/chemistry/metabolism ; HEK293 Cells ; Heart/drug effects/embryology ; Homeostasis ; Humans ; Hydrogen Peroxide/pharmacology ; Indicators and Reagents/pharmacology ; Mitochondria/*metabolism ; Myocardium/cytology/metabolism ; Oxidants/pharmacology ; *Oxidation-Reduction ; *Oxidative Stress ; Protein Subunits/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Thioredoxins/metabolism ; }, abstract = {To investigate the effects of the predominant nonprotein thiol, glutathione (GSH), on redox homeostasis, we employed complementary pharmacological and genetic strategies to determine the consequences of both loss- and gain-of-function GSH content in vitro. We monitored the redox events in the cytosol and mitochondria using reduction-oxidation sensitive green fluorescent protein (roGFP) probes and the level of reduced/oxidized thioredoxins (Trxs). Either H(2)O(2) or the Trx reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB), in embryonic rat heart (H9c2) cells, evoked 8 or 50 mV more oxidizing glutathione redox potential, E(hc) (GSSG/2GSH), respectively. In contrast, N-acetyl-L-cysteine (NAC) treatment in H9c2 cells, or overexpression of either the glutamate cysteine ligase (GCL) catalytic subunit (GCLC) or GCL modifier subunit (GCLM) in human embryonic kidney 293 T (HEK293T) cells, led to 3- to 4-fold increase of GSH and caused 7 or 12 mV more reducing E(hc), respectively. This condition paradoxically increased the level of mitochondrial oxidation, as demonstrated by redox shifts in mitochondrial roGFP and Trx2. Lastly, either NAC treatment (EC(50) 4 mM) or either GCLC or GCLM overexpression exhibited increased cytotoxicity and the susceptibility to the more reducing milieu was achieved at decreased levels of ROS. Taken together, our findings reveal a novel mechanism by which GSH-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.}, }
@article {pmid22197715, year = {2012}, author = {Kim, JB and Kim, C and Choi, E and Park, S and Park, H and Pak, HN and Lee, MH and Shin, DC and Hwang, KC and Joung, B}, title = {Particulate air pollution induces arrhythmia via oxidative stress and calcium calmodulin kinase II activation.}, journal = {Toxicology and applied pharmacology}, volume = {259}, number = {1}, pages = {66-73}, doi = {10.1016/j.taap.2011.12.007}, pmid = {22197715}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Action Potentials/drug effects ; Air Pollutants/*toxicity ; Animals ; Animals, Newborn ; Apoptosis/drug effects ; Arrhythmias, Cardiac/*chemically induced/enzymology/metabolism/prevention &amp; control ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Activation ; Immunoblotting ; Immunohistochemistry ; Male ; Myocytes, Cardiac/drug effects/metabolism ; Oxidative Stress/*drug effects ; Particulate Matter/*toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Vehicle Emissions/*toxicity ; Ventricular Premature Complexes/chemically induced/enzymology/metabolism/prevention &amp; control ; Voltage-Sensitive Dye Imaging ; }, abstract = {Ambient particulate matter (PM) can increase the incidence of arrhythmia. However, the arrhythmogenic mechanism of PM is poorly understood. This study investigated the arrhythmogenic mechanism of PM. In Sprague-Dawley rats, QT interval was increased from 115.0±14.0 to 142.1±18.4ms (p=0.02) after endotracheal exposure of DEP (200μg/ml for 30min, n=5). Ventricular premature contractions were more frequently observed after DEP exposure (100%) than baseline (20%, p=0.04). These effects were prevented by pretreatment of N-acetylcysteine (NAC, 5mmol/L, n=3). In 12 Langendorff-perfused rat hearts, DEP infusion of 12.5μg/ml for 20min prolonged action potential duration (APD) at only left ventricular base increasing apicobasal repolarization gradients. Spontaneous early afterdepolarization (EAD) and ventricular tachycardia (VT) were observed in 8 (67%) and 6 (50%) hearts, respectively, versus no spontaneous triggered activity or VT in any hearts before DEP infusion. DEP-induced APD prolongation, EAD and VT were successfully prevented with NAC (5mmol/L, n=5), nifedipine (10μmol/L, n=5), and active Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) blockade, KN 93 (1μmol/L, n=5), but not by thapsigargin (200nmol/L) plus ryanodine (10μmol/L, n=5) and inactive CaMKII blockade, KN 92 (1μmol/L, n=5). In neonatal rat cardiomyocytes, DEP provoked ROS generation in dose dependant manner. DEP (12.5μg/ml) induced apoptosis, and this effect was prevented by NAC and KN 93. Thus, this study shows that in vivo and vitro exposure of PM induced APD prolongation, EAD and ventricular arrhythmia. These effects might be caused by oxidative stress and CaMKII activation.}, }
@article {pmid22191014, year = {2011}, author = {Martín, SA and Emilio, R and Mahara, V}, title = {Role of oxidative stress in transformation induced by metal mixture.}, journal = {Oxidative medicine and cellular longevity}, volume = {2011}, number = {}, pages = {935160}, pmid = {22191014}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/*toxicity ; Animals ; Arsenic/*toxicity ; BALB 3T3 Cells ; Cadmium/*toxicity ; Carcinogens, Environmental/*toxicity ; Cell Survival ; Cell Transformation, Neoplastic/*chemically induced ; Free Radical Scavengers/pharmacology ; Humans ; Lead/*toxicity ; Mice ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Metals are ubiquitous pollutants present as mixtures. In particular, mixture of arsenic-cadmium-lead is among the leading toxic agents detected in the environment. These metals have carcinogenic and cell-transforming potential. In this study, we used a two step cell transformation model, to determine the role of oxidative stress in transformation induced by a mixture of arsenic-cadmium-lead. Oxidative damage and antioxidant response were determined. Metal mixture treatment induces the increase of damage markers and the antioxidant response. Loss of cell viability and increased transforming potential were observed during the promotion phase. This finding correlated significantly with generation of reactive oxygen species. Cotreatment with N-acetyl-cysteine induces effect on the transforming capacity; while a diminution was found in initiation, in promotion phase a total block of the transforming capacity was observed. Our results suggest that oxidative stress generated by metal mixture plays an important role only in promotion phase promoting transforming capacity.}, }
@article {pmid22189927, year = {2011}, author = {Magalhães, PV and Dean, OM and Bush, AI and Copolov, DL and Malhi, GS and Kohlmann, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Berk, M}, title = {N-acetylcysteine for major depressive episodes in bipolar disorder.}, journal = {Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999)}, volume = {33}, number = {4}, pages = {374-378}, doi = {10.1590/s1516-44462011000400011}, pmid = {22189927}, issn = {1809-452X}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antidepressive Agents/*therapeutic use ; Bipolar Disorder/*drug therapy ; Chemotherapy, Adjuvant ; Depressive Disorder/*drug therapy ; Female ; Humans ; Male ; Psychiatric Status Rating Scales ; Treatment Outcome ; }, abstract = {OBJECTIVE: In this report, we aimed to evaluate the effect of add-on N-acetylcysteine (NAC) on depressive symptoms and functional outcomes in bipolar disorder. To that end, we conducted a secondary analysis of all patients meeting full criteria for a depressive episode in a placebo controlled trial of adjunctive NAC for bipolar disorder.<br><br>METHOD: Twenty-four week randomised clinical trial comparing adjunctive NAC and placebo in individuals with bipolar disorder experiencing major depressive episodes. Symptomatic and functional outcome data were collected over the study period.<br><br>RESULTS: Seventeen participants were available for this report. Very large effect sizes in favor of NAC were found for depressive symptoms and functional outcomes at endpoint. Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo.<br><br>DISCUSSION: These results indicate that adjunctive NAC may be useful for major depressive episodes in bipolar disorder. Further studies designed to confirm this hypothesis are necessary.}, }
@article {pmid22189510, year = {2012}, author = {Ahishali, E and Boynuegri, B and Ozpolat, E and Surmeli, H and Dolapcioglu, C and Dabak, R and Bahcebasi, ZB and Bayramicli, OU}, title = {Approach to mushroom intoxication and treatment: can we decrease mortality?.}, journal = {Clinics and research in hepatology and gastroenterology}, volume = {36}, number = {2}, pages = {139-145}, doi = {10.1016/j.clinre.2011.11.004}, pmid = {22189510}, issn = {2210-741X}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Mushroom Poisoning/*diagnosis/mortality/*therapy ; Retrospective Studies ; Young Adult ; }, abstract = {BACKGROUND: Mushroom is widely consumed in Turkey because it is inexpensive and widely available. Intoxication with mushroom is a common health problem in Turkey with a high mortality rate.<br><br>AIM: To identify the outcome of patients with wild mushroom intoxication who were diagnosed based on systematic criteria and had received a comprehensive treatment.<br><br>METHODS: Seventy-seven patients admitted to the Emergency Department of our hospital with mushroom intoxication were retrospectively evaluated. The patients were administered a combined treatment of gastric lavage, activated charcoal, penicillin G, N-acetyl cysteine, silybin and hemofiltration. Demographic, clinical and laboratory data of patients and the outcomes of the treatment modality were recorded.<br><br>RESULTS: A total of 77 patients, 46 (59.7%) females and 31 (40.3%) males were evaluated in the study. The mean age of the patients was 41.94 &#xb1; 15.40 years. They presented with nausea and vomiting within 4 to 48 hours. Sixteen patients (20.7%) had abdominal pain, six patients had (7.7%) diarrhea and five patients (6.5%) had jaundice. Seven patients (9%) developed acute liver failure and were referred to intensive care units. Five of these patients recovered without any liver transplantation; one patient had cadaveric liver transplantation but died in the early period after the transplantation and one patient died while waiting for transplantation. The rest of the patients were followed by us and they all have recovered.<br><br>CONCLUSIONS: Our data indicate that clinical diagnosis based on systematic criteria and a comprehensive treatment regimen may be effective in decreasing the mortality in mushroom intoxication.}, }
@article {pmid22187484, year = {2012}, author = {Gates, LA and Lu, D and Peterson, LA}, title = {Trapping of cis-2-butene-1,4-dial to measure furan metabolism in human liver microsomes by cytochrome P450 enzymes.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {40}, number = {3}, pages = {596-601}, pmid = {22187484}, issn = {1521-009X}, support = {P30 CA077598/CA/NCI NIH HHS/United States ; R01 ES010577/ES/NIEHS NIH HHS/United States ; CA-77598/CA/NCI NIH HHS/United States ; ES-10577/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Aldehydes/*metabolism ; Animals ; Carcinogens/*metabolism ; Chromatography, High Pressure Liquid/methods ; Cytochrome P-450 CYP2E1/metabolism ; Cytochrome P-450 Enzyme System/*metabolism ; Furans/*metabolism ; Glutathione/metabolism ; Humans ; Lysine/metabolism ; Mice ; Microsomes, Liver/enzymology/*metabolism ; Oxidation-Reduction ; Oxidoreductases/metabolism ; Rats ; Tandem Mass Spectrometry/methods ; }, abstract = {Furan is a liver toxicant and carcinogen in rodents. It is classified as a possible human carcinogen, but the human health effects of furan exposure remain unknown. The oxidation of furan by cytochrome P450 (P450) enzymes is necessary for furan toxicity. The product of this reaction is the reactive α,β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA). To determine whether human liver microsomes metabolize furan to BDA, a liquid chromatography/tandem mass spectrometry method was developed to detect and quantify BDA by trapping this reactive metabolite with N-acetyl-l-cysteine (NAC) and N-acetyl-l-lysine (NAL). Reaction of NAC and NAL with BDA generates N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine (NAC-BDA-NAL). Formation of NAC-BDA-NAL was quantified in 21 different human liver microsomal preparations. The levels of metabolism were comparable to that observed in F-344 rat and B6C3F1 mouse liver microsomes, two species known to be sensitive to furan-induced toxicity. Studies with recombinant human liver P450s indicated that CYP2E1 is the most active human liver furan oxidase. The activity of CYP2E1 as measured by p-nitrophenol hydroxylase activity was correlated to the extent of NAC-BDA-NAL formation in human liver microsomes. The formation of NAC-BDA-NAL was blocked by CYP2E1 inhibitors but not other P450 inhibitors. These results suggest that humans are capable of oxidizing furan to its toxic metabolite, BDA, at rates comparable to those of species sensitive to furan exposure. Therefore, humans may be susceptible to furan's toxic effects.}, }
@article {pmid22185818, year = {2011}, author = {Madureira, PA and Hill, R and Miller, VA and Giacomantonio, C and Lee, PW and Waisman, DM}, title = {Annexin A2 is a novel cellular redox regulatory protein involved in tumorigenesis.}, journal = {Oncotarget}, volume = {2}, number = {12}, pages = {1075-1093}, pmid = {22185818}, issn = {1949-2553}, mesh = {Animals ; Annexin A2/genetics/*metabolism ; Calcium-Binding Proteins ; Cell Line, Tumor ; Cell Transformation, Neoplastic/*metabolism ; Humans ; Hydrogen Peroxide/*pharmacology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Liver/metabolism ; Lung/metabolism ; Mice ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Oxidation-Reduction ; Oxidative Stress ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Annexins are a structurally related family of calcium and phospholipid-binding proteins that are involved in the regulation of a wide range of molecular and cellular processes. Annexin A2 is unique among the annexins in that it possesses redox sensitive cysteine(s). The ubiquitous and abundant expression of ANXA2 in cells and its reactivity with hydrogen peroxide led us to hypothesize that this protein could play a role in cellular redox regulation. Here we show that ANXA2 protein levels are induced by hydrogen peroxide. Furthermore, depletion of ANXA2 resulted in the elevation of cellular reactive oxygen species (ROS) upon oxidative stress, increased activation of the ROS-induced pro-apoptotic kinases, JNK, p38 and Akt and elevated sensitivity to ROS-mediated cellular damage/death. ANXA2-null mice showed significantly elevated protein oxidation in the liver and lung tissues compared to WT mice. ANXA2 depleted cancer cells showed enhanced cellular protein oxidation concomitant with decreased tumor growth compared to control cancer cells and both the protein oxidation and tumor growth deficit were reversed by the antioxidant N-acetyl cysteine, indicating that ANXA2 redox regulatory function plays a major role in tumorigenesis. Ex-vivo human cancer studies showed that up-regulation of the reduced form of ANXA2 is associated with protection of the tumor proteins from oxidation. In summary, our results indicate that ANXA2 redox regulatory function plays an important role protecting cells from oxidative stress, particularly during tumorigenesis.}, }
@article {pmid22180025, year = {2012}, author = {Hou, Y and Wang, L and Zhang, W and Yang, Z and Ding, B and Zhu, H and Liu, Y and Qiu, Y and Yin, Y and Wu, G}, title = {Protective effects of N-acetylcysteine on intestinal functions of piglets challenged with lipopolysaccharide.}, journal = {Amino acids}, volume = {43}, number = {3}, pages = {1233-1242}, doi = {10.1007/s00726-011-1191-9}, pmid = {22180025}, issn = {1438-2199}, mesh = {Acetylcysteine/*administration &amp; dosage ; Amine Oxidase (Copper-Containing)/blood/metabolism ; Animals ; Caspase 3/metabolism ; Claudin-1/metabolism ; DNA/metabolism ; Dietary Supplements ; Drug Evaluation, Preclinical ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Intestinal Mucosa/drug effects/immunology/metabolism ; Intestine, Small/*drug effects/immunology ; Lipopolysaccharides/*pharmacology ; Occludin/metabolism ; Proteome/metabolism ; RNA/metabolism ; Sus scrofa ; Weight Gain/drug effects ; Xylose/blood ; }, abstract = {The neonatal small intestine is susceptible to damage by endotoxin, but effective methods for prevention and treatment are lacking. N-acetylcysteine (NAC) is a widely used precursor of L: -cysteine for animal cells and plays an important role in protecting cells against oxidative stress. This study was conducted with the lipopolysaccharide (LPS)-challenged piglet model to determine the effects of NAC on intestinal function. Eighteen piglets were randomly allocated into control, LPS and LPS + NAC groups. The control and LPS groups were fed a corn- and soybean meal-based diet, and the LPS + NAC group was fed the basal diet +500 mg/kg NAC. On days 10, 13 and 20 of the trial, the LPS and LPS + NAC groups received intraperitoneal administration of LPS (100 μg/kg BW), whereas the control piglets received saline. On day 20 of the trial, D-: xylose (0.1 g/kg BW) was orally administrated to all piglets 2 h after LPS or saline injection, and blood samples were collected 1 h thereafter. One hour blood xylose test was used to measure intestinal absorption capacity and mucosal integrity, and diamine oxidase (DAO) was used as a marker of intestinal injury. On day 21 of the trial, pigs were killed to obtain the intestinal mucosa. Compared to the control, LPS challenge reduced (P < 0.05) the concentrations of D-: xylose (a marker of intestinal absorption) in plasma, activities of DAO in the jejunal mucosa, the ratio of villus height to crypt depth in the jejunal mucosa, RNA/DNA and protein/DNA in the jejunal and ileal mucosae, while increasing (P < 0.05) DAO activity in plasma and caspase-3 expression in the intestinal mucosa. The adverse effects of LPS were partially ameliorated (P < 0.05) by NAC supplementation. Moreover, NAC prevented the LPS-induced decrease in claudin-1 and occludin expression in the jejunal and ileal mucosae. Collectively, these results indicate that dietary NAC supplementation alleviates the mucosal damage and improves the absorptive function of the small intestine in LPS-challenged piglets.}, }
@article {pmid22179661, year = {2012}, author = {Inoue, H and Waiwut, P and Saiki, I and Shimada, Y and Sakurai, H}, title = {Gomisin N enhances TRAIL-induced apoptosis via reactive oxygen species-mediated up-regulation of death receptors 4 and 5.}, journal = {International journal of oncology}, volume = {40}, number = {4}, pages = {1058-1065}, pmid = {22179661}, issn = {1791-2423}, mesh = {Apoptosis/*drug effects ; Cell Line, Tumor ; Cyclooctanes/pharmacology ; HeLa Cells ; Humans ; Lignans/*pharmacology ; Polycyclic Compounds/*pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Recombinant Proteins/pharmacology ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; Up-Regulation ; }, abstract = {Pharmacological studies have revealed that lignans isolated from Schisandra chinensis, including gomisin N, show anticancer, anti-hepatotoxic, anti-oxidative and anti-inflammatory activities. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor superfamily with great potential in cancer therapy. The present study investigated whether pretreatment with gomisin N significantly enhanced TRAIL-induced cleavage of caspase-3, caspase-8 and PARP-1, which are key markers of apoptosis. Pretreatment with z-VAD-FMK, a pan-caspase inhibitor, was able to inhibit apoptosis enhanced by the combination of gomisin N and TRAIL. These results suggested that gomisin N could promote TRAIL-induced apoptosis through the caspase cascade. In search of the molecular mechanisms, we elucidated that such enhancement was achieved through transcriptional up-regulation of TRAIL receptors, death receptor 4 (DR4) and DR5. Neutralization of DR4 and DR5 could significantly reduce apoptosis induced by gomisin N and TRAIL. We also revealed that gomisin N increased the generation of reactive oxygen species (ROS). N-acetyl cysteine (NAC), an antioxidant, could inhibit ROS production and up-regulation of DR4 and DR5. Overall, our results indicated that gomisin N was able to potentiate TRAIL-induced apoptosis through ROS-mediated up-regulation of DR4 and DR5.}, }
@article {pmid22178923, year = {2012}, author = {Nagoor Meeran, MF and Stanely Mainzen Prince, P and Hidhayath Basha, R}, title = {Preventive effects of N-acetyl cysteine on lipids, lipoproteins and myocardial infarct size in isoproterenol induced myocardial infarcted rats: an in vivo and in vitro study.}, journal = {European journal of pharmacology}, volume = {677}, number = {1-3}, pages = {116-122}, doi = {10.1016/j.ejphar.2011.11.043}, pmid = {22178923}, issn = {1879-0712}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers/metabolism ; Free Radical Scavengers/*pharmacology ; Isoproterenol/*pharmacology ; Lipoproteins/blood/*metabolism ; Liver/drug effects/metabolism ; Male ; Myocardial Infarction/chemically induced/*metabolism/*pathology/prevention &amp; control ; Rats ; Rats, Wistar ; }, abstract = {The present study evaluated the preventive effects of N-acetyl cysteine in isoproterenol induced myocardial infarcted rats. Rats were pretreated with N-acetyl cysteine (10 mg/kg body weight) daily for a period of 14 days. After pretreatment, rats were injected with isoproterenol (100 mg/kg body weight) at an interval of 24 h for two days to induce myocardial infarction. Isoproterenol induced myocardial infarction was indicated by increased activity of creatine kinase-MB and levels of cardiac troponins in the serum. The weight of heart and the levels of serum and heart cholesterol, triglycerides, free fatty acids were increased in isoproterenol induced myocardial infarcted rats. Isoproterenol also increased the levels of serum low density and very low density lipoprotein cholesterol and decreased high density lipoprotein cholesterol. It enhanced the activity of liver 3-hydroxy-3 methyl glutaryl-Coenzyme-A reductase and the levels of lipid peroxidation products. Pretreatment with N-acetyl cysteine showed significant preventive effects in all the biochemical parameters studied in myocardial infarcted rats. Also, N-acetyl cysteine reduced myocardial infarct size. Histopathological findings of N-acetyl cysteine pretreated myocardial infarcted heart correlated with these biochemical findings. The in vitro study confirmed the strong antioxidant action of N-acetyl cysteine. Thus, the present study revealed that N-acetyl cysteine prevented increased heart weight, accumulation of lipids, altered levels of lipoproteins thereby reducing myocardial infarct size due to its antilipidemic and antioxidant effects in isoproterenol induced myocardial infarcted rats. This study may have a significant impact on myocardial infarction.}, }
@article {pmid22177224, year = {2012}, author = {Barrière, DA and Rieusset, J and Chanteranne, D and Busserolles, J and Chauvin, MA and Chapuis, L and Salles, J and Dubray, C and Morio, B}, title = {Paclitaxel therapy potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through enhanced mitochondrial reactive oxygen species production and TRPA1 sensitization.}, journal = {Pain}, volume = {153}, number = {3}, pages = {553-561}, doi = {10.1016/j.pain.2011.11.019}, pmid = {22177224}, issn = {1872-6623}, mesh = {Acetylcysteine/therapeutic use ; Analysis of Variance ; Animals ; Antineoplastic Agents, Phytogenic/*adverse effects ; Cold Temperature ; Diabetes Mellitus, Experimental/chemically induced/complications/*drug therapy ; Disease Models, Animal ; Ganglia, Spinal/pathology ; Glucose Tolerance Test ; Glutathione Peroxidase/genetics/metabolism ; Hydrogen Peroxide/metabolism ; Hyperalgesia/*chemically induced/metabolism/*pathology/prevention &amp; control ; Hypoxanthine Phosphoribosyltransferase/metabolism ; Male ; Microscopy, Electron, Transmission ; Mitochondria/drug effects/*metabolism ; Paclitaxel/*adverse effects ; Pain Measurement ; Pain Threshold ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sciatic Nerve/pathology ; Sensory Receptor Cells/drug effects/pathology/ultrastructure ; Streptozocin/toxicity ; TRPA1 Cation Channel ; TRPC Cation Channels/genetics/*metabolism ; Time Factors ; }, abstract = {Diabetes comorbidities include disabling peripheral neuropathy (DPN) and an increased risk of developing cancer. Antimitotic drugs, such as paclitaxel, are well known to facilitate the occurrence of peripheral neuropathy. Practitioners frequently observe the development or co-occurrence of enhanced DPN, especially cold sensitivity, in diabetic patients during chemotherapy. Preclinical studies showed that reactive oxygen species (ROS) and cold activate transient receptor potential ankyrin-1 (TRPA1) cation channels, which are involved in cold-evoked pain transduction signaling in DPN. Additionally, paclitaxel treatment has been associated with an accumulation of atypical mitochondria in the sensory nerves of rats. We hypothesized that paclitaxel might potentiate cold hyperalgesia by increasing mitochondrial injuries and TRPA1 activation. Thus, the kinetics of paclitaxel-induced cold hyperalgesia, mitochondrial ROS production, and TRPA1 expression were evaluated in dorsal root ganglia of normoglycemic and streptozotocin-induced diabetic rats. In diabetic rats, paclitaxel significantly enhanced cold hyperalgesia in comparison to normoglycemic paclitaxel-treated control rats. These effects were prevented by N-acetyl-cysteine, a reducing agent, and by HC030031, an antagonist of TRPA1. In diabetic and control rats, paclitaxel treatment was associated with an accumulation of atypical mitochondria and a 2-fold increase in mitochondrial ROS production. Moreover, mRNA levels of glutathione peroxidase 4 and glutathione-S-reductase were significantly lower in diabetic groups treated with paclitaxel. Finally, TRPA1 gene expression was enhanced by 45% in diabetic rats. Paclitaxel potentiation of cold hyperalgesia in diabetes may result from the combination of increased mitochondrial ROS production and poor radical detoxification induced by paclitaxel treatment and diabetes-related overexpression of TRPA1.}, }
@article {pmid22177207, year = {2012}, author = {Shiota, M and Song, Y and Takeuchi, A and Yokomizo, A and Kashiwagi, E and Kuroiwa, K and Tatsugami, K and Uchiumi, T and Oda, Y and Naito, S}, title = {Antioxidant therapy alleviates oxidative stress by androgen deprivation and prevents conversion from androgen dependent to castration resistant prostate cancer.}, journal = {The Journal of urology}, volume = {187}, number = {2}, pages = {707-714}, doi = {10.1016/j.juro.2011.09.147}, pmid = {22177207}, issn = {1527-3792}, mesh = {Androgen Antagonists/therapeutic use ; Animals ; Antioxidants/therapeutic use ; Drug Resistance, Neoplasm ; Humans ; Male ; Mice ; Neoplasm Transplantation ; Nuclear Proteins/biosynthesis ; *Oxidative Stress ; Prostatic Neoplasms/drug therapy/*metabolism ; Receptors, Androgen/biosynthesis ; Tumor Cells, Cultured ; Twist-Related Protein 1/biosynthesis ; Y-Box-Binding Protein 1/biosynthesis ; }, abstract = {PURPOSE: Prostate cancer progression from androgen dependence to castration resistance results at least in part from oxidative stress induced by androgen deprivation therapy. We elucidated the state and the role of oxidative stress induced by androgen deprivation therapy and the possibility of antioxidant therapy in human prostate cancer.<br><br>MATERIALS AND METHODS: We investigated 4-HNE (4-hydroxy-2-nonenal histidine adduct) staining, and Twist1, YB-1 and androgen receptor expression by immunohistochemistry in prostate cancer samples treated with or without neoadjuvant androgen deprivation therapy. Intracellular reactive oxygen species and protein expression were examined by CM-H(2)DCFDA and Western blot analysis, respectively. A cell proliferation assay and a mouse xenograft model were used to assess tumor growth.<br><br>RESULTS: Androgen deprivation therapy increased oxidative stress, as shown by 4-HNE staining in human prostate cancer tissue. Twist1 and YB-1 expression was up-regulated by androgen deprivation, resulting in androgen receptor over expression. In LNCaP and 22Rv1 cells androgen deprivation increased intracellular reactive oxygen species and evoked Twist1, YB-1 and androgen receptor over expression, resulting in cell growth in a castration resistant manner. Growth was alleviated by N-acetyl-cysteine, an electrophile that supports glutathione production. N-acetyl-cysteine also decreased LNCaP and 22Rv1 tumor growth in castrated and noncastrated mice.<br><br>CONCLUSIONS: Androgen deprivation therapy induced oxidative stress in in vitro and human prostate cancer. Antioxidant therapy using N-acetyl-cysteine appears to be a promising therapeutic modality for prostate cancer.}, }
@article {pmid22176608, year = {2012}, author = {Witham, AA and Beach, DG and Gabryelski, W and Manderville, RA}, title = {Hydroxyl radical-induced oxidation of a phenolic C-linked 2'-deoxyguanosine adduct yields a reactive catechol.}, journal = {Chemical research in toxicology}, volume = {25}, number = {2}, pages = {315-325}, doi = {10.1021/tx200365r}, pmid = {22176608}, issn = {1520-5010}, mesh = {Acetylcysteine/chemistry ; Catechols/*chemistry ; Copper/chemistry ; *DNA Adducts ; Deoxyguanosine/*chemistry ; Edetic Acid/chemistry ; Ferrous Compounds/chemistry ; Hydrogen Peroxide/chemistry ; Hydroxyl Radical/*chemistry ; Phenols/*chemistry ; }, abstract = {Phenolic toxins stimulate oxidative stress and generate C-linked adducts at the C8-site of 2'-deoxyguanosine (dG). We previously reported that the C-linked adduct 8-(4″-hydroxyphenyl)-dG (p-PhOH-dG) undergoes oxidation in the presence of Na(2)IrCl(6) or horseradish peroxidase (HRP)/H(2)O(2) to generate polymeric adducts through phenoxyl radical production [ Weishar (2008) Org. Lett. 10 , 1839 - 1842 ]. We now report on reaction of p-PhOH-dG with two radical-generating systems, Cu(II)/H(2)O(2) or Fe(II)-EDTA/H(2)O(2), which were utilized to study the fate of the C-linked adduct in the presence of hydroxyl radical (HO(•)). The radical-generating systems facilitate (i) hydroxylation of the phenolic ring to afford the catechol adduct 8-(3″,4″-dihydroxyphenyl)-dG (3″,4″-DHPh-dG) and (ii) H-atom abstraction from the sugar moiety to generate the deglycosylated base p-PhOH-G. The ratios of 3″,4″-DHPh-dG to p-PhOH-G were ∼1 for Cu(II)/H(2)O(2) and ∼0.13 for Fe(II)-EDTA/H(2)O(2). The formation of 3″,4″-DHPh-dG was found to have important consequences in terms of reactivity. The catechol adduct has a lower oxidation potential than p-PhOH-dG and is sensitive to aqueous basic media, undergoing decomposition to generate a dicarboxylic acid derivative. In the presence of excess N-acetylcysteine (NAC), oxidation of 3″,4″-DHPh-dG produced mono-NAC and di-NAC conjugates. Our results imply that secondary oxidative pathways of phenolic-dG lesions are likely to contribute to toxicity.}, }
@article {pmid22172632, year = {2012}, author = {Patel, E and Lynch, C and Ruff, V and Reynolds, M}, title = {Co-exposure to nickel and cobalt chloride enhances cytotoxicity and oxidative stress in human lung epithelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {258}, number = {3}, pages = {367-375}, doi = {10.1016/j.taap.2011.11.019}, pmid = {22172632}, issn = {1096-0333}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Caspase 3/drug effects/metabolism ; Caspase 7/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cobalt/administration &amp; dosage/*toxicity ; DNA Breaks, Double-Stranded/drug effects ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects/pathology ; Humans ; Lung/cytology/*drug effects/pathology ; Nickel/administration &amp; dosage/*toxicity ; Oxidative Stress/*drug effects ; Poly(ADP-ribose) Polymerases/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Nickel and cobalt are heavy metals found in land, water, and air that can enter the body primarily through the respiratory tract and accumulate to toxic levels. Nickel compounds are known to be carcinogenic to humans and animals, while cobalt compounds produce tumors in animals and are probably carcinogenic to humans. People working in industrial and manufacturing settings have an increased risk of exposure to these metals. The cytotoxicity of nickel and cobalt has individually been demonstrated; however, the underlying mechanisms of co-exposure to these heavy metals have not been explored. In this study, we investigated the effect of exposure of H460 human lung epithelial cells to nickel and cobalt, both alone and in combination, on cell survival, apoptotic mechanisms, and the generation of reactive oxygen species and double strand breaks. For simultaneous exposure, cells were exposed to a constant dose of 150 μM cobalt or nickel, which was found to be relatively nontoxic in single exposure experiments. We demonstrated that cells exposed simultaneously to cobalt and nickel exhibit a dose-dependent decrease in survival compared to the cells exposed to a single metal. The decrease in survival was the result of enhanced caspase 3 and 7 activation and cleavage of poly (ADP-ribose) polymerase. Co-exposure increased the production of ROS and the formation of double strand breaks. Pretreatment with N-acetyl cysteine alleviated the toxic responses. Collectively, this study demonstrates that co-exposure to cobalt and nickel is significantly more toxic than single exposure and that toxicity is related to the formation of ROS and DSB.}, }
@article {pmid22166790, year = {2012}, author = {Lin, CH and Chen, PS and Kuo, SC and Huang, LJ and Gean, PW and Chiu, TH}, title = {The role of mitochondria-mediated intrinsic death pathway in gingerdione derivative I6-induced neuronal apoptosis.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {50}, number = {3-4}, pages = {1073-1081}, doi = {10.1016/j.fct.2011.11.053}, pmid = {22166790}, issn = {1873-6351}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Blood-Brain Barrier ; Blotting, Western ; Caspase 3/metabolism ; Cells, Cultured ; Enzyme Activation ; Frontal Lobe/drug effects/enzymology ; Guaiacol/*analogs &amp; derivatives/pharmacokinetics/pharmacology ; Male ; Membrane Potentials/drug effects ; Mitochondria/*drug effects/metabolism/physiology ; Neurons/cytology/*drug effects/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Neuronal death induced by I6 displayed apoptotic characteristics but the precise mechanism has not been fully elucidated. In the present studies, I6 at 24 h after intraperitoneal administration significantly decreased the density of surviving neurons and increased caspase-3 activity in frontal cortex, suggesting that peripherally administered I6 may cross BBB to induce CNS toxicity. In rat embryonic primary cortical cells, I6-induced reduction of mitochondrial viability and neuronal apoptosis was inhibited by vitamin E. In addition, I6-induced reactive oxygen species (ROS) caused the disruption of mitochondria membrane potential (MMP), the release of cytochrome c, the activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP), resulting in activation of mitochondrial-mediated intrinsic death pathway. Pre-treatment with antioxidant vitamin E or N-acetylcysteine (NAC) completely abolished the I6-induced generation of ROS, loss of MMP, release of cytochrome c, activation of caspase-9 and caspase-3, and cleavage of PARP. Carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), a mitochondrial uncoupler, significantly reduced I6-induced neuronal death as well as caspase-3 activation and PARP cleavage. These results suggest that I6 induces neuronal death by promoting intracellular ROS production to cause a loss of MMP that result in release of cytochrome c and activation of mitochondria-mediated intrinsic death pathway.}, }
@article {pmid22165969, year = {2012}, author = {Balansky, R and Ganchev, G and Iltcheva, M and Steele, VE and De Flora, S}, title = {Transplacental antioxidants inhibit lung tumors in mice exposed to cigarette smoke after birth: a novel preventative strategy?.}, journal = {Current cancer drug targets}, volume = {12}, number = {2}, pages = {164-169}, doi = {10.2174/156800912799095153}, pmid = {22165969}, issn = {1873-5576}, support = {N01-CN-53301/CN/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Antioxidants/pharmacokinetics/*pharmacology ; Ascorbic Acid/pharmacology ; Body Weight ; Female ; Lung Neoplasms/etiology/*prevention &amp; control ; Maternal-Fetal Exchange ; Mice ; Placenta/*metabolism ; Pregnancy ; Reactive Oxygen Species/metabolism ; Smoke/*adverse effects ; Survival ; Nicotiana ; }, abstract = {Birth is characterized by an intense oxidative stress resulting in nucleotide alterations and gene overexpression in mouse lung. We showed that cigarette smoke (CS) is carcinogenic when exposure starts soon after birth and applied this bioassay to evaluate the efficacy of chemopreventive agents. The present study evaluated whether administration of the antioxidants N-acetyl-L-cysteine (NAC) and vitamin C or ascorbic acid (AsA) during pregnancy can protect strain H Swiss mice exposed to CS after birth. Exposure to CS, for 4 months, of newborns from untreated mice resulted in significant alterations at 8 months of life, including alveolar epithelial hyperplasia, emphysema, blood vessel proliferation, microadenomas, adenomas, and malignant tumors in lung, liver parenchymal degeneration and urinary bladder epithelium hyperplasia. Treatment throughout pregnancy with either NAC, a scavenger of reactive oxygen species, or AsA, an electron donor, did not affect fertility, parity, and body weight of newborns. Prenatal antioxidants significantly inhibited most lesions in adult mice exposed to CS since birth. For instance, the incidence of emphysema was reduced from 27.5% in CS-exposed mice that were untreated during pregnancy to 7.1% and 14.0% in those treated prenatally with NAC and AsA, respectively. Lung adenomas were reduced from 34.8% to 16.7% and 9.3%, respectively. Malignant lung tumors were reduced from 13.0% to 4.7% by prenatal AsA. Liver parenchymal degeneration was reduced from 58.0% to 14.3% by prenatal NAC. These data mechanistically support a "transplacental chemoprevention" strategy, aimed at protecting the newborn from oxidative stress and the adult from CS-related diseases appearing later in life.}, }
@article {pmid22161819, year = {2012}, author = {Tsou, PS and Talia, NN and Pinney, AJ and Kendzicky, A and Piera-Velazquez, S and Jimenez, SA and Seibold, JR and Phillips, K and Koch, AE}, title = {Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts.}, journal = {Arthritis and rheumatism}, volume = {64}, number = {6}, pages = {1978-1989}, pmid = {22161819}, issn = {1529-0131}, support = {R01 AR048267-04/AR/NIAMS NIH HHS/United States ; R01 AR048267-02/AR/NIAMS NIH HHS/United States ; K23 AR060241/AR/NIAMS NIH HHS/United States ; R01 AR048267-01A2/AR/NIAMS NIH HHS/United States ; R01 AR048267-05/AR/NIAMS NIH HHS/United States ; UL1 RR024986/RR/NCRR NIH HHS/United States ; R01 AR048267-03/AR/NIAMS NIH HHS/United States ; R01 AR048267/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Cells, Cultured ; Collagen Type I/genetics/metabolism ; Fibroblasts/drug effects/*metabolism/pathology ; Free Radical Scavengers/pharmacology ; Humans ; Oxidative Stress/drug effects/*physiology ; Phosphorylation/drug effects ; Platelet-Derived Growth Factor/genetics/metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Platelet-Derived Growth Factor/genetics/metabolism ; Scleroderma, Systemic/genetics/*metabolism/pathology ; Skin/drug effects/*metabolism/pathology ; Superoxides/metabolism ; }, abstract = {OBJECTIVE: Platelet-derived growth factor (PDGF) and its receptor, PDGFR, promote fibrosis in systemic sclerosis (SSc; scleroderma) dermal fibroblasts, and such cells in scleroderma skin lesions produce excessive reactive oxygen species (ROS). PDGFR is phosphorylated upon PDGF stimulation, and is dephosphorylated by protein tyrosine phosphatases (PTPs), including PTP1B. This study was undertaken to determine whether the thiol-sensitive PTP1B is affected by ROS in SSc dermal fibroblasts, thereby enhancing the phosphorylation of PDGFR and synthesis of type I collagen. This study also sought to investigate the effect of a thiol antioxidant, N-acetylcysteine (NAC), in SSc.<br><br>METHODS: Fibroblasts were isolated from the skin of patients with diffuse SSc and normal healthy donors for cell culture experiments and immunofluorescence analyses. A phosphate release assay was used to determine the activity of PTP1B.<br><br>RESULTS: Levels of ROS and type I collagen were significantly higher and amounts of free thiol were significantly lower in SSc fibroblasts compared to normal fibroblasts. After stimulation with PDGF, not only were PDGFR and ERK-1/2 phosphorylated to a greater extent, but also the ability to produce PTP1B was hampered in SSc fibroblasts. The activity of PTP1B was significantly inactivated in SSc fibroblasts as a result of cysteine oxidation by the raised levels of ROS, which was confirmed by the oxidation of multiple PTPs, including PTP1B, in SSc fibroblasts. Decreased expression of PTP1B in normal fibroblasts led to increased expression of type I collagen. Treatment of the cells with NAC restored the activity of PTP1B, improved the profile of PDGFR phosphorylation, decreased the numbers of tyrosine-phosphorylated proteins and levels of type I collagen, and scavenged ROS in SSc fibroblasts.<br><br>CONCLUSION: This study describes a new mechanism by which ROS may promote a profibrotic phenotype in SSc fibroblasts through the oxidative inactivation of PTP1B, leading to pronounced activation of PDGFR. The study also presents a novel molecular mechanism by which NAC may act on ROS and PTP1B to provide therapeutic benefit in SSc.}, }
@article {pmid22159439, year = {2012}, author = {Castro, AP and Castro Junior, MA and Lauz, S and Facin, E and Simões, Mde J and Fagundes, DJ}, title = {The role of N-acetyl-cysteine in the lung remote injury after hepatic ischemia and reperfusion in rabbits.}, journal = {Acta cirurgica brasileira}, volume = {27}, number = {1}, pages = {49-55}, doi = {10.1590/s0102-86502012000100009}, pmid = {22159439}, issn = {1678-2674}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Disease Models, Animal ; Free Radical Scavengers/*administration &amp; dosage ; Glucose/administration &amp; dosage ; Infusions, Intravenous ; Liver/*blood supply ; Lung Injury/*prevention &amp; control ; Male ; Rabbits ; Random Allocation ; Reperfusion Injury/*prevention &amp; control ; Time Factors ; }, abstract = {PURPOSE: To study the lesions in the lung of rabbits caused by ischemia/reperfusion hepatic (I/R) after the use of N-acetyl-cysteine (NAC).<br><br>METHODS: Twenty-four rabbits distributed in two groups: control group GI (n = 12) 5% glucose solution and experiment group GII (n = 12) NAC. The animals were pre-anesthetized with 1% acepromazine maleate and anesthetized with ketamine 10% and 2% xylazine intramuscularly. The GI and GII were given glucose solution intravenously or NAC 15 min before occlusion of the hepatic pedicle (30 min). After the period of reperfusion of 24h (n = 6) or 48 h (n = 6), liver and lung samples were collected for histology and immunohistochemistry to assess the impairment of cell.<br><br>RESULTS: The animals of GII and GII-24h-48 h showed parenchyma liver close to normal, when using NAC. The GII and GII-24h-48 h showed lower thickness of alveolar cells that GI and GI-24h-48 h. The expression of caspase 3 in lung cells GII presented smaller value compared to the GI group.<br><br>CONCLUSION: N-acetyl-cysteine administered 15 min prior to the injury ischemia/reperfusion had a significant protective role by minimizing lung injury and apoptotic morphology in the period observed.}, }
@article {pmid22155089, year = {2012}, author = {Wang, W and Craig, ZR and Basavarajappa, MS and Gupta, RK and Flaws, JA}, title = {Di (2-ethylhexyl) phthalate inhibits growth of mouse ovarian antral follicles through an oxidative stress pathway.}, journal = {Toxicology and applied pharmacology}, volume = {258}, number = {2}, pages = {288-295}, pmid = {22155089}, issn = {1096-0333}, support = {R01 ES019178/ES/NIEHS NIH HHS/United States ; R01 ES019178-01/ES/NIEHS NIH HHS/United States ; R01 ES019178-02/ES/NIEHS NIH HHS/United States ; R01ES019178/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/metabolism/pharmacology ; Catalase/metabolism ; Cells, Cultured ; Diethylhexyl Phthalate/*toxicity ; Dose-Response Relationship, Drug ; Female ; Gene Expression Regulation/drug effects ; Glutathione Peroxidase/metabolism ; Mice ; Ovarian Follicle/*drug effects/growth &amp; development ; Oxidative Stress/*drug effects ; Plasticizers/*toxicity ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/drug effects/metabolism ; Superoxide Dismutase-1 ; }, abstract = {Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer that has been shown to inhibit growth of mouse antral follicles, however, little is known about the mechanisms by which DEHP does so. Oxidative stress has been linked to follicle growth inhibition as well as phthalate-induced toxicity in non-ovarian tissues. Thus, we hypothesized that DEHP causes oxidative stress and that this leads to inhibition of the growth of antral follicles. To test this hypothesis, antral follicles isolated from CD-1 mice (age 31-35days) were cultured with vehicle control (dimethylsulfoxide [DMSO]) or DEHP (1-100μg/ml)±N-acetyl cysteine (NAC, an antioxidant at 0.25-1mM). During culture, follicles were measured daily. At the end of culture, follicles were collected and processed for in vitro reactive oxygen species (ROS) assays to measure the presence of free radicals or for measurement of the expression and activity of various key antioxidant enzymes: Cu/Zn superoxide dismutase (SOD1), glutathione peroxidase (GPX) and catalase (CAT). The results indicate that DEHP inhibits the growth of follicles compared to DMSO control and that NAC (0.25-1mM) blocks the ability of DEHP to inhibit follicle growth. Furthermore, DEHP (10μg/ml) significantly increases ROS levels and reduces the expression and activity of SOD1 compared to DMSO controls, whereas NAC (0.5mM) rescues the effects of DEHP on ROS levels and SOD1. However, the expression and activity of GPX and CAT were not affected by DEHP treatment. Collectively, these data suggest that DEHP inhibits follicle growth by inducing production of ROS and by decreasing the expression and activity of SOD1.}, }
@article {pmid22152626, year = {2012}, author = {Quah, SY and Wu, S and Lui, JN and Sum, CP and Tan, KS}, title = {N-acetylcysteine inhibits growth and eradicates biofilm of Enterococcus faecalis.}, journal = {Journal of endodontics}, volume = {38}, number = {1}, pages = {81-85}, doi = {10.1016/j.joen.2011.10.004}, pmid = {22152626}, issn = {1878-3554}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Bacterial Adhesion/drug effects ; Bacterial Load/drug effects ; Biofilms/*drug effects/growth &amp; development ; Calcium Hydroxide/pharmacology ; Dental Pulp Cavity/microbiology ; Dentin/microbiology/physiology ; Enterococcus faecalis/*drug effects ; Humans ; Hydrogen-Ion Concentration ; Materials Testing ; Microbial Sensitivity Tests ; Microbial Viability/drug effects ; Microscopy, Confocal ; Root Canal Irrigants/pharmacology ; Time Factors ; }, abstract = {INTRODUCTION: The aims of this study were to evaluate the antibacterial and biofilm eradication efficacies of N-acetylcysteine (NAC) on Enterococcus faecalis.<br><br>METHODS: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of NAC on E. faecalis were determined. In addition, the ability of dentin powder to neutralize the antibacterial activity of NAC was examined. Calcium hydroxide, a commonly used intracanal medicament, was included as a comparison. The efficacy of NAC on E. faecalis biofilms was tested by exposure of 21-day old E. faecalis biofilms to NAC.<br><br>RESULTS: NAC was most bactericidal at pH 11 with MIC and MBC of 1.56 mg/mL and 12.5 mg/mL, respectively. Although preincubation of calcium hydroxide with dentin powder abolished its antibacterial effects, NAC completely killed E. faecalis regardless of dentin powder preincubation. In addition, prolonged incubation of NAC with dentin powder (up to 3 weeks) did not significantly reduce its antibacterial activity on E. faecalis. Furthermore, NAC also effectively eradicated E. faecalis biofilms.<br><br>CONCLUSIONS: NAC was bactericidal against both the planktonic and biofilm forms of E. faecalis. This antibacterial property of NAC was unaffected by the presence of dentin.}, }
@article {pmid22149535, year = {2012}, author = {Hornyák, I and Marosi, K and Kiss, L and Gróf, P and Lacza, Z}, title = {Increased stability of S-nitrosothiol solutions via pH modulations.}, journal = {Free radical research}, volume = {46}, number = {2}, pages = {214-225}, doi = {10.3109/10715762.2011.647692}, pmid = {22149535}, issn = {1029-2470}, mesh = {3-Mercaptopropionic Acid/*analogs &amp; derivatives/chemistry ; Acetylcysteine/*analogs &amp; derivatives/chemistry ; Catalase/chemistry ; Drug Stability ; Free Radicals/chemistry ; Humans ; Hydrogen-Ion Concentration ; Nitroso Compounds/*chemistry ; Polymers/chemistry ; Regional Blood Flow/drug effects ; S-Nitrosoglutathione/*chemistry/pharmacology ; Skin/blood supply/drug effects ; Solutions ; Superoxide Dismutase/chemistry ; Vasodilation/drug effects ; Vasodilator Agents/*chemistry/pharmacology ; }, abstract = {S-nitrosothiol (RSNO) solutions represent a valuable source of nitric oxide and could be used as topical vasodilators, but their fast decomposition rate poses a serious obstacle to their potentially widespread therapeutic use. Our aim was to characterize and quantify the effect of pH on S-nitrosothiol formation and decomposition in simple aqueous solutions of S-nitrosoglutathione (GSNO), S-nitroso-N-acetylcysteine (SNAC) and S-nitroso-3-mercaptopropionic acid (SN3MPA). Furthermore, we investigated the effect of storage pH on the stability of GSNO incorporated in poly(ethylene glycol)/ poly(vinyl alcohol) matrices. S-nitrosothiol concentrations were measured spectrophotometrically and laser Doppler scanning method was used to assess dermal blood flow. GSH and NAC solutions reached a complete transformation to nitrosothiols when synthesized using acidic NaNO(2) solution. The initial concentration of all investigated RSNOs decreased more slowly with pH adjusted to mildly basic values (8.4-8.8) for the storage period. Polymer gels of PVA/PEG compositions at mildly basic storage pH further reduced the decomposition rate succeeding to contain 46.8% of the initial GSNO concentration for 25 days. This amount of topically administered GSNO was still capable of increasing the dermal blood flow over 200% in human subjects.}, }
@article {pmid22139847, year = {2012}, author = {Gutiérrez-Uzquiza, &#xc1; and Arechederra, M and Bragado, P and Aguirre-Ghiso, JA and Porras, A}, title = {p38α mediates cell survival in response to oxidative stress via induction of antioxidant genes: effect on the p70S6K pathway.}, journal = {The Journal of biological chemistry}, volume = {287}, number = {4}, pages = {2632-2642}, pmid = {22139847}, issn = {1083-351X}, support = {R01 CA109182/CA/NCI NIH HHS/United States ; R21 ES017146/ES/NIEHS NIH HHS/United States ; CA109182/CA/NCI NIH HHS/United States ; ES017146/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 2/genetics/metabolism ; Animals ; Catalase/*biosynthesis/genetics ; Cell Line ; Cell Survival/drug effects/physiology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects/physiology ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Knockout ; Mitogen-Activated Protein Kinase 14/genetics/*metabolism ; Oxidants/pharmacology ; Oxidative Stress/drug effects/*physiology ; Ribosomal Protein S6 Kinases, 70-kDa/genetics/*metabolism ; Signal Transduction/drug effects/*physiology ; Superoxide Dismutase/*biosynthesis/genetics ; Superoxide Dismutase-1 ; TOR Serine-Threonine Kinases/genetics/metabolism ; }, abstract = {We reveal a novel pro-survival role for mammalian p38α in response to H(2)O(2), which involves an up-regulation of antioxidant defenses. The presence of p38α increases basal and H(2)O(2)-induced expression of the antioxidant enzymes: superoxide-dismutase 1 (SOD-1), SOD-2, and catalase through different mechanisms, which protects from reactive oxygen species (ROS) accumulation and prevents cell death. p38α was found to regulate (i) H(2)O(2)-induced SOD-2 expression through a direct regulation of transcription mediated by activating transcription factor 2 (ATF-2) and (ii) H(2)O(2)-induced catalase expression through regulation of protein stability and mRNA expression and/or stabilization. As a consequence, SOD and catalase activities are higher in WT MEFs. We also found that this p38α-dependent antioxidant response allows WT cells to maintain an efficient activation of the mTOR/p70S6K pathway. Accordingly, the loss of p38α leads to ROS accumulation in response to H(2)O(2), which causes cell death and inactivation of mTOR/p70S6K signaling. This can be rescued by either p38α re-expression or treatment with the antioxidants, N-acetyl cysteine, or exogenously added catalase. Therefore, our results reveal a novel homeostatic role for p38α in response to oxidative stress, where ROS removal is favored by antioxidant enzymes up-regulation, allowing cell survival and mTOR/p70S6K activation.}, }
@article {pmid22139554, year = {2012}, author = {Patterson, AJ and Xiao, D and Xiong, F and Dixon, B and Zhang, L}, title = {Hypoxia-derived oxidative stress mediates epigenetic repression of PKCε gene in foetal rat hearts.}, journal = {Cardiovascular research}, volume = {93}, number = {2}, pages = {302-310}, pmid = {22139554}, issn = {1755-3245}, support = {HL82779/HL/NHLBI NIH HHS/United States ; 5R25GM060507/GM/NIGMS NIH HHS/United States ; HL83966/HL/NHLBI NIH HHS/United States ; DA032510/DA/NIDA NIH HHS/United States ; HL110125/HL/NHLBI NIH HHS/United States ; HL89012/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cyclic N-Oxides/pharmacology ; DNA Methylation ; *Epigenesis, Genetic ; Female ; Fetal Heart/*metabolism ; *Gene Expression Regulation, Developmental ; Hypoxia/*metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists &amp; inhibitors ; Myocardial Reperfusion Injury/etiology ; NADPH Oxidases/physiology ; *Oxidative Stress ; Pregnancy ; Promoter Regions, Genetic ; Protein Kinase C-epsilon/antagonists &amp; inhibitors/*genetics ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Spin Labels ; }, abstract = {AIMS: Hypoxia causes protein kinase C epsilon (PKCε) gene repression in foetal hearts, resulting in heightened cardiac susceptibility to ischaemic injury in offspring. We tested the hypothesis that hypoxia inducible factor 1 (HIF-1) and/or reactive oxygen species (ROS) mediate hypoxia-induced PKCε gene repression.<br><br>METHODS AND RESULTS: Hypoxia induced in vivo to pregnant rats, ex vivo to isolated foetal rat hearts, and in vitro in the rat embryonic ventricular myocyte cell line H9c2 resulted in a comparable decrease in PKC&#x3b5; protein and mRNA abundance in foetal hearts and H9c2 cells, which was associated with a significant increase in CpG methylation of the SP1-binding sites at the PKC&#x3b5; promoter. In H9c2 cells and foetal hearts, hypoxia caused nuclear accumulation of HIF-1&#x3b1;, which was inhibited by 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole and 2-methoxy estradiol. The HIF-1&#x3b1; inhibitors had no significant effect on hypoxia-induced PKC&#x3b5; mRNA repression. Hypoxia produced a time-dependent increase in ROS production in H9c2 cells and foetal hearts that was blocked by ROS scavengers N-acetyl-cysteine or tempol. In accordance, N-acetyl-cysteine and tempol, but not apocynin, inhibited the hypoxic effect and restored PKC&#x3b5; protein and mRNA expression to the control values in foetal hearts and H9c2 cells. The ROS scavengers blocked hypoxia-induced CpG methylation of the SP1-binding sites, restored SP1 binding to the PKC&#x3b5; promoter, and abrogated the hypoxia-induced increase in the susceptibility of the heart to ischaemic injury in offspring.<br><br>CONCLUSIONS: The results demonstrate that hypoxia induces epigenetic repression of the PKC&#x3b5; gene through a NADPH oxidase-independent ROS-mediated pathway in the foetal heart, leading to heightened heart vulnerability to ischaemic injury in offspring.}, }
@article {pmid22137594, year = {2012}, author = {Kupchik, YM and Moussawi, K and Tang, XC and Wang, X and Kalivas, BC and Kolokithas, R and Ogburn, KB and Kalivas, PW}, title = {The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine.}, journal = {Biological psychiatry}, volume = {71}, number = {11}, pages = {978-986}, pmid = {22137594}, issn = {1873-2402}, support = {DA012513/DA/NIDA NIH HHS/United States ; P50 DA015369/DA/NIDA NIH HHS/United States ; R37 DA003906-26/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; R37 DA003906/DA/NIDA NIH HHS/United States ; P50 DA015369-10/DA/NIDA NIH HHS/United States ; DA015369/DA/NIDA NIH HHS/United States ; R01 DA012513-13/DA/NIDA NIH HHS/United States ; DA003906/DA/NIDA NIH HHS/United States ; R01 DA012513/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cocaine ; Cystine/metabolism ; Drug-Seeking Behavior/*drug effects ; Excitatory Postsynaptic Potentials/*drug effects ; Free Radical Scavengers/*pharmacology ; Glutamic Acid/metabolism ; Male ; Nucleus Accumbens/*drug effects/physiology ; Patch-Clamp Techniques ; Prefrontal Cortex/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Metabotropic Glutamate/drug effects/metabolism ; Recurrence ; Synaptic Transmission/*drug effects ; }, abstract = {BACKGROUND: Relapse to cocaine seeking has been linked with low glutamate in the nucleus accumbens core (NAcore) causing potentiation of synaptic glutamate transmission from prefrontal cortex (PFC) afferents. Systemic N-acetylcysteine (NAC) has been shown to restore glutamate homeostasis, reduce relapse to cocaine seeking, and depotentiate PFC-NAcore synapses. Here, we examine the effects of NAC applied directly to the NAcore on relapse and neurotransmission in PFC-NAcore synapses, as well as the involvement of the metabotropic glutamate receptors 2/3 (mGluR2/3) and 5 (mGluR5).<br><br>METHODS: Rats were trained to self-administer cocaine for 2 weeks and following extinction received either intra-accumbens NAC or systemic NAC 30 or 120 minutes, respectively, before inducing reinstatement with a conditioned cue or a combined cue and cocaine injection. We also recorded postsynaptic currents using in vitro whole cell recordings in acute slices and measured cystine and glutamate uptake in primary glial cultures.<br><br>RESULTS: NAC microinjection into the NAcore inhibited the reinstatement of cocaine seeking. In slices, a low concentration of NAC reduced the amplitude of evoked glutamatergic synaptic currents in the NAcore in an mGluR2/3-dependent manner, while high doses of NAC increased amplitude in an mGluR5-dependent manner. Both effects depended on NAC uptake through cysteine transporters and activity of the cysteine/glutamate exchanger. Finally, we showed that by blocking mGluR5 the inhibition of cocaine seeking by NAC was potentiated.<br><br>CONCLUSIONS: The effect of NAC on relapse to cocaine seeking depends on the balance between stimulating mGluR2/3 and mGluR5 in the NAcore, and the efficacy of NAC can be improved by simultaneously inhibiting mGluR5.}, }
@article {pmid22134636, year = {2012}, author = {Finn, NA and Kemp, ML}, title = {Pro-oxidant and antioxidant effects of N-acetylcysteine regulate doxorubicin-induced NF-kappa B activity in leukemic cells.}, journal = {Molecular bioSystems}, volume = {8}, number = {2}, pages = {650-662}, pmid = {22134636}, issn = {1742-2051}, support = {DP2 OD006483/OD/NIH HHS/United States ; DP2 OD006483-01/OD/NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antioxidants/metabolism ; Cell Line, Tumor ; Doxorubicin/*pharmacology ; Glutathione ; Humans ; I-kappa B Kinase/metabolism ; Leukemia/*metabolism ; NF-kappa B/*metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; }, abstract = {Clinical debate has arisen over the consequences of antioxidant supplementation during cancer chemotherapy. While antioxidants may impede the efficacy of chemotherapy by scavenging reactive oxygen species and free radicals, it is also possible that antioxidants alleviate unwanted chemotherapy-induced toxicity, thus allowing for increased chemotherapy doses. These contradictory assertions suggest that antioxidant supplementation during chemotherapy treatment can have varied outcomes depending on the cellular context. To gain a more robust understanding of the role that antioxidants play in chemotherapy, we investigated the dose-dependent effects of the antioxidant, N-acetylcysteine (NAC), on the redox-mediated regulation of intracellular signaling. In this study, we systematically evaluated the effect of Dox-induced ROS on the NF-κB pathway in a pediatric acute lymphoblastic leukemia (ALL) cell line by measuring the thiol-based oxidative modifications of redox-sensitive proteins within the pathway. We report a functional consequence of NAC supplementation during doxorubicin (Dox) chemotherapy administration via the NF-kappa B (NF-κB) signal transduction pathway. The ability of NAC to alter Dox-induced NF-κB activity is contingent on the ROS-mediated S-glutathionylation of IKK-β. Moreover, the NAC-dependent alteration of intracellular glutathione redox balance, through pro-oxidant and antioxidant mechanisms, can be exploited to either promote or inhibit Dox-induced NF-κB activity in an NAC-concentration-dependent manner. We developed an electron-transfer-based computational model that predicts the effect of NAC pretreatment on Dox-induced NF-κB signaling for a range of NAC and Dox treatment combinations.}, }
@article {pmid22132160, year = {2011}, author = {Miyama, A and Saito, Y and Yamanaka, K and Hayashi, K and Hamakubo, T and Noguchi, N}, title = {Oxidation of DJ-1 induced by 6-hydroxydopamine decreasing intracellular glutathione.}, journal = {PloS one}, volume = {6}, number = {11}, pages = {e27883}, pmid = {22132160}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzoquinones/chemistry/pharmacology ; Blotting, Western ; Catalase/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Glutathione/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Intracellular Signaling Peptides and Proteins/*metabolism ; Intracellular Space/*drug effects/*metabolism ; Microtubule-Associated Proteins/*metabolism ; Neurons/drug effects/metabolism ; Oncogene Proteins/*metabolism ; Oxidation-Reduction/drug effects ; Oxidopamine/chemistry/*pharmacology ; Protective Agents/pharmacology ; Protein Deglycase DJ-1 ; Rats ; Rats, Sprague-Dawley ; }, abstract = {DJ-1, the causative gene of a familial form of Parkinson's disease (PD), has been reported to undergo preferential oxidation of the cysteine residue at position 106 (Cys-106) under oxidative stress; however, details of the molecular mechanisms are not well known. In the present study, mechanisms of DJ-1 oxidation induced by 6-hydroxydopamine (6-OHDA) were investigated by using SH-SY5Y cells. The treatment of these cells with 6-OHDA caused an obvious acidic spot sift of DJ-1 due to its oxidation. However, when catalase, which is an hydrogen peroxide (H(2)O(2))-removing enzyme, was added during the treatment, it failed to prevent the oxidation induced by 6-OHDA, suggesting that electrophilic p-quinone formed from 6-OHDA, but not H(2)O(2), was responsible for the DJ-1 oxidation. Benzoquinone, another electrophilic p-quinone, also induced DJ-1 oxidation. The intracellular glutathione (GSH) levels were significantly decreased by 6-OHDA, irrespective of the presence or absence of catalase. The inhibition of GSH synthesis by buthionine sulfoximine resulted in a decrease in GSH levels and enhancement of DJ-1 oxidation. The pretreatment of cells with N-acetyl-cysteine prevented the loss of intracellular GSH and subsequently DJ-1 oxidation induced by 6-OHDA. Collectively, these results suggest that electrophilic p-quinone formed from 6-OHDA induces DJ-1 oxidation by decreasing intracellular GSH.}, }
@article {pmid22131350, year = {2012}, author = {Bhattacharya, A and Li, Y and Geng, F and Munday, R and Zhang, Y}, title = {The principal urinary metabolite of allyl isothiocyanate, N-acetyl-S-(N-allylthiocarbamoyl)cysteine, inhibits the growth and muscle invasion of bladder cancer.}, journal = {Carcinogenesis}, volume = {33}, number = {2}, pages = {394-398}, pmid = {22131350}, issn = {1460-2180}, support = {P30 CA016056/CA/NCI NIH HHS/United States ; R01 CA124627/CA/NCI NIH HHS/United States ; R01CA124627/CA/NCI NIH HHS/United States ; P30CA016056/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cysteine/*analogs &amp; derivatives/pharmacology/urine ; Down-Regulation/drug effects ; Female ; Humans ; Isothiocyanates/*pharmacology/*urine ; Neoplasm Invasiveness ; Rats ; Rats, Inbred F344 ; Thiocarbamates/*pharmacology/*urine ; Tubulin/metabolism ; Urinary Bladder Neoplasms/*drug therapy/pathology/urine ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Naturally occurring allyl isothiocyanate (AITC) was recently shown to be selectively delivered to bladder cancer tissue via urinary excretion and to inhibit bladder cancer growth and muscle invasion in an animal model. AITC is excreted in urine mainly as N-acetyl-S-(N-allylthiocarbamoyl)cysteine, more commonly known as the N-acetylcysteine conjugate (NAC-AITC). We show here that treatment of human bladder cancer UM-UC-3 cells or rat bladder cancer AY-27 cells with NAC-AITC at 15 μM results in significant inhibition of cell growth and proliferation, together with cell cycle arrest and apoptosis. We also show that NAC-AITC administered orally at 10 μmol/kg body wt inhibits cancer growth by 40% and muscle invasion by 49% in an orthotopic rat bladder cancer model. Furthermore, the anticancer activity of NAC-AITC is associated with the modulation of several important molecular targets, including downregulation of both α-tubulin and β-tubulin, activation of caspase-3 and downregulation of vascular endothelial growth factor. These results are similar to those shown previously for AITC and are consistent with the understanding that NAC-AITC is a carrier of AITC. Furthermore, comparison of the pharmacokinetic and physical properties of NAC-AITC with those of AITC suggests that NAC-AITC is superior to AITC for potential use for prevention and therapy of bladder cancer.}, }
@article {pmid22131322, year = {2011}, author = {Grman, M and Misak, A and Cacanyiova, S and Kristek, F and Tomaskova, Z and Bertova, A and Ondrias, K}, title = {The aqueous garlic, onion and leek extracts release nitric oxide from S-nitrosoglutathione and prolong relaxation of aortic rings.}, journal = {General physiology and biophysics}, volume = {30}, number = {4}, pages = {396-402}, doi = {10.4149/gpb_2011_04_396}, pmid = {22131322}, issn = {0231-5882}, mesh = {Animals ; Aorta/*pathology ; Chloride Channels/chemistry ; Cysteine/chemistry ; Endothelium, Vascular/pathology ; Garlic/*metabolism ; Glutathione/chemistry ; Glutathione Disulfide/chemistry ; Lipid Bilayers/chemistry ; Male ; Nitric Oxide/*chemistry ; Norepinephrine/pharmacology ; Onions/*metabolism ; Plant Extracts/*pharmacology ; Rats ; Rats, Wistar ; S-Nitrosoglutathione/*metabolism ; }, abstract = {Garlic, onion and leek have beneficial effects in treatment of numerous health disorders. The aim of the present study was to investigate underlying molecular mechanisms. To test the potency of the aqueous garlic, onion and leek extracts to release NO from GSNO we have measured NO oxidation product, NO(2)-, by the Griess reagent method. Further, we studied the ability of garlic extract to relax noradrenaline-precontracted rat aortic rings in the presence of GSNO and effects of garlic extract on electrical properties of rat heart intracellular chloride channels. We have observed that: i) garlic, onion and leek extracts released NO from GSNO in the order: garlic > onion > leek; ii) the ability of garlic extract to release NO was pH-dependent (8.0 > 7.4 > 6.0) and potentiated by thiols (Cys >> GSH = N-acetyl-cysteine > oxidized glutathione) at concentration 100 µmol/l; iii) the garlic extract (0.045 mg/ml) prolonged relaxation time of aortic rings induced by GSNO (50 nmol/l) and inhibited intracellular chloride channels. We suggest that NO-releasing properties of the garlic, onion and leek extracts and their interaction with Cys and GSH are involved in NO-signalling pathway which contributes to some of its numerous beneficial biological effects.}, }
@article {pmid22129741, year = {2011}, author = {Shimamoto, K and Hayashi, H and Taniai, E and Morita, R and Imaoka, M and Ishii, Y and Suzuki, K and Shibutani, M and Mitsumori, K}, title = {Antioxidant N-acetyl-L-cysteine (NAC) supplementation reduces reactive oxygen species (ROS)-mediated hepatocellular tumor promotion of indole-3-carbinol (I3C) in rats.}, journal = {The Journal of toxicological sciences}, volume = {36}, number = {6}, pages = {775-786}, doi = {10.2131/jts.36.775}, pmid = {22129741}, issn = {1880-3989}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*pharmacology ; Alkylating Agents/toxicity ; Animals ; Antioxidants/*pharmacology ; Carcinogens/*toxicity ; DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Diethylnitrosamine/toxicity ; Gene Expression Profiling ; Hepatectomy ; Indoles/*toxicity ; Liver Neoplasms, Experimental/chemically induced/*metabolism/pathology ; Male ; Microsomes, Liver/drug effects/metabolism ; Oligonucleotide Array Sequence Analysis ; Organ Size/drug effects ; Oxidative Stress/drug effects ; Rats ; Rats, Inbred F344 ; Reactive Oxygen Species/*metabolism ; Weight Gain/drug effects ; }, abstract = {Indole-3-carbinol (I3C) has a liver tumor promoting activity in rats, and is also known as a cytochrome p450 1A (CYP1A) inducer. The generation of reactive oxygen species (ROS) resulting from CYP1A induction due to I3C, is probably involved in the tumor promotion. To clarify whether ROS generation contributes to I3C's induction of hepatocellular altered foci, partially hepatectomized rats were fed a diet containing 0.5% of I3C for 8 weeks with or without 0.3% N-acetyl-L-cysteine (NAC), an antioxidant, in their drinking water after N-diethylnitrosamine (DEN) initiation. Immunohistochemical analysis showed that the glutathione-S-transferase placental form (GST-P) positive foci promoted by I3C were suppressed by the administration of NAC. The mRNAs of members of the phase II nuclear factor, erythroid derived 2, like 2 (Nrf2) gene batteries, whose promoter region is called as antioxidant response element (ARE), were down-regulated in the DEN-I3C-NAC group compared to the DEN-I3C group, but Cyp1a1 was not suppressed in the DEN-I3C-NAC group compared to the DEN-I3C group. There was no marked difference in production of microsomal ROS and genomic 8-hydroxy-2'-deoxygunosine (8-OHdG) as an oxidative DNA marker between the DEN-I3C-NAC and DEN-I3C groups, while mapkapk3 and Myc were decreased by the NAC treatment. These results indicate that oxidative stress plays an important role for I3C's tumor promotion, and NAC suppresses induction of hepatocellular altered foci with suppressed cytoplasmic oxidative stress.}, }
@article {pmid22129290, year = {2011}, author = {Bihari, S and Verghese, S and Bersten, AD}, title = {Delayed and prolonged elevated serum paracetamol level after an overdose - possible causes and implications.}, journal = {Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine}, volume = {13}, number = {4}, pages = {275-277}, pmid = {22129290}, issn = {1441-2772}, mesh = {Acetaminophen/*blood/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Adult ; Drug Overdose ; Humans ; Liver Function Tests ; Male ; Nomograms ; Time Factors ; }, abstract = {We report the case of a 29-year-old man who ingested about 50 g of standard-preparation paracetamol plus other medications. The serum paracetamol level remained low in the first 24 hours. It peaked 54 hours after ingestion and remained high for 5 days. An N-acetylcysteine (NAC) infusion was started at admission, but was ceased 36 hours later as the clinical and laboratory signs were reassuring. On Day 3, the patient's liver function deteriorated and a rising serum paracetamol level was noted; hence, an NAC infusion was reinitiated. Despite this, the patient developed fulminant hepatic failure. This case underlines the importance of monitoring paracetamol levels and liver function for at least 72 hours after a suspected large overdose of paracetamol before discontinuing NAC infusion.}, }
@article {pmid22129233, year = {2012}, author = {Chiu, CZ and Wang, BW and Shyu, KG}, title = {Use of atorvastatin to inhibit hypoxia-induced myocardin expression.}, journal = {European journal of clinical investigation}, volume = {42}, number = {5}, pages = {564-571}, doi = {10.1111/j.1365-2362.2011.02628.x}, pmid = {22129233}, issn = {1365-2362}, mesh = {Animals ; Animals, Newborn ; Atorvastatin ; Blotting, Western ; Cells, Cultured ; Electrophoretic Mobility Shift Assay ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Heptanoic Acids/*pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; Hypertrophy/metabolism ; Hypoxia/metabolism/*prevention &amp; control ; Myocytes, Cardiac/*drug effects/metabolism ; Nuclear Proteins/*metabolism ; Pyrroles/*pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Trans-Activators/*metabolism ; }, abstract = {BACKGROUND: Hypoxia induces the formation of reactive oxygen species (ROS), myocardin expression and cardiomyocyte hypertrophy. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been demonstrated to have both antioxidant and antihypertrophic effects. We evaluated the pathways of atorvastatin in repressing ROS and myocardin after hypoxia to prevent cardiomyocyte hypertrophy.<br><br>MATERIALS AND METHODS: Cultured rat neonatal cardiomyocytes were subjected to hypoxia, and the expression of myocardin and ROS were evaluated. Different signal transduction inhibitors, atorvastatin and N-acetylcysteine (NAC) were used to identify the pathways that inhibited myocardin expression and ROS. Electrophoretic motility shift assay (EMSA) and luciferase assay were used to identify the binding of myocardin/serum response factor (SRF) and transcription to cardiomyocytes. Cardiomyocyte hypertrophy was assessed by (3)H-proline incorporation assay.<br><br>RESULTS: Myocardin expression after hypoxia was inhibited by atorvastatin, RhoA/Rho kinase inhibitor (Y27632), extracellular signal-regulated kinase (ERK) small interfering RNA (siRNA)/ERK pathway inhibitor (PD98059), myocardin siRNA and NAC. Bindings of myocardin/SRF, transcription of myocardin/SRF to cardiomyocytes, presence of myocardin in the nuclei of cardiomyocytes and protein synthesis after hypoxia were identified by EMSA, luciferase assay, confocal microscopy and (3)H-proline assay and were suppressed by atorvastatin, Y27632, PD98059 and NAC.<br><br>CONCLUSIONS: Hypoxia in neonatal cardiomyocytes increases myocardin expression and ROS to cause cardiomyocyte hypertrophy, which can be prevented by atorvastatin by suppressing ROS and myocardin expression.}, }
@article {pmid22122955, year = {2011}, author = {Lindblad, AC and Rosenhall, U and Olofsson, A and Hagerman, B}, title = {The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: a controlled trial.}, journal = {Noise &amp; health}, volume = {13}, number = {55}, pages = {392-401}, doi = {10.4103/1463-1741.90293}, pmid = {22122955}, issn = {1463-1741}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Analysis of Variance ; Audiometry ; Auditory Threshold/*drug effects ; Case-Control Studies ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Hearing Loss, Noise-Induced/etiology/*prevention &amp; control ; Humans ; Male ; Middle Aged ; Military Personnel ; Oxidative Stress/drug effects ; Prospective Studies ; Reactive Oxygen Species/adverse effects ; Sweden ; Vestibulocochlear Nerve Injuries/complications/etiology/*prevention &amp; control ; Young Adult ; }, abstract = {In military outdoor shooting training, with safety measures enforced, the risk of a permanent, noise-induced hearing loss is very small. But urban warfare training performed indoors, with reflections from walls, might increase the risk. A question is whether antioxidants can reduce the negative effects of noise on human hearing as it does on research animals. Hearing tests were performed on a control group of 23 military officers before and after a shooting session in a bunker-like room. The experiments were repeated on another group of 11 officers with peroral adminstration of N-acetyl-cysteine (NAC), directly after the shooting. The measurements performed were tone thresholds; transient-evoked otoacoustic emissions, with and without contralateral noise; and psycho-acoustical modulation transfer function (PMTF), thresholds for brief tones in modulated noise. Effects from shooting on hearing thresholds were small, but threshold behavior supports use of NAC treatment. On the PMTF, shooting without NAC gave strong effects. Those effects were like those from continuous noise, which means that strict safety measures should be enforced. The most striking finding was that the non-linearity of the cochlea, that was strongly reduced in the group without NAC, as manifested by the PMTF-results, was practically unchanged in the NAC-group throughout the study. NAC treatment directly after shooting in a bunkerlike room seems to give some protection of the cochlea.}, }
@article {pmid22122305, year = {2011}, author = {Lima Trajano, ET and Sternberg, C and Caetano, M and Santos Silva, MA and Porto, LC and Santos, JC and Ribeiro, ML and Magalhães, CB and Zin, WA and Benjamim, CF and Valença, SS}, title = {Endotoxin-induced acute lung injury is dependent upon oxidative response.}, journal = {Inhalation toxicology}, volume = {23}, number = {14}, pages = {918-926}, doi = {10.3109/08958378.2011.625994}, pmid = {22122305}, issn = {1091-7691}, mesh = {Acetylcysteine/*pharmacology ; Acute Lung Injury/*chemically induced/pathology/physiopathology ; Animals ; Antioxidants/*pharmacology ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Catalase/metabolism ; Cytokines/genetics ; Disease Models, Animal ; Gene Expression/drug effects ; Glutathione/metabolism ; Lipopolysaccharides/*toxicity ; Lung/drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred C57BL ; Nitrites/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Peroxidase/metabolism ; Superoxide Dismutase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The aim of the present study was to investigate the involvement of oxidative stress in acute lung injury (ALI) induced by lipopolysaccharide (LPS) and its effects upon cell structure, function and inflammation. In total, 108 male C57BL/6 mice were divided into seven groups: CTR Group (50 µL of saline) administered intratracheally (i.t.), LPS 6 h (10 µg of LPS - i.t.), LPS 12 h (10 µg of LPS - i.t.), LPS 24 h (10 µg of LPS - i.t.), LPS 48 h (10 µg of LPS - i.t.), LPS 24 h (10 µg - i.t.) + NAC 40 mg/kg (gavage) and 24 h LPS (10 µg - i.t.) + NAC 100 mg/kg (gavage). The antioxidant treatment protected the lungs from stress in the first 12 h, but significant oxidative stress induction was observed at the 24-hour time point, and, after 48 h, there was no protection exerted by the antioxidant treatment. NAC (N-acetylcysteine) reversed the elastance parameters, and ΔP1 and ΔP2 compared with 24 h LPS alone. NAC reduced the number of inflammatory cells in histology analysis when compared with the 24 h LPS alone-treated group. NAC also inhibited the transcription of NFκB, IL-6, TNF-α and COX2 usually induced by LPS. Our results suggest that oxidative stress plays an important role in structural, functional and inflammatory responses in the ALI model.}, }
@article {pmid22118157, year = {2012}, author = {Narayanapillai, S and Agarwal, C and Tilley, C and Agarwal, R}, title = {Silibinin is a potent sensitizer of UVA radiation-induced oxidative stress and apoptosis in human keratinocyte HaCaT cells.}, journal = {Photochemistry and photobiology}, volume = {88}, number = {5}, pages = {1135-1140}, pmid = {22118157}, issn = {1751-1097}, support = {P30 CA046934/CA/NCI NIH HHS/United States ; R01 CA140368/CA/NCI NIH HHS/United States ; USPHS RO1 CA140368/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/radiation effects ; Cell Line ; Cell Survival/drug effects/radiation effects ; Dose-Response Relationship, Radiation ; Endoplasmic Reticulum/drug effects/radiation effects ; Endoplasmic Reticulum Stress/*drug effects/radiation effects ; Gene Expression/drug effects/radiation effects ; Humans ; Keratinocytes/*drug effects/metabolism/radiation effects ; Silybum marianum/*chemistry ; Oxidative Stress/drug effects/radiation effects ; Photosensitizing Agents/*pharmacology ; Reactive Oxygen Species/agonists/metabolism ; Silybin ; Silymarin/*pharmacology ; Transcription Factor CHOP/agonists/genetics ; Ultraviolet Rays/adverse effects ; }, abstract = {UVA radiation (315-400 nm), which constitutes ca 95% of the UV irradiation in natural sunlight reaching earth surface, is a major environmental risk factor associated with human skin cancer pathogenesis. UVA is an oxidizing agent that causes significant damage to cellular components through the release of reactive oxygen species (ROS) and leads to photoaging and photocarcinogenesis. Here we investigate the effect of silibinin, the flavonolignan from Silybum marianum, on UVA-induced ROS and cell death in human keratinocyte cell line HaCaT. In addition, the effect of silibinin on UVA-induced intracellular ROS-mediated endoplasmic reticulum (ER) stress was also analyzed. UVA irradiation resulted in ROS production and apoptosis in HaCaT cells in a dose-dependent manner, and the ROS levels and apoptotic index were found to be elevated significantly when the cells were treated with 75 μmsilibinin for 2 h before UVA exposure. When the cells were pretreated with 10 mmN-acetyl cysteine, the enhancement of UVA-induced apoptosis by silibinin was compromised. Furthermore, we found that silibinin enhances ER stress-mediated apoptosis in HaCaT cells by increasing the expression of CHOP protein. These results suggest that silibinin may be beneficial in the removal of UVA-damaged cells and the prevention of skin cancer.}, }
@article {pmid22115526, year = {2012}, author = {Li, Y and Wang, P and Zhao, P and Zhu, S and Wang, X and Liu, Q}, title = {Apoptosis induced by sonodynamic treatment by protoporphyrin IX on MDA-MB-231 cells.}, journal = {Ultrasonics}, volume = {52}, number = {4}, pages = {490-496}, doi = {10.1016/j.ultras.2011.10.013}, pmid = {22115526}, issn = {1874-9968}, mesh = {Acetylcysteine/metabolism ; Adenosine Diphosphate Ribose/metabolism ; Apoptosis/*drug effects ; Breast Neoplasms/metabolism/pathology/*therapy ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Enzyme Activation ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Microscopy, Fluorescence ; Photosensitizing Agents/*pharmacology ; Protoporphyrins/*pharmacology ; Reactive Oxygen Species/metabolism ; Ultrasonic Therapy/*methods ; }, abstract = {Sonodynamic therapy (SDT) is a promising modality for cancer treatment, involving the synergistic interaction of ultrasound and some chemical compounds termed as sono-sensitizers. It has been found that SDT can lead to apoptotic cell death because of the induction of direct sonochemical and subsequent redox reactions. However, the detailed mechanisms are not clear. This study was to identify the cytotoxic effects of ultrasound-activated protoporphyrin IX (PpIX) on MDA-MB-231 cells. The fluorescence microscope was used to detect the sub-cellular localization of PpIX. Several distinct sonochemical effects were found after SDT treatment, including the decrease of cell viability, generation of intracellular ROS, the loss of mitochondrial membrane potential. The activation of some special apoptosis-associated proteins [Caspase-9, Caspase-3 and polypeptide poly (ADP-robose) polymerase] was evaluated by western blotting. The results show that PpIX mediated SDT (PpIX-SDT) treatment could obviously inhibit the proliferation of MDA-MB-231 cells, and which was significantly reduced by the pan-Caspase inhibitor z-VAD-fmk and the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC). Further, SDT induced a conspicuous loss of mitochondrial membrane potential (MMP) and a mass of ROS accumulation in MDA-MB-231 cells at 1h post-treatment and the SDT-treated cells showed obvious Caspase-3 and Caspase-9 activation, and PARP cleavage at 6h after treatment. And, the general apoptosis marker-Caspase-3 activation-was also greatly relieved by NAC. These findings primarily indicate a Caspase-depended apoptosis could be induced by PpIX-SDT in MDA-MB-231 cells, and the intracellular ROS was involved during the apoptotic process.}, }
@article {pmid22111577, year = {2011}, author = {Festa, M and Capasso, A and D'Acunto, CW and Masullo, M and Rossi, AG and Pizza, C and Piacente, S}, title = {Xanthohumol induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways.}, journal = {Journal of natural products}, volume = {74}, number = {12}, pages = {2505-2513}, doi = {10.1021/np200390x}, pmid = {22111577}, issn = {1520-6025}, support = {G0601481/MRC_/Medical Research Council/United Kingdom ; G0901697/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/drug effects/metabolism ; Caspase 9/drug effects/metabolism ; Cyclohexenes/chemistry/pharmacology ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Flavonoids/chemistry/*pharmacology ; Glioblastoma/drug therapy/*metabolism ; Humans ; Imidazoles/pharmacology ; Italy ; Mitogen-Activated Protein Kinases/*metabolism ; Molecular Structure ; Poly(ADP-ribose) Polymerases/drug effects/metabolism ; Propiophenones/chemistry/*pharmacology ; Pyridines/pharmacology ; Reactive Oxygen Species/analysis/metabolism ; Terpenes/chemistry/pharmacology ; }, abstract = {The effect of the biologically active prenylated chalcone and potential anticancer agent xanthohumol (1) has been investigated on apoptosis of the T98G human malignant glioblastoma cell line. Compound 1 decreased the viability of T98G cells by induction of apoptosis in a time- and concentration-dependent manner. Apoptosis induced by 1 was associated with activation of caspase-3, caspase-9, and PARP cleavage and was mediated by the mitochondrial pathway, as exemplified by mitochondrial depolarization, cytochrome c release, and downregulation of the antiapoptotic Bcl-2 protein. Xanthohumol induced intracellular reactive oxygen species (ROS), an effect that was reduced by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC). Intracellular ROS production appeared essential for the activation of the mitochondrial pathway and induction of apoptosis after exposure to 1. Oxidative stress due to treatment with 1 was associated with MAPK activation, as determined by ERK1/2 and p38 phosphorylation. Phosphorylation of ERK1/2 and p38 was attenuated using NAC to inhibit ROS production. After treatment with 1, ROS provided a specific environment that resulted in MAPK-induced cell death, with this effect reduced by the ERK1/2 specific inhibitor PD98059 and partially inhibited by the p38 inhibitor SB203580. These findings suggest that xanthohumol (1) is a potential chemotherapeutic agent for the treatment of glioblastoma multiforme.}, }
@article {pmid22105918, year = {2012}, author = {Mhaidat, NM and Abdul-Razzak, KK and Alkofahi, AS and Alsarhan, AM and Aldaher, AN and Thorne, RF}, title = {Altholactone induces apoptotic cell death in human colorectal cancer cells.}, journal = {Phytotherapy research : PTR}, volume = {26}, number = {6}, pages = {926-931}, doi = {10.1002/ptr.3666}, pmid = {22105918}, issn = {1099-1573}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; *Apoptosis ; Blotting, Western ; Caspase Inhibitors ; Caspases, Initiator/metabolism ; Cell Death ; Cell Survival/drug effects ; Colorectal Neoplasms/pathology ; Drug Screening Assays, Antitumor ; Enzyme Activation ; Fibroblasts/drug effects ; Furans/*pharmacology ; Goniothalamus/chemistry ; HCT116 Cells ; HT29 Cells ; Humans ; Oxidative Stress ; Propidium/chemistry ; Pyrones/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Tetrazolium Salts/chemistry ; Thiazoles/chemistry ; }, abstract = {Resistance of colorectal cancer (CRC) to the available chemotherapy reveals the demand for identification of new anticancer agents. We evaluated the antitumour potential of altholactone, a naturally occurring bioactive compound isolated from Goniothalamus spp. (Annonaceae) hooks, against CRC cells. Antitumour activity of altholactone was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the propidium iodide method. Apoptosis mediators involved were assessed using biochemical inhibitors and Western blotting analysis. Results revealed that altholactone induced varying degrees of apoptosis in CRC cells but not in normal fibroblasts. Dissection of the altholactone-induced apoptotic signalling pathway revealed that altholactone activated caspase-dependent and -independent apoptotic pathways. Activation of caspase-4 appeared to be the initiating event in the caspase-dependent apoptotic pathway. Pre-treatment of CRC cells with the antioxidant N-acetylcysteine (NAC) significantly inhibited activation of caspase-4 and altholactone-induced apoptosis. These results indicate that altholactone induces selective cytotoxicity against colon carcinoma cells and warrants further clinical evaluation.}, }
@article {pmid22100870, year = {2012}, author = {Akool, el-S and Gauer, S and Osman, B and Doller, A and Schulz, S and Geiger, H and Pfeilschifter, J and Eberhardt, W}, title = {Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and metalloproteinase-dependent EGF-receptor signaling.}, journal = {Biochemical pharmacology}, volume = {83}, number = {2}, pages = {286-295}, doi = {10.1016/j.bcp.2011.11.001}, pmid = {22100870}, issn = {1873-2968}, mesh = {ADAM Proteins/metabolism ; ADAM17 Protein ; Animals ; Cells, Cultured ; Cyclosporine/*pharmacology ; Enzyme Induction/drug effects/physiology ; ErbB Receptors/*physiology ; Humans ; MAP Kinase Signaling System/drug effects/*physiology ; Mesangial Cells/drug effects/enzymology/metabolism ; Metalloproteases/*physiology ; Rats ; Reactive Oxygen Species/*metabolism ; Tacrolimus/*pharmacology ; }, abstract = {We previously demonstrated that the widely used immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (FK506), independent of immunophilin binding, can activate profibrogenic transforming growth factor β (TGFβ)/Smad signaling cascades in rat renal mesangial cells (MC). Here we report that both peptidyl-prolyl cis/trans isomerase (PPIase) inhibitors activate the extracellular-signaling regulated kinase (ERK) a member of the mitogen activated protein kinase (MAPK) and induce a rapid and transient increase in ERK phosphorylation. The MEK inhibitor U0126, the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), a cell-permeant superoxide dismutase (SOD) and stigmatellin, an inhibitor of mitochondrial cytochrome bc1 complex strongly attenuated the increase in ERK1/2 phosphorylation triggered by PPIase inhibitors. Moreover, neutralizing antibodies against heparin binding-epidermal growth factor (HB-EGF), and inhibition of the EGF receptor by either small interfering (si)RNA or AG1478, demonstrate that ERK activation by both PPIase inhibitors is mediated via HB-EGF-induced EGF receptor (EGFR) tyrosine kinase activation. The strong inhibitory effects achieved by GM6001 and TAPI-2 furthermore implicate the involvement of a desintegrin and metalloproteinase 17 (ADAM17). Concomitantly, the PPIase inhibitor-induced ADAM17 secretase activity was significantly reduced by SOD and stigmatellin thus suggesting that mitochondrial ROS play a primary role in PPIase inhibitor-induced and ADAM17-mediated HB-EGF shedding. Functionally, both immunosuppressants caused a strong increase in MC proliferation which was similarly impeded when cells were treated in the presence of NAC, TAPI-2 or AG1478, respectively. Our data suggest that CsA and FK506, via ROS-dependent and ADAM17-catalyzed HB-EGF shedding induce the mitogenic ERK1/2 signaling cascade in renal MC.}, }
@article {pmid22100553, year = {2011}, author = {Guo, XF and Zhao, PX and Wang, H and Zhang, HS}, title = {Simple and rapid determination of thiol compounds by HPLC and fluorescence detection with 1,3,5,7-tetramethyl-8-phenyl-(2-maleimide) difluoroboradiaza-s-indacene.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {879}, number = {32}, pages = {3932-3936}, doi = {10.1016/j.jchromb.2011.10.042}, pmid = {22100553}, issn = {1873-376X}, mesh = {Animals ; Bile/chemistry ; Carps ; Cell Line, Tumor ; Chromatography, High Pressure Liquid/*methods ; Fluorescent Dyes/*chemistry ; Heterocyclic Compounds, 3-Ring/*chemistry ; Humans ; Limit of Detection ; Linear Models ; Liver/chemistry ; Maleimides/*chemistry ; Reproducibility of Results ; Spectrometry, Fluorescence ; Sulfhydryl Compounds/*analysis ; Swine ; }, abstract = {A rapid and simple background-free high-performance liquid chromatographic (HPLC) approach has been developed for simultaneously determining free thiol compounds including coenzyme A (CoA), cysteine (Cys), glutathione (GSH) and N-acetyl-cysteine (NAC) in biological samples by using 1,3,5,7-tetramethyl-8-phenyl-(2-maleimide) difluoroboradiaza-s-indacene (TMPAB-o-M) as fluorogenic reagent. After derivatization under physiological conditions within 6 min, baseline separation was finished in just 6 min using isocratic elution with reversed-phase HPLC and fluorescence detection. Excellent linearity was observed for all analytes over their concentration ranges of 1-500 nM and detection limits ranging 0.13 nM for CoA to 0.25 nM for Cys (S/N=3) were achieved. The utility of the proposed method has been validated by measuring thiol compounds mentioned above in tissue, fluid and cell samples. The results indicated that this approach was well suited for high-throughput quantitative determination of thiols and study of the physiological role of them.}, }
@article {pmid22096601, year = {2011}, author = {Gupta, S and Kruger, WD}, title = {Cystathionine beta-synthase deficiency causes fat loss in mice.}, journal = {PloS one}, volume = {6}, number = {11}, pages = {e27598}, pmid = {22096601}, issn = {1932-6203}, support = {P30 CA006927/CA/NCI NIH HHS/United States ; CA06927/CA/NCI NIH HHS/United States ; HL50299/HL/NHLBI NIH HHS/United States ; }, mesh = {Absorptiometry, Photon ; Acetylcysteine/pharmacology ; Animals ; Blotting, Western ; Body Mass Index ; Body Weight/drug effects/genetics ; Cystathionine beta-Synthase/deficiency/*metabolism ; Cysteine/blood ; Fats/*metabolism ; Female ; Glutathione/metabolism ; Male ; Mice ; Mice, Knockout ; Reverse Transcriptase Polymerase Chain Reaction ; Stearoyl-CoA Desaturase/genetics/metabolism ; }, abstract = {Cystathionine beta synthase (CBS) is the rate-limiting enzyme responsible for the de novo synthesis of cysteine. Patients with CBS deficiency have greatly elevated plasma total homocysteine (tHcy), decreased levels of plasma total cysteine (tCys), and often a marfanoid appearance characterized by thinness and low body-mass index (BMI). Here, we characterize the growth and body mass characteristics of CBS deficient TgI278T Cbs(-/-) mice and show that these animals have significantly decreased fat mass and tCys compared to heterozygous sibling mice. The decrease in fat mass is accompanied by a 34% decrease in liver glutathione (GSH) along with a significant decrease in liver mRNA and protein for the critical fat biosynthesizing enzyme Stearoyl CoA desaturase-1 (Scd-1). Because plasma tCys has been positively associated with fat mass in humans, we tested the hypothesis that decreased tCys in TgI278T Cbs(-/-) mice was the cause of the lean phenotype by placing the animals on water supplemented with N-acetyl cysteine (NAC) from birth to 240 days of age. Although NAC treatment in TgI278T Cbs(-/-) mice caused significant increase in serum tCys and liver GSH, there was no increase in body fat content or in liver Scd-1 levels. Our results show that lack of CBS activity causes loss of fat mass, and that this effect appears to be independent of low serum tCys.}, }
@article {pmid22094553, year = {2011}, author = {Aslam, S and Darouiche, RO}, title = {Role of antibiofilm-antimicrobial agents in controlling device-related infections.}, journal = {The International journal of artificial organs}, volume = {34}, number = {9}, pages = {752-758}, pmid = {22094553}, issn = {1724-6040}, support = {K23 DK078828/DK/NIDDK NIH HHS/United States ; K23 DK078828-01A2/DK/NIDDK NIH HHS/United States ; K23DK078828-01 A2/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Anti-Infective Agents/*pharmacology ; Biofilms/*drug effects/growth &amp; development ; Dose-Response Relationship, Drug ; Drug Resistance, Bacterial ; Gram-Negative Bacteria/*drug effects/growth &amp; development/metabolism ; Gram-Positive Bacteria/*drug effects/growth &amp; development/metabolism ; Microbial Sensitivity Tests ; Microbial Viability/drug effects ; Microscopy, Confocal ; Polysaccharides, Bacterial/metabolism ; Prosthesis-Related Infections/*drug therapy/microbiology ; Time Factors ; }, abstract = {OBJECTIVES: To assess the effects of N-acetylcysteine (NAC) on organism viability in planktonic and biofilm phases, biofilm thickness, and extracellular polysaccharide content.<br><br>METHODS: We performed time-kill curves and broth macrodilution assays of bacterial and fungal clinical isolates with varying concentrations of NAC. We also created in vitro bacterial biofilms, incubated them with NAC or control, and then stained with propidium iodide and FITC-labeled concanavalin A. We measured biofilm thickness, number of non-viable cells, and fluorescent intensity as a marker of extracellular matrix via a confocal laser scanning microscope. All experiments were conducted in triplicate. Tested organisms included methicillin-sensitive and -resistant Staphylococcus aureus (MSSA, MRSA), S. epidermidis, vancomycin-resistant Enterococcus faecalis (VRE), Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella pneumoniae, Candida albicans and C. krusei.<br><br>RESULTS: NAC 80 mg/ml was uniformly bactericidal (>99.9% reduction) against all tested bacteria with no recoverable organisms after 30 minutes of incubation, but was fungistatic against candida species. Minimum inhibitory and bactericidal concentrations of NAC ranged from 5-10 mg/ml. Biofilm thickness was significantly decreased in NAC-treated biofilms for all organisms except VRE. The number of non-viable cells in NAC-treated Gram-positive biofilms was increased (p<0.05 for MRSA and VRE). NAC-treated Gram-negative biofilms had scant cellularity and lacked complex 3-dimensional structures that were characteristic of controls. Fluorescent intensity was similar in the experimental and control arms.<br><br>CONCLUSIONS: NAC is bactericidal against clinically relevant and drug-resistant bacteria and also leads to biofilm disruption. NAC has the potential for use as a novel agent for prevention or treatment of biofilm-related infections.}, }
@article {pmid22094549, year = {2012}, author = {Milara, J and Juan, G and Peiró, T and Serrano, A and Cortijo, J}, title = {Neutrophil activation in severe, early-onset COPD patients versus healthy non-smoker subjects in vitro: effects of antioxidant therapy.}, journal = {Respiration; international review of thoracic diseases}, volume = {83}, number = {2}, pages = {147-158}, doi = {10.1159/000332834}, pmid = {22094549}, issn = {1423-0356}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Case-Control Studies ; Chemotaxis/drug effects ; Female ; Free Radical Scavengers/*pharmacology ; Humans ; Interleukin-8/metabolism ; Leukocyte Elastase/drug effects ; Male ; Middle Aged ; N-Formylmethionine Leucyl-Phenylalanine/*pharmacology ; Neutrophil Activation/*drug effects ; Neutrophils/*drug effects ; Pulmonary Disease, Chronic Obstructive/*physiopathology ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {BACKGROUND: Neutrophils and oxidative stress have been implicated in the pathogenesis of COPD. Severe, early-onset COPD is characterized by a rapid decline in the lung function at an early age; however, nothing is known about neutrophil activation in COPD patients.<br><br>OBJECTIVES: The aim of this study was to evaluate peripheral blood neutrophil activation in severe, early-onset COPD patients versus healthy non-smokers and the effect of N-acetyl-L-cysteine (NAC) on neutrophil activation in vitro.<br><br>METHODS: Neutrophils were isolated from 15 severe, early-onset COPD patients and 15 age-matched healthy subjects and stimulated with N-formyl-Met-Leu-Phe (fMLP) in the presence or absence of NAC (10 &#x3bc;M to 10 mM). Neutrophil chemotaxis, elastase release, reactive oxygen species (ROS), intracellular thiols and apoptosis were measured by Boyden chamber, spectrofluorometry, CMFDA and H2DCF-DA dyes and by annexin V-FITC, respectively.<br><br>RESULTS: Chemotaxis of peripheral blood neutrophils from COPD patients in response to fMLP was 30% more increased than that observed in healthy subjects. Elastase release in response to fMLP was 2-fold higher in neutrophils from COPD patients versus healthy subjects. Intracellular thiol levels were 30% lower in COPD and ROS was approximately 30% higher in COPD versus healthy neutrophils. Spontaneous apoptosis showed no differences in both groups of patients and fMLP-induced apoptosis was higher in COPD. Pre-treatment with the antioxidant NAC effectively attenuated neutrophil chemotaxis, elastase release and ROS as well as effectively increased thiol levels in COPD.<br><br>CONCLUSIONS: Neutrophils in severe, early-onset COPD patients are highly activated and this is alleviated by NAC in vitro.}, }
@article {pmid22094062, year = {2012}, author = {Ahmad, A and Mondello, S and Di Paola, R and Mazzon, E and Esposito, E and Catania, MA and Italiano, D and Mondello, P and Aloisi, C and Cuzzocrea, S}, title = {Protective effect of apocynin, a NADPH-oxidase inhibitor, against contrast-induced nephropathy in the diabetic rats: a comparison with n-acetylcysteine.}, journal = {European journal of pharmacology}, volume = {674}, number = {2-3}, pages = {397-406}, doi = {10.1016/j.ejphar.2011.10.041}, pmid = {22094062}, issn = {1879-0712}, mesh = {Acetophenones/*pharmacology ; Acetylcysteine/*pharmacology ; Acute-Phase Proteins/urine ; Animals ; Apoptosis/drug effects ; Contrast Media/*adverse effects ; Cytosine/metabolism ; Diabetic Nephropathies/*chemically induced/metabolism/pathology/*prevention &amp; control ; Enzyme Activation/drug effects ; Enzyme Inhibitors/*pharmacology ; Glutathione Transferase/urine ; Iopamidol/analogs &amp; derivatives/pharmacology ; Isoenzymes/urine ; Kidney Glomerulus/drug effects/metabolism/pathology ; Lipocalin-2 ; Lipocalins/urine ; Male ; NADPH Oxidases/*antagonists &amp; inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Potassium/blood ; Proto-Oncogene Proteins/urine ; Rats ; Rats, Wistar ; Sodium/blood ; Time Factors ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {The aim of this study was to investigate the effects of apocynin, a NADPH (nicotinamide adenine dinucleotide phosphate)-oxidase inhibitor, in diabetic rats with nephropathy induced by contrast medium (CIN). Diabetes was induced in male Wistar rats by a single dose of streptozotocin (60 mg/kg i.v.). Animals were then divided into the following groups: 1) control group (diabetic rats treated i.v. with saline solution); 2) iomeprol group (iomeprol at 10 ml/kg was injected i.v. 30 min after saline administration); 3) apocynin group (identical to the iomeprol group, except for pre-treatment with apocynin 5mg/kg i.v., 30 min before iomeprol injection) and 4) N-acetylcysteine group (NAC) (same as iomeprol group, except for the treatment with NAC 20 mg/kg i.v. 30 min before iomeprol injection). CIN in animals were assessed 24h after administration of iomeprol. Apocynin significantly attenuates the impaired glomerular function, concentration of Na(+), K(+), alpha glutathione S-transferase levels in urine and neutrophil gelatinase-associated lipocalin levels in plasma caused by iomeprol. In kidney, immunohistochemical analysis of some inflammatory mediators, such as nitrotyrosine, poly-ADP-ribosyl polymerase, tumor necrosis factor-α, interleukin-1β as well as apoptosis (evaluated as terminal deoxynucleotidyltransferase-mediated UTP end labeling assay) revealed positive staining in tissue obtained from iomeprol group. These parameters were markedly reduced in animals treated with apocynin. Similarly, these parameters were also markedly modified by NAC pre-treatment. Here, we have shown that apocynin attenuates the degree of iomeprol-induced nephropathy in diabetic rats.}, }
@article {pmid22093110, year = {2012}, author = {Szczepański, M and Kamianowska, M and Kamianowski, G}, title = {Effects of fluorides on apoptosis and activation of human umbilical vein endothelial cells.}, journal = {Oral diseases}, volume = {18}, number = {3}, pages = {280-284}, doi = {10.1111/j.1601-0825.2011.01873.x}, pmid = {22093110}, issn = {1601-0825}, mesh = {Acetylcysteine/pharmacology ; Annexin A5/drug effects ; Antigens, CD/drug effects ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cariostatic Agents/*pharmacology ; Cell Adhesion Molecules/drug effects ; Cell Culture Techniques ; Cells, Cultured ; Endothelial Cells/*drug effects ; Endothelium, Vascular/cytology/*drug effects ; Enzyme Inhibitors/pharmacology ; Fluorides/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Intercellular Adhesion Molecule-1/drug effects ; Oxidative Stress/drug effects ; Sodium Fluoride/pharmacology ; Tin Fluorides/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; Umbilical Veins/cytology ; }, abstract = {OBJECTIVE: To determine the effects of fluorides on endothelial functioning.<br><br>MATERIALS AND METHODS: We analyzed expressions of adhesion molecules, ICAM-1 and ICAM-3, and annexin V, on the surface of human umbilical vein endothelial cells (HUVECs) exposed to various concentrations of NaF and SnF(2) . We compared the effects of fluoride-induced changes with those obtained when stimulating HUVECs with TNF-&#x3b1; and verified whether N-acetyl cysteine (NAC), well-known antioxidant, can prevent both fluoride- and TNF-&#x3b1;-induced alterations.<br><br>RESULTS: The expressions of annexin V and ICAM-1 increased significantly after adding NaF (5.0 or 7.5mM) or Sn(2) F (0.5 or 0.75mM) to the culture medium. Pre-incubating HUVECs with NAC prevented the effects induced by 5.0 mM of NaF and 0.5 mM of Sn(2) F. Only the highest concentration of NaF (7.5mM) triggered the expression of ICAM-3. The expressions of all three molecules increased significantly upon stimulating the cultures with TNF-&#x3b1; (20ng ml(-1)); these changes were not reversed by pre-incubation with NAC.<br><br>CONCLUSIONS: Fluorides induce oxidative stress, resulting in apoptosis and activation of HUVECs, manifested by an elevated expression of ICAM-1. The oxidative stress resulting from a stimulation by the highest NaF concentration triggers ICAM-3 expression on the HUVECs' surface.}, }
@article {pmid22092168, year = {2011}, author = {Mahmoud, KM and Ammar, AS}, title = {Effect of N-acetylcysteine on cardiac injury and oxidative stress after abdominal aortic aneurysm repair: a randomized controlled trial.}, journal = {Acta anaesthesiologica Scandinavica}, volume = {55}, number = {8}, pages = {1015-1021}, doi = {10.1111/j.1399-6576.2011.02492.x}, pmid = {22092168}, issn = {1399-6576}, mesh = {Acetylcysteine/*therapeutic use ; Adrenergic beta-Antagonists/therapeutic use ; Aged ; Aortic Aneurysm, Abdominal/*surgery ; Bisoprolol/therapeutic use ; Blood Pressure/drug effects ; Body Mass Index ; *Cardiac Surgical Procedures ; Creatine Kinase, MB Form/blood ; Cytokines/blood ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Heart Function Tests ; Heart Injuries/*drug therapy/metabolism ; Heart Rate/drug effects ; Humans ; Male ; Malondialdehyde/blood ; Middle Aged ; Oxidative Stress/*drug effects ; Postoperative Complications/*drug therapy/metabolism ; Treatment Outcome ; Troponin I/blood ; }, abstract = {BACKGROUND: Several studies have reported that the antioxidant properties of N-acetylcysteine (NAC) can provide cardiac protection through scavenging of free radicals. The present study was aimed to assess the efficacy of NAC for cardiac protection in patients undergoing elective abdominal aortic aneurysm (AAA) repair.<br><br>METHODS: Fifty adult patients undergoing (AAA) repair were randomly allocated to receive NAC infusion (n = 25) or placebo infusion (n = 25). NAC infusion in group I (NAC group) was started at a rate of 0.3 mg/kg/min intravenously during surgery then decreased to a rate of 0.2 mg/kg/min for 24 h post-operatively. Group II (placebo group) received an equivalent rate of placebo infusion. The following parameters: myocardial-specific protein troponin-I, creatine phosphokinase-MB (CPK-MB), plasma pro-inflammatory cytokines [tumour necrosis factor-&#x3b1; (TNF-&#x3b1;) and interleukin (IL)-1&#x3b2;], were assessed at the following time points: preoperatively and at 1 h, 12 h, 24 h, 48 h, and 96 h after surgery. Furthermore, serum malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured preoperatively as a baseline, during aortic clamping, 30 min after declamping, at the end of surgery, 2 h after surgery, 12 h after surgery, and 24 h after surgery.<br><br>RESULTS: NAC infusion patients had significantly lower post-operative concentrations of myocardial-specific protein [cTnI, CPK-MB] and pro-inflammatory cytokines [TNF-&#x3b1;, IL-1&#x3b2;]. In addition, MDA level was less and TAC was higher in patients who received NAC infusion.<br><br>CONCLUSION: NAC infusion provided cardiac protection through scavenging of oxygen free radicals.}, }
@article {pmid22090786, year = {2011}, author = {Yang, J and Yang, Y and Tian, L and Sheng, XF and Liu, F and Cao, JG}, title = {Casticin-induced apoptosis involves death receptor 5 upregulation in hepatocellular carcinoma cells.}, journal = {World journal of gastroenterology}, volume = {17}, number = {38}, pages = {4298-4307}, pmid = {22090786}, issn = {2219-2840}, mesh = {Antimetabolites, Antineoplastic/pharmacology/therapeutic use ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/drug therapy/*metabolism/pathology ; Caspases/metabolism ; Cell Line, Tumor ; DNA Fragmentation ; Flavonoids/chemistry/*pharmacology/therapeutic use ; Fluorouracil/pharmacology/therapeutic use ; Glutathione/metabolism ; Humans ; Liver Neoplasms/drug therapy/*metabolism/pathology ; Molecular Structure ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism ; }, abstract = {AIM: To investigate the apoptotic activities of casticin in hepatocellular carcinoma (HCC) cells and its molecular mechanisms.<br><br>METHODS: PLC/PRF/5 and Hep G2 cell lines were cultured in vitro and the inhibitory effect of casticin on the growth of cells was detected by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolim bromide (MTT) assay. The apoptotic cell death was examined using the cell apoptosis enzyme linked immunosorbent assay (ELISA) detection kit, flow cytometry (FCM) after propidium iodide (PI) staining and DNA agarose gel electrophoresis. The caspase activities were measured using ELISA. Reactive oxygen species (ROS) production was evaluated by FCM after dichlorodihydrofluorescein diacetate (DCFH-DA) probe labeling. Intracellular glutathione (GSH) content was measured using a glutathione assay kit. The expression of death receptor (DR)4 and DR5 proteins was analyzed by Western blotting and FCM.<br><br>RESULTS: Casticin significantly inhibited the growth of human HCC (PLC/PRF/5 and Hep G2) cells in a dose-dependent manner (P < 0.05). Casticin increased the percentage of the sub-G1 population in HCC cells in a concentration-dependent manner. The potency of casticin to PLC/PRF/5 cells was higher than that of 5-flurouracil (26.8% &#xb1; 4.8% vs 17.4% &#xb1; 5.1%) at 10 &#x3bc;mol/L for 24 h. Casticin increased the levels of Histone/DNA fragmentation and the levels of active caspase-3, -8 and -9 in a concentration-dependent manner (P < 0.05). Treatment with 30 &#x3bc;mol/L casticin for 24 h resulted in the formation of a DNA ladder. Casticin reduced the GSH content (P < 0.05), but did not affect the level of intracellular ROS in PLC/PRF/5 and Hep G2 cells. The thiol antioxidants, acetylcysteine (NAC) and GSH restored GSH content and attenuated casticin-induced apoptosis. In contrast, the nonthiol antioxidants, butylated hydroxyanisole and mannitol failed to do so. In the HCC cells treated with casticin for 24 h, DR5 protein level was increased. The expression of DR5 protein induced by casticin was inhibited by NAC. Pretreatment with DR5/Fc chimera protein, a blocking antibody, effectively attenuated the induction of apoptosis by casticin.<br><br>CONCLUSION: Casticin-induced apoptosis of HCC cells is involved in GSH depletion and DR5 upregulation.}, }
@article {pmid22089811, year = {2012}, author = {Crutzen, R and Shlyonsky, V and Louchami, K and Virreira, M and Hupkens, E and Boom, A and Sener, A and Malaisse, WJ and Beauwens, R}, title = {Does NAD(P)H oxidase-derived H2O2 participate in hypotonicity-induced insulin release by activating VRAC in β-cells?.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {463}, number = {2}, pages = {377-390}, pmid = {22089811}, issn = {1432-2013}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Glucose/pharmacology ; Hydrogen Peroxide/*metabolism/*pharmacology ; Hypotonic Solutions ; Insulin/*metabolism ; Insulin-Secreting Cells/cytology/*drug effects/*metabolism ; Models, Animal ; NADPH Oxidases/*metabolism ; Nitrobenzoates/pharmacology ; Onium Compounds/pharmacology ; Patch-Clamp Techniques ; Pentacyclic Triterpenes ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Triterpenes/pharmacology ; Voltage-Dependent Anion Channels/*metabolism ; Betulinic Acid ; }, abstract = {NAD(P)H oxidase (NOX)-derived H(2)O(2) was recently proposed to act, in several cells, as the signal mediating the activation of volume-regulated anion channels (VRAC) under a variety of physiological conditions. The present study aims at investigating whether a similar situation prevails in insulin-secreting BRIN-BD11 and rat β-cells. Exogenous H(2)O(2) (100 to 200 μM) at basal glucose concentration (1.1 to 2.8 mM) stimulated insulin secretion. The inhibitor of VRAC, 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) inhibited the secretory response to exogenous H(2)O(2). In patch clamp experiments, exogenous H(2)O(2) was observed to stimulate NPPB-sensitive anion channel activity, which induced cell membrane depolarization. Exposure of the BRIN-BD11 cells to a hypotonic medium caused a detectable increase in intracellular level of reactive oxygen species (ROS) that was abolished by diphenyleneiodonium chloride (DPI), a universal NOX inhibitor. NOX inhibitors such as DPI and plumbagin nearly totally inhibited insulin release provoked by exposure of the BRIN-BD11 cells to a hypotonic medium. Preincubation with two other drugs also abolished hypotonicity-induced insulin release and reduced basal insulin output: 1) N-acetyl-L-cysteine (NAC), a glutathione precursor that serves as general antioxidant and 2) betulinic acid a compound that almost totally abolished NOX4 expression. As NPPB, each of these inhibitors (DPI, plumbagin, preincubation with NAC or betulinic acid) strongly reduced the volume regulatory decrease observed following a hypotonic shock, providing an independent proof that VRAC activation is mediated by H(2)O(2). Taken together, these data suggest that NOX-derived H(2)O(2) plays a key role in the insulin secretory response of BRIN-BD11 and native β-cells to extracellular hypotonicity.}, }
@article {pmid22089305, year = {2011}, author = {Cobley, JN and McGlory, C and Morton, JP and Close, GL}, title = {N-Acetylcysteine's attenuation of fatigue after repeated bouts of intermittent exercise: practical implications for tournament situations.}, journal = {International journal of sport nutrition and exercise metabolism}, volume = {21}, number = {6}, pages = {451-461}, doi = {10.1123/ijsnem.21.6.451}, pmid = {22089305}, issn = {1543-2742}, mesh = {Acetylcysteine/adverse effects/*pharmacology/therapeutic use ; Adaptation, Physiological ; Adult ; Antioxidants/adverse effects/*pharmacology/therapeutic use ; Athletic Performance/*physiology ; Creatine Kinase/blood ; Dietary Supplements ; Double-Blind Method ; Exercise/*physiology ; Exercise Test ; Fatigue/drug therapy ; Gastrointestinal Diseases/etiology ; Humans ; Male ; Muscle Contraction/*drug effects/physiology ; Muscle Fatigue/*drug effects/physiology ; Muscle, Skeletal/*drug effects/physiology ; Young Adult ; }, abstract = {Production of reactive oxygen species (ROS) during muscle contractions is associated with muscle fatigue and damage in the short term and adaptive responses in the long term. When adaptation is inconsequential acute antioxidant supplementation may be able to attenuate muscle fatigue and damage to enhance performance. This study aimed to determine the effects of acute oral N-acetylcysteine (NAC) supplementation on Yo-Yo Intermittent Recovery Test Level 1 (YIRT-L1) performance after repeated bouts of damaging intermittent exercise. In a pair-matched design, 12 recreationally trained men engaged in 6 d of either NAC (n = 6) or placebo (n = 6) supplementation. After a treatment-loading day, participants completed 3 testing sessions, on alternating days, consisting of a preexercise isokinetic dynamometry (IKD) test, a damaging intermittent-exercise protocol, YIRT-L1, and a postexercise IKD test. Another IKD test was completed on the 2 intervening d. NAC treatment resulted in a significant preservation of YIRT-L1 performance (p ≤ .0005). IKD performance significantly deteriorated over time at all contraction speeds, and this deterioration was not influenced by treatment group. Plasma creatine kinase values increased significantly over time (p = .002) and were significantly greater in the NAC group than in the placebo group (p = .029). NAC induced mild gastrointestinal side effects. NAC supplementation may be a useful strategy to enhance performance during short-term competitive situations when adaption is inconsequential. Titration studies to elucidate a treatment dose that enhances performance without inducing side effects are now required.}, }
@article {pmid22085843, year = {2012}, author = {Wu, CC and Yen, CC and Lee, kI and Su, CC and Tang, FC and Chen, KL and Su, YC and Chen, YW}, title = {Involvement of oxidative stress-induced ERK/JNK activation in the Cu(2+)/pyrrolidine dithiocarbamate complex-triggered mitochondria-regulated apoptosis in pancreatic β-cells.}, journal = {Toxicology letters}, volume = {208}, number = {3}, pages = {275-285}, doi = {10.1016/j.toxlet.2011.10.022}, pmid = {22085843}, issn = {1879-3169}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line ; Cell Survival/drug effects ; Copper/*toxicity ; Diabetes Mellitus/*metabolism/pathology ; Enzyme Activation ; Flow Cytometry ; Glutathione/metabolism ; Insulin-Secreting Cells/*drug effects/metabolism/pathology ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Oxidative Stress/drug effects/*physiology ; Pyrrolidines/*toxicity ; RNA, Small Interfering/pharmacology ; Rats ; Thiocarbamates/*toxicity ; }, abstract = {Oxidative stress was demonstrated to promote the progression of diabetes mellitus (DM). It has been suggested that copper may play a specific role in the progression and pathogenesis of DM. Pyrrolidine dithiocarbamate (PDTC), a widely apply to the medicine, was known to be capable of enhancing copper accumulation. In this study, we investigated the effect of submicromolar-concentration Cu(2+)/PDTC complex on pancreatic β-cell damage and evaluated the role of oxidative stress in this effect. CuCl(2) (0.01-300μM) did not affect the cell viability in β-cell line RIN-m5F cells. However, combination of CuCl(2) (0.5μM) and PDTC (0.3μM) markedly reduced RIN-m5F cell viability. Cu(2+)/PDTC complex could also increase the LPO and decrease the intracellular reduced GSH levels, and display several features of apoptosis signals including: increase in sub-G1 cell population, annexin-V binding, and caspase-3 activity, mitochondrial dysfunctions, and the activation of PARP and caspase cascades, which accompanied with the marked increase the intracellular Cu(2+) levels. These apoptotic-related responses of Cu(2+)/PDTC complex-induced could be effectively prevented by antioxidant N-acetylcysteine (NAC). Furthermore, Cu(2+)/PDTC complex was capable of increasing the phosphorylations of ERK1/2 and JNK, and its upstream kinase MEK1/2 and MKK4, which could be reversed by NAC. Transfection with ERK2- and JNK-specific si-RNA and specific inhibitors SP600125 and PD98059 could inhibit ERK1/2 and JNK activation and attenuate MMP loss and caspase-3 activity induced by the Cu(2+)/PDTC complex. Taken together, these results are the first report to demonstrate that the Cu(2+)/PDTC complex triggers a mitochondria-regulated apoptosis via an oxidative stress-induced ERK/JNK activation-related pathway in pancreatic β-cells.}, }
@article {pmid22085531, year = {2012}, author = {Meng, N and Zhao, J and Su, L and Zhao, B and Zhang, Y and Zhang, S and Miao, J}, title = {A butyrolactone derivative suppressed lipopolysaccharide-induced autophagic injury through inhibiting the autoregulatory loop of p8 and p53 in vascular endothelial cells.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {44}, number = {2}, pages = {311-319}, doi = {10.1016/j.biocel.2011.11.001}, pmid = {22085531}, issn = {1878-5875}, mesh = {4-Butyrolactone/*analogs &amp; derivatives/chemistry/pharmacology ; Acetylcysteine/pharmacology ; Apoptosis/drug effects ; *Autophagy/drug effects ; Basic Helix-Loop-Helix Transcription Factors/*metabolism ; Endothelial Cells/*drug effects/metabolism ; Endothelium, Vascular/cytology/*drug effects/metabolism ; Homeostasis/drug effects ; Humans ; Lipopolysaccharides/toxicity ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism/pharmacology ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Lipopolysaccharide (LPS)-induced vascular endothelial cell (VEC) dysfunction is an important contributing factor in vascular diseases. Recently, we found that LPS impaired VEC by inducing autophagy. Our previous researches showed that a butyrolactone derivative, 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) selectively protected VEC function. The objective of the present study is to investigate whether and how 3BDO inhibits LPS-induced VEC autophagic injury. Our results showed that LPS induced autophagy and led to increase of reactive oxygen species (ROS) and decrease of mitochondrial membrane potential (MMP) in Human umbilical vein vascular endothelial cells (HUVECs). Furthermore, LPS significantly increased p8 and p53 protein levels and the nuclear translocation of p53. All of these effects of LPS on HUVECs were strongly inhibited by 3BDO. Importantly, the ROS scavenger N-acetylcysteine (NAC) could inhibited LPS-induced autophagy and knockdown of p8 by RNA interference inhibited the autophagy, p53 protein level increase, the translocation of p53 into nuclei and the ROS level increase induced by LPS in HUVECs. The data suggested that 3BDO inhibited LPS-induced autophagy in HUVECs through inhibiting the ROS overproduction, the increase of p8 and p53 expression and the nuclear translocation of p53. Our findings provide a potential tool for understanding the mechanism underlying LPS-induced autophagy in HUVECs and open the door to a novel therapeutic drug for LPS-induced vascular diseases.}, }
@article {pmid22080809, year = {2011}, author = {Wang, H and Lin, W and Shen, G and Khor, TO and Nomeir, AA and Kong, AN}, title = {Development and validation of an LC-MS-MS method for the simultaneous determination of sulforaphane and its metabolites in rat plasma and its application in pharmacokinetic studies.}, journal = {Journal of chromatographic science}, volume = {49}, number = {10}, pages = {801-806}, doi = {10.1093/chrsci/49.10.801}, pmid = {22080809}, issn = {1945-239X}, support = {P30 ES005022/ES/NIEHS NIH HHS/United States ; R01-CA073674/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Chromatography, Liquid/*methods ; Drug Stability ; Isothiocyanates/blood ; Least-Squares Analysis ; Male ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Sensitivity and Specificity ; Sulfoxides ; Tandem Mass Spectrometry/*methods ; Thiocyanates/*blood/pharmacokinetics ; }, abstract = {A highly sensitive and simple high-performance liquid chromatographic-tandem mass spectrometric (LC-MS-MS) assay is developed and validated for the quantification of sulforaphane and its metabolites in rat plasma. Sulforaphane (SFN) and its metabolites, sulforaphane glutathione (SFN-GSH) and sulforaphane N-acetyl cysteine (SFN-NAC) conjugates, are extracted from rat plasma by methanol-formic acid (100:0.1, v/v) and analyzed using a reversed-phase gradient elution on a Develosil 3 μm RP-Aqueous C(30) 140Å column. A 15-min linear gradient with acetonitrile-water (5:95, v/v), containing 10 mM ammonium acetate and 0.2% formic acid, as mobile phase A, and acetonitrile-water (95:5, v/v), containing 10 mM ammonium acetate and 0.2% formic acid as mobile phase B, is used. Sulforaphane and its metabolites are well separated. Sulforaphene is used as the internal standard. The lower limits of quantification are 1 ng/mL for SFN and 10 ng/mL for both SFN-NAC and SFN-GSH. The calibration curves are linear over the concentration range of 25-20,000 ng/mL of plasma for each analyte. This novel LC-MS-MS method shows satisfactory accuracy and precision and is sufficiently sensitive for the performance of pharmacokinetic studies in rats.}, }
@article {pmid22079975, year = {2012}, author = {Park, C and Jin, CY and Hwang, HJ and Kim, GY and Jung, JH and Kim, WJ and Yoo, YH and Choi, YH}, title = {J7, a methyl jasmonate derivative, enhances TRAIL-mediated apoptosis through up-regulation of reactive oxygen species generation in human hepatoma HepG2 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {26}, number = {1}, pages = {86-93}, doi = {10.1016/j.tiv.2011.10.016}, pmid = {22079975}, issn = {1879-3177}, mesh = {Acetates/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular ; Caspases/metabolism ; Cell Line, Tumor ; Cyclopentanes/*pharmacology ; Humans ; Inhibitor of Apoptosis Proteins/metabolism ; Liver Neoplasms ; Oxylipins/*pharmacology ; Reactive Oxygen Species/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; Up-Regulation ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; bcl-X Protein/metabolism ; }, abstract = {The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO2L), a member of the TNF gene superfamily, induces apoptosis upon engagement of cognate death receptors. While TRAIL is relatively non-toxic to normal cells, it selectively induces apoptosis in many transformed cells. Nevertheless, some human hepatoma cells are particularly resistant to the effects of TRAIL. In this study, we show that J7, a novel methyl jasmonate analogue, sensitizes TRAIL-resistant HepG2 human hepatocarcinoma cells to TRAIL-mediated apoptosis. Our results indicate that J7 substantially enhances TRAIL-induced apoptosis, compared with treatment with either agent alone. Combined treatment with J7 and TRAIL effectively induced Bid cleavage, down-regulation of XIAP, cIAP-1 and Bcl-xL, activation of caspases, and cleavage of poly(ADP-ribose) polymerase and phopholipase γ-1. In addition, generation of reactive oxygen species (ROS) showed a significant increase in cells following exposure to J7 in a time-dependent manner. However, the cytotoxic effects induced by co-treatment with J7 and TRAIL were markedly attenuated by caspase inhibitors, indicating an important role for caspases. Administration of N-acetyl cysteine, a scavenger of ROS, also resulted in significant inhibition of apoptosis induced by combinatory treatment with J7 and TRAIL. These results support a mechanism whereby J7 plus TRAIL induces apoptosis of HepG2 human hepatoma cells through a signaling cascade involving a ROS-mediated caspase pathway.}, }
@article {pmid22078209, year = {2012}, author = {Nadeau, PJ and Roy, A and Gervais-St-Amour, C and Marcotte, M&#xc8; and Dussault, N and Néron, S}, title = {Modulation of CD40-activated B lymphocytes by N-acetylcysteine involves decreased phosphorylation of STAT3.}, journal = {Molecular immunology}, volume = {49}, number = {4}, pages = {582-592}, doi = {10.1016/j.molimm.2011.10.007}, pmid = {22078209}, issn = {1872-9142}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; B-Lymphocytes/*drug effects/immunology/*metabolism ; CD40 Antigens/*blood/immunology ; CD40 Ligand/immunology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Chromans/immunology/pharmacology ; Homeostasis/drug effects ; Humans ; Immunoglobulins/immunology/metabolism ; Lymphocyte Activation/drug effects/immunology ; Oxidation-Reduction/drug effects ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/antagonists &amp; inhibitors/*metabolism ; Signal Transduction/drug effects ; }, abstract = {B lymphocyte activation, maturation and reshaping require the interaction of its receptor CD40 with its ligand CD154, which is expressed on activated T lymphocytes. Metabolism in activated B lymphocytes is also characterized with several REDOX changes including fluctuation of Reactive Oxygen Species (ROS). Herein, we first confirm that stimulation of human peripheral blood B lymphocyte with CD154 increases intracellular ROS level. Then, by treatments with two well-known antioxidants, N-acetylcysteine (NAC) and Trolox, we further investigate the influence of REDOX fluctuation in CD40-activated B lymphocyte homeostasis in long term culture (13 days). Treatments with NAC increase viability, decrease proliferation and Ig secretion and enhance homoaggregation of B lymphocytes while Trolox only induces a marginal increase of their Ig secretion. The NAC-induced homoaggregation phenotype is paralleled with increased expressions of CD54, CD11a, CD27 and CD38. Mechanistically, a 24h exposure of B lymphocytes with NAC is sufficient to show strong inhibition of STAT3 phosphorylation. Besides, the treatment of B lymphocytes with the STAT3 inhibitor VI increases viability and decreases proliferation and secretion as in NAC-treated cells thus showing a role for STAT3 in these NAC-induced phenotypes. This study done in a human-based model provides new findings on how REDOX fluctuations may modulate CD40-activated B lymphocytes during immune response and provide additional hints on NAC its immunomodulatory functions.}, }
@article {pmid22076894, year = {2011}, author = {Ellouze, O and Frikha, N and Ouerghi, S and Mestiri, T and Salah Ben Ammar, M}, title = {[N-acetylcysteine in septic shock].}, journal = {La Tunisie medicale}, volume = {89}, number = {10}, pages = {738-744}, pmid = {22076894}, issn = {0041-4131}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Free Radical Scavengers/pharmacology/*therapeutic use ; Humans ; Shock, Septic/*drug therapy/physiopathology ; }, abstract = {AIM: To focus on the various studies evaluating the effects of Nacetylcysteine in septic shock<br><br>METHODS: Main references obtained from the medical database Medline using the keywords: N-acetylcysteine; septic shock, free radicals.<br><br>RESULTS: Septic shock remains the leading cause of mortality in intensive care units. The progressive knowledge of the pathophysiology of septic shock, underline the production of free radicals and their cellular and microcirculatory effects. The Nacetylcysteine used mainly in paracetamol poisoning, has properties to control free radicals. The explosion of free radicals in septic shock has led to multiple studies assessing the role of N-acetylcysteine as an anti radical, and for its anti inflammatory action.<br><br>CONCLUSION: NAC seems to play an important role in septic shock to control free radicals and the inflammatory response. But these results remain contradictory. Some larger and more standardized studies should allow to evaluate the actual effects of NAC in septic shock.}, }
@article {pmid22076161, year = {2011}, author = {Ambruosi, B and Uranio, MF and Sardanelli, AM and Pocar, P and Martino, NA and Paternoster, MS and Amati, F and Dell'Aquila, ME}, title = {In vitro acute exposure to DEHP affects oocyte meiotic maturation, energy and oxidative stress parameters in a large animal model.}, journal = {PloS one}, volume = {6}, number = {11}, pages = {e27452}, pmid = {22076161}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Cells, Cultured ; Cumulus Cells/cytology/drug effects/metabolism ; Cytoplasm/drug effects/metabolism ; Diethylhexyl Phthalate/*toxicity ; Female ; Free Radical Scavengers/pharmacology ; Horses ; Meiosis/*drug effects ; Mitochondria/*drug effects/metabolism ; Models, Animal ; Oocytes/*cytology/*drug effects/metabolism ; Oogenesis/drug effects ; Ovarian Follicle/cytology/drug effects/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Plasticizers/toxicity ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Phthalates are ubiquitous environmental contaminants because of their use in plastics and other common consumer products. Di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate and it impairs fertility by acting as an endocrine disruptor. The aim of the present study was to analyze the effects of in vitro acute exposure to DEHP on oocyte maturation, energy and oxidative status in the horse, a large animal model. Cumulus cell (CC) apoptosis and oxidative status were also investigated. Cumulus-oocyte complexes from the ovaries of slaughtered mares were cultured in vitro in presence of 0.12, 12 and 1200 µM DEHP. After in vitro maturation (IVM), CCs were removed and evaluated for apoptosis (cytological assessment and TUNEL) and intracellular reactive oxygen species (ROS) levels. Oocytes were evaluated for nuclear chromatin configuration. Matured (Metaphase II stage; MII) oocytes were further evaluated for cytoplasmic energy and oxidative parameters. DEHP significantly inhibited oocyte maturation when added at low doses (0.12 µM; P<0.05). This effect was related to increased CC apoptosis (P<0.001) and reduced ROS levels (P<0.0001). At higher doses (12 and 1200 µM), DEHP induced apoptosis (P<0.0001) and ROS increase (P<0.0001) in CCs without affecting oocyte maturation. In DEHP-exposed MII oocytes, mitochondrial distribution patterns, apparent energy status (MitoTracker fluorescence intensity), intracellular ROS localization and levels, mt/ROS colocalization and total SOD activity did not vary, whereas increased ATP content (P<0.05), possibly of glycolytic origin, was found. Co-treatment with N-Acetyl-Cysteine reversed apoptosis and efficiently scavenged excessive ROS in DEHP-treated CCs without enhancing oocyte maturation. In conclusion, acute in vitro exposure to DEHP inhibits equine oocyte maturation without altering ooplasmic energy and oxidative stress parameters in matured oocytes which retain the potential to be fertilized and develop into embryos even though further studies are necessary to confirm this possibility.}, }
@article {pmid22072928, year = {2011}, author = {Calzadilla, P and Sapochnik, D and Cosentino, S and Diz, V and Dicelio, L and Calvo, JC and Guerra, LN}, title = {N-acetylcysteine reduces markers of differentiation in 3T3-L1 adipocytes.}, journal = {International journal of molecular sciences}, volume = {12}, number = {10}, pages = {6936-6951}, pmid = {22072928}, issn = {1422-0067}, mesh = {3T3-L1 Cells ; Acetylcysteine/*metabolism ; Adipocytes/cytology/metabolism ; Animals ; Biomarkers/*metabolism ; CCAAT-Enhancer-Binding Protein-beta/metabolism ; Cell Differentiation ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Mice ; PPAR gamma/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Triglycerides/metabolism ; }, abstract = {Oxidative stress plays a critical role in the pathogenesis of diabetes, hypertension and atherosclerosis. Some authors reported that fat accumulation correlates to systemic oxidative stress in humans and mice, but the relationship of lipid production and oxidative metabolism is still unclear. In our laboratory we used 3T3-L1 preadipocytes, which are able to differentiate into mature adipocytes and accumulate lipids, as obesity model. We showed that intracellular reactive oxygen species (ROS) and antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities increased in parallel with fat accumulation. Meanwhile N-acetylcysteine (NAC), a well known antioxidant and Glutathione (GSH) precursor, inhibited ROS levels as well as fat accumulation in a concentration-dependent manner. NAC also inhibited both adipogenic transcription factors CCAAT/enhancer binding protein beta (C/EBP β) and peroxisomal proliferator activated receptor gamma (PPAR γ) expression; we suggested that intracellular GSH content could be responsible for these effects.}, }
@article {pmid22072853, year = {2011}, author = {Asl, SM and Sivandzadeh, GR}, title = {Efficacy of premedication with activated Dimethicone or N-acetylcysteine in improving visibility during upper endoscopy.}, journal = {World journal of gastroenterology}, volume = {17}, number = {37}, pages = {4213-4217}, pmid = {22072853}, issn = {2219-2840}, mesh = {*Acetylcysteine ; Adult ; Aged ; *Dimethylpolysiloxanes ; Double-Blind Method ; Female ; Gastroscopy/*methods ; Humans ; Male ; Middle Aged ; Placebos ; *Premedication ; }, abstract = {AIM: To assess the efficacy of N-acetylcysteine (NAC) and activated Dimethicone in improving endoscopic mucosal visibility.<br><br>METHODS: A total of 148 patients were randomly allocated into four groups to receive one of the following premedications: group A: 100 mL water alone; group B: activated Dimethicone plus water (up to 100 mL); group C: NAC plus water (up to 100 mL); and group D: activated Dimethicone and NAC plus water (up to 100 mL). A single endoscopist blinded to the patients group assessed the gastric mucosal visibility scores (range 1-4) at four sites. The sum of the scores from the four sites was considered as the total mucosal visibility score (TMVS).<br><br>RESULTS: The patients in group B showed a significantly lower TMVS than those of groups A and C (P < 0.001). The TMVS in patients of group D was significantly lower than that of groups A and C (P < 0.001). The TMVS did not significantly differ between groups B and D (P > 0.05). The difference between TMVS of groups C and A was not significant (P > 0.05).<br><br>CONCLUSION: Premedication with activated Dimethicone 20 min prior to the upper endoscopy leads to the best visibility. NAC does not improve visualization by itself.}, }
@article {pmid22070475, year = {2011}, author = {Nguyen-Khac, E and Thevenot, T and Piquet, MA and Benferhat, S and Goria, O and Chatelain, D and Tramier, B and Dewaele, F and Ghrib, S and Rudler, M and Carbonell, N and Tossou, H and Bental, A and Bernard-Chabert, B and Dupas, JL and , }, title = {Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis.}, journal = {The New England journal of medicine}, volume = {365}, number = {19}, pages = {1781-1789}, doi = {10.1056/NEJMoa1101214}, pmid = {22070475}, issn = {1533-4406}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Antioxidants/adverse effects/*therapeutic use ; Bilirubin/blood ; Cause of Death ; Drug Therapy, Combination ; Female ; Glucocorticoids/adverse effects/*therapeutic use ; Hepatitis, Alcoholic/*drug therapy/mortality ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Prednisolone/adverse effects/*therapeutic use ; Risk Factors ; }, abstract = {BACKGROUND: Mortality among patients with severe acute alcoholic hepatitis is high, even among those treated with glucocorticoids. We investigated whether combination therapy with glucocorticoids plus N-acetylcysteine would improve survival.<br><br>METHODS: We randomly assigned 174 patients to receive prednisolone plus N-acetylcysteine (85 patients) or only prednisolone (89 patients). All patients received 4 weeks of prednisolone. The prednisolone-N-acetylcysteine group received intravenous N-acetylcysteine on day 1 (at a dose of 150, 50, and 100 mg per kilogram of body weight in 250, 500, and 1000 ml of 5% glucose solution over a period of 30 minutes, 4 hours, and 16 hours, respectively) and on days 2 through 5 (100 mg per kilogram per day in 1000 ml of 5% glucose solution). The prednisolone-only group received an infusion in 1000 ml of 5% glucose solution per day on days 1 through 5. The primary outcome was 6-month survival. Secondary outcomes included survival at 1 and 3 months, hepatitis complications, adverse events related to N-acetylcysteine use, and changes in bilirubin levels on days 7 and 14.<br><br>RESULTS: Mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (27% vs. 38%, P = 0.07). Mortality was significantly lower at 1 month (8% vs. 24%, P = 0.006) but not at 3 months (22% vs. 34%, P = 0.06). Death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (9% vs. 22%, P = 0.02). In a multivariate analysis, factors associated with 6-month survival were a younger age (P<0.001), a shorter prothrombin time (P<0.001), a lower level of bilirubin at baseline (P<0.001), and a decrease in bilirubin on day 14 (P<0.001). Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group (P = 0.001); other side effects were similar in the two groups.<br><br>CONCLUSIONS: Although combination therapy with prednisolone plus N-acetylcysteine increased 1-month survival among patients with severe acute alcoholic hepatitis, 6-month survival, the primary outcome, was not improved. (Funded by Programme Hospitalier de Recherche Clinique; AAH-NAC ClinicalTrials.gov number, NCT00863785 .).}, }
@article {pmid22065919, year = {2011}, author = {Yi, K and Chung, TY and Hyon, JY and Koh, JW and Wee, WR and Shin, YJ}, title = {Combined treatment with antioxidants and immunosuppressants on cytokine release by human peripheral blood mononuclear cells - chemically injured keratocyte reaction.}, journal = {Molecular vision}, volume = {17}, number = {}, pages = {2665-2671}, pmid = {22065919}, issn = {1090-0535}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Burns, Chemical/*drug therapy/immunology/metabolism ; Cells, Cultured ; Coculture Techniques ; Cornea/*drug effects/immunology ; Corneal Injuries ; Corneal Keratocytes/*drug effects/metabolism/pathology ; Dexamethasone/pharmacology ; Drug Combinations ; Humans ; Immunosuppressive Agents/*pharmacology ; Interleukin-6/biosynthesis ; Intramolecular Oxidoreductases/biosynthesis ; Leukocytes, Mononuclear/*drug effects/immunology/metabolism ; Macrophage Migration-Inhibitory Factors/biosynthesis ; Matrix Metalloproteinase 9/biosynthesis ; Mycophenolic Acid/pharmacology ; Sirolimus/pharmacology ; Sodium Hydroxide/*adverse effects ; Thioctic Acid/pharmacology ; Transforming Growth Factor beta1/biosynthesis ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {PURPOSE: To investigate the effect of antioxidants and immunosuppresants on mixed peripheral blood mononuclear cells (PBMC) - chemically injured keratocytes reaction (MLKR).<br><br>METHODS: The PBMC stimulation assay was performed using chemically injured keratocytes treated with 0.05 N NaOH for 90 s (MLKR). MLKR were treated with various drugs including rapamycin, dexamethasone, mycophenoleic acid (MPA), alpha lipoic acid (ALA), and N-acetyl cysteine (NAC). Matrix metalloprotease-9 (MMP-9), transforming growth factor-beta 1 (TGF-&#x3b2;1), interleukin-6 (IL-6), and macrophage migration inhibitory factor (MIF) secretion profiles of activated PBMCs stimulated by NaOH-treated keratocytes were determined by ELISA.<br><br>RESULTS: Anti-oxidants as well as immunosuppressants suppressed PBMC proliferation. MMP-9 levels were lower in antioxidants group. IL-6 levels decreased in dexamethasone group and anti-oxidants group. Combination of immunosuppressants and antioxidants suppressed more PBMC proliferation except for rapamycin + ALA group, suppressed MMP-9 production except for MPA + ALA group, decreased IL-6 levels and increased MIF levels except for rapamycin + ALA group. TGF-&#x3b2;1 levels were elevated in rapamycin group and rapamycin + ALA group.<br><br>CONCLUSIONS: Cytokine production was different depending on combination of drugs.Our results suggest that the different drugs should be selected for treatment according to the phases of corneal chemical burn.}, }
@article {pmid22065904, year = {2011}, author = {Lee, YJ and Lee, SH}, title = {Sulforaphane induces antioxidative and antiproliferative responses by generating reactive oxygen species in human bronchial epithelial BEAS-2B cells.}, journal = {Journal of Korean medical science}, volume = {26}, number = {11}, pages = {1474-1482}, pmid = {22065904}, issn = {1598-6357}, mesh = {Acetylcysteine/pharmacology ; Anticarcinogenic Agents/pharmacology ; Antioxidants/*pharmacology ; Bronchi/cytology/*drug effects/metabolism ; Cell Line ; Cell Proliferation/*drug effects ; Epithelial Cells/drug effects/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Free Radical Scavengers/pharmacology ; Heme Oxygenase-1/biosynthesis ; Humans ; Isothiocyanates ; NF-E2-Related Factor 2/biosynthesis/genetics ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; Respiratory Mucosa/cytology/*drug effects/metabolism ; Signal Transduction/drug effects ; Sulfoxides ; Thiocyanates/*pharmacology ; }, abstract = {Sulforaphane (SFN) is a naturally occurring compound which is known to induce the phase II antioxidant genes via Nrf2 activation, although the underlying mechanism has not been fully elucidated. In this study, we investigated Nrf2 induction in response to SFN in human bronchial epithelial BEAS-2B cells and determined the signaling pathways involved in this process. SFN treatment reduced cell viability. Prior to cell death, intracellular reactive oxygen species (ROS) were generated at a high rate within a minute of commencing SFN treatment. Pretreatment with antioxidant N-acetylcysteine (NAC) blocked SFN-induced decrease in cell growth. Erk1/2 was activated within 30 min of SFN addition, whereas Akt phosphorylation did not significantly change until the first 8 hr after SFN treatment but then became substantially low until 48 hr. Inhibition of Erk1/2 phosphorylation attenuated SFN-induced loss of cell viability. Nrf2 protein levels in both nuclear and whole cell lysates were increased by SFN treatment, which was dependent on ROS production. Knockdown of Nrf2 with siRNA attenuated SFN-induced heme oxygenase-1 (HO-1) up-regulation. Induction of the Nrf2/HO-1 after SFN treatment was potently suppressed by pretreatment with NAC. Overall, our results indicate that SFN mediates antioxidative and antiproliferative responses by generating ROS in BEAS-2B cells.}, }
@article {pmid22065336, year = {2012}, author = {Lu, Y and Bao, X and Sun, T and Xu, J and Zheng, W and Shen, P}, title = {Triptolide attenuate the oxidative stress induced by LPS/D-GalN in mice.}, journal = {Journal of cellular biochemistry}, volume = {113}, number = {3}, pages = {1022-1033}, doi = {10.1002/jcb.23434}, pmid = {22065336}, issn = {1097-4644}, mesh = {Animals ; Antioxidants/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy/metabolism/pathology ; Diterpenes/*therapeutic use ; Epoxy Compounds/therapeutic use ; Galactosamine ; Lipopolysaccharides ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/*drug effects ; Phenanthrenes/*therapeutic use ; Proteomics ; Reactive Oxygen Species/metabolism ; }, abstract = {Triptolide, a diterpene triepoxide, is one of the major components of most functional extracts of Tripterygium wilfordii Hook f, which is known to have various biological effects, including immunosuppressive, anti-inflammatory and anti-tumor functions. We studied the inhibitory effect of triptolide on endotoxemia (ETM)-induced oxidative stress, which was induced in C57BL/6 mice by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Pretreatment with triptolide decreased the reactive oxygen species (ROS) levels, mortality rate and liver injury after LPS/D-GalN injection. We utilized comprehensive proteomics to identify alterations in liver protein expression during pretreatment with triptolide or N-acetylcysteine (NAC) after LPS/D-GalN injection, 44 proteins were found to be related to oxidative stress, mitochondria, metabolism and signal transduction, and 23 proteins of them seemed to be significantly up- or down-regulated. Furthermore, both triptolide and NAC inhibited activation of c-jun NH2-terminal kinases (JNK) and mitogen-activated protein kinase p38 (p38), phosphorylation of inhibitor of nuclear factor-kappa B (IκB) and activation of nuclear factor-κB (NF-κB). These results demonstrated that triptolide inhibited the activation of JNK and p38 by decreasing ROS levels, which in turn inhibited the hepatic injury. In addition, we set and validated the phosphorylation model of extracellular signal-regulated kinase (ERK) and proposed that triptolide probably induced ERK phosphorylation through inhibiting its dephosphorylation rates. These results showed that triptolide can effectively reduce the oxidative stress and partially rescue the damage in the liver induced by LPS/D-GalN.}, }
@article {pmid22063193, year = {2011}, author = {Gao, S and Yuan, K and Shah, A and Kim, JS and Park, WH and Kim, SH}, title = {Suppression of high pacing-induced ANP secretion by antioxidants in isolated rat atria.}, journal = {Peptides}, volume = {32}, number = {12}, pages = {2467-2473}, doi = {10.1016/j.peptides.2011.10.022}, pmid = {22063193}, issn = {1873-5169}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Atrial Function/drug effects ; Atrial Natriuretic Factor/*metabolism ; Blood Pressure ; Cardiac Pacing, Artificial ; Cyclic N-Oxides/pharmacology ; Diabetes Mellitus, Experimental/metabolism ; Electric Stimulation ; Enzyme Activation ; Extracellular Fluid/metabolism ; Heart Atria/drug effects/*metabolism ; Hemodynamics ; Hydrogen Peroxide/pharmacology ; In Vitro Techniques ; Male ; Myocardial Contraction/drug effects ; NADPH Oxidase 4 ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Pyrogallol/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/pharmacology ; Spin Labels ; Thioctic Acid/pharmacology ; }, abstract = {Reactive oxygen species (ROS) are formed as a natural by-product of the normal metabolism of oxygen and have important roles in cell signaling. The aim of this study was to investigate direct effects of ROS on atrial hemodynamics and ANP secretion in isolated perfused beating rat atria with antioxidants. When atria were paced at 1.2 Hz, N-acetyl cystein (antioxidant, NAC), α-lipoic acid (antioxidant), tempol (superoxide dismutase mimic), and apocynin (NADPH oxidase inhibitor; NOX inhibitor) did not affect ANP secretion and atrial contractility. When pacing frequency was increased from 1.2 Hz to 4 Hz, the ANP secretion increased and atrial contractility decreased. H(2)O(2) level was increased in perfusate obtained from atria stimulated by high pacing frequency. NAC, α-lipoic acid and tempol attenuated high pacing frequency-induced ANP secretion but apocynin did not. In contrast, pyrogallol (a superoxide generator) augmented high pacing frequency-induced ANP secretion. NOX-4 protein was increased by high pacing stimulation and in diabetic rat atria. In diabetic rat atria, high pacing frequency caused an increased ANP secretion and a decreased atrial contractility, that were markedly attenuated as compared to control rats. NAC and apocynin reduced high pacing frequency-induced ANP secretion in diabetic rat atria. These results suggest that intracellular ROS formation partly through an increasing NOX activity in response to high pacing frequency is associated with an increased ANP secretion in rat atria.}, }
@article {pmid22060290, year = {2011}, author = {Lin, CP and Huang, PH and Tsai, HS and Wu, TC and Leu, HB and Liu, PL and Chen, YH}, title = {Monascus purpureus-fermented rice inhibits tumor necrosis factor-α-induced upregulation of matrix metalloproteinase 2 and 9 in human aortic smooth muscle cells.}, journal = {The Journal of pharmacy and pharmacology}, volume = {63}, number = {12}, pages = {1587-1594}, doi = {10.1111/j.2042-7158.2011.01364.x}, pmid = {22060290}, issn = {2042-7158}, mesh = {Aorta, Thoracic/cytology ; Atherosclerosis/pathology ; Basement Membrane/cytology/drug effects ; Biological Products/chemistry/*therapeutic use ; Blotting, Western ; Cells, Cultured ; Coloring Agents ; Electrophoretic Mobility Shift Assay ; Extracellular Matrix/drug effects/enzymology ; Graft Occlusion, Vascular/pathology ; Humans ; Matrix Metalloproteinase 2/*biosynthesis ; Matrix Metalloproteinase 9/*biosynthesis ; Myocytes, Smooth Muscle/drug effects/*enzymology ; Polymerase Chain Reaction ; RNA/biosynthesis/genetics ; Reactive Oxygen Species/metabolism ; Tetrazolium Salts ; Thiazoles ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors ; Up-Regulation/drug effects ; }, abstract = {OBJECTIVES: Inflammation is associated with atherosclerosis. Cholestin (Monascus purpureus-fermented rice) contains a naturally occurring statin, which has lipid-modulating, anti-inflammatory and antioxidative effects. This study aimed to investigate the effects of Cholestin extract on the expression of matrix metalloproteinase (MMP)-2 and MMP-9 by tumor necrosis factor (TNF)-α-treated human aortic smooth muscle cells (HASMCs).<br><br>METHODS: Zymography, reverse transcription polymerase chain reaction and immunoblot analyses were used for analysis of MMP expression of TNF-&#x3b1;-stimulated HASMCs. Gel shift assay was used for analysis of transcription factor nuclear factor-&#x3ba;B (NF-&#x3ba;B) activation. Intracellular reactive oxygen species (ROS) generation was also analysed.<br><br>KEY FINDINGS: The supplement of HASMCs with Cholestin extract significantly suppresses enzymatic activities of MMP-2 and MMP-9 in TNF-&#x3b1;-stimulated HASMCs. RT-PCR and immunoblot analyses show that Cholestin extract significantly attenuates TNF-&#x3b1;-induced mRNA and protein expressions of MMP-2 and MMP-9. Gel shift assays show that Cholestin treatment reduces TNF-&#x3b1;-activated NF-&#x3ba;B. Furthermore, Cholestin also attenuates intracellular ROS generation in TNF-&#x3b1;-treated HASMCs. The supplement with an ROS scavenger N-acetyl-cysteine (glutathione precursor) gives similar results to Cholestin.<br><br>CONCLUSIONS: Cholestin reduces TNF-&#x3b1;-stimulated MMP-2 and MMP-9 expression as well as downregulating NF-&#x3ba;B activation and intracellular ROS formation in HASMCs, supporting the notion that the natural compound Cholestin may have potential application in clinical atherosclerosis disease.}, }
@article {pmid22058229, year = {2011}, author = {Terenghi, G and Hart, A and Wiberg, M}, title = {The nerve injury and the dying neurons: diagnosis and prevention.}, journal = {The Journal of hand surgery, European volume}, volume = {36}, number = {9}, pages = {730-734}, doi = {10.1177/1753193411422202}, pmid = {22058229}, issn = {2043-6289}, mesh = {Acetylcarnitine/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Axons/pathology ; Cell Death ; Cell Dedifferentiation ; Humans ; Nerve Degeneration ; Nerve Growth Factors/metabolism/pharmacology ; Nerve Regeneration ; Neurons/*pathology ; Neurons, Afferent/pathology ; Neuroprotective Agents/pharmacology ; Peripheral Nerve Injuries/*pathology/*prevention &amp; control ; Recovery of Function ; Schwann Cells/cytology ; Signal Transduction ; }, abstract = {Following distal nerve injury significant sensory neuronal cell death occurs in the dorsal root ganglia, while after a more proximal injury, such as brachial plexus injury, a sizeable proportion of spinal motoneurons also undergo cell death. This phenomenon has been undervalued for a long time, but it has a significant role in the lack of functional recuperation, as neuronal cells cannot divide and be replaced, hence the resulting nerve regeneration is usually suboptimal. It is now accepted that this cell death is due to apoptosis, as indicated by analysis of specific genes involved in the apoptotic signalling cascade. Immediate nerve repair, either by direct suturing or nerve grafting, gives a degree of neuroprotection, but this approach does not fully prevent neuronal cell death and importantly it is not always possible. Our work has shown that pharmacological intervention using either acetyl-L-carnitine (ALCAR) or N-acetyl-cysteine (NAC) give complete neuroprotection in different types of peripheral nerve injury. Both compounds are clinically safe and experimental work has defined the best dose, timing after injury and duration of administration. The efficacy of neuroprotection of ALCAR and NAC can be monitored non-invasively using MRI, as demonstrated experimentally and more recently by clinical studies of the volume of dorsal root ganglia. Translation to patients of this pharmacological intervention requires further work, but the available results indicate that this approach will help to secure a better functional outcome following peripheral nerve injury and repair.}, }
@article {pmid22057902, year = {2012}, author = {Ferreira, AP and Pasin, JS and Saraiva, AL and Ratzlaff, V and Rossato, MF and Andrighetto, R and Rubin, MA and Ferreira, J and Mello, CF}, title = {N-Acetylcysteine prevents baker's-yeast-induced inflammation and fever.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {61}, number = {2}, pages = {103-112}, pmid = {22057902}, issn = {1420-908X}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/*therapeutic use ; Antipyretics/pharmacology/*therapeutic use ; Dinoprostone/pharmacology ; Fever/*drug therapy/microbiology ; Free Radical Scavengers/*pharmacology ; Hypothalamus/chemistry/metabolism ; Interleukin-1beta/analysis ; Leukocyte Count ; Male ; Peritoneal Lavage ; Peritonitis/*drug therapy/metabolism/microbiology ; Proteins/analysis ; Rats ; Rats, Wistar ; Saccharomyces cerevisiae/*drug effects ; Tumor Necrosis Factor-alpha/analysis ; }, abstract = {OBJECTIVE AND DESIGN: To investigate whether N-acetylcysteine (NAC) alters baker's-yeast-induced fever and inflammation.<br><br>MATERIAL OR SUBJECTS: Male Wistar rats (26-28 days old) injected with baker's yeast (135 mg/kg, intraperitoneal) or prostaglandin E(2) (300 ng/100 &#x3bc;L, intrathecal).<br><br>TREATMENT: Rats were injected with NAC (500 mg/kg, subcutaneous, or 50 &#x3bc;g/100 &#x3bc;L, intrathecal) 1 h before, or 2 h after, pyrogen injection.<br><br>METHODS: Rectal temperature changes induced by baker's yeast, PGE(2) and NAC were followed up over time. Four hours after baker's yeast injection, total leukocytes, protein, interleukin (IL)-1&#x3b2;, tumor necrosis factor (TNF)-&#x3b1; and nonprotein thiol content were assessed in peritoneal lavage and hypothalamus.<br><br>RESULTS: Systemic administration of NAC decreased leukocytes, protein, IL-1&#x3b2; and TNF-&#x3b1; levels in peritoneal lavage, and decreased IL-1&#x3b2; levels in the hypothalamus. The central administration of NAC prevented baker's-yeast-induced fever, but did not alter the febrile response elicited by prostaglandin E(2).<br><br>CONCLUSION: These results suggest an anti-inflammatory and antipyretic role for NAC in yeast-induced peritonitis.}, }
@article {pmid22057277, year = {2011}, author = {Cantore, M and Reinehr, R and Sommerfeld, A and Becker, M and Häussinger, D}, title = {The Src family kinase Fyn mediates hyperosmolarity-induced Mrp2 and Bsep retrieval from canalicular membrane.}, journal = {The Journal of biological chemistry}, volume = {286}, number = {52}, pages = {45014-45029}, pmid = {22057277}, issn = {1083-351X}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 11 ; ATP-Binding Cassette Transporters/genetics/*metabolism ; Acetylcysteine/pharmacology ; Animals ; Bile Canaliculi/*metabolism/pathology ; Cholestasis/genetics/metabolism/pathology ; Cortactin/genetics/metabolism ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Hepatocytes/metabolism/pathology ; MAP Kinase Kinase 4/genetics/metabolism ; Mice ; Mice, Knockout ; NADPH Oxidases/genetics/metabolism ; Osmotic Pressure/drug effects ; Phosphorylation/drug effects/genetics ; Protein Transport/drug effects ; Proto-Oncogene Proteins c-fyn/genetics/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {In perfused rat liver, hyperosmolarity induces Mrp2- (Kubitz, R., D'urso, D., Keppler, D., and Häussinger, D. (1997) Gastroenterology 113, 1438-1442) and Bsep retrieval (Schmitt, M., Kubitz, R., Lizun, S., Wettstein, M., and Häussinger, D. (2001) Hepatology 33, 509-518) from the canalicular membrane leading to cholestasis. The aim of this study was to elucidate the underlying signaling events. Hyperosmolarity-induced retrieval of Mrp2 and Bsep from the canalicular membrane in perfused rat liver was accompanied by an activating phosphorylation of the Src kinases Fyn and Yes but not of c-Src. Both hyperosmotic transporter retrieval and Src kinase activation were sensitive to apocynin (300 μmol/liter), N-acetylcysteine (NAC; 10 mmol/liter), and SU6656 (1 μmol/liter). Also PP-2 (250 nmol/liter), which inhibited hyperosmotic Fyn but not Yes activation, prevented hyperosmotic transporter retrieval from the canalicular membrane, suggesting that Fyn but not Yes mediates hyperosmotic Bsep and Mrp2 retrieval. Neither hyperosmotic Fyn activation nor Bsep/Mrp2 retrieval was observed in livers from p47(phox) knock-out mice. Hyperosmotic activation of JNKs was sensitive to apocynin and NAC but insensitive to SU6656 and PP-2, indicating that JNKs are not involved in transporter retrieval, as also evidenced by experiments using the JNK inhibitors L-JNKI-1 and SP6001255, respectively. Hyperosmotic transporter retrieval was accompanied by a NAC and Fyn knockdown-sensitive inhibition of biliary excretion of the glutathione conjugate of 1-chloro-2,4-dinitrobenzene in perfused rat liver and of cholyl-L-lysyl-fluorescein secretion into the pseudocanaliculi formed by hepatocyte couplets. Hyperosmolarity triggered an association between Fyn and cortactin and increased the amount of phosphorylated cortactin underneath the canalicular membrane. It is concluded that the hyperosmotic cholestasis is triggered by a NADPH oxidase-driven reactive oxygen species formation that mediates Fyn-dependent retrieval of the Mrp2 and Bsep from the canalicular membrane, which may involve an increased cortactin phosphorylation.}, }
@article {pmid22055850, year = {2012}, author = {Brown, AT and Ou, X and James, LP and Jambhekar, K and Pandey, T and McCullough, S and Chaudhuri, S and Borrelli, MJ}, title = {Correlation of MRI findings to histology of acetaminophen toxicity in the mouse.}, journal = {Magnetic resonance imaging}, volume = {30}, number = {2}, pages = {283-289}, pmid = {22055850}, issn = {1873-5894}, support = {UL1 RR029884/RR/NCRR NIH HHS/United States ; R01 DK075936-05/DK/NIDDK NIH HHS/United States ; UL1RR029884/RR/NCRR NIH HHS/United States ; 1R01DK081406/DK/NIDDK NIH HHS/United States ; R01 DK081406/DK/NIDDK NIH HHS/United States ; R01 DK075936/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*therapeutic use ; Analgesics, Non-Narcotic/toxicity ; Animals ; Antidotes/therapeutic use ; Expectorants/therapeutic use ; Liver Failure, Acute/*chemically induced/drug therapy/*pathology ; Magnetic Resonance Imaging/*methods ; Male ; Mice ; Reproducibility of Results ; Sensitivity and Specificity ; Statistics as Topic ; Treatment Outcome ; }, abstract = {Acetaminophen (APAP) toxicity is responsible for approximately half of all cases of acute liver failure in the United States. The mouse model of APAP toxicity is widely used to examine mechanisms of APAP toxicity. Noninvasive approaches would allow for serial measurements in a single animal to study the effects of experimental interventions on the development and resolution of hepatocellular necrosis. The following study examined the time course of hepatic necrosis using small animal magnetic resonance imaging (MRI) following the administration of 200 mg/kg ip APAP given to B6C3F1 male mice. Mice treated with saline served as controls (CON). Other mice received treatment with the clinical antidote N-acetylcysteine (APAP+NAC). Mouse liver pathology was characterized using T1- and T2-weighted sequences at 2, 4, 8 and 24 h following APAP administration. Standard assays for APAP toxicity [serum alanine aminotransaminase (ALT) levels and hematoxylin and eosin (H&amp;E) staining of liver sections] were examined relative to MRI findings. Overall, T2 sequences had a greater sensitivity for necrosis and hemorrhage than T1 (FLASH) images. Liver injury severity scoring of MR images demonstrated increased scores in the APAP mice at 4, 8 and 24 h compared to the CON mice. APAP+NAC mice had MRI scores similar to the CON mice. Semiquantitative analysis of hepatic hemorrhage strongly correlated with serum ALT. Small animal MRI can be used to monitor the evolution of APAP toxicity over time and to evaluate the response to therapy.}, }
@article {pmid22051200, year = {2012}, author = {Hsieh, CL and Wang, HE and Tsai, WJ and Peng, CC and Peng, RY}, title = {Multiple point action mechanism of valproic acid-teratogenicity alleviated by folic acid, vitamin C, and N-acetylcysteine in chicken embryo model.}, journal = {Toxicology}, volume = {291}, number = {1-3}, pages = {32-42}, doi = {10.1016/j.tox.2011.10.015}, pmid = {22051200}, issn = {1879-3185}, mesh = {Acetylcysteine/blood/*pharmacology ; Animals ; Anticonvulsants/*antagonists &amp; inhibitors/*toxicity ; Antioxidants/*pharmacology ; Ascorbic Acid/blood/*pharmacology ; Chick Embryo ; Chromatography, High Pressure Liquid ; Folic Acid/blood/*pharmacology ; Foot Deformities/chemically induced ; Glutathione/metabolism ; Hindlimb/abnormalities ; Histone Deacetylases/metabolism ; Homocysteine/metabolism ; Hydrogen Peroxide/metabolism ; Joints/abnormalities/pathology ; Muscle, Skeletal/abnormalities/pathology ; Neovascularization, Physiologic/drug effects ; Superoxide Dismutase/metabolism ; *Teratogens ; Tissue Embedding ; Valproic Acid/*antagonists &amp; inhibitors/*toxicity ; Vitamins/blood/*pharmacology ; }, abstract = {The teratogenicity of antiepilepsy drug valproic acid (VPA) mostly is found in genetic and somatic levels, causing teratogenesis involving neurotubular defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta. A diversity of nutraceutics have been tried to alleviate the risk of VPA-teratogenicity. The effect was varying. In order to promote the preventive prescription, to find out its action mechanism can be rather crucial. We used chicken embryo model to try the effect of folic acid (FA), ascorbic acid (AA), and N-acetyl cysteine (NAC). VPA at 30mM showed the higher malformation rate (66.7%) with the least mortality (22.2%). Pathological findings indicated that the cervical muscle was more susceptible to VPA injury than the ankle muscle. VPA downregulated levels of superoxide dismutase (SOD), glutathione (GSH), histone deacetylase (HDAC) and folate, and upregulated H(2)O(2) and homocysteine. FA, AA, and NAC significantly upregulated SOD, but only AA alone activated GSH. AA and NAC downregulated H(2)O(2), while FA was totally ineffective. All three nutraceutics comparably rescued HDAC with simultaneously suppressed homocysteine accumulation and folate re-elevation, although less effectively by NAC. Based on these data, we conclude VPA possesses "Multiple Point Action Mechanism". In addition to affecting the cited transcription and translation levels, we hypothesize that VPA competitively antagonize the glutamic acid to couple with pteroic acid in biosynthesis of dihydrofolic acid (DHFA). H(2)O(2) directly destroyed the NADPH reducing system at dihydrofolate reductase (DHFR) and methylene tetrahydrofolate reductase (MTHFR) levels, while completely restored by AA, an implication in preservation of intact apoenzymes. In addition, the GSH-GSSG system is sandwiched between the reducing systems NADPH/NADP and DHA-AA, its net balance is highly dependent on in situ in vivo Redox state, hence folic acid transformation is varying. To rescue the VPA-induced teratogenicity, simultaneous multiple prescriptions are suggested.}, }
@article {pmid22048491, year = {2011}, author = {Soneru, AP and Beckett, MA and Weichselbaum, RR and Lee, RC}, title = {Mg ATP and antioxidants augment the radioprotective effect of surfactant copolymers.}, journal = {Health physics}, volume = {101}, number = {6}, pages = {731-738}, pmid = {22048491}, issn = {1538-5159}, support = {R01 GM053113-04/GM/NIGMS NIH HHS/United States ; R01-GM53113/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/radiation effects ; Cell Survival/drug effects/radiation effects ; Drug Synergism ; Female ; Muscle, Skeletal/cytology/drug effects/metabolism/radiation effects ; Poloxamer/*pharmacology ; Radiation Dosage ; Radiation-Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects/radiation effects ; Surface-Active Agents/*pharmacology ; Time Factors ; }, abstract = {Mediated by reactive oxygen species, the damaging effects of high-intensity ionizing irradiation on tissues are dose, frequency, oxygen concentration, and tissue property dependent. Intense ionizing irradiation exposure may cause rapid cellular necrosis by peroxidation of membrane lipids leading to membrane disruption. This leads to a loss of the transmembrane ionic gradients and a subsequent depletion of the cellular ATP store, followed by cellular generation of reactive oxygen species. When membrane disruption is extensive, acute cellular necrosis follows. Triblock copolymer surfactants, such as Poloxamer 188 (P188), are able to seal damaged rhabdomyocyte membranes, increasing post-irradiation viability. Separated rat rhabdomyocytes were exposed to 40 Gy (Co 1.5 Gy min) irradiation and treated at 20 min intervals with combination permutations of P188, N-acetylcysteine (NAC), and Mg-ATP. Cell viability at 18 and 48 h was determined using Calcein-AM and Ethidium Homodimer-1 staining. At 18 h after irradiation, the combined administration of P188, ATP, and NAC restored cell viability rates to near sham-exposed levels of 60%. At 48 h post-irradiation, cell viability dropped substantially to the 7-20% range, regardless of attempted intervention. Nevertheless, the combination of P188, ATP, and NAC more than doubled cell viability at the 48-h time point. Neither 8 kDa polyethylene glycol nor 10 kDa neutral dextran was as effective in enhancing cell viability. These results indicate that antioxidants and cellular energy substrates improve the efficacy of membrane-sealing copolymer surfactants in prolonging cellular viability following massive radiation exposure.}, }
@article {pmid22047834, year = {2012}, author = {Rosenbaum, MA and Miyazaki, K and Graham, LM}, title = {Hypercholesterolemia and oxidative stress inhibit endothelial cell healing after arterial injury.}, journal = {Journal of vascular surgery}, volume = {55}, number = {2}, pages = {489-496}, pmid = {22047834}, issn = {1097-6809}, support = {R01 HL041178/HL/NHLBI NIH HHS/United States ; F32HL090205/HL/NHLBI NIH HHS/United States ; HL64357/HL/NHLBI NIH HHS/United States ; R01 HL064357-08/HL/NHLBI NIH HHS/United States ; R56 HL064357/HL/NHLBI NIH HHS/United States ; R01 HL041178-21/HL/NHLBI NIH HHS/United States ; F32 HL090205/HL/NHLBI NIH HHS/United States ; R01 HL064357/HL/NHLBI NIH HHS/United States ; F32 HL090205-02/HL/NHLBI NIH HHS/United States ; HL41187/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Biomarkers/blood ; Carotid Artery Injuries/*complications/metabolism/pathology ; Carotid Artery, Common/drug effects/metabolism/*pathology ; *Cell Proliferation/drug effects ; Disease Models, Animal ; Endothelial Cells/drug effects/metabolism/*pathology ; Hypercholesterolemia/*complications/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Oxidants/toxicity ; *Oxidative Stress/drug effects ; Paraquat/toxicity ; Time Factors ; *Wound Healing/drug effects ; }, abstract = {OBJECTIVE: Endothelial cell (EC) migration is essential for arterial healing after angioplasty. Oxidized low-density lipoproteins and oxidative stress decrease EC migration in vitro. The objective of this study was to determine the effect of hypercholesterolemia and oxidative stress on EC healing after an arterial injury.<br><br>METHODS: C57BL/6 wild-type mice were placed in one of eight groups: chow diet (n = 11), high-cholesterol (HC) diet (n = 11), chow diet plus paraquat (n = 11), HC diet plus paraquat (n = 11), chow diet plus N-acetylcysteine (NAC) (n = 11), HC diet plus NAC (n = 11), chow diet plus paraquat and NAC (n = 11), and HC diet plus paraquat and NAC (n = 11). After 2 weeks on the assigned diet with or without NAC, the carotid artery was injured using electrocautery. Animals in the paraquat groups were given 1 mg/kg intraperitoneally to increase oxidative stress. After 120 hours, Evans Blue dye was infused intravenously to stain the area of the artery that remained deendothelialized. This was used to calculate the percentage of re-endothelialization. Plasma and tissue samples were analyzed for measures of oxidative stress.<br><br>RESULTS: The HC diet increased oxidative stress and reduced EC healing compared with a chow diet, with EC covering 26.8% &#xb1; 2.8% and 48.1% &#xb1; 5.2% (P < .001) of the injured area, respectively. Administration of paraquat decreased healing in both chow and HC animals to 18.1% &#xb1; 3.5% (P < .001) and 9.8% &#xb1; 4.6% (P < .001), respectively. Pretreatment with NAC (120 mmol/L in drinking water) for 2 weeks prior to injury, to decrease oxidative stress, improved EC healing to 39.9% &#xb1; 5.7% (P < .001) in hypercholesterolemic mice and to 30.7% &#xb1; 3.6% (P < .001) in the paraquat group. NAC treatment improved healing to 24.6% &#xb1; 3.4% (P < .001) in hypercholesterolemic mice treated with paraquat.<br><br>CONCLUSION: Re-endothelialization of arterial injuries is reduced in hypercholesterolemic mice and is inversely correlated with oxidative stress. An oral antioxidant decreases oxidative stress and improves EC healing.<br><br>CLINICAL RELEVANCE: Vascular injury following cardiovascular intervention, including cardiac and peripheral arterial angioplasty and stenting, is associated with inflammation and oxidative stress. Hypercholesterolemia is also associated with increased oxidative stress. Oxidative stress, regardless of the source, induces cellular dysfunction in endothelial and smooth muscle cells that reduce healing after arterial injury. Decreasing oxidative stress with an exogenously administered antioxidant can improve endothelial cell healing, and this is important to control intimal hyperplasia and reduce the thrombogenicity of the vessel.}, }
@article {pmid22047166, year = {2012}, author = {Onur, E and Paksoy, M and Baca, B and Akoglu, H}, title = {Hyperbaric oxygen and N-acetylcysteine treatment in L-arginine-induced acute pancreatitis in rats.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {25}, number = {1}, pages = {20-28}, doi = {10.3109/08941939.2011.593694}, pmid = {22047166}, issn = {1521-0553}, mesh = {Acetylcysteine/*therapeutic use ; Amylases/blood ; Animals ; Calcium/blood ; Combined Modality Therapy ; Drug Evaluation, Preclinical ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; *Hyperbaric Oxygenation ; L-Lactate Dehydrogenase/blood ; Male ; Malondialdehyde/metabolism ; Organ Size ; Pancreas/metabolism/pathology ; Pancreatitis, Acute Necrotizing/blood/drug therapy/pathology/*therapy ; Rats ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND: This study was designed to evaluate the combined effects of hyperbaric oxygen (HBO) and N-acetylcysteine (NAC) on acute necrotizing pancreatitis in rats.<br><br>METHODS: Experiments were performed in 50 male Wistar rats, which were divided into five groups (N = 10 for each group). The first group received normal saline (0.9% NaCl) intraperitoneal and served as the control group. In the second group, acute pancreatitis was induced by 3.2-g/kg body weight L-arginine intraperitoneal twice at an interval of 1 hr, which has been shown previously to produce severe necrotizing acute pancreatitis. In the third group, NAC treatment (1000 mg/kg) was given after 1 hr of the induction of acute pancreatitis twice 24 hr apart. In the fourth group, animals received HBO, 6 hr after the induction of pancreatitis twice 12 hr apart. In the fifth group, animals received together NAC as in Group 3 and HBO treatment as in Group 4. Groups 1, 2, and 3 were left under normal atmospheric pressures. Twelve hours after last treatment, the animals were killed by exsanguinations. Blood samples were studied for amylase, calcium, and lactate dehydrogenase (LDH), pancreatic histology, pancreatic tissue malondialdehyde, superoxide dismutase, and glutathione levels.<br><br>RESULTS: Acute pancreatitis is reduced by the treatment of NAC, HBO, NAC + HBO. HBO + NAC groups performed statistically the best in preventing L-arginine-induced acute necrotising pancreatitis.<br><br>CONCLUSIONS: NAC especially combined with HBO, decreases oxidative stress parameters, serum amylase, calcium, and LDH levels, as well as histopathologic score.}, }
@article {pmid22046978, year = {2012}, author = {Beloosesky, R and Weiner, Z and Ginsberg, Y and Ross, MG}, title = {Maternal N-acetyl-cysteine (NAC) protects the rat fetal brain from inflammatory cytokine responses to lipopolysaccharide (LPS).}, journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians}, volume = {25}, number = {8}, pages = {1324-1328}, doi = {10.3109/14767058.2011.632793}, pmid = {22046978}, issn = {1476-4954}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Brain/*drug effects/embryology/immunology/metabolism ; Cytokines/genetics/metabolism ; Cytoprotection/drug effects/immunology ; Drug Evaluation, Preclinical ; Encephalitis/chemically induced/embryology/metabolism/*prevention &amp; control ; Female ; Fetus/drug effects/immunology/metabolism ; Inflammation Mediators/*metabolism ; Lipopolysaccharides ; Maternal-Fetal Exchange/drug effects/immunology ; Mothers ; Pregnancy/blood ; Prenatal Exposure Delayed Effects/chemically induced/prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: Inflammatory cytokines, play a central role in the genesis of preterm parturition and fetal brain injury. Lipopolysaccharide (LPS) may activate cytokine pathways via induction of oxidative stress pathways. We hypothesized that enhanced maternal antioxidant activity may blunt fetal brain inflammatory responses to maternal LPS injection in pregnant rats.<br><br>METHODS: Pregnant Sprague-Dawley rats at 18 and 20 days gestation received intraperitoneal (ip) LPS injection and pre- and post-treatment with the antioxidant N-acetyl-cysteine (NAC) or saline. Six hours after the LPS injection, rats were sacrificed, interleukin (IL)-6 and IL-10 mRNA expression in the fetal brains was determined by real time polymerase chain reaction.<br><br>RESULTS: Maternal ip LPS induced significant increase in fetal brain IL-6 mRNA expression at E18 (3.1 &#xb1; 0.6 vs 1.0 &#xb1; 0.10 AU) and E20 (29.01 + 13.06 vs 0.95 + 0.05 AU; p < 0.05) compared to Control, only at E20 maternal LPS induced increase in fetal brain IL-10 compared to control. NAC administered prior to and after LPS significantly reduced fetal brain IL-6 at E18 and E20 and IL-10 at E20.<br><br>CONCLUSION: Maternal NAC can protect the fetal brain from inflammatory cytokine responses to maternal LPS injection. These results suggest that NAC may potentially protect fetus from inflammation-associated brain injury and potential long term sequelae.}, }
@article {pmid22045831, year = {2012}, author = {Fraga, CM and Tomasi, CD and Biff, D and Topanotti, MF and Felisberto, F and Vuolo, F and Petronilho, F and Dal-Pizzol, F and Ritter, C}, title = {The effects of N-acetylcysteine and deferoxamine on plasma cytokine and oxidative damage parameters in critically ill patients with prolonged hypotension: a randomized controlled trial.}, journal = {Journal of clinical pharmacology}, volume = {52}, number = {9}, pages = {1365-1372}, doi = {10.1177/0091270011418657}, pmid = {22045831}, issn = {1552-4604}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/blood/drug therapy/etiology ; Adult ; Aged ; Antioxidants/*pharmacology ; Critical Illness ; Deferoxamine/*pharmacology ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Hypotension/blood/complications/*drug therapy ; Interleukin-6/*blood ; Male ; Middle Aged ; Nitrites/blood ; Oxidative Stress/drug effects ; Siderophores/*pharmacology ; }, abstract = {Reactive oxygen species and inflammation have been implicated in renal tubule cell injury. However, there is some controversy concerning whether antioxidants might attenuate oxidative damage and inflammation in humans after hypotension in the setting of critical illness. This study was a prospective, randomized, double-blinded, placebo-controlled study that included patients with hypotension. Patients were randomized to receive either N-acetylcysteine (NAC; 50 mg/kg by 4 hours followed by 100 mg/kg/d for 48 hours diluted in 5% glucose) and deferoxamine (DFX; at a single dose of 1000 mg diluted in 5% glucose) or placebo. The primary study outcome was the serum levels of markers of oxidative damage and inflammatory response. Secondary outcomes included the incidence of acute renal failure, serum creatinine at hospital discharge, intensive care unit length of stay, and length of hospital stay. Thirty patients were enrolled in the study. The use of NAC plus DFX decreased the oxidative damage parameters but not plasma interleukin-6 levels. In contrast, plasma nitrite levels increased 24 hours after NAC plus DFX administration. On analysis of secondary outcomes, it was observed that creatinine levels at hospital discharge were lower in patients receiving NAC plus DFX when compared with placebo. NAC plus DFX administration was able to decrease plasma markers of oxidative damage and creatinine levels at hospital discharge.}, }
@article {pmid22045254, year = {2012}, author = {Valencia, A and Sapp, E and Reeves, PB and Alexander, J and Masso, N and Li, X and Kegel, KB and DiFiglia, M}, title = {Reagents that block neuronal death from Huntington's disease also curb oxidative stress.}, journal = {Neuroreport}, volume = {23}, number = {1}, pages = {10-15}, doi = {10.1097/WNR.0b013e32834d92e6}, pmid = {22045254}, issn = {1473-558X}, mesh = {Animals ; Antioxidants/pharmacology ; Brain-Derived Neurotrophic Factor/pharmacology ; Cell Death ; Cell Survival/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors ; Glycogen Synthase Kinase 3 beta ; Huntington Disease/genetics/*metabolism/pathology ; Indicators and Reagents ; Male ; Mice ; Mice, Transgenic ; Mutation ; Neurons/drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Patients with Huntington's disease suffer severe neuronal loss and signs of oxidative damage in the brain. Previously we found that primary neurons from embryonic cortex of mice bearing the Huntington's disease mutation (140 glutamines inserted into exon 1 of huntingtin) showed higher levels of reactive oxygen species before cell death. Here, we treated mutant neurons with known neuroprotective agents and determined the effects on neuronal survival and levels of reactive oxygen species. Primary neurons were exposed to the neurotrophin, brain derived neurotrophic factor, the antioxidant N-acetyl-cysteine or a specific inhibitor of glycogen synthase kinase 3-β, SB216763. Each reagent increased the survival of the mutant neurons compared with untreated mutant neurons and also reduced the levels of reactive oxygen species to levels of wild-type neurons. These results suggest that reducing the levels of reactive oxygen species may be necessary to protect neurons with the Huntington's disease mutation from cell death.}, }
@article {pmid22044588, year = {2012}, author = {Hoshino, A and Matoba, S and Iwai-Kanai, E and Nakamura, H and Kimata, M and Nakaoka, M and Katamura, M and Okawa, Y and Ariyoshi, M and Mita, Y and Ikeda, K and Ueyama, T and Okigaki, M and Matsubara, H}, title = {p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia.}, journal = {Journal of molecular and cellular cardiology}, volume = {52}, number = {1}, pages = {175-184}, doi = {10.1016/j.yjmcc.2011.10.008}, pmid = {22044588}, issn = {1095-8584}, mesh = {Animals ; Apoptosis/genetics ; Apoptosis Regulatory Proteins ; Autophagy/genetics ; Gene Expression Regulation ; Membrane Proteins/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Heart/metabolism/pathology ; Mitochondrial Proteins/genetics/metabolism ; Myocardial Infarction/genetics/metabolism ; Myocardial Ischemia/genetics/*metabolism ; Oxidative Stress ; Phosphoric Monoester Hydrolases ; Proteins/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; Ventricular Remodeling/genetics ; }, abstract = {Inhibition of tumor suppressor p53 is cardioprotective against ischemic injury and provides resistance to subsequent cardiac remodeling. We investigated p53-mediated expansion of ischemic damage with a focus on mitochondrial integrity in association with autophagy and apoptosis. p53(-/-) heart showed that autophagic flux was promoted under ischemia without a change in cardiac tissue ATP content. Electron micrographs revealed that ischemic border zone in p53(-/-) mice had 5-fold greater numbers of autophagic vacuoles containing mitochondria, indicating the occurrence of mitophagy, with an apparent reduction of abnormal mitochondria compared with those in WT mice. Analysis of autophagic mediators acting downstream of p53 revealed that TIGAR (TP53-induced glycolysis and apoptosis regulator) was exclusively up-regulated in ischemic myocardium. TIGAR(-/-) mice exhibited the promotion of mitophagy followed by decrease of abnormal mitochondria and resistance to ischemic injury, consistent with the phenotype of p53(-/-) mice. In p53(-/-) and TIGAR(-/-) ischemic myocardium, ROS production was elevated and followed by Bnip3 activation which is an initiator of mitophagy. Furthermore, the activation of Bnip3 and mitophagy due to p53/TIGAR inhibition were reversed with antioxidant N-acetyl-cysteine, indicating that this adaptive response requires ROS signal. Inhibition of mitophagy using chloroquine in p53(-/-) or TIGAR(-/-) mice exacerbated accumulation of damaged mitochondria to the level of wild-type mice and attenuated cardioprotective action. These findings indicate that p53/TIGAR-mediated inhibition of myocyte mitophagy is responsible for impairment of mitochondrial integrity and subsequent apoptosis, the process of which is closely involved in p53-mediated ventricular remodeling after myocardial infarction.}, }
@article {pmid22042537, year = {2012}, author = {Mathé, E and Nguyen, GH and Funamizu, N and He, P and Moake, M and Croce, CM and Hussain, SP}, title = {Inflammation regulates microRNA expression in cooperation with p53 and nitric oxide.}, journal = {International journal of cancer}, volume = {131}, number = {3}, pages = {760-765}, pmid = {22042537}, issn = {1097-0215}, support = {Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Inflammation/*genetics ; Lymphoma/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; MicroRNAs/genetics/*metabolism ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type II/deficiency/genetics/metabolism ; Nitrosation ; *Oxidative Stress ; Propionibacterium acnes/immunology ; Tumor Suppressor Protein p53/deficiency/genetics/*metabolism ; }, abstract = {microRNA (miRNA) are small non-coding RNA targeting mRNAs leading to their instability and diminished translation. Altered expression of miRNA is associated with cancer. Inflammation and nitric oxide modulates the development of lymphomas in p53 knockout mice and there exists a negative feedback loop between p53 and NOS2. Using a genetic strategy, we tested the hypothesis that inflammation-induced oxidative and nitrosative stress modulates miRNA expression in mouse model deficient in either p53 or NOS2. Mice treated with Corynebacterium parvum (C. parvum), to induce inflammation, clearly separated from controls by their miRNA profiles in wild-type, p53- and NOS2-knockout genetic backgrounds. C. parvum-induced inflammation significantly (p < 0.005) increased miR-21, miR-29b and miR-34a/b/c and decreased (p < 0.005) mir-29c and mir-181a/c expression in the spleen of C57BL mice. However, p53-knockout C57BL mice did not show a significant increase in the mir-34b/c or a decrease in mir-29c expression following C. parvum-induced inflammation. Expression of mir-21, mir-29b and mir-181a was independent of p53-status. NOS2-knockout C57BL mice showed a significant increase in miR-21 and miR-34a/b/c and decrease in miR-181a similar to the wild-type (WT) mice following C. parvum-induced inflammation. However, in contrast to the WT mice, miR-29b/c expression was not affected following C. parvum-induced inflammation in NOS2 knockout mice. N-acetyl cysteine, an anti-oxidant, reduced the expression of miR-21 and miR-29b in C. parvum-treated WT mice (p < 0.005) as compared with control C. parvum-treated mice. These data are consistent with the hypothesis that inflammation modulates miRNA expression in vivo and the alteration in specific miRNA under an inflammatory microenvironment, can be influenced by p53 (miR-34b/c) and NO(•) (29b/c).}, }
@article {pmid22041018, year = {2012}, author = {Akeel, S and El-Awady, A and Hussein, K and El-Refaey, M and Elsalanty, M and Sharawy, M and Al-Shabrawey, M}, title = {Recombinant bone morphogenetic protein-2 induces up-regulation of vascular endothelial growth factor and interleukin 6 in human pre-osteoblasts: role of reactive oxygen species.}, journal = {Archives of oral biology}, volume = {57}, number = {5}, pages = {445-452}, doi = {10.1016/j.archoralbio.2011.10.002}, pmid = {22041018}, issn = {1879-1506}, mesh = {Analysis of Variance ; Biomarkers/metabolism ; Bone Morphogenetic Protein 2/*pharmacology ; Enzyme-Linked Immunosorbent Assay ; Gene Expression/drug effects ; Humans ; Inflammation/drug therapy ; Interleukin-6/*biosynthesis/genetics ; Lipid Peroxidation ; Microscopy, Fluorescence ; Neovascularization, Physiologic/drug effects ; Osteoblasts/*drug effects/*metabolism ; Reactive Oxygen Species/*metabolism ; Real-Time Polymerase Chain Reaction ; Recombinant Proteins/pharmacology ; Transforming Growth Factor beta/*pharmacology ; Up-Regulation ; Vascular Endothelial Growth Factor A/*biosynthesis/genetics ; }, abstract = {OBJECTIVE: Bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) have been reported in many studies to play a major role in the communication between endothelial cells and osteoblasts. The inflammatory reaction and relative hypoxia at the site of bone injury are the first stages of the fracture repair. rhBMP-2 has been used extensively in spinal fusion and reconstruction of maxillofacial bone defects with main complication is the formation of seroma. The aim of this study was to test whether rhBMP-2 regulates the expression of the angiogenic and inflammatory mediators in pre-osteoblasts via generating reactive oxygen species (ROS).<br><br>METHODS: rhBMP-2 effect on angiogenesis and inflammatory genes was assessed using normal human osteoblasts (NHOst). Angiogenesis genes were measured using angiogenic PCR array. VEGF and IL6 production were analysed using ELISA kit and real-time PCR. ROS production was assessed using dihydroethidine and dichlorofluorescein staining and lipid peroxidation. HIF-1&#x3b1; immunoreactivity was performed using immunofluorescence staining.<br><br>RESULTS: There was an increase in the pro-angiogenic and -inflammatory genes as well as VEGF and IL6 protein expression in NHOst by rhBMP-2. This increase in VEGF and IL6 was blocked by the ROS scavenger N-acetyl cysteine (NAC).<br><br>CONCLUSION: The regulatory effect of rhBMP-2 on angiogenesis and inflammation is mediated through a ROS-dependent mechanism, which involves upregulation of crucial angiogenic and inflammatory mediators such as VEGF and IL6. These findings highlight the need for future studies to identify new therapeutic targets downstream from rhBMP-2 to potentiate its beneficial effect or limit its complications such as seroma formation.}, }
@article {pmid22039262, year = {2011}, author = {Merchant, AA and Singh, A and Matsui, W and Biswal, S}, title = {The redox-sensitive transcription factor Nrf2 regulates murine hematopoietic stem cell survival independently of ROS levels.}, journal = {Blood}, volume = {118}, number = {25}, pages = {6572-6579}, pmid = {22039262}, issn = {1528-0020}, support = {R33 AI080541/AI/NIAID NIH HHS/United States ; P01 CA015396/CA/NCI NIH HHS/United States ; R01 CA127574/CA/NCI NIH HHS/United States ; P01CA015396/CA/NCI NIH HHS/United States ; R01CA127574/CA/NCI NIH HHS/United States ; P50 CA058184/CA/NCI NIH HHS/United States ; R01 CA127574-05/CA/NCI NIH HHS/United States ; R01 CA140492/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Bone Marrow Cells/cytology/drug effects/metabolism ; Bone Marrow Transplantation ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cytokines/genetics ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Gene Expression Profiling ; Granulocyte Colony-Stimulating Factor/pharmacology ; Hematopoietic Stem Cells/*cytology/drug effects/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-E2-Related Factor 2/deficiency/genetics/*physiology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Several studies have found that high levels of reactive oxidative species (ROS) are associated with stem cell dysfunction. In the present study, we investigated the role of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of the antioxidant response, and found that it is required for hematopoietic stem progenitor cell (HSPC) survival and myeloid development. Although the loss of Nrf2 leads to increased ROS in most tissues, basal ROS levels in Nrf2-deficient (Nrf2(-/-)) BM were not elevated compared with wild-type. Nrf2(-/-) HSPCs, however, had increased rates of spontaneous apoptosis and showed decreased survival when exposed to oxidative stress. Nrf2(-/-) BM demonstrated defective stem cell function, as evidenced by reduced chimerism after transplantation that was not rescued by treatment with the antioxidant N-acetyl cysteine. Gene-expression profiling revealed that the levels of prosurvival cytokines were reduced in Nrf2(-/-) HSPCs. Treatment with the cytokine G-CSF improved HSPC survival after exposure to oxidative stress and rescued the transplantation defect in Nrf2(-/-) cells despite increases in ROS induced by cytokine signaling. These findings demonstrate a critical role for Nrf2 in hematopoiesis and stem cell survival that is independent of ROS levels.}, }
@article {pmid22038345, year = {2011}, author = {Zou, J and Zou, P and Lou, Y and Xiao, Y and Wang, J and Liu, L}, title = {The cross-talk between ROS and p38MAPKα in the Ex Vivo expanded human umbilical cord blood CD133(+) cells.}, journal = {Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban}, volume = {31}, number = {5}, pages = {591}, pmid = {22038345}, issn = {1672-0733}, mesh = {AC133 Antigen ; Acetylcysteine/pharmacology ; Antigens, CD/*blood ; Cell Division ; Cells, Cultured ; Culture Media ; Fetal Blood/*cytology ; Glycoproteins/*blood ; Hematopoietic Stem Cells/*cytology ; Humans ; Imidazoles/pharmacology ; Mitogen-Activated Protein Kinase 14/*metabolism ; Peptides/*blood ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {This study investigated the correlation between and compared the effects of reactive oxygen species (ROS) and p38 mitogen-activated protein kinase α (p38MAPKα) in the ex vivo expanded umbilical cord blood (hUCB) CD133(+) cells. hUCB CD133(+) cells were cultured in the hematopoietic stem cells (HSCs) culture medium with N-acetylcysteine (NAC, an anti-oxidant), p38MAPKα-specific inhibitor (SB203580) or their combination. The levels of ROS and expression of phosphorylated p38MAPKα (p-p38) in CD133(+) cells were flow cytometrically detected. The efficacy of ex vivo expansion was evaluated by the density of CD133(+) cell sub-group colony-forming cells (CFC) and cobblestone area-forming cells (CAFC) assay. Our results showed decreased ROS levels in NAC, SB203580, and their combination treatment groups were almost 37%, 48%, and 85%, respectively. Furthermore, SB203580 abrogated the activation of p38MAPKα more obviously than NAC. Moreover, the CD133(+) cells in SB203580 treatment group had a 21.93±1.36-fold increase, and 14.50±1.19-fold increase in NAC treatment group, but only 10.13±0.57-fold increase in control group. In addition, SB203580 treatment led a higher level increase in the number of CFU and CAFC than NAC did. These findings suggested that, in expanded CD133(+) cells, ROS activates p38MAPKα, which, in turn, induces ROS production, and p38MAPKα might be the most suitable regulator in ROS-p38MAPKα pathway for the promotion of HSCs ex vivo expansion.}, }
@article {pmid22036036, year = {2012}, author = {Gunduz-Bruce, H and Reinhart, RM and Roach, BJ and Gueorguieva, R and Oliver, S and D'Souza, DC and Ford, JM and Krystal, JH and Mathalon, DH}, title = {Glutamatergic modulation of auditory information processing in the human brain.}, journal = {Biological psychiatry}, volume = {71}, number = {11}, pages = {969-977}, pmid = {22036036}, issn = {1873-2402}, support = {K02 MH067967-10/MH/NIMH NIH HHS/United States ; R01 MH076989-05/MH/NIMH NIH HHS/United States ; MH067967/MH/NIMH NIH HHS/United States ; R01 MH058262-12/MH/NIMH NIH HHS/United States ; R01 MH076989/MH/NIMH NIH HHS/United States ; R01 MH040052-15/MH/NIMH NIH HHS/United States ; K05 AA014906-05/AA/NIAAA NIH HHS/United States ; K05 AA014906/AA/NIAAA NIH HHS/United States ; MH58262/MH/NIMH NIH HHS/United States ; R01 MH058262/MH/NIMH NIH HHS/United States ; MH40052/MH/NIMH NIH HHS/United States ; P50 AA012870-12/AA/NIAAA NIH HHS/United States ; P50 AA012870/AA/NIAAA NIH HHS/United States ; K02 MH067967/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Behavior/*drug effects ; Cognition/drug effects ; Electroencephalography ; Event-Related Potentials, P300/*drug effects ; Evoked Potentials, Auditory/*drug effects ; Excitatory Amino Acid Antagonists/*pharmacology ; Female ; Free Radical Scavengers/*pharmacology ; Humans ; Ketamine/*pharmacology ; Male ; Memory/drug effects ; Psychomotor Performance/drug effects ; Reaction Time/drug effects ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors ; Schizophrenia/physiopathology ; }, abstract = {BACKGROUND: Auditory mismatch negativity (MMN) and P300 event-related potentials (ERPs) are reduced in schizophrenia patients and healthy volunteers administered the N-methyl-D-aspartate glutamate receptor antagonist, ketamine. In rodents, N-acetylcysteine (NAC), a stimulator of the cystine-glutamate exchanger, attenuates the cognitive and behavioral effects of N-methyl-D-aspartate receptor antagonists. On the basis of these findings, we tested whether NAC would reduce ketamine effects on behavior, MMN, and P300 in healthy humans.<br><br>METHODS: This randomized, double-blind, placebo-controlled study consisted of 2 test days during which subjects (n = 16) were administered oral NAC (3000 mg in divided doses) or matching placebo 165 min before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Behavioral and ERP data including auditory MMN and P300 were collected during each test day.<br><br>RESULTS: Ketamine produced psychotic-like positive symptoms, reductions in working memory and sustained attention performance, and amplitude reductions for the frequency- and intensity-deviant MMNs and P300. NAC pretreatment did not reduce the behavioral or ERP effects of ketamine. In addition, NAC reduced frequency-deviant MMN amplitude and increased target and novelty P3 amplitudes. The decrements in frequency-deviant MMN amplitude produced by ketamine and NAC were not additive.<br><br>CONCLUSIONS: NAC did not attenuate the effects of ketamine in humans, in contrast to previous studies in animals. NAC merits further investigation as a cognitive enhancing agent due to its ability to increase the P300 amplitude.}, }
@article {pmid22033125, year = {2012}, author = {Krifka, S and Hiller, KA and Bolay, C and Petzel, C and Spagnuolo, G and Reichl, FX and Schmalz, G and Schweikl, H}, title = {Function of MAPK and downstream transcription factors in monomer-induced apoptosis.}, journal = {Biomaterials}, volume = {33}, number = {3}, pages = {740-750}, doi = {10.1016/j.biomaterials.2011.10.026}, pmid = {22033125}, issn = {1878-5905}, mesh = {Animals ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cell Line ; Flavonoids/pharmacology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Mice ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Polyethylene Glycols/*toxicity ; Polymethacrylic Acids/*toxicity ; Transcription Factors/*metabolism ; }, abstract = {The resin monomer triethylene glycol dimethacrylate (TEGDMA) disrupts vital cell functions, and the production of oxidative stress is considered a common underlying mechanism. The precise signaling pathways, however, that initiate monomer-induced effects, which disturb responses of the innate immune system, inhibit dentin mineralization processes, or induce apoptosis in target cells in vitro are still unknown. The present study provides insight into the causal relationship between TEGDMA-induced apoptosis and the activation of MAPK and transcription factors downstream using pharmacological inhibitors of the ERK1/2, p38 and JNK pathways. The endotoxin lipopolysaccharide (LPS; 0.1 μg/ml) was included as an inducer of MAPK activity in RAW264.7 mouse macrophages. Cell viability was decreased from 95% in untreated cultures to about 43% after a 24 h exposure to 3 mM TEGDMA. Inhibition of the ERK1/2 pathway by the MEK1/2 inhibitor PD98059 reduced cell viability to 84%. While apoptosis induced by TEGDMA remained unchanged, Western blot analyses revealed that the activation of ERK1/2 in the presence of TEGDMA was inhibited by PD98059. LPS-induced expression of activated transcription factors c-Jun, ATF-2, ATF-3 and phospho-Elk1 was decreased in cells co-treated with TEGDMA. This inhibition was more intense in the presence of PD98059, indicating that the MEK/ERK pathway is involved in the inhibition of the LPS-induced activation of transcription factors by TEGDMA. No clear effects of the p38 inhibitor SB203580 and the JNK inhibitor SP600125 on TEGDMA-induced apoptosis were detected. The antioxidant N-acetylcysteine (NAC) protected cells from TEGDMA-induced cell death, and inhibited the activation of ERK1/2, p38 and JNK by TEGDMA. Moreover, the TEGDMA-induced downregulation of the expression of the transcription factors c-Jun and ATF-2 was prevented as well. In conclusion, physiologically relevant concentrations of inhibitors differentially modified the expression of MAPK and transcription factors in cell cultures exposed to LPS and the monomer TEGDMA. The absence of a drastic effect of the MAPK pathway inhibitors on TEGDMA-induced apoptosis on the one hand, and the protective effect of NAC and PD98059 in particular on TEGDMA-induced MAPK activation and apoptosis on the other hand, leads to a new model for the role of MAPK in the regulation of cell homeostasis in monomer-exposed cells and tissues.}, }
@article {pmid22028843, year = {2011}, author = {Palanisamy, GS and Kirk, NM and Ackart, DF and Shanley, CA and Orme, IM and Basaraba, RJ}, title = {Evidence for oxidative stress and defective antioxidant response in guinea pigs with tuberculosis.}, journal = {PloS one}, volume = {6}, number = {10}, pages = {e26254}, pmid = {22028843}, issn = {1932-6203}, support = {R21 AI083856/AI/NIAID NIH HHS/United States ; U01 AI070456/AI/NIAID NIH HHS/United States ; AI070456/AI/NIAID NIH HHS/United States ; AI083856/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*metabolism ; Bacterial Load/drug effects/immunology ; Disease Progression ; Gene Expression Regulation/drug effects/immunology ; Glutathione/blood ; Guinea Pigs ; Lung/drug effects/metabolism/microbiology/pathology ; Malondialdehyde/metabolism ; Mycobacterium bovis/immunology ; Mycobacterium tuberculosis/immunology/pathogenicity/physiology ; NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects/immunology ; Tuberculosis/blood/*metabolism/pathology/prevention &amp; control ; Vaccination ; }, abstract = {The development of granulomatous inflammation with caseous necrosis is an important but poorly understood manifestation of tuberculosis in humans and some animal models. In this study we measured the byproducts of oxidative stress in granulomatous lesions as well as the systemic antioxidant capacity of BCG vaccinated and non-vaccinated guinea pigs experimentally infected with Mycobacterium tuberculosis. In non-vaccinated guinea pigs, oxidative stress was evident within 2 weeks of infection as measured by a decrease in the serum total antioxidant capacity and blood glutathione levels accompanied by an increase in malondialdehyde, a byproduct of lipid peroxidation, within lesions. Despite a decrease in total and reduced blood glutathione concentrations, there was an increase in lesion glutathione by immunohistochemistry in response to localized oxidative stress. In addition there was an increase in the expression of the host transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), which regulates several protein and non-proteins antioxidants, including glutathione. Despite the increase in cytoplasmic expression of Nrf2, immunohistochemical staining revealed a defect in Nrf2 nuclear translocation within granulomatous lesions as well as a decrease in the expression of the Nrf2-regulated antioxidant protein NQO1. Treating M. tuberculosis-infected guinea pigs with the antioxidant drug N-acetyl cysteine (NAC) partially restored blood glutathione concentrations and the serum total antioxidant capacity. Treatment with NAC also decreased spleen bacterial counts, as well as decreased the lung and spleen lesion burden and the severity of lesion necrosis. These data suggest that the progressive oxidative stress during experimental tuberculosis in guinea pigs is due in part to a defect in host antioxidant defenses, which, we show here, can be partially restored with antioxidant treatment. These data suggest that the therapeutic strategies that reduce oxidant-mediated tissue damage may be beneficial as an adjunct therapy in the treatment and prevention of tuberculosis in humans.}, }
@article {pmid22020669, year = {2012}, author = {Dieckmann, A and Kriebel, M and Andriambeloson, E and Ziegler, D and Elmlinger, M}, title = {Treatment with Actovegin® improves sensory nerve function and pathology in streptozotocin-diabetic rats via mechanisms involving inhibition of PARP activation.}, journal = {Experimental and clinical endocrinology &amp; diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association}, volume = {120}, number = {3}, pages = {132-138}, doi = {10.1055/s-0031-1291248}, pmid = {22020669}, issn = {1439-3646}, mesh = {Animals ; Central Nervous System Stimulants/pharmacology/therapeutic use ; Diabetes Mellitus, Experimental/chemically induced/complications/*drug therapy/pathology ; Diabetic Neuropathies/pathology/physiopathology/*prevention &amp; control ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/pharmacology/therapeutic use ; Heme/*analogs &amp; derivatives/pharmacology/therapeutic use ; Male ; Poly Adenosine Diphosphate Ribose/antagonists &amp; inhibitors/metabolism ; *Poly(ADP-ribose) Polymerase Inhibitors ; Rats ; Rats, Sprague-Dawley ; Sensory Receptor Cells/*drug effects/metabolism/pathology/physiology ; Signal Transduction/drug effects/physiology ; Streptozocin ; }, abstract = {BACKGROUND: Diabetic neuropathy is one of the most severe complications of diabetes, affecting approximately one-third of diabetic patients. We investigated the potential neuroprotective effect of Actovegin®, a deproteinized hemoderivative of calf blood, in an animal model of diabetic neuropathy.<br><br>METHODS: A single intravenous injection of streptozotocin (STZ, 55 mg/kg) was used to induce experimental diabetes in male Sprague-Dawley rats. Actovegin&#xae; (200 or 600 mg/kg) was administered intraperitoneally from day 11 to day 40 post-STZ exposure. N-acetylcysteine (NAC) was used as a positive control and was added to drinking water (0.2 g/l) from day 2 until day 40. Measurements to assess efficacy included sensory nerve conduction velocity (SNCV), intraepidermal nerve fiber density (IENFD), and poly(ADP-ribose) content.<br><br>RESULTS: A decrease (35%) in sensory nerve conduction velocity (SNCV) was seen in STZ-induced diabetic rats from day 10 post-STZ administration and persisted at days 25 and 39. At study completion (day 41), a decrease (32%) in intraepidermal nerve fiber density (IENFD) was found in hind-paw skin biopsies from STZ-rats. Reduced SNCV and IENFD were significantly ameliorated by both doses of Actovegin&#xae;. More-over, 600 mg/kg Actovegin&#xae; markedly decreased poly(ADP-ribose) polymerase (PARP) activity in sciatic nerves from STZ-diabetic rats as assessed by poly(ADP-ribose) content.<br><br>CONCLUSION: Actovegin&#xae; improved several para-meters of experimental diabetic neuropathy via mechanisms involving suppression of PARP activation, providing a rationale for treatment of this disease in humans.}, }
@article {pmid22020376, year = {2012}, author = {Liu, H and Jiang, C and Xiong, C and Ruan, J}, title = {DEDC, a new flavonoid induces apoptosis via a ROS-dependent mechanism in human neuroblastoma SH-SY5Y cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {26}, number = {1}, pages = {16-23}, doi = {10.1016/j.tiv.2011.10.002}, pmid = {22020376}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclohexanones/*pharmacology ; Flavones/*pharmacology ; Humans ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Neuroblastoma/metabolism ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/*metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Thiocarbamates/pharmacology ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {The poor prognosis of neuroblastoma and lack of effective remedies have necessitated the application of new therapeutic scheme. Over the past few years, it has been found that flavonoids could exert specific cytotoxic activity towards cancer cells. 2-(cis-1,2-dihydroxy-4-oxo-cyclohex-5-enyl)-5,7-dihydroxy-chromone (DEDC) is a plant-derived flavonoid extracted from the aerial part of Macrothelypteris torresiana. The present study investigated the cytotoxic effects and underlying biochemical pathway leading to cell death on the response of DEDC treatment in human neuroblastoma cells. Our results indicated that (a) DEDC induced SH-SY5Y cells apoptosis by elevating reactive oxygen species (ROS) generation, and ROS generation that could be quenched by the antioxidants N-acetyl cystein (NAC). (b) The signal transducer and activator of transcription 3 (STAT3) played a crucial role in DEDC-triggered cell death. (c) Nuclear factor Kappa B (NF-κB) was activated following exposure to DEDC, and suppressing NF-κB pathway by pyrrolidine dithiocarbamate (PDTC, a potent NF-κB inhibitor) significantly increased neuroblastoma cell sensitivity to the pro-apoptotic effect of DEDC. Overall, this study shed light on the mechanism of action of DEDC and suggested more rational approaches to investigation and therapy for this childhood malignancy.}, }
@article {pmid22020177, year = {2011}, author = {Kim, MS and Park, HR and Chung, HY and Kim, HS and Yu, BP and Yang, HS and Lee, J}, title = {Organic solvent metabolite, 1,2-diacetylbenzene, impairs neural progenitor cells and hippocampal neurogenesis.}, journal = {Chemico-biological interactions}, volume = {194}, number = {2-3}, pages = {139-147}, doi = {10.1016/j.cbi.2011.10.001}, pmid = {22020177}, issn = {1872-7786}, mesh = {Acetophenones/*toxicity ; Animals ; Blotting, Western ; Male ; Mice ; Mice, Inbred C57BL ; Neurogenesis/*drug effects ; Neurons/cytology/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Stem Cells/cytology/*drug effects/metabolism ; }, abstract = {1,2-Diacetylbenzene (DAB) is a neurotoxic minor metabolite of 1,2-diethylbenzene or naphthalene reaction product with OH radical. DAB causes central and peripheral neuropathies that lead to motor neuronal deficits. However, the potent effects and molecular mechanisms of DAB on neural progenitor cells and hippocampus are unknown. In the current study, we report the DAB damage at lower doses (less than 50 μM) to neural progenitor cell (NPC) invitro and hippocampal neurogenesis invivo. DAB significantly suppressed NPC proliferation with increased reactive oxygen species (ROS) production in a dose-dependent manner. The suppression of NPC proliferation was effectively blunted by the action of an antioxidant, N-acetyl cysteine. Six-week-old male C57BL/6 mice were treated with 1 or 5 mg/kg DAB for 2 weeks. DAB significantly suppressed NPC proliferation in the dentate gyrus of the hippocampus, indicating impaired hippocampal neurogenesis. Increased ROS production and the formation of oxidative stress-associated dinitrophenyl adducts were detected in the hippocampal homogenates of DAB-treated mice. DAB activated Mac-1-positive immune cells which are involved in inflammatory process in the hippocampus. Taken together, these results confirm that oxidative stress by DAB might be cause of adverse effects in NPC proliferation and hippocampal neurogenesis.}, }
@article {pmid22019695, year = {2012}, author = {Lee, YJ and Jeong, HY and Kim, YB and Lee, YJ and Won, SY and Shim, JH and Cho, MK and Nam, HS and Lee, SH}, title = {Reactive oxygen species and PI3K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211H cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {50}, number = {2}, pages = {116-123}, doi = {10.1016/j.fct.2011.10.035}, pmid = {22019695}, issn = {1873-6351}, mesh = {Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Enzymologic ; Heme Oxygenase-1/genetics/metabolism ; Humans ; Isothiocyanates ; Mesothelioma/*metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Sulfoxides ; Thiocyanates/administration &amp; dosage/toxicity ; }, abstract = {The nuclear factor erythroid-derived 2 related factor 2 (Nrf2)/heme oxygenase (HO)-1 induction plays cytoprotective roles against oxidative injury, apoptosis, and anticancer therapy; however, little is known about its regulation in human mesothelioma MSTO-211H cells. In this study, we investigated Nrf2/HO-1 induction in response to sulforaphane and determined the signaling pathways involved in this process. Sulforaphane treatment decreased cell viability and triggered a rapid and transient increase in the intracellular ROS levels. Pretreatment with N-acetylcysteine (NAC) prevented sulforaphane-induced cytotoxicity. Erk1/2 was activated within 1h of sulforaphane addition, whereas Akt phosphorylation was suppressed until the first 8h, and was then maintained at an elevated level until 72h, displaying a biphasic regulatory feature. Nrf2 protein levels in both nuclear and whole cell lysates were increased after sulforaphane treatment and were decreased by pretreatment with NAC, actinomycin D and cycloheximide. Activation of the Nrf2/HO-1 system after sulforaphane treatment was suppressed by pretreatment with NAC or Ly294002, a PI3K inhibitor. Knockdown of Nrf2 with siRNA decreased cell viability and attenuated sulforaphane-induced HO-1 up-regulation. Overall, our results indicate that ROS generation and/or activation of PI3K/Akt signaling regulate cell survival and Nrf2-driven HO-1 expression in sulforaphane-treated MSTO-211H cells.}, }
@article {pmid22017215, year = {2011}, author = {Sarris, J and Mischoulon, D and Schweitzer, I}, title = {Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials.}, journal = {Bipolar disorders}, volume = {13}, number = {5-6}, pages = {454-465}, doi = {10.1111/j.1399-5618.2011.00945.x}, pmid = {22017215}, issn = {1399-5618}, mesh = {Amino Acids/therapeutic use ; Antimanic Agents/*therapeutic use ; Bipolar Disorder/*diet therapy/*drug therapy ; *Clinical Trials as Topic/methods/standards ; Databases, Factual/statistics &amp; numerical data ; *Dietary Supplements ; Fatty Acids, Omega-3/therapeutic use ; Humans ; Minerals/therapeutic use ; Treatment Outcome ; Vitamins/therapeutic use ; }, abstract = {OBJECTIVE: Studies using augmentation of pharmacotherapies with nutraceuticals in bipolar disorder (BD) have been conducted and preliminary evidence in many cases appears positive. To date, however, no specialized systematic review of this area has been conducted. We present the first systematic review of clinical trials using nutrient-based nutraceuticals in combination with standard pharmacotherapies to treat BD. A subsequent aim of this report was to discuss posited underlying mechanisms of action.<br><br>METHODS: &#x2002; PubMed, CINAHL, Web of Science, and Cochrane Library databases, and grey literature were searched during mid-2010 for human clinical trials in English using nutraceuticals such as omega-3, N-acetyl cysteine (NAC), inositol, and vitamins and minerals, in combination with pharmacotherapies to treat bipolar mania and bipolar depression. A review of the results including an effect size analysis (Cohen's d) was subsequently conducted.<br><br>RESULTS: &#x2002; In treating bipolar depression, positive evidence with large effect sizes were found for NAC (d=1.04) and a chelated mineral and vitamin formula (d=1.70). On the outcome of bipolar mania, several nutraceuticals reduced mania with strong clinical effects: a chelated mineral formula (d=0.83), L-tryptophan (d=1.47), magnesium (d=1.44), folic acid (d=0.40), and branched-chain amino acids (d=1.60). Mixed, but mainly positive, evidence was found for omega-3 for bipolar depression, while no evidentiary support was found for use in mania. No significant effect on BD outcome scales was found for inositol (possibly due to small samples).<br><br>CONCLUSIONS: &#x2002; BD treatment outcomes may potentially be improved by additional use of certain nutraceuticals with conventional pharmacotherapies. However, caution should be extended in interpreting the large effects of several isolated studies, as they have not yet been replicated in larger trials.}, }
@article {pmid22015471, year = {2012}, author = {Pocernich, CB and Butterfield, DA}, title = {Elevation of glutathione as a therapeutic strategy in Alzheimer disease.}, journal = {Biochimica et biophysica acta}, volume = {1822}, number = {5}, pages = {625-630}, pmid = {22015471}, issn = {0006-3002}, support = {P01 AG005119/AG/NIA NIH HHS/United States ; P01 AG005119-24/AG/NIA NIH HHS/United States ; AG-05119/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Alzheimer Disease/*drug therapy/metabolism ; Antioxidants/*therapeutic use ; DNA/metabolism ; Dipeptides/*therapeutic use ; Glutathione/*biosynthesis ; Humans ; Oxidation-Reduction ; }, abstract = {Oxidative stress has been associated with the onset and progression of mild cognitive impairment (MCI) and Alzheimer disease (AD). AD and MCI brain and plasma display extensive oxidative stress as indexed by protein oxidation, lipid peroxidation, free radical formation, DNA oxidation, and decreased antioxidants. The most abundant endogenous antioxidant, glutathione, plays a significant role in combating oxidative stress. The ratio of oxidized to reduced glutathione is utilized as a measure of intensity of oxidative stress. Antioxidants have long been considered as an approach to slow down AD progression. In this review, we focus on the elevation on glutathione through N-acetyl-cysteine (NAC) and γ-glutamylcysteine ethyl ester (GCEE) as a potential therapeutic approach for Alzheimer disease. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.}, }
@article {pmid22013938, year = {2011}, author = {Sridhar, N and Krishnakishore, C and Sandeep, Y and Sriramnaveen, P and Manjusha, Y and Sivakumar, V}, title = {Chloroform poisoning--a case report.}, journal = {Renal failure}, volume = {33}, number = {10}, pages = {1037-1039}, doi = {10.3109/0886022X.2011.618920}, pmid = {22013938}, issn = {1525-6049}, mesh = {Adult ; Chemical and Drug Induced Liver Injury/etiology/therapy ; Chloroform/*poisoning ; Humans ; Male ; Renal Dialysis ; Renal Insufficiency/chemically induced/therapy ; }, abstract = {Chloroform, a halogenated hydrocarbon, causes central nervous system (CNS) depression, cardiac arrhythmias, hepatotoxicity, and renal failure. We describe a successful outcome in a case of chloroform ingestion with renal and hepatotoxicity with N-acetylcysteine (NAC) administration and hemodialysis support.}, }
@article {pmid22012146, year = {2011}, author = {Jalilehvand, F and Amini, Z and Parmar, K and Kang, EY}, title = {Cadmium(II) N-acetylcysteine complex formation in aqueous solution.}, journal = {Dalton transactions (Cambridge, England : 2003)}, volume = {40}, number = {47}, pages = {12771-12778}, doi = {10.1039/c1dt11705j}, pmid = {22012146}, issn = {1477-9234}, mesh = {Acetylcysteine/chemistry ; Cadmium/*chemistry ; Coordination Complexes/chemical synthesis/*chemistry ; Hydrogen-Ion Concentration ; Magnetic Resonance Spectroscopy ; Water/chemistry ; X-Ray Absorption Spectroscopy ; }, abstract = {The complex formation between Cd(II) ions and N-acetylcysteine (H(2)NAC) in aqueous solution was investigated using Cd K- and L(3)-edge X-ray absorption and (113)Cd NMR spectroscopic techniques. Two series of 0.1 M Cd(II) solutions with the total N-acetylcysteine concentration c(H2NAC) varied between 0.2-2 M were studied at pH 7.5 and 11.0, respectively. At pH = 11 a novel mononuclear [Cd(NAC)(4)](6-) complex with the average Cd-S distance 2.53(2) Å and the chemical shift δ((113)Cd) = 677 ppm was found to dominate at a concentration of the free deprotonated ligand [NAC(2-)] > 0.1 M, consistent with our previous reports on cadmium tetrathiolate complex formation with cysteine and glutathione. At pH 7.5 much higher ligand excess ([HNAC(-)] > 0.6 M) is required to make this tetrathiolate complex the major species. The (113)Cd NMR spectrum of a solution containing c(Cd(II)) = 0.5 M and c(H2NAC) = 1.0 M measured at 288 K showed three broad signals at 421, 583 and 642 ppm, which can be attributed to CdS(3)O(3), CdS(3)O and CdS(4) coordination sites, respectively, in oligomeric Cd(II)-NAC species with single thiolate bridges between the cadmium ions.}, }
@article {pmid22001448, year = {2012}, author = {Ginzkey, C and Stueber, T and Friehs, G and Koehler, C and Hackenberg, S and Richter, E and Hagen, R and Kleinsasser, NH}, title = {Analysis of nicotine-induced DNA damage in cells of the human respiratory tract.}, journal = {Toxicology letters}, volume = {208}, number = {1}, pages = {23-29}, doi = {10.1016/j.toxlet.2011.09.029}, pmid = {22001448}, issn = {1879-3169}, mesh = {Acetylcysteine/metabolism ; Antioxidants/metabolism ; Apoptosis/drug effects ; Bronchi/cytology/drug effects ; Cell Line ; Comet Assay ; *DNA Damage ; Dose-Response Relationship, Drug ; Humans ; In Situ Nick-End Labeling ; Mecamylamine/metabolism ; Mutagens/*toxicity ; Nasal Mucosa/drug effects ; Nicotine/*toxicity ; Nicotinic Agonists/*toxicity ; Nicotinic Antagonists/metabolism ; Oxidative Stress ; Respiratory Mucosa/*drug effects ; }, abstract = {Epithelium of the upper and lower airways is a common origin of tobacco-related cancer. The main tobacco alkaloid nicotine may be associated with tumor progression. The potential of nicotine in inducing DNA mutations as a step towards cancer initiation is still controversially discussed. Different subtypes of nicotinic acetylcholine receptors (nAChR) are expressed in human nasal mucosa and a human bronchial cell line representing respiratory mucosa as a possible target for receptor-mediated pathways. In the present study, both cell systems were investigated with respect to DNA damage induced by nicotine and its mechanisms. Specimens of human nasal mucosa were harvested during surgery of the nasal air passage. After enzymatic digestion over night, single cells were exposed to an increasing nicotine concentration between 0.001 mM and 4.0mM. In a second step co-incubation was performed using the antioxidant N-acetylcysteine (NAC) and the nAChR antagonist mecamylamine. DNA damage was assessed using the alkali version of the comet assay. Dose finding experiments for mecamylamine to evaluate the maximal inhibitory effect were performed in the human bronchial cell line BEAS-2B with an increasing mecamylamine concentration and a constant nicotine concentration. The influence of nicotine in the apoptotic pathway was evaluated in BEAS-2B cells with the TUNEL assay combined with flow cytometry. After 1h of nicotine exposure with 0.001, 0.01, 0.1, 1.0 and 4.0mM, significant DNA damage was determined at 1.0mM. Further co-incubation experiments with mecamylamine and NAC were performed using 1.0mM of nicotine. The strongest inhibitory effect was measured at 1.0mM mecamylamine and this concentration was used for co-incubation. Both, the antioxidant NAC at a concentration of 1.0mM, based on the literature, as well as the receptor antagonist were capable of complete inhibition of the nicotine-induced DNA migration in the comet assay. A nicotine-induced increase or decrease in apoptosis as assessed by the TUNEL assay in BEAS-2B could not be detected. These results support the hypothesis that oxidative stress is responsible for nicotine-induced DNA damage. Similar results exist for other antioxidants in different cell systems. The decrease in DNA damage after co-incubation with a nAChR antagonist indicates a receptor-dependent pathway of induction for oxidative stress. Further investigations concerning pathways of receptor-mediated DNA damage via nAChR, the role of reactive oxygen species and apoptosis in this cell system will elucidate underlying mechanisms.}, }
@article {pmid22001321, year = {2011}, author = {Shankaran, P and Vlkova, L and Liskova, J and Melkova, Z}, title = {Heme arginate potentiates latent HIV-1 reactivation while inhibiting the acute infection.}, journal = {Antiviral research}, volume = {92}, number = {3}, pages = {434-446}, doi = {10.1016/j.antiviral.2011.09.011}, pmid = {22001321}, issn = {1872-9096}, mesh = {Acetylcysteine/pharmacology ; Anti-HIV Agents/*pharmacology ; Antigens, CD/metabolism ; Antigens, Differentiation, T-Lymphocyte/metabolism ; Arginine/*pharmacology ; Cell Line ; HIV-1/*drug effects/physiology ; Heme/*pharmacology ; Heme Oxygenase-1/antagonists &amp; inhibitors/metabolism ; Humans ; Jurkat Cells ; Lectins, C-Type/metabolism ; Metalloporphyrins/pharmacology ; Protoporphyrins/pharmacology ; Proviruses/drug effects/genetics ; Reverse Transcription/drug effects ; Virus Activation/*drug effects ; Virus Latency/*drug effects ; Virus Replication/drug effects ; }, abstract = {Human immunodeficiency virus-1 (HIV-1) successfully escapes from host immune surveillance, vaccines and antiretroviral agents. The available antiretroviral compounds can only control viremia, but it is impossible to eliminate the virus from the organism, namely because HIV-1 provirus persists in the reservoir cells from which the virus repeatedly disseminates into new cells. Current therapeutic approaches, however, do not specifically address the stage of virus reactivation. Heme has been demonstrated as very efficient in inhibiting HIV-1 reverse transcription, while its derivative hemin ameliorated HIV-1 infection via induction of heme oxygenase-1. Normosang (heme arginate; HA) is a human hemin-containing compound used to treat acute porphyria. In this work, we studied the effects of HA in HIV-1-acutely infected T-cell lines, and in cell lines harboring either a complete HIV-1 provirus (ACH-2 cells) or an HIV-1 "mini-virus" (Jurkat clones expressing EGFP under control of HIV LTR). We demonstrate that HA inhibited HIV-1 replication during the acute infection, which was accompanied by the inhibition of reverse transcription. On the other hand, HA alone stimulated the reactivation of HIV-1 "mini-virus" and synergized with phorbol ester or TNF-α in the reactivation of HIV-1 provirus. The stimulatory effects of HA were inhibited by N-acetyl cysteine, suggesting an increased redox stress and activation of NF-κB. Further, HA induced expression of heme oxygenase-1 (HO-1) in ACH-2 cells, while HO-1 was found expressed in untreated Jurkat clones. Inhibitor of HO-1 activity, tin protoporphyrin IX, further increased HA-mediated reactivation of HIV-1 "mini-virus" in Jurkat clones, and this effect was also inhibited by N-acetyl cysteine. The stimulatory effects of HA on HIV-1 reactivation thus seem to involve HO-1 and generation of free radicals. Additionally, the effective concentrations of HA did neither affect normal T-cell activation with PMA nor induce activation of the unstimulated cells. In conclusion, HA appears to possess a combination of unique properties that could help to decrease the pool of latently infected reservoir cells, while simultaneously inhibiting HIV-1 replication in newly infected cells. Our results thus suggest a new direction to explore in treatment of HIV/AIDS disease.}, }
@article {pmid22001287, year = {2011}, author = {Sun, X and Zhang, H and Zhang, Z and Wang, Y and Li, S}, title = {Involvement of a helix-loop-helix transcription factor CHC-1 in CO(2)-mediated conidiation suppression in Neurospora crassa.}, journal = {Fungal genetics and biology : FG &amp; B}, volume = {48}, number = {12}, pages = {1077-1086}, doi = {10.1016/j.fgb.2011.09.003}, pmid = {22001287}, issn = {1096-0937}, mesh = {Base Sequence ; Carbon Dioxide/pharmacology ; DNA, Fungal/genetics ; Fungal Proteins/*genetics/*metabolism ; Gene Deletion ; *Gene Expression Regulation, Fungal ; Genes, Fungal ; Helix-Loop-Helix Motifs/genetics ; Mutation ; Neurospora crassa/*genetics/growth &amp; development/metabolism ; Sequence Analysis, RNA ; Signal Transduction ; Spores, Fungal/genetics/growth &amp; development/metabolism ; Transcription Factors/*genetics/*metabolism ; }, abstract = {The morphological switch from vegetative growth to conidiation in filamentous fungi is highly regulated, but the understanding of the regulatory mechanisms is limited. In this study, by screening a set of knock-out mutants corresponding to 103 transcription factor encoding genes in Neurospora crassa, a mutant was found to produce abundant conidia in race tubes in which conidiation in the wild-type strain was suppressed. The corresponding gene NCU00749 encodes a protein containing a helix-loop-helix DNA binding region. Unlike enhanced conidiation in ras-1 and sod-1 mutants, which was completely suppressed by antioxidant N-acetyl cysteine, enhanced conidiation in the NCU00749 mutant was only slightly affected by N-acetyl cysteine. When grown on slants, the NCU00749 deletion mutant exhibited earlier conidial formation than the wild-type strain, and this was more evident at a higher (5%) CO(2) concentration. Therefore, we named NCU00749 as conidiation at high carbon dioxide-1 (chc-1). Genes that are highly expressed during conidial development, eas, con-6, con-8 and con-10, were transcribed at a higher rate in the chc-1 deletion mutant than the wild-type strain in response to conidiation induction. To determine the mechanisms by which CHC-1 regulates conidiation, we conducted a RNA sequencing analysis and found that 404 genes exhibited ≥ 2 fold changes in transcription in response to chc-1 deletion. Among them, fluffy and ada-6, two transcription factor genes that positively regulate conidiation in N. crassa, and rca-1, whose homolog flbD in Aspergillus nidulans is essential for conidiation, were upregulated in the chc-1 deletion mutant. Results of RNA sequencing also suggest that signal transduction via the cAMP and the MAK-2 mediated signal pathways, and ROS generation and removal, mechanisms known to regulate conidiation, are not involved in chc-1 mediated control of conidiation. In addition, chc-1 also influences expression of genes involved in other important biological processes besides conidiation such as carbon metabolism, sphingolipid synthesis, cell wall synthesis, and calcium signaling.}, }
@article {pmid22001183, year = {2011}, author = {Shebrain, S}, title = {Commentary on "N-acetylcysteine (NAC) protects against acute kidney injury following prolonged pneumoperitoneum".}, journal = {The Journal of surgical research}, volume = {171}, number = {2}, pages = {e179-80}, doi = {10.1016/j.jss.2011.07.050}, pmid = {22001183}, issn = {1095-8673}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/etiology/*prevention &amp; control ; Humans ; Pneumoperitoneum/*complications ; Protective Agents/*therapeutic use ; }, }
@article {pmid21998720, year = {2011}, author = {Lan, A and Liao, X and Mo, L and Yang, C and Yang, Z and Wang, X and Hu, F and Chen, P and Feng, J and Zheng, D and Xiao, L}, title = {Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells.}, journal = {PloS one}, volume = {6}, number = {10}, pages = {e25921}, pmid = {21998720}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Hypoxia/drug effects ; Cobalt/*toxicity ; Cystathionine beta-Synthase/metabolism ; Down-Regulation/drug effects ; Enzyme Activation/drug effects ; Hydrogen Sulfide/*pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; MAP Kinase Signaling System/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinase 1/genetics/*metabolism ; Mitogen-Activated Protein Kinase 3/genetics/*metabolism ; Neuroprotective Agents/pharmacology ; PC12 Cells ; Phosphorylation/drug effects ; Rats ; Reactive Oxygen Species/*metabolism ; Up-Regulation/drug effects ; p38 Mitogen-Activated Protein Kinases/genetics/*metabolism ; }, abstract = {Hydrogen sulfide (H(2)S) has been proposed as a novel neuromodulator and neuroprotective agent. Cobalt chloride (CoCl(2)) is a well-known hypoxia mimetic agent. We have demonstrated that H(2)S protects against CoCl(2)-induced injuries in PC12 cells. However, whether the members of mitogen-activated protein kinases (MAPK), in particular, extracellular signal-regulated kinase1/2(ERK1/2) and p38MAPK are involved in the neuroprotection of H(2)S against chemical hypoxia-induced injuries of PC12 cells is not understood. We observed that CoCl(2) induced expression of transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α), decreased cystathionine-β synthase (CBS, a synthase of H(2)S) expression, and increased generation of reactive oxygen species (ROS), leading to injuries of the cells, evidenced by decrease in cell viability, dissipation of mitochondrial membrane potential (MMP) , caspase-3 activation and apoptosis, which were attenuated by pretreatment with NaHS (a donor of H(2)S) or N-acetyl-L cystein (NAC), a ROS scavenger. CoCl(2) rapidly activated ERK1/2, p38MAPK and C-Jun N-terminal kinase (JNK). Inhibition of ERK1/2 or p38MAPK or JNK with kinase inhibitors (U0126 or SB203580 or SP600125, respectively) or genetic silencing of ERK1/2 or p38MAPK by RNAi (Si-ERK1/2 or Si-p38MAPK) significantly prevented CoCl(2)-induced injuries. Pretreatment with NaHS or NAC inhibited not only CoCl(2)-induced ROS production, but also phosphorylation of ERK1/2 and p38MAPK. Thus, we demonstrated that a concurrent activation of ERK1/2, p38MAPK and JNK participates in CoCl(2)-induced injuries and that H(2)S protects PC12 cells against chemical hypoxia-induced injuries by inhibition of ROS-activated ERK1/2 and p38MAPK pathways. Our results suggest that inhibitors of ERK1/2, p38MAPK and JNK or antioxidants may be useful for preventing and treating hypoxia-induced neuronal injury.}, }
@article {pmid21998290, year = {2011}, author = {Berdelle, N and Nikolova, T and Quiros, S and Efferth, T and Kaina, B}, title = {Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells.}, journal = {Molecular cancer therapeutics}, volume = {10}, number = {12}, pages = {2224-2233}, doi = {10.1158/1535-7163.MCT-11-0534}, pmid = {21998290}, issn = {1538-8514}, mesh = {Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Apoptosis/drug effects/genetics ; Artemisinins/*pharmacology/therapeutic use ; Artesunate ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/metabolism ; DNA Breaks, Double-Stranded/*drug effects ; *DNA Damage/drug effects ; DNA Repair/*drug effects/genetics ; DNA-Binding Proteins/metabolism ; Drug Evaluation, Preclinical ; Humans ; Models, Biological ; Neoplasms/drug therapy/genetics/metabolism/*pathology ; Oxidative Stress/*drug effects/genetics ; Protein Serine-Threonine Kinases/metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Proteins/metabolism ; Up-Regulation/drug effects ; }, abstract = {Artesunate, the active agent from Artemisia annua L. used in the traditional Chinese medicine, is being applied as a first-line drug for malaria treatment, and trials are ongoing that include this drug in cancer therapy. Despite increasing interest in its therapeutic application, the mode of cell killing provoked by artesunate in human cells is unknown. Here, we show that artesunate is a powerful inducer of oxidative DNA damage, giving rise to formamidopyrimidine DNA glycosylase-sensitive sites and the formation of 8-oxoguanine and 1,N6-ethenoadenine. Oxidative DNA damage was induced in LN-229 human glioblastoma cells dose dependently and was paralleled by cell death executed by apoptosis and necrosis, which could be attenuated by radical scavengers such as N-acetyl cysteine. Oxidative DNA damage resulted in DNA double-strand breaks (DSB) as determined by γH2AX foci that colocalized with 53BP1. Upon chronic treatment with artesunate, the level of DSB continuously increased over the treatment period up to a steady-state level, which is in contrast to ionizing radiation that induced a burst of DSB followed by a decline due to their repair. Knockdown of Rad51 by short interfering RNA and inactivation of DNA-PK strongly sensitized glioma cells to artesunate. These data indicate that both homologous recombination and nonhomologous end joining are involved in the repair of artesunate-induced DSB. Artesunate provoked a DNA damage response (DDR) with phosphorylation of ATM, ATR, Chk1, and Chk2. Overall, these data revealed that artesunate induces oxidative DNA lesions and DSB that continuously increase during the treatment period and accumulate until they trigger DDR and finally tumor cell death.}, }
@article {pmid21997484, year = {2012}, author = {Starosta, V and Wu, T and Zimman, A and Pham, D and Tian, X and Oskolkova, O and Bochkov, V and Berliner, JA and Birukova, AA and Birukov, KG}, title = {Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine.}, journal = {American journal of respiratory cell and molecular biology}, volume = {46}, number = {3}, pages = {331-341}, pmid = {21997484}, issn = {1535-4989}, support = {P01 HL58064/HL/NHLBI NIH HHS/United States ; R01 HL089257/HL/NHLBI NIH HHS/United States ; HL87823/HL/NHLBI NIH HHS/United States ; P01 HL058064/HL/NHLBI NIH HHS/United States ; HL89257/HL/NHLBI NIH HHS/United States ; R01 HL107920/HL/NHLBI NIH HHS/United States ; R01 HL076259/HL/NHLBI NIH HHS/United States ; HL76259/HL/NHLBI NIH HHS/United States ; R56 HL107920/HL/NHLBI NIH HHS/United States ; R01 HL087823/HL/NHLBI NIH HHS/United States ; HL107920/HL/NHLBI NIH HHS/United States ; P01 HL030568/HL/NHLBI NIH HHS/United States ; }, mesh = {Adherens Junctions/drug effects/metabolism ; Antigens, CD/metabolism ; Cadherins/metabolism ; Capillary Permeability/*drug effects ; Catenins/metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; Electric Impedance ; Endothelial Cells/*drug effects/metabolism ; Humans ; Phosphatidylcholines/*pharmacology ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Time Factors ; Tyrosine ; beta Catenin/metabolism ; src-Family Kinases/metabolism ; Delta Catenin ; }, abstract = {The generation of phospholipid oxidation products in atherosclerosis, sepsis, and lung pathologies affects endothelial barrier function, which exerts significant consequences on disease outcomes in general. Our group previously showed that oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (OxPAPC) at low concentrations increases endothelial cell (EC) barrier function, but decreases it at higher concentrations. In this study, we determined the mechanisms responsible for the pulmonary endothelial cell barrier dysfunction induced by high OxPAPC concentrations. OxPAPC at a range of 5-20 μg/ml enhanced EC barriers, as indicated by increased transendothelial electrical resistance. In contrast, higher OxPAPC concentrations (50-100 μg/ml) rapidly increased EC permeability, which was accompanied by increased total cell protein tyrosine (Tyr) phosphorylation, phosphorylation at Tyr-418, the activation of Src kinase, and the phosphorylation of adherens junction (AJ) protein vascular endothelial cadherin (VE-cadherin) at Tyr-731 and Tyr-658, which was not observed in ECs stimulated with low OxPAPC doses. The early tyrosine phosphorylation of VE-cadherin was linked to the dissociation of VE-cadherin-p120-catenin/β-catenin complexes and VE-cadherin internalization, whereas low OxPAPC doses promoted the formation of VE-cadherin-p120-catenin/β-catenin complexes. High but not low doses of OxPAPC increased the production of reactive oxygen species (ROS) and protein oxidation. The inhibition of Src by PP2 and ROS production by N-acetyl cysteine inhibited the disassembly of VE-cadherin-p120-catenin complexes, and attenuated high OxPAPC-induced EC barrier disruption. These results show the differential effects of OxPAPC doses on VE-cadherin-p120-catenin complex assembly and EC barrier function. These data suggest that the rapid tyrosine phosphorylation of VE-cadherin and other potential targets mediated by Src and ROS-dependent mechanisms plays a key role in the dissociation of AJ complexes and EC barrier dysfunction induced by high OxPAPC doses.}, }
@article {pmid21993884, year = {2012}, author = {Salhan, D and Pathak, S and Husain, M and Tandon, P and Kumar, D and Malhotra, A and Meggs, LG and Singhal, PC}, title = {HIV gene expression deactivates redox-sensitive stress response program in mouse tubular cells both in vitro and in vivo.}, journal = {American journal of physiology. Renal physiology}, volume = {302}, number = {1}, pages = {F129-40}, pmid = {21993884}, issn = {1522-1466}, support = {R01 DK083931/DK/NIDDK NIH HHS/United States ; R01 DK084910/DK/NIDDK NIH HHS/United States ; R01DK084910/DK/NIDDK NIH HHS/United States ; }, mesh = {AIDS-Associated Nephropathy/*etiology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Catalase/biosynthesis ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/metabolism ; HIV Infections/genetics ; HIV-1 ; Kidney Tubules/*physiopathology ; Mice ; Mice, Transgenic ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Shc Signaling Adaptor Proteins/*metabolism ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; Superoxide Dismutase/biosynthesis ; }, abstract = {Human immunodeficiency virus (HIV)-1 has been reported to cause tubular cell injury both in in vivo and in vitro studies. In the present study, we evaluated the role of oxidative stress in the induction of apoptosis in HIV gene expressing mouse tubular cells in in vivo (Tg26, a transgenic mouse model of HIV-associated nephropathy) and in vitro (tubular cells were transduced with pNL4-3: ΔG/P-GFP, VSV.G psueudo typed virus) studies. Although Tg26 mice showed enhanced tubular cell reactive oxygen species (ROS) generation and apoptosis, renal tissue did not display a robust antioxidant response in the form of enhanced free radical scavenger (MnSOD/catalase) expression. Tg26 mice not only showed enhanced tubular cell expression of phospho-p66ShcA but also displayed nuclear Foxo3a translocation to the cytoplasm. These findings indicated deactivation of tubular cell Foxo3A-dependent redox-sensitive stress response program (RSSRP) in Tg26 mice. In in vitro studies, NL4-3 (pNL4-3: ΔG/P-GFP, VSV.G pseudotyped virus)-transduced mouse proximal tubular cells (NL4-3/MPTEC) displayed enhanced phosphorylation of p66ShcA. NL4-3/MPTECs also displayed greater (P < 0.01) ROS generation when compared with empty vector-transduced tubular cells; however, both diminution of p66ShcA and N-acetyl cysteine attenuated NL4-3-induced tubular cell ROS generation as well as apoptosis. In addition, both antioxidants and free radical scavengers partially inhibited HIV-induced tubular cell apoptosis. NL4-3/MPTEC displayed deactivation of RSSRP in the form of enhanced phosphorylation of Foxo3A and attenuated expression of superoxide dismutase (SOD) and catalase. Since both SOD and catalase were able to provide protection against HIV-1-induced tubular cell apoptosis, it suggests that HIV-1-induced proapoptotic effect may be a consequence of the deactivated RSSRP.}, }
@article {pmid21993612, year = {2012}, author = {Lan, AP and Xiao, LC and Yang, ZL and Yang, CT and Wang, XY and Chen, PX and Gu, MF and Feng, JQ}, title = {Interaction between ROS and p38MAPK contributes to chemical hypoxia-induced injuries in PC12 cells.}, journal = {Molecular medicine reports}, volume = {5}, number = {1}, pages = {250-255}, doi = {10.3892/mmr.2011.623}, pmid = {21993612}, issn = {1791-3004}, mesh = {Animals ; Apoptosis ; Cell Hypoxia/drug effects ; Cobalt/toxicity ; Enzyme Inhibitors/pharmacology ; Imidazoles/pharmacology ; Membrane Potential, Mitochondrial ; PC12 Cells ; Phosphorylation ; Pyridines/pharmacology ; Rats ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {The present study investigated whether there is an interaction between reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (MAPK) during chemical hypoxia-induced injury in PC12 cells. The results of the present study showed that cobalt chloride (CoCl2), a chemical hypoxia agent, markedly induced ROS generation and phosphorylation of p38MAPK, as well as neuronal injuries. N-acetylcysteine (NAC), a ROS scavenger, blocked CoCl2-induced phosphorylation of p38MAPK. In addition, SB203580, an inhibitor of p38MAPK attenuated not only CoCl2-induced activation of p38MAPK, but also ROS production. These results suggest that ROS and p38MAPK are capable of interacting positively during chemical hypoxia. Furthermore, NAC and SB203580 markedly prevented CoCl2-induced cytotoxicity, apoptosis and a loss of mitochondrial membrane potential. Taken together, our findings suggest that the positive interaction between CoCl2 induction of ROS and p38MAPK activation may play a significant role in CoCl2-induced neuronal injuries. We provide new insights into the mechanisms responsible for CoCl2-induced injuries in PC12 cells.}, }
@article {pmid21987389, year = {2014}, author = {Karaytug, S and Sevgiler, Y and Karayakar, F}, title = {Comparison of the protective effects of antioxidant compounds in the liver and kidney of Cd- and Cr-exposed common carp.}, journal = {Environmental toxicology}, volume = {29}, number = {2}, pages = {129-137}, doi = {10.1002/tox.20779}, pmid = {21987389}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cadmium/*toxicity ; Carps ; Catalase/metabolism ; Chromium/*toxicity ; Curcumin/pharmacology ; Glutathione/metabolism ; Kidney/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism ; Oxidative Stress/drug effects ; Superoxide Dismutase/metabolism ; Taurine/pharmacology ; Thioctic Acid/pharmacology ; Water Pollutants, Chemical/*toxicity ; }, abstract = {The aim of this study was to see whether the taurine (TAU), alpha-lipoic acid (LA), curcumin (CUR), and N-acetylcysteine (NAC) protection against oxidative stress caused by heavy metals is owed to the metal-decreasing or antioxidative effect. In this context, liver and kidney tissues of common carp (Cyprinus carpio carpio L.) were exposed in vivo to model toxicants cadmium (Cd) and chromium (Cr). The tissues were dissected 96 h after intraperitoneal injection of the metals and antioxidant substances. Cd and Cr levels were determined in the liver using the ICP-OES, but we could not obtain enough kidney tissue to make the same measurements in the kidney. The enzymatic activities of SOD, CAT, and GPx, and the GSH redox status and lipid peroxidation levels were analyzed using spectrophotometric methods. Of all investigated antioxidants, only NAC decreased metal levels in the liver. Cd had little effect on oxidative stress parameters, while Cr showed a weak prooxidative effect. Cotreatment with TAU/LA/CUR/NAC and Cr significantly increased liver SOD activity. Chromium induced kidney SOD and CAT, but all antioxidants lowered CAT activity. Cadmium reduced liver and increased kidney GSSG. NAC increased liver GSH, but the increase did not correlate with decrease in Cd. Curcumin given with Cd increased kidney and decreased liver lipid peroxidation, whereas TAU with Cr increased lipid peroxidation in both tissues. N-Acetylcysteine was the most effective antioxidative agent, owing to its metal-decreasing function as well as to its effects on the GSH redox status. We believe that the investigated antioxidant substances which may have been involved in the reduction of Cr caused an increase in SOD activity and a decrease in CAT activity. Changes in the GSSG levels in both tissues might be an adaptive response to the prooxidative potential of Cd. Because of their respective tissue- and metal-dependent prooxidative effects, CUR and TAU deserve particular attention in regard to their use against metal toxicity, Cr in particular.}, }
@article {pmid21984567, year = {2011}, author = {Lu, Q and Sakhatskyy, P and Grinnell, K and Newton, J and Ortiz, M and Wang, Y and Sanchez-Esteban, J and Harrington, EO and Rounds, S}, title = {Cigarette smoke causes lung vascular barrier dysfunction via oxidative stress-mediated inhibition of RhoA and focal adhesion kinase.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {301}, number = {6}, pages = {L847-57}, pmid = {21984567}, issn = {1522-1504}, support = {HL67795/HL/NHLBI NIH HHS/United States ; R01 HL064936/HL/NHLBI NIH HHS/United States ; T32 HL094300/HL/NHLBI NIH HHS/United States ; HL64936/HL/NHLBI NIH HHS/United States ; R25 HL088992/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Actins/metabolism ; Adherens Junctions/metabolism ; Animals ; Antioxidants/pharmacology ; Cattle ; Cell Line ; Electric Impedance ; Enzyme Activation ; Epithelial Cells/drug effects/metabolism ; Focal Adhesion Kinase 1/metabolism ; Focal Adhesion Protein-Tyrosine Kinases/*metabolism ; Focal Adhesions/metabolism ; Lipopolysaccharides ; Lung/blood supply/drug effects/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; *Oxidative Stress ; Permeability/drug effects ; Primary Cell Culture ; Pulmonary Edema/chemically induced ; Smoke/*adverse effects ; Smoking/*adverse effects ; Nicotiana/*adverse effects ; rho GTP-Binding Proteins/metabolism ; rhoA GTP-Binding Protein/*metabolism ; }, abstract = {Cigarette smoke (CS) is a major cause of chronic lung and cardiovascular diseases. Recent studies indicate that tobacco use is also a risk factor for acute lung injury (ALI) associated with blunt trauma. Increased endothelial cell (EC) permeability is a hallmark of ALI. CS increases EC permeability in vitro and in vivo; however, the underlying mechanism is not well understood. In this study, we found that only 6 h of exposure to CS impaired endothelial barrier function in vivo, an effect associated with increased oxidative stress in the lungs and attenuated by the antioxidant N-acetylcysteine (NAC). CS also exacerbated lipopolysaccharide (LPS)-induced increase in vascular permeability in vivo. Similar additive effects were also seen in cultured lung EC exposed to cigarette smoke extract (CSE) and LPS. We further demonstrated that CSE caused disruption of focal adhesion complexes (FAC), F-actin fibers, and adherens junctions (AJ) and decreased activities of RhoA and focal adhesion kinase (FAK) in cultured lung EC. CSE-induced inhibition of RhoA and FAK, endothelial barrier dysfunction, and disassembly of FAC, F-actin, and AJ were prevented by NAC. In addition, the deleterious effects of CSE on FAC, F-actin fibers, and AJ were blunted by overexpression of constitutively active RhoA and of FAK. Our data indicate that CS causes endothelial barrier dysfunction via oxidative stress-mediated inhibition of RhoA and FAK.}, }
@article {pmid21981804, year = {2011}, author = {Yoshino, Y and Yamamoto, S and Kohsaka, S and Oshiro, S and Nakajima, K}, title = {Superoxide anion contributes to the induction of tumor necrosis factor alpha (TNFα) through activation of the MKK3/6-p38 MAPK cascade in rat microglia.}, journal = {Brain research}, volume = {1422}, number = {}, pages = {1-12}, doi = {10.1016/j.brainres.2011.09.009}, pmid = {21981804}, issn = {1872-6240}, mesh = {Animals ; Animals, Newborn ; Female ; MAP Kinase Kinase 3/*metabolism/physiology ; MAP Kinase Signaling System/drug effects/*physiology ; Microglia/drug effects/*enzymology ; Oxidative Stress/drug effects/physiology ; Pregnancy ; Primary Cell Culture ; Rats ; Rats, Wistar ; Superoxides/*pharmacology ; Tumor Necrosis Factor-alpha/*metabolism ; p38 Mitogen-Activated Protein Kinases/*physiology ; }, abstract = {Stimulation of rat microglia with lipopolysaccharide (LPS) in vitro induces production of the inflammatory/cytotoxic cytokine tumor necrosis factor alpha (TNFα) along with superoxide anion (O(2)(-)) and nitric oxide (NO). In this study, we investigated the role of O(2)(-) and NO in the induction of TNFα in microglia. The LPS-inducible TNFα was significantly suppressed by pretreatment with the O(2)(-) scavenger N-acetyl cysteine (NAC), but not by the NO scavenger 2-(4-Carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide, suggesting the close association of O(2)(-) with TNFα induction. NAC strongly depressed phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which is necessary for inducing TNFα in microglia. On the other hand, an O(2)(-) donor, 3-(4-Morpholinyl)sydnonimine (SIN-1), induced TNFα in microglia, and the effects of SIN-1 were completely abolished in the presence of superoxide dismutase. There is little likelihood that the NO produced in SIN-1 degradation induces TNFα in microglia, because TNFα was not induced in microglia exposed to the NO-donor S-nitroso-N-acetyl-dl-penicillamine. Moreover, the addition of SIN-1 to microglia resulted in activation of p38 MAPK and its upstream kinase MKK3/6. Taken together, these results showed that O(2)(-) is an important signaling molecule for activating the MKK3/6-p38 cascade, which is requisite for inducing TNFα in microglia.}, }
@article {pmid21980536, year = {2011}, author = {Srivastava, RK and Rahman, Q and Kashyap, MP and Lohani, M and Pant, AB}, title = {Ameliorative effects of dimetylthiourea and N-acetylcysteine on nanoparticles induced cyto-genotoxicity in human lung cancer cells-A549.}, journal = {PloS one}, volume = {6}, number = {9}, pages = {e25767}, pmid = {21980536}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytochrome P-450 CYP2E1/metabolism ; Cytokinesis/drug effects/genetics ; Cytoprotection/*drug effects ; Cytotoxins/*toxicity ; Free Radical Scavengers/pharmacology ; Humans ; Lung Neoplasms/*pathology ; Micronucleus Tests ; Mutagens/*toxicity ; Nanoparticles/*toxicity ; Nanotubes, Carbon/toxicity ; Reactive Oxygen Species/metabolism ; Thiourea/*analogs &amp; derivatives/pharmacology ; Titanium/chemistry/toxicity ; }, abstract = {We study the ameliorative potential of dimetylthiourea (DMTU), an OH• radical trapper and N-acetylcysteine (NAC), a glutathione precursor/H2O2 scavenger against titanium dioxide nanoparticles (TiO2-NPs) and multi-walled carbon nanotubes (MWCNTs) induced cyto-genotoxicity in cultured human lung cancer cells-A549. Cytogenotoxicity was induced by exposing the cells to selected concentrations (10 and 50 µg/ml) of either of TiO2-NPs or MWCNTs for 24 h. Anti-cytogenotoxicity effects of DMTU and NAC were studied in two groups, i.e., treatment of 30 minutes prior to toxic insult (short term exposure), while the other group received DMTU and NAC treatment during nanoparticles exposure, i.e., 24 h (long term exposure). Investigations were carried out for cell viability, generation of reactive oxygen species (ROS), micronuclei (MN), and expression of markers of oxidative stress (HSP27, CYP2E1), genotoxicity (P[53]) and CYP2E1 dependent n- nitrosodimethylamine-demethylase (NDMA-d) activity. In general, the treatment of both DMTU and NAC was found to be effective significantly against TiO2-NPs and MWCNTs induced cytogenotoxicity in A549 cells. Long-term treatment of DMTU and NAC during toxic insults has shown better prevention than short-term pretreatment. Although, cells responded significantly to both DMTU and NAC, but responses were chemical specific. In part, TiO2-NPs induced toxic responses were mediated through OH• radicals generation and reduction in the antioxidant defense system. While in the case of MWCNTs, adverse effects were primarily due to altering/hampering the enzymatic antioxidant system. Data indicate the applicability of human lung cancer cells-A549 as a pre-screening tool to identify the target specific prophylactic and therapeutic potential of drugs candidate molecules against nanoparticles induced cellular damages.}, }
@article {pmid21979174, year = {2011}, author = {Ma, YH and Huang, CP and Tsai, JS and Shen, MY and Li, YK and Lin, LY}, title = {Water-soluble germanium nanoparticles cause necrotic cell death and the damage can be attenuated by blocking the transduction of necrotic signaling pathway.}, journal = {Toxicology letters}, volume = {207}, number = {3}, pages = {258-269}, doi = {10.1016/j.toxlet.2011.09.018}, pmid = {21979174}, issn = {1879-3169}, mesh = {Animals ; CHO Cells/chemistry/drug effects/physiology ; Calcium/analysis ; Caspase 3/metabolism ; Cell Death/*drug effects ; Cricetinae ; Germanium/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/*toxicity ; Necrosis/*chemically induced/physiopathology ; Reactive Oxygen Species/analysis ; Signal Transduction/*drug effects/physiology ; Spectroscopy, Fourier Transform Infrared ; Tetrazolium Salts ; Thiazoles ; Toxicity Tests ; }, abstract = {Water-soluble germanium nanoparticles (wsGeNPs) with allyamine-conjugated surfaces were fabricated and emit blue fluorescence under ultraviolet light. The wsGeNP was physically and chemically stable at various experimental conditions. Cytotoxicity of the fabricated wsGeNP was examined. MTT assay demonstrated that wsGeNP possessed high toxicity to cells and clonogenic survival assay further indicated that this effect was not resulted from retarding cell growth. Flow cytometric analysis indicated that wsGeNP did not alter the cell cycle profile but the sub-G1 fraction was absent from treated cells. Results from DNA fragmentation and propidium iodide exclusion assays also suggested that apoptotic cell death did not occur in cells treated with wsGeNP. Addition of a necrosis inhibitor, necrostatin-1, attenuated cell damage and indicated that wsGeNP caused necrotic cell death. Cell signaling leads to necrotic death was investigated. Intracellular calcium and reactive oxygen species (ROS) levels were increased upon wsGeNP treatment. These effects can be abrogated by BAPTA-AM and N-acetyl cysteine respectively, resulting in a reduction in cell damage. In addition, wsGeNP caused a decrease in mitochondrial membrane potential (MMP) which could be recovered by cyclosporine A. The cellular signaling events revealed that wsGeNP increase the cellular calcium level which enhances the production of ROS and leads to a reduction of MMP, consequentially results in necrotic cell death.}, }
@article {pmid21978879, year = {2012}, author = {Armenian, P and Gerona, RR and Blanc, PD and Wu, AH and Mookherjee, S}, title = {5-oxoprolinemia causing elevated anion gap metabolic acidosis in the setting of acetaminophen use.}, journal = {The Journal of emergency medicine}, volume = {43}, number = {1}, pages = {54-57}, doi = {10.1016/j.jemermed.2011.06.017}, pmid = {21978879}, issn = {0736-4679}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Acid-Base Equilibrium ; Acidosis/*etiology ; Adult ; Amino Acid Metabolism, Inborn Errors/*chemically induced/complications/drug therapy ; Analgesics, Non-Narcotic/*poisoning ; Female ; Free Radical Scavengers/therapeutic use ; Glutathione Synthase/deficiency ; Humans ; }, abstract = {BACKGROUND: Anion gap metabolic acidosis is typically encountered in the emergency department (ED) setting as the result of shock, other endogenous metabolic derangements, or from exogenous toxicants. The differential diagnosis for toxicant-related acidosis (exemplified by common mnemonics) emphasizes acute overdose.<br><br>CASE REPORT: The case we present manifested an anion gap (AG) metabolic acidosis due to a chronic intoxication: acetaminophen (APAP) overuse over a period of weeks. Lactic acidemia did not account for the AG. In this case, chronic APAP overuse, combined with decreased caloric intake and weight loss, was associated with excess 5-oxoproline (pyroglutamic acid),&#xa0;an organic acid accounting for the AG metabolic acidosis. Overproduction of 5-oxoproline is attributed to depleted glutathione stores, leading to perturbation in the &#x3b3;-glutamyl cycle. The patient was treated with supportive care and with N-acetylcysteine (NAC). By repleting glutathione, NAC may facilitate the resolution of excess 5-oxoproline.<br><br>CONCLUSIONS: The ED differential diagnosis of AG metabolic acidosis in&#xa0;chronic APAP overuse, especially with concomitant nutritional compromise, should include 5-oxoprolinemia.}, }
@article {pmid21978796, year = {2012}, author = {Csontos, C and Rezman, B and Foldi, V and Bogar, L and Drenkovics, L and Röth, E and Weber, G and Lantos, J}, title = {Effect of N-acetylcysteine treatment on oxidative stress and inflammation after severe burn.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {38}, number = {3}, pages = {428-437}, doi = {10.1016/j.burns.2011.09.011}, pmid = {21978796}, issn = {1879-1409}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Antioxidants/metabolism ; Biomarkers/metabolism ; Burns/*drug therapy/metabolism ; Catalase/metabolism ; Cytokines/*metabolism ; Female ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Humans ; Leukocyte Count ; Male ; Malondialdehyde/metabolism ; Middle Aged ; Multiple Organ Failure/metabolism ; Oxidative Stress/*drug effects ; Peroxidase/metabolism ; Prospective Studies ; Superoxide Dismutase/metabolism ; Systemic Inflammatory Response Syndrome/*drug therapy/metabolism ; }, abstract = {Oxidative stress and inflammation generate edema in burns. The aim of our study was to assess effect of N-acetylcysteine (NAC) on oxidative stress, inflammation, fluid requirement, multiple organ dysfunction (MOD) score and vasoactive drug requirement. In this study 15 patients were on standard therapy, whereas for other 15 patients NAC was supplemented. Blood samples were taken on admission and on the next five consecutive mornings. Levels of malondialdehyde, protein sulfhydril (PSH) groups, reduced gluthation (GSH), activity of myeloperoxidase, catalase and superoxide dismutase enzymes and induced free radical generating capacity were measured as well as concentrations of TNF-α, IL-6, IL-8, and IL-10. MOD score, use of vasopressor agents and fluid utilisation were recorded daily. NAC treatment increased GSH level on days 4-5 (p<0.05) and PSH level on days 2-6 (p<0.05) compared to controls. Plasma IL-6 was lower on days 4-5 (p<0.05), IL-8 on days 4-6 (p<0.05) and IL-10 on days 4-6 (p<0.05) in NAC group. NAC group received less catecholamines than controls (p<0.01) from day 4 without significant differences in MOD score. NAC treatment is associated with a diminished oxidative stress reflected in preserved antioxidant levels, lower inflammation mirrored in lower interleukin levels and less vasopressor requirement.}, }
@article {pmid21978705, year = {2011}, author = {Rosato, E and Rossi, C and Molinaro, I and Giovannetti, A and Pisarri, S and Salsano, F}, title = {Long-term N-acetylcysteine therapy in systemic sclerosis interstitial lung disease: a retrospective study.}, journal = {International journal of immunopathology and pharmacology}, volume = {24}, number = {3}, pages = {727-733}, doi = {10.1177/039463201102400319}, pmid = {21978705}, issn = {0394-6320}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Antioxidants/*therapeutic use ; Calcium Channel Blockers/therapeutic use ; Endpoint Determination ; Female ; Fingers/pathology ; Humans ; Lung/physiopathology ; Lung Diseases, Interstitial/*drug therapy/physiopathology ; Male ; Middle Aged ; Nifedipine/therapeutic use ; Pulmonary Fibrosis/pathology ; Raynaud Disease/drug therapy ; Respiratory Function Tests ; Retrospective Studies ; Scleroderma, Systemic/*drug therapy/physiopathology ; Total Lung Capacity ; Treatment Outcome ; Ulcer/drug therapy/pathology ; Vital Capacity ; Young Adult ; }, abstract = {Systemic sclerosis (SSc) is associated with interstitial lung diseases. The primary endpoints of this study were changes between baseline and month 24 in single-breath carbon monoxide diffusing capacity (DLco). The secondary endpoints were: vital capacity (VC), forced expired volume in 1 sec (FEV1), total lung capacity (TLC), scores of high resolution computed tomography (HRCT) of the chest, number of adverse effects. In this study, we retrospectively investigated data from SSc patients who had undergone therapy with high-dose intravenous N-acetylcysteine (NAC) at a dosage of 15 mg/Kg/h for 5 consecutive hours every 14 days. After NAC therapy median values of DLco (69.5 vs 77.7%), VC (99 vs 101.3%) and TLC (93 vs 98.3%) significantly increased. We did not observe any significant changes from baseline in FEV1 value and HRTC score. The improvement in lung function was more evident in SSc patients without radiological signs of pulmonary fibrosis than in patients with pulmonary fibrosis. In SSc patients with mild-moderate pulmonary fibrosis intravenous NAC administration slows the rate of deterioration of DLco, VC and TLC. In conclusion, this retrospective study demonstrates that long-term therapy with intravenous NAC ameliorates pulmonary function tests in SSc patients.}, }
@article {pmid21976973, year = {2011}, author = {Talaei, F and Azizi, E and Dinarvand, R and Atyabi, F}, title = {Thiolated chitosan nanoparticles as a delivery system for antisense therapy: evaluation against EGFR in T47D breast cancer cells.}, journal = {International journal of nanomedicine}, volume = {6}, number = {}, pages = {1963-1975}, pmid = {21976973}, issn = {1178-2013}, mesh = {Breast Neoplasms/drug therapy ; Chitosan/analogs &amp; derivatives/chemistry/*pharmacology ; Doxorubicin/chemistry/*pharmacology ; Drug Carriers/chemistry/*pharmacology ; ErbB Receptors/*drug effects ; Female ; Humans ; Nanoparticles/*chemistry ; Oligodeoxyribonucleotides, Antisense/chemistry/*pharmacology ; Thioglycolates/chemistry ; }, abstract = {Thiolated chitosan has high transfection and mucoadhesive properties. We investigated the potential of two recently synthesized polymers: NAC-C (N-acetyl cysteine-chitosan) and NAP-C (N-acetyl penicillamine-chitosan) in anticancer drug delivery targeting epidermal growth factor receptor (EGFR). Doxorubicin (DOX) and antisense oligonucleotide (ASOND)-loaded polymer nanoparticles were prepared in water by a gelation process. Particle characterization, drug loading, and drug release were evaluated. To verify drug delivery efficiency in vitro experiments on a breast cancer cell line (T47D) were performed. EGFR gene and protein expression was analyzed by real time quantitative polymerase chain reaction and Western blotting, respectively. A loading percentage of 63% ± 5% for ASOND and 70% ± 5% for DOX was achieved. Drug release data after 15 hours showed that ASOND and DOX were completely released from chitosan-based particles while a lower and more sustained release of only 22% ± 8% was measured for thiolated particles. In a cytosol simulated release medium/reducing environment, such as found intracellularly, polymer-based nanoparticles dissociated, liberating approximately 50% of both active substances within 7 hours. ASOND-loaded polymer nanoparticles had higher stability and high mucoadhesive properties. The ASOND-loaded thiolated particles significantly suppressed EGFR gene expression in T47D cells compared with ASOND-loaded chitosan particles and downregulated EGFR protein expression in cells. This study could facilitate future investigations into the functionality of NAP-C and NAC-C polymers as an efficient ASOND delivery system in vitro and in vivo.}, }
@article {pmid21976820, year = {2011}, author = {Singh, S and Singh, SK and Kumar, M and Chandra, K and Singh, R}, title = {Ameliorative Potential of Quercetin Against Paracetamol-induced Oxidative Stress in Mice Blood.}, journal = {Toxicology international}, volume = {18}, number = {2}, pages = {140-145}, pmid = {21976820}, issn = {0976-5131}, abstract = {The aim of the present study was to evaluate the ameliorative potential of quercetin (QC) against paracetamol (PCM)-induced oxidative stress and biochemical alterations in mice blood. A total of 36 mice were randomly allocated into six groups, six mice in each. Group I served as healthy controls, while groups II and III were administered with N-acetylcysteine (NAC) and QC alone respectively. Group IV was administered with PCM alone. Groups V and VI were administered with PCM on day 0 followed by NAC and QC, respectively, for 6 consecutive days. On day 7(th) blood samples were obtained and subjected for the assays of oxidative stress and serum biochemical panels. Erythrocytic lipid peroxides contents of alone PCM-intoxicated mice were significantly higher, while reduced glutathione contents were found to be significantly lower in comparison with the healthy controls. The activities of antioxidant enzymes were also found to be singnificantly lower in these mice. Additionally, significantly increased activities of serum aspartate transaminase, alanine transaminase and alkaline phosphatase, as well as levels of bilirubin, urea and creatinine were revealed by these mice. Postadministration with QC remarkably alleviated the over production of MDA and improved GSH levels in PCM-intoxicated mice blood. In addition, antioxidant enzymes; glutathione peroxidase, glutathione-S-transferase, superoxide dismutase and catalase activities were also improved significantly in these mice. QC had also considerably ameliorated the altered biochemical parameters toward normalcy. Thus, it can be concluded that QC may constitute a remedy against PCM-induced oxidative stress and reno-hepatic injuries.}, }
@article {pmid21976360, year = {2012}, author = {Livanos, P and Galatis, B and Quader, H and Apostolakos, P}, title = {Disturbance of reactive oxygen species homeostasis induces atypical tubulin polymer formation and affects mitosis in root-tip cells of Triticum turgidum and Arabidopsis thaliana.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {69}, number = {1}, pages = {1-21}, doi = {10.1002/cm.20538}, pmid = {21976360}, issn = {1949-3592}, mesh = {Arabidopsis/*cytology/genetics/*metabolism ; Meristem/cytology/genetics/metabolism ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Microtubules/genetics/metabolism ; Mitosis/*physiology ; Oxidative Stress ; Plant Roots/cytology/genetics/metabolism ; Polymers/metabolism ; Reactive Oxygen Species/*metabolism ; Triticum/*cytology/genetics/*metabolism ; Tubulin/metabolism ; }, abstract = {In this study, the effects of disturbance of the reactive oxygen species (ROS) homeostasis on the organization of tubulin cytoskeleton in interphase and mitotic root-tip cells of Triticum turgidum and Arabidopsis thaliana were investigated. Reduced ROS levels were obtained by treatment with diphenylene iodonium (DPI) and N-acetyl-cysteine, whereas menadione was applied to achieve ROS overproduction. Both increased and low ROS levels induced: (a) Macrotubule formation in cells with low ROS levels and tubulin paracrystals under oxidative stress. The protein MAP65-1 was detected in treated cells, exhibiting a conformation comparable to that of the atypical tubulin polymers. (b) Disappearance of microtubules (MTs). (c) Inhibition of preprophase band formation. (d) Delay of the nuclear envelope breakdown at prometaphase. (e) Prevention of perinuclear tubulin polymer assembly in prophase cells. (f) Loss of bipolarity of prophase, metaphase and anaphase spindles. Interestingly, examination of the A. thaliana rhd2/At respiratory burst oxidase homolog C (rbohc) NADPH oxidase mutant, lacking RHD2/AtRBOHC, gave comparable results. Similarly to DPI, the decreased ROS levels in rhd2 root-tip cells, interfered with MT organization and induced macrotubule assembly. These data indicate, for first time in plants, that ROS are definitely implicated in: (a) mechanisms controlling the assembly/disassembly of interphase, preprophase and mitotic MT systems and (b) mitotic spindle function. The probable mechanisms, by which ROS affect these processes, are discussed.}, }
@article {pmid21975875, year = {2012}, author = {Zhang, Y and Peng, F and Gao, B and Ingram, AJ and Krepinsky, JC}, title = {High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation.}, journal = {American journal of physiology. Renal physiology}, volume = {302}, number = {1}, pages = {F159-72}, doi = {10.1152/ajprenal.00749.2010}, pmid = {21975875}, issn = {1522-1466}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Carbazoles/pharmacology ; Caveolae/*metabolism ; Cyclodextrins/pharmacology ; Diabetic Nephropathies/etiology ; Enzyme Activation ; Filipin/pharmacology ; Glucose/administration &amp; dosage/*pharmacology ; Indoles/pharmacology ; Maleimides/pharmacology ; Mesangial Cells/drug effects/metabolism ; Mice ; Mice, Knockout ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Protein Kinase C/antagonists &amp; inhibitors/*physiology ; Protein Kinase C beta ; RNA, Small Interfering/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Transcription Factor AP-1/metabolism ; Transforming Growth Factor beta1/metabolism ; rhoA GTP-Binding Protein/*metabolism ; }, abstract = {Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We previously showed that RhoA activation by high glucose in mesangial cells (MC) leads to matrix upregulation (Peng F, Wu D, Gao B, Ingram AJ, Zhang B, Chorneyko K, McKenzie R, Krepinsky JC. Diabetes 57: 1683-1692, 2008). Here, we study the mechanism whereby RhoA is activated. In primary rat MC, RhoA activation required glucose entry and metabolism. Broad PKC inhibitors (PMA, bisindolylmaleimide, Gö6976), as well as specific PKCβ blockade with an inhibitor and small interfering RNA (siRNA), prevented RhoA activation by glucose. PKCβ inhibition also abrogated reactive oxygen species (ROS) generation by glucose. The ROS scavenger N-acetylcysteine (NAC) or NADPH oxidase inhibitors apocynin and DPI prevented glucose-induced RhoA activation. RhoA and some PKC isoforms localize to caveolae. Chemical disruption of these microdomains prevented RhoA and PKCβ1 activation by glucose. In caveolin-1 knockout cells, glucose did not induce RhoA and PKCβ1 activation; these responses were rescued by caveolin-1 reexpression. Furthermore, glucose-induced ROS generation was significantly attenuated by chemical disruption of caveolae and in knockout cells. Downstream of RhoA signaling, activator protein-1 (AP-1) activation was also inhibited by disrupting caveolae, was absent in caveolin-1 knockout MC and rescued by caveolin-1 reexpression. Finally, transforming growth factor (TGF)-β1 upregulation, mediated by AP-1, was prevented by RhoA signaling inhibition and by disruption or absence of caveolae. In conclusion, RhoA activation by glucose is dependent on PKCβ1-induced ROS generation, most likely through NADPH oxidase. The activation of PKCβ1 and its downstream effects, including upregulation of TGF-β1, requires caveolae. These microdomains are thus important mediators of the profibrogenic process associated with diabetic nephropathy.}, }
@article {pmid21968809, year = {2012}, author = {Khanna, AK and Xu, J and Mehra, MR}, title = {Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {92}, number = {2}, pages = {224-235}, doi = {10.1038/labinvest.2011.146}, pmid = {21968809}, issn = {1530-0307}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Base Sequence ; Cotinine/blood ; Cytokines/blood ; DNA Primers ; *Disease Models, Animal ; Echocardiography ; Inflammation/*prevention &amp; control ; Myocardial Infarction/diagnostic imaging/etiology/*prevention &amp; control ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Smoke/*adverse effects ; }, abstract = {The contribution of chronic tobacco exposure in determining post-myocardial infarction (MI) left ventricular (LV) remodeling and possible therapeutic strategies has not been investigated systematically. In this small animal investigation, we demonstrate that chronic tobacco smoke exposure leading up to acute MI in rats is associated with greater histological extent of myocardial necrosis and consequent worse LV function. These findings are associated with increased transcriptomic expression of pro-inflammatory cytokines, tissue repair molecules and markers of oxidative stress in the myocardium. The results demonstrate that an N-acetyl cysteine (NAC) treatment significantly reduced tobacco-exposed induced infarct size and percent fractional shortening. A significantly increased LV end-systolic diameter was observed in tobacco-exposed sham compared to tobacco-naïve sham (4.92±0.41 vs 3.45±0.33; P<0.05), and tobacco-exposed MI compared to tobacco-naïve MI (8.24±0.3 vs 6.1±0.49; P<0.01) rats. Decreased intracardiac mRNA expression of the markers of inflammation, tissue repair and oxidative stress and circulating levels of pro-inflammatory cytokines accompanied these positive effects of NAC. The treatment of tobacco-exposed MI rats with NAC resulted in significantly increased levels of intracardiac mRNA expression of antioxidants, including superoxide dismutase, thioredoxin and nuclear factor-E2-related factor 2, as well as circulating levels of glutathione (7±0.12 vs 10±0.18; P≤0.001), where the levels were almost identical to the tobacco-naïve sham rats. These findings identify a novel post-infarction therapy for amelioration of the adverse effects of tobacco exposure on the infracted myocardium and advocate the use of dietary supplement antioxidants for habitual smokers to prevent and reverse cardiovascular adverse effects in the absence of successful achievement of cessation of smoking.}, }
@article {pmid21967756, year = {2011}, author = {Song, JH and Shim, JK and Choi, HJ}, title = {Quercetin 7-rhamnoside reduces porcine epidemic diarrhea virus replication via independent pathway of viral induced reactive oxygen species.}, journal = {Virology journal}, volume = {8}, number = {}, pages = {460}, pmid = {21967756}, issn = {1743-422X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Antiviral Agents/*pharmacology/therapeutic use ; Chlorocebus aethiops ; Chromans/pharmacology ; Coronavirus Infections/*drug therapy/virology ; Cytopathogenic Effect, Viral/drug effects ; DNA Fragmentation/drug effects ; Flow Cytometry ; Porcine epidemic diarrhea virus/*drug effects/physiology ; Pyrrolidines/pharmacology ; Quercetin/*analogs &amp; derivatives/pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Thiocarbamates/pharmacology ; Vero Cells ; Virus Replication/*drug effects ; }, abstract = {BACKGROUND: On the base of our previous study we were observed relevant studies on the hypothesis that the antiviral activity of quercetin 7-rhamnoside (Q7R), a flavonoid, won't relate ability of its antioxidant.<br><br>METHODS: We were investigated the effects of Q7R on the cytopathic effects (CPE) by CPE reduction assay. Production of DNA fragment and reactive oxygen species (ROS) induced by PEDV infection were studied using DNA fragmentation assay and flow cytometry.<br><br>RESULTS: In the course of this study it was discovered that Q7R is an extremely potent compound against PEDV. The addition of Q7R to PEDV-infected Vero cells directly reduced the formation of a visible cytopathic effect (CPE). Also, Q7R did not induce DNA fragmentation. Furthermore, ROS increased the infection of PEDV, which was strongly decreased by N-acetyl-L-cysteins (NAC). However, the increased ROS was not decreased by Q7R. Antiviral activity of antioxidants such as NAC, pyrrolidine dithiocarbamate (PDTC), and the vitamin E derivative, trolox, were hardly noticed.<br><br>CONCLUSIONS: We concluded that the inhibition of PEDV production by Q7R is not simply due to a general action as an antioxidants and is highly specific, as several other antioxidants (NAC, PDTC, trolox) are inactive against PEDV infection.}, }
@article {pmid21963500, year = {2011}, author = {Morimoto, R and Obinata, A}, title = {Overexpression of hematopoietically expressed homeoprotein induces nonapoptotic cell death in mouse prechondrogenic ATDC5 cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {34}, number = {10}, pages = {1589-1595}, doi = {10.1248/bpb.34.1589}, pmid = {21963500}, issn = {1347-5215}, mesh = {Acetylcysteine/*pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Apoptosis/physiology ; Cartilage/cytology/metabolism ; Cell Death/*physiology ; Cell Differentiation ; Cell Line ; Cell Nucleus/metabolism ; Chondrocytes/cytology/metabolism ; Chondrogenesis/physiology ; Cysteine Proteinase Inhibitors/pharmacology ; Drug Evaluation, Preclinical ; Free Radical Scavengers/pharmacology ; Green Fluorescent Proteins/metabolism ; Heart Function Tests/drug effects ; Homeodomain Proteins/*physiology ; Mice ; Molecular Targeted Therapy ; Necrosis/*metabolism ; Reactive Oxygen Species/metabolism ; Time Factors ; Transcription Factors/*physiology ; Transfection ; Up-Regulation ; }, abstract = {Physiological cell death is an essential event in normal development and maintenance of homeostasis. Recently, the morphological and pharmacological characteristics of programmed cell death, which are distinct from those of apoptosis under physiological and pathological conditions, have been reported. However, the molecular mechanism and executioner of this type of cell death are unknown. We show that overexpression of hematopoietically expressed homeoprotein (Hex), a homeoprotein of divergent type, and enhanced green fluorescent protein (EGFP) fusion protein (Hex-EGFP) induces cell death in mouse chondrogenic cell line ATDC5. The expression rate of Hex-EGFP decreased more rapidly than that of EGFP 96 h after transfection. The time-lapse image of living cells revealed the Hex-EGFP-positive cells rapidly died in a necrosis-like fashion. The nuclei of Hex-EGFP-expressing cells were rarely fragmented; however, these cells were negative for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining. The expression rate of Hex-EGFP clearly increased by treatment with radical scavengers, propyl gallate and butylated hydroxyanisole, slightly increased with a caspase inhibitor, zVAD-fmk, and was not affected by N-acetyl cysteine in ATDC5 cells. A fluorescent probe indicated that reactive oxygen species (ROS) were localized near the nuclei in Hex-EGFP-positive cells. In differentiated ATDC5 cells, as hypertrophic chondrocyte-like cells, the expression rate of Hex-EGFP increased above that in uninduced ATDC5 cells. These results suggest that Hex induces nonapoptotic cell death through local accumulation of reactive oxygen species, and mature chondrocytes, which express Hex, might be able to escape cell death induced by Hex in cartilage.}, }
@article {pmid21962883, year = {2011}, author = {Kim, JK and Han, M and Nili, M}, title = {Effects of N-acetyl-L-cysteine on fish hepatoma cells treated with mercury chloride and ionizing radiation.}, journal = {Chemosphere}, volume = {85}, number = {10}, pages = {1635-1638}, doi = {10.1016/j.chemosphere.2011.08.029}, pmid = {21962883}, issn = {1879-1298}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects/radiation effects ; Cell Line, Tumor ; Fishes ; Glutathione/metabolism ; Mercuric Chloride/*toxicity ; *Radiation, Ionizing ; Reactive Oxygen Species/metabolism ; }, abstract = {Organisms are exposed to natural radiations from cosmic or terrestrial origins. Furthermore the combined action of radiation with various chemicals is an inevitable feature of modern life. Radiation is known to cause cell death, mainly due to its ability to produce reactive oxygen species in cells. N-acetyl-L-cysteine (NAC) is a well-known sulfhydryl-containing antioxidant whose role in radioprotection has been reported. Synergistic effects of radiation and mercury chloride on human cells was previously reported by the authors. Based on the previous report, this study was designed to assess the synergistic effects of radiation and mercury chloride on fish hepatoma cells, as well as to investigate the protective effects of NAC on the cells. The cytotoxicity of radiation was enhanced in the presence of mercury chloride. NAC in lower concentrations prevented cells from death after irradiation with lower doses (<300 Gy) while it did not prevent cells from radiation-induced death after irradiation with higher doses (300, 500 Gy). The intracellular glutathione (GSH) levels significantly decreased after irradiation while the combined treatment of NAC and radiation alleviated the decrease in the GSH levels. The investigations give a clue for the action mechanism of synergistic or protective effects of NAC on the cells. Due to their high resistance to ionizing radiation, the PLHC-1 cells can be effectively used as a screening tool for assessing the combined effects of radiation with toxic chemicals.}, }
@article {pmid21961969, year = {2011}, author = {Li, JH and Yue, W and Huang, Z and Chen, ZQ and Zhan, Q and Ren, FB and Liu, JY and Fu, SB}, title = {Calcium overload induces C6 rat glioma cell apoptosis in sonodynamic therapy.}, journal = {International journal of radiation biology}, volume = {87}, number = {10}, pages = {1061-1066}, doi = {10.3109/09553002.2011.584938}, pmid = {21961969}, issn = {1362-3095}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*radiation effects ; Calcium/chemistry/*metabolism ; Caspase 3/metabolism ; Cytochromes c/metabolism ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Fluorometry ; Glioma/chemically induced/metabolism/*radiotherapy ; Hematoporphyrins/pharmacology/*therapeutic use ; Immunoblotting ; Intracellular Membranes/chemistry/metabolism ; Necrosis/metabolism/pathology ; Photosensitizing Agents/pharmacology/therapeutic use ; Rats ; Reactive Oxygen Species/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism ; Tumor Cells, Cultured ; Ultrasonic Therapy/*methods ; }, abstract = {PURPOSE: Our aim was to study calcium overload-induced apoptosis and its relation to reactive oxygen species (ROS) in rat C6 glioma cells after sonodynamic treatment (SDT).<br><br>MATERIALS AND METHODS: Hematoporphyrin monomethyl ether (HMME) was used as the sonosensitizer. The concentration of intracellular Ca(2+) ([Ca(2+)](i)) was measured by fluorometry. Apoptosis and necrosis rates were evaluated by a flow cytometry. Moreover, sarcoplasmic reticulum Ca(2+) -ATPase (SERCA(2)), cytochrome c (cyto-c) and cleaved caspase-3 were investigated by immunoblotting.<br><br>RESULTS: Our study indicated that [Ca(2 +)](i) and ROS increased in cells of SDT group, the apoptosis rate, quantity of cyto-c and cleaved caspase-3 markedly increased after SDT. Furthermore, N-Acetyl-L-cysteine (NAC) or 1,2-bisethane-N,N,N',N'-tetraacetic acid tetrakis ester (BAPTA-AM) could decrease the apoptosis rate, the release of cyto-c and cleaved caspase-3 in SDT group, SERCA(2) degradation was found in SDT group and could also be prevented by the addition of NAC.<br><br>CONCLUSIONS: Our results show that HMME-SDT can induce C6 cell death through both necrosis and apoptosis. ROS in C6 cells play a decisive role in HMME-SDT-induced cell death. The endoplasmic reticulum (ER) may be a major target of HMME-SDT, ROS can induce SERCA(2) degradation, causing the elevation of [Ca(2+)](i).}, }
@article {pmid21959875, year = {2011}, author = {Avci, E and Yeşil, M and Bayata, S and Postaci, N and Arikan, E and Cirit, M}, title = {The role of nebivolol in the prevention of contrast-induced nephropathy in patients with renal dysfunction.}, journal = {Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of cardiology}, volume = {11}, number = {7}, pages = {613-617}, doi = {10.5152/akd.2011.164}, pmid = {21959875}, issn = {1308-0032}, mesh = {Adult ; Aged ; Aged, 80 and over ; Benzopyrans/*administration &amp; dosage ; Contrast Media/*adverse effects ; Coronary Angiography ; Coronary Artery Disease/complications/*diagnostic imaging ; Creatinine/blood ; Ethanolamines/*administration &amp; dosage ; Female ; Humans ; Kidney Diseases/*chemically induced/complications ; Male ; Metoprolol/administration &amp; dosage ; Middle Aged ; Nebivolol ; Prospective Studies ; Protective Agents/*administration &amp; dosage/adverse effects ; Vasodilator Agents/*administration &amp; dosage ; }, abstract = {OBJECTIVE: This prospective study was designed to evaluate the potential protective effect of nebivolol compared with metoprolol on the development of contrast-induced nephropathy (CIN) following coronary angiography in patients with renal dysfunction.<br><br>METHODS: Ninety patients with stable coronary angina pectoris with renal insufficiency (creatinine value &#x2265;1.2 mg/dl) were included for this prospective study. Patients were divided into two groups. Patients in group 1 (n=55) received oral administration of nebivolol 5 mg/daily for coronary artery disease and/or hypertension. Group 2 consisted of 35 patients who received metoprolol 50 mg/daily for the same indications. All patients were hydrated with 0.9% NaCl at a rate of 1 mL/kg/hr for 12 hours before and 24 hours after the procedure. Patients were also given N-acetylcysteine (NAC) 600 mg twice a day, beginning 24 hours before and continuing 48 hours after the procedure. All patients underwent routine coronary angiography. Serum creatinine was assessed just before, immediately after and 48 hours after the procedure. CIN was defined as an increase in serum creatinine concentration of &#x2265;25% within 48 hours after the procedure compared to the patient's baseline value. Tests for significance between groups were conducted using the independent sample t-test for continuous variables and Chi-square test for categorical variables.<br><br>RESULTS: Baseline serum creatinine levels were statistically comparable in two groups. Following angiography, serum creatinine levels increased in both groups. Post-angiographic creatinine levels were not statistically different in the nebivolol and the metoprolol groups. Contrast induced nephropathy developed in 13 patients (24%) of the nebivolol group and in 12 patients (33%) of the metoprolol group. The incidence of CIN was statistically significantly lower in the nebivolol group comparing with the metoprolol group (p=0.03).<br><br>CONCLUSION: The use of oral nebivolol for one week at a dose of 5 mg per day may decrease the incidence of contrast-induced nephropathy in patients who underwent coronary angiography with renal dysfunction. The small numbers of this study do not allow to draw final conclusion on the use of nebivolol in the prevention of CIN. Therefore, larger studies may be necessary to address the definite role of nebivolol in this setting.}, }
@article {pmid21958470, year = {2011}, author = {Casarin, AL and Lopes-Pires, ME and Morganti, RP and Antunes, E and Marcondes, S}, title = {Reactive oxygen and nitrogen species modulate the ex-vivo effects of LPS on platelet adhesion to fibrinogen.}, journal = {Life sciences}, volume = {89}, number = {21-22}, pages = {773-778}, doi = {10.1016/j.lfs.2011.09.004}, pmid = {21958470}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood Platelets/*drug effects ; Cyclic GMP/metabolism ; Enzyme Inhibitors/pharmacology ; Fibrinogen/*physiology ; Free Radical Scavengers/pharmacology ; In Vitro Techniques ; Lipopolysaccharides/*pharmacology ; Male ; NG-Nitroarginine Methyl Ester/pharmacology ; Platelet Adhesiveness/*drug effects ; Polyethylene Glycols/pharmacology ; Rats ; Reactive Nitrogen Species/*metabolism ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/pharmacology ; Thrombin/pharmacology ; }, abstract = {AIMS: Excessive production of nitric oxide (NO) and reactive oxygen species (ROS) in sepsis modulates different cell functions. Since the sepsis severity is associated with the degree of platelet activation, we decided to investigate the role of systemic generation of NO and ROS in modulating the platelet adhesion of lipopolysaccharide (LPS)-treated rats.<br><br>MAIN METHODS: Platelet adhesion was evaluated using fibrinogen-coated 96-well microtiter plates. Cyclic GMP levels were measured using enzyme immunoassay kit.<br><br>KEY FINDINGS: Treatment of rats with LPS significantly increased spontaneous platelet adhesion, but reduced the thrombin-activated platelet adhesion when compared with control rats. Chronic treatment of rats with the NO synthase inhibitor L-NAME (20 mg/rat/day, 7 days) prior to LPS injection normalized the increased adhesion in non-activated platelets, but failed to affect the adhesion in thrombin-activated platelets. The cGMP levels were modified neither in non-activated nor in thrombin-activated platelets of LPS-treated rats when compared with control rats. The incubation of non-activated platelets with the O2- scavenger PEG-SOD reversed the stimulatory effect of LPS on spontaneous adhesion, but had no effect in stimulated-platelet adhesion of non-treated or LPS-treated groups. Moreover, pretreatment of rats with the antioxidant N-acetylcysteine (NAC; 150 mg/kg) prevented the increase of non-activated platelet adhesion, and significantly reduced the inhibitory effect of LPS on thrombin-stimulated adhesion.<br><br>SIGNIFICANCE: Our findings suggest that in LPS-treated rats, NO plays an important modulatory role only in non-stimulated platelet adhesion through cGMP-independent mechanisms, while ROS, directly or by affecting the redox state of the animals, modulates both non-activated and thrombin-activated platelet adhesion.}, }
@article {pmid21954409, year = {2011}, author = {Reep, GL and Soloway, RD}, title = {Recent and currently emerging medical treatment options for the treatment of alcoholic hepatitis.}, journal = {World journal of hepatology}, volume = {3}, number = {8}, pages = {211-214}, pmid = {21954409}, issn = {1948-5182}, abstract = {Patients with severe alcoholic hepatitis (AH) need to be treated with specific treatment for better outcome. Currently available specific treatment modalities are use of corticosteroids or pentoxifylline. However, the response rate to these drugs is only about 50%-60%. Hence, there is an urgent need for better and more effective treatment options. Tumor necrosis factor plays an important role in the pathogenesis of AH. However, agents blocking the action of tumor necrosis factor have not been found to be effective. Rather the randomized studies evaluating these agents showed an adverse effect and more infections in treated patients. Critical role of tumor necrosis factor in hepatic regeneration explaining this contrast is discussed. Oxidative stress and inflammation derived from gut bacteria ate two main components in the pathogenesis of AH laying foundation for the role of antioxidants, probiotics, and antibiotics in the management of AH. This article reviews the current data and status of these newer agents for the treatment of AH. Of the various options available, Vitamin E and N-acetylcysteine (NAC) have shown great promise for clinical use as adjunct to corticosteroids. With these encouraging data, future well designed studies are suggested to assess Vitamin E and NAC before their routine use in clinical practice in the management of AH.}, }
@article {pmid21954051, year = {2011}, author = {Robinson, RA and Joshi, G and Huang, Q and Sultana, R and Baker, AS and Cai, J and Pierce, W and St Clair, DK and Markesbery, WR and Butterfield, DA}, title = {Proteomic analysis of brain proteins in APP/PS-1 human double mutant knock-in mice with increasing amyloid β-peptide deposition: insights into the effects of in vivo treatment with N-acetylcysteine as a potential therapeutic intervention in mild cognitive impairment and Alzheimer's disease.}, journal = {Proteomics}, volume = {11}, number = {21}, pages = {4243-4256}, pmid = {21954051}, issn = {1615-9861}, support = {P01 AG005119/AG/NIA NIH HHS/United States ; P01 AG010836/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; AG-05119/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alzheimer Disease/*drug therapy/genetics/metabolism ; Amyloid beta-Peptides/*metabolism ; Amyloid beta-Protein Precursor/*genetics/metabolism ; Animals ; Brain/drug effects/metabolism ; Cognitive Dysfunction/drug therapy ; Free Radical Scavengers/pharmacology/*therapeutic use ; Gene Expression Regulation/drug effects ; Gene Knock-In Techniques ; Humans ; Mice ; Mutation ; Presenilin-1/*genetics/metabolism ; Proteome/genetics/*metabolism ; Proteomics ; }, abstract = {Proteomics analyses were performed on the brains of wild-type (WT) controls and an Alzheimer's disease (AD) mouse model, APP/PS-1 human double mutant knock-in mice. Mice were given either drinking water or water supplemented with N-acetylcysteine (NAC) (2 mg/kg body weight) for a period of five months. The time periods of treatment correspond to ages prior to Aβ deposition (i.e. 4-9 months), resembling human mild cognitive impairment (MCI), and after Aβ deposition (i.e. 7-12 months), more closely resembling advancing stages of AD. Substantial differences exist between the proteomes of WT and APP/PS-1 mice at 9 or 12 months, indicating that Aβ deposition and oxidative stress lead to downstream changes in protein expression. Altered proteins are involved in energy-related pathways, excitotoxicity, cell cycle signaling, synaptic abnormalities, and cellular defense and structure. Overall, the proteomic results support the notion that NAC may be beneficial for increasing cellular stress responses in WT mice and for influencing the levels of energy- and mitochondria-related proteins in APP/PS-1 mice.}, }
@article {pmid21953973, year = {2011}, author = {Du, F and Liu, T and Liu, T and Wang, Y and Wan, Y and Xing, J}, title = {Metabolite identification of triptolide by data-dependent accurate mass spectrometric analysis in combination with online hydrogen/deuterium exchange and multiple data-mining techniques.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {25}, number = {20}, pages = {3167-3177}, doi = {10.1002/rcm.5211}, pmid = {21953973}, issn = {1097-0231}, mesh = {Acetylcysteine/metabolism/urine ; Animals ; Biotransformation ; Data Mining/*methods ; Deuterium Exchange Measurement/*methods ; Diterpenes/*analysis/chemistry/pharmacokinetics/urine ; Epoxy Compounds/analysis/chemistry/pharmacokinetics/urine ; Mass Spectrometry/*methods ; Phenanthrenes/*analysis/chemistry/pharmacokinetics/urine ; Rats ; Rats, Wistar ; }, abstract = {Triptolide (TP), the primary active component of the herbal medicine Tripterygium wilfordii Hook F, has shown promising antileukemic and anti-inflammatory activity. The pharmacokinetic profile of TP indicates an extensive metabolic elimination in vivo; however, its metabolic data is rarely available partly because of the difficulty in identifying it due to the absence of appropriate ultraviolet chromophores in the structure and the presence of endogenous interferences in biological samples. In the present study, the biotransformation of TP was investigated by improved data-dependent accurate mass spectrometric analysis, using an LTQ/Orbitrap hybrid mass spectrometer in conjunction with the online hydrogen (H)/deuterium (D) exchange technique for rapid structural characterization. Accurate full-scan MS and MS/MS data were processed with multiple post-acquisition data-mining techniques, which were complementary and effective in detecting both common and uncommon metabolites from biological matrices. As a result, 38 phase I, 9 phase II and 8 N-acetylcysteine (NAC) metabolites of TP were found in rat urine. Accurate MS/MS data were used to support assignments of metabolite structures, and online H/D exchange experiments provided additional evidence for exchangeable hydrogen atoms in the structure. The results showed the main phase I metabolic pathways of TP are hydroxylation, hydrolysis and desaturation, and the resulting metabolites subsequently undergo phase II processes. The presence of NAC conjugates indicated the capability of TP to form reactive intermediate species. This study also demonstrated the effectiveness of LC/HR-MS(n) in combination with multiple post-acquisition data-mining methods and the online H/D exchange technique for the rapid identification of drug metabolites.}, }
@article {pmid21952893, year = {2011}, author = {Osburn, S and Berden, G and Oomens, J and O'Hair, RA and Ryzhov, V}, title = {Structure and reactivity of the N-acetyl-cysteine radical cation and anion: does radical migration occur?.}, journal = {Journal of the American Society for Mass Spectrometry}, volume = {22}, number = {10}, pages = {1794-1803}, pmid = {21952893}, issn = {1879-1123}, mesh = {Acetylcysteine/*chemistry ; Allyl Compounds/chemistry ; Anions/chemistry ; Cations/chemistry ; Disulfides/chemistry ; Mass Spectrometry ; Molecular Conformation ; Spectrophotometry, Infrared ; Structure-Activity Relationship ; }, abstract = {The structure and reactivity of the N-acetyl-cysteine radical cation and anion were studied using ion-molecule reactions, infrared multi-photon dissociation (IRMPD) spectroscopy, and density functional theory (DFT) calculations. The radical cation was generated by first nitrosylating the thiol of N-acetyl-cysteine followed by the homolytic cleavage of the S-NO bond in the gas phase. IRMPD spectroscopy coupled with DFT calculations revealed that for the radical cation the radical migrates from its initial position on the sulfur atom to the α-carbon position, which is 2.5 kJ mol(-1) lower in energy. The radical migration was confirmed by time-resolved ion-molecule reactions. These results are in contrast with our previous study on cysteine methyl ester radical cation (Osburn et al., Chem. Eur. J. 2011, 17, 873-879) and the study by Sinha et al. for cysteine radical cation (Phys. Chem. Chem. Phys. 2010, 12, 9794-9800) where the radical was found to stay on the sulfur atom as formed. A similar approach allowed us to form a hydrogen-deficient radical anion of N-acetyl-cysteine, (M - 2H)(•-). IRMPD studies and ion-molecule reactions performed on the radical anion showed that the radical remains on the sulfur, which is the initial and more stable (by 63.6 kJ mol(-1)) position, and does not rearrange.}, }
@article {pmid21949757, year = {2011}, author = {Palmer, VL and Kassmeier, MD and Willcockson, J and Akhter, MP and Cullen, DM and Swanson, PC}, title = {N-acetylcysteine increases the frequency of bone marrow pro-B/pre-B cells, but does not reverse cigarette smoking-induced loss of this subset.}, journal = {PloS one}, volume = {6}, number = {9}, pages = {e24804}, pmid = {21949757}, issn = {1932-6203}, support = {G20 RR024001/RR/NCRR NIH HHS/United States ; G20RR024001/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Lymphocyte Count ; Lymphocyte Subsets/*cytology/*drug effects ; Mice ; Mice, Inbred C57BL ; Precursor Cells, B-Lymphoid/*cytology/*drug effects ; Smoking/*adverse effects ; }, abstract = {BACKGROUND: We previously showed that mice exposed to cigarette smoke for three weeks exhibit loss of bone marrow B cells at the Pro-B-to-pre-B cell transition, but the reason for this is unclear. The antioxidant N-acetylcysteine (NAC), a glutathione precursor, has been used as a chemopreventive agent to reduce adverse effects of cigarette smoke exposure on lung function. Here we determined whether smoke exposure impairs B cell development by inducing cell cycle arrest or apoptosis, and whether NAC treatment prevents smoking-induced loss of developing B cells.<br><br>Groups of normal mice were either exposed to filtered room air or cigarette smoke with or without concomitant NAC treatment for 5 days/week for three weeks. Bone marrow B cell developmental subsets were enumerated, and sorted pro-B (B220(+)CD43(+)) and pre-B (B220(+)CD43(-)) cell fractions were analyzed for cell cycle status and the percentage of apoptotic cells. We find that, compared to sham controls, smoke-exposed mice have &#x223c;60% fewer pro-B/pre-B cells, regardless of NAC treatment. Interestingly, NAC-treated mice show a 21-38% increase in total bone marrow cellularity and lymphocyte frequency and about a 2-fold increase in the pro-B/pre-B cell subset, compared to sham-treated controls. No significant smoking- or NAC-dependent differences were detected in frequency of apoptotic cells or the percentage cells in the G1, S, or G2 phases of the cycle.<br><br>CONCLUSIONS/SIGNIFICANCE: The failure of NAC treatment to prevent smoking-induced loss of bone marrow pre-B cells suggests that oxidative stress is not directly responsible for this loss. The unexpected expansion of the pro-B/pre-B cell subset in response to NAC treatment suggests oxidative stress normally contributes to cell loss at this developmental stage, and also reveals a potential side effect of therapeutic administration of NAC to prevent smoking-induced loss of lung function.}, }
@article {pmid21948481, year = {2012}, author = {Sun, B and Sun, GB and Xiao, J and Chen, RC and Wang, X and Wu, Y and Cao, L and Yang, ZH and Sun, XB}, title = {Isorhamnetin inhibits H2O2-induced activation of the intrinsic apoptotic pathway in H9c2 cardiomyocytes through scavenging reactive oxygen species and ERK inactivation.}, journal = {Journal of cellular biochemistry}, volume = {113}, number = {2}, pages = {473-485}, doi = {10.1002/jcb.23371}, pmid = {21948481}, issn = {1097-4644}, mesh = {Animals ; Apoptosis/*drug effects ; Catalase/metabolism ; Cell Line ; Cell Survival ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/*metabolism ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation/drug effects ; Genes, bcl-2 ; Hydrogen Peroxide ; L-Lactate Dehydrogenase/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Heart/drug effects/metabolism ; Myocytes, Cardiac/*drug effects/metabolism/physiology ; Protein Kinase Inhibitors/pharmacology ; Quercetin/*analogs &amp; derivatives/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {As a traditional Chinese medicine, the sea buckthorn (Hippophae rhamnoides L.) has a long history in the treatment of ischemic heart disease and circulatory disorders. However, the active compounds responsible for and the underlying mechanisms of these effects are not fully understood. In this article, isorhamnetin pretreatment counteracted H(2)O(2)-induced apoptotic damage in H9c2 cardiomyocytes. Isorhamnetin did not inhibit the death receptor-dependent or extrinsic apoptotic pathways, as characterized by its absence in both caspase-8 inactivation and tBid downregulation along with unchanged Fas and TNFR1 mRNA levels. Instead, isorhamnetin specifically suppressed the mitochondria-dependent or intrinsic apoptotic pathways, as characterized by inactivation of caspase-9 and -3, maintenance of the mitochondrial membrane potential (ΔΨm), and regulation of a series of Bcl-2 family genes upstream of ΔΨm. The anti-apoptotic effects of isorhamnetin were linked to decreased ROS generation. H(2)O(2) activated ERK and p53, whereas isorhamnetin inhibited their activation. ERK overexpression overrode the isorhamnetin-induced inhibition of the intrinsic apoptotic pathway in H9c2 cardiomyocytes, which indicated that an ERK-dependent pathway was involved. Furthermore, N-acetyl cysteine (a potent ROS scavenger) could attenuate the H(2)O(2)-induced apoptosis. However, PD98059 (an ERK-specific inhibitor) could not effectively antagonize ROS generation, which indicates that ROS may be an upstream inducer of ERK. In conclusion, isorhamnetin inhibits the H(2)O(2)-induced activation of the intrinsic apoptotic pathway via ROS scavenging and ERK inactivation. Therefore, isorhamnetin is a promising reagent for the treatment of ROS-induced cardiomyopathy.}, }
@article {pmid21941541, year = {2011}, author = {Kaur, P and Aschner, M and Syversen, T}, title = {Biochemical factors modulating cellular neurotoxicity of methylmercury.}, journal = {Journal of toxicology}, volume = {2011}, number = {}, pages = {721987}, pmid = {21941541}, issn = {1687-8205}, abstract = {Methylmercury (MeHg), an environmental toxicant primarily found in fish and seafood, poses a dilemma to both consumers and regulatory authorities, given the nutritional benefits of fish consumption versus the possible adverse neurological damage. Several studies have shown that MeHg toxicity is influenced by a number of biochemical factors, such as glutathione (GSH), fatty acids, vitamins, and essential elements, but the cellular mechanisms underlying these complex interactions have not yet been fully elucidated. The objective of this paper is to outline the cellular response to dietary nutrients, as well as to describe the neurotoxic exposures to MeHg. In order to determine the cellular mechanism(s) of toxicity, the effect of pretreatment with biochemical factors (e.g., N-acetyl cysteine, (NAC); diethyl maleate, (DEM); docosahexaenoic acid, (DHA); selenomethionine, SeM; Trolox) and MeHg treatment on intercellular antioxidant status, MeHg content, and other endpoints was evaluated. This paper emphasizes that the protection against oxidative stress offered by these biochemical factors is among one of the major mechanisms responsible for conferring neuroprotection. It is therefore critical to ascertain the cellular mechanisms associated with various dietary nutrients as well as to determine the potential effects of neurotoxic exposures for accurately assessing the risks and benefits associated with fish consumption.}, }
@article {pmid21938404, year = {2012}, author = {Lu, JJ and Cai, YJ and Ding, J}, title = {The short-time treatment with curcumin sufficiently decreases cell viability, induces apoptosis and copper enhances these effects in multidrug-resistant K562/A02 cells.}, journal = {Molecular and cellular biochemistry}, volume = {360}, number = {1-2}, pages = {253-260}, pmid = {21938404}, issn = {1573-4919}, mesh = {Antineoplastic Agents/*pharmacology ; *Apoptosis ; Cell Line, Tumor ; Cell Survival/*drug effects ; Comet Assay ; Copper Sulfate/*pharmacology ; Curcumin/*pharmacology ; DNA Damage ; Down-Regulation/drug effects ; *Drug Resistance, Neoplasm ; Drug Synergism ; Glycoproteins/genetics/metabolism ; Humans ; Inhibitory Concentration 50 ; }, abstract = {The anti-cancer activities of curcumin (CUR), a polyphenol derived from the plant Curcuma longa, has been extensively studied. In the present study, we found that CUR displayed anti-multidrug-resistant (MDR) activity in K562/A02 cells. A short-time treatment with CUR sufficiently and equally induced DNA damage, decreased cell viability, and triggered apoptosis in parent K562 and MDR K562/A02 cells. The short-time treatment with CUR also caused decrease of pro-caspase 3 in both cell lines and decrease of pro-caspase 9, increase of PARP cleavage and the ratio of Bax/Bcl-xL in MDR K562/A02 cells. Further experiment revealed that CUR was capable of down-regulating P-glycoprotein in MDR K562/A02 cells. Moreover, we observed that Cu(2+) enhanced CUR-mediated apoptosis which was blocked by antioxidants N-acetyl-cysteine and catalase. In summary, the short-time treatment with CUR sufficiently induced DNA damage, decreased cell viability and triggered apoptosis in MDR K562/A02 cells and Cu(2+) enhanced CUR-mediated apoptosis which due to reactive oxygen species generation.}, }
@article {pmid21936588, year = {2011}, author = {Singh, SP and Singh, V}, title = {Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia.}, journal = {CNS drugs}, volume = {25}, number = {10}, pages = {859-885}, pmid = {21936588}, issn = {1179-1934}, mesh = {Adult ; Antipsychotic Agents/*therapeutic use ; Clozapine/therapeutic use ; Drug Therapy, Combination/methods ; Glycine/therapeutic use ; Humans ; Middle Aged ; Randomized Controlled Trials as Topic ; Receptors, N-Methyl-D-Aspartate/*metabolism ; Sarcosine/therapeutic use ; Schizophrenia/*drug therapy/*metabolism ; Treatment Outcome ; }, abstract = {BACKGROUND: Based on the glutamatergic NMDA receptor hypofunction theory of schizophrenia, NMDA receptor modulators (NMDARMs) may have therapeutic potential in the treatment of schizophrenia.<br><br>OBJECTIVE: This meta-analysis aimed to evaluate the potential of modulators of the NMDA receptor as adjunctive therapy for schizophrenia, using the results from published trials.<br><br>DATA SOURCES: A primary electronic search for controlled clinical trials using NMDARMs in schizophrenia was conducted on the PubMed, Cochrane Library, EMBASE, CINAHL&#xae; and PsycINFO databases. A secondary manual search of references from primary publications was also performed.<br><br>STUDY SELECTION: Inclusion criteria were the application of an established method of diagnosis, randomized case assignment, comparison of NMDARM add-on therapy with placebo, and double-blind assessment of symptoms in chronic schizophrenia using standardized rating scales. Results were based on a total sample size of 1253 cases from 29 trials that fulfilled the specified criteria.<br><br>DATA EXTRACTION: Scores on rating scales or on their relevant subscales were obtained for all selected studies from published results for the minimum dataset to compute the difference between post- and pre-trial scores and their pooled standard deviation for NMDARM add-on therapy and placebo groups for negative, positive and total symptoms.<br><br>RESULTS: A negative standardized mean difference (SMD) indicates therapeutic benefit in favour of NMDARM add-on therapy and all SMD results mentioned here are statistically significant. The overall effect size for NMDARMs as a group was small for negative (SMD -0.27) and medium for total (SMD -0.40) symptoms of chronic schizophrenia. Subgroup analysis revealed medium effect sizes for D-serine and N-acetyl-cysteine (NAC) for negative (SMD -0.53 and -0.45, respectively) and total (SMD -0.40 and -0.64, respectively) symptoms, and for glycine (SMD -0.66) and sarcosine (SMD -0.41) for total symptoms. As adjuvants to non-clozapine antipsychotics, additional therapeutic benefits were observed for NMDARM as a group (SMD -0.14) and glycine (SMD -0.54) for positive symptoms; D-serine (SMD -0.54), NAC (SMD -0.45) and sarcosine (SMD -0.39) for negative symptoms; and NMDARM as a group (SMD -0.38), D-serine (SMD -0.40), glycine (SMD -1.12), NAC (SMD -0.64) and sarcosine (SMD -0.53) for total symptoms. When added to clozapine, none of the drugs demonstrated therapeutic potential, while addition of glycine (SMD +0.56) worsened positive symptoms.<br><br>CONCLUSIONS: Taking into consideration the number of trials and sample size in subgroup analyses, D-serine, NAC and sarcosine as adjuncts to non-clozapine antipsychotics have therapeutic benefit in the treatment of negative and total symptoms of chronic schizophrenia. While glycine improves positive and total symptoms as an adjuvant to non-clozapine antipsychotics, it worsens them when added to clozapine.}, }
@article {pmid21935824, year = {2011}, author = {Gül, M and Ayan, M and Seydanoğlu, A and Cander, B and Girişgin, S and Erayman, I and Erdem, S}, title = {The effect of N-acetyl cysteine on serum glutathione, TNF-alpha and tissue malondialdehyde levels in the treatment of sepsis.}, journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma &amp; emergency surgery : TJTES}, volume = {17}, number = {4}, pages = {293-297}, pmid = {21935824}, issn = {1306-696X}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/therapeutic use ; Animals ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacology/therapeutic use ; Glutathione/blood/drug effects ; Malondialdehyde/blood ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*blood ; Sepsis/blood/*drug therapy ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: The aim of this study was to investigate the effects of Nacetyl cysteine (NAC) on the levels of reactive oxygen species in sepsis.<br><br>METHODS: In this study, 30 Sprague-Dawley female rats weighing 180- 200 g were used. Rats were randomized into three groups, each containing 10 rats, as follows: Group I: Sham, Group II: Sepsis and Group III: Sepsis+NAC. Group I underwent only laparotomy. In Groups II and III, sepsis was induced by cecal ligation and perforation (CLP) technique. NAC (20 mg/kg/ day) was administered orally to Group III at 0, 8 and 16 hours. At the 24th hour, tissue and blood samples were taken for erythrocyte glutathione (GSH) and serum tumor necrosis factor (TNF)-? levels, histopathological determination, and lung, liver and kidney tissue malondialdehyde (MDA) analyses.<br><br>RESULTS: Group III was significantly different from the other groups with respect to erythrocyte glutathione, serum TNF-? and kidney MDA levels (p<0.05). There was no significant difference between the groups regarding liver MDA levels and histopathological parameters for lung, liver and kidney (p>0.05).<br><br>CONCLUSION: NAC treatment had beneficial effects on erythrocyte GSH, serum TNF-?, lung function, and kidney MDA levels in sepsis-induced rats. However, this beneficial effect was not confirmed as histopathological improvement. Further research is needed to prove the effect of NAC in sepsis treatment.}, }
@article {pmid21934138, year = {2011}, author = {Takahashi, N and Yoshida, T and Ohnuma, A and Horiuchi, H and Ishitsuka, K and Kashimoto, Y and Kuwahara, M and Nakashima, N and Harada, T}, title = {The enhancing effect of the antioxidant N-acetylcysteine on urinary bladder injury induced by dimethylarsinic acid.}, journal = {Toxicologic pathology}, volume = {39}, number = {7}, pages = {1107-1114}, doi = {10.1177/0192623311422076}, pmid = {21934138}, issn = {1533-1601}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biomarkers/metabolism ; Cacodylic Acid/*toxicity ; Cell Proliferation/drug effects ; Female ; Immunohistochemistry ; MAP Kinase Signaling System/drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Inbred F344 ; Urinary Bladder Diseases/*chemically induced/*drug therapy/metabolism/pathology ; Urothelium/drug effects ; }, abstract = {Dimethylarsinic acid (DMA(V)), the major excreted metabolite of inorganic arsenic, is carcinogenic to the rat urinary bladder. Oxidative stress has been proposed as one possible mechanism of DMA(V)-induced carcinogenesis. The authors determined whether the antioxidant N-acetylcysteine (NAC) modifies DMA(V)-induced urinary bladder injury in rats. The treatment solutions--DMA(V) at 10 mg/kg, NAC at 90 or 1.6 mg/kg (high or low dose, respectively), and their combination--were intravesically instilled into female F344 rats over two hours under pentobarbital anesthesia. The treatment was conducted twice with an interval of three days. All animals were euthanized one day after the second treatment. NAC (low dose) alone did not induce histopathological changes or increase 5-bromo-2'-deoxyuridine (BrdU) labeling index in urothelial cells. Both DMA(V) and NAC (high dose) induced a weak neutrophil infiltration and an increase in the BrdU labeling index; these pathological changes were enhanced by the combined treatment of DMA(V) and NAC (high or low dose). Increased oxidative stress and urothelial cell hyperplasia with evidence of activated p44/42 MAPK (ERK1/2) and cyclin D1 were found in the DMA(V) and NAC (high dose) cotreated group. These results suggest that cotreatment with NAC enhanced DMA(V)-induced urinary bladder injury and that the effects may be mediated by excess oxidative stress and ERK signaling.}, }
@article {pmid21931801, year = {2011}, author = {Oliva, CR and Moellering, DR and Gillespie, GY and Griguer, CE}, title = {Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production.}, journal = {PloS one}, volume = {6}, number = {9}, pages = {e24665}, pmid = {21931801}, issn = {1932-6203}, support = {R01 CA160821/CA/NCI NIH HHS/United States ; R21 CA139290/CA/NCI NIH HHS/United States ; P60 DK079626/DK/NIDDK NIH HHS/United States ; P20 CA151129/CA/NCI NIH HHS/United States ; P30 CA13148-35/CA/NCI NIH HHS/United States ; P30 CA013148/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents, Alkylating/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; DNA, Mitochondrial/metabolism ; Dacarbazine/analogs &amp; derivatives/pharmacology ; Drug Resistance, Neoplasm ; Electron Transport Complex IV/metabolism ; Glioma/*metabolism ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Humans ; Reactive Oxygen Species/*metabolism ; Temozolomide ; }, abstract = {Temozolomide (TMZ) is an alkylating agent used for treating gliomas. Chemoresistance is a severe limitation to TMZ therapy; there is a critical need to understand the underlying mechanisms that determine tumor response to TMZ. We recently reported that chemoresistance to TMZ is related to a remodeling of the entire electron transport chain, with significant increases in the activity of complexes II/III and cytochrome c oxidase (CcO). Moreover, pharmacologic and genetic manipulation of CcO reverses chemoresistance. Therefore, to test the hypothesis that TMZ-resistance arises from tighter mitochondrial coupling and decreased production of reactive oxygen species (ROS), we have assessed mitochondrial function in TMZ-sensitive and -resistant glioma cells, and in TMZ-resistant glioblastoma multiform (GBM) xenograft lines (xenolines). Maximum ADP-stimulated (state 3) rates of mitochondrial oxygen consumption were greater in TMZ-resistant cells and xenolines, and basal respiration (state 2), proton leak (state 4), and mitochondrial ROS production were significantly lower in TMZ-resistant cells. Furthermore, TMZ-resistant cells consumed less glucose and produced less lactic acid. Chemoresistant cells were insensitive to the oxidative stress induced by TMZ and hydrogen peroxide challenges, but treatment with the oxidant L-buthionine-S,R-sulfoximine increased TMZ-dependent ROS generation and reversed chemoresistance. Importantly, treatment with the antioxidant N-acetyl-cysteine inhibited TMZ-dependent ROS generation in chemosensitive cells, preventing TMZ toxicity. Finally, we found that mitochondrial DNA-depleted cells (ρ°) were resistant to TMZ and had lower intracellular ROS levels after TMZ exposure compared with parental cells. Repopulation of ρ° cells with mitochondria restored ROS production and sensitivity to TMZ. Taken together, our results indicate that chemoresistance to TMZ is linked to tighter mitochondrial coupling and low ROS production, and suggest a novel mitochondrial ROS-dependent mechanism underlying TMZ-chemoresistance in glioma. Thus, perturbation of mitochondrial functions and changes in redox status might constitute a novel strategy for sensitizing glioma cells to therapeutic approaches.}, }
@article {pmid21928090, year = {2012}, author = {Henrich, CJ and Thomas, CL and Brooks, AD and Booth, NL and Lowery, EM and Pompei, RJ and McMahon, JB and Sayers, TJ}, title = {Effects of cucurbitacins on cell morphology are associated with sensitization of renal carcinoma cells to TRAIL-induced apoptosis.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {17}, number = {1}, pages = {79-89}, pmid = {21928090}, issn = {1573-675X}, support = {HHSN261200800001C/RC/CCR NIH HHS/United States ; HHSN261200800001E/CA/NCI NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; }, mesh = {Apoptosis/*drug effects ; Carcinoma, Renal Cell/genetics/metabolism/*physiopathology ; Caspase 8/genetics/metabolism ; Cell Line, Tumor ; Cell Shape/drug effects ; Cucurbitacins/*pharmacology ; Humans ; Kidney Neoplasms/genetics/metabolism/*physiopathology ; Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/metabolism ; TNF-Related Apoptosis-Inducing Ligand/*metabolism ; }, abstract = {Cucurbitacins B and D were among the compounds identified as sensitizers of cancer cells to TRAIL-mediated apoptosis in a high-throughput screen. Therefore a series of cucurbitacins was further investigated for TRAIL sensitization and possible mechanisms of action. A total of six cucurbitacins promoted TRAIL-induced apoptosis (B, I, E, C, D, and K) and one (P) was inactive. Sensitization of renal adenocarcinoma cells to TRAIL was apparent after as little as 1-4 h pretreatment and did not require continued presence of cucurbitacin. Active cucurbitacins induced caspase-8 activation only after subsequent TRAIL addition and caspase activation was required for apoptosis suggesting amplified proximal signaling from TRAIL death receptors. Cucurbitacin-sensitized TRAIL-induced cytotoxicity was inhibited by N-acetyl cysteine. Structure-activity relationship analysis in comparison to published studies suggests that TRAIL-sensitizing and general cytotoxic activities of cucurbitacins may be decoupled. Cucurbitacins are reported to be inhibitors of STAT3 activation. However, their TRAIL-sensitizing activity is STAT3-independent. Treatment of renal carcinoma cells with active cucurbitacins produced rapid and dramatic changes in cell morphology and cytoskeletal organization (also prevented by NAC). Therefore, cucurbitacins may be useful as tools for investigating the molecular mechanism(s) of action of TRAIL sensitizers, particularly with regard to temporal aspects of sensitization and modulation of TRAIL signaling by cell morphology, and could form the basis for future therapeutic development in combination with TRAIL death receptor agonists.}, }
@article {pmid21924885, year = {2011}, author = {Reddy, PS and Rani, GP and Sainath, SB and Meena, R and Supriya, Ch}, title = {Protective effects of N-acetylcysteine against arsenic-induced oxidative stress and reprotoxicity in male mice.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {25}, number = {4}, pages = {247-253}, doi = {10.1016/j.jtemb.2011.08.145}, pmid = {21924885}, issn = {1878-3252}, mesh = {17-Hydroxysteroid Dehydrogenases/metabolism ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Arsenic/*toxicity ; Body Weight/drug effects ; Epididymis/drug effects ; Lipid Peroxidation/drug effects ; Male ; Mice ; Oxidative Stress/*drug effects ; Protective Agents/*pharmacology ; Reproduction/*drug effects ; Spermatozoa/drug effects/metabolism ; Testis/drug effects/enzymology ; Testosterone/metabolism ; }, abstract = {Arsenic is a well-known environmental toxic metalloid element and carcinogen that affects multiple organ systems including tissue lipid peroxidation and reproduction. The present study was aimed to investigate the protective role of N-acetylcysteine (NAC) on arsenic-induced testicular oxidative damage and antioxidant and steroidogeneic enzymes and sperm parameters in mice. Arsenic was administered through drinking water to mice at a concentration of 4.0 ppm sodium arsenite (actual concentration 2.3 ppm arsenic) for 35 days. The body weight of treated mice did not show significant change as compared with the control mice. In arsenic exposed mice there was a significant decrease in the weight of the testis, epididymis and prostate gland as compared with the control animals. Significant reduction was observed in epididymal sperm count, motile sperms and viable sperms in mice exposed to arsenic indicate decreased spermatogenesis and poor sperm quality. The activity levels of testicular 3β- and 17β-hydroxysteroid dehydrogenases and circulatory levels of testosterone were also decreased in arsenic treated mice indicating reduced steroidogenesis. A significant increase in the activities of lipid peroxidation and a significant decrease in the activities of antioxidant enzymes were observed in the testis of mice exposed to arsenic. In addition, significant increase in the testicular arsenic levels was observed during arsenic intoxication. No significant changes in the oxidation status and selected reproductive variables were observed in the N-acetylcysteine alone treated mice. Whereas, intra-peritoneal injection of NAC to arsenic exposed mice showed a significant increase in the weights of reproductive organs, reduction in arsenic-induced oxidative stress in the tissues and improvement in steroidogenesis over arsenic-exposed mice indicating the beneficial role of N-acetylcysteine to counteract arsenic-induced oxidative stress and to restore the suppressed reproduction in male mice.}, }
@article {pmid21924548, year = {2011}, author = {Park, KR and Nam, D and Yun, HM and Lee, SG and Jang, HJ and Sethi, G and Cho, SK and Ahn, KS}, title = {β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation.}, journal = {Cancer letters}, volume = {312}, number = {2}, pages = {178-188}, doi = {10.1016/j.canlet.2011.08.001}, pmid = {21924548}, issn = {1872-7980}, mesh = {Apoptosis/*drug effects ; Cell Division/*drug effects ; Cell Line, Tumor ; Enzyme Activation ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Mitogen-Activated Protein Kinases/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Polycyclic Sesquiterpenes ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/*metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Sesquiterpenes/*pharmacology ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Both PI3K/AKT/mTOR/S6K1 and mitogen activated protein kinase (MAPK) signaling cascades play an important role in cell proliferation, survival, angiogenesis, and metastasis of tumor cells. In the present report, we investigated the effects of β-caryophyllene oxide (CPO), a sesquiterpene isolated from essential oils of medicinal plants such as guava (Psidium guajava), oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) clove (Eugenia caryophyllata), and black pepper (Piper nigrum L.) on the PI3K/AKT/mTOR/S6K1 and MAPK activation pathways in human prostate and breast cancer cells. We found that CPO not only inhibited the constitutive activation of PI3K/AKT/mTOR/S6K1 signaling cascade; but also caused the activation of ERK, JNK, and p38 MAPK in tumor cells. CPO induced increased reactive oxygen species (ROS) generation from mitochondria, which is associated with the induction of apoptosis as characterized by positive Annexin V binding and TUNEL staining, loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, and cleavage of PARP. Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented CPO-induced apoptosis. Subsequently, CPO also down-regulated the expression of various downstream gene products that mediate cell proliferation (cyclin D1), survival (bcl-2, bcl-xL, survivin, IAP-1, and IAP-2), metastasis (COX-2), angiogenesis (VEGF), and increased the expression of p53 and p21. Interestingly, we also observed that CPO can significantly potentiate the apoptotic effects of various pharmacological PI3K/AKT inhibitors when employed in combination in tumor cells. Overall, these findings suggest that CPO can interfere with multiple signaling cascades involved in tumorigenesis and used as a potential therapeutic candidate for both the prevention and treatment of cancer.}, }
@article {pmid21924341, year = {2011}, author = {Liu, H and Peng, H and Ji, Z and Zhao, S and Zhang, Y and Wu, J and Fan, J and Liao, J}, title = {Reactive oxygen species-mediated mitochondrial dysfunction is involved in apoptosis in human nasopharyngeal carcinoma CNE cells induced by Selaginella doederleinii extract.}, journal = {Journal of ethnopharmacology}, volume = {138}, number = {1}, pages = {184-191}, doi = {10.1016/j.jep.2011.08.072}, pmid = {21924341}, issn = {1872-7573}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Apoptosis/*drug effects ; Carcinoma ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytochromes c/metabolism ; Disease Models, Animal ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/*drug effects/physiology ; Nasopharyngeal Carcinoma ; Nasopharyngeal Neoplasms/*drug therapy/metabolism/physiopathology ; *Phytotherapy ; Plant Extracts/pharmacology/*therapeutic use ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; *Selaginellaceae ; bcl-2-Associated X Protein/metabolism ; }, abstract = {A traditional Chinese medicine Selaginella doederleinii Hieron has been combined with radiotherapy for the treatment of human nasopharyngeal carcinoma in clinic in China. However, the detailed mechanism of anti-tumor effect of Selaginella doederleinii remains elusive.<br><br>AIM OF THE STUDY: This study was designed to investigate the anti-tumor effect of ethanol extract of Selaginella doederleinii (SDE) on human nasopharyngeal carcinoma and its possible mechanisms.<br><br>MATERIALS AND METHODS: Viability, apoptosis and protein expression of tumor cells were analyzed by MTT, Annexin V staining and Western blot, respectively. Formation of intracellular reactive oxygen species was determined using dichlorofluorescin fluorescence. The in vivo anti-tumor effect was evaluated by measuring tumor volume changes and TUNEL staining in nude mice.<br><br>RESULTS: SDE significantly inhibited the growth and induced apoptosis in human nasopharyngeal carcinoma CNE cells. In addition, SDE triggered the mitochondrial/caspase apoptotic pathway indicated by enhanced Bax-to-Bcl-2 ratio, loss of mitochondrial membrane potential, cytochrome c release, and caspase cascade. Moreover, SDE provoked the generation of reactive oxygen species in CNE cells, while the antioxidant N-acetyl cysteine almost completely blocked SDE-induced disruption of mitochondrial membrane potential, caspases activation and apoptosis. Furthermore, a transplantable nude mice model was utilized to estimate the effectiveness of SDE in vivo. The treated mice displayed decreased tumor size, which was associated with enhanced apoptotic cell death.<br><br>CONCLUSIONS: These results, offering solid evidence of the induction of mitochondria-related apoptosis in tumor cells, provide the molecular theoretical basis of clinical application of Selaginella doederleinii for the treatment of human nasopharyngeal carcinoma.}, }
@article {pmid21922099, year = {2011}, author = {Chen, L and Zhou, N and Li, J and Chen, Z and Liao, C and Chen, J}, title = {Synergy of glutathione, dithiothreitol and N-acetyl-L-cysteine self-assembled monolayers for electrochemical assay: sensitive determination of arsenic(III) in environmental and drinking water.}, journal = {The Analyst}, volume = {136}, number = {21}, pages = {4526-4532}, doi = {10.1039/c1an15454k}, pmid = {21922099}, issn = {1364-5528}, mesh = {Acetylcysteine ; Arsenic/*analysis ; Dithiothreitol ; Drinking Water/*chemistry ; *Electrochemical Techniques ; Electrodes ; Glutathione ; Gold ; Limit of Detection ; Seawater/analysis/chemistry ; Water Pollutants, Chemical/*analysis ; }, abstract = {A simple and efficient electrochemical assay based on self-assembled monolayers (SAMs) was developed for the highly sensitive determination of arsenic(III) in water samples. The synergy of glutathione (GSH), dithiothreitol (DTT) and N-acetyl-L-cysteine (NAC) mixed SAMs enhanced the detection specificity and sensitivity of As(III) in water samples, resulting from the immobilization of a large number of As(III) moieties on the gold electrode surface via As-O and As-S linkages. After accumulating As(III), anodic stripping voltammetry (ASV) was performed, and linear sweep voltammetry (LSV) was employed for signal recording. Several main voltammetric parameters were optimized as follows: supporting electrolyte, 1 mol L(-1) HCl; deposition potential, -0.35 V; deposition time, 150 s. A good linear relationship (R = 0.9980) was attained between the concentration of the As(III) standard and peak current, in the range of 3-100 μg L(-1). The limit of detection (LOD) of this sensing system was determined to be 0.5 μg L(-1) at a signal-to-noise ratio of 3. A variety of common coexistent ions in water samples were examined, showing no obvious interferences on the As(III) determination. The amenability of this method to the analyses of water samples was also investigated. High recovery of 90.5% with the precision of 5.1% at spiked 10 μg L(-1), and low LOD of 0.3 μg L(-1) were obtained in seawater. The synergy effect of GSH, DTT and NAC provided the possibility for the rapid and sensitive LSV determination of As(III) in complicated water samples.}, }
@article {pmid21916896, year = {2012}, author = {Lu, H and Wan, Q and Wang, H and Na, X and Wang, X and Bi, Y}, title = {Oxidative stress and mitochondrial dysfunctions are early events in narciclasine-induced programmed cell death in tobacco Bright Yellow-2 cells.}, journal = {Physiologia plantarum}, volume = {144}, number = {1}, pages = {48-58}, doi = {10.1111/j.1399-3054.2011.01521.x}, pmid = {21916896}, issn = {1399-3054}, mesh = {Acetylcysteine/metabolism ; Amaryllidaceae Alkaloids/*pharmacology ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Catalase/metabolism ; Cells, Cultured ; Hydrogen Peroxide/metabolism ; Mitochondria/drug effects/metabolism/*physiology ; Narcissus/chemistry ; Oxidative Stress/*drug effects ; Phenanthridines/*pharmacology ; Plant Growth Regulators/metabolism ; Plant Roots/chemistry ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Nicotiana/*drug effects/growth &amp; development/metabolism ; }, abstract = {Narciclasine (NCS) is a plant growth inhibitor isolated from the secreted mucilage of Narcissus tazetta bulbs. It is a commonly used anticancer agent in animal systems. In this study, we provide evidence to show that NCS also acts as an agent in inducing programmed cell death (PCD) in tobacco Bright Yellow-2 (TBY-2) cell cultures. NCS treatment induces typical PCD-associated morphological and biochemical changes, namely cell shrinkage, chromatin condensation and nuclear DNA degradation. To investigate possible signaling events, we analyzed the production of reactive oxygen species (ROS) and the function of mitochondria during PCD induced by NCS. A biphasic behavior burst of hydrogen peroxide (H(2)O(2)) was detected in TBY-2 cells treated with NCS, and mitochondrial transmembrane potential (MTP) loss occurred after a slight increase. Pre-incubation with antioxidant catalase (CAT) and N-acetyl-L-cysteine (NAC) not only significantly decreased the H(2)O(2) production but also effectively retarded the decrease of MTP and reduced the percentage of cells undergoing PCD after NCS treatment. In conclusion, our results suggest that NCS induces PCD in plant cells; the oxidative stress (accumulation of H(2)O(2)) and the MTP loss play important roles during NCS-induced PCD.}, }
@article {pmid21913320, year = {2011}, author = {Ueno, T and Yamada, M and Igarashi, Y and Ogawa, T}, title = {N-acetyl cysteine protects osteoblastic function from oxidative stress.}, journal = {Journal of biomedical materials research. Part A}, volume = {99}, number = {4}, pages = {523-531}, doi = {10.1002/jbm.a.33211}, pmid = {21913320}, issn = {1552-4965}, mesh = {Acetylcysteine/*pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Antioxidants/*pharmacology ; Calcification, Physiologic/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Collagen Type I/genetics/metabolism ; Free Radical Scavengers/*pharmacology ; Gene Expression/drug effects ; Hydrogen Peroxide/pharmacology ; Male ; Osteoblasts/cytology/*drug effects/*physiology ; Osteocalcin/genetics/metabolism ; Osteopontin/genetics/metabolism ; Oxidants/pharmacology ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {We tested the protective potential of an antioxidant amino acid derivative, N-acetyl cysteine (NAC), in controlling oxidative stress against osteoblasts. Osteoblastic cells extracted from rat bone marrow were cultured. Oxidative stress was induced by adding 100 μM H2O2 into the culture media. Then, some H2O2-treated cultures were cotreated with 2.5 or 5 mM NAC. Addition of H2O2 decreased the number of cells to 50% of untreated cultures at days 2. Addition of 5 mM NAC into H2O2 cultures resulted in a dose-dependent increase in the number of cells, with the cell number being 50% greater than that in the 100 μM H2O2 culture. The gene expression levels of type I collagen, osteopontin, and osteocalcin were downregulated threefold by H2O2 on day 7. The H2O2-suppressed gene expression was fully recovered by NAC cotreatment. The mineralizing capability, assessed by Von Kossa staining on day 15, were approximately 1.8 times greater in the NAC + H2O2 cotreated group than in the culture with H2O2 alone. These NAC-mediated restorations were associated with an NAC dose-dependent increase of intracellular glutathione and a NAC dose-dependent decrease of intracellular reactive oxygen species. In conclusion, oxidative stress induced by H2O2 substantially impairs the proliferation, differentiation, and mineralization of osteoblasts. More importantly, the addition of NAC into the culture was found to restore these damages to a near normal level due to the improved redox balance, warranting further in vivo studies to test its therapeutic potential as a local antioxidative stress drug.}, }
@article {pmid21912612, year = {2011}, author = {Wang, T and Qiao, S and Lei, S and Liu, Y and Ng, KF and Xu, A and Lam, KS and Irwin, MG and Xia, Z}, title = {N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats.}, journal = {PloS one}, volume = {6}, number = {8}, pages = {e23967}, pmid = {21912612}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Adiponectin/biosynthesis/*metabolism ; Allopurinol/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Biomarkers/metabolism ; Blood Glucose/metabolism ; Creatine Kinase, MB Form/blood ; Diabetes Complications/drug therapy/*metabolism/pathology/physiopathology ; Dinoprost/analogs &amp; derivatives ; Drug Synergism ; Gene Expression Regulation/drug effects ; Hemodynamics/drug effects ; Interleukin-6/blood ; Isoprostanes/metabolism ; Male ; Myocardial Infarction/drug therapy/pathology ; Myocardial Reperfusion Injury/drug therapy/*metabolism/pathology/physiopathology ; Myocardium/*metabolism/pathology ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Adiponectin/metabolism ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: Hyperglycemia-induced oxidative stress plays a central role in the development of diabetic myocardial complications. Adiponectin (APN), an adipokine with anti-diabetic and anti-ischemic effects, is decreased in diabetes. It is unknown whether or not antioxidant treatment with N-acetylcysteine (NAC) and/or allopurinol (ALP) can attenuate APN deficiency and myocardial ischemia reperfusion (MI/R) injury in the early stage of diabetes.<br><br>Control or streptozotocin (STZ)-induced diabetic rats were either untreated (C, D) or treated with NAC (1.5 g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. Plasma and cardiac biochemical parameters were measured after the completion of treatment, and the rats were subjected to MI/R by occluding the left anterior descending artery for 30 min followed by 2 h reperfusion. Plasma and cardiac APN levels were decreased in diabetic rats accompanied by decreased cardiac APN receptor 2 (AdipoR2), reduced phosphorylation of Akt, signal transducer and activator of transcription 3 (STAT3) and endothelial nitric oxide synthase (eNOS) but increased IL-6 and TNF-&#x3b1; (all P<0.05 vs. C). NAC but not ALP increased cardiac APN concentrations and AdipoR2 expression in diabetic rats. ALP enhanced the effects of NAC in restoring cardiac AdipoR2 and phosphorylation of Akt, STAT3 and eNOS in diabetic rats. Further, NAC and ALP, respectively, decreased postischemic myocardial infarct size and creatinine kinase-MB (CK-MB) release in diabetic rats, while their combination conferred synergistic protective effects. In addition, exposure of cultured rat cardiomyocytes to high glucose resulted in significant reduction of cardiomyocyte APN concentration and AdipoR2 protein expression. APN supplementation restored high glucose induced AdipoR2 reduction in cardiomyocytes.<br><br>CONCLUSIONS/SIGNIFICANCE: NAC and ALP synergistically restore myocardial APN and AdipoR2 mediated eNOS activation. This may represent the mechanism through which NAC and ALP combination greatly reduces MI/R injury in early diabetic rats.}, }
@article {pmid21912568, year = {2012}, author = {Han, MH and Lee, WS and Lu, JN and Yun, JW and Kim, G and Jung, JM and Kim, GY and Lee, SJ and Kim, WJ and Choi, YH}, title = {Tetraarsenic Hexoxide Induces Beclin-1-Induced Autophagic Cell Death as well as Caspase-Dependent Apoptosis in U937 Human Leukemic Cells.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2012}, number = {}, pages = {201414}, pmid = {21912568}, issn = {1741-4288}, abstract = {Tetraarsenic hexaoxide (As(4)O(6)) has been used in Korean folk remedy for the treatment of cancer since the late 1980s, and arsenic trioxide (As(2)O(3)) is currently used as a chemotherapeutic agent. However, evidence suggests that As(4)O(6)-induced cell death pathway was different from that of As(2)O(3). Besides, the anticancer effects and mechanisms of As(4)O(6) are not fully understood. Therefore, we investigated the anticancer activities of As(4)O(6) on apoptosis and autophagy in U937 human leukemic cells. The growth of U937 cells was inhibited by As(4)O(6) treatment in a dose- and a time-dependent manner, and IC(50) for As(4)O(6) was less than 2 μM. As(4)O(6) induced caspase-dependent apoptosis and Beclin-1-induced autophagy, both of which were significantly attenuated by Bcl-2 augmentation and N-acetylcysteine (NAC) treatment. This study suggests that As(4)O(6) should induce Beclin-1-induced autophagic cell death as well as caspase-dependent apoptosis and that it might be a promising agent for the treatment of leukemia.}, }
@article {pmid21911445, year = {2011}, author = {Li, C and Xu, J and Li, F and Chaudhary, SC and Weng, Z and Wen, J and Elmets, CA and Ahsan, H and Athar, M}, title = {Unfolded protein response signaling and MAP kinase pathways underlie pathogenesis of arsenic-induced cutaneous inflammation.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {4}, number = {12}, pages = {2101-2109}, pmid = {21911445}, issn = {1940-6215}, support = {R21ES017494/ES/NIEHS NIH HHS/United States ; R21 ES017494/ES/NIEHS NIH HHS/United States ; P30 AR050948-07/AR/NIAMS NIH HHS/United States ; R21 ES017494-02/ES/NIEHS NIH HHS/United States ; P30 AR050948/AR/NIAMS NIH HHS/United States ; R21 ES017494-01/ES/NIEHS NIH HHS/United States ; }, mesh = {Activating Transcription Factor 6/genetics/metabolism ; Animals ; Arsenic/*toxicity ; Blotting, Western ; Endoplasmic Reticulum Chaperone BiP ; Fluorescent Antibody Technique ; Heat-Shock Proteins/genetics/metabolism ; Humans ; Inflammation/chemically induced/*metabolism/pathology ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Mice ; Mice, Hairless ; Mitogen-Activated Protein Kinases/genetics/*metabolism ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/genetics/metabolism ; RNA, Messenger/genetics ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Skin/*drug effects/metabolism/*pathology ; Transcription Factor CHOP/genetics/metabolism ; Transcription, Genetic ; Unfolded Protein Response/*physiology ; eIF-2 Kinase/genetics/metabolism ; }, abstract = {Arsenic exposure through drinking water is a major global public health problem and is associated with an enhanced risk of various cancers including skin cancer. In human skin, arsenic induces precancerous melanosis and keratosis, which may progress to basal cell and squamous cell carcinoma. However, the mechanism by which these pathophysiologic alterations occur remains elusive. In this study, we showed that subchronic arsenic exposure to SKH-1 mice induced unfolded protein response (UPR) signaling regulated by proteins, inositol-requiring enzyme-1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6). Arsenic activated all three UPR regulatory proteins in the skin. Arsenic induced IRE1 phosphorylation which resulted in augmented splicing of X-box binding protein 1 (XBP-1) leading to its migration to the nucleus, and also enhanced transcriptional activation of downstream target proteins. Hyperphosphorylation of PERK which induces eukaryotic translation initial factor 2α (eIF2α) in a phosphorylation-dependent manner enhanced translation of ATF4, in addition to augmenting proteolytic activation of ATF6 in arsenic-treated skin. A similar increase in the expression of CHOP was observed. Enhanced XBP-1s, ATF4, and ATF6 regulated downstream chaperones GRP94 and GRP78. In addition, arsenic induced inflammation-related p38/MAPKAPK-2 MAPK signaling and alterations in Th-1/Th-2/Th-17 cytokines/chemokines and their receptors. Antioxidant N-acetyl cysteine blocked arsenic-induced reactive oxygen species, with a concomitant attenuation of UPR and mitogen-activated protein kinase (MAPK) signaling and proinflammatory cytokine/chemokine signatures. Our results identify novel pathways involved in the pathogenesis of arsenic-mediated cutaneous inflammation which may also be related to enhanced cancer risk in arsenic exposed cohorts.}, }
@article {pmid21907236, year = {2011}, author = {Lee, JE and Kang, JS and Shin, IC and Lee, SJ and Hyun, DH and Lee, KS and Koh, HC}, title = {Fluazinam-induced apoptosis of SH-SY5Y cells is mediated by p53 and Bcl-2 family proteins.}, journal = {Neurotoxicology}, volume = {32}, number = {6}, pages = {702-710}, doi = {10.1016/j.neuro.2011.08.004}, pmid = {21907236}, issn = {1872-9711}, mesh = {Acetylcysteine/pharmacology ; Aminopyridines/*toxicity ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Electron Transport Complex I/metabolism ; Humans ; Mitochondria/drug effects/metabolism/pathology ; Neurons/*drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Pesticides/*toxicity ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Time Factors ; Tumor Suppressor Protein p53/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {A number of epidemiological studies have demonstrated a strong association between the incidence of neurodegenerative disease and pesticide exposure. Fluazinam (FZN) is a preventative fungicide from the pyridinamine group that was introduced in the 1990 s and that quickly established itself as a new standard for the control of blight caused by Phytophthora infestans in potatoes. We used human neuroblastoma SH-SY5Y cells to investigate mechanisms of neuronal cell death in response to FZN and showed that FZN was cytotoxic to SH-SY5Y cells in a concentration- and time-dependent manner. Additionally, we showed that FZN treatment significantly decreased the neuron numbers including dopaminergic neurons and mitochondrial complex I activity. The cytotoxic effects of FZN were associated with an increase in reactive oxygen species (ROS) generation because pretreatment with N-acetyl cysteine, an anti-oxidant, reduced cell death. We showed that neuronal cell death in response to FZN was due to apoptosis because FZN increased cytochrome C release into the cytosol and activated caspase-3 through the accumulation of p53. FZN also reduced the levels of Bcl-2 protein but increased the levels of Bax. Our results provide insight into the molecular mechanisms of FZN-induced apoptosis in neuronal cells.}, }
@article {pmid21904641, year = {2011}, author = {Leelarungrayub, D and Khansuwan, R and Pothongsunun, P and Klaphajone, J}, title = {N-acetylcysteine supplementation controls total antioxidant capacity, creatine kinase, lactate, and tumor necrotic factor-alpha against oxidative stress induced by graded exercise in sedentary men.}, journal = {Oxidative medicine and cellular longevity}, volume = {2011}, number = {}, pages = {329643}, pmid = {21904641}, issn = {1942-0994}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/*metabolism ; Creatine Kinase/*blood ; Exercise/*physiology ; Humans ; Lactic Acid/*blood ; Male ; Muscle, Skeletal/drug effects/metabolism ; Oxidative Stress/*drug effects ; Tumor Necrosis Factor-alpha/*blood ; Young Adult ; }, abstract = {Aim of this study was to evaluate the effects of short-term (7 days) N-acetylcysteine (NAC) at 1,200 mg daily supplementation on muscle fatigue, maximal oxygen uptake (VO(2max)), total antioxidant capacity (TAC), lactate, creatine kinase (CK), and tumor necrotic factor-alpha (TNF-α). Twenty-nine sedentary men (13 controls; 16 in the supplement group) from a randomized control were included. At before and after supplementation, fatigue index (FI) was evaluated in the quadriceps muscle, and performed a graded exercise treadmill test to induce oxidative stress, and as a measure of VO(2max). Blood samples were taken before exercise and 20 minutes after it at before and after supplementation, to determine TAC, CK, lactate, and TNF-α levels. Results showed that FI and VO(2max) increased significantly in the supplement group. After exercise decreased the levels of TAC and increased lactate, CK, and TNF-α of both groups at before supplementation. After supplementation, lactate, CK, and TNF-α levels significantly increased and TAC decreased after exercise in the control group. Whereas the TAC and lactate levels did not change significantly, but CK and TNF-α increased significantly in the supplement group. Therefore, this results showed that NAC improved the muscle fatigue, VO(2max), maintained TAC, controlled lactate production, but had no influence on CK and TNF-α.}, }
@article {pmid21902453, year = {2012}, author = {Won, H and Lim, S and Jang, M and Kim, Y and Rashid, MA and Jyothi, KR and Dashdorj, A and Kang, I and Ha, J and Kim, SS}, title = {Peroxiredoxin-2 upregulated by NF-κB attenuates oxidative stress during the differentiation of muscle-derived C2C12 cells.}, journal = {Antioxidants &amp; redox signaling}, volume = {16}, number = {3}, pages = {245-261}, doi = {10.1089/ars.2011.3952}, pmid = {21902453}, issn = {1557-7716}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; *Cell Differentiation ; Cell Line ; Female ; Homeodomain Proteins/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Muscle Development/drug effects ; Muscle, Skeletal/cytology/*physiology ; NF-kappa B/*metabolism ; *Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Promoter Regions, Genetic ; Protein Binding ; Reactive Oxygen Species/metabolism ; Regeneration ; Satellite Cells, Skeletal Muscle/metabolism/physiology ; Transcription, Genetic ; *Up-Regulation ; }, abstract = {AIM: Many studies have reported that the generation of reactive oxygen species (ROS) increases during the differentiation of muscle-derived C2C12 cells. Peroxiredoxin-2 (Prx-2) is an abundant mammalian enzyme that protects against oxidative stress. However, the role of Prx-2 in muscle differentiation has not been investigated.<br><br>RESULTS: In this study, we demonstrated that Prx-2 expression increases during muscle differentiation and regeneration in response to exogenous H(2)O(2). This increase occurs only in myoblast cell lines because no increase in Prx-2 expression was observed in the NIH3T3, MEF, Chang, or HEK293 cell lines. The antioxidants, N-acetyl L-cysteine (NAC) and 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron), both suppressed myogenesis and Prx-2 expression. Moreover, Prx-2 was upregulated at the transcriptional level by NF-&#x3ba;B during the differentiation of muscle-derived C2C12 cells. We also found that inhibition of phosphatidylinositol 3-kinase (PI3K) blocks NF-&#x3ba;B activation and suppresses Prx-2 expression. Interestingly, Prx-2 knockdown increased the expression levels of other antioxidant enzymes, including all of the other Prx family member, thioredoxin-1 (Trx-1) and catalase, but also enhanced the accumulation of endogenous ROS during muscle differentiation.<br><br>INNOVATION: In this study, we demonstrated for the first time that Prx-2 is unregulated during the muscle differentiation and regeneration.<br><br>CONCLUSION: Prx-2 is upregulated via the PI3K/NF-&#x3ba;B pathway and attenuates oxidative stress during muscle differentiation and regeneration.}, }
@article {pmid21897744, year = {2011}, author = {Fan, X and Xiaoqin, L and Potts, B and Strauch, CM and Nemet, I and Monnier, VM}, title = {Topical application of L-arginine blocks advanced glycation by ascorbic acid in the lens of hSVCT2 transgenic mice.}, journal = {Molecular vision}, volume = {17}, number = {}, pages = {2221-2227}, pmid = {21897744}, issn = {1090-0535}, support = {P30 EY011373/EY/NEI NIH HHS/United States ; R01 EY007099/EY/NEI NIH HHS/United States ; EY07099/EY/NEI NIH HHS/United States ; P30EY-11373/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Administration, Topical ; Aging ; Animals ; *Arginine/administration &amp; dosage/therapeutic use ; Ascorbic Acid/*metabolism ; Biological Transport, Active ; Cataract/*prevention &amp; control ; Crystallins/*metabolism ; Gene Knock-In Techniques ; Glycation End Products, Advanced/*metabolism ; Guanidines/administration &amp; dosage ; Humans ; *Lens, Crystalline/drug effects/metabolism/pathology ; Mass Spectrometry ; Mice ; Mice, Transgenic ; Ophthalmic Solutions/administration &amp; dosage ; Penicillamine/administration &amp; dosage ; Rabbits ; Sodium-Coupled Vitamin C Transporters/genetics/*metabolism ; Spectrometry, Fluorescence ; }, abstract = {PURPOSE: Previous experiments from our laboratory showed that the oral intake of selected guanidino compounds could block the formation of crystallin-bound advanced ascorbylation products. Here we tested whether these were also active when applied as eye drops.<br><br>METHODS: Two month old hSVCT2 transgenic mice (n=10) were treated twice daily with one drop of 0.1% L-arginine, &#x3b3;-guanidinobutyric acid (GBA), penicillamine (PA) or N-acetylcysteine (NAC) in one eye and vehicle only in the other eye. After seven months, lens crystallins were isolated, dialyzed, and proteolytically digested to determine the protein-bound fluorescence at 335/385 and 370/440 nm excitation/emission and the advanced glycation/ascorbylation endproducts carboxymethyl-lysine (CML), carboxyethyl-lysine (CEL), glucosepane, glyoxal, and methylglyoxal hydroimidazolones G-H1 and MG-H1. The topical uptake of L-arginine and NAC was also evaluated in vitro and in vivo in rabbit lens.<br><br>RESULTS: In hSVCT2 mice, L-arginine decreased 335/385 and 370/440 nm fluorescence by 40% (p<0.001), CML, CEL, and glucosepane crystallin crosslinks by 35% (p<0.05), 30% (p<0.05), and 37% (p<0.05), respectively, without affecting MG-H1 and G-H1. NAC decreased 335/385 nm fluorescence by 50% (p<0.001) but, like PA and GBA, had no effect on other modifications. L-Arginine uptake into rabbit eyes treated topically reached identical lenticular plateau levels (~400 nmol/g wet weight) at 0.5% and 2.0% but levels remained three times higher at 5 h at 2% versus 0.5% concentration, respectively. In vitro studies showed a 100 fold higher L-arginine level than NAC levels, implicating high affinity uptake of the former.<br><br>CONCLUSIONS: L-Arginine when applied both orally and topically is a potent and broad suppressor of advanced ascorbylation in the lens. Its uptake in rabbit lens upon topical application suggests transcorneal uptake into the human lens should be feasible for testing its potential anticataract properties in clinical trials.}, }
@article {pmid21896942, year = {2011}, author = {Cobley, JN and McGlory, C and Morton, JP and Close, GL}, title = {N-Acetylcysteine Attenuates Fatigue Following Repeated-Bouts of Intermittent Exercise: Practical Implications for Tournament Situations.}, journal = {International journal of sport nutrition and exercise metabolism}, volume = {}, number = {}, pages = {}, pmid = {21896942}, issn = {1543-2742}, abstract = {Production of reactive oxygen species (ROS) during contractions is associated with muscular fatigue and damage in the short-term and adaptive responses in the long-term. When adaptation is inconsequential acute antioxidant supplementation may be able to attenuate muscle fatigue and damage to enhance performance. This study aimed to determine the effects of acute oral N-acetylcysteine (NAC) supplementation on Yo-Yo intermittent recovery test performance level one (YIRT-L1) following repeated-bouts of damaging intermittent exercise. In a pair-matched design, twelve recreationally-trained males engaged in either six days of NAC (n = 6) or placebo (n = 6) supplementation. Following a treatment loading day, participants completed three testing sessions, on alternate days, consisting of a pre-exercise Isokinetic dynamometry (IKD) test, a damaging intermittent exercise protocol, YIRT-L1 and a post-exercise IKD. A further IKD test was completed on the two intervening days. NAC treatment resulted in a significant preservation of YIRT-L1 performance (P≤0.0005). IKD performance significantly deteriorated over time at all contractions speeds and this deterioration was not influenced by treatment group. Plasma creatine kinase values increased significantly over time (P=.002) and were significantly greater in the NAC group compared with the placebo group (P=.029). NAC induced mild-gastrointenstinal side effects. NAC supplementation may be a useful strategy to enhance performance during short-term competitive situations where adaption is inconsequential. Titration studies to elucidate a treatment dose that enhances performance without inducing side-effects are now required.}, }
@article {pmid21896327, year = {2011}, author = {Rogalska, A and Gajek, A and Szwed, M and Jóźwiak, Z and Marczak, A}, title = {The role of reactive oxygen species in WP 631-induced death of human ovarian cancer cells: a comparison with the effect of doxorubicin.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {8}, pages = {1712-1720}, doi = {10.1016/j.tiv.2011.08.009}, pmid = {21896327}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Antibiotics, Antineoplastic/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Daunorubicin/*analogs &amp; derivatives/pharmacology ; Doxorubicin/*pharmacology ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Female ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Ovarian Neoplasms/*drug therapy/metabolism/physiopathology ; Reactive Oxygen Species/*metabolism ; }, abstract = {In the present study, we investigated the anticancer activity of WP 631, a new anthracycline analog, in weakly doxorubicin-resistant SKOV-3 ovarian cancer cells. We studied the time-course of apoptotic and necrotic events: the production of reactive oxygen species (ROS) and changes in the mitochondrial membrane potential in human ovarian cancer cells exposed to WP 631 in the presence and absence of an antioxidant, N-acetylcysteine (NAC). The effect of WP 631 was compared with the activity of doxorubicin (DOX), the best known first-generation anthracycline. Cytotoxic activity was determined by the MTT assay. The morphological changes characteristic of apoptosis and necrosis in drug-treated cells were analyzed by double staining with Hoechst 33258 and propidium iodide (PI) using fluorescence microscopy. The production of reactive oxygen species and changes in mitochondrial membrane potential were studied using specific fluorescence probes: DCFH2-DA and JC-1, respectively. The experiments showed that WP 631 was three times more cytotoxic than DOX in the tested cell line. It was found that the new anthracycline analog induced mainly apoptosis and, marginally, necrosis. Apoptotic cell death was associated with morphological changes and a decrease in mitochondrial membrane potential. In comparison to DOX, the novel bisanthracycline induced a significantly higher level of ROS and a greater drop in the membrane potential. The results provide direct evidence that the novel anthracycline WP 631 is considerably more cytotoxic to human SKOV-3 ovarian cancer cells than doxorubicin. The drug can produce ROS, which are immediately involved in the induction of apoptotic cell death.}, }
@article {pmid21896286, year = {2011}, author = {Daudin, JB and Monnet, D and Kavian, N and Espy, C and Wang, A and Chéreau, C and Goulvestre, C and Omri, S and Brézin, A and Weill, B and Batteux, F and Nicco, C}, title = {Protective effect of pristane on experimental autoimmune uveitis.}, journal = {Immunology letters}, volume = {141}, number = {1}, pages = {83-93}, doi = {10.1016/j.imlet.2011.07.009}, pmid = {21896286}, issn = {1879-0542}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Autoimmunity/immunology ; Cell Line ; Disease Models, Animal ; Eye/*pathology ; *Eye Proteins/administration &amp; dosage/immunology ; Female ; Human Umbilical Vein Endothelial Cells ; Humans ; Hydrogen Peroxide/analysis ; Immunization ; Immunoglobulin G/blood ; Interleukin-17/analysis ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Peptide Fragments/administration &amp; dosage/immunology ; Phytol/administration &amp; dosage ; *Retinol-Binding Proteins/administration &amp; dosage/immunology ; Terpenes/*administration &amp; dosage ; *Uveitis/immunology/pathology/prevention &amp; control ; }, abstract = {This study evaluates the effects of pristane and phytol, two mineral oils with pro-oxidative effects, on the course of experimental autoimmune uveitis. C57BL6 mice were immunized with IRBP1-20 peptide emulsified in CFA and treated five days prior to immunization with phytol or with pristane or with PBS as control. Administration of pristane reduces the incidence and severity of IRBP-induced uveitis as demonstrated by the decrease in vasculitis and inflammatory foci in fundus and by a reduction in histological damages and leukocyte infiltration compared to untreated or phytol-treated mice. The protective effect observed is associated with a decreased activation of peripheral CD4+ and CD8+ T lymphocytes and a decrease in the intensity of the Th1 and Th17 autoimmune response to IRBP in pristane-treated mice compared to control mice, as evidenced by the decreased production of IFNγ and IL17 by IRBP-specific lymphocytes from lymph nodes draining the site of immunization and by the increased production of anti-IRBP IgG1 over IgG2a. In addition, HUVEC and ARPE-19 cells incubated with the sera of mice treated with pristane presented a reduced production of H(2)O(2). The benefit of lowering the systemic oxidative stress by pristane in the course of EAU was confirmed by injecting the antioxidant NAC in IRBP-immunized mice. As pristane, NAC decreased clinical and histological inflammation of the retina and preserved the integrity of the hemato-retinal barrier. Finally, the protective effect of pristane on the development of EAU suggests that some mineral oils may represent a new therapeutic strategy in human uveitis.}, }
@article {pmid21892921, year = {2012}, author = {Liu, Y and Lei, S and Gao, X and Mao, X and Wang, T and Wong, GT and Vanhoutte, PM and Irwin, MG and Xia, Z}, title = {PKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes.}, journal = {Clinical science (London, England : 1979)}, volume = {122}, number = {4}, pages = {161-173}, doi = {10.1042/CS20110176}, pmid = {21892921}, issn = {1470-8736}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Diabetes Mellitus, Experimental/complications ; Diabetic Cardiomyopathies/*prevention &amp; control ; Dinoprost/analogs &amp; derivatives ; Drug Evaluation, Preclinical ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology/therapeutic use ; Hypertrophy, Left Ventricular/diagnostic imaging/etiology/*prevention &amp; control ; Indoles/pharmacology/*therapeutic use ; Isoprostanes/blood ; Male ; Maleimides/pharmacology/*therapeutic use ; Myocytes, Cardiac/drug effects/enzymology ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Oxidative Stress/*drug effects ; Protein Kinase C/*antagonists &amp; inhibitors ; Protein Kinase C beta ; Rats ; Rats, Sprague-Dawley ; Superoxides/metabolism ; Ultrasonography ; }, abstract = {Oxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The β isoform of PKC (protein kinase C) is preferentially overexpressed in the myocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCβ is a major upstream mediator of oxidative stress in diabetes and that PKCβ inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocin-induced diabetic rats were treated with the selective PKCβ inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immunoassay or Western blotting. Echocardiography revealed that the LV mass/body weight ratio was significantly increased in diabetic rats (P<0.01 compared with the control group) in parallel with the impaired LV relaxation. A significant increase in cardiomyocyte cross-sectional area was observed in diabetic rats accompanied by an increased production of O2- (superoxide anion) and 15-F2t-isoprostane (all P<0.05 compared with the control group). RBX normalized these changes with concomitant inhibition of PKCβ2 activation and prevention of NADPH oxidase subunit p67phox membrane translocation and p22phox overexpression. The effects of RBX were comparable with that of NAC, except that NAC was inferior to RBX in attenuating cardiac dysfunction. It is concluded that RBX can ameliorate myocardial hypertrophy and dysfunction in diabetes, which may represent a novel therapy in the prevention of diabetic cardiovascular complications.}, }
@article {pmid21890206, year = {2011}, author = {Blackford, MG and Felter, T and Gothard, MD and Reed, MD}, title = {Assessment of the clinical use of intravenous and oral N-acetylcysteine in the treatment of acute acetaminophen poisoning in children: a retrospective review.}, journal = {Clinical therapeutics}, volume = {33}, number = {9}, pages = {1322-1330}, doi = {10.1016/j.clinthera.2011.08.005}, pmid = {21890206}, issn = {1879-114X}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/economics/therapeutic use ; Acute Disease ; Administration, Oral ; Child ; Clinical Trials as Topic ; Databases, Factual ; *Drug Utilization Review ; Humans ; Injections, Intravenous ; Medical Records ; Poisoning/drug therapy/economics ; Retrospective Studies ; Time Factors ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is the most effective therapy for acetaminophen (APAP) toxicity and is currently available for oral and intravenous (IV) administration. Although both routes are effective, use of the IV formulation has been increasing since becoming available in the United States in 2004, raising questions about cost/benefit comparisons between the 2 formulations. Decreased length of treatment and hospital stay have been used to justify the use of IV NAC; however, some patients may receive extended therapy of either NAC regimen.<br><br>OBJECTIVE: This retrospective review assessed the clinical use of oral and IV NAC in pediatric patients with APAP intoxication from June 1, 2004 through May 31, 2008.<br><br>METHODS: Electronic medical charts for patients aged &#x2264;21 years were identified with International Classification of Diseases, Ninth Revision (ICD-9) codes for APAP overdose. Descriptive statistics were used to describe the overall patient population and route of NAC administration. The primary outcome variable was the length of treatment with IV and oral NAC therapy.<br><br>RESULTS: A total of 62 charts for patients with APAP toxicity were reviewed; 37 patients (60%) received IV NAC and 25 patients (40%) received oral NAC. The average lengths of treatment and stay for IV dosing were 23.5 hours (range, 17.6-54.9 hours) and 1.6 days (range, 1-3 days), respectively; those for oral dosing were 69.5 hours (range, 33-133 hours) and 1.95 days (range, 1-5 days), respectively. Of 16 patients who received oral NAC and were admitted for <3 days, 14 were transferred to an inpatient psychiatric unit and completed the 72-hour therapy. A total of 3 patients received extended NAC dosing-2 with IV dosing and 1 with oral dosing.<br><br>CONCLUSIONS: Based on our review, the majority of patients received recommended dosing of NAC therapy; however, 3 patients received extended NAC therapy. Patient-specific factors should be considered when assessing whether NAC therapy should be extended and if one route of administration may be preferred. ClinicalTrials.gov identifier: NCT00725179.}, }
@article {pmid21890204, year = {2012}, author = {Chu, HQ and Liu, JM and Gui, T and Zhao, L and Sun, DY and Zhang, JB and Yi, XH}, title = {Case of interstitial lung disease possibly induced by exposure to iron dust.}, journal = {Heart &amp; lung : the journal of critical care}, volume = {41}, number = {2}, pages = {196-199}, doi = {10.1016/j.hrtlng.2011.06.002}, pmid = {21890204}, issn = {1527-3288}, mesh = {Aged ; Air Pollutants, Occupational/*adverse effects ; Biopsy ; Diagnosis, Differential ; *Dust ; Humans ; Iron/*adverse effects ; Lung Diseases, Interstitial/*chemically induced/diagnosis ; Male ; Tomography, X-Ray Computed ; }, abstract = {Interstitial lung diseases are primarily attributable to occupational or environmental exposures to dusts and irritants. We report on a case of interstitial lung disease, possibly secondary to iron exposure. Our male patient presented with cough and shortness of breath of more than 20 years' duration after his occupational exposure had ended. A chest radiograph showed patchy shadows throughout both lower fields, and computed tomography showed ground-glass-like opacification, with fibrosis in the lower lobes. A lung biopsy revealed foamy cells in the alveolar spaces, with bronchiolitis obliterans. Microelemental analysis showed an increased level of iron in the lung tissue. After treatment with N-acetyl cysteine effervescent tablets, the patient's symptoms gradually improved. This probable case of iron-induced interstitial lung disease suggests the importance of obtaining a patient's history of occupational and environmental exposures for the sake of an accurate diagnosis.}, }
@article {pmid21888768, year = {2011}, author = {Roma, LP and Oliveira, CA and Carneiro, EM and Albuquerque, GG and Boschero, AC and Souza, KL}, title = {N-acetylcysteine protects pancreatic islet against glucocorticoid toxicity.}, journal = {Redox report : communications in free radical research}, volume = {16}, number = {4}, pages = {173-180}, pmid = {21888768}, issn = {1743-2928}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Dexamethasone/*antagonists &amp; inhibitors/toxicity ; Free Radical Scavengers/pharmacology ; Free Radicals/metabolism ; Glucocorticoids/*antagonists &amp; inhibitors/toxicity ; Insulin/*metabolism ; Insulin Secretion ; Islets of Langerhans/*drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Synaptotagmins/drug effects/metabolism ; }, abstract = {OBJECTIVES: Reactive oxygen species (ROS) are involved in many physiological and pathological processes. In the present study, we analysed whether the synthetic glucocorticoid dexamethasone induces oxidative stress in cultured pancreatic islets and whether the effects of dexamethasone on insulin secretion, gene expression, and viability can be counteracted by concomitant incubation with N-acetylcysteine (NAC).<br><br>METHODS: ROS production was measured by dichlorofluorescein (DCFH-DA) assay, insulin secretion by radioimmunoassay, intracellular calcium dynamics by fura-2-based fluorescence, gene expression by real-time polymerase chain reaction analyses and cell viability by the MTS assay.<br><br>RESULTS: Dexamethasone (Dexa) increased ROS production and decreased glucose-stimulated insulin secretion after 72 hours incubation. Intracellular ROS levels were decreased and the insulin secretion capacity was recovered by concomitant treatment with Dexa+NAC. The total insulin content and intracellular Ca2+ levels were not modulated in either Dexa or Dexa+NAC groups. There was a decrease in the NAD(P)H production, used as an indicator of viability, after dexamethasone treatment. Concomitant incubation with NAC returned viability to control levels. Dexa also decreased synaptotagmin VII (SYT VII) gene expression. In contrast, the Dexa+NAC group demonstrated an increased expression of SYT VII compared to controls. Surprisingly, treatment with NAC decreased the gene expression of the antioxidant enzyme copper zinc superoxide dismutase soluble.<br><br>DISCUSSION: Our results indicate that dexamethasone increases ROS production, decreases viability, and impairs insulin secretion in pancreatic rat islets. These effects can be counteracted by NAC, which not only decreases ROS levels but also modulates the expression of genes involved in the secretory pathway and those coding for antioxidant enzymes.}, }
@article {pmid21888767, year = {2011}, author = {Ljubisavljevic, S and Stojanovic, I and Pavlovic, D and Sokolovic, D and Stevanovic, I}, title = {Aminoguanidine and N-acetyl-cysteine supress oxidative and nitrosative stress in EAE rat brains.}, journal = {Redox report : communications in free radical research}, volume = {16}, number = {4}, pages = {166-172}, pmid = {21888767}, issn = {1743-2928}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/metabolism/pathology ; Encephalomyelitis, Autoimmune, Experimental/*drug therapy/immunology/*pathology ; Female ; Freund's Adjuvant/pharmacology ; Glutathione/metabolism ; Guanidines/*pharmacology ; Malondialdehyde/metabolism ; Nitric Oxide/*metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; }, abstract = {Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of human multiple sclerosis (MS). We have evaluated the role of oxidative and nitrosative stress, as the causal factors in the development of EAE, responsible for the damage of cardinal cellular components, such as lipids, proteins and nucleic acids, resulting in demyelination, axonal damage, and neuronal death. EAE was induced in female Sprague-Dawley rats, 3 months old (300±20 g), by immunization with myelin basic protein in combination with Complete Freund's adjuvant (CFA). The animals were divided into seven groups: control, EAE, CFA, EAE+aminoguanidine (AG), AG, EAE+N-acetyl-L-cysteine (NAC) and NAC. The animals were sacrificed 15 days after EAE induction, and the levels of nitrosative and oxidative stress were determined in 10% homogenate of the whole encephalitic mass. In EAE rats, brain NO production and MDA level were significantly increased (P<0.001) compared to the control values, whereas AG and NAC treatment decreased both parameters in EAE rats compared to EAE group (P<0.001). Glutathione (GSH) was reduced (P<0.001) in EAE rats in comparison with the control and CFA groups, but increased in EAE+AG and EAE+NAC group compared to the EAE group (P<0.01). Superoxide dismutase (SOD) activity was significantly decreased (P<0.001) in the EAE group compared to all other experimental groups. The clinical expression of EAE was significantly decreased (P<0.05) in the EAE groups treated with AG and NAC compared to EAE rats, during disease development. The obtained results prove an important role of oxidative and nitrosative stress in the pathogenesis of EAE, whereas AG and NAC protective effects offer new possibilities for a modified combined approach in MS therapy.}, }
@article {pmid21888054, year = {2011}, author = {Badziuk, OB and Mazur, IuIu and Kosterin, SO}, title = {[Regulation of the mitochondrial ATP-sensitive potassium channel in rat uterus cells by ROS].}, journal = {Ukrains'kyi biokhimichnyi zhurnal (1999)}, volume = {83}, number = {3}, pages = {48-57}, pmid = {21888054}, mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium/metabolism ; Carbocyanines/analysis ; Diazoxide/pharmacology ; Female ; Fluoresceins/analysis ; Free Radical Scavengers/pharmacology ; Glyburide/pharmacology ; Ion Transport/drug effects/*physiology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/*metabolism ; Muscle Cells/drug effects/*metabolism ; Oxidative Stress/drug effects ; Potassium Channel Blockers/pharmacology ; Potassium Channels/agonists/*metabolism ; Rats ; Rats, Inbred Strains ; *Reactive Oxygen Species/metabolism/pharmacology ; Rotenone/pharmacology ; Spectrometry, Fluorescence ; Uterus/drug effects/*metabolism ; }, abstract = {In previous study we demonstrated the presence of ATP-sensitive potassium current in the inner mitochondrial membrane, which was sensitive to diazoxide and glybenclamide, in mitochondria isolated from the rat uterus. This current was supposed to be operated by mitochondrial ATP-sensitive potassium channel (mitoK(ATP)). Regulation of the mitoK(ATP) in uterus cells is not studied well enough yet. It is well known that the reactive oxygen species (ROS) can play a dual role. They can damage cells in high concentrations, but they can also act as messengers in cellular signaling, mediating survival of cells under stress conditions. ROS are known to activate mitoK(ATP) during the oxidative stress in the brain and heart, conferring the protection of cells. The present study examined whether ROS mediate the mitoK(ATP) activation in myometrium cells. Oxidative stress was induced by rotenone. ROS generation was measured by 2',7'-dichlorofluorescin diacetate. The massive induction of ROS production was demonstrated in the presence of rotenone. Hyperpolarization of the mitochondrial membrane was also detected with the use of the potential-sensitive dye DiOC6 (3,3'-dihexyloxacarbocyanine iodide). Diazoxide, a selective activator of mitoK(ATP), depolarized mitochondrial membrane either under oxidative stress or under normal conditions, while mitoK(ATP) blocker glybenclamide effectively restored mitochondrial potential in rat myocytes. Estimated <K1/2> value for diazoxide to mitoK(ATP) under normoxia was four times higher than under oxidative stress conditions: 5.01 +/- 1.47-10(-6) M and 1.24 +/- 0.21 x 10(-6) M respectively. The ROS scavenger N-acetylcysteine (NAC) successfully eliminates depolarization of mitochondrial membrane by diazoxide under oxidative stress. These results suggest that elimination of ROS by NAC prevents the activation of mitoK(ATP) under oxidative stress. Taking into account the higher affinity of diazoxide to mitoK(ATP) under stress conditions than under normoxia, we conclude that the oxidative stress conditions are more favourable than normoxia for the activation of mitoK(ATP). Thus we hypothesize that the ROS regulate the activity of the mitoK(ATP) in myocytes.}, }
@article {pmid21878099, year = {2011}, author = {Elms, AR and Owen, KP and Albertson, TE and Sutter, ME}, title = {Fatal myocardial infarction associated with intravenous N-acetylcysteine error.}, journal = {International journal of emergency medicine}, volume = {4}, number = {1}, pages = {54}, pmid = {21878099}, issn = {1865-1380}, abstract = {BACKGROUND: N-acetylcysteine is used to treat acetaminophen toxicity and is available in both intravenous and oral formulations. Our report describes a patient treated with intravenous N-acetylcysteine for acetaminophen toxicity who died after an anaphylactoid reaction following initiation of the infusion.<br><br>OBJECTIVE: Clinicians should be aware of potential complications when deciding on which formulation of N-acetylcysteine to administer.<br><br>CASE REPORT: A 53-year-old male presented with altered mental status after an overdose of acetaminophen/hydrocodone and carisoprodol. He had an acetaminophen level of 49 mcg/ml with an unknown time of ingestion. The patient was admitted to the intensive care unit (ICU) on a naloxone drip and was started on intravenous N-acetylcysteine (NAC) at the presumed dose of 150 mg/kg. Shortly after initiating the NAC infusion, the patient developed periorbital edema, skin rash, and hypotension. The infusion of N-acetylcysteine was immediately stopped and the patient required emergent intubation. Resuscitation was begun with intravenous fluids followed by the initiation of phenylephrine. He developed ST elevation in the inferior leads on his ECG. This evolved into an inferior myocardial infarction by ECG and cardiac enzymes. Echocardiogram showed global, severe hypokinesis with an ejection fraction of less than 20% in a patient with no pre-existing cardiac history. Despite aggressive support, he died approximately 17 hours after the initiation of intravenous NAC. Further investigation found a 10-fold formulation error in his NAC loading dose.<br><br>CONCLUSION: The intravenous formulation of NAC has a higher probability of significant adverse effects and complications not described with the oral formulation. Clinicians should be aware of these potential complications when deciding on which formulation to administer.}, }
@article {pmid21875385, year = {2011}, author = {Fan, S and Li, L and Chen, S and Yu, Y and Qi, M and Tashiro, S and Onodera, S and Ikejima, T}, title = {Silibinin induced-autophagic and apoptotic death is associated with an increase in reactive oxygen and nitrogen species in HeLa cells.}, journal = {Free radical research}, volume = {45}, number = {11-12}, pages = {1307-1324}, doi = {10.3109/10715762.2011.618186}, pmid = {21875385}, issn = {1029-2470}, mesh = {Acetylcysteine/metabolism ; Adenine/analogs &amp; derivatives/pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/genetics/metabolism ; Autophagy/*drug effects ; Beclin-1 ; Caspase 3/analysis ; Cell Survival ; Glutathione/metabolism ; HeLa Cells ; Humans ; Hydroxyl Radical/chemistry ; Membrane Proteins/genetics/metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Reactive Nitrogen Species/*metabolism ; Reactive Oxygen Species/*metabolism ; Silybin ; Silymarin/antagonists &amp; inhibitors/*pharmacology ; }, abstract = {Silibinin, as the major active constituent of silymarin, has its various biological effects. Here, we investigated the inhibitory effects of silibinin on HeLa cell growth in relation to autophagy and apoptosis induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. Silibinin dose and time-dependently decreased cell growth cultured in medium containing 10% fetal bovine serum or in serum free media (SFM) with an IC(50) of approximately 80-100 and 40-60 μM at 24 h, respectively. Silibinin induced autophagy at 12 h, confirmed by monodansylcadervarine (MDC) staining and up-regulation of beclin-1, and induced apoptosis at 24 h, detected by observation of apoptotic bodies and activation of caspase-3. 3-methyladenine (3-MA) inhibited silibinin-induced autophagy and attenuated the silibinin's inhibitory effect on cell viability, suggesting that autophagy enhanced silibinin-induced cell death. Silibinin increased ROS levels at 12 h, and ROS scavenger, N-acetylcysteine (NAC), significantly reversed the cytotoxicity of silibinin through inhibiting both autophagy and apoptosis. Specific antioxidants were applied and results indicated that hydroxyl radical (·OH) was the major ROS induced by silibinin, and OH scavenger glutathione (GSH) inhibited apoptosis and autophagy. Silibinin also generated RNS production in the cells at 12 h. High concentration of N omega-nitro-l-arginine methyl ester (L-NAME) as nitric oxide synthase (NOS) inhibitor attenuated the cytotoxicity of silibinin by decreasing ROS levels, leading to down-regulation of apoptosis. Silibinin also could interrupt the respiring functions of mitochondria, leading to ROS production and oxidative damage.}, }
@article {pmid21873804, year = {2011}, author = {Lu, Y and Qin, W and Shen, T and Dou, L and Man, Y and Wang, S and Xiao, C and Li, J}, title = {The antioxidant N-acetylcysteine promotes atherosclerotic plaque stabilization through suppression of RAGE, MMPs and NF-κB in ApoE-deficient mice.}, journal = {Journal of atherosclerosis and thrombosis}, volume = {18}, number = {11}, pages = {998-1008}, doi = {10.5551/jat.8870}, pmid = {21873804}, issn = {1880-3873}, mesh = {Acetylcysteine/*toxicity ; Animals ; Antioxidants/*adverse effects ; Apolipoproteins E/*physiology ; Blood Glucose/metabolism ; Diet, Atherogenic ; Fluorescent Antibody Technique ; Free Radical Scavengers/toxicity ; Glycation End Products, Advanced/*metabolism ; Immunoenzyme Techniques ; Male ; Matrix Metalloproteinases/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B/*metabolism ; Plaque, Atherosclerotic/drug therapy/*metabolism/*pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {AIMS: N-acetylcysteine (NAC) has antioxidant and anti-inflammatory properties. To explore the mechanisms underlying atherosclerotic plaque stabilization induced by NAC, we examined the effects of NAC administration in apoE-deficient mice on the expression of the receptor of advanced glycation end products (RAGE), matrix metalloproteinases (MMPs) and the activation of nuclear factor kappa B (NF-κB) in atherosclerotic plaques.<br><br>METHODS: 10-week-old ApoE(-/-) mice fed with atherogenic diet were treated with NAC (200 mg/kg/ day) for 8 weeks. Serum lipid, glucose and malondialdehyde (MDA) were detected. The size and composition of atherosclerotic plaques were measured by en face analysis, Movat staining, immunofluorescence and immunohistochemistry, respectively. Reactive oxygen species (ROS) generation in aortic root was tested by DHE staining. The levels of vascular cell adhesion molecule-1(VCAM-1), NF-&#x3ba;B, phosphor-NF-&#x3ba;B, I-&#x3ba;B, phosphor-I-&#x3ba;B, RAGE, MMP2 and MMP9 in descending arteries were analyzed by Western blot.<br><br>RESULTS: ApoE(-/-) mice administrated with NAC displayed reduced serum MDA level and impaired ROS generation in aortic root. However, NAC did not affect the levels of plasma glucose, lipids and the size of atherosclerotic lesions. Analysis of plaque composition showed decreased amounts of macrophages, lipid deposition, but not smooth muscle cells, and increased collagen content in atherosclerotic lesions in apoE(-/-) mice administered with NAC. Moreover, we found that NAC down-regulated the expression of VCAM-1, MMP2 and MMP9, accompanied by inhibition of NF-&#x3ba;B activation and reduced expression of RAGE.<br><br>CONCLUSION: In the present study, we show novel data to suggest that NAC promotes atherosclerotic plaque stabilization through suppression of RAGE, MMPs and NF-&#x3ba;B in apoE(-/-) mice.}, }
@article {pmid21872068, year = {2011}, author = {Beitollahi, H and Raoof, JB and Hosseinzadeh, R}, title = {Fabrication of a nanostructure-based electrochemical sensor for simultaneous determination of N-acetylcysteine and acetaminophen.}, journal = {Talanta}, volume = {85}, number = {4}, pages = {2128-2134}, doi = {10.1016/j.talanta.2011.07.054}, pmid = {21872068}, issn = {1873-3573}, mesh = {Acetaminophen/*analysis/blood/chemistry/urine ; Acetylcysteine/*analysis/blood/chemistry/urine ; Calibration ; Carbon/chemistry ; Catalysis ; Chemistry Techniques, Analytical/*instrumentation ; Electrochemistry/*methods ; Electrodes ; Fluorenes/chemistry ; Humans ; Limit of Detection ; Nanostructures/*chemistry ; Oxidation-Reduction ; Time Factors ; Water/chemistry ; }, abstract = {A carbon-paste electrode modified with 2,7-bis(ferrocenyl ethyl)fluoren-9-one (2,7-BF) and carbon nanotubes (CNTs) was used for the sensitive and selective voltammetric determination of N-acetylcysteine (NAC). The mediated oxidation of NAC at the modified electrode was investigated by cyclic voltammetry (CV). Also, the values of catalytic rate constant (k), and diffusion coefficient (D) for NAC were calculated. Differential pulse voltammetry (DPV) of NAC at the modified electrode exhibited two linear dynamic ranges with a detection limit (3σ) of 52.0 nmol L(-1). DPV was used for simultaneous determination of NAC and acetaminophen (AC) at the modified electrode, and quantitation of NAC and AC in some real samples by the standard addition method.}, }
@article {pmid21872012, year = {2011}, author = {Duan, J and Jiang, X and Ni, S and Yang, M and Zhan, J}, title = {Facile synthesis of N-acetyl-L-cysteine capped ZnS quantum dots as an eco-friendly fluorescence sensor for Hg2+.}, journal = {Talanta}, volume = {85}, number = {4}, pages = {1738-1743}, doi = {10.1016/j.talanta.2011.06.071}, pmid = {21872012}, issn = {1873-3573}, mesh = {Absorption ; Acetylcysteine/*chemistry ; Buffers ; Fluorescent Dyes/*chemical synthesis/chemistry ; Green Chemistry Technology/*methods ; Hydrogen-Ion Concentration ; Mercury/*analysis/chemistry ; *Quantum Dots ; Spectrometry, Fluorescence/*methods ; Spectrophotometry, Ultraviolet ; Sulfides/*chemistry ; Time Factors ; Zinc Compounds/*chemistry ; }, abstract = {This paper described an investigation of a novel eco-friendly fluorescence sensor for Hg(2+) ions based on N-acetyl-l-cysteine (NAC)-capped ZnS quantum dots (QDs) in aqueous solution. By using safe and low-cost materials, ZnS QDs modified by NAC were easily synthesized in aqueous medium via a one-step method. The quantitative detection of Hg(2+) ions was developed based on fluorescence quenching of ZnS QDs with high sensitivity and selectivity. Under optimal conditions, its response was linearly proportional to the concentration of Hg(2+) ions in a range from 0 to 2.4 × 10(-6) mol L(-1) with a detection limit of 5.0 × 10(-9) mol L(-1). Most of common physiologically relevant cations and anions did not interfere with the detection of Hg(2+). The proposed method was applied to the trace determination of Hg(2+) ions in water samples. The possible quenching mechanism was also examined by fluorescence and UV-vis absorption spectra.}, }
@article {pmid21871945, year = {2011}, author = {Antolino-Lobo, I and Meulenbelt, J and Molendijk, J and Nijmeijer, SM and Scherpenisse, P and van den Berg, M and van Duursen, MB}, title = {Induction of glutathione synthesis and conjugation by 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dihydroxymethamphetamine (HHMA) in human and rat liver cells, including the protective role of some antioxidants.}, journal = {Toxicology}, volume = {289}, number = {2-3}, pages = {175-184}, doi = {10.1016/j.tox.2011.08.012}, pmid = {21871945}, issn = {1879-3185}, mesh = {Animals ; Antioxidants/metabolism/*pharmacology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Deoxyepinephrine/*analogs &amp; derivatives/metabolism/toxicity ; Drug Interactions/physiology ; Glutathione/*biosynthesis/metabolism ; Hepatocytes/*drug effects/metabolism ; Humans ; Male ; N-Methyl-3,4-methylenedioxyamphetamine/metabolism/*toxicity ; Protective Agents/metabolism/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {MDMA (3,4-methylenedioxymethamphetamine) metabolism is a major cause of MDMA-mediated hepatotoxicity. In this study the effects of MDMA and its metabolites on the glutathione system were evaluated. Glutathione (GSH/GSSG) levels and gene expression of glutamate cysteine ligase catalytic subunit (GCLC), glutathione-S-transferase (GST) and pregnane X receptor (PXR) were compared in the immortalized human liver epithelial cell line THLE-Neo lacking phase I metabolism and primary rat hepatocytes expressing both phase I and II metabolism. Furthermore, we evaluated the potential protective effects of two antioxidants, N-acetyl-cysteine (NAC) and sulforaphane (SFN) in these cell systems. In THLE-Neo cells, the MDMA metabolite 3,4-dihydroxymetamphetamine (HHMA) significantly decreased cell viability and depleted GSH levels, resulting in an increased expression of GCLC and GST up to 3.4- and 2.2-fold, respectively. In primary rat hepatocytes, cell viability or GSH levels were not significantly affected upon MDMA exposure. GCLC expression levels where not significantly altered either, although GST expression was increased 2.3-fold. NAC counteracted MDMA-induced cytotoxicity and restored GSH levels. Phase II enzyme expression was also reverted. Conversely, SFN increased MDMA-induced cytotoxicity and GSH depletion, while GCLC and GST expression were significantly induced. In addition, PXR expression decreased after HHMA and MDMA exposure, while co-exposure to SFN induced it up to 3.6- and 3.9-fold compared to vehicle-control in the THLE-Neo cells and rat hepatocytes, respectively. Taken together, these data indicate that HHMA is a major factor in the MDMA-mediated hepatotoxicity through interaction with the glutathione system. The results of our study show that for MDMA intoxication the treatment with an antioxidant such as NAC may counteract the potentially hepatotoxicity. However, SFN supplementation should be considered with care because of the indications of possible drug-drug interactions.}, }
@article {pmid21869750, year = {2011}, author = {Giljanović, J and Brkljača, M and Prkić, A}, title = {Flow injection spectrophotometric determination of N-acetyl-L-cysteine as a complex with palladium(II).}, journal = {Molecules (Basel, Switzerland)}, volume = {16}, number = {9}, pages = {7224-7236}, pmid = {21869750}, issn = {1420-3049}, mesh = {Acetylcysteine/*chemistry ; Algorithms ; Calibration ; Coordination Complexes/*chemistry ; Flow Injection Analysis/methods ; Hydrogen-Ion Concentration ; Osmolar Concentration ; Palladium/*chemistry ; Spectrophotometry/methods ; }, abstract = {We describe a new method using flow-injection analysis with spectro-photometric detection, suitable for the determination of N-acetyl-L-cysteine (NAC). The proposed method is appropriate for the determination of NAC in reaction with Pd(2+) ions in the concentration range from 1.0 × 10(-5) mol L(-1) to 6.0 × 10(-5) mol L(-1). The detection limit NAC was 5.84 × 10(-6) mol L(-1) and the recorded relative standard deviation of the method is in the range from 1.67 to 4.11%. NAC and Pd(2+) form complexes of Pd(2+):NAC molar ratios of 1:1 and 1:2, depending on the ratio of their analytical concentrations. The cumulative conditional stability constant for the Pd(NAC)(2)(2+) complex is β(12)' = 2.69 × 10(9) L(2) mol(-2). The proposed method was compared with the classic spectrophotometric determination of NAC, using the same reagent, PdCl(2), and had shown certain advantages: a) shorter analysis time; b) the use of smaller volumes of sample and reagents, which make the proposed method cheaper and faster for NAC determination in real samples without sample pretreatment.}, }
@article {pmid21858089, year = {2011}, author = {Kang, HT and Lee, KB and Kim, SY and Choi, HR and Park, SC}, title = {Autophagy impairment induces premature senescence in primary human fibroblasts.}, journal = {PloS one}, volume = {6}, number = {8}, pages = {e23367}, pmid = {21858089}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing/metabolism ; Autophagy/genetics/*physiology ; Autophagy-Related Protein 12 ; Autophagy-Related Protein 7 ; Benzothiazoles/pharmacology ; Blotting, Western ; Cell Cycle Proteins ; Cells, Cultured ; Cellular Senescence/drug effects/genetics/*physiology ; Child ; Fibroblasts/cytology/*metabolism/ultrastructure ; Humans ; Lysosomal-Associated Membrane Protein 2 ; Lysosomal Membrane Proteins/genetics/metabolism ; Male ; Microscopy, Electron ; Phosphoproteins/metabolism ; Primary Cell Culture ; RNA Interference ; Reactive Oxygen Species/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Sequestosome-1 Protein ; Signal Transduction/genetics/*physiology ; Small Ubiquitin-Related Modifier Proteins/genetics/metabolism ; TOR Serine-Threonine Kinases/metabolism ; Time Factors ; Toluene/analogs &amp; derivatives/pharmacology ; Tumor Suppressor Protein p53/genetics/metabolism ; Ubiquitin-Activating Enzymes/genetics/metabolism ; beta-Galactosidase/metabolism ; }, abstract = {BACKGROUND: Recent studies have demonstrated that activation of autophagy increases the lifespan of organisms from yeast to flies. In contrast to the lifespan extension effect in lower organisms, it has been reported that overexpression of unc-51-like kinase 3 (ULK3), the mammalian homolog of autophagy-specific gene 1 (ATG1), induces premature senescence in human fibroblasts. Therefore, we assessed whether the activation of autophagy would genuinely induce premature senescence in human cells.<br><br>Depletion of ATG7, ATG12, or lysosomal-associated membrane protein 2 (Lamp2) by transfecting siRNA or infecting cells with a virus containing gene-specific shRNA resulted in a senescence-like state in two strains of primary human fibroblasts. Prematurely senescent cells induced by autophagy impairment exhibited the senescent phenotypes, similar to the replicatively senescent cells, such as increased senescence associated &#x3b2;-galactosidase (SA-&#x3b2;-gal) activity, reactive oxygen species (ROS) generation, and accumulation of lipofuscin. In addition, expression levels of ribosomal protein S6 kinase1 (S6K1), p-S6K1, p-S6, and eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) in the mammalian target of rapamycin (mTOR) pathway and beclin-1, ATG7, ATG12-ATG5 conjugate, and the sequestosome 1 (SQSTM1/p62) monomer in the autophagy pathway were decreased in both the replicatively and the autophagy impairment-induced prematurely senescent cells. Furthermore, it was found that ROS scavenging by N-acetylcysteine (NAC) and inhibition of p53 activation by pifithrin-&#x3b1; or knockdown of p53 using siRNA, respectively, delayed autophagy impairment-induced premature senescence and restored the expression levels of components in the mTOR and autophagy pathways.<br><br>CONCLUSION: Taken together, we concluded that autophagy impairment induces premature senescence through a ROS- and p53-dependent manner in primary human fibroblasts.}, }
@article {pmid21856376, year = {2012}, author = {Aggarwal, A and Misro, MM and Maheshwari, A and Sehgal, N}, title = {Differential modulation of apoptotic gene expression by N-acetyl-L-cysteine in Leydig cells stimulated persistently with hCG in vivo.}, journal = {Molecular and cellular endocrinology}, volume = {348}, number = {1}, pages = {155-164}, doi = {10.1016/j.mce.2011.08.002}, pmid = {21856376}, issn = {1872-8057}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Caspase 3/metabolism ; Catalase/metabolism ; Chorionic Gonadotropin/*pharmacology ; Cyclic AMP/metabolism ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Glutathione Transferase/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Leydig Cells/drug effects/*metabolism ; Male ; Organ Size ; Oxidative Stress ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; Rats, Sprague-Dawley ; Reproductive Control Agents/*pharmacology ; Spermatogenesis/drug effects ; Superoxide Dismutase/metabolism ; Testis/drug effects/pathology/physiopathology ; Testosterone/blood ; Thiobarbituric Acid Reactive Substances/metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {The present study was designed to investigate the molecular mechanisms of NAC (150 mg/kg bw twice/week) action in vivo under repeated hCG (100 IU/rat/day) stimulation to adult rats. Leydig cell refractoriness led to a significant decline in serum testosterone and intracellular cAMP by day 30 of chronic hCG intervention which improved significantly following NAC co-administration. It inhibited the rise in lipid peroxidation, improved the activity of antioxidant enzymes along with intracellular glutathione and total antioxidant capacity in the target cells. Leydig cell apoptosis declined significantly (P<0.001) with down-regulation of upstream, Fas, FasL, caspase-8, Bax and caspase-9, JNK/pJNK and downstream caspase-3 and PARP. On the other hand, anti-apoptotic Bcl2, NF-kβ, and Akt were up-regulated. Taken together, the above findings indicate that the specificity of NAC action was not restricted to regulating marker proteins in the extrinsic and JNK pathways as seen in vitro but extended to include intrinsic pathway of metazoan apoptosis as well.}, }
@article {pmid21854768, year = {2011}, author = {Yang, ES and Woo, SM and Choi, KS and Kwon, TK}, title = {Acrolein sensitizes human renal cancer Caki cells to TRAIL-induced apoptosis via ROS-mediated up-regulation of death receptor-5 (DR5) and down-regulation of Bcl-2.}, journal = {Experimental cell research}, volume = {317}, number = {18}, pages = {2592-2601}, doi = {10.1016/j.yexcr.2011.08.005}, pmid = {21854768}, issn = {1090-2422}, mesh = {Acrolein/*pharmacology ; Apoptosis/*drug effects ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Gene Expression Regulation/*drug effects ; Humans ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Recombinant Proteins/metabolism ; Structure-Activity Relationship ; TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Tumor Cells, Cultured ; Up-Regulation/drug effects ; }, abstract = {TRAIL resistance in many cancer cells is one of the major problems in TRAIL-based cancer therapy. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are strictly needed for the improvement of anti-cancer effect of TRAIL. Acrolein is a byproduct of lipid peroxidation, which has been involved in pulmonary, cardiac and neurodegenerative diseases. We investigated whether acrolein, an α,β-unsaturated aldehyde, can potentiate TRAIL-induced apoptosis in human renal cancer cells. The combined treatment with acrolein and TRAIL significantly induced apoptosis, and stimulated of caspase-3 activity, DNA fragmentation, and cleavage of PARP. We found that acrolein down-regulated the protein level of Bcl-2 and Bcl-2 overexpression inhibited the cell death induced by the combined treatment with acrolein and TRAIL. In addition, acrolein up-regulated C/EBP homologous protein (CHOP) and TRAIL death receptor 5 (DR5) and down-regulation of CHOP or DR5 expression using the respective small interfering RNA significantly attenuated the apoptosis induced by acrolein plus TRAIL. Interestingly, pretreatment with an antioxidant, N-acetylcysteine (NAC), inhibited not only CHOP and DR5 up-regulation but also the cell death induced by acrolein plus TRAIL. Taken together, our results demonstrated that acrolein enhances TRAIL-induced apoptosis in Caki cells through down-regulation of Bcl-2 and ROS dependent up-regulation of DR5.}, }
@article {pmid21854604, year = {2011}, author = {Pugazhenthi, S and Wang, M and Pham, S and Sze, CI and Eckman, CB}, title = {Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons.}, journal = {Molecular neurodegeneration}, volume = {6}, number = {}, pages = {60}, pmid = {21854604}, issn = {1750-1326}, support = {I01 BX001837/BX/BLRD VA/United States ; I01 BX004480/BX/BLRD VA/United States ; }, abstract = {BACKGROUND: Oxidative stress plays an important role in neuronal dysfunction and neuron loss in Alzheimer's brain. Previous studies have reported downregulation of CREB-mediated transcription by oxidative stress and Aβ. The promoter for CREB itself contains cyclic AMP response elements. Therefore, we examined the expression of CREB in the hippocampal neurons of Tg2576 mice, AD post-mortem brain and in cultured rat hippocampal neurons exposed to Aβ aggregates.<br><br>RESULTS: Laser Capture Microdissection of hippocampal neurons from Tg2576 mouse brain revealed decreases in the mRNA levels of CREB and its target, BDNF. Immunohistochemical analysis of Tg2576 mouse brain showed decreases in CREB levels in hippocampus and cortex. Markers of oxidative stress were detected in transgenic mouse brain and decreased CREB staining was observed in regions showing abundance of astrocytes. There was also an inverse correlation between SDS-extracted A&#x3b2; and CREB protein levels in Alzheimer's post-mortem hippocampal samples. The levels of CREB-regulated BDNF and BIRC3, a caspase inhibitor, decreased and the active cleaved form of caspase-9, a marker for the intrinsic pathway of apoptosis, was elevated in these samples. Exposure of rat primary hippocampal neurons to A&#x3b2; fibrils decreased CREB promoter activity. Decrease in CREB mRNA levels in A&#x3b2;-treated neurons was reversed by the antioxidant, N-acetyl cysteine. Overexpression of CREB by adenoviral transduction led to significant protection against A&#x3b2;-induced neuronal apoptosis.<br><br>CONCLUSIONS: Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression.}, }
@article {pmid21854081, year = {2011}, author = {Shen, F and Coulter, CV and Isbister, GK and Duffull, SB}, title = {A dosing regimen for immediate N-acetylcysteine treatment for acute paracetamol overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {49}, number = {7}, pages = {643-647}, doi = {10.3109/15563650.2011.604034}, pmid = {21854081}, issn = {1556-9519}, mesh = {Acetaminophen/pharmacokinetics/*poisoning ; Acetylcysteine/*administration &amp; dosage/adverse effects/pharmacokinetics ; Adult ; Analgesics, Non-Narcotic/pharmacokinetics/*poisoning ; Antidotes/*administration &amp; dosage/adverse effects/pharmacokinetics ; Antioxidants/*administration &amp; dosage/adverse effects/pharmacokinetics ; Area Under Curve ; Computer Simulation ; Drug Administration Schedule ; Drug Overdose/drug therapy ; Humans ; Infusions, Intravenous ; Models, Biological ; }, abstract = {CONTEXT: Current treatment of paracetamol (acetaminophen) poisoning involves initiating a 3-phase N-acetylcysteine (NAC) infusion after comparing a plasma concentration, taken ≥ 4 h post-overdose, to a nomogram. This may result in dosing errors, a delay in treatment, or possibly more adverse effects - due to the use of a high dose rate for the first infusion when treatment is initiated.<br><br>OBJECTIVE: Our aim was to investigate a novel dosing regimen for the immediate administration of NAC on admission at a lower infusion rate.<br><br>METHODS: We used a published population pharmacokinetic model of NAC to simulate a scenario where a patient presents to the hospital 2 h post-overdose. The conventional regimen is commenced 6 h post-overdose when the 4-h plasma paracetamol concentration is available. We investigated an NAC infusion using a lower dosing rate initiated immediately on presentation. We determined a dosing rate that gave an area under the curve (AUC) of the concentration-time curve that was the same or greater than that from the conventional regimen on 90% of occasions.<br><br>RESULTS: Lower dosing rates of NAC initiated immediately resulted in a similar exposure to NAC. An infusion of 110 mg/kg over the first 5 h (22 mg/kg/h) followed by the last two phases of the conventional regimen, or 200 mg/kg over 9 h (22.6 mg/kg/h) followed by the last phase of the conventional regimen could be used.<br><br>CONCLUSION: The novel dosing regimen allowed immediate treatment of a patient using a lower dosing rate. This greatly simplifies the current dosing regimen and may reduce NAC adverse effects while ensuring the same amount of NAC is delivered.}, }
@article {pmid21848502, year = {2012}, author = {Xue, XY and Zhou, Y and Chen, YY and Meng, JR and Jia, M and Hou, Z and Bai, H and Mao, XG and Luo, XX}, title = {Promoting effects of chemical permeation enhancers on insulin permeation across TR146 cell model of buccal epithelium in vitro.}, journal = {Drug and chemical toxicology}, volume = {35}, number = {2}, pages = {199-207}, doi = {10.3109/01480545.2011.589848}, pmid = {21848502}, issn = {1525-6014}, mesh = {Acetylcysteine/pharmacology ; Adjuvants, Pharmaceutic/*pharmacology ; Adsorption/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cheek ; Chitosan/pharmacology ; Glutathione/pharmacology ; Humans ; Insulin/administration &amp; dosage/*pharmacokinetics ; Mouth Mucosa/cytology/*drug effects/metabolism ; Nitroprusside/pharmacology ; Phosphatidylcholines/pharmacology ; }, abstract = {To find potential enhancers for facilitating the buccal delivery of insulin, a TR146 cell-culture model of buccal epithelium, cultured on commercially available insert plates, was used to evaluate the permeability-enhancing effects of several traditional and new types of chemical enhancers, including N-acetyl-L-cysteine (NAC), sodium deoxycholate (SDC), sodium nitroprusside (SNP), reduced glutathione (GSH), glutamine (Gln), chitosan (CS), L-arginine (Arg), 1-dodecylazacycloheptan-2-one (Azone), and soybean lecithin (SPC) (50 and 10 μg/mL respectively). Permeability studies were performed to determine the enhancing effects of these compounds on insulin permeation across the cell-culture model. The enhancing effects of the enhancers were assessed by calculating the apparent permeability coefficients and enhancement ratio. Cytotoxicity of the permeation enhancers at different concentrations was investigated by using the methylthiazolydiphenyl-tetrazolium bromide (MTT) assay. Results showed that 50 μg/mL of NAC, SDC, GSH, CS, Arg, Azone, SPC, SNP, and 10 μg/mL of SNP had a significant enhancing effect on promoting the transport of insulin across the TR146 cell model. MTT assays showed that 50 μg/mL of Gln, Azone, SDC, SNP, Arg, 10 μg/mL SDC, and Arg had obvious toxic effects on TR146 cells. Therefore, NAC, GSH, CS, SPC, and SNP appear to be safe, effective permeability enhancers that promote the transport of insulin across the TR146 cell-culture model of buccal epithelium and may be potential enhancers for buccal delivery of insulin with both low toxicity and high efficiency.}, }
@article {pmid21846841, year = {2011}, author = {Liu, L and Chen, C and Gong, W and Li, Y and Edin, ML and Zeldin, DC and Wang, DW}, title = {Epoxyeicosatrienoic acids attenuate reactive oxygen species level, mitochondrial dysfunction, caspase activation, and apoptosis in carcinoma cells treated with arsenic trioxide.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {339}, number = {2}, pages = {451-463}, pmid = {21846841}, issn = {1521-0103}, support = {Z01 ES025034/ImNIH/Intramural NIH HHS/United States ; }, mesh = {8,11,14-Eicosatrienoic Acid/*analogs &amp; derivatives/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Caspase Inhibitors ; Caspases/metabolism ; Cell Line, Tumor ; Cell Transformation, Neoplastic/*drug effects ; Cytochrome P-450 CYP2J2 ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/metabolism ; Drug Screening Assays, Antitumor ; Drug Synergism ; Enzyme Activation/drug effects ; HEK293 Cells ; Humans ; Indazoles/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Nitrofurans/*pharmacology ; Oxides/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Epoxyeicosatrienoic acids (EETs) and the cytochrome P450 epoxygenase CYP2J2 promote tumorogenesis in vivo and in vitro via direct stimulation of tumor cell growth and inhibition of tumor cell apoptosis. Herein, we describe a novel mechanism of inhibition of tumor cell apoptosis by EETs. In Tca-8113 cancer cells, the antileukemia drug arsenic trioxide (ATO) led to the generation of reactive oxygen species (ROS), impaired mitochondrial function, and induced apoptosis. 11,12-EET pretreatment increased expression of the antioxidant enzymes superoxide dismutase and catalase and inhibited ATO-induced apoptosis. 11,12-EET also prevented the ATO-induced activation of p38 mitogen-activated protein kinase, c-Jun NH(2)-terminal kinase, caspase-3, and caspase-9. Therefore, 11,12-EET-pretreatment attenuated the ROS generation, loss of mitochondrial function, and caspase activation observed after ATO treatment. Moreover, the CYP2J2-specific inhibitor compound 26 enhanced arsenic cytotoxicity to a clinically relevant concentration of ATO (1-2 μM). Both the thiol-containing antioxidant, N-acetyl-cysteine, and 11,12-EET reversed the synergistic effect of the two agents. Taken together, these data indicate that 11,12-EET inhibits apoptosis induced by ATO through a mechanism that involves induction of antioxidant proteins and attenuation of ROS-mediated mitochondrial dysfunction.}, }
@article {pmid21845517, year = {2012}, author = {Mirza, R and Qiao, S and Tateyama, K and Miyamoto, T and Xiuli, L and Seo, H}, title = {3β-Hydroxysterol-Delta24 reductase plays an important role in long bone growth by protecting chondrocytes from reactive oxygen species.}, journal = {Journal of bone and mineral metabolism}, volume = {30}, number = {2}, pages = {144-153}, pmid = {21845517}, issn = {1435-5604}, mesh = {Acetylcysteine/pharmacology ; Androstenes/pharmacology ; Animals ; Biomarkers/metabolism ; Bone Development/*drug effects ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chondrocytes/drug effects/*enzymology ; Cytoprotection/*drug effects ; Gene Expression Regulation/drug effects ; Hydrogen Peroxide/toxicity ; Hypertrophy ; Immunohistochemistry ; Insulin/pharmacology ; Metatarsal Bones/drug effects/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nerve Tissue Proteins/antagonists &amp; inhibitors/*metabolism ; Oxidoreductases Acting on CH-CH Group Donors/antagonists &amp; inhibitors/*metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*toxicity ; Tissue Culture Techniques ; }, abstract = {Desmosterolosis is an autosomal recessive disease caused by mutations in the 3β-hydroxysterol-Delta24 reductase (DHCR24) gene, with severe developmental anomalies including short limbs. We utilized DHCR24 knockout (KO) mice to study the underlying bone pathology. Because the KO mice died within a few hours after birth, we cultured metatarsal bones from newborn mice. The growth of bones from KO mice was significantly retarded after 1 week of culture. Absence of proliferating chondrocytes in the growth plate and abnormal hypertrophy of prehypertrophic chondrocytes were observed in the bones from KO mice. Hypertrophic differentiation was evidenced by higher expression of Indian hedgehog, alkaline phosphatase, and matrix metalloproteinase 13. Since elevated levels of reactive oxygen species (ROS) during chondrogenesis are known to inhibit proliferation and to initiate chondrocyte hypertrophy in the growth plate, and since DHCR24 acts as a potent ROS scavenger, we hypothesized that the abnormal chondrocyte proliferation and differentiation in KO mice were due to decreased ROS scavenging activity. Treatment with an antioxidant, N-acetyl cysteine, could correct the abnormalities observed in the bones from KO mice. Treatment of bones from wild-type mice with U18666A, a chemical inhibitor of DHCR24, resulted in short broad bones with a disrupted proliferating zone. Treatment of ATDC cells with hydrogen peroxide (H(2)O(2)) induced hypertrophic changes as evidenced by the expression of the marker genes specific for hypertrophic chondrocyte differentiation. H(2)O(2)-induced hypertrophic change was prevented by adenoviral delivery of DHCR24. Induction of chondrocyte differentiation in ATDC cells by insulin was associated with increased ROS production that was markedly enhanced by treatment of ATDC5 cells with DHCR24 siRNA. This is the first demonstration that DHCR24 plays an important role in long bone growth by protecting chondrocytes from ROS.}, }
@article {pmid21844013, year = {2011}, author = {Fath, MA and Ahmad, IM and Smith, CJ and Spence, J and Spitz, DR}, title = {Enhancement of carboplatin-mediated lung cancer cell killing by simultaneous disruption of glutathione and thioredoxin metabolism.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {17}, number = {19}, pages = {6206-6217}, pmid = {21844013}, issn = {1557-3265}, support = {R01 CA133114-04/CA/NCI NIH HHS/United States ; R01CA133114/CA/NCI NIH HHS/United States ; R01 CA133114/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; T32 CA078586/CA/NCI NIH HHS/United States ; T32CA078586/CA/NCI NIH HHS/United States ; R21CA139182/CA/NCI NIH HHS/United States ; R21 CA139182/CA/NCI NIH HHS/United States ; UL1RR024979/RR/NCRR NIH HHS/United States ; UL1 RR024979/RR/NCRR NIH HHS/United States ; P30CA086862/CA/NCI NIH HHS/United States ; T32 CA078586-11A1/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Benzodiazepines ; Carboplatin/*pharmacology ; Deoxyglucose/pharmacology ; Drug Synergism ; Female ; Glutathione/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Lung Neoplasms/drug therapy/*metabolism ; Mice ; Mice, Nude ; Oxidative Stress/drug effects ; Thioredoxins/*metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {PURPOSE: Cancer cells (relative to normal cells) show increased steady-state levels of hydroperoxides that are compensated by increased glucose and hydroperoxide metabolism. The current study determined whether inhibitors of glucose and hydroperoxide metabolism could induce chemoradiosensitization by enhancing oxidative stress in lung cancer cells.<br><br>EXPERIMENTAL DESIGN: A549 and NCI-H292 human lung carcinoma cells were treated with 2-deoxy-d-glucose (2DG) combined with carboplatin + ionizing radiation (IR). Lung cancer cells were further sensitized with inhibitors of glutathione (GSH)- and thioredoxin (Trx)-dependent metabolism [buthionine sulfoximine (BSO) and auranofin, respectively] in vitro and in vivo.<br><br>RESULTS: When 2DG was combined with carboplatin + IR, clonogenic cell killing was enhanced in A549 and NCI-H292 cells, and this combination was more effective than paclitaxel + carboplatin + IR. The thiol antioxidant (N-acetylcysteine, NAC) was capable of protecting cancer cells from 2DG + carboplatin -induced cell killing. Simultaneous treatment of cancer cells with BSO and auranofin, at doses that were not toxic as single agents, also enhanced lung cancer cell killing and sensitivity to 2DG + carboplatin. This treatment combination also increased oxidation of both GSH and Trx, which were inhibited by NAC. Mice treated with auranofin + BSO showed no alterations in circulating leukocytes or red blood cells. Xenograft lung tumor growth in mice was more effectively inhibited by treatment with auranofin + BSO + carboplatin than animals treated with carboplatin or auranofin + BSO alone.<br><br>CONCLUSIONS: These results show in vitro and in vivo that simultaneous inhibition of GSH and Trx metabolism can effectively inhibit lung cancer cell growth and induce chemosensitization by a mechanism that involves thiol-mediated oxidative stress.}, }
@article {pmid21843499, year = {2011}, author = {Niu, YL and Li, C and Zhang, GY}, title = {Blocking Daxx trafficking attenuates neuronal cell death following ischemia/reperfusion in rat hippocampus CA1 region.}, journal = {Archives of biochemistry and biophysics}, volume = {515}, number = {1-2}, pages = {89-98}, doi = {10.1016/j.abb.2011.07.016}, pmid = {21843499}, issn = {1096-0384}, mesh = {Adaptor Proteins, Signal Transducing/*metabolism ; Animals ; Base Sequence ; *Cell Death ; DNA Primers ; Male ; Molecular Chaperones ; Nuclear Proteins/*metabolism ; Protein Transport ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Previous studies have shown that the death-associated protein (Daxx) shuttles between nucleus and cytoplasm under ischemic stress, and the subcellular localization of Daxx plays an important role in ischemic neuron death. In this study, by blocking the Daxx trafficking, the rat hippocampus CA1 neurons were protected against cerebral ischemia/reperfusion, and the molecular mechanism underlying this neuroprotection was studied. We found that pretreatment of SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), or an anti-oxidant, N-acetylcysteine (NAC), could not only prevent Daxx from trafficking but also increase the number of the surviving CA1 pyramidal cells of hippocampus at 5days of reperfusion. Furthermore, knock-down of endogenous Daxx exerted similar neuroprotective effect during ischemia/reperfusion. We found the treatment of SP600125 or NAC could decrease the activation of Ask1 during ischemia/reperfusion and suppress the assembly of the Fas·Daxx·Ask1 signaling module, and in succession inhibit JNK activation and c-Jun phosphorylation. This study provides the Daxx trafficking as a new potential therapeutic target for ischemic brain injury.}, }
@article {pmid21840048, year = {2011}, author = {Yamada, M and Ishihara, K and Ogawa, T and Sakurai, K}, title = {The inhibition of infection by wound pathogens on scaffold in tissue-forming process using N-acetyl cysteine.}, journal = {Biomaterials}, volume = {32}, number = {33}, pages = {8474-8485}, doi = {10.1016/j.biomaterials.2011.07.074}, pmid = {21840048}, issn = {1878-5905}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Bacterial Infections/*drug therapy ; Gingiva/cytology/metabolism/microbiology ; Glutathione/metabolism ; Oxidative Stress/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Staphylococcus aureus/drug effects/growth &amp; development ; Streptococcus pyogenes/drug effects/growth &amp; development ; }, abstract = {Prevention of local infection from wound pathogens such as Staphylococci and Streptococci is crucial for tissue regeneration. N-acetyl cysteine (NAC), an anti-oxidant amino acid derivative, has anti-microbial potential against various species. This in vitro study evaluated whether NAC prevented bacterial infection of gingival fibroblasts and osteoblasts on a scaffold. N-acetyl cysteine delayed growth of Staphylococcus aureus and Streptococcus pyogenes cultured in brain heart infusion (BHI) broth for 12 h in an almost dose-dependent manner (2.5, 5.0 or 10.0 mm). The number of rat gingival fibroblasts on collagen scaffolds with bacterial co-incubation was less than 30% of that in cultures without bacterial co-incubation at day 7. However, pre-addition of NAC to the scaffold yielded a number comparable with that in culture without bacteria. Fibroblasts on the scaffold with bacterial co-incubation were small, rounded and filled with bacteria and reactive oxygen species. Pre-addition of NAC, however, resulted in fibroblasts similar to those observed in culture without bacterial co-incubation. N-acetyl cysteine completely prevented devastating suppression of alkaline-phosphatase activity and extracellular matrix mineralization in osteoblastic culture on scaffolds with bacterial co-incubation. These results indicate that NAC can functionalize a scaffold with anti-infective capabilities, thus assisting healing of soft and hard tissues.}, }
@article {pmid21838198, year = {2011}, author = {Sadasivam, K and Patial, K and Vijayan, VK and Ravi, K}, title = {Anti-oxidant treatment in obstructive sleep apnoea syndrome.}, journal = {The Indian journal of chest diseases &amp; allied sciences}, volume = {53}, number = {3}, pages = {153-162}, pmid = {21838198}, issn = {0377-9343}, mesh = {Antioxidants/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Oxidative Stress ; Polysomnography ; Sleep/*drug effects ; Sleep Apnea, Obstructive/*drug therapy/physiopathology ; Treatment Outcome ; }, abstract = {PURPOSE: To investigate whether oral intake of N-acetylcysteine (NAC) is a treatment option in patients with obstructive sleep apnoea syndrome (OSAS).<br><br>METHODS: Twenty patients with OSAS were enrolled in the study. After polysomnography (PSG), they were randomly assigned to receive a placebo (n = 10) and NAC (n = 10). A repeat PSG was done after the treatment period of 30 days. Fasting venous samples were collected for various biochemical analysis.<br><br>RESULTS: In the patients of NAC group, compared to their baseline values, slow wave sleep as sleep percent time (27.9 +/- 2.7 vs 42.3 +/- 4.2; p < 0.01) and sleep efficiency (90.8 +/- 1.3 vs 94.4 +/- 1.5; p < 0.05) improved considerably. The apnoea-hypopnoea index (61.2 +/- 8.5 vs 43.1 +/- 8.6; p < 0.05), apnoea related arousals (22.2 +/- 7.6 vs 11.6 +/- 4.7; p < 0.05), longest apnoeic episode duration (seconds) (54.9 +/- 7.1 vs 37.8 +/- 5.6; p < 0.01), oxygen desaturation events per hour (51.8 +/- 7.7 vs 37 +/- 7.8; p < 0.01) and epworth sleepiness score (16.6 +/- 0.8 vs 9.2 +/- 0.9; p < 0.001) decreased significantly. The relative snore time (%) (10.2 +/- 2.9 vs 4.9 +/- 1.9; p < 0.01), number of snore episodes (63.8 +/-23.9 vs 28.2 +/- 9.9; p < 0.05) and duration of longest snore episode (min) (2.5 +/- 0.7 vs 0.6 +/- 0.1; p < 0.05) also decreased significantly. Such responses were not evident in the placebo group. N-acetylcysteine produced significant decrease in lipid peroxidation and increase in total reduced glutathione.<br><br>CONCLUSIONS: Oral NAC administration appears to have a therapeutic potential in the treatment of OSAS. It is proposed that long-term treatment with NAC in patients with OSAS may reduce their dependency on continuous positive airway pressure therapy.}, }
@article {pmid21833842, year = {2011}, author = {Tsai, CW and Lin, CY and Lin, HH and Chen, JH}, title = {Carnosic acid, a rosemary phenolic compound, induces apoptosis through reactive oxygen species-mediated p38 activation in human neuroblastoma IMR-32 cells.}, journal = {Neurochemical research}, volume = {36}, number = {12}, pages = {2442-2451}, pmid = {21833842}, issn = {1573-6903}, mesh = {Abietanes/*pharmacology ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Neuroblastoma/*pathology/*physiopathology ; Plant Extracts/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Carnosic acid (CA), a rosemary phenolic compound, has been shown to display anti-cancer activity. We examined the apoptotic effect of CA in human neuroblastoma IMR-32 cells and elucidated the role of the reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK) associated with carcinogenesis. The result indicated that CA decreased the cell viability in a dose-dependent manner. Further investigation in IMR-32 cells revealed that cell apoptosis following CA treatment is the mechanism as confirmed by flow cytometry, hoechst 33258, and caspase-3/-9 and poly(ADP-ribose) polymerase (PARP) activation. Immunoblotting suggested a down-regulation of anti-apoptotic Bcl-2 protein in the CA-treated cells. In flow cytometric analysis, CA caused the generation of reactive oxygen species (ROS); however, pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated the CA-induced generation of ROS and apoptosis. This effect was accompanied by increased activation of p38 and by decreased activation of extracellular signal-regulated kinase (ERK) as well as activation of c-Jun NH(2)-terminal kinase (JNK). Moreover, NAC attenuated the CA-induced phosphorylation of p38. Silencing of p38 by siRNA gene knockdown reduced the CA-induced activation of caspase-3. In conclusion, ROS-mediated p38 MAPK activation plays a critical role in CA-induced apoptosis in IMR-32 cells.}, }
@article {pmid21831508, year = {2011}, author = {Oner, G and Muderris, II}, title = {Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome.}, journal = {European journal of obstetrics, gynecology, and reproductive biology}, volume = {159}, number = {1}, pages = {127-131}, doi = {10.1016/j.ejogrb.2011.07.005}, pmid = {21831508}, issn = {1872-7654}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Anticholesteremic Agents/adverse effects/therapeutic use ; Antioxidants/adverse effects/*therapeutic use ; Body Mass Index ; Female ; Hirsutism/etiology/prevention &amp; control ; Humans ; Hyperandrogenism/etiology/prevention &amp; control ; Hypercholesterolemia/etiology/prevention &amp; control ; Hyperinsulinism/etiology/prevention &amp; control ; Hypoglycemic Agents/adverse effects/*therapeutic use ; Insulin Resistance ; Menstruation Disturbances/etiology/prevention &amp; control ; Metformin/adverse effects/*therapeutic use ; Patient Dropouts ; Polycystic Ovary Syndrome/blood/*drug therapy/metabolism/physiopathology ; Severity of Illness Index ; Tumor Necrosis Factor-alpha/blood ; Young Adult ; }, abstract = {OBJECTIVE: To evaluate the clinical, endocrine and metabolic effects of metformin and N-acetyl-cysteine (NAC) in patients with polycystic ovary syndrome (PCOS).<br><br>STUDY DESIGN: In this prospective trial, 100 women with PCOS were randomly divided to receive metformin (500 mg p.o. three times daily) or NAC (600 mg p.o. three times daily) for 24 weeks. Hyperandrogenism, lipid profiles, hirsutism scores, menstrual irregularity, insulin sensitivity and tumour necrosis factor-&#x3b1; (TNF-&#x3b1;) levels were measured at baseline and after the treatment period.<br><br>RESULTS: Both treatments resulted in a significant decrease in body mass index, hirsutism score, fasting insulin, HOMA index, free testosterone and menstrual irregularity compared with baseline values, and both treatments had equal efficacy. NAC led to a significant decrease in both total cholesterol and low-density lipoprotein levels, whereas metformin only led to a decrease in total cholesterol level. Although TNF-&#x3b1; levels increased following treatment for both groups, the difference from baseline was not significant.<br><br>CONCLUSIONS: Metformin and NAC appear to have comparable effects on hyperandrogenism, hyperinsulinaemia and menstrual irregularity in women with PCOS. The effects of metformin and NAC on insulin sensitivity are not associated with TNF-&#x3b1;.}, }
@article {pmid21829177, year = {2011}, author = {Suk, JS and Boylan, NJ and Trehan, K and Tang, BC and Schneider, CS and Lin, JM and Boyle, MP and Zeitlin, PL and Lai, SK and Cooper, MJ and Hanes, J}, title = {N-acetylcysteine enhances cystic fibrosis sputum penetration and airway gene transfer by highly compacted DNA nanoparticles.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {19}, number = {11}, pages = {1981-1989}, pmid = {21829177}, issn = {1525-0024}, support = {UL1 RR025005/RR/NCRR NIH HHS/United States ; UL1 RR 025005/RR/NCRR NIH HHS/United States ; R01 EB003558/EB/NIBIB NIH HHS/United States ; P01 HL51811/HL/NHLBI NIH HHS/United States ; P01 HL051811-19/HL/NHLBI NIH HHS/United States ; P01 HL051811/HL/NHLBI NIH HHS/United States ; 1R01 EB003558/EB/NIBIB NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Animals ; Biopolymers/chemistry/genetics/metabolism ; Cystic Fibrosis/*metabolism/therapy ; DNA/chemistry/*metabolism ; Diffusion/drug effects ; Expectorants/*pharmacology ; Female ; Genetic Therapy ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mucins/metabolism ; Nanoparticles/*chemistry ; Plasmids/chemistry/genetics/metabolism ; Polyethylene Glycols/chemistry/metabolism ; Polylysine/chemistry/metabolism ; Respiratory System/drug effects/metabolism ; Sputum/*drug effects ; Transduction, Genetic/*methods ; Viscosity/drug effects ; Young Adult ; }, abstract = {For effective airway gene therapy of cystic fibrosis (CF), inhaled gene carriers must first penetrate the hyperviscoelastic sputum covering the epithelium. Whether clinically studied gene carriers can penetrate CF sputum remains unknown. Here, we measured the diffusion of a clinically tested nonviral gene carrier, composed of poly-l-lysine conjugated with a 10 kDa polyethylene glycol segment (CK(30)PEG(10k)). We found that CK(30)PEG(10k)/DNA nanoparticles were trapped in CF sputum. To improve gene carrier diffusion across sputum, we tested adjuvant regimens consisting of N-acetylcysteine (NAC), recombinant human DNase (rhDNase) or NAC together with rhDNase. While rhDNase alone did not enhance gene carrier diffusion, NAC and NAC + rhDNase increased average effective diffusivities by 6-fold and 13-fold, respectively, leading to markedly greater fractions of gene carriers that may penetrate sputum layers. We further tested the adjuvant effects of NAC in the airways of mice with Pseudomonas aeruginosa lipopolysaccharide (LPS)-induced mucus hypersecretion. Intranasal dosing of NAC prior to CK(30)PEG(10k)/DNA nanoparticles enhanced gene expression by up to ~12-fold compared to saline control, reaching levels observed in the lungs of mice without LPS challenge. Our findings suggest that a promising synthetic nanoparticle gene carrier may transfer genes substantially more effectively to lungs of CF patients if administered following adjuvant mucolytic therapy with NAC or NAC + rhDNase.}, }
@article {pmid21828049, year = {2011}, author = {Thorp, E and Vaisar, T and Subramanian, M and Mautner, L and Blobel, C and Tabas, I}, title = {Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cδ, and p38 mitogen-activated protein kinase (MAPK).}, journal = {The Journal of biological chemistry}, volume = {286}, number = {38}, pages = {33335-33344}, pmid = {21828049}, issn = {1083-351X}, support = {HHSN268201000045C/HL/NHLBI NIH HHS/United States ; P01 HL054591/HL/NHLBI NIH HHS/United States ; R01 GM064750/GM/NIGMS NIH HHS/United States ; R01 HL075662/HL/NHLBI NIH HHS/United States ; HL54591/HL/NHLBI NIH HHS/United States ; GM64750/GM/NIGMS NIH HHS/United States ; HL75662/HL/NHLBI NIH HHS/United States ; UL1 RR 024156/RR/NCRR NIH HHS/United States ; T35 HL007616/HL/NHLBI NIH HHS/United States ; UL1 RR024156/RR/NCRR NIH HHS/United States ; K99 HL097021/HL/NHLBI NIH HHS/United States ; 1K99HL097021/HL/NHLBI NIH HHS/United States ; }, mesh = {ADAM Proteins/chemistry/*metabolism ; ADAM17 Protein ; Adaptor Proteins, Vesicular Transport/metabolism ; Amino Acid Sequence ; Animals ; Lipopolysaccharides/pharmacology ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Myeloid Differentiation Factor 88/metabolism ; NADP/deficiency/metabolism ; Proline/metabolism ; Protein Kinase C-delta/*metabolism ; Protein Processing, Post-Translational/drug effects ; Proto-Oncogene Proteins/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptor Protein-Tyrosine Kinases/*metabolism ; Sequence Deletion ; *Signal Transduction/drug effects ; Solubility/drug effects ; Toll-Like Receptor 4/metabolism ; c-Mer Tyrosine Kinase ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Mer tyrosine kinase (MerTK) is an integral membrane protein that is preferentially expressed by phagocytic cells, where it promotes efferocytosis and inhibits inflammatory signaling. Proteolytic cleavage of MerTK at an unidentified site leads to shedding of its soluble ectodomain (soluble MER; sMER), which can inhibit thrombosis in mice and efferocytosis in vitro. Herein, we show that MerTK is cleaved at proline 485 in murine macrophages. Site-directed deletion of 6 amino acids spanning proline 485 rendered MerTK resistant to proteolysis and suppression of efferocytosis by cleavage-inducing stimuli. LPS is a known inducer of MerTK cleavage, and the intracellular signaling pathways required for this action are unknown. LPS/TLR4-mediated generation of sMER required disintegrin and metalloproteinase ADAM17 and was independent of Myd88, instead requiring TRIF adaptor signaling. LPS-induced cleavage was suppressed by deficiency of NADPH oxidase 2 (Nox2) and PKCδ. The addition of the antioxidant N-acetyl cysteine inhibited PKCδ, and silencing of PKCδ inhibited MAPK p38, which was also required. In a mouse model of endotoxemia, we discovered that LPS induced plasma sMER, and this was suppressed by Adam17 deficiency. Thus, a TRIF-mediated pattern recognition receptor signaling cascade requires NADPH oxidase to activate PKCδ and then p38, culminating in ADAM17-mediated proteolysis of MerTK. These findings link innate pattern recognition receptor signaling to proteolytic inactivation of MerTK and generation of sMER and uncover targets to test how MerTK cleavage affects efferocytosis efficiency and inflammation resolution in vivo.}, }
@article {pmid21827635, year = {2012}, author = {Petersen, AC and McKenna, MJ and Medved, I and Murphy, KT and Brown, MJ and Della Gatta, P and Cameron-Smith, D}, title = {Infusion with the antioxidant N-acetylcysteine attenuates early adaptive responses to exercise in human skeletal muscle.}, journal = {Acta physiologica (Oxford, England)}, volume = {204}, number = {3}, pages = {382-392}, doi = {10.1111/j.1748-1716.2011.02344.x}, pmid = {21827635}, issn = {1748-1716}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adaptation, Physiological ; Adult ; Analysis of Variance ; Antioxidants/*administration &amp; dosage ; Bicycling ; Biopsy ; Chemokine CCL2/genetics ; Cross-Over Studies ; Double-Blind Method ; *Exercise ; Gene Expression Regulation/drug effects ; HSP70 Heat-Shock Proteins/genetics ; Heat-Shock Proteins/genetics ; Humans ; I-kappa B Proteins/metabolism ; Infusions, Intravenous ; Interleukin-6/genetics ; JNK Mitogen-Activated Protein Kinases/metabolism ; Male ; *Muscle Contraction ; Muscle Fatigue ; NF-KappaB Inhibitor alpha ; NF-kappa B/metabolism ; Oxidative Stress/*drug effects ; Oxygen Consumption ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Phosphorylation ; Quadriceps Muscle/*drug effects/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/genetics ; Time Factors ; Transcription Factors/genetics ; Victoria ; Young Adult ; }, abstract = {AIM: Production of reactive oxygen species (ROS) in skeletal muscle is markedly increased during exercise and may be essential for exercise adaptation. We, therefore, investigated the effects of infusion with the antioxidant N-acetylcysteine (NAC) on exercise-induced activation of signalling pathways and genes involved in exercise adaptation in human skeletal muscle.<br><br>METHODS: Subjects completed two exercise tests, 7 days apart, with saline (control, CON) or NAC infusion before and during exercise. Exercise tests comprised of cycling at 71% VO(2peak) for 45 min, and then 92% VO(2peak) to fatigue, with vastus lateralis biopsies at pre-infusion, after 45-min cycling and at fatigue.<br><br>RESULTS: Analysis was conducted on the mitogen-activated protein kinase signalling pathways, demonstrating that NAC infusion blocked the exercise-induced increase in JNK phosphorylation, but not ERK1/2, or p38 MAPK. Nuclear factor-&#x3ba;B p65 phosphorylation was unaffected by exercise; however, it was reduced in NAC at fatigue by 14% (P < 0.05) compared with pre-infusion. Analysis of exercise and/or ROS-sensitive genes demonstrated that exercise-induced mRNA expression is ROS dependent of MnSOD, but not PGC-1&#x3b1;, interleukin-6, monocyte chemotactic protein-1, or heat-shock protein 70.<br><br>CONCLUSION: These results suggest that inhibition of ROS attenuates some skeletal muscle cell signalling pathways and gene expression involved in adaptations to exercise.}, }
@article {pmid21826213, year = {2011}, author = {Lamers, ML and Almeida, ME and Vicente-Manzanares, M and Horwitz, AF and Santos, MF}, title = {High glucose-mediated oxidative stress impairs cell migration.}, journal = {PloS one}, volume = {6}, number = {8}, pages = {e22865}, pmid = {21826213}, issn = {1932-6203}, support = {R01 GM023244/GM/NIGMS NIH HHS/United States ; R37 GM023244/GM/NIGMS NIH HHS/United States ; GM23244/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; Cell Movement/*drug effects ; Cell Polarity/drug effects ; Cells, Cultured ; Glucose/*pharmacology ; Mice ; NIH 3T3 Cells ; Oxidative Stress/*drug effects ; Rats ; Reactive Oxygen Species/metabolism ; rac1 GTP-Binding Protein/metabolism ; rhoA GTP-Binding Protein/metabolism ; }, abstract = {Deficient wound healing in diabetic patients is very frequent, but the cellular and molecular causes are poorly defined. In this study, we evaluate the hypothesis that high glucose concentrations inhibit cell migration. Using CHO.K1 cells, NIH-3T3 fibroblasts, mouse embryonic fibroblasts and primary skin fibroblasts from control and diabetic rats cultured in 5 mM D-glucose (low glucose, LG), 25 mM D-glucose (high glucose, HG) or 25 mM L-glucose medium (osmotic control--OC), we analyzed the migration speed, protrusion stability, cell polarity, adhesion maturation and the activity of the small Rho GTPase Rac1. We also analyzed the effects of reactive oxygen species by incubating cells with the antioxidant N-Acetyl-Cysteine (NAC). We observed that HG conditions inhibited cell migration when compared to LG or OC. This inhibition resulted from impaired cell polarity, protrusion destabilization and inhibition of adhesion maturation. Conversely, Rac1 activity, which promotes protrusion and blocks adhesion maturation, was increased in HG conditions, thus providing a mechanistic basis for the HG phenotype. Most of the HG effects were partially or completely rescued by treatment with NAC. These findings demonstrate that HG impairs cell migration due to an increase in oxidative stress that causes polarity loss, deficient adhesion and protrusion. These alterations arise, in large part, from increased Rac1 activity and may contribute to the poor wound healing observed in diabetic patients.}, }
@article {pmid21826188, year = {2012}, author = {Lu, KH and Lee, HJ and Huang, ML and Lai, SC and Ho, YL and Chang, YS and Chi, CW}, title = {Synergistic Apoptosis-Inducing Antileukemic Effects of Arsenic Trioxide and Mucuna macrocarpa Stem Extract in Human Leukemic Cells via a Reactive Oxygen Species-Dependent Mechanism.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2012}, number = {}, pages = {921430}, pmid = {21826188}, issn = {1741-4288}, abstract = {The objective of this study was to examine the potential of enhancing the antileukemic activity of arsenic trioxide (ATO) by combining it with a folk remedy, crude methanolic extract of Mucuna macrocarpa (CMEMM). Human leukemia cells HL-60, Jurkat, and Molt-3 were treated with various doses of ATO, CMEMM, and combinations thereof for 24 and 48 h. Results indicated that the combination of 2.5 μM ATO and 50 μg/mL CMEMM synergistically inhibited cell proliferation in HL-60 and Jurkat cell lines. Apoptosis triggered by ATO/CMEMM treatment was confirmed by accumulation of cells in the sub-G(1) phase in cell cycle analyses, characteristic apoptotic nuclear fragmentation, and increased percentage of annexin V-positive apoptotic cells. Such combination treatments also led to elevation of reactive oxygen species (ROS). The antioxidants N-acetyl cysteine (NAC), butylated hydroxytoluene, and α-tocopherol prevented cells from ATO/CMEMM-induced apoptosis. The ATO/CMEMM-induced activation of caspase-3 and caspase-9 can be blocked by NAC. In summary, these results suggest that ATO/CMEMM combination treatment exerts synergistic apoptosis-inducing effects in human leukemic cells through a ROS-dependent mechanism and may provide a promising antileukemic approach in the future.}, }
@article {pmid21820976, year = {2011}, author = {Khan, MI and Iqbal, Z}, title = {Simultaneous determination of ascorbic acid, aminothiols, and methionine in biological matrices using ion-pairing RP-HPLC coupled with electrochemical detector.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {879}, number = {25}, pages = {2567-2575}, doi = {10.1016/j.jchromb.2011.07.013}, pmid = {21820976}, issn = {1873-376X}, mesh = {Amino Acids, Sulfur/*analysis/isolation &amp; purification ; Ascorbic Acid/*analysis/isolation &amp; purification ; Chromatography, High Pressure Liquid/*methods ; Drug Stability ; Electrochemical Techniques ; Glutathione Disulfide/*analysis/isolation &amp; purification ; Linear Models ; Methanol/chemistry ; Reproducibility of Results ; Sensitivity and Specificity ; Temperature ; Trifluoroacetic Acid/chemistry ; }, abstract = {A novel highly sensitive ion-pairing reversed-phase high performance liquid-chromatography/electrochemical detection method for simultaneous determination of l-ascorbic acid, aminothiols, and methionine in biological matrices was developed, optimized, and validated. Reduced forms of the analytes were extracted from the sample matrices with 10% meta-phosphoric acid solution((aqueous)). To determine the total vitamin C, the total aminothiols, and the total methionine, samples were treated with tris(2-carboxyethyl)phosphine solution in 0.05% trifluoroacetic acid solution((aqueous)) subsequent to deproteination to reduce the oxidized forms of these compounds. Various analytes were separated on a C(18) (250 × 4.6 mm, 5 μm) analytical column using methanol-0.05% trifluoroacetic acid solution((aqueous)) (05/95, v/v), containing 0.1mM 1-octane sulphonic acid as the ion-pairing agent) as the isocratic mobile phase pumped at a flow rate of 1.5 mL min(-1) at room temperature. The column eluents were monitored at a voltage of 0.85 V. These analytes were efficiently resolved in less than 20 min using n-acetyl cysteine as the internal standard. The present method was specific for the analysis of these analytes and demonstrated acceptable values for linearity (r(2)>0.999 in the range of 0.2-10,000 ng mL(-1) for all the analytes), recovery (>96%), precision (%RSD ≤ 2.0), and sensitivity (on column limit of detection: 250-400 fg and limit of quantification: 0.8-1.25 pg), indicating that the proposed method could be efficiently used for determination of these analytes in the context of clinical research.}, }
@article {pmid21819286, year = {2011}, author = {Chomchai, S and Chomchai, C and Anusornsuwan, T}, title = {Acetaminophen psi parameter: a useful tool to quantify hepatotoxicity risk in acute acetaminophen overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {49}, number = {7}, pages = {664-667}, doi = {10.3109/15563650.2011.597031}, pmid = {21819286}, issn = {1556-9519}, mesh = {Acetaminophen/blood/pharmacokinetics/*poisoning ; Acetylcysteine/administration &amp; dosage ; Adolescent ; Adult ; Analgesics, Non-Narcotic/blood/pharmacokinetics/*poisoning ; Antidotes/administration &amp; dosage ; Chemical and Drug Induced Liver Injury/*etiology/prevention &amp; control ; Drug Administration Schedule ; Drug Overdose ; Female ; Humans ; Infusions, Intravenous ; Logistic Models ; Male ; Predictive Value of Tests ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Thailand ; Young Adult ; }, abstract = {CONTEXT: The risk of hepatotoxicity secondary to acute acetaminophen overdose is related to serum acetaminophen concentration and lag time from ingestion to N-acetylcysteine (NAC) therapy. Psi (Greek letter ψ) is a toxicokinetic parameter that takes the acetaminophen level at 4 h post-ingestion ([APAP](4 h)) and the time-to-initiation of NAC (tNAC) into account and was found to be significantly predictive of hepatotoxicity in Canadian patients with acetaminophen overdose treated with intravenous NAC.<br><br>OBJECTIVE: We report the relationship of psi and hepatotoxicity in a Thai population with acute acetaminophen overdose.<br><br>METHODS: This is a retrospective study of patients with acute paracetamol overdose during January 2004 to June 2009 at Siriraj Hospital. Patients were treated with the standard 21-h intravenous NAC regimen. Univariate analyses were performed with logistic regression to assess the relationships of psi, [APAP](4 h), and tNAC, and hepatotoxicity.<br><br>RESULTS: A total of 127 patients were enrolled. The median (interquartile range; IQR) of [APAP](4 h) was 267.8 (196.0-380.0) mg/L. The median (IQR) of tNAC was 8.5 (6.2-12.0) h. Thirteen patients (10.2%) developed hepatotoxicity. Univariate analysis revealed [APAP](4 h), tNAC, and psi as statistically significant predictors of hepatotoxicity.<br><br>DISCUSSION AND CONCLUSION: The psi parameter is a reliable prognostic tool to predict hepatotoxicity secondary to acute acetaminophen overdose treated with intravenous NAC. Our evidence shows that psi may be a more superior tool than either acetaminophen level or time-to-initiation of NAC at predicting hepatotoxicity.}, }
@article {pmid21816542, year = {2011}, author = {Yip, LY and Lim, YF and Chan, HN}, title = {Safety and potential anticoagulant effects of nebulised heparin in burns patients with inhalational injury at Singapore General Hospital Burns Centre.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {37}, number = {7}, pages = {1154-1160}, doi = {10.1016/j.burns.2011.07.006}, pmid = {21816542}, issn = {1879-1409}, mesh = {Adult ; Anticoagulants/*administration &amp; dosage/adverse effects ; Blood Coagulation Tests ; Burns/complications/*drug therapy ; Female ; Hemorrhage/chemically induced/epidemiology ; Heparin/*administration &amp; dosage/adverse effects ; Humans ; Incidence ; Male ; Middle Aged ; Nebulizers and Vaporizers ; Partial Thromboplastin Time ; Platelet Count ; Prothrombin/analysis ; Regression Analysis ; Retrospective Studies ; Singapore ; Smoke Inhalation Injury/complications/*drug therapy ; }, abstract = {BACKGROUND: Nebulised heparin, N-acetylcysteine (NAC) and salbutamol were shown to decrease reintubation rates, incidence of atelectasis and mortality in paediatric patients and reduce lung injury scores in adult burns patients with inhalational lung injury (ILI). Nebulised heparin, NAC and salbutamol treatment protocol was introduced in Singapore General Hospital (SGH) Burns Centre in 2006. However, safety data on the use of nebulised heparin and NAC for burns patients with ILI is not well established. In this study, we investigated the safety and potential anticoagulant effects of nebulised heparin in burns patients with ILI.<br><br>METHODS: A retrospective study with historical control was conducted. The treatment group consisted of 52 mechanically ventilated adult patients, with a diagnosis of ILI as confirmed by bronchoscopy, admitted to burn intensive care unit (BICU) from the year 2006 to 2009. The group was treated with nebulised heparin, NAC and salbutamol. The control group consists of 11 mechanically ventilated BICU ILI patients treated from year 2001 to 2005 before protocol initiation. Blood coagulation indices (prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet count) were monitored and bleeding incidences were assessed.<br><br>FINDINGS: Blood coagulation indices did not suggest an increase risk of bleeding with nebulised heparin. The APTT, PT and platelet count followed a similar trend for both groups over 7 days. No clinically significant increase in bleeding risk was found to be associated with nebulised heparin.<br><br>CONCLUSION: Nebulised heparin was not found to potentiate the risk of bleeding in burns patients with ILI.}, }
@article {pmid21816192, year = {2011}, author = {Fraternale, A and Paoletti, MF and Dominici, S and Buondelmonte, C and Caputo, A and Castaldello, A and Tripiciano, A and Cafaro, A and Palamara, AT and Sgarbanti, R and Garaci, E and Ensoli, B and Magnani, M}, title = {Modulation of Th1/Th2 immune responses to HIV-1 Tat by new pro-GSH molecules.}, journal = {Vaccine}, volume = {29}, number = {40}, pages = {6823-6829}, doi = {10.1016/j.vaccine.2011.07.101}, pmid = {21816192}, issn = {1873-2518}, mesh = {AIDS Vaccines/*immunology/pharmacology ; Acetylcysteine/immunology/pharmacology ; Adjuvants, Immunologic/pharmacology ; Animals ; Cysteamine/immunology/pharmacology ; Epitope Mapping/methods ; Female ; Glutathione/*immunology/pharmacology ; HIV Antibodies/immunology ; HIV Infections/*immunology/prevention &amp; control ; HIV-1/*immunology ; Immunity, Cellular/drug effects/immunology ; Immunoglobulin G/immunology ; Immunoglobulin Isotypes/immunology ; Immunologic Factors/immunology ; Interferon-gamma/immunology ; Interleukin-12/biosynthesis/immunology ; Interleukin-2/immunology ; Mice ; Mice, Inbred BALB C ; Prodrugs/pharmacology ; Th1 Cells/drug effects/*immunology ; Th2 Cells/drug effects/*immunology ; tat Gene Products, Human Immunodeficiency Virus/*immunology ; }, abstract = {We have previously demonstrated that in Ova-immunized mice the increase in intra-macrophage thiol pool induced by pro-GSH molecules modulates the Th1/Th2 balance in favour of a Th1-type immune response. We show now that the same molecules can support a Th1-type over Th2-type immunity against Tat, which is an early HIV-1 regulatory protein and a Th1 polarizing immunomodulator that is increasingly considered in new anti-HIV vaccination strategies. Our results indicate that Tat-immunized mice pre-treated with the C4 (n-butanoyl) derivative of reduced glutathione (GSH-C4) or a pro-drug of N-acetylcysteine (NAC) and beta-mercaptoethylamine (MEA) (I-152), have decreased levels of anti-Tat IgG1 as well as increased levels of anti-Tat IgG2a and IgG2b isotypes suggesting a Th1-type response. Moreover, Th1-(IFN-γ and IL-2) Ag-specific cellular responses were detected by ELISPOT assay in splenocytes of the same animals as well as an increase of IL-12 levels in the plasma. These findings suggest that the Th1 immune response to HIV-1 Tat could be further polarized by these molecules. These results together with those previously reported suggest that pro-GSH molecules could be used to modulate the immune response towards different antigens and may be further exploited for inducing specific Th1 immune responses against other HIV antigens as well as other intracellular pathogens in new Tat-based vaccination protocols.}, }
@article {pmid21815196, year = {2011}, author = {Liu, H and Zhao, S and Zhang, Y and Wu, J and Peng, H and Fan, J and Liao, J}, title = {Reactive oxygen species-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to polydatin-induced apoptosis in human nasopharyngeal carcinoma CNE cells.}, journal = {Journal of cellular biochemistry}, volume = {112}, number = {12}, pages = {3695-3703}, doi = {10.1002/jcb.23303}, pmid = {21815196}, issn = {1097-4644}, mesh = {Apoptosis/*drug effects ; Base Sequence ; Caspases/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Endoplasmic Reticulum/*metabolism ; Glucosides/*pharmacology ; Humans ; Mitochondria/*metabolism ; Nasopharyngeal Neoplasms/enzymology/*pathology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; Stilbenes/*pharmacology ; *Stress, Physiological ; }, abstract = {Previous studies revealed that polydatin, a natural small compound, possessed protective effect against ischemia/reperfusion injury and inflammation. However, the action and molecular mechanism of its potent anti-cancer activity remain poorly understood. In the present study, polydatin significantly killed several human tumor cell lines in a dose- and time-dependent manner. The compound also dose-dependently caused mitochondrial apoptosis in human nasopharyngeal carcinoma CNE cells. In addition, polydatin triggered endoplasmic reticulum (ER) stress and down-regulated the phosphorylation of Akt in CNE cells, while knock-down of CCAAT/enhancer-binding protein homologous protein (CHOP) dramatically abrogated the inactivation of Akt and reversed the pro-apoptotic effect of polydatin. Furthermore, polydatin provoked the generation of reactive oxygen species in CNE cells, while the antioxidant N-acetyl cysteine almost completely blocked the activation of ER stress and apoptosis, suggesting polydatin-induced reactive oxygen species is an early event that triggers ER stress mitochondrial apoptotic pathways in CNE cells. Taken together, these findings strongly suggest that polydatin might be a promising anti-tumor drug and our data provide the molecular theoretical basis for clinical application of polydatin.}, }
@article {pmid21810225, year = {2011}, author = {Fritsch-Decker, S and Both, T and Mülhopt, S and Paur, HR and Weiss, C and Diabaté, S}, title = {Regulation of the arachidonic acid mobilization in macrophages by combustion-derived particles.}, journal = {Particle and fibre toxicology}, volume = {8}, number = {}, pages = {23}, pmid = {21810225}, issn = {1743-8977}, mesh = {Air Pollutants/analysis/*toxicity ; Animals ; Arachidonic Acid/*metabolism ; Cell Line ; Cell Survival/drug effects ; Coal Ash/analysis/*toxicity ; Dose-Response Relationship, Drug ; Humans ; *Incineration ; Macrophages, Alveolar/*drug effects/enzymology/metabolism ; Mice ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Species Specificity ; Time Factors ; }, abstract = {BACKGROUND: Acute exposure to elevated levels of environmental particulate matter (PM) is associated with increasing morbidity and mortality rates. These adverse health effects, e.g. culminating in respiratory and cardiovascular diseases, have been demonstrated by a multitude of epidemiological studies. However, the underlying mechanisms relevant for toxicity are not completely understood. Especially the role of particle-induced reactive oxygen species (ROS), oxidative stress and inflammatory responses is of particular interest.In this in vitro study we examined the influence of particle-generated ROS on signalling pathways leading to activation of the arachidonic acid (AA) cascade. Incinerator fly ash particles (MAF02) were used as a model for real-life combustion-derived particulate matter. As macrophages, besides epithelial cells, are the major targets of particle actions in the lung murine RAW264.7 macrophages and primary human macrophages were investigated.<br><br>RESULTS: The interaction of fly ash particles with macrophages induced both the generation of ROS and as part of the cellular inflammatory responses a dose- and time-dependent increase of free AA, prostaglandin E2/thromboxane B2 (PGE2/TXB2), and 8-isoprostane, a non-enzymatically formed oxidation product of AA. Additionally, increased phosphorylation of the mitogen-activated protein kinases (MAPK) JNK1/2, p38 and ERK1/2 was observed, the latter of which was shown to be involved in MAF02-generated AA mobilization and phosphorylation of the cytosolic phospolipase A2. Using specific inhibitors for the different phospolipase A2 isoforms the MAF02-induced AA liberation was shown to be dependent on the cytosolic phospholipase A2, but not on the secretory and calcium-independent phospholipase A2. The initiation of the AA pathway due to MAF02 particle exposure was demonstrated to depend on the formation of ROS since the presence of the antioxidant N-acetyl-cysteine (NAC) prevented the MAF02-mediated enhancement of free AA, the subsequent conversion to PGE2/TXB2 via the induction of COX-2 and the ERK1/2 and JNK1/2 phosphorylation. Finally we showed that the particle-induced formation of ROS, liberation of AA and PGE2/TXB2 together with the phosphorylation of ERK1/2 and JNK1/2 proteins was decreased after pre-treatment of macrophages with the metal chelator deferoxamine mesylate (DFO).<br><br>CONCLUSIONS: These results indicate that one of the primary mechanism initiating inflammatory processes by incinerator fly ash particles seems to be the metal-mediated generation of ROS, which triggers via the MAPK cascade the activation of AA signalling pathway.}, }
@article {pmid21807966, year = {2011}, author = {Bae, H and Guan, JL}, title = {Suppression of autophagy by FIP200 deletion impairs DNA damage repair and increases cell death upon treatments with anticancer agents.}, journal = {Molecular cancer research : MCR}, volume = {9}, number = {9}, pages = {1232-1241}, pmid = {21807966}, issn = {1557-3125}, support = {R01 CA150926-20/CA/NCI NIH HHS/United States ; R01 GM052890/GM/NIGMS NIH HHS/United States ; GM052890/GM/NIGMS NIH HHS/United States ; R01 CA150926/CA/NCI NIH HHS/United States ; R01 GM052890-17/GM/NIGMS NIH HHS/United States ; CA150926/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Anticarcinogenic Agents/pharmacology ; *Autophagy ; Autophagy-Related Proteins ; Camptothecin/pharmacology ; *DNA Damage ; DNA Repair/*genetics ; Etoposide/pharmacology ; Fibroblasts/drug effects/metabolism ; Intracellular Signaling Peptides and Proteins/*genetics/*metabolism ; Mice ; RNA, Small Interfering ; Topoisomerase I Inhibitors/pharmacology ; Topoisomerase II Inhibitors/pharmacology ; Transcription Factor TFIIH ; Transcription Factors/genetics ; }, abstract = {Autophagy is a lysosomal bulk degradation process for intracellular protein and organelles. FIP200 (200 kDa FAK-family interacting protein) is an essential component of mammalian autophagy that is implicated in breast cancer in recent studies. Here we show that inactivation of FIP200 resulted in deficient repair of DNA damage induced by ionizing radiation and anticancer agents in mouse embryonic fibroblasts (MEF). The persistent DNA damage correlated to increased apoptosis and reduced survival of FIP200 knockout (KO) MEFs after treatments with camptothecin (CPT), a topoisomerase I inhibitor and chemotherapeutic agent. Reexpression of FIP200 in FIP200 KO MEFs restored both efficient DNA damage repair and cell survival. Furthermore, knockdown of the increased p62 expression in FIP200 KO MEFs rescued the impaired DNA damage repair and CPT-induced cell death. In contrast, treatment of cells with N-acetyl cysteine did not affect these defects in FIP200 KO MEFs. Finally, FIP200 KO MEFs also showed deficient DNA damage repair and increased cell death compared with control MEFs, when treated with etoposide, a topoisomerase II inhibitor and another anticancer agent. Together, these results identify a new function for FIP200 in the regulation of DNA damage response and cell survival through its activity in autophagy and suggest the possibility of FIP200 or other autophagy proteins as a potential target for treatment to enhance the efficiency of cancer therapy using DNA damage-inducing agents.}, }
@article {pmid21807766, year = {2011}, author = {Richards, SA and Muter, J and Ritchie, P and Lattanzi, G and Hutchison, CJ}, title = {The accumulation of un-repairable DNA damage in laminopathy progeria fibroblasts is caused by ROS generation and is prevented by treatment with N-acetyl cysteine.}, journal = {Human molecular genetics}, volume = {20}, number = {20}, pages = {3997-4004}, doi = {10.1093/hmg/ddr327}, pmid = {21807766}, issn = {1460-2083}, support = {07-0449/AICR_/Worldwide Cancer Research/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Age Factors ; Aged, 80 and over ; Antineoplastic Agents/pharmacology ; Child ; Contracture/genetics ; DNA Breaks, Double-Stranded ; *DNA Damage/drug effects ; DNA Repair/drug effects ; Etoposide/pharmacology ; Fibroblasts/drug effects/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Male ; Oxidants/pharmacology ; Progeria/drug therapy/*genetics ; Reactive Oxygen Species/adverse effects/*metabolism ; Skin Abnormalities/genetics ; }, abstract = {Fibroblasts from patients with the severe laminopathy diseases, restrictive dermopathy (RD) and Hutchinson Gilford progeria syndrome (HGPS), are characterized by poor growth in culture, the presence of abnormally shaped nuclei and the accumulation of DNA double-strand breaks (DSB). Here we show that the accumulation of DSB and poor growth of the fibroblasts but not the presence of abnormally shaped nuclei are caused by elevated levels of reactive oxygen species (ROS) and greater sensitivity to oxidative stress. Basal levels of ROS and sensitivity to H(2)O(2) were compared in fibroblasts from normal, RD and HGPS individuals using fluorescence activated cell sorting-based assays. Basal levels of ROS and stimulated levels of ROS were both 5-fold higher in the progeria fibroblasts. Elevated levels of ROS were correlated with lower proliferation indices but not with the presence of abnormally shaped nuclei. DSB induced by etoposide were repaired efficiently in normal, RD and HGPS fibroblasts. In contrast, DSB induced by ROS were repaired efficiently in normal fibroblasts, but in RD and HGPS fibroblasts many ROS-induced DSB were un-repairable. The accumulation of ROS-induced DSB appeared to cause the poor growth of RD and HGPS fibroblasts, since culture in the presence of the ROS scavenger N-acetyl cysteine (NAC) reduced the basal levels of DSB, eliminated un-repairable ROS-induced DSB and greatly improved population-doubling times. Our findings suggest that un-repaired ROS-induced DSB contribute significantly to the RD and HGPS phenotypes and that inclusion of NAC in a combinatorial therapy might prove beneficial to HGPS patients.}, }
@article {pmid21806545, year = {2012}, author = {Shyu, KG and Chen, SC and Wang, BW and Cheng, WP and Hung, HF}, title = {Mechanism of the inhibitory effect of atorvastatin on leptin expression induced by angiotensin II in cultured human coronary artery smooth muscle cells.}, journal = {Clinical science (London, England : 1979)}, volume = {122}, number = {1}, pages = {33-42}, doi = {10.1042/CS20110114}, pmid = {21806545}, issn = {1470-8736}, mesh = {Angiotensin II/*pharmacology ; Anticholesteremic Agents/pharmacology ; Atorvastatin ; Blotting, Western ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Coronary Vessels/cytology ; Heptanoic Acids/*pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/genetics/metabolism ; Leptin/genetics/*metabolism ; Muscle, Smooth, Vascular/cytology/metabolism ; Myocytes, Smooth Muscle/*drug effects/metabolism ; Phosphorylation ; Promoter Regions, Genetic/genetics ; Protein Binding/drug effects ; Pyrroles/*pharmacology ; RNA Interference ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Transcription Factor AP-1/metabolism ; Vasoconstrictor Agents/pharmacology ; rac1 GTP-Binding Protein/genetics/metabolism ; }, abstract = {Leptin contributes to the pathogenesis of atherosclerosis. Ang II (angiotensin II), a proatherogenic cytokine, increases leptin synthesis in cultured adipocytes. Statin suppresses leptin expression in adipocytes and human coronary artery endothelial cells. However, the effect of Ang II and statin on leptin expression in VSMCs (vascular smooth muscle cells), the major cell types in atheroma, is poorly understood. Thus the aim of the present study was to investigate the molecular mechanism of atorvastatin for reducing leptin expression after Ang II stimulation in VSMCs. VSMCs from human coronary artery were cultured. Ang II stimulation increased leptin protein and mRNA and phospho-JNK (c-Jun N-terminal kinase) expression. Exogenous addition of Dp44mT (2,2'-dipyridyl-N,N-dimethylsemicarbazone) and mevalonate increased leptin protein expression similarly to Ang II. Atorvastatin, SP600125, JNK siRNA (small interfering RNA) and NAC (N-acetylcysteine) completely attenuated the leptin and phospho-JNK protein expression induced by Ang II. Ang II significantly increased ROS (reactive oxygen species) formation in human VSMCs. Addition of atorvastatin and NAC significantly attenuated the formation of ROS induced by Ang II. Addition of atorvastatin and SP600125 inhibited the phosphorylation of Rac1 induced by Ang II. The gel shift and promoter activity assay showed that Ang II increased AP-1 (activator protein-1)-binding activity and leptin promoter activity, while SP600125, NAC and atorvastatin inhibited the AP-1-binding activity and leptin promoter activity induced by Ang II. Ang II significantly increased the migration and proliferation of cultured VSMCs, while addition of atorvastatin, SP600125, NAC and leptin siRNA before Ang II stimulation significantly inhibited the migration and proliferation of VSMCs induced by Ang II. Ang II significantly increased secretion of leptin from human VSMCs, and addition of SP600125, atorvastatin and NAC before Ang II stimulation almost completely inhibited the leptin secretion induced by Ang II. In conclusion, Ang II induces leptin expression in human VSMCs, and atorvastatin could inhibit the leptin expression induced by Ang II. The inhibitory effect of atorvastatin on Ang II-induced leptin expression was mediated by Rac, ROS and JNK pathways.}, }
@article {pmid21804453, year = {2011}, author = {Lorito, G and Hatzopoulos, S and Laurell, G and Campbell, KC and Petruccelli, J and Giordano, P and Kochanek, K and Sliwa, L and Martini, A and Skarzynski, H}, title = {Dose-dependent protection on cisplatin-induced ototoxicity - an electrophysiological study on the effect of three antioxidants in the Sprague-Dawley rat animal model.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {17}, number = {8}, pages = {BR179-186}, pmid = {21804453}, issn = {1643-3750}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*toxicity ; Antioxidants/*pharmacology ; Auditory Threshold/drug effects ; Azoles/pharmacology ; Cisplatin/*toxicity ; Dose-Response Relationship, Drug ; Electrophysiology ; Evoked Potentials, Auditory, Brain Stem/drug effects/physiology ; Hair Cells, Auditory, Outer/*drug effects ; Isoindoles ; Male ; Methionine/chemistry/pharmacology ; *Models, Animal ; Organoselenium Compounds/pharmacology ; Otoacoustic Emissions, Spontaneous/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Sprague-Dawley rats were used as an acute cisplatin ototoxicity model to compare the chemo-protective efficacy of 2 sulphur-containing antioxidants (D-methionine, N-L-acetylcysteine) and 1 seleno-organic compound (ebselen). Each putative chemo-protective agent was tested at 3 different dosages in order to assess the influence of dose on auditory preservation.<br><br>MATERIAL/METHODS: A total of 40 Sprague-Dawley albino male rats were used in the study. Animals were divided into 10 groups, 3 groups of different doses for each protective agent and a cisplatin-treated control group. The animals were weight-matched before drug exposure to ensure similar weights in all groups. Auditory function was assessed with auditory brainstem responses and distortion product otoacoustic emissions at time zero and at 96 hours post-treatment.<br><br>RESULTS: At the post-treatment follow-up no significant threshold change at 8 kHz was found in the D-Met- and NAC-treated groups. All ebselen-treated animals presented significant threshold elevations. At 12 and 16 kHz, only the groups treated with 300, 450 mg/kg of D-Met and 475 mg/kg of NAC presented thresholds comparable to the pre-treatment ABR data. The ebselen-treated animals presented significant threshold shifts and showed the highest threshold elevations. The DPOAE data analysis showed that only the animals from the 350 mg/kg D-met group presented lack of statistical differences between the pre and post recordings.<br><br>CONCLUSIONS: Considering the outcome from the ABR and DPOAE analyses together, only the 350 mg/kg D-met group presented a complete auditory preservation against the 14 mg/kg cisplatin administered i.v. Data from ebselen pre-treated Sprague-Dawley albino male rats demonstrate that ebselen dosages up to 12 mg/kg given by i.p. administration lack auditory preservation in this species.}, }
@article {pmid21804221, year = {2011}, author = {Adachi, T and Aida, K and Nishihara, H and Kamiya, T and Hara, H}, title = {Effect of hypoxia mimetic cobalt chloride on the expression of extracellular-superoxide dismutase in retinal pericytes.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {34}, number = {8}, pages = {1297-1300}, doi = {10.1248/bpb.34.1297}, pmid = {21804221}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Apoptosis/drug effects ; Butyric Acid/pharmacology ; Caspase 3/metabolism ; Cobalt/*pharmacology ; DNA Fragmentation ; Diabetic Retinopathy/*etiology/metabolism/prevention &amp; control ; Down-Regulation ; Free Radical Scavengers/pharmacology/therapeutic use ; Hypoxia/*complications/metabolism ; Pericytes/*drug effects/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Retina/cytology/*drug effects/metabolism ; Superoxide Dismutase/*metabolism ; }, abstract = {The initial clinical stage of diabetic retinopathy (DR) is characterized by the development of intraretinal microvascular abnormalities. The increased formation of reactive oxygen species (ROS) is thought to be a key event in the pathogenesis of DR. Extracellular-superoxide dismutase (EC-SOD) is an anti-inflammatory enzyme that is distributed mainly in vascular cells and protects cells from ROS by scavenging superoxide anion. Treatment with cobalt chloride (CoCl(2)) decreased the expression of EC-SOD but not other SOD isozymes in pericytes accompanied with an increase of intracellular ROS production. Pre-treatment with N-acetylcysteine (NAC) significantly suppressed the ROS production and down-regulation of EC-SOD. We observed the activation of caspase-3 and DNA fragmentation as signs of apoptotic process by CoCl(2) treatment. In addition, these phenomena were significantly inhibited by pre-treatment with NAC. EC-SOD enhancer 4-phenyl butyric acid also suppressed the caspase-3 activation. It is known that the presence of a high level of EC-SOD throughout the vessel walls might have an important protective role against superoxide in the vascular system. The decrease in EC-SOD expression accompanied with elevation of ROS level in pericytes under hypoxia might induce and/or promote the ROS-triggered apoptosis of pericytes and the development of pathogenesis in DR.}, }
@article {pmid21801798, year = {2011}, author = {Mögel, I and Baumann, S and Böhme, A and Kohajda, T and von Bergen, M and Simon, JC and Lehmann, I}, title = {The aromatic volatile organic compounds toluene, benzene and styrene induce COX-2 and prostaglandins in human lung epithelial cells via oxidative stress and p38 MAPK activation.}, journal = {Toxicology}, volume = {289}, number = {1}, pages = {28-37}, doi = {10.1016/j.tox.2011.07.006}, pmid = {21801798}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/*toxicity ; Benzene Derivatives/*toxicity ; Blotting, Western ; Cell Line ; Cyclooxygenase 2/*biosynthesis ; Dinoprost/metabolism ; Dinoprostone/metabolism ; Enzyme Activation/drug effects ; Enzyme Induction/drug effects ; Epithelial Cells ; Glutathione/metabolism ; Humans ; Imidazoles/pharmacology ; Lung/cytology/*drug effects/enzymology/metabolism ; MAP Kinase Kinase Kinases/*metabolism ; Oxidative Stress/*drug effects ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins/*metabolism ; Pyridines/pharmacology ; }, abstract = {Toluene, benzene and styrene are volatile organic compounds (VOCs) widely distributed in the environment. Tobacco smoke, traffic exposure and solvents used for paints, rubber and adhesives are known sources for these compounds. The aim of the present study was to investigate whether toluene, benzene and styrene can induce inflammatory reactions in lung cells and to characterize possible underlying mechanisms. A previous study gave evidence that expression of cyclooxygenase-2 (COX-2) is upregulated following exposure to the aromatic VOC chlorobenzene. Here, we investigated the effects of the aromatics toluene, benzene and styrene on human lung cells, with emphasis on COX-2, the rate-limiting enzyme of the prostaglandin pathway. In addition, we studied the potential role of oxidative stress and p38 MAPK activation in the toluene/benzene/styrene-dependent COX-2 induction. Following exposure to the aromatic compounds the expression level of COX-2 increased markedly. In addition, prostaglandin E(2) (PGE(2)) and prostaglandin F(2α) (PGF(2α)), major products of the COX enzyme, were found to be upregulated in response to toluene, benzene or styrene exposure. Furthermore, we observed an activation of p38 MAPK resulting from aromatic VOC exposure. Treatment of the cells with a specific p38 inhibitor (SB203580) or the antioxidant N-acetylcysteine (NAC) was able to prevent the toluene/benzene/styrene-dependent COX-2 activation, and subsequent increased PGE(2) and PGF(2α) secretion. These results suggest that toluene, benzene and styrene induce production and secretion of PGE(2) and PGF(2α) in lung epithelial cells via p38 MAPK and COX-2 activation in a redox sensitive manner.}, }
@article {pmid21799126, year = {2011}, author = {Makena, PS and Gorantla, VK and Ghosh, MC and Bezawada, L and Balazs, L and Luellen, C and Parthasarathi, K and Waters, CM and Sinclair, SE}, title = {Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent on oxidant-mediated c-Jun NH2-terminal kinase activation.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {111}, number = {5}, pages = {1467-1476}, pmid = {21799126}, issn = {1522-1601}, support = {HL-094366/HL/NHLBI NIH HHS/United States ; R01 HL075503/HL/NHLBI NIH HHS/United States ; HL-75503/HL/NHLBI NIH HHS/United States ; R01 HL075503-08/HL/NHLBI NIH HHS/United States ; R01 HL094366/HL/NHLBI NIH HHS/United States ; HL-081297/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase Inhibitors ; Cell Line ; Cytochromes c/antagonists &amp; inhibitors/metabolism ; Epithelial Cells/metabolism ; Hyperoxia/*enzymology/etiology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Lung Injury/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; Oxidants/*metabolism ; Oxidative Stress/drug effects ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; Respiration, Artificial/adverse effects/methods ; Tidal Volume ; }, abstract = {Both prolonged exposure to hyperoxia and large tidal volume mechanical ventilation can each independently cause lung injury. However, the combined impact of these insults is poorly understood. We recently reported that preexposure to hyperoxia for 12 h, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone (Makena et al. Am J Physiol Lung Cell Mol Physiol 299: L711-L719, 2010). The upstream mechanisms of this lung injury and apoptosis have not been clearly elucidated. We hypothesized that lung injury in this model was dependent on oxidative signaling via the c-Jun NH(2)-terminal kinases (JNK). We, therefore, evaluated lung injury and apoptosis in the presence of N-acetyl-cysteine (NAC) in both mouse and cell culture models, and we provide evidence that NAC significantly inhibited lung injury and apoptosis by reducing the production of ROS, activation of JNK, and apoptosis. To confirm JNK involvement in apoptosis, cells treated with a specific JNK inhibitor, SP600125, and subjected to preexposure to hyperoxia, followed by mechanical stretch, exhibited significantly reduced evidence of apoptosis. In conclusion, lung injury and apoptosis caused by preexposure to hyperoxia, followed by high tidal volume mechanical ventilation, induces ROS-mediated activation of JNK and mitochondrial-mediated apoptosis. NAC protects lung injury and apoptosis by inhibiting ROS-mediated activation of JNK and downstream proapoptotic signaling.}, }
@article {pmid21796654, year = {2012}, author = {Fajardo, AM and MacKenzie, DA and Ji, M and Deck, LM and Vander Jagt, DL and Thompson, TA and Bisoffi, M}, title = {The curcumin analog ca27 down-regulates androgen receptor through an oxidative stress mediated mechanism in human prostate cancer cells.}, journal = {The Prostate}, volume = {72}, number = {6}, pages = {612-625}, pmid = {21796654}, issn = {1097-0045}, support = {P20 RR016480-10/RR/NCRR NIH HHS/United States ; R03 CA133941/CA/NCI NIH HHS/United States ; 1 R03 CA133941/CA/NCI NIH HHS/United States ; RR0164880/RR/NCRR NIH HHS/United States ; P20 RR016480-11/RR/NCRR NIH HHS/United States ; R03 CA136030-01/CA/NCI NIH HHS/United States ; R03 CA136030-02/CA/NCI NIH HHS/United States ; P20 RR016480/RR/NCRR NIH HHS/United States ; P30CA118110/CA/NCI NIH HHS/United States ; }, mesh = {Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Curcumin/*analogs &amp; derivatives/pharmacology ; Down-Regulation/*drug effects ; Humans ; Male ; Oxidative Stress/*drug effects/physiology ; Prostatic Neoplasms/*metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Androgen/genetics/*metabolism ; Signal Transduction/drug effects/genetics ; }, abstract = {BACKGROUND: The androgen receptor (AR) plays a critical role in prostate cancer development and progression. Therefore, the inhibition of AR function is an established therapeutic intervention. Since the expression of the AR is retained and often increased in progressive disease, AR protein down-regulation is a promising therapeutic approach against prostate cancer. We show here that the curcumin analog 27 (ca27) down-regulates AR expression in several prostate cancer cell lines.<br><br>METHODS: ca27 at low micromolar concentrations was tested for its effect on AR expression, AR activation, and induction of oxidative stress in human LNCaP, C4-2, and LAPC-4 prostate cancer cells.<br><br>RESULTS: ca27 induced the down-regulation of AR protein expression in LNCaP, C4-2, and LAPC-4 cells within 12&#x2009;hr. Further, ca27 led to the rapid induction of reactive oxygen species (ROS). To further support this finding, ca27 treatment led to the activation of the cellular redox sensor NF-E2-related factor 2 (Nrf2) and the induction of the Nrf2-regulated genes NAD(P)H quinone oxidoreductase 1 and aldoketoreductase 1C1. We show that ROS production preceded AR protein loss and that ca27-mediated down-regulation of the AR was attenuated by the antioxidant, N-acetyl cysteine.<br><br>CONCLUSIONS: ca27 induces ROS and mediates AR protein down-regulation through an oxidative stress mechanism of action. Our results suggest that ca27 represents a novel agent for the elucidation of mechanisms of AR down-regulation, which could lead to effective new anti-androgenic strategies for the treatment of advanced prostate cancer.}, }
@article {pmid21796648, year = {2012}, author = {He, SJ and Hou, JF and Dai, YY and Zhou, ZL and Deng, YF}, title = {N-acetyl-cysteine protects chicken growth plate chondrocytes from T-2 toxin-induced oxidative stress.}, journal = {Journal of applied toxicology : JAT}, volume = {32}, number = {12}, pages = {980-985}, doi = {10.1002/jat.1697}, pmid = {21796648}, issn = {1099-1263}, mesh = {Acetylcysteine/*pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Antioxidants/*pharmacology ; Catalase/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Chickens ; Chondrocytes/*drug effects/metabolism/pathology ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Growth Plate/*drug effects/metabolism/pathology ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; T-2 Toxin/*toxicity ; Tibia/drug effects/metabolism/pathology ; }, abstract = {T-2 toxin is now considered to be related to bone malformation such as incomplete ossification, absence of bones and fused bones. In this study, primary cultures of chicken tibial growth plate chondrocytes (GPCs) were treated with various concentrations of T-2 toxin (5, 50, and 500 n m) in the absence and presence of N-acetyl-cysteine (NAC) to investigate the effects of the antioxidant NAC on T-2 toxin-induced toxicity. Our results showed that T-2 toxin markedly decreased cell viability, alkaline phosphatase activity and glutathione content (P < 0.05). In addition, T-2 toxin significantly increased reactive oxygen species levels and malondialdehyde in a dose-dependent manner. However, the T-2 toxin-induced cytotoxicity was reversed, in part, by the antioxidant NAC (P < 0.05). These results suggest that T-2 toxin inhibits the proliferation and differentiation of GPCs in vitro by altering cellular homeostasis and NAC can protect GPCs against T-2 toxin cytotoxicity by reducing the T-2 toxin-induced oxidative stress.}, }
@article {pmid21796404, year = {2011}, author = {Haleagrahara, N and Julian, V and Chakravarthi, S}, title = {N-acetylcysteine offers cardioprotection by decreasing cardiac lipid hydroperoxides and 8-isoprostane level in isoproterenol-induced cardiotoxicity in rats.}, journal = {Cardiovascular toxicology}, volume = {11}, number = {4}, pages = {373-381}, doi = {10.1007/s12012-011-9132-0}, pmid = {21796404}, issn = {1559-0259}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Body Weight/drug effects ; Cardiotonic Agents/*toxicity ; Creatine Kinase, MB Form/metabolism ; Dinoprost/analogs &amp; derivatives/metabolism ; Drug Therapy, Combination ; Edema/chemically induced/pathology ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Heart/*drug effects ; Isoproterenol/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; Male ; Myocardium/metabolism/pathology ; Necrosis ; Organ Size/drug effects ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; }, abstract = {This study investigated the cardioprotective effect of N-acetylcysteine (NAC) on isoproterenol (ISO)-induced cardiotoxicity in rats. Male Sprague-Dawley rats were divided into control, NAC alone (100 mg/kg BW orally for 14 days), ISO-control (85 mg/kg BW), and ISO with NAC (for 14 days). Serum creatine kinase-MB and Lactate dehydrogenase were measured. From the heart homogenate lipid hydroperoxides (LPO), superoxide dismutase (SOD), total glutathione (GSH), and 8-isoprostane (IP) were measured. Histopathological examination of the heart was also carried out. There was a significant increase (P < 0.05) in LPO and IP levels in ISO-control group and NAC treatment reduced these changes. Antioxidant enzyme, SOD and GSH, level decreased significantly (P < 0.05) in ISO-control group, and treatment with NAC was able to reverse these changes significantly (P < 0.05). Histopathologically, ISO-control group showed morphological changes suggestive of cardiotoxicity with large areas of coagulative necrosis, with diffused interstitial edema. NAC treatment successfully reduced these histopathological changes. In conclusion, the study proves that NAC has a strong cardioprotective effect against isoproterenol-induced cardiac changes. NAC decreases isoproterenol-induced LPO and IP levels in the heart tissue and prevented free radicals-induced damage to the myocardium.}, }
@article {pmid21793058, year = {2011}, author = {Milanesi, L and Hunter, CA and Tzokova, N and Waltho, JP and Tomas, S}, title = {Versatile low-molecular-weight hydrogelators: achieving multiresponsiveness through a modular design.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {17}, number = {35}, pages = {9753-9761}, doi = {10.1002/chem.201100640}, pmid = {21793058}, issn = {1521-3765}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/*chemistry ; Delayed-Action Preparations/*chemistry ; Disulfides/*chemistry ; Drug Carriers/chemical synthesis/*chemistry/metabolism ; Drug Delivery Systems ; Hydrogels/chemical synthesis/*chemistry ; Hydrogen-Ion Concentration ; Hydrophobic and Hydrophilic Interactions ; Maleimides/chemical synthesis/*chemistry ; Molecular Structure ; Molecular Weight ; Nanotechnology ; Polymers/chemical synthesis/*chemistry ; Temperature ; Water/chemistry ; }, abstract = {Multiresponsive low-molecular-weight hydrogelators (LMWHs) are ideal candidates for the development of smart, soft, nanotechnology materials. The synthesis is however very challenging. On the one hand, de novo design is hampered by our limited ability to predict the assembly of small molecules in water. On the other hand, modification of pre-existing LMWHs is limited by the number of different stimuli-sensitive chemical moieties that can be introduced into a small molecule without seriously disrupting the ability to gelate water. Herein we report the synthesis and characterization of multistimuli LMWHs, based on a modular design, composed of a hydrophobic, disulfide, aromatic moiety, a maleimide linker, and a hydrophilic section based on an amino acid, here N-acetyl-L-cysteine (NAC). As most LMWHs, these gelators experience reversible gel-to-sol transition following temperature changes. Additionally, the NAC moiety allows reversible control of the assembly of the gel by pH changes. The reduction of the aromatic disulfide triggers a gel-to-sol transition that, depending on the design of the particular LMWH, can be reverted by reoxidation of the resulting thiol. Finally, the hydrolysis of the cyclic imide moieties provides an additional trigger for the gel-to-sol transition with a timescale that is appropriate for use in drug-delivery applications. The efficient response to the multiple external stimuli, coupled to the modular design makes these LMWHs an excellent starting point for the development of smart nanomaterials with applications that include controlled drug release. These hydrogelators, which were discovered by serendipity rather than design, suggest nonetheless a general strategy for the introduction of multiple stimuli-sensitive chemical moieties, to offset the introduction of hydrophilic moieties with additional hydrophobic ones, in order to minimize the upsetting of the critical hydrophobic-hydrophilic balance of the LMWH.}, }
@article {pmid21791198, year = {2011}, author = {Sungkaworn, T and Lenbury, Y and Chatsudthipong, V}, title = {Oxidative stress increases angiotensin receptor type I responsiveness by increasing receptor degree of aggregation using image correlation spectroscopy.}, journal = {Biochimica et biophysica acta}, volume = {1808}, number = {10}, pages = {2496-2500}, doi = {10.1016/j.bbamem.2011.07.007}, pmid = {21791198}, issn = {0006-3002}, mesh = {Cell Line ; Humans ; *Oxidative Stress ; Receptor, Angiotensin, Type 1/*physiology ; Spectrum Analysis/*methods ; }, abstract = {Oxidative stress and hyper-functioning of angiotensin II receptor type I (AT(1)R) are commonly observed in hypertensive patients but the relationship between oxidative stress and AT(1)R function is still unclear. We investigated the effects of H(2)O(2) treatment on AT(1)R-mediated intracellular calcium [Ca(2+)](i) signaling and its cell surface distribution pattern in HEK cells stably expressing EGFP-tagged rat AT(1)R using image correlation spectroscopy (ICS). Following H(2)O(2) treatment (50-800μM), [Ca(2+)](i) was significantly increased upon angiotensin II stimulation. Similarly ICS revealed a significant increase in degree of AT(1)R aggregation in H(2)O(2) treated group during Ang II activation but no difference in cluster density compared with untreated control cells or those with N-acetyl cysteine pretreatment. Thus, oxidative stress-induced AT(1)R hyper-responsiveness can be attributed by an increase in cell surface receptor aggregation state, possibly stemming in part from oxidant-related increase receptor-receptor interactions.}, }
@article {pmid21790669, year = {2011}, author = {Setshedi, M and Longato, L and Petersen, DR and Ronis, M and Chen, WC and Wands, JR and de la Monte, SM}, title = {Limited therapeutic effect of N-acetylcysteine on hepatic insulin resistance in an experimental model of alcohol-induced steatohepatitis.}, journal = {Alcoholism, clinical and experimental research}, volume = {35}, number = {12}, pages = {2139-2151}, pmid = {21790669}, issn = {1530-0277}, support = {AA-12908/AA/NIAAA NIH HHS/United States ; R37 AA011431/AA/NIAAA NIH HHS/United States ; AA-11431/AA/NIAAA NIH HHS/United States ; R01 AA012908/AA/NIAAA NIH HHS/United States ; R56 AA011431/AA/NIAAA NIH HHS/United States ; R01 AA011431/AA/NIAAA NIH HHS/United States ; K24 AA016126/AA/NIAAA NIH HHS/United States ; K24-AA-16126/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Alcoholism/*drug therapy/metabolism/pathology ; Animals ; Cytokines/metabolism ; Disease Models, Animal ; Fatty Liver, Alcoholic/*drug therapy/metabolism/pathology ; *Insulin Resistance ; Male ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Alcohol-related steatohepatitis is associated with increased oxidative stress, DNA damage, lipotoxicity, and insulin resistance in liver. As inflammation and oxidative stress can promote insulin resistance, effective treatment with antioxidants, for example, N-acetylcysteine (NAC), may restore ethanol-impaired insulin signaling in the liver.<br><br>METHODS: Adult male Sprague-Dawley rats were fed for 130 days with liquid diets containing 0 or 37% ethanol by caloric content, and simultaneously treated with vehicle or NAC. Chow-fed controls were studied in parallel. Liver tissues were used for histopathology, cytokine activation, and insulin/IGF-1 signaling assays.<br><br>RESULTS: We observed significant positive trends of increasing severity of steatohepatitis (p = 0.016) with accumulation of neutral lipid (p = 0.0002) and triglycerides (p = 0.0004) from chow to control, to the ethanol diet, irrespective of NAC treatment. In ethanol-fed rats, NAC reduced inflammation, converted the steatosis from a predominantly microvesicular to a mainly macrovesicular histological pattern, reduced pro-inflammatory cytokine gene expression, ceramide load, and acid sphingomyelinase activity, and increased expression of IGF-1 receptor and IGF-2 in liver. However, NAC did not abrogate ethanol-mediated impairments in signaling through insulin/IGF-1 receptors, IRS-1, Akt, GSK-3&#x3b2;, or p70S6K, nor did it significantly reduce pro-ceramide or GM3 ganglioside gene expression in liver.<br><br>CONCLUSIONS: Antioxidant treatments reduce the severity of chronic alcohol-related steatohepatitis, possibly because of the decreased expression of inflammatory mediators and ceramide accumulation, but they do not restore insulin/IGF-1 signaling in liver, most likely due to persistent elevation of GM3 synthase expression. Effective treatment of alcohol-related steatohepatitis most likely requires dual targeting of oxidative stress and insulin/IGF resistance.}, }
@article {pmid21787718, year = {2011}, author = {Lee, YJ and Lee, GJ and Baek, BJ and Heo, SH and Won, SY and Im, JH and Cho, MK and Nam, HS and Lee, SH}, title = {Cadmium-induced up-regulation of aldo-keto reductase 1C3 expression in human nasal septum carcinoma RPMI-2650 cells: Involvement of reactive oxygen species and phosphatidylinositol 3-kinase/Akt.}, journal = {Environmental toxicology and pharmacology}, volume = {31}, number = {3}, pages = {469-478}, doi = {10.1016/j.etap.2011.03.006}, pmid = {21787718}, issn = {1872-7077}, mesh = {Acetylcysteine/pharmacology ; Alcohol Oxidoreductases/*biosynthesis ; Aldehyde Reductase ; Aldo-Keto Reductases ; Antioxidants/pharmacology ; Blotting, Western ; Cadmium/*toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Indicators and Reagents ; NF-E2-Related Factor 2/biosynthesis/genetics ; Oncogene Protein v-akt/*physiology ; Phosphatidylinositol 3-Kinases/*physiology ; RNA, Messenger/biosynthesis/genetics ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Up-Regulation/drug effects ; }, abstract = {Cadmium is a well-known toxic metal and occupational exposure to it is associated with lung cancer. In probing the possible non-genotoxic molecular targets of cadmium-induced nasal toxicity, we performed an mRNA differential display analysis for cadmium-treated human nasal septum carcinoma RPMI-2650 cells. Cadmium (≥ 0.5 μM) inhibited the cell proliferation. The intracellular ROS levels were induced by cadmium treatment. In addition, cadmium elicited the AKR1C3 expression. The cadmium-induced increase in AKR1C3 protein levels was suppressed by N-acetylcysteine (NAC) and, to a lesser extent, PI3K inhibitor (Ly294002). Cells pretreated with Ly294002 were more resistant to cadmium toxicity than control. The increase in AKR1C3 protein level was accompanied by an increase in the nuclear transcription factor Nrf2. Overall, our data suggest that cadmium-induced ROS cause up-regulation of AKR1C3 expression, at least partially via the activation of PI3K-related intracellular signaling pathways, and Nrf2 activation, thereby contributing to an adaptive intracellular response to cadmium toxicity.}, }
@article {pmid21786683, year = {2011}, author = {Filatova, NA and Kirpichnikova, KM and Aksenov, ND and Vakhromova, EA and Gamaleĭ, IA}, title = {[Decrease in tumorigenic activity of murine hepatoma cells after treatment with antioxidants and melatonin].}, journal = {Tsitologiia}, volume = {53}, number = {5}, pages = {404-410}, pmid = {21786683}, issn = {0041-3771}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Carcinoma, Hepatocellular/*drug therapy/pathology/prevention &amp; control ; Cell Cycle/drug effects ; Flow Cytometry ; Humans ; Injections, Subcutaneous ; Liver Neoplasms/*drug therapy/pathology/prevention &amp; control ; Melatonin/*pharmacology/therapeutic use ; Mice ; Mice, Inbred C3H ; Thioctic Acid/pharmacology/therapeutic use ; Transplantation, Isogeneic ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; }, abstract = {We studied the effect of antioxidants such as N-acetylcysteine (NAC, 10 mM) and alpha-lipoic acid (ALA, 1.25 mM) and of the hormone melatonin (1 microM) on the ability of murine hepatoma cells MH22a to develop tumors in syngenic mice (C3HA) after subsutaneous injection. Tumor formation and development slowed down and mouse mortality decreased when the injected cells were pretreated by NAC, ALA or melatonin during 20 h. Melatonin had the most marked effect. Tumors appeared in 100 % cases after 10 days in control mice when untreated cells had been injected; injection of cells pretreated by NAC or ALA resulted in tumor formation only in 40 and 53 % of mice, respectively. When cells were pretreated with melatonin the tumors appeared only in 18-20 days after injection. Until the end of the observation (36 days) 67 % of control mice died, but when the cells were pretreated by NAC or ALA mouse death-rate was 20 and 53 %, respectively. In the case of melatonin we did not observed any dead mice at all. We showed that treatment by antioxidants delayed (NAC) or completely inhibited (ALA) cell cycle of hepatoma cells. Cell cycle was restored after removal of the antioxidants. Melatonin did not change cell cycle phase distribution. We conclude that there is no direct correlation between loss of tumorigenic properties and changing of proliferative activity of hepatoma cells. Different mechanisms of antioxidants and melatonin action resulting in transient tumor phenotype normalization are discussed.}, }
@article {pmid21786382, year = {2013}, author = {Xu, Z and Xu, B and Xia, T and He, W and Gao, P and Guo, L and Wang, Z and Niu, Q and Wang, A}, title = {Relationship between intracellular Ca[2+] and ROS during fluoride-induced injury in SH-SY5Y cells.}, journal = {Environmental toxicology}, volume = {28}, number = {6}, pages = {307-312}, doi = {10.1002/tox.20721}, pmid = {21786382}, issn = {1522-7278}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Calcium/*metabolism ; Cell Line, Tumor ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Humans ; Intracellular Space/metabolism ; L-Lactate Dehydrogenase/metabolism ; Reactive Oxygen Species/*metabolism ; Sodium Fluoride/*toxicity ; }, abstract = {The mechanisms underlying the neurotoxicology of endemic fluorosis still remain obscure. To explore lactate dehydrogenase (LDH) leakage, intracellular Ca[2+] concentration ([Ca[2+]]i) and reactive oxygen species (ROS) production induced by fluoride, human neuroblastoma (SH-SY5Y) cells were incubated with sodium fluoride (NaF, 20, 40, 80 mg/L) for 24 h, with 40 mg/L NaF for 3, 6, 12, 18, 24 h, and N-acetyl-L-cysteine (NAC), ethyleneglycol-bis-(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA-AM) alone or combined with fluoride (40 mg/L) respectively for 12 h in vitro. The results showed that the LDH levels in the 40 and 80 mg/L fluoride-treated groups were significantly higher than that of the control group (in the test level of 0.05, the difference were statistical significance). [Ca[2+]]i and ROS reached a peak at 3 h and 12 h respectively after exposure to 40 mg/L fluoride. Fluoride coincubated with NAC (antioxidant) dramatically decreased ROS and LDH levels compared with the fluoride only group (in the test level of 0.05, the difference were statistical significance). However, fluoride-induced increase in [Ca[2+]]i was not affected by NAC. BAPTA-AM (intracellular calcium chelator) markedly lowered fluoride-induced increase of [Ca[2+]]i , ROS and LDH levels while EGTA (extracellular calcium chelator) have no effects on them. These results indicate that fluoride-related Ca[2+] release from the site of intracellular calcium storage causes the elevation of ROS contributing to the cytotoxicity in SH-SY5Y cells.}, }
@article {pmid21786300, year = {2011}, author = {López-Erauskin, J and Fourcade, S and Galino, J and Ruiz, M and Schlüter, A and Naudi, A and Jove, M and Portero-Otin, M and Pamplona, R and Ferrer, I and Pujol, A}, title = {Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy.}, journal = {Annals of neurology}, volume = {70}, number = {1}, pages = {84-92}, pmid = {21786300}, issn = {1531-8249}, mesh = {Adrenoleukodystrophy/drug therapy/*metabolism/pathology ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Axons/drug effects/*metabolism/pathology ; Cells, Cultured ; *Disease Models, Animal ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nerve Degeneration/drug therapy/*metabolism/pathology ; Oxidative Stress/drug effects/physiology ; Random Allocation ; }, abstract = {OBJECTIVE: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD).<br><br>METHODS: X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD.<br><br>RESULTS: Here, we prove the capability of the antioxidants N-acetyl-cysteine, &#x3b1;-lipoic acid, and &#x3b1;-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests.<br><br>INTERPRETATION: We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor.}, }
@article {pmid21784541, year = {2012}, author = {Wong, PC and Li, Z and Guo, J and Zhang, A}, title = {Pathophysiology of contrast-induced nephropathy.}, journal = {International journal of cardiology}, volume = {158}, number = {2}, pages = {186-192}, doi = {10.1016/j.ijcard.2011.06.115}, pmid = {21784541}, issn = {1874-1754}, mesh = {Animals ; Contrast Media/*adverse effects/metabolism ; Humans ; Kidney Diseases/*chemically induced/metabolism/*physiopathology ; Kidney Medulla/blood supply/metabolism/physiopathology ; Renal Circulation/drug effects/physiology ; }, abstract = {Contrast media induce various factors that may increase vasoconstriction and decrease vasodilatation in the renal medulla, leading to hypoxia and acute tubular necrosis known as contrast-induced nephropathy (CIN) that tends to occur in diabetics and patients with preexisting renal insufficiency. Contrast media inhibit mitochondrial enzyme activities and subsequently increase adenosine through hydrolysis of ATP. Both catabolism of adenosine and medullary hypoxia generate reactive oxygen species (ROS) that scavenge nitric oxide (NO). Released along with endothelin and prostaglandin from endothelial cells exposed to contrast media, adenosine activates the A1 receptor that mainly constricts afferent arteriole at the glomerulus but not the medullary vasculature. Adenosine also activates the A2 receptor that increases NO production, leading to medullary vasodilatation which is induced by activation of endothelin-B receptor and G-protein coupled E-prostanoid receptor 2, and 4 of prostaglandin PGE2 respectively as well. Conversely medullary vasoconstriction is mediated by activating endothelin-A receptor and G-protein coupled E-prostanoid receptor 1, and 3 of prostaglandin PGE2 respectively. The osmotic load of contrast media increases interstitial pressure and sodium transport and thus oxygen consumption. Risking hypoxia, increased medullary oxygen consumption may also result from stimulating Na(+)-K(+)-ATPase activity by endothelin-A receptor. N-acetylcysteine (NAC) scavenges ROS and therefore preserves NO that not only dilates medullary vasculature but also reduces sodium reabsorption and oxygen consumption, tipping the balance against medullary vasoconstriction, hypoxia, and thus CIN. While prostacyclin and its analog, iloprost, prevent CIN by inducing medullary vasodilatation, atrial natriuretic peptide (ANP) may do so by inhibiting renin secretion.}, }
@article {pmid21778718, year = {2011}, author = {Lyle, PA and Mitsopoulos, P and Suntres, ZE}, title = {N-acetylcysteine modulates the cytotoxic effects of Paclitaxel.}, journal = {Chemotherapy}, volume = {57}, number = {4}, pages = {298-304}, doi = {10.1159/000329510}, pmid = {21778718}, issn = {1421-9794}, mesh = {Acetylcysteine/*pharmacology ; Adenocarcinoma/drug therapy/pathology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Caspase 10/metabolism ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Interactions ; Humans ; Paclitaxel/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Paclitaxel is a microtubule-stabilizing drug known to cause mitotic G2/M arrest and apoptosis. It also increases the generation of reactive oxygen species (ROS) known to be involved in both apoptotic and necrotic cell death. Antioxidants, such as N-acetylcysteine (NAC), prevent the deleterious effects of ROS and modulate the regulation of apoptotic-linked cellular proteins.<br><br>METHODS: A549 human adenocarcinoma alveolar epithelial cells were treated with 5.0 mM NAC, 1.0 &#x3bc;M paclitaxel, or co-incubated with both NAC and paclitaxel for a 24-hour incubation period. The effects of NAC in paclitaxel-induced cytotoxicity were evaluated by measuring cell viability, production of ROS, and apoptosis.<br><br>RESULTS: Challenge of cells with paclitaxel resulted in time/concentration-dependent decreases in cell viability and increases in intracellular levels of ROS, and apoptosis, all effects being abrogated by co-treatment with NAC. NAC reduced the paclitaxel-induced increase in activated caspase-10 levels, but potentiated that for caspase-3.<br><br>CONCLUSIONS: NAC alters the cytotoxicity of paclitaxel in vitro by decreasing the levels of ROS, preventing apoptosis, and modulating apoptotic cellular proteins.}, }
@article {pmid21778551, year = {2011}, author = {Abdullaev, FA}, title = {[The effect of N-acetylcysteine on hepatic function in patients suffering from mechanical jaundice of cholelithic etiology].}, journal = {Georgian medical news}, volume = {}, number = {195}, pages = {92-95}, pmid = {21778551}, issn = {1512-0112}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Disease Models, Animal ; Jaundice, Obstructive/blood/*physiopathology ; Liver/*drug effects/*physiopathology ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/*blood ; }, abstract = {The effect of N- acetylcysteine on the level of tumor necrosis factor-a (TNF-α) and liver parenchyma injury in an experimental rat model of obstructive jaundice were investigated. Thirty-six Wistar-Albino rats weighing 250- 300 g were randomly divided into three groups of 12 animals in each, as sham-operated, bile duct ligated plus N- acetylcysteine (treatment), bile duct ligated plus saline administered (control). After the operation, the rats in treatment and control groups were administered NAC and saline, respectively. After 10 days of treatment, liver function tests were performed and plasma TNF-a levels were determined in all rats to assess the parenchymal damage. Parenchymal damage and plasma TNF-α level were significantly lower in the treatment group, compared with the control group. N-Acetylcysteine can be useful in decreasing the parenchymal damage in the liver and suppress the plasma TNF-α level in experimental obstructive jaundice.}, }
@article {pmid21775771, year = {2011}, author = {Thompson, LP and Liu, H and Evans, L and Mong, JA}, title = {Prenatal nicotine increases matrix metalloproteinase 2 (MMP-2) expression in fetal guinea pig hearts.}, journal = {Reproductive sciences (Thousand Oaks, Calif.)}, volume = {18}, number = {11}, pages = {1103-1110}, pmid = {21775771}, issn = {1933-7205}, support = {R01 HL49999/HL/NHLBI NIH HHS/United States ; R01 HL85037/HL/NHLBI NIH HHS/United States ; R01 HL049999/HL/NHLBI NIH HHS/United States ; F31 HL090044/HL/NHLBI NIH HHS/United States ; R01 HL085037/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Collagen/analysis ; Female ; Fetal Heart/*drug effects/*enzymology ; Guinea Pigs ; Immunohistochemistry ; *Maternal-Fetal Exchange ; Matrix Metalloproteinase 2/*analysis ; Nicotine/administration &amp; dosage/*toxicity ; Pregnancy ; }, abstract = {This study tested the hypothesis that maternal nicotine ingestion increases matrix metalloproteinase (MMP) expression in fetal hearts, which is mediated by the generation of reactive oxygen species. Timed pregnant guinea pigs were administered either water alone, nicotine (200 μg/mL), N-acetylcysteine (NAC), or nicotine plus NAC in their drinking water for 10 days at 52-day gestation (term = 65 days). Near-term (62 days), anesthetized fetuses were extracted, hearts were excised, and left cardiac ventricles snap frozen for analysis of MMP-2/-9/-13 protein and activity levels. Interstitial collagens were identified by Picrosirius red stain to assess changes in the extracellular matrix. Prenatal nicotine increased active MMP-2 forms and interstitial collagen but had no effect on either pro- or active MMP-9 or MMP-13 forms. In the presence of nicotine, NAC decreased active MMP-2 protein levels and reversed the nicotine-induced increase in collagen staining. We conclude that prenatal nicotine alters MMP-2 expression in fetal hearts that may be mediated by reactive oxygen species generation.}, }
@article {pmid21775089, year = {2011}, author = {Ji, H and Liu, Y and Zhao, X and Zhang, M}, title = {N-acetyl-L-cysteine enhances the osteogenic differentiation and inhibits the adipogenic differentiation through up regulation of Wnt 5a and down regulation of PPARG in bone marrow stromal cells.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {65}, number = {5}, pages = {369-374}, doi = {10.1016/j.biopha.2011.04.020}, pmid = {21775089}, issn = {1950-6007}, mesh = {Acetylcysteine/*pharmacology ; Adipogenesis/*drug effects/genetics ; Alkaline Phosphatase/metabolism ; Animals ; Bone Marrow Cells/drug effects/metabolism ; Cell Differentiation/*drug effects/genetics ; Cell Proliferation/drug effects ; Collagen/genetics/metabolism ; Down-Regulation/drug effects ; Fatty Acid-Binding Proteins/genetics/metabolism ; Lipid Metabolism/genetics ; Lipoprotein Lipase/genetics/metabolism ; Osteogenesis/*drug effects/genetics ; Osteopontin/genetics/metabolism ; PPAR gamma/*genetics/metabolism ; Rabbits ; Stromal Cells/drug effects/metabolism ; Up-Regulation/drug effects ; Wnt Proteins/biosynthesis/*genetics/metabolism ; }, abstract = {Nowadays, the treatment of osteoporosis is still a great challenge in the medical field. The combination of enhancement of osteogenesis and the inhibition of adipogenesis of bone marrow stromal cells (BMSCs) is considered an efficient therapeutic strategy for the treatment of osteoporosis. In the present study, we investigated the effects of N-acetyl-L-cysteine (NAC) on the proliferation, osteogenesis and adipogenesis of BMSCs. NAC treatment enhanced the alkaline phosphatase activity, mineral deposition and mRNA expression levels of osteogenesis markers collagen I, osteopontin, and signal pathway related protein Wingless-type family member 5a in addition to Wingless-type family member 3a during osteogenic induction, and inhibited the accumulation of lipid droplets and the expression levels of lipoprotein lipase, fatty acid binding protein 4 and peroxisome proliferator-activated receptor gamma mRNA during adipogenic induction. Meanwhile, NAC had the same effects as enhancing mineral deposition in regular culture condition. In addition, cell proliferation was also promoted by NAC treatment in regular culture condition. These results suggested that NAC may enhance osteogenic differentiation and inhibit adipogenic differentiation of BMSCs, which is at least partially mediated by up regulating Wnt 5a and down regulating PPARG. Taking into account the extensive protective effects of NAC and that the maintenance of BMSCs number is an important factor in osteoporosis prevention and treatment, these observations suggested that NAC is a promising potential drug for the prevention and treatment of osteoporosis and its associated diseases.}, }
@article {pmid21770721, year = {2011}, author = {Ribeiro, G and Roehrs, M and Bairros, A and Moro, A and Charão, M and Araújo, F and Valentini, J and Arbo, M and Brucker, N and Moresco, R and Leal, M and Morsch, V and Garcia, SC}, title = {N-acetylcysteine on oxidative damage in diabetic rats.}, journal = {Drug and chemical toxicology}, volume = {34}, number = {4}, pages = {467-474}, doi = {10.3109/01480545.2011.564179}, pmid = {21770721}, issn = {1525-6014}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Alloxan/pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Biomarkers/analysis/blood ; Diabetes Mellitus, Experimental/*drug therapy/metabolism ; Injections, Intraperitoneal ; Kidney/drug effects/enzymology/metabolism ; Lipid Peroxidation/drug effects ; Liver/drug effects/enzymology/metabolism ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {N-acetylcysteine (NAC) is a potent mucolitic agent and also an antioxidant. Its antioxidant action is due to its ability to stimulate reduced glutathione (GSH) synthesis, therefore maintaining intracellular levels. The aim of this study was to evaluate the effects of NAC administered intraperitoneally (i.p.) in a decreasing of oxidative tissue damage in the liver and kidney of alloxan-induced diabetic rats, especially on thiolic groups (nonproteic and proteic groups). Adult male Wistar rats (200-350 g) were used; diabetes was induced accordingly by a single i.p. injection of alloxan monohydrate, and the control group received a similar volume of the vehicle. Lipid peroxidation (LPO) biomarker (malondialdehyde; MDA), δ-ALA-D activity, GSH, superoxide dismutase (SOD), and glutathione peroxidase (GPx) were quantified to assess the oxidative stress. All tests were performed in tissue homogenates. Creatinine, urea, aspartate transaminase, and alanine transaminase were determined by commercial kits, using serum samples. A significant decrease in LPO (i.e., hepatic and renal) and an increase in δ-aminolevulinate dehydratase activity, especially in the renal tissue, were observed. Also, NAC at 75 mg/kg showed more effective restoration of oxidative stress biomarkers than NAC at 25 mg/kg. Our findings suggest that NAC can be used as an antioxidant agent in diabetes, exhibiting modulatory action on the oxidative stress biomarkers analyzed in this work. Moreover, these findings can contribute to others' research, regarding the utilization of NAC to ALA-D activity restoration in the kidneys.}, }
@article {pmid21768733, year = {2011}, author = {Bielefeld, EC and Wantuck, R and Henderson, D}, title = {Postexposure treatment with a Src-PTK inhibitor in combination with N-l-acetyl cysteine to reduce noise-induced hearing loss.}, journal = {Noise &amp; health}, volume = {13}, number = {53}, pages = {292-298}, doi = {10.4103/1463-1741.82962}, pmid = {21768733}, issn = {1463-1741}, support = {1R01OH008113-01A1/OH/NIOSH CDC HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Chinchilla ; Drug Evaluation ; Drug Therapy, Combination ; Hearing Loss, Noise-Induced/*drug therapy/prevention &amp; control ; Noise/adverse effects ; Protein Kinase Inhibitors/*pharmacology ; src-Family Kinases/pharmacology ; }, abstract = {Both the antioxidant, N-l-acetyl cysteine (NAC), and the Src inhibitor, KX1-004, have been used to protect the cochlea from hazardous noise. In order to extend our previous work on KX1-004 with noise exposure, the current studies were undertaken with two goals: (1) to test the effectiveness of NAC and KX1-004 in combination with one another when given in a protection paradigm, and (2) to test the NAC+KX1-004 combination in a postexposure rescue paradigm. The noise exposure for the first experiment consisted of a 4-kHz octave band of noise at 107 dB SPL for 2 hours. The combination of NAC and KX1-004 were administered either prior to the noise exposure or post exposure (rescue). The second experiment was undertaken to extend the findings of the first experiment's rescue paradigm. The 4 kHz octave band noise was delivered at 112 dB SPL for 1 hour, with the experimental drugs delivered only in a rescue paradigm. In Experiment 1, animals treated before the 2-hour noise exposure with the combination of NAC and KX1-004 had from 12 to 17 dB less permanent threshold shift when compared to control saline treated animals. Treatment in the rescue paradigm did not produce any reductions in threshold shift from the 2-hour exposure. In the second experiment, with the 1-hour noise, rescue with KX1-004 or KX1-004 plus NAC yielded small, but significant, reductions in threshold shift. There was no additional benefit from the combination of NAC and KX1-004 over KX1-004 by itself.}, }
@article {pmid21767533, year = {2011}, author = {Field, MG and Yang, D and Bian, ZM and Petty, HR and Elner, VM}, title = {Retinal flavoprotein fluorescence correlates with mitochondrial stress, apoptosis, and chemokine expression.}, journal = {Experimental eye research}, volume = {93}, number = {4}, pages = {548-555}, pmid = {21767533}, issn = {1096-0007}, support = {EY09441/EY/NEI NIH HHS/United States ; R21 EY019986/EY/NEI NIH HHS/United States ; R01 EY009441-13/EY/NEI NIH HHS/United States ; R01 EY009441/EY/NEI NIH HHS/United States ; P30 EY007003/EY/NEI NIH HHS/United States ; F31 EY007003/EY/NEI NIH HHS/United States ; EY007003/EY/NEI NIH HHS/United States ; EY019986/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; Chemokine CCL2/metabolism ; Chemokines/*metabolism ; Coculture Techniques ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Flavoproteins/*metabolism ; Fluorescence ; Humans ; Hydrogen Peroxide/pharmacology ; Interferon-gamma/pharmacology ; Interleukin-8/metabolism ; Membrane Potential, Mitochondrial ; Mitochondrial Diseases/*metabolism ; Monocytes/drug effects ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Retinal Pigment Epithelium/metabolism/*pathology ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; }, abstract = {Oxidative stress and mitochondrial dysfunction occur before apoptosis in many retinal diseases. Under these conditions, a larger fraction of flavoproteins become oxidized and, when excited by blue-light, emit green flavoprotein fluorescence (FPF). In this study, we evaluated the utility of FPF as an early indicator of mitochondrial stress, pre-apoptotic cellular instability, and apoptosis of human retinal pigment epithelial (HRPE) cells subjected to hydrogen peroxide (H(2)O(2)) or monocytes (unstimulated or interferon-γ-stimulated) in vitro and of freshly-isolated pieces of human and rat neural retina subjected to H(2)O(2)ex vivo. Increased FPF of HRPE cells exposed to H(2)O(2) correlated with reduced mitochondrial membrane potential (ΔΨm) and increased apoptosis in a time- and dose-dependent manner. HRPE cells co-cultured with monocytes had increased FPF that correlated in a time-dependent manner with reduced ΔΨm, increased apoptosis, and early expression of pro-inflammatory chemokines, interleukin-8 (IL8) and monocyte chemotactic factor-1 (MCP1), which are known to be induced by oxidative stress. Increased FPF, reduced ΔΨm, and upregulation of IL8 and MCP1 occurred as early as 1-2 h after exposure to stressors, while apoptosis did not occur in HRPE cells until later time points. The antioxidant, N-acetyl-cysteine (NAC), inhibited increased FPF and apoptosis of HRPE cells subjected to H(2)O(2). Increased FPF of human and rat neural retina also correlated with increased apoptosis. This study suggests that FPF is a useful measure of mitochondrial function in retinal cells and tissues and can detect early mitochondrial dysfunction that may precede apoptosis.}, }
@article {pmid21764077, year = {2012}, author = {Seguro, AC and Poli de Figueiredo, LF and Shimizu, MH}, title = {N-acetylcysteine (NAC) protects against acute kidney injury (AKI) following prolonged pneumoperitoneum in the rat.}, journal = {The Journal of surgical research}, volume = {175}, number = {2}, pages = {312-315}, doi = {10.1016/j.jss.2011.05.052}, pmid = {21764077}, issn = {1095-8673}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*etiology/physiopathology/*prevention &amp; control ; Animals ; Antioxidants/*therapeutic use ; Carbon Dioxide/administration &amp; dosage ; Glomerular Filtration Rate/physiology ; Infusions, Parenteral ; Inulin/metabolism ; Kidney/metabolism/physiopathology ; Male ; Models, Animal ; Oxidative Stress/physiology ; Pneumoperitoneum/*complications ; Rats ; Rats, Wistar ; Reperfusion Injury/*complications ; Thiobarbituric Acid Reactive Substances/metabolism ; Time Factors ; }, abstract = {BACKGROUND: Acute kidney injury (AKI) following prolonged laparoscopy is a documented phenomenon. Carbon dioxide pneumoperitoneum induces oxidative stress. Previous experimental studies have shown that the antioxidant, N-acetylcysteine, protects the rat from AKI following ischemia-reperfusion. The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) on rat renal function after prolonged pneumoperitoneum.<br><br>METHODS: Normal rats treated or not with NAC were submitted to abdominal CO(2) insufflation of 10 mmHg, at short and long periods of time of 1 and 3 h, respectively, and evaluated at 24, 72 h, and 1 wk after deinsufflation. Glomerular filtration rate (GFR) was measured by inulin clearance and oxidative stress was evaluated by serum thiobarbituric acid reactive substances (TBARS) RESULTS: No significant alterations in GFR were observed in normal animals submitted to the pneumoperitoneum of 1 h and evaluated after 24 h desufflation. With 3 h of pneumoperitoneum, a significant and progressive decrease in GFR occurred 24 and 72 h after desufflation with an increase in serum TBARS. GFR returned to normal levels a week later. In the NAC-treated rats, a complete protection against GFR drops was observed 24 and 72 h following 3 h of pneumoperitoneum associated with a decrease in TBARS.<br><br>CONCLUSION: These results suggest that NAC protects against acute kidney injury following prolonged pneumoperitoneum. These findings have significant clinical implications.}, }
@article {pmid21762214, year = {2012}, author = {Whitaker, BD and Casey, SJ and Taupier, R}, title = {N-acetyl-l-cysteine supplementation improves boar spermatozoa characteristics and subsequent fertilization and embryonic development.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {47}, number = {2}, pages = {263-268}, doi = {10.1111/j.1439-0531.2011.01848.x}, pmid = {21762214}, issn = {1439-0531}, mesh = {Acetylcysteine/*pharmacology ; Acrosome Reaction/drug effects ; Animals ; Cell Membrane/drug effects/physiology ; Cryoprotective Agents/pharmacology ; Embryo Culture Techniques/*veterinary ; Female ; Fertilization in Vitro/*veterinary ; Lipid Peroxidation ; Male ; Oocytes ; Semen Preservation/methods/*veterinary ; Spermatozoa/*drug effects ; *Swine ; }, abstract = {The effects of 1.0 mmN-acetyl-l-cysteine (NAC) supplementation during the incubation of frozen-thawed and preserved boar sperm were studied in addition to subsequent oocyte IVF. Frozen-thawed and preserved boar sperm were supplemented with 1.0 mm NAC and incubated for 60 min to allow capacitation to occur followed by the addition of calcium ionophore 23187 to induce the acrosome reaction. The number of sperm having undergone the acrosome reaction was determined using the Wells-Awa staining technique. DNA damage was detected using single-cell gel electrophoresis. Membrane lipid peroxidation was estimated by the end point generation of malondialdehyde (MDA). Frozen-thawed sperm was not different in the ability of sperm to undergo the acrosome reaction but did have significantly (p < 0.05) more DNA damage (59.8 ± 1.0) compared to preserved sperm (32.0 ± 1.0%). Supplementing 1.0 mm NAC did not have an effect on the ability of sperm to undergo the acrosome reaction but did have significantly (p < 0.05) less DNA (39.2 ± 1.0%) damage compared to no antioxidant supplementation (52.7 ± 1.0%). Frozen-thawed sperm produced a significantly higher (p < 0.05) concentration of MDA (2.08 ± 0.05 μm MDA/10(7) cells) compared to preserved sperm (1.82 ± 0.05 μm MDA/10(7) cells), and non-supplemented sperm produced a significantly higher (p < 0.05) concentration of MDA (3.62 ± 0.05 μm MDA/10(7) cells) compared to the 1.0 mm NAC-supplemented sperm (0.28 ± 0.05 μm MDA/10(7) cells. Supplementation or semen storage method had no effect on IVF or embryonic development. These results indicate that supplementation with 1.0 mm NAC improved the ability to use frozen-thawed boar sperm during IVF as it reduces the DNA fragmentation and lipid peroxidation of the sperm.}, }
@article {pmid21761386, year = {2011}, author = {Gillissen, A}, title = {[Anti-inflammatory efficacy of N-acetylcysteine and therapeutic usefulness].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {65}, number = {9}, pages = {549-557}, doi = {10.1055/s-0030-1256592}, pmid = {21761386}, issn = {1438-8790}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Antineoplastic Agents/therapeutic use ; Antioxidants/*therapeutic use ; Arthritis/drug therapy ; Bronchitis/drug therapy ; Cell Transformation, Neoplastic/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; Expectorants/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Lung Diseases/*drug therapy ; Lung Diseases, Interstitial/drug therapy ; Pulmonary Disease, Chronic Obstructive/drug therapy ; }, abstract = {N-acetylcyteine (NAC) is a thiol containing compound which by providing Sulfhydryl groups, can act both as a precursor or reduced glutathione and as a direct scavenger of reactive oxygen species. By regulation the redox status in cells, it can interfere with several signaling pathways that play a role in regulation apoptosis, angiogenesis, cell growth, nuclear transcription and cytokine production. In humans NAC had been proven to improve idiopathic pulmonary fibrosis (IPF), various forms of alveolitis and to avoid hepatoxic effects of paracetamol and paraquate through binding these compounds enabling biliary excretion. Overall, the anti-inflammatory action of NAC is well documented in vitro as well as in vivo. This review summarizes the biochemical effects of NAC and hints proven and likely diseases where NAC have or might have a beneficial effect.}, }
@article {pmid21761005, year = {2011}, author = {Wesner, AR and Brackbill, ML and Sytsma, CS}, title = {Effect of preoperative N-acetylcysteine on postoperative blood loss parameters in cardiac surgery patients.}, journal = {International journal of vascular medicine}, volume = {2011}, number = {}, pages = {859020}, pmid = {21761005}, issn = {2090-2832}, abstract = {Purpose. To determine if recent preoperative exposure to n-acetylcysteine (NAC), Mucomyst, increases postoperative blood loss in cardiac surgery patients. Methods. Retrospective review of cardiac surgery patients who underwent a cardiac catheterization within four days of surgery and whose serum creatinine was ≥1.0 mg/dL. The study groups were those who received NAC in the pericatheterization period versus those who did not. The primary endpoint was postoperative chest tube output at 24, 48, and 72 hours. Secondary endpoints included number of transfusions and other bleeding parameters. Results. Mean blood loss in the first 24 hours was 962 ± 595 mL in the treatment group (n = 79) and 1,178 ± 788 mL in the control group (n = 106), P = .040. Blood loss between groups at 48 (366 ± 318 mL versus 412 ± 363 mL, P = .382) and 72 (194 ± 300 mL versus 176 ± 224 mL, P = .643) hours was not significantly different. There were no significant differences in postoperative transfusions or other bleeding parameters. Conclusions. Preoperative exposure to NAC did not increase postoperative blood loss or negatively affect other bleeding parameters.}, }
@article {pmid21756052, year = {2011}, author = {Okazaki, T and Otani, H and Shimazu, T and Yoshioka, K and Fujita, M and Iwasaka, T}, title = {Ascorbic acid and N-acetyl cysteine prevent uncoupling of nitric oxide synthase and increase tolerance to ischemia/reperfusion injury in diabetic rat heart.}, journal = {Free radical research}, volume = {45}, number = {10}, pages = {1173-1183}, doi = {10.3109/10715762.2011.605361}, pmid = {21756052}, issn = {1029-2470}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ascorbic Acid/*pharmacology ; Biopterins/analogs &amp; derivatives/metabolism ; Diabetes Mellitus, Experimental/complications/*drug therapy/enzymology/metabolism ; Disease Models, Animal ; Male ; Myocardial Reperfusion Injury/*drug therapy/metabolism ; Myocardium/metabolism ; Nitric Oxide Synthase/*antagonists &amp; inhibitors/metabolism ; Oxidative Stress/physiology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/drug therapy/metabolism ; }, abstract = {Oxidative stress may cause a loss of tetrahydrobiopterin (BH4), a co-factor of nitric oxide synthase (NOS), decrease the bioavailability of NO and aggravate ischemia/reperfusion (I/R) injury in diabetic heart. We hypothesized that ascorbic acid (AA) and N-acetyl cysteine (NAC) protect the diabetic heart from I/R injury by increasing BH4/dihydrobiopterin (BH2) ratio and inhibiting uncoupling of NOS. Diabetes mellitus was induced in rats by streptozotocin treatment, and the hearts were isolated and perfused. BH4 and BH4/BH2 ratio decreased in the diabetic heart associated with increased production of superoxide and nitrotyrosine (NT). Treatment with AA or NAC significantly increased BH4/BH2 ratio in the diabetic heart associated with decreased production of superoxide and NT and increased generation of nitrate plus nitrite (NOx). Pre-treatment with AA or NAC before 30 min ischemia followed by 120 min reperfusion improved left ventricular (LV) function and reduced infarct size in the diabetic but not non-diabetic hearts. The NOS inhibitor, L-NAME, inhibited the increase in the generation of superoxide, NT and NOx, but aggravated LV function and increased infarct size in the diabetic heart. L-NAME also abrogated the increase in NOx and improvement of LV function and the infarct size-limiting effect induced by AA or NAC in the diabetic heart. These results suggest that AA and NAC increase BH4/BH2 ratio and prevent NOS uncoupling in the diabetic heart. Resultant increase in the bioavailability of NO renders the diabetic heart toleratant to I/R injury.}, }
@article {pmid21751879, year = {2012}, author = {Akyol-Salman, I and Azizi, S and Mumcu, UY and Ateş, O and Baykal, O}, title = {Comparison of the efficacy of topical N-acetyl-cysteine and a topical steroid-antibiotic combination therapy in the treatment of meibomian gland dysfunction.}, journal = {Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics}, volume = {28}, number = {1}, pages = {49-52}, doi = {10.1089/jop.2010.0110}, pmid = {21751879}, issn = {1557-7732}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Topical ; Adolescent ; Adult ; Anti-Infective Agents/administration &amp; dosage/therapeutic use ; Betamethasone/administration &amp; dosage/*therapeutic use ; Drug Combinations ; Eyelid Diseases/*drug therapy/pathology ; Female ; Glucocorticoids/administration &amp; dosage/therapeutic use ; Humans ; Intraocular Pressure/drug effects ; Male ; Meibomian Glands/*drug effects/pathology ; Middle Aged ; Prospective Studies ; Sulfacetamide/administration &amp; dosage/*therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {PURPOSE: This study aimed to compare the efficacy of topical N-acetyl-cysteine (NAC) with a topical steroid-antibiotic combination, betamethasone-sulfacetamide sodium therapy in patients with meibomian gland dysfunction (MGD).<br><br>METHODS: Twenty patients with MGD were prospectively randomized and assigned into 2 groups. The patients were instructed to use either NAC 5% or a topical steroid-antibiotic combination, betamethasone 0.1%-sulfacetamide sodium 10%, topically 4 times a day for a month. All patients were instructed to apply lid hygiene once daily.<br><br>RESULTS: One month of topical therapy provided statistically significant improvements in fluorescein break-up time and Schirmer scores as compared with the initial study visit in both groups (P&#x2264;0.001). Significant improvements for the symptoms of ocular burning, itching, and intermittent filmy or blurred vision were noted in both groups at 1 month as compared with 1 day (P<0.05). Considering these rates, there was no significant difference between the groups (P>0.05). None of the patients developed an allergic reaction to the medications, and intraocular pressure measurements were within the normal limits in both groups.<br><br>CONCLUSION: When used in conjunction with eyelid hygiene, topical administration of NAC appears to be as effective as a topical steroid-antibiotic combination, betamethasone-sulfacetamide sodium therapy in patients with MGD.}, }
@article {pmid21751261, year = {2011}, author = {Uno, K and Kato, K and Kusaka, G and Asano, N and Iijima, K and Shimosegawa, T}, title = {The balance between 4-hydroxynonenal and intrinsic glutathione/glutathione S-transferase A4 system may be critical for the epidermal growth factor receptor phosphorylation of human esophageal squamous cell carcinomas.}, journal = {Molecular carcinogenesis}, volume = {50}, number = {10}, pages = {781-790}, doi = {10.1002/mc.20699}, pmid = {21751261}, issn = {1098-2744}, mesh = {Acetylcysteine/pharmacology ; Aged ; Aldehydes/chemistry/*metabolism/pharmacology ; Antimetabolites/pharmacology ; Blotting, Western ; Buthionine Sulfoximine/pharmacology ; Carcinoma, Squamous Cell/genetics/*metabolism/pathology ; Cell Line, Tumor ; ErbB Receptors/antagonists &amp; inhibitors/*metabolism ; Esophageal Neoplasms/genetics/*metabolism/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Glutathione/antagonists &amp; inhibitors/*metabolism ; Glutathione Transferase/genetics/*metabolism ; Humans ; Immunohistochemistry ; Male ; Phosphorylation/drug effects ; Quinazolines ; Reverse Transcriptase Polymerase Chain Reaction ; Transfection ; Tyrphostins/pharmacology ; }, abstract = {Oxidative stress might participate in the carcinogenesis of human esophageal squamous cell carcinomas (hESCC). 4-Hydroxynonenal (HNE) is a major product of membrane lipid peroxidation with short life. It might act as an important mediator through the generation of adducts and activate epidermal growth factor receptor (EGFR) signaling. It is mainly trapped with glutathione (GSH) and catalyzed by glutathione S-transferases (GSTs). This study aimed to elucidate the possible participation of HNE, GSH/GST system, and EGFR signaling in hESCC development. Immunohistochemistry of HNE adducts, EGFR, and phosphorylated EGFR (pEGFR) was performed with hESCC specimens. The effect of HNE on the phosphorylation of EGFR and its downstream PhospholipaseCγ1 (PLCγ1) was investigated with KYSE30 cell-line. Pretreatment with GSH inducer N-acetylcysteine (NAC) or GSH inhibitor Buthionine sulfoximine (BSO) and mandatory transfection of hGSTA4 gene in KYSE30 were conducted to investigate the relationship between HNE and GSH/GST system. Immunoreactants of HNE adducts, EGFR, and pEGFR were increased in hESCC compared to non-cancerous epithelium with positive correlations. The treatment of HNE ligand-independently induced the phosphorylation of EGFR and PLCγ1 accompanying the diminishment of intracellular GSH level. NAC increased GSH contents but BSO decreased in dose-dependent manners. Reflecting changes in GSH, HNE-induced EGFR phosphorylation was suppressed by NAC, whereas it was promoted by BSO. Mandatory expression of hGSTA4 suppressed HNE-induced events. We first demonstrated that the ligand-independent activation of EGFR by the balance between the stimulation of HNE and the prevention of intrinsic GSH/GST system might participate in the development of hESCC.}, }
@article {pmid21750343, year = {2011}, author = {Clifford, RE and Coleman, JK and Balough, BJ and Liu, J and Kopke, RD and Jackson, RL}, title = {Low-dose D-methionine and N-acetyl-L-cysteine for protection from permanent noise-induced hearing loss in chinchillas.}, journal = {Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery}, volume = {145}, number = {6}, pages = {999-1006}, doi = {10.1177/0194599811414496}, pmid = {21750343}, issn = {1097-6817}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Auditory Threshold/drug effects ; Chinchilla ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Therapy, Combination ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Female ; Hearing Loss, Noise-Induced/*drug therapy/prevention &amp; control ; Injections, Intraperitoneal ; Methionine/*administration &amp; dosage ; Random Allocation ; Reference Values ; Treatment Outcome ; }, abstract = {OBJECTIVE: Despite efforts at public health awareness and stringent industrial standards for hearing protection, noise-induced hearing loss (NIHL) remains a formidable public health concern. Although many antioxidants have proven to be beneficial in the laboratory for prevention of permanent NIHL, low-dose combinations of compounds with different biochemical mechanisms of action may allow long-term administration with fewer side effects and equal efficacy. The mixture of D-methionine and N-acetyl-L-cysteine administered at levels less than 10% of standard dosing has not been previously reported.<br><br>STUDY DESIGN: Twenty-six female adult Chinchilla laniger were placed in 4 study groups, consisting of (1) a group receiving combination 12.5 mg/kg each D-methionine and N-acetyl-L-cysteine (DMET/NAC group), (2) a group receiving 12.5 mg/kg D-methionine (DMET-only group), (3) a group receiving 12.5 mg/kg N-acetyl-L-cysteine (NAC-only group), and (4) saline controls.<br><br>SETTING: Laboratory.<br><br>SUBJECTS AND METHODS: All groups received twice-daily intraperitoneal injections 2 days prior to noise exposure, 1 hour before and after exposure on day 3, and for 2 days subsequently, totaling 10 doses of 125 mg/kg for each antioxidant over 5 days.<br><br>RESULTS: Although NAC-only animals paralleled saline control recovery during 3 weeks, the DMET-only group revealed gradual improvement with statistically significant recovery in the middle frequencies. The DMET/NAC group showed significant improvement at most frequencies compared with controls (P < .001 and P < .05).<br><br>CONCLUSION: Significant recovery of hearing was observed following continuous noise exposure with either DMET only or a combination of low-dose DMET/NAC, demonstrating a considerably lower dose of antioxidants required than previously reported for hearing recovery following acoustic trauma.}, }
@article {pmid21741957, year = {2011}, author = {Ho, SY and Wu, WJ and Chiu, HW and Chen, YA and Ho, YS and Guo, HR and Wang, YJ}, title = {Arsenic trioxide and radiation enhance apoptotic effects in HL-60 cells through increased ROS generation and regulation of JNK and p38 MAPK signaling pathways.}, journal = {Chemico-biological interactions}, volume = {193}, number = {2}, pages = {162-171}, doi = {10.1016/j.cbi.2011.06.007}, pmid = {21741957}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects/*radiation effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Caspase 3/metabolism ; Cell Cycle/drug effects/radiation effects ; Cell Cycle Proteins/metabolism ; Cell Survival/drug effects/radiation effects ; Cyclins/metabolism ; DNA Fragmentation/drug effects/radiation effects ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; F-Box Proteins/metabolism ; F-Box-WD Repeat-Containing Protein 7 ; HL-60 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Membrane Potential, Mitochondrial/drug effects/radiation effects ; Models, Biological ; Oxides/*pharmacology ; Phosphorylation/drug effects/radiation effects ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/physiology/radiation effects ; Tumor Stem Cell Assay ; Ubiquitin-Protein Ligases/metabolism ; X-Rays ; bcl-2-Associated X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The induction of apoptotic cell death is a significant mechanism of tumor cells under the influence of radio-/chemotherapy, and resistance to these treatments has been linked to some cancer cell lines with a low propensity for apoptosis. The present study aimed to investigate the enhanced effects and mechanisms in apoptosis and the cycle distribution of HL-60 cells, a human leukemia cell line lacking a functional p53 protein, after combination treatment with arsenic trioxide (ATO) and irradiation (IR). Our results indicated that combined treatment led to increased cytotoxicity and apoptotic cell death in HL-60 cells, which was correlated with the activation of cdc-2 and increased expression of cyclin B, the induction of intracellular reactive oxygen species (ROS) generation, the loss of mitochondria membrane potential, and the activation of caspase-3. The combined treatment of HL-60 cells pre-treated with Z-VAD or NAC resulted in a significant reduction in apoptotic cells. In addition, activation of JNK and p38 MAPK may be involved in combined treatment-mediated apoptosis. The data suggest that a combination of IR and ATO could be a potential therapeutic strategy against p53-deficient leukemia cells.}, }
@article {pmid21741707, year = {2011}, author = {Sun, J and McKallip, RJ}, title = {Plumbagin treatment leads to apoptosis in human K562 leukemia cells through increased ROS and elevated TRAIL receptor expression.}, journal = {Leukemia research}, volume = {35}, number = {10}, pages = {1402-1408}, pmid = {21741707}, issn = {1873-5835}, support = {K22 CA109334-01A2/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Catalase/metabolism/pharmacology ; Cell Survival/drug effects ; Flow Cytometry ; Gene Expression/*drug effects ; Humans ; In Situ Nick-End Labeling ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*metabolism/pathology ; *Naphthoquinones/pharmacology ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Polyethylene Glycols/metabolism/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/antagonists &amp; inhibitors/genetics/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {This study examined the ability of plumbagin to induce apoptosis in chronic myelogenous leukemia (CML). Plumbagin exposure led to a significant reduction in cell viability and the induction of apoptosis. Mechanistically, plumbagin treatment led to elevated levels of ROS. Plumbagin-induced apoptosis was inhibited by N-acetyl L-cysteine (NAC) and PEG-catalase. Furthermore, plumbagin exposure led to elevated expression of DR4 and DR5 and increased killing through soluble TRAIL. The plumbagin-induced increase in DR4 and DR5 was inhibited by treatment with NAC. Together, this study suggests that plumbagin may be an effective treatment of CML through increased sensitivity to TRAIL-mediated killing.}, }
@article {pmid21741372, year = {2011}, author = {Kumar, A and Malik, F and Bhushan, S and Shah, BA and Taneja, SC and Pal, HC and Wani, ZA and Mondhe, DM and Kaur, J and Singh, J}, title = {A novel parthenin analog exhibits anti-cancer activity: activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells.}, journal = {Chemico-biological interactions}, volume = {193}, number = {3}, pages = {204-215}, doi = {10.1016/j.cbi.2011.06.006}, pmid = {21741372}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/chemistry/*pharmacology ; *Apoptosis ; Apoptosis Inducing Factor/antagonists &amp; inhibitors/genetics/metabolism ; Bridged-Ring Compounds/chemistry/*pharmacology ; Caspase 3/metabolism ; Caspase 8/metabolism ; Caspase 9/metabolism ; Cytochromes c/metabolism ; Female ; Glutathione/metabolism ; HL-60 Cells ; Humans ; Inhibitor of Apoptosis Proteins/metabolism ; Male ; Mice ; NF-kappa B/metabolism ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type II/metabolism ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; STAT3 Transcription Factor/metabolism ; Sesquiterpenes/chemistry/*pharmacology ; Signal Transduction ; Survivin ; }, abstract = {This study describes the anti-cancer activity of P19, an analog of parthenin. P19 induced apoptosis in HL-60 cells and inhibited cell proliferation with 48h IC50 of 3.5μM. At 10mg/kg dose, it doubled the median survival time of L1210 leukemic mice and at 25mg/kg it inhibited Ehrlich ascites tumor growth by 60%. Investigation of the mechanism of P19 induced apoptosis in HL-60 cells revealed that N-acetyl-l-cysteine (NAC) and s-methylisothiourea (sMIT) could reverse several molecular events that lead to cell death by inhibiting nitric oxide (NO) formation. It selectively produced massive NO in cells while quenching the basal ROS levels with concurrent elevation of GSH. P19 disrupted mitochondrial integrity leading to cytochrome c release and caspase-9 activation. P19 also caused caspase-8 activation by selectively elevating the expression of DR4 and DR5. All these events lead to the activation of caspase-3 leading to PARP-1 cleavage and DNA fragmentation. However, knocking down of AIF by siRNA also suppressed the apoptosis substantially thus indicating caspase independent apoptosis, too. Further, contrary to enhanced iNOS expression, its transcription factor, NF-κB (p65) was cleaved with a simultaneous increase in cytosolic IκB-alpha. In addition, P19 potently inhibited pro-survival proteins pSTAT3 and survivin. The multi-modal pro-apoptotic activity of P19 raises its potential usefulness as a promising anti-cancer therapeutic.}, }
@article {pmid21740986, year = {2011}, author = {Corn, SD and Barstow, TJ}, title = {Effects of oral N-acetylcysteine on fatigue, critical power, and W' in exercising humans.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {178}, number = {2}, pages = {261-268}, doi = {10.1016/j.resp.2011.06.020}, pmid = {21740986}, issn = {1878-1519}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Antioxidants/administration &amp; dosage ; Cross-Over Studies ; Double-Blind Method ; Exercise/*physiology ; Exercise Tolerance/*drug effects/*physiology ; Humans ; Male ; Muscle Fatigue/*drug effects/*physiology ; Young Adult ; }, abstract = {The accumulation of reactive oxygen species (ROS) is associated with muscular fatigue. The antioxidant N-acetylcysteine (NAC) can extend time to fatigue (TTF), but the effect appears to be exercise intensity dependent. The purpose of this study was to determine the effects of an acute oral dose of NAC on time to fatigue (TTF), critical power (CP), W' (curvature constant), V(O2) kinetics and muscle EMG during cycling exercise. Male (n=7) subjects performed four tests at power outputs corresponding to 80, 90, 100, and 110% of the peak power output achieved during the incremental test (Pmax) under NAC and placebo (PLA) conditions. TTF was increased only in the 80% Pmax trial (p=0.033). CP was higher with NAC (NAC: 232±28 W versus PLA: 226±31 W; p=0.032), but W' tended to decrease (NAC: 15.5±3.8 kJ versus W': 16.4±4.5 kJ; p=0.10). The change in W' was negatively related to the change in CP (r = -0.96). MdPF and RMS of EMG tended to change less with NAC. There were no significant differences in V(O2) kinetics. These results demonstrate that oral NAC was successful in extending time to fatigue at 80% Pmax but not at higher work rates.}, }
@article {pmid21740343, year = {2011}, author = {Breitbart, R and Abu-Kishk, I and Kozer, E and Ben-Assa, E and Goldstein, LH and Youngster, I and Berkovitch, M}, title = {Intraperitoneal N-acetylcysteine for acute iron intoxication in rats.}, journal = {Drug and chemical toxicology}, volume = {34}, number = {4}, pages = {429-432}, doi = {10.3109/01480545.2011.564176}, pmid = {21740343}, issn = {1525-6014}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Aspartate Aminotransferases/blood ; Data Interpretation, Statistical ; Ferrous Compounds/blood/*poisoning ; Injections, Intraperitoneal ; Kaplan-Meier Estimate ; Male ; Poisoning/blood/prevention &amp; control ; Rats ; Rats, Wistar ; Survival Analysis ; }, abstract = {Free radical formation and release of oxidant agents have been suggested as possible mechanisms for tissue damage in acute iron intoxication. N-acetylcysteine (NAC), a glutathione substitute and an antioxidant, is widely used as an antidote for various intoxications. Our aim was to determine whether intraperitoneal (i.p.) NAC would reduce the mortality of rats after acute, toxic oral doses of iron. Male Wistar rats were studied in three phases. In the first phase, animals were assigned to groups 1 (distilled water by gavage) and 2 (i.p. NAC) and observed for survival. In the second phase, rats were assigned to groups 3 (400 mg/kg elemental iron orally) and 4 (400 mg/kg elemental iron, followed by 150 mg/kg i.p. NAC). Survival was observed. Because most rats in Group 3 died within 90 minutes after iron administration, a third phase was conducted in order to allow for comparison of iron and transaminase serum levels after the administration of iron and NAC (group 5: n = 10). Mortality was significantly lower in rats treated with iron and NAC, compared to those treated with iron (P = 0.016). Median serum iron level was significantly lower among rats treated with iron and NAC, compared with rats treated with iron alone (P = 0.002). In a rat model of acute iron intoxication, i.p. administration of NAC may decrease serum iron levels and mortality.}, }
@article {pmid21740309, year = {2011}, author = {Kaplan, N and Urao, N and Furuta, E and Kim, SJ and Razvi, M and Nakamura, Y and McKinney, RD and Poole, LB and Fukai, T and Ushio-Fukai, M}, title = {Localized cysteine sulfenic acid formation by vascular endothelial growth factor: role in endothelial cell migration and angiogenesis.}, journal = {Free radical research}, volume = {45}, number = {10}, pages = {1124-1135}, pmid = {21740309}, issn = {1029-2470}, support = {R33 CA126659/CA/NCI NIH HHS/United States ; R01 HL077524/HL/NHLBI NIH HHS/United States ; R01 CA126659/CA/NCI NIH HHS/United States ; R01 HL077524 AND/HL/NHLBI NIH HHS/United States ; R01 HL070187/HL/NHLBI NIH HHS/United States ; R01 HL077524-S1/HL/NHLBI NIH HHS/United States ; }, mesh = {Actins/metabolism ; Animals ; Cell Movement/drug effects/*physiology ; Cysteine/*analogs &amp; derivatives/biosynthesis ; Endothelial Cells/*cytology/*metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Microscopy, Confocal ; NADPH Oxidases/metabolism ; Neovascularization, Physiologic/drug effects/physiology ; RNA, Small Interfering/administration &amp; dosage/genetics ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Sulfenic Acids ; Transfection ; Vascular Endothelial Growth Factor A/*metabolism/pharmacology ; ras GTPase-Activating Proteins/biosynthesis/genetics/metabolism ; }, abstract = {Reactive oxygen species (ROS) are important mediators for VEGF receptor 2 (VEGFR2) signalling involved in angiogenesis. The initial product of Cys oxidation, cysteine sulfenic acid (Cys-OH), is a key intermediate in redox signal transduction; however, its role in VEGF signalling is unknown. We have previously demonstrated IQGAP1 as a VEGFR2 binding scaffold protein involved in ROS-dependent EC migration and post-ischemic angiogenesis. Using a biotin-labelled Cys-OH trapping reagent, we show that VEGF increases protein-Cys-OH formation at the lamellipodial leading edge where it co-localizes with NADPH oxidase and IQGAP1 in migrating ECs, which is prevented by IQGAP1 siRNA or trapping of Cys-OH with dimedone. VEGF increases IQGAP1-Cys-OH formation, which is prevented by N-acetyl cysteine or dimedone, which inhibits VEGF-induced EC migration and capillary network formation. In vivo, hindlimb ischemia in mice increases Cys-OH formation in small vessels and IQGAP1 in ischemic tissues. In summary, VEGF stimulates localized formation of Cys-OH-IQGAP1 at the leading edge, thereby promoting directional EC migration, which may contribute to post-natal angiogenesis in vivo. Thus, targeting Cys-oxidized proteins at specific compartments may be the potential therapeutic strategy for various angiogenesis-dependent diseases.}, }
@article {pmid21737104, year = {2011}, author = {Silva, LF and Hoffmann, MS and Rambo, LM and Ribeiro, LR and Lima, FD and Furian, AF and Oliveira, MS and Fighera, MR and Royes, LF}, title = {The involvement of Na+, K+-ATPase activity and free radical generation in the susceptibility to pentylenetetrazol-induced seizures after experimental traumatic brain injury.}, journal = {Journal of the neurological sciences}, volume = {308}, number = {1-2}, pages = {35-40}, doi = {10.1016/j.jns.2011.06.030}, pmid = {21737104}, issn = {1878-5883}, mesh = {Animals ; Brain Injuries/complications/enzymology/*metabolism ; Enzyme Activation/drug effects/physiology ; Free Radicals/*metabolism ; Male ; Pentylenetetrazole/*toxicity ; Rats ; Rats, Wistar ; Reaction Time/drug effects/physiology ; Seizures/*chemically induced/enzymology/*metabolism ; Sodium-Potassium-Exchanging ATPase/*metabolism/physiology ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Although the importance of brain trauma as risk factor for the development of epilepsy is well established, the mechanisms of epileptogenesis are not well understood. In the present study, we revealed that the injection of a subthreshold dose of PTZ (30 mg/Kg, i.p.) after 5 weeks of injury induced by Fluid Percussion Brain Injury (FPI) decreased latency for first clonic seizures, increased the time of spent generalized tonic-clonic seizures and electrocorticographic (EEG) wave amplitude. In addition, statistical analysis revealed that N-acetylcysteine (NAC) (100mg/kg) supplementation during 5 weeks after neuronal injury protected against behavioral and electrographical seizure activity elicited by subthreshold dose of PTZ. The supplementation of this antioxidant compound also protected against the Na(+),K(+)-ATPase activity inhibition and concomitant increase in the levels of oxidative stress markers (protein carbonylation and thiobarbituric acid-reactive substances-TBARS) in site and peri-contusional cortical tissue. In summary, the current experiments clearly showed that FPI model induces early posttraumatic seizures and suggest that an alteration in the lipid/protein oxidation, membrane fluidity, and Na(+),K(+)-ATPase activity may be correlated with neuronal excitability, a significant component of the secondary injury cascade that accompanies TBI.}, }
@article {pmid21736794, year = {2011}, author = {Park, NY and Park, SK and Lim, Y}, title = {Long-term dietary antioxidant cocktail supplementation effectively reduces renal inflammation in diabetic mice.}, journal = {The British journal of nutrition}, volume = {106}, number = {10}, pages = {1514-1521}, doi = {10.1017/S0007114511001929}, pmid = {21736794}, issn = {1475-2662}, mesh = {Acetylcysteine/*administration &amp; dosage ; Alloxan ; Animals ; Antioxidants/*administration &amp; dosage ; Blood Glucose/analysis ; Blood Urea Nitrogen ; Body Weight ; Creatinine/metabolism ; Diabetes Mellitus, Experimental/*complications ; Lipid Peroxidation ; Mice ; Nephritis/complications/*prevention &amp; control ; Oxidative Stress ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Diabetic nephropathy is a serious complication for diabetic patients, yet the precise mechanism that underlies the development of diabetic complications remains unknown. We hypothesised that dietary antioxidant supplementation with single N-acetylcysteine (NAC) or vitamin C combined with either vitamin E or vitamin E and NAC improves diabetic renal inflammation through the modulation of blood glucose levels, oxidative stress and inflammatory response. Experimental animals were treated with alloxan monohydrate to induce diabetes. Mice were divided into five groups and supplemented with single or a combination of antioxidants. Body weights and blood glucose levels were measured once a week. After 8 weeks of dietary antioxidant supplementation, mice were killed and blood urea N (BUN) and plasma creatinine levels were measured to evaluate renal function. NF-κB protein was indirectly demonstrated by the phosphorylated IκBα (pIκBα) level, and the expressions of oxidative stress- and inflammatory response-related proteins were also determined. We demonstrated that dietary antioxidant supplementation decreased lipid peroxidation levels demonstrated by thiobarbituric acid-reacting substances, BUN and plasma creatinine levels in diabetic kidneys. Moreover, dietary antioxidant cocktail supplementation improved blood glucose levels and selectively regulated the expressions of Cu-Zn superoxide dismutase, haeme oxygenase-1, pIκBα, inducible NO synthase, cyclo-oxygenase-2 and C-reactive protein in diabetic kidneys effectively. These findings demonstrated that diabetic renal failure was associated with inflammatory responses induced by hyperglycaemia. In addition, results in the study suggest that antioxidant cocktail supplementation may have beneficial effects on diabetic nephropathy through selective reduction of blood glucose levels and inflammatory response.}, }
@article {pmid21733335, year = {2011}, author = {Yan, H and Zhu, Y and Liu, B and Wu, H and Li, Y and Wu, X and Zhou, Q and Xu, K}, title = {Mitogen-activated protein kinase mediates the apoptosis of highly metastatic human non-small cell lung cancer cells induced by isothiocyanates.}, journal = {The British journal of nutrition}, volume = {106}, number = {12}, pages = {1779-1791}, doi = {10.1017/S0007114511002315}, pmid = {21733335}, issn = {1475-2662}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects/*physiology ; Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism/pathology/secondary ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cyclin B1/metabolism ; Gene Expression/drug effects ; Humans ; Isothiocyanates/*pharmacology ; Lung Neoplasms/*drug therapy/genetics/metabolism/pathology ; MAP Kinase Signaling System/*drug effects/*physiology ; Neoplasm Metastasis/drug therapy/prevention &amp; control ; Transcription Factor AP-1/metabolism ; }, abstract = {Dietary isothiocyanates have been shown to possess anti-tumour activity, inhibiting several types of cultured human cancer cell growth. However, there are limited studies on their effects on cancer cell metastasis. Our previous study showed that benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) suppressed human lung cancer cell metastasis potential. In the present study, we found BITC (7·5 and 10 μm) and PEITC (12·5 and 20 μm) induced highly metastatic human non-small cell lung cancer L9981 cell apoptosis in a dose-dependent manner. Caspase-3 was activated. They also caused cell cycle arrest at the G2/M phase, via modulation of cyclin B1 expression. The mitogen-activated protein kinase (MAPK) signalling pathway was involved. c-Jun N-terminal kinase, extracellular signal-regulated protein kinase 1/2 and p38 were activated in a dose-dependent manner; activator protein 1 (AP-1) transcriptional activation and cyclin D1 expression were repressed. Apoptosis and MAPK activation were abrogated by anti-oxidant N-acetyl cysteine (NAC), suggesting that cell death signalling was triggered by oxidative stress. Further microarray analysis evaluated the potential targeted genes related to apoptosis and the cell cycle. Our studies suggested that BITC and PEITC suppressed the metastasis potential of highly metastatic lung cancer cells by inducing apoptosis and cell cycle arrest, via targeting the MAPK/AP-1 pathway. This may provide a novel approach for metastasis therapy of lung cancer by dietary isothiocyanates and possibly other types of cancer.}, }
@article {pmid21729331, year = {2011}, author = {Fan, G and Wen, L and Li, M and Li, C and Luo, B and Wang, F and Zhou, L and Liu, L}, title = {Isolation of mouse mesenchymal stem cells with normal ploidy from bone marrows by reducing oxidative stress in combination with extracellular matrix.}, journal = {BMC cell biology}, volume = {12}, number = {}, pages = {30}, pmid = {21729331}, issn = {1471-2121}, mesh = {Animals ; Antioxidants/pharmacology ; Bone Marrow Cells/*cytology/metabolism ; Cell Proliferation ; Cell Separation ; Cells, Cultured ; Chromosome Aberrations ; Extracellular Matrix/*metabolism ; Fibroblasts/metabolism ; Kruppel-Like Factor 4 ; Mesenchymal Stem Cells/*cytology/metabolism ; Mice ; *Oxidative Stress ; *Ploidies ; Pluripotent Stem Cells/cytology ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Isolation of mouse MSCs (mMSCs) with normal ploidy from bone marrow remains challenging. mMSCs isolated under 20% O(2) are frequently contaminated by overgrown hematopoietic cells, and could also be especially vulnerable to oxidative damage, resulting in chromosomal instability. Culture under low oxygen or extracellular matrix (ECM) improves proliferation of MSCs in several species. We tested the hypothesis that culture under low oxygen in combination with ECM prepared from mouse embryonic fibroblast (MEF-ECM) could be used to purify proliferative mMSCs, and to reduce oxidative damage and maintain their chromosomal stability.<br><br>RESULTS: Optimization of culture conditions under 20% O(2) resulted in immortalization of mMSCs, showing extensive chromosome abnormalities, consistent with previous studies. In contrast, culture under low oxygen (2% O(2)) improved proliferation of mMSCs and reduced oxidative damage, such that mMSCs were purified simply by plating at low density under 2% O(2). MEF-ECM reduced oxidative damage and enhanced proliferation of mMSCs. However, these isolated mMSCs still exhibited high frequency of chromosome abnormalities, suggesting that low oxygen or in combination with MEF-ECM was insufficient to fully protect mMSCs from oxidative damage. Notably, antioxidants (alpha -phenyl-t-butyl nitrone (PBN) and N-acetylcysteine (NAC)) further reduced DNA damage and chromosomal abnormalities, and increased proliferation of mMSCs. mMSCs isolated by the combination method were successfully used to generate induced pluripotent stem (iPS) cells by ectopic expression of Oct4, Sox2, Klf4 and c-Myc.<br><br>CONCLUSIONS: We have developed a technique that allows to reduce the number of karyotypic abnormalities for isolation of primary mMSCs and for limited culture period by combination of low oxygen, MEF-ECM, antioxidants and low density plating strategy. The effectiveness of the new combination method is demonstrated by successful generation of iPS cells from the isolated mMSCs. However, a culture system for mMSCs still is needed to prevent all the anomalies, especially after a long-term culture period.}, }
@article {pmid21728860, year = {2011}, author = {Graham, AS and Grosche, A and Morton, AJ and Polyak, MM and Freeman, DE}, title = {In vitro and in vivo responses of mucosa from the large colon of horses to ischemia and reperfusion.}, journal = {American journal of veterinary research}, volume = {72}, number = {7}, pages = {982-989}, doi = {10.2460/ajvr.72.7.982}, pmid = {21728860}, issn = {1943-5681}, mesh = {Analysis of Variance ; Anesthetics, Intravenous/administration &amp; dosage ; Animals ; Colon/blood supply/*pathology ; Diazepam/administration &amp; dosage ; Electric Impedance ; Horse Diseases/chemically induced/*pathology ; Horses ; Hypnotics and Sedatives/administration &amp; dosage ; Intestinal Mucosa/pathology ; Ischemia/pathology/*veterinary ; Ketamine/administration &amp; dosage ; Mannitol/metabolism ; Reperfusion Injury/pathology/*veterinary ; Statistics, Nonparametric ; Xylazine/administration &amp; dosage ; }, abstract = {OBJECTIVE: To induce ischemia and reperfusion injury in the large colon mucosa of horses in vivo and evaluate the recovery and effects of components of an organ transplant solution on mucosal recovery in vitro.<br><br>ANIMALS: 6 healthy horses.<br><br>PROCEDURES: Horses were anesthetized, and ischemia was induced for 60 minutes in the pelvic flexure, which was followed by reperfusion for 240 minutes. Ischemic (n = 4 horses), reperfused (6), and adjacent control (6) colonic mucosae were isolated for in vitro testing and histologic examinations. Tissues were mounted in Ussing chambers with plain Krebs Ringer bicarbonate (KRB), KRB with N-acetylcysteine (NAC), or KRB with a modified organ transplant solution (MOTS). Transepithelial electrical resistance (TER) and mannitol flux were used to assess mucosal integrity. Data were analyzed by use of ANOVA and Kruskal-Wallis tests.<br><br>RESULTS: The TER in reperfused tissues was similar to the TER in control tissues and greater than the TER in ischemic tissues, which was consistent with morphological evidence of recovery in reperfused tissues. Mannitol flux was greater in ischemic tissues than in reperfused tissues. The TER and mannitol flux were not significantly affected by incubation of mucosa with NAC or MOTS.<br><br>Ischemia induced during the brief period allowed rapid mucosal repair and complete recovery of tissue barrier properties during reperfusion. Therefore, reperfusion injury was not observed for this method of ischemic damage in equine colonic mucosa.}, }
@article {pmid21728338, year = {2011}, author = {Song, NY and Kim, DH and Kim, EH and Na, HK and Kim, NJ and Suh, YG and Surh, YJ}, title = {Multidrug resistance-associated protein 1 mediates 15-deoxy-Δ(12,14)-prostaglandin J2-induced expression of glutamate cysteine ligase expression via Nrf2 signaling in human breast cancer cells.}, journal = {Chemical research in toxicology}, volume = {24}, number = {8}, pages = {1231-1241}, doi = {10.1021/tx200090n}, pmid = {21728338}, issn = {1520-5010}, mesh = {Acetylcysteine/pharmacology ; Breast Neoplasms/drug therapy/*metabolism ; Cell Line, Tumor ; Female ; Glutamate-Cysteine Ligase/*metabolism ; Glutathione/metabolism ; Humans ; Multidrug Resistance-Associated Proteins/antagonists &amp; inhibitors/genetics/*metabolism ; NF-E2-Related Factor 2/antagonists &amp; inhibitors/genetics/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Propionates/pharmacology ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology/therapeutic use ; Proto-Oncogene Proteins c-akt/metabolism ; Quinolines/pharmacology ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Up-Regulation ; }, abstract = {15-Deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a representative J-series cyclopentenone prostaglandin bearing an electrophilic α,β-unsaturated carbonyl group. In the present study, treatment of human breast cancer MCF-7 cells with 15d-PGJ(2) caused the up-regulation of the glutamate cysteine ligase catalytic (GCLC) subunit, the rate-limiting enzyme in glutathione (GSH) synthesis. 15d-PGJ(2) treatment caused nuclear translocation and transactivation of Nrf2, a redox-sensitive transcription factor responsible for induced expression of antioxidant and other cytoprotective genes. siRNA knockdown of Nrf2 abrogated 15d-PGJ(2)-induced GCLC expression. Following 15d-PGJ(2) treatment, the intracellular GSH level was initially diminished but eventually enhanced even above the basal level. The reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) abolished the 15d-PGJ2-induced Nrf2 activation and GCLC expression. Pharmacologic inhibition or siRNA knockdown of Akt, the target of phosphoinositide 3-kinase (PI3-K), attenuated 15d-PGJ(2)-induced Nrf2 activation and GCLC expression, and NAC treatment inhibited phosphorylation of Akt, and subsequently Nrf2 activation and GCLC upregulation. 9,10-Dihydro-15-PGJ2, a nonelectrophilic analogue of 15d-PGJ(2) that lacks the ability to form a conjugate with GSH, failed to induce activation of Akt and Nrf2 as well as ROS generation. These findings, taken all together, suggest that intracellular accumulation of ROS formed as a consequence of initial depletion of GSH can activate Akt, which in turn induces Nrf2 activation and subsequently the expression of GCLC, leading to the restoration of GSH. Interestingly, the extracellular GSH level was increased, concomitantly with the depletion of the intracellular GSH following 15d-PGJ(2) treatment. However, 15d-PGJ(2) was unable to influence both intra- and extra-cellular GSH levels when multidrug resistance-associated protein 1 (MRP1), the efflux pump for GSH conjugates, was blocked by its antagonist, MK571. Moreover, 15d-PGJ(2)-induced GCLC expression was attenuated by the MK571 and also by siRNA knockdown of MRP1, suggesting that MRP1 contributes to 15d-PGJ(2)-mediated up-regulation of GCLC by pumping out the 15d-PGJ(2)-GSH conjugate. It is speculated that 15d-PGJ(2), once effluxed through MRP, liberates from the GSH conjugate, and the free 15d-PGJ(2) re-enters the cell and forms the GSH conjugate again. In conclusion, MRP1 mediates Nrf2-dependent up-regulation of GCLC in 15d-PGJ(2)-treated MCF-7 cells, possibly via a putative recycling loop of 15d-PGJ(2)-GSH conjugation.}, }
@article {pmid21724379, year = {2013}, author = {Qi, Y and Zhang, Y and Liu, Y and Zhang, W}, title = {Nonylphenol decreases viability and arrests cell cycle via reactive oxygen species in Raji cells.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {65}, number = {1-2}, pages = {69-72}, doi = {10.1016/j.etp.2011.06.002}, pmid = {21724379}, issn = {1618-1433}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cell Line, Tumor ; Cell Survival ; Dose-Response Relationship, Drug ; Environmental Pollutants/*toxicity ; G2 Phase Cell Cycle Checkpoints/*drug effects ; Humans ; M Phase Cell Cycle Checkpoints/*drug effects ; Phenols/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {4-Nonylphenol (NP), an environmental contaminant commonly found in water systems, has been documented to have adverse effects on human health. In the current study, the effects of NP on the survival, reactive oxygen species (ROS) production and cell cycle distribution of human Raji cells, a human lymphoblastoid cell line with B cell characteristics, were investigated. Furthermore, N-Acetyl-Cysteine (NAC) was used to explore the underlying mechanisms. The results showed that NP dramatically reduced cell viability along with the induction of ROS in a dose dependent manner, and cell survival was recovered by NAC pretreatment. Most strikingly, NP exposure altered the cell cycle profile, mainly leading to the accumulation of cells in the G2/M phase. Pretreatment of Raji cells with NAC attenuated the NP-induced G2/M cell cycle arrest. Taken together, the results suggest NP exhibits cytotoxic effects on Raji cells by decreasing cell viability and inducing G2/M cell cycle arrest, in a ROS dependent manner.}, }
@article {pmid21722752, year = {2011}, author = {Lee, GH and Bhandary, B and Lee, EM and Park, JK and Jeong, KS and Kim, IK and Kim, HR and Chae, HJ}, title = {The roles of ER stress and P450 2E1 in CCl(4)-induced steatosis.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {43}, number = {10}, pages = {1469-1482}, doi = {10.1016/j.biocel.2011.06.010}, pmid = {21722752}, issn = {1878-5875}, mesh = {Animals ; Antioxidants/metabolism ; Carbon Tetrachloride/*toxicity ; Cytochrome P-450 CYP2E1/*metabolism ; Disease Models, Animal ; Endoplasmic Reticulum/drug effects/*enzymology ; Fatty Liver/chemically induced/*enzymology/pathology ; Hep G2 Cells ; Humans ; Lipid Metabolism ; Male ; Oxidative Stress ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {The role of ER stress on hepatic steatosis was investigated in a rat model. We injected CCl(4) into rats and found that CCl(4) could induce hepatic lipid accumulation, confirmed by Oil Red O staining and by measurement of triglyceride and cholesterol. The expression of ApoB, an apolipoprotein, was decreased in plasma and increased in the liver of CCl(4)-treated animals. The ER stress response was also significantly increased by CCl(4). P450 2E1 expression and activity were increased through interactions of P450 2E1 with NADPH-dependent P450 reductase (NPR) under CCl(4)-treated conditions. In HepG2 cells, intracellular lipid accumulation and its signaling were comparable to in vivo results. In order to elucidate the effect of the ER stress response itself, tunicamycin, an N-acetyl-glycosylation inhibitor, was injected into rats, followed by Oil Red O staining, lipid/triglyceride/cholesterol accumulation analysis, and examination of ApoB expression. Additionally, the ER stress response and upregulation of P450 2E1 were also confirmed in the tunicamycin-treated rats. All of the responses were similar to those seen with CCl(4). The P450 2E1 inhibitor diallyl sulphide (DAS), N-acetylcysteine (NAC), and reduced glutathione (GSH) antioxidants also regulated processes, including ApoB expression and lipid accumulation in CCl(4)-treated animals. In the presence of tunicamycin, DAS or NAC/GSH regulated all of the pathological phenomena with the exception of the ER stress response. In summary, CCl(4) induces liver steatosis, a process involving ER stress-induced P450 2E1 activation and ROS production.}, }
@article {pmid21722651, year = {2011}, author = {Kanda, Y and Hinata, T and Kang, SW and Watanabe, Y}, title = {Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells.}, journal = {Life sciences}, volume = {89}, number = {7-8}, pages = {250-258}, doi = {10.1016/j.lfs.2011.06.007}, pmid = {21722651}, issn = {1879-0631}, mesh = {Acetylcysteine/pharmacology ; Adipocytes/*cytology/drug effects/metabolism ; Animals ; Antioxidants/pharmacology ; Bone Marrow Cells/cytology ; Cell Differentiation/drug effects/*physiology ; Cell Survival/drug effects ; Cells, Cultured ; Gene Expression Regulation ; Gene Knockdown Techniques ; Gene Silencing ; Mesenchymal Stem Cells/*cytology/drug effects/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/genetics ; RNA, Small Interfering/genetics ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {AIMS: Mesenchymal stem cells (MSC) have the potential to differentiate into various cell lineages, including adipocytes and osteoblasts. The formation of adipose tissue involves the commitment of MSC to the preadipocyte lineage and the differentiation of preadipocytes into mature adipocytes. In the present study, we investigated the involvement of reactive oxygen species (ROS) in adipocyte differentiation from MSC.<br><br>MAIN METHODS: ROS signaling was evaluated by the effects of antioxidant N-acetyl-l-cysteine (NAC) or shRNA against NAD(P)H oxidase in the multipotent mesenchymal stem cell line 10T1/2 cells. Intracellular ROS was measured using an H(2)DCF dye.<br><br>KEY FINDINGS: We found that NAC blocked adipocyte differentiation in MSC. An H(2)DCF assay revealed that differentiation-inducing agents induced ROS generation. These data suggest that ROS is involved in adipocyte differentiation in MSC. Next, we examined the source of ROS. Knockdown of NAD(P)H oxidase 4 (Nox4) by RNA interference inhibited ROS production and adipocyte differentiation by differentiation-inducing agents. Furthermore, treatment with NAC blocked the transcriptional activation of CREB, and the expression of dominant-negative mutants of CREB inhibited adipocyte differentiation.<br><br>SIGNIFICANCE: The findings suggest that the increase in the intracellular ROS level via Nox4 mediates adipocyte differentiation through CREB in MSC. This data will provide new insight into the drug development for obesity.}, }
@article {pmid21721906, year = {2012}, author = {Bala, A and Haldar, PK and Kar, B and Naskar, S and Mazumder, UK}, title = {Carbon tetrachloride: a hepatotoxin causes oxidative stress in murine peritoneal macrophage and peripheral blood lymphocyte cells.}, journal = {Immunopharmacology and immunotoxicology}, volume = {34}, number = {1}, pages = {157-162}, doi = {10.3109/08923973.2011.590498}, pmid = {21721906}, issn = {1532-2513}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/pharmacology ; Carbon Tetrachloride/*toxicity ; Carbon Tetrachloride Poisoning/*metabolism/pathology ; Free Radical Scavengers/pharmacology ; Lipid Peroxidation/drug effects ; Lymphocytes/*metabolism/pathology ; Macrophages, Peritoneal/*metabolism/pathology ; Mice ; Oxidative Stress/*drug effects ; Superoxides/metabolism ; }, abstract = {CONTEXT: Carbon tetrachloride (CCl4) is frequently used as a chemical inducer of tissue damage. Their effects on mouse peritoneal macrophages and also in peripheral blood lymphocytes are still unknown.<br><br>OBJECTIVE: Therefore we tried to focus on intracellular oxidative stress produced by CCl&#x2084; in mouse macrophage and lymphocyte cells.<br><br>METHODS: Intraperitoneal administration of CCl&#x2084; induces intracellular superoxide anions production in mouse macrophages and peripheral blood lymphocytes and leads a subsequent lipid peroxidation and protein oxidation. N-acetyl cystein (NAC) and vitamin C were administered intraperitoneally at a dose of 150 mg/kg and their effect on demodulating the oxidative stress is also checked.<br><br>RESULT AND DISCUSSION: Several in vitro approaches have already been established as a free radical scavenging models, but this free radical screening models is not always correlated with the in vivo screening models. NAC and vitamin C were administered intraperitoneally and significant reduction of the oxidative stress in term of scavenging of toxic superoxide anion observed in both the macrophages and lymphocytes.<br><br>CONCLUSION: Therefore we are hopeful that our work will light a new insight into the screening of in vivo free radical scavenging model for evaluating anti-inflammatory compounds.}, }
@article {pmid21721350, year = {2011}, author = {da Rocha, FP and Fagundes, DJ and Rivoire, HC and Rech, FV and Almeida, MW and Pires, JA}, title = {Immunohistochemical expression of apoptosis and VEGF expression on random skin flaps in rats treated with hyperbaric oxygen and N-acetylcysteine.}, journal = {Undersea &amp; hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc}, volume = {38}, number = {3}, pages = {167-174}, pmid = {21721350}, issn = {1066-2936}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; *Apoptosis/drug effects/physiology ; Biomarkers/metabolism ; Caspase 3/*metabolism ; Combined Modality Therapy/methods ; Hyperbaric Oxygenation/*methods ; Immunohistochemistry ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Skin/metabolism ; *Surgical Flaps ; Vascular Endothelial Growth Factor A/*metabolism ; }, abstract = {OBJECTIVE: We sought to investigate the role of hyperbaric oxygen (HBO2), N-acetylcysteine (NAC), and HBO2 plus NAC (HN) on the immunohistochemical expression of caspase-3 and the vascular endothelial growing factor (VEGF) on random skin flaps of rats (modified McFarlane design).<br><br>METHODS: Thirty-two male Wistar rats were randomly divided into four groups: GS (sham--n = 8); GNAC (N-acetylcysteine--n = 8); GHBO2 (hyperbaric oxygen--n = 8); and GHN (HBO2 plus NAC--n = 8). A rectangular skin flap (2 x 8 cm2) was dissected from the muscular dorsal layer, preserving a cranial pedicle. Polyethylene film was placed over the muscular layer, and an interrupted 3.0 nylon suture fixed the flap into the original place. On the eighth day, full-thickness biopsies (2 x 1 cm2) were collected from the proximal, middle and cranial areas of the skin flap, and in a site away from the flap labeled the control area.<br><br>RESULTS: The expression of VEGF in the skin layers (epidermis, dermis, subcutaneous muscles) and vessels showed no significant difference among the groups. Apoptotic cells were significantly increased in the middle area of the flap in all groups. The major increase occurred in GS and GNAC. HBO2 significantly decreased cleaved caspase-3-positive cell numbers in the skin layers and vessels of the three areas.<br><br>CONCLUSIONS: HBO2 showed a protective effect in the ischemic skin flap that was associated with reduced expression of apoptosis. GNAC and GHN were not associated with lower expression of apoptosis, and poor results were observed in GNAC. The combination of NAC and HBO2 did not show better results than using them separately. The expression of VEGF in skin layers and vessels did not show a significant difference in our modified McFarlane flap model. The results suggest that the diffusion of oxygen through the interstitial space was the determining factor for the more favorable results of HBO2 in the decrease of apoptosis expression.}, }
@article {pmid21720929, year = {2011}, author = {Hebert, VY and Jones, BC and Mifflin, RC and Dugas, TR}, title = {Role of COX-2 in the bioactivation of methylenedianiline and in its proliferative effects in vascular smooth muscle cells.}, journal = {Cardiovascular toxicology}, volume = {11}, number = {4}, pages = {316-324}, pmid = {21720929}, issn = {1559-0259}, support = {K22 ES011025/ES/NIEHS NIH HHS/United States ; K22 ES011025-03/ES/NIEHS NIH HHS/United States ; }, mesh = {Aniline Compounds/pharmacokinetics/*toxicity ; Animals ; Biotransformation ; Carcinogens/pharmacokinetics/*toxicity ; Celecoxib ; Cell Proliferation/drug effects ; Cells, Cultured ; Cyclooxygenase 1/metabolism ; Cyclooxygenase 2/*biosynthesis ; Cyclooxygenase 2 Inhibitors/pharmacology ; Female ; Hyperplasia ; Male ; Membrane Proteins/metabolism ; Muscle, Smooth, Vascular/*drug effects/enzymology ; Pulmonary Artery/drug effects/metabolism ; Pyrazoles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Sulfonamides/pharmacology ; Tunica Media/drug effects/metabolism ; }, abstract = {4,4'-Methylenedianiline (DAPM) is an aromatic diamine used directly in the production of polyurethane foams and epoxy resins, or as a precursor to MDI in the manufacture of some polyurethanes. In our prior experiments, we showed that chronic, intermittent treatment of female rats with DAPM resulted in vascular medial hyperplasia of pulmonary arteries. In addition, treatment of vascular smooth muscle cells (VSMC) in culture with DAPM increased the rates of proliferation in a manner that was inhibited by co-treatment with N-acetylcysteine but was not associated with oxidative stress. We thus hypothesized that NAC treatment inhibited DAPM toxicity by competing for binding reactive intermediates formed through DAPM metabolism. Because the peroxidase enzyme cyclooxygenase is constitutively expressed in VSMC, and because cyclooxygenase is known to metabolize similar aromatic amines to electrophilic intermediates, we further hypothesized that DAPM-induced VSMC proliferation was dependent upon COX-1/2-mediated bioactivation. To test this hypothesis, we treated VSMC with DAPM and measured cell proliferation, COX-2 expression, COX-1/2 activity, and levels of covalent binding. DAPM treatment resulted in a dose-dependent increase in proliferation that was abolished by co-treatment with the COX-2-selective inhibitor celecoxib. In addition, DAPM exposure increased the rates of proliferation in VSMC isolated from wild-type but not COX-2 (-/-) mice. Paradoxically, treatment with DAPM reduced the cellular production of PGE(2) and PGF(2α), but dose-dependently increased the COX-2 protein levels. Covalent binding of [(14)C]-DAPM to VSMC biomolecules was greater in wild-type than in COX-2 (-/-) cells. However, covalent binding of [(14)C]-DAPM was not altered by co-treatment with a nonselective inhibitor of cytochromes P450. These studies thus suggest that DAPM-induced VSMC proliferation may be due to bioactivation of DAPM, perhaps through the action of cyclooxygenase. The data furthermore suggest that DAPM's mechanism of action may possibly involve inhibition or suicide inactivation of COX-2. In addition, because we observed an increase in DAPM-induced VSMC proliferation in cells isolated from female compared to male rats, further studies into the potential interplay between DAPM, the estrogen receptor, and COX-2 seem warranted.}, }
@article {pmid21719110, year = {2011}, author = {Berk, M and Dean, O and Cotton, SM and Gama, CS and Kapczinski, F and Fernandes, BS and Kohlmann, K and Jeavons, S and Hewitt, K and Allwang, C and Cobb, H and Bush, AI and Schapkaitz, I and Dodd, S and Malhi, GS}, title = {The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial.}, journal = {Journal of affective disorders}, volume = {135}, number = {1-3}, pages = {389-394}, doi = {10.1016/j.jad.2011.06.005}, pmid = {21719110}, issn = {1573-2517}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Antidepressive Agents/therapeutic use ; Antimanic Agents/therapeutic use ; Bipolar Disorder/*drug therapy/psychology ; Depression/drug therapy ; Depressive Disorder/drug therapy ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Male ; Middle Aged ; Mood Disorders/drug therapy ; Quality of Life ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {BACKGROUND: Evidence is accumulating to support the presence of redox dysregulation in a number of psychiatric disorders, including bipolar disorder. This dysregulation may be amenable to therapeutic intervention. Glutathione is the predominant non-enzymatic intracellular free radical scavenger in the brain, and the most generic of all endogenous antioxidants in terms of action. N-acetylcysteine (NAC) is a glutathione precursor that effectively replenishes brain glutathione. Given the failure of almost all modern trials of antidepressants in bipolar disorder to demonstrate efficacy, and the limited efficacy of mood stabilisers in the depressive phase of the disorder, this is a major unmet need.<br><br>METHOD: This study reports data on the treatment of 149 individuals with moderate depression during the 2 month open label phase of a randomised placebo controlled clinical trial of the efficacy of 1g BID of NAC that examined the use of NAC as a maintenance treatment for bipolar disorder.<br><br>RESULTS: In this trial, the estimated mean baseline Bipolar Depression Rating Scale (BDRS) score was 19.7 (SE=0.8), and the mean BDRS score at the end of the 8 week open label treatment phase was 11.1 (SE=0.8). This reduction was statistically significant (p<0.001). Improvements in functioning and quality of life were similarly evident.<br><br>CONCLUSION: These open label data demonstrate a robust decrement in depression scores with NAC treatment. Large placebo controlled trials of acute bipolar depression are warranted.}, }
@article {pmid21716263, year = {2011}, author = {Otte, DM and Sommersberg, B and Kudin, A and Guerrero, C and Albayram, O and Filiou, MD and Frisch, P and Yilmaz, O and Drews, E and Turck, CW and Bilkei-Gorzó, A and Kunz, WS and Beck, H and Zimmer, A}, title = {N-acetyl cysteine treatment rescues cognitive deficits induced by mitochondrial dysfunction in G72/G30 transgenic mice.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {36}, number = {11}, pages = {2233-2243}, pmid = {21716263}, issn = {1740-634X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Carrier Proteins/*biosynthesis/genetics ; Cognition Disorders/*drug therapy/enzymology/genetics ; Electron Transport Complex I/*genetics ; Humans ; Intracellular Signaling Peptides and Proteins ; Male ; Mice ; Mice, Transgenic ; Mitochondrial Diseases/enzymology/*genetics/pathology ; Reactive Oxygen Species/metabolism ; Treatment Outcome ; }, abstract = {Genetic studies have implicated the evolutionary novel, anthropoid primate-specific gene locus G72/G30 in psychiatric diseases. This gene encodes the protein LG72 that has been discussed to function as a putative activator of the peroxisomal enzyme D-amino-acid-oxidase (DAO) and as a mitochondrial protein. We recently generated 'humanized' bacterial artificial chromosome transgenic mice (G72Tg) expressing G72 transcripts in cells throughout the brain. These mice exhibit several behavioral phenotypes related to psychiatric diseases. Here we show that G72Tg mice have a reduced activity of mitochondrial complex I, with a concomitantly increased production of reactive oxygen species. Affected neurons display deficits in short-term plasticity and an impaired capability to sustain synaptic activity. These deficits lead to an impairment in spatial memory, which can be rescued by pharmacological treatment with the glutathione precursor N-acetyl cysteine. Our results implicate LG72-induced mitochondrial and synaptic defects as a possible pathomechanism of psychiatric disorders.}, }
@article {pmid21714136, year = {2011}, author = {Valenti, VE and De Abreu, LC and Sato, MA and Saldiva, PH and Fonseca, FL and Giannocco, G and Riera, AR and Ferreira, C}, title = {Central N-acetylcysteine effects on baroreflex in juvenile spontaneously hypertensive rats.}, journal = {Journal of integrative neuroscience}, volume = {10}, number = {2}, pages = {161-176}, doi = {10.1142/S0219635211002671}, pmid = {21714136}, issn = {0219-6352}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Baroreflex/*drug effects ; Blood Pressure/drug effects ; Catheters, Indwelling ; Free Radical Scavengers/*pharmacology ; Injections, Intraventricular ; Male ; Nitroprusside/pharmacology ; Phenylephrine/pharmacology ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Vasoconstrictor Agents/pharmacology ; Vasodilator Agents/pharmacology ; }, abstract = {In this study, we evaluated the acute effects of central NAC administration on baroreflex in juvenile SHR and Wistar Kyoto (WKY) rats. Male SHR and WKY rats (8-10 weeks old) were implanted with a stainless steel guide cannula into the fourth cerebral ventricle (4th V). The femoral artery and vein were cannulated for mean arterial pressure (MAP) and heart rate (HR) measurement and drug infusion, respectively. After basal MAP and HR recordings, the baroreflex was tested with a pressor dose of phenylephrine (PHE, 8 μg/kg, bolus) and a depressor dose of sodium nitroprusside (SNP, 50 μg/kg, bolus). Baroreflex was evaluated before, 5, 15, 30 and 60 minutes after NAC injection into the 4th V. Vehicle treatment did not change baroreflex responses in WKY and SHR. Central NAC slightly but significantly increased basal HR at 15 minutes and significantly reduced PHE-induced increase in MAP 30 and 60 minutes after NAC injection (p < 0.05) in WKY rats. In relation to SHR, NAC decreased HR range 15 and 30 minutes after its administration. In conclusion, acute NAC into the 4th V does not improve baroreflex in juvenile SHR.}, }
@article {pmid21713097, year = {2011}, author = {Kudaravalli, J}, title = {Improvement in endothelial dysfunction in patients with systemic lupus erythematosus with N-acetylcysteine and atorvastatin.}, journal = {Indian journal of pharmacology}, volume = {43}, number = {3}, pages = {311-315}, pmid = {21713097}, issn = {1998-3751}, abstract = {OBJECTIVE: To study the effects of N-acetylcysteine (NAC) and atorvastatin on endothelial dysfunction in patients with systemic lupus erythematosus (SLE).<br><br>MATERIALS AND METHODS: Thirty-two SLE patients and age, sex-matched 10 healthy control subjects were studied. The patients were between 17 and 65 years of age and positive for diagnostic tests, such as antinuclear antibodies (ANA). Photoplethysmogram (PPG) detects the changes in the amount of light absorbed by hemoglobin, which reflects changes in the blood volume. Pulse wave analysis was performed at rest, 30 s, 90 s after shear stress, and 10 min after 300 &#x3bc;m of salbutamol inhalation.<br><br>RESULTS: Stiffness index (SI) of patients before the treatment was 8.46&#xb1;2.78 cm/s and of controls was 6.07&#xb1;1.4 cm/s (P = 0.002) and that of reflection index (RI) was 73&#xb1;13 for patients and 65&#xb1;7 for controls (P = 0.001). The percentage change in RI after salbutamol inhalation for controls and patients were -16&#xb1;6 and -7&#xb1;4 (P = 0.001), respectively, indicating the presence of endothelial dysfunction. The percentage decrease in RI after salbutamol inhalation was from -2.36&#xb1;0.76 to ?7.92&#xb1;1.46 in patients treated with N-acetylcysteine (NAC, P = 0.007). The percentage decrease in RI after salbutamol inhalation was from ?6.36&#x381;1.21 to -9.92&#xb1;1.21 in patients treated with atorvastatin (P = 0.05). This indicated the improvement in endothelial function. There was decrease in C-reactive protein (CRP) from 1.03&#xb1;0.72 mg/dL to 0.52&#xb1;0.22 mg/dL and that of malondialdehyde (MDA) from 11.20&#xb1;4.07 nmol/mL to 8.81&#xb1;2.79 nmol/mL with N-acetylcysteine treatment (P < 0.05). The CRP was decreased from 1.11&#xb1;0.92 mg/dL to 0.440.16 mg/dL (P = 0.05) and that of MDA was decreased from 9.37&#xb1;3.29 nmol/mL to 8.51&#xb1;3.27 nmol/mL after treatment with atorvastatin. It showed improvement in oxidative stress with these treatments.<br><br>CONCLUSION: The presence of arterial stiffness indicated endothelial dysfunction. There was reduction in RI and SI with treatment of N-acetylcysteine and atorvastatin suggesting improvement in endothelial dysfunction. There was decrease in CRP (a marker of inflammation) and MDA after treatment with N-acetylcysteine suggesting improvement in endothelial dysfunction. There was reduction in CRP after treatment with atorvastatin, suggesting improvement in endothelial function. Improvement in endothelial dysfunction is associated with decreased incidence of cardiovascular and cerebrovascular accidents.}, }
@article {pmid21712088, year = {2011}, author = {Sandoval, YH and Li, Y and Anand-Srivastava, MB}, title = {Transactivation of epidermal growth factor receptor by enhanced levels of endogenous angiotensin II contributes to the overexpression of Giα proteins in vascular smooth muscle cells from SHR.}, journal = {Cellular signalling}, volume = {23}, number = {11}, pages = {1716-1726}, doi = {10.1016/j.cellsig.2011.06.006}, pmid = {21712088}, issn = {1873-3913}, support = {MOP-53074//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/pharmacology ; Adenylyl Cyclases/*metabolism ; Angiotensin II/genetics/*metabolism ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; CSK Tyrosine-Protein Kinase ; Colforsin/pharmacology ; ErbB Receptors/genetics/*metabolism ; GTP-Binding Protein alpha Subunits, Gi-Go/genetics/*metabolism ; Gene Expression/drug effects ; Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology ; Humans ; Hypertension/genetics/*metabolism/pathology ; Mitogen-Activated Protein Kinases/genetics/metabolism ; Muscle, Smooth, Vascular/cytology/metabolism ; Myocytes, Smooth Muscle/cytology/*metabolism ; Oxidative Stress/drug effects ; Phosphorylation ; Protein-Tyrosine Kinases/genetics/metabolism ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Signal Transduction/*drug effects ; Transcriptional Activation/*drug effects ; src-Family Kinases ; }, abstract = {We earlier showed that the increased expression of Gi proteins exhibited by vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) was attributed to the enhanced levels of endogenous endothelin. Since the levels of angiotensin II (Ang II) are also enhanced in VSMC from SHR, the present study was undertaken to examine the role of enhanced levels of endogenous Ang II in the overexpression of Giα proteins in VSMC from SHR and to further explore the underlying mechanisms responsible for this increase. The enhanced expression of Giα-2 and Giα-3 proteins in VSMC from SHR compared to WKY was attenuated by the captopril, losartan and AG1478, inhibitors of angiotensin converting enzyme, AT(1) receptor and epidermal growth factor receptor (EGFR) respectively as well as by the siRNAs of AT1, cSrc and EGFR. The enhanced inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of GTPγS (receptor-independent functions) and of inhibitory responses of hormones on adenylyl cyclase activity (receptor-dependent functions) in VSMC from SHR was also attenuated by losartan. Furthermore, the enhanced phosphorylation of EGFR in VSMC from SHR was also restored to control levels by captopril, losartan, PP2, a c-Src inhibitor and N-acetyl-L-cysteine (NAC), superoxide anion (O(2)(-)) scavenger, whereas enhanced ERK1/2 phosphorylation was attenuated by captopril and losartan. Furthermore, NAC also restored the enhanced phosphorylation of c-Src in SHR to control levels. These results suggest that the enhanced levels of endogenous Ang II in VSMC from SHR, transactivate EGFR, which through MAP kinase signaling, enhance the expression of Giα proteins and associated adenylyl cyclase signaling.}, }
@article {pmid21710354, year = {2012}, author = {Ahmadi-Ashtiani, H and Allameh, A and Rastegar, H and Soleimani, M and Barkhordari, E}, title = {Inhibition of cyclooxygenase-2 and inducible nitric oxide synthase by silymarin in proliferating mesenchymal stem cells: comparison with glutathione modifiers.}, journal = {Journal of natural medicines}, volume = {66}, number = {1}, pages = {85-94}, pmid = {21710354}, issn = {1861-0293}, mesh = {Acetylcysteine/*pharmacology ; Buthionine Sulfoximine/*pharmacology ; Cell Proliferation/*drug effects ; Cells, Cultured ; Cyclooxygenase 2/*metabolism ; Cyclooxygenase 2 Inhibitors/*pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/*pharmacology ; Glutathione/*metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Mesenchymal Stem Cells/*drug effects/enzymology ; Nitric Oxide Synthase Type II/*antagonists &amp; inhibitors/metabolism ; Silymarin/*pharmacology ; Time Factors ; }, abstract = {Silymarin, a mixture of flavonolignans, is extracted from milk thistle (Silybum marianum) and has a strong antioxidant activity and exhibits anticarcinogenic, anti-inflammatory, and cytoprotective effects. In this study we attempted to determine whether silymarin and the glutathione modifiers, buthionine sulfoxamine (BSO) and N-acetylcysteine (NAC), are involved in regulation of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in proliferating mesenchymal stem cells (MSCs). Cellular glutathione was manipulated during a 14-day culture using BSO, NAC and silymarin. At intervals of 2, 7 and 14 days, cells were collected and COX-2 and iNOS levels were measured. In parallel, generation of cellular H(2)O(2) and glutathione were measured. Supplementation of the culture media with BSO caused a dose-dependent decrease in MSC proliferation, whereas NAC or silymarin elevated the proliferation (p < 0.05). Treatment of MSC with NAC or silymarin caused a significant decrease in COX-2 levels. However, COX-2 levels in cells treated with high levels of NAC (1.0 mM) were significantly lower than those in MSCs treated with high levels of silymarin (100 μM). BSO (1.0 and 5.0 μM) caused a significant increase in COX-2 on days 2, 7 and 14. BSO caused a significant increase in iNOS, whereas NAC or silymarin decreased cellular iNOS. Overall result show that glutathione, iNOS and COX-2 in proliferating MSCs are affected by silymarin treatment. It appears that glutathione is the main target of silymarin, and in consequence iNOS and COX-2 are affected in response to silymarin treatment.}, }
@article {pmid21708261, year = {2011}, author = {Nunes, C and Barbosa, RM and Almeida, L and Laranjinha, J}, title = {Nitric oxide and DOPAC-induced cell death: from GSH depletion to mitochondrial energy crisis.}, journal = {Molecular and cellular neurosciences}, volume = {48}, number = {1}, pages = {94-103}, doi = {10.1016/j.mcn.2011.06.009}, pmid = {21708261}, issn = {1095-9327}, mesh = {3,4-Dihydroxyphenylacetic Acid/*pharmacology ; Acetylcysteine/metabolism ; Animals ; Cell Death/*drug effects ; Dopamine/metabolism ; Electron Spin Resonance Spectroscopy ; Electron Transport Complex I/metabolism ; Free Radicals/metabolism ; Glutathione/analogs &amp; derivatives/*metabolism ; Mitochondria/*drug effects/*metabolism ; Nitric Oxide/*metabolism ; Nitric Oxide Donors/metabolism ; Oxidation-Reduction ; PC12 Cells ; Parkinson Disease/physiopathology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; S-Nitroso-N-Acetylpenicillamine/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {The molecular mechanisms inherent to cell death associated with Parkinson's disease are not clearly understood. Diverse pathways, sequence of events and models have been explored in several studies. Recently, we have proposed an integrative mechanism, encompassing the interaction of nitric oxide (•NO) and a major dopamine metabolite, dihydroxyphenylacetic (DOPAC), leading to a synergistic mitochondrial dysfunction and cell death that may be operative in PD. In this study, we have studied the sequence of events underlying the mechanisms of cell death in PC12 cells exposed to •NO and DOPAC in terms of: a) free radical production; b) modulation by glutathione (GSH); c) energetic status and d) outer membrane mitochondria permeability. Using Electron Paramagnetic Resonance (EPR) it is shown the early production of oxygen free radicals followed by a depletion of GSH reflected by an increase of GSSG/GSH ratio in the cells treated with the mixture of •NO/DOPAC, as compared with the cells individually exposed to each of the stimulus. Glutathione ethyl ester (GSH-EE) and N-acetylcysteine (NAC) may rescue cells from death, increasing GSH content and preventing ATP loss in cells treated with the mixture DOPAC/•NO but failed to exert similar effects in the cells challenged only with •NO. The depletion of GSH is accompanied by a decreased activity of mitochondrial complex I. At a later stage, the concerted action of DOPAC and •NO include a rise in the ratio Bax/Bcl-2, an observation not evident when cells were exposed only to •NO. The results support a free radical-induced pathway leading to cell death involving the concerted action of DOPAC and •NO and the critical role of GSH in maintaining a functional mitochondria.}, }
@article {pmid21699019, year = {2011}, author = {Gao, X and Deeb, D and Liu, P and Liu, Y and Arbab-Ali, S and Dulchavsky, SA and Gautam, SC}, title = {Role of reactive oxygen species (ROS) in CDDO-Me-mediated growth inhibition and apoptosis in colorectal cancer cells.}, journal = {Journal of experimental therapeutics &amp; oncology}, volume = {9}, number = {2}, pages = {119-127}, pmid = {21699019}, issn = {1359-4117}, support = {R01 CA130948/CA/NCI NIH HHS/United States ; 1R01 CA130948/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Antineoplastic Agents/*pharmacology ; Antioxidants/metabolism ; Apoptosis/drug effects ; Cell Line, Tumor ; Colorectal Neoplasms/*drug therapy/pathology ; Free Radicals/metabolism ; Humans ; Oleanolic Acid/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {CDDO-Me, an oleanane synthetic triterpenoid has shown strong antitumorigeic activity towards diverse cancer cell types including colorectal cancer cells. In the present study, we investigated the role of free radicals in the growth inhibitory and apoptosis-inducing activity of CDDO-Me in colorectal cancer cells lines. Results demonstrated that CDDO-Me potently inhibited the growth of colorectal cancer cells and pretreatment of cancer cells with small-molecule antioxidant N-acetylcysteine (NAC) completely blocked the growth inhibitory activity of CDDO-Me. CDDO-Me caused the generation of reactive oxygen species, which was inhibited by NAC and mitochondrial chain 1 complex inhibitors DPI and rotenone. CDDO-Me induced apoptosis as demonstrated by the cleavage of PARP-1, activation of procaspases -3, -8, and -9 and mitochondrial depolarization and NAC blocked the activation of these apoptosis related processes. Furthermore, induction of apoptosis by CDDO-Me was associated with the inhibition of antiapoptotic/ prosurvival Akt, mTOR and NF-kappaB signaling proteins and the inhibition of these signaling molecules was blocked by NAG. Together these studies provided evidence that CDDO-Me is a potent anticancer agent, which imparts growth inhibition and apoptosis in colorectal cancer cells through the generation of free radicals.}, }
@article {pmid21695163, year = {2011}, author = {Petruccelli, LA and Dupéré-Richer, D and Pettersson, F and Retrouvey, H and Skoulikas, S and Miller, WH}, title = {Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells.}, journal = {PloS one}, volume = {6}, number = {6}, pages = {e20987}, pmid = {21695163}, issn = {1932-6203}, support = {MOP-12863//ASPE HHS/United States ; //Canadian Institutes of Health Research/Canada ; }, mesh = {Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; *DNA Damage ; DNA Replication/drug effects ; Dose-Response Relationship, Drug ; G2 Phase/drug effects ; Histone Deacetylase Inhibitors/*pharmacology ; Humans ; Hydroxamic Acids/*pharmacology ; Leukemia, Myeloid, Acute/genetics/metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Vorinostat ; }, abstract = {Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML) cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clinically relevant concentrations, vorinostat induces double-strand breaks and oxidative DNA damage in AML cell lines. Additionally, AML patient blasts treated with vorinostat display increased DNA damage, followed by an increase in caspase-3/7 activity and a reduction in cell viability. Vorinostat-induced DNA damage is followed by a G2-M arrest and eventually apoptosis. We found that pre-treatment with the antioxidant N-acetyl cysteine (NAC) reduces vorinostat-induced DNA double strand breaks, G2-M arrest and apoptosis. These data implicate DNA damage as an important mechanism in vorinostat-induced growth arrest and apoptosis in both AML cell lines and patient-derived blasts. This supports the continued study and development of vorinostat in AMLs that may be sensitive to DNA-damaging agents and as a combination therapy with ionizing radiation and/or other DNA damaging agents.}, }
@article {pmid21693215, year = {2011}, author = {Danilovic, A and Lucon, AM and Srougi, M and Shimizu, MH and Ianhez, LE and Nahas, WC and Seguro, AC}, title = {Protective effect of N-acetylcysteine on early outcomes of deceased renal transplantation.}, journal = {Transplantation proceedings}, volume = {43}, number = {5}, pages = {1443-1449}, doi = {10.1016/j.transproceed.2011.02.020}, pmid = {21693215}, issn = {1873-2623}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; *Cadaver ; Female ; Humans ; *Kidney Transplantation ; Male ; Middle Aged ; Thiobarbituric Acid Reactive Substances/metabolism ; *Tissue Donors ; }, abstract = {We investigated the effects of the antioxidant N-acetylcysteine (NAC) on early outcomes of deceased donor renal transplantation. Between April 2005 and June 2008, adult primary graft recipients of deceased renal donors were assigned to treatment (n = 38) or control (n = 36) groups and evaluated for 90 days and one year after renal transplantation. The treatment group received NAC orally (600 mg twice daily) from day 0 to 7 postoperatively. Renal function was determined by serum creatinine, MDRD and Cockcroft-Gault estimated GFR (eGFR), delayed graft function (DGF) and dialysis free Kaplan-Meier estimate curve. Serum levels of thiobarbituric acid reactive substances (TBARS), were employed as markers of oxidative stress. The NAC group displayed a lower mean serum creatinine during the first 90 days (P = .026) and at 1 year after transplantation (P = .005). Furthermore, the NAC group showed a higher mean eGFR throughout the first 90 days and at 1 year. DGF was lower among the NAC group (P = .017) and these recipients required fewer days of dialysis (P = .012). Oxidative stress was significantly attenuated with NAC (P < .001). Our results suggested that NAC enhanced early outcomes of deceased donor renal transplantation by attenuating oxidative stress.}, }
@article {pmid21683790, year = {2011}, author = {Oh, DH and Chun, KH and Jeon, SO and Kang, JW and Lee, S}, title = {Enhanced transbuccal salmon calcitonin (sCT) delivery: effect of chemical enhancers and electrical assistance on in vitro sCT buccal permeation.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {79}, number = {2}, pages = {357-363}, doi = {10.1016/j.ejpb.2011.05.010}, pmid = {21683790}, issn = {1873-3441}, mesh = {Absorption/drug effects ; Acetylcysteine/chemistry/pharmacology ; Administration, Buccal ; Animals ; Calcitonin/*administration &amp; dosage/*pharmacokinetics ; Drug Interactions ; Ethanol/chemistry/pharmacology ; Excipients ; Glycocholic Acid/analogs &amp; derivatives/chemistry/pharmacology ; Iontophoresis/methods ; Mouth Mucosa/cytology/*drug effects/*metabolism ; Permeability/drug effects ; Swine ; Technology, Pharmaceutical/methods ; }, abstract = {This study investigates the combined effect of absorption enhancers and electrical assistance on transbuccal salmon calcitonin (sCT) delivery, using fresh swine buccal tissue. We placed 200 IU (40 μg/mL) of each sCT formulation--containing various concentrations of ethanol, N-acetyl-L-cysteine (NAC), and sodium deoxyglycocholate (SDGC)--onto the donor part of a Franz diffusion cell. Then, 0.5 mA/cm(2) of fixed anodal current was applied alone or combined with chemical enhancers. The amount of permeated sCT was analyzed using an ELISA kit, and biophysical changes of the buccal mucosa were investigated using FT-IR spectroscopy, and hematoxylin-eosin staining methods were used to evaluate histological alteration of the buccal tissues. The flux (J(s)) of sCT increased with the addition of absorption enhancer groups, but it was significantly enhanced by the application of anodal iontophoresis (ITP). FT-IR study revealed that all groups caused an increase in lipid fluidity but only the groups containing SDGC showed statistically significant difference. Although the histological data of SDGC groups showed a possibility for tissue damage, the present enhancing methods appear to be safe. In conclusion, the combination of absorption enhancers and electrical assistance is a potential strategy for the enhancement of transbuccal sCT delivery.}, }
@article {pmid21682678, year = {2011}, author = {Sunitha, K and Hemshekhar, M and Santhosh, MS and Kumar, MS and Kemparaju, K and Girish, KS}, title = {Inhibition of hemorrhagic activity of viper venoms by N-acetyl cysteine: involvement of N-acetyl and thiol groups.}, journal = {Current topics in medicinal chemistry}, volume = {11}, number = {20}, pages = {2589-2600}, doi = {10.2174/156802611797633401}, pmid = {21682678}, issn = {1873-4294}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antivenins/*pharmacology/therapeutic use ; Dose-Response Relationship, Drug ; Edema/*drug therapy/pathology/prevention &amp; control ; Electrophoresis, Polyacrylamide Gel ; Extracellular Matrix Proteins/metabolism ; Fibrinolytic Agents/adverse effects ; Gelatinases/antagonists &amp; inhibitors/metabolism/toxicity ; Hemorrhage/*drug therapy/pathology/prevention &amp; control ; Hyaluronoglucosaminidase/antagonists &amp; inhibitors/metabolism/toxicity ; Male ; Mice ; Models, Molecular ; Proteolysis/drug effects ; Daboia/*physiology ; Skin/drug effects/pathology ; *Snake Bites ; Sulfhydryl Compounds/pharmacology/therapeutic use ; Viper Venoms/administration &amp; dosage/adverse effects/*antagonists &amp; inhibitors/isolation &amp; purification ; }, abstract = {The mortality rate due to snakebite is reduced markedly by the use of anti-venoms, which are the only medically approved remedial agents available. The anti-venoms effectively neutralize the systemic toxicity but offer no protection towards local tissue degradation. In viperid snake envenomations, SVMPs and SVHYs are the major agents responsible for brutal local tissue damage as they degrade ECM and basement membrane surrounding the blood vessels. Thus, the usage of inhibitor(s) against ECM degrading enzymes in the treatment of viper bites is an affirmative therapeutic choice. The present study assessed the efficacy of N-acetyl cysteine (NAC) to inhibit gelatinase, hyaluronidase, hemorrhagic and defibrinogenating activities of Vipera russelli and Echis carinatus venoms. NAC inhibited these activities dosedependently, but it did not inhibit the PLA2, 5' nucleotidase, procoagulant and edema inducing activities of both the venoms. NAC showed complete inhibition of hemorrhagic activity when incubated with venom prior to testing. Whereas little inhibition was observed when venom and NAC were injected independently. Inhibition of the basement membrane degradation and accumulation of inflammatory leukocytes at the site of venom injection in histological sections further corroborate the inhibitory property of NAC. The observed inhibition of hemorrhage was likely due to zinc chelation as supported by spectral studies. Further, docking predictions suggested the role of -SH and -NH-CO-CH3 groups of NAC in the inhibition of SVMPs and SVHYs. Future studies related to the protective role of NAC against the venom induced systemic hemorrhage and secondary complications are highly exciting.}, }
@article {pmid21681422, year = {2012}, author = {Sung, HJ and Kim, J and Kim, Y and Jang, SW and Ko, J}, title = {N-acetyl cysteine suppresses the foam cell formation that is induced by oxidized low density lipoprotein via regulation of gene expression.}, journal = {Molecular biology reports}, volume = {39}, number = {3}, pages = {3001-3007}, pmid = {21681422}, issn = {1573-4978}, mesh = {Acetylcysteine/*metabolism ; Apolipoproteins E/metabolism ; Atherosclerosis/*metabolism ; Biomarkers/*metabolism ; Cell Line, Tumor ; DNA Primers/genetics ; Foam Cells/*cytology/*metabolism ; Gene Expression Profiling ; Gene Expression Regulation/*physiology ; Glutathione Peroxidase/metabolism ; Humans ; Lipoproteins, LDL/*metabolism ; Microarray Analysis ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Glutathione Peroxidase GPX1 ; }, abstract = {Foam cells derived from macrophages have been implicated as markers of early stage atherosclerosis development. In this study, we found that N-acetyl cysteine (NAC), a well-known inhibitor of reactive oxygen species (ROS), decreased the generation of ROS and suppressed foam cell formation in the presence of oxidized low density lipoprotein through down-regulation of cluster of differentiation 36 expression. We investigated gene expression profiles in order to determine the effects of NAC on foam cell formation using a microarray analysis. The level of apolipoprotein E, which is involved in lipid efflux, was increased and the levels of the antioxidant genes glutathione peroxidase 1 and 3 were also increased. The expression levels of the oxidative stress response and the DNA repair genes were decreased. These results were confirmed using quantitative real-time PCR. Our results indicate that oxidative stress plays an important role in foam cell formation, and that regulation of oxidation using antioxidants is a potential therapeutic method for blocking atherosclerosis development.}, }
@article {pmid21675850, year = {2011}, author = {Demir, EO and Cakmak, GK and Bakkal, H and Turkcu, UO and Kandemir, N and Demir, AS and Tascılar, O}, title = {N-acetyl-cysteine improves anastomotic wound healing after radiotherapy in rats.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {24}, number = {4}, pages = {151-158}, doi = {10.3109/08941939.2011.560237}, pmid = {21675850}, issn = {1521-0553}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; *Anastomosis, Surgical ; Animals ; Colon/metabolism/*radiation effects/*surgery ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glutathione/blood ; Hydroxyproline/metabolism ; Injections, Intraperitoneal ; Male ; Malondialdehyde/blood ; Models, Animal ; *Radiotherapy ; Rats ; Rats, Wistar ; Superoxide Dismutase/blood ; Wound Healing/*drug effects ; }, abstract = {AIM: This study was designed to determine the effects of intraperitoneally or orally administered N-acetylcysteine (NAC) on anastomotic healing of irradiated rats.<br><br>METHODS: Thirty-two male Wistar albino rats were randomized into four groups containing 8 rats each: I; standard resection plus anastomosis, II; radiation plus standard resection plus anastomosis, III; radiation plus standard resection plus anastomosis plus oral NAC, IV; radiation plus standard resection plus anastomosis plus intraperitoneal NAC. Four types of assessment were performed: bursting pressure, hydroxiproline (OHP) content, histopathology, and biochemical evaluation, including serum malondialdehyde (MDA), advanced oxidation protein products (AOPP), reduced glutathione (GSH) and superoxide dismutase (SOD) activities.<br><br>RESULTS: Group comparisons demonstrated that bursting pressure was significantly higher in NAC treated rats. The mean tissue OHP concentration in the anastomotic tissue was significantly lower in irradiated rats (group II) than in the other groups. NAC treatment caused increased activity of SOD and GSH. In contrast, MDA levels were found to be decreased in groups III and IV. Histopathological analysis revealed that NAC administration, either orally or intraperitoneally, leads to a better anastomotic healing in terms of reepithelialization, perianastomotic fibrosis, ischemic necrosis, and muscle layer destruction.<br><br>CONCLUSION: The present study supports the hypothesis that NAC administration alleviates the negative effects of radiotherapy on anastomotic healing. Nevertheless, the underlying mechanisms responsible for this protective effect is unknown today.}, }
@article {pmid21674868, year = {2011}, author = {Kilciksiz, S and Demirel, C and Evirgen Ayhan, S and Erdal, N and Gurgul, S and Tamer, L and Ayaz, L}, title = {N-acetylcysteine ameliorates nitrosative stress on radiation-inducible damage in rat liver.}, journal = {Journal of B.U.ON. : official journal of the Balkan Union of Oncology}, volume = {16}, number = {1}, pages = {154-159}, pmid = {21674868}, issn = {1107-0625}, mesh = {Acetylcysteine/*pharmacology ; Amifostine/pharmacology ; Animals ; Female ; Liver/metabolism/pathology/*radiation effects ; Nitric Oxide/biosynthesis ; Radiation-Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; Tyrosine/*analogs &amp; derivatives/metabolism ; }, abstract = {PURPOSE: The present study was designed to investigate the potential radioprotective effects of N-acetylcysteine (NAC) on radiation-induced nitrosative stress caused by gamma irradiation (single dose, 6 Gy) in rat liver.<br><br>METHODS: The rats (n=40) were divided randomly and equally into 4 groups: Control (C), Radiation (R), R+NAC (received irradiation and 1,000 mg/kg of NAC) and R+WR-2721 (received irradiation and 200 mg/kg of WR-2721). Liver tissue of each animal was harvested and utilized for 3-nitrotyrosine (3-NT) detection using high-performance liquid chromatography- ultraviolet (HPLC-UV) system.<br><br>RESULTS: In the R rats, 3-NT levels significantly increased when compared to those of the C rats (p<0.05). There were no significant differences in the 3-NT levels among R+NAC and R+WR-2721 rats. Histologically examined liver tissue samples showed no obvious differences.<br><br>CONCLUSION: The present study suggests that irradiation has a negative effect on the cellular proteins by enhancing 3-NT formation. The prophylactic use of NAC seems to reduce the nitrosative damage during radiotherapy.}, }
@article {pmid21673362, year = {2011}, author = {Reiter, RJ and Tan, DX and Korkmaz, A and Fuentes-Broto, L}, title = {Drug-mediated ototoxicity and tinnitus: alleviation with melatonin.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {62}, number = {2}, pages = {151-157}, pmid = {21673362}, issn = {1899-1505}, mesh = {Aminoglycosides/adverse effects ; Animals ; Cisplatin/adverse effects ; Controlled Clinical Trials as Topic/methods ; Drug-Related Side Effects and Adverse Reactions/*drug therapy/pathology ; Humans ; Labyrinth Diseases/*chemically induced/*drug therapy/pathology ; Melatonin/*therapeutic use ; Tinnitus/*chemically induced/*drug therapy/pathology ; }, abstract = {This review evaluates the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear. A thorough search of the literature was performed using available databases for the purpose of uncovering articles applicable to the current review. Cochlear function was most frequently evaluated by measuring otoacoustic emissions and their distortion products after animals were treated with cytotoxic drugs alone or in combination with melatonin. Vestibular damage due to aminoglycosides was evaluated by estimating hair cell loss in explanted utricles of newborn rats. Tinnitus was assessed in patients who received melatonin using a visual analogue scale or the Tinnitus Handicap Inventory. Compared to a mixture of antioxidants which included tocopherol, ascorbate, glutathione and N-acetyl-cysteine, melatonin, also a documented antioxidant, was estimated to be up to 150 times more effective in limiting the cochlear side effects, evaluated using otoacoustic emission distortion products, of gentamicin, tobramycin and cisplatin. In a dose-response manner, melatonin also reduced vestibular hair cell loss due to gentamicin treatment in explanted utricles of newborn rats. Finally, melatonin (3 mg daily) limited subjective tinnitus in patients. These findings suggest the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin's low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage.}, }
@article {pmid21672511, year = {2011}, author = {Huang, YQ and Ruan, GD and Liu, JQ and Gao, Q and Feng, YQ}, title = {Use of isotope differential derivatization for simultaneous determination of thiols and oxidized thiols by liquid chromatography tandem mass spectrometry.}, journal = {Analytical biochemistry}, volume = {416}, number = {2}, pages = {159-166}, doi = {10.1016/j.ab.2011.05.020}, pmid = {21672511}, issn = {1096-0309}, mesh = {Chromatography, High Pressure Liquid/*methods ; Creatinine/urine ; Cysteine/urine ; Glutathione/urine ; Homocysteine/urine ; Humans ; Hydrocarbons, Brominated/chemical synthesis/*chemistry ; Hydrogen-Ion Concentration ; Isotope Labeling ; Microwaves ; Oxidation-Reduction ; Quinolinium Compounds/chemical synthesis/*chemistry ; Spectrometry, Mass, Electrospray Ionization/*methods ; Sulfhydryl Compounds/*urine ; Tandem Mass Spectrometry ; }, abstract = {Here we report a new isotopic pair of derivatization reagents, ω-bromoacetonylquinolinium bromide (BQB) and d(7)-ω-bromoacetonylquinolinium bromide (d(7)-BQB). BQB and d(7)-BQB both rapidly and selectively reacted with thiols in acidic medium within 3min with the aid of a microwave. Reduced thiols and total thiols in urine were labeled with BQB and d(7)-BQB, respectively. The BQB- and d(7)-BQB-labeled urine samples were then mixed and separated on a HILIC (hydrophilic interaction chromatography) column followed by electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection. The new strategy, which we have named isotope differential derivatization, allows us to simultaneously determine thiols and oxidized thiols in a single run. Compared with positive mode ESI detection of unlabeled thiols, the positive mode ESI-MS signal intensities of BQB-labeled thiols were found to increase by 10-, 20-, and 40-fold for cysteine (Cys), homocysteine (HCys), and glutathione (GSH), respectively (unlabeled N-acetylcysteine (Nac) is difficult to detect by ESI-MS in positive mode due to its low ionization efficiency). The detection limits calculated at a signal-to-noise ratio of 3 were found to be 8.02, 1.56, 0.833, and 3.27nmol/L for Cys, HCys, Nac, and GSH, respectively. Recoveries of thiols and disulfides from spiked urine samples were between 80% and 105%. The method was successfully used to determine thiols and oxidized thiols in urine samples of 25 healthy volunteers.}, }
@article {pmid21671307, year = {2011}, author = {Nagoor Meeran, MF and Mainzen Prince, PS}, title = {Protective effects of N-acetyl cysteine on lipid peroxide metabolism on isoproterenol-induced myocardial infarcted rats.}, journal = {Journal of biochemical and molecular toxicology}, volume = {25}, number = {3}, pages = {151-157}, doi = {10.1002/jbt.20371}, pmid = {21671307}, issn = {1099-0461}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ascorbic Acid/blood ; Biphenyl Compounds/metabolism ; Catalase/metabolism ; Creatine Kinase, MB Form/blood ; Free Radical Scavengers/metabolism ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Isoenzymes/metabolism ; Isoproterenol/*toxicity ; L-Lactate Dehydrogenase/blood ; Lipid Peroxides/*metabolism ; Male ; Myocardial Infarction/blood/*chemically induced/enzymology/*metabolism ; Myocardium/enzymology/pathology ; Picrates/metabolism ; Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Vitamin E/blood ; }, abstract = {The present study was designed to evaluate the preventive effects of N-acetyl cysteine on lipid peroxide metabolism in isoproterenol (ISO) induced myocardial infarcted rats. Male albino Wistar rats were pretreated with N-acetyl cysteine (5 and 10 mg/kg) daily for a period of 14 days. After the pretreatment period, ISO (100 mg/kg) was subcutaneously injected to rats twice at an interval of 24 h. Increased activities of serum creatine kinase, creatine kinase-MB, lactate dehydrogenase, and increased intensities of serum lactate dehydrogenase-isoenzyme bands (LDH-1, LDH-2) were observed in ISO-induced rats. The heart lipid peroxidation products were significantly increased, and the antioxidant system was significantly reduced in ISO-induced rats. Pretreatment with N-acetyl cysteine (5 and 10 mg/kg) to ISO-induced rats showed significant effects on all the biochemical parameters studied. Histopathological findings of the myocardium also showed the protective role of N-acetyl cysteine in ISO-induced rats. Furthermore, in vitro study confirmed the potent-free radical scavenging activity of N-acetyl cysteine. The effect at a dose of 10 mg/kg of N-acetyl cysteine was more pronounced than the dose, 5 mg/kg. The results of our study show that N-acetyl cysteine protects the heart against ISO-induced myocardial infarction by its free radical scavenging effect.}, }
@article {pmid21667456, year = {2012}, author = {Bui, DS and Seguro, AC and Shimitzu, MH and Schliemann, I and Martini, D and Romão, JE and Pecoits Filho, RF and Abensur, H}, title = {N-Acetylcysteine protects the peritoneum from the injury induced by hypertonic dialysis solution.}, journal = {Journal of nephrology}, volume = {25}, number = {1}, pages = {90-95}, doi = {10.5301/JN.2011.8404}, pmid = {21667456}, issn = {1724-6059}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Dialysis Solutions/*adverse effects ; Glucose/analysis ; Glucose Solution, Hypertonic/*adverse effects/chemistry ; Male ; Oxidative Stress/drug effects ; Peritoneal Dialysis/adverse effects ; Peritoneum/*pathology/*physiopathology ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; Urea/blood ; }, abstract = {BACKGROUND: Oxidative stress has been implicated in the development of peritoneal damage. The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) in a rat peritoneal infusion model.<br><br>METHODS: Eighteen male Wistar rats were divided in 3 groups: (i) control group; (ii) HDS group, receiving peritoneal dialysis solution (PDS); and (iii) HDS+NAC group, receiving PDS and oral NAC. Six weeks later they were evaluated for dialysate to plasma urea ratio (D/P), ratio of glucose concentration in peritoneal fluid (G1/G0), thiobarbituric acid reactive substances in plasma and urine and histology of peritoneal membrane.<br><br>RESULTS: The HDS+NAC group presented a lower increase in solute transport (D/P 0.51 &#xb1; 0.1, and G1/GO 0.35 &#xb1; 0.06) in comparison with the HDS group (D/P 0.67 &#xb1; 0.1; p=0.03, and G1/G0 0.27 &#xb1; 0.07; p=0.01). The HDS+NAC group showed lower thiobarbituric acid reactive substance concentrations compared with the HDS group. In the treated group, the peritoneal membrane presented lower thickness.<br><br>CONCLUSIONS: Functional and histological peritoneal changes were significantly reduced by the treatment with NAC.}, }
@article {pmid21660448, year = {2012}, author = {Yang, JF and Cao, JG and Tian, L and Liu, F}, title = {5, 7-Dimethoxyflavone sensitizes TRAIL-induced apoptosis through DR5 upregulation in hepatocellular carcinoma cells.}, journal = {Cancer chemotherapy and pharmacology}, volume = {69}, number = {1}, pages = {195-206}, doi = {10.1007/s00280-011-1686-9}, pmid = {21660448}, issn = {1432-0843}, mesh = {Apoptosis/*drug effects ; Carcinoma, Hepatocellular/*drug therapy/pathology ; Cell Line ; Cell Line, Tumor ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum Chaperone BiP ; Flavonoids/*pharmacology ; Humans ; Leukocytes, Mononuclear/metabolism ; Liver/drug effects/metabolism ; Liver Neoplasms/*drug therapy/pathology ; RNA, Small Interfering/administration &amp; dosage ; Reactive Oxygen Species/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics ; TNF-Related Apoptosis-Inducing Ligand/*metabolism ; Transcription Factor CHOP/metabolism ; Up-Regulation/drug effects ; }, abstract = {PURPOSE: 5, 7-dimethoxyflavone (DMF) has been reported to induce apoptosis in various cancer cells. The aim of this study was to examine whether DMF sensitizes human hepatocellular carcinoma (HCC) cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and its mechanism.<br><br>METHODS: Human hepatocellular carcinoma cell lines Hep3B, Huh-7, and Hep G2 and human embryo liver L-02 cells were cultured in vitro. The cytotoxic activities were determined using MTT assay. The apoptotic cell death was examined using Flow cytometry using PI staining and DNA agarose gel electrophoresis. The activities of caspase-3, caspase-8, and caspase-9 were measured using ELISA. Intracellular ROS was measured by FCM using the fluorescent probe DCHF-DA, and the expression of DR4, DR5, CHOP, GPR78, and ATF4 proteins was analyzed using Western blot.<br><br>RESULTS: Our results demonstrated subtoxic concentrations of DMF sensitize HCC cells to TRAIL-induced apoptosis and induce the death receptor 5 (DR5) expression level, accompanying the generation of reactive oxygen species (ROS) and the upregulation of CHOP, GPR78, and ATF4 protein expression. Pretreatment with N-acetylcysteine (NAC) inhibited DMF-induced upregulation of DR5, CHOP, GPR78, and ATF4 protein expression and blocked the cotreatment-induced apoptosis. Furthermore, DMF-mediated sensitization of HCC cells to TRAIL was reduced by administration of a blocking antibody or small interfering RNAs for DR5, salubrinal, an inhibitor of ER stress, and the small interfering RNAs for CHOP. However, DMF could not induce the upregulation of DR5 expression, generation of ROS, and sensitization of TRAIL-induced apoptotic cell death in human embryo liver L-02 cells or normal human peripheral blood mononuclear cells (PBMCs).<br><br>CONCLUSION: The present study demonstrates that DMF selectively enhances TRAIL-induced apoptosis by ROS-stimulated ER-stress triggering CHOP-mediated DR5 upregulation in HCC.}, }
@article {pmid21656901, year = {2011}, author = {Sahoo, RK and Sharma, A}, title = {Sinusoidal obstruction syndrome during induction therapy for acute lymphoblastic leukemia managed with N-acetyl Cysteine.}, journal = {Pediatric blood &amp; cancer}, volume = {57}, number = {4}, pages = {700}, doi = {10.1002/pbc.23142}, pmid = {21656901}, issn = {1545-5017}, mesh = {Acetylcysteine/*therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Asparaginase/administration &amp; dosage ; Dexamethasone/administration &amp; dosage ; Epirubicin/administration &amp; dosage ; Female ; Fibrinolytic Agents/*therapeutic use ; Hepatic Veno-Occlusive Disease/*complications/*drug therapy ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*complications/drug therapy ; Sepsis/complications ; Young Adult ; }, }
@article {pmid21652603, year = {2011}, author = {Manukhina, EB and Jasti, D and Vanin, AF and Downey, HF}, title = {Intermittent hypoxia conditioning prevents endothelial dysfunction and improves nitric oxide storage in spontaneously hypertensive rats.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {236}, number = {7}, pages = {867-873}, doi = {10.1258/ebm.2011.011023}, pmid = {21652603}, issn = {1535-3699}, mesh = {Acetylcholine/pharmacology ; Animals ; Aorta/drug effects ; *Conditioning, Psychological ; Endothelial Cells/*drug effects/*metabolism ; Hypertension/prevention &amp; control ; *Hypoxia ; Muscle, Smooth, Vascular/drug effects ; Nitric Oxide/*metabolism ; Rats ; Rats, Inbred SHR ; Vasodilator Agents/pharmacology ; }, abstract = {Although intermittent hypoxia is often associated with hypertension, experimental and clinical studies have demonstrated definite antihypertensive effects of some intermittent hypoxia conditioning (IHC) regimens. Mechanisms of this antihypertensive response are unknown. Endothelial dysfunction related to disturbed synthesis and/or reduced availability of nitric oxide (NO) has been linked to hypertension. Thus, experiments were conducted to determine if IHC can improve endothelium-dependent relaxation and formation of releasable vascular NO stores of young (4-8-week-old) spontaneously hypertensive rats (SHR). Rats were subjected to either IHC (9.5-10% O(2), 5-10 min, 5-8 times per day, 20 d) or to sham conditioning. Endothelium-dependent relaxation to acetylcholine was measured in norepinephrine-precontracted, isolated aortic rings, and the size of NO stores was evaluated by percent relaxation to N-acetylcysteine (NAC), which releases stored NO. The capacity of aortic rings for NO storage was evaluated by the relaxation to NAC after prior incubation with an NO donor. IHC significantly suppressed the development of hypertension in young SHR. Endothelial function decreased from 54.7 ± 4.6% to 28.1 ± 6.4% relaxation to acetylcholine after 20 d of sham IHC, whereas endothelial function was sustained (60.3 ± 6.0% relaxation) in IHC rats. IHC also induced formation of available NO stores and enhanced the capacity of aortic rings to store NO. Therefore, the antihypertensive effect of IHC in young SHR is associated with prevention of endothelial dysfunction and with increased accumulation of NO stores in vascular walls.}, }
@article {pmid21641783, year = {2013}, author = {Basha, RH and Priscilla, DH}, title = {An in vivo and in vitro study on the protective effects of N-acetylcysteine on mitochondrial dysfunction in isoproterenol treated myocardial infarcted rats.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {65}, number = {1-2}, pages = {7-14}, doi = {10.1016/j.etp.2011.05.002}, pmid = {21641783}, issn = {1618-1433}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/metabolism/pharmacology/*therapeutic use ; Creatine Kinase/blood ; Data Interpretation, Statistical ; Disease Models, Animal ; In Vitro Techniques ; Isoproterenol/*pharmacology ; Lipid Peroxidation/drug effects ; Male ; Microscopy, Electron, Transmission ; Mitochondria, Heart/*drug effects/enzymology/metabolism/ultrastructure ; Mitochondrial Diseases/etiology/metabolism/pathology/*prevention &amp; control ; Myocardial Infarction/*complications/metabolism/pathology ; Rats ; Rats, Wistar ; }, abstract = {Altered mitochondrial function plays an important role in the pathology of myocardial infarction. We investigated the protective effects of N-acetylcysteine on mitochondrial dysfunction in isoproterenol induced myocardial infarcted rats. Rats were pretreated with N-acetylcysteine (10 mg/kg) orally daily for 14 days. After pretreatment, rats were induced myocardial infarction by isoproterenol (100 mg/kg) at an interval of 24 h for 2 days. Lipid peroxidation products, antioxidants, lipids, mitochondrial marker enzymes and calcium in the mitochondrial heart were determined. Transmission electron microscopic and in vitro studies were also done. Isoproterenol treatment caused significant increase in mitochondrial lipid peroxides and lipids except phospholipids with significant decrease in mitochondrial antioxidants. Significant decreased activities of marker enzymes and significant increased calcium were observed in mitochondria of myocardial infarcted rats. Pretreatment with N-acetylcysteine showed significant protective effects on all the biochemical parameters and preserved the integrity of heart tissue and restored normal mitochondrial function in myocardial infarcted rats. Transmission electron microscopic findings on the structure of the heart mitochondria confirmed the protective effects and in vitro study also confirmed the antioxidant potential of NAC. The possible mechanism for the improved cardiac mitochondrial function might be due to scavenging free radicals, improving the antioxidant and mitochondrial marker enzymes, maintaining GSH levels, lipids and Ca(2+) levels by its antioxidant effect. Thus, N-acetylcysteine protected the mitochondrial heart from ISO treated mitochondrial damage. A diet containing N-acetylcysteine may be beneficial to myocardial infarcted heart.}, }
@article {pmid21640077, year = {2011}, author = {Han, CY and Hien, TT and Lim, SC and Kang, KW}, title = {Role of Pin1 in UVA-induced cell proliferation and malignant transformation in epidermal cells.}, journal = {Biochemical and biophysical research communications}, volume = {410}, number = {1}, pages = {68-74}, doi = {10.1016/j.bbrc.2011.05.106}, pmid = {21640077}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cell Proliferation ; Cell Transformation, Neoplastic/*metabolism/pathology ; Cyclin D1/biosynthesis ; Epidermis/*enzymology/pathology/*radiation effects ; Humans ; Mice ; NIMA-Interacting Peptidylprolyl Isomerase ; Peptidylprolyl Isomerase/genetics/*physiology ; Reactive Oxygen Species/metabolism ; Skin Neoplasms/*enzymology/*etiology/pathology ; Transcription Factor AP-1/metabolism ; Ultraviolet Rays ; }, abstract = {Ultraviolet A (UVA) radiation (λ = 320-400 nm) is considered a major cause of human skin cancer. Pin1, a peptidyl prolyl isomerase, is overexpressed in most types of cancer tissues and plays an important role in cell proliferation and transformation. Here, we demonstrated that Pin1 expression was enhanced by low energy UVA (300-900 mJ/cm(2)) irradiation in both skin tissues of hairless mice and JB6 C141 epidermal cells. Exposure of epidermal cells to UVA radiation increased cell proliferation and cyclin D1 expression, and these changes were blocked by Pin1 inhibition. UVA irradiation also increased activator protein-1 (AP-1) minimal reporter activity and nuclear levels of c-Jun, but not c-Fos, in a Pin1-dependent manner. The increases in Pin1 expression and in AP-1 reporter activity in response to UVA were abolished by N-acetylcysteine (NAC) treatment. Finally, we found that pre-exposure of JB6 C141 cells to UVA potentiated EGF-inducible, anchorage-independent growth, and this effect was significantly suppressed by Pin1inhibition or by NAC.}, }
@article {pmid21635874, year = {2011}, author = {Mata, M and Morcillo, E and Gimeno, C and Cortijo, J}, title = {N-acetyl-L-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV).}, journal = {Biochemical pharmacology}, volume = {82}, number = {5}, pages = {548-555}, doi = {10.1016/j.bcp.2011.05.014}, pmid = {21635874}, issn = {1873-2968}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Cell Line ; Humans ; Inflammation Mediators/*metabolism ; Influenza A virus/drug effects/physiology ; Influenza B virus/drug effects/physiology ; Mucin 5AC/*antagonists &amp; inhibitors/biosynthesis ; NF-kappa B/metabolism ; Phosphorylation ; Pulmonary Alveoli/*drug effects/metabolism/virology ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Respiratory Syncytial Viruses/drug effects/physiology ; Virus Replication/*drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {64% of chronic obstructive pulmonary disease (COPD) exacerbations are caused by respiratory infections including influenza (strains A and B) and respiratory syncytial virus (RSV). They affect the airway epithelium increasing inflammatory and apoptosis events through mechanisms involving ROS generation, and induce the release of mucins from epithelial cells that are involved in the deterioration of the patient's health during the course of the disease. The antioxidant NAC has proved useful in the management of COPD reducing symptoms, exacerbations and accelerated lung function decline. It has been shown to inhibit influenza virus replication and to diminish the release of inflammatory and apoptotic mediators during virus infection. The main objective of this study is to analyze the effects of NAC in modulating MUC5AC over-expression and release in an in vitro infection model of alveolar type II A549 cells infected with influenza (strains A and B) and RSV. We have also analyzed virus replication and different pro-inflammatory responses. Our results indicate a significant induction of MUC5AC, IL8, IL6 and TNF-alpha that is strongly inhibited by NAC at the expression and at the release level. It also decreased the intracellular H(2)O(2) concentration and restored the intracellular total thiol contents. Mechanisms of NAC included inhibition of NF-κB translocation to the cellular nucleus and phosphorylation of MAPK p38. NAC also inhibited replication of the three viruses under study. This work supports the use of antioxidants in order to ameliorate the inflammatory effects of different viral infections during COPD exacerbations.}, }
@article {pmid21635667, year = {2011}, author = {Song, MK and Kim, YJ and Song, M and Choi, HS and Park, YK and Ryu, JC}, title = {Polycyclic aromatic hydrocarbons induce migration in human hepatocellular carcinoma cells (HepG2) through reactive oxygen species-mediated p38 MAPK signal transduction.}, journal = {Cancer science}, volume = {102}, number = {9}, pages = {1636-1644}, doi = {10.1111/j.1349-7006.2011.02000.x}, pmid = {21635667}, issn = {1349-7006}, mesh = {Carcinoma, Hepatocellular/*metabolism/*pathology ; Cell Movement/*drug effects ; Cell Survival/drug effects ; Gene Expression/drug effects ; Hep G2 Cells ; Humans ; Liver Neoplasms/*metabolism/*pathology ; MAP Kinase Signaling System/drug effects ; Polycyclic Aromatic Hydrocarbons/*pharmacology ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Although polycyclic aromatic hydrocarbons (PAHs) are carcinogenic and have been extensively studied with regard to tumor formation, few studies have investigated the involvement of these environmental chemicals in tumor migration and invasion. Polycyclic aromatic hydrocarbons induce reactive oxygen species (ROS) and activate MAPK signal transduction. The p38 signaling transduction pathway, one of the most typical MAPK pathways, plays an essential role in regulating cell migration. Therefore, we investigated whether three PAHs, benzo[a]anthracene (B[a]A), benzo[k]fluoranthene (B[k]F), and indeno[1,2,3-c,d]pyrene (IND), induce migration in human hepatocellular carcinoma cell line HepG2 through ROS-mediated p38 MAPK signal transduction. Reactive oxygen species generation and p38 MAPK activity both increased in a dose-dependent manner and were prevented by SB203580, an inhibitor of p38 MAPK, and N-acetylcysteine (NAC), a ROS scavenger. Expression of migration-related genes was also increased by B[a]A, B[k]F, and IND in a dose-dependent manner and was inhibited by SB203580 and NAC. The migration of HepG2 cells, observed using the Transwell migration assay, also increased in a dose-dependent manner and was prevented by SB203580 and NAC. Our results indicate that the ROS-mediated p38 MAPK signaling pathway plays an essential role in the PAH-induced migration of HepG2 cells.}, }
@article {pmid21630435, year = {2011}, author = {Harris, CA and Resau, JH and Hudson, EA and West, RA and Moon, C and Black, AD and McAllister, JP}, title = {Reduction of protein adsorption and macrophage and astrocyte adhesion on ventricular catheters by polyethylene glycol and N-acetyl-L-cysteine.}, journal = {Journal of biomedical materials research. Part A}, volume = {98}, number = {3}, pages = {425-433}, doi = {10.1002/jbm.a.33130}, pmid = {21630435}, issn = {1552-4965}, support = {EB-002027/EB/NIBIB NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*metabolism ; Adsorption ; Animals ; Astrocytes/*cytology ; *Catheters ; Cell Adhesion ; Cell Line ; Cells, Cultured ; Coated Materials, Biocompatible/chemistry/*metabolism ; Dimethylpolysiloxanes/chemistry/metabolism ; Fibronectins/metabolism ; Macrophages/*cytology ; Mice ; Polyethylene Glycols/chemistry/*metabolism ; Proteins/*metabolism ; Rats ; Serum Albumin/metabolism ; Wettability ; }, abstract = {Cellular obstruction of poly(dimethyl)siloxane (PDMS) catheters is one of the most prevalent causes of shunt failure in the treatment of hydrocephalus. By modifying PDMS using short- and long-chain mono-functional polyethylene glycol (PEG604 and PEG5K, respectively) and N-acetyl-L-cysteine via adsorption and covalent binding (NAC and NAC/EDC/NHS, respectively), we increased surface wettability. We hypothesized that these surface modifications would inhibit protein adsorption and decrease host macrophage and astrocyte adhesion. Tested in a bioreactor set to mimic physiological flow, all modified surfaces significantly decreased albumin adsorption compared with PDMS (p < 0.05) except for PEG604-modified PDMS (p = 0.14). All four modification strategies significantly reduced (p < 0.01) fibronectin adsorption. PEG604, PEG5K, NAC, and NAC/EDC/NHS reduced the average level of macrophage adhesion by 53%, 63%, 40%, and 58% (p <.0.05 except when comparing PDMS with NAC) and astrocyte adhesion by 47%, 83%, 91%, and 72% (p < 0.05 except when comparing PDMS with PEG604), respectively. Combined with saline soak results which suggest that the surface wettability is stable over 30 days for each modification, our results are consistent with the hypothesis that these modifications decrease cell adhesion on catheters in vitro for the treatment of hydrocephalus.}, }
@article {pmid21627983, year = {2011}, author = {Tsentsevitsky, A and Nikolsky, E and Giniatullin, R and Bukharaeva, E}, title = {Opposite modulation of time course of quantal release in two parts of the same synapse by reactive oxygen species.}, journal = {Neuroscience}, volume = {189}, number = {}, pages = {93-99}, doi = {10.1016/j.neuroscience.2011.05.033}, pmid = {21627983}, issn = {1873-7544}, mesh = {Acetylcholine/*metabolism ; Acetylcysteine/pharmacology ; Action Potentials ; Adenosine Triphosphate/pharmacology ; Animals ; Antioxidants/pharmacology ; Cations, Divalent ; Ferrous Compounds/pharmacology ; Hydrogen Peroxide/pharmacology ; In Vitro Techniques ; Kinetics ; Motor Endplate/drug effects/physiology ; Rana ridibunda ; Reactive Oxygen Species/*metabolism ; Synapses/drug effects/*metabolism ; Time Factors ; }, abstract = {Reactive oxygen species (ROS) are potent regulators of transmitter release in chemical synapses, but the mechanism of this action remains almost unknown. Presynaptic modulation can change either the release probability or the time course of quantal release, which was recently recognized as an efficient mechanism determining synaptic efficiency. The nonuniform structure and a big size of the frog neuromuscular junction make it a useful model to study the action of ROS in compartments different in release probability and in time course of transmitter release. The time course (or kinetics) of quantal release could be estimated by measuring the dispersion of the synaptic delays for evoked uniquantal endplate currents (EPCs) under low release probability. Using two-electrode recording technique, the action of ROS on kinetics and release probabilities were studied at the proximal and distal parts within the same neuromuscular junction. The stable ROS hydrogen peroxide (H2O2) increased the dispersion of synaptic delays of EPCs (i.e. desynchronized quantal release) within the distal part but decreased delay dispersion (synchronized quantal release) within the proximal part of the same synapse. Unlike the opposite modulation of kinetics, H2O2 reduced release probability in both distal and proximal parts. Since ATP is released from motor nerve terminals together with acetylcholine and can be involved in ROS signaling, we tested the presynaptic action of ATP. In the presence of the pro-oxidant Fe2+, extracellular ATP, similarly to H2O2, induced significant desynchronization of release in the distal regions. The antioxidant N-acetyl-cysteine attenuated the inhibitory action of ATP on release probability and abolished the action of H2O2 and ATP in the presence of Fe2+, on release kinetics. Our data suggest that ROS induced during muscle activity could change the time course of transmitter release along the motor nerve terminal to provide fine tuning of synaptic efficacy.}, }
@article {pmid21627651, year = {2011}, author = {Yoshida, A and Yamada, K and Yamazaki, Y and Sashihara, T and Ikegami, S and Shimizu, M and Totsuka, M}, title = {Lactobacillus gasseri OLL2809 and its RNA suppress proliferation of CD4(+) T cells through a MyD88-dependent signalling pathway.}, journal = {Immunology}, volume = {133}, number = {4}, pages = {442-451}, pmid = {21627651}, issn = {1365-2567}, mesh = {Animals ; CD4-Positive T-Lymphocytes/*cytology/immunology/*metabolism ; Cell Proliferation ; Female ; Lactobacillus/classification/*genetics/*immunology ; Mice ; Mice, Inbred BALB C ; Myeloid Differentiation Factor 88/*metabolism ; RNA, Bacterial/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; }, abstract = {Recent studies have shown that probiotics are beneficial in prevention and improvement of inflammatory diseases. Accumulating evidence indicates that probiotics can modulate immune cell responses, although the specific molecular mechanism by which probiotics work remains elusive. Because T cells express receptors for microbial components, we examined whether the probiotic strain Lactobacillus gasseri OLL2809 (LG2809) and its components regulate murine CD4(+) T-cell activation. LG2809, as well as two other Lactobacillus strains, inhibited proliferation of CD4(+) T cells; LG2809 had the strongest suppressive activity among them. RNA isolated from LG2809 was also shown to have suppressive activity. We observed this suppressive effect in the culture of CD4(+) T cells stimulated with anti-CD3/CD28 treatment, suggesting a direct effect on CD4(+) T cells. In contrast, the suppressive effect was not observed for CD4(+) T cells from myeloid differentiation primary response gene 88 (MyD88) protein-deficient mice, and was abrogated in the presence of an anti-oxidant reagent, N-acetyl-cysteine (NAC). These results demonstrate that the suppressive effect of LG2809 and its RNA occurred through a MyD88-dependent signalling pathway and suggest involvement of a reactive oxygen species-dependent mechanism. LG2809 RNA injected subcutaneously suppressed delayed-type-hypersensitivity response in DO11.10 mice, and the suppression was abrogated by treatment with NAC. Collectively, these results suggest that suppression of T-cell proliferation by RNA may be one of the mechanisms when a probiotic bacterial strain exerts suppressive effects on inflammatory responses.}, }
@article {pmid21626191, year = {2011}, author = {Diabaté, S and Bergfeldt, B and Plaumann, D and Ubel, C and Weiss, C}, title = {Anti-oxidative and inflammatory responses induced by fly ash particles and carbon black in lung epithelial cells.}, journal = {Analytical and bioanalytical chemistry}, volume = {401}, number = {10}, pages = {3197-3212}, doi = {10.1007/s00216-011-5102-4}, pmid = {21626191}, issn = {1618-2650}, mesh = {Air Pollutants/analysis/*toxicity ; Cell Line ; Coal Ash/analysis/*toxicity ; Epithelial Cells/*drug effects/enzymology/immunology/*metabolism ; Glutathione/metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Incineration ; Oxidative Stress/drug effects ; Particulate Matter/analysis/*toxicity ; Reactive Oxygen Species/metabolism ; Soot/analysis/*toxicity ; }, abstract = {Combustion-derived nanoparticles as constituents of ambient particulate matter have been shown to induce adverse health effects due to inhalation. However, the components inducing these effects as well as the biological mechanisms are still not fully understood. The fine fraction of fly ash particles collected from the electrostatic precipitator of a municipal solid waste incinerator was taken as an example for real particles with complex composition released into the atmosphere to study the mechanism of early biological responses of BEAS-2B human lung epithelial cells. The studies include the effects of the water-soluble and -insoluble fractions of the fly ash and the well-studied carbon black nanoparticles were used as a reference. Fly ash induced reactive oxygen species (ROS) and increased the total cellular glutathione (tGSH) content. Carbon black also induced ROS generation; however, in contrast to the fly ash, it decreased the intracellular tGSH. The fly ash-induced oxidative stress was correlated with induction of the anti-oxidant enzyme heme oxygenase-1 and increase of the redox-sensitive transcription factor Nrf2. Carbon black was not able to induce HO-1. ROS generation, tGSH increase and HO-1 induction were only induced by the insoluble fraction of the fly ash, not by the water-soluble fraction. ROS generation and HO-1 induction were markedly inhibited by pre-incubation of the cells with the anti-oxidant N-acetyl cysteine which confirmed the involvement of oxidative stress. Both effects were also reduced by the metal chelator deferoxamine indicating a contribution of bioavailable transition metals. In summary, both fly ash and carbon black induce ROS but only fly ash induced an increase of intracellular tGSH and HO-1 production. Bioavailable transition metals in the solid water-insoluble matrix of the fly ash mostly contribute to the effects.}, }
@article {pmid21625536, year = {2011}, author = {Ye, F and Zhou, F and Bedolla, RG and Jones, T and Lei, X and Kang, T and Guadalupe, M and Gao, SJ}, title = {Reactive oxygen species hydrogen peroxide mediates Kaposi's sarcoma-associated herpesvirus reactivation from latency.}, journal = {PLoS pathogens}, volume = {7}, number = {5}, pages = {e1002054}, pmid = {21625536}, issn = {1553-7374}, support = {R01 CA096512/CA/NCI NIH HHS/United States ; R01 CA124332/CA/NCI NIH HHS/United States ; CA119889/CA/NCI NIH HHS/United States ; DE017333/DE/NIDCR NIH HHS/United States ; CA096512/CA/NCI NIH HHS/United States ; R01 DE017333/DE/NIDCR NIH HHS/United States ; R01 CA106159/CA/NCI NIH HHS/United States ; R01 CA132637/CA/NCI NIH HHS/United States ; CA124332/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Blotting, Western ; Butadienes/pharmacology ; Catalase/metabolism ; Cell Line ; Fluorescent Antibody Technique ; Glutathione/metabolism ; HEK293 Cells ; Herpesviridae Infections ; Herpesvirus 8, Human/metabolism/*physiology ; Humans ; Hydrogen Peroxide/*metabolism ; Imidazoles/pharmacology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; Nitriles/pharmacology ; Oxidative Stress ; Pyridines/pharmacology ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sarcoma, Kaposi/virology ; Signal Transduction ; *Virus Activation ; *Virus Latency ; Virus Replication ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H2O2) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H2O2. Mechanistically, H2O2 induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H2O2 scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies.}, }
@article {pmid21624489, year = {2011}, author = {Valença, SS and Rueff-Barroso, CR and Pimenta, WA and Melo, AC and Nesi, RT and Silva, MA and Porto, LC}, title = {L-NAME and L-arginine differentially ameliorate cigarette smoke-induced emphysema in mice.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {24}, number = {5}, pages = {587-594}, doi = {10.1016/j.pupt.2011.05.006}, pmid = {21624489}, issn = {1522-9629}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Arginine/*pharmacology ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; NG-Nitroarginine Methyl Ester/*pharmacology ; Neutrophils/metabolism ; Nitric Oxide/metabolism ; Oxidants/metabolism ; Oxidative Stress/drug effects ; Pulmonary Emphysema/etiology/*prevention &amp; control ; Smoke/*adverse effects ; Smoking/adverse effects ; Nicotiana ; }, abstract = {Nitric oxide (NO) represents one of the most important intra- and extracellular mediators and takes part in both biologic and pathologic processes. This study aimed to verify the treatment with an NO inhibitor and an NO substrate in pulmonary emphysema induced by cigarette smoke (CS) in a murine model. We compared N-acetylcysteine (NAC), a precursor of glutathione, to G-nitro-L-arginine-methyl ester or L-NAME (LN), which is an NO inhibitor, and to l-arginine (LA), which is a substrate for NO formation. Mice were divided into several groups: control, CS, CS + LN, CS + LA, and CS + NAC. Control and CS groups were treated daily with a vehicle, while CS + LN, CS + LA, and CS + NAC groups were treated daily with LN (60 mg/kg), LA (120 mg/kg) and NAC (200 mg/kg), respectively. The bronchoalveolar lavage was analyzed and the lungs were removed for histological and biochemical analysis. CS increases neutrophil number. Neutrophil number was lowest in CS + LN, followed by CS + LA. The lungs of CS + LN, CS + LA and CS + NAC mice were protected compared to the lungs of CS mice, but not equal to the quality of lungs in control mice. The CS group also exhibited increased oxidative stress, which was also present in the CS + LN group and to a lesser extent in the CS + LA group. Tissue inhibitor of metalloproteinase 1 and 2 increased in the CS + LN group and to a lesser extent in the CS + LA group relative to the control group. These results suggest that LN and LA treatment protected the mouse lung from CS. However, NAC treatment was more than LN and LA. We suggest that the protection conferred by LN treatment requires a balance between proteases and antiproteases, and that protection conferred by LA treatment involves the balance between oxidants and antioxidants.}, }
@article {pmid21624350, year = {2011}, author = {Bogurcu, N and Sevimli-Gur, C and Ozmen, B and Bedir, E and Korkmaz, KS}, title = {ALCAPs induce mitochondrial apoptosis and activate DNA damage response by generating ROS and inhibiting topoisomerase I enzyme activity in K562 leukemia cell line.}, journal = {Biochemical and biophysical research communications}, volume = {409}, number = {4}, pages = {738-744}, doi = {10.1016/j.bbrc.2011.05.078}, pmid = {21624350}, issn = {1090-2104}, mesh = {Antineoplastic Agents, Phytogenic/chemistry/isolation &amp; purification/*pharmacology ; *Apoptosis ; Boraginaceae/*chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage ; DNA Topoisomerases, Type I/metabolism ; Histones/metabolism ; Humans ; Mitochondria/*drug effects ; Naphthoquinones/chemistry/isolation &amp; purification/*pharmacology ; Reactive Oxygen Species/metabolism ; Topoisomerase I Inhibitors/chemistry/isolation &amp; purification/*pharmacology ; }, abstract = {Endemic Alkanna cappadocica was used to isolate novel antitumor molecules from Turkish landscapes in our previous studies. In this study, deoxyalkannin (ALCAP1), β,β-dimethylacrylalkannin (ALCAP2), acetylalkannin (ALCAP3), and alkannin (ALCAP4) as well as the novel isolated compounds 5-methoxydeoxyalkannin (ALCAP5), 8-methoxydeoxyalkannin (ALCAP6), 5-methoxyacetylalkannin (ALCAP7), 5-methoxy-β,β-dimethylacrylalkannin (ALCAP8) were characterized. The topoisomerase I (topo I) inhibitory activity of ALCAPs was investigated using in vitro plasmid relaxation assay and found that ALCAP2, 3, 4 and 7 were potent inhibitors at 2-6μM concentrations. Further, DNA damage response to ALCAP treatments was also studied by measuring the H2AX((S139)) and ATM((S1981)) phosphorylations. ALCAP2, 7 and 8 induced the DNA damage and apoptosis, consistently resulted in PARP cleavage at nanomolar concentrations in K562 leukemia cells. Moreover, when the free radical (ROS) generating capacity of the compounds was studied by 2',7'-dichlorofluorescein-diacetate assay using flow cytometry, we found that a known antioxidant N-acetyl-cysteine almost completely abrogated the H2AX((S139)) phosphorylations and the caspase 3 cleavage and activation. Thus, γH2AX((S139)) foci formation remained higher than the control, and an increase in CHK2((T68)) phosphorylation was observed by ALCAP2 and 7 treatments suggested that, these compounds can be potential therapeutics against tumor cell growth because of their unique DNA damaging abilities additional to enzyme inhibition similar to those of doxorubicin.}, }
@article {pmid21621684, year = {2011}, author = {Chu, DI and Lim, R and Heydrick, S and Gainsbury, ML and Abdou, R and D'Addese, L and Reed, KL and Stucchi, AF and Becker, JM}, title = {N-acetyl-l-cysteine decreases intra-abdominal adhesion formation through the upregulation of peritoneal fibrinolytic activity and antioxidant defenses.}, journal = {Surgery}, volume = {149}, number = {6}, pages = {801-812}, doi = {10.1016/j.surg.2011.02.015}, pmid = {21621684}, issn = {1532-7361}, mesh = {Abdomen/*surgery ; Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/pharmacology/therapeutic use ; Cells, Cultured ; Dinoprost/analogs &amp; derivatives/metabolism ; Dose-Response Relationship, Drug ; Epithelial Cells/cytology/drug effects/metabolism ; Fibrinolysis/*physiology ; Glutathione/metabolism ; Humans ; Injections, Intraperitoneal ; Male ; Models, Animal ; Oxidative Stress/drug effects ; Peritoneum/*metabolism ; Plasminogen Activator Inhibitor 1/metabolism ; Rats ; Rats, Wistar ; Tissue Adhesions/*metabolism/*prevention &amp; control ; Tissue Plasminogen Activator/metabolism ; Up-Regulation/*physiology ; Wound Healing/drug effects ; }, abstract = {BACKGROUND: Intraperitoneal adhesions occur in more than 94% of patients after abdominal surgery. Mechanisms that decrease oxidative stress and upregulate peritoneal fibrinolysis reduce adhesions. N-acetyl-l-cysteine (NAC) is a clinically relevant antioxidant whose effect on peritoneal fibrinolysis and ability to decrease adhesions has not been established. The aims of this study were to determine if NAC reduces adhesions and to characterize its potential mechanism(s) of action.<br><br>METHODS: Male Wistar rats (n = 92) received 0.9% saline (OP Control), intraperitoneal NAC (150 mg/kg, OP + NAC), or oral NAC (1200 mg/kg) twice daily on preoperative day 1, day of operation, and postoperative day 1. Adhesions were induced on the day of operation using our previously described ischemic button model. Animals were killed on postoperative day 7 for adhesion scoring. Peritoneal tissue and fluid from the intraperitoneal NAC group were measured at 24 hours for fibrinolytic activity, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), total glutathione, and 8-isoprostane (8-IP). The effect of NAC on tPA and PAI-1 production was tested in vitro in human mesothelial cells. The effect of NAC on intestinal wound healing was measured using colonic anastomotic burst pressures.<br><br>RESULTS: Intraperitoneal NAC reduced adhesions by 53% (P < .001) compared to OP Controls without affecting anastomotic wound healing. NAC increased the tPA/PAI-1 protein ratio and peritoneal fibrinolytic activity by 69% and 127%, respectively, compared to OP Controls (P < .05). NAC did not restore total glutathione levels in peritoneal adhesion tissue but decreased 8-IP by 46% and 65% (P < .05) in peritoneal tissue and fluid, respectively, compared to OP Controls. Human mesothelial cells incubated with NAC exhibited a concentration-dependent increase in the tPA/PAI-1 ratio, which supported in vivo observations (P < .05). Oral NAC did not decrease adhesions.<br><br>CONCLUSION: NAC administered intraperitoneally decreased adhesion formation while upregulating peritoneal fibrinolytic activity and antioxidant defenses without affecting normal anastomotic wound healing. These data suggest a potential new therapeutic use for NAC in adhesion prevention.}, }
@article {pmid21621586, year = {2011}, author = {Dean, OM and van den Buuse, M and Berk, M and Copolov, DL and Mavros, C and Bush, AI}, title = {N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: relevance to schizophrenia and bipolar disorder.}, journal = {Neuroscience letters}, volume = {499}, number = {3}, pages = {149-153}, doi = {10.1016/j.neulet.2011.05.027}, pmid = {21621586}, issn = {1872-7972}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bipolar Disorder/*metabolism ; Brain/*drug effects/metabolism ; Corpus Striatum/drug effects/metabolism ; Cyclohexanones/*antagonists &amp; inhibitors/pharmacology ; Dextroamphetamine/*antagonists &amp; inhibitors/pharmacology ; Disease Models, Animal ; Frontal Lobe/drug effects/metabolism ; Glutathione/*metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Schizophrenia/*metabolism ; }, abstract = {Oxidative stress and reduced brain levels of glutathione have been implicated in schizophrenia and bipolar disorder. N-acetyl cysteine (NAC) is a precursor of glutathione and has additional effects on glutamate neurotransmission, neurogenesis and inflammation. While NAC treatment has shown benefits in both schizophrenia and bipolar disorder, the mechanisms of action are largely unknown. Similarly, the interaction between oxidative stress and altered dopaminergic activities in psychiatric illness is not yet characterized. This study investigated the capacity of NAC in restoring brain glutathione depletion in rats that received 2-cyclohexene-1-one (CHX, 75 mg/kg), d-amphetamine (2.5mg/kg) or both. CHX, but not amphetamine, induced significant depletion of glutathione levels in the striatum and frontal cortex. Glutathione depletion was reversed by NAC (1000 mg/kg) in saline-treated and amphetamine-treated (frontal cortex only) rats. While NAC was shown to be beneficial in this model, the lack of additional glutathione depletion by amphetamine in combination with CHX does not support a summative interaction between oxidative stress and altered dopamine transmission.}, }
@article {pmid21620964, year = {2011}, author = {Min, KJ and Lee, JT and Joe, EH and Kwon, TK}, title = {An IκBα phosphorylation inhibitor induces heme oxygenase-1(HO-1) expression through the activation of reactive oxygen species (ROS)-Nrf2-ARE signaling and ROS-PI3K/Akt signaling in an NF-κB-independent mechanism.}, journal = {Cellular signalling}, volume = {23}, number = {9}, pages = {1505-1513}, doi = {10.1016/j.cellsig.2011.05.013}, pmid = {21620964}, issn = {1873-3913}, mesh = {Analysis of Variance ; Electrophoretic Mobility Shift Assay ; Gene Expression Regulation ; Glutathione/pharmacology ; HT29 Cells ; Heme Oxygenase-1/*metabolism ; Humans ; Immunohistochemistry ; Leupeptins/pharmacology ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/antagonists &amp; inhibitors ; Nitriles/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Proline/analogs &amp; derivatives/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Response Elements ; *Signal Transduction ; Sulfones/*pharmacology ; Thiocarbamates/pharmacology ; Transfection ; }, abstract = {Reactive oxygen species (ROS) are important signaling molecules in cells. Excessive ROS induce expression of inflammatory mediators, such as iNOS and COX2. Antioxidant enzymes, such as, heme oxygenase-1 (HO-1), tightly regulate ROS levels within cells. Here, we show that Bay 11-7082 (Bay) increased HO-1 mRNA and protein expression in human colon cancer HT29 cells. Bay induced translocation of NF-E2-related factor 2 (Nrf2) into nuclei and increased the binding activity of the antioxidant response element (ARE). In addition, PI3K/Akt inhibitor (LY294002) blocked Bay-induced HO-1 expression. Pretreatment with anti-oxidants (N-acetylcysteine (NAC) or glutathione) significantly reduced Bay-induced HO-1 mRNA/protein expression, nuclear translocation of Nrf2 and phosphorylation of Akt. However, PI3K/Akt signaling was independent of Bay-induced Nrf2 translocation and ARE binding activity. Furthermore, other NF-κB inhibitors, such as pyrrolidine dithiocarbamate (PDTC) and MG132, also increased HO-1 mRNA and protein expression. However, although overexpression of dominant negative inhibitory κB (IκB) reduced NF-κB-driven transcriptional activity, IκB overexpression did not increase HO-1 expression. Taken together, our results suggest that in human colon cancer HT29 cells, Bay induces HO-1 expression by increasing ROS production in an Nrf2-ARE and PI3K dependent manner, but Bay acts independently of NF-κB.}, }
@article {pmid21620606, year = {2011}, author = {Dai, DF and Chen, T and Szeto, H and Nieves-Cintrón, M and Kutyavin, V and Santana, LF and Rabinovitch, PS}, title = {Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy.}, journal = {Journal of the American College of Cardiology}, volume = {58}, number = {1}, pages = {73-82}, pmid = {21620606}, issn = {1558-3597}, support = {R01 HL101186/HL/NHLBI NIH HHS/United States ; P01 AG001751/AG/NIA NIH HHS/United States ; P01 AG001751-29/AG/NIA NIH HHS/United States ; R01 HL101186-01/HL/NHLBI NIH HHS/United States ; R01 HL101186-02/HL/NHLBI NIH HHS/United States ; P30 AG013280-17/AG/NIA NIH HHS/United States ; P01 AG001751-28A1/AG/NIA NIH HHS/United States ; R01 HL101186-03/HL/NHLBI NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; P30 AG013280-18/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*metabolism ; Apoptosis ; MAP Kinase Signaling System ; Mice ; Mitochondria/*metabolism ; Myocytes, Cardiac/cytology ; NADPH Oxidases/metabolism ; Oligopeptides/*metabolism ; Oxidative Stress ; Peptides/*chemistry ; Phenotype ; Reactive Oxygen Species ; Signal Transduction ; Up-Regulation ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {OBJECTIVES: We investigated the effect of reducing mitochondrial oxidative stress by the mitochondrial-targeted antioxidant peptide SS-31 in hypertensive cardiomyopathy.<br><br>BACKGROUND: Oxidative stress has been implicated in hypertensive cardiovascular diseases. Mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase have been proposed as primary sites of reactive oxygen species (ROS) generation.<br><br>METHODS: The mitochondrial targeted antioxidant peptide SS-31 was used to determine the role of mitochondrial oxidative stress in angiotensin II (Ang)-induced cardiomyopathy as well as in G&#x3b1;q overexpressing mice with heart failure.<br><br>RESULTS: Ang induces mitochondrial ROS in neonatal cardiomyocytes, which is prevented by SS-31, but not the nontargeted antioxidant N-acetyl cysteine (NAC). Continuous administration of Ang for 4 weeks in mice significantly increased both systolic and diastolic blood pressure, and this was not affected by SS-31 treatment. Ang was associated with up-regulation of NADPH oxidase 4 (NOX4) expression and increased cardiac mitochondrial protein oxidative damage, and induced the signaling for mitochondrial biogenesis. Reducing mitochondrial ROS by SS-31 substantially attenuated Ang-induced NOX4 up-regulation, mitochondrial oxidative damage, up-regulation of mitochondrial biogenesis, and phosphorylation of p38 mitogen-activated protein kinase and prevented apoptosis, concomitant with amelioration of Ang-induced cardiac hypertrophy, diastolic dysfunction, and fibrosis, despite the absence of blood pressure-lowering effect. The NAC did not show any beneficial effect. The SS-31 administration for 4 weeks also partially rescued the heart failure phenotype of G&#x3b1;q overexpressing mice.<br><br>CONCLUSIONS: Mitochondrial targeted peptide SS-31 ameliorates cardiomyopathy resulting from prolonged Ang stimulation as well as G&#x3b1;q overexpression, suggesting its potential clinical application for target organ protection in hypertensive cardiovascular diseases.}, }
@article {pmid21618676, year = {2013}, author = {Hirst, SM and Karakoti, A and Singh, S and Self, W and Tyler, R and Seal, S and Reilly, CM}, title = {Bio-distribution and in vivo antioxidant effects of cerium oxide nanoparticles in mice.}, journal = {Environmental toxicology}, volume = {28}, number = {2}, pages = {107-118}, doi = {10.1002/tox.20704}, pmid = {21618676}, issn = {1522-7278}, support = {1 R15 AI072756-01A2/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/chemistry/pharmacokinetics/*pharmacology ; Carbon Tetrachloride/toxicity ; Cell Line ; Cerium/chemistry/pharmacokinetics/*pharmacology ; Female ; Free Radical Scavengers/pharmacokinetics/pharmacology ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Lung/drug effects/metabolism ; Mice ; Nanoparticles/*chemistry ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Spleen/drug effects/metabolism ; }, abstract = {Cerium oxide nanoparticles have oxygen defects in their lattice structure that enables them to act as a regenerative free radical scavenger in a physiological environment. We performed a comprehensive in vivo analysis of the biological distribution and antioxidant capabilities of nanoceria administered to mice perorally (PO), intravenously (IV), or intraperitoneally (IP) by dosing animals weekly for 2 or 5 weeks with 0.5 mg kg(-1) nanoceria. Next, we examined if nanoceria administration would decrease ROS production in mice treated with carbon tetrachloride (CCl(4)). Our results showed that the most extensive and cumulative nano-deposition was via IV and IP administered while PO administration showed mice excreted greater than 95% of their nanoceria within 24 h. Organ deposition for IV and IP mice was greatest in the spleen followed by the liver, lungs, and kidneys. Elimination for all administration routes was through feces. Nanoceria administration showed no overt toxicity, however, WBC counts were elevated with IV and IP administration. Our in vivo studies show that nanoceria administration to mice with induced liver toxicity (by CCl(4)) showed similar findings to mice treated with N-acetyl cystine (NAC), a common therapeutic to reduce oxidative stress. Taken together, our studies show that nanoceria remains deposited in tissues and may decrease ROS, thereby suggesting that cerium oxide nanoparticles may be a useful antioxidant treatment for oxidative stress.}, }
@article {pmid21617921, year = {2011}, author = {Kıray, S and Onalan, G and Karabay, G and Zeyneloglu, H and Kuscu, E}, title = {Antioxidant prophylaxis for cellular injury in ovarian surface epithelium resulting from CO2 pneumoperitoneum in a laparoscopic rat model.}, journal = {Archives of gynecology and obstetrics}, volume = {284}, number = {3}, pages = {765-772}, doi = {10.1007/s00404-011-1933-7}, pmid = {21617921}, issn = {1432-0711}, mesh = {Acetylcysteine/pharmacology ; Amifostine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Carbon Dioxide ; Epithelium/blood supply/pathology ; Female ; Free Radical Scavengers/pharmacology ; Laparoscopy/adverse effects ; Ovary/blood supply/*pathology ; Oxidative Stress/*drug effects ; Pneumoperitoneum, Artificial/*adverse effects ; Preoperative Care ; Random Allocation ; Rats ; Rats, Wistar ; Reperfusion Injury/etiology/*prevention &amp; control ; Vitamin E/pharmacology ; }, abstract = {OBJECTIVE: Selective cytoprotective functions of vitamin E, N-acetyl-L: -cysteine, and amifostine have been used as a preventer of ischemia injury by expelling the free oxygen radicals leading to stabilization of the cellular membranes. The purpose of this experimental study was to investigate the oxidative stress related to cellular injury in ovarian surface epithelium and the effect of prophylaxis with an anti-oxidant using laparoscopic rat model.<br><br>DESIGN: Laparoscopic rat model.<br><br>MATERIALS AND METHODS: Randomly allocated 40 Wistar Albino female rats have been used for the pneumoperitoneum model which was constituted to fix the intraabdominal pressure on 5 mmHg for 60 min. The antioxidants, vitamin E and NAC were given to rats 3 days before the operation and were applied for 30 days; amifostine was applied 30 min before the operation until after for 7 days. After abdominal desufflation, over biopsies were made on the 13th min, 24th h, and 7th and 30th days. By using of transmission electron microscopy, the damage on cells and organels were assessed and graded.<br><br>RESULTS: In ovarian surface epithelium, the apical surface specializations were affected in all groups except Vit E group:The microvilli were irregular and coarse and had disappeared in some places. Some cells were separated from the epithelium. In addition, mitochondria degeneration was observed in all group except Vit E.<br><br>CONCLUSIONS: In the early period of laparoscopy, reversible cellular damage occurs and this damage can be prevented by vitamin E.}, }
@article {pmid21616516, year = {2011}, author = {Oliveira, E and Saliba, SW and Andrade, CF and Rabello, A}, title = {Direct agglutination test (DAT): improvement of biosafety for laboratory diagnosis of visceral leishmaniasis.}, journal = {Transactions of the Royal Society of Tropical Medicine and Hygiene}, volume = {105}, number = {7}, pages = {414-416}, doi = {10.1016/j.trstmh.2011.04.010}, pmid = {21616516}, issn = {1878-3503}, mesh = {*Acetylcysteine ; Agglutination Tests/*methods ; Clinical Laboratory Techniques/*standards ; Humans ; *Kaolin ; Leishmania infantum/isolation &amp; purification ; Leishmaniasis, Visceral/blood/*diagnosis ; Mercaptoethanol/*adverse effects ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {In this study, the direct agglutination test (DAT), using 2-mercaptoethanol (2-ME), kaolin or N-acetylcysteine (NAC) as sample diluents, was used to assay 89 samples from visceral leishmaniasis (VL) patients and 130 samples from patients with other diseases and healthy individuals. Maintaining a cut-off of 1:100, the DAT assays with 2-ME, kaolin or NAC presented sensitivities of 94.4%, 95.5% and 100% (P = 0.09) and specificities of 99.2%, 100% and 97.7% (P = 0.17), respectively. Based on these results, we suggest that NAC can be used as a replacement for 2-ME in the DAT, increasing biosafety in the diagnosis of VL.}, }
@article {pmid21615215, year = {2011}, author = {Buonocore, C and Alipour, M and Omri, A and Pucaj, K and Smith, MG and Suntres, ZE}, title = {Treatment of ricin A-chain-induced hepatotoxicity with liposome-encapsulated N-acetylcysteine.}, journal = {Journal of drug targeting}, volume = {19}, number = {9}, pages = {821-829}, doi = {10.3109/1061186X.2011.582645}, pmid = {21615215}, issn = {1029-2330}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Alanine Transaminase/blood ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Aspartate Aminotransferases/blood ; Chemical Warfare Agents/toxicity ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/physiopathology ; Inflammation/chemically induced/drug therapy/physiopathology ; Lipid Peroxidation/drug effects ; Liposomes ; Male ; Rats ; Rats, Sprague-Dawley ; Ricin/*toxicity ; }, abstract = {BACKGROUND: The toxicity of ricin resides in the ricin A-chain (RTA) and is attributed to the inhibition of protein synthesis but inflammation and oxidative stress have also been implicated. RTA can independently enter cells producing comparable tissue injury and inflammation, although at much higher concentrations than intact ricin. Treatment for exposure to ricin or RTA is supportive.<br><br>PURPOSE: To examine the effectiveness of conventional or liposome-encapsulated N-acetylcysteine (Lipo-NAC) in ameliorating RTA-induced hepatotoxicity.<br><br>METHODS: Four hours after RTA administration (90 &#xb5;g/kg b.wt, iv), rats were treated with conventional NAC or Lipo-NAC (25&#x2009;mg/kg NAC). The hepatoprotective effects of the antioxidant formulations were assessed by measuring indexes for liver injury (alanine [ALT] and aspartate [AST] aminotransferase activities), inflammation (myeloperoxidase, tumor necrosis factor-&#x3b1;, chloramine levels), and oxidant response (lipid peroxidation, nitrotyrosine, glutathione levels) 24-h post-RTA exposure.<br><br>RESULTS: Administration of RTA to animals resulted in hepatotoxicity as demonstrated by elevated plasma ALT and AST levels, increases in an inflammatory response, and increases in oxidant response. Treatment of animals with the antioxidant formulations reversed the RTA-induced hepatotoxicity, being most evident following the administration of Lipo-NAC.<br><br>CONCLUSION: NAC, administered in a liposomal form, may serve as a potentially effective pharmacological agent in the treatment of RTA-induced liver injuries.}, }
@article {pmid21615001, year = {2011}, author = {Amen, DG and Wu, JC and Taylor, D and Willeumier, K}, title = {Reversing brain damage in former NFL players: implications for traumatic brain injury and substance abuse rehabilitation.}, journal = {Journal of psychoactive drugs}, volume = {43}, number = {1}, pages = {1-5}, doi = {10.1080/02791072.2011.566489}, pmid = {21615001}, issn = {0279-1072}, mesh = {Adult ; Brain/diagnostic imaging ; Brain Damage, Chronic/diagnostic imaging/rehabilitation/*therapy ; Brain Injuries/diagnostic imaging/*rehabilitation/*therapy ; Cognition Disorders/psychology/rehabilitation ; Diet ; Dietary Supplements ; Football/*injuries ; Humans ; Image Processing, Computer-Assisted ; Male ; Middle Aged ; Neuropsychological Tests ; Substance-Related Disorders/*rehabilitation ; Tomography, Emission-Computed, Single-Photon ; Weight Loss ; }, abstract = {Brain injuries are common in professional American football players. Finding effective rehabilitation strategies can have widespread implications not only for retired players but also for patients with traumatic brain injury and substance abuse problems. An open label pragmatic clinical intervention was conducted in an outpatient neuropsychiatric clinic with 30 retired NFL players who demonstrated brain damage and cognitive impairment. The study included weight loss (if appropriate); fish oil (5.6 grams a day); a high-potency multiple vitamin; and a formulated brain enhancement supplement that included nutrients to enhance blood flow (ginkgo and vinpocetine), acetylcholine (acetyl-l-carnitine and huperzine A), and antioxidant activity (alpha-lipoic acid and n-acetyl-cysteine). The trial average was six months. Outcome measures were Microcog Assessment of Cognitive Functioning and brain SPECT imaging. In the retest situation, corrected for practice effect, there were statistically significant increases in scores of attention, memory, reasoning, information processing speed and accuracy on the Microcog. The brain SPECT scans, as a group, showed increased brain perfusion, especially in the prefrontal cortex, parietal lobes, occipital lobes, anterior cingulate gyrus and cerebellum. This study demonstrates that cognitive and cerebral blood flow improvements are possible in this group with multiple interventions.}, }
@article {pmid21610364, year = {2011}, author = {Koca, K and Yurttas, Y and Cayci, T and Bilgic, S and Kaldirim, U and Durusu, M and Cekli, Y and Ozkan, H and Hanci, V and Purtuloglu, T and Akgul, EO and Oguz, E and Yildiz, C and Basbozkurt, M}, title = {The role of preconditioning and N-acetylcysteine on oxidative stress resulting from tourniquet-induced ischemia-reperfusion in arthroscopic knee surgery.}, journal = {The Journal of trauma}, volume = {70}, number = {3}, pages = {717-723}, doi = {10.1097/TA.0b013e3181f30fb0}, pmid = {21610364}, issn = {1529-8809}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Analysis of Variance ; Antioxidants/metabolism ; *Arthroscopy ; Female ; Glutathione Peroxidase/metabolism ; Humans ; *Ischemic Preconditioning ; Knee Injuries/*surgery ; Male ; Malondialdehyde/metabolism ; *Oxidative Stress ; Reperfusion Injury/*prevention &amp; control ; Statistics, Nonparametric ; Superoxide Dismutase/metabolism ; Tourniquets/*adverse effects ; }, abstract = {BACKGROUND: The aim of this study was to investigate the effects of ischemic preconditioning (IPC) and N-acetylcysteine (NAC) on oxidative stress resulting from tourniquet-induced ischemia-reperfusion (IR) period in arthroscopic knee surgery.<br><br>METHODS: Forty-five patients who had arthroscopic knee surgery for meniscal and chondral lesions and for pathologic medial plica were included in this study. They were assigned to the following treatment groups: control (group C; n=15), IPC (group P; n=15), and NAC (group N; n=15). Subjects in the control group underwent routine surgical procedures. Subjects in the preconditioning group were subjected to temporary ischemia, with tourniquet performed by three compression cycles of 5 minutes followed by 5 minutes of reperfusion just before the application of tourniquet inflation. Subjects in the NAC group received 10 mg/kg NAC dissolved in 100 mL 0.9% normal saline intravenously 30 minutes before tourniquet inflation. An hour before the tourniquet was applied (preischemia) and 2 hours after tourniquet was removed (reperfusion), blood samples (to test for metabolites) were obtained. Levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (TAC), and total oxidant status (TOS) were measured in all serum samples. Results were compared between preischemia and reperfusion in three groups.<br><br>RESULTS: MDA in the control group was found to be increased significantly compared with preischemia, whereas MDA in IPC and NAC groups did not change insignificantly. SOD and GSH activities in the control group were found to be increased significantly, whereas SOD and GSH activities in IPC and NAC groups did not change significantly after reperfusion. TAC in the control group was found to be decreased and TOS was found to be increased significantly, but TAC and TOS in IPC and NAC groups were not significantly different after reperfusion. Mean serum MDA, TOS, SOD, and GSH-Px levels were lower in group P than group C at reperfusion period (p<0.05). Mean serum SOD levels were lower in group P than group N at reperfusion period (p<0.05).<br><br>CONCLUSIONS: Tourniquet-induced IR period in routine arthroscopic knee surgery resulted in oxidative stress by increasing MDA, SOD, GSH-Px, TOS and decreasing TAC. NAC and IPC had protective effect on occurrence of oxidative stress resulting from IR period by preventing MDA, SOD, GSH-Px, TAC, and TOS changes in routine arthroscopic knee surgery.}, }
@article {pmid21609276, year = {2011}, author = {Chen, N and Hanly, L and Rieder, M and Yeger, H and Koren, G}, title = {The effect of N-acetylcysteine on the antitumor activity of ifosfamide.}, journal = {Canadian journal of physiology and pharmacology}, volume = {89}, number = {5}, pages = {335-343}, doi = {10.1139/y11-028}, pmid = {21609276}, issn = {1205-7541}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents, Alkylating/adverse effects/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; *Drug Interactions ; Drug-Related Side Effects and Adverse Reactions/prevention &amp; control ; Humans ; Ifosfamide/adverse effects/*pharmacology ; Mesna/pharmacology ; Neuroblastoma ; Phosphoramide Mustards/pharmacology ; Rhabdomyosarcoma ; }, abstract = {Ifosfamide-induced nephrotoxicity is a serious adverse effect in children undergoing chemotherapy. Our previous cell and rodent models have shown that the antioxidant N-acetylcysteine (NAC), used extensively as an antidote for acetaminophen poisoning, protects renal tubular cells from ifosfamide-induced nephrotoxicity at a clinically relevant concentration. For the use of NAC to be clinically relevant in preventing ifosfamide nephrotoxicity, we must ensure there is no effect of NAC on the antitumor activity of ifosfamide. Common pediatric tumors that are sensitive to ifosfamide, human neuroblastoma SK-N-BE(2) and rhabdomyosarcoma RD114-B cells, received either no pretreatment or pretreatment with 400 µmol/L of NAC, followed by concurrent treatment with NAC and either ifosfamide or the active agent ifosfamide mustard. Ifosfamide mustard significantly decreased the growth of both cancer cell lines in a dose-dependent manner (p < 0.001). The different combined treatments of NAC alone, sodium 2-mercaptoethanesulfonate alone, or NAC plus sodium 2-mercaptoethanesulfonate did not significantly interfere with the tumor cytotoxic effect of ifosfamide mustard. These observations suggest that NAC may improve the risk/benefit ratio of ifosfamide by decreasing ifosfamide-induced nephrotoxicity without interfering with its antitumor effect in cancer cells clinically treated with ifosfamide.}, }
@article {pmid21606648, year = {2011}, author = {Schmaal, L and Berk, L and Hulstijn, KP and Cousijn, J and Wiers, RW and van den Brink, W}, title = {Efficacy of N-acetylcysteine in the treatment of nicotine dependence: a double-blind placebo-controlled pilot study.}, journal = {European addiction research}, volume = {17}, number = {4}, pages = {211-216}, doi = {10.1159/000327682}, pmid = {21606648}, issn = {1421-9891}, mesh = {Acetylcysteine/*therapeutic use ; Double-Blind Method ; Female ; Humans ; Male ; Pilot Projects ; Secondary Prevention ; Smoking Cessation/*methods/psychology ; Tobacco Use Disorder/diagnosis/*drug therapy/psychology ; Treatment Outcome ; Young Adult ; }, abstract = {Relapse is the rule rather than the exception in smokers aiming to quit smoking. Recently, evidence has emerged that glutamate transmission plays an important role in relapse. N-acetylcysteine (NAC), a cysteine prodrug, restores glutamate homeostasis and appears to be a potential new treatment for substance dependence. In the current pilot study, the effects of NAC on short-term abstinence of smoking were investigated. Subjects were heavy smokers randomized to receive placebo (n = 12) or NAC 3,600 mg/day (n = 10) in a double-blind fashion during 3.5 days. Subjects were asked to stop smoking and report on nicotine craving, nicotine withdrawal symptoms, and cigarette smoking during treatment. At the end of the treatment, subjects were invited to smoke a cigarette and to rate the rewarding effect of this cigarette. There was no significant effect of NAC on craving (p = 0.23, d = 0.52) and only a statistical trend towards fewer withdrawal symptoms in the NAC condition (p = 0.07, d = 0.80). Interestingly, subjects receiving NAC rated the first cigarette after the abstinence period of 3.5 days as significantly less rewarding than subjects on placebo (p = 0.04, d = 0.85). It is concluded that the results of this pilot study are encouraging and suggest that NAC might be a promising new treatment option for relapse prevention in nicotine dependence.}, }
@article {pmid21605919, year = {2012}, author = {Andreassi, MG and Cioppa, A and Manfredi, S and Neri, MG and Foffa, I and Picano, E}, title = {N-acetyl cysteine reduces chromosomal DNA damage in circulating lymphocytes during cardiac catheterization procedures: a pilot study.}, journal = {International journal of cardiology}, volume = {161}, number = {2}, pages = {93-96}, doi = {10.1016/j.ijcard.2011.05.001}, pmid = {21605919}, issn = {1874-1754}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Cardiac Catheterization/*adverse effects ; DNA Damage/*drug effects ; Female ; Free Radical Scavengers/*pharmacology ; Humans ; *Lymphocytes ; Male ; Middle Aged ; Pilot Projects ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is considered a promising radio-protector for its antioxidant and anticarcinogenic properties. We examined the ability of NAC to confer protection against radiation-induced chromosomal DNA damage during cardiac catheterization procedures.<br><br>METHODS: Sixty-five patients (52 males, age 64.4 &#xb1; 11.9 years) undergoing invasive cardiovascular procedures (peripheral transluminal angioplasty, n=45; cardiac resynchronization therapy, n=15 and ablation therapy n=5) were enrolled: 35 patients (26 males, age 63.4 &#xb1; 11.1 years) received the standard hydration protocol consisting of intravenous isotonic saline for 12h after catheterization (Group I), and 30 patients (26 males, age 65.5 &#xb1; 12.9 years) received a clinically driven double intravenous dose of NAC (6 mg/kg/h diluted in 250 mL of NaCl 0.9%) for 1h before and a standard dose (6 mg/kg/h diluted in 500 mL of NaCl 0.9%) for 12h following catheterization (Group II). Micronucleus assay (MN) was performed as biomarker of chromosomal DNA damage before, 2 and 24h after the radiation exposure. Dose-area product (DAP; Gy cm(2)) was assessed as physical measure of radiation load.<br><br>RESULTS: DAP was higher in NAC-treated patients (I=54.7 &#xb1; 23.6 vs II=126.2 &#xb1; 79.2 Gy cm(2), p=0.0001). MN frequency was 13.7 &#xb1; 4.7 &#x2030; at baseline and showed a significant rise at 2h (18.0 &#xb1; 6.8 p=0.01) and 24h (17.6 &#xb1; 5.9, p=0.03) in the Group I. There was no significant increase of MN in the Group II (13.7 &#xb1; 7.0, 15.5 &#xb1; 6.0 and 14.9 &#xb1; 6.3 for baseline, 2h and 24h respectively, p=0.4).<br><br>CONCLUSION: NAC treatment given to prevent contrast-induced nephropathy may also reduce DNA damage induced by ionizing radiation exposure during cardiac catheterization procedures.}, }
@article {pmid21604367, year = {2011}, author = {Kim, NR and Lim, BS and Park, HC and Son, KM and Yang, HC}, title = {Effects of N-acetylcysteine on TEGDMA- and HEMA-induced suppression of osteogenic differentiation of human osteosarcoma MG63 cells.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {98}, number = {2}, pages = {300-307}, doi = {10.1002/jbm.b.31852}, pmid = {21604367}, issn = {1552-4981}, mesh = {Acetylcysteine/*pharmacology ; Active Transport, Cell Nucleus ; Cell Differentiation/*drug effects ; Cell Line, Tumor ; Composite Resins/pharmacology ; Humans ; Methacrylates/*pharmacology ; NF-E2-Related Factor 2/metabolism ; *Osteogenesis ; Osteosarcoma/pathology ; Oxidative Stress ; Polyethylene Glycols/*pharmacology ; Polymethacrylic Acids/*pharmacology ; }, abstract = {Triethyleneglycol dimethacrylate (TEGDMA) and 2-hydroxyethyl methacrylate (HEMA) are major resinous components of dental restorative materials and dentin bonding adhesives. Resin monomers are known to cause cytotoxicity in mammalian cells via oxidative stress and inhibit differentiation of dental pulp cells and osteoblasts. This study was aimed to investigate whether oxidative stress was involved in the inhibition of TEGDMA- and HEMA-induced differentiation. TEGDMA and HEMA reduced alkaline phosphatase (ALP) activity and the mRNA expression of the osteopontin (OPN) gene in MG63 cells at noncytotoxic concentrations. On the other hand, N-acetylcysteine (NAC) did not affect ALP activity at concentrations below 10 mM. Reduced ALP activity and OPN mRNA expression by TEGDMA were partially recovered via cotreatment with NAC. However, NAC did not exhibit significant effects in HEMA-treated cells. Glutathione (GSH) levels were also down-regulated by both TEGDMA and HEMA. The addition of NAC induced the partial recovery of GSH in cells treated with 0.5 mM TEGDMA. On the other hand, the levels of GSH in HEMA-treated cells were not affected by NAC. These results suggest that oxidative stress is involved in the suppression of differentiation by TEGDMA. Translocation of Nrf2 from the cytoplasm to the nucleus has been known to play a role in the suppression of osteogenic differentiation by oxidative stress. However, Nrf2 did not move into the nucleus in resin monomer-treated MG63 cells, suggesting the contribution of other signaling pathways to the suppressive effects of resin monomers.}, }
@article {pmid21602763, year = {2011}, author = {Fitri, LE and Sardjono, TW and Simamora, D and Sumarno, RP and Setyawati, SK}, title = {High dose of N-acetylcysteine increase H2O2 and MDA levels and decrease GSH level of HUVECs exposed with malaria serum.}, journal = {Tropical biomedicine}, volume = {28}, number = {1}, pages = {7-15}, pmid = {21602763}, issn = {2521-9855}, mesh = {Acetylcysteine/*metabolism ; Cells, Cultured ; Endothelial Cells/*drug effects/*metabolism ; Glutathione/*metabolism ; Humans ; Hydrogen Peroxide/*metabolism ; Malaria/*pathology ; Malondialdehyde/*metabolism ; Serum/chemistry ; }, abstract = {Dysfunction of endothelial cells in severe malaria may result from excessive activation of tumor necrosis factor (TNF)-α which leads to an increase in production of reactive oxygen species (ROS) and decrease of antioxidant level of endothelial cells. To investigate the effect of N-acetylcysteine (NAC) on hydrogen peroxide (H2O2), malondialdehyde (MDA) and glutathione (GSH) levels produced by endothelial cells exposed with serum of malaria falciparum patient, an in vitro model of human umbilical vein endothelial cells (HUVECs) culture was used. Sample groups were normal HUVECs (group A), HUVECs that was exposed with malaria serum without any treatment (group B), HUVECs that were exposed with malaria serum and treated with NAC 2 μM (group C), HUVECs that were exposed with malaria serum and treated with NAC 4 μM (group D), and HUVECs that were exposed with malaria serum and treated with NAC 8 μM (group E). The level of MDA was measured by thio-barbituric acid reaction assay and H2O2 level was measured by NWLSS Hydrogen Peroxyde/Peroxydase Assay kit. The level of GSH was determined by using NWLSS Glutathione Assay kit. The level of H2O2 and MDA decreased after administration of low dose of NAC. Unfortunately, increased H2O2 and MDA levels were found on HUVECs treated with high dose of NAC (8 μM). There was a positive correlation between NAC dose and H2O2 level (r= 0,603) and between NAC dose and MDA level (r= 0,721). A significant decreased level of GSH was found on HUVECs treated with high dose of NAC (p = 0,023). It can be concluded that the use of high dose of NAC as supportive therapy in severe malaria infection must be taken carefully.}, }
@article {pmid21602594, year = {2011}, author = {Gabryel, B and Bielecka, A and Bernacki, J and Łabuzek, K and Herman, ZS}, title = {Immunosuppressant cytoprotection correlates with HMGB1 suppression in primary astrocyte cultures exposed to combined oxygen-glucose deprivation.}, journal = {Pharmacological reports : PR}, volume = {63}, number = {2}, pages = {392-402}, doi = {10.1016/s1734-1140(11)70505-9}, pmid = {21602594}, issn = {2299-5684}, mesh = {Animals ; Astrocytes/*drug effects/metabolism/pathology ; Cell Hypoxia ; Cells, Cultured ; Cyclosporine/administration &amp; dosage/pharmacology ; Dose-Response Relationship, Drug ; Glucose/deficiency ; HMGB1 Protein/*metabolism ; Immunosuppressive Agents/administration &amp; dosage/*pharmacology ; Inflammation/drug therapy/etiology ; Inflammation Mediators/metabolism ; Ischemia/*drug therapy/physiopathology ; Necrosis/etiology/prevention &amp; control ; Oxidative Stress ; Rats ; Rats, Wistar ; Sirolimus/administration &amp; dosage/pharmacology ; Tacrolimus/administration &amp; dosage/pharmacology ; }, abstract = {The protective potential of immunosuppressants has been reported in many experimental models of ischemia both in vivo and in vitro, suggesting a novel therapeutic application of these drugs. Because high-mobility group box 1 (HMGB1) protein has recently been reported to be involved in ischemic brain injury, the purpose of the present study was to determine whether treatment with immunosuppressants could decrease the expression and release of HMGB1 in astrocytes exposed to simulated ischemic conditions (combined oxygen-glucose deprivation, OGD). We also investigated whether immunosuppressive drugs could attenuate necrosis in astrocyte cultures exposed to OGD. Finally, we studied the influence of immunosuppressants on the expression of NFκB, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Cells were treated with cyclosporine A, FK506 and rapamycin (all drugs at concentrations of 0.1, 1 and 10 μM). Our study provides evidence that immunosuppressants decrease the expression and release of HMGB1 in ischemic astrocytes. Our data suggest that HMGB1 release may be partly an active process triggered by oxidative stress because the antioxidant N-acetylcysteine (NAC) clearly attenuated HMGB1 expression and release. Furthermore, we show that the immunosuppressants, at the same concentrations that significantly suppressed HMGB1 expression and release, were also able to prevent the necrosis of ischemic astrocytes and inhibit the expression of inflammatory mediators (NFκ, iNOS and COX-2). These results provide further information about the cytoprotective mechanisms of immunosuppressants on ischemic astrocytes, especially in relation to the pathophysiology of ischemic brain injury. It appears that the protective effects of immunosuppressants can be mediated in part by the suppressing the expression and release of HMGB1 in astrocytes, which leads to the attenuation of ischemia-induced necrosis and neuroinflammation.}, }
@article {pmid21601046, year = {2011}, author = {Jackson, AC and Kammouni, W and Fernyhough, P}, title = {Role of oxidative stress in rabies virus infection.}, journal = {Advances in virus research}, volume = {79}, number = {}, pages = {127-138}, doi = {10.1016/B978-0-12-387040-7.00008-1}, pmid = {21601046}, issn = {1557-8399}, support = {III-94590//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Disease Models, Animal ; Ganglion Cysts/pathology/virology ; Host-Pathogen Interactions ; Humans ; Mitochondria/metabolism/physiology ; Neurons/pathology/virology ; *Oxidative Stress ; Rabies/*pathology ; Rabies virus/*pathogenicity ; }, abstract = {Recent studies in an experimental model of rabies indicated that there are major structural changes in the brain involving neuronal processes that are associated with severe clinical disease. Cultured adult mouse dorsal root ganglion (DRG) neurons are a good in vitro model for studying the mechanisms involved in rabies virus-induced degeneration of neurites (axons) because, unlike other neuronal cell types, these neurons are fairly permissive to rabies virus infection. DRG neurons infected with the challenge virus standard-11 (CVS) strain of rabies virus show axonal swellings and immunostaining for 4-hydroxy-2-nonenal (4-HNE), indicating evidence of lipid peroxidation associated with oxidative stress, and also reduced axonal growth in comparison with mock-infected DRG neurons. Treatment with the antioxidant N-acetyl cysteine prevented the reduction in axonal outgrowth that occurred with CVS infection. The axonal swellings with 4-HNE-labeled puncta were found to be associated with aggregations of actively respiring mitochondria. We postulate that rabies virus infection likely induces mitochondrial dysfunction resulting in oxidative stress and degenerative changes involving neuronal processes. This mitochondrial dysfunction may be the result of either direct or indirect effects of the virus on the mitochondrial electron-transport chain or it may occur through other mechanisms. Further investigations are needed to gain a better understanding of the basic mechanisms involved in the oxidative damage associated with rabies virus infection. This information may prove helpful in the design of future therapeutic effects for this dreaded ancient disease.}, }
@article {pmid21600978, year = {2011}, author = {Mackenzie, GG and Salvador, GA and Romero, C and Keen, CL and Oteiza, PI}, title = {A deficit in zinc availability can cause alterations in tubulin thiol redox status in cultured neurons and in the developing fetal rat brain.}, journal = {Free radical biology &amp; medicine}, volume = {51}, number = {2}, pages = {480-489}, pmid = {21600978}, issn = {1873-4596}, support = {R01 HD001743/HD/NICHD NIH HHS/United States ; HD 01743/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Brain/*embryology/metabolism ; Cells, Cultured ; DNA Primers ; Neurons/cytology/*metabolism ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/*metabolism ; Tubulin/*metabolism ; Zinc/*pharmacokinetics ; }, abstract = {Zinc (Zn) deficiency during early development can result in multiple brain abnormalities and altered neuronal functions. In rats, a gestational deficit of Zn can affect the fetal brain cytoskeleton and signaling cascades involved in cellular processes that are central to brain development. In this paper, we tested the hypothesis that oxidative stress is involved in Zn deficiency-induced altered tubulin dynamics and the associated dysregulation of transcription factor NF-κB. For this purpose, we used two cell culture models (rat cortical neurons, human IMR-32 neuroblastoma cells) and an animal model of Zn deficiency. A low rate of in vitro tubulin polymerization, an increase in tubulin oligomers, and a higher protein cysteine oxidation were observed in the Zn-deficient neuronal cells and in gestation day 19 fetal brains obtained from dams fed marginal-Zn diets throughout pregnancy. These alterations could be prevented by treating the Zn-deficient cells with the reducing agent tris(2-carboxyethyl)phosphine or by the presence of N-acetylcysteine (NAC) and α-lipoic acid (LA). Consistent with the above, Zn deficiency-induced tubulin-mediated alterations in transcription factor NF-κB nuclear translocation were prevented by treating IMR-32 cells with LA and NAC. Binding of the NF-κB protein p50, dynein, and karyopherin α (components of the NF-κB transport complex) to β-tubulin as well as the expression of NF-κB-dependent genes (Bcl-2, cyclin D1, and c-myc) was also restored by the addition of LA and NAC to Zn-deficient cells. In conclusion, a deficit in Zn viability could affect early brain development through: (1) an induction of oxidative stress, (2) tubulin oxidation, (3) altered tubulin dynamics, and (4) deregulation of signals (e.g., NF-κB) involved in critical developmental events.}, }
@article {pmid21600974, year = {2011}, author = {An, JM and Kim, SS and Rhie, JH and Shin, DM and Seo, SR and Seo, JT}, title = {Carmustine induces ERK- and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {7}, pages = {1359-1365}, doi = {10.1016/j.tiv.2011.05.006}, pmid = {21600974}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Carmustine/*pharmacology ; Caspase 3/metabolism ; Cell Death/drug effects ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/genetics/*metabolism ; Glutathione Reductase/antagonists &amp; inhibitors ; MAP Kinase Kinase 4/antagonists &amp; inhibitors/genetics/*metabolism ; Neurons/cytology/*drug effects ; PC12 Cells ; Phosphorylation ; Rats ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Accumulation of reactive oxygen species (ROS) caused by the inhibition of glutathione reductase (GR) has been proposed as one of the mechanisms responsible for carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU)-induced cytotoxicity. Since mitogen-activated protein kinases (MAPKs) are known to mediate ROS-dependent cell death in multiple cell types, we examined whether redox-sensitive MAPK activation mediated the carmustine-induced cell death of neuronally differentiated PC12 cells. Carmustine induced a concentration- and time-dependent cell death, which was associated with increased caspase-3 activation, a reduction in GR activity accompanied by a concomitant decrease in reduced glutathione levels, and accumulation of ROS. Carmustine-induced caspase-3 activation and cell death were prevented by pretreatment with anti-oxidants or a reducing agent, indicating that carmustine-induced caspase-3 activation and cell death occur via redox-dependent processes. Carmustine induced phosphorylation of the MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. The activation of these kinases was inhibited by pretreatment with N-acetyl-L-cysteine (NAC). Although all the MAPKs were activated by carmustine, only the inhibitors of JNK and ERK prevented carmustine-induced cell death and caspase-3 activation. Our data suggest that carmustine-induced neurotoxicity is, at least in part, due to the activation of ROS-dependent JNK and ERK signaling.}, }
@article {pmid21600014, year = {2011}, author = {Gibson, KR and Winterburn, TJ and Barrett, F and Sharma, S and MacRury, SM and Megson, IL}, title = {Therapeutic potential of N-acetylcysteine as an antiplatelet agent in patients with type-2 diabetes.}, journal = {Cardiovascular diabetology}, volume = {10}, number = {}, pages = {43}, pmid = {21600014}, issn = {1475-2840}, support = {CZB/4/622//Chief Scientist Office/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Adenosine Diphosphate ; Diabetes Mellitus, Type 2/blood/complications/*drug therapy ; Dose-Response Relationship, Drug ; Female ; Glutathione/blood ; Humans ; Male ; Middle Aged ; Nitric Oxide/blood ; Oxidative Stress/drug effects ; Platelet Aggregation/*drug effects ; Platelet Aggregation Inhibitors/*pharmacology ; Platelet Function Tests ; Reactive Oxygen Species/blood ; Thrombin ; Thrombosis/blood/etiology/*prevention &amp; control ; }, abstract = {BACKGROUND: Platelet hyperaggregability is a pro-thrombotic feature of type-2 diabetes, associated with low levels of the antioxidant glutathione (GSH). Clinical delivery of N-acetylcysteine (NAC), a biosynthetic precursor of GSH, may help redress a GSH shortfall in platelets, thereby reducing thrombotic risk in type-2 diabetes patients. We investigated the effect of NAC in vitro, at concentrations attainable with tolerable oral dosing, on platelet GSH concentrations and aggregation propensity in blood from patients with type-2 diabetes.<br><br>METHODS: Blood samples (n = 13) were incubated (2 h, 37&#xb0;C) with NAC (10-100 micromolar) in vitro. Platelet aggregation in response to thrombin and ADP (whole blood aggregometry) was assessed, together with platelet GSH concentration (reduced and oxidized), antioxidant status, reactive oxygen species (ROS) generation, and plasma NOx (a surrogate measure of platelet-derived nitric oxide; NO).<br><br>RESULTS: At therapeutically relevant concentrations (10-100 micromolar), NAC increased intraplatelet GSH levels, enhanced the antioxidant effects of platelets, and reduced ROS generation in blood from type-2 diabetes patients. Critically, NAC inhibited thrombin- and ADP-induced platelet aggregation in vitro. Plasma NOx was enhanced by 30 micromolar NAC.<br><br>CONCLUSIONS: Our results suggest that NAC reduces thrombotic propensity in type-2 diabetes patients by increasing platelet antioxidant status as a result of elevated GSH synthesis, thereby lowering platelet-derived ROS. This may increase bioavailability of protective NO in a narrow therapeutic range. Therefore, NAC might represent an alternative or additional therapy to aspirin that could reduce thrombotic risk in type-2 diabetes.}, }
@article {pmid21598168, year = {2011}, author = {Knuckles, TL and Buntz, JG and Paffett, M and Channell, M and Harmon, M and Cherng, T and Lucas, SN and McDonald, JD and Kanagy, NL and Campen, MJ}, title = {Formation of vascular S-nitrosothiols and plasma nitrates/nitrites following inhalation of diesel emissions.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {74}, number = {13}, pages = {828-837}, pmid = {21598168}, issn = {1528-7394}, support = {R01 ES014639/ES/NIEHS NIH HHS/United States ; R01 ES014639-05/ES/NIEHS NIH HHS/United States ; R56 ES014639/ES/NIEHS NIH HHS/United States ; ES014639/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Aorta/chemistry ; Coronary Vessels/*chemistry/metabolism ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Inhalation Exposure/adverse effects ; Male ; Nitrates/analysis/*blood ; Nitric Oxide/adverse effects/blood/metabolism ; Nitric Oxide Synthase/metabolism ; Nitrites/analysis/*blood ; Rats ; Rats, Sprague-Dawley ; S-Nitrosothiols/*analysis/blood ; Vehicle Emissions/*toxicity ; }, abstract = {Epidemiological studies have associated traffic-related airborne pollution with adverse cardiovascular outcomes. Nitric oxide (NO) is a common component of fresh diesel and gasoline engine emissions that rapidly transforms both in the atmosphere and once inhaled. Because of this rapid transformation, limited information is available in terms of potential human exposures and adverse health effects. Young rats were exposed to whole diesel emissions (DE) adjusted to 300 μg/m(3) of particulate matter (containing 3.5 ppm NO) or 0, 3, or 10 ppm NO as a positive control. Animals were also pre-injected (ip) with either saline or N-acetylcysteine (NAC), a precursor of glutathione. Predictably, pure NO exposures led to a concentration-dependent increase in plasma nitrates compared to controls, which lasted for roughly 4 h postexposure. Whole DE exposure for 1 h also led to a doubling of plasma NOx. NAC injection increased the levels of plasma nitrates and nitrites (NOx) in the DE exposure group. Inhibition of nitric oxide symthase (NOS) by N(G)-nitro-L-arginine (L-NNA) did not block the rise in plasma NOx, demonstrating that the increase was entirely due to exogenous sources. Both DE and pure NO exposures paradoxically led to elevated eNOS expression in aortic tissue. Furthermore, coronary arterioles from NO-exposed animals exhibited greater constriction to endothelin-1 compared to controls, consistent with a derangement of the NOS system. Thus, NO may be an important contributor to traffic-related cardiovascular morbidity, although further research is necessary for proper hazard identification.}, }
@article {pmid21596130, year = {2011}, author = {Gloyne, LS and Grant, GD and Perkins, AV and Powell, KL and McDermott, CM and Johnson, PV and Anderson, GJ and Kiefel, M and Anoopkumar-Dukie, S}, title = {Pyocyanin-induced toxicity in A549 respiratory cells is causally linked to oxidative stress.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {7}, pages = {1353-1358}, doi = {10.1016/j.tiv.2011.05.004}, pmid = {21596130}, issn = {1879-3177}, mesh = {Cell Line, Tumor ; Epithelial Cells ; Gene Expression Regulation ; Glutathione ; Glutathione Disulfide ; Humans ; Hydrogen Peroxide/metabolism ; NF-kappa B/genetics/metabolism ; Oxidative Stress/*drug effects ; Pyocyanine/*toxicity ; Respiratory Mucosa/cytology/*drug effects ; }, abstract = {Pyocyanin, a virulence factor produced by Pseudomonas aeruginosa, has many damaging effects on mammalian cells. Several lines of evidence suggest that this damage is primarily mediated by its ability to generate ROS and deplete host antioxidant defence mechanisms. However, a causal role for oxidative stress has not yet been demonstrated conclusively. Parallel measures of ROS production, antioxidant levels and cytotoxicity provide convincing evidence that pyocyanin-induced cytotoxicity in A549 respiratory cells is mediated by acute ROS production and subsequent oxidative stress. Pyocyanin increased ROS levels in A549 cells as measured by the fluorescent H(2)O(2) probes Amplex Red and DCFH-DA. These effects were attenuated by the antioxidant N-acetylcysteine. Furthermore, pyocyanin-induced depletion of intracellular GSH levels 24h after exposure was also prevented by pre-treatment of cells with NAC. Under these conditions, NAC protected cells against pyocyanin-induced cytotoxicity as measured by resazurin reduction to resorufin and viable cell counts, strongly supporting a causal role for oxidative stress. Finally, we also show that pyocyanin-induced activation of the immune and inflammatory transcription factor NF-κB in A549 cells is likely mediated by increased ROS. This increased understanding of mechanisms underlying pyocyanin-induced cytotoxicity may ultimately lead to better strategies for reducing the virulence associated with chronic P. aeruginosa infection.}, }
@article {pmid21595915, year = {2011}, author = {Jin, WS and Kong, ZL and Shen, ZF and Jin, YZ and Zhang, WK and Chen, GF}, title = {Regulation of hypoxia inducible factor-1α expression by the alteration of redox status in HepG2 cells.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {30}, number = {1}, pages = {61}, pmid = {21595915}, issn = {1756-9966}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics/metabolism ; Antimetabolites, Antineoplastic/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Hypoxia/genetics ; Erythropoietin/genetics/metabolism ; *Gene Expression Regulation, Neoplastic/drug effects ; Hep G2 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*genetics/*metabolism ; Intracellular Space/metabolism ; Oxidation-Reduction/drug effects ; }, abstract = {Hypoxia inducible factor-1 (HIF-1) has been considered as a critical transcriptional factor in response to hypoxia. It can increase P-glycoprotein (P-Gp) thus generating the resistant effect to chemotherapy. At present, the mechanism regulating HIF-1α is still not fully clear in hypoxic tumor cells. Intracellular redox status is closely correlated with hypoxic micro-environment, so we investigate whether alterations in the cellular redox status lead to the changes of HIF-1α expression. HepG2 cells were exposed to Buthionine sulphoximine (BSO) for 12 h prior to hypoxia treatment. The level of HIF-1α expression was measured by Western blot and immunocytochemistry assays. Reduce glutathione (GSH) concentrations in hypoxic cells were determined using glutathione reductase/5,5'-dithiobis-(2-nitrob-enzoic acid) (DTNB) recycling assay. To further confirm the effect of intracellular redox status on HIF-1α expression, N-acetylcysteine (NAC) was added to culture cells for 8 h before the hypoxia treatment. The levels of multidrug resistance gene-1 (MDR-1) and erythropoietin (EPO) mRNA targeted by HIF-1α in hypoxic cells were further determined with RT-PCR, and then the expression of P-Gp protein was observed by Western blotting. The results showed that BSO pretreatment down-regulated HIF-1α and the effect was concentration-dependent, on the other hand, the increases of intracellular GSH contents by NAC could partly elevate the levels of HIF-1α expression. The levels of P-Gp (MDR-1) and EPO were concomitant with the trend of HIF-1α expression. Therefore, our data indicate that the changes of redox status in hypoxic cells may regulate HIF-1α expression and provide valuable information on tumor chemotherapy.}, }
@article {pmid21586653, year = {2011}, author = {Johnson, MT and McCammon, CA and Mullins, ME and Halcomb, SE}, title = {Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity.}, journal = {The Annals of pharmacotherapy}, volume = {45}, number = {6}, pages = {713-720}, doi = {10.1345/aph.1P613}, pmid = {21586653}, issn = {1542-6270}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/adverse effects/therapeutic use ; Adolescent ; Adult ; Aged ; Analgesics, Non-Narcotic/poisoning ; Antidotes/*administration &amp; dosage/adverse effects/therapeutic use ; Chemical and Drug Induced Liver Injury/etiology/prevention &amp; control ; Databases, Factual ; Drug Administration Schedule ; Drug Approval ; Female ; Humans ; Male ; Medication Errors/*statistics &amp; numerical data ; Middle Aged ; Off-Label Use ; Retrospective Studies ; United States ; United States Food and Drug Administration ; Young Adult ; }, abstract = {BACKGROUND: Acetaminophen overdose is the most common pharmaceutical poisoning in the US. The labeled dosing regimen for Acetadote, the only intravenous N-acetylcysteine (IV-NAC) product approved by the Food and Drug Administration (FDA) for treatment of acetaminophen toxicity, is a complex 3-step process that produces frequent medication errors. We have been using an off-label, uncomplicated dosing regimen consisting of a standard preparation of IV-NAC 30 g in 1 L of 5% dextrose in water, with a 150-mg/kg loading dose administered over 1 hour followed by an infusion of 14 mg/kg/h for 20 hours.<br><br>OBJECTIVE: To evaluate the frequency of medication errors, resolution of hepatotoxicity, and tolerability of the protocol used in our institution for treatment of acetaminophen toxicity.<br><br>METHODS: This single-center, retrospective chart review evaluated patients receiving IV-NAC for acetaminophen toxicity from August 2006 to August 2008. Charts were reviewed for prescribing practices, dosing errors, and clinical outcomes.<br><br>RESULTS: Among 70 patients who met inclusion criteria, 35 medication errors occurred, including 22 administration errors and 13 protocol initiation errors. The frequency of administration errors was 13.5 errors per 100 administration interventions. Loading dose errors were most common with 11 rate-related and 8 dose-related errors. Interruptions longer than 60 minutes occurred in only 3 patients. No adverse outcomes were associated with medication errors. The mean (SD) duration of therapy was 25.6 hours (n = 60 pts. [17.8], range 1-76.5), and mean length of stay was 2.99 days ([3.82], range 0.1-25.7). All patients with hepatotoxicity (aspartate aminotransferase >1000 units/L) due to acute acetaminophen toxicity had resolution of the toxicity and were successfully discharged.<br><br>CONCLUSIONS: This single intravenous bag protocol is effective and well tolerated, and there is infrequent interruption of therapy. The overall rate of administration errors is similar to that in reports on the FDA regimen; thus, our protocol may be an acceptable alternative.}, }
@article {pmid21584258, year = {2011}, author = {Mitsopoulos, P and Suntres, ZE}, title = {Protective Effects of Liposomal N-Acetylcysteine against Paraquat-Induced Cytotoxicity and Gene Expression.}, journal = {Journal of toxicology}, volume = {2011}, number = {}, pages = {808967}, pmid = {21584258}, issn = {1687-8205}, abstract = {Paraquat (PQ) is a herbicide that preferentially accumulates in the lung and exerts its cytotoxicity via the generation of reactive oxygen species (ROS). There is no specific treatment for paraquat poisoning. Attempts have been made to increase the antioxidant status in the lung using antioxidants (e.g., superoxide dismutase, vitamin E, N-acetylcysteine) but the outcome from such treatments is limited. Encapsulation of antioxidants in liposomes improves their therapeutic potential against oxidant-induced lung damage because liposomes facilitate intracellular delivery and prolong the retention of entrapped agents inside the cell. In the present study, we compared the effectiveness of conventional N-acetylcysteine (NAC) and liposomal-NAC (L-NAC) against PQ-induced cytotoxicity and examined the mechanism(s) by which these antioxidant formulations conferred cytoprotection. The effects of NAC or L-NAC against PQ-induced cytotoxicity in A549 cells were assessed by measuring cellular PQ uptake, intracellular glutathione content, ROS levels, mitochondrial membrane potential, cellular gene expression, inflammatory cytokine release and cell viability. Pretreatment of cells with L-NAC was significantly more effective than pretreatment with the conventional drug in reducing PQ-induced cytotoxicity, as indicated by the biomarkers used in this study. Our results suggested that the delivery of NAC as a liposomal formulation improves its effectiveness in counteracting PQ-induced cytotoxicity.}, }
@article {pmid21574020, year = {2011}, author = {Chae, HS and Park, HJ and Hwang, HR and Kwon, A and Lim, WH and Yi, WJ and Han, DH and Kim, YH and Baek, JH}, title = {The effect of antioxidants on the production of pro-inflammatory cytokines and orthodontic tooth movement.}, journal = {Molecules and cells}, volume = {32}, number = {2}, pages = {189-196}, pmid = {21574020}, issn = {0219-1032}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Cells, Cultured ; Fibroblasts/drug effects/*metabolism/pathology ; Humans ; Hypoxia ; Inflammation ; Inflammation Mediators/metabolism ; Interleukin-1beta/genetics/metabolism ; Male ; Molar/*growth &amp; development/surgery ; Periodontal Ligament/*pathology ; Rats ; Rats, Sprague-Dawley ; Resveratrol ; Stilbenes/pharmacology ; Stress, Mechanical ; Tooth Mobility/*metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism ; Up-Regulation/drug effects ; }, abstract = {Orthodontic force causes gradual compression of the periodontal ligament tissues, which leads to local hypoxia in the compression side of the tissues. In this study, we investigated whether antioxidants exert a regulatory effect on two factors: the expression of pro-inflammatory cytokines in human periodontal ligament fibroblasts (PDLFs) that were exposed to mechanical compression and hypoxia and the rate of orthodontic tooth movement in rats. Exposure of PDLFs to mechanical compression (0.5-3.0 g/cm(2)) or hypoxic conditions increased the production of intracellular reactive oxygen species. Hypoxic treatment for 24 h increased the mRNA levels of IL-1β, IL-6 and IL-8 as well as vascular endothelial growth factor (VEGF) in PDLFs. Resveratrol (10 nM) or N-acetylcysteine (NAC, 20 mM) diminished the transcriptional activity of hypoxiainducible factor-1 and hypoxia-induced expression of VEGF. Combined treatment with mechanical compression and hypoxia significantly increased the expression levels of IL-1β, IL-6, IL-8, TNF-α and VEGF in PDLFs. These levels were suppressed by NAC and resveratrol. The maxillary first molars of rats were moved mesially for seven days using an orthodontic appliance. NAC decreased the amount of orthodontic tooth movement compared to the vehicle-treated group. The results from immunohistochemical staining demonstrated that NAC suppressed the expression of IL-1β and TNF-α in the periodontal ligament tissues compared to the vehicle-treated group. These results suggest that antioxidants have the potential to negatively regulate the rate of orthodontic tooth movement through the down-regulation of pro-inflammatory cytokines in the compression sides of periodontal ligament tissues.}, }
@article {pmid21569548, year = {2011}, author = {Chen, G and Zhang, X and Zhao, M and Wang, Y and Cheng, X and Wang, D and Xu, Y and Du, Z and Yu, X}, title = {Celastrol targets mitochondrial respiratory chain complex I to induce reactive oxygen species-dependent cytotoxicity in tumor cells.}, journal = {BMC cancer}, volume = {11}, number = {}, pages = {170}, pmid = {21569548}, issn = {1471-2407}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Electron Transport Complex I/antagonists &amp; inhibitors/*metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Hep G2 Cells ; Humans ; MAP Kinase Kinase 4/metabolism ; Neoplasms/*metabolism ; Pentacyclic Triterpenes ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Triterpenes/*pharmacology ; }, abstract = {BACKGROUND: Celastrol is an active ingredient of the traditional Chinese medicinal plant Tripterygium Wilfordii, which exhibits significant antitumor activity in different cancer models in vitro and in vivo; however, the lack of information on the target and mechanism of action of this compound have impeded its clinical application. In this study, we sought to determine the mode of action of celastrol by focusing on the processes that mediate its anticancer activity.<br><br>METHODS: The downregulation of heat shock protein 90 (HSP90) client proteins, phosphorylation of c-Jun NH2-terminal kinase (JNK), and cleavage of PARP, caspase 9 and caspase 3 were detected by western blotting. The accumulation of reactive oxygen species (ROS) was analyzed by flow cytometry and fluorescence microscopy. Cell cycle progression, mitochondrial membrane potential (MMP) and apoptosis were determined by flow cytometry. Absorption spectroscopy was used to determine the activity of mitochondrial respiratory chain (MRC) complexes.<br><br>RESULTS: Celastrol induced ROS accumulation, G2-M phase blockage, apoptosis and necrosis in H1299 and HepG2 cells in a dose-dependent manner. N-acetylcysteine (NAC), an antioxidative agent, inhibited celastrol-induced ROS accumulation and cytotoxicity. JNK phosphorylation induced by celastrol was suppressed by NAC and JNK inhibitor SP600125 (SP). Moreover, SP significantly inhibited celastrol-induced loss of MMP, cleavage of PARP, caspase 9 and caspase 3, mitochondrial translocation of Bad, cytoplasmic release of cytochrome c, and cell death. However, SP did not inhibit celastrol-induced ROS accumulation. Celastrol downregulated HSP90 client proteins but did not disrupt the interaction between HSP90 and cdc37. NAC completely inhibited celastrol-induced decrease of HSP90 client proteins, catalase and thioredoxin. The activity of MRC complex I was completely inhibited in H1299 cells treated with 6 &#x3bc;M celastrol in the absence and presence of NAC. Moreover, the inhibition of MRC complex I activity preceded ROS accumulation in H1299 cells after celastrol treatment.<br><br>CONCLUSION: We identified ROS as the key intermediate for celastrol-induced cytotoxicity. JNK was activated by celastrol-induced ROS accumulation and then initiated mitochondrial-mediated apoptosis. Celastrol induced the downregulation of HSP90 client proteins through ROS accumulation and facilitated ROS accumulation by inhibiting MRC complex I activity. These results identify a novel target for celastrol-induced anticancer activity and define its mode of action.}, }
@article {pmid21567952, year = {2011}, author = {Karakosta, TD and Tzanavaras, PD and Themelis, DG}, title = {Automated pre-column derivatization of thiolic fruit-antibrowning agents by sequential injection coupled to high-performance liquid chromatography using a monolithic stationary phase and an in-loop stopped-flow approach.}, journal = {Journal of separation science}, volume = {34}, number = {16-17}, pages = {2240-2246}, doi = {10.1002/jssc.201100184}, pmid = {21567952}, issn = {1615-9314}, mesh = {Agrochemicals/*analysis/pharmacology ; Chromatography, High Pressure Liquid/instrumentation/*methods ; Fruit/drug effects ; Sulfhydryl Compounds/*analysis/pharmacology ; }, abstract = {The present study reports the very first application of ethyl propiolate (EP) as an advantageous pre-column derivatization reagent for the determination of thiols by liquid chromatography (LC). Cysteine (CYS), glutathione (GSH) and N-acetylcysteine (NAC) were derivatized online under stopped-flow conditions in a sequential injection (SI) system coupled to HPLC. The formed derivatives were separated isocratically with a monolithic stationary phase (100×4.6 mm id) and UV detected at 285 nm. Critical parameters that affected the online pre-column derivatization reaction (e.g. the reaction time and the amount concentration of EP) and the separation (e.g. pH and the composition of the mobile phase) were investigated. The developed analytical scheme offers a total analysis time of less than 10 min, limits of detection in the range of 0.24-0.35 μmol/L and satisfactory linearity up to 200 μmol/L for all analytes. The proposed method was applied to the analysis of the selected thiols--that are often employed as antibrowning agents--in fresh fruit samples.}, }
@article {pmid21567508, year = {2012}, author = {Murapa, P and Dai, J and Chung, M and Mumper, RJ and D'Orazio, J}, title = {Anthocyanin-rich fractions of blackberry extracts reduce UV-induced free radicals and oxidative damage in keratinocytes.}, journal = {Phytotherapy research : PTR}, volume = {26}, number = {1}, pages = {106-112}, doi = {10.1002/ptr.3510}, pmid = {21567508}, issn = {1099-1573}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthocyanins/isolation &amp; purification/*pharmacology/therapeutic use ; Antioxidants/*metabolism/pharmacology/therapeutic use ; Catalase/metabolism ; Fruit ; Glutathione/metabolism ; Keratinocytes/*drug effects/metabolism/radiation effects ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; Plant Extracts/chemistry/*pharmacology/therapeutic use ; Radiation Injuries/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Rosaceae/*chemistry ; Skin/drug effects/metabolism/radiation effects ; Skin Diseases/etiology/metabolism/*prevention &amp; control ; Superoxide Dismutase/metabolism ; Ultraviolet Rays ; Up-Regulation ; }, abstract = {Hull blackberries were purified using solid phase extraction to obtain anthocyanin-rich methanol fractions. This method concentrated phenolics and anthocyanins, recovering 97% and 76% of the total yield in puree or powder extracts, respectively, which represented a 24-63 fold increase of the total antioxidant capacity when compared with either the water fraction or the original extract. The ability of these fractions to protect primary keratinocytes against UV-induced oxidative damage was assessed. Anthocyanin-rich methanol fractions derived from either blackberry powder or puree exhibited strong antioxidant properties, protecting against UV-induced ROS nearly as efficiently as N-acetyl cysteine. Furthermore, the fractions up-regulated the expression of catalase, MnSOD, Gpx1/2 and Gsta1 antioxidant enzymes. Thus, it is concluded that blackberry extracts may protect keratinocytes against UV-mediated oxidative damage.}, }
@article {pmid21567078, year = {2011}, author = {Srisuttee, R and Koh, SS and Park, EH and Cho, IR and Min, HJ and Jhun, BH and Yu, DY and Park, S and Park, DY and Lee, MO and Castrillon, DH and Johnston, RN and Chung, YH}, title = {Up-regulation of Foxo4 mediated by hepatitis B virus X protein confers resistance to oxidative stress-induced cell death.}, journal = {International journal of molecular medicine}, volume = {28}, number = {2}, pages = {255-260}, doi = {10.3892/ijmm.2011.699}, pmid = {21567078}, issn = {1791-244X}, mesh = {Animals ; Cell Death ; Cell Line ; Cell Nucleus/metabolism ; Forkhead Transcription Factors/antagonists &amp; inhibitors/*genetics/*metabolism ; Gene Expression Regulation ; Humans ; MAP Kinase Kinase 4/antagonists &amp; inhibitors ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidative Stress/*genetics ; Protein Transport/genetics ; Reactive Oxygen Species/metabolism ; Trans-Activators/*genetics/*metabolism ; *Up-Regulation ; Viral Regulatory and Accessory Proteins ; }, abstract = {The hepatitis B virus X (HBX) protein, a regulatory protein of the hepatitis B virus (HBV), has been shown to generate reactive oxygen species (ROS) in human liver cell lines; however, the mechanism by which cells protect themselves under this oxidative stress is poorly understood. Here, we show that HBX induces the up-regulation of Forkhead box class O 4 (Foxo4) not only in Chang cells stably expressing HBX (Chang-HBX) but also in primary hepatic tissues from HBX-transgenic mice. HBX also increased ROS, but reduction of the abundance of ROS using N-acetylcystein (NAC) diminished the levels of Foxo4. Elevated Foxo4 was also detected in nuclei of Chang-HBX cells but not in Chang cells stably expressing the vector (Chang-Vec), suggesting that HBX activates the transcriptional activity of Foxo4. When we examined whether HBX bypasses JNK signaling that targets Foxo4, we found that the activity of JNK but not of ERK is required for the up-regulation of Foxo4 even in the presence of HBX. Furthermore, the reduction of Foxo4 levels using siRNA or a JNK inhibitor rendered Chang-HBX cells sensitive to apoptosis under oxidative stress, suggesting that up-regulation of Foxo4 mediated by HBX enhances resistances to oxidative stress-induced cell death. Accordingly, we propose that Foxo4 may be a useful target for suppression in the treatment of HBV-associated hepatocellular carcinoma cells.}, }
@article {pmid21565364, year = {2011}, author = {Chen, TH and Lin, CY and Tseng, MC}, title = {Behavioral effects of titanium dioxide nanoparticles on larval zebrafish (Danio rerio).}, journal = {Marine pollution bulletin}, volume = {63}, number = {5-12}, pages = {303-308}, doi = {10.1016/j.marpolbul.2011.04.017}, pmid = {21565364}, issn = {1879-3363}, mesh = {Animals ; Dose-Response Relationship, Drug ; Embryo, Nonmammalian/abnormalities/*drug effects ; Larva/drug effects ; Metal Nanoparticles/*toxicity ; Titanium/*toxicity ; Water Pollutants, Chemical/*toxicity ; Zebrafish ; }, abstract = {In this study, zebrafish embryos were exposed to titanium dioxide nanoparticles (TiO2 NPs at 0.1, 0.5, 1, 5, 10 mg/L or control) from fertilization to free swimming stage. Hatchability, survival, and malformation rate were not affected by TiO2 NPs at these exposure levels. However, larval swimming parameters, including average and maximum velocity and activity level were significantly affected by TiO2 NPs. Co-exposure to either the glutathione precursor, N-acetylcysteine (NAC), or the glutathione synthesis inhibitor, buthionine sulfoximine (BSO), did not significantly alter the behavioral effects resulting from TiO2 NPs, suggesting that other factor(s) besides oxidative stress may contribute to the behavioral toxicity of TiO2 NPs. Our study also demonstrated that the behavioral endpoints were more sensitive than the others (e.g., hatchability and survival) to detect toxicity of TiO2 NPs on developing fish.}, }
@article {pmid21563917, year = {2011}, author = {Romanque, P and Cornejo, P and Valdés, S and Videla, LA}, title = {Thyroid hormone administration induces rat liver Nrf2 activation: suppression by N-acetylcysteine pretreatment.}, journal = {Thyroid : official journal of the American Thyroid Association}, volume = {21}, number = {6}, pages = {655-662}, doi = {10.1089/thy.2010.0322}, pmid = {21563917}, issn = {1557-9077}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Body Temperature/drug effects ; Cell Nucleus/drug effects/metabolism ; Cytosol/drug effects/metabolism ; Liver/drug effects/metabolism ; Male ; NF-E2-Related Factor 2/*metabolism ; Protein Transport/*drug effects ; Rats ; Rats, Sprague-Dawley ; Thioredoxins/metabolism ; Triiodothyronine/*pharmacology ; }, abstract = {BACKGROUND: Oxidative stress associated with 3,3',5-triiodo-l-thyronine (T(3))-induced calorigenesis upregulates the hepatic expression of mediators of cytoprotective mechanisms. The aim of this study was to evaluate the hypothesis that in vivo T(3) administration triggers a redox-mediated translocation of the cytoprotective nuclear transcription factor erythroid 2-related factor 2 (Nrf2) from the cytosol to the nucleus in rat liver. Such translocation of transcription factors is considered to be an activating step.<br><br>MATERIALS AND METHODS: The effect of T(3) administration in the presence and absence of N-acetylcysteine (NAC) on cytosol-to-nuclear translocation of Nrf2 was evaluated, with inhibition of this process by NAC taken as evidence that the process was redox mediated. Male Sprague-Dawley rats weighing 180-200&#x2009;g were given a single intraperitoneal dose of 0.1&#x2009;mg T(3)/kg. Another group of rats were given the same dose of T(3) and were also pretreated with NAC (0.5&#x2009;g/kg) at 0.5 hour before T(3) administration. Two other groups of rats received vehicle treatment and NAC, respectively. Following these treatments, rectal temperature of the animals, liver O(2) consumption, serum and hepatic levels of 8-isoprostanes, and liver protein levels of Nrf2, Akt, p38, and thioredoxin (Western blot) were determined at different times up to 48 hours.<br><br>RESULTS: T(3) administration induced a significant increase in the hepatic nuclear levels of Nrf2 at 1 and 2 hours after treatment and a concomitant decrease in cytosolic Nrf2. It also increased hepatic thioredoxin, a protein whose gene transcription is induced by nuclear Nrf2. Levels of nuclear Nrf2 were at a plateau from 4 to 6 hours after T(3). Rectal temperature of the animals rose from 36.6&#xb0;C to 37.5&#xb0;C as did liver O(2) consumption. Serum and liver 8-isoprostanes levels increased (p&#x2009;<&#x2009;0.05) from 38.4&#x2009;&#xb1;&#x2009;4.0&#x2009;pg/mL (n&#x2009;=&#x2009;4) to 69.2&#x2009;&#xb1;&#x2009;2.0&#x2009;pg/mL (n&#x2009;=&#x2009;3) and from 0.75&#x2009;&#xb1;&#x2009;0.09&#x2009;ng/g liver (n&#x2009;=&#x2009;3) to 1.53&#x2009;&#xb1;&#x2009;0.10&#x2009;ng/g liver (n&#x2009;=&#x2009;5), respectively. In the group of rats pretreated with NAC, the increase in cytosol-to-nuclear translocation of Nrf2 was only 28% that induced by T(3). In addition, T(3) induced liver Akt and p38 activation during the period of 1-4 hours after T(3) administration. p38 activation at 2 hours after T(3) administration was abolished in NAC-pretreated animals.<br><br>CONCLUSIONS: In vivo T(3) administration leads to a rapid and transient cytosol-to-nuclear translocation of liver Nrf2. This appears to be promoted by a redox-dependent mechanism as it is blocked by NAC. It may also be contributed by concomitant p38 activation, which in turn promoted Nrf2 phosphorylation. Nrf2 cytosol-to-nuclear translocation may represent a novel cytoprotective mechanism of T(3) to limit free radical or electrophile toxicity, as this would likely entail promoting thioredoxin production.}, }
@article {pmid21563467, year = {2011}, author = {Yang, W and Hu, B and Chen, G and Bielefeld, EC and Henderson, D}, title = {[L-NAC protect hair cells in the rat cochlea from injury of exposure to styrene].}, journal = {Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery}, volume = {25}, number = {4}, pages = {176-179}, pmid = {21563467}, issn = {2096-7993}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cochlea/cytology/*drug effects ; Evoked Potentials, Auditory, Brain Stem ; Hair Cells, Auditory/*drug effects/pathology ; Lysine/*analogs &amp; derivatives/pharmacology ; Rats ; Rats, Long-Evans ; Styrene/*adverse effects ; }, abstract = {OBJECTIVE: To observe the effects of N-acetyl-L-cysteine (L-NAC) protect hair cells in the rat cochlea from injury of exposure to styrene.<br><br>METHOD: Seventeen adult Long Evans rats were used in present study. The animals were randomly assigned into test group (n=9) and control group (n=8). The animals were exposed to styrene by gavage at 400 mg/kg (2 g styrene was mixed with 1 ml olive oil). Test group animals received styrene exposure plus L-NAC 325 mg/kg (L-NAC was dissolved in physiological saline solution) by intraperitoneal injection. Treatment was performed once a day, 5 days per week for 3 weeks. Control group animals received the same volume of saline injection on an identical time schedule used for the test group. The auditory brainstem response (ABR) thresholds of both ears elicited with clicks were measured before and at the end of the 3-week styrene or styrene plus L-NAC treatment. After hearing was re-assessed, animals were sacrificed and cochleae were quickly removed from the skull. Following fixation, whole specimens comprising the basilar membrane with Corti's organ were separated from the modiolus. The organs of Corti were stained with propidium iodide (PI) and the TUNEL assay to visualize the morphologic viability of hair cell nuclei, FITC-labeled phalloidin, a F-actin intercalating fluorescent probe used to visualize the morphologic viability of cuticular plate and the stereocilia in the hair cells. Each organ of Corti was thoroughly examined using fluorescence microscopy. The numbers of damaged OHCs (apoptotic, necrotic and missing OHCs) were documented.<br><br>RESULT: There was a statistically significant decrease in ABR threshold shift (P<0.05) in the styrene-plus-L-NAC treated animals. The average percentage of damaged OHCs in the styrene-treated animals was 28.3%. In contrast, the average percentage of OHC damage in the styrene-plus-L-NAC treated group was only 10.6% (P<0.01). The percentage of reduction in the number of apoptotic cells in styrene-plus-L-NAC treated group was 78% (P<0.01). However, the mean reduction of necrotic cells was only 23% (P>0.05).<br><br>CONCLUSION: The results indicate that the treatment with L-NAC may effectively protect against the styrene-induced hair cells damage and preferably reduce the number of apoptotic OHCs.}, }
@article {pmid21562285, year = {2011}, author = {Kim-Han, JS and Antenor-Dorsey, JA and O'Malley, KL}, title = {The parkinsonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine axons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {31}, number = {19}, pages = {7212-7221}, pmid = {21562285}, issn = {1529-2401}, support = {P30 NS057105/NS/NINDS NIH HHS/United States ; R01 NS039084-11/NS/NINDS NIH HHS/United States ; NS057105/NS/NINDS NIH HHS/United States ; R56 NS039084/NS/NINDS NIH HHS/United States ; R01 NS039084/NS/NINDS NIH HHS/United States ; NS39084/NS/NINDS NIH HHS/United States ; }, mesh = {1-Methyl-4-phenylpyridinium/*pharmacology ; Analysis of Variance ; Animals ; Autophagy/drug effects ; Axonal Transport/*drug effects ; Axons/*drug effects/metabolism ; Cell Survival/drug effects ; Dopamine/*metabolism ; Mice ; Mitochondria/*drug effects/metabolism ; Nerve Degeneration/chemically induced/metabolism ; Neurons/drug effects/metabolism ; Neurotoxins/*pharmacology ; }, abstract = {Impaired axonal transport may play a key role in Parkinson's disease. To test this notion, a microchamber system was adapted to segregate axons from cell bodies using green fluorescent protein-labeled mouse dopamine (DA) neurons. Transport was examined in axons challenged with the DA neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+). MPP+ rapidly reduced overall mitochondrial motility in DA axons; among motile mitochondria, anterograde transport was slower yet retrograde transport was increased. Transport effects were specific for DA mitochondria, which were smaller and transported more slowly than their non-DA counterparts. MPP+ did not affect synaptophysin-tagged vesicles or any other measureable moving particle. Toxin effects on DA mitochondria were not dependent upon ATP, calcium, free radical species, JNK, or caspase3/PKC pathways but were completely blocked by the thiol-anti-oxidant N-acetyl-cysteine or membrane-permeable glutathione. Since these drugs also rescued processes from degeneration, these findings emphasize the need to develop therapeutics aimed at axons as well as cell bodies to preserve "normal" circuitry and function as long as possible.}, }
@article {pmid21561400, year = {2011}, author = {Sakloetsakun, D and Iqbal, J and Millotti, G and Vetter, A and Bernkop-Schnürch, A}, title = {Thiolated chitosans: influence of various sulfhydryl ligands on permeation-enhancing and P-gp inhibitory properties.}, journal = {Drug development and industrial pharmacy}, volume = {37}, number = {6}, pages = {648-655}, doi = {10.3109/03639045.2010.534484}, pmid = {21561400}, issn = {1520-5762}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*antagonists &amp; inhibitors ; Animals ; Chitosan/*chemistry/pharmacology ; Dextrans/administration &amp; dosage/pharmacokinetics ; Drug Carriers/*chemistry/pharmacology ; Fluorescein-5-isothiocyanate/administration &amp; dosage/analogs &amp; derivatives/pharmacokinetics ; Fluorescent Dyes/administration &amp; dosage/pharmacokinetics ; Freeze Drying ; Intestinal Absorption/drug effects ; Intestinal Mucosa/metabolism ; Male ; Permeability ; Rats ; Rats, Wistar ; Rhodamine 123/administration &amp; dosage/pharmacokinetics ; Sulfhydryl Compounds/chemistry/pharmacology ; }, abstract = {PURPOSE: The influence of various sulfhydryl ligands on permeation-enhancing and P-glycoprotein (P-gp) inhibitory properties of the six established thiolated chitosan conjugates was investigated using Rhodamine-123 (Rho-123) and fluorescein isothiocyanate-dextran 4 (FD4) as model compounds.<br><br>METHODS: Permeation of these compounds was tested on freshly excised rat intestine in Ussing-type chambers. Apparent permeability coefficients (Papp) were calculated and compared to values obtained from the buffer only control.<br><br>RESULTS: The lyophilized polymers had a thiol group content in the range of 230-520 &#x3bc;mol/g. Results of this study led to the following rank order in permeation enhancement: chitosan-6-mercaptonicotinic acid (chitosan-6MNA) > chitosan-cysteine (chitosan-Cys) > chitosan-glutathione (chitosan-GSH) > chitosan-4-thiobutylamidine (chitosan-TBA) > chitosan-thioglycolic acid (chitosan-TGA) > chitosan-N-acetyl cysteine (chitosan-NAC). In P-gp inhibition studies, 0.5% (m/v) chitosan-NAC showed the highest inhibitory effect on P-gp, where the Papp was determined to be 3.78-fold increased compared with the buffer control. Among these thiolated chitosans, chitosan-NAC and chitosan-6MNA are the most effective polymers being responsible for P-gp inhibition and permeation enhancement, respectively.<br><br>CONCLUSION: These thiolated chitosans would therefore be advantageous tools for enhancing the noninvasive bioavailability of active pharmaceutical ingredients.}, }
@article {pmid21558814, year = {2011}, author = {Whitaker-Menezes, D and Martinez-Outschoorn, UE and Lin, Z and Ertel, A and Flomenberg, N and Witkiewicz, AK and Birbe, RC and Howell, A and Pavlides, S and Gandara, R and Pestell, RG and Sotgia, F and Philp, NJ and Lisanti, MP}, title = {Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {10}, number = {11}, pages = {1772-1783}, pmid = {21558814}, issn = {1551-4005}, support = {R01 CA075503/CA/NCI NIH HHS/United States ; R01 CA098779/CA/NCI NIH HHS/United States ; R01-CA-120876/CA/NCI NIH HHS/United States ; R01 CA120876/CA/NCI NIH HHS/United States ; R01-CA-70896/CA/NCI NIH HHS/United States ; R01-CA-098779/CA/NCI NIH HHS/United States ; R01-CA-86072/CA/NCI NIH HHS/United States ; R01-AR-055660/AR/NIAMS NIH HHS/United States ; R01-CA-080250/CA/NCI NIH HHS/United States ; R01 CA070896/CA/NCI NIH HHS/United States ; R01 EY012042/EY/NEI NIH HHS/United States ; P30 CA056036/CA/NCI NIH HHS/United States ; P30-CA-56036/CA/NCI NIH HHS/United States ; R01-CA-107382/CA/NCI NIH HHS/United States ; R01 AR055660/AR/NIAMS NIH HHS/United States ; R01-CA-75503/CA/NCI NIH HHS/United States ; R01 CA080250/CA/NCI NIH HHS/United States ; R01 CA086072/CA/NCI NIH HHS/United States ; R01 EY012042-10A2/EY/NEI NIH HHS/United States ; R01 CA107382/CA/NCI NIH HHS/United States ; }, mesh = {Breast Neoplasms/*metabolism/pathology ; Cell Line, Tumor ; Coculture Techniques ; Epithelial Cells ; Female ; Fibroblasts/*metabolism ; Humans ; Lactates/metabolism ; Monocarboxylic Acid Transporters/*metabolism ; Muscle Proteins/*metabolism ; *Oxidative Stress ; Stromal Cells ; }, abstract = {Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to "feed" adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. These data are consistent with the "reverse Warburg effect," which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, "energy transfer" or "metabolic-coupling" between the tumor stroma and epithelial cancer cells "fuels" tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCT inhibitors.}, }
@article {pmid21558576, year = {2011}, author = {Ferreira, LF and Campbell, KS and Reid, MB}, title = {N-acetylcysteine in handgrip exercise: plasma thiols and adverse reactions.}, journal = {International journal of sport nutrition and exercise metabolism}, volume = {21}, number = {2}, pages = {146-154}, pmid = {21558576}, issn = {1526-484X}, support = {R01 AR055974/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects/metabolism ; Adult ; Athletic Performance/physiology ; Cross-Over Studies ; Cysteine/blood ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Glutathione/blood ; Hand Strength/*physiology ; Humans ; Male ; Middle Aged ; Sulfhydryl Compounds/*blood ; Young Adult ; }, abstract = {UNLABELLED: N-acetylcysteine (NAC) is a thiol donor with antioxidant properties that has potential use as an ergogenic aid. However, NAC is associated with adverse reactions that limit its use in humans.<br><br>PURPOSE: The authors evaluated NAC efficacy as a thiol donor before handgrip exercise, measuring changes in serum cysteine and glutathione status and recording adverse reactions in adult subjects across a range of doses.<br><br>METHODS: Healthy individuals ingested NAC capsules (9 &#xb1; 2 or 18 &#xb1; 4 mg/kg) or solution (0, 35, 70, or 140 mg/kg). Venous blood samples were collected and subjects answered a questionnaire about adverse reactions.<br><br>RESULTS: Low doses of NAC (capsules) did not affect plasma cysteine or glutathione or cause adverse reactions. Adverse reactions to NAC solution were predominantly mild and gastrointestinal (GI). Intensity of GI reactions to 140 mg/kg NAC was significantly higher than placebo (in a.u., 0.67 &#xb1; 0.16 vs. 0.07 &#xb1; 0.04; p < .05). Plasma cysteine concentration increased with NAC dose from 9.3 &#xb1; 0.7 &#x3bc;M (placebo) to 65.3 &#xb1; 6.7 &#x3bc;M (140 mg/kg); however, there was no difference (p > .05) in plasma cysteine for 70 mg/kg vs. 140 mg/kg. Similar increases were observed for the ratio of cysteine to total cysteine, which was directly related to handgrip exercise performance. Plasma glutathione was elevated and oxidized glutathione diminished (p < .05) with NAC 140 mg/kg vs. placebo.<br><br>CONCLUSION: NAC effects on plasma thiols are maximized by oral administration of 70 mg/kg, a dose that does not cause significant adverse reactions.}, }
@article {pmid21558131, year = {2011}, author = {Priya, S and Vijayalakshmi, P and Vivekanandan, P and Karthikeyan, S}, title = {Influence of N-acetylcysteine against dimethylnitrosamine induced hepatotoxicity in rats.}, journal = {Toxicology and industrial health}, volume = {27}, number = {10}, pages = {914-922}, doi = {10.1177/0748233711399323}, pmid = {21558131}, issn = {1477-0393}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Antioxidants/metabolism ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/pathology/*prevention &amp; control ; Dimethylnitrosamine/*toxicity ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism/pathology ; Liver Function Tests ; Male ; Oxidative Stress/drug effects ; Oxidoreductases/metabolism ; Rats ; Rats, Wistar ; }, abstract = {This study evaluates the hepatoprotective and antioxidant properties of N-acetylcysteine (NAC) on dimethylnitrosamine (DMN) induced hepatotoxicity in male Wistar albino rats. A single intraperitoneal dose of DMN (5 mg/kg b.w.) caused a significant increase in the levels of the serum marker enzymes (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutamyl transpeptidase (γ-GT)) and a subsequent decrease in AST, ALT, ALP and increase in LDH and γ-GT in the liver tissue indicating hepatocellular damage. Elevation in the status of lipid peroxidation, fall in the activities of the enzymic (superoxide dismutase, catalase) and non-enzymic antioxidants (vitamin C, vitamin E) in the liver tissue further confirms oxidative stress and hepatocellular damage induced on DMN administration. Oral administration of NAC (50 mg/kg b.w.) for 7 days significantly prevented the above alterations in the status of the marker enzymes of hepatotoxicity and antioxidant parameters and restored them towards normalcy, which was further substantiated by the histopathological studies of the liver tissue. These results suggest that NAC offers hepatoprotection by ameliorating DMN-induced oxidative stress and hepatotoxicity and this protective effect was attributed to its antioxidant and free radical scavenging properties.}, }
@article {pmid21557581, year = {2011}, author = {Neudörffer, A and Mueller, M and Martinez, CM and Mechan, A and McCann, U and Ricaurte, GA and Largeron, M}, title = {Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate.}, journal = {Chemical research in toxicology}, volume = {24}, number = {6}, pages = {968-978}, pmid = {21557581}, issn = {1520-5010}, support = {R01 DA005707-14/DA/NIDA NIH HHS/United States ; F32 DA005707/DA/NIDA NIH HHS/United States ; R01 DA005707/DA/NIDA NIH HHS/United States ; K05 DA017964-05/DA/NIDA NIH HHS/United States ; DA 05707/DA/NIDA NIH HHS/United States ; DA 01796401/DA/NIDA NIH HHS/United States ; K05 DA017964/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemical synthesis/chemistry/toxicity ; Adrenergic Uptake Inhibitors/*chemical synthesis/chemistry/*toxicity ; Animals ; Brain/drug effects/metabolism ; Hydroxyindoleacetic Acid/metabolism ; Male ; Methamphetamine/*analogs &amp; derivatives/chemical synthesis/chemistry/toxicity ; N-Methyl-3,4-methylenedioxyamphetamine/*analogs &amp; derivatives/chemical synthesis/chemistry/toxicity ; Neurotoxicity Syndromes/metabolism ; Neurotoxins/chemical synthesis/chemistry/toxicity ; Rats ; Rats, Sprague-Dawley ; Serotonin/metabolism ; }, abstract = {The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, "ecstasy"), or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), play a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating that persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in the brains of these animals was not related to the unstable nature of the THMA molecule because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA or oxidized cyclic forms (e.g., the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo.}, }
@article {pmid21554703, year = {2011}, author = {Garigliany, MM and Desmecht, DJ}, title = {N-acetylcysteine lacks universal inhibitory activity against influenza A viruses.}, journal = {Journal of negative results in biomedicine}, volume = {10}, number = {}, pages = {5}, pmid = {21554703}, issn = {1477-5751}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antiviral Agents/*pharmacology/therapeutic use ; Chlorocebus aethiops ; Female ; Influenza A Virus, H1N1 Subtype/*drug effects ; Mice ; Orthomyxoviridae Infections/drug therapy/virology ; Vero Cells ; Virus Replication/drug effects ; }, abstract = {N-acetylcysteine (NAC) has been recently proposed as an adjuvant therapeutic drug for influenza pneumonia in humans. This proposal is based on its ability to restrict influenza virus replication in vitro and to attenuate the severity of the disease in mouse models. Although available studies were made with different viruses (human and avian), published information related to the anti-influenza spectrum of NAC is scarce. In this study, we show that NAC is unable to alter the course of a fatal influenza pneumonia caused by inoculation of a murinized swine H1N1 influenza virus. NAC was indeed able to inhibit the swine virus in vitro but far less than reported for other strains. Therefore, susceptibility of influenza viruses to NAC appears to be strain-dependent, suggesting that it cannot be considered as a universal treatment for influenza pneumonia.}, }
@article {pmid21551083, year = {2011}, author = {Tokgoz, B and Ucar, C and Kocyigit, I and Somdas, M and Unal, A and Vural, A and Sipahioglu, M and Oymak, O and Utas, C}, title = {Protective effect of N-acetylcysteine from drug-induced ototoxicity in uraemic patients with CAPD peritonitis.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {26}, number = {12}, pages = {4073-4078}, doi = {10.1093/ndt/gfr211}, pmid = {21551083}, issn = {1460-2385}, mesh = {Acetylcysteine/*therapeutic use ; Amikacin/*adverse effects ; Anti-Bacterial Agents/*adverse effects ; Ear Diseases/*chemically induced/*prevention &amp; control ; Free Radical Scavengers/*therapeutic use ; Humans ; *Peritoneal Dialysis, Continuous Ambulatory/adverse effects ; Peritonitis/*drug therapy/etiology ; Prospective Studies ; Vancomycin/*adverse effects ; }, abstract = {AIM: Peritonitis is currently one of the leading complications of continuous ambulatory peritoneal dialysis (CAPD) treatment. Aminoglycosides and vancomycin are used in the treatment of CAPD peritonitis despite their potential risk for ototoxicity. N-acetylcysteine (NAC) is a molecule used in the treatment and prophylaxis of many diseases related to oxidative stress. The aim of this study was to examine whether ototoxicity due to antibiotics used in the treatment of CAPD peritonitis can be prevented by NAC.<br><br>METHODS: Sixty patients, who first developed CAPD peritonitis attacks from February 2008 to April 2010 were included in this study. Patients were divided into two groups, those taking an additional NAC treatment (n = 30) and a control group (n = 30). Low- and high-frequency hearing function tests were performed on the two groups before treatment (baseline), at the end of the first (early follow-up) and the fourth week after the treatment (late follow-up). Total doses of vancomycin and amikacin were recorded.<br><br>RESULTS: There was no statistically significant difference between the groups in terms of hearing functions at the beginning. However, patients taking NAC had better hearing function test results 4 weeks after the treatment compared with those of the control group (P < 0.05). There were no statistical differences between posttreatment low-frequency hearing function tests conducted at the baseline and the first and the fourth weeks in patients taking NAC. The first and the fourth week's low-frequency hearing functions worsened when compared with the baseline low-frequency results in the control group (P < 0.001). It was found that NAC had a protective effect against ototoxicity on low-frequency (0.25-8 KHz) hearing functions. The first and the fourth week's high-frequency hearing functions improved when compared with baseline high-frequency hearing functions in patients taking NAC (P < 0.05), while they worsened. The first and fourth week's high-frequency tests worsened when compared with the baseline high-frequency tests in the control group (P < 0.001).<br><br>CONCLUSIONS: The present study suggests that intraperitoneal aminoglycoside and vancomycin administration in CAPD patients may cause low- and high-frequency hearing loss, and this ototoxic effect is related to the dose given. It was found that when the antioxidant NAC is administered alone, it prevents ototoxicity, associated with intraperitoneal amikacin and vancomycin in patients with CAPD peritonitis. In addition, it was revealed that NAC may also have a curative effect on impaired high-frequency hearing functions.}, }
@article {pmid21550026, year = {2011}, author = {Haddad, JJ}, title = {A redox microenvironment is essential for MAPK-dependent secretion of pro-inflammatory cytokines: modulation by glutathione (GSH/GSSG) biosynthesis and equilibrium in the alveolar epithelium.}, journal = {Cellular immunology}, volume = {270}, number = {1}, pages = {53-61}, doi = {10.1016/j.cellimm.2011.04.001}, pmid = {21550026}, issn = {1090-2163}, support = {//Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Alveolar Epithelial Cells/*metabolism ; Buthionine Sulfoximine/metabolism/pharmacology ; Cells, Cultured ; Enzyme Activation ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors/metabolism ; Glutathione Disulfide/*metabolism/pharmacology ; Humans ; Imidazoles/pharmacology ; Interleukin-1beta/biosynthesis ; Interleukin-6/biosynthesis ; MAP Kinase Signaling System/drug effects ; Oxidation-Reduction ; Phosphorylation ; Pulmonary Alveoli/cytology/*metabolism ; Pyridines/pharmacology ; Tumor Necrosis Factor-alpha/biosynthesis ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The characterization of oxidant (glutathione)-dependent regulation of MAPK(p38/RK)-mediated TNF-α secretion was undertaken in vitro, and the ramifications of the influence of a redox microenvironment were unraveled. Intermittent exposure of alveolar epithelial cells (FATEII) to LPS (endotoxin) transiently and temporally induced the expression of MAPK(p38/RK). This upregulation was associated with the activation of MAPKAP-K(2), manifested by the specific phosphorylation of the downstream heat-shock protein (Hsp)-27. Selective blockading of the MAPK(p38/RK) pathway using the pyridinyl imidazole SB-203580 abrogated the LPS-dependent release of TNF-α. N-acetyl-l-cysteine (NAC), a precursor of glutathione, reduced TNF-α secretion and increased [GSH]. Conversely, l-buthionine-(S,R)-sulfoximine (BSO), an irreversible inhibitor of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting enzyme in the pathway mediating GSH biosynthesis, augmented the secretion of TNF-α and [GSSG] accumulation. Whereas NAC abrogated the phosphorylation of MAPK(p38/RK), BSO reversibly amplified this effect. Furthermore, intermittent exposure of FATEII cells to the exogenous oxidants X/XO and H(2)O(2) upregulated the secretion of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α; this upregulation was correlated with increasing activity of key glutathione-related enzymes, closely involved with maintaining the cyclic GSH/GSSG equilibrium. These results indicate that a redox microenvironment plays a major role in regulating MAPK-dependent production of cytokines in the alveolar epithelium.}, }
@article {pmid21545313, year = {2011}, author = {Kizilgun, M and Poyrazoglu, Y and Oztas, Y and Yaman, H and Cakir, E and Cayci, T and Akgul, OE and Kurt, YG and Yaren, H and Kunak, ZI and Macit, E and Ozkan, E and Taslipinar, MY and Turker, T and Ozcan, A}, title = {Beneficial effects of N-acetylcysteine and ebselen on renal ischemia/reperfusion injury.}, journal = {Renal failure}, volume = {33}, number = {5}, pages = {512-517}, doi = {10.3109/0886022X.2011.574767}, pmid = {21545313}, issn = {1525-6049}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*prevention &amp; control ; Animals ; Azoles/*therapeutic use ; Drug Evaluation, Preclinical ; Drug Therapy, Combination ; Free Radical Scavengers/*therapeutic use ; Isoindoles ; Male ; Organoselenium Compounds/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {INTRODUCTION: It has been demonstrated that peroxynitrite accompanies acute renal ischemia and contributes to the pathophysiology of renal damage. Therefore, we aimed to investigate the roles of N-acetylcysteine (NAC), a well-known powerful antioxidant, and ebselen (E), a scavenger of peroxynitrite, on renal injury induced by renal ischemia/reperfusion injury (IRI) of rat kidney.<br><br>MATERIALS AND METHODS: Forty male Sprague-Dawley rats were divided into five groups: sham, renal IRI, renal IRI+NAC, renal IRI+E, and renal IRI+NAC+E. IR injury was induced by 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood samples were obtained for histopathological and biochemical evaluations.<br><br>RESULTS: Renal IR resulted in increased malondialdehyde and nitrite/nitrate levels suggesting increased lipid peroxidation and peroxynitrite production and decreased superoxide dismutase and glutathione peroxidase activities. Both NAC and E alone significantly decreased malondialdehyde and nitrite/nitrate levels and increased superoxide dismutase and glutathione peroxidase activities. Additionally in the renal IRI+NAC+E group, all biochemical results were quite close to those of sham group. Histopathologically, the kidney injury in rats treated with combination of NAC and E was found significantly less than the other groups.<br><br>CONCLUSIONS: Both NAC and E are able to ameliorate IRI of the kidney by decreasing oxidative and nitrosative stresses and increasing free radical scavenger properties. Additionally, combination of NAC and E prevents kidney damage more than when each drug is used alone, suggesting that scavenging peroxynitrite nearby antioxidant activity is important in preventing renal IRI.}, }
@article {pmid21544860, year = {2011}, author = {Qian, J and Keyes, KT and Long, B and Chen, G and Ye, Y}, title = {Impact of HMG-CoA reductase inhibition on oxidant-induced injury in human retinal pigment epithelium cells.}, journal = {Journal of cellular biochemistry}, volume = {112}, number = {9}, pages = {2480-2489}, doi = {10.1002/jcb.23173}, pmid = {21544860}, issn = {1097-4644}, mesh = {Atorvastatin ; Caspase 3/metabolism ; Cell Line ; Cell Survival/drug effects ; Enzyme Activation/drug effects ; Epithelial Cells/drug effects/*pathology ; Heptanoic Acids/*pharmacology ; Humans ; Hydrogen Peroxide/metabolism/*pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; MAP Kinase Signaling System/drug effects ; NADPH Oxidases/metabolism ; Oxidants/metabolism/*pharmacology ; Oxidative Stress ; Pyrroles/*pharmacology ; Retinal Pigment Epithelium/drug effects/*pathology ; Simvastatin/*pharmacology ; Tumor Necrosis Factor-alpha/pharmacology/physiology ; }, abstract = {In addition to cholesterol-lowering effect, HMG-CoA reductase inhibition by statins has been shown to have protective effect in many cells type. The loss of vision in retinal degeneration disease associates with oxidative stress and apoptosis in retinal pigment epithelium (RPE) cell. This study was designed to examine the effect of statins on oxidant-induced damage in human RPE cells. Cultured human ARPE-19 (ARPE) cells were challenged with hydrogen peroxide (H(2) O(2)) plus tumor necrosis factor alpha (TNFα) in the presence or absence of statins or various stress signaling inhibitors, including anti-oxidants N-acetyl cysteine (NAC), the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI), and the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580. Apoptosis was evaluated by TUNEL analysis and cell viability was determined by MTT assay. Reactive oxygen species (ROS) were detected by 2',7'-dichlorodihydrofluorescein diacetate (H(2) DCFH-DA). Expression of p-p38 MAPK protein was measured by Western blot analysis. Our findings indicate that statins treatment significantly suppressed oxidant-induced ROS accumulation and RPE apoptosis. Statins increased cell viability in a dose-dependent manner. In addition, statins treatment prevented the activation of NADPH oxidase and p38 MAPK signaling induced by oxidative stress. These results suggest that statins protects ARPE cells from oxidative stress via an NADPH oxidase and/or p38 MAPK-dependent mechanisms, which may contribute to statins-induced beneficial effects on RPE function.}, }
@article {pmid21542122, year = {2012}, author = {Jaffery, Z and Verma, A and White, CJ and Grant, AG and Collins, TJ and Grise, MA and Jenkins, JS and McMullan, PW and Patel, RA and Reilly, JP and Thornton, SN and Ramee, SR}, title = {A randomized trial of intravenous n-acetylcysteine to prevent contrast induced nephropathy in acute coronary syndromes.}, journal = {Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography &amp; Interventions}, volume = {79}, number = {6}, pages = {921-926}, doi = {10.1002/ccd.23157}, pmid = {21542122}, issn = {1522-726X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Coronary Syndrome/*diagnostic imaging/therapy ; Aged ; *Angioplasty, Balloon, Coronary ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; Chi-Square Distribution ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Cystatin C/blood ; Double-Blind Method ; Female ; Humans ; Infusions, Intravenous ; Kidney Diseases/blood/chemically induced/diagnosis/*prevention &amp; control ; Male ; Middle Aged ; New Orleans ; Placebos ; Prospective Studies ; Risk Assessment ; Risk Factors ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Pharmacokinetic data suggests that the intravenous form of n-acetylcysteine (NAC) may be more effective than the oral formulation in preventing contrast induced nephropathy (CIN). NAC owing to its anti-oxidant properties might be beneficial for patients with acute coronary syndromes (ACS) who are at increased risk for CIN. The aim of this prospective randomized, single-center, double-blind, placebo controlled trial (NCT00939913) was to assess the effect of high-dose intravenous NAC on CIN in ACS patients undergoing coronary angiography and/or percutaneous coronary intervention (PCI).<br><br>METHODS: We randomized 398 ACS patients scheduled for diagnostic angiography &#xb1; PCI to an intravenous regimen of high-dose NAC (1,200 mg bolus followed by 200 mg/hr for 24 hr; n = 206) or placebo (n = 192). The primary end-point was incidence of CIN defined as an increase in serum creatinine concentration &#x2265; 25% above the baseline level within 72 hr of the administration of intravenous contrast.<br><br>RESULTS: There was no difference found for the primary end point with CIN in 16% of the NAC group and in 13% of the placebo group (p = 0.40). Change in serum cystatin-C, a sensitive marker for renal function, was 0.046 &#xb1; 0.204 in the NAC group and 0.002 &#xb1; 0.260 in the control group (p = 0.07).<br><br>CONCLUSION: In ACS patients undergoing angiography &#xb1; PCI, high-dose intravenous NAC failed to reduce the incidence of CIN.}, }
@article {pmid21542114, year = {2012}, author = {Hafiz, AM and Jan, MF and Mori, N and Shaikh, F and Wallach, J and Bajwa, T and Allaqaband, S}, title = {Prevention of contrast-induced acute kidney injury in patients with stable chronic renal disease undergoing elective percutaneous coronary and peripheral interventions: randomized comparison of two preventive strategies.}, journal = {Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography &amp; Interventions}, volume = {79}, number = {6}, pages = {929-937}, doi = {10.1002/ccd.23148}, pmid = {21542114}, issn = {1522-726X}, mesh = {Acetylcysteine/administration &amp; dosage ; Administration, Oral ; Aged ; Aged, 80 and over ; Biomarkers/blood ; *Cardiac Catheterization ; *Catheterization, Peripheral ; Chi-Square Distribution ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Female ; Fluid Therapy/*methods ; Humans ; Infusions, Intravenous ; Kidney Diseases/blood/chemically induced/diagnosis/*prevention &amp; control ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Prospective Studies ; Renal Insufficiency/blood/*complications/diagnosis ; Risk Assessment ; Risk Factors ; Sodium Bicarbonate/*administration &amp; dosage ; Sodium Chloride/*administration &amp; dosage ; Time Factors ; Treatment Outcome ; Vascular Diseases/complications/diagnostic imaging/*therapy ; Wisconsin ; }, abstract = {OBJECTIVE: We compared use of intravenous (IV) normal saline (NS) to sodium bicarbonate (NaHCO(3)) with or without oral N-acetylcysteine (NAC) for prevention of contrast-induced acute kidney injury (CI-AKI).<br><br>BACKGROUND: CI-AKI is associated with significant adverse clinical events. Use of NAC has produced variable results. Recently, intravenous hydration with NaHCO(3) for CI-AKI prophylaxis has been adopted as standard treatment for patients with stable chronic renal disease undergoing catheterization procedures.<br><br>METHODS: We prospectively enrolled 320 patients with baseline renal insufficiency scheduled to undergo catheterization. Patients were randomly assigned to receive either IV NS &#xb1; NAC (n = 161) or IV dextrose 5% in water containing 154 mEq/l of NaHCO(3) &#xb1; NAC (n = 159). IV NS was administered at 1 ml/kg body weight for 12 hr preprocedure and 12 more hr postprocedure. IV NaHCO(3) was administered at 3 ml/kg body weight for 1 hr preprocedure followed by 1 ml/kg body weight postprocedure. A 1,200 mg oral dose of NAC was given 2-12 hr preprocedure and 6-12 hr postprocedure in 50% of patients in each study arm. CI-AKI was defined as an increase of >0.5 mg/dl or >25% above baseline creatinine.<br><br>RESULTS: Overall incidence of CI-AKI was 10.3%. There was no significant difference in incidence among the two groups (NS &#xb1; NAC 11.8% vs. NaHCO(3) &#xb1; NAC 8.8%, p = ns). Incidence of CI-AKI increased with increasing age (p = 0.001), contrast agent use >3 ml/kg body weight (p = 0.038) and diuretic use (p = 0.005).<br><br>CONCLUSION: Incidence of CI-AKI was no different in the NaHCO(3) group compared to NS group, and NAC did not reduce CI-AKI in the two study arms.}, }
@article {pmid21540553, year = {2011}, author = {Wajner, SM and Goemann, IM and Bueno, AL and Larsen, PR and Maia, AL}, title = {IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells.}, journal = {The Journal of clinical investigation}, volume = {121}, number = {5}, pages = {1834-1845}, pmid = {21540553}, issn = {1558-8238}, support = {R01 DK036256/DK/NIDDK NIH HHS/United States ; R03 TW007559/TW/FIC NIH HHS/United States ; DK 36256/DK/NIDDK NIH HHS/United States ; TW007559/TW/FIC NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Cell Line ; Cell Line, Tumor ; Cytokines/metabolism ; Dithiothreitol/pharmacology ; Glutathione/metabolism ; Humans ; Interleukin-6/*metabolism ; Oxidative Stress ; RNA, Messenger/metabolism ; Reactive Oxygen Species ; Thyroid Diseases/*metabolism ; Thyroid Hormones/*metabolism ; Thyroxine/*metabolism ; }, abstract = {Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3' triiodothyronine (T3) that occurs in chronically ill patients; the degree of reduction in T3 is associated with overall prognosis and survival. Iodthyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T4 to active T3, whereas the type III enzyme (D3) inactivates T4 and T3. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS, but the role of cytokines in altered thyroid hormone metabolism is poorly understood. Here, we measured the effect of IL-6 on both endogenous cofactor-mediated and dithiothreitol-stimulated (DTT-stimulated) cell sonicate deiodinase activities in human cell lines. Active T3 generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6-induced inhibitory effect on D1- and D2-mediated T3 production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3-mediated inactivation of T3. Taken together, these results identify a single pathway by which IL-6-induced oxidative stress can reduce D1- and D2-mediated T4-to-T3 conversion as well as increasing D3-mediated T3 (and T4) inactivation, thus mimicking events during illness.}, }
@article {pmid21538553, year = {2011}, author = {Kosinska, W and Khmelnitsky, M and Kim, JH and Zhao, ZL and Guttenplan, JB}, title = {Effects of potential dietary inhibitors of endogenous DNA damage on mutagenesis and lipid peroxidation in lacZ mice.}, journal = {Environmental and molecular mutagenesis}, volume = {52}, number = {6}, pages = {502-509}, doi = {10.1002/em.20648}, pmid = {21538553}, issn = {1098-2280}, support = {CA 099146/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Ascorbic Acid/pharmacology ; Caloric Restriction ; DNA Damage/drug effects ; Lipid Peroxidation/*drug effects ; Liver/drug effects/metabolism ; Male ; Mice ; Mutagenesis/*drug effects ; Spleen/drug effects/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Vitamin E/pharmacology ; }, abstract = {The effects of a nine month administration of dietary: (1) 3H-1,2-dithiole-3-thione (D3T), (2) N-acetylcysteine (NAC), (3) antioxidant vitamin mix, (vitamin C+E), (4) free radical scavenger, amifostine, and (5) calorie restriction, (CR), on mutagenesis and lipid peroxidation in lung, kidney, spleen and liver of lacZ transgenic mice were examined. These agents/diets were chosen because they might inhibit certain proposed mechanisms of endogenous damage to DNA. The agents were added to a high fat, reduced antioxidant AIN-76 diet, to better approximate a Western style diet than the conventional AIN-76 diet. As the lacZ gene is not expressed, mutations in that gene are neutral, and simply accumulate over time. The mutant fractions in control mice increased about 50-100%. Most of the agents inhibited to various extents the age-related increase in mutagenesis in lung, kidney, and/or spleen, but no inhibition was observed in liver. There was no significant effect of age on lipid peroxidation levels in controls, possibly reflecting steady state turnover of lipid peroxidation products. Almost all of the treatments except D3T inhibited lipid peroxidation in most organs to different degrees. The vitamin C+E mix was the most effective at inhibiting lipid peroxidation, but a single most effective inhibitor of mutagenesis could not be discerned. Some associations were observed between the reduction in lipid peroxidation and the inhibition of mutagenesis. The results are consistent with a partial role for oxidative stress in the age-related increase in mutagenesis. These observations may have implications for chemoprevention of carcinogenesis.}, }
@article {pmid21537844, year = {2011}, author = {Naumann, P and Fortunato, F and Zentgraf, H and Büchler, MW and Herr, I and Werner, J}, title = {Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer.}, journal = {International journal of oncology}, volume = {39}, number = {1}, pages = {101-109}, doi = {10.3892/ijo.2011.1025}, pmid = {21537844}, issn = {1791-2423}, mesh = {Anticarcinogenic Agents/metabolism/*pharmacology ; Autophagy/*drug effects ; Cell Line, Tumor ; Humans ; Isothiocyanates ; Oxidative Stress/*physiology ; Pancreatic Neoplasms/*pathology/physiopathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Sulfoxides ; Thiocyanates/metabolism/*pharmacology ; }, abstract = {The broccoli isothiocyanate, sulforaphane (SFN), was recently identified as being capable of eliminating highly therapy-resistant pancreatic carcinoma (PC) cells without inducing toxic side effects. While SFN has been shown to stimulate autophagy or 'self-eating', it is unclear whether this catabolic process is a pro- or anti-tumorigenic response. To investigate the role of autophagy in SFN-induced cell death, established PC cell lines were treated with SFN, and the induction of autophagy was evaluated by detecting the abundance of autophagic vesicles by electron microscopy, the increase in converted LC3-II by Western blot analysis and the autophagosome puncta of GFP-LC3 by immunofluorescence. SFN-induced autophagy was suppressed by the autophagy inhibitor chloroquine, while the autophagy inducer rapamycin did not further enhance autophagy in PC cells. Importantly, neither modulator altered SFN cytotoxicity, suggesting that SFN-induced autophagy and cell death act independently of each other. In contrast, the antioxidant N-acetyl-cysteine sustained cell viability and prevented autophagy induction after SFN exposure, indicating that both signaling pathways depend on reactive oxygen species (ROS). Our studies provide a valuable new mechanistic insight into the SFN-induced elimination of PC cells and suggest that an SFN-enriched diet potentially enhances ROS-releasing chemotherapeutic agents.}, }
@article {pmid21536676, year = {2011}, author = {Singh, NK and Wang, D and Kundumani-Sridharan, V and Van Quyen, D and Niu, J and Rao, GN}, title = {15-Lipoxygenase-1-enhanced Src-Janus kinase 2-signal transducer and activator of transcription 3 stimulation and monocyte chemoattractant protein-1 expression require redox-sensitive activation of epidermal growth factor receptor in vascular wall remodeling.}, journal = {The Journal of biological chemistry}, volume = {286}, number = {25}, pages = {22478-22488}, pmid = {21536676}, issn = {1083-351X}, support = {R01 HL064165/HL/NHLBI NIH HHS/United States ; HL064165/HL/NHLBI NIH HHS/United States ; }, mesh = {Adenoviridae/genetics ; Animals ; Arachidonate 15-Lipoxygenase/*metabolism ; Blood Vessels/*drug effects/metabolism/physiology ; Carotid Artery Injuries/genetics/metabolism/pathology/physiopathology ; Cell Movement/drug effects ; Chemokine CCL2/genetics/*metabolism ; ErbB Receptors/chemistry/*metabolism ; Gene Expression Regulation/drug effects ; HEK293 Cells ; Humans ; Hydroxyeicosatetraenoic Acids/pharmacology ; Janus Kinase 2/chemistry/genetics/*metabolism ; Muscle, Smooth, Vascular/cytology/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Phosphorylation/drug effects ; Proto-Oncogene Proteins pp60(c-src)/*metabolism ; Rats ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/genetics/*metabolism ; Signal Transduction/drug effects ; Tyrosine/metabolism ; }, abstract = {To understand the mechanisms by which 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) activates signal transducer and activator of transcription 3 (STAT3), we studied the role of epidermal growth factor receptor (EGFR). 15(S)-HETE stimulated tyrosine phosphorylation of EGFR in a time-dependent manner in vascular smooth muscle cells (VSMCs). Interference with EGFR activation blocked 15(S)-HETE-induced Src and STAT3 tyrosine phosphorylation, monocyte chemoattractant protein-1 (MCP-1) expression and VSMC migration. 15(S)-HETE also induced tyrosine phosphorylation of Janus kinase 2 (Jak2) in VSMCs, and its inhibition substantially reduced STAT3 phosphorylation, MCP-1 expression, and VSMC migration. In addition, Src formed a complex with EGFR and Jak2, and its inhibition completely blocked Jak2 and STAT3 phosphorylation, MCP-1 expression, and VSMC migration. 15(S)-HETE induced the production of H(2)O(2) via an NADPH oxidase-dependent manner and its scavengers, N-acetyl cysteine (NAC) and catalase suppressed 15(S)-HETE-stimulated EGFR, Src, Jak2, and STAT3 phosphorylation and MCP-1 expression. Balloon injury (BI) induced EGFR, Src, Jak2, and STAT3 phosphorylation, and inhibition of these signaling molecules attenuated BI-induced MCP-1 expression and smooth muscle cell migration from the medial to the luminal surface resulting in reduced neointima formation. In addition, inhibition of EGFR blocked BI-induced Src, Jak2, and STAT3 phosphorylation. Similarly, interference with Src activation suppressed BI-induced Jak2 and STAT3 phosphorylation. Furthermore, adenovirus-mediated expression of dnJak2 also blocked BI-induced STAT3 phosphorylation. Consistent with the effects of 15(S)-HETE on the activation of EGFR-Src-Jak2-STAT3 signaling in VSMCs in vitro, adenovirus-mediated expression of 15-lipoxygenase 1 (15-Lox1) enhanced BI-induced EGFR, Src, Jak2, and STAT3 phosphorylation leading to enhanced MCP-1 expression in vivo. Blockade of Src or Jak2 suppressed BI-induced 15-Lox1-enhanced STAT3 phosphorylation, MCP-1 expression, and neointima formation. In addition, whereas dominant negative Src blocked BI-induced 15-Lox1-enhanced Jak2 phosphorylation, dnJak2 had no effect on Src phosphorylation. Together, these observations demonstrate for the first time that the 15-Lox1-15(S)-HETE axis activates EGFR via redox-sensitive manner, which in turn mediates Src-Jak2-STAT3-dependent MCP-1 expression leading to vascular wall remodeling.}, }
@article {pmid21533816, year = {2011}, author = {Yen, CC and Ho, TJ and Wu, CC and Chang, CF and Su, CC and Chen, YW and Jinn, TR and Lu, TH and Cheng, PW and Su, YC and Liu, SH and Huang, CF}, title = {Inorganic arsenic causes cell apoptosis in mouse cerebrum through an oxidative stress-regulated signaling pathway.}, journal = {Archives of toxicology}, volume = {85}, number = {6}, pages = {565-575}, doi = {10.1007/s00204-011-0709-y}, pmid = {21533816}, issn = {1432-0738}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Arsenic Poisoning/blood/*metabolism/pathology ; Arsenic Trioxide ; Arsenicals/administration &amp; dosage/metabolism/pharmacokinetics ; Cerebral Cortex/*drug effects/metabolism/pathology ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Chaperone BiP ; Environmental Pollutants/administration &amp; dosage/metabolism/pharmacokinetics/*toxicity ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione/metabolism ; Glutathione Peroxidase/genetics/metabolism ; Lipid Peroxides/blood/metabolism ; MAP Kinase Signaling System/*drug effects ; Male ; Mice ; Mice, Inbred ICR ; NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/therapeutic use ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Oxides/administration &amp; dosage/metabolism/pharmacokinetics/*toxicity ; RNA, Messenger/metabolism ; Random Allocation ; }, abstract = {Arsenic pollution is a major public health problem worldwide. Inorganic arsenic (iAs) is usually more harmful than organic ones. iAs pollution increases the risk of human diseases such as peripheral vascular disease and cancer. However, the toxicological effects of iAs in the brain are mostly unclear. Here, we investigated the toxic effects and possible mechanisms of iAs in the cerebrum of mice after exposure to iAs (0.5 and 5 ppm (mg/l) As(2)O(3), via the drinking water), which was the possible human exposed dose via the ingestion in iAs-contaminated areas, for 6 consecutive weeks. iAs dose-dependently caused an increase of LPO production in the plasma and cerebral cortex. iAs also decreased the reduced glutathione levels and the expressions of NQO1 and GPx mRNA in the cerebral cortex. These impairments in the cerebral cortex caused by iAs exposure were significantly correlated with the accumulation of As. Moreover, iAs induced the production of apoptotic cells and activation of caspase-3, up-regulation of Bax and Bak, and down-regulation of Mcl-1 in the cerebral cortex. Exposure to iAs also triggered the expression of ER stress-related genes, including GRP78, GRP94, and CHOP. Meanwhile, an increase of p38 activation and dephosphorylation of ERK1/2 were shown in the cerebral cortex as a result of iAs-exposed mice. These iAs-induced damages and apoptosis-related signals could be significantly reversed by NAC. Taken together, these results suggest that iAs-induced oxidative stress causes cellular apoptosis in the cerebrum, signaling of p38 and ERK1/2, and ER stress may be involved in iAs-induced cerebral toxicity.}, }
@article {pmid21532338, year = {2011}, author = {Singh, RK and Dorf, L and DeMartino, A and Illenye, S and Koto, K and Currier, EA and Ashikaga, T and Kim, KK and Brard, L and Sholler, GL}, title = {Oral RKS262 reduces tumor burden in a neuroblastoma xenograft animal model and mediates cytotoxicity through SAPK/JNK and ROS activation in vitro.}, journal = {Cancer biology &amp; therapy}, volume = {11}, number = {12}, pages = {1036-1045}, doi = {10.4161/cbt.11.12.15706}, pmid = {21532338}, issn = {1555-8576}, mesh = {Administration, Oral ; Animals ; Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/drug effects ; Brain-Derived Neurotrophic Factor/pharmacology ; Caspase 3/metabolism ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Coumarins/administration &amp; dosage/chemistry/*pharmacology ; Cyclic S-Oxides/administration &amp; dosage/chemistry/*pharmacology ; Epidermal Growth Factor/pharmacology ; Female ; Humans ; Insulin-Like Growth Factor I/pharmacology ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mice ; Mice, Nude ; Neuroblastoma/*metabolism/*pathology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Burden/*drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {Patients diagnosed with high-risk neuroblastoma (NB), an extracranial solid tumor in children, have metastases and low survival (30%) despite aggressive multi-modal therapy. Therefore new therapies are urgently needed. We show significant in vitro and in vivo antitumor efficacy of RKS262 in NB. RKS262 showed superior cytotoxicity (IC(50) = 6-25 μM) against six representative NB cell lines compared to its parent analog Nifurtimox (currently in phase 2). Pre-formulated RKS262 (150 mg/kg/daily) pellets administered orally, suppressed tumor growth (60%, p = 0.021) in NB xenograft mice within 28 days. RKS262-treated SMSKCNR cells showed TUNEL-positive DNA nicks and activation of ROS, MAPKs (SAPK/JNK), caspase-3, and p53, along with suppression of the IGF-1R/PI3K/PKC pathway and the Bcl2 family of proteins. RKS262 caused G(2)/M-phase arrest and suppressed cdc-2, cyclin B1, p21, and cyclin D1/D4 expression. N-acetyl-cysteine (NAC; 10 mM) pre-treatment rescued cell viability of RKS262 (23 µM)-treated SMSKCNR cells, and pre-treatment with ascorbic acid (100 μM) and a MAPK inhibitor SB203580 (20 μM) reversed SAPK/JNK, caspase-3 activation, PARP-1 cleavage, and suppression of IGF-1R, PI3K, and PKC phosphorylation. Further, treatment with exogenous BDNF (50 nM) did not suppress SAPK/JNK or ROS activation due to RKS262. Rather, BDNF (50 nM), EGF (100 nM) and IGF-1 (100 nM) co-treatment with RKS262 induced a remarkable S-phase arrest rather than a G(2)/M phase arrest when RKS262 was used alone. In summary, RKS262 shows oral efficacy in NB xenograft animals, and induces apoptosis in vitro in SMSKCNR cells via cell cycle arrest, MAPK and ROS activation, and suppression of IGF-1R/PI3K/PKC and Bcl2 family proteins in a growth factor (BDNF/EGF/IGF-1)-independent fashion.}, }
@article {pmid21527338, year = {2011}, author = {Rees, S and Harding, R and Walker, D}, title = {The biological basis of injury and neuroprotection in the fetal and neonatal brain.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {29}, number = {6}, pages = {551-563}, pmid = {21527338}, issn = {1873-474X}, support = {R01 HL074942-03/HL/NHLBI NIH HHS/United States ; R01 HL074942/HL/NHLBI NIH HHS/United States ; R01 HL074942-02/HL/NHLBI NIH HHS/United States ; R01 HL074942-01A1/HL/NHLBI NIH HHS/United States ; R01 HL 074942/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Brain/*pathology/*physiopathology ; Central Nervous System Infections/pathology/physiopathology ; Female ; Fetal Diseases/pathology/physiopathology ; Fetus/*pathology/*physiopathology ; Humans ; Hypoxia, Brain/pathology/physiopathology ; *Infant, Newborn ; Infant, Newborn, Diseases/pathology/physiopathology ; Maternal-Fetal Relations ; Pregnancy ; }, abstract = {A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fetal brain injury, abnormal brain development and in cases of chronic compromise, intrauterine growth restriction. Preterm birth can also be associated with injury to the developing brain and affect the normal trajectory of brain growth. This review will focus on the effects that episodes of perinatal hypoxia (acute, chronic, associated with inflammation or as an antecedent of preterm birth) can have on the developing brain. In animal models of these conditions we have found that relatively brief (acute) periods of fetal hypoxemia can have significant effects on the fetal brain, for example death of susceptible neuronal populations (cerebellum, hippocampus, cortex) and cerebral white matter damage. Chronic placental insufficiency which includes fetal hypoxemia, nutrient restriction and altered endocrine status can result in fetal growth restriction and long-term deficits in neural connectivity in addition to altered postnatal function, for example in the auditory and visual systems. Maternal/fetal inflammation can result in fetal brain damage, particularly but not exclusively in the white matter; injury is more pronounced when associated with fetal hypoxemia. In the baboon, in which the normal trajectory of growth is affected by preterm birth, there is a direct correlation between a higher flux in oxygen saturation and a greater extent of neuropathological damage. Currently, the only established therapy for neonatal encephalopathy in full term neonates is moderate hypothermia although this only offers some protection to moderately but not severely affected brains. There is no accepted therapy for injured preterm brains. Consequently the search for more efficacious treatments continues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of efficacious strategies for neuroprotection.}, }
@article {pmid21526377, year = {2011}, author = {Nakano, A and Abe, M and Oda, A and Amou, H and Hiasa, M and Nakamura, S and Miki, H and Harada, T and Fujii, S and Kagawa, K and Takeuchi, K and Watanabe, T and Ozaki, S and Matsumoto, T}, title = {Delayed treatment with vitamin C and N-acetyl-L-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib.}, journal = {International journal of hematology}, volume = {93}, number = {6}, pages = {727-735}, pmid = {21526377}, issn = {1865-3774}, mesh = {*Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Antineoplastic Agents/adverse effects/pharmacology/therapeutic use ; Antioxidants/administration &amp; dosage/pharmacology ; *Ascorbic Acid/administration &amp; dosage/pharmacology ; Autophagy/drug effects ; Boronic Acids/adverse effects/*pharmacology/therapeutic use ; Bortezomib ; Cell Line ; Endoplasmic Reticulum/drug effects ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Multiple Myeloma/complications/*drug therapy ; Neuroprotective Agents/pharmacology/therapeutic use ; Peripheral Nervous System Diseases/chemically induced/prevention &amp; control ; Pyrazines/adverse effects/*pharmacology/therapeutic use ; Rats ; Schwann Cells/*drug effects ; }, abstract = {Bortezomib-induced peripheral neuropathy (BIPN) emerges as a disabling adverse effect. As rat models for BIPN have demonstrated damage in nerve Schwann cells, we screened for cytoprotective agents to devise a method of rescuing Schwann cells from the cytotoxic effects of bortezomib without compromising its anti-myeloma effects. Schwann cells underwent macroautophagy along with cytoplasmic inclusion body and vacuole formation, and appeared much less susceptible to bortezomib-induced cytotoxicity than did myeloma cells. Vitamin C or N-acetyl-L-cysteine (NAC) achieved near-complete rescue of Schwann cells treated with bortezomib at 30 nM or less, and these agents in combination are able to cooperatively inhibit the morphological changes and the cytotoxicity in Schwann cells with higher doses of bortezomib. The delayed addition of vitamin C and/or NAC after the exposure to bortezomib alleviated the cytotoxicity in Schwann cells but not myeloma cells. These results suggest that delayed treatment with these agents may be instrumental in prophylaxis of BIPN.}, }
@article {pmid21524264, year = {2011}, author = {Achab, S and Khazaal, Y}, title = {Psychopharmacological treatment in pathological gambling: a critical review.}, journal = {Current pharmaceutical design}, volume = {17}, number = {14}, pages = {1389-1395}, doi = {10.2174/138161211796150774}, pmid = {21524264}, issn = {1873-4286}, mesh = {Animals ; Antidepressive Agents/therapeutic use ; Antimanic Agents/therapeutic use ; Antipsychotic Agents/therapeutic use ; *Drug Design ; Gambling/*drug therapy/psychology ; Humans ; Psychotropic Drugs/*therapeutic use ; }, abstract = {Given the rates of pathological gambling and its impact on affected individuals and their relatives, effective treatments are needed. There are, however, no approved pharmacological treatments for pathological gambling. This paper describes the development of pharmacological treatments for pathological gambling and is based on a review of the literature published in the past 10 years. Important studies were carried-out on antidepressants, mood stabilizers, and antipsychotic agents. In the absence of comorbid psychiatric disorder, these studies did not conclude to the efficacy of these psychotropic drugs. A possible efficacy of opiate antagonist treatment for pathological gambling has been replicated in a number of placebo-controlled studies. Preliminary results on N-acetyl cysteine, Memantine and Topiramate produced significant improvement for pathological gamblers and may open new avenues for treatment.}, }
@article {pmid21521427, year = {2012}, author = {Murray, JE and Everitt, BJ and Belin, D}, title = {N-Acetylcysteine reduces early- and late-stage cocaine seeking without affecting cocaine taking in rats.}, journal = {Addiction biology}, volume = {17}, number = {2}, pages = {437-440}, doi = {10.1111/j.1369-1600.2011.00330.x}, pmid = {21521427}, issn = {1369-1600}, support = {093875/WT_/Wellcome Trust/United Kingdom ; G0001354/MRC_/Medical Research Council/United Kingdom ; G1002231/MRC_/Medical Research Council/United Kingdom ; 9536855/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cocaine/administration &amp; dosage ; Cocaine-Related Disorders/*drug therapy ; Dose-Response Relationship, Drug ; Drug-Seeking Behavior/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reinforcement Schedule ; Self Administration ; }, abstract = {N-acetylcysteine (NAC) has been suggested to have therapeutic potential in the treatment of drug addiction through its effects on brain glutamate homeostasis. Here we show that NAC treatment resulted in dose-dependent reductions in cocaine seeking at both early and late stages of acquisition and maintenance of cocaine-seeking behavior, while confirming it had no effect on cocaine reinforcement. The results indicate that NAC is able to significantly diminish the propensity to seek cocaine early and late in the development of addiction and, taken together with previous work, indicates significant potential in relapse prevention.}, }
@article {pmid21520997, year = {2011}, author = {Kennedy, AR and Ware, JH and Carlton, W and Davis, JG}, title = {Suppression of the later stages of radiation-induced carcinogenesis by antioxidant dietary formulations.}, journal = {Radiation research}, volume = {176}, number = {1}, pages = {62-70}, doi = {10.1667/rr2439.1}, pmid = {21520997}, issn = {1938-5404}, mesh = {Animals ; Antioxidants/*pharmacology/*therapeutic use ; *Dietary Supplements ; Harderian Gland/drug effects/pathology/radiation effects ; Male ; Mice ; Neoplasm Staging ; Neoplasms, Radiation-Induced/*diet therapy/*pathology ; }, abstract = {We have previously reported data from a long-term carcinogenesis study indicating that dietary antioxidant supplements can suppress radiation-induced malignant lymphoma and harderian gland tumors induced by space radiations (specifically, 1 GeV/n iron ions or protons) in CBA/J mice. Two different antioxidant dietary supplements were used in these studies: a supplement containing a mixture of antioxidant agents [l-selenomethionine (SeM), N-acetyl cysteine (NAC), ascorbic acid, co-enzyme Q10, α-lipoic acid and vitamin E succinate], termed the AOX supplement, and another supplement known as Bowman-Birk Inhibitor Concentrate (BBIC). In the present report, the results from the earlier analysis of the harderian gland data from the published long-term animal study have been combined with new data derived from the same long-term animal study. In the earlier analysis, harderian glands were removed from animals exhibiting abnormalities (e.g. visibly swollen areas) around the eyes at the time of euthanasia or death in the long-term animal study. Abnormalities around the eyes were usually due to the development of tumors in the harderian glands of these mice. The new data presented here focused on the histopathological results obtained from analyses of the harderian glands of mice that did not have visible abnormalities around the eyes at the time of necropsy in the long-term animal study. In this paper, the original published data and the new data have been combined to provide a more complete evaluation of the harderian glands from animals in the long-term carcinogenesis study, with all available harderian glands from the animals processed and prepared for histopathological evaluation. The results indicate that, although dietary antioxidant supplements suppressed harderian gland tumors in a statistically significant fashion when all glands were analyzed, the antioxidant diets were less effective at suppressing the incidence of all harderian gland tumors than they were at suppressing the incidence of large harderian gland tumors (>2 mm) observed at animal necropsy. These results suggest that the dietary antioxidant formulations had major suppressive effects in the later stages of radiation-induced carcinogenesis in vivo. It is hypothesized that the dietary antioxidant formulations prevented the early-stage neoplastic growths from progressing to fully developed, malignant tumors. In addition, the antioxidant dietary formulations were very effective at preventing the development of proton- or iron-ion-induced malignant tumors, because, in contrast to irradiated controls, no malignant tumors were observed in the irradiated animals maintained on either of the dietary antioxidant diets.}, }
@article {pmid21520784, year = {2011}, author = {Poyrazoglu, Y and Yigit, T and Harlak, A and Mentes, O and Gorgulu, S and Uzar, AI and Kozak, O}, title = {Effects of prevention of oxidative and nitro-oxidative stress on experimental rat colon anastomosis using acetylcysteine, Ebselen and 1400w.}, journal = {Acta chirurgica Belgica}, volume = {111}, number = {1}, pages = {26-31}, doi = {10.1080/00015458.2011.11680699}, pmid = {21520784}, issn = {0001-5458}, mesh = {Acetylcysteine/*therapeutic use ; Amidines/*therapeutic use ; Anastomosis, Surgical ; Animals ; Azoles/*therapeutic use ; Benzylamines/*therapeutic use ; Colon/*surgery ; Free Radical Scavengers/*therapeutic use ; Isoindoles ; Nitric Oxide Synthase/*antagonists &amp; inhibitors ; Organoselenium Compounds/*therapeutic use ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Wound Healing/*drug effects/physiology ; }, abstract = {UNLABELLED: Oxygen radicals and radicals derived from nitrogen metabolism are important in wound and anostomotic healing. In particular, nitrous oxide, originating from induced nitrous oxide synthetase, retards the wound healing process by producing peroxynitride. Therefore induced nitric oxide synthase (INOS) inhibitors and peroxynitride cleansing agents seem helpful in promoting healing. The purpose of this study was to investigate the effects of N-acetylcysteine (antioxidant), ebselen (peroxynitride cleansing agent) and 1400w (INOS inhibitor) on experimental colonic anastomotic wound healing.<br><br>MATERIAL AND METHODS: 45 randomized Sprague-Dawley rats received colonic anastomosis, and all animals were treated for four days with drugs specific for each group except for the sham and control groups. All rats were given a relaparatomy on the fifth day of the study and evaluated for study parameters indicating anastomotic healing, burst pressure, tissue malondialdehit (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx) and hydroxyproline (OH-proline).<br><br>RESULTS: when compared to the control group, increased (p < 0.01) burst pressure, OH-proline and decreased MDA, and SOD levels were noted in the 1400w group. Furthermore, the GPx levels were higher (p < 0.05) in rats given NAC therapy.<br><br>CONCLUSIONS: the positive results of selective INOS inhibition using 1400w in this study confirm the adverse effects of the INOS enzyme on anastomotic wound healing. Therefore, we have concluded that 1400w may be helpful in promoting anastomotic healing.}, }
@article {pmid21520298, year = {2012}, author = {Liu, C and Liu, H and Li, Y and Wu, Z and Zhu, Y and Wang, T and Gao, AC and Chen, J and Zhou, Q}, title = {Intracellular glutathione content influences the sensitivity of lung cancer cell lines to methylseleninic acid.}, journal = {Molecular carcinogenesis}, volume = {51}, number = {4}, pages = {303-314}, doi = {10.1002/mc.20781}, pmid = {21520298}, issn = {1098-2744}, mesh = {Acetylcysteine/chemistry ; Apoptosis ; Buthionine Sulfoximine/chemistry ; Cell Cycle ; Cell Line, Tumor ; Cell Proliferation ; Flow Cytometry ; Glutathione/*metabolism ; Glutathione Transferase/metabolism ; Humans ; Lung Neoplasms/drug therapy/*metabolism ; Microscopy, Fluorescence ; Organoselenium Compounds/*chemistry ; Oxidative Stress ; Reactive Oxygen Species ; }, abstract = {The synthetic selenium compound methylseleninic acid (MSA) is a direct precursor of active methylselenol and appears to be the best candidate for studies on the mechanisms of selenium cancer prevention and therapy in vitro. Reduced glutathione (GSH) is critical to MSA metabolism, in addition to being a protective antioxidant which scavenges reactive oxygen species (ROS) and maintains the stability of intracellular redox status. In this study, we demonstrated that MSA has an anticancer effect in the human lung cancer cell lines L9981 and 95D using growth inhibition detection, cell-cycle analysis, and apoptosis detection. We examined the role of intracellular GSH content and detected the ROS induced by MSA by fluorescence microscopy, and we used flow cytometry to quantify the ROS induced by pretreatment and co-treatment with N-acetylcysteine (NAC) and MSA. We also confirmed oxidative stress in MSA-induced apoptosis. MSA inhibited lung cancer cell lines L9981 and 95-D growth significantly, induced cell-cycle arrest in the G1 phase and induced apoptosis. Compared to the control group, MSA significantly decreased intracellular GSH content in L9981 cells at higher concentrations of MSA (5 and 7.5 µM), while the intracellular GSH level was also dramatically decreased in L9981 cells treated with 5 µM MSA at different time points of 12- and 24-h (decreased to about 50% and 20% of the control, respectively). Pretreatment with either NAC (GSH synthesis precursor) or buthionine sulfoximine (BSO, GSH synthesis inhibitor) in L9981 cells significantly inhibited the anti-proliferative effect of MSA. MSA induced the generation of ROS, which was significantly reduced by NAC pretreatment. Furthermore, we also confirmed these results in another lung cancer cell line 95-D. These results suggest that generation of ROS may be essential for the induction of oxidative stress and apoptosis by MSA in L9981 and 95-D lung cancer cells. The balance between oxidative stress induced by MSA and the antioxidant effect exerted by intracellular GSH content may determine the ultimate outcome after MSA treatment.}, }
@article {pmid21520062, year = {2011}, author = {Lee, CW and Lin, CC and Lee, IT and Lee, HC and Yang, CM}, title = {Activation and induction of cytosolic phospholipase A2 by TNF-α mediated through Nox2, MAPKs, NF-κB, and p300 in human tracheal smooth muscle cells.}, journal = {Journal of cellular physiology}, volume = {226}, number = {8}, pages = {2103-2114}, doi = {10.1002/jcp.22537}, pmid = {21520062}, issn = {1097-4652}, mesh = {Acetophenones/pharmacology ; Acetylation ; Acetylcysteine/pharmacology ; Cell Line ; Curcumin/pharmacology ; Dinoprostone/biosynthesis ; E1A-Associated p300 Protein/antagonists &amp; inhibitors/*metabolism ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Histones/metabolism ; Humans ; Membrane Glycoproteins/*metabolism ; Metabolic Networks and Pathways ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Myocytes, Smooth Muscle/drug effects/*enzymology ; NADPH Oxidase 2 ; NADPH Oxidases/*metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Onium Compounds/pharmacology ; Phospholipases A2/*biosynthesis ; Phosphorylation ; Sesquiterpenes/pharmacology ; Sesquiterpenes, Guaiane ; Trachea/drug effects/*enzymology ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Cytosolic phospholipase A(2) (cPLA(2)) plays a pivotal role in mediating agonist-induced arachidonic acid (AA) release for prostaglandin (PG) synthesis during inflammation triggered by tumor necrosis factor-α (TNF-α). However, the mechanisms underlying TNF-α-induced cPLA(2) expression and PGE(2) synthesis in human tracheal smooth muscle cells (HTSMCs) remain unknown. Here, we report that TNF-α-induced cPLA(2) protein and mRNA expression, PGE(2) production, and phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK1/2, which were attenuated by pretreatment with a ROS scavenger [N-acetyl-L-cysteine, (NAC)] and the inhibitors of NADPH oxidase [apocynin (APO) and diphenyleneiodonium chloride (DPI)], MEK1/2 (U0126), p38 MAPK (SB202190), and JNK1/2 (SP600125) or transfection with siRNA of Nox2, p47(phox) , MEK1, p42, p38, or JNK2. TNF-α-induced cPLA(2) expression was also inhibited by pretreatment with a selective NF-κB inhibitor [helenalin (HLN)] or transfection with dominant negative mutants of NF-κB inducing kinase (NIK) or IκB kinase (IKK)α/β. TNF-α-induced NF-κB translocation was blocked by pretreatment with NAC, DPI, APO, or HLN, but not by U0126, SB202190, or SP600125. In addition, pretreatment with curcumin (a p300 inhibitor) or transfection with p300 siRNA blocked cPLA(2) expression and PGE(2) synthesis induced by TNF-α. We further confirmed that p300 was associated with the cPLA(2) promoter which was dynamically linked to histone H4 acetylation stimulated by TNF-α, determined by chromatin immunoprecipitation assay. Association of p300 and histone H4 to cPLA(2) promoter was inhibited by U0126, SB202190, and SP600125. These results suggested that in HTSMCs, activation of p47(phox) , MAPKs, NF-κB, and p300 is essential for TNF-α-induced cPLA(2) expression and PGE(2) release.}, }
@article {pmid21519821, year = {2011}, author = {Koc, E and Reis, KA and Ebinc, FA and Pasaoglu, H and Demirtas, C and Omeroglu, S and Derici, UB and Guz, G and Erten, Y and Bali, M and Arinsoy, T and Sindel, S}, title = {Protective effect of beta-glucan on contrast induced-nephropathy and a comparison of beta-glucan with nebivolol and N-acetylcysteine in rats.}, journal = {Clinical and experimental nephrology}, volume = {15}, number = {5}, pages = {658-665}, pmid = {21519821}, issn = {1437-7799}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*drug therapy/pathology ; Animals ; Benzopyrans/*therapeutic use ; Blood Urea Nitrogen ; Contrast Media ; Creatinine/blood ; Ethanolamines/*therapeutic use ; Female ; Nebivolol ; Protective Agents ; Rats ; beta-Glucans/*therapeutic use ; }, abstract = {BACKGROUND: It has been shown that beta-glucan (BG), which has antioxidant and immunomodulatory effects, attenuats renal ischemia-reperfusion injury. We aimed to investigate whether BG might have a preventive role against the development of contrast-induced nephropathy and to compare its effect with nebivolol (Nb) and N-acetylcysteine (NAC).<br><br>METHODS: Thirty-six Wistar albino female rats were randomly divided into six groups (n&#xa0;=&#xa0;6 each): control, contrast media (CM), BG, BG&#xa0;+&#xa0;CM, Nb&#xa0;+&#xa0;CM, and NAC&#xa0;+&#xa0;CM. With the exception of control and CM groups, the others were given drugs orally once a day for 5&#xa0;days. Kidney function parameters, inflammatory parameters, and serum and renal tissue oxidative stress markers were measured.<br><br>RESULTS: Increases of serum creatinine and blood urea nitrogen levels were significantly higher (p&#xa0;<&#xa0;0.05) in the CM group only. Absolute changes of serum creatinine levels in BG, BG&#xa0;+&#xa0;CM and Nb&#xa0;+&#xa0;CM groups were significantly lower than those in the CM group (p&#xa0;<&#xa0;0.05). Serum levels of advanced oxidation protein products and malondialdehyde were significantly less (p&#xa0;<&#xa0;0.05) in the BG group compared to the CM group. Histopathological lesions in the CM group were more advanced (p&#xa0;<&#xa0;0.05). No significant differences between the BG&#xa0;+&#xa0;CM, Nb&#xa0;+&#xa0;CM and NAC&#xa0;+&#xa0;CM groups were found with regard to histopathological findings.<br><br>CONCLUSION: This study suggests that BG protects or ameliorates against contrast-induced nephropathy. Its beneficial effects may be similar to or greater than those of Nb or NAC.}, }
@article {pmid21519330, year = {2011}, author = {Baras, AS and Solomon, A and Davidson, R and Moskaluk, CA}, title = {Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {91}, number = {8}, pages = {1170-1180}, doi = {10.1038/labinvest.2011.70}, pmid = {21519330}, issn = {1530-0307}, support = {T32 GM007267/GM/NIGMS NIH HHS/United States ; }, mesh = {*Apoptosis ; Carcinoma, Squamous Cell/*metabolism ; Gene Expression Profiling ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; Mitochondria/metabolism ; NF-kappa B/metabolism ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Transcription Factors/*metabolism ; }, abstract = {The vesicular overexpressed in cancer prosurvival protein 1 (VOPP1) gene product (previously known as GASP and ECOP) has a poorly characterized functional role in cancer cells, although its expression levels are known to be elevated in many cancer types. To determine the role that VOPP1 has in human squamous cell carcinoma (SCC), a series of siRNA-mediated expression knockdown experiments were performed in carcinoma-derived model systems with confirmed endogenous VOPP1 overexpression (three SCC-derived cell lines: SCC-9, FaDu, and H2170, as well as the cervical adenocarcinoma HeLa cell line, which has been examined in relevant previous reports). The data indicate that VOPP1 knockdown induces cell death at 72 h post-transfection and this is caused by the induction of apoptosis via the intrinsic pathway. Analysis of microarray gene expression profiling showed that genes whose expression was affected by VOPP1 knockdown exhibited enrichment in annotations of oxidative stress and mitochondrial dysfunction. Reporters of reactive oxygen species (ROS) and mitochondrial membrane potential show that ROS levels become elevated and mitochondrial dysfunction occurs with VOPP1 knockdown at time points before the activation of effector caspases and cell death seen at later time points. Furthermore, the introduction of the antioxidant N-acetyl cysteine was able to abrogate the induction of apoptosis observed with VOPP1 knockdown in a dose-responsive manner. Reporter constructs for NF-κB-mediated transcription are not affected in SCC cell lines by VOPP1 knockdown. Taken together, these data support the hypothesis that VOPP1 overexpression in cancer participates in the control of the intracellular redox state, and that its loss leads to oxidative cellular injury leading to cell death by the intrinsic apoptotic pathway.}, }
@article {pmid21519220, year = {2013}, author = {Leite, B and Gomes, F and Teixeira, P and Souza, C and Pizzolitto, E and Oliveira, R}, title = {Staphylococcus epidermidis biofilms control by N-acetylcysteine and rifampicin.}, journal = {American journal of therapeutics}, volume = {20}, number = {4}, pages = {322-328}, doi = {10.1097/MJT.0b013e318209e17b}, pmid = {21519220}, issn = {1536-3686}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Anti-Bacterial Agents/administration &amp; dosage/pharmacology ; Biofilms/*drug effects ; Drug Therapy, Combination ; Equipment and Supplies/microbiology ; Expectorants/administration &amp; dosage/pharmacology ; Microbial Sensitivity Tests ; Rifampin/administration &amp; dosage/*pharmacology ; Staphylococcal Infections/microbiology ; Staphylococcus epidermidis/*drug effects/isolation &amp; purification ; }, abstract = {Medical device-associated infections caused by Staphylococcus epidermidis usually involve biofilm formation and its eradication is particularly challenging. Although rifampicin has been proving to be one of the most effective antibiotics against S. epidermidis biofilms, its use as a single agent can lead to the acquisition of resistance. Therefore, we assessed the combined effect of rifampicin with N-acetylcysteine (NAC) known by its mucolytic effect, in the control of S. epidermidis biofilms. Biofilms of 2 S. epidermidis strains (9142 and 1457) were treated with 1x minimum inhibitory concentration (4 mg/mL) and 10x minimum inhibitory concentration (40 mg/mL) of NAC and 10 mg/L (peak serum) of rifampicin alone and in combination. NAC at 40 mg/L alone or in combination with rifampicin (10 mg/L) significantly reduced (4 log10) the number of biofilm cells. Considering their different modes of action, the association of NAC with rifampicin constitutes a promising therapeutic strategy in the treatment of infections associated to S. epidermidis biofilms.}, }
@article {pmid21518686, year = {2011}, author = {Briguori, C and Visconti, G and Ricciardelli, B and Condorelli, G and , }, title = {Renal insufficiency following contrast media administration trial II (REMEDIAL II): RenalGuard system in high-risk patients for contrast-induced acute kidney injury: rationale and design.}, journal = {EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology}, volume = {6}, number = {9}, pages = {1117-22, 7}, doi = {10.4244/EIJV6I9A194}, pmid = {21518686}, issn = {1969-6213}, mesh = {Acetylcysteine/administration &amp; dosage ; Acute Kidney Injury/chemically induced/physiopathology/*prevention &amp; control ; Biomarkers/blood ; Chi-Square Distribution ; Chronic Disease ; Contrast Media/*adverse effects ; Creatinine/blood ; Diuretics/administration &amp; dosage ; Drug Therapy, Combination ; Equipment Design ; Fluid Therapy/*instrumentation ; Furosemide/administration &amp; dosage ; Glomerular Filtration Rate ; Humans ; Italy ; Kidney Diseases/*complications/physiopathology ; Radiography, Interventional/*adverse effects ; Renal Insufficiency/chemically induced/physiopathology/*prevention &amp; control ; *Research Design ; Risk Assessment ; Risk Factors ; Sodium Bicarbonate/administration &amp; dosage ; Time Factors ; Treatment Outcome ; Triiodobenzoic Acids/*adverse effects ; }, abstract = {AIMS: The combined prophylactic strategy of sodium bicarbonate plus N-acetylsyteine (NAC) seems to be effective in preventing contrast induced acute kidney injury (CI-AKI) in patients at low-to-medium risk. However, in patients at high and very high risk the rate of CI-AKI is still high. In this subset of patients the anticipated advantages of the RenalGuard(tm) System should be investigated. The RenalGuard(tm) System (PLC Medical Systems, Inc., Franklin, MA, USA) is a real-time measurement and real time matched fluid replacement device designed to accommodate the RenalGuard therapy, which is based on the theory that creating and maintaining a high urine output is beneficial by allowing a quick elimination of contrast media, and, therefore, reducing its toxic effects.<br><br>METHODS AND RESULTS: The REMEDIAL II trial is a randomised, multicentre, investigator-sponsored trial addressing the hypothesis that the RenalGuard System is superior to the prophylaxis with sodium bicarbonate infusion plus NAC in preventing CI-AKI in high and very high risk patients. Consecutive patients with chronic kidney disease (CKD) and at high to very high risk for CI-AKI, referred to our institutions for coronary and/or peripheral procedures, will be randomly assigned to 1) prophylactic administration of sodium bicarbonate plus NAC (control group) and 2) RenalGuard System treatment (RenalGuard group). All enrolled patients must have an estimated glomerular filtration rate &#x2264; 30 ml/min/1.73 m2 and/or a contrast nephropathy risk score &#x2265; 11. In all cases iodixanol (an iso-osmolar, non-ionic contrast agent) will be administered. The primary endpoint is an increase of &#x2265; 0.3 mg/dL in the serum creatinine concentration 48 hours after the procedure.<br><br>CONCLUSIONS: The REMEDIAL II trial will give important answers on how to prevent CI-AKI in high and very high risk patients undergoing contrast media exposure.}, }
@article {pmid21517930, year = {2011}, author = {Degrossoli, A and Arrais-Silva, WW and Colhone, MC and Gadelha, FR and Joazeiro, PP and Giorgio, S}, title = {The influence of low oxygen on macrophage response to Leishmania infection.}, journal = {Scandinavian journal of immunology}, volume = {74}, number = {2}, pages = {165-175}, doi = {10.1111/j.1365-3083.2011.02566.x}, pmid = {21517930}, issn = {1365-3083}, mesh = {Acetylcysteine/pharmacology ; Animals ; Azoles/pharmacology ; Basic Helix-Loop-Helix Transcription Factors/biosynthesis/immunology ; Female ; Free Radical Scavengers/pharmacology ; Hypoxia/*immunology/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/immunology ; Interleukin-10/immunology ; Interleukin-12/immunology ; Isoindoles ; Leishmaniasis, Cutaneous/*immunology/metabolism ; Macrophages/drug effects/*immunology/metabolism/ultrastructure ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Nitric Oxide/immunology ; Nitric Oxide Synthase Type II/genetics/immunology ; Organoselenium Compounds/pharmacology ; Reactive Oxygen Species/immunology/metabolism ; Tumor Necrosis Factor-alpha/immunology ; }, abstract = {Hypoxia (low oxygen tension) is a common feature of inflamed and infected tissues. The influence of hypoxia on macrophage responses to micro-organisms has only recently been studied. This study demonstrates that hypoxia induced macrophages to control Leishmania amazonensis, an intracellular parasite that causes cutaneous and cutaneous metastatic lesions. The mechanisms that contribute to the control of macrophages against L. amazonensis infection under a hypoxic microenvironment are not known. Nitric oxide, TNF-α, IL-10 or IL-12 is not responsible for the decrease in parasitism under hypoxia. Live L. amazonensis entry or exocytosis of internalized particles as well as energetic metabolism was not impaired in infected macrophages; no apoptosis-like death was detected in intracellular parasites. Reactive oxygen species (ROS) is likely to be involved, because treatment with antioxidants N-acetylcysteine (NAC) and ebselen inhibits the leishmanicidal effect of macrophages under hypoxia. Leishmania amazonensis infection induces macrophages to express hypoxia-inducible factor-1 (HIF-1α) and -2 (HIF-2α). Data indicate that hypoxia affects the microbial activities and protein expression of macrophages leading to a different phenotype from that of the normoxic counterpart and that it plays a role in modulating Leishmania infection.}, }
@article {pmid21516132, year = {2011}, author = {Wang, YY and Liu, S and Lian, F and Yang, WG and Xue, S}, title = {Toll-like receptor 7/8 agonist resiquimod induces late preconditioning in neonatal cardiac myocytes.}, journal = {Acta pharmacologica Sinica}, volume = {32}, number = {5}, pages = {565-572}, pmid = {21516132}, issn = {1745-7254}, mesh = {Animals ; Animals, Newborn ; Cardiotonic Agents/administration &amp; dosage/*pharmacology ; Cell Hypoxia ; Dose-Response Relationship, Drug ; Gene Knockdown Techniques ; Hypoxia-Inducible Factor 1/metabolism ; Imidazoles/administration &amp; dosage/*pharmacology ; Ischemic Preconditioning, Myocardial/*methods ; Myocytes, Cardiac/*drug effects/pathology ; NF-kappa B/metabolism ; Nitric Oxide Synthase Type II/genetics ; Oxidative Stress/drug effects ; Oxygen/administration &amp; dosage ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Toll-Like Receptor 7/agonists ; Toll-Like Receptor 8/agonists ; }, abstract = {AIM: To investigate whether R-848 (resiquimod, toll-like receptor 7/8 agonist) can induce late preconditioning in neonatal cardiac myocytes.<br><br>METHODS: The protective effects of R-848 on neonatal myocytes against anoxia-reoxygenation-induced injury were tested, and intracellular reactive oxygen species (ROS) were determined. The protein synthesis inhibitor cyclohexamide (CH) and the ROS scavenger N-acetylcysteine (NAC) were used in this model to test if new protein synthesis and oxidative stress were necessary for their cardioprotective effects. The activation of nuclear factor kappa B (NF&#x3ba;B) and hypoxia inducible factor 1 (HIF1) was investigated by electrophoretic mobility shift assays (EMSA), and inducible nitric oxide synthase (iNOS) was assessed by immunoblotting. After iNOS was down-regulated by small interfering RNA (siRNA) transfection, the cardioprotective effect was reassessed.<br><br>RESULTS: ROS were triggered soon after R-848 (0.01-1.0 &#x3bc;g/L) administration, however, the cardioprotective effect of which was induced 24 h later. This protection was abolished by CH or NAC pretreatment. NF&#x3ba;B and HIF1 activation and iNOS up-regulation were involved in this protective mechanism. The cardioprotective effect was also attenuated after iNOS was knocked down.<br><br>CONCLUSION: R-848 provided a cardioprotective effect through a late preconditioning mechanism via a ROS/NF&#x3ba;B-HIF1/iNOS-dependent pathway.}, }
@article {pmid21513718, year = {2011}, author = {Bächle, AC and Mörsdorf, P and Rezaeian, F and Ong, MF and Harder, Y and Menger, MD}, title = {N-acetylcysteine attenuates leukocytic inflammation and microvascular perfusion failure in critically ischemic random pattern flaps.}, journal = {Microvascular research}, volume = {82}, number = {1}, pages = {28-34}, doi = {10.1016/j.mvr.2011.03.010}, pmid = {21513718}, issn = {1095-9319}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Apoptosis/drug effects ; Arterioles/drug effects/pathology/physiopathology ; Capillaries/drug effects/pathology/physiopathology ; Cell Adhesion/drug effects ; Dermatologic Surgical Procedures ; Inflammation/pathology/*prevention &amp; control ; Ischemia/pathology/physiopathology/*prevention &amp; control ; Leukocyte Rolling/drug effects ; Leukocytes/*pathology ; Mice ; Mice, Inbred C57BL ; Microcirculation/*drug effects/physiology ; Microvessels/*drug effects/pathology/physiopathology ; Necrosis/pathology/prevention &amp; control ; Regional Blood Flow/drug effects/physiology ; Surgical Flaps/*blood supply/pathology ; Vasodilation/drug effects/physiology ; }, abstract = {INTRODUCTION: Microcirculatory dysfunction causes ischemia resulting in tissue necrosis. N-acetylcysteine (NAC) has been shown capable of protecting tissue from ischemic necrosis. However, the mechanism of action of NAC is yet not fully understood.<br><br>OBJECTIVE: Herein, we studied whether NAC is capable of attenuating microvascular perfusion failure in critically ischemic musculo-cutaneous tissue.<br><br>MATERIAL AND METHODS: A laterally based skin flap was elevated in the dorsum of C57BL/6 mice and fixed into a dorsal skinfold chamber. Arteriolar perfusion, functional capillary density, leukocytic inflammation, apoptotic cell death, and non-perfused tissue area were repetitively analyzed over 10 days by intravital fluorescence microscopy. Treatment with either 100mg/kg NAC or saline (control) was started 30 min before surgery and was continued until day 10 after flap elevation.<br><br>RESULTS: Surgery induced leukocytic inflammation, microvascular perfusion failure, apoptosis, and tissue perfusion failure. NAC was capable of significantly attenuating the area of non-perfused tissue. This was associated by a marked arteriolar dilation and an increased capillary perfusion. NAC further reduced the ischemia-associated leukocytic response and significantly attenuated apoptotic cell death in all areas of the flap.<br><br>CONCLUSION: NAC is effective to attenuate leukocytic inflammation and microvascular perfusion failure in critically ischemic tissue. Thus, NAC treatment may represent a promising approach to improve the outcome of ischemically endangered flap tissue.}, }
@article {pmid21510113, year = {2010}, author = {Pimparkar, BD and Bhave, A}, title = {Arsenicosis: review of recent advances.}, journal = {The Journal of the Association of Physicians of India}, volume = {58}, number = {}, pages = {617-24, 629}, pmid = {21510113}, issn = {0004-5772}, mesh = {Animals ; Arsenic/blood/*toxicity ; *Arsenic Poisoning/metabolism/prevention &amp; control ; Carcinogens ; Cardiovascular Diseases/chemically induced ; Diabetes Mellitus, Type 2/chemically induced ; Environmental Exposure ; Food Contamination ; Humans ; Neoplasms/chemically induced ; Nervous System Diseases/chemically induced ; Rats ; Water Pollutants, Chemical/*adverse effects/analysis ; *Water Supply ; }, abstract = {Human health in the past and presently is influenced by the amounts and proportion of chemical elements to which humans have been exposed. Arsenic, as a therapeutic agent was known to ancient Greeks and Romans. Ehrlick introduced organic arsenicals as anti linetic agents but with advent of penicillin these have nearly become obsolete. Once considered toxic, harmful to humans, arsenic is now considered an essential ultra trace element at least in animals. Now the impact of arsenic on health is more from industrial and environmental than medicinal exposure. This article reviews human exposure to arsenic in non occupational population, mostly through drinking water which is a worldwide problem, more so in south East Asia. Sources of arsenic, normal and abnormal levels in blood and tissues levels, old and new methods of estimation of arsenic, mechanism of action of arsenic in experimental animal is briefly reviewed. Old described clinical manifestation of arsenic in humans is briefly reviewed and newly described clinical manifestations in human with special emphasis on atherosclerosis, liver and diabetes are discussed. Proposed biological mechanisms in experimental animals included up regulation of inflammatory signals like cytokines and TNF-alpha, oxidative stress, hypomethylation, decreased DNA repair and apoptosis, cell proliferation, angiogenesis, activation of several enzymes like methyl transferase which converts inorganic arsenic to MMA and DMA, and GSH in in-vivo and in-vitro in experimental rat liver slices. Experimentally NAC (N-Acetyl Cysteine) treatment attenuates oxidative stress in atherosclerosis apoptosis and liver injury. GSH probably plays an important role in deactivation of the intermediate products of arsenic metabolism and prevents peroxidation of membrane lipids. Chronic human exposure has been linked to several systems in the human body: dermal (exfoliative dermatitis, keratosis, vitiligo, skin cancer), peripheral neuropathy, encephalopathy, bronchitis, pulmonary fibrosis, hepatosplenomegaly resembling NCPF, portal hypertension, peripheral vascular disease and BFD, arteriosclerosis and cancers of lung, urinary bladder, other internal organs and diabetes. Experimental and epidemiological evidence support diabetes effect of high level arsenic exposure. Low and moderate exposure to arsenic in drinking water is widely prevalent and may play a role in diabetes prevalence and needs to be studied further. Role of arsenic in Indian arteriosclerosis, diabetes and liver diseases, (cirrhosis, NCPF), need to be studied further. Study of mechanisms and enzymes mentioned need to be studied in humans exposed to arsenic and other xenobiotics. Measuring arsenic exposure, metabolic and biologic effects by newly described and simpler urine proteomics may accelerate our understanding of arsenic on health consequences.}, }
@article {pmid21508882, year = {2011}, author = {Corallini, S and Taranta, A and Bellomo, F and Palma, A and Pastore, A and Emma, F}, title = {Transcriptional and posttranscriptional regulation of the CTNS gene.}, journal = {Pediatric research}, volume = {70}, number = {2}, pages = {130-135}, doi = {10.1203/PDR.0b013e3182200187}, pmid = {21508882}, issn = {1530-0447}, mesh = {Acetylcysteine ; Amino Acid Transport Systems, Neutral/genetics/*metabolism ; Cell Culture Techniques ; Cell Line ; Chromatography, High Pressure Liquid ; Cystine/*metabolism ; DNA Primers/genetics ; Dactinomycin ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation/drug effects/genetics/*physiology ; Genetic Vectors ; Humans ; Luciferases ; Promoter Regions, Genetic/genetics ; RNA, Messenger/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Statistics, Nonparametric ; Sulfhydryl Compounds/metabolism ; Transfection ; }, abstract = {Cell cysteine (Cys) levels and/or the [Cys/CySS] redox potential have been shown to regulate mRNA levels of the CTNS gene, which encodes for a lysosomal cystine (CySS) carrier that is defective in cystinosis. To investigate the mechanisms involved CTNS mRNA regulation, different portions of the CTNS promotor were cloned into a luciferase vector and transfected in HK2 cells. A 1.5-2.4-fold increase in luciferase activity was observed when cells were incubated in culture medium containing low CySS concentrations. Conversely, CTNS mRNA levels decreased by 47-56% in the presence of N-acetyl-L-cysteine (NAC). Chase experiments with actinomycin D (ActD) demonstrated a 3-fold stabilization of the CTNS mRNA when cells were cultured in low CySS medium for 48 h. Treatment of control cells with cyclohexamide (CHX) increased CTNS mRNA levels, suggesting that CHX blocked the synthesis of proteins involved in mRNA degradation or in repression of the CTNS gene. Finally, in vitro binding assays showed increased binding (30-110%) of the Sp-1 transcription factor to two regions of the CTNS promotor when cells were incubated in low CySS medium. These results indicate that the CTNS gene is actively regulated at the transcriptional and posttranscriptional levels and suggest that CTNS plays a pivotal role in regulating cell thiol concentrations.}, }
@article {pmid21506115, year = {2011}, author = {Lee, SY and Usui, S and Zafar, AB and Oveson, BC and Jo, YJ and Lu, L and Masoudi, S and Campochiaro, PA}, title = {N-Acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa.}, journal = {Journal of cellular physiology}, volume = {226}, number = {7}, pages = {1843-1849}, doi = {10.1002/jcp.22508}, pmid = {21506115}, issn = {1097-4652}, support = {EY05851/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Administration, Topical ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Catalase/metabolism ; Cell Survival ; Disease Models, Animal ; Electroretinography ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidative Stress/drug effects ; Photic Stimulation ; Retinal Cone Photoreceptor Cells/*drug effects/pathology ; Retinal Rod Photoreceptor Cells/drug effects/pathology ; Retinitis Pigmentosa/*drug therapy/pathology ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; Time Factors ; Up-Regulation ; }, abstract = {Retinitis pigmentosa (RP) is a major source of blindness caused by a large variety of mutations that lead to the death of rod photoreceptors. After rods die, cones gradually die from progressive oxidative damage. Several types of antioxidant formulations have been shown to reduce cone cell death over a relatively short-time frame, but in order for this strategy to be translated into a new treatment for patients with RP, prolonged effects will be needed. In this study, we determined that orally administered N-acetylcysteine (NAC) reduced cone cell death and preserved cone function by reducing oxidative damage in two models of RP, rd1(+/+) and rd10(+/+) mice. In rd10(+/+) mice, supplementation of drinking water with NAC promoted partial maintenance of cone structure and function for at least 6 months. Topical application of NAC to the cornea also reduced superoxide radicals in the retina and promoted survival and functioning of cones. Since oral and/or topical administration of NAC is feasible for long-term treatment in humans, and NAC has a good safety profile, it is reasonable to consider clinical trials to evaluate the effects of prolonged treatment with NAC in patients with RP.}, }
@article {pmid21503880, year = {2012}, author = {Roh, M and van der Meer, R and Abdulkadir, SA}, title = {Tumorigenic polyploid cells contain elevated ROS and ARE selectively targeted by antioxidant treatment.}, journal = {Journal of cellular physiology}, volume = {227}, number = {2}, pages = {801-812}, pmid = {21503880}, issn = {1097-4652}, support = {R01 CA123484/CA/NCI NIH HHS/United States ; R01 CA123484-05/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/pharmacology ; Antioxidants/*pharmacology ; Cell Line ; Drug Resistance, Neoplasm ; Epithelial Cells/*cytology/*metabolism ; Female ; Humans ; Hydrogen Peroxide ; Male ; Mammary Glands, Human/cytology ; Mitochondria/physiology ; Mitosis/drug effects/physiology ; Paclitaxel/pharmacology ; *Polyploidy ; Prostate/cytology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Polyploidy has been linked to tumorigenicity mainly due to the chromosomal aberrations. Elevated reactive oxygen species (ROS) generation, on the other hand, has also been associated with oncogenic transformation in most cancer cells. However, a possible link between ploidy and ROS is largely unexplored. Here we have examined the role of ROS in the tumorigenicity of polyploid cells. We show that polyploid prostate and mammary epithelial cells contain higher levels of ROS due to their higher mitochondrial contents. ROS levels and mitochondrial mass are also higher in dihydrocytochalasin B (DCB)-induced polyploid cells, suggesting that higher levels of ROS observed in polyploid cell can occur due to cytokinesis failure. Interestingly, polyploid cells were more sensitive to the inhibitory effect of the antioxidant, N-Acetyl-L-cysteine (NAC), than control diploid cells. Treatment of polyploid/diploid cells with NAC led to the selective elimination of polyploid cells over time and abrogated the tumorigenicity of polyploid cells. This effect was partially mediated via the Akt signaling pathway. We next explored a possible role for ROS in promoting chromosomal instability by analyzing the effects of ROS on the mitotic stage of the cell cycle. Enhancing ROS levels by treating cells with hydrogen peroxide delayed not only entry into and but also exit from mitosis. Furthermore, increasing ROS levels significantly increased taxol resistance. Our results indicated that increased ROS in polyploid cells can contribute to tumorigenicity and highlight the therapeutic potential of antioxidants by selectively targeting the tumorigenic polyploid cells and by reversing taxol resistance.}, }
@article {pmid21496663, year = {2011}, author = {Minamikawa, H and Yamada, M and Deyama, Y and Suzuki, K and Kaga, M and Yawaka, Y and Ogawa, T}, title = {Effect of N-acetylcysteine on rat dental pulp cells cultured on mineral trioxide aggregate.}, journal = {Journal of endodontics}, volume = {37}, number = {5}, pages = {637-641}, doi = {10.1016/j.joen.2011.02.012}, pmid = {21496663}, issn = {1878-3554}, mesh = {Acetylcysteine/*pharmacology ; Aluminum Compounds/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Calcium Compounds/*pharmacology ; Cell Adhesion/drug effects ; Cell Count ; Cell Movement/drug effects ; Cell Shape ; Cell Survival/drug effects ; Cells, Cultured ; Colorimetry ; Culture Media ; Dental Pulp/cytology/*drug effects ; Drug Combinations ; Fluorescent Dyes ; Glutathione/analysis ; Indicators and Reagents ; Male ; Oxidative Stress/drug effects ; Oxides/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/analysis ; Root Canal Filling Materials/*pharmacology ; Silicates/*pharmacology ; Tetrazolium Salts ; Time Factors ; }, abstract = {INTRODUCTION: The purpose of this study was to evaluate the cytotoxicity of mineral trioxide aggregate (MTA) and its potential detoxification by an antioxidant amino acid, N-acetylcysteine (NAC).<br><br>METHODS: Rat dental pulp cells extracted from rat maxillary incisors were directly cultured on MTA with or without NAC in culture medium. The number of cells and their spreading behavior were both assessed 24 hours after seeding. The intracellular levels of reactive oxygen species (ROS) and glutathione (GSH) were also assessed after 24 hours of culture.<br><br>RESULTS: The number of cells attached to MTA was 60% greater when NAC was added to the culture medium. In addition, the area and perimeter of the cells were found to be 2-fold greater in the culture containing NAC. Cells cultured on MTA alone showed large ROS concentrations, which disappeared when the medium was supplemented with NAC. The intracellular GSH level, however, increased 3.5-fold with NAC addition.<br><br>CONCLUSIONS: This study demonstrated that the presence of NAC in environments can substantially improve attachment and spreading behaviors of dental pulp cells on MTA. This biological effect was associated with an improvement in the cellular redox system by NAC and warrants further exploration of NAC for determining its therapeutic value in improving the biocompatibility of MTA.}, }
@article {pmid21496136, year = {2011}, author = {Pizon, AF and Jang, DH and Wang, HE}, title = {The in vitro effect of N-acetylcysteine on prothrombin time in plasma samples from healthy subjects.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {18}, number = {4}, pages = {351-354}, doi = {10.1111/j.1553-2712.2011.01041.x}, pmid = {21496136}, issn = {1553-2712}, mesh = {Acetaminophen/poisoning ; Acetylcysteine/adverse effects/*pharmacology ; Adult ; Blood Coagulation/*drug effects ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; *Prothrombin Time ; }, abstract = {OBJECTIVES: In the treatment of acetaminophen toxicity, clinicians believe that N-acetylcysteine (NAC) artificially elevates prothrombin time (PT), potentially obscuring signs of liver damage. However, the effect of NAC on human blood coagulation remains unverified. The purpose of this study was to evaluate the effect of NAC on PT prolongation in human plasma.<br><br>METHODS: The authors obtained blood samples from 33 volunteer subjects. The blood plasma samples were divided into four 1-mL aliquots. The first aliquot was used as a control. To three additional aliquots, varying amounts of NAC were added, maintaining constant volume with a maximum dilution of 0.5%. The four concentrations of NAC (control, 250, 500, or 1,000 mg/L) were incubated at 37&#xb0;C for 1 hour, and PT was measured. PT values were compared using fixed effects regression.<br><br>RESULTS: Mean (&#xb1; standard deviation [SD]) PT values for the control, 100, 500, and 1,000 mg/L NAC values were 13.9 (&#xb1;1.01), 14.2 (&#xb1;1.08), 15.5 (&#xb1;1.21), and 17.4 (&#xb1;1.72) seconds, respectively. At the 1,000 mg/L concentration, two PTs exceeded 22 seconds, and half exceeded 17 seconds. PT increased with NAC concentrations (fixed effects regression p < 0.001) in a dose-dependent manner.<br><br>CONCLUSIONS: In this in vitro human model, NAC had a dose-dependent effect on PT.}, }
@article {pmid21494874, year = {2011}, author = {Wu, H and Jiang, C and Gan, D and Liao, Y and Ren, H and Sun, Z and Zhang, M and Xu, G}, title = {Different effects of low- and high-dose insulin on ROS production and VEGF expression in bovine retinal microvascular endothelial cells in the presence of high glucose.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {249}, number = {9}, pages = {1303-1310}, pmid = {21494874}, issn = {1435-702X}, mesh = {Animals ; Cattle ; Diabetic Retinopathy/drug therapy/metabolism/*pathology ; Dose-Response Relationship, Drug ; Endothelial Cells/cytology/*drug effects/*metabolism ; Glucose/pharmacology ; Hypoglycemic Agents/pharmacology ; Insulin/*pharmacology ; Ion Channels/genetics/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondrial Proteins/genetics/metabolism ; Primary Cell Culture ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Retinal Vessels/*cytology ; Uncoupling Protein 2 ; Vascular Endothelial Growth Factor A/genetics/*metabolism ; }, abstract = {BACKGROUND: Clinical trials have demonstrated that acute intensive insulin therapy may cause transient worsening of retinopathy in type 1 and type 2 diabetes patients. However, the related mechanism still remains controversial. The purpose of the present study was to investigate the effect of insulin on the mitochondrial membrane potential (△Ψm), reactive oxygen species (ROS) production, UCP-2 and VEGF expression in bovine retinal microvascular endothelial cells (BRECs) in the presence of normal or high glucose and the related mechanisms.<br><br>METHODS: BRECs were isolated as primary cultures and identified by immunostaining. Passage BRECs were initially exposed to normal (5&#xa0;mM) or high glucose (30&#xa0;mM) for 3&#xa0;days, with equimolar L: -glucose supplemented for osmotic equation. Then the cells were treated with 1&#xa0;nM, 10&#xa0;nM, or 100&#xa0;nM insulin for 24&#xa0;h: &#x25b3;&#x3a8;m and ROS production were determined by JC-1 and CM-H2DCFDA, respectively. Expression of UCP-2 and VEGF mRNA was determined by real-time RT-PCR; expression UCP-2 and VEGF protein was determined by Western-blotting analysis. A general ROS scavenger N-acetylcysteine (NAC, 10&#xa0;mM) and an NADPH oxidase inhibitor apocynin (1&#xa0;mmol/l) were added 1&#xa0;h before treatment with 100&#xa0;nM insulin.<br><br>RESULTS: Insulin increased &#x25b3;&#x3a8;m, ROS production, and expression of UCP-2 and VEGF in BRECs at normal glucose (5&#xa0;mM) in a dose-dependent manner. Low-dose insulin (1&#xa0;nM) decreased &#x25b3;&#x3a8;m, ROS production, and UCP-2, VEGF expression in BRECs at high glucose (30&#xa0;mM); and high-dose insulin (10&#xa0;nM, 100nM) recovered &#x25b3;&#x3a8;m, ROS production, and UCP-2, VEGF expression. Pretreatment of cells with NADPH oxidase inhibitor apocynin significantly suppressed 100&#xa0;nM insulin-induced ROS production (p&#x2009;<&#x2009;0.01, one-way ANOVA). Pretreatment of cells with ROS scavenger N-acetylcysteine completely blocked insulin-induced UCP-2 expression (p&#x2009;<&#x2009;0.01, one-way ANOVA) and significantly suppressed VEGF expression (p&#x2009;<&#x2009;0.01, one-way ANOVA).<br><br>CONCLUSIONS: High-dose insulin-induced ROS production and VEGF expression in BRECs in the presence of high glucose might be one of the reasons for the transient worsening of diabetic retinopathy during intensive insulin treatment.}, }
@article {pmid21491109, year = {2011}, author = {Mitamura, K and Aoyama, E and Sakai, T and Iida, T and Hofmann, AF and Ikegawa, S}, title = {Characterization of non-enzymatic acylation of amino or thiol groups of bionucleophiles by the acyl-adenylate or acyl-CoA thioester of cholic acid.}, journal = {Analytical and bioanalytical chemistry}, volume = {400}, number = {7}, pages = {2253-2259}, doi = {10.1007/s00216-011-4961-z}, pmid = {21491109}, issn = {1618-2650}, mesh = {Acylation ; Adenosine Monophosphate/*chemistry ; Cholic Acid/*chemistry ; Coenzyme A/*chemistry ; Esters ; }, abstract = {Acyl-adenylates and acyl-CoA thioesters of bile acids (BAs) are highly electrophilic acyl-linked metabolites which can undergo transacylation reactions with amino and thiol groups of nucleophilic groups on acceptor molecules such as amino acids, peptides, and proteins. Here, non-enzymatic acylation at pH 7.4 of glycine, taurine, glutathione (GSH), and N-acetylcysteine (NAC) by cholyl-adenylate (CA-AMP) was compared with that mediated by cholyl-CoA thioester (CA-CoA) using a 1:1 mixture of stable isotopically labeled CA-AMP and unlabeled CA-CoA. The transacylation products of these substrates were analyzed by liquid chromatography/electrospray ionization linear ion-trap mass spectrometry in negative-ion detection mode. CA-AMP was more reactive than CA-CoA with the amino group of glycine or taurine than with the thiol group of GSH or NAC. In contrast, CA-CoA was more reactive than CA-AMP with the thiol group of GSH or NAC and was far less reactive with the amino group of glycine or taurine. These differences in the reactivity of CA-AMP as compared with that of CA-CoA towards amino and thiol groups may be attributed to the electrophilicity of the carbonyl carbon of these acyl-linked cholic acid metabolites and the nucleophilicity of the amino and thiol group in the bionucleophiles that were studied.}, }
@article {pmid21488088, year = {2011}, author = {Sakaue, M and Mori, N and Okazaki, M and Kadowaki, E and Kaneko, T and Hemmi, N and Sekiguchi, H and Maki, T and Ozawa, A and Hara, S and Arishima, K and Yamamoto, M}, title = {Vitamin K has the potential to protect neurons from methylmercury-induced cell death in vitro.}, journal = {Journal of neuroscience research}, volume = {89}, number = {7}, pages = {1052-1058}, doi = {10.1002/jnr.22630}, pmid = {21488088}, issn = {1097-4547}, mesh = {Animals ; Animals, Newborn ; Cell Death/drug effects/physiology ; Cell Line, Tumor ; Disease Models, Animal ; Humans ; In Vitro Techniques ; Mercury Poisoning, Nervous System/metabolism/pathology/*prevention &amp; control ; Methylmercury Compounds/*antagonists &amp; inhibitors/toxicity ; Nerve Degeneration/chemically induced/*drug therapy/pathology ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/*pharmacology/therapeutic use ; Rats ; Rats, Wistar ; Vitamin K/analogs &amp; derivatives/*pharmacology/therapeutic use ; }, abstract = {Vitamin K (VK) has a protective effect on neural cells. Methylmercury is a neurotoxicant that directly induces neuronal death in vivo and in vitro. Therefore, in the present study, we hypothesized that VK inhibits the neurotoxicity of methylmercury. To prove our hypothesis in vitro, we investigated the protective effects of VKs (phylloquinone, vitamin K(1); menaquinone-4, vitamin K(2)) on methylmercury-induced death in primary cultured neurons from the cerebella of rat pups. As expected, VKs inhibited the death of the primary cultured neurons. It has been reported that the mechanisms underlying methylmercury toxicity involve a decrement of intracellular glutathione (GSH). Actually, treatment with GSH and a GSH inducer, N-acetyl cysteine, inhibited methylmercury-induced neuronal death in the present study. Thus, we investigated whether VKs also have protective effects against GSH-depletion-induced cell death by employing two GSH reducers, L-buthionine sulfoximine (BSO) and diethyl maleate (DEM), in primary cultured neurons and human neuroblastoma IMR-32 cells. Treatment with VKs affected BSO- and DEM-induced cell death in both cultures. On the other hand, the intracellular GSH assay showed that VK(2), menaquinone-4, did not restore the reduced GSH amount induced by methylmercury or BSO treatments. These results indicate that VKs have the potential to protect neurons against the cytotoxicity of methylmercury and agents that deplete GSH, without increasing intracellular GSH levels. The protective effect of VKs may lead to the development of treatments for neural diseases involving GSH depletion.}, }
@article {pmid21486840, year = {2011}, author = {Andersson, DC and Fauconnier, J and Yamada, T and Lacampagne, A and Zhang, SJ and Katz, A and Westerblad, H}, title = {Mitochondrial production of reactive oxygen species contributes to the β-adrenergic stimulation of mouse cardiomycytes.}, journal = {The Journal of physiology}, volume = {589}, number = {Pt 7}, pages = {1791-1801}, pmid = {21486840}, issn = {1469-7793}, mesh = {Acetylcysteine/pharmacology ; Adrenergic beta-Agonists/pharmacology ; Animals ; Antioxidants/pharmacology ; Calcium Signaling/drug effects ; In Vitro Techniques ; Isoproterenol/pharmacology ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Mitochondria, Heart/metabolism ; Myocardial Contraction/drug effects ; Myocytes, Cardiac/drug effects/*metabolism/physiology ; Patch-Clamp Techniques ; Reactive Oxygen Species/metabolism ; Receptors, Adrenergic, beta/*metabolism ; }, abstract = {The sympathetic adrenergic system plays a central role in stress signalling and stress is often associated with increased production of reactive oxygen species (ROS). Furthermore, the sympathetic adrenergic system is intimately involved in the regulation of cardiomyocyte Ca2+ handling and contractility. In this study we hypothesize that endogenously produced ROS contribute to the inotropic mechanism of β-adrenergic stimulation in mouse cardiomyocytes. Cytoplasmic Ca2+ transients, cell shortening and ROS production were measured in freshly isolated cardiomyocytes using confocal microscopy and fluorescent indicators. As a marker of oxidative stress, malondialdehyde (MDA) modification of proteins was detected with Western blotting. Isoproterenol (ISO), a β-adrenergic agonist, increased mitochondrial ROS production in cardiomyocytes in a concentration- and cAMP–protein kinase A-dependent but Ca2+-independent manner. Hearts perfused with ISO showed a twofold increase in MDA protein adducts relative to control. ISO increased Ca2+ transient amplitude, contraction and L-type Ca2+ current densities (measured with whole-cell patch-clamp) in cardiomyocytes and these increases were diminished by application of the general antioxidant N-acetylcysteine (NAC) or the mitochondria-targeted antioxidant SS31. In conclusion, increased mitochondrial ROS production plays an integral role in the acute inotropic response of cardiomyocytes to β-adrenergic stimulation. On the other hand, chronically sustained adrenergic stress is associated with the development of heart failure and cardiac arrhythmias and prolonged increases in ROS may contribute to these defects.}, }
@article {pmid21486515, year = {2011}, author = {Lin, Y and Han, XF and Fang, ZF and Che, LQ and Nelson, J and Yan, TH and Wu, D}, title = {Beneficial effects of dietary fibre supplementation of a high-fat diet on fetal development in rats.}, journal = {The British journal of nutrition}, volume = {106}, number = {4}, pages = {510-518}, doi = {10.1017/S0007114511000614}, pmid = {21486515}, issn = {1475-2662}, mesh = {Animals ; Biomarkers/blood/metabolism ; Dietary Fats/*adverse effects ; Dietary Fiber/*therapeutic use ; *Dietary Supplements ; Female ; *Fetal Development ; Free Radical Scavengers/blood ; Glucose Transporter Type 3/genetics/metabolism ; Heart/embryology ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Liver/embryology/enzymology ; *Maternal Nutritional Physiological Phenomena ; Myocardium/enzymology ; *Oxidative Stress ; Oxidoreductases/genetics/metabolism ; Placenta/enzymology/metabolism ; Pregnancy ; Protein Carbonylation ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Thioredoxins/genetics/metabolism ; }, abstract = {The objective of the present study was to investigate the effects of the addition of fibre and the antioxidant N-acetylcysteine (NAC) to fat-rich diets on fetal intrauterine development in rats. A total of eighty virgin female Sprague-Dawley rats were fed a control diet, a high-fat diet (HF), a high-fat and high-fibre diet (HFF) or a high-fat NAC diet until day 19·5 of gestation. Maternal HFF consumption resulted in a significantly higher mean fetal number and placental weight than in the other groups (P < 0·05). The HFF diet significantly abrogated HF-induced decreases in maternal serum and placental superoxide anion and hydroxyl radical scavenging capacities (P < 0·05); partially abrogated HF-induced increases in maternal serum and placental malondialdehyde (MDA) and protein carbonyl concentrations (maternal serum MDA and placental protein carbonyl, P < 0·05); resulted in significantly higher fetal liver total superoxide dismutase (SOD), Cu- and Zn-containing SOD and Mn-containing SOD (Mn-SOD) activities than in the HF group (P < 0·05). Furthermore, mRNA expressions of hypoxia-inducible factor 1-α, thioredoxin 2 and Mn-SOD in fetal liver and Mn-SOD in fetal heart and placental GLUT3 in the HFF group were higher than those in the other groups (P < 0·05). The inclusion of dietary fibre in the HF diet was more effective than NAC supplementation in maintaining maternal serum and placental superoxide anion and hydroxyl radical scavenging capacities close to those of the control. These results suggest that maternal fibre intake during pregnancy is beneficial for fetal intrauterine development possibly through the improvement of maternal, placental and fetal antioxidant capacities and placental nutrient transfer capacity.}, }
@article {pmid21484771, year = {2011}, author = {Biniecka, M and Fox, E and Gao, W and Ng, CT and Veale, DJ and Fearon, U and O'Sullivan, J}, title = {Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis.}, journal = {Arthritis and rheumatism}, volume = {63}, number = {8}, pages = {2172-2182}, doi = {10.1002/art.30395}, pmid = {21484771}, issn = {1529-0131}, mesh = {Arthritis, Psoriatic/genetics/*metabolism ; Arthritis, Rheumatoid/genetics/*metabolism ; Cells, Cultured ; Humans ; Hypoxia/*genetics/metabolism ; Inflammation/genetics/metabolism ; Mitochondria/genetics/*metabolism ; *Mutagenesis ; Oxidative Stress/genetics ; Reactive Oxygen Species/metabolism ; Synovial Fluid/metabolism ; Synovial Membrane/metabolism ; }, abstract = {OBJECTIVE: To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels.<br><br>METHODS: Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO(2)) were measured at arthroscopy using a Licox probe. Synovial expression of lipid peroxidation (4-hydroxynonenal [4-HNE]) and mitochondrial cytochrome c oxidase subunit II (CytcO II) deficiency were assessed by immunohistochemistry. In vitro levels of mtDNA point mutations, reactive oxygen species (ROS), mitochondrial membrane potential, and markers of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanine [8-oxodG]) and lipid peroxidation (4-HNE) were determined in human synoviocytes under normoxia and hypoxia (1%) in the presence or absence of superoxide dismutase (SOD) or N-acetylcysteine (NAC) or a hydroxylase inhibitor (dimethyloxalylglycine [DMOG]). Patients were categorized according to their in vivo tPO(2) level (<20 mm Hg or >20 mm Hg), and mtDNA point mutations, immunochemistry features, and stress markers were compared between groups.<br><br>RESULTS: The median tPO(2) level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P = 0.05) and with higher synovial 4-HNE cytoplasmic expression (P = 0.04). Synovial expression of CytcO II correlated with in vivo tPO(2) levels (P = 0.03), and levels were lower in patients with tPO(2) <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC.<br><br>CONCLUSION: These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.}, }
@article {pmid21482679, year = {2011}, author = {Orcutt, KP and Parsons, AD and Sibenaller, ZA and Scarbrough, PM and Zhu, Y and Sobhakumari, A and Wilke, WW and Kalen, AL and Goswami, P and Miller, FJ and Spitz, DR and Simons, AL}, title = {Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4.}, journal = {Cancer research}, volume = {71}, number = {11}, pages = {3932-3940}, pmid = {21482679}, issn = {1538-7445}, support = {K01 CA134941-02/CA/NCI NIH HHS/United States ; R01CA133114/CA/NCI NIH HHS/United States ; K01 CA134941/CA/NCI NIH HHS/United States ; T32 CA078586-09/CA/NCI NIH HHS/United States ; R01 CA133114/CA/NCI NIH HHS/United States ; T32 CA078586/CA/NCI NIH HHS/United States ; K01CA134941/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; K01 CA134941-01A1/CA/NCI NIH HHS/United States ; P30CA086862/CA/NCI NIH HHS/United States ; R01 CA133114-03/CA/NCI NIH HHS/United States ; R01 CA133114-02/CA/NCI NIH HHS/United States ; T32CA078586/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Carcinoma, Squamous Cell/*drug therapy/metabolism/pathology ; Cell Cycle/drug effects/genetics ; Cell Growth Processes/drug effects ; Cell Survival/drug effects/genetics ; Cells, Cultured ; ErbB Receptors/*antagonists &amp; inhibitors/biosynthesis/genetics/metabolism ; Erlotinib Hydrochloride ; Female ; Gene Knockdown Techniques ; Head and Neck Neoplasms/*drug therapy/metabolism/pathology ; Humans ; Mice ; Mice, Nude ; NADPH Oxidase 4 ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; Oxidative Stress/*drug effects ; Protein Kinase Inhibitors/*pharmacology ; Quinazolines/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Transfection ; Xenograft Model Antitumor Assays ; }, abstract = {Redox regulation of epidermal growth factor receptor (EGFR) signaling helps protect cells against oxidative stress. In this study, we investigated whether the cytotoxicity of an EGFR tyrosine kinase inhibitor, erlotinib (ERL), was mediated by induction of oxidative stress in human head and neck cancer (HNSCC) cells. ERL elicited cytotoxicity in vitro and in vivo while increasing a panel of oxidative stress parameters which were all reversible by the antioxidant N-acetyl cysteine. Knockdown of EGFR by using siRNA similarly increased these oxidative stress parameters. Overexpression of mitochondrial targeted catalase but not superoxide dismutase reversed ERL-induced cytotoxicity. Consistent with a general role for NADPH oxidase (NOX) enzymes in ERL-induced oxidative stress, ERL-induced cytotoxicity was reversed by diphenylene iodonium, a NOX complex inhibitor. ERL reduced the expression of NOX1, NOX2, and NOX5 but induced the expression of NOX4. Knockdown of NOX4 by using siRNA protected HNSCC cells from ERL-induced cytotoxicity and oxidative stress. Our findings support the concept that ERL-induced cytotoxicity is based on a specific mechanism of oxidative stress mediated by hydrogen peroxide production through NOX4 signaling.}, }
@article {pmid21482077, year = {2011}, author = {Chang, SP and Shen, SC and Lee, WR and Yang, LL and Chen, YC}, title = {Imatinib mesylate induction of ROS-dependent apoptosis in melanoma B16F0 cells.}, journal = {Journal of dermatological science}, volume = {62}, number = {3}, pages = {183-191}, doi = {10.1016/j.jdermsci.2011.03.001}, pmid = {21482077}, issn = {1873-569X}, mesh = {Animals ; Anthracenes/pharmacology ; Antineoplastic Agents/*pharmacology ; *Apoptosis ; Benzamides ; Flavonoids/pharmacology ; Flow Cytometry/methods ; Imatinib Mesylate ; Imidazoles/pharmacology ; Melanoma, Experimental/*metabolism ; Membrane Potentials ; Mice ; Mitochondria/metabolism ; Piperazines/*pharmacology ; Protein Kinase Inhibitors/*pharmacology ; Pyridines/pharmacology ; Pyrimidines/*pharmacology ; *Reactive Oxygen Species ; }, abstract = {BACKGROUND: Imatinib mesylate (STI571), a protein tyrosine kinase inhibitor, was shown to reduce the viability of several cancer cell lines via apoptosis induction; however, the role of reactive oxygen species (ROS) in STI571-induced melanoma cell apoptosis is still undefined.<br><br>OBJECTIVE: In this study, we investigated the contribution of ROS to STI571-induced apoptosis in melanoma B16F0 cells, and the apoptotic mechanism elicited by STI571 was illustrated.<br><br>METHODS: Using an in vitro cell culture system, the effects of STI571 on ROS production, cell cycle progression, caspase activation, and mitochondrial functions were examined via Western blotting, a flow cytometric analysis, an enzyme activity assay, and a DNA integrity assay. In pharmacological studies, the ROS scavenger, N-acetyl cysteine (NAC), the NADPH oxidase inhibitor, dipheylene iodide (DPI), and mitogen-activated protein kinase (MAPK) inhibitors (PD98059, SP600125, and SB203580) were applied to investigate the mechanism.<br><br>RESULTS: STI571 reduced the viability of melanoma cells B16F0, but not human skin fibroblasts WS1, via apoptosis induction. Besides, apoptosis induced by STI571 was inhibited by the addition of NAC and DPI, and an increase in the intracellular peroxide level by STI571 was identified in melanoma B16F0 cells. Activation of caspases 3 and 9 enzyme activities accompanied by disrupting the mitochondria membrane potential in according with stimulating JNK and p38 protein phosphorylation was identified in STI571-treated B16F0 cells. STI571-mediated a ROS-dependent apoptosis potentiated by JNK inhibitor SP600125 was first identified in melanoma B16F0 cells.<br><br>CONCLUSION: Our results support the idea that ROS-dependent apoptosis in STI571-treated melanoma cells B16F0. The combination of a JNK inhibitor with STI571 for treating melanomas is suggested for further in vivo studies.}, }
@article {pmid21479099, year = {2011}, author = {Ma, Y and Chen, H and Xia, W and Ying, W}, title = {Oxidative stress and PARP activation mediate the NADH-induced decrease in glioma cell survival.}, journal = {International journal of physiology, pathophysiology and pharmacology}, volume = {3}, number = {1}, pages = {21-28}, pmid = {21479099}, issn = {1944-8171}, abstract = {Reduced nicotinamide adenine dinucleotide (NADH) plays key roles in energy metabolism and mitochondrial functions. However, there has been little information regarding the effect of NADH on cell survival. In this study we determined the effect of NADH treatment on the survival of glioma cells. We found that treatment of C6 glioma cells with as low as 1 μM NADH for 24 hrs significantly decreased the survival of these cells, and that treatment of the cells with 1000 μM NADH for 4 days decreased the survival of the cells by nearly 90%. This effect of NADH on glioma cells appears to be mediated by oxidative stress, as indicated by our findings that NADH treatment induced an increase in intracellular reactive oxygen species, and that two antioxidants, N-acetyl cysteine and Trolox, significantly attenuated the effect of NADH. We also found that NADH treatment induced an increase in poly(ADP-ribose) polymerase (PARP) activity, and that PARP inhibitors decreased the effect of NADH on the survival of glioma cells. These observations suggest that NADH reduces the cell survival at least partially by activating PARP. Collectively, our studies demonstrated a novel biological property of NADH - NADH decreases glioma cell survival by increasing oxidative stress and PARP activation. These results also suggest that NADH may have therapeutic potential for treating gliomas.}, }
@article {pmid21477646, year = {2011}, author = {Yoon, H and Lee, GH and Kim, DS and Kim, KW and Kim, HR and Chae, HJ}, title = {The effects of 3, 4 or 5 amino salicylic acids on manganese-induced neuronal death: ER stress and mitochondrial complexes.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {7}, pages = {1259-1268}, doi = {10.1016/j.tiv.2011.04.002}, pmid = {21477646}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Aminosalicylic Acids/*pharmacology ; Antioxidants/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Electron-Transferring Flavoproteins/*metabolism ; Endoplasmic Reticulum Stress/*drug effects ; Humans ; Manganese/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Neurons/*drug effects ; }, abstract = {This study was designed to investigate the mechanisms that are associated with manganese (Mn) toxicity. In addition, the association between Mn toxicity and 3, 4, 5 amino salicylic acid (ASA), anti-oxidants, including N-acetyl cysteine (NAC), was examined by dopaminergic cell line, SK-M-NC. Our studies showed that Mn influenced the mitochondria dysfunction and endoplasmic reticulum stress (ER stress). It reduced the mitochondria complex I activity but did not affect the complex II, III, or IV activities. The presence of 3, 4, 5 ASA protected against Mn-induced-apoptosis, as did NAC. However, the salicylate analogues and the antioxidants did not mediate ER stress in this model. The salicylate analogues reduced reactive oxygen species (ROS) and reversed the deficient mitochondrial membrane potential that was induced by Mn. Taken together, the 3, 4, 5 ASA worked in a similar way, regulating the Mn-induced mitochondrial dysfunction and protecting cells.}, }
@article {pmid21474252, year = {2011}, author = {Brannan, RG}, title = {Effect of N-acetyl-cysteine on liposomal and muscle model oxidation induced by reactive oxygen, nitrogen, and sulfur.}, journal = {Meat science}, volume = {88}, number = {4}, pages = {733-739}, doi = {10.1016/j.meatsci.2011.03.006}, pmid = {21474252}, issn = {1873-4138}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cysteine ; Food Additives ; Food Handling ; Free Radicals ; Glutathione/metabolism ; Lipid Peroxidation ; Lipid Peroxides ; Liposomes/metabolism ; *Meat ; Models, Biological ; Muscle, Skeletal/*metabolism ; Oxidation-Reduction ; Reactive Nitrogen Species/*metabolism ; Reactive Oxygen Species/*metabolism ; Sulfur/*metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Turkeys ; }, abstract = {N-acetyl-cysteine (NAC), a naturally occurring thiol, is found in some fruits and vegetables, sometimes in concentrations higher than glutathione. The objective of this research was to determine the antioxidative effect of NAC in liposomal and muscle models challenged by different oxidizing systems, three that produce reactive oxygen species, two that produce reactive nitrogen species, and two that produce reactive sulfur. The antioxidative effect of cysteine and NAC was compared in the liposomes and NAC and BHT were compared in the muscle homogenates. Lipid hydroperoxides (LOOH), TBARS, and sulfydryls (protein and non-protein) were analyzed. Results indicated that NAC is a more effective inhibitor of lipid oxidation in systems induced by free radicals and reactive nitrogen than those that are induced by peroxides. NAC appears to be at least mildly antioxidative in both liposomal and muscle models, although it did not completely inhibit oxidation in liposomes and generally was not as effective as BHT in the muscle models.}, }
@article {pmid21470631, year = {2011}, author = {Fang, Q and Wang, H and Zhu, S and Zhu, Q}, title = {N-acetyl-L-cysteine inhibits wear particle-induced prosthesis loosening.}, journal = {The Journal of surgical research}, volume = {168}, number = {2}, pages = {e163-72}, doi = {10.1016/j.jss.2010.12.006}, pmid = {21470631}, issn = {1095-8673}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Arthroplasty, Replacement/adverse effects ; Cells, Cultured ; Free Radical Scavengers/pharmacology/*therapeutic use ; Mice ; Osteoclasts/drug effects ; Osteolysis/diagnostic imaging/pathology/*prevention &amp; control ; Polymethyl Methacrylate/*adverse effects ; Prosthesis Failure/*drug effects/etiology ; Rats ; Skull/pathology ; X-Ray Microtomography ; }, abstract = {BACKGROUND: To study whether N-acetyl-L-cysteine (NAC) has beneficial effects on wear particle-induced osteoclastogenesis and osteolysis.<br><br>MATERIALS AND METHODS: In vitro, cells were cultured for 5 d and were then exposed to polymethylmethacrylate (PMMA) particles or were pretreated with NAC 1 h prior to stimulation with optimal PMMA particles. After 48 h, the number of osteoclasts was determined by tartrate-resistant acid phosphatase (TRAP) staining. In vivo, a murine calvarial model of PMMA particle-induced osteolysis, was used. PMMA particles were implanted on the calvariae of C57BL/J6 mice, and NAC (10 and 50 mg/kg) was given intraperitoneally every day. Two weeks later, the calvariae were removed and processed for micro-CT and histomorphometry analysis.<br><br>RESULTS: TRAP staining showed that the osteoclastogenic response was dose-dependent with PMMA particles. Compared with the PBS group, the PMMA group showed a significant decrease in bone mineral density (BMD), bone volume fraction (BVF), cortical mean thickness (CMT), and cortical area/total area (Ct) (P&#xa0;< 0.05). Treatment with NAC (10 and 50 mg/kg) attenuated the PMMA particle-induced decrease in BMD, BVF, CMT, and Ct (P < 0.05 versus PMMA group). NAC inhibited the osteoclastogenesis and osteolysis that is caused by wear particles. The TRAP (+) osteoclast number and the osteolysis area in PBS, PMMA, NAC (10 mg/kg), and NAC (50 mg/kg) were 6.0 &#xb1; 0.6, 22.5 &#xb1; 1.2, 15.8 &#xb1; 0.7, 8.7 &#xb1; 1.0 and 0.075 &#xb1; 0.011, 0.340 &#xb1; 0.014, 0.231 &#xb1; 0.018, 0.142 &#xb1; 0.026 mm(2), respectively (P&#xa0;< 0.05).<br><br>CONCLUSION: Our in vitro and in vivo work shows that NAC may effectively inhibit osteoclastogenesis and may suppress wear particle-induced osteolysis, indicating that NAC may be useful in the prevention or treatment of wear particle-induced prosthesis loosening.}, }
@article {pmid21470069, year = {2011}, author = {Shalby, AB and Assaf, N and Ahmed, HH}, title = {Possible mechanisms for N-acetyl cysteine and taurine in ameliorating acute renal failure induced by cisplatin in rats.}, journal = {Toxicology mechanisms and methods}, volume = {21}, number = {7}, pages = {538-546}, doi = {10.3109/15376516.2011.568985}, pmid = {21470069}, issn = {1537-6524}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/chemically induced/*prevention &amp; control ; Animals ; Antineoplastic Agents/*adverse effects ; Antioxidants/administration &amp; dosage/*therapeutic use ; Biomarkers/blood/urine ; Cisplatin/*adverse effects ; Drug Administration Schedule ; Female ; Kidney/*drug effects/metabolism/pathology ; Kidney Function Tests ; Lipid Peroxidation/drug effects ; Rats ; Rats, Sprague-Dawley ; Taurine/administration &amp; dosage/*therapeutic use ; }, abstract = {CONTEXT: Cisplatin (CP), a broadly used anticancer drug, is widely known to induce acute renal failure as a result of renal tubular injury.<br><br>OBJECTIVE: In this study, the effect of N-acetyl cysteine (NAC) or taurine (TAU) for protection against CP-induced nephrotoxicity was investigated.<br><br>MATERIALS AND METHODS: A single dose of CP 1&#x2009;mg/kg b.wt. for 4 days was given IP to the rats, 10 days rest, and then the dose was repeated for other 4 days. After CP administration, NAC or TAU was given IP in a dose of 50&#x2009;mg/kg b.wt. 3 times weekly for 8 weeks.<br><br>RESULTS: CP-induced nephrotoxicity is reflected in high values of blood urea and creatinine levels. In addition, the significant increase in the &#x3b2;(2)-MG and N-acetyl-&#x3b2;-glucosaminidase enzymes exhibited a strong correlation with histology scores of overall proximal tubule damage as compared with the normal control values. Treatment with TAU or NAC after CP administration significantly ameliorated CP-induced nephritic oxidation stress markers as compared with CP-treated group. On the other hand, treatment with TAU or NAC after CP administration significantly ameliorated CP-induced nephritic inflammation with possible attenuation of renal injury.<br><br>DISCUSSION: These data suggest that oxidative stress and inflammation are involved in the pathogenesis of CP-induced acute renal failure. The inhibition in oxidative stress and the elevation of the total antioxidant capacity as well as the inhibition of the inflammatory biomarkers by NAC or TAU after CP administration may play a central role in modulation of nephrotoxicity induced by CP.<br><br>CONCLUSION: NAC and TAU have antioxidant and anti-inflammatory against CP-induced nephrotoxicity.}, }
@article {pmid21469681, year = {2011}, author = {Griffiths, SM and Singh, N and Jenkins, GJ and Williams, PM and Orbaek, AW and Barron, AR and Wright, CJ and Doak, SH}, title = {Dextran coated ultrafine superparamagnetic iron oxide nanoparticles: compatibility with common fluorometric and colorimetric dyes.}, journal = {Analytical chemistry}, volume = {83}, number = {10}, pages = {3778-3785}, pmid = {21469681}, issn = {1520-6882}, support = {G0700865/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Colorimetry/*methods ; Coloring Agents/*chemistry ; Dextrans/*chemistry ; Ethidium/analogs &amp; derivatives/toxicity ; Ferric Compounds/*chemistry ; Fluoresceins/toxicity ; Fluorescent Dyes/*chemistry ; Fluorometry/*methods ; Magnetite Nanoparticles/*chemistry ; Reactive Oxygen Species/metabolism ; tert-Butylhydroperoxide/chemistry ; }, abstract = {Due to the unique physicochemical properties of nanomaterials (NM) and their unknown reactivity, the possibility of NM altering the optical properties of fluorometric/colorimetric probes that are used to measure their cyto- and genotoxicity may lead to inaccurate readings. This could have potential implications given that NM, such as ultrafine superparamagnetic iron oxide nanoparticles (USPION), are increasingly finding their use in nanomedicine and the absorbance/fluorescence based assays are used to assess their toxicity. This study looks at the potential of dextran-coated USPION (dUSPION) (maghemite and magnetite) to alter the background signal of common probes used for evaluating cytotoxicity (MTS, CyQUANT, Calcein, and EthD-1) and oxidative stress (DCFH-DA and APF). In the present study, both forms of dUSPION caused an increase in MTS signal but a decrease in background signal from calcein and 3'-(p-aminophenyl) fluorescein (APF) and no effect on CyQUANT and EthD-1 fluorescence responses. Magnetite caused a decrease in fluorescence signal of DCFH, but it did not decrease fluorescence signal in the presence of the reactive oxygen species-inducer tert-butyl hydroperoxide (TBHP). In contrast, maghemite caused an increase in fluorescence, which was substantially reduced in the presence of the antioxidant N-acetyl cysteine. This study emphasizes the importance of considering and controlling for possible interactions between NM and fluorometric/colorimetric dyes and, most importantly, the oxidation state of dUSPION that may confound their sensitivity and specificity.}, }
@article {pmid21467697, year = {2011}, author = {Tanaka, A and Suzuki, Y and Suzuki, N and Hirai, T and Yasuda, N and Miki, K and Fujita, M and Tanaka, T}, title = {Does N-acetylcysteine reduce the incidence of contrast-induced nephropathy and clinical events in patients undergoing primary angioplasty for acute myocardial infarction?.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {50}, number = {7}, pages = {673-677}, doi = {10.2169/internalmedicine.50.4226}, pmid = {21467697}, issn = {1349-7235}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Aged ; Angioplasty/*methods ; Contrast Media/*adverse effects ; Creatinine/blood ; Female ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Hospital Mortality ; Humans ; Incidence ; Kidney Diseases/*chemically induced/epidemiology/*prevention &amp; control ; Male ; Middle Aged ; Myocardial Infarction/*therapy ; Prospective Studies ; Treatment Outcome ; }, abstract = {OBJECTIVES: We examined oral N-acetylcysteine effects on contrast-induced nephropathy (CIN) and clinical events in patients undergoing primary angioplasty for acute myocardial infarction.<br><br>BACKGROUND: Recent studies have reported that N-acetylcysteine reduces CIN and improves the clinical outcome in patients undergoing primary angioplasty. However, additional investigations are warranted to further support these findings.<br><br>METHODS: We randomly assigned 76 patients undergoing primary angioplasty into two groups: 38 patients were assigned to N-acetylcysteine (NAC, 705 mg orally administration before and 12, 24, 36 hours after primary angioplasty), and 38 patients to placebo. CIN was defined as an increase in the serum creatinine concentration of 25 percent or more from baseline value within the 72-hour period after primary angioplasty.<br><br>RESULTS: CIN occurred in 7 patients (9.2%). In the NAC group, the incidence of CIN tended to be lower than in the placebo group (NAC; 2/38; 5.3% vs. Placebo; 5/38; 13.2%, p=0.21). The composite endpoints such as death, acute renal failure requiring temporary renal replacement therapy, or need for mechanical ventilation did not occur in either group.<br><br>CONCLUSION: While N-acetylcysteine might have the possibility to reduce the incidence of contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction, the in-hospital mortality and morbidity were not significantly different between the two groups.}, }
@article {pmid21461234, year = {2011}, author = {Lee, YJ and Kim, NY and Suh, YA and Lee, C}, title = {Involvement of ROS in Curcumin-induced Autophagic Cell Death.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {15}, number = {1}, pages = {1-7}, pmid = {21461234}, issn = {2093-3827}, abstract = {Many anticancer agents as well as ionizing radiation have been shown to induce autophagy which is originally described as a protein recycling process and recently reported to play a crucial role in various disorders. In HCT116 human colon cancer cells, we found that curcumin, a polyphenolic phytochemical extracted from the plant Curcuma longa, markedly induced the conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to LC3-II and degradation of sequestome-1 (SQSTM1) which is a marker of autophagosome degradation. Moreover, we found that curcumin caused GFP-LC3 formation puncta, a marker of autophagosome, and decrease of GFP-LC3 and SQSTM1 protein level in GFP-LC3 expressing HCT116 cells. It was further confirmed that treatment of cells with hydrogen peroxide induced increase of LC3 conversion and decrease of GFP-LC3 and SQSTM1 levels, but these changes by curcumin were almost completely blocked in the presence of antioxidant, N-acetylcystein (NAC), indicating that curcumin leads to reactive oxygen species (ROS) production, which results in autophagosome development and autolysosomal degradation. In parallel with NAC, SQSTM1 degradation was also diminished by bafilomycin A, a potent inhibitor of autophagosome-lysosome fusion, and cell viability assay was further confirmed that cucurmin-induced cell death was partially blocked by bafilomycin A as well as NAC. We also observed that NAC abolished curcumin-induced activation of extracelluar signal-regulated kinases (ERK) 1/2 and p38 mitogen-activated protein kinases (MAPK), but not Jun N-terminal kinase (JNK). However, the activation of ERK1/2 and p38 MAPK seemed to have no effect on the curcumin-induced autophagy, since both the conversion of LC3 protein and SQSTM1 degradation by curcumin was not changed in the presence of NAC. Taken together, our data suggest that curcumin induced ROS production, which resulted in autophagic activation and concomitant cell death in HCT116 human colon cancer cell. However, ROS-dependent activation of ERK1/2 and p38 MAPK, but not JNK, might not be involved in the curcumin-induced autophagy.}, }
@article {pmid21461057, year = {2011}, author = {Moon, IJ and Kim, KR and Chu, HS and Kim, SH and Chung, WH and Cho, YS and Hong, SH}, title = {N-acetylcysteine and N-nitroarginine methyl ester attenuate Carboplatin-induced ototoxicity in dissociated spiral ganglion neuron cultures.}, journal = {Clinical and experimental otorhinolaryngology}, volume = {4}, number = {1}, pages = {11-17}, pmid = {21461057}, issn = {2005-0720}, abstract = {OBJECTIVES: Carboplatin, a platinum-containing anti-cancer drug used to treat a variety of cancers, induces ototoxicity. Since, reactive oxygen species (ROS) and nitric oxide (NO) seem to be responsible for this toxicity, the antioxidant, N-acetyl-L-cysteine (L-NAC), and NO synthetase inhibitor, N-nitro-L-arginine methyl ester (L-NAME) were predicted to have protective effects against carboplatin ototoxicity. The aim of this study was to test for the protective effects of L-NAC and L-NAME on cochlear hair cells and spiral ganglion neurons (SGNs).<br><br>METHODS: Cochlear organotypic cultures and dissociated spiral ganglion neuron cultures, from mice postnatal day 5 cultures were used in this study. The cultures were treated with carboplatin alone or in combination with L-NAC or L-NAME, and carboplatin-induced damage was monitored.<br><br>RESULTS: Treatment with carboplatin induced a significant loss of outer hair cells, while inner hair cells were preserved in the cochlear organotypic cultures. Addition of L-NAC or L-NAME reduced the amount of carboplatin-induced hair cell damage; the differences did not reach statistical significance. However, carboplatin significantly decreased the number of surviving SGNs in dissociated cultures. The toxic effects were significantly reduced by addition of L-NAC or L-NAME. In addition, carboplatin induced the loss of neurites from the SGN somata, and this was not blocked with L-NAC or L-NAME.<br><br>CONCLUSION: The results of this study suggest that ROS and NO are involved in carboplatin-induced damage to hair cells and SGNs, and administration of L-NAC/L-NAME can be used to attenuate the toxicity.}, }
@article {pmid21460633, year = {2011}, author = {Wallington-Beddoe, CT and Hewson, J and Bradstock, KF and Bendall, LJ}, title = {FTY720 produces caspase-independent cell death of acute lymphoblastic leukemia cells.}, journal = {Autophagy}, volume = {7}, number = {7}, pages = {707-715}, doi = {10.4161/auto.7.7.15154}, pmid = {21460633}, issn = {1554-8635}, mesh = {Adolescent ; Aged ; Autophagy/drug effects ; Caspases/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Child ; Child, Preschool ; Cytoprotection/drug effects ; Enzyme Activation/drug effects ; Female ; Fingolimod Hydrochloride ; Humans ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology/*pathology ; Propylene Glycols/*pharmacology ; Protein Phosphatase 2/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Lysosphingolipid/metabolism ; Signal Transduction/drug effects ; Sphingosine/*analogs &amp; derivatives/pharmacology ; Young Adult ; }, abstract = {Acute lymphoblastic leukemia (ALL), the most common form of childhood cancer, usually responds to chemotherapy but patients who develop disease relapse have a poor prognosis. New agents to treat ALL are urgently required. FTY720 is an immunosuppressive drug that has promising in vitro activity in a number of malignancies, with the proposed mechanism being the reactivation of the protein serine/threonine phosphatase, PP2A. FTY720 reduced the proliferation and viability of Ph(+) and Ph(-) ALL cell lines and patient samples with IC 50 values for viability between 5.3 to 7.9 μM. Cell death was caspase-independent with negligible activation of caspase-3 and no inhibition of FTY720-induced cell death by the caspase inhibitor Z-VAD-FMK. The cytotoxic effects of FTY720 were independent of PP2A reactivation as determined by the lack of effect of the PP2A inhibitor okadaic acid. Features of autophagy, including autophagosomes, LC3II expression and increased autophagic flux, were induced by FTY720. However the phosphorylated form of FTY720 (FTY720-P) similarly induced autophagy but not cell death. This suggests that autophagy is prosurvival in this setting, a finding supported by protection from cell death induced by the cytotoxic agent vincristine. FTY720 also induced reactive oxygen species (ROS) and the antioxidant N-acetyl-cysteine (NAC) partially reversed the cytotoxic effects, demonstrating a role for ROS generation in the cell death mechanism. FTY720 is an active drug in vitro in ALL cell lines and patient samples. Evidence supports a caspase-independent mechanism of cell death with the occurrence of autophagy and necrosis.}, }
@article {pmid21457135, year = {2011}, author = {Pham, MH and Rhinn, H and Auzeil, N and Regazzetti, A and Harami, DE and Scherman, D and Chabot, GG}, title = {Identification and induction of cytochrome P450s involved in the metabolism of flavone-8-acetic acid in mice.}, journal = {Drug metabolism letters}, volume = {5}, number = {2}, pages = {73-84}, pmid = {21457135}, issn = {1874-0758}, mesh = {Acetylcysteine/metabolism ; Animals ; Cytochrome P-450 Enzyme System/*physiology ; Enzyme Induction ; Epoxide Hydrolases/physiology ; Female ; Flavonoids/*metabolism ; Hydroxylation ; Mice ; Mice, Inbred C57BL ; Microsomes, Liver/metabolism ; }, abstract = {The metabolism of flavone-8-acetic acid (FAA) has been hypothesized to be partly responsible for its potent anticancer activity in mice. The purpose of this study was to identify the mouse enzymes involved in FAA Phase I metabolism and evaluate their possible induction in vivo by FAA. Mouse microsomes metabolized FAA into 6 metabolites: 3',4'-dihydrodiol-FAA, 5,6-epoxy-FAA, 4'-OH-FAA, 3'-OH-FAA, 3',4'-epoxy-FAA and 6-OH-FAA. Using Cyp-specific inhibitors (furafylline, Cyp1a2; α-naphthoflavone, Cyp1b1; tranylcypromine, Cyp2b9; quercetin, Cyp2c29; quinidine, 2d9; diethyldithiocarbamate, Cyp2e1; ketoconazole, Cyp3a11), the formation of 5,6-epoxy-FAA was mainly attributed to Cyps 1a2, 1b1, 2b9, 2c29 and 2e1, whereas the 3',4'-epoxy-FAA was formed by Cyps 2b9 and 3a11. The 4'-OH-FAA was generated by Cyps 1a2, 1b1, 2b9 and 2e1, and the 6-OH-FAA was formed by Cyps 1b1 and 2c9. Using the epoxide scavenger N-acetyl cysteine, 4'-OH-FAA, 3'-OH-FAA and 6-OH-FAA were shown to derive partly from non enzymatic isomerisation of their corresponding epoxides. The specific epoxide hydrolase inhibitor elaidamide allowed the confirmation that 3',4'-dihydrodiol-FAA was formed via the epoxide hydrolase. FAA treatment in vivo in mice led to a significant increase in the hepatic expression of Cyp1a2 (1.9-fold), 2e1 (2.1-fold), 2b10 (3.2-fold), 2d9 (2.3-fold) and 3a11 (2.2-fold), as evaluated by qRT-PCR. In conclusion, several Cyps were shown to be involved in FAA metabolism, particularly Cyps 3a11 and 2b9 which were responsible for the formation of the principal metabolites (5,6-epoxy-FAA, 3',4'-epoxy-FAA), and that FAA could induce the expression of several Cyps after in vivo administration. The possible implication of these enzymes in the in vivo anticancer activity of FAA in mice is discussed.}, }
@article {pmid21455648, year = {2011}, author = {Mitamura, K and Sakai, T and Nakai, R and Wakamiya, T and Iida, T and Hofmann, AF and Ikegawa, S}, title = {Synthesis of the 3-sulfates of N-acetylcysteine conjugated bile acids (BA-NACs) and their transient formation from BA-NACs and subsequent hydrolysis by a rat liver cytosolic fraction as shown by liquid chromatography/electrospray ionization-mass spectrometry.}, journal = {Analytical and bioanalytical chemistry}, volume = {400}, number = {7}, pages = {2061-2072}, doi = {10.1007/s00216-011-4925-3}, pmid = {21455648}, issn = {1618-2650}, mesh = {Acetylcysteine/*chemistry ; Animals ; Bile Acids and Salts/*chemistry ; Chromatography, Liquid/*methods ; Cytosol/chemistry ; Hydrolysis ; Limit of Detection ; Liver/*chemistry ; Magnetic Resonance Spectroscopy ; Rats ; Spectrometry, Mass, Electrospray Ionization/*methods ; Sulfates/*chemical synthesis/chemistry ; }, abstract = {Previous work from this laboratory has reported the chemical synthesis of N-acetylcysteine (NAC) conjugates of natural bile acids (BAs) and shown that such novel conjugates can be formed in vivo in rats to which NAC has been administered. The subsequent fate of such novel conjugates is not known. One possible biotransformation is sulfation, a major pathway for BAs N-acylamidates in patients with cholestatic liver disease. Here, we report the chemical synthesis of the 3-sulfates of the S-acyl NAC conjugates of five natural BAs (cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, and lithocholic). We also measured the sulfation of N-acetylcysteine-natural bile acid (BA-NAC) conjugates when they were incubated with a rat liver cytosolic fraction. The chemical structures of the BA-NAC 3-sulfates were confirmed by proton nuclear magnetic resonance, as well as by means of electrospray ionization-linear ion trap mass spectrometry with negative-ion detection. Upon collision-induced dissociation of singly and doubly charged deprotonated molecules, structurally informative product ions were observed. Using a triple-stage quadrupole instrument, selected reaction monitoring analyses by monitoring characteristic transition ions allowed the achievement of a highly sensitive and specific assay. When BA-NACs were incubated with a rat liver cytosolic fraction to which 3'-phosphoadenosine 5'-phosphosulfate was added, sulfation occurred, but the dominant reaction was hydrolysis of the S-acyl linkage to form the unconjugated BAs. Subsequent sulfation occurred at C-3 on the unconjugated BAs that had been formed from the BA-NACs. Such sulfation was proportional to the hydrophobicity of the unconjugated bile acid. Thus, NAC conjugates of BAs as well as their C-3 sulfates if formed in vivo are rapidly hydrolyzed by cytosolic enzymes.}, }
@article {pmid21453688, year = {2011}, author = {Wu, J and Chien, CC and Yang, LY and Huang, GC and Cheng, MC and Lin, CT and Shen, SC and Chen, YC}, title = {Vitamin K3-2,3-epoxide induction of apoptosis with activation of ROS-dependent ERK and JNK protein phosphorylation in human glioma cells.}, journal = {Chemico-biological interactions}, volume = {193}, number = {1}, pages = {3-11}, doi = {10.1016/j.cbi.2011.03.008}, pmid = {21453688}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Antineoplastic Agents/chemistry/*toxicity ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase Inhibitors ; Cell Line, Tumor ; Chromatin/metabolism ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/*metabolism ; Flavonoids/pharmacology ; Glioma/*enzymology/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Vitamin K 3/*analogs &amp; derivatives/chemistry/therapeutic use/toxicity ; }, abstract = {2-Methyl-1,4-naphthoquinone (menadione or vitamin K3; EPO) and K3-2,3-epoxide (EPO1), but not vitamin K3-3-OH (EPO2), exhibited cytotoxicity that caused DNA fragmentation and chromatin condensation in U87 and C6 cells. EPO1 showed more-potent cytotoxicity than EPO, and the IC(50) values of EPO and EPO1 in U87 cells were 37.5 and 15.7μM, respectively. Activation of caspase 3 enzyme activity with cleavage of caspase 3 protein was detected in EPO1-treated U87 and C6 cells, and the addition of the caspase 3 peptidyl inhibitor, DEVD-FMK, reduced the cytotoxic effect of EPO1. An increase in the intracellular ROS level by EPO1 was observed in the DCHF-DA analysis, and EPO1-induced apoptosis and caspase 3 protein cleavage were prevented by adding the antioxidant, N-acetyl-cysteine (NAC), with decreased ROS production elicited by EPO1. Activation of ERK and JNK, but not p38, via phosphorylation induction was identified in EPO1- but not EPO- or EPO2-treated U87 and C6 cells, and this was blocked by adding NAC. However, the ERK inhibitor, PD98059, and the JNK inhibitor, SP600125, showed no effect on EPO1-induced cytotoxicity in either cell type. Our findings demonstrate that 2,3-epoxide substitution significantly potentiates the apoptotic effect of vitamin K3 via stimulating ROS production, which may be useful in the chemotherapy of glioblastoma cells.}, }
@article {pmid21452000, year = {2011}, author = {Jo, M and Nishikawa, T and Nakajima, T and Okada, Y and Yamaguchi, K and Mitsuyoshi, H and Yasui, K and Minami, M and Iwai, M and Kagawa, K and Itoh, Y and Yoshikawa, T}, title = {Oxidative stress is closely associated with tumor angiogenesis of hepatocellular carcinoma.}, journal = {Journal of gastroenterology}, volume = {46}, number = {6}, pages = {809-821}, pmid = {21452000}, issn = {1435-5922}, mesh = {Acetylcysteine/pharmacology ; Adult ; Aged ; Androstadienes/pharmacology ; Antioxidants/pharmacology ; Carcinoma, Hepatocellular/blood supply/*pathology ; Cell Proliferation/drug effects ; Endothelial Cells/metabolism ; Female ; Humans ; Liver Neoplasms/blood supply/*pathology ; Male ; Middle Aged ; Neovascularization, Pathologic/*pathology ; *Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/metabolism ; Umbilical Cord/cytology ; Vascular Endothelial Growth Factor A/genetics/metabolism ; Wortmannin ; }, abstract = {BACKGROUND: Oxidative stress (OS) plays an important role in the progression of chronic liver disease and hepatocarcinogenesis. However, the role of OS in the progression of hepatocellular carcinoma (HCC) is unclear. The aim of this study was to assess whether OS promotes angiogenesis in HCC.<br><br>METHODS: The expressions of vascular endothelial growth factor (VEGF), VEGF receptor2 (VEGFR2), and phosphorylated Akt were assessed, and microvessel density (MVD) and the cancer-associated fibroblast (CAF) population were examined by immunohistological staining in 55 HCC samples. The OS level in these tissues was assessed using 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) immunostaining, and an 8-OHdG enzyme-linked immunosorbent assay (ELISA). The expression and activation of angiogenic factors and the effect of growth stimulation of human umbilical vein endothelial cells (HUVECs) were also assessed in vitro, using HLE hepatoma-derived cells and conditioned medium with or without treatment with hydrogen peroxide (H&#x2082;O&#x2082;); a phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin; and an anti-oxidative agent, N-acetyl-L-cysteine (NAC).<br><br>RESULTS: A higher OS grade was significantly associated with higher MVD, VEGF expression, Akt activity, and OS grade of CAFs, but not with the percentage of the CAF population in HCC tissues. Additionally, cancer cells constituted a major population of OS marker-positive cells in HCC tissues. In vitro, H&#x2082;O&#x2082; treatment induced up-regulation of VEGF at both the mRNA and protein levels, activated Akt, and resulted in the proliferation of HUVECs; the addition of wortmannin and NAC counteracted the effects of OS.<br><br>CONCLUSIONS: OS enhances the malignant potential of HCC through the stimulation of angiogenesis by activation of the Akt-VEGF pathway.}, }
@article {pmid21448585, year = {2011}, author = {Yu, JS and Kim, AK}, title = {Wogonin induces apoptosis by activation of ERK and p38 MAPKs signaling pathways and generation of reactive oxygen species in human breast cancer cells.}, journal = {Molecules and cells}, volume = {31}, number = {4}, pages = {327-335}, pmid = {21448585}, issn = {0219-1032}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Breast Neoplasms ; Caspase 8/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Female ; Flavanones/*pharmacology ; Humans ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Wogonin is a one of the bioactive compounds of Scutellaria baicalensi Georgi which has been shown to have antiinflammatory, anticancer, antiviral and neuroprotective effects. However, the underlying mechanisms by which wogonin induces apoptosis in cancer cells still remain speculative. Here we investigated the potential activation of MAPKs and generation of reactive oxygen species (ROS) by wogonin on MCF-7 human breast cancer cells. These results showed that wogonin induced mitochondria and death-receptor-mediated apoptotic cell death, which was characterized by activation of several caspases, induction of PARP cleavage, change of antiapoptotic/proapoptotic Bcl-2 family member ratios and cleavage of Bid. We also found that generation of ROS was an important mediator in wogonin-induced apoptosis. Further investigation revealed that wogonin activated ERK and p38 MAPKs, which was inhibited by N-acetyl cysteine (NAC), a ROS scavenger, indicating that wogonin-induced ROS are associated with MAPKs activation. These data demonstrate that wogonin may be a novel anticancer agent for treatment of breast cancer.}, }
@article {pmid21447688, year = {2011}, author = {Yang, D and Elner, SG and Chen, X and Field, MG and Petty, HR and Elner, VM}, title = {MCP-1-activated monocytes induce apoptosis in human retinal pigment epithelium.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {52}, number = {8}, pages = {6026-6034}, pmid = {21447688}, issn = {1552-5783}, support = {P30EY07003/EY/NEI NIH HHS/United States ; R01EY009441/EY/NEI NIH HHS/United States ; EY019986/EY/NEI NIH HHS/United States ; R21 EY019986/EY/NEI NIH HHS/United States ; R01 EY009441/EY/NEI NIH HHS/United States ; P30 EY007003/EY/NEI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Antibodies/pharmacology ; Apoptosis/drug effects/*immunology ; Calcium/metabolism ; Calcium Signaling/physiology ; Cells, Cultured ; Chemokine CCL2/*immunology/metabolism ; Cyclic ADP-Ribose/analogs &amp; derivatives/antagonists &amp; inhibitors/pharmacology ; Humans ; Lipopolysaccharide Receptors/immunology ; Macular Degeneration/*immunology/pathology ; Middle Aged ; Monocytes/*immunology/pathology ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Retinal Pigment Epithelium/*immunology/pathology ; }, abstract = {PURPOSE: The inflammatory response in age-related macular degeneration (AMD) is characterized by mononuclear leukocyte infiltration of the outer blood-retina barrier formed by the retinal pigment epithelium (RPE). A key mechanistic element in AMD progression is RPE dysfunction and apoptotic cell loss. The purpose of this study was to evaluate whether monocyte chemoattractant protein (MCP)-1-activated monocytes induce human RPE apoptosis and whether Ca(2+) and reactive oxygen species (ROS) are involved in this process.<br><br>METHODS: A cell-based fluorometric assay was used to measure intracellular Ca(2+) concentrations ([Ca(2+)](i)) in RPE cells loaded with fluorescent Ca(2+) indicator. Intracellular RPE ROS levels were measured by using the 5- and 6-chloromethyl-2',7'-dichlorodihydrofluorescence diacetate acetyl ester (CM-H(2)DCFDA) assay. RPE apoptosis was evaluated by activated caspase-3, Hoechst staining, and apoptosis ELISA.<br><br>RESULTS: MCP-1-activated human monocytes increased [Ca(2+)](i), ROS levels, and apoptosis in RPE cells, all of which were inhibited by 8-bromo-cyclic adenosine diphosphoribosyl ribose (8-Br-cADPR), an antagonist of cADPR. Although the ROS scavengers pyrrolidinedithiocarbamate (PDTC) and N-acetylcysteine (NAC) significantly inhibited ROS production and apoptosis induced by activated monocytes, they did not affect induced Ca(2+) levels. The induced Ca(2+) levels and apoptosis in RPE cells were inhibited by an antibody against cluster of differentiation antigen 14 (CD14), an adhesion molecule expressed by these cells.<br><br>CONCLUSIONS: These results indicate that CD14, Ca(2+), and ROS are involved in activated monocyte-induced RPE apoptosis and that cADPR contributes to these changes. Understanding the complex interactions among CD14, cADPR, Ca(2+), and ROS may provide new insights and treatments of retinal diseases, including AMD.}, }
@article {pmid21445431, year = {2011}, author = {Fleming, AM and Muller, JG and Ji, I and Burrows, CJ}, title = {Characterization of 2'-deoxyguanosine oxidation products observed in the Fenton-like system Cu(II)/H2O2/reductant in nucleoside and oligodeoxynucleotide contexts.}, journal = {Organic &amp; biomolecular chemistry}, volume = {9}, number = {9}, pages = {3338-3348}, pmid = {21445431}, issn = {1477-0539}, support = {P30 CA042014/CA/NCI NIH HHS/United States ; R01 CA090689/CA/NCI NIH HHS/United States ; CA090689/CA/NCI NIH HHS/United States ; P30CA042014/CA/NCI NIH HHS/United States ; }, mesh = {Copper/*chemistry ; Deoxyguanosine/*chemistry ; Hydrogen Peroxide/*chemistry ; Molecular Structure ; Nucleosides/*chemistry ; Oligodeoxyribonucleotides/*chemistry ; Oxidation-Reduction ; }, abstract = {Reactive oxygen species attack both base and sugar moieties in DNA with a preference among the bases for reaction at guanine. In the present study, 2'-deoxyguanosine (dG) was oxidized by a copper-mediated Fenton reaction with the reductants ascorbate or N-acetyl-cysteine, yielding oxidation on both the base and the sugar. The primary oxidized lesions observed in these studies include the 2'-deoxyribonucleosides of 8-oxo-7,8-dihydroguanosine (dOG), spiroiminodihydantoin (dSp), guanidinohydantoin (dGh), oxazolone (dZ), and 5-carboxamido-5-formamido-2-iminohydantoin (d2Ih), as well as the free base guanine. d2Ih was the major product observed in the nucleoside, single- and double-stranded oligodeoxynucleotide contexts and is proposed to arise from oxidation at C5 of guanine. Product distribution studies provide insight into the role of the reductant in partitioning of dG base oxidation along the C5 and C8 pathways.}, }
@article {pmid21440488, year = {2011}, author = {Yen, CY and Lin, MH and Liu, SY and Chiang, WF and Hsieh, WF and Cheng, YC and Hsu, KC and Liu, YC}, title = {Arecoline-mediated inhibition of AMP-activated protein kinase through reactive oxygen species is required for apoptosis induction.}, journal = {Oral oncology}, volume = {47}, number = {5}, pages = {345-351}, doi = {10.1016/j.oraloncology.2011.02.014}, pmid = {21440488}, issn = {1879-0593}, mesh = {AMP-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; Acetylcysteine/pharmacology ; Aminoimidazole Carboxamide/analogs &amp; derivatives/pharmacology ; Apoptosis/*drug effects ; Arecoline/antagonists &amp; inhibitors/*metabolism ; Blotting, Western ; Cell Line, Tumor ; Cells, Cultured ; Dose-Response Relationship, Drug ; Glutathione/pharmacology ; Humans ; Reactive Oxygen Species/*metabolism ; Ribonucleotides/pharmacology ; }, abstract = {Arecoline is the major alkaloid of areca nut (AN) and known to induce reactive oxygen species (ROS) production and apoptosis. The metabolic sensor AMP-activated protein kinase (AMPK), activated by ROS, also regulates apoptosis. This study used several types of cells as the experimental model to analyze the roles of ROS and AMPK in arecoline-induced apoptosis. We found that arecoline dose-dependently increased intracellular ROS level, and two antioxidants, N-acetyl-L-cysteine (NAC) and glutathione, attenuated arecoline-induced apoptotic cell death. Interestingly, arecoline dose- and time-dependently inhibited rather than stimulated AMPK-Thr(172) phosphorylation, and both NAC and glutathione relieved this inhibition. The AMPK activator, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), also restored the phosphorylation level of AMPK-Thr(172) and attenuated apoptotic cell death under arecoline insult. In contrast, the AMPK inhibitor, compound C, and RNA interference of AMPK expression increased the cytotoxicity of arecoline. Collectively, these results suggest that arecoline may inhibit AMPK through intracellular ROS, responsible for the execution of apoptosis.}, }
@article {pmid21440025, year = {2011}, author = {Jain, S and Kumar, CH and Suranagi, UD and Mediratta, PK}, title = {Protective effect of N-acetylcysteine on bisphenol A-induced cognitive dysfunction and oxidative stress in rats.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {49}, number = {6}, pages = {1404-1409}, doi = {10.1016/j.fct.2011.03.032}, pmid = {21440025}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Avoidance Learning/drug effects ; Benzhydryl Compounds ; Brain/*drug effects/metabolism/physiopathology ; Cognition Disorders/chemically induced/*prevention &amp; control/psychology ; Disease Models, Animal ; Drug Antagonism ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Maze Learning/drug effects ; Memory/drug effects ; Oxidative Stress/*drug effects ; Phenols/*toxicity ; Rats ; Rats, Wistar ; Space Perception/drug effects ; }, abstract = {Bisphenol A (BPA) is commonly used as a monomer in polycarbonate plastics. The present study was designed to investigate the effect of BPA on cognitive functions and oxidative stress in the brain tissue of rats and if co-administration of N-acetylcysteine (NAC), an antioxidant, can modulate the effect of BPA on cognitive functions and prevent any possible oxidative stress. The BPA was administered per orally (p.o) in two doses 2 and 20 μg/kg for 28 days. Cognitive functions were assessed using step-down latency (SDL) on a passive avoidance apparatus and spatial navigation task on Morris water maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and reduced glutathione (GSH) levels. A significant reduction in SDL, and prolongation of latency in spatial navigation task were observed in BPA (2 and 20 μg/kg) treated group as compared to control group. The co-administration of NAC (100 mg/kg, p.o) antagonized the effect of BPA on SDL and spatial navigation test. NAC treatment also attenuated the BPA-induced increased MDA levels and decreased GSH levels in brain. Results of the present study show that NAC has potential to reverse cognitive dysfunction and oxidative stress induced by BPA exposure in rats.}, }
@article {pmid21433060, year = {2011}, author = {Heo, JS and Lee, JC}, title = {β-Catenin mediates cyclic strain-stimulated cardiomyogenesis in mouse embryonic stem cells through ROS-dependent and integrin-mediated PI3K/Akt pathways.}, journal = {Journal of cellular biochemistry}, volume = {112}, number = {7}, pages = {1880-1889}, doi = {10.1002/jcb.23108}, pmid = {21433060}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Androstadienes/pharmacology ; Animals ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Cell Culture Techniques ; Cell Differentiation ; Cell Line ; Connexin 43/metabolism ; Embryoid Bodies/cytology/metabolism ; Embryonic Stem Cells/*cytology/metabolism ; Homeobox Protein Nkx-2.5 ; Homeodomain Proteins/metabolism ; Integrin alpha5beta1/*metabolism ; Mice ; Myocytes, Cardiac/*cytology/metabolism ; Periodicity ; Phosphatidylinositol 3-Kinase/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Stress, Mechanical ; Transcription Factors/metabolism ; Wortmannin ; beta Catenin/genetics/*metabolism ; }, abstract = {Wnt/β-catenin signaling regulates various cellular events involved in the proliferation and differentiation and these events are affected sensitively by applying to mechanical stimuli. However, the mechanisms by which mechanical force stimulates cardiomyogenesis are not extensively explored. In this study we investigated the cellular mechanisms by which β-catenin signaling regulates cardiac differentiation of strain-subjected embryonic stem (ES) cells. The application of cells to cyclic strain increased beating cardiomyocyte foci with the attendant increases of Cx 43 and Nkx 2.5 proteins. Anti-oxidants such as vitamin C or N-acetyl cysteine (NAC) blocked the strain-mediated increases of Cx 43, Nkx 2.5, and α5/β1 integrins. These anti-oxidants also suppressed the activation of phosphoinositide 3-kinase (PI3K) and Akt in cyclic strain-subjected cells. Western blot analysis revealed that PI3K is a critical downstream effector of β1 integrin signaling and mediates Cx 43 and Nkx 2.5 expression in cyclic strain-applied ES cells. Cyclic strain increased the expression of β-catenin and stimulated its nuclear translocation from the cytosol, which was prevented by anti-oxidant treatment. In addition, the application to cyclic strain increased mRNA expression of β-catenin target genes, Axin2 and c-myc, as well as the phosphorylation of glycogen synthase kinase-3β. Furthermore, the blockage of β-catenin by its specific siRNA transfection diminished the cellular levels of Cx 43 and Nkx 2.5 proteins and the number of beating cardiomyocyte foci. Collectively, these results suggest that β-catenin-mediated signaling is required for cyclic strain-stimulated cardiomyogenesis through ROS-dependent and integrin-mediated PI3K-Akt signaling cascades.}, }
@article {pmid21432910, year = {2012}, author = {Kuc, C and Jenkins, A and Van Dross, RT}, title = {Arachidonoyl ethanolamide (AEA)-induced apoptosis is mediated by J-series prostaglandins and is enhanced by fatty acid amide hydrolase (FAAH) blockade.}, journal = {Molecular carcinogenesis}, volume = {51}, number = {2}, pages = {139-149}, pmid = {21432910}, issn = {1098-2744}, support = {K01 CA098695-05/CA/NCI NIH HHS/United States ; R01 CA098685/CA/NCI NIH HHS/United States ; CA098685/CA/NCI NIH HHS/United States ; }, mesh = {Amidohydrolases/*antagonists &amp; inhibitors ; Animals ; Apoptosis/*drug effects ; Arachidonic Acids/*pharmacology ; Blotting, Western ; Cell Line, Tumor ; Endocannabinoids ; In Situ Nick-End Labeling ; Mice ; Polyunsaturated Alkamides/*pharmacology ; Prostaglandins/*physiology ; Receptors, Cannabinoid/metabolism ; }, abstract = {The endocannabinoid arachidonoyl ethanolamide (AEA) is a potent inducer of tumor cell apoptosis however its mechanism of cytotoxicity is unclear. A previous report from our laboratory showed that AEA induced cell death in a cyclooxygenase-2 (COX-2)-dependent manner and in this report our data indicate that AEA-induced apoptosis is mediated by COX-2 metabolic products of the J-series. In experiments conducted with JWF2 keratinocytes which over-express COX-2, AEA caused a concentration-regulated increase in J-series prostaglandin production and apoptosis. Similarly, cell treatment with exogenously added J-series prostaglandins (15-deoxy, Δ(12,14) PGJ(2) and PGJ(2)) induced apoptosis. AEA-induced apoptosis was inhibited by the antioxidant, N-acetyl cysteine, indicating that reactive oxygen species generation was required for apoptosis. Using antagonists of cannabinoid receptor 1, cannabinoid receptor 2, or transient receptor potential cation channel, subfamily V, member 1, it was observed that cannabinoid receptor inhibition did not block AEA-mediated cell death. In contrast, an inhibitor of fatty acid amide hydrolase (FAAH) potentiated AEA-induced J-series PG synthesis and apoptosis. These results suggest that the metabolism of AEA to J-series PGs regulates the induction of apoptosis in cells with elevated COX-2 levels. Our data further indicate that the proapoptotic activity of AEA can be enhanced by combining it with an inhibitor of FAAH. As such, AEA may be an effective agent to eliminate tumor cells that over-express COX-2.}, }
@article {pmid21427628, year = {2011}, author = {Peng, YW and Buller, CL and Charpie, JR}, title = {Impact of N-acetylcysteine on neonatal cardiomyocyte ischemia-reperfusion injury.}, journal = {Pediatric research}, volume = {70}, number = {1}, pages = {61-66}, doi = {10.1203/PDR.0b013e31821b1a92}, pmid = {21427628}, issn = {1530-0447}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Membrane Glycoproteins/metabolism ; Myocardial Reperfusion Injury/*drug therapy/metabolism/pathology ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; NADPH Oxidase 2 ; NADPH Oxidases/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Perfusion ; Rabbits ; Rats ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {Reactive oxygen species (ROS) are hypothesized to play a key role in myocardial ischemia-reperfusion (IR) injury after cardiopulmonary bypass in children. Clinical studies in adults and several animal models suggest that myocardial IR injury involves cardiomyocyte apoptosis and necrosis. This study investigated a potential relationship between IR-induced ROS production and neonatal cardiomyocyte apoptosis using both in vitro and ex vivo techniques. For in vitro experiments, embryonic rat cardiomyocytes (H9c2 cells) exposed to hypoxia-reoxygenation (HR) showed a time-dependent increase in gp91 phox (a marker for ROS production by NADPH oxidases), caspase-3 (a key mediator of apoptosis) expression, and a decrease in the glutathione redox ratio. N-acetylcysteine (NAC; 0.25-2 mM), a potent antioxidant, decreased gp91 phox and caspase-3 expression, inhibited apoptosis and restored the glutathione redox ratio. For ex vivo study, IR injury significantly reduced left ventricular (LV) function and increased the expression of gp91 phox and caspase-3 in Langendorff-perfused neonatal (7-14 d) rabbit hearts. NAC (0.4 mM) treatment completely attenuated LV dysfunction after IR. In summary, neonatal myocardial IR injury is associated with an increase in cardiomyocyte oxidative stress and apoptosis. NAC attenuates apoptosis in an in vitro embryonic rat cardiomyocyte model of HR, and myocardial dysfunction in an ex vivo neonatal rabbit model of myocardial IR injury.}, }
@article {pmid21426905, year = {2011}, author = {Seif el-Din, SH and Al-Hroob, AM and Ebeid, FA}, title = {Schistosoma mansoni: N-acetylcysteine downregulates oxidative stress and enhances the antischistosomal activity of artemether in mice.}, journal = {Experimental parasitology}, volume = {128}, number = {3}, pages = {230-235}, doi = {10.1016/j.exppara.2011.03.006}, pmid = {21426905}, issn = {1090-2449}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Artemether ; Artemisinins/pharmacology/*therapeutic use ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*pharmacology/therapeutic use ; Liver/enzymology/parasitology/physiopathology ; Liver Function Tests ; Male ; Mice ; Oxidative Stress/*drug effects ; Random Allocation ; Schistosomiasis mansoni/*drug therapy/metabolism ; Schistosomicides/pharmacology/*therapeutic use ; }, abstract = {UNLABELLED: Artemether (Art), a derivative of the antimalarial artemisinin, also exhibit antischistosomal properties. N-acetylcysteine (NAC) has a diversity of applications, largely because of the chemical properties of the thiol moiety present in its structure. The ability of this moiety to sweep reactive oxygen species is well-established with NAC. This study investigates the ability of NAC to enhance the therapeutic potential of Art against adult Schistosoma mansoni infection and evaluates the protective role of this antioxidant on S. mansoni-induced oxidative stress. Mice were divided into five groups; normal (i), infected control (ii), infected treated with NAC, 300mg/kg 5 days a week/4weeks (iii), infected treated with Art (300mg/kg) 7 weeks post infection (iv) and infected treated with both NAC and Art (v). Results showed that Art produced a significant reduction in total number of worms when used alone. Also, it decreased hepatic ova count significantly accompanied with an increase in the percentage of dead ova. Treatment with NAC alone increased the percentage of dead ova; meanwhile, it enhanced the decrease in total number of worms and hepatic ova count when used with Art. Infection with S. mansoni significantly increased tissue GSH, GR, SOD and serum ALT and GGT, while decreased the activities of GST, GPx and the levels of proteins and albumin compared to normal control. Treatment with NAC alone approximately recovered the contents of GSH, activities of GPx and levels of serum albumin, ALT and GGT relative to normal control. A tendency for normalization in activities of the antioxidant enzymes mentioned above and serum levels of liver function tests was observed in the groups treated with Art alone or Art+NAC.<br><br>CONCLUSION: NAC downregulates oxidative stress induced by S. mansoni infection and enhances the therapeutic potential of artemether against adult schistosomes.}, }
@article {pmid21425328, year = {2011}, author = {Chiu, YJ and Hour, MJ and Lu, CC and Chung, JG and Kuo, SC and Huang, WW and Chen, HJ and Jin, YA and Yang, JS}, title = {Novel quinazoline HMJ-30 induces U-2 OS human osteogenic sarcoma cell apoptosis through induction of oxidative stress and up-regulation of ATM/p53 signaling pathway.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {29}, number = {9}, pages = {1448-1456}, doi = {10.1002/jor.21398}, pmid = {21425328}, issn = {1554-527X}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Ataxia Telangiectasia Mutated Proteins ; Caspases/metabolism ; Cell Cycle Proteins/*biosynthesis/genetics ; Cell Line, Tumor ; Cell Survival/drug effects ; Comet Assay ; DNA Damage ; DNA, Neoplasm/drug effects ; DNA-Binding Proteins/*biosynthesis/genetics ; Humans ; Osteosarcoma/*drug therapy/metabolism/pathology ; Oxidative Stress/*drug effects ; Protein Serine-Threonine Kinases/*biosynthesis/genetics ; Quinazolines/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tumor Stem Cell Assay ; Tumor Suppressor Protein p53/*biosynthesis/genetics ; Tumor Suppressor Proteins/*biosynthesis/genetics ; Up-Regulation/drug effects ; }, abstract = {Human osteogenic sarcoma is the most common primary bone tumor. Despite of the success of frontline therapy, about 40% of patients have disease progression and further therapy is palliative and toxic. In this study, we developed a novel quinazoline HMJ-30 to investigate the cell growth inhibition and apoptotic responses in U-2 OS human osteogenic sarcoma cells. Our results demonstrated that HMJ-30 significantly reduced cell viabilities of U-2 OS, HOS, and 143B cells in a dose-dependent manner, but it exhibited low cytotoxicity in normal hFOB cells. HMJ-30 induced DNA damage and apoptosis in U-2 OS cells as revealed by morphologic changes, comet assay and DAPI staining. Immuno-staining, colorimetric assays, and Western blotting analyses indicated that activities of caspase-8, caspase-9, and caspase-3 and the levels of Bcl-2 family-related proteins (Bcl-2, Mcl-1, Bax, BAD, and t-Bid) were altered in HMJ-30-treated U-2 OS cells. Pretreatment of cells with caspase-8, -9, and -3 specific inhibitors significantly reduced the cell growth inhibition. HMJ-30-induced apoptosis was mediated through both death-receptor and mitochondria-dependent apoptotic pathways in U-2 OS cells. HMJ-30 induced early phosphorylation of p53(Ser18) was through the activation of ataxia telangiectasia mutated (ATM) in U-2 OS cells. The cell growth inhibition by HMJ-30 was substantially attenuated either by the pre-incubation of U-2 OS cells with N-acetylcysteine (NAC, an antioxidant) and caffeine (an ATM kinase inhibitor) or by p53 knockdown via RNAi. In conclusion, ROS dependent-ATM/p53 signaling pathway is involved in HMJ-30-induced apoptosis in U-2 OS cells.}, }
@article {pmid21424515, year = {2011}, author = {Palacio, JR and Markert, UR and Martínez, P}, title = {Anti-inflammatory properties of N-acetylcysteine on lipopolysaccharide-activated macrophages.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {60}, number = {7}, pages = {695-704}, pmid = {21424515}, issn = {1420-908X}, mesh = {Acetylcysteine/*immunology/*pharmacology ; Animals ; Cell Line ; Cytokines/immunology ; Humans ; Immunity, Innate ; Inflammation/immunology ; Lipopolysaccharides/*immunology/*pharmacology ; Macrophages/cytology/*drug effects/*immunology ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; }, abstract = {INTRODUCTION: Innate immune cells play a role in modulating host immune response. Part of the macrophage inflammatory response is the release of an array of inflammatory cytokines, important molecules during the development of innate and adaptative immunity. Several antioxidant agents have been used in the control of the inflammatory response.<br><br>OBJECTIVE: To evaluate the anti-inflammatory effect of N-acetylcysteine (NAC) on the expression and secretion of inflammatory cytokines and interleukin (IL)-10 in lipopolysaccharide (LPS)-activated THP-1 macrophages under mild oxidative conditions.<br><br>METHODS: Macrophages were activated by LPS (0.1 and 1&#xa0;&#x3bc;g/ml) for up to 24&#xa0;h. The effect of 15&#xa0;mM NAC was evaluated at 2, 4, 6 and 24&#xa0;h. mRNA expression of tumor necrosis factor (TNF)-&#x3b1;, IL-1&#x3b2;, IL-6, IL-8 and IL-10 was assessed by real time PCR. The expression of the corresponding cytokines plus IL-12p70 was analyzed using a bead array for flow cytometry.<br><br>RESULTS: NAC inhibits the inflammatory cytokines TNF&#x3b1;, IL-1&#x3b2; and IL-6 in LPS-activated macrophages under mild oxidative conditions. IL-10 mRNA and protein expression are strongly downregulated in NAC-treated cells, which may further modify the inflammatory cytokine profile.<br><br>CONCLUSION: NAC modulates immune functions during the inflammatory response.}, }
@article {pmid21424224, year = {2011}, author = {Joshi, D and Mittal, D and Shrivastav, S and Shukla, S and Srivastav, AK}, title = {Combined effect of N-acetyl cysteine, zinc, and selenium against chronic dimethylmercury-induced oxidative stress: a biochemical and histopathological approach.}, journal = {Archives of environmental contamination and toxicology}, volume = {61}, number = {4}, pages = {558-567}, doi = {10.1007/s00244-011-9656-0}, pmid = {21424224}, issn = {1432-0703}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cytochrome P-450 Enzyme System/metabolism ; Disease Models, Animal ; Drug Interactions ; Lipid Peroxidation/drug effects ; Male ; Mercury Poisoning/*drug therapy/metabolism ; Methylmercury Compounds/*toxicity ; Microsomes, Liver/drug effects/enzymology ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Sodium Selenite/*pharmacology ; Zinc Acetate/*pharmacology ; }, abstract = {Mercury (Hg), widely used in industry, is a great environmental health problem for humans and animals. Despite several reports regarding Hg toxicity, there is scarcity of data on its toxic manifestations on Sprague Dawley rats under realistic exposure conditions. Experimental studies have shown that sulphur-containing antioxidants have beneficial effects against the detrimental properties of Hg. The present work was aimed to study the therapeutic potential of combined administration of N-acetyl cysteine (NAC; 2 mmol/kg ip), zinc (Zn; 2 mmol/kg po), and selenium (Se; 0.5 mg/kg po) against dimethylmercury (DMM; 1 mg/kg po)-intoxicated male rats for 12 weeks. Exposure to DMM caused significant alterations in cytochrome P450 (CYP) activity, microsomal lipid peroxidation, and proteins. Activities of transaminases (aspartate aminotransferase/alanine aminotransferase), alkaline phosphatase, and lactate dehydrogenase in serum, as well as activities of CYP enzymes aniline hydroxylase (AH), amidopyrine-N-demethylase (AND) in liver microsomes and activities of acid phosphatase, alkaline phosphatase, glucose-6-phophatase, and succinic dehydrogenase in the liver and kidney, were significantly altered after DMM administration. DMM exposure also induced severe hepato-renal alterations at the histopathological level. NAC, along with Zn and Se, dramatically reversed the alterations in all of the variables more toward control. The study results conclude that protective intervention of combined treatment of NAC, along with Zn and Se, is beneficial in attenuating DMM-induced systemic toxicity.}, }
@article {pmid21424048, year = {2011}, author = {Maniu, A and Perde-Schrepler, M and Cosgarea, M}, title = {Protective effect of L-N-acetylcysteine against gentamycin ototoxicity in the organ cultures of the rat cochlea.}, journal = {Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie}, volume = {52}, number = {1}, pages = {159-164}, pmid = {21424048}, issn = {2066-8279}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Cochlea/*drug effects/*pathology ; Dissection ; Gentamicins/*toxicity ; Hair Cells, Auditory/drug effects/pathology ; Lysine/*analogs &amp; derivatives/pharmacology ; Organ Culture Techniques ; Protective Agents/*pharmacology ; Rats ; }, abstract = {UNLABELLED: The AIM of this study was to test if L-N-acetylcysteine (L-NAC) can protect hair cells against gentamycin-induced damage in vitro. Mammalian auditory cells are unable to regenerate when affected by several toxic agents. Aminoglycosides are large-scale antibiotics, extremely useful for the treatment of several Gram-negative bacterial infections, but their use is limited by the extremely severe side effects like ototoxicity and nephrotoxicity.<br><br>MATERIALS AND METHODS: 1-4-day-old rat cochlea explants were exposed to different doses of gentamycin. Half of the cochleas were pretreated for 24 hours with different doses of L-NAC. The explants were fixed and stained with phalloidin, and the intact hair cells were counted.<br><br>RESULTS: GM treatment resulted in the loss of sensorial cells in the organ of Corti explants in a dose-dependent manner. All doses of L-NAC offered significant protection (p<0.001) when added in culture 24 hours prior to GM. There was no significant difference between the level of protection offered by the different doses of L-NAC, both in the outer and inner hair cells.<br><br>CONCLUSIONS: Our results demonstrate that L-NAC can protect cochlear cells against gentamycin toxicity.}, }
@article {pmid21421815, year = {2011}, author = {Zu, L and Zheng, X and Wang, B and Parajuli, N and Steenbergen, C and Becker, LC and Cai, ZP}, title = {Ischemic preconditioning attenuates mitochondrial localization of PTEN induced by ischemia-reperfusion.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {300}, number = {6}, pages = {H2177-86}, pmid = {21421815}, issn = {1522-1539}, support = {R01 HL039752/HL/NHLBI NIH HHS/United States ; HL-88071/HL/NHLBI NIH HHS/United States ; HL-65608/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/physiology ; Hydrogen Peroxide/metabolism ; *Ischemic Preconditioning, Myocardial ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Heart/*metabolism ; Models, Animal ; Myocardial Reperfusion Injury/*metabolism/*pathology ; Myocardium/metabolism/pathology ; PTEN Phosphohydrolase/deficiency/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Although the induction of myocyte apoptosis by ischemia-reperfusion (I/R) is attenuated by ischemic preconditioning (IPC), the underlying mechanism is not fully understood. Phosphatase and tensin homologs deleted on chromosome 10 (PTEN) promotes apoptosis through Akt-dependent and -independent mechanisms. We tested the hypothesis that IPC attenuates the mitochondrial localization of PTEN in the myocardium induced by I/R. Isolated hearts from wild-type mice were exposed to IPC or normal perfusion followed by 30 min of ischemia and reperfusion. IPC attenuated myocardial infarct size and apoptosis after I/R. Heart fractionation showed that mitochondrial PTEN and Bax protein levels and the physical association between them were increased by 30 min of I/R and that IPC attenuated all of these effects of I/R. Muscle-specific PTEN knockout decreased mitochondrial Bax protein levels in the reperfused myocardium and increased cell survival. To determine whether PTEN relocalization to mitochondria was influenced by I/R-induced production of ROS, hearts were perfused with N-acetylcysteine (NAC) to scavenge ROS or H(2)O(2) to mimic I/R-induced ROS. Mitochondrial PTEN protein levels were decreased by NAC and increased by H(2)O(2). PTEN protein overexpression was generated in mouse hearts by adenoviral gene transfer. PTEN overexpression increased mitochondrial PTEN and Bax protein levels and ROS production, whereas muscle-specific PTEN knockout produced the opposite effects. In conclusion, myocardial I/R causes PTEN localization to the mitochondria, related to the generation of ROS; IPC attenuates the mitochondrial localization of PTEN after I/R, potentially inhibiting the translocation of Bax to the mitochondria and resulting in improved cell viability.}, }
@article {pmid21421527, year = {2011}, author = {Sevgiler, Y and Karaytug, S and Karayakar, F}, title = {Antioxidative effects of N-acetylcysteine, lipoic acid, taurine, and curcumin in the muscle of Cyprinus carpio L. exposed to cadmium.}, journal = {Arhiv za higijenu rada i toksikologiju}, volume = {62}, number = {1}, pages = {1-9}, doi = {10.2478/10004-1254-62-2011-2082}, pmid = {21421527}, issn = {1848-6312}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cadmium/metabolism/*toxicity ; Carps ; Catalase/metabolism ; Curcumin/pharmacology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione Disulfide/metabolism ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation/drug effects ; Muscle, Skeletal/drug effects/*metabolism ; Oxidative Stress/*drug effects ; Superoxide Dismutase/metabolism ; Taurine/pharmacology ; Thioctic Acid/pharmacology ; }, abstract = {We investigated the muscle tissue of a teleost Cyprinus carpio L. to find out whether N-acetylcysteine (NAC), alpha-lipoic acid (LA), taurine (TAU), and curcumin (CUR) were able to counteract oxidative stress induced by acute exposure to cadmium (Cd). The muscle tissue was dissected 96 h after a single intraperitoneal injection of Cd (5 mg kg(-1)) and of antioxidant substances (50 mg kg(-1)). Using spectrophotometry, we determined the glutathione redox status, lipid peroxidation levels and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione disulphide reductase (GR). Accumulation of Cd in the muscle was analysed using inductively coupled plasma - optical emission spectrometry (ICP-OES).All substances lowered Cd levels in the following order of efficiency; LA=NAC>TAU=CUR. Cadmium increased SOD activity, but CAT activity declined, regardless of antioxidant treatment. Treatment with CUR induced GPx activity. Treatment with TAU lowered Cd due to higher total glutathione (tGSH). The most effective substances on lipid peroxidation were LA and NAC due to a greater Cd-lowering potential. It seems that the protective role of TAU, LA, and NAC is not necessarily associated with antioxidant enzymes, but rather with their own activity.}, }
@article {pmid21420063, year = {2011}, author = {Lee, SW and Kim, WJ and Kim, YH and Park, SW and Park, DW and Yun, SC and Lee, JY and Kang, SJ and Lee, CW and Lee, JH and Choi, SW and Seong, IW and Suh, J and Cho, YH and Lee, NH and Cheong, SS and Yoo, SY and Lee, BK and Lee, SG and Hyon, MS and Shin, WY and Lee, SW and Jang, JS and Park, SJ}, title = {Preventive strategies of renal insufficiency in patients with diabetes undergoing intervention or arteriography (the PREVENT Trial).}, journal = {The American journal of cardiology}, volume = {107}, number = {10}, pages = {1447-1452}, doi = {10.1016/j.amjcard.2011.01.019}, pmid = {21420063}, issn = {1879-1913}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Angioplasty, Balloon, Coronary/*adverse effects ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Diabetic Nephropathies/*complications ; Female ; Humans ; Male ; Middle Aged ; Renal Insufficiency/chemically induced/*prevention &amp; control ; Sodium Bicarbonate/*administration &amp; dosage ; Sodium Chloride/*administration &amp; dosage ; }, abstract = {Few studies have compared the ability of sodium bicarbonate plus N-acetylcysteine (NAC) and sodium chloride plus NAC to prevent contrast-induced nephropathy (CIN) in diabetic patients with impaired renal function undergoing coronary or endovascular angiography or intervention. Diabetic patients (n = 382) with renal disease (serum creatinine ≥1.1 mg/dl and estimated glomerular filtration rate <60 ml/min/1.73 m(2)) were randomly assigned to receive prophylactic sodium chloride (saline group, n = 189) or sodium bicarbonate (bicarbonate group, n = 193) before elective coronary or endovascular angiography or intervention. All patients received oral NAC 1,200 mg 2 times/day for 2 days. The primary end point was CIN, defined as an increase in serum creatinine >25% or an absolute increase in serum creatinine ≥0.5 mg/dl within 48 hours after contrast exposure. There were no significant between-group differences in baseline characteristics. The primary end point was met in 10 patients (5.3%) in the saline group and 17 (9.0%) in the bicarbonate group (p = 0.17), with 2 (1.1%) and 4 (2.1%), respectively, requiring hemodialysis (p = 0.69). Rates of death, myocardial infarction, and stroke did not differ significantly at 1 month and 6 months after contrast exposure. In conclusion, hydration with sodium bicarbonate is not superior to hydration with sodium chloride in preventing CIN in patients with diabetic nephropathy undergoing coronary or endovascular angiography or intervention.}, }
@article {pmid21419842, year = {2011}, author = {Zhang, W and Liu, Y and An, Z and Huang, D and Qi, Y and Zhang, Y}, title = {Mediating effect of ROS on mtDNA damage and low ATP content induced by arsenic trioxide in mouse oocytes.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {4}, pages = {979-984}, doi = {10.1016/j.tiv.2011.03.009}, pmid = {21419842}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Arsenic Trioxide ; Arsenicals ; DNA Damage/*drug effects ; DNA, Mitochondrial/*drug effects/metabolism ; Female ; Mice ; Mitochondria/drug effects/metabolism ; Oocytes/drug effects/pathology ; Oxidative Stress/drug effects ; Oxides/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Mitochondria provide most of the adenosine triphosphates (ATP) necessary for the maturation of oocytes. Various environmental toxicants would lead damage to mitochondrial DNA (mtDNA) and hence interfere with oocytes development. In the current study, the effect of arsenic trioxide (As2O3) on the common 3867 bp deletion and the copy number of mtDNA in mitochondria of mouse oocytes in vivo or in vitro, as well as the molecular pathway leading to the damage were investigated. PCR strategy was used to detect the damage of mtDNA. Reactive oxygen species (ROS) and ATP content in oocytes were checked to determine the influence of As2O3 on oxidative stress and activity of mitochondria. The results showed that As2O3 could obviously decrease the copy number of mtDNA and cause severe 3867 bp deletion in mitochondria together with elevated ROS level, while ATP content was decreased. Co-treatment with N-Acetyl-Cysteine (NAC) efficiently eliminated ROS induced by As2O3, lessened the mtDNA damage and enhanced ATP content in mouse oocytes both in vivo and in vitro. Taken together, the present study revealed that As2O3 could cause severe mtDNA damage and decrease ATP content by inducing excessive ROS, and this damage would then probably restrain the further development of mouse oocytes.}, }
@article {pmid21414445, year = {2011}, author = {Zacharis, CK and Tzanavaras, PD and Zotou, A}, title = {Ethyl propiolate as a post-column derivatization reagent for thiols: development of a green liquid chromatographic method for the determination of glutathione in vegetables.}, journal = {Analytica chimica acta}, volume = {690}, number = {1}, pages = {122-128}, doi = {10.1016/j.aca.2011.02.003}, pmid = {21414445}, issn = {1873-4324}, mesh = {Alkynes/*chemistry ; Chromatography, High Pressure Liquid/*methods ; Glutathione/*analysis ; Hydrogen-Ion Concentration ; Propionates/*chemistry ; Spectrometry, Fluorescence/methods ; Sulfhydryl Compounds/*chemistry ; Temperature ; Time Factors ; Vegetables/*chemistry ; }, abstract = {The present study reports the development, validation and application of a new green liquid chromatographic method for the determination of glutathione (GSH) in vegetable samples. In this work we introduce-for the first time-ethyl propiolate (EP) as an advantageous post-column derivatization reagent for thiolic compounds. GSH (t(R)=6.60 min) and N-acetylcysteine (NAC, internal standard) (t(R)=11.80 min) were separated efficiently from matrix endogenous compounds by using a 100% aqueous mobile phase (0.1%, v/v CH(3)COOH in 1 mmol L(-1) EDTA, Q(V)=0.5 mL min(-1)) and a Prevail(®) reversed phase column that offers the advantage of stable packing material in aqueous mobile phases. The parameters of the post-column reaction (pH, amount concentration of the reagent, flow rates, length of the reaction coil and temperature) were studied. The linear determination range for GSH was 1-200 μmol L(-1) and the LOD was 0.1 μmol L(-1) (S/N=3). Total endogenous GSH was determined in broccoli, potato, asparagus and Brussels sprouts using the standards addition approach. The accuracy was evaluated by both recovery experiments (R=91-110%) and comparison to an o-phthalaldehyde/glycine corroborative post-column derivatization fluorimetric method.}, }
@article {pmid21411055, year = {2011}, author = {Awad, N and Khatib, N and Ginsberg, Y and Weiner, Z and Maravi, N and Thaler, I and Ross, MG and Itsokovitz-Eldor, J and Beloosesky, R}, title = {N-acetyl-cysteine (NAC) attenuates LPS-induced maternal and amniotic fluid oxidative stress and inflammatory responses in the preterm gestation.}, journal = {American journal of obstetrics and gynecology}, volume = {204}, number = {5}, pages = {450.e15-20}, doi = {10.1016/j.ajog.2011.01.030}, pmid = {21411055}, issn = {1097-6868}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Amniotic Fluid/*drug effects/immunology/metabolism ; Animals ; Cytokines/immunology/metabolism ; Female ; Inflammation/chemically induced/*drug therapy/immunology/metabolism ; Lipopolysaccharides/pharmacology ; Oxidative Stress/*drug effects/immunology ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: Maternal infection is associated with oxidative stress and inflammation. We sought to determine whether N-acetyl-cysteine can decrease maternal oxidative stress and the inflammatory response in preterm gestation.<br><br>STUDY DESIGN: Pregnant rats 16 days, were treated with (1) lipopolysaccharide, (2) N-acetyl-cysteine 120 minutes after lipopolysaccharide, or (3) saline solution (intraperitoneal). Six hours after lipopolysaccharide administration, serum lipid peroxide formation (LPO), tumor necrosis factor-&#x3b1;, interleukin-6, and interleukin-1&#x3b2; levels in maternal serum and amniotic fluid were determined.<br><br>RESULTS: Lipopolysaccharide significantly increased maternal serum lipid peroxide formation (24-118.5 nmol/mL; P < .05), and maternal serum and amniotic fluid tumor necrosis factor-&#x3b1;, interleukin-6, and interleukin-1&#x3b2;. N-acetyl-cysteine treatment after lipopolysaccharide significantly attenuated lipid peroxide formation (47.5 nmol/mL) and proinflammatory cytokines response in maternal serum and amniotic fluid.<br><br>CONCLUSION: Maternal and amniotic fluid oxidative stress and inflammatory stimulation are attenuated by N-acetyl-cysteine even when administered after lipopolysaccharide. These results suggest that N-acetyl-cysteine may protect the fetus from adverse sequelae associated with inflammatory stimulation.}, }
@article {pmid21406724, year = {2011}, author = {Ardolino, M and Zingoni, A and Cerboni, C and Cecere, F and Soriani, A and Iannitto, ML and Santoni, A}, title = {DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction.}, journal = {Blood}, volume = {117}, number = {18}, pages = {4778-4786}, doi = {10.1182/blood-2010-08-300954}, pmid = {21406724}, issn = {1528-0020}, mesh = {Antigens, Differentiation, T-Lymphocyte/*metabolism ; Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Adhesion Molecules/biosynthesis/genetics ; Cell Cycle Proteins/metabolism ; Cell Proliferation ; Cytotoxicity, Immunologic ; *DNA Damage ; DNA Primers/genetics ; DNA-Binding Proteins/metabolism ; Humans ; In Vitro Techniques ; Killer Cells, Natural/*immunology/*metabolism ; Lipopolysaccharide Receptors/metabolism ; Lymphocyte Activation ; Lymphocyte Cooperation ; NK Cell Lectin-Like Receptor Subfamily K/metabolism ; Nectins ; Oxidative Stress ; Protein Serine-Threonine Kinases/metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Virus/biosynthesis/genetics ; Superantigens/administration &amp; dosage ; T-Lymphocytes/cytology/*immunology/*metabolism ; Tumor Suppressor Proteins/metabolism ; Up-Regulation ; }, abstract = {An important role for natural killer (NK) cells in the regulation of T-cell responses is emerging, although the receptor pairs regulating the NK-T-cell interaction have still not been identified. We found that superantigen-stimulated T cells express Nectin-2 (CD112) and poliovirus receptor (PVR; CD155), the ligands of the activating NK receptor DNAX accessory molecule-1 (DNAM-1; CD226). Interestingly, only PVR was present at the T cell surface, particularly on cells in the S and G(2)/M phases of the cell cycle. The up-regulation of PVR expression involves DNA-damage response (DDR)-dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker γH2AX. Oxidative stress contributed to DDR activation, and our results showed impaired PVR levels in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), being monocytes the main ROS source needed for optimal PVR expression on activated T cells. Interestingly, in accordance with ligand expression, NK cells lysed allogeneic proliferating more efficiently than nonproliferating T lymphocytes, with a mechanism requiring the cooperation between DNAM-1 and NKG2D. These results could contribute to unraveling the role of NK cells in the down-regulation of T-cell responses in physiologic and pathologic processes such as autoimmunity or GVHD.}, }
@article {pmid21406197, year = {2011}, author = {Simard, B and Bouamrani, A and Jourdes, P and Pernod, G and Dimitriadou, V and Berger, F}, title = {Induction of the fibrinolytic system by cartilage extract mediates its antiangiogenic effect in mouse glioma.}, journal = {Microvascular research}, volume = {82}, number = {1}, pages = {6-17}, doi = {10.1016/j.mvr.2011.03.002}, pmid = {21406197}, issn = {1095-9319}, mesh = {Acetylcysteine/metabolism/pharmacology ; Aminocaproic Acid/pharmacology ; Angiogenesis Inhibitors/administration &amp; dosage/pharmacology/therapeutic use ; Angiostatins/metabolism ; Animals ; Blood Vessels/metabolism/pathology ; Caudate Nucleus/pathology ; Cell Line, Tumor ; Fibrinolysin/antagonists &amp; inhibitors/pharmacology ; Fibrinolysis/*drug effects ; Glioma/blood supply/*drug therapy/metabolism/pathology ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neovascularization, Pathologic/*drug therapy/pathology ; Plasminogen/antagonists &amp; inhibitors/metabolism ; Plasminogen Activator Inhibitor 1/genetics/pharmacology ; Rats ; Survival Analysis ; Tissue Extracts/administration &amp; dosage/*pharmacology/*therapeutic use ; Tissue Plasminogen Activator/antagonists &amp; inhibitors/metabolism ; Transfection ; Xenograft Model Antitumor Assays ; }, abstract = {Both the antiangiogenic and antitumoral activity of shark cartilage extracts (SCE) have been demonstrated in animal models and clinical trials. Studies reported that SCE induces the expression of tissue plasminogen activator gene (PLAT) in endothelial cells and increases the activity of the protein (t-PA) in vitro. The aim of this study was to demonstrate the crucial role of t-PA induction in the antiangiogenic and antitumor activity of SCE in experimental glioma. This study showed antiangiogenic and antitumoral effects of SCE in three mice glioma models (C6, HGD and GL26). Histological examination suggested perivascular proteolysis and edema as well as important intratumoral necrosis, which artefactually increased the tumor volume at high doses. Thus, the antiangiogenic effect of SCE correlated with the presence of t-PA and angiostatin in degenerating vessels. Functional in vivo experiments were conducted to modulate the plasminogen pathway. No antiangiogenic effect was observed on tumors overexpressing the plasminogen activator inhibitor-1 (PAI-1). Moreover, therapeutical effects were neutralized in mice that were cotreated with ε-aminocaproic acid (EACA, 120 mg/kg p.o.), an inhibitor that blocks the high-affinity lysine binding sites of both plasminogen and plasmin. In contrast, cotreatment with N-acetylcysteine (NAC, 7,5mg/kg i.p.), a sulfhydril donor that reduces plasmin into angiostatin or other antiangiogenic fragments, increased the benefit of SCE on mice survival. In subcutaneous models, NAC prevented the increase in tumor volume caused by high doses of cartilage extract. In conclusion, this study indicates that induction of t-PA by shark cartilage extract plays an essential role in its antiangiogenic activity, but that control of excessive proteolysis by a plasmin reductor could prevent edema and uncover the full benefit of shark cartilage extract in the treatment of intracranial tumors.}, }
@article {pmid21401696, year = {2011}, author = {Xu, JF and Qu, JM and Li, HP}, title = {N-Acetylcysteine modulates acute lung injury induced by Pseudomonas aeruginosa in rats.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {38}, number = {5}, pages = {345-351}, doi = {10.1111/j.1440-1681.2011.05515.x}, pmid = {21401696}, issn = {1440-1681}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Acute Lung Injury/*drug therapy/*etiology/pathology ; Animals ; Bacterial Load/drug effects ; Bronchoalveolar Lavage Fluid/cytology/microbiology ; Cell Membrane Permeability/drug effects ; Drug Evaluation, Preclinical ; Expectorants/pharmacology/therapeutic use ; Lung/drug effects/metabolism/physiology ; Male ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Pseudomonas Infections/*complications/drug therapy ; Pseudomonas aeruginosa/drug effects/growth &amp; development/*physiology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {1. In critically ill patients, Pseudomonas aeruginosa-induced pneumonia and the lung injury associated with infection are major causes of mortality. The aim of the present study was to evaluate the protective properties of N-acetylcysteine (NAC) in rats infected with P. aeruginosa and the role of nitric oxide synthases (NOS) protein in this process. 2. Pneumonia was induced in rats by infecting them with P. aeruginosa intratracheally. One group of rats was treated with NAC (150 mg/kg per day, i.p., for 7 days). An untreated group served as the control. Samples were collected both before (0 h) and after infection (24 h). Bacterial loads in lung tissue, the lung wet : dry (W/D) ratio and pulmonary vascular permeability were assessed. Total cell and polymorphonuclear leucocyte cell counts in bronchoalveolar lavage fluid were determined. The expression of inducible (i) NOS and endothelial (e) NOS protein was analysed and correlated with indices of lung injury using Pearson's correlation analysis. 3. Bacterial load, lung injury indices and NOS expression increased after infection. Pretreatment with NAC mitigated lung injury although it did not significantly change bacterial loads. Furthermore, NAC treatment increased eNOS protein expression, but decreased iNOS expression, in lung tissues after infection. The expression of iNOS protein was positively correlated with indices of lung injury, whereas there was a negative correlation between eNOS expression and lung injury indices. 4. N-Acetylcysteine modulated P. aeruginosa-induced lung injury in rats. The results suggest that this effect maybe due to regulation of iNOS and eNOS protein expression by NAC.}, }
@article {pmid21401361, year = {2011}, author = {Patel Manali, B and Deshpande, S and Shah, G}, title = {Evaluation of efficacy of vitamin E and N-acetyl cysteine in gentamicin-induced nephrotoxicity in rats.}, journal = {Renal failure}, volume = {33}, number = {3}, pages = {341-347}, doi = {10.3109/0886022X.2011.560987}, pmid = {21401361}, issn = {1525-6049}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/chemically induced/*drug therapy ; Animals ; Anti-Bacterial Agents ; Antioxidants/*therapeutic use ; Drug Evaluation, Preclinical ; Gentamicins ; Male ; Rats ; Rats, Sprague-Dawley ; Vitamin E/*therapeutic use ; }, abstract = {Gentamicin (GM), an aminoglycoside, is widely employed in clinical practice for the treatment of serious gram-negative infections. The clinical utility of GM is limited by the frequent incidence of acute renal failure. This study was designed to investigate treatment and posttreatment renoprotective potential of vitamin E and N-acetyl cysteine (NAC) against GM-induced oxidative stress and renal dysfunction. Male Sprague-Dawley rats were divided into six groups: first group is the control group that received olive oil (0.1 mL/100 g B.W.), second is the one that was treated with GM (80 mg/kg/i.p./8 days), third is the one that was treated with GM (80 mg/kg/i.p./8 days) and vitamin E (50 mg/kg/i.p./8 days), fourth is the one that was treated with GM (80 mg/kg/i.p./8 days) and NAC (50 mg/kg/i.p./8 days), fifth is the one that was treated with GM (80 mg/kg/i.p./8 days), vitamin E (50 mg/kg/i.p./8 days), and NAC (50 mg/kg/i.p./8 days), and sixth is the one that was treated with GM initially for 8 days (at 80 mg/kg/i.p.) after which vitamin E (at 50 mg/kg/i.p.) and NAC (at 50 mg/kg/i.p.) were administered for 8 days. Serum creatinine, blood urea nitrogen, serum glucose, renal malondialdehyde, renal reduced glutathione, urine sodium, fractional excretion of sodium, and histopathological examination of kidney were performed after treatment. Gentamicin treatment caused nephrotoxicity as evidenced by marked elevation in serum creatinine, blood urea nitrogen, renal malondialdehyde, urine sodium, and fractional excretion of sodium. Study of renal morphology showed marked loss of epithelium in proximal convoluted tubule, inflammatory infiltrate in the form of lymphocytes, mainly in interstitium. Treatment and posttreatment with vitamin E and NAC significantly restored renal functions, reduced lipid peroxidation, enhanced reduced glutathione level, and restored the biochemical parameters. The results of this study demonstrate the therapeutic potential of vitamin E and NAC in gentamicin-induced nephrotoxicity.}, }
@article {pmid21401304, year = {2011}, author = {Balková, P and Hlaváčková, M and Milerová, M and Neckář, J and Kolář, F and Novák, F and Nováková, O}, title = {N-acetylcysteine treatment prevents the up-regulation of MnSOD in chronically hypoxic rat hearts.}, journal = {Physiological research}, volume = {60}, number = {3}, pages = {467-474}, doi = {10.33549/physiolres.932042}, pmid = {21401304}, issn = {1802-9973}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Free Radical Scavengers/*pharmacology/therapeutic use ; *Hypoxia ; Male ; Mitochondria/metabolism ; Myocardial Reperfusion Injury/metabolism/*prevention &amp; control ; Myocardium/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/*metabolism ; *Up-Regulation ; }, abstract = {Chronic intermittent hypoxia (CIH) is associated with increased production of reactive oxygen species that contributes to the adaptive mechanism underlying the improved myocardial ischemic tolerance. The aim was to find out whether the antioxidative enzyme manganese superoxide dismutase (MnSOD) can play a role in CIH-induced cardioprotection. Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (7000 m, 8 h/day, 25 exposures) (n=14) or kept at normoxia (n=14). Half of the animals from each group received N-acetylcysteine (NAC, 100 mg/kg) daily before the hypoxic exposure. The activity and expression of MnSOD were increased by 66 % and 23 %, respectively, in the mitochondrial fraction of CIH hearts as compared with the normoxic group; these effects were suppressed by NAC treatment. The negative correlation between MnSOD activity and myocardial infarct size suggests that MnSOD can contribute to the improved ischemic tolerance of CIH hearts.}, }
@article {pmid21398367, year = {2011}, author = {Dai, J and Meng, Q}, title = {Differential function of protective agents at each stage of the hypothermic preservation of hepatocytes.}, journal = {Journal of biochemistry}, volume = {149}, number = {6}, pages = {739-745}, doi = {10.1093/jb/mvr030}, pmid = {21398367}, issn = {1756-2651}, mesh = {Alkaloids/pharmacology ; Animals ; Antioxidants/*pharmacology ; Calcium/antagonists &amp; inhibitors/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cyclosporine/pharmacology ; Cytoprotection/*drug effects ; Fructosediphosphates/pharmacology ; Hepatocytes/cytology/*drug effects/metabolism ; Organ Preservation/methods ; Quinolizines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Ruthenium Red/pharmacology ; Solanaceous Alkaloids/pharmacology ; Structure-Activity Relationship ; Trehalose/pharmacology ; Matrines ; }, abstract = {Hypothermic preservation of bioartificial liver (BAL) has long been appreciated in BAL storage and transportation. However, the deterioration of cell activity during hypothermia/rewarming limits its clinical use and the complete prevention of hypothermia-induced hepatocyte injury has not been achieved. In this article, a miniaturized BAL that underwent three preservation stages (i.e. pre-incubation, hypothermia and rewarming) was applied as a hypothermic preservation model to locate the protection of several protective agents against hypothermia-induced cell injury. The agents, including vitamin E, schisandrin B, glycyrrhizic acid, N-acetyl-cysteine, ruthenium red, trehalose, anisodamine, fructose-1, 6-diphosphate, cyclosporin A and matrine (Mat), were found to exert their functions at different preservation stages, which were speculated to associate with the specific protection of each agent as well as the corresponding cell injuries at each stage. Such hypothesis was further strengthened by focusing on Mat, which only suppressed the hypothermia-induced injury through the inhibition of Ca(2+) overload at the rewarming stage, whereas its presence at the hypothermic stage excessively down-regulated the cytosolic free Ca(2+) and then aggravated cell death. The results indicate that the specific cell injury at each preservation stage requires a corresponding protective agent. However, the untimely misuse of the agents may inversely aggravate cell injury.}, }
@article {pmid21395525, year = {2011}, author = {Orhan, H and Vermeulen, NP}, title = {Conventional and novel approaches in generating and characterization of reactive intermediates from drugs/drug candidates.}, journal = {Current drug metabolism}, volume = {12}, number = {4}, pages = {383-394}, doi = {10.2174/138920011795202974}, pmid = {21395525}, issn = {1875-5453}, mesh = {Animals ; Biotransformation ; Drug Discovery/*methods ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Pharmaceutical Preparations/*metabolism ; }, abstract = {Despite several thousands of drugs are in use currently, research on new drug molecules is continuing. Because, there are diseases still without medication, successor/better drugs make the predecessor ones obsolete, and advancement in both life sciences and analytical technologies provide identification of previously unknown mechanisms of diseases, and discovery of novel drug targets. The two main criteria which a drug candidate should meet are high affinity for the target, and no or acceptable/tolerable toxicity in humans. Among these two, toxicity is the limiting one; developing a drug candidate with unacceptable toxicity has to be discontinued, even if it has an extremely high pharmacological activity. Drug would be withdrawn, if serious toxicity arises after marketing. Since drug development is a long (approximately 10 years), expensive, and infertile (one lead in 10.000 molecules) process, it is extremely important to detect the potential toxicity of drug candidate as early as possible. Today, it is believed that a great majority of toxic effects are caused by reactive intermediates generated by biotransformation of the parent drug. However, there are experimental difficulties in identifying such metabolite(s) in vivo. Their formation is affected by multi-factorial events; they can further be metabolized to structurally different products, and/or they may bind to a huge variety of biological sites or macromolecules. Hence, some reactive intermediates and their corresponding stable derivatives are generated in trace amounts, which make their determination more difficult. The ability of cytochrome P450s (CYP450) and other biotransformation enzymes to function in vitro offers a great flexibility to researchers, biotransformation of any compound can be simulated in a test tube, and metabolites/reactive intermediates are generated in an environment which has relatively much less background and less interfering multi-factorial events compared to in vivo. To simulate biotransformation, microsomal fraction is used most frequently from human and non-human sources. Purified or recombinant enzymes are used in determining the individual isoenzymes responsible for certain metabolites. Because of the chemical reactivity of intermediates, relevant, usually nucleophilic trapping agent(s) such as glutathione (GSH), N-acetylcysteine (NAC) and cyanide (CN-) are used to stabilize the metabolite. Trapped metabolites are subjected to spectrometric and/or nuclear magnetic resonance spectroscopic analyses for structural identification. Vertiginous advances especially in mass spectrometric technologies offer researchers new challenges in this area. This review is aimed at briefly summarizing the state of the art and compiling the highlighted studies in characterization of the reactive metabolites from drug molecules.}, }
@article {pmid21395287, year = {2011}, author = {Subramanian, R and Tam, J and Aidasani, D and Reid, DL and Skiles, GL}, title = {Novel cytochrome p450 bioactivation of a terminal phenyl acetylene group: formation of a one-carbon loss benzaldehyde and other oxidative products in the presence of N-acetyl cysteine or glutathione.}, journal = {Chemical research in toxicology}, volume = {24}, number = {5}, pages = {677-686}, doi = {10.1021/tx1004375}, pmid = {21395287}, issn = {1520-5010}, mesh = {Acetylcysteine/*metabolism ; Acetylene/*metabolism ; Animals ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Benzaldehydes/*metabolism ; Cattle ; Chelating Agents/pharmacology ; Cytochrome P-450 Enzyme System/*metabolism ; Deferoxamine/pharmacology ; Dogs ; Glutathione/*metabolism ; Humans ; Male ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Compounds 1 (N1-(3-ethynylphenyl)-6-methyl-N5-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl) isoquinoline-1,5-diamine) and 2 (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine; Erlotinib/Tarceva) are kinase inhibitors that contain a terminal phenyl acetylene moiety. When incubated in the presence of P450 and NADPH, the anticipated phenyl acetic acid metabolite was formed. When 10 mM of N-acetyl-l-cysteine was added to the incubation mixtures, the phenyl acetic acid product was reduced and at 25 mM or higher concentration of NAC, formation of the phenyl acetic acid was abolished. Instead, the phenyl acetylene moiety lost a carbon and formed a benzaldehyde product. Other oxidation products incorporating one or more equivalents of NAC were also observed. The identities of the metabolites were characterized by MS and NMR. Addition of deferoxamine or ascorbic acid diminished the formation of the NAC influenced products. Similar products were also observed when 1 or 2 were incubated in P450 reactions supplemented with GSH, in Fenton reactions supplemented with NAC or GSH, and in peroxidase reactions supplemented with NAC. We propose the thiols act as a pro-oxidant readily undergoing a one-electron oxidation to form thiyl radicals which in turn initiates the formation of other peroxy radicals that drive the reaction to the observed products. These in vitro findings suggest that one-electron oxidation of thiols may promote the cooxidation of xenobiotic substrates.}, }
@article {pmid21394639, year = {2011}, author = {Momeni, M and De Kock, M and Devuyst, O and Liistro, G}, title = {Effect of N-acetyl-cysteine and hyperoxia on erythropoietin production.}, journal = {European journal of applied physiology}, volume = {111}, number = {11}, pages = {2681-2686}, pmid = {21394639}, issn = {1439-6327}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Erythropoietin/*biosynthesis/blood ; Exercise Test ; Female ; Humans ; Hyperoxia/blood/*metabolism ; Male ; Middle Aged ; Oxygen/metabolism ; Oxygen Consumption/physiology ; Respiratory Function Tests ; Time Factors ; Young Adult ; }, abstract = {Previous studies in healthy subjects have shown an increase in erythropoietin (EPO) production after administration of N-acetyl-cysteine (NAC). These authors hypothesized that NAC increases intracellular reduced glutathione, decreasing reactive oxygen species and enabling EPO production. We investigated if EPO production could be stimulated with a single dose of NAC, after 90 min of pure oxygen breathing. Thirty-eight healthy volunteers were randomized into either the control (C) group or the NAC group, which received 600 mg NAC PO dissolved in a glass of orange juice, 60 min before breathing 15 L/min of 100% normobaric oxygen. Orange juice was administered to both groups. Blood samples for EPO measurement were taken at T0, before the orange juice administration, and T1, T2, T3 and T4, respectively, 8, 24, 32 and 48 h after the orange juice. The EPO concentrations of the NAC group decreased significantly at T1, followed by a significant increase compared to baseline, which was obvious until T4. The EPO concentrations of the C group did not show any significant variations. In this study, a significant increase of EPO production was observed after a short-term hyperoxic stimulus only when preceded with the administration of a single dose of NAC.}, }
@article {pmid21391924, year = {2011}, author = {Kim, JC and Hong, SW and Shim, JK and Yoo, KJ and Chun, DH and Kwak, YL}, title = {Effect of N-acetylcysteine on pulmonary function in patients undergoing off-pump coronary artery bypass surgery.}, journal = {Acta anaesthesiologica Scandinavica}, volume = {55}, number = {4}, pages = {452-459}, doi = {10.1111/j.1399-6576.2011.02407.x}, pmid = {21391924}, issn = {1399-6576}, mesh = {Acetylcysteine/*pharmacology ; Acute Lung Injury/epidemiology/prevention &amp; control ; Aged ; Blood Loss, Surgical ; Blood Transfusion ; *Coronary Artery Bypass, Off-Pump ; Creatine Kinase/blood ; Double-Blind Method ; Female ; Free Radical Scavengers/*pharmacology ; Hemodynamics/drug effects ; Humans ; Lung/drug effects/*physiology ; Male ; Middle Aged ; Myocardial Infarction/complications ; Postoperative Complications/epidemiology/mortality/prevention &amp; control ; Pulmonary Circulation/drug effects ; Respiratory Function Tests ; Vascular Resistance/drug effects ; Ventricular Dysfunction, Left/physiopathology ; Water-Electrolyte Balance/physiology ; }, abstract = {BACKGROUND: Pulmonary dysfunction related to inflammatory response and radical oxygen species remains a problem in off-pump coronary bypass graft surgery (OPCAB), especially in patients with reduced left ventricular (LV) function. The aim of this study was to evaluate the effect of N-acetylcysteine (NAC) on pulmonary function following OPCAB.<br><br>METHODS: Patients with LV ejection fraction &#x2264;40% were randomly assigned to receive either a bolus of 100 mg/kg of intravenous NAC over a 15-min period immediately after anesthetic induction, followed by an intravenous infusion at 40 mg/kg/day for 24 h (NAC group, n=24), or a placebo (control group, n=24). Hemodynamic and pulmonary parameters, and the incidence of acute lung injury (PaO(2)/FiO(2)<300 mmHg) were assessed and compared.<br><br>RESULTS: The pulmonary vascular resistance index (PVRI) did not change during mechanical heart displacement compared with the baseline value in the NAC group while it was significantly increased in the control group. Significantly less number of patients developed acute lung injury at 2 h after the surgery in the NAC group. The other pulmonary parameters and the duration of ventilator care were all similar.<br><br>CONCLUSIONS: NAC demonstrated promising results in terms of mitigating the increase in PVRI during mechanical heart displacement and attenuating the development of acute lung injury in the immediate post-operative period. However, NAC could not induce a definite improvement in the other important pulmonary variables including PaO(2)/FiO(2) and Q(s)/Q(t), and did not lead to a decreased duration of ventilatory care or length of stay in the intensive care unit.}, }
@article {pmid21385138, year = {2011}, author = {Suk, JS and Lai, SK and Boylan, NJ and Dawson, MR and Boyle, MP and Hanes, J}, title = {Rapid transport of muco-inert nanoparticles in cystic fibrosis sputum treated with N-acetyl cysteine.}, journal = {Nanomedicine (London, England)}, volume = {6}, number = {2}, pages = {365-375}, pmid = {21385138}, issn = {1748-6963}, support = {R01 EB003558-01A2/EB/NIBIB NIH HHS/United States ; P01 HL051811-07/HL/NHLBI NIH HHS/United States ; R01 EB003558/EB/NIBIB NIH HHS/United States ; P01 HL051811/HL/NHLBI NIH HHS/United States ; 1R01 EB003558/EB/NIBIB NIH HHS/United States ; P01 HL51811/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Biological Transport/*drug effects ; Cystic Fibrosis/*drug therapy ; Drug Carriers/*chemistry/metabolism ; Female ; Humans ; Male ; Middle Aged ; Nanoparticles/*chemistry/ultrastructure ; Polyethylene Glycols/chemistry/metabolism ; Sputum/drug effects/*metabolism ; Young Adult ; }, abstract = {AIMS: Sputum poses a critical diffusional barrier that strongly limits the efficacy of drug and gene carriers in the airways of individuals with cystic fibrosis (CF). Previous attempts to enhance particle penetration of CF sputum have focused on either reducing its barrier properties via mucolytics, or decreasing particle adhesion to sputum constituents by coating the particle surface with non-mucoadhesive polymers, including polyethylene glycol (PEG). Neither approach has enabled particles to penetrate expectorated sputum at rates previously observed for non-mucoadhesive nanoparticles in human cervicovaginal mucus. Here, we sought to investigate whether a common mucolytic, N-acetyl cysteine (NAC), in combination with dense PEG coatings on particles, can synergistically enhance particle penetration across fresh undiluted CF sputum.<br><br>MATERIALS &amp; METHODS: We used high-resolution multiple particle tracking to measure the diffusion of uncoated and PEG-coated nanoparticles in native and NAC-treated CF sputum.<br><br>RESULTS: We discovered that 200 nm particles, if densely coated with PEG, were able to penetrate CF sputum pretreated with NAC with average speeds approaching their theoretical speeds in water. Based on the rapid penetration of PEG-coated particles in NAC-treated sputum, we determined that the average spacing between sputum mesh elements was increased from 145 &#xb1; 50 nm to 230 &#xb1; 50 nm upon NAC treatment. Mathematical models based on particle transport rates suggest as much as 75 and 30% of 200 and 500 nm PEG-coated particles, respectively, may penetrate a physiologically thick NAC-treated CF sputum layer within 20 min. Uncoated particles were trapped in CF sputum pretreated with NAC nearly to the same extent as in native sputum, suggesting that NAC treatment alone offered little improvement to particle penetration.<br><br>CONCLUSION: NAC facilitated rapid diffusion of PEG-coated, muco-inert nanoparticles in CF sputum. Our results provide a promising strategy to improve drug and gene carrier penetration in CF sputum, offering hope for improved therapies for CF.}, }
@article {pmid21384399, year = {2011}, author = {Li, H and Wu, S and Shi, N and Lian, S and Lin, W}, title = {Nrf2/HO-1 pathway activation by manganese is associated with reactive oxygen species and ubiquitin-proteasome pathway, not MAPKs signaling.}, journal = {Journal of applied toxicology : JAT}, volume = {31}, number = {7}, pages = {690-697}, doi = {10.1002/jat.1654}, pmid = {21384399}, issn = {1099-1263}, mesh = {Animals ; Antioxidants/metabolism ; Heme Oxygenase-1/genetics/*metabolism ; Manganese/*toxicity ; Mitogen-Activated Protein Kinases/genetics/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidative Stress/drug effects ; PC12 Cells ; Proteasome Endopeptidase Complex/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Ubiquitin/*genetics/metabolism ; Up-Regulation ; }, abstract = {Manganese has been known to induce neurological disorders similar to Parkinson's disease. One of the features of manganese-induced neurotoxicity is oxidative stress. Accumulating data implicate NF-E2-related factor 2 (Nrf2) as a key regulator in the adaptive survival response to oxidative stress. Recent studies suggest that the activation of Nrf2 is induced by manganese in PC12 cells. In the present study, we investigated possible links between reactive oxygen species (ROS), proteasome or mitogen-activated protein kinase (MAPK) signaling and Nrf2/HO-1 activation in manganese-treated PC12 cells. After MnCl(2) treatment, there was an increase in nuclear localization and subsequent binding of Nrf2 to the antioxidant-responsive element (ARE) and upregulation of heme oxygenase-1 (HO-1) protein in PC12 cells. Pretreatment with N-acetyl cysteine, a scavenger of reactive oxygen species, suppressed MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding and subsequent upregulation of HO-1 expression. However, pretreatment with lactacystin, an inhibitor of proteasome activity, enhanced MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding and subsequent upregulation of HO-1 expression. Pretreatment of cells with a pharmacological inhibitor of MAPK (ERK inhibitor PD 98059, P38 inhibitor SB203580 or JNK inhibitor SP600125) did not affect the MnCl(2) -induced Nrf2 activation, increase in Nrf2-ARE binding or subsequent upregulation of HO-1 expression. These results suggest that Nrf2/HO-1 activation by Mn in PC12 cells is associated with ROS and the ubiquitin-proteasome pathway, not MAPK signaling.}, }
@article {pmid21377526, year = {2011}, author = {Jana, S and Sinha, M and Chanda, D and Roy, T and Banerjee, K and Munshi, S and Patro, BS and Chakrabarti, S}, title = {Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson's disease.}, journal = {Biochimica et biophysica acta}, volume = {1812}, number = {6}, pages = {663-673}, doi = {10.1016/j.bbadis.2011.02.013}, pmid = {21377526}, issn = {0006-3002}, mesh = {Animals ; Apoptosis/drug effects ; Brain/drug effects ; Caspases/metabolism ; Dopamine/metabolism/*toxicity ; Energy Metabolism/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/physiology ; Oxidation-Reduction ; Oxidative Phosphorylation/drug effects ; PC12 Cells ; Parkinson Disease/*etiology/metabolism ; Quinones/*toxicity ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {The study has demonstrated that dopamine induces membrane depolarization and a loss of phosphorylation capacity in dose-dependent manner in isolated rat brain mitochondria during extended in vitro incubation and the phenomena are not prevented by oxyradical scavengers or metal chelators. Dopamine effects on brain mitochondria are, however, markedly prevented by reduced glutathione and N-acetyl cysteine and promoted by tyrosinase present in the incubation medium. The results imply that quinone oxidation products of dopamine are involved in mitochondrial damage under this condition. When PC12 cells are exposed to dopamine in varying concentrations (100-400μM) for up to 24h, a pronounced impairment of mitochondrial bio-energetic functions at several levels is observed along with a significant (nearly 40%) loss of cell viability with features of apoptotic nuclear changes and increased activities of caspase 3 and caspase 9 and all these effects of dopamine are remarkably prevented by N-acetyl cysteine. N-acetyl cysteine also blocks nearly completely the dopamine induced increase in reactive oxygen species production and the formation of quinoprotein adducts in mitochondrial fraction within PC12 cells and also the accumulation of quinone products in the culture medium. Clorgyline, an inhibitor of MAO-A, markedly decreases the formation of reactive oxygen species in PC12 cells upon dopamine exposure but has only mild protective actions against quinoprotein adduct formation, mitochondrial dysfunctions, cell death and caspase activation induced by dopamine. The results have indicated that quinone oxidation products and not reactive oxygen species are primarily involved in cytotoxic effects of dopamine and the mitochondrial impairment plays a central role in the latter process. The data have clear implications in the pathogenesis of Parkinson's disease.}, }
@article {pmid21374707, year = {2011}, author = {Wu, CL and Huang, AC and Yang, JS and Liao, CL and Lu, HF and Chou, ST and Ma, CY and Hsia, TC and Ko, YC and Chung, JG}, title = {Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC)-mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of caspase-3, mitochondria dysfunction and nitric oxide (NO) in human osteogenic sarcoma U-2 OS cells.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {29}, number = {8}, pages = {1199-1209}, doi = {10.1002/jor.21350}, pmid = {21374707}, issn = {1554-527X}, mesh = {Anticarcinogenic Agents/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Bone Neoplasms/drug therapy/metabolism ; Caspase 3/metabolism ; Cell Cycle/*drug effects ; Cell Line, Tumor ; DNA Damage/drug effects ; Drug Evaluation, Preclinical ; Enzyme Activation/drug effects ; Humans ; Isothiocyanates/*pharmacology/therapeutic use ; Membrane Potential, Mitochondrial/drug effects ; Nitric Oxide/metabolism ; Osteosarcoma/drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC), a member of the isothiocyanate family, have been shown to exhibit antineoplastic ability against many human cancer cells. In this study, we found that exposure of human osteogenic sarcoma U-2 OS cells to BITC and PEITC led to induce morphological changes and to decrease the percentage of viable cells in a time- and dose-dependent manner. BITC and PEITC induced cell cycle arrest at G2/M phase at 48 h treatment and inhibited the levels of cell cycle regulatory proteins such as cyclin A and B1 in U-2 OS cells but promoted the level of Chk1 and p53 that led to G2/M arrest. BITC and PEITC induced a marked increase in apoptosis (DNA fragmentation) and poly(ADP-ribose)polymerase (PARP) cleavage, which was associated with mitochondrial dysfunction and the activation of caspase-9 and -3. BITC and PEITC also promoted the ROS production in U-2 OS cells and the N-acetylcysteine (NAC, an antoxidant agent) was pretreated and then treated with both compounds which led to decrease the levels of ROS and increase the cell viability. Interestingly, BITC and PEITC promoted the levels of NO production and increased the iNOS enzyme. Confocal laser microscope also demonstrated that BITC and PEITC promoted the release of cytochrome c and AIF, suggesting that both compounds induced apoptosis through ROS, caspase-3 and mitochondrial, and NO signaling pathways. Taken together, these molecular alterations and signaling pathways offer an insight into BITC and PEITC-caused growth inhibition, G2/M arrest, and apoptotic death of U-2 OS cells.}, }
@article {pmid21372386, year = {2011}, author = {Masubuchi, Y and Nakayama, J and Sadakata, Y}, title = {Protective effects of exogenous glutathione and related thiol compounds against drug-induced liver injury.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {34}, number = {3}, pages = {366-370}, doi = {10.1248/bpb.34.366}, pmid = {21372386}, issn = {1347-5215}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Chemical and Drug Induced Liver Injury/metabolism/*prevention &amp; control ; Female ; Furosemide/adverse effects ; Glutathione/metabolism/pharmacology/*therapeutic use ; Interleukin-6/*metabolism ; Liver/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred Strains ; }, abstract = {An overdose of acetaminophen (APAP) causes liver injury both in experimental animals and humans. N-acetylcysteine (NAC) is clinically used as an antidote for APAP intoxication, and it is thought to act by providing cysteine as a precursor of glutathione, which traps a reactive metabolite of APAP. Other hepatoprotective mechanisms of NAC have also been suggested. Here, we examined the effects of thiol compounds with different abilities to restore hepatic glutathione, on hepatotoxicity of APAP and furosemide in mice. Overnight-fasted male CD-1 mice were given APAP or furosemide intraperitoneally. NAC, cysteine, glutathione, or glutathione-monoethyl ester was administered concomitantly with APAP or furosemide. All thiol compounds used in this study effectively protected mice against APAP-induced liver injury. Only glutathione-monoethyl ester completely prevented APAP-induced early hepatic glutathione depletion. Cysteine also significantly restored hepatic glutathione levels. NAC partially restored glutathione levels. Exogenous glutathione had no effect on hepatic glutathione loss. NAC and glutathione highly stimulated the hepatic expression of cytokines, particularly interleukin-6, which might be involved in the alleviation of APAP hepatotoxicity. Furosemide-induced liver injury, which does not accompany hepatic glutathione depletion, was also attenuated by NAC and exogenous glutathione, supporting their protective mechanisms other than replenishment of glutathione. In conclusion, exogenous thiols could alleviate drug-induced liver injury. NAC and glutathione might exert their effects, at least partially, via mechanisms that are independent of increasing hepatic glutathione, but probably act through cytokine-mediated and anti-inflammatory mechanisms.}, }
@article {pmid21371473, year = {2011}, author = {Denizalti, M and Durlu-Kandilci, NT and Bozkurt, TE and Sahin-Erdemli, I}, title = {Hydrogen sulphide inhibits carbachol-induced contractile responses in β-escin permeabilized guinea-pig taenia caecum.}, journal = {European journal of pharmacology}, volume = {658}, number = {2-3}, pages = {229-235}, doi = {10.1016/j.ejphar.2011.02.017}, pmid = {21371473}, issn = {1879-0712}, mesh = {Animals ; Caffeine/pharmacology ; Calcium/metabolism ; Calcium-Transporting ATPases/metabolism ; Carbachol/*antagonists &amp; inhibitors/*pharmacology ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology ; Cecum/cytology/metabolism/*physiology ; Escin/*metabolism ; Extracellular Space/drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Guinea Pigs ; Hydrogen Sulfide/*pharmacology ; In Vitro Techniques ; Indoles/pharmacology ; Inositol Phosphates/pharmacology ; Intracellular Space/drug effects/metabolism ; Male ; Muscle Contraction/*drug effects ; Myocytes, Smooth Muscle/cytology/drug effects ; Permeability/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Hydrogen sulphide (H(2)S) is an endogenous mediator producing a potent relaxation response in vascular and non-vascular smooth muscles. While ATP-sensitive potassium channels are mainly involved in this relaxant effect in vascular smooth muscle, the mechanism in other smooth muscles has not been revealed yet. In the present study, we investigated how H(2)S relaxes non-vascular smooth muscle by using intact and β-escin permeabilized guinea-pig taenia caecum. In intact tissues, concentration-dependent relaxation response to H(2)S donor NaHS in carbachol-precontracted preparations did not change in the presence of a K(ATP) channel blocker glibenclamide, adenylate cyclase inhibitor SQ-22536, guanylate cyclase inhibitor ODQ, protein kinase A inhibitor KT-5720, protein kinase C inhibitor H-7, tetrodotoxin, apamin/charybdotoxin, NOS inhibitor L-NAME and cyclooxygenase inhibitor indomethacin. We then studied how H(2)S affected carbachol- or Ca(2+)-induced contractions in permeabilized tissues. When Ca(2+) was clamped to a constant value (pCa6), a further contraction could be elicited by carbachol that was decreased by NaHS. This decrease in contraction was reversed by catalase but not by superoxide dismutase or N-acetyl cysteine. The sarcoplasmic reticulum Ca(2+)-ATPase pump inhibitor, cyclopiazonic acid, also decreased the carbachol-induced contraction that was further inhibited by NaHS. Mitochondrial proton pump inhibitor carbonyl cyanide p-trifluromethoxyphenylhydrazone also decreased the carbachol-induced contraction but this was not additionally changed by NaHS. The carbachol-induced Ca(2+) sensitization, calcium concentration-response curves, IP(3)- and caffeine-induced contractions were not affected by NaHS. In conclusion, we propose that hydrogen peroxide and mitochondria may have a role in H(2)S-induced relaxation response in taenia caecum.}, }
@article {pmid21368860, year = {2010}, author = {Marino, ML and Fais, S and Djavaheri-Mergny, M and Villa, A and Meschini, S and Lozupone, F and Venturi, G and Della Mina, P and Pattingre, S and Rivoltini, L and Codogno, P and De Milito, A}, title = {Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells.}, journal = {Cell death &amp; disease}, volume = {1}, number = {10}, pages = {e87}, pmid = {21368860}, issn = {2041-4889}, mesh = {Acetylcysteine/pharmacology ; Adaptor Proteins, Signal Transducing/metabolism ; Antineoplastic Agents/*therapeutic use ; Apoptosis Regulatory Proteins/genetics/metabolism ; *Autophagy ; Autophagy-Related Protein 5 ; Beclin-1 ; Cell Cycle Proteins ; Cell Line, Tumor ; Esomeprazole/*therapeutic use ; Humans ; Hydrogen-Ion Concentration ; Melanoma/*drug therapy/metabolism ; Membrane Proteins/genetics/metabolism ; Microtubule-Associated Proteins/genetics/metabolism ; NADPH Oxidases/metabolism ; *Oxidative Stress ; Phosphoproteins/metabolism ; Phosphorylation ; Proton Pump Inhibitors/*therapeutic use ; Reactive Oxygen Species/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism ; }, abstract = {Proton pump inhibitors (PPI) target tumour acidic pH and have an antineoplastic effect in melanoma. The PPI esomeprazole (ESOM) kills melanoma cells through a caspase-dependent pathway involving cytosolic acidification and alkalinization of tumour pH. In this paper, we further investigated the mechanisms of ESOM-induced cell death in melanoma. ESOM rapidly induced accumulation of reactive oxygen species (ROS) through mitochondrial dysfunctions and involvement of NADPH oxidase. The ROS scavenger N-acetyl-L-cysteine (NAC) and inhibition of NADPH oxidase significantly reduced ESOM-induced cell death, consistent with inhibition of cytosolic acidification. Autophagy, a cellular catabolic pathway leading to lysosomal degradation and recycling of proteins and organelles, represents a defence mechanism in cancer cells under metabolic stress. ESOM induced the early accumulation of autophagosomes, at the same time reducing the autophagic flux, as observed by WB analysis of LC3-II accumulation and by fluorescence microscopy. Moreover, ESOM treatment decreased mammalian target of rapamycin signalling, as reduced phosphorylation of p70-S6K and 4-EBP1 was observed. Inhibition of autophagy by knockdown of Atg5 and Beclin-1 expression significantly increased ESOM cytotoxicity, suggesting a protective role for autophagy in ESOM-treated cells. The data presented suggest that autophagy represents an adaptive survival mechanism to overcome drug-induced cellular stress and cytotoxicity, including alteration of pH homeostasis mediated by proton pump inhibition.}, }
@article {pmid21361357, year = {2011}, author = {Nassar, AE and King, I and Du, J}, title = {Characterization of short-lived electrophilic metabolites of the anticancer agent laromustine (VNP40101M).}, journal = {Chemical research in toxicology}, volume = {24}, number = {4}, pages = {568-578}, doi = {10.1021/tx100453t}, pmid = {21361357}, issn = {1520-5010}, mesh = {Acetylcysteine/chemistry ; Antineoplastic Agents/chemistry/*metabolism/therapeutic use ; Carbon Isotopes/chemistry ; Chromatography, High Pressure Liquid ; Cysteine/chemistry ; Glutathione/chemistry ; Humans ; Hydrazines/chemistry/*metabolism/therapeutic use ; Magnetic Resonance Spectroscopy ; Microsomes, Liver/metabolism ; NADP/chemistry ; Neoplasms/drug therapy ; Spectrometry, Mass, Electrospray Ionization ; Sulfonamides/chemistry/*metabolism/therapeutic use ; }, abstract = {Laromustine (VNP40101M; 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-(methylamino) carbonylhydrazine) is a novel sulfonylhydrazine alkylating agent. Phase 1 metabolism of laromustine was reported recently and showed that laromustine undergoes rearrangement, dehalogenation, and hydrolysis at physiological pH to form active moieties. (1) A mechanism for the rearrangement was proposed on the basis of fragmentation ions. (1) (,) (2) In this article, we report the phase II conjugates of VNP40101M and VNP4090CE which were formed after incubation of VNP40101M or VNP4090CE with pooled human liver microsomes (HLM) and cofactors nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), N-acetylecysteine (NAC), and cysteine (CYS). Eight novel phase II conjugates (M-1 to M-8) were identified and characterized by hydrogen-deuterium exchange (H-D), stable isotope ((13)C-labeled VNP40101M), and MS(n) experiments. M-4 and M-5 were further confirmed by nuclear magnetic resonance spectroscopy (NMR). The short-lived CH(3)SO(2)CH(2)CH(2)-, methylformamide and CH(3)SO(2)NHN═CHCH(2)- moieties were generated from VNP40101M. The reactive intermediates CH(3)SO(2)CH(2)CH(2)- and methylformamide formed conjugates with GSH, CYS, and NAC. The CH(3)SO(2)NHN═CHCH(2)- moiety formed conjugates with GSH and NAC. M-2, M-4, and M-6 were only detected from the incubation of VNP40101M because VNP4090CE does not contain a methylformamide group. All other conjugates were formed by both VNP40101M and VNP4090CE. The in vitro studies found that VNP40101M and VNP4090CE undergo activation in human liver microsomes. The results from this study showed that laromustine produces several reactive intermediates that may play a role in the toxicities seen in the clinical trials.}, }
@article {pmid21358671, year = {2011}, author = {Bell, EL and Emerling, BM and Ricoult, SJ and Guarente, L}, title = {SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production.}, journal = {Oncogene}, volume = {30}, number = {26}, pages = {2986-2996}, pmid = {21358671}, issn = {1476-5594}, support = {R01 AG011119/AG/NIA NIH HHS/United States ; R01 AG015339/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Cell Proliferation/drug effects ; Cells, Cultured ; Down-Regulation/genetics ; Embryo, Mammalian ; Gene Expression Regulation, Neoplastic ; HCT116 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*genetics/metabolism ; Mice ; Mice, Nude ; Mitochondria/drug effects/*metabolism ; Neoplasms/genetics/metabolism/*pathology ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/*metabolism ; Sirtuin 3/antagonists &amp; inhibitors/genetics/metabolism/*physiology ; Xenograft Model Antitumor Assays ; }, abstract = {It has become increasing clear that alterations in cellular metabolism have a key role in the generation and maintenance of cancer. Some of the metabolic changes can be attributed to the activation of oncogenes or loss of tumor suppressors. Here, we show that the mitochondrial sirtuin, SirT3, acts as a tumor suppressor via its ability to suppress reactive oxygen species (ROS) and regulate hypoxia inducible factor 1α (HIF-1α). Primary mouse embryo fibroblasts (MEFs) or tumor cell lines expressing SirT3 short-hairpin RNA exhibit a greater potential to proliferate, and augmented HIF-1α protein stabilization and transcriptional activity in hypoxic conditions. SirT3 knockdown increases tumorigenesis in xenograft models, and this is abolished by giving mice the anti-oxidant N-acetyl cysteine. Moreover, overexpression of SirT3 inhibits stabilization of HIF-1α protein in hypoxia and attenuates increases in HIF-1α transcriptional activity. Critically, overexpression of SirT3 decreases tumorigenesis in xenografts, even when induction of the sirtuin occurs after tumor initiation. These data suggest that SirT3 acts to suppress the growth of tumors, at least in part through its ability to suppress ROS and HIF-1α.}, }
@article {pmid21354901, year = {2011}, author = {Mo, GW and Cai, SX and Zhao, HJ and Li, WJ and Tong, WC and Liu, LY}, title = {[Effect of toluene diisocyanate on reactive oxygen species production and permeability of human bronchial epithelial cells in vitro].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {31}, number = {2}, pages = {239-243}, pmid = {21354901}, issn = {1673-4254}, mesh = {Bronchi/*cytology ; Cell Line ; Cell Membrane Permeability/*drug effects ; Epithelial Cells/cytology/*metabolism ; Humans ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Serum Albumin/pharmacology ; Toluene 2,4-Diisocyanate/*pharmacology ; }, abstract = {OBJECTIVE: To investigate the effect of toluene diisocyanate (TDI) on the production of reactive oxygen species (ROS) and the permeability of human bronchial epithelial (HBE) cells.<br><br>METHODS: TDI-human serum albumin (TDI-HSA) conjugate was prepared using a modified Son's method. MTT assay was used to assess HBE cell viability after exposure to different concentrations of TDI-HSA. The level of intracellular ROS of HBE cells was detected by flow cytometry with an oxidation-sensitive fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA) uploading, and the permeability of cell monolayer was assessed by detecting the transepithelial electrical resistance (TEER).<br><br>RESULTS: The exposure to 120 &#xb5;g/ml TDI-HSA did not obviously affect the cell viability. Compared with the control group, the intracellular fluorescent intensity increased significantly in the cells exposed to 20, 60, and 100 &#xb5;g/ml TDI-HSA (P<0.05). The intracellular ROS production increased significantly after 100 &#xb5;g/ml TDI-HSA treatment (P<0.05), but the increment in ROS production was significantly suppressed by pretreatment of the cells with N-acetylcysteine (NAC) (P<0.05), which also enhanced the TEER decreased by TDI-HSA treatment (P<0.05).<br><br>CONCLUSIONS: TDI enhances the permeability of HBE cell monolayer partially through a ROS-mediated pathway, suggesting the importance of oxidative stress in TDI-induced pulmonary diseases.}, }
@article {pmid21351629, year = {2010}, author = {Chen, J and Zhong, C and Zeng, M and Liu, X and Deng, Y and Xiao, F}, title = {[Antagonistic effect of N-acetylcysteine on apoptosis of L-02 hepatocyte induced by Cr(VI) with or without caspase inhibitor].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {39}, number = {6}, pages = {678-681}, pmid = {21351629}, issn = {1000-8020}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Carcinogens, Environmental/toxicity ; Caspase Inhibitors/*pharmacology ; Caspases/metabolism ; Cell Line ; Chromium/chemistry/*toxicity ; DNA Damage/drug effects ; Fetus ; Hepatocytes/cytology/*drug effects ; Humans ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: To explore the antagonistic effect of N-acetylcysteine (NAC) on hexevalent chromium (Cr(VI))-induced apoptosis in L-02 hepatocytes with or without caspase inhibitors.<br><br>METHODS: L-02 hepatocytes were randomly divided into a control group, and Cr(VI), Z-VAD-fmk + Cr(VI), NAC + Cr(VI), Z-VAD-fmk + NAC + Cr (VI) four treatment groups, in which L-02 hepatocytes were cultured with Cr (VI) at the dose of 20 micromol/L for 6h. The rates of apoptosis in all groups were detected by flow cytometry (FC) after staining with propidium iodide (PI). The changes of mitochondrial membrane potential (deltapsim) and permeability transition pore (PTP) were determined by fluorescent spectrometer. The DNA damages in hepatocytes were observed by the single cell gel electrophoresis (SCGE).<br><br>RESULTS: Cr(VI) significantly induced apoptosis of L-02 hepatocytes at the dose of 20 micromol/L for 6 hours (P < 0.05). However, NAC significantly decreased the rates of apoptosis of L-02 hepatocytes and alleviated the damages to mitochondria and DNA caused by Cr(VI) in L-02 hepatocytes with or without caspase (P < 0.05). However, in comparition with the non caspase-inhibited group, the protective effects of NAC decreased in the caspase-inhibited group (P < 0.05).<br><br>CONCLUSION: NAC could protect the apoptosis of L-02 hepatocyte induced with Cr(VI) with or without caspase inhibitor, and caspase could not play a decisive role in this process.}, }
@article {pmid21349322, year = {2011}, author = {Yang, L and Li, W and Tian, Z and Zhao, J and Wang, C}, title = {Mononaphthalimide spermidine conjugate induces cell proliferation inhibition and apoptosis in HeLa cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {4}, pages = {882-889}, doi = {10.1016/j.tiv.2011.02.009}, pmid = {21349322}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caspase 3/drug effects/metabolism ; Cell Cycle/drug effects ; Cell Line ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Fibroblasts/drug effects ; HeLa Cells ; Humans ; Lung/cytology ; Membrane Potential, Mitochondrial/drug effects ; Naphthalimides/chemistry/*pharmacology ; Oxidative Stress/drug effects ; Spermidine/chemistry/*pharmacology ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; }, abstract = {Developing polyamine-drug conjugates that are capable of specific entry to tumor cells is attractive in improving chemotherapeutic efficacy. Currently, the exact cytotoxic mechanism of these conjugates is not well known. Here, our research revealed the effect of a mononaphthalimide-spermidine (MNISpd) conjugate on the growth and survival of HeLa cells and possible mechanisms. In characterizing the mechanism of MNISpd cytotoxicity, inhibition of proliferation is observed in the 0.5-6 μM range and there is evidence of apoptosis at equal or greater than 6 μM, but with less toxicity on HELF cell. The lower concentrations of MNISpd induced a cell cycle arrest correlated with enhanced p21 expression and decreased cdc2 but not Cdk2 expression. MNISpd-induced apoptosis was correlated with caspase-3 activation, decreased XIAP expression and a loss of mitochondrial membrane potential. Apoptosis but not cell cycle arrest was susceptible to N-acetyl-L-cysteine (NAC) treatment. It is proposed that MNISpd-induced apoptosis in HeLa cells is related to oxidative stress and that at lower exposure concentrations effects on cell proliferation predominate while at higher concentrations apoptosis develops.}, }
@article {pmid21345685, year = {2011}, author = {Hamada, N and Tanaka, A and Fujita, Y and Itoh, T and Ono, Y and Kitagawa, Y and Tomimori, N and Kiso, Y and Akao, Y and Nozawa, Y and Ito, M}, title = {Involvement of heme oxygenase-1 induction via Nrf2/ARE activation in protection against H2O2-induced PC12 cell death by a metabolite of sesamin contained in sesame seeds.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {19}, number = {6}, pages = {1959-1965}, doi = {10.1016/j.bmc.2011.01.059}, pmid = {21345685}, issn = {1464-3391}, mesh = {Animals ; *Apoptosis ; Dioxoles/chemistry/*metabolism/pharmacology ; Heme Oxygenase-1/chemistry/*metabolism ; Hydrogen Peroxide/*metabolism ; Lignans/chemistry/*metabolism/pharmacology ; NF-E2-Related Factor 2/*metabolism ; PC12 Cells ; Rats ; Seedlings/chemistry ; Sesamum/*chemistry ; }, abstract = {Induction of phase II antioxidant enzymes by activation of Nrf2/ARE (antioxidant response element) signaling has been considered as a promising strategy to combat with oxidative stress-related diseases. In the present study, we tested for potential effects of sesamin, a major lignan contained in sesame seeds, its stereoisomer episesamin, and their metabolites on Nrf2/ARE activation in rat pheochromocytoma PC12 cells. Luciferase reporter assays showed that primary metabolites of sesamin and episesamin, SC-1 and EC-1 were the most potent ARE activators among all tested compounds. SC-1 {(1R,2S,5R,6S)-6-(3,4-dihydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-3,7-dioxabicyclo-[3,3,0]octane} enhanced nuclear translocation of Nrf2 and up-regulated expression of phase II antioxidant enzymes including heme oxygenase-1 (HO-1). Treatment with SC-1 resulted in increased phosphorylation of p38 MAP kinase and transient increase in intracellular ROS levels. N-acetylcysteine (NAC) treatment abolished p38 phosphorylation as well as HO-1 induction caused by SC-1, indicating that ROS are upstream signals of p38 in Nrf2/ARE activation by SC-1. Furthermore, preconditioning with SC-1 attenuated H(2)O(2)-induced cell death in a dose-dependent manner. Finally, treatment with a HO-1 inhibitor, Zn-protoporphyrin (ZnPP), and overexpression of a dominant-negative mutant of Nrf2 diminished SC-1-mediated neuroprotection. Our results demonstrate that SC-1 is capable of protecting against oxidative stress-induced neuronal cell death in part through induction of HO-1 via Nrf2/ARE activation, suggesting its potential to reduce oxidative stress and ameliorate oxidative stress-related neurodegenerative diseases.}, }
@article {pmid21337541, year = {2011}, author = {Karlsson, H and Nava, S and Remberger, M and Hassan, Z and Hassan, M and Ringdén, O}, title = {N-acetyl-L-cysteine increases acute graft-versus-host disease and promotes T-cell-mediated immunity in vitro.}, journal = {European journal of immunology}, volume = {41}, number = {4}, pages = {1143-1153}, doi = {10.1002/eji.201040589}, pmid = {21337541}, issn = {1521-4141}, mesh = {Acetylcysteine/*adverse effects/immunology ; Acute Disease ; Apoptosis ; Cells, Cultured ; Glutathione/biosynthesis ; Graft vs Host Disease/chemically induced/*immunology ; Humans ; NF-kappa B/immunology ; Stem Cell Transplantation ; T-Lymphocytes/cytology/drug effects/*immunology ; }, abstract = {N-acetyl-L-cysteine (NAC) is a thiol antioxidant that stimulates glutathione synthesis in cells. Several studies indicate that NAC possesses immunomodulatory properties in vitro, but both inhibitory and activating effects on immunity have been reported. We observed that allogeneic stem cell transplantation (ASCT) patients who were randomized to receive NAC 100 mg/kg/day (n=73) had an increased prevalence of grade II-V acute graft-versus-host disease (GvHD) compared to patients who did not receive NAC (n=87), indicating that NAC has an immunostimulatory effect in vivo. When studying the effect of NAC on T-cell-mediated immunity in vitro, we found that moderate levels of NAC (0.4-3.2 mM) increased alloantigen-induced proliferation, expression of activation markers CD25 and CD71 on T cells, and production of IFN-γ and IL-10. In contrast, high concentrations of NAC (12.5-50 mM) were suppressive, which may explain previously conflicting data. NAC did not cause an increase in expression of CD86, CD80, and CD83 on mature DCs at any concentration, whereas high concentrations suppressed DC maturation. Furthermore, T cells exposed to suppressive concentrations of NAC in a primary stimulation were highly responsive when re-stimulated in the absence of NAC. To conclude, NAC appears to increase acute GvHD and has an immunostimulatory effect on alloantigen-specific T cells.}, }
@article {pmid21335974, year = {2011}, author = {Krzossok, S and Braun, C and Weiss, E and Hoeger, S and Schnuelle, P and Benck, U and Birck, R and Krämer, BK and Göttmann, U}, title = {Effects of N-acetylcysteine on renal hemodynamics in contrast media-induced nephropathy.}, journal = {Kidney &amp; blood pressure research}, volume = {34}, number = {2}, pages = {125-134}, doi = {10.1159/000324168}, pmid = {21335974}, issn = {1423-0143}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Contrast Media/*adverse effects ; Hemodynamics/drug effects ; Kidney/blood supply ; Kidney Diseases/chemically induced/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Renal Circulation/*drug effects ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) has been proposed to prevent radiocontrast nephropathy in high-risk patients.<br><br>METHODS: The effect of single-dose and prolonged administration of NAC before application of either the ionic, high-osmolar radiocontrast agent diatrizoate sodium (DTZ) or the nonionic, low-osmolar radiocontrast agent iohexol (IOH) in a rat model combining uninephrectomy, salt depletion, and administration of indomethacin was explored. Arterial blood pressure and total, cortical, and medullary blood flow were continuously recorded in anesthetized Sprague-Dawley rats.<br><br>RESULTS: NAC had no effect on renal hemodynamics in control rats. Both DTZ and IOH induced biphasic changes in renal blood flow and cortical renal blood flux and persistently reduced medullary blood flux. Neither single-dose nor prolonged administration of NAC prevented the hemodynamic changes following administration of DTZ or IOH, respectively. Acute prophylactic administration of NAC prevented increased urinary ET excretion after injection of IOH and, to a smaller degree, of DTZ. Both an ionic, high-osmolar (DTZ) and a nonionic, low-osmolar (IOH) radiocontrast agent induce marked changes in renal hemodynamics in salt-depleted rats treated with indomethacin.<br><br>CONCLUSIONS: Renal perfusion is not affected by NAC application in a model of experimental contrast nephropathy in rats. Other effects of NAC might thus account for the presumed renoprotective properties.}, }
@article {pmid21335520, year = {2011}, author = {Wu, W and Patel, KB and Booth, JL and Zhang, W and Metcalf, JP}, title = {Cigarette smoke extract suppresses the RIG-I-initiated innate immune response to influenza virus in the human lung.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {300}, number = {6}, pages = {L821-30}, pmid = {21335520}, issn = {1522-1504}, support = {U19 AI062629/AI/NIAID NIH HHS/United States ; 1-U19-AI-62629/AI/NIAID NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology ; Blotting, Western ; Cytokines/metabolism ; DEAD Box Protein 58 ; DEAD-box RNA Helicases/*antagonists &amp; inhibitors/metabolism ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunity, Innate/*drug effects ; Immunoenzyme Techniques ; Immunosuppression Therapy ; Influenza A Virus, H1N1 Subtype/*immunology ; Influenza, Human/*metabolism ; Interferon-beta/metabolism ; L-Lactate Dehydrogenase/metabolism ; Lung/*virology ; RNA, Messenger/genetics ; Receptors, Immunologic ; Reverse Transcriptase Polymerase Chain Reaction ; Smoking/*adverse effects ; }, abstract = {Cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD) and predisposes subjects to severe respiratory tract infections. Epidemiological studies have shown that cigarette smokers are seven times more likely to contract influenza infection than nonsmokers. The mechanisms underlying this increased susceptibility are poorly characterized. Retinoic acid-inducible gene (RIG)-I is believed to play an important role in the recognition of, and response to, influenza virus and other RNA viruses. Our study focused on how cigarette smoke extract (CSE) alters the influenza-induced proinflammatory response and suppresses host antiviral activity in the human lung using a unique lung organ culture model. We first determined that treatment with 2-20% CSE did not induce cytotoxicity as assessed by LDH release. However, CSE treatment inhibited influenza-induced IFN-inducible protein 10 protein and mRNA expression. Induction of the major antiviral cytokine IFN-β mRNA was also decreased by CSE. CSE also blunted viral-mediated RIG-I mRNA and protein expression. Inhibition of viral-mediated RIG-I induction by CSE was prevented by the antioxidants N-acetyl-cysteine and glutathione. These findings show that CSE suppresses antiviral and innate immune responses in influenza virus-infected human lungs through oxidative inhibition of viral-mediated induction of the pattern recognition receptor RIG-I. This immunosuppressive effect of CSE may play a role in the enhanced susceptibility of smokers to serious influenza infection in the lung.}, }
@article {pmid21333994, year = {2011}, author = {Buttari, B and Profumo, E and Di Cristofano, C and Pietraforte, D and Lionetti, V and Capoano, R and Salvati, B and Businaro, R and Di Giammarco, G and Riganò, R}, title = {Haemoglobin triggers chemotaxis of human monocyte-derived dendritic cells: possible role in atherosclerotic lesion instability.}, journal = {Atherosclerosis}, volume = {215}, number = {2}, pages = {316-322}, doi = {10.1016/j.atherosclerosis.2010.12.032}, pmid = {21333994}, issn = {1879-1484}, mesh = {Actins/metabolism ; Antigens, CD/immunology ; Antigens, Differentiation, Myelomonocytic/immunology ; Cell Adhesion ; Chemotaxis, Leukocyte/*drug effects ; Dendritic Cells/*immunology ; Endothelial Cells ; Extracellular Signal-Regulated MAP Kinases/physiology ; Hemoglobins/metabolism/*pharmacology ; Humans ; Monocytes/cytology ; Plaque, Atherosclerotic/blood/physiopathology ; Receptors, Cell Surface/immunology ; Signal Transduction ; Transendothelial and Transepithelial Migration/*drug effects ; p38 Mitogen-Activated Protein Kinases/physiology ; }, abstract = {OBJECTIVE: Mechanisms that drive innate immune cell recruitment into atherosclerotic lesions are still not well defined. We tested the role of haemoglobin (Hb) to promote chemotaxis, adhesion to endothelial cells and transendothelial migration of human monocytes and monocyte-derived immature dendritic cells (iDCs) and its possible role in atherogenic cell recruitment.<br><br>METHODS AND RESULTS: We demonstrated that Hb triggers chemotaxis, adhesion to endothelial cells and transendothelial migration of monocytes and monocyte-derived iDCs. Innate immune cell chemotaxis significantly increased in the presence of Hb in a dose-dependent manner involving extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) activation and actin remodeling. The pre-treatment of cells with pre-titrated concentration of the anti-CD163 blocking antibody reduced the Hb-induced cell migration, thus suggesting the involvement of CD163 receptor. Conversely, N-acetyl cysteine and soluble Hb-scavenger protein haptoglobin (Hp) inhibited the Hb-induced iDC migration. Finally, spontaneous iDC migration significantly increased in the presence of serum of patients with haemorrhagic complicated plaques and partially decreased in the presence of Hp.<br><br>CONCLUSION: Hb by interacting with CD163 on monocytes and iDCs might induce cell recruitment and activation within vascular wall, thus contributing to the complex cross talk of chemotactic signals that mediate atherosclerotic lesions instability.}, }
@article {pmid21325823, year = {2011}, author = {Li, M and Liu, J and Han, C and Wang, B and Pang, X and Mao, J}, title = {Angiotensin II induces the expression of c-reactive protein via MAPK-dependent signal pathway in U937 macrophages.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {27}, number = {1}, pages = {63-70}, doi = {10.1159/000325206}, pmid = {21325823}, issn = {1421-9778}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/*pharmacology ; Antihypertensive Agents/pharmacology ; C-Reactive Protein/genetics/*metabolism ; Flavonoids/pharmacology ; Humans ; Imidazoles/pharmacology ; Losartan/pharmacology ; *MAP Kinase Signaling System ; Macrophages/*metabolism ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Phosphorylation ; Proline/analogs &amp; derivatives/pharmacology ; Pyridines/pharmacology ; Thiocarbamates/pharmacology ; U937 Cells ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Atherosclerosis is an inflammatory disease in the vessel wall. As an inflammatory molecule, C-reactive protein (CRP) participates in all stages of atherosclerotic process. Although angiotensin II (Ang II) can stimulate the vascular cells to produce CRP, it is unknown whether Ang II induces CRP expression in macrophages. The present study was to observe effect of Ang II on CRP production and the related signal pathway in U937 macrophages so as to provide more evidence for the proinflammatory action of Ang II. The results showed that Ang II significantly increased mRNA and protein expression of CRP in U937 macrophages in time- and concentration-dependent manners. AT(1) receptor blocker losartan blocked Ang II -induced CRP expression in mRNA and protein levels in U937 macrophages. Losartan and complex II inhibitor TIFA decreased Ang II -stimulated reactive oxygen species (ROS) generation, and antioxidant NAC completely abolished Ang II -induced CRP expression in U937 macrophages. The further study indicated that losartan, NAC, MEK1/2 inhibitor PD98059, p38MAPK inhibitor SB203580 obviously inhibited ERK1/2 and p38MAPK phosphorylation, and PD98059, SB203580 and NF-κB inhibitor PDTC reduced Ang II -induced mRNA and protein expression of CRP in U937 macrophages. These demonstrate that Ang II is capable of inducing CRP generation in macrophages via AT(1)-ROS-ERK1/2/p38MAPK-NF-κB signal pathway, which contributes to better understanding of the proinflammatory and proatherosclerotic actions of Ang II.}, }
@article {pmid21325641, year = {2011}, author = {Sigala, I and Zacharatos, P and Toumpanakis, D and Michailidou, T and Noussia, O and Theocharis, S and Roussos, C and Papapetropoulos, A and Vassilakopoulos, T}, title = {MAPKs and NF-κB differentially regulate cytokine expression in the diaphragm in response to resistive breathing: the role of oxidative stress.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {300}, number = {5}, pages = {R1152-62}, doi = {10.1152/ajpregu.00376.2010}, pmid = {21325641}, issn = {1522-1490}, mesh = {*Airway Resistance ; Animals ; Antioxidants/pharmacology ; Blood Gas Analysis ; Cytokines/*metabolism ; Diaphragm/drug effects/*enzymology/immunology ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/*metabolism ; *Inhalation ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; *Oxidative Stress/drug effects ; Phosphorylation ; Pressure ; Protein Kinase Inhibitors/pharmacology ; Rats ; Rats, Wistar ; Time Factors ; Up-Regulation ; *Work of Breathing ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-κB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-α, IL-10, IL-2, IL-1β) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-κB. Inhibition of NF-κB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-κB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-κB/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-κB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-κB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm.}, }
@article {pmid21311702, year = {2011}, author = {Sansone, RA and Sansone, LA}, title = {Getting a Knack for NAC: N-Acetyl-Cysteine.}, journal = {Innovations in clinical neuroscience}, volume = {8}, number = {1}, pages = {10-14}, pmid = {21311702}, issn = {2158-8341}, abstract = {N-acetyl-cysteine, N-acetylcysteine, N-acetyl cysteine, and N-acetyl-L-cysteine are all designations for the same compound, which is abbreviated as NAC. NAC is a precursor to the amino acid cysteine, which ultimately plays two key metabolic roles. Through its metabolic contribution to glutathione production, cysteine participates in the general antioxidant activities of the body. Through its role as a modulator of the glutamatergic system, cysteine influences the reward-reinforcement pathway. Because of these functions, NAC may exert a therapeutic effect on psychiatric disorders allegedly related to oxidative stress (e.g., schizophrenia, bipolar disorder) as well as psychiatric syndromes characterized by impulsive/compulsive symptoms (e.g., trichotillomania, pathological nail biting, gambling, substance misuse). While the dosages, pharmacological strategies (monotherapy versus augmentation), and long-term risks are not fully evident, NAC appears to be a promising, relatively low-risk intervention. If so, NAC might be an ideal treatment strategy for a variety of psychiatric conditions in both psychiatric and primary care settings.}, }
@article {pmid21311680, year = {2010}, author = {Kim, KC and Lee, C}, title = {Curcumin Induces Downregulation of E2F4 Expression and Apoptotic Cell Death in HCT116 Human Colon Cancer Cells; Involvement of Reactive Oxygen Species.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {14}, number = {6}, pages = {391-397}, pmid = {21311680}, issn = {2093-3827}, abstract = {E2F transcription factors and their target genes have been known to play an important role in cell growth control. We found that curcumin, a polyphenolic phytochemical isolated from the plant Curcuma longa, markedly suppressed E2F4 expression in HCT116 colon cancer cells. Hydrogen peroxide was also found to decrease E2F4 protein level, indicating the involvement of reactive oxygen species (ROS) in curucmin-induced downregulation of E2F4 expression. Involvement of ROS in E2F4 downregulation in response to curcumin was confirmed by the result that pretreatment of cells with N-acetylcystein (NAC) before exposure of curcumin almost completely blocked the reduction of E2F4 expression at the protein as well as mRNA level. Anti-proliferative effect of curcumin was also suppressed by NAC which is consistent to previous reports showing curcumin-superoxide production and induction of poly (ADP-ribose) polymerase (PARP) cleavage as well as apoptosis. Expression of several genes, cyclin A, p21, and p27, which has been shown to be regulated in E2F4-dependent manner and involved in the cell cycle progression was also affected by curcumin. Moreover, decreased (cyclin A) and increased (p21 and p27) expression of these E2F4 downstream genes by curcumin was restored by pretreatment of cells with NAC and E2F4 overexpression which is induced by doxycycline. In addition, E2F4 overexpression was observed to partially ameliorate curcumin-induced growth inhibition by cell viability assay. Taken together, we found curcumin-induced ROS down-regulation of E2F4 expression and modulation of E2F4 target genes which finally lead to the apoptotic cell death in HCT116 colon cancer cells, suggesting that E2F4 appears to be a novel determinant of curcumin-induced cytotoxicity.}, }
@article {pmid21306579, year = {2011}, author = {Volpi, G and Facchinetti, F and Moretto, N and Civelli, M and Patacchini, R}, title = {Cigarette smoke and α,β-unsaturated aldehydes elicit VEGF release through the p38 MAPK pathway in human airway smooth muscle cells and lung fibroblasts.}, journal = {British journal of pharmacology}, volume = {163}, number = {3}, pages = {649-661}, pmid = {21306579}, issn = {1476-5381}, mesh = {Acetylcysteine/pharmacology ; Acrolein/*pharmacology ; Aldehydes/*pharmacology ; Bronchi/cytology/drug effects/metabolism ; Calcium Channels ; Cells, Cultured ; Complex Mixtures/pharmacology ; Fibroblasts/*drug effects/metabolism ; Humans ; Lung/cytology/*drug effects/metabolism ; Myocytes, Smooth Muscle/*drug effects/metabolism ; Nerve Tissue Proteins/antagonists &amp; inhibitors ; Nicotinic Antagonists/pharmacology ; Phosphorylation ; RNA, Messenger/metabolism ; Smoke/*adverse effects ; TRPA1 Cation Channel ; *Nicotiana ; Transient Receptor Potential Channels/antagonists &amp; inhibitors ; Vascular Endothelial Growth Factor A/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Vascular endothelial growth factor (VEGF) is an angiogenic factor known to be elevated in the sputum of asymptomatic smokers as well as smokers with bronchitis type of chronic obstructive pulmonary disease. The aim of this study was to investigate whether acute exposure to cigarette smoke extract altered VEGF production in lung parenchymal cells.<br><br>EXPERIMENTAL APPROACH: We exposed human airway smooth muscle cells (ASMC), normal human lung fibroblasts (NHLF) and small airways epithelial cells (SAEC) to aqueous cigarette smoke extract (CSE) in order to investigate the effect of cigarette smoke on VEGF expression and release.<br><br>KEY RESULTS: Vascular endothelial growth factor release was elevated by sub-toxic concentrations of CSE in both ASMC and NHLF, but not in SAEC. CSE-evoked VEGF release was mimicked by its component acrolein at concentrations (10-100 &#xb5;M) found in CSE, and prevented by the antioxidant and &#x3b1;,&#x3b2;-unsaturated aldehyde scavenger, N-acetylcysteine (NAC). Both CSE and acrolein (30 &#xb5;M) induced VEGF mRNA expression in ASMC cultures, suggesting an effect at transcriptional level. Crotonaldehyde and 4-hydroxy-2-nonenal, an endogenous &#x3b1;,&#x3b2;-unsaturated aldehyde, stimulated VEGF release, as did H(2)O(2). CSE-evoked VEGF release was accompanied by rapid and lasting phosphorylation of p38 MAPK (mitogen-activated protein kinase), which was abolished by NAC and mimicked by acrolein. Both CSE- and acrolein-evoked VEGF release were blocked by selective inhibition of p38 MAPK signalling.<br><br>CONCLUSIONS AND IMPLICATIONS: &#x3b1;,&#x3b2;-Unsaturated aldehydes and possibly reactive oxygen species contained in cigarette smoke stimulate VEGF expression and release from pulmonary cells through p38 MAPK signalling.}, }
@article {pmid21303920, year = {2011}, author = {Reichel, CM and Moussawi, K and Do, PH and Kalivas, PW and See, RE}, title = {Chronic N-acetylcysteine during abstinence or extinction after cocaine self-administration produces enduring reductions in drug seeking.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {337}, number = {2}, pages = {487-493}, pmid = {21303920}, issn = {1521-0103}, support = {T32 DA007288/DA/NIDA NIH HHS/United States ; P50-DA015369/DA/NIDA NIH HHS/United States ; P50 DA015369/DA/NIDA NIH HHS/United States ; F32-DA029344/DA/NIDA NIH HHS/United States ; T32-DA007288/DA/NIDA NIH HHS/United States ; F32 DA029344/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Cocaine/administration &amp; dosage/*pharmacology ; Cocaine-Related Disorders/*psychology ; Cues ; Dose-Response Relationship, Drug ; Drug-Seeking Behavior/*drug effects ; Extinction, Psychological/*drug effects ; Glutamic Acid/metabolism ; Homeostasis/drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; Recurrence ; Self Administration ; Substance Withdrawal Syndrome/*psychology ; }, abstract = {The cysteine prodrug N-acetylcysteine (NAC) has been shown to reduce reinstatement of cocaine seeking by normalization of glutamatergic tone. However, enduring inhibition of cocaine seeking produced by NAC has not been explored under different withdrawal conditions. Thus, the present study determined whether chronic NAC administered during daily extinction training or daily abstinence after withdrawal from cocaine self-administration would reduce cocaine seeking. Rats self-administered intravenous cocaine during daily 2-h sessions for 12 days, followed by daily extinction or abstinence sessions. During this period, rats received daily injections of saline or NAC (60 or 100 mg/kg). Subsequently, rats were tested for cocaine seeking via conditioned cue, cue + cocaine-primed, and context-induced relapse. Chronic NAC administration blunted cocaine seeking under multiple experimental protocols. Specifically, NAC attenuated responding during cue and cue + cocaine-primed reinstatement tests after extinction and context, cue, and cue + cocaine relapse tests after abstinence. Protection from relapse by NAC persisted well after treatment was discontinued, particularly when the high dose was combined with extinction trials. The finding that NAC reduced cocaine seeking after drug treatment was discontinued has important implications for the development of effective antirelapse medications. These results support recent preclinical and clinical findings that NAC may serve as an effective treatment for inhibiting relapse in cocaine addicts.}, }
@article {pmid21303669, year = {2011}, author = {Antonio, AM and Gillespie, RA and Druse-Manteuffel, MJ}, title = {Effects of lipoic acid on antiapoptotic genes in control and ethanol-treated fetal rhombencephalic neurons.}, journal = {Brain research}, volume = {1383}, number = {}, pages = {13-21}, pmid = {21303669}, issn = {1872-6240}, support = {F31 AA017343/AA/NIAAA NIH HHS/United States ; 5F31AA017343/AA/NIAAA NIH HHS/United States ; R01 AA003490/AA/NIAAA NIH HHS/United States ; T32 AA013527/AA/NIAAA NIH HHS/United States ; T32 AA13527/AA/NIAAA NIH HHS/United States ; R01 AA003490-26/AA/NIAAA NIH HHS/United States ; }, mesh = {Alcohols/toxicity ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/genetics ; Apoptosis Regulatory Proteins/*drug effects/genetics ; Ethanol/toxicity ; Fetus ; Gene Expression/drug effects ; Neurons/*drug effects ; Rats ; Rats, Sprague-Dawley ; Rhombencephalon/*drug effects ; Thioctic Acid/*pharmacology ; }, abstract = {This laboratory showed that ethanol augments apoptosis in fetal rhombencephalic neurons and co-treatment with alpha-lipoic acid (LA) or one of several other antioxidants prevents ethanol-associated apoptosis. Because ethanol increases oxidative stress, which causes apoptosis, it is likely that some of the neuroprotective effects of LA and other antioxidants involve classical antioxidant actions. Considering the reported link of LA with pro-survival cell signaling, it is also possible that LA's neuroprotective effects involve additional mechanisms. The present study investigated the effects of LA on ethanol-treated fetal rhombencephalic neurons with regard to oxidative stress and up-regulation of the pro-survival genes Xiap and Bcl-2. We included parallel gene expression studies with N-acetyl cysteine (NAC) to determine whether LA's effects on Xiap and Bcl-2 were shared by other antioxidants. We also used enzyme inhibitors to determine which signaling pathway(s) might be involved with the effects of LA. The results of this investigation showed that LA treatment of ethanol-treated neurons exerted several pro-survival effects. LA blocked two pro-apoptotic changes, i.e., the ethanol-associated rise in ROS and caspase-3. LA also up-regulated the expression genes that encode the anti-apoptotic proteins Bcl-2 and Xiap by a mechanism that involves NF-κB. NAC also up-regulated Bcl-2 and Xiap. Thus, the neuroprotective effects of LA and NAC could involve up-regulation of pro-survival genes as well as their classical antioxidant actions.}, }
@article {pmid21299245, year = {2011}, author = {Lee, E and Seo, EY and Kwon, Y and Ha, H}, title = {Rapid and reliable measurement for evaluating directly the reactivity of N-acetylcysteine with glucose degradation products in peritoneal dialysis fluids.}, journal = {Analytical chemistry}, volume = {83}, number = {5}, pages = {1518-1522}, doi = {10.1021/ac200046y}, pmid = {21299245}, issn = {1520-6882}, mesh = {Acetylcysteine/*chemistry ; Chromatography, High Pressure Liquid ; Glucose/*chemistry ; Hydrogen-Ion Concentration ; *Peritoneal Dialysis ; Reproducibility of Results ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {In this report, we analyzed the reactivity of N-acetyl-L-cysteine (NAC) with glucose degradation products (GDPs) and the stability of NAC in peritoneal dialysis fluids (PDFs) using RP-HPLC and LC-ESI-TOF-MS. NAC reduced the amount of 3,4-dideoxyglucosone-3-ene (3,4-DGE), most toxic among GDPs in PDFs by forming NAC-DGE conjugate under nonenzymatic conditions. NAC was retained as a reduced monomer form in the high-glucose compartment of dual-chambered neutral-pH type PDF, whereas it easily formed a homodimer in an incubation-time-dependent manner in other solutions. The present investigation suggests that NAC can be employed as an adjuvant added into the high-glucose compartment of neutral-pH type PDFs (N-PDF) to reduce GDP-mediated peritoneal membrane failure in patients on long-term peritoneal dialysis (PD) treatment.}, }
@article {pmid21298199, year = {2011}, author = {Sarr, M and Sar, FB and Gueye, L and Kane, MO and Wele, A and Diallo, AS and Schini-Kerth, V and Muller, B}, title = {The vascular endothelium masks the persistent inhibition of rat thoracic arterial tone induced by S-nitrosoglutathione.}, journal = {Cardiovascular journal of Africa}, volume = {22}, number = {1}, pages = {7-13}, pmid = {21298199}, issn = {1995-1892}, mesh = {Animals ; Aorta, Thoracic/*drug effects/metabolism ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Guanylate Cyclase/antagonists &amp; inhibitors/metabolism ; In Vitro Techniques ; Male ; Microscopy, Confocal ; Nitric Oxide/*metabolism ; Nitric Oxide Donors/*pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors/metabolism ; Potassium Channel Blockers/pharmacology ; Potassium Channels/drug effects/metabolism ; Rats ; Rats, Wistar ; S-Nitrosoglutathione/*pharmacology ; Sulfhydryl Compounds/metabolism ; Vasoconstriction/*drug effects ; Vasoconstrictor Agents/pharmacology ; Vasodilation/*drug effects ; Vasodilator Agents/pharmacology ; }, abstract = {AIM: In endothelium-denuded arteries, the nitric oxide (NO) donor S-nitrosoglutathione (GSNO) induced a persistent hypo-reactivity to vasoconstrictors, and low-molecular weight thiols such as N-acetyl cysteine (NAC) produced a relaxant effect. These effects were attributed to the formation of vascular NO stores. In arteries with a functional endothelium, such long-lasting effects on arterial tone have not been well characterised. In this study, we proposed to examine the possibility of storing exogenous NO when the vascular endothelium is still able to produce its own NO.<br><br>METHODS: For this purpose, changes in isometric tension of isolated arteries were assessed in organ chambers, and nitrosothiol formation was characterised by confocal microscopy.<br><br>RESULTS: In rat aortic rings with endothelium pre-exposed to GSNO, the contractile response to norepinephrine (NE) was not attenuated in comparison with control rings, but NAC induced a relaxant effect. However, an attenuation of the response to NE was observed in GSNO-exposed, intact aortic rings after inhibition of NO synthase by N(&#x3c9;)-nitro-L-arginine methylester (L-AME) or in GSNO-denuded rings. The relaxing effects of NAC were due to the mobilisation of NO from nitrosothiols after nitrosylation of protein SH residues. Moreover, the hypo-reactivity to NE and the relaxant effect of NAC were abolished by 1H-[1,2,4] oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase, and partially by the K+-sensitive channel inhibitor tetra-ethyl-ammonium (TEA).<br><br>CONCLUSION: These data show that endothelium-derived NO masked the persistent effect of GSNO in rat thoracic aorta. However, the ability of GSNO to form releasable NO stores without altering the vascular tone can be particularly useful in preventing endothelial dysfunction in which NO formation decreases.}, }
@article {pmid21296133, year = {2011}, author = {Lee, JE and Kang, JS and Ki, YW and Lee, SH and Lee, SJ and Lee, KS and Koh, HC}, title = {Akt/GSK3β signaling is involved in fipronil-induced apoptotic cell death of human neuroblastoma SH-SY5Y cells.}, journal = {Toxicology letters}, volume = {202}, number = {2}, pages = {133-141}, doi = {10.1016/j.toxlet.2011.01.030}, pmid = {21296133}, issn = {1879-3169}, mesh = {Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors/*metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Insecticides/*pharmacology ; Microscopy, Fluorescence ; Neurons/cytology/*drug effects/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrazoles/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Fipronil (FPN) is a phenylpyrazole insecticide acted on insect gamma-aminobutyric acid (GABA) receptors. Although action of FPN is restricted on insect neuronal or muscular transmitter system, a few studies have assessed the effects of this neurotoxicant on neuronal cell death. To determine the mechanisms underlying FPN-induced neuronal cell death, we investigated whether reactive oxygen species (ROS) plays a role in FPN-induced apoptosis, using an in vitro model of human dopaminergic SH-SY5Y cells. FPN was cytotoxic to these cells and its cytotoxicity showed a concentration-dependent manner. Additionally, FPN treatment significantly decreased the tyrosine hydroxylase (TH) expression without change of glutamic acid decarboxylase 65 (GAD65) expression. FPN-induced dopaminergic cell death involved in increase of ROS generation since pretreatment with N-acetyl cysteine (NAC), an anti-oxidant, reduced cell death. After FPN treatment, dopamine (DA) levels decreased significantly in both cell and culture media, and oxidative effects of DA were blocked by NAC pretreatment. We showed that cell death in response to FPN was due to apoptosis since FPN increased cytochrome c release into the cytosol and activated caspase-3. It also led to nuclear accumulation of p53 and reduced the level of Bcl-2 protein in a concentration-dependent manner. Additionally, FPN altered the level of Akt/glycogen synthase kinase-3 (GSK3β) phosphorylation. FPN reduced the Akt phosphorylation on Ser473, and in parallel with the inactivation of Akt, phosphorylation of GSK3β on Ser9 which inactivates GSK3β, decreased after treatment with FPN. Furthermore, inhibition of the GSK3β signal protected the cell against FPN-induced cell death. These results suggest that regulation of GSK3β activity may control the apoptosis induced by FPN-induced oxidative stress associated with neuronal cell death.}, }
@article {pmid21293542, year = {2010}, author = {Hruda, J and Sramek, V and Leverve, X}, title = {High glucose increases susceptibility to oxidative-stress-induced apoptosis and DNA damage in K-562 cells.}, journal = {Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia}, volume = {154}, number = {4}, pages = {315-320}, doi = {10.5507/bp.2010.047}, pmid = {21293542}, issn = {1804-7521}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; *DNA Damage ; Dose-Response Relationship, Drug ; Drug Synergism ; Fructose/pharmacology ; Glucose/*administration &amp; dosage ; Glutamine/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; K562 Cells/*drug effects/*physiology ; *Oxidative Stress ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {AIM: The study was carried out to evaluate the effect of several substrates on oxidative stress induced apoptosis and in K-562 cells.<br><br>METHODS: Glucose at 5, 11 and 30 mM concentrations was tested, as well as 5 mM glutamine and 5 mM fructose. The cells were exposed to tert-butylhydroperoxide (tBH) and apoptotic cells were evaluated by flow cytometry with FITC-Annexin V and propidium iodide. The effect of glucose concentration on DNA damage was evaluated using hydrogen peroxide and electrophoretic "DNA comets" assay at 5 mM and 30 mM glucose concentrations.<br><br>RESULTS: The exposure of cells to tBH resulted in increased number of apoptotic cells, and this effect was prevented by administration of an antioxidant - N-Acetyl cysteine. Rising concentrations of glucose added to the toxic effect of tBH; we also observed some toxic effect of fructose and no effect of glutamine. We found higher susceptibility to hydrogen peroxide induced DNA damage with 30 mM glucose concentration.<br><br>CONCLUSION: Hyperglycemia increases the cell's susceptibility to oxidative stress and it also amplifies oxidative DNA damage. Glutamine - when used as a sole energetic substrate - showed no protective effect against oxidative stress.}, }
@article {pmid21288506, year = {2011}, author = {Miyake, N and Skinbjerg, M and Easwaramoorthy, B and Kumar, D and Girgis, RR and Xu, X and Slifstein, M and Abi-Dargham, A}, title = {Imaging changes in glutamate transmission in vivo with the metabotropic glutamate receptor 5 tracer [11C] ABP688 and N-acetylcysteine challenge.}, journal = {Biological psychiatry}, volume = {69}, number = {9}, pages = {822-824}, doi = {10.1016/j.biopsych.2010.12.023}, pmid = {21288506}, issn = {1873-2402}, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain/diagnostic imaging/*metabolism ; Brain Mapping ; Carbon Radioisotopes ; Glutamic Acid/*metabolism ; Image Processing, Computer-Assisted ; Male ; Oximes/pharmacology ; Papio ; Pyridines/pharmacology ; Radionuclide Imaging ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/*metabolism ; Synaptic Transmission/*physiology ; Tissue Distribution ; }, abstract = {BACKGROUND: An imaging method to probe glutamate levels in vivo would allow the study of glutamate transmission in disease states and in response to therapeutic interventions. Here we demonstrate the feasibility of this approach for the first time using positron emission tomography and [(11)C] ABP688, a radiotracer for an allosteric site on the metabotropic glutamate receptor 5.<br><br>METHODS: We conducted two sets of experiments in anesthetized baboons: test and retest without pharmacologic challenge and in combination with N-acetylcysteine (NAC), a promoter of the cystine-glutamate antiporter that increases extrasynaptic glutamate release. The goal was to assess whether NAC-induced changes in [(11)C] ABP688 binding potential, &#x394;BP(ND), could be detected above the noise in the measurement.<br><br>RESULTS: Linear mixed modeling comparing &#x394;BP(ND) from test-retest to &#x394;BP(ND) from NAC challenge across all brain regions showed a highly significant effect of treatment [F(1,40) = 21.2, p < .001]. &#x394;BP(ND) was significantly different from zero following NAC [F(1,20) = 76.6, p < .001] but not after test-retest studies.<br><br>CONCLUSIONS: NAC induced decrease in [(11)C] ABP688 &#x394;BP(ND) may be the result of allosteric modulation, although other mechanisms may be at play. We outline steps needed to replicate and validate this method as a new tool to measure in vivo glutamate transmission.}, }
@article {pmid21284815, year = {2011}, author = {Oakley, E and Robinson, J and Deasy, C}, title = {Using 0.45% saline solution and a modified dosing regimen for infusing N-acetylcysteine in children with paracetamol poisoning.}, journal = {Emergency medicine Australasia : EMA}, volume = {23}, number = {1}, pages = {63-67}, doi = {10.1111/j.1742-6723.2010.01376.x}, pmid = {21284815}, issn = {1742-6723}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Child ; Combined Modality Therapy ; Drug Administration Schedule ; Emergency Treatment ; Female ; Glucose/administration &amp; dosage ; Home Infusion Therapy ; Humans ; Infusions, Intravenous/methods ; Infusions, Parenteral ; Male ; Medical Records ; Patient Admission ; Poisoning/therapy ; Retreatment ; Retrospective Studies ; Sodium/blood ; Sodium Chloride/*administration &amp; dosage ; }, abstract = {INTRODUCTION: N-acetylcysteine (NAC) administration is recommended to all patients judged to be at risk of developing hepatotoxicity following paracetamol overdose. However, it has been shown that standard i.v. dosing can cause symptomatic hyponatraemia in children. We describe a case series using 0.45% NaCl plus 5% dextrose for infusing i.v. NAC in children with paracetamol poisoning.<br><br>CASE SERIES: A retrospective review of medical records of patients treated with NAC using 0.45% saline plus 5% dextrose, and a novel two-stage dosing regimen between January 2003 and July 2006 were undertaken.<br><br>RESULTS: A total of 40 patients (20 male and 20 female) who received NAC in 0.45% sodium chloride (NaCl) with 5% dextrose were identified. Mean age was 9 years 6 months (95% CI 4 years 4 months to 15 years 1 month) and the range 3 months to 17 years. All patients had NAC infused in a two-stage infusion regimen (150 mg/kg bolus over 1 h followed by a continuous infusion of 10 mg/kg/h for 20 h). The serum sodium was measured in all 40 patients with a mean of 140 (range of 133 to 152 mmol/L). Repeat sodium was measured in 35 cases, with a mean of 140 mmol/L (range from 134 to 149 mmol/L).<br><br>CONCLUSION: These findings support the use of saline-containing solutions to administer NAC as an alternative to 5% dextrose, and suggest that a two-stage infusion regimen should be further investigated with prospective studies.}, }
@article {pmid21281712, year = {2011}, author = {Izigov, N and Farzam, N and Savion, N}, title = {S-allylmercapto-N-acetylcysteine up-regulates cellular glutathione and protects vascular endothelial cells from oxidative stress.}, journal = {Free radical biology &amp; medicine}, volume = {50}, number = {9}, pages = {1131-1139}, doi = {10.1016/j.freeradbiomed.2011.01.028}, pmid = {21281712}, issn = {1873-4596}, mesh = {Acetylcysteine/analogs &amp; derivatives/chemical synthesis/*pharmacology ; Animals ; Antioxidants/chemical synthesis/*pharmacology ; Aorta/cytology/metabolism ; Cattle ; Cells, Cultured ; Cysteine/metabolism ; *Cytoprotection ; Disulfides ; Endothelial Cells/cytology/drug effects/*metabolism ; Glutathione/*metabolism ; Metabolic Detoxication, Phase II ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidative Stress/drug effects ; Sulfinic Acids/chemistry ; Transcriptional Activation ; Up-Regulation ; tert-Butylhydroperoxide/toxicity ; }, abstract = {Oxidative stress and/or low cellular glutathione (GSH) levels are associated with the development and progression of numerous pathological conditions. Cells possess various antioxidant protection mechanisms, including GSH and phase II detoxifying enzymes. N-acetylcysteine (NAC) supplies cells with cysteine to increase GSH level but its efficacy is relatively low because of its limited tissue penetration. Allicin (diallyl thiosulfinate), a reactive sulfaorganic compound, increases cellular GSH and phase II detoxifying enzymes in vascular endothelial cells (EC). A novel compound was designed: S-allylmercapto-N-acetylcysteine (ASSNAC), a conjugate of S-allyl mercaptan (a component of allicin) and NAC. Both ASSNAC and NAC increased cellular GSH of ECs, reaching a maximum of up to four- and threefold increase after exposure for 24 or 6 h at a concentration of 0.2 or 1 mM, respectively. ASSNAC induced nuclear translocation of the activated transcription factor Nrf2 and expression of phase II detoxifying enzymes. EC exposure to tBuOOH resulted in 75% cytotoxicity, and pretreatment of cultures with 0.2 mM ASSNAC or 2mM NAC reduced cytotoxicity to 20 and 42%, respectively. In conclusion, ASSNAC is superior to NAC in protecting cells from oxidative stress because of its ability to up-regulate both GSH and the expression of phase II detoxifying enzymes.}, }
@article {pmid21281706, year = {2011}, author = {Song, Y and Shi, Y and Yu, H and Hu, Y and Wang, Y and Yang, K}, title = {p,p'-Dichlorodiphenoxydichloroethylene induced apoptosis of Sertoli cells through oxidative stress-mediated p38 MAPK and mitochondrial pathway.}, journal = {Toxicology letters}, volume = {202}, number = {1}, pages = {55-60}, doi = {10.1016/j.toxlet.2011.01.020}, pmid = {21281706}, issn = {1879-3169}, mesh = {Acetylcysteine/antagonists &amp; inhibitors/metabolism ; Animals ; Anthracenes/pharmacology ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cytochromes c/genetics/metabolism ; Dichlorodiphenyl Dichloroethylene/*toxicity ; Gene Expression/drug effects ; Imidazoles/pharmacology ; Insecticides/*toxicity ; Male ; Mitochondria/*metabolism ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Pyridines/pharmacology ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Sertoli Cells/*drug effects/metabolism ; bcl-2 Homologous Antagonist-Killer Protein/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {p,p'-DDE, the major metabolite of dichlorodiphenoxytrichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. However, the mechanism underlying its male reproductive toxicity remains limited. Our previous studies have demonstrated that p,p'-DDE could induce mitochondria-mediated apoptosis of cultured rat Sertoli cells. In the present study, we investigated mitogen-activated protein kinase pathways as well as other mitochondria-related molecules including Bax family members and cytochrome c. Results showed that p,p'-DDE could induce oxidative stress-mediated p38 and JNK phosphorylation. In addition, elevated mRNA levels of cytochrome c and ratios of bax/bcl-w and bak/bcl-w were induced by p,p'-DDE treatment, which could be inhibited by RNA synthesis inhibitor (actinomycin D). p,p'-DDE-induced apoptosis was blocked by NAC (N-acetyl-L-cystein) preincubation and attenuated by pretreatment with p38 inhibitor (SB202190) or actinomycin D, but not with JNK inhibitor (SP600125). All of the findings suggested that oxidative stress-mediated p38 MAPK pathway and the balance between pro- and anti-apoptotic bax-gene family might play critical roles in p,p'-DDE-induced apoptosis.}, }
@article {pmid21279477, year = {2011}, author = {Calabrò, P and Bianchi, R and Crisci, M and Caprile, M and Bigazzi, MC and Palmieri, R and Golia, E and De Vita, A and Romano, IJ and Limongelli, G and Russo, MG and Calabrò, R}, title = {Use and efficacy of saline hydration and N-acetyl cysteine to prevent contrast-induced nephropathy in low-risk populations undergoing coronary artery angiography.}, journal = {Internal and emergency medicine}, volume = {6}, number = {6}, pages = {503-507}, pmid = {21279477}, issn = {1970-9366}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Contrast Media/*adverse effects ; Coronary Angiography ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Italy ; Male ; Middle Aged ; Retrospective Studies ; Sodium Chloride/administration &amp; dosage/*therapeutic use ; Treatment Outcome ; }, abstract = {Contrast-induced nephropathy (CIN) is most commonly defined as acute renal failure occurring within 48-72 h of exposure to an intravascular radiographic contrast medium that is not attributable to other causes. In the international literature, a 25% increase in serum creatinine levels or an increase in absolute values of 0.5 mg/dl from baseline has been suggested to define CIN. The reported incidence of CIN varies widely, ranging from 2 to 50%. This variability results from differences in the presence or absence of risk factors. With a retrospective analysis we evaluated the use of saline hydration plus N-acetyl cysteine (NAC) to prevent CIN in a low-risk population of patients undergoing coronary artery angiography compared with an historic low risk group not treated. From January 2009 to December 2009, 152 consecutive patients who underwent coronary artery angiography with a low osmolarity contrast agent were enrolled in our study, and compared with an historic control group consisting of 172 low-risk patients. Nephrotoxic drugs such as diuretics, ACE-I and ARBs were stopped at least 24 h before the procedure. Inclusion criteria to define low-risk population were the absence of: diabetes, age >65 years, or baseline creatinine >1.4 mg/dl. We have treated group A (152 patients, 47.3%) with a saline hydration (1 ml/kg/h) plus N-acetyl cysteine 600 mg 12 h before and 12 h after the procedure; group B (group control of 170 patients, 52.7%) were not treated. The overall incidence of CIN was 7.1% (23 patients). In particular, the incidence of CIN was 2.6% (4 patients) in the group A and 11.2% (19 patients) in the group B (p = 0.002). In the multivariate analysis, including risk factor such as age, hypertension, hypercholesterolemia, current smoking habit baseline creatinine level, contrast index and hydration, the last variable was the only one inversely correlated independently with the incidence of CIN (p = 0.001). In conclusion, intravenous hydration with saline and NAC is an effective and low cost tool in preventing CIN in patients undergoing coronary artery angiography, and, according to the current guidelines, should be used in all high-risk patients for CIN. Our results show that even in patients at low risk, hydration with saline 0.9% plus NAC is useful and significantly reduces the incidence of CIN.}, }
@article {pmid21277933, year = {2011}, author = {Schreier, SM and Steinkellner, H and Jirovetz, L and Hermann, M and Exner, M and Gmeiner, BM and Kapiotis, S and Laggner, H}, title = {S-carbamoylation impairs the oxidant scavenging activity of cysteine: its possible impact on increased LDL modification in uraemia.}, journal = {Biochimie}, volume = {93}, number = {4}, pages = {772-777}, doi = {10.1016/j.biochi.2011.01.007}, pmid = {21277933}, issn = {1638-6183}, mesh = {Antioxidants/metabolism ; Benzothiazoles/metabolism ; Cholesterol, LDL/chemistry/*metabolism ; Cyanates/pharmacology ; Cysteine/*analogs &amp; derivatives/chemistry/*metabolism ; Free Radicals/*metabolism ; Glutathione/metabolism ; Humans ; Lipid Peroxidation ; Lipoproteins, LDL/metabolism ; Oxidative Stress/physiology ; Sulfhydryl Compounds/metabolism ; Sulfonic Acids/metabolism ; Uremia/*metabolism ; }, abstract = {Carbamoylation is the non-enzymatic reaction of cyanate with amino-, hydroxy- or thiol groups. In vivo, amino group modification (N-carbamoylation) resulting in altered function of proteins/amino acids has been observed in patients suffering from uraemia due to urea-derived cyanate. Uraemia has been linked to impaired antioxidant defense. As thiol-compounds like cysteine, N-acetyl cysteine and GSH have oxidant scavenging properties one may speculate that thiol-group carbamoylation (S-carbamoylation) may impair their protective activity. Here we report on the effect of S-carbamoylation on the ABTS free radical and HOCl scavenging property of cysteine as well on its ability to protect LDL from atherogenic modification induced by AAPH generated peroxylradicals or HOCl. The results show that S-carbamoylation impaired the ABTS free radical and HOCl scavenging property of the thiol-compounds tested. The ability of the thiols to protect LDL from lipid oxidation and apolipoprotein modification was strongly diminished by S-carbamoylation. The data indicate that S-carbamoylation could impair the free radical and HOCl scavenging of thiol-amino acids reducing their protective property against LDL atherogenic modification by these oxidant species. As S-carbamoylation is most effective at pH 7 to 5 in vivo thiol-carbamoylation may especially occur at sites of acidic extracellular pH as in hypoxic/inflammatory macrophage rich areas like the atherosclerotic plaque where increased LDL oxidation has been found and may contribute to the higher oxidative stress in uraemia.}, }
@article {pmid21271996, year = {2011}, author = {Di Lisa, F and Kaludercic, N and Paolocci, N}, title = {β2-Adrenoceptors, NADPH oxidase, ROS and p38 MAPK: another 'radical' road to heart failure?.}, journal = {British journal of pharmacology}, volume = {162}, number = {5}, pages = {1009-1011}, pmid = {21271996}, issn = {1476-5381}, mesh = {Animals ; Disease Models, Animal ; Heart Failure/*etiology/*metabolism ; Humans ; Mice ; Mice, Transgenic ; NADPH Oxidases/*metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Receptors, Adrenergic, beta-2/genetics/*metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Persistent activation of the cardiac β-adrenergic system may contribute to the pathogenesis of congestive heart failure. Both β1- and β2-adrenoceptors are known to mediate these noxious effects, yet the β1-adrenoceptor-PKA axis has received greater attention with less information available on β2-adrenoceptor driven pathways. In the present issue, Xu and colleagues provide new evidence, showing that β2-adrenoceptor over-expression leads to increased reactive oxygen species (ROS) emission, mainly caused by up-regulation of reduced nicotinamide adenine dinucleotide phosphate oxidase (Nox) 2 and 4. Increase in ROS levels is accompanied by p38 mitogen-activated protein kinase activation, fibrosis, apoptosis and cardiac dysfunction. Both Nox inhibition and administration of the antioxidant N-acetyl cysteine prevent these adverse effects. Interestingly, antioxidant treatment also prevents the increase in Nox expression, suggesting that β2-adrenoceptor stimulation triggers a vicious cycle eventually amplified by both Nox isoforms. The possible existence of a circuitry to enhance ROS signalling and detrimental consequences on myocardial remodelling are also discussed, in light of the recent description of intracellular localization of Nox4.}, }
@article {pmid21271215, year = {2011}, author = {Huang, WW and Ko, SW and Tsai, HY and Chung, JG and Chiang, JH and Chen, KT and Chen, YC and Chen, HY and Chen, YF and Yang, JS}, title = {Cantharidin induces G2/M phase arrest and apoptosis in human colorectal cancer colo 205 cells through inhibition of CDK1 activity and caspase-dependent signaling pathways.}, journal = {International journal of oncology}, volume = {38}, number = {4}, pages = {1067-1073}, doi = {10.3892/ijo.2011.922}, pmid = {21271215}, issn = {1791-2423}, mesh = {Apoptosis/*drug effects ; CDC2 Protein Kinase/*antagonists &amp; inhibitors ; Cantharidin/*pharmacology ; Caspases/*metabolism ; Cell Cycle/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Colorectal Neoplasms ; Enzyme Activation/drug effects ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Phosphatidylserines/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {Cantharidin (CTD) is a traditional Chinese medicine and an effective component isolated from blister beetle, and it has been demonstrated to have anticancer, antibiotic, antivirus activities and immune-regulated functions. It has been reported that CTD induces cell cycle arrest and apoptosis in many cancer cell types. However, there are no reports showing that CTD would induce cell cycle arrest and apoptosis in human colorectal cancer colo 205 cells. In this study, we studied colo 205 cells which were treated with CTD and demonstrated its molecular mechanisms in apoptosis. CTD induced growth inhibition, G2/M phase arrest and apoptosis in colo 205 cells. The IC50 is 20.53 µM in CTD-treated colo 205 cells. DAPI/TUNEL double staining and Annexin V assays were used to confirm the apoptotic cell death in colo 205 cells after CTD exposure. CTD caused G2/M arrest, down-regulated CDK1 activity, decreased Cyclin A, Cyclin B, CDK1 and increased CHK1 and p21 protein levels. Colorimetric assays also indicated that CTD triggered activities of casapse-8, -9 and -3 in colo 205 cells. Moreover, CTD increased ROS production and decreased the level of mitochondrial membrane potential (ΔΨm) in colo 205 cells. Consequently, CTD-induced growth inhibition was significantly attenuated by N-acetylcysteine (NAC, a scavenger). CTD stimulated the protein levels of Fas/CD95, the caspase-3 active form, cytochrome c and Bax, but suppressed the protein levels of pro-caspase-8, pro-caspase-9 and Bcl-2, determined by Western blot analysis. Based on our observations, we suggest that CTD is able to induce G2/M phase arrest and apoptosis in colo 205 cells through inhibition of CDK1 activity and caspase-dependent signaling pathways.}, }
@article {pmid21268084, year = {2011}, author = {Somjen, D and Katzburg, S and Sharon, O and Grafi-Cohen, M and Knoll, E and Stern, N}, title = {The effects of estrogen receptors α- and β-specific agonists and antagonists on cell proliferation and energy metabolism in human bone cell line.}, journal = {Journal of cellular biochemistry}, volume = {112}, number = {2}, pages = {625-632}, doi = {10.1002/jcb.22959}, pmid = {21268084}, issn = {1097-4644}, mesh = {Bone and Bones/cytology/*drug effects/*metabolism ; Cell Line ; Cell Proliferation/drug effects ; Chromatography, High Pressure Liquid ; Energy Metabolism/*drug effects ; Estradiol/pharmacology ; Estrogen Receptor alpha/*agonists/*antagonists &amp; inhibitors ; Estrogen Receptor beta/*agonists/*antagonists &amp; inhibitors ; Genistein/pharmacology ; Humans ; Hydroxyeicosatetraenoic Acids/pharmacology ; Nitriles/pharmacology ; Phytoestrogens/pharmacology ; Pyrazoles/pharmacology ; Raloxifene Hydrochloride/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {In cultured human osteoblasts estradiol-17β (E2) modulated DNA synthesis, the specific activity of creatine kinase BB (CK), 12 and 15 lipoxygenase (LO) mRNA expression and formation of 12- and 15-hydroxyeicosatetraenoic acid (HETE). We now investigate the response of human bone cell line (SaOS2) to phytoestrogens and estrogen receptors (ER)-specific agonists and antagonists. Treatment of SaSO2 with E2, 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN; ERβ-specific agonist), 4,4',4″-[4-propyl-(1H)-pyrazol-1,3,5-triyl] tris-phenol (PPT; ERα-specific agonist), biochainin A (BA), daidzein (D), genistein (G) and raloxifene (Ral) showed increased DNA synthesis and CK. Ral inhibited completely all stimulations except DPN and to some extent D. The ERα-specific antagonist methyl-piperidino-pyrazole (MPP) and the ERβ-specific antagonist 4-[2-phenyl-5,7-bis (tri-fluoro-methyl) pyrazolo [1,5-a]pyrimidin-3-yl] phenol (PTHPP) inhibited DNA synthesis, CK and reactive oxygen species (ROS) formation induced by estrogens according to their receptors affinity. The LO inhibitor baicaleine inhibited only E2, DPN and G's effects. E2 and Ral unlike all other compounds had no effect on ERα mRNA expression, while ERβ mRNA expression was stimulated by all compounds. All compounds modulated the expression of 12LO and 15LO mRNA, except E2, PPT and Ral for 12LO, and 12- and 15-HETE productions and stimulated ROS formation which was inhibited by NADPH oxidase inhibitors diphenyleneiodonium chloride (DPI) and N-acetyl cysteine and the estrogen inhibitor ICI. DPI did not affect hormonal-induced DNA and CK. In conclusion, we provide evidence for the separation of mediation via ERα and ERβ pathways in the effects of estrogenic compounds on osteoblasts, but the role of LO/HETE/ROS is unclear.}, }
@article {pmid21266777, year = {2011}, author = {Chen, J and Reheman, A and Gushiken, FC and Nolasco, L and Fu, X and Moake, JL and Ni, H and López, JA}, title = {N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice.}, journal = {The Journal of clinical investigation}, volume = {121}, number = {2}, pages = {593-603}, pmid = {21266777}, issn = {1558-8238}, support = {P50 HL065967/HL/NHLBI NIH HHS/United States ; R01 HL091153/HL/NHLBI NIH HHS/United States ; P50 HL65967/HL/NHLBI NIH HHS/United States ; }, mesh = {ADAMTS13 Protein ; Acetylcysteine/*metabolism/pharmacology/therapeutic use ; Animals ; Anti-Bacterial Agents/pharmacology ; Endothelial Cells/metabolism ; Humans ; Male ; Metalloendopeptidases/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Plasma/*metabolism ; Platelet Aggregation/drug effects ; *Protein Multimerization ; Purpura, Thrombotic Thrombocytopenic/*blood/drug therapy ; Ristocetin/pharmacology ; Thrombosis/metabolism/pathology ; von Willebrand Factor/*chemistry/genetics/*metabolism ; }, abstract = {Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by systemic microvascular thrombosis caused by adhesion of platelets to ultra-large vWF (ULVWF) multimers. These multimers accumulate because of a deficiency of the processing enzyme ADAMTS13. vWF protein forms long multimers from homodimers that first form through C-terminal disulfide bonds and then join through their N termini by further disulfide bonding. N-acetylcysteine (NAC) is an FDA-approved drug that has long been used to treat chronic obstructive lung disease and acetaminophen toxicity and is known to function in the former disorder by reducing mucin multimers. Here, we examined whether NAC could reduce vWF multimers, which polymerize in a manner similar to mucins. In vitro, NAC reduced soluble plasma-type vWF multimers in a concentration-dependent manner and rapidly degraded ULVWF multimer strings extruded from activated ECs. The effect was preceded by reduction of the intrachain disulfide bond encompassing the platelet-binding A1 domain. NAC also inhibited vWF-dependent platelet aggregation and collagen binding. Injection of NAC into ADAMTS13-deficient mice led to the rapid resolution of thrombi produced by ionophore treatment of the mesenteric venules and reduced plasma vWF multimers. These results suggest that NAC may be a rapid and effective treatment for patients with TTP.}, }
@article {pmid21266772, year = {2011}, author = {Berndt, MC and Andrews, RK}, title = {Thrombotic thrombocytopenic purpura: reducing the risk?.}, journal = {The Journal of clinical investigation}, volume = {121}, number = {2}, pages = {522-524}, pmid = {21266772}, issn = {1558-8238}, mesh = {ADAM Proteins/metabolism ; ADAMTS13 Protein ; Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Humans ; Membrane Glycoproteins/metabolism ; Mice ; Platelet Aggregation/drug effects ; Platelet Glycoprotein GPIb-IX Complex ; Purpura, Thrombotic Thrombocytopenic/*drug therapy ; Thrombosis/pathology ; von Willebrand Factor/chemistry/*metabolism ; }, abstract = {von Willebrand factor (vWF) has a key role in initiating platelet aggregation, and thereby thrombus formation, that is dependent on its ability to form appropriately sized multimers. Ultralarge multimers promote the formation of the microvascular thrombi that are hallmarks of the life-threatening condition thrombotic thrombocytopenic purpura (TTP). In this issue of the JCI, Chen et al. show that the drug N-acetylcysteine (NAC) can decrease the size of vWF multimers in vitro and in vivo, resolving thrombi in mice. These data suggest that NAC could potentially be used to treat thrombotic conditions such as TTP.}, }
@article {pmid21266191, year = {2011}, author = {Choi, MJ and Park, EJ and Min, KJ and Park, JW and Kwon, TK}, title = {Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {3}, pages = {692-698}, doi = {10.1016/j.tiv.2011.01.010}, pmid = {21266191}, issn = {1879-3177}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Renal Cell/*drug therapy/metabolism/pathology ; Cell Nucleus ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA-Binding Proteins/genetics/metabolism ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Endoplasmic Reticulum, Rough/*drug effects/metabolism ; Gene Silencing ; HT29 Cells ; Humans ; Kidney Neoplasms/*drug therapy/metabolism/pathology ; Oxidative Stress/*drug effects ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; Regulatory Factor X Transcription Factors ; Transcription Factor CHOP/genetics/metabolism ; Transcription Factors/genetics/metabolism ; Withanolides/*pharmacology ; X-Box Binding Protein 1 ; }, abstract = {The accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER) results in cellular stress that initiates a specialized response designated as the unfolded protein response. ER stress has been implicated in a variety of common diseases, such as diabetes, ischemia and neurodegenerative disorders. Withaferin A, a major chemical constituent of Withania somnifera, has been reported to inhibit tumor cell growth. We show that withaferin A induced a dose-dependent apoptotic cell death in several types of human cancer cells, as measured by FACS analysis and PARP cleavage. Treatment of Caki cells with withaferin A induced a number of signature ER stress markers, including phosphorylation of eukaryotic initiation factor-2α (eIF-2 α), ER stress-specific XBP1 splicing, and up-regulation of glucose-regulated protein (GRP)-78. In addition, withaferin A caused up-regulation of CAAT/enhancer-binding protein-homologous protein (CHOP), suggesting the induction of ER stress. Pretreatment with N-acetyl cysteine (NAC) significantly inhibited withaferin A-mediated ER stress proteins and cell death, suggesting that reactive oxygen species (ROS) mediate withaferin A-induced ER stress. Furthermore, CHOP siRNA or inhibition of caspase-4 activity attenuated withaferin A-induced apoptosis. Taken together, the present study provides strong evidence supporting an important role of the ER stress response in mediating withaferin A-induced apoptosis.}, }
@article {pmid21265612, year = {2011}, author = {Kim, JH and Park, SH and Park, SG and Choi, JS and Xia, Y and Sung, JH}, title = {The pivotal role of reactive oxygen species generation in the hypoxia-induced stimulation of adipose-derived stem cells.}, journal = {Stem cells and development}, volume = {20}, number = {10}, pages = {1753-1761}, pmid = {21265612}, issn = {1557-8534}, support = {HD34852/HD/NICHD NIH HHS/United States ; R01 AT004422-04/AT/NCCIH NIH HHS/United States ; AT004422/AT/NCCIH NIH HHS/United States ; R01 AT004422-03/AT/NCCIH NIH HHS/United States ; R01 AT004422/AT/NCCIH NIH HHS/United States ; }, mesh = {Adipose Tissue/*pathology ; Cell Hypoxia ; Cell Movement ; Cell Proliferation ; Fluoresceins/metabolism ; Humans ; NADPH Oxidases/metabolism ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Stem Cells/enzymology/*metabolism/*pathology ; Wound Healing ; }, abstract = {Adipose-derived stem cells (ASCs) offer a potential alternative for tissue repair and regeneration. We have recently shown that hypoxia stimulates ASCs and enhances the regenerative potential of ASCs, which is beneficial for ASC therapy. In the present study, we further investigated a key mediator and a signal pathway involved in the stimulation of ASC during hypoxia. Culturing ASC in a hypoxic incubator (2% oxygen tension) increased the proliferation and migration, and this was mediated by Akt and ERK pathways. To determine the generation of reactive oxygen species (ROS), 2',7'-dichlorofluorescin diacetate intensity was detected by fluorescence-activated cell sorting. Hypoxia significantly increased the dichlorofluorescin diacetate intensity, which was greatly reduced by N-acetyl-cysteine and diphenyleneiodonium treatment. Likewise, the hypoxia-induced proliferation and migration of ASCs were reversed by N-acetyl-cysteine and diphenyleneiodonium treatment, suggesting the involvement of ROS generation in ASC stimulation. Further, we examined the activation of receptor tyrosine kinases and observed that hypoxia stimulated the phosphorylation of platelet-derived growth factor receptor-β. In summary, the ROS produced by ASCs in response to hypoxia was mostly likely due to NADPH oxidase activity. The increased cellular ROS was accompanied by the phosphorylation of platelet-derived growth factor receptor-β as well as by the activation of ERK and Akt signal pathways. Our results suggest a pivotal role for ROS generation in the stimulation of ASCs by hypoxia.}, }
@article {pmid21263015, year = {2012}, author = {Hanly, LN and Chen, N and Aleksa, K and Cutler, M and Bajcetic, M and Palassery, R and Regueira, O and Turner, C and Baw, B and Malkin, B and Freeman, D and Rieder, MJ and Vasylyeva, TL and Koren, G}, title = {N-acetylcysteine as a novel prophylactic treatment for ifosfamide-induced nephrotoxicity in children: translational pharmacokinetics.}, journal = {Journal of clinical pharmacology}, volume = {52}, number = {1}, pages = {55-64}, doi = {10.1177/0091270010391790}, pmid = {21263015}, issn = {1552-4604}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetaminophen/toxicity ; Acetylcysteine/blood/*pharmacokinetics/*therapeutic use ; Acute Kidney Injury/chemically induced/metabolism/*prevention &amp; control ; Adolescent ; Analgesics, Non-Narcotic/toxicity ; Animals ; Antineoplastic Agents, Alkylating/adverse effects/blood/pharmacokinetics ; Area Under Curve ; Child ; Drug Overdose/drug therapy ; Female ; Humans ; Ifosfamide/adverse effects/blood/pharmacokinetics ; Male ; Protective Agents/*pharmacokinetics/*therapeutic use ; Rats ; Rats, Wistar ; }, abstract = {Ifosfamide (IFO), which is used in the treatment of pediatric solid tumors, causes high rates of nephrotoxicity. N-acetylcysteine (NAC), an antidote for acetaminophen overdose, has been shown to prevent IFO-induced renal cell death and nephrotoxicity in both LLCPK-1 cells and a rat model. To facilitate the use of NAC in preventing IFO-induced nephrotoxicity in children, the authors compared the systemic exposure to NAC in children treated for acetaminophen overdose to the systemic exposure of the therapeutically effective rat model. The mean systemic exposure in the rat model was 18.72 mM·h (range, 9.92-30.02 mM·h), compared to the mean systemic exposure found in treated children (14.48 mM·h; range, 6.22-32.96 mM·h). They also report 2 pediatric cases in which NAC-attenuated acute renal failure associated with IFO when given concurrently with their chemotherapy treatment. Systemic exposure to NAC measured in 1 of these cases was comparable to that in the children treated for acetaminophen overdose. These results corroborate NAC's potential to protect against IFO-induced nephrotoxicity in children when used in its clinically approved dose schedule and supports a clinical trial in children.}, }
@article {pmid21259059, year = {2011}, author = {Park, JY and Kim, MJ and Kim, YK and Woo, JS}, title = {Ceramide induces apoptosis via caspase-dependent and caspase-independent pathways in mesenchymal stem cells derived from human adipose tissue.}, journal = {Archives of toxicology}, volume = {85}, number = {9}, pages = {1057-1065}, doi = {10.1007/s00204-011-0645-x}, pmid = {21259059}, issn = {1432-0738}, mesh = {Adipose Tissue/*drug effects/enzymology/pathology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor/metabolism ; Caspase 3/*metabolism ; Cell Culture Techniques ; Cell Survival/drug effects ; Cells, Cultured ; Ceramides/metabolism/*pharmacology/physiology ; Cytochromes c/metabolism ; Flow Cytometry ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mesenchymal Stem Cells/*drug effects/enzymology/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Apoptosis of stem cells may be related to certain degenerative conditions such as progressive tissue damage and an inability to repair. Ceramide induces cell death in various cell types. However, the underlying mechanisms of ceramide-induced cell death in stem cells are not explored. This study was designed to investigate the cell death process caused by cell-permeable ceramide and to determine the underlying mechanisms in mesenchymal stem cells derived from human adipose tissue (hASCs). Ceramide caused a loss of cell viability in a concentration- and time-dependent manner, which was largely attributable to apoptosis. Ceramide induced generation of reactive oxygen species (ROS) and disruption of the mitochondrial membrane potential. The ROS generation caused by ceramide was prevented by the antioxidant N-acetylcysteine (NAC). Although ceramide induced release of cytochrome c from mitochondria and activation of caspase-3, the ceramide-induced cell death was partially prevented by caspase inhibitors. Addition of ceramide caused apoptosis-inducing factor (AIF) nuclear translocation, which was prevented by antioxidant. Taken together, these data suggest that ceramide induces cell death through both caspase-dependent and caspase-independent mechanisms mediated by ROS generation in hASCs.}, }
@article {pmid21258765, year = {2011}, author = {Han, YH and Park, WH}, title = {Intracellular glutathione levels are involved in carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone-induced apoptosis in As4.1 juxtaglomerular cells.}, journal = {International journal of molecular medicine}, volume = {27}, number = {4}, pages = {575-581}, doi = {10.3892/ijmm.2011.604}, pmid = {21258765}, issn = {1791-244X}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Apoptosis/*drug effects ; Buthionine Sulfoximine/metabolism/pharmacology ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/*pharmacology ; Catalase/metabolism ; Cell Death/drug effects ; Cell Line ; Glutathione/*metabolism ; Intracellular Space/*metabolism ; Juxtaglomerular Apparatus/*drug effects/metabolism ; Mice ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) is an uncoupler of mitochondrial oxidative phosphorylation in eukaryotic cells. In the present study, we investigated the involvement of reactive oxygen species (ROS) and glutathione (GSH) in FCCP-induced As4.1 juxtaglomerular cell death. Intracellular ROS levels were decreased by FCCP at the early time points (10-150 min) and increased at 48 h. FCCP inhibited the activity of Mn-superoxide dismutase (Mn-SOD) via down-regulating its protein expression. Ebselen (an antioxidant) significantly attenuated ROS levels in FCCP-treated cells, but did not prevent FCCP-induced cell death. Moreover, intracellular GSH content was rapidly diminished within 10 min of FCCP treatment, which was accompanied by a reduction of the mitochondrial membrane potential [MMP (∆ψm)]. L-buthionine sulfoximine (BSO, a GSH synthesis inhibitor) significantly augmented As4.1 cell death by FCCP. However, N-acetylcysteine (NAC, a GSH precursor and antioxidant) attenuated GSH depletion, MMP (∆ψm) loss and cell death in FCCP-treated As4.1 cells. In addition, NAC increased Mn-SOD activity and decreased ROS levels in FCCP-treated As4.1 cells. In conclusion, these results suggest that compared to ROS levels, intracellular GSH levels are more closely linked to FCCP-induced apoptosis in As4.1 juxtaglomerular cells.}, }
@article {pmid21255698, year = {2011}, author = {De la Fuente, M and Hernanz, A and Viniegra, S and Miquel, J}, title = {Sulfur-containing antioxidants increase in vitro several functions of lymphocytes from mice.}, journal = {International immunopharmacology}, volume = {11}, number = {6}, pages = {661-669}, doi = {10.1016/j.intimp.2011.01.008}, pmid = {21255698}, issn = {1878-1705}, mesh = {Animals ; Antioxidants/*pharmacology ; Cell Adhesion/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chemotaxis, Leukocyte/drug effects ; Drug Combinations ; Lymph Nodes/pathology ; Lymphocyte Activation/drug effects ; Lymphocytes/*drug effects/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; Spleen/pathology ; Sulfur Compounds/*pharmacology ; Thymus Gland/pathology ; }, abstract = {The in vitro effects of several sulfur-containing antioxidants, such as glutathione (GSH), N-acetylcysteine (NAC), thioproline (TP) and taurine (TAU), at different concentrations, on key functions of lymphocytes from axillary nodes, spleen, thymus and peritoneum from young-adult BALB/c mice have been investigated. The functions studied have been proliferation, both spontaneous and in response to the mitogen Concanavalin A, mobility both spontaneous and directed to a chemical attractant (chemotaxis) and adherence to substrate. The effect of these antioxidants on the viability of leukocytes was also investigated. The results show an antioxidant-induced stimulation of all the functions studied. The highest concentrations used of each antioxidant were the most effective in proliferation (5mM for GSH, 1mM for TP and NAC and 40 mM for TAU). These concentrations increase mobility significantly. The presence of TP+NAC enhances the chemotaxis of peritoneal lymphocytes more than each antioxidant separately. The adherence capacity of peritoneal lymphocytes also increased at 10 min of incubation with GSH, TP and NAC. All these antioxidants increase the viability of leukocytes in culture, especially in cells from spleen. In conclusion, the sulfur-containing antioxidants studied in vitro improve the functional capacity of lymphocytes from young-adult mice and these results showing that the improvement of the immune response, and specifically of the lymphocyte functions, found after ingesting diet supplemented with the antioxidants studied, are due to a direct action of these compounds in the immune cells.}, }
@article {pmid21254278, year = {2011}, author = {Maheshwari, A and Misro, MM and Aggarwal, A and Sharma, RK and Nandan, D}, title = {N-acetyl-L-cysteine counteracts oxidative stress and prevents H2O2 induced germ cell apoptosis through down-regulation of caspase-9 and JNK/c-Jun.}, journal = {Molecular reproduction and development}, volume = {78}, number = {2}, pages = {69-79}, doi = {10.1002/mrd.21268}, pmid = {21254278}, issn = {1098-2795}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 8/metabolism ; *Caspase 9/metabolism ; Catalase/metabolism ; Cell Survival/drug effects ; Genes, bcl-2 ; Germ Cells/metabolism ; Glutathione S-Transferase pi/metabolism ; Hydrogen Peroxide/*toxicity ; *JNK Mitogen-Activated Protein Kinases/metabolism ; Male ; Oxidative Stress/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; Up-Regulation/drug effects ; bcl-2-Associated X Protein/metabolism ; }, abstract = {The mechanism of H(2)O(2) induced oxidative stress leading to male germ cell apoptosis was earlier reported from our laboratory. In the present study, we investigated the mechanisms by which N-acetyl-L-cysteine (NAC, which is highly cell specific with strong antioxidant and anti-genotoxic properties), stimulated cell survival under such conditions. Co-incubation with 5 mM NAC significantly (P<0.001) reduced the germ cell apoptosis induced by 10 µM H(2)O(2). Lipid peroxidation was brought down with significant restoration of activities of antioxidant enzymes, SOD, GST, and catalase. Expression of pro-apoptotic marker, Bax up-regulated following H(2)O(2) exposure, was reversed back to control levels. In contrast, expression of anti-apoptotic Bcl-2 and phospho-Akt revealed a completely opposite trend. While caspase-8 activity remained unaffected, NAC successfully attenuated the increased activities of caspase-3 and -9 in the H(2) O(2) treated cells. Simultaneously, the increased expression of caspase-9, phospho-JNK, and phospho-c-Jun after H(2)O(2) treatment was down-regulated by NAC. The above findings indicate that the mechanism of inhibition of H(2)O(2) induced male germ cell apoptosis by NAC is mediated through regulation of caspase-9 and JNK.}, }
@article {pmid21253614, year = {2011}, author = {Efimova, O and Szankasi, P and Kelley, TW}, title = {Ncf1 (p47phox) is essential for direct regulatory T cell mediated suppression of CD4+ effector T cells.}, journal = {PloS one}, volume = {6}, number = {1}, pages = {e16013}, pmid = {21253614}, issn = {1932-6203}, mesh = {Animals ; Antioxidants/*pharmacology ; CD4-Positive T-Lymphocytes/*immunology ; Cell Proliferation ; Immune System Phenomena ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidases/deficiency/*physiology ; Reactive Oxygen Species ; Sulfhydryl Compounds/pharmacology ; T-Lymphocytes, Regulatory/*immunology ; Transforming Growth Factor beta/pharmacology ; }, abstract = {BACKGROUND: Multiple mechanisms have been advanced to account for CD4+FOXP3+ regulatory T cell (Treg)-mediated suppression of CD4+ effector T cells (Teffs) but none appear to completely explain suppression. Previous data indicates that Tregs may affect the microenvironment redox state. Given the inherent redox sensitivity of T cells, we tested the hypothesis that oxidants may mediate the direct suppression of Teffs by Tregs.<br><br>Tregs and Teffs were isolated from the spleens of wild type (WT) C57BL/6 mice or Ncf1(p47phox)-deficient C57BL/6 mice which lack NADPH oxidase function. Teffs were labeled with CFSE and co-cultured with unlabeled Tregs at varying Treg:Teff ratios in the presence of anti-CD3/CD28 coated beads for 3 days in suppression assays. Treg-mediated suppression was quantified by flow cytometric analysis of CFSE dilution in Teffs. The presence of the antioxidants n-acetylcysteine (NAC) or 2-mercaptoethanol or inhibitors of NADPH oxidase (diphenyleneiodonium and VAS-2870) resulted in reduced WT Treg-mediated suppression. The observed suppression was in part dependent upon TGF&#x3b2; as it was partially blocked with neutralizing antibodies. The suppression of Teff proliferation induced by exogenous TGF&#x3b2; treatment could be overcome with NAC. Ncf1-deficient Teff were slightly but significantly less sensitive than WT Teff to suppression by exogenous TGF&#x3b2;. Ncf1-deficient Tregs suppressed Ncf1-deficient Teff very poorly compared to wild type controls. There was partial but incomplete reconstitution of suppression in assays with WT Tregs and Ncf1-deficient Teff.<br><br>CONCLUSIONS/SIGNIFICANCE: We present evidence that NADPH oxidase derived ROS plays a role in the direct Treg mediated suppression of CD4+ effector T cells in a process that is blocked by thiol-containing antioxidants, NADPH oxidase inhibitors or a lack of Ncf1 expression in Tregs and Teffs. Oxidants may represent a potential new target for therapeutic modulation of Treg function.}, }
@article {pmid21252047, year = {2011}, author = {Aleffi, S and Navari, N and Delogu, W and Galastri, S and Novo, E and Rombouts, K and Pinzani, M and Parola, M and Marra, F}, title = {Mammalian target of rapamycin mediates the angiogenic effects of leptin in human hepatic stellate cells.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {301}, number = {2}, pages = {G210-9}, doi = {10.1152/ajpgi.00047.2010}, pmid = {21252047}, issn = {1522-1547}, mesh = {Cell Line ; Cell Movement/physiology ; Hep G2 Cells ; Hepatic Stellate Cells/metabolism/pathology/*physiology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism/physiology ; Leptin/metabolism/*physiology ; Liver/*blood supply ; NADPH Oxidases/physiology ; Neovascularization, Pathologic ; Neovascularization, Physiologic ; Phosphorylation ; Platelet-Derived Growth Factor/physiology ; Reactive Oxygen Species/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/chemistry ; Signal Transduction/*physiology ; TOR Serine-Threonine Kinases/*physiology ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins/chemistry ; Vascular Endothelial Growth Factor A/*metabolism/physiology ; }, abstract = {Leptin modulates the angiogenic properties of hepatic stellate cells (HSC), but the molecular mechanisms involved are poorly understood. We investigated the pathways regulating hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in leptin-stimulated myofibroblastic HSC. Exposure to leptin enhanced the phosphorylation of TSC2 on T1462 residues and of p70 S6 kinase and the translational inhibitor 4E-binding protein-1, indicating the ability of leptin to activate the mammalian target of rapamycin (mTOR) pathway. Similar findings were observed when HSC were exposed to PDGF. Both leptin and PDGF increased the expression of HIF-1α and VEGF in HSC. In the presence of rapamycin, a specific mTOR inhibitor, leptin and PDGF were no longer able to activate mTOR, and expression of VEGF was reduced, whereas HIF-1α abundance was not affected. Moreover, knockdown of Raptor, a component of the mTORC1 complex, reduced the ability of leptin to increase VEGF. mTOR was also necessary for leptin- and PDGF-dependent increase in HSC migration. Leptin increased the generation of reactive oxygen species in HSC, which was reduced by NADP(H) oxidase inhibitors. Both N-acetyl cysteine and diphenylene iodonium, a NADP(H) inhibitor, inhibited the expression of HIF-1α and VEGF stimulated by leptin or PDGF. Finally, conditioned media from HSC treated with leptin or PDGF induced tube formation in cultured human umbilical vein endothelial cells. In conclusion, in HSC exposed to leptin or PDGF, increased expression of VEGF requires both activation of mTOR and generation of reactive oxygen species via NADPH-oxidase. Induction of HIF-1α requires NADP(H) oxidase but not mTOR activation.}, }
@article {pmid21251943, year = {2011}, author = {Grosicka-Maciąg, E and Kurpios-Piec, D and Szumiło, M and Grzela, T and Rahden-Staroń, I}, title = {Protective effect of N-acetyl-L-cysteine against maneb induced oxidative and apoptotic injury in Chinese hamster V79 cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {49}, number = {4}, pages = {1020-1025}, doi = {10.1016/j.fct.2011.01.009}, pmid = {21251943}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Cell Line ; Cricetinae ; Cricetulus ; Fungicides, Industrial/*antagonists &amp; inhibitors/toxicity ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; In Situ Nick-End Labeling ; Lipid Peroxidation/drug effects ; Maneb/*antagonists &amp; inhibitors/toxicity ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The role of antioxidant N-acetyl-L-cysteine (NAC) in protection against cellular changes triggered by maneb during in vitro exposure was investigated in cultured Chinese hamster V79 cells. We observed high apoptotic activity and high oxidative stress induced by exposure to maneb evidenced by a statistically significant increase in lipid peroxidation (measured as TBARS--thiobarbituric acid reactive substances) as well as a decrease of glutathione (GSH) and glutathione disulfide (GSSG) ratio (GSH/GSSG). Maneb did not exhibit any effect on protein oxidation (measured by protein carbonyls content). NAC suppressed cellular changes induced by maneb in V79 cells. NAC pre-treatment prevented TBARS production and significantly decreased the number of apoptotic cells. However, protective effect of NAC on GSH and GSSG levels has been shown only in cells exposed to lower concentration of maneb (100 μM).}, }
@article {pmid21247619, year = {2011}, author = {Mushtaq, N and Ezzati, M and Hall, L and Dickson, I and Kirwan, M and Png, KM and Mudway, IS and Grigg, J}, title = {Adhesion of Streptococcus pneumoniae to human airway epithelial cells exposed to urban particulate matter.}, journal = {The Journal of allergy and clinical immunology}, volume = {127}, number = {5}, pages = {1236-42.e2}, doi = {10.1016/j.jaci.2010.11.039}, pmid = {21247619}, issn = {1097-6825}, mesh = {Bacterial Adhesion/*drug effects/*physiology ; Cell Line ; Epithelial Cells/cytology/drug effects/*microbiology ; Ghana ; Humans ; Oxidative Stress ; Particulate Matter/metabolism/*pharmacology ; Platelet Activating Factor/genetics/metabolism ; Platelet Membrane Glycoproteins/genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Respiratory System/*cytology/drug effects/microbiology ; Streptococcus pneumoniae/*physiology ; United Kingdom ; }, abstract = {BACKGROUND: Epidemiologic studies report an association between pneumonia and urban particulate matter (PM) less than 10 microns (μm) in aerodynamic diameter (PM(10)). Streptococcus pneumoniae is a common cause of bacterial pneumonia worldwide. To date, the mechanism whereby urban PM enhances vulnerability to S pneumoniae infection is unclear. Adhesion of S pneumoniae to host cells is a prerequisite for infection. Host-expressed proteins, including the receptor for platelet-activating factor (PAFR), are co-opted by S pneumoniae to adhere to lower airway epithelial cells.<br><br>OBJECTIVES: To define whether inhalable urban PM enhances the adhesion of S pneumoniae to airway epithelial cells.<br><br>METHODS: A549 cells were cultured with PM(10) from Leicester (United Kingdom [UK]) and PM(10) and PM less than 2.5 &#x3bc;m in aerodynamic diameter (PM(2.5)) from Accra (Ghana), then infected with S pneumoniae strain D39. Pneumococcal adhesion to human primary bronchial epithelial cells was also assessed. Bacterial adhesion was determined by quantitative culture and confocal microscopy. The role of oxidative stress was assessed by N-acetyl cysteine, and the role of PAFR was assessed by mRNA transcript level, receptor expression, and receptor blocking.<br><br>RESULTS: PM(10) (UK) increased S pneumoniae adhesion to both A549 airway epithelial cells and human primary bronchial epithelial cells. PM(10) (Ghana) and PM(2.5) (Ghana) also increased adhesion. Culture of A549 cells by PM(10) (UK) increased PAFR mRNA transcript level and PAFR expression. PM(10) (UK)-stimulated adhesion to A549 cells was attenuated by a PAFR blocker and N-acetyl cysteine.<br><br>CONCLUSION: Urban PM increases adhesion of S pneumoniae to human airway epithelial cells. PM-stimulated adhesion is mediated by oxidative stress and PAFR.}, }
@article {pmid21243253, year = {2010}, author = {Pereira Filho, Nde A and Pereira Filho, Ade A and Soares, FP and Coutinho, LM}, title = {Effect of N-acetylcysteine on vasospasm in subarachnoid hemorrhage.}, journal = {Arquivos de neuro-psiquiatria}, volume = {68}, number = {6}, pages = {918-922}, doi = {10.1590/s0004-282x2010000600017}, pmid = {21243253}, issn = {1678-4227}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Male ; Rats ; Rats, Wistar ; Subarachnoid Hemorrhage/*complications ; Vasospasm, Intracranial/etiology/*prevention &amp; control ; }, abstract = {Vasospasm remains an extremely serious complication that affects patients presenting with subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms. The current therapeutic armamentarium is still insufficient in many cases, and the search for new therapies is necessary. In this study, we evaluated the effect of N-acetylcysteine (NAC) on cerebral arterial vasospasm using an experimental model. Twenty-four wistar rats were divided into 4 groups: [1] Control, [2] SAH, [3] SAH+NAC and [4] SAH+Placebo. The experimental model employed double subarachnoid injections of autologous blood. The proposed dose of NAC was 250 mg/kg intraperitoneally per day. We analyzed the inner area of the basilar artery to assess the action of NAC. The experimental model proved to be very adequate, with a mortality rate of 4%. The inner area of the basilar artery in the SAH group showed significant difference to the control group (p=0.009). The use of NAC significantly reduced vasospasm as compared to the untreated group (p=0.048) and established no significant difference to the control group (p=0.098). There was no significant improvement with the administration of placebo (p=0.97). The model of the dual hemorrhage proved to be very useful for vasospasm simulation, with overall low mortality. The administration of NAC significantly reduced vasospasm resulting from SAH, and may represent a new therapeutic alternative.}, }
@article {pmid21241688, year = {2011}, author = {Liu, H and Xiao, Y and Xiong, C and Wei, A and Ruan, J}, title = {Apoptosis induced by a new flavonoid in human hepatoma HepG2 cells involves reactive oxygen species-mediated mitochondrial dysfunction and MAPK activation.}, journal = {European journal of pharmacology}, volume = {654}, number = {3}, pages = {209-216}, doi = {10.1016/j.ejphar.2010.12.036}, pmid = {21241688}, issn = {1879-0712}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/*pathology ; Caspases/metabolism ; Cell Survival/drug effects ; Cyclohexanones/*pharmacology ; Enzyme Activation/drug effects ; Flavones/*pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Hep G2 Cells ; Humans ; Imidazoles/pharmacology ; Intracellular Space/drug effects/metabolism ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Liver Neoplasms/*pathology ; MAP Kinase Signaling System/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Phosphorylation/drug effects ; Pyridines/pharmacology ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Earlier reports suggest that protoapigenone showed remarkable anticancer activities. In the present study, the cytotoxic effect of a new flavonoid, 2-(cis-1, 2-dihydroxy 4-oxo-cyclohex-5-enyl)-5, 7-dihydroxy-chromone (DEDC), which is a protoapigenone analog, was investigated in human hepatoma HepG2 cells. We found that hepatoma cells were highly susceptible to DEDC in contrast with normal cells. The sustainable and rapid generation of reactive oxygen species was observed in DEDC-induced cell death. Following oxidative stress, DEDC sequentially decreased mitochondrial membrane potential (ΔΨm), reduced Bcl-2 expression, increased cytochrome c release, and activated caspase-3, -8, and -9. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK) was stimulated by treatment with DEDC. To further investigate the mechanisms of the DEDC-induced cell death, we examined the effects of reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) and selective inhibitors for MAPK pathways on the cell death. The DEDC-induced cell death was significantly inhibited by both NAC and JNK inhibitor SP600125, but promoted by p38 MAPK inhibitor, SB203580. Together, DEDC may have antitumor effects in HepG2 cells through reactive oxygen species production as well as activation of MAPK signaling pathways.}, }
@article {pmid21241685, year = {2011}, author = {Cao, XH and Zhao, SS and Liu, DY and Wang, Z and Niu, LL and Hou, LH and Wang, CL}, title = {ROS-Ca(2+) is associated with mitochondria permeability transition pore involved in surfactin-induced MCF-7 cells apoptosis.}, journal = {Chemico-biological interactions}, volume = {190}, number = {1}, pages = {16-27}, doi = {10.1016/j.cbi.2011.01.010}, pmid = {21241685}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Calcium/*metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cell Membrane Permeability ; Cell Proliferation ; Cytochromes c/metabolism ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Humans ; Lipopeptides/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Peptides, Cyclic/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {The surfactin can inhibit proliferation and induce apoptosis in cancer cells. Moreover, surfactin can induce cell death in human breast cancer MCF-7 cells through mitochondrial pathway. However, the molecular mechanism involved in this pathway remains to be elucidated. Here, the reactive oxygen species (ROS) and Ca(2+) on mitochondria permeability transition pore (MPTP) activity, and MCF-7 cell apoptosis which induced by surfactin were investigated. It is found that surfactin evoked mitochondrial ROS generation, and the surfactin-induced cell death was prevented by N-acetylcysteine (NAC, an inhibitor of ROS). An increasing cytoplasmic Ca(2+) concentration was detected in surfactin-induced MCF-7 apoptosis, which was inhibited by 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM, a chelator of calcium). In addition, the relationship between ROS generation and the increase of cytoplasm Ca(2+) was determined. The results showed that surfactin initially induced the ROS formation, leading to the MPTP opening accompanied with the collapse of mitochondrial membrane potential (ΔΨ(m)). Then the cytoplasmic Ca(2+) concentration increased in virtue of the changes of mitochondrial permeability, which was prevented by BAPTA-AM. Besides, cytochrome c (cyt c) was released from mitochondria to cytoplasm through the MPTP and activated caspase-9, eventually induced apoptosis. In summary, surfactin has notable anti-tumor effect on MCF-7 cells, however, there was no obvious cytotoxicity on normal cells.}, }
@article {pmid21241452, year = {2011}, author = {Gu, BW and Fan, JM and Bessler, M and Mason, PJ}, title = {Accelerated hematopoietic stem cell aging in a mouse model of dyskeratosis congenita responds to antioxidant treatment.}, journal = {Aging cell}, volume = {10}, number = {2}, pages = {338-348}, pmid = {21241452}, issn = {1474-9726}, support = {R01CA106995/CA/NCI NIH HHS/United States ; P30 CA91842/CA/NCI NIH HHS/United States ; R01 CA106995/CA/NCI NIH HHS/United States ; R01 CA106995-07/CA/NCI NIH HHS/United States ; P30 CA091842/CA/NCI NIH HHS/United States ; R01 CA105312/CA/NCI NIH HHS/United States ; R01CA105312/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*therapeutic use ; Cell Cycle Proteins/genetics/*metabolism ; Cells, Cultured ; Cellular Senescence/*physiology ; Dyskeratosis Congenita/*drug therapy/pathology/*physiopathology ; Female ; Fibroblasts/cytology/physiology ; Hematopoietic Stem Cells/cytology/pathology/*physiology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Nuclear Proteins/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/metabolism/pathology ; }, abstract = {Mutations in DKC1, encoding telomerase associated protein dyskerin, cause X-linked dyskeratosis congenita (DC), a bone marrow (BM) failure, and cancer susceptibility syndrome. Decreased accumulation of telomerase RNA resulting in excessive telomere shortening and premature cellular senescence is thought to be the primary cause of disease in X-linked DC. Affected tissues are those that require constant renewal by stem cell activity. We previously showed that in Dkc1(Δ15) mice, which contain a mutation that is a copy of a human mutation causing DC, mutant cells have a telomerase-dependent proliferative defect and increased accumulation of DNA damage in the first generation before the telomeres are short. We now demonstrate the presence of the growth defect in Dkc1(Δ15) mouse embryonic fibroblasts in vitro and show that accumulation of DNA damage and levels of reactive oxygen species increase with increasing population doublings. Treatment with the antioxidant, N-acetyl cysteine (NAC), partially rescued the growth disadvantage of mutant cells in vitro and in vivo. Competitive BM repopulation experiments showed that the Dkc1(Δ15) mutation is associated with a functional stem cell defect that becomes more severe with increasing age, consistent with accelerated senescence, a hallmark of DC hematopoiesis. This stem cell phenotype was partially corrected by NAC treatment. These results suggest that a pathogenic Dkc1 mutation accelerates stem cell aging, that increased oxidative stress might play a role in the pathogenesis of X-linked DC, and that some manifestations of DC may be prevented or delayed by antioxidant treatment.}, }
@article {pmid21241423, year = {2011}, author = {Jegatheeswaran, S and Siriwardena, AK}, title = {Experimental and clinical evidence for modification of hepatic ischaemia-reperfusion injury by N-acetylcysteine during major liver surgery.}, journal = {HPB : the official journal of the International Hepato Pancreato Biliary Association}, volume = {13}, number = {2}, pages = {71-78}, pmid = {21241423}, issn = {1477-2574}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/*administration &amp; dosage ; Disease Models, Animal ; Evidence-Based Medicine ; Hepatectomy/*adverse effects ; Humans ; Liver/blood supply/*drug effects/metabolism/*surgery ; Liver Transplantation/*adverse effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/etiology/metabolism/*prevention &amp; control ; Treatment Outcome ; }, abstract = {BACKGROUND: Hepatic ischaemia-reperfusion (I/R) injury occurs in both liver resectional surgery and in transplantation. The biochemistry of I/R injury involves short-lived oxygen free radicals. N-acetylcysteine (NAC) is a thiol-containing synthetic compound used in the treatment of acetaminophen toxicity. The present study is a detailed overview of the experimental and clinical evidence for the use of NAC as a pharmaco-protection agent in patients undergoing major liver surgery or transplantation.<br><br>METHODS: A computerized search of the Medline, Embase and SCI databases for the period from 1st January 1988 to 31st December 2008 produced 40 reports. For clinical studies, the quality of reports was assessed according to the criteria reported by the Cochrane communication review group.<br><br>RESULTS: Nineteen studies evaluated NAC in experimental liver I/R injury. NAC was administered before induction of ischaemia in 13. The most widely used concentration was 150 mg/kg by intravenous bolus. Fifteen studies report an improvement in outcome, predominantly a reduction in transaminase. Seven studies used an isolated perfused liver model with all showing improvement (predominantly an improvement in bile production after N-acetylcysteine). Two out of four transplantation models showed an improvement in hepatic function. Clinical studies in transplantation show a modest improvement in transaminase levels with no beneficial effect on either patient or graft survival.<br><br>CONCLUSION: N-acetylcysteine, given before induction of a liver I/R injury in an experimental model can ameliorate liver injury. Clinical outcome data are limited and there is currently little evidence to justify use either in liver transplantation or in liver resectional surgery.}, }
@article {pmid21238771, year = {2011}, author = {da Silva, IS and Araújo, MF and Ferreira, HA and Varela, Jde J and Tanaka, SM and Tanaka, AA and Angnes, L}, title = {Quantification of N-acetylcysteine in pharmaceuticals using cobalt phthalocyanine modified graphite electrodes.}, journal = {Talanta}, volume = {83}, number = {5}, pages = {1701-1706}, doi = {10.1016/j.talanta.2010.11.070}, pmid = {21238771}, issn = {1873-3573}, mesh = {Acetylcysteine/*analysis/chemistry ; Electrochemistry/methods ; Electrodes ; Graphite/*chemistry ; Indoles/*chemistry ; Organometallic Compounds/*chemistry ; Pharmaceutical Preparations/*chemistry ; }, abstract = {Flow injection analysis (FIA) with amperometric detection was employed for the quantification of N-acetylcysteine (NAC) in pharmaceutical formulations, utilizing an ordinary pyrolytic graphite (OPG) electrode modified with cobalt phthalocyanine (CoPc). Cyclic voltammetry was used in preliminary studies to establish the best conditions for NAC analysis. In FIA-amperometric experiments the OPG-CoPc electrode exhibited sharp and reproducible current peaks over a wide linear working range (5.0×10(-5)-1.0×10(-3) mol L(-1)) in 0.1 mol L(-1) NaOH solution. High sensitivity (130 mA mol(-1) cm(2)) and a low detection limit (9.0×10(-7) mol L(-1)) were achieved using the sensor. The repeatability (R.S.D.%) for 13 successive flow injections of a solution containing 5.0×10(-4) mol L(-1) NAC was 1.1%. The new procedure was applied in analyses of commercial pharmaceutical products and the results were in excellent agreement with those obtained using the official titrimetric method. The proposed amperometric method is highly suitable for quality control analyses of NAC in pharmaceuticals since it is rapid, precise and requires much less work than the recommended titrimetric method.}, }
@article {pmid21237671, year = {2011}, author = {Raut, S and Heck, A and Vishwanatha, J and Sarkar, P and Mody, A and Luchowski, R and Gryczynski, Z and Gryczynski, I}, title = {Fluorescent properties of antioxidant cysteine ABZ analogue.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {102}, number = {3}, pages = {241-245}, doi = {10.1016/j.jphotobiol.2010.12.012}, pmid = {21237671}, issn = {1873-2682}, mesh = {Absorption ; Antioxidants/analysis/*chemistry ; Benzamides/analysis/*chemistry ; Buffers ; Cysteine/*analogs &amp; derivatives/analysis/*chemistry ; Fluorescence Polarization ; Fluorescent Dyes/analysis/*chemistry ; Limit of Detection ; Nanoparticles/chemistry ; Phosphates/chemistry ; Polymers/chemistry ; Spectrometry, Fluorescence ; }, abstract = {The antioxidant properties of aminobenzamide cysteine (ABZ Cys) makes it a molecule that can potentially be used as a drug in oxidative stress related diseases and delivered in the form of a nanoparticles. Here we have studied the photo-physical properties of ABZ Cys, a fluorescent analogue of a popular antioxidant N-acetyl cysteine (NAC). We have compared ABZ Cys steady state and time-resolved fluorescence properties with its parent compounds anthranilic acid and anthranilamide in solution as well as in poly-vinyl alcohol (PVA) polymer films. ABZ Cys did not show any significant shift in absorption after entrapment in PVA film, but there was a shift towards shorter wavelengths in the emission peak compared to the phosphate buffer solution. Fluorescence lifetimes and quantum yields indicated a slight quenching of ABZ Cys fluorescence in comparison to the cysteine-less parent compounds. We also demonstrated that very low concentrations of ABZ Cys, such as 100 nM, are readily detected by a commercial spectrofluorometer. Hence we have established the possible use of ABZ Cys in biomedical applications.}, }
@article {pmid21235398, year = {2011}, author = {Fang, X and Huang, T and Zhu, Y and Yan, Q and Chi, Y and Jiang, JX and Wang, P and Matsue, H and Kitamura, M and Yao, J}, title = {Connexin43 hemichannels contribute to cadmium-induced oxidative stress and cell injury.}, journal = {Antioxidants &amp; redox signaling}, volume = {14}, number = {12}, pages = {2427-2439}, pmid = {21235398}, issn = {1557-7716}, support = {AR 46798/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cadmium/*pharmacology ; Cell Line ; Connexin 43/genetics/*metabolism ; Fibroblasts/cytology/drug effects ; Gap Junctions/*drug effects/metabolism ; Glutathione/metabolism ; Mice ; Mice, Knockout ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Swine ; }, abstract = {We investigated the potential involvement of connexin hemichannels in cadmium ions (Cd(2+))-elicited cell injury. Transfection of LLC-PK1 cells with a wild-type connexin43 (Cx43) sensitized them to Cd(2+)-elicited cell injury. The cell susceptibility to Cd(2+) was increased by depletion of glutathione (GSH) with DL-buthionine-[S,R]-sulfoximine, and decreased by N-acetyl-cysteine or glutathione reduced ethyl ester. Fibroblasts derived from Cx43 wild-type (Cx43+/+) and knockout (Cx43-/-) fetal littermates displayed different susceptibility to Cd(2+). Cd(2+) induced a higher concentration of reactive oxygen species, a stronger activation c-Jun N-terminal kinase, and significantly more severe cell injury in Cx43+/+ fibroblasts, as compared with Cx43-/- fibroblasts. Cd(2+) caused a reduction in intracellular GSH, whereas it elevated extracellular GSH. This effect of Cd(2+) was more dramatic in Cx43+/+ than Cx43-/- fibroblasts. Treatment of Cx43+/+ fibroblasts with Cd(2+) caused a Cx43 hemichannel-dependent influx of Lucifer Yellow and efflux of ATP. Collectively, our study demonstrates that Cx43 sensitizes cells to Cd(2+)-initiated cytotoxicity, possibly through hemichannel-mediated effects on intracellular oxidative status.}, }
@article {pmid21219105, year = {2011}, author = {Chang, EY and Zhang, J and Sullivan, S and Newman, R and Singh, I}, title = {N-acetylcysteine attenuates the maternal and fetal proinflammatory response to intrauterine LPS injection in an animal model for preterm birth and brain injury.}, journal = {The journal of maternal-fetal &amp; neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians}, volume = {24}, number = {5}, pages = {732-740}, doi = {10.3109/14767058.2010.528089}, pmid = {21219105}, issn = {1476-4954}, support = {R01 NS022576/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Animals, Newborn ; Brain/pathology ; Brain Injuries/immunology/pathology/*prevention &amp; control ; Female ; Fetal Diseases/immunology/pathology/*prevention &amp; control ; Free Radical Scavengers/*therapeutic use ; Mice ; Pregnancy ; Premature Birth/immunology/*prevention &amp; control ; }, abstract = {OBJECTIVE: Maternal immune activation (MIA) is associated with preterm birth (PTB) and abnormal neurologic outcome. We hypothesized that N-acetylcysteine (NAC) would decrease PTB and neonatal brain injury acting as an anti-inflammatory.<br><br>METHODS: Pregnant CD-1 mice received intrauterine LPS or saline on day 15/20. They received NAC or saline and were monitored until delivery. Pups were followed and sacrificed on postnatal days 1/30 and brains were collected. Immunostaining for heavy-chain neurofilament protein (NF-H), myelin basic protein (MBP), and proteolipid protein (PLP) was performed. In another group, animals were sacrificed 6 h after treatment, and fetal brain, placenta, and myometrium were collected. Il-6, Il-1&#x3b2;, Il-10, and tumor necrosis factor (TNF)-&#x3b1; mRNA expression was determined. Nonparametric analysis was used for analysis, and pairwise comparisons were performed when appropriate.<br><br>RESULTS: Lipopolysaccharide (LPS) caused PTB (79 vs. 0%, p < 0.005), and this was reduced by NAC [0.45 (95% CI: 0.26-0.83), p < 0.008]. LPS increased IL-6 expression in myometrium and placenta. This was attenuated by NAC in myometrium. IL-1&#x3b2;, IL-6, and TNF-&#x3b1; expression increased in the fetal brain with LPS. LPS produced altered NF-H, MBP, and PLP staining, and these effects were attenuated by NAC.<br><br>CONCLUSION: NAC attenuates inflammation in this MIA model and reduces PTB and white matter injury. It is an interesting candidate for study for prevention of PTB and neurologic injury.}, }
@article {pmid21212636, year = {2011}, author = {Temma-Asano, K and Tskitishvili, E and Kanagawa, T and Tomimatsu, T and Tsutsui, T and Kimura, T and Chang, YS and Nakamura, T and Nakai, Y and Shimoya, K}, title = {Effects of 4-hydroxy-2-nonenal, a major lipid peroxidation-derived aldehyde, and N-acetylcysteine on the cyclooxygenase-2 expression in human uterine myometrium.}, journal = {Gynecologic and obstetric investigation}, volume = {72}, number = {1}, pages = {37-42}, doi = {10.1159/000322393}, pmid = {21212636}, issn = {1423-002X}, mesh = {Acetylcysteine/*pharmacology ; Aldehydes/metabolism/*pharmacology ; Cyclooxygenase 2/*genetics ; Dinoprostone/biosynthesis ; Epoprostenol/biosynthesis ; Female ; Gene Expression/drug effects ; Humans ; Myometrium/*enzymology ; Obstetric Labor, Premature/metabolism ; Pregnancy ; RNA, Messenger/analysis ; Tissue Culture Techniques ; }, abstract = {BACKGROUND: Chorioamnionitis is one of the important causes of preterm labor. Preterm labor with chorioamnionitis is associated with oxidative stress. We reported that 4-hydroxy-2-nonenal (4-HNE), a major end product of oxidative fatty acid metabolism, is accumulated in the placenta with chorioamnionitis. The aim of this study was to confirm the effect of 4-HNE on cyclooxygenase-2 (COX-2) and prostaglandin (PG) induction in the uterine myometrial tissues. We also examined the effect of N-acetylcysteine (NAC) on 4-HNE-induced COX-2 expression.<br><br>METHODS: Uterine myometrial tissues were obtained from 5 patients. One of them underwent elective cesarean section without labor, and 4 of them underwent hysterectomy because of placental previa or atonic bleeding. We stimulated the uterine myometrial tissues with 4-HNE. In addition, the tissues were pretreated with NAC before 4-HNE treatment. The expression of COX-2 mRNA was observed by real-time PCR. PGE2 and prostacyclin release into the supernatants of the tissue cultures was measured by ELISA.<br><br>RESULTS: 4-HNE induced the COX-2 mRNA expression and PGE2 production in the uterine myometrial tissue culture in a dose-dependent and time-dependent manner. NAC inhibited 4-HNE-induced COX-2 expression.<br><br>CONCLUSION: 4-HNE may play an important role in preterm labor. NAC might be protective against preterm labor under oxidative stress.}, }
@article {pmid21211411, year = {2010}, author = {Xiang, YH and Su, XL and Hu, CP and Luo, YQ and He, RX}, title = {[A study of the related pathways of oxidative stress in chronic intermittent hypoxia rats and the effect of N-acetylcysteine].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {33}, number = {12}, pages = {912-916}, pmid = {21211411}, issn = {1001-0939}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Blood Pressure ; Hypertension/*metabolism ; Hypoxia/*metabolism ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Renin-Angiotensin System ; Sleep Apnea, Obstructive/metabolism ; }, abstract = {OBJECTIVE: To study the relation of oxidative stress with systolic blood pressure (SBP) and renin-agiotensin system (RAS) in a rat model of chronic intermittent hypoxia (CIH), and to investigate the preventive effect and mechanism of N-acetylcysteine (NAC) in CIH-induced hypertension.<br><br>METHODS: Twenty-four male Sprague-Dawley (SD) rats were divided into 4 groups: CIH+NAC group (CIH1), CIH+normal saline (NS) group (CIH2), CIH control group (CIH3) and blank control group (UC). CIH rats were subjected to alternating cycles of hypoxia (6%-8% O2 in N2 for 20-25 s) and normoxia (21% O2 in N2 for 2 min) every 180 s for 7 h per day. Rats in the CIH1 group were treated with NAC (800 ml&#xd7;kg(-1)&#xd7;d(-1)) by intraperitoneal injection, and those in the CIH2 group were treated with NS (5 ml&#xd7;kg(-1)&#xd7;d(-1)).<br><br>RESULTS: SBP in the CIH2 and CIH3 groups at the end of 6th week was significantly elevated compared with the baseline SBP (P<0.001) and those in the CIH1 and the UC groups (P<0.05). The expression of angiotensin-converting enzyme (ACE) and ACE2 in renal arterioles was significantly different (P<0.05), and the levels of angiotensin II (AngII) in the serum and kidney tissues, oxidation of low density lipoprotein (ox-LDL) and malondialdehyde (MDA) in the serum were increased. Ang-(1-7) and the inhibitory capability for hydroxyl free radicals in the serum were decreased significantly in CIH2 and CIH3 groups compared with CIH1 and UC (P<0.05) groups at the end of 6th week. SBP showed a positive correlation with AngII in serum and kidney tissues, but showed a negative correlation with Ang-(1-7) in serum and kidney tissues. The levels of MDS and ox-LDL in serum showed a positive correlation with AngII in serum and kidney tissues respectively, but showed a negative correlation with Ang-(1-7) in serum and kidney tissues respectively. The inhibitory capability for hydroxyl free radicals in serum showed a positive correlation with Ang-(1-7), but a negative correlation with AngII. The level of ox-LDL showed a positive correlation with MDA, but a negative correlation with the inhibitory capability for hydroxyl free radicals. There were no significant difference between CIH1 and UC groups in parameters except of SBP and AngII (P<0.05). All the data were not different between CIH2 and CIH3 groups (P>0.05).<br><br>CONCLUSIONS: CIH caused oxidative stress and RAS imbalance in rats. The imbalance of RAS in CIH rats was related with oxidative stress. The imbalance of RAS and oxidative stress may be one of the important mechanisms for CIH-induced hypertension. NAC can prevent CIH-induced hypertension through modulation of RAS by its anti-oxidative effect.}, }
@article {pmid21210850, year = {2012}, author = {Saha, L and Kaur, S and Saha, PK}, title = {Pharmacotherapy of polycystic ovary syndrome--an update.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {26}, number = {1}, pages = {54-62}, doi = {10.1111/j.1472-8206.2010.00916.x}, pmid = {21210850}, issn = {1472-8206}, mesh = {Anovulation/drug therapy/etiology ; Clomiphene/therapeutic use ; Contraceptives, Oral/pharmacology/*therapeutic use ; Female ; Fertility Agents, Female/therapeutic use ; Humans ; Insulin Resistance ; Ovulation Induction/*methods ; Polycystic Ovary Syndrome/diagnosis/*drug therapy/physiopathology ; }, abstract = {Polycystic ovary syndrome (PCOS) is a persisting challenge to clinical and basic research scientists as none of the presently available medications have been fully able to combat these consequences. The aim of the present review is to summarize the different lines of treatment available for the different symptomologies that women with PCOS presents. In this comprehensive review, search was made for various treatment options available for PCOS by using Cochrane library, Pubmed, Medline, in addition to the relevant printed medical journals and periodicals. The search results revealed that oral contraceptives containing oestrogen and progesterone regularize the menstruation, antiandrogens like spironolactone and drosperinone have proven to be effective in hirsutism and acne, clomiphene is the gold standard for ovulation induction, but multiple pregnancies and clomiphene failure add to its limitation. Hence, aromatase inhibitors like letrozole, low-dose gondotropins, and ovarian drilling procedure have shown to be beneficial effect in clomiphene-resistant cases. Insulin sensitizers such as metformin, thiazolidinediones, and d-chiro-inositol increase insulin sensitivity and improve ovulation rate. Recently, melatonin, N-acetyl cysteine, acarbose, and statins have shown positive results in different symptomologies of PCOS. The results show that PCOS treatment constitutes varied line of treatment depending upon the clinical features with which a woman is presenting. Still, unfortunately, none of the treatments are fully able to combat the PCOS.}, }
@article {pmid21205947, year = {2011}, author = {Anderson, SM and Park, ZH and Patel, RV}, title = {Intravenous N-acetylcysteine in the prevention of contrast media-induced nephropathy.}, journal = {The Annals of pharmacotherapy}, volume = {45}, number = {1}, pages = {101-107}, doi = {10.1345/aph.1P275}, pmid = {21205947}, issn = {1542-6270}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/pharmacokinetics/*therapeutic use ; Antioxidants/administration &amp; dosage/adverse effects/pharmacokinetics/therapeutic use ; Contrast Media/*toxicity ; Creatinine/blood ; Humans ; Infusions, Intravenous ; Kidney/drug effects/physiopathology ; Protective Agents/administration &amp; dosage/adverse effects/pharmacokinetics/*therapeutic use ; Renal Insufficiency/blood/*chemically induced/metabolism/*prevention &amp; control ; Vasodilator Agents/administration &amp; dosage/adverse effects/pharmacokinetics/therapeutic use ; }, abstract = {OBJECTIVE: To define the clinical role of intravenous N-acetylcysteine for prophylaxis of contrast-induced nephropathy (CIN).<br><br>DATA SOURCES: Randomized controlled clinical trials were identified using a search of MEDLINE (1990-September 2010) with the search terms acetylcysteine, N-acetylcysteine, NAC, intravenous, IV, nephropathy, nephrotoxic, radiocontrast, contrast, and media. The search was limited to studies published in English. Additional pertinent literature was retrieved by reviewing references of the articles obtained in the initial search.<br><br>DATA SYNTHESIS: N-Acetylcysteine is a vasodilator and antioxidant that has been investigated for the prevention of CIN. In the majority of clinical trials, neither oral nor intravenous N-acetylcysteine has demonstrated clinical benefits at preventing CIN. The pharmacodynamic and pharmacokinetic profiles of intravenous N-acetylcysteine are significantly different from those of the oral product in that intravenous administration bypasses extensive first-pass metabolism. Studies have suggested that N-acetylcysteine directly affects serum creatinine levels in a way that is not associated with improvement of kidney function. Only intravenous N-acetylcysteine doses that were higher than the oral doses showed potential benefits, but they were associated with significant adverse events. Furthermore, the study populations were heterogeneous, including patients with various levels of kidney function and other risk factors, and the clinical definition of CIN was not well established.<br><br>CONCLUSIONS: No conclusive evidence has shown that intravenous N-acetylcysteine is safe and effective in preventing CIN. Further clinical trials to define its role are warranted.}, }
@article {pmid21204616, year = {2011}, author = {Wang, SC and Wu, CC and Wei, YY and Hong, JH and Chiang, CS}, title = {Inactivation of ataxia telangiectasia mutated gene can increase intracellular reactive oxygen species levels and alter radiation-induced cell death pathways in human glioma cells.}, journal = {International journal of radiation biology}, volume = {87}, number = {4}, pages = {432-442}, doi = {10.3109/09553002.2011.538128}, pmid = {21204616}, issn = {1362-3095}, mesh = {Apoptosis/*drug effects ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line, Tumor ; DNA-Binding Proteins/*metabolism ; Gene Silencing ; Glioma/*metabolism ; Humans ; Oxidative Stress/*radiation effects ; Protein Serine-Threonine Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*radiation effects ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {PURPOSE: To investigate the effects of ataxia telangiectasia mutated (ATM)-regulated reactive oxygen species (ROS) and cell death pathways on the response of U87MG glioma cells to ionising radiation (IR) and oxidative stress.<br><br>MATERIAL AND METHODS: ATM expression was blocked in U87MG glioma cells using a small interfering RNA (siRNA) technique. Cell survival, sub-lethal damage (SLD), and potential lethal damage (PLD) repair following IR were assessed by clonogenic assay while changes in intracellular ROS, the apoptosis, and autophagy were followed by flow cytometry and Western blotting.<br><br>RESULTS: Blocking ATM expression in U87MG cells increased intracellular ROS levels and sensitivity to the cytotoxic effects of IR and oxygen stress; effects that could be partly counteracted by the antioxidant N-acetylcysteine (NAC). Knock down of ATM rendered cells unable to repair sub-lethal or potentially lethal damage and DNA double strand breaks (DSB) after IR exposure; something that NAC could not counteract. ATM did control the pathways a cell used to die following IR and this did seem to be ROS-dependent.<br><br>CONCLUSION: ATM is involved in redox control but ROS elevations following ATM knock down seem more involved in the decision as to what cell death pathway is utilised after IR than DSB repair and radiosensitivity.}, }
@article {pmid21203802, year = {2011}, author = {Panatto, JP and Jeremias, IC and Ferreira, GK and Ramos, AC and Rochi, N and Gonçalves, CL and Daufenbach, JF and Jeremias, GC and Carvalho-Silva, M and Rezin, GT and Scaini, G and Streck, EL}, title = {Inhibition of mitochondrial respiratory chain in the brain of rats after hepatic failure induced by acetaminophen.}, journal = {Molecular and cellular biochemistry}, volume = {350}, number = {1-2}, pages = {149-154}, pmid = {21203802}, issn = {1573-4919}, mesh = {*Acetaminophen ; Acetylcysteine/pharmacology ; Analgesics, Non-Narcotic ; Animals ; Antioxidants/pharmacology ; Brain/*drug effects/metabolism/physiology ; Deferoxamine/pharmacology ; Down-Regulation/drug effects ; Drug Evaluation, Preclinical ; Electron Transport/*drug effects/physiology ; Liver Failure/*chemically induced/metabolism/physiopathology ; Male ; Mitochondria/*drug effects/metabolism ; Rats ; Rats, Wistar ; Taurine/pharmacology ; }, abstract = {Hepatic encephalopathy is an important cause of morbidity and mortality in patients with severe hepatic failure. This disease is clinically characterized by a large variety of symptoms including motor symptoms, cognitive deficits, as well as changes in the level of alertness up to hepatic coma. Acetaminophen is frequently used in animals to produce an experimental model to study the mechanisms involved in the progression of hepatic disease. The brain is highly dependent on ATP and most cell energy is obtained through oxidative phosphorylation, a process requiring the action of various respiratory enzyme complexes located in a special structure of the inner mitochondrial membrane. In this context, the authors evaluated the activities of mitochondrial respiratory chain complexes in the brain of rats submitted to acute administration of acetaminophen and treated with the combination of N-acetylcysteine (NAC) plus deferoxamine (DFX) or taurine. These results showed that acetaminophen administration inhibited the activities of complexes I and IV in cerebral cortex and that the treatment with NAC plus DFX or taurine was not able to reverse this inhibition. The authors did not observe any effect of acetaminophen administration on complexes II and III activities in any of the structures studied. The participation of oxidative stress has been postulated in the hepatic encephalopathy and it is well known that the electron transport chain itself is vulnerable to damage by reactive oxygen species. Since there was no effect of NAC + DFX, the effect of acetaminophen was likely to be due to something else than oxidative stress.}, }
@article {pmid21203535, year = {2010}, author = {Liu, JQ and Lee, TF and Bigam, DL and Cheung, PY}, title = {Effects of post-resuscitation treatment with N-acetylcysteine on cardiac recovery in hypoxic newborn piglets.}, journal = {PloS one}, volume = {5}, number = {12}, pages = {e15322}, pmid = {21203535}, issn = {1932-6203}, support = {MOP51306//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Animals, Newborn ; Caspase 3/metabolism ; Heart/*drug effects ; Hemodynamics ; Hydrogen Peroxide/chemistry ; Hypoxia ; Lactates/metabolism ; Lipids/chemistry ; Myocardium/pathology ; Oxidative Stress ; Oxygen/chemistry/therapeutic use ; Oxygen Inhalation Therapy/methods ; Reactive Oxygen Species ; Stroke Volume ; Swine ; Troponin I/metabolism ; }, abstract = {AIMS: Although N-acetylcysteine (NAC) can decrease reactive oxygen species and improve myocardial recovery after ischemia/hypoxia in various acute animal models, little is known regarding its long-term effect in neonatal subjects. We investigated whether NAC provides prolonged protective effect on hemodynamics and oxidative stress using a surviving swine model of neonatal asphyxia.<br><br>METHODS AND RESULTS: Newborn piglets were anesthetized and acutely instrumented for measurement of systemic hemodynamics and oxygen transport. Animals were block-randomized into a sham-operated group (without hypoxia-reoxygenation [H-R, n = 6]) and two H-R groups (2 h normocapnic alveolar hypoxia followed by 48 h reoxygenation, n = 8/group). All piglets were acidotic and in cardiogenic shock after hypoxia. At 5 min after reoxygenation, piglets were given either saline or NAC (intravenous 150 mg/kg bolus + 20 mg/kg/h infusion) via for 24 h in a blinded, randomized fashion. Both cardiac index and stroke volume of H-R controls remained lower than the pre-hypoxic values throughout recovery. Treating the piglets with NAC significantly improved cardiac index, stroke volume and systemic oxygen delivery to levels not different from those of sham-operated piglets. Accompanied with the hemodynamic improvement, NAC-treated piglets had significantly lower plasma cardiac troponin-I, myocardial lipid hydroperoxides, activated caspase-3 and lactate levels (vs. H-R controls). The change in cardiac index after H-R correlated with myocardial lipid hydroperoxides, caspase-3 and lactate levels (all p<0.05).<br><br>CONCLUSIONS: Post-resuscitation administration of NAC reduces myocardial oxidative stress and caused a prolonged improvement in cardiac function and in newborn piglets with H-R insults.}, }
@article {pmid21198874, year = {2011}, author = {Lee, SS and Tseng, LH and Li, YC and Tsai, CH and Chang, YC}, title = {Heat shock protein 47 expression in oral squamous cell carcinomas and upregulated by arecoline in human oral epithelial cells.}, journal = {Journal of oral pathology &amp; medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology}, volume = {40}, number = {5}, pages = {390-396}, doi = {10.1111/j.1600-0714.2010.00998.x}, pmid = {21198874}, issn = {1600-0714}, mesh = {Acetylcysteine/pharmacology ; Areca/*adverse effects ; Arecoline/antagonists &amp; inhibitors/*pharmacology ; Carcinoma, Squamous Cell/chemically induced/*metabolism/pathology ; Case-Control Studies ; Cell Line, Tumor ; Cholinergic Agonists/*pharmacology ; Cyclooxygenase 2/pharmacology ; Epithelial Cells/drug effects/metabolism ; Extracellular Signal-Regulated MAP Kinases/pharmacology ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Glutathione/pharmacology ; HSP47 Heat-Shock Proteins/*biosynthesis ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Mouth Mucosa/cytology/drug effects/*metabolism ; Mouth Neoplasms/chemically induced/*metabolism/pathology ; Neoplasm Staging ; Phosphatidylinositol 3-Kinase/pharmacology ; Protein-Tyrosine Kinases/pharmacology ; Signal Transduction ; Up-Regulation ; }, abstract = {BACKGROUND: Heat shock protein 47 (HSP47) is a product of CBP2 gene located at chromosome 11q13.5, a region frequently amplified in human cancers. Areca quid chewing is a major risk factor of oral squamous cell carcinoma (OSCC). The aim of this study was to compare HSP47 expression in normal human oral epithelium and OSCC and further to explore the potential mechanisms that may lead to induce HSP47 expression.<br><br>METHODS: Thirty-two OSCC specimens and ten normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The oral epithelial cell line OC2 cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, glutathione precursor N-acetyl-l-cysteine (NAC), extracellular signal-regulated protein kinase (ERK) inhibitor PD98059, phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, cyclooxygenase-2 inhibitor NS-398, and tyrosine kinase inhibitor herbimycin A were added to find the possible regulatory mechanisms.<br><br>RESULTS: HSP47 expression was significantly higher in OSCC specimens than normal epithelium (P<0.05). No significant difference in HSP47 expression was observed with respect to age, sex, T category, stage, and differentiation (P>0.05). The lower HSP47 expression was associated with lymph node metastasis (P=0.015). Arecoline was found to elevate HSP47 expression in a dose- and time-dependent manner (P<0.05). The addition of NAC, PD98059, LY294002, NS398, and herbimycin A markedly inhibited the arecoline-induced HSP47 expression (P<0.05).<br><br>CONCLUSION: &#x2002; Our findings demonstrated that HSP47 expression is significantly upregulated in areca quid chewing-associated OSCCs. HSP47 could be used clinically as a marker for lymph node metastasis of oral carcinogenesis. In addition, arecoline-induced HSP47 expression was downregulated by NAC, PD98059, LY294002, NS398, and herbimycin A.}, }
@article {pmid21195169, year = {2011}, author = {Chen, L and Xu, B and Liu, L and Luo, Y and Zhou, H and Chen, W and Shen, T and Han, X and Kontos, CD and Huang, S}, title = {Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death.}, journal = {Free radical biology &amp; medicine}, volume = {50}, number = {5}, pages = {624-632}, pmid = {21195169}, issn = {1873-4596}, support = {R01 CA115414/CA/NCI NIH HHS/United States ; R01 CA115414-04/CA/NCI NIH HHS/United States ; CA115414/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/analysis ; Androstadienes/pharmacology ; Animals ; Apoptosis/*drug effects ; Cadmium/*toxicity ; Carrier Proteins/metabolism ; Environmental Pollutants/*toxicity ; Gene Expression Regulation ; Humans ; Intracellular Signaling Peptides and Proteins ; NADPH Oxidases/genetics/physiology ; Neurodegenerative Diseases/chemically induced/metabolism/pathology ; Neurons/*drug effects/pathology ; PC12 Cells ; Phosphoinositide-3 Kinase Inhibitors ; Phosphoproteins/genetics/metabolism ; Phosphorylation ; Rats ; Reactive Oxygen Species/*metabolism ; Receptors, Somatomedin/genetics ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; TOR Serine-Threonine Kinases/*metabolism ; Wortmannin ; rac1 GTP-Binding Protein/genetics ; }, abstract = {Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd induces neuronal apoptosis in part through activation of the mammalian target of rapamycin (mTOR) pathway. However, the underlying mechanism is unknown. Here we show that Cd induces the generation of reactive oxygen species (ROS) by upregulating the expression of NADPH oxidase 2 and its regulatory proteins (p22(phox), p67(phox), p40(phox), p47(phox), and Rac1) in PC12 and SH-SY5Y cells. Cd induction of ROS contributed to the activation of mTOR signaling, as pretreatment with N-acetyl-l-cysteine (NAC), a ROS scavenger, prevented this event. Further studies reveal that Cd induction of ROS increased phosphorylation of the type I insulin-like growth factor receptor (IGFR) β subunit, which was abrogated by NAC. Wortmannin, a phosphoinositide 3'-kinase (PI3K) inhibitor, partially attenuated Cd-induced phosphorylation of Akt, p70 S6 kinase 1, and eukaryotic initiation factor 4E-binding protein 1, as well as apoptosis of the neuronal cells. In addition, overexpression of wild-type phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or pretreatment with aminoimidazole carboxamide ribonucleotide, an AMP-activated protein kinase (AMPK) activator, partially prevented Cd-induced ROS and activation of the mTOR pathway, as well as cell death. The results indicate that Cd induction of ROS activates mTOR signaling, leading to neuronal cell death, in part by activating the positive regulators IGFR/PI3K and by inhibiting the negative regulators PTEN/AMPK. The findings suggest that inhibitors of PI3K and mTOR, activators of AMPK, or antioxidants may be exploited for the prevention of Cd-induced neurodegenerative diseases.}, }
@article {pmid21194832, year = {2011}, author = {Li, B and Zhao, J and Wang, CZ and Searle, J and He, TC and Yuan, CS and Du, W}, title = {Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53.}, journal = {Cancer letters}, volume = {301}, number = {2}, pages = {185-192}, pmid = {21194832}, issn = {1872-7980}, support = {R01 GM074197-05/GM/NIGMS NIH HHS/United States ; R01 CA106569-03/CA/NCI NIH HHS/United States ; AT004418/AT/NCCIH NIH HHS/United States ; R01 GM074197-04/GM/NIGMS NIH HHS/United States ; R01 GM074197/GM/NIGMS NIH HHS/United States ; CA106569/CA/NCI NIH HHS/United States ; R01 CA106569/CA/NCI NIH HHS/United States ; P01 AT004418/AT/NCCIH NIH HHS/United States ; R01 CA149275/CA/NCI NIH HHS/United States ; P01 AT004418-03/AT/NCCIH NIH HHS/United States ; P01 AT004418-01A1/AT/NCCIH NIH HHS/United States ; GM074197/GM/NIGMS NIH HHS/United States ; P01 AT004418-02/AT/NCCIH NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Blotting, Western ; Caspase Inhibitors ; Caspases/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Colorectal Neoplasms/metabolism/pathology ; Cysteine Proteinase Inhibitors/pharmacology ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal/pharmacology ; Free Radical Scavengers/pharmacology ; Ginsenosides/*pharmacology ; HCT116 Cells ; HEK293 Cells ; Humans ; Mutation ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/genetics/*metabolism ; Vacuoles/drug effects/metabolism ; }, abstract = {Ginsenosides are the main bioactive components in American ginseng, a commonly used herb. In this study, we showed that the ginsenoside Rh2 exhibited significantly more potent cell death activity than the ginsenoside Rg3 in HCT116 and SW480 colorectal cancer cells. Cell death induced by Rh2 is mediated in part by the caspase-dependent apoptosis and in part by the caspase-independent paraptosis, a type of cell death that is characterized by the accumulation of cytoplasmic vacuoles. Treatment of cells with Rh2 activated the p53 pathway and significantly increased the levels of the pro-apoptotic regulator, Bax, while decreasing the levels of anti-apoptosis regulator Bcl-2. Removal of p53 significantly blocked Rh2-induced cell death as well as vacuole formation, suggesting that both types of cell death induced by Rh2 are mediated by p53 activity. Furthermore, we show that Rh2 increased ROS levels and activated the NF-κB survival pathway. Blockage of ROS by NAC or catalase inhibited the activation of NF-κB signaling and enhanced Rh2-induced cell death, suggesting that the anti-cancer effect of Rh2 can be enhanced by antioxidants.}, }
@article {pmid21194352, year = {2011}, author = {Yong, QC and Cheong, JL and Hua, F and Deng, LW and Khoo, YM and Lee, HS and Perry, A and Wood, M and Whiteman, M and Bian, JS}, title = {Regulation of heart function by endogenous gaseous mediators-crosstalk between nitric oxide and hydrogen sulfide.}, journal = {Antioxidants &amp; redox signaling}, volume = {14}, number = {11}, pages = {2081-2091}, doi = {10.1089/ars.2010.3572}, pmid = {21194352}, issn = {1557-7716}, mesh = {Animals ; Arginine/pharmacology ; Caffeine/pharmacology ; Calcium Signaling/drug effects ; Cardiotonic Agents/pharmacology ; Cells, Cultured ; Depression, Chemical ; Electric Stimulation ; Gases ; Heart/*drug effects ; Hydrogen Sulfide/*metabolism/pharmacology ; Male ; Myocardial Contraction/drug effects ; Myocardium/cytology/*metabolism ; Myocytes, Cardiac/drug effects/metabolism ; Nitric Oxide/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Both nitric oxide (NO) and hydrogen sulfide (H(2)S) are two important gaseous mediators regulating heart function. The present study examined the interaction between these two biological gases and its role in the heart. We found that l-arginine, a substrate of NO synthase, decreased the amplitudes of myocyte contraction and electrically induced calcium transients. Sodium hydrogen sulfide (an H(2)S donor), which alone had minor effect, reversed the negative inotropic effects of l-arginine. The effect of l-arginine + sodium hydrogen sulfide was abolished by three thiols (l-cysteine, N-acetyl-cysteine, and glutathione), suggesting that the effect of H(2)S + NO is thiol sensitive. The stimulatory effect on heart contractility was also induced by GYY4137, a slow-releasing H(2)S donor, when used together with sodium nitroprusside, an NO-releasing donor. More importantly, enzymatic generation of H(2)S from recombinant cystathionine-γ-lyase protein also interacted with endogenous NO generated from l-arginine to stimulate heart contraction. In summary, our data suggest that endogenous NO may interact with H(2)S to produce a new biological mediator that produces positive inotropic effect. The crosstalk between H(2)S and NO also suggests an intriguing potential for the endogenous formation of a thiol-sensitive molecule, which may be of physiological significance in the heart.}, }
@article {pmid21189918, year = {2010}, author = {Shivbalan, S and Sathiyasekeran, M and Thomas, K}, title = {Therapeutic misadventure with paracetamol in children.}, journal = {Indian journal of pharmacology}, volume = {42}, number = {6}, pages = {412-415}, pmid = {21189918}, issn = {1998-3751}, abstract = {Paracetamol (acetaminophen), though considered a safe, "over the counter" analgesic and antipyretic, can cause liver injury with overdose. Therapeutic misadventure is a unique problem where the existing nomogram used for acute poisoning is not applicable. In this context, early initiation of N-acetylcysteine even before a biochemical evidence of liver injury may be beneficial. A series of 6 children with this type of paracetamol overdose are presented here to increase the awareness and understanding of this problem since no such data is available from India.}, }
@article {pmid21187656, year = {2011}, author = {Niwano, S and Niwano, H and Sasaki, S and Fukaya, H and Yuge, M and Imaki, R and Machida, Y and Izumi, T}, title = {N-acetylcysteine suppresses the progression of ventricular remodeling in acute myocarditis: studies in an experimental autoimmune myocarditis (EAM) model.}, journal = {Circulation journal : official journal of the Japanese Circulation Society}, volume = {75}, number = {3}, pages = {662-671}, doi = {10.1253/circj.cj-10-0673}, pmid = {21187656}, issn = {1347-4820}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/therapeutic use ; Acute Disease ; Animals ; Autoimmune Diseases/drug therapy/metabolism/*physiopathology ; Disease Models, Animal ; *Disease Progression ; Dose-Response Relationship, Drug ; Free Radical Scavengers/administration &amp; dosage/pharmacology/therapeutic use ; Injections, Intraperitoneal ; Myocarditis/drug therapy/metabolism/*physiopathology ; Oxidative Stress/drug effects/physiology ; Rats ; Rats, Inbred Lew ; Reactive Oxygen Species/metabolism ; Ventricular Remodeling/*drug effects/physiology ; }, abstract = {BACKGROUND: Electrical and structural remodeling, characterized by prolonged action potential duration (APD), Kv4.2 downregulation and cellular infiltration were studied in rat experimental autoimmune myocarditis (EAM). Because the reactive oxygen species (ROS) has been speculated to play a role in the promotion of such remodeling, the effect of N-acetylcysteine (NAC) on the progression of ventricular remodeling was evaluated.<br><br>METHODS AND RESULTS: Six-week-old Lewis rats were immunized with porcine cardiac myosin. On Days 10-11 after the immunization, NAC (0, 1, 10, or 100mg) was injected intraperitoneally to EAM and control rats. On Day 14, the electrophysiological parameters were evaluated and the expression levels of the mRNA were examined by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR).The EAM rats exhibited a typical acute myocarditis with prolonged APD and reduced Kv4.2 expression as previously reported. The myocarditis and electrical changes were significantly suppressed by NAC-treatment in a dose-dependent manner (P<0.05). In rats with 100mg NAC, the myocarditis was almost totally negated although the mortality increased. In rats with 1mg NAC, the suppression of myocarditis was not obvious, but APD prolongation and Kv4.2 reduction was attenuated (P<0.05).<br><br>CONCLUSIONS: The NAC treatment suppressed ventricular remodeling in the EAM rats. This may indicate the role of oxidative stress in causing remodeling and myocarditis itself in the acute phase of myocarditis.}, }
@article {pmid21177487, year = {2011}, author = {Mahajan, MK and Uttamsingh, V and Daniels, JS and Gan, LS and LeDuc, BW and Williams, DA}, title = {In vitro metabolism of oxymetazoline: evidence for bioactivation to a reactive metabolite.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {39}, number = {4}, pages = {693-702}, doi = {10.1124/dmd.110.036004}, pmid = {21177487}, issn = {1521-009X}, mesh = {Acetylcysteine/metabolism ; Animals ; Aryl Hydrocarbon Hydroxylases/metabolism ; Cytochrome P-450 CYP2C19 ; Cytochrome P-450 Enzyme System/*metabolism ; Glutathione/*metabolism ; Humans ; Hydroxylation ; In Vitro Techniques ; Indolequinones/metabolism ; Liver/metabolism ; Male ; Microsomes, Liver/metabolism ; NADP/metabolism ; Oxidation-Reduction ; Oxymetazoline/chemistry/*metabolism ; Rabbits ; Rats ; Sympathomimetics/chemistry/*metabolism ; }, abstract = {Oxymetazoline (6-tert-butyl-3-(2-imidazolin-2-ylmethyl)-2,4-dimethylphenol) has been widely used as a nonprescription nasal vasoconstrictor for >40 years; however, its metabolic pathway has not been investigated. This study describes the in vitro metabolism of oxymetazoline in human, rat, and rabbit liver postmitochondrial supernatant fraction from homogenized tissue (S9) fractions and their microsomes supplemented with NADPH. The metabolites of oxymetazoline identified by liquid chromatography (LC)/UV/tandem mass spectrometry (MS/MS), included M1 (monohydroxylation of the t-butyl group), M2 (oxidative dehydrogenation of the imidazoline to an imidazole moiety), M3 (monohydroxylation of M2), M4 (dihydroxylation of oxymetazoline), and M5 (dihydroxylation of M2). Screening with nine human expressed cytochromes P450 (P450s) identified CYP2C19 as the single P450 isoform catalyzing the formation of M1, M2, and M3. Glutathione conjugates of oxymetazoline (M6) and M2 (M7) were identified in the liver S9 fractions, indicating the capability of oxymetazoline to undergo bioactivation to reactive intermediate species. M6 and M7 were not detected in those liver S9 incubations without NADPH. Cysteine conjugates (M8 and M9) derived from glutathione conjugates and hydroxylated glutathione conjugates (M10 and M11) were also identified. The reactive intermediate of oxymetazoline was trapped with glutathione and N-acetyl cysteine and identified by LC/MS/MS. M6 was isolated and identified by one-dimensional or two-dimensional NMR as the glutathione conjugate of a p-quinone methide. We have shown the tendency of oxymetazoline to form p-quinone methide species via a bioactivation mechanism involving a CYP2C19-catalyzed two-electron oxidation. Nevertheless, we conclude that the formation of this reactive species might not be a safety concern for oxymetazoline nasal products because of the typical low-dose and brief dosage regimen limited to nasal delivery.}, }
@article {pmid21175036, year = {2010}, author = {Said, SA and El-Agamy, DS}, title = {Prevention of sodium valproate-induced hepatotoxicity by curcumin, rosiglitazone and N-acetylcysteine in rats.}, journal = {Arzneimittel-Forschung}, volume = {60}, number = {11}, pages = {647-653}, doi = {10.1055/s-0031-1296342}, pmid = {21175036}, issn = {0004-4172}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anticonvulsants/antagonists &amp; inhibitors/therapeutic use/*toxicity ; Body Weight/drug effects ; Chemical and Drug Induced Liver Injury/pathology/*prevention &amp; control ; Convulsants ; Curcumin/*therapeutic use ; Eating/drug effects ; Fatty Liver/chemically induced/pathology/prevention &amp; control ; Free Radical Scavengers/*therapeutic use ; Hypoglycemic Agents/*therapeutic use ; Liver/pathology ; Liver Function Tests ; Male ; Mice ; Pentylenetetrazole ; Rats ; Rats, Sprague-Dawley ; Rosiglitazone ; Seizures/chemically induced/prevention &amp; control ; Thiazolidinediones/*therapeutic use ; Valproic Acid/antagonists &amp; inhibitors/therapeutic use/*toxicity ; }, abstract = {The present study was designed to examine the potential preventive effect of curcumin (CMN; CAS 458-37-7), rosiglitazone (RGN; CAS 155141-29-0), N-acetylcysteine (NAC; CAS 616-91-1), resveratrol (RSV; CAS 501-36-0), and losartan (LOS; CAS 114798-26-4) on sodium valproate-induced hepatotoxicity. Sodium valproate (SVP; CAS 1069-66-5) was given at a dose of 250 mg/kg i. p. 3 times daily for one week. The tested compounds were given simultaneously with SVP for one week. The results demonstrate that CMN, RGN and NAC treatment can confer protection from SVP-induced hepatotoxicity. The second part of the study includes an evaluation of the effect of CMN, RGN and NAC on the anticonvulsant activity of SVP against pentetrazole-induced seizures in mice. The results demonstrate that CMN, RGN and NAC do not affect the anticonvulsant activity of SVP. Combined administration of either of CMN, RGN and NAC with valproate appears to be beneficial in reducing valproate-induced hepatotoxicity.}, }
@article {pmid21171858, year = {2010}, author = {Bodmer, M and Monte, AA}, title = {"Massive acetaminophen ingestion with early metabolic acidosis and coma: treatment with iv nac and continuous venovenous hemodiafiltration" by Wiegand et al., Clin Toxicol (Phila) 48:156-159.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {48}, number = {9}, pages = {961; author reply 961-2}, doi = {10.3109/15563650.2010.535004}, pmid = {21171858}, issn = {1556-9519}, mesh = {Acetaminophen/pharmacokinetics/*poisoning ; Acetylcysteine/*therapeutic use ; Acidosis/chemically induced ; Analgesics, Non-Narcotic/*poisoning ; Coma/chemically induced ; Drug Overdose ; Half-Life ; *Hemodiafiltration ; Humans ; }, }
@article {pmid21166495, year = {2011}, author = {Pak, JH and Choi, WH and Lee, HM and Joo, WD and Kim, JH and Kim, YT and Kim, YM and Nam, JH}, title = {Peroxiredoxin 6 overexpression attenuates cisplatin-induced apoptosis in human ovarian cancer cells.}, journal = {Cancer investigation}, volume = {29}, number = {1}, pages = {21-28}, doi = {10.3109/07357907.2010.535056}, pmid = {21166495}, issn = {1532-4192}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/*pharmacology ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; Enzyme Activation ; Female ; Humans ; Ovarian Neoplasms/genetics/*metabolism/pathology ; Peroxiredoxin VI/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Time Factors ; Transfection ; Up-Regulation ; }, abstract = {We examined the involvement of peroxiredoxin 6 (Prdx 6) in providing chemoprotection against cisplatin cytotoxicity in SKOV-3 ovarian cancer cells. Treatment of SKOV-3 cells with cisplatin-induced cytotoxicity that was associated with increased accumulation of intracellular reactive oxygen species (ROS) and apoptosis mediated by proteolytically activated caspase 3 and 9. Overexpression of Prdx 6 protein or exposure to N-acetylcysteine (NAC) reversed the apoptotic effect of cisplatin by reducing ROS levels and suppressing the caspase signaling pathway. These results indicate that targeting Prdx 6 may sensitize cancer cells to ROS-producing therapeutic treatments, such as anticancer drugs and radiation.}, }
@article {pmid21160464, year = {2011}, author = {Amen, SL and Piacentine, LB and Ahmad, ME and Li, SJ and Mantsch, JR and Risinger, RC and Baker, DA}, title = {Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {36}, number = {4}, pages = {871-878}, pmid = {21160464}, issn = {1740-634X}, support = {F30 DA019754-02/DA/NIDA NIH HHS/United States ; R01 DA015758/DA/NIDA NIH HHS/United States ; DA09465/DA/NIDA NIH HHS/United States ; R01 DA017328/DA/NIDA NIH HHS/United States ; Z01 DA000486//Intramural NIH HHS/United States ; R01 DA025617/DA/NIDA NIH HHS/United States ; R01 DA009465/DA/NIDA NIH HHS/United States ; F30 DA019754/DA/NIDA NIH HHS/United States ; R01 DA025617-02/DA/NIDA NIH HHS/United States ; RR00058/RR/NCRR NIH HHS/United States ; R01 DA010214-04/DA/NIDA NIH HHS/United States ; DA010214/DA/NIDA NIH HHS/United States ; K23 DA000486-02/DA/NIDA NIH HHS/United States ; R01 DA017328-04/DA/NIDA NIH HHS/United States ; M01 RR000058/RR/NCRR NIH HHS/United States ; DA025617/DA/NIDA NIH HHS/United States ; R01 DA015758-07/DA/NIDA NIH HHS/United States ; DA017328/DA/NIDA NIH HHS/United States ; DA015758/DA/NIDA NIH HHS/United States ; R01 DA010214/DA/NIDA NIH HHS/United States ; DA019754/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Animals ; Behavior, Addictive/*drug therapy/psychology ; Cocaine-Related Disorders/*drug therapy/psychology ; Conditioning, Operant ; Humans ; Male ; Middle Aged ; Rats ; Rats, Sprague-Dawley ; Species Specificity ; }, abstract = {Addiction is a chronic relapsing disorder hypothesized to be produced by drug-induced plasticity that renders individuals vulnerable to craving-inducing stimuli such as re-exposure to the drug of abuse. Drug-induced plasticity that may result in the addiction phenotype includes increased excitatory signaling within corticostriatal pathways that correlates with craving in humans and is necessary for reinstatement in rodents. Reduced cystine-glutamate exchange by system x(c)- appears to contribute to heightened excitatory signaling within the striatum, thereby posing this as a novel target in the treatment of addiction. In the present report, we examined the impact of repeated N-acetyl cysteine, which is commonly used to activate cystine-glutamate exchange, on reinstatement in rodents in a preclinical study and on craving in cocaine-dependent humans in a preliminary, proof-of-concept clinical experiment. Interestingly, repeated administration (7 days) of N-acetyl cysteine (60 mg/kg, IP) produced a significant reduction in cocaine (10 mg/kg, IP)-induced reinstatement, even though rats (N=10-12/group) were tested 24 h after the last administration of N-acetyl cysteine. The reduction in behavior despite the absence of the N-acetyl cysteine indicates that repeated N-acetyl cysteine may have altered drug-induced plasticity that underlies drug-seeking behavior. In parallel, our preliminary clinical data indicate that repeated administration (4 days) of N-acetyl cysteine (1200-2400 mg/day) to cocaine-dependent human subjects (N=4 per group) produced a significant reduction in craving following an experimenter-delivered IV injection of cocaine (20 mg/70 kg/60 s). Collectively, these data demonstrate that N-acetyl cysteine diminishes the motivational qualities of a cocaine challenge injection possibly by altering pathogenic drug-induced plasticity.}, }
@article {pmid21156189, year = {2011}, author = {Chen, L and Charrier, AL and Leask, A and French, SW and Brigstock, DR}, title = {Ethanol-stimulated differentiated functions of human or mouse hepatic stellate cells are mediated by connective tissue growth factor.}, journal = {Journal of hepatology}, volume = {55}, number = {2}, pages = {399-406}, pmid = {21156189}, issn = {1600-0641}, support = {R01 AA016003/AA/NIAAA NIH HHS/United States ; R01 AA016003-04/AA/NIAAA NIH HHS/United States ; 5R01AA016003/AA/NIAAA NIH HHS/United States ; }, mesh = {Actins/genetics ; Animals ; Base Sequence ; Cell Line ; Cells, Cultured ; Collagen Type I/genetics ; Collagen Type I, alpha 1 Chain ; Connective Tissue Growth Factor/antagonists &amp; inhibitors/genetics/*metabolism ; Ethanol/*toxicity ; Gene Expression/drug effects ; Gene Knockdown Techniques ; Hepatic Stellate Cells/*drug effects/*metabolism/pathology ; Humans ; Liver Diseases, Alcoholic/metabolism/pathology ; Mice ; Promoter Regions, Genetic ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/genetics ; Smad Proteins/metabolism ; Transforming Growth Factor beta1/antagonists &amp; inhibitors/genetics/pharmacology ; }, abstract = {BACKGROUND &amp; AIMS: Connective tissue growth factor (CTGF) expression is intimately associated with hepatic fibrotic pathophysiology. In this study, CTGF production and action was investigated in ethanol-treated mouse primary hepatic stellate cells (HSC) or human LX-2 cells.<br><br>METHODS: CTGF, transforming growth factor-beta1 (TGF-&#x3b2;1), alpha-smooth muscle actin (&#x3b1;-SMA) or collagen &#x3b1;1(I) mRNA were quantified by real-time PCR after treatment of HSC with ethanol or acetaldehyde. CTGF protein production was assessed by immunoprecipitation or ELISA. Ethanol-stimulated CTGF transcription was investigated using CTGF promoter reporter constructs. The TGF-&#x3b2;1- or CTGF-dependency of ethanol-induced CTGF, &#x3b1;-SMA, or collagen &#x3b1;1(I) was determined using small interfering RNA (siRNA) to TGF-&#x3b2;1 or CTGF.<br><br>RESULTS: In human steatohepatitis, CTGF was produced by presumptive activated HSC. In cultured human or mouse HSC, production of CTGF, &#x3b1;-SMA and/or collagen was increased by ethanol treatment, an effect mimicked by acetaldehyde and blocked by 4-methylpyrazole (4-MP) or N-acetylcysteine (NAC). CTGF promoter activity was stimulated in a sustained fashion by ethanol or TGF-&#x3b2;1. Mutation of the Smad site or basal control element (BCE-1) in the CTGF promoter caused a 5-fold reduction in ethanol-stimulated CTGF promoter activity. Administration of TGF-&#x3b2;1 siRNA or CTGF siRNA significantly decreased ethanol- or acetaldehyde-stimulated mRNA or protein levels of CTGF, &#x3b1;-SMA or collagen I in LX-2 cells. In mouse HSC, TGF-&#x3b2;1- or ethanol-stimulated CTGF, &#x3b1;-SMA or collagen I were significantly attenuated by CTGF siRNA.<br><br>CONCLUSIONS: Ethanol-induced &#x3b1;-SMA or collagen &#x3b1;1(I) in HSC are mediated via TGF-&#x3b2;-dependent CTGF production, highlighting potential therapeutic benefits of targeting CTGF in alcoholic liver disease.}, }
@article {pmid21154881, year = {2011}, author = {Podder, S and Chattopadhyay, A and Bhattacharya, S and Ray, MR and Chakraborty, A}, title = {Fluoride-induced genotoxicity in mouse bone marrow cells: effect of buthionine sulfoximine and N-acetyl-L-cysteine.}, journal = {Journal of applied toxicology : JAT}, volume = {31}, number = {7}, pages = {618-625}, doi = {10.1002/jat.1605}, pmid = {21154881}, issn = {1099-1263}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Annexin A5/metabolism ; Apoptosis/drug effects ; Bone Marrow Cells/chemistry/*drug effects ; Buthionine Sulfoximine/*pharmacology ; Cell Cycle/drug effects ; Chromosome Aberrations/drug effects ; DNA Damage/*drug effects ; Dose-Response Relationship, Drug ; Glutathione/analysis ; Male ; Mice ; Reactive Oxygen Species/metabolism ; Sodium Fluoride/*toxicity ; }, abstract = {A significant level of reactive oxygen species generation was observed in sodium fluoride (NaF) treated mouse bone marrow cells (BMCs). Reduced glutathione (GSH) as a free radical scavenger could be an important determining factor in F-induced genotoxicity. We therefore attempted to monitor GSH to understand the mechanism of NaF-induced genotoxicity. NaF was injected intra-peritoneally in normal, buthionine sulfoximine (BSO) or N-acetyl-L-cysteine (NAC) treated mice (n = 5). After 13 h of NaF-treatment BMCs were collected to harvest them at the same divisional cycle and processed for analysis of cell cycle, induction of apoptosis and chromosomal aberrations (CAs). Level of GSH was also measured concomitantly. NaF induced significant CAs in all treatment groups except at 2.5 mg NaF kg(-1) body weight. BSO-treatment alone induced significantly high frequency of CAs. BSO treatment prior to injection of 2.5-7.5 mg NaF kg(-1) b.w. was found to increase the frequency of CAs, significantly when compared with the positive control group, but the level was not significant in case of higher doses of NaF treatment (15 and 30 mg kg(-1) b.w.). NaF-treated cells also showed a higher population of Annexin-V positive cells. NAC pre-treatment significantly reduced the extent of NaF-induced CAs, which clearly indicates the involvement of GSH in the NaF response. However, further study is warranted to evaluate the low synergistic effect of BSO on higher doses of NaF-induced CAs.}, }
@article {pmid21151885, year = {2010}, author = {Yang, W and Hekimi, S}, title = {A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans.}, journal = {PLoS biology}, volume = {8}, number = {12}, pages = {e1000556}, pmid = {21151885}, issn = {1545-7885}, support = {#216377//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Ascorbic Acid/metabolism ; Caenorhabditis elegans/genetics/*metabolism ; Caenorhabditis elegans Proteins/genetics/*metabolism ; Electron Transport ; Electron Transport Complex I/genetics/*metabolism ; Electron Transport Complex III/genetics/*metabolism ; Flow Cytometry ; Longevity ; Mitochondrial Proteins/genetics/*metabolism ; Models, Biological ; Paraquat/metabolism ; Reactive Oxygen Species/*metabolism ; Receptor, Insulin/genetics/metabolism ; *Signal Transduction ; Superoxides/metabolism ; }, abstract = {The nuo-6 and isp-1 genes of C. elegans encode, respectively, subunits of complex I and III of the mitochondrial respiratory chain. Partial loss-of-function mutations in these genes decrease electron transport and greatly increase the longevity of C. elegans by a mechanism that is distinct from that induced by reducing their level of expression by RNAi. Electron transport is a major source of the superoxide anion (O(⋅) (-)), which in turn generates several types of toxic reactive oxygen species (ROS), and aging is accompanied by increased oxidative stress, which is an imbalance between the generation and detoxification of ROS. These observations have suggested that the longevity of such mitochondrial mutants might result from a reduction in ROS generation, which would be consistent with the mitochondrial oxidative stress theory of aging. It is difficult to measure ROS directly in living animals, and this has held back progress in determining their function in aging. Here we have adapted a technique of flow cytometry to directly measure ROS levels in isolated mitochondria to show that the generation of superoxide is elevated in the nuo-6 and isp-1 mitochondrial mutants, although overall ROS levels are not, and oxidative stress is low. Furthermore, we show that this elevation is necessary and sufficient to increase longevity, as it is abolished by the antioxidants NAC and vitamin C, and phenocopied by mild treatment with the prooxidant paraquat. Furthermore, the absence of effect of NAC and the additivity of the effect of paraquat on a variety of long- and short-lived mutants suggest that the pathway triggered by mitochondrial superoxide is distinct from previously studied mechanisms, including insulin signaling, dietary restriction, ubiquinone deficiency, the hypoxic response, and hormesis. These findings are not consistent with the mitochondrial oxidative stress theory of aging. Instead they show that increased superoxide generation acts as a signal in young mutant animals to trigger changes of gene expression that prevent or attenuate the effects of subsequent aging. We propose that superoxide is generated as a protective signal in response to molecular damage sustained during wild-type aging as well. This model provides a new explanation for the well-documented correlation between ROS and the aged phenotype as a gradual increase of molecular damage during aging would trigger a gradually stronger ROS response.}, }
@article {pmid21149830, year = {2011}, author = {Crespo, MJ and Cruz, N and Altieri, PI and Escobales, N}, title = {Chronic treatment with N-acetylcysteine improves cardiac function but does not prevent progression of cardiomyopathy in Syrian cardiomyopathic hamsters.}, journal = {Journal of cardiovascular pharmacology and therapeutics}, volume = {16}, number = {2}, pages = {197-204}, doi = {10.1177/1074248410387281}, pmid = {21149830}, issn = {1940-4034}, support = {2 SO6 GM08224/GM/NIGMS NIH HHS/United States ; G12RR03051/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/*pharmacology ; Age Factors ; Animals ; Antioxidants/*pharmacology ; Aorta, Thoracic/drug effects/metabolism ; Blood Pressure/drug effects ; Cardiac Output/drug effects ; Cardiomyopathy, Dilated/*drug therapy/physiopathology ; Cricetinae ; Disease Models, Animal ; Disease Progression ; Echocardiography ; Heart Failure/etiology/prevention &amp; control ; Male ; Mesocricetus ; Oxidative Stress/*drug effects ; Time Factors ; }, abstract = {Oxidative stress has been postulated to contribute to the onset and development of heart failure (HF). The efficacy of antioxidant therapy in HF, however, remains controversial. This study evaluates the effect of the antioxidant N-acetylcysteine (NAC, 1 g/kg per day) on cardiovascular function in 2- and 6-month-old Bio-TO2 Syrian cardiomyopathic hamsters (SCH) after treatment for 1 month and 5 months with this drug. Endothelial function, systolic blood pressure (SBP), and echocardiographic parameters were evaluated. Age-matched F1-B golden hamsters were used as controls. One month of NAC administration significantly decreased SBP in 2-month-old SCH (n = 5, P < 0.001) without modifying echocardiographic values. Five-month treatment of cardiomyopathic animals with the antioxidant improved the acetylcholine-induced relaxation in aortic rings by 24% (E(Max) value from 45.8% ± 4% to 55.3% ± 2% n = 7, P < .05) but did not modify EC(50) values for the acetylcholine concentration-response curve. In addition, 5-month administration of NAC to SCH increased ejection fraction from 39% ± 4% to 57% ± 4% (n = 11, P < .001) and decreased left ventricular end-diastolic and end-systolic volumes (from 0.38 ± 0.04 mL/100 g body weight (BW) and 0.22 ± 0.03 mL/100 g BW, before, to 0.24 ± 0.04 mL/100 g BW and 0.12 ± 0.03 mL/100 g BW after treatment, P < .01). Cardiac output index also improved after 5 months of treatment, although it did not reach statistical significance. These results suggest that antioxidant therapy alone decreases ventricular dilatation and improves cardiovascular function in this animal model of dilated cardiomyopathy, but it does not prevent the appearance of HF.}, }
@article {pmid21148738, year = {2011}, author = {Devi, MS and Sudhakaran, PR}, title = {Differential modulation of angiogenesis by advanced glycation end products.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {236}, number = {1}, pages = {52-61}, doi = {10.1258/ebm.2010.010087}, pmid = {21148738}, issn = {1535-3699}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Aorta, Thoracic/drug effects/metabolism/physiopathology ; Ascorbic Acid/pharmacology ; Cells, Cultured ; Chick Embryo ; Chorioallantoic Membrane/drug effects/metabolism/physiopathology ; Chromones/pharmacology ; Glycation End Products, Advanced/antagonists &amp; inhibitors/metabolism/*physiology ; Humans ; Morpholines/pharmacology ; Neovascularization, Pathologic/metabolism/*physiopathology ; Oxidative Stress/drug effects/physiology ; Proto-Oncogene Proteins c-akt/metabolism/physiology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects/physiology ; Umbilical Veins/drug effects/metabolism/physiopathology ; Vascular Endothelial Growth Factor A/metabolism/physiology ; }, abstract = {Divergent angiogenic responses occur in different organs in a diabetic state. Many of the pathological effects were mediated by the advanced glycation end products (AGEs) of non-enzymatically glycated molecules. Investigations were carried out using different angiogenic model systems to examine whether the angiogenic response to AGEs is influenced by the cellular microenvironment. AGE-albumin increased angiogenesis in chick chorioallantoic membrane (CAM). It also increased sprouting in rat aortic rings and the expression of angiogenic markers CD31 and E-selectin and the angiogenic growth factor, vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs) in culture, suggesting a proangiogenic effect. But in a serum-supplemented condition, AGE-albumin inhibited aortic sprouting and expression of angiogenic markers and VEGF production by HUVECs, suggesting an antiangiogenic effect in the presence of serum. Blocking of the AGE effect by the antioxidants, N-acetyl cysteine and ascorbic acid, suggested that the AGE effect involved oxidant stress. Reversal of the AGE effect by LY 294 002, an inhibitor of the Akt pathway and increased phosphorylation of Akt in cells maintained in serum-free medium, suggested the involvement of the Akt pathway in mediating the AGE effect; such an effect was absent in a serum-supplemented condition. These opposing effects of AGE-albumin on angiogenesis in the presence and absence of serum suggested that the AGE accumulated in a hyperglycemic condition can affect angiogenesis depending on the microenvironment of the cells.}, }
@article {pmid21148202, year = {2011}, author = {Liu, T and He, W and Yan, C and Qi, Y and Zhang, Y}, title = {Roles of reactive oxygen species and mitochondria in cadmium-induced injury of liver cells.}, journal = {Toxicology and industrial health}, volume = {27}, number = {3}, pages = {249-256}, doi = {10.1177/0748233710386408}, pmid = {21148202}, issn = {1477-0393}, mesh = {Acetylcarnitine/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Cadmium Chloride/*toxicity ; Chemical and Drug Induced Liver Injury/etiology/*metabolism/pathology ; DNA Breaks, Single-Stranded/drug effects ; Drug Antagonism ; Environmental Pollutants/*toxicity ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Hepatocytes/*drug effects/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Liver/*drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {The roles of reactive oxygen species (ROS) and mitochondrial damage in the cadmium (Cd)-induced injury of liver cells were studied by using N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine hydrochloride (ALCAR). After exposure of experimental rats to cadmium (Cd) for 16 h, mitochondrial membrane potential (MMP), ROS production, glutathione peroxidase (GSH-Px) activity, glutathione (GSH) content, malondialdehyde (MDA) content and DNA single-strand break (DNA-SSB) were analyzed. Loss of MMP, increase of ROS production, inhibition of GSH-Px activity, elevation of GSH content, rise of MDA content and DNA-SSB level suggest the participation of ROS and mitochondrion in Cd-induced injury of liver cell. NAC pretreatment attenuated oxidative stress, reversed the decline in GSH-Px activity and reduced GSH and MDA levels significantly. However, Cd-induced loss in MMP was significantly exacerbated by NAC. For another, ALCAR did not perform as well as NAC in terms of reducing ROS production, restoring GSH-Px activity and reducing GSH content. Nevertheless, it significantly improved the recovery of MMP and reduction of MDA content. In addition, conspicuous DNA damage was observed in the samples treated with NAC or ALCAR, indicating Cd could attack DNA through other pathways. These results suggest that oxidative stress or mitochondrial impairment plays a main role in different injuries respectively.}, }
@article {pmid21146625, year = {2011}, author = {Sprenger, L and Goldmann, T and Vollmer, E and Steffen, A and Wollenberg, B and Zabel, P and Hauber, HP}, title = {Dexamethasone and N-acetyl-cysteine attenuate Pseudomonas aeruginosa-induced mucus expression in human airways.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {24}, number = {2}, pages = {232-239}, doi = {10.1016/j.pupt.2010.11.003}, pmid = {21146625}, issn = {1522-9629}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Anti-Inflammatory Agents/administration &amp; dosage/pharmacology ; Cell Line ; Dexamethasone/administration &amp; dosage/*pharmacology ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects/metabolism/microbiology ; Expectorants/administration &amp; dosage/pharmacology ; Gene Expression Regulation/drug effects ; Humans ; Mucin 5AC/genetics ; Mucus/*metabolism/microbiology ; Polymerase Chain Reaction ; Pseudomonas aeruginosa/*isolation &amp; purification ; Respiratory Mucosa/drug effects/metabolism/microbiology ; }, abstract = {BACKGROUND: Infection with Pseudomonas aeruginosa (PA) induces mucus hypersecretion in airways. Therapeutic options to attenuate excessive mucus expression are sparse.<br><br>OBJECTIVE: To investigate the effect of steroids and N-acetyl-cysteine (NAC) on PA-induced mucus expression.<br><br>MATERIAL AND METHODS: Calu-3 cells and explanted human mucosa from the upper airways were stimulated with either PA, lipopolysaccharide from alginate producing PA (smooth, sPA-LPS) or non-alginate producing PA (rough, rPA-LPS). Dexamethasone (DEX) and NAC were added in different concentrations. Expression of mucin (MUC5AC) gene and mucin protein expression was quantified using PAS (periodic acids Schiff) staining and real time PCR.<br><br>RESULTS: PA, sPA-LPS or rPA-LPS significantly induced mucin protein and MUC5AC gene expression in Calu-3 cells and explanted mucosal tissue (P < 0.05). Both DEX and NAC significantly decreased PA-, sPA-LPS- and rPA-LPS-induced mucin protein expression both in vitro and ex vivo (P < 0.05). A significant reduction was also observed for MUC5AC gene expression with the two agents (P < 0.05) except for sPA-LPS-induced mucin gene expression in vitro (P > 0.05).<br><br>DISCUSSION AND CONCLUSION: Our data show that both an anti-inflammatory drug (DEX) and an anti-oxidative agent (NAC) can attenuate PA-induced mucus expression in human airways. These results support the use of steroids and NAC in clinical practice to treat PA-induced mucus hypersecretion.}, }
@article {pmid21145953, year = {2011}, author = {Penugonda, S and Ercal, N}, title = {Comparative evaluation of N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA) on glutamate and lead-induced toxicity in CD-1 mice.}, journal = {Toxicology letters}, volume = {201}, number = {1}, pages = {1-7}, pmid = {21145953}, issn = {1879-3169}, support = {R15 ES009497-02/ES/NIEHS NIH HHS/United States ; R15 ES012167/ES/NIEHS NIH HHS/United States ; R15 ES012167-01A1/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacology ; Animals ; Antioxidants/pharmacology ; Chelating Agents/pharmacology ; Glutamate-Ammonia Ligase/metabolism ; Glutamic Acid/analysis/*toxicity ; Glutamine/analysis ; Glutathione/analysis ; Glutathione Disulfide/analysis ; Lead/analysis/blood/*toxicity ; Male ; Malondialdehyde/analysis ; Mice ; Phospholipases A2/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Recent studies indicate that there is interaction between the glutamatergic neurotransmitters system and lead neurotoxicity. Previously, we have demonstrated the potential effects of glutamate in lead-induced cell death in PC12 cells and the protective role of the novel thiol antioxidant, N-acetylcysteine amide (NACA). The current study (1) investigated the potential effects of glutamate on lead exposed CD-1 mice, (2) evaluated the protective effects of NACA against glutamate and lead toxicity in CD-1 mice, and (3) compared the results with N-aceytylcysteine (a well-known thiol antioxidant). Oxidative stress parameters, including glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG, and malondialdehyde (MDA) levels, were evaluated. Blood and tissue lead levels, glutamate/glutamine (Glu/Gln) ratios, GS activity, and phospholipase-A(2) (PLA(2)) were also analyzed. Results indicated that lead and glutamate decreased GSH levels in the red blood cells, brains, livers, and kidneys. Exposure to glutamate and lead elevated the MDA levels and PLA(2) activity. NACA and N-acetylcysteine (NAC) provided protection against the detrimental effects of lead by decreasing the blood and tissue lead levels, restoring intracellular GSH levels, and decreasing the MDA levels. NACA and NAC also increased the GS activity thereby decreasing Glu/Gln levels. However, NACA appeared to have better chelating and antioxidant properties than NAC, due to its higher liphophilicity and its ability to cross the blood-brain barrier.}, }
@article {pmid21145883, year = {2011}, author = {Milesi-Hallé, A and Abdel-Rahman, SM and Brown, A and McCullough, SS and Letzig, L and Hinson, JA and James, LP}, title = {Indocyanine green clearance varies as a function of N-acetylcysteine treatment in a murine model of acetaminophen toxicity.}, journal = {Chemico-biological interactions}, volume = {189}, number = {3}, pages = {222-229}, pmid = {21145883}, issn = {1872-7786}, support = {R01 DK075936-04/DK/NIDDK NIH HHS/United States ; DK-075936/DK/NIDDK NIH HHS/United States ; R01 DK079008/DK/NIDDK NIH HHS/United States ; R01 DK079008-01A2/DK/NIDDK NIH HHS/United States ; R01 DK075936/DK/NIDDK NIH HHS/United States ; R01 DK079008-03/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/pharmacokinetics/*toxicity ; Acetylcysteine/pharmacokinetics/*therapeutic use ; Alanine Transaminase/blood/metabolism ; Animals ; Antidotes/pharmacokinetics/therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy ; Coloring Agents/pharmacokinetics ; *Disease Models, Animal ; *Indocyanine Green/pharmacokinetics ; Injections, Intravenous ; Liver/*drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred Strains ; Time Factors ; }, abstract = {Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment.Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (Cl(T)) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had Cl(T) and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity.}, }
@article {pmid21145769, year = {2011}, author = {Reinero, CR and Lee-Fowler, TM and Dodam, JR and Cohn, LA and DeClue, AE and Guntur, VP}, title = {Endotracheal nebulization of N-acetylcysteine increases airway resistance in cats with experimental asthma.}, journal = {Journal of feline medicine and surgery}, volume = {13}, number = {2}, pages = {69-73}, doi = {10.1016/j.jfms.2010.09.010}, pmid = {21145769}, issn = {1532-2750}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*pharmacology ; Aerosols ; Airway Resistance/*drug effects ; Animals ; Antioxidants/pharmacology ; Asthma/drug therapy/*veterinary ; Bronchoconstriction/drug effects ; Cats ; Disease Models, Animal ; Drug Delivery Systems/methods/*veterinary ; Expectorants/administration &amp; dosage/adverse effects/*pharmacology ; Female ; Intubation, Intratracheal/veterinary ; Male ; Treatment Outcome ; }, abstract = {N-acetylcysteine (NAC), a mucolytic and antioxidant, is speculated to cause bronchoconstriction in cats when delivered via aerosol. We hypothesized that in cats with experimental asthma, aerosol delivery of NAC (400mg cumulative dose) via an endotracheal tube would increase airflow limitation as measured by ventilator-acquired mechanics. After endotracheal drug delivery, airway resistance and inspiratory plateau pressure (Pplat) measurements were obtained in six mechanically ventilated asthmatic cats. Results demonstrated significantly increased airway resistance (P=0.0007) compared with aerosolized saline control; Pplats were not significantly different (P=0.059). All cats exhibited at least one adverse effect: excessive airway secretions (n=3), spontaneous cough (n=2), unilateral strabismus (n=1) and post-anesthetic death (n=1). No adverse reactions were noted with saline aerosol; cough was noted in one cat with methacholine challenge. In conclusion, airway resistance and adverse reactions were documented in all cats after NAC aerosol delivery. Further studies must be performed to evaluate if it is an effective mucolytic and/or antioxidant in cats and to determine if bronchodilator pre-treatment will negate NAC-induced bronchoconstriction.}, }
@article {pmid21144877, year = {2011}, author = {Sarma, SN and Kim, YJ and Song, M and Ryu, JC}, title = {Induction of apoptosis in human leukemia cells through the production of reactive oxygen species and activation of HMOX1 and Noxa by benzene, toluene, and o-xylene.}, journal = {Toxicology}, volume = {280}, number = {3}, pages = {109-117}, doi = {10.1016/j.tox.2010.11.017}, pmid = {21144877}, issn = {1879-3185}, mesh = {Apoptosis/*drug effects/*physiology ; Benzene/*toxicity ; HL-60 Cells ; Heme Oxygenase-1/*metabolism/toxicity ; Humans ; K562 Cells ; Proto-Oncogene Proteins c-bcl-2/*metabolism/toxicity ; Reactive Oxygen Species/*metabolism/toxicity ; Toluene/*toxicity ; U937 Cells ; Xylenes/*toxicity ; }, abstract = {Whereas benzene (BZ) is a well-known human carcinogen, toluene (TOL) and o-xylene (o-XY) are not; however, all three compounds are important environmental pollutants. Although BZ, TOL, and o-XY have been shown to induce apoptosis in vitro, their mechanism of toxicity remains unclear. In this study, we sought to identify the apoptotic pathway(s) activated by BZ, TOL, and o-XY in human HL-60 promyelocytic leukemia cells. Cell cycle analysis by propidium iodide (PI) staining and flow cytometric analyses of Annexin V/PI double-stained cells revealed similar patterns of apoptosis following BZ, TOL, and o-XY exposure. Though reactive oxygen species (ROS) production contributes significantly to BZ metabolite-induced apoptotic cell death, we hypothesized that BZ, TOL, and o-XY can themselves trigger ROS production, leading to the activation of apoptotic signaling. Dose-dependent increases in ROS production and significant tail moments were observed in HL-60 cells exposed to all three compounds. Real-time RT-PCR revealed increased HMOX1 and Noxa expression in BZ-, TOL-, and o-XY-treated HL-60 cells, confirming the results of previous microarray analyses. Similar expression profiles were found in human K562 erythromyeloblastoid leukemia cells and human U937 leukemic monocyte lymphoma cells. Pretreatment with the ROS scavenger N-acetyl cysteine decreased the effects of exposure to BZ, TOL, and o-XY. In summary, this study provides useful insights into the mechanism of BZ-, TOL-, and o-XY-induced apoptosis in leukemia cells.}, }
@article {pmid21143599, year = {2011}, author = {Paintlia, MK and Paintlia, AS and Singh, AK and Singh, I}, title = {Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis.}, journal = {Journal of neurochemistry}, volume = {116}, number = {4}, pages = {508-521}, pmid = {21143599}, issn = {1471-4159}, support = {R01 NS022576/NS/NINDS NIH HHS/United States ; R37 NS022576/NS/NINDS NIH HHS/United States ; NS-22576/NS/NINDS NIH HHS/United States ; C06-RR015455/RR/NCRR NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; R01 NS037766/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; R01 NS034741/NS/NINDS NIH HHS/United States ; R01 NS037766-12/NS/NINDS NIH HHS/United States ; C06 RR018823/RR/NCRR NIH HHS/United States ; C06-RR018823/RR/NCRR NIH HHS/United States ; R01 NS022576-26/NS/NINDS NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; Apoptosis/*physiology ; Cell Survival/physiology ; Cells, Cultured ; Drug Synergism ; Growth Inhibitors/physiology ; Interleukin-17/*physiology ; Membrane Potential, Mitochondrial/physiology ; Oligodendroglia/cytology/*metabolism ; Oxidative Stress/*physiology ; Rats ; Reactive Oxygen Species/metabolism ; Stem Cells/cytology/metabolism ; Tumor Necrosis Factor-alpha/*physiology ; }, abstract = {Th1 cytokine-induced loss of oligodendrocytes (OLs) is associated with axonal loss in CNS demyelinating diseases such as multiple sclerosis (MS)that contributes to neurological disabilities in affected individuals. Recent studies indicated that, in addition to Th1-phenotype cytokines including tumor necrosis factor (TNF)-α, Th17 phenotype cytokine, interleukin (IL)-17 also involved in the development of MS. In this study, we investigated the direct effect of IL-17 on the survival of OLs in the presence of TNF-α and individually in vitro settings. Our findings suggest that IL-17 alone, however, was not able to affect the survival of OLs, but it exacerbates the TNF-α-induced OL apoptosis as compared with individual TNF-α treatment. This effect of cytokines was ascribed to an inhibition of cell-survival mechanisms, co-localization of Bid/Bax proteins in the mitochondrial membrane and caspase 8 activation mediated release of apoptosis inducing factor from mitochondria in treated OLs. In addition, cytokine treatment disturbed the mitochondrial membrane potential in OLs with corresponding increase in the generation of reactive oxygen species, which were attenuated by N-acetyl cysteine treatment. In addition, combining of these cytokines induced cell-cycle arrest at G1/S phases in OL-like cells and inhibited the maturation of OL progenitor cells that was attenuated by peroxisome proliferator-activated receptor-γ/-β agonists. Collectively, these data provide initial evidence that IL-17 exacerbates TNF-α-induced OL loss and inhibits the differentiation of OL progenitor cells suggesting that antioxidant- or peroxisome proliferator-activated receptor agonist-based therapies have potential to limit CNS demyelination in MS or other related demyelinating disorders.}, }
@article {pmid21142721, year = {2010}, author = {de Lima, FM and Villaverde, AB and Albertini, R and de Oliveira, AP and Faria Neto, HC and Aimbire, F}, title = {Low-level laser therapy associated to N-acetylcysteine lowers macrophage inflammatory protein-2 (MIP-2) mRNA expression and generation of intracellular reactive oxygen species in alveolar macrophages.}, journal = {Photomedicine and laser surgery}, volume = {28}, number = {6}, pages = {763-771}, doi = {10.1089/pho.2009.2638}, pmid = {21142721}, issn = {1557-8550}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Chemokine CXCL2/*genetics/metabolism ; Free Radical Scavengers/pharmacology ; *Low-Level Light Therapy ; Macrophages, Alveolar/*metabolism/radiation effects ; RNA, Messenger/*metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {OBJECTIVE: The aim of this work was to investigate the low-level laser therapy (LLLT) effect on alveolar macrophages (AM) activated by oxidative stress and lipopolysaccharide (LPS).<br><br>BACKGROUND DATA: LLLT has been reported to actuate positively relieving the late and early symptoms of airway and lung inflammation. It is not known if the increased MIP-2&#x2009;mRNA expression and intracellular reactive oxygen species (ROS) generation observed in acute lung inflammation (ALI) can be influenced by LLLT.<br><br>MATERIALS AND METHODS: Rat AM cell line (AMJ2-C11) was cultured with LPS or H(2)O(2) and laser irradiated. MIP-2&#x2009;mRNA and ROS production in the AM were evaluated by Real Time-PCR and the 2',7'-dichlorofluorescin diacetate (DCFH-DA) respectively. The NF-&#x3ba;B protein in the AM was measured by the enzyme linked immunoassay method. To investigate the antioxidant effect of laser, the AM were prebathed with N-acetylcysteine (NAC) and then irradiated with laser. LLLT was also studied in the presence of an inhibitor of NF-&#x3ba;B (BMS 205820). In addition, the effect of LLLT on NF-&#x3ba;B protein was investigated.<br><br>RESULTS: LLLT attenuated the MIP-2&#x2009;mRNA expression and intracellular ROS generation after LPS or H(2)O(2). When the AM were pretreated with NAC, the laser effect was potentiated. BMS 205820 suppresses the effect of LLLT on MIP-2&#x2009;mRNA expression and ROS generation, stimulated by LPS or H(2)O(2). On NF-&#x3ba;B transcription factor, both the LLLT and NAC reduced this protein in the AM exposed to LPS or H(2)O(2). The synergistic effect between LLLT and NAC on the reduction the NF-&#x3ba;B was also evidenced.<br><br>CONCLUSION: Results indicate that there is a synergistic action of LLLT with NAC on MIP-2&#x2009;mRNA expression from LPS- or H(2)O(2)-stimulated AM, and that both ROS intracellular generation and NF-kB signaling seem to be involved.}, }
@article {pmid21140133, year = {2011}, author = {Briguori, C and Quintavalle, C and De Micco, F and Condorelli, G}, title = {Nephrotoxicity of contrast media and protective effects of acetylcysteine.}, journal = {Archives of toxicology}, volume = {85}, number = {3}, pages = {165-173}, doi = {10.1007/s00204-010-0626-5}, pmid = {21140133}, issn = {1432-0738}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/blood/chemically induced/*prevention &amp; control ; Animals ; Antioxidants/pharmacology/therapeutic use ; Clinical Trials as Topic ; Contrast Media/*adverse effects ; Creatinine/blood ; Expectorants/pharmacology ; Free Radical Scavengers/pharmacology/therapeutic use ; Humans ; Protective Agents/*pharmacology ; Treatment Outcome ; }, abstract = {Contrast-induced acute kidney injury (CI-AKI) accounts for approximately 10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay, and represents a powerful predictor of poor early and late outcome. N-acetylcysteine (NAC) is a thiol compound classically known as a mucolytic agent, which is a potent antioxidant that scavenges a wide variety of oxygen-derived-free-radicals and may be capable of preventing acute kidney injury. In the present study, we will review (1) the pathophysiology of the CI-AKI and (2) the experimental and clinical data on the effects of NAC in preventing CI-AKI.}, }
@article {pmid21140131, year = {2011}, author = {Rossato, LG and Costa, VM and de Pinho, PG and Carvalho, F and de Lourdes Bastos, M and Remião, F}, title = {Structural isomerization of synephrine influences its uptake and ensuing glutathione depletion in rat-isolated cardiomyocytes.}, journal = {Archives of toxicology}, volume = {85}, number = {8}, pages = {929-939}, doi = {10.1007/s00204-010-0630-9}, pmid = {21140131}, issn = {1432-0738}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Adrenergic alpha-Agonists/chemistry/pharmacokinetics/*toxicity ; Animals ; Antioxidants/pharmacology ; Biological Transport ; Catecholamine Plasma Membrane Transport Proteins/metabolism ; Gas Chromatography-Mass Spectrometry ; Glutathione/deficiency/*drug effects ; Male ; Myocytes, Cardiac/*drug effects/metabolism ; Organic Cation Transport Proteins/metabolism ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; Synephrine/chemistry/pharmacokinetics/*toxicity ; }, abstract = {Synephrine is a natural compound, frequently added to ephedra-free dietary supplements for weight-loss, due to its effects as a nonspecific adrenergic agonist. Though only p-synephrine has been documented in plants, the presence of m-synephrine has also been reported in weight-loss products. The use of synephrine in dietary supplements was accompanied by reports of adverse effects, especially at the cardiovascular level. It is well known that the imbalance in cardiac glutathione levels can increase the risk of cardiomyopathy. The present work aimed to study the role of organic cation-mediated transport of m- and p-synephrine and the possibility that p- and m-synephrine induce intracellular changes in glutathione levels in calcium-tolerant freshly isolated cardiomyocytes from adult rat. After a 3 h incubation with 1 mM p- or m-synephrine, the intracellular content of synephrine was measured by gas chromatography/ion trap-mass spectrometry (GC/IT-MS); cell viability and intracellular glutathione levels were also determined. To evaluate the potential protective effects of antioxidants against the adverse effects elicited by m-synephrine, cells were pre-incubated for 30 min with Tiron (100 μM) or N-acetyl-cysteine (NAC) (1 mM). To assess the influence of α(1)-adrenoceptors activation in glutathione depletion, a study with prazosin (100 nM) was also performed. The results obtained provide evidence that organic cation transporters OCT3 and OCT1 play a major role in m- and p-synephrine-mediated transport into the cardiomyocytes. The importance of these transporters seems similar for both isomers, although p-synephrine enters more into the cardiomyocytes. Furthermore, only m-synephrine induced intracellular total glutathione (GSHt) and reduced glutathione (GSH) depletion. NAC and Tiron were able to counteract the m-synephrine-induced GSH and GSHt decrease. On the other hand, the incubation with prazosin was not able to change m-synephrine-induced glutathione depletion showing that this effect is independent of α(1)-adrenoceptor stimulation. In conclusion, both positional isomers require OCT3 and OCT1-mediated transport to enter into the cardiomyocytes; however, the hydroxyl group in the p-position favours the OCT-mediated transport into cardiomyocytes. Furthermore, the structural isomerization of synephrine influences its toxicological profile since only m-synephrine caused GSH depletion.}, }
@article {pmid21138756, year = {2011}, author = {Giusti, MF and Sato, MA and Cardoso, LM and Braga, VA and Colombari, E}, title = {Central antioxidant therapy inhibits parasympathetic baroreflex control in conscious rats.}, journal = {Neuroscience letters}, volume = {489}, number = {2}, pages = {115-118}, doi = {10.1016/j.neulet.2010.11.077}, pmid = {21138756}, issn = {1872-7972}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Ascorbic Acid/administration &amp; dosage/*pharmacology ; Baroreflex/*drug effects ; Heart Rate/drug effects ; Injections, Intraventricular ; Male ; Nitroprusside/pharmacology ; Parasympathetic Nervous System/*drug effects ; Phenylephrine/pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Vasoconstrictor Agents/pharmacology ; Vasodilator Agents/pharmacology ; }, abstract = {Baroreceptor reflex is an important system for neural control of blood pressure. Recently, reactive oxygen species (ROS) have been shown to play an important role in neuronal activity of central areas related to blood pressure control. The aim of this study was to investigate the effects elicited by ascorbic acid (AAC) and N-acetylcysteine (NAC) injections into the 4thV on the parasympathetic component of the baroreflex. Male Wistar rats were implanted with a stainless steel guide cannula into the 4thV. One day prior to the experiments, the femoral artery and vein were cannulated for pulsatile arterial pressure, mean arterial pressure and heart rate measurements and drug administration, respectively. After baseline recordings, the baroreflex was tested with a pressor dose of phenylephrine (PHE, 3 μg/kg, i.v.) and a depressor dose of sodium nitroprusside (SNP, 30 μg/kg, i.v.) before (control) and 5, 15, 30 and 60 min after AAC or NAC into the 4thV. Control PHE injection induced baroreflex-mediated bradycardia (-93 ± 13 bpm, n=7). Interestingly, after AAC injection into the 4thV, PHE injection produced a transient tachycardia at 5 (40 ± 23 bpm), 15 (26 ± 22 bpm) and 30 min (59 ± 21 bpm). No changes were observed in baroreflex-mediated tachycardia evoked by SNP after AAC injection on 4thV (control: 151 ± 23bpm vs. 135 ± 18 bpm at 5 min after AAC, n=7). In the NAC treated group, PHE induced a reduction in reflex bradycardia at 5 min when compared to control (-11 ± 17 bpm vs. -83 ± 15 bpm, n=7). No changes were observed in baroreflex-mediated tachycardia evoked by SNP after NAC injection on 4thV. The antioxidants AAC and NAC may act in the central nervous system affecting the parasympathetic component of the cardiac baroreflex.}, }
@article {pmid21138529, year = {2011}, author = {Rezin, GT and Petronilho, FC and Araújo, JH and Gonçalves, CL and Daufenbach, JF and Cardoso, MR and Roesler, R and Schwartsmann, G and Dal-Pizzol, F and Streck, EL}, title = {Gastrin-releasing peptide receptor antagonist or N-acetylcysteine combined with omeprazol protect against mitochondrial complex II inhibition in a rat model of gastritis.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {108}, number = {3}, pages = {214-219}, doi = {10.1111/j.1742-7843.2010.00645.x}, pmid = {21138529}, issn = {1742-7843}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/toxicity ; Anti-Ulcer Agents/*pharmacology/therapeutic use ; Bombesin/*analogs &amp; derivatives/pharmacology/therapeutic use ; Drug Therapy, Combination ; Electron Transport/drug effects ; Electron Transport Complex II/antagonists &amp; inhibitors/*metabolism ; Electron Transport Complex III/antagonists &amp; inhibitors/metabolism ; Gastric Mucosa/metabolism ; Gastritis/*metabolism/pathology/prevention &amp; control ; Indomethacin/toxicity ; Male ; Mitochondria/drug effects/enzymology ; Omeprazole/*pharmacology/therapeutic use ; Peptide Fragments/*pharmacology/therapeutic use ; Proton Pump Inhibitors/pharmacology/therapeutic use ; Rats ; Rats, Wistar ; Receptors, Bombesin/*antagonists &amp; inhibitors ; Severity of Illness Index ; Stomach/drug effects/pathology ; Stomach Ulcer/prevention &amp; control ; }, abstract = {The pathophysiology of gastritis involves an imbalance between gastric acid attack and mucosal defence. In addition, the gastric mucosal injury results in adenosine triphosphate (ATP) depletion leading to mitochondrial dysfunction. Several studies have shown the association of mitochondrial disorders with gastrointestinal dysfunction. In the present study, we investigated the activity of mitochondrial respiratory chain complexes activity in the stomach of rats with gastritis induced by indomethacin (IDM) and treated with omeprazole (OM), N-acetylcysteine (NAC) and the gastrin-releasing peptide receptor (GRPR) antagonist RC-3095. Adult male Wistar rats were pre-treated for 7 days with OM, NAC, RC-3095, combination of OM plus RC-3095, OM plus NAC and water (control). The animals were then submitted to fasting for 24 hr; IDM was administered. The rats were killed 6 hr later, and the stomachs were used for evaluation of macroscopic damage and respiratory chain activity. Our results showed that complex I and IV activities were not affected by administration of IDM. On the other hand, complex II and III activities were inhibited. In addition, OM plus RC-3095 and OM plus NAC did not reverse complex II activity inhibition. However, the complex III activity inhibition was reversed only with the combined use of OM plus RC-3095 and OM plus NAC. Our results are in agreement with previous studies indicating mitochondrial dysfunction in the pathophysiology of gastrointestinal tract disease and we suggest that GRPR antagonism might be a novel therapeutic strategy in gastritis.}, }
@article {pmid21135414, year = {2011}, author = {Zhang, F and Lau, SS and Monks, TJ}, title = {The cytoprotective effect of N-acetyl-L-cysteine against ROS-induced cytotoxicity is independent of its ability to enhance glutathione synthesis.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {120}, number = {1}, pages = {87-97}, pmid = {21135414}, issn = {1096-0929}, support = {P30 ES006694/ES/NIEHS NIH HHS/United States ; P30ES006694/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Antioxidants/*pharmacology ; Blotting, Western ; Cell Line ; Cell Survival/drug effects ; Cytoprotection/*drug effects ; Epithelial Cells/drug effects/metabolism/pathology ; Flow Cytometry ; Glutathione/analogs &amp; derivatives/*biosynthesis/toxicity ; Humans ; Hydroquinones/toxicity ; Kidney Tubules, Proximal/*drug effects/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {2,3,5-Tris(glutathion-S-yl)-hydroquinone (TGHQ), a metabolite of hydroquinone, is toxic to renal proximal tubule epithelial cells. TGHQ retains the ability to redox cycle and create an oxidative stress. To assist in elucidating the contribution of reactive oxygen species (ROS) to TGHQ-induced toxicity, we determined whether the antioxidant, N-acetyl-L-cysteine (NAC), could protect human kidney proximal tubule epithelial cells (HK-2 cell line) against TGHQ-induced toxicity. NAC provided remarkable protection against TGHQ-induced toxicity to HK-2 cells. NAC almost completely inhibited TGHQ-induced cell death, mitochondrial membrane potential collapse, as well as ROS production. NAC also attenuated TGHQ-induced DNA damage and the subsequent activation of poly (ADP-ribose) polymerase and ATP depletion. Moreover, NAC significantly attenuated c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase phosphorylation induced by TGHQ. In contrast, NAC itself markedly increased extracellular regulated kinase1/2 (ERK1/2) activation, and the upstream mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor, PD-98059, only partially inhibited this activation, suggesting that NAC can directly activate ERK1/2 activity. However, although NAC is frequently utilized as a glutathione (GSH) precursor, the cytoprotection afforded by NAC in HK-2 cells was not a consequence of increased GSH levels. We speculate that NAC exerts its protective effect in part by directly scavenging ROS and in part via ERK1/2 activation.}, }
@article {pmid21131394, year = {2011}, author = {Michaeloudes, C and Sukkar, MB and Khorasani, NM and Bhavsar, PK and Chung, KF}, title = {TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {300}, number = {2}, pages = {L295-304}, pmid = {21131394}, issn = {1522-1504}, support = {G1000758/MRC_/Medical Research Council/United Kingdom ; 085935/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Base Sequence ; Catalase/genetics/*metabolism ; Cells, Cultured ; DNA Primers/genetics ; Gene Expression/drug effects ; Humans ; Interleukin-6/*biosynthesis ; Models, Biological ; Myocytes, Smooth Muscle/*drug effects/*metabolism ; NADPH Oxidase 4 ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/pharmacology ; Respiratory Muscles/cytology/*drug effects/*metabolism ; Signal Transduction ; Smad Proteins/metabolism ; Superoxide Dismutase/genetics/*metabolism ; Transforming Growth Factor beta1/*metabolism/*pharmacology ; }, abstract = {Reactive oxygen species (ROS) are generated as a result of normal cellular metabolism, mainly through the mitochondria and peroxisomes, but their release is enhanced by the activation of oxidant enzymes such as NADPH oxidases or downregulation of endogenous antioxidant enzymes such as manganese-superoxide dismutase (MnSOD) and catalase. Transforming growth factor-β (TGF-β), found to be overexpressed in airway smooth muscle (ASM) from asthmatic and chronic obstructive pulmonary disease patients, may be a pivotal regulator of abnormal ASM cell (ASMC) function in these diseases. An important effect of TGF-β on ASMC inflammatory responses is the induction of IL-6 release. TGF-β also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-β on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redox-dependent pathways in the mediation of the proinflammatory effects of TGF-β in ASMCs is unclear. In this study, we show that TGF-β induced the expression of Nox4 while at the same time inhibiting the expression of MnSOD and catalase. This change in oxidant/antioxidant enzymes was accompanied by elevated ROS levels and IL-6 release. Further studies revealed a role for Smad3 and phosphatidyl-inositol kinase-mediated pathways in the induction of oxidant/antioxidant imbalance and IL-6 release. The changes in oxidant/antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetyl-cysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox-dependent activation of Smad3 by TGF-β. Moreover, these findings suggest a potential role for NAC in preventing TGF-β-mediated pro-oxidant and proinflammatory responses in ASMCs. Knockdown of Nox4 using small interfering RNA partially prevented the inhibition of MnSOD but had no effect on catalase and IL-6 expression. These findings provide novel insights into redox regulation of ASM function by TGF-β.}, }
@article {pmid21131132, year = {2011}, author = {Csontos, C and Rezman, B and Foldi, V and Bogar, L and Bognar, Z and Drenkovics, L and Röth, E and Weber, G and Lantos, J}, title = {Effect of N-acetylcysteine treatment on the expression of leukocyte surface markers after burn injury.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {37}, number = {3}, pages = {453-464}, doi = {10.1016/j.burns.2010.10.008}, pmid = {21131132}, issn = {1879-1409}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Aged ; Antigens, CD/*metabolism ; Antioxidants/pharmacology/*therapeutic use ; Biomarkers/metabolism ; Burns/blood/*drug therapy/physiopathology ; Female ; Flow Cytometry ; Humans ; Leukocytes/*drug effects/metabolism ; Male ; Middle Aged ; Multiple Organ Failure/physiopathology ; Oxidative Stress/*drug effects ; Prospective Studies ; }, abstract = {Oxidative stress and inflammatory processes generate edema in burns. Treatment of consequent hypovolemia is a challenge. The aim of study was to assess if glutathione pro-drug N-acetylcysteine (NAC) can influence inflammation and fluid requirement. We also aimed to compare organ functions scores and vasoactive drug requirement. This prospective randomised study involved 28 patients with burn injury affecting more than 20% of body surface area. Fourteen patients were on standard therapy, whereas for other 14 patients NAC was supplemented. Blood samples were taken on admission and on the next five consecutive mornings. Leukocyte surface marker expressions were determined, multiple organ function scores, use of vasopressor agents and fluid requirements were recorded daily. Expression of CD11a (p < 0.05), CD18 (p < 0.05) and CD97 (p < 0.01) on the granulocytes were significantly lower in the NAC treated group, similarly to lymphocyte CD 49d (p < 0.05) and monocyte CD 49d (p < 0.01) and CD 97 (p < 0.05) expression. No significant difference was found in the fluid requirement between groups but patients the NAC group required less vasopressor and inotropic drugs from day 4. NAC treatment is associated with a less pronounced inflammation reflected in lower CD marker expression and vasopressor requirement.}, }
@article {pmid21127883, year = {2011}, author = {Saitoh, T and Satoh, H and Nobuhara, M and Machii, M and Tanaka, T and Ohtani, H and Saotome, M and Urushida, T and Katoh, H and Hayashi, H}, title = {Intravenous glutathione prevents renal oxidative stress after coronary angiography more effectively than oral N-acetylcysteine.}, journal = {Heart and vessels}, volume = {26}, number = {5}, pages = {465-472}, pmid = {21127883}, issn = {1615-2573}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Analysis of Variance ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood/urine ; Chi-Square Distribution ; *Contrast Media ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Female ; Glutathione/*administration &amp; dosage/blood ; Humans ; Infusions, Intravenous ; Japan ; Kidney/*drug effects/metabolism ; Kidney Diseases/chemically induced/metabolism/*prevention &amp; control ; Lipid Peroxidation/drug effects ; Lipid Peroxides/urine ; Male ; Oxidative Stress/*drug effects ; Prospective Studies ; Time Factors ; Treatment Outcome ; }, abstract = {This study proposes the intravenous administration of glutathione (GSH) as a novel strategy to prevent contrast medium-induced renal oxidative stress. Renal oxidative stress is a critical cause of contrast-induced nephropathy (CIN). Recent reports have described that N-acetylcysteine (NAC) may prevent CIN by scavenging reactive oxygen species in the kidney. Twenty-one patients with reduced renal function who underwent coronary angiography (CAG) were equally assigned to the control, NAC and GSH (100 mg/min for 30 min before CAG) groups. CIN occurred in two patients, one in the control and the other in the NAC group. In the control group, the urinary lipid hydroperoxides (LOOHs) increased to 299.5 ± 94.4% of the baseline at 2 h after CAG (mean ± SE, p < 0.01). The increase in LOOHs was completely abolished in the GSH group (5.5 ± 8.8%, p = ns), but not in the NAC group (196.8 ± 81.3%, p < 0.05). In the control group, the serum GSH level fell by 9.4 ± 2.3% at 2 h after CAG (p < 0.01). The decrease was prevented in the GSH group (-1.8 ± 8.5%, p = ns), but not in the NAC group (-10.0 ± 3.3%, p < 0.05). The renal damage by contrast medium-induced oxidative stress occurs soon after CAG, and intravenous GSH is more effective in preventing the oxidative stress than oral NAC. This advantage may make GSH a potentially more effective therapeutic strategy against CIN.}, }
@article {pmid21126841, year = {2011}, author = {Tzanavaras, PD and Karakosta, TD}, title = {Automated tagging of pharmaceutically active thiols under flow conditions using monobromobimane.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {54}, number = {4}, pages = {882-885}, doi = {10.1016/j.jpba.2010.11.006}, pmid = {21126841}, issn = {1873-264X}, mesh = {Acetylcysteine/analysis/chemistry ; *Analytic Sample Preparation Methods/economics ; Automation, Laboratory ; Bridged Bicyclo Compounds/*chemistry ; Captopril/analysis/chemistry ; Drug Stability ; Fluorescent Dyes/*chemistry ; Hot Temperature/adverse effects ; Hydrogen-Ion Concentration ; Kinetics ; Limit of Detection ; Penicillamine/analysis/chemistry ; Quality Control ; Reproducibility of Results ; Spectrometry, Fluorescence ; Sulfhydryl Compounds/*analysis/*chemistry ; Sulfhydryl Reagents/*chemistry ; *Technology, Pharmaceutical ; }, abstract = {The thiol-specific derivatization reagent monobromobimane (MBB) is applied--for the first time--under flow conditions. Sequential injection analysis allows the handling of precise volumes of the reagent in the micro-liter range. The effect of the main chemical and instrumental variables was investigated using captopril (CAP), N-acetylcysteine (NAC) and penicillamine (PEN) as representative pharmaceutically active thiols. Previously reported hydrolysis of MBB due to interaction with nucleophilic components of the buffers was avoided kinetically under flow conditions. The proposed analytical scheme is suitable for the fluorimetric determination of thiols at a sampling rate of 36 h(-1).}, }
@article {pmid21126554, year = {2011}, author = {Liang, Q and Sheng, Y and Jiang, P and Ji, L and Xia, Y and Min, Y and Wang, Z}, title = {The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury.}, journal = {Toxicology}, volume = {280}, number = {1-2}, pages = {61-69}, doi = {10.1016/j.tox.2010.11.010}, pmid = {21126554}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Animals ; Chemical and Drug Induced Liver Injury/*metabolism ; Female ; Glutamate-Cysteine Ligase/physiology ; Glutathione/*metabolism ; Glutathione Peroxidase/physiology ; Liver/*metabolism ; Male ; Mice ; Mice, Inbred ICR ; Pyrrolizidine Alkaloids/*toxicity ; Sex Characteristics ; }, abstract = {Intracellular reduced glutathione (GSH) antioxidant system is crucial for counteracting oxidative stress-induced liver injury. The present study was designed to observe the gender-dependent difference of GSH antioxidant system and its influence on hepatotoxic pyrrolizidine alkaloid (HPA) isoline-induced liver injury. Lower activities and protein expressions of glutamate-cysteine ligase (GCL) and glutathione peroxidase (GPx) were found in male mice livers than in female. Isoline is a natural HPA, our further results showed that male mice demonstrated more higher serum ALT/AST levels, less GSH amounts, lower GCL and GPx activities and proteins induced by isoline as compared to female. N-acetyl-l-cysteine (NAC), which is the precursor of cellular GSH biosynthesis, ameliorated liver injury induced by isoline. l-Buthionine-(S, R)-sulfoximine (BSO) and mercaptosuccinic acid (MA), inhibitors of GCL and GPx, both augmented isoline-induced cytotoxicity in cultured mice hepatocytes. BSO and MA also increased other natural HPAs clivorine and senecionine-induced cytotoxicity. Taken together, our results demonstrated the higher GCL and GPx activities in female mice, which indicated their crucial roles in regulating the resistance of liver injury induced by hepatotoxins in female. Meanwhile, our results also revealed the female-resistant liver injury induced by HPAs for the first time.}, }
@article {pmid21125209, year = {2011}, author = {Odewumi, CO and Badisa, VL and Le, UT and Latinwo, LM and Ikediobi, CO and Badisa, RB and Darling-Reed, SF}, title = {Protective effects of N-acetylcysteine against cadmium-induced damage in cultured rat normal liver cells.}, journal = {International journal of molecular medicine}, volume = {27}, number = {2}, pages = {243-248}, pmid = {21125209}, issn = {1791-244X}, support = {G12 RR003020/RR/NCRR NIH HHS/United States ; G12 RR003020-27/RR/NCRR NIH HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cadmium/toxicity ; Catalase/metabolism ; Cell Cycle/drug effects ; Cell Line ; Cell Survival/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Hepatocytes/cytology/*drug effects/metabolism ; Rats ; }, abstract = {In this study, the protective effects of N-acetylcysteine (NAC), a precursor of reduced glutathione, were studied by measuring the viability, the levels of antioxidant enzymes, and by analyzing the cell cycle in cadmium (Cd)-treated rat liver cells. The cells were treated with 150 µM CdCl2 alone or co-treated with 150 µM CdCl2 and 5 mM NAC (2 h pre-, simultaneous or 2 h post-treatment) for 24 h. The viability of the cells treated with 150 µM CdCl2 alone decreased to 40.1%, while that of the cells co-treated with 5 mM NAC (pre-, simultaneous and post-treatment) significantly increased to 83.7, 86.2 and 83.7%, respectively in comparison to the control cells (100%). The catalase enzyme level decreased to undetectable level in the cells treated with CdCl2 alone, while it significantly increased in the co-treated cells (pre-, simultaneous and post-treatment) to 40.1, 34.3 and 13.2%, respectively. In the cells treated with CdCl2 alone, the glutathione peroxidase enzyme level decreased to 78.3%, while it increased in the co-treated cells (pre-, simultaneous, and post-treatment) to 84.5, 83.3 and 87.9%, respectively. The glutathione reductase enzyme level decreased to 56.1% in the cells treated with cadmium alone, but significantly increased in the cells co treated with NAC (pre-, simultaneous and post-treatment) to 79.5, 78.5 and 78.2%, respectively. Cd caused cell cycle arrest at the S and G2/M phases. The co-treatment with NAC inhibited cell cycle arrest by shifting the cells to the G1 phase. These results clearly show the protective effects of NAC against Cd-induced damage in rat liver cells.}, }
@article {pmid21121370, year = {2010}, author = {Wang, L and Zhang, J and Zheng, Y and Yang, J and Zhang, Q and Zhu, X}, title = {Bioeffects of CdTe quantum dots on human umbilical vein endothelial cells.}, journal = {Journal of nanoscience and nanotechnology}, volume = {10}, number = {12}, pages = {8591-8596}, doi = {10.1166/jnn.2010.2681}, pmid = {21121370}, issn = {1533-4880}, mesh = {Acetylcysteine/pharmacology ; Cadmium Compounds/chemistry/*toxicity ; Cell Line ; Cell Survival/drug effects ; Chi-Square Distribution ; DNA Damage ; Dose-Response Relationship, Drug ; Endothelial Cells/*drug effects/metabolism/physiology ; Histones/metabolism ; Humans ; Mutagenicity Tests ; Oxidative Stress/*drug effects ; *Quantum Dots ; Reactive Oxygen Species/metabolism ; Tellurium/chemistry/*toxicity ; Toxicity Tests ; Umbilical Veins/cytology ; }, abstract = {Quantum dots (QDs) hold great potential for applications in nanomedicine, however, their health effects are largely unknown. In the present study, the cytotoxicity and genotoxicity of CdTe QDs were examined in human umbilical vein endothelial cells (HUVECs). The QDs exhibited a dose-dependent inhibitory effect on cell growth. It was shown that after a 12 h treatment QDs at 1, 10, and 50 microg x ml(-1) induced formation of yH2AX foci, indicative of DNA damage, in a dose-dependent manner. Moreover, QD treatment clearly induced the generation of reactive oxygen species (ROS). Pre-treatment with N-acetyl-cysteine (NAC), a ROS scavenger, could inhibit the induction of ROS by QDs, as well as the formation of yH2AX foci. Taken together, our data indicate that CdTe QDs have cytotoxic and genotoxic effects on HUVECs, and that ROS generation may be involved in QD induced DNA damage.}, }
@article {pmid21118657, year = {2011}, author = {Dean, O and Giorlando, F and Berk, M}, title = {N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action.}, journal = {Journal of psychiatry &amp; neuroscience : JPN}, volume = {36}, number = {2}, pages = {78-86}, pmid = {21118657}, issn = {1488-2434}, mesh = {Acetylcysteine/*therapeutic use ; Humans ; Mental Disorders/*drug therapy ; }, abstract = {There is an expanding field of research investigating the benefits of alternatives to current pharmacological therapies in psychiatry. N-acetylcysteine (NAC) is emerging as a useful agent in the treatment of psychiatric disorders. Like many therapies, the clinical origins of NAC are far removed from its current use in psychiatry. Whereas the mechanisms of NAC are only beginning to be understood, it is likely that NAC is exerting benefits beyond being a precursor to the antioxidant, glutathione, modulating glutamatergic, neurotropic and inflammatory pathways. This review outlines the current literature regarding the use of NAC in disorders including addiction, compulsive and grooming disorders, schizophrenia and bipolar disorder. N-acetylcysteine has shown promising results in populations with these disorders, including those in whom treatment efficacy has previously been limited. The therapeutic potential of this acetylated amino acid is beginning to emerge in the field of psychiatric research.}, }
@article {pmid21118526, year = {2010}, author = {Bahar, M and Khaghani, S and Pasalar, P and Paknejad, M and Khorramizadeh, MR and Mirmiranpour, H and Nejad, SG}, title = {Exogenous coenzyme Q10 modulates MMP-2 activity in MCF-7 cell line as a breast cancer cellular model.}, journal = {Nutrition journal}, volume = {9}, number = {}, pages = {62}, pmid = {21118526}, issn = {1475-2891}, mesh = {Acetylcysteine/pharmacology ; Biomarkers/metabolism ; Breast Neoplasms/*metabolism ; Buthionine Sulfoximine/pharmacology ; Carcinoma/*metabolism ; Cell Line, Tumor ; Down-Regulation/drug effects ; Enzyme Inhibitors/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors ; Humans ; Hydrogen Peroxide/metabolism ; Matrix Metalloproteinase 2/*metabolism ; Osmolar Concentration ; Oxidation-Reduction ; *Oxidative Stress/drug effects ; Time Factors ; Ubiquinone/*analogs &amp; derivatives/metabolism ; }, abstract = {BACKGROUND/AIMS: Matrix Metalloproteinases 2 is a key molecule in cellular invasion and metastasis. Mitochondrial ROS has been established as a mediator of MMP activity. Coenzyme Q(10) contributes to intracellular ROS regulation. Coenzyme Q(10) beneficial effects on cancer are still in controversy but there are indications of Coenzyme Q(10) complementing effect on tamoxifen receiving breast cancer patients.<br><br>METHODS: In this study we aimed to investigate the correlation of the effects of co-incubation of coenzyme Q10 and N-acetyl-L-cysteine (NAC) on intracellular H2O2 content and Matrix Metalloproteinase 2 (MMP-2) activity in MCF-7 cell line.<br><br>RESULTS AND DISCUSSION: Our experiment was designed to assess the effect in a time and dose related manner. Gelatin zymography and Flowcytometric measurement of H2O2 by 2'7',-dichlorofluorescin-diacetate probe were employed. The results showed that both coenzyme Q10 and N-acetyl-L-cysteine reduce MMP-2 activity along with the pro-oxidant capacity of the MCF-7 cell in a dose proportionate manner.<br><br>CONCLUSIONS: Collectively, the present study highlights the significance of Coenzyme Q(10) effect on the cell invasion/metastasis effecter molecules.}, }
@article {pmid22416658, year = {2010}, author = {Ekor, M and Adesanoye, OA and Farombi, EO}, title = {N-acetylcysteine pretreatment ameliorates mercuric chloride-induced oxidative renal damage in rats.}, journal = {African journal of medicine and medical sciences}, volume = {39 Suppl}, number = {}, pages = {153-160}, pmid = {22416658}, issn = {0309-3913}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/metabolism/pharmacology ; Catalase/metabolism ; Chemoprevention ; Disease Models, Animal ; Glucose-6-Phosphatase/metabolism ; Glutathione/metabolism ; Injections, Intraperitoneal ; Kidney/*drug effects/*injuries/pathology ; Lipid Peroxidation/*drug effects ; Male ; Malondialdehyde/metabolism ; Mercuric Chloride/*toxicity ; Mercury ; Mercury Poisoning/*prevention &amp; control ; Oxidation-Reduction ; Random Allocation ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {The effectiveness of the antioxidant thiol, N-acetylcysteine (NAC), in enhancing methylmercury (CH3HgCl) excretion and its utility as a possible antidote in CH3HgCl poisoning has been reported. NAC, however, has been reported to be ineffective in accelerating excretion of divalent toxic metals, including inorganic mercury, Hg2+. In this study, we evaluated the possible protective effect of short-term pretreatment with NAC against mercuric chloride (HgCl2) toxicity in rat model. This is aimed at determining its chemopreventive or prophylactic benefit in situations of high risk exposure (occupational/industrial) to mercury. Rats were divided into three treatment groups. Group I received saline (10 ml/kg) and served as control. Group II received HgCl2 (5mg/kg) and group III received NAC (10mg/kg) plus (5mg/kg). All administration was via intraperitoneal (i.p.) injection. Saline and NAC were administered for 5days and HgCl2 was administered to rats in groups II and III on the 5th day. Animals were sacrificed 24 hours after HgCl2 injection and samples obtained for biochemical evaluation. Results revealed that single i.p. injection of HgCl2 induced significant renal oxidative damage resulting in significant decrease in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST), depletion of reduced glutathione (GSH) and increase in malondialdehyde (MDA) levels in these rats. The activities of glucose-6-phosphatase (G6Pase) and 5'-nucleotidase (5'-NTD) (markers of microsomal damage) also decreased in these HgCl2 treated rats. The oxidative damage induced by HgCl2 led to significant alterations in renal histology and caused functional impairment (indicated by elevated blood urea nitrogen (BUN) and serum creatinine) in these rats. NAC was effective in attenuating the oxidative damage, functional impairments and histopathological changes that characterized HgCl2 intoxication in this study. Renal antioxidant defense system was re-enforced by NAC, leading to increase in the activities of SOD, CAT, GST and decreases in GSH depletion and MDA level. Our results therefore reveal the ameliorative effect of NAC pretreatment against HgCl2 toxicity in vivo, thus, suggesting its usefulness as a possible chemoprophylactic agent during occupational or industrial exposure to inorganic mercury.}, }
@article {pmid21115557, year = {2011}, author = {Kandiş, H and Erkan, ME and Yildirim, U and Güneş, H and Erbaş, M and Yildirim, HA and Gezer, S and Kara, IH}, title = {Comparison of the effects of N-acetyl cysteine and erdosteine in rats with renal injury caused by paracetamol intoxication.}, journal = {Human &amp; experimental toxicology}, volume = {30}, number = {9}, pages = {1350-1358}, doi = {10.1177/0960327110391384}, pmid = {21115557}, issn = {1477-0903}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/chemically induced/diagnostic imaging/metabolism/*prevention &amp; control ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Data Interpretation, Statistical ; Female ; Kidney/diagnostic imaging/pathology ; Kidney Function Tests ; Radionuclide Imaging ; Rats ; Rats, Wistar ; Thioglycolates/administration &amp; dosage/*therapeutic use ; Thiophenes/administration &amp; dosage/*therapeutic use ; }, abstract = {AIM: The aim of the present study was to investigate the therapeutic and preventive effects of N-acetyl cysteine and erdosteine on renal injury associated with paracetamol (acetaminophen) intoxication.<br><br>MATERIALS AND METHODS: Female albino Wistar rats were divided into six groups: control; paracetamol (1 g/kg, oral); paracetamol (1 g/kg, oral) + erdosteine (150 mg/kg/day, oral); paracetamol (1 g/kg, oral) + N-acetyl cysteine (140 mg/kg bolus, followed by 70 mg/kg, oral); N-acetyl cysteine control (140 mg/kg bolus, followed by 70 mg/kg, oral); and erdosteine control (150 mg/kg/day, oral). Potential renal injury was assessed using biochemical analyses, radionuclide imaging, and histopathological parameters.<br><br>RESULTS: In the paracetamol group, blood urea nitrogen and creatinine levels were significantly increased compared with controls. Histopathological examination showed tubular vacuolization, tubular necrosis, and remarkable interstitial inflammation. The excretion function was observed to be insufficient on radionuclide imaging. However, in the groups treated with erdosteine or N-acetyl cysteine after paracetamol, biochemical analyses, radionuclide imaging, and histopathological parameters showed significantly less evidence of renal toxicity than that observed in the group receiving paracetamol alone. Less renal toxicity was detected in rats receiving N-acetyl cysteine than in those receiving erdosteine.<br><br>CONCLUSION: Renal injury may develop after paracetamol overdose. Erdosteine and N-acetyl cysteine are both effective in the prevention of renal injury when given in the early phase of paracetamol nephrotoxicity. N-acetyl cysteine is more protective than erdosteine.}, }
@article {pmid21115496, year = {2011}, author = {Yano, M and Watanabe, K and Yamamoto, T and Ikeda, K and Senokuchi, T and Lu, M and Kadomatsu, T and Tsukano, H and Ikawa, M and Okabe, M and Yamaoka, S and Okazaki, T and Umehara, H and Gotoh, T and Song, WJ and Node, K and Taguchi, R and Yamagata, K and Oike, Y}, title = {Mitochondrial dysfunction and increased reactive oxygen species impair insulin secretion in sphingomyelin synthase 1-null mice.}, journal = {The Journal of biological chemistry}, volume = {286}, number = {5}, pages = {3992-4002}, pmid = {21115496}, issn = {1083-351X}, mesh = {Animals ; Antioxidants/pharmacology ; Glucose/pharmacology ; Insulin/deficiency/*metabolism ; Insulin Secretion ; Insulin-Secreting Cells/metabolism/pathology ; Mice ; Mice, Knockout ; Mitochondria/*pathology/physiology ; Mutation ; Phenotype ; Reactive Oxygen Species/*metabolism ; Transferases (Other Substituted Phosphate Groups)/deficiency/*physiology ; }, abstract = {Sphingomyelin synthase 1 (SMS1) catalyzes the conversion of ceramide to sphingomyelin. Here, we generated and analyzed SMS1-null mice. SMS1-null mice exhibited moderate neonatal lethality, reduced body weight, and loss of fat tissues mass, suggesting that they might have metabolic abnormality. Indeed, analysis on glucose metabolism revealed that they showed severe deficiencies in insulin secretion. Isolated mutant islets exhibited severely impaired ability to release insulin, dependent on glucose stimuli. Further analysis indicated that mitochondria in mutant islet cells cannot up-regulate ATP production in response to glucose. We also observed additional mitochondrial abnormalities, such as hyperpolarized membrane potential and increased levels of reactive oxygen species (ROS) in mutant islets. Finally, when SMS1-null mice were treated with the anti-oxidant N-acetyl cysteine, we observed partial recovery of insulin secretion, indicating that ROS overproduction underlies pancreatic β-cell dysfunction in SMS1-null mice. Altogether, our data suggest that SMS1 is important for controlling ROS generation, and that SMS1 is required for normal mitochondrial function and insulin secretion in pancreatic β-cells.}, }
@article {pmid21114986, year = {2011}, author = {Sathish, P and Paramasivan, V and Palani, V and Sivanesan, K}, title = {N-acetylcysteine attenuates dimethylnitrosamine induced oxidative stress in rats.}, journal = {European journal of pharmacology}, volume = {654}, number = {2}, pages = {181-186}, doi = {10.1016/j.ejphar.2010.10.080}, pmid = {21114986}, issn = {1879-0712}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Antioxidants/metabolism/*pharmacology ; Ascorbic Acid/metabolism ; Carcinogens/*pharmacology ; Catalase/metabolism ; Dimethylnitrosamine/metabolism/*pharmacology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Transferase/blood/metabolism ; Lipid Peroxidation/drug effects ; Liver/cytology/*drug effects/enzymology ; Liver Function Tests ; Male ; Malondialdehyde/*pharmacology ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Vitamin E/metabolism ; }, abstract = {Oxidative stress has been implicated in the pathogenesis and progression of various hepatic disorders and hence screening for a good hepatoprotective and antioxidant agent is the need of the hour. The present study was aimed to investigate the hepatoprotective and antioxidant property of N-acetylcysteine (NAC) against dimethylnitrosamine (DMN) induced oxidative stress and hepatocellular damage in male Wistar albino rats. Administration of single dose of DMN (5mg/kg b.w.; i.p.) resulted in significant elevation in the levels of serum aspartate transaminase and alanine transaminase, indicating hepatocellular damage. Oxidative stress induced by DMN treatment was confirmed by an elevation in the status of lipid peroxidation (LPO) and reduction in the activities of enzymic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and in the levels of non-enzymic antioxidants, reduced glutathione, vitamin-C and vitamin-E in the liver tissue. DMN induced oxidative stress and hepatocellular membrane instability was further substantiated by a decline in the status of the membrane bound ATPases in the liver tissue. Post-treatment with NAC (50mg/kg b.w.; p.o.) for 7days effectively protected against the DMN induced insult to liver by preventing the elevation in the status of the serum marker enzymes and LPO, and restoring the activities of both the enzymic and non-enzymic antioxidants and membrane bound ATPases towards normalcy. These results demonstrate that NAC acts as a good hepatoprotective and antioxidant agent in attenuating DMN induced oxidative stress and hepatocellular damage.}, }
@article {pmid21113238, year = {2010}, author = {Hu, J and Friedman, E}, title = {Depleting Mirk Kinase Increases Cisplatin Toxicity in Ovarian Cancer Cells.}, journal = {Genes &amp; cancer}, volume = {1}, number = {8}, pages = {803-811}, pmid = {21113238}, issn = {1947-6019}, support = {R01 CA067405/CA/NCI NIH HHS/United States ; R01 CA067405-09/CA/NCI NIH HHS/United States ; }, abstract = {Cisplatin-based regimens are the standard of care for epithelial carcinoma of the ovary. Since cisplatin is known to increase intracellular levels of toxic reactive oxygen species (ROS), an increase in cisplatin toxicity selectively in cancer cells could result from further increasing the cisplatin-elevated ROS levels by targeting antioxidant genes upregulated in ovarian cancers. The serine/threonine kinase Mirk/dyrk1B is a transcriptional co-activator which increased the expression of the antioxidant genes superoxide dismutase 2 and ferroxidase in ovarian cancer cells. As a result, depletion of Mirk increased cellular ROS levels in each of 4 ovarian cancer cell lines. Mirk depletion averaged only about 4 fold, yet combined with cisplatin treatment enabled low levels of drug to increase ROS to toxic levels in both SKOV3 and TOV21G ovarian cancer cells. Lowering ROS levels by treatment with N-acetyl cysteine limited cisplatin toxicity, resulting in higher cell numbers and decreased cleavage of the apoptotic proteins PARP and caspase 3. Mirk has also been shown to block cells in G1 by inducing proteolysis of cyclin D1. Mirk depletion increased cyclin D1 levels in 3 of 4 ovarian cancer cell lines, implying that some Mirk depleted cells could more readily enter cycle, potentially increasing their sensitivity to cisplatin. Since Mirk is upregulated in a large subset of human ovarian cancers, but is expressed at low levels in most normal tissues, and embryonic knockout of Mirk results in viable and fertile mice, targeting Mirk may sensitize ovarian cancers to lower levels of cisplatin, while sparing normal tissues.}, }
@article {pmid21113129, year = {2010}, author = {Yalcin, S and Marinkovic, D and Mungamuri, SK and Zhang, X and Tong, W and Sellers, R and Ghaffari, S}, title = {ROS-mediated amplification of AKT/mTOR signalling pathway leads to myeloproliferative syndrome in Foxo3(-/-) mice.}, journal = {The EMBO journal}, volume = {29}, number = {24}, pages = {4118-4131}, pmid = {21113129}, issn = {1460-2075}, support = {R01 DK077174/DK/NIDDK NIH HHS/United States ; R01 HL095675/HL/NHLBI NIH HHS/United States ; R01 HL110806/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Adaptor Proteins, Signal Transducing ; Animals ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/*deficiency ; Free Radical Scavengers/therapeutic use ; Gene Expression Regulation ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Mice ; Mice, Knockout ; Myeloproliferative Disorders/drug therapy/*pathology ; Proteins/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Splenomegaly/pathology ; TOR Serine-Threonine Kinases/*metabolism ; }, abstract = {Reactive oxygen species (ROS) participate in normal intracellular signalling and in many diseases including cancer and aging, although the associated mechanisms are not fully understood. Forkhead Box O (FoxO) 3 transcription factor regulates levels of ROS concentrations, and is essential for maintenance of hematopoietic stem cells. Here, we show that loss of Foxo3 causes a myeloproliferative syndrome with splenomegaly and increased hematopoietic progenitors (HPs) that are hypersensitive to cytokines. These mutant HPs contain increased ROS, overactive intracellular signalling through the AKT/mammalian target of rapamycin signalling pathway and relative deficiency of Lnk, a negative regulator of cytokine receptor signalling. In vivo treatment with ROS scavenger N-acetyl-cysteine corrects these biochemical abnormalities and relieves the myeloproliferation. Moreover, enforced expression of Lnk by retroviral transfer corrects the abnormal expansion of Foxo3(-/-) HPs in vivo. Our combined results show that loss of Foxo3 causes increased ROS accumulation in HPs. In turn, this inhibits Lnk expression that contributes to exaggerated cytokine responses that lead to myeloproliferation. Our findings could explain the mechanisms by which mutations that alter Foxo3 function induce malignancy. More generally, the work illustrates how deregulated ROS may contribute to malignant progression.}, }
@article {pmid21112471, year = {2010}, author = {Parnell, SE and Sulik, KK and Dehart, DB and Chen, SY}, title = {Reduction of ethanol-induced ocular abnormalities in mice through dietary administration of N-acetylcysteine.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {44}, number = {7-8}, pages = {699-705}, pmid = {21112471}, issn = {1873-6823}, support = {AA013908/AA/NIAAA NIH HHS/United States ; R01 AA012974-01/AA/NIAAA NIH HHS/United States ; K01 AA013908/AA/NIAAA NIH HHS/United States ; AA011605/AA/NIAAA NIH HHS/United States ; AA12974/AA/NIAAA NIH HHS/United States ; P50 AA011605-010004/AA/NIAAA NIH HHS/United States ; K01 AA013908-01A1/AA/NIAAA NIH HHS/United States ; R01 AA017446/AA/NIAAA NIH HHS/United States ; R37 AA012974/AA/NIAAA NIH HHS/United States ; AA007573/AA/NIAAA NIH HHS/United States ; R01 AA017446-01A1/AA/NIAAA NIH HHS/United States ; AA017446/AA/NIAAA NIH HHS/United States ; P60 AA011605/AA/NIAAA NIH HHS/United States ; T32 AA007573-10/AA/NIAAA NIH HHS/United States ; P50 AA011605/AA/NIAAA NIH HHS/United States ; R01 AA012974/AA/NIAAA NIH HHS/United States ; T32 AA007573/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Diet ; Disease Models, Animal ; Ethanol/blood/*toxicity ; Eye Abnormalities/*chemically induced/*prevention &amp; control ; Female ; Fetal Alcohol Spectrum Disorders ; Gestational Age ; Male ; Maternal-Fetal Exchange ; Mice ; Mice, Inbred C57BL ; Pregnancy ; }, abstract = {N-acetylcysteine (NAC) is a derivative of the amino acid l-cysteine, which, previously, has been shown to protect against ethanol-induced apoptosis during early development. Ongoing research demonstrates that NAC is also proving clinically beneficial in reducing oxidative stress-mediated lung, liver, and kidney damage, with protection likely resulting from a NAC-mediated increase in glutathione levels. In the present study, the hypothesis that coadministration of NAC and ethanol by means of liquid diet on days 7 and 8 of pregnancy in mice would reduce ethanol's teratogenicity was tested. For this work, adult nonpregnant female mice were acclimated to a liquid diet containing ethanol for 16 days, withdrawn from the ethanol, bred, and then returned to the liquid diet containing 4.8% ethanol and/or either 0.5 or 1-mg NAC/mL diet on their seventh and eighth days of pregnancy. At the concentrations used, the mice received NAC dosages of approximately 300 or 600 mg/kg/day and achieved peak blood ethanol concentrations (BEC) that averaged approximately 200mg/dL. There was no difference in BEC between the ethanol-alone and ethanol plus 600 mg/kg NAC group. After maternal euthanasia, gestational day (GD) 14 fetuses were removed, fixed, weighed, and examined for the presence and severity of ocular abnormalities, a readily assessed endpoint that results from GD 7 and 8 ethanol exposures. Although the lower dosage of NAC (300 mg/kg) resulted in a decrease in the incidence of ocular defects in both the left and right eyes, this reduction was not statistically significant. However, doubling the NAC concentration did yield a significant change; as compared with the group treated with ethanol alone, the incidence of ocular abnormalities was diminished by 22%. These results show the potential of an orally administered compound with proven clinical efficacy to reduce ethanol's teratogenic effects and support the premise that oxidative damage plays an important mechanistic role in fetal alcohol spectrum disorders.}, }
@article {pmid21112258, year = {2011}, author = {Garg, A and Prasad, B and Takwani, H and Jain, M and Jain, R and Singh, S}, title = {Evidence of the formation of direct covalent adducts of primaquine, 2-tert-butylprimaquine (NP-96) and monohydroxy metabolite of NP-96 with glutathione and N-acetylcysteine.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {879}, number = {1}, pages = {1-7}, doi = {10.1016/j.jchromb.2010.10.029}, pmid = {21112258}, issn = {1873-376X}, mesh = {Acetylcysteine/*chemistry/metabolism ; Animals ; Chromatography, High Pressure Liquid/*methods ; Glutathione/*chemistry/metabolism ; Humans ; Microsomes, Liver/metabolism ; Primaquine/*analogs &amp; derivatives/*chemistry/metabolism ; Rats ; Tandem Mass Spectrometry/*methods ; }, abstract = {2-tert-Butylprimaquine (NP-96) is a novel quinoline anti-malarial compound with superior therapeutic profile than primaquine (PQ). Moreover, it is the first 8-aminoquinoline that is established to be devoid of methemoglobin toxicity. The purpose of the present study was to investigate covalent adduct formation tendency of PQ, NP-96 and their phase I metabolites with glutathione (GSH) and N-acetylcysteine (NAc). For the same, the two compounds were incubated in human and rat liver microsomes in the presence of trapping agents and NADPH. In a control set, NADPH was excluded, while a blank was also studied that was devoid of both NADPH and microsomes. The components in the reaction mixtures were initially separated on a C-18 column (250 mm×4.6mm, 5 μm) using a mobile phase composed of acetonitrile and 10 mM ammonium acetate in a gradient mode. The samples were then subjected to LC-MS(n) and LC-HR-MS analyses, and data were collected in full scan MS, data dependent MS/MS, targeted MS/MS, neutral loss scan (NLS) and accurate mass (MS/TOF) modes. In a significant finding, both PQ and NP-96 themselves showed potential to bind covalently with GSH and NAc, as adducts were observed even in the control and blank incubations. Intense peaks corresponding to covalent adduct of mono-hydroxy metabolite of NP-96 with GSH and NAc were also detected in NADPH supplemented reaction solution.}, }
@article {pmid21111046, year = {2011}, author = {Somjen, D and Katzburg, S and Grafi-Cohen, M and Knoll, E and Sharon, O and Posner, GH}, title = {Vitamin D metabolites and analogs induce lipoxygenase mRNA expression and activity as well as reactive oxygen species (ROS) production in human bone cell line.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {123}, number = {1-2}, pages = {85-89}, doi = {10.1016/j.jsbmb.2010.11.010}, pmid = {21111046}, issn = {1879-1220}, mesh = {Bone and Bones/drug effects/enzymology/*metabolism ; Cell Line ; Cell Proliferation ; Humans ; Hydroxyeicosatetraenoic Acids/metabolism/pharmacology ; Lipoxygenase/*genetics/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors ; Onium Compounds/pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Vitamin D/*analogs &amp; derivatives/metabolism/*pharmacology ; }, abstract = {Vitamin D metabolites and its less-calcemic analogs (vitamin D compounds) are beneficial for bone and modulate cell growth and energy metabolism. We now analyze whether 25(OH)D(3) (25D), 1,25(OH)(2)D(3) (1,25D), 24,25(OH)(2)D(3) (24,25D), JKF1624F(2)-2 (JKF) or QW1624F(2)-2 (QW) regulate lipooxygenase (LO) mRNA expression and its products; hydroxyl-eicosatetraenoic acid (12 and 15HETE) formation, as well as reactive oxygen species (ROS) production in human bone cell line (SaOS2) and their interplay with modulation of cell proliferation and energy metabolism. All compounds except 25D increased 12LO mRNA expression and modulated 12 and 15HETE production whereas ROS production was increased by all compounds, and inhibited by NADPH oxidase inhibitors diphenyleneiodonium (DPI) and N-acetylcysteine (NAc). Baicaleine (baic) the inhibitor of 12 and 15LO activity blocked only slightly the stimulation of DNA synthesis by all compounds, whereas DPI inhibited almost completely the stimulation of DNA and CK by all compounds. Treatments of cells with 12 or 15HETE increased DNA synthesis and CK that were only slightly inhibited by DPI. These results indicate that vitamin D compounds increased oxidative stress in osteoblasts in part via induction of LO expression and activity. The increased ROS production mediates partially elevated cell proliferation and energy metabolism, whereas the LO mediation is not essential. This new feature of vitamin D compounds is mediated by intracellular and/or membranal binding sites and its potential hazard could lead to damage due to increased lipid oxidation, although the transient mediation of ROS in cell proliferation is beneficial to bone growth in a yet unknown mechanism.}, }
@article {pmid21106878, year = {2011}, author = {Frost, RA and Pereyra, E and Lang, CH}, title = {Ethyl pyruvate preserves IGF-I sensitivity toward mTOR substrates and protein synthesis in C2C12 myotubes.}, journal = {Endocrinology}, volume = {152}, number = {1}, pages = {151-163}, pmid = {21106878}, issn = {1945-7170}, support = {R01 GM038032/GM/NIGMS NIH HHS/United States ; R25 DK078381/DK/NIDDK NIH HHS/United States ; GM-38032/GM/NIGMS NIH HHS/United States ; }, mesh = {Adaptor Proteins, Signal Transducing ; Animals ; Carrier Proteins/genetics/metabolism ; Cell Line ; GTP Phosphohydrolases/metabolism ; Gene Expression Regulation/drug effects/physiology ; Insulin-Like Growth Factor I/*metabolism ; Interferon-gamma/pharmacology ; Lipopolysaccharides/pharmacology ; Mice ; Muscle Fibers, Skeletal/*drug effects ; Myoblasts ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors ; Pyruvates/*pharmacology ; Regulatory-Associated Protein of mTOR ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Bacterial infection decreases skeletal muscle protein synthesis via inhibition of the mammalian target of rapamycin (mTOR), a key regulator of translation initiation. To better define the mechanism by which muscle mTOR activity is decreased, we used an in vitro model of C2C12 myotubes treated with endotoxin [lipopolysaccharide (LPS)]and interferon (IFN)-γ to determine whether stable lipophilic pyruvate derivatives restore mTOR signaling. Myotubes treated with a combination of LPS and IFNγ down-regulated the phosphorylation of the mTOR substrates S6 kinase-1 and 4E binding protein-1. The phosphorylation of ribosomal protein S6 was decreased, whereas phosphorylation of elongation factor-2 was enhanced; all results consistent with defects in both translation initiation and elongation. LPS/IFNγ decreased protein synthesis 60% in myotubes. Treatment with methyl or ethyl pyruvate partially protected against the LPS/IFNγ-induced fall in mTOR signaling. The protective effect of ethyl and methyl pyruvate could not be replicated by an equimolar amount of sodium pyruvate. Although LPS/IFNγ treated myotubes were initially IGF-I responsive, prolonged exposure (≥ 17 h) resulted in IGF-I resistance at the level of mTOR despite normal IGF-I receptor phosphorylation. Ethyl pyruvate treatment restored IGF-I sensitivity as evidenced by the left shift in the IGF-I dose-response curve and maintained IGF-I responsiveness for a prolonged period of time. Ethyl pyruvate also restored IGF-I-stimulated protein synthesis in LPS/IFNγ-treated myotubes. Cotreatment with N-acetyl cysteine or ascorbic acid also preserved IGF-I sensitivity and mTOR activity. The data suggest that the combination of LPS and IFNγ inhibits mTOR activity and that prolonged exposure induces IGF-I resistance in myotubes. Lipophilic pyruvate derivatives and antioxidants show promise at rescuing mTOR activity and muscle protein synthesis by maintaining IGF-I sensitivity in this model.}, }
@article {pmid21106264, year = {2012}, author = {Koc, F and Ozdemir, K and Kaya, MG and Dogdu, O and Vatankulu, MA and Ayhan, S and Erkorkmaz, U and Sonmez, O and Aygul, MU and Kalay, N and Kayrak, M and Karabag, T and Alihanoglu, Y and Gunebakmaz, O}, title = {Intravenous N-acetylcysteine plus high-dose hydration versus high-dose hydration and standard hydration for the prevention of contrast-induced nephropathy: CASIS--a multicenter prospective controlled trial.}, journal = {International journal of cardiology}, volume = {155}, number = {3}, pages = {418-423}, doi = {10.1016/j.ijcard.2010.10.041}, pmid = {21106264}, issn = {1874-1754}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Angioplasty, Balloon, Coronary/adverse effects/methods ; Contrast Media/*adverse effects ; Coronary Angiography/adverse effects/methods ; Coronary Disease/diagnosis/therapy ; Creatinine/blood ; Dose-Response Relationship, Drug ; Female ; Fluid Therapy/*methods ; Follow-Up Studies ; Free Radical Scavengers/administration &amp; dosage ; Humans ; Infusions, Intravenous ; Kidney Diseases/blood/chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Prospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) is a leading cause of acute renal failure and affects mortality and morbidity. We investigated the efficacy of prophylactic intravenous (IV) N-acetylcysteine (NAC) and hydration for the prevention of CIN in patients with mild to moderate renal dysfunction who are undergoing coronary angiography and/or percutaneous coronary intervention (PCI).<br><br>METHODS: A total of 220 patients who had mild to moderate renal dysfunction with serum creatinine (SCr) &#x2265; 1.1mg/dL or creatinine clearance &#x2264; 60 mL/min were randomized in 3 groups: 80 patients were assigned to IV NAC plus high-dose hydration with normal saline, 80 patients to only high-dose hydration with normal saline and 60 patients to standard hydration with normal saline (control group). The primary end point was the alteration of SCr level. The secondary end point was the development of CIN after the procedure.<br><br>RESULTS: SCr levels changed the least in the NAC plus high-hydration group (P=0.004). The rate of the CIN in the NAC plus high-dose hydration group was also lower than the high-dose hydration group (P=0.006). No significant differences in the primary and secondary end points were found between high-dose hydration and control group.<br><br>CONCLUSION: The results of this study suggest that NAC plus high-dose hydration was superior to high-dose hydration alone as well as standard hydration for the protection of renal functions in patients with mild to moderate renal dysfunction who are undergoing coronary angiography and/or PCI. High-dose hydration without NAC was not better than standard hydration alone.}, }
@article {pmid21104935, year = {2010}, author = {Koçkar, MC and Nazıroğlu, M and Celik, O and Tola, HT and Bayram, D and Koyu, A}, title = {N-acetylcysteine modulates doxorubicin-induced oxidative stress and antioxidant vitamin concentrations in liver of rats.}, journal = {Cell biochemistry and function}, volume = {28}, number = {8}, pages = {673-677}, doi = {10.1002/cbf.1707}, pmid = {21104935}, issn = {1099-0844}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibiotics, Antineoplastic/*toxicity ; Antioxidants/metabolism/*pharmacology ; Doxorubicin/*toxicity ; Lipid Peroxidation/drug effects ; Liver/*drug effects/metabolism/pathology ; Male ; Oxidative Stress/*drug effects ; Rats ; Vitamins/*metabolism ; }, abstract = {Doxorubicin (DOX) is a chemotherapeutic agent, and is widely used in cancer treatment. The most common side effect of DOX was indicated on cardiovascular system by experimental studies. There are some studies suggesting oxidative stress-induced toxic changes on liver related to DOX administration. The aim of the present study was to evaluate whether antioxidant N-acetylcysteine (NAC) relieves oxidative stress in DOX- induced liver injury in rat. Twenty-four male rats were equally divided into three groups. First group was used as a control. Second group received single dose of DOX. NAC for 10 days was given to constituting the third group after giving one dose of DOX. After 10 days of the experiment, liver tissues were taken from all animals. Lipid peroxidation (LP) levels were higher in the DOX group than in control whereas LP levels were lower in the DOX+NAC group than in control. Vitamin C and vitamin E levels were lower in the DOX group than in control whereas vitamin C and vitamin E levels were higher in the DOX+NAC group than in the DOX group. Reduced glutathione levels were higher in the DOX+NAC group than in control and DOX group. Glutathione peroxidase, vitamin A and β-carotene values were not changed in the three groups by DOX and NAC administrations. In histopathological evaluation of DOX group, there were mononuclear cell infiltrations, vacuolar degeneration, hepatocytes with basophilic nucleus and sinusoidal dilatations. The findings were totally recovered by NAC administration. In conclusion, N-acetylcysteine induced modulator effects on the doxorubicin-induced hepatoxicity by inhibiting free radical production and supporting the antioxidant vitamin levels.}, }
@article {pmid21103380, year = {2010}, author = {Brown-Steinke, K and deRonde, K and Yemen, S and Palmer, LA}, title = {Gender differences in S-nitrosoglutathione reductase activity in the lung.}, journal = {PloS one}, volume = {5}, number = {11}, pages = {e14007}, pmid = {21103380}, issn = {1932-6203}, support = {P01 HL101871/HL/NHLBI NIH HHS/United States ; U10 HL109250/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aldehyde Oxidoreductases/*metabolism ; Animals ; Bronchodilator Agents/pharmacology ; Cells, Cultured ; Endothelium, Vascular/cytology/drug effects/*enzymology ; Enzyme Activation/drug effects ; Estrogens/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Hypoxia ; Lung/cytology/drug effects/*enzymology ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Nitric Oxide Synthase Type III/genetics/metabolism ; Orchiectomy ; S-Nitrosoglutathione/pharmacology ; Sex Factors ; }, abstract = {S-nitrosothiols have been implicated in the etiology of various pulmonary diseases. Many of these diseases display gender preferences in presentation or altered severity that occurs with puberty, the mechanism by which is unknown. Estrogen has been shown to influence the expression and activity of endothelial nitric oxide synthase (eNOS) which is associated with increased S-nitrosothiol production. The effects of gender hormones on the expression and activity of the de-nitrosylating enzyme S-nitrosoglutathione reductase (GSNO-R) are undefined. This report evaluates the effects of gender hormones on the activity and expression of GSNO-R and its relationship to N-acetyl cysteine (NAC)-induced pulmonary hypertension (PH). GSNO-R activity was elevated in lung homogenates from female compared to male mice. Increased activity was not due to changes in GSNO-R expression, but correlated with GSNO-R S-nitrosylation: females were greater than males. The ability of GSNO-R to be activated by S-nitrosylation was confirmed by: 1) the ability of S-nitrosoglutathione (GSNO) to increase the activity of GSNO-R in murine pulmonary endothelial cells and 2) reduced activity of GSNO-R in lung homogenates from eNOS(-/-) mice. Gender differences in GSNO-R activity appear to explain the difference in the ability of NAC to induce PH: female and castrated male animals are protected from NAC-induced PH. Castration results in elevated GSNO-R activity that is similar to that seen in female animals. The data suggest that GSNO-R activity is modulated by both estrogens and androgens in conjunction with hormonal regulation of eNOS to maintain S-nitrosothiol homeostasis. Moreover, disruption of this eNOS-GSNO-R axis contributes to the development of PH.}, }
@article {pmid21098090, year = {2011}, author = {Chen, JR and Lazarenko, OP and Shankar, K and Blackburn, ML and Lumpkin, CK and Badger, TM and Ronis, MJ}, title = {Inhibition of NADPH oxidases prevents chronic ethanol-induced bone loss in female rats.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {336}, number = {3}, pages = {734-742}, pmid = {21098090}, issn = {1521-0103}, support = {R01 AA018282/AA/NIAAA NIH HHS/United States ; R01-AA18282/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Bone Resorption/chemically induced/*enzymology/*prevention &amp; control ; Cell Line ; Enzyme Inhibitors/pharmacology/therapeutic use ; Estradiol/pharmacology/therapeutic use ; Ethanol/*toxicity ; Female ; NADPH Oxidases/*antagonists &amp; inhibitors/*metabolism ; Onium Compounds/pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Previous in vitro data suggest that ethanol (EtOH) activates NADPH oxidase (Nox) in osteoblasts leading to accumulation of reactive oxygen species (ROS). This might be a mechanism underlying inhibition of bone formation and increased bone resorption observed in vivo after EtOH exposure. In a rat model in which cycling females were infused intragastrically with EtOH-containing liquid diets, EtOH significantly decreased bone formation and stimulated osteoblast-dependent osteoclast differentiation. These effects were reversed by exogenous 17-β-estradiol coadministration. Moreover, coadministration of N-acetyl cysteine (NAC), an antioxidant, or diphenylene iodonium (DPI), a specific Nox inhibitor, also abolished chronic EtOH-associated bone loss. EtOH treatment up-regulated mRNA levels of Nox1, 2, 4, and the receptor activator of nuclear factor-κB ligand (RANKL), an essential factor for differentiation of osteoclasts in bone. Protein levels of Nox4, a major Nox isoform expressed in nonphagocytic cells, was also up-regulated by EtOH in bone. 17-β-Estradiol, NAC, and DPI were able to normalize EtOH-induced up-regulation of Nox and RANKL. In vitro experiments demonstrated that EtOH directly up-regulated Nox expression in osteoblasts. Pretreatment of osteoblasts with DPI eliminated EtOH-induced RANKL promoter activity. Furthermore, EtOH induced RANKL gene expression, and RANKL promoter activation in osteoblasts was ROS-dependent. These data suggest that inhibition of Nox expression and activity may be critical for prevention of chronic EtOH-induced osteoblast-dependent bone loss.}, }
@article {pmid21093414, year = {2011}, author = {Barnett, P and Arnold, RS and Mezencev, R and Chung, LW and Zayzafoon, M and Odero-Marah, V}, title = {Snail-mediated regulation of reactive oxygen species in ARCaP human prostate cancer cells.}, journal = {Biochemical and biophysical research communications}, volume = {404}, number = {1}, pages = {34-39}, pmid = {21093414}, issn = {1090-2104}, support = {R01 CA122602/CA/NCI NIH HHS/United States ; G12 RR003062-23/RR/NCRR NIH HHS/United States ; P01 CA098912/CA/NCI NIH HHS/United States ; P20 MD002285/MD/NIMHD NIH HHS/United States ; G12 MD007590/MD/NIMHD NIH HHS/United States ; P20 MD002285-03/MD/NIMHD NIH HHS/United States ; G12 RR003062/RR/NCRR NIH HHS/United States ; G12RR03062/RR/NCRR NIH HHS/United States ; 1P20MD002285/MD/NIMHD NIH HHS/United States ; 2P01CA098912/CA/NCI NIH HHS/United States ; P01 CA098912-02/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Cell Line, Tumor ; *Epithelial-Mesenchymal Transition ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Mice ; Mice, Nude ; Oxidative Stress/genetics ; Prostatic Neoplasms/genetics/*pathology ; Reactive Oxygen Species/*metabolism ; Snail Family Transcription Factors ; Transcription Factors/genetics/*metabolism ; Transfection ; }, abstract = {Reactive oxygen species increases in various diseases including cancer and has been associated with induction of epithelial-mesenchymal transition (EMT), as evidenced by decrease in cell adhesion-associated molecules like E-cadherin, and increase in mesenchymal markers like vimentin. We investigated the molecular mechanisms by which Snail transcription factor, an inducer of EMT, promotes tumor aggressiveness utilizing ARCaP prostate cancer cell line. An EMT model created by Snail overexpression in ARCaP cells was associated with decreased E-cadherin and increased vimentin. Moreover, Snail-expressing cells displayed increased concentration of reactive oxygen species (ROS), specifically, superoxide and hydrogen peroxide, in vitro and in vivo. Real Time PCR profiling demonstrated increased expression of oxidative stress-responsive genes, such as aldehyde oxidase I, in response to Snail. The ROS scavenger, N-acetyl cysteine partially reversed Snail-mediated EMT after 7 days characterized by increased E-cadherin levels and decreased ERK activity, while treatment with the MEK inhibitor, UO126, resulted in a more marked effect by 3 days, characterized by cells returning back to the epithelial morphology and increased E-cadherin. In conclusion, this study shows for the first time that Snail transcription factor can regulate oxidative stress enzymes and increase ROS-mediated EMT regulated in part by ERK activation. Therefore, Snail may be an attractive molecule for therapeutic targeting to prevent tumor progression in human prostate cancer.}, }
@article {pmid21093096, year = {2011}, author = {Viačková, D and Pekarová, M and Crhák, T and Búcsaiová, M and Matiašovic, J and Lojek, A and Kubala, L}, title = {Redox-sensitive regulation of macrophage-inducible nitric oxide synthase expression in vitro does not correlate with the failure of apocynin to prevent lung inflammation induced by endotoxin.}, journal = {Immunobiology}, volume = {216}, number = {4}, pages = {457-465}, doi = {10.1016/j.imbio.2010.09.005}, pmid = {21093096}, issn = {1878-3279}, mesh = {Acetophenones/*pharmacology ; Adjuvants, Immunologic/pharmacology ; Animals ; Antioxidants/*pharmacology ; Bronchoalveolar Lavage Fluid/cytology ; Cell Line ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; *Gene Expression Regulation, Enzymologic/drug effects ; Lipopolysaccharides/metabolism/pharmacology ; Macrophages/drug effects/*metabolism ; Mice ; Mice, Inbred C57BL ; NADPH Oxidases/antagonists &amp; inhibitors ; NF-kappa B/metabolism ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase Type II/genetics/*metabolism ; Oxidation-Reduction ; *Pneumonia/chemically induced/immunology/metabolism/prevention &amp; control ; Reactive Oxygen Species/metabolism ; }, abstract = {Reactive oxygen and nitrogen species are among the crucial mediators in the development of the pathological inflammatory process in the lungs and contribute to the damage of lung epithelium. The aim of the present study was to evaluate the potential of selected antioxidants or inhibitors of NADPH oxidase (glutathione, N-acetyl cysteine, trolox, apocynin, and diphenyleneiodonium chloride) to modulate nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression by mouse macrophages induced by lipopolysaccharide (LPS) in vitro and to evaluate the potential of apocynin to modulate the course of LPS-induced lung inflammation in vivo. All the tested drugs revealed inhibitory effects on LPS-induced NO production and iNOS expression in RAW 264.7 macrophages. Further, apocynin significantly inhibited activation of nuclear factor kappa B induced by LPS. Ex vivo, diphenyleneiodonium chloride and apocynin significantly reduced ROS production by inflammatory cells isolated from bronchoalveolar lavage fluid. In contrast, in vivo intranasal application of apocynin did not exert any significant effect on the course of lung inflammation in mice induced by LPS that was evaluated based on the accumulation of cells, interleukine-6, interleukine-12, RANTES, tumor necrosis factor-alpha, and protein concentration in bronchoalveolar lavage fluid and expression of iNOS in lung tissue. Only effected were the levels of nitrites 36 h after induction of lung inflammation that were reduced in the apocynin-treated group. In conclusion, our data suggest that the inhibitors of NADPH oxidase possess inhibitory potential against LPS-induced NO production by mouse macrophages; however, apocynin failed to reduce LPS-induced lung inflammation in mice.}, }
@article {pmid21088145, year = {2011}, author = {Ueno, T and Yamada, M and Sugita, Y and Ogawa, T}, title = {N-acetyl cysteine protects TMJ chondrocytes from oxidative stress.}, journal = {Journal of dental research}, volume = {90}, number = {3}, pages = {353-359}, doi = {10.1177/0022034510388035}, pmid = {21088145}, issn = {1544-0591}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Aggrecans/biosynthesis ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Chondrocytes/*drug effects/metabolism/pathology ; Collagen Type II/biosynthesis ; Free Radical Scavengers/*pharmacology/therapeutic use ; Glutathione/biosynthesis ; Glycosaminoglycans/biosynthesis ; Hydrogen Peroxide/pharmacology ; Osteoarthritis/*drug therapy/metabolism/surgery ; Oxidants/pharmacology ; Oxidative Stress/*drug effects ; Paracentesis ; Rats ; Temporomandibular Joint Disorders/*drug therapy/metabolism/surgery ; }, abstract = {Temporomandibular joint (TMJ) inflammation is closely associated with oxidative stress. This study tested the potential of N-acetyl cysteine (NAC), an anti-oxidant amino-acid derivative, in alleviating oxidative stress-related damage in TMJ chondrocytes. The inflammatory condition was simulated by the addition of hydrogen peroxide (H2O2) to TMJ-derived chondrocyte cultures. Exposure to H2O2 decreased the cell population by half within 2 days as a result of induced apoptosis and reduced proliferation. Gene expression of aggrecan and collagen II, as well as glycosaminoglycan production, were reduced by more than 70%. These compromised chondrocyte viability and function were fully restored by the addition of NAC to the cultures. NAC reduced the H2O2-elevated intracellular reactive oxygen species to the normal level and increased cellular glutathione reserves. These results indicate that NAC restores oxidative stress-induced cell death and severe functional impairment in TMJ chondrocytes, and warrant in vivo testing to explore its therapeutic potential as an anti-inflammatory agent.}, }
@article {pmid21087961, year = {2011}, author = {Pan, Q and Qiu, WY and Huo, YN and Yao, YF and Lou, MF}, title = {Low levels of hydrogen peroxide stimulate corneal epithelial cell adhesion, migration, and wound healing.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {52}, number = {3}, pages = {1723-1734}, pmid = {21087961}, issn = {1552-5783}, support = {R01 EY010595/EY/NEI NIH HHS/United States ; R01 EY10595/EY/NEI NIH HHS/United States ; }, mesh = {Actins/metabolism ; Animals ; Cell Adhesion/*physiology ; Cell Line ; Cell Movement/*physiology ; Cell Survival ; Epithelium, Corneal/*cytology/*drug effects/metabolism ; ErbB Receptors/metabolism ; Fluorescent Antibody Technique, Indirect ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Hydrogen Peroxide/*administration &amp; dosage ; Male ; Mice ; Mice, Inbred C57BL ; Organ Culture Techniques ; Phosphorylation ; Rabbits ; Swine ; Vinculin/metabolism ; Wound Healing/*physiology ; }, abstract = {PURPOSE: Intracellular reactive oxygen species have been reported to associate with growth factor and integrin signalings in promoting cell adhesion in many cell types. This study is to explore if exogenous H(2)O(2) at low levels can be beneficial to cell adhesion, migration, and wound healing.<br><br>METHODS: Primary rabbit corneal epithelial cells treated with 0-70 &#x3bc;M H(2)O(2) were tested for viability by MTT assay, adhesion by centrifugation assay, focal contacts of vinculin and F-actin by immunofluorescence, activated Src(pY416), EGF receptor (pY845), vinculin(pY1065), FAK(pY397), and FAK(pY576) by immunoblotting. Cell migration was examined with 0-50 &#x3bc;M H(2)O(2) using the scratch wound technique. Corneal wound healing of ex vivo pig model and in vivo mouse model was examined using H(2)O(2) with and without antioxidant N-acetylcysteine (NAC).<br><br>RESULTS: Compared with the untreated control, H(2)O(2) at 10-50 &#x3bc;M stimulated cell viability and facilitated adhesion and migration with clear induction of vinculin-rich focal adhesions and F-actin-containing stress fibers by increasing activated Src, FAK(pY576), and vinculin(pY1065). H(2)O(2) also increased phosphorylation of EGFR(Y845) parallel to that of activated Src, but both were eliminated by NAC and PP1 (Src inhibitor). Finally, H(2)O(2) induced faster wound healing in cornea both in vitro and in vivo, but the healing was diminished by NAC.<br><br>CONCLUSIONS: These findings suggest that H(2)O(2) at low levels promotes cell adhesion, migration, and wound healing in cornea cells or tissue, and the interaction of H(2)O(2) with Src plays a major role.}, }
@article {pmid21084597, year = {2010}, author = {Won, SJ and Yoo, BH and Brennan, AM and Shin, BS and Kauppinen, TM and Berman, AE and Swanson, RA and Suh, SW}, title = {EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {30}, number = {46}, pages = {15409-15418}, pmid = {21084597}, issn = {1529-2401}, mesh = {Acetylcysteine/metabolism ; Animals ; *Disease Progression ; Excitatory Amino Acid Transporter 3/deficiency/*genetics ; *Gene Deletion ; Homeostasis/*genetics ; Ischemic Attack, Transient/*genetics/metabolism/*pathology ; Male ; Mice ; Mice, Transgenic ; Neurons/*pathology ; Zinc/*physiology ; }, abstract = {EAAC1 is a neuronal glutamate and cysteine transporter. EAAC1 uptake of cysteine provides substrate for neuronal glutathione synthesis, which plays a key role in both antioxidant defenses and intracellular zinc binding. Here we evaluated the role of EAAC1 in neuronal resistance to ischemia. EAAC1(-/-) mice subjected to transient cerebral ischemia exhibited twice as much hippocampal neuronal death as wild-type mice and a corresponding increase in microglial activation. EAAC1(-/-) mice also had elevated vesicular and cytosolic zinc concentrations in hippocampal CA1 neurons and an increased zinc translocation to postsynaptic neurons after ischemia. Treatment of the EAAC1(-/-) mice with N-acetyl cysteine restored neuronal glutathione concentrations and normalized basal zinc levels in the EAAC1(-/-) mice. Treatment of the EAAC1(-/-) mice with either N-acetyl cysteine or with zinc chelators reduced ischemia-induced zinc translocation, superoxide production, and neuron death. These findings suggest that cysteine uptake by EAAC1 is important for zinc homeostasis and neuronal antioxidant function under ischemic conditions.}, }
@article {pmid21082355, year = {2011}, author = {Ravindran, J and Gupta, N and Agrawal, M and Bala Bhaskar, AS and Lakshmana Rao, PV}, title = {Modulation of ROS/MAPK signaling pathways by okadaic acid leads to cell death via, mitochondrial mediated caspase-dependent mechanism.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {16}, number = {2}, pages = {145-161}, doi = {10.1007/s10495-010-0554-0}, pmid = {21082355}, issn = {1573-675X}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Anthracenes/pharmacology ; *Apoptosis ; Apoptosis Inducing Factor/metabolism ; Blotting, Western ; Caspase 3/genetics/metabolism ; Caspase 7/genetics/metabolism ; Caspase 9/genetics/metabolism ; Cell Line, Tumor ; Cyclosporins/pharmacology ; Cytochromes c/metabolism ; DNA Damage/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavonoids/pharmacology ; Glutathione/analysis ; Humans ; Imidazoles/pharmacology ; Immunoblotting ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Okadaic Acid/*toxicity ; Poly(ADP-ribose) Polymerases/metabolism ; Pyridines/pharmacology ; Reactive Oxygen Species/*metabolism ; U937 Cells ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Okadaic acid (OA) is a specific and potent protein phosphatase inhibitor and tumor promoter. The present study establishes the role of reactive oxygen species (ROS) and mitogen activated protein kinases in cell death induced by okadaic acid. The study showed that okadaic acid is cytotoxic at 10 nM with an IC50 of 100 nM in U-937 cells. The CVDE assay and mitochondrial dehydrogenase assay showed a time dependent cytotoxicity. The phase contrast visualization of the OA treated cells showed the apoptotic morphology and was confirmed with esterase staining for plasma membrane integrity. OA activated caspases-7, 9 and 3, PARP cleavage and induced nuclear damage in a time and dose dependent manner. Compromised mitochondrial membrane potential, release of cytochrome-c and apoptosis inducing factor confirms the involvement of mitochondria. A time dependent decrease in glutathione levels and a dose dependent increase in ROS with maximum at 30 min were observed. ROS scavenger-N-acetyl cysteine, mitochondrial stabilizer-cyclosporin-A, and broad spectrum caspase inhibitor Z-VAD-FMK inhibited the OA induced caspase-3 activation, DNA damage and cell death but caspase-8 inhibitor had no effect. OA activated p38 MAPK and JNK in a time dependent manner, but not ERK½. MAP kinase inhibitors SB203580, SP600125 and PD98059 confirm the role of p38 MAPK and JNK in OA induced caspase-3 activation and cell death. Over all, our results indicate that OA induces cell death by generation of ROS, and activation of p38 MAPK and JNK, and executed through mitochondrial mediated caspase pathway.}, }
@article {pmid21081246, year = {2011}, author = {D'Antò, V and Spagnuolo, G and Schweikl, H and Rengo, S and Ambrosio, L and Martina, R and Valletta, R}, title = {Effect of N-acetyl cysteine on orthodontic primers cytotoxicity.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {27}, number = {2}, pages = {180-186}, doi = {10.1016/j.dental.2010.10.011}, pmid = {21081246}, issn = {1879-0097}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Coloring Agents ; Dentin-Bonding Agents/toxicity ; Dose-Response Relationship, Drug ; Ethanol/toxicity ; Fibroblasts/*drug effects ; Flow Cytometry ; Fluoresceins ; Fluorescent Dyes ; Gingiva/cytology/*drug effects ; Humans ; Hydrophobic and Hydrophilic Interactions ; Methacrylates/toxicity ; Propidium ; Reactive Oxygen Species/*toxicity ; Resin Cements/*toxicity ; Tetrazolium Salts ; Thiazoles ; }, abstract = {OBJECTIVES: The aims of this study were to evaluate the cytotoxicity of four orthodontic primers, including two hydrophilic and two hydrophobic materials, and to investigate the role of the reactive oxygen species (ROS) in induced cell damage. Moreover, the effects of the anti-oxidant N-acetyl cysteine (NAC) on primers toxicity was analyzed.<br><br>METHODS: Human gingival fibroblasts (HGF) were exposed to different concentrations of primers (0-0.25 mg/ml) in the presence or absence of NAC, and the cytotoxicity was assessed by the MTT assay, while cell death was quantified by flow cytometry after propidium iodide staining. The increase in the induced ROS levels was detected by flow cytometry measuring the fluorescence of the oxidation-sensitive dye 2',7'-dichlorofluorescein diacetate (DCFH-DA).<br><br>RESULTS: All materials decreased cell viability in a dose-related manner after a 24 h exposure period. Cytotoxicity of orthodontic primers based on concentrations which caused a 50% decrease in cell viability (TC&#x2085;&#x2080;) in HGF was ranked as follows (median values): Eagle Fluorsure (0.078 mg/ml)>Transbond XT (0.081 mg/ml)>Transbond MIP (0.128 mg/ml)>Ortho solo (0.130 mg/ml). Moreover, in HGF cells, all materials induced a dose-dependent increase in ROS levels compared to untreated cells. Incubation of HGF with NAC significantly reduced ROS production and decreased the cell damage and cytotoxicity caused by all materials tested (p<0.001).<br><br>SIGNIFICANCE: Our results suggested that hydrophilic primers were less cytotoxic than hydrophobic materials. Moreover, we demonstrated a major role of ROS in the induction of cell death since the antioxidant N-acetyl cysteine was able to prevent cell damage induced by all materials tested.}, }
@article {pmid21074392, year = {2012}, author = {Meshkini, A and Yazdanparast, R}, title = {Involvement of oxidative stress in taxol-induced apoptosis in chronic myelogenous leukemia K562 cells.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {64}, number = {4}, pages = {357-365}, doi = {10.1016/j.etp.2010.09.010}, pmid = {21074392}, issn = {1618-1433}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*toxicity ; Apoptosis/*drug effects ; Cell Line, Tumor ; Drug Antagonism ; Drug Screening Assays, Antitumor ; Flow Cytometry ; Glutathione/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; K562 Cells/*drug effects/metabolism/pathology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/metabolism/pathology ; Oxidative Stress/*drug effects ; Paclitaxel/*toxicity ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {It is now well accepted that taxol exhibits cytotoxicity and antitumor activity in many human tumors through microtubule stabilization and induction of G2/M cell cycle arrest with final extensive cell apoptosis. Since many anti-cancer agents exert their cytotoxic effects through reactive oxygen species (ROS), we were interested to evaluate whether oxidative stress is involved in taxol-induced cytotoxicity among human leukemia K562 cells. Our results showed that induction of apoptosis was associated with generation of ROS and glutathione (GSH) depletion. The increase in ROS production and apoptosis were both suppressed by antioxidant N-acetyl-l-cysteine (NAC). Moreover, taxol caused an increase in c-Jun NH(2)-terminal kinase (JNK) and p38 activities, two of the well known mediators of the stress activation pathways. Attenuation of JNK expression in the presence of NAC might indicate the modulation of the level of JNK activity by ROS. Furthermore, our data indicated that Bcl-2α was down-regulated in taxol-treated cells and its expression was modulated by ROS and JNK activity. The activities of caspase-9 and -3 were also increased upon treatment with taxol; however, pre-treatment of cells with NAC or JNK inhibitor (SP600125) impeded taxol-mediated caspase activation and apoptosis in K562 cells, suggesting that JNK acts upstream of the caspases. Taken together, these results indicate that taxol induces apoptosis in chronic myelogenous leukemia cells by inducing intracellular oxidative stress and JNK activation pathway.}, }
@article {pmid21071431, year = {2011}, author = {Schreiner, CE and Kumerz, M and Gesslbauer, J and Schachner, D and Joa, H and Erker, T and Atanasov, AG and Heiss, EH and Dirsch, VM}, title = {Resveratrol blocks Akt activation in angiotensin II- or EGF-stimulated vascular smooth muscle cells in a redox-independent manner.}, journal = {Cardiovascular research}, volume = {90}, number = {1}, pages = {140-147}, pmid = {21071431}, issn = {1755-3245}, mesh = {Analysis of Variance ; Angiotensin II/*metabolism ; Animals ; Antioxidants/pharmacology ; Cell Shape/drug effects ; Cells, Cultured ; Enzyme Activation ; Epidermal Growth Factor/*metabolism ; Hydrogen Peroxide/metabolism ; Male ; Muscle, Smooth, Vascular/*drug effects/enzymology/pathology ; Myocytes, Smooth Muscle/*drug effects/enzymology/pathology ; NADH, NADPH Oxidoreductases/metabolism ; NADPH Oxidase 1 ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/metabolism ; Oxidation-Reduction ; Phosphorylation ; Proto-Oncogene Proteins c-akt/*metabolism ; RNA Interference ; Rats ; Rats, Sprague-Dawley ; Resveratrol ; Signal Transduction/drug effects ; Stilbenes/*pharmacology ; Time Factors ; Transfection ; }, abstract = {AIMS: Resveratrol (RV), an antioxidant, inhibits angiotensin II (Ang II)-induced hypertrophy and Ang II- or epidermal growth factor (EGF)-induced Akt phosphorylation in rat vascular smooth muscle cells (VSMCs). Both signalling pathways are reported to utilize reactive oxygen species (ROS). The aim of this study was to show whether RV reduces the ROS level in Ang II- or EGF-activated VSMCs and whether reduction of ROS causes the impeded signalling towards Akt in the presence of RV.<br><br>METHODS AND RESULTS: We show here that RV reduces intracellular ROS and extracellular H&#x2082;O&#x2082; release from VSMCs as measured using 2',7'-dichlorodihydrofluorescein-diacetate and Amplex Red&#x2122;. Since NADPH oxidases (Nox) 1 and 4 are major ROS sources in VSMCs, we examined their need for Akt phosphorylation in response to Ang II or EGF. Experiments using the blocking peptide gp91ds-tat verified a role for Nox1 in Ang II signalling towards Akt, but excluded a role for Nox1 in the respective EGF signalling. A small interfering RNA-mediated knock-down of Nox4 showed that Nox4 was not required for Ang II- or EGF-induced Akt phosphorylation. Use of the flavoprotein inhibitor diphenyleneiodonium, N-acetyl-cysteine, and non-antioxidant RV derivatives revealed that the antioxidant capacity of RV is not required for the inhibition of Akt phosphorylation, in both rat and human VSMCs.<br><br>CONCLUSION: Thus, although RV acts as an antioxidant, the antihypertrophic response of RV in VSMCs and the signalling downstream of the EGF receptor towards Akt seem to be largely redox independent.}, }
@article {pmid21069346, year = {2011}, author = {Doi, T and Puri, P and Bannigan, J and Thompson, J}, title = {Pre-treatment with N-acetylcysteine upregulates superoxide dismutase 2 and catalase genes in cadmium-induced oxidative stress in the chick omphalocele model.}, journal = {Pediatric surgery international}, volume = {27}, number = {2}, pages = {131-136}, pmid = {21069346}, issn = {1437-9813}, mesh = {Acetates/toxicity ; Animals ; Cadmium/toxicity ; Catalase/biosynthesis/*genetics ; Chick Embryo ; Disease Models, Animal ; Gene Expression Regulation, Developmental/*drug effects ; Hernia, Umbilical/chemically induced/enzymology/*genetics ; Immunohistochemistry ; Oxidative Stress/*drug effects ; Phenotype ; RNA, Messenger/biosynthesis/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/biosynthesis/*genetics ; Up-Regulation/*drug effects ; }, abstract = {PURPOSE: In the chick embryo, administration of the heavy metal Cadmium (Cd) induces omphalocele phenotype. Cd is a potent inhibitor of antioxidant enzymes and causes accumulation of reactive oxygen species (ROSs) such as hydrogen peroxide. Previous work with the Cd chick model has demonstrated that increased levels of MDA, as a marker for oxidative stress, 24 h post Cd treatment (24H) are identical in chick embryos exposed to Cd. Furthermore, of the several antioxidants assessed, only N-acetylcysteine (NAC) has been shown to reduce MDA levels to control values in the Cd-treated chick embryo. However, the molecular mechanisms by which NAC acts to maintain oxidative stress in the Cd-induced ventral body wall defect chick model remains to be unclear. We designed this study to investigate the hypothesis that gene expression levels of antioxidant enzymes are downregulated in malformed embryos exposed to Cd compared to controls and to determine the effect of pre-treatment with NAC on the expression levels of genes encoding antioxidant enzymes.<br><br>METHODS: After 60&#xa0;h incubation, chick embryos were pre-treated with NAC and exposed to either chick saline or Cd. Chicks were then harvested at 24H and divided into five groups: control, Cd group without malformation [Cd(-)], Cd group with malformation [Cd(+)], NAC&#xa0;+&#xa0;Cd(-) and NAC&#xa0;+&#xa0;Cd(+). Real-time PCR was performed to evaluate the relative mRNA expression levels of antioxidant enzymes, including superoxide dismutase (SOD)-1, SOD2, catalase (CAT) and glutathione peroxidase (GPX)-4. Differences between five groups were tested by Tukey-Kramer post-hoc test following one-way ANOVA. Statistical significance was accepted at p&#xa0;<&#xa0;0.05. Immunohistochemistry was also performed to evaluate protein expression.<br><br>RESULTS: The mRNA expression levels of SOD2 and CAT were significantly decreased in Cd(+) as compared to controls, whereas there was no significant difference between controls and Cd(-) (p&#xa0;<&#xa0;0.05 vs. controls). In addition, gene expression levels of SOD2 and CAT were significantly increased in NAC&#xa0;+&#xa0;Cd(-) as compared to Cd(+) and NAC&#xa0;+&#xa0;Cd(+) (p&#xa0;<&#xa0;0.05 vs. controls). However, there were no significant differences in the expression levels of SOD1 and GPX4 among any groups. Increased immunoreactivity of SOD2 and CAT was also observed in NAC&#xa0;+&#xa0;Cd(-) as compared to Cd(+) and NAC&#xa0;+&#xa0;Cd(+).<br><br>CONCLUSION: Our results suggest that SOD2 and CAT may play an important role in preventing Cd-induced teratogenesis. Prenatal treatment with drugs which can upregulate SOD2 and CAT transcripts may have a therapeutic potential in preventing omphalocele phenotype.}, }
@article {pmid21059408, year = {2011}, author = {Kamboj, SS and Sandhir, R}, title = {Protective effect of N-acetylcysteine supplementation on mitochondrial oxidative stress and mitochondrial enzymes in cerebral cortex of streptozotocin-treated diabetic rats.}, journal = {Mitochondrion}, volume = {11}, number = {1}, pages = {214-222}, doi = {10.1016/j.mito.2010.09.014}, pmid = {21059408}, issn = {1872-8278}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Brain Diseases/pathology/prevention &amp; control ; Cerebral Cortex/*drug effects/metabolism/pathology ; Diabetes Complications/*prevention &amp; control ; Diabetes Mellitus, Experimental/chemically induced/*complications/drug therapy ; Free Radical Scavengers/pharmacology/*therapeutic use ; Male ; *Mitochondria/drug effects/enzymology/pathology ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Streptozocin/administration &amp; dosage ; Treatment Outcome ; }, abstract = {Diabetic encephalopathy, characterized by cognitive deficits involves hyperglycemia-induced oxidative stress. Impaired mitochondrial functions might play an important role in accelerated oxidative damage observed in diabetic brain. The aim of the present study was to examine the role of mitochondrial oxidative stress and dysfunctions in the development of diabetic encephalopathy along with the neuroprotective potential of N-acetylcysteine (NAC). Chronic hyperglycemia accentuated mitochondrial oxidative stress in terms of increased ROS production and lipid peroxidation. Significant decrease in Mn-SOD activity along with protein and non-protein thiols was observed in the mitochondria from diabetic brain. The activities of mitochondrial enzymes; NADH dehydrogenase, succinate dehydrogenase and cytochrome oxidase were decreased in the diabetic brain. Increased mitochondrial oxidative stress and dysfunctions were associated with increased cytochrome c and active caspase-3 levels in cytosol. Electron microscopy revealed mitochondrial swelling and chromatin condensation in neurons of diabetic animals. NAC administration, on the other hand was found to significantly improve diabetes-induced biochemical and morphological changes, bringing them closer to the controls. The results from the study provide evidence for the role of mitochondrial oxidative stress and dysfunctions in the development of diabetic encephalopathy and point towards the clinical potential of NAC as an adjuvant therapy to conventional anti-hyperglycemic regimens for the prevention and/or delaying the progression of CNS complications.}, }
@article {pmid21056559, year = {2011}, author = {Molgat, AS and Gagnon, A and Sorisky, A}, title = {Macrophage-induced preadipocyte survival depends on signaling through Akt, ERK1/2, and reactive oxygen species.}, journal = {Experimental cell research}, volume = {317}, number = {4}, pages = {521-530}, doi = {10.1016/j.yexcr.2010.10.024}, pmid = {21056559}, issn = {1090-2422}, mesh = {3T3-L1 Cells ; Adipocytes/*cytology ; Animals ; *Cell Survival ; Macrophages/*physiology ; Mice ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3/*metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; }, abstract = {Obesity is associated with adipose tissue remodeling, characterized by macrophage accumulation, adipocyte hypertrophy, and apoptosis. We previously reported that macrophage-conditioned medium (MacCM) protects preadipocytes from apoptosis, due to serum withdrawal, in a platelet-derived growth factor (PDGF)-dependent manner. We have now investigated the role of intracellular signaling pathways, activated in response to MacCM versus PDGF, in promoting preadipocyte survival. Exposure of 3T3-L1 preadipocytes to J774A.1-MacCM or PDGF strongly stimulated Akt and ERK1/2 phosphorylation from initially undetectable levels. Inhibition of the upstream regulators of Akt or ERK1/2, i.e. phosphoinositide 3-kinase (PI3K; using wortmannin or LY294002) or MEK1/2 (using UO126 or PD98509), abrogated the respective phosphorylation responses, and significantly impaired pro-survival activity. J774A.1-MacCM increased reactive oxygen species (ROS) levels by 3.4-fold, and diphenyleneiodonium (DPI) or N-acetyl cysteine (NAC) significantly inhibited pro-survival signaling and preadipocyte survival in response to J774A.1-MacCM. Serum withdrawal itself also increased ROS levels (2.1-fold), and the associated cell death was attenuated by DPI or NAC. In summary, J774A.1-MacCM-dependent 3T3-L1 preadipocyte survival requires the Akt and ERK1/2 signaling pathways. Furthermore, ROS generation by J774A.1-MacCM is required for Akt and ERK1/2 signaling to promote 3T3-L1 preadipocyte survival. These data suggest potential mechanisms by which macrophages may alter preadipocyte fate.}, }
@article {pmid21056077, year = {2011}, author = {Brandão, R and Nogueira, CW}, title = {Inhibition of hepatic δ-aminolevulinate dehydratase activity induced by mercuric chloride is potentiated by N-acetylcysteine in vitro.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {49}, number = {1}, pages = {305-308}, doi = {10.1016/j.fct.2010.10.033}, pmid = {21056077}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Drug Synergism ; Enzyme Inhibitors/*pharmacology ; Kidney/drug effects/enzymology/metabolism ; Liver/drug effects/enzymology/metabolism ; Male ; Mercuric Chloride/*pharmacology ; Mice ; Oxidation-Reduction ; Porphobilinogen Synthase/*antagonists &amp; inhibitors/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Mercuric chloride (HgCl)(2) is a toxic metal that causes oxidative damage in several tissues. N-acetylcysteine (NAC) is a sulfhydryl compound with antioxidant activity. In the present study, we investigated the in vitro effects of the association between HgCl(2) and NAC in tissues of mice. For this purpose, we evaluated the in vitro effect of HgCl(2)+NAC association on δ-aminolevulinate dehydratase (δ-ALA-D) activity and on thiobarbituric acid reactive substances (TBARS) levels in liver and kidney of mice. The results demonstrate that HgCl(2) inhibited δ-ALA-D activity in both tissues. Hepatic δ-ALA-D activity inhibited by HgCl(2) was potentiated by the highest concentration of NAC. The inhibition of hepatic δ-ALA-D activity seems to be related to sulfhydryl groups oxidation of the enzyme. We observed also that HgCl(2) increased TBARS levels in kidney and liver. Hepatic TBARS levels were reduced by NAC, at higher concentration. In contrast, NAC, at higher concentration, increased renal TBARS levels. In conclusion, the inhibition of hepatic δ-aminolevulinate dehydratase activity induced by HgCl(2) is potentiated by NAC in vitro, and this effect is not related to hepatic lipid peroxidation.}, }
@article {pmid21055460, year = {2011}, author = {Lee, YJ and Lee, DM and Lee, CH and Heo, SH and Won, SY and Im, JH and Cho, MK and Nam, HS and Lee, SH}, title = {Suppression of human prostate cancer PC-3 cell growth by N-acetylcysteine involves over-expression of Cyr61.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {1}, pages = {199-205}, doi = {10.1016/j.tiv.2010.10.020}, pmid = {21055460}, issn = {1879-3177}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/*pharmacology ; Carcinoma/drug therapy/metabolism/prevention &amp; control ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Cysteine-Rich Protein 61/genetics/*metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, Reporter ; Humans ; I-kappa B Kinase/genetics/metabolism ; Male ; NF-kappa B/genetics/metabolism ; Prostatic Neoplasms/*drug therapy/metabolism/prevention &amp; control ; Protein Synthesis Inhibitors/pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Up-Regulation/*drug effects ; }, abstract = {N-Acetylcysteine (NAC), sulfidryl-containing thiol antioxidant, has been heralded as chemopreventive agent, generally because of its ability to scavenge free radicals. It also suppresses the proliferation of many cancer cells; however, the antiproliferative mechanism(s) remain to be fully elucidated. In this study, we investigated a growth-suppressive mechanism of NAC action in androgen-independent prostate carcinoma PC-3 cells. NAC (≥ 1mM) inhibited the proliferation of PC-3 cells in a dose- and time-dependent manner. Moreover, NAC treatment suppressed the activation of NF-κB induced by IKK-β as detected by the NF-κB reporter gene assay. NAC exerted a biphasic effect on the intracellular ROS levels depending on incubation time; the antioxidant effect was seen within 2h after NAC treatment, however, a pro-oxidant effect was evident after 48 h treatment. In addition to these effects, NAC treatment elicited a dose- and time-dependent increase in the Cyr61 expression that was accompanied by an increase in its mRNA and blocked by cycloheximide pretreatment. Importantly, NAC treatment caused an early but transient activation of Akt and Erk1/2. The NAC-induced increase in Cyr61 protein levels was suppressed by the PI3K inhibitor (Ly294002) and, to a lesser extent, MEK/Erk1/2 inhibitor (PD98059). Taken together, our data suggest that the antiproliferative effect of NAC is partially mediated by intracellular ROS production, the inhibition of NF-κB activity, and the activation of PI3K- and/or MEK/Erk-related intracellular signaling pathways, which lead to up-regulation of Cyr61 expression.}, }
@article {pmid21051528, year = {2011}, author = {Ronis, MJ and Hennings, L and Stewart, B and Basnakian, AG and Apostolov, EO and Albano, E and Badger, TM and Petersen, DR}, title = {Effects of long-term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {300}, number = {1}, pages = {G109-19}, pmid = {21051528}, issn = {1522-1547}, support = {R01 AA009300/AA/NIAAA NIH HHS/United States ; R01 AA08645/AA/NIAAA NIH HHS/United States ; R01 AA18282/AA/NIAAA NIH HHS/United States ; R01 DK078908/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Cell Proliferation/drug effects ; Cytochrome P-450 Enzyme System/metabolism ; Dietary Fats/administration &amp; dosage ; Enteral Nutrition ; Ethanol/pharmacology/*toxicity ; Fatty Liver/*etiology/pathology ; Hedgehog Proteins/metabolism ; Lipid Metabolism/drug effects ; Liver/*drug effects/pathology ; Liver Diseases, Alcoholic/*metabolism/pathology ; Liver Regeneration/drug effects ; Male ; Oxidative Stress/drug effects ; Rats ; }, abstract = {Male Sprague-Dawley rats were chronically fed a high-unsaturated-fat diet for 130 days by using total enteral nutrition (TEN), or the same diet in which ethanol (EtOH) isocalorically replaced carbohydrate calories. Additional groups were supplemented with the antioxidant N-acetylcysteine (NAC) at 1.7 g·kg(-1)·day(-1). Relative to an ad libitum chow-fed group, the high-fat-fed controls had three- to fourfold greater expression of fatty acid transporter CD36 mRNA and developed mild steatosis but little other hepatic pathology. NAC treatment resulted in increased somatic growth relative to controls (4.0 ± 0.1 vs. 3.1 ± 0.1 g/day) and increased hepatic steatosis score (3.5 ± 0.6 vs. 2.7 ± 1.2), associated with suppression of the triglyceride hydrolyzing protein adiponutrin, but produced no elevation in serum alanine aminotransferase (ALT). Chronic EtOH treatment increased expression of fatty acid transport protein FATP-2 mRNA twofold, resulting in marked hepatic steatosis, oxidative stress, and a twofold elevation in serum ALT. However, no changes in tumor necrosis factor-α or transforming growth factor-β expression were observed. Fibrosis, as measured by Masson's trichrome and picrosirius red staining, and a twofold increase in expression of type I and type III collagen mRNA, was only observed after EtOH treatment. Long-term EtOH treatment increased hepatocyte proliferation but did not modify the hepatic mRNAs for hedgehog pathway ligands or target genes or genes regulating epithelial-to-mesenchymal transition. Although the effects of NAC on EtOH-induced fibrosis could not be fully evaluated, NAC had additive effects on hepatocyte proliferation and prevented EtOH-induced oxidative stress and necrosis, despite a failure to reverse hepatic steatosis.}, }
@article {pmid21049288, year = {2011}, author = {Ahmed, T and Pathak, R and Mustafa, MD and Kar, R and Tripathi, AK and Ahmed, RS and Banerjee, BD}, title = {Ameliorating effect of N-acetylcysteine and curcumin on pesticide-induced oxidative DNA damage in human peripheral blood mononuclear cells.}, journal = {Environmental monitoring and assessment}, volume = {179}, number = {1-4}, pages = {293-299}, pmid = {21049288}, issn = {1573-2959}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Curcumin/*pharmacology ; DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Endosulfan/toxicity ; Environmental Pollutants/*toxicity ; Humans ; Leukocytes, Mononuclear ; Lipid Peroxidation/drug effects ; Malathion/toxicity ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Pesticides/*toxicity ; Phosphamidon/toxicity ; }, abstract = {Endosulfan, malathion, and phosphamidon are widely used pesticides. Subchronic exposure to these contaminants commonly affects the central nervous system, immune, gastrointestinal, renal, and reproductive system. There effects have been attributed to increased oxidative stress. This study was conducted to examine the role of oxidative stress in genotoxicity following pesticide exposure using peripheral blood mononuclear cells (PBMC) in vitro. Further possible attenuation of genotoxicity was studied using N-acetylcysteine (NAC) and curcumin as known modulators of oxidative stress. Cultured mononuclear cells was isolated from peripheral blood of healthy volunteers, and exposed to varying concentrations of different pesticides: endosulfan, malathion, and phosphamidon for 6, 12, and 24 h. Lipid peroxidation was assessed by cellular malondialdehyde (MDA) level and DNA damage was quantified by measuring 8-hydroxy-2'-deoxyguanosine (8-OH-dG) using ELISA. Both MDA and 8-OH-dG were significantly increased in a dose-dependent manner following treatment with these pesticides. There was a significant decrease in MDA and 8-OH-dG levels in PBMC when co-treated with NAC or/and curcumin as compared to pesticide alone. These results indicate that pesticide-induced oxidative stress is probably responsible for the DNA damage, and NAC or curcumin attenuate this effect by counteracting the oxidative stress.}, }
@article {pmid21048860, year = {2010}, author = {Warangkar, SC and Khobragade, CN}, title = {Purification, Characterization, and Effect of Thiol Compounds on Activity of the Erwinia carotovora L-Asparaginase.}, journal = {Enzyme research}, volume = {2010}, number = {}, pages = {165878}, pmid = {21048860}, issn = {2090-0414}, abstract = {L-asparaginase was extracted from Erwinia carotovora and purified by ammonium sulfate fractionation (60-70%), Sephadex G-100, CM cellulose, and DEAE sephadex chromatography. The apparent Mr of enzyme under nondenaturing and denaturing conditions was 150 kDa and 37 ± 0.5 kDa, respectively. L-asparaginase activity was studied in presence of thiols, namely, L-cystine (Cys), L-methionine (Met), N-acetyl cysteine (NAC), and reduced glutathione (GSH). Kinetic parameters in presence of thiols (10-400 μM) showed an increase in V(max) values (2000, 2223, 2380, 2500, and control 1666.7 μmoles mg(-1)min(-1)) and a decrease in K(m) values (0.086, 0.076, 0.062, 0.055 and control 0.098 mM) indicating nonessential mode of activation. K(A) values displayed propensity to bind thiols. A decrease in V(max)/K(m) ratio in concentration plots showed inverse relationship between free thiol groups (NAC and GSH) and bound thiol group (Cys and Met). Enzyme activity was enhanced in presence of thiol protecting reagents like dithiothreitol (DTT), 2-mercaptoethanol (2-ME), and GSH, but inhibited by p-chloromercurybenzoate (PCMB) and iodoacetamide (IA).}, }
@article {pmid21048362, year = {2010}, author = {Bando, M and Hosono, T and Mato, N and Nakaya, T and Yamasawa, H and Ohno, S and Sugiyama, Y}, title = {Long-term efficacy of inhaled N-acetylcysteine in patients with idiopathic pulmonary fibrosis.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {49}, number = {21}, pages = {2289-2296}, doi = {10.2169/internalmedicine.49.4011}, pmid = {21048362}, issn = {1349-7235}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Aged ; Case-Control Studies ; Female ; Humans ; Idiopathic Pulmonary Fibrosis/diagnosis/*drug therapy/mortality ; Male ; Middle Aged ; Respiratory Function Tests/trends ; Retrospective Studies ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Inhalation of N-acetylcysteine (NAC) has been carried out in our department since 1994 for treating interstitial pneumonia such as idiopathic pulmonary fibrosis (IPF). In this study, the clinical efficacy and safety of long-term NAC inhalation monotherapy for IPF was investigated.<br><br>METHODS: NAC inhalation was carried out in 23 of 34 cases diagnosed as IPF by surgical lung biopsy in our department between 1994 and 2008. The treatment was continued for one year or longer in 14 cases. In these 14 cases and in 11 cases without treatment, the clinical courses, prognosis, lung function (%FVC, %DLco, and %TLC), and changes in serum markers for interstitial pneumonia (KL-6 and SP-D) were examined.<br><br>RESULTS: There were no significant differences in survival curves between the two groups. Acute exacerbation was observed in 4 of 14 cases (28.6%) receiving NAC inhalation. Compared with the results just before the beginning of NAC inhalation, &#x394;%FVC and &#x394;%DLco in the treated cases were -4.7% and -2.9% one year later and -4.0% and -5.8% two years later, respectively. In cases without treatment, &#x394;%FVC and &#x394;%DLco were -3.5% and +5.3% one year later and +0.2% and +1.0% two years later, respectively.<br><br>CONCLUSION: Since this study is an open case-control study in a single institute and the number of cases is not large, its use in evaluating the efficacy of NAC inhalation monotherapy is limited. In addition, the role of NAC inhalation in combination with a steroid, an immunosuppressive agent, and a new anti-fibrosis drug should also be investigated.}, }
@article {pmid21048313, year = {2010}, author = {Katsuda, H and Yamashita, M and Katsura, H and Yu, J and Waki, Y and Nagata, N and Sai, Y and Miyamoto, K}, title = {Protecting cisplatin-induced nephrotoxicity with cimetidine does not affect antitumor activity.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {33}, number = {11}, pages = {1867-1871}, doi = {10.1248/bpb.33.1867}, pmid = {21048313}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antineoplastic Agents/adverse effects/therapeutic use ; Bone Neoplasms/*drug therapy/metabolism ; Cell Line ; Cell Line, Tumor ; Cimetidine/pharmacology/*therapeutic use ; Cisplatin/*adverse effects/therapeutic use ; Infusions, Intravenous ; Kidney/*drug effects ; Male ; Organic Cation Transport Proteins/metabolism ; Osteosarcoma/*drug therapy/metabolism ; Platinum/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Renal Agents/pharmacology/*therapeutic use ; }, abstract = {The present study examined the influence of cimetidine on the nephrotoxicity and antitumor effects of cisplatin in vitro and in vivo. When the serum concentration of cimetidine was maintained over 20 µg/ml for 4 h by bolus and continuous intravenous infusion, cimetidine prevented nephrotoxicity of cisplatin without influencing antitumor activity. Cimetidine and the antioxidant N-acetylcysteine (NAC) significantly inhibited the in vitro growth inhibition of cisplatin in cells originating from the kidney, but not in SOSN2 osteosarcoma cells. Cimetidine (1 mM) also did not influence platinum concentration in the cells, regardless of whether the organic cation transporter 2 (OCT2) was expressed. Cisplatin did induce reactive oxygen species (ROS) in the KN41 kidney cell line and cimetidine and NAC significantly reduced ROS production. However, cisplatin did not produce ROS in osteosarcoma cells. From these results, cimetidine clearly inhibits nephrotoxicity induced by cisplatin without any influence on the antitumor activity of cisplatin on osteosarcoma in vitro and in vivo.}, }
@article {pmid21040901, year = {2010}, author = {Lee, JY and Nakada, D and Yilmaz, OH and Tothova, Z and Joseph, NM and Lim, MS and Gilliland, DG and Morrison, SJ}, title = {mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion.}, journal = {Cell stem cell}, volume = {7}, number = {5}, pages = {593-605}, pmid = {21040901}, issn = {1875-9777}, support = {/HHMI/Howard Hughes Medical Institute/United States ; P30 CA046592/CA/NCI NIH HHS/United States ; CA46592/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Down-Regulation ; Flow Cytometry ; *Gene Deletion ; *Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor/*physiology ; Hematopoietic Stem Cells/*cytology ; Leukemia/*prevention &amp; control ; Mice ; Mice, Inbred C57BL ; PTEN Phosphohydrolase/*genetics ; TOR Serine-Threonine Kinases/genetics/*metabolism ; }, abstract = {Pten deficiency depletes hematopoietic stem cells (HSCs) but expands leukemia-initiating cells, and the mTOR inhibitor, rapamycin, blocks these effects. Understanding the opposite effects of mTOR activation on HSCs versus leukemia-initiating cells could improve antileukemia therapies. We found that the depletion of Pten-deficient HSCs was not caused by oxidative stress and could not be blocked by N-acetyl-cysteine. Instead, Pten deletion induced, and rapamycin attenuated, the expression of p16(Ink4a) and p53 in HSCs, and p19(Arf) and p53 in other hematopoietic cells. p53 suppressed leukemogenesis and promoted HSC depletion after Pten deletion. p16(Ink4a) also promoted HSC depletion but had a limited role suppressing leukemogenesis. p19(Arf) strongly suppressed leukemogenesis but did not deplete HSCs. Secondary mutations attenuated this tumor suppressor response in some leukemias that arose after Pten deletion. mTOR activation therefore depletes HSCs by a tumor suppressor response that is attenuated by secondary mutations in leukemogenic clones.}, }
@article {pmid21038848, year = {2010}, author = {Yi, L and Ji, XX and Lin, M and Tan, H and Tang, Y and Wen, L and Ma, YH and Su, Q}, title = {Diallyl disulfide induces apoptosis in human leukemia HL-60 cells through activation of JNK mediated by reactive oxygen.}, journal = {Die Pharmazie}, volume = {65}, number = {9}, pages = {693-698}, pmid = {21038848}, issn = {0031-7144}, mesh = {Allyl Compounds/*pharmacology ; Anthracenes/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; Disulfides/*pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; HL-60 Cells ; Humans ; Indicators and Reagents ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*physiology ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Diallyl disulfide (DADS) is a chemopreventive agent that can induce apoptosis in many tumor cells. Reactive oxygen species (ROS) are important mediators in apoptosis induced by various stimuli, including chemopreventive agents. The phosphotransferase c-JUN N-terminal kinase (JNK) has been shown to regulate apoptosis. In this study, we found that DADS-induced apoptosis in human leukemia HL-60 cells is mediated by ROS-activated JNK. The DADS-treated HL-60 cells showed a dose- and time-dependent decrease in cell viability and proliferation. Agarose gel electrophoresis of cells treated with 10.0 or 20.0 mg/L DADS for 24 h showed a characteristic ladder pattern in their DNA. Levels of DADS-induced ROS, as measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence, also showed dose- and time-dependent increases in HL-60 cells. Activity of JNK was induced by DADS in a dose-dependent manner; HL-60 cells exposed to 10.0 mg/L DADS for 8 h showed maximum levels of phosphorylated JNK, which decreased when exposed for additional 4h. In contrast, Sp600125, a specific inhibitor of JNK, blocked apoptosis of HL-60 cells exposed to DADS. N-Acetylcysteine (NAC), a known antioxidant, also decreased ROS generation, effectively blocked apoptosis, and decreased DADS-induced phosphorylated JNK levels. These results suggest that JNK is involved in DADS-induced ROS-mediated apoptosis in HL-60 cells.}, }
@article {pmid21035436, year = {2011}, author = {Park, EJ and Choi, KS and Kwon, TK}, title = {β-Lapachone-induced reactive oxygen species (ROS) generation mediates autophagic cell death in glioma U87 MG cells.}, journal = {Chemico-biological interactions}, volume = {189}, number = {1-2}, pages = {37-44}, doi = {10.1016/j.cbi.2010.10.013}, pmid = {21035436}, issn = {1872-7786}, mesh = {Adenine/analogs &amp; derivatives/pharmacology ; Autophagy/*drug effects ; Blotting, Western ; Cell Line, Tumor ; Cell Survival/drug effects ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Glioma/*drug therapy/metabolism/pathology ; Humans ; Macrolides/pharmacology ; Microscopy, Fluorescence ; NAD(P)H Dehydrogenase (Quinone)/antagonists &amp; inhibitors/metabolism ; Naphthoquinones/*pharmacology ; RNA, Small Interfering/administration &amp; dosage/genetics ; Reactive Oxygen Species/*metabolism ; }, abstract = {Autophagy is mainly responsible for the degradation of long-lived proteins and subcellular organelles. Autophagy is responsible for the non-apoptotic cell death, and plays a crucial role in regulating cellular functions. β-Lapachone is a quinone-containing compound originally obtained from the lapacho tree in South America. Here, we show that β-lapachone induces death in U87 MG cells, which is not inhibited by blockers of pan-caspase or necrosis. β-Lapachone-induced cell death gradually increased in a time-dependent manner in U87 MG cells, which were partly prevented by pretreatment of a specific inhibitor of NQO1 (dicoumarol). These results suggested that β-lapachone-induced cell death was mediated by NQO1-independent as well as NQO1-dependent cell death pathways. During progression of β-lapachone-induced cell death, translocation and processing of LC3 as well as an increase in acidic vesicular organelles, as assessed by acridine orange staining, were observed. Furthermore, β-lapachone-induced cell death was inhibited by either a knockdown of beclin-1/Atg-6 or Atg-7 gene expression or by autophagy inhibitors (3-methyl adenine or bafilomycin A1). Reactive oxygen species (ROS) were involved in β-lapachone-induced autophagic cell death of U87 MG glioma cells, because β-lapachone induced ROS production and antioxidant N-acetylcysteine (NAC) decreased autophagic cell death. Our results collectively demonstrate that ROS mediate β-lapachone-induced autophagic cell death in U87 MG glioma cells.}, }
@article {pmid20981856, year = {2010}, author = {Watcharasit, P and Suntararuks, S and Visitnonthachai, D and Thiantanawat, A and Satayavivad, J}, title = {Acrylonitrile induced apoptosis via oxidative stress in neuroblastoma SH-SY5Y cell.}, journal = {Journal of applied toxicology : JAT}, volume = {30}, number = {7}, pages = {649-655}, doi = {10.1002/jat.1535}, pmid = {20981856}, issn = {1099-1263}, mesh = {Acetylcysteine/pharmacology ; Acrylonitrile/*toxicity ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Caspase 3/analysis/metabolism ; Cell Death/physiology ; Cell Line, Tumor ; Cell Survival/physiology ; Enzyme Activation ; Humans ; Neuroblastoma ; Oxidative Stress/drug effects/*physiology ; Poly(ADP-ribose) Polymerases/metabolism ; bcl-2-Associated X Protein/biosynthesis/metabolism ; }, abstract = {Acrylonitrile (ACN) is a chemical that is widely used in the production of plastics, acrylic fibers, synthetic rubbers and resins. It has been reported that ACN can cause oxidative stress, a condition which is well recognized as an apoptotic initiator; however, information regarding ACN-induced apoptosis is limited. This present study investigated whether ACN induces apoptosis in human neuroblastoma SH-SY5Y cells, and whether its apoptotic induction involves oxidative stress. The results showed that ACN caused activation of caspase-3, a key enzyme involved in apoptosis, in a dose- and time-dependent manner. Detection of sub-G1 apoptotic cell death and apoptotic nuclear condensation revealed that ACN caused an increase in the number of apoptotic cells indicating ACN induces apoptosis in SH-SY5Y cells. ACN dose- and time-dependently increased the level of proapoptotic protein, Bax. Pretreatment with N-acetylcysteine (NAC), an antioxidant, attenuated caspase-3 activation by ACN, as evidenced by a reduction in proteolysis of PARP, a known caspase-3 substrate, as well as in the number of sub-G1 apoptotic cells. Moreover, induction of Bax by ACN was abolished by NAC. Taken together, the results indicate that ACN induces apoptosis in SH-SY5Y cells via a mechanism involving generation of oxidative stress-mediated Bax induction.}, }
@article {pmid20980943, year = {2010}, author = {Buyukhatipoglu, H and Sezen, Y and Yildiz, A and Bas, M and Kirhan, I and Ulas, T and Turan, MN and Taskin, A and Aksoy, N}, title = {N-acetylcysteine fails to prevent renal dysfunction and oxidative stress after noniodine contrast media administration during percutaneous coronary interventions.}, journal = {Polskie Archiwum Medycyny Wewnetrznej}, volume = {120}, number = {10}, pages = {383-389}, pmid = {20980943}, mesh = {Acetylcysteine/*administration &amp; dosage/therapeutic use ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Aged ; Angioplasty, Balloon, Coronary/adverse effects ; Contrast Media/*adverse effects ; Coronary Angiography/adverse effects ; Female ; Humans ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Treatment Outcome ; }, abstract = {INTRODUCTION: Oxidative stress is believed to have a role in contrast-induced nephropathy. Based on this assumption, several known antioxidants have been studied to assess their effect on nephropathy, especially N-acetylcysteine (NAC). However, its usefulness has yet to be confirmed.<br><br>OBJECTIVES: We aimed to assess whether NAC has any protective effect on contrast-induced renal dysfunction, and whether NAC affects the parameters of oxidative stress in serum and urine.<br><br>PATIENTS AND METHODS: Sixty patients with coronary artery disease, who presented for an elective percutaneous coronary intervention (PCI), were randomized into 2 groups in an age- and gender-matched fashion: one group received 600 mg intravenous NAC and the other did not. Before and 24 hours after the procedure, blood and urine samples were obtained to assess total oxidant capacity (TOC), total antioxidant capacity (TAC), oxidative stress index (OSI), and renal function.<br><br>RESULTS: Twenty-four hours after PCI, TOC and OSI levels were significantly increased and TAC levels significantly decreased, both in serum and urine. However, we did not observe any differences in oxidative parameters between patients who received NAC and those who did not. Multivariate analyses identified no protective effect of NAC on renal function, and no effect on oxidative parameters in either serum or urine.<br><br>CONCLUSIONS: In this first clinical study that determined TOC and TAC levels in both serum and urine after exposure to contrast media, NAC was not found to affect oxidant parameters or protect against contrast nephropathy, at least in patients without the risk factors for nephropathy, such as diabetes mellitus or baseline renal or cardiac dysfunction.}, }
@article {pmid20980926, year = {2011}, author = {Ferreira, LF and Campbell, KS and Reid, MB}, title = {Effectiveness of sulfur-containing antioxidants in delaying skeletal muscle fatigue.}, journal = {Medicine and science in sports and exercise}, volume = {43}, number = {6}, pages = {1025-1031}, pmid = {20980926}, issn = {1530-0315}, support = {R01 AR055974/AR/NIAMS NIH HHS/United States ; R01 HL090749/HL/NHLBI NIH HHS/United States ; AR055974/AR/NIAMS NIH HHS/United States ; HL 090749/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Antioxidants/*pharmacology ; Diaphragm/*drug effects ; Ergothioneine/*pharmacology ; Mice ; Mice, Inbred C57BL ; Muscle Fatigue/*drug effects ; Muscle Relaxation/drug effects ; }, abstract = {UNLABELLED: Reactions involving thiol biochemistry seem to play a crucial role in skeletal muscle fatigue. N-acetylcysteine amide (NACA) and L-ergothioneine (ERGO) are thiol-based antioxidants available for human use that have not been evaluated for effects on muscle fatigue.<br><br>PURPOSE: To test the hypothesis that NACA and ERGO delay skeletal muscle fatigue.<br><br>METHODS: We exposed mouse diaphragm fiber bundles to buffer (CTRL), NACA, ERGO, or N-acetylcysteine (NAC; positive control). Treatments were performed in vitro using 10 mM for 60 min at 37 &#xb0;C. After treatment, we determined the muscle force-frequency and fatigue characteristics.<br><br>RESULTS: The force-frequency relationship was shifted to the left by ERGO and to the right by NACA compared with CTRL and NAC. Maximal tetanic force was similar among groups. The total force-time integral (FTI; N &#xb7; s &#xb7; cm) during the fatigue trial was decreased by NACA (420 &#xb1; 35, P < 0.05), unaffected by ERGO (657 &#xb1; 53), and increased by NAC (P < 0.05) compared with CTRL (581 &#xb1; 54). The rate of contraction (dF/dtMAX) during the fatigue trial was not affected by any of the treatments tested. NAC, but not NACA or ERGO, delayed the slowing of muscle relaxation (dF/dtMIN) during fatigue.<br><br>CONCLUSIONS: In summary, NACA and ERGO did not delay skeletal muscle fatigue in vitro. We conclude that these antioxidants are unlikely to improve human exercise performance.}, }
@article {pmid20978740, year = {2011}, author = {Zhou, T and Zhou, KK and Lee, K and Gao, G and Lyons, TJ and Kowluru, R and Ma, JX}, title = {The role of lipid peroxidation products and oxidative stress in activation of the canonical wingless-type MMTV integration site (WNT) pathway in a rat model of diabetic retinopathy.}, journal = {Diabetologia}, volume = {54}, number = {2}, pages = {459-468}, pmid = {20978740}, issn = {1432-0428}, support = {EY019309/EY/NEI NIH HHS/United States ; P20 RR024215/RR/NCRR NIH HHS/United States ; R01 EY019309/EY/NEI NIH HHS/United States ; P20RR024215/RR/NCRR NIH HHS/United States ; R01 EY017313/EY/NEI NIH HHS/United States ; R01 EY018659/EY/NEI NIH HHS/United States ; EY018659/EY/NEI NIH HHS/United States ; R01 EY012231/EY/NEI NIH HHS/United States ; EY012231/EY/NEI NIH HHS/United States ; EY17313/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aldehydes/pharmacology ; Animals ; Blotting, Western ; Cell Line ; Connective Tissue Growth Factor/metabolism ; Diabetic Retinopathy/*metabolism ; Female ; Humans ; Hydrogen Peroxide/pharmacology ; Immunohistochemistry ; Ketocholesterols/pharmacology ; LDL-Receptor Related Proteins/metabolism ; Lipid Peroxidation/*drug effects ; Low Density Lipoprotein Receptor-Related Protein-6 ; Oxidative Stress/*drug effects ; Rats ; TCF Transcription Factors/metabolism ; beta Catenin/metabolism ; }, abstract = {AIMS/HYPOTHESIS: Our recent studies suggest that activation of the wingless-type MMTV integration site (WNT) pathway plays pathogenic roles in diabetic retinopathy and age-related macular degeneration. Here we investigated the causative role of oxidative stress in retinal WNT pathway activation in an experimental model of diabetes.<br><br>METHODS: Cultured retinal pigment epithelial cells and retinal capillary endothelial cells were treated with a lipid peroxidation product, 4-hydroxynonenal (HNE), and an antioxidant, N-acetyl-cysteine (NAC). In vivo, rats with streptozotocin-induced diabetes were treated by NAC for 8 weeks. Activation of the canonical WNT pathway was measured by TOPFLASH assay and by western blot analysis of WNT pathway components and a WNT target gene, Ctgf. Oxidative stress in the retina was evaluated by immunostaining of HNE and 3-nitrotyrosine.<br><br>RESULTS: Levels of phosphorylated and total LDL receptor-related protein (LRP)6, and cytosolic &#x3b2;-catenin, as well as transcriptional activity of T cell factor (TCF)/&#x3b2;-catenin were significantly increased by HNE. The production of connective tissue growth factor (CTGF) was also upregulated by HNE. NAC blocked the WNT pathway activation induced by HNE. Furthermore, LRP6 stability was increased by HNE and decreased by NAC. Retinal levels of HNE and 3-nitrotyrosine were significantly increased in diabetic rats, compared with those in non-diabetic rats. In the same diabetic rat retinas, levels of LRP6, cytosolic &#x3b2;-catenin and CTGF were significantly increased. NAC treatment reduced HNE and 3-nitrotyrosine levels and attenuated the upregulation of LRP6, &#x3b2;-catenin and CTGF in diabetic rat retina.<br><br>CONCLUSIONS/INTERPRETATION: Lipid peroxidation products activate the canonical WNT pathway through oxidative stress, which plays an important role in the development of retinal diseases.}, }
@article {pmid20977337, year = {2011}, author = {Reddy, R and Reddy, R}, title = {Antioxidant therapeutics for schizophrenia.}, journal = {Antioxidants &amp; redox signaling}, volume = {15}, number = {7}, pages = {2047-2055}, doi = {10.1089/ars.2010.3571}, pmid = {20977337}, issn = {1557-7716}, mesh = {Antioxidants/*therapeutic use ; Clinical Trials as Topic ; Dietary Supplements ; Drug Therapy, Combination ; Free Radicals/metabolism ; Humans ; Schizophrenia/*drug therapy ; }, abstract = {Pharmaceutical treatment for millions worldwide who have schizophrenia is limited to a handful of antipsychotics. Despite the proven efficacy of these drugs, the overall outcome for schizophrenia remains suboptimal. Thus, alternative treatment options are urgently needed. One possible approach may be antioxidant therapy. The extant evidence for the role of oxidative stress in the pathophysiology of schizophrenia offers a hypothesis-derived therapeutic approach in the form of antioxidants. Vitamins C and E, for example, are suitable for human clinical trials because they are readily available, inexpensive, and relatively safe. Research into the therapeutic use of antioxidants in schizophrenia can be grouped into two main clusters: for psychopathology and for side effects. Of these studies, some have been carefully conducted, but majority are open label. Use of antioxidants for treatment-related side effects has been more extensively investigated. The totality of the evidence to date suggests that specific antioxidants, such as N-acetyl cysteine, may offer tangible benefits for the clinical syndrome of schizophrenia, and vitamin E may offer salutary effects on glycemic effects of antipsychotics. However, a great deal of fundamental clinical research remains to be done before antioxidants can be routinely used therapeutically for schizophrenia and treatment-related complications.}, }
@article {pmid20974699, year = {2011}, author = {Tewari-Singh, N and Agarwal, C and Huang, J and Day, BJ and White, CW and Agarwal, R}, title = {Efficacy of glutathione in ameliorating sulfur mustard analog-induced toxicity in cultured skin epidermal cells and in SKH-1 mouse skin in vivo.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {336}, number = {2}, pages = {450-459}, pmid = {20974699}, issn = {1521-0103}, support = {U54 ES015678/ES/NIEHS NIH HHS/United States ; U54-ES015678/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Cycle/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; DNA/biosynthesis ; Dermatitis/prevention &amp; control ; Female ; Glutathione/*pharmacology ; Humans ; Mice ; Mice, Hairless ; Mustard Gas/*analogs &amp; derivatives/toxicity ; Peroxidase/metabolism ; Skin/*drug effects/pathology ; Skinfold Thickness ; }, abstract = {Exposure to chemical warfare agent sulfur mustard (HD) is reported to cause GSH depletion, which plays an important role in HD-linked oxidative stress and skin injury. Using the HD analog 2-chloroethyl ethyl sulfide (CEES), we evaluated the role of GSH and its efficacy in ameliorating CEES-caused skin injury. Using mouse JB6 and human HaCaT epidermal keratinocytes, we observed both protective and therapeutic effects of exogenous GSH (1 or 10 mM) in attenuating a CEES-caused decrease in cell viability and DNA synthesis, as well as S and G(2)M phase arrest in cell cycle progression. However, the protective effect of GSH was stronger than its ability to reverse CEES-induced cytotoxic effect. The observed effect of GSH could be associated with an increase in intracellular GSH levels after its treatment before or after CEES exposure, which strongly depleted cellular GSH levels. N-Acetyl cysteine, a GSH precursor, also showed both protective and therapeutic effects against CEES-caused cytotoxicity. Buthionine sulfoximine, which reduces cellular GSH levels, caused an increased CEES cytotoxicity in both JB6 and HaCaT cells. In further studies translating GSH effects in cell culture, pretreatment of mice with 300 mg/kg GSH via oral gavage 1 h before topical application of CEES resulted in significant protection against CEES-caused increase in skin bifold and epidermal thickness, apoptotic cell death, and myeloperoxidase activity, which could be associated with increased skin GSH levels. Together, these results highlight GSH efficacy in ameliorating CEES-caused skin injury and further support the need for effective antioxidant countermeasures against skin injury by HD exposure.}, }
@article {pmid20970637, year = {2010}, author = {Santiago, FM and Olmedo, C and Muffak-Granero, K and Comino, A and Villar, JM and Garrote, D and Bueno, P and Ferrón, JA}, title = {Intraoperative pH values after N-acetylcysteine administration during liver transplantation.}, journal = {Transplantation proceedings}, volume = {42}, number = {8}, pages = {3164-3166}, doi = {10.1016/j.transproceed.2010.05.130}, pmid = {20970637}, issn = {1873-2623}, mesh = {Acetylcysteine/*administration &amp; dosage ; Double-Blind Method ; *Hydrogen-Ion Concentration ; Intraoperative Period ; *Liver Transplantation ; Placebos ; Prospective Studies ; }, abstract = {We investigated whether intraoperative administration of N-acetylcysteine (NAC) to liver transplant recipients affected pH values. This prospective, randomized, double-blind clinical trial included liver transplant recipients who were randomly assigned to NAC-treated (n=25) or placebo (n=25) groups. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose during the next 24 hours. The placebo group received equal amounts of 5% dextrose solution during the same times. Peripheral blood samples were drawn in Ca2+-80 IU-containing syringes after induction of anesthesia (I-1), at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo, at 5 minutes before reperfusion (I-3), at 5 minutes after reperfusion (I-4), at 20 minutes after reperfusion (I-5), at 60 minutes after reperfusion (I-6), and at 1 hour after completion of the procedure (I-7). pH levels, which were determined using a radiometer ABL77 (Copenhagen, Denmark), were significantly lower among the NAC than the placebo group at I-4 (P=.027) and I-5 (P=.031). An early decrease in pH values was detected in the NAC-treated group at 5 minutes before reperfusion (I-3; P=.051). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly decreased recipient pH values at 5 and 20 minutes after reperfusion, a decrease that was detected at 5 minutes before reperfusion (I-3). The decrease seemed to be associated with NAC metabolism.}, }
@article {pmid20959139, year = {2011}, author = {Gomez Sandoval, YH and Anand-Srivastava, MB}, title = {Enhanced levels of endogenous endothelin-1 contribute to the over expression of Giα protein in vascular smooth muscle cells from SHR: Role of growth factor receptor activation.}, journal = {Cellular signalling}, volume = {23}, number = {2}, pages = {354-362}, doi = {10.1016/j.cellsig.2010.10.005}, pmid = {20959139}, issn = {1873-3913}, support = {MOP-53074//Canadian Institutes of Health Research/Canada ; }, mesh = {Adenylyl Cyclases/physiology ; Animals ; CSK Tyrosine-Protein Kinase ; Cells, Cultured ; Endothelin A Receptor Antagonists ; Endothelin B Receptor Antagonists ; Endothelin-1/*physiology ; GTP-Binding Protein alpha Subunits, Gi-Go/*biosynthesis ; Mitogen-Activated Protein Kinases/physiology ; Muscle, Smooth, Vascular/cytology/*metabolism ; Myocytes, Smooth Muscle/*metabolism ; Phosphorylation ; Protein-Tyrosine Kinases/biosynthesis ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Receptor, Endothelin A/physiology ; Receptor, Endothelin B/physiology ; Receptor, IGF Type 1/*physiology ; Receptors, Platelet-Derived Growth Factor/*physiology ; Signal Transduction ; Species Specificity ; src-Family Kinases ; }, abstract = {We earlier showed that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit increased expression of Gi proteins. Since the levels of endothelin-1 (ET-1) are enhanced in VSMC from SHR, we undertook the present study to examine the implication of endogenous ET-1 and the underlying mechanisms in the enhanced expression of Giα proteins in VSMC from SHR. The enhanced expression of Giα-2 and Giα-3 proteins in VSMC from SHR was inhibited by ET(A) and ET(B) receptor antagonists, BQ123 and BQ788 respectively. In addition, these antagonists also attenuated the enhanced inhibition of forskolin-stimulated adenylyl cyclase activity by low concentrations of GTPγS and by inhibitory hormones in VSMC from SHR compared to WKY. Furthermore, AG1295, AG1024 and PP2, inhibitors of platelet derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R) and c-Src respectively, inhibited the enhanced expression of Giα protein and the enhanced phosphorylation of PDGFR and IGF-1R in VSMC from SHR to WKY levels. In addition, NAD(P)H oxidase inhibitor DPI and N-acetylcysteine (NAC), a scavenger of superoxide anion (O2[-]) also inhibited the enhanced phosphorylation of PDGFR and IGF-1R and c-Src in VSMC from SHR to control levels. Furthermore, the augmented phosphorylation of ERK1/2 in VSMC from SHR was attenuated by BQ123 and BQ788, growth factor receptors inhibitors and PP2. These results suggest that the enhanced levels of endogenous ET-1 in VSMC from SHR increase oxidative stress, which through c-Src-mediated activation of growth factor receptors and associated MAP kinase signaling, contribute to the enhanced expression of Giα proteins.}, }
@article {pmid20959117, year = {2011}, author = {Bau, JT and Kurz, EU}, title = {Sodium salicylate is a novel catalytic inhibitor of human DNA topoisomerase II alpha.}, journal = {Biochemical pharmacology}, volume = {81}, number = {3}, pages = {345-354}, doi = {10.1016/j.bcp.2010.10.009}, pmid = {20959117}, issn = {1873-2968}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antigens, Neoplasm/metabolism ; Catalysis ; Cell Line, Tumor ; DNA Damage/*drug effects ; DNA Topoisomerases, Type II/metabolism ; DNA-Binding Proteins/*antagonists &amp; inhibitors/metabolism ; Doxorubicin/pharmacology ; Enzyme Inhibitors/*pharmacology ; Etoposide/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction/*drug effects ; Sodium Salicylate/*pharmacology ; Transcription, Genetic/drug effects ; }, abstract = {We have previously reported that pretreatment of human lymphoblastoid cells with the hydroxyl radical scavenger, N-acetyl cysteine, attenuates doxorubicin-induced DNA damage signalling through the ATM protein kinase. We sought to extend these studies to examine the effects of other hydroxyl radical scavengers in human breast cancer cells. Using MCF-7 cells, we observed that doxorubicin treatment triggered autophosphorylation of ATM on serine 1981 and the ATM-dependent activation of its downstream effectors p53, Chk2, and SMC1. Furthermore, we demonstrate that this effect was attenuated by pretreatment of cells with the hydroxyl radical scavengers sodium benzoate, sodium salicylate and, to a lesser extent, N-acetyl cysteine, but not Trolox™. Intriguingly, these effects were independent of doxorubicin's ability to redox cycle, were observed with multiple classes of topoisomerase II poisons, but did not represent a general damage-attenuating response. In addition, the observed effects were independent of the ability of sodium salicylate to inhibit cyclooxygenase-2 or NFκB. We demonstrate that sodium salicylate prevented doxorubicin-induced DNA double-strand break generation, which was attributable to inhibition of doxorubicin-stabilized topoisomerase IIα-DNA cleavable complex formation in vivo. Using topoisomerase IIα-DNA cleavage and decatenation assays, we determined that sodium salicylate is a catalytic inhibitor of topoisomerase IIα. Consistent with the observed inhibition of double-strand break formation, pretreatment of cells with sodium salicylate attenuated doxorubicin and etoposide cytotoxicity. These results demonstrate a novel mechanism of action for sodium salicylate and suggest that further study on the mechanism of topoisomerase II inhibition and the effects of related therapeutics on doxorubicin and etoposide cytotoxicity are warranted.}, }
@article {pmid20958190, year = {2010}, author = {Hara, R and Inomata, Y and Kawaji, T and Sagara, N and Inatani, M and Fukushima, M and Tanihara, H}, title = {Suppression of choroidal neovascularization by N-acetyl-cysteine in mice.}, journal = {Current eye research}, volume = {35}, number = {11}, pages = {1012-1020}, doi = {10.3109/02713683.2010.500112}, pmid = {20958190}, issn = {1460-2202}, mesh = {Acetylcysteine/*pharmacology ; Aldehydes/metabolism ; Animals ; Antioxidants/*pharmacology ; Blotting, Western ; Chemokine CCL2/metabolism ; Chemokine CXCL1/metabolism ; Choroidal Neovascularization/metabolism/*prevention &amp; control ; *Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Free Radical Scavengers/*pharmacology ; Injections, Intraperitoneal ; Macrophages/physiology ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Neutrophils/physiology ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor Receptor-1/metabolism ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; }, abstract = {PURPOSE: N-acetyl-cysteine (NAC) is a potent antioxidant known to be a precursor of glutathione. The purpose of this study was to investigate the role of NAC in the development of choroidal neovascularization (CNV).<br><br>METHODS: CNV was induced in C57BL/6 mice by laser photocoagulation of the ocular fundus. Mice were injected intraperitoneally with NAC or vehicle alone. The levels of 4-hydoroxy-2-nonenal (4-HNE)-modified protein and nucleus factor (NF)-&#x3ba;B were determined by wester blotting. The recruitment of macrophages and neutrophils after laser injury was analyzed immunohistochemically and in myeloperoxidase (MPO) assays. Enzyme-linked immunosorbent assays (ELISA) were used to measure monocyte chemotactic protein (MCP)-1, CXCL1, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. The extent of CNV was evaluated 7 d after laser injury by lectin staining.<br><br>RESULTS: In NAC-treated mice with laser-induced injuries, the induction of 4-HNE-modified protein after 3 hr and the activation of NF-&#x3ba;B in nuclear extracts after 6 hr were markedly suppressed compared to vehicle-treated mice. Macrophage and neutrophil recruitment were inhibited and the levels of MCP-1, CXCL1, VEGF, and VEGFR-1 were also lower in NAC-treated mice compared to vehicle-treated mice. Furthermore, the extent of CNV induced was significantly lower in NAC-treated compared to vehicle-treated mice (p = 0.027).<br><br>CONCLUSIONS: Our results clearly showed that NAC inhibited indicators of oxidative stress and the activation of NF-&#x3ba;B induced by laser injury, and, consequently, suppressed macrophage and neutrophil infiltration and the development of CNV. This suggests novel preventative and interventional therapeutic strategies for age-related macular degeneration.}, }
@article {pmid20957334, year = {2011}, author = {Wang, J and Wang, H and Hao, P and Xue, L and Wei, S and Zhang, Y and Chen, Y}, title = {Inhibition of aldehyde dehydrogenase 2 by oxidative stress is associated with cardiac dysfunction in diabetic rats.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {17}, number = {3-4}, pages = {172-179}, pmid = {20957334}, issn = {1528-3658}, mesh = {Acetylcysteine/pharmacology ; Aldehyde Dehydrogenase/*metabolism ; Aldehyde Dehydrogenase, Mitochondrial ; Animals ; Animals, Newborn ; Blotting, Western ; Cells, Cultured ; Diabetes Mellitus, Experimental/drug therapy/metabolism/*physiopathology ; Free Radical Scavengers/pharmacology ; Heart/drug effects/physiopathology ; Humans ; Hyperglycemia/physiopathology ; Immunohistochemistry ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria, Heart/drug effects/metabolism/physiology ; Mitochondrial Proteins/*metabolism ; Myocardium/metabolism ; Myocytes, Cardiac ; *Oxidative Stress ; Random Allocation ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Thioctic Acid/pharmacology ; Ventricular Dysfunction, Left/metabolism/*physiopathology ; }, abstract = {Left ventricular (LV) dysfunction is a common comorbidity in diabetic patients, although the molecular mechanisms underlying this cardiomyopathic feature are not completely understood. Aldehyde dehydrogenase 2 (ALDH2) has been considered a key cardioprotective enzyme susceptible to oxidative inactivation. We hypothesized that hyperglycemia-induced oxidative stress would influence ALDH2 activity, and ALDH2 inhibition would lead to cardiac functional alterations in diabetic rats. Diabetes was induced by intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin. Rats were divided randomly into four groups: control, untreated diabetic, diabetic treated with N-acetylcysteine (NAC) and diabetic treated with α-lipoic acid (α-LA). Cardiac contractile function, oxidative stress markers and reactive oxygen species (ROS) levels were assessed. ALDH2 activity and expression also were determined. The role of ALDH2 activity in change in hyperglycemia-induced mitochondrial membrane potential (Δψ) was tested in cultured neonatal cardiomyocytes. Myocardial MDA content and ROS were significantly higher in diabetic rats than in controls, whereas GSH content and Mn-SOD activity were decreased in diabetic rats. Compared with controls, diabetic rats exhibited significant reduction in LV ejection fraction and fractional shortening, accompanied by decreases in ALDH2 activity and expression. NAC and α-LA attenuated these changes. Mitochondrial Δψ was decreased greatly with hyperglycemia treatment, and high glucose combined with ALDH2 inhibition with daidzin further decreased Δψ. The ALDH2 activity can be regulated by oxidative stress in the diabetic rat heart. ALDH2 inhibition may be associated with LV reduced contractility, and mitochondrial impairment aggravated by ALDH2 inhibition might reflect an underlying mechanism which causes cardiac dysfunction in diabetic rats.}, }
@article {pmid20956556, year = {2010}, author = {Armata, HL and Golebiowski, D and Jung, DY and Ko, HJ and Kim, JK and Sluss, HK}, title = {Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis.}, journal = {Molecular and cellular biology}, volume = {30}, number = {24}, pages = {5787-5794}, pmid = {20956556}, issn = {1098-5549}, support = {P30 DK032520/DK/NIDDK NIH HHS/United States ; DK32520/DK/NIDDK NIH HHS/United States ; P30 DK32520/DK/NIDDK NIH HHS/United States ; R01 DK080756/DK/NIDDK NIH HHS/United States ; DK80756/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/metabolism ; Ataxia Telangiectasia/genetics/pathology/physiopathology ; Cell Cycle Proteins/genetics/metabolism ; Glucose/*metabolism ; Heat-Shock Proteins/genetics/metabolism ; Homeostasis/*physiology ; Humans ; Insulin/metabolism ; Insulin Resistance ; Mice ; Mice, Inbred C57BL ; Mutation ; Nuclear Proteins ; Peroxidases ; Proteins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis.}, }
@article {pmid20955367, year = {2011}, author = {Xu, Q and Dalic, A and Fang, L and Kiriazis, H and Ritchie, RH and Sim, K and Gao, XM and Drummond, G and Sarwar, M and Zhang, YY and Dart, AM and Du, XJ}, title = {Myocardial oxidative stress contributes to transgenic β2-adrenoceptor activation-induced cardiomyopathy and heart failure.}, journal = {British journal of pharmacology}, volume = {162}, number = {5}, pages = {1012-1028}, pmid = {20955367}, issn = {1476-5381}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cardiomyopathies/drug therapy/*etiology/*metabolism ; Collagen/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; HSP27 Heat-Shock Proteins/metabolism ; Heart Failure/drug therapy/*etiology/*metabolism ; Inflammation Mediators/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myocardium/*metabolism ; Myocytes, Cardiac/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Oxidative Stress ; RNA, Messenger/genetics/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Receptors, Adrenergic, beta-2/genetics/*metabolism ; Signal Transduction ; Ventricular Remodeling/physiology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: While maintaining cardiac performance, chronic β-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic β2-adrenoceptor activation.<br><br>EXPERIMENTAL APPROACH: Mice with transgenic &#x3b2;&#x2082;-adrenoceptor overexpression (&#x3b2;&#x2082;-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared.<br><br>KEY RESULTS: &#x3b2;&#x2082;-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. &#x3b2;&#x2082;-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of &#x3b2;&#x2082;-TG mice. NAC treatment (500 mg&#xb7;kg&#x207b;&#xb9; &#xb7;day&#x207b;&#xb9;) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of &#x3b2;&#x2082;-TG mice. Chronic NAC treatment to &#x3b2;&#x2082;-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 &#xb1; 5% vs. 25 &#xb1; 3%, ejection fraction 52 &#xb1; 5% vs. 32 &#xb1; 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity.<br><br>CONCLUSION AND IMPLICATIONS: &#x3b2;&#x2082;-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure.}, }
@article {pmid20955365, year = {2011}, author = {Choi, HJ and Kang, KS and Fukui, M and Zhu, BT}, title = {Critical role of the JNK-p53-GADD45α apoptotic cascade in mediating oxidative cytotoxicity in hippocampal neurons.}, journal = {British journal of pharmacology}, volume = {162}, number = {1}, pages = {175-192}, pmid = {20955365}, issn = {1476-5381}, support = {P20 RR021940/RR/NCRR NIH HHS/United States ; R01 ES015242/ES/NIEHS NIH HHS/United States ; ES015242/ES/NIEHS NIH HHS/United States ; P20RR021940/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; Blotting, Western ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; Hippocampus/cytology/drug effects/enzymology/*metabolism ; Immunohistochemistry ; In Situ Nick-End Labeling ; Kainic Acid/pharmacology ; MAP Kinase Kinase 4/*metabolism ; Mice ; Microscopy, Fluorescence ; Neurons/cytology/drug effects/enzymology/*metabolism ; Nuclear Proteins/genetics/*metabolism ; *Oxidative Stress ; Polymerase Chain Reaction ; RNA, Small Interfering ; Rats ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Glutamate-induced oxidative stress plays a critical role in the induction of neuronal cell death in a number of disease states. We sought to determine the role of the c-Jun NH(2) -terminal kinase (JNK)-p53-growth arrest and DNA damage-inducible gene (GADD) 45α apoptotic cascade in mediating glutamate-induced oxidative cytotoxicity in hippocampal neuronal cells.<br><br>EXPERIMENTAL APPROACH: HT22 cells, a mouse hippocampal neuronal cell line, were treated with glutamate to induce oxidative stress in vitro. Kainic acid-induced oxidative damage to the hippocampus in rats was used as an in vivo model. The signalling molecules along the JNK-p53-GADD45&#x3b1; cascade were probed with various means to determine their contributions to oxidative neurotoxicity.<br><br>KEY RESULTS: Treatment of HT22 cells with glutamate increased the mRNA and protein levels of GADD45&#x3b1;, and these increases were suppressed by p53 knock-down. Knock-down of either p53 or GADD45&#x3b1; also prevented glutamate-induced cell death. Glutamate-induced p53 activation was preceded by accumulation of reactive oxygen species, and co-treatment with N-acetyl-cysteine prevented glutamate-induced p53 activation and GADD45&#x3b1; expression. Knock-down of MKK4 or JNK, or the presence of SP600125 (a JNK inhibitor), each inhibited glutamate-induced p53 activation and GADD45&#x3b1; expression. In addition, we also confirmed the involvement of GADD45&#x3b1; in mediating kainic acid-induced hippocampal oxidative neurotoxicity in vivo.<br><br>CONCLUSIONS: AND IMPLICATIONS Activation of the JNK-p53-GADD45&#x3b1; cascade played a critical role in mediating oxidative cytotoxicity in hippocampal neurons. Pharmacological inhibition of this signalling cascade may provide an effective strategy for neuroprotection.}, }
@article {pmid20954832, year = {2011}, author = {Vasu, VT and de Cruz, SJ and Houghton, JS and Hayakawa, KA and Morrissey, BM and Cross, CE and Eiserich, JP}, title = {Evaluation of thiol-based antioxidant therapeutics in cystic fibrosis sputum: Focus on myeloperoxidase.}, journal = {Free radical research}, volume = {45}, number = {2}, pages = {165-176}, pmid = {20954832}, issn = {1029-2470}, support = {HL092506/HL/NHLBI NIH HHS/United States ; HL07013/HL/NHLBI NIH HHS/United States ; T32 HL007013/HL/NHLBI NIH HHS/United States ; T32 ES007059/ES/NIEHS NIH HHS/United States ; R21 HL092506/HL/NHLBI NIH HHS/United States ; T32 ES07059/ES/NIEHS NIH HHS/United States ; T32 ES007059-32/ES/NIEHS NIH HHS/United States ; T32 HL007013-33/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/*pharmacology ; Adult ; C-Reactive Protein/analysis ; Cells, Cultured ; Chloramines/metabolism ; Cystic Fibrosis/drug therapy/*metabolism/physiopathology ; Female ; Glutathione/metabolism/*pharmacology ; Humans ; Inflammation ; Lung/metabolism/physiopathology ; Male ; Middle Aged ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Neutrophils/enzymology ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Peroxidase/*antagonists &amp; inhibitors/blood/*metabolism ; Sputum/*metabolism ; Young Adult ; }, abstract = {Neutrophil-dependent reactions catalysed by myeloperoxidase (MPO) are thought to play important roles in the pulmonary pathobiology of cystic fibrosis (CF). Aerosolized thiol antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC) are currently being utilized as therapeutics to modify CF respiratory tract oxidative processes. This study hypothesized that MPO in CF airway lining fluids may be a target of such therapeutics. MPO activity in sputum from 21 adult CF patients was found to be inversely associated with lung function (FEV(1)). In contrast, systemic inflammation (assessed by plasma C-reactive protein) was not correlated with lung function. Ex vivo studies revealed that GSH and NAC effectively scavenged N-chloramines in sputum and inhibited sputum MPO activity with potency exquisitely dependent upon MPO activity levels. Detailed kinetic analyses revealed that NAC and GSH inhibit MPO by distinct mechanisms. Activation of the key pro-inflammatory transcription factor NF-κB in cultured HBE1 cells was inhibited by GSH. The findings reveal that MPO activity and its reactive products represent useful predictors of the doses of inhaled thiol antioxidants required to ameliorate airway oxidative stress and inflammation in CF patients and provide mechanistic insight into the antioxidative/anti-inflammatory mechanisms of action of GSH and NAC when administered into the CF lung.}, }
@article {pmid20954712, year = {2010}, author = {Bao, L and Shi, H}, title = {Arsenite induces endothelial cell permeability increase through a reactive oxygen species-vascular endothelial growth factor pathway.}, journal = {Chemical research in toxicology}, volume = {23}, number = {11}, pages = {1726-1734}, doi = {10.1021/tx100191t}, pmid = {20954712}, issn = {1520-5010}, mesh = {Animals ; Antibodies/pharmacology ; Antioxidants/pharmacology ; Arsenites/chemistry/*toxicity ; Cadherins/metabolism ; Cell Membrane Permeability/*drug effects ; Endothelial Cells/metabolism ; Environmental Pollutants/chemistry/*toxicity ; Membrane Proteins/metabolism ; Mice ; Phosphoproteins/metabolism ; Reactive Oxygen Species/*metabolism ; Time Factors ; Vascular Endothelial Growth Factors/immunology/*metabolism ; Zonula Occludens-1 Protein ; }, abstract = {As a potent environmental oxidative stressor, arsenic exposure has been reported to exacerbate cardiovascular diseases and increase vascular endothelial cell monolayer permeability. However, the underlying mechanism of this effect is not well understood. In this paper, we test our hypothesis that reactive oxygen species (ROS)-induced vascular endothelial growth factor (VEGF) expression may play an important role in an arsenic-caused increase of endothelial cell monolayer permeability. The mouse brain vascular endothelial cell bEnd3 monolayer was exposed to arsenite for 1, 3, and 6 days. The monolayer permeability, VEGF protein release, and ROS generation were determined. In addition, VE-cadherin and zonula occludens-1 (ZO-1), two membrane structure proteins, were immunostained to elucidate the effects of arsenite on the cell-cell junction. The roles of ROS and VEGF in arsenite-induced permeability was determined by inhibiting ROS with antioxidants and immuno-depleting VEGF with a VEGF antibody. We observed that arsenite increased bEnd3 monolayer permeability, elevated the production of cellular ROS, and increased VEGF release. VE-cadherin and ZO-1 disruptions were also found in cells treated with arsenite. Furthermore, both antioxidant (N-acetyl cysteine and tempol) and the VEGF antibody treatments significantly lowered the arsenite-induced permeability of the bEnd3 monolayer as well as VEGF expression. VE-cadherin and ZO-1 disruptions were also diminished by N-acetyl cysteine and the VEGF antibody. Our data suggest that the increase in VEGF expression caused by ROS may play an important role in the arsenite-induced increase in endothelial cell permeability.}, }
@article {pmid20954279, year = {2010}, author = {Ha, HL and Yu, DY}, title = {HBx-induced reactive oxygen species activates hepatocellular carcinogenesis via dysregulation of PTEN/Akt pathway.}, journal = {World journal of gastroenterology}, volume = {16}, number = {39}, pages = {4932-4937}, pmid = {20954279}, issn = {2219-2840}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blotting, Western ; Carcinoma, Hepatocellular/genetics/*metabolism/pathology ; Cell Proliferation ; Electrophoresis, Polyacrylamide Gel ; Female ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Hep G2 Cells ; Humans ; Liver Neoplasms/genetics/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, Transgenic ; PTEN Phosphohydrolase/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; *Signal Transduction/drug effects ; Time Factors ; Trans-Activators/genetics/*metabolism ; Transfection ; Viral Regulatory and Accessory Proteins ; }, abstract = {AIM: To investigate the role of hepatitis B virus X-protein (HBx)-induced reactive oxygen species (ROS) on liver carcinogenesis in HBx transgenic mice and HepG2-HBx cells.<br><br>METHODS: Cell growth rate was analyzed, and through western blotting, mitogenic signaling was observed. Endogenous ROS from wild and HBx transgenic mice and HepG2-Mock and HBx cells were assayed by FACScalibur. Identification of oxidized and reduced phosphatase and tensin homolog (PTEN) was analyzed through N-ethylmaleimide alkylation, nonreducing electrophoresis.<br><br>RESULTS: We observed that the cell-proliferation-related phosphoinositide 3-kinase/Akt pathway is activated by HBx in vivo and in vitro. Increased ROS were detected by HBx. Tumor suppressor PTEN, via dephosphorylation of Akt, was oxidized and inactivated by increased ROS. Increased oxidized PTEN activated the mitogenic pathway through over-activated Akt. However, treatment with ROS scavenger N-acetyl cysteine can reverse PTEN to a reduced form. Endogenously produced ROS also stimulated HBx expression.<br><br>CONCLUSION: HBx induced ROS promoted Akt pathways via oxidized inactive PTEN. HBx and ROS maintained a positive regulatory loop, which aggravated carcinogenesis.}, }
@article {pmid20953987, year = {2011}, author = {Fang, S and Jin, Y and Zheng, H and Yan, J and Cui, Y and Bi, H and Jia, H and Zhang, H and Wang, Y and Na, L and Gao, X and Zhou, H}, title = {High glucose condition upregulated Txnip expression level in rat mesangial cells through ROS/MEK/MAPK pathway.}, journal = {Molecular and cellular biochemistry}, volume = {347}, number = {1-2}, pages = {175-182}, pmid = {20953987}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carrier Proteins/*genetics/metabolism ; Cell Cycle Proteins ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/metabolism ; Glucose/*pharmacology ; MAP Kinase Signaling System/*drug effects ; Mesangial Cells/drug effects/*enzymology ; Mitogen-Activated Protein Kinase Kinases/antagonists &amp; inhibitors/*metabolism ; Protein Kinase Inhibitors/pharmacology ; RNA, Messenger/genetics/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Time Factors ; Up-Regulation/*drug effects ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Thioredoxin interacting protein (Txnip) is one of the most abundantly up-regulated genes in response to hyperglycemia. The increased renal expression of Txnip was associated with type IV collagen accumulation in streptozotocin-induced diabetic mice. As the mechanism of action of high glucose is unknown, we undertook the investigation of the signaling pathway on the upregulation of Txnip expression induced by high glucose in rat mesangial cells. Rat mesangial cells were exposed to normal (5.5 mM) or high (25 mM) glucose at different time points. Txnip expression was determined using real-time RT-PCR and western-blotting at transcription and translation level, respectively. Intracellular reactive oxygen species (ROS) was detected by FACS Calibur flow cytometer using fluorescent probe (DCFH-DA).The treatment with high glucose resulted in an increase of Txnip mRNA from 4 h to 12 h and Txnip protein from 12 to 24 h in comparison with normal glucose condition. In addition, N-acetyl-cysteine (NAC) was found to decrease Txnip protein expression under high glucose condition. Furthermore, p38MAPK inhibitor SB203580 suppressed Txnip expression at transcription and protein level significantly to high glucose exposure. These results suggest that high glucose exposure improves Txnip mRNA and protein expression level by ROS/MEK/MAPK signaling pathway.}, }
@article {pmid20951298, year = {2010}, author = {Kim, NR and Park, HC and Kim, I and Lim, BS and Yang, HC}, title = {In vitro cytocompatibility of N-acetylcysteine-supplemented dentin bonding agents.}, journal = {Journal of endodontics}, volume = {36}, number = {11}, pages = {1844-1850}, doi = {10.1016/j.joen.2010.08.005}, pmid = {20951298}, issn = {1878-3554}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Alkaline Phosphatase/drug effects ; Anthraquinones ; Antioxidants/chemistry/*pharmacology ; Bisphenol A-Glycidyl Methacrylate/toxicity ; Calcification, Physiologic/drug effects ; Cell Culture Techniques ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Coloring Agents ; Culture Media ; Dental Pulp/cytology/*drug effects ; Dentin-Bonding Agents/chemistry/*toxicity ; Diffusion ; Extracellular Matrix Proteins/drug effects ; Free Radical Scavengers/chemistry/*pharmacology ; Glass Ionomer Cements/toxicity ; Humans ; Materials Testing ; Osteocalcin/drug effects ; Phosphoproteins/drug effects ; Polymethacrylic Acids/toxicity ; Sialoglycoproteins/drug effects ; }, abstract = {INTRODUCTION: Cytotoxic resin components of dentin bonding agents are known to cause oxidative damage and suppress odontogenic differentiation of dental pulp cells. Because antioxidants were found to protect cells from cytotoxicity of resin monomers in previous studies, we investigated the effect of N-acetylcysteine (NAC) on cytotoxicity and anti-differentiation activity of bonding agents.<br><br>METHODS: Human dental pulp cells were treated with the extracts of dentin bonding agents (Prime &amp; Bond NT, Adper Single Bond, and Dentin Cement), and then cell viability, alkaline phosphatase (ALP) activity, and matrix mineralization were observed. To assess the effects of NAC, NAC was directly added into culture media or mixed with bonding agents before extraction. Release of NAC from bonding agents was also observed by high-performance liquid chromatography.<br><br>RESULTS: NAC enhanced ALP activity and mRNA expression of dentin sialophosphoprotein gene, whereas extracts of dentin bonding agents inhibited the induction of ALP activity. When the cells were treated with extracts of the bonding agents, the NAC in the culture media reduced the cytotoxicity of the bonding agents. When NAC was incorporated into bonding agents, a protective effect was only seen for Prime &amp; Bond NT containing more than 1% NAC. The disruption of ALP activity and matrix mineralization in pulp cells was partially reversed by NAC only in Prime &amp; Bond NT-treated cells. High-performance liquid chromatography analysis of NAC showed that the amount of NAC effluxed from Prime &amp; Bond NT was not greater than that effluxed from Adper Single Bond.<br><br>CONCLUSIONS: NAC was useful for reversing cytotoxicity and anti-differentiation effects of Prime &amp; Bond NT on human dental pulp cells.}, }
@article {pmid20946910, year = {2011}, author = {Biswas, D and Sen, G and Sarkar, A and Biswas, T}, title = {Atorvastatin acts synergistically with N-acetyl cysteine to provide therapeutic advantage against Fas-activated erythrocyte apoptosis during chronic arsenic exposure in rats.}, journal = {Toxicology and applied pharmacology}, volume = {250}, number = {1}, pages = {39-53}, doi = {10.1016/j.taap.2010.10.002}, pmid = {20946910}, issn = {1096-0333}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anticholesteremic Agents/*therapeutic use ; Apoptosis/drug effects ; Arsenic/toxicity ; Arsenic Poisoning/*drug therapy ; Atorvastatin ; Cell Membrane ; Drug Synergism ; Environmental Pollutants/toxicity ; Erythrocytes/*drug effects/metabolism/pathology ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Heptanoic Acids/*therapeutic use ; Male ; Oxidative Stress/drug effects ; Pyrroles/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; fas Receptor/metabolism ; }, abstract = {Arsenic is an environmental toxicant that reduces the lifespan of circulating erythrocytes during chronic exposure. Our previous studies had indicated involvement of hypercholesterolemia and reactive oxygen species (ROS) in arsenic-induced apoptotic death of erythrocytes. In this study, we have shown an effective recovery from arsenic-induced death signaling in erythrocytes in response to treatment with atorvastatin (ATV) and N-acetyl cysteine (NAC) in rats. Our results emphasized on the importance of cholesterol in the promotion of ROS-mediated Fas signaling in red cells. Arsenic-induced activation of caspase 3 was associated with phosphatidylserine exposure on the cell surface and microvesiculation of erythrocyte membrane. Administration of NAC in combination with ATV, proved to be more effective than either of the drugs alone towards the rectification of arsenic-mediated disorganization of membrane structural integrity, and this could be linked with decreased ROS accumulation through reduced glutathione (GSH) repletion along with cholesterol depletion. Moreover, activation of caspase 3 was capable of promoting aggregation of band 3 with subsequent binding of autologous IgG and opsonization by C3b that led to phagocytosis of the exposed cells by the macrophages. NAC-ATV treatment successfully amended these events and restored lifespan of erythrocytes from the exposed animals almost to the control level. This work helped us to identify intracellular membrane cholesterol enrichment and GSH depletion as the key regulatory points in arsenic-mediated erythrocyte destruction and suggested a therapeutic strategy against Fas-activated cell death related to enhanced cholesterol and accumulation of ROS.}, }
@article {pmid20946208, year = {2011}, author = {Yamada, M and Kojima, N and Att, W and Minamikawa, H and Sakurai, K and Ogawa, T}, title = {Improvement in the osteoblastic cellular response to a commercial collagen membrane and demineralized freeze-dried bone by an amino acid derivative: an in vitro study.}, journal = {Clinical oral implants research}, volume = {22}, number = {2}, pages = {165-172}, doi = {10.1111/j.1600-0501.2010.01975.x}, pmid = {20946208}, issn = {1600-0501}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Bone Regeneration/drug effects ; Bone Substitutes/*pharmacology ; Coculture Techniques ; Collagen/*pharmacology ; Flow Cytometry ; Freeze Drying ; Guided Tissue Regeneration ; Osteoblasts/*metabolism ; Oxidative Stress ; Rats ; Reactive Oxygen Species/metabolism ; Wound Healing ; }, abstract = {PURPOSE: The objectives of this in vitro study were (1) to determine whether a commercially available collagen membrane (CM) or human demineralized freeze-dried bone (DFDB) particles adversely affected viability or function in cultured osteoblasts through oxidative stress, and, if so, (2) to determine whether N-acetyl cysteine (NAC) successfully prevented loss of viability and dysfunction in osteoblasts.<br><br>MATERIALS AND METHODS: Rat calvaria-derived osteoblasts were seeded onto polystyrene and commercially available CM (Cytoplast &#xae;) or DFDB (DynaGraft &#x2122;) with or without pretreatment with NAC solution. The osteoblastic response was evaluated using a flow cytometric cell viability assay, measurement of attached viable cell number, quantification of reactive oxygen species (ROS) and alkaline phosphatase (ALP) staining.<br><br>RESULTS: The percentage of viable cells on CM was <50% at 24 h after seeding. However, this increased to 70% by pretreatment with NAC. The numbers of attached osteoblasts on DFDB remained at 60% the level of that on polystyrene at 24 h after seeding, but increased to up to 90% the level of that on polystyrene with NAC pretreatment. Although collagen materials increased intracellular ROS generation 1.5-5 times that with polystyrene, this was significantly reduced by NAC pretreatment. The percentage of the ALP-positive area was consistently 7% or less on CM and DFDB at days 7 and 14, which was restored by NAC pretreatment up to 60% or more.<br><br>CONCLUSIONS: Commercially available CM and DFDB impaired osteoblastic viability and function and markedly increased intracellular ROS, indicating an oxidative stress-mediated negative impact on osteoblasts. Pretreatment with NAC substantially alleviated these cytotoxic effects.}, }
@article {pmid20944144, year = {2010}, author = {Kim, MJ and Kim, SH and Lim, SJ}, title = {Comparison of the apoptosis-inducing capability of sulforaphane analogues in human colon cancer cells.}, journal = {Anticancer research}, volume = {30}, number = {9}, pages = {3611-3619}, pmid = {20944144}, issn = {1791-7530}, mesh = {Anticarcinogenic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Caco-2 Cells ; Cell Proliferation/drug effects ; Colonic Neoplasms/*metabolism/pathology ; HCT116 Cells ; HT29 Cells ; Humans ; Immunoblotting ; Isothiocyanates ; Reactive Oxygen Species/metabolism ; Sulfides/pharmacology ; Sulfones/pharmacology ; Sulfoxides ; Thiocyanates/chemistry/*pharmacology ; }, abstract = {The anticancer activity of sulforaphane is known to be mediated at least partly by apoptosis induction and associated with the presence of the -N=C=S moiety. The present study explored how oxidation of sulphur in the side chain of sulforaphane affected apoptosis induction to provide the chemical basis of sulforaphane effects. Sulforaphane analogues containing oxidised sulphur (alyssin, sulforaphane, erysolin and alyssin sulfone) exerted a superior growth inhibitory effect compared with sulforaphane analogues with nonoxidised sulphur (erucin and berteroin) in human colon cancer cell lines. Furthermore, erysolin was a more potent inducer of reactive oxygen species (ROS) and apoptosis compared with erucin. Erysolin-induced ROS generation and subsequent apoptosis were inhibited by pretreatment with the antioxidant N-acetyl-cysteine. Erysolin induced caspase-8 activation, while blockade of caspsase 8 activation inhibited apoptosis induced by erysolin. Taken together, sulforaphane analogues with oxidised sulphur were the most efficient apoptosis inducers, likely due to high-level ROS induction.}, }
@article {pmid20943856, year = {2010}, author = {Merry, TL and Lynch, GS and McConell, GK}, title = {Downstream mechanisms of nitric oxide-mediated skeletal muscle glucose uptake during contraction.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {299}, number = {6}, pages = {R1656-65}, doi = {10.1152/ajpregu.00433.2010}, pmid = {20943856}, issn = {1522-1490}, mesh = {AMP-Activated Protein Kinases/metabolism ; Analysis of Variance ; Animals ; Blotting, Western ; Cyclic GMP/metabolism ; Electric Stimulation ; Enzyme Inhibitors/pharmacology ; Glucose/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Contraction/drug effects/*physiology ; Muscle, Skeletal/drug effects/*physiology ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase/metabolism ; Phosphorylation/drug effects/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/*physiology ; omega-N-Methylarginine/pharmacology ; }, abstract = {There is evidence that nitric oxide (NO) is required for the normal increases in skeletal muscle glucose uptake during contraction, but the mechanisms involved have not been elucidated. We examined whether NO regulates glucose uptake during skeletal muscle contractions via cGMP-dependent or cGMP-independent pathways. Isolated extensor digitorum longus (EDL) muscles from mice were stimulated to contract ex vivo, and potential NO signaling pathways were blocked by the addition of inhibitors to the incubation medium. Contraction increased (P < 0.05) NO synthase (NOS) activity (∼40%) and dichlorofluorescein (DCF) fluorescence (a marker of oxidant levels; ∼95%), which was prevented with a NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA), and antioxidants [nonspecific antioxidant, N-acetylcysteine (NAC); thiol-reducing agent, DTT], respectively. L-NMMA and NAC both attenuated glucose uptake during contraction by ∼50% (P < 0.05), and their effects were not additive. Neither the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, which prevents the formation of cGMP, the cGMP-dependent protein (PKG) inhibitor Rp-8-bromo-β-phenyl-1,N2-ethenoguanosine 3',5'-cyclic monophosphorothioate sodium salt nor white light, which breaks S-nitrosylated bonds, affects glucose uptake during contraction; however, DTT attenuated (P < 0.05) contraction-stimulated glucose uptake (by 70%). NOS inhibition and antioxidant treatment reduced contraction-stimulated increases in protein S-glutathionylation and tyrosine nitration (P < 0.05), without affecting AMPK or p38 MAPK phosphorylation. In conclusion, we provide evidence to suggest that NOS-derived oxidants regulate skeletal muscle glucose uptake during ex vivo contractions via a cGMP/PKG-, AMPK-, and p38 MAPK-independent pathway. In addition, it appears that NO and ROS may regulate skeletal muscle glucose uptake during contraction through a similar pathway.}, }
@article {pmid20941831, year = {2010}, author = {Demirel, C and Kilciksiz, S and Evirgen-Ayhan, S and Gurgul, S and Erdal, N}, title = {The preventive effect of N-acetylcysteine on radiation-induced dermatitis in a rat model.}, journal = {Journal of B.U.ON. : official journal of the Balkan Union of Oncology}, volume = {15}, number = {3}, pages = {577-582}, pmid = {20941831}, issn = {1107-0625}, mesh = {Acetylcysteine/*therapeutic use ; Amifostine/therapeutic use ; Animals ; Disease Models, Animal ; Female ; Radiation-Protective Agents/*therapeutic use ; Radiodermatitis/pathology/*prevention &amp; control ; Rats ; Rats, Wistar ; Skin/pathology ; }, abstract = {PURPOSE: We investigated the potential radioprotective effects of N-acetylcysteine (NAC) comparing its effects with that of amifostine (WR-2721), as a representative of clinically used radioprotector, in ameliorating skin injury from irradiation in rats (single dose, 18 Gy to the left hind legs of the rats).<br><br>METHODS: The rats (n=28) were divided randomly and equally into 4 groups: Control (C), Radiation (R), R+WR-2721 (received irradiation and 200 mg/kg of WR- 2721) and R+NAC (received irradiation and 1000 mg/kg of NAC). Acute skin reactions were assessed every 3 days by a radiation oncologist and a biophysicist. Light microscopic findings were assessed by an expert pathologist.<br><br>RESULTS: Clinically and histopathologically, irradiation increased dermatitis when compared with the control group (p<0.05). The severity of radiodermatitis of the rats in the R+NAC and R+WR-2721 groups was significantly lower than in the R group (p<0.05). The protective effects of NAC and WR-2721 on irradiation-increased dermatitis were clinically and histopathologically similar (p>0.05).<br><br>CONCLUSION: The study gives clues about the beneficial effects of NAC against radiation-induced dermatitis.}, }
@article {pmid20939675, year = {2010}, author = {Abu Hashim, H and Anwar, K and El-Fatah, RA}, title = {N-acetyl cysteine plus clomiphene citrate versus metformin and clomiphene citrate in treatment of clomiphene-resistant polycystic ovary syndrome: a randomized controlled trial.}, journal = {Journal of women's health (2002)}, volume = {19}, number = {11}, pages = {2043-2048}, doi = {10.1089/jwh.2009.1920}, pmid = {20939675}, issn = {1931-843X}, mesh = {Abortion, Spontaneous/epidemiology ; Acetylcysteine/*therapeutic use ; Adult ; Clomiphene/*therapeutic use ; Drug Resistance ; Drug Therapy, Combination ; Endometrium/pathology ; Estrogens/blood ; Female ; Follow-Up Studies ; Humans ; Metformin/*therapeutic use ; Ovulation Induction/methods ; Polycystic Ovary Syndrome/*drug therapy ; Pregnancy ; Pregnancy Outcome/epidemiology ; Progesterone/blood ; Prospective Studies ; }, abstract = {OBJECTIVE: To compare the effects of combined N-acetyl cysteine (NAC) and clomiphene citrate (CC) and of combined metformin and CC on ovulation induction in anovulatory CC-resistant women with polycystic ovary syndrome (PCOS).<br><br>METHODS: One hundred ninety-two women were randomized to receive either the NAC-CC drug combination (group A, n = 95) or the combined metformin-CC therapy (group B, n = 97) for three treatment cycles. The primary outcome measure was ovulation; secondary outcomes were number of follicles, serum estrogen and progesterone levels, posttreatment endometrial thickness, pregnancy, and miscarriage.<br><br>RESULTS: Over a 3-month follow-up period, women in group B had significantly higher ovulation and pregnancy rates compared with women in group A (69.1% vs. 20.0%, p = 0.002, and 22.7% vs. 5.3%, p = 0.020, respectively). The level of serum estrogen, the endometrial thickness on the day of human chorionic gonadotropin (hCG) administration, and the serum progesterone level on cycle days 21-23 were all significantly higher for women in group B than for those in group A. Additionally, a lower miscarriage rate was observed among women in group B than among those in group A.<br><br>CONCLUSIONS: The efficacy of metformin-CC combination therapy is higher than that of NAC-CC for inducing ovulation and achieving pregnancy among CC-resistant PCOS patients.}, }
@article {pmid20939553, year = {2010}, author = {Yang, M and Chordia, MD and Li, F and Huang, T and Linden, J and Macdonald, TL}, title = {Neutrophil- and myeloperoxidase-mediated metabolism of reduced nimesulide: evidence for bioactivation.}, journal = {Chemical research in toxicology}, volume = {23}, number = {11}, pages = {1691-1700}, doi = {10.1021/tx1001496}, pmid = {20939553}, issn = {1520-5010}, mesh = {Acetylcysteine/chemistry ; Anti-Inflammatory Agents, Non-Steroidal/*metabolism/toxicity ; Chromatography, Liquid ; Humans ; Hydrogen Peroxide/metabolism ; Hypochlorous Acid/metabolism ; Microsomes, Liver/metabolism ; Neutrophils/immunology/*metabolism ; Oxidation-Reduction ; Peroxidase/antagonists &amp; inhibitors/*metabolism ; Sulfonamides/*metabolism/toxicity ; Tandem Mass Spectrometry ; }, abstract = {Nimesulide, a widely used nonsteroidal anti-inflammatory drug (NSAID), has been associated with rare idiosyncratic hepatotoxicity. The chemical mechanisms underlying the liver injury remain unknown. We have undertaken the detailed study of the metabolic pathways of nimesulide in an effort to identify potential reactive metabolites. A previous report from this laboratory has demonstrated that one of the known nimesulide metabolites, termed reduced nimesulide (M1), is further bioactivated by human liver microsomes (HLMs) to form a reactive diiminoquinone species M2. The formation of M2 was confirmed indirectly by trapping with N-acetylcysteine (NAC). The aim of this study was to explore the fate of M1 in an inflammatory environment created by the recruitment of leukocytes. Leukocytes upon activation produce hydrogen peroxide (H(2)O(2)) and other myeloperoxidase (MPO) products, such as hypochlorous acid (HOCl), that are capable of metabolite oxidation. We demonstrate here that the reduced nimesulide, M1, undergoes a facile oxidation with activated neutrophils or with MPO in the presence of H(2)O(2) or HOCl to produce a variety of reactive as well as stable metabolites. One major metabolite, M3, was also produced by HLM as determined by trapping with NAC. Other metabolites, for example, M6, M8, and M9, were unique to the myeloperoxidase, because of their mode of formation from activation of the amino group of reduced nimesulide. The structures of some of these reactive metabolites were proposed on the basis of liquid chromatography-tandem mass spectrometry analyses and established by their comparison with synthetic standards. Metabolite M6 is interesting because it provides clear evidence of amine activation and indicates the potential of the reactive intermediate of M1 to conjugate with protein nucleophiles. In summary, our results demonstrate that a known nimesulide metabolite could be bioactivated by MPO through a pathway distinct from HLM-mediated pathways and that the generation of reactive species by the MPO-mediated bioactivation pathway at the site of inflammation may contribute to the toxicity associated with nimesulide.}, }
@article {pmid20938987, year = {2011}, author = {Lima, CF and Pereira-Wilson, C and Rattan, SI}, title = {Curcumin induces heme oxygenase-1 in normal human skin fibroblasts through redox signaling: relevance for anti-aging intervention.}, journal = {Molecular nutrition &amp; food research}, volume = {55}, number = {3}, pages = {430-442}, doi = {10.1002/mnfr.201000221}, pmid = {20938987}, issn = {1613-4133}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants/pharmacology ; Cells, Cultured ; *Cellular Senescence ; Curcuma/chemistry ; Curcumin/*pharmacology ; DNA Damage ; Enzyme Inhibitors/*pharmacology ; Female ; Fibroblasts/*cytology/metabolism ; Glutathione Disulfide/analysis ; Glutathione Transferase/analysis ; Heme Oxygenase-1/antagonists &amp; inhibitors/*metabolism ; Humans ; Oxidation-Reduction ; Oxidative Stress ; Phosphoinositide-3 Kinase Inhibitors ; Plant Extracts/chemistry ; Reactive Oxygen Species/analysis ; Signal Transduction ; Skin/metabolism ; Spices ; }, abstract = {SCOPE: Curcumin, a component of the spice turmeric, was tested for its potential hormetic anti-aging effects as an inducer of mild stress.<br><br>METHODS AND RESULTS: Early passage young human skin fibroblasts treated with low doses of curcumin (below 20&#x2009;&#x3bc;M) showed a time- and concentration-dependent induction of heme oxygenase-1 (HO-1), followed by compensatory increase in glutathione-S-transferase activity, GSH levels and GSH/GSSG ratio. These effects were preceded by induction of oxidative stress (increased levels of reactive oxygen species and DNA damage) and impairment of cells' GSH redox state. Curcumin also induced nuclear factor-erythroid-2-related factor 2 accumulation in the nuclei. The use of the antioxidant N-acetyl cysteine prevented the induction of HO-1 by curcumin. Pharmacological inhibition of phosphatidylinositol 3-kinase, but not other kinases, significantly prevented curcumin-induced HO-1 levels, which was corroborated by the induction of phospho-Akt levels by curcumin. Late passage senescent cells already had higher HO-1 levels, and further induction of HO-1 by curcumin was considerably impaired. The induction of stress responses by curcumin in human cells led to protective hormetic effects to further oxidant challenge.<br><br>CONCLUSION: Curcumin induces cellular stress responses in normal human skin fibroblasts through phosphatidylinositol 3-kinase/Akt pathway and redox signaling, supporting the view that curcumin-induced hormetic stimulation of cellular antioxidant defenses can be a useful approach toward anti-aging intervention.}, }
@article {pmid20938377, year = {2011}, author = {Lee, TF and Liu, JQ and Li, YQ and Nasim, K and Chaba, T and Bigam, DL and Cheung, PY}, title = {Improved renal recovery with postresuscitation N-acetylcysteine treatment in asphyxiated newborn pigs.}, journal = {Shock (Augusta, Ga.)}, volume = {35}, number = {4}, pages = {428-433}, doi = {10.1097/SHK.0b013e3181fffec2}, pmid = {20938377}, issn = {1540-0514}, support = {MOP 53160//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/*therapeutic use ; Acetylglucosaminidase/urine ; Animals ; Animals, Newborn ; Asphyxia/*drug therapy/physiopathology/urine ; Hemodynamics/drug effects ; Kidney/blood supply/*drug effects/*metabolism ; Male ; Oxidative Stress/drug effects ; Swine ; }, abstract = {Renal injury is one of the severe and common complications that occurs early in neonates with asphyxia, and reactive oxygen species have been implicated to play an important role on its pathogenesis. Improved renal recovery has been shown previously with N-acetyl-l-cysteine (NAC) in various acute kidney injuries. Using a subacute swine model of neonatal hypoxia-reoxygenation (H/R), we examined whether NAC can sustain its beneficial effect on renal recovery for 48 h. Newborn piglets were randomly assigned into a sham-operated group (without H/R, n = 6) and two H/R experimental groups (n = 8 each) with 2 h normocapnic alveolar hypoxia and 1 h 100% oxygen of reoxygenation followed by 21% oxygen for 47 h. Five minutes after reoxygenation, piglets received either normal saline (H/R control) or NAC (150-mg/kg bolus and 20 mg/kg per hour i.v. for 24 h) in a blinded, randomized fashion. All piglets were acidotic and in cardiogenic shock after hypoxia. Treating the piglets with NAC significantly increased both renal blood flow and oxygen delivery throughout the reoxygenation period. N-acetyl-l-cysteine treatment also improved the renal function with the attenuation of elevated urinary N-acetyl-β-d-glucosaminidase activity and plasma creatinine concentration observed in H/R controls (both P < 0.05). The tissue levels of lipid hydroperoxides and caspase 3 in the kidney of NAC-treated animals were significantly lower than those of H/R controls. Conclusively, postresuscitation administration of NAC elicits a prolonged beneficial effect in improving renal functional recovery and reducing oxidative stress in newborn piglets with H/R insults for 48 h.}, }
@article {pmid20937413, year = {2011}, author = {Bailey, SJ and Winyard, PG and Blackwell, JR and Vanhatalo, A and Lansley, KE and Dimenna, FJ and Wilkerson, DP and Campbell, IT and Jones, AM}, title = {Influence of N-acetylcysteine administration on pulmonary O2 uptake kinetics and exercise tolerance in humans.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {175}, number = {1}, pages = {121-129}, doi = {10.1016/j.resp.2010.10.002}, pmid = {20937413}, issn = {1878-1519}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Analysis of Variance ; Biomechanical Phenomena ; Exercise Test ; Exercise Tolerance/*drug effects ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Male ; Nitric Oxide/blood ; Oxygen Consumption/*drug effects ; Plasma Volume/drug effects/physiology ; Pulmonary Gas Exchange/*physiology ; Pulmonary Ventilation/drug effects/physiology ; Time Factors ; Young Adult ; }, abstract = {We investigated the influence of the antioxidant N-acetylcysteine (NAC) on plasma nitrite concentration ([NO2[-]]), pulmonary oxygen uptake (V(O2)) kinetics and exercise tolerance. Eight males completed 'step' moderate- and severe-intensity cycle exercise tests following infusion of either NAC (125 mg kg[-1] h[-1] for 15 min followed by 25 mg kg[-1] h[-1] until the termination of exercise) or Placebo (PLA; saline). Following the initial loading phase, NAC infusion elevated plasma free sulfhydryl groups compared to placebo (PLA: 4 ± 2 vs. NAC: 13 ± 3 μ M g[-1]; P < 0.05) and this elevation was preserved throughout the protocol. The administration of NAC did not significantly influence plasma [NO2[-]] or V(O2) kinetics during either moderate- or severe-intensity exercise. Although NAC did not significantly alter severe-intensity exercise tolerance at the group mean level (PLA: 776 ± 181 vs. NAC: 878 ± 284 s; P > 0.05), there was appreciable inter-subject variability in the response: four subjects had small reductions in exercise tolerance with NAC compared to PLA (-4%, -8%, -11%, and -14%) while the other four showed substantial improvements (+24%, +24%, +40%, and +69%). The results suggest that exercise-induced redox perturbations may contribute to fatigue development in recreationally-active adults.}, }
@article {pmid20934509, year = {2010}, author = {Saunders, JA and Rogers, LC and Klomsiri, C and Poole, LB and Daniel, LW}, title = {Reactive oxygen species mediate lysophosphatidic acid induced signaling in ovarian cancer cells.}, journal = {Free radical biology &amp; medicine}, volume = {49}, number = {12}, pages = {2058-2067}, pmid = {20934509}, issn = {1873-4596}, support = {F31 CA106199/CA/NCI NIH HHS/United States ; R01 CA142838/CA/NCI NIH HHS/United States ; R01 CA142838-01/CA/NCI NIH HHS/United States ; R33 CA126659/CA/NCI NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme Activation/drug effects ; Epithelial Cells ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Genes, Reporter/genetics ; Humans ; Lysophospholipids/metabolism/*pharmacology ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; NF-kappa B/metabolism ; Onium Compounds/pharmacology ; Organophosphates/pharmacology ; Ovarian Neoplasms/*metabolism/pathology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Pyridines/pharmacology ; Reactive Oxygen Species/*metabolism ; Receptors, Lysophosphatidic Acid/antagonists &amp; inhibitors ; Signal Transduction/*drug effects ; Up-Regulation/drug effects ; }, abstract = {Lysophosphatidic acid (LPA) is produced by tumor cells and is present in the ascites fluid of ovarian cancer patients. To determine the role of endogenous LPA in the ovarian cancer cell line SKOV3, we treated cells with the LPA receptor antagonist VPC32183 and found that it inhibited cell growth and induced apoptosis. Exogenous LPA further stimulated ERK and Akt phosphorylation and NF-κB activity. To determine if reactive oxygen species (ROS), which have been implicated as second messengers in cell signaling, were also involved in LPA signaling, we treated cells with the NADPH oxidase inhibitor diphenyleneiodonium (DPI), and antioxidants N-acetyl cysteine, EUK-134 and curcumin, and showed that all blocked LPA-dependent NF-κB activity and cell proliferation. DPI and EUK-134 also inhibited Akt and ERK phosphorylation. LPA was shown to stimulate dichlorofluorescein fluorescence, though not in the presence of DPI, apocynin (an inhibitor of NADPH oxidase), VPC32183, or PEG-catalase. Akt phosphorylation was also inhibited by PEG-catalase and apocynin. These data indicate that NADPH oxidase is a major source of ROS and H(2)O(2) is critical for LPA-mediated signaling. Thus, LPA acts as a growth factor and prevents apoptosis in SKOV3 cells by signaling through redox-dependent activation of ERK, Akt, and NF-κB-dependent signaling pathways.}, }
@article {pmid20932892, year = {2011}, author = {Xue, C and Liu, W and Wu, J and Yang, X and Xu, H}, title = {Chemoprotective effect of N-acetylcysteine (NAC) on cellular oxidative damages and apoptosis induced by nano titanium dioxide under UVA irradiation.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {25}, number = {1}, pages = {110-116}, doi = {10.1016/j.tiv.2010.09.014}, pmid = {20932892}, issn = {1879-3177}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line ; Cell Survival/drug effects ; Gene Expression Regulation/drug effects ; Humans ; Keratin-6/genetics/metabolism ; Keratinocytes/drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Metal Nanoparticles/radiation effects/*toxicity ; Nitric Oxide/metabolism ; Oxidants, Photochemical/radiation effects/toxicity ; Oxidative Stress/*drug effects ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Titanium/antagonists &amp; inhibitors/*radiation effects/*toxicity ; *Ultraviolet Rays ; }, abstract = {The chemoprotective effect of N-acetylcysteine (NAC), a sulfhydryl-containing antioxidant, on nano titanium dioxide (nano-TiO(2)) induced oxidative stress and apoptosis in human keratinocyte (HaCaT) cells was assessed. HaCaT cells were pretreated with NAC followed by treatment with 200 μg/ml nano-TiO(2), then exposed to ultraviolet A (UVA, 365 nm) for 1 h and cultured for 24 h. Intracellular reactive oxygen species (ROS) and nitric oxide (NO) formation, mitochondrial membrane potential (MMP), apoptosis and the content of the lipid peroxidation product malondialdehyde (MDA) were measured. Keratin 6 (K6) mRNA expression was also analyzed. The results showed that NAC strongly inhibited ROS and NO production in nano-TiO(2) treated cells. The extent of lipid peroxidation was also decreased in the presence of NAC. In addition, NAC suppressed nano-TiO(2) induced apoptosis and increased K6 mRNA expression. The results indicated that NAC could prevent oxidative stress and apoptosis induced by nano-TiO(2) in HaCaT cells.}, }
@article {pmid20921063, year = {2011}, author = {You, BR and Park, WH}, title = {Enhancement of gallic acid-induced human pulmonary fibroblast cell death by N-acetyl cysteine and L-buthionine sulfoximine.}, journal = {Human &amp; experimental toxicology}, volume = {30}, number = {8}, pages = {992-999}, doi = {10.1177/0960327110384528}, pmid = {20921063}, issn = {1477-0903}, mesh = {Acetylcysteine/*pharmacology ; Anticarcinogenic Agents/*pharmacology ; Cell Culture Techniques ; Cell Death/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Fibroblasts/*drug effects/pathology ; Gallic Acid/*pharmacology ; Glutathione/metabolism ; Humans ; Lung/*drug effects/pathology ; Membrane Potential, Mitochondrial/drug effects ; Methionine/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Gallic acid (GA) has various biological properties including anti-cancer effect. However, little is known about the toxicological effect of GA in primary normal cells. Here, we evaluated the effects of GA on human pulmonary fibroblast (HPF) cells in relation to reactive oxygen species (ROS) and glutathione (GSH). GA inhibited the growth of HPF cells at 24 hours in a dose-dependent manner. GA also induced HPF cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; ΔΨ(m)). GA increased ROS levels including O(2)(•-) and GSH-depleted cell numbers in HPF cells at 24 hours. Treatment with 2 mM N-acetyl-cysteine (NAC) intensified growth inhibition and death in GA-treated HPF cells. NAC decreased ROS levels and increased GSH depletion in these cells. Treatment with 10 μM L-buthionine sulfoximine (BSO) also enhanced growth inhibition and death in GA-treated HPF cells. BSO increased ROS levels and GSH depletion in these cells. In conclusion, GA-induced HPF cell death was accompanied by ROS increase and GSH depletion. The changes of ROS and GSH levels by NAC and BSO appeared to affect cell growth and death in GA-treated HPF cells.}, }
@article {pmid20920876, year = {2010}, author = {Lin, MH and Hsieh, WF and Chiang, WF and Hong, WZ and Hsu, YR and Cheng, YC and Chen, TC and Hsu, KC and Lin, PY and Liu, SY and Liu, YC}, title = {Autophagy induction by the 30-100kDa fraction of areca nut in both normal and malignant cells through reactive oxygen species.}, journal = {Oral oncology}, volume = {46}, number = {11}, pages = {822-828}, doi = {10.1016/j.oraloncology.2010.08.002}, pmid = {20920876}, issn = {1879-0593}, mesh = {Areca/*chemistry ; Autophagy/*drug effects ; Blotting, Western ; Cell Line, Tumor ; Female ; Fibroblasts/drug effects/metabolism ; Humans ; Male ; Mouth Neoplasms/*chemically induced ; Oxidative Stress/drug effects ; Plant Extracts/*pharmacology ; Reactive Oxygen Species/*metabolism ; T-Lymphocytes/drug effects/metabolism ; Up-Regulation/drug effects ; }, abstract = {Areca nut (AN) is an addictive carcinogen used by about 200-600 million people worldwide. Some AN components are shown to induce apoptosis; however, we previously demonstrated that AN extract (ANE) and the 30-100kDa fraction of ANE (ANE 30-100K) induced autophagy-like responses, such as swollen cell morphology, empty cytoplasm, acidic vesicles, and LC3-II accumulation, in an oral cancer cell line, OECM-1. To further assess the responses of other cell types to ANE 30-100K, we used both normal and malignant cells as the targets of ANE 30-100K and found that normal oral fibroblasts (CMT415), peripheral blood lymphocytes (PBLs), Jurkat leukemia T cells, and esophageal carcinoma cells (CE81T/VGH) exhibited similar responses after ANE 30-100K challenge. ANE 30-100K drastically increased acidic vesicle-containing PBLs isolated from two independent donors (from 0.1% to 92.1% and 2.9% to 64.2%). Furthermore, both ANE- and ANE 30-100K-induced LC3-II accumulation in CMT415 and CE81T/VGH was further increased in the presence of the lysosomal protease inhibitors (pepstatin A, E64d, and leupeptin). On the other hand, ANE 30-100K also increased the level of intracellular reactive oxygen species (ROS), and the ROS scavengers, N-acetylcysteine (NAC) and Tiron, inhibited ANE 30-100K-induced cell death and LC3-II accumulation. Collectively, these results suggest the existence of an autophagy-inducing AN ingredient (AIAI) in ANE 30-100K, which renders ANE as an autophagic flux inducer through ROS in both normal and malignant cells.}, }
@article {pmid20919940, year = {2011}, author = {Takabe, W and Jen, N and Ai, L and Hamilton, R and Wang, S and Holmes, K and Dharbandi, F and Khalsa, B and Bressler, S and Barr, ML and Li, R and Hsiai, TK}, title = {Oscillatory shear stress induces mitochondrial superoxide production: implication of NADPH oxidase and c-Jun NH2-terminal kinase signaling.}, journal = {Antioxidants &amp; redox signaling}, volume = {15}, number = {5}, pages = {1379-1388}, pmid = {20919940}, issn = {1557-7716}, support = {HL-068689/HL/NHLBI NIH HHS/United States ; HL-083015/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cattle ; Coronary Vessels/metabolism ; Cytosol/metabolism ; Endothelial Cells/metabolism ; Enzyme Activation ; Gene Expression Regulation ; Gene Knockdown Techniques ; Hemodynamics/physiology ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/*metabolism ; Mitochondria/*metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; Oxidative Stress ; Shear Strength ; Signal Transduction/*physiology ; *Stress, Mechanical ; Superoxides/*metabolism ; }, abstract = {Fluid shear stress is intimately linked with vascular oxidative stress and atherosclerosis. We posited that atherogenic oscillatory shear stress (OSS) induced mitochondrial superoxide (mtO2•-) production via NADPH oxidase and c-Jun NH(2)-terminal kinase (JNK-1 and JNK-2) signaling. In bovine aortic endothelial cells, OSS (±3 dyn/cm2) induced JNK activation, which peaked at 1 h, accompanied by an increase in fluorescein isothiocyanate-conjugated JNK fluorescent and MitoSOX Red (specific for mtO2•- production) intensities. Pretreatment with apocynin (NADPH oxidase inhibitor) or N-acetyl cysteine (antioxidant) significantly attenuated OSS-induced JNK activation. Apocynin further reduced OSS-mediated dihydroethidium and MitoSOX Red intensities specific for cytosolic O2•- and mtO2•- production, respectively. As a corollary, transfecting bovine aortic endothelial cells with JNK siRNA (siJNK) and pretreating with SP600125 (JNK inhibitor) significantly attenuated OSS-mediated mtO2•- production. Immunohistochemistry on explants of human coronary arteries further revealed prominent phosphorylated JNK staining in OSS-exposed regions. These findings indicate that OSS induces mtO2•- production via NADPH oxidase and JNK activation relevant for vascular oxidative stress.}, }
@article {pmid20890618, year = {2011}, author = {Gómez, FJ and Aguirre, P and Gonzalez-Billault, C and Núñez, MT}, title = {Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+).}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {118}, number = {3}, pages = {421-431}, pmid = {20890618}, issn = {1435-1463}, mesh = {1-Methyl-4-phenylpyridinium/*pharmacology ; Analysis of Variance ; Animals ; Cell Death/drug effects ; Cells, Cultured ; Dopamine/metabolism ; Immunohistochemistry ; Iron/*metabolism/pharmacology ; Mesencephalon/*drug effects/metabolism/pathology ; Neurites/*drug effects/metabolism/pathology ; Neurons/*drug effects/metabolism/pathology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Studies in post-mortem tissues of patients with Parkinson's disease (PD) and in mice treated with 6-hydroxydopamine have shown a decrease in the length of axon and dendrites of striatal neurons. However, the etiology of the morphological changes and their relationship to inhibition of mitochondrial complex I and the cellular levels of iron and glutathione (GSH) have not been described. In this study, we characterized the effect of MPP+, an inhibitor of mitochondria complex I, on the integrity of the neuritic tree of midbrain dopaminergic neurons, and determined the influence of iron and cellular levels of GSH on this degeneration. Sub-maximal concentrations of MPP+ induced a drastic dose-dependent reduction of neurites, without modification of the soma or apparent cell death. Concurrent treatment with MPP+ and non-toxic concentrations of iron accelerated the process of degeneration, whereas neurons grown on a medium low in iron showed enhanced resistance to MPP+ treatment. MPP+-induced neurite shortening depended on the redox state of neurons. Pre-treatment with the general antioxidant N-acetyl cysteine protected neurons from degeneration. Treatment with sub-maximal concentrations of the inhibitor of GSH synthesis buthionine sulfoximine (BSO), in conjunction with iron and MPP+, produced massive cell death, whereas treatment with BSO plus MPP+ under low iron conditions did not damage neurons. These results suggest that under conditions of inhibition of mitochondrial complex I caused by MPP+, the accumulation of iron and the concurrent decrease in GSH results in the loss of the dendritic tree prior to cell death, of dopaminergic neurons in PD.}, }
@article {pmid20888409, year = {2010}, author = {Lazarev, VN and Borisenko, GG and Shkarupeta, MM and Demina, IA and Serebryakova, MV and Galyamina, MA and Levitskiy, SA and Govorun, VM}, title = {The role of intracellular glutathione in the progression of Chlamydia trachomatis infection.}, journal = {Free radical biology &amp; medicine}, volume = {49}, number = {12}, pages = {1947-1955}, doi = {10.1016/j.freeradbiomed.2010.09.024}, pmid = {20888409}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Survival/drug effects ; Chlamydia Infections/*metabolism/microbiology ; Chlamydia trachomatis/*physiology ; Glutathione/*metabolism ; Glutathione Disulfide/pharmacology ; HeLa Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Inclusion Bodies/drug effects/metabolism ; Proteome/metabolism ; }, abstract = {The productive internalization in the host cell of Chlamydia trachomatis elementary bodies and their infectivity depends on the degree of reduction of disulfide bonds in the outer envelope of the elementary body. We have hypothesized that the reducing agent may be intracellular glutathione (GSH). Three approaches were used to modulate the intracellular GSH concentration: (1) treatment of cells with buthionine sulfoximine, which causes irreversible inhibition of GSH biosynthesis; (2) hydrogen peroxide-induced oxidation of GSH by intracellular glutathione peroxidases; and (3) treatment of cells with N-acetyl-l-cysteine (NAC), a precursor of glutathione. In the first two cases, we observed a four- to sixfold inhibition of C. trachomatis infection, whereas in NAC-treated cells we detected an increase in the size of chlamydial inclusions. Using a proteomics approach, we showed that the inhibition of chlamydial infection does not combine with alterations in protein expression patterns after cell treatment. These results suggest that GSH plays a key role in the reduction of disulfide bonds in the C. trachomatis outer envelope at an initial stage of the infection.}, }
@article {pmid20887268, year = {2010}, author = {Li, YJ and Takizawa, H and Kawada, T}, title = {Role of oxidative stresses induced by diesel exhaust particles in airway inflammation, allergy and asthma: their potential as a target of chemoprevention.}, journal = {Inflammation &amp; allergy drug targets}, volume = {9}, number = {4}, pages = {300-305}, doi = {10.2174/187152810793358787}, pmid = {20887268}, issn = {2212-4055}, mesh = {Air Pollutants/toxicity ; Animals ; Antioxidants/pharmacology ; Asthma/etiology/immunology/prevention &amp; control ; Chemoprevention/methods ; *Drug Delivery Systems ; Humans ; Hypersensitivity/etiology/immunology/prevention &amp; control ; Inflammation/etiology/immunology/prevention &amp; control ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Vehicle Emissions/*toxicity ; }, abstract = {Epidemiological studies have shown that particulate air pollutants, such as diesel exhaust particles (DEPs) are implicated in the increased incidence of allergic airway disorders. DEPs induce and exaggerate allergic airway inflammation in vitro and in vivo. Studies of molecular mechanisms have focused on the role of reactive oxygen species (ROS) generated directly and indirectly by exposure to DEPs. The ROS play an important role in proinflammatory reaction in airways. Nuclear erythroid 2 P45-related factor Nrf2 is a key transcription factor that regulates host antioxidant and contributes to regulate airway inflammation and exacerbation of allergic inflammation induced by DEPs. The authors demonstrated that DEPs-induced oxidants stress and resultant inflammatory changes were blocked by antioxidants such as N-acetyl cysteine (NAC). Therefore, chemoprevention against DEPs health effects in susceptible individuals may become a choice for future environmental protection policy.}, }
@article {pmid20884875, year = {2010}, author = {Lefèvre, C and Auclair, M and Boccara, F and Bastard, JP and Capeau, J and Vigouroux, C and Caron-Debarle, M}, title = {Premature senescence of vascular cells is induced by HIV protease inhibitors: implication of prelamin A and reversion by statin.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {30}, number = {12}, pages = {2611-2620}, doi = {10.1161/ATVBAHA.110.213603}, pmid = {20884875}, issn = {1524-4636}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants/pharmacology ; Case-Control Studies ; Cell Proliferation/*drug effects ; Cells, Cultured ; Cellular Senescence/*drug effects ; Coronary Vessels/drug effects/metabolism/pathology ; Cyclin-Dependent Kinase Inhibitor p21/blood ; Drug Therapy, Combination ; Endothelial Cells/*drug effects/metabolism/pathology ; Farnesyltranstransferase/antagonists &amp; inhibitors/metabolism ; HIV Infections/blood/*drug therapy/pathology ; HIV Protease Inhibitors/*therapeutic use ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use ; Lamin Type A ; Lopinavir ; Metalloporphyrins/pharmacology ; Methionine/analogs &amp; derivatives/pharmacology ; Middle Aged ; Nuclear Proteins/blood/*metabolism ; Oxidative Stress/drug effects ; Paris ; Pravastatin/*therapeutic use ; Protein Precursors/blood/*metabolism ; Pyrimidinones/*therapeutic use ; Ritonavir/*therapeutic use ; Time Factors ; Tumor Suppressor Protein p53/blood ; }, abstract = {OBJECTIVE: To determine whether and how protease inhibitors (PIs) could affect vascular aging.<br><br>METHODS AND RESULTS: HIV therapy with PIs is associated with an increased risk of premature cardiovascular disease. The effect of ritonavir and a combination of lopinavir and ritonavir (for 30 days) on senescence, oxidative stress, and inflammation was evaluated in human coronary artery endothelial cells (HCAECs). These HCAECs were either cotreated or not cotreated with pravastatin or farnesyl transferase inhibitor (FTI)-277 or with 2 antioxidants (manganese [III] tetrakis [4-benzoic acid] porphyrin [MnTBAP] and N-acetyl cysteine). Senescence markers were evaluated in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients under PI treatment. PIs induced senescence markers, prelamin A accumulation, oxidative stress, and inflammation in HCAECs. Senescence markers and prelamin A were also observed in PBMCs from HIV-infected patients under ritonavir-boosted PIs. Pravastatin, FTI-277, and antioxidants improved PI adverse effects in HCAECs. Senescence markers were lower in PBMCs from PI-treated patients cotreated with statins.<br><br>CONCLUSIONS: PIs triggered premature senescence in endothelial cells by a mechanism involving prelamin A accumulation. Accordingly, circulating cells from HIV-infected patients receiving PI therapy expressed senescence markers and prelamin A. Statin was associated with improved senescence in endothelial cells and patient PBMCs. Thus, PIs might promote vascular senescence in HIV-infected patients; and statins might exert beneficial effects in these patients.}, }
@article {pmid20883752, year = {2010}, author = {Qi, XF and Kim, DH and Yoon, YS and Kim, SK and Cai, DQ and Teng, YC and Shim, KY and Lee, KJ}, title = {Involvement of oxidative stress in simvastatin-induced apoptosis of murine CT26 colon carcinoma cells.}, journal = {Toxicology letters}, volume = {199}, number = {3}, pages = {277-287}, doi = {10.1016/j.toxlet.2010.09.010}, pmid = {20883752}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Glutathione/pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; Mice ; Oligopeptides/pharmacology ; *Oxidative Stress ; Polyisoprenyl Phosphates/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Simvastatin/*pharmacology ; }, abstract = {Recent studies have suggested that oxidative stress may play a role in the cytotoxic activity of statins against cancer cells. The objective of this study was to elucidate the role of oxidative stress in the cytotoxicity of simvastatin in murine CT26 colon carcinoma cells and B16BL6 melanoma cells. We found that CT26 cells were more sensitive to simvastatin than B16BL16 cells. Interestingly, exposure to simvastatin causes significant apoptotic cell death and perturbations in parameters indicative of oxidative stress in CT26 cells. Moreover, the increase in oxidative stress parameters and cell death were suppressed by isoprenoids including mevalonolactone, farnesyl pyrophosphate ammonium salt, geranylgeranyl pyrophosphate ammonium salt, and coenzyme Q10, and by antioxidants including N-acetyl cysteine, reduced glutathione, superoxide dismutases (SOD), and catalase (CAT) alone or in combination, but were promoted by an inhibitor of glutathione synthesis, L-buthionine-sulfoximine. The signaling pathway induced by simvastatin breaks down the antioxidant defense system by suppressing the expression of reactive oxygen species scavengers, particularly Mn-SOD, CAT, GPx1, and SESN 3, thereby inducing oxidative stress and apoptotic cell death. Collectively, our results demonstrate that simvastatin induces colon cancer cell death at least in part by increasing intracellular oxidative stress and inducing apoptosis.}, }
@article {pmid20882329, year = {2011}, author = {de Mello, RO and Lunardelli, A and Caberlon, E and de Moraes, CM and Christ Vianna Santos, R and da Costa, VL and da Silva, GV and da Silva Scherer, P and Buaes, LE and da Silva Melo, DA and Donadio, MV and Nunes, FB and de Oliveira, JR}, title = {Effect of N-acetylcysteine and fructose-1,6-bisphosphate in the treatment of experimental sepsis.}, journal = {Inflammation}, volume = {34}, number = {6}, pages = {539-550}, pmid = {20882329}, issn = {1573-2576}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Drug Synergism ; Drug Therapy, Combination ; Fructose-Bisphosphatase/pharmacology/*therapeutic use ; Rats ; Sepsis/*drug therapy/mortality ; Survival Rate ; Treatment Outcome ; }, abstract = {Sepsis is a syndrome caused by uncontrolled systemic inflammatory response of the individual, which represents a serious epidemiological problem worldwide. The aim of this study was to investigate the effect of N-acetylcysteine (NAC) and fructose-1,6-bisphosphate (FBP) in the treatment of experimental sepsis. We used rats that were divided into five experimental groups: normal control (not induced), septic control (induced using a capsule with non sterile fecal content and Escherichia coli), treated with FBP (500 mg/kg i.p.), treated with NAC (150 mg/kg i.p.), and treated with the combination of FBP with NAC. In the group treated with NAC, 16.68% of the mice survived, the FBP reduced the mortality of mice during the acute stage of the disease and increased the animals' survival time in 33.34%, and the combination of drugs had no effect. Our results show that NAC prevented the mortality of animals after septic induction. These data confirm the validity of the use of NAC in the treatment of sepsis. Our data also show that the synergistic action with FBP does not improve the picture.}, }
@article {pmid20882249, year = {2010}, author = {Casuso, P and Carrasco, P and Loinaz, I and Grande, HJ and Odriozola, I}, title = {Converting drugs into gelators: supramolecular hydrogels from N-acetyl-L-cysteine and coinage-metal salts.}, journal = {Organic &amp; biomolecular chemistry}, volume = {8}, number = {23}, pages = {5455-5458}, doi = {10.1039/c0ob00311e}, pmid = {20882249}, issn = {1477-0539}, mesh = {Acetylcysteine/*chemistry ; Copper/*chemistry ; Gold/*chemistry ; Hydrogels/*chemistry ; Hydrogen-Ion Concentration ; Microscopy, Electron, Scanning ; Molecular Structure ; Salts/chemistry ; Silver/*chemistry ; }, abstract = {Here we present the concept of metallophilic hydrogels, supramolecular systems in which the gelator species are metal-thiolates that self-assemble through metallophilic attractions. The principle is applied for a small drug, the mucolytic agent N-acetyl-l-cysteine (NAC), which readily forms hydrogels in the presence of Au(iii), Ag(i) and Cu(ii) salts. The resulting transparent hydrogels present pH induced sol/gel transition. Scanning electron microscopy (SEM) measurements reveal a microporous structure in form of flakes for the three of them. The low pH at which these hydrogels are formed (pH < 4) limits their direct use as drug-delivery systems, but still this system constitutes a novel method for easy and fast conversion of small drugs into potent hydrogelators. Future developments will help to fully develop the idea in order to create a new class of supramolecular drug-delivery systems.}, }
@article {pmid20876761, year = {2010}, author = {Yuzefovych, L and Wilson, G and Rachek, L}, title = {Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {299}, number = {6}, pages = {E1096-105}, pmid = {20876761}, issn = {1522-1555}, support = {DK-073808/DK/NIDDK NIH HHS/United States ; ES-03456/ES/NIEHS NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Apoptosis/*drug effects ; Blotting, Western ; Cell Count ; Cell Line ; Cell Survival/drug effects ; Cells, Cultured ; Insulin/*metabolism ; Insulin Resistance ; Mitochondria/*drug effects/metabolism ; Muscle Fibers, Skeletal/*drug effects/metabolism ; Nitric Oxide/metabolism ; Oleic Acid/metabolism/*pharmacology ; Oxidative Stress/*drug effects ; Palmitic Acid/metabolism/*pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; }, abstract = {The type of free fatty acids (FFAs), saturated or unsaturated, is critical in the development of insulin resistance (IR), since the degree of saturation correlates with IR. We compared the effects of the saturated FFA palmitate, the unsaturated FFA oleate, and a mixture of each on the production of mitochondrial reactive oxygen species (mtROS), mitochondrial DNA (mtDNA) damage, mitochondrial function, apoptosis, and insulin-signaling pathway in skeletal muscle cells. Only palmitate caused a significant increase of mtROS production, which correlated with concomitant mtDNA damage, mitochondrial dysfunction, induction of JNK, apoptosis, and inhibition of insulin signaling. Blocking de novo synthesis of ceramide abolished the effects of palmitate on mtROS production, viability, and insulin signaling. Oleate alone did not cause mtROS generation and mtDNA damage, and its addition to palmitate prevented palmitate-induced mtDNA damage, increased total ATP levels and cell viability, and prevented palmitate-induced apoptosis and inhibition of insulin-stimulated Akt (Ser(473)) phosphorylation. The peroxisome proliferator activator receptor-γ coactivator 1α (PGC-1α) protein level and promoter activity were decreased at concentrations of palmitate ≥0.5 mM, whereas addition of oleate increased both PGC-1α level and promoter activity. Expression of the mitochondrial transcription factor (TFAM) was significantly diminished after palmitate but not oleate treatment. Addition of the ROS scavenger, N-acetylcystein (NAC), to palmitate restored both the expression and promoter activity of PGC-1α as well as TFAM expression. We propose that 1) mtROS generation is the initial event in the induction of mitochondrial dysfunction and consequent apoptosis and the inhibition of insulin signaling and that 2) oleate ameliorates palmitate-induced mitochondrial dysfunction and thus may contribute to the prevention of palmitate-induced IR.}, }
@article {pmid20876635, year = {2012}, author = {Yamada, M and Minamikawa, H and Ueno, T and Sakurai, K and Ogawa, T}, title = {N-acetyl cysteine improves affinity of beta-tricalcium phosphate granules for cultured osteoblast-like cells.}, journal = {Journal of biomaterials applications}, volume = {27}, number = {1}, pages = {27-36}, doi = {10.1177/0885328210383598}, pmid = {20876635}, issn = {1530-8022}, mesh = {Acetylcysteine/*pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Biocompatible Materials ; Calcium Phosphates/*metabolism ; Cells, Cultured ; Male ; Osteoblasts/*drug effects/enzymology/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Enhancement of bone substitute's biocompatibility may accelerate healing of surrounding bone. Although widely used as a biodegradable alloplastic bone substitute for alveolar bone augmentation, the osteocompatibility of beta-tricalcium phosphate (β-TCP) remains to be proven. The adverse cellular response to biomaterials is associated with oxidative stress. We hypothesized that commercially available β-TCP granules for clinical use, caused oxidative stress and was not optimal in osteocompatibility and that application of antioxidant amino acid derivative N-acetyl cysteine (NAC) would improve osteoblastic responses to the material. Only 20% of rat calvarial osteoblasts cultured on β-TCP granules remained viable at 24 h after seeding as opposed to 90% on polystyrene. Cell death on β-TCP granules was characterized by necrosis. However, the percentage of viable osteoblasts cultured on β-TCP granules showed a 100% increase with pre-treatment with NAC. NAC restored suppressed alkaline phosphatase activity on β-TCP granules at day 5. Intracellular ROS level on β-TCP granules was 16-fold greater than that on polystyrene, but decreased by half with pre-treatment with NAC. Cell death and intracellular ROS elevation were also induced in polystyrene culture under β-TCP granules even when the osteoblasts were not in direct contact with the β-TCP granules. NAC, however, prevented induction of cell death and elevation of intracellular ROS under β-TCP granules. These results indicate that commercially available β-TCP granules negatively affect cultured osteoblastic viability and function via oxidative stress and that NAC improves these negative responses to the material. This implies enhanced bone regeneration around biodegradable calcium phosphate-based bone substitute by NAC.}, }
@article {pmid20876229, year = {2011}, author = {Guha, P and Dey, A and Sen, R and Chatterjee, M and Chattopadhyay, S and Bandyopadhyay, SK}, title = {Intracellular GSH depletion triggered mitochondrial Bax translocation to accomplish resveratrol-induced apoptosis in the U937 cell line.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {336}, number = {1}, pages = {206-214}, doi = {10.1124/jpet.110.171983}, pmid = {20876229}, issn = {1521-0103}, mesh = {Apoptosis/drug effects/*physiology ; Glutathione/*metabolism ; Humans ; Intracellular Fluid/drug effects/*metabolism ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mitochondria/drug effects/*metabolism ; Protein Transport/drug effects ; Resveratrol ; Stilbenes/*pharmacology ; U937 Cells ; bcl-2-Associated X Protein/*metabolism ; }, abstract = {We have previously demonstrated that resveratrol (Resv)-induced cellular apoptosis occurs after formation of reactive oxygen species (ROS) but the role of GSH has not been well defined. Our experimental data enumerated that Resv treatment (50 μm) induced apoptosis in human leukemic monocyte lymphoma cells, which was preceded by cellular GSH efflux. High concentration of extracellular thiol (GSH, N-acetyl cysteine) and two specific inhibitors of carrier-mediated GSH extrusion, methionine or cystathionine, prevented the process of oxidative burst and cell death. This proved that GSH efflux could be a major molecular switch to modulate Resv-induced ROS generation. Spectrofluorometric data depicted that after 6 h of Resv treatment, ROS generation was evident. Pretreatment of cells with intracellular ROS scavenger (polyethylene glycol-superoxide dismutase and polyethylene glycol-catalase) efficiently reduced ROS generation but failed to prevent intracellular GSH depletion. Thus, it suggested that intracellular GSH depletion was independent of ROS production but dependent on GSH extrusion. Furthermore, to bridge the link between GSH efflux and ROS generation, we carried out confocal microscopy of the localization of Bax protein. Microscopic analysis and small interfering RNA treatment emphasized that cellular GSH efflux triggered Bax translocation to mitochondria, which resulted in the loss of mitochondrial membrane potential, ROS generation, and caspase 3 activation and thus triggered apoptosis.}, }
@article {pmid20875491, year = {2010}, author = {Fraternale, A and Paoletti, MF and Dominici, S and Caputo, A and Castaldello, A and Millo, E and Brocca-Cofano, E and Smietana, M and Clayette, P and Oiry, J and Benatti, U and Magnani, M}, title = {The increase in intra-macrophage thiols induced by new pro-GSH molecules directs the Th1 skewing in ovalbumin immunized mice.}, journal = {Vaccine}, volume = {28}, number = {48}, pages = {7676-7682}, doi = {10.1016/j.vaccine.2010.09.033}, pmid = {20875491}, issn = {1873-2518}, mesh = {Adjuvants, Immunologic/pharmacology ; Animals ; Antibody Formation ; Cells, Cultured ; Female ; Glutathione/*immunology ; Immunity, Cellular ; Immunoglobulin G/blood ; Macrophages, Peritoneal/*immunology/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Ovalbumin/immunology ; Oxidation-Reduction ; Sulfhydryl Compounds/analysis/*immunology ; Th2 Cells/*immunology ; }, abstract = {In the present work, the capacity of new pro-GSH molecules to increase the intra-macrophage thiol content in vitro and in vivo as well as to shift the immune response to Th1 in ovalbumin (Ova)-sensitized mice were examined. The molecules were the N-butanoyl GSH derivative, GSH-C4, and a pro-drug of N-acetylcysteine (NAC) and beta-mercaptoethylamine (MEA), I-152. In vitro, 2h-incubation with both molecules was found to increase intra-macrophage thiol content; in vivo, Ova-sensitized mice pre-treated by intraperitoneal administration of the pro-GSH molecules showed an increase in plasma anti-Ova IgG2a and IgG2b, characterizing Th1 immune response, and a decrease in IgG1, typical of the Th2 response. Such findings were connected to a shift to a Th1 response also involving splenocyte IFN-γ production as revealed by ELISPOT assay and higher levels of IL-12 in circulation. Although immune responses are in vivo mediated both by dendritic cells and macrophages, the data reported in this paper corroborate the suggestion that the pro-GSH molecules, increasing the intra-cellular thiol pool, modulate the Th1/Th2 balance favouring Th1-type responses and may be employed as Th1-directing adjuvants in new vaccination protocols and as immunomodulators in those diseases where Th1 response patterns are compromised in favour of Th2.}, }
@article {pmid20875427, year = {2010}, author = {Nemoto, N and Udagawa, T and Ohira, T and Jiang, L and Hirota, K and Wilkinson, CR and Bähler, J and Jones, N and Ohta, K and Wek, RC and Asano, K}, title = {The roles of stress-activated Sty1 and Gcn2 kinases and of the protooncoprotein homologue Int6/eIF3e in responses to endogenous oxidative stress during histidine starvation.}, journal = {Journal of molecular biology}, volume = {404}, number = {2}, pages = {183-201}, pmid = {20875427}, issn = {1089-8638}, support = {P20 RR016475/RR/NCRR NIH HHS/United States ; R01 GM049164/GM/NIGMS NIH HHS/United States ; P20 GM103418/GM/NIGMS NIH HHS/United States ; GM67481/GM/NIGMS NIH HHS/United States ; 12485/CRUK_/Cancer Research UK/United Kingdom ; GM49164/GM/NIGMS NIH HHS/United States ; }, mesh = {Activating Transcription Factor 1/genetics/metabolism ; Amitrole/pharmacology ; Base Sequence ; DNA, Fungal/genetics ; Eukaryotic Initiation Factor-3/genetics/*metabolism ; Feedback, Physiological ; Gene Expression Regulation, Fungal ; Genes, Fungal ; Histidine/*metabolism ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/genetics/*metabolism ; Models, Biological ; Mutation ; Oxidative Stress ; Phosphoproteins/genetics/metabolism ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Schizosaccharomyces/drug effects/genetics/metabolism ; Schizosaccharomyces pombe Proteins/genetics/*metabolism ; Transcription, Genetic ; }, abstract = {In fission yeast, Sty1 and Gcn2 are important protein kinases that regulate gene expression in response to amino acid starvation. The translation factor subunit Int6/eIF3e promotes Sty1-dependent response by increasing the abundance of Atf1, a transcription factor targeted by Sty1. While Gcn2 promotes expression of amino acid biosynthesis enzymes, the mechanism and function of Sty1 activation and Int6/eIF3e involvement during this nutrient stress are not understood. Here we show that mutants lacking sty1(+) or gcn2(+) display reduced viabilities during histidine depletion stress in a manner suppressible by the antioxidant N-acetyl cysteine, suggesting that these protein kinases function to alleviate endogenous oxidative damage generated during nutrient starvation. Int6/eIF3e also promotes cell viability by a mechanism involving the stimulation of Sty1 response to oxidative damage. In further support of these observations, microarray data suggest that, during histidine starvation, int6Δ increases the duration of Sty1-activated gene expression linked to oxidative stress due to the initial attenuation of Sty1-dependent transcription. Moreover, loss of gcn2 induces the expression of a new set of genes not activated in wild-type cells starved for histidine. These genes encode heatshock proteins, redox enzymes, and proteins involved in mitochondrial maintenance, in agreement with the idea that oxidative stress is imposed on gcn2Δ cells. Furthermore, early Sty1 activation promotes rapid Gcn2 activation on histidine starvation. These results suggest that Gcn2, Sty1, and Int6/eIF3e are functionally integrated and cooperate to respond to oxidative stress generated during histidine starvation.}, }
@article {pmid20868670, year = {2010}, author = {Oh, DH and Bang, JS and Choi, HM and Yang, HI and Yoo, MC and Kim, KS}, title = {Fetal bovine serum requirement for pyrrolidine dithiocarbamate-induced apoptotic cell death of MCF-7 breast tumor cells.}, journal = {European journal of pharmacology}, volume = {649}, number = {1-3}, pages = {135-139}, doi = {10.1016/j.ejphar.2010.09.048}, pmid = {20868670}, issn = {1879-0712}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Blood Proteins/*metabolism ; Breast Neoplasms/*drug therapy/pathology ; Cattle ; Cell Line, Tumor ; Cell Survival/drug effects ; Chelating Agents/pharmacology ; Culture Media/chemistry ; Dialysis ; Enzyme Inhibitors/pharmacology ; Female ; Fetal Blood/*chemistry ; Humans ; NF-kappa B/antagonists &amp; inhibitors ; Proteasome Inhibitors ; Pyrrolidines/*pharmacology ; Serum/chemistry ; Thiocarbamates/*pharmacology ; Zinc/metabolism ; }, abstract = {Pyrrolidine dithiocarbamate (PDTC) can form a complex with metal ions and then act as a proteasome inhibitor, which leads to tumor cell apoptosis, and could therefore be developed as an anticancer agent. In our efforts to find factors that induce PDTC-mediated apoptosis of tumor cells, the effect of serum concentration on the apoptotic activity of PDTC was investigated. PDTC could not induce MCF-7 breast tumor cell death in serum-free media but significantly induced cell death in a dose-dependent manner at concentrations of ≥25 μM in media containing 10% fetal bovine serum. PDTC-mediated cell death was also dependent on serum concentration. PDTC-mediated cell death occurred through apoptosis. Similar to that in normal FBS, PDTC-mediated apoptotic cell death was also induced in media containing dialyzed FBS, indicating that PDTC-mediated apoptosis does not require metal ions or salts, but rather proteins in fetal bovine serum. In addition, differential apoptotic effects of PDTC were not observed with inhibitors of NF-κB activation such as N-acetylcysteine (NAC), Fenofibrate and carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal (MG132) or with the metal-binding agent, 5-chloro-7-iodo-8-hydroxyquinoline (Clioquinol). These results indicate that serum is required for PDTC-mediated apoptosis and that zinc-binding compounds such as PDTC, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and Clioquinol may each have their own mechanisms by which they induce tumor cell death, even though they are all classified as zinc-binding compounds.}, }
@article {pmid20868666, year = {2010}, author = {Choy, KH and Dean, O and Berk, M and Bush, AI and van den Buuse, M}, title = {Effects of N-acetyl-cysteine treatment on glutathione depletion and a short-term spatial memory deficit in 2-cyclohexene-1-one-treated rats.}, journal = {European journal of pharmacology}, volume = {649}, number = {1-3}, pages = {224-228}, doi = {10.1016/j.ejphar.2010.09.035}, pmid = {20868666}, issn = {1879-0712}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Behavior, Animal/drug effects ; Cerebrum/*drug effects/*metabolism ; Corpus Striatum/drug effects/metabolism ; Cyclohexanones/toxicity ; Dose-Response Relationship, Drug ; Exploratory Behavior/drug effects ; Frontal Lobe/drug effects/metabolism ; Glutathione/*metabolism ; Hippocampus/drug effects/metabolism ; Male ; Memory Disorders/chemically induced/*prevention &amp; control ; Memory, Short-Term/drug effects ; Neurons/drug effects/metabolism ; Neuroprotective Agents/therapeutic use ; Oxidative Stress/*drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Schizophrenia/drug therapy ; }, abstract = {Glutathione (GSH) is the primary antioxidant in the body and is present in high levels in the brain. Levels of GSH and other antioxidants are significantly altered in major psychiatric illnesses, such as schizophrenia. Recent clinical trials have demonstrated that chronic treatment with N-acetyl-l-cysteine (NAC), a GSH precursor, improved symptoms in individuals with this illness. We previously showed in rats and mice that depletion of GSH by treatment with 2-cyclohexene-1-one (CHX) induced short-term spatial memory deficits in the Y-maze test. The aim of present study was to characterise the effect of NAC in this CHX-induced glutathione depletion model. Consistent with our previous studies, CHX treatment induced approximately 50% reduction of GSH levels in striatum, hippocampus and frontal cortex tissue. GSH depletion was significantly rescued by either 1.2 g/kg or 1.6 g/kg of NAC administration, with a full recovery observed in the frontal cortex after the high dose of NAC. CHX treatment also induced a disruption in short-term spatial recognition memory in Y-maze test, as measured by the duration of time spent in the novel arm. This disruption was reversed by treatment with 1.6 g/kg of NAC. In conclusion, this study suggests that rescue of depleted levels of GSH in the brain restores cognitive deficits, as measured by the Y-maze. These effects appear to be dose-dependent and region-specific. These results may be relevant to the understanding and management of the cognitive symptoms of schizophrenia and bipolar disorder.}, }
@article {pmid20868662, year = {2011}, author = {Cheng, J and Wang, F and Yu, DF and Wu, PF and Chen, JG}, title = {The cytotoxic mechanism of malondialdehyde and protective effect of carnosine via protein cross-linking/mitochondrial dysfunction/reactive oxygen species/MAPK pathway in neurons.}, journal = {European journal of pharmacology}, volume = {650}, number = {1}, pages = {184-194}, doi = {10.1016/j.ejphar.2010.09.033}, pmid = {20868662}, issn = {1879-0712}, mesh = {Animals ; Apoptosis/drug effects ; Carnosine/*pharmacology ; Cells, Cultured ; Cerebral Cortex/cytology ; Cross-Linking Reagents/toxicity ; Dose-Response Relationship, Drug ; MAP Kinase Signaling System/*drug effects ; Malondialdehyde/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Necrosis/chemically induced ; Neurons/cytology/*drug effects/metabolism ; Proteins/chemistry/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {The accumulation of malondialdehyde (MDA), a lipid peroxidation by-product that has been used as an indicator of cellular oxidation status, is significantly increased in many neurological diseases such as brain ischemia/reperfusion, Alzheimer's disease and Parkinson's disease in vivo. In the present study, we found that MDA treatment in vitro reduced cortical neuronal viability in a time- and dose-dependent manner and induced cellular apoptosis as well as necrosis simultaneously. Furthermore, exposure to MDA led to accumulation of intracellular reactive oxygen species, dysfunction of mitochondria (denoted by the loss of mitochondrial transmembrane potential (Δψm)) and activation of JNK and ERK. Carnosine exhibited better protection against MDA-induced cell injury than antioxidant N-acetyl-cysteine (NAC) with its multi-potency, which alleviated MDA-induced protein cross-linking, Δψm decrease, reactive oxygen species burst, JNK and ERK activation. In conclusion, our results suggest that MDA induced cell injury in vitro via protein cross-linking and successive mitochondrial dysfunction, and the activation of reactive oxygen species-dependent MAPK signaling pathway. Carnosine alleviated all these alterations induced by MDA, but NAC merely inhibited Bcl-2 family-related activation of JNK and ERK. These results prompt the possibility that carnosine, but not other conventional antioxidants, can protect neurons against MDA-induced injury through decomposition of protein cross-linking toxicity and may serve as a novel agent in the treatment of neurodegenerative diseases.}, }
@article {pmid20868637, year = {2011}, author = {Berk, M and Munib, A and Dean, O and Malhi, GS and Kohlmann, K and Schapkaitz, I and Jeavons, S and Katz, F and Anderson-Hunt, M and Conus, P and Hanna, B and Otmar, R and Ng, F and Copolov, DL and Bush, AI}, title = {Qualitative methods in early-phase drug trials: broadening the scope of data and methods from an RCT of N-acetylcysteine in schizophrenia.}, journal = {The Journal of clinical psychiatry}, volume = {72}, number = {7}, pages = {909-913}, doi = {10.4088/JCP.09m05741yel}, pmid = {20868637}, issn = {1555-2101}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Data Collection/*methods/*statistics &amp; numerical data ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Schizophrenia/diagnosis/*drug therapy ; *Schizophrenic Psychology ; }, abstract = {OBJECTIVE: The pharmacokinetic profile of a drug often gives little indication of its potential therapeutic application, with many therapeutic uses of drugs being discovered serendipitously while being studied for different indications. As hypothesis-driven, quantitative research methodology is exclusively used in early-phase trials, unexpected but important phenomena may escape detection. In this context, this study aimed to examine the potential for integrating qualitative research methods with quantitative methods in early-phase drug trials. To our knowledge, this mixed methodology has not previously been applied to blinded psychopharmacologic trials.<br><br>METHOD: We undertook qualitative data analysis of clinical observations on the dataset of a randomized, double-blind, placebo-controlled trial of N-acetylcysteine (NAC) in patients with DSM-IV-TR-diagnosed schizophrenia (N = 140). Textual data on all participants, deliberately collected for this purpose, were coded using NVivo 2, and emergent themes were analyzed in a blinded manner in the NAC and placebo groups. The trial was conducted from November 2002 to July 2005.<br><br>RESULTS: The principal findings of the published trial could be replicated using a qualitative methodology. In addition, significant differences between NAC- and placebo-treated participants emerged for positive and affective symptoms, which had not been captured by the rating scales utilized in the quantitative trial. Qualitative data in this study subsequently led to a positive trial of NAC in bipolar disorder.<br><br>CONCLUSIONS: The use of qualitative methods may yield broader data and has the potential to complement traditional quantitative methods and detect unexpected efficacy and safety signals, thereby maximizing the findings of early-phase clinical trial research.<br><br>TRIAL REGISTRATION: www.anzctr.org.au Identifier: ACTRN12605000363684.}, }
@article {pmid20868226, year = {2010}, author = {Ale-Agha, N and Albrecht, C and Klotz, LO}, title = {Loss of gap junctional intercellular communication in rat lung epithelial cells exposed to carbon or silica-based nanoparticles.}, journal = {Biological chemistry}, volume = {391}, number = {11}, pages = {1333-1339}, doi = {10.1515/BC.2010.133}, pmid = {20868226}, issn = {1437-4315}, mesh = {Animals ; *Carbon/toxicity ; *Cell Communication/drug effects ; Cells, Cultured ; Connexin 43/metabolism ; Connexins/metabolism ; Epithelial Cells/metabolism/ultrastructure ; ErbB Receptors/metabolism ; *Gap Junctions/drug effects/metabolism ; Isoquinolines ; Lung/cytology/metabolism ; Nanoparticles/toxicity ; Phosphorylation ; Rats ; *Silicon Dioxide/toxicity ; beta Catenin/metabolism ; }, abstract = {The aim of this study was to investigate whether fine and ultrafine carbon black (fC and ufC), and fine and ultrafine silica (fS, ufS) particles affect gap junctional intercellular communication (GJIC) in rat lung epithelial cells. Exposure of cells to subcytotoxic doses of ufC, fS and ufS resulted in a 63%, 59% and 77% reduction of GJIC, respectively, as determined in a dye transfer assay. In contrast to ufC, fC did not significantly alter GJIC. Changes in subcellular localization of the major gap junction protein in RLE cells, connexin-43 (Cx43), and of β-catenin were observed in cells exposed to ufC, fS or ufS. The loss of GJIC was counteracted by N-acetyl cysteine and was largely prevented by specific inhibitors of epidermal growth factor receptor-dependent signaling, pointing to the crucial role of two known major mediators of nanoparticle action, namely reactive oxygen species and membrane-receptor signaling, in particle-induced modulation of GJIC.}, }
@article {pmid20862407, year = {2010}, author = {Yamada, M and Kubo, K and Ueno, T and Iwasa, F and Att, W and Hori, N and Ogawa, T}, title = {Alleviation of commercial collagen sponge- and membrane-induced apoptosis and dysfunction in cultured osteoblasts by an amino acid derivative.}, journal = {The International journal of oral &amp; maxillofacial implants}, volume = {25}, number = {5}, pages = {939-946}, pmid = {20862407}, issn = {0882-2786}, mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Bone Regeneration ; Cells, Cultured ; Collagen/*adverse effects ; Cysteine/analogs &amp; derivatives/*pharmacology ; Guided Tissue Regeneration, Periodontal ; Male ; Membranes, Artificial ; Osteoblasts/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {PURPOSE: The objectives of this in vitro study were to determine whether the commercial collagen material used in bone augmentation procedures induces oxidative stress-mediated adverse effects on the viability and function of osteoblasts and to determine whether N-acetyl cysteine (NAC), an antioxidant amino acid derivative, can alleviate these effects.<br><br>MATERIALS AND METHODS: Commercial collagen sponge (Collaplug) and membrane (BioGide) were treated with NAC. Rat calvaria-derived osteoblasts were directly seeded on these materials with or without NAC pretreatment. Cytotoxic evaluation was performed by flowcytometric cell viability assay, confocal laser microscopic analysis of attached cell morphology and reactive oxygen species (ROS) localization, and alkaline phosphatase staining.<br><br>RESULTS: Cell viability was less than 40% on both collagen sponge and membrane 24 hours after seeding and increased to 50% with NAC pretreatment. Cell death was characterized by apoptosis. Colonization of attached cells was sparse on the untreated sponge and membrane on day 1, and the cells were round, small, and filled with intense and closely packed intracellular ROS. In contrast, NAC-pretreated material had dense cell colonies consisting of well-spread osteoblasts and fully developing cytoskeleton and cellular processes with little ROS generation. On day 7 of culture, NAC-pretreated collagen sponge and membrane yielded an expanded alkaline phosphatase-positive area occupying 60% and 80% of the surface area, respectively, whereas the untreated collagen materials had limited alkaline phosphatase activity (7% or less).<br><br>CONCLUSIONS: Commercial collagen sponge and membrane induced considerable cell death, impaired initial function, and generated extraordinary intracellular ROS in attached osteoblasts, whereas NAC pretreatment substantially ameliorated these effects. The potential benefits of NAC's detoxifying capacity on bone regeneration using collagen matrix materials in an animal model should be confirmed with further study.}, }
@article {pmid20862209, year = {2010}, author = {Lindauer, M and Wong, J and Magun, B}, title = {Ricin Toxin Activates the NALP3 Inflammasome.}, journal = {Toxins}, volume = {2}, number = {6}, pages = {1500-1514}, pmid = {20862209}, issn = {2072-6651}, support = {R01 AI059335-03/AI/NIAID NIH HHS/United States ; R01 AI059335-02/AI/NIAID NIH HHS/United States ; R01 AI059335-05/AI/NIAID NIH HHS/United States ; R21 AI059355/AI/NIAID NIH HHS/United States ; R01 AI059335-04/AI/NIAID NIH HHS/United States ; R01 AI059335-01/AI/NIAID NIH HHS/United States ; T32 GM071338/GM/NIGMS NIH HHS/United States ; R01 AI059335-05S1/AI/NIAID NIH HHS/United States ; }, abstract = {Ricin exhibits well characterized ribotoxic actions that lead to the inhibition of protein synthesis and the phosphorylation of stress activated protein kinases (SAPKs). Proinflammatory effects of ricin are thought to be caused by upregulation of genes encoding proinflammatory transcripts as a result of the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We reported previously that macrophages and interleukin-1β (IL-1β) signaling are required for murine host immune responses to ricin delivered to the lungs. Here we report that ricin-mediated IL-1β release from bone-marrow derived macrophages is dependent on the NALP3 inflammasome, a scaffolding complex that mediates pro-IL-1β cleavage to active IL-1β by caspase-1. Release of IL-1β from macrophages was suppressed by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and high extracellular K(+), which are two agents known to inhibit NALP3/cryopyrin/CIAS1 inflammasome formation. By employing inhibitors of p38 MAPK and JNK, we demonstrated that ricin-mediated release of IL-1β was enhanced, rather than suppressed, by inhibition of SAPK phosphorylation. In contrast, proteasomal inhibitors bortezomib and MG-132 completely suppressed ricin-induced IL-1β release from macrophages. These data suggest that ricin-mediated translational inhibition itself, by fostering the disappearance of labile protein(s) that normally suppress inflammasome formation, may constitute the mechanism underlying IL-1-dependent inflammatory signaling by ricin.}, }
@article {pmid20860660, year = {2010}, author = {Youl, E and Bardy, G and Magous, R and Cros, G and Sejalon, F and Virsolvy, A and Richard, S and Quignard, JF and Gross, R and Petit, P and Bataille, D and Oiry, C}, title = {Quercetin potentiates insulin secretion and protects INS-1 pancreatic β-cells against oxidative damage via the ERK1/2 pathway.}, journal = {British journal of pharmacology}, volume = {161}, number = {4}, pages = {799-814}, pmid = {20860660}, issn = {1476-5381}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Line ; Glucose/metabolism ; Glyburide/pharmacology ; Hydrogen Peroxide/toxicity ; Hypoglycemic Agents/pharmacology ; Insulin/*metabolism ; Insulin Secretion ; Insulin-Secreting Cells/*drug effects/metabolism ; Male ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Quercetin/*pharmacology ; Rats ; Rats, Wistar ; Resveratrol ; Signal Transduction/drug effects ; Stilbenes/pharmacology ; }, abstract = {BACKGROUND AND PURPOSE: Quercetin lowers plasma glucose, normalizes glucose tolerance tests and preserves pancreatic β-cell integrity in diabetic rats. However, its mechanism of action has never been explored in insulin-secreting β-cells. Using the INS-1 β-cell line, the effects of quercetin were determined on glucose- or glibenclamide-induced insulin secretion and on β-cell dysfunctions induced by hydrogen peroxide (H(2)O(2)). These effects were analysed along with the activation of the extracellular signal-regulated kinase (ERK)1/2 pathway. N-acetyl-L-cysteine (NAC) and resveratrol, two antioxidants also known to exhibit some anti-diabetic properties, were used for comparison.<br><br>EXPERIMENTAL APPROACH: Insulin release was quantified by the homogeneous time resolved fluorescence method and ERK1/2 activation tested by Western blot experiments. Cell viability was estimated by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) colorimetric assay. KEY RESULTS Quercetin (20 &#xb5;mol&#xb7;L(-1)) potentiated both glucose (8.3 mmol&#xb7;L(-1))- and glibenclamide (0.01 &#xb5;mol&#xb7;L(-1))-induced insulin secretion and ERK1/2 phosphorylation. The ERK1/2 (but not the protein kinase A) signalling pathway played a crucial role in the potentiation of glucose-induced insulin secretion by quercetin. In addition, quercetin (20 &#xb5;mol&#xb7;L(-1)), protected &#x3b2;-cell function and viability against oxidative damage induced by 50 &#xb5;mol&#xb7;L(-1) H(2)O(2) and induced a major phosphorylation of ERK1/2. In the same conditions, resveratrol or NAC were ineffective.<br><br>CONCLUSION AND IMPLICATIONS: Quercetin potentiated glucose and glibenclamide-induced insulin secretion and protected &#x3b2;-cells against oxidative damage. Our study suggested that ERK1/2 played a major role in those effects. The potential of quercetin in preventing &#x3b2;-cell dysfunction associated with diabetes deserves further investigation.}, }
@article {pmid20857257, year = {2011}, author = {Offerman, SR}, title = {The clinical management of acetaminophen poisoning in a community hospital system: factors associated with hospital length of stay.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {7}, number = {1}, pages = {4-11}, pmid = {20857257}, issn = {1937-6995}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/therapeutic use ; Administration, Oral ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*administration &amp; dosage/therapeutic use ; California ; Chemical and Drug Induced Liver Injury/mortality/*prevention &amp; control ; Cohort Studies ; Drug Overdose ; Female ; *Hospitals, Community ; Humans ; Infusions, Intravenous ; *Length of Stay ; Male ; Medical Records ; Poison Control Centers/statistics &amp; numerical data ; *Practice Patterns, Physicians' ; Retrospective Studies ; }, abstract = {Acetaminophen (APAP) overdose is the most common pharmaceutical poisoning. The objective of this study was to examine the management of patients admitted for treatment of APAP overdose. Factors impacting hospital length of stay (LOS) were of particular interest. This was a retrospective cohort study of patients admitted to Kaiser Permanente Northern California hospitals for APAP overdose from July 2003 through December 2007. Medical records were abstracted for patient demographic data, key factors of overdose, California Poison Control System (CPCS) contact, data regarding hospital course, transfer for liver transplantation, and death. Four hundred thirty-five patients were included. The mean hospital LOS was 66.5 h (95% CI 62.1, 71.0). Four patients (0.9%) died. Eight patients (1.8%) were transferred for liver transplantation, but all of these patients later recovered without transplant. Of 289 cases eligible for placement on the Rumack-Matthew nomogram (acute ingestion with known time of ingestion <24 h and normal liver enzymes), 161 (55.7%) had APAP levels above the "200" line and 77 (26.6%) fell below the "150" line. CPCS was contacted in 295 cases (67.8%). Mean LOS in cases with CPCS consultation was 61.9 h (95% CI 57.2, 66.5 h) versus 76.3 h (95% CI 66.6, 86.0 h) in those without. LOS in cases treated with IV NAC was 67.1 h (95% CI 57.7, 76.5 h) versus 66.4 h (95% CI 61.2, 71.5 h) in cases treated with oral NAC. Many patients admitted for APAP overdose had serum APAP levels below the minimum toxicity level. Use of IV NAC did not impact hospital LOS. CPCS consultation appeared to decrease mean hospital LOS.}, }
@article {pmid20857196, year = {2011}, author = {Bagh, MB and Thakurta, IG and Biswas, M and Behera, P and Chakrabarti, S}, title = {Age-related oxidative decline of mitochondrial functions in rat brain is prevented by long term oral antioxidant supplementation.}, journal = {Biogerontology}, volume = {12}, number = {2}, pages = {119-131}, doi = {10.1007/s10522-010-9301-8}, pmid = {20857196}, issn = {1573-6768}, mesh = {*Aging/drug effects/physiology ; Animals ; *Antioxidants/administration &amp; dosage/metabolism/pharmacology ; Brain/cytology/metabolism ; *Dietary Supplements ; Electron Transport Chain Complex Proteins/metabolism ; Female ; Male ; *Mitochondria/drug effects/metabolism ; Oxidative Stress/*drug effects ; Protein Carbonylation ; Rats ; }, abstract = {A combination of antioxidants (N-acetyl cysteine, α-lipoic acid, and α-tocopherol) was selected for long term oral supplementation study in rats for protective effects on age-related mitochondrial alterations in the brain. Four groups of rats were chosen: young control (6-7 months); aged rats (22-24 months); aged rats (22-24 months) on daily antioxidant supplementation from 18 month onwards and young rats (6-7 months) on daily antioxidant supplementation from 2 month onwards. The brain mitochondrial functional parameters, status of antioxidant enzymes and accumulation of oxidative damage markers were measured in the four groups of rats. A significant decrease in complex IV activity and a loss of transmembrane potential and phosphorylation capacity along with an increased accumulation of oxidative damage markers and compromised antioxidant enzyme status were noticed in aged rat brain mitochondria as compared to that in young controls, but in aged rats supplemented with oral antioxidants the mitochondrial alterations were largely prevented. Antioxidant supplementation in young rats had no effect on mitochondrial parameters investigated in this study. The results have implications in biochemical and functional deficits of brain during aging as well as in neurodegenerative disorders.}, }
@article {pmid20857057, year = {2010}, author = {Capellini, VK and Baldo, CF and Celotto, AC and Batalhão, ME and Cárnio, EC and Rodrigues, AJ and Evora, PR}, title = {Oxidative stress is not associated with vascular dysfunction in a model of alloxan-induced diabetic rats.}, journal = {Arquivos brasileiros de endocrinologia e metabologia}, volume = {54}, number = {6}, pages = {530-539}, doi = {10.1590/s0004-27302010000600004}, pmid = {20857057}, issn = {1677-9487}, mesh = {Acetylcysteine/*pharmacology ; Alloxan ; Animals ; Aorta, Thoracic/drug effects/physiopathology ; Diabetes Mellitus, Experimental/drug therapy/*physiopathology ; Disease Models, Animal ; Endothelium, Vascular/*physiology ; Free Radical Scavengers/*pharmacology ; Male ; Malondialdehyde/blood ; Nitric Oxide/*physiology ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/blood ; Oxidative Stress/drug effects/*physiology ; Random Allocation ; Rats ; Rats, Wistar ; Time Factors ; }, abstract = {OBJECTIVES: To verify if an experimental model of alloxan-diabetic rats promotes oxidative stress, reduces nitric oxide bioavailability and causes vascular dysfunction, and to evaluate the effect of N-acetylcysteine (NAC) on these parameters.<br><br>METHODS: Alloxan-diabetic rats were treated or not with NAC for four weeks. Plasmatic levels of malondialdehyde (MDA) and nitrite/nitrate (NOx), the endothelial and inducible nitric oxide synthase (eNOS and iNOS) immunostaining and the vascular reactivity of aorta were compared among diabetic (D), treated diabetic (TD) and control (C) rats.<br><br>RESULTS: MDA levels increased in D and TD. NOx levels did not differ among groups. Endothelial eNOS immunostaining reduced and adventitial iNOS increased in D and TD. The responsiveness of rings to acetylcholine, sodium nitroprusside, and phenylephrine did not differ among groups.<br><br>CONCLUSIONS: NAC had no effect on the evaluated parameters and this experimental model did not promote vascular dysfunction despite the development of oxidative stress.}, }
@article {pmid20856173, year = {2011}, author = {Qin, X and Sheth, SU and Sharpe, SM and Dong, W and Lu, Q and Xu, D and Deitch, EA}, title = {The mucus layer is critical in protecting against ischemia-reperfusion-mediated gut injury and in the restitution of gut barrier function.}, journal = {Shock (Augusta, Ga.)}, volume = {35}, number = {3}, pages = {275-281}, pmid = {20856173}, issn = {1540-0514}, support = {T32 GM069330-05/GM/NIGMS NIH HHS/United States ; R01 GM059841-07/GM/NIGMS NIH HHS/United States ; T32 069330//PHS HHS/United States ; T32 GM069330-03/GM/NIGMS NIH HHS/United States ; R01 GM059841-09A1/GM/NIGMS NIH HHS/United States ; T32 GM069330-04/GM/NIGMS NIH HHS/United States ; R01 GM059841/GM/NIGMS NIH HHS/United States ; R01 GM059841-08/GM/NIGMS NIH HHS/United States ; GM 59841/GM/NIGMS NIH HHS/United States ; T32 GM069330/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Intestinal Mucosa/pathology/*physiology/physiopathology ; Male ; Mucus/*physiology ; Permeability ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*physiopathology ; }, abstract = {It is well documented that the gut injury plays a critical role in the development of systemic inflammation and distant organ injury in conditions associated with splanchnic ischemia. Consequently, understanding the mechanisms leading to gut injury is important. In this context, recent work suggests a protective role for the intestinal mucus layer and an injury-inducing role for luminal pancreatic proteases. Thus, we explored the role of the mucus layer in gut barrier function by observing how the removal of the mucus layer affects ischemia-reperfusion-mediated gut injury in rats as well as the potential role of luminal pancreatic proteases in the pathogenesis of gut injury. Ischemia was induced by the ligation of blood vessels to segments of the ileum for 45 min, followed by up to 3 h of reperfusion. The ileal segments were divided into five groups. These included a nonischemic control, ischemic segments exposed to saline, the mucolytic N-acetylcysteine (NAC), pancreatic proteases, or NAC + pancreatic proteases. Changes in gut barrier function were assessed by the permeation of fluorescein isothiocyanate dextran (molecular weight, 4,000 d) in ileal everted sacs. Gut injury was measured morphologically and by the luminal content of protein, DNA, and hemoglobin. The mucus layer was assessed functionally by measuring its hydrophobicity and morphologically. Gut barrier function was promptly and effectively reestablished during reperfusion, which was accompanied by the restoration of the mucus layer. In contrast, treatment of the gut with the mucolytic NAC for 10 min during ischemia resulted in a failure of mucus restitution and further increases in gut permeability and injury. The presence of digestive proteases by themselves did not exacerbate gut injury, but in combination with NAC, they caused an even greater increase in gut injury and permeability. These results suggest that the mucus layer not only serves as a barrier between the luminal contents and gut surface epithelia, but also plays a critical role in the maintenance and restitution of gut barrier function.}, }
@article {pmid20855591, year = {2010}, author = {North, TE and Babu, IR and Vedder, LM and Lord, AM and Wishnok, JS and Tannenbaum, SR and Zon, LI and Goessling, W}, title = {PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, number = {40}, pages = {17315-17320}, pmid = {20855591}, issn = {1091-6490}, support = {P01 CA026731/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; CA26731/CA/NCI NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; *Acetylcysteine/pharmacology/therapeutic use ; Analgesics, Non-Narcotic/toxicity ; Animals ; Animals, Genetically Modified ; *Chemical and Drug Induced Liver Injury/drug therapy/metabolism/pathology ; Dinoprostone/*metabolism ; Genes, Reporter ; Glutathione/metabolism ; Liver/drug effects/metabolism/pathology ; *Liver Failure, Acute/drug therapy/metabolism/pathology ; Proteome/analysis ; Signal Transduction/*physiology ; *Zebrafish/anatomy &amp; histology/physiology ; }, abstract = {Acetaminophen (APAP) toxicity is the most common drug-induced cause of acute liver failure in the United States. The only available treatment, N-acetylcysteine (NAC), has a limited time window of efficacy, indicating a need for additional therapeutic options. Zebrafish have emerged as a powerful tool for drug discovery. Here, we developed a clinically relevant zebrafish model of APAP toxicity. APAP depleted glutathione stores, elevated aminotransferase levels, increased apoptosis, and caused dose-dependent hepatocyte necrosis. These outcomes were limited by NAC and conserved in zebrafish embryos. In a targeted embryonic chemical screen, prostaglandin E2 (PGE2) was identified as a potential therapeutic agent; in the adult, PGE2 similarly decreased APAP-associated toxicity. Significantly, when combined with NAC, PGE2 extended the time window for a successful intervention, synergistically reducing apoptosis, improving liver enzymes, and preventing death. Use of a wnt reporter zebrafish line and chemical genetic epistasis showed that the effects of PGE2 are mediated through the wnt signaling pathway. Zebrafish can be used as a clinically relevant toxicological model amenable to the identification of additional therapeutics and biomarkers of APAP injury; our data suggest combinatorial PGE2 and NAC treatment would be beneficial for patients with APAP-induced liver damage.}, }
@article {pmid20849330, year = {2010}, author = {Hantson, P and Villa, A and Galloy, AC and Negri, S and Esabon, G and Lambiotte, F and Haufroid, V and Garnier, R}, title = {Dimethylformamide metabolism following self-harm using a veterinary euthanasia product.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {48}, number = {7}, pages = {725-729}, doi = {10.3109/15563650.2010.498790}, pmid = {20849330}, issn = {1556-9519}, mesh = {Acetylcysteine/therapeutic use ; Amides/*poisoning ; Dimethylformamide/*metabolism ; Drug Combinations ; Humans ; Male ; Middle Aged ; Quaternary Ammonium Compounds/*poisoning ; *Suicide ; Tetracaine/*poisoning ; Veterinarians ; }, abstract = {BACKGROUND: A veterinary euthanasia drug containing embutramide, mebezonium, tetracaine, and dimethylformamide (DMF; T-61® or Tanax®) may cause serious manifestations or even fatalities after self-poisoning. Immediate toxicity is mainly due to a general anesthetic and due to a neuromuscular blocking agent, while delayed hepatotoxicity seems related to the solvent DMF. The protective role of N-acetylcysteine (NAC) administration remains debatable.<br><br>MATERIAL AND METHODS: Two male veterinarians (50- and 44-year-old) attempted suicide by injecting T-61 in the precordial area for the first one, and by ingesting 50 mL for the second. Both received NAC (for 14 days in the first case and only for 20 h in the second). Urine was collected for the serial determination of DMF, N-methylformamide (NMF), and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC).<br><br>RESULTS: Both patients developed only mild signs of liver injury. The metabolite of DMF, NMF, appeared rapidly in the urine, while a further delay was necessary for AMCC excretion. The kinetics of elimination of DMF and DMF metabolites were slightly slower than those reported in exposed workers.<br><br>CONCLUSIONS: While both patients had a favorable outcome, there is no clear evidence that NAC could directly influence NMF and AMCC excretion. Further investigations of NMF and AMCC excretion, with and without NAC, would be indicated.}, }
@article {pmid20848084, year = {2011}, author = {Chuang, CY and Chen, TL and Cherng, YG and Tai, YT and Chen, TG and Chen, RM}, title = {Lipopolysaccharide induces apoptotic insults to human alveolar epithelial A549 cells through reactive oxygen species-mediated activation of an intrinsic mitochondrion-dependent pathway.}, journal = {Archives of toxicology}, volume = {85}, number = {3}, pages = {209-218}, doi = {10.1007/s00204-010-0585-x}, pmid = {20848084}, issn = {1432-0738}, mesh = {Acetylcysteine/metabolism ; Alveolar Epithelial Cells/metabolism ; Apoptosis/*physiology ; Caspase 6/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cell Survival ; Cells, Cultured ; Cytochromes c/metabolism ; DNA Fragmentation ; Enzyme Activation ; Epithelial Cells/drug effects ; Humans ; Lipopolysaccharides/*pharmacokinetics ; Membrane Potential, Mitochondrial ; Mitochondria/*metabolism/physiology ; Nitric Oxide/metabolism ; Pulmonary Alveoli/drug effects ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {Alveolar type II epithelial cells can regulate immune responses to sepsis-induced acute lung injury. Lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, can cause septic shock. This study was designed to evaluate the cytotoxic effects of LPS on human alveolar epithelial A549 cells and its possible molecular mechanisms. Exposure of A549 cells to LPS decreased cell viability in concentration- and time-dependent manners. In parallel, LPS concentration- and time-dependently induced apoptosis of A549 cells. Meanwhile, LPS only at a high concentration of 10 μg/ml caused mildly necrotic insults to A549 cells. In terms of the mechanism, exposure of A549 cells to LPS increased the levels of cellular nitric oxide and reactive oxygen species (ROS). Pretreatment with N-acetylcysteine (NAC), an antioxidant, significantly lowered LPS-caused enhancement of intracellular ROS in A549 cells and simultaneously attenuated the apoptotic insults. Sequentially, treatment of A549 cells with LPS caused significant decreases in the mitochondrial membrane potential and biosynthesis of adenosine triphosphate. In succession, LPS triggered the release of cytochrome c from the mitochondria to the cytoplasm. Activities of caspase-9 and caspase-6 were subsequently augmented following LPS administration. Consequently, exposure of A549 cells induced DNA fragmentation in a time-dependent manner. Pretreatment of A549 cells with NAC significantly ameliorated LPS-caused alterations in caspase-9 activation and DNA damage. Therefore, this study shows that LPS specifically induces apoptotic insults to human alveolar epithelial cells through ROS-mediated activation of the intrinsic mitochondrion-cytochrome c-caspase protease mechanism.}, }
@article {pmid20847117, year = {2011}, author = {Kubota, M and Shimmura, S and Kubota, S and Miyashita, H and Kato, N and Noda, K and Ozawa, Y and Usui, T and Ishida, S and Umezawa, K and Kurihara, T and Tsubota, K}, title = {Hydrogen and N-acetyl-L-cysteine rescue oxidative stress-induced angiogenesis in a mouse corneal alkali-burn model.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {52}, number = {1}, pages = {427-433}, doi = {10.1167/iovs.10-6167}, pmid = {20847117}, issn = {1552-5783}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Benzamides/pharmacology ; Blindness/prevention &amp; control ; Burns, Chemical/*drug therapy/metabolism/pathology ; Chemokine CCL2/metabolism ; Corneal Neovascularization/*drug therapy/metabolism/pathology ; Cyclohexanones/pharmacology ; Deuterium Oxide/administration &amp; dosage/*therapeutic use ; *Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Eye Burns/*chemically induced ; Male ; Mice ; Mice, Inbred ICR ; Mice, Knockout ; Microscopy, Fluorescence ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sodium Hydroxide/toxicity ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {PURPOSE: To investigate the role of reactive oxygen species (ROS) as the prime initiators of the angiogenic response after alkali injury of the cornea and observe the effects of antioxidants in preventing angiogenesis.<br><br>METHODS: The corneal epithelia of SOD-1-deficient mice or wild-type (WT) mice were removed after application of 0.15 N NaOH to establish the animal model of alkali burn. ROS production was semiquantitatively measured by dihydroethidium (DHE) fluorescence. Angiogenesis was visualized by CD31 immunohistochemistry. The effects of the specific NF-&#x3ba;B inhibitor DHMEQ, the antioxidant N-acetyl-L-cysteine (NAC), and hydrogen (H2) solution were observed.<br><br>RESULTS: ROS production in the cornea was enhanced immediately after alkali injury, as shown by increased DHE fluorescence (P<0.01). NF-&#x3ba;B activation and the upregulation of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) were significantly enhanced (P<0.01), leading to a significantly larger area of angiogenesis. Angiogenesis in SOD-1-/- mice corneas were significantly higher in WT mice (P<0.01), confirming the role of ROS. Pretreatment with the specific NF-&#x3ba;B inhibitor DHMEQ or the antioxidant NAC significantly reduced corneal angiogenesis by downregulating the NF-&#x3ba;B pathway (P<0.01) in both WT and SOD-1-/- mice. Furthermore, we showed that irrigation of the cornea with hydrogen (H2) solution significantly reduced angiogenesis after alkali-burn injury (P<0.01).<br><br>CONCLUSIONS: Immediate antioxidant therapy with H2-enriched irrigation solution is a new potent treatment of angiogenesis in cornea to prevent blindness caused by alkali burn.}, }
@article {pmid20846705, year = {2010}, author = {Lee, HG and Yang, JH}, title = {PKC-δ mediates TCDD-induced apoptosis of chondrocyte in ROS-dependent manner.}, journal = {Chemosphere}, volume = {81}, number = {8}, pages = {1039-1044}, doi = {10.1016/j.chemosphere.2010.08.045}, pmid = {20846705}, issn = {1879-1298}, mesh = {Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Chondrocytes/*drug effects/enzymology/metabolism ; Environmental Pollutants/*toxicity ; Enzyme Activation/drug effects ; Polychlorinated Dibenzodioxins/*toxicity ; Protein Kinase C-delta/*metabolism ; Rabbits ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {Exposure to dioxin-like compounds is associated with arthritis in humans. A recent study reported that 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) induces apoptosis in chondrocytes, which is a critical event in the pathogenesis of cartilage disease. In this study, protein kinase C (PKC) signaling pathway was investigated to determine the mechanism of TCDD-induced rabbit articular chondrocyte apoptosis. TCDD exposure induced glutathione-mediated ROS generation and the translocation of PKC isozymes. Among the PKC isozymes tested, PKC-δ showed the most sensitive translocation. The translocation was then blocked by ROS inhibitors (trolox and N-acetyl cysteine), a PKC-δ inhibitor (rottlerin), a caspase-3 inhibitor (z-DEVD-fmk) or an AhR blocker (α-naphthoflavone). TCDD increased caspase-3 activity, the activating enzyme for PKC-δ, and prior treatment with trolox blocked such an increase. These results suggest that the translocation of PKC-δ was mediated by ROS-dependent caspase-3 activity. Pretreatment with rottlerin or trolox dampened TCDD-induced apoptosis of chondrocyte, as determined by TUNEL staining and ELISA. Taken together, this study suggests that ROS generation is an upstream event for TCDD-induced chondrocyte apoptosis and PKC-δ mediates the apoptotic processes through ROS-dependent caspase-3 activation. This is a first finding demonstrating the role of PKC-δ in chondrocyte apoptosis stimulated by an environmental pollutant. The results may contribute to understanding the mechanism of joint disease associated with the exposure of dioxin-like compounds and identifying a target for the therapeutic interventions.}, }
@article {pmid20846156, year = {2010}, author = {Lee, SS and Tsai, CH and Yang, SF and Ho, YC and Chang, YC}, title = {Hypoxia inducible factor-1α expression in areca quid chewing-associated oral squamous cell carcinomas.}, journal = {Oral diseases}, volume = {16}, number = {7}, pages = {696-701}, doi = {10.1111/j.1601-0825.2010.01680.x}, pmid = {20846156}, issn = {1601-0825}, mesh = {Acetylcysteine/pharmacology ; *Areca/adverse effects ; Arecoline/pharmacology ; Blotting, Western ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors ; Carcinoma, Squamous Cell/etiology/*pathology ; Cell Line ; Cholinergic Agonists/pharmacology ; Curcumin/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/drug effects/pathology ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*analysis/drug effects ; Immunohistochemistry ; Mouth Mucosa/drug effects/*pathology ; Mouth Neoplasms/etiology/*pathology ; Protein Kinase C/antagonists &amp; inhibitors ; Staurosporine/pharmacology ; Time Factors ; Transcription Factor AP-1/antagonists &amp; inhibitors ; }, abstract = {OBJECTIVES: Hypoxia inducible factor (HIF)-1α gene expression is mainly induced by tissue hypoxia. Overexpression of HIF-1α has been demonstrated in a variety of cancers. The aim of this study was to compare HIF-1α expression in normal human oral epithelium and areca quid chewing-associated oral squamous cell carcinoma (OSCC) and further to explore the potential mechanisms that may lead to induce HIF-1α expression.<br><br>METHODS: Twenty-five OSCC from areca quid chewing-associated OSCC and 10 normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, glutathione precursor N-acetyl-l-cysteine (NAC), AP-1 inhibitor curcumin, extracellular signal-regulated protein kinase inhibitor PD98059, and protein kinase C inhibitor staurosporine were added to find the possible regulatory mechanisms.<br><br>RESULTS: Hypoxia inducible factor-1&#x3b1; expression was significantly higher in OSCC specimens than normal specimen (P<0.05). Arecoline was found to elevate HIF-1&#x3b1; expression in a dose- and time-dependent manner (P<0.05). The addition of NAC, curcumin, PD98059, and staurosporine markedly inhibited the arecoline-induced HIF-1&#x3b1; expression (P<0.05).<br><br>CONCLUSIONS: Hypoxia inducible factor-1&#x3b1; expression is significantly upregulated in areca quid chewing-associated OSCC and HIF-1&#x3b1; expression induced by arecoline is downregulated by NAC, curcumin, PD98059, and staurosporine.}, }
@article {pmid20845026, year = {2011}, author = {Ozyilmaz, E and Ebinc, FA and Derici, U and Gulbahar, O and Goktas, G and Elmas, C and Oguzulgen, IK and Sindel, S}, title = {Could nephrotoxicity due to colistin be ameliorated with the use of N-acetylcysteine?.}, journal = {Intensive care medicine}, volume = {37}, number = {1}, pages = {141-146}, pmid = {20845026}, issn = {1432-1238}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Bacterial Agents/*toxicity ; Colistin/*toxicity ; Female ; Kidney Diseases/*chemically induced/metabolism/*prevention &amp; control ; Lung/metabolism ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; }, abstract = {PURPOSE: The protective effect of N-acetylcysteine (NAC) on nephrotoxicity due to contrast nephropathy and reperfusion-induced ischemia has been reported in experimental models. However, its efficacy on colistin-induced nephrotoxicity has not been elucidated yet. The primary aim of this study was to evaluate the nephrotoxic effect of colistin and to investigate the possible protective effect of NAC on colistin-induced nephrotoxicity. The secondary aim was to research the systemic effects of nephrotoxicity-induced oxidative stress on the lung.<br><br>METHODS: Eighteen female Sprague-Dawley rats were randomly assigned and were given (a) 1 ml/kg sterile saline, (b) 300,000 IU/kg/day colistin, and (c) 300,000 IU/kg/day colistin and 150 mg/kg NAC for six consecutive days.<br><br>RESULTS: Plasma blood urea nitrogen (BUN), creatinine, urinary creatinine, urinary protein, plasma TNF-alpha levels, renal tissue superoxide dismutase (SOD) and malondialdehyde (MDA) activity and immunocytochemical findings were evaluated. Colistin exerted nephrotoxicity and achieved a significant increase in plasma BUN and creatinine levels and renal tissue SOD levels. NAC exhibited no significant effect on biochemical parameters but reduced renal tissue SOD level and reversed immunocytochemical staining of inducible nitric oxide synthase (i-NOS) and neurotrophin-3. Increased oxidative stress in the lung tissue of the rats treated with colistin has also been documented. Additionally, NAC significantly reduced the immunostaining of endothelial NOS (e-NOS) and i-NOS in the lung tissue.<br><br>CONCLUSIONS: Colistin-induced renal toxicity may be attributable to oxidative damage. The combined treatment of colistin plus NAC seems to have a beneficial role in restoration of the oxidant injury which may be related to its antioxidant effect.}, }
@article {pmid20840847, year = {2010}, author = {Chang, H and Lin, H and Yi, L and Zhu, J and Zhou, Y and Mi, M and Zhang, Q}, title = {3,6-Dihydroxyflavone induces apoptosis in leukemia HL-60 cell via reactive oxygen species-mediated p38 MAPK/JNK pathway.}, journal = {European journal of pharmacology}, volume = {648}, number = {1-3}, pages = {31-38}, doi = {10.1016/j.ejphar.2010.08.020}, pmid = {20840847}, issn = {1879-0712}, mesh = {Apoptosis/*drug effects ; Caspases/metabolism ; Flavonoids/*pharmacology ; Glutathione/metabolism ; HL-60 Cells ; Humans ; Intracellular Space/drug effects/metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Leukemia/*pathology ; Lipid Peroxidation/drug effects ; MAP Kinase Signaling System/*drug effects ; Membrane Fluidity/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {We have previously selected a promising anti-cancer agent 3,6-dihydroxyflavone by pharmacodynamic experiments. In the present study, we investigated its pro-apoptosis mechanisms in leukemia HL-60 cell. Our data revealed that 3,6-dihydroxyflavone dose- and time-dependently decreases cell viability and induces apoptosis by activating caspase cascade, cleaving poly (ADP-ribose) polymerase (PARP). The anti-cancer effects of 3,6-dihydroxyflavone are associated with the generation of reactive oxygen species, the altered glutathione-redox balance as significantly decreased glutathione (GSH) and its ratio to gluthatione disulfide (GSSG), and the accumulation of lipid peroxidation indicator malondialdehyde. Addition of antioxidant N-acetylcysteine (NAC) prevents the elevation of reactive oxygen species induced by 3,6-dihydroxyflavone and partially suppresses the cytotoxic effects. Furthermore, 3,6-dihydroxyflavone reduces cell membrane fluidity and induces the loss of mitochondrial membrane potential. 3,6-Dihydroxyflavone was also found to modulate the activities of mitogen-activated protein kinase (MAPK) family members, which includes increased protein kinase of 38 kDa (p38), c-Jun N-terminal kinase (JNK), and decreased extracellular signal-regulated kinase (ERK) activation. The effect of 3,6-dihydroxyflavone on MAPKs pathway could be abrogated by co-treatment with NAC. Taking together, our data suggested that 3,6-dihydroxyflavone increases intracellular oxidative stress and lipid peroxidation, thereby affecting the physical and functional properties of plasma membrane, as well as MAPKs signal pathway, which are likely to play a role in the 3,6-dihydroxyflavone-induced HL-60 cell cytotoxicities.}, }
@article {pmid20838280, year = {2010}, author = {Sagara, J and Bannai, S and Shikano, N and Makino, N}, title = {Conflicting effects of N-acetylcysteine on purified neurons derived from rat cortical culture.}, journal = {Neuroreport}, volume = {21}, number = {6}, pages = {416-421}, doi = {10.1097/WNR.0b013e328337765c}, pmid = {20838280}, issn = {1473-558X}, mesh = {Acetylcysteine/therapeutic use/*toxicity ; Animals ; Antioxidants/therapeutic use/*toxicity ; Cell Culture Techniques ; Cell Death/drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Female ; Neurodegenerative Diseases/*drug therapy/metabolism/pathology ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/therapeutic use/*toxicity ; Oxidative Stress/*drug effects/physiology ; Rats ; }, abstract = {We examined the protective effects of N-acetylcysteine (NAC) on the death of glia-free neurons in culture. Under normoxic conditions, the protection by NAC was observed only in cystine-free but not complete medium. When the cells were cultured under hypoxic conditions, NAC much elongated their survival even in the presence of cystine. H2O2 was found to be generated to considerable concentration in the presence of both NAC and cystine, and the administration of catalase prevented the cell death. These results suggest that the harmful effect of NAC is because of H2O2 generated by autoxidation of cysteine, which derives from the reaction between NAC and cystine. The present results raise the possibility that NAC can act as either antioxidant or prooxidant depending on the milieu.}, }
@article {pmid20836655, year = {2010}, author = {Lu, T and Parthasarathy, S and Hao, H and Luo, M and Ahmed, S and Zhu, J and Luo, S and Kuppusamy, P and Sen, CK and Verfaillie, CM and Tian, J and Liu, Z}, title = {Reactive oxygen species mediate oxidized low-density lipoprotein-induced inhibition of oct-4 expression and endothelial differentiation of bone marrow stem cells.}, journal = {Antioxidants &amp; redox signaling}, volume = {13}, number = {12}, pages = {1845-1856}, pmid = {20836655}, issn = {1557-7716}, support = {R01 HL094650/HL/NHLBI NIH HHS/United States ; GM077185/GM/NIGMS NIH HHS/United States ; R01 HL073087/HL/NHLBI NIH HHS/United States ; R01 GM069589/GM/NIGMS NIH HHS/United States ; GM069589/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Cell Differentiation/*drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Electron Spin Resonance Spectroscopy ; *Endothelial Cells/cytology/drug effects ; Flow Cytometry ; Gene Expression Regulation/*drug effects ; Humans ; Lipoproteins, LDL/*pharmacology ; *Multipotent Stem Cells/cytology/drug effects ; Octamer Transcription Factor-3/*metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {This study was to test the hypothesis that oxidized low-density lipoprotein (ox-LDL) modified the behavior of bone marrow stem cells, including proliferation, Oct-4 expression, and their endothelial differentiation through reactive oxygen species (ROS) formation in vitro. Rat bone marrow multipotent adult progenitor cells (MAPCs) were treated with ox-LDL with or without the antioxidant N-acetylcysteine (NAC). Ox-LDL generated a significant amount of ROS in the culture system as measured with electron paramagnetic resonance spectroscopy, and substantially inhibited the proliferation, Oct-4 expression, and endothelial differentiation of MAPCs. ROS production from ox-LDL in the culture system was completely prevented by NAC (1 mM). NAC treatment completely restored endothelial differentiation potential of MAPCs that was diminished by low-dose ox-LDL. NAC also significantly, but not completely, reversed the inhibitory effect of ox-LDL on proliferation and Oct-4 expression in MAPCs. NAC treatment only slightly restored Akt phosphorylation impaired by ox-LDL in the cells. ROS formation was important in the action of ox-LDL on MAPCs, including Oct-4 expression, proliferation, and endothelial differentiation. However, other mechanism(s) like Akt signaling and apoptosis might also play a critical role in mediating the effect of ox-LDL on these cells.}, }
@article {pmid20835244, year = {2010}, author = {Chuikov, S and Levi, BP and Smith, ML and Morrison, SJ}, title = {Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress.}, journal = {Nature cell biology}, volume = {12}, number = {10}, pages = {999-1006}, pmid = {20835244}, issn = {1476-4679}, support = {R01 NS040750/NS/NINDS NIH HHS/United States ; P30 CA046592/CA/NCI NIH HHS/United States ; NS40750/NS/NINDS NIH HHS/United States ; R01 NS040750-11/NS/NINDS NIH HHS/United States ; P30 AR48310/AR/NIAMS NIH HHS/United States ; CA46592/CA/NCI NIH HHS/United States ; P30 AR048310/AR/NIAMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Adult Stem Cells/cytology/metabolism ; Animals ; Cell Cycle ; Cell Death ; Cell Survival ; Cells, Cultured ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Fetal Stem Cells/cytology/metabolism ; Hematopoietic Stem Cells/cytology/metabolism ; Hepatocyte Growth Factor/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Nervous System/cytology/metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Stem Cells/*cytology/*metabolism ; Transcription Factors/deficiency/genetics/*metabolism ; }, abstract = {To better understand the mechanisms that regulate stem cell identity and function, we sought to identify genes that are preferentially expressed by stem cells and critical for their function in multiple tissues. Prdm16 is a transcription factor that regulates leukaemogenesis, palatogenesis and brown-fat development, but which was not known to be required for stem cell function. We demonstrate that Prdm16 is preferentially expressed by stem cells throughout the nervous and haematopoietic systems and is required for their maintenance. In the haematopoietic and nervous systems, Prdm16 deficiency led to changes in the levels of reactive oxygen species (ROS), depletion of stem cells, increased cell death and altered cell-cycle distribution. In neural stem/progenitor cells, Prdm16 binds to the Hgf promoter, and Hgf expression declined in the absence of Prdm16. Addition of recombinant HGF to Prdm16-deficient neural stem cells in cell culture reduced the depletion of these cells and partially rescued the increase in ROS levels. Administration of the anti-oxidant, N-acetyl-cysteine, to Prdm16-deficient mice partially rescued defects in neural stem/progenitor cell function and neural development. Prdm16 therefore promotes stem cell maintenance in multiple tissues, partly by modulating oxidative stress.}, }
@article {pmid20833707, year = {2010}, author = {Steinritz, D and Bölck, B and Schwarz, J and Balszuweit, F and Dühr, S and Ibrahim, M and Bloch, W and Thiermann, H and Kehe, K}, title = {Effect of N-acetyl cysteine and alpha-linolenic acid on sulfur mustard caused impairment of in vitro endothelial tube formation.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {118}, number = {2}, pages = {521-529}, doi = {10.1093/toxsci/kfq271}, pmid = {20833707}, issn = {1096-0929}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Proliferation/drug effects ; Cells, Cultured ; Chemical Warfare Agents/*toxicity ; Drug Administration Schedule ; Embryoid Bodies/drug effects/metabolism ; Endothelial Cells/*drug effects/metabolism/pathology ; Free Radical Scavengers/*pharmacology ; Ki-67 Antigen/metabolism ; Mice ; Mustard Gas/*toxicity ; Neovascularization, Physiologic/*drug effects/physiology ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Time Factors ; Wound Healing/drug effects/physiology ; alpha-Linolenic Acid/*pharmacology ; }, abstract = {Sulfur mustard (SM), an alkylating chemical warfare agent, leads to tissue damage, including inflammation, blister formation, and impaired wound healing. Especially wound healing is of concern because after SM exposure, wound healing is prolonged. In this study, we focused on the effect of SM (30 and 100μM) on endothelial tube formation, apoptosis, and proliferation in mouse embryoid bodies (EBs), which provide an appropriate model for investigating vasculogenesis and angiogenesis. EBs were exposed to SM for 30 min on day 0, 3, or 6 of EBs' growth, were allowed to grow until day 7, then fixed, and immunostained (PECAM-1, Ki67, and activated caspase-3). SM significantly decreased endothelial tube formation compared with unexposed EBs. Additionally, we observed a significant increase of apoptosis. As the formation of reactive oxygen species (ROS) is discussed to be involved in the pathophysiology of SM toxicity, we evaluated the effect of ROS scavengers (α-linolenic acid [ALA] and N-acetyl cysteine [NAC]) in the same experimental setup. Temporary effects of both scavengers could be detected, in particular NAC seemed to have temporary significant positive effects on endothelial tube formation in 100μM SM-exposed EBs. ALA augmented proliferation when administered after 30μM SM exposure on day 3, whereas NAC treatment on day 0 decreased apoptosis induced by 100μM SM. Taken together, our findings pointed to a negative effect of SM on vascularization and endothelial tube formation. ROS scavengers NAC and ALA showed temporary, but not long-lasting, rescuing effects regarding endothelial tube formation after SM exposure.}, }
@article {pmid20831550, year = {2010}, author = {Tewthanom, K and Janwitayanujit, S and Totemchockcyakarn, K and Panomvana Na Ayudhya, D}, title = {The effect of high dose of N-acetylcysteine in lupus nephritis: a case report and literature review.}, journal = {Journal of clinical pharmacy and therapeutics}, volume = {35}, number = {4}, pages = {483-485}, doi = {10.1111/j.1365-2710.2009.01108.x}, pmid = {20831550}, issn = {1365-2710}, mesh = {Acetylcysteine/*administration &amp; dosage/therapeutic use ; Antioxidants/*administration &amp; dosage/therapeutic use ; Female ; Glutathione/blood ; Humans ; Lupus Nephritis/*drug therapy ; Malondialdehyde/blood ; Middle Aged ; }, abstract = {An imbalance of oxidative-antioxidant defence mechanism has been proposed in systemic lupus erythematosus patients. Co-administration of N-acetylcysteine (NAC) which has a strong antioxidant activity may produce a satisfactory therapeutic outcome when added to standard therapy. We report a case of a 46-year-old lupus nephritis patient who received 1800 mg of NAC orally. After NAC, this patient showed a higher glutathione level, and a normal level of malondialdehyde, a lipid peroxidation product. In addition, the urinary protein levels, the complete blood counts and physical examination of the affected organs showed improvement. However, a well-controlled trial is needed to confirm the value of high-dose NAC in lupus nephritis patients.}, }
@article {pmid20829599, year = {2010}, author = {Hau, DK and Wong, RS and Cheng, GY and Wong, WY and Tong, SW and Chan, KW and Leung, AK and Zhu, GY and Lai, PB and Lau, FY and Chui, CH and Gambari, R and Fong, DW}, title = {Novel use of silymarin as delayed therapy for acetaminophen-induced acute hepatic injury.}, journal = {Forschende Komplementarmedizin (2006)}, volume = {17}, number = {4}, pages = {209-213}, doi = {10.1159/000319317}, pmid = {20829599}, issn = {1661-4127}, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/drug effects/metabolism ; Animals ; Antioxidants/*therapeutic use ; Aspartate Aminotransferases/drug effects/metabolism ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/pathology ; Liver/drug effects/pathology ; Mice ; Mice, Inbred C57BL ; Silymarin/*therapeutic use ; }, abstract = {AIM: Recently, we have demonstrated that silymarin has a comparable pharmaceutical activity as Phyllanthus urinaria extract when used to rescue mice from acetaminophen-induced acute liver injury. In the present study, we further compared the therapeutic action of silymarin with N-acetyl cysteine (commonly used in clinical practice for emergency treatments) as a rescuer in mice after administering a lethal dose of acetaminophen for 24 h.<br><br>METHODS: Acute liver injury was induced in the treatment groups by intraperitoneally administered acetaminophen at a dose of 550 mg/kg body weight on day 1. The control group received an equal volume of physiological saline intraperitoneally. From day 2 to 4, the treatment groups received various doses of silymarin or N-acetyl cysteine orally once daily, while the control group and the acetaminophen group received an equal volume of water orally. The mortality rate was recorded in all groups. On day 5, all mice were sacrificed for examination.<br><br>RESULTS: Silymarin greatly improved the counteracting effects on mortality rate as compared to N-acetyl cysteine.<br><br>CONCLUSION: Silymarin should be further considered as an antidote for patients with acetaminopheninduced acute hepatic injury and delayed treatment.}, }
@article {pmid20804611, year = {2010}, author = {Acharya, M and Lau-Cam, CA}, title = {Comparison of the protective actions of N-acetylcysteine, hypotaurine and taurine against acetaminophen-induced hepatotoxicity in the rat.}, journal = {Journal of biomedical science}, volume = {17 Suppl 1}, number = {Suppl 1}, pages = {S35}, pmid = {20804611}, issn = {1423-0127}, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/pharmacology/*therapeutic use ; Analgesics, Non-Narcotic/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology/*therapeutic use ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Free Radical Scavengers/pharmacology/therapeutic use ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Glutathione Transferase/metabolism ; Humans ; Liver/drug effects/metabolism/pathology ; Liver Diseases/*drug therapy ; Male ; Malondialdehyde/metabolism ; Rats ; Rats, Sprague-Dawley ; Taurine/*analogs &amp; derivatives/pharmacology/*therapeutic use ; }, abstract = {When used in overdoses, acetaminophen (APAP) is a common cause of morbidity and mortality in humans. At present, N-acetylcysteine (NAC) is the antidote of choice for acetaminophen overdoses. Prompt administration of NAC can prevent the deleterious actions of APAP in the liver. In view of the similarities in antioxidant effects demonstrated by NAC, hypotaurine (HYTAU) and taurine (TAU) in this and other our laboratories, the present study was undertaken to compare these compounds for the ability to attenuate plasma and liver biochemical changes associated with a toxic dose of APAP. For this purpose, fasted male Sprague-Dawley rats, 225-250 g in weight, were intraperitoneally treated with APAP (800 mg/kg), NAC, HYTAU or TAU (2.4 mM/kg) followed 30 min later by APAP, or 50% PEG 400 (the vehicle for APAP). At 6 hr after APAP administration, all animals were sacrificed by decapitation and their blood and livers collected. The plasma fractions were analyzed for indices of liver damage (alanine transaminase, aspartate transaminase, lactate dehydrogenase), levels of malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione, and activities of glutathione reductase (GR), glutathione S-transferase (GST) and gamma-glutamylcisteinyl synthetase (GCS). Suitable liver homogenates were analyzed for the same biochemical parameters as the plasma but indices of liver damage. By itself, APAP increased MDA formation and had a significant lowering influence on the levels of GSH and GSSG, the GSH/GSSH ratio, and the activities of GR, GST and GCS both in the plasma and liver. In addition, APAP promoted the leakage of transaminases and lactate dehydrogenase from the liver into the plasma. Without exceptions, a pretreatment with a sulfur-containing compound led to a significant attenuation of the liver injury and the biochemical changes induced by APAP. Within a narrow range of potency differences, HYTAU appeared to be the most protective and TAU the least. The present results suggest that, irrespective of the differences in structural features and in vitro antioxidant properties that may exist among NAC, TAU and HYTAU, these compounds demonstrate equivalent patterns of protection and, to a certain extent, equipotent protective actions against the toxic actions of APAP in the liver when tested in equimolar doses and under the same conditions in an animal model.}, }
@article {pmid20825408, year = {2010}, author = {Dhar, A and Dhar, I and Desai, KM and Wu, L}, title = {Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose.}, journal = {British journal of pharmacology}, volume = {161}, number = {8}, pages = {1843-1856}, pmid = {20825408}, issn = {1476-5381}, support = {MOP-68938//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcholine/antagonists &amp; inhibitors/pharmacology ; Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Aorta/drug effects/metabolism ; Cells, Cultured ; Cyclic GMP/metabolism ; Endothelial Cells/*drug effects/metabolism ; Glucose/adverse effects/*antagonists &amp; inhibitors ; Guanidines/*pharmacology/therapeutic use ; Humans ; Male ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase/metabolism ; Phosphorylation/drug effects ; Pyruvaldehyde/adverse effects/*antagonists &amp; inhibitors/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Vascular Diseases/metabolism/*prevention &amp; control ; Vasodilation/*drug effects ; }, abstract = {BACKGROUND AND PURPOSE: Endothelial dysfunction is a feature of hypertension and diabetes. Methylglyoxal (MG) is a reactive dicarbonyl metabolite of glucose and its levels are elevated in spontaneously hypertensive rats and in diabetic patients. We investigated if MG induces endothelial dysfunction and whether MG scavengers can prevent endothelial dysfunction induced by MG and high glucose concentrations.<br><br>EXPERIMENTAL APPROACH: Endothelium-dependent relaxation was studied in aortic rings from Sprague-Dawley rats. We also used cultured rat aortic and human umbilical vein endothelial cells. The MG was measured by HPLC and Western blotting and assay kits were used.<br><br>KEY RESULTS: Incubation of aortic rings with MG (30&#x2003;&#xb5;M) or high glucose (25&#x2003;mM) attenuated endothelium-dependent, acetylcholine-induced relaxation, which was restored by two different MG scavengers, aminoguanidine (100&#x2003;&#xb5;M) and N-acetyl cysteine (NAC) (600&#x2003;&#xb5;M). Treatment of cultured endothelial cells with MG or high glucose increased cellular MG levels, effects prevented by aminoguanidine and NAC. In cultured endothelial cells, MG and high glucose reduced basal and bradykinin-stimulated nitric oxide (NO) production, cGMP levels, and serine-1177 phosphorylation and activity of endothelial NO synthase (eNOS), without affecting threonine-495 and Akt phosphorylation or total eNOS protein. These effects of MG and high glucose were attenuated by aminoguanidine or NAC.<br><br>CONCLUSIONS AND IMPLICATIONS: Our results show for the first time that MG reduced serine-1177 phosphorylation, activity of eNOS and NO production. MG caused endothelial dysfunction similar to that induced by high glucose. Specific and safe MG scavengers have potential to prevent endothelial dysfunction induced by MG and high glucose concentrations.}, }
@article {pmid20824644, year = {2010}, author = {Aggarwal, A and Misro, MM and Maheshwari, A and Sehgal, N and Nandan, D}, title = {N-acetylcysteine counteracts oxidative stress and prevents hCG-induced apoptosis in rat Leydig cells through down regulation of caspase-8 and JNK.}, journal = {Molecular reproduction and development}, volume = {77}, number = {10}, pages = {900-909}, doi = {10.1002/mrd.21232}, pmid = {20824644}, issn = {1098-2795}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 8/genetics/*metabolism ; Catalase/genetics/metabolism ; Cell Survival/drug effects ; Chorionic Gonadotropin/pharmacology ; Down-Regulation/*drug effects ; Gene Expression ; Glutathione Transferase/genetics/metabolism ; In Situ Nick-End Labeling ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Leydig Cells/*drug effects/metabolism ; Lipid Peroxidation ; Male ; Oxidative Stress/*drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {We have earlier reported that following persistent stimulation with hCG, oxidative stress-induced apoptosis in rat Leydig cells was mainly achieved through the extrinsic pathway. In the present study, the role of N-acetylcysteine (NAC) in counteracting the oxidative stress and the mechanisms of inhibition of apoptosis under such conditions were investigated. NAC (1 mM) intervention with repeated hCG stimulation (50 ng/ml, four times, each with 30 min challenge) prevented the decline in Leydig cell viability and the rise in lipid peroxidation and reactive oxygen species. Simultaneously, the activities of the enzymes glutathione-S-transferase, catalase, superoxide dismutase and the intracellular glutathione and antioxidant capacity of the treated cells improved significantly. Apoptotic markers Fas, FasL, and caspase-8, up-regulated following repeated hCG exposure, were significantly down-regulated following NAC co-incubation. While Bcl-2 expression was fully restored, Bax and caspase-9 remained unchanged. NAC treatment induced down-regulation of upstream JNK/pJNK and down-stream caspase-3 in the target cells. Taken together, the above findings indicate that NAC counteracted the oxidative stress in Leydig cells induced as a result of repeated hCG stimulation, and inhibited apoptosis by mainly regulating the extrinsic and JNK pathways of metazoan apoptosis.}, }
@article {pmid20824218, year = {2010}, author = {Abdel Baki, SG and Schwab, B and Haber, M and Fenton, AA and Bergold, PJ}, title = {Minocycline synergizes with N-acetylcysteine and improves cognition and memory following traumatic brain injury in rats.}, journal = {PloS one}, volume = {5}, number = {8}, pages = {e12490}, pmid = {20824218}, issn = {1932-6203}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Avoidance Learning/drug effects ; Brain Injuries/metabolism/pathology/*physiopathology ; Cognition/*drug effects ; Conditioning, Psychological ; Drug Synergism ; Interleukin-1beta/biosynthesis ; Memory/*drug effects ; Minocycline/*pharmacology ; Myelin Sheath/metabolism ; Perception/drug effects ; Rats ; Rats, Sprague-Dawley ; Task Performance and Analysis ; Time Factors ; }, abstract = {BACKGROUND: There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models.<br><br>Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Co-administration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when the drugs were dosed one hour after injury.<br><br>CONCLUSIONS/SIGNIFICANCE: These observations suggest a potentially valuable role for MINO plus NAC to treat TBI.}, }
@article {pmid20823935, year = {2010}, author = {Mochizuki, H and Fukui, M and Hatou, S and Yamada, M and Tsubota, K}, title = {Evaluation of ocular surface glycocalyx using lectin-conjugated fluorescein.}, journal = {Clinical ophthalmology (Auckland, N.Z.)}, volume = {4}, number = {}, pages = {925-930}, pmid = {20823935}, issn = {1177-5483}, abstract = {PURPOSE: A glycocalyx plays important roles in the ocular surface epithelium, but there is no direct simple method to evaluate ocular surface glycocalyx. We tested a wheat germ agglutinin conjugate of fluorescein (F-WGA) as a marker to demonstrate ocular surface glycocalyx in vivo.<br><br>METHODS: After a 5% F-WGA solution was applied to the eyes of eight healthy volunteers, fluorescent intensities of the central cornea and bulbar conjunctiva were measured by fluorophotometry. A 10% fluorescein-conjugated dextran solution served as the control. Changes in fluorescent intensities of the ocular surface following a challenge with 5% N-acetyl cysteine, a conventional mucolytic agent, were tested in the second experiment. Saline instillation served as a control.<br><br>RESULTS: The ocular surface was diffusely stained by F-WGA. Breakup of the precorneal tear film was not apparent, possibly because F-WGA was bound to the glycocalyx of the ocular surface epithelium. F-WGA fluorescent intensities were high in the superior, nasal, and inferior regions of the bulbar conjunctiva and low in the temporal conjunctiva and cornea. No such regional differences were observed with fluorescein-conjugated dextran. F-WGA fluorescent intensities decreased significantly with N-acetyl cysteine instillation, whereas they were not affected by saline instillation.<br><br>CONCLUSION: The fluorophotometric method may be used to evaluate the glycocalyx quantitatively in the ocular surface in vivo.}, }
@article {pmid20822922, year = {2010}, author = {Inci, I and Erne, B and Arni, S and Jungraithmayr, W and Inci, D and Hillinger, S and Vogt, P and Leskosek, B and Weder, W}, title = {Prevention of primary graft dysfunction in lung transplantation by N-acetylcysteine after prolonged cold ischemia.}, journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}, volume = {29}, number = {11}, pages = {1293-1301}, doi = {10.1016/j.healun.2010.06.017}, pmid = {20822922}, issn = {1557-3117}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Cold Ischemia/*adverse effects ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Graft Survival/physiology ; Lung/metabolism/surgery ; *Lung Transplantation ; Models, Animal ; NF-kappa B/metabolism ; Nitric Oxide/metabolism ; Primary Graft Dysfunction/metabolism/*prevention &amp; control ; Swine ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC), a thiol-containing compound that has been used as an anti-oxidant, may also lead to an increased glutathione synthesis. This study assessed the protective effect of NAC on primary graft dysfunction after lung transplantation.<br><br>METHODS: Porcine single left-lung transplantation was performed in 2 experimental groups after 24 hours of cold storage. Donor and recipient animals were treated with intravenous injection of 150 mg/kg NAC 60 minutes before harvest and reperfusion, followed by 12.5 mg/kg/hour continuous perfusion during the 8-hour observation period (NAC). Control animals did not receive any treatment. Hemodynamic and respiratory parameters were recorded throughout the observation period. Bronchoalveolar lavage (BAL) nitrite, neutrophil elastase (NE), protein accumulation, interleukin (IL)-8, nuclear factor-&#x3ba;B (p50 sub-unit), and reduced glutathione (GSH) in lung tissue and red blood were measured.<br><br>RESULTS: During the observation period, the mean pulmonary artery pressure, oxygenation, airway pressure, and static lung compliance were significantly better in NAC animals compared with controls (p < 0.05). Extravascular lung water index was higher at points during the reperfusion in the control group. BAL protein, nitrite, NE, and IL-8 cytokine levels at the end of the experiment were significantly higher in the controls than in the NAC group (p < 0.05). Lung tissue reduced GSH levels were significantly higher in the NAC group than in the control group. Red blood cell GSH levels were always higher in the NAC group during the reperfusion period. Reverse transcription polymerase chain reaction for IL-8 messenger RNA was significantly higher in controls during the reperfusion period than in the NAC group (p = 0.001). The amount of lung tissue nuclear NF-&#x3ba;B (p50 sub-unit) was significantly higher in controls than in NAC pigs (p = 0.03).<br><br>CONCLUSION: In this model, donor and recipient treatment with NAC effectively protected the lung from primary graft dysfunction after prolonged cold ischemia.}, }
@article {pmid20816907, year = {2010}, author = {Beauchesne, E and Desjardins, P and Butterworth, RF and Hazell, AS}, title = {Up-regulation of caveolin-1 and blood-brain barrier breakdown are attenuated by N-acetylcysteine in thiamine deficiency.}, journal = {Neurochemistry international}, volume = {57}, number = {7}, pages = {830-837}, doi = {10.1016/j.neuint.2010.08.022}, pmid = {20816907}, issn = {1872-9754}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Blood-Brain Barrier/*metabolism/*pathology ; Caveolin 1/*biosynthesis ; Disease Progression ; Male ; Mice ; Mice, Inbred C57BL ; Neuroprotective Agents/*metabolism/pharmacology/therapeutic use ; Oxidative Stress/physiology ; Random Allocation ; Signal Transduction/physiology ; Thiamine Deficiency/*metabolism/pathology/*prevention &amp; control ; Up-Regulation/*physiology ; }, abstract = {Wernicke's encephalopathy is a cerebral metabolic disorder caused by thiamine (vitamin B1) deficiency (TD). Neuropathologic consequences of TD include region-selective neuronal cell loss and blood-brain barrier (BBB) breakdown. Caveolin-1 is involved in the regulation of tight junction proteins and BBB permeability, and is modulated by oxidative stress, a feature of vulnerable brain regions in TD. We hypothesized that TD-related oxidative stress alters BBB integrity via induction of the caveolin-1 pathway. TD was induced in C57BL6 mice by treatment with a thiamine-deficient diet and administration of the thiamine antagonist pyrithiamine, in the absence or presence of the antioxidant N-acetylcysteine (NAC). A significant and focal increase in both caveolin-1 gene and protein expression was detected in the thalamus of thiamine-deficient mice, concomitant with IgG extravasation. Reduction of oxidative stress by NAC, as shown by normalization of reduced glutathione levels and attenuation of endothelial heme oxygenase-1 and nitric oxide synthase expression, resulted in prevention of the up-regulation of caveolin-1 in TD. Normalization of caveolin-1 levels by NAC was accompanied by a reduction in BBB breakdown, indicated by decreased IgG extravasation, normalization of occludin levels and prevention of matrix metalloproteinase-9 up-regulation. These findings demonstrate a role for caveolin-1 in TD pathogenesis, and suggest that oxidative stress contributes to BBB alterations in TD via modulation of this pathway.}, }
@article {pmid20815788, year = {2010}, author = {Minamiyama, Y and Ichikawa, H and Takemura, S and Kusunoki, H and Naito, Y and Yoshikawa, T}, title = {Generation of reactive oxygen species in sperms of rats as an earlier marker for evaluating the toxicity of endocrine-disrupting chemicals.}, journal = {Free radical research}, volume = {44}, number = {12}, pages = {1398-1406}, doi = {10.3109/10715762.2010.510523}, pmid = {20815788}, issn = {1029-2470}, mesh = {Animals ; Benzhydryl Compounds ; Biomarkers/metabolism ; Diethylstilbestrol/*toxicity ; Endocrine Disruptors/*toxicity ; Lipid Peroxidation/drug effects ; Male ; Membrane Potential, Mitochondrial/drug effects ; Oxidation-Reduction ; Phenols/*toxicity ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Sperm Count ; Sperm Motility/drug effects ; Spermatozoa/*drug effects/metabolism/ultrastructure ; Superoxides/metabolism ; }, abstract = {Bisphenol A (BPA) and diethylstilbestrol (DES) have been reported to cause sperm toxicity. To identify an earlier marker of toxicity of environmental substances or food additives, this study determined whether the levels of reactive oxygen species (ROS) in sperms could serve as indices for the prediction of sperm toxicity and quality. Male Wistar rats were given drinking water containing various doses of BPA or DES for 8 weeks. Some rats were treated with 0.45% N-acetyl cysteine (NAC) for 2 days prior to the administration of DES or BPA. Administration of BPA or DES to rats for 1 week dose-dependently increased the production of ROS, even at doses and time points which had no effect on sperm motility. 4-Hydroxy-2-nonenal modified proteins increased in sperms 8 weeks after BPA or DES treatment. NAC reversed oxidative stress and prevented the loss of sperm function in the DES or BPA-treated group. During observation, changes in the sperm motility, sperm count and morphology were not correlated to the increase in ROS levels. These results suggest that ROS levels may be used as an early indicator of sperm count and quality decreases which result from chronic toxicity.}, }
@article {pmid20815767, year = {2010}, author = {Penella, E and Sandoval, J and Zaragozá, R and García, C and Viña, JR and Torres, L and García-Trevijano, ER}, title = {Molecular mechanisms of Id2 down-regulation in rat liver after acetaminophen overdose. Protection by N-acetyl-L-cysteine.}, journal = {Free radical research}, volume = {44}, number = {9}, pages = {1044-1053}, doi = {10.3109/10715762.2010.498825}, pmid = {20815767}, issn = {1029-2470}, mesh = {Acetaminophen/pharmacology/*poisoning ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/pharmacology/poisoning ; Animals ; Cytoprotection/*drug effects ; Down-Regulation/drug effects/genetics ; Drug Overdose ; Gene Expression Regulation/drug effects ; Genes, myc/drug effects ; Glutathione/metabolism/physiology ; Inhibitor of Differentiation Protein 2/*genetics/metabolism ; Liver/*drug effects/metabolism ; Male ; Oxidative Stress/drug effects/genetics/physiology ; Proteasome Endopeptidase Complex/metabolism/physiology ; Rats ; Rats, Wistar ; Signal Transduction/drug effects/genetics ; }, abstract = {Id2 is a pleiotropic protein whose function depends on its expression levels. Id2-deficient cells show increased cell death. This study explored the molecular mechanisms for the modulation of Id2 expression elicited by GSH and oxidative stress in the liver of acetaminophen (APAP)-intoxicated rats. APAP-overdose induced GSH depletion, Id2 promoter hypoacetylation, RNApol-II released and, therefore, Id2 down-regulation. Id2 expression depends on c-Myc binding to its promoter. APAP-overdose decreased c-Myc content and binding to Id2 promoter. Reduction of c-Myc was not accompanied by decreased c-myc mRNA, suggesting a mechanism dependent on protein stability. Administration of N-acetyl-cysteine prior to APAP-overload prevented GSH depletion and c-Myc degradation. Consistently, c-Myc was recruited to Id2 promoter, histone-H3 was hyperacetylated, RNApol II was bound to Id2 coding region and Id2 repression prevented. The results suggest a novel transcriptional-dependent mechanism of Id2 regulation by GSH and oxidative stress induced by APAP-overdose through the indirect modulation of the proteasome pathway.}, }
@article {pmid20814239, year = {2010}, author = {Martinez-Outschoorn, UE and Balliet, RM and Rivadeneira, DB and Chiavarina, B and Pavlides, S and Wang, C and Whitaker-Menezes, D and Daumer, KM and Lin, Z and Witkiewicz, AK and Flomenberg, N and Howell, A and Pestell, RG and Knudsen, ES and Sotgia, F and Lisanti, MP}, title = {Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {9}, number = {16}, pages = {3256-3276}, pmid = {20814239}, issn = {1551-4005}, support = {R01 CA075503/CA/NCI NIH HHS/United States ; R01 CA098779/CA/NCI NIH HHS/United States ; R01-CA-120876/CA/NCI NIH HHS/United States ; R01 CA120876/CA/NCI NIH HHS/United States ; R01-CA-70896/CA/NCI NIH HHS/United States ; R01-CA-098779/CA/NCI NIH HHS/United States ; R01-CA-86072/CA/NCI NIH HHS/United States ; R01-AR-055660/AR/NIAMS NIH HHS/United States ; R01-CA-080250/CA/NCI NIH HHS/United States ; R01 CA070896/CA/NCI NIH HHS/United States ; R01 CA107382/CA/NCI NIH HHS/United States ; P30 CA056036/CA/NCI NIH HHS/United States ; P30-CA-56036/CA/NCI NIH HHS/United States ; R01-CA-107382/CA/NCI NIH HHS/United States ; R01 AR055660/AR/NIAMS NIH HHS/United States ; R01-CA-75503/CA/NCI NIH HHS/United States ; R01 CA080250/CA/NCI NIH HHS/United States ; R01 CA086072/CA/NCI NIH HHS/United States ; }, mesh = {Autophagy ; Biological Evolution ; Breast Neoplasms/genetics/*metabolism ; Caveolin 1/genetics/*metabolism ; Cell Line ; Coculture Techniques ; DNA Damage ; Down-Regulation ; Female ; Fibroblasts/*metabolism ; *Genomic Instability ; Histones/metabolism ; Humans ; Lactic Acid/pharmacology ; Mitochondria/metabolism/physiology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/metabolism ; *Oxidative Stress ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a "lethal tumor micro-environment." Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a "metabolic" and "mutagenic" motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the "Reverse Warburg Effect"). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NO inhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. Thus, cancer cells use "oxidative stress" in adjacent fibroblasts (i) as an "engine" to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the "field effect" in cancer biology could also be related to the stromal production of ROS and NO species. eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively "contagious"--spread from cell-to-cell like a virus--creating an "oncogenic/mutagenic" field promoting widespread DNA damage.}, }
@article {pmid20814119, year = {2010}, author = {Swarnalatha, G and Ram, R and Neela, P and Naidu, MU and Dakshina Murty, KV}, title = {Oxidative stress in hemodialysis patients receiving intravenous iron therapy and the role of N-acetylcysteine in preventing oxidative stress.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {21}, number = {5}, pages = {852-858}, pmid = {20814119}, issn = {1319-2442}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Anemia, Iron-Deficiency/blood/*drug therapy/etiology ; Antioxidants/*therapeutic use ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Cross-Over Studies ; Double-Blind Method ; Endothelium, Vascular/drug effects/metabolism/physiopathology ; Female ; Ferric Compounds/*administration &amp; dosage/adverse effects ; Ferric Oxide, Saccharated ; Glucaric Acid ; Hematinics/*administration &amp; dosage/adverse effects ; Humans ; India ; Infusions, Intravenous ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/blood ; Middle Aged ; Oxidative Stress/*drug effects ; Placebo Effect ; Plethysmography ; Prospective Studies ; *Renal Dialysis/adverse effects ; Time Factors ; Treatment Outcome ; }, abstract = {To determine the contribution of injectable iron administered to hemodialysis (HD) patients in causing oxidative stress and the beneficial effect of N-acetylcysteine (NAC) in reducing it, we studied in a prospective, double blinded, randomized controlled, cross over trial 14 adult HD patients who were randomized into two groups; one group received NAC in a dose of 600 mgs twice daily for 10 days prior to intravenous iron therapy and the other group received placebo. Both the groups were subjected to intravenous iron therapy, 100 mg of iron sucrose in 100 mL of normal saline given over a period of one hour. Blood samples for the markers of oxidative stress were taken before and after iron therapy. After the allowance of a week of wash out period for the effect of N-acetylcysteine we crossed over the patients to the opposite regimen. We measured the lipid peroxidation marker, malondiaaldehyde (MDA), to evaluate the oxidative stress and total anti-oxidant capacity (TAC) for the antioxidant level in addition to the highly sensitive C-reactive protein (HsCRP). Non-invasive assessment of endothelial dysfunction was measured by digital plethysmography before and after intravenous iron therapy. There was an increase of MDA (21.97 + 3.65% vs 7.06 + 3.65%) and highly sensitive C-reactive protein (HsCRP) (11.19 + 24.63% vs 13.19 + 7.7%) after iron administration both in the placebo and the NAC groups. NAC reduced the baseline acute systemic generation of oxidative stress when compared to placebo, which was statistically significant with MDA (12.76 + 4.4% vs 9.37 + 4.40%: P = 0.032) but not with HsCRP though there was a declining trend (2.85 + 22.75 % vs 8.93 + 5.19%: P = 0.112). Pre-treatment with NAC reduced the endothelial dysfunction when compared to placebo, but it was not statistically significant, except for reflection index (RI). We conclude that in our HD patients NAC reduced the oxidative stress before and after the administration of intravenous iron therapy in addition to the endothelial dysfunction induced by this treatment.}, }
@article {pmid20810184, year = {2010}, author = {Chen, Y and Johansson, E and Yang, Y and Miller, ML and Shen, D and Orlicky, DJ and Shertzer, HG and Vasiliou, V and Nebert, DW and Dalton, TP}, title = {Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis.}, journal = {Journal of hepatology}, volume = {53}, number = {6}, pages = {1085-1094}, pmid = {20810184}, issn = {1600-0641}, support = {R21 AA017754-01/AA/NIAAA NIH HHS/United States ; P30 ES006096-06A19007/ES/NIEHS NIH HHS/United States ; R01 EY017963/EY/NEI NIH HHS/United States ; P30 ES06096/ES/NIEHS NIH HHS/United States ; R01 EY011490/EY/NEI NIH HHS/United States ; R01 ES012463/ES/NIEHS NIH HHS/United States ; P30 ES006096/ES/NIEHS NIH HHS/United States ; R21 AA017754/AA/NIAAA NIH HHS/United States ; R01 ES012463-05/ES/NIEHS NIH HHS/United States ; R01 EY011490-07/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Animals ; Antioxidants/metabolism ; Base Sequence ; Cytokines/genetics ; DNA Primers/genetics ; Disease Models, Animal ; Gene Expression Profiling ; Glutamate-Cysteine Ligase/*deficiency/genetics/metabolism ; Glutathione/metabolism ; Hepatocytes/drug effects/metabolism/ultrastructure ; Liver/drug effects/metabolism/pathology ; Liver Cirrhosis/*etiology/genetics/metabolism/pathology ; Mice ; Mice, Knockout ; Microscopy, Electron, Transmission ; Mitochondria, Liver/drug effects/metabolism ; Oxidative Stress/drug effects ; RNA, Messenger/genetics/metabolism ; }, abstract = {BACKGROUND &amp; AIMS: Certain liver diseases have been associated with depletion of glutathione (GSH), the major antioxidant in the liver. A recent report about Gclc(h/h) mice with a hepatocyte-specific ablation of Gclc (the gene encoding the catalytic subunit of the rate-limiting enzyme in GSH synthesis) has shown an essential role of GSH in hepatic function. Gclc(h/h) mice develop severe steatosis and die of liver failure within one month, due to ~95% depletion of hepatic GSH; mitochondria are the major affected organelles, displaying abnormal ultrastructure and impaired functioning.<br><br>METHODS: Gclc(h/h) mice were fed with L-N-acetylcysteine (NAC; 10 g/L) in drinking water, starting at postnatal day 18.<br><br>RESULTS: Gclc(h/h) mice were rescued by use of NAC supplementation, and survived until adulthood. NAC replenished the mitochondrial GSH pool and attenuated mitochondrial damage, with accompanying diminished hepatic steatosis; however, abnormal liver biochemical tests, hepatocyte death, and hepatic oxidative stress persisted in the rescued mice. At 50 days of age, the liver from rescued Gclc(h/h) mice started to display characteristics of fibrosis and at age 120 days, macronodular cirrhosis was observed. Immunohistostaining for liver-specific markers as well as the expression profile of hepatic cytokines indicated that the repopulation of hepatocytes in the cirrhotic nodules involved the expansion of oval cells.<br><br>CONCLUSIONS: Replenishment of mitochondrial GSH and restoration of mitochondrial function by NAC prevents mortality caused by the loss of hepatocyte GSH de novo synthesis, allowing steatosis to progress to a chronic stage. Thus, with NAC supplementation, Gclc(h/h) mice provide a model for the development of liver fibrosis and cirrhosis.}, }
@article {pmid20808797, year = {2010}, author = {Clark, J and Clore, EL and Zheng, K and Adame, A and Masliah, E and Simon, DK}, title = {Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice.}, journal = {PloS one}, volume = {5}, number = {8}, pages = {e12333}, pmid = {20808797}, issn = {1932-6203}, mesh = {Acetylcysteine/*administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Cytosol/drug effects/metabolism ; Dietary Supplements ; Dopamine/*metabolism ; Gene Expression ; Glutathione/metabolism ; Humans ; Male ; Mice ; Mice, Transgenic ; Motor Activity/drug effects/physiology ; NF-kappa B/metabolism ; Neostriatum/*drug effects/*metabolism ; Neuroprotective Agents/administration &amp; dosage/pharmacology ; Parkinson Disease/metabolism/pathology/physiopathology ; Protein Transport/drug effects ; Proto-Oncogene Proteins c-sis/metabolism ; Time Factors ; Tyrosine 3-Monooxygenase/metabolism ; alpha-Synuclein/*genetics ; }, abstract = {Levels of glutathione are lower in the substantia nigra (SN) early in Parkinson's disease (PD) and this may contribute to mitochondrial dysfunction and oxidative stress. Oxidative stress may increase the accumulation of toxic forms of alpha-synuclein (SNCA). We hypothesized that supplementation with n-acetylcysteine (NAC), a source of cysteine--the limiting amino acid in glutathione synthesis, would protect against alpha-synuclein toxicity. Transgenic mice overexpressing wild-type human alpha-synuclein drank water supplemented with NAC or control water supplemented with alanine from ages 6 weeks to 1 year. NAC increased SN levels of glutathione within 5-7 weeks of treatment; however, this increase was not sustained at 1 year. Despite the transient nature of the impact of NAC on brain glutathione, the loss of dopaminergic terminals at 1 year associated with SNCA overexpression was significantly attenuated by NAC supplementation, as measured by immunoreactivity for tyrosine hydroxylase in the striatum (p = 0.007; unpaired, two-tailed t-test), with a similar but nonsignificant trend for dopamine transporter (DAT) immunoreactivity. NAC significantly decreased the levels of human SNCA in the brains of PDGFb-SNCA transgenic mice compared to alanine treated transgenics. This was associated with a decrease in nuclear NFkappaB localization and an increase in cytoplasmic localization of NFkappaB in the NAC-treated transgenics. Overall, these results indicate that oral NAC supplementation decreases SNCA levels in brain and partially protects against loss of dopaminergic terminals associated with overexpression of alpha-synuclein in this model.}, }
@article {pmid20807176, year = {2010}, author = {Ozgur, E and Güler, G and Seyhan, N}, title = {Mobile phone radiation-induced free radical damage in the liver is inhibited by the antioxidants N-acetyl cysteine and epigallocatechin-gallate.}, journal = {International journal of radiation biology}, volume = {86}, number = {11}, pages = {935-945}, doi = {10.3109/09553002.2010.496029}, pmid = {20807176}, issn = {1362-3095}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Catechin/*analogs &amp; derivatives/pharmacology ; *Cell Phone ; Electromagnetic Fields/*adverse effects ; Free Radicals/metabolism/radiation effects ; Glutathione Peroxidase ; Guinea Pigs ; Liver/*drug effects/enzymology/metabolism/radiation effects ; Male ; Malondialdehyde ; Nitric Oxide ; Oxidative Stress/*drug effects/physiology/radiation effects ; Peroxidase ; Superoxide Dismutase ; Time Factors ; }, abstract = {PURPOSE: To investigate oxidative damage and antioxidant enzyme status in the liver of guinea pigs exposed to mobile phone-like radiofrequency radiation (RFR) and the potential protective effects of N-acetyl cysteine (NAC) and epigallocatechin-gallate (EGCG) on the oxidative damage.<br><br>MATERIALS AND METHODS: Nine groups of guinea pigs were used to study the effects of exposure to an 1800-MHz Global System for Mobile Communications (GSM)-modulated signal (average whole body Specific Absorption Rate (SAR) of 0.38 W/kg, 10 or 20 min per day for seven days) and treatment with antioxidants.<br><br>RESULTS: Significant increases in malondialdehyde (MDA) and total nitric oxide (NO(x)) levels and decreases in activities of superoxide dismutase (SOD), myeloperoxidase (MPO) and glutathione peroxidase (GSH-Px) were observed in the liver of guinea pigs after RFR exposure. Only NAC treatment induces increase in hepatic GSH-Px activities, whereas EGCG treatment alone attenuated MDA level. Extent of oxidative damage was found to be proportional to the duration of exposure (P < 0.05).<br><br>CONCLUSION: Mobile phone-like radiation induces oxidative damage and changes the activities of antioxidant enzymes in the liver. The adverse effect of RFR may be related to the duration of mobile phone use. NAC and EGCG protect the liver tissue against the RFR-induced oxidative damage and enhance antioxidant enzyme activities.}, }
@article {pmid20804648, year = {2010}, author = {Tan, LP and Xu, F and Kuang, FW}, title = {[Protective effect of N-acetylcysteine on hyperoxic lung injury and its relation with p38 mitogen-activated protein kinase signaling pathway].}, journal = {Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue}, volume = {22}, number = {8}, pages = {469-472}, pmid = {20804648}, issn = {1003-0603}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Hyperoxia/*complications ; Lung Injury/etiology/*metabolism/prevention &amp; control ; Phosphorylation ; Random Allocation ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {OBJECTIVE: To investigate the expression of p38 mitogen-activated protein kinase (MAPK) in hyperoxic lung injury (HLI), and explore the protective effect of N-acetylcysteine (NAC) on HLI and its mechanism.<br><br>METHODS: Thirty Wistar rats aged 3 weeks old were divided into five groups with 6 rats in each group according to random digits table: room-air group (A), hyperoxia injury group (B), hyperoxia+NAC group (C), hyperoxia+p38 MAPK inhibitor (SB203580) group (D), hyperoxia+NAC+SB203580 group (E). Rats in NAC groups were injected with NAC (200 mg/kg) intraperitoneally, and they received an intravenous injection of SB203580 (0.5 mg/kg) in SB203580 groups. The animals were sacrificed after 7 days of experiment. Lung pathology and grade of lung tissue injury were examined with light microscopy, lung wet/dry (W/D) ratio, total protein (TP) level in bronchoalveolar lavage fluid (BALF) and permeability coefficient were evaluated. The location and quantity of phosphorylation p38 MAPK (p-p38 MAPK) protein were detected by immunohistochemistry and Western blotting analysis respectively.<br><br>RESULTS: The pathological changes in the lung in B group included severe alveolar oedema with inflammatory cells aggregation and red blood cell leakage, while the lung pathological pictures in C, D, E groups were improved significantly compared with B group. p-p38 MAPK positive cells increased in B group compared with those in A group, involving many types of pulmonary cells, especially in infiltrating inflammatory cells. In C, D, E groups, the positive cells remarkably decreased compared with B group. p-p38 MAPK content was higher in B group than that in A group (0.20+/-0.03 vs. 0.11+/-0.01, P<0.05), and p-p38 MAPK expressions in C, D, E groups decreased significantly compared with B group (0.16+/-0.02, 0.15+/-0.01, 0.14+/-0.02 vs. 0.20+/-0.03, all P<0.05), but were higher than those in A group (all P<0.05). There was no significant difference in p-p38 MAPK quantity among three groups. Changes in W/D ratio, TP and permeability coefficient among groups were comparable with those of p-p38 MAPK protein quantity.<br><br>CONCLUSION: Reactive oxygen species (ROS) activated p38 MAPK signaling pathway. NAC may exert a protective effect on HLI through attenuation of hyperoxia-induced p38 MAPK activation.}, }
@article {pmid20800897, year = {2011}, author = {Magalhães, PV and Dean, OM and Bush, AI and Copolov, DL and Malhi, GS and Kohlmann, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Berk, M}, title = {N-acetyl cysteine add-on treatment for bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial.}, journal = {Journal of affective disorders}, volume = {129}, number = {1-3}, pages = {317-320}, doi = {10.1016/j.jad.2010.08.001}, pmid = {20800897}, issn = {1573-2517}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Bipolar Disorder/*drug therapy ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; Treatment Outcome ; }, abstract = {BACKGROUND: The evidence base for the pharmacological treatment of bipolar II disorder is limited. In bipolar disorder, there is evidence for glutathione depletion and increased oxidative stress, as well as dysregulation of glutamate; N-acetyl cysteine (NAC) has effects on both of these systems. Add-on NAC has been shown to have a significant benefit on depressive symptoms in a randomized placebo-controlled trial. In this report, we explore the effects of this compound in a subset of patients with bipolar II disorder from that trial.<br><br>METHODS: Individuals were randomized to NAC or placebo in addition to treatment as usual, in a double-blind fashion. Mood and functional outcomes were assessed up to 24 weeks of treatment.<br><br>RESULTS: Fourteen individuals were available for this report, seven in each group. Six people achieved full remission of both depressive and manic symptoms in the NAC group; this was true for only two people in the placebo group (&#x3c7;(2)=4.67, p=0.031).<br><br>LIMITATIONS: Subgroup analyses in a small subsample of patients. Not all participants had elevated depression scores at baseline.<br><br>CONCLUSION: Notwithstanding all the limitations that subgroup analysis of trials carry, this data could serve as a hypothesis-generating stimulus for further clinical trials of pharmacologic treatment for bipolar II depression.}, }
@article {pmid20799620, year = {2010}, author = {Gamaleĭ, IA and Kirpichnikova, KM and Vakhromova, EA and Filatova, NA}, title = {[N-acetylcysteine-induced reduction in susceptibility of transformed and embryonic cells to lytic activity of natural killer cells].}, journal = {Tsitologiia}, volume = {52}, number = {7}, pages = {555-561}, pmid = {20799620}, issn = {0041-3771}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Actins/metabolism ; Animals ; Cell Line, Transformed ; Cell Line, Tumor ; *Cytotoxicity, Immunologic ; Embryo, Mammalian/*drug effects/immunology/ultrastructure ; Fibroblasts/drug effects/immunology ; Humans ; Killer Cells, Natural/*immunology ; Male ; Mice ; Neoplasms/*immunology ; Stress Fibers/metabolism ; }, abstract = {We studied N-acetylcysteine (NAC) ability to change the phenotype properties of several transformed and embryonic cells. We examined human epidermoid carcinoma A431 cells, murine hepatoma MH22a cells, and murine embryonic fibroblasts (MEFs) in terms of the sensitivity to natural killer (NK) recognition and abolishment. We have demonstrated that treatment with NAC (10 mM) results in a loss of susceptibility to NK cell activity by transformed A431 and MH22a cells similar to 3T3-SV40 transformed cells whose partial reversion caused by NAC was revealed by us before. We have shown that MEFs are also sensitive to NK activity and abolished by NK cells as well as transformed cells. MEFs pretreated with 10 mM NAC as well as transformed cells lose their susceptibility to NK cell activity. The loss of cell sensitivity to NK cytolytic activity was accompanied by a reorganization of the actin cytoskeleton and the appearance of well-pronounced stress-fibers.}, }
@article {pmid20798331, year = {2012}, author = {Huh, JY and Seo, EY and Lee, HB and Ha, H}, title = {Glucose-based peritoneal dialysis solution suppresses adiponectin synthesis through oxidative stress in an experimental model of peritoneal dialysis.}, journal = {Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis}, volume = {32}, number = {1}, pages = {20-28}, pmid = {20798331}, issn = {1718-4304}, mesh = {Adipocytes/metabolism/pathology ; Adiponectin/*biosynthesis/genetics ; Animals ; Blotting, Western ; Cells, Cultured ; Dialysis Solutions/*administration &amp; dosage ; Disease Management ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation/drug effects ; Glucose/*administration &amp; dosage ; Male ; Oxidative Stress/*drug effects ; *Peritoneal Dialysis ; Peritoneum/*metabolism ; RNA, Messenger/genetics ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Sweetening Agents/pharmacology ; }, abstract = {OBJECTIVE: Accumulation of visceral fat is one of the major risk factors for the development of cardiovascular disease in peritoneal dialysis (PD) patients. Adiponectin, an adipokine commonly regarded as a negative indicator of metabolic disease, is reported to be downregulated in its gene level in end-stage renal disease patients. Since excessive fat deposit is involved in increased reactive oxygen species (ROS), PD solution (PDS) may contribute to ROS production, resulting in dysregulation of adiponectin. In this study, we tested our hypothesis that oxidative stress induced by PDS may play a role in the regulation of adiponectin.<br><br>METHODS: Commercial PDS containing 3.86% glucose (20 - 30 mL) was administered to SD rats for 12 weeks with and without N-acetylcysteine (NAC; 10 mmol/L). ELISA was used to quantify adiponectin in plasma and spent dialysate. For in vitro studies, fully differentiated 3T3-L1 adipocytes and adipocytes isolated from abdominal fat were treated with a high glucose solution, PDS, and H(2)O(2). Adiponectin levels in the conditioned media were measured by ELISA and immunoblot assays. The mRNA levels of adiponectin in mature adipocytes were examined using real-time RT-PCR.<br><br>RESULTS: The levels of adiponectin in plasma and spent dialysate were significantly downregulated by PDS and this effect was suppressed by NAC. In 3T3-L1 adipocytes, adiponectin secretion was inhibited by 50 mmol/L glucose, PDS diluted 2-fold, and H(2)O(2) (200 &#x3bc;mol/L). In addition, H(2)O(2) downregulated expression of adiponectin mRNA and secretion of adiponectin oligomer complexes.<br><br>CONCLUSIONS: Our data suggest that ROS induced by conventional glucose-based PDS may contribute to pathophysiological changes in abdominal fat and downregulate adiponectin secreted from adipocytes during long-term PD.}, }
@article {pmid20795947, year = {2011}, author = {Shyu, KG and Lien, LM and Wang, BW and Kuan, P and Chang, H}, title = {Resistin contributes to neointimal formation via oxidative stress after vascular injury.}, journal = {Clinical science (London, England : 1979)}, volume = {120}, number = {3}, pages = {121-129}, doi = {10.1042/CS20100226}, pmid = {20795947}, issn = {1470-8736}, mesh = {Animals ; Aorta, Thoracic/metabolism/pathology ; Carotid Artery Injuries/*metabolism/pathology ; Cell Movement/physiology ; Cell Proliferation ; Cells, Cultured ; Culture Media, Conditioned ; Gene Expression Regulation ; Muscle, Smooth, Vascular/*metabolism/pathology ; Oxidative Stress/*physiology ; RNA Interference ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Resistin/genetics/*physiology ; Tunica Intima/metabolism/pathology ; Tunica Media/metabolism/pathology ; }, abstract = {Resistin may play a major potential role in vascular remodelling and may contribute to atherogenesis. However, the role of VSMC (vascular smooth muscle cell)-derived resistin in neointimal formation is not well understood. We hypothesize that endogenous resistin derived from VSMCs may contribute to neointimal formation after vascular injury. VSMCs from thoracic aorta of adult Wistar rats were cultured. The carotid artery from adult Wistar rats was injured by balloon catheter. Resistin significantly increased migration and proliferation of VSMCs. Resistin siRNA (small interfering RNA) and resistin antibody significantly inhibited migration and proliferation of VSMCs induced by conditioned medium from stretched VSMCs. Resistin protein and mRNA expression significantly increased at 14 days after carotid injury. Resistin siRNA and NAC (N-acetylcysteine) significantly reduced resistin protein and mRNA expression induced by balloon injury. Carotid artery injury increased ROS (reactive oxygen species) production. Treatment with NAC and resistin siRNA decreased ROS production. The neointimal area was significantly increased after carotid injury and was significantly reduced by resistin siRNA and NAC. In conclusion, resistin increases migration and proliferation of VSMCs, and expression of resistin in carotid artery significantly increases after injury. Resistin siRNA attenuates neointimal formation after carotid injury partly through an antioxidative mechanism. Resistin may play a pivotal role in the pathogenesis of neointimal thickening after mechanical injury.}, }
@article {pmid20737637, year = {2010}, author = {Loh, JW and Schneider, J and Carter, M and Saunders, M and Lim, LY}, title = {Spinning disc processing technology: potential for large-scale manufacture of chitosan nanoparticles.}, journal = {Journal of pharmaceutical sciences}, volume = {99}, number = {10}, pages = {4326-4336}, doi = {10.1002/jps.22145}, pmid = {20737637}, issn = {1520-6017}, mesh = {Acetaminophen/chemistry ; Acetylcysteine/chemistry ; *Chitosan ; Microscopy, Electron, Transmission ; *Nanoparticles ; Particle Size ; }, abstract = {Mass production of nanoparticles using a reliable cost-effective approach is a challenge in the pharmaceutical industry. In this study, the spinning disc processing (SDP) technology was used to fabricate chitosan nanoparticles, with a view to commercially produce chitosan nanoparticle-based drug delivery platforms. Chitosan solution (0.25%, w/v, in dilute acid, 27.5 mL, 1.5 mL/s) was intensely mixed with sodium tripolyphosphate solution (0.10%, w/v, in water, 20 mL, 1.1 mL/s) on the spinning disc (1000 rpm). Transmission electron microscopy and dynamic light scattering data confirmed that the nanoparticles (20 +/- 3 nm) were comparable in size and shape to those synthesised using a beaker and magnetic stirrer (31 +/- 13 nm). Larger nanoparticles (131 +/- 5 nm) were produced by increasing the chitosan and TPP feed concentrations to 0.5% and 0.125%, respectively. Drug loading further increased the size of the nanoparticles, with N-acetyl cysteine (NAC) having a greater effect (403 +/- 4 nm) than paracetamol (165 +/- 4 nm). Co-loading of both drugs increased the size of the particles to the micron range. In conclusion, the SDP is a robust technology capable of expanding the production of blank and drug-loaded chitosan nanoparticles for the biomedical and pharmaceutical industries.}, }
@article {pmid20727930, year = {2010}, author = {Golestan Jahromi, M and Nabavizadeh, F and Vahedian, J and Nahrevanian, H and Dehpour, AR and Zare-Mehrjardi, A}, title = {Protective effect of ghrelin on acetaminophen-induced liver injury in rat.}, journal = {Peptides}, volume = {31}, number = {11}, pages = {2114-2117}, doi = {10.1016/j.peptides.2010.08.009}, pmid = {20727930}, issn = {1873-5169}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/therapeutic use ; Alanine Transaminase/metabolism ; Animals ; Aspartate Aminotransferases/metabolism ; Chemical and Drug Induced Liver Injury/*drug therapy/pathology ; Ghrelin/*therapeutic use ; Liver/drug effects/pathology ; Male ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Ghrelin is a peptide that has protective effects on many tissues of the body. It has anti-inflammatory and anti-oxidant effects. Acetaminophen, a commonly used analgesic-antipyretic drug, has hepatotoxic side effects. The aim of this study was to evaluate the protective role of ghrelin in liver toxicity due to acetaminophen overdose. Thirty male rats were used in this study and divided into five groups. They were control, propylene-glycol (as a solvent of acetaminophen), acetaminophen, acetaminophen and NAC, acetaminophen and ghrelin groups. Tumor necrosis factor alpha (TNF-α), and hepatic enzymes, AST (aspartate aminotransferase) and ALT (alanine aminotransferase), were assessed and histologic study of liver were performed as indicators of liver damage following acetaminophen toxicity. Results showed that Ghrelin decreased ALT and AST to the normal level, and also reduced TNF-α. Although NAC (the standard antidote of acetaminophen toxicity) also reduced ALT, AST and TNF-α levels, our results show that ghrelin is more potent than NAC in protecting the liver from acetaminophen-induced liver injury.}, }
@article {pmid20727219, year = {2010}, author = {Tsai, MH and Jiang, MJ}, title = {Reactive oxygen species are involved in regulating alpha1-adrenoceptor-activated vascular smooth muscle contraction.}, journal = {Journal of biomedical science}, volume = {17}, number = {1}, pages = {67}, pmid = {20727219}, issn = {1423-0127}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Adrenergic alpha-1 Receptor Agonists ; Analysis of Variance ; Animals ; Benzoxazoles/pharmacology ; Blotting, Western ; Dose-Response Relationship, Drug ; Muscle Contraction/drug effects/*physiology ; Muscle, Smooth/*physiology ; Myosin-Light-Chain Phosphatase/*metabolism ; Myosins/*metabolism ; NADPH Oxidases/antagonists &amp; inhibitors ; Phenylephrine/pharmacology ; Phosphorylation/drug effects ; Rats ; Reactive Oxygen Species/*metabolism ; Receptors, Adrenergic, alpha-1/*metabolism ; Triazoles/pharmacology ; Vasoconstrictor Agents/pharmacology ; rhoA GTP-Binding Protein/metabolism ; }, abstract = {BACKGROUND: Reactive oxygen species (ROS) were shown to mediate aberrant contractility in hypertension, yet the physiological roles of ROS in vascular smooth muscle contraction have remained elusive. This study aimed to examine whether ROS regulate alpha1-adrenoceptor-activated contraction by altering myosin phosphatase activities.<br><br>METHODS: Using endothelium-denuded rat tail artery (RTA) strips, effects of anti-oxidants on isometric force, ROS production, phosphorylation of the 20-kDa myosin light chain (MLC20), and myosin phosphatase stimulated by alpha1-adrenoceptor agonist phenylephrine were examined.<br><br>RESULTS: An antioxidant, N-acetyl-L-cysteine (NAC), and two NADPH oxidase inhibitors, apocynin and VAS2870, dose-dependently inhibited contraction activated by phenylephrine. Phenylephrine stimulated superoxide anion production that was diminished by the pretreatment of apocynin, VAS2870, superoxide scavenger tiron or mitochondria inhibitor rotenone, but not by xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. Concurrently, NADPH oxidase activity in RTA homogenates increased within 1 min upon phenylephrine stimulation, sustained for 10 min, and was abolished by the co-treatment with apocynin, but not allopurinol or rotenone. Phenylephrine-induced MLC20 phosphorylation was dose-dependently decreased by apocynin. Furthermore, apocynin inhibited phenylephrine-stimulated RhoA translocation to plasma membrane and phosphorylation of both myosin phosphatase regulatory subunit MYPT1Thr855 and myosin phosphatase inhibitor CPI-17Thr38.<br><br>CONCLUSIONS: ROS, probably derived from NADPH oxidase and mitochondria, partially regulate alpha1-adrenoceptor-activated smooth muscle contraction by altering myosin phosphatase-mediated MLC20 phosphorylation through both RhoA/Rho kinase- and CPI-17-dependent pathways.}, }
@article {pmid20718735, year = {2010}, author = {Lin, H and Sue, YM and Chou, Y and Cheng, CF and Chang, CC and Li, HF and Chen, CC and Juan, SH}, title = {Activation of a nuclear factor of activated T-lymphocyte-3 (NFAT3) by oxidative stress in carboplatin-mediated renal apoptosis.}, journal = {British journal of pharmacology}, volume = {161}, number = {7}, pages = {1661-1676}, pmid = {20718735}, issn = {1476-5381}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology/toxicity ; Apoptosis/*drug effects ; Carboplatin/*pharmacology/toxicity ; Caspase 3/metabolism ; Cell Nucleus/metabolism ; Epithelial Cells/drug effects/metabolism ; Kidney Tubules/cytology/*drug effects/metabolism ; Luciferases/genetics/metabolism ; Mice ; Mice, Transgenic ; NADPH Oxidases/metabolism ; NFATC Transcription Factors/genetics/*metabolism ; *Oxidative Stress ; Protein Carbonylation ; Reactive Oxygen Species/metabolism ; Transfection ; }, abstract = {BACKGROUND AND PURPOSE: Although carboplatin is currently used as a therapeutic drug for ovarian, breast, and non-small cell lung cancers, it has serious side effects including renal and cardiac toxicity. Herein, we examined the effect of carboplatin on murine renal tubular cell (RTC) apoptosis both in vivo and in vitro and the underlying molecular mechanisms associated with its activation of the nuclear factor of activated T-lymphocytes-3 (NFAT3).<br><br>EXPERIMENTAL APPROACH: Mechanisms of carboplatin-mediated renal apoptosis were examined using NFAT-reporter transgenic mice and RTCs with NFAT3 overexpression or knockdown.<br><br>KEY RESULTS: We demonstrated that carboplatin initiated an intrinsic apoptotic pathway of activating caspase-3 and -9, accompanied by a decrease in the ratio of Bcl-XL/Bax and a significant increase in Bcl-XS. Carboplatin increased NFAT activation in NFAT-luciferase reporter transgenic mice, RTCs and cells exogenously overexpressing NFAT3 that exacerbated cell death. Furthermore, the addition of either N-acetylcysteine (NAC, an antioxidant) or NFAT inhibitors, including FK-506 (tacrolimus), cyclosporin A (CsA, a calcineurin inhibitor), and BAPTA-AM (a calcium chelator) successfully reversed carboplatin-mediated cell apoptosis, which was further confirmed using siNFAT3. Additionally, NAC blocked NFAT3 activation by inhibition of NADPH oxidase activation, and ERK/JNK and PKC pathways, resulting in a decrease in cell apoptosis; the therapeutic effect of NAC was verified in vivo.<br><br>CONCLUSION AND IMPLICATIONS: The results presented herein show that carboplatin-mediated reactive oxygen species might signal calcineurin and NFAT3 activation in RTCs, whereas NAC and NFAT inhibitors reversed carboplatin-mediated RTC apoptosis, suggesting that oxidative stress-mediated NFAT3 activation is essential for carboplatin-mediated RTC apoptosis.}, }
@article {pmid20716947, year = {2010}, author = {Choi, HR and Shin, JW and Lee, HK and Kim, JY and Huh, CH and Youn, SW and Park, KC}, title = {Potential redox-sensitive Akt activation by dopamine activates Bad and promotes cell death in melanocytes.}, journal = {Oxidative medicine and cellular longevity}, volume = {3}, number = {3}, pages = {219-224}, pmid = {20716947}, issn = {1942-0994}, mesh = {Acetylcysteine/pharmacokinetics ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Cell Line ; Cell Survival/drug effects ; Dopamine/*pharmacology ; Flow Cytometry ; Melanocytes/*cytology/*drug effects/metabolism ; Mice ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; }, abstract = {Dopamine (DA) is a well known oxidative neurotoxin. In addition, Akt has been reported to deliver a survival signal that inhibits apoptosis. However, it has also been reported that chronic Akt activation leads to apoptosis in response to oxidative stress. The objective of the present study was to investigate the possible role of the Akt pathway in vitiligo and its possible relationship with DA-induced cell death using Mel-Ab cells. Cultured Mel-Ab cells were treated with DA with and without N-Acetyl-L-cysteine (NAC), which is known to have antioxidative properties. Cell viability was then assessed by a crystal violet assay and Annexin staining was performed. The changes in the expression of Akt were analyzed by western blot analysis. The cell viability was reduced by approximately 60% in response to treatment with 500 microM DA, and NAC effectively prevented this cytotoxic effect. Likewise, treatment with DA produced numerous Annexin positive cells, while treatment with NAC prevented this apoptotic cell death. Akt was slowly phosphorylated after treatment with DA, while NAC clearly inhibited the DA-induced Akt activation. Western blot analysis also showed that treatment with DA induced the activation of Bad. Finally, LY294002 exerted a protective effect against DA-induced apoptotic cell death. DA may induce redox-sensitive Akt activation and increase the level of Bad, which can promote cell death by heterodimerization with survival proteins. Moreover, NAC effectively protects against DA-induced melanocyte death via inhibition of DA-induced Akt activation.}, }
@article {pmid22477591, year = {2010}, author = {Vasdev, S and Stuckless, J}, title = {Role of methylglyoxal in essential hypertension.}, journal = {The International journal of angiology : official publication of the International College of Angiology, Inc}, volume = {19}, number = {2}, pages = {e58-65}, pmid = {22477591}, issn = {1615-5939}, abstract = {Altered glucose metabolism due to insulin resistance is a common feature of essential hypertension in humans and in animal models. Elevated endogenous aldehydes in genetic (spontaneously hypertensive rats) and acquired (fructose-induced hypertensive rats) models of essential hypertension may be due to increased production of the reactive aldehyde methylglyoxal, resulting from altered glucose metabolism. Excess methylglyoxal binds sulfhydryl groups of membrane proteins, altering calcium channels and increasing cytosolic free Ca(2+) and blood pressure. It has been demonstrated that methylglyoxal, when given in drinking water to Wistar-Kyoto rats, leads to an increase in kidney aldehyde conjugates, cytosolic free Ca(2+) concentration, decreased serum nitric oxide, renal vascular hyperplasia and hypertension. N-acetylcysteine (NAC) in the diet of these animals prevented hypertension and associated biochemical and morphological changes. NAC normalizes blood pressure by directly binding to excess methylglyoxal, thus normalizing Ca(2+) channels, cytosolic Ca(2+) and nitric oxide. NAC also leads to increased levels of tissue glutathione, a storage form of cysteine. Glutathione acts as a cofactor in the enzymatic catabolism of methylglyoxal. Cysteine and other antioxidants, such as vitamins B(6), C and E, and lipoic acid, prevented hypertension and associated biochemical and morphological changes in both genetic and acquired rat models of hypertension. The antihypertensive effect of dietary antioxidants may be due to an increase in tissue cysteine and glutathione, which improves glucose metabolism and decreases tissue methylglyoxal. A diet rich in these antioxidants may be effective in preventing and controlling hypertension in humans.}, }
@article {pmid22254046, year = {2010}, author = {Hummelen, R and Hemsworth, J and Reid, G}, title = {Micronutrients, N-acetyl cysteine, probiotics and prebiotics, a review of effectiveness in reducing HIV progression.}, journal = {Nutrients}, volume = {2}, number = {6}, pages = {626-651}, pmid = {22254046}, issn = {2072-6643}, mesh = {Acetylcysteine/*therapeutic use ; Child ; *Dietary Supplements ; Disease Progression ; Female ; Free Radical Scavengers/*therapeutic use ; HIV Infections/*drug therapy/transmission ; Humans ; Infectious Disease Transmission, Vertical/prevention &amp; control ; Micronutrients/*therapeutic use ; Prebiotics ; Pregnancy ; Pregnancy Complications, Infectious/drug therapy ; Probiotics ; Randomized Controlled Trials as Topic ; }, abstract = {Low serum concentrations of micronutrients, intestinal abnormalities, and an inflammatory state have been associated with HIV progression. These may be ameliorated by micronutrients, N-acetyl cysteine, probiotics, and prebiotics. This review aims to integrate the evidence from clinical trials of these interventions on the progression of HIV. Vitamin B, C, E, and folic acid have been shown to delay the progression of HIV. Supplementation with selenium, N-acetyl cysteine, probiotics, and prebiotics has considerable potential, but the evidence needs to be further substantiated. Vitamin A, iron, and zinc have been associated with adverse effects and caution is warranted for their use.}, }
@article {pmid22312380, year = {2010}, author = {Shohrati, M and Dermanaki, F and Babaei, F and Alavian, SM}, title = {Evaluation of the effects of oral N-acetylcysteine and a placebo in paraclinical and oxidative stress parameters of patients with chronic hepatitis B.}, journal = {Hepatitis monthly}, volume = {10}, number = {2}, pages = {95-100}, pmid = {22312380}, issn = {1735-3408}, abstract = {BACKGROUND AND AIMS: The treatment of chronic hepatitis B (CHB) is a challenging problem today, and previous study has shown that oxidative stress causes the collective pathophysiological conditions of many hepatopathies, so other new therapeutic approaches are needed. Hence, in this study the paraclinical and oxidative stress parameters of the efficacy of N-acetyl cysteine (NAC) as an antioxidant in the treatment of CHB have been evaluated.<br><br>METHODS: In this double-blind placebo-controlled clinical trial study, 43 patients with CHB were enrolled in 2008 in Tehran, Iran. The patients were randomly assigned to receive either 1200 mg/day NAC or a placebo for 45 days. Paraclinical tests and oxidative stress parameters were measured on experimental day 0 and on day 45.<br><br>RESULTS: Liver function tests, i.e. alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels were not significantly different in the NAC group and in the placebo group. A reduction in catalase (CAT) activity and an increase in glutathione concentration were statistically significant in the NAC group (P < 0.05).<br><br>CONCLUSIONS: According to our results, oral NAC is not an effective adjuvant treatment for patients with CHB, but further research with a larger population is needed for the evaluation of the effectiveness of NAC in these patients.}, }
@article {pmid21787589, year = {2010}, author = {Joshi, D and Mittal, DK and Bhadauria, M and Nirala, SK and Shrivastava, S and Shukla, S}, title = {Role of micronutrients against dimethylmercury intoxication in male rats.}, journal = {Environmental toxicology and pharmacology}, volume = {29}, number = {2}, pages = {97-103}, doi = {10.1016/j.etap.2009.11.002}, pmid = {21787589}, issn = {1872-7077}, abstract = {Mercury is one of the most toxic non-radioactive heavy metals. Chelation therapy has been the basis for the medical treatment of mercury poisoning. Male albino rats were administered dimethylmercury (1.5mg/kg) orally for 21 days. Chelation therapy with N-acetyl cysteine along with combination of antioxidants viz. zinc and selenium was given for 5 days after 24h of toxicant administration. All animals were sacrificed after 48h of last treatment and various blood biochemical parameters were performed. Toxicant caused rise in bilirubin, γ-GT, cholesterol, triglycerides, urea, creatinine, the uric acid content with a decline in albumin. A significant elevation was observed in LPO content and mercury concentration, along with concomitant decline in GSH levels after toxicant administration in liver, kidney and brain. Noticeable fall was also observed in AChE enzyme. Histopathological analysis was consistent with the biochemical observations and led to conclude that combination therapy provided protection against mercury toxicity.}, }
@article {pmid21577291, year = {2010}, author = {Ramudo, L and Manso, MA}, title = {N-acetylcysteine in acute pancreatitis.}, journal = {World journal of gastrointestinal pharmacology and therapeutics}, volume = {1}, number = {1}, pages = {21-26}, pmid = {21577291}, issn = {2150-5349}, abstract = {Premature trypsinogen activation and production of oxygen free radicals (OFR) are early pathogenic events which occur within acinar cells and trigger acute pancreatitis (AP). OFR exert their harmful effects on various cell components causing lipid peroxidation, disturbances in calcium homeostasis and DNA damage, which lead to increased cell injury and eventually cell death. This review presents the most recent data concerning the effects of N-Acetylcysteine (NAC), in the treatment of AP. NAC is an antioxidant capable of restoring the levels of Glutathione, the most important cellular antioxidant. Studies show the beneficial effects of NAC treatment in preventing OFR production and therefore attenuating oxidative damage. Additionally, NAC treatment has been shown to prevent the increase in cytosolic Ca(2+) concentration and reduce the accumulation of enzymes in acinar cells during AP. The prevention, by NAC, of these pathological events occurring within acinar would contribute to reducing the severity of AP. NAC is also capable of reducing the activation of transcription factors especially sensitive to the cellular redox state, such as Nuclear factor-κB, signal transducer and activator of transcription-3 and mitogen-activated protein kinase. This leads to a down-regulation of cytokines, adhesion molecules and chemokine expression in various cell types during AP. These findings point to NAC as a powerful therapeutic treatment, attenuating oxidative-stress-induced cell injury and other pathological events at early stages of AP, and potentially contributing to reducion in the severity of disease.}, }
@article {pmid22308119, year = {2010}, author = {Khoshbaten, M and Aliasgarzadeh, A and Masnadi, K and Tarzamani, MK and Farhang, S and Babaei, H and Kiani, J and Zaare, M and Najafipoor, F}, title = {N-acetylcysteine improves liver function in patients with non-alcoholic Fatty liver disease.}, journal = {Hepatitis monthly}, volume = {10}, number = {1}, pages = {12-16}, pmid = {22308119}, issn = {1735-143X}, abstract = {BACKGROUND AND AIMS: Non-alcoholic fatty liver change is a common disease of the liver in which oxidative stress plays a basic role. Studies are largely focused on protecting the liver by means of anti-oxidative material. The aim of this study is to evaluate the role of N- acetylcysteine in the process of liver injury.<br><br>METHODS: Thirty patients with non-alcoholic fatty liver steatosis were randomly selected to receive either N-acetylcysteine or vitamin C. Liver function tests (alanine aminotransfrase, aspartate aminotransfrase and alkaline phosphatase) were measured as well as the grade of steatosis, the pattern of its echogenicity, the span of the liver and the spleen and the portal vein diameter before the intervention. Patients were followed up using the same method of evaluation repeated in the first, second and third months.<br><br>RESULTS: The mean age (SD) was 40.1(12.4) in patients receiving NAC and 46(10.4) years in patients receiving vitamin C (P = 0.137). NAC resulted in a significant decrease of serum alanine aminotransfrase after three months, compared to vitamin C. This effect was independent of the grade of steatosis in the initial diagnosis. NAC was able to significantly decrease the span of the spleen.<br><br>CONCLUSIONS: N-acetylcysteine can improve liver function in patients with non-alcoholic fatty liver disease. Better results may be achievable in a longer follow up.}, }
@article {pmid21614182, year = {2010}, author = {Lee, IK and Kang, KA and Lim, CM and Kim, KC and Kim, HS and Kim, DH and Kim, BJ and Chang, WY and Choi, JH and Hyun, JW}, title = {Compound K, a metabolite of ginseng saponin, induces mitochondria-dependent and caspase-dependent apoptosis via the generation of reactive oxygen species in human colon cancer cells.}, journal = {International journal of molecular sciences}, volume = {11}, number = {12}, pages = {4916-4931}, pmid = {21614182}, issn = {1422-0067}, mesh = {Apoptosis/*drug effects ; Caspases/*metabolism ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Drug Screening Assays, Antitumor ; Ginsenosides/*pharmacology ; Humans ; Mitochondria/*metabolism ; Neoplasm Proteins/*metabolism ; Panax/*chemistry ; Reactive Oxygen Species/*metabolism ; Saponins/*chemistry ; }, abstract = {The objective of this study was to elucidate the cytotoxic mechanism of Compound K, with respect to the involvement of reactive oxygen species (ROS) and the mitochondrial involved apoptosis, in HT-29 human colon cancer cells. Compound K exhibited a concentration of 50% growth inhibition (IC(50)) at 20 μg/mL and cytotoxicity in a time dependent manner. Compound K produced intracellular ROS in a time dependent fashion; however, N-acetylcysteine (NAC) pretreatment resulted in the inhibition of this effect and the recovery of cell viability. Compound K induced a mitochondria-dependent apoptotic pathway via the modulation of Bax and Bcl-2 expressions, resulting in the disruption of the mitochondrial membrane potential (Δψ(m)). Loss of the Δψ(m) was followed by cytochrome c release from the mitochondria, resulting in the activation of caspase-9, -3, and concomitant poly ADP-ribosyl polymerase (PARP) cleavage, which are the indicators of caspase-dependent apoptosis. The apoptotic effect of Compound K, exerted via the activation of c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), was abrogated by specific MAPK inhibitors. This study demonstrated that Compound K-mediated generation of ROS led to apoptosis through the modulation of a mitochondria-dependent apoptotic pathway and MAPK pathway.}, }
@article {pmid21462720, year = {2010}, author = {Zhao, Y and Lin, K and Zhang, W and Liu, L}, title = {Quantum dots enhance Cu2+ -induced hepatic L02 cells toxicity.}, journal = {Journal of environmental sciences (China)}, volume = {22}, number = {12}, pages = {1987-1992}, doi = {10.1016/s1001-0742(09)60350-8}, pmid = {21462720}, issn = {1001-0742}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cell Survival/drug effects ; Copper/*toxicity ; Drug Interactions ; Heavy Metal Poisoning ; Humans ; Liver/cytology/*drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Poisoning/etiology ; *Quantum Dots ; Reactive Oxygen Species/metabolism ; }, abstract = {As a new class of xenogenous nanoparticle, quantum dots (QDs) possess the potential to co-exist with CU2+ in human liver. The combined toxicity is thus concerned. Considering QDs and Cu2+ are known ROS (reactive oxygen species) inducer, we investigated the combined oxidative stress and corresponding protective strategy using human hepatic L02 cells. The results demonstrated that the presence of a small amount of MPA-CdTe QDs (2 microg/mL) in a Cu2+ solution (2.5-20 microg/mL) resulted in a higher toxicity with up to 8-fold cell viability decrease, which was accompanied by cell morphology changes. The combined toxicity was then confirmed as ROS associated oxidative stress with up to 300% and 35% increase of the intracellular ROS level and glutathione S-transferase (GST) activity, respectively. N-acetylcysteine (NAC) can also provide almost complete protection against the induced toxicity. Therefore, the ROS associated oxidant injury might be responsible for the QDs-Cu2+/CU2+ induced toxicity and could be balanced through cytoprotective antioxidant enzyme GST.}, }
@article {pmid21784027, year = {2009}, author = {Chen, Y and Ji, L and Wang, H and Wang, Z}, title = {Intracellular glutathione plays important roles in pyrrolizidine alkaloids-induced growth inhibition on hepatocytes.}, journal = {Environmental toxicology and pharmacology}, volume = {28}, number = {3}, pages = {357-362}, doi = {10.1016/j.etap.2009.06.002}, pmid = {21784027}, issn = {1872-7077}, abstract = {Pyrrolizidine alkaloids (PAs) are well-known natural hepatotoxins distributed widely in thousands of plants in the world. Adonifoline (Adon), senecionine (Sene) and monocrotaline (Mono) are retronecine-type PAs, and the present study is designed to observe the effects of intracellular glutathione on toxicity of these three PAs in human normal liver L-02 cells. The ratio of cellular reduced glutathione (GSH) and oxidized glutathione (GSSG) was assayed after L-02 cells were incubated with these three PAs for various times. Results showed that Adon, Sene and Mono all significantly decreased the ratio of GSH/GSSG in L-02 cells in the time- and concentration-dependent manner. The results of 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) and trypan blue staining assay showed that these three PAs all significantly decreased cell viability in L-02 cells when pretreated with 10μM BSO (L-Buthionine-S-R-Sulfoximine) for 24h to deplete intracellular GSH. Further results showed that anti-oxidant compounds such as NAC (N-Acetyl-Cysteine) and GSH could rescue the cytotoxicity caused by these three PAs with BSO pretreatment. Taken together, those results suggest that intracellular GSH plays important roles in regulating the cytotoxicity induced by PAs.}, }
@article {pmid21977284, year = {2009}, author = {Jeremias, A and Soodini, G and Gelfand, E and Xu, Y and Stanton, RC and Horton, ES and Cohen, DJ}, title = {Effects of N-acetyl-cysteine on endothelial function and inflammation in patients with type 2 diabetes mellitus.}, journal = {Heart international}, volume = {4}, number = {1}, pages = {e7}, pmid = {21977284}, issn = {1826-1868}, support = {M01 RR001032/RR/NCRR NIH HHS/United States ; }, abstract = {Endothelial dysfunction has been associated with premature vascular disease. There is increasing data that N-acetyl-cysteine (NAC) may prevent or improve endothelial dysfunction. The aim of this study was to assess the effects of NAC on endothelial function in patients with type 2 diabetes mellitus, a population at high risk for endothelial dysfunction. Twenty-four patients with diabetes mellitus were assigned randomly to initial therapy with either 900 mg NAC or placebo twice daily in a double-blind, cross-over study design. Flowmediated vasodilation (FMD) of the brachial artery was assessed at baseline, after four weeks of therapy, after a four-week wash-out period, and after another four weeks on the opposite treatment. Plasma and red blood cell glutathione levels and high-sensitivity C-reactive protein (CRP) were measured at all four visits. At baseline, FMD was moderately impaired (3.7±2.9%). There was no significant change in FMD after four weeks of NAC therapy as compared to placebo (0.1±3.6% vs. 1.2±4.2%). Similarly, there was no significant change in glutathione levels. However, median CRP decreased from 2.35 to 2.14 mg/L during NAC therapy (p=0.04), while it increased from 2.24 to 2.65 mg/L with placebo. No side effects were noted during the treatment period. In this double-blind, randomized cross-over study, four weeks of oral NAC therapy failed to improve endothelial dysfunction in patients with diabetes mellitus. However, NAC therapy decreased CRP levels, suggesting that this compound may have some efficacy in reducing systemic inflammation.}, }
@article {pmid21509278, year = {2009}, author = {Al-Shukaili, A and Al-Abri, S and Al-Ansari, A and Monteil, MA}, title = {Effect of N-acetyl-L-cysteine on Cytokine Production by Human Peripheral Blood Mononuclear Cells.}, journal = {Sultan Qaboos University medical journal}, volume = {9}, number = {1}, pages = {70-74}, pmid = {21509278}, issn = {2075-051X}, abstract = {OBJECTIVES: This study investigates the in vitro effect of the antioxidant drug, N-acetyl-L-cysteine (NAC), on cytokine production by peripheral blood mononuclear cells (PBMC).<br><br>METHODS: PBMC were isolated by Ficoll-Hypaque, and stimulated with anti-CD3 antibodies, phytohaemagglutinin (PHA), lipopolysaccharide (LPS) for 24 hours in the presence or absence of 5 mM NAC. The cytokines produced were measured by enzyme-linked immunosorbent assay (ELISA).<br><br>RESULTS: Treatment with NAC significantly up-regulates the secretion of IL-1&#x3b2;, IL-5 (interleukin) and IFN-&#x3b3; (interferon) and down regulates IL-10 production, after anti-CD3 or PHA (p<0.05), but not after LPS stimulation. NAC also significantly increased total IL-12 secretion after anti-CD3 (but not PHA or LPS) stimulation and IL-12p40 after anti-CD3, PHA, and LPS stimulation (p <0.05).<br><br>CONCLUSION: These results indicate that NAC up-regulated the production of pro-inflammatory cytokines, and down regulated anti-inflammatory cytokine production by PBMC, in a process which may be associated with increased levels of glutathione (GSH). Further work is required to determine whether this increase or decrease in cytokine production is due to direct effect of NAC.}, }
@article {pmid22477552, year = {2009}, author = {Ratcliffe, JA and Thiagarajah, P and Chen, J and Kavala, G and Kanei, Y and Fox, J and Gowda, R and Schmitz, SJ and Friedmann, P and Bergmann, S}, title = {Prevention of contrast-induced nephropathy: A randomized controlled trial of sodium bicarbonate and N-acetylcysteine.}, journal = {The International journal of angiology : official publication of the International College of Angiology, Inc}, volume = {18}, number = {4}, pages = {193-197}, pmid = {22477552}, issn = {1061-1711}, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) continues to be a common cause of acute renal failure in high-risk patients undergoing radiocontrast studies. However, there is still a lack of consensus regarding the most effective measures to prevent CIN.<br><br>METHODS: ONE HUNDRED EIGHTEEN PATIENTS WITH DIABETES MELLITUS AND/OR RENAL INSUFFICIENCY, SCHEDULED FOR CORONARY ANGIOGRAPHY OR INTERVENTION, WERE RANDOMLY ASSIGNED TO ONE OF FOUR TREATMENT GROUPS: intravenous (IV) 0.9% NaCl alone, IV 0.9% NaCl plus N-acetylcysteine (NAC), IV 0.9% sodium bicarbonate (NaHCO(3)) alone or IV 0.9% NaHCO(3) plus NAC. All patients received IV hydration as a preprocedure bolus and as maintenance. Iso-osmolar contrast was used in all patients. CIN was defined as an increase of greater than 25% in the serum creatinine concentration from baseline to 72 h.<br><br>RESULTS: The overall incidence of CIN was 6%. There was no statistically significant difference in the incidence of CIN among the groups. There was a CIN incidence of 7% in the NaCl only group, 5% in the NaCl/NAC group, 11% in the NaHCO(3) only group and 4% in the NaHCO(3)/NAC group (P=0.86). The maximum increase in serum creatinine was 14.14&#xb1;12.38 &#x3bc;mol/L in the NaHCO(3) group, 10.60&#xb1;29.14 &#x3bc;mol/L in the NaCl only group, 9.72&#xb1;13.26 &#x3bc;mol/L in the NaCl/NAC group and 0.177&#xb1;15.91 &#x3bc;mol/L for the NaHCO(3)/NAC group (P=0.0792).<br><br>CONCLUSION: CIN in high-risk patients may be effectively minimized solely through the use of an aggressive hydration protocol and an iso-osmolar contrast agent. The addition of NaHCO(3) and/or NAC did not have an effect on the incidence of CIN.}, }
@article {pmid21783925, year = {2009}, author = {Lee, S and Cha, M and Kang, C and Sohn, ET and Lee, H and Munawir, A and Kim, JS and Kim, E}, title = {Mutual synergistic toxicity between environmental toxicants: A study of mercury chloride and 4-nonylphenol.}, journal = {Environmental toxicology and pharmacology}, volume = {27}, number = {1}, pages = {90-95}, doi = {10.1016/j.etap.2008.08.009}, pmid = {21783925}, issn = {1382-6689}, abstract = {Mercury chloride (HgCl(2)) and 4-nonylphenol (NP) are widespread environmental and industrial pollutants that are known to have toxic effects as well as endocrine disrupting activities. Although the individual effects of HgCl(2) and NP in liver have been relatively well recognized, little is known about the interaction of NP and HgCl(2) during the induction of their toxicity. In the current study, we investigated the synergism between HgCl(2) and NP using HepG2 cells. Surprisingly, the concurrent treatment of HepG2 with HgCl(2) and NP induced a significant cytotoxicity at concentrations where neither of them have any cytotoxic effect when treated alone. The cytotoxicity of NP is enhanced in the presence of HgCl(2) (a shift from 74.9 to 47.4μM in LC(50)) and vice versa (a shift from 94.9 to 66.3μM in LC(50)). Estrogen receptor antagonists such as ICI 182,780 did not protect HepG2 cells from these cytotoxic insults. Whereas the intracellular level of reduced form glutathione (GSH) was considerably decreased upon the co-treatment with NP and HgCl(2). Furthermore, the synergistic cytotoxicity was significantly inhibited by 20-mM N-acetylcysteine (NAC). These results indicate that the mutual synergistic cytotoxicity of HgCl(2) and NP on HepG2 cell is not associated with estrogen receptor signaling but mediated by reactive oxygen species (ROS) generation. In our real life, we are continuously and often simultaneously exposed to many different kinds of environmental pollutants. The present study suggests a mechanism of potential synergistic adverse effects of these toxic pollutants.}, }
@article {pmid22433041, year = {2008}, author = {Hewawasam, RP and Jayatilaka, KA and Pathirana, C}, title = {Effect of Asparagus falcatus on acetaminophen toxicity in mice: a comparison of antioxidative effect with N-acetyl cysteine.}, journal = {Journal of dietary supplements}, volume = {5}, number = {1}, pages = {1-19}, doi = {10.1080/19390210802328933}, pmid = {22433041}, issn = {1939-022X}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/pharmacology/*therapeutic use ; Analysis of Variance ; Animals ; Antioxidants/metabolism/pharmacology/*therapeutic use ; *Asparagus Plant ; Chemical and Drug Induced Liver Injury/metabolism/pathology/*prevention &amp; control ; Liver/*drug effects/enzymology/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred ICR ; *Phytotherapy ; Plant Extracts/administration &amp; dosage/pharmacology/therapeutic use ; }, abstract = {OBJECTIVE: In this study, the effect of Asparagus falcatus extract on acetaminophen-induced liver injury was investigated in vivo.<br><br>METHOD: Six arms of study. ICR mice (n = 20) were treated with acetaminophen at a single dose of 300 mg/kg (in saline, after a 16-hr fast) to induce hepatotoxicity. Drug control group and pre- and posttreated groups were administered 0.9 g/kg of Asparagus falcatus orally. Serum ALT, AST, ALP, liver GSH, antioxidant enzymes, GPx (glutathione peroxidase), GR (glutathione reductase), GST (glutathione-S-transferase), and liver/serum malondialdehyde (MDA) concentrations were estimated. Liver damage was also assessed histopathologically. The effect of the plant extract was compared with N-acetyl cysteine.<br><br>RESULTS: Acetaminophen produced liver damage, as manifested by a significant rise (P <. 001, one-way ANOVA) in serum ALT, AST, and ALP, and a reduction (P <. 001) in the liver reduced glutathione (GSH) as compared to respective controls. All enzyme activities and liver GSH were significantly improved in Asparagus-treated mice, with pretreatment providing better results than posttreatment (P <. 05). Histopathologically, mice pretreated with Asparagus showed no liver necrosis. A significant improvement was observed in antioxidant enzyme activities of GPx, GR, and GST in the Asparagus pretreated group (P <. 05). Mice posttreated with Asparagus showed a significant reduction in MDA formation (P <. 05).<br><br>CONCLUSION: These results suggest that the feeding regimen with Asparagus extract inhibited the progression of hepatic injury induced by acetaminophen.}, }
@article {pmid21782725, year = {2004}, author = {Coleman, MD and Khan, N and Welton, G and Lambert, PA and Tims, KJ and Rathbone, DL}, title = {Effects of glutathione, N-acetyl-cysteine, α-lipoic acid and dihydrolipoic acid on the cytotoxicity of a 2-pyridylcarboxamidrazone antimycobacterial agent in human mononuclear leucocytes in vitro.}, journal = {Environmental toxicology and pharmacology}, volume = {17}, number = {3}, pages = {143-148}, doi = {10.1016/j.etap.2004.04.002}, pmid = {21782725}, issn = {1382-6689}, abstract = {A series of antioxidants was used to explore the cytotoxicity of one particularly toxic antimycobacterial 2-pyridylcarboxamidrazone anti-tuberculosis agent against human mononuclear leucocytes (MNL), in comparison with isoniazid (INH) to aid future compound design. INH caused a significant reduction of nearly 40% in cell recovery compared with control (P < 0.0001), although the co-incubation with either glutathione (GSH, 1mM) or (NAC, 1mM) showed abolition of INH toxicity. In contrast, the addition of GSH or NAC 1h after INH failed to protect the cells from INH toxicity (P < 0.0001). The 2-pyridyl-carboxamidrazone 'Compound 1' caused a 50% reduction in cell recovery compared with control (P < 0.001), although this was abolished by the presence of either GSH or NAC. A 1h post incubation with either NAC or GSH after Compound 1 addition failed to protect the cells from toxicity (P < 0.001). Co-administration of lipoic acid (LA) abolished Compound 1-mediated toxicity, although again, this effect did not occur after LA addition 1h post incubation with Compound 1 (P < 0.001). However, co-administration of dihydrolipoic acid (DHLA) prevented Compound 1-mediated cell death when incubated with the compound and also after 1h of Compound 1 alone. Pre-treatment with GSH, then removal of the antioxidant resulted in abolition of Compound 1 toxicity (vehicle control, 63.6 ± 16.7 versus Compound 1 alone 26.1 ± 13.6% versus GSH pre-treatment, 65.7 ± 7.3%). In a cell-free incubation, NMR analysis revealed that GSH does not react with Compound 1, indicating that this agent is not likely to directly deplete membrane thiols. Compound 1's MNL toxicity is more likely to be linked with changes in cell membrane conformation, which may induce consequent thiol depletion that is reversible by exogenous thiols.}, }
@article {pmid21782671, year = {2003}, author = {Coleman, MD and Taylor, CT}, title = {Effects of dihydrolipoic acid (DHLA), α-lipoic acid. N-acetyl cysteine and ascorbate on xenobiotic-mediated methaemoglobin formation in human erythrocytes in vitro.}, journal = {Environmental toxicology and pharmacology}, volume = {14}, number = {3}, pages = {121-127}, doi = {10.1016/S1382-6689(03)00048-6}, pmid = {21782671}, issn = {1382-6689}, abstract = {α-Lipoic acid, dihydrolipoic acid (DHLA), N-acetyl cysteine and ascorbate were compared with methylene blue for their ability to attenuate and/or reduce methaemoglobin formation induced by sodium nitrite, 4-aminophenol and dapsone hydroxylamine in human erythrocytes. Neither α-lipoic acid, DHLA, N-acetyl cysteine nor ascorbate had any significant effects on methaemoglobin formed by nitrite, either from pre-treatment, simultaneous addition or post 30 min addition of the agents up to the 60 min time point, although N-acetyl cysteine did reduce methaemoglobin formation at 120 min (P<0.05). In all three treatment groups at 30, 60 and 120 min, there were no significant effects mediated by DHLA or N-acetyl cysteine on 4-aminophenol (1 mM)-mediated haemoglobin oxidation. Ascorbate caused marked significant reductions in 4-aminophenol methaemoglobin in all treatment groups at 30-120 min except at 30 min in the simultaneous addition group (P<0.0001). Neither α-lipoic acid, nor N-acetyl cysteine showed any effects on hydroxylamine-mediated methaemoglobin formation at 30 and 60 in all treatment groups. In contrast, DHLA significantly reduced hydroxylamine-mediated methaemoglobin formation at all three time points after pre-incubation and simultaneous addition (P<0.001), while ascorbate was ineffective. Compared with methylene blue, which was effective in reducing methaemoglobin formation by all three toxins (P<0.01), ascorbate was only highly effective against 4-aminophenol mediated methaemoglobin, whilst the DHLA-mediated attenuation of dapsone hydroxylamine-mediated methaemoglobin formation indicates a possible clinical application in high-dose dapsone therapy.}, }
@article {pmid21782669, year = {2003}, author = {Wong, CK and Ooi, VE and Wong, CK}, title = {Protective effects of N-acetylcysteine against carbon tetrachloride- and trichloroethylene-induced poisoning in rats.}, journal = {Environmental toxicology and pharmacology}, volume = {14}, number = {3}, pages = {109-116}, doi = {10.1016/S1382-6689(03)00045-0}, pmid = {21782669}, issn = {1382-6689}, abstract = {This research investigates the protective effect of N-acetylcysteine (NAC) against carbon tetrachloride (CCl(4))- and trichloroethylene (TCE)-induced hepatotoxicity in rats. A single dose of 1.25 ml/kg of 20% CCl(4) in corn oil, administered orally, or 20% TCE, administered intraperitoneally, produced significantly elevated levels of serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) activities. Histopathological examinations showed massive centrilobular necrosis and fat accumulation in CCl(4)-treated animals. In the curative test, especially in animals treated with higher dosages of NAC, there was significant reduction in SGPT and SGOT levels. Although there was no sign of abnormality in the livers of rats treated with TCE, NAC demonstrated its action against TCE-induced elevation of transaminases in the enzyme assays. Compared to the curative tests, the overall performance of NAC against toxin-induced toxicity in the preventive tests was poor. Even at the highest dosage applied, the effect was not as prominent as that achieved in the curative test. It is therefore concluded that NAC is effective for lowering chemical-induced elevated levels of SGPT and SGOT in the curative mode.}, }
@article {pmid21782660, year = {2003}, author = {Coleman, MD and Tims, KJ and Rathbone, DL}, title = {The use of computational QSAR analysis in the toxicological evaluation of a series of 2-pyridylcarboxamidrazone candidate anti-tuberculosis compounds.}, journal = {Environmental toxicology and pharmacology}, volume = {14}, number = {1-2}, pages = {33-42}, doi = {10.1016/S1382-6689(03)00008-5}, pmid = {21782660}, issn = {1382-6689}, abstract = {A series of N(1)-benzylidene pyridine-2-carboxamidrazone anti-tuberculosis compounds has been evaluated for their cytotoxicity using human mononuclear leucocytes (MNL) as target cells. All eight compounds were significantly more toxic than dimethyl sulphoxide control and isoniazid (INH) with the exception of a 4-methoxy-3-(2-phenylethyloxy) derivative, which was not significantly different in toxicity compared with INH. The most toxic agent was an ethoxy derivative, followed by 3-nitro, 4-methoxy, dimethylpropyl, 4-methylbenzyloxy, 3-methoxy-4-(-2-phenylethyloxy) and 4-benzyloxy in rank order. In comparison with the effect of selected carboxamidrazone agents on cells alone, the presence of either N-acetyl cysteine (NAC) or glutathione caused a significant reduction in the toxicity of INH, as well as on the 4-benzyloxy derivative, although both increased the toxicity of a 4-N,N-dimethylamino-1-naphthylidene and a 2-t-butylthio derivative. The derivatives from this and three previous studies were subjected to computational analysis in order to derive equations designed to establish quantitative structure activity relationships for these agents. Twenty-five compounds were thus resolved into two groups (1 and 2), which on analysis yielded equations with r(2) values in the range 0.65-0.92. Group 1 shares a common mode of toxicity related to hydrophobicity, where cytotoxicity peaked at logP of 3.2, while Group 2 toxicity was strongly related to ionisation potential. The presence of thiols such as NAC and GSH both promoted and attenuated toxicity in selected compounds from Group 1, suggesting that secondary mechanisms of toxicity were operating. These studies will facilitate the design of future low toxicity high activity anti-tubercular carboxamidrazone agents.}, }
@article {pmid22061980, year = {2003}, author = {Yin, MC and Cheng, WS}, title = {Antioxidant and antimicrobial effects of four garlic-derived organosulfur compounds in ground beef.}, journal = {Meat science}, volume = {63}, number = {1}, pages = {23-28}, doi = {10.1016/s0309-1740(02)00047-5}, pmid = {22061980}, issn = {0309-1740}, abstract = {The antioxidant and antimicrobial protection of diallyl sulfide (DAS), diallyl disulfide (DADS), s-ethyl cysteine (SEC), n-acetyl cysteine (NAC) in ground beef against discoloration, lipid oxidation and microbial contamination were studied. The exogenous addition of these garlic-derived organosulfur compounds significantly delayed both oxymyoglobin and lipid oxidations (P<0.05). The antioxidant protection from these organosulfur compounds was dose-dependent (P<0.05), and showed significantly greater antioxidant activity than α-tocopherol (P<0.05). The presence of DAS and DADS in ground beef significantly reduced total aerobes and inhibited the growth of five inoculated pathogenic bacteria, Salmonella typhimurium, Escherichia coli O157:H7, Listeria monocytogenes, Staphyllococcus aureus and Campylobacter jejuni (P<0.05). These results suggested the application of these organosulfur compounds in meat or other food systems could enhance color, lipid and microbial safety.}, }
@article {pmid21174818, year = {2002}, author = {Huang, XL and Ling, YL and Zhu, TN}, title = {[The role of N-acetylcysteine against the injury of pulmonary artery induced by LPS].}, journal = {Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology}, volume = {18}, number = {4}, pages = {370-373}, pmid = {21174818}, issn = {1000-6834}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Endothelium/metabolism/*pathology/ultrastructure ; Lipopolysaccharides/*adverse effects ; Malondialdehyde/metabolism ; Microscopy, Electron, Scanning ; Nitric Oxide/metabolism ; Pulmonary Artery/metabolism/*pathology/ultrastructure ; Rabbits ; Superoxide Dismutase/metabolism ; }, abstract = {AIM: To investigate the alleviating effect of N-acetylcysteine (NAC) on lung injury induced by lipopolysaccharides (LPS) and its mechanism.<br><br>METHODS: The effects of NAC on changes of the pulmonary arterial reactivity and the ultrastructure of pulmonary arterial endothelium induced by LPS were observed with the isolated artery ring technique and scanning electron microscope (SEM). Malondialdehyde (MDA), nitric oxide (NO) contents and superoxide dismutase (SOD) activity of pulmonary artery tissues were detected.<br><br>RESULTS: The exposure of pulmonary artery to LPS (4 microg/ml, 7 h) led to reduction of endothelium-dependent relaxation response to acetylcholine (ACh), which was reversed by the concomitant exposure to NAC (0.5 mmol/L, 7 h), whereas NAC itself had no effect on the response. Significant structural injury were observed under SEM in LPS group and alleviated the changes in LPS + NAC group. The MDA, NO contents increased but SOD activity decreased in LPS group, which were reversed by the concomitant exposure to NAC.<br><br>CONCLUSION: NAC protects pulmonary artery endothelium and enhances endothelium-dependent relaxation response of pulmonary artery by antioxidation effect, which may be one of the mechanisms of its reversing pulmonary artery hypertension and following lung injury induced by LPS.}, }
@article {pmid22387694, year = {2001}, author = {Dhitavat, S and Rivera, ER and Rogers, E and Shea, TB}, title = {Differential efficacy of lipophilic and cytosolic antioxidants on generation of reactive oxygen species by amyloid-ß.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {3}, number = {6}, pages = {525-529}, pmid = {22387694}, issn = {1387-2877}, abstract = {Exposure of neurons to amyloid-beta (Abeta) is accompanied by a cascade of oxidative damage that initiates with lipid peroxidation followed by subsequent generation of cytosolic free radicals and reactive oxygen species (ROS). The antioxidant vitamin E has been utilized to counteract Abeta-induced oxidative stress. We considered herein whether or not the lipid-solubility of vitamin E limits its neuroprotection to membrane-related oxidative damage, and renders it relatively ineffective where prior lipid peroxidation has already generated cytosolic free radicals and ROS. To test this possibility, we treated differentiated SH-SY-5Y human neuroblastoma with vitamin E or a cell-permeant antioxidant, N-acetyl cysteine (NAC), simultaneously with or 15 min after the application of Abeta. Both vitamin E and NAC prevented Abeta-induced ROS generation when applied simultaneously with Abeta, but only NAC prevented Abeta-induced ROS generation when added to cultures that had previously been exposed to Abeta. These results support the hypothesis that vitamin E can quench Abeta-induced lipid peroxidation, but cannot effectively quench ROS generated by prior lipid peroxidation. These findings in cell culture may provide limited insight into why vitamin E is not fully effective against neurodegeneration in AD in clinical settings, since some neuronal populations are likely to already have been compromised by prior Abeta exposure before vitamin E treatment was initiated.}, }
@article {pmid21781937, year = {1999}, author = {Dobrzyńska, I and Skrzydlewska, E and Figaszewski, Z}, title = {Influence of trolox derivative and N-acetylcysteine on surface charge density of erythrocytes in methanol intoxicated rats.}, journal = {Environmental toxicology and pharmacology}, volume = {8}, number = {1}, pages = {15-21}, doi = {10.1016/s1382-6689(99)00024-1}, pmid = {21781937}, issn = {1382-6689}, abstract = {Methanol is oxidized in vivo to formaldehyde and then to formate and these processes are accompanied by free radicals generation. This paper reports the effect of antioxidants: trolox derivative (U-83836E) and N-acetylcysteine (NAC) on lipid peroxidation, surface charge density and hematological parameters of erythrocytes from rats intoxicated with methanol (3.0 g/kg body weight). Methanol administration caused increase in erythrocyte lipid peroxidation products and changes in surface charge density. Ingestion of methanol with U-83836E and NAC partially prevented these methanol-induced changes. This suggests that U83836E and NAC act as effective antioxidants and free radicals scavengers. They may have efficacy in protecting free radical damage to erythrocytes following methanol intoxication.}, }
@article {pmid21528327, year = {1997}, author = {Arif, J and Gairola, C and Glauert, H and Kelloff, G and Lubet, R and Gupta, R}, title = {Effects of dietary supplementation of N-acetylcysteine on cigarette smoke-related DNA adducts in rat tissues.}, journal = {International journal of oncology}, volume = {11}, number = {6}, pages = {1227-1233}, doi = {10.3892/ijo.11.6.1227}, pmid = {21528327}, issn = {1019-6439}, abstract = {Cigarette smoking plays a major role in the etiology of several human cancers. It is believed that formation of DNA adducts is an initial step in the carcinogenic process. In this study, we have examined the ability of dietary N-acetylcysteine (NAG) to inhibit the formation of cigarette smoke-related DNA adducts in various tissues of rats. Female Sprague-Dawley rats were exposed to cigarette smoke (10 mg TPM/m(3)) in a whole-body exposure chamber for 6 h per day, seven days a week for four weeks. The smoke-exposed groups were provided either an unrefined diet or diets supplemented with low (5,000 ppm) or high (20,000 ppm) dose of NAG. A sham group was given control diet and maintained on filtered ambient air. Tissue DNA analysis of smoke-exposed rats by nuclease P1-version of the P-32-postlabeling assay showed up to 6 adducts in the following descending order expressed as total adducts/10(10) nucleotides: 1 predominant (no. 5) and 4 (no. 1-no. 4) minor adducts in the (219 +/- 36), 6 minor adducts in the heart (93 +/- 11), 5 adducts in the trachea (50 +/- 16), and 4 adducts in the bladder (50 +/- 3.5); sham-treated animals showed 2 or 3 adducts in each tissue but at 4-20-fold lower levels. Dietary intervention with either high or low dose of NAC did not affect the levels of most adducts, except for the following: a 30-40% increase (P<0.05) for adducts 3 and 4 in the lung; a 40-50% decrease (P<0.05) for adduct 2 in the trachea; and a 30% increase (P<0.05) for adduct 2 in the bladder. In a second experiment conducted under identical conditions, most major and minor adducts remained unaffected with NAC intervention, except for adduct 2 in the trachea which was somewhat diminished. These results suggest that dietary NAC intervention does not significantly influence the levels of most major and minor adducts. However, some minor adducts in the lung, trachea and bladder were modulated differentially.}, }
@article {pmid21573453, year = {1993}, author = {Parfett, C and Macmillan, J and Pilon, R}, title = {Oxidative stress mediates tumor promoter-induced proliferin gene-expression in c3h10t1/2 cells.}, journal = {International journal of oncology}, volume = {3}, number = {5}, pages = {917-925}, doi = {10.3892/ijo.3.5.917}, pmid = {21573453}, issn = {1019-6439}, abstract = {Increased expression of the proliferin gene family occurs upon exposure of C3H10T1/2 cells to a broad range of chemical agents known to promote morphological transformation and likely to increase cellular reactive oxygen species. To determine if proliferin gene expression is influenced by reactive oxygen species, superoxide radicals were generated in culture by the xanthine/xanthine oxidase couple. The 1 kb cytoplasmic proliferin transcript accumulated up to ten-fold following extracellular superoxide production. Within certain concentration ranges of catalase and superoxide dismutase activity, xanthine oxidase-induced proliferin expression was reduced to control levels, while expression was increased at other concentrations. Induction of proliferin by the tumour promoters butylated hydroxytoluene or TPA was efficiently inhibited at certain concentrations of catalase and superoxide dismutase, but retinoic acid had no effect. Proliferin induction by a recently identified promoter of transformation, tri-n-butyltin chloride, was stimulated by catalase, superoxide dismutase and retinoic acid, but inhibited at higher concentrations of N-acetyl cysteine. c-fos preceded proliferin induction by butylated hydroxytoluene, but several other oncogenes and growth-regulated genes were unaffected. The results support a mechanism for tumour promoter-induced proliferin gene expression that involves a response to superoxide anions, hydrogen peroxide or other shifts in the cellular equilibrium between pro-oxidant and anti-oxidant moieties.}, }
@article {pmid21573353, year = {1993}, author = {Mizutani, Y and Bonavida, B}, title = {Overcoming tnf-alpha and cddp resistance of a human ovarian-cancer cell-line (c30) by treatment with buthionine sulfoximine in combination with tnf-alpha and or cddp.}, journal = {International journal of oncology}, volume = {3}, number = {2}, pages = {229-235}, doi = {10.3892/ijo.3.2.229}, pmid = {21573353}, issn = {1019-6439}, abstract = {Previous studies have demonstrated that glutathione (GSH) plays an important role in a wide range of cellular functions including protection, detoxification, transport and metabolism. GSH has been implicated in tumor cell resistance to drugs and/or cytotoxic factors. Buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, depletes intracellular GSH and thus could reverse resistance. The present study investigated the effect of BSO used in combination with tumor necrosis factor-alpha (TNF-alpha) or cisdiamminedichloroplatinum (II) (CDDP) on cytotoxicity of a TNF-alpha and CDDP resistant human ovarian cancer cell line (C30). Cytotoxicity was monitored by the MTT assay. Treatment of C30 cells with BSO and CDDP or BSO and TNF-alpha resulted in overcoming resistance and a synergistic cytotoxic effect was obtained. Pretreatment of the tumor cells by either agent for 4 h and wash and followed by the addition of the second agent for 20 h resulted in the same cytotoxicity as observed in the presence of the two agents. Furthermore, combination treatment with BSO, CDDP and TNF-alpha further augmented the synergistic cytotoxic activity achieved by two agents against C30 cells. The protective effect of GSH was shown for TNF-alpha but not for CDDP as treatment of C30 cells with TNF-alpha in combination with GSH or N-acetyl-cysteine (NAC) reduced the cytotoxic effect of TNF-alpha. One mechanism of resistance to TNF-alpha in tumor cells is through the induction of TNF-alpha mRNA and/or protein. The C30 cells did not constitutively express TNF-alpha mRNA, however, treatment of C30 cells with TNF-alpha upregulated the expression of TNF-alpha mRNA. When BSO was used in combination with TNF-alpha, the level of TNF-alpha mRNA induced by TNF-alpha was markedly reduced. Further, incubation of C30 cells with TNF-alpha in conjunction with GSH or NAC also downregulated the expression of TNF-alpha mRNA induced by TNF-alpha. These findings demonstrate that treatment with BSO in combination with TNF-alpha or CDDP can overcome the resistance of C30 tumor cells to TNF-alpha and CDDP. The depletion of intracellular GSH and downregulation of TNF-alpha mRNA by BSO may play a role in the enhanced cytotoxicity seen with the combination of BSO and TNF-alpha. The synergistic effect obtained with a CDDP selected resistant ovarian cancer cell line suggests that treatment with BSO in conjunction with either TNF-alpha or CDDP, or TNF-alpha and CDDP may have a clinical application in the therapy of TNF-alpha and/or CDDP resistant ovarian tumors'}, }
@article {pmid20713718, year = {2010}, author = {Hirota, Y and Acar, N and Tranguch, S and Burnum, KE and Xie, H and Kodama, A and Osuga, Y and Ustunel, I and Friedman, DB and Caprioli, RM and Daikoku, T and Dey, SK}, title = {Uterine FK506-binding protein 52 (FKBP52)-peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {107}, number = {35}, pages = {15577-15582}, pmid = {20713718}, issn = {1091-6490}, support = {R37 HD012304/HD/NICHD NIH HHS/United States ; HD12304/HD/NICHD NIH HHS/United States ; DA006668/DA/NIDA NIH HHS/United States ; R01 DA006668/DA/NIDA NIH HHS/United States ; R37 DA006668/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Blotting, Northern ; Blotting, Western ; Embryo Implantation/drug effects ; Endometrium/cytology/metabolism ; Female ; Gene Expression Profiling ; Herbicides/pharmacology ; Humans ; In Situ Hybridization ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Ovariectomy ; *Oxidative Stress ; Paraquat/pharmacology ; Peroxiredoxin VI/genetics/*metabolism ; Pregnancy ; Progesterone/pharmacology ; Receptors, Progesterone/genetics/metabolism ; Signal Transduction/*physiology ; Tacrolimus Binding Proteins/genetics/*metabolism ; Time Factors ; Uterus/drug effects/*metabolism ; }, abstract = {Immunophilin FK506-binding protein 52 (FKBP52) is a cochaperone that binds to the progesterone receptor (PR) to optimize progesterone (P(4))-PR signaling. We recently showed that Fkbp52-deficient (Fkbp52(-/-)) mice have reduced uterine PR responsiveness and implantation failure which is rescued by excess P(4) supplementation in a genetic background-dependent manner. This finding led us to hypothesize that FKBP52 has functions in addition to optimizing PR activity. Using proteomics analysis, we found that uterine levels of peroxiredoxin-6 (PRDX6), a unique antioxidant, are significantly lower in Fkbp52(-/-) mice than in WT and PR-null (Pgr(-/-)) mice. We also found that Fkbp52(-/-) mice with reduced uterine PRDX6 levels are susceptible to paraquat-induced oxidative stress (OS), leading to implantation failure even with P(4) supplementation. The same dose of paraquat did not interfere with implantation in WT mice. Moreover, treatment with antioxidants alpha-tocopherol and N-acetylcysteine (NAC) attenuated paraquat-induced implantation failure in P(4)-treated Fkbp52(-/-) mice. Functional analyses using mouse embryonic fibroblasts show that Fkbp52 deficiency associated with reduced PRDX6 levels promotes H(2)O(2)-induced cell death, which is reversed by the addition of NAC or by forced expression of PRDX6, suggesting that Fkbp52 deficiency diminishes the threshold against OS by reducing PRDX6 levels. These findings provide evidence that heightened uterine OS in Fkbp52(-/-) females with reduced PRDX6 levels induces implantation failure even in the presence of excess P(4). This study shows that FKBP52-PRDX6 signaling protects pregnancy from overt OS.}, }
@article {pmid20712021, year = {2010}, author = {Zyoud, SH and Awang, R and Sulaiman, SA and Al-Jabi, SW}, title = {Effects of delay in infusion of N-acetylcysteine on appearance of adverse drug reactions after acetaminophen overdose: a retrospective study.}, journal = {Pharmacoepidemiology and drug safety}, volume = {19}, number = {10}, pages = {1064-1070}, doi = {10.1002/pds.1955}, pmid = {20712021}, issn = {1099-1557}, mesh = {Acetaminophen/*poisoning/therapeutic use ; Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Adult ; Anaphylaxis/chemically induced/drug therapy ; Antidotes/administration &amp; dosage/adverse effects/*therapeutic use ; Drug Overdose/*drug therapy ; Female ; Humans ; Male ; Retrospective Studies ; Risk Factors ; Time Factors ; Young Adult ; }, abstract = {PURPOSE: To investigate the relationship between different types of adverse drug reaction (ADR) and late time to N-acetylcysteine (NAC) infusion in patients presenting to the hospital with acetaminophen overdose.<br><br>METHODS: This is a retrospective study of patients admitted to the hospital for acute acetaminophen overdose over a period of 5 years (1 January 2004 to 31 December 2008). The primary outcome of interest was the relationship between ADR, if any, and late time to NAC infusion. Parametric and non-parametric tests were used to test differences between groups depending on the normality of the data. SPSS 15 was used for data analysis.<br><br>RESULTS: Of 305 patients with acetaminophen overdose, 146 (47.9%) were treated with intravenous NAC and 139 (45.6%) were included in this study. Different types of ADR were observed in 94 (67.6%) patients. Late time to NAC infusion was significantly associated with cutaneous anaphylactoid reactions when compared to patients without this type of ADR (p &#x2009;<&#x2009; 0.001). However, there were no significant differences in time to NAC infusion between patients with and without the following ADR: gastrointestinal reactions (p&#x2009;=&#x2009;0.11), respiratory reactions (p&#x2009;=&#x2009;0.77), central nervous reactions (p&#x2009;=&#x2009;0.64), and cardiovascular reactions (p&#x2009;=&#x2009;0.63).<br><br>CONCLUSION: Late time to NAC infusion is a risk factor for developing cutaneous anaphylactoid reactions, suggesting, rather than proving, that early NAC infusion (&#x2264; 8&#x2009;hours) may be protective against this type of ADR.}, }
@article {pmid20711262, year = {2010}, author = {Byamba, D and Kim, TG and Kim, DH and Je, JH and Lee, MG}, title = {The Roles of Reactive Oxygen Species Produced by Contact Allergens and Irritants in Monocyte-derived Dendritic Cells.}, journal = {Annals of dermatology}, volume = {22}, number = {3}, pages = {269-278}, pmid = {20711262}, issn = {2005-3894}, abstract = {BACKGROUND: Although reactive oxygen species (ROS) have been produced in both mouse bone marrow-derived dendritic cells (DCs) and XS-106 DCs by contact sensitizers and irritants in previous studies, the generation of ROS in human monocyte-derived DCs (MoDCs) and their role in contact hypersensitivity (CHS) has yet to be elucidated.<br><br>OBJECTIVE: The purpose of this study was to determine whether contact allergens and irritants induce ROS in MoDCs and, if so, to evaluate the role of contact allergen and irritant induced-ROS in MoDCs in CHS.<br><br>METHODS: Production of ROS was measured by 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA) assay. Surface CD86 and HLA-DR molecules were detected by flow cytometry. Protein carbonylation was detected by Western blotting.<br><br>RESULTS: ROS were produced by contact allergens such as dinitrochlorobenzene (DNCB) and thimerosal and the irritant benzalkonium chloride (BKC). DNCB-induced, but not BKC-induced, ROS increased surface CD86 and HLA-DR molecules on MoDCs and induced protein carbonylation. These changes were reduced in the presence of antioxidant N-acetyl cysteine.<br><br>CONCLUSION: Our results suggest that DNCB-induced ROS may be different from those induced by irritant BKC. The DNCB-induced ROS may be associated with the CHS response, because they activate surface molecules on DCs that are important for generating immune reactions.}, }
@article {pmid20708635, year = {2010}, author = {Grosicka-Maciąg, E and Kurpios-Piec, D and Grzela, T and Czeczot, H and Skrzycki, M and Szumiło, M and Rahden-Staroń, I}, title = {Protective effect of N-acetyl-L-cysteine against disulfiram-induced oxidative stress and apoptosis in V79 cells.}, journal = {Toxicology and applied pharmacology}, volume = {248}, number = {3}, pages = {210-216}, doi = {10.1016/j.taap.2010.08.004}, pmid = {20708635}, issn = {1096-0333}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Cell Line ; Cricetinae ; Cricetulus ; Disulfiram/antagonists &amp; inhibitors/*toxicity ; Dose-Response Relationship, Drug ; Fibroblasts/drug effects/metabolism/physiology ; Lipid Peroxidation/drug effects/physiology ; Oxidative Stress/*drug effects/physiology ; }, abstract = {This work investigated the effect of N-acetyl-L-cysteine (NAC) on disulfiram (DSF) induced oxidative stress in Chinese hamster fibroblast cells (V79). An increase in oxidative stress induced by DSF was observed up to a 200 μM concentration. It was evidenced by a statistically significant increase of both GSH(t) and GSSG levels, as well as elevated protein carbonyl (PC) content. There was no increase in lipid peroxidation (measured as TBARS). DSF increased CAT activity, but did not change SOD1 and SOD2 activities. Analysis of GSH related enzymes showed that DSF significantly increased GR activity, did not change Se-dependent GPx, but statistically significantly decreased non-Se-dependent GPx activity. DSF showed also pro-apoptotic activity. NAC alone did not produce any significant changes, besides an increase of GSH(t) level, in any of the variables measured. However, pre-treatment of cells with NAC ameliorated DSF-induced changes. NAC pre-treatment restored the viability of DSF-treated cells evaluated by Trypan blue exclusion assay and MTT test, GSSG level, and protein carbonyl content to the control values as well as it reduced pro-apoptotic activity of DSF. The increase of CAT and GR activity was not reversed. Activity of both GPx was significantly increased compared to their values after DSF treatment. In conclusion, oxidative properties are at least partially attributable to the cellular effects of disulfiram and mechanisms induced by NAC pre-treatment may lower or even abolish the observed effects. These observations illustrate the importance of the initial cellular redox state in terms of cell response to disulfiram exposure.}, }
@article {pmid20707288, year = {2010}, author = {Pintucci, JP and Corno, S and Garotta, M}, title = {Biofilms and infections of the upper respiratory tract.}, journal = {European review for medical and pharmacological sciences}, volume = {14}, number = {8}, pages = {683-690}, pmid = {20707288}, issn = {1128-3602}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/pharmacology ; Bacterial Adhesion/drug effects ; *Biofilms ; Drug Resistance, Bacterial ; Humans ; Respiratory Tract Infections/drug therapy/*microbiology ; }, abstract = {Biofilms are microbial communities consisting of bacteria that either are self-reproducing on biological surfaces or are present in the lifeless environment. Biofilms are quite diffuse entities frequently found in human pathological conditions. The formation of bacterial biofilms involves mainly the contamination of artificial medical devices, such as valves and catheters, and their direct implant on mucous membranes, with subsequent development of chronic or recurrent infections. Bacterial biofilms show a complex organization consisting of bacterial cells adherent to a surface and surrounded by a large extracellular matrix mostly made up of polysaccharides and proteins. The resistance observed in biofilms does not appear to be genotypic; instead, it is due to multicellular strategies and/or to the ability of each cell, contained inside the biofilm, to differentiate into a protected phenotypic state which tolerates the antibiotic action. In fact, biofilms are subject to changes following their recurrent exposure to antimicrobial agents, thus incrementing their resistance. Biofilms play an important role in otitis media, sinusitis, chronic cholesteatomatous otitis media, tonsillitis and adenoiditis, thus demonstrating that adenoidectomy may be helpful to children suffering from such a morbid conditions. It is presently estimated that biofilm formation is involved in at least 60% of all chronic and/or recurrent infections. In addition, 30% of the exudates developing in the course of otitis media has shown to be positive for the presence of biofilms; likewise biofilms have been found in tonsillar crypts and in odontostomatologic infections as well. Studies have been carried out on both the use and the efficacy of N-acetylcysteine (NAC) in biofilm breakdown. It has been shown that NAC, used at different concentrations, is able to reduce bacterial adhesion in several anatomical districts.}, }
@article {pmid20704760, year = {2010}, author = {Ramani, S and Patil, N and Jayabaskaran, C}, title = {UV-B induced transcript accumulation of DAHP synthase in suspension-cultured Catharanthus roseus cells.}, journal = {Journal of molecular signaling}, volume = {5}, number = {}, pages = {13}, pmid = {20704760}, issn = {1750-2187}, abstract = {The enzyme 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP) synthase (EC 4.1.2.15) catalyzes the first committed step in the shikimate pathway of tryptophan synthesis, an important precursor for the production of terpenoid indole alkaloids (TIAs). A full-length cDNA encoding nuclear coded chloroplast-specific DAHP synthase transcript was isolated from a Catharanthus roseus cDNA library. This had high sequence similarity with other members of plant DAHP synthase family. This transcript accumulated in suspension cultured C. roseus cells on ultraviolet (UV-B) irradiation. Pretreatment of C.roseus cells with variety of agents such as suramin, N-acetyl cysteine, and inhibitors of calcium fluxes and protein kinases and MAP kinase prevented this effect of UV-B irriadiation. These data further show that the essential components of the signaling pathway involved in accumulation DAHP synthase transcript in C. roseus cells include suramin-sensitive cell surface receptor, staurosporine-sensitive protein kinase and MAP kinase.}, }
@article {pmid20698835, year = {2010}, author = {Jilka, RL and Almeida, M and Ambrogini, E and Han, L and Roberson, PK and Weinstein, RS and Manolagas, SC}, title = {Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration.}, journal = {Aging cell}, volume = {9}, number = {5}, pages = {851-867}, pmid = {20698835}, issn = {1474-9726}, support = {P01 AG013918/AG/NIA NIH HHS/United States ; }, mesh = {*Aging ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Arachidonate 12-Lipoxygenase/biosynthesis ; Arachidonate 15-Lipoxygenase/biosynthesis ; Bone Density/*drug effects ; Bone and Bones/*drug effects/*metabolism ; Cell Proliferation/drug effects ; Cells, Cultured ; Female ; Mice ; Mice, Inbred C57BL ; Multienzyme Complexes/biosynthesis ; Osteoblasts/cytology/drug effects/metabolism ; Oxidative Stress/*drug effects ; Parathyroid Hormone/*administration &amp; dosage/*pharmacology ; Phosphorylation/drug effects ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Shc Signaling Adaptor Proteins/metabolism ; Signal Transduction/drug effects ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; Wnt Proteins/metabolism ; }, abstract = {Because of recent insights into the pathogenesis of age-related bone loss, we investigated whether intermittent parathyroid hormone (PTH) administration antagonizes the molecular mechanisms of the adverse effects of aging on bone. Parathyroid hormone produced a greater increase in vertebral trabecular bone mineral density and bone volume as well as a greater expansion of the endocortical bone surface in the femur of 26- when compared to 6 -month-old female C57BL/6 mice. Moreover, PTH increased trabecular connectivity in vertebrae, and the toughness of both vertebrae and femora in old, but not young, mice. Parathyroid hormone also increased the rate of bone formation and reduced osteoblast apoptosis to a greater extent in the old mice. Most strikingly, PTH reduced reactive oxygen species, p66(Shc) phosphorylation, and expression of the lipoxygenase Alox15, and it increased glutathione and stimulated Wnt signaling in bone of old mice. Parathyroid hormone also antagonized the effects of oxidative stress on p66(Shc) phosphorylation, Forkhead Box O transcriptional activity, osteoblast apoptosis, and Wnt signaling in vitro. In contrast, administration of the antioxidants N-acetyl cysteine or pegylated catalase reduced osteoblast progenitors and attenuated proliferation and Wnt signaling. These results suggest that PTH has a greater bone anabolic efficacy in old age because in addition to its other positive actions on bone formation, it antagonizes the age-associated increase in oxidative stress and its adverse effects on the birth and survival of osteoblasts. On the other hand, ordinary antioxidants cannot restore bone mass in old age because they slow remodeling and attenuate osteoblastogenesis by interfering with Wnt signaling.}, }
@article {pmid20698230, year = {2010}, author = {Vardar, R and Gunsar, F and Ersoz, G and Akarca, US and Karasu, Z}, title = {Efficacy of fractionated plasma separation and adsorption system (Prometheus) for treatment of liver failure due to mushroom poisoning.}, journal = {Hepato-gastroenterology}, volume = {57}, number = {99-100}, pages = {573-577}, pmid = {20698230}, issn = {0172-6390}, mesh = {Adolescent ; Adult ; Aged ; Extracorporeal Circulation/*methods ; Humans ; Liver Failure, Acute/*etiology ; Middle Aged ; Mushroom Poisoning/complications/*therapy ; Sorption Detoxification/*methods ; }, abstract = {BACKGROUND/AIMS: Consuming wild mushrooms is an ordinary habit in late summer and autumn in our region. Every year, several cases of hepatic toxicity secondary to mushroom poisoning are observed because of poor identification of the mushrooms. Unfortunately some of them are fatal. Prometheus system is a newly developed extracorporeal liver support device for fractionated plasma separation and adsorption (FPSA) that enables removal of albumin-bound and water-soluble toxins. Therefore, it may be a promising treatment option for patients with liver failure due to mushroom poisoning.<br><br>METHODOLOGY: We studied 8 patients with mushroom poisoning. All patients underwent 1 to 4 consecutive FPSA (Prometheus)-system in addition to medical and supportive treatment such as fluid replacement, Penicillin G, N-acetylcysteine (NAC) and silymarin. A variety of clinical and biochemical parameters were assessed.<br><br>RESULTS: We had improvement of the biochemical parameters after first treatment with FPSA-system. Seven of 8 patients survived and were discharged to resume an independent life. One patient who had grade III encephalopathy when admitted to hospital died. No major adverse events were observed during the application of this therapy modality.<br><br>CONCLUSIONS: FPSA-system may be a safe and effective treatment option for patient with mushroom poisoning. Early hospitalization is essential in order to be successful. Controlled studies are needed to evaluate the efficacy of this new treatment choice on survival of patients with acute liver failure (ALF) due to mushroom poisoning.}, }
@article {pmid20696200, year = {2010}, author = {Zieminska, E and Toczylowska, B and Stafiej, A and Lazarewicz, JW}, title = {Low molecular weight thiols reduce thimerosal neurotoxicity in vitro: modulation by proteins.}, journal = {Toxicology}, volume = {276}, number = {3}, pages = {154-163}, doi = {10.1016/j.tox.2010.07.023}, pmid = {20696200}, issn = {1879-3185}, mesh = {Animals ; Animals, Newborn ; Blood Proteins/*physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cerebellum/*drug effects/pathology/*physiology ; Membrane Potential, Mitochondrial/drug effects/physiology ; Molecular Weight ; Rats ; Rats, Wistar ; Serum Albumin, Bovine/physiology ; Sulfhydryl Compounds/*physiology ; Thimerosal/*antagonists &amp; inhibitors/*toxicity ; }, abstract = {Thimerosal (TH), an ethylmercury complex of thiosalicylic acid has been used as preservative in vaccines. In vitro neurotoxicity of TH at high nM concentrations has been reported. Although a number of toxicological experiments demonstrated high affinity of mercury to thiol groups of the extracellular amino acids and proteins that may decrease concentration of free TH in the organism, less is known about the role of interactions between proteins and amino acids in protection against TH neurotoxicity. In the present study we examined whether the presence of serum proteins and of l-cysteine (Cys), d,l-homocysteine (Hcy), N-acetyl cysteine (NAC), l-methionine (Met) and glutathione (GSH) in the incubation medium affects the TH-induced changes in the viability, the intracellular levels of calcium and zinc and mitochondrial membrane potential in primary cultures of rat cerebellar granule cells. The cells were exposed to 500 nM TH for 48 h or to 15-25 μM TH for 10 min. Our results demonstrated a decrease in the cells viability evoked by TH, which could be prevented partially by serum proteins, albumin or in a dose-dependent manner by 60, 120 or 600 μM Cys, Hcy, NAC and GSH, but not by Met. This neuroprotection was less pronounced in the presence of proteins. Incubation of neurons with TH also induced the rise in the intracellular calcium and zinc concentration and decrease in mitochondrial membrane potential, and these effects were abolished by all the sulfur containing compounds studied and administered at 600 μM concentration, except Met. The loss of the ethylmercury moiety from TH as a result of interaction with thiols studied was monitored by (1)H NMR spectroscopy. This extracellular process may be responsible for the neuroprotection seen in the cerebellar cell cultures, but also provides a molecular pathway for redistribution of TH-derived toxic ethylmercury in the organism. In conclusion, these results confirmed that proteins and sulfur-containing amino acids applied separately reduce TH neurotoxicity, while their combination modulates in more complex way neuronal survival in the presence of TH.}, }
@article {pmid20691758, year = {2010}, author = {Sinha, M and Saha, A and Basu, S and Pal, K and Chakrabarti, S}, title = {Aging and antioxidants modulate rat brain levels of homocysteine and dehydroepiandrosterone sulphate (DHEA-S): implications in the pathogenesis of Alzheimer's disease.}, journal = {Neuroscience letters}, volume = {483}, number = {2}, pages = {123-126}, doi = {10.1016/j.neulet.2010.07.075}, pmid = {20691758}, issn = {1872-7972}, mesh = {Aging/drug effects/*metabolism ; Alzheimer Disease/diagnosis/*etiology/*metabolism ; Animals ; Antioxidants/*metabolism/pharmacology ; Brain/drug effects/*metabolism ; Dehydroepiandrosterone Sulfate/*metabolism ; Disease Models, Animal ; Homocysteine/*metabolism ; Rats ; Rats, Wistar ; }, abstract = {The study has shown that in aged (22-24 months) rat brains an elevation of homocysteine level (42%) and a decrease in dehydroepiandrosterone sulphate (DHEA-S) content (32%) occur compared to those in the brains of young rats (4-6 months). Such changes in the brain levels of homocysteine and DHEA-S in aged rats are prevented, when the diet daily of the rats is supplemented with a combination of antioxidants (N-acetyl cysteine 50 mg, alpha-lipoic acid 3 mg and alpha-tocopherol 1.5 mg - each per 100 g of body weight) starting from 18 months until these are sacrificed between 22 and 24 months. The brain content of reduced glutathione is also decreased in aged rats as compared to that in young ones and the phenomenon can again be prevented completely by the same regimen of antioxidant supplementation. The changes in the levels of homocysteine and DHEA-S in aged rat brain have been related to associated glutathione depletion and oxidative stress and the implications of the results highlighted in the pathogenesis of Alzheimer's disease.}, }
@article {pmid20688495, year = {2012}, author = {Joshi, D and Mittal, DK and Shukla, S and Srivastav, AK}, title = {Therapeutic potential of N-acetyl cysteine with antioxidants (Zn and Se) supplementation against dimethylmercury toxicity in male albino rats.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {64}, number = {1-2}, pages = {103-108}, doi = {10.1016/j.etp.2010.07.001}, pmid = {20688495}, issn = {1618-1433}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Brain/drug effects/enzymology/metabolism ; DNA Damage/drug effects ; Drug Therapy, Combination ; Glutathione/blood ; Kidney/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism ; Male ; Mercury Poisoning/enzymology/genetics/metabolism/*prevention &amp; control ; Methylmercury Compounds/pharmacokinetics/*toxicity ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Selenium/administration &amp; dosage/*therapeutic use ; Zinc/administration &amp; dosage/*therapeutic use ; }, abstract = {Mercury (Hg) is currently one of the most prevalent pollutants in the environment. Many studies have examined its effects on the health of both humans and animals. Experimental studies have shown that sulfur-containing nutrients play an important role as detoxification and protecting cell against the detrimental properties of mercury. The present study was undertaken to elucidate the toxicity induced by dimethylmercury in male rats through the activities of transaminases, alkaline phosphatase, lactate dehydrogenase in serum and oxidative damage as acetyl cholinesterase activity in different regions of brain and lipid peroxidation, reduced glutathione content, mean DNA damage in liver, kidney and brain of rats given dimethylmercury (10 mg/kg, p.o., once only) along with combination therapy of N-acetyl cysteine (2 mM/kg, i.p.), zinc (2 mM/kg, p.o.) and selenium (0.5 mg/kg, p.o.) for 3 days. In the dimethylmercury group, activities of transaminases, alkaline phosphatase, lactate dehydrogenase in serum, level of lipid peroxidation, mean DNA damage and mercury ion concentration were significantly higher whereas reduced glutathione content and the activity of acetyl cholinesterase were significantly lower compared to controls (P≤0.05). Combined treatment of zinc and selenium with N-acetyl cysteine to dimethylmercury-exposed rats showed a substantial reduction in the levels of DMM-induced oxidative damage and comet tail length. In conclusion, the results of this study support that the supplementation of zinc and selenium with N-acetyl cysteine can improve the DMM induced blood and tissue biochemical oxidative stress and molecular alterations by recoupment in mean DNA damage.}, }
@article {pmid20686333, year = {2010}, author = {Lawal, AO and Ellis, E}, title = {Differential sensitivity and responsiveness of three human cell lines HepG2, 1321N1 and HEK 293 to cadmium.}, journal = {The Journal of toxicological sciences}, volume = {35}, number = {4}, pages = {465-478}, doi = {10.2131/jts.35.465}, pmid = {20686333}, issn = {1880-3989}, mesh = {Acetylcysteine/pharmacology ; Cadmium Chloride/*toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; Glutathione/pharmacology ; HEK293 Cells ; Hep G2 Cells ; Humans ; Reactive Oxygen Species/pharmacology ; }, abstract = {Cadmium (Cd) is a toxic heavy metal with no uniform mechanism of toxicity. In this the present study, the toxic effect of 5, 10 and 50 microM of Cd chloride was compared in three human cell lines; a human hepatoma cell line HepG2, a human astrocytoma cell line 1321N1, and a human embryonic kidney cell HEK 293. The results indicate a decrease in the viability of all three cell lines following exposure to Cd with HepG2 cells (IC50=13.96 microM) showing the most sensitivity when measured using the MTT assay. There was significant increase in lactate dehydrogenase leakage, DNA damage, malondialdeyde and antioxidant enzymes activities in all three cell lines especially at 50 microM Cd. Significant decreases in ATP production were also observed at all Cd concentrations in HepG2 and HEK 293 cell lines. ROS levels significantly increase and GSH/GSSG ratio significantly decrease in all the three cell lines after Cd exposure, but these effects were attenuated by the presence of N-acetylcysteine (NAC). The present study therefore shows that ROS production and glutathione (GSH) depletion may play a role in Cd-induced toxicity in all the three cell lines. The endogenous levels of protective enzymes as well as their responsiveness are likely to determine a cell's susceptibility to Cd.}, }
@article {pmid20683904, year = {2010}, author = {Monticone, M and Bisio, A and Daga, A and Giannoni, P and Giaretti, W and Maffei, M and Pfeffer, U and Romeo, F and Quarto, R and Romussi, G and Corte, G and Castagnola, P}, title = {Demethyl fruticulin A (SCO-1) causes apoptosis by inducing reactive oxygen species in mitochondria.}, journal = {Journal of cellular biochemistry}, volume = {111}, number = {5}, pages = {1149-1159}, doi = {10.1002/jcb.22801}, pmid = {20683904}, issn = {1097-4644}, mesh = {Adaptation, Physiological/drug effects/genetics ; Animals ; Antineoplastic Agents ; Apoptosis/*drug effects ; Cell Line ; Cell Line, Tumor ; Diterpenes/*pharmacology ; Glioblastoma/drug therapy/pathology ; Glutathione/biosynthesis/metabolism ; Humans ; Metabolic Networks and Pathways/drug effects/genetics ; Mitochondria/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Demethyl fruticulin A (SCO-1) is a compound found in Salvia corrugata leaves. SCO-1 was reported to induce anoikis in cell lines via the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36 showed that SCO-1 was able to induce apoptosis also via alternative pathways. To gain some insight into the biological processes elicited by this compound, we undertook an unbiased genomic approach. Upon exposure of glioblastoma tumor initiating cells (GBM TICs) to SCO-1 for 24 h, we observed a deregulation of the genes belonging to the glutathione metabolism pathway and of those belonging to the biological processes related to the response to stress and to chemical stimulus. On this basis, we hypothesized that the SCO-1 killing effect could result from the induction of reactive oxygen species (ROS) in the mitochondria. This hypothesis was confirmed by flow cytometry using MitoSOX, a mitochondria-selective fluorescent reporter of ROS, and by the ability of N-acetyl cysteine (NAC) to inhibit apoptosis when co-administered with SOC-1 to the GBM TICs. We further show that NAC also protects other cell types such as HeLa, MG-63, and COS-7 from apoptosis. We therefore propose that ROS production is the major molecular mechanism responsible for the pro-apoptotic effect induced by SCO-1. Consequently, SCO-1 may have a potential therapeutic value, which deserves further investigation in animal models.}, }
@article {pmid20683104, year = {2010}, author = {Aliyali, M and Poorhasan Amiri, A and Sharifpoor, A and Zalli, F}, title = {Effects of N-acetylcysteine on asthma exacerbation.}, journal = {Iranian journal of allergy, asthma, and immunology}, volume = {9}, number = {2}, pages = {103-109}, pmid = {20683104}, issn = {1735-1502}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Asthma/*drug therapy ; Female ; Humans ; Male ; Middle Aged ; Single-Blind Method ; }, abstract = {Airway mucus hypersecretion and increased oxidative stress are clinical and pathophysiological features of asthma exacerbation. We studied effects of N-acetylcysteine (NAC) as a mucolytic and antioxidant agent in asthma exacerbation. In this randomized, single-blinded, placebo-controlled study 50 patients (17 male, 33 female, mean age 48.94+/-13.68) with asthma exacerbation were randomized to receive either oral 600 mg b.d. N-acetylcysteine or placebo in addition to standard treatment during 5 days hospitalization. Daily measurements of wheezing, dyspnea, cough, sputum, expectoration, night sleep scores and morning PEFR were performed. There was no significant difference in wheezing score between patients assigned NAC and those assigned placebo in day 5(0.84[SD 0.94] VS 0.87[SD 0.79]) and also in cough score (0.72[SD 0.84] VS 0.79[SD 0.97]), dyspnea score (0.84[SD 1.06] VS 0.91[SD 1.01]), sputum score(0.79[SD 0.83] VS 0.62[SD 0.71]), expectoration score(0.79[SD 0.97] VS 0.83[SD 1.09]), night sleep score(1[SD 1.17] VS 0.67[SD 0.98] and morning PEFR (256[SD 96.36] VS 282[SD 98.86]). We concluded that addition of N-acetylcysteine to usual asthma medication has no significant effect in treatment of asthma exacerbation.}, }
@article {pmid20682612, year = {2011}, author = {Sadat, U and Walsh, SR and Norden, AG and Gillard, JH and Boyle, JR}, title = {Does oral N-acetylcysteine reduce contrast-induced renal injury in patients with peripheral arterial disease undergoing peripheral angiography? A randomized-controlled study.}, journal = {Angiology}, volume = {62}, number = {3}, pages = {225-230}, doi = {10.1177/0003319710377078}, pmid = {20682612}, issn = {1940-1574}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Albuminuria/etiology ; *Angiography ; Biomarkers/blood/urine ; Contrast Media/*adverse effects ; Creatinine/blood/urine ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Peripheral Arterial Disease/*diagnostic imaging ; Retinol-Binding Proteins, Cellular/urine ; Statistics, Nonparametric ; Treatment Outcome ; }, abstract = {The nephroprotective role of N-acetylcysteine (NAC) against contrast-induced nephropathy (CIN) in patients undergoing peripheral arterial angiography remains unclear. A total of 40 patients undergoing peripheral arterial angiography were randomized to receive intravenous (iv) hydration only (group 1) or oral NAC in addition to iv hydration (group 2; ISRCTN: 35882618). Primary outcome was reduction in the elevation of urinary retinol binding protein (RBP), albumin-creatinine ratio (ACR), and serum creatinine (serC). Groups 1 and 2 had equivocal percentage reduction in RBP and ACR levels from baseline (P = .80 and .30). A significant reduction in serC was, however, observed with NAC by third postprocedure day (P = .04). One patient in the treatment arm developed CIN compared with 3 patients in the control group (P = .33). Equivocal changes in RBP and ACR levels by both treatments seem to indicate that either is equally effective in affording renal protection.}, }
@article {pmid20676222, year = {2010}, author = {Gallo, C and Renzi, P and Loizzo, S and Loizzo, A and Piacente, S and Festa, M and Caputo, M and Tecce, MF and Capasso, A}, title = {Potential therapeutic effects of vitamin e and C on placental oxidative stress induced by nicotine: an in vitro evidence.}, journal = {The open biochemistry journal}, volume = {4}, number = {}, pages = {77-82}, pmid = {20676222}, issn = {1874-091X}, abstract = {There have been a few studies that examined the oxidative stress effects of nicotine during pregnancy and lactation. The adverse effect of prenatal smoking exposure on human fetal development and growth has been a major public health issue. Active or passive smoking during pregnancy can result in a wide variety of adverse outcomes, including intrauterine growth retardation (IUGR), prematurity, stillbirth, and the sudden infant death syndrome. Smoking in pregnancy has also been associated with an increased risk of attention deficit and learning problems in childhood. Some studies argued that as a principal component of tobacco smoke, nicotine alone is responsible for the majority of negative reproductive outcomes. Nicotine and its major metabolite cotinine can cross the placental barrier. The level of nicotine in fetal tissues was found to be equal to or greater than the plasma nicotine level in the mothers. The oxidative stress induce by nicotine has been increasingly postulated as a major contributor to endothelial dysfunction. A large body of research has investigated the potential role of antioxidant nutrients in the prevention of endothelial dysfunction in women. Therefore, the present study was undertaken to assess the potential benefit of antioxidant supplementation on markers of placental oxidative stress in an in vitro model of endothelial dysfunction induced by nicotine, since it was previously found that nicotine is able to trigger the placental secretion of stress molecules. In this regard, we evaluated the effects of vitamin C, vitamin E and N-acetylcysteine (NAC), alone or in combination, in placental villi culture after exposure to nicotine. The effect of antioxidant nutrients on trophoblast cells proliferation and vitality was also evaluated. The results obtained suggest that in a patho-physiological condition, such as endothelial dysfunction induced by nicotine, the deleterious effect of reactive oxygen species may be counteracted by an antioxidant therapy, and there is the need to investigate the optimum dosing and timing of antioxidants administration, since an inappropriate antioxidant treatment in pregnant women may have deleterious consequences, reducing placental cells proliferation until to cell death.}, }
@article {pmid20674572, year = {2010}, author = {Guaragnella, N and Passarella, S and Marra, E and Giannattasio, S}, title = {Knock-out of metacaspase and/or cytochrome c results in the activation of a ROS-independent acetic acid-induced programmed cell death pathway in yeast.}, journal = {FEBS letters}, volume = {584}, number = {16}, pages = {3655-3660}, doi = {10.1016/j.febslet.2010.07.044}, pmid = {20674572}, issn = {1873-3468}, mesh = {Acetic Acid/pharmacology ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; *Apoptosis/drug effects/genetics/physiology ; *Caspase Inhibitors ; Caspases/genetics/metabolism ; Cytochromes c/*antagonists &amp; inhibitors/genetics/metabolism ; Gene Knockout Techniques ; Genes, Fungal ; Models, Biological ; Mutation ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae/*cytology/drug effects/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {To gain further insight into yeast acetic acid-induced programmed cell death (AA-PCD) we analyzed the effects of the antioxidant N-acetyl-L-cysteine (NAC) on cell viability, hydrogen peroxide (H(2)O(2)) production, DNA fragmentation, cytochrome c (cyt c) release and caspase-like activation in wild type (wt) and metacaspase and/or cyt c-lacking cells. We found that NAC prevents AA-PCD in wt cells, by scavenging H(2)O(2) and by inhibiting both cyt c release and caspase-like activation. This shows the occurrence of a reactive oxygen species (ROS)-dependent AA-PCD. Contrarily no NAC dependent change in AA-PCD of mutant cells was detectable, showing that a ROS-independent AA-PCD can also occur.}, }
@article {pmid20674558, year = {2010}, author = {Li, S and Tai, W and Li, Y and Zhang, L and Zhang, W and Ma, E and Li, J}, title = {1-(3',4',5'-Trimethoxyphenyl)-3-(3'',4''-dimethoxy-2''-hydroxyphenyl)-propane with microtubule-depolymerizing ability induces G2/M phase arrest and apoptosis in HepG2 cells.}, journal = {Chemico-biological interactions}, volume = {188}, number = {1}, pages = {161-170}, doi = {10.1016/j.cbi.2010.07.021}, pmid = {20674558}, issn = {1872-7786}, mesh = {Anisoles/*pharmacology ; Apoptosis/*drug effects ; Cell Division/*drug effects ; Cell Line, Tumor ; Electrophoresis, Agar Gel ; Flow Cytometry ; G2 Phase/*drug effects ; Humans ; Immunohistochemistry ; Microtubules/*drug effects ; }, abstract = {1-(3',4',5'-Trimethoxyphenyl)-3-(3'',4''-dimethoxy-2''-hydroxyphenyl)-propane (DP), a novel synthesized 1,3-diarylpropanes compound, showed growth inhibitory effect on human hepatoma HepG2 cells in a concentration-dependent manner. The growth inhibitory effect of DP on HepG2 cells was associated with microtubule depolymerization, G2/M phase arrest and apoptosis induction. The G2/M phase arrest induced by DP resulted from its microtubule-depolymerizing ability, and DP-treated HepG2 cells finally underwent caspase-dependent apoptosis. DP increased the levels of death receptor 4 (DR4), death receptor 5 (DR5) and pro-apoptotic protein Bax, but decreased the levels of anti-apoptotic protein Bcl-2. Meanwhile, the decrease in the mitochondrial membrane potential (MMP) and the release of cytochrome c from mitochondria were observed in DP-treated HepG2 cells. DP increased the levels of reactive oxygen species (ROS) in HepG2 cells, and antioxidant N-acetylcysteine (NAC) completely blocked DP-induced ROS accumulation and the disruption of the balance between Bax and Bcl-2 proteins, and effectively blocked the decreased MMP and apoptosis, but had no effect on the activation of caspase-8 and the up-regulations of DR4 and DR5 induced by DP. These results suggest that DP induces G2/M phase arrest through interruption of microtubule network followed by the death receptor- and ROS-mediated apoptosis in HepG2 cells.}, }
@article {pmid20674153, year = {2010}, author = {Li, S and Dong, P and Wang, J and Zhang, J and Gu, J and Wu, X and Wu, W and Fei, X and Zhang, Z and Wang, Y and Quan, Z and Liu, Y}, title = {Icariin, a natural flavonol glycoside, induces apoptosis in human hepatoma SMMC-7721 cells via a ROS/JNK-dependent mitochondrial pathway.}, journal = {Cancer letters}, volume = {298}, number = {2}, pages = {222-230}, doi = {10.1016/j.canlet.2010.07.009}, pmid = {20674153}, issn = {1872-7980}, mesh = {Animals ; Apoptosis/*drug effects ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism/pathology/*prevention &amp; control ; Caspase 3/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal/pharmacology ; Female ; Flavonoids/*pharmacology ; Hep G2 Cells ; Hepatocytes/cytology/drug effects/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Liver Neoplasms, Experimental/metabolism/pathology/prevention &amp; control ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Xenograft Model Antitumor Assays ; }, abstract = {In this study, the anticancer effect of icariin, a natural flavonol glycoside, against human hepatoma SMMC-7721 cells and the underlying mechanisms were investigated. Icariin triggered the mitochondrial/caspase apoptotic pathway indicated by enhanced Bax-to-Bcl-2 ratio, loss of mitochondrial membrane potential, cytochrome c release, and caspase cascade. Moreover, icariin induced a sustained activation of the phosphorylation of c-Jun N-terminal kinase (JNK) but not p38 and ERK1/2, and SP600125 (an inhibitor of JNK) almost reversed icariin-induced apoptosis in SMMC-7721 cells. In addition, icariin provoked the generation of reactive oxygen species (ROS) in SMMC-7721 cells, while the antioxidant N-acetyl cysteine almost completely blocked icariin-induced JNK activation and apoptosis. Taken together, these findings suggest that icariin induces apoptosis through a ROS/JNK-dependent mitochondrial pathway.}, }
@article {pmid20673252, year = {2012}, author = {Pinheiro, CH and Vitzel, KF and Curi, R}, title = {Effect of N-acetylcysteine on markers of skeletal muscle injury after fatiguing contractile activity.}, journal = {Scandinavian journal of medicine &amp; science in sports}, volume = {22}, number = {1}, pages = {24-33}, doi = {10.1111/j.1600-0838.2010.01143.x}, pmid = {20673252}, issn = {1600-0838}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Capillary Permeability/*drug effects ; Creatine Kinase/blood/drug effects ; Electric Stimulation ; Evans Blue/*pharmacokinetics ; L-Lactate Dehydrogenase/blood/drug effects ; Male ; Muscle Contraction ; Muscle Fatigue/drug effects ; Muscle Strength/drug effects ; Muscle, Skeletal/*drug effects/injuries/*metabolism ; Peroxidase/drug effects/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The effects of N-Acetylcysteine (NAC), an unspecific antioxidant, on fatiguing contractile activity-induced injury were investigated. Twenty-four male Wistar rats were randomly assigned to two groups. The placebo group (N=12) received one injection of phosphate buffer (PBS) 1 h prior to contractile activity induced by electrical stimulation. The NAC group (NAC; N=12) received electrical stimulation for the same time period and NAC (500 mg/kg, i.p.) dissolved in PBS 1 h prior to electrical stimulation. The contralateral hindlimb was used as a control, except in the analysis of plasma enzyme activities, when a control group (rats placebo group not electrically stimulated and not treated) was included. The following parameters were measured: tetanic force, muscle fatigue, plasma activities of creatine kinase (CK) and lactate dehydrogenase (LDH), changes in muscle vascular permeability using Evans blue dye (EBD), muscle content of reactive oxygen species (ROS) and thiobarbituric acid-reactive substances (TBARS) and myeloperoxidase (MPO) activity. Muscle fatigue was delayed and tetanic force was preserved in NAC-treated rats. NAC treatment decreased plasma CK and LDH activities. The content of muscle-derived ROS, TBARS, EBD and MPO activity in both gastrocnemius and soleus muscles were also decreased by NAC pre-treatment. Thus, NAC has a protective effect against injury induced by fatiguing contractile activity in skeletal muscle.}, }
@article {pmid20667650, year = {2010}, author = {Zheng, J and Lou, JR and Zhang, XX and Benbrook, DM and Hanigan, MH and Lind, SE and Ding, WQ}, title = {N-Acetylcysteine interacts with copper to generate hydrogen peroxide and selectively induce cancer cell death.}, journal = {Cancer letters}, volume = {298}, number = {2}, pages = {186-194}, pmid = {20667650}, issn = {1872-7980}, support = {P20 RR016478/RR/NCRR NIH HHS/United States ; 3P20RR016478-09S2/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Survival/drug effects ; Copper/chemistry/*pharmacology ; Dose-Response Relationship, Drug ; Humans ; Hydrogen Peroxide/*metabolism ; Microscopy, Confocal ; Neoplasms/metabolism/pathology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {A variety of metal-binding compounds have been found to exert anti-cancer activity. We postulated that N-acetylcysteine (NAC), which is a membrane-permeable metal-binding compound, might have anti-cancer activity in the presence of metals. We found that NAC/Cu(II) significantly alters growth and induces apoptosis in human cancer lines, yet NAC/Zn(II) and NAC/Fe(III) do not. We further confirmed that this cytotoxicity of NAC/Cu(II) is attributed to reactive oxygen species (ROS). These findings indicate that the combination of Cu(II) and thiols generates cytotoxic ROS that induce apoptosis in cancer cells. They also indicate a fourth class of anti-neoplastic metal-binding compounds, the "ROS generators".}, }
@article {pmid20664528, year = {2010}, author = {Drowley, L and Okada, M and Beckman, S and Vella, J and Keller, B and Tobita, K and Huard, J}, title = {Cellular antioxidant levels influence muscle stem cell therapy.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {18}, number = {10}, pages = {1865-1873}, pmid = {20664528}, issn = {1525-0024}, support = {P30 AG024827/AG/NIA NIH HHS/United States ; HL 069368/HL/NHLBI NIH HHS/United States ; T32 EB001026/EB/NIBIB NIH HHS/United States ; T32 EB001026-05/EB/NIBIB NIH HHS/United States ; U54 AR050733/AR/NIAMS NIH HHS/United States ; R01 HL069368/HL/NHLBI NIH HHS/United States ; IU54AR050733-01/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*metabolism ; Apoptosis/drug effects ; Blotting, Western ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cell- and Tissue-Based Therapy/*methods ; Cells, Cultured ; Endothelial Cells/cytology/drug effects/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Male ; Maleates/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, SCID ; Muscle, Skeletal/*cytology ; Myocardial Infarction/therapy ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Stem Cells/cytology/drug effects/*metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {Although cellular transplantation has been shown to promote improvements in cardiac function following injury, poor cell survival following transplantation continues to limit the efficacy of this therapy. We have previously observed that transplantation of muscle-derived stem cells (MDSCs) improves cardiac function in an acute murine model of myocardial infarction to a greater extent than myoblasts. This improved regenerative capacity of MDSCs is linked to their increased level of antioxidants such as glutathione (GSH) and superoxide dismutase. In the current study, we demonstrated the pivotal role of antioxidant levels on MDSCs survival and cardiac functional recovery by either reducing the antioxidant levels with diethyl maleate or increasing antioxidant levels with N-acetylcysteine (NAC). Both the anti- and pro-oxidant treatments dramatically influenced the survival of the MDSCs in vitro. When NAC-treated MDSCs were transplanted into infarcted myocardium, we observed significantly improved cardiac function, decreased scar tissue formation, and increased numbers of CD31(+) endothelial cell structures, compared to the injection of untreated and diethyl maleate-treated cells. These results indicate that elevating the levels of antioxidants in MDSCs with NAC can significantly influence their tissue regeneration capacity.}, }
@article {pmid20660605, year = {2010}, author = {Yong, QC and Hu, LF and Wang, S and Huang, D and Bian, JS}, title = {Hydrogen sulfide interacts with nitric oxide in the heart: possible involvement of nitroxyl.}, journal = {Cardiovascular research}, volume = {88}, number = {3}, pages = {482-491}, doi = {10.1093/cvr/cvq248}, pmid = {20660605}, issn = {1755-3245}, mesh = {Animals ; Caffeine/pharmacology ; Calcium/metabolism ; Cyclic AMP/metabolism ; Cyclic GMP/metabolism ; Diethylamines/pharmacology ; Hydrogen Sulfide/*metabolism ; Models, Animal ; Myocardium/*metabolism ; Myocytes, Cardiac/cytology/drug effects/*metabolism ; Nitric Oxide/*metabolism ; Nitric Oxide Donors/pharmacology ; Nitrogen Oxides/*metabolism ; Nitroprusside/pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIMS: The present study aims to investigate the interaction between nitric oxide (NO) and hydrogen sulfide (H(2)S), the two important gaseous mediators in rat hearts.<br><br>METHODS AND RESULTS: Intracellular calcium in isolated cardiomyocytes was measured with a spectrofluorometric method using Fura-2. Myocyte contractility was measured with a video edge system. NaHS (50 &#xb5;M, an H(2)S donor) had no significant effect on the resting calcium level, electrically induced (EI) calcium transients, and cell contractility in ventricular myocytes. Stimulating endogenous NO production with l-arginine or exogenous application of NO donors [sodium nitroprusside (SNP) and 2-(N,N-diethylamino)-diazenolate-2-oxide] decreased myocyte twitch amplitudes accompanied by slower velocities of both cell contraction and relaxation. Surprisingly, NaHS reversed the negative inotropic and lusitropic effects of the above three NO-increasing agents. In addition, the mixture of SNP + NaHS increased, whereas SNP alone decreased, the resting calcium level and the amplitudes of EI calcium transients. Angeli's salt, a nitroxyl anion (HNO) donor, mimicked the effect of SNP + NaHS on calcium handling and myocyte contractility. Three thiols, N-acetyl-cysteine, l-cysteine, and glutathione, abolished the effects of HNO and SNP + NaHS on myocyte contraction. Neither Rp-cAMP [a protein kinase A (PKA) inhibitor] nor Rp-cGMP [a protein kinase G (PKG) inhibitor] affected the effects of SNP + NaHS, suggesting a cAMP/PKA- or cGMP/PKG-independent mechanism.<br><br>CONCLUSION: H(2)S may interact with NO to form a thiol sensitive molecule (probably HNO) which produces positive inotropic and lusitropic effects. Our findings may shed light on the interaction of NO and H(2)S and provide new clues to treat cardiovascular diseases.}, }
@article {pmid20657156, year = {2010}, author = {Choe, C and Shin, YW and Kim, EJ and Cho, SR and Kim, HJ and Choi, SH and Han, MH and Han, J and Son, DS and Kang, D}, title = {Synergistic effects of glutathione and β-mercaptoethanol treatment during in vitro maturation of porcine oocytes on early embryonic development in a culture system supplemented with L-cysteine.}, journal = {The Journal of reproduction and development}, volume = {56}, number = {6}, pages = {575-582}, doi = {10.1262/jrd.09-214h}, pmid = {20657156}, issn = {1348-4400}, mesh = {Animal Husbandry ; Animals ; Antioxidants/*pharmacology ; Blastocyst/cytology/*drug effects/metabolism ; Cell Count ; Cysteine/*metabolism ; Drug Synergism ; Ectogenesis/*drug effects ; Embryo Culture Techniques/*veterinary ; Female ; Fertilization in Vitro/methods/veterinary ; Glutathione/pharmacology ; Male ; Mercaptoethanol/pharmacology ; Oocytes/cytology/*drug effects/metabolism ; Osmolar Concentration ; Oxidative Stress/drug effects ; Oxygen/metabolism ; Reactive Oxygen Species/metabolism ; Sus scrofa/*embryology/metabolism ; }, abstract = {Various methods have been used to remove reactive oxygen species (ROS) generated from in vitro culture (IVC) conditions that can cause cell injury or death, including the application of low oxygen (O(2)) tension and the addition of antioxidants. The beneficial effects of antioxidants and O(2) tension on IVC of porcine embryos, however, are controversial among researchers. In this study, we sought to determine the effects and optimal concentrations of antioxidants for the development of porcine embryos in an IVC system. Specifically, we examined the synergistic effects of antioxidants on development to the blastocyst stage in a culture system supplemented with L-cysteine during IVM. Of the antioxidants tested (melatonin, glutathione (GSH), β-mercaptoethanol (β-ME), N-acetylcysteine (NAC) and dithiothreitol (DTT)), addition of GSH (1 mM) or β-ME (25 µM) significantly increased development to the blastocyst stage compared with the controls without antioxidant treatment (22.2 ± 4.2% for 1 mM GSH, 25.9 ± 2.2% for 25 µM β-ME and 12-13% for the control, P<0.05). In addition, the mean cell number per blastocyst was increased by approximately 1.7-fold in the presence of GSH or β -ME. These GSH- and β-ME-induced increases in development to the blastocyst stage and total cell number, however, were not mimicked by melatonin, NAC or DTT, all of which are ROS scavengers. The combination of GSH or β-ME with L-cysteine significantly reduced high O(2) tension-induced ROS production (P<0.05). These results suggest that a combination of 1 mM GSH or 25 µM β-ME with 1 mM L-cysteine could be used for production of high quality porcine blastocysts in IVC systems.}, }
@article {pmid20655527, year = {2010}, author = {Pittaluga, E and Costa, G and Krasnowska, E and Brunelli, R and Lundeberg, T and Porpora, MG and Santucci, D and Parasassi, T}, title = {More than antioxidant: N-acetyl-L-cysteine in a murine model of endometriosis.}, journal = {Fertility and sterility}, volume = {94}, number = {7}, pages = {2905-2908}, doi = {10.1016/j.fertnstert.2010.06.038}, pmid = {20655527}, issn = {1556-5653}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Cell Differentiation/drug effects/genetics ; Cell Movement/drug effects/genetics ; Cell Proliferation/drug effects ; Cytostatic Agents/pharmacology/therapeutic use ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Endometriosis/*drug therapy/genetics/metabolism/pathology ; Female ; Inflammation/genetics ; Inflammation Mediators/metabolism ; *Mice ; Mice, Inbred BALB C ; Peritoneal Diseases/*drug therapy/genetics/metabolism/pathology ; }, abstract = {N-acetyl-L-cysteine exerts a complex action on endometrial cells, involving regulation of gene expression and protein activity and location, all converging into a decreased proliferation and a switch toward a differentiating, less invasive, and less inflammatory phenotype. Also considering the lack of undesired side effects, including unaffected fertility potential, this suggests a beneficial use of NAC in endometriosis clinical treatment.}, }
@article {pmid20655182, year = {2010}, author = {Grant, JE and Odlaug, BL and Kim, SW}, title = {A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence.}, journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology}, volume = {20}, number = {11}, pages = {823-828}, doi = {10.1016/j.euroneuro.2010.06.018}, pmid = {20655182}, issn = {1873-7862}, support = {RC1 DA028279/DA/NIDA NIH HHS/United States ; RC1 DA028279-02/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Amphetamine-Related Disorders/*drug therapy/psychology ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Male ; *Methamphetamine ; Middle Aged ; Naltrexone/*administration &amp; dosage ; Young Adult ; }, abstract = {Reducing both glutamatergic and dopaminergic drive in the nucleus accumbens may offer complementary mechanisms by which to reduce drug cravings. This 8-week study sought to examine the efficacy of a combination of a glutamate modulator, N-acetyl cysteine (NAC), plus the opioid antagonist, naltrexone, compared to placebo in the treatment of methamphetamine dependence. Thirty-one subjects with methamphetamine dependence (mean age 36.8 ± 7.12 years; 29% female) were randomly assigned in a 1:1 fashion to NAC plus naltrexone or placebo and returned for one post-baseline visit. The Penn Craving Scale was the primary outcome measure. Self-report methamphetamine use frequency and urine toxicology were secondary measures. NAC plus naltrexone failed to demonstrate statistically significant differences from placebo on primary and secondary outcomes. The current study failed to demonstrate greater efficacy for NAC plus naltrexone compared to placebo. Given the small sample size, the statistical power to detect significant effects of active treatment versus placebo was limited. The question of whether a larger, well-powered sample would have detected differences between NAC plus naltrexone and placebo deserves further examination.}, }
@article {pmid20654680, year = {2010}, author = {Akhtar, MJ and Ahamed, M and Kumar, S and Siddiqui, H and Patil, G and Ashquin, M and Ahmad, I}, title = {Nanotoxicity of pure silica mediated through oxidant generation rather than glutathione depletion in human lung epithelial cells.}, journal = {Toxicology}, volume = {276}, number = {2}, pages = {95-102}, doi = {10.1016/j.tox.2010.07.010}, pmid = {20654680}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Epithelial Cells/*drug effects/pathology ; Glutathione/drug effects/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Lung/cytology/drug effects ; Membrane Lipids/metabolism ; *Nanoparticles ; Oxidants/*metabolism ; Oxidative Stress/drug effects ; Particle Size ; Reactive Oxygen Species/*metabolism ; Silicon Dioxide/administration &amp; dosage/*toxicity ; }, abstract = {Though, oxidative stress has been implicated in silica nanoparticles induced toxicity both in vitro and in vivo, but no similarities exist regarding dose-response relationship. This discrepancy may, partly, be due to associated impurities of trace metals that may present in varying amounts. Here, cytotoxicity and oxidative stress parameters of two sizes (10 nm and 80 nm) of pure silica nanoparticles was determined in human lung epithelial cells (A549 cells). Both sizes of silica nanoparticles induced dose-dependent cytotoxicity as measured by MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and lactate dehydrogenase (LDH) assays. Silica nanoparticles were also found to induce oxidative stress in dose-dependent manner indicated by induction of reactive oxygen species (ROS) generation, and membrane lipid peroxidation (LPO). However, both sizes of silica nanoparticles had little effect on intracellular glutathione (GSH) level and the activities of glutathione metabolizing enzymes; glutathione reductase (GR) and glutathione peroxidase (GPx). Buthionine-[S,R]-sulfoximine (BSO) plus silica nanoparticles did not result in significant GSH depletion than that caused by BSO alone nor N-acetyl cysteine (NAC) afforded significant protection from ROS and LPO induced by silica nanoparticles. The rather unaltered level of GSH is also supported by finding no appreciable alteration in the level of GR and GPx. Our data suggest that the silica nanoparticles exert toxicity in A549 cells through the oxidant generation (ROS and LPO) rather than the depletion of GSH.}, }
@article {pmid20654106, year = {2010}, author = {Zhang, FX and Chen, ML and Yang, B and Chen, HW and Ju, WZ and Wang, J and Cao, KJ}, title = {[The anti-apoptotic effects of N-acetylcysteine in neonatal rat cardiomyocytes underwent hypoxia-reoxygenation injury].}, journal = {Zhonghua xin xue guan bing za zhi}, volume = {38}, number = {5}, pages = {445-449}, pmid = {20654106}, issn = {0253-3758}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Apoptosis/*drug effects ; Cell Death/drug effects ; Cell Hypoxia ; Cells, Cultured ; Hypoxia ; Myocytes, Cardiac/cytology/*drug effects/*metabolism ; Oxygen/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {OBJECTIVE: To evaluate the effects of N-acetylcysteine (NAC) on hypoxia-reoxygenation (H/R) injury induced apoptosis in neonatal rat cardiomyocytes.<br><br>METHODS: Neonatal rat cardiomyocytes were cultured for 48 h and then randomized into control group, H/R group and H/R + NAC group. Cardiomyocytes underwent hypoxia for 6 h, reoxygenation for 72 h in the absence (H/R group) or presence (H/R + NAC group) of NAC (100 micromol/L). Cell viability was assayed with trypan blue staining. Early stage of apoptosis was detected by flow cytometry with Annexin V, late stage of apoptosis was assessed by TUNEL staining. ROS in culture medium was assayed by Image-iT(TM) LIVE green reactive oxygen species detection kit.bcl2 and bax mRNA levels were determined by real-time quantitative PCR (RT-PCR). bcl2, bax, p38 and pp38 protein levels were measured by Western blot.<br><br>RESULTS: The percentage of viable cardiomyocytes (93.5%, 74.9%, 89.9%) was significantly reduced while percentage of early stage of apoptotic cardiomyocytes (6.5%, 25.2% and 11.1%) and late stage of apoptotic cardiomyocytes (3.5%, 33.5% and 13.5%) were significantly increased in H/R group compared to control group and these changes could be largely reversed by NAC (all P < 0.01). Significantly increased ROS generation in H/R group could also be attenuated by NAC (P < 0.01). The band density ratio of pp38 and p38 was significantly upregulated in H/R group (13.4 vs. 3.89), the mRNA and protein expressions of bcl2 were significantly lower and bax expressions were significantly higher in H/R group than those in control group and these changes could also be attenuated by NAC.<br><br>CONCLUSION: NAC significantly reduced apoptosis through inhibiting the phosphorylation of p38 signal pathway.}, }
@article {pmid20653490, year = {2010}, author = {Tran, CD and Kritas, S and Campbell, MA and Huynh, HQ and Lee, SS and Butler, RN}, title = {Novel combination therapy for the eradication of Helicobacter pylori infection in a mouse model.}, journal = {Scandinavian journal of gastroenterology}, volume = {45}, number = {12}, pages = {1424-1430}, doi = {10.3109/00365521.2010.506245}, pmid = {20653490}, issn = {1502-7708}, mesh = {Acetylcysteine/therapeutic use ; Amoxicillin/therapeutic use ; Animals ; Anti-Bacterial Agents/*therapeutic use ; Cattle ; *Colostrum ; Disease Models, Animal ; Drug Therapy, Combination ; Female ; Helicobacter Infections/*drug therapy ; Mice ; Mice, Inbred C57BL ; Treatment Outcome ; Zinc/therapeutic use ; }, abstract = {OBJECTIVE: To investigate the combination therapy, consisting of hyperimmune bovine colostrum, N-acetyl cysteine, zinc and amoxicillin on the eradication of Helicobacter pylori in a mouse model.<br><br>MATERIAL AND METHODS: C57BL/6 female mice (6 weeks of age) were inoculated with 0.1 ml of 1&#xd7;10(9) H. pylori via a single oro-gastric gavage and were left infected for 4 weeks. Mice (n=9/group) were randomly allocated to receive by oral gavage (0.1 ml) HNZ (hyperimmune bovine colostrum+N-acetyl cysteine+zinc), HNZA (HNZ+amoxicillin; A), HNZA2 (2&#xd7; amoxicillin; A2), HNZA5 (5&#xd7; amoxicillin; A5), triple therapy (TT) or saline twice daily for 10 days. Bacterial load was assessed by culture. Gastric emptying was assessed by 13C-octanoic acid breath test.<br><br>RESULTS: Mice receiving HNZ, HNZA, and HNZA2 have a 22%, 44% and 67% eradication rate, respectively. Eradication rate was 100% with HNZA5, TT and those animals receiving A5 alone. In H. pylori infected mice there was an increased gastric emptying time by 7.9, 3.7, 10.1 and 7.7 min for the TT, HNZ, HNZA2, and HNZA5, respectively, compared to saline.<br><br>CONCLUSIONS: HNZ with the addition of a high dose of amoxicillin is effective at eradicating H. pylori in vivo as HNZA1 and HNZA2 did not give raise to eradication. The potency of the novel anti-H. pylori combination therapy may be due to the delayed gastric emptying.}, }
@article {pmid20653477, year = {2010}, author = {Akyol-Salman, I and Azizi, S and Mumcu, U and Baykal, O}, title = {Efficacy of topical N-acetylcysteine in the treatment of meibomian gland dysfunction.}, journal = {Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics}, volume = {26}, number = {4}, pages = {329-333}, doi = {10.1089/jop.2010.0001}, pmid = {20653477}, issn = {1557-7732}, mesh = {Acetylcysteine/*administration &amp; dosage/therapeutic use ; Administration, Topical ; Adult ; Eyelid Diseases/*drug therapy ; Female ; Humans ; Male ; *Meibomian Glands ; Middle Aged ; Ophthalmic Solutions/administration &amp; dosage/therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {PURPOSE: To evaluate the efficacy of topical N-acetyl-cysteine (NAC) therapy in patients with meibomian gland dysfunction (MGD).<br><br>METHODS: Twenty patients with MGD were prospectively randomized and assigned into 2 groups. The patients were instructed to use either NAC 5% or preservative-free artificial tear topically 4 times a day for a month. All patients were instructed to apply lid hygiene once daily. Preservative-free artificial tears treated group served as control. Paired sample Student's t-tests were used to detect differences between the baseline and 1 month after treatment initiation in mean ocular symptoms, fluorescein break-up time (FBUT) values, and Schirmer scores in each group. Difference in mean ocular symptoms, Schirmer's test scores, and FBUT values between the baseline and 1 month after treatment initiation were compared between the groups using Mann-Whitney U test.<br><br>RESULTS: One month of topical NAC therapy provided statistically significant improvements in FBUT and Schirmer scores as compared with the initial study visit. The average Schirmer increase rate was significantly better in the NAC group than in the control group. Significant improvements for the symptoms of ocular burning, foreign body sensation, and intermittent filmy or blurred vision were noted in both groups; and only NAC-treated group showed improvement for the symptom of itching, at 1 month as compared with 1 day. NAC provided significantly better improvement in itching symptom when compared with controls.<br><br>CONCLUSIONS: Topical administration of NAC is thought to be effective and well tolerated in patients with MGD.}, }
@article {pmid20653475, year = {2010}, author = {Gerona, G and López, D and Palmero, M and Maneu, V}, title = {Antioxidant N-acetyl-cysteine protects retinal pigmented epithelial cells from long-term hypoxia changes in gene expression.}, journal = {Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics}, volume = {26}, number = {4}, pages = {309-314}, doi = {10.1089/jop.2009.0101}, pmid = {20653475}, issn = {1557-7732}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/genetics ; Caspase 3/metabolism ; Caspase 8/genetics/metabolism ; Cattle ; *Cell Hypoxia ; Cells, Cultured ; Free Radical Scavengers/*pharmacology ; Gene Expression/*drug effects ; Genes, p53 ; Oxidative Stress/drug effects ; Retinal Pigment Epithelium/cytology/*drug effects/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Time Factors ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {PURPOSE: To further know the signaling pathways involved in hypoxia-induced apoptosis in retinal pigmented epithelial (RPE) cells and to improve the understanding of the antioxidant N-acetyl-cysteine (NAC) treatment effect.<br><br>METHODS: We analyzed the expression levels of several apoptosis-related genes by semiquantitative reverse transcriptase-polymerase chain reaction in RPE after 72 h of maintained hypoxia, with or without 10 mM NAC treatment.<br><br>RESULTS: Under hypoxic conditions, we detected a higher expression level of p53 and CASP8. Cell treatment with NAC 10 mM prevented this increase. Other apoptosis-related genes such as bax, CASP3, CASP4, CASP7, and fas did not show an increase in expression levels in hypoxia.<br><br>CONCLUSIONS: NAC prevents the increased expression levels of p53 and CASP8 induced by long-term maintained hypoxia. The supply of antioxidants could be a useful preventive approach in protecting RPE from the effects of chronic oxygen stress, which is of great interest in oxygen stress-related diseases such as age-related macular degeneration and other senescence-associated pathologies.}, }
@article {pmid20653470, year = {2010}, author = {Fu, YQ and Fang, F and Lu, ZY and Kuang, FW and Xu, F}, title = {N-acetylcysteine protects alveolar epithelial cells from hydrogen peroxide-induced apoptosis through scavenging reactive oxygen species and suppressing c-Jun N-terminal kinase.}, journal = {Experimental lung research}, volume = {36}, number = {6}, pages = {352-361}, doi = {10.3109/01902141003678582}, pmid = {20653470}, issn = {1521-0499}, mesh = {Acetylcysteine/*pharmacology ; Alveolar Epithelial Cells/*drug effects/enzymology/pathology ; Animals ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Cells, Cultured ; Cytoprotection ; Dose-Response Relationship, Drug ; Down-Regulation ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Hydrogen Peroxide/*toxicity ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Male ; Oxidants/*toxicity ; Oxidative Stress/*drug effects ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Time Factors ; Tumor Suppressor Protein p53/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {The production of reactive oxygen species (ROS) during hyperoxia contribute to alveolar epithelial apoptosis. In the present study, the molecular mechanisms of oxidative stress-induced alveolar epithelial cell apoptosis were investigated. The cytoprotective effects of N-acetylcysteine (NAC) were evaluated. Treatments using 500 muM H(2)O(2) can induce primary alveolar type II epithelial cell apoptosis. During this procedure, c-Jun N-terminal kinase (JNK) was activated. SP600125, a specific inhibitor of JNK, can partially block H(2)O(2)-induced alveolar type II epithelial cells (ATII cells). SP600125 also attenuated Bax protein content and p53 nuclear accumulation induced by H(2)O(2). NAC (5 mM) pretreatment decreased H(2)O(2)-induced ATII cell apoptosis. The high level of intracellular reactive oxygen species (ROS) induced by H(2)O(2) was also attenuated by NAC pretreatment. Taken together, H(2)O(2) can induce primary ATII cells apoptosis and increase JNK phosphorylation. NAC, a precursor of glutathione (GSH) synthesis, can protect ATII cells from H(2)O(2)-induced apoptosis through scavenging ROS.}, }
@article {pmid20651358, year = {2010}, author = {Han, YH and Yang, YM and Kim, SZ and Park, WH}, title = {Attenuation of MG132-induced HeLa cell death by N-acetyl cysteine via reducing reactive oxygen species and preventing glutathione depletion.}, journal = {Anticancer research}, volume = {30}, number = {6}, pages = {2107-2112}, pmid = {20651358}, issn = {1791-7530}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/physiology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Glutathione/*metabolism ; HeLa Cells ; Humans ; Leupeptins/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Proteasome Inhibitors ; Reactive Oxygen Species/*metabolism ; }, abstract = {MG132 as a proteasome inhibitor can induce apoptotic cell death through formation of reactive oxygen species (ROS). In this study, the effects of N-acetyl cysteine (NAC; an antioxidant) on MG132-induced HeLa cell death in relation to ROS and glutathione (GSH) were investigated. MG132 induced cell growth inhibition and apoptosis in HeLa cells, which was accompanied by the loss of mitochondrial membrane potential (MMP; Delta Psi(m)), activation of caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage. MG132 increased ROS levels, including O(2)(*-), and GSH depleted cell numbers of HeLa cells. NAC reduced the number of annexin V-positive cells and MMP (Delta Psi(m)) loss by MG132. In addition, NAC significantly reduced the ROS level and prevented GSH depletion. In conclusion, NAC prevented MG132-induced HeLa cell death via decreasing ROS and preventing GSH depletion.}, }
@article {pmid20649480, year = {2010}, author = {Liu, JQ and Lee, TF and Chen, C and Bagim, DL and Cheung, PY}, title = {N-acetylcysteine improves hemodynamics and reduces oxidative stress in the brains of newborn piglets with hypoxia-reoxygenation injury.}, journal = {Journal of neurotrauma}, volume = {27}, number = {10}, pages = {1865-1873}, doi = {10.1089/neu.2010.1325}, pmid = {20649480}, issn = {1557-9042}, support = {MOP51306//Canadian Institutes of Health Research/Canada ; }, mesh = {Analysis of Variance ; Animals ; Animals, Newborn ; Blood Pressure/drug effects ; Caspase 3/metabolism ; Cerebral Cortex/drug effects/metabolism ; Cerebrovascular Circulation/*drug effects ; Cystine/*analogs &amp; derivatives/pharmacology/therapeutic use ; Glutathione/metabolism ; Heart Rate/drug effects ; Hemodynamics/drug effects ; Hypoxia, Brain/*drug therapy/metabolism ; Lactic Acid/metabolism ; Lipid Peroxides/metabolism ; Oxidative Stress/*drug effects ; Random Allocation ; Swine ; }, abstract = {Reactive oxygen species have been implicated in the pathogenesis of hypoxic-ischemic injury. It has been shown previously that treating an animal with N-acetyl-L-cysteine (NAC), a scavenger of free radicals, significantly minimizes hypoxic-ischemic-induced brain injury in various acute models. Using a subacute swine model of neonatal hypoxia-reoxygenation (H-R), we evaluated the long-term beneficial effect of NAC against oxidative stress-induced brain injury. Newborn piglets were randomly assigned to a sham-operated group (without H-R, n = 6), and two H-R experimental groups (n = 8 each), with 2 h normocapnic alveolar hypoxia and 1 h of 100% oxygen reoxygenation followed by 21% oxygen for 47 h. Five minutes after reoxygenation, the H-R piglets received either normal saline (H-R controls) or NAC (150 mg/kg bolus and 20 mg/kg/h IV for 24 h) in a blinded randomized fashion. Treating the piglets with NAC significantly increased both common carotid arterial flow (CCAF) and oxygen delivery during the early phase of rexoygenation, while both CCAF and carotid oxygen delivery of the H-R group remained lower than the sham-operated groups throughout the experimental period. Compared with H-R controls, significantly higher amounts of anesthetic and sedative medications were required to maintain the NAC-treated piglets in stable condition throughout the experimental period, indicating a stronger recovery. Post-resuscitation NAC treatment also significantly attenuated the increase in cortical caspase-3 and lipid hydroperoxide concentrations. Our findings suggest that post-resuscitation administration of NAC reduces cerebral oxidative stress with improved cerebral oxygen delivery, and probably attenuates apoptosis in newborn piglets with H-R insults.}, }
@article {pmid20648652, year = {2010}, author = {Huang, Q and Aluise, CD and Joshi, G and Sultana, R and St Clair, DK and Markesbery, WR and Butterfield, DA}, title = {Potential in vivo amelioration by N-acetyl-L-cysteine of oxidative stress in brain in human double mutant APP/PS-1 knock-in mice: toward therapeutic modulation of mild cognitive impairment.}, journal = {Journal of neuroscience research}, volume = {88}, number = {12}, pages = {2618-2629}, doi = {10.1002/jnr.22422}, pmid = {20648652}, issn = {1097-4547}, support = {AG-05119/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Alzheimer Disease/drug therapy/genetics/metabolism ; Amyloid beta-Protein Precursor/*genetics ; Animals ; Brain/*drug effects/metabolism/physiopathology ; Cognition Disorders/*drug therapy/genetics/metabolism ; Disease Models, Animal ; Drug Administration Schedule ; Gene Knock-In Techniques/methods ; Humans ; Male ; Mice ; Mice, Transgenic ; Mutation/*genetics ; Oxidative Stress/*drug effects/physiology ; Presenilin-1/*genetics ; Time Factors ; }, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly. Although the underlying cause has yet to be established, numerous data have shown that oxidative stress is implicated in AD as well as in preclinical stages of AD, such as mild cognitive impairment (MCI). The oxidative stress observed in brains of subjects with AD and MCI may be due, either fully or in part, to increased free radicals mediated by amyloid-beta peptide (Abeta). By using double human mutant APP/PS-1 knock-in mice as the AD model, the present work demonstrates that the APP/PS-1 double mutation results in elevated protein oxidation (as indexed by protein carbonyls), protein nitration (as indexed by 3-nitrotyrosine), as well as lipid peroxidation (as indexed by protein-bound 4-hydroxy-2-nonenal) in brains of mice aged 9 months and 12 months. APP/PS-1 mice also exhibited lower levels of brain glutathione peroxidase (GPx) in both age groups studied, whereas glutathione reductase (GR) levels in brain were unaffected by the mutation. The activities of both of these antioxidant enzymes were significantly decreased in APP/PS-1 mouse brains, whereas the activity of glucose-6-phosphate dehydrogenase (G6PDH) was increased relative to controls in both age groups. Levels of peptidyl prolyl isomerase 1 (Pin1) were significantly decreased in APP/PS-1 mouse brain aged 9 and 12 months. Administration of N-acetyl-L-cysteine (NAC), a glutathione precursor, to APP/PS-1 mice via drinking water suppressed increased protein oxidation and nitration and also significantly augmented levels and activity of GPx in brain from both age groups. Oral administration of NAC also increased the diminished activity of GR and protected against lipid peroxidation in brains of 9-month-old APP/PS-1 mice only. Pin1 levels, GR levels, and G6PDH activity in brain were unaffected by oral administration of NAC in both age groups. These results are discussed with reference to the therapeutic potential of this brain-accessible glutathione precursor in the treatment of MCI and AD.}, }
@article {pmid20648626, year = {2010}, author = {Tinti, L and Spreafico, A and Braconi, D and Millucci, L and Bernardini, G and Chellini, F and Cavallo, G and Selvi, E and Galeazzi, M and Marcolongo, R and Gallagher, JA and Santucci, A}, title = {Evaluation of antioxidant drugs for the treatment of ochronotic alkaptonuria in an in vitro human cell model.}, journal = {Journal of cellular physiology}, volume = {225}, number = {1}, pages = {84-91}, doi = {10.1002/jcp.22199}, pmid = {20648626}, issn = {1097-4652}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alkaptonuria/*drug therapy/enzymology/pathology ; Antioxidants/pharmacology/*therapeutic use ; Apoptosis/drug effects ; Ascorbic Acid/pharmacology/*therapeutic use ; Cartilage, Articular/cytology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Chondrocytes/drug effects/metabolism ; Homogentisate 1,2-Dioxygenase/genetics/metabolism ; Homogentisic Acid/metabolism ; Humans ; Ochronosis/*drug therapy/enzymology/pathology ; Protein Carbonylation ; }, abstract = {Alkaptonuria (AKU) is a rare autosomal recessive disease, associated with deficiency of homogentisate 1,2-dioxygenase activity in the liver. This leads to an accumulation of homogentisic acid (HGA) and its oxidized derivatives in polymerized form in connective tissues especially in joints. Currently, AKU lacks an appropriate therapy. Hence, we propose a new treatment for AKU using the antioxidant N-acetylcysteine (NAC) administered in combinations with ascorbic acid (ASC) since it has been proven that NAC counteracts the side-effects of ASC. We established an in vitro cell model using human articular primary chondrocytes challenged with an excess of HGA (0.33 mM). We used this experimental model to undertake pre-clinical testing of potential antioxidative therapies for AKU, evaluating apoptosis, viability, proliferation, and metabolism of chondrocytes exposed to HGA and treated with NAC and ASC administered alone or in combination addition of both. NAC decreased apoptosis induced in chondrocytes by HGA, increased chondrocyte growth reduced by HGA, and partially restored proteoglycan release inhibited by HGA. A significantly improvement in efficacy was found with combined addition of the two antioxidants in comparison with NAC and ASC alone. Our novel in vitro AKU model allowed us to demonstrate the efficacy of the co-administration of NAC and ASC to counteract the negative effects of HGA for the treatment of ochronotic arthropathy.}, }
@article {pmid20647010, year = {2010}, author = {Leung, KC and Li, MY and Leung, BC and Hsin, MK and Mok, TS and Underwood, MJ and Chen, GG}, title = {Thromboxane synthase suppression induces lung cancer cell apoptosis via inhibiting NF-κB.}, journal = {Experimental cell research}, volume = {316}, number = {20}, pages = {3468-3477}, doi = {10.1016/j.yexcr.2010.07.003}, pmid = {20647010}, issn = {1090-2422}, mesh = {Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus/drug effects ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor/cytology/drug effects/metabolism ; Cell Nucleus/metabolism ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cytosol/metabolism ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; Humans ; I-kappa B Proteins/metabolism ; Imidazoles/pharmacology ; Lung Neoplasms/metabolism/*pathology ; Membrane Potential, Mitochondrial/drug effects ; NF-KappaB Inhibitor alpha ; NF-kappa B/*antagonists &amp; inhibitors/metabolism ; Nitriles/pharmacology ; Phosphorylation/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; Sulfones/pharmacology ; Thromboxane-A Synthase/*antagonists &amp; inhibitors/metabolism ; Transcription Factor RelA/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Accumulating evidence shows that the inhibition of thromboxane synthase (TXS) induced apoptosis in cancer cells. TXS inhibitor 1-Benzylimidzole (1-BI) can trigger apoptosis in lung cancer cells but the mechanism is not fully defined. In this study, lung cancer cells were treated with 1-BI. In this study, the level of reactive oxygen species (ROS) was measured and NF-κB activity was determined in human lung cancer cells. The roles of ROS and NF-κB in 1-BI-mediated cell death were analyzed. The results showed that 1-BI induced ROS generation but decreased the activity of NF-κB by reducing phosphorylated IκBα (p-IκBα) and inhibiting the translocation of p65 into the nucleus. In contrast to 1-BI, antioxidant N-acetyl cysteine (NAC) stimulated cell proliferation and significantly protected the cells from 1-BI-mediated cell death by neutralizing ROS. Collectively, apoptosis induced by 1-BI is associated with the over-production of ROS and the reduction of NF-κB. Antioxidants can significantly block the inhibitory effect of 1-BI.}, }
@article {pmid20639439, year = {2010}, author = {Maki, J and Hirano, M and Hoka, S and Kanaide, H and Hirano, K}, title = {Involvement of reactive oxygen species in thrombin-induced pulmonary vasoconstriction.}, journal = {American journal of respiratory and critical care medicine}, volume = {182}, number = {11}, pages = {1435-1444}, doi = {10.1164/rccm.201002-0255OC}, pmid = {20639439}, issn = {1535-4970}, mesh = {Animals ; Blotting, Western ; Calcium/metabolism ; Myosin Light Chains/metabolism ; Pulmonary Artery/*metabolism ; Reactive Oxygen Species/*metabolism ; Swine ; Thrombin ; *Vasoconstriction ; rho-Associated Kinases/metabolism ; }, abstract = {RATIONALE: Pulmonary vascular thrombosis and thrombotic arteriopathy are common pathological findings in pulmonary arterial hypertension. Thrombin may thus play an important role in the pathogenesis and pathophysiology of pulmonary arterial hypertension.<br><br>OBJECTIVES: The present study aimed to elucidate the contractile effect of thrombin in the pulmonary artery and clarify its underlying mechanisms.<br><br>METHODS: The changes in cytosolic Ca&#xb2;(+) concentrations ([Ca&#xb2;(+)](i)), 20-kD myosin light chain (MLC20) phosphorylation, and contraction were monitored in the isolated porcine pulmonary artery. The production of reactive oxygen species (ROS) was evaluated by fluorescence imaging.<br><br>MEASUREMENTS AND MAIN RESULTS: In the presence of extracellular Ca&#xb2;(+), thrombin induced a sustained contraction accompanied by an increase in [Ca&#xb2;(+)](i) and the phosphorylation of MLC20. In the absence of extracellular Ca&#xb2;(+), thrombin induced a contraction without either [Ca&#xb2;(+)](i) elevation or MLC20 phosphorylation. This Ca&#xb2;(+)- and MLC20 phosphorylation-independent contraction was mimicked by hydrogen peroxide and inhibited by N-acetyl cysteine. Fluorescence imaging revealed thrombin to induce the production of ROS. A Rho-kinase inhibitor, Y27632, inhibited not only the thrombin-induced Ca&#xb2;(+)- and MLC20 phosphorylation-dependent contraction, but also the Ca&#xb2;(+)- and MLC20 phosphorylation-independent contraction and the ROS production. These effects of thrombin were mimicked by a proteinase-activated receptor 1 (PAR&#x2081;)-activating peptide.<br><br>CONCLUSIONS: This study elucidated the Ca&#xb2;(+)- and MLC20 phosphorylation-independent ROS-mediated noncanonical mechanism as well as Ca&#xb2;(+)- and MLC20 phosphorylation-dependent canonical mechanism that are involved in the thrombin-induced PAR&#x2081;-mediated pulmonary vasoconstriction. Rho-kinase was suggested to play multiple roles in the development of thrombin-induced pulmonary vasoconstriction.}, }
@article {pmid20638862, year = {2011}, author = {Wang, G and Bainbridge, D and Martin, J and Cheng, D}, title = {N-acetylcysteine in cardiac surgery: do the benefits outweigh the risks? A meta-analytic reappraisal.}, journal = {Journal of cardiothoracic and vascular anesthesia}, volume = {25}, number = {2}, pages = {268-275}, doi = {10.1053/j.jvca.2010.04.022}, pmid = {20638862}, issn = {1532-8422}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Cardiac Surgical Procedures/*adverse effects ; Free Radical Scavengers/adverse effects/therapeutic use ; Humans ; Postoperative Complications/drug therapy/etiology/*prevention &amp; control ; *Randomized Controlled Trials as Topic/methods ; Risk Assessment/methods ; Risk Factors ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC) reduces proinflammatory cytokines, oxygen free-radical production, and ameliorates ischemia reperfusion injury; therefore, it may theoretically reduce postoperative complications in cardiac surgery. The aim of this study was to determine, through systematic review and meta-analysis of all relevant randomized trials, whether NAC reduces mortality, morbidity, or resource utilization in cardiac surgery.<br><br>DESIGN: Meta-analysis.<br><br>SETTING: University hospitals.<br><br>PARTICIPANTS: A total of 1,407 patients from 15 randomized studies were included in the analysis.<br><br>INTERVENTIONS: None.<br><br>MEASUREMENTS AND MAIN RESULTS: All randomized trials searched up to May 2009 comparing the use of NAC versus placebo during cardiac surgery in any language and reporting at least 1 predefined outcome were included. The random effect model was used to calculate odds ratios (ORs, 95% confidence intervals [CIs]) and weighted mean differences (WMD, 95% CI) for dichotomous and continuous variables, respectively. During cardiac surgery, the use of NAC did not significantly decrease acute renal failure requiring renal replacement therapy (OR = 1.05; 95% CI, 0.52-2.11; p = 0.90), new atrial fibrillation (OR = 0.67; 95% CI, 0.37-1.22; p = 0.19), or mortality (OR = 0.81; 95% CI, 0.39-1.68; p = 0.57). There were no differences in the incidence of incremental increase in serum creatinine concentration greater than 25% above baseline (OR = 0.86; 95% CI, 0.66-1.12; p = 0.26), acute myocardial infarction (OR = 0.69; 95% CI, 0.29-1.61, p =0.39), stroke (OR = 0.78; 95% CI, 0.30-2.03; p = 0.61), red blood cell transfusion requirement (OR = 0.77; 95% CI, 0.45-1.31; p = 0.33), re-exploration (OR = 1.33; 95% CI, 0.70-2.26; p = 0.29), or postoperative drainage (WMD = 33 mL; 95% CI,-125 to 191 mL; p = 0.69) between NAC and placebo.<br><br>CONCLUSION: Current evidence shows that the perioperative use of NAC has no proven benefit or risk on clinically important outcomes in patients undergoing cardiac surgery.}, }
@article {pmid20638463, year = {2010}, author = {Lin, CY and Wu, JL and Shih, TS and Tsai, PJ and Sun, YM and Ma, MC and Guo, YL}, title = {N-Acetyl-cysteine against noise-induced temporary threshold shift in male workers.}, journal = {Hearing research}, volume = {269}, number = {1-2}, pages = {42-47}, doi = {10.1016/j.heares.2010.07.005}, pmid = {20638463}, issn = {1878-5891}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Administration, Oral ; Adult ; *Auditory Threshold/drug effects ; Cross-Over Studies ; Double-Blind Method ; Free Radical Scavengers/administration &amp; dosage/pharmacology/*therapeutic use ; Genotype ; Glutathione Transferase/genetics ; Hearing Loss, Noise-Induced/*prevention &amp; control ; Humans ; Male ; Middle Aged ; Noise, Occupational/*adverse effects ; Polymorphism, Genetic/genetics ; Prospective Studies ; Treatment Outcome ; }, abstract = {Previous animal studies showed protective effects of antioxidant medicines against noise-induced hearing loss (NIHL). It is unclear whether antioxidants would protect humans from NIHL. We conducted a study to determine whether N-Acetyl-cysteine (NAC) protected men against noise-induced temporary threshold shift (TTS), and whether subgroups with genetic polymorphisms of glutathione S-transferase (GST) T1 and M1 responded to NAC differently. In this prospective, double-blind, crossover study, 53 male workers were randomly assigned to receive either NAC (1200 mg/day, 14 days) during the first period and placebo during the second period, or placebo during the first period and NAC during the second period. Dosing periods were separated by a washout period of 2 weeks. The hearing threshold changes were determined before and after each dosing period. Pre-shift hearing threshold for high frequencies was 19.1 dB. Daily exposure to noise ranged from 88.4 to 89.4 dB. The noise levels of different frequencies ranged from 80.0 to 89.4 dB with a peak-value at 4 kHz. NAC significantly reduced TTS (p = 0.03). When the participants were grouped by GST M1/T1 genotypes, the NAC effect was only significant among workers with null genotypes in both GSTM1 and GSTT1 (p = 0.004). NAC may prevent noise-induced TTS among occupationally noise-exposed men. The protective effect of NAC was more prominent in subjects with both GSTM1-null and GSTT1-null genotypes. (clinicaltrials.gov Identifier: NCT00552786).}, }
@article {pmid20637781, year = {2010}, author = {Oh, JM and Moon, EY}, title = {Actin-sequestering protein, thymosin beta-4, induces paclitaxel resistance through ROS/HIF-1alpha stabilization in HeLa human cervical tumor cells.}, journal = {Life sciences}, volume = {87}, number = {9-10}, pages = {286-293}, doi = {10.1016/j.lfs.2010.07.002}, pmid = {20637781}, issn = {1879-0631}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Blotting, Western ; Cell Nucleus/drug effects/metabolism ; Cell Survival/drug effects ; Cytosol/drug effects/metabolism ; Drug Resistance, Neoplasm/*drug effects/genetics ; Electrophoretic Mobility Shift Assay ; Flow Cytometry ; HeLa Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis ; Melanoma, Experimental/drug therapy/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; NF-kappa B ; Neoplasm Transplantation ; Paclitaxel/*pharmacology/therapeutic use ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Thymosin/genetics/pharmacology/*physiology ; }, abstract = {AIMS: We investigated whether actin-sequestering protein, thymosin beta-4 (TB4)-induced reactive oxygen species (ROS) affect the stabilization of hypoxia-inducible transcription factor (HIF)-1alpha and paclitaxel-resistance induction.<br><br>MAIN METHODS: HeLa human cervical tumor cells were used. The percentage of cell survival was determined by MTT assay. ROS production, cell cycle and hypodiploid cell formation were assessed by flow cytometry analysis. HIF-1alpha stabilization and molecular changes were analyzed by western blotting or RT-PCR. NF-kappaB activation was assessed by EMSA and western blotting.<br><br>KEY FINDINGS: TB4 protein (TB4P) significantly increased intracellular ROS level and HIF-1alpha. The increased level of HIF-1alpha by TB4P was reduced by the treatment with N-acetylcysteine (NAC), a well-known ROS scavenger. TB4P-induced ROS production was confirmed by the activation of nuclear factor kappa B. TB4P-induced Erk phosphorylation was attenuated by the treatment with NAC. In addition, tumor cell death was decreased by TB4 gene overexpression and TB4P treatment. NAC treatment attenuated tumor cell density increased by TB4P. Tumor cell death by paclitaxel was also increased by NAC treatment or the transfection with HIF-1alpha-siRNA. Paclitaxel-induced B16F10 mouse melanoma regression was physiologically inhibited in TB4-transgenic mice compared to wildtype mice.<br><br>SIGNIFICANCE: These findings demonstrate that TB4-induced ROS and ROS-mediated HIF-1alpha stabilization could play a role in tumor cell resistance to anticancer agents like paclitaxel. It suggests that soluble TB4 could be a novel endogenous regulator to control intracellular ROS production in tumor cells.}, }
@article {pmid20633688, year = {2010}, author = {Kishimoto, H and Akagi, M and Zushi, S and Teramura, T and Onodera, Y and Sawamura, T and Hamanishi, C}, title = {Induction of hypertrophic chondrocyte-like phenotypes by oxidized LDL in cultured bovine articular chondrocytes through increase in oxidative stress.}, journal = {Osteoarthritis and cartilage}, volume = {18}, number = {10}, pages = {1284-1290}, doi = {10.1016/j.joca.2010.05.021}, pmid = {20633688}, issn = {1522-9653}, mesh = {Acetylcysteine/pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Antioxidants/pharmacology ; Cartilage, Articular/drug effects/*pathology/physiopathology ; Cattle ; Cells, Cultured ; Chondrocytes/drug effects/*pathology/physiology ; Collagen Type X/biosynthesis/genetics ; Core Binding Factor Alpha 1 Subunit/biosynthesis/genetics ; Gene Expression Regulation/drug effects ; Gene Knockdown Techniques ; Hydrogen Peroxide/pharmacology ; Hypertrophy/chemically induced/pathology/physiopathology ; Lipoproteins, LDL/*pharmacology ; Microscopy, Fluorescence ; Oxidative Stress/*drug effects/physiology ; Phenotype ; RNA, Messenger/genetics ; Scavenger Receptors, Class E/deficiency/genetics ; }, abstract = {OBJECTIVE: It has been reported that the lectin-like oxidized low-density lipoprotein (Ox-LDL) receptor 1 (LOX-1) is expressed by chondrocytes in osteoarthritis (OA) cartilage and that Ox-LDL binding to LOX-1 increases intracellular oxidative stress in cultured bovine articular chondrocytes (BACs). It was recently demonstrated that reactive oxygen species (ROS) induce hypertrophic differentiation of chondrocytes in the growth plate. It has also been shown that activated chondrocytes in OA have hypertrophic chondrocyte-like phenotypes. The purpose of this study was to determine whether Ox-LDL induces hypertrophic chondrocyte-like phenotypes in BACs.<br><br>DESIGN: Changes in type X collagen (COL10) and runt-related transcription factor 2 (Runx2) mRNA expression in BACs after Ox-LDL stimulation were investigated using real-time polymerase chain reaction (PCR). Western blotting and immunofluorescent cell staining were used to investigate changes in protein level. The antioxidant N-acetyl cysteine (NAC) was used to ascertain whether oxidative stress is involved in COL10 and Runx2 expression. We induced LOX-1 knockdown cells using small interfering RNA (siRNA) to examine the receptor specificity of Ox-LDL.<br><br>RESULTS: COL10 expression was upregulated by Ox-LDL in a time- and dose-dependent manner. Immunofluorescent staining showed that Ox-LDL increased COL10 production in the extracellular matrix. Ox-LDL-induced upregulation of COL10 was suppressed by pretreatment with NAC and siRNA. Expression of Runx2 was upregulated by Ox-LDL and H(2)O(2), and these effects were suppressed by NAC pretreatment.<br><br>CONCLUSION: Ox-LDL binding to LOX-1 induces a hypertrophic chondrocyte-like phenotype through oxidative stress, indicating that Ox-LDL plays a role in the degeneration of cartilage.}, }
@article {pmid20631883, year = {2010}, author = {Hahm, ET and Seo, JW and Hur, J and Cho, YW}, title = {Modulation of Presynaptic GABA Release by Oxidative Stress in Mechanically-isolated Rat Cerebral Cortical Neurons.}, journal = {The Korean journal of physiology &amp; pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology}, volume = {14}, number = {3}, pages = {127-132}, pmid = {20631883}, issn = {2093-3827}, abstract = {Reactive oxygen species (ROS), which include hydrogen peroxide (H(2)O(2)), the superoxide anion (O(2) (-).), and the hydroxyl radical (OH.), are generated as by-products of oxidative metabolism in cells. The cerebral cortex has been found to be particularly vulnerable to production of ROS associated with conditions such as ischemia-reperfusion, Parkinson's disease, and aging. To investigate the effect of ROS on inhibitory GABAergic synaptic transmission, we examined the electrophysiological mechanisms of the modulatory effect of H(2)O(2) on GABAergic miniature inhibitory postsynaptic current (mIPSCs) in mechanically isolated rat cerebral cortical neurons retaining intact synaptic boutons. The membrane potential was voltage-clamped at -60 mV and mIPSCs were recorded and analyzed. Superfusion of 1-mM H(2)O(2) gradually potentiated mIPSCs. This potentiating effect of H(2)O(2) was blocked by the pretreatment with either 10,000-unit/mL catalase or 300-microM N-acetyl-cysteine. The potentiating effect of H(2)O(2) was occluded by an adenylate cyclase activator, forskolin, and was blocked by a protein kinase A inhibitor, N-(2-[p-bromocinnamylamino] ethyl)-5-isoquinolinesulfonamide hydrochloride. This study indicates that oxidative stress may potentiate presynaptic GABA release through the mechanism of cAMP-dependent protein kinase A (PKA)-dependent pathways, which may result in the inhibition of the cerebral cortex neuronal activity.}, }
@article {pmid20630911, year = {2011}, author = {Zyoud, SH and Awang, R and Sulaiman, SA and Al-Jabi, SW}, title = {An analysis of the length of hospital stay after acetaminophen overdose.}, journal = {Human &amp; experimental toxicology}, volume = {30}, number = {7}, pages = {550-559}, doi = {10.1177/0960327110377647}, pmid = {20630911}, issn = {1477-0903}, mesh = {Acetaminophen/antagonists &amp; inhibitors/*poisoning ; Acetylcysteine/administration &amp; dosage/therapeutic use ; Analgesics, Non-Narcotic/antagonists &amp; inhibitors/*poisoning ; Antidotes/administration &amp; dosage/therapeutic use ; Costs and Cost Analysis ; Drug Overdose/drug therapy/*economics ; Female ; Humans ; Injections, Intravenous ; Length of Stay/*statistics &amp; numerical data ; Male ; Time Factors ; Young Adult ; }, abstract = {BACKGROUND: Acetaminophen is one of the most commonly encountered medications in self-poisoning, with a high rate of morbidity. The prevalence and characteristics of acetaminophen intoxication associated with long hospital stay in patients are not well defined.<br><br>OBJECTIVES: This study aims to identify the clinical and demographic factors associated with the length of in-hospital stay (LOS), and to evaluate the effect of early treatment of acetaminophen overdose patients (&#x2264;8 hours) by intravenous N-acetylcysteine (IV-NAC) on hospital stay.<br><br>METHODS: This is a retrospective cohort study of hospital admissions for acetaminophen overdose conducted over a period of 5 years from 1 January 2004 to 31 December 2008. Patients were divided into two groups: LS group patients had a long hospital stay (> median hours stay in hospital) and SS group patients had a short hospital stay (&#x2264; median hours stay in hospital). Variables were abstracted from medical records for comparison between the two groups. A total of 20 variables were identified for comparison. Parametric and non-parametric tests were used to test differences between groups depending on the normality of the data. SPSS 15 was used for data analysis.<br><br>RESULTS: Of the 305 patients, 11 factors were identified in the univariate analysis as associated with LS. Three independent factors were found to be significant predictors of LS in the multivariate analysis. The factors associated with LS were seen among patients with a history of abdominal pain after ingestion of acetaminophen (p = 0.04), who were on IV-NAC administration (p < 0.001) and had an acutely depressed mood (p = 0.003). Late time to NAC infusion of more than 8 hours was associated with LS rather than SS (96 patients [57%] and 6 [24%], respectively; p = 0.003).<br><br>CONCLUSION: Patients with long hospital stay have different clinical characteristics compared to patients with short hospital stay. We identified time to IV-NAC administration is a potentially modifiable factor that may lead to prolonged hospital stay. When risk assessment indicates that NAC is required, it is highly recommended that NAC be started in the first hours of admission to reduce the LOS.}, }
@article {pmid20628939, year = {2010}, author = {Sood, S and Muthuraman, A and Gill, NS and Bali, M and Sharma, PD}, title = {Role of 7,8-dimethoxycoumarin in anti-secretary and anti-inflammatory action on pyloric ligation-induced gastritis in rats.}, journal = {Journal of Asian natural products research}, volume = {12}, number = {7}, pages = {593-599}, doi = {10.1080/10286020.2010.486377}, pmid = {20628939}, issn = {1477-2213}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/chemistry/*pharmacology ; Anti-Ulcer Agents/chemistry/*pharmacology ; Citrus/*chemistry ; Coumarins/chemistry/*pharmacology ; Gastritis/*chemically induced ; Molecular Structure ; Nuclear Magnetic Resonance, Biomolecular ; Omeprazole/pharmacology ; Pylorus/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {The present study was designed to investigate the effect of 7,8-dimethoxycoumarin (DMC) isolated from ethyl acetate extract of Citrus decumana peels on gastritis in rats. Isolation of 7,8-DMC from ethyl acetate extract of C. decumana peels was done by column and preparative thin layer chromatography using different solvents on polarity basis. Furthermore, effect of 7,8-DMC (50, 75, and 100 mg/kg, i.p.) in pyloric ligation-induced gastritis was studied in rats. The highest dose of 7,8-DMC showed significant decrease in the gastric volume, total acidity, ulcerative index, thiobarbituric acid reactive species levels, and myeloperoxidase activity, whereas there was an increase in the glutathione level. However, the lowest and medium doses did not produce significant results as compared to omeprazole and N-acetyl cysteine-treated groups. Compound 7,8-DMC (100 mg/kg) showed ameliorative effect on gastric inflammation and may be used as a therapeutic agent in the treatment of gastritis.}, }
@article {pmid20626325, year = {2010}, author = {Yıldırım, M and Inançlı, HM and Samancı, B and Oktay, MF and Enöz, M and Topçu, I}, title = {Preventing cisplatin induced ototoxicity by N-acetylcysteine and salicylate.}, journal = {Kulak burun bogaz ihtisas dergisi : KBB = Journal of ear, nose, and throat}, volume = {20}, number = {4}, pages = {173-183}, pmid = {20626325}, issn = {1300-7475}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Audiology ; Audiometry, Pure-Tone ; Auditory Threshold/drug effects ; Cisplatin/adverse effects/therapeutic use/*toxicity ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Female ; Hearing Loss/chemically induced/prevention &amp; control ; Humans ; Male ; Middle Aged ; Neoplasms/drug therapy ; Salicylates/*therapeutic use ; }, abstract = {OBJECTIVES: In this study we investigated if CP induced ototoxicity could be prevented or reduced by the use of salicylate and N-acetylcysteine.<br><br>PATIENTS AND METHODS: Fifty-four patients (28 females, 26 males; mean age 37+/-9.5 years; range 29 to 71 years) who had cisplatin chemotherapy due to solid organ tumors were enrolled in the study. The patients were randomized into three groups, with 18 patients in each group. The first group (control group) received cisplatin, second group received N-acetylcysteine (NAC; 600 mg/day) with cisplatin and the third group received salicylate (300 mg/day) with cisplatin. All patients evaluated audiologically including high frequency audiometry and auditory brainstem response.<br><br>RESULTS: The cisplatin-induced ototoxic damage could be reduced in 10,000 and 12,000 Hz frequencies when N-acetylcysteine was added to the cisplatin therapy protocol. There was no decrease in the hearing loss levels of the patients who were receiving cisplatin with salicylate.<br><br>CONCLUSION: According to auditory brainstem response testing results, there was no difference detected between N-acetylcysteine or salicylate for the amelioration of cisplatin induced ototoxicity.}, }
@article {pmid20625996, year = {2011}, author = {Qi, XF and Teng, YC and Yoon, YS and Kim, DH and Cai, DQ and Lee, KJ}, title = {Reactive oxygen species are involved in the IFN-γ-stimulated production of Th2 chemokines in HaCaT keratinocytes.}, journal = {Journal of cellular physiology}, volume = {226}, number = {1}, pages = {58-65}, doi = {10.1002/jcp.22303}, pmid = {20625996}, issn = {1097-4652}, mesh = {Cell Line ; Chemokine CCL17/genetics/*metabolism ; Chemokine CCL22/genetics/*metabolism ; Free Radical Scavengers ; Gene Expression Regulation/*drug effects ; Humans ; Interferon-gamma/*pharmacology ; Keratinocytes/drug effects/*metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; NF-kappa B/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {The increased generation of reactive oxygen species (ROS) induces inflammation in different cell types. However, it is unclear whether ROS play an essential role in the production of thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) in keratinocytes. Here, we investigated the function of ROS in the production of these two Th2 chemokines in interferon-gamma (IFN-γ)-treated HaCaT keratinocytes. We found that IFN-γ-induced production of both chemokines in parallel with the increased generation of intracellular ROS. A ROS scavenger, N-acetyl cysteine (NAC), significantly inhibited the IFN-γ-induced production of chemokines as well as the activation of I kappa-B (IκB)-nuclear factor-kappa B (NF-κB). Inhibitors of Janus family kinases (JAKs), p38 mitogen-activated kinase (MAPK), and NF-κB suppressed IFN-γ-induced production of TARC and MDC. NF-κB activation was inhibited by both inhibitors of JAKs and p38 MAPK. Importantly, IFN-γ-stimulated phosphorylation of p38 MAPK was significantly suppressed by JAKs inhibitors, but not significantly affected by NAC or L-buthionine sulfoximine (L-BSO). However, IFN-γ-stimulated activation of IκB and NF-κB was suppressed by NAC but enhanced by BSO. Furthermore, inhibition of p38 MAPK and JAKs did not affect ROS generation in IFN-γ-stimulated HaCaT cells. These results indicate that intracellular ROS and JAKs/p38 MAPK both contribute independently to IFN-γ-stimulated production of TARC and MDC in HaCaT keratinocytes, by increasing NF-κB activation.}, }
@article {pmid20624163, year = {2010}, author = {Mizutani, H and Hiraku, Y and Tada-Oikawa, S and Murata, M and Ikemura, K and Iwamoto, T and Kagawa, Y and Okuda, M and Kawanishi, S}, title = {Romidepsin (FK228), a potent histone deacetylase inhibitor, induces apoptosis through the generation of hydrogen peroxide.}, journal = {Cancer science}, volume = {101}, number = {10}, pages = {2214-2219}, doi = {10.1111/j.1349-7006.2010.01645.x}, pmid = {20624163}, issn = {1349-7006}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Depsipeptides/*pharmacology ; Glutathione/metabolism ; Histone Deacetylase Inhibitors/*pharmacology ; Humans ; Hydrogen Peroxide/*metabolism ; Hydroxamic Acids/pharmacology ; }, abstract = {Romidepsin (FK228) is a potent histone deacetylase (HDAC) inhibitor, which has a potent anticancer activity, but its molecular mechanism is unknown. We investigated the mechanism of FK228-induced apoptosis in the human leukemia cell line HL-60 and its hydrogen peroxide (H(2)O(2))-resistant sub-clone, HP100, and the human colon cancer cell line Caco-2. Cytotoxicity and DNA ladder formation induced by FK228 could be detected in HL-60 cells after a 24-h incubation, whereas they could not be detected in HP100 cells. Trichostatin A (TSA), an HDAC inhibitor, induced DNA ladder formation in both HL-60 and HP100 cells. In contrast, FK228 inhibited HDAC activity in both HL-60 and HP100 cells to a similar extent. These findings suggest that FK228-induced apoptosis involves H(2)O(2)-mediated pathways and that TSA-induced apoptosis does not. Flow cytometry revealed H(2)O(2) formation and a change in mitochondrial membrane potential (Δψm) in FK228-treated cells. FK228 also induced apoptosis in Caco-2 cells, which was prevented by N-acetyl-cysteine, suggesting that reactive oxygen species participate in apoptosis in various types of tumor cells. Interestingly, in a cell-free system, FK228 generated superoxide (O(2)(-)) in the presence of glutathione, suggesting that H(2)O(2) is derived from dismutation of O(2)(-) produced through redox-cycle of FK228. Therefore, in addition to HDAC inhibition, H(2)O(2) generated from FK228 may participate in its apoptotic effect.}, }
@article {pmid20621351, year = {2010}, author = {Minamikawa, H and Yamada, M and Iwasa, F and Ueno, T and Deyama, Y and Suzuki, K and Yawaka, Y and Ogawa, T}, title = {Amino acid derivative-mediated detoxification and functionalization of dual cure dental restorative material for dental pulp cell mineralization.}, journal = {Biomaterials}, volume = {31}, number = {28}, pages = {7213-7225}, doi = {10.1016/j.biomaterials.2010.06.018}, pmid = {20621351}, issn = {1878-5905}, support = {C06RR014529/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*metabolism ; Animals ; Biocompatible Materials/chemistry/metabolism ; *Calcification, Physiologic ; Cell Survival ; Cells, Cultured ; Cytokines/immunology ; Dental Pulp/*cytology/*physiology ; Dental Pulp Capping/*instrumentation/methods ; Glass Ionomer Cements/chemistry/*metabolism ; Glutathione/metabolism ; Male ; Materials Testing ; Phenotype ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Regeneration/physiology ; }, abstract = {Current dental restorative materials are only used to fill the defect of hard tissues, such as dentin and enamel, because of their cytotoxicity. Therefore, exposed dental pulp tissues in deep cavities must be first covered by a pulp capping material like calcium hydroxide to form a layer of mineralized tissue. However, this tissue mineralization is based on pathological reaction and triggers long-lasting inflammation, often causing clinical problems. This study tested the ability of N-acetyl cysteine (NAC), amino acid derivative, to reduce cytotoxicity and induce mineralized tissue conductivity in resin-modified glass ionomer (RMGI), a widely used dental restorative material having dual cure mechanism. Rat dental pulp cells were cultured on untreated or NAC-supplemented RMGI. NAC supplementation substantially increased the percentage of viable cells from 46.7 to 73.3% after 24-h incubation. Cell attachment, spreading, proliferative activity, and odontoblast-related gene and protein expressions increased significantly on NAC-supplemented RMGI. The mineralization capability of cells, which was nearly suppressed on untreated RMGI, was induced on NAC-supplemented RMGI. These improved behaviors and functions of dental pulp cells on NAC-supplemented RMGI were associated with a considerable reduction in the production of intracellular reactive oxygen species and with the increased level of intracellular glutathione reserves. These results demonstrated that NAC could detoxify and functionalize RMGIs via two different mechanisms involving in situ material detoxification and antioxidant cell protection. We believe that this study provides a new approach for developing dental restorative materials that enables mineralized tissue regeneration.}, }
@article {pmid20615714, year = {2010}, author = {Sagardoy, AA and Gil, MJ and Villar, R and Viñas, MJ and Arrazola, A and Encío, I and Martinez-Merino, V}, title = {Benzo[b]thiophene-6-carboxamide 1,1-dioxides: inhibitors of human cancer cell growth at nanomolar concentrations.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {18}, number = {15}, pages = {5701-5707}, doi = {10.1016/j.bmc.2010.06.009}, pmid = {20615714}, issn = {1464-3391}, mesh = {Antineoplastic Agents/*chemistry/therapeutic use ; Apoptosis ; Cell Line, Tumor ; Drug Screening Assays, Antitumor ; Humans ; Neoplasms/drug therapy ; Reactive Oxygen Species/metabolism ; Thiophenes/chemical synthesis/*chemistry/therapeutic use ; }, abstract = {Benzo[b]thiophenesulfonamide 1,1-dioxide derivatives (BTS) were described as candidate antineoplastic drugs. In the hope of finding new compounds with improved antitumour activity and reduced toxicity, we have designed and synthesized a small series of benzo[b]thiophene-6-carboxamide 1,1-dioxide derivatives (BTC) structurally related with the best reported BTS. Growth inhibition of HTB-54, CCRF-CEM and HeLa tumour cells lines at nanomolar concentrations was exhibited by some of the BTC. Hydrophobic substituents on the carboxamide group increased cytotoxicity but substitution by a hydroxy group diminished it, thus pointing to the electronic density on benzo[b]thiophene nucleus as a determinant factor. The process of cell death induced by BTC derivatives was further analyzed in CCRF-CEM cells, where these compounds induced apoptosis in a time and dose-dependent manner and cell cycle arrest at S phase. BTC derivatives also induced a significant increase in intracellular ROS levels in this cell line. Previous treatment of the cells with the antioxidant N-acetyl-cysteine abrogated the induction of apoptosis by BTC indicating that ROS generation is a previous event required to trigger the BTC induced apoptotic process.}, }
@article {pmid20615578, year = {2010}, author = {Naves, P and del Prado, G and Huelves, L and Rodríguez-Cerrato, V and Ruiz, V and Ponte, MC and Soriano, F}, title = {Effects of human serum albumin, ibuprofen and N-acetyl-L-cysteine against biofilm formation by pathogenic Escherichia coli strains.}, journal = {The Journal of hospital infection}, volume = {76}, number = {2}, pages = {165-170}, doi = {10.1016/j.jhin.2010.05.011}, pmid = {20615578}, issn = {1532-2939}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects/growth &amp; development ; Escherichia coli/*drug effects/growth &amp; development ; Humans ; Ibuprofen/*pharmacology ; Microbial Sensitivity Tests ; Serum Albumin/*pharmacology ; }, abstract = {The aim of this study was to evaluate the effects of human serum albumin (HSA), ibuprofen sodium (IBU) and N-acetyl-L-cysteine (NAC) against biofilm formation by seven biofilm-producing strains of Escherichia coli. Biofilm formation was studied using polystyrene microtitre plates in static conditions. The impact of the three compounds on bacterial growth and biofilm formation was tested by applying each compound in solution and as pre-treatment (coating) of polystyrene wells. When studied in solution, the minimum biofilm inhibitory concentrations of HSA, IBU and NAC were 8 mg/L (all strains), 2-125 mg/L (five strains) and 30-125 mg/L (five strains), respectively. Pre-treatment of polystyrene plates with HSA at 8 and 32,000 mg/L significantly reduced biofilm formation by all strains, whereas coating with 125 mg/L IBU and 1000 mg/L NAC did not. When HSA at 8 and 32,000 mg/L was combined with either 125 mg/L IBU or 1000 mg/L NAC in pre-treatment assays, more potent inhibition of biofilm was observed for some strains. Our results suggest that biofilm formation by E. coli may be prevented by coating medical devices with HSA alone or in combination with IBU or NAC. In addition, IBU and NAC could be useful in the treatment of urinary tract infections caused by E. coli due to their inhibitory effect on both bacterial growth and biofilm formation.}, }
@article {pmid20613681, year = {2010}, author = {Mukherjee, R and McQuinn, TC and Dugan, MA and Saul, JP and Spinale, FG}, title = {Cardiac function and circulating cytokines after endotoxin exposure in neonatal mice.}, journal = {Pediatric research}, volume = {68}, number = {5}, pages = {381-386}, pmid = {20613681}, issn = {1530-0447}, support = {HL-97012/HL/NHLBI NIH HHS/United States ; R03 HL097012/HL/NHLBI NIH HHS/United States ; P01-48788//PHS HHS/United States ; R01 HL057952/HL/NHLBI NIH HHS/United States ; R01 HL059165/HL/NHLBI NIH HHS/United States ; HL-45024/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Animals, Newborn/blood/immunology/physiology ; *Cardiovascular Physiological Phenomena/drug effects/immunology ; Chemokines/blood ; Cytokines/*blood/immunology ; Echocardiography ; Endotoxins/*pharmacology ; Heart/*drug effects ; Mice ; }, abstract = {Complications after cardiac surgery in neonates can occur because of activation of the inflammatory system. This study used lipopolysaccharide (LPS) endotoxin exposure to cause cytokine activation in neonatal mice and examine left ventricular (LV) function and the effects of antioxidant treatment on cytokine levels. Neonatal mice (6 d old) were injected with either 25 mg/kg LPS (n = 13) or PBS (n = 14), and LV function (echocardiography) was measured at 4 h. Plasma levels of TNF-α, IL-4, IL-6, and IL-10 were measured at 30 min, 1, 2, and 4 h after injection (n = 5 mice per group). Effects of pretreatment with N-acetylcysteine (NAC, 50 mg/kg) on cytokine levels were examined at 2 and 4 h after PBS or LPS (n = 5 mice per group). Four hours after LPS, heart rate was increased (434 ± 14 versus 405 ± 14 bpm, p < 0.05). LV end-diastolic dimension and ejection time were reduced with LPS (both p < 0.05). LPS exposure increased plasma TNF-α, IL-6, and IL-10 levels. NAC pretreatment attenuated the increases in TNF-α and IL-6 levels, but augmented IL-10 levels at 2 h post-LPS. LPS exposure altered cardiac performance and activated cytokines in neonatal mice, which may be ameliorated using antioxidants.}, }
@article {pmid20606481, year = {2010}, author = {Hsu, SP and Chiang, CK and Yang, SY and Chien, CT}, title = {N-acetylcysteine for the management of anemia and oxidative stress in hemodialysis patients.}, journal = {Nephron. Clinical practice}, volume = {116}, number = {3}, pages = {c207-16}, doi = {10.1159/000317201}, pmid = {20606481}, issn = {1660-2110}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Anemia/*drug therapy ; Antioxidants/adverse effects/*therapeutic use ; Case-Control Studies ; Chlorides/therapeutic use ; Dinoprost/analogs &amp; derivatives/blood ; Erythropoietin/therapeutic use ; Female ; Ferric Compounds/therapeutic use ; Hematocrit ; Humans ; Kidney Failure, Chronic/blood/complications/*therapy ; Lipoproteins, LDL/blood ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Recombinant Proteins/therapeutic use ; Renal Dialysis/*adverse effects ; }, abstract = {BACKGROUND/AIMS: To explore the efficacy of oral N-acetylcysteine (NAC) supplementation for anemia and oxidative stress in hemodialysis (HD) patients.<br><br>METHODS: Of the eligible patients (n = 325) in an outpatient HD unit, 49 received NAC 200 mg orally thrice a day during the first 3 months, while the other 276 patients not receiving NAC were observed.<br><br>RESULTS: During the 4-month study, 11 patients receiving NAC withdrew but had no severe adverse effects, while 49 patients not receiving NAC had negative confounding events. Thus only the data of the remaining patients, 38 taking NAC and 227 not taking NAC, were analyzed for efficacy. The demographic and laboratory data of both groups were similar at baseline. When the erythropoietin dosage was stable throughout, only the NAC group had a significant increase in hematocrit, accompanied with a decrease in plasma levels of 8-isoprostane and oxidized low-density lipoprotein. Analyzed as a nested case-control study, NAC supplementation was also found to be a significant predictor of positive outcomes in uremic anemia.<br><br>CONCLUSIONS: Oral NAC supplementation may be a promising therapy for uremic anemia and oxidative stress in HD patients.}, }
@article {pmid20603572, year = {2010}, author = {Coleman, J and Huang, X and Liu, J and Kopke, R and Jackson, R}, title = {Dosing study on the effectiveness of salicylate/N-acetylcysteine for prevention of noise-induced hearing loss.}, journal = {Noise &amp; health}, volume = {12}, number = {48}, pages = {159-165}, doi = {10.4103/1463-1741.64972}, pmid = {20603572}, issn = {1463-1741}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Analysis of Variance ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*administration &amp; dosage/pharmacology ; Auditory Threshold/drug effects ; Chinchilla ; Disease Models, Animal ; Drug Administration Schedule ; Drug Combinations ; Drug Evaluation, Preclinical ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Female ; Free Radical Scavengers/*administration &amp; dosage/pharmacology ; Hair Cells, Auditory, Outer/drug effects/pathology ; Hearing Loss, Noise-Induced/diagnosis/*prevention &amp; control ; Hearing Tests ; Injections, Intraperitoneal ; Random Allocation ; Sodium Salicylate/*administration &amp; dosage/pharmacology ; Sound Spectrography ; }, abstract = {The efficacy of three different doses of sodium salicylate (SAL) in combination with one dose of N-acetylcysteine (NAC) to prevent noise-induced hearing loss was studied in chinchillas. After obtaining baseline-hearing thresholds, the chinchillas were randomly assigned to one of four treatment groups: three sets were injected intraperitoneally with 325 mg/kg NAC combined with 25, 50, or 75 mg/kg SAL, and a separate control group was injected with an equal volume of saline. Animals were injected twice daily for 2 days prior to and 1 hour before the noise exposure (6 hours to a 105-dB Standard Pressure Level octave band noise centered at 4 kHz). Immediate post-noise hearing thresholds were obtained followed by post-noise treatments at 1 hour then twice-daily for 2 days. Hearing tests continued at 1, 2, and 3 weeks post-noise, and immediately after the last hearing test, animals' cochleae were stained for hair cell counts. All the groups showed hearing improvement until week 2. However, at week 3, saline treated animals demonstrated a 17-33 dB SPL permanent threshold shift (PTS) across the test frequencies. Hearing loss was lowest in the 50 SAL/325 NAC mg/kg group (all frequencies, P < 0.001), and although PTS was reduced in the 25 and 75 mg/kg SAL dosage groups compared to the saline group, only the 75 mg/kg SAL group was significantly different at all but 2 kHz frequency. Coupled with the hearing loss, outer hair cell (OHC) loss was maximal in the 4-8 kHz cochlear region of saline treated animals. However, there was a substantial reduction in the mean OHC loss of the NAC plus 50 or 75 mg/kg (but not the 25 mg/kg) SAL groups. These findings suggest that SAL in combination with NAC is effective in reducing noise damage to the cochlea, but SAL has a relatively narrow therapeutic dosing window.}, }
@article {pmid20602078, year = {2010}, author = {Parasassi, T and Brunelli, R and Costa, G and De Spirito, M and Krasnowska, E and Lundeberg, T and Pittaluga, E and Ursini, F}, title = {Thiol redox transitions in cell signaling: a lesson from N-acetylcysteine.}, journal = {TheScientificWorldJournal}, volume = {10}, number = {}, pages = {1192-1202}, doi = {10.1100/tsw.2010.104}, pmid = {20602078}, issn = {1537-744X}, mesh = {Acetylcysteine/*pharmacology ; Cell Proliferation ; Gene Expression/drug effects ; Oxidation-Reduction ; *Signal Transduction ; Sulfhydryl Compounds/*metabolism ; src-Family Kinases/metabolism ; }, abstract = {The functional status of cells is under the control of external stimuli affecting the function of critical proteins and eventually gene expression. Signal sensing and transduction by messengers to specific effectors operate by post-translational modification of proteins, among which thiol redox switches play a fundamental role that is just beginning to be understood. The maintenance of the redox status is, indeed, crucial for cellular homeostasis and its dysregulation towards a more oxidized intracellular environment is associated with aberrant proliferation, ultimately related to diseases such as cancer, cardiovascular disease, and diabetes. Redox transitions occur in sensitive cysteine residues of regulatory proteins relevant to signaling, their evolution to metastable disulfides accounting for the functional redox switch. N-acetylcysteine (NAC) is a thiol-containing compound that is able to interfere with redox transitions of thiols and, thus, in principle, able to modulate redox signaling. We here review the redox chemistry of NAC, then screen possible mechanisms to explain the effects observed in NAC-treated normal and cancer cells; such effects involve a modification of global gene expression, thus of functions and morphology, with a leitmotif of a switch from proliferation to terminal differentiation. The regulation of thiol redox transitions in cell signaling is, therefore, proposed as a new tool, holding promise not only for a deeper explanation of mechanisms, but indeed for innovative pharmacological interventions.}, }
@article {pmid20601632, year = {2010}, author = {Yadav, AK and Bracher, A and Doran, SF and Leustik, M and Squadrito, GL and Postlethwait, EM and Matalon, S}, title = {Mechanisms and modification of chlorine-induced lung injury in animals.}, journal = {Proceedings of the American Thoracic Society}, volume = {7}, number = {4}, pages = {278-283}, pmid = {20601632}, issn = {1943-5665}, support = {2R01HL031197/HL/NHLBI NIH HHS/United States ; 5 U01ES015676/ES/NIEHS NIH HHS/United States ; 5 U54ES017218/ES/NIEHS NIH HHS/United States ; 5P01ES011617/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ascorbic Acid/*pharmacology ; Bronchoalveolar Lavage Fluid/chemistry ; Chlorine/chemistry/*toxicity ; Gases/chemistry/*toxicity ; Inhalation Exposure ; Lung/*drug effects ; Lung Diseases/*diagnosis/*prevention &amp; control ; Models, Animal ; Rabbits ; Rats ; }, abstract = {Chlorine (Cl(2)) is a reactive oxidant gas used extensively in industrial processes. Exposure of both humans and animals to high concentrations of Cl(2) results in acute lung injury, which may resolve spontaneously or progress to acute respiratory failure. Injury to airway and alveolar epithelium may result from chemical reactions of Cl(2), from HOCl (the hydrolysis product of Cl(2)), and/or from the various reaction products, such as chloramines, that are formed from the reactions of these chlorinating species with biological molecules. Subsequent reactions may initiate self-propagating reactions and induce the production of inflammatory mediators compounding injury to pulmonary surfactant, ion channels, and components of lung epithelial and airway cells. Low-molecular-weight antioxidants, such as ascorbate, glutathione, and urate, present in the lung epithelial lining fluid and tissue, remove Cl(2) and HOCl and thus decrease injury to critical target biological targets. However, levels of lung antioxidants of animals exposed to Cl(2) in concentrations likely to be encountered in the vicinity of industrial accidents decrease rapidly and irreversibly. Our measurements show that prophylactic administration of a mixture containing ascorbate and desferal N-acetyl-cysteine, a precursor of reduced glutathione, prevents Cl(2)-induced injury to the alveolar epithelium of rats exposed to Cl(2). The clinical challenge is to deliver sufficient quantities of antioxidants noninvasively, after Cl(2) exposure, to decrease morbidity and mortality.}, }
@article {pmid20600803, year = {2010}, author = {Fu, Z and Guo, J and Jing, L and Li, R and Zhang, T and Peng, S}, title = {Enhanced toxicity and ROS generation by doxorubicin in primary cultures of cardiomyocytes from neonatal metallothionein-I/II null mice.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {24}, number = {6}, pages = {1584-1591}, doi = {10.1016/j.tiv.2010.06.009}, pmid = {20600803}, issn = {1879-3177}, mesh = {Animals ; Animals, Newborn ; Antineoplastic Agents/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Doxorubicin/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Metallothionein/deficiency/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Tumor Stem Cell Assay ; }, abstract = {The clinical use of doxorubicin (Dox), a potent anticancer drug, is limited by its concurrent dose-dependent cardiotoxicity. We previously found that metallothionein-I/II (MT-I/II) null mice are more vulnerable to Dox-induced cardiomyopathy, but it is unknown whether depletion of MT would sensitize cardiomyocytes to Dox toxicity in vitro since the protective effect of MT still remains controversial. In the present study, a primary culture system of cardiomyocytes from neonatal MT-I/II null (MT(-/-)) and corresponding wild type (MT(+/+)) mice was established to unequivocally determine the effect of MT deficiency on Dox-induced toxicity. MT concentrations in the MT(-/-) cardiomyocytes were about 2.5-fold lower than those in MT(+/+) cardiomyocytes. MT(-/-) cardiomyocytes were more sensitive to Dox-induced cytotoxicity than MT(+/+) cardiomyocytes as measured by morphological alterations, lactate dehydrogenase leakage, cell viability, and apoptosis. Dox time- and concentration-dependently increased reactive oxygen species (ROS) formation in MT(+/+) cardiomyocytes, and this effect was exaggerated in MT(-/-) cardiomyocytes. Antioxidant N-acetylcysteine (NAC) and glutathione (GSH) significantly rescued MT(+/+) but not MT(-/-)cardiomyocytes from Dox-induced cell death and ROS generation. These findings suggest that basal MT provide protection against Dox-induced toxicity in cardiomyocytes, particularly highlight the important role of MT as a cellular antioxidant on scavenging ROS.}, }
@article {pmid20599776, year = {2010}, author = {Oppedisano, F and Galluccio, M and Indiveri, C}, title = {Inactivation by Hg2+ and methylmercury of the glutamine/amino acid transporter (ASCT2) reconstituted in liposomes: Prediction of the involvement of a CXXC motif by homology modelling.}, journal = {Biochemical pharmacology}, volume = {80}, number = {8}, pages = {1266-1273}, doi = {10.1016/j.bcp.2010.06.032}, pmid = {20599776}, issn = {1873-2968}, mesh = {Amino Acid Motifs ; Amino Acid Transport System ASC/*antagonists &amp; inhibitors/metabolism ; Binding Sites ; Biological Transport ; Glutamine ; Liposomes/*chemistry ; Mercuric Chloride/*pharmacology ; Mercury/*pharmacology ; Mersalyl/*pharmacology ; Methylmercury Compounds/*pharmacology ; Minor Histocompatibility Antigens ; Models, Molecular ; Protein Binding ; Protein Conformation ; Sodium ; }, abstract = {The effect of HgCl(2), methylmercury and mersalyl on the glutamine/amino acid (ASCT2) transporter reconstituted in liposomes has been studied. Mercuric compounds externally added to the proteoliposomes, inhibited the glutamine/glutamine antiport catalyzed by the reconstituted transporter. Similar effects were observed by pre-treating the proteoliposomes with the mercurials and then removing unreacted compounds before the transport assay. The inhibition was reversed by DTE, cysteine and N-acetyl-cysteine but not by S-carboxymethyl-cysteine. The data demonstrated that the inhibition was due to covalent reaction of mercuric compounds with Cys residue(s) of the transporter. The IC(50) of the transporter for HgCl(2), methylmercury and mersalyl, were 1.4+/-0.10, 2.4+/-0.16 or 3.1+/-0.19 microM, respectively. Kinetic studies of the inhibition showed that the reagents behaved as non-competitive inhibitor. The presence of glutamine or Na(+) during the incubation of the mercuric compounds with the proteoliposomes did not exerted any protective effect on the inhibition. None of the compounds was transported by the reconstituted transporter. A metal binding motif CXXC has been predicted as possible site of interaction of the mercuric compounds with the transporter on the basis of the homology structural model of ASCT2 obtained using the glutamate transporter homologue from Pyrococcus horikoshii as template.}, }
@article {pmid20595944, year = {2010}, author = {Giardina, S and Michelotti, A and Zavattini, G and Finzi, S and Ghisalberti, C and Marzatico, F}, title = {[Efficacy study in vitro: assessment of the properties of resveratrol and resveratrol + N-acetyl-cysteine on proliferation and inhibition of collagen activity].}, journal = {Minerva ginecologica}, volume = {62}, number = {3}, pages = {195-201}, pmid = {20595944}, issn = {0026-4784}, mesh = {Acetylcysteine/*pharmacology ; Cell Proliferation/*drug effects ; Enzyme Inhibitors/*pharmacology ; Female ; Fibroblasts/*drug effects/*enzymology ; Humans ; *Matrix Metalloproteinase Inhibitors ; Menopause ; Resveratrol ; Stilbenes/*pharmacology ; }, abstract = {During and after menopause the skin shows up clearly how the lack of estrogen affects tissues, and menopause can in fact be considered a "multisystemic" disorder of connective tissue. The low menopausal estrogen levels combined with age-related skin changes, accelerating skin aging. This affects both the epidermis and the dermis: fibroblasts not only become fewer, but they produce 30% less collagen, reflecting its metabolic decline. Estrogens act on collagen synthesis by directly stimulating fibroblasts. However, hormone replacement can prevent the postmenopausal loss of collagen--or eliminate it once it has started. The results of the Women's Health Initiative study drastically changed Italian gynecologists' prescribing habits. Natural products with estrogen-like activity are increasingly accepted, since they have good effects on collagen synthesis and/or inhibit collagenase activity, with a reassuring safety profile. This was confirmed by an in vitro study that assessed the tonic-trophic properties of two treatments on cultured skin fibroblasts. Cells were treated with resveratrol either alone or combined with NAC 10-100-1000 μM. There was a dose-related increase in the rate of cell proliferation and in inhibition of collagenase activity.}, }
@article {pmid20594983, year = {2010}, author = {Kim, KN and Heo, SJ and Kang, SM and Ahn, G and Jeon, YJ}, title = {Fucoxanthin induces apoptosis in human leukemia HL-60 cells through a ROS-mediated Bcl-xL pathway.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {24}, number = {6}, pages = {1648-1654}, doi = {10.1016/j.tiv.2010.05.023}, pmid = {20594983}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Caspase Inhibitors ; Caspases/metabolism ; Cell Cycle/drug effects ; Cell Nucleus/drug effects/metabolism ; Cell Survival/drug effects ; Drug Antagonism ; Free Radical Scavengers/pharmacology ; HL-60 Cells ; Humans ; Leukemia/*drug therapy/metabolism/pathology ; Phaeophyceae/*chemistry ; Plant Extracts/chemistry/pharmacology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Xanthophylls/*pharmacology ; bcl-X Protein/metabolism ; }, abstract = {Fucoxanthin, a natural biologically active substance isolated from Ishige okamurae, evidences antitumor activity in human leukemia cell HL-60 cells via the induction of apoptosis. However, the mechanism underlying fucoxanthin-induced apoptosis in HL-60 cells remains unclear. In this study, we focused on the effect of fucoxanthin induction on the accumulation of reactive oxygen species (ROS), and on the triggering of Bcl-xL signaling pathway in HL-60 cells. We determined that ROS are generated during fucoxanthin-induced cytotoxicity and apoptosis in HL-60 cells, and that N-acetylcysteine (NAC), a ROS scavenger, suppressed fucoxanthin-induced cytotoxicity and apoptosis. Moreover, fucoxanthin-induced the cleavage of caspases -3 and -7, and poly-ADP-ribose polymerase (PARP) and a decrease of Bcl-xL levels, whereas NAC pre-treatment significantly inhibited caspase-3, -7, and PARP cleavage and the reduction in Bcl-xL levels. In this study, it was demonstrated for the first time that fucoxanthin generated ROS and that the accumulation of ROS performed a crucial role in the fucoxanthin-induced Bcl-xL signaling pathway.}, }
@article {pmid20593142, year = {2010}, author = {Kurian, GA and Paddikkala, J}, title = {N-acetylcysteine and magnesium improve biochemical abnormalities associated with myocardial ischaemic reperfusion in South Indian patients undergoing coronary artery bypass grafting: a comparative analysis.}, journal = {Singapore medical journal}, volume = {51}, number = {5}, pages = {381-388}, pmid = {20593142}, issn = {2737-5935}, mesh = {Acetylcysteine/*therapeutic use ; Adenosine Triphosphatases/blood ; Analysis of Variance ; Biomarkers/blood ; Coronary Artery Bypass/*adverse effects ; Erythrocytes/metabolism ; Female ; Free Radical Scavengers/*therapeutic use ; Free Radicals/metabolism ; Humans ; India ; Lipid Peroxidation/drug effects ; Magnesium Compounds/*therapeutic use ; Male ; Middle Aged ; Myocardial Reperfusion Injury/*drug therapy/etiology ; Oxidative Stress/drug effects ; Postoperative Complications ; Thiobarbituric Acid Reactive Substances/analysis ; }, abstract = {INTRODUCTION: The clinical presentation of ischaemic reperfusion in postoperative patients correlates with oxidative stress. The limited clinical success of anti-ischaemic reperfusion agents has prompted a comparison of the efficacy of N-acetylcysteine (NAC) and magnesium (Mg) in South Indian patients undergoing coronary artery bypass grafting (CABG).<br><br>METHODS: In Clinical Trial I, 52 South Indian patients who had undergone CABG surgery (with intraoperative Mg supplementation) and 40 controls (without Mg supplementation) were selected and matched. The control patients underwent the same protocol without Mg. In Clinical Trial II, the study population consisted of 50 patients, where 25 patients received NAC just before the release of the aortic cross clamp. In the NAC untreated group, dextrose solution was administered at the same time as the placebo. Six blood samples were taken at different times during the cardiac surgery and the antioxidant enzymes, ATPase and cardiac markers from the coronary sinus blood samples were analysed.<br><br>RESULTS: Increased blood lipid peroxidation was observed in patients who were not treated with Mg/NAC. The administration of Mg/NAC just before the release of the aortic cross clamp reduced the lipid peroxidation significantly (p-value is less than 0.05). The above observations were supported by the antioxidant enzyme levels. Significant improvements to the erythrocyte ATPase and cardiac markers in patients treated with Mg/NAC correlated with a reduction in postoperative abnormalities. Based on the biochemical status of the patients, Mg was shown to mediate better recovery from postoperative changes.<br><br>CONCLUSION: NAC and Mg decreased pump-induced oxidative stress during cardiopulmonary bypass (CPB), suggesting that it could be a novel therapy for assisting in the prevention of CPB-induced oxidative stress.}, }
@article {pmid20592243, year = {2010}, author = {Sinha-Hikim, I and Shen, R and Paul Lee, WN and Crum, A and Vaziri, ND and Norris, KC}, title = {Effects of a novel cystine-based glutathione precursor on oxidative stress in vascular smooth muscle cells.}, journal = {American journal of physiology. Cell physiology}, volume = {299}, number = {3}, pages = {C638-42}, pmid = {20592243}, issn = {1522-1563}, support = {U54 RR019234/RR/NCRR NIH HHS/United States ; U54 RR-026138-01/RR/NCRR NIH HHS/United States ; RR019234/RR/NCRR NIH HHS/United States ; MO1 RR-00425/RR/NCRR NIH HHS/United States ; MD00182/MD/NIMHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aldehydes/metabolism ; Antioxidants/*pharmacology ; Cystine/*pharmacology ; Glucose/metabolism ; Glutathione/metabolism ; Humans ; Intracellular Space/metabolism ; Myocytes, Smooth Muscle/*drug effects/metabolism/ultrastructure ; Oxidative Stress/*drug effects ; Selenomethionine/*pharmacology ; Spermine/pharmacology ; }, abstract = {Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and cardiovascular disease, which is largely mediated by oxidative stress. We investigated the effect of three glutathione (GSH) precursors: N-acetyl-cysteine (NAC), cystine as the physiological carrier of cysteine in GSH with added selenomethionine (F1), and NAC fortified with selenomethionine (F2) on oxidative stress induced by spermine (a uremic toxin) in cultured human aortic vascular smooth muscle cells (VSMC). VSMC were exposed to spermine (15 microM) with or without the given antioxidants (dose 50, 100, 200, and 500 microg/ml) or vehicle (control) and assessed for intracellular GSH levels, 4-hydroxy-trans-2-nonenal (4-HNE), and incorporation of 13C from glucose into alanine and protein. Spermine exposure reduced intracellular GSH levels, increased 4-HNE, and impaired glucose metabolism through reduction in pyruvate generation and/or transamination. Treatment with NAC had no effect on intracellular glutathione level. In contrast, F1 maintained intracellular GSH at control levels at all four doses. Subsequent studies performed with 200 microg/ml of F1, F2, or NAC (optimal dose) revealed normalization of 4-HNE, whereas restoration of 13C from glucose to alanine or protein to control values was only noted in the F1 group. Spermine-induced alterations in VSMC ultrastructure were prevented in approximately 90% of cells treated with F1 but only approximately 50% of cells treated with either NAC or F2. In conclusion, F1 was more effective than NAC or F2 in ameliorating spermine-induced reduction in intracellular GSH levels and cellular alterations in VSMC. The cystine-based GSH precursor (F1) is a promising antioxidant, and further studies are needed to examine the effect of this compound in preventing CKD-associated vascular disease.}, }
@article {pmid20591217, year = {2010}, author = {Yang, F and Gao, YH and Wu, KW and Deng, R and Li, DD and Wei, ZX and Jiang, S and Wu, XQ and Feng, GK and Li, HJ and Zhu, XF}, title = {A novel sesquiterpene Hirsutanol A induces autophagical cell death in human hepatocellular carcinoma cells by increasing reactive oxygen species.}, journal = {Chinese journal of cancer}, volume = {29}, number = {7}, pages = {655-660}, doi = {10.5732/cjc.009.10702}, pmid = {20591217}, issn = {1000-467X}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Agaricales/chemistry ; Antineoplastic Agents/administration &amp; dosage/isolation &amp; purification/pharmacology ; Autophagy/*drug effects ; *Carcinoma, Hepatocellular/metabolism/pathology ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Humans ; *Liver Neoplasms/metabolism/pathology ; Microtubule-Associated Proteins/metabolism ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/administration &amp; dosage/isolation &amp; purification/*pharmacology ; }, abstract = {BACKGROUND AND OBJECTIVE: Hirsutanol A is a novel sesquiterpene compound purified from fungus chondrostereum sp in Sarcophyton tortuosum. Its pharmacologic effect has not been reported yet. This study aimed to investigate cytotoxic effect of Hirsutanol A on hepatocellular carcinoma (HCC) cells and its mechanism.<br><br>METHODS: Hep3B cells were treated with different concentrations of Hirsutanol A. Cell proliferation was detected by MTT assay. The protein expression of LC3 was determined by Western blot. The generation of reactive oxygen species (ROS) was monitored by flow cytometry.<br><br>RESULTS: Hirsutanol A significantly inhibited proliferation of Hep3B cells with 50% inhibition concentrations (IC50) of 14.54, 6.71, and 3.59 micromol/L when exposed to Hirsutanol A for 24, 48, and 72 h, respectively. Incubation of Hep3B cells with Hirsutanol A markedly increased the level of ROS and the autophagy marker MAP-LC3 conversion from type I to type II. Pre-incubation with an antioxidant N-acetyl cystein (NAC) decreased the level of ROS, and reduced MAP-LC3 I-II conversion, and suppressed cell death. Blocking autophagy with a specific autophagy inhibitor 3-methyladenine (3-MA), the cytotoxic effect of this compound was attenuated.<br><br>CONCLUSION: Hirsutanol A has potent cytotoxic effect, and can induce autophagic cell death via increasing ROS production.}, }
@article {pmid20587150, year = {2010}, author = {Sagias, FG and Mitry, RR and Hughes, RD and Lehec, SC and Patel, AG and Rela, M and Mieli-Vergani, G and Heaton, ND and Dhawan, A}, title = {N-acetylcysteine improves the viability of human hepatocytes isolated from severely steatotic donor liver tissue.}, journal = {Cell transplantation}, volume = {19}, number = {11}, pages = {1487-1492}, doi = {10.3727/096368910X514620}, pmid = {20587150}, issn = {1555-3892}, support = {//Department of Health/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Cell Separation ; Cell Survival ; Fatty Liver/*pathology ; Female ; Hepatocytes/*cytology ; Humans ; Liver Transplantation ; Male ; Middle Aged ; Tissue Donors ; }, abstract = {Hepatocyte transplantation is dependent on the availability of good quality human hepatocytes isolated from donor liver tissue. Hepatocytes obtained from livers rejected for transplantation on the grounds of steatosis are often of low viability and not suitable for clinical use. The aim of this study was to evaluate the effects of the antioxidant N-acetylcysteine (NAC) on the function of hepatocytes isolated from steatotic donor livers. Human hepatocytes were isolated from 10 severely steatotic (>60%) donor livers rejected for transplantation. The left lateral segment of the donor liver was dissected into two equal size pieces and randomized to NAC or control. NAC (5 mM) was added to the first perfusion buffer of the standard collagenase digestion technique. Cells from tissues perfused with NAC had a significantly higher mean viability (81.1 ± 1.7% vs. 66.0 ± 4.7%; p = 0.003) and cell attachment (1.08 ± 0.26 vs. 0.67 ± 0.18 OD units; p = 0.012). Addition of NAC during isolation of human hepatocytes from steatotic donor liver tissue significantly improved the outcome of cell isolation. Further studies are needed to investigate the mechanism(s) of this effect. Incorporation of NAC in the hepatocyte isolation protocol could increase the availability of hepatocytes for transplantation.}, }
@article {pmid20586144, year = {2010}, author = {Kekec, Z and Seydaoglul, G and Sever, H and Ozturk, F}, title = {The effect of antioxidants (N-acetylcysteine and melatonin) on hypoxia due to carbonmonoxide poisoning.}, journal = {Bratislavske lekarske listy}, volume = {111}, number = {4}, pages = {189-193}, pmid = {20586144}, issn = {0006-9248}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain/pathology ; Carbon Monoxide Poisoning/complications/metabolism/*pathology ; Female ; Hypoxia/etiology/metabolism/*pathology ; Lung/pathology ; Melatonin/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {We aimed to determine the effect NAC (N-acetylcysteine) and melatonin on the histopathological and biochemical paramethers in the rats poisoned with CO (Carbon monoxide) experimentally. Winster albino female rats were placed in a plexiglass chamber and they were poisoned with CO. After the poisoning, rats were randomly divided into 3 groups. The group given only normal saline, was used as a control group (n = 9). The second group was given 30 mg/kg intraperitonally NAC (n = 10). And the third group was treated with 10 mg/kg of melatonin intramuscularly (n = 9). It is determined that some biochemical values affected by NAC but not by melatonin. CK, ALT, Lactate, MDA levels were significantly higher in NAC group than control and Melatonin group (p < 0.01 for all comparisons). Thiol level was lower in NAC group than control group and Melatonin group (p < 0.01 and p < 0.001, respectively). There were no statistical significant differences between the melatonin and control group. There were statistically significant difference between control, NAC and Melatonin groups according to brain and lung tissue damage. It is shown that both NAC and Melatonin are reducing the brain and lung tissue damage of CO poisoning but due to biochemical results worsened by NAC, Melatonin may recommend for CO poisoning (Tab. 3, Ref. 21).}, }
@article {pmid20584210, year = {2011}, author = {Zyoud, SH and Awang, R and Sulaiman, SA and Al-Jabi, SW}, title = {N-acetylcysteine-induced headache in hospitalized patients with acute acetaminophen overdose.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {25}, number = {3}, pages = {405-410}, doi = {10.1111/j.1472-8206.2010.00831.x}, pmid = {20584210}, issn = {1472-8206}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/*adverse effects ; Antidotes/administration &amp; dosage/adverse effects ; Cohort Studies ; Drug Overdose/*drug therapy ; Female ; Headache/*chemically induced ; Hospitalization ; Humans ; Infusions, Intravenous ; Male ; Retrospective Studies ; Risk Factors ; Young Adult ; }, abstract = {Intravenous N-acetylcysteine (IV-NAC) is usually regarded as a safe antidote to acetaminophen overdose. However, during infusion of the loading dose, adverse drug reactions such as a headache may occur. The objectives of this study were to investigate the prevalence of headache in patients presenting to hospital after acetaminophen overdose and to determine which clinical findings are most predictive of headache among these patients. This is a retrospective cohort study of hospital admissions for acute acetaminophen overdose that was conducted over a period of 4 years from January 1, 2005 to December 31, 2008. Demographic data, clinical characteristics, and predictors of headache were analyzed. spss 15 was used for data analysis. Two-hundred and fifty-five patients were studied; their mean age was 23.1 ± 1.6; 83.9% of them were women and 14.9% had a headache during hospitalization. Headache among patients was significantly associated with IV-NAC administration (P = 0.001), intentional ingestion of drug (P = 0.04), acetaminophen concentration above 'possible toxicity' treatment line (P = 0.04), a high acetaminophen concentration (P = 0.04), and a long hospital stay (P = 0.03). Multiple logistic regression showed a significant risk factor for headache in patients administered IV-NAC (P = 0.04). We recorded a high frequency of headache in patients with acute acetaminophen overdose in our geographical area. This study suggests that among those patients, the use of IV-NAC is associated with an increased risk of headache.}, }
@article {pmid20582168, year = {2010}, author = {Ganguly, A and Basu, S and Chakraborty, P and Chatterjee, S and Sarkar, A and Chatterjee, M and Choudhuri, SK}, title = {Targeting mitochondrial cell death pathway to overcome drug resistance with a newly developed iron chelate.}, journal = {PloS one}, volume = {5}, number = {6}, pages = {e11253}, pmid = {20582168}, issn = {1932-6203}, mesh = {*Apoptosis ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; *Drug Resistance, Neoplasm ; Enzyme Activation ; Glutathione/metabolism ; Humans ; Hydrolysis ; Iron Chelating Agents/*pharmacology ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Mitochondria/*drug effects/metabolism/physiology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; Spectrophotometry, Infrared ; Spectrophotometry, Ultraviolet ; }, abstract = {BACKGROUND: Multi drug resistance (MDR) or cross-resistance to multiple classes of chemotherapeutic agents is a major obstacle to successful application of chemotherapy and a basic problem in cancer biology. The multidrug resistance gene, MDR1, and its gene product P-glycoprotein (P-gp) are an important determinant of MDR. Therefore, there is an urgent need for development of novel compounds that are not substrates of P-glycoprotein and are effective against drug-resistant cancer.<br><br>In this present study, we have synthesized a novel, redox active Fe (II) complex (chelate), iron N- (2-hydroxy acetophenone) glycinate (FeNG). The structure of the complex has been determined by spectroscopic means. To evaluate the cytotoxic effect of FeNG we used doxorubicin resistant and/or sensitive T lymphoblastic leukemia cells and show that FeNG kills both the cell types irrespective of their MDR phenotype. Moreover, FeNG induces apoptosis in doxorubicin resistance T lymphoblastic leukemia cell through mitochondrial pathway via generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxidant N-acetyl-cysteine (NAC) could completely block ROS generation and, subsequently, abrogated FeNG induced apoptosis. Therefore, FeNG induces the doxorubicin resistant T lymphoblastic leukemia cells to undergo apoptosis and thus overcome MDR.<br><br>CONCLUSION/SIGNIFICANCE: Our study provides evidence that FeNG, a redox active metal chelate may be a promising new therapeutic agent against drug resistance cancers.}, }
@article {pmid20581787, year = {2010}, author = {Renke, M and Tylicki, L and Rutkowski, P and Larczynski, W and Neuwelt, A and Aleksandrowicz, E and Łysiak-Szydłowska, W and Rutkowski, B}, title = {The effect of N-acetylcysteine on blood pressure and markers of cardiovascular risk in non-diabetic patients with chronic kidney disease: a placebo-controlled, randomized, cross-over study.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {16}, number = {7}, pages = {PI13-8}, pmid = {20581787}, issn = {1643-3750}, mesh = {Acetylcysteine/adverse effects/*pharmacology/therapeutic use ; Adolescent ; Adult ; Aged ; Albuminuria/complications ; Biomarkers/metabolism ; Blood Pressure/*drug effects ; Cardiovascular Diseases/*complications/*physiopathology ; Cross-Over Studies ; Diabetes Complications/physiopathology ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Homocysteine/blood ; Humans ; Kidney Failure, Chronic/*complications/drug therapy/physiopathology ; Kidney Function Tests ; Male ; Middle Aged ; Placebos ; Proteins/metabolism ; Risk Factors ; Sodium/metabolism ; Young Adult ; }, abstract = {BACKGROUND: Cardiovascular complications in patients with chronic kidney disease (CKD) are frequent. They show increased cardiovascular mortality and morbidity attributable to accumulation of several risk factors; e.g., hypertension, oxidative stress and elevated plasma homocysteine concentration. Despite recent progress in their management, there is still no optimal therapy that can stop progression of CKD and decrease cardiovascular outcome in these patients. Antioxidants, e.g., N-acetylcysteine (NAC), have been suggested as a promising medicament in this field.<br><br>MATERIAL/METHODS: In a placebo-controlled, randomized, two-period cross-over study we evaluated the influence of eight weeks of NAC therapy (1200 mg/day) added to pharmacological renin-angiotensin system blockade on ambulatory blood pressure and surrogate markers of cardiovascular risk and injury in 20 non-diabetic patients with albuminuria [30-915 mg per creatinine mg] and normal or slightly decreased kidney function [eGFR 61-163 ml/min]. After eight weeks run-in period during which the therapy using angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers was settled, patients were randomly assigned to one of two treatment sequences: NAC/washout/placebo or placebo/washout/NAC.<br><br>RESULTS: No significant changes in blood pressure, albuminuria and homocysteine plasma level were observed.<br><br>CONCLUSIONS: NAC had no effect on blood pressure and surrogate markers of cardiovascular injury in non-diabetic patients with CKD.}, }
@article {pmid20580989, year = {2010}, author = {Chen, FH and Zhang, LB and Qiang, L and Yang, Z and Wu, T and Zou, MJ and Tao, L and You, QD and Li, ZY and Yang, Y and Guo, QL}, title = {Reactive oxygen species-mitochondria pathway involved in LYG-202-induced apoptosis in human hepatocellular carcinoma HepG(2) cells.}, journal = {Cancer letters}, volume = {296}, number = {1}, pages = {96-105}, doi = {10.1016/j.canlet.2010.04.004}, pmid = {20580989}, issn = {1872-7980}, mesh = {Adenosine Triphosphate/metabolism ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cell Fractionation ; Cytosol/drug effects/metabolism ; Flavones/*pharmacology ; Glutathione/metabolism ; Hep G2 Cells/drug effects/*pathology ; Humans ; Kinetics ; Matrix Metalloproteinases/drug effects/metabolism ; Membrane Potentials/drug effects/physiology ; Mitochondria/drug effects/*metabolism ; Mitochondrial Membranes/drug effects/physiology ; Piperazines/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Previously, we demonstrated that LYG-202, a newly synthesized flavonoid with a piperazine substitution, exhibited obvious antitumor activity in vivo and in vitro. The exact mechanism of this new compound remains unclear. In the present study, we examined the effects of LYG-202 on reactive oxygen species (ROS) production and the downstream signaling pathway in the apoptosis of human hepatocellular carcinoma HepG(2) cells. Pretreatment with NAC (N-acetylcysteine), a ROS production inhibitor, partly inhibited the apoptosis induced by LYG-202 via blocking the ROS generation. Further data revealed that LYG-202 induced ROS accumulation followed by a decrease in mitochondrial membrane potential (MMP), release of cytochrome c (Cyt c) and apoptosis-inducing factor (AIF) to cytosol, which induced apoptosis of the cells. Moreover, the mitogen-activated protein kinases (MAPK), the downstream effect of ROS accumulation including c-Jun N-terminal kinase (JNK) and p38 MAPK, could be activated by LYG-202. Taken together, the generation of ROS might play an important role in LYG-202-induced mitochondrial apoptosis pathway, which provided further support for LYG-202 as a novel anticancer therapeutic candidate.}, }
@article {pmid20580762, year = {2010}, author = {Cao, J and Xue, B and Li, H and Deng, D and Gu, Y}, title = {Facile synthesis of high-quality water-soluble N-acetyl-L-cysteine-capped Zn(1-x)Cd(x)Se/ZnS core/shell quantum dots emitting in the violet-green spectral range.}, journal = {Journal of colloid and interface science}, volume = {348}, number = {2}, pages = {369-376}, doi = {10.1016/j.jcis.2010.05.007}, pmid = {20580762}, issn = {1095-7103}, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemistry/pharmacology ; Cadmium Compounds/chemical synthesis ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Hydrogen-Ion Concentration ; Microscopy, Electron, Transmission ; *Quantum Dots ; Selenium Compounds/chemical synthesis ; Spectrometry, Fluorescence ; Sulfides/*chemical synthesis ; Zinc Compounds/*chemical synthesis ; }, abstract = {In this paper, we report a new facile method to synthesize water-soluble Zn(1-x)Cd(x)Se and core/shell Zn(1-x)Cd(x)Se/ZnS quantum dots (QDs) emitting in the violet-green spectral range, using N-acetyl-L-cysteine (NAC) as a stabilizer. The influence of various experimental variables, including the precursor Zn/Cd/Se/NAC molar ratios, the pH of original solution and the refluxing time on optical properties were explored systematically. The obtained aqueous Zn(1-x)Cd(x)Se QDs exhibit a tunable photoluminescence (PL) emission (from approximately 415 nm to 506 nm) and a favorable narrow PL bandwidth (FWHM: 27-38 nm). After coating with a ZnS shell, the PL emission intensity of the formed core/shell Zn(1-x)Cd(x)Se/ZnS QDs is greatly increased (PL quantum yield (QY): approximately 30%). These resulting Zn(1-x)Cd(x)Se and core/shell Zn(1-x)Cd(x)Se/ZnS QDs were further characterized by transmission electron microscopy (TEM), energy disperse spectroscopy (EDS) and X-ray diffraction (XRD). In addition, the cytotoxicity and the fluorescence imaging of Zn(1-x)Cd(x)Se/ZnS QDs to MCF-7 cells were preliminarily investigated. The experimental results show that the as-prepared violet-green-emitting Zn(1-x)Cd(x)Se/ZnS QDs have low cytotoxicity, which makes them an ideal inorganic fluorescent probe for biolabeling and cell imaging.}, }
@article {pmid20580509, year = {2010}, author = {Tzanavaras, PD and Tsiomlektsis, A and Zacharis, CK}, title = {Derivatization of thiols under flow conditions using two commercially available propiolate esters.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {53}, number = {3}, pages = {790-794}, doi = {10.1016/j.jpba.2010.06.002}, pmid = {20580509}, issn = {1873-264X}, mesh = {Acetylcysteine/*chemistry ; Captopril/*chemistry ; Cysteine/*chemistry ; Esters/chemistry ; Flow Injection Analysis/*methods ; Hydrogen-Ion Concentration ; Propionates/*chemistry ; Solubility ; Temperature ; }, abstract = {In the present study we report new data on the reaction of three representative thiols--captopril (CAP), cysteine (CYS) and N-acetylcysteine (NAC)--with two commercially available propiolate esters--methyl-propiolate (MP) and butyl-propiolate (BP)--under flow conditions. The reactions were investigated on-line using sequential injection analysis (SI) and the formed derivatives were monitored spectrophotometrically at 285 nm. The effect of critical parameters of the reaction such as the pH, the temperature and the amount concentration of the reagents were studied in detail including stopped-flow (SF) experiments. Both reagents were found to be suitable for the automated derivatization of thiols, although MP offered faster kinetics compared to BP. The applicability of the procedures was demonstrated by the development of SI methods for the dissolution studies of CAP tablets with satisfactory results.}, }
@article {pmid20576917, year = {2010}, author = {Zhong, W and Zhao, Y and McClain, CJ and Kang, YJ and Zhou, Z}, title = {Inactivation of hepatocyte nuclear factor-4{alpha} mediates alcohol-induced downregulation of intestinal tight junction proteins.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {299}, number = {3}, pages = {G643-51}, pmid = {20576917}, issn = {1522-1547}, support = {R01 AA018016/AA/NIAAA NIH HHS/United States ; R01 AA018869/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Caco-2 Cells ; Down-Regulation/*drug effects ; Drug Administration Schedule ; Ethanol/administration &amp; dosage/*pharmacology ; GATA4 Transcription Factor/genetics/metabolism ; Gastrointestinal Tract/anatomy &amp; histology/metabolism ; Hepatocyte Nuclear Factor 4/antagonists &amp; inhibitors/*metabolism ; Humans ; Intestinal Mucosa/cytology/*drug effects ; Membrane Proteins/genetics/*metabolism ; Mice ; RNA Interference ; RNA, Small Interfering ; Tight Junctions/*metabolism ; Tissue Distribution ; Zinc/deficiency/metabolism ; }, abstract = {Chronic alcohol exposure has been shown to increase the gut permeability in the distal intestine, in part, through induction of zinc deficiency. The present study evaluated the molecular mechanisms whereby zinc deficiency mediates alcohol-induced intestinal barrier dysfunction. Examination of zinc finger transcription factors in the gastrointestinal tract of mice revealed a prominent distribution of hepatocyte nuclear factor-4alpha (HNF-4alpha). HNF-4alpha exclusively localizes in the epithelial nuclei and exhibited an increased abundance in mRNA and protein levels in the distal intestine. Chronic alcohol exposure to mice repressed the HNF-4alpha gene expression in the ileum and reduced the protein level and DNA binding activity of HNF-4alpha in all of the intestinal segments with the most remarkable changes in the ileum. Chronic alcohol exposure also decreased the mRNA levels of tight junction proteins, particularly in the ileum. Caco-2 cell culture studies were conducted to determine the role of HNF-4alpha in regulation of the epithelial tight junction and barrier function. Knockdown of HNF-4alpha in Caco-2 cells decreased the mRNA and protein levels of tight junction proteins in association with disruption of the epithelial barrier. Alcohol treatment inactivated HNF-4alpha, which was prevented by N-acetyl-cysteine or zinc. The link between zinc and HNF-4alpha function was confirmed by zinc deprivation, which inhibited HNF-4alpha DNA binding activity. These results indicate that inactivation of HNF-4alpha due to oxidative stress and zinc deficiency is likely a novel mechanism contributing to the deleterious effects of alcohol on the tight junctions and the intestinal barrier function.}, }
@article {pmid20576514, year = {2010}, author = {McKallip, RJ and Lombard, C and Sun, J and Ramakrishnan, R}, title = {Plumbagin-induced apoptosis in lymphocytes is mediated through increased reactive oxygen species production, upregulation of Fas, and activation of the caspase cascade.}, journal = {Toxicology and applied pharmacology}, volume = {247}, number = {1}, pages = {41-52}, doi = {10.1016/j.taap.2010.05.013}, pmid = {20576514}, issn = {1096-0333}, mesh = {Acetylcysteine/metabolism ; Animals ; *Apoptosis ; Atrophy/chemically induced ; Caspases/*metabolism ; Dinitrofluorobenzene/toxicity ; Enterotoxins/toxicity ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Immunosuppressive Agents/*toxicity ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lymphocytes/*drug effects/immunology/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred C57BL ; Naphthoquinones/*toxicity ; Reactive Oxygen Species/*metabolism ; Spleen/drug effects/pathology ; Thymus Gland/drug effects/pathology ; Up-Regulation/drug effects ; fas Receptor/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Extracts from plants containing plumbagin (PLB) continue to be used as a treatment of a number of chronic immunologically-based diseases. However, most of these claims are supported only by anecdotal evidence with few scientific reports describing the mechanism of action or the efficacy of plumbagin in the suppression of the immune response. In the current study, we tested the hypothesis that plumbagin-induced suppression of the immune response was mediated through the induction of apoptosis. Splenocytes from C57BL/6 mice cultured in the presence of 0.5 microM or greater concentrations of PLB significantly reduced proliferative responses to mitogens, including anti-CD3 mAbs, concanavalin A (Con A), lipopolysaccharide (LPS) and staphylococcal enterotoxin B (SEB) in vitro. Exposure of naïve and activated splenocytes to PLB led to a significant increase in the levels of apoptosis. In addition, PLB treatment led to a significant increase in the levels of reactive oxygen species (ROS) in naïve and activated splenocytes. Furthermore, treatment with the ROS scavenger, N-acetylcysteine (NAC), prevented PLB-induced apoptosis, suggesting a role of ROS in PLB-induced apoptosis. PLB-induced apoptosis led to ROS-mediated activation of both the extrinsic and intrinsic apoptotic pathways. In addition, plumbagin led to increased expression of Fas. Finally, treatment of mice with PLB (5mg/kg) led to thymic and splenic atrophy as well as a significant suppression of the response to SEB and dinitrofluorobenzene (DNFB) in vivo. Together, these results suggest that plumbagin has significant immunosuppressive properties which are mediated by generation of ROS, upregulation of Fas, and the induction of apoptosis.}, }
@article {pmid20571742, year = {2010}, author = {Zou, P and Wu, LL and Wu, D and Fan, D and Cui, XB and Zhou, Y and Wang, C and Li, L}, title = {[High glucose increases periostin expression and the related signal pathway in adult rat cardiac fibroblasts].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {62}, number = {3}, pages = {247-254}, pmid = {20571742}, issn = {0371-0874}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Adhesion Molecules/*metabolism ; Cells, Cultured ; Culture Media/chemistry ; Fibroblasts/*metabolism ; Glucose/*chemistry ; JNK Mitogen-Activated Protein Kinases/metabolism ; Myocardium/cytology ; Phosphorylation ; Protein Kinase C/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; }, abstract = {Cardiac fibrosis is a major mechanism contributing to myocardial systolic and diastolic dysfunction in diabetic cardiomyopathy. Periostin is a novel extracellular matrix protein, secreted from cardiac fibroblasts, and closely related with cardiac fibrosis and remodeling. The present study aimed to investigate the effect of high glucose on periostin expression and the related signal transduction pathway in cardiac fibroblasts. Adult rat cardiac fibroblasts were cultured and stimulated with high glucose (25 mmol/L). The mRNA and protein expressions of periostin were detected by RT-PCR and Western blot, respectively. Intracellular reactive oxygen species (ROS) production was measured using 2, 7-dichlorofluorescein diacetate (DCF-DA), an oxidant-sensitive fluorescent probe. Results showed that the mRNA expression of periostin in adult rat cardiac fibroblasts was increased by 117.26% when treated with high glucose for 12 h. Incubation with high glucose for 24 h enhanced periostin protein expression by up to 93.12%. High glucose induced the production of ROS in adult rat cardiac fibroblasts, which was reduced by chelerythrine (CLT), a protein kinase C (PKC) inhibitor. High glucose-induced periostin protein expression was decreased significantly when pretreated with CLT or N-acetylcysteine (NAC), a ROS scavenger. The phosphorylation of c-jun N-terminal protein kinase (JNK) was increased markedly when stimulated with high glucose for 30 and 60 min, which was abolished when pretreated with CLT or NAC. SP600125, a specific JNK inhibitor, significantly decreased periostin expression induced by high glucose. In conclusion, high glucose stimulates periostin protein expression via a PKC/ROS/JNK-dependent pathway in adult rat cardiac fibroblasts.}, }
@article {pmid20570977, year = {2010}, author = {Ashworth, A and Webb, ST}, title = {Does the prophylactic administration of N-acetylcysteine prevent acute kidney injury following cardiac surgery?.}, journal = {Interactive cardiovascular and thoracic surgery}, volume = {11}, number = {3}, pages = {303-308}, doi = {10.1510/icvts.2010.232413}, pmid = {20570977}, issn = {1569-9285}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/etiology/*prevention &amp; control ; Aged ; Benchmarking ; Cardiac Surgical Procedures/*adverse effects/mortality ; Drug Administration Schedule ; Evidence-Based Medicine ; Hospital Mortality ; Humans ; Length of Stay ; Male ; Protective Agents/*administration &amp; dosage ; Renal Replacement Therapy ; Reoperation ; Risk Assessment ; Risk Factors ; Time Factors ; Treatment Outcome ; }, abstract = {A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'does prophylactic administration of N-acetylcysteine (NAC) prevent acute kidney injury (AKI) following cardiac surgery?' More than 60 papers were found using the reported search, of which 10 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The administration of NAC prior intravenous radioactive contrast has been shown to reduce the incidence of contrast-induced nephropathy. There have been two recent meta-analyses and several randomised controlled trials (RCTs) and investigating the effectiveness of prophylactic administration of NAC in the prevention of AKI following cardiac surgery. The RCTs have investigated the use of NAC to prevent AKI in low-risk patients, high-risk patients and high-risk patients with pre-existing chronic kidney disease. The meta-analyses and RCTs demonstrated that the prophylactic administration of NAC did not reduced the incidence of AKI, postoperative complications, postoperative interventions, mortality or length of ICU stay. We conclude that prophylactic administration of NAC does not prevent AKI or reduce mortality following cardiac surgery.}, }
@article {pmid20570696, year = {2010}, author = {Lee, SM and Lee, YS and Choi, JH and Park, SG and Choi, IW and Joo, YD and Lee, WS and Lee, JN and Choi, I and Seo, SK}, title = {Tryptophan metabolite 3-hydroxyanthranilic acid selectively induces activated T cell death via intracellular GSH depletion.}, journal = {Immunology letters}, volume = {132}, number = {1-2}, pages = {53-60}, doi = {10.1016/j.imlet.2010.05.008}, pmid = {20570696}, issn = {1879-0542}, mesh = {3-Hydroxyanthranilic Acid/administration &amp; dosage/metabolism/*pharmacology ; Animals ; Bone Marrow Transplantation/adverse effects ; Cell Death/*drug effects ; Enterotoxins/immunology ; Female ; Glutathione/*metabolism ; Graft vs Host Disease/immunology/prevention &amp; control ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Lymphocyte Activation/*drug effects ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes/*drug effects/immunology/metabolism ; Transplantation, Homologous/adverse effects ; Tryptophan/*metabolism ; }, abstract = {Tryptophan-derived metabolites, initiated by indoleamine 2,3-dioxygenase (IDO), preferentially induce activated T cell death, which is an important mechanism in IDO-mediated T cell suppression. However, the mechanism of this phenomenon remains unclear. We found that 3-hydroxyanthranilic acid (3-HAA), the most potent metabolite, selectively eliminated activated T cells, which were stimulated with the bacterial superantigen staphylococcal enterotoxin A (SEA), but not resting T cells, by inducing apoptosis. We observed 3-HAA-induced depletion of intracellular glutathione (GSH) in activated T cells. When GSH levels were maintained by addition of N-acetylcysteine (NAC) and GSH, 3-HAA-mediated T cell death was completely inhibited. This was associated with extrusion of GSH from activated T cells without increased reactive oxygen species (ROS) formation. Finally, we showed that administration of 3-HAA in mice after allogeneic bone marrow transplantation reduced acute graft-versus-host disease (GVHD) lethality by inhibition of alloreactive T cell expansion through intracellular GSH depletion. Our data suggest that direct depletion of intracellular GSH is the major mechanism of 3-HAA-mediated activated T cell death.}, }
@article {pmid20569465, year = {2010}, author = {Drukala, J and Urbanska, K and Wilk, A and Grabacka, M and Wybieralska, E and Del Valle, L and Madeja, Z and Reiss, K}, title = {ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARalpha -mediated inhibition of glioma cell motility in vitro.}, journal = {Molecular cancer}, volume = {9}, number = {}, pages = {159}, pmid = {20569465}, issn = {1476-4598}, support = {R01 CA095518/CA/NCI NIH HHS/United States ; R01 NS055644/NS/NINDS NIH HHS/United States ; R01CA095518/CA/NCI NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/biosynthesis ; Base Sequence ; Brain Neoplasms/metabolism/*pathology ; Cell Line, Tumor ; Cell Movement/drug effects/physiology ; Fenofibrate/*pharmacology ; Glioma/metabolism/*pathology ; Humans ; PPAR alpha/*physiology ; RNA, Small Interfering ; Reactive Oxygen Species/*metabolism ; Receptor, IGF Type 1/*antagonists &amp; inhibitors ; }, abstract = {BACKGROUND: Glioblastomas are characterized by rapid cell growth, aggressive CNS infiltration, and are resistant to all known anticancer regimens. Recent studies indicate that fibrates and statins possess anticancer potential. Fenofibrate is a potent agonist of peroxisome proliferator activated receptor alpha (PPARalpha) that can switch energy metabolism from glycolysis to fatty acid beta-oxidation, and has low systemic toxicity. Fenofibrate also attenuates IGF-I-mediated cellular responses, which could be relevant in the process of glioblastoma cell dispersal.<br><br>METHODS: The effects of fenofibrate on Glioma cell motility, IGF-I receptor (IGF-IR) signaling, PPARalpha activity, reactive oxygen species (ROS) metabolism, mitochondrial potential, and ATP production were analyzed in human glioma cell lines.<br><br>RESULTS: Fenofibrate treatment attenuated IGF-I signaling responses and repressed cell motility of LN-229 and T98G Glioma cell lines. In the absence of fenofibrate, specific inhibition of the IGF-IR had only modest effects on Glioma cell motility. Further experiments revealed that PPARalpha-dependent accumulation of ROS is a strong contributing factor in Glioma cell lines responses to fenofibrate. The ROS scavenger, N-acetyl-cysteine (NAC), restored cell motility, improved mitochondrial potential, and increased ATP levels in fenofibrate treated Glioma cell lines.<br><br>CONCLUSIONS: Our results indicate that although fenofibrate-mediated inhibition of the IGF-IR may not be sufficient in counteracting Glioma cell dispersal, PPARalpha-dependent metabolic switch and the resulting ROS accumulation strongly contribute to the inhibition of these devastating brain tumor cells.}, }
@article {pmid20568112, year = {2011}, author = {Crea, F and Duhagon Serrat, MA and Hurt, EM and Thomas, SB and Danesi, R and Farrar, WL}, title = {BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer.}, journal = {International journal of cancer}, volume = {128}, number = {8}, pages = {1946-1954}, pmid = {20568112}, issn = {1097-0215}, support = {N01CO12400/CA/NCI NIH HHS/United States ; Z01 BC010253-12/ImNIH/Intramural NIH HHS/United States ; N01-CO-12400/CO/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis ; Biomarkers, Tumor/genetics/metabolism ; Blotting, Western ; Cell Cycle ; Cell Proliferation ; Docetaxel ; Drug Resistance, Neoplasm/*genetics ; Fluorescent Antibody Technique ; Gene Expression Profiling ; Humans ; Male ; Nuclear Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; Oligonucleotide Array Sequence Analysis ; Polycomb Repressive Complex 1 ; Prostatic Neoplasms/*drug therapy/*genetics/pathology ; Proto-Oncogene Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; RNA, Messenger/genetics ; Repressor Proteins/antagonists &amp; inhibitors/*genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Taxoids/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {The BMI1 oncogene promotes prostate cancer (PC) progression. High B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) expression predicts poor prognosis in PC patients. Recent evidence suggests that BMI1 may also play a role in docetaxel chemoresistance. However, mechanisms and clinical significance of BMI1-related chemoresistance have not been investigated. For this purpose, BMI1 was silenced in 2 PC cell lines (LNCaP and DU 145). Cell proliferation and apoptosis after docetaxel treatment were measured. Guanine oxidation was assessed by in-cell western. Global gene expression analysis was performed on BMI1 silenced cells. Oncomine database was used to compare in vitro data with gene expression in PC samples. BMI1 silencing had no effect on cell proliferation but significantly enhanced docetaxel-induced antitumor activity. Gene expression analysis demonstrated that BMI1 silencing downregulates a set of antioxidant genes. Docetaxel treatment increased guanine oxidation, whereas the antioxidant N-acetyl cysteine rescued docetaxel-induced cell death. Examination of clinical datasets revealed a positive correlation of BMI1 and antioxidant gene expression. BMI1-controlled antioxidant genes were predictive of poor prognosis in PC patients. In conclusion, BMI1 enhances antioxidant response, thereby allowing PC survival after docetaxel-based chemotherapy. BMI1-controlled antioxidant genes are overexpressed in aggressive PC and should be tested as predictors of chemotherapy failure.}, }
@article {pmid20561368, year = {2010}, author = {Graudins, A and Chiew, A and Chan, B}, title = {Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol.}, journal = {Internal medicine journal}, volume = {40}, number = {1}, pages = {72-76}, doi = {10.1111/j.1445-5994.2009.02096.x}, pmid = {20561368}, issn = {1445-5994}, mesh = {Absorption/drug effects/*physiology ; Acetaminophen/administration &amp; dosage/*adverse effects/*blood ; Adult ; Delayed-Action Preparations/administration &amp; dosage/adverse effects/metabolism ; Drug Overdose ; Female ; Humans ; Male ; Middle Aged ; Time Factors ; }, abstract = {A modified-release formulation of paracetamol is currently available in Australasia and marketed under a number of different trade names. These include: Panadol Osteo, Panadol Extend Tablets, and Duatrol SR. We report four cases of intentional overdose with this formulation resulting in delay to peak plasma paracetamol concentrations and prolonged paracetamol absorption. Physicians must be aware that a single plasma paracetamol estimation four or more hours post-ingestion may not be adequate in the risk assessment of patients requiring treatment with N-acetylcysteine (NAC). Current Australasian guidelines for the management of modified-release paracetamol overdose advise empiric commencement of NAC if the suspected ingested dose is greater than 10 grams or 200 mg/kg (whichever is the least), an initial plasma paracetamol concentration should be assayed four or more hours post-ingestion and a second assay should be estimated four hours after the first. Treatment with NAC should continue if either concentration falls above the paracetamol treatment nomogram line. With massive ingestions of this paracetamol formulation (>50 grams) plasma concentrations may be elevated for several days and prolonged treatment with NAC is recommended. When modified-release paracetamol overdose is suspected a clinical toxicologist or Poisons Information Centre should be consulted to help guide management decisions.}, }
@article {pmid20560295, year = {2009}, author = {Cu, A and Ye, Q and Sarria, R and Nakamura, S and Guzman, J and Costabel, U}, title = {N-acetylcysteine inhibits TNF-alpha, sTNFR, and TGF-beta1 release by alveolar macrophages in idiopathic pulmonary fibrosis in vitro.}, journal = {Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG}, volume = {26}, number = {2}, pages = {147-154}, pmid = {20560295}, issn = {1124-0490}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Cells, Cultured ; Cytokines/antagonists &amp; inhibitors/biosynthesis ; Enzyme-Linked Immunosorbent Assay ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Idiopathic Pulmonary Fibrosis/drug therapy/*metabolism/pathology ; Macrophages, Alveolar/*metabolism/pathology ; Male ; Receptors, Tumor Necrosis Factor/*antagonists &amp; inhibitors/biosynthesis ; Transforming Growth Factor beta1/*antagonists &amp; inhibitors/biosynthesis ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/biosynthesis ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) can act as an antioxidant. NAC slows the rate of decline of lung function in idiopathic pulmonary fibrosis (IPF) patients concurrently treated with prednisone and azathioprine.<br><br>OBJECTIVE: In this study we investigated the effect of NAC on the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12 (p70), IL-18, transforming growth factor (TGF)-beta1, and the soluble TNF receptors (sTNFR1 and sTNFR2) by alveolar macrophages (AM) in IPF patients.<br><br>DESIGN: AMs were harvested by bronchoalveolar lavage (BAL) from 16 IPF patients and were cultured for 24 h with RPMI medium alone, or with lipopolysaccharide (LPS) (100 ng/ml), in the presence or absence of NAC at various concentrations.<br><br>RESULTS: NAC suppressed the production of TNF-alpha, its soluble receptors, and TGF-beta1 by AMs in a dose-dependent manner. At the highest concentration of NAC (10 mM), the spontaneous or LPS-stimulated production ofTNF-alpha, sTNFR1, sTNFR2, and TGF-beta1 were significantly reduced. The LPS-stimulated IL-1beta production was also suppressed by 10 mM NAC.<br><br>CONCLUSIONS: NAC has the potential to down-regulate the production of TNF-alpha and their soluble receptors, as well as TGF-beta1 and LPS-stimulated IL-1beta, by AM in IPF in vitro. NAC may have anti-inflammatory and anti-fibrotic effects.}, }
@article {pmid20560006, year = {2009}, author = {Marian, AJ}, title = {Experimental therapies in hypertrophic cardiomyopathy.}, journal = {Journal of cardiovascular translational research}, volume = {2}, number = {4}, pages = {483-492}, pmid = {20560006}, issn = {1937-5395}, support = {R01 HL068884/HL/NHLBI NIH HHS/United States ; R01 HL068884-04/HL/NHLBI NIH HHS/United States ; R01 HL068884-05/HL/NHLBI NIH HHS/United States ; R01 HL088498/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cardiomyopathy, Hypertrophic/complications/*drug therapy/genetics/pathology ; Cardiovascular Agents/*therapeutic use ; Death, Sudden, Cardiac/etiology/*prevention &amp; control ; Drugs, Investigational/*therapeutic use ; Fibrosis ; Genetic Predisposition to Disease ; Humans ; Myocardium/pathology ; Phenotype ; Treatment Outcome ; }, abstract = {The quintessential clinical diagnostic phenotype of human hypertrophic cardiomyopathy (HCM) is primary cardiac hypertrophy. Cardiac hypertrophy is also a major determinant of mortality and morbidity including the risk of sudden cardiac death (SCD) in patients with HCM. Reversal and attenuation of cardiac hypertrophy and its accompanying fibrosis is expected to improve morbidity as well as decrease the risk of SCD in patients with HCM.The conventionally used pharmacological agents in treatment of patients with HCM have not been shown to reverse or attenuate established cardiac hypertrophy and fibrosis. An effective treatment of HCM has to target the molecular mechanisms that are involved in the pathogenesis of the phenotype. Mechanistic studies suggest that cardiac hypertrophy in HCM is secondary to activation of various hypertrophic signaling molecules and, hence, is potentially reversible. The hypothesis is supported by the results of genetic and pharmacological interventions in animal models. The results have shown potential beneficial effects of angiotensin II receptor blocker losartan, mineralocorticoid receptor blocker spironolactone, 3-hydroxy-3-methyglutaryl-coenzyme A reductase inhibitors simvastatin and atorvastatin, and most recently, N-acetylcysteine (NAC) on reversal or prevention of hypertrophy and fibrosis in HCM. The most promising results have been obtained with NAC, which through multiple thiol-responsive mechanisms completely reversed established cardiac hypertrophy and fibrosis in three independent studies. Pilot studies with losartan and statins in humans have established the feasibility of such studies. The results in animal models have firmly established the reversibility of established cardiac hypertrophy and fibrosis in HCM and have set the stage for advancing the findings in the animal models to human patients with HCM through conducting large-scale efficacy studies.}, }
@article {pmid20557081, year = {2010}, author = {Hsieh, YC and Rao, YK and Wu, CC and Huang, CY and Geethangili, M and Hsu, SL and Tzeng, YM}, title = {Methyl antcinate A from Antrodia camphorata induces apoptosis in human liver cancer cells through oxidant-mediated cofilin- and Bax-triggered mitochondrial pathway.}, journal = {Chemical research in toxicology}, volume = {23}, number = {7}, pages = {1256-1267}, doi = {10.1021/tx100116a}, pmid = {20557081}, issn = {1520-5010}, mesh = {Animals ; Antineoplastic Agents/chemistry/therapeutic use/*toxicity ; Antrodia/*chemistry ; *Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Caspase 2/metabolism ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line, Tumor ; Cofilin 1/*metabolism ; Cytochromes c/metabolism ; Hepatocytes/drug effects ; Humans ; Liver Neoplasms/drug therapy ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; NADPH Oxidases/metabolism ; Oxidants/*metabolism ; Proto-Oncogene Proteins/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Triterpenes/chemistry/therapeutic use/*toxicity ; bcl-2-Associated X Protein/*metabolism ; }, abstract = {We investigated the effects of antcin A, antcin C, and methyl antcinate A (MAA) isolated from Antrodia camphorata on the proliferation of human liver cancer cell lines Huh7, HepG2, and Hep3B and the normal cell rat hepatocytes. The three compounds selectively inhibit the proliferation of tumor cells rather than normal cells, with IC(50) values ranging from 30.2 to 286.4 microM. The compound MAA was a more potent cytotoxic agent than antcins A and C with IC(50) values of 52.2, 78.0, and 30.2 microM against HepG2, Hep3B, and Huh7 cells, respectively. To elucidate the molecular mechanism, treatment of Huh7 cells with 100 microM MAA induced an apoptotic cell death, which was characterized by the appearance of sub-G1 population, DNA fragmentation, TUNEL positive cells, and caspase activation. MAA triggered the mitochondrial apoptotic pathway, as indicated by an increase in the protein expression of Bax, Bak, and PUMA, as well as a decrease in Bcl-(XL) and Bcl-2 and disruption of mitochondrial membrane potential and promotion of mitochondrial cytochrome c release, as well as activation of caspases-2, -3, and -9. We also found that pretreatment with inhibitors of caspases-2, -3, and -9 noticeably blocked MAA-triggered apoptosis. Furthermore, intracellular reactive oxygen species (ROS) generation and NADPH oxidase activation were observed in MAA-stimulated Huh7 cells. Mechanistic studies showed that MAA induces mitochondrial translocation of cofilin. When Huh7 cells were treated with cyclosporine A and bongkrekic acid, an inhibitor of the mitochondria permeability transition pore, the levels of cell death induced by MAA were significantly attenuated. Additionally, pretreatment of Huh7 cells with antioxidants ascorbic acid and N-acetyl cysteine markedly attenuated the MAA-induced apoptosis by upregulation of Bax, Bak, and PUMA, mitochondrial translocation of cofilin, activation of caspase-3, and cell death. Taken together, our results provide the first evidence of the activation of the ROS-dependent cofilin- and Bax-triggered mitochondrial pathway as a critical mechanism of MAA-induced cell death in liver cancer cells.}, }
@article {pmid20554190, year = {2010}, author = {Gangehei, L and Ali, M and Zhang, W and Chen, Z and Wakame, K and Haidari, M}, title = {Oligonol a low molecular weight polyphenol of lychee fruit extract inhibits proliferation of influenza virus by blocking reactive oxygen species-dependent ERK phosphorylation.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {17}, number = {13}, pages = {1047-1056}, doi = {10.1016/j.phymed.2010.03.016}, pmid = {20554190}, issn = {1618-095X}, mesh = {Acetylcysteine/pharmacology ; Adenoviridae ; Animals ; Antiviral Agents/*pharmacology/therapeutic use ; Biological Transport/drug effects ; Catechin/*analogs &amp; derivatives/pharmacology/therapeutic use ; Cell Line ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Fruit ; Gene Transfer Techniques ; Influenza A virus/*drug effects/genetics/physiology ; Litchi/*chemistry ; Orthomyxoviridae Infections/drug therapy/metabolism ; Phenols/*pharmacology/therapeutic use ; Phosphorylation/drug effects ; Phytotherapy ; Plant Extracts/*pharmacology/therapeutic use ; Reactive Oxygen Species/*metabolism ; Ribonucleoproteins/metabolism ; Signal Transduction/drug effects ; Viral Proteins/metabolism ; }, abstract = {The emergence of resistance to anti-influenza drugs calls for the search for new antiviral molecules with different resistance profiles. Polyphenolic compounds are found in various plants and have antiviral and antioxidative properties. We tested the hypothesis that oligonol, a lychee fruit-derived low molecular weight polyphenol, possesses anti-influenza effects by inhibiting phosphorylation of extracellular-signal-regulated kinases (ERK). Real time PCR, plaque assay, and immunofluorescence techniques were used to study the effects of oligonol on proliferation of influenza virus. Oligonol inhibits influenza virus proliferation by blocking attachment of the virus to MDCK cells and by suppression of nuclear export of influenza virus ribonucleoprotein (RNP). Infection of MDCK cells with influenza virus leads to an increase in production of reactive oxygen species (ROS) and induction of a ROS-dependent ERK phosphorylation. Inhibition of ERK activation by a dominant negative mutant of ERK or N-acetyl-cysteine (NAC) leads to inhibition of influenza RNP nuclear export. Phorbol 12-myristate 13-acetate (PMA) induces ROS production, ERK phosphorylation and enhances influenza proliferation in MDCK cells. Oligonol and NAC inhibit PMA-induced ERK phosphorylation and ROS production. Our studies suggest that the underlying mechanism for the inhibitory effect of oligonol on influenza virus RNP nuclear export is blocking of ROS-dependent induction of ERK phosphorylation.}, }
@article {pmid20552315, year = {2010}, author = {Dell'Aglio, DM and Sutter, ME and Schwartz, MD and Koch, DD and Algren, DA and Morgan, BW}, title = {Acute chloroform ingestion successfully treated with intravenously administered N-acetylcysteine.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {6}, number = {2}, pages = {143-146}, pmid = {20552315}, issn = {1556-9039}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Chloroform/blood/*poisoning ; Electrocardiography ; Emergency Medical Services ; Free Radical Scavengers/*therapeutic use ; Humans ; Infusions, Intravenous ; Liver Function Tests ; Male ; Prothrombin Time ; Solvents/*poisoning ; Suicide, Attempted ; Young Adult ; }, abstract = {Chloroform, a halogenated hydrocarbon, causes central nervous system depression, cardiac arrhythmias, and hepatotoxicity. We describe a case of chloroform ingestion with a confirmatory serum level and resultant hepatotoxicity successfully treated with intravenously administered N-acetylcysteine (NAC). A 19-year-old man attempting suicide ingested approximately 75 mL of chloroform. He was unresponsive and intubated upon arrival. Intravenously administered NAC was started after initial stabilization was complete. His vital signs were normal. Admission laboratory values revealed normal serum electrolytes, AST, ALT, PT, BUN, creatinine, and bilirubin. Serum ethanol level was 15 mg/dL, and aspirin and acetaminophen were undetectable. The patient was extubated but developed liver function abnormalities with a peak AST of 224 IU/L, ALT of 583 IU/L, and bilirubin level reaching 16.3 mg/dL. NAC was continued through hospital day 6. Serum chloroform level obtained on admission was 91 μg/mL. The patient was discharged to psychiatry without known sequelae and normal liver function tests. The average serum chloroform level in fatal cases of inhalational chloroform poisoning was 64 μg/mL, significantly lower than our patient. The toxicity is believed to be similar in both inhalation and ingestion routes of exposure, with mortality predominantly resulting from anoxia secondary to central nervous system depression. Hepatocellular toxicity is thought to result from free radical-induced oxidative damage. Previous reports describe survival after treatment with orally administered NAC, we report the first use of intravenously administered NAC for chloroform ingestion. Acute oral ingestion of chloroform is extremely rare. Our case illustrates that with appropriate supportive care, patients can recover from chloroform ingestion, and intravenously administered NAC may be of benefit in such cases.}, }
@article {pmid20550428, year = {2010}, author = {Sevgiler, Y and Uner, N}, title = {Tissue-specific effects of fenthion on glutathione metabolism modulated by NAC and BSO in Oreochromis niloticus.}, journal = {Drug and chemical toxicology}, volume = {33}, number = {4}, pages = {348-356}, doi = {10.3109/01480541003734048}, pmid = {20550428}, issn = {1525-6014}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Buthionine Sulfoximine/*pharmacology ; Cichlids/*metabolism ; Fenthion/*toxicity ; Glutathione/*metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Transferase/metabolism ; Insecticides/*toxicity ; Kidney/drug effects/enzymology/metabolism ; Liver/drug effects/enzymology/metabolism ; Organ Specificity ; Oxidation-Reduction ; Toxicity Tests ; }, abstract = {INTRODUCTION: The present study was designed to understand the effects of organophosphate (OP) insecticide and avicide fenthion on cellular redox status and the role of reduced glutathione (GSH) on fenthion toxicity in the liver and kidney of Oreochromis niloticus as a model organism. N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) were injected intraperitoneally to fenthion-exposed fish as modulators of GSH metabolism. GSH redox status, GSH-related enzyme activities, and thiobarbituric acid reactive substances (TBARS) contents were then measured spectrophotometrically at 24, 48, and 96 hours. To assess recovery from fenthion exposure, similar analyses were performed on fish transferred to non-treated water for 24, 48, and 96 hours.<br><br>RESULTS: Fenthion increased glutathione S-transferase (GST; EC 2.5.1.18) activity and caused changes in total GSH (tGSH), GSH and oxidized glutathione (GSSG) contents and glutathione peroxidase (GPx; EC 1.11.1.9) specific activity in the liver tissue over time. Increases observed in tGSH and GSSG contents at 24 hours were decreased by fenthion treatment at 96 hours. BSO caused a sharp decline in liver tGSH, GSH, and GSSG contents and an elevation in GST and gamma-glutamyl transpeptidase (gamma-GT; EC 2.3.2.2) enzyme activities. A significant decrease was observed in tGSH and GSH contents and, also, GST enzyme activities in the kidney at 48-hour fenthion treatment. On the contrary to the liver, a significant increase was observed in tGSH and GSH contents in the kidney by BSO injection. NAC application eliminated the decreasing effects of fenthion on GST activity in this tissue. NAC injection caused decreases in lipid peroxidation (LPO) levels. Decline in tGSH and GSH contents were maintained in the liver during the recovery period, and elevations in LPO levels in the kidney were observed during the same period.<br><br>CONCLUSIONS: In conclusion, tissue-specific and time-dependent GSH redox status disturbance of fenthion were observed. BSO revealed the significance of GST-mediated GSH conjugation on the detoxification process of fenthion. NAC seemed useful to avoid the fenthion-related oxidative toxicity.}, }
@article {pmid20546880, year = {2010}, author = {Zhang, C and Liu, F and Liu, X and Chen, D}, title = {Protective effect of N-acetylcysteine against BDE-209-induced neurotoxicity in primary cultured neonatal rat hippocampal neurons in vitro.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {28}, number = {6}, pages = {521-528}, doi = {10.1016/j.ijdevneu.2010.05.003}, pmid = {20546880}, issn = {1873-474X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Animals, Newborn ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Flame Retardants/toxicity ; Halogenated Diphenyl Ethers/*toxicity ; Hippocampus/*drug effects/*physiopathology ; Neurons/*drug effects ; Neuroprotective Agents/administration &amp; dosage ; Neurotoxicity Syndromes/*drug therapy ; Neurotoxins/toxicity ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Globally, brominated diphenyl ether-209 (BDE-209) is the most widely used polybrominated diphenyl ether (PBDEs). It has been reported that BDE-209 induces developmental neurotoxicity in vivo. The purpose of this study was to use an antioxidant, N-acetylcysteine (NAC), as an antidote for the neurotoxic effect of BDE-209. We used primary hippocampal neurons from rats for the in vitro cultures. BDE-209 was added to the cultures in increasing concentrations and co-cultured with NAC in order to assess the effect of NAC on BDE-209-induced neurotoxicity. We measured cell viability, apoptosis, expression of phosphorylated p38 mitogen-activated protein kinases (MAPK), intracellular calcium content, and intracellular reactive oxygen species (ROS) levels. The difference between the BDE-209 groups without NAC and the blank control groups was significant (P<0.05). The difference between the NAC treatment groups and the BDE-209 groups without NAC was also significant (P<0.05), showing that BDE-209 increased apoptosis, the expression of p38 MAPK, the calcium ion concentration, and the ROS level and decreased cell viability. In contrast, NAC reduced the degree of cellular cytotoxicity induced by BDE-209. The results suggested that NAC may be able to attenuate BDE-209-induced neurotoxicity.}, }
@article {pmid20543569, year = {2010}, author = {Li, J and Liu, R and Lei, Y and Wang, K and Lau, QC and Xie, N and Zhou, S and Nie, C and Chen, L and Wei, Y and Huang, C}, title = {Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells.}, journal = {Autophagy}, volume = {6}, number = {6}, pages = {711-724}, doi = {10.4161/auto.6.6.12397}, pmid = {20543569}, issn = {1554-8635}, mesh = {Apoptosis/drug effects ; Autophagy/*drug effects/genetics ; Gene Expression Regulation, Leukemic/drug effects ; Green Fluorescent Proteins/metabolism ; Humans ; Hydroxamic Acids/*pharmacology ; Immunoblotting ; Jurkat Cells ; Leukemia, T-Cell/enzymology/genetics/*metabolism/*pathology ; Microtubule-Associated Proteins/metabolism ; Models, Biological ; Neoplasm Proteins/metabolism ; Phagosomes/drug effects/metabolism ; Proteomics/*methods ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; TOR Serine-Threonine Kinases/antagonists &amp; inhibitors ; Vacuoles/drug effects/metabolism ; Vorinostat ; }, abstract = {Suberoylanilide hydroxamic acid (SAHA) is a newly emerging histone deacetylase inhibitor (HDACi) and has been approved in phase II clinical trials for treating patients with cutaneous T-cell lymphoma. Autophagy is a conserved self-digestion process that degrades cytoplasmic materials and recycles long-lived proteins and organelles within cells. In this study, we demonstrate that SAHA stimulates autophagy in Jurkat T-leukemia cells, which was evidenced by the appearance of autophagic vacuoles, formation of acidic vesicular organelles, recruitment of LC3-II to the autophagosomes and conversion of LC3-I to LC3-II . Moreover, SAHA treatment upregulated expression of Beclin 1 and Atg7 and promoted formation of the Atg12-Atg5 conjugate. Furthermore, inhibition of autophagy by chloroquine (CQ) enhanced SAHA-induced apoptosis. To determine the underlying mechanism of SAHA-induced autophagy, two complementary proteomic approaches (2-DE and SILAC), coupled with ESI-Q-TOF MS/MS analysis are utilized to profile differentially expressed proteins between control and SAHA-treated Jurkat T-leukemia cells. In total, 72 proteins were identified with significant alterations. Cluster analysis of the changed proteins reveal several groups of enzymes associated with energy metabolism, anti-oxidative stress and cellular redox control, which suggested an abnormal reactive oxygen species (ROS) production in SAHA-treated Jurkat T-leukemia cells. These observations were further confirmed by ROS chemiluminescence assay. Mechanistic studies revealed that SAHA-triggered autophagy was mediated by ROS production, which could be attenuated by N-acetyl cysteine (NAC), a ROS inhibitor. Finally, we illustrated that Akt-mTOR signaling, a major suppressive cascade of autophagy, was inactivated by SAHA treatment. Taken together, our study identifies autophagy as a reaction to counter increased ROS and is thus involved as a cellular prosurvival mechanism in response to SAHA treatment.}, }
@article {pmid20541518, year = {2010}, author = {Mi, L and Sirajuddin, P and Gan, N and Wang, X}, title = {A cautionary note on using N-acetylcysteine as an antagonist to assess isothiocyanate-induced reactive oxygen species-mediated apoptosis.}, journal = {Analytical biochemistry}, volume = {405}, number = {2}, pages = {269-271}, pmid = {20541518}, issn = {1096-0309}, support = {R01 CA100853/CA/NCI NIH HHS/United States ; T32 CA009686/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*chemistry ; *Apoptosis ; Carbon Isotopes/chemistry ; Cell Line, Tumor ; HeLa Cells ; Humans ; Isothiocyanates/*antagonists &amp; inhibitors/*chemistry ; Reactive Oxygen Species/*metabolism ; Sulfoxides ; Thiocyanates/chemistry ; }, abstract = {N-Acetylcysteine (NAC) has been widely used in cell culture-based studies for the role of reactive oxygen species (ROS) generation in apoptosis induction by isothiocyanates (ITCs). Here we have demonstrated, using [(14)C]phenethyl ITC and [(14)C]sulforaphane, that NAC pretreatment significantly reduces ITC cellular uptake by conjugating with ITCs in the medium, suggesting that reduced uptake of ITCs, rather than the antioxidant activity of NAC itself, is responsible for the diminished downstream apoptotic effects. The study provides a cautionary note on the assay in studying mechanisms of apoptosis by ITCs and other electrophilic and thiol-reactive compounds.}, }
@article {pmid20541301, year = {2010}, author = {Moist, L and Sontrop, JM and Gallo, K and Mainra, R and Cutler, M and Freeman, D and House, AA}, title = {Effect of N-acetylcysteine on serum creatinine and kidney function: results of a randomized controlled trial.}, journal = {American journal of kidney diseases : the official journal of the National Kidney Foundation}, volume = {56}, number = {4}, pages = {643-650}, doi = {10.1053/j.ajkd.2010.03.028}, pmid = {20541301}, issn = {1523-6838}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Aged ; Aged, 80 and over ; Confidence Intervals ; Creatinine/*blood ; Cystatin C/analysis ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Humans ; Kidney Failure, Chronic/*diagnosis/*drug therapy ; Kidney Function Tests ; Male ; Middle Aged ; Reference Values ; Risk Assessment ; Severity of Illness Index ; Statistics, Nonparametric ; Treatment Outcome ; }, abstract = {BACKGROUND: Evidence for a protective effect of N-acetylcysteine (NAC) on acute and chronic kidney disease is equivocal, and controversy persists about whether NAC affects creatinine level independently of actual kidney function. Study objectives are to investigate whether NAC affects serum creatinine level independently of alterations in other measures of kidney function.<br><br>STUDY DESIGN: Double-blind randomized controlled trial.<br><br>SETTING &amp; PARTICIPANTS: Patients with stage 3 chronic kidney disease (n = 60), Canada, 2007-2008.<br><br>INTERVENTION: Participants were randomly allocated to receive 4 doses of oral NAC (each 1,200 mg) or placebo, administered at 12-hour intervals.<br><br>OUTCOME: The primary outcome was change in serum creatinine level between baseline and 4 hours after the last treatment dose. In addition, changes in other parameters of kidney function were measured between baseline and 4, 24, or 48 hours after the last treatment dose.<br><br>MEASUREMENTS: Serum creatinine, cystatin C, 24-hour urine protein and creatinine excretion, and creatinine clearance.<br><br>RESULTS: 60 patients, mean age of 70 years, 75% men, 50% had diabetes, with mean creatinine clearance of 43.7 &#xb1; 18.8 (SD) mL/min were enrolled. Between baseline and 4 hours posttreatment, serum creatinine level decreased by 0.044 &#xb1; 0.15 mg/dL in the NAC group and 0.040 &#xb1; 0.18 mg/dL in the placebo group (95% CI for difference, -0.09 to 0.08; P = 0.9). No significant differences between groups were observed for change in serum creatinine, cystatin C, urine protein, urine creatinine, or creatinine clearance values at any time.<br><br>LIMITATIONS: Blinding patients to orally administered liquid NAC is difficult and it is possible that patients receiving NAC were not sufficiently blinded. Effects of NAC beyond 48 hours of treatment were not evaluated.<br><br>CONCLUSIONS: In this randomized controlled trial, NAC had no short-term effect on creatinine level and did not decrease urine protein excretion within 48 hours of treatment.}, }
@article {pmid20538838, year = {2010}, author = {Nolin, TD and Ouseph, R and Himmelfarb, J and McMenamin, ME and Ward, RA}, title = {Multiple-dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease.}, journal = {Clinical journal of the American Society of Nephrology : CJASN}, volume = {5}, number = {9}, pages = {1588-1594}, pmid = {20538838}, issn = {1555-905X}, support = {R21 DK074161/DK/NIDDK NIH HHS/United States ; 1 R21 DK074161-01/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/blood/*pharmacokinetics ; Administration, Oral ; Adult ; Antioxidants/*administration &amp; dosage/*pharmacokinetics ; Area Under Curve ; Biomarkers/blood ; Delayed-Action Preparations ; Down-Regulation ; Female ; Half-Life ; Homocysteine/blood ; Humans ; Kidney Failure, Chronic/blood/*drug therapy ; Male ; Metabolic Clearance Rate ; Middle Aged ; Oxidative Stress/*drug effects ; Prospective Studies ; Treatment Outcome ; United States ; }, abstract = {BACKGROUND AND OBJECTIVES: ESRD is associated with systemic oxidative stress, an important nontraditional risk factor for the development of cardiovascular disease. Since interventions aimed at reducing oxidative stress may be beneficial, we examined the pharmacokinetics and pharmacodynamics of the widely used antioxidant N-acetylcysteine (NAC) after oral administration in patients with ESRD.<br><br>Twenty-four ESRD patients were randomly assigned to receive 600 or 1200 mg of sustained-release NAC orally every 12 hours for 14 days. Seven healthy control subjects received NAC 600 mg in the same manner. Blood samples were obtained on days 1 and 15 for determination of NAC pharmacokinetics and pharmacodynamics.<br><br>RESULTS: Significant dose-related increases in NAC plasma concentrations were observed in ESRD patients with no change in total clearance; a doubling of the dose resulted in a 2-fold increase in NAC area under the plasma concentration-time curve (AUC). However, NAC clearance was reduced by 90% in ESRD, leading to a 7-fold larger AUC and 13-fold longer half-life compared with healthy control subjects. NAC administration resulted in a significant reduction in total homocysteine plasma concentrations in ESRD and healthy subjects, but had no effect on several other oxidative stress markers.<br><br>CONCLUSIONS: These findings indicate that the total clearance of oral NAC is significantly reduced in ESRD patients, leading to marked increases in systemic exposure, and suggest that NAC may have a limited role in the chronic treatment of oxidative stress-related illness.}, }
@article {pmid20534999, year = {2011}, author = {Thompson, TM and Lu, JJ and Blackwood, L and Leikin, JB}, title = {Computerized N-acetylcysteine physician order entry by template protocol for acetaminophen toxicity.}, journal = {American journal of therapeutics}, volume = {18}, number = {2}, pages = {107-109}, doi = {10.1097/MJT.0b013e3181e3b0de}, pmid = {20534999}, issn = {1536-3686}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Analgesics, Non-Narcotic/poisoning ; Antidotes/*administration &amp; dosage ; Humans ; Infusions, Intravenous ; *Medical Order Entry Systems ; Medication Errors/prevention &amp; control ; Retrospective Studies ; }, abstract = {Some medication dosing protocols are logistically complex for traditional physician ordering. The use of computerized physician order entry (CPOE) with templates, or order sets, may be useful to reduce medication administration errors. This study evaluated the rate of medication administration errors using CPOE order sets for N-acetylcysteine (NAC) use in treating acetaminophen poisoning. An 18-month retrospective review of computerized inpatient pharmacy records for NAC use was performed. All patients who received NAC for the treatment of acetaminophen poisoning were included. Each record was analyzed to determine the form of NAC given and whether an administration error occurred. In the 82 cases of acetaminophen poisoning in which NAC was given, no medication administration errors were identified. Oral NAC was given in 31 (38%) cases; intravenous NAC was given in 51 (62%) cases. In this retrospective analysis of N-acetylcysteine administration using computerized physician order entry and order sets, no medication administration errors occurred. CPOE is an effective tool in safely executing complicated protocols in an inpatient setting.}, }
@article {pmid20534223, year = {2010}, author = {Sorbello, M and Morello, G and Parrinello, L and Molino, C and Rinzivillo, D and Pappalardo, R and Cutuli, M and Corona, D and Veroux, P and Veroux, M}, title = {Effect of N-acetyl-cysteine (NAC) added to fenoldopam or dopamine on end-tidal carbon dioxide and mean arterial pressure at time of renal artery declamping during cadaveric kidney transplantation.}, journal = {Transplantation proceedings}, volume = {42}, number = {4}, pages = {1056-1060}, doi = {10.1016/j.transproceed.2010.03.072}, pmid = {20534223}, issn = {1873-2623}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Antihypertensive Agents/pharmacology ; Antioxidants/pharmacology ; Blood Pressure/*drug effects ; Cadaver ; Carbon Dioxide/*metabolism ; Dopamine/*pharmacology ; Dopamine Agents/pharmacology ; Female ; Fenoldopam/*pharmacology ; Humans ; Kidney Transplantation/*methods/physiology ; Male ; Middle Aged ; Renal Artery/drug effects/*physiology ; Retrospective Studies ; Tidal Volume/drug effects ; Tissue Donors ; }, abstract = {N-acetyl-cysteine (NAC) is known to be a powerful antioxidant used to prevent renal damage. Our deceased-donor kidney transplantation protocol administered an NAC bolus at the time of declamping of the renal artery to reduce the potential oxidative damage with ischemia-reperfusion. The aim of injury this study was to compare the effects of NAC added to a continuous infusion of either fenoldopam or dopamine during kidney recipient anesthesia on mean arterial pressure (MAP) and end-tidal carbon dioxide (ECO(2)), which were assumed to be expressions of oxidative and acid-base status. One hundred forty patients undergoing deceased donor kidney transplantation were enrolled in the study. Using a standardized perioperative anesthesia protocol, the patients were divided into 4 groups: group N, receiving an NAC (50 mg/kg) bolus just before renal artery declamping (n = 40); group C, not receiving any NAC or other infusion (n = 20); group NF, same treatment as group N plus fenoldopam (0.1 microg/kg/min) continuous infusion (n = 40); and group ND, same treatment as group N plus dopamine (3 microg/kg/min) continuous infusion (n = 40). We recorded the duration of kidney cold and warm ischemia and EtCO(2) and MAP values before and after arterial declamping, as well as subjective evaluations of graft perfusion and the incidence of early or delayed graft function and adverse events. EtCO(2) was higher and MAP lower in group C compared with group N; comparing groups N, ND, and NF, the NF regimen resulted in lower EtCO(2) and higher MAP values and a greater incidence of early graft function. Subjective evaluation of graft perfusion was more favorable for groups N, ND, and NC, particularly for NF. No significant periprocedural adverse events were recorded in the groups. In our experience, the association of an NAC bolus at the time of renal artery declamping and continuous infusion of fenoldopam resulted in a minor, though non-significant, increase in EtCO(2) values, higher MAP, and greater incidence of early graft function during deceased-donor kidney transplantation compared with no NAC or NAC plus renal-dose dopamine. Further studies are necessary to better define the potential role of oxidative damage in renal ischemia- reperfusion injury, including implications for outcome, as well as the potential role of the combination of NAC plus fenoldopam as a nephroprotective and outcome-modulating regimen.}, }
@article {pmid20534110, year = {2010}, author = {Wu, X and Zhu, Y and Yan, H and Liu, B and Li, Y and Zhou, Q and Xu, K}, title = {Isothiocyanates induce oxidative stress and suppress the metastasis potential of human non-small cell lung cancer cells.}, journal = {BMC cancer}, volume = {10}, number = {}, pages = {269}, pmid = {20534110}, issn = {1471-2407}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/*pharmacology ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung/genetics/metabolism/*secondary ; Cell Line, Tumor ; Cell Movement/*drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Flow Cytometry ; Glutathione/metabolism ; Humans ; Inhibitory Concentration 50 ; Isothiocyanates/*pharmacology ; Lung Neoplasms/genetics/metabolism/*pathology ; Matrix Metalloproteinase 2/metabolism ; NF-kappa B/genetics/metabolism ; Neoplasm Invasiveness ; Nuclear Proteins/metabolism ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; Transfection ; Twist-Related Protein 1/metabolism ; beta Catenin/metabolism ; }, abstract = {BACKGROUND: Isothiocyanates are natural compounds found in consumable cruciferous vegetables. They have been shown to inhibit chemical carcinogenesis by a wide variety of chemical carcinogens in animal models. Recent studies have also shown that isothiocyanates have antitumor activity, inhibiting the growth of several types of cultured human cancer cells. Our previous study showed that PEITC inhibited human leukemia cells growth by inducing apoptosis. However, the effect of isothiocyanates on lung cancer cell metastasis has not been studied. In the present study, we investigated the inhibitory effects of BITC and PEITC on metastatic potential of highly metastatic human lung cancer L9981 cells.<br><br>METHODS: Cell migration and invasion were measured by wound healing assay and transwell chemotaxis assay. Expression of metastasis-related genes was assessed by quantitative RT-PCR and Western blotting. The mechanisms of action were evaluated by flow cytometry, reporter assay and Western blotting.<br><br>RESULTS: Our data showed that both BITC and PEITC inhibited L9981 cell growth in a dose-dependent manner, the IC50 values were 5.0 and 9.7 microM, respectively. Cell migrations were reduced to 8.1% and 16.5% of control, respectively; and cell invasions were reduced to 2.7% and 7.3% of control, respectively. Metastasis-related genes MMP-2, Twist and beta-catenin were also modulated. BITC and PEITC inhibited cell survival signaling molecules Akt and NFkappaB activation. Moreover, BITC and PEITC increased ROS generation and caused GSH depletion. Pretreatment with NAC blocked BITC and PEITC induced ROS elevation and NFkappaB inhibition.<br><br>CONCLUSION: Our results indicated that BITC and PEITC suppress lung cancer cell metastasis potential by modulation of metastasis-related gene expression, inhibition of Akt/NFkappaB pathway. Induction of oxidative stress may play an important role.}, }
@article {pmid20525644, year = {2010}, author = {Hänninen, SL and Ronkainen, JJ and Leskinen, H and Tavi, P}, title = {Mitochondrial uncoupling downregulates calsequestrin expression and reduces SR Ca2+ stores in cardiomyocytes.}, journal = {Cardiovascular research}, volume = {88}, number = {1}, pages = {75-82}, doi = {10.1093/cvr/cvq180}, pmid = {20525644}, issn = {1755-3245}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Calcium/*metabolism ; *Calcium Signaling/drug effects ; Calcium-Binding Proteins/genetics/*metabolism ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology ; Caspase 3/metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; Down-Regulation ; Free Radical Scavengers/pharmacology ; Microscopy, Confocal ; Mitochondria, Heart/drug effects/*metabolism ; Myocytes, Cardiac/drug effects/*metabolism ; RNA, Messenger/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Sarcoplasmic Reticulum/drug effects/*metabolism ; Time Factors ; Transcription, Genetic ; Tumor Suppressor Protein p53/metabolism ; Uncoupling Agents/pharmacology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {AIMS: Mitochondrial cardiomyopathy is associated with deleterious remodelling of cardiomyocyte Ca(2+) signalling that is partly due to the suppressed expression of the sarcoplasmic reticulum (SR) Ca(2+) buffer calsequestrin (CASQ2). This study was aimed at determining whether CASQ2 downregulation is directly caused by impaired mitochondrial function.<br><br>METHODS AND RESULTS: Mitochondrial stress was induced in cultured neonatal rat cardiomyocytes by means of the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). Ca(2+) transients and reactive oxygen species (ROS) were measured by confocal microscopy using the indicators fluo-4 and MitoSOX red, respectively. Mitochondrial stress led to concentration-dependent downregulation of calsequestrin (CASQ2) and changes in the Ca(2+) signals of the cardiomyocytes that were accompanied by reduction in SR Ca(2+) content and amplitude and duration of Ca(2+) sparks. Caspase 3, p38, and p53 inhibitors had no effect on FCCP-induced CASQ2 downregulation; however, it was attenuated by the ROS scavenger N-acetylcysteine (NAC). Importantly, NAC not only decreased FCCP-induced ROS production, but it also restored the Ca(2+) signals, SR Ca(2+) content, and Ca(2+) spark properties to control levels.<br><br>CONCLUSION: Mitochondrial uncoupling results in fast transcriptional changes in CASQ2 expression that manifest as compromised Ca(2+) signalling, and these changes can be prevented by ROS scavengers. As impaired mitochondrial function has been implicated in several cardiac pathologies as well as in normal ageing, the mechanisms described here might be involved in a wide spectrum of cardiac conditions.}, }
@article {pmid20524832, year = {2010}, author = {Bebarta, VS and Kao, L and Froberg, B and Clark, RF and Lavonas, E and Qi, M and Delgado, J and McDonagh, J and Arnold, T and Odujebe, O and O'Malley, G and Lares, C and Aguilera, E and Dart, R and Heard, K and Stanford, C and Kokko, J and Bogdan, G and Mendoza, C and Mlynarchek, S and Rhyee, S and Hoppe, J and Haur, W and Tan, HH and Tran, NN and Varney, S and Zosel, A and Buchanan, J and Al-Helial, M}, title = {A multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {48}, number = {5}, pages = {424-430}, pmid = {20524832}, issn = {1556-9519}, support = {K08 DA020573/DA/NIDA NIH HHS/United States ; K08 DA020573-04/DA/NIDA NIH HHS/United States ; K08DA020573/DA/NIDA NIH HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/poisoning/*therapeutic use ; Anaphylaxis/chemically induced ; Drug Administration Routes ; Drug Overdose/drug therapy ; Humans ; Infusions, Intravenous ; Injections, Intravenous ; Nausea/chemically induced/drug therapy ; Safety ; Treatment Outcome ; Vomiting/chemically induced/drug therapy ; }, abstract = {UNLABELLED: Oral and intravenous (IV) N-acetylcysteine (NAC) are used for the treatment of acetaminophen poisoning. The objective of this multicenter study was to compare the safety of these two routes of administration.<br><br>METHODS: We conducted a multicenter chart review of all patients treated with NAC for acetaminophen poisoning. The primary safety outcome was the percentage of patients with NAC-related adverse events.<br><br>RESULTS: A total of 503 subjects were included in the safety analysis (306 IV-only, 145 oral-only, and 52 both routes). There were no serious adverse events related to NAC for either route. Nausea and vomiting were the most common related adverse events and were more common with oral treatment (23 vs. 9%). Anaphylactoid reactions were more common with IV administration (6 vs. 2%).<br><br>CONCLUSIONS: IV and oral NAC are generally mild adverse drug reactions.}, }
@article {pmid20524210, year = {2011}, author = {Chen, JK and Zhan, YJ and Yang, CS and Tzeng, SF}, title = {Oxidative stress-induced attenuation of thrombospondin-1 expression in primary rat astrocytes.}, journal = {Journal of cellular biochemistry}, volume = {112}, number = {1}, pages = {59-70}, doi = {10.1002/jcb.22732}, pmid = {20524210}, issn = {1097-4644}, mesh = {Acetylcysteine/metabolism ; Animals ; Astrocytes/cytology/*metabolism ; Cells, Cultured ; Cobalt/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fluorescent Antibody Technique ; Mitogen-Activated Protein Kinases/metabolism ; *Oxidative Stress/genetics ; RNA, Messenger/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Thrombospondin 1/*genetics/metabolism ; }, abstract = {Astrocytes, the major glial population in the central nervous system (CNS), can secrete thrombospondin (TSP)-1 that plays the role in synaptogenesis and axonal sprouting during CNS development and tissue repair. However, little is known about the regulation of TSP-1 expression in astrocytes under oxidative stress condition. Here, a hypoxic mimetic reagent, cobalt chloride (CoCl(2)), was used to initiate hypoxia-induced oxidative stress in primary rat astrocytes. CoCl(2) at the concentration range of 0.1-0.5 mM was found to cause no significant cell death in primary rat astrocytes. However, CoCl(2) at 0.2-0.5 mM increased intracellular reactive oxygen species (ROS) levels and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene expression that is known as a hallmark for oxidative damage. We further found that TSP-1 mRNA expression in astrocytes was inhibited dose- and time-dependently by CoCl(2). TSP-1 mRNA levels were increased in CoCl(2)-exposed astrocytes in the presence of the inhibitors (U0126 and PD98059) of mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERK), when compared to that detected in the culture only exposed to CoCl(2). Moreover, the inhibition in TSP-1 mRNA expression by CoCl(2) was blocked by the addition of the potent antioxidant, N-acetylcysteine (NAC). Thus, we conclude that CoCl(2) inhibits TSP-1 mRNA expression in astrocytes via a ROS mechanism possibly involving MAPK/ERK. This inhibition may occur after CNS injury and impair the supportive function of astrocytes on neurite growth in the injured CNS tissues.}, }
@article {pmid20523355, year = {2010}, author = {Sardina, JL and López-Ruano, G and Sánchez-Abarca, LI and Pérez-Simón, JA and Gaztelumendi, A and Trigueros, C and Llanillo, M and Sánchez-Yagüe, J and Hernández-Hernández, A}, title = {p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation.}, journal = {Cell death and differentiation}, volume = {17}, number = {12}, pages = {1842-1854}, doi = {10.1038/cdd.2010.67}, pmid = {20523355}, issn = {1476-5403}, mesh = {Antigens, CD34/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Chromans/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Janus Kinase 2/metabolism ; Megakaryocytes/*cytology/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/genetics/*metabolism ; Onium Compounds/pharmacology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Quercetin/pharmacology ; RNA Interference ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Transient reactive oxygen species (ROS) production is currently proving to be an important mechanism in the regulation of intracellular signalling, but reports showing the involvement of ROS in important biological processes, such as cell differentiation, are scarce. In this study, we show for the first time that ROS production is required for megakaryocytic differentiation in K562 and HEL cell lines and also in human CD34(+) cells. ROS production is transiently activated during megakaryocytic differentiation, and such production is abolished by the addition of different antioxidants (such as N-acetyl cysteine, trolox, quercetin) or the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium. The inhibition of ROS formation hinders differentiation. RNA interference experiments have shown that a p22(phox)-dependent NADPH oxidase activity is responsible for ROS production. In addition, the activation of ERK, AKT and JAK2 is required for differentiation, but the activation of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase seems to be less important. When ROS production is prevented, the activation of these signalling pathways is partly inhibited. Taken together, these results show that NADPH oxidase ROS production is essential for complete activation of the main signalling pathways involved in megakaryocytopoiesis to occur. We suggest that this might also be important for in vivo megakaryocytopoiesis.}, }
@article {pmid20521395, year = {2010}, author = {Yedjou, CG and Tchounwou, CK and Haile, S and Edwards, F and Tchounwou, PB}, title = {N-acetyl-cysteine protects against DNA damage associated with lead toxicity in HepG2 cells.}, journal = {Ethnicity &amp; disease}, volume = {20}, number = {1 Suppl 1}, pages = {S1-101-3}, pmid = {20521395}, issn = {1049-510X}, support = {G12 RR013459/RR/NCRR NIH HHS/United States ; G12 RR013459-12/RR/NCRR NIH HHS/United States ; 2G12RR13459-11/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Cell Survival/drug effects ; Comet Assay ; DNA Damage/*drug effects ; Free Radical Scavengers/*pharmacology ; Hep G2 Cells ; Humans ; Lead/*toxicity ; Liver Neoplasms/pathology ; Oxidative Stress/drug effects ; }, abstract = {Lead toxicity has been associated with its ability to interact and damage DNA. However, its molecular mechanisms of action are not fully understood. In vitro studies in our laboratory indicated that lead nitrate (PbNO3) induces cytotoxicity and oxidative stress to human liver carcinoma (HepG2) cells in a dose-dependent manner. In this research, we hypothesized that n-acetyl-cysteine (NAC), a known antioxidant compound, affords protection against lead-induced cell death associated with genotoxic damage. To test this hypothesis, HepG2 cells were treated either with a physiologic dose of NAC, NAC plus PbNO3, or PbNO3 alone, followed by incubation in humidified 5% CO2 incubator at 37 degrees C for 48 hr. The cell viability was determined by trypan blue exclusion test. The degree of DNA damage was detected by micro gel electrophoresis (comet) assay. Our results showed that lead exposure induces a substantial cytotoxicity as well as a significant genotoxicity to HepG2 cells. However, co-treatment with a physiologic dose (500 microM) of NAC slightly increases cell viability, and significantly reduced (P < .05) the degree of DNA damage. Hence, NAC treatment may be a promising therapeutic candidate for chemoprevention against lead toxicity, based on its ability to scavenge free radicals.}, }
@article {pmid20519448, year = {2010}, author = {Ferreira, LF and Moylan, JS and Gilliam, LA and Smith, JD and Nikolova-Karakashian, M and Reid, MB}, title = {Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue.}, journal = {American journal of physiology. Cell physiology}, volume = {299}, number = {3}, pages = {C552-60}, pmid = {20519448}, issn = {1522-1563}, support = {R01 AR055974/AR/NIAMS NIH HHS/United States ; R01 AG019223/AG/NIA NIH HHS/United States ; R01 AG026711-01A2/AG/NIA NIH HHS/United States ; R01 AG026711/AG/NIA NIH HHS/United States ; T32 HL086341/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Bacterial Proteins/pharmacology ; Cell Line ; Ceramides/metabolism ; Cytosol/metabolism ; Diaphragm/physiology ; In Vitro Techniques ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Contraction ; Muscle Fatigue/*physiology ; Muscle Fibers, Skeletal/metabolism ; Muscle, Skeletal/*physiology ; Oxidants/*physiology ; Reactive Nitrogen Species/metabolism ; Signal Transduction ; Sphingomyelin Phosphodiesterase/pharmacology/*physiology ; }, abstract = {Sphingomyelinase (SMase) hydrolyzes membrane sphingomyelin into ceramide, which increases oxidants in nonmuscle cells. Serum SMase activity is elevated in sepsis and heart failure, conditions where muscle oxidants are increased, maximal muscle force is diminished, and fatigue is accelerated. We tested the hypotheses that exogenous SMase and accumulation of ceramide in muscle increases oxidants in muscle cells, depresses specific force of unfatigued muscle, and accelerates the fatigue process. We also anticipated that the antioxidant N-acetylcysteine (NAC) would prevent SMase effects on muscle function. We studied the responses of C2C12 myotubes and mouse diaphragm to SMase treatment in vitro. We observed that SMase caused a 2.8-fold increase in total ceramide levels in myotubes. Exogenous ceramide and SMase elevated oxidant activity in C2C12 myotubes by 15-35% (P < 0.05) and in diaphragm muscle fiber bundles by 58-120% (P < 0.05). The SMase-induced increase in diaphragm oxidant activity was prevented by NAC. Exogenous ceramide depressed diaphragm force by 55% (P < 0.05), while SMase depressed maximal force by 30% (P < 0.05) and accelerated fatigue--effects opposed by treatment with NAC. In conclusion, our findings suggest that SMase stimulates a ceramide-oxidant signaling pathway that results in muscle weakness and fatigue.}, }
@article {pmid20515765, year = {2010}, author = {Han, ZJ and Cui, Y and Song, G and Xia, HF and Ma, X}, title = {Protective effects of N-acetylcysteine on homocysteine induced injury in chick embryos.}, journal = {Frontiers in bioscience (Elite edition)}, volume = {2}, number = {3}, pages = {940-947}, doi = {10.2741/e153}, pmid = {20515765}, issn = {1945-0508}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Chick Embryo ; Embryo, Nonmammalian/*drug effects ; Homocysteine/*toxicity ; In Situ Nick-End Labeling ; Rats ; Reactive Oxygen Species ; }, abstract = {Protective effects of N-acetylcysteine (NAC) on homocysteine (Hcy)-induced injury have been reported in vitro. However, it is not known whether NAC has a similar effect in Hcy-induced injury during embryonic development. In this study, we tested the hypothesis that exogenous NAC can attenuate Hcy-induced injury in chick embryos. Hcy-induced apoptosis and reduced embryo viability were effectively attenuated by application of exogenous NAC. NAC could also rescue Hcy-induced inhibition of extra-embryonic vascular development. 2',7'-Dichlorofluorescein diacetate, an indicator of reactive oxygen species, was detected in H9C2 cells after treatment with Hcy. The results of this study provide the first evidence that NAC can protect against the adverse effect of Hcy during chick embryo development, and suggest that these effects are at least partly mediated by oxidative stress.}, }
@article {pmid20514427, year = {2010}, author = {Passarelli, C and Tozzi, G and Pastore, A and Bertini, E and Piemonte, F}, title = {GSSG-mediated Complex I defect in isolated cardiac mitochondria.}, journal = {International journal of molecular medicine}, volume = {26}, number = {1}, pages = {95-99}, doi = {10.3892/ijmm_00000439}, pmid = {20514427}, issn = {1791-244X}, mesh = {Animals ; Blotting, Western ; Cell Line ; Dose-Response Relationship, Drug ; Electron Transport/drug effects ; Electron Transport Complex I/*metabolism ; Glutathione/*metabolism ; Glutathione Disulfide/*pharmacology ; Hydrogen Peroxide/pharmacology ; Mitochondria, Heart/*drug effects/metabolism ; Myocytes, Cardiac/cytology/drug effects/metabolism ; Oxidants/pharmacology ; Rats ; }, abstract = {The mitochondrial respiratory chain represents the major source of reactive oxygen species (ROS) in cells and its dysfunction may contribute to the pathogenesis of several diseases. In mitochondria, glutathione is the major redox buffer and is a good indicator for the redox environment of the cell. Indeed, overproduction of ROS decreases the ratio between reduced and oxidized glutathione leading the latter to bind to proteins by a mechanism called glutathionylation. In this study, we demonstrate that in isolated cardiac mitochondria the respiratory chain enzyme Complex I is highly susceptible to glutathionylation under conditions of oxidative stress, showing a significant dose- and time-dependent decrease of the activity after treatment with oxidized glutathione. Among respiratory chain enzymes, Complex I appears the most affected by the oxidant-mediated inactivation in isolated mitochondria. Also, in cultured cardiomyocytes CI activity was strongly inhibited after in vivo treatment with hydrogen peroxide. Noteworthy, HPLC analysis showed a significant increase of protein glutathionylation in oxidatively stressed cells and this rise is in vivo reverted after incubation of cells with anti-oxidant N-acetyl-cysteine. These findings take particular importance given that CI represents the entry point of electrons into oxidative phosphorylation and that the threshold at which CI dysfunction affects ATP production is lower than that of any other OXPHOS complexes, making the enzyme particularly critical for the health of cells.}, }
@article {pmid20513041, year = {2010}, author = {Nader, ME and Théorêt, Y and Saliba, I}, title = {The role of intratympanic lactate injection in the prevention of cisplatin-induced ototoxicity.}, journal = {The Laryngoscope}, volume = {120}, number = {6}, pages = {1208-1213}, doi = {10.1002/lary.20892}, pmid = {20513041}, issn = {1531-4995}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Cisplatin/*toxicity ; Guinea Pigs ; Hearing Loss/*chemically induced/*prevention &amp; control ; Lactates/*administration &amp; dosage/pharmacology ; Microscopy, Electron, Scanning ; Prospective Studies ; Statistics, Nonparametric ; *Tympanic Membrane ; }, abstract = {OBJECTIVES/HYPOTHESIS: There is no approved agent to prevent cisplatin-induced ototoxicity. Our objectives were to: 1) identify and compare the effect of intratympanic injections of lactate or N-acetylcysteine (NAC) in the prevention of cisplatin-induced ototoxicity, 2) investigate inner ear protection using a scanning electron microscope, and 3) study systemic diffusion of intratympanic NAC.<br><br>STUDY DESIGN: Prospective animal study.<br><br>METHODS: Sixteen guinea pigs formed two groups, and respectively received intratympanic lactate and 20% NAC in one ear. The contralateral ears received a control saline solution. After 30 minutes, an intraperitoneal cisplatin injection of 3 mg/kg was performed and repeated eight times, once a week, to achieve 24 mg/kg. Auditory brainstem responses (ABRs) were recorded before any injection, after 9 mg/kg and after 24 mg/kg of cisplatin for the frequencies 2, 4, 6 and 8 kHz. Cochleas were analyzed under scanning electron microscope. Systemic diffusion of NAC was studied using high-performance liquid chromatography.<br><br>RESULTS: For the control ears, ABR thresholds increased uniformly and averaged 28.4 dB. The lactate group showed a lower threshold increase and averaged 17.0 dB. The NAC showed an important threshold increase of 89.0 dB. Lactate showed a significant hearing protection at 2000 Hz (P < .01). Electron microscopy revealed partial preservation of outer hair cell stereocilia for the ears treated with lactate and severe disruption for NAC group. No systemic diffusion of NAC was observed with chromatography.<br><br>CONCLUSIONS: Intratympanic lactate offers significant partial protection against cisplatin-induced ototoxicity at midfrequencies. High-concentration NAC does not seem a viable solution as it causes a considerable inflammatory reaction. NAC does not diffuse systemically.}, }
@article {pmid20512789, year = {2010}, author = {Glauert, HP and Calfee-Mason, K and Stemm, DN and Tharappel, JC and Spear, BT}, title = {Dietary antioxidants in the prevention of hepatocarcinogenesis: a review.}, journal = {Molecular nutrition &amp; food research}, volume = {54}, number = {7}, pages = {875-896}, doi = {10.1002/mnfr.200900482}, pmid = {20512789}, issn = {1613-4133}, mesh = {Animals ; Antioxidants/*administration &amp; dosage ; Carcinoma, Hepatocellular/epidemiology/prevention &amp; control ; *Diet ; Humans ; Liver Neoplasms/epidemiology/*prevention &amp; control ; Liver Neoplasms, Experimental/prevention &amp; control ; Reproducibility of Results ; }, abstract = {In this review, the role of dietary antioxidants in the prevention of hepatocarcinogenesis is examined. Both human and animal models are discussed. Vitamin C, vitamin E, and selenium are antioxidants that are essential in the human diet. A number of non-essential chemicals also contain antioxidant activity and are consumed in the human diet, mainly as plants or as supplements, including beta-carotene, ellagic acid, curcumin, lycopene, coenzyme Q(10), epigallocatechin gallate, N-acetyl cysteine, and resveratrol. Although some human and animal studies show protection against carcinogenesis with the consumption of higher amounts of antioxidants, many studies show no effect or an enhancement of carcinogenesis. Because of the conflicting results from these studies, it is difficult to make dietary recommendations as to whether consuming higher amounts of specific antioxidants will decrease the risk of developing hepatocellular carcinoma.}, }
@article {pmid20512627, year = {2010}, author = {Kim, BM and Choi, YJ and Lee, YH and Joe, YA and Hong, SH}, title = {N,N-Dimethyl phytosphingosine sensitizes HL-60/MX2, a multidrug-resistant variant of HL-60 cells, to doxorubicin-induced cytotoxicity through ROS-mediated release of cytochrome c and AIF.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {15}, number = {8}, pages = {982-993}, doi = {10.1007/s10495-010-0512-x}, pmid = {20512627}, issn = {1573-675X}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/metabolism ; Antibiotics, Antineoplastic/pharmacology ; Antioxidants/pharmacology ; Apoptosis Inducing Factor/*metabolism ; Caspase Inhibitors ; Caspases/metabolism ; Cell Survival ; Cysteine Proteinase Inhibitors/metabolism ; Cytochromes c/*metabolism ; Doxorubicin/*pharmacology ; Drug Resistance, Multiple/*drug effects ; Enzyme Activation ; Free Radical Scavengers/pharmacology ; HL-60 Cells/*drug effects ; Humans ; Mitochondria/metabolism ; Reactive Oxygen Species/*metabolism ; Sphingosine/*analogs &amp; derivatives/pharmacology ; }, abstract = {Doxorubicin (Dox) is widely used to treat a variety of tumors. However, resistance to this drug is common, making successful treatment more difficult. Previously, we introduced a novel phytosphingosine derivative, N,N-dimethyl phytosphingosine (DMPS), as a potent anticancer therapeutic agent in human leukemia cells. This study was performed to investigate whether DMPS can sensitize HL-60/MX2, a multidrug-resistant variant of HL-60, to Dox-induced apoptosis. Low concentrations of DMPS sensitized HL-60/MX2 cells to Dox-induced apoptosis. Combined Dox + DMPS treatment-induced apoptosis was accompanied by the activation of caspase-8 and caspase-3 as well as PARP cleavage. Cytochrome c and AIF release were also observed in Dox + DMPS-treated HL60/MX2 cells. Pretreatment with z-VAD-fmk markedly prevented caspase-3 activation and moderately suppressed apoptosis, suggesting that Dox + DMPS-induced apoptosis is somewhat (not completely) dependent on caspase. Cytochrome c and AIF release were not affected by pretreatment with z-VAD-fmk. The ROS scavenger NAC efficiently suppressed not only ROS generation, but also caspase-3-mediated PARP cleavage, apoptosis, and release of cytochrome c and AIF, indicating a role of ROS in combined Dox + DMPS treatment-induced apoptotic death signaling. Taken together, these observations suggest that DMPS may be used as a therapeutic agent for overcoming drug-resistance in cancer cells by enhancing drug-induced apoptosis.}, }
@article {pmid20512578, year = {2011}, author = {Basu, HS and Mahlum, A and Mehraein-Ghomi, F and Kegel, SJ and Guo, S and Peters, NR and Wilding, G}, title = {Pretreatment with anti-oxidants sensitizes oxidatively stressed human cancer cells to growth inhibitory effect of suberoylanilide hydroxamic acid (SAHA).}, journal = {Cancer chemotherapy and pharmacology}, volume = {67}, number = {3}, pages = {705-715}, pmid = {20512578}, issn = {1432-0843}, support = {P30 CA014520/CA/NCI NIH HHS/United States ; P30 CA014520-37/CA/NCI NIH HHS/United States ; P30 CA014520-38/CA/NCI NIH HHS/United States ; }, mesh = {Antioxidants/*pharmacology ; Breast Neoplasms/drug therapy/pathology ; Cell Line, Tumor ; Chromatography, Liquid ; Colonic Neoplasms/drug therapy/pathology ; Drug Resistance, Neoplasm ; Drug Synergism ; Female ; Histone Deacetylase Inhibitors/*pharmacology ; Humans ; Hydroxamic Acids/*pharmacology ; Male ; Mass Spectrometry ; Oxidative Stress/*drug effects ; Prostatic Neoplasms/drug therapy/pathology ; Reactive Oxygen Species/metabolism ; Vitamin E/*pharmacology ; Vorinostat ; }, abstract = {PURPOSE: Most prostate, colon and breast cancer cells are resistant to growth inhibitory effects of suberoylanilide hydroxamic acid (SAHA). We have examined whether the high oxidative stress in these cells causes a loss of SAHA activity and if so, whether pretreatment with an anti-oxidant can sensitize these cells to SAHA.<br><br>METHODS: A DNA-Hoechst dye fluorescence measured cell growth and dichlorfluorescein-diacetate (DCF-DA) dye fluorescence measured reactive oxygen species (ROS). Growth inhibitory and ROS-generating activities of SAHA in androgen-treated or untreated LNCaP cells and PC-3 prostate cancer cells, HT-29 and HCT-115 colon cancer cells, MDA-MB231 breast cancer cells and A549 and NCI-H460 lung cancer cells with or without pretreatment with an anti-oxidant Vitamin E was determined. SAHA activity against LNCaP cells treated with another anti-oxidant N-acetyl cysteine (NAC) was also determined. Liquid chromatography-mass spectrometry (LC-MS) was used to determine intracellular SAHA level.<br><br>RESULTS: SAHA treatment markedly inhibits LNCaP cell growth, when the cells are at a low ROS level. SAHA is, however, inactive against the same cell line, when the cells are at a high ROS level. A significant decrease in SAHA level was observed in LNCaP cells with high ROS after 24- and 72-h treatment when compared to cells with low ROS. Vitamin E pretreatment that reduces cellular ROS, synergistically sensitizes oxidatively stressed LNCaP, PC-3, HT-29, HCT-115 and MDA-MB231 cells, but not the A-549 and NCI-H460 cells with low ROS to SAHA. NAC treatment also sensitized androgen-treated LNCaP cells to the growth inhibitory effects of SAHA.<br><br>CONCLUSION: Response to SAHA could be improved by combining anti-oxidants such as Vitamin E with SAHA for the treatment of oxidatively stressed human malignancies that are otherwise resistant to SAHA.}, }
@article {pmid20511679, year = {2010}, author = {Koka, PS and Mondal, D and Schultz, M and Abdel-Mageed, AB and Agrawal, KC}, title = {Studies on molecular mechanisms of growth inhibitory effects of thymoquinone against prostate cancer cells: role of reactive oxygen species.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {235}, number = {6}, pages = {751-760}, doi = {10.1258/ebm.2010.009369}, pmid = {20511679}, issn = {1535-3699}, mesh = {Antineoplastic Agents/*pharmacology ; Benzoquinones/isolation &amp; purification/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival ; Gene Expression Profiling ; Humans ; Inhibitory Concentration 50 ; Male ; Nigella sativa/chemistry ; Prostatic Neoplasms/*prevention &amp; control ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Thymoquinone (TQ), an active ingredient of black seed oil (Nigella Sativa), has been shown to possess antineoplastic activity against a variety of experimental tumors. However, the precise mechanism of action of TQ is not known. We investigated the mechanism of action of TQ in androgen receptor (AR)-independent (C4-2B) and AR naïve (PC-3) prostate cancer cells, as models of aggressive prostate cancers. Exposure (24-48 h) to TQ (25-150 micromol/L) inhibited the growth of both C4-2B and PC-3 cells, with IC(50) values of approximately 50 and 80 micromol/L, respectively. Within one hour, TQ increased reactive oxygen species (ROS) levels (3-fold) and decreased glutathione (GSH) levels (60%) in both cell types. Pretreatment with N-acetylcysteine (NAC) inhibited both TQ-induced ROS generation and growth inhibition. TQ did not increase the activity of caspases and the caspase inhibitor, z-VAD-FMK did not decrease TQ-induced apoptosis. Furthermore, although TQ treatment resulted in the activation of Jun kinase (JNK), pretreatment with the JNK inhibitor, SP600125, did not protect cells from TQ. However, TQ significantly up-regulated the expressions of growth arrest and DNA damage inducible gene (GADD45alpha) and apoptosis-inducing factor-1 and down-regulated the expressions of several Bc12-related proteins, such as BAG-1, Bcl2, Bcl2A1, Bcl2L1 and BID. In C4-2B cells, TQ dose dependently inhibited both total and nuclear AR levels (4-5 fold) and AR-directed transcriptional activity (10-12 fold). Interestingly, this suppressive effect on AR was not prevented by NAC, which clearly suggested that TQ-induced cytotoxicity is not due to changes in AR regulation. These data suggest that TQ-induced cell death is primarily due to increased ROS generation and decreased GSH levels, and is independent of AR activity.}, }
@article {pmid20509295, year = {2010}, author = {Petrescu, BC and Gurzu, B and Iancu, RI and Indrei, A and Dumitriu, I and Chelaru, L and Slătineanu, SM and Petrescu, G and Costuleanu, M}, title = {Apelin effects on lipopolysaccharide-increased pulmonary permeability in rats.}, journal = {Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi}, volume = {114}, number = {1}, pages = {163-169}, pmid = {20509295}, issn = {0048-7848}, mesh = {Acetylcysteine/pharmacology ; Administration, Intranasal ; Animals ; Butyrates/pharmacology ; Capillary Permeability/*drug effects ; Disease Models, Animal ; Endothelium, Vascular/*drug effects ; Injections, Intraperitoneal ; Intercellular Signaling Peptides and Proteins/*pharmacology ; Lipopolysaccharides/*metabolism ; Lung/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {MATERIAL AND METHOD: Pretreatment with apelin-13 (AP-13, 2 mg/kg, i.p.), sodium butyrate (BUT, 200 mg/kg, s.c.) and N-acetyl-L-cysteine (NAC, 150 mg/kg, s.c.), all reduced the LPS-induced vascular leak measured as Evans blue extravasation, in rats lung tissue when compared to intranasal LPS (10 mg/100 mL) administered alone.<br><br>RESULTS: Although there is a significant difference either between AP-13 and BUT on one hand, and NAC and BUT on the other hand pretreatments, there is no significant difference between AP-13 and NAC pretreatments. Firstly, apelin-13 pretreatment might justify its effects through the modulation of endothelial layer functions. We recently demonstrated that AP-13 could diminish the endothelial dysfunction of pulmonary vein from both ovalbumin sensitized rats and rats with pulmonary hypertension. Furthermore, pretreatment with AP-13 + BUT, AP-13+NAC as well as BUT+ NAC reduced the LPS-induced vascular leak when compared to LPS alone. The reduction effects of BUT and NAC association were higher than those of either BUT or NAC alone. These synergistic effects might be associated to different and additive mechanisms of action of BUT and NAC. Thus, BUT might be primarily effective on macrophage migration and secondarily on activation and cytokine secretion by macrophages and NAC might be primarily effective on macrophages activation. Furthermore, since there are no significant effects between AP-13, NAC and AP-13+NAC we can conclude that AP-13 and NAC effects might be mediated through the same mechanisms (with the possible involvement of nuclear transcription factor NF-kB).}, }
@article {pmid20506541, year = {2010}, author = {Crespo, FL and Sobrado, VR and Gomez, L and Cervera, AM and McCreath, KJ}, title = {Mitochondrial reactive oxygen species mediate cardiomyocyte formation from embryonic stem cells in high glucose.}, journal = {Stem cells (Dayton, Ohio)}, volume = {28}, number = {7}, pages = {1132-1142}, doi = {10.1002/stem.441}, pmid = {20506541}, issn = {1549-4918}, mesh = {Animals ; Cell Culture Techniques ; Cell Differentiation/*drug effects ; Embryonic Stem Cells/cytology/drug effects/*metabolism ; Gene Expression Regulation ; Glucose/*pharmacology ; Mice ; Mitochondria/*metabolism ; Myocytes, Cardiac/*cytology/drug effects/*metabolism ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/metabolism ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/genetics/metabolism ; }, abstract = {Accumulating evidence points to reactive oxygen species (ROS) as important signaling molecules for cardiomyocyte differentiation in embryonic stem (ES) cells. Given that ES cells are normally maintained and differentiated in medium containing supraphysiological levels of glucose (25 mM), a condition which is known to result in enhanced cellular ROS formation, we questioned whether this high glucose concentration was necessary for cardiomyocyte lineage potential. We show here that ES cells cultured in physiological glucose (5 mM), maintained their general stemness qualities but displayed an altered mitochondrial metabolism, which resulted in decreased ROS production. Furthermore, ES and induced pluripotent stem (iPS) cells differentiated in lower glucose concentrations failed to generate cardiomyocyte structures; an effect mimicked with antioxidant treatments using catalase, N-acetyl cysteine and mitoubiquinone, under high glucose conditions in ES cells. Molecular analysis revealed that ES cells differentiated in 5 mM glucose had reduced expression of the pro-cardiac NOX4 gene and diminished phosphorylation of p38 mitogen-activated protein kinase (MAPK), together with specific changes in the cardiac transcriptional network. These outcomes could be reversed by supplementation of low glucose cultures with ascorbic acid, paradoxically acting as a pro-oxidant. Furthermore, forced expression of an upstream p38 MAPK kinase (MKK6) could bypass the requirement for ROS during differentiation to cardiomyocytes under low glucose conditions, illustrating a key role for p38 in the cardiac differentiation program. Together these data demonstrate that endogenous ROS control is important for cardiomyocyte formation from ES cells, and furthermore that supraphysiological glucose, by supplying ROS, is absolutely required.}, }
@article {pmid20502036, year = {2010}, author = {Sochman, J and Peregrin, JH and Bürgelová, M and Kopkan, L and Kramer, HJ and Cervenka, L}, title = {N-acetylcysteine attenuates iodine contrast agent-induced nephropathy in 5/6-nephrectomized rats.}, journal = {Kidney &amp; blood pressure research}, volume = {33}, number = {2}, pages = {149-156}, doi = {10.1159/000315435}, pmid = {20502036}, issn = {1423-0143}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Contrast Media/*adverse effects ; Iodine/*adverse effects ; Iohexol/adverse effects ; Iothalamate Meglumine/adverse effects ; Kidney Diseases/*chemically induced/prevention &amp; control ; Nephrectomy ; Premedication/methods ; Rats ; }, abstract = {AIMS: In the present study we tested the efficacy of N-acetylcysteine (NAC) to minimize nephrotoxic effects of iodine contrast agents in intact rats as well as in 5/6-nephrectomized (5/6-Nx) rats.<br><br>METHODS: Rats were allocated to a group of intact rats (n = 42) and a group of 5/6-Nx rats (n = 42). After 1 month of recovery from surgery, 5/6-Nx rats and intact (sham-operated) animals received either 6 ml/kg body weight (b.w.) meglumine ioxithalamate (Telebrix 350) or 6 ml/kg b.w. iohexol (Omnipaque 350) intravenously with or without pretreatment with 100 mg/kg b.w. NAC. Plasma and urinary concentrations of creatinine, sodium and protein in 24-hour urine collections were determined prior to and on days 1, 3 and 7 after drug administration.<br><br>RESULTS: In intact animals, contrast agents caused no significant changes in kidney function throughout the duration of the experiment. In contrast, significant increases in plasma creatinine levels and decreases in creatinine clearance were induced by both contrast agents in 5/6-Nx rats. These changes were significantly attenuated by NAC pretreatment.<br><br>CONCLUSION: The results of the present study demonstrate that iodine contrast agent-induced nephropathy in 5/6-Nx rats is significantly attenuated by intravenous pretreatment with NAC.}, }
@article {pmid20499891, year = {2010}, author = {Das, A and Chakrabarty, S and Choudhury, D and Chakrabarti, G}, title = {1,4-Benzoquinone (PBQ) induced toxicity in lung epithelial cells is mediated by the disruption of the microtubule network and activation of caspase-3.}, journal = {Chemical research in toxicology}, volume = {23}, number = {6}, pages = {1054-1066}, doi = {10.1021/tx1000442}, pmid = {20499891}, issn = {1520-5010}, mesh = {Apoptosis/drug effects ; Benzoquinones/*adverse effects ; Caspase 3/*metabolism ; Cell Line ; Enzyme Activation/drug effects ; Epithelial Cells/cytology/*drug effects/metabolism ; Humans ; Lung/*cytology ; Microtubules/*metabolism ; }, abstract = {Parabenzoquinone (1,4-benzoquinone) (PBQ) is a bioactve quinone present in cigarette smoke and diesel smoke, which causes severe genotoxic effects both in vitro and in vivo. In the previous study, we showed that the microtubules are one of the major targets of cigarette smoke-induced damage of lung epithelium cells. In the present study, we have investigated the effect of PBQ on cellular microtubules using human type II lung epithelial cells (A549) and also on purified tubulin. Cell viability experiments using A549 cells indicated a very low IC(50) value (approximately 7.5 microM) for PBQ. PBQ inhibited cell cycle progression and induced apoptosis of A549 cells. PBQ also induced the contraction and shrinkage of the A549 cells in a time- and concentration-dependent manner, which is proved to be a direct effect of the damage of the microtubule cytoskeleton network, and that was demonstrated by a immunofluorescence study. PBQ also inhibited the assembly of tubulin in lung cells and a in cell free system (IC(50) approximately 5 microM). Treatment with PBQ resulted in the degradation of tubulin in lung cells without affecting the actin network, and this was confirmed by a Western blot experiment. Upregulation of pro-apoptotic proteins such as p53 and Bax and downregulation of antiapoptotic protein Bcl-2 were observed in PBQ-treated A549 cells. Simultaneously, loss of mitochondrial membrane potential and activation of caspase-3 were also observed in the PBQ treated lung epithelium cells. Fluorescence and circular dichroism studies demonstrated that the denaturation of tubulin in a cell free system was caused by PBQ. However, in the presence of N-acetyl cysteine (NAC), damage of the microtubule network in A549 cells by PBQ was prevented, which led to a significant increase in the viability of A549 cells. These results suggest that microtubule damage is one of the key mechanisms of PBQ induced cytotoxity in lung cells.}, }
@article {pmid20489149, year = {2010}, author = {Poncin, S and Colin, IM and Decallonne, B and Clinckspooor, I and Many, MC and Denef, JF and Gérard, AC}, title = {N-acetylcysteine and 15 deoxy-{delta}12,14-prostaglandin J2 exert a protective effect against autoimmune thyroid destruction in vivo but not against interleukin-1{alpha}/interferon {gamma}-induced inhibitory effects in thyrocytes in vitro.}, journal = {The American journal of pathology}, volume = {177}, number = {1}, pages = {219-228}, pmid = {20489149}, issn = {1525-2191}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cells, Cultured ; Female ; Humans ; Immunologic Factors/*pharmacology ; Interferon-gamma/*pharmacology ; Interleukin-1alpha/*pharmacology ; Mice ; Mice, Inbred NOD ; Peroxiredoxins/metabolism ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Recombinant Proteins ; Thyroid Gland/*cytology/immunology/*pathology ; Thyroiditis, Autoimmune/*immunology/*pathology ; }, abstract = {Reactive oxygen species (ROS) are crucial for thyroid hormonogenesis, and their production is kept under tight control. Oxidative stress (OS) is toxic for thyrocytes in an inflammatory context. In vitro, Th1 pro-inflammatory cytokines have already been shown to decrease thyroid-specific protein expression. In the present study, OS level and its impact on thyroid function were analyzed in vitro in Th1 cytokine (interleukin [IL]-1alpha/interferon [IFN] gamma)-incubated thyrocytes (rat and human), as well as in vivo in thyroids from nonobese diabetic mice, a model of spontaneous autoimmune thyroiditis. N-acetylcysteine (NAC) and prostaglandin, 15 deoxy-(Delta12,14)-prostaglandinJ2 (15dPGJ2), were used for their antioxidant and anti-inflammatory properties, respectively. ROS production and OS were increased in IL-1alpha/IFNgamma-incubated thyrocytes and in destructive thyroiditis. In vitro, NAC not only reduced ROS production below control levels, but further decreased the expression of thyroid-specific proteins in addition to IL-1alpha/IFNgamma-inhibitory effects. Thus, besides ROS, other intracellular intermediaries likely mediate Th1 cytokine effects. In vivo, NAC and 15dPGJ2 reduced OS and the immune infiltration, thereby leading to a restoration of thyroid morphology. It is therefore likely that NAC and 15dPGJ2 mainly exert their protective effects by acting on infiltrating inflammatory cells rather than directly on thyrocytes.}, }
@article {pmid20489144, year = {2010}, author = {Lei, H and Velez, G and Cui, J and Samad, A and Maberley, D and Matsubara, J and Kazlauskas, A}, title = {N-acetylcysteine suppresses retinal detachment in an experimental model of proliferative vitreoretinopathy.}, journal = {The American journal of pathology}, volume = {177}, number = {1}, pages = {132-140}, pmid = {20489144}, issn = {1525-2191}, support = {K08 EY017383/EY/NEI NIH HHS/United States ; R01 EY012509/EY/NEI NIH HHS/United States ; EY012509/EY/NEI NIH HHS/United States ; /CAPMC/CIHR/Canada ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*therapeutic use ; Cell Proliferation ; Cells, Cultured ; *Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Humans ; Rabbits ; Reactive Oxygen Species/metabolism ; Retinal Detachment/complications/*prevention &amp; control/surgery ; Retinal Pigment Epithelium/cytology ; Vitreoretinopathy, Proliferative/*drug therapy/etiology/pathology ; Vitreous Body/metabolism ; }, abstract = {Proliferative vitreoretinopathy (PVR) is a complication that develops in 5% to 10% of patients who undergo surgery to correct a detached retina. The only treatment option for PVR is surgical intervention, which has a limited success rate that diminishes in patients with recurring PVR. Our recent studies revealed that antioxidants prevented intracellular signaling events that were essential for experimental PVR. The purpose of this study was to test whether N-acetyl-cysteine (NAC), an antioxidant used in a variety of clinical settings, was capable of protecting rabbits from PVR. Vitreous-driven activation of PDGFRalpha and cellular responses intrinsic to PVR (contraction of collagen gels and cell proliferation) were blocked by concentrations of NAC that were well below the maximum tolerated dose. Furthermore, intravitreal injection of NAC effectively protected rabbits from developing retinal detachment, which is the sight-robbing phase of PVR. Finally, these observations with an animal model appear relevant to clinical PVR because NAC prevented human PVR vitreous-induced contraction of primary RPE cells derived from a human PVR membrane. Our observations demonstrate that antioxidants significantly inhibited experimental PVR, and suggest that antioxidants have the potential to function as a PVR prophylactic in patients undergoing retinal surgery to repair a detached retina.}, }
@article {pmid20488618, year = {2010}, author = {Deng, X and Xia, Y and Hu, W and Zhang, H and Shen, Z}, title = {Cadmium-induced oxidative damage and protective effects of N-acetyl-L-cysteine against cadmium toxicity in Solanum nigrum L.}, journal = {Journal of hazardous materials}, volume = {180}, number = {1-3}, pages = {722-729}, doi = {10.1016/j.jhazmat.2010.04.099}, pmid = {20488618}, issn = {1873-3336}, mesh = {Acetylcysteine/*pharmacology ; Cadmium/*toxicity ; Enzymes/metabolism ; Lipid Peroxidation ; Oxidative Stress/*drug effects ; Solanum nigrum/*drug effects/enzymology/growth &amp; development/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The effects of cadmium (Cd) on the accumulation of hydrogen peroxide (H(2)O(2)) and antioxidant enzyme activities in roots of Solanum nigrum L. and the role of N-acetyl-l-cysteine (NAC) as a cysteine (Cys) donor against Cd toxicity were investigated. Cd at 50 and 200 microM significantly increased the contents of thiobarbituric acid-reactive substances (TBARS), the production of H(2)O(2) and superoxide anion (O(2)(-)), and the activities of catalase, guaiacol peroxidase, ascorbate peroxidase, glutathione peroxidase (GSH-Px), glutathione reductase, and superoxide dismutase. Experiments with diphenylene iodonium as an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and NaN(3) as an inhibitor of peroxidase showed that the major source of Cd-induced reactive oxygen species in the roots may include plasma membrane-bound NADPH oxidase and peroxidase. In addition, the effects of NAC on plant growth, antioxidant enzyme activity, and non-protein thiol content were analyzed. Under Cd stress, the addition of 500 microM NAC decreased the contents of TBARS and production of H(2)O(2) and O(2)(-), but increased levels of Cys and reduced glutathione (GSH), phytochelatins, and activity of GSH-Px in roots. These results suggest that NAC could protect plants from oxidative stress damage, and this protection seems to be performed via increased GSH biosynthesis. Furthermore, NAC treatment also increased the contents of protein thiols in S. nigrum roots. By using size-exclusion chromatography, we found involvement of NAC in the Cd tolerance mechanism through increased biosynthesis of Cd-binding proteins.}, }
@article {pmid20485382, year = {2010}, author = {Becker, PS and Taylor, JA and Trobridge, GD and Zhao, X and Beard, BC and Chien, S and Adair, J and Kohn, DB and Wagner, JE and Shimamura, A and Kiem, HP}, title = {Preclinical correction of human Fanconi anemia complementation group A bone marrow cells using a safety-modified lentiviral vector.}, journal = {Gene therapy}, volume = {17}, number = {10}, pages = {1244-1252}, pmid = {20485382}, issn = {1476-5462}, support = {P30 DK047754/DK/NIDDK NIH HHS/United States ; P30 DK047754-159004/DK/NIDDK NIH HHS/United States ; R01 HL085693-04/HL/NHLBI NIH HHS/United States ; P30 DK047754-15/DK/NIDDK NIH HHS/United States ; P30 DK056465/DK/NIDDK NIH HHS/United States ; DK56465/DK/NIDDK NIH HHS/United States ; P30 DK056465-11/DK/NIDDK NIH HHS/United States ; DK47754/DK/NIDDK NIH HHS/United States ; R01 HL085693/HL/NHLBI NIH HHS/United States ; HL085693/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Bone Marrow Cells/cytology/metabolism ; Fanconi Anemia/pathology/*therapy ; Fanconi Anemia Complementation Group A Protein/*genetics ; Genetic Therapy/*methods ; Genetic Vectors/administration &amp; dosage/genetics ; Hematopoietic Stem Cells/cytology/metabolism ; Humans ; Lentivirus/*genetics ; Mitomycin/pharmacology ; Transduction, Genetic ; }, abstract = {One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (P<0.03), showed increased resistance to mitomycin C compared with green fluorescent protein (GFP) vector-transduced controls (P<0.007), and increased survival. Thus, combining short transduction and reducing oxidative stress may enhance the viability and engraftment of gene-corrected cells in patients with FANCA.}, }
@article {pmid20479865, year = {2010}, author = {Majumder, S and Ilayaraja, M and Seerapu, HR and Sinha, S and Siamwala, JH and Chatterjee, S}, title = {Chick embryo partial ischemia model: a new approach to study ischemia ex vivo.}, journal = {PloS one}, volume = {5}, number = {5}, pages = {e10524}, pmid = {20479865}, issn = {1932-6203}, mesh = {Acetanilides/pharmacology ; Animals ; Apoptosis/drug effects ; Blood Vessels/drug effects/metabolism/pathology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chick Embryo ; Creatine Kinase, MB Form/metabolism ; *Disease Models, Animal ; Edema/complications/pathology ; Endothelial Cells/drug effects/metabolism/pathology ; Glutathione/metabolism ; Goats ; Health ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Ischemia/*pathology ; Myocardium/enzymology/pathology ; Neovascularization, Pathologic/metabolism ; Organ Specificity/drug effects ; Piperazines/pharmacology ; Ranolazine ; Reactive Oxygen Species/metabolism ; Time Factors ; Vascular Surgical Procedures/*methods ; }, abstract = {BACKGROUND: Ischemia is a pathophysiological condition due to blockade in blood supply to a specific tissue thus damaging the physiological activity of the tissue. Different in vivo models are presently available to study ischemia in heart and other tissues. However, no ex vivo ischemia model has been available to date for routine ischemia research and for faster screening of anti-ischemia drugs. In the present study, we took the opportunity to develop an ex vivo model of partial ischemia using the vascular bed of 4(th) day incubated chick embryo.<br><br>Ischemia was created in chick embryo by ligating the right vitelline artery using sterile surgical suture. Hypoxia inducible factor- 1 alpha (HIF-1alpha), creatine phospho kinase-MB and reactive oxygen species in animal tissues and cells were measured to confirm ischemia in chick embryo. Additionally, ranolazine, N-acetyl cysteine and trimetazidine were administered as an anti-ischemic drug to validate the present model. Results from the present study depicted that blocking blood flow elevates HIF-1alpha, lipid peroxidation, peroxynitrite level in ischemic vessels while ranolazine administration partially attenuates ischemia driven HIF-1alpha expression. Endothelial cell incubated on ischemic blood vessels elucidated a higher level of HIF-1alpha expression with time while ranolazine treatment reduced HIF-1alpha in ischemic cells. Incubation of caprine heart strip on chick embryo ischemia model depicted an elevated creatine phospho kinase-MB activity under ischemic condition while histology of the treated heart sections evoked edema and disruption of myofibril structures.<br><br>CONCLUSIONS/SIGNIFICANCE: The present study concluded that chick embryo partial ischemia model can be used as a novel ex vivo model of ischemia. Therefore, the present model can be used parallel with the known in vivo ischemia models in understanding the mechanistic insight of ischemia development and in evaluating the activity of anti-ischemic drug.}, }
@article {pmid20471444, year = {2011}, author = {Maes, M and Galecki, P and Chang, YS and Berk, M}, title = {A review on the oxidative and nitrosative stress (O&amp;NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {35}, number = {3}, pages = {676-692}, doi = {10.1016/j.pnpbp.2010.05.004}, pmid = {20471444}, issn = {1878-4216}, mesh = {Autoimmunity ; Depressive Disorder, Major/genetics/*metabolism/pathology ; Female ; Humans ; Male ; Neurodegenerative Diseases/genetics/*metabolism/physiopathology ; Nitrosation/*physiology ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {This paper reviews the body of evidence that major depression is accompanied by a decreased antioxidant status and by induction of oxidative and nitrosative (IO&amp;NS) pathways. Major depression is characterized by significantly lower plasma concentrations of a number of key antioxidants, such as vitamin E, zinc and coenzyme Q10, and a lowered total antioxidant status. Lowered antioxidant enzyme activity, e.g. glutathione peroxidase (GPX), is another hallmark of depression. The abovementioned lowered antioxidant capacity may impair protection against reactive oxygen species (ROS), causing damage to fatty acids, proteins and DNA by oxidative and nitrosative stress (O&amp;NS). Increased ROS in depression is demonstrated by increased levels of plasma peroxides and xanthine oxidase. Damage caused by O&amp;NS is shown by increased levels of malondialdehyde (MDA), a by-product of polyunsaturated fatty acid peroxidation and arachidonic acid; and increased 8-hydroxy-2-deoxyguanosine, indicating oxidative DNA damage. There is also evidence in major depression, that O&amp;NS may have changed inactive autoepitopes to neoantigens, which have acquired immunogenicity and serve as triggers to bypass immunological tolerance, causing (auto)immune responses. Thus, depression is accompanied by increased levels of plasma IgG antibodies against oxidized LDL; and increased IgM-mediated immune responses against membrane fatty acids, like phosphatidyl inositol (Pi); oleic, palmitic, and myristic acid; and NO modified amino-acids, e.g. NO-tyrosine, NO-tryptophan and NO-arginine; and NO-albumin. There is a significant association between depression and polymorphisms in O&amp;NS genes, like manganese superoxide dismutase, catalase, and myeloperoxidase. Animal models of depression very consistently show lowered antioxidant defences and activated O&amp;NS pathways in the peripheral blood and the brain. In animal models of depression, antidepressants consistently increase lowered antioxidant levels and normalize the damage caused by O&amp;NS processes. Antioxidants, such as N-acetyl-cysteine, compounds that mimic GPX activity, and zinc exhibit antidepressive effects. This paper reviews the pathways by which lowered antioxidants and O&amp;NS may contribute to depression, and the (neuro)degenerative processes that accompany that illness. It is concluded that aberrations in O&amp;NS pathways are--together with the inflammatory processes--key components of depression. All in all, the results suggest that depression belongs to the spectrum of (neuro)degenerative disorders.}, }
@article {pmid20470667, year = {2010}, author = {Saliba, I and El Fata, F and Ouelette, V and Robitaille, Y}, title = {Are intratympanic injections of N-acetylcysteine and methylprednisolone protective against Cisplatin-induced ototoxicity?.}, journal = {Journal of otolaryngology - head &amp; neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale}, volume = {39}, number = {3}, pages = {236-243}, pmid = {20470667}, issn = {1916-0216}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage/*pharmacology/*therapeutic use ; Antineoplastic Agents/*adverse effects ; Antiviral Agents/administration &amp; dosage/*pharmacology/*therapeutic use ; Cisplatin/*adverse effects ; Disease Models, Animal ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Guinea Pigs ; Hearing Disorders/*chemically induced/diagnosis/*prevention &amp; control ; Injections ; Methylprednisolone/administration &amp; dosage/*pharmacology/*therapeutic use ; Severity of Illness Index ; Treatment Outcome ; Tympanic Membrane/*drug effects ; }, abstract = {OBJECTIVE: To identify and to compare the protective effect of intratympanic injections of N-acetylcysteine (NAC) or methylprednisolone to prevent cisplatin-induced ototoxicity, to investigate inner ear protection using an electron microscope and to evaluate the effect of 4% NAC on the middle ear.<br><br>DESIGN: Experimental study.<br><br>SETTING: Basic ear research center at Sainte-Justine hospital.<br><br>METHODS: Ten Hartley guinea pigs were divided into two groups, according to the product used intratympanically (4% NAC or 62.5 mg/mL methylprednisolone) in one ear. The other ear was left as control. Cisplatin was administered intraperitoneally (3 mg/kg), once a week for 5 weeks.<br><br>MAIN OUTCOME MEASURES: Auditory evoked brainstem responses were used to test hearing. The inner ear was screened using an electron microscope.<br><br>RESULTS: Significant threshold shift was seen on all tested frequencies of both groups. This difference is clinically and statistically significant in the methylprednisolone group. The NAC-treated group had a lower threshold shift than the methylprednisolone group in both ears. Electron microscope studies showed in all untreated-NAC ears severe lesion of the inner and outer hair cells with complete degeneration of steriocilia, whereas in NAC-treated ears we noted a nuclear and cytoplasmic membrane preservation with some preservation of steriocila. Also, 4% intratympanic NAC produces an external auditory canal and middle ear inflammatory reaction.<br><br>CONCLUSIONS: Intratympanic injections of methylprednisolone failed to demonstrate efficacy in protecting cisplatin ototoxicity whereas 4% NAC showed a partial protection. The safety of intratympanic injections should be investigated in further studies, as possible systemic shift of the locally administered treatment is suspected.}, }
@article {pmid20465721, year = {2010}, author = {Mautone, A and Brown, JR}, title = {Contrast-induced nephropathy in patients undergoing elective and urgent procedures.}, journal = {Journal of interventional cardiology}, volume = {23}, number = {1}, pages = {78-85}, doi = {10.1111/j.1540-8183.2009.00523.x}, pmid = {20465721}, issn = {1540-8183}, support = {K01 HS018443/HS/AHRQ HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Acute Disease ; Acute Kidney Injury/*chemically induced ; Adenosine/antagonists &amp; inhibitors ; Ascorbic Acid/therapeutic use ; Contrast Media/*adverse effects ; *Elective Surgical Procedures ; *Emergency Treatment ; Free Radical Scavengers/therapeutic use ; General Surgery ; Glomerular Filtration Rate ; Humans ; Hydrotherapy ; *Preoperative Care ; Renal Dialysis ; Risk Assessment ; Sodium Bicarbonate/therapeutic use ; }, abstract = {Contrast-induced nephropathy (CIN) is an acute and severe complication after contrast media administration. The most important step in preventing CIN is identifying high-risk patients. In this review, we evaluate and summarize the evidence regarding the CIN prophylaxis, including the withdrawal of the potentially nephrotoxic drugs, hydration by isotonic solution or NaHCO(3), pharmaceutical treatment with N-acetylcysteine (N-AC), adenosine antagonists, ascorbic acid, renal procedures including hemofiltration or dialysis, and to the optimal use of the contrast. We suggest it is possible to reduce the burden of CIN by carefully incorporating these recommendations. After review of published literature in this field, we conclude that the cornerstone of the CIN prevention should be combination of hydration (normal saline or NaHCO(3)) and the use of N-AC.}, }
@article {pmid20465405, year = {2010}, author = {Liang, Q and Sheng, Y and Ji, L and Min, Y and Xia, Y and Wang, Z}, title = {Acetaminophen-induced cytotoxicity on human normal liver L-02 cells and the protection of antioxidants.}, journal = {Toxicology mechanisms and methods}, volume = {20}, number = {5}, pages = {273-278}, doi = {10.3109/15376516.2010.482963}, pmid = {20465405}, issn = {1537-6524}, mesh = {Acetaminophen/*toxicity ; Analgesics, Non-Narcotic/*toxicity ; Antioxidants/*metabolism ; Buthionine Sulfoximine/toxicity ; Cell Line ; Cytochrome P-450 CYP2E1/*metabolism ; Humans ; Liver/*drug effects/enzymology ; Oxidative Stress/drug effects ; }, abstract = {In vitro cell models, which can partially mimic in vivo responses, offer potentially sensitive tools for toxicological assessment. The objective of this study was to explore the possible mechanisms of acetaminophen (AP)-induced toxicity in human normal liver L-02 cells. The expression of the CYP2E1 enzyme, which is reported to transform AP to its toxic metabolites, was higher in L-02 than in Hep3B cells. Further cell viability and reduced glutathione (GSH) depletion after AP treatment were examined. After exposure to AP for 24 h, cell viability decreased in a concentration-dependent manner. Concentration-dependent GSH depletion was also observed after AP treatment for 48 h, indicating oxidative stress had occurred in L-02 cells. The effects of D, L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH biosynthesis, and N-acetylcysteine (NAC), a precursor of GSH synthesis, on the cytotoxicity induced by AP were also investigated. BSO aggravated the cytotoxicity induced by AP while NAC ameliorated such cell death. Further results showed that 10 mM AP caused cell apoptosis after 48 h treatment based on the DNA fragmentation assay and western blot of caspase-3 activation, respectively. In addition, the protective effects of various well-known antioxidants against AP-induced hepatotoxicity were observed. Taken together, these results indicate that oxidative stress and cellular apoptosis are involved in AP-induced toxicity in human normal liver L-02 cells, and this cell line is a suitable in vitro cell model for AP hepatotoxicity study.}, }
@article {pmid20463052, year = {2010}, author = {Zhao, Z and Zhang, X and Zhao, C and Choi, J and Shi, J and Song, K and Turk, J and Ma, ZA}, title = {Protection of pancreatic beta-cells by group VIA phospholipase A(2)-mediated repair of mitochondrial membrane peroxidation.}, journal = {Endocrinology}, volume = {151}, number = {7}, pages = {3038-3048}, pmid = {20463052}, issn = {1945-7170}, support = {R21 DK074805-01A2/DK/NIDDK NIH HHS/United States ; DK074805/DK/NIDDK NIH HHS/United States ; R21 DK074805/DK/NIDDK NIH HHS/United States ; R01 NS063962/NS/NINDS NIH HHS/United States ; R37DK034388/DK/NIDDK NIH HHS/United States ; R21 DK074805-02/DK/NIDDK NIH HHS/United States ; R01 NS063962-01A1/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis ; Blotting, Western ; Cardiolipins/metabolism ; Caspase 3/metabolism ; Cells, Cultured ; Cytochromes c/metabolism ; Glucose/pharmacology ; Glucose Tolerance Test ; Group VI Phospholipases A2/genetics/*metabolism ; Immunohistochemistry ; Insulin/metabolism ; Insulin-Secreting Cells/drug effects/*metabolism ; Islets of Langerhans/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Knockout ; Mitochondrial Membranes/drug effects/*metabolism ; Palmitic Acid/pharmacology ; Phospholipids/metabolism ; Random Allocation ; Staurosporine/pharmacology ; }, abstract = {Mitochondrial production of reactive oxygen species and oxidation of cardiolipin are key events in initiating apoptosis. We reported that group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)beta) localizes in and protects beta-cell mitochondria from oxidative damage during staurosporine-induced apoptosis. Here, we used iPLA(2)beta-null (iPLA(2)beta(-/-)) mice to investigate the role of iPLA(2)beta in the repair of mitochondrial membranes. We show that islets isolated from iPLA(2)beta(-/-) mice are more sensitive to staurosporine-induced apoptosis than those from wild-type littermates and that 2 wk of daily ip administration of staurosporine to iPLA(2)beta(-/-) mice impairs both the animals' glucose tolerance and glucose-stimulated insulin secretion by their pancreatic islets. Moreover, the iPLA(2)beta inhibitor bromoenol lactone caused mitochondrial membrane peroxidation and cytochrome c release, and these effects were reversed by N-acetyl cysteine. The mitochondrial antioxidant N-t-butyl hydroxylamine blocked staurosporine-induced cytochrome c release and caspase-3 activation in iPLA(2)beta(-/-) islets. Furthermore, the collapse of mitochondrial membrane potential in INS-1 insulinoma cells caused by high glucose and fatty acid levels was attenuated by overexpressing iPLA(2)beta. Interestingly, iPLA(2)beta was expressed only at low levels in islet beta-cells from obesity- and diabetes-prone db/db mice. These findings support the hypothesis that iPLA(2)beta is important in repairing oxidized mitochondrial membrane components (e.g. cardiolipin) and that this prevents cytochrome c release in response to stimuli that otherwise induce apoptosis. The low iPLA(2)beta expression level in db/db mouse beta-cells may render them vulnerable to injury by reactive oxygen species.}, }
@article {pmid20462423, year = {2010}, author = {Zhao, T and Liu, Y}, title = {N-acetylcysteine inhibit biofilms produced by Pseudomonas aeruginosa.}, journal = {BMC microbiology}, volume = {10}, number = {}, pages = {140}, pmid = {20462423}, issn = {1471-2180}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects/*growth &amp; development ; Biomass ; Ciprofloxacin/pharmacology ; Colony Count, Microbial ; Drug Interactions ; Humans ; Microbial Sensitivity Tests ; Microbial Viability ; Pseudomonas aeruginosa/*drug effects/growth &amp; development/*physiology ; }, abstract = {BACKGROUND: Pseudomonas aeruginosa is a common pathogen in chronic respiratory tract infections. It typically makes a biofilm, which makes treatment of these infections difficult. In this study, we investigated the inhibitory effects of N-acetylcysteine (NAC) on biofilms produced by P. aeruginosa.<br><br>RESULTS: We found that minimum inhibitory concentrations (MICs) of NAC for most isolates of P. aeruginosa were 10 to 40 mg/ml, the combination of NAC and ciprofloxacin (CIP) demonstrated either synergy (50%) or no interaction (50%) against the P. aeruginosa strains. NAC at 0.5 mg/ml could detach mature P. aeruginosa biofilms. Disruption was proportional to NAC concentrations, and biofilms were completely disrupted at 10 mg/ml NAC. Analysis using COMSTAT software also showed that PAO1 biofilm biomass decreased and its heterogeneity increased as NAC concentration increased. NAC and ciprofloxacin showed significant killing of P. aeruginosa in biofilms at 2.5 mg/ml and > 2 MIC, respectively (p < 0.01). NAC-ciprofloxacin combinations consistently decreased viable biofilm-associated bacteria relative to the control; this combination was synergistic at NAC of 0.5 mg/ml and CIP at 1/2MIC (p < 0.01). Extracellular polysaccharides (EPS) production by P. aeruginosa also decreased by 27.64% and 44.59% at NAC concentrations of 0.5 mg/ml and 1 mg/ml.<br><br>CONCLUSIONS: NAC has anti-bacterial properties against P. aeruginosa and may detach P. aeruginosa biofilms. Use of NAC may be a new strategy for the treatment of biofilm-associated chronic respiratory infections due to P. aeruginosa, although it would be appropriate to conduct clinical studies to confirm this.}, }
@article {pmid20461008, year = {2010}, author = {Baniasadi, S and Eftekhari, P and Tabarsi, P and Fahimi, F and Raoufy, MR and Masjedi, MR and Velayati, AA}, title = {Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity.}, journal = {European journal of gastroenterology &amp; hepatology}, volume = {22}, number = {10}, pages = {1235-1238}, doi = {10.1097/MEG.0b013e32833aa11b}, pmid = {20461008}, issn = {1473-5687}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Aged, 80 and over ; Antitubercular Agents/*adverse effects ; Chemical and Drug Induced Liver Injury/etiology/*prevention &amp; control ; Drug Interactions ; Drug Therapy, Combination ; Ethambutol/adverse effects ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Isoniazid/*adverse effects ; Liver/drug effects ; Male ; Pyrazinamide/adverse effects ; Rifampin/adverse effects ; Tuberculosis, Pulmonary/*drug therapy ; }, abstract = {INTRODUCTION: Isoniazid, rifampicin, and pyrazinamide, the first-line antituberculosis (anti-TB) drugs, are associated with hepatotoxicity.<br><br>AIMS AND OBJECTIVES: To study the hepatoprotective effect of N-acetylcysteine (NAC) on liver injury induced by anti-TB drugs.<br><br>METHODS: A randomized clinical trial was conducted on 60 new TB patients who were aged 60 years or more. Patients were randomized into two groups. In group I (n=32), drug regimen included daily doses of isoniazid, rifampicin, pyrazinamide, and ethambutol. Patients in group II (n=28) were treated with the same regimen and NAC. The patients were followed up for 2 weeks. Liver enzymes and bilirubins were measured at baseline, after 1 and 2 weeks of treatment, and whenever the patients presented with clinical symptoms of hepatotoxicity.<br><br>RESULTS: The mean+/-SD values of aspartate aminotransferase and alanine aminotransferase were significantly higher in group I than in group II after 1 and 2 weeks of treatment. Hepatotoxicity occurred in 12 patients with (37.5%) group I and none in group II. The mean duration of treatment before the onset of hepatotoxicity was 4.67+/-4.58 days.<br><br>CONCLUSION: NAC protects against anti-TB drug-induced hepatotoxicity.}, }
@article {pmid20460760, year = {2010}, author = {Chang, IC and Huang, YJ and Chiang, TI and Yeh, CW and Hsu, LS}, title = {Shikonin induces apoptosis through reactive oxygen species/extracellular signal-regulated kinase pathway in osteosarcoma cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {33}, number = {5}, pages = {816-824}, doi = {10.1248/bpb.33.816}, pmid = {20460760}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Bone Neoplasms/*drug therapy/metabolism ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal/pharmacology/therapeutic use ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Inhibitory Concentration 50 ; Naphthoquinones/*pharmacology/therapeutic use ; Osteosarcoma/*drug therapy/metabolism ; Phosphorylation ; Phytotherapy ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Shikonin, a major ingredient in the Chinese traditional herb Lithospermum erythrorhixon, exhibits multiple biological functions including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we delineated the molecular mechanisms of shikonin in the apoptosis of 143B osteosarcoma cells. Shikonin reduced the cell viability of 143B cells in a dose- and time-dependent manner. The IC(50) at 24 h and 48 h for 143B cells was 4.55 and 2.01microM, respectively. A significantly elicited hypodiploid cell population was found in cells treated with 2, 4, and 8microM shikonin for 24 h. Moreover, treatment with shikonin induced reactive oxygen species (ROS) generation, increased extracellular signal-regulated kinase (ERK) phosphorylation, decreased B-cell lymphoma-2 (Bcl2) expression, and was accompanied by poly(ADP-ribose) polymerase (PARP) cleavage. Pretreatment with the antioxidant agent N-acetyl cysteine (NAC) not only reversed shikonin-induced ROS generation but also significantly attenuated the cytotoxic effects of shikonin in 143B cells. Furthermore, NAC attenuated shikonin-induced ERK phosphorylation. Taken together, our results reveal that shikonin increased ROS generation and ERK activation, and reduced Bcl2, which consequently caused the cells to undergo apoptosis. Therefore, shikonin may be a promising chemotherapeutic agent for osteosarcoma treatment.}, }
@article {pmid20457211, year = {2010}, author = {Migdal, C and Foggia, L and Tailhardat, M and Courtellemont, P and Haftek, M and Serres, M}, title = {Sensitization effect of thimerosal is mediated in vitro via reactive oxygen species and calcium signaling.}, journal = {Toxicology}, volume = {274}, number = {1-3}, pages = {1-9}, doi = {10.1016/j.tox.2010.04.016}, pmid = {20457211}, issn = {1879-3185}, mesh = {Acetylcysteine/metabolism ; Antioxidants/metabolism/pharmacology ; B7-2 Antigen/metabolism ; Calcium/metabolism/pharmacology ; Calcium Signaling/drug effects ; Cysteine/metabolism/pharmacology ; Dendritic Cells/drug effects/metabolism ; Dinitrobenzenes ; Dinitrochlorobenzene/metabolism/pharmacology ; Europe ; Glutathione/metabolism/pharmacology ; Humans ; Lipid Peroxidation/drug effects ; Mitochondria/drug effects/metabolism/physiology ; Monocytes/metabolism ; Oxidative Stress/drug effects ; Preservatives, Pharmaceutical/metabolism/pharmacology ; Reactive Oxygen Species/*metabolism/pharmacology ; Salicylates ; Sulfhydryl Compounds/metabolism/pharmacology ; Thimerosal/metabolism/*pharmacology ; Vitamin E/metabolism/pharmacology ; }, abstract = {Thimerosal, a mercury derivative composed of ethyl mercury chloride (EtHgCl) and thiosalicylic acid (TSA), is widely used as a preservative in vaccines and cosmetic products and causes cutaneous reactions. Since dendritic cells (DCs) play an essential role in the immune response, the sensitization potency of chemicals was studied in vitro using U937, a human promyelomonocytic cell line that is used as a surrogate of monocytic differentiation and activation. Currently, this cell line is under ECVAM (European Center for the Validation of Alternative Methods) validation as an alternative method for discriminating chemicals. Thimerosal and mercury derivatives induced in U937 an overexpression of CD86 and interleukin (IL)-8 secretion similarly to 1-chloro-2,4-dinitrobenzene (DNCB), a sensitizer used as a positive control for DC activation. Non-sensitizers, dichloronitrobenzene (DCNB), TSA and sodium dodecyl sulfate (SDS), an irritant, had no effect. U937 activation was prevented by cell pretreatment with N-acetyl-L-cysteine (NAC) but not with thiol-independent antioxidants except vitamin E which affected CD86 expression by preventing lipid peroxidation of cell membranes. Thimerosal, EtHgCl and DNCB induced glutathione (GSH) depletion and reactive oxygen species (ROS) within 15 min; another peak was detected after 2h for mercury compounds only. MitoSOX, a specific mitochondrial fluorescent probe, confirmed that ROS were essentially produced by mitochondria in correlation with its membrane depolarization. Changes in mitochondrial membrane permeability induced by mercury were reversed by NAC but not by thiol-independent antioxidants. Thimerosal and EtHgCl also induced a calcium (Ca2+) influx with a peak at 3h, suggesting that Ca2+ influx is a secondary event following ROS induction as Ca2+ influx was suppressed after pretreatment with NAC but not with thiol-independent antioxidants. Ca2+ influx was also suppressed when culture medium was deprived of Ca2+ confirming the specificity of the measure. In conclusion, these data suggest that thimerosal induced U937 activation via oxidative stress from mitochondrial stores and mitochondrial membrane depolarization with a primordial effect of thiol groups. A cross-talk between ROS and Ca2+ influx was demonstrated.}, }
@article {pmid20452867, year = {2010}, author = {Güney, O and Erdi, F and Esen, H and Kiyici, A and Kocaogullar, Y}, title = {N-acetylcysteine prevents vasospasm after subarachnoid hemorrhage.}, journal = {World neurosurgery}, volume = {73}, number = {1}, pages = {42-9; discussion e3}, doi = {10.1016/j.surneu.2009.06.003}, pmid = {20452867}, issn = {1878-8769}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Basilar Artery/pathology ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation ; Male ; Malondialdehyde/metabolism ; Rabbits ; Subarachnoid Hemorrhage/*complications/enzymology/therapy ; Superoxide Dismutase/metabolism ; Vasospasm, Intracranial/etiology/pathology/*prevention &amp; control ; }, abstract = {BACKGROUND: This study investigated the ability of NAC to prevent cerebral vasospasm in a rabbit model of SAH.<br><br>METHODS: Twenty-one, male New Zealand white rabbits were randomly divided into 3 groups of 7 rabbits each: group 1 (control), group 2 (SAH only), group 3 (SAH + NAC treatment). NAC (150 mg/kg, single dose, IP) was administered just before SAH and continued until 72 hours after SAH in group 3. Animals were killed 72 hours after SAH. Tissue MDA levels, SOD, and GSH-Px activities were measured, and basilar artery cross-sectional areas, arterial wall thickness, and endothelial apoptosis in a cross section of basillary artery were determined in all groups.<br><br>RESULTS: Intraperitoneal administration of NAC was found to be markedly effective against developing a cerebral vasospasm following a SAH in rabbits. It could significantly reduce elevated lipid peroxidation and increase the level of tissue GSH-Px and SOD enzymatic activities. Also, NAC treatment was found to be effective in increasing the luminal area and reducing wall thickness of the basilar artery. The morphology of arteries in the NAC treatment group was well protected. NAC markedly reduced apoptotic index and protects the endothelial integrity.<br><br>CONCLUSIONS: This study demonstrates, for the first time, that NAC treatment attenuates cerebral vasospasm in a rabbit SAH model. NAC treatment has significant neuroprotective effect and markedly prevents cerebral vasospasm after SAH. In conclusion, the NAC treatment might be beneficial in preventing cerebral vasospasm after SAH, thus showing potential for clinical implications.}, }
@article {pmid20448054, year = {2011}, author = {Filosto, S and Castillo, S and Danielson, A and Franzi, L and Khan, E and Kenyon, N and Last, J and Pinkerton, K and Tuder, R and Goldkorn, T}, title = {Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury.}, journal = {American journal of respiratory cell and molecular biology}, volume = {44}, number = {3}, pages = {350-360}, pmid = {20448054}, issn = {1535-4989}, support = {UL1RR024146/RR/NCRR NIH HHS/United States ; R01 ES016285/ES/NIEHS NIH HHS/United States ; K08 HL-076415/HL/NHLBI NIH HHS/United States ; HL-71871/HL/NHLBI NIH HHS/United States ; HL-66189/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; *Disease Models, Animal ; Female ; Humans ; Lung/*drug effects/metabolism ; Lung Injury/*chemically induced ; Male ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*metabolism ; RNA, Small Interfering/metabolism ; Rats ; Smoking/*adverse effects ; Sphingomyelin Phosphodiesterase/*metabolism ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is caused by exposure to cigarette smoke (CS). One mechanism of CS-induced lung injury is aberrant generation of ceramide, which leads to elevated apoptosis of epithelial and endothelial cells in the alveolar spaces. Recently, we discovered that CS-induced ceramide generation and apoptosis in pulmonary cells is governed by neutral sphingomyelinase (nSMase) 2. In the current experiments, we expanded our studies to investigate whether nSMase2 governs ceramide generation and apoptosis in vivo using rodent and human models of CS-induced lung injury. We found that exposure of mice or rats to CS leads to colocalizing elevations of ceramide levels and terminal deoxynucleotidyl transferase mediated X-dUTP nick end labeling-positive cells in lung tissues. These increases are nSMase2 dependent, and are abrogated by treatment with N-acetyl cysteine or anti-nSMase2 small interfering RNA (siRNA). We further showed that mice that are heterozygous for nSMase2 demonstrate significant decrease in ceramide generation after CS exposure, whereas acidic sphingomyelinase (aSMase) knockout mice maintain wild-type ceramide levels, confirming our previous findings (in human airway epithelial cells) that only nSMase2, and not aSMase, is activated by CS exposure. Lastly, we found that lung tissues from patients with emphysema (smokers) display significantly higher levels of nSMase2 expression compared with lung tissues from healthy control subjects. Taken together, these data establish the central in vivo role of nSMase2 in ceramide generation, aberrant apoptosis, and lung injury under CS exposure, underscoring its promise as a novel target for the prevention of CS-induced airspace destruction.}, }
@article {pmid20446771, year = {2010}, author = {Popova, EN and Pletjushkina, OY and Dugina, VB and Domnina, LV and Ivanova, OY and Izyumov, DS and Skulachev, VP and Chernyak, BV}, title = {Scavenging of reactive oxygen species in mitochondria induces myofibroblast differentiation.}, journal = {Antioxidants &amp; redox signaling}, volume = {13}, number = {9}, pages = {1297-1307}, doi = {10.1089/ars.2009.2949}, pmid = {20446771}, issn = {1557-7716}, mesh = {Acetylcysteine/metabolism/pharmacology ; Actins/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Cell Differentiation/*drug effects ; Chromans/pharmacology ; Fibroblasts/cytology/drug effects/metabolism ; Fibronectins/metabolism/pharmacology ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Matrix Metalloproteinase 9/metabolism/pharmacology ; Mitochondria/metabolism ; Muscle, Smooth/metabolism ; Myofibroblasts/*cytology/*metabolism ; Phosphorylation ; Plastoquinone/analogs &amp; derivatives/metabolism/pharmacology ; Reactive Oxygen Species/*metabolism/pharmacology ; Signal Transduction/drug effects ; Transforming Growth Factor beta/metabolism ; }, abstract = {The goal of this study was to investigate the possible role of reactive oxygen species (ROS) in signaling, in modulation of the cytoskeleton, and in differentiation of fibroblasts. For this purpose, we have applied a novel mitochondria-targeted antioxidant: plastoquinone conjugated with decyltriphenylphosphonium (SkQ1). This antioxidant at nanomolar concentration prevented ROS accumulation and cell death induced by H(2)O(2) in fibroblasts. We found that scavenging of ROS produced by mitochondria activated the Rho/ROCK/LIMK signaling pathway that was followed by phosphorylation of cofilin and stabilization of actin stress fibers. The mitochondria-targeted antioxidant induced differentiation of human subcutaneous fibroblasts to myofibroblasts as revealed by expression of fibronectin isoform (EDA-FN) and smooth muscle actin (α-SMA). This effect was shown to be mediated by transforming growth factor β1 (TGFβ1), which was activated by matrix metalloprotease 9 (MMP9) in the culture medium. Scavenging of ROS stimulated secretion of MMP9 rather than its processing. The same effect was achieved by the nontargeted antioxidant Trolox at higher concentration, but the thiol antioxidant N-acetylcysteine (NAC) inhibited MMP activity and was not able to induce myofibroblast differentiation. The myofibroblast phenotype was supported due to autocrine TGFβ1-dependent stimulation after removal of SkQ1. It is concluded that ROS scavenging in mitochondria induces TGFβ1-dependent myofibroblast differentiation.}, }
@article {pmid20444961, year = {2010}, author = {Kandala, PK and Srivastava, SK}, title = {Activation of checkpoint kinase 2 by 3,3'-diindolylmethane is required for causing G2/M cell cycle arrest in human ovarian cancer cells.}, journal = {Molecular pharmacology}, volume = {78}, number = {2}, pages = {297-309}, pmid = {20444961}, issn = {1521-0111}, support = {R01 CA106953/CA/NCI NIH HHS/United States ; R01 CA129038/CA/NCI NIH HHS/United States ; R01-CA129038/CA/NCI NIH HHS/United States ; R01-CA106953/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis ; *Cell Division ; Cell Line, Tumor ; Checkpoint Kinase 2 ; DNA Damage ; Dose-Response Relationship, Drug ; Enzyme Activation ; Female ; Flow Cytometry ; *G2 Phase ; Humans ; Immunoprecipitation ; In Situ Nick-End Labeling ; Indoles/*pharmacology ; Ovarian Neoplasms/*pathology ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; }, abstract = {We evaluated the effect of 3,3'-diindolylmethane (DIM) in ovarian cancer cells. DIM treatment inhibited the growth of SKOV-3, TOV-21G, and OVCAR-3 ovarian cancer cells in both a dose- and time-dependent manner with effective concentrations ranging from 40 to 100 muM. Growth-inhibitory effects of DIM were mediated by cell cycle arrest in G(2)/M phase in all the three cell lines. G(2)/M arrest was associated with DNA damage as indicated by phosphorylation of H(2)A.X at Ser139 and activation of checkpoint kinase 2 (Chk2) in all the three cell lines. Other G(2)/M regulatory molecules such as Cdc25C, Cdk1, cyclin B1 were down-regulated by DIM. Cycloheximide or Chk2 inhibitor pretreatment abrogated not only activation of Chk2 but also G(2)/M arrest and apoptosis mediated by DIM. To further establish the involvement of Chk2 in DIM-mediated G(2)/M arrest, cells were transfected with dominant-negative Chk2 (DN-Chk2). Blocking Chk2 activation by DN-Chk2 completely protected cells from DIM-mediated G(2)/M arrest. These results were further confirmed in Chk2 knockout DT40 lymphoma cells, in which DIM failed to cause cell cycle arrest. These results clearly indicate the requirement of Chk2 activation to cause G(2)/M arrest by DIM in ovarian cancer cells. Moreover, blocking Chk2 activation also abrogates the apoptosis-inducing effects of DIM. Furthermore, our results show that DIM treatment cause ROS generation. Blocking ROS generation by N-acetyl cysteine protects the cells from DIM-mediated G(2)/M arrest and apoptosis. Our results establish Chk2 as a potent molecular target of DIM in ovarian cancer cells and provide the rationale for further clinical investigation of DIM.}, }
@article {pmid20444031, year = {2010}, author = {Avizeh, R and Najafzadeh, H and Razijalali, M and Shirali, S}, title = {Evaluation of prophylactic and therapeutic effects of silymarin and N-acetylcysteine in acetaminophen-induced hepatotoxicity in cats.}, journal = {Journal of veterinary pharmacology and therapeutics}, volume = {33}, number = {1}, pages = {95-99}, doi = {10.1111/j.1365-2885.2009.01100.x}, pmid = {20444031}, issn = {1365-2885}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/*therapeutic use ; Animals ; Bilirubin/blood ; Cat Diseases/*chemically induced ; Cats ; Chemical and Drug Induced Liver Injury/drug therapy/*veterinary ; Female ; Free Radical Scavengers/therapeutic use ; Liver/enzymology/metabolism ; Male ; Methemoglobinemia/prevention &amp; control/veterinary ; Protective Agents/therapeutic use ; Silymarin/*therapeutic use ; }, abstract = {Cats most commonly receive toxic amounts of acetaminophen (APAP) because owners medicate them without consulting a veterinarian. The aim of this study was to compare the hepatoprotective action of silymarin and N-acetylcysteine (NAC) against APAP poisoning. Twenty healthy cats were randomly allotted to five equal groups. Animals in group A were given APAP (single dose 150 mg/kg, p.o.); groups B and C consisted of cats that received NAC (100 mg/kg, p.o.) or silymarin (30 mg/kg, p.o.) concurrent with APAP administration respectively; groups D and E were treated like groups B and C, respectively, but 4 h after APAP administration. The serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), methemoglobin, and total and direct bilirubin were measured before APAP administration and 4, 24, and 72 h later. A single oral administration of APAP significantly elevated serum concentrations of ALT, AST, ALP, LDH, methemoglobin, and total and direct bilirubin. In both the groups receiving APAP plus NAC or silymarin, levels of serum enzyme activities, methemoglobin, and total and direct bilirubin remained within the normal values. It was concluded that silymarin as well as NAC can protect liver tissue against oxidative stress in cats with an APAP intoxication.}, }
@article {pmid20443032, year = {2010}, author = {Wang, Q and Liu, TT and Fu, Y and Wang, K and Yang, XG}, title = {Vanadium compounds discriminate hepatoma and normal hepatic cells by differential regulation of reactive oxygen species.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {15}, number = {7}, pages = {1087-1097}, pmid = {20443032}, issn = {1432-1327}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Carcinoma, Hepatocellular/*metabolism/pathology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Hep G2 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Liver/*cytology/*drug effects/metabolism/pathology ; Liver Neoplasms/*metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Vanadium Compounds/*pharmacology ; }, abstract = {Our previous study indicated that vanadium compounds can block cell cycle progression at the G1/S phase in human hepatoma HepG2 cells via a highly activated extracellular signal-regulated protein kinase (ERK) signal. To explore their differential action on normal cells, we investigated the response of an immortalized hepatic cell line, L02 cells. The results demonstrated that a higher concentration of vanadium compounds was needed to inhibit L02 proliferation, which was associated with S and G2/M cell cycle arrest. In addition, in contrast to insignificant reactive oxygen species (ROS) generation in HepG2 cells, all of the vanadium compounds resulted significant increases in both O2.- and H2O2 levels in L02 cells. At the same time, ERK and c-Jun N-terminal kinase (JNK) as well as cell division control protein 2 homolog (Cdc2) were found to be highly phosphorylated, which could be counteracted with the antioxidant N-acetylcysteine (NAC). The current study also demonstrated that both the ERK and the JNK pathways contributed to the cell cycle arrest induced by vanadium compounds in L02 cells. More importantly, it was found that although NAC can ameliorate the cytotoxicity of vanadium compounds in L02 cells, it did not decrease their cytotoxicity in HepG2 cells. It thus shed light on the potential therapeutic applications of vanadium compounds with antioxidants as synergistic agents to reduce their toxicities in human normal cells without affecting their antitumor activities in cancer cells.}, }
@article {pmid20439934, year = {2010}, author = {Kurita-Ochiai, T and Ochiai, K}, title = {Butyric acid induces apoptosis via oxidative stress in Jurkat T-cells.}, journal = {Journal of dental research}, volume = {89}, number = {7}, pages = {689-694}, doi = {10.1177/0022034510365456}, pmid = {20439934}, issn = {1544-0591}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor/drug effects ; Apoptosis Regulatory Proteins ; Butyric Acid/*pharmacology ; CASP8 and FADD-Like Apoptosis Regulating Protein/drug effects ; Caspase 10/drug effects ; Caspase Inhibitors ; Caspases, Initiator/drug effects ; Cysteine Proteinase Inhibitors/pharmacology ; Cytochromes c/drug effects ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum Chaperone BiP ; Free Radical Scavengers/pharmacology ; Heat-Shock Proteins/drug effects ; Humans ; Inhibitor of Apoptosis Proteins/pharmacology ; Intracellular Signaling Peptides and Proteins/pharmacology ; Jurkat Cells ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects ; Mitochondrial Proteins/pharmacology ; Oxidative Stress/*physiology ; Proto-Oncogene Proteins c-bcl-2/drug effects ; Reactive Oxygen Species/pharmacology ; Receptors, Death Domain/drug effects ; Serpins/pharmacology ; Signal Transduction/drug effects ; T-Lymphocytes/*drug effects ; Viral Proteins/pharmacology ; bcl-2-Associated X Protein/drug effects ; bcl-Associated Death Protein/drug effects ; bcl-X Protein/drug effects ; }, abstract = {Reactive oxygen species (ROS) are essential for the induction of T-cell apoptosis by butyric acid, an extracellular metabolite of periodontopathic bacteria. To determine the involvement of oxidative stress in apoptosis pathways, we investigated the contribution of ROS in mitochondrial signaling pathways, death-receptor-initiated signaling pathway, and endoplasmic reticulum stress in butyric-acid-induced T-cell apoptosis. N-acetyl-L-Cysteine (NAC) abrogated mitochondrial injury, cytochrome c, AIF, and Smac release, and Bcl-2 and Bcl-xL suppression and Bax and Bad activation induced by butyric acid. However, the decrease in cFLIP expression by butyric acid was not restored by treatment with NAC; increases in caspase-4 and -10 activities by butyric acid were completely abrogated by NAC. NAC also affected the elevation of GRP78 and CHOP/GADD153 expression by butyric acid. These results suggest that butyric acid is involved in mitochondrial-dysfunction- and endoplasmic reticulum stress-mediated apoptosis in human Jurkat T-cells via a ROS-dependent mechanism.}, }
@article {pmid20439172, year = {2010}, author = {Wang, X and Meng, D and Chang, Q and Pan, J and Zhang, Z and Chen, G and Ke, Z and Luo, J and Shi, X}, title = {Arsenic inhibits neurite outgrowth by inhibiting the LKB1-AMPK signaling pathway.}, journal = {Environmental health perspectives}, volume = {118}, number = {5}, pages = {627-634}, pmid = {20439172}, issn = {1552-9924}, support = {R01 ES015518/ES/NIEHS NIH HHS/United States ; R01 CA116697/CA/NCI NIH HHS/United States ; 1R01CA119028-01/CA/NCI NIH HHS/United States ; R01 ES015375/ES/NIEHS NIH HHS/United States ; 1R01CA116697-01A2/CA/NCI NIH HHS/United States ; 1R01ES015375-01/ES/NIEHS NIH HHS/United States ; 1R01ES015518-01A1/ES/NIEHS NIH HHS/United States ; R01 CA119028/CA/NCI NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinase Kinases ; AMP-Activated Protein Kinases/*antagonists &amp; inhibitors ; Arsenic/*toxicity ; Cell Differentiation/drug effects ; Cell Line ; Environmental Health ; Enzyme Inhibitors/toxicity ; Humans ; Neurites/*drug effects/*enzymology/ultrastructure ; Neurons/cytology/drug effects/metabolism ; Oxidative Stress/drug effects ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Water Pollutants, Chemical/*toxicity ; }, abstract = {BACKGROUND: Arsenic (As) is an environmental pollutant that induces numerous pathological effects, including neurodevelopmental disorders.<br><br>OBJECTIVES AND METHODS: We evaluated the role of the LKB1-AMPK pathway in As-induced developmental neurotoxicity using Neuro-2a (N2a) neuroblastoma cells as a model of developing neurons.<br><br>RESULTS: The addition of low concentrations of As (<or= 5 microM) during differentiation caused an inhibitory effect on the neurite outgrowth in N2a cells in the absence of cell death. Activation of adenosine monophosphate-activated kinase (AMPK) induced by retinoic acid in differentiating cells was blocked by As. Pretreatment with the AMPK-specific activator 5-aminoimidazole-4-carboxamide riboside or overexpression of a constitutively active AMPK-alpha1 plasmid reversed As-induced inhibition of neurite outgrowth. The activation of LKB1 (serine/threonine kinase 11), a major AMPK kinase, was also suppressed by As by inhibiting both the phosphorylation and the translocation of LKB1 from nucleus to cytoplasm. Antioxidants, such as N-acetyl cysteine and superoxide dismutase, but not catalase, protected against As-induced inactivation of the LKB1-AMPK pathway and reversed the inhibitory effect of As on neurite outgrowth.<br><br>CONCLUSIONS: Reduced neurite outgrowth induced by As results from deficient activation of AMPK as a consequence of a lack of activation of LKB1. Oxidative stress induced by As, especially excessive superoxide, plays a critical role in blocking the LKB1-AMPK pathway. Our studies provide insight into the mechanisms underlying As-induced developmental neurotoxicity, which is important for designing a new strategy for protecting children against this neurotoxic substance.}, }
@article {pmid20435108, year = {2010}, author = {Kalariya, NM and Nair, B and Kalariya, DK and Wills, NK and van Kuijk, FJ}, title = {Cadmium-induced induction of cell death in human lens epithelial cells: implications to smoking associated cataractogenesis.}, journal = {Toxicology letters}, volume = {198}, number = {1}, pages = {56-62}, doi = {10.1016/j.toxlet.2010.04.021}, pmid = {20435108}, issn = {1879-3169}, mesh = {Apoptosis/*drug effects ; Cadmium/*toxicity ; Cataract/chemically induced/etiology ; Cell Line ; Cell Survival/drug effects ; Epithelial Cells/*drug effects/metabolism ; Glutathione/metabolism ; Humans ; Lens, Crystalline/cytology/*drug effects/metabolism ; Lipid Peroxidation/drug effects ; Mitogen-Activated Protein Kinases/metabolism ; Oxidative Stress ; Signal Transduction/drug effects ; Smoking/adverse effects ; }, abstract = {Cadmium is reported to accumulate in human eye tissues suggesting its implication in diverse ocular pathology. Using an in vitro cell culture model we investigated the effects of cadmium on human lens epithelial cells (HLECs) (HLE-B3). We observed cadmium-induced dose- as well as time-dependent decline in HLECs viability which was exacerbated significantly upon reduction of intracellular glutathione levels by buthionine sulfoximine (BSO). There was a dose-dependent significant increase in lactate dehydrogenase (LDH) release from HLECs suggesting cadmium-induced alteration of membrane integrity as well as necrotic cell death. The decline in cell viability was also due to apoptosis of the HLECs as determined by quantifying % apoptotic cells as well as PARP cleavage. Moreover, release of apoptosis inducing factor (AIF) into the cytosol was also detected. Cadmium was also observed to increase oxidative stress, lipid peroxidation and activation of MAPK pathway in HLECs. Antioxidants like N-acetylcysteine (NAC) and alpha-Tocopherol significantly prevented cadmium-induced toxicity in HLECs. Our findings suggest that cadmium-induced elevated oxidative stress as well as activation of MAPK signaling cascade eventually led to cell death of HLECs through apoptosis as well as necrosis. The loss of HLECs by cadmium could possibly explain its implication in cataract development particularly associated with smoking.}, }
@article {pmid20431929, year = {2010}, author = {Bémeur, C and Vaquero, J and Desjardins, P and Butterworth, RF}, title = {N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms.}, journal = {Metabolic brain disease}, volume = {25}, number = {2}, pages = {241-249}, pmid = {20431929}, issn = {1573-7365}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetaminophen/pharmacology ; Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Azoxymethane/toxicity ; Brain Edema/etiology/metabolism ; Carcinogens/toxicity ; Cytokines/blood/drug effects ; Disease Models, Animal ; Hepatic Encephalopathy/*drug therapy/metabolism ; Inflammation/drug therapy/metabolism/prevention &amp; control ; Inflammation Mediators/*therapeutic use ; Liver Failure, Acute/complications/*drug therapy/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects/physiology ; }, abstract = {N-acetylcysteine (NAC) is an effective antidote to treat acetaminophen (APAP)-induced acute liver failure (ALF). NAC is hepatoprotective and prevents the neurological complications of ALF, namely hepatic encephalopathy and brain edema. The protective effect of NAC and its mechanisms of action in ALF due to other toxins, however, are still controversial. In the present study, we investigated the effects of NAC in relation to liver pathology, hepatic and cerebral glutathione, plasma ammonia concentrations, progression of encephalopathy, cerebral edema, and plasma proinflammatory cytokines in mice with ALF resulting from azoxymethane (AOM) hepatotoxicity, a well characterized model of toxic liver injury. Male C57BL/6 mice were treated with AOM (100 microg/g; i.p.) or saline and sacrificed at coma stage of encephalopathy in parallel with AOM mice administered NAC (1.2 g/kg; i.p.). AOM administration led to hepatic damage, significant increase in plasma transaminase activity, decreased hepatic glutathione levels and brain GSH/GSSG ratios as well as increased expression of plasma proinflammatory cytokines. NAC treatment of AOM mice led to reduced hepatic damage and improvement in neurological function, normalization of brain and hepatic glutathione levels as well as selective attenuation in expression of plasma proinflammatory cytokines. These findings demonstrate that the beneficial effects of NAC in experimental non-APAP-induced ALF involves both antioxidant and anti-inflammatory mechanisms.}, }
@article {pmid20431246, year = {2010}, author = {Duan, W and Jin, X and Li, Q and Tashiro, S and Onodera, S and Ikejima, T}, title = {Silibinin induced autophagic and apoptotic cell death in HT1080 cells through a reactive oxygen species pathway.}, journal = {Journal of pharmacological sciences}, volume = {113}, number = {1}, pages = {48-56}, doi = {10.1254/jphs.09315fp}, pmid = {20431246}, issn = {1347-8648}, mesh = {Acetylcysteine/pharmacology ; Adenine/analogs &amp; derivatives/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Autophagy/*drug effects ; Cell Line ; Culture Media, Serum-Free ; Drug Interactions ; Humans ; Hydrogen Peroxide/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Silybin ; Silymarin/antagonists &amp; inhibitors/*pharmacology ; }, abstract = {Hepatoprotectant silibinin has anticancer and chemo-preventive effects. In this study, silibinin showed significant inhibitory effect on human fibroblast HT 1080 cell growth cultured in media containing 10% fetal bovine serum or in serum free media, and in the latter case, silibinin exerted a more significant effect. Silibinin induced autophagy at 12 h, confirmed by monodansylcadervarine (MDC) staining, up-regulation of Beclin 1 (initiation factor for autophagosome formation), and conversion of LC3 I to LC3 II (autophagosome marker). It also induced apoptosis at 24 h, proved by observation of apoptotic body and activation of caspase-3. 3-Methyladenine (3-MA) inhibited silibinin-induced autophagy and promoted cell survival, suggesting that autophagy enhanced silibinin-induced apoptosis in HT1080 cells. Silibinin generated reactive oxygen species (ROS) in HT1080 cells, and the ROS scavenger N-acetylcysteine (NAC) reversed the cytotoxicity of silibinin, resulting in cell survival by inhibition of autophagic and apoptotic pathways. Application of specific antioxidants demonstrated that H(2)O(2) was a major factor in silibinin-induced ROS since the H(2)O(2) scavenger catalase reduced both autophagy and cell death. O(2)*(-) also contributed to silibinin-induced cell death.}, }
@article {pmid20430080, year = {2010}, author = {Wu, HP and Hsu, CJ and Cheng, TJ and Guo, YL}, title = {N-acetylcysteine attenuates noise-induced permanent hearing loss in diabetic rats.}, journal = {Hearing research}, volume = {267}, number = {1-2}, pages = {71-77}, doi = {10.1016/j.heares.2010.03.082}, pmid = {20430080}, issn = {1878-5891}, mesh = {Acetylcysteine/metabolism/pharmacology/*therapeutic use ; Animals ; Blood Glucose/metabolism ; Body Weight ; Diabetes Mellitus, Experimental/*complications ; Disease Models, Animal ; Evoked Potentials, Auditory, Brain Stem/drug effects/physiology ; Glutathione/metabolism ; Hair Cells, Auditory, Outer/drug effects/physiology ; Hearing Loss, Noise-Induced/metabolism/physiopathology/*prevention &amp; control ; Male ; Rats ; Rats, Wistar ; Streptozocin ; }, abstract = {The purpose of this study is to investigate whether repeated noise exposure aggravates the level of permanent noise-induced hearing loss (NIHL) in diabetic rats and whether N-acetylcysteine (NAC), a precursor of glutathione, attenuates the level of noise-induced permanent hearing loss in diabetic rats. Fifty male Wistar rats were divided into four groups: 12 non-diabetic control rats with saline injection (Control-Saline), 11 non-diabetic control rats with NAC injection (Control-NAC), 13 streptozotocin-induced diabetic rats with saline injection (Diabetes-Saline) and 14 streptozotocin-induced diabetic rats with NAC injection (Diabetes-NAC). NAC (325mg/kg) was given by intraperitoneal injection twice per day (b.i.d.) for 14 days starting 2 days before noise exposure. All rats were exposed to noise for 8hours per day for 10 consecutive days to develop noise-induced permanent hearing loss. The hearing status of all animals was evaluated with auditory brainstem responses (ABR) evoked by clicks and tone bursts. ABRs were measured before and at 1hour, 1 week, 2 weeks and 4 weeks after noise exposure. After a recovery time of 4 weeks, animals were decapitated, and the loss of hair cells was assessed microscopically. In all groups, ABR thresholds failed to return to pre-exposure values throughout the experimental period. The ABR threshold to clicks was markedly elevated in the Diabetes-Saline group (36.9+/-2.3dB SPL), less elevated in the Control-Saline and Diabetes-NAC groups and least in the Control-NAC group (19.5+/-2.0dB SPL) at 4 weeks after noise exposure. Diabetes caused increased susceptibility to noise-induced hearing loss, and NAC treatment reduced the loss in both control and diabetic rats. Cochleograms revealed no gross destruction of hair cells in the non-diabetic groups or the Diabetes-NAC group; however, a significant number of outer hair cells (OHCs) were lost in the Diabetes-Saline group. This study demonstrated that diabetics were prone to developing more severe NIHL than non-diabetics and that NAC could preserve most OHCs and attenuate the permanent noise-induced hearing loss in both groups.}, }
@article {pmid20430017, year = {2010}, author = {Sajewicz, W}, title = {Effect of thiol drugs on tert-butyl hydroperoxide induced luminol chemiluminescence in human erythrocytes, erythrocyte lysate, and erythrocyte membranes.}, journal = {Chemico-biological interactions}, volume = {186}, number = {2}, pages = {144-151}, doi = {10.1016/j.cbi.2010.04.021}, pmid = {20430017}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Erythrocyte Membrane/drug effects/metabolism ; Erythrocytes/*drug effects/*metabolism ; Humans ; In Vitro Techniques ; Kinetics ; Luminescence ; Luminol ; Mesna/pharmacology ; Models, Biological ; Oxidative Stress/drug effects ; Penicillamine/analogs &amp; derivatives/pharmacology ; Sulfhydryl Compounds/*pharmacology ; Tiopronin/pharmacology ; tert-Butylhydroperoxide/*pharmacology ; }, abstract = {The paper investigates the effect of thiol drugs (RSH) under oxidative stress condition using luminol-enhanced chemiluminescence technique. The examinations included N-acetylcysteine (NAC), N-acetylpenicillamine (NAP), penicillamine (PEN), mesna (MES), and tiopronin (TPR). The model systems contained isolated human erythrocytes (RBC), erythrocyte lysates (LYS) or erythrocyte membranes (MEM) exposed to tert-butyl hydroperoxide (t-BuOOH). Under the influence of RSH, a bimodal character of some experimental chemiluminescence curves was observed and the kinetic solution was considered as the sum of two logistic-exponential processes. These chemiluminescence changes probably reflected two connected processes--scavenging by RSH of the t-BuOOH-induced free radicals and simultaneous generation of thiol-derived secondary free radicals. Individual differences in thiols interaction showed a multivariate set of the kinetic curve descriptors. The Principal Component Analysis (PCA) well distinguished subsets of RSH influence in systems with RBC or LYS. Generally, the action of NAC was exclusively pro-oxidant in both systems, with RBC and LYS. The behaviour of MES or NAP in these systems was also pro-oxidant but many times less prominent than NAC. Under the influence of TPR a dramatic switch in the anti-oxidant effect was observed in system with RBC to very pro-oxidant effect in LYS. The influence of PEN was analogical to TPR but very weak. This experimental model together with kinetic solution of the unique bimodal chemiluminescence curves, and PCA, supply new insights to the dual (anti- and pro-oxidant) effects of thiol drugs under oxidative stress condition.}, }
@article {pmid20428844, year = {2011}, author = {Foldbjerg, R and Dang, DA and Autrup, H}, title = {Cytotoxicity and genotoxicity of silver nanoparticles in the human lung cancer cell line, A549.}, journal = {Archives of toxicology}, volume = {85}, number = {7}, pages = {743-750}, doi = {10.1007/s00204-010-0545-5}, pmid = {20428844}, issn = {1432-0738}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Biological Transport/drug effects ; Carcinoma/metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; DNA Adducts/metabolism ; DNA Damage/*drug effects ; Humans ; Lung Neoplasms/metabolism ; Materials Testing ; Metal Nanoparticles/chemistry/*toxicity ; Mitochondria/drug effects/metabolism ; Mutagens/administration &amp; dosage/chemistry/metabolism/*toxicity ; Oxidative Stress/drug effects ; Povidone/chemistry ; Pulmonary Alveoli/*drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Silver/antagonists &amp; inhibitors/chemistry/metabolism/*toxicity ; Silver Nitrate/metabolism/toxicity ; Surface Properties ; }, abstract = {Nanomaterials, especially silver nanoparticles (Ag NPs), are used in a rapidly increasing number of commercial products. Accordingly, the hazards associated with human exposure to nanomaterials should be investigated to facilitate the risk assessment process. A potential route of exposure to NPs is through the respiratory system. In the present study, we investigated the effects of well-characterized PVP-coated Ag NPs and silver ions (Ag+) in the human, alveolar cell line, A549. Dose-dependent cellular toxicity caused by Ag NPs and Ag+ was demonstrated by the MTT and annexin V/propidium iodide assays, and evidence of Ag NP uptake could be measured indirectly by atomic absorption spectroscopy and flow cytometry. The cytotoxicity of both silver compounds was greatly decreased by pretreatment with the antioxidant, N-acetyl-cysteine, and a strong correlation between the levels of reactive oxygen species (ROS) and mitochondrial damage (r(s) = -0.8810; p = 0.0039) or early apoptosis (r(s) = 0.8857; p = 0.0188) was observed. DNA damage induced by ROS was detected as an increase in bulky DNA adducts by (32)P postlabeling after Ag NP exposure. The level of bulky DNA adducts was strongly correlated with the cellular ROS levels (r(s) = 0.8810, p = 0.0039) and could be inhibited by antioxidant pretreatment, suggesting Ag NPs as a mediator of ROS-induced genotoxicity.}, }
@article {pmid20426657, year = {2010}, author = {Jia, D and Koonce, NA and Griffin, RJ and Jackson, C and Corry, PM}, title = {Prevention and mitigation of acute death of mice after abdominal irradiation by the antioxidant N-acetyl-cysteine (NAC).}, journal = {Radiation research}, volume = {173}, number = {5}, pages = {579-589}, pmid = {20426657}, issn = {1938-5404}, support = {R01 CA107160/CA/NCI NIH HHS/United States ; R01 CA107160-05/CA/NCI NIH HHS/United States ; CA107160/CA/NCI NIH HHS/United States ; }, mesh = {Abdomen/*radiation effects ; Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/*administration &amp; dosage ; Bone Marrow/metabolism/radiation effects ; Dose-Response Relationship, Radiation ; Leukocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Radiation Injuries/mortality/*prevention &amp; control ; Reactive Oxygen Species/metabolism ; Weight Loss ; }, abstract = {Gastrointestinal (GI) injury is a major cause of acute death after total-body exposure to large doses of ionizing radiation, but the cellular and molecular explanations for GI death remain dubious. To address this issue, we developed a murine abdominal irradiation model. Mice were irradiated with a single dose of X rays to the abdomen, treated with daily s.c. injection of N-acetyl-l-cysteine (NAC) or vehicle for 7 days starting either 4 h before or 2 h after irradiation, and monitored for up to 30 days. Separately, mice from each group were assayed 6 days after irradiation for bone marrow reactive oxygen species (ROS), ex vivo colony formation of bone marrow stromal cells, and histological changes in the duodenum. Irradiation of the abdomen caused dose-dependent weight loss and mortality. Radiation-induced acute death was preceded not only by a massive loss of duodenal villi but also, surprisingly, abscopal suppression of stromal cells and elevation of ROS in the nonirradiated bone marrow. NAC diminished these radiation-induced changes and improved 10- and 30-day survival rates to >50% compared with <5% in vehicle-treated controls. Our data establish a central role for abscopal stimulation of bone marrow ROS in acute death in mice after abdominal irradiation.}, }
@article {pmid20426279, year = {2009}, author = {Sateesh, J and Bhardwaj, P and Singh, N and Saraya, A}, title = {Effect of antioxidant therapy on hospital stay and complications in patients with early acute pancreatitis: a randomised controlled trial.}, journal = {Tropical gastroenterology : official journal of the Digestive Diseases Foundation}, volume = {30}, number = {4}, pages = {201-206}, pmid = {20426279}, issn = {0250-636X}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Adult ; Antioxidants/*therapeutic use ; Ascorbic Acid/*therapeutic use ; Biomarkers/blood ; Female ; Humans ; Length of Stay/statistics &amp; numerical data ; Male ; Oxidative Stress ; Pancreatitis/complications/*drug therapy ; Pilot Projects ; Placebos ; Prospective Studies ; Statistics, Nonparametric ; Treatment Outcome ; }, abstract = {BACKGROUND: Oxidative stress (OS) in acute pancreatitis (AP) has been pathologically linked with the systemic inflammatory response and antioxidant supplementation may have a clinical benefit.<br><br>METHODS: In this prospective, randomised open label, controlled pilot study, patients admitted within 72 hours of onset of pain were randomised to receive either placebo (only standard medical treatment; SMT) or antioxidants (vitamin C 500 mg, N-acetyl cysteine 200 mg 8 hourly and antoxyl forte 1 capsule hourly with standard medical treatment; SMT + AO) daily, following informed consent. Patients with co-morbid illness and pregnancy were excluded. Primary efficacy measures were length of hospital stay and complications whilst secondary measures were biochemical markers of oxidative stress (thiobarbituric acid reactive substances [TBARS] and superoxide dismutase [SOD] and total antioxidant capacity [TAC] and vitamin C) at Days 1, 3 and 7.<br><br>RESULTS: Of 53 patients, 30 patients were randomised to SMT and 23 patients to SMT + AO. The mean duration of hospital stay in the SMT group (10.3 +/- 7 days) was more compared to SMT + AOT (7.2 +/- 5 days), but was not statistically significant (p=0.07), complications were similar in the 2 groups. At Day 7, OS was significantly lower in the SMT + AO group when compared with the SMT group (TBARS, p=0.05; SOD, p=0.03) with a significant increase in FRAP and vitamin C (p=0.01).<br><br>CONCLUSIONS: Antioxidant supplementation may decrease the length of hospital stay and complication rate in patients with AP, but a larger clinical trial is needed to support this hypothesis. Further, it decreased the OS and improved the antioxidant status in patients with AP.}, }
@article {pmid20424907, year = {2010}, author = {Barbosa, PR and Cardoso, MR and Daufenbach, JF and Gonçalves, CL and Machado, RA and Roza, CA and Scaini, G and Rezin, GT and Schuck, PF and Dal-Pizzol, F and Streck, EL}, title = {Inhibition of mitochondrial respiratory chain in the brain of rats after renal ischemia is prevented by N-acetylcysteine and deferoxamine.}, journal = {Metabolic brain disease}, volume = {25}, number = {2}, pages = {219-225}, pmid = {20424907}, issn = {1573-7365}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Respiration/drug effects/physiology ; Deferoxamine/*pharmacology ; Disease Models, Animal ; Drug Combinations ; Drug Synergism ; Electron Transport/*drug effects/physiology ; Electron Transport Complex I/*drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Ischemia/etiology/*metabolism/*prevention &amp; control ; Kidney Diseases/complications/*metabolism/*prevention &amp; control ; Male ; Rats ; Rats, Wistar ; }, abstract = {We evaluated the activities of mitochondrial respiratory chain complexes in the brain of rats after renal ischemia and the effect of administration of the antioxidants N-acetylcysteine (NAC) and deferoxamine (DFX). The rats were divided into the groups: sham (control) or renal ischemia treated with saline, NAC 20 mg/kg, DFX 20 mg/kg or both antioxidants. Complex I activity was inhibited in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 1 and 6 h after renal ischemia and that the treatment with a combination of NAC and DFX prevented such effect. Complex I activity was not altered in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 12 h after renal ischemia. Complexes II and III activities were not altered in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 1, 6 and 12 h after renal ischemia. Complex IV activity was inhibited in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 1 h after renal ischemia, but the treatment with the combination of NAC and DFX was able to prevent this inhibition. Complex IV activity was not altered in hippocampus, striatum, prefrontal cortex and cerebral cortex of rats 6 and 12 h after renal ischemia. These results suggest that the inhibition of mitochondrial respiratory chain after renal ischemia might play a role in the pathogenesis of uremic encephalopathy.}, }
@article {pmid20421134, year = {2010}, author = {Pellerito, L and Prinzivalli, C and Casella, G and Fiore, T and Pellerito, O and Giuliano, M and Scopelliti, M and Pellerito, C}, title = {Diorganotin(IV) N-acetyl-L-cysteinate complexes: synthesis, solid state, solution phase, DFT and biological investigations.}, journal = {Journal of inorganic biochemistry}, volume = {104}, number = {7}, pages = {750-758}, doi = {10.1016/j.jinorgbio.2010.03.008}, pmid = {20421134}, issn = {1873-3344}, mesh = {Acetylcysteine/*chemistry ; Antineoplastic Agents/chemical synthesis/*chemistry ; Binding Sites ; Cell Line ; Cell Survival/*drug effects ; Humans ; Molecular Structure ; Organotin Compounds/chemical synthesis/*chemistry/pharmacology ; Spectrum Analysis ; }, abstract = {Diorganotin(IV) complexes of N-acetyl-L-cysteine (H(2)NAC; (R)-2-acetamido-3-sulfanylpropanoic acid) have been synthesized and their solid and solution-phase structural configurations investigated by FTIR, Mössbauer, (1)H, (13)C and (119)Sn NMR spectroscopy. FTIR results suggested that in R(2)Sn(IV)NAC (R = Me, Bu, Ph) complexes NAC(2-) behaves as dianionic tridentate ligand coordinating the tin(IV) atom, through ester-type carboxylate, acetate carbonyl oxygen atom and the deprotonated thiolate group. From (119)Sn Mössbauer spectroscopy it could be inferred that the tin atom is pentacoordinated, with equatorial R(2)Sn(IV) trigonal bipyramidal configuration. In DMSO-d(6) solution, NMR spectroscopic data showed the coordination of one solvent molecule to tin atom, while the coordination mode of the ligand through the ester-type carboxylate and the deprotonated thiolate group was retained in solution. DFT (Density Functional Theory) study confirmed the proposed structures in solution phase as well as the determination of the most probable stable ring conformation. Biological investigations showed that Bu(2)SnCl(2) and NAC2 induce loss of viability in HCC cells and only moderate effects in non-tumor Chang liver cells. NAC2 showed lower cytotoxic activity than Bu(2)SnCl(2), suggesting that the binding with NAC(2-) modulates the marked cytotoxic activity exerted by Bu(2)SnCl(2). Therefore, these novel butyl derivatives could represent a new class of anticancer drugs.}, }
@article {pmid20420656, year = {2010}, author = {Alessandrini, F and Weichenmeier, I and van Miert, E and Takenaka, S and Karg, E and Blume, C and Mempel, M and Schulz, H and Bernard, A and Behrendt, H}, title = {Effects of ultrafine particles-induced oxidative stress on Clara cells in allergic lung inflammation.}, journal = {Particle and fibre toxicology}, volume = {7}, number = {}, pages = {11}, pmid = {20420656}, issn = {1743-8977}, mesh = {Air Pollutants/*toxicity ; Animals ; Bronchial Hyperreactivity/*chemically induced/metabolism/pathology ; Bronchoalveolar Lavage Fluid/chemistry ; Disease Models, Animal ; Gene Expression/drug effects ; Lung/*drug effects/metabolism/pathology ; Mice ; Ovalbumin/immunology ; Oxidative Stress/*drug effects/immunology ; Particulate Matter/*toxicity ; Tumor Necrosis Factor-alpha/genetics/metabolism ; Uteroglobin/genetics/metabolism ; }, abstract = {BACKGROUND: Clara cell protein (CC16), the main secretory product of bronchiolar Clara cells, plays an important protective role in the respiratory tract against oxidative stress and inflammation. The purpose of the study was to investigate the role of elemental carbon ultrafine particles (EC-UFP)-induced oxidative stress on Clara cells and CC16 in a mouse model of allergic lung inflammation.<br><br>METHODS: Ovalbumin (OVA)-sensitized mice were exposed to EC-UFP (507 microg/m(3) for 24 h) or filtered air immediately prior to allergen challenge and systemically treated with N-acetylcysteine (NAC) or vehicle prior and during EC-UFP inhalation. CC16 was measured up to one week after allergen challenge in bronchoalveolar lavage fluid (BALF) and in serum. The relative expression of CC16 and TNF-alpha mRNA were measured in lung homogenates. A morphometrical analysis of mucus hypersecretion and electron microscopy served to investigate goblet cell metaplasia and Clara cell morphological alterations.<br><br>RESULTS: In non sensitized mice EC-UFP inhalation caused alterations in CC16 concentration, both at protein and mRNA level, and induced Clara cell hyperplasia. In sensitized mice, inhalation of EC-UFP prior to OVA challenge caused most significant alterations of BALF and serum CC16 concentration, BALF total protein and TNF-alpha relative expression compared to relevant controls; their Clara cells displayed the strongest morphological alterations and strongest goblet cell metaplasia occurred in the small airways. NAC strongly reduced both functional and morphological alterations of Clara cells.<br><br>CONCLUSION: Our findings demonstrate that oxidative stress plays an important role in EC-UFP-induced augmentation of functional and morphological alterations of Clara cells in allergic lung inflammation.}, }
@article {pmid20417267, year = {2010}, author = {You, BR and Park, WH}, title = {Gallic acid-induced lung cancer cell death is related to glutathione depletion as well as reactive oxygen species increase.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {24}, number = {5}, pages = {1356-1362}, doi = {10.1016/j.tiv.2010.04.009}, pmid = {20417267}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*toxicity ; Ascorbic Acid/pharmacology ; Buthionine Sulfoximine/toxicity ; Cell Death ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gallic Acid/*toxicity ; Glutathione/*metabolism ; Humans ; Lung Neoplasms/*metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Gallic acid (GA) widely distributed in plants and foods has its various biological effects. Here, we investigated the anti-cancer effects of GA on Calu-6 and A549 lung cancer cells in relation to reactive oxygen species (ROS) and glutathione (GSH). GA dose-dependently decreased the growth of Calu-6 and A549 cells with an IC(50) of approximately 10-50 microM and 100-200 microM GA at 24h, respectively. GA also induced cell death in lung cancer cells, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). The percents of MMP (DeltaPsi(m)) loss and death cells were lower in A549 cells than Calu-6 cells. GA increased ROS levels including O(2)(-) in lung cancer cells at 24h and also GSH depleted cell numbers at this time. N-acetyl-cysteine (NAC; a well-known antioxidant) intensified growth inhibition and death in GA-treated lung cancer cells. NAC changed ROS levels and increased GSH depletion in these cells. Vitamin C significantly attenuated cell death, ROS levels and GSH depletion in GA-treated lung cancer cells. L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) slightly enhanced growth inhibition and death in GA-treated lung cancer cells and also mildly increased ROS levels and GSH depletion in these cells. In conclusion, GA inhibited the growth of lung cancer cells. GA-induced lung cancer cell death was related to GSH depletion as well as ROS level changes.}, }
@article {pmid20413633, year = {2011}, author = {Kim, SR and Lee, KS and Park, SJ and Min, KH and Lee, MH and Lee, KA and Bartov, O and Atlas, D and Lee, YC}, title = {A novel dithiol amide CB3 attenuates allergic airway disease through negative regulation of p38 mitogen-activated protein kinase.}, journal = {American journal of respiratory and critical care medicine}, volume = {183}, number = {8}, pages = {1015-1024}, doi = {10.1164/rccm.200906-0902OC}, pmid = {20413633}, issn = {1535-4970}, mesh = {Animals ; Anti-Asthmatic Agents/*therapeutic use ; Asthma/*drug therapy ; Bronchial Hyperreactivity/drug therapy ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Disease Models, Animal ; Female ; Glutathione/analysis ; Glutathione Disulfide/analysis ; Imidazoles/pharmacology ; Lung/chemistry ; Mice ; Mice, Inbred C57BL ; Nitriles/pharmacology ; Oligopeptides/*therapeutic use ; Pyrimidines/pharmacology ; Reactive Oxygen Species/analysis ; Sulfhydryl Compounds/*therapeutic use ; Sulfones/pharmacology ; p38 Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors ; }, abstract = {RATIONALE: Cellular redox homeostasis altered by excessive production of reactive oxygen species (ROS) and weakening of the antioxidant defense leads to oxidative stress. Oxidative stress is characterized as a decrease in glutathione/glutathione disulfide (GSH/GSSG) and the triggering of a number of the redox-sensitive signaling cascades. Recent studies have demonstrated that ROS play an important role in the pathogenesis of airway inflammation and hyperresponsiveness.<br><br>OBJECTIVES: Here we characterized for the first time the protective properties of a new hydrophobic thiol compound, N-acetyl cysteine proline cysteine amide (CB3), in allergic airway diseases.<br><br>METHODS: We used ovalbumin (OVA)-inhaled mice to evaluate the role of CB3 as an antiinflammatory reagent and to determine its molecular signaling activity in allergic airways.<br><br>MEASUREMENTS AND MAIN RESULTS: The administration of CB3 (1-50 mg/kg) to OVA-inhaled mice restored the decreased GSH levels, enhanced IL-10 expression, and significantly reduced the increase of Th2 cytokines and OVA-specific IgE. CB3 decreased the number of inflammatory cells and airway hyperresponsiveness in the lungs. We also found that the administration of CB3 dramatically decreased the nuclear translocation of the nuclear factor-&#x3ba;B (NF-&#x3ba;B) and the phosphorylation of p38 mitogen-activated protein kinases (MAPKs) in lungs after OVA inhalation. In addition, allergen-induced airway inflammation and hyperresponsiveness were substantially reduced by the administration of inhibitors of NF-&#x3ba;B and p38 MAPK, BAY 11-7085, and SB 239063, respectively.<br><br>CONCLUSIONS: These results suggest that CB3 attenuates allergic airway disease by up-regulation of GSH levels as well as inhibition of NF-&#x3ba;B and p38 MAPK activity.}, }
@article {pmid20410574, year = {2010}, author = {Kukoc-Modun, L and Radić, N}, title = {Kinetic spectrophotometric determination of N-acetyl-L-cysteine based on a coupled redox-complexation reaction.}, journal = {Analytical sciences : the international journal of the Japan Society for Analytical Chemistry}, volume = {26}, number = {4}, pages = {491-495}, doi = {10.2116/analsci.26.491}, pmid = {20410574}, issn = {1348-2246}, mesh = {Acetylcysteine/*analysis/*chemistry ; Kinetics ; Oxidation-Reduction ; Pharmaceutical Preparations/chemistry ; Spectrophotometry/*methods ; Thermodynamics ; }, abstract = {A novel simple kinetic spectrophotometric method for the determination of N-acetyl-L-cysteine (NAC) has been developed and validated. The proposed method is based on a coupled redox-complexation reaction, the first step of which is the reduction of Fe(3+) by NAC; the second one includes the complexation of Fe(2+), resulting from the preceding redox reaction, with 2,4,6-trypyridyl-s-triazine (TPTZ). The stable Fe(TPTZ)(2)(2+) complex exhibits an absorption maximum at lambda = 593 nm.The initial rate and fixed-time (at 5 min) methods were utilized for constructing calibration graphs. The graphs were linear in concentration ranges from 4.0 x 10(-6) to 1.0 x 10(-4) mol L(-1) for the initial rate method and 1.0 x 10(-6) to 1.0 x 10(-4) mol L(-1) for the fixed-time method, with detection limits of 1.0 x 10(-6) and 1.7 x 10(-7) mol L(-1), respectively. The proposed methods were successfully applied for the determination of NAC in its commercial pharmaceutical formulations.}, }
@article {pmid20408853, year = {2010}, author = {Aktunc, E and Ozacmak, VH and Ozacmak, HS and Barut, F and Buyukates, M and Kandemir, O and Demircan, N}, title = {N-acetyl cysteine promotes angiogenesis and clearance of free oxygen radicals, thus improving wound healing in an alloxan-induced diabetic mouse model of incisional wound.}, journal = {Clinical and experimental dermatology}, volume = {35}, number = {8}, pages = {902-909}, doi = {10.1111/j.1365-2230.2010.03823.x}, pmid = {20408853}, issn = {1365-2230}, mesh = {Acetylcysteine/*pharmacology ; Alloxan/toxicity ; Animals ; Diabetes Mellitus, Experimental/chemically induced ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Glutathione/biosynthesis ; Hydroxyproline/metabolism ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred BALB C ; Neovascularization, Physiologic/*drug effects/physiology ; Nitric Oxide Synthase/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Skin/*blood supply/metabolism/pathology ; Vascular Endothelial Growth Factors/biosynthesis ; Wound Healing/*drug effects ; Wounds, Penetrating/metabolism/*pathology ; }, abstract = {BACKGROUND: This study investigated whether N-acetyl cysteine induces any favourable effects on cutaneous incisional wound healing in diabetic and nondiabetic mice. The wounds were assessed using detection of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (iNOS) expression, and wound-breaking strength (WBS) measurements.<br><br>METHODS: In total, 48 BALB/c mice were used. These were divided into four groups, each consisting of 12 mice. Incisional wounds were made on the back of each mouse. Two of the groups consisted of healthy animals and the other two groups consisted of mice with alloxan-induced diabetes. One group of healthy mice and one group of diabetic mice received intraperitoneal N-acetyl cysteine (NAC) 150 mg/kg for 5 consecutive days, while the other two groups were untreated. On the fifth day all animals were killed, and the WBS, oxidative stress parameters, histopathological and immunohisotchemical results were assessed.<br><br>RESULTS: Both diabetic and nondiabetic mice receiving NAC had lower levels of oxidative stress markers and higher WBS measurements than untreated counterparts.<br><br>CONCLUSIONS: A mouse model of incisional wound treated with NAC resulted in lower levels of tissue oxidative stress, higher levels of tissue glutathione, and downregulation of iNOS expression coupled with upregulation of VEGF expression, producing an overall favourable clinical outcome of higher WBS and a shorter wound-healing period both in diabetic and nondiabetic mice. Both antioxidant and anti-inflammatory properties of NAC may be involved in this improved healing process for incisional wounds.}, }
@article {pmid20403967, year = {2010}, author = {Liu, SY and Wen, CY and Lee, YJ and Lee, TC}, title = {XPC silencing sensitizes glioma cells to arsenic trioxide via increased oxidative damage.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {116}, number = {1}, pages = {183-193}, doi = {10.1093/toxsci/kfq113}, pmid = {20403967}, issn = {1096-0929}, mesh = {Arsenic Trioxide ; Arsenicals ; Autophagy ; Base Sequence ; Brain Neoplasms/metabolism/*pathology ; Cell Line, Tumor ; Cellular Senescence ; DNA-Binding Proteins/*genetics ; Fluorescent Antibody Technique ; *Gene Silencing ; Glioma/metabolism/*pathology ; Humans ; *Oxidative Stress ; Oxides/*toxicity ; RNA, Small Interfering/genetics ; }, abstract = {Arsenic exerts its cytotoxicity via the generation of reactive oxygen species and inhibition of DNA repair. How arsenic disturbs oxidative DNA damage repair is, however, unclear. We found that arsenic trioxide (ATO), like ultraviolet (UV) irradiation, induced the expression of xeroderma pigmentosum group C (XPC) but not of xeroderma pigmentosum A in a human glioma cell line, U87. To explore the role of XPC in the toxic effects of ATO, small interfering RNA was used to silence XPC (siXPC) in U87 cells. siXPC cells were more susceptible to UV irradiation and ATO-induced cell death than control cells. Increased siXPC cell death induced by ATO was accompanied by increased senescence and autophagy. Because increased DNA strand breaks in siXPC cells were observed only when cells were concomitantly treated with ATO and DNA repair inhibitors, XPC silencing apparently did not interfere with repair of ATO-induced DNA damage. Although intracellular ROS levels were not significantly enhanced in siXPC cells, ATO treatment did result in increased 8-hydroxy-2'-deoxyguanosine and hyperoxidized peroxiredoxin. Enhanced superoxide production and autophagy by ATO in siXPC cells were suppressed by co-incubation with N-acetylcysteine (NAC). Furthermore, XPC silencing caused decreased glutathione levels and increased catalase and Mn-superoxide dismutase activities. Increased catalase activity in siXPC cells was suppressed by ATO treatment. XPC silencing also enhanced reporter activity of activator protein-1, whereas enhanced activity was suppressed by NAC. Taken together, our results indicate that XPC silencing causes increased ATO susceptibility by disturbing redox homeostasis rather than reducing DNA repair.}, }
@article {pmid20402656, year = {2010}, author = {Rivadeneira, J and Di Virgilio, AL and Barrio, DA and Muglia, CI and Bruzzone, L and Etcheverry, SB}, title = {Cytotoxicity of a vanadyl(IV) complex with a multidentate oxygen donor in osteoblast cell lines in culture.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {6}, number = {1}, pages = {9-23}, doi = {10.2174/157340610791208754}, pmid = {20402656}, issn = {1875-6638}, mesh = {Actins/metabolism ; Animals ; Cell Death/drug effects ; Cell Line, Tumor ; Cytoskeleton/drug effects/metabolism ; Cytotoxins/*chemistry/*pharmacology ; Enzyme Activation/drug effects ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Intracellular Space/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Neutral Red ; Organometallic Compounds/*chemistry/*pharmacology ; Osteoblasts/cytology/*drug effects/metabolism ; Oxygen/*chemistry ; Rats ; Reactive Oxygen Species/metabolism ; Vanadium/*chemistry ; }, abstract = {Strong chelating ligands as oxodiacetate (oda) are model systems to study the process of metal trapping by living organisms. Vanadium compounds display interesting biological and pharmacological actions. In vertebrates, vanadium is stored mainly in bones. In the present study we report the effects of the complex of oda with vanadyl(IV) cation, VO(oda), on two osteoblast cell lines, one normal (MC3T3E1) and the other tumoral (UMR106). VO(oda) exerted cytotoxic actions in osteoblasts as it was determined through a dose-dependent decrease in cell proliferation, and morphological and actin alterations. The putative mechanisms underlying VO(oda) deleterious effects were also investigated. The complex increased the level of ROS which correlated with a decreased in GSH/GSSG ratio. Besides, VO(oda) induced a dissipation of the mitochondria membrane potential (MMP) and promoted an increase in ERK cascade phosphorylation, which is involved in the regulation of cellular death and survival. All the effects were more pronounced in MC3T3-E1 than in UMR106 cells. ERK activation was inhibited by PD98059, Wortmanin and the ROS scavenger NAC (N-acetyl cysteine). These results suggest that VO(oda) stimulated ERKs phosphorilation by induction of free radicals involving kinases upstream of ERK pathway. The inhibitory effect of the complex on cell proliferation was partially reversed in both cell lines by NAC. Moreover, PD98059 and Wortmanin also partially reversed the inhibition of cell proliferation in the tumoral osteoblasts. The use of specific inhibitors and ROS scavengers suggested the involvement of oxidative stress, MMP alterations and ERK pathway in the apoptotic actions of this complex.}, }
@article {pmid20402549, year = {2010}, author = {Hwang, ES and Lee, HJ}, title = {Effects of phenylethyl isothiocyanate and its metabolite on cell-cycle arrest and apoptosis in LNCaP human prostate cancer cells.}, journal = {International journal of food sciences and nutrition}, volume = {61}, number = {3}, pages = {324-336}, doi = {10.3109/09637481003639092}, pmid = {20402549}, issn = {1465-3478}, mesh = {Acetylcysteine/metabolism/pharmacology/therapeutic use ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Brassicaceae/*chemistry ; CDC2 Protein Kinase/genetics/metabolism ; Cell Cycle/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin B1/genetics/metabolism ; Dose-Response Relationship, Drug ; Down-Regulation ; Gene Expression ; Glucosinolates/metabolism ; Humans ; Isothiocyanates/metabolism/*pharmacology/therapeutic use ; Male ; Phytotherapy ; Plant Extracts/*pharmacology/therapeutic use ; Prostatic Neoplasms/*drug therapy ; }, abstract = {Cruciferous vegetable consumption is associated with decreased risk of several cancers, including prostate cancer. Gluconasturtiin, one of the predominant glucosinolates in cruciferous vegetables, is hydrolyzed to yield phenylethyl isothiocyanate (PEITC). PEITC absorption and metabolism in humans involves glutathione conjugation followed by conversion via the mercapturic acid pathway to an N-acetylcysteine (NAC) conjugate that is excreted in the urine. We observed an inhibitory effect of PEITC and its metabolite, NAC-PEITC, on cancer cell proliferation, cell-cycle progression, and apoptosis in LNCaP human prostate cancer cells. PEITC and NAC-PEITC suppressed LNCaP cell proliferation in a dose-dependent manner, and exposure to 5 microM PEITC or NAC-PEITC reduced cell proliferation by 25% and 30%, respectively. Cell-cycle analysis revealed that cells treated with 5 microM PEITC or NAC-PEITC arrested at the G(2)/M phase. In addition, the percentage of cells in the S phase decreased from 46% to 25% following 48 h of incubation with PEITC or NAC-PEITC. The G(2)/M-phase cell-cycle arrest of LNCaP cells grown in the presence of PEITC or NAC-PEITC is correlated with the downregulation of Cdk1 and cyclin B(1) protein expression. Apoptosis was observed at the later stages of 24-h and 48-h treatments with 5 microM PEITC and NAC-PEITC. In conclusion, PEITC and NAC-PEITC are potential chemopreventive/chemotherapeutic agents against LNCaP human prostate cancer cells.}, }
@article {pmid20401649, year = {2010}, author = {Joshi, D and Mittal, DK and Shrivastava, S and Shukla, S}, title = {Protective role of thiol chelators against dimethylmercury induced toxicity in male rats.}, journal = {Bulletin of environmental contamination and toxicology}, volume = {84}, number = {5}, pages = {613-617}, doi = {10.1007/s00128-010-9982-3}, pmid = {20401649}, issn = {1432-0800}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/drug effects/enzymology ; Chelating Agents/chemistry/*pharmacology ; Disease Models, Animal ; Dithiothreitol/*pharmacology ; Enzymes/metabolism ; Kidney/drug effects/enzymology ; Lipid Peroxidation ; Liver/drug effects/enzymology ; Male ; Mercury Poisoning, Nervous System/metabolism/*prevention &amp; control ; Methylmercury Compounds/*toxicity ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/chemistry/*pharmacology ; }, abstract = {The present study was undertaken to establish mode of action, comparative therapeutic efficacy and safety evaluation of N-acetyl cysteine and dithiothreitol against acute dimethylmercury poisoning in rats. Male Sprague-Dawley albino rats (150 +/- 10 g) were randomly divided into six groups. Group 1 served as control. Group 2-4 were administered dimethylmercury (10 mg/kg, p.o.) once only and group 2 served as experimental control. Animals of group 3 and 4 were received N-acetyl cysteine and dithiothreitol. Compared to the control, significant increase (p < or = 0.05) was observed in the activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lipid peroxidation level and mercury ion concentration, however reduced glutathione, catalase, adenosine triphosphatase, acetyl cholinesterase (in brain only) were also decreased. It was concluded that N-acetyl cysteine provided maximum protection when compared with dithiothreitol group.}, }
@article {pmid20399802, year = {2010}, author = {Voghel, G and Thorin-Trescases, N and Mamarbachi, AM and Villeneuve, L and Mallette, FA and Ferbeyre, G and Farhat, N and Perrault, LP and Carrier, M and Thorin, E}, title = {Endogenous oxidative stress prevents telomerase-dependent immortalization of human endothelial cells.}, journal = {Mechanisms of ageing and development}, volume = {131}, number = {5}, pages = {354-363}, pmid = {20399802}, issn = {1872-6216}, support = {14496-4/CAPMC/CIHR/Canada ; }, mesh = {Acetylcysteine/pharmacology ; Aged ; Atherosclerosis/enzymology/*physiopathology ; Cells, Cultured ; *Cellular Senescence ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Damage ; Endothelial Cells/drug effects/*enzymology ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Male ; Middle Aged ; *Oxidative Stress ; Risk ; Telomerase/*metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {INTRODUCTION: With aging, oxidative stress accelerates vascular endothelial cell (EC) telomere shortening-induced senescence, and may promote atherosclerosis in humans. Our aim was to investigate whether an antioxidant treatment combined with telomerase (hTERT) over-expression would prevent senescence of EC isolated from patients with severe atherosclerosis.<br><br>METHODS: Cells were isolated from internal mammary arteries (n=11 donors), cultured until senescence with or without N-acetylcystein (NAC) and infected, or not, with a lentivirus over-expressing hTERT.<br><br>RESULTS: Compared to control EC, hTERT-NAC cells had increased telomerase activity, longer telomeres and underwent more cell divisions. According to the donor, hTERT-NAC either delayed (n=5) or prevented (n=4) EC senescence, the latter leading to cell immortalization. Lack of cell immortalization by hTERT-NAC was accompanied by an absence of beneficial effect of NAC alone in paired EC. Accordingly, lack of EC immortalization by hTERT-NAC was associated with high endogenous susceptibility to oxidation. In EC where hTERT-NAC did not immortalize EC, p53, p21 and p16 expression increased with senescence, while oxidative-dependent DNA damage associated with senescence was not prevented.<br><br>CONCLUSION: Our data suggest that irreversible oxidative stress-dependent damages associated with cardiovascular risk factors are responsible for senescence of EC from atherosclerotic patients.}, }
@article {pmid20399762, year = {2010}, author = {Gonçalves, JF and Fiorenza, AM and Spanevello, RM and Mazzanti, CM and Bochi, GV and Antes, FG and Stefanello, N and Rubin, MA and Dressler, VL and Morsch, VM and Schetinger, MR}, title = {N-acetylcysteine prevents memory deficits, the decrease in acetylcholinesterase activity and oxidative stress in rats exposed to cadmium.}, journal = {Chemico-biological interactions}, volume = {186}, number = {1}, pages = {53-60}, doi = {10.1016/j.cbi.2010.04.011}, pmid = {20399762}, issn = {1872-7786}, mesh = {Acetylcholinesterase/*metabolism ; Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Behavior, Animal/drug effects ; Brain/drug effects/enzymology/metabolism ; Cadmium/*adverse effects/pharmacokinetics ; Creatinine/blood ; Lipid Peroxidation/drug effects ; Male ; Memory Disorders/chemically induced/*prevention &amp; control ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; Urea/blood ; }, abstract = {The present study investigated the effect of the administration of N-acetylcysteine (NAC), on memory, on acetylcholinesterase (AChE) activity and on lipid peroxidation in different brain structures in cadmium (Cd)-exposed rats. The rats received Cd (2 mg/kg) and NAC (150 mg/kg) by gavage every other day for 30 days. The animals were divided into four groups (n=12-13): control/saline, NAC, Cd, and Cd/NAC. The results showed a decrease in step-down latency in the Cd-group, but NAC reversed the impairment of memory induced by Cd intoxication. Rats exposed to Cd and/or treated with NAC did not demonstrate altered shock sensitivity. Decreased AChE activity was found in hippocampus, cerebellum and hypothalamus in the Cd-group but NAC reversed this effect totally or partially while in cortex synaptosomes and striatum there was no alteration in AChE activity. An increase in TBARS levels was found in hippocampus, cerebellum and hypothalamus in the Cd-group and NAC abolished this effect while in striatum there was no alteration in TBARS levels. Urea and creatinine levels were increased in serum of Cd-intoxicated rats, but NAC was able to abolish these undesirable effects. The present findings show that treatment with NAC prevented the Cd-mediated decrease in AChE activity, as well as oxidative stress and consequent memory impairment in Cd-exposed rats, demonstrating that this compound may modulate cholinergic neurotransmission and consequently improve cognition. However, it is necessary to note that the mild renal failure may be a contributor to the behavioral impairment found in this investigation.}, }
@article {pmid20397369, year = {2010}, author = {McCaddon, A and Hudson, PR}, title = {L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer's disease-related cognitive decline.}, journal = {CNS spectrums}, volume = {15}, number = {1 Suppl 1}, pages = {2-5; discussion 6}, doi = {10.1017/s1092852900027589}, pmid = {20397369}, issn = {1092-8529}, mesh = {Acetylcysteine/*therapeutic use ; Alzheimer Disease/blood/cerebrospinal fluid/*complications/pathology ; Cognition Disorders/blood/cerebrospinal fluid/*drug therapy/*etiology ; Free Radical Scavengers/*therapeutic use ; Homocysteine/blood/cerebrospinal fluid ; Humans ; Oxidative Stress ; Plaque, Amyloid/pathology ; Tetrahydrofolates/*therapeutic use ; Vitamin B 12/*analogs &amp; derivatives/therapeutic use ; Vitamin B Complex/therapeutic use ; }, abstract = {Neuroinflammatory oxidative stress occurs early in AD pathology. Elevated blood Hcy is a useful marker for such neuroinflammation. Hcy contributes to pathological cascades involving AP and NFTs. In AD, Hcy should be lowered by B-vitamin supplements and NAC.}, }
@article {pmid20397276, year = {2010}, author = {Moreno-Otero, R and Trapero-Marugán, M}, title = {Hepatoprotective effects of antioxidants in chronic hepatitis C.}, journal = {World journal of gastroenterology}, volume = {16}, number = {15}, pages = {1937-1938}, pmid = {20397276}, issn = {2219-2840}, mesh = {Acetylcysteine/chemistry ; Antioxidants/metabolism/*therapeutic use ; Disease Progression ; Fatty Liver ; Fibrosis ; Hepacivirus/genetics ; Hepatitis C, Chronic/*drug therapy/*pathology ; Humans ; Liver/*drug effects/pathology ; Nitric Oxide/chemistry ; Oxidative Stress ; S-Adenosylmethionine/chemistry ; Virus Replication ; }, abstract = {We have read with interest the paper published in issue 2, volume 16 of World Journal of Gastroenterology 2010 by Nakamura et al, demonstrating that the antioxidant resveratrol (RVT) enhances hepatitis C virus (HCV) replication, consequently, they conclude that RVT is not a suitable antioxidant therapy for HCV chronic infection. The data raise some concern regarding the use of complementary and alternative medicine since the most frequent supplements taken by these patients are antioxidants or agents that may be beneficial for different chronic liver diseases. A recent study by Vidali et al on oxidative stress and steatosis in the progression of chronic hepatitis C concludes that oxidative stress and insulin resistance contribute to steatosis, thus accelerating the progression of fibrosis. We are particularly interested in investigating how the oxidative and nitrosative stress mechanisms are involved in the pathogenesis of different chronic liver diseases.}, }
@article {pmid20395226, year = {2010}, author = {Ozhan, H and Erden, I and Ordu, S and Aydin, M and Caglar, O and Basar, C and Yalcin, S and Alemdar, R}, title = {Efficacy of short-term high-dose atorvastatin for prevention of contrast-induced nephropathy in patients undergoing coronary angiography.}, journal = {Angiology}, volume = {61}, number = {7}, pages = {711-714}, doi = {10.1177/0003319710364216}, pmid = {20395226}, issn = {1940-1574}, mesh = {Acetylcysteine/administration &amp; dosage ; Acute Kidney Injury/*chemically induced/physiopathology/*prevention &amp; control ; Adult ; Atorvastatin ; Contrast Media/*adverse effects ; *Coronary Angiography ; Creatinine/blood ; Female ; Glomerular Filtration Rate ; Heptanoic Acids/*administration &amp; dosage ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*administration &amp; dosage ; Male ; Middle Aged ; Pyrroles/*administration &amp; dosage ; }, abstract = {Contrast-induced nephropathy (CIN) is associated with increased morbidity, extended hospital stay, and higher costs. We compared an atorvastatin plus N-acetylcysteine (NAC) regimen with NAC alone in patients undergoing coronary angiography. A total of 130 patients (mean age 54 +/- 10; 77 men) undergoing coronary angiography were studied. Seven CIN cases occurred in the NAC group and 2 in the atorvastatin + NAC group; this difference was not significant. Baseline mean creatinine and estimated glomerular filtration rate (eGFR) were similar between the 2 groups, whereas after the procedure there was a significant creatinine decrease and eGFR increase in the atorvastatin + NAC group. Change in creatinine (baseline creatinine-creatinine after the procedure) was also significantly higher in patients taking statin plus NAC. Atorvastatin may be effective in protecting patients undergoing coronary angiography from CIN.}, }
@article {pmid20393599, year = {2010}, author = {Liu, Y and Templeton, DM}, title = {Role of the cytoskeleton in Cd2+-induced death of mouse mesangial cells.}, journal = {Canadian journal of physiology and pharmacology}, volume = {88}, number = {3}, pages = {341-352}, doi = {10.1139/Y09-133}, pmid = {20393599}, issn = {1205-7541}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Cadmium Chloride/*toxicity ; Cell Death/drug effects/genetics/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cytochalasin D/pharmacology ; Cytoskeleton/drug effects/genetics/*physiology ; Depsipeptides/pharmacology ; Membrane Potential, Mitochondrial/drug effects/genetics ; Mesangial Cells/*cytology/drug effects/*physiology ; Mice ; Reactive Oxygen Species/metabolism ; }, abstract = {Cadmium induces apoptotic cell death in mouse mesangial cells that is in part dependent on reactive oxygen species (ROS). Cadmium also activates multiple kinases in these cells, including the Ca2+/calmodulin-dependent protein kinase II (CaMK-II) and p38 kinase, and also leads to disruption of the filamentous actin cytoskeleton. We investigated the role of the cytoskeleton in Cd2+-induced cell death. Cell viability was decreased by Cd2+ and two types of apoptotic death, defined by flow cytometry, were increased. Disruption of actin filaments with cytochalasin D was partially protective, whereas stabilization of the cytoskeleton with jasplakinolide was without effect, indicating that cytoskeletal disruption contributes to, but is not necessary for, induction of apoptosis. Inhibition of CaMK-II and p38 kinase, mitochondrial stabilization with cyclosporine A, and the antioxidant N-acetyl cysteine all protected against apoptosis and prevented disruption of the cytoskeleton. Cytochalasin D decreased Cd2+-dependent ROS production, reduced the decline in mitochondrial membrane potential, and decreased phosphorylation of p38 kinase. We conclude that Cd2+-dependent actin disruption is a downstream event facilitating apoptotic death. Cadmium-dependent cell death involves actin-dependent mitochondrial changes, ROS production, and p38 activation.}, }
@article {pmid20392243, year = {2010}, author = {Srinivasan, S and Koenigstein, A and Joseph, J and Sun, L and Kalyanaraman, B and Zaidi, M and Avadhani, NG}, title = {Role of mitochondrial reactive oxygen species in osteoclast differentiation.}, journal = {Annals of the New York Academy of Sciences}, volume = {1192}, number = {1}, pages = {245-252}, pmid = {20392243}, issn = {1749-6632}, support = {T35 RR007065/RR/NCRR NIH HHS/United States ; RR07065/RR/NCRR NIH HHS/United States ; CA-22762/CA/NCI NIH HHS/United States ; R01 CA022762-29A1/CA/NCI NIH HHS/United States ; R01 CA022762/CA/NCI NIH HHS/United States ; R37 CA022762/CA/NCI NIH HHS/United States ; }, mesh = {Acid Phosphatase/metabolism ; Animals ; Antioxidants/pharmacology ; Calcineurin/metabolism ; Cell Differentiation/*drug effects ; Cell Hypoxia/drug effects/physiology ; Cells, Cultured ; Isoenzymes/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/*metabolism/physiology ; NF-kappa B/metabolism ; Organophosphorus Compounds/pharmacology ; Osteoclasts/*drug effects/physiology ; Reactive Oxygen Species/metabolism/*pharmacology ; Tartrate-Resistant Acid Phosphatase ; Ubiquinone/analogs &amp; derivatives/pharmacology ; }, abstract = {Previously we showed that hypoxia-induced mitochondrial respiratory stress in RAW 264.7 macrophages and other cells caused activation of retrograde signaling (also known as mitochondrial respiratory stress signaling) and the appearance of tartrate-resistant acid phosphatase (TRAP)-positive cells. In the present study, we used N-acetyl cysteine and ascorbate (general antioxidants) and MitoQ, a mitochondria-specific antioxidant, to investigate the role of intracellular reactive oxygen species (ROS) in osteoclast differentiation. Our results show that hypoxia-mediated mitochondrial dysfunction, as tested by disruption of mitochondrial transmembrane potential, was suppressed by MitoQ as well as by the other antioxidants. These agents also suppressed the activation of mitochondrial retrograde signaling. Interestingly, in terms of molar concentrations, MitoQ was more than 1000-fold more effective than general antioxidants in suppressing the receptor activator of nuclear factor-B ligand-induced differentiation of RAW 264.7 cells into multinucleated and TRAP-positive osteoclasts. We propose that mitochondrial function and intramitochondrial ROS play important roles in osteoclastogenesis.}, }
@article {pmid20390474, year = {2010}, author = {Post, RM}, title = {Mechanisms of illness progression in the recurrent affective disorders.}, journal = {Neurotoxicity research}, volume = {18}, number = {3-4}, pages = {256-271}, pmid = {20390474}, issn = {1476-3524}, mesh = {Animals ; Cocaine-Related Disorders/complications/psychology ; Disease Progression ; Humans ; Mood Disorders/*etiology/prevention &amp; control/*psychology ; Secondary Prevention ; *Social Environment ; Stress, Psychological/complications/psychology ; }, abstract = {Along with genetic vulnerability, multiple environmental factors convey liability to illness progression, including: (1) distal and proximal stressors; (2) recurrence of episodes; and (3) comorbid cocaine abuse. Recurrence of each of these can increase responsivity (sensitize) to themselves and cross-sensitize to the two other factors and drive illness progression as seen clinically in increases in cycle acceleration, severity or duration of episodes, treatment refractoriness, disability, cognitive dysfunction, and premature death. Some mechanisms appear common to all three types of sensitization, such as decreases of brain-derived neuroprotective factor (BDNF) in hippocampus and blood, as well as increases in BDNF in the nucleus accumbens, suggesting the possibility that single treatments could ameliorate several of these factors at once. A potential example is N-acetylcysteine (NAC), which decreases bipolar affective illness severity (Berk et al. Biol Psychiatry 64:468–475, 2008) and cocaine reinstatement and craving (Baker et al. Ann N Y Acad Sci 1003:349–351, 2003; LaRowe et al. Am J Addict 15:105–110, 2006). Mechanisms of illness progression also involve epigenetic changes and add further rationale to the existing empirical clinical evidence of the importance of early recognition, treatment, and prevention of affective episodes. Adequate treatment could prevent or ameliorate both the increases in pathological factors and erosion of adaptive factors that propel illness exacerbation and treatment resistance. This view of the sensitization and cross-sensitization among stressors, episodes, and abused substances should lead to a fundamental re-conceptualization of the recurrent affective disorders not as benign, isolated episodes of “mental” illness, but as severe, potentially progressive and lethal medical disorders of brain and body that deserve careful life-long monitoring and treatment.}, }
@article {pmid20388917, year = {2010}, author = {Ozdil, B and Kece, C and Cosar, A and Akkiz, H and Sandikci, M}, title = {Potential benefits of combined N-acetylcysteine and ciprofloxacin therapy in partial biliary obstruction.}, journal = {Journal of clinical pharmacology}, volume = {50}, number = {12}, pages = {1414-1419}, doi = {10.1177/0091270010361257}, pmid = {20388917}, issn = {1552-4604}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Anti-Infective Agents/*therapeutic use ; Bile Ducts/ultrastructure ; Bilirubin/blood ; C-Reactive Protein/analysis ; Cholangiopancreatography, Endoscopic Retrograde ; Cholangitis/*prevention &amp; control ; Cholestasis/blood/*drug therapy/physiopathology/surgery ; Ciprofloxacin/*therapeutic use ; Dilatation, Pathologic/diagnostic imaging ; Double-Blind Method ; Drug Synergism ; Expectorants/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Pilot Projects ; Severity of Illness Index ; Sphincterotomy, Endoscopic ; Ultrasonography ; }, abstract = {This study investigates the potential benefits of antibiotics and N-acetylcysteine (NAC), a mucolytic agent, in patients who are candidates for endoscopic retrograde cholangiopancreatography (ERCP) due to partial bile duct obstruction. In total, 102 patients who had choledocholithiasis and choledochal dilatations by abdominal ultrasonography were included in the study. The patients were divided into placebo and NAC therapy groups. Physiological saline (equal volume with NAC solution) and ciprofloxacin (2 × 200 mg/d intravenously) were administered to the placebo group, and NAC (1800 mg/d intravenously) and ciprofloxacin (2 × 200 mg/d intravenously) were administered to the NAC group. In both groups, treatment protocols were administered for 7 days before ERCP. Total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein (CRP), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), white blood cell (WBC) count, and neutrophil percent (NE%) levels were measured before the 7-day treatment protocol. The same measurements were also evaluated before ERCP. In the NAC group, the levels of ALP, GGT, WBC, CRP, and NE% decreased significantly (P < .001), whereas a significant decrease did not occur in the placebo group. The combined usage of NAC and ciprofloxacin can be an alternative therapeutic option until ERCP is performed in partial cholestatic patients.}, }
@article {pmid20388507, year = {2010}, author = {Moody, TW and Berna, MJ and Mantey, S and Sancho, V and Ridnour, L and Wink, DA and Chan, D and Giaccone, G and Jensen, RT}, title = {Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells.}, journal = {European journal of pharmacology}, volume = {637}, number = {1-3}, pages = {38-45}, pmid = {20388507}, issn = {1879-0712}, support = {Z99 DK999999/ImNIH/Intramural NIH HHS/United States ; ZIA DK053100-25/ImNIH/Intramural NIH HHS/United States ; ZIA DK053101-25/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung/*metabolism/pathology ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/drug effects/genetics/*metabolism ; Gefitinib ; Humans ; Neurokinin B/analogs &amp; derivatives/pharmacology ; Phosphorylation/drug effects ; Phosphotyrosine/*metabolism ; Quinazolines/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, Bombesin/genetics/*metabolism ; Transcriptional Activation/drug effects/physiology ; Tumor Cells, Cultured ; }, abstract = {Neuromedin B (NMB), a member of the bombesin family of peptides, is an autocrine growth factor for many lung cancer cells. The present study investigated the ability of NMB to cause transactivation of the epidermal growth factor (EGF) receptor in lung cancer cells. By Western blot, addition of NMB or related peptides to NCI-H1299 human non-small cell lung cancer (NSCLC) cells, caused phosphorylation of Tyr(1068) of the EGF receptor. The signal was amplified using NCI-H1299 cells stably transected with NMB receptors. The transactivation of the EGF receptor or the tyrosine phosphorylation of ERK caused by NMB-like peptides was inhibited by AG1478 or gefitinib (tyrosine kinase inhibitors) and NMB receptor antagonist PD168368 but not the GRP receptor antagonist, BW2258U89. The transactivation of the EGF receptor caused by NMB-like peptides was inhibited by GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), or transforming growth factor (TGF)alpha antibody. The transactivation of the EGF receptor and the increase in reactive oxygen species caused by NMB-like peptides was inhibited by N-acetylcysteine (NAC) or Tiron. Gefitinib inhibited the proliferation of NCI-H1299 cells and its sensitivity was increased by the addition of PD168368. The results indicate that the NMB receptor regulates EGF receptor transactivation by a mechanism dependent on Src as well as metalloprotease activation and generation of reactive oxygen species.}, }
@article {pmid20385511, year = {2010}, author = {Elgindy, EA and El-Huseiny, AM and Mostafa, MI and Gaballah, AM and Ahmed, TA}, title = {N-acetyl cysteine: could it be an effective adjuvant therapy in ICSI cycles? A preliminary study.}, journal = {Reproductive biomedicine online}, volume = {20}, number = {6}, pages = {789-796}, doi = {10.1016/j.rbmo.2010.03.001}, pmid = {20385511}, issn = {1472-6491}, mesh = {Acetylcysteine/*administration &amp; dosage ; Apoptosis ; Female ; Humans ; Male ; Pregnancy ; Pregnancy Outcome ; *Sperm Injections, Intracytoplasmic ; }, abstract = {This randomized controlled trial tested the hypothesis that addition of N-acetyl cysteine (NAC) can increase the probability of pregnancy in intracytoplasmic sperm injection (ICSI) cycles using the long agonist protocol. Women undergoing ICSI cycles due to male factor were randomly assigned to receive either long protocol (group A, 38 women) or long protocol plus NAC (group B, 38 women). Clinical pregnancy was the primary outcome. Granulosa cell apoptosis, fertilization rate, number of grade-one embryos and ongoing pregnancy were the secondary outcomes. Clinical pregnancy rate was insignificantly higher in NAC group (52.6%) than control (47.4%). Early and late apoptosis were also insignificantly lower in group B than in group A. Irrespective of the used protocol, there was significant negative correlation between both early and late apoptosis and fertilization rate (both P<0.001) and the number of good-quality embryos (P=0.007 and P<0.001, respectively). Pregnant patients had significantly lower early and late apoptosis than those who didn't achieve pregnancy (P<0.001). In conclusion, NAC supplementation did not significantly increase the probability of pregnancy in ICSI cycles using long agonist protocol. It appears that granulosa cell apoptosis may be an important prognosticator for ICSI cycle outcome.}, }
@article {pmid20384467, year = {2010}, author = {Ji, L and Liu, R and Zhang, XD and Chen, HL and Bai, H and Wang, X and Zhao, HL and Liang, X and Hai, CX}, title = {N-acetylcysteine attenuates phosgene-induced acute lung injury via up-regulation of Nrf2 expression.}, journal = {Inhalation toxicology}, volume = {22}, number = {7}, pages = {535-542}, doi = {10.3109/08958370903525183}, pmid = {20384467}, issn = {1091-7691}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Acute Lung Injury/chemically induced/*metabolism/*prevention &amp; control ; Animals ; Glutathione/antagonists &amp; inhibitors/physiology ; Glutathione Reductase/antagonists &amp; inhibitors/physiology ; Male ; NF-E2-Related Factor 2/*biosynthesis/physiology ; Oxidative Stress/drug effects/physiology ; Phosgene/*toxicity ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects/physiology ; Up-Regulation/drug effects/*physiology ; }, abstract = {Previous studies indicated that oxidative stress was involved in phosgene-induced acute lung injury (ALI) and many antioxidants had been used to prevent ALI. N-acetylcysteine (NAC) had been used to protect ALI induced by various types of oxidative stress. Considering the limited information of NAC on phosgene-induced ALI, the purpose of this study was to elucidate the molecular mechanisms of phosgene-induced ALI and the protective effects of NAC. This study discovered that intraperitoneal administration of NAC significantly alleviated phosgene-induced pulmonary edema, as confirmed by decreased lung wet to dry weight ratio and oxidative stress markers. The content of l-gamma-glutamyl-l-cysteinyl-glycine (glutathione; GSH) and the ratio of the reduced and disulfide forms (GSH/GSSG), significant indicators of the antioxidative ability, were apparently inhibited by phosgene exposure. However, both indicators could be reversed by NAC administration, indicating that dysregulation of redox status of glutathione might be the cause of phosgene-induced ALI. The nuclear factor (NF)-E2-related factor 2 (Nrf2), which has been proven to up-regulate the expression of glutathione reductase (GR), was obviously decreased by phosgene exposure. However, NAC administration elevated Nrf2 expression significantly. In conclusion, these data provided the first evidences showing that it was the transcriptional factor Nrf2 that connected phosgene-induced ALI with GSH metabolism. NAC protected against oxidative stress through acting on this newly disclosed Nrf2/GR/GSH pathway, by which NAC elevated the biosynthesis of protective GSH to repair and reconstitute the defense system destroyed by phosgene.}, }
@article {pmid20383874, year = {2010}, author = {Sar, F and Saler, T and Ecebay, A and Saglam, ZA and Ozturk, S and Kazancioglu, R}, title = {The efficacy of n-acetylcysteine in preventing contrast-induced nephropathy in type 2 diabetic patients without nephropathy.}, journal = {Journal of nephrology}, volume = {23}, number = {4}, pages = {478-482}, pmid = {20383874}, issn = {1121-8428}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Contrast Media/*adverse effects ; Diabetes Mellitus, Type 2/*complications ; Diabetic Nephropathies/chemically induced/*prevention &amp; control ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is reported to have potential for prevention of contrast-induced nephropathy(CIN), however, there is not enough data related to its effects on diabetic patients without nephropathy.<br><br>METHODS: A total of 45 diabetic patients without nephropathy undergoing a computerized tomography (CT) investigation and who would be receiving radio-opaque medication (300 mg iohexaol/100 mL) were enrolled. They were randomized to have either high-dose NAC (1200 mg) plus saline hydration (Group 1, n=25) or only saline hydration (Group 2; n=20). Serum creatinine levels were determined 72 hours post-contrast. CIN was defined as 0.3 mg/dL elevation of creatinine from baseline and/or an increment of 20% over baseline creatinine and/or 20% decrement of estimated GFR.<br><br>RESULTS: In Group 1, serum creatinine decreased from 0.83 to 0.79 mg/dL, whereas serum creatinine increased from 0.81 to 0.94 mg/dL in Group 2 (not significant for both groups). However there was a significant difference between the creatinine variation of two groups (p=0.031). Furthermore, the groups were analyzed according to overall incidence of CIN. The increase of serum creatinine and decrement of estimated GFR in Group 2 were significantly higher than in Group 1.<br><br>CONCLUSION: Adding NAC to saline hydration seems more beneficial than saline hydration alone in preventing contrast-induced renal function deterioration in type 2 diabetic patients without nephropathy.}, }
@article {pmid20371723, year = {2010}, author = {Prasad, S and Ravindran, J and Sung, B and Pandey, MK and Aggarwal, BB}, title = {Garcinol potentiates TRAIL-induced apoptosis through modulation of death receptors and antiapoptotic proteins.}, journal = {Molecular cancer therapeutics}, volume = {9}, number = {4}, pages = {856-868}, pmid = {20371723}, issn = {1538-8514}, support = {CA-124787-01A2/CA/NCI NIH HHS/United States ; P01 CA124787/CA/NCI NIH HHS/United States ; P01 CA124787-020002/CA/NCI NIH HHS/United States ; P01 CA091844/CA/NCI NIH HHS/United States ; CA-16 672/CA/NCI NIH HHS/United States ; P01 CA091844-020004/CA/NCI NIH HHS/United States ; P01 CA124787-01A20002/CA/NCI NIH HHS/United States ; P01 CA091844-010004/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/*metabolism ; CCAAT-Enhancer-Binding Proteins/metabolism ; Cell Line, Tumor ; Colonic Neoplasms/enzymology/pathology ; Down-Regulation/drug effects ; Drug Resistance, Neoplasm/drug effects ; Drug Screening Assays, Antitumor ; Drug Synergism ; Enzyme Activation/drug effects ; Gene Knockdown Techniques ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Death Domain/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; Terpenes/chemistry/*pharmacology ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation/drug effects ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Whether garcinol, the active component of Garcinia indica, can modulate the sensitivity of cancer cells to TRAIL, a cytokine currently in phase II clinical trial, was investigated. We found that garcinol potentiated TRAIL-induced apoptosis of cancer cells as indicated by intracellular esterase activity, DNA strand breaks, accumulation of the membrane phospholipid phosphatidylserine, mitochondrial activity, and activation of caspase-8, -9, and -3. We found that garcinol, independent of the cell type, induced both of the TRAIL receptors, death receptor 4 (DR4) and DR5. Garcinol neither induced the receptors on normal cells nor sensitized them to TRAIL. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and garcinol. In addition, garcinol downregulated various cell survival proteins including survivin, bcl-2, XIAP, and cFLIP, and induced bid cleavage, bax, and cytochrome c release. Induction of death receptors by garcinol was found to be independent of modulation of CCAAT/enhancer-binding protein-homologous protein, p53, bax, extracellular signal-regulated kinase, or c-Jun-NH(2)-kinase. The effect of garcinol was mediated through the generation of reactive oxygen species, in as much as induction of both death receptors, modulation of antiapoptotic and proapoptotic proteins, and potentiation of TRAIL-induced apoptosis were abolished by N-acetyl cysteine and glutathione. Interestingly, garcinol also converted TRAIL-resistant cells into TRAIL-sensitive cells. Overall, our results indicate that garcinol can potentiate TRAIL-induced apoptosis through upregulation of death receptors and downregulation of antiapoptotic proteins. Mol Cancer Ther; 9(4); 856-68. (c)2010 AACR.}, }
@article {pmid20370558, year = {2010}, author = {Aluf, Y and Vaya, J and Khatib, S and Loboda, Y and Kizhner, S and Finberg, JP}, title = {Specific oxidative stress profile associated with partial striatal dopaminergic depletion by 6-hydroxydopamine as assessed by a novel multifunctional marker molecule.}, journal = {Free radical research}, volume = {44}, number = {6}, pages = {635-644}, doi = {10.3109/10715761003692529}, pmid = {20370558}, issn = {1029-2470}, mesh = {Adrenergic Agents/toxicity ; Animals ; Brain Chemistry/drug effects ; Chromatography, High Pressure Liquid ; Chromatography, Liquid ; Corpus Striatum/*metabolism ; Deoxyguanosine/*analogs &amp; derivatives ; Dopamine/metabolism ; Free Radicals/*analysis ; Immunohistochemistry ; *Linoleic Acid ; *Linoleic Acids ; Male ; Microdialysis/*methods ; Oxidative Stress/*physiology ; Oxidopamine/toxicity ; Rats ; Rats, Sprague-Dawley ; Tandem Mass Spectrometry ; }, abstract = {Real time oxidative stress in the extracellular compartment of rat striatum was characterized by microdialysis with synthetic non-dialyzable marker molecules composed of linoleic acid, tyrosine and guanosine (N-linoleoyl tyrosine (LT) and N-linoleoyl tyrosine 2'-deoxyguanosyl ester (LTG)). Partial dopaminergic deafferentation was induced by injection of 6-hydroxydopamine (250 microg) to the left lateral ventricle, which depleted ipsilateral striatal dopamine by 46% and dopaminergic cells in left substantia nigra by 44%, 5 weeks after administration. Resting microdialysate dopamine levels in dopamine-depleted striatum were not different from sham-operated rats, although the ratio of oxidized metabolites of dopamine to free dopamine was significantly increased. Hydroperoxide and epoxy products of the linoleoyl portion of LT and LTG were detected in the striatal microdialysate by LC/MS/MS following initial separation by HPLC and were significantly increased in dopamine-depleted compared with control striatum without an increase in guanosine or tyrosine oxidation or nitration. Systemic administration of N-acetyl cysteine (350 mg/kg i.p.) decreased the increment in hydroperoxide and epoxy metabolites to levels not significantly different from control. Oxidation activity towards polyunsaturated fatty acids is present in the extracellular space of partially dopamine-denervated striatum, whereas oxidized glutathione and oxysterol levels in striatal tissue are decreased, possibly indicative of a compensatory response.}, }
@article {pmid20368026, year = {2010}, author = {Chen, J and Li, B and Ran, PX}, title = {[N-acetyl-L-cysteine inhibits adenoviral E1A-involved transactivation of nuclear factor-kappaB in rat alveolar epithelial cells.].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {33}, number = {1}, pages = {51-55}, pmid = {20368026}, issn = {1001-0939}, mesh = {Acetylcysteine/*pharmacology ; Adenoviridae/genetics ; Adenovirus E1A Proteins/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Line ; Epithelial Cells ; NF-kappa B/*metabolism ; Pulmonary Alveoli/cytology ; Rats ; Transcriptional Activation ; }, abstract = {OBJECTIVE: the relationship between latent adenovirus infection and airway inflammation had not been well documented. The aim of this study was to illustrate the roles of adenovirus E1A protein on the transactivation of NF-kappaB, AP-1 in response to inflammatory stimuli and the effect of N-Acetylcysteine (NAC) upon the transactivation of NF-kappaB and AP-1 in cells stably expressing E1A protein.<br><br>METHODS: rat alveolar epithelial cells stably expressing adenoviral E1A or control plasmid were developed. For isolation of nuclear extracts, 5 x 10(5) cells were plated and grown overnight in 60 mm dishes. Experiments were repeated 3 times. The cell model of stably expressing adenoviral E1A was stimulated by LPS or TNF-alpha and treated with NAC, a precursor for cysteine. The NF-kappaB and AP-1 transcriptional activity were measured by LUC report system. The expression of NF-kappaB and AP-1 were measured by Western blot. Differences between groups were assessed for significance by Student' t test, and multiple comparisons were made by one-way ANOVA.<br><br>RESULTS: the luciferase activity derived by NF-kappaB element was (9 698 +/- 98) RLU in untreated E1A-positive clones and (101 195 +/- 234), and (170 385 +/- 443) RLU in LPS and TNF-alpha-stimulated cells, which were significantly higher than that of the control group 2 077 +/- 107, 67 846 +/- 332, 95 743 +/- 211 respectively. The luciferase activity derived by AP-1 element was 9 034 +/- 78 RLU in untreated E1A-positive clones and 26 343 +/- 398 and 31 731 +/- 332 RLU in LPS and TNF-alpha-stimulated cells, which were significantly higher than that of the control group 2 845 +/- 93, 10 772 +/- 432, 11 005 +/- 556 respectively. The densitometry of the NF-kappaB expression in E1A-positive clones were 79.3 +/- 4.6 and 80.3 +/- 3.8 respectively without treatment and were 81.8 +/- 3.9 - 89.9 +/- 1.6 and 94.1 +/- 1.9 to 99.8 +/- 1.6 respectively under LPS or TNF-alpha stimulation, which were significantly higher than that of the control group (68.3 +/- 3.8, 69.4 +/- 4.3 respectively) without stimulation and 70.1 +/- 2.8 to 80.8 +/- 3.6, 73.4 +/- 4.9 to 83.2 +/- 6.7 respectively under stimulation. The level of AP-1 expression did not show difference upon treatment with LPS or TNF-alpha in either cell clones. The densitometry of the NF-kappaB expression in E1A-positive clones were 3.2 +/- 0.1 and 3.3 +/- 0.1 respectively under LPS and TNF-alpha-stimulation and 1.98 +/- 0.2 and 1.9 +/- 0.2 respectively upon treatment for LPS and TNF-alpha with NAC pre-incubation.<br><br>CONCLUSIONS: these results indicate that E1A protein upregulated NF-kappaB transcription activity induced by LPS and TNF-alpha in rat alveolar epithelial cells and this effect could be repressed by NAC. The mechanisms underlying transactivation of NF-kappaB involved by E1A may be related to oxidative stress.}, }
@article {pmid20364116, year = {2010}, author = {Shutt, DC and O'Dorisio, MS and Aykin-Burns, N and Spitz, DR}, title = {2-deoxy-D-glucose induces oxidative stress and cell killing in human neuroblastoma cells.}, journal = {Cancer biology &amp; therapy}, volume = {9}, number = {11}, pages = {853-861}, pmid = {20364116}, issn = {1555-8576}, support = {R01CA133114/CA/NCI NIH HHS/United States ; R01 CA133114-01A1/CA/NCI NIH HHS/United States ; R01 CA133114/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; P30CA086862/CA/NCI NIH HHS/United States ; R01 CA100045/CA/NCI NIH HHS/United States ; R01CA100045-S1/CA/NCI NIH HHS/United States ; R01 CA100045-04S1/CA/NCI NIH HHS/United States ; R01CA100045/CA/NCI NIH HHS/United States ; R01 CA100045-02/CA/NCI NIH HHS/United States ; P30 CA086862-01/CA/NCI NIH HHS/United States ; }, mesh = {AC133 Antigen ; Acetylcysteine/*pharmacology ; Antigens, CD/metabolism ; Antimetabolites/pharmacology ; Antioxidants/*pharmacology ; Catalase/chemistry/pharmacology ; Cell Line ; Cell Line, Tumor ; Cell Survival/drug effects ; Deoxyglucose/*pharmacology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; GTP-Binding Proteins ; Glycoproteins/metabolism ; Humans ; Immunohistochemistry ; Neuroblastoma/metabolism/pathology ; Neurons/cytology/drug effects/metabolism ; Oxidative Stress/*drug effects ; Peptides/metabolism ; Polyethylene Glycols/chemistry ; Protein Glutamine gamma Glutamyltransferase 2 ; Stem Cells/drug effects/metabolism ; Superoxide Dismutase/chemistry/pharmacology ; Time Factors ; Transglutaminases/metabolism ; Tubulin/metabolism ; }, abstract = {Malignant cells have a demonstrably greater sensitivity to glucose deprivation-induced cytotoxicity than normal cells. This has been hypothesized to be due to a higher level of reactive oxygen species (ROS) production in cancer cells leading to the increased need for reducing equivalents, produced by glucose metabolism, to detoxify hydroperoxides. Because complete glucose deprivation cannot be achieved in vivo, it has been proposed that agents that antagonize glucose metabolism, such as 2-deoxy-D-glucose (2DG), can mimic in vitro glucose deprivation that selectively kills cancer cells by oxidative stress. To test this hypothesis, neuroblastoma cell lines were treated with 2DG and the effects on clonogenic survival and the distribution of cellular phenotypes among surviving colonies was determined. The results showed that all three major cell types found in neuroblastoma (Schwann, Neuronal and Intermediate) were sensitive to 2DG-induced clonogenic cell killing. Furthermore, treatment with the thiol antioxidant, N-acetyl cysteine or with polyethylene glycol-conjugated superoxide dismutase and catalase, protected neuroblastoma cells from 2DG-induced cell killing. Finally normal non-immortalized neural precursor cells were relatively resistant to 2DG-induced cell killing when compared to neuroblastoma cell lines. These results support the hypothesis that inhibitors of glucose metabolism could represent useful adjuvants in the treatment of neuroblastoma by selectively enhancing metabolic oxidative stress.}, }
@article {pmid20363232, year = {2010}, author = {Hsin, IL and Sheu, GT and Chen, HH and Chiu, LY and Wang, HD and Chan, HW and Hsu, CP and Ko, JL}, title = {N-acetyl cysteine mitigates curcumin-mediated telomerase inhibition through rescuing of Sp1 reduction in A549 cells.}, journal = {Mutation research}, volume = {688}, number = {1-2}, pages = {72-77}, doi = {10.1016/j.mrfmmm.2010.03.011}, pmid = {20363232}, issn = {0027-5107}, mesh = {Acetylcysteine/*pharmacology ; Adenocarcinoma/*metabolism ; Cell Line, Tumor ; Cell Shape/drug effects ; Cell Survival/drug effects ; Curcumin/*pharmacology ; Down-Regulation ; Humans ; Lung Neoplasms/*metabolism ; Reactive Oxygen Species ; Sp1 Transcription Factor/*antagonists &amp; inhibitors ; Telomerase/antagonists &amp; inhibitors/metabolism ; }, abstract = {Curcumin is a natural compound that has been extensively observed due to its potential as an anticancer drug. Curcumin restrains cancer cell progression via telomerase activity suppression. However, the exact mechanism is still unknown. In this study, we demonstrate that the effects of curcumin on cell viability and telomerase activity can be blunted by reactive oxygen species (ROS) inhibitor N-acetyl cysteine (NAC). The ROS induced by curcumin in A549 cells was detected by flow cytometry. Using Western blot and RT-PCR, human telomerase reverse transcriptase (hTERT) decreased in the presence of curcumin. Sp1 is one of the important transcription factors in hTERT expression. Our data showed that curcumin decreases the expression of Sp1 through proteasome pathway. In addition, NAC blunted the Sp1 reduction and hTERT downregulation by curcumin. Further, reporter assay and DNA affinity precipitation assay confirmed the influence of curcumin on Sp1 in hTERT regulation. This is the first study to demonstrate that curcumin induces ROS production resulting in Sp1 binding activity inhibition and hTERT downregulation.}, }
@article {pmid20360923, year = {2010}, author = {Junior, RF and Kubrusly, MS and Bellodi-Privato, M and Molan, NA and Machado, MC and D'Albuquerque, LA}, title = {Beneficial effects of N-acetyl cysteine on pancreas and kidney following experimental pancreatic ischemia-reperfusion in rats.}, journal = {Clinics (Sao Paulo, Brazil)}, volume = {65}, number = {3}, pages = {311-316}, pmid = {20360923}, issn = {1980-5322}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Glutathione Transferase/blood ; Kidney/*drug effects ; Pancreas/blood supply/*drug effects ; Random Allocation ; Rats ; Rats, Wistar ; Reperfusion Injury/blood/*drug therapy ; }, abstract = {OBJECTIVE: To evaluate the protective effects of N-acetyl cysteine on the pancreas and kidney after pancreatic ischemia reperfusion injury in a rat model.<br><br>METHODS AND MATERIALS: Pancreatic ischemia reperfusion was performed in Wistar rats for 1 hour. Revascularization was achieved followed by 4 h of reperfusion. A total of 24 animals were divided into four groups: Group 1: sham; Group 2: pancreatic ischemia reperfusion without treatment; Group 3: pancreatic ischemia reperfusion plus N-acetyl cysteine intravenously; and Group 4: pancreatic ischemia reperfusion plus N-acetyl cysteine per os. Blood and tissue samples were collected after reperfusion.<br><br>RESULTS: There were significant differences in amylase levels between Group 1 (6.11+/-0.55) and Group 2 (10.30+/-0.50) [p=0.0002] as well as between Group 2 (10.30+/-0.50) and Group 4 (7.82+/-0.38) [p=0.003]; creatinine levels between Group 1 (0.52 +/- 0.07) and Group 2 (0.77+/-0.18) [p=0.035] as well as between Group 2 (0.77+/-0.18) and Group 3 (0.48+/-0.13) [p=0.012]; and pancreatic tissue thiobarbituric acid reactive substance levels between Group 1 (1.27+/-0.96) and Group 2 (2.60+/-3.01) [p=0.026] as well as between Group 2 (2.60+/-3.01) and Group 4 (0.52+/-0.56) [p=0.002]. A decrease in pancreatic tissue GST-alpha3 gene expression was observed in Group 2 in comparison to Group 1 (p =0.006), and an increase was observed in Groups 3 and 4 when compared to Group 2 (p= 0.025 and p=0.010, respectively).<br><br>CONCLUSION: This study provides evidence that N-acetyl cysteine has a beneficial effect on pancreatic ischemia reperfusion injury and renal function in a rat model.}, }
@article {pmid20360623, year = {2010}, author = {Radomska-Leśniewska, DM and Skopińska-Rózewska, E and Jankowska-Steifer, E and Sobiecka, M and Sadowska, AM and Hevelke, A and Malejczyk, J}, title = {N-acetylcysteine inhibits IL-8 and MMP-9 release and ICAM-1 expression by bronchoalveolar cells from interstitial lung disease patients.}, journal = {Pharmacological reports : PR}, volume = {62}, number = {1}, pages = {131-138}, doi = {10.1016/s1734-1140(10)70250-4}, pmid = {20360623}, issn = {2299-5684}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Bronchoalveolar Lavage Fluid/*cytology ; Female ; Humans ; Intercellular Adhesion Molecule-1/*biosynthesis ; Interleukin-8/*metabolism ; Leukocyte Count ; Lung Diseases, Interstitial/*metabolism/pathology ; Male ; Matrix Metalloproteinase 9/*metabolism ; Middle Aged ; Pulmonary Fibrosis/metabolism/pathology ; Sarcoidosis, Pulmonary/metabolism/pathology ; Young Adult ; }, abstract = {N-acetylcysteine (NAC), owing to its antioxidant, mucolytic and anti-inflammatory properties, is used in the treatment of various pulmonary disorders. However, the direct effects of NAC on bronchoalveolar lavage (BAL) cells from patients suffering from interstitial lung diseases have not yet been studied. Therefore, the aim of the present work was to evaluate the effect of NAC on interleukin-8 (IL-8) and matrix metalloproteinase-9 (MMP-9) production as well as intercellular cell adhesion molecule-1 (ICAM-1) expression by BAL cells from interstitial lung diseases. The study was performed on BAL cells from nine patients with interstitial lung disease: four patients with idiopathic pulmonary fibrosis (IPF) and five patients with sarcoidosis. Cultured unstimulated BAL cells were treated with increasing doses of NAC (1-30 mM). Production of IL-8 and MMP-9 was evaluated by specific enzyme-linked immuno-sorbent assays and ICAM-1 expression was studied by immunohistochemistry. NAC exerted a dose-dependent inhibitory effect on IL-8 and MMP-9 release and ICAM- expression by BAL macrophages and lymphocytes from patients with IPF and sarcoidosis. In conclusion, NAC inhibits production of factors playing a key role in the etiopathogenesis of interstitial lung diseases, thus suggesting its possible therapeutic potency in the treatment of these disorders.}, }
@article {pmid20359814, year = {2010}, author = {Quan, Z and Gu, J and Dong, P and Lu, J and Wu, X and Wu, W and Fei, X and Li, S and Wang, Y and Wang, J and Liu, Y}, title = {Reactive oxygen species-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to cirsimaritin-induced apoptosis in human gallbladder carcinoma GBC-SD cells.}, journal = {Cancer letters}, volume = {295}, number = {2}, pages = {252-259}, doi = {10.1016/j.canlet.2010.03.008}, pmid = {20359814}, issn = {1872-7980}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Endoplasmic Reticulum/*drug effects/metabolism ; Flavones/*pharmacology ; Gallbladder Neoplasms/*drug therapy/pathology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*physiology ; Proto-Oncogene Proteins c-akt/physiology ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/physiology ; }, abstract = {In this study, the anticancer effect of cirsimaritin, a natural flavonoid, against human gallbladder carcinoma cell line GBC-SD and the underlying mechanisms were investigated. Cirsimaritin inhibited the growth of tumor cells and induced mitochondrial apoptosis in GBC-SD cells. In addition, cirsimaritin triggered endoplasmic reticulum (ER) stress and down-regulated the phosphorylation of Akt, while knock-down of CHOP dramatically abrogated the inactivation of Akt and reversed the pro-apoptotic effect of cirsimaritin. Furthermore, cirsimaritin provoked the generation of reactive oxygen species in GBC-SD cells, while the antioxidant N-acetyl cysteine almost completely blocked the activation of ER stress and apoptosis, suggesting cirsimaritin-induced reactive oxygen species is an early event that triggers ER stress mitochondrial apoptotic pathways in GBC-SD cells.}, }
@article {pmid20358478, year = {2010}, author = {Jeong, JC and Jang, SW and Kim, TH and Kwon, CH and Kim, YK}, title = {Mulberry fruit (Moris fructus) extracts induce human glioma cell death in vitro through ROS-dependent mitochondrial pathway and inhibits glioma tumor growth in vivo.}, journal = {Nutrition and cancer}, volume = {62}, number = {3}, pages = {402-412}, doi = {10.1080/01635580903441287}, pmid = {20358478}, issn = {1532-7914}, mesh = {Apoptosis/*drug effects ; Caspases/physiology ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Glioma/*drug therapy/pathology ; Humans ; Mitochondria/*drug effects/physiology ; *Morus ; *Phytotherapy ; Plant Extracts/*pharmacology ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein/physiology ; }, abstract = {Mulberry has been reported to contain wide range of polyphenols and have chemopreventive activity. However, little has been known regarding the effect of mulberry fruit extracts on cell viability in vitro in human glioma cells and the anticancer efficacy in vivo. This study was undertaken to examine the effect of mulberry fruit (Moris fructus; MF) extracts on cell viability in vitro and anticancer efficacy in vivo. Cell viability and cell death were estimated by MTT assay and trypan blue exclusion assay, respectively. Reactive oxygen species (ROS) generation was measured using the fluorescence probe DCFH-DA. The mitochondrial transmembrane potential was measured with DiOC(6)(3). Bax expression and cytochrome c release were measured by Western blot analysis. Caspase activity was estimated using colorimetric kit. Cell migration was estimated using the scratched wound model. In vivo anticancer efficacy of MF extracts was evaluated using a subcutaneously injected mouse tumor model. Changes in proliferation and apoptosis were estimated by immunohistochemistric analysis. MF extracts resulted in apoptotic cell death in a dose- and time-dependent manner. MF extracts increased ROS generation, and the MF extract-induced cell death was also prevented by antioxidants, suggesting that ROS generation plays a critical role in the MF extract-induced cell death. Western blot analysis showed that treatment of MF extracts caused an increase in Bax expression, which was inhibited by the antioxidant N-acetylcysteine (NAC). MF extracts induced depolarization of mitochondrial membrane potential, and its effect was inhibited by the antioxidants NAC and catalase. MF extracts induced cytochrome c release, which was inhibited by NAC. Caspase activity was stimulated by MF extracts, and caspase inhibitors prevented the MF extract-induced cell death. Treatment of MF extracts inhibited cell migration. Oral MF extracts administration in animals with subcutaneous U87MG glioma cells reduced tumor volume. Subsequent tumor tissue analysis showed a decrease in PCNA-positive cells, an increase in TUNEL-positive cells, and caspase activation. From these data, we concluded that MF extracts reduce glioma tumor growth through inhibition of cell proliferation resulting from induction of apoptosis. These findings suggest that MF extracts result in human glioma cell death in vitro through ROS-dependent mitochondrial pathway and glioma tumor growth in vivo via reduction of tumor cell proliferation and induction of apoptosis.}, }
@article {pmid20358476, year = {2010}, author = {Hilchie, AL and Furlong, SJ and Sutton, K and Richardson, A and Robichaud, MR and Giacomantonio, CA and Ridgway, ND and Hoskin, DW}, title = {Curcumin-induced apoptosis in PC3 prostate carcinoma cells is caspase-independent and involves cellular ceramide accumulation and damage to mitochondria.}, journal = {Nutrition and cancer}, volume = {62}, number = {3}, pages = {379-389}, doi = {10.1080/01635580903441238}, pmid = {20358476}, issn = {1532-7914}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspases/*physiology ; Cell Line, Tumor ; Ceramides/*metabolism ; Curcumin/*pharmacology ; Glutathione/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Male ; Mitochondria/*physiology ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Curcumin, the principal curcuminoid of tumeric, has potent anticancer activity. To determine the mechanism of curcumin-induced cytotoxicity in prostate cancer cells, we exposed PC3 prostate carcinoma cells to 25 to 100 microM curcumin for 24 to 72 h. Curcumin treatment of PC3 cells caused time- and dose-dependent induction of apoptosis and depletion of cellular reduced glutathione (GSH). Exogenous GSH and its precursor N-acetyl-cysteine, but not ascorbic acid (AA) or ebselen, decreased curcumin accumulation in PC3 cells and also prevented curcumin-induced DNA fragmentation. The failure of AA and ebselen to protect PC3 cells from curcumin-induced apoptosis argued against the involvement of reactive oxygen species; rather, GSH-mediated inhibition of curcumin-induced cytotoxicity was due to reduced curcumin accumulation in PC3 cells. Curcumin-treated PC3 cells showed apoptosis-inducing cellular ceramide accumulation and activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK). Caspase-3, caspase-8, and caspase-9 were activated, and cytochrome c and apoptosis-inducing factor (AIF) were released from mitochondria following curcumin treatment. Interestingly, curcumin-induced apoptosis was not prevented by p38 MAPK, JNK, or caspase inhibition. We conclude that curcumin-induced cytotoxicity was due to cellular ceramide accumulation and damage to mitochondria that resulted in apoptosis mediated by AIF and other caspase-independent processes.}, }
@article {pmid20356861, year = {2010}, author = {Satpute, RM and Hariharakrishnan, J and Bhattacharya, R}, title = {Effect of alpha-ketoglutarate and N-acetyl cysteine on cyanide-induced oxidative stress mediated cell death in PC12 cells.}, journal = {Toxicology and industrial health}, volume = {26}, number = {5}, pages = {297-308}, doi = {10.1177/0748233710365695}, pmid = {20356861}, issn = {1477-0393}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Caspase 3/metabolism ; Catalase/metabolism ; DNA Fragmentation/drug effects ; Electrophoresis, Agar Gel ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Ketoglutaric Acids/*pharmacology ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Microscopy, Fluorescence ; Oxidative Stress/*drug effects ; PC12 Cells ; Potassium Cyanide/*toxicity ; Rats ; Superoxide Dismutase/metabolism ; }, abstract = {Cyanide is a mitochondrial poison, which is ubiquitously present in the environment. Cyanide-induced oxidative stress is known to play a key role in mediating the neurotoxicity and cell death in rat pheochromocytoma (PC12) cells. PC12 cells are widely used as a model for neurotoxicity assays in vitro. In the present study, we investigated the protective effects of alpha-ketoglutarate (A-KG), a potential cyanide antidote, and N-acetyl cysteine (NAC), an antioxidant against toxicity of cyanide in PC12 cells. Cells were treated with various concentrations (0.625-1.25 mM) of potassium cyanide (KCN) for 4 hours, in the presence or absence of simultaneous treatment of A-KG (0.5 mM) and NAC (0.25 mM). Cyanide caused marked decrease in the levels of cellular antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR). Lipid peroxidation indicated by elevated levels of malondialdehyde (MDA) was found to be accompanied by decreased levels of reduced glutathione (GSH) and total antioxidant status (TAS) of the cells. Cyanide-treated cells showed notable increase in caspase-3 activity and induction of apoptotic type of cell death after 24 hours. A-KG and NAC alone were very effective in restoring the levels of GSH and TAS, but together they significantly resolved the effects of cyanide on antioxidant enzymes, MDA levels, and caspase-3 activity. The present study reveals that combination of A-KG and NAC has critical role in abbrogating the oxidative stress-mediated toxicity of cyanide in PC12 cells. The results suggest potential role of A-KG and NAC in cyanide antagonism.}, }
@article {pmid20356800, year = {2010}, author = {Rossato, MF and Velloso, NA and de Oliveira Ferreira, AP and de Mello, CF and Ferreira, J}, title = {Spinal levels of nonprotein thiols are related to nociception in mice.}, journal = {The journal of pain}, volume = {11}, number = {6}, pages = {545-554}, doi = {10.1016/j.jpain.2009.09.016}, pmid = {20356800}, issn = {1528-8447}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Acute Disease ; Analgesics/administration &amp; dosage/pharmacology ; Animals ; Antimetabolites/pharmacology ; Arthritis, Experimental/complications/drug therapy/metabolism ; Behavior, Animal/drug effects ; Buthionine Sulfoximine/pharmacology ; Capsaicin ; Disease Models, Animal ; Female ; Foot Injuries/complications/drug therapy/metabolism ; Lipid Peroxidation/drug effects/physiology ; Lumbar Vertebrae ; Male ; Mice ; Oxidative Stress/drug effects/physiology ; Pain/drug therapy/etiology/*metabolism ; Spinal Cord/drug effects/*metabolism ; Sulfhydryl Compounds/administration &amp; dosage/*metabolism/pharmacology ; }, abstract = {UNLABELLED: Oxidative stress markers are thought to be related to nociception. Because thiolic compounds are important antioxidants, we investigated the relationship between thiols, endogenous or exogenous, and nociception. Systemic or spinal, but not peripheral, administration of the exogenous thiolic compound N-acetyl-L-cysteine (NAC) reduced nociception induced by intraplantar capsaicin injection. Moreover, we detected an increase in lipid peroxidation and 3-nitrotyrosine and a decrease in nonprotein thiolic levels in the lumbar spinal cord of capsaicin-injected animals. All these effects were prevented by NAC treatment (i.p. and i.t.). Our findings confirm a role for the spinal cord in NAC actions because systemic NAC administration also reduced the nociception trigged by intrathecal injection of capsaicin. Moreover, adjuvant-induced arthritis, but not paw incision, also -decreases nonprotein thiol levels in the spinal cord. Similarly, NAC produced antinociception in adjuvant-treated animals, but not in paw-incised animals. Finally, we investigated the role of endogenous thiol compounds in the nociceptive process administrating buthionine-suphoxamine (BSO), an inhibitor of glutathione-synthesis. Intrathecal BSO treatment decreased nonprotein thiol levels in the spinal cord, as well as induced mechanical allodynia and chemical and thermal hyperalgesia. In conclusion, our results indicate a critical role for nonprotein thiols in nociception at the level of the spinal cord.<br><br>PERSPECTIVE: The results presented here indicate that the loss of nonprotein thiols in the spinal cord is involved in pain development. Therefore, the administration of thiolic compounds or other strategies allow thiol levels to be maintained and could be a beneficial action in the therapy of painful conditions.}, }
@article {pmid20356045, year = {2010}, author = {Chen, CY and Tai, CJ and Cheng, JT and Zheng, JJ and Chen, YZ and Liu, TZ and Yiin, SJ and Chern, CL}, title = {6-dehydrogingerdione sensitizes human hepatoblastoma Hep G2 cells to TRAIL-induced apoptosis via reactive oxygen species-mediated increase of DR5.}, journal = {Journal of agricultural and food chemistry}, volume = {58}, number = {9}, pages = {5604-5611}, doi = {10.1021/jf904260b}, pmid = {20356045}, issn = {1520-5118}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects/physiology ; Cell Line, Tumor ; Guaiacol/*analogs &amp; derivatives/pharmacology ; Hepatoblastoma/metabolism/*pathology ; Humans ; Liver Neoplasms/metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/*physiology ; }, abstract = {The anticancer effects of 6-dehydrogingerdione (6-DG), a compound isolated from the rhizomes of Zingiber officinale , and its mechanisms of sensitization to TRAIL-induced apoptosis were studied using human hepatoblastoma Hep G2 cells. This study demonstrates for the first time that 6-DG-induced apoptosis might be executed via mitochondrial- and Fas receptor-mediated pathways. Further studies also demonstrated that 6-DG could sensitize Hep G2 cells to TRAIL-induced apoptosis. 6-DG also up-regulated Ser-15 phosphorylation and evoked p53 nuclear translocation. Abrogation of p53 expression by p53 small interfering RNA significantly attenuated 6-DG-induced DR5 expression, thus rendering these cells resistant to TRAIL-induced apoptosis. DR5 expression after 6-DG treatment was accompanied by provoking intracellular reactive oxygen species (ROS) generation. Pretreatment with N-acetyl-l-cysteine (NAC) attenuated 6-DG-induced DR5 expression and inhibited TRAIL-induced apoptosis. In contrast to Hep G2 cells, DR5 up-regulation and sensitization to TRAIL-induced apoptosis instigated by 6-DG were not observed in normal MDCK cells. Taken together, these data suggested that in addition to the mitochondrial- and Fas receptor-mediated apoptotic pathways involved, ROS-dependent and p53-regulated DR5 expression was also demonstrated to play a pivotal role in the synergistic enhancement of TRAIL-induced apoptosis instigated by 6-DG in Hep G2 cells.}, }
@article {pmid20354834, year = {2010}, author = {Zembron-Lacny, A and Slowinska-Lisowska, M and Szygula, Z and Witkowski, Z and Szyszka, K}, title = {Modulatory effect of N-acetylcysteine on pro-antioxidant status and haematological response in healthy men.}, journal = {Journal of physiology and biochemistry}, volume = {66}, number = {1}, pages = {15-21}, pmid = {20354834}, issn = {1138-7548}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Antioxidants/*metabolism ; Erythrocytes/metabolism ; Erythropoietin/blood ; Exercise/physiology ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glutathione/blood ; Glutathione Peroxidase/metabolism ; Hematologic Tests ; Humans ; Lipid Peroxidation ; Male ; Young Adult ; }, abstract = {The aim of this study was to follow up whether the modification of pro-antioxidant status by 8-day oral application of N-acetylcysteine (NAC) in healthy men affects the haematological response, whether there is a direct relationship between antioxidant defences and erythropoietin (EPO) secretion and whether NAC intake enhances exercise performance. Fifteen healthy men were randomly assigned to one of two groups: control or NAC (1,200 mg d(-1) for 8 days prior to and 600 mg on the day of exercise trial). To measure the ergogenic effectiveness of NAC, subjects performed incremental cycle exercise until exhaustion. NAC administration significantly influenced the resting and post-exercise level of glutathione (+31%) as well as the resting activity of glutathione enzymes (glutathione reductase, -22%; glutathione peroxidase, -18%). The oxidative damage markers, i.e., protein carbonylation and lipid peroxidation products (thiobarbituric acid reactive substance) were reduced by NAC by more than 30%. NAC noticeably affected the plasma level of EPO (+26%), haemoglobin (+9%), haematocrit (+9%) and erythrocytes (-6%) at rest and after exercise. The mean corpuscular volume and the mean corpuscular haemoglobin increased by more than 12%. Plasma total thiols increased by 17% and directly correlated with EPO level (r = 0.528, P < 0.05). NAC treatment, contrary to expectations, did not significantly affect exercise performance. Our study has shown that 8-day NAC intake at a daily dose of 1,200 mg favours a pro-antioxidant status and affects haematological indices but does not enhance exercise performance.}, }
@article {pmid20350765, year = {2010}, author = {Suzuki, T and Kubo, K and Hori, N and Yamada, M and Kojima, N and Sugita, Y and Maeda, H and Ogawa, T}, title = {Nonvolatile buffer coating of titanium to prevent its biological aging and for drug delivery.}, journal = {Biomaterials}, volume = {31}, number = {18}, pages = {4818-4828}, doi = {10.1016/j.biomaterials.2010.02.061}, pmid = {20350765}, issn = {1878-5905}, support = {C06RR014529/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Adsorption ; Animals ; Antioxidants/*administration &amp; dosage ; Cell Adhesion ; Cell Proliferation ; Cells, Cultured ; Coated Materials, Biocompatible/*chemistry ; HEPES/*chemistry ; Hydrophobic and Hydrophilic Interactions ; Implants, Experimental ; Male ; *Osseointegration ; Osteoblasts/cytology ; Proteins/metabolism ; Rats ; Rats, Sprague-Dawley ; Surface Properties ; Titanium/*chemistry ; }, abstract = {The osseointegration capability of titanium decreases over time. This phenomenon, defined as biological aging of titanium, is associated with the disappearance of hydrophilicity and the progressive accumulation of hydrocarbons on titanium surfaces. The objective of this study was to examine whether coating of titanium surfaces with 4-(2-Hydroxylethyl)-1-piperazineethanesulfonic acid (HEPES) buffer, a nonvolatile zwitterionic chemical buffering agent, could prevent the time-dependent degradation of the bioactivity of titanium. Commercially pure titanium samples, prepared as disks and cylinders, were acid-etched with H(2)SO(4). A third of the samples were used for experiments immediately after processing (new surfaces), while another third were stored under dark ambient conditions for 3 months (3-month-old surfaces). The remaining third were coated with HEPES after acid-etching and were stored for 3 months (HEPES-coated 3-month-old surfaces). The 3-month-old surfaces were hydrophobic, while new and HEPES-coated 3-month-old surfaces were superhydrophilic. Protein adsorption and the number of osteoblasts attached during an initial culture period were substantially lower for 3-month-old surfaces than for new and HEPES-coated 3-month-old surfaces. Alkaline phosphatase activity and calcium deposition in osteoblast cultures were reduced by more than 50% on 3-month-old surfaces compared to new surfaces, whereas such degradation was not found on HEPES-coated 3-month-old surfaces. The strength of in vivo bone-implant integration for 3-month-old implants, evaluated by the push-in test, was 60% lower than that for new implants. The push-in value of HEPES-coated 3-month-old implants was equivalent to that of new implants. Coating titanium surfaces with HEPES containing an antioxidant amino acid derivative, N-acetyl cysteine (NAC), further enhanced osteoblast attachment to the surfaces, along with the increase level of intracellular glutathione reserves as a result of cellular uptake of NAC. These results suggest that HEPES coating of titanium surfaces maintained their superhydrophilicity for at least 3 months and resulted in a continuous retention of bioactivity and osteoconductivity similar to freshly prepared surfaces. This coating technology may be useful for preventing biological aging of titanium and delivering biological molecules for synergistic enhancement of bone-titanium integration.}, }
@article {pmid20350475, year = {2010}, author = {Rolff, HC and Christensen, HR and Dalhoff, K}, title = {[Intravenous or oral N acetylcysteine therapy in paracetamol poisoned patients. Should treatment guidelines be reviewed?].}, journal = {Ugeskrift for laeger}, volume = {172}, number = {13}, pages = {1020-1024}, pmid = {20350475}, issn = {1603-6824}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Analgesics, Non-Narcotic/blood/*poisoning ; Drug Administration Schedule ; Drug Overdose/drug therapy ; Humans ; Infusions, Intravenous ; Poisoning/*drug therapy ; Practice Guidelines as Topic ; }, abstract = {Danish paracetamol (PCM) poisoned patients are treated with N-acetylcysteine (NAC) intravenously for 36 hours. This probably leads to overtreatment. Today, patients with poor prognoses can be identified and, in addition, NAC may have serious side effects. We reviewed the literature (route of administration, duration and timing of treatment) and found that intravenous NAC often leads to side effects (some serious), primarily when serum paracetamol is low. These patients are often only mildly poisoned and they may therefore benefit from a shorter, orally administered regimen (equally efficient and with fewer side effects than intravenously administered NAC).}, }
@article {pmid20348223, year = {2010}, author = {Zang, QS and Maass, DL and Wigginton, JG and Barber, RC and Martinez, B and Idris, AH and Horton, JW and Nwariaku, FE}, title = {Burn serum causes a CD14-dependent mitochondrial damage in primary cardiomyocytes.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {298}, number = {6}, pages = {H1951-8}, pmid = {20348223}, issn = {1522-1539}, support = {R01-GM57054-05/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Burns/*blood ; Cells, Cultured ; Glutathione Peroxidase/metabolism ; Lipopolysaccharide Receptors/genetics/*physiology ; Male ; Mice ; Mice, Knockout ; Mitochondria, Heart/enzymology/*physiology ; Mitochondrial Membranes/physiology ; Models, Animal ; Myocytes, Cardiac/cytology/*physiology ; Oxidative Stress/physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Serum/*physiology ; Signal Transduction/physiology ; Superoxide Dismutase/metabolism ; }, abstract = {Studies from animal models suggest that myocardial mitochondrial damage contributes to cardiac dysfunction after burn injury. In this report, we used an ex vivo model of primary cardiomyocyte culture to investigate the mechanisms of burn-induced mitochondrial impairment. Briefly, blood serum was collected from Sprague-Dawley (SD) rats subjected to 40% total body surface area burn and added (10% vol/vol) to primary cardiomyocytes prepared from SD rats. The effect of the burn serum on mitochondrial function and membrane integrity in the myocytes was analyzed. Exposure of myocytes to burn serum doubled the mitochondrial membrane damage measured by two independent assays. This treatment also significantly elevated mitochondrial oxidative stress, indicated by a more than 30% increase in lipid oxidation. Downregulation of mitochondrial antioxidant defense was also evident since the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced by about 30% and 50%, respectively. Burn serum also induced deficiency of mitochondrial metabolism, indicated by a 30% decrease in the activity of cytochrome c oxidase. These mitochondrial dysfunctions appear to be generated by oxidative stress because burn serum induced a significant increase of mitochondrial oxygen species (mtROS) in cardiomyocytes, and pretreatment of cardiomyocytes with the antioxidant N-acetyl-cysteine prevented the mitochondrial damages induced by burn serum. Remarkably, the increase in mtROS was abolished by an antibody-mediated blockade of CD14. Furthermore, burn injury-induced mitochondrial damage in cardiomyocytes was prevented in CD14 knockout mice. Taken together, these data suggested that burn injury produces CD14-dependent mitochondrial damage via oxidative stress in myocardium.}, }
@article {pmid20336544, year = {2010}, author = {Wang, Y and Zhang, ZZ and Chen, SQ and Zou, ZD and Tu, XH and Wang, L}, title = {[Protective effect of N-acetylcysteine on the intestinal barrier dysfunction after radiation injury in rats].}, journal = {Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery}, volume = {13}, number = {3}, pages = {219-222}, pmid = {20336544}, issn = {1671-0274}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dose-Response Relationship, Radiation ; Intestinal Mucosa/drug effects/*metabolism/*microbiology ; Intestine, Small/drug effects ; Male ; Nitric Oxide/analysis ; Radiation Injuries/*metabolism/physiopathology ; Rats ; Rats, Sprague-Dawley ; X-Rays/adverse effects ; }, abstract = {OBJECTIVE: To evaluate the protective effect of N-acetylcysteine (NAC) on the intestinal barrier dysfunction in rats after extensive abdominal radiation with X ray.<br><br>METHODS: Twenty-four Spraque-Dawley male rats were divided into normal control group (n=8), radiation group (n=8), and radiation+NAC group (300 mg/kg) (n=8). Radiation injury was induced by X ray with a single dose of 10 Gy. NAC was administered from 4 days before irradiation to 3 days after radiation. Three days after radiation, all the rats were euthanized. The terminal ileum was collected for crypt survival assay and ileal villi count. The tissue samples from mesenteric lymph nodes (MLN), spleen, and liver were harvested under sterile conditions for microbiological analysis and ileum samples were harvested for biochemical analysis. The blood levels of D-lactate, endotoxin and diamine oxidase (DAO) and the ileum samples levels of nitric oxide(NO) were also measured.<br><br>RESULTS: Rats in radiation+NAC group had a higher survival rate of intestinal crypt [(76.84+/-4.82)% vs (49.64+/-5.48)%, P<0.01], higher intestinal villus count [(8.56+/-0.68)/mm vs (4.02+/-0.54)/mm, P<0.01], lower NO concentration [(0.48+/-0.12) mumol/g vs (0.88+/-0.16) mumol/g, P<0.01], lower levels of D-lactate, endotoxin and DAO (P<0.05 or P<0.01), and significantly decreased enteric bacteria cultured from mesenteric lymph nodes and other tissues as compared with the radiation group (P<0.05 or P<0.01).<br><br>CONCLUSION: NAC protects the small intestine from radiation-induced injury maybe through the inhibition of NO in rats.}, }
@article {pmid20335224, year = {2010}, author = {Strathmann, J and Klimo, K and Sauer, SW and Okun, JG and Prehn, JH and Gerhäuser, C}, title = {Xanthohumol-induced transient superoxide anion radical formation triggers cancer cells into apoptosis via a mitochondria-mediated mechanism.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {24}, number = {8}, pages = {2938-2950}, doi = {10.1096/fj.10-155846}, pmid = {20335224}, issn = {1530-6860}, mesh = {Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Cattle ; Cell Line, Tumor ; Electron Transport Chain Complex Proteins/metabolism ; Flavonoids/*pharmacology/therapeutic use ; Glutathione/metabolism ; Humans ; Mitochondria, Liver/*metabolism ; Neoplasms/*drug therapy/pathology ; Propiophenones/*pharmacology/therapeutic use ; Reactive Oxygen Species ; Sulfhydryl Compounds/metabolism ; Superoxides/metabolism ; }, abstract = {Oxidative stress and increased release of reactive oxygen species (ROS) are associated with apoptosis induction. Here we report ROS-mediated induction of apoptosis by xanthohumol (XN) from hops. XN at concentrations of 1.6-25 microM induced an immediate and transient increase in superoxide anion radical (O(2)(-*)) formation in 3 human cancer cell lines (average+/-SD EC(50) of maximum O(2)(-*) induction=3.1+/-0.8 microM), murine macrophages (EC(50)=4.0+/-0.3 microM), and BPH-1 benign prostate hyperplasia cells (EC(50)=4.3+/-0.1 microM), as evidenced by the O(2)(-*)-specific indicator dihydroethidium. MitoSOX Red costaining and experiments using isolated mouse liver mitochondria (EC(50)=11.4+/-1.8 microM) confirmed mitochondria as the site of intracellular O(2)(-*) formation. Antimycin A served as positive control (EC(50)=12.4+/-0.9 microM). XN-mediated O(2)(-*) release was significantly reduced in BPH-1 rho(0) cells harboring nonfunctional mitochondria (EC(50)>25 microM) and by treatment of BPH-1 cells with vitamin C, N-acetylcysteine (NAC), or the superoxide dismutase mimetic MnTMPyP. In addition, we demonstrated a rapid 15% increase in oxidized glutathione and a dose-dependent overall thiol depletion within 6 h (IC(50)=24.3+/-11 microM). Respiratory chain complexes I-III were weakly inhibited by XN in bovine heart submitochondrial particles, but electron flux from complex I and II to complex III was significantly inhibited in BPH-1 cells, with IC(50) values of 28.1 +/- 2.4 and 24.4 +/- 5.2 microM, respectively. Within 15 min, intracellular ATP levels were significantly reduced by XN at 12.5 to 50 microM concentrations (IC(50)=26.7+/-3.7 microM). Concomitantly, XN treatment caused a rapid breakdown of the mitochondrial membrane potential and the release of cytochrome c, leading to apoptosis induction. Pre- or coincubation with 2 mM NAC and 50 microM MnTMPyP at various steps increased XN-mediated IC(50) values for cytotoxicity in BPH-1 cells from 6.7 +/- 0.2 to 12.2 +/- 0.1 and 41.4 +/- 7.6 microM, and it confirmed XN-induced O(2)(-*) as an essential trigger for apoptosis induction. In summary, we have identified mitochondria as a novel cellular target of XN action, resulting in increased O(2)(-*) production, disruption of cellular redox balance and mitochondrial integrity, and subsequent apoptosis.}, }
@article {pmid20334518, year = {2010}, author = {Brown, SL and Kolozsvary, A and Liu, J and Jenrow, KA and Ryu, S and Kim, JH}, title = {Antioxidant diet supplementation starting 24 hours after exposure reduces radiation lethality.}, journal = {Radiation research}, volume = {173}, number = {4}, pages = {462-468}, pmid = {20334518}, issn = {1938-5404}, support = {U19 AI067734-020005/AI/NIAID NIH HHS/United States ; U19 AI067734-010005/AI/NIAID NIH HHS/United States ; U19AI067734-020005/AI/NIAID NIH HHS/United States ; U19 AI067734-030005/AI/NIAID NIH HHS/United States ; U19 AI067734-040005/AI/NIAID NIH HHS/United States ; U19 AI067734-05S10005/AI/NIAID NIH HHS/United States ; U19 AI067734-050005/AI/NIAID NIH HHS/United States ; U19 AI067734/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*therapeutic use ; Dietary Supplements ; Dose-Response Relationship, Radiation ; Mice ; Mice, Inbred C57BL ; Prevalence ; Radiation Injuries/*mortality/*prevention &amp; control/veterinary ; Radiation Protection/*methods ; Survival Analysis ; *Survival Rate ; Whole-Body Irradiation/*statistics &amp; numerical data ; }, abstract = {Antioxidants mitigate radiation-induced lethality when started soon after radiation exposure, a delivery time that may not be practical due to difficulties in distribution and because the oral administration of such agents may require a delay beyond the prodromal stage of the radiation syndrome. We report the unexpected finding that antioxidant supplementation starting 24 h after total-body irradiation resulted in better survival than antioxidant supplementation started soon after the irradiation. The antioxidant dietary supplement was l-selenomethionine, sodium ascorbate, N-acetyl cysteine, alpha-lipoic acid, alpha-tocopherol succinate, and co-enzyme Q10. Total-body irradiation with 8 Gy in the absence of antioxidant supplementation was lethal by day 16. When antioxidant supplementation was started soon after irradiation, four of 14 mice survived. In contrast, 14 of 18 mice receiving antioxidant supplementation starting 24 h after irradiation were alive and well 30 days later. The numbers of spleen colonies and blood cells were higher in mice receiving antioxidant supplementation starting 24 h after irradiation than in mice receiving radiation alone. A diet supplemented with antioxidants administered starting 24 h after total-body irradiation improved bone marrow cell survival and mitigated lethality, with a radiation protection factor of approximately 1.18.}, }
@article {pmid20332167, year = {2011}, author = {Mehrpour, O and Shadnia, S and Sanaei-Zadeh, H}, title = {Late extensive intravenous administration of N-acetylcysteine can reverse hepatic failure in acetaminophen overdose.}, journal = {Human &amp; experimental toxicology}, volume = {30}, number = {1}, pages = {51-54}, doi = {10.1177/0960327110366182}, pmid = {20332167}, issn = {1477-0903}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/adverse effects/*therapeutic use ; Chemical and Drug Induced Liver Injury/*physiopathology ; Delayed Diagnosis ; Drug Overdose ; Free Radical Scavengers/adverse effects/therapeutic use ; Humans ; Infusions, Intravenous ; Intensive Care Units ; Liver Failure, Acute/*drug therapy/etiology ; Male ; Treatment Outcome ; }, abstract = {Acetaminophen is a commonly used analgesic and has been shown to be a main cause of drug-induced liver failure. N-acetylcysteine (NAC) should be employed as the antidote in case of acetaminophen poisoning within the first 8-10 hours. Oral administration of NAC is universally recommended and due to the adverse effects, the intravenous administration of the agent is reserved for patients with oral intolerance and severe complications. We here report an 18-year-old man with severe liver failure due to a huge ingestion of acetaminophen, who was taken into the Loghman Hakim Hospital Poison Center 72 hours after attempted suicide. Regarding the poor prognostic clues as his level of consciousness and impaired liver functions, an extensive intravenous regimen of NAC was started. The patient survived the condition with an additional intravenous administration of NAC past the first 72 hours of treatment. We discuss that even in late phases of intoxication; high-dose intravenous NAC can serve a substantial improvement.}, }
@article {pmid20332020, year = {2010}, author = {You, BR and Park, WH}, title = {The effects of antimycin A on endothelial cells in cell death, reactive oxygen species and GSH levels.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {24}, number = {4}, pages = {1111-1118}, doi = {10.1016/j.tiv.2010.03.009}, pmid = {20332020}, issn = {1879-3177}, mesh = {Acetylcysteine/toxicity ; Animals ; Antimycin A/*toxicity ; *Apoptosis ; Buthionine Sulfoximine/toxicity ; Caspase Inhibitors ; Cell Line ; Endothelial Cells/*drug effects/metabolism ; Enzyme Inhibitors/toxicity ; Glutathione/*metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Antimycin A (AMA) inhibits mitochondrial electron transport chain between cytochrome b and c. Here, we evaluated the effects of AMA on the growth and death of endothelial cells (ECs) in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. AMA inhibited the growth of calf pulmonary artery endothelial cells (CPAEC) and human umbilical vein endothelial cells (HUVEC). AMA also induced apoptosis in both ECs which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). HUVEC were more sensitive to AMA than CPAEC. AMA increased ROS level in CPAEC but decreased the levels in HUVEC. Z-VAD (pan-caspase inhibitor) mildly prevented apoptosis in AMA-treated ECs without the significant changes of ROS. N-acetyl-cysteine (NAC; a well-known antioxidant) decreased ROS levels in AMA-treated ECs. NAC reduced CPAEC death by AMA but enhanced HUVEC death by it. Furthermore, AMA increased GSH depleted cell numbers in ECs. Buthionine sulfoximine (BSO; an inhibitor of GSH synthesis), showing a pro-apoptotic effect on AMA-treated HUVEC, significantly increased GSH depleted cell number but it did not affect cell death and GSH depletion in AMA-treated CPAEC. In conclusion, AMA inhibited the growth of ECs via caspase-dependent apoptosis. ROS level change by AMA was partially related to CPAEC death, but did not affect HUVEC death. The change of GSH contents by AMA influenced the death of ECs.}, }
@article {pmid20332008, year = {2010}, author = {El-Sayed, el-SM and Abdel-Aziz, AA and Helal, GK and Saleh, S and Saad, AS}, title = {Protective effect of N-acetylcysteine against carmustine-induced myelotoxicity in rats.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {48}, number = {6}, pages = {1576-1580}, doi = {10.1016/j.fct.2010.03.027}, pmid = {20332008}, issn = {1873-6351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents, Alkylating/*pharmacology ; Bone Marrow Cells/*drug effects ; Carmustine/*toxicity ; Male ; Rats ; Rats, Wistar ; }, abstract = {Carmustine (BCNU) is used to treat a variety of tumors, in particular gliomas. However, the success of such treatment is limited by severe myelosuppression. The role of N-acetylcysteine (NAC) in protection against BCNU-induced myelotoxicity is still needed to be explored. The aim of this work is to study the possible protective role of NAC against BCNU-induced myelotoxicity through evaluation of apoptosis, lipid peroxidation, antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase(CAT)) as well as glutathione (GSH) content in bone marrow cells of rats. Administration of BCNU in a single dose (30 mg/kg, i.p.) significantly decreased RBCs, WBCs and platelets counts as well as hemoglobin level. In addition, BCNU produced a significant apoptotic effect as well as a significant lipid peroxidation in bone marrow cells. Pretreatment of animals with NAC (150 mg/kg, i.p.) daily for 5 days significantly ameliorated the changes in oxidant and antioxidant parameters as well as apoptosis induced by BCNU. In addition the pattern of blood parameters was shifted markedly to normal values in animals pretreated with NAC when compared to BCNU-treated group. Conclusively, NAC could have a potential protective effect against BCNU-induced myelotoxicity; an effect that is mainly attributed to the antioxidant property.}, }
@article {pmid20308250, year = {2010}, author = {Merry, TL and Wadley, GD and Stathis, CG and Garnham, AP and Rattigan, S and Hargreaves, M and McConell, GK}, title = {N-Acetylcysteine infusion does not affect glucose disposal during prolonged moderate-intensity exercise in humans.}, journal = {The Journal of physiology}, volume = {588}, number = {Pt 9}, pages = {1623-1634}, pmid = {20308250}, issn = {1469-7793}, mesh = {AMP-Activated Protein Kinase Kinases ; Acetylcysteine/administration &amp; dosage/metabolism/*pharmacology ; Adult ; Anaerobic Threshold/drug effects/physiology ; Cross-Over Studies ; Cysteine/blood ; Cystine/blood ; Double-Blind Method ; Exercise/*physiology ; Exercise Test ; Fatty Acids, Nonesterified/metabolism ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glucose/*metabolism ; Glutathione/biosynthesis ; Heart Rate/physiology ; Humans ; Infusions, Intravenous ; Lactic Acid/blood ; Male ; Muscle, Skeletal/metabolism ; Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Young Adult ; }, abstract = {There is evidence that reactive oxygen species (ROS) signalling is required for normal increases in glucose uptake during contraction of isolated mouse skeletal muscle, and that AMP-activated protein kinase (AMPK) is involved. The aim of this study was to determine whether ROS signalling is involved in the regulation of glucose disposal and AMPK activation during moderate-intensity exercise in humans. Nine healthy males completed 80 min of cycle ergometry at 62 +/- 1% of peak oxygen consumption (V(O(2)peak).A 6,6-(2)H-glucose tracer was infused at rest and during exercise, and in a double-blind randomised cross-over design, N-acetylcysteine (NAC) or saline (CON) was co-infused. NAC was infused at 125 mg kg(1) h(1) for 15 min and then at 25 mg kg(1) h(1) for 20 min before and throughout exercise. NAC infusion elevated plasma NAC and cysteine, and muscle NAC and cysteine concentrations during exercise. Although neither NAC infusion nor exercise significantly affected muscle reduced or oxidised glutathione (GSH or GSSG) concentration (P > 0.05), S-glutathionylation (an indicator of oxidative stress) of a protein band of approximately 270 kDa was increased approximately 3-fold with contraction and this increase was prevented by NAC infusion. Despite this, exercised-induced increases in tracer determined glucose disposal, plasma lactate, plasma non-esterified fatty acids (NEFAs), and decreases in plasma insulin were not affected by NAC infusion. In addition, skeletal muscle AMPKalpha and acetyl-CoA carboxylase-beta (ACCbeta) phosphorylation increased during exercise by approximately 3- and approximately 6-fold (P < 0.05), respectively, and this was not affected by NAC infusion. Unlike findings in mouse muscle ex vivo, NAC does not attenuate skeletal muscle glucose disposal or AMPK activation during moderate-intensity exercise in humans.}, }
@article {pmid20304619, year = {2011}, author = {Yan, C and Huang, D and Zhang, Y}, title = {The involvement of ROS overproduction and mitochondrial dysfunction in PBDE-47-induced apoptosis on Jurkat cells.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {63}, number = {5}, pages = {413-417}, doi = {10.1016/j.etp.2010.02.018}, pmid = {20304619}, issn = {1618-1433}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Culture Techniques ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Environmental Pollutants/*toxicity ; Free Radical Scavengers/pharmacology ; Halogenated Diphenyl Ethers/*toxicity ; Humans ; Jurkat Cells ; Membrane Potential, Mitochondrial/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {2,2',4,4'-Tetrabromodiphenyl ether (PBDE-47), as one of the congeners of polybrominated diphenyl ethers (PBDEs), is widely present and threatens the human health in many aspects. This study aims to investigate the toxic effects of PBDE-47 on cell viability, apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) of Jurkat cells in vitro. The results showed that PBDE-47 significantly inhibited the viability of Jurkat cells in a dose-dependent manner by alamar blue assay. Significant induction of apoptosis was detected in Jurkat cells at 25-100 μM by propidium iodide staining, accompanied with overproduction of ROS and downregulation of MMP. Furthermore, N-acetyl-L-cysteine (NAC), a widely used ROS scavenger, significantly reduced the PBDE-47-induced apoptosis by decreasing ROS level and mediating recovery of the MMP. In conclusion, the results of this study suggest that PBDE-47 could induce apoptosis in Jurkat cells and ROS and mitochondrial dysfunction play important roles in the apoptotic process.}, }
@article {pmid20302609, year = {2010}, author = {Sarikaya, S and Karcioglu, O and Ay, D and Cetin, A and Aktas, C and Serinken, M}, title = {Acute mercury poisoning: a case report.}, journal = {BMC emergency medicine}, volume = {10}, number = {}, pages = {7}, pmid = {20302609}, issn = {1471-227X}, mesh = {Adult ; Breast Feeding/adverse effects ; Chelation Therapy/methods ; Environmental Exposure/*adverse effects ; Fatal Outcome ; Female ; Gastrointestinal Diseases/*chemically induced ; Humans ; Infant ; Inhalation Exposure/*adverse effects ; Mercury/*adverse effects ; *Mercury Poisoning/blood/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Mercury poisoning can occur as a result of occupational hazard or suicide attempt. This article presents a 36-year-old case admitted to emergency department (ED) due to exposure to metallic mercury.<br><br>CASE PRESENTATION: A 36-year-old woman presented to the ED with a three-day history of abdominal pain, diarrhea and fever. One week ago her daughter had brought mercury in the liquid form from the school. She had put it on the heating stove. One day later, her 14-month old sister baby got fever and died before admission to the hospital. Her blood pressure was 134/87 mmHg; temperature, 40.2 degrees C; heart rate 105 bpm and regular; respiration, 18 bpm; O2 saturation, 96%. Nothing was remarkable on examination and routine laboratory tests. As serine or urinary mercury levels could not be tested in the city, symptomatic chelation treatment with N-acetyl cysteine (NAC) was instituted with regard to presumptive diagnosis and history. At the 7th day of admission she was discharged without any sequelae or complaint. At the discharge day blood was drawn and sent for mercury levels which turned out to be 30 microg/dL (normal range: 0-10 microg/dL).<br><br>CONCLUSION: Public education on poisoning and the potential hazards of mercury are of vital importance for community health.}, }
@article {pmid20300525, year = {2010}, author = {Lösel, RM and Schnetzke, U and Brinkkoetter, PT and Song, H and Beck, G and Schnuelle, P and Höger, S and Wehling, M and Yard, BA}, title = {N-octanoyl dopamine, a non-hemodyanic dopamine derivative, for cell protection during hypothermic organ preservation.}, journal = {PloS one}, volume = {5}, number = {3}, pages = {e9713}, pmid = {20300525}, issn = {1932-6203}, mesh = {Acetylcysteine/chemistry ; Animals ; Dopamine/*analogs &amp; derivatives/*pharmacology ; Endothelium, Vascular/cytology ; Hemodynamics ; Humans ; Hypothermia, Induced/*methods ; L-Lactate Dehydrogenase/metabolism ; Male ; NADPH Oxidases/metabolism ; Organ Preservation/*methods ; Oxidation-Reduction ; Rats ; Rats, Inbred F344 ; Reactive Oxygen Species/chemistry ; Subcellular Fractions/metabolism ; }, abstract = {BACKGROUND: Although donor dopamine treatment reduces the requirement for post transplantation dialysis in renal transplant recipients, implementation of dopamine in donor management is hampered by its hemodynamic side-effects. Therefore novel dopamine derivatives lacking any hemodynamic actions and yet are more efficacious in protecting tissue from cold preservation injury are warranted. We hypothesized that variation of the molecular structure would yield more efficacious compounds avoid of any hemodynamic effects.<br><br>To this end, we assessed protection against cold preservation injury in HUVEC by the attenuation of lactate dehydrogenase (LDH) release. Modification of dopamine by an alkanoyl group increased cellular uptake and significantly improved efficacy of protection. Further variation revealed that only compounds bearing two hydroxy groups in ortho or para position at the benzene nucleus, i.e. strong reductants, were protective. However, other reducing agents like N-acetyl cysteine and ascorbate, or NADPH oxidase inhibition did not prevent cellular injury following cold storage. Unlike dopamine, a prototypic novel compound caused no hemodynamic side-effects.<br><br>CONCLUSIONS/SIGNIFICANCE: In conclusion, we demonstrate that protection against cold preservation injury by catecholamines is exclusively governed by strong reducing capacity and sufficient lipophilicity. The novel dopamine derivatives might be of clinical relevance in donor pre-conditioning as they are completely devoid of hemodynamic action, their increased cellular uptake would reduce time of treatment and therefore also may have a potential use for non-heart beating donors.}, }
@article {pmid20238483, year = {2010}, author = {Cassol, OJ and Rezin, GT and Petronilho, FC and Scaini, G and Gonçalves, CL and Ferreira, GK and Roesler, R and Schwartsmann, G and Dal-Pizzol, F and Streck, EL}, title = {Effects of N-acetylcysteine/deferoxamine, taurine and RC-3095 on respiratory chain complexes and creatine kinase activities in rat brain after sepsis.}, journal = {Neurochemical research}, volume = {35}, number = {4}, pages = {515-521}, pmid = {20238483}, issn = {1573-6903}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bombesin/*analogs &amp; derivatives/pharmacology ; Brain/*drug effects/enzymology/metabolism ; Creatine Kinase/*metabolism ; Deferoxamine/*pharmacology ; Electron Transport/*drug effects ; Male ; Peptide Fragments/*pharmacology ; Rats ; Rats, Wistar ; Sepsis/enzymology/*metabolism ; Taurine/*pharmacology ; }, abstract = {The pathogenesis of sepsis is characterized by an overwhelming systemic inflammatory response that can lead to multiple organ failure. Considering that we have recently demonstrated that mitochondrial respiratory chain and creatine kinase (CK) are altered in the brain of rats after cecal ligation and perforation (CLP) and that a combination of N-acetylcysteine/deferoxamine (NAC/DFX), taurine and RC-3095 were shown to be an effective treatment of sepsis, we investigated whether the alterations of these enzymes may be reversed by these drugs. The results demonstrated that CLP inhibited complexes I and II, and that all the treatments were able to reverse this inhibition in all brain areas studied in the present work. On the other hand, complexes III and IV were not affected by sepsis neither by any of the treatments. An increase in CK activity in brain of rats 12 h after CLP was also verified; the administration of NAC/DFX and taurine reversed the increase in CK activity in hippocampus, cerebral cortex, cerebellum and striatum. On the other hand, RC-3095 significantly decreased CK activity, when compared to sham group in all brain areas studied. This is a preliminary study which showed beneficial effects of the treatments we proposed.}, }
@article {pmid20224971, year = {2010}, author = {Savickiene, J and Treigyte, G and Gineitis, A and Navakauskiene, R}, title = {A critical role of redox state in determining HL-60 cell granulocytic differentiation and apoptosis via involvement of PKC and NF-kappaB.}, journal = {In vitro cellular &amp; developmental biology. Animal}, volume = {46}, number = {6}, pages = {547-559}, pmid = {20224971}, issn = {1543-706X}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; *Cell Differentiation ; Granulocytes/*cytology/metabolism ; HL-60 Cells ; Humans ; NF-kappa B/*metabolism ; Oxidation-Reduction ; Protein Kinase C/*metabolism ; Signal Transduction ; }, abstract = {The modifications of intracellular redox balance leads to important cellular changes in many cell types. Here, a causal relationship among redox state, granulocytic differentiation induced by all-trans retinoic acid (RA) or dibutyryl cAMP (dbcAMP) and apoptosis have been studied in the human acute promyelocytic leukaemia HL-60 cells. The modulation of intracellular reactive oxygen species levels by D: , L: -buthionine-(S, R) sulfoximide (BSO), and N: -acetyl-L: -cysteine (NAC) caused inducer- and time-dependent or stage-specific effects on HL-60 cell growth inhibition, differentiation and subsequent apoptosis. The presence of BSO during the commitment stage suppressed RA-but not dbcAMP-mediated differentiation, while NAC inhibited both. BSO alone and in combination with RA or dbcAMP-induced apoptosis, which was prevented by NAC in dbcAMP-but not in RA-treated cells. Using protein kinase C inhibitor, calphostin C, cross-talk effects between the intracellular redox state and PKC signalling was identified by demonstrating inducer-dependent changes in cell differentiation or apoptosis, which were associated with the changes in DNA-NF-kappaB binding activity. These observations suggest a critical role of redox state in determining HL-60 cell behaviour and provide new insights into the complex effects of redox perturbations on the intracellular signalling network via the involvement of PKC and NF-kappaB.}, }
@article {pmid20223252, year = {2010}, author = {Steinboeck, F and Hubmann, M and Bogusch, A and Dorninger, P and Lengheimer, T and Heidenreich, E}, title = {The relevance of oxidative stress and cytotoxic DNA lesions for spontaneous mutagenesis in non-replicating yeast cells.}, journal = {Mutation research}, volume = {688}, number = {1-2}, pages = {47-52}, doi = {10.1016/j.mrfmmm.2010.03.006}, pmid = {20223252}, issn = {0027-5107}, mesh = {Cell Cycle ; DNA Breaks, Double-Stranded ; *DNA Damage ; DNA Repair Enzymes/genetics ; Endodeoxyribonucleases/genetics ; *Frameshift Mutation ; Lysine/metabolism ; Oxidative Stress/*genetics ; Phosphoproteins/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; }, abstract = {Mutations arising during times of cell cycle-arrest may considerably contribute to aging and cancerogenesis. Endogenous oxidative stress could be one of the major triggers for these mutations. We used Saccharomyces cerevisiae cells, arrested by starvation for the essential amino acid lysine, to study the occurrence of reactive oxygen species (ROS), abasic (AP) sites and double strand breaks (DSBs). Furthermore, we analyzed the mutation frequencies in resting wild type cells and in cells deficient for Apn1 (with an impaired base excision repair) or Dnl4 (with an inactivated non-homologous end joining (NHEJ) DSB repair pathway) by monitoring reversions of an auxotrophy-causing frameshift in the LYS2 gene. By fluorescence methods, we observed a distinct increase of ROS-affected cells in the course of starvation-induced cell cycle-arrest. In addition, we could reveal that AP sites and DSBs accumulated under these conditions. The frequency of spontaneous frameshift mutations in wild type cells was decreased to 50% upon addition of 6mM N-acetyl cysteine. However, this radical scavenger had no effect in Dnl4-deficient cells. Our results support the hypothesis that (via an active NHEJ DSB repair pathway) the incidence of spontaneous frameshift mutations in a cell cycle-arrested state is considerably governed by oxidative stress.}, }
@article {pmid20220565, year = {2010}, author = {Sharpe, SM and Qin, X and Lu, Q and Feketeova, E and Palange, DC and Dong, W and Sheth, SU and Lee, MA and Reino, D and Xu, DZ and Deitch, EA}, title = {Loss of the intestinal mucus layer in the normal rat causes gut injury but not toxic mesenteric lymph nor lung injury.}, journal = {Shock (Augusta, Ga.)}, volume = {34}, number = {5}, pages = {475-481}, pmid = {20220565}, issn = {1540-0514}, support = {GM 59841/GM/NIGMS NIH HHS/United States ; T32 GM069330/GM/NIGMS NIH HHS/United States ; T32 069330//PHS HHS/United States ; P50 GM069790/GM/NIGMS NIH HHS/United States ; R01 GM059841/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/toxicity ; Acute Lung Injury/*etiology ; Animals ; Bacterial Translocation/physiology ; Evans Blue/pharmacokinetics ; Expectorants/pharmacology/toxicity ; Hydrophobic and Hydrophilic Interactions ; Ileum/drug effects/metabolism/*pathology ; Intestinal Mucosa/drug effects/metabolism/*pathology ; Ligation ; Lung/metabolism ; Lymph/*physiology ; Male ; Mesentery ; Models, Biological ; Mucus/*physiology ; Pancreas/enzymology ; Peptide Hydrolases/pharmacology ; Permeability/drug effects ; Rats ; Rats, Sprague-Dawley ; Respiratory Burst ; }, abstract = {There is substantial evidence that gut barrier failure is associated with distant organ injury and systemic inflammation. After major trauma or stress, the factors and mechanisms involved in gut injury are unknown. Our primary hypothesis is that loss of the intestinal mucus layer will result in injury of the normal gut that is exacerbated by the presence of luminal pancreatic proteases. Our secondary hypothesis is that the injury produced in the gut will result in the production of biologically active mesenteric lymph and consequently distant organ (i.e., lung) injury. To test this hypothesis, five groups of rats were studied: 1) uninstrumented naive rats; 2) control rats in which a ligated segment of distal ileum was filled with saline; 3) rats with pancreatic proteases placed in their distal ileal segments; 4) rats with the mucolytic N-acetylcysteine (NAC) placed in their distal ileal segments; and 5) rats exposed to NAC and pancreatic proteases in their ileal segments. The potential systemic consequences of gut injury induced by NAC and proteases were assessed by measuring the biological activity of mesenteric lymph as well as gut-induced lung injury. Exposure of the normal intestine to NAC, but not saline or proteases, led to increased gut permeability, loss of mucus hydrophobicity, a decrease in the mucus layer, as well as morphological evidence of villous injury. Although proteases themselves did not cause gut injury, the combination of pancreatic proteases with NAC caused more severe injury than NAC alone, suggesting that once the mucus barrier is impaired, luminal proteases can injure the now vulnerable gut. Because comparable levels of gut injury caused by systemic insults are associated with gut-induced lung injury, which is mediated by biologically active factors in mesenteric lymph, we next tested whether this local model of gut injury would produce active mesenteric lymph or lead to lung injury. It did not, suggesting that gut injury by itself may not be sufficient to induce distant organ dysfunction. Therefore, loss of the intestinal mucus layer, especially in the presence of intraluminal pancreatic proteases, is sufficient to lead to injury and barrier dysfunction of the otherwise normal intestine but not to produce gut-induced distant organ dysfunction.}, }
@article {pmid20214734, year = {2010}, author = {Nishina, S and Korenaga, M and Hidaka, I and Shinozaki, A and Sakai, A and Gondo, T and Tabuchi, M and Kishi, F and Hino, K}, title = {Hepatitis C virus protein and iron overload induce hepatic steatosis through the unfolded protein response in mice.}, journal = {Liver international : official journal of the International Association for the Study of the Liver}, volume = {30}, number = {5}, pages = {683-692}, doi = {10.1111/j.1478-3231.2010.02210.x}, pmid = {20214734}, issn = {1478-3231}, mesh = {Animals ; Autophagy ; Carnitine O-Palmitoyltransferase/analysis/physiology ; Endoplasmic Reticulum/metabolism ; Fatty Liver/*etiology ; Hepatitis C/*complications ; Iron Overload/*complications ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Reactive Oxygen Species/metabolism ; Sterol Regulatory Element Binding Protein 1/analysis/physiology ; Triglycerides/analysis ; *Unfolded Protein Response ; Viral Proteins/*physiology ; }, abstract = {BACKGROUND/AIM: Hepatic iron overload and steatosis play critical roles in the progression of hepatitis C virus (HCV)-associated chronic liver disease. However, how these two pathophysiological features affect each other remains unknown. The aim of this study was to investigate how hepatic iron overload contributes to the development of hepatic steatosis in the presence of HCV proteins.<br><br>METHODS: Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or a control diet. Mice in each group were assessed for the molecules responsible for fat accumulation in the liver.<br><br>RESULTS: Hepatic iron levels were positively correlated with triglyceride concentrations in the liver for all mice. As compared with the livers of nontransgenic mice fed the control diet, the livers of transgenic mice fed the excess-iron diet showed a lower expression of carnitine palmitoyl transferase I, a higher expression of sterol-regulatory element-binding protein 1 and fatty acid synthetase and an activated unfolded protein response indicated by a higher expression of unspliced and spliced X-box DNA-binding protein 1 (XBP-1), phosphorylated eukaryotic initiation factor-2alpha (p-eIF2alpha), CCAAT/enhancer-binding protein homology protein (CHOP) and abundant autophagosomes concomitant with increased production of reactive oxygen species. Six-month treatment with the anti-oxidant N-acetyl cysteine dramatically reduced hepatic steatosis in transgenic mice fed the excess-iron diet through decreased expression of unspliced and spliced XBP-1, p-eIF2alpha, and CHOP.<br><br>CONCLUSIONS: The iron-induced unfolded protein response appears to be one of the mechanisms responsible for fat accumulation in the liver in transgenic mice expressing the HCV polyprotein.}, }
@article {pmid20213267, year = {2010}, author = {Sandoval, JM and Levêque, P and Gallez, B and Vásquez, CC and Buc Calderon, P}, title = {Tellurite-induced oxidative stress leads to cell death of murine hepatocarcinoma cells.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {23}, number = {4}, pages = {623-632}, doi = {10.1007/s10534-010-9316-2}, pmid = {20213267}, issn = {1572-8773}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Carcinoma, Hepatocellular/*metabolism ; Caspase 3/metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; Glutathione/metabolism ; Humans ; Liver Neoplasms/*metabolism ; Mice ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Tellurium/*pharmacology ; }, abstract = {Data regarding tellurium (Te) toxicity are scarce. Studies on its metabolism, performed mainly in bacteria, underline a major role of reactive oxygen species (ROS). We investigated whether tellurite undergoes redox cycling leading to ROS formation and cancer cell death. The murine hepatocarcinoma Transplantable Liver Tumor (TLT) cells were challenged with tellurite either in the presence or in the absence of different compounds as N-acetylcysteine (NAC), 3-methyladenine, BAPTA-AM, and catalase. NAC inhibition of tellurite-mediated toxicity suggested a major role of oxidative stress. Tellurite also decreased both glutathione (GSH) and ATP content by 57 and 80%, respectively. In the presence of NAC however, the levels of such markers were almost fully restored. Tellurite-mediated ROS generation was assessed both by using the fluorescent, oxidation-sensitive probe dichlorodihydrofluorescein diacetate (DCHF-DA) and electron spin resonance (ESR) spectroscopy to detect hydroxyl radical formation. Cell death occurs by a caspase-independent mechanism, as shown by the lack of caspase-3 activity and no cleavage of poly(ADP-ribose)polymerase (PARP). The presence of gamma-H2AX suggests tellurite-induced DNA strand breaking, NAC being unable to counteract it. Although the calcium chelator BAPTA-AM did show no effect, the rapid phosphorylation of eIF2alpha suggests that, in addition to oxidative stress, an endoplasmic reticulum (ER) stress may be involved in the mechanisms leading to cell death by tellurite.}, }
@article {pmid20211720, year = {2010}, author = {Tapryal, N and Mukhopadhyay, C and Mishra, MK and Das, D and Biswas, S and Mukhopadhyay, CK}, title = {Glutathione synthesis inhibitor butathione sulfoximine regulates ceruloplasmin by dual but opposite mechanism: Implication in hepatic iron overload.}, journal = {Free radical biology &amp; medicine}, volume = {48}, number = {11}, pages = {1492-1500}, doi = {10.1016/j.freeradbiomed.2010.02.029}, pmid = {20211720}, issn = {1873-4596}, mesh = {3' Untranslated Regions/physiology ; Acetylcysteine/pharmacology ; Buthionine Sulfoximine/*pharmacology ; Ceruloplasmin/biosynthesis/*metabolism ; Glutathione/*biosynthesis/genetics ; Hep G2 Cells ; Humans ; Iron/*metabolism ; Iron Overload/*physiopathology ; Liver/drug effects/*metabolism ; RNA, Messenger/metabolism ; }, abstract = {Glutathione (GSH) depletion is often detected in chronic pathological conditions like hepatitis C infection, alcohol consumption or xenobiotic assault with simultaneous reactive oxygen species (ROS) generation and hepatic iron overload. However, relation between GSH depletion and regulators of iron homeostasis is not clear so far. To determine that hepatic HepG2 cells were treated with GSH synthesis inhibitor butathione sulfoximine (BSO) and a dual regulation of ceruloplasmin (Cp) that involves in hepatic iron release was detected unlike other iron homeostasis regulators. BSO treatment that caused marginal GSH deficiency increased Cp synthesis due to increased transcription mediated by activator protein (AP)-1-binding site. In higher GSH deficiency (> 40 %) with increased ROS generation, Cp expression was decreased due to promotion of Cp mRNA decay mediated by 3'untranslated region (3'UTR) as found by transfecting chimera of chloramphenicol acetyl transferase (CAT) gene with Cp 3'UTR. RNA gel shift assay showed significant reduction in 3'UTR binding protein complex in similar condition. Decreased CAT expression and RNA-protein complex binding are reversed by pretreatment with antioxidant N-acetyl cysteine suggesting 3'UTR binding protein complex is redox-sensitive. This unique and opposite regulation of Cp provides a mechanism of hepatic iron-deposition during glutathione deficiency detected in chronic pathological conditions.}, }
@article {pmid20211185, year = {2010}, author = {Cambos, M and Bazinet, S and Abed, E and Sanchez-Dardon, J and Bernard, C and Moreau, R and Olivier, M and Scorza, T}, title = {The IL-12p70/IL-10 interplay is differentially regulated by free heme and hemozoin in murine bone-marrow-derived macrophages.}, journal = {International journal for parasitology}, volume = {40}, number = {9}, pages = {1003-1012}, doi = {10.1016/j.ijpara.2010.02.007}, pmid = {20211185}, issn = {1879-0135}, mesh = {Animals ; Cells, Cultured ; Female ; Heme/immunology/*metabolism ; Hemeproteins/immunology/*metabolism ; Hemin/metabolism ; Interferon-gamma/immunology ; Interleukin-10/*immunology/metabolism ; Interleukin-12/antagonists &amp; inhibitors/*immunology/metabolism ; Lipopolysaccharides/immunology ; Macrophages/*immunology ; Mice ; Mice, Inbred BALB C ; Oxidation-Reduction ; Protein Binding ; *Protein Interaction Mapping ; Reactive Oxygen Species/metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The outcome of malarial anemia is determined by a complex interplay between pro-inflammatory and anti-inflammatory cytokines, its severity associated with accumulation of hemozoin (Hz) in macrophages, elevated IL-10 responses and impaired IL-12 production. Although free heme contributes to malarial anemia by inducing oxidative damage of red blood cells (RBCs) and enhancing their clearance by phagocytes, its impact on IL-12/IL-10 interactions has not been fully characterized. Herein, the effect of hemin (HE) on IL-12 and IL-10 responses was studied in murine bone marrow-derived macrophages (BMDM) and compared with synthetic Hz. Our data reveal that HE induces modest inhibition of IL-12p70 responses to lipopolysaccharide (LPS) whereas Hz significantly impairs IL-12p70 responses to IFNgamma/LPS through down-regulation of IL-12p35 and p40 gene expression. Although reactive oxygen species (ROS) are generated after short-term exposure to HE and Hz, prolonged exposure to these iron protoporphyrins has opposite effects on the cellular redox status, HE being the only compound able to promote persistent ROS production. Accordingly, the inhibitory effect of HE on IL-12p70 seems sustained by redox-dependent induction of IL-10 and is partially controlled by the p38 mitogen-activated protein kinase (MAPK) signalling pathway. Indeed, treatment with n-acetylcysteine (NAC) or with the p38 MAPK inhibitor SB203580 inhibits IL-10 responses and significantly restores IL-12p70 responses to IFNgamma/LPS in HE-conditioned BMDM. Our results suggest that oxidant stress induced by free heme may potentially contribute to sustained production of IL-10 and down-regulation of IL-12 responses in malaria.}, }
@article {pmid20210657, year = {2010}, author = {Davalos, M and Konno, S and Eshghi, M and Choudhury, M}, title = {Oxidative renal cell injury induced by calcium oxalate crystal and renoprotection with antioxidants: a possible role of oxidative stress in nephrolithiasis.}, journal = {Journal of endourology}, volume = {24}, number = {3}, pages = {339-345}, doi = {10.1089/end.2009.0205}, pmid = {20210657}, issn = {1557-900X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Calcium Oxalate/*toxicity ; Cell Death/drug effects ; Cell Survival/drug effects ; Crystallization ; Cytoprotection/*drug effects ; DNA/metabolism ; Glutathione/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Kidney/drug effects/metabolism/*pathology ; LLC-PK1 Cells ; Lipid Peroxidation/drug effects ; Nephrolithiasis/metabolism/*pathology ; Oxidative Stress/*drug effects ; Protective Agents/*pharmacology ; Swine ; beta-Glucans/pharmacology ; }, abstract = {PURPOSE: Calcium oxalate (CaOx) is one of the key elements for kidney stone formation, but the exact mechanism needs to be defined. CaOx has been shown to cause renal cell injury through oxidative stress, leading to potential crystal deposition in the kidneys. We thus investigated if CaOx crystal would induce such renal cell injury in vitro and also explored how it would be carried out.<br><br>MATERIALS AND METHODS: Renal tubular epithelial LLC-PK(1) cells were employed, and CaOx monohydrate (COM) was used as CaOx crystal in this study. Cytotoxic effects of COM were assessed on cell viability and biochemical parameters, while protective effect of antioxidants against COM was also examined.<br><br>RESULTS: COM demonstrated its cytotoxicity on LLC-PK(1) cells, exhibiting a approximately 35% cell viability reduction with 500 microg/mL COM in 6 hours. This was presumably attributed to oxidative stress, indicated by lipid peroxidation assay, and N-acetylcysteine (NAC), a potent antioxidant, indeed neutralized such COM cytotoxicity. Although COM also induced inactivation of glutathione-dependent enzymes and partial degradation of heat shock protein 90, these adverse effects were completely prevented with NAC. Moreover, such reduced cell viability with COM was rather associated with apoptosis, evidenced by DNA analysis.<br><br>CONCLUSION: COM is cytotoxic to LLC-PK(1) cells through oxidative stress, leading to the cell viability reduction, adverse effects on biochemical parameters, and, consequently, apoptosis. However, NAC effectively averted such severe cytotoxic effects, sustaining the renal cell integrity. Thus, NAC may provide full renoprotection against COM assault, preventing renal cell injury and ultimate stone formation.}, }
@article {pmid20209491, year = {2010}, author = {Shanmugam, R and Kusumanchi, P and Cheng, L and Crooks, P and Neelakantan, S and Matthews, W and Nakshatri, H and Sweeney, CJ}, title = {A water-soluble parthenolide analogue suppresses in vivo prostate cancer growth by targeting NFkappaB and generating reactive oxygen species.}, journal = {The Prostate}, volume = {70}, number = {10}, pages = {1074-1086}, doi = {10.1002/pros.21141}, pmid = {20209491}, issn = {1097-0045}, mesh = {Acetylcysteine/metabolism ; Animals ; Apoptosis/drug effects ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Electrophoretic Mobility Shift Assay ; Enzyme Activation ; Female ; Humans ; Immunohistochemistry ; Male ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinase 9/metabolism ; NF-kappa B/*antagonists &amp; inhibitors/metabolism ; Prostatic Neoplasms/*drug therapy/enzymology/metabolism ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; Specific Pathogen-Free Organisms ; }, abstract = {BACKGROUND: To characterize the molecular changes associated with DMAPT-induced prostate cancer cell death and its in vivo activity.<br><br>METHODS: CWR22Rv1 and PC-3 were subjected to flow cytometry, electrophoretic mobility shift assays, and Western blot studies to measure DMAPT's ability to generate reactive oxygen species (ROS), inhibit NFkappaB DNA binding, and cause changes in anti-apoptotic proteins. N-acetyl cysteine (NAC) and short hairpin RNA (shRNA) were used to determine the contribution of ROS and JNK2 activation, respectively. The BrdU incorporation assay was used to measure proliferation and trypan blue studies assessed cell viability after DMAPT treatment. The in vivo activity of DMAPT as a single agent and in combination with bicalutamide or docetaxel was assessed in a subcutaneous xenograft model with athymic nude female mice.<br><br>RESULTS: DMAPT generated ROS with subsequent JNK activation and inhibited NFkappaB DNA binding and expression of NFkappaB-regulated anti-apoptotic proteins. DMAPT increased necrotic and apoptotic cell death in a cell-type-dependent manner and both types of cell death were blocked by NAC. Additionally, shRNA JNK2 partially blocked the anti-proliferative activity of DMAPT. DMAPT inhibited CWR22Rv1 and PC-3 cellular proliferation by 100% with 10 and 20 microM respectively and in vivo, DMAPT was more effective at inhibiting growth than biclutamide (CWR22v1) and docetaxel (PC-3).<br><br>CONCLUSIONS: DMAPT promotes cell death by both generating ROS and inhibition of NFkappaB. Its in vivo activity supports the conduct of clinical trials in patients with castrate-resistant disease.}, }
@article {pmid20209390, year = {2010}, author = {Hanci, V and Kerimoğlu, A and Koca, K and Başkesen, A and Kiliç, K and Taştekin, D}, title = {The biochemical effectiveness of N-acetylcysteine in experimental spinal cord injury in rats.}, journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma &amp; emergency surgery : TJTES}, volume = {16}, number = {1}, pages = {15-21}, pmid = {20209390}, issn = {1306-696X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Disease Models, Animal ; Drug Therapy, Combination ; Injections, Intraperitoneal ; Injury Severity Score ; Male ; Malondialdehyde/blood/metabolism ; Methylprednisolone/*therapeutic use ; Neuroprotective Agents/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Injuries/*drug therapy/metabolism/pathology ; Superoxide Dismutase/blood/metabolism ; }, abstract = {BACKGROUND: In this study, we investigated the biochemical effectiveness of methylprednisolone, N-acetylcysteine (NAC) and methylprednisolone combined with NAC treatment in experimental spinal cord injury in rats.<br><br>METHODS: Thirty-two Sprague-Dawley male rats weighing 250-300 g were divided into four groups. Spinal cord injury was created extradurally with an aneurysm clip at the T4-T5 level. Following the trauma, Group C (Control group, n:8) was not given any treatment. Group M (methylprednisolone group, n:8) was treated with 30 mg x kg(-1) methylprednisolone followed by a maintenance dose of 5.4 mg x kg(-1) per hour. Group N (NAC group, n:8) was given 150 mg x kg(-1) NAC. Group MN (methylprednisolone and NAC group, n:8) was given 30 mg x kg(-1) followed by an hourly maintenance dose of 5.4 mg x kg(-1) methylprednisolone and 150 mg x kg(-1) NAC intraperitoneally. Twenty-four hours after the trauma, the rats were decapitated under anesthesia, and their spinal cord samples were taken for biochemical examination.<br><br>RESULTS: Mean malonyldialdehyde (MDA) values in Groups M, N and MN were significantly reduced compared to Group C. Mean superoxide dismutase (SOD) values in Groups M, N and MN were significantly higher than in Group C (p<0.05). No difference existed between Groups M and N with respect to mean MDA and SOD values.<br><br>CONCLUSION: Methylprednisolone, NAC and methylprednisolone plus NAC treatments have potential biochemical benefits in preventing secondary injury in experimental spinal cord injury in rats.}, }
@article {pmid20206069, year = {2010}, author = {Kinbara, T and Hayano, T and Ohtani, N and Furutani, Y and Moritani, K and Matsuzaki, M}, title = {Efficacy of N-acetylcysteine and aminophylline in preventing contrast-induced nephropathy.}, journal = {Journal of cardiology}, volume = {55}, number = {2}, pages = {174-179}, doi = {10.1016/j.jjcc.2009.10.006}, pmid = {20206069}, issn = {0914-5087}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aged ; Aminophylline/administration &amp; dosage/*therapeutic use ; Angioplasty, Balloon, Coronary/*adverse effects ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood/metabolism ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; beta 2-Microglobulin/blood/urine ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) is one of the important complications of coronary angiography (CAG) and percutaneous coronary intervention (PCI), especially in patients with chronic kidney disease (CKD). Prophylactic administration of N-acetylcysteine (NAC) and aminophylline has been reported to be effective in some trials, but the results still remain controversial. We investigated the efficacy of NAC or aminophylline in preventing CIN.<br><br>METHODS AND RESULTS: Forty-five consecutive patients undergoing CAG and/or PCI were randomly assigned to receive hydration and NAC (704 mg orally twice daily; NAC group, n=15), hydration and aminophylline (250 mg intraveneously 30 min before CAG and/or PCI; aminophylline group, n=15), or hydration alone (control group, n=15). We compared serum creatinine (SCr), creatinine clearance (Ccr), blood beta-2 microglobulin, and urinary beta-2 microglobulin levels at baseline and 48h after CAG and/or PCI. In the NAC group, SCr decreased from 1.00 + or - 0.36 to 0.67 + or - 0.16 mg/dl (p<0.01), and Ccr significantly increased from 62.4 + or - 15.6 to 80.4 + or - 8.39 ml/min (p<0.01). In the aminophylline group, SCr and Ccr were unchanged. In the control group, SCr significantly increased from 0.94 + or - 0.21 to 1.28 + or - 0.21 mg/dl (p<0.01), and Ccr significantly decreased from 63.7 + or - 16.1 to 46.1 + or - 10.6 ml/min (p<0.01) after CAG and/or PCI. In the NAC group, mean blood beta-2 microglobulin significantly decreased from 2.38 + or - 0.58 to 1.71 + or - 0.38 mg/dl (p<0.01), and in the aminophylline group, mean urinary beta-2 microglobulin concentration significantly decreased from 337 + or - 31.0 to 239 + or - 34 microg/ml (p<0.01).<br><br>CONCLUSIONS: These results suggest that both prophylactic NAC and aminophylline administration are effective in preventing CIN, but not with hydration alone. It appears that the two compounds work in different ways against CIN.}, }
@article {pmid20205945, year = {2010}, author = {Chromik, AM and Daigeler, A and Bulut, D and Flier, A and May, C and Harati, K and Roschinsky, J and Sülberg, D and Ritter, PR and Mittelkötter, U and Hahn, SA and Uhl, W}, title = {Comparative analysis of cell death induction by Taurolidine in different malignant human cancer cell lines.}, journal = {Journal of experimental &amp; clinical cancer research : CR}, volume = {29}, number = {1}, pages = {21}, pmid = {20205945}, issn = {1756-9966}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Caspases/metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Glutathione/antagonists &amp; inhibitors ; Humans ; Neoplasms/*drug therapy ; Reactive Oxygen Species ; Taurine/*analogs &amp; derivatives/pharmacology ; Thiadiazines/*pharmacology ; }, abstract = {BACKGROUND: Taurolidine (TRD) represents an anti-infective substance with anti-neoplastic activity in many malignant cell lines. So far, the knowledge about the cell death inducing mechanisms and pathways activated by TRD is limited. The aim of this study was therefore, to perform a comparative analysis of cell death induction by TRD simultaneously in different malignant cell lines.<br><br>MATERIALS AND METHODS: Five different malignant cell lines (HT29/Colon, Chang Liver/Liver, HT1080/fibrosarcoma, AsPC-1/pancreas and BxPC-3/pancreas) were incubated with increasing concentrations of TRD (100 microM, 250 microM and 1000 microM) for 6 h and 24 h. Cell viability, apoptosis and necrosis were analyzed by FACS analysis (Propidiumiodide/AnnexinV staining). Additionally, cells were co-incubated with the caspase Inhibitor z-VAD, the radical scavenger N-Acetylcystein (NAC) and the Gluthation depleting agent BSO to examine the contribution of caspase activation and reactive oxygen species in TRD induced cell death.<br><br>RESULTS: All cell lines were susceptible to TRD induced cell death without resistance toward this anti-neoplastic agent. However, the dose response effects were varying largely between different cell lines. The effect of NAC and BSO co-treatment were highly different among cell lines--suggesting a cell line specific involvement of ROS in TRD induced cell death. Furthermore, impact of z-VAD mediated inhibition of caspases was differing strongly among the cell lines.<br><br>CONCLUSION: This is the first study providing a simultaneous evaluation of the anti-neoplastic action of TRD across several malignant cell lines. The involvement of ROS and caspase activation was highly variable among the five cell lines, although all were susceptible to TRD induced cell death. Our results indicate, that TRD is likely to provide multifaceted cell death mechanisms leading to a cell line specific diversity.}, }
@article {pmid20205925, year = {2010}, author = {Korou, LM and Agrogiannis, G and Pantopoulou, A and Vlachos, IS and Iliopoulos, D and Karatzas, T and Perrea, DN}, title = {Comparative antilipidemic effect of N-acetylcysteine and sesame oil administration in diet-induced hypercholesterolemic mice.}, journal = {Lipids in health and disease}, volume = {9}, number = {}, pages = {23}, pmid = {20205925}, issn = {1476-511X}, mesh = {Acetylcysteine/*metabolism ; *Animal Feed ; Animals ; Body Weight ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; *Diet ; Hypercholesterolemia/drug therapy/*metabolism ; Lipid Peroxidation ; Male ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/blood/metabolism ; Sesame Oil/*metabolism ; Triglycerides/blood ; }, abstract = {BACKGROUND: There is an increasing number of novel antilipidemic therapies under consideration. The putative hypolipidemic effect of N-acetylcysteine (NAC) and sesame oil was studied in a mouse model of dietary-induced hypercholesterolemia.<br><br>METHODS: Male C57bl/6 mice were assigned to the following groups: (NC) control group, (HC) group receiving test diet supplemented with 2% cholesterol and 0.5% cholic acid for 8 weeks, (HCN) group receiving the test diet with NAC supplementation (230 mg/kg p.o.) and (HCS) group fed the test diet enriched with 10% sesame oil. Total serum cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides were assayed at the beginning and at the end of the experiment. Total peroxides and nitric oxide (NO) levels were measured in the serum at the end of the experiment. Hepatic and aortic lesions were evaluated by haematoxylin-eosin staining.<br><br>RESULTS: Higher serum levels of total and LDL-cholesterol were recorded in all groups fed the high cholesterol diet. The HCN group presented reduced lipid levels compared to HC and HCS groups. No differences were observed between HCS and HC groups. Peroxide content in serum was markedly increased in mice consuming high cholesterol diet. NAC and sesame oil administration led to a significant decrease of serum lipid peroxidation in the levels of control group, whereas only NAC restored NO bioavailability. In terms of liver histology, the lesions observed in HCN group were less severe than those seen in the other high cholesterol groups.<br><br>CONCLUSION: Co-administration of NAC, but not sesame oil, restored the disturbed lipid profile and improved hepatic steatosis in the studied diet-induced hypercholesterolemic mice. Both agents appear to ameliorate serum antioxidant defense.}, }
@article {pmid20203065, year = {2010}, author = {Merry, TL and Dywer, RM and Bradley, EA and Rattigan, S and McConell, GK}, title = {Local hindlimb antioxidant infusion does not affect muscle glucose uptake during in situ contractions in rat.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {108}, number = {5}, pages = {1275-1283}, doi = {10.1152/japplphysiol.01335.2009}, pmid = {20203065}, issn = {1522-1601}, mesh = {AMP-Activated Protein Kinases/metabolism ; Acetylcysteine/*administration &amp; dosage/metabolism ; Animals ; Antioxidants/*administration &amp; dosage/metabolism ; Biological Transport ; Blood Pressure ; Cysteine/blood ; Cystine/blood ; Electric Stimulation ; Glucose/*metabolism ; Glutathione/metabolism ; Heart Rate ; Hindlimb ; Infusions, Intra-Arterial ; Male ; *Muscle Contraction ; Muscle Fatigue ; Muscle Strength ; Muscle, Skeletal/blood supply/*drug effects/innervation/metabolism ; Phosphorylation ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Regional Blood Flow ; Time Factors ; Tyrosine/metabolism ; Vascular Resistance ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {There is evidence that reactive oxygen species (ROS) contribute to the regulation of skeletal muscle glucose uptake during highly fatiguing ex vivo contraction conditions via AMP-activated protein kinase (AMPK). In this study we investigated the role of ROS in the regulation of glucose uptake and AMPK signaling during low-moderate intensity in situ hindlimb muscle contractions in rats, which is a more physiological protocol and preparation. Male hooded Wistar rats were anesthetized, and then N-acetylcysteine (NAC) was infused into the epigastric artery (125 mg.kg(-1).h(-1)) of one hindlimb (contracted leg) for 15 min before this leg was electrically stimulated (0.1-ms impulse at 2 Hz and 35 V) to contract at a low-moderate intensity for 15 min. The contralateral leg did not receive stimulation or local NAC infusion (rest leg). NAC infusion increased (P<0.05) plasma cysteine and cystine (by approximately 360- and 1.4-fold, respectively) and muscle cysteine (by 1.5-fold, P=0.001). Although contraction did not significantly alter muscle tyrosine nitration, reduced (GSH) or oxidized glutathione (GSSG) content, S-glutathionylation of protein bands at approximately 250 and 150 kDa was increased (P<0.05) approximately 1.7-fold by contraction, and this increase was prevented by NAC. Contraction increased (P<0.05) skeletal muscle glucose uptake 20-fold, AMPK phosphorylation 6-fold, ACCbeta phosphorylation 10-fold, and p38 MAPK phosphorylation 60-fold, and the muscle fatigued by approximately 30% during contraction and NAC infusion had no significant effect on any of these responses. This was despite NAC preventing increases in S-glutathionylation with contraction. In conclusion, unlike during highly fatiguing ex vivo contractions, local NAC infusion during in situ low-moderate intensity hindlimb contractions in rats, a more physiological preparation, does not attenuate increases in skeletal muscle glucose uptake or AMPK signaling.}, }
@article {pmid20202741, year = {2010}, author = {Kang, N and Zhang, JH and Qiu, F and Tashiro, S and Onodera, S and Ikejima, T}, title = {Inhibition of EGFR signaling augments oridonin-induced apoptosis in human laryngeal cancer cells via enhancing oxidative stress coincident with activation of both the intrinsic and extrinsic apoptotic pathways.}, journal = {Cancer letters}, volume = {294}, number = {2}, pages = {147-158}, doi = {10.1016/j.canlet.2010.01.032}, pmid = {20202741}, issn = {1872-7980}, mesh = {Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Apoptosis/drug effects ; Apoptosis Inducing Factor/metabolism ; Carcinoma, Squamous Cell/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Diterpenes, Kaurane/*pharmacology ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/*antagonists &amp; inhibitors/metabolism ; Fas-Associated Death Domain Protein/metabolism ; Humans ; Laryngeal Neoplasms/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Quinazolines ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Sirtuin 1/antagonists &amp; inhibitors/metabolism ; Tyrphostins/*pharmacology ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been reported to have anti-tumor effects, while the epidermal growth factor receptor (EGFR) signal pathway has been reported to play a vital role in the biological progression of several tumors and to be a target for therapeutic intervention. In this work, we show that inhibition of EGFR with tyrphostin AG1478 enhances oridonin-induced cell death in human laryngeal cancer cells HEp-2, a cell line characterized by EGFR gene amplification. The enhanced apoptotic effect correlates with high expression and activation of Bax, FADD, caspase-8 as well as caspase-3 and decreased protein levels of Bcl(2) and SIRT1, suggesting that both the extrinsic and intrinsic apoptosis pathways are involved in the apoptotic processes. However, treatment with oridonin and AG1478 greatly enhances nuclear translocation of apoptosis inducing factor (AIF) without caspase-9 activation, indicating that the apoptosis occurs via a caspase-9-independent mitochondrial pathway. Here, it is the active form of caspase-8 but not caspase-9 that activates downstream effector caspase-3, resulting in the cleavage of critical cellular proteins and apoptosis. Furthermore, the combined use of AG1478 and oridonin augments the production of reactive oxygen species (ROS). Incubation of cells with N-Acetylcysteine (NAC) attenuates the apoptosis and the mitochondrial membrane potential (Deltapsim) disruption induced by the combination of oridonin and AG1478, which indicates that ROS plays a pivotal role in cell death. In conclusion, targeting EGFR combined with other conventional pro-apoptotic drugs should be a potentially very effective anti-neoplastic therapy for laryngeal cancer.}, }
@article {pmid20200986, year = {2010}, author = {Chen, JR and Lazarenko, OP and Shankar, K and Blackburn, ML and Badger, TM and Ronis, MJ}, title = {A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/beta-catenin signaling.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {25}, number = {5}, pages = {1117-1127}, pmid = {20200986}, issn = {1523-4681}, support = {R01 AA012928/AA/NIAAA NIH HHS/United States ; R01 AA018282/AA/NIAAA NIH HHS/United States ; R01 AA12928/AA/NIAAA NIH HHS/United States ; R01 AA18282/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adipogenesis/drug effects ; Animals ; Bone Density/drug effects ; Cell Differentiation/*drug effects ; Cell Lineage ; Down-Regulation ; Ethanol/*pharmacology ; Female ; Glycogen Synthase Kinase 3/metabolism ; Glycogen Synthase Kinase 3 beta ; Lactation/physiology ; Mesenchymal Stem Cells/drug effects/*metabolism ; Osteogenesis/drug effects/*physiology ; *Oxidative Stress/drug effects ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; TCF Transcription Factors/biosynthesis ; Wnt Proteins/*metabolism ; beta Catenin/*metabolism ; }, abstract = {The mechanisms by which chronic ethanol intake induces bone loss remain unclear. In females, the skeletal response to ethanol varies depending on physiologic status (e.g., cycling, pregnancy, or lactation). Ethanol-induced oxidative stress appears to be a key event leading to skeletal toxicity. In this study, ethanol-containing liquid diets were fed to postlactational female Sprague-Dawley rats intragastrically for 4 weeks beginning at weaning. Ethanol consumption decreased bone mineral density (BMD) compared with control animals during this period of bone rebuilding following the end of lactation. Coadministration of the antioxidant N-acetylcysteine (NAC) was able to block bone loss and downregulation of the bone-formation markers alkaline phosphatase and osteocalcin in serum and gene expression in bone. Real-time array analysis of total RNA isolated from bone tissue revealed that the majority of Wnt signaling components were downregulated by chronic ethanol infusion. Real-time PCR confirmed downregulated gene expression in a subset of the Wnt signaling components by ethanol. However, the Wnt antagonist DKK1 was upregulated by ethanol. The key canonical Wnt signaling molecule beta-catenin protein expression was inhibited, while glycogen synthase kinase-3-beta was dephosphorylated by ethanol in bone and preosteoblastic cells. These actions of ethanol were blocked by NAC. Ethanol treatment inactivated TCF/LEF gene transcription, eliminated beta-catenin nuclear translocation in osteoblasts, and reciprocally suppressed osteoblastogenesis and enhanced adipogenesis. These effects of ethanol on lineage commitment of mesenchymal stem cells were eliminated by NAC pretreatment. These observations are consistent with the hypothesis that ethanol inhibits bone formation through stimulation of oxidative stress to suppress Wnt signaling.}, }
@article {pmid20200411, year = {2010}, author = {Yamada, M and Ueno, T and Minamikawa, H and Sato, N and Iwasa, F and Hori, N and Ogawa, T}, title = {N-acetyl cysteine alleviates cytotoxicity of bone substitute.}, journal = {Journal of dental research}, volume = {89}, number = {4}, pages = {411-416}, doi = {10.1177/0022034510363243}, pmid = {20200411}, issn = {1544-0591}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bone Regeneration/drug effects ; Bone Substitutes/*toxicity ; Cattle ; Cell Survival/drug effects ; Free Radical Scavengers/*pharmacology ; Glutathione/biosynthesis ; Humans ; Interleukins/biosynthesis ; Male ; Minerals/*toxicity ; Osteoblasts/*drug effects/metabolism ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Lack of cytocompatibility in bone substitutes impairs healing in surrounding bone. Adverse biological events around biomaterials may be associated with oxidative stress. We hypothesized that a clinically used inorganic bone substitute is cytotoxic to osteoblasts due to oxidative stress and that N-acetyl cysteine (NAC), an antioxidant amino acid derivative, would detoxify such material. Only 20% of rat calvaria osteoblasts were viable when cultured on commercial deproteinized bovine bone particles for 24 hr, whereas this percentage doubled on bone substitute containing NAC. Intracellular ROS levels markedly increased on and under bone substitutes, which were reduced by prior addition of NAC to materials. NAC restored suppressed alkaline phosphatase activity in the bone substitute. Proinflammatory cytokine levels from human osteoblasts on the bone substitute decreased by one-third or more with addition of NAC. NAC alleviated cytotoxicity of the bone substitute to osteoblastic viability and function, implying enhanced bone regeneration around NAC-treated inorganic biomaterials.}, }
@article {pmid20199220, year = {2010}, author = {Davis, JG and Wan, XS and Ware, JH and Kennedy, AR}, title = {Dietary supplements reduce the cataractogenic potential of proton and HZE-particle radiation in mice.}, journal = {Radiation research}, volume = {173}, number = {3}, pages = {353-361}, doi = {10.1667/RR1398.1}, pmid = {20199220}, issn = {1938-5404}, mesh = {Animals ; Antioxidants/pharmacology ; Astronauts ; Cataract/*etiology/*prevention &amp; control ; *Dietary Supplements ; Extraterrestrial Environment/chemistry ; Iron/adverse effects ; Male ; Mice ; Protease Inhibitors/pharmacology ; Protons/*adverse effects ; Radiation Injuries, Experimental/*etiology/*prevention &amp; control ; Radiation, Ionizing ; }, abstract = {Abstract The present study was undertaken to investigate the ability of dietary supplements to reduce the formation and severity of cataracts in mice irradiated with high-energy protons or iron ions, which are important components of the radiation encountered by astronauts during space travel. The mice were exposed to proton or iron-ion radiation and fed with a control diet or diets supplemented with the soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), in the form of BBI Concentrate (BBIC) or an antioxidant formulation [containing l-selenomethionine (SeM), N-acetyl cysteine (NAC), ascorbic acid, co-enzyme Q10, alpha-lipoic acid and vitamin E succinate] both before and after the radiation exposure. At approximately 2 years after the radiation exposure, the animals were killed humanely and lenses were harvested and characterized using an established classification system that assigns discrete scores based on the severity of the lens opacifications. The results showed that exposure to 1 GeV/nucleon proton (3 Gy) or iron-ion (50 cGy) radiation significantly increased the cataract prevalence and severity in CBA/J mice to levels above the baseline levels of age-induced cataract formation in this mouse strain. Treatment with BBIC or the antioxidant formulation significantly reduced the prevalence and severity of the lens opacifications in the mice exposed to iron-ion radiation. Treatment with BBIC or the antioxidant formulation also decreased the severity of the lens opacifications in the mice exposed to proton radiation; however, the decrease did not reach statistical significance. These results indicate that BBIC and the antioxidant formulation evaluated in this study could be useful for protecting astronauts against space radiation-induced cataracts during or after long-term manned space missions.}, }
@article {pmid20199132, year = {2010}, author = {Wiegand, TJ and Margaretten, M and Olson, KR}, title = {Massive acetaminophen ingestion with early metabolic acidosis and coma: treatment with IV NAC and continuous venovenous hemodiafiltration.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {48}, number = {2}, pages = {156-159}, doi = {10.3109/15563650903524142}, pmid = {20199132}, issn = {1556-9519}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*therapeutic use ; Acidosis/chemically induced ; Analgesics, Non-Narcotic/blood/*poisoning ; Antidotes/therapeutic use ; Coma/chemically induced ; Combined Modality Therapy ; Drug Overdose ; Female ; Hemodiafiltration/*methods ; Humans ; Hypotension/chemically induced ; Young Adult ; }, abstract = {CONTEXT: We report the extraction of acetaminophen by continuous venovenous hemodiafiltration (CVVHD) during treatment of an acute ingestion of 200 g with a peak recorded serum acetaminophen level of 1,614 mg/L (10,652 micromol/L).<br><br>CASE DETAILS: The patient presented with early onset of coma, metabolic acidosis, and hypotension in the absence of significant hepatic injury. In addition to N-acetylcysteine (NAC) therapy, CVVHD was performed to manage the acid-base disturbance. Flow rate, effluent volume, and serum and effluent drug concentrations were obtained at hourly intervals. During 16 h of CVVHD the acetaminophen level dropped from 1,212 to 247 mg/L.<br><br>DISCUSSION: The average clearance of acetaminophen by CVVHD was 2.53 L/h, with removal of 24 g of acetaminophen over 16 h. As NAC is effective in preventing hepatic injury after acute acetaminophen overdose, the role of dialysis or CVVHD is limited.}, }
@article {pmid20198316, year = {2010}, author = {Han, YH and Moon, HJ and You, BR and Kim, SZ and Kim, SH and Park, WH}, title = {The effects of N-acetyl cysteine on the MG132 proteasome inhibitor-treated lung cancer cells in relation to cell growth, reactive oxygen species and glutathione.}, journal = {International journal of molecular medicine}, volume = {25}, number = {4}, pages = {657-662}, doi = {10.3892/ijmm_00000389}, pmid = {20198316}, issn = {1791-244X}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Ditiocarb/pharmacology ; Glutathione/*metabolism ; Humans ; Leupeptins/*pharmacology ; Lung Neoplasms/*metabolism/*pathology ; Membrane Potential, Mitochondrial/drug effects ; Proteasome Endopeptidase Complex/metabolism ; *Proteasome Inhibitors ; Reactive Oxygen Species/*metabolism ; }, abstract = {MG132 as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). Here, we investigated the effects of N-acetyl cysteine (NAC; a well-known antioxidant), L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) or diethyldithiocarbamate (DDC; an inhibitor of Cu/Zn-SOD) on MG132-treated Calu-6 or A549 lung cancer cells in relation to cell growth, ROS and GSH levels. MG132 inhibited the growth of Calu-6 and A549 cells at 24 h. MG132 induced apoptosis in both cell lines, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim). ROS levels including O(2)(.-) were increased in both MG132-treated lung cells. MG132 also induced GSH depletion in both lung cell types. Treatment with 10 microM BSO or 1 microM DDC affected ROS and GSH levels in MG132-treated Calu-6 cells. However, these changes did not influence cell growth and death in the cells. NAC prevented cell growth inhibition and death in MG132-treated lung cells, which was accompanied by decreased ROS, but not by decreased GSH depletion. In conclusion, the changes of ROS and GSH by MG132, NAC, BSO or DDC were partially related to cell growth and death in the lung cancer cell lines Calu-6 and A549.}, }
@article {pmid20195159, year = {2010}, author = {Heyman, SN and Rosen, S and Khamaisi, M and Idée, JM and Rosenberger, C}, title = {Reactive oxygen species and the pathogenesis of radiocontrast-induced nephropathy.}, journal = {Investigative radiology}, volume = {45}, number = {4}, pages = {188-195}, doi = {10.1097/RLI.0b013e3181d2eed8}, pmid = {20195159}, issn = {1536-0210}, mesh = {Acetylcysteine/therapeutic use ; Acute Kidney Injury/*chemically induced/*metabolism/prevention &amp; control ; Animals ; Antioxidants/therapeutic use ; Bicarbonates/therapeutic use ; Buffers ; Cell Hypoxia ; Contrast Media/*adverse effects ; Endothelium, Vascular/metabolism ; Free Radical Scavengers/therapeutic use ; Humans ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Risk Factors ; }, abstract = {Experimental findings in vitro and in vivo illustrate enhanced hypoxia and the formation of reactive oxygen species (ROS) within the kidney following the administration of iodinated contrast media, which may play a role in the development of contrast media-induced nephropathy. Clinical studies indeed support this possibility, suggesting a protective effect of ROS scavenging or reduced ROS formation with the administration of N-acetyl cysteine and bicarbonate infusion, respectively. Furthermore, most risk factors, predisposing to contrast-induced nephropathy are prone to enhanced renal parenchymal hypoxia and ROS formation. In this review, the association of renal hypoxia and ROS-mediated injury is outlined. Generated during contrast-induced renal parenchymal hypoxia, ROS may exert direct tubular and vascular endothelial injury and might further intensify renal parenchymal hypoxia by virtue of endothelial dysfunction and dysregulation of tubular transport. Preventive strategies conceivably should include inhibition of ROS generation or ROS scavenging.}, }
@article {pmid20193479, year = {2010}, author = {Liao, JP and Chi, CH and Li, HC and Tang, XY}, title = {Effects of N-acetylcysteine on Clara cells in rats with cigarette smoke exposure.}, journal = {Chinese medical journal}, volume = {123}, number = {4}, pages = {412-417}, pmid = {20193479}, issn = {2542-5641}, mesh = {Acetylcysteine/*metabolism ; Animals ; Bronchioles/*cytology/drug effects/metabolism ; Fluorometry ; Glutathione/metabolism ; Immunohistochemistry ; Male ; Microscopy, Electron, Transmission ; Random Allocation ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Smoking/*adverse effects ; Uteroglobin/genetics/*metabolism ; }, abstract = {BACKGROUND: The number of Clara cells and the Clara cell 16-kDa protein (CC16) levels of the lung decrease in patients with chronic obstructive pulmonary disease (COPD). N-acetylcysteine (NAC) is a powerful antioxidant and can reduce the frequency of acute exacerbations of COPD. But the exact mechanism is unclear. The present study was designed to investigate the effects of NAC on Clara cells in rats with cigarette smoke exposure.<br><br>METHODS: Eighteen adult male Wistar rats were randomly divided into 3 groups, 12 exposed to cigarette smoke (CS) thrice a day, 10 cigarettes for 30 minutes each time for 1 week, without (CS group) or with (CS + NAC group) oral intake of NAC 80 mg x kg(-1) x d(-1), and another 6 rats exposed to fresh air (control group). Clara cells were observed by an electron microscope. The mRNA expression of CC16 and CC16 protein in lungs were determined by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry respectively. The glutathion (GSH) level in plasma and lung tissue were tested by fluorimetry assay.<br><br>RESULTS: Compared with the controls, the pathologic score of small airways significantly increased in the CS exposed rats (20.3 +/- 14.7 vs. 53.7 +/- 11.5, P < 0.05). The Clara cell particles in cytoplasm decreased in the CS group (P < 0.05). The percentage of CC16-positive cells in bronchioles in the CS group (27.8 +/- 4.3 and 29.5 +/- 2.4 in terminal bronchioles and respiratory bronchioles, respectively) significantly decreased as compared with the control group (37.1 +/- 3.8 and 43.8 +/- 5.8 in terminal bronchioles and respiratory bronchioles, respectively) (P < 0.05). No significant difference was observed in GSH level ((181 +/- 26) nmol/L in the control group vs. (170 +/- 18) nmol/L in the CS group) between the two groups. After treatment with NAC, the pathologic score of small airways (24.1 +/- 17.5) decreased (P < 0.05). Clara cell particles in cytoplasm of Clara cells increased and GSH level in plasma ((213 +/- 40) nmol/L vs. (170 +/- 18) nmol/L in the CS group) increased too (P < 0.05), while the increase in the proportions of CC16 positive cells in bronchioles (30.1 +/- 6.4 and 34.3 +/- 6.3 in terminal bronchioles and respiratory bronchioles, respectively) did not reach the statistical significance (P > 0.05). No significant difference was found in the expression of CC16 mRNA among the three groups. Correlation analysis indicated that the percentage of CC16-positive cells in bronchioles negatively correlated with the pathologic score of small airways (r = -0.592, P < 0.05), but not with GSH level.<br><br>CONCLUSIONS: One-week CS exposure decreased the number of Clara cells and the expression of CC16 in bronchioles in rats. NAC might provide protection of the Clara cells from oxidative damage and possibly through the elevation of the synthesis and secretion of CC16. These data indicate that NAC decreases airway inflammation induced by CS via induction of CC16.}, }
@article {pmid20193347, year = {2009}, author = {Hu, JM and Zhong, NS}, title = {[A preliminary study on the mechanisms of N-acetylcysteine in the inhibition of proliferation and collagen synthesis of human pulmonary fibroblasts.].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {32}, number = {12}, pages = {897-901}, pmid = {20193347}, issn = {1001-0939}, mesh = {*Acetylcysteine/pharmacology ; *Cells, Cultured ; Collagen Type I/metabolism ; Fibroblasts/drug effects ; Humans ; Transforming Growth Factor beta/metabolism ; }, abstract = {OBJECTIVE: To study the mechanisms of N-acetylcysteine (NAC) in the inhibition of proliferation and collagen synthesis of human pulmonary fibroblasts.<br><br>METHODS: The human pulmonary fibroblasts (HFB) were primarily cultured in complete medium of DMEM/F12, with the cell line A549 derived from alveolar epithelia as the control. Different concentrations of NAC were administrated, with or without stimulation by TGF-beta(1) for 24 h. The cell proliferations were tested by methylthiazolyltetrazolium (MTT) and cell cycle detected with flow cytometer. The mRNA expression of type I procollagen was tested with RT-PCR. Proteins of cyclin E, alpha-SMA and STAT-3 were detected with Western blotting.<br><br>RESULTS: The proliferation of HFB was inhibited significantly by NAC at different concentrations (5, 10, 20 and 40 mmol/L). NAC had no effects on proliferation of A549 at a dose of 20 mmol/L. The cell proportion in G(0)/G(1) phase was increased by NAC at different concentrations (10, 20 and 40 mmol/L), while the changes in S-phase ratio were decreased significantly. Procollagen type Isynthesis was increased by TGF-beta(1) significantly. NAC showed inhibition on procollagen type I synthesis before or after stimulation with TGF-beta(1). Expression of protein cyclin E and alpha-SMA was significantly induced by TGF-beta(1), the relative indensity being 0.98 +/- 0.09 and 1.56 +/- 0.23 respectively. Induction of cyclin E by TGF-beta(1) was attenuated significantly by NAC 20 mmol/L (0.52 +/- 0.04). But alpha-SMA was not changed by NAC 20 mmol/L (1.63 +/- 0.20). Stimulation with TGF-beta(1) and NAC had no effects on expression of STAT-3.<br><br>CONCLUSIONS: Inhibition on proliferation of HFB by NAC may be through the attenuation of cyclin E. Differentiation of fibroblasts into myofibroblasts was inhibited by NAC through inhibition on alpha-SMA. NAC directly inhibited collagen synthesis.}, }
@article {pmid20192244, year = {2010}, author = {Lee, R and West, D and Phillips, SM and Britz-McKibbin, P}, title = {Differential metabolomics for quantitative assessment of oxidative stress with strenuous exercise and nutritional intervention: thiol-specific regulation of cellular metabolism with N-acetyl-L-cysteine pretreatment.}, journal = {Analytical chemistry}, volume = {82}, number = {7}, pages = {2959-2968}, doi = {10.1021/ac9029746}, pmid = {20192244}, issn = {1520-6882}, mesh = {Acetylcarnitine/metabolism ; Acetylcysteine/*pharmacology ; Administration, Oral ; Carnitine/metabolism ; Electrophoresis, Capillary/*methods ; *Exercise ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Humans ; Male ; Metabolomics/*methods ; Methylhistidines/metabolism ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Spectrometry, Mass, Electrospray Ionization/*methods ; Young Adult ; }, abstract = {Despite several decades of active research, the success of large-scale clinical trials involving antioxidants remains equivocal given the complex biological interactions of reactive oxygen/nitrogen species in human health. Herein, we outline a differential metabolomics strategy by capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS) to assess the efficacy of nutritional intervention to attenuate oxidative stress induced by strenuous exercise. A healthy volunteer was recruited to perform a submaximal prolonged ergometer cycling trial until volitional exhaustion with frequent blood collection over a 6 h time interval, which included pre-, during, and postexercise periods while at rest. A follow-up study was subsequently performed by the same subject after high-dose oral intake of N-acetyl-L-cysteine (NAC) prior to performing the same exercise protocol under standardized conditions. Time-dependent changes in global metabolism of filtered red blood cell lysates by CE-ESI-MS were measured to reveal a significant attenuation of cellular oxidation associated with high-dose oral NAC intake relative to a control. Untargeted metabolite profiling allowed for the identification and quantification of several putative early- and late-stage biomarkers that reflected oxidative stress inhibition due to nutritional intervention, including oxidized glutathione (GSSG), reduced glutathione (GSH), 3-methylhistidine (3-MeHis), L-carnitine (C0), O-acetyl-L-carnitine (C2), and creatine (Cre). Our work demonstrates the proof-of-principle that NAC pretreatment is effective at dampening acute episodes of oxidative stress by reversible perturbations in global metabolism that can provide deeper insight into the mechanisms of thiol-specific protein inhibition relevant to its successful translation as a prophylaxis in clinical medicine.}, }
@article {pmid20191258, year = {2010}, author = {Chan, A and Remington, R and Kotyla, E and Lepore, A and Zemianek, J and Shea, TB}, title = {A vitamin/nutriceutical formulation improves memory and cognitive performance in community-dwelling adults without dementia.}, journal = {The journal of nutrition, health &amp; aging}, volume = {14}, number = {3}, pages = {224-230}, pmid = {20191258}, issn = {1760-4788}, mesh = {Acetylcarnitine/*pharmacology ; Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Dementia ; *Dietary Supplements ; Double-Blind Method ; Female ; Folic Acid/pharmacology ; Humans ; Institutionalization ; Learning/*drug effects ; Male ; Memory/*drug effects ; Middle Aged ; Reference Values ; S-Adenosylmethionine/*pharmacology ; Vitamin B 12/pharmacology ; Vitamin E/pharmacology ; Vitamins/*pharmacology ; Young Adult ; }, abstract = {Adults of both genders without dementia consumed a nutriceutical formulation ("NF," consisting of folic acid, B12, Vitamin E, S-adenosylmethionine, N-acetyl cysteine and Acetyl-L-carnitine), previously shown to improve cognitive performance in Alzheimer's disease, or placebo. Participants receiving NF but not placebo improved statistically and clinically in the California Verbal Learning Test II and the Trail-Making Test. Both groups improved further during a 3-month open-label extension. Additional individuals displayed identical improvement during a separate 6-month open-label trial. Performance declined to baseline following withdrawal of NF, and statistically improved when participants resumed taking NF. Additional participants receiving NF but not placebo demonstrated improvement within 2 weeks in Trail-making and Digit-Memory tests; both groups improved in a 2-week open-label extension. An increased percentage of participants > or = 74 years of age did not show improvement with NF, which may relate to age-related difficulties in adsorption and/or basal nutritional deficiencies, or age-related cognitive decline during the course of this study. These findings support the benefit of nutritional supplements for cognitive performance and suggest that additional supplementation may be required for the elderly.}, }
@article {pmid20190396, year = {2010}, author = {Takechi, S and Nakahara, K and Yamaguchi, T}, title = {Dihydropyrazine-induced inactivation of glyceraldehyde-3-phosphate dehydrogenase.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {33}, number = {3}, pages = {379-383}, doi = {10.1248/bpb.33.379}, pmid = {20190396}, issn = {1347-5215}, mesh = {Animals ; Anions ; Enzyme Inhibitors/*pharmacology ; Escherichia coli/*drug effects/growth &amp; development ; Glucose ; Glyceraldehyde-3-Phosphate Dehydrogenases/*antagonists &amp; inhibitors ; Glycolysis/drug effects ; Oxidation-Reduction ; *Oxidative Stress ; Pyrazines/*pharmacology ; Rabbits ; Sulfur Compounds/pharmacology ; Superoxides ; }, abstract = {Dihydropyrazine (DHP), which is produced during the Maillard reaction, generates radicals that not only cause breakage of chromosomal DNA leading to mutagenic lesions but also induce oxidative damage to cellular proteins. In the present study, we show that three DHP derivatives, which generated superoxide anions, caused inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). SH-compounds, such as cysteine, dithiothreitol (DTT), 2-mercaptoethanol, 2-mercaptoethylamine, and N-acetyl-cysteine, suppressed the inhibition of GAPDH by DHP in vitro, although the effect of DHP on GAPDH was not reversed by DTT. In addition, DHP-exposed Escherichia coli showed almost unaffected growth on plates containing a rich medium, but poor growth on plates containing M9 synthetic medium with glucose as the sole carbon source. Furthermore, DHP-exposed E. coli exhibited reduced GAPDH activity. These findings indicate that DHP disturbs the glycolytic pathway by inhibiting GAPDH activity.}, }
@article {pmid20190028, year = {2010}, author = {Nascimento, MM and Suliman, ME and Silva, M and Chinaglia, T and Marchioro, J and Hayashi, SY and Riella, MC and Lindholm, B and Anderstam, B}, title = {Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study.}, journal = {Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis}, volume = {30}, number = {3}, pages = {336-342}, doi = {10.3747/pdi.2009.00073}, pmid = {20190028}, issn = {1718-4304}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; C-Reactive Protein/analysis ; Cardiovascular Diseases ; Female ; Humans ; Inflammation/*drug therapy ; Interleukin-6/blood ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; *Peritoneal Dialysis ; Risk Factors ; Serum Amyloid P-Component/analysis ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: Inflammation and oxidative stress (OS) are cardiovascular risk factors in patients with chronic kidney disease. N-acetylcysteine (NAC) is a thiol-containing antioxidant with anti-inflammatory properties and has been shown to reduce the number of cardiovascular events in hemodialysis patients.<br><br>METHODS: The current study aimed to determine the effect of oral NAC (2 x 600 mg/daily) on plasma levels of inflammatory and OS markers in peritoneal dialysis (PD) patients. We performed a placebo-controlled study over 8 weeks in 30 patients (40% males, age 52 +/- 13 years) on regular PD. Before the study was started, the patients were divided into 2 groups of 15 patients matched for age and gender. 22 patients completed the study (12 on NAC, 10 on placebo). Proinflammatory cytokines [high-sensitivity C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-alpha, and pentraxin 3] and markers of OS (pentosidine, advanced oxidation protein products, homocysteine, glutathione, asymmetric dimethylarginine, and free sulfhydryls) were measured before and after treatment with NAC.<br><br>RESULTS: Treatment with NAC for 8 weeks increased mean baseline plasma NAC levels from 2.6 to 24.8 mumol/L (p = 0.007). This intervention, which caused no side effects, significantly diminished IL-6 levels, from 9.4 (4.5 - 31) to 7.6 (4.9 - 13.5) pg/mL (p = 0.006), whereas no such changes were observed in the placebo group. NAC treatment did not significantly affect the other inflammatory and OS markers.<br><br>CONCLUSION: Short-term oral NAC treatment resulted in reduction of circulating IL-6, suggesting that such treatment could be a useful strategy in blunting the inflammatory response in PD patients.}, }
@article {pmid20185348, year = {2010}, author = {Fukuoka, H and Iida, K and Nishizawa, H and Imanaka, M and Takeno, R and Iguchi, G and Takahashi, M and Okimura, Y and Kaji, H and Chihara, K and Takahashi, Y}, title = {IGF-I stimulates reactive oxygen species (ROS) production and inhibits insulin-dependent glucose uptake via ROS in 3T3-L1 adipocytes.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {20}, number = {3}, pages = {212-219}, doi = {10.1016/j.ghir.2010.02.001}, pmid = {20185348}, issn = {1532-2238}, mesh = {3T3-L1 Cells ; Adipocytes/*drug effects/metabolism ; Animals ; Glucose/*pharmacokinetics ; Insulin/*pharmacology ; Insulin Receptor Substrate Proteins/metabolism ; Insulin Resistance/physiology ; Insulin-Like Growth Factor I/*pharmacology ; Mice ; NADPH Oxidases/metabolism ; Oxidative Stress/physiology ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism/pharmacology ; }, abstract = {OBJECTIVE: IGF-I is known to enhance insulin sensitivity in whole body mainly via the IGF-I receptors in muscles. However, the effect of IGF-I on the regulation of insulin sensitivity in the adipose tissue is yet unclear. Insulin sensitivity was found to be higher in the IGF-I receptor-deficient adipocytes than that in wild-type adipocytes, suggesting that IGF-I signaling induces insulin resistance in adipocytes. However, the underlying mechanism has not yet been elucidated. In addition, the effect of superphysiological levels of IGF-I, as is observed in patients with acromegaly, on insulin sensitivity remains unclear.<br><br>DESIGN: To clarify the role of IGF-I on insulin sensitivity in adipocytes, we determined insulin-induced glucose uptake and IRS-1 status in 3T3-L1 adipocytes treated with IGF-I. Since reactive oxygen species (ROS) are causally related to insulin resistance, we investigated the effect of IGF-I on ROS production to elucidate the molecular mechanism underlying insulin resistance.<br><br>RESULTS: Preincubation of the adipocytes with IGF-I attenuated insulin-dependent glucose uptake. Interestingly, we found that IGF-I significantly stimulated ROS production. Furthermore, preincubation of adipocytes with an antioxidant, N-acetyl-cysteine (NAC) restored the IGF-I-induced attenuation of insulin-dependent glucose uptake; this indicates that IGF-I induces insulin resistance via ROS. Serine phosphorylation of IRS-1 was strongly induced and the insulin-dependent tyrosine phosphorylation of IRS-1 was suppressed by preincubating the adipocytes with IGF-I. Further, NAC restored these changes induced by IGF-I on both serine and tyrosine phosphorylation of IRS-1.<br><br>CONCLUSIONS: These data indicate that IGF-I inhibited insulin activity in the 3T3-L1 adipocytes via ROS production, which affects IRS-1 phosphorylation status.}, }
@article {pmid20179891, year = {2010}, author = {Zhou, XY and DU, DS and Ma, XB and Zhang, JF}, title = {[The protective mechanism of N-acetylcysteine against ischemia/reperfusion induced gastric injury in rats].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {62}, number = {1}, pages = {69-72}, pmid = {20179891}, issn = {0371-0874}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Apoptosis ; Gastric Mucosa/pathology ; Male ; Protective Agents/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/physiopathology/*prevention &amp; control ; Stomach/*blood supply ; }, abstract = {The present study aimed to investigate the protective mechanism of N-acetylcysteine (NAC) against gastric ischemia /reperfusion (GI/R) injury in rats. After intravenous injection (IV) of NAC (150 mg/kg) into femoral vein, the rats were subjected to 30 min of ischemia induced by clamping the celiac artery followed by 60 min of reperfusion. After the gastric mucosal damage index (GMDI) had been calculated, gastric mucosal cell in situ apoptosis was detected by TUNEL method. The protein expression of p-ERK, p-JNK and NF-kappaB, and mRNA expression of TNF-alpha and Caspase-3 in gastric mucosa were evaluated by using Western-blot or RT-PCR, respectively. The results showed that NAC not only attenuated the GI-R injury, but also decreased gastric mucosal cellular apoptosis. Furthermore, NAC increased the protein expression of p-ERK, while inhibited protein expression of p-JNK, NF-kappaB in gastric mucosa. NAC also decreased the expression of TNF-alpha mRNA and Caspase-3 mRNA in gastric mucosa. Capsazepine (CPZ) (400 mg/kg, IV) reversed the protective effect of NAC against GI/R injury in rats. These results suggest that NAC can protect rats against GI/R injury. This protective effect is possibly mediated by the up-regulation of p-ERK and down-regulation of p-JNK and NF-kappaB. In addition, vanilloid receptor subtype 1 may be involved in the protective mechanism of NAC against GI/R injury.}, }
@article {pmid20179007, year = {2010}, author = {Hilmi, IA and Peng, Z and Planinsic, RM and Damian, D and Dai, F and Tyurina, YY and Kagan, VE and Kellum, JA}, title = {N-acetylcysteine does not prevent hepatorenal ischaemia-reperfusion injury in patients undergoing orthotopic liver transplantation.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {25}, number = {7}, pages = {2328-2333}, doi = {10.1093/ndt/gfq077}, pmid = {20179007}, issn = {1460-2385}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/epidemiology/physiopathology/*prevention &amp; control ; Aged ; Creatinine/blood ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Glomerular Filtration Rate/physiology ; Glutathione/blood ; Graft Survival/physiology ; Humans ; Incidence ; Kaplan-Meier Estimate ; Liver Function Tests ; Liver Transplantation/*physiology ; Male ; Middle Aged ; Reperfusion Injury/epidemiology/physiopathology/*prevention &amp; control ; Risk Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: Glutathione (GSH) acts as a free radical scavenger that may be helpful in preventing reperfusion injury. N-acetylcysteine (NAC) replenishes GSH stores. The aims of this study were to evaluate the efficacy of NAC in improving liver graft performance and reducing the incidence of post-operative acute kidney injury (AKI).<br><br>METHODS: Our study was a randomized, double-blind, placebo-controlled trial of 100 patients; 50 received placebo and 50 received a loading dose of 140 mg/kg of intravenous (IV) NAC over 1 h followed by 70 mg/kg IV repeated every 4 h for a total of 12 doses. Both groups were followed up for 1 year post-orthotopic liver transplant (OLT). We recorded liver function tests, renal function tests, graft survival, patient survival, plasma GSH and duration of hospital and ICU stay. In addition to serum creatinine (SCr) levels, we analysed cystatin C and beta-trace as independent measures of glomerular filtration. All clinical data were recorded daily for the first week after the surgery, then on Days 14, 21, 30, 90 and 180 and at the end of the first year.<br><br>RESULTS: IV NAC did not affect survival, graft function or risk of AKI. However, GSH levels were highly variable with only 50% of patients receiving NAC exhibiting increased levels and fewer patients developed AKI when GSH levels were increased. Additional risk factors for AKI in the post-transplant period were female gender (P = 0.05), increased baseline serum bilirubin (P = 0.004) and increased baseline SCr levels (P = 0.02).<br><br>CONCLUSIONS: IV NAC was not effective in reducing renal or hepatic injury in the setting of liver transplantation. The dose and duration of NAC used, though higher than most renal protection studies, may have been ineffective for raising GSH levels in some patients.}, }
@article {pmid20178457, year = {2010}, author = {Michalska, M and Wolf, G and Walther, R and Newsholme, P}, title = {Effects of pharmacological inhibition of NADPH oxidase or iNOS on pro-inflammatory cytokine, palmitic acid or H2O2-induced mouse islet or clonal pancreatic β-cell dysfunction.}, journal = {Bioscience reports}, volume = {30}, number = {6}, pages = {445-453}, doi = {10.1042/BSR20090138}, pmid = {20178457}, issn = {1573-4935}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Cell Line ; Cells, Cultured ; Cytokines/metabolism/*pharmacology ; Hydrogen Peroxide/*pharmacology ; Inflammation/immunology ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/*drug effects/metabolism ; Islets of Langerhans/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; NADPH Oxidases/antagonists &amp; inhibitors ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors ; Oxidative Stress ; Palmitic Acid/metabolism/*pharmacology ; Rats ; }, abstract = {Various pancreatic β-cell stressors including cytokines and saturated fatty acids are known to induce oxidative stress, which results in metabolic disturbances and a reduction in insulin secretion. However, the key mechanisms underlying dysfunction are unknown. We investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines, H(2)O(2) or PA (palmitic acid) on β-cell insulin secretion, ATP, the NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) component p47phox and iNOS (inducible nitric oxide synthase) levels using primary mouse islets or clonal rat BRIN-BD11 β-cells. Addition of a pro-inflammatory cytokine mixture [IL-1β (interleukin-1β), TNF-α (tumour necrosis factor-α) and IFN-γ (interferon-γ)] or H(2)O(2) (at sub-lethal concentrations) inhibited chronic (24 h) levels of insulin release by at least 50% (from islets and BRIN-BD11 cells), while addition of the saturated fatty acid palmitate inhibited acute (20 min) stimulated levels of insulin release from mouse islets. H(2)O(2) decreased ATP levels in the cell line, but elevated p47phox and iNOS levels as did cytokine addition. Similar effects were observed in mouse islets with respect to elevation of p47phox and iNOS levels. Addition of antioxidants SOD (superoxide dismutase), Cat (catalase) and NAC (N-acetylcysteine) attenuated H(2)O(2) or the saturated fatty acid palmitate-dependent effects, but not cytokine-induced dysfunction. However, specific chemical inhibitors of NADPH oxidase and/or iNOS appear to significantly attenuate the effects of cytokines, H(2)O(2) or fatty acids in islets. While pro-inflammatory cytokines are known to increase p47phox and iNOS levels in β-cells, we now report that H(2)O(2) can increase levels of the latter two proteins, suggesting a key role for positive-feedback redox sensitive regulation of β-cell dysfunction.}, }
@article {pmid20172312, year = {2010}, author = {Li, J and Zhang, S and Wu, Y and Guo, W and Zhang, Y and Zhai, W}, title = {Protective effects of N-acetylcysteine on the liver of brain-dead Ba-Ma mini pig.}, journal = {Transplantation proceedings}, volume = {42}, number = {1}, pages = {195-199}, doi = {10.1016/j.transproceed.2009.12.039}, pmid = {20172312}, issn = {1873-2623}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Brain Death ; DNA Primers ; Interleukin-1beta/blood ; Interleukin-6/blood ; Liver/drug effects/*metabolism/pathology ; NF-kappa B/drug effects/*genetics ; RNA, Messenger/drug effects/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Swine ; Swine, Miniature ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {OBJECTIVE: To investigate liver injury after brain-death in BA-Ma mini pigs and the protective effects of N-acetylcysteine (NAC) on hepatic function and on nuclear factor (NF)-kappaB mRNA and protein expression.<br><br>METHODS: Fifteen Ba-Ma mini pigs were equally divided into three groups at random: brain-dead group (group B), NAC-pretreated group (group N), and control group (group C). A brain-death model was established by increasing intracranial pressure in a modified, slow, and intermittent way. At 6, 12, and 24 hours after the initial brain death, we determined the levels of serum aspartate transferase (AST), alanine transferase (ALT), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. At the same times, hepatic tissue samples were obtained to assess morphological changes in hepatic tissues and the expression of NF-kappaB mRNA and protein was detected by reverse transcriptase polymerase chain reaction and immunohistochemistry, respectively.<br><br>RESULTS: The levels of AST and ALT in groups B and N began to increase at 12 hours after brain death; the levels among group N were lower than those in group B (P < .05). The levels of serum IL-1beta, IL-6, and TNF-alpha in group B and group N began to increase gradually at 6 hours after brain death; those of group B were all significantly greater than those among group N at each time (P < .05). The mRNA and protein levels of NF-kappaB among groups B and N began to increase at 6 hours after brain death; however, those of group B were all significantly higher than those of group N (P < .05). Light and electron microscopy showed only mild edema of liver cells in group N. At 12 hours after brain death, mitochondrial swelling and edema in liver cells were observed among group B, with more severe morphological lesions in this group than group N.<br><br>CONCLUSIONS: NAC inhibited the degree of NF-kappaB mRNA transcription and its protein translation, decreasing the release of inflammatory factors, and thus alleviating hepatic injury during brain death.}, }
@article {pmid20171736, year = {2010}, author = {Biswas, S and Zhao, X and Mone, AP and Mo, X and Vargo, M and Jarjoura, D and Byrd, JC and Muthusamy, N}, title = {Arsenic trioxide and ascorbic acid demonstrate promising activity against primary human CLL cells in vitro.}, journal = {Leukemia research}, volume = {34}, number = {7}, pages = {925-931}, pmid = {20171736}, issn = {1873-5835}, support = {P01 CA095426/CA/NCI NIH HHS/United States ; R01 CA102504/CA/NCI NIH HHS/United States ; P01 CA95426/CA/NCI NIH HHS/United States ; }, mesh = {Amino Acid Chloromethyl Ketones/pharmacology ; Amitrole/pharmacology ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal, Humanized ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Ascorbic Acid/*pharmacology ; B-Lymphocytes/drug effects/pathology ; Buthionine Sulfoximine/pharmacology ; Catalase/antagonists &amp; inhibitors/pharmacology ; Cell Line, Tumor/drug effects ; Cysteine Proteases/physiology ; Cysteine Proteinase Inhibitors/pharmacology ; Drug Evaluation, Preclinical ; Drug Synergism ; Enzyme Activation/drug effects ; Glutathione/metabolism ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/*pathology ; Neoplasm Proteins/physiology ; Oxidants/pharmacology ; Oxidative Stress/drug effects ; Oxides/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {The compromised antioxidant defense system in chronic lymphocytic leukemia (CLL) suggested a potential use for reactive oxygen species (ROS) generating arsenic trioxide (ATO) and ascorbic acid. While both ATO and ascorbic acid mediate cytotoxicity in CLL B cells as single agents, the efficacy of ATO is enhanced by ascorbic acid. This effect is dependent on increased ROS accumulation, as pretreatment of B-CLL cells with a glutathione reducing buthionine sulfoximine or catalase inhibiting aminotriazole, enhanced ATO/ascorbic acid-mediated cytotoxicity. Pretreatment with reducing agents such as catalase, or thiol antioxidant, N-acetyl cysteine or GSH also abrogated ATO/ascorbic acid-mediated cytotoxicity. Furthermore, Hu1D10-mediated cell death was enhanced with ATO and ascorbic acid, thus justifying potential combination of ATO/arsenic trioxide therapy with antibodies such as Hu1D10 that also cause accumulation of ROS.}, }
@article {pmid20171194, year = {2010}, author = {Sun, B and Zhang, X and Yonz, C and Cummings, BS}, title = {Inhibition of calcium-independent phospholipase A2 activates p38 MAPK signaling pathways during cytostasis in prostate cancer cells.}, journal = {Biochemical pharmacology}, volume = {79}, number = {12}, pages = {1727-1735}, doi = {10.1016/j.bcp.2010.02.005}, pmid = {20171194}, issn = {1873-2968}, mesh = {Cell Cycle/drug effects/physiology ; Cell Line, Tumor ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic/physiology ; Humans ; MAP Kinase Signaling System/drug effects/*physiology ; Male ; Naphthalenes/pharmacology ; Phosphodiesterase Inhibitors/pharmacology ; Phospholipases A2, Calcium-Independent/*antagonists &amp; inhibitors/genetics/metabolism ; Prostatic Neoplasms/drug therapy/*pathology ; Pyrones/pharmacology ; RNA Interference ; RNA, Small Interfering/physiology ; Tumor Suppressor Protein p53/genetics/metabolism ; p21-Activated Kinases/genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {The p38 mitogen-activated protein kinase (MAPK) signaling pathways activated during cytostasis induced by Ca(2+)-independent phospholipase A2 (iPLA2) inhibition in prostate cancer cells were investigated. iPLA2 inhibition using siRNA, or the selective inhibitor bromoenol lactone (BEL) and it's enantiomers, decreased growth in LNCaP (p53 positive) and PC-3 (p53 negative) human prostate cancer cells. Decreased cell growth correlated to time- and concentration-dependent activation of the mitogen-activated protein kinase p38 in both cell lines. Inhibition of cytosolic iPLA(2)beta using S-BEL, induced significantly higher levels of P-p53, p53, p21 and P-p38 expression than inhibition of microsomal iPLA2 gamma using R-BEL. Inhibition of p38 using SB202190 or SB203580 inhibited BEL-induced increases in P-p53 (ser15), p53 and p21, and altered the number of cells in G1 in LNCaP cells, and S-phase in PC-3 cells. BEL treatment also induced reactive species in PC-3 and LNCaP cells, which was partially reversed by pretreatment with N-acetyl-cysteine (NAC). NAC subsequently inhibited BEL-induced activation of p38 and p53 in LNCaP cells. In addition, treatment of cells with NAC partially reversed the effect of BEL on cell growth and preserved cell morphology. Collectively, these data demonstrate the novel findings that iPLA2 inhibition activates p38 by inducing reactive species, and further suggest that this signaling kinase is involved in p53 activation, cell cycle arrest and cytostasis.}, }
@article {pmid20171161, year = {2010}, author = {Crispo, JA and Piché, M and Ansell, DR and Eibl, JK and Tai, IT and Kumar, A and Ross, GM and Tai, TC}, title = {Protective effects of methyl gallate on H2O2-induced apoptosis in PC12 cells.}, journal = {Biochemical and biophysical research communications}, volume = {393}, number = {4}, pages = {773-778}, doi = {10.1016/j.bbrc.2010.02.079}, pmid = {20171161}, issn = {1090-2104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Survival/drug effects ; *Cytoprotection ; DNA Fragmentation/drug effects ; Gallic Acid/*analogs &amp; derivatives/pharmacology ; Hydrogen Peroxide/*antagonists &amp; inhibitors/metabolism/toxicity ; Membrane Potential, Mitochondrial/drug effects ; Neuroprotective Agents/*pharmacology ; PC12 Cells ; Rats ; }, abstract = {Neurodegenerative disorders are a class of diseases that have been linked to apoptosis induced by elevated levels of reactive oxygen species (ROS). ROS activates the apoptotic cascade through mitochondrial dysfunction and damage to lipids, proteins and DNA. Recently, fruit and tea-derived polyphenols have been found to be beneficial in decreasing oxidative stress and increasing overall health. Further, polyphenols including epigallocatechin gallate (EGCG) have been reported to inhibit apoptotic signaling and increase neural cell survival. In an effort to better understand the beneficial properties associated with polyphenol consumption, the aim of this study was to explore the neuroprotective effects of EGCG, methyl gallate (MG), gallic acid (GA) and N-acetylcysteine (NAC) on H(2)O(2)-induced apoptosis in PC12 cells and elucidate potential protective mechanisms. Cell viability data demonstrates that MG and NAC pre-treatments significantly increase viability of H(2)O(2)-stressed cells, while pre-treatments with EGCG and GA exacerbates stress. Quantitation of apoptosis and mitochondrial membrane potential shows that MG pre-treatment prevents mitochondria depolarization, however does not inhibit apoptosis and is thus evidence that MG can inhibit mitochondria-mediated apoptosis. Subsequent analysis of DNA degradation and caspase activation reveals that MG inhibits activation of caspase 9 and has a partial inhibitory effect on DNA degradation. These findings confirm the involvement of both intrinsic and extrinsic apoptotic pathways in H(2)O(2)-induced apoptosis and suggest that MG may have potential therapeutic properties against mitochondria-mediated apoptosis.}, }
@article {pmid20170403, year = {2010}, author = {Tibodeau, JD and Isham, CR and Bible, KC}, title = {Annatto constituent cis-bixin has selective antimyeloma effects mediated by oxidative stress and associated with inhibition of thioredoxin and thioredoxin reductase.}, journal = {Antioxidants &amp; redox signaling}, volume = {13}, number = {7}, pages = {987-997}, pmid = {20170403}, issn = {1557-7716}, support = {R01 CA125750/CA/NCI NIH HHS/United States ; CA125750/CA/NCI NIH HHS/United States ; CA98118/CA/NCI NIH HHS/United States ; CA97129/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/drug effects ; *Bixaceae ; Carotenoids/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Glutathione/metabolism/pharmacology ; Humans ; Multiple Myeloma/*drug therapy/pathology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; *Phytotherapy ; *Plant Extracts ; Reactive Oxygen Species/metabolism ; Seeds ; Thioredoxin-Disulfide Reductase/*antagonists &amp; inhibitors/metabolism ; Thioredoxins/*antagonists &amp; inhibitors/metabolism ; }, abstract = {In pursuit of the anticancer effects of seeds of the rain forest plant Bixa orellana (annatto), we found that its constituent cis-bixin induced cytotoxicity in a wide variety of tumor cell lines (IC(50) values from 10 to 50 microM, 24-h exposures) and, importantly, also selectively killed freshly collected patient multiple myeloma cells and highly drug-resistant multiple myeloma cell lines. Mechanistic studies indicated that cis-bixin-induced cytotoxicity was greatly attenuated by co-treatment with glutathione or N-acetylcysteine (NAC); whereas fluorescence-activated cell sorting (FACS) assays using the cell-permeable dyes 5-(and-6) chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H(2)DCFDA), or dihydroethidium demonstrated that cis-bixin rapidly induced cellular reactive oxygen species (ROS) in dose- and time-dependent fashions, collectively implicating ROS as contributory to cis-bixin-induced cytotoxicity. In pursuit of potential contributors to ROS imposition by cis-bixin, we found that cis-bixin inhibited both thioredoxin (Trx) and thioredoxin reductase (TrxR1) activities at concentrations comparable to those required for cytotoxicity, implicating the inhibition of these redox enzymes as potentially contributing to its ability to impose cellular ROS and to kill cancer cells. Collectively, our studies indicate that the annatto constituent cis-bixin has intriguing selective antimyeloma activity that appears to be mediated through effects on redox signaling.}, }
@article {pmid20167675, year = {2010}, author = {Lin, YS and Hsu, CC and Bien, MY and Hsu, HC and Weng, HT and Kou, YR}, title = {Activations of TRPA1 and P2X receptors are important in ROS-mediated stimulation of capsaicin-sensitive lung vagal afferents by cigarette smoke in rats.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {108}, number = {5}, pages = {1293-1303}, doi = {10.1152/japplphysiol.01048.2009}, pmid = {20167675}, issn = {1522-1601}, mesh = {Acetylcysteine/pharmacology ; Adenosine Deaminase/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Ankyrins/*agonists/metabolism ; Antioxidants/pharmacology ; Apyrase/pharmacology ; Blood Pressure/drug effects ; Calcium Channels/metabolism ; Capsaicin/*pharmacology ; Cyclooxygenase Inhibitors/pharmacology ; Heart Rate/drug effects ; Indomethacin/pharmacology ; Inhalation Exposure ; Lung/*innervation ; Male ; Neurons, Afferent/*drug effects/metabolism ; *Purinergic P2 Receptor Agonists ; Pyridoxal Phosphate/analogs &amp; derivatives/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Receptors, Purinergic P2/metabolism ; Receptors, Purinergic P2X ; Reflex/drug effects ; Respiration, Artificial ; Respiratory Mechanics/drug effects ; Sensory System Agents/*pharmacology ; Signal Transduction/drug effects ; Smoke ; Smoking/*adverse effects ; TRPA1 Cation Channel ; TRPC Cation Channels ; Time Factors ; Vagus Nerve/*drug effects/metabolism ; }, abstract = {Capsaicin-sensitive lung vagal afferents (CSLVAs) are important in detecting pulmonary reactive oxygen species (ROS). We investigated the mechanisms underlying the stimulation of CSLVAs by inhaled cigarette smoke (CS) in 216 anesthetized rats. In spontaneously breathing rats, CS evoked a CSLVA-mediated reflex bradypnea that was prevented by N-acetyl-L-cysteine (NAC; an antioxidant), HC-030031 [a transient receptor potential ankyrin 1 (TRPA1) receptor antagonist], and iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate (iso-PPADS; a P2X receptor antagonist). In paralyzed, artificially ventilated rats, CS evoked an increase in CSLVA fiber activity (DeltaFA) that was abolished by NAC and was attenuated by HC-030031, iso-PPADS, indomethacin (Indo; a cyclooxygenase inhibitor), and a combination of apyrase and adenosine deaminase (ADA) (ATP scavengers); the response to CS was reduced to 11.7+/-4.0%, 39.5+/-10.0%, 52.9+/-14.4%, 68.7+/-10.1%, and 47.2+/-12.9% of control, respectively. The suppressive effect on this afferent response was not improved by a combination of HC-030031 and Indo (DeltaFA=39.5+/-10.1% of control) compared with that induced by HC-030031 alone. In contrast, the suppressive effect was enhanced by a combination of HC-030031 and apyrase+ADA (DeltaFA=5.3+/-4.9% of control) or a combination of iso-PPADS and Indo (DeltaFA=23.3+/-7.7% of control) compared with that induced by HC-030031 alone or iso-PPADS alone. This afferent response was not altered by the vehicles for these drugs. These results suggest that activations of TRPA1 receptors by cyclooxygenase metabolites and P2X receptors by ATP are both necessary for the ROS-mediated stimulation of CSLVA fibers by CS in rats.}, }
@article {pmid20163391, year = {2010}, author = {Gray, KM and Watson, NL and Carpenter, MJ and Larowe, SD}, title = {N-acetylcysteine (NAC) in young marijuana users: an open-label pilot study.}, journal = {The American journal on addictions}, volume = {19}, number = {2}, pages = {187-189}, pmid = {20163391}, issn = {1521-0391}, support = {K23 DA020482/DA/NIDA NIH HHS/United States ; R01 DA026777/DA/NIDA NIH HHS/United States ; M01 RR001070-31/RR/NCRR NIH HHS/United States ; M01 RR01070/RR/NCRR NIH HHS/United States ; R01 DA026777-01/DA/NIDA NIH HHS/United States ; K12 DA000357-09/DA/NIDA NIH HHS/United States ; K12 DA000357/DA/NIDA NIH HHS/United States ; M01 RR001070/RR/NCRR NIH HHS/United States ; K23 DA020482-03/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Behavior, Addictive/*drug therapy ; Cannabinoids/urine ; Female ; Humans ; Male ; Marijuana Abuse/*drug therapy/urine ; Pilot Projects ; Young Adult ; }, }
@article {pmid20161972, year = {2010}, author = {Cheung, FW and Li, C and Che, CT and Liu, BP and Wang, L and Liu, WK}, title = {Geoditin A induces oxidative stress and apoptosis on human colon HT29 cells.}, journal = {Marine drugs}, volume = {8}, number = {1}, pages = {80-90}, pmid = {20161972}, issn = {1660-3397}, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/drug therapy/metabolism/pathology ; Animals ; Antineoplastic Agents/antagonists &amp; inhibitors/*pharmacology ; Apoptosis/*drug effects ; Cell Proliferation/drug effects ; Colonic Neoplasms/drug therapy/metabolism/pathology ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Endocytosis/drug effects ; Free Radical Scavengers/pharmacology ; Golgi Apparatus/drug effects/pathology ; HT29 Cells ; Humans ; Inhibitory Concentration 50 ; Iron Chelating Agents/pharmacology ; Marine Toxins/antagonists &amp; inhibitors/*toxicity ; Oxidants/metabolism ; Oxidative Stress/*drug effects ; Receptors, Transferrin/metabolism ; Resorcinols/antagonists &amp; inhibitors/*pharmacology ; Triterpenes/antagonists &amp; inhibitors/*pharmacology ; }, abstract = {Geoditin A, an isomalabaricane triterpene isolated from the marine sponge Geodia japonica, has been demonstrated to dissipate mitochondrial membrane potential, activate caspase 3, decrease cytoplasmic proliferating cell nuclear antigen (PCNA), and induce apoptosis of leukemia cells, but the underlying mechanism remains unclear [1]. In this study, we found fragmentation of Golgi structure, suppression of transferrin receptor expression, production of oxidants, and DNA fragmentation in human colon cancer HT29 cells after treatment with geoditin A for 24 h. This apoptosis was not abrogated by chelation of intracellular iron with salicylaldehyde isonicotinoyl hydrazone (SIH), but suppressed by N-acetylcysteine (NAC), a thiol antioxidant and GSH precursor, indicating that the cytotoxic effect of geoditin A is likely mediated by a NAC-inhibitable oxidative stress. Our results provide a better understanding of the apoptotic properties and chemotherapeutical potential of this marine triterpene.}, }
@article {pmid20160461, year = {2010}, author = {Probyn, ME and Cock, ML and Duncan, JR and Tolcos, M and Hale, N and Shields, A and Rees, SM and Harding, R}, title = {The anti-inflammatory agent N-acetyl cysteine exacerbates endotoxin-induced hypoxemia and hypotension and induces polycythemia in the ovine fetus.}, journal = {Neonatology}, volume = {98}, number = {2}, pages = {118-127}, doi = {10.1159/000280385}, pmid = {20160461}, issn = {1661-7819}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Carbon Dioxide/metabolism ; Disease Models, Animal ; Drug Synergism ; Fetus/*drug effects/metabolism/physiopathology ; Gestational Age ; Hemodynamics/drug effects ; Hypotension/*chemically induced/metabolism/physiopathology ; Hypoxia/*chemically induced/metabolism/physiopathology ; Lipopolysaccharides/*toxicity ; Oximetry ; Oxygen/metabolism ; Polycythemia/*chemically induced/metabolism ; Sheep ; }, abstract = {BACKGROUND: Lipopolysaccharide (LPS) delivered acutely to the ovine fetus induces cerebral white matter injury and brain inflammation. N-acetyl cysteine (NAC) is potentially neuroprotective as it blocks the production of inflammatory cytokines and increases glutathione levels; however, it is unknown whether NAC affects the physiological status of the fetus already exposed to an inflammatory environment.<br><br>OBJECTIVES: Our objective was to determine whether NAC influences the physiological effects of LPS exposure in the ovine fetus.<br><br>METHODS: Catheterized fetal sheep underwent one of four treatments (saline, n = 6; LPS, n = 6; LPS + NAC, n = 6; NAC, n = 3) on 5 consecutive days from 95 days of gestation (term approximately 147 days). Fetal arterial pressure and heart rate were recorded and blood samples collected.<br><br>RESULTS: LPS administration resulted in fetal hypoxemia and hypotension; simultaneous treatment with NAC exacerbated these effects and induced polycythemia. NAC treatment alone had no effect on the fetus.<br><br>CONCLUSION: In the presence of LPS, NAC compromises fetal physiological status, suggesting that it may not be a suitable antenatal treatment for a fetus with evidence of inflammation.}, }
@article {pmid20160000, year = {2010}, author = {Solazzo, SA and Ahmed, M and Schor-Bardach, R and Yang, W and Girnun, GD and Rahmanuddin, S and Levchenko, T and Signoretti, S and Spitz, DR and Torchilin, V and Goldberg, SN}, title = {Liposomal doxorubicin increases radiofrequency ablation-induced tumor destruction by increasing cellular oxidative and nitrative stress and accelerating apoptotic pathways.}, journal = {Radiology}, volume = {255}, number = {1}, pages = {62-74}, pmid = {20160000}, issn = {1527-1315}, support = {R01 CA100045/CA/NCI NIH HHS/United States ; R01 CA133114/CA/NCI NIH HHS/United States ; R01 HL055519/HL/NHLBI NIH HHS/United States ; 2R01 HL55519/HL/NHLBI NIH HHS/United States ; }, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Aldehydes/metabolism ; Animals ; Apoptosis ; Caspase 3/metabolism ; *Catheter Ablation ; Combined Modality Therapy ; DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Doxorubicin/*pharmacology ; Female ; HSP70 Heat-Shock Proteins/metabolism ; Histones/metabolism ; Immunoenzyme Techniques ; Mammary Neoplasms, Experimental/*drug therapy/metabolism/*surgery ; Oxidative Stress ; Rats ; Rats, Inbred F344 ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {PURPOSE: To determine if oxidative and nitrative stress and/or apoptosis contribute to increased coagulation when combining radiofrequency (RF) ablation with liposomal doxorubicin.<br><br>MATERIALS AND METHODS: Animal care committee approval was obtained. R3230 mammary adenocarcinomas in Fischer rats were treated with either RF ablation (n = 43), 1 mg of intravenously injected liposomal doxorubicin (n = 26), or combined therapy (n = 30) and were compared with control subjects (n = 11). A subset of animals receiving combination therapy (n = 24) were treated in the presence or absence of N-acetylcysteine (NAC) administered 24 hours and 1 hour before RF ablation. Tumors were analyzed 2 minutes to 72 hours after treatment to determine the temporal range of response by using immunohistochemical staining of the apoptosis marker cleaved caspase-3, phosphorylated gammaH2AX, and HSP70 and of markers of oxidative and nitrative stress (8-hydroxydeoxyguanosine [8-OHdG], 4-hydroxynonenal [4-HNE]-modified proteins, and nitrotyrosine [NT]). Statistical analyses, including t tests and analysis of variance for comparisons where appropriate, were performed.<br><br>RESULTS: By 4 hours after RF ablation alone, a 0.48-mm +/- 0.13 (standard deviation) peripheral band with 57.0% +/- 7.3 cleaved caspase-3 positive cells was noted at the ablation margin, whereas a 0.73-mm +/- 0.18 band with 77.7% +/- 6.3 positivity was seen for combination therapy (P < .03 for both comparisons). Combination therapy caused increased and earlier staining for 4-HNE-modified proteins, 8-OHdG, NT, and gammaH2AX with colocalization to cleaved caspase-3 staining. A rim of increased HSP70 was identified peripheral to the area of cleaved caspase-3. Parameters of oxidative and nitrative stress were significantly inhibited by NAC 1 hour following RF ablation, resulting in decreased cleaved caspase-3 positivity (0.28-mm +/- 0.09 band of 25.9% +/- 7.4 positivity vs 0.59-mm +/- 0.11 band of 62.9% +/- 6.0 positivity, P < .001 for both comparisons).<br><br>CONCLUSION: Combining RF ablation with liposomal doxorubicin increases cell injury and apoptosis in the zone of increased coagulation by using a mechanism that involves oxidative and nitrative stress that leads to accelerated apoptosis.}, }
@article {pmid20159035, year = {2010}, author = {Han, YH and Moon, HJ and You, BR and Park, WH}, title = {Propyl gallate inhibits the growth of calf pulmonary arterial endothelial cells via glutathione depletion.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {24}, number = {4}, pages = {1183-1189}, doi = {10.1016/j.tiv.2010.02.013}, pmid = {20159035}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Ascorbic Acid/pharmacology ; Cattle ; Endothelial Cells/*drug effects/metabolism ; Endothelium, Vascular/cytology/*drug effects ; Glutathione/*metabolism ; Growth Inhibitors/*toxicity ; Humans ; Propyl Gallate/*toxicity ; Pulmonary Artery/cytology ; Reactive Oxygen Species/metabolism ; }, abstract = {Propyl gallate (PG) as a synthetic antioxidant exerts a variety of effects on tissue and cell functions. Here, we evaluated the effects of PG on the growth and death of endothelial cells (ECs), especially calf pulmonary artery endothelial cells (CPAEC) in relation to reactive oxygen species (ROS) and glutathione (GSH). PG dose-dependently inhibited the growth of CPAEC and human umbilical vein endothelial cells (HUVEC) at 24h. PG induced cell death in CPAEC, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). PG generally increased ROS level in CPAEC but not in HUVEC. PG also dose-dependently increased GSH depleted cells in both ECs. The treatment with antioxidant of N-acetyl-cysteine (NAC) or ascorbate acid (AA) prevented CPAEC growth inhibition and death by PG, which was accompanied by the attenuation of GSH depletion but not by the reduction of ROS level. In conclusion, PG induced growth inhibition and death of ECs, especially CPAEC via GSH depletion.}, }
@article {pmid20151456, year = {2010}, author = {Löhrke, B and Xu, J and Weitzel, JM and Krüger, B and Goldammer, T and Viergutz, T}, title = {N-acetylcysteine impairs survival of luteal cells through mitochondrial dysfunction.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {77}, number = {4}, pages = {310-320}, doi = {10.1002/cyto.a.20873}, pmid = {20151456}, issn = {1552-4930}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aurintricarboxylic Acid/metabolism ; Biomarkers/metabolism ; Cattle ; Cell Nucleus/drug effects/metabolism ; Cell Survival/drug effects ; Female ; Flow Cytometry ; Fluorescence ; Intracellular Space/drug effects/metabolism ; Lipid Peroxides/metabolism ; Luteal Cells/*cytology/*drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/*metabolism/pathology ; Molecular Imaging ; Oxidation-Reduction/drug effects ; Progesterone/metabolism ; Reactive Oxygen Species/metabolism ; Rhodamines/metabolism ; Signal Transduction/drug effects ; Steroids/biosynthesis ; Time Factors ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {N-acetylcysteine (NAC) is known as an antioxidant and used for mucus viscosity reduction. However, this drug prevents or induces cell death depending on the cell type. The response of steroidogenic luteal cells to NAC is unknown. Our data shows that NAC can behave as an antioxidant or prooxidant in dependency on the concentration and mitochondrial energization. NAC elevated the flowcytometric-measured portion of hypodiploid (dying) cells. This rise was completely abolished by aurintricarboxylic acid, an inhibitor of topoisomerase II. NAC increased the secretion of nitric oxide and cellular nitrotyrosine. An image analysis indicated that cells pretreated with NAC and loaded with DHR showed a fluorescent structure probably elicited by the oxidative product of DHR, rhodamine 123 that sequesters mitochondrially. Pretreating luteal cells with NAC or adding NAC directly to mitochondrial fractions followed by assessing the mitochondrial transmembrane potential difference (Deltapsi) by the JC-1 technique demonstrated a marked decrease in Deltapsi. A protonophore restored Deltapsi and rotenone (an inhibitor of respiratory chain complex I) inhibited mitochondrial recovering. Thus, in steroidogenic luteal cells from healthy mature corpus luteum, NAC impairs cellular survival by interfering with mitochondrial metabolism. The protonophore-induced recovering of NAC-provoked decrease in Deltapsi indicates that an ATP synthase-favored route of H(+) re-entry to the matrix is essentially switched off by NAC while other respiratory chain complexes remain intact. These data may be important for therapeutic timing of treatments with NAC. (c) 2010 International Society for Advancement of Cytometry.}, }
@article {pmid20151195, year = {2010}, author = {Thuc, LC and Teshima, Y and Takahashi, N and Nagano-Torigoe, Y and Ezaki, K and Yufu, K and Nakagawa, M and Hara, M and Saikawa, T}, title = {Mitochondrial K(ATP) channels-derived reactive oxygen species activate pro-survival pathway in pravastatin-induced cardioprotection.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {15}, number = {6}, pages = {669-678}, doi = {10.1007/s10495-010-0473-0}, pmid = {20151195}, issn = {1573-675X}, mesh = {Animals ; Cell Survival/drug effects ; Cells, Cultured ; Disease Models, Animal ; Heart/*drug effects/physiopathology ; Humans ; In Vitro Techniques ; Male ; Myocardial Infarction/drug therapy/*metabolism/physiopathology ; Myocytes, Cardiac/cytology/drug effects/metabolism ; Potassium Channels/*metabolism ; Pravastatin/*pharmacology ; Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {Reactive oxygen species (ROS) are important intracellular signaling molecules and are implicated in cardioprotective pathways including ischemic preconditioning. Statins have been shown to have cardioprotective effects against ischemia/reperfusion injury, however, the precise mechanisms remain to be elucidated. We hypothesized that ROS-mediated signaling cascade may be involved in pravastatin-induced cardioprotection. Cultured rat cardiomyocytes were exposed to H(2)O(2) for 30 min to induce cell injury. Pravastatin significantly suppressed H(2)O(2)-induced cell death evaluated by propidium iodide staining and the MTT assay. Incubation with pravastatin activated catalase, and prevented a ROS burst induced by H(2)O(2), which preserved mitochondrial membrane potential. Protective effects were induced very rapidly within 10 min, which was concordant with the up-regulation of phosphorylated ERK1/2. L-NAME, 5HD, N-acetylcysteine (NAC) and staurosporine inhibited ERK1/2 phosphorylation and also reduced pravastatin-induced cardioprotection, suggesting NO, mitochondrial K(ATP) (mitoK(ATP)) channels, ROS and PKC should be involved in the cardioprotective signaling. We also demonstrated that pravastatin moderately up-regulated ROS generation in a 5HD-inhibitable manner. In isolated perfused rat heart experiments, pravastatin administered 10 min prior to no-flow global ischemia significantly improved left ventricular functional recovery, and also reduced infarct size, which were attenuated by the treatment with NAC, 5HD, L-NAME or staurosporine. Administration of pravastatin from the beginning of reperfusion also conferred cardioprotection. Pravastatin protected the cardiomyocytes against oxidative stress by preventing the ROS burst and preserving mitochondrial function. Moderately up-regulated ROS production by mitoK(ATP) channels opening is involved in the pro-survival signaling cascade activated by pravastatin.}, }
@article {pmid20150865, year = {2010}, author = {Wiktorska, JA and Lewinski, A and Stuss, M and Nowak, D and Pietras, T and Sewerynek, E}, title = {Effects of certain antioxidants on lipid peroxidation process in lung homogenates of L thyroxine-receiving rats.}, journal = {Neuro endocrinology letters}, volume = {31}, number = {1}, pages = {137-146}, pmid = {20150865}, issn = {0172-780X}, mesh = {Acetylcysteine/pharmacology ; Ambroxol/pharmacology ; Animals ; Antioxidants/*pharmacology ; Antithyroid Agents/administration &amp; dosage/pharmacology ; Drug Evaluation, Preclinical ; Free Radical Scavengers/pharmacology ; Injections, Intraperitoneal ; Lipid Peroxidation/*drug effects ; Lung/*chemistry/drug effects/metabolism ; Male ; Malondialdehyde/analysis ; Melatonin/administration &amp; dosage/pharmacology ; Propylthiouracil/administration &amp; dosage/pharmacology ; Rats ; Rats, Wistar ; Schiff Bases/analysis ; Thyroxine/*administration &amp; dosage/pharmacology ; Tissue Extracts/*metabolism ; Triiodothyronine/blood ; }, abstract = {OBJECTIVE: A possible role of antioxidants in thyreotoxicosis was investigated. We examined the parameters of lipid peroxidation (LPO): conjugated dienes (CD), malondialdehyde (MDA), Schiff bases (SB) in lung homogenates of male Wistar rats.<br><br>METHODS: Two control groups were created: Group 1 - intact animals and Group 2 - animals injected with 0,9% NaCl. In Experiment I, the animals received L-thyroxin (LT4) i.p. (Groups 3-7). After one week the rats received additionally: Group 4 - melatonin (MEL); Group 5 - propylthiouracil (PTU); Group 6 - Ambroxol (AMB); Group 7 - N-acetylocysteine (NAC). In Experiment II, the animals received only antioxidants.<br><br>RESULTS: In Experiment I, we noticed a significantly higher MDA and SB level in Group 2, compared to that in Group 1. Moreover, we observed a significantly higher MDA and SB level in Group 3, vs. that in Group 1, but SB level was lower in Group 3 than in Group 2. Melatonin, PTU and NAC reduced CD; PTU, AMB diminished MDA and MEL, AMB lowered SB levels as compared to Group 3. In Experiment II, we observed significantly higher MDA and SB level in Group 2, vs. that in Group 1. Melatonin, AMB and NAC decreased MDA and SB level, when compared to Group 2 but PTU elevated MDA and SB level vs. that in Group 1.<br><br>CONCLUSIONS: 1) L-T4 suppresses LPO, 2) MEL, AMB and NAC protect against LPO, 3) PTU is an antioxidant in thyreotoxicosis, however, when administered alone, it enhances LPO, 4) stress accelerate LPO.}, }
@article {pmid20148457, year = {2009}, author = {Gurbuz, N and Ozkul, A and Burgaz, S}, title = {Effects of vitamin C and N-acetylcysteine against cyclophosphamide-induced genotoxicity in exfoliated bladder cells of mice in vivo.}, journal = {Journal of B.U.ON. : official journal of the Balkan Union of Oncology}, volume = {14}, number = {4}, pages = {647-652}, pmid = {20148457}, issn = {1107-0625}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents, Alkylating/toxicity ; Antioxidants/pharmacology ; Ascorbic Acid/*pharmacology ; Cyclophosphamide/*toxicity ; Hemorrhage/chemically induced/pathology/prevention &amp; control ; Inflammation/chemically induced/pathology/prevention &amp; control ; Male ; Mice ; Mice, Inbred BALB C ; Micronuclei, Chromosome-Defective/*drug effects ; Micronucleus Tests ; Urinary Bladder/*drug effects/*pathology ; }, abstract = {PURPOSE: To investigate the effects of vitamin C and N-acetylcysteine (NAC) against cyclophosphamide (CP) -induced genotoxic damage in exfoliated bladder cells of mice by micronucleus (MN) assay.<br><br>METHODS: For each experimental step, 6-8 Swiss albino balb/c male mice were used. CP was used as positive control. Vitamin C (10, 30 and 60 mg/kg) and CP (51.6 mg/kg) were administered intraperitoneally to the experimental animals. Vitamin C was administered twice, one dose 24 h prior to the CP administration and the second dose simultaneously with the CP. NAC (200, 400 and 800 mg/kg) was administered by gavage for 7 consecutive days before the injection of CP. Distilled water and normal saline as negative controls I and II were used, respectively. Ten days after CP treatment, the mice were sacrificed and bladders were isolated and cut, and exfoliated cells were scraped from the bladder walls. Air-dried smears were stained by Feulgen reaction. MN frequencies were scored in 1000 epithelial cells per animal and defined as MN per thousand (per thousand).<br><br>RESULTS: Three doses of vitamin C (10, 30 and 60 mg/ kg) showed a significant inhibitory effect on MN frequencies in mouse bladder cells when compared with those of positive control group (p <0.05). Dose-dependent inhibitory effect of vitamin C was observed only between the doses of 10 and 60 mg/kg (p <0.05). Histopathological changes that depended on CP- induced inflammatory infiltration and haemorrhage in mucosa propria were not observed in all 3 vitamin C doses. Three doses of NAC (200, 400 and 800 mg/kg) inhibited the CP-induced genotoxicity (p <0.05), however, the antigenotoxic effect of NAC was not dose-dependent. Histopathological changes that depended on CP-induced inflammatory infiltration and haemorrhage in mucosa propria were not observed in 200 and 400 mg/kg NAC dosage. The extent of desquamation in bladder was similar in all 3 doses of NAC when compared with the positive control group.<br><br>CONCLUSION: Our study indicated that vitamin C and NAC reduced the CP-induced MN frequencies in target (bladder) cells of mice by 41-71% in all cases. The modifying effects of vitamin C and NAC against CP-induced genotoxic damage may be due to their antioxidant, nucleophilic properties and to the ability to act as precursors of glutathione.}, }
@article {pmid20145594, year = {2010}, author = {Calabrò, P and Bianchi, R and Caprile, M and Sordelli, C and Cappelli Bigazzi, M and Palmieri, R and Gigantino, G and Limongelli, G and Capozzi, G and Cuomo, S and Calabrò, R}, title = {Use of NaCl saline hydration and N-Acetyl Cysteine to prevent contrast induced nephropathy in different populations of patients at high and low risk undergoing coronary artery angiography.}, journal = {Minerva cardioangiologica}, volume = {58}, number = {1}, pages = {35-40}, pmid = {20145594}, issn = {0026-4725}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Contrast Media/*adverse effects ; *Coronary Angiography ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors ; Sodium Chloride/*therapeutic use ; }, abstract = {AIM: Contrast-induced nephropathy (CIN) is most commonly defined as acute renal failure occurring within 48-72 h of exposure to intravascular radiographic contrast medium that is not attributable to other causes. In international literature a 25% increase in serum creatinine levels or an increase in absolute values of 0.5 mg/dL from baseline has been suggested to define CIN. The reported incidence of CIN varies widely, ranging from 2% to 50%. This variability results from differences in the presence or absence of risk factors. With a retrospective analysis authors evaluated the use of NaCl saline hydration and N-acetyl cysteine (NAC) to prevent CIN in different populations of patients at high and low risk undergoing coronary artery angiography.<br><br>METHODS: From January 2007 to December 2008, 597 patients underwent coronary artery angiography with a low osmolarity contrast agent. Nephrotoxic drugs such as diuretics, metformin, ACE-I and ARBs were stopped at least 24 h before the procedure. The population was divided into two groups: group A (high risk 342 patients, 57.2%) identified for the presence of at least one risk factor such as diabetes, age >65 years, baseline creatinine >1.4 mg/dL and group B (low risk 255 patients, 42.8%) for the absence of any of the risk mentioned above. Only group A was treated with a saline hydration (1 mL/kg/h) plus NAC 600 mg 12 h before and 12 h after the procedure.<br><br>RESULTS: The overall incidence of CIN was 6.7% (40 patients). In particular, the incidence of CIN was 4.4% (15 patients) in the group A and 9.8% (25 patients) in the group B respectively (P=0.017). Interestingly, the Contrast Index (volume administrated/theoretical maximum volume) was significantly lower in group B (P<0.005). In the multivariate analysis, including risk factors such as age, diabetes, hypertension, hypercholesterol-mia, current smoke, baseline creatinine level, Contrast Index and hydration, the last variable was the only one inversely correlated independently with the incidence of CIN (P=0.001).<br><br>CONCLUSIONS: The hydration with saline and NAC is an effective and low-cost tool in preventing CIN in patients undergoing coronary artery angiography and, according to the current guidelines, should be used in all high-risk patients. Present results show that even in patients at low risk for CIN, hydration could be useful: in fact, despite the Contrast Index was significantly lower in this population, the incidence of CIN was greater, thus suggesting a potential role for hydration also in the low-risk population.}, }
@article {pmid20144638, year = {2010}, author = {Chen, YJ and Liu, WH and Kao, PH and Wang, JJ and Chang, LS}, title = {Involvement of p38 MAPK- and JNK-modulated expression of Bcl-2 and Bax in Naja nigricollis CMS-9-induced apoptosis of human leukemia K562 cells.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {55}, number = {7}, pages = {1306-1316}, doi = {10.1016/j.toxicon.2010.01.024}, pmid = {20144638}, issn = {1879-3150}, mesh = {Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/biosynthesis/genetics ; Blotting, Western ; Caspases/biosynthesis ; Cell Survival/drug effects ; Chelating Agents/pharmacology ; Cytochromes c/metabolism ; Cytosol/drug effects/metabolism ; Elapid Venoms/*toxicity ; Fatty Acids/toxicity ; Free Radical Scavengers/pharmacology ; Humans ; K562 Cells ; MAP Kinase Kinase 4/*physiology ; Membrane Potentials/drug effects ; Mitochondria/drug effects/metabolism ; Phospholipases A2/*toxicity ; Proto-Oncogene Proteins c-bcl-2/*biosynthesis ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/*biosynthesis ; p38 Mitogen-Activated Protein Kinases/*physiology ; }, abstract = {CMS-9, a phospholipase A(2) (PLA(2)) isolated from Naja nigricollis venom, induced apoptosis of human leukemia K562 cells, characterized by mitochondrial depolarization, modulation of Bcl-2 family members, cytochrome c release and activation of caspases 9 and 3. Moreover, an increase in intracellular Ca2+ concentration and the production of reactive oxygen species (ROS) was noted. Pretreatment with BAPTA-AM (Ca2+ chelator) and N-acetylcysteine (NAC, ROS scavenger) proved that Ca2+ was an upstream event in inducing ROS generation. Upon exposure to CMS-9, activation of p38 MAPK and JNK was observed in K562 cells. BAPTA-AM or NAC abrogated CMS-9-elicited p38 MAPK and JNK activation, and rescued viability of CMS-9-treated K562 cells. SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor) suppressed CMS-9-induced dissipation of mitochondrial membrane potential, Bcl-2 down-regulation, Bax up-regulation and increased mitochondrial translocation of Bax. Inactivation of PLA(2) activity reduced drastically the cytotoxicity of CMS-9, and a combination of lysophosphatidylcholine and stearic acid mimicked the cytotoxic effects of CMS-9. Taken together, our data suggest that CMS-9-induced apoptosis of K562 cells is catalytic activity-dependent and is mediated through mitochondria-mediated death pathway triggered by Ca2+/ROS-evoked p38 MAPK and JNK activation.}, }
@article {pmid20141032, year = {2009}, author = {Vakhromova, EA and Polozov, IuS and Kirpichnikova, KM and Aksenov, ND and Gamaleĭ, IA}, title = {[Effect of alpha-lipoic acid on fibroblasts 3T3 and 3T3-SV40. Comparison with N-acetylcysteine action].}, journal = {Tsitologiia}, volume = {51}, number = {12}, pages = {971-977}, pmid = {20141032}, issn = {0041-3771}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Actin Cytoskeleton/drug effects/metabolism ; Animals ; Antioxidants/*pharmacology ; Cell Cycle/drug effects ; Cell Line, Transformed ; Cell Transformation, Viral ; Fibroblasts/*drug effects/ultrastructure ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Mice ; Microtubules/drug effects/metabolism ; Simian virus 40 ; Thioctic Acid/*pharmacology ; }, abstract = {In this study we investigated the effect of alpha-lipoic acid (ALA) in concentration range 0.7-5.0 mM on the intracellular level of reduced glutathione, the cell cycle phase distribution, the structure of microfilaments and microtubules of normal (3T3) and transformed (3T3-SV40) fibroblasts. We obtained that ALA increased the glutathione content in transformed cells, but did not change its level in normal cells, induced cell cycle arrest of 3T3 cells (but not 3T3-SV40 cells), and disrupted actin microfilaments in cells of both lines. The effect of ALA was compared with N-acetylcysteine (NAC) action. The whole complex of findings allows us to affirm that each of these antioxidants acts on its own target molecules in normal and transformed cells and activates different signal and metabolic pathways in these cells. But at the same time the intermediate steps of ALA and NAC action can be common (alteration of the intracellular level of glutathione, reorganization of actin cytoskeleton, etc.).}, }
@article {pmid20140304, year = {2009}, author = {Fernández, V and Tapia, G and Varela, P and Cornejo, P and Videla, LA}, title = {Upregulation of liver inducible nitric oxide synthase following thyroid hormone preconditioning: suppression by N-acetylcysteine.}, journal = {Biological research}, volume = {42}, number = {4}, pages = {487-495}, pmid = {20140304}, issn = {0717-6287}, mesh = {Acetylcysteine ; Animals ; Free Radical Scavengers ; *Ischemic Preconditioning ; Liver/blood supply/*enzymology/pathology ; Male ; Nitric Oxide Synthase Type II/*metabolism ; Oxidative Stress/*drug effects ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*prevention &amp; control ; Triiodothyronine/*pharmacology ; Up-Regulation ; }, abstract = {3,3-5-L-Triiodothyronine (T(3)) exerts significant protection against ischemia-reperfusion (IR) liver injury in rats. Considering that the underlying mechanisms are unknown, the aim of this study was to assess the involvement of inducible nitric oxide synthase (iNOS) expression and oxidative stress in T(3) preconditioning (PC). Male Sprague-Dawley rats given a single dose of 0.1 mg of T(3)/kg were subjected to 1-hour ischemia followed by 20 hours reperfusion, in groups of animals pretreated with 0.5 g of N-acetylcysteine (NAC)/kg 0.5-hour prior to T3 or with the respective control vehicles. At the end of the reperfusion period, liver samples were taken for analysis of iNOS mRNA levels (RT-PCR), liver NOS activity, and hepatic histology. T(3) protected against hepatic IR injury, with 119% enhancement in liver iNOS mRNA/18S rRNA ratios (p<0.05) and 12.7-fold increase (p<0.05) in NOS activity in T(3)-treated animals subjected to IR over values in control-sham operated rats, with a net 7.7-fold enhancement (p<0.05) in the net effect of T(3) on liver iNOS expression and a net enhancement of 0.58 units in NOS activity, changes that were abolished by NAC treatment before T(3). It is concluded that T(3)-induced liver PC is associated with upregulation of iNOS expression as a protective mechanisms against IR injury, which is achieved through development of transient and reversible oxidative stress.}, }
@article {pmid20138193, year = {2010}, author = {Ren, G and Takano, T and Papillon, J and Cybulsky, AV}, title = {Cytosolic phospholipase A(2)-alpha enhances induction of endoplasmic reticulum stress.}, journal = {Biochimica et biophysica acta}, volume = {1803}, number = {4}, pages = {468-481}, doi = {10.1016/j.bbamcr.2010.01.020}, pmid = {20138193}, issn = {0006-3002}, support = {MOP-53264//Canadian Institutes of Health Research/Canada ; MOP-84213//Canadian Institutes of Health Research/Canada ; }, mesh = {Animals ; Anti-Bacterial Agents/pharmacology ; *Apoptosis ; Blotting, Western ; Calcium/metabolism ; Calnexin/metabolism ; Cells, Cultured ; Chlorocebus aethiops ; Cytosol/*enzymology ; Endoplasmic Reticulum/*metabolism ; Fluorescent Antibody Technique ; Group IV Phospholipases A2/genetics/*metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Humans ; Immunoenzyme Techniques ; Immunoprecipitation ; Ionomycin/pharmacology ; Ionophores/pharmacology ; Kidney Glomerulus/enzymology ; Membrane Proteins/metabolism ; Mutation/genetics ; *Oxidative Stress ; Phospholipids/metabolism ; Phosphorylation/drug effects ; Rats ; Superoxides/metabolism ; Tunicamycin/pharmacology ; }, abstract = {Induction of endoplasmic reticulum (ER) stress by the complement membrane attack complex is enhanced by activation of cytosolic phospholipase A(2)-alpha (cPLA(2)). To address mechanisms by which cPLA(2) may modulate ER stress, we produced a mutant cPLA(2), containing an ER targeting domain (cPLA(2)-ERmut). After transfection and fractionation of COS-1 cells, cPLA(2)-ERmut was present mainly in the membrane fraction, whereas wild type (wt) cPLA(2) was principally in the cytosol. By fluorescence microscopy, cPLA(2)-ERmut was enriched in a perinuclear distribution under basal conditions, colocalizing with the ER protein, calnexin, while cPLA(2)-wt was mainly cytosolic. Both forms of cPLA(2) transiently expressed in COS cells showed basal phosphorylation at serine(505), which correlates with catalytic activity. Expression of cPLA(2)-wt was approximately 5-fold greater, compared with cPLA(2)-ERmut, but both enzymes produced comparable increases in free arachidonic acid, implying that cPLA(2)-ERmut effectively hydrolyzed ER membrane phospholipids. Although transfection of cPLA(2)-ERmut or wt did not induce ER stress independently, cPLA(2)-ERmut and wt enhanced the induction of ER stress by tunicamycin, dithiothreitol and ionomycin (monitored by induction of grp94 and C/EBP homologous protein-10), and the effect was dependent on the catalytic activity. cPLA(2)-ERmut enhanced production of superoxide. Induction of ER stress in tunicamycin-treated cells expressing cPLA(2)-ERmut was attenuated in the presence of the antioxidant, N-acetyl cysteine, and reduced glutathione, and was exacerbated by dl-buthionine-(S,R)-sulfoximine (which depletes glutathione). Expression of cPLA(2)-ERmut exacerbated tunicamycin-induced apoptosis. Thus, induction of ER stress is facilitated by the activation of cPLA(2) at the ER. The mechanism involves ER membrane phospholipid hydrolysis, and accumulation of reactive oxygen species.}, }
@article {pmid20137606, year = {2009}, author = {Zhou, H and Zheng, XQ and Zhang, ZJ and Teng, GJ}, title = {[Effects of N-acetylcysteine upon methylglyoxal-induced damage in hippocampal neuronal cells].}, journal = {Zhonghua yi xue za zhi}, volume = {89}, number = {39}, pages = {2789-2792}, pmid = {20137606}, issn = {0376-2491}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Brain-Derived Neurotrophic Factor/metabolism ; Cells, Cultured ; Hippocampus/cytology/*drug effects ; *Neurons/drug effects/metabolism ; Pyruvaldehyde/*toxicity ; RNA, Messenger/genetics ; Rats ; Rats, Sprague-Dawley ; Receptor, trkB/metabolism ; }, abstract = {OBJECTIVE: To explore the effects of N-acetylcysteine (NAC) upon the methylglyoxal (MG)-induced injury of hippocampal neuronal cells.<br><br>METHODS: Primary cultures of 1-day-old SD rat hippocampal neuron were exposed to MG and/or NAC for 24 h respectively. Apoptosis was quantified by flow cytometer using annexin V-FITC and propidium iodide (PI) staining. The level of intracellular reactive oxygen species (ROS) was measured by an oxidant-sensitive dye 2,7-dichlorofluorescin diacetate (DCFH). The protein and mRNA levels of BDNF and TrkB were assayed with Western blot and real-time reverse-transcription polymerase chain reaction (RT-PCR) respectively.<br><br>RESULTS: After a 24 h cell incubation with 100 micromol/L MG, the ratio of apoptotic cells in MG group (8.80 +/- 0.31)% significantly increased versus the control group (1.60 +/- 0.15)% and MG+NAC group (4.83 +/- 0.31)% respectively. The level of intracellular oxidation of MG group (10 229 +/- 946) also significantly increased versus the NAC group (2118 +/- 320), control group (4265 +/- 82), MG + NAC group (3886 +/- 415) and pretreated NAC + MG group (2997 +/- 606). MG increased the cellular levels of BDNF but decreased the TrkB mRNA and protein expression significantly. However, NAC significantly decreased the BDNF and increased the TrkB mRNA and protein expression in rat hippocampal neuron after MG induction. All these differences were considered statistically significant.<br><br>CONCLUSION: MG-induced neurotoxicity in hippocampal neurons is mediated by oxidative stress and it can impair the BDNF/TrkB signal pathway. Antioxidant NAC has protective effect upon MG-induced neurotoxicity through its antiapoptotic action and its antioxidant effect on ROS level. And it works partly by activating the BDNF/TrkB signal pathway.}, }
@article {pmid20137579, year = {2010}, author = {Liu, JN and Zhang, JX and Lu, G and Qiu, Y and Yang, D and Yin, GY and Zhang, XL}, title = {The effect of oxidative stress in myocardial cell injury in mice exposed to chronic intermittent hypoxia.}, journal = {Chinese medical journal}, volume = {123}, number = {1}, pages = {74-78}, pmid = {20137579}, issn = {2542-5641}, mesh = {Acetylcysteine/pharmacology ; Animals ; Free Radical Scavengers/pharmacology ; Heart/drug effects ; Hypoxia/*physiopathology ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred ICR ; Myocardium/*metabolism/pathology ; Oxidative Stress/*physiology ; Random Allocation ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is an important risk factor for cardiovascular diseases. Chronic intermittent hypoxia (CIH) is considered to be one of the most important causes of cardiovascular diseases in OSA patients. This repeated hypoxia and reoxygenation cycle is similar to hypoxia-reperfusion injury, which initiates oxidative stress. In this study, we observed cardiocytes injury induced by CIH and the effect of N-acetylcysteine (NAC).<br><br>METHODS: Thirty ICR mice were randomly assigned to 3 groups: control, CIH and NAC (CIH + NAC) groups. Malondialdehyde (MDA) and superoxide dismutase (SOD) of cardiocyte homogenates were measured. Serum lipids were measured by an instrument method. Serum cardiac troponin I (cTnI) was detected by enzyme-linked immunosorbent assays (ELISA). Myocardium pathological sections were observed.<br><br>RESULTS: (1) The SOD activity and MDA concentration of cardiocyte homogenates in the CIH group were significantly higher than in other groups (P < 0.005). The MDA concentration of the NAC group was lower than that of the control group (P < 0.01). (2) The serum cTnI concentration of the CIH and NAC groups was significantly higher than that of the control group (P < 0.01). (3) Serum triglyceride levels in the NAC group were lower than in the other groups (P < 0.01), while there were no significant differences in low density lipoprotein and high density lipoprotein among the three groups. (4) The degeneration of myocardium, transverse striation blurred, and fabric effusion were observed in tissue sections in the CIH and NAC groups. However, normal tissue was found in the control group.<br><br>CONCLUSION: The oxidative stress induced by CIH can injure cardiocytes and the injury effect can be partially inhibited by NAC.}, }
@article {pmid20136478, year = {2010}, author = {Coulson, J and Thompson, JP}, title = {Paracetamol (acetaminophen) attenuates in vitro mast cell and peripheral blood mononucleocyte cell histamine release induced by N-acetylcysteine.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {48}, number = {2}, pages = {111-114}, doi = {10.3109/15563650903520959}, pmid = {20136478}, issn = {1556-9519}, mesh = {Acetaminophen/administration &amp; dosage/*pharmacology ; Acetylcysteine/administration &amp; dosage/*toxicity ; Analgesics, Non-Narcotic/administration &amp; dosage/*pharmacology ; Antidotes/*toxicity ; Cell Line ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Histamine Release/drug effects ; Humans ; Leukocytes, Mononuclear/drug effects/metabolism ; Male ; Mast Cells/drug effects/metabolism ; Trypan Blue ; }, abstract = {INTRODUCTION: The treatment of acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is frequently complicated by an anaphylactoid reaction to the antidote. The mechanism that underlies this reaction is unclear. We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro.<br><br>METHOD: HMC-1 and human PBMCs were incubated in the presence of increasing concentrations of NAC +/- paracetamol. Cell viability was determined by the Trypan Blue Assay, and histamine secretion was measured by ELISA.<br><br>RESULTS: NAC was toxic to HMC-1 cells at 100 mg/mL and to PBMCs at 67 mg/mL. NAC increased HMC-1 and PBMC histamine secretion at concentrations of NAC from 20 to 50 mg/mL and 2.5 to 100 mg/mL, respectively. NAC-induced histamine secretion by both cell types was reduced by co-incubation with 2.5 mg/mL of paracetamol.<br><br>CONCLUSION: Paracetamol (acetaminophen) is capable of modifying histamine secretion in vitro. This may explain the clinical observation of a lower incidence of adverse reactions to NAC in vivo when higher concentrations of paracetamol are present than when paracetamol concentrations are low. Paracetamol (acetaminophen) attenuates in vitro mast cell and PBMC cell histamine release induced by NAC.}, }
@article {pmid20132795, year = {2010}, author = {Ryu, J and Cho, S and Park, BC and Lee, DH}, title = {Oxidative stress-enhanced SUMOylation and aggregation of ataxin-1: Implication of JNK pathway.}, journal = {Biochemical and biophysical research communications}, volume = {393}, number = {2}, pages = {280-285}, doi = {10.1016/j.bbrc.2010.01.122}, pmid = {20132795}, issn = {1090-2104}, mesh = {Ataxin-1 ; Ataxins ; Cell Line ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Nerve Tissue Proteins/*metabolism ; Nuclear Proteins/*metabolism ; *Oxidative Stress ; SUMO-1 Protein/*metabolism ; Spinocerebellar Ataxias/metabolism ; Ubiquitin-Conjugating Enzymes/*metabolism ; }, abstract = {Although the polyglutamine protein ataxin-1 is modified by SUMO at multiple sites, the functions of such modification or how it is regulated are still unknown. Here we report that SUMO-1 or Ubc9 over-expression stimulated the aggregation of ataxin-1 and that oxidative stress, such as hydrogen peroxide treatment, further enhanced SUMO conjugation and aggregation of ataxin-1. Accordingly, co-treatment with antioxidant N-acetyl-cysteine attenuated the effect of oxidative stress. Ataxin-1, which can activate c-Jun N-terminal kinase (JNK) pathway by itself, strongly associated with apoptosis signal-regulating kinase 1 (ASK1) while not interacting with JNK. Finally, treatment of JNK-specific inhibitor caused a reduction in the oxidant-enhanced SUMOylation and aggregation of ataxin-1. Together these results indicate that SUMO modification of ataxin-1 promotes the aggregation of ataxin-1 and that oxidative stress and JNK pathway play roles in this process.}, }
@article {pmid20131755, year = {2010}, author = {Kumar, A and Sabbioni, G}, title = {New biomarkers for monitoring the levels of isothiocyanates in humans.}, journal = {Chemical research in toxicology}, volume = {23}, number = {4}, pages = {756-765}, doi = {10.1021/tx900393t}, pmid = {20131755}, issn = {1520-5010}, mesh = {Animals ; Biomarkers/*blood ; Chromatography, High Pressure Liquid ; Hemoglobins/chemistry ; Humans ; Isothiocyanates/*chemistry ; Kinetics ; Lysine/chemistry ; Mice ; Rats ; Serum Albumin/chemistry ; Spectrometry, Mass, Electrospray Ionization ; Sulfoxides ; Thiocyanates/chemistry ; }, abstract = {Isothiocyanates (ITCs) found in cruciferous vegetables have demonstrated cancer preventive activity in animals, and increased dietary intake of ITCs has been shown to be associated with a reduced cancer risk in humans. ITCs exert their cancer chemopreventive action by multiple mechanisms, for example, by modulating the activities of phase I and phase II drug metabolism enzymes, by inhibiting the cell cycle and histone deacetylase, and by causing apoptotic cell death. In cells, protein adducts account for most of total cellular ITC uptake at 4 h after treatment. The time course of this protein binding correlates well with the inhibition of proliferation and the induction of apoptosis. Animal studies have shown that glutathione conjugates are the major products of ITCs. The major urinary excretion products of ITCs in human are N-acetyl cysteine conjugates. Urinary metabolites might provide the exposure history of the last 24 h, if the urine of the full next day is collected. However, this is not feasible in large epidemiological studies. Furthermore, the mercapturic acids of ITC are not stable. Therefore, stable biomarkers are needed that reflect a larger time span of the ITC exposure history. We developed a method to determine stable (not cysteine adducts) reaction products of ITCs with albumin and hemoglobin in humans and mice. We reacted albumin with the ITCs: benzyl isothiocyanate (BITC), phenylethyl isothiocyanate (PEITC), sulforaphane (SFN), and allyl isothiocyanate (AITC). After enzymatic digestion, we found one major product with lysine using LC-MS/MS. The identity of the adducts was confirmed by comparing the analyses with synthetic standards: N(6)-[(benzylamino)carbonothioyl]lysine (BITC-Lys), N(6)-{[(2-phenylethyl)amino]carbonothioyl}lysine (PEITC-Lys), N(6)-({[3-(methylsulfinyl)propyl]amino}carbonothioyl)lysine (SFN-Lys), and N(6)-[(allylamino]carbonothioyl]lysine (AITC-Lys). The adduct levels were quantified by isotope dilution mass spectrometry using the corresponding new ITC-[(13)C(6)(15)N(2)]lysines as internal standards. The applicability of the method was tested for biological samples obtained from different experiments. In humans consuming garden cress, watercress, and broccoli and/or in mice exposed chronically to N-acetyl-S-{[(2-phenylethyl)amino]carbonothioyl}-l-cysteine, albumin and hemoglobin adducts were found. BITC-Lys, PEITC-Lys, and SFN-Lys released after enzymatic digestion of the proteins were quantified with LC-MS/MS. This new method will enable quantification of ITC adducts in blood proteins from large prospective studies about diet and cancer. Protein adducts are involved in the chemopreventive effects of ITCs. Therefore, blood protein adducts are a potential surrogate marker for the effects of ITCs at the cellular level. This new technique will improve the assessment of ITC exposure and the power of studies on the relationship between ITC intake and cancer.}, }
@article {pmid20127900, year = {2010}, author = {Castini, D and Lucreziotti, S and Bosotti, L and Salerno Uriarte, D and Sponzilli, C and Verzoni, A and Lombardi, F}, title = {Prevention of contrast-induced nephropathy: a single center randomized study.}, journal = {Clinical cardiology}, volume = {33}, number = {3}, pages = {E63-8}, pmid = {20127900}, issn = {1932-8737}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Disease ; Aged ; Angioplasty, Balloon, Coronary/methods ; Contrast Media/*adverse effects ; Coronary Angiography/methods ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Glomerular Filtration Rate ; Humans ; Incidence ; Kidney Diseases/chemically induced/*prevention &amp; control ; Male ; Prospective Studies ; Sodium Bicarbonate/administration &amp; dosage/*therapeutic use ; Sodium Chloride/administration &amp; dosage/*therapeutic use ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) is the third cause of acute deterioration of renal function in hospitalized patients.<br><br>HYPOTHESIS: The purpose of the study was to compare the efficacy of saline infusion, saline infusion plus N-acetylcysteine (NAC), and sodium bicarbonate (SB) infusion to prevent CIN in patients undergoing coronary angiography and/or percutaneous coronary intervention.<br><br>METHODS: We prospectively studied 156 patients with a baseline creatinine level > or = 1.2 mg/dL. The primary endpoint was the development of CIN, defined as an increase in serum creatinine concentration > or = 25% over the baseline value within 5 days from contrast exposure.<br><br>RESULTS: Contrast-induced nephropathy developed in 23 patients (14.7%). Incidence of the primary endpoint was similar in the 3 groups of treatment, occurring in 7 patients (14%) in the saline infusion group, in 9 (17%) in the saline infusion plus NAC group, and in 7 (14%) in the SB infusion group.<br><br>CONCLUSIONS: Our findings suggest that neither the addition of NAC nor the administration of SB add further benefit in CIN prevention, compared to standard hydration with isotonic saline infusion.}, }
@article {pmid20127338, year = {2010}, author = {Cigdem, MK and Kizil, G and Onen, A and Kizil, M and Nergiz, Y and Celik, Y}, title = {Is there a role for antioxidants in prevention of pulmonary hypoplasia in nitrofen-induced rat model of congenital diaphragmatic hernia?.}, journal = {Pediatric surgery international}, volume = {26}, number = {4}, pages = {401-406}, pmid = {20127338}, issn = {1437-9813}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Ascorbic Acid/*therapeutic use ; Disease Models, Animal ; Drug Synergism ; Female ; Fetus/drug effects ; Free Radical Scavengers/therapeutic use ; Hernia, Diaphragmatic/chemically induced/*complications ; Hernias, Diaphragmatic, Congenital ; Lipid Peroxidation/drug effects ; Lung/drug effects ; Lung Diseases/*prevention &amp; control ; Male ; Maternal-Fetal Exchange ; Pesticides ; Phenyl Ethers/administration &amp; dosage ; Pregnancy ; Proteins/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Thiobarbituric Acid Reactive Substances/metabolism ; Vitamin E/*therapeutic use ; }, abstract = {BACKGROUND/PURPOSE: Many studies suggest a role for antioxidants in the prevention of lung hypoplasia in nitrofen-induced rat models with congenital diaphragmatic hernia (CDH). This study investigates the oxidative status and the histological outcome of prenatal administration of vitamins E and C with synergistic effect, and effect of N-acetylcysteine (NAC) to improve lung maturation of nitrofen-induced rats.<br><br>METHODS: CDH was induced by maternal administration of a single oral dose of nitrofen on day 9.5 of gestation, and the Sprague-Dawley rats were randomly divided into five groups: nitrofen (N), nitrofen + vitamin C (NC), nitrofen + vitamin E (NE), nitrofen + vitamin C + vitamin E (NCE) and nitrofen + NAC (NNAC). A control group in which only vehicle was administered was included. Cesarean section was performed on day 21. Body weight (BW) and total lung weight (LW) of all fetuses with CDH were recorded; lung histological evaluation was performed, and protein content of lungs, determination of thiobarbituric acid reactive substances, and the protein carbonyls in tissue samples were determined.<br><br>RESULTS: A total of 133 rat fetuses with CDH were investigated. The body weight and the lung weight of fetuses of all groups that were exposed to nitrofen were significantly decreased than of the control group (P < 0.05). The animals exposed to nitrofen with different antioxidants showed increased protein levels in lung tissue. However, in the NCE and the NNAC groups, protein levels were significantly increased than in the others. Malondialdehyde levels significantly decreased in the NCE and the NNAC groups when compared with the NC and the NE groups. In addition, the NCE and NNAC groups decreased protein oxidation to control levels, and no significant difference was observed between control and these two antioxidants groups. The N, NC, NE and NNAC groups showed minimal improvement in lung histology; the NCE groups showed the most improvement in lung histology when compared with the other nitrofen plus antioxidant groups.<br><br>CONCLUSION: Prenatal administration of NAC and vitamin E in combination with vitamin C represented the best effects to avoid oxidative damage and protein content of the lungs in rat pups with CDH at birth.}, }
@article {pmid20121705, year = {2010}, author = {Sinha-Hikim, I and Shen, R and Kovacheva, E and Crum, A and Vaziri, ND and Norris, KC}, title = {Inhibition of apoptotic signalling in spermine-treated vascular smooth muscle cells by a novel glutathione precursor.}, journal = {Cell biology international}, volume = {34}, number = {5}, pages = {503-511}, pmid = {20121705}, issn = {1095-8355}, support = {M01 RR00425/RR/NCRR NIH HHS/United States ; U54 RR019234/RR/NCRR NIH HHS/United States ; U54 MD007598/MD/NIMHD NIH HHS/United States ; RR019234/RR/NCRR NIH HHS/United States ; P20 RR011145/RR/NCRR NIH HHS/United States ; P20 MD000182/MD/NIMHD NIH HHS/United States ; M01 RR000425/RR/NCRR NIH HHS/United States ; S21 MD000103/MD/NIMHD NIH HHS/United States ; MD00182/MD/NIMHD NIH HHS/United States ; U54 RR026138/RR/NCRR NIH HHS/United States ; RR-011145/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antioxidants/metabolism/pharmacology ; Apoptosis/*drug effects ; Cystine/metabolism/*pharmacology ; Enzyme Activation ; Glutathione/*analogs &amp; derivatives/metabolism ; Humans ; In Situ Nick-End Labeling ; JNK Mitogen-Activated Protein Kinases/metabolism ; Muscle, Smooth, Vascular/cytology ; Myocytes, Smooth Muscle/cytology/*drug effects/physiology ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Renal Insufficiency, Chronic/complications/metabolism/pathology ; Signal Transduction/*drug effects ; Spermine/*pharmacology ; bcl-2-Associated X Protein/metabolism ; }, abstract = {CKD (chronic kidney disease) is a public health problem, mediated by haemodynamic and non-haemodynamic events including oxidative stress. We investigated the effect of two GSH (glutathione) precursors, NAC (N-acetylcysteine) and cystine as the physiological carrier of cysteine in GSH with added selenomethionine (F1) in preventing spermine (uraemic toxin)-induced apoptosis in cultured human aortic VSMC (vascular smooth muscle cells). VSMCs exposed to spermine (15 microM) with or without antioxidants (doses 50, 100, 200 and 500 microg/ml) were assessed for apoptosis, JNK (c-Jun-NH2-terminal kinase) activation and iNOS (inducible nitric oxide synthase) induction and activation of intrinsic pathway signalling. Spermine exposure resulted in activation of JNK and iNOS induction and apoptosis. NAC and F1 (dose range 50-500 microg/ml) attenuated spermine-induced acceleration of VSMC apoptosis but only F1 (at 200 and 500 microg/ml) maintained spermine-induced apoptosis at control levels. Spermine-induced JNK activation was prevented by 200 microg/ml of both NAC and F1, while iNOS induction was blocked only by F1. Notably, the adverse effects of spermine on BAX/BCL-2 ratio, cytochrome c release and caspase activation was fully attenuated by F1. In conclusion, F1 was more effective than NAC in preventing spermine-induced apoptosis and downstream changes in related signal transduction pathways in VSMCs. Further studies are needed to examine the effect of these compounds in preventing CKD-associated vascular disease.}, }
@article {pmid20117097, year = {2010}, author = {Jang, MK and Kim, SH and Lee, KY and Kim, TB and Moon, KA and Park, CS and Bae, YJ and Zhu, Z and Moon, HB and Cho, YS}, title = {The tyrosine phosphatase, SHP-1, is involved in bronchial mucin production during oxidative stress.}, journal = {Biochemical and biophysical research communications}, volume = {393}, number = {1}, pages = {137-143}, doi = {10.1016/j.bbrc.2010.01.102}, pmid = {20117097}, issn = {1090-2104}, mesh = {Animals ; Bronchi/drug effects/*enzymology ; Cell Line, Tumor ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Inbred Strains ; Mucin 5AC/*biosynthesis/genetics ; Mucus/metabolism ; *Oxidative Stress ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/biosynthesis ; }, abstract = {Mucus hypersecretion is a clinically important manifestation of chronic inflammatory airway diseases, such as asthma and Chronic obstructive pulmonary disease (COPD). Mucin production in airway epithelia is increased under conditions of oxidative stress. Src homology 2 domain-containing protein tyrosine phosphatase (SHP)-1 suppression is related to the development of airway inflammation and increased ROS levels. In this study, we investigated the role of SHP-1 in mucin secretion triggered by oxidative stress. Human lung mucoepidermoid H292 carcinoma cells were transfected with specific siRNA to eliminate SHP-1 gene expression. Cultured cells were treated with hydrogen peroxide (H(2)O(2)), and Mucin 5AC(MUC5AC) gene expression and mucin production were determined. Activation of p38 mitogen activated protein kinase (MAPK) in association with MUC5AC production was evaluated. N-acetylcysteine (NAC) was employed to determine whether antioxidants could block MUC5AC production. To establish the precise role of p38, mucin expression was observed after pre-treatment of SHP-1-depleted H292 cells with the p38 chemical blocker. We investigated the in vivo effects of oxidative stress on airway mucus production in SHP-1-deficient heterozygous (mev/+) mice. MUC5AC expression was enhanced in SHP-1 knockdown H292 cells exposed to H(2)O(2), compared to that in control cells. The ratio between phosphorylated and total p38 was significantly increased in SHP-1-deficient cells under oxidative stress. Pre-treatment with NAC suppressed both MUC5AC production and p38 activation. Blockage of p38 MAPK led to suppression of MUC5AC mRNA expression. Notably, mucin production was enhanced in the airway epithelia of mev/+ mice exposed to oxidative stress. Our results clearly indicate that SHP-1 plays an important role in airway mucin production through regulating oxidative stress.}, }
@article {pmid20114059, year = {2010}, author = {Biswas, D and Sen, G and Biswas, T}, title = {Reduced cellular redox status induces 4-hydroxynonenal-mediated caspase 3 activation leading to erythrocyte death during chronic arsenic exposure in rats.}, journal = {Toxicology and applied pharmacology}, volume = {244}, number = {3}, pages = {315-327}, doi = {10.1016/j.taap.2010.01.009}, pmid = {20114059}, issn = {1096-0333}, mesh = {Aldehydes/*metabolism ; Anemia/chemically induced/enzymology/metabolism ; Animals ; Arsenic/metabolism/*toxicity ; Caspase 3/*metabolism ; Environmental Pollutants/metabolism/*toxicity ; Enzyme Activation/drug effects ; Erythrocytes/*drug effects/enzymology/metabolism ; Hydrogen Peroxide/metabolism ; Hydroxyl Radical/metabolism ; Male ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; Toxicity Tests, Chronic ; }, abstract = {Chronic exposure to arsenic in rats led to gradual accumulation of the toxicant in erythrocytes causing oxidative stress in these cells. 4-Hydroxynonenal (4-HNE), a major aldehyde product of lipid peroxidation, contributed significantly to the cytopathological events observed during oxidative stress in the erythrocytes of exposed rats. 4-HNE triggered death signal cascade that was initiated with the formation of HNE-protein adducts in cytosol. HNE-protein adduct formation resulted in depletion of cytosolic antioxidants followed by increased generation of ROS. Results showed accumulation of hydrogen peroxide (H(2)O(2)) from the early stages of arsenic exposure, while superoxide (O(2)(*-)) and hydroxyl radical ((*)OH) also contributed to the oxidative stress during longer period of exposure. Suppression of antioxidant system coupled with increased generation of ROS eventually led to activation of caspase 3 during arsenic exposure. Attenuation of HNE-mediated activation of caspase 3 in presence of N-acetylcysteine (NAC) indicated the involvement of GSH in the process. Prevention of HNE-mediated degradation of membrane proteins in presence of Z-DEVD-FMK identified caspase 3 as the principal mediator of HNE-induced cellular damage during arsenic exposure. Degradation of band 3 followed by its aggregation on the red cell surface promoted immunologic recognition of redistributed band 3 by autologous IgG with subsequent attachment of C3b. Finally, the formation of C3b-IgG-band 3 immune complex accelerated the elimination of affected cells from circulation and led to the decline of erythrocyte life span during chronic arsenic toxicity.}, }
@article {pmid20113346, year = {2010}, author = {Wang, BJ and Guo, YL and Chang, HY and Sheu, HM and Pan, MH and Lee, YH and Wang, YJ}, title = {N-acetylcysteine inhibits chromium hypersensitivity in coadjuvant chromium-sensitized albino guinea pigs by suppressing the effects of reactive oxygen species.}, journal = {Experimental dermatology}, volume = {19}, number = {8}, pages = {e191-200}, doi = {10.1111/j.1600-0625.2009.01045.x}, pmid = {20113346}, issn = {1600-0625}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Chromium/*adverse effects ; Dermatitis, Allergic Contact/*metabolism/*prevention &amp; control ; Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Female ; Glutathione/metabolism ; Guinea Pigs ; Hydrogen Peroxide/metabolism ; Malondialdehyde/metabolism ; Reactive Oxygen Species/*metabolism ; Severity of Illness Index ; Skin/drug effects/metabolism ; }, abstract = {BACKGROUND: Chromium hypersensitivity is an important issue in occupational skin disease. When hexavalent chromium enters the cell, it can be reduced to trivalent chromium, resulting in the formation of reactive oxygen species (ROS). ROS are considered to play an important role in the progression of allergic contact dermatitis. N-acetylcysteine (NAC) could increase glutathione levels in the skin and act as an antioxidant.<br><br>AIMS: We attempted to demonstrate that NAC could inhibit chromium hypersensitivity in a coadjuvant chromium-sensitized albino guinea pig model by counteracting the formation of ROS.<br><br>METHODS: We utilized a coadjuvant chromium-sensitized albino guinea pig model to evaluate both the severity of the skin reaction by intradermal and epicutaneous elicitation tests and the sensitization rate of chromium hypersensitivity in NAC-treated and NAC-untreated albino guinea pigs (GP). Furthermore, three ROS parameters, including H(2)O(2,) malondialdehyde (MDA) levels in the skin and the oxygen radical absorbance capacity (ORAC) in plasma, were analyzed in NAC-treated and NAC-untreated coadjuvant chromium-sensitized albino GP.<br><br>RESULTS: The severity of the skin reaction in the intradermal and epicutaneous elicitation test significantly diminished when the albino GP were treated with a dose of 1200 mg/kg/day of NAC. This dose also significantly decreased the sensitization rate of chromium hypersensitivity. In addition, treatment with 1200 mg/kg/day of NAC significantly reduced the H(2)O(2) and MDA levels in the skin and significantly increased the ORAC in the plasma of albino GP. Therefore, NAC could be a potential chemopreventative agent to prevent the progression of chromium hypersensitivity.}, }
@article {pmid20113272, year = {2010}, author = {Merkle, M and Sauter, M and Argirov, M and Wörnle, M}, title = {Cystatin C and creatinine as markers for radiocontrast-induced nephropathy in patients treated with N-acetylcysteine.}, journal = {Renal failure}, volume = {32}, number = {1}, pages = {85-90}, doi = {10.3109/08860220903491216}, pmid = {20113272}, issn = {1525-6049}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Aged, 80 and over ; Biomarkers/blood ; Contrast Media/*adverse effects ; Creatinine/*blood ; Cystatin C/*blood ; Female ; Humans ; Kidney Diseases/*blood/chemically induced/*prevention &amp; control ; Kidney Failure, Chronic/complications ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {The beneficial effect of N-acetylcysteine (NAC) in the prevention of radiocontrast-induced nephropathy (RCIN) as well as the definition of an adequate surrogate parameter for the evaluation of the incidence of RCIN remain points of controversial discussion. Nearly all clinical studies used an increase in serum creatinine to define renal injury, although cystatin C is suggested to be superior to creatinine in estimating glomerular filtration rate (GFR). Furthermore, a recent study showed that in healthy volunteers, NAC leads to a decrease in serum creatinine without influencing serum cystatin C concentrations, implicating a possible overestimation of the protective effect of NAC on the incidence of RCIN. We compared serum creatinine and cystatin C levels in patients with chronic kidney disease undergoing coronary angiography, as these patients are to be considered at highest risk for the development of RCIN. A total of three doses of NAC was given orally, and patients received isotonic saline intravenously. Serum levels at baseline and 24 hours after angiography were not significantly different for serum creatinine (1.72 +/- 0.08 mg/dl and 1.72 +/- 0.08 mg/dl) and for cystatin C (1.72 +/- 0.09 mg/dl and 1.76 +/-0.10 mg/dl). There was a significant positive correlation between creatinine and cystatin C serum levels before and after exposure to radiocontrast medium (p < 0.05) in all patients, including subgroup analyses. We conclude that serum creatinine and cystatin C are equivalent surrogate parameters for the evaluation of NAC in the prevention of RCIN. Furthermore, we present a prophylactic treatment regime easily applicable even in an outpatient setting, which seems to protect very effectively against RCIN in a high-risk group of patients.}, }
@article {pmid20111678, year = {2009}, author = {Chen, CC and Chan, WH}, title = {Inhibition of citrinin-induced apoptotic biochemical signaling in human hepatoma G2 cells by resveratrol.}, journal = {International journal of molecular sciences}, volume = {10}, number = {8}, pages = {3338-3357}, pmid = {20111678}, issn = {1422-0067}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/chemistry/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Citrinin/chemistry/*toxicity ; Hep G2 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Resveratrol ; Signal Transduction/drug effects ; Stilbenes/chemistry/*pharmacology ; alpha-Tocopherol/pharmacology ; p21-Activated Kinases/metabolism ; }, abstract = {The mycotoxin citrinin (CTN), a natural contaminant in foodstuffs and animal feeds, exerts cytotoxic and genotoxic effects on various mammalian cells. CTN causes cell injury, including apoptosis, but its precise regulatory mechanisms of action are currently unclear. Resveratrol, a member of the phytoalexin family found in grapes and other dietary plants, possesses antioxidant and anti-tumor properties. In the present study, we examined the effects of resveratrol on apoptotic biochemical events in Hep G2 cells induced by CTN. Resveratrol inhibited CTN-induced ROS generation, activation of JNK, loss of mitochondrial membrane potential (MMP), as well as activation of caspase-9, caspase-3 and PAK2. Moreover, resveratrol and the ROS scavengers, NAC and alpha-tocopherol, abolished CTN-stimulated intracellular oxidative stress and apoptosis. Active JNK was required for CTN-induced mitochondria-dependent apoptotic biochemical changes, including loss of MMP, and activation of caspases and PAK2. Activation of PAK2 was essential for apoptosis triggered by CTN. These results collectively demonstrate that CTN stimulates ROS generation and JNK activation for mitochondria-dependent apoptotic signaling in Hep G2 cells, and these apoptotic biochemical events are blocked by pretreatment with resveratrol, which exerts antioxidant effects.}, }
@article {pmid20104683, year = {2009}, author = {Zeng, S and Lin, Y and Di, JF and Feng, Z}, title = {[Protective effect of N-acetylcysteine on liver and lung in mice after ischemia-reperfusion injury].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {25}, number = {11}, pages = {1058-1060}, pmid = {20104683}, issn = {1007-8738}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Alanine Transaminase/blood ; Animals ; Gene Expression Regulation/drug effects ; Liver/*drug effects/metabolism/pathology ; Lung/*drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred BALB C ; Organ Size/drug effects ; RNA, Messenger/genetics/metabolism ; Reperfusion Injury/blood/*drug therapy/metabolism/pathology ; Time Factors ; Toll-Like Receptor 2/genetics ; Toll-Like Receptor 4/genetics ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {AIM: To investigate protective effect of N-acetylcysteine (NAC) on liver and lung in mice after hepatic ischemia/reperfusion injury.<br><br>METHODS: BALB/s mice were used in a model of partial hepatic ischemia/reperfusion (I/R) injury. They are divided randomly to sham-operated control group (SH), hepatic I/R group or NAC pretreated in hepatic I/R group (I/R-NAC). The level of TNF-alpha in portal vein and plasma ALT were measured at 1 hour and 3 hour, respectively after reperfusion. Lung tissue wet-to-dry (W/D) weight ratio compared.<br><br>RESULTS: Lung tissue W/D ratio showed significant difference between two groups; The expressions of TLR2/4 mRNA in liver and lung increased obviously after hepatic I/R injury. Histological evaluation showed several changes in lung tissue in I/R group. The level of TNF-alpha and ALT declined significantly in the group pretreated by NAC.<br><br>CONCLUSION: N-acetylcysteine can inhibit the activation of TLR2/4 and reduce TNF-alpha secretion resulted from I/R injury it might abate liver and lung injury following partial hepatic ischemia-reperfusion in mice.}, }
@article {pmid20100472, year = {2010}, author = {Han, YH and Park, WH}, title = {The changes of reactive oxygen species and glutathione by MG132, a proteasome inhibitor affect As4.1 juxtaglomerular cell growth and death.}, journal = {Chemico-biological interactions}, volume = {184}, number = {3}, pages = {319-327}, doi = {10.1016/j.cbi.2010.01.033}, pmid = {20100472}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Buthionine Sulfoximine/pharmacology ; Caspase 3/metabolism ; Caspase 8/metabolism ; Cell Line, Tumor ; Ditiocarb/pharmacology ; Enzyme Inhibitors/*pharmacology ; G1 Phase ; Glutathione/*metabolism ; Juxtaglomerular Apparatus/*metabolism ; Leupeptins/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Poly(ADP-ribose) Polymerases/metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Proteasome Inhibitors ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {The proteasome inhibitor MG132 has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). Here, we evaluated the effects of MG132 on the growth and death of As4.1 juxtaglomerular cells in relation to ROS and glutathione (GSH) levels. MG132 inhibited the growth of As4.1 cells with an IC(50) of approximately 0.3-0.4microM at 48h and induced cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)), Bcl-2 decrease, activation of caspase-3 and -8, and PARP cleavage. MG132 increased intracellular ROS levels including O(2)(-) and GSH depleted cell numbers. N-acetyl cysteine (NAC, a well-known antioxidant) significantly decreased ROS level and GSH depleted cell numbers in MG132-treated As4.1 cells, along with the prevention of cell growth inhibition, cell death and MMP (DeltaPsi(m)) loss. NAC also decreased the caspase-3 activity of MG132. l-Buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) or diethyldithiocarbamate (DDC; an inhibitor of Cu/Zn-SOD) did not affect cell growth, death, ROS and GSH levels in MG132-treated As4.1 cells. Conclusively, MG132 reduced the growth of As4.1 cells via apoptosis. The changes of ROS and GSH by MG132 were involved in As4.1 cell growth and death.}, }
@article {pmid20097726, year = {2010}, author = {Wang, L and Wang, Z and Liu, J}, title = {Protective effect of N-acetylcysteine on experimental chronic lead nephrotoxicity in immature female rats.}, journal = {Human &amp; experimental toxicology}, volume = {29}, number = {7}, pages = {581-591}, doi = {10.1177/0960327109357270}, pmid = {20097726}, issn = {1477-0903}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Antioxidants/*pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Kidney Cortex/drug effects/pathology ; Kidney Diseases/chemically induced/metabolism/pathology/*prevention &amp; control ; Lead Poisoning/*complications/metabolism/pathology ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects/physiology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Single-Blind Method ; }, abstract = {Oxidative stress plays a key role in lead (Pb)-induced nephrotoxicity. N-acetylcysteine (NAC) is a potent oxygen free radicals scavenger and a metal chelator. In the present study, female Sprague-Dawley rats received PbAc(2) (300 mg/L, via drinking water) and/or NAC (100 mg/kg/day, by intraperitoneal injection) to investigate the protective effect of NAC on Pb-induced renal damage and oxidative stress as well as its mechanism of action. Renal toxicity was evaluated by measuring urinary excretion of total protein, beta(2)-microglobulin, albumin and urinary enzyme markers of tubular necrosis, as well as serum urea nitrogen level. Activities of antioxidant enzymes, contents of glutathione and malondialdehyde in kidney were also measured. Renal cell damage was assessed by electron microscopy. Animals that received both Pb and NAC showed a better renal function than those receiving Pb alone. Lead-induced tubular lesions and mitochondrial damage were markedly reduced in rats that also received NAC. Also, NAC significantly reduced the levels of lipid peroxidation and markedly restored the enzymic and non-enzymatic antioxidants levels in kidney of Pb-treated rats. Moreover, NAC administration significantly increased urinary Pb excretion and decreased its level in the serum and kidney. In conclusion, NAC treatment prevents renal tubular damage induced by chronic Pb administration, most probably through its antioxidant properties and chelating ability.}, }
@article {pmid20097462, year = {2010}, author = {Kim, SM and Cha, RH and Lee, JP and Kim, DK and Oh, KH and Joo, KW and Lim, CS and Kim, S and Kim, YS}, title = {Incidence and outcomes of contrast-induced nephropathy after computed tomography in patients with CKD: a quality improvement report.}, journal = {American journal of kidney diseases : the official journal of the National Kidney Foundation}, volume = {55}, number = {6}, pages = {1018-1025}, doi = {10.1053/j.ajkd.2009.10.057}, pmid = {20097462}, issn = {1523-6838}, mesh = {Acetylcysteine/therapeutic use ; Aged ; Chronic Disease ; Cohort Studies ; Contrast Media/*adverse effects ; Female ; Glomerular Filtration Rate/physiology ; Humans ; Incidence ; Kidney Diseases/*diagnostic imaging/physiopathology/therapy ; Male ; Middle Aged ; Prognosis ; *Quality Assurance, Health Care ; Renal Insufficiency/*chemically induced/*epidemiology/prevention &amp; control ; Renal Replacement Therapy ; Retrospective Studies ; Risk Factors ; Sodium Chloride/therapeutic use ; Tomography, X-Ray Computed/*adverse effects/methods ; }, abstract = {BACKGROUND: Although there has been considerable investigation of the general characteristics of contrast-induced nephropathy (CIN), it has not been studied adequately in a computed tomography (CT) population. We assessed the incidence and outcomes of CIN after contrast-enhanced CT in patients with chronic kidney disease pretreated with saline and N-acetylcysteine (NAC).<br><br>DESIGN: Quality improvement report.<br><br>SETTING &amp; PARTICIPANTS: 520 patients registered in a CIN prevention program.<br><br>QUALITY IMPROVEMENT PLAN: We initiated the CIN prevention program in January 2007. In this program, patients with chronic kidney disease undergoing contrast-enhanced CT in an outpatient setting were automatically referred to nephrologists, and patients received saline and NAC before and after CT. The development of CIN was assessed 48-96 hours after CT.<br><br>OUTCOMES: Incidence of CIN and time to renal replacement therapy.<br><br>MEASUREMENTS: Baseline serum creatinine, hemoglobin, and serum albumin levels; type and volume of contrast agents; and post-CT serum creatinine level.<br><br>RESULTS: Overall, CIN occurred in 13 (2.5%) patients. Incidences of CIN were 0.0%, 2.9%, and 12.1% in patients with an estimated glomerular filtration rate of 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively. The risk of CIN was increased in patients with severely decreased kidney function and diabetes. The development of CIN consequently increased the risk of renal replacement therapy (P < 0.001 by log-rank), and the risk was significantly accentuated in patients with estimated glomerular filtration rate <30 mL/min/1.73 m(2).<br><br>LIMITATIONS: A single-center study and comparison with previous studies.<br><br>CONCLUSIONS: The incidence of CIN was relatively low in patients treated with saline and NAC. The development of CIN predisposed to poor kidney survival in the long term.}, }
@article {pmid20095328, year = {2009}, author = {Guan, XF and Zhao, GJ and Cai, QQ and Wang, ZY and Lu, ZQ and Qiu, QM and Hong, GL and Liang, H}, title = {[Effect of bromoxynil on membrane potential and respiratory control rate in isolated mitochondria from mice liver and intervention effect of NAC].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {27}, number = {8}, pages = {472-475}, pmid = {20095328}, issn = {1001-9391}, mesh = {Acetylcysteine/pharmacology ; Animals ; Electron Transport/*drug effects ; Male ; Membrane Potential, Mitochondrial/*drug effects ; Mice ; Mice, Inbred ICR ; Mitochondria, Liver/drug effects/*metabolism ; Nitriles/*toxicity ; }, abstract = {OBJECTIVE: To demonstrate the effect of bromoxynil on membrane potential and respiratory control rate (RCR) in isolate mitochondria from mice liver tissue in vitro and the intervention of NAC.<br><br>METHODS: The mitochondrial was randomized to control group, bromoxynil-poisoned group and NAC-protected group. S3, S4 and RCR of the mitochondria in each sample was detected by the method of oxygen electrode. Each sample was stained by JC-1 and the changes of membrane potential of mitochondria were observed under fluorescence microscope.<br><br>RESULTS: The S3 [(0.031 +/- 0.008) nano atoms oxygen x mg(-1) x min(-1)], RCR (1.820 +/- 0.181) of bromoxynil-poisoned group and RCR (4.253 +/- 0.210) of NAC-protected group were significantly lower than those of control group (P<0.01); the S4 [(0.017 +/- 0.004) nano atoms oxygen x mg(-1) x min(-1)] of NAC-protected group was significantly higher than control group (P<0.01). The S3 [(0.046 +/- 0.005) nano atoms oxygen x mg(-1) x min(-1)] and RCR of NAC-protected group were significantly higher than group B (P<0.01), S4 [(0.011 +/- 0.001) nano atoms oxygen x mg(-1) x min(-1)] of NAC-protected group was significantly lower than bromoxynil-poisoned group (P< 0.01). Observation under fluorescence microscope: the red fluorescence of mitochondria was dim or disappeared in bromoxynil-poisoned group while brightened in NAC-protected group but still dimmer than control group.<br><br>CONCLUSION: In vitro, the mitochondrial RCR and the mitochondrial membrane potential are decreased after the mitochondria is incubated with bromoxynil, and NAC could improve it.}, }
@article {pmid20093493, year = {2010}, author = {Poncin, S and Van Eeckoudt, S and Humblet, K and Colin, IM and Gérard, AC}, title = {Oxidative stress: a required condition for thyroid cell proliferation.}, journal = {The American journal of pathology}, volume = {176}, number = {3}, pages = {1355-1363}, pmid = {20093493}, issn = {1525-2191}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Nucleus/metabolism ; Cell Proliferation/drug effects ; Cyclin D1/metabolism ; Female ; Goiter/blood/pathology ; Organ Size/drug effects ; *Oxidative Stress/drug effects ; Perchlorates ; Peroxiredoxins/metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Propylthiouracil ; Prostaglandin D2/analogs &amp; derivatives/pharmacology ; Rats ; Rats, Wistar ; Thyroid Gland/drug effects/*pathology ; Thyroxine/blood ; }, abstract = {Goiter is associated with increased oxidative stress (OS). We studied the effects of an anti-inflammatory agent, 15 deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) and an antioxidant, N-acetylcysteine (NAC), on OS, thyroid function, and goiter expansion in a model of goiter induced by propylthiouracil (PTU) or perchlorate. OS was assessed by the immunodetection of 4-hydroxynonenal, thyroid function by measuring thyroxin (T4) and thyrotropin (TSH) plasma levels and detecting T4-rich thyroglobulin (Tg-I), and goiter expansion by weighing the thyroids and measuring cell proliferation (PCNA and cyclin D1 immunodetection). In both PTU and perchlorate-induced goiters, OS, TSH plasma levels, thyroid weight, and cell proliferation were strongly enhanced, whereas Tg-I expression was negative. All these parameters were reversed by NAC and 15dPGJ2 in PTU-goiters. In perchlorate-goiters, TSH plasma levels remained elevated and Tg-I-negative after NAC or 15dPGJ2 treatment. OS was reduced by NAC, but not by 15dPGJ2. In addition, NAC reduced PCNA and cyclin D1 immunostainings, as well as thyroid weight, whereas 15dPGJ2 influenced neither thyroid weight nor cell proliferation. In conclusion, NAC and 15dPGJ2 overcome PTU- but not perchlorate-induced effects. The retrieval of hormonal synthesis may result from direct chemical interactions between PTU and NAC/15dPGJ2. Although 15dPGJ2 has no effect in perchlorate-goiters, the reduction of OS by NAC is associated with altered goiter development, making OS a required condition for the growth of the thyroid gland.}, }
@article {pmid20093183, year = {2010}, author = {Milara, J and Juan, G and Ortiz, JL and Guijarro, R and Losada, M and Serrano, A and Morcillo, EJ and Cortijo, J}, title = {Cigarette smoke-induced pulmonary endothelial dysfunction is partially suppressed by sildenafil.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {39}, number = {5}, pages = {363-372}, doi = {10.1016/j.ejps.2010.01.005}, pmid = {20093183}, issn = {1879-0720}, mesh = {Base Sequence ; Cells, Cultured ; DNA Primers ; Endothelium, Vascular/*drug effects/physiopathology ; Enzyme-Linked Immunosorbent Assay ; Humans ; Lung/blood supply/*drug effects/physiopathology ; Nitric Oxide/biosynthesis ; Piperazines/*pharmacology ; Polymerase Chain Reaction ; Purines/pharmacology ; Sildenafil Citrate ; Smoke/*adverse effects ; Sulfones/*pharmacology ; *Nicotiana ; Vasodilator Agents/*pharmacology ; }, abstract = {Cigarette smoke mediated oxidative stress and endothelial dysfunction are important processes in the pathogenesis of several lung disorders. In this study we evaluated the effect of PDE5 inhibition on pulmonary artery endothelial dysfunction induced by cigarette smoke in vitro. Human pulmonary artery endothelial cells (HPAEC) were incubated in the absence or presence of PDE5 inhibitor sildenafil (10 nM-1 microM), PKG agonist 8-Br-cGMP (1mM), or the antioxidants dyphenyleneiodonium (DPI 1 microM) and N-acetylcysteine (NAC 1mM) for 30 min. Then, cigarette smoke extract (CSE) was added for 24h. CSE (2.5-10%)-induced ROS generation was suppressed by DPI, and partially reversed by sildenafil and 8-Br-cGMP. Decreases in intracellular levels of cGMP and extracellular NO induced by CSE were reversed by sildenafil and DPI. Furthermore, CSE-induced pg91(phox) and PDE5 mRNA overexpression were suppressed by both sildenafil and DPI. CSE (2.5-10%) induced upregulation of IL-6, IL-8 and Ang-2, and decreased Ang-1 expression in parallel to apoptosis which were partially suppressed by sildenafil, 8-Br-cGMP, DPI and NAC. This study demonstrates that PDE5 inhibition attenuates the oxidant burden and the inflammatory and remodeling effects of CSE in human HPAEC which may contribute to the therapeutic value of PDE5 inhibitors for pulmonary disorders coursing with endothelial dysfunction.}, }
@article {pmid20089932, year = {2010}, author = {Lee, SH and Lee, YJ and Song, CH and Ahn, YK and Han, HJ}, title = {Role of FAK phosphorylation in hypoxia-induced hMSCS migration: involvement of VEGF as well as MAPKS and eNOS pathways.}, journal = {American journal of physiology. Cell physiology}, volume = {298}, number = {4}, pages = {C847-56}, doi = {10.1152/ajpcell.00418.2009}, pmid = {20089932}, issn = {1522-1563}, mesh = {Cell Movement/*physiology ; Cells, Cultured ; Fetal Blood/cytology ; Focal Adhesion Protein-Tyrosine Kinases/*metabolism ; Humans ; Hypoxia/*metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mesenchymal Stem Cells/cytology/*physiology ; Mitogen-Activated Protein Kinases/*metabolism ; Nitric Oxide Synthase Type III/*metabolism ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Vascular Endothelial Growth Factor A/*metabolism ; src-Family Kinases/metabolism ; }, abstract = {Here we show that the effect of hypoxia on human umbilical cord blood mesenchymal stem cell (hMSC) migration is via the modulation of focal adhesion kinase (FAK) and its related signaling pathways. Hypoxia increased hMSC migration and cell viability, whereas lactate dehydrogenase (LDH) release was not affected for up to 48 h (data not shown). In addition, hypoxia increased the level of reactive oxygen species (ROS) generation in a time-dependent manner. Hypoxia-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) were inhibited by the antioxidant (N-acetylcysteine, NAC, 10(-6) M) and (taurine, 4x10(-6) M). Hypoxia-induced endothelial nitric oxide synthase (eNOS) phosphorylation was regulated by p38 MAPK and SAPK/JNK activation. In addition, hypoxia increased the level of hypoxia inducible factor (HIF)-1alpha expression, which was blocked by inhibition of eNOS. Also, hypoxia-induced expression of Flk-1, vascular endothelial growth factor (VEGF), and its secreted form were inhibited by HIF-1alpha small interfering RNA (siRNA). In this hypoxic condition, FAK and Src phosphorylation were increased in a time-dependent manner. Inhibition of Src with specific inhibitor (PP2, 10(-8) M) blocked hypoxia-induced FAK activation. Subsequently, hypoxia-induced FAK phosphorylation was blocked by VEGF siRNA. Finally, hypoxia-induced increase of hMSC migration was inhibited by FAK siRNA. The results indicate that hypoxia increases migration of hMSCs via VEGF-mediated FAK phospholylation and involves the cooperative activity of the ROS, MAPK, eNOS and HIF-1alpha pathways.}, }
@article {pmid20089454, year = {2010}, author = {Nasr, A}, title = {Effect of N-acetyl-cysteine after ovarian drilling in clomiphene citrate-resistant PCOS women: a pilot study.}, journal = {Reproductive biomedicine online}, volume = {20}, number = {3}, pages = {403-409}, doi = {10.1016/j.rbmo.2009.12.012}, pmid = {20089454}, issn = {1472-6491}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Clomiphene/therapeutic use ; Drug Resistance ; Female ; Fertility Agents, Female/*therapeutic use ; Humans ; Laparoscopy ; Ovary/*surgery ; Ovulation/drug effects ; Ovulation Induction/methods ; Pilot Projects ; Placebos ; Polycystic Ovary Syndrome/*drug therapy ; Pregnancy ; Pregnancy Rate ; }, abstract = {The aim of this randomized double-blind placebo-controlled pilot study was to evaluate N-acetyl-cysteine (NAC) as an adjunctive therapy following unilateral laparoscopic ovarian drilling (LOD) for clomiphene citrate-resistant women with polycystic ovary syndrome (PCOS). A total of 60 patients with clomiphene citrate-resistant PCOS who underwent unilateral LOD were assigned randomly to receive either NAC 1.2 g/d (group A=30) or placebo (group B=30) for 5 days starting at day 3 of the cycle for 12 consecutive cycles. The primary outcome was pregnancy rate; secondary outcomes were ovulation rates, endometrial thickness and pregnancy outcome. Baseline clinical, endocrine, and sonographic characteristics were similar in the two groups. A significant increase in both ovulation and pregnancy rates was observed in the NAC group, compared with placebo [87% versus 67% (RR 1.3; 95% CI 1.2-2.7) and 77% versus 57% (RR 1.4; 95% CI 1.1-2.7), respectively, P<0.01]. Moreover, miscarriage rates were significantly lower and live birth rates were significantly higher in the NAC group [8.7% versus 23.5% (RR 0.4; 95% CI 0.1-3.7) and 67% versus 40% (RR 1.7; 95% CI 0.3-3.5), respectively, P<0.01]. In conclusion, NAC is a novel adjuvant therapy after unilateral LOD which might help improve overall reproductive outcome.}, }
@article {pmid20088736, year = {2010}, author = {Han, YH and Kim, SZ and Kim, SH and Park, WH}, title = {Reactive oxygen species and glutathione level changes by a proteasome inhibitor, MG132, partially affect calf pulmonary arterial endothelial cell death.}, journal = {Drug and chemical toxicology}, volume = {33}, number = {4}, pages = {403-409}, doi = {10.3109/01480540903524350}, pmid = {20088736}, issn = {1525-6014}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Buthionine Sulfoximine/pharmacology ; Cattle ; Cell Culture Techniques ; Cell Death/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Endothelial Cells/*drug effects/enzymology/metabolism ; Endothelium, Vascular/cytology/drug effects/enzymology/metabolism ; Glutathione/*metabolism ; Humans ; Leupeptins/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; *Proteasome Inhibitors ; Pulmonary Artery/cytology/*drug effects/enzymology/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {MG132 as a proteasome inhibitor has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). Here, we evaluated the effects of MG132 on the growth of endothelial cells (ECs), especially calf pulmonary artery endothelial cells (CPAECs), in relation to cell death, ROS, and glutathione (GSH) levels. MG132 dose dependently inhibited the growth of CPAEC and human umbilical vein endothelial cells (HUVECs) at 24 hours. MG132 also induced apoptotic cell death in CPAEC, which were accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). MG132 increased ROS levels, including O(2)(*-) in CPAEC, but not in HUVEC. MG132 also dose dependently increased GSH-depleted cells in both ECs. N-acetyl-cysteine (NAC; a well-known antioxidant) reduced ROS levels in MG132-treated CPAEC with the slight prevention of cell death and GSH depletion. Buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) increased ROS levels and decreased GSH levels in MG132-treated CPAEC without the enhancement of cell death. In conclusion, MG132 inhibited the growth of ECs, especially CPAEC. The changes of ROS and GSH levels by MG132 partially affect CPAEC death.}, }
@article {pmid20088405, year = {2009}, author = {Shinkawa, H and Takemura, S and Minamiyama, Y and Kodai, S and Tsukioka, T and Osada-Oka, M and Kubo, S and Okada, S and Suehiro, S}, title = {S-allylcysteine is effective as a chemopreventive agent against porcine serum-induced hepatic fibrosis in rats.}, journal = {Osaka city medical journal}, volume = {55}, number = {2}, pages = {61-69}, pmid = {20088405}, issn = {0030-6096}, mesh = {Acetylcysteine/therapeutic use ; Actins/metabolism ; Alanine Transaminase/blood ; Animals ; Anticarcinogenic Agents/*therapeutic use ; Chemoprevention/*methods ; Cysteine/*analogs &amp; derivatives/therapeutic use ; Disease Models, Animal ; Hepatic Stellate Cells/pathology ; Lipid Peroxidation ; Liver/metabolism/pathology ; Liver Cirrhosis/chemically induced/*pathology/*prevention &amp; control ; Male ; Rats ; Rats, Wistar ; Serum ; Sulfhydryl Compounds/metabolism ; Swine ; Treatment Outcome ; }, abstract = {BACKGROUND: Hepatic fibrosis is a chronic progressive disorder with a poor prognosis for which no definitive treatment exists. S-allylcysteine (SAC), an ingredient of aged garlic extract, is known to have antioxidant and hepatoprotective effects. The aim of this study was to investigate the antifibrotic effects of SAC in the liver.<br><br>METHODS: Hepatic fibrosis was induced in male Wistar rats by porcine serum (PS) intraperitoneal injection. SAC (0.15% of basal diet) or N-acetylcysteine (NAC, 0.45% of basal diet) was orally administered for 12 weeks. Liver damage was assessed by the levels of plasma alanine aminotransferase (ALT), hepatic lipid peroxides (LPO), and hepatic total thiols 12 weeks after first PS injection. Area of fibrosis was examined by Azan-Mallory staining. Hydroxyproline content of liver were assessed as an index of collagen content. Liver was examined for expression of alpha-smooth muscle actin (alpha-SMA) as a marker of hepatic stellate cell (HSC) activation.<br><br>RESULTS: There were no significant differences in levels of plasma ALT, hepatic LPO, or hepatic total thiols among the groups. PS significantly increased area of fibrosis and hydroxyproline content in the liver. SAC and NAC each markedly attenuated the development ofhepatic fibrosis. SAC and NAC markedly suppressed the PS-induced increase in alpha-SMA expressions.<br><br>CONCLUSIONS: Oral administration of SAC reduced PS-induced hepatic fibrosis in rats via inhibition of HSC activation. SAC could provide a new therapeutic strategy for hepatic fibrosis.}, }
@article {pmid20082627, year = {2010}, author = {Sheu, MJ and Chou, PY and Huang, CS and Tsai, IC and Chien, YC and Lin, SY and Tsai, HY and Cheng, HC and Wu, CH}, title = {Pipoxolan inhibits proliferation of HL-60 human leukaemia cancer cells by arresting the cell cycle at the G0/G1 phase.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {37}, number = {5-6}, pages = {605-612}, doi = {10.1111/j.1440-1681.2010.05358.x}, pmid = {20082627}, issn = {1440-1681}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Cell Culture Techniques ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; Dioxolanes/chemistry/*pharmacology ; Flow Cytometry ; G1 Phase/*drug effects ; HL-60 Cells ; Humans ; Leukocytes, Mononuclear/drug effects/metabolism/pathology ; Molecular Structure ; Reactive Oxygen Species/metabolism ; Resting Phase, Cell Cycle/*drug effects ; }, abstract = {1. The aim of the present study was to investigate the molecular mechanisms by which pipoxolan exerts its inhibitory effects and apoptotic activity in human leukaemia HL-60 cells. 2. The effects of pipoxolan on the proliferation of HL-60 cells and on the distribution of cells within different phases of the cell cycle were investigated indirectly using a Trypan blue assay and a flow cytometer, respectively. The effects of pipoxolan on the apoptosis of HL-60 cells was investigated using DNA fragmentation and flow cytometer. The expression of factors affecting the cell cycle and apoptosis, including p53, p21, Bax, Bcl2, cytochrome c, caspase 3 and caspase 9, was examined by western blotting. 3. At 6.25 microg/mL, pipoxolan significantly induced apoptosis in human leukaemia HL-60 cells after 24 h exposure. In addition, HL-60 cells were arrested in the G(0)/G(1) phase via the induction of p53/p21 by pipoxolan. Apoptosis was associated with an increased Bax/Bcl-2 ratio, cytochrome c release, cleavage of procaspases-9 and -3 and hydrolysis of poly(ADP-ribose) polymerase. Intracellular reactive oxygen species (ROS) seem to play a key role in the pipoxolan-induced apoptosis, because high levels of ROS were produced early in the drug treatment. Apoptosis was significantly abrogated by the free radical scavenger N-acetylcysteine (NAC).}, }
@article {pmid20080177, year = {2010}, author = {Pinheiro, CH and Silveira, LR and Nachbar, RT and Vitzel, KF and Curi, R}, title = {Regulation of glycolysis and expression of glucose metabolism-related genes by reactive oxygen species in contracting skeletal muscle cells.}, journal = {Free radical biology &amp; medicine}, volume = {48}, number = {7}, pages = {953-960}, doi = {10.1016/j.freeradbiomed.2010.01.016}, pmid = {20080177}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cells, Cultured ; Deoxyglucose/metabolism ; Electric Stimulation ; Glucose/genetics/*metabolism ; Glucose Transporter Type 4/genetics/*metabolism ; Glucosephosphate Dehydrogenase/metabolism ; Glycolysis/drug effects ; Hexokinase/genetics/metabolism ; Muscle Contraction/drug effects ; Muscle Fibers, Skeletal/drug effects/*metabolism ; Muscle, Skeletal/*metabolism/pathology ; Phosphofructokinase-1, Muscle Type/genetics/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {Contractile activity induces a marked increase in glycolytic activity and gene expression of enzymes and transporters involved in glucose metabolism in skeletal muscle. Muscle contraction also increases the production of reactive oxygen species (ROS). In this study, the effects of treatment with N-acetylcysteine (NAC), a potent antioxidant compound, on contraction-stimulated glycolysis were investigated in electrically stimulated primary rat skeletal muscle cells. The following parameters were measured: 2-[(3)H]deoxyglucose (2-DG) uptake; activities of hexokinase, phosphofructokinase (PFK), and glucose-6-phosphate dehydrogenase (G6PDH); lactate production; and expression of the glucose transporter 4 (GLUT4), hexokinase II (HKII), and PFK genes after one bout of electrical stimulation in primary rat myotubes. NAC treatment decreased ROS signal by 49% in resting muscle cells and abolished the muscle contraction-induced increase in ROS levels. In resting cells, NAC decreased mRNA and protein contents of GLUT4, mRNA content and activity of PFK, and lactate production. NAC treatment suppressed the contraction-mediated increase in 2-DG uptake; lactate production; hexokinase, PFK, and G6PDH activities; and gene expression of GLUT4, HKII, and PFK. Similar to muscle contraction, exogenous H(2)O(2) (500 nM) administration increased 2-DG uptake; lactate production; hexokinase, PFK, and G6PDH activities; and gene expression of GLUT4, HKII, and PFK. These findings support the proposition that ROS endogenously produced play an important role in the changes in glycolytic activity and gene expression of GLUT4, HKII, and PFK induced by contraction in skeletal muscle cells.}, }
@article {pmid20077196, year = {2009}, author = {Kim, YJ and Woo, HD and Kim, BM and Lee, YJ and Kang, SJ and Cho, YH and Chung, HW}, title = {Risk assessment of hydroquinone: differential responses of cell growth and lethality correlated to hydroquinone concentration.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {72}, number = {21-22}, pages = {1272-1278}, doi = {10.1080/15287390903212279}, pmid = {20077196}, issn = {1528-7394}, mesh = {Antioxidants/administration &amp; dosage/toxicity ; Apoptosis/*drug effects ; Cell Proliferation/*drug effects ; Cell Survival/*drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavonoids ; Gene Expression Regulation/physiology ; Humans ; Hydroquinones/*administration &amp; dosage/*toxicity ; Jurkat Cells ; }, abstract = {Hydroquinone (HQ) is a major metabolite of benzene and has been used as an antioxidant, a stabilizer, a photographic reducer, and an ingredient in skin lighteners. In this study, the effects of low (5 microM) and high (50 microM) concentrations of HQ were investigated on cell growth and lethality in Jurkat cells. Intracellular reactive oxygen species (ROS) levels were increased with both HQ concentrations. Fifty micromolar HQ markedly increased phosphorylation of ERK and activation of caspase-9/-3, followed by PARP cleavage. The addition of ERK inhibitor PD98059 or N-acetylcysteine (NAC) abolished HQ-induced apoptosis. Five micromolar HQ activated ERK protein, but not JNK or p38. However, S-phase recruitment was decreased by preincubation with NAC, but not PD98059. Thus, high levels of ROS contributed to HQ-induced apoptosis via ERK signaling and the caspase pathway, whereas low quantities of ROS resulted in S-phase recruitment in the cell-cycle distribution.}, }
@article {pmid20073042, year = {2010}, author = {Song, H and Cha, MJ and Song, BW and Kim, IK and Chang, W and Lim, S and Choi, EJ and Ham, O and Lee, SY and Chung, N and Jang, Y and Hwang, KC}, title = {Reactive oxygen species inhibit adhesion of mesenchymal stem cells implanted into ischemic myocardium via interference of focal adhesion complex.}, journal = {Stem cells (Dayton, Ohio)}, volume = {28}, number = {3}, pages = {555-563}, doi = {10.1002/stem.302}, pmid = {20073042}, issn = {1549-4918}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Adhesion/drug effects/physiology ; Cell Adhesion Molecules/drug effects/*metabolism ; Cell Differentiation/physiology ; Cell Proliferation ; Cells, Cultured ; Disease Models, Animal ; Focal Adhesion Kinase 1/drug effects/metabolism ; Focal Adhesions/drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Gene Knock-In Techniques ; Graft Survival/physiology ; Hydrogen Peroxide/pharmacology ; Integrins/drug effects/metabolism ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Mesenchymal Stem Cells/*metabolism ; Myocardial Ischemia/*metabolism/physiopathology/*surgery ; Oxidants/pharmacology ; Oxidative Stress/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Regeneration/physiology ; src-Family Kinases/drug effects/metabolism ; }, abstract = {The integrity of transplanted mesenchymal stem cells (MSCs) for cardiac regeneration is dependent on cell-cell or cell-matrix adhesion, which is inhibited by reactive oxygen species (ROS) generated in ischemic surroundings after myocardial infarction. Intracellular ROS play a key role in the regulation of cell adhesion, migration, and proliferation. This study was designed to investigate the role of ROS on MSC adhesion. In H(2)O(2) treated MSCs, adhesion and spreading were inhibited and detachment was increased in a dose-dependent manner, and these effects were significantly rescued by co-treatment with the free radical scavenger, N-acetyl-L-cysteine (NAC, 1 mM). A similar pattern was observed on plates coated with different matrices such as fibronectin and cardiogel. Hydrogen peroxide treatment resulted in a marked decrease in the level of focal adhesion-related molecules, such as phospho-FAK and p-Src in MSCs. We also observed a significant decrease in the integrin-related adhesion molecules, alpha V and beta1, in H(2)O(2) treated MSCs. When injected into infarcted hearts, the adhesion of MSCs co-injected with NAC to the border region was significantly improved. Consequently, we observed that fibrosis and infarct size were reduced in MSC and NAC-injected rat hearts compared to in MSC-only injected hearts. These results indicate that ROS inhibit cellular adhesion of engrafted MSCs and provide evidence that the elimination of ROS might be a novel strategy for improving the survival of engrafted MSCs.}, }
@article {pmid20071472, year = {2010}, author = {Zyoud, SH and Awang, R and Syed Sulaiman, SA and Sweileh, WM and Al-Jabi, SW}, title = {Incidence of adverse drug reactions induced by N-acetylcysteine in patients with acetaminophen overdose.}, journal = {Human &amp; experimental toxicology}, volume = {29}, number = {3}, pages = {153-160}, doi = {10.1177/0960327109359642}, pmid = {20071472}, issn = {1477-0903}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects ; Adolescent ; Adult ; Adverse Drug Reaction Reporting Systems ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/administration &amp; dosage/*adverse effects ; Chi-Square Distribution ; Drug Overdose/drug therapy ; Female ; Humans ; Infusions, Intravenous ; Malaysia ; Male ; Retrospective Studies ; Time Factors ; Young Adult ; }, abstract = {BACKGROUND: Intravenous N-acetylcysteine (IV-NAC) is widely recognized as the antidote of choice for acetaminophen overdose. However, its use is not without adverse drug reactions (ADR) that might affect therapeutic outcome or lead to treatment delay.<br><br>OBJECTIVE: The aim of this study was to investigate the type and incidence of ADR induced by IV-NAC in patients treated for acetaminophen overdose.<br><br>METHODS: This is a retrospective study of patients admitted to the hospital for acute acetaminophen overdose over a period of 4 years (1 January 2005 to 31 December 2008). The primary outcome of interest in this study was the occurrence of ADR during NAC administration. Pearson chi-square test or Fisher's exact test, student's t test, and Mann-Whitney U test were used in univariate analysis. SPSS 15 was used for data analysis.<br><br>RESULTS: Two hundred and fifty five patients were studied. Different types of ADR were observed in 119 (46.7%) cases. Of those patients, 83 (69.7%) had been treated with IV-NAC versus 36 (30.3%) who had not (p < .001). The following ADR were significantly associated with IV-NAC administration: vomiting (p = .001), flushing (p < .001), rash (p < .001), pruritus (p < .001), chest pain (p = .001), bronchospasm (p = .03), coughing (p = .01), headache (p = .001), dizziness (p < .001), convulsion (p = .03), and hypotension (p = .001). ADR were mild in 54 (43.2%), moderate in 17 (13.6%), and severe in 12 (9.6%) patients. There were no ADR in 42 (33.6%) patients. Comparative results of the characteristics of patients who reacted to IV-NAC and nonreactors showed that patients with ADR had no significant difference in age, gender, ethnicity, amount ingested, latency time, and acetaminophen level than nonreactors.<br><br>CONCLUSION: ADR to IV-NAC were common among patients with acetaminophen overdose, but mostly minor and all reported adverse reactions were easily managed.}, }
@article {pmid20068565, year = {2010}, author = {Lau, ST and Lin, ZX and Leung, PS}, title = {Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-kappaB signalling pathways in human pancreatic adenocarcinoma cells.}, journal = {British journal of cancer}, volume = {102}, number = {3}, pages = {583-593}, pmid = {20068565}, issn = {1532-1827}, mesh = {Adenocarcinoma/*drug therapy/metabolism ; Animals ; Cell Line, Tumor ; Electrophoretic Mobility Shift Assay ; Glutathione/metabolism ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; NADPH Oxidases/physiology ; NF-kappa B/*physiology ; Pancreatic Neoplasms/*drug therapy/metabolism ; Quassins/*pharmacology/therapeutic use ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*physiology ; Superoxides/metabolism ; Xenograft Model Antitumor Assays ; p38 Mitogen-Activated Protein Kinases/*physiology ; }, abstract = {BACKGROUND: In human pancreatic adenocarcinoma, nuclear factor-kappa-B (NF-kappaB) transcription factor is constitutively activated that contributes to the resistance of the tumour cells to induced apoptosis. In our earlier studies, we have shown that brucein D (BD) mediated apoptosis through activation of the p38-mitogen-activated protein kinase (MAPK) signalling pathway in pancreatic cancer cells. This study investigated the function of reactive oxygen species (ROS) in BD-mediated p38-MAPK and NF-kappaB signalling pathways in PANC-1 cells.<br><br>METHODS: Glutathione and dihydroethidium assays were used to measure the antioxidant and superoxide levels, respectively. The protein expression of p22(phox), p67(phox) and p38-MAPK were examined by western blot. The NF-kappaB activity was evaluated by electrophoretic mobility shift assay.<br><br>RESULTS: Treatment with BD depleted the intracellular glutathione levels in PANC-1 cells. Brucein D triggered the activation of NADPH oxidase isoforms, p22(phox) and p67(phox) while enhancing the generation of superoxide. Increases in both intracellular ROS and NADPH oxidase activity were inhibited by an antioxidant, N-acetylcysteine (NAC). Brucein D-mediated activation of p38-MAPK was also inhibited by NAC. However, inhibition of NF-kappaB activity in BD-treated cells was independent of ROS. In vivo studies showed that BD treatment effectively reduced the rate of xenograft human pancreatic tumour in nude mice with no significant toxicity.<br><br>CONCLUSION: These data suggest that BD is an apoptogenic agent for pancreatic cancer cells through activation of the redox-sensitive p38-MAPK pathway and inhibition of NF-kappaB anti-apoptotic activity in pancreatic cancer cells.}, }
@article {pmid20066544, year = {2010}, author = {Hagaman, JT and Kinder, BW and Eckman, MH}, title = {Thiopurine S- methyltransferase [corrected] testing in idiopathic pulmonary fibrosis: a pharmacogenetic cost-effectiveness analysis.}, journal = {Lung}, volume = {188}, number = {2}, pages = {125-132}, pmid = {20066544}, issn = {1432-1750}, support = {UL1 TR000077/TR/NCATS NIH HHS/United States ; }, mesh = {Acetylcysteine/economics/therapeutic use ; Azathioprine/adverse effects/*economics/pharmacokinetics ; Computer Simulation ; Cost-Benefit Analysis ; Decision Support Techniques ; *Drug Costs ; Drug Therapy, Combination ; Gene Frequency ; Genetic Testing/*economics ; Genotype ; Humans ; Idiopathic Pulmonary Fibrosis/*diagnosis/drug therapy/*economics/enzymology/genetics ; Leukopenia/chemically induced/economics/genetics ; Methyltransferases/*genetics/metabolism ; Models, Economic ; Patient Selection ; Pharmacogenetics ; Phenotype ; Quality-Adjusted Life Years ; Respiratory System Agents/adverse effects/*economics/pharmacokinetics ; Steroids/economics/therapeutic use ; Treatment Outcome ; }, abstract = {Azathioprine in combination with N-acetylcysteine (NAC) and steroids is a standard therapy for idiopathic pulmonary fibrosis (IPF). Its use, however, is limited by its side effects, principally leukopenia. A genotypic assay, thiopurine S-methyltransferase (TPMT), has been developed that can potentially identify those at risk for developing leukopenia with azathioprine, and thereby limit its toxicity. In those with abnormal TPMT activity, azathioprine can be started at lower dose or an alternate regimen selected. Determine the cost-effectiveness of a treatment strategy using TPMT testing before initiation of azathioprine, NAC, and steroids in IPF by performing a computer-based simulation. We developed a decision analytic model comparing three strategies: azathioprine, NAC and steroids with and without prior TPMT testing, and conservative therapy, consisting of only supportive measures. Prevalence of abnormal TPMT alleles and complication rates of therapy were taken from the literature. We assumed a 12.5% incidence of abnormal TPMT alleles, 4% overall incidence of leukopenia while taking azathioprine, and that azathioprine, NAC, and steroids in combination reduced IPF disease progression by 14% during 12 months. TPMT testing before azathioprine, NAC, and steroids was the most effective and most costly strategy. The marginal cost-effectiveness of the TPMT testing strategy was $49,156 per quality adjusted life year (QALY) gained versus conservative treatment. Compared with azathioprine, NAC and steroids without prior testing, the TPMT testing strategy cost only $29,662 per QALY gained. In sensitivity analyses, when the prevalence of abnormal TPMT alleles was higher than our base case, TPMT was "cost-effective." At prevalence rates lower than our base case, it was not. TPMT testing before initiating therapy with azathioprine, NAC, and steroids is a cost-effective treatment strategy for IPF.}, }
@article {pmid20065493, year = {2009}, author = {Pechanova, O and Kunes, J and Dobesova, Z and Vrankova, S and Zicha, J}, title = {Contribution of neuronal nitric oxide (no) synthase to N-acetylcysteine-induced increase of NO synthase activity in the brain of normotensive and hypertensive rats.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {60}, number = {4}, pages = {21-25}, pmid = {20065493}, issn = {1899-1505}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Pressure/drug effects ; Body Weight/drug effects ; Brain/drug effects/*enzymology ; Brain Stem/drug effects/enzymology ; Cerebellum/drug effects/enzymology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Heart/anatomy &amp; histology/drug effects ; Hypertension/drug therapy/*enzymology ; Male ; Nitric Oxide Synthase/*metabolism ; Nitric Oxide Synthase Type I/antagonists &amp; inhibitors/*metabolism ; Organ Size ; Random Allocation ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Species Specificity ; }, abstract = {The goal of our study was to determine a contribution of nNOS to the increase of brain NO synthase activity induced by chronic N-acetylcysteine (NAC) treatment. Young 4-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were subjected to treatment with NAC (1.5 g/kg/day) for 8 weeks. At the end of experiment total NOS activity was determined in the brainstem and cerebellum with and without specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC, 10(-6) mol/l) by measuring the formation of L-[(3)H] citrulline from L-[(3)H] arginine. Chronic NAC treatment had no effect on blood pressure (BP) of WKY, while it attenuated BP increase in young SHR. Total NOS activity was increased in the brainstem of SHR compared to WKY, but this strain difference was abolished by SMTC. Chronic NAC treatment of SHR increased total NOS activity by 32% in the brainstem and by 67% in the cerebellum. After the incubation of brainstem and cerebellum with SMTC there were no significant differences in NOS activity of NAC-treated rats compared to strain-matched controls. Taken together, nNOS seems to be responsible for the increase of total NOS activity in the brain of SHR. SMTC inhibited 86% and 70% of NAC-induced increase of total NOS activity in the brainstem and cerebellum, respectively. Thus, nNOS is responsible not only for strain differences but also for NAC-induced increase of total NOS activity in the brain.}, }
@article {pmid20063365, year = {2010}, author = {De la Cruz Rodríguez, LC and Araujo, CR and Posleman, SE and Rey, MR}, title = {Attenuation of gentamicin-induced nephrotoxicity: trimetazidine versus N-acetyl cysteine.}, journal = {Journal of applied toxicology : JAT}, volume = {30}, number = {4}, pages = {343-353}, doi = {10.1002/jat.1502}, pmid = {20063365}, issn = {1099-1263}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acetylglucosaminidase/urine ; Animals ; Biomarkers/blood/urine ; Creatinine/blood ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Gentamicins/*adverse effects ; Kidney Cortex/drug effects/ultrastructure ; Kidney Diseases/chemically induced/pathology/*prevention &amp; control ; Male ; Nephrons/*drug effects/ultrastructure ; Rats ; Rats, Wistar ; Trimetazidine/administration &amp; dosage/*therapeutic use ; gamma-Glutamyltransferase/urine ; }, abstract = {Gentamicin (G) is a highly nephrotoxic aminoglucoside. It was used to experimentally induce nephrotoxicity in male Wistar rats. To find a drug capable of protecting the nephron we assayed a cardioprotector (trimetazidine, TMZ) and a hepatoprotector (N-acetyl cysteine, NAC). The rats were divided into six groups (n = 8): (A) control without drugs; (B) treated with 50 mg kg(-1) per day (i.p.) of G for 7 days; (C) diet supplemented with 20 mg kg(-1) per day of TMZ for 7 days; (D) treated with 10 mg kg(-1) per day (i.p.) of NAC for 7 days; (E) pretreated for 7 days with 20 mg kg(-1) per day of TMZ and during the following 7 days with G + TMZ; (F) pretreated for 7 days with 10 mg kg(-1) per day (i.p.) of NAC and during the following 7 days with G + NAC. Urea and creatinine as well as the excretion of urinary gamma-glutamyl transpeptidase (GGT(u)) and urinary N-acetyl-glucosaminidase (NAG(u)) were determined and structural and ultrastructural studies were carried out. Group B was used as a G-induced nephrotoxicity control. Pretreatment with TMZ (E) showed a protector effect against induced nephrotoxicity, with no biochemical or functional changes nor alterations in histoarchitecture or ultrastructure. Pretreatment with NAC (F) showed no protector effect against G-induced nephrotoxicity since no statistically significant differences were found with respect to the control group with G. We conclude that G-induced nephrotoxicity is attenuated by the cytoprotective effect of TMZ. We may infer that TMZ inhibits the reabsorption and consequently the accumulation of G in the proximal tubule cell.}, }
@article {pmid20062961, year = {2010}, author = {Vercelino, R and Crespo, I and de Souza, GF and Cuevas, MJ and de Oliveira, MG and Marroni, NP and González-Gallego, J and Tuñón, MJ}, title = {S-nitroso-N-acetylcysteine attenuates liver fibrosis in cirrhotic rats.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {88}, number = {4}, pages = {401-411}, pmid = {20062961}, issn = {1432-1440}, mesh = {Acetylcysteine/*analogs &amp; derivatives/metabolism ; Animals ; Antioxidants/metabolism ; Fibrosis/*pathology ; Immunohistochemistry/methods ; Lipid Peroxidation ; Liver/*metabolism ; Liver Cirrhosis/*metabolism/therapy ; MAP Kinase Signaling System ; Male ; Nitric Oxide/chemistry ; Oxidative Stress ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {This study was aimed to investigate the molecular mechanisms underlying prevention of hepatic fibrosis by S-nitroso-N-acetylcysteine (SNAC), a nitric oxide donor that inhibits lipid peroxidation. Secondary biliary cirrhosis was induced by 4 weeks of common bile duct ligation (CBDL). Both sham-operated and CBDL animals received SNAC (6.0 micromol/kg/day) starting 2 weeks after surgery. SNAC treatment reduced the increase in blood enzyme activities (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), induced by CBDL. Histological changes were attenuated and there was a significant decrease in the area of liver fibrosis and in the activation of stellate cells measured by alpha-smooth muscle actin (alpha-SMA) immunostaining. The increase in TBARS concentration and hydroperoxide-induced chemiluminescence were also reduced by SNAC treatment. SNAC down-regulated expression of collagen 1 alpha, alpha-SMA, tumor necrosis factor-alpha, tumor growth factor-beta, metalloproteinase-2, metalloproteinase inhibitor 1, platelet-derived growth factor (PDGF), and PDGF receptor in CBDL rats. These effects were accompanied by inhibited activation of extracellular signal-regulated kinases, Jun amino-terminal kinases, p38 and Akt. Antifibrotic effects were more efficient than those of the free thiol NAC administered at a dose of 60 mumol/kg. In conclusion, results obtained indicate that SNAC, beyond its antioxidant capacity, exerts antifibrotic effects in rats with secondary biliary cirrhosis by down-regulating increased expression of genes and modulating intracellular signaling pathways that contribute to the accumulation of matrix proteins. Thus, SNAC may be an interesting candidate for the treatment of human fibrosis and cirrhosis.}, }
@article {pmid20060922, year = {2010}, author = {Patel, S and Kumar, S and Jyoti, A and Srinag, BS and Keshari, RS and Saluja, R and Verma, A and Mitra, K and Barthwal, MK and Krishnamurthy, H and Bajpai, VK and Dikshit, M}, title = {Nitric oxide donors release extracellular traps from human neutrophils by augmenting free radical generation.}, journal = {Nitric oxide : biology and chemistry}, volume = {22}, number = {3}, pages = {226-234}, doi = {10.1016/j.niox.2010.01.001}, pmid = {20060922}, issn = {1089-8611}, mesh = {Dose-Response Relationship, Drug ; Extracellular Space/*drug effects/metabolism ; Free Radicals/*metabolism ; Humans ; Neutrophils/*drug effects/metabolism ; Nitric Oxide Donors/*pharmacology ; Nitroprusside/*pharmacology ; S-Nitroso-N-Acetylpenicillamine/*pharmacology ; Structure-Activity Relationship ; Time Factors ; }, abstract = {High availability of NO, oxidative stress and neutrophil extracellular trap (NETs) contents are often noticed at the site of inflammation/infection. Studies from this lab and others have reported NO mediated free radical generation from neutrophils; role of NO in NETs formation however remains undefined so far. The present study was therefore undertaken to explore the effect of NO donors on NET release from human neutrophils (PMNs), using confocal/scanning microscopy, measuring the extracellular DNA content and NET-bound elastase activity. Addition of NO donors (SNAP and SNP) to adhered PMNs led to a time and concentration dependent NETs release, which was blocked by N-acetyl cysteine, suggesting involvement of free radicals in NETs formation. Free radical formation by NO donors was assessed by using DCF-DA, DMPO-nitrone antibody and by p47 phox migration to the neutrophils membrane. NO mediated formation of free radicals and NETs was significantly reduced by the pretreatment of neutrophils with diphenyleneiodonium (DPI), a NADPH-oxidase inhibitor and 4-aminobenzoic acid hydrazide (ABAH), a myeloperoxidase inhibitor, suggesting role of enzymatic free radical generation by NO donors. We thus demonstrate that NO by augmenting free radical formation in human neutrophils mediates NETs release.}, }
@article {pmid20057910, year = {2009}, author = {Wang, P and Liu, XC and Yan, H and Li, MY}, title = {Hyperoxia-induced lens damage in rabbit: protective effects of N-acetylcysteine.}, journal = {Molecular vision}, volume = {15}, number = {}, pages = {2945-2952}, pmid = {20057910}, issn = {1090-0535}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cataract/pathology ; Eye Proteins/metabolism ; Glutathione/metabolism ; Hyperoxia/*pathology ; Lens, Crystalline/*drug effects/metabolism/*pathology ; Protective Agents/*pharmacology ; Rabbits ; }, abstract = {PURPOSE: To investigate the efficacies of different concentrations of N-acetylcysteine (NAC) in preventing hyperoxia-induced lens opacification and changes to biochemical parameters in organ-cultured rabbit lenses.<br><br>METHODS: Thirty-six lenses from adult rabbits were divided into the control group (group A), the hyperoxia-exposed group (group B), and the hyperoxia-exposed, NAC-treated groups: 5 mM NAC (group C), 10 mM NAC (group D), 20 mM NAC (group E), and 40 mM NAC (group F). Groups B-F were incubated with hyperoxia (pO(2)>80%) for 4 h per day for 7 d. Lens transparency, histology, and enzymatic activities were measured after incubation.<br><br>RESULTS: Gross examination of these lenses revealed some severe cortical opacification in group B, and moderate cortical opacification in the lenses of groups C and D. There was minimal cortical opacification in groups A, E, and F. The activities of Na, K-ATPase, and catalase were significantly (p<0.05) lower in group B (38.2%) than in group A (39.9%). It was also lower in group E and F lenses (p<0.05), which had higher levels of NAC-protected enzymes. The glutathione and water-soluble protein content were significantly lower in group B lenses than in group A, E, or F lenses (p<0.05). However, there was no difference between group E and F lenses (p>0.05).<br><br>CONCLUSIONS: The present data suggests that NAC (20 mM-40 mM) significantly prevented experimental lenses' hyperoxia-induced cortical opacification, indicating NAC's potential role in protecting lenses against cataracts induced by high oxygen levels.}, }
@article {pmid20056735, year = {2010}, author = {Chen, YT and Liao, JW and Hung, DZ}, title = {Protective effects of fomepizole on 2-chloroethanol toxicity.}, journal = {Human &amp; experimental toxicology}, volume = {29}, number = {6}, pages = {507-512}, doi = {10.1177/0960327109358612}, pmid = {20056735}, issn = {1477-0903}, mesh = {Acetaldehyde/analogs &amp; derivatives/blood ; Acetylcysteine/pharmacology/therapeutic use ; Alcohol Dehydrogenase/*antagonists &amp; inhibitors ; Aldehyde Dehydrogenase/antagonists &amp; inhibitors ; Animals ; Antidotes/pharmacology/*therapeutic use ; Antioxidants/pharmacology/therapeutic use ; Disulfiram/pharmacology/therapeutic use ; Drug Synergism ; Enzyme Inhibitors/*therapeutic use ; Ethylene Chlorohydrin/metabolism/*toxicity ; Fomepizole ; Glutathione/metabolism ; Kidney/drug effects/metabolism ; Lethal Dose 50 ; Liver/drug effects/metabolism ; Male ; Pyrazoles/pharmacology/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Solvents/metabolism/*toxicity ; }, abstract = {2-Chloroethanol (2-CE) is a widely used industrial solvent. In Taiwan, Taiwanese farmers apply 2-CE on grape-vines to accelerate grape growth, a practice that in some cases have caused poisoning in humans. Thus, there is strong interest in identifying antidotes to 2-CE. This study examines the protective role in 2-CE intoxicated rats. Alcohol dehydrogenase and glutathione were hypothesized to be important in the metabolism of 2-CE. This study used fomepizole, an alcohol dehydrogenase inhibitor, and chemicals that affected glutathione metabolism to study 2-CE toxicity. Notably, fomepizole 5 mg/kg significantly increased median lethal dose (LD(50)) of 2-CE from 65.1 to 180 mg/kg and reduced the production of a potential toxic metabolite chloroacetaldehyde (CAA) in animal plasma. In contrast, disulfiram (DSF), an aldehyde dehydrogenase inhibitor, increased the toxicity of 2-CE on the lethality in rats. Additional or pretreatment with N-acetylcysteine (NAC) and fomepizole significantly reduced plasma CAA concentrations. Fomepizole also significantly reduced 2-CEinhibited glutathione activity. Otherwise, pretreatment with NAC for 4 days followed by co-treatment with fomepizole significantly decreased formation of the metabolic CAA. These results indicated that its catalytic enzyme might play a vital role during 2-CE intoxication, and the combination of fomepizole and NAC could be a protective role in cases of acute 2-CE intoxication.}, }
@article {pmid20056085, year = {2010}, author = {Zhang, SQ and Luo, X and Huang, HL and Chai, Y and Hu, DJ and Tao, QS}, title = {[N-acetylcysteine antagonizes the Interleukin-18-induced expression of TNF-alpha and IL-6 in mouse vascular smooth muscle cells].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {26}, number = {1}, pages = {35-37}, pmid = {20056085}, issn = {1007-8738}, mesh = {Acetylcysteine/*metabolism/pharmacology ; Animals ; Cells, Cultured ; Down-Regulation ; *Gene Expression Regulation/drug effects ; Interleukin-18/*metabolism ; Interleukin-6/*genetics/metabolism ; Mice ; Muscle, Smooth, Vascular/*cytology/metabolism ; Myocytes, Smooth Muscle/*metabolism ; Tumor Necrosis Factor-alpha/*genetics/metabolism ; }, abstract = {AIM: To explore the effect of N-acetylcysteine(NAC)on the interleukin(IL)18-induced expression of tumor necrosis factor (TNF) alpha and interleukin(IL) 6 in mouse vascular smooth muscle cells(VSMC).<br><br>METHODS: VSMC was stimulated with various concentrations of IL-18 for different times after addition of NAC(5 mmol/L) for 1 h. The messenger ribonucleic acid(mRNA) expression of TNF-alpha and IL-6 was measured by RT-PCR and the protein secretion of the two cytokines was determined by ELISA method. Western blot was used to analyze the activation of NF-kappaB in VSMC.<br><br>RESULTS: IL-18 significantly increased the mRNA expression and protein secretion of TNF-alpha and IL-6 (P>0.01) in a dose-dependent and a time-dependent ways. NAC inhibited the mRNA expression and protein secretion of TNF-alpha and IL-6 induced by IL-18(P>0.01). Western blot results showed the NAC inhibited the IL-18-induced activation of NF-kappaB in VSMC.<br><br>CONCLUSION: N-acetylcysteine antagonizes the production of TNF-alpha and IL-6 induced by IL-18 in VSMC.}, }
@article {pmid20055662, year = {2010}, author = {Pang, Z and Niklason, LE and Truskey, GA}, title = {Porcine endothelial cells cocultured with smooth muscle cells became procoagulant in vitro.}, journal = {Tissue engineering. Part A}, volume = {16}, number = {6}, pages = {1835-1844}, pmid = {20055662}, issn = {1937-335X}, support = {R21 HL072189-03/HL/NHLBI NIH HHS/United States ; R01 HL083895-04/HL/NHLBI NIH HHS/United States ; HL083895/HL/NHLBI NIH HHS/United States ; R21 HL072189/HL/NHLBI NIH HHS/United States ; HL72189/HL/NHLBI NIH HHS/United States ; R01 HL083895/HL/NHLBI NIH HHS/United States ; R01 HL083895-03/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Coculture Techniques/*methods ; Cytoplasm/metabolism ; Endothelial Cells/*cytology/*metabolism ; Myocytes, Smooth Muscle/*cytology/*metabolism ; Reactive Oxygen Species/metabolism ; Swine ; Thromboplastin/*metabolism ; Tissue Engineering/methods ; Transcription Factor RelA/metabolism ; }, abstract = {Endothelial cell (EC) seeding represents a promising approach to provide a nonthrombogenic surface on vascular grafts. In this study, we used a porcine EC/smooth muscle cell (SMC) coculture model that was previously developed to examine the efficacy of EC seeding. Expression of tissue factor (TF), a primary initiator in the coagulation cascade, and TF activity were used as indicators of thrombogenicity. Using immunostaining, primary cultures of porcine EC showed a low level of TF expression, but a highly heterogeneous distribution pattern with 14% of ECs expressing TF. Quiescent primary cultures of porcine SMCs displayed a high level of TF expression and a uniform pattern of staining. When we used a two-stage amidolytic assay, TF activity of ECs cultured alone was very low, whereas that of SMCs was high. ECs cocultured with SMCs initially showed low TF activity, but TF activity of cocultures increased significantly 7-8 days after EC seeding. The increased TF activity was not due to the activation of nuclear factor kappa-B on ECs and SMCs, as immunostaining for p65 indicated that nuclear factor kappa-B was localized in the cytoplasm in an inactive form in both ECs and SMCs. Rather, increased TF activity appeared to be due to the elevated reactive oxygen species levels and contraction of the coculture, thereby compromising the integrity of EC monolayer and exposing TF on SMCs. The incubation of cocultures with N-acetyl-cysteine (2 mM), an antioxidant, inhibited contraction, suggesting involvement of reactive oxygen species in regulating the contraction. The results obtained from this study provide useful information for understanding thrombosis in tissue-engineered vascular grafts.}, }
@article {pmid20054154, year = {2010}, author = {Forti, E and Bulgheroni, A and Cetin, Y and Hartung, T and Jennings, P and Pfaller, W and Prieto, P}, title = {Characterisation of cadmium chloride induced molecular and functional alterations in airway epithelial cells.}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology}, volume = {25}, number = {1}, pages = {159-168}, doi = {10.1159/000272060}, pmid = {20054154}, issn = {1421-9778}, mesh = {Antioxidants/pharmacology ; Bronchi/*cytology/*drug effects/metabolism ; Cadherins/analysis/metabolism ; Cadmium Chloride/*adverse effects ; Cell Line ; Cell Survival/drug effects ; Electric Impedance ; Epithelial Cells/cytology/*drug effects/*metabolism ; Gene Expression Regulation/drug effects ; HSP70 Heat-Shock Proteins/genetics/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Humans ; Membrane Proteins/analysis/metabolism ; Metallothionein/genetics/metabolism ; Phosphoproteins/analysis/metabolism ; Respiratory Mucosa/cytology/drug effects/metabolism ; Zonula Occludens-1 Protein ; }, abstract = {Epidemiological studies show that cadmium (Cd) exposure causes pulmonary damage, such as emphysema, pneumonitis, and lung cancer. However, the mechanisms leading to pulmonary toxicity are not yet fully elucidated. The aim of this study was to further investigate cadmium chloride (CdCl(2)) induced toxicity using Calu-3 cells as an in vitro model of human bronchial epithelial cells. CdCl(2) induced effects following either apical or basolateral exposure were evaluated by Neutral Red Uptake (NRU), Trans-Epithelial Electrical Resistance (TEER), and alteration in Metallothionein 1X (MT1X), Heat shock protein 70 (HSP70), and Heme oxygenase 1 (HMOX-1) genes. CdCl(2) exposure resulted in a collapse of barrier function and the induction of MT1X, HMOX-1 and HSP70 genes, prior to alterations in cell viability. These effects were more pronounced when the exposure was from the basolateral side. Co-administration of N-Acetylcysteine (NAC) exerted a strong protective effect against CdCl(2) induced barrier damage and stress related genes, while other antioxidants only attenuated CdCl(2) induced HSP70 and HMOX-1 and showed no protective effect on the barrier collapse. These findings indicate that CdCl(2) exposure is likely to impair Calu-3 barrier function at non cytotoxic concentrations by a direct effect on adherens junction proteins. The protective effect of NAC against CdCl(2) induced MT1X, HSP70 and HMOX-1 genes, demonstrates an anti-oxidant effect of NAC in addition to Cd chelation.}, }
@article {pmid20053903, year = {2010}, author = {Madayag, A and Kau, KS and Lobner, D and Mantsch, JR and Wisniewski, S and Baker, DA}, title = {Drug-induced plasticity contributing to heightened relapse susceptibility: neurochemical changes and augmented reinstatement in high-intake rats.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {30}, number = {1}, pages = {210-217}, pmid = {20053903}, issn = {1529-2401}, support = {R01 DA017328-04S1/DA/NIDA NIH HHS/United States ; R01 DA015758/DA/NIDA NIH HHS/United States ; R01 DA017328/DA/NIDA NIH HHS/United States ; R01 DA015758-03/DA/NIDA NIH HHS/United States ; DA025617/DA/NIDA NIH HHS/United States ; R01 DA017328-04S2/DA/NIDA NIH HHS/United States ; R01 DA015758-02/DA/NIDA NIH HHS/United States ; R01 DA015758-05S1/DA/NIDA NIH HHS/United States ; R01 DA015758-04/DA/NIDA NIH HHS/United States ; DA017328/DA/NIDA NIH HHS/United States ; R01 DA017328-05/DA/NIDA NIH HHS/United States ; DA015758/DA/NIDA NIH HHS/United States ; R01 DA015758-05/DA/NIDA NIH HHS/United States ; R01 DA025617/DA/NIDA NIH HHS/United States ; R01 DA015758-01/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Cocaine/*administration &amp; dosage ; Cocaine-Related Disorders/etiology/*physiopathology/prevention &amp; control ; Disease Susceptibility ; Dose-Response Relationship, Drug ; Male ; Neuronal Plasticity/*drug effects/physiology ; Nucleus Accumbens/*chemistry/*drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Secondary Prevention ; Self Administration ; }, abstract = {A key in understanding the neurobiology of addiction and developing effective pharmacotherapies is revealing drug-induced plasticity that results in heightened relapse susceptibility. Previous studies have demonstrated that increased extracellular glutamate, but not dopamine, in the nucleus accumbens core (NAcc) is necessary for cocaine-induced reinstatement. In this report, we examined whether drug-induced adaptations that are necessary to generate cocaine-induced reinstatement also determine relapse vulnerability. To do this, rats were assigned to self-administer cocaine under conditions resulting in low (2 h/d; 0.5 mg/kg/infusion, i.v.) or high (6 h/d; 1.0 mg/kg/infusion, i.v.) levels of drug intake since these manipulations produce groups of rats exhibiting differences in the magnitude of cocaine-induced reinstatement. Approximately 19 d after the last session, cocaine-induced drug seeking and extracellular levels of glutamate and dopamine in the NAcc were measured. Contrary to our hypothesis, high-intake rats exhibited a more robust cocaine-induced increase in extracellular levels of dopamine but not glutamate. Further, increased reinstatement in high-intake rats was no longer observed when the D(1) receptor antagonist SCH-23390 was infused into the NAcc. The sensitized dopamine response to cocaine in high-intake rats may involve blunted cystine-glutamate exchange by system x(c(-)). Reduced (14)C-cystine uptake through system x(c(-)) was evident in NAcc tissue slices obtained from high-intake rats, and the augmented dopamine response in these rats was no longer observed when subjects received the cysteine prodrug N-acetyl cysteine. These data reveal a role for drug-induced NAcc dopamine in heightened relapse vulnerability observed in rats with a history of high levels of drug intake.}, }
@article {pmid20053818, year = {2010}, author = {Zhou, L and Kaul, S and Liu-Kreyche, P and Tran, SB and Espina, RR and Warrack, BM and Roongta, VA and Iyer, RA}, title = {Disposition of [1'-(14)C]stavudine after oral administration to humans.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {38}, number = {4}, pages = {655-666}, doi = {10.1124/dmd.109.030239}, pmid = {20053818}, issn = {1521-009X}, mesh = {Administration, Oral ; Animals ; Anti-HIV Agents/administration &amp; dosage/*pharmacokinetics ; Area Under Curve ; Biotransformation ; Chromatography, High Pressure Liquid ; Feces/chemistry ; Humans ; Hydrolysis ; In Vitro Techniques ; Isotope Labeling ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Microsomes, Liver/metabolism ; Rats ; Rats, Long-Evans ; Ribose/metabolism ; Stavudine/administration &amp; dosage/*pharmacokinetics ; Tissue Distribution ; }, abstract = {The disposition of stavudine, a potent and orally active nucleoside reverse transcriptase inhibitor, was investigated in six healthy human subjects. Before dosing humans with [1'-(14)C]stavudine, a tissue distribution study was performed in Long-Evans rats. Results from this study showed no accumulation of radioactivity in any of the tissues studied, indicating that the position of the (14)C-label on the molecule was appropriate for the human study. After a single 80-mg (100 microCi) oral dose of [1'-(14)C]stavudine, approximately 95% of the radioactive dose was excreted in urine with an elimination half-life of 2.35 h. Fecal excretion was limited, accounting for only 3% of the dose. Unchanged stavudine was the major drug-related component in plasma (61% of area under the plasma concentration-time curve from time zero extrapolated to infinite time of the total plasma radioactivity) and urine (67% of dose). The remaining radioactivity was associated with minor metabolites, including mono- and bis-oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine (NAC) conjugate of the ribose (M4) after glycosidic cleavage. Formation of metabolite M4 was shown in human liver microsomes incubated with 2',3'-didehydrodideoxyribose, the sugar base of stavudine, in the presence of NAC. In addition, after similar microsomal incubations fortified with GSH, two GSH conjugates, 3'-GS-deoxyribose and 1'-keto-2',3'-dideoxy-3'-GS-ribose, were observed. This suggests that 2',3'-didehydrodideoxyribose underwent cytochrome P450-mediated oxidation leading to an epoxide intermediate, 2',3'-ribose epoxide, followed by GSH addition. In conclusion, absorption and elimination of stavudine were rapid and complete after oral dosing, with urinary excretion of unchanged drug as the predominant route of elimination in humans.}, }
@article {pmid20050632, year = {2010}, author = {Liu, J and Powell, KL and Thames, HD and MacLeod, MC}, title = {Detoxication of sulfur half-mustards by nucleophilic scavengers: robust activity of thiopurines.}, journal = {Chemical research in toxicology}, volume = {23}, number = {3}, pages = {488-496}, pmid = {20050632}, issn = {1520-5010}, support = {U01 NS058191-04/NS/NINDS NIH HHS/United States ; #U01NS058191/NS/NINDS NIH HHS/United States ; P30 ES007784-13/ES/NIEHS NIH HHS/United States ; P30ES007784/ES/NIEHS NIH HHS/United States ; P30 ES007784/ES/NIEHS NIH HHS/United States ; U01 NS058191/NS/NINDS NIH HHS/United States ; }, mesh = {Chemical Warfare Agents/chemistry/*metabolism ; Mustard Gas/analogs &amp; derivatives/*metabolism ; Purines/chemistry/*pharmacology ; Thionucleosides/chemistry/*pharmacology ; }, abstract = {Sulfur mustard (bis-(2-chloroethyl)sulfide) has been used in chemical warfare since World War I and is well known as an acutely toxic vesicant. It has been implicated as a carcinogen after chronic low-level exposure and is known to form interstrand cross-links in DNA. Sulfur and nitrogen mustards are currently of interest as potential chemical threat agents for terrorists because of ease of synthesis. Sulfur mustard and monofunctional analogues (half-mustards, 2-[chloroethyl] alkyl sulfides) react as electrophiles, damaging cellular macromolecules, and thus are potentially subject to scavenging by nucleophilic agents. We have determined rate constants for the reaction of four purine derivatives that contain nucleophilic thiol moieties with several sulfur-half-mustards. Three of these compounds, 2,6-dithiopurine, 2,6-dithiouric acid, and 9-methyl-6-mercaptopurine, exhibit facile reaction with the electrophilic mustard compounds. At near neutral pH, these thiopurines are much better nucleophilic scavengers of mustard electrophiles than other low molecular weight thiols such as N-acetyl cysteine and glutathione. Progress curves calculated by numerical integration techniques indicate that equimolar concentrations of thiopurine provide significant reductions in the overall exposure to the episulfonium ions, which are the major reactive, electrophiles produced when sulfur mustards are dissolved in aqueous solution.}, }
@article {pmid20045538, year = {2010}, author = {Okada, S and Kozuka, C and Masuzaki, H and Yasue, S and Ishii-Yonemoto, T and Tanaka, T and Yamamoto, Y and Noguchi, M and Kusakabe, T and Tomita, T and Fujikura, J and Ebihara, K and Hosoda, K and Sakaue, H and Kobori, H and Ham, M and Lee, YS and Kim, JB and Saito, Y and Nakao, K}, title = {Adipose tissue-specific dysregulation of angiotensinogen by oxidative stress in obesity.}, journal = {Metabolism: clinical and experimental}, volume = {59}, number = {9}, pages = {1241-1251}, pmid = {20045538}, issn = {1532-8600}, support = {R01 DK072408/DK/NIDDK NIH HHS/United States ; R01 DK072408-01A1/DK/NIDDK NIH HHS/United States ; }, mesh = {Adipocytes/cytology/*metabolism ; Adult ; Angiotensinogen/genetics/*metabolism ; Animals ; Cell Size ; Cells, Cultured ; Female ; Humans ; Male ; Mice ; Mice, Obese ; Middle Aged ; Obesity/genetics/*metabolism/physiopathology ; Oxidative Stress ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Subcutaneous Fat/*metabolism/physiopathology ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Adipose tissue expresses all components of the renin-angiotensin system including angiotensinogen (AGT). Recent studies have highlighted a potential role of AGT in adipose tissue function and homeostasis. However, some controversies surround the regulatory mechanisms of AGT in obese adipose tissue. In this context, we here demonstrated that the AGT messenger RNA (mRNA) level in human subcutaneous adipose tissue was significantly reduced in obese subjects as compared with nonobese subjects. Adipose tissue AGT mRNA level in obese mice was also lower as compared with their lean littermates; however, the hepatic AGT mRNA level remained unchanged. When 3T3-L1 adipocytes were cultured for a long period, the adipocytes became hypertrophic with a marked increase in the production of reactive oxygen species. Expression and secretion of AGT continued to decrease during the course of adipocyte hypertrophy. Treatment of the 3T3-L1 and primary adipocytes with reactive oxygen species (hydrogen peroxide) or tumor necrosis factor alpha caused a significant decrease in the expression and secretion of AGT. On the other hand, treatment with the antioxidant N-acetyl cysteine suppressed the decrease in the expression and secretion of AGT in the hypertrophied 3T3-L1 adipocytes. Finally, treatment of obese db/db mice with N-acetyl cysteine augmented the expression of AGT in the adipose tissue, but not in the liver. The present study demonstrates for the first time that oxidative stress dysregulates AGT in obese adipose tissue, providing a novel insight into the adipose tissue-specific interaction between the regulation of AGT and oxidative stress in the pathophysiology of obesity.}, }
@article {pmid20041011, year = {2009}, author = {Hon, KL and Leung, AK}, title = {Be careful, mom and doc: hepatotoxicity associated with prescribed medications in young infants.}, journal = {International journal of pediatrics}, volume = {2009}, number = {}, pages = {673269}, pmid = {20041011}, issn = {1687-9759}, abstract = {Accidental poisonings in young infants are relatively uncommon, and the careless caregiver is usually the culprit. We report two cases of hepatotoxicity due to prescribed medications. An infant was given 15 mL instead of 1.5 mL of paracetamol by his mother because she omitted the decimal point on the label of the drug bottle. The infant became symptomatic, and liver enzyme and clotting profile were abnormal, necessitating treatment with N-acetyl cysteine. Another infant was prescribed oral ketoconazole for thrush, resulting in elevation of liver enzymes. The serum alanine aminotransferase levels were transiently elevated but returned to normal, and both infants recovered uneventfully. This report serves to alert the doctor to avoid using decimal points in drug labeling and to avoid prescribing excessive amount of drug for trivial acute illness. Thrush in infancy is common and usually treated with oral nystatin. Other oral antifungals such as ketoconazole may be associated with liver derangement and should be avoided in infants.}, }
@article {pmid20037173, year = {2010}, author = {Kim, JH and Lee, SS and Jung, MH and Yeo, HD and Kim, HJ and Yang, JI and Roh, GS and Chang, SH and Park, DJ}, title = {N-acetylcysteine attenuates glycerol-induced acute kidney injury by regulating MAPKs and Bcl-2 family proteins.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {25}, number = {5}, pages = {1435-1443}, doi = {10.1093/ndt/gfp659}, pmid = {20037173}, issn = {1460-2385}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Extracellular Signal-Regulated MAP Kinases/*physiology ; Glutathione/analysis ; Glycerol/*toxicity ; Heme Oxygenase (Decyclizing)/analysis ; JNK Mitogen-Activated Protein Kinases/*physiology ; Kidney/*drug effects/metabolism/pathology ; Male ; Proto-Oncogene Proteins c-bcl-2/*analysis ; Rats ; Rats, Sprague-Dawley ; bcl-2-Associated X Protein/analysis ; bcl-X Protein/analysis ; }, abstract = {BACKGROUND: Rhabdomyolysis-induced acute kidney injury (AKI) accounts for about 10 to 40% of all cases of AKI. It is known that N-acetylcysteine (NAC) is effective in various experimental renal injury models; however, little information is available about the rat model of glycerol-induced rhabdomyolysis. In this study, we hypothesize that NAC plays a renoprotective role via the anti-apoptotic pathway.<br><br>METHODS: Male Sprague-Dawley rats were divided into four groups: (i) saline control group, (ii) NAC-treated group (N-acetylcysteine) (150 mg/kg), (iii) glycerol-treated group (50%, 8 ml/kg, IM) and (iv) NAC plus glycerol-treated group. Rats were sacrificed at 24 h after glycerol injection, and the blood and renal tissues were harvested.<br><br>RESULTS: Glycerol administration caused severe renal dysfunction, which included marked renal oxidative stress, significantly increased blood urea nitrogen (BUN) and serum creatinine levels. Histopathological findings, such as cast formation and tubular necrosis, confirmed renal impairment. We noted a marked activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), but not p-38, in the glycerol-treated group. We also observed high expression of Bax and Bad but only weak expression of Bcl-2 and Bcl-xL in the glycerol-treated group. However, NAC pretreatment significantly improved renal function and decreased the activation of ERK, JNK, Bax and Bad, whereas it increased Bcl-2 and Bcl-xL.<br><br>CONCLUSION: These results demonstrate that NAC protects against renal dysfunction, morphological damage and biochemical changes via the anti-apoptotic pathway in the glycerol-induced rhabdomyolysis model in rats.}, }
@article {pmid20036686, year = {2010}, author = {Sharma, H and Zhang, P and Barber, DS and Liu, B}, title = {Organochlorine pesticides dieldrin and lindane induce cooperative toxicity in dopaminergic neurons: role of oxidative stress.}, journal = {Neurotoxicology}, volume = {31}, number = {2}, pages = {215-222}, doi = {10.1016/j.neuro.2009.12.007}, pmid = {20036686}, issn = {1872-9711}, support = {//Howard Hughes Medical Institute/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspases/biosynthesis ; Cell Line ; Cell Survival/drug effects ; Dieldrin/antagonists &amp; inhibitors/*toxicity ; Dopamine/metabolism ; Drug Synergism ; Glutathione/metabolism ; Hexachlorocyclohexane/antagonists &amp; inhibitors/*toxicity ; Hydrocarbons, Chlorinated/*toxicity ; Membrane Potential, Mitochondrial/drug effects ; Neurons/drug effects/metabolism ; Oxidative Stress/*drug effects ; Pesticides/*toxicity ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Elevated environmental exposure to pesticides has been implicated as a contributing factor in the pathogenesis of Parkinson's disease (PD), a progressive movement disorder resulted from degeneration of the nigrostriatal dopaminergic (DA) pathway. Organochlorine pesticides (OCPs) including dieldrin and lindane remain ubiquitous in the environment and food supply due to their resistance to degradation and bioaccumulation along the food chain. While prior studies have gained insight into the neurotoxic effects of individual OCPs such as dieldrin, the effect of combinations of coexisting OCPs is lacking. In this study, we determined the combined effect of dieldrin and lindane on DA neurons and potential mechanism of action. Combinations of dieldrin and lindane (5-25 microM) were more effective in causing toxicity in immortalized rat N27 DA neurons than when used alone. Mechanistically, dieldrin and lindane combination induced a rapid increase in the levels of intracellular reactive oxygen species, a decrease in mitochondrial membrane potential and activation of caspase 3/7. Pretreatment with antioxidant N-acetyl cysteine blocked the effect of dieldrin and lindane on ROS generation and mitochondrial membrane potential and protected against dieldrin- and lindane-induced neurotoxicity. These results demonstrate that dieldrin and lindane work cooperatively to induce DA neurotoxicity through the induction of oxidative stress and mitochondrial dysfunction. These findings may advance understanding of the role of pesticides in the multi-factorial etiology of PD.}, }
@article {pmid20036383, year = {2011}, author = {Kostopanagiotou, G and Avgerinos, ED and Markidou, E and Voiniadis, P and Chondros, C and Theodoraki, K and Smyrniotis, V and Arkadopoulos, N}, title = {Protective effect of NAC preconditioning against ischemia-reperfusion injury in piglet small bowel transplantation: effects on plasma TNF, IL-8, hyaluronic acid, and NO.}, journal = {The Journal of surgical research}, volume = {168}, number = {2}, pages = {301-305}, doi = {10.1016/j.jss.2009.09.002}, pmid = {20036383}, issn = {1095-8673}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Free Radical Scavengers/*administration &amp; dosage ; Hyaluronic Acid/blood ; Interleukin-8/blood ; Intestine, Small/*blood supply/transplantation ; *Ischemic Preconditioning ; Nitric Oxide/blood ; Random Allocation ; Reperfusion Injury/blood/*prevention &amp; control ; Swine ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: Ischemia-reperfusion (I/R) injury is one of the main factors affecting the function and structure of small bowel transplantation (SBT), by generation of proinflammatory mediators such as reactive oxygen species, reactive nitrogen species, cytokines, and endotoxin. Experimental data have demonstrated that N-acetylcysteine (NAC) attenuates intestinal I/R injury. The objective of this study was to determine the effect of NAC preconditioning on the SBT-I/R induced inflammatory cascade, with particular focus on TNF, IL-8, hyaluronic acid, and NO.<br><br>METHODS: Fifteen domestic pigs were used as donors. Fifteen recipient animals were randomly assigned into two groups. Group 1: SBTx (n=7) served as controls and Group 2: SBTx (n=8) served as the experimental group (NAC administration).<br><br>RESULTS: NAC administration at a continuous 4 h intravenous bolus dose of 200 mg/kg of body weight, starting before initiation of bowel transplantation, resulted in statistically significant (P<0.05) higher plasma levels of NO, and lower plasma levels of hyaluronic acid, TNF-&#x3b1;, IL-8, and LDH compared with those of the control group, at the 360 min time point.<br><br>CONCLUSIONS: NAC confers a protective role in small bowel transplantation associated, partly, with NO generation and hyaluronic acid, TNF-&#x3b1; and IL-8 amelioration.}, }
@article {pmid20035277, year = {2010}, author = {Wang, T and Si, Y and Shirihai, OS and Si, H and Schultz, V and Corkey, RF and Hu, L and Deeney, JT and Guo, W and Corkey, BE}, title = {Respiration in adipocytes is inhibited by reactive oxygen species.}, journal = {Obesity (Silver Spring, Md.)}, volume = {18}, number = {8}, pages = {1493-1502}, pmid = {20035277}, issn = {1930-739X}, support = {R01 DK035914/DK/NIDDK NIH HHS/United States ; R01 DK059261/DK/NIDDK NIH HHS/United States ; P30 DK046200/DK/NIDDK NIH HHS/United States ; R56 DK035914/DK/NIDDK NIH HHS/United States ; R01 DK056690/DK/NIDDK NIH HHS/United States ; DK74778/DK/NIDDK NIH HHS/United States ; DK46200/DK/NIDDK NIH HHS/United States ; R01 DK063356/DK/NIDDK NIH HHS/United States ; R01 DK074778/DK/NIDDK NIH HHS/United States ; DK56690/DK/NIDDK NIH HHS/United States ; DK59261/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Adipocytes/drug effects/*metabolism ; Adipose Tissue/drug effects/*metabolism ; Animals ; Carbonyl Cyanide m-Chlorophenyl Hydrazone/analogs &amp; derivatives ; Cell Respiration/drug effects/physiology ; Dietary Fats/metabolism/pharmacology ; Electron Transport Complex I/antagonists &amp; inhibitors/drug effects ; Free Radical Scavengers/*pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/physiology ; Oxidative Phosphorylation/drug effects ; Oxidative Stress/drug effects/*physiology ; Oxygen Consumption/*drug effects ; Pyruvic Acid/metabolism/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Rotenone/pharmacology ; }, abstract = {It is a desirable goal to stimulate fuel oxidation in adipocytes and shift the balance toward less fuel storage and more burning. To understand this regulatory process, respiration was measured in primary rat adipocytes, mitochondria, and fat-fed mice. Maximum O(2) consumption, in vitro, was determined with a chemical uncoupler of oxidative phosphorylation (carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)). The adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio was measured by luminescence. Mitochondria were localized by confocal microscopy with MitoTracker Green and their membrane potential (Delta psi(M)) measured using tetramethylrhodamine ethyl ester perchlorate (TMRE). The effect of N-acetylcysteine (NAC) on respiration and body composition in vivo was assessed in mice. Addition of FCCP collapsed Delta psi(M) and decreased the ATP/ADP ratio. However, we demonstrated the same rate of adipocyte O(2) consumption in the absence or presence of fuels and FCCP. Respiration was only stimulated when reactive oxygen species (ROS) were scavenged by pyruvate or NAC: other fuels or fuel combinations had little effect. Importantly, the ROS scavenging role of pyruvate was not affected by rotenone, an inhibitor of mitochondrial complex I. In addition, mice that consumed NAC exhibited increased O(2) consumption and decreased body fat in vivo. These studies suggest for the first time that adipocyte O(2) consumption may be inhibited by ROS, because pyruvate and NAC stimulated respiration. ROS inhibition of O(2) consumption may explain the difficulty to identify effective strategies to increase fat burning in adipocytes. Stimulating fuel oxidation in adipocytes by decreasing ROS may provide a novel means to shift the balance from fuel storage to fuel burning.}, }
@article {pmid20034232, year = {2009}, author = {Zembron-Lacny, A and Ostapiuk, J and Szyszka, K}, title = {Effects of sulphur-containing compounds on plasma redox status in muscle-damaging exercise.}, journal = {The Chinese journal of physiology}, volume = {52}, number = {5}, pages = {289-294}, doi = {10.4077/cjp.2009.amh026}, pmid = {20034232}, issn = {0304-4920}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*metabolism ; Dose-Response Relationship, Drug ; Exercise/*physiology ; Humans ; Male ; Oxidation-Reduction ; Protein Carbonylation/drug effects ; *Resistance Training ; Sulfhydryl Compounds/blood ; Taurine/*pharmacology ; Thiobarbituric Acid Reactive Substances/metabolism ; Thioctic Acid/*pharmacology ; Uric Acid/blood ; Young Adult ; }, abstract = {The aim of the study was to compare effects of three-day N-acetylcysteine, alpha-lipoic acid or taurine administration on plasma antioxidant status and oxidative damage markers in healthy men after performing muscle-damaging exercise. Fifty-five healthy and trained men were randomly assigned to N-acetylcysteine (NAC, 1.8 g/day, 3 days), alpha-lipoic acid (ALA, 1.2 g/day, 3 days), taurine (TAU, 3 g/day, 3 days) and control group (CON), and exposed to intense resistance exercise. The resistance exercise induced the muscle damage which was observed by significant increase in total creatine kinase (CK) activity at 24 h rest. The administration of NAC and ALA significantly elevated the resting or/and postexercise plasma total antioxidant status (TAS) and total thiols (TT). Uric acid (UA) concentration was decreased by NAC, ALA and TAU at 24 h rest compared with CON. The plasma lipid peroxidation (TBARS) and protein carbonylation (PC) were considerably reduced by NAC and ALA administration at rest and after exercise. TAU did not have any influence on TAS, TT, TBARS and PC levels. Our study has shown that three-day oral N-acetylcysteine and alpha-lipoic acid administration enhanced plasma total antioxidant status and attenuated oxidative damage whereas taurine did not demonstrate any antioxidant action in healthy men after performing a single muscle-damaging exercise.}, }
@article {pmid20032398, year = {2009}, author = {Chiu, TH and Lai, WW and Hsia, TC and Yang, JS and Lai, TY and Wu, PP and Ma, CY and Yeh, CC and Ho, CC and Lu, HF and Wood, WG and Chung, JG}, title = {Aloe-emodin induces cell death through S-phase arrest and caspase-dependent pathways in human tongue squamous cancer SCC-4 cells.}, journal = {Anticancer research}, volume = {29}, number = {11}, pages = {4503-4511}, pmid = {20032398}, issn = {1791-7530}, support = {AG-18357/AG/NIA NIH HHS/United States ; AG-23524/AG/NIA NIH HHS/United States ; }, mesh = {Anthraquinones/*pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Calcium/metabolism ; Carcinoma, Squamous Cell/*drug therapy/metabolism/pathology ; Caspases/*metabolism ; Cell Line, Tumor ; Endodeoxyribonucleases/metabolism ; Humans ; Isoenzymes/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/enzymology ; Reactive Oxygen Species/metabolism ; S Phase/*drug effects ; Tongue Neoplasms/*drug therapy/metabolism/pathology ; }, abstract = {Aloe-emodin, one of the anthraquinones, has been shown to have anticancer activity in different kinds of human cancer cell lines. Therefore, the purpose of this study was to investigate the anti-cancer effect of aloe-emodin on human tongue squamous carcinoma SCC-4 cells. The results indicated that aloe-emodin induced cell death through S-phase arrest and apoptosis in a dose- and time-dependent manner. Treatment with 30 microM of aloe-emodin led to S-phase arrest through promoted p53, p21 and p27, but inhibited cyclin A, E, thymidylate synthase and Cdc25A levels. Aloe-emodin promoted the release of apoptosis-inducing factor (AIF), endonuclease G (Endo G), pro-caspase-9 and cytochrome c from the mitochondria via a loss of the mitochondrial membrane potential (DeltaPsi(m)) which was associated with a increase in the ratio of B-cell lymphoma 2-associated X protein (Bax)/B cell lymphoma/leukemia-2 (Bcl-2) and activation of caspase-9 and -3. The free radical scavenger N-acetylcysteine (NAC) and caspase inhibitors markedly blocked aloe-emodin-induced apoptosis. Aloe-emodin thus induced apoptosis in the SCC-4 cells through the Fas/death-receptor, mitochondria and caspase cascade. Aloe-emodin could be a novel chemotherapeutic drug candidate for the treatment of human tongue squamous cancer in the future.}, }
@article {pmid20032046, year = {2010}, author = {Mitsuki, M and Nara, K and Yamaji, T and Enomoto, A and Kanno, M and Yamaguchi, Y and Yamada, A and Waguri, S and Hashimoto, Y}, title = {Siglec-7 mediates nonapoptotic cell death independently of its immunoreceptor tyrosine-based inhibitory motifs in monocytic cell line U937.}, journal = {Glycobiology}, volume = {20}, number = {3}, pages = {395-402}, doi = {10.1093/glycob/cwp195}, pmid = {20032046}, issn = {1460-2423}, mesh = {Amino Acid Motifs ; Antibodies, Monoclonal/immunology ; Antigens, Differentiation, Myelomonocytic/*chemistry/immunology ; Cell Death ; Humans ; Lectins/*chemistry/immunology ; Monocytes/*metabolism ; Tyrosine/metabolism ; U937 Cells ; }, abstract = {Siglec-7, a sialic acid binding immunoglobulin-like lectin, predominantly transduces inhibitory signals through cytosolic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Here, we report that clustering of Siglec-7 with a specific F(ab')(2) elicited cell death. Interestingly, a truncated Siglec-7 lacking the cytosolic ITIM domain still induced the cell death, suggesting that the ITIMs are not essential for the death signaling. Further analyses of the death signaling revealed that an oxygen radical scavenger, N-acetyl cysteine, completely inhibited the cell death, whereas a pancaspase inhibitor did not. In addition, caspase-3 activation, DNA ladder formation, and nuclear condensation were not detected during the death process, suggesting that the cell death is nonapoptotic. To identify the critical region for the death signaling, we prepared a series of shuffling chimeras between Siglec-7 and Siglec-9, the latter of which did not transduce a death signal. The critical region was mapped to the middle of the membrane-proximal C2-set domain, which contained only six amino acid differences between Siglec-7 and Siglec-9. Point mutation analyses of each of these six amino acids revealed that four of the six amino acids were critical for the death signal. A computer-assisted 3D modeling revealed that these four amino acids were proximally located on the surface of the C2-set domain. In conclusion, Siglec-7 induces nonapoptotic cell death, the signal for which is transduced by an extracellular C2-set domain.}, }
@article {pmid20029548, year = {2009}, author = {Saini-Chohan, HK and Dhalla, NS}, title = {Attenuation of ischemia-reperfusion-induced alterations in intracellular Ca2+ in cardiomyocytes from hearts treated with N-acetylcysteine and N-mercaptopropionylglycine.}, journal = {Canadian journal of physiology and pharmacology}, volume = {87}, number = {12}, pages = {1110-1119}, doi = {10.1139/Y09-103}, pmid = {20029548}, issn = {1205-7541}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Caffeine/pharmacology ; Calcium/*analysis/physiology ; Cardiotonic Agents/pharmacology ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Heart/*drug effects/physiopathology ; Male ; Myocytes, Cardiac/chemistry/*drug effects/physiology ; Ouabain/pharmacology ; Oxidative Stress/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*drug therapy/physiopathology ; Tiopronin/*pharmacology ; }, abstract = {This study was undertaken to test whether Ca(2+)-handling abnormalities in cardiomyocytes after ischemia-reperfusion (I/R) are prevented by antioxidants such as N-acetyl L-cysteine (NAC), which is known to reduce oxidative stress by increasing the glutathione redox status, and N-(2-mercaptopropionyl)-glycine (MPG), which scavenges both peroxynitrite and hydroxyl radicals. For this purpose, isolated rat hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion, and cardiomyocytes were prepared to monitor changes in the intracellular concentration of free Ca(2+) ([Ca(2+)](i)). Marked depression in the left ventricular developed pressure and elevation in the left ventricular end-diastolic pressure in I/R hearts were attenuated by treatment with NAC or MPG. Cardiomyocytes obtained from I/R hearts showed an increase in the basal level of [Ca(2+)](i) as well as augmentation of the low Na(+)-induced increase in [Ca(2+)](i), with no change in the KCl-induced increase in [Ca(2+)](i). These I/R-induced alterations in Ca(2+) handling by cardiomyocytes were attenuated by treatment of hearts with NAC or MPG. Furthermore, reduction in the isoproterenol-, ATP-, ouabain-, and caffeine-induced increases in [Ca(2+)](i) in cardiomyocytes from I/R hearts were limited by treatment with NAC or MPG. The increases in the basal [Ca(2+)](i), unlike the KCl-induced increase in [Ca(2+)](i), were fully or partially prevented by both NAC and MPG upon exposing cardiomyocytes to hypoxia-reoxygenation, H(2)O(2), or a mixture of xanthine and xanthine oxidase. These results suggest that improvement in cardiac function of I/R hearts treated with NAC or MPG was associated with attenuation of changes in Ca(2+) handling by cardiomyocytes, and the results support the view that oxidative stress due to oxyradical generation and peroxynitrite formation plays an important role in the development of intracellular Ca(2+) overload in cardiomyocytes as a consequence of I/R injury.}, }
@article {pmid20022969, year = {2010}, author = {Hui, DS and Lee, N and Chan, PK}, title = {Clinical management of pandemic 2009 influenza A(H1N1) infection.}, journal = {Chest}, volume = {137}, number = {4}, pages = {916-925}, pmid = {20022969}, issn = {1931-3543}, mesh = {Antiviral Agents ; *Disease Outbreaks ; Extracorporeal Membrane Oxygenation ; *Global Health ; Humans ; Immunotherapy ; Infection Control/*methods ; *Influenza A Virus, H1N1 Subtype ; Influenza, Human/epidemiology/*prevention &amp; control/*therapy ; Quarantine ; Travel ; Viral Vaccines ; }, abstract = {Antiviral therapy and vaccination are important strategies for controlling pandemic 2009 influenza A(H1N1) but efficacy depends on the timing of administration and is often limited by supply shortage. Patients with dyspnea, tachypnea, evidence of hypoxemia, and pulmonary infiltrates on chest radiograph should be hospitalized. Patients with severe illness or underlying medical conditions that increase the risk of more severe disease should be treated with oseltamivir or zanamivir as soon as possible, without waiting for the results of laboratory tests. Lung-protective ventilation strategy with a low tidal volume and adequate pressure, in addition to a conservative fluid management approach, is recommended when treating adult patients with ARDS. Extracorporeal membrane oxygenation has emerged as an important rescue therapy for critically ill patients. Use of systemic steroids was associated with delayed viral clearance in severe acute respiratory syndrome and H3N2 infection. Low-dose corticosteroids may be considered in the treatment of refractory septic shock. Passive immunotherapy in the form of convalescent plasma or hyperimmune globulin may be explored as rescue therapy. More data are needed to explore the potential role of IV gamma globulin and other drugs with immunomodulating properties, such as statins, gemfibrozil, and N-acetyl-cysteine. Health-care workers must apply strict standard and droplet precautions when dealing with suspected and confirmed case and upgrade to airborne precautions when performing aerosol-generating procedures. Nonpharmacologic measures, such as early case isolation, household quarantine, school/workplace closure, good community hygiene, and restrictions on travel are useful measures in controlling an influenza pandemic at its early phase.}, }
@article {pmid20022629, year = {2010}, author = {Nocca, G and D'Antò, V and Desiderio, C and Rossetti, DV and Valletta, R and Baquala, AM and Schweikl, H and Lupi, A and Rengo, S and Spagnuolo, G}, title = {N-acetyl cysteine directed detoxification of 2-hydroxyethyl methacrylate by adduct formation.}, journal = {Biomaterials}, volume = {31}, number = {9}, pages = {2508-2516}, doi = {10.1016/j.biomaterials.2009.12.015}, pmid = {20022629}, issn = {1878-5905}, mesh = {3T3 Cells ; Acetylcysteine/chemistry/*pharmacology ; Animals ; Cell Death/drug effects ; Cell Survival/drug effects ; Chromatography, High Pressure Liquid ; Electrophoresis, Capillary ; Extracellular Space/drug effects/metabolism ; Fibroblasts/cytology/drug effects/metabolism ; Intracellular Space/drug effects/metabolism ; Mass Spectrometry ; Methacrylates/*chemistry/*toxicity ; Mice ; }, abstract = {Cytotoxicity of the dental resin monomer 2-hydroxyethyl methacrylate (HEMA) and the protective effects of N-acetyl cysteine (NAC) on monomer-induced cell damage are well demonstrated. The aim of our study was to analyze the hypothesis that the protection of NAC from HEMA cytotoxicity might be due to direct NAC adduct formation. To this end, using HPLC we first measured the actual intracellular HEMA concentrations able to cause toxic effects on 3T3-fibroblasts and then determined the decrease in intracellular and extracellular HEMA levels in the presence of NAC. In addition, by capillary electrophoresis coupled with mass spectrometry analysis (CE-MS), we evaluated NAC-HEMA adduct formation. HEMA reduced 3T3 cell vitality in a dose- and time-dependent manner. The concentration of HEMA inside the cells was 15-20 times lower than that added to the culture medium for cell treatment (0-8 mmol/L). In the presence of 10 mmol/L NAC, both intracellular and extracellular HEMA concentrations greatly decreased in conjunction with cytotoxicity. NAC-HEMA adducts were detected both in the presence and absence of cells. Our findings suggest that the in vitro detoxification ability of NAC against HEMA-induced cell damage occurs through NAC adduct formation. Moreover, we provide evidence that the actual intracellular concentration of HEMA able to cause cytotoxic effects is at least one magnitude lower than that applied extracellularly.}, }
@article {pmid20019586, year = {2011}, author = {Ozdil, B and Cosar, A and Akkiz, H and Sandikci, M and Kece, C}, title = {New therapeutic option with N-acetylcysteine for primary sclerosing cholangitis: two case reports.}, journal = {American journal of therapeutics}, volume = {18}, number = {3}, pages = {e71-4}, doi = {10.1097/MJT.0b013e3181c42758}, pmid = {20019586}, issn = {1536-3686}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Cholagogues and Choleretics/*therapeutic use ; Cholangitis, Sclerosing/diagnosis/*drug therapy ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Liver/physiopathology ; Male ; Ursodeoxycholic Acid/therapeutic use ; Young Adult ; }, abstract = {Primary sclerosing cholangitis is a progressive, cholestatic hepatic disease of unknown etiology. It is characterized by progressive inflammation, destruction, and fibrosis of the intrahepatic and extrahepatic bile ducts. Several medical therapies have been tried such as penicilamin, colchicine, methatraxate, cyclosporine, tacrolimus, and ursodeoxycholic acid. Treatment with mucolytic agents in excessively high viscosity conditions appears to have an important role. N-acetylcysteine (NAC), as a mucolytic agent, may fascilitate the drainage in partial obstructions by decreasing the mucous viscosity. We suggest that NAC and ursodeoxycholic acid have markedly positive effects on the clinical course of cholangitis and cholestasis when used together by affecting bile viscosity. Here, we present two cases treated with NAC. NAC capsul therapies at 800 mg/day were administered to two patients with primary sclerosing cholangitis. Clinical and laboratory parameters of patients saw significant improvement.}, }
@article {pmid20018732, year = {2009}, author = {Tsai, SY and Hayashi, T and Harvey, BK and Wang, Y and Wu, WW and Shen, RF and Zhang, Y and Becker, KG and Hoffer, BJ and Su, TP}, title = {Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1xGTP pathway.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {106}, number = {52}, pages = {22468-22473}, pmid = {20018732}, issn = {1091-6490}, mesh = {Animals ; Apoptosis ; Calcium Signaling ; Caspase 3/metabolism ; Cells, Cultured ; Dendritic Spines/drug effects/*physiology ; Endoplasmic Reticulum/metabolism ; Enzyme Activation ; Free Radical Scavengers/pharmacology ; Free Radicals/metabolism ; Guanine Nucleotide Exchange Factors/genetics/metabolism ; Guanosine Triphosphate/*metabolism ; Hippocampus/cytology/drug effects/*physiology ; Learning/physiology ; Memory/physiology ; Mitochondria/metabolism ; Neoplasm Proteins/genetics/metabolism ; Neuronal Plasticity/physiology ; RNA, Small Interfering/genetics ; Rats ; Receptors, sigma/antagonists &amp; inhibitors/genetics/*physiology ; Recombinant Proteins/genetics/metabolism ; Stress, Physiological ; T-Lymphoma Invasion and Metastasis-inducing Protein 1 ; Transfection ; rac1 GTP-Binding Protein/*metabolism ; }, abstract = {Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident proteins known to be involved in learning and memory. Dendritic spines in hippocampal neurons play important roles in neuroplasticity and learning and memory. This study tested the hypothesis that Sig-1Rs might regulate denritic spine formation in hippocampal neurons and examined potential mechanisms therein. In rat hippocampal primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit in the formation of dendritic spines that is unrelated to ER Ca(2+) signaling or apoptosis, but correlates with the mitochondrial permeability transition and cytochrome c release, followed by caspase-3 activation, Tiam1 cleavage, and a reduction in Rac1.GTP. Sig-1R-knockdown neurons contain higher levels of free radicals when compared to control neurons. The activation of superoxide dismutase or the application of the hydroxyl-free radical scavenger N-acetyl cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic spines and mitochondria from the deficits caused by Sig-1R siRNA. Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable guanine exchange factor able to constitutively activate Rac1 in the form of Rac1.GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1.GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radical-sensitive ER-mitochondrion-Rac1.GTP pathway in the regulation of dendritic spine formation in the hippocampus.}, }
@article {pmid20018284, year = {2010}, author = {Bao, XM and Wu, CF and Lu, GP}, title = {Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK.}, journal = {Atherosclerosis}, volume = {210}, number = {1}, pages = {114-121}, doi = {10.1016/j.atherosclerosis.2009.11.032}, pmid = {20018284}, issn = {1879-1484}, mesh = {Apoptosis/*drug effects ; Atorvastatin ; Cells, Cultured ; Endothelial Cells/*drug effects ; Enzyme Activation/drug effects ; Heptanoic Acids/*pharmacology ; Homocysteine/*pharmacology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; Mevalonic Acid/pharmacology ; NADPH Oxidase 4 ; NADPH Oxidases/*analysis ; Onium Compounds/pharmacology ; Oxidative Stress/*drug effects ; Pyrroles/*pharmacology ; Reactive Oxygen Species/metabolism ; Stem Cells/drug effects ; p38 Mitogen-Activated Protein Kinases/*analysis/pharmacology ; }, abstract = {Previous studies showed that homocysteine (Hcy) reduces endothelial progenitor cells (EPCs) numbers and impairs functional activity. Atorvastatin, HMG-CoA inhibition has been showed to have protective effects on EPCs. Recent studies have demonstrated that reduced EPCs numbers and activity are associated with EPCs apoptosis. However, the protective mechanisms of atorvastatin on HHcy-induced EPCs apoptosis remain to be determined. This study was designed to examine the effect of atorvastatin on homocysteine-induced reactive oxygen species (ROS) production and apoptosis in EPCs. EPCs were isolated from peripheral blood and characterized, then challenged with Hcy (50-500 micromol/L) in the presence or absence of atorvastatin (0.01-1 micromol/L) or various stress signaling inhibitors, including mevalonate (100 micromol/L), antioxidants N-acetyl cysteine (NAC, 10 micromol/L), the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI 10 micromol/L), the eNOS inhibitor N(G)mono-methyl-l-arginine LNMA (1mmol/L), and the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 (10 micromol/L). Apoptosis was evaluated by FACS analysis and cell viability was determined by MTT assay. ROS were detected by 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFH-DA). NADPH oxidases were evaluated with lucigenin-enhanced chemiluminescence. Expression of Nox4 mRNA and p-p38MAPK protein was measured by RT-PCR and Western blot analysis, respectively. Our data revealed that atorvastatin significantly suppressed Hcy-induced ROS accumulation and EPCs apoptosis. Atorvastatin also antagonized homocysteine-induced activation of NADPH oxidase and overexpression of Nox4 mRNA and p-p38MAPK protein. Similar effects occurred with EPCs transfected with Nox4 siRNA. These findings demonstrated that atorvastatin may inhibit Hcy-induced NADPH oxidase activation, ROS accumulation, and EPCs apoptosis through Nox4/p38MAPK dependent mechanisms, all of which may contribute to atorvastatin-induced beneficial effects on EPCs function.}, }
@article {pmid20017596, year = {2010}, author = {Zanchi, AC and Saiki, M and Saldiva, PH and Barros, HM and Rhoden, CR}, title = {Hippocampus lipid peroxidation induced by residual oil fly ash intranasal instillation versus habituation to the open field.}, journal = {Inhalation toxicology}, volume = {22}, number = {1}, pages = {84-88}, doi = {10.3109/08958370902936931}, pmid = {20017596}, issn = {1091-7691}, mesh = {Acetylcysteine/pharmacology ; Administration, Intranasal ; Air Pollutants/*toxicity ; Animals ; Behavior, Animal/*drug effects/physiology ; Carbon/*toxicity ; Coal Ash ; Drug Antagonism ; Exploratory Behavior/drug effects/physiology ; Free Radical Scavengers/pharmacology ; Habituation, Psychophysiologic/*drug effects/physiology ; Hippocampus/*drug effects/metabolism ; Lipid Peroxidation/*drug effects ; Male ; Malondialdehyde/metabolism ; Memory/drug effects ; Motor Activity/drug effects/physiology ; Oxidative Stress/drug effects ; Particulate Matter/*toxicity ; Psychomotor Performance/drug effects/physiology ; Rats ; Rats, Wistar ; }, abstract = {Epidemiological studies have demonstrated the adverse effects of particulate matter (PM) inhalation on the respiratory and cardiovascular systems. It has been reported that air pollution may affect the central nervous system and decrease cognitive function. In rats, residual oil fly ash (ROFA) instillation causes decreased motor activity and increased lipid peroxidation in the striatum and the cerebellum. Our objective was to determine whether chronic instillation of particles induces changes in learning and memory in rats and whether oxidants in the hippocampus may contribute to these adverse effects. Forty-five-day-old male Wistar rats were exposed to ROFA by intranasal instillation and were treated with N-acetylcysteine (NAC) at 150 mg/kg i.p. for 30 days. Control groups were exposed to ROFA, NAC, or neither. On days 1, 8, and 30 of the protocol, rats were submitted to the open field test to evaluate habituation. After the last open field session, the rats were killed by decapitation. The hippocampus was used to determine lipid peroxidation (LP) by the thiobarbituric acid-reactive substances test. ROFA instillation induced an increase in LP in the hippocampus compared to all treatment groups (p = .012). NAC treatment blocked these changes. All of the treatment groups presented a decrease in the frequency of peripheral walking (p = .001), rearing (p = .001), and exploration (p = .001) over time. Our study demonstrates that exposure to particles for 30 days and/or NAC treatment do not modify habituation to an open field, a simple form of learning and memory in rats, and that oxidative damage induced by ROFA does not modulate these processes.}, }
@article {pmid20017534, year = {2010}, author = {Felim, A and Herrera, G and Neudörffer, A and Blanco, M and O'Connor, JE and Largeron, M}, title = {Synthesis and in vitro cytotoxicity profile of the R-enantiomer of 3,4-dihydroxymethamphetamine (R-(-)-HHMA): comparison with related catecholamines.}, journal = {Chemical research in toxicology}, volume = {23}, number = {1}, pages = {211-219}, doi = {10.1021/tx9003374}, pmid = {20017534}, issn = {1520-5010}, mesh = {Catecholamines/chemistry/toxicity ; Cell Line, Tumor ; Deoxyepinephrine/*analogs &amp; derivatives/chemical synthesis/chemistry/toxicity ; Flow Cytometry ; Humans ; Levodopa/chemistry ; N-Methyl-3,4-methylenedioxyamphetamine/chemistry/metabolism ; Stereoisomerism ; Toxicity Tests ; }, abstract = {(+/-)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a chiral drug that is essentially metabolized in humans through O-demethylenation into 3,4-dihydroxymethamphetamine (HHMA). There has recently been a resurgence of interest in the possibility that MDMA metabolites, especially 5-(N-acetylcystein-S-yl)-N-methyl-alpha-methyldopamine (designated as 5-NAC-HHMA), might play a role in MDMA neurotoxicity. However, the chirality of MDMA was not considered in previously reported in vivo studies because HHMA, the precursor of the 5-NAC-HHMA metabolite, was used as the racemate. Since the stereochemistry of this chiral drug needs to be considered, the first total synthesis of R-(-)-HHMA is reported. Using L-DOPA as the chiral source, the preparation of R-(-)-HHMA is achieved through seven steps, in 30% overall yield and 99.5% enantiomeric excess. The cytotoxicity of R-(-)-HHMA and related catecholamines has been further determined by flow cytometric analysis of propidium iodide uptake in human dopaminergic neuroblastoma SH-SY5Y cells and by an Escherichia coli plate assay, specific for the detection of oxidative toxicity. The good correlation between the toxicities observed in both systems suggests that SH-SY5Y cells are sensitive to oxidative toxicity and that cell death (necrosis) would be mediated by reactive oxygen species mainly generated from redox active quinonoid centers. In contrast, apoptosis was detected for 3,4-dimethoxymethamphetamine (MMMA), the synthetic precursor of HHMA possessing a protected catechol group. MMMA was not toxic in the bacterial assay, indicating that its toxicity is not related to increased oxidative stress. Finally, we can conclude that there is a need to distinguish the toxicity ascribed to MDMA itself, also bearing a protected catechol moiety, from that depending on MDMA biotransformation leading to catechol metabolites such as HHMA and the thioether conjugates.}, }
@article {pmid20015842, year = {2010}, author = {Pasciu, V and Posadino, AM and Cossu, A and Sanna, B and Tadolini, B and Gaspa, L and Marchisio, A and Dessole, S and Capobianco, G and Pintus, G}, title = {Akt downregulation by flavin oxidase-induced ROS generation mediates dose-dependent endothelial cell damage elicited by natural antioxidants.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {114}, number = {1}, pages = {101-112}, doi = {10.1093/toxsci/kfp301}, pmid = {20015842}, issn = {1096-0929}, mesh = {Antioxidants/*toxicity ; Coumaric Acids/toxicity ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Endothelial Cells/*drug effects/enzymology/metabolism ; Flavins/*metabolism ; Humans ; Oxidative Stress ; Oxidoreductases/*metabolism ; Phosphorylation/drug effects ; Protein Carbonylation/drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/*metabolism ; Resveratrol ; Stilbenes/toxicity ; }, abstract = {High intake of natural antioxidants (NA) from plant-derived foods and beverages is thought to provide cardiovascular benefits. The endothelium plays a pivotal role in cardiovascular homeostasis, and for this reason, the molecular events resulting from NA actions on endothelial cells (ECs) are actively investigated. Here, we show the direct impact of two NA, coumaric acid and resveratrol, on intracellular reactive oxygen species levels, protein carbonylation, and cell physiology in human ECs. While at lower doses, both NA promoted antioxidant effects, at moderately high doses, NA elicited a dose-dependent pro-oxidant effect, which was followed by apoptosis, cell damage, and phospho-Akt downregulation. NA-induced pro-oxidant effects were counteracted by N-acetyl cysteine and diphenyleneiodonium (DPI), suggesting a role for flavin oxidases in NA-induced toxicity. DPI also prevented NA-induced phospho-Akt downregulation indicating that Akt can work downstream of flavin oxidases in mediating cellular responses to NA. Stimulation of phospho-Akt by insulin dramatically counteracted NA-induced cell death, an effect abolished by Akt inhibition further suggesting that mechanistically Akt regulates cell survival in response to NA-induced stress. Although further studies are required to better characterize the molecular mechanism of NA-induced cell toxicity, our study is the first to show in a human vascular model that moderately high doses of NA can induce cell damage mediated by flavoproteins and the Akt pathway.}, }
@article {pmid20012373, year = {2010}, author = {Lee, SH and Ha, SO and Koh, HJ and Kim, K and Jeon, SM and Choi, MS and Kwon, OS and Huh, TL}, title = {Upregulation of cytosolic NADP+-dependent isocitrate dehydrogenase by hyperglycemia protects renal cells against oxidative stress.}, journal = {Molecules and cells}, volume = {29}, number = {2}, pages = {203-208}, doi = {10.1007/s10059-009-0183-z}, pmid = {20012373}, issn = {0219-1032}, mesh = {Animals ; Cell Line ; *Cytoprotection/drug effects ; Cytosol/drug effects/*enzymology ; Diabetic Nephropathies/enzymology ; Dogs ; Enzyme Induction/drug effects ; Glucose/pharmacology ; Humans ; Hyperglycemia/*enzymology/pathology ; Isocitrate Dehydrogenase/biosynthesis/*metabolism ; Kidney Tubules, Proximal/drug effects/*enzymology/pathology ; Male ; Mice ; NADP/metabolism ; Oxidation-Reduction/drug effects ; *Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Stress, Physiological/drug effects ; Transfection ; *Up-Regulation/drug effects ; }, abstract = {Hyperglycemia-induced oxidative stress is widely recognized as a key mediator in the pathogenesis of diabetic nephropathy, a complication of diabetes. We found that both expression and enzymatic activity of cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) were upregulated in the renal cortexes of diabetic rats and mice. Similarly, IDPc was induced in murine renal proximal tubular OK cells by high hyperglycemia, while it was abrogated by co-treatment with the antioxidant N-Acetyl-Cysteine (NAC). In OK cells, increased expression of IDPc by stable transfection prevented hyperglycemia-mediated reactive oxygen species (ROS) production, subsequent cellular oxidative stress and extracellular matrix accumulation, whereas these processes were all stimulated by decreased IDPc expression. In addition, production of NADPH and GSH in the cytosol was positively correlated with the expression level of IDPc in OK cells. These results together indicate that upregulation of IDPc in response to hyperglycemia might play an essential role in preventing the progression of diabetic nephropathy, which is accompanied by ROS-induced cellular damage and fibrosis, by providing NADPH, the reducing equivalent needed for recycling reduced glutathione and low molecular weight antioxidant thiol proteins.}, }
@article {pmid20012359, year = {2010}, author = {Duarte, F and Blaya, R and Telöken, PE and Becker, D and Fernandes, M and Rhoden, EL}, title = {The effects of N-acetylcysteine on spermatogenesis and degree of testicular germ cell apoptosis in an experimental model of varicocele in rats.}, journal = {International urology and nephrology}, volume = {42}, number = {3}, pages = {603-608}, pmid = {20012359}, issn = {1573-2584}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Count ; Germ Cells/*drug effects/physiology ; Male ; Rats ; Sertoli Cells/pathology ; Spermatids/pathology ; Spermatogenesis/*drug effects ; Testis/pathology ; Varicocele/pathology/*physiopathology ; }, abstract = {INTRODUCTION: The mechanism by which varicocele interferes in spermatogenesis has not been clearly defined. Germ cell apoptosis and oxidative stress appear to be involved in this process and the use of antioxidants has been proposed to counteract upon these effects. The present study evaluated the effects of N-acetylcysteine (NAC) on spermatogenesis and germ cell apoptosis in an experimental model of varicocele in rats.<br><br>MATERIALS AND METHODS: Twenty 30-day-old animals were randomly divided into three groups: sham operation (Group 1), left experimental varicocele (Group 2) and left experimental varicocele group treated with NAC 50 mg/kg/day (Group 3). After 2 months, spermatogenesis was evaluated by absolute and true count of round spermatids, pachytenes, spermatocytes and Sertoli cells. The different cell relations were also analyzed. Germ cell apoptosis was quantified using the TUNEL method. The apoptotic index (AI) was calculated as the number of apoptotic cells per tubule. Statistical analysis was performed by analysis of variance considering P < 0.05.<br><br>RESULTS: The absolute and true cell counts were similar among the groups (P > 0.05). The round spermatid/pachytene ratio was significantly smaller in Groups 2 and 3 compared to the Group 1 (P = 0.012). The AI values were 0.207 &#xb1; 0.09, 0.138 &#xb1; 0.11 and 0.298 &#xb1; 0.27, respectively (P = 0.256).<br><br>CONCLUSION: Experimental varicocele in rats presented an association with the decreased round spermatid/pachytene ratio, suggesting the loss of germ cells during spermatogenesis. These effects were not influenced by the administration of NAC. Germ cell apoptosis was not influenced by experimental varicocele.}, }
@article {pmid20011538, year = {2009}, author = {Lu, D and Liu, JX and Endo, T and Zhou, H and Yao, S and Willert, K and Schmidt-Wolf, IG and Kipps, TJ and Carson, DA}, title = {Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway.}, journal = {PloS one}, volume = {4}, number = {12}, pages = {e8294}, pmid = {20011538}, issn = {1932-6203}, support = {U19 CA113318/CA/NCI NIH HHS/United States ; P01 CA081534/CA/NCI NIH HHS/United States ; CA81534-06/CA/NCI NIH HHS/United States ; CA113318-01/CA/NCI NIH HHS/United States ; P01-CA081534/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclin D1/genetics/metabolism ; Drug Screening Assays, Antitumor ; Ethacrynic Acid/*toxicity ; Fibronectins/genetics/metabolism ; Frizzled Receptors/genetics/metabolism ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics/*metabolism/*pathology ; Lymphoid Enhancer-Binding Factor 1/genetics/metabolism ; Protein Binding/drug effects ; Receptors, G-Protein-Coupled/genetics/metabolism ; Signal Transduction/*drug effects ; Wnt Proteins/*metabolism ; beta Catenin/*metabolism ; }, abstract = {BACKGROUND: Aberrant activation of Wnt/beta-catenin signaling promotes the development of several cancers. It has been demonstrated that the Wnt signaling pathway is activated in chronic lymphocytic leukemia (CLL) cells, and that uncontrolled Wnt/beta-catenin signaling may contribute to the defect in apoptosis that characterizes this malignancy. Thus, the Wnt signaling pathway is an attractive candidate for developing targeted therapies for CLL.<br><br>The diuretic agent ethacrynic acid (EA) was identified as a Wnt inhibitor using a cell-based Wnt reporter assay. In vitro assays further confirmed the inhibitory effect of EA on Wnt/beta-catenin signaling. Cell viability assays showed that EA selectively induced cell death in primary CLL cells. Exposure of CLL cells to EA decreased the expression of Wnt/beta-catenin target genes, including LEF-1, cyclin D1 and fibronectin. Immune co-precipitation experiments demonstrated that EA could directly bind to LEF-1 protein and destabilize the LEF-1/beta-catenin complex. N-acetyl-L-cysteine (NAC), which can react with the alpha, beta-unsaturated ketone in EA, but not other anti-oxidants, prevented the drug's inhibition of Wnt/beta-catenin activation and its ability to induce apoptosis in CLL cells.<br><br>CONCLUSIONS/SIGNIFICANCE: Our studies indicate that EA selectively suppresses CLL survival due to inhibition of Wnt/beta-catenin signaling. Antagonizing Wnt signaling in CLL with EA or related drugs may represent an effective treatment of this disease.}, }
@article {pmid20010244, year = {2009}, author = {Ozdemir, G and Tolun, FI and Gul, M and Imrek, S}, title = {Retinal oxidative stress induced by intraocular hypertension in rats may be ameliorated by brimonidine treatment and N-acetyl cysteine supplementation.}, journal = {Journal of glaucoma}, volume = {18}, number = {9}, pages = {662-665}, doi = {10.1097/IJG.0b013e31819c46b1}, pmid = {20010244}, issn = {1536-481X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Brimonidine Tartrate ; Catalase/metabolism ; Disease Models, Animal ; Drug Therapy, Combination ; Glutathione Peroxidase/metabolism ; Hyaluronic Acid/toxicity ; Intraocular Pressure/drug effects ; Male ; Malondialdehyde/metabolism ; Nitric Oxide/metabolism ; Ocular Hypertension/chemically induced/metabolism/*prevention &amp; control ; Oxidative Stress/*drug effects ; Quinoxalines/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Retinal Diseases/etiology/metabolism/*prevention &amp; control ; Tonometry, Ocular ; }, abstract = {PURPOSE: To investigate the effect of brimonidine and N-acetyl cysteine (NAC) on retinal oxidative status under ocular hypertension.<br><br>MATERIALS AND METHODS: Ocular hypertension is produced in right eyes of 60 rats through intraocular injection of sodium hyaluronate. The left eyes received intracameral saline as sham. Twenty right eyes (brimonidine group) received topical brimonidine twice a day for a week. Other 20 eyes received intraperitoneal NAC (NAC group) once a day. Another group of 20 eyes were followed without any drugs but only intracameral sodium hyaluronate (sodium hyaluronate group) into right eyes.<br><br>RESULTS: Intraocular injection of sodium hyaluronate increased intraocular pressure for a week and caused retinal peroxidation and decreased glutathione peroxidase and catalase levels. Brimonidine and NAC treatment reversed the retinal oxidative stress created by high intraocular pressure.<br><br>CONCLUSIONS: Brimonidine and NAC supplementation provide antioxidative properties to retina and decrease retinal damage induced by ocular hypertension.}, }
@article {pmid20009148, year = {2009}, author = {Rymarz, A and Durlik, M and Rydzewski, A}, title = {Intravenous administration of N-acetylcysteine reduces plasma total homocysteine levels in renal transplant recipients.}, journal = {Annals of transplantation}, volume = {14}, number = {4}, pages = {5-9}, pmid = {20009148}, issn = {2329-0358}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Analysis of Variance ; Creatinine/blood ; Cross-Over Studies ; Female ; Fluorescence Polarization Immunoassay ; Homocysteine/*blood ; Humans ; Hyperhomocysteinemia/*drug therapy/*etiology ; Kidney Transplantation/*adverse effects ; Male ; Middle Aged ; Patient Selection ; }, abstract = {BACKGROUND: Hyperhomocysteinemia occurs in approximately 60-70% of renal transplant recipients and is associated with increased risk of cardiovascular events, mortality and kidney allograft loss. In normal subjects N-acetylcysteine (NAC) given either orally or intravenously markedly reduces plasma total homocysteine (tHcy) level. In cardiac transplant recipients it was reported, that oral treatment with NAC does not affect Hcy levels. We have therefore, investigated the effect of intravenous NAC on plasma tHcy levels in renal transplant recipients.<br><br>MATERIAL/METHODS: Eleven renal transplant recipients who had normal plasma levels of vitamin B12 and folic acid, were treated with intravenous NAC or placebo in a crossover manner.<br><br>RESULTS: Intravenous administration of NAC significantly reduced plasma tHcy (p=0.0008). Decrease in tHcy was related to its initial concentration.<br><br>CONCLUSIONS: Intravenous NAC profoundly reduces tHcy level in renal transplant recipients. Further research is needed to establish the effect of orally administered NAC on plasma homocysteine concentration in this clinical condition.}, }
@article {pmid20009135, year = {2009}, author = {Sotelo, N and de los Angeles Durazo, M and Gonzalez, A and Dhanakotti, N}, title = {Early treatment with N-acetylcysteine in children with acute liver failure secondary to hepatitis A.}, journal = {Annals of hepatology}, volume = {8}, number = {4}, pages = {353-358}, pmid = {20009135}, issn = {1665-2681}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Adolescent ; Alanine Transaminase/blood ; Anti-Bacterial Agents/therapeutic use ; Antiviral Agents/administration &amp; dosage/*therapeutic use ; Aspartate Aminotransferases/blood ; Child ; Drug Therapy, Combination ; Female ; Gastrointestinal Agents/therapeutic use ; Hepatitis A/blood/*complications/*drug therapy ; Humans ; Lactulose/therapeutic use ; Liver Failure, Acute/blood/*drug therapy/*etiology ; Male ; Mexico ; Neomycin/therapeutic use ; Prothrombin Time ; Retrospective Studies ; Treatment Outcome ; }, abstract = {INTRODUCTION: Hepatitis A virus can evolve to acute liver failure with a fatal outcome if it is not reversed.<br><br>OBJECTIVE: We describe the clinical course of 12 children who presented with hepatitis A acute liver failure and received treatment with oral N-acetylcysteine (NAC).<br><br>MATERIALS AND METHODS: Of the seventy-two patients with viral hepatitis A, 12 patients who had acute hepatic failure were included. The variables evaluated were age, sex, duration of clinical features prior to hospitalization, signs and symptoms, laboratory parameters [alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin time (PT), partial thromboplastin time (PTT), internal normalization ratio and ammonia], treatment (oral NAC 100 mg/kg/day, lactulose, neomycin and general measures) and clinical course during hospitalization.<br><br>RESULTS: Six males and six females were included. School-aged and adolescent children predominated. All presented with jaundice, nausea, vomiting and hepatomegaly. Two had stage 2 neurological signs as per the West-Haven scale. All had altered laboratory parameters. All received NAC, six patients for a week and the remaining six for 9-36 days. Treatment was not ceased until patients showed clinical and laboratory improvement. All data were analyzed using both student's t test and Wilcoxon signed rank with alpha = 0.05, the ALT with P = 0.0003 and 0.005, AST with P = 0.0001 and 0.0005, PT with P = 0.0237 and 0.0005, PTT with P = 0.0515 and 0.0039, ammonia with P = 0.0197 and 0.0015 and direct bilirubin with P = 0.0190 and 0.068. There was good tolerance to medications and a satisfactory clinical course.<br><br>DISCUSSION: The use of oral NAC appears to be an effective therapeutic alternative for hepatitis A-induced liver failure if it is offered appropriately. It can modify the clinical course to a favorable one and prevent the fatal outcome of hepatic encephalopathy.}, }
@article {pmid20008542, year = {2010}, author = {Varani, K and Caramori, G and Vincenzi, F and Tosi, A and Barczyk, A and Contoli, M and Casolari, P and Triggiani, M and Hansel, T and Leung, E and Maclennan, S and Barnes, PJ and Chung, KF and Adcock, I and Papi, A and Borea, PA}, title = {Oxidative/nitrosative stress selectively altered A(2B) adenosine receptors in chronic obstructive pulmonary disease.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {24}, number = {4}, pages = {1192-1204}, doi = {10.1096/fj.09-139485}, pmid = {20008542}, issn = {1530-6860}, mesh = {Acetylcysteine/pharmacology ; Adenosine A2 Receptor Agonists ; Adenosine A2 Receptor Antagonists ; Adenosine-5'-(N-ethylcarboxamide)/pharmacology ; Aged ; Bronchoalveolar Lavage ; Cell Proliferation/drug effects ; Cyclic AMP/genetics/metabolism ; Cytokines/metabolism/pharmacology ; *Down-Regulation ; Female ; Free Radical Scavengers/pharmacology ; Gene Knockdown Techniques ; Humans ; Macrophages, Alveolar/*metabolism/pathology ; Male ; Middle Aged ; *Oxidative Stress ; Pulmonary Disease, Chronic Obstructive/genetics/*metabolism/pathology/therapy ; RNA, Small Interfering/pharmacology ; Receptor, Adenosine A2B/*biosynthesis/genetics ; Smoking/metabolism/pathology ; U937 Cells ; Vasodilator Agents/pharmacology ; }, abstract = {The primary aim of this study was to investigate adenosine receptors (ARs) in bronchoalveolar lavage (BAL) macrophages from patients with chronic obstructive pulmonary disease (COPD) and age-matched healthy smokers. A(2B)ARs were significantly decreased in BAL macrophages from patients with COPD when compared with healthy smokers. The effect of proinflammatory cytokines and oxidative/nitrosative stress on AR expression and function in U937 cells before and after PMA treatment was evaluated. IL-1beta and TNF-alpha treatment up-regulated A(2A)- and A(3)ARs but not A(1)- or A(2B)ARs, whereas IL-6 did not modify AR expression. In contrast, oxidative/nitrosative stress selectively decreased A(2B)AR expression, which was associated with a reduction in the potency of the adenosine agonist 5'-N-ethylcarboxamideadenosine (NECA) to induce cAMP. Further, the ability of NECA to enhance cell proliferation was increased after oxidative/nitrosative stress. The specific involvement of A(2B)ARs was investigated by using potent and selective A(2B)AR antagonist and by A(2B)AR knockdown using siRNA and demonstrated responses similar to those obtained with oxidative/nitrosative stress. N-acetylcysteine (NAC), an antioxidant agent, counteracted the decrease in A(2B)AR expression, as well as the altered NECA effects on cAMP and cell proliferation. These findings highlight the central role of A(2B)ARs in alveolar macrophages, suggesting that their modulation could represent an innovative pharmacological strategy to manage COPD.-Varani, K., Caramori, G., Vincenzi, F., Tosi, A., Barczyk, A., Contoli, M., Casolari, P., Triggiani, M., Hansel, T., Leung, E., MacLennan, S., Barnes, P. J., Fan Chung, K., Adcock, I., Papi, A., Borea, P. A. Oxidative/nitrosative stress selectively altered A(2B) adenosine receptors in chronic obstructive pulmonary disease.}, }
@article {pmid20006194, year = {2010}, author = {Abu-Kishk, I and Kozer, E and Goldstein, LH and Weinbaum, S and Bar-Haim, A and Alkan, Y and Petrov, I and Evans, S and Siman-Tov, Y and Berkovitch, M}, title = {Oral N-acetylcysteine has a deleterious effect in acute iron intoxication in rats.}, journal = {The American journal of emergency medicine}, volume = {28}, number = {1}, pages = {8-12}, doi = {10.1016/j.ajem.2008.09.012}, pmid = {20006194}, issn = {1532-8171}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Disease ; Administration, Oral ; Animals ; Antidotes/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Disease Models, Animal ; Gastrointestinal Tract/drug effects ; Glutathione/metabolism ; Iron/metabolism/*poisoning ; Liver/drug effects/metabolism ; Male ; Rats ; Rats, Wistar ; }, abstract = {Acute iron intoxication is associated with depletion of reduced glutathione in hepatocytes and changes in the glutathione system enzymes. We hypothesized that treatment with N-acetylcysteine (NAC), a glutathione reducing agent and an antioxidant, would reduce mortality in acute iron intoxication. We used a rat model to test this hypothesis. Male rats were assigned to 4 groups. Group 1 received 400 mg/kg elemental iron by oral gavage, group 2 received the same dose of iron followed by NAC, group 3 received NAC only, whereas group 4 received distilled water. Iron and liver transaminases in the blood, and glutathione system enzymes in the liver and erythrocytes were measured. Mortality in group 2 was significantly higher after 2, 6, and 24 hours compared with group 1 (P < .001). No deaths were observed in groups 3 and 4. Serum iron levels were significantly higher in group 2 rats compared to group 1 rats (P < .001). Hepatic and erythrocyte glutathione system enzymes were significantly lower among rats in group 2 compared to rats in group 1. The administration of NAC probably increased the absorption of iron through the gastrointestinal tract, causing higher serum iron levels with significant hepatic damage. These results indicate that in a rat model of acute iron intoxication, orally administered NAC may increase mortality.}, }
@article {pmid20005406, year = {2009}, author = {Gulbahar, O and Aricioglu, A and Akmansu, M and Turkozer, Z}, title = {Effects of radiation on protein oxidation and lipid peroxidation in the brain tissue.}, journal = {Transplantation proceedings}, volume = {41}, number = {10}, pages = {4394-4396}, doi = {10.1016/j.transproceed.2009.09.076}, pmid = {20005406}, issn = {1873-2623}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/drug effects/*physiology/radiation effects ; Guinea Pigs ; Lipid Peroxidation/drug effects/*physiology/radiation effects ; Male ; Malondialdehyde/metabolism ; Nerve Tissue Proteins/drug effects/*metabolism/radiation effects ; Oxidation-Reduction ; Radiation Protection/methods ; Radiation-Protective Agents/*pharmacology ; }, abstract = {Radiation produces reactive oxygen species that modify macromolecules such as protein and lipid by oxidation and act in many pathological processes, causing serious damage to the brain. This study sought to evaluate the effects of radiation and the protective effect of N-acetylcysteine (NAC) on the brain tissue of guinea pigs based on the levels of lipid peroxidation and protein oxidation. Thirty-two guinea pigs were divided into groups of eight animals each: control group (group I); radiation group (group II); NAC group (group III), and NAC administered before radiation exposure group; (group IV). Guinea pigs in groups II and IV were exposed to Co(60) radiotherapy using the Source-Axis-Distance = 80 technique. The levels of protein carbonyl content and malondialdehyde (MDA), which is a marker for lipid peroxidation, were investigated by the Evans-Levine and Uchiyama-Mihara methods, respectively. The protein carbonyl and MDA levels of group II were significantly greater than those of group I (P < .01). The protein carbonyl and MDA levels of group IV were lower than those of group II. The difference between the MDA levels of group IV and group II was significant (P < .01); however, the difference in protein carbonyl levels between the two groups was not significant. The results indicated that radiation increased protein oxidation and lipid peroxidation in the brain, and NAC administration before radiation exposure may aid in the treatment by decreasing protein and lipid oxidation.}, }
@article {pmid20004343, year = {2009}, author = {Seiva, FR and Amauchi, JF and Rocha, KK and Ebaid, GX and Souza, G and Fernandes, AA and Cataneo, AC and Novelli, EL}, title = {Alcoholism and alcohol abstinence: N-acetylcysteine to improve energy expenditure, myocardial oxidative stress, and energy metabolism in alcoholic heart disease.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {43}, number = {8}, pages = {649-656}, doi = {10.1016/j.alcohol.2009.09.028}, pmid = {20004343}, issn = {1873-6823}, mesh = {Acetylcysteine/*pharmacology ; Alcoholism/*metabolism ; Animals ; Energy Metabolism/*drug effects ; Heart Diseases/*metabolism ; Male ; Myocardium/*metabolism ; Oxidative Stress/*drug effects ; Oxygen Consumption ; Rats ; Rats, Wistar ; *Temperance ; }, abstract = {Alcoholism has been associated with a wide range of pathologic conditions, including alcoholic heart disease (AHD). Because AHD may be associated with oxidative stress, antioxidant compounds, such as N-acetylcysteine (NAC) could be useful to control the damage done by alcohol (ethanol) consumption. To investigate the NAC effects on alcoholism and alcohol abstinence, initially, 30 male Wistar rats were divided into two groups: (C, N=6) given standard chow and water; (E, N=24) receiving standard chow and aqueous ethanol solution in semi-voluntary research. After 30 days of ethanol-exposure, (E) group was divided into four subgroups (N=6/group):(E-E) continued drinking 30% ethanol-solution; (E-NAC) drinking ethanol-solution containing 2g/L NAC; (AB) changed ethanol solution to water; (AB-NAC) changed ethanol to aqueous solution of 2g/L NAC. After 15 days of the E-group division, E-E rats had lower body weight and feed efficiency, as well as higher energy-expenditure resting metabolic rate (RMR)/body weight and VO(2) consumption/surface area. These calorimetric changes were reflected on the cardiac tissue. E-E rats had higher heart weight/body weight ratio and myocardial lipid hydroperoxide (LH), indicating AHD with hypertrophy and oxidative stress. Myocardial superoxide dismutase was higher, whereas glutathione-peroxidase (GSH-peroxidase) was lower in E-E rats than in C. The higher myocardial hydroxyacyl coenzyme-A dehydrogenase (OHADH), OHADH/citrate synthase (CS), and lactate dehydrogenase (LDH)/CS in E-E rats indicated higher fatty acid degradation relative to aerobic metabolism predisposing the lipotoxicity. AB rats had lower RMR/body weight than E-E, normalized myocardial oxidative stress, and energy metabolism. E-NAC and AB-NAC had lower RMR/body weight, myocardial LH, LDH/CS, and higher GSH-peroxidase than E-E and AB, respectively, demonstrating lower oxidative stress and higher myocardial carbohydrate oxidation. In conclusion, the present study brought new insights on alcohol consumption and AHD because ethanol-exposure enhanced energy-expenditure and induced a number of calorimetric changes, which were reflected in body weight and myocardial lipotoxicity. NAC preventing ethanol-induced calorimetric changes and reducing myocardial oxidative stress enhanced carbohydrate oxidation, thus optimizing myocardial energy metabolism in both alcoholic and abstinence condition.}, }
@article {pmid19968960, year = {2010}, author = {Lee, EK and Jeon, WK and Chae, MY and Hong, HY and Lee, YS and Kim, JH and Kwon, JY and Kim, BC and Park, SH}, title = {Decreased expression of glutaredoxin 1 is required for transforming growth factor-beta1-mediated epithelial-mesenchymal transition of EpRas mammary epithelial cells.}, journal = {Biochemical and biophysical research communications}, volume = {391}, number = {1}, pages = {1021-1027}, doi = {10.1016/j.bbrc.2009.12.009}, pmid = {19968960}, issn = {1090-2104}, mesh = {Animals ; Cell Line ; Cell Transformation, Neoplastic/metabolism/*pathology ; Down-Regulation ; Epithelial Cells/drug effects/metabolism/*pathology ; Glutaredoxins/*biosynthesis/genetics ; MAP Kinase Kinase Kinases/metabolism ; Mammary Glands, Animal/metabolism/*pathology ; Mesoderm/metabolism/*pathology ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/*metabolism/pharmacology ; }, abstract = {Transforming growth factor-beta (TGF-beta) is a cytokine important in inducing epithelial-mesenchymal transition (EMT), a crucial morphological event in a wide range of physiological and pathological cellular processes. In this study, we demonstrate that TGF-beta1 induces the EMT phenotype through decreasing the expression of the glutaredoxin 1 (Grx1) gene, an anti-oxidant enzyme, in H-Ras transformed EpH4 mammary epithelial cells (EpRas), but not in the parental EpH4 cells. TGF-beta1-induced reduction of Grx1 expression caused an increase of intracellular reactive oxygen species (ROS) in EpRas cells, and pre-treatment of the ROS scavenger N-acetylcysteine (NAC) inhibited TGF-beta1-induced EMT. Grx1-overexpressing EpRas cells showed a reduction in intracellular ROS generation and suppressed the expression of mesenchymal markers upon treatment of TGF-beta1. In addition, MEK/MAP kinase and phosphatidylinositol-3 kinase (PI3K) signaling were found to mediate the decrease in Grx1 expression upon TGF-beta1 treatment, depending on the presence of Ras protein. Thus our findings strongly suggest that TGF-beta1 promotes EMT by increasing intracellular ROS levels via down-regulation of the Grx1 gene in EpRas cells.}, }
@article {pmid19967420, year = {2010}, author = {Kerksick, CM and Kreider, RB and Willoughby, DS}, title = {Intramuscular adaptations to eccentric exercise and antioxidant supplementation.}, journal = {Amino acids}, volume = {39}, number = {1}, pages = {219-232}, doi = {10.1007/s00726-009-0432-7}, pmid = {19967420}, issn = {1438-2199}, mesh = {Acetylcysteine/*administration &amp; dosage ; *Adaptation, Physiological ; Adult ; Antioxidants/*administration &amp; dosage ; Catechin/administration &amp; dosage/*analogs &amp; derivatives ; Dietary Supplements ; Double-Blind Method ; Exercise/*physiology ; Exercise Test ; Humans ; Male ; Muscle Contraction/physiology ; Muscle, Skeletal/*physiology ; Young Adult ; }, abstract = {Prophylactic supplementation of N-acetyl-cysteine (NAC) and epigallocatechin gallate (EGCG) was studied for physiological and cellular changes in skeletal muscle after eccentric muscle contractions. Thirty healthy, active males (20.0 +/- 1.8 years, 160 +/- 7.1 cm, 76.1 +/- 17.0 kg) ingested for 14 days either 1,800 mg of NAC, 1,800 mg of EGCG, or 1,000 mg of fiber (glucomannan) placebo (PLC) in a double blind, prophylactic fashion. Subjects completed one eccentric exercise bout (100 repetitions at 30 degrees /s) using the dominant knee extensors. Strength and soreness were assessed, and blood and muscle samples obtained before and 6, 24, 48, and 72 h with no muscle sample being collected at 72 h. Separate mixed factorial repeated measures ANOVA (P < 0.05) were used for all statistical analysis. All groups experienced significantly reduced peak torque production after 6 and 24 h, increased soreness at all time points from baseline [with even greater soreness levels 24 h after exercise in PLC when compared to EGCG and NAC (P < 0.05)], increased lactate dehydrogenase at 6 h, and increased creatine kinase 6, 24 and 48 h after exercise. No significant group x time interaction effects were found for serum cortisol, neutrophil counts, and the neutrophil:lymphocyte ratio; although, all values experienced significant changes 6 h after exercise (P < 0.05), but at no other time points. At 48 h after the exercise bout the Neu:Lym ratio in EGCG was significantly less than NAC (P < 0.05), whereas there was a trend (P = 0.08) for the EGCG values to be less when compared to PLC at this time point. Markers of intramuscular mitochondrial and cytosolic apoptosis were assessed (e.g., bax, bcl-2, cytochrome C, caspase-3 content/enzyme activity, and total DNA content). Significant increases (P < 0.05) in muscle levels of bax and bcl-2 were observed in all groups with no significant differences between groups, whereas no changes (P > 0.05) were reported for cytochrome C, caspase-3 content, caspase-3 enzyme activity, and total DNA. Caspase-3 enzyme activity was significantly greater in all groups 48 h after exercise when compared to baseline (P < 0.05) and 6 h (P < 0.05) after exercise. An eccentric bout of muscle contractions appears to significantly increase muscle damage, markers of mitochondrial apoptosis, apoptotic enzyme activity, and whole-blood cell markers of inflammation with no changes in oxidative stress. While soreness ratings were blunted in the two supplementation groups 24 h after exercise when compared to PLC values, more research is needed to determine the potential impact of EGCG and NAC supplementation on changes related to oxidative stress, apoptosis, and eccentric exercise.}, }
@article {pmid19966593, year = {2010}, author = {Morrison, BW and Doudican, NA and Patel, KR and Orlow, SJ}, title = {Disulfiram induces copper-dependent stimulation of reactive oxygen species and activation of the extrinsic apoptotic pathway in melanoma.}, journal = {Melanoma research}, volume = {20}, number = {1}, pages = {11-20}, doi = {10.1097/CMR.0b013e328334131d}, pmid = {19966593}, issn = {1473-5636}, mesh = {Apoptosis/*drug effects ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Copper/metabolism ; Copper Sulfate/*pharmacology ; Disulfiram/*pharmacology ; Humans ; Melanoma/*drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Skin Neoplasms/*drug therapy/metabolism/pathology ; }, abstract = {Melanoma is the most aggressive and deadly form of skin cancer. The current standard of care produces response rates of less than 20%, underscoring the critical need for identification of new effective, nontoxic therapies. Disulfiram (DSF) was identified using a drug screen as one of the several compounds that preferentially decreased proliferation in multiple melanoma subtypes compared with benign melanocytes. DSF, a member of the dithiocarbamate family, is a copper (Cu) chelator, and Cu has been shown previously to enhance DSF-mediated growth inhibition and apoptosis in cancer cells. Here, we report that in the presence of free Cu, DSF inhibits cellular proliferation and induces apoptosis in a panel of cell lines representing primary and metastatic nodular and superficial spreading melanoma. Both decreased cellular proliferation and increased apoptosis were seen at 50-500 nmol/l DSF concentrations that are achievable through oral dosing of the medication. In the presence of Cu, DSF caused activation of the extrinsic pathway of apoptosis as measured by caspase-8 cleavage. The addition of Z-IETD-FMK, a selective caspase-8 inhibitor, was protective against DSF-Cu-induced apoptosis. Production of reactive oxygen species (ROS) in response to DSF-Cu treatment preceded the induction of apoptosis. Both ROS production and apoptosis were prevented by coincubation of N-acetyl cysteine, a free radical scavenger. Our study shows that DSF might be used to target both nodular and superficial spreading melanoma through ROS production and activation of the extrinsic pathway of apoptosis.}, }
@article {pmid19965809, year = {2010}, author = {Moon, C and Lee, YJ and Park, HJ and Chong, YH and Kang, JL}, title = {N-acetylcysteine inhibits RhoA and promotes apoptotic cell clearance during intense lung inflammation.}, journal = {American journal of respiratory and critical care medicine}, volume = {181}, number = {4}, pages = {374-387}, doi = {10.1164/rccm.200907-1061OC}, pmid = {19965809}, issn = {1535-4970}, mesh = {Acetylcysteine/*pharmacology ; Amides/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Blotting, Western ; Cell Line ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; L-Lactate Dehydrogenase/metabolism ; Macrophages, Alveolar/physiology ; Male ; Mice ; Mice, Inbred BALB C ; NF-kappa B/physiology ; Pneumonia/drug therapy/pathology/*physiopathology ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis ; rho-Associated Kinases/antagonists &amp; inhibitors/metabolism ; rhoA GTP-Binding Protein/*antagonists &amp; inhibitors ; }, abstract = {RATIONALE: The resolution of pulmonary inflammation seen in various inflammatory lung conditions depends on the clearance of apoptotic cells to prevent permanent tissue damage or progressive disease. Uptake of apoptotic cells by alveolar macrophages is suppressed by oxidants through the activation of Rho signaling.<br><br>OBJECTIVES: We hypothesized that antioxidant exposure would increase the ability of alveolar macrophages to clear pulmonary apoptotic cells through the inhibition of RhoA.<br><br>METHODS: The effects of the antioxidant N-acetylcysteine (NAC) on the pulmonary immune response were seen in mice treated intratracheally with LPS, LPS + NAC, or saline. Apoptotic cell clearance, RhoA activity, and changes in the lung inflammatory responses were analyzed in vivo or ex vivo.<br><br>MEASUREMENTS AND MAIN RESULTS: Neutrophil accumulation, apoptosis, necrosis, and oxidant production peaked at 3 days post LPS treatment. NAC enhanced the clearance of apoptotic cells and inhibited RhoA activity in alveolar macrophages at 3 days post LPS treatment. NAC suppressed LPS-induced proinflammatory mediators, enhanced the production of transforming growth factor-beta1, reduced the accumulation of inflammatory cells, and reduced levels of protein and lactate dehydrogenase in bronchoalveolar lavage fluid. In the presence of ex vivo apoptotic cells, alveolar macrophages exposed to LPS or LPS + NAC had reduced tumor necrosis factor-alpha levels and increased transforming growth factor-beta1 levels. A Rho kinase inhibitor mimicked the effects of NAC on the clearance of apoptotic cells and the inflammatory responses.<br><br>CONCLUSIONS: These results indicate that NAC can expedite the resolution of LPS-induced pulmonary inflammation through the inhibition of RhoA activity and the enhancement of apoptotic cell clearance.}, }
@article {pmid19962414, year = {2010}, author = {Kim, SY and Woo, MS and Park, JS and Kim, HS}, title = {Regulation of matrix metalloproteinase-9 gene expression in MPP+- or 6-OHDA-treated human neuroblastoma SK-N-BE(2)C cells.}, journal = {Neurochemistry international}, volume = {56}, number = {3}, pages = {437-442}, doi = {10.1016/j.neuint.2009.11.019}, pmid = {19962414}, issn = {1872-9754}, mesh = {1-Methyl-4-phenylpyridinium/antagonists &amp; inhibitors/toxicity ; Animals ; Cell Line ; Enzyme Inhibitors/*pharmacology/therapeutic use ; Gene Expression Regulation, Enzymologic/drug effects/physiology ; Humans ; Matrix Metalloproteinase 9/drug effects/genetics/*metabolism ; Mice ; NF-kappa B/drug effects/metabolism ; Neurons/drug effects/*enzymology/pathology ; Neurotoxins/antagonists &amp; inhibitors/*toxicity ; Oxidative Stress/drug effects/physiology ; Oxidopamine/antagonists &amp; inhibitors/toxicity ; Parkinson Disease/drug therapy/*enzymology/genetics ; Phosphatidylinositol 3-Kinases/drug effects/metabolism ; Promoter Regions, Genetic/drug effects/genetics ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/genetics ; Substantia Nigra/drug effects/enzymology/physiopathology ; Transcription Factor AP-1/drug effects/metabolism ; Transcriptional Activation/drug effects/genetics ; Tumor Cells, Cultured ; p38 Mitogen-Activated Protein Kinases/drug effects/metabolism ; }, abstract = {The aberrant expression of matrix metalloproteinases (MMPs) is known to play an important role in various neurodegenerative diseases, such as Parkinson's disease. In the present study, we found that two well-known dopaminergic neurotoxins, 6-OHDA and MPP(+), induced the expression of MMP-9 in SK-N-BE(2)C human neuroblastoma and Cath.a mouse dopaminergic cell lines. Treatment with MMP-9 inhibitors attenuated the neuronal cell death induced by either 6-OHDA or MPP(+), suggesting that MMP-9 plays an important role in this neurotoxin-mediated cell death. Further mechanistic studies showed that 6-OHDA and MPP(+) increased MMP-9 gene expression by inducing NF-kappaB and AP-1 binding to the MMP-9 promoter. Reactive oxygen species (ROS) appeared to be involved in MMP-9 expression because treatment with the free radical scavenger, N-acetylcysteine (NAC), suppressed both 6-OHDA- and MPP(+)-induced MMP-9 promoter activities. Treatment with several signaling pathway-specific inhibitors revealed that the PI3 kinase inhibitor, LY294002, suppressed 6-OHDA- and MPP(+)-induced MMP-9 promoter activities, whereas the p38 MAPK inhibitor, SB203580, inhibited 6-OHDA-, but not MPP(+)-induced promoter activity. These results collectively suggest that ROS, PI3 kinase, NF-kappaB, and AP-1 are commonly involved in 6-OHDA- and MPP(+)-induced MMP-9 gene expression, and that p38 MAPK is differentially involved. Therefore, controlling MMP-9 expression may have therapeutic potential in Parkinson's disease, which is caused by various neurotoxins, such as 6-OHDA and MPP(+).}, }
@article {pmid19961160, year = {2010}, author = {Chen, H and Grover, S and Yu, L and Walker, G and Mutlib, A}, title = {Bioactivation of lamotrigine in vivo in rat and in vitro in human liver microsomes, hepatocytes, and epidermal keratinocytes: characterization of thioether conjugates by liquid chromatography/mass spectrometry and high field nuclear magnetic resonance spectroscopy.}, journal = {Chemical research in toxicology}, volume = {23}, number = {1}, pages = {159-170}, doi = {10.1021/tx9003243}, pmid = {19961160}, issn = {1520-5010}, mesh = {Administration, Oral ; Animals ; Anticonvulsants/chemistry/*metabolism/pharmacology ; Aryl Hydrocarbon Hydroxylases/metabolism ; Cell Line ; Chromatography, High Pressure Liquid ; Cytochrome P-450 CYP2A6 ; Cytochrome P450 Family 2 ; Female ; Glutathione/metabolism ; Hepatocytes/*metabolism ; Humans ; Keratinocytes/*metabolism ; Kinetics ; Lamotrigine ; Magnetic Resonance Spectroscopy ; Male ; Microsomes, Liver/*metabolism ; Molecular Conformation ; Rats ; Spectrometry, Mass, Electrospray Ionization ; Steroid 16-alpha-Hydroxylase/metabolism ; Sulfides/chemistry ; Triazines/chemistry/*metabolism/pharmacology ; }, abstract = {Previous studies suggested that lamotrigene (LTG) underwent bioactivation to a reactive aryl epoxide intermediate in rats. Nevertheless, definitive structures of these thioether conjugates, which are often needed to substantiate the mechanism of bioactivation and identity of reactive intermediate(s), were not fully established. In the present study, GSH, cysteinylglycine, and N-acetyl cysteine conjugates of LTG were isolated from bile of rats orally dosed with LTG (100 mg/kg), and their structures were fully elucidated by LC/MS and NMR. The definitive structural characterization of these metabolites provided evidence for the existence of a reactive aryl epoxide that was trapped as a GSH adduct. In vitro studies using various hepatic cellular and subcellular fractions obtained from human and rat were performed to demonstrate that LTG underwent bioactivation to form a GSH conjugate that was identical to the one initially characterized from in vivo studies. Human P450 2A6 and rat P450 2C11 appeared to be the primary enzymes activating LTG in human and rat liver microsomes, respectively. Interindividual variation in the bioactivation of LTG was demonstrated with 20 individual human liver microsomes. Furthermore, it was shown that human epidermal keratinocytes were capable of forming the same GSH conjugate, suggesting that LTG could be bioactivated in skin cells. The results from these studies suggest that LTG has the potential to undergo hepatic and nonhepatic bioactivation, leading to a reactive aryl epoxide intermediate in human. The bioactivation of LTG in epidermal cells provides a possible explanation for the idiosyncratic cutaneous reactions associated with LTG therapy.}, }
@article {pmid19960046, year = {2009}, author = {Al-Tonbary, Y and Al-Haggar, M and El-Ashry, R and El-Dakroory, S and Azzam, H and Fouda, A}, title = {Vitamin e and N-acetylcysteine as antioxidant adjuvant therapy in children with acute lymphoblastic leukemia.}, journal = {Advances in hematology}, volume = {2009}, number = {}, pages = {689639}, pmid = {19960046}, issn = {1687-9112}, abstract = {Although cancer therapies have experienced great success nowadays, yet the associated toxic response and free radicals formation have resulted in significant number of treatment-induced deaths rather than disease-induced fatalities. Complications of chemotherapy have forced physicians to study antioxidant use as adjunctive treatment in cancer. This study aimed to evaluate the antioxidant role of vitamin E and N-acetyl cysteine (NAC) in overcoming treatment-induced toxicity in acute lymphoblastic leukaemia (ALL) during the intensive period of chemo-/radiotherapy, almost the first two months of treatment. Forty children newly diagnosed with ALL were enrolled in this study. Twenty children (group I) have taken vitamin E and NAC supplementations with chemotherapy and the other twenty children (group II) have not taken any adjuvant antioxidant therapy. They were evaluated clinically for the occurrence of complications and by the laboratory parameters (blood levels of glutathione peroxidase (Glu.PX) antioxidant enzyme, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-alpha), liver enzymes, and bone marrow picture). Results revealed reduced chemotherapy and radiotherapy toxicity as evidenced by decreasing level of MDA, increasing level of Glu.Px and decreased occurrence of toxic hepatitis, haematological complications, and need for blood and platelet transfusions in group I compared to group II. We can conclude that vitamin E and NAC have been shown to be effective as antioxidant adjuvant therapy in children with ALL to reduce chemo-/radiotherapy-related toxicities during the initial period of treatment.}, }
@article {pmid19956894, year = {2010}, author = {Han, YH and Moon, HJ and You, BR and Kim, SZ and Kim, SH and Park, WH}, title = {Pyrogallol-induced endothelial cell death is related to GSH depletion rather than ROS level changes.}, journal = {Oncology reports}, volume = {23}, number = {1}, pages = {287-292}, pmid = {19956894}, issn = {1791-2431}, mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis ; Cattle ; Cell Proliferation ; Endothelial Cells/*drug effects ; *Gene Expression Regulation ; Glutathione/*metabolism ; Humans ; Membrane Potentials ; Mitochondria/metabolism ; Oxygen/chemistry ; Pyrogallol/*pharmacology ; *Reactive Oxygen Species ; Umbilical Veins/cytology ; }, abstract = {Pyrogallol (PG) as a polyphenol compound induces apoptosis in several types of cells. Here, we evaluated the effects of PG on endothelial cells (ECs), especially calf pulmonary artery endothelial cells (CPAEC) in relation to the cell growth, ROS and glutathione (GSH) levels. PG dose-dependently inhibited the growth of CPAEC and human umbilical vein endothelial cells (HUVEC) at 24 h. PG also induced apoptosis in CPAEC, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim). PG decreased ROS level including O2*- and PG dose-dependently increased GSH depleted cell number in both EC types. N-acetyl-cysteine (NAC; a well-known antioxidant) increased ROS levels in PG-treated CPAEC with the prevention of cell death and GSH depletion. In conclusion, PG inhibited the growth of ECs, especially CPAEC via apoptosis. PG-induced EC death was related to GSH depletion rather than ROS level changes.}, }
@article {pmid19955769, year = {2010}, author = {Karahan, SC and Koramaz, I and Altun, G and Uçar, U and Topbaş, M and Menteşe, A and Kopuz, M}, title = {Ischemia-modified albumin reduction after coronary bypass surgery is associated with the cardioprotective efficacy of cold-blood cardioplegia enriched with N-acetylcysteine: a preliminary study.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {44}, number = {1}, pages = {30-36}, doi = {10.1159/000262324}, pmid = {19955769}, issn = {1421-9921}, mesh = {Acetylcysteine/*therapeutic use ; Albumins/*metabolism ; Cardiotonic Agents/therapeutic use ; Cold Temperature ; Coronary Artery Bypass/*adverse effects ; Female ; Heart Arrest, Induced/*adverse effects ; Humans ; Male ; Malondialdehyde ; Middle Aged ; Myocardial Reperfusion Injury/blood/etiology/*prevention &amp; control ; Troponin T/blood ; }, abstract = {BACKGROUND: The aims of this preliminary study were to determine the alteration of serum ischemia-modified albumin (IMA) levels and to investigate whether IMA may be used as an indicator of the cardioprotective efficacy of N-acetylcysteine (NAC) in patients undergoing coronary bypass grafting (CABG).<br><br>PATIENTS AND METHODS: Forty-four patients were randomized into one of two groups on the basis of cardioplegic strategies, either cold-blood cardioplegia enriched with NAC (50 mg/kg) or cold-blood cardioplegia alone. Serum IMA, cardiac troponin T (cTnT) and malondialdehyde (MDA) levels determined in NAC-enriched patients before and after CABG were compared with those of the NAC-free group. The albumin cobalt binding assay was used for IMA determination.<br><br>RESULTS: Serum IMA levels were significantly elevated after cross-clamping and peaked at 6 h after reperfusion in the two groups. In NAC-enriched patients, IMA levels determined 6, 12, 24 and 48 h after reperfusion were significantly lower than those of the NAC-free group (p < or = 0.001, p < 0.001, p < 0.001 and p < 0.001, respectively). IMA returned to baseline 24 h after reperfusion differently from cTnT and MDA in the NAC-enriched group.<br><br>CONCLUSIONS: IMA may be used as not only an indicator of myocardial ischemia-reperfusion injury, but also as a useful indicator of the cardioprotective effect of NAC in CABG.}, }
@article {pmid19955665, year = {2009}, author = {Thomson, VS and Narayanan, K and Singh, JC}, title = {Contrast induced nephropathy in urology.}, journal = {Indian journal of urology : IJU : journal of the Urological Society of India}, volume = {25}, number = {4}, pages = {437-445}, pmid = {19955665}, issn = {1998-3824}, abstract = {Intravenous contrast agents have a distinct role in urological imaging: to study precise anatomical delineation, vascularity, and to assess the function of the renal unit. Contrast induced nephropathy (CIN) is a known adverse effect of intravenous contrast administration. The literature on incidence, pathophysiology, clinical features, and current preventive strategies available for CIN relevant to urologists was reviewed. A search of the PubMed database was done using the keywords nephropathy and media, prevention and control or prevention Contrast media (explode), all adverse effects, and kidney diseases (explode). An online search of the EMBASE database for the time ranging from 1977 to February 2009 was performed using the keywords ionic contrast medium, adverse drug reaction, major or controlled clinical study, human, nephrotoxicity, and kidney disease. Current publications and data most relevant to urologists were examined. CIN was the third most common cause of hospital-acquired renal failure. The incidence is less common with intravenous contrast administration as compared with intra-arterial administration. The pathogenesis of contrast mediated nephropathy is due to a combination of toxic injury to renal tubules and medullary ischemic injury mediated by reactive oxygen species. CIN most commonly manifests as a nonoliguric and asymptomatic transient decline in renal function. Patients who developed CIN were found to have increased mortality, longer hospital stay, and complicated clinical course. An overview of risk factors and risk prediction score for prognostication of CIN are elaborated. Preventive strategies including choice of contrast agents, maximum tolerated dose, role of hydration, hydration regime, etc. are discussed. The role of N- acetyl cysteine, Theophylline, Fenoldapam, Endothelin receptor antagonists, iloprost, atrial natriuretic peptide, and newer therapies such as targeted renal therapy (TRT) are discussed. A working algorithm based on current evidence is proposed. No current treatment can reverse or ameliorate CIN once it occurs, but prophylaxis is possible.}, }
@article {pmid19954742, year = {2010}, author = {Cao, XH and Wang, AH and Wang, CL and Mao, DZ and Lu, MF and Cui, YQ and Jiao, RZ}, title = {Surfactin induces apoptosis in human breast cancer MCF-7 cells through a ROS/JNK-mediated mitochondrial/caspase pathway.}, journal = {Chemico-biological interactions}, volume = {183}, number = {3}, pages = {357-362}, doi = {10.1016/j.cbi.2009.11.027}, pmid = {19954742}, issn = {1872-7786}, mesh = {Antibiotics, Antineoplastic/*pharmacology ; *Apoptosis ; Breast Neoplasms/enzymology/*metabolism ; Caspase 6/*metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Lipopeptides/*pharmacology ; MAP Kinase Signaling System ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/*metabolism ; Peptides, Cyclic/*pharmacology ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein/metabolism ; bcl-X Protein/metabolism ; }, abstract = {Surfactin has been known to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in surfactin-induced apoptosis remain poorly understood. The present study was undertaken to elucidate the underlying network of signaling events in surfactin-induced apoptosis of human breast cancer MCF-7 cells. In this study, surfactin caused reactive oxygen species (ROS) generation and the surfactin-induced cell death was prevented by antioxidants N-acetylcysteine (NAC) and catalase, suggesting involvement of ROS generation in surfactin-induced cell death. Surfactin induced a sustained activation of the phosphorylation of ERK1/2 and JNK, but not p38. Moreover, surfactin-induced cell death was reversed by PD98059 (an inhibitor of ERK1/2) and SP600125 (an inhibitor of JNK), but not by SB203580 (an inhibitor of p38). However, the phosphorylation of JNK rather than ERK1/2 activation by surfactin was blocked by NAC/catalase. These results suggest that the action of surfactin on MCF-7 cells was via ERK1/2 and JNK, but not via p38, and the ERK1/2 and JNK activation induce apoptosis through two independent signaling mechanisms. Surfactin triggered the mitochondrial/caspase apoptotic pathway indicated by enhanced Bax-to-Bcl-2 expression ratio, loss of mitochondrial membrane potential, cytochrome c release, and caspase cascade reaction. The NAC and SP600125 blocked these events induced by surfactin. Moreover, the general caspase inhibitor z-VAD-FMK inhibited the caspase-6 activity and exerted the protective effect against the surfactin-induced cell death. Taken together, these findings suggest that the surfactin induces apoptosis through a ROS/JNK-mediated mitochondrial/caspase pathway.}, }
@article {pmid19953933, year = {2009}, author = {Meng, XP and Yin, CS and Cui, JH and Li, ZX and Wang, L and Wang, YW and Li, YL}, title = {[Inhibitory effect of N-acetylcysteine upon atherosclerotic processes in rabbit carotid].}, journal = {Zhonghua yi xue za zhi}, volume = {89}, number = {26}, pages = {1850-1853}, pmid = {19953933}, issn = {0376-2491}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Atherosclerosis/*metabolism ; Carotid Arteries/*pathology ; Disease Models, Animal ; Lipoproteins, LDL/blood ; Male ; Matrix Metalloproteinase 2/blood ; Matrix Metalloproteinase 9/blood ; Matrix Metalloproteinases/*blood ; Rabbits ; }, abstract = {OBJECTIVE: To discuss the effect of N-acetylcysteine (NAC) upon matrix metalloproteinases (MMP) in the atherosclerotic processes in rabbit carotid.<br><br>METHODS: The atherosclerotic models were generated in vitro by injuring rabbit internal carotid with arterial canal balloon. These rabbits were divided into 3 groups (15 mg/kg NAC, 30 mg/kg NAC and control group) and treated for 8 weeks. HE staining and immunohistochemistry were used to observe the plaque formation and the distribution of MMPs and ox-LDL. ELISA was used to detect the level of ox-LDL. And the protein levels of MMP-2 and MMP-9 in rabbit venous blood were detected by SDS PAGE zymography. The mRNA level of MMP-2 and MMP-9 were measured by RT-PCR and electrophoresis.<br><br>RESULTS: As compared with the control group, NAC (15 mg/kg) group had a reduction of neointima of arterial lumen [(1.79 +/- 0.24) vs (2.78 +/- 0.17) mm2]. A decrease of endothelial thickness [(0.16 +/- 0.01) vs (0.24 +/- 0.02) mm2] and an increase of vascular cavity transverse [(0.58 +/- 0.10) vs (0.33 +/- 0.1) mm2] (P < 0.05) were observed. At week 8, the oxLDL levels decreased by 16% in NAC (30 mg/kg) group [(30.5 +/- 1.2) vs (36.2 +/- 1.8) mmol/L] (P < 0.01). Serum levels of pro-MMP-2, MMP-2 and pro-MMP-9 decreased markedly [INT/mm2: (311 +/- 19, 208 +/- 8, 283 +/- 7 vs 619 +/- 17, 574 +/- 8, 564 +/- 10) respectively, P < 0.01] in NAC (30 mg/kg) group. The levels of mRNA expression of MMP-2 and MMP-9 were (2.4 +/- 0.4, 2.8 +/- 0.2) vs (3.4 +/- 0.3, 3.7 +/- 0.5) respectively (P < 0.05).<br><br>CONCLUSION: NAC inhibits the atherosclerotic formation, suppresses the levels of ox-LDL, MMP-9 and MMP-2 and downgrades the expression of matrix metalloproteinase mRNA.}, }
@article {pmid19949351, year = {2010}, author = {Lesiak, K and Koprowska, K and Zalesna, I and Nejc, D and Düchler, M and Czyz, M}, title = {Parthenolide, a sesquiterpene lactone from the medical herb feverfew, shows anticancer activity against human melanoma cells in vitro.}, journal = {Melanoma research}, volume = {20}, number = {1}, pages = {21-34}, doi = {10.1097/CMR.0b013e328333bbe4}, pmid = {19949351}, issn = {1473-5636}, mesh = {Acetylcysteine/pharmacology ; Adult ; Animals ; Antineoplastic Agents/antagonists &amp; inhibitors/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Adhesion/drug effects ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Drug Interactions ; Female ; Flow Cytometry ; Humans ; Male ; Melanoma/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Middle Aged ; Reactive Oxygen Species/metabolism ; Sesquiterpenes/antagonists &amp; inhibitors/*pharmacology ; Skin Neoplasms/metabolism/pathology/*therapy ; Tanacetum parthenium/*chemistry ; }, abstract = {Metastatic melanoma is a highly life-threatening disease. The lack of response to radiotherapy and chemotherapy highlights the critical need for novel treatments. Parthenolide, an active component of feverfew (Tanacetum parthenium), inhibits proliferation and kills various cancer cells mainly by inducing apoptosis. The aim of the study was to examine anticancer effects of parthenolide in melanoma cells in vitro. The cytotoxicity of parthenolide was tested in melanoma cell lines and melanocytes, as well as melanoma cells directly derived from a surgical excision. Adherent cell proliferation was measured by tetrazolium derivative reduction assay. Loss of the plasma membrane integrity, hypodiploid events, reactive oxygen species generation, mitochondrial membrane potential dissipation, and caspase-3 activity were assessed by flow cytometric analysis. Microscopy was used to observe morphological changes and cell detachment. Parthenolide reduced the number of viable adherent cells in melanoma cultures. Half maximal inhibitory concentration values around 4 mumol/l were determined. Cell death accompanied by mitochondrial membrane depolarization and caspase-3 activation was observed as the result of parthenolide application. Interestingly, the melanoma cells from vertical growth phase and melanocytes were less susceptible to parthenolide-induced cell death than metastatic cells when drug concentration was at least 6 mumol/l. Reactive oxygen species level was not significantly increased in melanoma cells. However, preincubation of parthenolide with the thiol nucleophile N-acetyl-cysteine protected melanoma cells from parthenolide-induced cell death suggesting the reaction with intracellular thiols as the mechanism responsible for parthenolide activity. In conclusion, the observed anticancer activity makes parthenolide an attractive drug candidate for further testing in melanoma therapy.}, }
@article {pmid19949310, year = {2010}, author = {Song, D and Gao, Y and Wang, R and Liu, D and Zhao, L and Jing, Y}, title = {Downregulation of c-FLIP, XIAP and Mcl-1 protein as well as depletion of reduced glutathione contribute to the apoptosis induction of glycyrrhetinic acid derivatives in leukemia cells.}, journal = {Cancer biology &amp; therapy}, volume = {9}, number = {2}, pages = {96-108}, doi = {10.4161/cbt.9.2.10287}, pmid = {19949310}, issn = {1555-8576}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*genetics ; CASP8 and FADD-Like Apoptosis Regulating Protein/*biosynthesis/genetics ; Down-Regulation ; Drug Screening Assays, Antitumor ; Gene Expression Regulation, Leukemic/*drug effects ; Glutathione/*metabolism ; Glycyrrhetinic Acid/*analogs &amp; derivatives/pharmacology ; HL-60 Cells/drug effects/metabolism ; Humans ; Jurkat Cells/drug effects/metabolism ; K562 Cells/drug effects/metabolism ; Leukemia, Myeloid, Acute/*pathology ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins/*biosynthesis/genetics ; Oxidation-Reduction ; Proto-Oncogene Proteins c-bcl-2/*biosynthesis/genetics ; U937 Cells/drug effects/metabolism ; X-Linked Inhibitor of Apoptosis Protein/*biosynthesis/genetics ; }, abstract = {The antiproliferative effects and apoptosis inducing abilities of four 18beta-glycyrrhetinic acid (GA) derivatives, methyl 2-cyano-3,11-dioxooleana-1,12-dien-30-oate (CDODO-Me-11), methyl 2-cyano-3,12-dioxooleana-1,12-dien-30-oate (CDODO-Me-12) and their non-esters were investigated in human leukemia cells. Methyl esterification and switching a keto group from position C(11) to C(12) significantly increased the antiproliferative effects. CDODO-Me-11 and CDODO-Me-12 were 10-fold more potent than their non-esters, respectively. CDODO-Me-12 was 10-fold more effective than CDODO-Me-11 in inducing apoptosis which was correlated with the activation of caspase-8 and caspase-9. Western blot analyses revealed that CDODO-Me-12 and CDODO-Me-11 downregulated the levels of anti-apoptosis proteins, c-FLIP, XIAP and Mcl-1, without altering the protein levels of Bcl-2 and the death receptors DR4 and DR5. Both agents decreased the levels of the mitochondrial membrane potential without altering the intracellular H(2)O(2) levels. Jurkat cells without expression of caspase-8 were not sensitive to CDODO-Me-12, but were somewhat responsive to CDODO-Me-11. K562 cells with higher intracellular reduced glutathione (GSH) levels were less responsive to CDODO-Me-12 apoptosis induction than U937 cells even though both cell lines were equally sensitive to CDODO-Me-11 apoptosis induction. Both agents depleted intracellular GSH levels and exogenous GSH reversed apoptosis induction by either agent in HL-60 cells. N-acetylcysteine (NAC) significantly attenuated apoptosis induction by CDODO-Me-12, but only weakly, that by CDODO-Me-11. UV spectrophotometric analysis revealed that both agents interacted with GSH while only CDODO-Me-12 had high reactivity with NAC. These data suggest that both agents induce apoptosis requiring to bind to functional proteins with thiol groups and that GSH may play a protective role by forming inactive adducts with them.}, }
@article {pmid19947928, year = {2010}, author = {Varelogianni, G and Oliynyk, I and Roomans, GM and Johannesson, M}, title = {The effect of N-acetylcysteine on chloride efflux from airway epithelial cells.}, journal = {Cell biology international}, volume = {34}, number = {3}, pages = {245-252}, doi = {10.1042/CBI20090007}, pmid = {19947928}, issn = {1095-8355}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Cell Line ; Chlorides/*metabolism ; Cystic Fibrosis/metabolism ; Epithelial Cells/*metabolism ; Humans ; Immunohistochemistry ; Oxidative Stress ; Respiratory Mucosa/cytology/*metabolism ; }, abstract = {Defective chloride transport in epithelial cells increases mucus viscosity and leads to recurrent infections with high oxidative stress in patients with CF (cystic fibrosis). NAC (N-acetylcysteine) is a well known mucolytic and antioxidant drug, and an indirect precursor of glutathione. Since GSNO (S-nitrosoglutathione) previously has been shown to be able to promote Cl- efflux from CF airway epithelial cells, it was investigated whether NAC also could stimulate Cl- efflux from CF and non-CF epithelial cells and through which mechanisms. CFBE (CF bronchial epithelial cells) and normal bronchial epithelial cells (16HBE) were treated with 1 mM, 5 mM, 10 mM or 15 mM NAC for 4 h at 37 degrees C. The effect of NAC on Cl- transport was measured by Cl- efflux measurements and by X-ray microanalysis. Cl- efflux from CFBE cells was stimulated by NAC in a dose-dependent manner, with 10 mM NAC causing a significant increase in Cl- efflux with nearly 80% in CFBE cells. The intracellular Cl- concentration in CFBE cells was significantly decreased up to 60% after 4 h treatment with 10 mM NAC. Moreover immunocytochemistry and Western blot experiments revealed expression of CFTR channel on CFBE cells after treatment with 10 mM NAC. The stimulation of Cl- efflux by NAC in CF airway epithelial cells may improve hydration of the mucus and thereby be beneficial for CF patients.}, }
@article {pmid19946347, year = {2009}, author = {Saberi, M and Zaree Mahmodabady, A}, title = {The protective effects of N-Acetl-cysteine, oxo-thiazolidine-carboxylate, acetaminophen and their combinations against sulfur mustard cytotoxicity on human skin fibroblast cell line (HF2FF).}, journal = {Iranian biomedical journal}, volume = {13}, number = {4}, pages = {215-221}, pmid = {19946347}, issn = {1028-852X}, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/pharmacology ; Catalase/metabolism ; Cell Line ; Cell Survival/drug effects ; Chemical Warfare Agents/toxicity ; Cytoprotection ; Drug Interactions ; Fibroblasts/cytology/*drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Humans ; Mustard Gas/*toxicity ; Pyrrolidonecarboxylic Acid/*pharmacology ; Skin/cytology ; Thiazolidines/*pharmacology ; }, abstract = {BACKGROUND: Using human skin-fibroblast cell line HF2FF, the efficacy of some drugs was evaluated against sulfur mustard (SM) cytotoxicity. The drugs were the sulfhydryl containing molecule including N-acetylcysteine (NAC), 2-oxo-thiazolidine-4-carboxylate (OTC) and acetaminophen as glutathione (GSH) stimulator pathway.<br><br>METHODS: The protective effects of NAC (0.1 mM), OTC (1.8 mM), and acetaminophen (25 mM) alone or in combination with each other were evaluated on SM (180 M)-induced cytotoxicity. NAC and OTC were applied with SM simultaneously and acetaminophen 30 min before SM exposure, incubated for 1 h and then were rinsed and incubated with fresh medium. The efficacy was evaluated by determination of cells viability, intracellular GSH level and catalase activity 1 and 24 h post SM exposure or co-treatments.<br><br>RESULTS: The cells viability was decreased 21.8% and 55.2%, respectively for 1 and 24 h post SM (1 h exposure) incubation. So, the 1-h SM exposure and 24-h treatment incubation were selected for evaluation. While, NAC alone treatment increased the cells viability (25%), GSH level (320%) and catalase activity (18%), the most effective combination was NAC plus OTC and acetaminophen which increased more significantly the cells viability (about 40%), GSH level (470%) and catalase activity (100%).<br><br>CONCLUSION: The most effective combination was NAC (0.1 mM) plus OTC (1.8 mM) and acetaminophen (25 mM) which should be used before or concomitant with SM exposure. These drugs may reduce SM toxicity possibly by increment of GSH level and catalase activity. This efficacy needs to be confirmed by in vivo study.}, }
@article {pmid19944114, year = {2010}, author = {Daily, A and Monks, NR and Leggas, M and Moscow, JA}, title = {Abrogation of microcystin cytotoxicity by MAP kinase inhibitors and N-acetyl cysteine is confounded by OATPIB1 uptake activity inhibition.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {55}, number = {4}, pages = {827-837}, doi = {10.1016/j.toxicon.2009.11.019}, pmid = {19944114}, issn = {1879-3150}, mesh = {Acetylcysteine/*pharmacology ; Blotting, Western ; HeLa Cells ; Humans ; Liver-Specific Organic Anion Transporter 1 ; Microcystins/*pharmacology ; Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors ; Organic Anion Transporters/*antagonists &amp; inhibitors/metabolism ; Protein Kinase Inhibitors/*pharmacology ; }, abstract = {Solute transporters that are selectively expressed on tumor cell membranes could be targeted with small molecule toxins that are selective substrates for these transporters. HeLa cells transfected to express the solute transporter OATP1B1 are exquisitely sensitive in vitro to microcystin LR (MCLR) and its analogs, and undergo rapid morphologic changes after exposure to MCLR. Immunoblot analyses revealed HSP27 phosphorylation increased prior to the rapid MCLR-induced morphologic changes. However, transfection of OATP1B1-expressing cells with HSP27 dominant negative mutants did not reverse MCLR toxicity. Although the MAP kinase p38 inhibitor SB202190 partially reversed MCLR cytotoxicity, the control molecule, SB202474, had similar effects. Unexpectedly, both SB202190 and SB202474 inhibited OATP1B1 uptake activity, indicating an alternative explanation for cytotoxicity reversal that did not involve p38 MAP kinase. Similarly, although the potassium chloride co-transporter (KCC) inhibitor (dihydro-indenyl)oxyalkanoic acid (DIOA), and the anti-oxidant, N-acetyl cysteine (NAC) both reversed MCLR cytotoxicity, both were also found to be unexpected OATP1B1 transport inhibitors. Therefore, the mechanism of MCLR-induced cytotoxicity is obscured by the inhibition of OATP1B1 uptake activity by MAP kinase inhibitors, DIOA, and NAC. Finally, growth of OATP1B1-expressing HeLa xenografts was inhibited by MCLR, suggesting that MCLR structural analogs selected for a broader therapeutic index could target OATP-expressing tumors.}, }
@article {pmid19941943, year = {2010}, author = {Vejnovic, I and Simmler, L and Betz, G}, title = {Investigation of different formulations for drug delivery through the nail plate.}, journal = {International journal of pharmaceutics}, volume = {386}, number = {1-2}, pages = {185-194}, doi = {10.1016/j.ijpharm.2009.11.019}, pmid = {19941943}, issn = {1873-3476}, mesh = {Acetylcysteine/pharmacology ; Administration, Topical ; Boric Acids/pharmacology ; Cadaver ; Caffeine/administration &amp; dosage/chemistry/*metabolism ; Chemistry, Pharmaceutical ; Dimethyl Sulfoxide/pharmacology ; Dioctyl Sulfosuccinic Acid/pharmacology ; *Drug Carriers ; Ethanol/chemistry ; Female ; Fungal Proteins/pharmacology ; Humans ; Male ; Methanol/pharmacology ; Nails/*drug effects/metabolism ; Permeability ; Pharmaceutic Aids/administration &amp; dosage/*pharmacology ; Technology, Pharmaceutical/methods ; Urea/pharmacology ; Water/chemistry ; }, abstract = {Topical therapies for nail diseases are limited by keratinized cells in the human nail plate. An optimal permeation enhancer would not only improve drug delivery through the nail plate, but would also open new possibilities for treating neighboring target sites if systemic circulation is reached. The aim of the present work was to identify permeation enhancers and to improve the understanding of physicochemical parameters that influence drug permeation. Caffeine served as the model drug, and formulations were prepared in water and 20% (v/v) ethanol/water solutions. Tested enhancers were urea, dimethyl sulfoxide (DMSO), methanol, N-acetyl-L-cysteine (NAC), docusate sodium salt (DSS), boric acid, and fungal proteins, such as hydrophobins. Permeability studies employed cadaver nails in modified Franz-type diffusion cells. The permeability coefficient of caffeine in ethanol/water was determined to be 1.56 E-08 cm/s and was improved to 2.27 E-08 cm/s by the addition of NAC. Formulations containing either methanol or DMSO showed the highest permeability coefficients in the range of 5-7.5 E-08 cm/s. Enhancers could be classified according to their permeation enhancement: methanol>class II hydrophobins>DMSO>followed by class I hydrophobins and urea. Ethanol at a concentration of 20% (v/v) in water did not influence swelling of nail samples. Hydrophobins are suggested to be efficient in drug delivery through the nail plate.}, }
@article {pmid19939614, year = {2010}, author = {Rosenbaum, MA and Miyazaki, K and Colles, SM and Graham, LM}, title = {Antioxidant therapy reverses impaired graft healing in hypercholesterolemic rabbits.}, journal = {Journal of vascular surgery}, volume = {51}, number = {1}, pages = {184-193}, pmid = {19939614}, issn = {1097-6809}, support = {R01 HL041178/HL/NHLBI NIH HHS/United States ; F32HL090205/HL/NHLBI NIH HHS/United States ; HL64357/HL/NHLBI NIH HHS/United States ; R01 HL064357-08/HL/NHLBI NIH HHS/United States ; R56 HL064357/HL/NHLBI NIH HHS/United States ; R01 HL041178-21/HL/NHLBI NIH HHS/United States ; F32 HL090205/HL/NHLBI NIH HHS/United States ; R01 HL064357/HL/NHLBI NIH HHS/United States ; F32 HL090205-02/HL/NHLBI NIH HHS/United States ; HL41187/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Aorta, Abdominal/*drug effects/metabolism/pathology/physiopathology/*surgery ; *Blood Vessel Prosthesis Implantation/adverse effects ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cholesterol/blood ; Disease Models, Animal ; Endothelial Cells/drug effects/pathology ; Hypercholesterolemia/metabolism/pathology/physiopathology/*therapy ; Hyperplasia ; Macrophages/drug effects/pathology ; Muscle, Smooth, Vascular/drug effects/pathology ; Myocytes, Smooth Muscle/drug effects/pathology ; Oxidative Stress/drug effects ; Rabbits ; Thiobarbituric Acid Reactive Substances/metabolism ; Tyrosine/analogs &amp; derivatives/metabolism ; Wound Healing/*drug effects ; }, abstract = {OBJECTIVE: Limited endothelial cell (EC) coverage and anastomotic intimal hyperplasia contribute to thrombosis and failure of prosthetic grafts. Lipid accumulation and lipid oxidation are associated with decreased EC migration and intimal hyperplasia. The goal of this study was to assess the ability of antioxidants to improve graft healing in hypercholesterolemic animals.<br><br>METHODS: Rabbits were placed in one of four groups: chow plus N-acetylcysteine (NAC), chow plus probucol, chow with 1% cholesterol plus NAC, or chow with 1% cholesterol plus probucol. After 2 weeks, expanded polytetrafluoroethylene grafts (12 cm long x 4-mm internal diameter) were implanted in the abdominal aorta. Grafts were removed after 6 weeks and analyzed for cholesterol content, EC coverage, anastomotic intimal thickness, and the cellular composition of the neointima. Plasma samples were obtained to assess systemic oxidative stress. The data were compared with previously reported data from animals fed diets of chow and chow with 1% cholesterol.<br><br>RESULTS: Prosthetic grafts from rabbits fed chow with 1% cholesterol had significantly greater anastomotic intimal thickening and lower EC coverage than grafts from rabbits fed a regular chow diet. In hypercholesterolemic rabbits, antioxidant therapy decreased global oxidative stress as evidenced by a 40% decrease in plasma thiobarbituric acid reactive substances. In rabbits fed the chow with 1% cholesterol diet, NAC decreased intimal hyperplasia at the proximal anastomosis by 29% and significantly increased graft EC coverage from 46% to 71% (P = .03). Following a similar pattern, probucol decreased intimal hyperplasia by 43% and increased graft EC coverage to 53% in hypercholesterolemic rabbits.<br><br>CONCLUSIONS: Global oxidative stress and anastomotic intimal hyperplasia are increased, and endothelialization of prosthetic grafts is significantly reduced in rabbits fed a high-cholesterol diet. Antioxidant treatment improves EC coverage and decreases intimal hyperplasia. Reducing oxidative stress may promote healing of prosthetic grafts.}, }
@article {pmid19935767, year = {2010}, author = {Kim, SY and Lee, JG and Cho, WS and Cho, KH and Sakong, J and Kim, JR and Chin, BR and Baek, SH}, title = {Role of NADPH oxidase-2 in lipopolysaccharide-induced matrix metalloproteinase expression and cell migration.}, journal = {Immunology and cell biology}, volume = {88}, number = {2}, pages = {197-204}, doi = {10.1038/icb.2009.87}, pmid = {19935767}, issn = {1440-1711}, mesh = {Animals ; Antioxidants/pharmacology ; Cell Line ; Cell Movement/*drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Expression Regulation, Enzymologic/drug effects ; Lipopolysaccharides/*pharmacology ; Macrophages/*cytology/drug effects/*enzymology ; Matrix Metalloproteinases/*genetics/metabolism ; Membrane Glycoproteins/genetics/*metabolism ; Mice ; NADH, NADPH Oxidoreductases/genetics/metabolism ; NADPH Oxidase 1 ; NADPH Oxidase 2 ; NADPH Oxidases/genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/metabolism ; }, abstract = {This study examined the hypothesis that the control of NADPH oxidase-2 (Nox2)-mediated reactive oxygen species (ROS) regulates the expression of matrix metalloproteinases (MMPs) and the migration of macrophages. Lipopolysaccharide (LPS) stimulation of Raw264.7 cells and mice peritoneal macrophages increased the expression of MMP-9, 10, 12 and 13 mRNA, and also increased Raw264.7 cell migration. Treatment with an antioxidant (N-acetyl cysteine) or Nox inhibitors strongly inhibited the expression of MMPs by LPS and inhibited cell migration. LPS caused ROS production in macrophages and increased the mRNA expression of Nox isoforms Nox1 and Nox2 by 20-fold and two-fold, respectively. While Nox1 small interfering RNA (siRNA) did not inhibit LPS-mediated expression of MMPs, Nox2 siRNA inhibited the expressions of MMP-9, 10 and 12. Neither Nox1 nor Nox2 siRNA influenced the LPS-mediated expression of MMP-13. In addition, NAC or apocynin attenuated LPS-induced ROS production and MMP-9 expression. MMP-9 expression and cell migration were controlled by ERK1/2-ROS signaling. Collectively, these results suggest that LPS stimulates ROS production via ERK and induce various types of MMPs expression and cell migration.}, }
@article {pmid19935597, year = {2009}, author = {Da Silveira, M and Yoshida, WB}, title = {Trimetazidine and N-acetylcysteine in attenuating hind-limb ischemia and reperfusion injuries: experimental study in rats.}, journal = {International angiology : a journal of the International Union of Angiology}, volume = {28}, number = {5}, pages = {412-417}, pmid = {19935597}, issn = {0392-9590}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biomarkers/blood ; Creatine Kinase/blood ; Disease Models, Animal ; Glutathione/blood ; Hindlimb ; Male ; Malondialdehyde/blood ; Muscle, Skeletal/*blood supply/*drug effects/metabolism/ultrastructure ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Reperfusion Injury/blood/pathology/*prevention &amp; control ; Severity of Illness Index ; Time Factors ; Trimetazidine/*pharmacology ; }, abstract = {AIM: Lower-limb traumatic injury associated with ischemia and followed by reperfusion (I/R) is a common severe situation in muscle lesions due to trauma and hypoxia followed by local and systemic injuries induced by oxygen-derived free radical release during reperfusion. The aim of this study was to evaluate the attenuating effects of trimetazidine (TMZ) and N-acetylcysteine (NAC) in such situation.<br><br>METHODS: The muscles at the root of the right hind limb of Wistar rats were cross-sectioned, preserving femoral vessels and nerves and clamping the femoral artery for four hours. The clamp was then released and the femoral artery has been reperfused for 2 hours. Rats were randomly divided in groups of ten as follows: Group 1: sham I/R, treated with saline; Group 2: I/R, treated with saline; Group 3: sham I/R, treated with TMZ (7.5 mg/kg/dose); Group 4: sham I/R, treated with NAC (375 mg/kg/dose); Group 5: I/R treated with TMZ (7.5 mg/kg/dose); Group 6: I/R treated with NAC (375 mg/kg/dose). All rats received two intravenous bolus injections of the drugs, one before ischemia and one before reperfusion. Oxidative stress in plasma (MDA, total, oxidized and reduced glutathione), creatinephosphokinase (CPK), optical and electron microscopy and pelvic extremity circumference and volume were studied.<br><br>RESULTS: No statistical differences were found between the groups for MDA or total and reduced glutathione. Oxidized glutathione increased significantly in groups 5 and 2. Limb circumference as well as limb volume increased in all groups over time, mainly in groups 5, 2 and 1. CPK increased in all groups, being highest in groups 5, 6 and 2. Histological lesions were present in all but sham groups, being less severe in group 6. Soleus muscle analyses at electron microscopy exhibit some degree of alteration in all groups.<br><br>CONCLUSIONS: This experimental model simulated severe limb trauma associated with ischemia and reperfusion, and, as such, it was aggressive, causing severe injury and local inflammatory reaction. The model did not show antioxidant action from NAC, and possible antioxidant action from TMZ was insufficient to attenuate tissue injuries.}, }
@article {pmid19931366, year = {2010}, author = {Hildebrand, A and Pfeiffer, E and Metzler, M}, title = {Aromatic hydroxylation and catechol formation: a novel metabolic pathway of the growth promotor zeranol.}, journal = {Toxicology letters}, volume = {192}, number = {3}, pages = {379-386}, doi = {10.1016/j.toxlet.2009.11.014}, pmid = {19931366}, issn = {1879-3169}, mesh = {Animals ; Catechols/metabolism ; Cattle ; Cytochrome P-450 CYP1A2/metabolism ; Estrogens, Non-Steroidal/*metabolism ; Humans ; Hydroxylation ; Microsomes, Liver/metabolism ; Oxidation-Reduction ; Protein Isoforms/metabolism ; Rats ; Species Specificity ; Swine ; Zearalenone/metabolism ; Zeranol/*metabolism ; }, abstract = {Alpha-zearalanol (alpha-ZAL, zeranol) is a macrocyclic resorcylic acid lactone, which is highly estrogenic and used as a growth promotor for cattle in various countries. Little is known about the phase I metabolism of alpha-ZAL. We now report that alpha-ZAL and its major metabolite zearalanone (ZAN) are extensively monohydroxylated at the aromatic ring by microsomes from human liver in vitro. This novel pathway leads to catechols, the chemical structures of which were unambiguously established by the use of deuterium-labeled alpha-ZAL and ZAN, and by the synthesis of authentic standards. The aromatic hydroxylation of alpha-ZAL is almost exclusively mediated by the human cytochrome P450 (hCYP) 1A2 isoform. The catechol metabolites of alpha-ZAL and ZAN are unstable and readily oxidized to quinones, which could be detected among the metabolites of alpha-ZAL and ZAN generated by human hepatic microsomes and hCYP1A2. Furthermore, the quinone metabolites are able to form covalent adducts with N-acetylcysteine (NAC), as several of such adducts were found in microsomal incubations fortified with NAC. Aromatic hydroxylation of alpha-ZAL was also observed with bovine, porcine and rat hepatic microsomes. Further studies are needed to demonstrate the catechol pathway of alpha-ZAL in vivo and to assess its toxicological significance.}, }
@article {pmid19928123, year = {2009}, author = {Atyabi, F and Talaie, F and Dinarvand, R}, title = {Thiolated chitosan nanoparticles as an oral delivery system for Amikacin: in vitro and ex vivo evaluations.}, journal = {Journal of nanoscience and nanotechnology}, volume = {9}, number = {8}, pages = {4593-4603}, doi = {10.1166/jnn.2009.1090}, pmid = {19928123}, issn = {1533-4880}, mesh = {Administration, Oral ; Amikacin/*administration &amp; dosage ; Anti-Bacterial Agents/*administration &amp; dosage ; Chitosan/*chemistry ; In Vitro Techniques ; Microscopy, Electron, Scanning ; *Nanoparticles ; Sulfhydryl Compounds/*chemistry ; Tensile Strength ; }, abstract = {The purpose of this study was the synthesis of two thiol conjugated Chitosan polymers, and evaluation of the potential of Thiomer nanoparticle formulation as a carrier for oral delivery system. Mediated by EDAC (Ethylene-3-(3-di-methylaminopropyl)-carbodiimide), either N-acetyl Cysteine (NAC) or N-acetyl D-penicillamine (NAP) were covalently attached to Chitosan. The success of the synthesis was demonstrated by comparing FTIR spectra. Iodometric titration demonstrated that depending on the pH value of the synthesis medium, the Thiomers display 250 +/- 30 microMol and 300 +/- 20 microMol thiol groups per gram of polymer respectively. The interaction between mucin and Thiomers, compared to mucin and Chitosan was studied for assessment of mucoadhesion properties of synthesized polymers. This interaction was determined by the measurement of the amount of mucin adsorbed on Chitosan and the conjugated polymers. Rotating cylinder method demonstrated an average of 20 times improvement in mucoadhesion of Thiomers compared to the unmodified polymer. Chitosan and Thiomer nanoparticles were formulated by two methods; TPP and Sodium Sulfate gelation. SEM micrographs and data achieved by a Malvern nano/zetasizer show nanoparticles formed by TPP gelation have a mean size of 150 +/- 15 nm compared to 300 +/- 25 nm sized nanoparticles obtained by Sodium sulfate gelation. TPP gelation yields smaller, more spherical shaped nanoparticles with a smaller range of size distribution. Amikacin loaded nanoparticles with an average size of 280 nm were prepared by TPP gelation in which disulfide bond formation was achieved by a time dependent oxidation process. In vitro studies were carried out; a recovery rate of 33% and a drug entrapment of 25% were achieved. The amount of release was determined during 18 hr in a carefully prepared media. The permeation time across a biological membrane was observed to be about 150 minutes. Microbiological tests were carried out on two microorganisms; Pseudomona aeruginosa and Staphylococcus aureus to further confirm the amount of Amikacin inside drug loaded nanoparticles.}, }
@article {pmid19926054, year = {2009}, author = {Brown, JR and Block, CA and Malenka, DJ and O'Connor, GT and Schoolwerth, AC and Thompson, CA}, title = {Sodium bicarbonate plus N-acetylcysteine prophylaxis: a meta-analysis.}, journal = {JACC. Cardiovascular interventions}, volume = {2}, number = {11}, pages = {1116-1124}, pmid = {19926054}, issn = {1876-7605}, support = {K01 HS018443/HS/AHRQ HHS/United States ; T32 HS000070/HS/AHRQ HHS/United States ; T32HS000070/HS/AHRQ HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/chemically induced/prevention &amp; control ; Administration, Oral ; Biomarkers/blood ; Contrast Media/*adverse effects ; Creatinine/blood ; Drug Therapy, Combination ; Evidence-Based Medicine ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Infusions, Intravenous ; Kidney Diseases/blood/chemically induced/*prevention &amp; control ; Practice Guidelines as Topic ; Randomized Controlled Trials as Topic ; Renal Dialysis ; Risk Assessment ; Sodium Bicarbonate/administration &amp; dosage/*therapeutic use ; Treatment Outcome ; }, abstract = {OBJECTIVES: We sought to conduct a meta-analysis to compare N-acetylcysteine (NAC) in combination with sodium bicarbonate (NaHCO(3)) for the prevention of contrast-induced acute kidney injury (AKI).<br><br>BACKGROUND: Contrast-induced AKI is a serious consequence of cardiac catheterizations and percutaneous coronary interventions (PCI). Despite recent supporting evidence for combination therapy, not enough has been done to prevent the occurrence of contrast-induced AKI prophylactically.<br><br>METHODS: Published randomized controlled trial data were collected from OVID/PubMed, Web of Science, and conference abstracts. The outcome of interest was contrast-induced AKI, defined as a >or=25% or >or=0.5 mg/dl increase in serum creatinine from baseline. Secondary outcome was renal failure requiring dialysis.<br><br>RESULTS: Ten randomized controlled trials met our criteria. Combination treatment of NAC with intravenous NaHCO(3) reduced contrast-induced AKI by 35% (relative risk: 0.65; 95% confidence interval: 0.40 to 1.05). However, the combination of N-acetylcysteine plus NaHCO(3) did not significantly reduce renal failure requiring dialysis (relative risk: 0.47; 95% confidence interval: 0.16 to 1.41).<br><br>CONCLUSIONS: Combination prophylaxis with NAC and NaHCO(3) substantially reduced the occurrence of contrast-induced AKI overall but not dialysis-dependent renal failure. Combination prophylaxis should be incorporated for all high-risk patients (emergent cases or patients with chronic kidney disease) and should be strongly considered for all interventional radio-contrast procedures.}, }
@article {pmid19920101, year = {2009}, author = {Goodson, AG and Cotter, MA and Cassidy, P and Wade, M and Florell, SR and Liu, T and Boucher, KM and Grossman, D}, title = {Use of oral N-acetylcysteine for protection of melanocytic nevi against UV-induced oxidative stress: towards a novel paradigm for melanoma chemoprevention.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {15}, number = {23}, pages = {7434-7440}, pmid = {19920101}, issn = {1557-3265}, support = {P30 CA042014/CA/NCI NIH HHS/United States ; R21 AR056797/AR/NIAMS NIH HHS/United States ; R21 AR056797-01A1/AR/NIAMS NIH HHS/United States ; T32 CA093247/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Aged ; Anticarcinogenic Agents/*administration &amp; dosage ; Antioxidants/metabolism ; Cysteine/metabolism ; Female ; Glutathione/metabolism ; Humans ; Male ; Melanoma/*prevention &amp; control ; Middle Aged ; Nevus, Pigmented/*drug therapy ; Oxidative Stress ; Risk ; Skin Neoplasms/*prevention &amp; control ; Time Factors ; Ultraviolet Rays ; }, abstract = {PURPOSE: Induction of oxidative stress has been implicated in UV-induced melanoma. We sought to determine whether the antioxidant N-acetylcysteine (NAC) could be safely administered to protect melanocytic nevi from the oxidative stress resulting from acute UV exposure.<br><br>EXPERIMENTAL DESIGN: Patients at increased risk for melanoma were recruited from a screening clinic. Induction and detection of oxidative stress (reactive oxygen species and glutathione depletion) was optimized in nevi following ex vivo UV irradiation. Nevi were removed from patients before, and following, oral ingestion of a single (1,200 mg) dose of NAC, and then these nevi were UV irradiated (4,000 J/m(2)).<br><br>RESULTS: Oxidative stress was induced in nevi 24 to 48 hours following ex vivo UV irradiation. A single oral dose of NAC was well tolerated in all patients (n = 72). Basal levels of reduced glutathione and the NAC metabolite cysteine were well correlated between similar-appearing nevi from the same patient and were significantly increased in nevi removed 3 hours after NAC ingestion compared with nevi removed before drug ingestion. In approximately half (9 of 19) of patients tested, UV-induced glutathione depletion was attenuated in the postdrug (compared with predrug) nevus.<br><br>CONCLUSIONS: NAC can be safely administered to patients for the purpose of modulating UV-induced oxidative stress in nevi. This study suggests the feasibility of patients taking NAC prophylactically before acute UV exposure, to prevent pro-oncogenic oxidative stress in nevi and ultimately reduce long-term melanoma risk.}, }
@article {pmid19919835, year = {2010}, author = {Kheradpezhouh, E and Panjehshahin, MR and Miri, R and Javidnia, K and Noorafshan, A and Monabati, A and Dehpour, AR}, title = {Curcumin protects rats against acetaminophen-induced hepatorenal damages and shows synergistic activity with N-acetyl cysteine.}, journal = {European journal of pharmacology}, volume = {628}, number = {1-3}, pages = {274-281}, doi = {10.1016/j.ejphar.2009.11.027}, pmid = {19919835}, issn = {1879-0712}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Biomarkers/blood ; Catalase/metabolism ; Curcumin/metabolism/*pharmacology ; Drug Synergism ; Glutathione Peroxidase/metabolism ; Kidney/*drug effects/metabolism/pathology ; Kidney Diseases/*prevention &amp; control ; Liver/*drug effects/metabolism/pathology ; Liver Diseases/*prevention &amp; control ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Serologic Tests ; }, abstract = {Acetaminophen is one of the most popular analgesic and antipyretic drugs and its overdose, which can cause severe damage to liver and kidneys, is one of the most common reasons of emergency admissions. In this study we investigated the effects of curcumin, derived from plant Curcuma longa, on acetaminophen toxicity, and the possibility of combining therapy of curcumin and N-acetyl cysteine (NAC) to treat this toxicity. The experiments were conducted on 72 male Sprague-Dawley rats randomly divided into 12 groups. Control group was left without treatment, and the other groups were treated with different combinations of acetaminophen, curcumin and NAC. 15min after intraperitoneal injection, the blood level of curcumin was measured using HPLC. Blood levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), blood urea nitrogen and creatinine were determined 18 and 42h after acetaminophen injection. One week later, the left kidney and the caudate lobe of the liver were harvested to assay glutathione peroxidase, catalase and malondialdehyde. The right kidney and the remaining lobes of the liver were used for histopathology. Analysis of organ function and oxidation parameters showed that curcumin significantly reduced toxic effects of acetaminophen on the liver and kidneys in a dose-dependent manner and significantly potentiated the protective effects of NAC. These findings were confirmed by histopathology. It is concluded that curcumin can protect the liver and kidney from the damage caused by acetaminophen overdose. Moreover, curcumin has the potential to be used in a combination therapy with NAC, significantly decreasing the therapeutic dose of NAC and therefore its side-effects.}, }
@article {pmid19917703, year = {2009}, author = {Lee, SH and Park, DW and Park, SC and Park, YK and Hong, SY and Kim, JR and Lee, CH and Baek, SH}, title = {Calcium-independent phospholipase A2beta-Akt signaling is involved in lipopolysaccharide-induced NADPH oxidase 1 expression and foam cell formation.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {183}, number = {11}, pages = {7497-7504}, doi = {10.4049/jimmunol.0900503}, pmid = {19917703}, issn = {1550-6606}, mesh = {Animals ; Atherosclerosis/immunology/metabolism ; Blotting, Western ; Calcium Signaling/immunology ; Cell Line ; Flow Cytometry ; Foam Cells/*immunology/metabolism ; Gene Expression ; Gene Expression Regulation/*immunology ; Group IV Phospholipases A2/*immunology/metabolism ; Lipopolysaccharides/immunology ; Mice ; Microscopy, Confocal ; NADH, NADPH Oxidoreductases/*immunology/metabolism ; NADPH Oxidase 1 ; Proto-Oncogene Proteins c-akt/*immunology/metabolism ; RNA, Small Interfering ; Reactive Oxygen Species/immunology/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*immunology ; Toll-Like Receptor 4/immunology/metabolism ; }, abstract = {Foam cell formation is the most important process in atherosclerosis, and low density lipoprotein oxidation by reactive oxygen species (ROS) is the key step in the conversion of macrophages to foam cells. This study reveals the control mechanism of the gene for NADPH oxidase 1 (Nox1), which produces ROS in the formation of foam cells by stimulating TLR4. Treatment of macrophages by the TLR4 agonist LPS stimulated ROS production and ROS-mediated macrophage to foam cell conversion. This LPS-induced ROS production and foam cell formation could be abrogated by pretreatment of macrophages with N-acetyl cysteine or apocynin. LPS increased Nox1 promoter activity, and resultant expression of mRNA and protein. Small interfering RNA mediated inhibition of Nox1 expression decreased LPS-induced ROS production and foam cell formation. LPS-mediated Nox1 expression and the responses occurred in a calcium-independent phospholipase A(2) (iPLA(2))-dependent manner. The iPLA(2)beta-specific inhibitor S-BEL or iPLA(2)beta small interfering RNA attenuated LPS-induced Nox1 expression, ROS production, and foam cell formation. In addition, activation of iPLA(2)beta by LPS caused Akt phosphorylation and was followed by increased Nox1 expression. These results suggest that the binding of LPS and TLR4 increases Nox1 expression through the iPLA(2)beta-Akt signaling pathway, and control ROS production and foam cell formation.}, }
@article {pmid19917357, year = {2009}, author = {Mei, J and Zhu, J and Ding, F and Bao, C and Wu, S}, title = {N-acetylcysteine improves early cardiac isograft function in a rat heterotopic transplantation model.}, journal = {Transplantation proceedings}, volume = {41}, number = {9}, pages = {3632-3636}, doi = {10.1016/j.transproceed.2009.06.206}, pmid = {19917357}, issn = {1873-2623}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/pharmacology ; Echocardiography ; Heart Transplantation/*physiology ; Inflammation/physiopathology ; Infusions, Intravenous ; Interleukin-1/blood ; L-Lactate Dehydrogenase/blood ; Models, Animal ; Oxidative Stress/*physiology ; Rats ; Rats, Inbred Lew ; Transplantation, Heterotopic/methods ; Transplantation, Isogeneic ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {Reactive oxygen species play an important role in the early phase of ischemia-reperfusion injury. N-acetylcysteine (NAC), an antioxidant, has shown protective effects in ischemia-reperfusion injuries in some organ transplantations; however, its roles in cardiac transplantation have not been thoroughly evaluated. Lewis rats were divided into three groups (n = 8 in each group): sham, control, and NAC group. They were subjected to abdominal heterotopic cardiac transplantation and followed for 24 hours postoperation. For the NAC group, a bolus of NAC (150 mg/kg) was infused at 30 minutes before reperfusion, followed by 20 mg/kg/h for 1 hour; another 150 mg/kg NAC intraperitoneally administered 12 hours after reperfusion. Cardiac function and blood inflammation markers were measured at both 2 and 24 hours after reperfusion. Oxidative stress markers and neutrophil infiltration were evaluated in heart tissue at 24 hours postoperatively. Echocardiography showed that NAC significantly improved the postoperative fractional shortening of isografts (P < .01), although NAC had no effect on the heart rate. Serum lactate dehydrogenase also indicated a significant decrease in the NAC group at 24 hours posttransplantation (P = .02) Serum tumor necrosis factor-alpha and interleukin-1 concentrations which rapidly increased postoperatively were reduced by administration of NAC. In transplanted hearts, the increased malondialdehyde level and myeloperoxidase activity were partially reversed by NAC (both P < .01); NAC also replenished endogenous glutathione. Finally, neutrophil infiltration in isografts was reduced in the NAC group. Recipient treatment with continuous intravenous NAC protected cardiac isografts against posttransplantation ischemia-reperfusion injury, probably through its antioxidant and anti-inflammatory properties.}, }
@article {pmid19916738, year = {2009}, author = {Marchetti, A and Rossiter, R}, title = {Managing acute acetaminophen poisoning with oral versus intravenous N-acetylcysteine: a provider-perspective cost analysis.}, journal = {Journal of medical economics}, volume = {12}, number = {4}, pages = {384-391}, doi = {10.3111/13696990903435829}, pmid = {19916738}, issn = {1941-837X}, mesh = {Acetaminophen/*economics/*poisoning/therapeutic use ; Acetylcysteine/*administration &amp; dosage/*economics/therapeutic use ; Acute Disease ; Administration, Oral ; Analgesics, Non-Narcotic/economics/poisoning/therapeutic use ; Antidotes/administration &amp; dosage/economics/therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy/*economics/etiology/prevention &amp; control ; Costs and Cost Analysis ; Drug Overdose/drug therapy/economics ; Humans ; Injections, Intravenous ; Length of Stay/economics ; Models, Economic ; Time Factors ; United States ; }, abstract = {BACKGROUND: Acetaminophen (APAP) overdose, which can lead to hepatotoxicity, is the most commonly reported poisoning in the United States and has the highest rate of mortality, with more than 100,000 exposures and 300 deaths reported annually (1) . The treatment of choice, N-acetylcysteine (NAC), is effective in both oral (PO) and intravenous (IV) formulations. The main difference in therapies, other than administration route, is time to complete delivery--72 hours for PO NAC versus 21 hours for IV NAC, according to full prescribing information. This distinction is the primary basis for variation in management costs for hospitalized patients receiving these products.<br><br>OBJECTIVES: To quantify and compare full treatment costs from the provider perspective to manage acute APAP poisoning with either PO or IV NAC in a standard treatment regimen.<br><br>METHODS: A cost model was developed and populated with published data comprising probabilities of potential clinical outcomes and the costs of resources consumed during patient care.<br><br>RESULTS: For patients who present <10 hours post-ingestion, the estimated total cost of care with PO NAC in the treatment regimen is $5,817 (ICU patients) or $3,850, (ward patients) compared with $3,765 and $2,768 for similar care with IV NAC. Potential cost savings equal - $2,052 (-35%) or -$1,083 (-28%), respectively, in favor of IV NAC. Similar potential savings were estimated for patients presenting 10-24 hours post-ingestion.<br><br>CONCLUSION: IV NAC is the less costly therapeutic option for APAP poisonings, based on simulation modeling and retrospective data. The current economic evaluation is restricted by the absence of comparative data from head-to-head, matched-cohort studies and the limitations common to retrospective APAP toxicology datasets. Additional research could refine these results.}, }
@article {pmid19915385, year = {2010}, author = {Zhang, X and Bao, Y and Ke, L and Yu, Y}, title = {Elevated circulating free fatty acids levels causing pancreatic islet cell dysfunction through oxidative stress.}, journal = {Journal of endocrinological investigation}, volume = {33}, number = {6}, pages = {388-394}, pmid = {19915385}, issn = {1720-8386}, mesh = {Acetylcysteine/pharmacology ; Animals ; Fat Emulsions, Intravenous/pharmacology ; Fatty Acids, Nonesterified/adverse effects/*blood ; Glucose/metabolism ; Glucose Tolerance Test ; Glutathione/metabolism ; Insulin/*metabolism ; Insulin Secretion ; Islets of Langerhans/*drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Elevated plasma free fatty acids (FFA) concentration is predictive of the conversion from normal glucose tolerance and impaired glucose tolerance to diabetes.<br><br>AIMS: To evaluate the effects of prolonged exposure to FFA on basal and glucose-stimulated insulin secretion (GSIS) of pancreatic beta-cell, and to investigate the role of oxidative stress in FFA-induced decrease in beta-cell function.<br><br>METHODS: Rats were assigned to 3 groups and underwent 96-h infusions of normal saline (NS), intralipid plus heparin (IH), or intralipid plus heparin and N-acetylcysteine (IH+NAC). The plasma insulin, malonyldialdehyde (MDA), reduced glutathione (GSH), and oxidized glutathione (GSSG) were measured. In vivo intravenous glucose tolerance test (IVGTT) and ex vivo isolated pancreatic tissues perfusion were performed.<br><br>RESULTS: In IH group GSIS both in IVGTT and perifused pancreatic tissues were impaired (p<0.05), the GSH/GSSG ratio was declined and MDA levels increased (p<0.05), the volume density score of nuclear factor kappaB and inducible nitric oxide synthase in pancreatic islets were increased compared to the NS group (p<0.01). In IH+NAC group, NAC intervention partly restored the GSH/GSSG ratio and MDA level, and improved FFA induced GSIS impairment.<br><br>CONCLUSION: Elevated circulating FFA levels may contribute to causing the abnormalities of pancreatic islet cell function through active oxidative stress and oxidative stress-sensitive signaling pathway, which may play a key role in the development of impaired insulin secretion seen in obese Type 2 diabetes.}, }
@article {pmid19915165, year = {2010}, author = {Li, H and Jiang, LS and Dai, LY}, title = {High glucose potentiates collagen synthesis and bone morphogenetic protein-2-induced early osteoblast gene expression in rat spinal ligament cells.}, journal = {Endocrinology}, volume = {151}, number = {1}, pages = {63-74}, doi = {10.1210/en.2009-0833}, pmid = {19915165}, issn = {1945-7170}, mesh = {Animals ; Bone Morphogenetic Protein 2/*pharmacology ; Cell Differentiation/drug effects/*genetics ; Cells, Cultured ; Collagen Type I/*biosynthesis ; Dose-Response Relationship, Drug ; Drug Synergism ; Gene Expression Regulation, Developmental/drug effects ; Glucose/*pharmacology ; Longitudinal Ligaments/drug effects/metabolism/*physiology ; Male ; Osteoblasts/*drug effects/metabolism/physiology ; Osteogenesis/drug effects/genetics ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Up-Regulation/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism/physiology ; }, abstract = {Type 2 diabetes mellitus (T2DM) is an independent risk factor for ossification of the posterior longitudinal ligament, but the mechanism is unclear. We isolated cells from rat cervical spine ligaments and studied the effects of high glucose on expression of osteoblast genes to provide insight into molecular mechanism. Using these cells, high glucose stimulated the synthesis of type I collagen and significantly potentiated expression of early osteoblast genes (Runx2; alkaline phosphatase, ALP; and osteopontin, OP) induced by bone morphogenetic protein-2 (BMP-2). Notably, these effects of high glucose were fully mimicked and augmented by H(2)O(2), although blocked by the reactive oxygen species inhibitor N-acetyl cysteine. Furthermore, exposure of these cells to high glucose significantly suppressed the phosphorylation of p38MAPK while enhancing the phosphorylation of protein kinase C (PKC) in the cells. Consistent with these observations, an inhibitor of p38 augmented the potentiation of high glucose on BMP-2-induced early osteogenic gene expression, whereas the PKC inhibitor repressed the effect of high glucose on type I collagen synthesis of the cells. In conclusion, high glucose, via production of reactive oxygen species, subsequent activation of PKC, and inhibition of p38, enhances type I collagen synthesis and expression of early osteogenesis genes induced by BMP-2 in rat spinal ligament cells. Hyperglycemia may play an important role in the onset or progression of ossification of the posterior longitudinal ligament by promoting the responsiveness of ligament cells to osteogenic differentiation.}, }
@article {pmid19913985, year = {2010}, author = {Kim, K and Jo, YH and Rhee, JE and Kim, TY and Lee, JH and Lee, JH and Kwon, WY and Suh, GJ and Lee, CC and Singer, AJ}, title = {Effect of speed of rewarming and administration of anti-inflammatory or anti-oxidant agents on acute lung injury in an intestinal ischemia model treated with therapeutic hypothermia.}, journal = {Resuscitation}, volume = {81}, number = {1}, pages = {100-105}, doi = {10.1016/j.resuscitation.2009.09.020}, pmid = {19913985}, issn = {1873-1570}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Acute Lung Injury/physiopathology/*therapy ; Animals ; Dexamethasone/administration &amp; dosage/*pharmacology ; Disease Models, Animal ; Hypothermia, Induced/*methods ; Intestines/*blood supply ; Ischemia/*therapy ; Pyruvic Acid/administration &amp; dosage/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*therapy ; Rewarming/*methods ; Survival Rate ; Time Factors ; }, abstract = {AIM OF THE STUDY: Acute lung injury (ALI) develops in various clinical situations and is associated with high morbidity and mortality and therapeutic hypothermia (HT) has been studied to attenuate the ALI. However, the optimal method of rewarming has not been determined. We determined the effect of speed of rewarming and the administration of anti-inflammatory or anti-oxidant agents on ALI in an intestinal ischemia and reperfusion (I/R) model treated with HT.<br><br>MATERIALS AND METHODS: A Sprague-Dawley rat model of intestine ischemia and reperfusion was used. Two parallel animal experiments were conducted. In the survival study, rats (n=5 per group) underwent normothermic intestinal ischemia (60min, 36-38 degrees C) and then randomized into 7 groups with reperfusion: normothermia (NT), HT without rewarming (30-32 degrees C, HT), 2h HT+rewarming for 1h (RW1), 2h HT+rewarming for 2h (RW2), RW1+N-acetyl cysteine (RW-NAC), RW1+ethylpyruvate (RW-EP), and RW1+dexamethasone (RW+Dexa). In the second experiment, we investigated the histological and biochemical effects on the lung 4h after reperfusion (n=8 per group).<br><br>RESULTS: The survival rate was lowest after NT. The HT, RW2, and RW-Dexa groups survived longer than the RW1, RW-NAC, and RW-EP groups. ALI scores were lower in the HT, RW2, and RW-Dexa groups than RW1. Lung malondialdehyde content was also lower in these groups. Interleukin (IL)-6 was significantly higher in the RW1 group. Inducible NO synthase gene expression in lung was lower in the HT, RW2, and RW-Dexa than RW1, and serum NO was lower in the RW2 and RW-Dexa than RW1.<br><br>CONCLUSION: Gradual rewarming and administration of dexamethasone improved survival and attenuated ALI after intestinal I/R injury treated with HT in rats.}, }
@article {pmid19911182, year = {2010}, author = {Aktaş, BK and Bulut, S and Bulut, S and Baykam, MM and Ozden, C and Senes, M and Yücel, D and Memiş, A}, title = {The effects of N-acetylcysteine on testicular damage in experimental testicular ischemia/reperfusion injury.}, journal = {Pediatric surgery international}, volume = {26}, number = {3}, pages = {293-298}, pmid = {19911182}, issn = {1437-9813}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Disease Models, Animal ; Male ; Malondialdehyde/metabolism ; Peroxidase/metabolism ; Random Allocation ; Rats ; Rats, Wistar ; Reperfusion Injury/*drug therapy ; Spermatic Cord Torsion/*drug therapy/metabolism/pathology ; Statistics, Nonparametric ; Testis/*blood supply/*drug effects/metabolism/pathology ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {PURPOSE: The aim of this study to evaluate the effects of N-acetylcysteine (NAC) on testicular damage in a rat testicular ischemia-reperfusion (I/R) injury model.<br><br>METHODS: Thirty male Wistar albino rats were divided into five groups. Group 1: sham control, Group 2: torsion (T), Group 3: torsion/detorsion (T/D), Group 4: the early NAC treatment plus T/D, 20 mg/kg of NAC was given intravenously 60 min before detorsion; Group 5: the late NAC treatment plus T/D, 20 mg/kg of NAC was given intravenously 5 min before detorsion. After torsion (2 h) and detorsion (2 h), bilateral orchiectomies were performed to determine the tissue levels of malondialdehyde (MDA) or more exactly thiobarbituric acid reactive substance (TBARS), myeloperoxidase activity and histopathological changes.<br><br>RESULTS: The most significant increase in the mean TBARS level and decrease in the mean seminiferous tubular diameter, germinal epithelial cell thickness values in bilateral testes were observed in T/D group rather than other groups. TBARS levels of early NAC treatment group were significantly lowered and histological parameters of spermatogenesis were significantly improved in bilateral testes when compared with T and T/D groups.<br><br>CONCLUSION: Our results suggest that the early administration of NAC may have a protective effect in the rat experimental testicular T/D models.}, }
@article {pmid19903460, year = {2010}, author = {Nakahara, T and Sato, H and Shimizu, T and Tanaka, T and Matsui, H and Kawai-Kowase, K and Sato, M and Iso, T and Arai, M and Kurabayashi, M}, title = {Fibroblast growth factor-2 induces osteogenic differentiation through a Runx2 activation in vascular smooth muscle cells.}, journal = {Biochemical and biophysical research communications}, volume = {394}, number = {2}, pages = {243-248}, doi = {10.1016/j.bbrc.2009.11.038}, pmid = {19903460}, issn = {1090-2104}, mesh = {Animals ; Atherosclerosis/genetics/metabolism ; CSK Tyrosine-Protein Kinase ; Cell Differentiation ; Cells, Cultured ; Core Binding Factor Alpha 1 Subunit/genetics/*metabolism ; Fibroblast Growth Factor 2/pharmacology/*physiology ; Gene Expression ; Gene Knockdown Techniques ; Genetic Markers ; Humans ; Hydrogen Peroxide/metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Muscle, Smooth, Vascular/*cytology/metabolism ; Myocytes, Smooth Muscle/*cytology/metabolism ; Osteoblasts/*metabolism ; *Osteogenesis ; Osteopontin/genetics ; Protein-Tyrosine Kinases/metabolism ; Rats ; Receptor, Fibroblast Growth Factor, Type 1/metabolism ; Transcriptional Activation ; src-Family Kinases ; }, abstract = {Expression of bone-associated proteins and osteoblastic transcription factor Runx2 in arterial cells has been implicated in the development of vascular calcification. However, the signaling upstream of the Runx2-mediated activation of osteoblastic program in vascular smooth muscle cells (VSMC) is poorly understood. We examined the effects of fibroblast growth factor-2 (FGF-2), an important regulator of bone formation, on osteoblastic differentiation of VSMC. Stimulation of cultured rat aortic SMC (RASMC) with FGF-2 induced the expression of the osteoblastic markers osteopontin (OPN) and osteocalcin. Luciferase assays showed that FGF-2 induced osteocyte-specific element (OSE)-dependent transcription. Downregulation of Runx2 by siRNA repressed the basal and FGF-2-stimulated expression of the OPN gene in RASMC. FGF-2 produced hydrogen peroxide in RASMC, as evaluated by fluorescent probe. Induction of OPN expression by FGF-2 was inhibited not only by PD98059 (MEK1 inhibitor) and PP1 (c-Src inhibitor), but also by an antioxidant, N-acetyl cysteine. Nuclear extracts from FGF-2-treated RASMC exhibited increased DNA-binding of Runx2 to its target sequence. Immunohistochemistry of human coronary atherectomy specimens and calcified aortic tissues showed that expression of FGF receptor-1 and Runx2 was colocalized. In conclusion, these results suggest that FGF-2 plays a role in inducing osteoblastic differentiation of VSMC by activating Runx2 through mitogen-activated protein kinase (MAPK)-dependent- and oxidative stress-sensitive-signaling pathways.}, }
@article {pmid19899620, year = {2009}, author = {El-Feky, MA and El-Rehewy, MS and Hassan, MA and Abolella, HA and Abd El-Baky, RM and Gad, GF}, title = {Effect of ciprofloxacin and N-acetylcysteine on bacterial adherence and biofilm formation on ureteral stent surfaces.}, journal = {Polish journal of microbiology}, volume = {58}, number = {3}, pages = {261-267}, pmid = {19899620}, issn = {1733-1331}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/pharmacology ; Bacteria/*drug effects/ultrastructure ; Bacterial Physiological Phenomena ; Biofilms/*drug effects ; Ciprofloxacin/*pharmacology ; Stents/*microbiology ; Ureter ; }, abstract = {The aim of this study was to evaluate the effect of ciprofloxacin (CIP), N-acetylcysteine (NAC) alone and in combination on biofilm production and pre-formed mature biofilms on ureteral stent surfaces. Two strains each of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Klebseilla pneumoniae, Pseudomonas aeruginosa and Proteus vulgaris, recently isolated from patients undergoing ureteral stent removal and shown to be capable of biofilm production, were used in this study. The inhibitory effects of ciprofloxacin, N-acetylcysteine and ciprofloxacin/N-acetylcysteine combination were determined by static adherence assay. Ciprofloxacin (MIC and 2 MIC) and N-acetylcysteine (2 and 4 mg/ml) inhibited biofilm production by > or = 60% in all tested microorganisms. Disruption of pre-formed biofilms of all tested microorganisms was found to be > or = 78% in the presence of ciprofloxacin (MIC and 2 MIC) and > or = 62% in the presence of N-acetylcysteine (2 and 4 mg/ml), compared to controls. Ciprofloxacin/N-acetylcysteine showed the highest inhibitory effect on biofilm production (94-100%) and the highest disruptive effect on the pre-formed biofilms (86-100%) in comparison to controls. N-acetylcysteine was found to increase the therapeutic efficacy of ciprofloxacin by degrading the extracellular polysaccharide matrix of biofilms. These data are statistically significant. The inhibitory effects of ciprofloxacin and N-acetylcysteine on biofilm production were also verified by scanning electron microscope (SEM). In conclusion, Ciprofloxacin/N-acetylcysteine combinations have the highest inhibitory effect on biofilm production and the highest ability to eradicate pre-formed mature biofilms.}, }
@article {pmid19896998, year = {2010}, author = {Navath, RS and Wang, B and Kannan, S and Romero, R and Kannan, RM}, title = {Stimuli-responsive star poly(ethylene glycol) drug conjugates for improved intracellular delivery of the drug in neuroinflammation.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {142}, number = {3}, pages = {447-456}, pmid = {19896998}, issn = {1873-4995}, support = {N01 HD023342/HD/NICHD NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/*pharmacology ; Cell Line ; Drug Carriers/*chemistry ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glutathione/metabolism ; Lipopolysaccharides/toxicity ; Mice ; Microglia/*drug effects/metabolism ; Nitric Oxide/metabolism ; Polyethylene Glycols/*chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {N-Acetyl cysteine (NAC) is a vital drug currently under clinical trials for the treatment of neuroinflammation in maternal-fetal applications. The free sulfhydryl groups in NAC lead to high plasma protein binding, resulting in low bioavailability. Preparation and activity of conjugates of NAC with thiol terminated multi-arm (6 and 8) poly(ethylene-glycol) (PEG) with disulfide linkages involving sulfhydryls of NAC are reported. Multiple copies (5 and 7) of NAC were conjugated on 6 and 8-arm-PEG respectively. Both the conjugates released 74% of NAC within 2h by thiol exchange reactions in the redox environment provided by glutathione (GSH) intracellularly (2-10mM). At physiological extracellular glutathione concentration (2 microM) both the conjugates were stable and did not release NAC. MTT assay showed comparable cell viability for unmodified PEGs and both the PEG-S-S-NAC conjugates. The conjugates were readily endocytosed by cells, as confirmed by flow cytometry and confocal microscopy. Efficacy of 6 and 8-arm-PEG-S-S-NAC conjugates was evaluated on activated microglial cells (the target cells, in vivo) by monitoring cytokine release in lipopolysaccharide (LPS) induced inflammatory response in microglial cells using the reactive oxygen species (ROS), free radical nitrile (NO), anti-inflammatory activity and GSH depletion. The conjugates showed significant increase in antioxidant activity (more than a factor of 2) compared to free drug as seen from the inhibition of LPS induced ROS, NO, GSH and tumor necrosis factor-alpha (TNF-alpha) release in microglial cells.}, }
@article {pmid19892008, year = {2010}, author = {Chandrasekaran, K and Swaminathan, K and Chatterjee, S and Dey, A}, title = {Apoptosis in HepG2 cells exposed to high glucose.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {24}, number = {2}, pages = {387-396}, doi = {10.1016/j.tiv.2009.10.020}, pmid = {19892008}, issn = {1879-3177}, mesh = {Annexins/metabolism ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular ; Caspase 3/metabolism ; Cell Line, Tumor ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Glucose/administration &amp; dosage/*toxicity ; Humans ; L-Lactate Dehydrogenase ; Liver Neoplasms ; Mannitol/pharmacology ; Staining and Labeling ; Time Factors ; }, abstract = {Hyperglycemia which characterizes diabetes, leads to several abnormalities in the cellular pathways. We examined the toxicity of glucose in human hepatoma HepG2 cells. HepG2 cells when incubated with 50mM glucose for 72h showed altered morphology i.e. presence of detached and shrunken rounded cells. Glucose treated HepG2 cells also exhibited a significant decrease in viability. Caspase-3 activity and Annexin V staining were significantly increased in glucose treated HepG2 cells, suggesting an apoptotic mode of cell death. Glucose induced apoptosis in HepG2 cells was a consequence of increased oxidative stress as evidenced by the increased reactive oxygen species (ROS) level, lipid peroxidation, protein carbonyl and 3-nitrotyrosine adduct formation. The intracellular antioxidant glutathione was found to be increased in HepG2 cells treated with glucose, possibly to aid the cells to overcome the persistent oxidative stress elicited by glucose in HepG2 cells. N-Acetyl cysteine, a precursor of glutathione and an antioxidant was effective in reversing the morphological changes, increasing the viability, decreasing the ROS level and 4-hydroxynonenal and 3-nitrotyrosine adduct formation, thus validating the role of oxidative stress as a major mechanism for glucose induced apoptosis in HepG2 cells. These results suggest that glucose induces apoptosis in liver cells through increased oxidative stress.}, }
@article {pmid19885844, year = {2010}, author = {Chen, SC and Guh, JY and Hwang, CC and Chiou, SJ and Lin, TD and Ko, YM and Huang, JS and Yang, YL and Chuang, LY}, title = {Advanced glycation end-products activate extracellular signal-regulated kinase via the oxidative stress-EGF receptor pathway in renal fibroblasts.}, journal = {Journal of cellular biochemistry}, volume = {109}, number = {1}, pages = {38-48}, doi = {10.1002/jcb.22376}, pmid = {19885844}, issn = {1097-4644}, mesh = {Animals ; ErbB Receptors/*metabolism ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Fibroblasts/*metabolism/pathology ; Glycation End Products, Advanced/*metabolism ; Immunoblotting ; Kidney/*metabolism/pathology ; Oxidative Stress/*physiology ; Phosphorylation ; RNA, Small Interfering ; Rats ; Reactive Oxygen Species/metabolism ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic/metabolism ; Signal Transduction/physiology ; Transfection ; }, abstract = {Advanced glycation end-products (AGEs), epidermal growth factor receptor (EGFR), reactive oxygen species (ROS), and extracellular signal-regulated kinases (ERK) are implicated in diabetic nephropathy (DN). Therefore, we asked if AGEs-induced ERK protein phosphorylation and mitogenesis are dependent on the receptor for AGEs (RAGE)-ROS-EGFR pathway in normal rat kidney interstitial fibroblast (NRK-49F) cells. We found that AGEs (100 microg/ml) activated EGFR and ERK1/2, which was attenuated by RAGE short-hairpin RNA (shRNA). AGEs also increased RAGE protein and intracellular ROS levels while RAGE shRNA and N-acetylcysteine (NAC) attenuated AGEs-induced intracellular ROS. Hydrogen peroxide (5-25 microM) increased RAGE protein level while activating both EGFR and ERK1/2. Low-dose hydrogen peroxide (5 microM) increased whereas high-dose hydrogen peroxide (100 microM) decreased mitogenesis at 3 days. AGEs-activated EGFR and ERK1/2 were attenuated by an anti-oxidant (NAC) and an EGFR inhibitor (Iressa). Moreover, AGEs-induced mitogenesis was attenuated by RAGE shRNA, NAC, Iressa, and an ERK1/2 inhibitor (PD98059). In conclusion, it was found that AGEs-induced mitogenesis is dependent on the RAGE-ROS-EGFR-ERK1/2 pathway whereas AGEs-activated ERK1/2 is dependent on the RAGE-ROS-EGFR pathway in NRK-49F cells.}, }
@article {pmid19885829, year = {2010}, author = {Oda, A and Tamaoka, A and Araki, W}, title = {Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells.}, journal = {Journal of neuroscience research}, volume = {88}, number = {5}, pages = {1137-1145}, doi = {10.1002/jnr.22271}, pmid = {19885829}, issn = {1097-4547}, mesh = {Acetylcysteine/pharmacology ; Alzheimer Disease/genetics/*metabolism/physiopathology ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/biosynthesis ; Amyloid beta-Protein Precursor/genetics/metabolism ; Antioxidants/pharmacology ; Brain/*metabolism/physiopathology ; Cell Line, Tumor ; Ethacrynic Acid/pharmacology ; Glutathione/antagonists &amp; inhibitors/deficiency ; Heme Oxygenase-1/metabolism ; Humans ; Membrane Microdomains/*metabolism ; Mutation/physiology ; Neurons/*metabolism ; Oxidative Stress/drug effects/*physiology ; Presenilin-1/genetics/*metabolism ; RNA, Messenger/drug effects/metabolism ; Up-Regulation/physiology ; }, abstract = {Oxidative stress is associated with beta-amyloid peptide (A beta) accumulation in the brains of Alzheimer's disease patients. A beta is generated upon the sequential proteolytic cleavage of transmembrane amyloid precursor protein (APP) by two membrane-bound proteases, beta-secretase (BACE1) and the gamma-secretase complex comprising presenilin 1 (PS1), nicastrin, APH-1 and PEN-2. Recent evidence suggests that significant amounts of BACE1 and gamma-secretase components localize in the cholesterol-rich region of membranes known as lipid rafts, where A beta production occurs preferentially. In this study, we investigated the effects of oxidative stress on the BACE1 and gamma-secretase components in lipid rafts using human neuroblastoma SH-SY5Y cells exposed to ethacrynic acid (EA), a compound that induces cellular glutathione depletion. Following exposure of cells to EA, heme oxygenase-1, a marker protein of oxidative stress, was strongly induced. Moreover, treatment with EA resulted in a significant increase in PS1 protein levels, but not those of nicastrin, APH-1, PEN-2 or BACE1, in both cell lysates and the lipid raft fraction. This increase in PS1 protein expression was prevented by co-treatment with an antioxidant, N-acetylcysteine (NAC). EA additionally induced a significant increase in PS1 mRNA expression, which was inhibited by NAC. Finally, EA treatment was found to promote A beta secretion from cells expressing Swedish mutant APP. It appears that in our cell culture model, oxidative stress enhances PS1 protein levels in lipid rafts via up-regulation of PS1 transcription, which may constitute the mechanism underlying the oxidative stress-associated promotion of A beta production.}, }
@article {pmid19885621, year = {2009}, author = {Chen, HM and Yan, XJ and Mai, TY and Wang, F and Xu, WF}, title = {Lambda-carrageenan oligosaccharides elicit reactive oxygen species production resulting in mitochondrial-dependent apoptosis in human umbilical vein endothelial cells.}, journal = {International journal of molecular medicine}, volume = {24}, number = {6}, pages = {801-806}, doi = {10.3892/ijmm_00000295}, pmid = {19885621}, issn = {1791-244X}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects/physiology ; Apoptosis Regulatory Proteins/metabolism ; Carrageenan/*pharmacology ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Cycle/drug effects ; Cell Nucleus/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Endothelial Cells ; Flow Cytometry ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/physiology ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/metabolism ; Umbilical Veins ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Previous studies have shown that highly sulfated lambda-carrageenan oligosaccharides (lambda-CO) possess an anti-angiogenetic effect, while high concentrations of lambda-CO present a cytotoxic effect towards human umbilical vein endothelial cells (HUVECs). The aim of this study was to explore the underlying mechanism of lambda-CO on inhibiting cell proliferation. lambda-CO elicited reactive oxygen species (ROS) production with concentrations at 0.8 and 1 mg/ml, and this event was accompanied by the increase of early apoptotic cells, nuclear morphology changes and cell cycle arrest at the S and G2/M phases. However, prevention of oxidative stress by N-acetyl-L-cysteine (NAC) could abolish the effect of lambda-CO on these events. Yet, lambda-CO induced a depolarization of mitochondrial transmembrane potential. At 0.8 mg/ml, lambda-CO induced up-regulation of p53 and Bax, down-regulation of Bcl-2 and activation of caspase-9 and -3. These results suggest that exposure to a high concentration of lambda-CO activates the mitochondrial-mediated apoptotic pathway and cell cycle arrest by generation of ROS.}, }
@article {pmid19882352, year = {2010}, author = {El-Najjar, N and Chatila, M and Moukadem, H and Vuorela, H and Ocker, M and Gandesiri, M and Schneider-Stock, R and Gali-Muhtasib, H}, title = {Reactive oxygen species mediate thymoquinone-induced apoptosis and activate ERK and JNK signaling.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {15}, number = {2}, pages = {183-195}, doi = {10.1007/s10495-009-0421-z}, pmid = {19882352}, issn = {1573-675X}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Colonic Neoplasms/enzymology/pathology ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; MAP Kinase Signaling System/*drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Thymoquinone (TQ), a component of black seed essential oil, is known to induce apoptotic cell death and oxidative stress, however, the direct involvement of oxidants in TQ-induced cell death has not been established yet. Here, we show that TQ inhibited the proliferation of a panel of human colon cancer cells (Caco-2, HCT-116, LoVo, DLD-1 and HT-29), without exhibiting cytotoxicity to normal human intestinal FHs74Int cells. Further investigation in DLD-1 revealed that apoptotic cell death is the mechanism for TQ-induced growth inhibition as confirmed by flow cytometry, M30 cytodeath and caspase-3/7 activation. Apoptosis was induced via the generation of reactive oxygen species (ROS) as evidenced by the abrogation of TQ apoptotic effect in cells preincubated with the strong antioxidant N-acetyl cysteine (NAC). TQ increased the phosphorylation states of the mitogen-activated protein kinases (MAPK) JNK and ERK, but not of p38. Their activation was completely abolished in the presence of NAC. Using PD98059 and SP600125, specific ERK and JNK inhibitors, the two kinases were found to possess pro-survival activities in TQ-induced cell death. These data present evidence linking the pro-oxidant effects of TQ with its apoptotic effects in colon cancer and prove a protective role of MAPK.}, }
@article {pmid19879309, year = {2010}, author = {Abdalla, FH and Bellé, LP and De Bona, KS and Bitencourt, PE and Pigatto, AS and Moretto, MB}, title = {Allium sativum L. extract prevents methyl mercury-induced cytotoxicity in peripheral blood leukocytes (LS).}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {48}, number = {1}, pages = {417-421}, doi = {10.1016/j.fct.2009.10.033}, pmid = {19879309}, issn = {1873-6351}, mesh = {Acetylglucosamine/pharmacology ; Adenosine Deaminase/metabolism ; Allium/*chemistry ; Antioxidants/metabolism ; Cell Survival/drug effects ; Coloring Agents ; Humans ; Immunity, Cellular/drug effects ; In Vitro Techniques ; Leukocytes/*drug effects/enzymology ; Methylmercury Compounds/*antagonists &amp; inhibitors/*toxicity ; Oxazines ; Plant Extracts/pharmacology ; Tetrazolium Salts ; Thiazoles ; Xanthenes ; }, abstract = {Adenosine deaminase (ADA) is involved in purine metabolism and plays a significant role in the immune system. The focus of this investigation was to examine the effects of low concentrations of organic mercury on ADA activity in human leukocytes and to investigate the relationship between these effects and cell death. We have examined the protective potential effects of Allium sativum extract (GaE) against Methylmercury (MeHg)-induced cytotoxic effects on human leucocytes under in vitro conditions. MeHg (0.05-10 microM) significantly decreased leukocyte viability (58.97% for MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) and 51.67% for Alamar Blue (AB) and this decrease was positively correlated to the MeHg-induced inhibition of ADA activity. N-acetylcysteine (NAC) and GaE prevented both the MeHg-induced cytotoxic effects on leukocytes according to MTT and AB assays and the effects on the ADA activity. The present results suggest that the protective effects of GaE against MeHg-induced leukocyte damage is related to the removal of oxidant species generated in the presence of MeHg due to the antioxidant efficacy of garlic constituents. It is important to point out that the intense presence of ADA in Leukocyte suspension (LS) highlights the relevant effects in the immune system and in vitro cytotoxicity of MeHg exposure.}, }
@article {pmid19878651, year = {2009}, author = {Curbo, S and Gaudin, R and Carlsten, M and Malmberg, KJ and Troye-Blomberg, M and Ahlborg, N and Karlsson, A and Johansson, M and Lundberg, M}, title = {Regulation of interleukin-4 signaling by extracellular reduction of intramolecular disulfides.}, journal = {Biochemical and biophysical research communications}, volume = {390}, number = {4}, pages = {1272-1277}, doi = {10.1016/j.bbrc.2009.10.134}, pmid = {19878651}, issn = {1090-2104}, mesh = {Auranofin/pharmacology ; Cystine/chemistry/*metabolism ; Ethylmaleimide/pharmacology ; HeLa Cells ; Humans ; Interleukin-4/chemistry/*metabolism ; Interleukin-4 Receptor alpha Subunit/chemistry/*metabolism ; Oxidation-Reduction ; Protein Disulfide-Isomerases/chemistry/metabolism ; Signal Transduction ; Thioredoxins/chemistry/metabolism ; }, abstract = {Interleukin-4 (IL-4) contains three structurally important intramolecular disulfides that are required for the bioactivity of the cytokine. We show that the cell surface of HeLa cells and endotoxin-activated monocytes can reduce IL-4 intramolecular disulfides in the extracellular space and inhibit binding of IL-4 to the IL-4Ralpha receptor. IL-4 disulfides were in vitro reduced by thioredoxin 1 (Trx1) and protein disulfide isomerase (PDI). Reduction of IL-4 disulfides by the cell surface of HeLa cells was inhibited by auranofin, an inhibitor of thioredoxin reductase that is an electron donor to both Trx1 and PDI. Both Trx1 and PDI have been shown to be located at the cell surface and our data suggests that these enzymes are involved in catalyzing reduction of IL-4 disulfides. The pro-drug N-acetylcysteine (NAC) that promotes T-helper type 1 responses was also shown to mediate the reduction of IL-4 disulfides. Our data provides evidence for a novel redox dependent pathway for regulation of cytokine activity by extracellular reduction of intramolecular disulfides at the cell surface by members of the thioredoxin enzyme family.}, }
@article {pmid19877502, year = {2009}, author = {Gao, P and He, P and Wang, A and Xia, T and Xu, Z and Niu, Q and Guo, L and Chen, X}, title = {[Effects of PCB153 on oxidative stress and 8-OHdG content induced by PBDE-47 in human neuroblastoma cells in vitro].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {38}, number = {5}, pages = {513-515}, pmid = {19877502}, issn = {1000-8020}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Cell Line, Tumor ; DNA Damage/*drug effects ; Deoxyguanosine/*analogs &amp; derivatives/metabolism ; Halogenated Diphenyl Ethers/*toxicity ; Humans ; Neuroblastoma/metabolism/pathology ; Oxidative Stress/*drug effects ; Polychlorinated Biphenyls/*toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: To explore the effects of PCB153 (2,2,4,4,5,5-hexachlorobiphenyl) on oxidative stress and 8-OHdG (8-hydroxy-2'-deoxyguanosine) content induced by PBDE-47 (2,2,4,4-tetrabromodiphenyl ether) in SH-SY5Y cells.<br><br>METHODS: SH-SY5Y cells were incubated with different concentrations of 1, 5, 10 micromol/L PBDE-47 or/and 5 micromol/L PCB153 and antioxidant N-acetyl cysteine (NAC 100 micromol/L) for 24h in vitro, ROS (reactive oxygen species) level and 8-OHdG were measured by using DCFH-DA fluorescent marking method and the skill of high performance liquid chromatogram-electrochemistry (HPLC-EC), respectively.<br><br>RESULTS: As for ROS formation, there was no significant difference in PBDE-47 groups alone compared to the control group and their corresponding combined groups, respectively (P > 0.05). ROS formation were significantly increased in 5 and 10 micromol/L combined groups compared to the control group and their corresponding concentrations of PBDE-47 groups or PCB153 group, respectively (P < 0.05). 8-OHdG levels were significantly increased in 10 micromol/L PBDE-47, 5 micromol/L PBDE-47 + 5 micromol/L PCB153, and 10 micromol/L PBDE-47 + 5 micromol/L PCB153 groups compared with the control (P < 0.05). 8-OHdG level was dramatically increased in 10 micromol/L PBDE-47 + 5 micromol/L PCB153 groups compared to their corresponding doses of PBDE-47 groups or PCB153 group (P < 0.05). The groups coincubation with N-acetylcysteine caused a decrease in cellular ROS level and ameliorated PBDE-47-mediated oxidative DNA damage effects. Positive relationship was observed between ROS level and 8-OHdG contents (r = 0.895, P < 0.01).<br><br>CONCLUSION: These results provide evidence of a direct or indirect relationship between PBDE-47 and oxidative DNA damage. Furthermore, PBDE-47 combined with PCB153 may increase the effects on oxidative DNA damage in SH-SY5Y cells in vitro, oxidative stress may responsible for DNA damage induced by PBDE-47.}, }
@article {pmid19876849, year = {2009}, author = {Betten, DP and Burner, EE and Thomas, SC and Tomaszewski, C and Clark, RF}, title = {A retrospective evaluation of shortened-duration oral N-acetylcysteine for the treatment of acetaminophen poisoning.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {5}, number = {4}, pages = {183-190}, pmid = {19876849}, issn = {1556-9039}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adolescent ; Adult ; Aged ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*administration &amp; dosage ; California ; Chemical and Drug Induced Liver Injury/etiology/*prevention &amp; control ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Poison Control Centers ; Poisoning/drug therapy ; Practice Guidelines as Topic ; Retrospective Studies ; Treatment Outcome ; Young Adult ; }, abstract = {INTRODUCTION: The use of less than the traditional 72-hour course of oral N-acetylcysteine has been an alternative treatment option following potentially toxic acute and chronic acetaminophen ingestions felt to be at low risk of developing hepatotoxicity. While clinical experience with shortened treatment duration is extensive, there are few studies evaluating the effectiveness and extent to which these regimens may be used.<br><br>METHODS: A large statewide poison center database was reviewed for all acetaminophen exposures involving potentially toxic acute and chronic ingestions, in addition to those taking place at unknown times. Patients were identified who met laboratory criteria for early N-acetylcysteine (NAC) discontinuation (APAP>10 micro/mL, INR<or=1.3, and AST/ALT<or=60 IU) after a minimum of a 140-mg/kg oral NAC loading dose and 5 additional 70-mg/kg doses over 20 hours. A further search of the poison center database was conducted for individuals who received shortened-course (20-48 hours) oral NAC treatment who developed subsequent hepatotoxicity or death.<br><br>RESULTS: Of 3303 individuals with potentially toxic acetaminophen ingestions, 1932 met criteria for early NAC discontinuation. Mean treatment duration was 36.4+/-7.7 hours (acute=37.3+/-7.6 hours; chronic=34.8+/-7.4 hours; unknown=35.2+/-7.6 hours). The poison center database search identified no short-course eligible subjects who developed subsequent hepatotoxicity or death following<or=48 hours of oral NAC.<br><br>CONCLUSION: Treatment with shortened-course oral NAC in patients meeting criteria for early discontinuation may be an effective treatment option in a sizeable proportion of individuals with potentially toxic acetaminophen ingestions.}, }
@article {pmid19874809, year = {2010}, author = {Feng, B and Guo, YW and Huang, CG and Li, L and Chen, RH and Jiao, BH}, title = {2'-epi-2'-O-Acetylthevetin B extracted from seeds of Cerbera manghas L. induces cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells.}, journal = {Chemico-biological interactions}, volume = {183}, number = {1}, pages = {142-153}, doi = {10.1016/j.cbi.2009.10.012}, pmid = {19874809}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Antineoplastic Agents/chemistry/isolation &amp; purification/*pharmacology ; Apocynaceae/*chemistry ; *Apoptosis ; Apoptosis Inducing Factor/metabolism ; CDC2 Protein Kinase/metabolism ; Carcinoma, Hepatocellular/*drug therapy ; Cardiac Glycosides/chemistry/isolation &amp; purification/*pharmacology ; Caspase 9/metabolism ; Cyclin B1/metabolism ; G2 Phase ; Hep G2 Cells ; Humans ; Liver Neoplasms/*drug therapy ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; S Phase ; Seeds/chemistry ; }, abstract = {2'-epi-2'-O-Acetylthevetin B (GHSC-74) is a cardiac glycoside isolated from the seeds of Cerbera manghas L. We have demonstrated that GHSC-74 reduced the viability of HepG2 cells in a time- and dose-dependent manner. The present study was designed to explore cellular mechanisms whereby GHSC-74 led to cell cycle arrest and apoptosis in HepG2 cells. Cell cycle flow cytometry demonstrated that HepG2 cells treated with GHSC-74 (4microM) resulted in S and G2 phase arrest in a time-dependent manner, as confirmed by mitotic index analysis. G2 phase arrest was accompanied with down-regulation of CDC2 and Cyclin B1 protein. Furthermore, GHSC-74-induced apoptotic killing, as demonstrated by DNA fragmentation, DAPI staining, and flow cytometric detection of sub-G1 DNA content in HepG2 cells. GHSC-74 treatment resulted in a significant increase in reactive oxygen species, activation of caspase-9, dissipation of mitochondrial membrane potential, and translocation of apoptosis-inducing factor (AIF) from the mitochondrion to the nucleus in HepG2 cells. Nevertheless, after GHSC-74 exposure, no significant Fas and FasL up-regulation was observed in HepG2 cells by flow cytometry. In addition, treatment with antioxidant N-acetyl-l-cysteine (NAC) and broad-spectrum caspase inhibitor z-VAD-fmk partially prevented apoptosis but did not abrogate GHSC-74-induced nuclear translocation of AIF. In conclusion, we have demonstrated that GHSC-74 inhibited growth of HepG2 cells by inducing S and G2 phase arrest of the cell cycle and by triggering apoptosis via mitochondrial disruption including both caspase-dependent and -independent pathways, and ROS generation.}, }
@article {pmid19864926, year = {2010}, author = {Jantzie, LL and Cheung, PY and Johnson, ST and Bigam, DL and Todd, KG}, title = {Cerebral amino acid profiles after hypoxia-reoxygenation and N-acetylcysteine treatment in the newborn piglet.}, journal = {Neonatology}, volume = {97}, number = {3}, pages = {195-203}, doi = {10.1159/000252972}, pmid = {19864926}, issn = {1661-7819}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Amino Acids/analysis/*metabolism ; Animals ; Animals, Newborn ; Antioxidants/administration &amp; dosage/pharmacology ; Asphyxia Neonatorum/drug therapy/metabolism ; Cerebrum/chemistry/*metabolism ; Disease Models, Animal ; Drug Administration Schedule ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Humans ; Hypoxia, Brain/*metabolism/rehabilitation ; Hypoxia-Ischemia, Brain/drug therapy/metabolism ; Infant, Newborn ; Metabolome/drug effects ; Oxygen/*pharmacology ; Reperfusion Injury/metabolism ; Resuscitation ; Swine ; }, abstract = {BACKGROUND: Neonatal hypoxia-ischemia (HI) is a common clinical occurrence. Recently, much evidence has been gathered to suggest that oxygen free radicals are implicated in the pathogenesis of hypoxia-reoxygenation injury through the initiation and propagation of toxic cascades including glutamate excitotoxicity and the manifestation of post-HI neurologic disorders. Following HI, excessive free radicals are formed and antioxidant defenses are diminished. N-acetylcysteine (NAC) is a clinically available antioxidant and has been previously shown to reduce oxidative stress and scavenge free radicals in multiple models of brain injury.<br><br>OBJECTIVES: Using an acutely instrumented swine model of neonatal hypoxia-reoxygenation, the objective of the present study was to examine the neurochemical effects of NAC administration in 5 brain regions exquisitely vulnerable to severe hypoxia.<br><br>METHODS: In a blinded fashion, newborn piglets (1-4 d, 1.4-2.2 kg) were block randomized into surgical sham (SHAM), hypoxic control (HC) and NAC-treated (H-NAC) groups. Both HC and H-NAC piglets were subject to 2 h of alveolar hypoxia (paO(2) = 20-40 mm Hg) and then resuscitated with 100% O(2)for 1 h followed by 21% for an additional 3 h.<br><br>RESULTS: Our results show that two hours of severe hypoxemia causes metabolic acidosis and significant changes in cerebral amino acids including glutamate, aspartate and alanine, in all brain regions investigated including the cortex, basal ganglia and thalamus. The administration of NAC 10 min into the reoxygenation period and subsequently continued as an infusion, maintains post-resuscitation amino acid neurochemistry at the levels observed in SHAM piglets.<br><br>CONCLUSIONS: In newborn piglets that have sustained brain injury related to hypoxia/reoxygenation, the administration of NAC does not disrupt cerebral amino acid balance and maintains cerebral amino acid homeostasis.}, }
@article {pmid19864306, year = {2009}, author = {Hill, AL and Lowes, DA and Webster, NR and Sheth, CC and Gow, NA and Galley, HF}, title = {Regulation of pentraxin-3 by antioxidants.}, journal = {British journal of anaesthesia}, volume = {103}, number = {6}, pages = {833-839}, pmid = {19864306}, issn = {1471-6771}, support = {//Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; }, mesh = {APACHE ; Adult ; Aged ; Aged, 80 and over ; Antioxidants/*pharmacology ; Biomarkers/blood/metabolism ; C-Reactive Protein/*metabolism ; Cells, Cultured ; Endothelium, Vascular/cytology/drug effects/metabolism ; Female ; Humans ; Inflammation Mediators/pharmacology ; Lipid Peroxides/blood ; Male ; Middle Aged ; Oxidative Stress ; Pilot Projects ; Sepsis/*blood ; Serum Amyloid P-Component/*metabolism ; Up-Regulation/drug effects ; Young Adult ; }, abstract = {BACKGROUND: Pentraxin-3 (PTX3) may be a useful biomarker in sepsis, but its regulatory mechanisms are still unclear. Oxidative stress is well defined in patients with sepsis and has a role in regulation of inflammatory pathways which may include PTX3. We undertook an in vitro study of the effect of antioxidants on regulation of PTX3 in endothelial cells combined with a prospective observational pilot study of PTX3 in relation to markers of antioxidant capacity and oxidative stress in patients with sepsis.<br><br>METHODS: Human endothelial cells were cultured with lipopolysaccharide 2 microg ml(-1), peptidoglycan G 20 microg ml(-1), tumour necrosis factor (TNF) alpha 10 ng ml(-1), interleukin-1 (IL-1) beta 20 ng ml(-1), or killed Candida albicans yeast cells plus either N-acetylcysteine (NAC) 25 mM, trolox 100 mM, or idebenone 1 microM. Plasma samples were obtained from 15 patients with sepsis and 11 healthy volunteers.<br><br>RESULTS: PTX3 levels in plasma were higher in patients with sepsis than in healthy people [26 (1-202) ng ml(-1) compared with 6 (1-12) ng ml(-1), P=0.01]. Antioxidant capacity was lower in patients with sepsis than healthy controls [0.99 (0.1-1.7) mM compared with 2.2 (1.3-3.3) mM, P=0.01]. In patients with sepsis, lipid hydroperoxide levels were 3.32 (0.3-10.6) nM and undetectable in controls. We found no relationship between PTX3 and antioxidant capacity or lipid hydroperoxides. Cell expression of PTX3 increased with all inflammatory stimulants but was highest in cells treated with TNFalpha plus IL-1beta. PTX3 concentrations were lower in cells co-treated with antioxidants (all P<0.05), associated with lower nuclear factor kappaB expression for NAC and trolox (P<0.05).<br><br>CONCLUSIONS: PTX3 expression is down-regulated in vitro by antioxidants. Plasma levels of PTX3 are elevated in sepsis but seem to be unrelated to markers of oxidant stress or antioxidant capacity.}, }
@article {pmid19864300, year = {2010}, author = {Kim, J and Jang, HS and Park, KM}, title = {Reactive oxygen species generated by renal ischemia and reperfusion trigger protection against subsequent renal ischemia and reperfusion injury in mice.}, journal = {American journal of physiology. Renal physiology}, volume = {298}, number = {1}, pages = {F158-66}, doi = {10.1152/ajprenal.00474.2009}, pmid = {19864300}, issn = {1522-1466}, mesh = {Acetylcysteine/pharmacology ; Animals ; Catalase/metabolism ; Creatinine/blood ; Disease Models, Animal ; Heat-Shock Proteins/metabolism ; *Ischemic Preconditioning ; Kidney/drug effects/*metabolism ; Kidney Diseases/metabolism/*prevention &amp; control ; Male ; Metalloporphyrins/pharmacology ; Mice ; Mice, Inbred C57BL ; Molecular Chaperones ; Neoplasm Proteins/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress/physiology ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/metabolism/*prevention &amp; control ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; }, abstract = {Ischemic preconditioning by a single event of ischemia and reperfusion (SIRPC) dramatically protects renal function against ischemia and reperfusion (I/R) induced several weeks later. We recently reported that reactive oxygen species (ROS) and oxidative stress were sustained in a kidney that had functionally recovered from I/R injury, thus suggesting an association between SIRPC and ROS and oxidative stress. However, the role of ROS in SIRPC remains to be clearly elucidated. To assess the involvement of ROS in SIRPC, mice were subjected to SIRPC (30 min of bilateral renal ischemia and 8 days of reperfusion) and then exposed to I/R injury. Thirty minutes of bilateral renal ischemia in the non-SIRPC mice resulted in a marked increase in plasma creatinine levels 4 and 24 h after reperfusion, which was not observed in the I/R in the SIRPC mice. SIRPC resulted in increases in the levels of kidney superoxide. Administrations of manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin [MnTMPyP; a cell-permeable superoxide dismutase (SOD) mimetic] and N-acetylcysteine (NAc; a ROS scavenger) to SIRPC mice blocked the SIRPC-induced increase in superoxide levels and removed approximately 48-64% of the functional protection of the SIRPC kidney. Additionally, these administrations significantly inhibited I/R-induced increases in superoxide formation, hydrogen peroxide production, and lipid peroxidation, along with the inhibition of I/R-induced reductions in the expression and activity of manganese SOD, copper-zinc SOD, and catalase. Furthermore, administrations of MnTMPyP or NAc inhibited the SIRPC-induced increase in inducible nitric oxide synthase expression but did not inhibit the SIRPC-induced increases in heat shock protein-25 expression. In conclusion, the renoprotection afforded by SIRPC was triggered by ROS generated by SIRPC.}, }
@article {pmid19861856, year = {2009}, author = {Rajapakse, S and Wijewickrama, ES}, title = {Non-dialytic management of sepsis-induced acute kidney injury.}, journal = {Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia}, volume = {20}, number = {6}, pages = {975-983}, pmid = {19861856}, issn = {1319-2442}, mesh = {Acetylcysteine/therapeutic use ; Acute Disease ; Contrast Media/adverse effects ; Dopamine/adverse effects/therapeutic use ; Evidence-Based Medicine ; Fluid Therapy ; Humans ; Hypoglycemic Agents/therapeutic use ; Insulin/therapeutic use ; Kidney Diseases/etiology/physiopathology/prevention &amp; control/*therapy ; Osmotic Pressure ; Perfusion ; Risk Assessment ; Risk Factors ; Sepsis/complications/physiopathology/*therapy ; Sodium Potassium Chloride Symporter Inhibitors/adverse effects/therapeutic use ; Treatment Outcome ; Vasoconstrictor Agents/adverse effects/therapeutic use ; }, abstract = {Sepsis is an important cause of morbidity and mortality. Acute Kidney Injury (AKI) often complicates sepsis, leading to greater complexity, higher cost of care and worsening prognosis. Despite the improved understanding of its underlying pathophysiological basis, there have been very few interventions, which have consistently been shown to be of value in the management of sepsis-induced AKI. Measures such as adequate hydration, maintenance of adequate circulating blood volume and mean arterial pressure, and avoidance of nephrotoxins, are still the mainstay of prevention. Loop diuretics, mannitol and "low dose" dopamine have been clearly shown to be of no value in the prevention or treatment of AKI and may, in fact, do harm. Among the remaining pharmacological options, N-acetylcysteine (NAC) may have a role in the prevention of radiocontrast induced AKI.}, }
@article {pmid19860915, year = {2009}, author = {Behr, J and Demedts, M and Buhl, R and Costabel, U and Dekhuijzen, RP and Jansen, HM and MacNee, W and Thomeer, M and Wallaert, B and Laurent, F and Nicholson, AG and Verbeken, EK and Verschakelen, J and Flower, CD and Petruzzelli, S and De Vuyst, P and van den Bosch, JM and Rodriguez-Becerra, E and Lankhorst, I and Sardina, M and Boissard, G and , }, title = {Lung function in idiopathic pulmonary fibrosis--extended analyses of the IFIGENIA trial.}, journal = {Respiratory research}, volume = {10}, number = {1}, pages = {101}, pmid = {19860915}, issn = {1465-993X}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Azathioprine/*therapeutic use ; Disease Progression ; Double-Blind Method ; Drug Therapy, Combination ; Europe ; Exercise Test ; Female ; Forced Expiratory Volume/drug effects ; Humans ; Idiopathic Pulmonary Fibrosis/*drug therapy/mortality/physiopathology ; Lung/*drug effects/physiopathology ; Male ; Middle Aged ; Patient Dropouts ; Prednisone/*therapeutic use ; Pulmonary Diffusing Capacity/drug effects ; Respiratory System Agents/*therapeutic use ; Severity of Illness Index ; Time Factors ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {BACKGROUND: The randomized placebo-controlled IFIGENIA-trial demonstrated that therapy with high-dose N-acetylcysteine (NAC) given for one year, added to prednisone and azathioprine, significantly ameliorates (i.e. slows down) disease progression in terms of vital capacity (VC) (+9%) and diffusing capacity (DLco) (+24%) in idiopathic pulmonary fibrosis (IPF). To better understand the clinical implications of these findings we performed additional, explorative analyses of the IFGENIA data set.<br><br>METHODS: We analysed effects of NAC on VC, DLco, a composite physiologic index (CPI), and mortality in the 155 study-patients.<br><br>RESULTS: In trial completers the functional indices did not change significantly with NAC, whereas most indices deteriorated with placebo; in non-completers the majority of indices worsened but decline was generally less pronounced in most indices with NAC than with placebo. Most categorical analyses of VC, DLco and CPI also showed favourable changes with NAC. The effects of NAC on VC, DLco and CPI were significantly better if the baseline CPI was 50 points or lower.<br><br>CONCLUSION: This descriptive analysis confirms and extends the favourable effects of NAC on lung function in IPF and emphasizes the usefulness of VC, DLco, and the CPI for the evaluation of a therapeutic effect. Most importantly, less progressed disease as indicated by a CPI of 50 points or lower at baseline was more responsive to therapy in this study.}, }
@article {pmid19856665, year = {2009}, author = {Roomi, MW and Roomi, NW and Kalinovsky, T and Rath, M and Niedzwiecki, A}, title = {Chemopreventive effect of a novel nutrient mixture on lung tumorigenesis induced by urethane in male A/J mice.}, journal = {Tumori}, volume = {95}, number = {4}, pages = {508-513}, doi = {10.1177/030089160909500417}, pmid = {19856665}, issn = {0300-8916}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antineoplastic Agents/*therapeutic use ; Arginine/administration &amp; dosage ; Ascorbic Acid/administration &amp; dosage ; Camellia sinensis ; Carcinogens/toxicity ; Chemoprevention/*methods ; Copper/administration &amp; dosage ; Dietary Supplements ; Lung Neoplasms/chemically induced/*prevention &amp; control ; Lysine/administration &amp; dosage ; Male ; Manganese/administration &amp; dosage ; Mice ; Plant Extracts/administration &amp; dosage ; Proline/administration &amp; dosage ; Selenium/administration &amp; dosage ; Urethane/toxicity ; }, abstract = {AIMS AND BACKGROUND: Lung cancer, a leading cause of cancer death, is associated with exposure to inhalation carcinogens, most commonly those found in tobacco smoke. We investigated the in vivo effect of dietary supplementation with a nutrient mixture containing lysine, proline, arginine, ascorbic acid, green tea extract, N-acetyl cysteine, selenium, copper and manganese on the development of urethane-induced lung tumors in male A/J mice.<br><br>METHODS: After one week of isolation, seven-week-old male A/J mice (n = 25) weighing 17-19 g were randomly divided into three groups: group A (n = 5), group B (n = 10), and group C (n = 10). Mice in groups B and C were each given a single intraperitoneal injection of urethane (1 mg/g body weight) in saline, whereas group A mice received an injection of saline alone. Groups A and B were fed a regular diet, whereas group C was fed the same diet supplemented with 0.5% nutrient mixture. After 20 weeks, mice were sacrificed, lungs were excised and weighed, and tumors were counted and processed for histology.<br><br>RESULTS: Urethane-challenged mice developed tumors. However, the mean number of tumors and the mean lung weights in the mice on the supplemented diet were significantly reduced, by 49% (P < 0.0001) and 18% (P = 0.0025), respectively, compared to mice on the control diet. We observed neither significant differences in body weight gains nor in diet consumption among the mice. Pulmonary lesions were morphologically similar for both the groups (adenomas), but lesions were smaller in the test group.<br><br>CONCLUSIONS: The results suggest that nutrient mixture has inhibitory potential on the development of mouse lung tumors induced by urethane.}, }
@article {pmid19842889, year = {2009}, author = {Oksuz, H and Senoglu, N and Yasim, A and Turut, H and Tolun, F and Ciralik, H and Bilge, F}, title = {Propofol with N-acetylcysteine reduces global myocardial ischemic reperfusion injury more than ketamine in a rat model.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {22}, number = {5}, pages = {348-352}, doi = {10.1080/08941930903214750}, pmid = {19842889}, issn = {1521-0553}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Cardiotonic Agents/*therapeutic use ; Disease Models, Animal ; Ketamine/*therapeutic use ; Male ; Myocardial Reperfusion Injury/blood/*prevention &amp; control ; Propofol/administration &amp; dosage/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: We examined the cardioprotective effects of propofol and ketamine with and without N-acetylcysteine (NAC).<br><br>METHODS: 60 rats were divided into six groups of 10 rats each. Anesthesia induction was produced with an intraperitonal injection of ketamine in Groups 1-3 and propofol in Groups 4-6. NAC (200 mg kg(- 1)) was given intraperitonally during anesthesia induction in Groups 3 and 6. Groups 2, 3, 5, and 6 were subjected to 90 s of myocardial ischemia by clamping the ascending aorta, and then reperfusion was begun by unclamping the ascending aorta. After 60 min of reperfusion, blood samples were taken from the ascending aorta for biochemical analyses, and heart tissue samples were taken for biochemical and histopathological analyses.<br><br>RESULTS: Creatine kinase (CK), myocardial band of creatine kinase (CK-MB), and troponin-I (Tn-I) levels were significantly higher in the ischemia-reperfusion groups (2, 3, 5, 6) compared to the nonischemic groups (1, 4). CK, CK-MB, and Tn-I levels did not differ significantly between the ketamine groups (1-3) and the propofol groups (4-6) p > .05). Malondialdehyde levels were significantly higher in Groups 2 and 3 than in Group 1 and were significantly lower in Groups 4 and 6 than in Group 5 (p < .05). Malondialdehyde levels in the propofol groups (4-6) were significantly lower than in the ketamine groups (1-3; p < .05). Catalase levels in propofol groups were higher than ketamine groups. Superoxide dismutase levels were significantly higher in Group 6 than in Group 3 (p < .05).<br><br>CONCLUSIONS: In this rat model of global cardiac ischemia, propofol with NAC attenuates myocardial injury more than ketamine (with or without NAC).}, }
@article {pmid19840221, year = {2010}, author = {Kamboj, SS and Vasishta, RK and Sandhir, R}, title = {N-acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy.}, journal = {Journal of neurochemistry}, volume = {112}, number = {1}, pages = {77-91}, doi = {10.1111/j.1471-4159.2009.06435.x}, pmid = {19840221}, issn = {1471-4159}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Apoptosis/drug effects/*physiology ; Biomarkers/blood/metabolism ; Blood Glucose/drug effects/metabolism ; Diabetic Neuropathies/drug therapy/*metabolism/*pathology ; Hyperglycemia/*metabolism/*pathology/prevention &amp; control ; Lipid Peroxidation/drug effects/physiology ; Male ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Wistar ; }, abstract = {Several studies have indicated the involvement of oxidative stress in the development of diabetic neuropathy. In the present study, we have targeted oxidative stress mediated nerve damage in diabetic neuropathy using N-acetyl-l-cysteine (NAC), a potent antioxidant. After 8 weeks, streptozotocin-induced diabetic rats developed neuropathy which was evident from decreased tail-flick latency (thermal hyperalgesia). This was accompanied by decreased motor coordination as assessed by performance on rota-rod treadmill. Na(+) K(+) ATPase, a biochemical marker of development of diabetic neuropathy, was significantly inhibited in sciatic nerve of diabetic animals. NAC treatment at a daily dose between 1.4 and 1.5 g/kg body weight to diabetic animals for 7 weeks in drinking water ameliorated hyperalgesia, improved motor coordination and reversed reduction in Na(+) K(+) ATPase activity. There was an increase in lipid peroxidation in sciatic nerve of diabetic animals along with decrease in phospholipid levels, while NAC treatment attenuated lipid peroxidation and restored phospholipids to control levels. This was associated with decrease in glutathione and protein thiols. The activities of antioxidant enzymes; superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and glutathione-S-transferase were reduced in sciatic nerve of diabetic animals. Cytochrome c release and active caspase 3 were markedly increased in nerve from diabetic animals suggesting activation of apoptotic pathway. NAC treatment significantly ameliorated decrease in antioxidant defense and prevented cytochrome c release and caspase 3 activation. Electron microscopy revealed demyelination, Wallerian degeneration and onion-bulb formation in sciatic nerve of diabetic rats. NAC on the other hand was able to reverse structural deficits observed in sciatic nerve of diabetic rats. Our results clearly demonstrate protective effect of NAC is mediated through attenuation of oxidative stress and apoptosis, and suggest therapeutic potential of NAC in attenuation of diabetic neuropathy.}, }
@article {pmid19839867, year = {2009}, author = {Kalariya, NM and Ramana, KV and Srivastava, SK and van Kuijk, FJ}, title = {Genotoxic effects of carotenoid breakdown products in human retinal pigment epithelial cells.}, journal = {Current eye research}, volume = {34}, number = {9}, pages = {737-747}, pmid = {19839867}, issn = {1460-2202}, support = {Z01 DK036118/ImNIH/Intramural NIH HHS/United States ; R01 GM071036-01A1/GM/NIGMS NIH HHS/United States ; GM71036/GM/NIGMS NIH HHS/United States ; R01 DK036118/DK/NIDDK NIH HHS/United States ; R01 GM071036/GM/NIGMS NIH HHS/United States ; R37 DK036118/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Ascorbic Acid/pharmacology ; Carotenoids/*toxicity ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Comet Assay ; DNA/*drug effects ; *DNA Damage ; Dose-Response Relationship, Drug ; Glutathione/metabolism/pharmacology ; Humans ; Lutein/*toxicity ; Microscopy, Fluorescence ; Retinal Pigment Epithelium/*drug effects ; Time Factors ; alpha-Tocopherol/pharmacology ; }, abstract = {PURPOSE: To investigate the genotoxic effects of lutein (LBP) and beta -carotene breakdown products (beta -apo-8-carotenal, BA8C) and the preventive role of GSH in human retinal pigment epithelial cells (ARPE-19).<br><br>METHODS: LBP- and BA8C-induced DNA damage in human retinal pigment epithelial cells (ARPE-19) was determined by comet assay. The DNA damage was quantified by the image analysis system using Comet Score software. ARPE-19 cell viability was determined by CellTiter 96 AQ(ueous) one-solution cell proliferation assay kit. Intracellular GSH levels were measured by Ellman's reagent.<br><br>RESULTS: Incubation of serum-starved ARPE-19 cells with LBP and BA8C caused significant DNA damage in a dose- and time-dependent manner. The DNA damage and cell death incurred by LBP and BA8C were significantly prevented by N-acetylcysteine (NAC) but not by alpha -tocopherol + ascorbic acid (T + AA). Furthermore, BSO-induced GSH depletion in ARPE-19 cells caused a significant elevation in LBP- and BA8C-induced DNA damage, whereas increased GSH levels in ARPE-19 cells prevented it.<br><br>CONCLUSIONS: Our results suggest that breakdown products of dietary carotenoids could be genotoxic in ARPE-19 cells. LBP-induced genotoxic effects could worsen oxidative stress. The intracellular GSH pool in ARPE-19 cells might play a critical role in carotenoid breakdown products-induced genotoxicity.}, }
@article {pmid19838944, year = {2009}, author = {Harhaji Trajković, LM and Mijatović, SA and Maksimović-Ivanić, DD and Stojanović, ID and Momcilović, MB and Tufegdzić, SJ and Maksimović, VM and Marjanović, ZS and Stosić-Grujicić, SD}, title = {Anticancer properties of Ganoderma lucidum methanol extracts in vitro and in vivo.}, journal = {Nutrition and cancer}, volume = {61}, number = {5}, pages = {696-707}, doi = {10.1080/01635580902898743}, pmid = {19838944}, issn = {1532-7914}, mesh = {Animals ; Antineoplastic Agents/chemistry/metabolism/*pharmacology ; Apoptosis/drug effects ; Astrocytes/pathology ; Caspases/metabolism ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cells, Cultured ; Drugs, Chinese Herbal/chemistry/metabolism/*pharmacology ; Gene Expression Regulation, Neoplastic ; Melanoma, Experimental/*drug therapy ; Mice ; Mice, Inbred C57BL ; Necrosis/chemically induced ; Neoplasm Transplantation ; Oxidative Stress/drug effects ; Rats ; Reactive Oxygen Species/analysis/antagonists &amp; inhibitors ; Reishi/*chemistry ; Serbia ; Terpenes/analysis ; Tumor Burden/drug effects ; }, abstract = {Anticancer activities of various extracts of the medicinal mushroom, Ganoderma lucidum, have been widely demonstrated and are mainly associated with the presence of different bioactive polysaccharides and triterpenoids. We have evaluated and compared in vitro and in vivo the antitumor effects of two preparations from Ganoderma lucidum: a methanol extract containing total terpenoids (GLme) and a purified methanol extract containing mainly acidic terpenoids (GLpme). Both extracts inhibited tumor growth of B16 mouse melanoma cells inoculated subcutaneously into syngeneic C57BL/6 mice and reduced viability of B16 cells in vitro, whereby GLme exhibited stronger effect. Furthermore, anticancer activity of GLme was demonstrated for the first time against two other rodent tumor cell lines, L929-mouse fibrosarcoma and C6-rat astrocytoma. The mechanism of antitumor activity of GLme comprised inhibition of cell proliferation and induction of caspase-dependent apoptotic cell death mediated by upregulated p53 and inhibited Bcl-2 expression. Moreover, the antitumor effect of the GLme was associated with intensified production of reactive oxygen species, whereas their neutralization by the antioxidant, N-acetyl cysteine, resulted in partial recovery of cell viability. Thus, our results suggest that GLme might be a good candidate for treatment of diverse forms of cancers.}, }
@article {pmid19837105, year = {2010}, author = {González-Rubio, S and Linares, CI and Bello, RI and González, R and Ferrín, G and Hidalgo, AB and Muñoz-Gomariz, E and Rodríguez, BA and Barrera, P and Ranchal, I and Durán-Prado, M and Aguilar-Melero, P and De la Mata, M and Muntané, J}, title = {Calcium-dependent nitric oxide production is involved in the cytoprotective properties of n-acetylcysteine in glycochenodeoxycholic acid-induced cell death in hepatocytes.}, journal = {Toxicology and applied pharmacology}, volume = {242}, number = {2}, pages = {165-172}, doi = {10.1016/j.taap.2009.10.003}, pmid = {19837105}, issn = {1096-0333}, mesh = {Acetylcysteine/*pharmacology ; Base Sequence ; Calcium/*metabolism ; Cell Death/*drug effects ; Cell Line ; Glycochenodeoxycholic Acid/*pharmacology ; Hepatocytes/*drug effects/metabolism ; Humans ; Nitric Oxide/*biosynthesis ; Oligodeoxyribonucleotides ; }, abstract = {The intracellular oxidative stress has been involved in bile acid-induced cell death in hepatocytes. Nitric oxide (NO) exerts cytoprotective properties in glycochenodeoxycholic acid (GCDCA)-treated hepatocytes. The study evaluated the involvement of Ca2+ on the regulation of NO synthase (NOS)-3 expression during N-acetylcysteine (NAC) cytoprotection against GCDCA-induced cell death in hepatocytes. The regulation of Ca2+ pools (EGTA or BAPTA-AM) and NO (L-NAME or NO donor) production was assessed during NAC cytoprotection in GCDCA-treated HepG2 cells. The stimulation of Ca2+ entrance was induced by A23187 in HepG2. Cell death, Ca2+ mobilization, NOS-1, -2 and -3 expression, AP-1 activation, and NO production were evaluated. GCDCA reduced intracellular Ca2+ concentration and NOS-3 expression, and enhanced cell death in HepG2. NO donor prevented, and l-NAME enhanced, GCDCA-induced cell death. The reduction of Ca2+ entry by EGTA, but not its release from intracellular stores by BAPTA-AM, enhanced cell death in GCDCA-treated cells. The stimulation of Ca2+ entrance by A23187 reduced cell death and enhanced NOS-3 expression in GCDCA-treated HepG2 cells. The cytoprotective properties of NAC were related to the recovery of intracellular Ca2+ concentration, NOS-3 expression and NO production induced by GCDCA-treated HepG2 cells. The increase of NO production by Ca2+-dependent NOS-3 expression during NAC administration reduces cell death in GCDCA-treated hepatocytes.}, }
@article {pmid19833500, year = {2010}, author = {Dong, W and Dong, C and Shuang, S and Choi, MM}, title = {Near-infrared luminescence quenching method for the detection of phenolic compounds using N-acetyl-L-cysteine-protected gold nanoparticles-tyrosinase hybrid material.}, journal = {Biosensors &amp; bioelectronics}, volume = {25}, number = {5}, pages = {1043-1048}, doi = {10.1016/j.bios.2009.09.022}, pmid = {19833500}, issn = {1873-4235}, mesh = {Acetylcysteine/*chemistry ; Biosensing Techniques/instrumentation ; Equipment Design ; Equipment Failure Analysis ; Gold/*chemistry ; Luminescent Measurements/*instrumentation ; Monophenol Monooxygenase/*chemistry ; Nanoparticles/*chemistry/ultrastructure ; Nanotechnology/*instrumentation ; Phenols/*analysis ; Reproducibility of Results ; Sensitivity and Specificity ; Spectroscopy, Near-Infrared/*instrumentation ; }, abstract = {A rapid and simple near-infrared (NIR) luminescence quenching method for the detection of phenolic compounds based on combining the unique property of N-acetyl-L-cysteine-protected gold nanoparticles (NAC-AuNPs) and tyrosinase (Tyr) enzymatic reactions is described. This method relies on the luminescence quenching of NAC-AuNPs-tyrosinase (NAC-AuNPs-Tyr) hybrid material by phenolic compounds. The quinone intermediates produced from enzymatic catalytic oxidation of phenolic compounds were believed to play a major role in the luminescence quenching. Dynamic quenching mechanism was confirmed by using time-resolved luminescence spectroscopy. Optimization of the experimental parameters including the concentration of NAC-AuNPs-Tyr (20 microg/mL), excitation wavelength (450nm), pH (6.0), and temperature (20 degrees C) has been determined. A linear range 0.5 microM to 1.0 mM and a detection limit 0.1 microM of catechol were obtained under optimal conditions. The sensitivity of different phenolic compounds was compared and follows the trend: catechol>p-cresol>phenol. The proposed NIR luminescence quenching method exhibits high sensitivity, good repeatability, and long-term stability, demonstrating potential for further development to NIR luminescence phenol biosensors.}, }
@article {pmid19833168, year = {2010}, author = {Park, EJ and Lim, JH and Nam, SI and Park, JW and Kwon, TK}, title = {Rottlerin induces heme oxygenase-1 (HO-1) up-regulation through reactive oxygen species (ROS) dependent and PKC delta-independent pathway in human colon cancer HT29 cells.}, journal = {Biochimie}, volume = {92}, number = {1}, pages = {110-115}, doi = {10.1016/j.biochi.2009.10.001}, pmid = {19833168}, issn = {1638-6183}, mesh = {Acetophenones/*pharmacology ; Active Transport, Cell Nucleus/drug effects ; Animals ; Benzopyrans/*pharmacology ; Colonic Neoplasms/*pathology ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; HT29 Cells ; Heme Oxygenase-1/*genetics ; Humans ; Luciferases/metabolism ; NF-E2-Related Factor 2/metabolism ; Protein Kinase C-delta/antagonists &amp; inhibitors/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Up-Regulation/*drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by its substrate heme and diverse stimuli. The induction of HO-1 gene expression is one of the important events in cellular response to pro-oxidative and pro-inflammatory insults. In this study, the effect of rottlerin, a putative PKC delta inhibitor, on HO-1 expression in HT29 human colon cancer cells was investigated. Rottlerin-induced HO-1 at both protein and mRNA levels in a dose- and time-dependent manner. Rottlerin-mediated HO-1 induction was abrogated in the presence of N-acetylcysteine (NAC) or glutathione (GSH). Rottlerin induced nuclear translocation of NF-E2-related factor 2 (Nrf2) and increased antioxidant response element (ARE)-driven transcriptional activity. Additionally, rottlerin activated p38 mitogen-activated protein kinase (MAPK) and ERK. The pharmacological inhibition of ERK and p38 MAPK inhibited rottlerin-induced HO-1 up-regulation. However, suppression of protein kinase C delta (PKC delta) expression by siRNA or overexpression of WT-PKC delta did not abrogate the rottlerin-mediated induction of HO-1. These results suggest that rottlerin induces up-regulation of HO-1 via PKC delta-independent pathway. Taken together, the present study identified rottlerin as a novel inducer of HO-1 expression and identified the mechanisms involved in this process.}, }
@article {pmid19830705, year = {2009}, author = {Hossain, K and Kawamoto, Y and Hamada, M and Akhand, AA and Yanagishita, T and Hoque, MA and Tsuboi, H and Kato, M and Nakashima, I}, title = {1,4-butanediyl-bismethanethiosulfonate (BMTS) induces apoptosis through reactive oxygen species-mediated mechanism.}, journal = {Journal of cellular biochemistry}, volume = {108}, number = {5}, pages = {1059-1065}, doi = {10.1002/jcb.22370}, pmid = {19830705}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects/physiology ; Caspase 3/metabolism ; Caspase 9/metabolism ; DNA Fragmentation/drug effects ; Dithiothreitol/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Jurkat Cells ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mitochondria/*drug effects/metabolism ; Oxidation-Reduction ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/physiology ; Thiosulfonic Acids/*pharmacology ; }, abstract = {Although methane sulfonate compounds are widely used for the protein modification for their selectivity of thiol groups in proteins, their intracellular signaling events have not yet been clearly documented. This study demonstrated the methane sulfonate chemical 1,4-butanediyl-bismethanethiosulfonate (BMTS)-induced cascades of signals that ultimately led to apoptosis of Jurkat cells. BMTS induced apoptosis through fragmentation of DNA, activation of caspase-9 and caspase-3, and downregulation of Bcl-2 protein with reduction of mitochondrial membrane potential. Moreover, BMTS intensely and transiently induced intracellular reactive oxygen species (ROS) production and ROS produced by BMTS was mediated through mitochondria. We also found that a reducing agent dithiothreitol (DTT) and an anti-oxidant N-acetyl cysteine (NAC) inhibited BMTS-mediated caspase-9 and -3 activation, ROS production and induction of Annexin V/propidium iodide double positive cells, suggesting the involvement of ROS in the apoptosis process. Therefore, this study further extends our understanding on the basic mechanism of redox-linked apoptosis induced by sulfhydryl-reactive chemicals.}, }
@article {pmid19825401, year = {2009}, author = {Nasralla, SN and Ghoneim, AI and Khalifa, AE and Gad, MZ and Abdel-Naim, AB}, title = {Lactoperoxidase catalyzes in vitro activation of acrylonitrile to cyanide.}, journal = {Toxicology letters}, volume = {191}, number = {2-3}, pages = {347-352}, doi = {10.1016/j.toxlet.2009.10.005}, pmid = {19825401}, issn = {1879-3169}, mesh = {Acrylonitrile/*metabolism ; Biotransformation ; Carcinogens/*metabolism ; Catalysis ; Chromans/pharmacology ; Cyanides/*metabolism ; Data Interpretation, Statistical ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Hydrogen Peroxide/metabolism ; Hydrogen-Ion Concentration ; Indomethacin/pharmacology ; Kinetics ; Lactoperoxidase/antagonists &amp; inhibitors/*metabolism ; Quercetin/pharmacology ; Resorcinols/pharmacology ; Sodium Azide/pharmacology ; Sulfhydryl Compounds/pharmacology ; Temperature ; }, abstract = {Acrylonitrile (ACN) is a widely used industrial chemical. Although it is a well reported animal carcinogen, its current designation to humans is "possibly carcinogenic". The present study aimed at investigating the ability of LPO enzyme system to oxidize ACN to cyanide (CN(-)) in vitro. Detection of CN(-) served as a marker for the possible generation of free radical intermediates implicated in ACN induced toxicity in the activation process. Optimum conditions for the oxidation of ACN to CN(-) were characterized with respect to pH, temperature and time of incubation as well as ACN, LPO and H(2)O(2) concentrations in incubation mixtures. Maximum reaction velocity (V(max)) and Michaelis-Menten constant (K(m)) were assessed. Addition of nitrite (NO(2)(-)) salts to the reaction mixtures significantly enhanced the rate of the reaction. Free radical scavengers (quercetin and trolox C), LPO enzyme inhibitor (resorcinol) and competitors for LPO binding (sodium azide and indomethacin) were found to reduce the rate of CN(-) production. Inclusion of the sulfhydryl compounds glutathione (GSH), NAC (N-acetylcysteine), D-penicillamine or L-cysteine enhanced the rate of ACN oxidation. The present results demonstrate the ability of LPO enzyme system to oxidize ACN to CN(-) and provide insight for the elucidation of ACN chronic toxicity.}, }
@article {pmid19822093, year = {2009}, author = {Rosato, E and Zardi, EM and Barbano, B and Menghi, G and Cianci, R and Amoroso, A and Afeltra, A and Pisarri, S and Salsano, F}, title = {N-acetylcysteine infusion improves hepatic perfusion in the early stages of systemic sclerosis.}, journal = {International journal of immunopathology and pharmacology}, volume = {22}, number = {3}, pages = {763-772}, doi = {10.1177/039463200902200322}, pmid = {19822093}, issn = {0394-6320}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Capillaries/drug effects/physiopathology ; Female ; Hepatic Artery/diagnostic imaging/*drug effects/physiopathology ; Humans ; Infusions, Intravenous ; Liver Circulation/*drug effects ; Male ; Microscopic Angioscopy ; Middle Aged ; Portal Vein/diagnostic imaging/*drug effects/physiopathology ; Pulsatile Flow/drug effects ; Scleroderma, Systemic/diagnostic imaging/*drug therapy/physiopathology ; Severity of Illness Index ; Treatment Outcome ; Ultrasonography, Doppler, Color ; Vascular Resistance/drug effects ; Vasodilator Agents/*administration &amp; dosage ; }, abstract = {The aim of our study is to evaluate portal and hepatic hemodynamic changes after N-acetylcysteine infusion in patients with systemic sclerosis. In an open-label study 40 patients with systemic sclerosis (SSc) were treated with 15 mg/kg/hour intravenous N-acetylcysteine for 5 consecutive hours in a single day. Hepatic flow volume, congestion index, portal flow volume, resistance index and pulse rate index were measured in each subject before and after infusion. In all patients mean hepatic flow volume (HFV) and mean portal flow volume (PFV) values after the five-hour infusion with NAC increased not significantly. In 22 selected patients with active capillaroscopic pattern, modified Rodnan Total Skin Score (mRTSS)<18 and mild-moderate score to vascular domain of disease severity scale (DSS), mean HFV increased significantly when compared with mean HFV of 18 SSc patients with late capillaroscopic pattern, mRTSS>18 and severe-end stage score to vascular domain of DSS. The results of our study demonstrate that NAC is able to increase HFV and total liver perfusion after a single infusion in SSc patients with low disease activity and severity scores.}, }
@article {pmid19821517, year = {2010}, author = {Saito, C and Zwingmann, C and Jaeschke, H}, title = {Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine.}, journal = {Hepatology (Baltimore, Md.)}, volume = {51}, number = {1}, pages = {246-254}, pmid = {19821517}, issn = {1527-3350}, support = {R01 DK070195/DK/NIDDK NIH HHS/United States ; P20 RR016475/RR/NCRR NIH HHS/United States ; R01 AA12916/AA/NIAAA NIH HHS/United States ; P20 RR016475-03/RR/NCRR NIH HHS/United States ; R01 AA012916-07/AA/NIAAA NIH HHS/United States ; P20 RR021940-04/RR/NCRR NIH HHS/United States ; P20 RR 021940/RR/NCRR NIH HHS/United States ; R01 AA012916/AA/NIAAA NIH HHS/United States ; R01 DK070195-05S1/DK/NIDDK NIH HHS/United States ; P20 RR021940/RR/NCRR NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Chemical and Drug Induced Liver Injury/drug therapy/*prevention &amp; control ; Drug Overdose/drug therapy ; Energy Metabolism/drug effects ; Glutathione/metabolism/*therapeutic use ; Male ; Mice ; Mice, Inbred C3H ; Mitochondria, Liver/drug effects/physiology ; Peroxynitrous Acid/metabolism ; Reactive Oxygen Species/metabolism ; Up-Regulation ; }, abstract = {UNLABELLED: Acetaminophen (APAP) overdose is a major cause of acute liver failure. The glutathione (GSH) precursor N-acetylcysteine (NAC) is used to treat patients with APAP overdose for up to 48 hours. Although it is well established that early treatment with NAC can improve the scavenging of the reactive metabolite N-acetyl-p-benzoquinone imine, protective mechanisms at later times remain unclear. To address this issue, fasted C3Heb/FeJ mice were treated with 300 mg/kg APAP and then received intravenously 0.65 mmol/kg GSH or NAC at 1.5 hours after APAP. The animals were sacrificed at 6 hours. APAP alone caused severe liver injury with peroxynitrite formation and DNA fragmentation, all of which was attenuated by both treatments. However, GSH (-82%) was more effective than NAC (-46%) in preventing liver injury. Using nuclear magnetic resonance spectroscopy to measure tissue adenosine triphosphate (ATP) levels and the substrate flux through the mitochondrial Krebs cycle, it was observed that the reduced liver injury correlated with accelerated recovery of mitochondrial GSH content, maintenance of ATP levels, and an increased substrate supply for the mitochondrial Krebs cycle compared with APAP alone. NAC treatment was less effective in recovering ATP and mitochondrial GSH levels and showed reduced substrate flux through the Krebs cycle compared with GSH. However, increasing the dose of NAC improved the protective effect similar to GSH, suggesting that the amino acids not used for GSH synthesis were used as mitochondrial energy substrates.<br><br>CONCLUSION: Delayed treatment with GSH and NAC protect against APAP overdose by dual mechanisms-that is, by enhancing hepatic and mitochondrial GSH levels (scavenging of reactive oxygen and peroxynitrite)-and by supporting the mitochondrial energy metabolism.}, }
@article {pmid19819956, year = {2009}, author = {Aerts, G and Arrojo E Drigo, R and Van Herck, SL and Sammels, E and Mirebeau-Prunier, D and Gereben, B and Zeöld, A and Harney, JW and Huang, SA and Mulcahey, MA and Van der Geyten, S and Van den Bergh, G and Arckens, L and Darras, VM and Zavacki, AM}, title = {Knockdown of the type 3 iodothyronine deiodinase (D3) interacting protein peroxiredoxin 3 decreases D3-mediated deiodination in intact cells.}, journal = {Endocrinology}, volume = {150}, number = {11}, pages = {5171-5180}, pmid = {19819956}, issn = {1945-7170}, support = {R01 DK076117/DK/NIDDK NIH HHS/United States ; DK076117/DK/NIDDK NIH HHS/United States ; }, mesh = {Cell Line ; Gene Knockdown Techniques ; Halogenation ; Humans ; Iodide Peroxidase/genetics/*metabolism ; Peroxiredoxins/*genetics/*metabolism ; Protein Binding ; Triiodothyronine/metabolism ; }, abstract = {The type 3 iodothyronine deiodinase (D3) is the primary deiodinase that inactivates thyroid hormone. Immunoprecipitation of D3, followed by fluorescent two-dimensional difference gel electrophoresis and mass spectrometry, identified peroxiredoxin 3 (Prx3) as a D3-associated protein. This interaction was confirmed using reverse coimmunoprecipitation, in which pull-down of Prx3 resulted in D3 isolation, and by fluorescence resonance energy transfer between cyan fluorescent protein-D3 and yellow fluorescent protein-Prx3. Prx3 overexpression did not change D3 activity in transfected HEK 293 cells; however, Prx3 knockdown resulted in a 50% decrease in D3-mediated whole-cell deiodination. Notably, D3 activity of cell lysates with dithiothreitol as an exogenous reducing factor and D3 protein levels were not decreased with Prx3 knockdown, indicating that the observed reduction in whole-cell deiodination was not simply due to a decrease in D3 enzyme levels. Prx3 knockdown did not change D3's affinity for T3 because saturation of D3-mediated whole-cell deiodination occurred between 20 and 200 nm T3 both with and without Prx3. Furthermore, the decrease in D3 activity in whole cells was not attributable to nonspecific oxidative stress because pretreatment with the antioxidant N-acetyl cysteine did not reverse the effects of Prx3 knockdown. Thioredoxin, the cofactor needed for Prx3 regeneration, supported D3 microsomal activity; however, Prx3 knockdown did not change D3 activity in this system. In conclusion, knockdown of Prx3 decreases D3 activity in whole cells, whereas absolute levels of D3 are unchanged, consistent with Prx3 playing a rate-limiting role in the regeneration of the D3 enzyme.}, }
@article {pmid19818344, year = {2010}, author = {Li, Q and Peng, S and Sheng, Z and Wang, Y}, title = {Ofloxacin induces oxidative damage to joint chondrocytes of juvenile rabbits: excessive production of reactive oxygen species, lipid peroxidation and DNA damage.}, journal = {European journal of pharmacology}, volume = {626}, number = {2-3}, pages = {146-153}, doi = {10.1016/j.ejphar.2009.09.044}, pmid = {19818344}, issn = {1879-0712}, mesh = {Animals ; Antioxidants/metabolism ; Cell Membrane/drug effects/metabolism ; Chondrocytes/cytology/*drug effects/metabolism ; *DNA Damage ; Enzymes/metabolism ; Intracellular Space/drug effects/metabolism ; Joints/*cytology ; Lipid Peroxidation/*drug effects ; Ofloxacin/*toxicity ; Oxidative Stress/*drug effects ; Rabbits ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/chemistry/pharmacology ; }, abstract = {Quinolones are widely used in infection therapy due to their good antimicrobial characteristics. However, there potential joint chondrotoxicity on immature animals has stood in the way of the therapeutic application of these agents, the exact mechanism of which is still unclear. This study was undertaken to investigate the role of oxidative damage in ofloxacin (one typical quinolones)-induced arthropathy. Chondrocytes from juvenile rabbit joints were incubated with ofloxacin at concentrations of 0, 5, 10, 20, 40 and 80 microg/ml, respectively. The extent of oxidative damage was assessed by measuring the reactive oxygen species level, activities of antioxidant enzymes, and oxidative damage to some macromolecules. It was observed that ofloxacin induced a concentration-dependent increase in intracellular reactive oxygen species production, which may be an early mediator of ofloxacin cytotoxicity. Similarly, ofloxacin resulted in a significant lipid peroxidation, revealed by a concentration-dependent increase in the level of thiobarbituric acid reactive substances. At the same time, ofloxacin induced DNA damage in a concentration-dependent manner for 24h measured by comet assay, which may be a cause for overproduction of reactive oxygen species. Furthermore, antioxidant enzyme activities, such as glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD), were rapidly decreased after treatment with ofloxacin. In addition, SOD decline and reactive oxygen species production were strongly inhibited, and the loss in cell viability was partly abated by additional glutathione (GSH), N-acetylcysteine (NAC) and dithiothreitol (DTT). In conclusion, these results clearly demonstrated that ofloxacin could induce oxidative stress, lipid peroxidation and DNA oxidative damage to chondrocytes.}, }
@article {pmid19816928, year = {2010}, author = {Balansky, R and Ganchev, G and Iltcheva, M and Steele, VE and De Flora, S}, title = {Prevention of cigarette smoke-induced lung tumors in mice by budesonide, phenethyl isothiocyanate, and N-acetylcysteine.}, journal = {International journal of cancer}, volume = {126}, number = {5}, pages = {1047-1054}, pmid = {19816928}, issn = {1097-0215}, support = {N01 CN053301/CN/NCI NIH HHS/United States ; N01CN53301/CA/NCI NIH HHS/United States ; N01-CN53301/CN/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Animals, Newborn ; Anticarcinogenic Agents/*therapeutic use ; Budesonide/*therapeutic use ; Disease Models, Animal ; Female ; Isothiocyanates/*therapeutic use ; Lung Neoplasms/etiology/pathology/*prevention &amp; control ; Male ; Mice ; Tobacco Smoke Pollution/*adverse effects ; }, abstract = {Lung cancer is the most important cause of death among neoplastic diseases worldwide, and cigarette smoke (CS) is the major risk factor for cancer. Complementarily to avoidance of exposure to CS, chemoprevention will lower the risk of cancer in passive smokers, ex-smokers, and addicted current smokers who fail to quit smoking. Unfortunately, chemoprevention clinical trials have produced disappointing results to date and, until recently, a suitable animal model evaluating CS carcinogenicity was not available. We previously demonstrated that mainstream CS induces a potent carcinogenic response when exposure of mice starts at birth. In the present study, neonatal mice (strain H) were exposed to CS for 120 consecutive days, starting at birth. The chemopreventive agents budesonide (2.4 mg/kg diet), phenethyl isothiocyanate (PEITC, 1,000 mg/kg diet), and N-acetyl-L-cysteine (NAC, 1,000 mg/kg body weight) were administered orally according to various protocols. The experiment was stopped after 210 days. Exposure to CS resulted in a high incidence and multiplicity of benign lung tumors and in significant increases of malignant lung tumors and other histopathological alterations. All three chemopreventive agents, administered to current smokers after weaning, were quite effective in protecting both male and female mice from CS pulmonary carcinogenicity. When given to ex-smokers after withdrawal of exposure to CS, the protective capacity of budesonide was unchanged, while PEITC lost part of its cancer chemopreventive activity. In conclusion, the proposed experimental model provides convincing evidence that it is possible to prevent CS-induced lung cancer by means of dietary and pharmacological agents.}, }
@article {pmid19815959, year = {2009}, author = {Pawlas, N and Małecki, A}, title = {Neuroprotective effect of N-acetylcysteine in neurons exposed to arachidonic acid during simulated ischemia in vitro.}, journal = {Pharmacological reports : PR}, volume = {61}, number = {4}, pages = {743-750}, doi = {10.1016/s1734-1140(09)70129-x}, pmid = {19815959}, issn = {2299-5684}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Arachidonic Acid/*toxicity ; Brain Ischemia/chemically induced/pathology/*prevention &amp; control ; Cell Hypoxia/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Neurons/*drug effects/pathology ; Neuroprotective Agents/*pharmacology ; Rats ; }, abstract = {The aim of the study was to assess neuroprotective effects of N-acetylcysteine (NAC; 100-200 microM) on cultured cortical neurons exposed to arachidonic acid (AA, 10 microM) during ischemia (oxygen-glucose deprivation). Ischemic conditions decreased neuron viability to 41-47% of normoxic controls; co-exposure with arachidonic acid further attenuated neuron viability to 36.73% after 24 h. Separate exposure to arachidonic acid in normoxia or to ischemic conditions only, increased the number of apoptotic nuclei to 33.56% or 36.78%, respectively. Combined exposure to arachidonic acid and ischemia increased apoptosis frequency to 62.20%. NAC (200 microM) decreased the number of apoptotic nuclei in normoxia in control and arachidonic acid exposed cells. NAC also decreased apoptosis frequency in ischemia to 14%. In neurons exposed to arachidonic acid and ischemic conditions, 100 and 200 microM NAC reduced apoptosis to 24.99% and 19.48%, respectively. NAC provided protection to neurons from toxicity due to arachidonic acid, ischemia and exposure to arachidonic acid in ischemic conditions.}, }
@article {pmid19815813, year = {2010}, author = {Abdelsaid, MA and Pillai, BA and Matragoon, S and Prakash, R and Al-Shabrawey, M and El-Remessy, AB}, title = {Early intervention of tyrosine nitration prevents vaso-obliteration and neovascularization in ischemic retinopathy.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {332}, number = {1}, pages = {125-134}, doi = {10.1124/jpet.109.157941}, pmid = {19815813}, issn = {1521-0103}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/therapeutic use ; Animals ; Animals, Newborn ; Apoptosis/drug effects ; Blotting, Western ; Catechin/administration &amp; dosage/pharmacology/therapeutic use ; Cells, Cultured ; Disease Models, Animal ; Endothelial Cells/drug effects/enzymology/metabolism/pathology ; Glutathione/metabolism ; Hyperoxia/enzymology/metabolism/pathology ; Hypoxia/enzymology/metabolism/pathology ; Ischemia/*drug therapy/enzymology/metabolism/pathology ; Lipid Peroxidation/drug effects ; Metalloporphyrins/administration &amp; dosage/pharmacology/therapeutic use ; Mice ; Mice, Inbred C57BL ; Peroxynitrous Acid/*metabolism ; Protective Agents/administration &amp; dosage/pharmacology/*therapeutic use ; Retinal Neovascularization/enzymology/metabolism/pathology/*prevention &amp; control ; Retinal Vessels/enzymology/metabolism/*pathology ; Tyrosine/*analogs &amp; derivatives/metabolism ; }, abstract = {Diabetic retinopathy and retinopathy of prematurity are blinding disorders that follow a pathological pattern of ischemic retinopathy and affect premature infants and working-age adults. Yet, the treatment options are limited to laser photocoagulation. The goal of this study is to elucidate the molecular mechanism and examine the therapeutic effects of inhibiting tyrosine nitration on protecting early retinal vascular cell death and late neovascularization in the ischemic retinopathy model. Ischemic retinopathy was developed by exposing neonatal mice to 75% oxygen [postnatal day (p) 7-p12] followed by normoxia (21% oxygen) (p12-p17). Peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTPPS) (1 mg/kg), the nitration inhibitor epicatechin (10 mg/kg) or the thiol donor N-acetylcysteine (NAC, 150 mg/kg) were administered (p7-p12) or (p7-p17). Vascular endothelial cells were incubated at hyperoxia (40% oxygen) or normoxia (21% oxygen) for 48 h. Vascular density was determined in retinal flat mounts labeled with isolectin B4. Expression of vascular endothelial growth factor, caspase-3, and poly(ADP ribose) polymerase (PARP), activation of Akt and p38 mitogen-activated protein kinase (MAPK), and tyrosine nitration of the phosphatidylinositol (PI) 3-kinase p85 subunit were analyzed by Western blot. Hyperoxia-induced peroxynitrite caused endothelial cell apoptosis as indicated by expression of cleaved caspase-3 and PARP leading to vaso-obliteration. These effects were associated with significant tyrosine nitration of the p85 subunit of PI 3-kinase, decreased Akt activation, and enhanced p38 MAPK activation. Blocking tyrosine nitration of PI 3-kinase with epicatechin or NAC restored Akt phosphorylation, and inhibited vaso-obliteration at p12 and neovascularization at p17 comparable with FeTPPS. Early inhibition of tyrosine nitration with use of epicatechin or NAC can represent safe and effective vascular-protective agents in ischemic retinopathy.}, }
@article {pmid19812118, year = {2009}, author = {Sebe, A and Satar, S and Rana Alpay, N and Murt, M and Güvenç, B}, title = {Severe acetaminophen poisoning treated with a fractionated plasma separation and absorption system: A case report.}, journal = {Human &amp; experimental toxicology}, volume = {28}, number = {11}, pages = {729-732}, doi = {10.1177/0960327109350800}, pmid = {19812118}, issn = {1477-0903}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Adolescent ; Female ; Humans ; Liver Function Tests ; *Plasmapheresis ; Poisoning/drug therapy/enzymology/therapy ; Treatment Outcome ; }, abstract = {Acetaminophen is an analgesic drug that is frequently used in suicide attempts. In this paper, we report on a 17-year-old girl who was admitted to an emergency department 15 hours after taking acetaminophen pills in a suicide attempt. Her serum acetaminophen level was 73 mg/L on admission; she had elevated liver enzymes suggesting hepatic necrosis. She was started on N-acetyl cystein (NAC), and treated successfully with a fractionated plasma separation and absorption system.}, }
@article {pmid19807652, year = {2009}, author = {Okouchi, M and Okayama, N and Aw, TY}, title = {Preservation of cellular glutathione status and mitochondrial membrane potential by N-acetylcysteine and insulin sensitizers prevent carbonyl stress-induced human brain endothelial cell apoptosis.}, journal = {Current neurovascular research}, volume = {6}, number = {4}, pages = {267-278}, pmid = {19807652}, issn = {1875-5739}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-15/DK/NIDDK NIH HHS/United States ; DK44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Brain/*cytology/drug effects ; Caspase 8/metabolism ; Caspase 9/metabolism ; Cell Line ; Endothelial Cells/*drug effects ; Fluorescent Dyes ; Glutathione/*physiology ; Homeostasis/drug effects/physiology ; Humans ; Hypoglycemic Agents/*pharmacology ; Indoles ; Insulin/*pharmacology ; Insulin Resistance/*physiology ; Membrane Potentials/physiology ; Mitochondrial Membranes/drug effects/*physiology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Carbonylation/*drug effects ; }, abstract = {Oxidative stress-induced cerebral endothelial cell dysfunction is associated with cerebral microvascular complication of primary diabetic encephaolopathy, a neurodegenerative disorder of long-standing diabetes, but the injury mechanisms are poorly understood. This study sought to determine the contribution of carbonyl (methylglyoxal, MG) stress to human brain endothelial cell (IHEC) apoptosis, the relationship to cellular redox status and mitochondrial membrane potential, and the protection by thiol antioxidant and insulin sensitizers. MG exposure induced IHEC apoptosis in association with perturbed cellular glutathione (GSH) redox status, decreased mitochondrial membrane potential (Deltapsi(m)), activation of caspase-9 and -3, and cleavage of polyADP-ribose polymerase. Insulin sensitizers such as biguanides or AMP-activated protein kinase activator, but not glitazones, afforded cytoprotection through preventing (Deltapsi(m) collapse and activation of caspase-9 that was independent of cellular GSH. Similarly, cyclosporine A prevented Deltapsi(m) collapse, while N-acetylcysteine (NAC) mediated the recovery of cellular GSH redox balance that secondarily preserved Deltapsi(m). Collectively, these results provide mechanistic insights into the role of GSH redox status and mitochondrial potential in carbonyl stress-induced apoptosis of brain endothelial cells, with implications for cerebral microvascular complications associated with primary diabetic encephalopathy. The findings that thiol antioxidant and insulin sensitizers afforded cytoprotection suggest potential therapeutic approaches.}, }
@article {pmid19806806, year = {2009}, author = {Anoush, M and Eghbal, MA and Fathiazad, F and Hamzeiy, H and Kouzehkonani, NS}, title = {The protective effects of garlic extract against acetaminophen-induced oxidative stress and glutathione depletion.}, journal = {Pakistan journal of biological sciences : PJBS}, volume = {12}, number = {10}, pages = {765-771}, doi = {10.3923/pjbs.2009.765.771}, pmid = {19806806}, issn = {1028-8880}, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/metabolism ; Analgesics, Non-Narcotic/*pharmacology ; Animals ; Collagenases/metabolism ; Garlic/*metabolism ; Glutathione/*metabolism ; Hepatocytes/drug effects/metabolism ; Liver/injuries ; Male ; Oxidative Stress/*drug effects ; Plant Extracts/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; }, abstract = {Acetaminophen, the most commonly sold over-the-counter antipyretic analgesic, is capable of causing severe and sometimes fatal hepatic damage in humans and experimental animals. The incidence of liver injury due to acetaminophen overdose, either with suicidal intent or by accident, is increasing. Garlic is among those medicinal plants famous for its different health protective effects. In this study, the protective effects of garlic extract on acute acetaminophen-induced liver injury were investigated using freshly isolated rat hepatocytes. The hepatocytes were isolated from Sprague-Dawley male rats by a two step collagenase model. Formation of Reactive Oxygen Species (ROS) and Glutathione (GSH) depletion were studied after addition of acetaminophen to cell suspensions. The effects of garlic extract on prevention of ROS formation as well as GSH depletion was investigated and compared with the effects of N-Acetyl Cysteine (NAC) as the standard treatment. Reactive oxygen species formation was assessed by a spectrofluorometry method and garlic extract was shown to be as effective as NAC in decreasing ROS formation induced by acetaminophen. Glutathione (GSH) levels of hepatocytes were determined using HPLC. Garlic extract was effective in preventing GSH depletion significantly (p < 0.05). It is concluded that garlic extract has an antioxidant effect and can protect hepatocytes from GSH depletion following NAPQI production.}, }
@article {pmid19806432, year = {2010}, author = {Vasdev, S and Gill, VD and Randell, E and Han, Y and Gadag, V}, title = {Fructose and moderately high dietary salt-induced hypertension: prevention by a combination of N-acetylcysteine and L-arginine.}, journal = {Molecular and cellular biochemistry}, volume = {337}, number = {1-2}, pages = {9-16}, pmid = {19806432}, issn = {1573-4919}, support = {//Canadian Institutes of Health Research/Canada ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antihypertensive Agents/administration &amp; dosage ; Arginine/*administration &amp; dosage ; Blood Pressure/drug effects ; Body Weight/drug effects ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Evaluation, Preclinical ; Fructose/*adverse effects ; Heart/drug effects ; Hypertension/*etiology/pathology/physiopathology/*prevention &amp; control ; Kidney/drug effects/pathology ; Liver/drug effects/pathology ; Myocardium/pathology ; Organ Size/drug effects ; Rats ; Rats, Inbred WKY ; Sodium Chloride, Dietary/*adverse effects ; }, abstract = {Diets containing 8% salt or 4% fructose (FR) cause insulin resistance and increase tissue methylglyoxal and advanced glycation end products (AGEs), platelet cytosolic-free calcium, and systolic blood pressure (SBP) in rats. In WKY rats, we have shown that moderately high salt, 4% NaCl (MHS) alone in diet does not cause hypertension, and when given along with 4% FR it does not have an additive effect. N-acetylcysteine (NAC) or L-arginine (ARG), treatment alone does not prevent hypertension in this model. The objectives of this study were to investigate the effect of NAC plus ARG in diet on SBP, platelet cytosolic-free calcium in a MHS + FR model, and to measure the plasma levels of methylglyoxal and the AGE, methylglyoxal-derived hydroimidazolone (MGH). At 7 weeks of age, WKY rats were divided into three groups: control group was given regular rat chow (0.7% NaCl) and water; MHS + FR group, diet containing 4% NaCl and 4% FR in drinking water; and MHS + FR + NAC + ARG group, MHS diet supplemented with 1.5% N-acetylcysteine (NAC) and 1.5% L-arginine (ARG), and 4% FR in drinking water, and followed for 6 weeks. NAC + ARG prevented the increase in platelet cytosolic-free calcium and SBP in MHS + FR treated rats. There was no difference in mean values of plasma methylglyoxal and MGH among the groups. In conclusion, NAC + ARG treatment is effective in preventing hypertension in a moderately high salt + FR-induced animal model. Plasma methylglyoxal and MGH may not represent tissue modification or, alternatively, other tissue AGEs, derived from methylglyoxal or other aldehydes, may be involved in hypertension in this model.}, }
@article {pmid19805484, year = {2010}, author = {Rangasamy, T and Williams, MA and Bauer, S and Trush, MA and Emo, J and Georas, SN and Biswal, S}, title = {Nuclear erythroid 2 p45-related factor 2 inhibits the maturation of murine dendritic cells by ragweed extract.}, journal = {American journal of respiratory cell and molecular biology}, volume = {43}, number = {3}, pages = {276-285}, pmid = {19805484}, issn = {1535-4989}, support = {R01 HL073952/HL/NHLBI NIH HHS/United States ; P50ES015903/ES/NIEHS NIH HHS/United States ; HL081205/HL/NHLBI NIH HHS/United States ; P30 ES03819/ES/NIEHS NIH HHS/United States ; P01ES09606/ES/NIEHS NIH HHS/United States ; P50HL084945/HL/NHLBI NIH HHS/United States ; P30 ES003819/ES/NIEHS NIH HHS/United States ; R01 HL071933/HL/NHLBI NIH HHS/United States ; }, mesh = {*Ambrosia ; Animals ; Bone Marrow Cells/cytology ; Cells, Cultured ; Cytokines/metabolism ; Dendritic Cells/*drug effects/metabolism ; Flow Cytometry ; Lung/cytology ; Mice ; Mice, Inbred ICR ; Mice, Knockout ; NF-E2-Related Factor 2/*metabolism ; Oxidative Stress ; Plant Extracts/*pharmacology ; }, abstract = {Oxidative stress plays an important role in immune regulation and dendritic cell (DC) maturation. Recent studies indicate that allergens, including ragweed extract (RWE), possess prooxidant activities, but how RWE interacts with DCs is not well understood. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a key transcription factor that regulates constitutive and coordinated induction of a battery of antioxidant genes. We hypothesized that RWE would activate DCs and that this response would be augmented in the absence of Nrf2. We generated bone marrow-derived DCs (BM-DCs) and isolated lung DCs from Nrf2(+/+) and Nrf2(-/-) mice and studied the effects of RWE on DCs in vitro. Under resting conditions, Nrf2(-/-) BM-DCs exhibited constitutively greater levels of inflammatory cytokines and costimulatory molecules than Nrf2(+/+) BM-DCs. Exposure to RWE impaired endocytic activity, significantly induced oxidative stress, and enhanced the expression of CD80, CD86, and MHCII in Nrf2(-/-) BM-DCs when compared with Nrf2(+/+) BM-DC, in association with reduced expression of Nrf2-regulated antioxidant genes. RWE significantly induced the secretion of inflammatory cytokines IL-6 and TNF-alpha in BM-DCs and lung DCs from Nrf2(-/-) mice than Nrf2(+/+) mice and significantly inhibited the secretion of IL-12 in Nrf2(+/+) BM-DCs and IL-18 in Nrf2(+/+) and Nrf2(-/-) BM-DCs. The stimulatory effects of RWE on DC activation were inhibited to varying degrees by the antioxidant N-acetyl cysteine. Our findings indicate that a defect in Nrf2-mediated signaling mechanisms alters the response of DCs to a common environmental allergen, which may contribute to the susceptibility to allergic diseases.}, }
@article {pmid19802778, year = {2010}, author = {Rösner, H and Torremante, P and Möller, W and Gärtner, R}, title = {Antiproliferative/cytotoxic activity of molecular iodine and iodolactones in various human carcinoma cell lines. No interfering with EGF-signaling, but evidence for apoptosis.}, journal = {Experimental and clinical endocrinology &amp; diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association}, volume = {118}, number = {7}, pages = {410-419}, doi = {10.1055/s-0029-1225615}, pmid = {19802778}, issn = {1439-3646}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Arachidonic Acids/*pharmacology ; Carcinoma/*metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytotoxins/*pharmacology ; Epidermal Growth Factor/metabolism ; Humans ; Iodine/*pharmacology ; Lactones/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Twelve human cancer cell lines and one non-malignant cell line were investigated with respect to a potential antiproliferative/cytotoxic activity of molecular iodine and iodolactones. Except CCL221 colon carcinoma cells, the growth of all cancer cell lines decreased if the cells were cultured in the presence of 10 microM molecular iodine (I(2)) for at least two days. delta-iodolactone (IL, 5 microM) was found to have a similar effect. SH-SY5Y neuroblastoma cells turned out to be most susceptible to both iodine compounds (total inhibition), followed by MCF-7 mammary carcinoma cells (60% and 77.7% inhibition in the presence of I(2) respect. IL) and HS24 lung carcinoma cells (36.3% respect. 40.3% inhibition). In contrast, MCF-10 normal mammary epithelial cells were much less affected by the iodine treatment. In both, SH-SY5Y and MCF-7 cells, I(2) and IL also abolished EGF-induced promotion of cell growth completely. This effect was, however, not due to an interfering with EGF-signaling, because I(2) and IL did not affect the phosphorylation of EGF-receptors, EGF-induced activation of MAP-kinase (Erk(1/2)), or EGF-induced lamellar actin protrusion. A disruption by molecular iodine of mitochondrial transmembrane electrical potential, which was prevented by a pre-treatment of the cells with N-acetyl-cysteine, supports a mitochondria-mediated apoptotic mechanism.}, }
@article {pmid19801848, year = {2009}, author = {Choi, JH and Lee, KT}, title = {Costunolide-induced apoptosis in human leukemia cells: involvement of c-jun N-terminal kinase activation.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {32}, number = {10}, pages = {1803-1808}, doi = {10.1248/bpb.32.1803}, pmid = {19801848}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents, Phytogenic/isolation &amp; purification/pharmacology/*therapeutic use ; Apoptosis/*drug effects ; Carcinoma, Lewis Lung/drug therapy ; Drug Therapy, Combination ; Free Radical Scavengers/pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Leukemia/*drug therapy/enzymology/pathology ; Magnolia/*chemistry ; Mice ; Phytotherapy ; Plant Bark ; Plant Extracts/isolation &amp; purification/pharmacology/*therapeutic use ; Plant Stems ; Protein Kinase Inhibitors/pharmacology ; Protein-Tyrosine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Sesquiterpenes/isolation &amp; purification/pharmacology/*therapeutic use ; Signal Transduction/drug effects ; Sorbitol/pharmacology/therapeutic use ; U937 Cells ; }, abstract = {The authors previously reported that costunolide, an active compound isolated from the stem bark of Magnolia sieboldii, induced apoptosis via reactive oxygen species (ROS) and Bcl-2-dependent mitochondrial permeability transition in human leukemia cells. In the present study, the authors investigated whether mitogen-activated protein kinases (MAPKs) are involved in the costunolide-induced apoptosis in human promonocytic leukemia U937 cells. Treatment with costunolide resulted in the significant activation of c-Jun N-terminal kinase (JNK), but not of extracellular-signal-related kinase (ERK1/2) or p38. In vitro kinase assays showed that JNK activity was low in untreated cells but increased dramatically after 30 min of costunolide treatment. U937 cells co-treated with costunolide and sorbitol, a JNK activator, exhibited higher levels of cell death. In addition, inhibition of the JNK pathway using a dominant-negative mutation of c-jun and JNK inhibitor SP600125, significantly prevented costunolide-induced apoptosis. Furthermore, pretreatment with the antioxidant NAC (N-acetyl-L-cysteine) blocked the costunolide-stimulated activation of JNK while the overexpression of Bcl-2 failed to reverse JNK activation. Pretreatment with SP600125 recovered the costunolide-suppressed Bcl-2 expression. These results indicate that costunolide-induced JNK activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis. Moreover, the administration of costunolide (intraperitoneally once a day for 7 d) significantly suppressed tumor growth and increased survival in 3LL Lewis lung carcinoma-bearing model.}, }
@article {pmid19801829, year = {2009}, author = {Moon, EY and Oh, JM and Kim, YH and Ryoo, IJ and Yoo, ID}, title = {Clitocybins, novel isoindolinone free radical scavengers, from mushroom Clitocybe aurantiaca inhibit apoptotic cell death and cellular senescence.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {32}, number = {10}, pages = {1689-1694}, doi = {10.1248/bpb.32.1689}, pmid = {19801829}, issn = {1347-5215}, mesh = {Acetylcysteine/pharmacology ; *Agaricales ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line ; Cellular Senescence/*drug effects ; Cytochromes c/metabolism ; Free Radical Scavengers/chemical synthesis/*pharmacology ; Fungal Proteins/chemical synthesis/*pharmacology ; Humans ; Hydrogen Peroxide ; I-kappa B Proteins/metabolism ; Isoindoles/chemical synthesis/chemistry/isolation &amp; purification/*pharmacology ; Mitochondria/metabolism ; NF-KappaB Inhibitor alpha ; }, abstract = {High concentration of intracellular reactive oxygen species (ROS) plays a role in damaging biological systems. We isolated clitocybin A from the culture broth of Clitocybe aurantiaca and then clitocybin B and C derivatives were synthesized from clitocybin A. IMR-90 lung fibroblast cells were pre-treated or post-treated with clitocybin A, B and C to the addition of 100 muM H(2)O(2). These compounds inhibited the level of intracellular reactive oxygen species (ROS) and H(2)O(2)-induced cell death as judged by hypodiploid cell formation. The inhibitory effect of clitocybins on H(2)O(2)-induced cell death was comparable to that with N-acetylcysteine (NAC), a well-known ROS scavenger. The inhibition of H(2)O(2)-induced cell death by clitocybins was mediated by the reduction of caspase 3 and 9 activation, cytochrome c release from mitochondria and the degradation of IkappaB-alpha and IkappaB-beta, which could be resulted in the prevention of cellular senescence. It suggests that clitocybins are novel compounds scavenging ROS and protect cells from apoptosis and cellular senescence.}, }
@article {pmid19796678, year = {2009}, author = {Zhu, Y and Kalen, AL and Li, L and Lehmler, HJ and Robertson, LW and Goswami, PC and Spitz, DR and Aykin-Burns, N}, title = {Polychlorinated-biphenyl-induced oxidative stress and cytotoxicity can be mitigated by antioxidants after exposure.}, journal = {Free radical biology &amp; medicine}, volume = {47}, number = {12}, pages = {1762-1771}, pmid = {19796678}, issn = {1873-4596}, support = {R01 CA111365/CA/NCI NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; P42 ES-013661/ES/NIEHS NIH HHS/United States ; P30 ES005605-190006/ES/NIEHS NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; R01 CA111365-03/CA/NCI NIH HHS/United States ; P42 ES013661-040002/ES/NIEHS NIH HHS/United States ; P30 CA086862-10S46947/CA/NCI NIH HHS/United States ; P30 ES-05605/ES/NIEHS NIH HHS/United States ; P30 CA-086862/CA/NCI NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; R01 CA-111365/CA/NCI NIH HHS/United States ; }, mesh = {Antioxidants/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Environmental Pollutants/*antagonists &amp; inhibitors/toxicity ; Humans ; Oxidative Stress/*drug effects ; Polychlorinated Biphenyls/*antagonists &amp; inhibitors/toxicity ; Superoxide Dismutase/metabolism ; }, abstract = {PCBs and PCB metabolites have been suggested to cause cytotoxicity by inducing oxidative stress, but the effectiveness of antioxidant intervention after exposure has not been established. Exponentially growing MCF-10A human breast and RWPE-1 human prostate epithelial cells continuously exposed for 5 days to 3 microM PCBs [Aroclor 1254 (Aroclor), PCB153, and the 2-(4-chlorophenyl)-1,4-benzoquinone metabolite of PCB3 (4ClBQ)] were found to exhibit growth inhibition and clonogenic cell killing, with 4ClBQ having the most pronounced effects. These PCBs were also found to increase steady-state levels of intracellular O(2)(*-) and H(2)O(2) (as determined by dihydroethidium, MitoSOX red, and 5-(and 6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate oxidation). These PCBs also caused 1.5- to 5.0-fold increases in MnSOD activity in MCF-10A cells and 2.5- to 5-fold increases in CuZnSOD activity in RWPE-1 cells. Measurement of MitoSOX red oxidation with confocal microscopy coupled with colocalization of MitoTracker green in MCF-10A and RWPE-1 cells supported the hypothesis that PCBs caused increased steady-state levels of O(2)(*-) in mitochondria. Finally, treatment with either N-acetylcysteine (NAC) or the combination of polyethylene glycol (PEG)-conjugated CuZnSOD and PEG-catalase added 1 h after PCBs significantly protected these cells from PCB toxicity. These results support the hypothesis that exposure of exponentially growing human breast and prostate epithelial cells to PCBs causes increased steady-state levels of intracellular O(2)(*-) and H(2)O(2), induction of MnSOD or CuZnSOD activity, and clonogenic cell killing that could be inhibited by a clinically relevant thiol antioxidant, NAC, as well as by catalase and superoxide dismutase after PCB exposure.}, }
@article {pmid19794959, year = {2009}, author = {Neuwelt, AJ and Wu, YJ and Knap, N and Losin, M and Neuwelt, EA and Pagel, MA and Warmann, S and Fuchs, J and Czauderna, P and Wozniak, M}, title = {Using acetaminophen's toxicity mechanism to enhance cisplatin efficacy in hepatocarcinoma and hepatoblastoma cell lines.}, journal = {Neoplasia (New York, N.Y.)}, volume = {11}, number = {10}, pages = {1003-1011}, pmid = {19794959}, issn = {1476-5586}, support = {R37 NS044687/NS/NINDS NIH HHS/United States ; R37-NS044687/NS/NINDS NIH HHS/United States ; }, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/pharmacology ; Analgesics, Non-Narcotic/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/*pharmacology ; Cytochrome P-450 CYP2E1/metabolism ; Dose-Response Relationship, Drug ; Drug Synergism ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism ; Hepatoblastoma/metabolism/pathology ; Hepatocytes/cytology/drug effects/enzymology ; Humans ; Liver Neoplasms/metabolism/pathology ; Mice ; Rats ; Time Factors ; }, abstract = {BACKGROUND/AIMS: Acetaminophen overdose causes hepatotoxicity mediated by toxic metabolites generated through the cytochrome P450 enzyme. The objective of this study was to investigate whether acetaminophen (AAP) can enhance cisplatin (CDDP) cytotoxicity against human hepatocarcinoma and hepatoblastoma cells in vitro and whether this effect can be prevented by N-acetylcysteine (NAC).<br><br>METHODS: In vitro studies (glutathione [GSH] level, cell viability, and immunoblot assays) were performed using human hepatocarcinoma and hepatoblastoma cells cultured in AAP, CDDP, and the combination of both with or without delayed NAC administration. The pharmacology and toxicology of high-dose AAP in rats were also examined.<br><br>RESULTS: Acetaminophen decreased GSH levels in liver cancer cells in a dose- and time-dependent manner. Acetaminophen combined with CDDP had enhanced cytotoxicity over CDDP alone. The cytotoxicity caused by AAP plus CDDP was decreased by NAC, with the effectiveness being time-dependent. The GSH level was lowered in the liver but not in the blood or the brain in rats treated with a high dose of AAP (1000 mg/kg). The expression of CYP2E1 protein, a key cytochrome P450 enzyme, varies among species but is not correlated to AAP sensitivity in liver cancer cells.<br><br>CONCLUSIONS: Our results suggest that a chemotherapeutic regimen containing both AAP and CDDP with delayed NAC rescue has the potential to enhance chemotherapeutic efficacy while decreasing adverse effects. This would be a promising approach particularly for hepatoblastomas regardless of cellular CYP2E1 protein level but could also be beneficial in other malignancies.}, }
@article {pmid19783039, year = {2010}, author = {Xiao, L and Zhao, D and Chan, WH and Choi, MM and Li, HW}, title = {Inhibition of beta 1-40 amyloid fibrillation with N-acetyl-L-cysteine capped quantum dots.}, journal = {Biomaterials}, volume = {31}, number = {1}, pages = {91-98}, doi = {10.1016/j.biomaterials.2009.09.014}, pmid = {19783039}, issn = {1878-5905}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Amyloid beta-Peptides/*antagonists &amp; inhibitors/biosynthesis ; Benzothiazoles ; Fluorescent Dyes ; Kinetics ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Peptide Fragments/*antagonists &amp; inhibitors/biosynthesis ; *Quantum Dots ; Thiazoles/metabolism ; }, abstract = {One of the primary factors that induce Alzheimer's disease (AD) is the deposition of beta-amyloid (Abeta). The Abeta molecules can self-assemble to form neurotoxic aggregates with various morphologies, such as dimers, oligomers, protofibrils and fibrils. For this aspect, we demonstrated that the amyloid fibrillation can be inhibited by quenching the nucleation and elongation processes with a low concentration of water dispersed N-acetyl-L-cysteine capped quantum dots (NAC-QDs). Based on the concentration dependence of NAC-QDs on the seeded fibril growth, there is a remarkable inhibition effect when the NAC-QDs concentration is increased by 100-fold from 10(-9) to 10(-7) M. The NAC-QDs concentration required to show inhibition effect is much lower than that of the amyloid peptide concentration (50 microM). The step-like change suggests that the inhibition effect of NAC-QDs displays a threshold response. The inhibition is likely due to the intermolecular attractive interactions such as the hydrogen bonding between NAC-QDs and amyloid fibrils resulting in the blockage of the active elongation sites on the fibrils.}, }
@article {pmid19782097, year = {2009}, author = {Datta, S and Mazumder, S and Ghosh, D and Dey, S and Bhattacharya, S}, title = {Low concentration of arsenic could induce caspase-3 mediated head kidney macrophage apoptosis with JNK-p38 activation in Clarias batrachus.}, journal = {Toxicology and applied pharmacology}, volume = {241}, number = {3}, pages = {329-338}, doi = {10.1016/j.taap.2009.09.007}, pmid = {19782097}, issn = {1096-0333}, mesh = {Animals ; Annexin A5/metabolism ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Arsenic/*toxicity ; Benzimidazoles ; Caspase 3/*physiology ; DNA Fragmentation/drug effects ; Enzyme Activation/drug effects ; Fishes/*physiology ; Fluorescein-5-isothiocyanate ; Fluorescent Dyes ; In Situ Nick-End Labeling ; Kidney/drug effects/*pathology ; Lipid Peroxidation/drug effects ; MAP Kinase Kinase 4/*metabolism ; Macrophages/*drug effects ; NADPH Oxidases/metabolism ; Oxidative Stress/drug effects ; Thiobarbituric Acid Reactive Substances/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {We had earlier demonstrated that chronic exposure (30 days) to micro-molar concentration (0.50 microM) of arsenic induced head kidney macrophage (HKM) death in Clarias batrachus. The purpose of the present study is to characterize the nature of HKM death induced by arsenic and elucidate the signal transduction pathways involved in the process. Arsenic-induced HKM death was apoptotic in nature as evident from DNA gel, Annexin V-propidium iodide, Hoechst 33342 staining and TdT-mediated dUTP nick end labeling (TUNEL) assays. Inhibitor studies and immunoblot analyses further demonstrated that arsenic-induced HKM apoptosis involved activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase, a well-characterized caspase-3 substrate. Preincubation with antioxidants N-acetyl-cysteine or dimethyl sulfoxide significantly lowered reactive oxygen species (ROS) levels in arsenic-treated HKM and prevented caspase activation, malondialdehyde formation and HKM apoptosis. Arsenic induced membrane translocation of the NADPH oxidase subunit p47(phox). Preincubation with apocynin and diphenyleneiodonium chloride, both selective inhibitors of NADPH oxidases, prevented p47(phox) translocation, ROS production and HKM death. Exposure of HKM to arsenic induced the activation of mitogen-activated protein kinase family (MAPK) proteins including c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38). Preincubation of HKM with p38 inhibitor SB203580 and JNK inhibitor SP600125 protected the HKM against arsenic-induced apoptosis. We conclude that exposure to micro-molar concentration of arsenic induces ROS generation through the activation of NADPH oxidases, which in turn causes caspase-3 mediated HKM apoptosis. In addition, the study also indicates a role of p38-JNK pathway in arsenic-induced HKM apoptosis in C. batrachus.}, }
@article {pmid19782051, year = {2010}, author = {Deeb, D and Gao, X and Jiang, H and Janic, B and Arbab, AS and Rojanasakul, Y and Dulchavsky, SA and Gautam, SC}, title = {Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism.}, journal = {Biochemical pharmacology}, volume = {79}, number = {3}, pages = {350-360}, pmid = {19782051}, issn = {1873-2968}, support = {R01 CA130948/CA/NCI NIH HHS/United States ; 1R01 CA122031/CA/NCI NIH HHS/United States ; R21 CA129801/CA/NCI NIH HHS/United States ; R01 CA122031/CA/NCI NIH HHS/United States ; R21 CA129801-02/CA/NCI NIH HHS/United States ; 1R21 CA129801/CA/NCI NIH HHS/United States ; R01 CA122031-03/CA/NCI NIH HHS/United States ; R01 CA130948-01A1/CA/NCI NIH HHS/United States ; 1R01 CA130948/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis/*drug effects/physiology ; Cell Line, Tumor ; Growth Inhibitors/chemistry/*pharmacology/therapeutic use ; Humans ; Male ; Oleanolic Acid/*analogs &amp; derivatives/chemistry/pharmacology/therapeutic use ; Prostatic Neoplasms/drug therapy/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {CDDO-Me, a synthetic triterpenoid derived from oleanolic acid, is a promising anticancer agent that has shown strong activity against a wide variety of cancer types in vitro and in vivo. We have previously shown that CDDO-Me induces apoptosis in prostate cancer cells irrespective of their hormonal status. To further understand the proapoptotic mechanism of CDDO-Me, we investigated the role of reactive oxygen species (ROS) in mediating the apoptosis inducing activity of CDDO-Me in LNCaP and PC-3 prostate cancer cell lines. Here, we show that CDDO-Me induces ROS generation from both nonmitochondrial and mitochondrial sources, which is associated with the induction of apoptosis as characterized by increased annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c. In addition, CDDO-Me inhibited cell survival Akt, NF-kappaB and mTOR signaling proteins. The inhibition of ROS generation by N-acetylcysteine (NAC) or by overexpression of antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase-1 (SOD-1) prevented CDDO-Me-induced apoptosis. Pretreatment with NAC blocked annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c by CDDO-Me. NAC also prevented the inhibition of constitutively active Akt, NF-kappaB and mTOR by CDDO-Me. Together, these data indicate that ROS plays an essential role in the induction of apoptosis by CDDO-Me in prostate cancer cells.}, }
@article {pmid19780877, year = {2010}, author = {Okay, E and Mutlu, O and Gocmez, SS and Oz, S and Utkan, T}, title = {N-Acetylcysteine improves disturbed ileal contractility following partial hepatectomy in rats.}, journal = {Journal of gastroenterology and hepatology}, volume = {25}, number = {1}, pages = {203-208}, doi = {10.1111/j.1440-1746.2009.05948.x}, pmid = {19780877}, issn = {1440-1746}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Carbachol/pharmacology ; Dose-Response Relationship, Drug ; Electric Stimulation ; Gastrointestinal Motility/*drug effects ; Hepatectomy/*adverse effects ; Ileum/*drug effects/physiopathology ; Injections, Intraperitoneal ; Models, Animal ; Muscle Contraction/*drug effects ; Muscle Relaxation/drug effects ; Nitroprusside/pharmacology ; Potassium Chloride/pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND AND AIMS: It is well known that disturbed intestinal motility and bacterial overgrowth may occur following partial hepatectomy. These events have been followed by the translocation of enteric bacteria that play a major role in the development of infections. We designed the present study to evaluate the effect of N-acetylcysteine (NAC) on ileal muscle contractility as an indication of intestinal motility.<br><br>METHODS: Sprague-Dawley rats were divided into four groups (n = 6): sham, sham plus preoperative intraperitoneal NAC injection, hepatectomy, and hepatectomy plus preoperative intraperitoneal NAC injection. Contractile and relaxant responses in isolated ileal smooth muscle strips were determined using an in vitro muscle technique. Statistical analyses were performed by Kruskal-Wallis and Mann-Whitney U-tests.<br><br>RESULTS: Contractile responses to KCl and carbachol were significantly decreased in the ileal strips of the hepatectomy group when compared to the sham-operated control group. The impaired contraction of strips was markedly improved by preoperative NAC treatment. However, neither the electrical field stimulation nor the sodium nitroprusside-mediated relaxant responses changed in any of the groups.<br><br>CONCLUSIONS: Our data indicated that disturbed ileal contractility after partial hepatectomy was remedied by preoperative NAC treatment, which in turn might cause attenuation of bacterial translocation.}, }
@article {pmid19773724, year = {2009}, author = {Perazella, MA}, title = {Radiocontrast-induced nephropathy: an update.}, journal = {Minerva urologica e nefrologica = The Italian journal of urology and nephrology}, volume = {61}, number = {3}, pages = {215-233}, pmid = {19773724}, issn = {0393-2249}, mesh = {Acute Kidney Injury/*chemically induced/therapy ; Antioxidants/therapeutic use ; Contrast Media/*adverse effects ; Fluid Therapy ; Humans ; Radiopharmaceuticals/*adverse effects ; Renal Dialysis ; Risk Factors ; Vasodilator Agents/therapeutic use ; }, abstract = {Both diagnostic and therapeutic studies frequently utilize radiocontrast media to enhance images. As a result, use of these agents has increased markedly over the past decade with more than 10 million studies performed on a yearly basis in the United States. Development of acute kidney injury (AKI) is a common complication of radiocontrast exposure in patients who possess underlying risk factors. Impor-tantly, radiocontrast-induce nephropathy (RCIN) is associated with increased short- and long-term mortality. Thus, at risk patients should be identified prior to administration of radiocontrast to allow choice of other potential imaging options or employment of prophylactic interventions. Currently, use of isotonic intravenous fluids is the only proven beneficial preventive therapy. Use of low volumes of radiocontrast and avoidance of nephrotoxic medications are also accepted as nephroprotective. Mixed results exist on the utility of N-acetylcysteine (NAC) therapy and low versus iso-osmolar radiocontrast agents in preventing RCIN. While hemodialysis appears to have no beneficial role, a single center's experience with hemofiltration is associated with a reduction in RCIN and other clinical endpoints. Several therapies have no role in the prevention of RCIN and should be avoided. This review will provide an up to date examination of the current status of these issues as they relate to RCIN.}, }
@article {pmid19773711, year = {2009}, author = {Berk, M and Jeavons, S and Dean, OM and Dodd, S and Moss, K and Gama, CS and Malhi, GS}, title = {Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting.}, journal = {CNS spectrums}, volume = {14}, number = {7}, pages = {357-360}, doi = {10.1017/s1092852900023002}, pmid = {19773711}, issn = {1092-8529}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Anxiety/*drug therapy ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; *Nail Biting ; }, abstract = {N-acetyl cysteine (NAC) is a widely available nutraceutical with a variety of actions. As a precursor of cysteine and glutathione, it has antioxidant properties that may impact on mood and contribute to an effect on impulsivity and obsessive behaviour. Via its additional effect on glutamate via the cystine-glutamate exchange system, NAC has been shown to mediate impulsivity in preclinical models of addiction, reduce craving, and cue extinction. Further, by boosting glutathione, NAC acts as a potent antioxidant and has been shown in two positive, large-scale randomized placebo-controlled trials to affect negative symptoms in schizophrenia and depression in bipolar disorder. We describe three cases in which its actions specifically on nail-biting and associated anxiety may offer a potential treatment. The spontaneous findings are reported as part of an ongoing treatment trial examining the utility of NAC in bipolar disorder. Its actions, if robustly replicated, also point to potential treatment targets in glutathione or glutamate pathways in the brain.}, }
@article {pmid19772854, year = {2009}, author = {Aronis, A and Aharoni-Simon, M and Madar, Z and Tirosh, O}, title = {Triacylglycerol-induced impairment in mitochondrial biogenesis and function in J774.2 and mouse peritoneal macrophage foam cells.}, journal = {Archives of biochemistry and biophysics}, volume = {492}, number = {1-2}, pages = {74-81}, doi = {10.1016/j.abb.2009.09.011}, pmid = {19772854}, issn = {1096-0384}, mesh = {Animals ; Cell Line ; Cells, Cultured ; DNA, Mitochondrial/antagonists &amp; inhibitors/biosynthesis ; Down-Regulation/physiology ; Foam Cells/metabolism/*pathology ; Lipid Metabolism/physiology ; Macrophages, Peritoneal/metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism/*pathology ; Nuclear Respiratory Factor 1/antagonists &amp; inhibitors/physiology ; Reactive Oxygen Species/metabolism/toxicity ; Glycine max ; Transcription Factors/antagonists &amp; inhibitors/biosynthesis ; Triglycerides/*toxicity ; }, abstract = {The aim of this study was to detect mitochondrial alterations in J774.2 macrophages and mouse peritoneal macrophages (MPM) foam cells. J774.2 and MPM cells were exposed to triacylglycerol (TG) emulsion (1 mg/ml) for induction of fat accumulation. Impairment of mitochondrial function was reflected by reduced cellular ATP production and decreased expression of subunits of mitochondrial complexes I and III. The expression of subunit IV of complex IV remained unchanged, however, the content of its precursor in cells increased. Inhibitors of mitochondrial complexes, rotenone (0.1 microM) and myxothiazol (25 nM), protected the viability in TG-loaded macrophages. The exposure to TG caused downregulation of PPARgamma coactivator (PGC)-1alpha and nuclear respiratory factor (NRF)-1. Activation of peroxisome proliferator-activated receptors attenuated reactive oxygen species production in the foam cells. Treatment with antioxidant N-acetylcysteine (NAC) prevented lipid-mediated mitochondrial and cellular damage. In conclusion, this study demonstrates the important role of mitochondrial biogenesis dysfunction in TG-induced lipotoxicity in macrophages.}, }
@article {pmid19772176, year = {2009}, author = {Supabphol, A and Muangman, V and Chavasiri, W and Supabphol, R and Gritsanapan, W}, title = {N-acetylcysteine inhibits proliferation, adhesion, migration and invasion of human bladder cancer cells.}, journal = {Journal of the Medical Association of Thailand = Chotmaihet thangphaet}, volume = {92}, number = {9}, pages = {1171-1177}, pmid = {19772176}, issn = {0125-2208}, mesh = {Acetylcysteine/*pharmacology ; Cell Adhesion/drug effects ; Cell Culture Techniques ; Cell Line, Tumor/drug effects ; Cell Survival/drug effects ; Free Radical Scavengers/*pharmacology ; Humans ; Neoplasm Invasiveness ; Urinary Bladder Neoplasms/*pathology ; }, abstract = {OBJECTIVE: Bladder cancer is not only a major public health and economically burden for the patients but also a major clinical impact for Thai urologists. The authors' aim was to study the anti-metastatic effect of N-acetylcysteine (NAC), one of the cheap, safe and widely used over-the-counter-drugs in Thailand, on the human bladder cancer cells.<br><br>MATERIAL AND METHOD: Effects of NAC at various concentrations on the growth, adhesion, migration, and invasion of the human bladder cancer cell line were assessed in vitro.<br><br>RESULTS: NAC at the concentrations of 5, 10, 20 and 30 mM could directly and significantly inhibit the growth, adhesion, migration, and invasion of the human bladder cancer cells in a dose-dependent manner The 50% inhibitory concentration (IC50) value for cell viability was 33.33 +/- 0.78 mM. The inhibitory effects on migration, invasion and adhesion properties of the cancer cells were dramatically observed at the concentrations of > or = 10, > or = 20 and > or = 30 mM respectively.<br><br>CONCLUSION: NAC has an anti-metastatic effect on the human bladder cancer cells by inhibiting their growth, adhesion, migration, and invasion properties. This implies the high possibility that the urologists may apply the results to use it intravesically before, during and after the transurethral resection of bladder tumour in addition to its conventional usage by oral and parenteral routes.}, }
@article {pmid19769612, year = {2010}, author = {Chen, SL and Yang, CT and Yang, ZL and Guo, RX and Meng, JL and Cui, Y and Lan, AP and Chen, PX and Feng, JQ}, title = {Hydrogen sulphide protects H9c2 cells against chemical hypoxia-induced injury.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {37}, number = {3}, pages = {316-321}, doi = {10.1111/j.1440-1681.2009.05289.x}, pmid = {19769612}, issn = {1440-1681}, mesh = {Animals ; Cell Hypoxia/drug effects/physiology ; Cell Line ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cobalt/*toxicity ; Cytoprotection/*drug effects/*physiology ; Hydrogen Sulfide/*pharmacology ; Myocardium/cytology ; Oxidative Stress/drug effects/physiology ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {1. The aim of the present study was to investigate the effect of hydrogen sulphide (H(2)S) on cobalt chloride (CoCl(2))-induced injury in H9c2 embryonic rat cardiac cells. 2. After 36 h incubation in the presence of 600 micromol/L CoCl(2), reduced cell viability of H9c2 cells was observed, as well as the induction of apoptosis. In addition, CoCl(2) (600 micromol/L) enhanced the production of reactive oxygen species (ROS) and the expression of cleaved caspase 3, induced a loss of mitochondrial membrane potential (MMP) and decreased reduced glutathione (GSH) production. These results suggest that CoCl(2) induces similar responses to hypoxia/ischaemia. 3. Pretreatment of cells with 400 micromol/L NaHS (a H(2)S donor) for 30 min prior to exposure to CoCl(2) (600 micromol/L) significantly protected H9c2 cells against CoCl(2)-induced injury. Specifically, increased cell viability and decreased apoptosis were observed. In addition, NaHS pretreatment blocked the CoCl(2)-induced increases in ROS production and cleaved caspase 3 expression, as well as the decreases in GSH production and loss of MMP. 4. Pretreatment of cells with 2000 micromol/L N-acetylcysteine (NAC), a ROS scavenger, for 1 h prior to CoCl(2) exposure significantly protected H9c2 cells against CoCl(2)-induced injury, specifically enhancing cell viability, decreasing ROS production and preventing loss of MMP. 5. The findings of the present study suggest that H(2)S protects H9c2 cells against CoCl(2)-induced injury by suppressing oxidative stress and caspase 3 activation.}, }
@article {pmid19768643, year = {2009}, author = {Trümpler, S and Nowak, S and Meermann, B and Wiesmüller, GA and Buscher, W and Sperling, M and Karst, U}, title = {Detoxification of mercury species--an in vitro study with antidotes in human whole blood.}, journal = {Analytical and bioanalytical chemistry}, volume = {395}, number = {6}, pages = {1929-1935}, doi = {10.1007/s00216-009-3105-1}, pmid = {19768643}, issn = {1618-2650}, mesh = {Adult ; Antidotes/*chemistry ; Chromatography, Liquid/*methods ; Female ; Humans ; Inactivation, Metabolic ; Male ; Mass Spectrometry/*methods ; Mercury/blood/*pharmacokinetics ; Methylmercury Compounds/blood/*pharmacokinetics ; Models, Biological ; }, abstract = {To investigate the effects of mercury species intoxication and to test the efficiency of different commonly applied antidotes, human whole blood and plasma surrogate samples were spiked with inorganic mercury (Hg2+) and methylmercury (MeHg+, CH3Hg+) prior to treatment with the antidotes 2,3-dimercaptopropan-1-ol (British Anti Lewisite), 2,3-dimercaptosuccinic acid (DMSA), and N-acetylcysteine (NAC). For mercury speciation analysis in these samples, liquid chromatography was coupled to either inductively coupled plasma mass spectrometry (ICP-MS) or electrospray ionisation time-of-flight mass spectrometry (ESI-TOF-MS). Adduct formation between mercury species and physiological thiols (cysteine and glutathione) was observed as well as the release of glutathione under treatment with the antidotes DMSA and NAC.}, }
@article {pmid19767766, year = {2009}, author = {Bao, XM and Wu, CF and Lu, GP}, title = {Atorvastatin attenuates homocysteine-induced apoptosis in human umbilical vein endothelial cells via inhibiting NADPH oxidase-related oxidative stress-triggered p38MAPK signaling.}, journal = {Acta pharmacologica Sinica}, volume = {30}, number = {10}, pages = {1392-1398}, pmid = {19767766}, issn = {1745-7254}, mesh = {Apoptosis/*drug effects ; Atorvastatin ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/*drug effects/metabolism ; Endothelium, Vascular/cytology/drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Heptanoic Acids/*pharmacology ; Homocysteine/*pharmacology ; Humans ; Imidazoles/pharmacology ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Onium Compounds/pharmacology ; Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Pyridines/pharmacology ; Pyrroles/*pharmacology ; Reactive Oxygen Species/analysis/metabolism ; Signal Transduction ; Time Factors ; Umbilical Veins/cytology/drug effects/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {AIM: To examine the effect of atorvastatin on homocysteine (Hcy)-induced reactive oxygen species (ROS) production and apoptosis in human umbilical vein endothelial cells (HUVECs).<br><br>METHODS: HUVECs were cultured with Hcy (0.1-5 mmol/L) in the presence or absence of atorvastatin (1-100 micromol//L) or various stress signaling inhibitors, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI, 10 micromol/L), the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 (10 micromol/L) and antioxidants N-acetyl cysteine (NAC, 1 mmol/L). Cell apoptosis was evaluated by Annexin V/propidium iodide staining and flow cytometry. ROS were detected by 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFH-DA). NADPH oxidases were evaluated with lucigenin-enhanced chemiluminescence. Hcy-induced expression of p38MAPK protein was measured by Western blotting analysis.<br><br>RESULTS: Atorvastatin inhibited endothelial cell apoptosis induced by 1 mmol/L Hcy in a dose-dependent manner and the maximal inhibitory effect was reached at 100 micromol/L. Atorvastatin (10 micromol/L) significantly suppressed Hcy (1 mmol/L for 30 min) induced ROS accumulation (3.17+/-0.33 vs 4.34+/-0.31, P<0.05). Atorvastatin (10 micromol/L) also antagonized Hcy (1 mmol/L for 30 min) induced activation of NADPH oxidase (2.57+/-0.49 vs 3.33+/-0.6, P<0.05). Furthermore, atorvastatin inhibited Hcy-induced phosphorylation of p38 MAPK (1.7+/-0.1 vs 2.22+/-0.25, P<0.05), similar effects occurred with DPI, NAC and SB203580.<br><br>CONCLUSION: Atorvastatin may inhibit Hcy-induced ROS accumulation and endothelium cell apoptosis through an NADPH oxidase and/or p38MAPK-dependent mechanisms, all of which may contribute to atorvastatin-induced beneficial effect on endothelial function.}, }
@article {pmid19766627, year = {2009}, author = {Furuhata, M and Takada, E and Noguchi, T and Ichijo, H and Mizuguchi, J}, title = {Apoptosis signal-regulating kinase (ASK)-1 mediates apoptosis through activation of JNK1 following engagement of membrane immunoglobulin.}, journal = {Experimental cell research}, volume = {315}, number = {20}, pages = {3467-3476}, doi = {10.1016/j.yexcr.2009.09.007}, pmid = {19766627}, issn = {1090-2422}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies, Anti-Idiotypic/immunology/pharmacology ; Apoptosis/genetics/*immunology ; B-Lymphocytes/drug effects/*immunology/metabolism ; Cell Line, Tumor ; Cytosol/metabolism ; Enzyme Activation ; G1 Phase/drug effects ; Hydrogen Peroxide/metabolism ; MAP Kinase Kinase Kinase 5/genetics/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/drug effects/metabolism ; Mitogen-Activated Protein Kinase 8/*metabolism ; Phosphorylation/drug effects/immunology ; Protein Transport/genetics ; Reactive Oxygen Species/metabolism ; Receptors, Antigen, B-Cell/*immunology ; Signal Transduction/drug effects/*immunology ; Transfection ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Engagement of membrane immunoglobulin (mIg) on WEHI-231 mouse B lymphoma cells results in growth arrest at the G1 phase of the cell cycle, followed by a reduction of mitochondrial membrane potential (DeltaPsim) and apoptosis. WEHI-231 cells resemble immature B cells in terms of the cell surface phenotype and sensitivity to mIg engagement. However, the molecular mechanisms underlying mIg-induced loss of DeltaPsim and apoptosis have not yet been established. In this study, we show that apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase 1 (JNK1) signaling pathway participates in mIg-induced apoptosis through the generation of reactive oxygen species (ROS). Stimulation of WEHI-231 cells with anti-IgM induces phosphorylation and subsequent activation of ASK1, leading to JNK activation. Anti-IgM stimulation immediately (5 min) induces hydrogen peroxide (H2O2) production with a substantial increase during later time points (36-48 h), accompanied by loss of DeltaPsim and an increase in cells with sub-G1 DNA content. The anti-IgM-induced late-phase H2O2 production, loss of DeltaPsim, and increase in the sub-G1 fraction were all reduced substantially in WEHI-231 cells overexpressing a dominant-negative form of ASK1, compared with control vector alone, but enhanced substantially in cells overexpressing a constitutively active form of ASK1. These mIg-mediated events were also partially abrogated by ROS scavenger N-acetyl-L-cysteine (NAC). Taken together, these results suggest that mIg engagement induces H2O2 production leading to activation of ASK1-JNK1 pathway, creating a feedback amplification loop of ROS-ASK/JNK that leads to loss of DeltaPsim and finally apoptosis.}, }
@article {pmid19766597, year = {2009}, author = {Ale-Agha, N and Albrecht, C and Klotz, LO}, title = {Loss of gap junctional intercellular communication in rat lung epithelial cells exposed to quartz particles.}, journal = {Biochemical and biophysical research communications}, volume = {390}, number = {1}, pages = {44-47}, doi = {10.1016/j.bbrc.2009.09.057}, pmid = {19766597}, issn = {1090-2104}, mesh = {Animals ; Cell Communication/*drug effects ; Cells, Cultured ; Connexin 43/metabolism ; Epithelial Cells/drug effects/metabolism ; Gap Junctions/*drug effects ; Lung/cytology/*drug effects/metabolism ; Phosphorylation ; Quartz/*toxicity ; Rats ; Silicon Dioxide/toxicity ; }, abstract = {Chronic inhalation of quartz particles has been implicated in lung diseases including silicosis and cancer. The aim of this study was to investigate whether quartz particles affect gap junctional intercellular communication (GJIC) in rat lung epithelial cells (RLE-6TN). Here, we demonstrate that exposure of RLE-6TN cells to subtoxic doses of DQ12 standard quartz resulted in an up to 55% reduction of GJIC, as determined in a dye transfer assay. We show that connexin-43 (Cx43) is the major connexin responsible for intercellular communication in these lung epithelial cells and that exposure to quartz particles induces a significant internalization of Cx43. Downregulation of GJIC was attenuated by N-acetyl cysteine, suggesting the involvement of reactive oxygen species and/or cellular thiol homeostasis in the regulation of GJIC. Furthermore, an inhibitor of activation of extracellular signal-regulated kinases prevented the loss of GJIC in cells exposed to DQ12 quartz, although no direct phosphorylation of Cx43 upon exposure to DQ12 was detected.}, }
@article {pmid19765584, year = {2009}, author = {Roman-Blas, JA and Contreras-Blasco, MA and Largo, R and Alvarez-Soria, MA and Castañeda, S and Herrero-Beaumont, G}, title = {Differential effects of the antioxidant n-acetylcysteine on the production of catabolic mediators in IL-1beta-stimulated human osteoarthritic synoviocytes and chondrocytes.}, journal = {European journal of pharmacology}, volume = {623}, number = {1-3}, pages = {125-131}, doi = {10.1016/j.ejphar.2009.09.016}, pmid = {19765584}, issn = {1879-0712}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antioxidants/metabolism/*pharmacology ; Cells, Cultured ; Chondrocytes/*drug effects/metabolism ; Cyclooxygenase 2/metabolism ; Dinoprostone/metabolism ; Enzyme Activation/drug effects ; Humans ; Inflammation Mediators ; Interleukin-1beta/metabolism/*pharmacology ; Matrix Metalloproteinase 1/metabolism ; Matrix Metalloproteinase 13/metabolism ; NF-kappa B/metabolism ; Nitric Oxide ; Nitrites/metabolism ; Osteoarthritis, Knee/*metabolism ; Subcellular Fractions/enzymology/metabolism ; Synovial Membrane/*cytology/*drug effects/metabolism ; }, abstract = {Oxidative stress may play a relevant role in synovial inflammation and subsequently on cartilage damage during osteoarthritis development. We have assessed how the antioxidant N-acetylcysteine (NAC) affects the expression of different proinflammatory and structural mediators in human stimulated osteoarthritic synoviocytes and chondrocytes. Synovial membrane and articular cartilage were obtained from the osteoarthritis knees of patients who underwent joint replacement surgery. In cells stimulated with IL-1beta (10U/mL), the effects of NAC (2mmol/L) were tested at the mean peak plasma level following oral administration of therapeutic doses and its influence on prostaglandin E2 (PGE(2)) production, cyclooxigenase-2 (COX-2) expression, nitric oxide (NO) synthesis, nuclear factor kappa B (NF-kappaB) activation, and metalloproteinase-1 (MMP-1) and metalloproteinase-13 (MMP-13) expression were evaluated. While NAC significantly diminished PGE(2) release and the expression of both COX-2 and MMP-13 protein in IL-1beta-stimulated synoviocytes, it failed to modify their production in stimulated chondrocytes. Likewise, NAC only inhibited IL-1beta-stimulated NF-kappaB activation in synoviocytes. No inhibition of IL-1beta-induced NO synthesis by chondrocytes was observed following NAC incubation, while synoviocytes did not release detectable levels of NO. NAC did not induce changes in MMP-1 protein expression in either IL-1beta-stimulated synoviocytes or chondrocytes. Thus, NAC decreases the synthesis of several catabolic mediators by osteoarthritic synoviocytes, whereas, it failed to produce the same effects in osteoarthritic chondrocytes. Our results suggest that NAC inhibits some oxygen-dependent mechanisms in synoviocytes but not in chondrocytes during osteoarthritis. Therefore, NAC might have a symptomatic effect on the synovium rather than a structural effect on the cartilage in osteoarthritis.}, }
@article {pmid19759330, year = {2009}, author = {Bertram, KM and Baglole, CJ and Phipps, RP and Libby, RT}, title = {Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration.}, journal = {American journal of physiology. Cell physiology}, volume = {297}, number = {5}, pages = {C1200-10}, pmid = {19759330}, issn = {1522-1563}, support = {ES01247/ES/NIEHS NIH HHS/United States ; EY017123/EY/NEI NIH HHS/United States ; HL075432/HL/NHLBI NIH HHS/United States ; T32ES07026/ES/NIEHS NIH HHS/United States ; }, mesh = {Aging/*drug effects ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Cell Survival/drug effects ; Fluorescent Antibody Technique ; Heme Oxygenase-1/drug effects/metabolism ; Humans ; Hydroquinones/toxicity ; Macular Degeneration/*chemically induced/pathology/physiopathology ; Membrane Potential, Mitochondrial/drug effects ; Mutagens/toxicity ; NF-E2-Related Factor 2/drug effects/metabolism ; Oxidative Stress/*drug effects/physiology ; RNA, Small Interfering ; Retinal Pigment Epithelium/*drug effects/pathology/physiopathology ; Superoxides/metabolism ; Tobacco Smoke Pollution/*adverse effects ; Vascular Endothelial Growth Factor A/drug effects/metabolism ; }, abstract = {Cigarette smoke is the most important environmental risk factor for developing age-related macular degeneration (AMD). Damage to the retinal pigment epithelium (RPE) caused by cigarette smoke may underlie the etiology of AMD. This study investigated the molecular and cellular effects of cigarette smoke exposure on human RPE cells. ARPE-19 or primary human RPE cells were exposed to cigarette smoke extract (CSE) or hydroquinone (HQ), a component of cigarette smoke. The effect of this exposure on key aspects of RPE vitality including viability, cell size, mitochondrial membrane potential (DeltaPsi(m)), superoxide production, 4-hydroxy-2-nonenal (4-HNE), vascular endothelial growth factor (VEGF), and heme oxygenase-1 (HO-1) expression was determined. Exposure of RPE cells to CSE or HQ caused oxidative damage and apoptosis, characterized by a reduction in cell size and nuclear condensation. Evidence of oxidative damage also included increased lipid peroxidation (4-HNE) and mitochondrial superoxide production, as well as a decrease in intracellular glutathione (GSH). Exogenous administration of antioxidants (GSH and N-acetyl-cysteine) prevented oxidative damage to the RPE cells caused by CSE. Cigarette smoke also induced expression of VEGF, HO-1, and the transcription factor nuclear factor erythroid-derived 2, like 2 (NRF2). However, NRF2 was only modestly involved in CSE-induced HO-1 expression, as shown by the NRF2 small interfering RNA studies. These new findings demonstrate that cigarette smoke is a potent inducer of oxidative damage and cell death in human RPE cells. These data support the hypothesis that cigarette smoke contributes to AMD pathogenesis by causing oxidative damage and cell death to RPE cells.}, }
@article {pmid19758794, year = {2010}, author = {Guo, WJ and Ye, SS and Cao, N and Huang, J and Gao, J and Chen, QY}, title = {ROS-mediated autophagy was involved in cancer cell death induced by novel copper(II) complex.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {62}, number = {5}, pages = {577-582}, doi = {10.1016/j.etp.2009.08.001}, pmid = {19758794}, issn = {1618-1433}, mesh = {Antineoplastic Agents/*pharmacology ; Autophagy/*drug effects ; Blotting, Western ; Cell Proliferation/*drug effects ; Coordination Complexes/*pharmacology ; HeLa Cells ; Humans ; Organometallic Compounds/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {In this study, we investigated autophagy induced in HeLa cells by copper(II) complex of ethyl 2-[bis(2-pyridylmethyl)amino] propionate ligand (ETDPA) (formula: [(ETDPA)Cu(phen)](ClO4)2 (abbreviated as LCu),a novel synthetic copper(II) complex whose DNA binding activity has been proved. Cell viability, autophagic levels and generation of ROS were evaluated following the exposure to LCu. LCu-induced cell death in a dose- and time-dependent manner, which was demonstrated by enhanced fluorescence intensity of monodansylcadervarine (MDC), as well as elevated expression of autophagy-related protein MAP-LC3. These phenomena were all attenuated after pretreatment with autophagy inhibitors 3-MA or NH(4)Cl. Furthermore, our data indicated that LCu-triggered autophagy through ROS: cellular ROS levels were increased after LCu treatment, which was reversed by ROS scavenger NAC (N-acetylcysteine). As a consequence, Lcu-mediated autophagy was partly blocked by NAC. In summary, we synthesized a novel copper(II) complex and showed that this compound was effective in killing HeLa cells via ROS-triggered autophagic pathway.}, }
@article {pmid19757103, year = {2010}, author = {Suh, KS and Chon, S and Oh, S and Kim, SW and Kim, JW and Kim, YS and Woo, JT}, title = {Prooxidative effects of green tea polyphenol (-)-epigallocatechin-3-gallate on the HIT-T15 pancreatic beta cell line.}, journal = {Cell biology and toxicology}, volume = {26}, number = {3}, pages = {189-199}, doi = {10.1007/s10565-009-9137-7}, pmid = {19757103}, issn = {1573-6822}, mesh = {Apoptosis/drug effects ; Catechin/*analogs &amp; derivatives/toxicity ; Cell Line ; Cell Survival/drug effects ; Comet Assay ; Dose-Response Relationship, Drug ; Flavonoids/toxicity ; Hydrogen Peroxide/metabolism ; Insulin-Secreting Cells/*drug effects/metabolism ; Oxidants/*toxicity ; Oxidative Stress/drug effects ; Phenols/toxicity ; Polyphenols ; Reactive Oxygen Species/metabolism ; Tea/chemistry ; }, abstract = {Epigallocatechin-3-gallate (EGCG) is the main polyphenolic constituent in green tea and is believed to function as an antioxidant. However, increasing evidence indicates that EGCG produces reactive oxygen species (ROS) and subsequent cell death. In this study, we investigated the prooxidative effects of EGCG on the HIT-T15 pancreatic beta cell line. Dose-dependent cell viability was monitored with the cell counting kit-8 assay, while the induction of apoptosis was analyzed by a cell death ELISA kit and comet assay. Extracellular H(2)O(2) was determined using the Amplex Red Hydrogen Peroxide Assay Kit. Intracellular oxidative stress was measured by fluorometric analysis of 2',7'-dichlorofluorescin (DCFH) oxidation using DCFH diacetate (DA) as the probe. Treatment with EGCG (5-100 microM) decreased the viability of pancreatic beta cells, caused concomitant increases in apoptotic cell death, and increased the production of H(2)O(2) and ROS. Catalase, the iron-chelating agent diethylenetriaminepentaacetic acid, and the Fe(II)-specific chelator o-phenanthroline all suppressed the effects of EGCG, indicating the involvement of both H(2)O(2) and Fe(II) in the mechanism of action of EGCG. The antioxidant N-acetyl-cysteine and alpha-lipoic acid also suppressed the effects of EGCG. Furthermore, EGCG did not scavenge exogenous H(2)O(2), but rather, it synergistically increased H(2)O(2)-induced oxidative cell damage in pancreatic beta cells. Together, these findings suggest that in the HIT-T15 pancreatic beta cell line, EGCG mediated the generation of H(2)O(2), triggering Fe(II)-dependent formation of a highly toxic radical that in turn induced oxidative cell damage.}, }
@article {pmid19756603, year = {2010}, author = {Maeda, T and Miyazono, Y and Ito, K and Hamada, K and Sekine, S and Horie, T}, title = {Oxidative stress and enhanced paracellular permeability in the small intestine of methotrexate-treated rats.}, journal = {Cancer chemotherapy and pharmacology}, volume = {65}, number = {6}, pages = {1117-1123}, doi = {10.1007/s00280-009-1119-1}, pmid = {19756603}, issn = {1432-0843}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Antimetabolites, Antineoplastic/pharmacology ; Body Weight/drug effects ; Dextrans/pharmacokinetics ; Fluorescein-5-isothiocyanate/analogs &amp; derivatives/pharmacokinetics ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Glutathione/administration &amp; dosage/pharmacology ; Injections, Intraperitoneal ; Injections, Intravenous ; Intestinal Absorption/*drug effects ; Intestinal Mucosa/metabolism ; Intestine, Small/*drug effects/metabolism ; Male ; Methotrexate/administration &amp; dosage/*pharmacology ; Oxidative Stress/*drug effects ; Permeability/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Time Factors ; }, abstract = {PURPOSE: We previously demonstrated the increase of reactive oxygen species (ROS) production and myeloperoxidase (MPO) activity in the small intestine of methotrexate (MTX)-treated rats. In the present study, we investigated the role of ROS modulating intestinal mucosal permeability in this damage.<br><br>METHOD: MTX (20 mg/kg body weight) was administered to rats intravenously. N-Acetylcysteine (NAC; 80 mg/kg body wt), an antioxidant and a precursor of glutathione (GSH) was administered to rats intraperitoneally to investigate the contribution of ROS to the intestinal permeability enhancement. Intestinal permeability was evaluated by determining that of a poorly absorbable marker, fluorescein isothiocyanate-labeled dextran (FD-4; average molecular mass, 4.4 kDa) using the in vitro everted intestine technique. The occurrence of oxidative stress in the small intestine was assayed by measuring chemiluminescence and thiobarbituric acid reactive substances (TBARS) productions in mucosal homogenates of the small intestine.<br><br>RESULTS: The mucosal permeability of FD-4 significantly (p < 0.01) increased in MTX-treated rats compared with control rats, as demonstrated by a twofold increase of FD-4 permeation clearance. This suggests an increase in paracellular permeability. Interestingly, the ROS production was observed preceding the increase of paracellular permeability. Treatment with NAC prevented the MTX-induced ROS production and the increase of paracellular permeability.<br><br>CONCLUSIONS: NAC protected the small intestine of rats from MTX-induced change in paracellular permeability, suggesting that ROS played an important role in the enhanced paracellular permeability.}, }
@article {pmid19756411, year = {2009}, author = {Sun, J and Xu, Y and Dai, Z and Sun, Y}, title = {Intermittent high glucose stimulate MCP-l, IL-18, and PAI-1, but inhibit adiponectin expression and secretion in adipocytes dependent of ROS.}, journal = {Cell biochemistry and biophysics}, volume = {55}, number = {3}, pages = {173-180}, doi = {10.1007/s12013-009-9066-3}, pmid = {19756411}, issn = {1559-0283}, mesh = {3T3-L1 Cells ; 8-Hydroxy-2'-Deoxyguanosine ; Adipocytes/*drug effects/*metabolism ; Adiponectin/genetics/metabolism ; Animals ; Chemokine CCL2/genetics/metabolism ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Glucose/*pharmacology ; Interleukin-18/genetics/metabolism ; Mice ; Plasminogen Activator Inhibitor 1/genetics/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Elevated circulating concentrations of interleukin-18 (IL-18), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) and decrease of adiponectin are associated with obesity-related diseases. The mechanism that mediates the aberrant production of the adipokines remains poorly understood. The aim of this study was to investigate the effect of intermittent high glucose on the expression of IL-18, MCP-1, and PAI-1 and adiponectin in 3T3-L1 adipocytes. 3T3-L1 adipocytes were incubated for 24 h in media containing different glucose concentrations: 5 mmol/l, 20 mmol/l and a daily alternating 5 or 20 mmol/l glucose, with or without the addition of1.0 mmol/l N-acetylcysteine (NAC). The expression and secretion of IL-18, MCP-1, PAI-1, and adiponectin were determined by real-time RT-PCR and ELISA, respectively.The production of reactive oxygen species (ROS) and 8-hydroxydeoxyguanosine(8-OHdG) were measured. Stable high glucose significantly increased expression and secretion of IL-18, MCP-1, and PAI-1, and reduced adiponectin expression and secretion compared to normal glucose conditions.These effects were significantly greater under intermittent high glucose conditions compared to stable high glucose. The level of ROS and 8-OHdG were significantly elevated under both intermittent and stable high glucose conditions, the effect being greater under intermittent high glucose. The intermittent glucose was more effective in triggering the generation of ROS than stable high glucose. The adding of the NAC, aspecific pharmacological inhibitor of ROS, normalized the expression of these adipokines and the levels of ROS and 8-OHdG under both stable and intermittent glucose conditions.Intermittent high glucose induces a greater aberrant production of key adipokines than stable high glucose, and this effect seems to be related to over-production of ROS.}, }
@article {pmid19755521, year = {2009}, author = {Liu, JC and Chen, CH and Chen, JJ and Cheng, TH}, title = {Urotensin II induces rat cardiomyocyte hypertrophy via the transient oxidization of Src homology 2-containing tyrosine phosphatase and transactivation of epidermal growth factor receptor.}, journal = {Molecular pharmacology}, volume = {76}, number = {6}, pages = {1186-1195}, doi = {10.1124/mol.109.058297}, pmid = {19755521}, issn = {1521-0111}, mesh = {Animals ; Blotting, Western ; Dose-Response Relationship, Drug ; ErbB Receptors/*biosynthesis ; Flow Cytometry ; Gene Knockdown Techniques ; Hypertrophy/chemically induced ; Myocytes, Cardiac/*drug effects/metabolism ; Oxidation-Reduction ; Protein Tyrosine Phosphatases/*physiology ; Rats ; Reactive Oxygen Species/metabolism ; Shc Signaling Adaptor Proteins/metabolism/*physiology ; Signal Transduction/drug effects ; Transcriptional Activation/*drug effects ; Urotensins/*pharmacology ; }, abstract = {Urotensin II (U-II) is implicated in cardiomyocyte hypertrophy, which results in cardiac remodeling. We recently demonstrated that both reactive oxygen species (ROS) generation and epidermal growth factor receptor (EGFR) transactivation play critical roles in U-II signal transduction. However, the detailed intracellular mechanism(s) underlying cardiac hypertrophy and remodeling remain unclear. In this study, we used rat cardiomyocytes treated with U-II to investigate the association between ROS generation and EGFR transactivation. U-II treatment was found to stimulate cardiomyocyte hypertrophy through phosphorylation of EGFR and ROS generation. Apocynin, an NAD(P)H oxidase inhibitor, and N-acetyl cysteine (NAC), an ROS scavenger, both inhibited EGFR transactivation induced by U-II. In contrast, 4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG1478, an EGFR inhibitor) failed to inhibit intracellular ROS generation induced by U-II. Src homology 2-containing tyrosine phosphatase (SHP-2), but not protein tyrosine phosphatase 1B (PTP 1B), was shown to be associated with EGFR during U-II treatment by EGFR coimmunoprecipitation. ROS have been reported to transiently oxidize the catalytic cysteine of phosphotyrosine phosphatases, subsequently inhibiting their activity. We examined the effect of U-II on SHP-2 and PTP 1B in cardiomyocytes using a modified malachite green phosphatase assay. SHP-2, but not PTP 1B, was transiently oxidized during U-II treatment, which could be repressed by NAC treatment. In SHP-2 knockdown cells, U-II-induced phosphorylation of EGFR and myocyte hypertrophy were dramatically elevated, and these effects were not influenced by NAC. Our data suggest that U-II-mediated ROS generation can transiently inhibit SHP-2 activity, thereby facilitating EGFR transactivation and hypertrophic signal transduction in rat cardiomyocytes.}, }
@article {pmid19755143, year = {2010}, author = {Huang, CC and Aronstam, RS and Chen, DR and Huang, YW}, title = {Oxidative stress, calcium homeostasis, and altered gene expression in human lung epithelial cells exposed to ZnO nanoparticles.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {24}, number = {1}, pages = {45-55}, doi = {10.1016/j.tiv.2009.09.007}, pmid = {19755143}, issn = {1879-3177}, mesh = {Acetylcysteine/pharmacology ; Calcium/*metabolism ; Calcium Channel Blockers/pharmacology ; Cell Line ; Cell Membrane/drug effects/metabolism ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects/*metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression/*drug effects ; Homeostasis/drug effects ; Humans ; L-Lactate Dehydrogenase/metabolism ; Lung/cytology/drug effects/*metabolism ; Nanoparticles/*toxicity ; Nifedipine/pharmacology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Zinc Oxide/*toxicity ; }, abstract = {The influence of 20nm ZnO nanoparticles on cytotoxicity, oxidative stress, intracellular calcium homeostasis, and gene expression was studied in human bronchial epithelial cells (BEAS-2B). ZnO caused a concentration- and time-dependent cytotoxicity while elevating oxidative stress and causing membrane damage (cellular LDH release). There was a remarkably steep relationship between concentration and toxicity at concentrations from 5 to 10microg/ml. Cytotoxicity was completely abolished by the antioxidant N-acetylcysteine (NAC). Exposure to ZnO also increased intracellular calcium levels ([Ca(2+)](in)) in a concentration- and time-dependent manner that was partially attenuated by NAC. Nifedipine, a calcium channel blocker, partially attenuated the elevated [Ca(2+)](in), indicating that some of the excess [Ca(2+)](in) is a result of influx from outside the cell. The relationships between oxidative stress, [Ca(2+)](in), and cytotoxicity are discussed. Exposure to a sublethal concentration of ZnO increased the expression of four genes that are involved in apoptosis and oxidative stress responses BNIP, PRDX3, PRNP, and TXRND1, by at least 2.5-fold. Thus, ZnO alters transcriptional regulation in BEAS-2B cells.}, }
@article {pmid19751964, year = {2010}, author = {Lee, E and Yi, JY and Chung, E and Son, Y}, title = {Transforming growth factorbeta(1) transactivates EGFR via an H(2)O(2)-dependent mechanism in squamous carcinoma cell line.}, journal = {Cancer letters}, volume = {290}, number = {1}, pages = {43-48}, doi = {10.1016/j.canlet.2009.08.022}, pmid = {19751964}, issn = {1872-7980}, mesh = {Carcinoma, Squamous Cell/genetics/*metabolism ; Cell Line, Tumor ; ErbB Receptors/genetics/*metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; *Gene Expression Regulation, Neoplastic ; Humans ; Hydrogen Peroxide/*metabolism ; Immunoblotting ; Immunoprecipitation ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Receptor Cross-Talk ; Signal Transduction/*physiology ; Transcriptional Activation ; Transforming Growth Factor beta1/genetics/*metabolism ; }, abstract = {TGFbeta is known to transactivate EGFR. However, the signaling component involved in this crosstalk has yet to be revealed. Here, we found that TGFbeta(1) phosphorylated EGFR in a dose-dependent manner in SCC13 and A431 cells, and it was not blocked by EGF-neutralizing antibody. H(2)O(2) was increased by TGFbeta(1) treatment in the same time-kinetics as EGFR activation. Pretreatment of N-acetyl cysteine abolished TGFbeta(1)-induced H(2)O(2) induction and EGFR activation. Direct treatment of H(2)O(2) phosphorylated EGFR and catalase inhibitor prolonged TGFbeta(1)-induced EGFR activation. These results show that TGFbeta(1) activates EGFR via an H(2)O(2)-dependent mechanism, which subsequently leads to the activation of Erk(1/2).}, }
@article {pmid19748591, year = {2009}, author = {García, A and Morales, P and Rafter, J and Haza, AI}, title = {N-Nitrosopiperidine and N-Nitrosodibutylamine induce apoptosis in HepG2 cells via the caspase dependent pathway.}, journal = {Cell biology international}, volume = {33}, number = {12}, pages = {1280-1286}, doi = {10.1016/j.cellbi.2009.08.015}, pmid = {19748591}, issn = {1095-8355}, mesh = {Alkylating Agents/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Carcinogens/*pharmacology ; Caspases/*metabolism ; Cell Survival/drug effects ; Diethylnitrosamine/*pharmacology ; Hep G2 Cells ; Humans ; In Situ Nick-End Labeling ; Liver Neoplasms/drug therapy/metabolism/pathology ; Nitrosamines/*pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; }, abstract = {The human hepatoma cell line (HepG2) exhibited a dose and time-dependent apoptotic response following treatment with N-Nitrosopiperidine (NPIP) and N-Nitrosodibutylamine (NDBA), two recognized human carcinogens. Our results showed a significant apoptotic cell death (95%) after 24h treatment with NDBA (3.5 mM), whereas it was necessary to use high doses of NPIP (45 mM) to obtain a similar percentage of apoptotic cells (86%). In addition, both extrinsic (caspase-8) and intrinsic pathway (caspase-9) could be implicated in the N-Nitrosamines-induced apoptosis. This study also addresses the role of reactive oxygen species (ROS) as intermediates for apoptosis signaling. A significant increase in ROS levels was observed after NPIP treatment, whereas NDBA did not induce ROS. However, N-acetylcysteine (NAC) did not block NPIP-induced apoptosis. All these findings suggest that NPIP and NDBA induce apoptosis in HepG2 cells via a pathway that involves caspases but not ROS.}, }
@article {pmid19747897, year = {2009}, author = {Preta, G and de Klark, R and Glas, R}, title = {A role for nuclear translocation of tripeptidyl-peptidase II in reactive oxygen species-dependent DNA damage responses.}, journal = {Biochemical and biophysical research communications}, volume = {389}, number = {4}, pages = {575-579}, doi = {10.1016/j.bbrc.2009.09.021}, pmid = {19747897}, issn = {1090-2104}, mesh = {Active Transport, Cell Nucleus/drug effects/radiation effects ; Aminopeptidases ; Animals ; Apoptosis ; Cell Line, Tumor ; Cell Nucleus/*enzymology ; *DNA Damage ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases ; *Gamma Rays ; Humans ; Mice ; Reactive Oxygen Species/*metabolism ; Serine Endopeptidases/*metabolism ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Responses to DNA damage are influenced by cellular metabolism through the continuous production of reactive oxygen species (ROS), of which most are by-products of mitochondrial respiration. ROS have a strong influence on signaling pathways during responses to DNA damage, by relatively unclear mechanisms. Previous reports have shown conflicting data on a possible role for tripeptidyl-peptidase II (TPPII), a large cytosolic peptidase, within the DNA damage response. Here we show that TPPII translocated into the nucleus in a p160-ROCK-dependent fashion in response to gamma-irradiation, and that nuclear expression of TPPII was present in most gamma-irradiated transformed cell lines. We used a panel of nine cell lines of diverse tissue origin, including four lymphoma cell lines (T, B and Hodgkins lymphoma), a melanoma, a sarcoma, a colon and two breast carcinomas, where seven out of nine cell lines showed nuclear TPPII expression after gamma-irradiation. Further, this required cellular production of ROS; treatment with either N-acetyl-Cysteine (anti-oxidant) or Rotenone (inhibitor of mitochondrial respiration) inhibited nuclear accumulation of TPPII. The local density of cells was important for nuclear accumulation of TPPII at early time-points following gamma-irradiation (at 1-4h), indicating a bystander effect. Further, we showed that the peptide-based inhibitor Z-Gly-Leu-Ala-OH, but not its analogue Z-Gly-(D)-Leu-Ala-OH, excluded TPPII from the nucleus. This correlated with reduced nuclear expression of p53 as well as caspase-3 and -9 activation in gamma-irradiated lymphoma cells. Our data suggest a role for TPPII in ROS-dependent DNA damage responses, through alteration of its localization from the cytosol into the nucleus.}, }
@article {pmid19747498, year = {2009}, author = {Ding, M and Kisin, ER and Zhao, J and Bowman, L and Lu, Y and Jiang, B and Leonard, S and Vallyathan, V and Castranova, V and Murray, AR and Fadeel, B and Shvedova, AA}, title = {Size-dependent effects of tungsten carbide-cobalt particles on oxygen radical production and activation of cell signaling pathways in murine epidermal cells.}, journal = {Toxicology and applied pharmacology}, volume = {241}, number = {3}, pages = {260-268}, doi = {10.1016/j.taap.2009.09.004}, pmid = {19747498}, issn = {1096-0333}, support = {HL70755/HL/NHLBI NIH HHS/United States ; OH008282/OH/NIOSH CDC HHS/United States ; }, mesh = {Animals ; Cell Line ; Cell Proliferation/drug effects ; Cobalt/*toxicity ; Dose-Response Relationship, Drug ; Electron Spin Resonance Spectroscopy ; Enzyme Activation/drug effects ; Epidermal Cells ; Epidermis/*drug effects ; Glutathione/metabolism ; Immunohistochemistry ; Indicators and Reagents ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/biosynthesis ; Nanoparticles ; Particle Size ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Sulfhydryl Compounds/metabolism ; Transcription Factor AP-1/biosynthesis ; Tungsten Compounds/*toxicity ; }, abstract = {Hard metal or cemented carbide consists of a mixture of tungsten carbide (WC) (85%) and metallic cobalt (Co) (5-15%). WC-Co is considered to be potentially carcinogenic to humans. However, no comparison of the adverse effects of nano-sized WC-Co particles is available to date. In the present study, we compared the ability of nano- and fine-sized WC-Co particles to form free radicals and propensity to activate the transcription factors, AP-1 and NF-kappaB, along with stimulation of mitogen-activated protein kinase (MAPK) signaling pathways in a mouse epidermal cell line (JB6 P(+)). Our results demonstrated that nano-WC-Co generated a higher level of hydroxyl radicals, induced greater oxidative stress, as evidenced by a decrease of GSH levels, and caused faster JB6 P(+) cell growth/proliferation than observed after exposure of cells to fine WC-Co. In addition, nano-WC-Co activated AP-1 and NF-kappaB more efficiently in JB6(+/+) cells as compared to fine WC-Co. Experiments using AP-1-luciferase reporter transgenic mice confirmed the activation of AP-1 by nano-WC-Co. Nano- and fine-sized WC-Co particles also stimulated MAPKs, including ERKs, p38, and JNKs with significantly higher potency of nano-WC-Co. Finally, co-incubation of the JB6(+/+) cells with N-acetyl-cysteine decreased AP-1 activation and phosphorylation of ERKs, p38 kinase, and JNKs, thus suggesting that oxidative stress is involved in WC-Co-induced toxicity and AP-1 activation.}, }
@article {pmid19746172, year = {2009}, author = {Simons, AL and Parsons, AD and Foster, KA and Orcutt, KP and Fath, MA and Spitz, DR}, title = {Inhibition of glutathione and thioredoxin metabolism enhances sensitivity to perifosine in head and neck cancer cells.}, journal = {Journal of oncology}, volume = {2009}, number = {}, pages = {519563}, pmid = {19746172}, issn = {1687-8450}, support = {K01 CA134941/CA/NCI NIH HHS/United States ; R01 CA133114/CA/NCI NIH HHS/United States ; T32 CA078586/CA/NCI NIH HHS/United States ; R01 CA100045/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; K01 CA134941-01A1/CA/NCI NIH HHS/United States ; }, abstract = {The hypothesis that the Akt inhibitor, perifosine (PER), combined with inhibitors of glutathione (GSH) and thioredoxin (Trx) metabolism will induce cytotoxicity via metabolic oxidative stress in human head and neck cancer (HNSCC) cells was tested. PER induced increases in glutathione disulfide (%GSSG) in FaDu, Cal-27, and SCC-25 HNSCCs as well as causing significant clonogenic cell killing in FaDu and Cal-27, which was suppressed by simultaneous treatment with N-acetylcysteine (NAC). An inhibitor of GSH synthesis, buthionine sulfoximine (BSO), sensitized Cal-27 and SCC-25 cells to PER-induced clonogenic killing as well as decreased total GSH and increased %GSSG. Additionally, inhibition of thioredoxin reductase activity (TrxRed) with auranofin (AUR) was able to induce PER sensitization in SCC-25 cells that were initially refractory to PER. These results support the conclusion that PER induces oxidative stress and clonogenic killing in HNSCC cells that is enhanced with inhibitors of GSH and Trx metabolism.}, }
@article {pmid19744503, year = {2010}, author = {Xu, H and Jiang, H and Wang, J and Xie, J}, title = {Rg1 protects the MPP+-treated MES23.5 cells via attenuating DMT1 up-regulation and cellular iron uptake.}, journal = {Neuropharmacology}, volume = {58}, number = {2}, pages = {488-494}, doi = {10.1016/j.neuropharm.2009.09.002}, pmid = {19744503}, issn = {1873-7064}, mesh = {1-Methyl-4-phenylpyridinium/*toxicity ; Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus/drug effects ; Animals ; Antioxidants/pharmacology ; Cation Transport Proteins/*metabolism ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Cell Survival/drug effects/physiology ; Ginsenosides/administration &amp; dosage/*pharmacology ; Herbicides/*toxicity ; I-kappa B Proteins/metabolism ; Iron/*metabolism/toxicity ; NF-KappaB Inhibitor alpha ; NF-kappa B/metabolism ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Nitriles/pharmacology ; Phosphorylation/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Sulfones/pharmacology ; Up-Regulation/drug effects ; }, abstract = {Ginsenoside-Rg1 is one of the pharmacologically active component isolated from ginseng. Our previous study observed the protective effect of Rg1 on iron accumulation in the substantia nigra (SN) in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-treated Parkinson's disease (PD) mice. However, the mechanisms of this neuroprotective effect of Rg1 are unknown. In this study, we elucidated possible mechanisms for this effect using 1-methyl-4-phenylpyridinium (MPP(+))-treated MES23.5 cells. Previous study showed MPP+ treatment induced up-regulation of divalent metal transporter 1 without iron responsive element (DMT1-IRE) in MES23.5 cells. In the present study, we observed that pretreatment with Rg1 could inhibit MPP+-induced up-regulation of DMT1-IRE in MES23.5 cells. Up-regulation of DMT1-IRE by MPP+ treatment was associated with ROS production and translocation of nuclear factor-kappaB (NF-kappaB) to nuclei, both of which were significantly inhibited by Rg1 pretreatment. The role of ROS and NF-kappaB in the up-regulation of DMT1-IRE was supported by application of an antioxidant NAC and BAY 11-7082, an inhibitor of IkappaBalpha phosphorylation. Furthermore, we also showed Rg1 could decrease DMT1-mediated ferrous iron uptake and iron-induced cell damage by inhibiting the up-regulation of DMT1-IRE. These results indicate that Rg1 protected the MPP+-treated MES23.5 cells via attenuating DMT1-IRE up-regulation likely through inhibition of ROS-NF-kappaB pathway; Attenuation of DMT1-IRE expression decreased the iron influx and iron-induced oxidative stress.}, }
@article {pmid19737600, year = {2009}, author = {Naoi, M and Yi, H and Maruyama, W and Inaba, K and Shamoto-Nagai, M and Akao, Y and Gerlach, M and Riederer, P}, title = {Glutathione redox status in mitochondria and cytoplasm differentially and sequentially activates apoptosis cascade in dopamine-melanin-treated SH-SY5Y cells.}, journal = {Neuroscience letters}, volume = {465}, number = {2}, pages = {118-122}, doi = {10.1016/j.neulet.2009.08.082}, pmid = {19737600}, issn = {1872-7972}, mesh = {Apoptosis/*physiology ; Caspase 3/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Cytoplasm/*metabolism ; Dopamine/*metabolism ; Glutathione/*metabolism ; Humans ; Melanins/*metabolism ; Membrane Potential, Mitochondrial/physiology ; Mitochondria/*metabolism ; Oxidation-Reduction ; Signal Transduction/physiology ; Sulfhydryl Compounds/metabolism ; Time Factors ; }, abstract = {Neuromelanin (NM)-containing dopaminergic neurons in the substantia nigra are selectively vulnerable in Parkinson's disease (PD), suggesting the involvement of NM in the pathogenesis. NM is composed of protein, lipid, trace metals and melanin component, a mixture of eumelanin produced from dopamine (DA)-quinone and pheomelanin containing 5-S-cyteinyl-DA-quinone. We reported that NM induces mitochondria-mediated apoptosis in human dopaminergic SH-SY5Y cells, which was suppressed completely by Protease K-treatment, suggesting the essential requirement for the protein component. In this paper, the role of the melanin component in NM-dependent apoptosis was studied using SH-SY5Y cells and synthesized DA-melanin (DAM) and L-cysteinyl-DAM (Cys-DAM). DAM oxidatively decreased glutathione (GSH) and sulfhydryl (SH) content in mitochondria, whereas NM increased GSH by de-S-glutathionylation of complex I. DAM induced mitochondrial permeability transition (mPT), leading to membrane potential collapse and cytochrome c release, whereas Cys-DAM did not. However, the cytotoxicity of DAM itself was rather mild and thiol-targeting reducing reagents, including GSH, dithiothreitol and N-acetyl-cysteine, increased apoptosis significantly. The reducing SH reagents activated caspase 3 and induced apoptosis, but did not affect mPT. On the other hand, NM itself activated mitochondria-initiated apoptotic cascade, which GSH suppressed completely. The results indicate that DAM induces apoptosis through the sequential activation by oxidation of SH status in mitochondria and reduction in cytoplasm, in contrast to the case with NM. The regulation of apoptotic processing by SH redox state is discussed in relation to degeneration of nigra-striatal DA neurons in aging and PD, where oxidative stress is increased with impaired antioxidant capacity.}, }
@article {pmid19735056, year = {2009}, author = {Bulut, M and Savas, HA and Altindag, A and Virit, O and Dalkilic, A}, title = {Beneficial effects of N-acetylcysteine in treatment resistant schizophrenia.}, journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry}, volume = {10}, number = {4 Pt 2}, pages = {626-628}, doi = {10.1080/15622970903144004}, pmid = {19735056}, issn = {1814-1412}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Antipsychotic Agents/adverse effects/*therapeutic use ; Benzodiazepines/adverse effects/therapeutic use ; Clopenthixol/adverse effects/analogs &amp; derivatives/therapeutic use ; Delayed-Action Preparations ; Dose-Response Relationship, Drug ; Drug Resistance ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/adverse effects/*therapeutic use ; Humans ; Olanzapine ; Psychiatric Status Rating Scales ; Schizophrenia/*drug therapy ; *Schizophrenic Psychology ; }, abstract = {Poor response to antipsychotics is still an important problem in the treatment of many schizophrenia patients. N-acetylcysteine (NAC) is a compound that exerts anti-oxidant and scavenging actions against reactive oxygen species. This paper reports a case of poorly responsive schizophrenia patient who improved considerably with add-on NAC 600 mg/day. The NAC might work through activating cysteine-glutamate antiporters or reducing in nitric oxide (NO) metabolites, free radicals and cytokines or through both of these mechanisms.}, }
@article {pmid19734319, year = {2009}, author = {Ferguson, HE and Thatcher, TH and Olsen, KC and Garcia-Bates, TM and Baglole, CJ and Kottmann, RM and Strong, ER and Phipps, RP and Sime, PJ}, title = {Peroxisome proliferator-activated receptor-gamma ligands induce heme oxygenase-1 in lung fibroblasts by a PPARgamma-independent, glutathione-dependent mechanism.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {297}, number = {5}, pages = {L912-9}, pmid = {19734319}, issn = {1522-1504}, support = {DE-011390/DE/NIDCR NIH HHS/United States ; EY-017123/EY/NEI NIH HHS/United States ; T32-ES-07026/ES/NIEHS NIH HHS/United States ; HL-066988/HL/NHLBI NIH HHS/United States ; ES-01247/ES/NIEHS NIH HHS/United States ; T32-HL-001752/HL/NHLBI NIH HHS/United States ; HL-095402/HL/NHLBI NIH HHS/United States ; HL-75432/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Cell Differentiation/drug effects ; Cell Nucleus/drug effects/metabolism ; Chromans/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Induction/drug effects ; Fibroblasts/cytology/*drug effects/*enzymology ; Glutathione/chemistry/*metabolism ; Heme Oxygenase-1/*biosynthesis ; Humans ; Ligands ; Lung/*cytology ; NF-E2-Related Factor 2/metabolism ; Oleanolic Acid/*analogs &amp; derivatives/chemistry/pharmacology ; PPAR gamma/metabolism ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology ; Protein Transport/drug effects ; Rosiglitazone ; Thiazolidinediones/pharmacology ; Transcription Factor AP-1/metabolism ; Up-Regulation/drug effects ; }, abstract = {Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPARgamma ligands 15d-PGJ2 and 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPARgamma independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-PGJ2 contain an alpha/beta unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPARgamma ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-PGJ2 and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-PGJ2 or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-PGJ2 and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPARgamma ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses.}, }
@article {pmid19734276, year = {2009}, author = {Bijarnia, RK and Kaur, T and Singla, SK and Tandon, C}, title = {Oxalate-mediated oxidant-antioxidant imbalance in erythrocytes: role of N-acetylcysteine.}, journal = {Human &amp; experimental toxicology}, volume = {28}, number = {4}, pages = {245-251}, doi = {10.1177/0960327109104825}, pmid = {19734276}, issn = {1477-0903}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism ; Blood Proteins/metabolism ; Catalase/metabolism ; Cholesterol/blood ; Erythrocytes/drug effects/*metabolism/ultrastructure ; Free Radical Scavengers/*pharmacology ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Microscopy, Electron ; Microscopy, Electron, Scanning ; Oxalates/*toxicity ; Oxidants/*blood ; Phospholipids/metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {The present in-vivo study was to observe the effect of N-acetylcysteine (NAC) on oxalate-induced oxidative stress on rat erythrocytes. A total of 15 Wistar rats were divided into three groups. The control group received normal saline by single intraperitoneal injection. Hyperoxaluria was induced by single intraperitoneal (i.p.) dose of sodium oxalate (70 mg/kg body weight in 0.5 mL saline) to a second group. The third group was administered single i.p. dose of NAC according to 200 mg/kg body weight dissolved in 0.5 mL saline, half an hour after oxalate dose. NAC administration normalized antioxidant enzyme activities (superoxide dismutase and catalase) and reduced malondialdehyde content (indicator of lipid peroxidation) in hyperoxaluric rat's red blood cell (RBC) lysate. NAC administration also resulted in a significant improvement of thiol content in RBC lysate via increasing reduced glutathione content and maintaining its redox status. Oxalate-caused alteration of cholesterol/phospholipid ratio (determining membrane fluidity) was also rebalanced by NAC administration. Further, after NAC administration, electron microscopy showed improved cell morphology presenting its prophylactic properties. Above results indicate that NAC treatment is associated with an increase in plasma antioxidant capacity and a reduction in the susceptibility of erythrocyte membranes to oxidation. Thus, the study presents positive pharmacological implications of NAC against oxalate-mediated impairment of erythrocytes.}, }
@article {pmid19734274, year = {2009}, author = {Wang, L and Chen, D and Cao, J and Liu, Z}, title = {Protective effect of N-acetylcysteine on experimental chronic cadmium nephrotoxicity in immature female rats.}, journal = {Human &amp; experimental toxicology}, volume = {28}, number = {4}, pages = {221-229}, doi = {10.1177/0960327109102365}, pmid = {19734274}, issn = {1477-0903}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers ; Body Weight/drug effects ; Cadmium/metabolism/*toxicity ; Enzymes/urine ; Female ; Free Radical Scavengers/*pharmacology ; Kidney Cortex/drug effects/metabolism ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Lipid Peroxidation/drug effects ; Oxidative Stress/drug effects ; *Protective Agents ; Proteinuria/metabolism ; Rats ; Rats, Sprague-Dawley ; Trace Elements/metabolism ; Urodynamics/drug effects ; }, abstract = {In the present study, female Sprague-Dawley rats received CdCl(2) (50 mg/L through drinking water) and/or N-acetylcysteine (NAC, 120 mg/kg/day, orally) to investigate the protective effect of NAC on Cd-induced renal damage. Renal toxicity was evaluated by measuring the contents of total protein, beta(2)-microglobulin, and alpha(1)-microglobulin in the urine and urinary enzyme markers of tubular necrosis, as well as levels of serum urea nitrogen and serum creatinine. Activities of antioxidant enzymes and contents of glutathione, malondialdehyde, and trace elements in the kidney were also measured. Animals that received both Cd and NAC showed a better renal function than those receiving Cd alone. In addition, NAC significantly reduced the levels of lipid peroxidation (LPO) in the kidney of cadmium-treated rats. The enzymic and nonenzymatic antioxidants levels are not restored, but their further decrease is prevented by NAC. Also NAC administration does not modify the urinary excretion of cadmium or contents of cadmium in the serum and kidney. In conclusion, NAC exerts its protective effect by decreased LPO and improving antioxidants status to prevent renal tubular damage induced by chronic Cd administration, most probably through its antioxidant properties.}, }
@article {pmid19732818, year = {2010}, author = {Eastwood, H and Pinder, D and James, D and Chang, A and Galloway, S and Richardson, R and O'Leary, S}, title = {Permanent and transient effects of locally delivered n-acetyl cysteine in a guinea pig model of cochlear implantation.}, journal = {Hearing research}, volume = {259}, number = {1-2}, pages = {24-30}, doi = {10.1016/j.heares.2009.08.010}, pmid = {19732818}, issn = {1878-5891}, support = {DC 01368/DC/NIDCD NIH HHS/United States ; HHS-N-263-2007-00053-C//PHS HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Acoustic Stimulation ; Animals ; Antioxidants/*administration &amp; dosage ; Auditory Threshold/drug effects ; Cochlea/pathology/physiopathology/surgery ; *Cochlear Implants/adverse effects ; Evoked Potentials, Auditory, Brain Stem ; Guinea Pigs ; Hearing Loss/etiology/prevention &amp; control/surgery ; Humans ; Models, Animal ; Round Window, Ear/drug effects ; }, abstract = {Protection of residual hearing after cochlear implant surgery can improve the speech and music perception of cochlear implant recipients, particularly in the presence of background noise. Surgical trauma and chronic inflammation are thought to be responsible for a significant proportion of residual hearing loss after surgery. Local delivery of the anti-oxidant precursor n-acetyl cysteine (NAC) to the cochlea via round window 30min prior to surgery, increased the level of residual hearing at 24-32kHz 4weeks post surgery compared to controls. The hearing protection was found in the basal turn near the site of implantation. Coincidentally, the basal turn was also the location that sustained the greatest hearing loss. As well as protecting residual hearing, NAC-treated animals demonstrated a reduction in the chronic inflammatory changes associated with implantation. While these findings indicate that anti-oxidant therapy can be used to reduce the hearing loss associated with surgical trauma, the local delivery of NAC was associated with a transient increase in hearing thresholds, and osseoneogenesis was seen in a greater number of NAC-treated animals. These side-effects would limit its clinical use through local cochlear administration. However, it is not known yet whether these effects would also be produced by other anti-oxidants, or ameliorated by using a different route of administration.}, }
@article {pmid19732754, year = {2010}, author = {Geiler, J and Michaelis, M and Naczk, P and Leutz, A and Langer, K and Doerr, HW and Cinatl, J}, title = {N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus.}, journal = {Biochemical pharmacology}, volume = {79}, number = {3}, pages = {413-420}, doi = {10.1016/j.bcp.2009.08.025}, pmid = {19732754}, issn = {1873-2968}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antiviral Agents/*pharmacology/therapeutic use ; Cell Line, Tumor ; Cells, Cultured ; Chlorocebus aethiops ; Gene Expression Regulation, Viral/*drug effects/physiology ; Humans ; Inflammation Mediators/*antagonists &amp; inhibitors/metabolism ; Influenza A Virus, H5N1 Subtype/*drug effects/physiology ; Influenza, Human/metabolism/prevention &amp; control ; Vero Cells ; Virus Replication/*drug effects/physiology ; }, abstract = {The antioxidant N-acetyl-L-cysteine (NAC) had been shown to inhibit replication of seasonal human influenza A viruses. Here, the effects of NAC on virus replication, virus-induced pro-inflammatory responses and virus-induced apoptosis were investigated in H5N1-infected lung epithelial (A549) cells. NAC at concentrations ranging from 5 to 15 mM reduced H5N1-induced cytopathogenic effects (CPEs), virus-induced apoptosis and infectious viral yields 24 h post-infection. NAC also decreased the production of pro-inflammatory molecules (CXCL8, CXCL10, CCL5 and interleukin-6 (IL-6)) in H5N1-infected A549 cells and reduced monocyte migration towards supernatants of H5N1-infected A549 cells. The antiviral and anti-inflammatory mechanisms of NAC included inhibition of activation of oxidant sensitive pathways including transcription factor NF-kappaB and mitogen activated protein kinase p38. Pharmacological inhibitors of NF-kappaB (BAY 11-7085) or p38 (SB203580) exerted similar effects like those determined for NAC in H5N1-infected cells. The combination of BAY 11-7085 and SB203580 resulted in increased inhibitory effects on virus replication and production of pro-inflammatory molecules relative to either single treatment. NAC inhibits H5N1 replication and H5N1-induced production of pro-inflammatory molecules. Therefore, antioxidants like NAC represent a potential additional treatment option that could be considered in the case of an influenza A virus pandemic.}, }
@article {pmid19732281, year = {2009}, author = {Shavit, L and Korenfeld, R and Lifschitz, M and Butnaru, A and Slotki, I}, title = {Sodium bicarbonate versus sodium chloride and oral N-acetylcysteine for the prevention of contrast-induced nephropathy in advanced chronic kidney disease.}, journal = {Journal of interventional cardiology}, volume = {22}, number = {6}, pages = {556-563}, doi = {10.1111/j.1540-8183.2009.00500.x}, pmid = {19732281}, issn = {1540-8183}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Cardiac Catheterization/*adverse effects ; Contrast Media/*adverse effects ; Creatine/blood/drug effects ; Dehydration/prevention &amp; control ; Female ; Free Radical Scavengers/therapeutic use ; Glomerular Filtration Rate ; Humans ; Kidney Diseases/chemically induced/*prevention &amp; control ; Kidney Failure, Chronic/prevention &amp; control ; Male ; Prospective Studies ; Regression Analysis ; Risk Assessment ; Sodium Bicarbonate/*therapeutic use ; Sodium Chloride/*therapeutic use ; Statistics as Topic ; }, abstract = {INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is one of the leading causes of hospital-acquired acute kidney injury. Multiple clinical studies have proposed several preventive strategies.<br><br>AIMS: To examine the efficacy of sodium bicarbonate compared with sodium chloride and oral N-acetylcysteine (NAC) for preventive hydration after cardiac catheterization.<br><br>METHODS: We conducted a prospective, single-center trial. Patients with chronic kidney disease (CKD) stage III-IV undergoing cardiac catheterization were allocated to receive either an infusion of 0.9% sodium chloride and oral NAC or 154 mEq/L sodium bicarbonate. MAIN: Outcome measure CI-AKI, defined as an increase of 25% or 0.3 mg/dL or more in plasma creatinine within 2 days of contrast administration.<br><br>RESULTS: Ninety-three patients were allocated to one of the two groups: 42 patients in the saline plus NAC group and 51 patients in the bicarbonate group. There were no statistically significant differences between the groups in the most important clinical and procedural characteristics. Baseline plasma creatinine levels, estimated glomerular filtration rate, incidence of diabetes mellitus, hypertension, congestive heart failure, and contrast medium volume were similar. Mean plasma creatinine concentration was 1.76 +/- 0.54 mg/dL in the saline and NAC group and 1.9 +/- 1 mg/dL in the bicarbonate group (P = 0.23). The rate of CI-AKI was 9.8% in the bicarbonate group and 8.4% in the saline plus NAC group. No patient required renal replacement therapy.<br><br>CONCLUSION: Hydration with sodium bicarbonate is not more effective than hydration with sodium chloride and oral NAC for prophylaxis of CI-AKI in patients with CKD stage III-IV undergoing cardiac catheterization.}, }
@article {pmid19731687, year = {2009}, author = {Huang, G and Hou, J and Zhou, X}, title = {A measurement method for atmospheric ammonia and primary amines based on aqueous sampling, OPA derivatization and HPLC analysis.}, journal = {Environmental science &amp; technology}, volume = {43}, number = {15}, pages = {5851-5856}, doi = {10.1021/es900988q}, pmid = {19731687}, issn = {0013-936X}, mesh = {Air/analysis ; Amines/*analysis ; Ammonia/*analysis ; Atmosphere ; Calibration ; Chemistry Techniques, Analytical/methods ; Chromatography, High Pressure Liquid/*methods ; Dose-Response Relationship, Drug ; Environmental Monitoring/*methods ; Hydrogen-Ion Concentration ; Kinetics ; Models, Chemical ; Time Factors ; Water/analysis ; o-Phthalaldehyde/*analysis ; }, abstract = {A method of precolumn derivatization HPLC with fluorescence detection has been developed for the measurement of ammonia, primary methylamine, ethylamine, propylamine, and butylamine in the atmosphere. Air samples were collected by two continuously wetted glass frit/coil samplers, one directly from ambient air for the sum of gaseous and aerosol species, and the other after an acid-coated annular denuder for the aerosol species. The collection efficiency for all analytes was found to be > or = 99% at a sampling gas flow rate of 2 L min(-1) and a scrubbing water flow rate of 0.24 mL min(-1). The collected ammonia and primary amines were derivatized with o-phthalaldehyde (OPA) and n-acetyl-cysteine (NAC) reagents in an in-line derivatization coil to form highly fluorescent sulfonatoisoindole derivatives. Detailed kinetic study showed that derivatization reactions were fast but the derivatives were not very stable. Derivatization conditions, such as reagent concentrations, derivatication medium pH, and derivatization time, were optimized to achieve maximum derivative yields for all the analytes. The derivatives were separated on a C-18 reverse-phase column using a gradient elution and detected by a fluorescence detector at an excitation wavelength of 330 nm and an emission wavelength of 471 nm. The respective lower detection limits for ammonia and for the four primary amines were 24 parts per trillion by volume (pptv) and < or = 3 pptv, with a sample time resolution of about 1 min and a sampling/ analysis time of 20 win per cycle. The analytical methodology has been applied in the field measurements; results from two case studies are presented.}, }
@article {pmid19730430, year = {2009}, author = {Zhou, YB and Feng, X and Wang, LN and Du, JQ and Zhou, YY and Yu, HP and Zang, Y and Li, JY and Li, J}, title = {LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation.}, journal = {Acta pharmacologica Sinica}, volume = {30}, number = {9}, pages = {1359-1368}, pmid = {19730430}, issn = {1745-7254}, mesh = {Antineoplastic Agents/*pharmacology ; Blotting, Western ; Dose-Response Relationship, Drug ; Flow Cytometry ; HeLa Cells/drug effects ; Humans ; Quinones/*pharmacology ; Reactive Oxygen Species/*metabolism ; cdc25 Phosphatases/*antagonists &amp; inhibitors ; }, abstract = {AIM: To discover novel cell division cycle 25 (CDC25) B inhibitors and elucidate the mechanisms of inhibition in cancer cells.<br><br>METHODS: Cell growth inhibition was detected by MTT assay, the cell cycle was analyzed by flow cytometry, and protein expression and phosphorylation was examined by Western blot analysis.<br><br>RESULTS: LGH00031 inhibited CDC25B irreversibly in vitro in a dose-dependent manner, and impaired the proliferation of tumor cell lines. In synchronized HeLa cells, LGH00031 delayed the cell cycle progression at the G(2)/M phase. LGH00031 increased cyclin-dependent kinase 1 (CDK1) tyrosine 15 phosphorylation and cyclin B1 protein level. The activity of LGH00031 against CDC25B in vitro relied on the existence of 1,4-dithiothreitol (DTT) or dihydrolipoic acid and oxygen. The oxygen free radical scavenger catalase and superoxide dismutase reduced the inactivation of CDC25 by LGH00031, confirming that reactive oxygen species (ROS) mediate the inactivation process in vitro. LGH00031 accelerated cellular ROS production in a dose-dependent manner, and N-acetyl cysteine (NAC) markedly decreased the ROS production induced by LGH00031. Correspondingly, the LGH00031-induced decrease in cell viability and cell cycle arrest, cyclin B1 protein level, and phosphorylation of CDK1 tyrosine 15 were also rescued by NAC that decreased ROS production.<br><br>CONCLUSION: The activity of LGH00031 at the molecular and cellular level is mediated by ROS.}, }
@article {pmid19730428, year = {2009}, author = {Rosato, E and Cianci, R and Barbano, B and Menghi, G and Gigante, A and Rossi, C and Zardi, EM and Amoroso, A and Pisarri, S and Salsano, F}, title = {N-acetylcysteine infusion reduces the resistance index of renal artery in the early stage of systemic sclerosis.}, journal = {Acta pharmacologica Sinica}, volume = {30}, number = {9}, pages = {1283-1288}, pmid = {19730428}, issn = {1745-7254}, mesh = {Acetylcysteine/*therapeutic use ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Microscopic Angioscopy ; Middle Aged ; Renal Artery/drug effects/physiology ; Renal Artery Obstruction/*drug therapy/physiopathology ; Scleroderma, Systemic/*complications/physiopathology ; Vascular Resistance/drug effects ; }, abstract = {AIM: To evaluate resistance index (RI) changes in renal artery after N-acetylcysteine infusion in patients with systemic sclerosis.<br><br>METHODS: In an open-label study 40 patients with systemic sclerosis (SSc) were treated with N-acetylcysteine (NAC) iv infusion over 5 consecutive hours, at a dose of 0.015 g x kg(-1) x h(-1). Renal haemodynamic effects were evaluated by color Doppler examination before and after NAC infusion.<br><br>RESULTS: NAC infusion significantly reduced RI in a group of sclerodermic patients with early/active capillaroscopic pattern, modified Rodnan Total Skin Score (mRTSS) <14 and mild-moderate score to the vascular domain of Medsger Scleroderma Disease Severity Scale (DSS). RI increased after NAC infusion in patients with late capillaroscopic pattern, mTRSS>14 and severe-end stage score to the vascular domain of DSS. In patients with reduction of RI after NAC infusion, diffusion capacity for carbon monoxide mean value was significantly higher than in those patients with an increase of RI. No significant differences in renal blood flow were found between patients with different subsets of SSc.<br><br>CONCLUSION: In patients with low disease severity NAC ameliorates vascular renal function.}, }
@article {pmid19730128, year = {2010}, author = {Sailai, Y and Yu, X and Baiheti, P and Tang, H and Li, Y and Xu, M}, title = {Influence of nuclear factor kappaB activation on inflammatory mediators of alveolar macrophages in rats with acute necrotizing pancreatitis.}, journal = {Journal of investigative medicine : the official publication of the American Federation for Clinical Research}, volume = {58}, number = {1}, pages = {38-42}, doi = {10.2310/JIM.0b013e3181b91bd6}, pmid = {19730128}, issn = {1708-8267}, mesh = {Animals ; Bronchoalveolar Lavage Fluid/chemistry ; Inflammation Mediators/*metabolism ; Macrophages, Alveolar/*immunology ; Male ; NF-kappa B/*physiology ; Nitric Oxide/metabolism ; Pancreas/pathology ; Pancreatitis, Acute Necrotizing/*immunology/pathology ; Peroxidase/metabolism ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {AIM: To investigate the potential influence of nuclear factor kappaB (NF-kappaB) activation on the inflammatory mediators secreted by alveolar macrophages (AMs) in rats with acute necrotizing pancreatitis (ANP) and to evaluate the effect of an inhibitor of NF-kappaB-N-acetylcysteine (NAC).<br><br>METHODS: Ninety male Sprague-Dawley rats were randomly divided into 3 groups, 30 of each: control, ANP, and ANP plus NAC groups. The ANP rat models were established by a retrograde injection of 5% sodium taurocholate into the pancreatic duct. In addition to sodium taurocholate, the ANP plus NAC group received intravenous infusion of NAC (25 mg/100 g). At the sixth hour after modeling, the protein content of the bronchoalveolar lavage fluid, the myeloperoxidase in the lung tissue, and the transforming growth factor alpha and the nitric oxide (NO) secreted by AMs were determined. The histopathologic changes of the pancreas and the lung were observed under light microscope, and NF-kappaB activation of AMs was detected.<br><br>RESULTS: The protein content of the bronchoalveolar lavage fluid and the myeloperoxidase level of the lung tissue showed a significant increase in the ANP group as compared with the NAC-administered group. The levels of transforming growth factor alpha and NO secreted by AMs in the ANP and the ANP plus NAC group rose significantly over that in the control group, and there was a significant difference between them. Although they were still higher than those in the control group, the pancreas destruction and the lung injury were slighter in the ANP plus NAC group and the activation of NF-kappaB was lower in the ANP plus NAC group as compared with that in the ANP group.<br><br>CONCLUSIONS: The correlation between the NF-kappaB activation, the up-regulation of the inflammatory mediators secreted by AMs, and the tissue damage suggests a key influence of NF-kappaB in the pathogenesis of ANP. Inhibition of NF-kappaB activation may reverse the lung injury of ANP.}, }
@article {pmid19727985, year = {2009}, author = {Mumtaz, K and Azam, Z and Hamid, S and Abid, S and Memon, S and Ali Shah, H and Jafri, W}, title = {Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation.}, journal = {Hepatology international}, volume = {3}, number = {4}, pages = {563-570}, pmid = {19727985}, issn = {1936-0541}, abstract = {PURPOSE: We aimed to study the role of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF).<br><br>METHODS: A total of 47 adult patients were prospectively enrolled with NAI-ALF (group 1 or NAC group) and oral NAC was given. The primary outcome was reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate safety of NAC and to assess factors predicting mortality. We compared these results with records of NAI-ALF patients admitted in our hospital from 2000 to 2003 (n&#xa0;=&#xa0;44) who were not given NAC (group 2 or historical controls).<br><br>RESULTS: The two groups were comparable for the etiology of ALF, prothrombin time (PT), alanine aminotransferase, creatinine, albumin, etc. The mean age in group 1 was 27.7&#xa0;&#xb1;&#xa0;11.8&#xa0;years and in group 2 37.5&#xa0;&#xb1;&#xa0;18.8&#xa0;years (P&#xa0;=&#xa0;0.004). Bilirubin was 20.63&#xa0;&#xb1;&#xa0;11.03 and 14.36&#xa0;&#xb1;&#xa0;8.90&#xa0;mg/dl in groups 1 and 2, respectively (P&#xa0;=&#xa0;0.004). There were 8 (17%) and 1 (2.3%) pregnant ALF women with acute hepatitis E virus (HEV) infection in groups 1 and 2, respectively (P&#xa0;=&#xa0;0.031). All patients were given supportive care, including mechanical ventilation. A total of 34 (37.36%) patients survived; 22 (47%) in group 1 (NAC group) and 12 (27%) in group 2 (controls) (P&#xa0;=&#xa0;0.05). On multivariable regression analysis, patients not given NAC (odds ratio [OR]&#xa0;=&#xa0;10.3, 95% confidence interval [CI]&#xa0;=&#xa0;1.6-65.7), along with age older than 40&#xa0;years (OR&#xa0;=&#xa0;10.3, 95% CI&#xa0;=&#xa0;2.0-52.5), PT more than 50&#xa0;s (OR&#xa0;=&#xa0;15.4, 95% CI&#xa0;=&#xa0;3.8-62.2), patients requiring mechanical ventilation (OR&#xa0;=&#xa0;20.1, 95% CI&#xa0;=&#xa0;3.1-130.2), and interval between jaundice and hepatic encephalopathy (OR&#xa0;=&#xa0;5.0, 95% CI&#xa0;=&#xa0;1.3-19.1) were independent predictors of mortality.<br><br>CONCLUSIONS: The use of NAC causes reduction in NAI-ALF mortality and its use was safe.}, }
@article {pmid19726137, year = {2009}, author = {Knobloch, K and Redeker, J and Vogt, PM}, title = {Antifibrotic medication using a combination of N-acetyl-L-cystein (NAC) and ACE inhibitors can prevent the recurrence of Dupuytren's disease.}, journal = {Medical hypotheses}, volume = {73}, number = {5}, pages = {659-661}, doi = {10.1016/j.mehy.2009.08.011}, pmid = {19726137}, issn = {1532-2777}, mesh = {Acetylcysteine/*pharmacology ; Angiotensin-Converting Enzyme Inhibitors/*pharmacology ; Dupuytren Contracture/*drug therapy ; Fibrosis/*drug therapy ; Humans ; Models, Theoretical ; Secondary Prevention ; Transforming Growth Factor beta1/antagonists &amp; inhibitors ; }, abstract = {Dupuytren's disease is a progress fibromatosis of unknown origin first described in 1831. Nonoperative treatment options have been suggested involving radiation therapy, vitamin E, local injection therapy suing calcium channel blockers, interferon, corticosteroids or collagenase. Transforming growth factor-beta1 (TGF-beta1) and its downstream Smad signalling system is well established as a key player during fibrogenesis. A number of in vitro experiments have been assessed the blockade of TGF-beta1 and TGF-beta 2. Clinically, a number of antifibrotic agents are available such as N-acetyl-L-cysteins (NAC) as well as angiotensin-converting enzyme (ACE) inhibitors or AT II antagonists. However, to date none of the well known substances has been tested clinically in fibromatosis such as Dupuytren's disease especially to prevent recurrences after surgical release. Antifibrotic medication using a combination of N-acetyl-L-cystein (NAC) and ACE inhibitor can prevent the recurrence of Dupyutren's disease. Given the fact that recurrence rate in Dupuytren's disease is high and unpredictable after surgical release, an antifibrotic intervention might be worthwhile to consider in the clinical setting. Antifibrotic agents inhibit TGF-beta1, which play a key role in fibromatosis. Thus, antifibrotic medication might reduce the recurrence rate in fibromatosis such as Dupuytren's disease in a clinical significant way.}, }
@article {pmid19725096, year = {2010}, author = {Nakagawa, S and Arai, Y and Mazda, O and Kishida, T and Takahashi, KA and Sakao, K and Saito, M and Honjo, K and Imanishi, J and Kubo, T}, title = {N-acetylcysteine prevents nitric oxide-induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {28}, number = {2}, pages = {156-163}, doi = {10.1002/jor.20976}, pmid = {19725096}, issn = {1554-527X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Apoptosis/*drug effects ; Cartilage, Articular/cytology/*drug effects/metabolism ; Caspase 3/metabolism ; Chondrocytes/*drug effects/metabolism ; Disease Models, Animal ; Free Radical Scavengers/*administration &amp; dosage ; Glutathione/drug effects/metabolism ; Injections, Intra-Articular ; Male ; Nitric Oxide/adverse effects ; Osteoarthritis/chemically induced/physiopathology/*prevention &amp; control ; Rabbits ; Rats ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/drug effects/metabolism ; Up-Regulation/drug effects ; }, abstract = {We investigated whether N-acetylcysteine (NAC), a precursor of glutathione, could protect rabbit articular chondrocytes against nitric oxide (NO)-induced apoptosis and could prevent cartilage destruction in an experimental model of osteoarthritis (OA) in rats. Isolated chondrocytes were treated with various concentrations of NAC (0-2 mM). Apoptosis was induced by 0.75 mM sodium nitroprusside (SNP) dehydrate, which produces NO. Cell viability was assessed by MTT assay, while apoptosis was evaluated by Hoechst 33342 and TUNEL staining. Intracellular reactive oxygen species (ROS) and glutathione levels were measured, and expression of p53 and caspase-3 were determined by Western blotting. To determine whether intraarticular injection of NAC prevents cartilage destruction in vivo, cartilage samples of an OA model were subjected to H&amp;E, Safranin O, and TUNEL staining. NAC prevented NO-induced apoptosis, ROS overproduction, p53 up-regulation, and caspase-3 activation. The protective effects of NAC were significantly blocked by buthionine sulfoximine, a glutathione synthetase inhibitor, indicating that the apoptosis-preventing activity of NAC was mediated by glutathione. Using a rat model of experimentally induced OA, we found that NAC also significantly prevented cartilage destruction and chondrocyte apoptosis in vivo. These results indicate that NAC inhibits NO-induced apoptosis of chondrocytes through glutathione in vitro, and inhibits chondrocyte apoptosis and articular cartilage degeneration in vivo.}, }
@article {pmid19723131, year = {2009}, author = {Tsai, GY and Cui, JZ and Syed, H and Xia, Z and Ozerdem, U and McNeill, JH and Matsubara, JA}, title = {Effect of N-acetylcysteine on the early expression of inflammatory markers in the retina and plasma of diabetic rats.}, journal = {Clinical &amp; experimental ophthalmology}, volume = {37}, number = {2}, pages = {223-231}, pmid = {19723131}, issn = {1442-9071}, support = {97806-1/CAPMC/CIHR/Canada ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Biomarkers/*blood ; Diabetes Mellitus, Experimental/*drug therapy/metabolism/pathology ; Diabetic Retinopathy/*drug therapy/metabolism/pathology ; Dinoprost/analogs &amp; derivatives ; Endothelium, Vascular/metabolism/pathology ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique, Indirect ; Free Radical Scavengers/*therapeutic use ; Immunoenzyme Techniques ; Inflammation/metabolism/pathology ; Isoprostanes/blood ; Macrophages/metabolism/pathology ; Male ; Microglia/metabolism/pathology ; Oxidative Stress ; Pericytes/metabolism/pathology ; Rats ; Rats, Wistar ; Retina/*drug effects/metabolism ; Superoxide Dismutase/blood ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {PURPOSE: The aim of this study is to investigate markers of inflammation and oxidative stress in an early model of diabetic retinopathy, correlate retinal and plasma results and evaluate the influence of treatment by N-acetylcysteine (NAC), a free radical scavenger.<br><br>METHODS: Four groups were studied: control (C), streptozotocin (STZ)-induced diabetic rats (D), STZ rats following 8 weeks of NAC (DT), and control rats following 8 weeks of NAC (CT). Plasma levels of free 15-F2t-isoprostane (15-F-2t-IsoP), superoxide dismutase (SOD) and tumour necrosis factor-alpha (TNF-alpha) were obtained. Primary antibodies against macrophages (ED-1), microglia (Ox-42), pericytes (NG-2), endothelial and perivascular cells (IB-4), haem oxygenase 1 (HO-1) and vascular endothelial growth factor (VEGF) were used.<br><br>RESULTS: Expression of NG-2 was robust in C, CT, DT, and mild in D. The intensity of IB-4 was higher in D and DT compared with the C and CT. Ox-42 and ED-1 expression was higher in the D than in the DT, C or CT. Expression of VEGF and HO-1 was non-specific across the four groups. Plasma levels of 15-F-2t-IsoP and TNF-alpha were higher in the D as compared with the C, CT and DT. SOD levels were lower in the D when compared with the C, CT and D.<br><br>CONCLUSIONS: Macrophage/microglia activation, pericyte loss and endothelial/perivascular cell changes occur early in the pathogenesis of DR. These changes are associated with an increase in plasma markers of oxidative stress and inflammation and are minimized by treatment with NAC. The results suggest that therapies that reduce free radicals will help minimize the early events in diabetic retinopathy in the STZ model.}, }
@article {pmid19723101, year = {2009}, author = {Park, IJ and Lee, YK and Hwang, JT and Kwon, DY and Ha, J and Park, OJ}, title = {Green tea catechin controls apoptosis in colon cancer cells by attenuation of H2O2-stimulated COX-2 expression via the AMPK signaling pathway at low-dose H2O2.}, journal = {Annals of the New York Academy of Sciences}, volume = {1171}, number = {}, pages = {538-544}, doi = {10.1111/j.1749-6632.2009.04698.x}, pmid = {19723101}, issn = {1749-6632}, mesh = {AMP-Activated Protein Kinases/*metabolism ; Acetylcysteine/pharmacology ; Aminoimidazole Carboxamide/analogs &amp; derivatives/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Proliferation/drug effects ; Colonic Neoplasms/metabolism/pathology ; Cyclooxygenase 2/*metabolism ; Dinoprostone/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; HT29 Cells ; Humans ; Hydrogen Peroxide/*pharmacology ; Oxidants/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/metabolism ; Ribonucleotides/pharmacology ; Signal Transduction/*drug effects ; Tea/*chemistry ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {This study investigated the apoptotic regulation by green tea catechin epigallcatechin-3-gallate (EGCG) on colon cancer cells in the presence of low-dose H(2)O(2) known to exert the activation of signal pathways leading to cell proliferation. In the presence of low-dose H(2)O(2), EGCG induced apoptosis and abolished the cell-proliferative effect exhibited by low-dose H(2)O(2). This reduction of growth was accompanied by an activation of AMP-activated kinase (AMPK), a decrease in cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) (PGE(2)) levels, and the induction of apoptotic markers such as p53 and poly(ADP-ribose) polymerase (PARP) cleavage. The low-dose H(2)O(2) stimulated COX-2 expression, and treating cells with synthetic AMPK activator AICAR (5-aminoimiazole-4-carboxamide-1-beta-d-ribofuranoside) resulted in greater suppression of COX-2 expression and PGE(2). By treating cells with high concentrations of the reactive oxygen species (ROS) scavenger NAC (N-acetyl-1-cysteine), the apoptotic effect of EGCG was abolished and led to suppression of AMPK and COX-2, indicating that the liberation of excessive ROS might be the upstream signal of the AMPK-COX-2 signaling pathway even in the presence of low-dose H(2)O(2).}, }
@article {pmid19722195, year = {2010}, author = {Guan, D and Xu, Y and Yang, M and Wang, H and Wang, X and Shen, Z}, title = {N-acetyl cysteine and penicillamine induce apoptosis via the ER stress response-signaling pathway.}, journal = {Molecular carcinogenesis}, volume = {49}, number = {1}, pages = {68-74}, doi = {10.1002/mc.20578}, pmid = {19722195}, issn = {1098-2744}, mesh = {Acetylcysteine/*pharmacology ; Activating Transcription Factor 4/genetics/metabolism ; Activating Transcription Factor 6/genetics/metabolism ; Apoptosis/*drug effects ; Blotting, Western ; DNA-Binding Proteins/genetics/metabolism ; Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Chaperone BiP ; Flow Cytometry ; HeLa Cells ; Heat-Shock Proteins/genetics/metabolism ; Humans ; Penicillamine/*pharmacology ; RNA Interference ; Regulatory Factor X Transcription Factors ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*drug effects ; Transcription Factor CHOP/genetics/metabolism ; Transcription Factors/genetics/metabolism ; X-Box Binding Protein 1 ; eIF-2 Kinase/genetics/metabolism ; }, abstract = {N-acetyl cysteine (NAC) and penicillamine (PEN) have been shown to induce apoptosis in multiple types of human cancer cells; however, the molecular mechanism underlying this activity is unclear. This study was designed to identify the genes responsible for apoptosis induction by NAC and PEN. We found that glucose-regulated protein 78 (GRP78) was upregulated in HeLa cells following treatment with NAC or PEN. GRP78 is a central regulator of endoplasmic reticulum (ER) stress and has been used as a marker of ER stress. Additionally, both the activating transcription factor 6 (ATF6) protein and X box-binding protein 1 (XBP1) mRNA were processed, which facilitates the expression of C/EBP homologous protein (CHOP), a key-signaling component of ER stress-induced apoptosis. Furthermore, the PERK-ATF4 pathway, which also induces the expression of CHOP, was activated in NAC-treated cells. The role of the ER stress pathway was further confirmed through the small interfering RNA (siRNA)-mediated knockdown of CHOP, which attenuated NAC and PEN-induced apoptosis. These results demonstrate that NAC- and PEN-induced apoptosis in HeLa cells is mediated by the ER stress pathway.}, }
@article {pmid19720122, year = {2009}, author = {Liu, WH and Chang, LS}, title = {Arachidonic acid induces Fas and FasL upregulation in human leukemia U937 cells via Ca2+/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/ATF-2 pathway.}, journal = {Toxicology letters}, volume = {191}, number = {2-3}, pages = {140-148}, doi = {10.1016/j.toxlet.2009.08.016}, pmid = {19720122}, issn = {1879-3169}, mesh = {Activating Transcription Factor 2/genetics/*physiology ; Apoptosis/drug effects ; Arachidonic Acid/*pharmacology ; Blotting, Western ; Calcium Signaling/*drug effects ; Cell Survival/drug effects ; Extracellular Signal-Regulated MAP Kinases/biosynthesis ; Fas Ligand Protein/*biosynthesis/genetics ; Humans ; Luciferases/genetics ; Membrane Potentials/drug effects ; Mitochondrial Membranes/drug effects ; Proto-Oncogene Proteins c-fos/*biosynthesis ; RNA Interference ; RNA, Messenger/biosynthesis/genetics ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Subcellular Fractions/drug effects ; Transfection ; U937 Cells ; Up-Regulation ; fas Receptor/*biosynthesis/genetics ; p38 Mitogen-Activated Protein Kinases/drug effects/genetics/*physiology ; }, abstract = {Arachidonic acid (AA)-induced apoptotic death of human leukemia U937 cells was characteristic of increase in intracellular Ca(2+) concentration ([Ca(2+)]i), ROS generation, ERK inactivation, p38 MPAK activation, degradation of procaspase-8 and production of truncated Bid (tBid). Moreover, AA treatment upregulated Fas/FasL protein expression and transcription of Fas/FasL mRNA. Downregulation of FADD blocked AA-induced procaspase-8 degradation and rescued viability of AA-treated cells. BAPTA-AM (Ca(2+) chelator) pretreatment abolished AA-induced ROS generation, while N-acetylcysteine (NAC, ROS scavenger) was unable to alter AA-elicited [Ca(2+)]i increase. Pretreatment with BAPTA-AM or NAC abrogated p38 MAPK activation and restored ERK activation. Suppression of p38 MAPK or transfection of constitutively active MEK1 abolished AA-induced Fas and FasL upregulation. AA treatment repressed ERK-mediated c-Fos phosphorylation but evoked p38 MAPK-mediated ATF-2 phosphorylation. Knockdown of c-Fos and ATF-2 by siRNA reflected that c-Fos counteracted the effect of ATF-2 on Fas/FasL upregulation. Taken together, our data indicate that Fas/FasL upregulation in AA-treated U937 cells is elicited by Ca(2+)/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/ATF-2, and suggest that autocrine Fas-mediated apoptotoic mechanism is involved in AA-induced cell death.}, }
@article {pmid19716169, year = {2009}, author = {Volk, J and Ziemann, C and Leyhausen, G and Geurtsen, W}, title = {Non-irradiated campherquinone induces DNA damage in human gingival fibroblasts.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {25}, number = {12}, pages = {1556-1563}, doi = {10.1016/j.dental.2009.07.009}, pmid = {19716169}, issn = {1879-0097}, mesh = {Acetylcysteine/pharmacology ; Bridged Bicyclo Compounds ; Cell Count ; Cell Survival/drug effects ; Cells, Cultured ; Comet Assay ; *DNA Damage ; Dental Materials/*toxicity ; Fibroblasts/*drug effects ; Fluoresceins ; Fluorescent Dyes ; Free Radical Scavengers/pharmacology ; Gingiva/cytology/*drug effects ; Glutathione/drug effects ; Humans ; Propidium ; Reactive Oxygen Species/analysis ; Sulfhydryl Reagents ; Terpenes/*toxicity ; Time Factors ; }, abstract = {OBJECTIVES: Camphorquinone (CQ) is cytotoxic in cell cultures. The mechanism of this toxic action, however, is not yet clearly understood. Aim of this investigation was to analyze the effects of non-irradiated CQ on intracellular formation of reactive oxygen species (ROS), intracellular glutathione (GSH) content, and the integrity of DNA in cultured primary human gingival fibroblasts (HGF).<br><br>METHODS: Cells were exposed to CQ at concentrations ranging between 0.05mM and 2.5mM. Intracellular levels of ROS were detected by the fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA) and GSH was determined by the fluorescent probe monobromobimane (MBBr). Genotoxicity was measured quantitatively by the alkaline comet assay. The cytotoxic effects of CQ were investigated by means of the fluorescent dye propidium iodide and the Cytotoxicity Detection Kit.<br><br>RESULTS: CQ generated an increase of intracellular ROS, a depletion of intracellular GSH level, decreased cells' viability and total cell number dependent on the applied CQ concentration: 0.5-2.5mM (ROS upward arrow, GSH downward arrow) and 0.125-2.5mM CQ (cytotoxicity upward arrow). Increased DNA damage was observed at all concentrations (0.05-2.5mM, p<0.05). The ROS-scavenger N-acetylcysteine (NAC) reduced CQ-induced ROS formation at CQ concentrations higher than 0.5mM (p<0.05).<br><br>SIGNIFICANCE: Our data indicate that non-irradiated CQ induces oxidative stress, DNA damage and cytotoxicity as well in primary HGF.}, }
@article {pmid19714806, year = {2009}, author = {Zhang, L and Wang, M and Kang, X and Boontheung, P and Li, N and Nel, AE and Loo, JA}, title = {Oxidative stress and asthma: proteome analysis of chitinase-like proteins and FIZZ1 in lung tissue and bronchoalveolar lavage fluid.}, journal = {Journal of proteome research}, volume = {8}, number = {4}, pages = {1631-1638}, pmid = {19714806}, issn = {1535-3893}, support = {R01 ES013432-04/ES/NIEHS NIH HHS/United States ; R01 ES012053/ES/NIEHS NIH HHS/United States ; R01 ES013432/ES/NIEHS NIH HHS/United States ; U19 AI070453-039003/AI/NIAID NIH HHS/United States ; U19 AI070453-03/AI/NIAID NIH HHS/United States ; U19 AI070453/AI/NIAID NIH HHS/United States ; R01 ES012053-05/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Asthma/*metabolism ; Bronchoalveolar Lavage Fluid/*chemistry ; Chitinases/*metabolism ; Electrophoresis, Gel, Two-Dimensional ; Female ; Intercellular Signaling Peptides and Proteins/*metabolism ; Lung/*metabolism ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/*physiology ; Proteome/metabolism ; Tandem Mass Spectrometry ; }, abstract = {Oxidative stress plays an important role in the development of airway inflammation and hyperreactivity in asthma. The identification of oxidative stress markers in bronchoalveolar lavage fluid (BALF) and lung tissue from ovalbumin (OVA) sensitized mice could provide new insight into disease pathogenesis and possible use of antioxidants to alleviate disease severity. We used two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the impact of the thiol antioxidant, N-acetylcysteine (NAC), on protein expression in a murine OVA model. At least six proteins or protein families were found to be significantly increased in BALF from OVA-challenged mice compared to a control group: Chitinase 3-like protein 3 (Yml), Chitinase 3-like protein 4 (Ym2), acidic mammalian Chitinase (AMCase), pulmonary surfactant-associated protein D (SP-D), resistin-like molecule alpha (RELMalpha) or "found in inflammatory 1" (FIZZ1), and haptoglobin alpha-subunit. A total of nine proteins were significantly increased in lung tissue from the murine asthma model, including Yml, Ym2, FIZZ1, and other lung remodeling-related proteins. Western blotting confirmed increased Yml/Ym2, SP-D, and FIZZ1 expression measured from BAL fluid and lung tissue from OVA-challenged mice. Intraperitoneal NAC administration prior to the final OVA challenge inhibited Yml/Ym2, SP-D, and FIZZ1 expression in BALF and lung tissue. The oxidative stress proteins, Ym1/Ym2, FIZZ1, and SP-D, could play an important role in the pathogenesis of asthma and may be useful oxidative stress markers.}, }
@article {pmid19706490, year = {2009}, author = {Seixas, E and Gozzelino, R and Chora, A and Ferreira, A and Silva, G and Larsen, R and Rebelo, S and Penido, C and Smith, NR and Coutinho, A and Soares, MP}, title = {Heme oxygenase-1 affords protection against noncerebral forms of severe malaria.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {106}, number = {37}, pages = {15837-15842}, pmid = {19706490}, issn = {1091-6490}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/physiology ; Gene Expression ; Heme/metabolism ; Heme Oxygenase-1/deficiency/genetics/*metabolism ; Hepatocytes/drug effects/metabolism/pathology ; Liver Failure/pathology/prevention &amp; control ; Malaria/*enzymology/parasitology/*prevention &amp; control ; Mice ; Mice, Inbred BALB C ; Mice, Inbred DBA ; Mice, Knockout ; Mice, SCID ; Oxidative Stress ; Plasmodium chabaudi/*pathogenicity/physiology ; Transplantation Chimera ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Infection by Plasmodium, the causative agent of malaria, is associated with hemolysis and therefore with release of hemoglobin from RBC. Under inflammatory conditions, cell-free hemoglobin can be oxidized, releasing its heme prosthetic groups and producing deleterious free heme. Here we demonstrate that survival of a Plasmodium-infected host relies strictly on its ability to prevent the cytotoxic effects of free heme via the expression of the heme-catabolyzing enzyme heme oxygenase-1 (HO-1; encoded by the Hmox1 gene). When infected with Plasmodium chabaudi chabaudi (Pcc), wild-type (Hmox1(+/+)) BALB/c mice resolved infection and restored homeostasis thereafter (0% lethality). In contrast, HO-1 deficient (Hmox1(-/-)) BALB/c mice developed a lethal form of hepatic failure (100% lethality), similar to the one occurring in Pcc-infected DBA/2 mice (75% lethality). Expression of HO-1 suppresses the pro-oxidant effects of free heme, preventing it from sensitizing hepatocytes to undergo TNF-mediated programmed cell death by apoptosis. This cytoprotective effect, which inhibits the development of hepatic failure in Pcc-infected mice without interfering with pathogen burden, is mimicked by pharmacological antioxidants such as N-acetylcysteine (NAC). When administered therapeutically, i.e., after Pcc infection, NAC suppressed the development of hepatic failure in Pcc-infected DBA/2 mice (0% lethality), without interfering with pathogen burden. In conclusion, we describe a mechanism of host defense against Plasmodium infection, based on tissue cytoprotection against free heme and limiting disease severity irrespectively of parasite burden.}, }
@article {pmid19703551, year = {2009}, author = {Clark, CB and Rane, MJ and El Mehdi, D and Miller, CJ and Sachleben, LR and Gozal, E}, title = {Role of oxidative stress in geldanamycin-induced cytotoxicity and disruption of Hsp90 signaling complex.}, journal = {Free radical biology &amp; medicine}, volume = {47}, number = {10}, pages = {1440-1449}, pmid = {19703551}, issn = {1873-4596}, support = {F30-NS051998/NS/NINDS NIH HHS/United States ; P20 RR-15576/RR/NCRR NIH HHS/United States ; F30 NS051998-03/NS/NINDS NIH HHS/United States ; P20 RR015576/RR/NCRR NIH HHS/United States ; F30 NS051998/NS/NINDS NIH HHS/United States ; R01 HL074296-04/HL/NHLBI NIH HHS/United States ; R01 HL074296/HL/NHLBI NIH HHS/United States ; P20 RR015576-096508/RR/NCRR NIH HHS/United States ; HL-074296/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Benzoquinones/*toxicity ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; HSP90 Heat-Shock Proteins/*antagonists &amp; inhibitors/metabolism ; Lactams, Macrocyclic/*toxicity ; Oxidative Stress/*drug effects ; PC12 Cells ; Proteasome Endopeptidase Complex/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Tumor Cells, Cultured ; Vitamin K 3/pharmacology ; }, abstract = {Heat shock protein 90 (Hsp90) is a chaperone protein regulating PC-12 cell survival by binding and stabilizing Akt, Raf-1, and Cdc37. Hsp90 inhibitor geldanamycin (GA) cytotoxicity has been attributed to the disruption of Hsp90 binding, and the contribution of oxidative stress generated by its quinone group has not been studied in this context. Reactive oxygen species (ROS) and cell survival were assessed in PC-12 cells exposed to GA or menadione (MEN), and Akt, Raf-1, and Cdc37 expression and binding to Hsp90 were determined. GA disrupted Hsp90 binding and increased ROS production starting at 1 h, and cell death occurred at 6 h, inhibited by N-acetylcysteine (NAC) without preventing dissociation of proteins. At 24 h, NAC prevented cytotoxicity and Hsp90 complex disruption. However, MnTBAP antioxidant treatment failed to inhibit GA cytotoxicity, suggesting that NAC acts by restoring glutathione. In contrast, 24 h MEN treatment induced cytotoxicity without disrupting Hsp90 binding. GA and MEN decreased Hsp90-binding protein expression, and proteasomal inhibition prevented MEN-, but not GA-induced degradation. In conclusion, whereas MEN cytotoxicity is mediated by ROS and proteasomal degradation, GA-induced cytotoxicity requires ROS but induces Hsp90 complex dissociation and proteasome-independent protein degradation. These differences between MEN- and GA-induced cytotoxicity may allow more specific targeting of cancer cells.}, }
@article {pmid19703426, year = {2009}, author = {Wentzel, P and Eriksson, UJ}, title = {Altered gene expression in neural crest cells exposed to ethanol in vitro.}, journal = {Brain research}, volume = {1305 Suppl}, number = {}, pages = {S50-60}, doi = {10.1016/j.brainres.2009.08.057}, pmid = {19703426}, issn = {1872-6240}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/genetics ; Cell Movement ; Central Nervous System Depressants/*pharmacology ; Ethanol/*pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Developmental/*drug effects ; Immunohistochemistry ; In Vitro Techniques ; Inflammation/genetics ; Metabolism/genetics ; Neural Crest/*drug effects/embryology/metabolism ; Oxidation-Reduction ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {AIM: to characterize and compare ethanol-induced changes of gene expression in cells from the cranial (cNCC) and trunk (tNCC) portion of the neural crest cell (NCC) population of day-10 rat embryos.<br><br>BACKGROUND: previous work has suggested that ethanol-induced embryonic maldevelopment is associated with oxidative stress, and, in particular, that ethanol-induced anomalies of the facial skeleton and heart are associated with disturbed development of the cNCC. We studied alterations of mRNA levels of genes involved in apoptosis, oxidative defense, cellular metabolism, NCC development or inflammation in cNCC and tNCC from rat embryos exposed to ethanol in vitro. We specifically evaluated expression differences between cNCC and tNCC genes, possibly reflecting the different teratological susceptibilities of the two cell populations.<br><br>METHODS: neural tube explants from rat embryos were divided in cranial and trunk portions and used for NCC isolation in vitro on gestational day 10. The migrating cells from the cranial or trunk explants of the neural tube were subsequently exposed to 0 or 88 mmol/l ethanol concentration with or without addition of 0.5 mM N-acetylcysteine (NAC) for 48 h, harvested, and prepared for gene expression measurement by RT-PCR or immunostaining with either distal-less (DLX) or AP 2-alpha antibodies.<br><br>RESULTS: evaluation of the immunostained slides showed that approximately 75% of the cNCC and tNCC preparations were of neural crest origin. Exposure to 88 mM ethanol increased the Bax/Bcl-2 ratio in the NCC, and NAC addition diminished this increase. Both cNCC and tNCC upregulated MnSOD and Gpx-1 in response to ethanol, whereas tNCC increased CuZnSOD and EC-SOD after ethanol exposure (cNCC unchanged). Expression of glyceraldehyde-3-phosphate dehydrogenase was downregulated by ethanol in cNCC only. In addition, ethanol exposure caused increased mRNA levels of Pax-3, p53, Vegf-A and decreased expression of Pax-6, Nfe2 in both cNCC and tNCC. Ethanol increased Shh and Bmp-4 and decreased Parp only in cNCC (tNCC unchanged), whereas ethanol exposure increased T box-2 and decreased Gdnf and Ret only in tNCC (cNCC unchanged). In addition, ethanol exposure almost abolished expression of Hox a(1), a(4) and a(5), and left Hox a(2) unchanged in cNCC, whereas all four of these Hox genes were upregulated in tNCC.<br><br>CONCLUSIONS: ethanol causes a shift towards apoptosis in both cNCC and tNCC, a shift, which is diminished by NAC treatment. Oxidative defense genes, and genes involved in neural crest cell development are affected differently in cNCC compared to tNCC upon ethanol exposure. Moreover, ethanol downregulates cNCC Hox genes, whereas tNCC Hox genes are upregulated. These patterns of ethanol-altered gene expression may be of etiological importance for NCC-associated maldevelopment in ethanol-exposed pregnancy.}, }
@article {pmid19696471, year = {2009}, author = {Xie, Y and Zhang, H and Hao, JF and Qiu, R}, title = {Effect of N-acetylcysteine on (12)C(6+) ion irradiation-induced lymphocytes DNA damages and immunity changes in mice.}, journal = {Journal of radiation research}, volume = {50}, number = {6}, pages = {567-571}, doi = {10.1269/jrr.09047}, pmid = {19696471}, issn = {1349-9157}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cells, Cultured ; DNA Damage/*radiation effects ; Dose-Response Relationship, Drug ; Heavy Ions ; Immunity, Innate/*drug effects/*radiation effects ; Lymphocytes/*drug effects/immunology/*radiation effects ; Mice ; Radiation Dosage ; Radiation-Protective Agents/administration &amp; dosage ; *Whole-Body Irradiation ; }, abstract = {The aims of present study are to estimate the biological risks to the immunity of mice exposed to heavy ion radiation and to investigate the effect of N-acetylcysteine (NAC) on (12)C(6+) ion irradiation-induced lymphocyte DNA damage. Results showed that in the brine group, the levels of lymphocyte DNA damage and MN, thymocytes G(2)/M phase arrest and apoptosis percentages (except for activity of NK cells) were up at each time point. A time-response curve for MN and DNA damage appeared in the NAC group. We found that whole-body (12)C(6+) ion irradiation at a dose of 4 Gy could: induce lymphocyte DNA double-strand breaks (DSBs); immunocytes DSBs may lead to acute effects on immunity; and 200 mg/kg NAC showed significant protection against radiation harm.}, }
@article {pmid19696069, year = {2010}, author = {Lee, TM and Lai, PY and Chang, NC}, title = {Effect of N-acetylcysteine on sympathetic hyperinnervation in post-infarcted rat hearts.}, journal = {Cardiovascular research}, volume = {85}, number = {1}, pages = {137-146}, doi = {10.1093/cvr/cvp286}, pmid = {19696069}, issn = {1755-3245}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Arrhythmias, Cardiac/prevention &amp; control ; Buthionine Sulfoximine/pharmacology ; Echocardiography ; Fluorescent Antibody Technique ; Glutathione/analysis/*physiology ; Heart/*innervation ; Male ; Myocardial Infarction/complications/*drug therapy/physiopathology ; Nerve Growth Factor/analysis/genetics ; Norepinephrine/analysis ; Rats ; Rats, Wistar ; Sympathetic Nervous System/*drug effects/physiopathology ; }, abstract = {AIMS: The purpose of this study was to determine whether N-acetylcysteine (NAC) attenuates cardiac sympathetic hyperinnervation through replenishment of glutathione in infarcted rats.<br><br>METHODS AND RESULTS: After ligation of the coronary artery, male Wistar rats were randomized to either vehicle, NAC, or vitamins C + E groups for 4 weeks. Post-infarction was associated with increased oxidant release, as measured by tissue isoprostane and myocardial glutathione. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering NAC, as assessed by immunofluorescent analysis of tyrosine hydroxylase and western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in the vehicle-treated infarcted rats were significantly higher than those in animals treated with NAC. Although NAC and vitamins showed similar effects on ventricular remodelling, only NAC demonstrated beneficial effects on sympathetic hyperinnervation. Furthermore, the effects of NAC on nerve growth factor were abolished by administering l-buthionine sulfoximinem, an inhibitor of gamma-glutamylcysteine ligase.<br><br>CONCLUSION: Chronic use of NAC, but not vitamins, after infarction is associated with down-regulation of nerve growth factor proteins, probably through a glutathione-dependent pathway, and thus plays a critical role in the beneficial effect on the arrhythmogenic response to programmed electrical stimulation.}, }
@article {pmid19693275, year = {2009}, author = {Scharstuhl, A and Mutsaers, HA and Pennings, SW and Russel, FG and Wagener, FA}, title = {Involvement of VDAC, Bax and ceramides in the efflux of AIF from mitochondria during curcumin-induced apoptosis.}, journal = {PloS one}, volume = {4}, number = {8}, pages = {e6688}, pmid = {19693275}, issn = {1932-6203}, mesh = {Apoptosis/*drug effects ; Apoptosis Inducing Factor/*metabolism ; Caspases/metabolism ; Ceramides/*physiology ; Curcumin/*pharmacology ; DNA/chemistry/metabolism ; Enzyme Inhibitors/pharmacology ; HSP70 Heat-Shock Proteins/metabolism ; Humans ; Mitochondria/*drug effects/metabolism ; Molecular Weight ; Protein Transport ; Reactive Oxygen Species/metabolism ; Voltage-Dependent Anion Channels/*physiology ; bcl-2-Associated X Protein/metabolism/*physiology ; }, abstract = {BACKGROUND: We previously identified curcumin as a potent inducer of fibroblast apoptosis, which could be used to treat hypertrophic scar formation. Here we investigated the underlying mechanism of this process.<br><br>PRINCIPAL FINDINGS: Curcumin-induced apoptosis could not be blocked by caspase-inhibitors and we could not detect any caspase-3/7 activity. Curcumin predominantly induced mitochondria-mediated ROS formation and stimulated the expression of the redox-sensitive pro-apoptotic factor p53. Inhibition of the pro-apoptotic signaling enzyme glycogen synthase kinase-3beta (GSK-3beta) blocked curcumin-induced apoptosis. Apoptosis was associated with high molecular weight DNA damage, a possible indicator of apoptosis-inducing factor (AIF) activity. Indeed, curcumin caused nuclear translocation of AIF, which could be blocked by the antioxidant N-acetyl cysteine. We next investigated how AIF is effluxed from mitochondria in more detail. The permeability transition pore complex (PTPC), of which the voltage-dependent anion channel (VDAC) is a component, could be involved since the VDAC-inhibitor DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) efficiently blocked AIF translocation. However, PTPC is not involved in AIF release since cyclosporine A, a specific inhibitor of the complex did not block apoptosis. Alternatively, the pro-apoptotic protein Bax could have formed mitochondrial channels and interacted with VDAC. Curcumin caused mitochondrial translocation of Bax, which was blocked by DIDS, suggesting a Bax-VDAC interaction. Interestingly, ceramide channels can also release apoptogenic factors from mitochondria and we found that addition of ceramide induced caspase-independent apoptosis. Surprisingly, this process could also be blocked by DIDS, suggesting the concerted action of Bax, VDAC and ceramide in the efflux of AIF from the mitochondrion.<br><br>CONCLUSIONS: Curcumin-induced fibroblast apoptosis is totally caspase-independent and relies on the mitochondrial formation of ROS and the subsequent nuclear translocation of AIF, which is released from a mitochondrial pore that involves VDAC, Bax and possibly ceramides. The composition of the AIF-releasing channel seems to be much more complex than previously thought.}, }
@article {pmid19690939, year = {2009}, author = {Rosato, E and Borghese, F and Pisarri, S and Salsano, F}, title = {The treatment with N-acetylcysteine of Raynaud's phenomenon and ischemic ulcers therapy in sclerodermic patients: a prospective observational study of 50 patients.}, journal = {Clinical rheumatology}, volume = {28}, number = {12}, pages = {1379-1384}, pmid = {19690939}, issn = {1434-9949}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Female ; Fingers ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Infusions, Intravenous ; Ischemia/complications/*drug therapy/pathology ; Male ; Middle Aged ; Raynaud Disease/complications/*drug therapy/pathology ; Scleroderma, Systemic/complications/*drug therapy/pathology ; Skin/blood supply ; Skin Ulcer/complications/*drug therapy/pathology ; Treatment Outcome ; }, abstract = {N-Acetylcysteine is useful in the short-term treatment of severe Raynaud's phenomenon and digital ulcers (DU) in patients with systemic sclerosis (SSc), but its long-term effects are largely unknown. The aim of this study was to report long-term outcome (median follow-up 3 years) in a prospective study of a cohort of 50 consecutive patients with SSc who received N-acetylcysteine (NAC) infusional therapy every 2 weeks. We observed a reduction of DU/patient/year (4.5 +/- 3.1 vs 0.81 +/- 0.79) and DU ulcer visual analog scale (VAS; 6.88 +/- 2.62 vs 3.20 +/- 1.80), a decrease of the Raynaud's phenomenon (RP) number attacks (7.18 +/- 3.87 vs 3 +/- 1.92), and RP VAS (6.24 +/- 1.92 vs 3.62 +/- 1.48). In this study, we did not observe serious adverse events in patients. Minor side effects were flushing (two patients) and headache (one patient). NAC infusion was generally well tolerated, and nobody had to discontinue the treatment. In conclusion, long-term therapy with NAC, in patients with SSc, has a durable effectiveness on ischemic ulcers and Raynaud's phenomenon.}, }
@article {pmid19690861, year = {2010}, author = {Du, JH and Zhang, HD and Ma, ZJ and Ji, KM}, title = {Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo.}, journal = {Cancer chemotherapy and pharmacology}, volume = {65}, number = {5}, pages = {895-902}, pmid = {19690861}, issn = {1432-0843}, mesh = {Antineoplastic Agents/chemistry/*therapeutic use/toxicity ; Apoptosis ; Artemisinins/chemistry/*therapeutic use/toxicity ; Artesunate ; Cell Death ; Cell Line, Tumor ; Humans ; Pancreatic Neoplasms/*drug therapy/ultrastructure ; Reactive Oxygen Species/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Pancreatic cancer is highly resistant to the currently available chemotherapeutic agents. Less than 5% of patients diagnosed with this disease could survive beyond 5 years. Thus, there is an urgent need for the development of novel, efficacious drugs that can treat pancreatic cancer. Herein we report the identification of artesunate (ART), a derivative of artemisinin, as a potent and selective antitumor agent against human pancreatic cancer cells in vitro and in vivo. ART exhibits selective cytotoxic activity against Panc-1, BxPC-3 and CFPAC-1 pancreatic cancer cells with IC(50) values that are 2.3- to 24-fold less than that of the normal human hepatic cells (HL-7702). The pan caspase inhibitor zVAD-fmk did not inhibit the cytotoxic activity of ART. Electron microscopy of ART-treated cells revealed severe cytoplasmic swelling and vacuolization, swollen and internally disorganized mitochondria, dilation (but not fragmentation) of the nuclei without chromatin condensation, and cell lysis, yielding a morphotype that is typical of oncosis. The ART-treated cells exhibited a loss of mitochondrial membrane potential (DeltaPsim) and ART-induced cell death was inhibited in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC). Importantly, ART produced a dose-dependent tumor regression in an in vivo pancreatic cancer xenografts model. The in vivo antitumor activity of ART was similar to that of gemcitabine. Taken together, our study suggests that ART exhibits antitumor activity against human pancreatic cancer via a novel form of oncosis-like cell death, and that ART should be considered a potential therapeutic candidate for treating pancreatic cancer.}, }
@article {pmid19688255, year = {2009}, author = {Pacheco, GS and Panatto, JP and Fagundes, DA and Scaini, G and Bassani, C and Jeremias, IC and Rezin, GT and Constantino, L and Dal-Pizzol, F and Streck, EL}, title = {Brain creatine kinase activity is inhibited after hepatic failure induced by carbon tetrachloride or acetaminophen.}, journal = {Metabolic brain disease}, volume = {24}, number = {3}, pages = {383-394}, pmid = {19688255}, issn = {1573-7365}, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/antagonists &amp; inhibitors/metabolism ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Antioxidants/pharmacology ; Brain/*enzymology ; Carbon Tetrachloride Poisoning/*enzymology ; Cerebellum/drug effects/enzymology ; Chemical and Drug Induced Liver Injury/*enzymology ; Creatine Kinase/*antagonists &amp; inhibitors/*metabolism ; Energy Metabolism/drug effects ; Hippocampus/drug effects/enzymology ; Kidney Function Tests ; Liver Failure/chemically induced/*enzymology ; Male ; Rats ; Rats, Wistar ; }, abstract = {Encephalopathy is an important cause of morbidity and mortality in patients with severe hepatic failure and the mechanisms underlying hepatic encephalopathy are still not fully known. Considering that creatine kinase (CK) play a crucial role in brain energy homeostasis and is inhibited by free radicals, and that oxidative stress is probably involved in the pathogenesis of hepatic encephalopathy, we evaluated CK activity in hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex of rats submitted to acute administration of carbon tetrachloride or acetaminophen. The effects of the administration of antioxidants, N-acetylcysteine (NAC) plus deferoxamine (DFX) in association, and taurine, were also evaluated. Our findings demonstrated that carbon tetrachloride inhibited CK activity in cerebellum; acetaminophen inhibited the enzyme in cerebellum and hippocampus. CK activity was not affected in other brain areas. The administration of NAC plus DFX reversed the inhibition of CK activity caused by carbon tetrachloride in cerebellum and by acetaminophen in cerebellum and hippocampus. On the other hand, taurine was not able to reverse the inhibition in CK activity. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity after hepatic failure may be involved in the pathogenesis of hepatic encephalopathy.}, }
@article {pmid19681060, year = {2010}, author = {Abdelrahman, AM and Al Salam, S and AlMahruqi, AS and Al husseni, IS and Mansour, MA and Ali, BH}, title = {N-acetylcysteine improves renal hemodynamics in rats with cisplatin-induced nephrotoxicity.}, journal = {Journal of applied toxicology : JAT}, volume = {30}, number = {1}, pages = {15-21}, doi = {10.1002/jat.1465}, pmid = {19681060}, issn = {1099-1263}, mesh = {*Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Antineoplastic Agents/*adverse effects ; Cisplatin/*adverse effects ; Kidney/drug effects/metabolism/pathology ; Kidney Diseases/*chemically induced/*drug therapy ; Rats ; Rats, Wistar ; Renal Circulation/*drug effects ; Treatment Outcome ; }, abstract = {This work investigated the effect of N-acetylcysteine (NAC), on renal hemodynamics in cisplatin (CP)-induced nephrotoxicity in Wistar-Kyoto (WKY) rats. The animals were divided into four groups (n = 5 or 6). The first and second groups received normal saline (control) and intraperitoneal (i.p.) N-acetylcysteine (500 mg kg(-1) per day for 9 days), respectively. The third and fourth groups were given a single intraperitoneal (i.p.) injection of CP (5 mg kg(-1)) and an i.p. injection of CP (5 mg kg(-1)) together with i.p. NAC (500 mg kg(-1) per day for 9 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE) for measurement of renal vasoconstrictor responses. CP caused a significant reduction in renal blood flow but did not affect NE-induced renal vasoconstriction. In addition, CP significantly increased plasma concentrations of urea and creatinine and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and kidney relative weight. CP decreased body weight and creatinine clearance. Histopathologically, CP caused remarkable renal damage compared with control. NAC alone did not produce any significant change in any of the variables measured. However, NAC significantly ameliorated CP-induced hemodynamic, biochemical and histopathological changes. The concentration of platinum in the kidneys of CP ? NAC treated rats was less than in CP-treated rats by 37%. The results show that administration of i.p. NAC (500 mg kg(-1) per day for 9 days) reversed the renal hemodynamic changes as well as the biochemical and histopathological indices of CP-induced nephrotoxicity in WKY rats.}, }
@article {pmid19679343, year = {2009}, author = {Sato, N and Ueno, T and Kubo, K and Suzuki, T and Tsukimura, N and Att, W and Yamada, M and Hori, N and Maeda, H and Ogawa, T}, title = {N-Acetyl cysteine (NAC) inhibits proliferation, collagen gene transcription, and redox stress in rat palatal mucosal cells.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {25}, number = {12}, pages = {1532-1540}, doi = {10.1016/j.dental.2009.07.006}, pmid = {19679343}, issn = {1879-0097}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Collagen/analysis/*antagonists &amp; inhibitors/genetics ; Collagen Type I/analysis/antagonists &amp; inhibitors ; Collagen Type III/analysis/antagonists &amp; inhibitors ; Dose-Response Relationship, Drug ; Drug Carriers ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glutathione/analysis/drug effects ; Hydrogen Peroxide/pharmacology ; Mouth Mucosa/cytology/*drug effects ; Oxidants/pharmacology ; Oxidative Stress/*drug effects ; Procollagen-Proline Dioxygenase/analysis/antagonists &amp; inhibitors ; Rats ; Rats, Sprague-Dawley ; Transcription, Genetic/*drug effects ; }, abstract = {OBJECTIVES: Control of hyperplastic and invasively growing gingival tissue is crucial for maintaining normal oral function and for successful bone regenerative therapy. We tested the hypothesis that materials containing N-acetyl cysteine (NAC), an antioxidant cysteine derivative, can control proliferation and function of oral mucosal cells.<br><br>METHODS: Oral mucosal cells derived from the rat palatal tissue were cultured with or without NAC at different concentrations (2.5-10.0mM). To simulate inflammatory conditions, cultures were treated with hydrogen peroxide. NAC was also applied via collagen materials in membrane and sponge forms to explore the clinical applicability. The redox balance inside the cells was evaluated by measuring the concentration of intracellular glutathione (GSH).<br><br>RESULTS: Adding NAC into cultures of oral mucosal cells reduced their proliferation, transcriptional expression, and collagen production in an NAC-concentration-dependent manner without cytotoxic effects. Furthermore, NAC substantially reduced the hydrogen peroxide-induced elevation of cellular proliferation and collagen production. The controlling effects of NAC were also demonstrated in cells cultured on NAC-containing collagen materials and were associated with an increase in intracellular glutathione (GSH) reserves and a decrease in the oxidized form of glutathione (GSSG).<br><br>SIGNIFICANCE: These results indicate that NAC may abrogate inflammation- or oxidative-stress-induced hyperfunction of oral mucosal cells and that it can be delivered effectively via biodegradable materials. This study provides a basis to explore NAC-containing biomaterials that are functionalized to control oral soft tissue growth and function without cytotoxicity.}, }
@article {pmid19679040, year = {2009}, author = {Pouns, O and Mangas, A and Coveñas, R and Geffard, M}, title = {Circulating antibodies directed against "polycyclic aromatic hydrocarbon-like" structures in the sera of cancer patients.}, journal = {Cancer epidemiology}, volume = {33}, number = {1}, pages = {3-8}, doi = {10.1016/j.canep.2009.04.013}, pmid = {19679040}, issn = {1877-783X}, mesh = {Acetylcysteine/*immunology/metabolism ; Antibodies, Neoplasm/*immunology ; Antibody Affinity ; Antibody Specificity ; Breast Neoplasms/blood/*immunology ; Carrier Proteins/immunology ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Immunoglobulin A/immunology ; Immunoglobulins/*immunology ; Ligands ; Menopause ; Ovarian Neoplasms/blood/*immunology ; Polycyclic Aromatic Hydrocarbons/*immunology/metabolism ; Receptors, Aryl Hydrocarbon/immunology ; Serum Albumin, Bovine ; }, abstract = {BACKGROUND: An increase in immunoglobulin (Ig) A isotype directed against benzo(a)pyrene (BP) structure has previously been described in sera of cancer patients. In this study, new polycyclic aromatic hydrocarbon (PAH) conjugates were synthesized in order to more closely mimic the endogenous ligands of the cytosolic aryl hydrocarbon receptor (AhR). PAH [benzo(a)pyrene; 1,2-benzanthracene; dibenz[a,c]anthracene; 7,12-dimethylbenza[a]anthracene; benzo(ghi)perylene] were bound to protein carriers such as bovine serum albumin (BSA) via N-acetyl-cysteine (NAC).<br><br>METHODS: The levels of circulating antibodies (Abs) directed against PAH-NAC conjugates in the sera of cancer patients were evaluated using an Enzyme-Linked Immunosorbent Assay (ELISA) with these new conjugates. The avidity (IC(50)) and specificity of these circulating Abs were assessed via competition experiments.<br><br>RESULTS: An increase in Ig directed against these PAH-NAC conjugates was found in the sera of cancer patients, irrespective of the state and stage of the tumors. These Ig were principally of the A isotype. Sera from cancer patients had significantly higher optical density (OD) ranges than the controls, p<0.0001. The ELISA test for breast cancer (n=155) and ovarian cancer (n=62) identified 82% and 92% of positive patients, respectively. The percentage positive in the control group (n=60) was around 5%. Moreover, competition experiments with the different PAH-NAC conjugates and NAC-BSA revealed an estimated avidity of 10(-6)M for the circulating IgA antibodies.<br><br>CONCLUSIONS: The Abs discriminated between the different PAH-NAC conjugates and NAC-BSA. Therefore, these Abs recognize a carcinogenic PAH-NAC structure and not only a BP structure. These markers may be useful in the future for monitoring cancer evolution and recurrence.}, }
@article {pmid19673104, year = {2009}, author = {Zhou, SM and Jiang, LP and Geng, CY and Cao, J and Zhong, LF}, title = {Patulin-induced genotoxicity and modulation of glutathione in HepG2 cells.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {53}, number = {5}, pages = {584-586}, doi = {10.1016/j.toxicon.2009.01.030}, pmid = {19673104}, issn = {0041-0101}, mesh = {Cell Line ; Cell Proliferation/drug effects ; *DNA Damage ; Glutathione/*metabolism/physiology ; Glutathione Synthase/antagonists &amp; inhibitors ; Humans ; Micronuclei, Chromosome-Defective ; Patulin/*toxicity ; }, abstract = {Patulin (PAT), a mycotoxin produced by certain species of Penicillium, Aspergillus and Byssochlamys, is mainly found in ripe apple and apple products. In our present study, a significant increase of the micronuclei frequency induced by PAT was found in human hepatoma HepG2 cells. To elucidate the role of glutathione (GSH) in the effect, the intracellular GSH level was modulated by pre-treatment with buthionine-(S, R)-sulfoximine (BSO), a specific GSH synthesis inhibitor, and by pre-treatment with N-acetylcysteine (NAC), a GSH precursor. It was found that depletion of GSH in HepG2 cells with BSO dramatically increased the PAT-induced micronuclei frequencies and that when the intracellular GSH content was elevated by NAC, the chromosome damage induced by PAT was significantly prevented in our test concentrations (0.19-0.75 microM). These results indicate that GSH play an important role in cellular defense against PAT-induced genotoxicity.}, }
@article {pmid19669998, year = {2009}, author = {Saha, P and Sen, R and Hariharan, C and Kumar, D and Das, P and Chatterjee, M}, title = {Berberine chloride causes a caspase-independent, apoptotic-like death in Leishmania donovani promastigotes.}, journal = {Free radical research}, volume = {43}, number = {11}, pages = {1101-1110}, doi = {10.1080/10715760903186124}, pmid = {19669998}, issn = {1029-2470}, mesh = {Animals ; Antiprotozoal Agents/*pharmacology ; Apoptosis/*drug effects ; Berberine/*pharmacology ; Caspase Inhibitors ; Caspases/*metabolism ; Cell Line, Tumor ; DNA Fragmentation ; Humans ; Leishmania donovani/cytology/*drug effects/metabolism ; Leishmaniasis, Visceral/parasitology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Berberine chloride, a quarternary isoquinoline alkaloid, is a promising anti-leishmanial compound, IC(50) being 7.1 microM in L. donovani promastigotes. This leishmanicidal activity was initiated by its pro-oxidant effect, evidenced by enhanced generation of reactive oxygen intermediates that was accompanied by depletion of thiols; pre-incubation in N-acetyl cysteine, attenuated its cell viability, corroborating that generation of free radicals triggered its parasiticidal activity. Externalization of phosphatidylserine and elevation of intracellular calcium preceded depolarization of the mitochondrial membrane potential, which translated into an increase in the sub G(0)/G(1) population and was accompanied by DNA laddering, hallmarks of apoptosis. Berberine chloride failed to induce caspase activity and anti-leishmanial activity in the presence of a pan caspase inhibitor, Z-Val-Ala-DL-Asp (methoxy)-fluoromethylketone remained unchanged, which indicated that the apoptosis was caspase independent. Collectively, the data indicates that Berberine chloride triggers an apoptosis-like death following enhanced generation of reactive oxygen species, thus meriting further pharmacological investigations.}, }
@article {pmid19668088, year = {2009}, author = {Gibson, KR and Neilson, IL and Barrett, F and Winterburn, TJ and Sharma, S and MacRury, SM and Megson, IL}, title = {Evaluation of the antioxidant properties of N-acetylcysteine in human platelets: prerequisite for bioconversion to glutathione for antioxidant and antiplatelet activity.}, journal = {Journal of cardiovascular pharmacology}, volume = {54}, number = {4}, pages = {319-326}, doi = {10.1097/FJC.0b013e3181b6e77b}, pmid = {19668088}, issn = {1533-4023}, support = {//Chief Scientist Office/United Kingdom ; }, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antioxidants/metabolism/*pharmacology ; Biotransformation ; Blood Platelets/*drug effects/enzymology/metabolism ; Electron Spin Resonance Spectroscopy ; Glutathione/*metabolism ; Humans ; In Vitro Techniques ; Nitric Oxide Synthase/metabolism ; Platelet Aggregation/drug effects ; Platelet Aggregation Inhibitors/*pharmacology ; Platelet Count ; Reactive Oxygen Species/metabolism ; }, abstract = {N-Acetylcysteine (NAC) is a frequently used "antioxidant" in vitro, but the concentrations applied rarely correlate with those encountered with oral dosing in vivo. Here, we investigated the in vitro antioxidant and antiplatelet properties of NAC at concentrations (10-100 microM) that are achievable in plasma with tolerable oral dosing. The impact of NAC pretreatment (2 hours) on aggregation of platelets from healthy volunteers in response to thrombin and adenosine diphosphate and on platelet-derived nitric oxide (NO) was examined. NAC was found to be a weak reducing agent and a poor antioxidant compared with glutathione (reduced form) (GSH). However, platelets treated with NAC showed enhanced antioxidant activity and depression of reactive oxygen species generation associated with increases in intraplatelet GSH levels. An approximately 2-fold increase in NO synthase-derived nitrite was observed with 10 microM NAC treatment, but the effect was not concentration dependent. Finally, NAC significantly reduced both thrombin-induced and adenosine diphosphate-induced platelet aggregation. NAC should be considered a weak antioxidant that requires prior conversion to GSH to convey antioxidant and antithrombotic benefit at therapeutically relevant concentrations. Our results suggest that NAC might be an effective antiplatelet agent in conditions where increased oxidative stress contributes to heightened risk of thrombosis but only if the intraplatelet machinery to convert it to GSH is functional.}, }
@article {pmid19666395, year = {2009}, author = {Dauletbaev, N and Fischer, P and Aulbach, B and Gross, J and Kusche, W and Thyroff-Friesinger, U and Wagner, TO and Bargon, J}, title = {A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis.}, journal = {European journal of medical research}, volume = {14}, number = {8}, pages = {352-358}, pmid = {19666395}, issn = {0949-2321}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Cystic Fibrosis/*drug therapy/metabolism/pathology ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Forced Expiratory Volume ; Free Radical Scavengers/*administration &amp; dosage ; Glutathione/metabolism ; Humans ; Interleukin-8/metabolism ; Male ; Sputum/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Young Adult ; }, abstract = {OBJECTIVE: We conducted a single-centre, randomised, double-blinded, placebo-controlled phase II clinical study to test safety and efficacy of a 12-week therapy with low-dose (700 mg/daily) or high-dose (2800 mg/daily) of NAC.<br><br>METHODS: Twenty-one patients (DeltaF508 homo/heterozygous, FEV1>40% pred.) were included in the study. After a 3-weeks placebo run-in phase, 11 patients received low-dose NAC, and 10 patients received high-dose NAC. Outcomes included safety and clinical parameters, inflammatory (total leukocyte numbers, cell differentials, TNF-alpha, IL-8) measures in induced sputum, and concentrations of extracellular glutathione in induced sputum and blood.<br><br>RESULTS: High-dose NAC was a well-tolerated and safe medication. High-dose NAC did not alter clinical or inflammatory parameters. However, extracellular glutathione in induced sputum tended to increase on high-dose NAC.<br><br>CONCLUSIONS: High-dose NAC is a well-tolerated and safe medication for a prolonged therapy of patients with CF with a potential to increase extracellular glutathione in CF airways.}, }
@article {pmid19666112, year = {2009}, author = {Osman, B and Doller, A and Akool, el-S and Holdener, M and Hintermann, E and Pfeilschifter, J and Eberhardt, W}, title = {Rapamycin induces the TGFbeta1/Smad signaling cascade in renal mesangial cells upstream of mTOR.}, journal = {Cellular signalling}, volume = {21}, number = {12}, pages = {1806-1817}, doi = {10.1016/j.cellsig.2009.07.016}, pmid = {19666112}, issn = {1873-3913}, mesh = {Animals ; Gene Expression/drug effects ; Humans ; Immunosuppressive Agents/*pharmacology ; Intracellular Signaling Peptides and Proteins/metabolism ; Mesangial Cells/*drug effects/metabolism ; Promoter Regions, Genetic ; Protein Serine-Threonine Kinases/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta/metabolism ; Signal Transduction/drug effects ; Sirolimus/*pharmacology ; Smad Proteins/*metabolism ; Smad Proteins, Receptor-Regulated/metabolism ; TOR Serine-Threonine Kinases ; Tacrolimus Binding Protein 1A/metabolism ; Transforming Growth Factor beta/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The mTOR kinase inhibitor rapamycin (sirolimus) is a drug with potent immunosuppressive and antiproliferative properties. We found that rapamycin induces the TGFbeta/Smad signaling cascade in rat mesangial cells (MC) as depicted by the nuclear translocation of phospho-Smads 2, -3 and Smad-4, respectively. Concomitantly, rapamycin increases the nuclear DNA binding of receptor (R)- and co-Smad proteins to a cognate Smad-binding element (SBE) which in turn causes an increase in profibrotic gene expression as exemplified by the connective tissue growth factor (CTGF) and plasminogen activator inhibitor 1 (PAI-1). Using small interfering (si)RNA we demonstrate that Smad 2/3 activation by rapamycin depends on its endogenous receptor FK binding protein 12 (FKBP12). Mechanistically, Smad induction by rapamycin is initiated by an increase in active TGFbeta(1) as shown by ELISA and by the inhibitory effects of a neutralizing TGFbeta antibody. Using an activin receptor-like kinase (ALK)-5 inhibitor and by siRNA against the TGFbeta type II receptor (TGFbeta-RII) we furthermore demonstrate a functional involvement of both types of TGFbeta receptors. However, rapamycin did not compete with TGFbeta for TGFbeta-receptor binding as found in radioligand-binding assay. Besides SB203580, a specific inhibitor of the p38 MAPK, the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC) and a cell-permeable superoxide dismutase (SOD) mimetic strongly abrogated the stimulatory effects of rapamycin on Smad 2 and 3 phosphorylation. Furthermore, the rapid increase in dichlorofluorescein (DCF) formation implies that rapamycin mainly acts through ROS. In conclusion, activation of the profibrotic TGFbeta/Smad signaling cascade accompanies the immunosuppressive and antiproliferative actions of rapamycin.}, }
@article {pmid19665947, year = {2009}, author = {Michaelsen, JT and Dehnert, S and Giustarini, D and Beckmann, B and Tsikas, D}, title = {HPLC analysis of human erythrocytic glutathione forms using OPA and N-acetyl-cysteine ethyl ester: evidence for nitrite-induced GSH oxidation to GSSG.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {877}, number = {28}, pages = {3405-3417}, doi = {10.1016/j.jchromb.2009.06.043}, pmid = {19665947}, issn = {1873-376X}, mesh = {Acetylcysteine/chemistry ; Adult ; Chromatography, High Pressure Liquid/*methods ; Erythrocytes/*chemistry/metabolism ; Female ; Glutathione/*analysis/*metabolism ; Glutathione Disulfide/*analysis/metabolism ; Humans ; Male ; Nitrites/chemistry ; Oxidation-Reduction ; Young Adult ; o-Phthalaldehyde/chemistry ; }, abstract = {Glutathione exists in biological samples in the reduced form (GSH), as its disulfide (GSSG) and as a mixed disulfide (GSSR) with thiols (RSH). GSH is the most abundant low-molecular-mass thiol and plays important roles as a cofactor and as a main constituent of the intracellular redox status. Due to its own sulfhydryl (SH) group, GSH reacts readily with o-phthaldialdehyde (OPA) to form a highly stable and fluorescent isoindole derivative (GSH-OPA), which allows for sensitive and specific quantitative determination of GSH in biological systems by HPLC with fluorescence (FL) detection. In the present article we report on the utility of the novel, strongly disulfide bond-reducing thiol N-acetyl-cysteine ethyl ester (NACET) for the specific quantitative analysis of GSH and GSSG in the cytosol of red blood cells (RBC) as GSH-OPA derivative with FL (excitation/emission 338/458nm) or UV absorbance (338nm) detection. Unlike in aqueous solution, the derivatization of GSH in RBC cytosol yielded two closely related derivatives in the absence of NACET and only the GSH-OPA derivative in the presence of NACET. The HPLC method was optimized and validated for human RBC and applied to measure GSH and GSSG in RBC of healthy subjects. Basal GSH and GSSG concentrations were determined to be 2340+/-350microM and 11.4+/-3.2microM, respectively, in RBC of 12 healthy young volunteers (aged 23-38 years). The method was also applied to study the effects of nitrite on the glutathione status in intact and lysed human RBC. Nitrite at mM-concentrations caused instantaneous and considerable GSSG formation in lysed but much less pronounced in intact RBC. GSH externally added to lysed RBC inhibited nitrite-induced methemoglobin formation. Our findings suggest that nitric oxide/nitrite-related consumption rate of GSH, and presumably that of NADH and NADPH, could be of the order of 600micromol/day in RBC of healthy subjects.}, }
@article {pmid19664398, year = {2009}, author = {Zeng, S and Lin, Y and DI, JF and Feng, Z}, title = {[Protective effects and mechanism of N-acetylcysteine on cardiac injury induced by ischemia/reperfusion in diabetic rats].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {25}, number = {8}, pages = {719-721}, pmid = {19664398}, issn = {1007-8738}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Diabetes Complications/*drug therapy/metabolism ; Disease Models, Animal ; Female ; Humans ; Ischemia/*drug therapy/metabolism ; Male ; Myocardial Reperfusion Injury/*drug therapy/metabolism ; Myocytes, Cardiac/drug effects/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIM: To study the protective effects and mechanism of N-acetylcysteine on cardiac injury induced by ischemia/reperfusion in diabetic rats.<br><br>METHODS: Diabetes mellitus was induced by intraperitoneal injection of streptozotocin(STZ). The animals were randomly reassigned into sham-operated group, I/R group and I/R+treated with NAC group. The content of GSH and GSSG, and the activity of Caspase-3 were measured. The apoptosis index (AI) by TUNEL staining was calculated. In addition, the apoptosis of Cardiomyocyte was also confirmed by DNA Ladder.<br><br>RESULTS: Treatment with NAC decreased the activity of Caspase-3, the content of GSSG, the values of AI but increased the content of GSH in both non-diabetic and diabetic rats (P<0.05), but there were still significant difference about the values of above parameters between diabetic rats and non-diabetic rats (P<0.05).<br><br>CONCLUSION: NAC can attenuated cardiomyocyte apoptosis by decreasing the activity of Caspase-3 and increasing the content of GSH, which has protective effect on ischemic/reperfused myocardium injury in both non-diabetic and diabetic rats, but the cardioprotective effect is less effective in diabetic rats than that in non-diabetic rats.}, }
@article {pmid19654923, year = {2009}, author = {Chen, L and Ovesen, JL and Puga, A and Xia, Y}, title = {Distinct contributions of JNK and p38 to chromium cytotoxicity and inhibition of murine embryonic stem cell differentiation.}, journal = {Environmental health perspectives}, volume = {117}, number = {7}, pages = {1124-1130}, pmid = {19654923}, issn = {1552-9924}, support = {R01 ES10807/ES/NIEHS NIH HHS/United States ; R01 ES011798/ES/NIEHS NIH HHS/United States ; R01 ES010807/ES/NIEHS NIH HHS/United States ; P30 ES10807/ES/NIEHS NIH HHS/United States ; P42 ES04908/ES/NIEHS NIH HHS/United States ; P42 ES004908/ES/NIEHS NIH HHS/United States ; P30 ES006096/ES/NIEHS NIH HHS/United States ; R01 EY015227/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Blotting, Western ; Cell Differentiation/*drug effects/genetics ; Cells, Cultured ; Chromium/*toxicity ; Embryonic Stem Cells/*cytology/*drug effects/metabolism ; Environmental Pollutants/*toxicity ; Enzyme Activation/drug effects ; JNK Mitogen-Activated Protein Kinases/genetics/*physiology ; MAP Kinase Kinase 7/genetics/physiology ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation/drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; p38 Mitogen-Activated Protein Kinases/genetics/*physiology ; }, abstract = {BACKGROUND: Potassium dichromate [Cr(VI)] is a widespread environmental toxicant responsible for increased risk of several human diseases. Cr(VI) exposure leads to activation of mitogen-activated protein kinases (MAPKs), including c-Jun N-terminal kinase (JNK)1/2, p38, and extracellular-signal regulated kinase (ERK)1/2.<br><br>OBJECTIVES: We evaluated the contribution of MAPKs to Cr(VI) toxicity.<br><br>METHODS: Phosphorylation of MAPKs and their downstream effectors was evaluated by Western immunoblotting; reactive oxygen species were measured by DCFDA (5',6'-chloromethyl-2'-7'-dichlorofluorescin diacetate) labeling and flow cytometry, and glutathione and glutathione disulfide levels were determined by monochrome graphic spectroflurometer. Cytotoxicity was assessed by the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay and colony formation. Embryoid body (EB) differentiation was evaluated by contracting cardiomyocyte formation, and real-time polymerase chain reaction (RT-PCR) was used for cardiomyocyte-specific and stem-cell-specific gene expression.<br><br>RESULTS: Acute treatment of mouse embryonic stem (ES) cells with 50 microM Cr(VI) induced the rapid phosphorylation of JNK, p38, and ERK and their respective downstream transcription factors, c-JUN, activating transcription factor-2, and ELK1. MAPK activation and cytotoxicity induction were partially blocked by pretreatment with the antioxidant N-acetyl cysteine. Ablation of the upstream MAP kinase kinase (MAP2K7) in ES cells prevented JNK activation, whereas ablation of MAP2K4 prevented both JNK and p38 activation. Using specific MAPK inhibitors and MAP2K4- and MAP2K7-deficient ES cells, we showed that JNK reduced acute Cr(VI) cytotoxicity, p38 potentiated it, and ERK had no effect. At low submicromolar concentrations, Cr(VI) caused MAP2K4/7-dependent JNK activation and MAP2K4-dependent p38 activation and strongly inhibited contracting cardiomyocyte development in wild-type ES cells, but much less so in Map2k7((-/-)) cells.<br><br>CONCLUSION: Each MAPK distinctly contributes to chromium toxicity. Whereas JNK prevents and p38 promotes acute cytotoxicity, JNK contributes to optimal inhibition of ES cell differentiation by chromium.}, }
@article {pmid19654922, year = {2009}, author = {Li, N and Wang, M and Bramble, LA and Schmitz, DA and Schauer, JJ and Sioutas, C and Harkema, JR and Nel, AE}, title = {The adjuvant effect of ambient particulate matter is closely reflected by the particulate oxidant potential.}, journal = {Environmental health perspectives}, volume = {117}, number = {7}, pages = {1116-1123}, pmid = {19654922}, issn = {1552-9924}, support = {U19 AI070453/AI/NIAID NIH HHS/United States ; R01 ES015498/ES/NIEHS NIH HHS/United States ; R01 ES10553/ES/NIEHS NIH HHS/United States ; R01 ES010553/ES/NIEHS NIH HHS/United States ; R01 ES016746/ES/NIEHS NIH HHS/United States ; }, mesh = {Adjuvants, Immunologic ; Animals ; Female ; Immunohistochemistry ; In Vitro Techniques ; Lung/drug effects/metabolism ; Mice ; Mice, Inbred BALB C ; Nasal Mucosa/metabolism ; Nose/drug effects ; Ovalbumin/*immunology ; Oxidative Stress/drug effects ; Particulate Matter/*immunology/*toxicity ; Respiratory Hypersensitivity/*chemically induced/*immunology ; }, abstract = {BACKGROUND: It has been demonstrated that ambient particulate matter (PM) can act as an adjuvant for allergic sensitization. Redox-active organic chemicals on the particle surface play an important role in PM adverse health effects and may determine the adjuvant effect of different particle types according to their potential to perturb redox equilibrium in the immune system.<br><br>OBJECTIVES: We determined whether the adjuvant effect of ambient fine particles versus ultrafine particles (UFPs) is correlated to their prooxidant potential.<br><br>METHODS: We have established an intranasal sensitization model that uses ambient PM as a potential adjuvant for sensitization to ovalbumin (OVA), which enhances the capacity for secondary OVA challenge to induce allergic airway inflammation.<br><br>RESULTS: UFPs with a greater polycyclic aromatic hydrocarbon (PAH) content and higher oxidant potential enhanced OVA sensitization more readily than did fine particles. This manifests as enhanced allergic inflammation upon secondary OVA challenge, leading to eosinophilic inflammation and mucoid hyperplasia starting at the nasal turbinates all the way down to the small pulmonary airways. The thiol antioxidant N-acetyl cysteine was able to suppress some of these sensitization events.<br><br>CONCLUSIONS: The adjuvant effects of ambient UFP is determined by their oxidant potential, which likely plays a role in changing the redox equilibrium in the mucosal immune system.}, }
@article {pmid19654295, year = {2009}, author = {Yodkeeree, S and Sung, B and Limtrakul, P and Aggarwal, BB}, title = {Zerumbone enhances TRAIL-induced apoptosis through the induction of death receptors in human colon cancer cells: Evidence for an essential role of reactive oxygen species.}, journal = {Cancer research}, volume = {69}, number = {16}, pages = {6581-6589}, pmid = {19654295}, issn = {1538-7445}, support = {CA-124787-01A2/CA/NCI NIH HHS/United States ; P01 CA124787/CA/NCI NIH HHS/United States ; P01 CA091844/CA/NCI NIH HHS/United States ; CA-16 672/CA/NCI NIH HHS/United States ; P01 CA091844-020004/CA/NCI NIH HHS/United States ; P01 CA124787-01A20002/CA/NCI NIH HHS/United States ; P01 CA091844-010004/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis/*drug effects/genetics ; Colonic Neoplasms/drug therapy/genetics/metabolism/*pathology ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drug Synergism ; Gene Expression Regulation, Neoplastic/drug effects ; HCT116 Cells ; HT29 Cells ; Humans ; RNA, Small Interfering/administration &amp; dosage/pharmacology ; Reactive Oxygen Species/*pharmacology ; Receptors, Death Domain/antagonists &amp; inhibitors/*genetics/metabolism ; Sesquiterpenes/administration &amp; dosage/*pharmacology ; TNF-Related Apoptosis-Inducing Ligand/administration &amp; dosage/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {Identification of the active component and mechanisms of action of traditional medicines is highly desirable. We investigated whether zerumbone, a sesquiterpene from tropical ginger, can enhance the anticancer effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found that zerumbone potentiated TRAIL-induced apoptosis in human HCT116 colon cancer cells and that this correlated with the up-regulation of TRAIL death receptor (DR) 4 and DR5. Induction of DRs occurred at the transcriptional level, and this induction was not cell-type specific, as its expression was also up-regulated in prostate, kidney, breast, and pancreatic cancer cell lines. Deletion of DR5 or DR4 by small interfering RNA significantly reduced the apoptosis induced by TRAIL and zerumbone. In addition to up-regulating DRs, zerumbone also significantly down-regulated the expression of cFLIP but not that of other antiapoptotic proteins. The induction of both DRs by zerumbone was abolished by glutathione and N-acetylcysteine (NAC), and this correlated with decreased TRAIL-induced apoptosis, suggesting a critical role of reactive oxygen species. Inhibition of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase but not of Jun NH(2)-terminal kinase abolished the effect of zerumbone on DR induction. Zerumbone also induced the p53 tumor suppressor gene but was found to be optional for DR induction or for enhancement of TRAIL-induced apoptosis. Both bax and p21, however, were required for zerumbone to stimulate TRAIL-induced apoptosis. Overall, our results show that zerumbone can potentiate TRAIL-induced apoptosis through the reactive oxygen species-mediated activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase leading to DR4 and DR5 induction and resulting in enhancement of the anticancer effects of TRAIL.}, }
@article {pmid19653222, year = {2009}, author = {Sestili, P and Barbieri, E and Martinelli, C and Battistelli, M and Guescini, M and Vallorani, L and Casadei, L and D'Emilio, A and Falcieri, E and Piccoli, G and Agostini, D and Annibalini, G and Paolillo, M and Gioacchini, AM and Stocchi, V}, title = {Creatine supplementation prevents the inhibition of myogenic differentiation in oxidatively injured C2C12 murine myoblasts.}, journal = {Molecular nutrition &amp; food research}, volume = {53}, number = {9}, pages = {1187-1204}, doi = {10.1002/mnfr.200800504}, pmid = {19653222}, issn = {1613-4133}, mesh = {Adenosine Triphosphate/analysis ; Animals ; Antioxidants/*pharmacology ; Catalase/metabolism ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Creatine/analysis/*pharmacology ; Dietary Supplements ; Glutathione Peroxidase/metabolism ; Hydrogen Peroxide/pharmacology ; Insulin-Like Growth Factor I/genetics ; Mice ; Myoblasts/cytology/*drug effects/ultrastructure ; Oxidation-Reduction ; Proteomics ; RNA, Messenger/analysis ; }, abstract = {Creatine (Cr), one of the most popular nutritional supplements among athletes, has been recently shown to prevent the cytotoxicity caused by different oxidative stressors in various mammalian cell lines, including C2C12 myoblasts, via a direct antioxidant activity. Here, the effect of Cr on the differentiating capacity of C2C12 cells exposed to H(2)O(2) has been investigated. Differentiation into myotubes was monitored using morphological, ultrastructural, and molecular techniques. Treatment with H(2)O(2) (1 h) not only caused a significant (30%) loss of cell viability, but also abrogated the myogenic ability of surviving C2C12. Cr-supplementation (24 h prior to H(2)O(2) treatment) was found to prevent these effects. Interestingly, H(2)O(2)-challenged cells preconditioned with the established antioxidants trolox or N-acetyl-cysteine, although cytoprotected, did not display the same differentiating ability characterizing oxidatively-injured, Cr-supplemented cells. Besides acting as an antioxidant, Cr increased the level of muscle regulatory factors and IGF1 (an effect partly refractory to oxidative stress), the cellular availability of phosphocreatine and seemed to exert some mitochondrially-targeted protective activity. It is concluded that Cr preserves the myogenic ability of oxidatively injured C2C12 via a pleiotropic mechanism involving not only its antioxidant capacity, but also the contribution to cell energy charge and effects at the transcriptional level which common bona fide antioxidants lack.}, }
@article {pmid19648289, year = {2009}, author = {Felton, VM and Borok, Z and Willis, BC}, title = {N-acetylcysteine inhibits alveolar epithelial-mesenchymal transition.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {297}, number = {5}, pages = {L805-12}, pmid = {19648289}, issn = {1522-1504}, support = {HL-38578/HL/NHLBI NIH HHS/United States ; HL-62569/HL/NHLBI NIH HHS/United States ; HL-89445/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Epithelium/*drug effects/*pathology ; Glutathione/pharmacology ; Humans ; Membrane Proteins/metabolism ; Mesoderm/*drug effects/*pathology ; Phosphoproteins/metabolism ; Phosphorylation/drug effects ; Pulmonary Alveoli/*drug effects/*pathology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Smad3 Protein/metabolism ; Transforming Growth Factor beta1/pharmacology ; Zonula Occludens-1 Protein ; }, abstract = {The ability of transforming growth factor-beta1 (TGF-beta1) to induce epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AEC) in vitro and in vivo, together with the demonstration of EMT in biopsies of idiopathic pulmonary fibrosis (IPF) patients, suggests a role for TGF-beta1-induced EMT in disease pathogenesis. We investigated the effects of N-acetylcysteine (NAC) on TGF-beta1-induced EMT in a rat epithelial cell line (RLE-6TN) and in primary rat alveolar epithelial cells (AEC). RLE-6TN cells exposed to TGF-beta1 for 5 days underwent EMT as evidenced by acquisition of a fibroblast-like morphology, downregulation of the epithelial-specific protein zonula occludens-1, and induction of the mesenchymal-specific proteins alpha-smooth muscle actin (alpha-SMA) and vimentin. These changes were inhibited by NAC, which also prevented Smad3 phosphorylation. Similarly, primary alveolar epithelial type II cells exposed to TGF-beta1 also underwent EMT that was prevented by NAC. TGF-beta1 decreased cellular GSH levels by 50-80%, whereas NAC restored them to approximately 150% of those found in TGF-beta1-treated cells. Treatment with glutathione monoethyl ester similarly prevented an increase in mesenchymal marker expression. Consistent with its role as an antioxidant and cellular redox stabilizer, NAC dramatically reduced intracellular reactive oxygen species production in the presence of TGF-beta1. Finally, inhibition of intracellular ROS generation during TGF-beta1 treatment prevented alveolar EMT, but treatment with H2O2 alone did not induce EMT. We conclude that NAC prevents EMT in AEC in vitro, at least in part through replenishment of intracellular GSH stores and limitation of TGF-beta1-induced intracellular ROS generation. We speculate that beneficial effects of NAC on pulmonary function in IPF may be mediated by inhibitory effects on alveolar EMT.}, }
@article {pmid19647067, year = {2009}, author = {Alvergnas, M and Richert, L and Blanchard, N and Abadie, C and Heyd, B and Mantion, G and Gallemann, D and Martin, H}, title = {Regulation of CYP4A expression by bezafibrate in primary culture of rat and human hepatocytes: interspecies difference and influence of N-acetylcysteine.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {23}, number = {7}, pages = {1259-1267}, doi = {10.1016/j.tiv.2009.07.027}, pmid = {19647067}, issn = {1879-3177}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Animals ; Bezafibrate/pharmacology ; Cells, Cultured ; Clofibric Acid/*pharmacology ; Cytochrome P-450 CYP4A/drug effects/genetics/*metabolism ; Female ; Gene Expression Regulation ; Hepatocytes/cytology/*enzymology/metabolism ; Humans ; Hypolipidemic Agents/*pharmacology ; Male ; Middle Aged ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Species Specificity ; }, abstract = {The effects of fibrates on cytochrome P450 4A (CYP4A) expression have not been clearly evaluated in human hepatocytes, human being reported as a non-responsive species. We have evaluated the effects of clofibrate, bezafibrate (BEZA), WY-14643, nafenopin and ciprofibrate at the concentration of 250 microM on CYP4A expression in primary cultures of rat and human hepatocytes. BEZA greatly induced mRNA expression in both species. Eight out of 10 human cultures responded to BEZA 250 microM. CYP4A-dependent activity was increased in rat, but not in human hepatocytes. The antioxidant N-acetylcysteine (Nac) enhanced the inducing effect of BEZA on mRNA expression, this potentialization being higher in human compared to rat hepatocytes. By contrast, Nac decreased the inducing effect of BEZA on CYP4A-dependent activity in rat and had either no effect or decreased the activity in BEZA-treated human hepatocytes. In conclusion, the cellular environment appears as an important parameter to take into account when studying CYP4A induction and could partly explain interspecies differences in the complex regulation of CYP4A expression.}, }
@article {pmid19644561, year = {2009}, author = {Shi, Y and Song, Y and Wang, Y and Liang, X and Hu, Y and Guan, X and Cheng, J and Yang, K}, title = {p,p'-DDE induces apoptosis of rat Sertoli cells via a FasL-dependent pathway.}, journal = {Journal of biomedicine &amp; biotechnology}, volume = {2009}, number = {}, pages = {181282}, pmid = {19644561}, issn = {1110-7251}, mesh = {Acetylcysteine/pharmacology ; Animals ; Annexins/metabolism ; Apoptosis/*drug effects ; Caspase 3/genetics/metabolism ; Caspase 8/genetics/metabolism ; Cell Shape/drug effects ; Cell Survival/drug effects ; Dichlorodiphenyl Dichloroethylene/*toxicity ; Fas Ligand Protein/*metabolism ; Male ; Models, Biological ; NF-kappa B/metabolism ; Propidium/metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Sertoli Cells/*cytology/*drug effects/enzymology ; Signal Transduction/drug effects ; }, abstract = {One,1-dichloro-2,2 bis(p-chlorophenyl) ethylene (p,p'-DDE), the major metabolite of 2,2-bis(4-Chlorophenyl)-1,1,1-trichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. It has antiandrogenic effect. However, the mechanism by which p,p'-DDE exposure causes male reproductive toxicity remains unknown. In the present study, rat Sertoli cells were used to investigate the molecular mechanism involved in p,p'-DDE-induced toxicity in male reproductive system. The results indicated that p,p'-DDE exposure at over 30 muM showed the induction of apoptotic cell death. p,p'-DDE could induce increases in FasL mRNA and protein, which could be blocked by an antioxidant agent, N-acetyl-l-cysteine (NAC). In addition, caspase-3 and -8 were activated by p,p'-DDE treatment in these cells. The activation of NF-kappaB was enhanced with the increase of p,p'-DDE dose. Taken together, these results suggested that exposure to p,p'-DDE might induce apoptosis of rat Sertoli cells through a FasL-dependent pathway.}, }
@article {pmid19639223, year = {2009}, author = {Alisi, A and Piemonte, F and Pastore, A and Panera, N and Passarelli, C and Tozzi, G and Petrini, S and Pietrobattista, A and Bottazzo, GF and Nobili, V}, title = {Glutathionylation of p65NF-kappaB correlates with proliferating/apoptotic hepatoma cells exposed to pro- and anti-oxidants.}, journal = {International journal of molecular medicine}, volume = {24}, number = {3}, pages = {319-326}, doi = {10.3892/ijmm_00000235}, pmid = {19639223}, issn = {1107-3756}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/metabolism/*pathology ; Cell Line, Tumor ; Cell Nucleus/drug effects/metabolism ; Cell Proliferation/drug effects ; DNA, Neoplasm/biosynthesis ; Dose-Response Relationship, Drug ; Fluorescent Antibody Technique ; Glutathione/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Liver Neoplasms/metabolism/*pathology ; Oxidants/*pharmacology ; Protein Transport/drug effects ; Transcription Factor RelA/*metabolism ; }, abstract = {Oxidative stress influences a variety of regulatory proteins, including nuclear factor-kappaB (NF-kappaB). NF-kappaB is critical for maintaining the proliferation/apoptosis balance in hepatocytes. In this study we investigated the causal links between glutathione, NF-kappaB and hepatocyte damage. HepG2 and 3B cells were exposed to different doses of H2O2 or N-acetylcysteine (NAC) and the proliferation/apoptosis rate, glutathione forms, and p65NF-kappaB glutathionylation and activity were analysed. Our results demonstrate that H2O2 stopped proliferative response at low doses, but induced apoptosis only at high doses. In contrast, NAC exerted, proportionally to its concentration, a dual role simultaneously increasing both proliferation and apoptosis. Interestingly, the levels of protein-bound glutathione were increased by H2O2 and decreased by NAC. Moreover, the antibody recognizing the glutathionylated proteins co-precipitated and -localized with the cytoplasmic inactive form of p65NF-kappaB in H2O2- and NAC-treated cells, even when, in 1 mM NAC-treated cells, a part of p65 was glutathione-free and localized into the nucleus. Apoptotic cells were characterised principally by a cytoskeletal staining of glutathionylation and retention of NF-kappaB in the cytoplasmic region; whereas in proliferating cells, glutathionylated proteins were concentrated into the perinuclear region and p65NF-kappaB was traslocated into the nucleus. While cytoplasmic NF-kappaB retention correlated well with an increased apoptotic rate, a greater expression of this protein was observed in association with the NAC-dependent. In conclusion, our findings suggest that glutathionylation inhibits NF-kappaB activity causing reduced hepatocyte survival, which is common in several liver diseases.}, }
@article {pmid19636205, year = {2009}, author = {Masha, A and Brocato, L and Dinatale, S and Mascia, C and Biasi, F and Martina, V}, title = {N-acetylcysteine is able to reduce the oxidation status and the endothelial activation after a high-glucose content meal in patients with Type 2 diabetes mellitus.}, journal = {Journal of endocrinological investigation}, volume = {32}, number = {4}, pages = {352-356}, pmid = {19636205}, issn = {1720-8386}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Aldehydes/metabolism ; Case-Control Studies ; Diabetes Mellitus, Type 2/*drug therapy/metabolism ; E-Selectin/metabolism ; Endothelium, Vascular/*drug effects/metabolism ; Female ; Free Radical Scavengers/*therapeutic use ; Glucose/*administration &amp; dosage/metabolism ; Glycemic Index ; Humans ; Insulin/metabolism ; Male ; Malondialdehyde/metabolism ; Middle Aged ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Postprandial Period ; Vascular Cell Adhesion Molecule-1/metabolism ; }, abstract = {UNLABELLED: Post-prandial hyperglycemia seems to play a pivotal role in the pathogenesis of the cardiovascular complications of diabetes mellitus, as it leads to an oxidative stress which in turn causes a reduced NO bioavailability. These conditions produce an endothelial activation.<br><br>AIM OF THE STUDY: The aim of this study was to assure that the administration of N-acetylcysteine (NAC), thiolic antioxidant, is able to decrease the oxidation status and endothelial activation after a high-glucose content meal.<br><br>SUBJECTS AND METHODS: Ten patients with Type 2 diabetes mellitus (DMT2) (Group 1) and 10 normal subjects (Group 2) were studied. They assumed a high-glucose content meal without (phase A) or after (phase B) the administration of NAC. Glycemia, insulinemia, intercellular adhesion molecule 1, vascular adhesion molecule 1 (VCAM-1), E-selectin, malonaldehyde (MDA), and 4-hydroxynonenal (HNE) were assessed at -30, 0, +30, +60, +90, +120, and +180 min with respect to the meal consumption.<br><br>RESULTS: During the phase A in Group 1, only HNE and MDA levels increased after the meal assumption; all parameters remained unchanged in Group 2. During the phase B, in Group 1, HNE, MDA, VCAM-1, and E-selectin levels after the meal were lower than those in phase A, while no change for all variables were observed in Group 2.<br><br>CONCLUSIONS: A high-glucose meal produces an increase in oxidation parameters in patients with DMT2. The administration of NAC reduces the oxidative stress and, by doing so, reduces the endothelial activation. In conclusion, NAC could be efficacious in the slackening of the progression of vascular damage in DMT2.}, }
@article {pmid19635476, year = {2009}, author = {Huo, Y and Qiu, WY and Pan, Q and Yao, YF and Xing, K and Lou, MF}, title = {Reactive oxygen species (ROS) are essential mediators in epidermal growth factor (EGF)-stimulated corneal epithelial cell proliferation, adhesion, migration, and wound healing.}, journal = {Experimental eye research}, volume = {89}, number = {6}, pages = {876-886}, doi = {10.1016/j.exer.2009.07.012}, pmid = {19635476}, issn = {1096-0007}, support = {R01 EY10595/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology ; Cell Adhesion/drug effects/physiology ; Cell Movement/drug effects/physiology ; Cell Proliferation/drug effects ; Cells, Cultured ; Cornea/pathology/physiopathology ; Corneal Injuries ; Epidermal Growth Factor/*pharmacology ; Epithelial Cells/cytology/drug effects/metabolism ; Epithelium, Corneal/*cytology/drug effects/metabolism ; Humans ; Microscopy, Confocal/methods ; Mitogen-Activated Protein Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rabbits ; Reactive Oxygen Species/*metabolism ; Recombinant Proteins/pharmacology ; Sus scrofa ; Wound Healing/drug effects/physiology ; }, abstract = {EGF is an essential growth factor needed for epithelial cell proliferation and wound healing of the cornea, but the molecular mechanism is not understood. Although studies have shown that EGF in some non-phagocytic cells induces ROS generation, little is known about the role of ROS in corneal epithelial cells. Therefore, we examined the potential physiological role of ROS in corneal cell proliferation, adhesion and wound healing using rabbit or human corneal epithelial cells, and pig whole cornea organ culture as models. EGF (5 ng/ml)-induced ROS in serum-starved RCE or HCE cells were captured as DCFH fluorescence and detected by confocal microscopy. The elevation of ROS was eradicated when the cells were pretreated with an antioxidant N-acetylcysteine (NAC) or mannitol, or with inhibitor to NADPH oxidase (DPI), or to lipoxygenase (NDGA). EGF-induced ROS generation correlated with cell growth and activation of Akt and MAPK signaling pathways, while NAC eliminated all these effects. EGF-stimulated cell adhesion or migration in cell culture was greatly suppressed in the presence of NAC while EGF-facilitated epithelial cell wound healing in corneal organ culture was also blocked by NAC. This is the first demonstration of a novel ROS physiological function in corneal wound healing.}, }
@article {pmid19633536, year = {2009}, author = {Li, Y and Goodwin, CR and Sang, Y and Rosen, EM and Laterra, J and Xia, S}, title = {Camptothecin and Fas receptor agonists synergistically induce medulloblastoma cell death: ROS-dependent mechanisms.}, journal = {Anti-cancer drugs}, volume = {20}, number = {9}, pages = {770-778}, doi = {10.1097/CAD.0b013e32832fe472}, pmid = {19633536}, issn = {1473-5741}, support = {ES09169/ES/NIEHS NIH HHS/United States ; NS 95704/NS/NINDS NIH HHS/United States ; }, mesh = {Antibodies/*pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Brain Neoplasms/*drug therapy ; Camptothecin/*pharmacology ; Cell Death/*drug effects ; Cell Line, Tumor ; Drug Synergism ; Enzyme Inhibitors/*pharmacology ; Fas Ligand Protein/*pharmacology ; Humans ; Medulloblastoma/*diet therapy ; Reactive Oxygen Species/*pharmacology ; Receptors, Death Domain/metabolism ; Signal Transduction/drug effects ; *Topoisomerase I Inhibitors ; }, abstract = {Medulloblastoma, a common malignant pediatric brain tumor, is highly resistant to death receptor-mediated apoptosis despite death receptor expression by tumor cells. Developing new strategies to overcome this resistance to death receptor activation could positively impact therapeutic outcomes. We explored the modulation of death receptor-induced medulloblastoma cell death by the topoisomerase I inhibitor camptothecin (CPT). CPT significantly increased the human medulloblastoma DAOY cell death response to agonistic anti-Fas antibody (CH-11). Cell death after CPT, CH-11, and CPT+CH-11 treatment was 9, 7, and 33%, respectively. Isobologram analysis showed that CH-11 and CPT act synergistically to induce cell death in DAOY cells. A similar pattern of synergism between CPT and CH-11 was found in ONS-76 medulloblastoma cells. Synergistic cell death was found to be predominantly apoptotic involving both extrinsic and intrinsic pathways as evidenced by annexin V staining, cleavage of caspases (3, 8, and 9), Bid and PARP, and cytoprotection by caspase inhibitors. Flow cytometric analyses showed that expression of cell surface Fas or Fas ligand did not change with drug treatment. Western blot analyses showed that the combination of CH-11+CPT induced a significant decrease in XIAP levels. Furthermore, reactive oxygen species, especially O2, were elevated after CPT treatment, and even more so by the CH-11+CPT treatment. The antioxidants glutathione and N-acetyl-cysteine prevented cell death induced by CPT+CH-11. Moreover, the mitochondrial respiratory chain complex I inhibitor rotenone potentiated CH-11-induced apoptosis in DAOY cells. Taken together, these findings show that CPT synergizes with Fas activation to induce medulloblastoma apoptosis through a mechanism involving reactive oxygen species and oxidative stress pathways.}, }
@article {pmid19630522, year = {2009}, author = {Wambi, CO and Sanzari, JK and Sayers, CM and Nuth, M and Zhou, Z and Davis, J and Finnberg, N and Lewis-Wambi, JS and Ware, JH and El-Deiry, WS and Kennedy, AR}, title = {Protective effects of dietary antioxidants on proton total-body irradiation-mediated hematopoietic cell and animal survival.}, journal = {Radiation research}, volume = {172}, number = {2}, pages = {175-186}, pmid = {19630522}, issn = {0033-7587}, support = {T32 CA009677-09/CA/NCI NIH HHS/United States ; T32 CA009677-17/CA/NCI NIH HHS/United States ; T32 CA009677-11/CA/NCI NIH HHS/United States ; 5T32CA009677/CA/NCI NIH HHS/United States ; T32 CA009677-07/CA/NCI NIH HHS/United States ; T32 CA009677-18/CA/NCI NIH HHS/United States ; T32 CA009677-16/CA/NCI NIH HHS/United States ; T32 CA009677-10/CA/NCI NIH HHS/United States ; T32 CA009677/CA/NCI NIH HHS/United States ; T32 CA009677-14/CA/NCI NIH HHS/United States ; T32 CA009677-12/CA/NCI NIH HHS/United States ; T32 CA009677-13/CA/NCI NIH HHS/United States ; T32 CA009677-08/CA/NCI NIH HHS/United States ; T32 CA009677-15/CA/NCI NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Antioxidants/*administration &amp; dosage ; Cell Survival/*radiation effects ; *Dietary Supplements ; Hematopoietic Stem Cells/pathology/*radiation effects ; Male ; Mice ; Mice, Inbred ICR ; Protons/adverse effects ; Radiation Injuries/diet therapy/*mortality/prevention &amp; control/veterinary ; Radiation Tolerance/drug effects/radiation effects ; Radiation-Protective Agents/administration &amp; dosage ; Survival Analysis ; Survival Rate ; Whole-Body Irradiation/*adverse effects ; }, abstract = {Abstract Dietary antioxidants have radioprotective effects after gamma-radiation exposure that limit hematopoietic cell depletion and improve animal survival. The purpose of this study was to determine whether a dietary supplement consisting of l-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve survival of mice after proton total-body irradiation (TBI). Antioxidants significantly increased 30-day survival of mice only when given after irradiation at a dose less than the calculated LD(50/30); for these data, the dose-modifying factor (DMF) was 1.6. Pretreatment of animals with antioxidants resulted in significantly higher serum total white blood cell, polymorphonuclear cell and lymphocyte cell counts at 4 h after 1 Gy but not 7.2 Gy proton TBI. Antioxidants significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGFbeta1 and increased bone marrow cell counts and spleen mass after TBI. Maintenance of the antioxidant diet resulted in improved recovery of peripheral leukocytes and platelets after sublethal and potentially lethal TBI. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival after proton TBI.}, }
@article {pmid19628751, year = {2009}, author = {Mueller, M and Yuan, J and Felim, A and Neudörffer, A and Peters, FT and Maurer, HH and McCann, UD and Largeron, M and Ricaurte, GA}, title = {Further studies on the role of metabolites in (+/-)-3,4-methylenedioxymethamphetamine-induced serotonergic neurotoxicity.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {37}, number = {10}, pages = {2079-2086}, pmid = {19628751}, issn = {1521-009X}, support = {R01 DA025686/DA/NIDA NIH HHS/United States ; DA01796401/DA/NIDA NIH HHS/United States ; DA05707/DA/NIDA NIH HHS/United States ; }, mesh = {3,4-Methylenedioxyamphetamine/metabolism/pharmacology ; Animals ; Deoxyepinephrine/analogs &amp; derivatives/metabolism/pharmacology ; Disease Models, Animal ; Male ; N-Methyl-3,4-methylenedioxyamphetamine/*metabolism/toxicity ; Neurotoxicity Syndromes/blood/*complications/urine ; Rats ; Rats, Sprague-Dawley ; Serotonin/*metabolism ; }, abstract = {The mechanism by which the recreational drug (+/-)-3,4-methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (C(max) and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity.}, }
@article {pmid19627980, year = {2009}, author = {Kim, YS and Park, ZY and Kim, SY and Jeong, E and Lee, JY}, title = {Alteration of Toll-like receptor 4 activation by 4-hydroxy-2-nonenal mediated by the suppression of receptor homodimerization.}, journal = {Chemico-biological interactions}, volume = {182}, number = {1}, pages = {59-66}, doi = {10.1016/j.cbi.2009.07.009}, pmid = {19627980}, issn = {1872-7786}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/antagonists &amp; inhibitors/metabolism/*pharmacology ; Animals ; Cell Line ; Chemokine CCL5/biosynthesis/genetics/immunology ; Chemokine CXCL10/biosynthesis/genetics/immunology ; Dimerization ; Dithiothreitol/pharmacology ; Humans ; Immunoblotting ; Inflammation/immunology/metabolism ; Interferon-beta/biosynthesis/genetics/immunology ; Lipopolysaccharides/antagonists &amp; inhibitors/immunology/pharmacology ; Mice ; Phagocytosis/immunology ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Toll-Like Receptor 4/*immunology/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis/genetics/immunology ; }, abstract = {Toll-like receptors (TLRs) detect invading microbial pathogens and initiate immune responses as part of host defense mechanisms. They also respond to host-derived substances released from injured cells and tissues to ensure wound healing and tissue homeostasis. Dysregulation of TLRs increases the risk of chronic inflammatory diseases and immune disorders. Inflammatory events are often accompanied by oxidative stress, which generates lipid peroxidation products such as 4-hydroxy-2-nonenal (4-HNE). Therefore, we investigated if 4-HNE affects TLR activation. We found that 4-HNE blocked LPS (a TLR4 agonist)-induced activation of NFkappaB and IRF3 as well as expression of IFNbeta, IP-10, RANTES, and TNFalpha. To investigate the mechanism of inhibition by 4-HNE, we examined its effects on TLR4 dimerization, one of the initial steps in TLR4 activation. 4-HNE suppressed both ligand-induced and ligand-independent receptor dimerization. The thiol donors, DTT and NAC, prevented the inhibitory effects of 4-HNE on TLR4 dimerization, and LC-MS/MS analysis showed that 4-HNE formed adducts with cysteine residues of synthetic peptides derived from TLR4. These observations suggest that the reactivity of 4-HNE with sulfhydryl moieties is implicated in the inhibition of TLR4 activation. Furthermore, inhibition of TLR4 activation by 4-HNE resulted in down-regulation of the phagocytic activity of macrophages. Collectively, these results demonstrate that 4-HNE blocks TLR4-mediated macrophage activation, gene expression, and phagocytic functions, at least partly by suppressing receptor dimerization. They further suggest that 4-HNE influences innate immune responses at sites of infection and inflammation by inhibiting TLR4 activation.}, }
@article {pmid19623661, year = {2009}, author = {Ji, L and Liu, T and Chen, Y and Wang, Z}, title = {Protective mechanisms of N-acetyl-cysteine against pyrrolizidine alkaloid clivorine-induced hepatotoxicity.}, journal = {Journal of cellular biochemistry}, volume = {108}, number = {2}, pages = {424-432}, doi = {10.1002/jcb.22269}, pmid = {19623661}, issn = {1097-4644}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 9/metabolism ; Cell Line ; Cell Survival/drug effects ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Cytochromes c/metabolism ; Cytotoxins/isolation &amp; purification/*toxicity ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Synthase/antagonists &amp; inhibitors ; Glutathione Transferase/metabolism ; Hepatocytes/*drug effects ; Humans ; Pyrrolizidine Alkaloids/isolation &amp; purification/*toxicity ; Reactive Oxygen Species/metabolism ; Thioredoxins/metabolism ; bcl-X Protein/metabolism ; }, abstract = {Pyrrolizidine alkaloid (PA) clivorine, isolated from traditional Chinese medicinal plant Ligularia hodgsonii Hook, has been shown to induce apoptosis in hepatocytes via mitochondrial-mediated apoptotic pathway in our previous research. The present study was designed to observe the protection of N-acetyl-cysteine (NAC) on clivorine-induced hepatocytes apoptosis. Our results showed that 5 mM NAC significantly reversed clivorine-induced cytotoxicity via MTT and Trypan Blue staining assay. DNA apoptotic fragmentation analysis and Western-blot results showed that NAC decreased clivorine-induced apoptotic DNA ladder and caspase-3 activation. Further results showed that NAC inhibited clivorine-induced Bcl-xL decrease, mitochondrial cytochrome c release and caspase-9 activation. Intracellular glutathione (GSH) is an important ubiquitous redox-active reducing sulfhydryl (--SH) tripeptide, and our results showed that clivorine (50 microM) decreased cellular GSH amounts and the ratio of GSH/GSSG in the time-dependent manner, while 5 mM NAC obviously reversed this depletion. Further results showed that GSH synthesis inhibitor BSO augmented clivorine-induced cytotoxicity, while exogenous GSH reversed its cytotoxicity on hepatocytes. Clivorine (50 microM) significantly induced cellular reactive oxygen species (ROS) generation. Further results showed that 50 microM Clivorine decreased glutathione peroxidase (GPx) activity and increased glutathione S transferase (GST) activity, which are both GSH-related antioxidant enzymes. Thioredoxin-1 (Trx) is also a ubiquitous redox-active reducing (--SH) protein, and clivorine (50 microM) decreased cellular expression of Trx in a time-dependent manner, while 5 mM NAC reversed this decrease. Taken together, our results demonstrate that the protection of NAC is major via maintaining cellular reduced environment and thus prevents clivorine-induced mitochondrial-mediated hepatocytes apoptosis.}, }
@article {pmid19622601, year = {2011}, author = {Vojdani, A and Lambert, J}, title = {The Role of Th17 in Neuroimmune Disorders: Target for CAM Therapy. Part II.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2011}, number = {}, pages = {984965}, pmid = {19622601}, issn = {1741-4288}, abstract = {Decades of research went into understanding the role that Th1 autoreactive T-cells play in neuroinflammation. Here we describe another effector population, the IL-17-producing T-helper lineage (Th17), which drives the inflammatory process. Through the recruitment of inflammatory infiltration neutrophils and the activation of matrix metalloproteinases, IL-17, a cytokine secreted by Th17 cells, contributes to blood-brain barrier breakdown and the subsequent attraction of macrophages and monocytes into the nervous system. The entry of cells along with the local production of inflammatory cytokines leads to myelin and axonal damage. This activation of the inflammatory response system is induced by different pathogenic factors, such as gut bacterial endotoxins resulting in progressive neurodegeneration by Th17 cells. Through the understanding of the role of bacterial endotoxins and other pathogenic factors in the induction of autoimmune diseases by Th17 cells, CAM practitioners will be able to design CAM therapies targeting IL-17 activity. Targeted therapy can restore the integrity of the intestinal and blood-brain barriers using probiotics, N-acetyl-cysteine, α-lipoic acid, resveratrol and others for their patients with autoimmunities, in particular those with neuroinflammation and neurodegeneration.}, }
@article {pmid19622383, year = {2009}, author = {Park, JS and Seo, J and Kim, YO and Lee, HS and Jo, I}, title = {Coordinated regulation of angiopoietin-1 and vascular endothelial growth factor by arsenite in human brain microvascular pericytes: implications of arsenite-induced vascular dysfunction.}, journal = {Toxicology}, volume = {264}, number = {1-2}, pages = {26-31}, doi = {10.1016/j.tox.2009.07.008}, pmid = {19622383}, issn = {1879-3185}, mesh = {Acetylcysteine/pharmacology ; Actins/biosynthesis/genetics ; Angiopoietin-1/*biosynthesis/genetics ; Arsenites/*toxicity ; Blotting, Western ; Brain Chemistry/*drug effects ; Capillaries/cytology/drug effects/metabolism ; Cells, Cultured ; Cloning, Molecular ; Dose-Response Relationship, Drug ; Humans ; Immunohistochemistry ; Pericytes/*drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; Teratogens/*toxicity ; Vascular Diseases/*chemically induced/metabolism ; Vascular Endothelial Growth Factor A/*biosynthesis/genetics ; }, abstract = {Arsenite is an environmental toxicant that is associated with vascular disease; however, the underlying mechanism of its toxicity has yet to be elucidated. Vascular stability appears to be tightly regulated by several vasoactive proteins produced by two adjacent vascular cells, endothelial cells (EC) and pericytes. The disruption of vascular stability may be involved in arsenite toxicity. The roles of angipoietins (Ang) and vascular endothelial growth factor (VEGF) in this process have been evaluated, but these studies have mostly been limited to EC. In this study, we used human brain microvascular pericytes (HBMP) to evaluate the effects of arsenite on Ang-1 and VEGF regulation. Ang-2 was reported to be not detected in HBMP. Arsenite decreased Ang-1 secretion in a time and dose-dependent manner, while it increased VEGF secretion. Although arsenite did not alter Ang-1 mRNA expression, it increased intracellular Ang-1 protein levels in a dose-dependent manner, suggesting a role for arsenite in the intracellular trapping of Ang-1. Contrary to Ang-1, the expression of VEGF mRNA was dose-dependently up-regulated by arsenite. Treatment with N-actyl-l:-cysteine (NAC) alone decreased the release of Ang-1, but failed to attenuate the arsenite-induced decrease in Ang-1 secretion, while NAC completely blocked the arsenite-stimulated VEGF secretion. These results indicate that reactive oxygen species are involved in the regulation of VEGF, but not of Ang-1, secretion in response to arsenite treatment in pericytes. Furthermore, immunocytochemical analysis using confocal microscopy revealed a colocalization of Ang-1 with actin filaments that occurred independently of tubulin. In conclusion, arsenite decreases Ang-1 secretion and increases VEGF secretion, which may offer new insight into understanding the arsenite toxicity associated with vascular instability and subsequent development of vascular disease.}, }
@article {pmid19622380, year = {2009}, author = {Han, YH and Park, WH}, title = {Propyl gallate inhibits the growth of HeLa cells via regulating intracellular GSH level.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {47}, number = {10}, pages = {2531-2538}, doi = {10.1016/j.fct.2009.07.013}, pmid = {19622380}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Catalase/metabolism ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Antagonism ; Glutathione/*metabolism ; HeLa Cells/*drug effects/metabolism/pathology ; Humans ; Propyl Gallate/*pharmacology ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Propyl gallate (PG) as a synthetic antioxidant exerts a variety of effects on tissue and cells. Here, we investigated an involvement of glutathione (GSH) and reactive oxygen species (ROS) in PG-induced inhibition of HeLa cell growth. PG dose-dependently inhibited HeLa cell growth and induced apoptosis at 24h. The intracellular ROS levels including O(2)(-) were increased or decreased in PG-treated HeLa cells depending on the incubation times (1 or 24h) and doses (100-1600 microM). PG increased activities of superoxide dismutase (SOD) and catalase in HeLa cells. PG significantly increased GSH depleted cells in a time- and dose-dependent manner. Treatment with 2 mM N-acetyl-cysteine (NAC; a well known antioxidant) slightly prevented 400 microM PG-induced cell death, which was accompanied by an increase in ROS level and a decrease in GSH depletion level. PG induced a G1 phase arrest of the cell cycle. NAC did not affect the cell cycle distributions in PG treated- or untreated-HeLa cells. Conclusively, PG inhibited the growth of HeLa cells via regulating GSH level rather than ROS level. Our present data could provide useful information on the molecular anti-growth mechanisms of PG in cancer cells in relation to ROS and GSH level.}, }
@article {pmid19620074, year = {2009}, author = {Song, WB and Lv, YH and Li, YN and Xiao, LP and Yu, XP and Liu, G and Wang, YY and Zhang, XL and Li, YF}, title = {[Changyanqing decoction produces anti-inflammatory effect by inhibiting the activation of nuclear factor-kappaB].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {29}, number = {7}, pages = {1431-1434}, pmid = {19620074}, issn = {1673-4254}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology ; Drugs, Chinese Herbal/*pharmacology ; Female ; Inflammation ; Interleukin-10/metabolism ; Interleukin-1beta/metabolism ; Intestinal Mucosa/drug effects/*metabolism/pathology ; Intestine, Small/drug effects/metabolism/pathology ; Male ; NF-kappa B/*antagonists &amp; inhibitors/metabolism ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVE: To detect the changes in intestinal mucosal permeation in rats with methotrexate-induced small intestinal damage and investigate the protective effects of Changyanqing decoction.<br><br>METHODS: Rat enteritis model was established by methotrexate (MTX) and sodium chloride. The rats were randomly divided into normal control group, model group, N-acetylcysteine (NAC) group and Changyanqing decoction group, and Changyanqing decoction (100 mg/kg) or saline was administered daily in the corresponding groups by gastric irrigation for 6 days. The disease activity index (DAI), colonic mucosal damage index (CMDI) and histological score (HS) of the rats were observed and evaluated. The levels of mRNA expressions of TNF-alpha and IL-1beta were detected by semi-quantitative RT-PCR. The expression of IL-10 was detected by enzyme linked immunosorbent assay, and IkappaB expression was determined with Western blotting.<br><br>RESULTS: Compared with the normal control group, the model group showed significantly increased DAI, CMDI and HS. The DAI, CMDI, and HS in rats treated with Changyanqing decoction were significantly decreased in comparison with those in the model group (P<0.01). The expressions of TNF-alpha and IL-1beta were significantly higher in MTX-treated group than in the control group. The expression of TNF-alpha and IL-1beta mRNA in the Changyanqing group and NAC group were significantly lower, but IL-10 significantly higher than those of the MTX group. In MTX group, obvious NF-kappaB activation was observed, whose expression was significantly stronger in the cell nuclei, and the IkappaB in the cytoplasm was markedly degraded.<br><br>CONCLUSION: Changyanqing decoction offers protection on intestinal mucosa by inhibiting NF-kappaB activation to reduce TNF-alpha and IL-1beta mRNA expressions and increase IL-10 expression.}, }
@article {pmid19616335, year = {2009}, author = {Rouschop, KM and Ramaekers, CH and Schaaf, MB and Keulers, TG and Savelkouls, KG and Lambin, P and Koritzinsky, M and Wouters, BG}, title = {Autophagy is required during cycling hypoxia to lower production of reactive oxygen species.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {92}, number = {3}, pages = {411-416}, doi = {10.1016/j.radonc.2009.06.029}, pmid = {19616335}, issn = {1879-0887}, mesh = {Analysis of Variance ; Autophagy/drug effects/*physiology ; Blotting, Western ; Cell Death/drug effects/physiology ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Chloroquine/*pharmacology ; DNA, Mitochondrial/drug effects/*metabolism ; Flow Cytometry ; Humans ; *Hypoxia ; Oxidative Stress/drug effects/physiology ; Probability ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured/drug effects/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Human tumors are characterized by the presence of cells that experience periodic episodes of hypoxia followed by reoxygenation. These cells are exposed to reactive oxygen species (ROS) upon reoxygenation and require adaptation to this stress by lowering ROS production or enhancing ROS-clearance for their survival. We hypothesized that autophagy, a lysosomal degradation pathway, may be involved in reducing ROS during periodic hypoxia through removal of ROS producing species.<br><br>MATERIALS AND METHODS: Human tumor cells (MCF-7, HT29, U373) were exposed to cycles of hypoxia (O(2)<0.02%) and reoxygenation in the absence or presence of the autophagy inhibitor chloroquine (CQ). Clonogenic survival, ROS production and mitochondrial-DNA content were assessed. In addition, A549 cells overexpressing wild-type or K63-mutated ubiquitin (K63R) were analyzed for ROS production.<br><br>RESULTS: Our data indicate that CQ treatment sensitizes cells to cycling hypoxia, due to increased production of ROS, associated with an incapacity to reduce mitochondrial content. Addition of the ROS-scavenger N-acetyl-cysteine increased cell viability and neutralized CQ-effects. Additionally, genetic prevention of K63-linked ubiquitin chains that are required for the removal of toxic protein aggregates by autophagy, resulted in increased ROS production.<br><br>CONCLUSIONS: Inhibition of autophagy substantially increases cell death induced by cycling hypoxia through increased ROS production, providing an opportunity to decrease the hypoxic fraction within tumors and enhance tumor therapy.}, }
@article {pmid19615393, year = {2009}, author = {Gupta, RK and Meachum, S and Hernández-Ochoa, I and Peretz, J and Yao, HH and Flaws, JA}, title = {Methoxychlor inhibits growth of antral follicles by altering cell cycle regulators.}, journal = {Toxicology and applied pharmacology}, volume = {240}, number = {1}, pages = {1-7}, pmid = {19615393}, issn = {1096-0333}, support = {HD 46861/HD/NICHD NIH HHS/United States ; R01 ES012893/ES/NIEHS NIH HHS/United States ; T32 ES007326/ES/NIEHS NIH HHS/United States ; T32 ES07326/ES/NIEHS NIH HHS/United States ; R01 ES012893-02/ES/NIEHS NIH HHS/United States ; R01 ES012893-03/ES/NIEHS NIH HHS/United States ; R01 ES012893-01A2/ES/NIEHS NIH HHS/United States ; R01 HD046861/HD/NICHD NIH HHS/United States ; R01 ES012893-04/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology/physiology ; Cell Cycle/drug effects/*physiology ; Cell Cycle Proteins/antagonists &amp; inhibitors/*physiology ; Cells, Cultured ; Female ; Follicular Fluid/drug effects/*physiology ; Growth Inhibitors/antagonists &amp; inhibitors/physiology ; Hydrogen Peroxide/pharmacology ; Methoxychlor/*pharmacology ; Mice ; }, abstract = {Methoxychlor (MXC) reduces fertility in female rodents, decreases antral follicle numbers, and increases atresia through oxidative stress pathways. MXC also inhibits antral follicle growth in vitro. The mechanism by which MXC inhibits growth of follicles is unknown. The growth of follicles is controlled, in part, by cell cycle regulators. Thus, we tested the hypothesis that MXC inhibits follicle growth by reducing the levels of selected cell cycle regulators. Further, we tested whether co-treatment with an antioxidant, N-acetyl cysteine (NAC), prevents the MXC-induced reduction in cell cycle regulators. For in vivo studies, adult cycling CD-1 mice were dosed with MXC or vehicle for 20 days. Treated ovaries were subjected to immunohistochemistry for proliferating cell nuclear antigen (PCNA) staining. For in vitro studies, antral follicles isolated from adult cycling CD-1 mouse ovaries were cultured with vehicle, MXC, and/or NAC for 48, 72 and 96 h. Levels of cyclin D2 (Ccnd2) and cyclin dependent kinase 4 (Cdk4) were measured using in vivo and in vitro samples. The results indicate that MXC decreased PCNA staining, and Ccnd2 and Cdk4 levels compared to controls. NAC co-treatment restored follicle growth and expression of Ccnd2 and Cdk4. Collectively, these data indicate that MXC exposure reduces the levels of Ccnd2 and Cdk4 in follicles, and that protection from oxidative stress restores Ccnd2 and Cdk4 levels. Therefore, MXC-induced oxidative stress may decrease the levels of cell cycle regulators, which in turn, results in inhibition of the growth of antral follicles.}, }
@article {pmid19609650, year = {2009}, author = {Lira, SR and Rao, VS and Carvalho, AC and Guedes, MM and de Morais, TC and de Souza, AL and Trevisan, MT and Lima, AF and Chaves, MH and Santos, FA}, title = {Gastroprotective effect of lupeol on ethanol-induced gastric damage and the underlying mechanism.}, journal = {Inflammopharmacology}, volume = {17}, number = {4}, pages = {221-228}, pmid = {19609650}, issn = {1568-5608}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage/*pharmacology ; Calcium/metabolism ; Central Nervous System Depressants/toxicity ; Dose-Response Relationship, Drug ; Ethanol/*toxicity ; Gastric Mucosa/*drug effects/pathology ; KATP Channels/drug effects/metabolism ; Male ; Mice ; Nitric Oxide/metabolism ; Pentacyclic Triterpenes ; Prostaglandins/metabolism ; Rats ; Rats, Wistar ; Receptors, Adrenergic, alpha-2/drug effects/metabolism ; Sulfhydryl Compounds/metabolism ; Triterpenes/administration &amp; dosage/*pharmacology ; }, abstract = {The effect of lupeol, a natural pentacyclic triterpene on ethanol-induced gastric damage in mice was evaluated. The gastroprotection was assessed by determination of changes in mean gastric lesion area, quantification of mucosal non-protein sulfhydryls (NP-SH), and characterized using drugs that influence the endogenous prostaglandins, alpha(2)-adrenoceptors, nitric oxide, K(ATP)-channels, and intracellular calcium. Orally administered lupeol (3, 10, and 30 mg/kg) significantly and dose-dependently attenuated the ethanol-induced gastric damage by 39-69%, whereas the positive control N-acetylcysteine (NAC, 300 mg/kg, i.p.) afforded 32% protection. Both lupeol and NAC restored the NP-SH depleted by ethanol but the lupeol effect was only marginal. Lupeol gastroprotection was attenuated by indomethacin and L-NAME, the respective COX and NO-synthase inhibitors and was weakly sensitive to alpha(2)-adrenergic antagonist yohimbine and K(ATP)-channel blocker glibenclamide, but more profoundly to calcium blocker verapamil. These pharmacological effects of lupeol may synergistically contribute to alleviating the ethanol-associated gastric damage, which is multifactorial.}, }
@article {pmid19607909, year = {2009}, author = {Ahmed, T and Tripathi, AK and Suke, SG and Kumar, V and Ahmed, RS and Das, S and Banerjee, BD}, title = {Role of HSP27 and reduced glutathione in modulating malathion-induced apoptosis of human peripheral blood mononuclear cells: ameliorating effect of N-acetylcysteine and curcumin.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {23}, number = {7}, pages = {1319-1325}, doi = {10.1016/j.tiv.2009.07.016}, pmid = {19607909}, issn = {1879-3177}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Curcumin/*pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism ; HSP27 Heat-Shock Proteins/*metabolism ; Humans ; Leukocytes, Mononuclear/drug effects/metabolism ; Malathion/*toxicity ; Oxidative Stress/drug effects ; Pesticides/*toxicity ; Protective Agents/*pharmacology ; Toxicity Tests ; }, abstract = {Malathion exerts cholinergic effects at high doses. However, a consequence of low dose (non-cholinergic) exposure causes immunotoxicity and oxidative stress. Hence, this study was designed to find out (i) the cytotoxic and apoptotic effects of cholinergic and non-cholinergic doses of malathion using cultured peripheral blood mononuclear cells (PBMCs) and (ii) the role of GSH and HSP27 and (iii) protective effects of N-acetylcysteine (GSH inducer) and curcumin (HSP27 inducer). In low doses, malathion caused mild depletion of GSH, threefold increase in HSP27 level and a range bound cytotoxicity and apoptosis of PBMC. In contrast, cholinergic dose exposures caused severe GSH depletion and exhibited dose dependent cytotoxicity and necrosis without any significant effect on HSP27 levels. Curcumin increased the levels of HSP27 in PBMC only in presence of low doses and not at high doses of malathion. Both NAC and curcumin were able to prevent malathion-mediated apoptosis of PBMC effectively at non-cholinergic doses and at this concentration of malathion, HSP27 induction keeps apoptosis and GSH depletion under control. Also NAC and curcumin may act as potential therapeutic agents to prevent malathion-induced immunotoxicity.}, }
@article {pmid19604316, year = {2009}, author = {Ramudo, L and Yubero, S and Manso, MA and Vicente, S and De Dios, I}, title = {Signal transduction of MCP-1 expression induced by pancreatitis-associated ascitic fluid in pancreatic acinar cells.}, journal = {Journal of cellular and molecular medicine}, volume = {13}, number = {7}, pages = {1314-1320}, pmid = {19604316}, issn = {1582-4934}, mesh = {Animals ; Ascitic Fluid/*metabolism ; Cell Survival ; Chemokine CCL2/genetics/*metabolism ; Gene Expression Regulation ; NF-kappa B/metabolism ; Pancreas, Exocrine/enzymology/*metabolism/*pathology ; Pancreatitis/*metabolism ; Phosphorylation ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Wistar ; STAT3 Transcription Factor/metabolism ; *Signal Transduction ; Time Factors ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Pancreatitis-associated ascitic fluid (PAAF) is known to contribute to the progression of acute pancreatitis (AP). We have investigated the capability of PAAF to activate the expression of MCP-1 in pancreatic acinar cells and the involvement of MAPK, NF-kappaB and STAT3 as downstream signalling transduction pathways. The actions of dexamethasone (Dx) and N-acetylcysteine (NAC) on the PAAF's acinar effects have also been evaluated. Acinar cells were incubated for 1 hr with PAAF collected from rats with severe AP induced by sodium taurocholate in the absence or presence of Dx (10(-7) M) or NAC (30 mM). MCP-1 mRNA expression, phospho-p38-MAPK, IkappaB alpha, nuclear p65 levels and nuclear translocation of STAT3 were analysed. In response to PAAF, overexpression of MCP-1, phosphorylation of p38-MAPK, degradation of IkappaB alpha and increases in p65 nuclear levels and STAT3 activity were found in acinar cells. PAAF-mediated MCP-1 up-regulation was completely suppressed by Dx and NAC. MAPK activation was only inhibited by NAC, NF-kappaB activation was repressed by Dx and NAC, and STAT3 pathway was strongly blocked by Dx and significantly reduced by NAC. In conclusion, acinar cells were activated by PAAF to produce MCP-1, mainly via NF-kappaB and STAT3 pathways. Both downstream pathways were targeted by Dx and NAC to repress the PAAF-mediated acinar MCP-1 up-regulation.}, }
@article {pmid19595646, year = {2009}, author = {Tsikas, D and Dehnert, S and Urban, K and Surdacki, A and Meyer, HH}, title = {GC-MS analysis of S-nitrosothiols after conversion to S-nitroso-N-acetyl cysteine ethyl ester and in-injector nitrosation of ethyl acetate.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {877}, number = {28}, pages = {3442-3455}, doi = {10.1016/j.jchromb.2009.06.032}, pmid = {19595646}, issn = {1873-376X}, mesh = {Acetates/*chemistry ; Adult ; Animals ; Cysteine/administration &amp; dosage/*analogs &amp; derivatives/blood/chemistry ; Female ; Gas Chromatography-Mass Spectrometry/instrumentation/*methods ; Humans ; Male ; Nitrosation ; Rabbits ; S-Nitrosothiols/blood/*chemistry ; Young Adult ; }, abstract = {S-Nitrosothiols from low-molecular-mass and high-molecular-mass thiols, including glutathione, albumin and hemoglobin, are endogenous potent vasodilators and inhibitors of platelet aggregation. By utilizing the S-transnitrosation reaction and by using the lipophilic (pK(L) 0.78) and strong nucleophilic synthetic thiol N-acetyl cysteine ethyl ester (NACET) we have developed a GC-MS method for the analysis of S-nitrosothiols and their (15)N- or (2)H-(15)N-labelled analogs as S-nitroso-N-acetyl cysteine ethyl ester (SNACET) and S(15)NACET or d(3)-S(15)NACET derivatives, respectively, after their extraction with ethyl acetate. Injection of ethyl acetate solutions of S-nitrosothiols produced two main reaction products, compound X and compound Y, within the injector in dependence on its temperature. Quantification was performed by selected-ion monitoring of m/z 46 (i.e., [NO(2)](-)) for SNACET and m/z 47 (i.e., [(15)NO(2)](-)) for S(15)NACET/d(3)-S(15)NACET for compound X, and m/z 157 for SNACET and m/z 160 for d(3)-S(15)NACET for compound Y. In this article we describe the development, validation and in vitro and in vivo applications of the method to aqueous buffered solutions, human and rabbit plasma. Given the ester functionality of SNACET/S(15)NACET/d(3)-S(15)NACET, stability studies were performed using metal chelators and esterase inhibitors. The method was found to be suitable for the quantitative determination of various S-nitrosothiols including SNACET externally added to human plasma (0-10microM). Nitrite contamination in ethyl acetate was found to interfere. Our results suggest that the concentration of endogenous S-nitrosothiols in human plasma does not exceed about 200nM in total. Oral administration of S(15)NACET to rabbits (40-63micromol/kg body weight) resulted in formation of ALB-S(15)NO, [(15)N]nitrite and [(15)N]nitrate in plasma.}, }
@article {pmid19592481, year = {2011}, author = {Sun, L and Chen, T and Wang, X and Chen, Y and Wei, X}, title = {Bufalin Induces Reactive Oxygen Species Dependent Bax Translocation and Apoptosis in ASTC-a-1 Cells.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2011}, number = {}, pages = {249090}, pmid = {19592481}, issn = {1741-4288}, abstract = {Bufalin has been shown to induce cancer cell death through apoptotic pathways. However, the molecular mechanisms are not well understood. In this study, we used the confocal fluorescence microscopy (CFM) to monitor the spatio-temporal dynamics of reactive oxygen species (ROS) production, Bax translocation and caspase-3 activation during bufalin-induced apoptosis in living human lung adenocarcinoma (ASTC-a-1) cells. Bufalin induced ROS production and apoptotic cell death, demonstrated by Hoechst 33258 staining as well as flow cytometry analysis. Bax redistributed from cytosol to mitochondria from 12 to 48 h after bufalin treatment in living cells expressed with green fluorescent protein Bax. Treatment with the antioxidant N-acetyl-cysteine (NAC), a ROS scavenger, inhibited ROS generation and Bax translocation and led to a significant protection against bufalin-induced apoptosis. Our results also revealed that bufalin induced a prominent increase of caspase-3 activation blocked potently by NAC. Taken together, bufalin induced ROS-mediated Bax translocation, mitochondrial permeability transition and caspase-3 activation, implying that bufalin induced apoptosis via ROS-dependent mitochondrial death pathway in ASTC-a-1 cells.}, }
@article {pmid19591643, year = {2009}, author = {Gupta, AK and Chan, GM and Greller, HA and Su, MK}, title = {NAC: still the way to go.}, journal = {Critical care (London, England)}, volume = {13}, number = {3}, pages = {411; author reply 411}, pmid = {19591643}, issn = {1466-609X}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*adverse effects/therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Animals ; Antidotes/*adverse effects/therapeutic use ; *Drug-Related Side Effects and Adverse Reactions ; Humans ; Liver Failure/*chemically induced/drug therapy ; Mice ; }, }
@article {pmid19591160, year = {2009}, author = {de Graaf, R and Tintu, A and Stassen, F and Kloppenburg, G and Bruggeman, C and Rouwet, E}, title = {N-acetylcysteine prevents neointima formation in experimental venous bypass grafts.}, journal = {The British journal of surgery}, volume = {96}, number = {8}, pages = {941-950}, doi = {10.1002/bjs.6659}, pmid = {19591160}, issn = {1365-2168}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Arteriovenous Anastomosis ; Blood Vessel Prosthesis ; Cell Proliferation/drug effects ; Cells, Cultured ; Cytokines/metabolism ; Femoral Artery ; Free Radical Scavengers/*pharmacology ; Male ; Myocytes, Smooth Muscle ; Rats ; Rats, Inbred Lew ; Tunica Intima/*drug effects ; Veins ; }, abstract = {BACKGROUND: Neointima formation, mainly characterized by smooth muscle cell proliferation, is an important cause of venous bypass graft failure. The therapeutic potential of the antioxidant N-acetylcysteine (NAC) to attenuate smooth muscle cell proliferation and neointima formation was examined in vivo. The effects of NAC on hyperoxia-induced venous smooth muscle cell (VSMC) cytokine production and proliferation were addressed in vitro.<br><br>METHODS: Rats underwent autologous epigastric vein-to-femoral artery interposition grafting. Fourteen rats received oral NAC, and a similar control group received saline. Histomorphometric analysis was performed after 7 days or 3 weeks. Cytokine analysis and cell proliferation assay were performed in cultured human VSMCs after hyperoxic or normoxic exposure and NAC administration.<br><br>RESULTS: NAC-treated rats displayed a threefold reduction in neointimal area, a sixfold reduction in stenosis rate, and a twofold reduction in VSMC proliferation after vein graft surgery. Incubation of VSMCs in 70 per cent oxygen stimulated the release of mitogenic inflammatory cytokines interleukin (IL) 6 and IL-8. Cytokine-rich medium from these VSMCs induced proliferation of normoxic VSMCs. NAC inhibited hyperoxia-induced cytokine release and VSMC proliferation.<br><br>CONCLUSION: NAC attenuated neointima formation and vein graft stenosis by reducing VSMC proliferation in vivo, and prevented hyperoxia-induced cytokine production and VSMC proliferation in vitro.}, }
@article {pmid19585524, year = {2009}, author = {Sirangelo, I and Iannuzzi, C and Vilasi, S and Irace, G and Giuberti, G and Misso, G and D'Alessandro, A and Abbruzzese, A and Caraglia, M}, title = {W7FW14F apomyoglobin amyloid aggregates-mediated apoptosis is due to oxidative stress and AKT inactivation caused by Ras and Rac.}, journal = {Journal of cellular physiology}, volume = {221}, number = {2}, pages = {412-423}, doi = {10.1002/jcp.21871}, pmid = {19585524}, issn = {1097-4652}, mesh = {Amyloid/chemistry/*pharmacology ; Animals ; Apoproteins/*chemistry ; Apoptosis/*drug effects ; Benzamides/pharmacology ; Cell Line ; Cell Survival/drug effects ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors ; Humans ; Mice ; Microscopy, Fluorescence ; Mitochondria/drug effects/metabolism ; Models, Biological ; Mutant Proteins/chemistry/pharmacology ; Myoglobin/*chemistry ; Oxidative Stress/*drug effects ; Protein Structure, Quaternary ; Proto-Oncogene Proteins c-akt/*metabolism ; Quinolones/pharmacology ; rac GTP-Binding Proteins/antagonists &amp; inhibitors/*metabolism ; ras Proteins/antagonists &amp; inhibitors/*metabolism ; }, abstract = {We have previously reported that addition of prefibrillar aggregates (PFAs) derived from W7FW14F apomyoglobin mutant to NIH-3T3 cells affects their viability. In this article, we have found that cytotoxicity induced by PFAs in NIH 3T3 and SH-SY5Y human neuroblastoma cells was due to early activation of apoptotic cell death dependent from a caspase-3- and -9-mediated mitochondrial pathway. A time-dependent increase of intracellular ROS and an about twofold decrease of mitochondrial localization of scavenger protein MnSOD was found. The use of the anti-oxidant agent N-acetyl-cysteine (NAC) antagonized both the increase of intracellular ROS and apoptosis induced by PFAs. PFAs caused an about 60% increase of the activity of both Ras and Erk-1/2 at 30 and 45 min while they were restored to basal levels at later time points. This effect was paralleled by a time-dependent decrease of the activity of the survival enzyme Akt. Effects similar to those on Ras activity were also recorded on the activity of the stress involved small GTP binding protein Rac that was about 75% increased after 30 min but resumed to basal levels at later time points. This effect was paralleled by a time-dependent activation of p38 kinase activity and HSP-70 expression. The use of both the ras farnesyltransferase inhibitor tipifarnib and the Rac geranyl-geranyltransferase GGTI-298, but not of the MEK-1 inhibitor U0126 partially antagonized the effects of PFAs on apoptosis occurrence. On the other hand, the PI3K/Akt inhibitor LY 294002 potentiated apoptosis induced by PFAs. Our results indicate a role for Ras and Rac in the induction of both intracellular ROS increased levels and apoptosis mediated by PFAs and disclose a new scenario of intervention in neurodegenerative diseases.}, }
@article {pmid19580823, year = {2009}, author = {Shibamura, A and Ikeda, T and Nishikawa, Y}, title = {A method for oral administration of hydrophilic substances to Caenorhabditis elegans: Effects of oral supplementation with antioxidants on the nematode lifespan.}, journal = {Mechanisms of ageing and development}, volume = {130}, number = {9}, pages = {652-655}, doi = {10.1016/j.mad.2009.06.008}, pmid = {19580823}, issn = {1872-6216}, mesh = {Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Caenorhabditis elegans/*drug effects/genetics ; Dose-Response Relationship, Drug ; Fluorescein/metabolism ; Fluorescent Dyes/metabolism ; Liposomes/metabolism ; Longevity/*drug effects ; Nematoda/*metabolism ; Solubility ; Time Factors ; Water/chemistry ; }, abstract = {Numerous studies using Caenorhabditis elegans have used a protocol in which chemicals are orally delivered by incorporating them into the nematode growth media or mixing them with the food bacteria. However, actual exposure levels are difficult to estimate as they are influenced by both the rates of ingestion into the intestine as well as absorption from the intestinal lumen. We used liposomes loaded with the hydrophilic fluorescent reagent uranin to test oral administration of water-soluble substances to C. elegans. Ingestion of liposomes loaded with fluorescent dye resulted in successful oral delivery of chemicals into the intestines of C. elegans. Using liposomes, oral administration of hydrophilic antioxidants (ascorbic acid, N-acetyl-cysteine, reduced glutathione, and thioproline) prolonged the lifespan of the nematodes, whereas the conventional method of delivery showed neither fluorescence nor longevity effects. Our method efficiently and quantitatively delivers solutes to nematodes.}, }
@article {pmid19578781, year = {2009}, author = {Han, YH and Park, WH}, title = {The effects of N-acetyl cysteine, buthionine sulfoximine, diethyldithiocarbamate or 3-amino-1,2,4-triazole on antimycin A-treated Calu-6 lung cells in relation to cell growth, reactive oxygen species and glutathione.}, journal = {Oncology reports}, volume = {22}, number = {2}, pages = {385-391}, pmid = {19578781}, issn = {1021-335X}, mesh = {Acetylcysteine/*pharmacology ; Adenocarcinoma/*drug therapy/metabolism/pathology ; Amitrole/*pharmacology ; Antimycin A/*pharmacology ; Buthionine Sulfoximine/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Ditiocarb/*pharmacology ; Glutathione/*analysis ; Humans ; Lung Neoplasms/*drug therapy/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Antimycin A (AMA) inhibits mitochondrial electron transport between cytochrome b and c. We recently demonstrated that AMA inhibits the growth of lung cancer Calu-6 cells and the changes of reactive oxygen species (ROS) and glutathione (GSH) levels affect apoptosis in Calu-6 cells. Here, we examined the effects of N-acetyl-cysteine (NAC, a well known antioxidant), L-buthionine sulfoximine (BSO, an inhibitor of GSH synthesis), diethyl-dithiocarbamate (DDC, an inhibitor of Cu, Zn-SOD) or 3-amino-1,2,4-triazole (AT, an inhibitor of catalase) on AMA-treated Calu-6 cells in relation to cell death, ROS and GSH levels. Treatment with AMA induced cell growth inhibition, apoptosis and the loss of mitochondrial membrane potential (MMP) (DeltaPsim) in Calu-6 cells. While the intracellular ROS level was decreased in 50 microM AMA-treated Calu-6 cells, O2.- levels among ROS were significantly increased. AMA also induced GSH depletion in Calu-6 cells. Treatment with NAC showed decreasing effect on O2.- levels in AMA-treated cells preventing apoptosis, MMP (DeltaPsim) loss and GSH depletion in these cells. BSO significantly increased GSH depletion and apoptosis in AMA-treated cells. While both DDC and AT increased ROS levels in AMA-treated Calu-6 cells, only DDC intensified GSH depletion and apoptosis. BSO and AT increased the ROS level in Calu-6 control cells, but these agents did not induce apoptosis and GSH depletion. In conclusion, our results suggest that GSH depletion rather than ROS level in AMA-treated Calu-6 cells is more tightly related to apoptosis.}, }
@article {pmid19575001, year = {2009}, author = {Xu, P and Qu, JM and Xu, JF and Zhang, J and Jiang, HN and Zhang, HJ}, title = {NAC is associated with additional alleviation of lung injury induced by invasive pulmonary aspergillosis in a neutropenic model.}, journal = {Acta pharmacologica Sinica}, volume = {30}, number = {7}, pages = {980-986}, pmid = {19575001}, issn = {1745-7254}, mesh = {Acetylcysteine/*therapeutic use ; Amphotericin B/therapeutic use ; Animals ; Antifungal Agents/therapeutic use ; Disease Models, Animal ; Humans ; Interleukin-10/analysis ; *Invasive Pulmonary Aspergillosis/drug therapy/pathology ; *Lung Injury/drug therapy/pathology/prevention &amp; control ; Male ; Mice ; Mice, Inbred BALB C ; Neutropenia/*drug therapy ; Oxidative Stress ; Random Allocation ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/analysis ; }, abstract = {AIM: Neutropenic individuals are at high risk for invasive pulmonary aspergillosis (IPA), a life-threatening infection. To evaluate the therapeutic potential of antioxidants, IPA was induced in neutropenic mice and the effect of N-acetyl-l-cysteine (NAC) on oxidative stress levels and lung injury was analyzed.<br><br>METHODS: Mice were pretreated with three daily intraperitoneal injections of 150 mg/kg cyclophosphamide, followed by intratracheal inoculation with 4.5x10(6) conidia of Aspergillus fumigatus. The infected mice were then randomly assigned to an amphotericin B (AMB) group, an AMB plus NAC group, or an untreated control (C) group. In each group, the duration of treatment was 24, 48, or 72 h, and activities such as appearance, feeding, and dermal temperature were observed throughout the experiment. Sera and lung tissues were collected and analyzed by quantitative enzyme-linked immunosorbent assay (ELISA) for total protein, superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) levels. The wet/dry weight ratio of the lung was also calculated and lung sections were stained with hematoxylin-eosin for pathological examination and with methenamine silver stain for fungus detection.<br><br>RESULTS: Compared with the mice untreated with NAC, mice in the AMB plus NAC group had increased SOD and reduced MDA levels both systemically and locally at 24, 48, and 72 h after inoculation with conidia. NAC treatment also decreased the pulmonary protein content at 48 and 72 h and the lung wet/dry weight ratio at 24 and 48 h. Additionally, NAC enhanced pulmonary production of TNF-alpha and IL-10 at 24 h and 48 h.<br><br>CONCLUSION: In combination with antifungal therapy, NAC treatment can alleviate oxidative stress and lung injury associated with IPA in neutropenic mice.Acta Pharmacologica Sinica (2009) 30: 980-986; doi: 10.1038/aps.2009.83.}, }
@article {pmid19574996, year = {2009}, author = {Qian, HR and Yang, Y}, title = {Neuron differentiation and neuritogenesis stimulated by N-acetylcysteine (NAC).}, journal = {Acta pharmacologica Sinica}, volume = {30}, number = {7}, pages = {907-912}, pmid = {19574996}, issn = {1745-7254}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Cell Differentiation/*drug effects/physiology ; Cells, Cultured ; *Embryonic Stem Cells/cytology/drug effects/physiology ; Free Radical Scavengers/*pharmacology ; Mice ; Neurites/*metabolism/ultrastructure ; Neurogenesis/*drug effects/physiology ; *Neurons/cytology/drug effects/physiology ; Tretinoin/pharmacology ; }, abstract = {AIM: To investigate the effect of N-acetylcysteine (NAC), a potent antioxidant, on neuron differentiation of cultured mouse embryonic stem cells (ESCs) induced by retinoic acid (RA) in vitro. Superior cervical ganglion (SCG) neurons were used to study the effect of NAC on neuritogenesis.<br><br>METHODS: Immunoblotting was performed to detect the expression of microtubule-associated protein 2 (MAP2). MTT assays were used to determine cell viability. Cell death was estimated with trypan blue exclusion and Hoechst 33342 staining. Immunocytochemical analysis was carried out to identify neurons.<br><br>RESULTS: We obtained a high percentage of MAP2-positive neurons derived from embryoid bodies (EBs) induced by RA by administering 1 mmol/L NAC at differentiation day 0. On differentiation day 8, the expression of MAP2 protein was strongly upregulated in the presence of NAC. NAC promoted neuron differentiation of ES cells in a dose- and time-dependent manner. Notably, NAC suppressed cell death caused by RA during neuron differentiation. In addition, neurite extension of SCG neurons was greatly stimulated in the presence of NAC.<br><br>CONCLUSION: These results show that NAC enhanced both neuron differentiation and neuritogenesis, suggesting that it may be used in the development of novel therapeutic approaches targeting neuron loss and neurite dystrophy in neurodegenerative diseases.Acta Pharmacologica Sinica (2009) 30: 907-912; doi: 10.1038/aps.2009.72.}, }
@article {pmid19569086, year = {2009}, author = {Yajima, D and Motani, H and Hayakawa, M and Sato, Y and Sato, K and Iwase, H}, title = {The relationship between cell membrane damage and lipid peroxidation under the condition of hypoxia-reoxygenation: analysis of the mechanism using antioxidants and electron transport inhibitors.}, journal = {Cell biochemistry and function}, volume = {27}, number = {6}, pages = {338-343}, doi = {10.1002/cbf.1578}, pmid = {19569086}, issn = {1099-0844}, mesh = {Animals ; Antioxidants/*pharmacology ; Cell Death ; *Cell Hypoxia ; Cell Membrane/*metabolism ; Cell Membrane Permeability/drug effects/*physiology ; Cells, Cultured ; Electron Transport/drug effects/*physiology ; Fluorescent Dyes ; Lipid Peroxidation/drug effects/*physiology ; Mice ; Oxygen/*physiology ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/metabolism ; Time Factors ; }, abstract = {We consecutively observed lipid peroxidation and cell membrane damage under the condition of hypoxia-reoxygenation (H/R) in cells and analyzed their mechanisms by using electron transport inhibitors and an antioxidant. In H/R experiments, lipid peroxidation and cell membrane damage were observed during the hypoxia phase. In the reoxygenation phase, lipid peroxidation stopped, while cell membrane damage did not. An antioxidant, n-acetylcystein (NAC), and potassium cyanide (KCN) inhibited lipid peroxidation and cell membrane damage, while rotenone did not inhibit either of them. Although antimycin A did not inhibit lipid peroxidation, it inhibited cell membrane damage during the hypoxia phase but not during the reoxygenation phase. These results suggested that lipid peroxidation can affect cell membrane damage as a trigger during the hypoxia phase and the generation of oxidative stress can vary depending on the inhibition locations in the electron transport system.}, }
@article {pmid19566031, year = {2009}, author = {Filatova, NA and Kirpichnikova, KM and Vakhromova, EA and Gamaleĭ, IA}, title = {[Effect of alpha-lipoic acid on the sensitivity of transformed fibroblasts to lysis by natural killer cells. Comparison with NAC action].}, journal = {Tsitologiia}, volume = {51}, number = {5}, pages = {398-402}, pmid = {19566031}, issn = {0041-3771}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; BALB 3T3 Cells ; Cell Line, Transformed ; Cell Transformation, Viral/*drug effects/immunology ; Cytotoxicity, Immunologic ; Fibroblasts/*drug effects/immunology ; Free Radical Scavengers/pharmacology ; Killer Cells, Natural/*immunology ; Mice ; Thioctic Acid/*pharmacology ; }, abstract = {The purpose of this study was to compare the effects of two antioxidants, alpha-lipoic acid (ALA) and N-acetylcysteine (NAC) on the sensitivity of 3T3-SV40 fibroblasts to lytic activity of natural killer (NK) cells. ALA (1.25 mM) reduced significantly the fibroblast sensitivity in several hours, whereas NAC (10 mM) did not change it. Subsequent removal of the antioxidants from the cultivation medium resulted in gradual recovery of the sensitivity in the case of ALA and in complete loss of it in the case of NAC. Inactivation of gelatinase MMP-2 (matrix metalloproteinase) using pretreatment of the cells with the inhibitor of MMP, G6001, or specific antibodies to MMP-2 or MMP-9 resulted in decrease of 3T3-SV40 sensitivity to NK cells activity. This effect was similar to that of ALA, not to the NAC one. Pretreatment of NK cells with G6001 did not influence their lytic activity. The results obtained demonstrate that the direct antioxidant, NAC (having reduced thiol groups), and the indirect one, ALA (reducing thiol groups and acting as a direct antioxidant only inside the cell) activate principally different intracellular signal pathways. However, both NAC and ALA pathway includes inactivation of MMP-2.}, }
@article {pmid19564816, year = {2009}, author = {Theneshkumar, S and Lorito, G and Giordano, P and Petruccelli, J and Martini, A and Hatzopoulos, S}, title = {Effect of noise conditioning on cisplatin-induced ototoxicity: a pilot study.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {15}, number = {7}, pages = {BR173-7}, pmid = {19564816}, issn = {1643-3750}, mesh = {Animals ; Cisplatin/administration &amp; dosage/*adverse effects/pharmacology ; Hearing Loss/*chemically induced ; Male ; Noise/*adverse effects ; Pilot Projects ; Rats ; Rats, Sprague-Dawley ; Survival Analysis ; Weight Loss/drug effects ; }, abstract = {BACKGROUND: Cisplatin is a platinum-based chemotherapeutic agent that is highly effective in the treatment of cancer. Ototoxicity is an important dose-limiting adverse effect of cisplatin, in addition to nephrotoxicity. Studies have shown that cisplatin-induced ototoxicity is mainly a result of generated reactive oxygen species. Sulfur-containing compounds such as L-N acetylcysteine (L-NAC) and D-methionine (D-MET) have shown promising results as potent otoprotectors against cisplatin-induced ototoxicity in animal studies.<br><br>MATERIAL/METHODS: In this study, we investigated a method to increase the efficacy of L-NAC and D-MET without increasing dose. Sprague Dawley rats were noise conditioned for 15 minutes immediately after intraperitoneal injection of 275 mg/kg L-NAC or 300 mg/kg D-MET. Another set of rats received 275 mg/kg L-NAC or 300 mg/kg D-MET alone, and 1 group underwent noise conditioning alone. All 5 groups were administered 14 mg/kg cisplatin intravenously 1 hour after otoprotector injection or 45 minutes after noise conditioning.<br><br>RESULTS: Otoprotectors and noise conditioning, alone or in combination, were analyzed for their ability to reduce cisplatin-induced ototoxicity. The results indicated that the combination of 275 mg/kg L-NAC and noise conditioning afforded more otoprotection than 275 mg/kg L-NAC alone. In the case of D-MET, 300 mg/kg plus noise conditioning was little better than 300 mg/kg D-MET alone. In addition, we found that noise conditioning alone showed otoprotection against cisplatin-induced ototoxicity.<br><br>CONCLUSIONS: The ability of noise conditioning to protect against cisplatin-induced ototoxicity requires additional study.}, }
@article {pmid19563648, year = {2009}, author = {Amini, M and Salarifar, M and Amirbaigloo, A and Masoudkabir, F and Esfahani, F}, title = {N-acetylcysteine does not prevent contrast-induced nephropathy after cardiac catheterization in patients with diabetes mellitus and chronic kidney disease: a randomized clinical trial.}, journal = {Trials}, volume = {10}, number = {}, pages = {45}, pmid = {19563648}, issn = {1745-6215}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Cardiac Catheterization/adverse effects ; Contrast Media/*adverse effects ; Coronary Angiography/adverse effects ; Creatinine/blood ; Diabetes Mellitus/epidemiology ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Incidence ; Kidney Diseases/*chemically induced/epidemiology/*prevention &amp; control ; Male ; Middle Aged ; Placebos ; Prospective Studies ; Renal Insufficiency, Chronic/epidemiology ; Risk Factors ; }, abstract = {BACKGROUND: Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) constitute to be a high-risk population for the development of contrast-induced nephropathy (CIN), in which the incidence of CIN is estimated to be as high as 50%. We performed this trial to assess the efficacy of N-acetylcysteine (NAC) in the prevention of this complication.<br><br>METHODS: In a prospective, double-blind, placebo controlled, randomized clinical trial, we studied 90 patients undergoing elective diagnostic coronary angiography with DM and CKD (serum creatinine > or = 1.5 mg/dL for men and > or = 1.4 mg/dL for women). The patients were randomly assigned to receive either oral NAC (600 mg BID, starting 24 h before the procedure) or placebo, in adjunct to hydration. Serum creatinine was measured prior to and 48 h after coronary angiography. The primary end-point was the occurrence of CIN, defined as an increase in serum creatinine > or = 0.5 mg/dL (44.2 micromol/L) or > or = 25% above baseline at 48 h after exposure to contrast medium.<br><br>RESULTS: Complete data on the outcomes were available on 87 patients, 45 of whom had received NAC. There were no significant differences between the NAC and placebo groups in baseline characteristics, amount of hydration, or type and volume of contrast used, except in gender (male/female, 20/25 and 34/11, respectively; P = 0.005) and the use of statins (62.2% and 37.8%, respectively; P = 0.034). CIN occurred in 5 out of 45 (11.1%) patients in the NAC group and 6 out of 42 (14.3%) patients in the placebo group (P = 0.656).<br><br>CONCLUSION: There was no detectable benefit for the prophylactic administration of oral NAC over an aggressive hydration protocol in patients with DM and CKD.<br><br>TRIAL REGISTRATION: NCT00808795.}, }
@article {pmid19560222, year = {2009}, author = {Dittmann, K and Mayer, C and Kehlbach, R and Rothmund, MC and Peter Rodemann, H}, title = {Radiation-induced lipid peroxidation activates src kinase and triggers nuclear EGFR transport.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {92}, number = {3}, pages = {379-382}, doi = {10.1016/j.radonc.2009.06.003}, pmid = {19560222}, issn = {1879-0887}, mesh = {Active Transport, Cell Nucleus ; Blotting, Western ; Carcinoma, Bronchogenic/pathology/radiotherapy ; Caveolin 1/*metabolism ; Cell Line, Tumor/metabolism/radiation effects ; DNA Breaks, Double-Stranded/radiation effects ; DNA Repair/*physiology ; ErbB Receptors/*metabolism/radiation effects ; Humans ; Lipid Peroxidation/*radiation effects ; Phosphorylation/radiation effects ; Radiation, Ionizing ; Sensitivity and Specificity ; Tumor Cells, Cultured/metabolism/radiation effects ; src-Family Kinases/*metabolism/radiation effects ; }, abstract = {PURPOSE: Elucidation of the molecular mechanism of radiation-induced activation of src kinase, which initiates EGFR internalization and nuclear transport.<br><br>MATERIAL AND METHODS: Radiation-induced src activation was investigated in the bronchial carcinoma cell line A549. Proteins were Western blotted and quantified by the help of specific antibodies. Residual DNA-damage was quantified with gammaH(2)AX-foci analysis. Radiation-induced lipid peroxidation was prevented by acetyl-cysteine.<br><br>RESULTS: The radiation-induced src activation and EGFR stabilization could be mimicked by addition of hydroxy-nonenal (HNE), one of the major lipid peroxidation products. Radiation-generated HNE is bound to EGFR and src and correlated with complex formation between both following radiation. Treatment with HNE activated src and stimulated radiation-associated EGFR and caveolin 1 phosphorylations resulting in increased nuclear transport of EGFR. Consequently, radiation-induced phosphorylation and activation of DNA-PK were increased. This phosphorylation was associated with improved removal of residual damage 24h after irradiation. Inhibition of radiation-induced HNE generation by acetyl-cysteine blocked radiation-induced src activation and EGFR phosphorylation.<br><br>CONCLUSIONS: HNE generated in response to radiation exposure activates src kinase and is involved in regulation of radiation-stimulated DNA-repair processes.}, }
@article {pmid19559059, year = {2009}, author = {Reid, AJ and Shawcross, SG and Hamilton, AE and Wiberg, M and Terenghi, G}, title = {N-acetylcysteine alters apoptotic gene expression in axotomised primary sensory afferent subpopulations.}, journal = {Neuroscience research}, volume = {65}, number = {2}, pages = {148-155}, doi = {10.1016/j.neures.2009.06.008}, pmid = {19559059}, issn = {1872-8111}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Apoptosis/*drug effects/genetics ; Axotomy ; Caspase 3/genetics ; Cell Survival/physiology ; Cytoprotection/physiology ; Disease Models, Animal ; Down-Regulation/drug effects/genetics ; Free Radical Scavengers/pharmacology/therapeutic use ; Ganglia, Spinal/*drug effects/metabolism/physiopathology ; Gene Expression Regulation/drug effects/genetics ; Male ; Muscle, Skeletal/innervation ; *Peripheral Nerve Injuries ; Peripheral Nerves/metabolism/physiopathology ; Peripheral Nervous System Diseases/*drug therapy/metabolism/physiopathology ; Proto-Oncogene Proteins c-bcl-2/genetics ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Sensory Receptor Cells/*drug effects/metabolism/pathology ; Skin/innervation ; Up-Regulation/drug effects/genetics ; bcl-2-Associated X Protein/genetics ; }, abstract = {Novel approaches are required in peripheral nerve injury management because current surgical techniques, which do not address axotomy-induced neuronal death, lead to deficient sensory recovery. Sensory neuronal death has functional preference with cutaneous neurons dying in great numbers whilst muscle afferents survive axotomy. This offers the potential of comparing similar cell types that suffer distinct fates upon nerve injury. Here, a novel approach, combining in vivo rat nerve injury model with laser microdissection and quantitative real-time polymerase chain reaction, identifies crucial disparities in apoptotic gene expression attributable to subpopulations of differing sensory modalities and examines the response to N-acetylcysteine (NAC) therapy. We show that axotomised muscle afferent neurons survive injury due to a neuroprotective response which markedly downregulates Bax and caspase-3 mRNA. In contrast, axotomised cutaneous sensory neurons significantly upregulate caspase-3 and alter both Bcl-2 and Bax expression such that pro-apoptotic Bax predominates. N-Acetylcysteine (NAC) intervention promotes neuroprotection of cutaneous sensory neurons through considerable upregulation of Bcl-2 and downregulation of both Bax and caspase-3 mRNA. The data presented identifies differential activation of apoptotic genes in axotomised neuronal subpopulations. Furthermore, NAC therapy instigates apoptotic gene expression changes in axotomised neurons, thereby offering pharmacotherapeutic potential in the clinical treatment of nerve injury.}, }
@article {pmid19555676, year = {2009}, author = {Welin, D and Novikova, LN and Wiberg, M and Kellerth, JO and Novikov, LN}, title = {Effects of N-acetyl-cysteine on the survival and regeneration of sural sensory neurons in adult rats.}, journal = {Brain research}, volume = {1287}, number = {}, pages = {58-66}, doi = {10.1016/j.brainres.2009.06.038}, pmid = {19555676}, issn = {1872-6240}, mesh = {Acetylcysteine/*pharmacology ; Age Factors ; Animals ; Cell Survival/drug effects/physiology ; Female ; Ganglia, Spinal/drug effects/physiology ; Nerve Regeneration/drug effects/*physiology ; Neurogenesis/drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; Sensory Receptor Cells/drug effects/*physiology ; Sural Nerve/drug effects/*physiology ; }, abstract = {Microsurgical reconstruction of injured peripheral nerves often results in limited functional recovery. One contributing factor is the retrograde neuronal degeneration of sensory neurons in the dorsal root ganglia (DRG) and of motor neurons in the spinal cord. The present study investigates the neuroprotective and growth-promoting effects of N-acetyl-cysteine (NAC) on sensory DRG neurons and spinal motoneurons after sciatic axotomy and nerve grafting in adult rats. Sciatic axotomy and nerve grafting were performed at 1 week after sural DRG neurons and motoneurons were retrogradely labeled with the fluorescent tracer Fast Blue. To assess the efficacy of axonal regeneration, a second fluorescent dye Fluoro-Ruby was applied distal to the graft at 12 weeks after nerve repair. At 8-13 weeks after axotomy, only 52-56% of the sural sensory neurons remained in the lumbar DRG, while the majority of motoneurons survived the sciatic nerve injury. Nerve grafting alone or continuous intrathecal NAC treatment (2.4 mg/day) improved survival of sural DRG neurons. Combined treatment with nerve graft and NAC had significant additive effect on neuronal survival and also increased the number of sensory neurons regenerating across the graft. However, NAC treatment neither affected the number of regenerating motoneurons nor the number of myelinated axons in the nerve graft or in the distal nerve stump. The present results demonstrate that NAC provides a highly significant effect of neuroprotection in an animal nerve injury model and that combination with nerve grafting further attenuates retrograde cell death and promotes regeneration of sensory neurons.}, }
@article {pmid19553346, year = {2009}, author = {Huang, JS and Chuang, LY and Guh, JY and Huang, YJ}, title = {Effects of nitric oxide and antioxidants on advanced glycation end products-induced hypertrophic growth in human renal tubular cells.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {111}, number = {1}, pages = {109-119}, doi = {10.1093/toxsci/kfp134}, pmid = {19553346}, issn = {1096-0929}, mesh = {Antioxidants/*pharmacology ; Blotting, Western ; Cell Line ; Cell Size ; Cyclic GMP/metabolism ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Fibronectins/biosynthesis ; Flow Cytometry ; Glycation End Products, Advanced/antagonists &amp; inhibitors/*toxicity ; Humans ; Hypertrophy ; Kidney Tubules/cytology/drug effects/*pathology ; Nitric Oxide/biosynthesis/*pharmacology ; Nitric Oxide Donors/pharmacology ; Nitric Oxide Synthase Type II/biosynthesis ; Oncogene Protein p21(ras)/biosynthesis ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic/antagonists &amp; inhibitors ; S-Nitroso-N-Acetylpenicillamine/pharmacology ; }, abstract = {The accumulation of advanced glycation end products (AGE) is a key mediator of renal tubular hypertrophy in diabetic nephropathy (DN). Reactive oxygen species and nitric oxide (NO) were involved in the progression of DN. In this study, the molecular mechanisms of NO and antioxidants responsible for inhibition of AGE-induced renal tubular hypertrophy were examined. We found that AGE (but not nonglycated bovine serum albumin) significantly suppressed the NO/cGMP/PKG signaling in human renal proximal tubular cells. NO donors S-nitroso-N-acetylpenicillamine (SNAP)/sodium nitroprusside (SNP) and antioxidants N-acetylcysteine (NAC)/taurine treatments significantly attenuated AGE-inhibited NO production, cGMP synthesis, and inducible NO synthase/cGMP-dependent protein kinase (PKG) activation. Moreover, AGE-induced extracellular signal-regulated kinase/c-Jun N-terminal kinase/p38 mitogen-activated protein kinase activation was markedly blocked by antireceptor for AGE (RAGE), SNAP, SNP, NAC, and taurine. The abilities of NO and antioxidants to inhibit AGE/RAGE-induced hypertrophic growth were verified by the observation that SNAP, SNP, NAC, and taurine inhibited fibronectin, p21(Waf1/Cip1), and RAGE expression. Therefore, antioxidants significantly attenuated AGE/RAGE-enhanced cellular hypertrophy partly through induction of the NO/cGMP/PKG signaling.}, }
@article {pmid19551771, year = {2009}, author = {Rachmilovich-Calis, S and Meyerstein, N and Meyerstein, D}, title = {A mechanistic study of the effects of antioxidants on the formation of malondialdehyde-like products in the reaction of hydroxyl radicals with deoxyribose.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {15}, number = {31}, pages = {7717-7723}, doi = {10.1002/chem.200802272}, pmid = {19551771}, issn = {1521-3765}, mesh = {Acetylcysteine/chemistry ; Antioxidants/*chemistry ; Ascorbic Acid/chemistry ; Deoxyribose/*chemistry ; Hydroxyl Radical/chemistry ; Malondialdehyde/analysis/chemical synthesis ; Sulfhydryl Compounds/chemistry ; Thermodynamics ; }, abstract = {The reactions of (*)OH radicals with deoxyribose, DR, form five different DR(*) radicals, only one of which is transformed into malondialdehyde (MDA)-like products. The radiolytic yield of the MDA-like products increases with the increase in the DR concentration indicating that some of the initially formed "unproductive" radicals react with DR to form the "productive" radicals. The yield of the MDA-like products also increases with the dose rate delivered to the solution suggesting that the formation of the MDA-like products involves the reaction of the "productive" radicals with a radical. The addition of ascorbate, AH(-), to the solution decreases the yield of the MDA-like products as expected from the relative rates of the reaction of DR and AH(-) with (*)OH radicals. On the other hand the addition of the exogenous thiol, N-acetylcysteine (NAC), to the solutions decreases the yield of the MDA-like products considerably more than expected from the rate constants of the reaction with (*)OH radicals. The addition of the endogenous thiol, glutathione (GSH), to the solutions affects the yield of the MDA-like products at low concentration less than expected and at "high" concentrations more than expected from the rate constant of the reaction. Addition of low concentration of AH(-) to solutions containing GSH increases considerably its antioxidant activity whereas addition of small concentrations of AH(-) to solutions containing NAC has no effect on its antioxidant activity. The results point out that the DR(*) radicals react differently with NAC and GSH and that the GS(*) and NAC(*) radicals react differently with DR, the GS(*) radical being considerably more active than the NAC(*) radical. Thus it has to be concluded that the relative activity of antioxidants depends also on the rate constants of many secondary reactions and on the concentrations of all the solutes present in the system.}, }
@article {pmid19551668, year = {2009}, author = {Urgancioglu, B and Bilgihan, K and Engin, D and Cirak, MY and Hondur, A and Hasanreisoglu, B}, title = {Topical N-acetylcysteine reduces interleukin-1-alpha in tear fluid after laser subepithelial keratectomy.}, journal = {European journal of ophthalmology}, volume = {19}, number = {4}, pages = {554-559}, doi = {10.1177/112067210901900406}, pmid = {19551668}, issn = {1120-6721}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Topical ; Adolescent ; Adult ; Eye Proteins/metabolism ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Interleukin-1alpha/*metabolism ; Keratectomy, Subepithelial, Laser-Assisted/*methods ; Microscopy, Confocal ; Myopia/metabolism/*surgery ; Postoperative Period ; Prospective Studies ; Tears/*metabolism ; Wound Healing/*drug effects ; Young Adult ; }, abstract = {PURPOSE: To evaluate the effect of topical N-acetylcysteine (NAC) on interleukin 1-alpha (IL-1alpha) levels in tear fluid after myopic laser subepithelial keratectomy (LASEK) and its possible role in modulating corneal wound healing.<br><br>METHODS: Twenty-six eyes of 13 patients who underwent myopic LASEK were divided into 2 groups. Group 1 (n=10 eyes) was used as a control group. All patients received topical lomefloxacin and dexamethasone postoperatively. Additionally, patients in Group 2 received topical NAC for 1 month postoperatively. Tear fluid samples were collected with microcapillary tubes preoperatively, on the first and on the fifth postoperative day, and the release of IL-1alpha in tear fluid was calculated. Haze grading and confocal microscopic examination were performed at 1 and 3 months postoperatively.<br><br>RESULTS: The mean IL-1-alpha release values were 0.285-/+0.159 pg/min in Group 1 and 0.235-/+0.142 pg/min in Group 2 preoperatively. In Group 1, the values were 0.243-/+0.155 pg/min on day 1 and 0.164-/+0.125 pg/min on day 5. In Group 2, the mean IL-1alpha release values were 0.220-/+0.200 pg/min on day 1 and 0.080-/+0.079 pg/min on day 5. The difference between the groups was significant only for day 5 (p<0.05). Mean corneal haze score and grey scale value in confocal microscopy were significantly higher (p<0.05) in Group 1 at 1 month. However, at 3 months there was no difference between groups (p>0.05).<br><br>CONCLUSIONS: NAC seems to have an additive effect to steroids in suppressing IL-1alpha levels in tear fluid and may be clinically advantageous in modulating corneal wound healing during the early postoperative period after LASEK.}, }
@article {pmid19551371, year = {2009}, author = {Lee, TF and Tymafichuk, CN and Schulz, R and Cheung, PY}, title = {Post-resuscitation NOS inhibition does not improve hemodynamic recovery of hypoxic newborn pigs.}, journal = {Intensive care medicine}, volume = {35}, number = {9}, pages = {1628-1635}, pmid = {19551371}, issn = {1432-1238}, mesh = {Acetylcysteine/administration &amp; dosage ; Alberta ; Animals ; Antioxidants ; Blood Gas Analysis ; Hemodynamics/*drug effects ; *Hypoxia ; Nitric Oxide/administration &amp; dosage/*pharmacology/*therapeutic use ; Random Allocation ; *Resuscitation ; Stroke Volume/physiology ; Swine ; }, abstract = {BACKGROUND: Significant improvement in myocardial recovery has been shown previously with interventions to decrease reactive oxygen species after ischemia/hypoxia. We investigated whether co-administration of N-acetylcysteine (NAC, a scavenger for reactive oxygen species) and N (G)-monomethyl-L: -arginine (L-NMMA, a non-selective nitric oxide synthase inhibitor) results in better hemodynamic recovery.<br><br>DESIGN: Controlled, block-randomized study.<br><br>SETTING: University research laboratory.<br><br>SUBJECT: Mixed breed piglets (1-4d, 1.6-2.4 kg).<br><br>INTERVENTIONS: Acutely instrumented piglets received normocapnic alveolar hypoxia (10-15% oxygen) for 2 h followed by reoxygenation with 100% oxygen (1 h) then 21% oxygen (3 h). After reoxygenation, hypoxic-reoxygenated piglets were given either saline (controls), NAC [30 mg/kg bolus + 20 mg/(kg h) infusion], NMMA [0.1 mg/kg bolus + 0.1 mg/(kg h) infusion] or NAC + L-NMMA via intravenous infusion in a blinded, randomized fashion (n = 8/group). Sham-operated piglets had no hypoxia-reoxygenation (n = 5).<br><br>MEASUREMENTS AND RESULTS: Both cardiac index and stroke volume of hypoxia-reoxygenation controls remained depressed during reoxygenation (vs. normoxic baseline, p < 0.05). Post-resuscitation treatment with L-NMMA alone did not improve systemic hemodynamic recovery, but caused pulmonary hypertension (vs. controls). In contrast, treating the piglets with either NAC or NAC + L-NMMA improved cardiac index and stroke volume, with no effect on heart rate and blood pressure (vs. controls). These treatments also decreased various oxidative stress markers in myocardial tissues (vs. controls). However, there was no significant difference between NAC- and NAC + L-NMMA groups in all examined parameters.<br><br>CONCLUSIONS: Post-resuscitation administration of NAC improved cardiac function and reduced oxidative stress in newborn pigs with hypoxia-reoxygenation insult. Low-dose, non-selective inhibitor of nitric oxide synthase activity did not provide any further beneficial effect.}, }
@article {pmid19546159, year = {2009}, author = {Pu, X and Kamendulis, LM and Klaunig, JE}, title = {Acrylonitrile-induced oxidative stress and oxidative DNA damage in male Sprague-Dawley rats.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {111}, number = {1}, pages = {64-71}, pmid = {19546159}, issn = {1096-0929}, support = {R01-CA100908/CA/NCI NIH HHS/United States ; }, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acrylonitrile/*toxicity ; Animals ; Biomarkers ; Carcinogens/*toxicity ; Comet Assay ; *DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/chemistry/metabolism ; Glutathione/metabolism ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Studies have demonstrated that the induction of oxidative stress may be involved in brain tumor induction in rats by acrylonitrile. The present study examined whether acrylonitrile induces oxidative stress and DNA damage in rats and whether blood can serve as a valid surrogate for the biomonitoring of oxidative stress induced by acrylonitrile in the exposed population. Male Sprague-Dawley rats were treated with 0, 3, 30, 100, and 200 ppm acrylonitrile in drinking water for 28 days. One group of rats were also coadministered N-acetyl cysteine (NAC) (0.3% in diet) with acrylonitrile (200 ppm in drinking water) to examine whether antioxidant supplementation was protective against acrylonitrile-induced oxidative stress. Direct DNA strand breakage in white blood cells (WBC) and brain was measured using the alkaline comet assay. Oxidative DNA damage in WBC and brain was evaluated using formamidopyrimidine DNA glycosylase (fpg)-modified comet assay and with high-performance liquid chromatography-electrochemical detection. No significant increase in direct DNA strand breaks was observed in brain and WBC from acrylonitrile-treated rats. However, oxidative DNA damage (fpg comet and 8'hydroxyl-2-deoxyguanosine) in brain and WBC was increased in a dose-dependent manner. In addition, plasma levels of reactive oxygen species (ROS) increased in rats administered acrylonitrile. Dietary supplementation with NAC prevented acrylonitrile-induced oxidative DNA damage in brain and WBC. A slight, but significant, decrease in the GSH:GSSG ratio was seen in brain at acrylonitrile doses > 30 ppm. These results provide additional support that the mode of action for acrylonitrile-induced astrocytomas involves the induction of oxidative stress and damage. Significant associations were seen between oxidative DNA damage in WBC and brain, ROS formation in plasma, and the reported tumor incidences. Since oxidative DNA damage in brain correlated with oxidative damage in WBC, these results suggest that monitoring WBC DNA damage maybe a useful tool to assess acrylonitrile-induced oxidative stress in humans.}, }
@article {pmid19545668, year = {2009}, author = {Altan, H and Bozkurt, AK and Arslan, C and Ustundag, N and Konukoglu, D and Koksal, C}, title = {Serine protease inhibitor aprotinin ameliorates renal injury in a rat model of ischemia-perfusion injury.}, journal = {Transplantation proceedings}, volume = {41}, number = {5}, pages = {1512-1516}, doi = {10.1016/j.transproceed.2009.01.090}, pmid = {19545668}, issn = {1873-2623}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aprotinin/*therapeutic use ; Glutathione/metabolism ; Inflammation/pathology/prevention &amp; control ; Kidney/drug effects/*pathology ; Kidney Tubules/drug effects/pathology ; Malondialdehyde/metabolism ; Necrosis ; Nephrectomy ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; Serine Proteinase Inhibitors/*therapeutic use ; }, abstract = {BACKGROUND: Renal ischemia-reperfusion (I/R) injury may occur after renal transplantation, thoracoabdominal aortic surgery, and renal artery interventions.<br><br>OBJECTIVE: To investigate the therapeutic effects of aprotinin on tissue protection against I/R injury in a rat model. N-acetylcysteine (NAC), a potent antioxidant, was also tested to assess the experimental model.<br><br>MATERIALS AND METHODS: Twenty-four rats were categorized into 3 groups of 8 rats each: those receiving isotonic sodium chloride solution (control group); NAC, 150 mg/kg; and aprotinin, 40,000 KIU/kg. The animals underwent unilateral nephrectomy after 60 minutes of warm ischemia and 60 minutes of reperfusion of the kidney. Malondialdehyde, a lipid peroxidation marker, and antioxidant glutathione levels were measured in the kidney parenchyma. Tissue samples were obtained for histologic analysis.<br><br>RESULTS: Compared with the control group, the NAC group demonstrated significantly low levels of malondialdehyde (P = .04) and high levels of glutathione (P = .01). At histopathologic analysis, less acute tubular necrosis (ATN) and cellular swelling was noted in the NAC group (P = .002 and P = .005, respectively). In the aprotinin group, histopathologic analysis revealed less tissue damage in terms of ATN (P < .001, cellular swelling (P < .001), and vacuolysis (P = .002). Compared with the NAC group, ATN (P = .01), vacuolysis (P = .04), and congestion (P = .05) were significantly less in the aprotinin group.<br><br>CONCLUSIONS: Our results suggest that administration of aprotinin attenuates renal I/R injury. This observation has potential application for kidney preservation for transplantation, for aortic surgery, and for renal artery interventions by protecting cells from free radical damage.}, }
@article {pmid19544430, year = {2009}, author = {Kim, J and Wong, PK}, title = {Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling.}, journal = {Stem cells (Dayton, Ohio)}, volume = {27}, number = {8}, pages = {1987-1998}, doi = {10.1002/stem.125}, pmid = {19544430}, issn = {1549-4918}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics ; Cell Growth Processes/physiology ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/biosynthesis ; Cyclin-Dependent Kinase Inhibitor p27/biosynthesis ; DNA-Binding Proteins/*deficiency/genetics ; Hydrogen Peroxide/pharmacology ; MAP Kinase Signaling System ; Mice ; Mice, Knockout ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Neurons/*cytology/drug effects/metabolism ; Oncogene Protein v-akt/metabolism ; Oxidative Stress/*physiology ; Protein Serine-Threonine Kinases/*deficiency/genetics ; Reactive Oxygen Species/metabolism ; Stem Cells/*cytology/drug effects/metabolism ; Tumor Suppressor Proteins/*deficiency/genetics ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/*metabolism ; }, abstract = {Ataxia-telangiectasia (A-T) is a genetic disorder caused by a mutation of the Atm gene, which controls DNA repair, cell cycling, and redox homeostasis. Even though oxidative stress has been implicated in the neurological anomalies in A-T, the effects of ATM loss on neural stem cell (NSC) survival has remained elusive. In this study, we investigated the effects of oxidative stress on NSC proliferation in an animal model for A-T neurodegeneration. We found that cultured subventricular zone neurosphere cells from Atm(-/-) mice show impaired proliferation, as well as intrinsic elevation of reactive oxygen species (ROS) levels, compared with those from Atm(+/+) mice. We also show that increasing the levels of ROS by H(2)O(2) treatment significantly reduces Atm(+/+) neurosphere formation and proliferation. In Atm(-/-) neurosphere cells, the Akt and Erk1/2 pathways are disrupted, together with enhanced activity of the p38 mitogen-activated protein kinase (MAPK). Treatment of these cells with the antioxidant N-acetyl-L-cysteine (NAC) or with a p38 MAPK inhibitor restores normal proliferation and reduced expression of p21(cip1) and p27(kip1) in the Atm(-/-) NSCs. These observations indicate that ATM plays a crucial role in NSC proliferation, by activating Akt and Erk1/2 pathways and by suppressing ROS-p38 MAPK signaling. Together, our results suggest that p38 MAPK signaling acts as a negative regulator of NSC proliferation in response to oxidative stress. These findings suggest a potential mechanism for neuronal cell loss as a result of oxidative stress in NSCs in progressive neurodegenerative diseases such as A-T.}, }
@article {pmid19544329, year = {2009}, author = {Bhushan, S and Malik, F and Kumar, A and Isher, HK and Kaur, IP and Taneja, SC and Singh, J}, title = {Activation of p53/p21/PUMA alliance and disruption of PI-3/Akt in multimodal targeting of apoptotic signaling cascades in cervical cancer cells by a pentacyclic triterpenediol from Boswellia serrata.}, journal = {Molecular carcinogenesis}, volume = {48}, number = {12}, pages = {1093-1108}, doi = {10.1002/mc.20559}, pmid = {19544329}, issn = {1098-2744}, mesh = {Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/*metabolism ; Blotting, Western ; Boswellia/*chemistry ; Cell Cycle/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/*metabolism ; Cytochromes c/metabolism ; Female ; Flow Cytometry ; HeLa Cells/pathology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Nitric Oxide/metabolism ; Oxidative Stress ; Pentacyclic Triterpenes/chemistry/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; *Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins/*metabolism ; Proto-Oncogene Proteins c-akt/*antagonists &amp; inhibitors/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Cervical carcinoma is a growing menace to women health worldwide. This study reports the apoptotic cell death in human cervical cancer HeLa and SiHa cells by a pentacyclic triterpenediol (TPD) from Boswellia serrata by a mechanism different from reported in HL-60 cells. It caused oxidative stress by early generation of nitric oxide and reactive oxygen species that robustly up regulated time-dependent expression of p53/p21/PUMA while conversely abrogating phosphatidylinositol-3-kinase (PI3K)/Akt pathways in parallel. TPD also decreased the expression of PI3K/pAkt, ERK1/2, NF-kappaB/Akt signaling cascades which coordinately contribute to cancer cell survival through these distinct pathways. The tumor suppressor p53 pathway predominantly activated by TPD further up-regulated PUMA, which concomitantly decreased the Bcl-2 level, caused mitochondrial membrane potential loss with attendant translocation of Bax and drp1 to mitochondria and release of pro-apoptotic factors such as cytochrome c and Smac/Diablo to cytosol leading to caspases-3 and -9 activation. In addition both the phospho-p53 and p21 were found to accumulate heavily in the nuclear fraction with attendant decrease in topoisomarase II and survivin levels. On the contrary, TPD did not affect the extrinsic signaling transduction pathway effectively through apical death receptors. Interestingly, N-acetyl cysteine, ascorbate and s-methylisothiourea (sMIT) rescued cells significantly from TPD induced DNA damage and caspases activation. TPD may thus find usefulness in managing and treating cervical cancer.}, }
@article {pmid19540572, year = {2009}, author = {Jaulmes, A and Sansilvestri-Morel, P and Rolland-Valognes, G and Bernhardt, F and Gaertner, R and Lockhart, BP and Cordi, A and Wierzbicki, M and Rupin, A and Verbeuren, TJ}, title = {Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells.}, journal = {Thrombosis research}, volume = {124}, number = {4}, pages = {439-446}, doi = {10.1016/j.thromres.2009.05.018}, pmid = {19540572}, issn = {1879-2472}, mesh = {Acetylcysteine/pharmacology ; Benzopyrans/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects/*metabolism ; *Gene Expression Regulation ; Humans ; *MAP Kinase Signaling System ; Manganese ; NADPH Oxidase 4 ; NADPH Oxidases/genetics/*metabolism ; Onium Compounds/pharmacology ; Organometallic Compounds/pharmacology ; Plasminogen Activator Inhibitor 1/*biosynthesis/genetics ; RNA, Messenger/biosynthesis/genetics ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {INTRODUCTION: Plasminogen Activator Inhibitor-1 (PAI-1) is the most potent endogenous inhibitor of fibrinolysis which is implicated in the pathogenesis of myocardial infarction and metabolic syndrome. The formation of reactive oxygen species (ROS) plays an important role in the pathology of vascular disorders and has been shown to increase PAI-1 expression by endothelial cells. Growing evidence indicates that NADPH oxidase and in particular the constitutively active Nox4-p22(phox) complexes are major sources of ROS in endothelial cells. The aim of the present study was to characterize the role of NADPH oxidase and in particular Nox4 in the regulation of PAI-1 expression in cultured Human Umbilical Venous Endothelial Cells (HUVECs).<br><br>METHODS AND RESULTS: N-acetylcysteine (NAC, scavenger of ROS), diphenylene iodonium chloride (DPI, inhibitor of flavoproteins), M40403 (superoxyde dismutase mimic) and S17834 (inhibitor of NADPH oxidase) inhibited PAI-1 release and promoter activity in HUVECs. Specific knock down of Nox4 mRNA by siRNA caused a decrease in ROS production and NADPH oxidase activity. Moreover, Nox4 silencing decreased PAI-1 expression, release and activity as well as p38 MAPK pathways and NFkappaB activation. These signalling pathways are also involved in PAI-1 release.<br><br>CONCLUSIONS: The NADPH oxidase inhibitors DPI and S 17834 as well as Nox4 silencing decreased PAI-1 synthesis in human cultured endothelial cells demonstrating the involvement of the constitutively active Nox4-containing NADPH oxidase in ROS-mediated PAI-1 transcription via p38 MAPK pathways. NADPH oxidase targeting with inhibitors such as S17834 could be an interesting strategy to decrease both oxidative stress and PAI-1 synthesis.}, }
@article {pmid19538946, year = {2009}, author = {Sheth, DS and Tajuddin, NF and Druse, MJ}, title = {Antioxidant neuroprotection against ethanol-induced apoptosis in HN2-5 cells.}, journal = {Brain research}, volume = {1285}, number = {}, pages = {14-21}, pmid = {19538946}, issn = {1872-6240}, support = {R01 AA003490-26/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Alcohol-Induced Disorders, Nervous System/*drug therapy/metabolism/physiopathology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Apoptosis Regulatory Proteins/drug effects/metabolism ; Cell Line ; Central Nervous System Depressants/antagonists &amp; inhibitors ; Cytoprotection/drug effects/physiology ; Ethanol/antagonists &amp; inhibitors ; Female ; Gene Expression Regulation/drug effects/genetics ; Hippocampus/cytology/drug effects/metabolism ; Melatonin/pharmacology/therapeutic use ; Mice ; Nerve Degeneration/chemically induced/*drug therapy/metabolism ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/*drug effects/physiology ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced/drug therapy/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {Earlier studies from this and other laboratories show that ethanol induces apoptotic death of fetal and neonatal neurons. One mechanism that underlies these effects is the ethanol-associated reduction in the phosphatidylinositol 3' kinase pro-survival pathway. Another mechanism involves the oxidative stress caused by the ethanol-associated increase in reactive oxygen species (ROS). In the present study, we used the murine HN2-5 hippocampal-derived cell line to investigate the effects of ethanol on ROS levels and apoptosis. We also investigated the potential neuroprotective effects of two structurally unrelated antioxidants: N-acetylcysteine (NAC) and melatonin. The results demonstrate that NAC blocked an ethanol-associated increase in ROS. In addition, NAC and melatonin prevented the augmentation of apoptosis in ethanol-treated neurons. Both antioxidants significantly elevated the expression of the anti-apoptotic gene XIAP in ethanol-treated and/or control neurons and melatonin increased Bcl-2 expression in ethanol-treated neurons. Thus, it is possible that the neuroprotective effects of NAC and melatonin involve their ability to augment the expression of one or more anti-apoptotic gene as well as their classical antioxidant actions. Additional studies are needed to establish the effectiveness of these antioxidants to prevent the loss of neurons which accompanies in utero exposure to ethanol.}, }
@article {pmid19538479, year = {2010}, author = {Price, CL and Hassi, HO and English, NR and Blakemore, AI and Stagg, AJ and Knight, SC}, title = {Methylglyoxal modulates immune responses: relevance to diabetes.}, journal = {Journal of cellular and molecular medicine}, volume = {14}, number = {6B}, pages = {1806-1815}, pmid = {19538479}, issn = {1582-4934}, mesh = {Antigens, CD/metabolism ; Apoptosis ; Cell Proliferation ; Cytokines/biosynthesis/genetics ; Diabetes Mellitus/*immunology ; Gene Expression Regulation ; Histocompatibility Antigens Class I/metabolism ; Humans ; Immunoglobulins/metabolism ; Immunomodulation/*immunology ; Membrane Glycoproteins/metabolism ; Myeloid Cells/cytology/immunology ; Pyruvaldehyde/*immunology ; RNA, Messenger/genetics/metabolism ; T-Lymphocytes/cytology/immunology ; CD83 Antigen ; }, abstract = {Increased methylglyoxal (MG) concentrations and formation of advanced glycation end-products (AGEs) are major pathways of glycaemic damage in diabetes, leading to vascular and neuronal complications. Diabetes patients also suffer increased susceptibility to many common infections, the underlying causes of which remain elusive. We hypothesized that immune glycation damage may account for this increased susceptibility. We previously showed that the reaction mixture (RM) for MG glycation of peptide blocks up regulation of CD83 in myeloid cells and inhibits primary stimulation of T cells. Here, we continue to investigate immune glycation damage, assessing surface and intracellular cytokine protein expression by flow cytometry, T-cell proliferation using a carboxyfluorescein succinimidyl ester assay, and mRNA levels by RT-PCR. We show that the immunomodulatory component of this RM was MG itself, with MG alone causing equivalent block of CD83 and loss of primary stimulation. Block of CD83 expression could be reversed by MG scavenger N-acetyl cysteine. Further, MG within RM inhibited stimulated production of interleukin (IL)-10 protein from myeloid cells plus interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha from T cells. Loss of IL-10 and IFN-gamma was confirmed by RT-PCR analysis of mRNA, while TNF-alpha message was raised. Loss of TNF-alpha protein was also shown by ELISA of culture supernatants. In addition, MG reduced major histocompatibility complex (MHC) class I expression on the surface of myeloid cells and increased their propensity to apoptose. We conclude that MG is a potent suppressor of myeloid and T-cell immune function and may be a major player in diabetes-associated susceptibility to infection.}, }
@article {pmid19537779, year = {2009}, author = {Rees, JN and Florang, VR and Eckert, LL and Doorn, JA}, title = {Protein reactivity of 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite, is dependent on both the aldehyde and the catechol.}, journal = {Chemical research in toxicology}, volume = {22}, number = {7}, pages = {1256-1263}, pmid = {19537779}, issn = {1520-5010}, support = {T32 GM067795/GM/NIGMS NIH HHS/United States ; K22 ES12982/ES/NIEHS NIH HHS/United States ; T32 GM067795-05/GM/NIGMS NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; K22 ES012982-03/ES/NIEHS NIH HHS/United States ; P30 ES005605-180006/ES/NIEHS NIH HHS/United States ; R01 ES015507-01A1/ES/NIEHS NIH HHS/United States ; P30 ES05605/ES/NIEHS NIH HHS/United States ; R01 ES015507-02/ES/NIEHS NIH HHS/United States ; R01 ES015507/ES/NIEHS NIH HHS/United States ; K22 ES012982/ES/NIEHS NIH HHS/United States ; R01 ES15507/ES/NIEHS NIH HHS/United States ; }, mesh = {3,4-Dihydroxyphenylacetic Acid/*analogs &amp; derivatives/chemistry/metabolism/toxicity ; Aldehydes/*chemistry ; Animals ; Catechols/*chemistry ; Cattle ; Cross-Linking Reagents/chemistry ; Dopamine/metabolism ; Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism ; Mice ; Mitochondria, Liver/metabolism ; Rats ; Serum Albumin, Bovine/chemistry ; }, abstract = {Dopamine (DA) has been implicated as an endogenous neurotoxin to explain selective neurodegeneration, as observed for Parkinson's disease (PD). However, previous work demonstrated that 3,4-dihydroxyphenylacetaldehyde (DOPAL) was more toxic than DA. DOPAL is generated as a part of DA catabolism via the activity of monoamine oxidase, and the mechanism of DOPAL toxicity is proposed to involve protein modification. Previous studies have demonstrated protein reactivity via the aldehyde moiety; however, DOPAL contains two reactive functional groups (catechol and aldehyde), both with the potential for protein adduction. The goal of this work was to determine whether protein modification by DOPAL occurs via a thiol-reactive quinone generated from oxidation of the catechol, which is known to occur for DA, or if the aldehyde forms adducts with amine nucleophiles. To accomplish this objective, the reactivity of DOPAL toward N-acetyl-lysine (NAL), N-acetyl-cysteine (NAC), and two model proteins was determined. In addition, several DOPAL analogues were obtained and used for comparison of reactivity. Results demonstrate that at pH 7.4 and 37 degrees C, the order of DOPAL reactivity is NAL >> NAC and the product of NAL and DOPAL is stable in the absence of reducing agent. Moreover, DOPAL will react with model proteins, but in the presence of amine-selective modifiers citraconic anhydride and 2-iminothiolane hydrochloride, the reactivity of DOPAL toward the proteins is diminished. In addition, DOPAL-mediated protein cross-linking is observed when a model protein or a protein mixture (i.e., mitochondria lysate) is treated with DOPAL at concentrations of 5-100 microM. Protein cross-linking was diminished in the presence of ascorbate, suggesting the involvement of a quinone in DOPAL-mediated protein modification. These data indicate that DOPAL is highly reactive toward protein nucleophiles with the potential for protein cross-linking.}, }
@article {pmid19536871, year = {2009}, author = {Fabiani, R and Fuccelli, R and Pieravanti, F and De Bartolomeo, A and Morozzi, G}, title = {Production of hydrogen peroxide is responsible for the induction of apoptosis by hydroxytyrosol on HL60 cells.}, journal = {Molecular nutrition &amp; food research}, volume = {53}, number = {7}, pages = {887-896}, doi = {10.1002/mnfr.200800376}, pmid = {19536871}, issn = {1613-4133}, mesh = {Acetylcysteine/pharmacology ; Anticarcinogenic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caffeic Acids/pharmacology ; HL-60 Cells ; Humans ; Hydrogen Peroxide/*metabolism ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; }, abstract = {Hydroxytyrosol [3,4-dihydroxyphenylethanol (3,4-DHPEA)], a phenolic compound found exclusively in olive oil, exerts growth-suppressive and pro-apoptotic effects on different cancer cells. Although some molecular mechanisms involved in the pro-apoptotic activity of 3,4-DHPEA have been proposed, the initial stress signals responsible of this phenomenon are not known. Our aim was to assess the involvement of reactive oxygen species as mediators of apoptosis induced by 3,4-DHPEA on HL60 cells. Apoptosis was determined by analyzing the nuclear fragmentation by both fluorescence microscopy and flow cytometry. The externalization of phosphatidylserine was evidenced using an Annexin V-FITC kit. The concentration of H(2)O(2) in the culture medium was measured by the ferrous ion oxidation-xylenol orange method. The pro-apoptotic effect of 3,4-DHPEA (100 muM) was prevented by N-acetyl-cysteine, ascorbate, and alpha-tocopherol. Catalase suppressed the 3,4-DHPEA-induced apoptosis, while the Fe(II)-chelating reagent o-phenantroline showed no effect, suggesting the involvement of H(2)O(2)but not of OH(*). Indeed, 3,4-DHPEA caused accumulation of H(2)O(2) in the culture medium. Tyrosol (p-hydroxyphenylethanol) and caffeic acid, compounds structurally similar to 3,4-DHPEA but not able to generate H(2)O(2), did not induce an appreciable apoptotic effect. This is the first study demonstrating that apoptosis induction by 3,4-DHPEA is mediated by the extracellular production of H(2)O(2).}, }
@article {pmid19536524, year = {2009}, author = {Wang, Y and Xu, Y and Wang, H and Xue, P and Li, X and Li, B and Zheng, Q and Sun, G}, title = {Arsenic induces mitochondria-dependent apoptosis by reactive oxygen species generation rather than glutathione depletion in Chang human hepatocytes.}, journal = {Archives of toxicology}, volume = {83}, number = {10}, pages = {899-908}, doi = {10.1007/s00204-009-0451-x}, pmid = {19536524}, issn = {1432-0738}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Arsenic/toxicity ; Arsenites/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Cytochromes c/metabolism ; Glutathione/*metabolism ; Hepatocytes/*drug effects/metabolism ; Humans ; Malondialdehyde/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Sodium Compounds/*toxicity ; }, abstract = {This study was conducted to evaluate the possible involvement of mitochondrial pathway in NaAsO2-induced apoptosis and the role of reactive oxygen species (ROS) and reduced glutathione (GSH) in the apoptotic effect in Chang human hepatocytes. The MTT assay demonstrated that sodium arsenite (NaAsO2) treatment for 24 h caused a dose-dependent decrease of cell viability. NaAsO2 treatment (0-30 microM) was also found to induce phosphatidylserine externalization, a hallmark of apoptosis; to disrupt the mitochondrial membrane potential (Deltapsi (m)); to cause the release of cytochrome c into the cytosol, and to trigger cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in a dose-dependent manner. All these changes were accompanied with the enhanced generation of intracellular ROS and malondialdehyde (MDA). Increase of intracellular GSH also coincided unexpectedly. Moreover, the extracellular addition of N-acetyl-L-cysteine (NAC, 5 mM) effectively reduced the generation of ROS and MDA, and rescued the cells from NaAsO2 induced apoptosis and related alteration of mitochondria. These data suggest that the arsenic-induced cell apoptosis occurs though the mitochondrial pathway, and is mostly dependent on generation of ROS rather than GSH depletion in Chang human hepatocytes.}, }
@article {pmid19533749, year = {2009}, author = {Stockwin, LH and Han, B and Yu, SX and Hollingshead, MG and ElSohly, MA and Gul, W and Slade, D and Galal, AM and Newton, DL and Bumke, MA}, title = {Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction.}, journal = {International journal of cancer}, volume = {125}, number = {6}, pages = {1266-1275}, pmid = {19533749}, issn = {1097-0215}, support = {HHSN261200800001E/CA/NCI NIH HHS/United States ; N01CO12400/CA/NCI NIH HHS/United States ; N01-CO-12400/CO/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Artemisia/chemistry ; Artemisinins/*pharmacology ; Biomarkers/metabolism ; Blotting, Western ; Calcium/metabolism ; Cell Cycle/drug effects ; Dimerization ; Endoplasmic Reticulum/*drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Gene Expression Profiling ; Heme/*metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Lysine/analogs &amp; derivatives/pharmacology ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists &amp; inhibitors/metabolism ; Thapsigargin/pharmacology ; }, abstract = {Analogs of the malaria therapeutic, artemisinin, possess in vitro and in vivo anticancer activity. In this study, two dimeric artemisinins (NSC724910 and 735847) were studied to determine their mechanism of action. Dimers were >1,000 fold more active than monomer and treatment was associated with increased reactive oxygen species (ROS) and apoptosis induction. Dimer activity was inhibited by the antioxidant L-NAC, the iron chelator desferroxamine and exogenous hemin. Similarly, induction of heme oxygenase (HMOX) with CoPPIX inhibited activity, whereas inhibition of HMOX with SnPPIX enhanced it. These results emphasize the importance of iron, heme and ROS in activity. Microarray analysis of dimer treated cells identified DNA damage, iron/heme and cysteine/methionine metabolism, antioxidant response, and endoplasmic reticulum (ER) stress as affected pathways. Detection of an ER-stress response was relevant because in malaria, artemisinin inhibits pfATP6, the plasmodium orthologue of mammalian sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPases (SERCA). A comparative study of NSC735847 with thapsigargin, a specific SERCA inhibitor and ER-stress inducer showed similar behavior in terms of transcriptomic changes, induction of endogenous SERCA and ER calcium mobilization. However, thapsigargin had little effect on ROS production, modulated different ER-stress proteins and had greater potency against purified SERCA1. Furthermore, an inactive derivative of NSC735847 that lacked the endoperoxide had identical inhibitory activity against purified SERCA1, suggesting that direct inhibition of SERCA has little inference on overall cytotoxicity. In summary, these data implicate indirect ER-stress induction as a central mechanism of artemisinin dimer activity.}, }
@article {pmid19531965, year = {2009}, author = {Guo, Q and Mori, T and Jiang, Y and Hu, C and Osaki, Y and Yoneki, Y and Sun, Y and Hosoya, T and Kawamata, A and Ogawa, S and Nakayama, M and Miyata, T and Ito, S}, title = {Methylglyoxal contributes to the development of insulin resistance and salt sensitivity in Sprague-Dawley rats.}, journal = {Journal of hypertension}, volume = {27}, number = {8}, pages = {1664-1671}, doi = {10.1097/HJH.0b013e32832c419a}, pmid = {19531965}, issn = {1473-5598}, mesh = {Animals ; Blood Pressure ; Body Composition ; Glycation End Products, Advanced/metabolism ; Hypertension/*etiology ; Immunohistochemistry ; *Insulin Resistance ; Kidney/metabolism ; Male ; Oxidative Stress ; Pyruvaldehyde/*toxicity ; Rats ; Rats, Sprague-Dawley ; Sodium/urine ; Sodium Chloride, Dietary/*administration &amp; dosage ; Thiobarbituric Acid Reactive Substances/analysis ; }, abstract = {OBJECTIVES: Methylglyoxal, a metabolite of the glycolysis pathway, may play an important role in the development of diabetes and hypertension, but the exact mechanism has not been fully elucidated. The present study was designed to investigate whether methylglyoxal could directly induce insulin resistance and salt sensitivity in Sprague-Dawley rats.<br><br>METHODS: Rats were allocated to four groups: control (normal drinking water), 1% methylglyoxal in drinking water, 1% methylglyoxal plus N-acetyl cysteine (NAC) (800 mg/kg per day), a methylglyoxal scavenger, or TM2002 (100 mg/kg per day), an advanced glycation endproducts (AGEs) inhibitor. After 4-week treatment insulin resistance was evaluated by an euglycemic hyperinsulinemic glucose clamp technique. In another set of rats, either a high-salt diet (4%) alone, standard rat chow with 1% methylglyoxal in drinking water or high-salt diet plus methylglyoxal was given for 4 weeks. Immunohistochemistry was performed to measure nitrotyrosine and methylglyoxal-induced AGEs, N-carboxyethyl-lysine (CEL) in the kidney.<br><br>RESULTS: Four-week treatment with NAC or TM2002 completely improved methylglyoxal-induced insulin resistance. Co-administration of methylglyoxal and high-salt diet significantly increased systolic blood pressure, urinary albumin excretion, urinary thiobarbituric acid-reactive substances excretion and the renal nitrotyrosine expression in the kidney (markers of oxidative stress) compared with methylglyoxal or high-salt diet alone. Renal CEL was significantly increased in methylglyoxal-treated rats compared with nonmethylglyoxal-treated rats.<br><br>CONCLUSION: These results indicate that methylglyoxal-induced insulin resistance and salt sensitivity at least in part by increasing oxidative stress and/or AGEs formation in Sprague-Dawley rats. The present study provides further evidence for methylglyoxal as one of the causative factors in the pathogenesis of insulin resistance and salt-sensitive hypertension.}, }
@article {pmid19530032, year = {2009}, author = {Thorsen, S and Teisner, A and Jensen, SA and Philips, M and Dalhoff, K and Bendtsen, F}, title = {Effect of N-acetylcysteine on the accuracy of the prothrombin time assay of plasma coagulation factor II+VII+X activity in subjects infused with the drug. Influence of time and temperature.}, journal = {Scandinavian journal of clinical and laboratory investigation}, volume = {69}, number = {6}, pages = {643-650}, doi = {10.3109/00365510902943262}, pmid = {19530032}, issn = {1502-7686}, mesh = {Acetylcysteine/*administration &amp; dosage/*pharmacology ; Adult ; Antigens/metabolism ; Biological Assay/*methods ; Blood Coagulation Factors/*metabolism ; Factor VII/metabolism ; Factor X/metabolism ; Female ; Humans ; Infusions, Intravenous ; Male ; Prothrombin/metabolism ; Prothrombin Time/*methods ; Reagent Kits, Diagnostic ; *Temperature ; Time Factors ; Young Adult ; }, abstract = {OBJECTIVES: The prothrombin time (PT) assay of factor II+VII+X activity is an important predictor of liver damage in paracetamol poisoned patients. It complicates interpretation of results that the antidote, acetylcysteine (NAC) depresses this activity. The aim was to investigate if NAC influences the accuracy of the plasma PT assay.<br><br>MATERIALS AND METHODS: The accuracy of Nycotest PT was studied using plasma added NAC in vitro and plasma from subjects infused with NAC. The latter results were compared with those obtained by analysis of PT by CoaguChek S.<br><br>RESULTS: Therapeutic NAC concentrations added to plasma in vitro decreased factor II+VII+X activity at 37 degrees C in a time-dependent manner. This effect was quenched at temperatures <24 degrees C. Activity lost at 37 degrees C could partly be recovered by subsequent incubation at 5 or 20 degrees C. Incubation at 37 degrees C prior to assay led to a significant additional depression of factor II+VII+X activity in plasma from subjects infused with NAC during the first 3h of infusion indicating that it contained reactive NAC. The risk that this NAC interfered with the accuracy of the PT assay was considered minimal with samples stored below 24 degrees C. This was supported by similarity of results obtained by analysis of appropriately stored plasma and simultaneously drawn blood by CoaguChek S.<br><br>CONCLUSIONS: Residual reactive NAC does not interfere with the accuracy of the PT assay of plasma stored below 24 degrees C, but NAC-induced loss in activity at 37 degrees C may be partly recovered during subsequent storage below 24 degrees C.}, }
@article {pmid19528494, year = {2009}, author = {Nadasi, E and Clark, JS and Szanyi, I and Varjas, T and Ember, I and Baliga, R and Arany, I}, title = {Epigenetic modifiers exacerbate oxidative stress in renal proximal tubule cells.}, journal = {Anticancer research}, volume = {29}, number = {6}, pages = {2295-2299}, pmid = {19528494}, issn = {0250-7005}, support = {//Intramural NIH HHS/United States ; }, mesh = {Animals ; Antifungal Agents/*pharmacology ; Antimetabolites, Antineoplastic/*pharmacology ; Azacitidine/*analogs &amp; derivatives/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Decitabine ; Hydroxamic Acids/*pharmacology ; Kidney Tubules, Proximal/*drug effects/metabolism/*pathology ; Mice ; *Oxidative Stress ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Increased production of reactive oxygen species (ROS) by anticancer drugs has been described in patients with various malignancies, which might attribute to their nephrotoxicity.<br><br>MATERIALS AND METHODS: The effects of two epigenetic modifiers - trichostatin A (TSA) and 5-aza-deoxycytidine (5AZA) - on ROS production and cell injury alone or in combination with mild oxidative stress were studied in mouse renal proximal tubule cells.<br><br>RESULTS: Both agents increased mitochondrial ROS production and consequent lactate dehydrogenase (LDH) release either alone or in combination with a low dose of H(2)O(2). The antioxidant N-acetyl-cysteine (NAC) abolished LDH release. It was also found that CREB-mediated transcription, vital for survival of proximal tubule cells, is attenuated by these anticancer agents.<br><br>CONCLUSION: The ROS-inducing activity of TSAI and 5AZA might explain the in vivo nephrotoxicity of epigenetic modifiers. The mechanisms that are responsible for this injury could involve attenuation of pro-survival signaling and/or activation of death signaling pathway(s) associated with mitochondrial ROS release.}, }
@article {pmid19527772, year = {2010}, author = {Hung, WY and Wu, CW and Yin, PH and Chang, CJ and Li, AF and Chi, CW and Wei, YH and Lee, HC}, title = {Somatic mutations in mitochondrial genome and their potential roles in the progression of human gastric cancer.}, journal = {Biochimica et biophysica acta}, volume = {1800}, number = {3}, pages = {264-270}, doi = {10.1016/j.bbagen.2009.06.006}, pmid = {19527772}, issn = {0006-3002}, mesh = {Adenosine Triphosphate/metabolism ; Aged ; Amino Acid Substitution ; Cell Culture Techniques/methods ; Cell Movement ; DNA Primers ; DNA, Mitochondrial/*genetics ; DNA, Neoplasm/genetics ; Disease Progression ; Female ; Genome, Mitochondrial/*genetics ; Humans ; Male ; Middle Aged ; Mitochondria/pathology/physiology ; *Mutation ; Oxygen Consumption ; Point Mutation ; Polymorphism, Single Nucleotide ; Sequence Deletion ; Stomach/physiopathology ; Stomach Neoplasms/*genetics/pathology ; }, abstract = {BACKGROUND: Somatic mutation in mitochondrial DNA (mtDNA) has been proposed to contribute to initiation and progression of human cancer. In our previous study, high frequency of somatic mutations was found in the D-loop region of mtDNA of gastric cancers. However, it is unclear whether somatic mutations occur in the coding region of mtDNA of gastric cancers.<br><br>METHODS: Using DNA sequencing, we studied 31 gastric cancer specimens and corresponding non-cancerous stomach tissues. Moreover, a human gastric cancer SC-M1 cell line was treated with oligomycin to induce mitochondrial dysfunction. Cisplatin sensitivity and cell migration were analyzed.<br><br>RESULTS: We identified eight somatic mutations in the coding region of mtDNAs of seven gastric cancer samples (7/31, 22.6%). Patients with somatic mutations in the entire mtDNA of gastric cancers did not show significant association with their clinicopathologic features. Among the eight somatic mutations, five point mutations (G3697A, G4996A, G9986A, C12405T and T13015C) are homoplasmic and three mutations (5895delC, 7472insC and 12418insA) are heteroplasmic. Four (4/8, 50%) of these somatic mutations result in amino acid substitutions in the highly conserved regions of mtDNA, which potentially lead to mitochondrial dysfunction. In addition, in vitro experiments in SC-M1 cells revealed that oligomycin-induced mitochondrial dysfunction promoted resistance to cisplatin and enhanced cell migration. N-acetyl cysteine was effective in the prevention of the oligomycin-enhanced migration, which suggests that reactive oxygen species generated by defective mitochondria may be involved in the enhanced migration of SC-M1 cells.<br><br>GENERAL SIGNIFICANCE: Our results suggest that somatic mtDNA mutations and mitochondrial dysfunction may play an important role in the malignant progression of gastric cancer.}, }
@article {pmid19527004, year = {2009}, author = {Jian, W and Yao, M and Zhang, D and Zhu, M}, title = {Rapid detection and characterization of in vitro and urinary N-acetyl-L-cysteine conjugates using quadrupole-linear ion trap mass spectrometry and polarity switching.}, journal = {Chemical research in toxicology}, volume = {22}, number = {7}, pages = {1246-1255}, doi = {10.1021/tx900035j}, pmid = {19527004}, issn = {1520-5010}, mesh = {Acetaminophen/chemistry/toxicity/urine ; Acetylcysteine/*chemistry/toxicity/urine ; Analgesics, Non-Narcotic/chemistry/toxicity/urine ; Animals ; Chromatography, High Pressure Liquid/*methods ; Clozapine/chemistry ; Diclofenac/chemistry ; Glutathione/chemistry ; Humans ; Microsomes, Liver/metabolism ; Rats ; Tandem Mass Spectrometry/*methods ; }, abstract = {The present study describes a novel methodology for the rapid detection and structural characterization of unknown N-acetyl-L-cysteine (NAC) conjugates using polarity switching of triple quadrupole mass spectrometry. This method utilizes a negative neutral loss (NL) scan of 129 Da or multiple reaction monitoring (MRM) from predicted m/z values to product ions derived from the NL of 129 Da as a survey scan to trigger the acquisition of enhanced product ion (EPI) spectra in the positive ion mode. Thus, selective detection of NAC conjugates and acquisition of fragment-rich MS/MS spectra were accomplished in a single LC/MS run. The utility of this methodology was evaluated through analysis of NAC conjugates of acetaminophen in human urine after an oral dose. The MRM-EPI approach, which showed better sensitivity than the NL-EPI approach in analyzing urine samples, revealed three NAC-acetaminophen conjugates in the human urine, including two minor NAC conjugates that were derived from hydroxyl acetaminophen and methoxy acetaminophen. In addition, the methodology was applied to screening for reactive metabolites of clozapine and diclofenac using NAC as a trapping agent. Results showed reactive metabolite profiles comparable to those obtained from glutathione (GSH) trapping experiments, while MS/MS spectra of NAC conjugates provided more valuable structural information than those of GSH adducts. The study demonstrates that NAC trapping followed by NL-EPI analysis is a useful approach for high-throughput screening of reactive metabolites and that the MRM-EPI method is well-suited for analysis of low levels of NAC conjugates in urine.}, }
@article {pmid19526394, year = {2009}, author = {Laisalmi-Kokki, M and Pesonen, E and Kokki, H and Valta, P and Pitkänen, M and Teppo, AM and Honkanen, E and Lindgren, L}, title = {Potentially detrimental effects of N-acetylcysteine on renal function in knee arthroplasty.}, journal = {Free radical research}, volume = {43}, number = {7}, pages = {691-696}, doi = {10.1080/10715760902998206}, pmid = {19526394}, issn = {1029-2470}, mesh = {Acetylcysteine/*adverse effects ; Acetylglucosaminidase/urine ; Aged ; Alpha-Globulins/urine ; *Arthroplasty, Replacement, Knee ; Creatinine/blood/urine ; Cystatin C/blood ; Double-Blind Method ; Female ; Free Radical Scavengers/*adverse effects ; Glutathione S-Transferase pi/urine ; Glutathione Transferase/urine ; Humans ; Injections, Intravenous ; Isoenzymes/urine ; Kidney Diseases/*chemically induced ; Kidney Function Tests ; Kidney Tubules, Proximal/*drug effects ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {Ischaemia/reperfusion induces systemic inflammation and oxidative stress and thereby remote organ injury in the kidney. In a double-blind, placebo-controlled clinical trial of 30 patients undergoing knee arthroplasty with tourniquet, this study evaluated the effect of N-acetylcysteine (NAC) infusion on renal function by measuring urine alpha-1-microglobulin, N-acetyl-beta-D-glucosaminidase (NAG), glutathione-S-transferase-alpha and -phi and serum creatinine and cystatin C concentrations up to 24 h post-operatively. Compared to the baseline, urine alpha-1-microglobulin/creatinine increased in both groups and was higher in the NAC group than in the placebo group at tourniquet deflation and at 3 h thereafter. Urine NAG/creatinine increased at deflation and at 3 h thereafter in the NAC group and the ratio was higher than in the placebo group. The two sensitive indicators of proximal tubular damage and function used in the present study suggest that use of NAC in clinical setting of ischaemia/reperfusion injury may increase the risk of remote kidney injury.}, }
@article {pmid19524577, year = {2009}, author = {Lee, WM and Hynan, LS and Rossaro, L and Fontana, RJ and Stravitz, RT and Larson, AM and Davern, TJ and Murray, NG and McCashland, T and Reisch, JS and Robuck, PR and , }, title = {Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.}, journal = {Gastroenterology}, volume = {137}, number = {3}, pages = {856-64, 864.e1}, pmid = {19524577}, issn = {1528-0012}, support = {R01 DK058369/DK/NIDDK NIH HHS/United States ; R-01 DK58369/DK/NIDDK NIH HHS/United States ; R-03 DK52827/DK/NIDDK NIH HHS/United States ; U-01 DK58369/DK/NIDDK NIH HHS/United States ; U01 DK058369/DK/NIDDK NIH HHS/United States ; FD-R-001661/FD/FDA HHS/United States ; }, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/adverse effects ; Adolescent ; Adult ; Aged ; Analgesics, Non-Narcotic/*poisoning ; Double-Blind Method ; Female ; Hepatic Encephalopathy/drug therapy ; Humans ; Infusions, Intravenous ; Liver Failure, Acute/chemically induced/*drug therapy/mortality/surgery ; Liver Transplantation ; Male ; Middle Aged ; Survival Rate ; Young Adult ; }, abstract = {BACKGROUND &amp; AIMS: N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure.<br><br>METHODS: In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation.<br><br>RESULTS: A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I-II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III-IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031).<br><br>CONCLUSIONS: Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.}, }
@article {pmid19524565, year = {2009}, author = {Kalariya, NM and Wills, NK and Ramana, KV and Srivastava, SK and van Kuijk, FJ}, title = {Cadmium-induced apoptotic death of human retinal pigment epithelial cells is mediated by MAPK pathway.}, journal = {Experimental eye research}, volume = {89}, number = {4}, pages = {494-502}, doi = {10.1016/j.exer.2009.05.011}, pmid = {19524565}, issn = {1096-0007}, support = {DK36118/DK/NIDDK NIH HHS/United States ; GM71036/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Buthionine Sulfoximine/pharmacology ; Cadmium Chloride/*toxicity ; Cell Line ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Cytosol/enzymology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/toxicity ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinases/*metabolism ; Reactive Oxygen Species/metabolism ; Retinal Pigment Epithelium/metabolism/*pathology ; Time Factors ; }, abstract = {Cadmium (Cd), released from cigarette smoke and metal industrial activities, is known to accumulate in human body organs including retina and is particularly higher in retinal tissues of age-related macular degeneration (AMD) eyes compared to non-AMD eyes. We have determined the cytotoxic effects of Cd on human retinal pigment epithelial (RPE) cells. Upon Cd treatment, there was a dose- and time-dependent decline in ARPE-19 cell viability as well as early apoptotic changes such as altered mitochondrial membrane potential (MMP) and Cytochrome C release in cytosol. Depletion of GSH by buthionine-[S,R]-sulfoximine (BSO) resulted in increased Cd toxicity in ARPE-19 cells. Cadmium also caused reactive oxygen species (ROS) generation and activation of mitogen-activated protein kinases (MAPKs) pathway including c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (Erk1/2), and p38 in ARPE-19 cells. Antioxidants such as N-acetylcysteine (NAC) significantly reduced Cd-induced toxicity. These results indicate that elevated ROS-induced activation of the MAPK signaling pathway could be associated with Cd-induced RPE cell apoptosis, one of the major contributing factors in AMD. The toxic effects of Cd on ARPE-19 cells indicate that environmental heavy metals such as Cd could be important potential factors in RPE cells death associated retinal diseases particularly related to smoking.}, }
@article {pmid19524490, year = {2009}, author = {Tang, L and Chen, F and Yang, L and Wang, Q}, title = {The determination of low-molecular-mass thiols with 4-(hydroxymercuric)benzoic acid as a tag using HPLC coupled online with UV/HCOOH-induced cold vapor generation AFS.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {877}, number = {28}, pages = {3428-3433}, doi = {10.1016/j.jchromb.2009.05.053}, pmid = {19524490}, issn = {1873-376X}, mesh = {Chromatography, High Pressure Liquid/instrumentation/*methods ; Formates/chemistry ; Hydroxymercuribenzoates/chemistry ; Molecular Weight ; Oxidation-Reduction ; Spectrometry, Fluorescence/instrumentation/*methods ; Sulfhydryl Compounds/*chemistry ; }, abstract = {An alternative analytical method was established for simultaneous determination of main urinary low-molecular-mass (LMM) thiols including cysteine (Cys), cysteinylglycine (Cys-Gly), homocysteine (HCys), gamma-glutamyl cysteine (gamma-Glu-Cys) and glutathione (GSH) as well as N-acetylcysteine (NAC) using RPLC coupled on line with UV/HCOOH-induced cold vapor generation atomic fluorescence spectrometry (UV/HCOOH-CVG-AFS) with 4-(hydroxymercuric)benzoic acid (PHMB) as a tag. The LMM thiols were stabilized and labeled by PHMB allowing the determination of reduced form thiols (R-thiols) and total thiols (T-thiols) without and with Tris-(2-carboxyethyl)-phosphine reduction. UV/HCOOH-induced Hg cold vapor generation was used instead of K(2)SO(8)-KBH(4)/NaOH-HCl and/or KBrO(3)/KBr-KBH(4)/NaOH-HCl systems as an effective interface between RPLC and CVG-AFS. The limits of detection (3sigma) of RPLC-(UV/HCOOH)-CVG-AFS with PHMB labeling for Cys, HCys, Cys-Gly, gamma-Glu-Cys and GSH as well as NAC were 4.6, 5.9, 5.9, 8.1, 7.3 and 5.9nM with the RSD of 4.4, 5.1, 3.6, 7.5 4.2 and 3.7% (n=6 at 2microM), respectively, satisfying the simultaneous determination of the main urinary LMM thiols. This developed method was applied successfully to determine the LMM R-thiols and T-thiols in 10 urine samples contributed by 10 healthy volunteers.}, }
@article {pmid19523979, year = {2009}, author = {Hossain, S and Liu, HN and Nguyen, M and Shore, G and Almazan, G}, title = {Cadmium exposure induces mitochondria-dependent apoptosis in oligodendrocytes.}, journal = {Neurotoxicology}, volume = {30}, number = {4}, pages = {544-554}, doi = {10.1016/j.neuro.2009.06.001}, pmid = {19523979}, issn = {1872-9711}, mesh = {Amino Acid Chloromethyl Ketones/pharmacology ; Analysis of Variance ; Animals ; Animals, Newborn ; Apoptosis/*drug effects ; Brain/cytology ; Cadmium/*toxicity ; Caspase 3/metabolism ; Cells, Cultured ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; In Situ Nick-End Labeling/methods ; L-Lactate Dehydrogenase/metabolism ; Mitochondria/*drug effects ; Neuroprotective Agents/pharmacology ; Oligodendroglia/*drug effects ; Propidium ; Rats ; Rats, Sprague-Dawley ; Time Factors ; }, abstract = {Cadmium toxicity has been associated with learning disabilities and Parkinsonian symptoms in humans. We have previously shown that cultured oligodendrocytes are directly damaged by cadmium exposure. Here, we characterized the molecular mechanisms underlying cadmium-induced cell death in oligodendrocyte progenitors (OLP). Cadmium caused a concentration-dependent decrease in cell viability as assessed by mitochondrial dehydrogenase activity and by the cellular release of lactate dehydrogenase (LDH). A short exposure (1h) to cadmium (25-100 microM), followed by several hours of recovery, produced a predominant apoptotic mechanism of cell death, involving the mitochondrial intrinsic pathway, as evidenced by nuclear condensation, DNA fragmentation, bax integration into the outer mitochondrial membrane, cytochrome c release, and activation of caspases-9 and -3. Pretreatment of OLPs with the pan-caspase inhibitor, zVAD-fmk, prevented caspase-3 activation but only slightly reduced cell death 11h after cadmium exposure and failed to prevent cadmium-induced bax insertion into the mitochondrial membrane. In contrast, the anti-oxidant N-acetyl cysteine blocked caspase-3 activation and significantly protected OLPs from cadmium-induced cell death. Continuous exposure (18-48 h) of OLPs to low micromolar concentrations (0.001-25 microM) of cadmium significantly decreased mitochondrial metabolic activity, increased LDH leakage starting at 5 microM and maximally activated caspase-3. These results suggest that cadmium induces OLP cell death mainly by apoptosis, and at higher concentrations or with prolonged exposure to the heavy metal there is an increase in cytoplasmic membrane damage, an index of necrosis. More importantly, transient exposure to cadmium is sufficient to damage OLPs and could in principle impair myelination in the neonate.}, }
@article {pmid19523936, year = {2009}, author = {González, R and Ferrín, G and Hidalgo, AB and Ranchal, I and López-Cillero, P and Santos-Gónzalez, M and López-Lluch, G and Briceño, J and Gómez, MA and Poyato, A and Villalba, JM and Navas, P and de la Mata, M and Muntané, J}, title = {N-acetylcysteine, coenzyme Q10 and superoxide dismutase mimetic prevent mitochondrial cell dysfunction and cell death induced by d-galactosamine in primary culture of human hepatocytes.}, journal = {Chemico-biological interactions}, volume = {181}, number = {1}, pages = {95-106}, doi = {10.1016/j.cbi.2009.06.003}, pmid = {19523936}, issn = {1872-7786}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Caspase 3/metabolism ; Cells, Cultured ; Female ; Galactosamine/*pharmacology ; Glutathione/metabolism ; Hepatocytes/*drug effects/pathology ; Humans ; L-Lactate Dehydrogenase/metabolism ; Male ; Middle Aged ; Mitochondria, Liver/*drug effects/metabolism/physiology ; Molecular Mimicry ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/*pharmacology ; Ubiquinone/*analogs &amp; derivatives/pharmacology ; }, abstract = {D-Galactosamine (D-GalN) induces reactive oxygen species (ROS) generation and cell death in cultured hepatocytes. The aim of the study was to evaluate the cytoprotective properties of N-acetylcysteine (NAC), coenzyme Q(10) (Q(10)) and the superoxide dismutase (SOD) mimetic against the mitochondrial dysfunction and cell death in D-GalN-treated hepatocytes. Hepatocytes were isolated from liver resections. NAC (0.5 mM), Q(10) (30 microM) or MnTBAP (Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (1mg/mL) were co-administered with D-GalN (40 mM) in hepatocytes. Cell death, oxidative stress, mitochondrial transmembrane potential (MTP), ATP, mitochondrial oxidized/reduced glutathione (GSH) and Q(10) ratios, electronic transport chain (ETC) activity, and nuclear- and mitochondria-encoded expression of complex I subunits were determined in hepatocytes. d-GalN induced a transient increase of mitochondrial hyperpolarization and oxidative stress, followed by an increase of oxidized/reduced GSH and Q(10) ratios, mitochondrial dysfunction and cell death in hepatocytes. The cytoprotective properties of NAC supplementation were related to a reduction of ROS generation and oxidized/reduced GSH and Q(10) ratios, and a recovery of mitochondrial complexes I+III and II+III activities and cellular ATP content. The co-administration of Q(10) or MnTBAP recovered oxidized/reduced GSH ratio, and reduced ROS generation, ETC dysfunction and cell death induced by D-GalN. The cytoprotective properties of studied antioxidants were related to an increase of the protein expression of nuclear- and mitochondrial-encoded subunits of complex I. In conclusion, the co-administration of NAC, Q(10) and MnTBAP enhanced the expression of complex I subunits, and reduced ROS production, oxidized/reduced GSH ratio, mitochondrial dysfunction and cell death induced by D-GalN in cultured hepatocytes.}, }
@article {pmid19523508, year = {2009}, author = {Koros, C and Kitraki, E}, title = {Neurofilament isoform alterations in the rat cerebellum following cytosine arabinoside administration.}, journal = {Toxicology letters}, volume = {189}, number = {3}, pages = {215-218}, doi = {10.1016/j.toxlet.2009.05.024}, pmid = {19523508}, issn = {1879-3169}, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Antimetabolites, Antineoplastic/*toxicity ; Antioxidants/pharmacology ; Blotting, Western ; Cerebellum/drug effects/*metabolism ; Cytarabine/*toxicity ; Immunohistochemistry ; Isomerism ; Male ; Neurofilament Proteins/chemistry/*metabolism ; Rats ; Rats, Wistar ; }, abstract = {A number of neurotoxic agents could potentially exert their action by degrading or modifying cytoskeleton components like neurofilaments (NF). Cytosine arabinoside (AraC) is an anticancer drug commonly used in leukemia treatment. Its side effects include neuronal cell death in the cerebellum and severe motor coordination deficits. We have previously shown that AraC administration (400mg/kg bw) in adult rats reduced NF immunostaining in cerebellar neurons. To further delineate the susceptibility of individual NF isoforms (NF-H, NF-M, NF-L) to AraC, in the present study we used Western blot analysis to quantify their level. A significant and selective reduction of NF-H isoform was observed in the cerebellum of AraC-treated animals, compared to the controls. Administration of the antioxidant N-acetylcysteine (NAC) for a period of 14 days (prior to and during AraC treatment), which was previously shown to ameliorate the AraC-induced motor deficits in these animals, largely prevented the reduction in NF-H isoform. Given the significant role of NF proteins and particularly NF-H in maintaining structural integrity and synaptic transport, the observed loss of this isoform may be a key-target of AraC action in cerebellar neurons. Moreover, this study provides further data on the neuroprophylactic role of NAC in vivo against chemotherapy-induced toxicity.}, }
@article {pmid19521638, year = {2009}, author = {Wood, SJ and Yücel, M and Pantelis, C and Berk, M}, title = {Neurobiology of schizophrenia spectrum disorders: the role of oxidative stress.}, journal = {Annals of the Academy of Medicine, Singapore}, volume = {38}, number = {5}, pages = {396-396}, pmid = {19521638}, issn = {2972-4066}, mesh = {Acetylcysteine ; Glutathione ; Humans ; Magnetic Resonance Imaging ; Mitochondrial Diseases ; Nervous System/*physiopathology ; *Oxidative Stress ; Schizophrenia/*physiopathology ; }, abstract = {Mitochondrial dysfunction and oxidative stress are increasingly implicated in the pathophysiology of schizophrenia. The brain is the body's highest energy consumer, and the glutathione system is the brain's dominant free radical scavenger. In the current paper, we review the evidence of central and peripheral nervous system anomalies in the oxidative defences of individuals with schizophrenia, principally involving the glutathione system. This is reflected by evidence of the manifold consequences of oxidative stress that include lipid peroxidation, protein carboxylation, DNA damage and apoptosis - all potentially part of the process of neuroprogression in the disorder. Importantly, oxidative stress is amenable to intervention. We consider the clinical potential of some possible interventions that help reduce oxidative stress, via augmentation of the glutathione system, particularly N-acetyl cysteine. We argue that a better understanding of the mechanisms and pathways underlying oxidative stress will assist in developing the therapeutic potential of this area.}, }
@article {pmid19520919, year = {2010}, author = {Wang, T and Chiang, ET and Moreno-Vinasco, L and Lang, GD and Pendyala, S and Samet, JM and Geyh, AS and Breysse, PN and Chillrud, SN and Natarajan, V and Garcia, JG}, title = {Particulate matter disrupts human lung endothelial barrier integrity via ROS- and p38 MAPK-dependent pathways.}, journal = {American journal of respiratory cell and molecular biology}, volume = {42}, number = {4}, pages = {442-449}, pmid = {19520919}, issn = {1535-4989}, support = {P01 HL058064/HL/NHLBI NIH HHS/United States ; HL058064-13/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/*adverse effects/pharmacology ; Antioxidants/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/*enzymology/pathology ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation/drug effects ; HSP27 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins ; Humans ; Imidazoles/pharmacology ; Lung ; Lung Diseases/*enzymology/etiology ; Molecular Chaperones ; Oxidative Stress/drug effects ; Particulate Matter/*adverse effects/pharmacology ; Phosphorylation/drug effects ; Pyridines/pharmacology ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased cardiopulmonary mortality and morbidity. The mechanisms of PM-mediated lung pathophysiology, however, remain unknown. We tested the hypothesis that PM, via enhanced oxidative stress, disrupts lung endothelial cell (EC) barrier integrity, thereby enhancing organ dysfunction. Using PM collected from Ft. McHenry Tunnel (Baltimore, MD), we assessed PM-mediated changes in transendothelial electrical resistance (TER) (a highly sensitive measure of barrier function), reactive oxygen species (ROS) generation, and p38 mitogen-activated protein kinase (MAPK) activation in human pulmonary artery EC. PM induced significant dose (10-100 microg/ml)- and time (0-10 h)-dependent EC barrier disruption reflected by reduced TER values. Exposure of human lung EC to PM resulted in significant ROS generation, which was directly involved in PM-mediated EC barrier dysfunction, as N-acetyl-cysteine (NAC, 5 mM) pretreatment abolished both ROS production and barrier disruption induced by PM. Furthermore, PM induced p38 MAPK activation and HSP27 phosphorylation, events that were both attenuated by NAC. In addition, PM-induced EC barrier disruption was partially prevented by the p38 MAP kinase inhibitor SB203580 (10 microM) as well as by reduced expression of either p38 MAPK beta or HSP27 (siRNA). These results demonstrate that PM induces ROS generation in human lung endothelium, resulting in oxidative stress-mediated EC barrier disruption via p38 MAPK- and HSP27-dependent pathways. These findings support a novel mechanism for PM-induced lung dysfunction and adverse cardiopulmonary outcomes.}, }
@article {pmid19508647, year = {2010}, author = {Michael, AJ and Alexopoulos, C and Pontiki, EA and Hadjipavlou-Litina, DJ and Saratsis, P and Ververidis, HN and Boscos, CM}, title = {Effect of N-acetyl-L-cysteine supplementation in semen extenders on semen quality and reactive oxygen species of chilled canine spermatozoa.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {45}, number = {2}, pages = {201-207}, doi = {10.1111/j.1439-0531.2008.01202.x}, pmid = {19508647}, issn = {1439-0531}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; *Cold Temperature ; Dogs/*physiology ; Dose-Response Relationship, Drug ; Male ; Reactive Oxygen Species/*analysis ; Semen/chemistry/*physiology ; Semen Preservation/methods/*veterinary ; }, abstract = {The objective of this study was to evaluate the quality of chilled dog semen processed with extenders containing various concentrations of N-acetyl-L-cysteine (NAC). Ejaculates from five dogs were collected, pooled and evaluated for concentration, motility, rapid steady forward movement (RSF-movement), viability, acrosomal integrity and by the hypo-osmotic swelling test (HOST). In addition, superoxide anion (O(2)(-*)) production, hydroxyl radicals (OH(*)) and total reactive oxygen species (tROS) were determined. The pool was divided into five aliquots, which were diluted to a final concentration of 66.66 x 10(6) spermatozoa/ml with Tris-glucose-egg yolk extender containing one of the following concentrations of NAC (0, 0.5, 1, 2.5 or 5 mm). The semen aliquots were chilled and preserved at 4 degrees C. Semen quality was evaluated after rewarming at 72 h. Sperm motility was significantly higher with the 0.5 mm concentration compared with the control group (p = 0.001). Rapid steady forward movement was higher with the 0.5 and 1 mm concentrations compared with the control and 5 mm group (p < 0.001). Viability and HOST percentages were not significantly altered. Compared with the control, the 5 mm concentration showed significantly reduced percentages of spermatozoa with normal acrosomes (p = 0.049). None of the ROS values at 72 h were significantly affected by the presence of NAC in semen extenders, although all NAC concentrations showed lower O(2)(-*) and OH(*) values compared with the control. Only the concentrations of 1 and 5 mm inhibited the significant increase of tROS values after 72 h, compared with the fresh semen value. In conclusion, NAC supplementation of semen extenders is beneficial to semen motility of canine spermatozoa during chilling with the 0.5 mm concentration being the most effective, although no significant ROS inhibition was observed at 72 h.}, }
@article {pmid19505990, year = {2009}, author = {Mannargudi, B and McNally, D and Reynolds, W and Uetrecht, J}, title = {Bioactivation of minocycline to reactive intermediates by myeloperoxidase, horseradish peroxidase, and hepatic microsomes: implications for minocycline-induced lupus and hepatitis.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {37}, number = {9}, pages = {1806-1818}, doi = {10.1124/dmd.109.027292}, pmid = {19505990}, issn = {1521-009X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Bacterial Agents/*adverse effects/*metabolism ; Biotransformation/*drug effects ; Chromatography, High Pressure Liquid ; Free Radical Scavengers/pharmacology ; Free Radicals ; Hepatitis, Autoimmune/*etiology/pathology ; Horseradish Peroxidase/*pharmacology ; In Vitro Techniques ; Lupus Erythematosus, Systemic/*chemically induced/pathology ; Magnetic Resonance Spectroscopy ; Male ; Microsomes, Liver/*metabolism ; Minocycline/*adverse effects/*metabolism ; Oxidation-Reduction ; Peroxidase/*pharmacology ; Rats ; Rats, Inbred BN ; Tandem Mass Spectrometry ; }, abstract = {Of the tetracyclines, minocycline is unique in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. It is also unique among the tetracyclines in having a para-N,N-dimethylaminophenol ring. Many drugs that cause autoimmune reactions are oxidized to reactive metabolites by the myeloperoxidase (MPO) system of macrophages. In this study, we showed that minocycline is oxidized to reactive intermediates by MPO/H(2)O(2)/Cl(-), HOCl, horseradish peroxidase/H(2)O(2), or hepatic microsomes. When trapped with N-acetylcysteine (NAC), two adducts with protonated molecular ions at m/z 619 were isolated and analyzed by NMR. One represents attack of the aromatic D ring by NAC meta to the N,N-dimethylamino group, which implies that the reactive intermediate was a quinone iminium ion. The NMR of the other adduct, which was not observed when minocycline was oxidized by hepatic microsomes, indicates that the NAC is attached at the junction of the B and C rings. In the oxidation by HOCl, we found an intermediate with a protonated molecular ion of m/z 510 that represents the addition of HOCl to minocycline. The HOCl presumably adds across the double bond of the B ring, and reaction of this intermediate with NAC led to the second NAC adduct. We were surprised to find that the same NAC adduct was not observed after oxidation of tetracycline with HOCl, even though this part of the tetracycline structure is the same as for minocycline. We propose that one or more of these reactive metabolites are responsible for the idiosyncratic drug reactions that are specific to this tetracycline.}, }
@article {pmid19505518, year = {2009}, author = {Petronilho, F and Araújo, JH and Steckert, AV and Rezin, GT and Ferreira, GK and Roesler, R and Schwartsmann, G and Dal-Pizzol, F and Streck, EL}, title = {Effect of a gastrin-releasing peptide receptor antagonist and a proton pump inhibitor association in an animal model of gastritis.}, journal = {Peptides}, volume = {30}, number = {8}, pages = {1460-1465}, doi = {10.1016/j.peptides.2009.04.026}, pmid = {19505518}, issn = {1873-5169}, mesh = {Animals ; Bombesin/*analogs &amp; derivatives/pharmacology ; Disease Models, Animal ; Gastric Mucosa/drug effects/pathology ; Gastritis/chemically induced/pathology/*prevention &amp; control ; Indomethacin/toxicity ; Lipid Peroxidation/drug effects ; Male ; Mitochondria/*drug effects/metabolism ; Omeprazole/*pharmacology ; Peptide Fragments/*pharmacology ; Protein Carbonylation/drug effects ; Proton Pump Inhibitors/*pharmacology ; Rats ; Rats, Wistar ; Receptors, Bombesin/*antagonists &amp; inhibitors ; Superoxides/metabolism ; Thiobarbiturates/metabolism ; }, abstract = {It has been proposed that reactive oxygen species play a causative role of gastric mucosal damage induced by increased gastric secretion. Gastrin-releasing peptide is a typical neuropeptide that stimulates acid secretion by release of gastrin. In the present work we have investigated the mechanism of indomethacin (IDM)-induced gastric ulcer caused by ROS and determined the effects of a selective gastrin-releasing peptide receptor antagonist, RC-3095, alone and in association with omeprazole (OM) and compared it with an established antioxidant compound N-acetyl cysteine (NAC). Adult male Wistar rats were pre-treated for 7 days with OM, RC-3095, NAC, both drugs and water (control). The animals were then submitted to fasting for 24h; IDM was administered. Rats were killed 6h after that and the stomachs were used for evaluation of macroscopic damage and oxidative stress parameters. Our results showed that IDM increased mitochondrial superoxide production; OM and RC-3095 alone did not prevent such effect, but the combination of these drugs was effective. TBARS assay revealed that IDM-induced lipid peroxidation in gastric tissue and that OM and RC-3095, alone or in combination, prevented this effect with superior action that NAC. Finally, we verified that IDM increased protein carbonyl content and that this effect was prevented RC-3095, alone or in combination with OM, being similar to standard antioxidant. The present results support the view that, besides the inhibition of acid secretion, the protective effects exerted by OM and RC-3095 against IDM-induced gastric damage can be ascribed to a reduction of gastric oxidative injury.}, }
@article {pmid19504015, year = {2009}, author = {Oliveira, DM and Gomes, ES and Mussivand, T and Fiorelli, AI and Gomes, OM}, title = {Effects of n-acetylcysteine on ischemic preconditioning: study in isolated rat hearts.}, journal = {Revista brasileira de cirurgia cardiovascular : orgao oficial da Sociedade Brasileira de Cirurgia Cardiovascular}, volume = {24}, number = {1}, pages = {23-30}, doi = {10.1590/s0102-76382009000100006}, pmid = {19504015}, mesh = {Acetylcysteine/*administration &amp; dosage ; Analysis of Variance ; Animals ; Coronary Circulation/*drug effects ; Free Radical Scavengers/*administration &amp; dosage ; Heart Rate/*drug effects ; Ischemic Preconditioning, Myocardial/*methods ; Models, Animal ; Myocardial Contraction/*drug effects ; Rats ; Rats, Wistar ; Time Factors ; }, abstract = {OBJECTIVE: The aim of this study is to assess if N-Acetylcysteine (NAC) changes the Ischemic Preconditioning (IP) in isolated rat hearts using only one cycle of IP.<br><br>METHODS: Heart Rate (HR), Coronary Flow (CF) and Myocardial Contractility (dP/dt) were registered in 30 Wistar rat's hearts. After anesthesia the hearts were removed and perfused with Krebes-Hensleit equilibrated solution with 95% of O2 and 5% of CO2 according Langendorff's method. GI: Control (n=6); GII: 20 min. ischemia (n=6); GIII: IP (n=6); GIV 50 microg/ml/min NAC before IP (n =6); GV: 100 microg/ ml/min NAC before IP (n=6). Parameters were measured after 15 min. of stabilization (T 0) and T3, T5, T10, T15, T20, T25 and T30 min. after reperfusion. Statistical significance was considered when P<0.05.<br><br>RESULTS: There were changes on HR comparing GI with GII at T20 and T25 and comparing GI with GIII, GIV with GV at T10 and T20 (P<0.05). CF was different comparing GI with GII at T3 and T5, GI with GIV at T10 and GI with GV at T10 and T25 (P<0.05). Myocardial Contractility was similar comparing GIII with GI and GV. GIII had higher dP/dt than GIV but without statistical difference (P>0.05). dP/dt was higher in GV than GIV but with statistically significant difference only at T30.<br><br>CONCLUSION: dP/dt was better in preconditioned hearts and was changed if using NAC in GIV. The use of NAC didn't change the effects of preconditioning on myocardial contractility in GV.}, }
@article {pmid19503098, year = {2009}, author = {Thornber, K and Colomba, A and Ceccato, L and Delsol, G and Payrastre, B and Gaits-Iacovoni, F}, title = {Reactive oxygen species and lipoxygenases regulate the oncogenicity of NPM-ALK-positive anaplastic large cell lymphomas.}, journal = {Oncogene}, volume = {28}, number = {29}, pages = {2690-2696}, doi = {10.1038/onc.2009.125}, pmid = {19503098}, issn = {1476-5594}, mesh = {Apoptosis ; Arachidonate 5-Lipoxygenase/*metabolism ; Cell Line, Tumor ; Humans ; Lipoxygenase Inhibitors/pharmacology ; Lymphoma, Large-Cell, Anaplastic/enzymology/*pathology ; Masoprocol/analysis ; Protein-Tyrosine Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {The chimera nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), the tyrosine kinase activity of which is constitutively upregulated, is the causative agent of 75% of the anaplastic large-cell lymphomas (ALCLs). We have demonstrated that NPM-ALK induces the production of reactive oxygen species (ROS) by a pathway involving the arachidonic acid-metabolizing enzymes of the lipoxygenase (LOX) family. The use of the LOX inhibitor nordihydroguaiaretic acid (NDGA) and of the anti-oxidant N-acetylcysteine (NAC) demonstrated that ROS are important in maintaining the ALK kinase active. Consistent with this, NDGA treatment resulted in the inhibition of key pathways, such as Akt, signal transducer and activator of transcription factor 3 (STAT3) and extracellular signal-regulated kinase (ERK), which are involved in NPM-ALK antiapoptotic and pro-mitogenic functions. Conversely, the stress-activated kinase p38, described in some instances as a mediator of apoptosis, was activated. Interestingly, 5-LOX, an isoform involved in many cancers, was found to be activated in NPM-ALK(+) cells. Functional studies have shown that transforming properties, namely proliferation and resistance to apoptosis, were abrogated by treatment with either NDGA or the 5-LOX inhibitor (N-(3-phenoxycinnamyl)-acetohydroxamic acid) (BW A4C). Together, these data point to the ROS/LOX pathway as a potential new target for therapy in NPM-ALK-positive tumors.}, }
@article {pmid19502361, year = {2009}, author = {Venkatesh, M and Rong, L and Raad, I and Versalovic, J}, title = {Novel synergistic antibiofilm combinations for salvage of infected catheters.}, journal = {Journal of medical microbiology}, volume = {58}, number = {Pt 7}, pages = {936-944}, doi = {10.1099/jmm.0.009761-0}, pmid = {19502361}, issn = {0022-2615}, mesh = {Anti-Infective Agents/administration &amp; dosage/*pharmacology ; Biofilms/*drug effects ; Candida albicans/*drug effects ; Catheters, Indwelling/adverse effects/*microbiology ; Drug Synergism ; Drug Therapy, Combination ; Humans ; Microscopy, Confocal ; Staphylococcus epidermidis/*drug effects ; }, abstract = {Biofilms on catheters are responsible for catheter-related bloodstream infections (CRBSIs), which cause significant mortality and morbidity. Antimicrobial catheter-lock solutions may salvage precious catheters by eradicating biofilms. Staphylococcus epidermidis and Candida albicans are frequently isolated organisms in CRBSIs. We evaluated N-acetylcysteine (NAC), EDTA, ethanol and talactoferrin (TLF) individually and in combination with antibiotics against biofilms of S. epidermidis and C. albicans to identify effective catheter-lock solutions. Minimum biofilm-eradication concentrations causing 50% inhibition (MBEC(50)) for EDTA, NAC, ethanol and TLF were determined against biofilms of S. epidermidis and C. albicans formed on 96-well microtitre plates. Biomass, mean thickness and viability of S. epidermidis and C. albicans biofilms were evaluated after exposure to MBEC(50) concentrations of EDTA, NAC, ethanol and TLF. Antimicrobial combinations of EDTA, NAC, ethanol and TLF with nafcillin, vancomycin, fluconazole and amphotericin B were evaluated systematically for synergy using combination indices (CIs). EDTA, NAC, ethanol and TLF significantly reduced biofilm biomass and mean thickness (P<0.05, one-way ANOVA) of monomicrobial and polymicrobial biofilms as evaluated by confocal microscopy. CIs evaluated at equipotency ratios, and 50, 75 and 90 % effects, showed that EDTA, NAC, ethanol and TLF were synergistic (CI <1) with antibiotics (with few exceptions) against biofilms of S. epidermidis and C. albicans. EDTA, NAC, ethanol and TLF inhibit monomicrobial and polymicrobial biofilms of neonatal strains of S. epidermidis and C. albicans, and are synergistic with antibiotics. Catheter-lock solutions of EDTA, NAC and ethanol alone or in combination with antibiotics may be used to salvage infected catheters, which will directly impact on patient morbidity and health-care costs.}, }
@article {pmid19498006, year = {2009}, author = {Ngô, C and Chéreau, C and Nicco, C and Weill, B and Chapron, C and Batteux, F}, title = {Reactive oxygen species controls endometriosis progression.}, journal = {The American journal of pathology}, volume = {175}, number = {1}, pages = {225-234}, pmid = {19498006}, issn = {1525-2191}, mesh = {Adult ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Catalase/drug effects/metabolism ; Cell Line ; Cell Proliferation/drug effects ; Disease Progression ; Endometriosis/*metabolism ; Extracellular Signal-Regulated MAP Kinases/drug effects/metabolism ; Female ; Humans ; Hydrogen Peroxide/metabolism ; Mice ; Mice, Nude ; Oxidative Stress/*physiology ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/drug effects/metabolism ; }, abstract = {Endometriosis is associated with chronic inflammation, and reactive oxygen species (ROS) are proinflammatory mediators that modulate cell proliferation. We have investigated whether the dysregulation of ROS production in endometriotic cells correlates with a pro-proliferative phenotype and can explain the spreading of this disease. Stromal and epithelial cells were purified from ovarian endometrioma and eutopic endometrium from 14 patients with endometriosis to produce four primary cell lines from each patient. ROS production, detoxification pathways, cell proliferation, and mitogen-activated protein kinase pathway activation were studied and compared with epithelial and stromal cell lines from 14 patients without endometriosis. Modulation of the proliferation of endometriosis by N-acetyl-cysteine, danazol, and mifepristone was tested in vitro and in 28 nude mice implanted with endometriotic tissue of human origin. Endometriotic cells displayed higher endogenous oxidative stress with an increase in ROS production, alterations in ROS detoxification pathways, and a drop in catalase levels, as observed for tumor cells. This increase in endogenous ROS correlated with increased cellular proliferation and activation of ERK1/2. These phenomena were abrogated by the antioxidant molecule N-acetyl-cysteine both in vitro and in a mouse model of endometriosis. Human endometriotic cells display activated pERK, enhanced ROS production, and proliferative capability. Our murine model shows that antioxidant molecules could be used as safe and efficient treatments for endometriosis.}, }
@article {pmid19497427, year = {2009}, author = {Fasano, WJ and Sweeney, LM and Mawn, MP and Nabb, DL and Szostek, B and Buck, RC and Gargas, ML}, title = {Kinetics of 8-2 fluorotelomer alcohol and its metabolites, and liver glutathione status following daily oral dosing for 45 days in male and female rats.}, journal = {Chemico-biological interactions}, volume = {180}, number = {2}, pages = {281-295}, doi = {10.1016/j.cbi.2009.03.015}, pmid = {19497427}, issn = {1872-7786}, mesh = {Animals ; Body Weight ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Fluorocarbons ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Hydrocarbons, Fluorinated/*administration &amp; dosage/chemistry/metabolism/*pharmacokinetics/toxicity ; Liver/*metabolism ; Male ; Molecular Structure ; Rats ; Sex Characteristics ; }, abstract = {Fluorotelomer alcohols (FTOHs) are raw materials used in the manufacture of polymeric and surfactant products. Based on previous findings from single oral dosing in rats with radiolabeled 8-2 FTOH, glutathione (GSH) depletion and/or the presence of perfluorinated/polyfluorinated acids and aldehyde metabolites was hypothesized to account for the hepatocellular lesions observed in male rats from a 90-day subchronic oral dosing study. Further, the reported nephropathy in female rats from the subchronic experiment was hypothesized to have been initiated by a thiol metabolite produced by degradation of GSH conjugates. In the current investigation, the kinetics of 8-2 FTOH and its metabolites along with liver GSH status were evaluated in the rat following daily oral dosing with 8-2 FTOH for 45 days at 5 and 125 mg/kg/day. Liver GSH stores 1-2h after dosing were unaffected, suggesting that GSH depletion is not likely a relevant mode of action in the liver. The tissue metabolite data indicate that the liver toxicity mode of action is likely associated with elevated levels of perfluoroalkyl acids found in males, since other polyfluorinated metabolites and 8-2 FTOH were present in livers from female rats at comparable or higher levels. Detection of the N-acetyl cysteine conjugate of the unsaturated parent telomer alcohol in urine from female rats and not male rats provides some evidence to support the mechanistic basis for the observed kidney effects. Further, the increasing levels of perfluorooctanoic acid (PFOA) in plasma from female rats over the 45-day dosing phase, while unexpected, may reflect an increased net absorption of 8-2 FTOH, slow elimination of intermediates in the metabolic pathway between 8-2 FTOH and PFOA, or altered kidney clearance. The results of this study have enhanced our understanding of 8-2 FTOH kinetics and metabolism and potential modes of action in the rat, which will guide the design of future studies for FTOHs and our need to define the mechanistic basis for the observed effects.}, }
@article {pmid19496063, year = {2010}, author = {Matsunaga, N and Tsuruma, K and Shimazawa, M and Yokota, S and Hara, H}, title = {Inhibitory actions of bilberry anthocyanidins on angiogenesis.}, journal = {Phytotherapy research : PTR}, volume = {24 Suppl 1}, number = {}, pages = {S42-7}, doi = {10.1002/ptr.2895}, pmid = {19496063}, issn = {1099-1573}, mesh = {Acetylcysteine/pharmacology ; Angiogenesis Inhibitors/*pharmacology ; Anthocyanins/*pharmacology ; Biphenyl Compounds/metabolism ; Coculture Techniques ; Endothelial Cells/*drug effects ; Fibroblasts/drug effects ; Free Radical Scavengers/*pharmacology ; Humans ; Molecular Structure ; Picrates/metabolism ; Umbilical Veins/cytology ; Vaccinium myrtillus/*chemistry ; Vascular Endothelial Growth Factor A ; }, abstract = {The aim of this study was to examine the antiangiogenic properties and antioxidant activities (a) of the main anthocyanidins (delphinidin, cyanidin and malvidin) found as constituents in Vaccinium myrtillus (bilberry) anthocyanosides (VMA) and (b) of N-acetyl-L-cysteine (NAC). Each of these anthocyanidins concentration-dependently inhibited vascular endothelial growth factor (VEGF)-induced tube formation in a co-culture of human umbilical vein endothelial cells (HUVECs) and fibroblasts, the effect of each anthocyanidin being significant at 3 and/or 10 microM, while NAC significantly inhibited such tube formation at 1 microM (the only concentration tested). Moreover, each anthocyanidin (0.3-10 microM) and NAC (1-1000 microM) concentration-dependently scavenged the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. The inhibitory effects against angiogenesis were similar among the anthocyanidins, as were those against the DPPH radical. Moreover, their radical-scavenging effects were induced by concentrations that were at or below those that induced their antiangiogenic effects. These findings indicate that the inhibitory effect of VMA on angiogenesis may depend on those of its main constituent anthocyanidins (delphinidin, cyanidin and malvidin), presumably via antioxidant effects.}, }
@article {pmid19494711, year = {2009}, author = {Masha, A and Manieri, C and Dinatale, S and Bruno, GA and Ghigo, E and Martina, V}, title = {Prolonged treatment with N-acetylcysteine and L-arginine restores gonadal function in patients with polycystic ovary syndrome.}, journal = {Journal of endocrinological investigation}, volume = {32}, number = {11}, pages = {870-872}, pmid = {19494711}, issn = {1720-8386}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Amenorrhea/drug therapy ; Arginine/*therapeutic use ; Female ; Humans ; Menstruation/drug effects ; Oligomenorrhea/drug therapy ; Ovary/physiology ; Polycystic Ovary Syndrome/*drug therapy/*physiopathology ; Treatment Outcome ; }, abstract = {Nitric oxide (NO) plays a wide spectrum of biological actions including a positive role in oocyte maturation and ovulation. Free radicals levels have been shown elevated in polycystic ovary syndrome (PCOS) and therefore would be responsible for quenching NO that, in turn, would play a role in determining oligo- or amenorrhea connoting PCOS. Eight patients with PCOS displaying oligo-amenorrhea from at least 1 yr underwent a combined treatment with N-acetylcysteine (NAC) (1200 mg/die) plus L-arginine (ARG) (1600 mg/die) for 6 months. Menstrual function, glucose and insulin levels, and, in turn, homeostasis model assessment (HOMA) index were monitored. Menstrual function was at some extent restored as indicated by the number of uterine bleedings under treatment (3.00, 0.18-5.83 vs 0.00, 0.00-0.83; p<0.02). Also, a well-defined biphasic pattern in the basal body temperature suggested ovulatory cycles. The HOMA index decreased under treatment (2.12, 1.46-4.42 vs 3.48, 1.62-5.95; p<0.05). In conclusion, this preliminary, open study suggests that prolonged treatment with NAC+ARG might restore gonadal function in PCOS. This effect seems associated to an improvement in insulin sensitivity.}, }
@article {pmid19493264, year = {2010}, author = {Louie, B and Rajamahanty, S and Pyo, P and Choudhury, M and Konno, S}, title = {Mode of cytotoxic action of nephrotoxic agents: oxidative stress and glutathione-dependent enzyme.}, journal = {BJU international}, volume = {105}, number = {2}, pages = {264-268}, doi = {10.1111/j.1464-410X.2009.08657.x}, pmid = {19493264}, issn = {1464-410X}, mesh = {Antineoplastic Agents/adverse effects ; Antioxidants/*pharmacology ; Cell Survival ; Cells, Cultured ; Glutathione/*metabolism ; Glycerol/adverse effects ; Humans ; Kidney Diseases/*chemically induced/enzymology/physiopathology ; Kidney Tubules, Proximal/*enzymology/physiopathology ; Lactoylglutathione Lyase/*metabolism ; Mercuric Chloride/adverse effects ; Oxidative Stress/*physiology ; }, abstract = {OBJECTIVE: To investigate the cytotoxic action of nephrotoxic agents using an in vitro renal cell model, focusing on the cellular oxidative status and a specific glutathione (GSH)-dependent enzyme, glyoxalase I (Gly-I).<br><br>MATERIALS AND METHODS: Renal proximal tubular LLC-PK(1) cells were exposed to mercuric chloride, glycerol, cisplatin, gentamicin and cyclosporin A, and cell number/viability were determined. Oxidative stress was assessed by lipid peroxidation (LPO) assay, and Gly-I activity was measured by enzymatic method on a spectrophotometer.<br><br>RESULTS: Both mercuric chloride (30 microm) and glycerol (2.5%) were highly toxic to LLC-PK(1) cells, inducing >90% cell death within 24 h. The remaining agents led to slightly >50% growth inhibition at 72 h. The LPO levels at 3 h in cells exposed to mercuric chloride or glycerol were approximately 2.5 times higher than that in controls. N-acetylcysteine (NAC), a potent antioxidant and precursor for GSH, almost completely (>95%) prevented renal cell death from mercuric chloride or glycerol. Gly-I activity was dependent on NAC and closely associated with cell viability. A approximately 65% loss in Gly-I activity by mercuric chloride/glycerol led to >90% cell death, while restoring a basal activity of Gly-I with NAC was accompanied by complete cell viability.<br><br>CONCLUSIONS: The cytotoxic action of nephrotoxic agents appears to be triggered by oxidative stress, leading to Gly-I inactivation. As Gly-I plays a key role in cellular detoxification, its inactivation under oxidative stress probably becomes fatal to cells. However, cytoprotection provided with NAC is significant and might have implications in preventing renal cell injury mediated through nephrotoxic agents.}, }
@article {pmid19492988, year = {2009}, author = {Skaff, O and Pattison, DI and Davies, MJ}, title = {Hypothiocyanous acid reactivity with low-molecular-mass and protein thiols: absolute rate constants and assessment of biological relevance.}, journal = {The Biochemical journal}, volume = {422}, number = {1}, pages = {111-117}, doi = {10.1042/BJ20090276}, pmid = {19492988}, issn = {1470-8728}, mesh = {Animals ; Cattle ; Glutathione/metabolism ; Hydrogen-Ion Concentration ; Kinetics ; Molecular Weight ; Nitrobenzoates/metabolism ; Proteins/*metabolism ; Sulfhydryl Compounds/*metabolism ; Thiocyanates/*metabolism ; }, abstract = {MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate by H(2)O(2) to HOCl (hypochlorous acid), HOBr (hypobromous acid) and HOSCN (hypothiocyanous acid, also know as cyanosulfenic acid) respectively. Specificity constants indicate that thiocyanate, SCN-, is a major substrate for MPO. HOSCN is also a major oxidant generated by other peroxidases including salivary, gastric and eosinophil peroxidases. Whereas HOCl and HOBr are powerful oxidizing agents, HOSCN appears to be a less reactive, but more thiol-specific oxidant. Although it is established that HOSCN selectively targets thiols, absolute kinetic data for the reactions of thiols with HOSCN are absent from the literature. This study shows for the first time that the reactions of HOSCN with low-molecular-mass thiol residues occur with rate constants in the range from 7.3 x 10(3) M(-1).s(-1) (for N-acetyl-cysteine at pH 7.4) to 7.7 x 10(6) M(-1).s(-1) (for 5-thio-2-nitrobenzoic acid at pH 6.0). An inverse relationship between the rate of reaction and the pKa of the thiol group was observed. The rates of reaction of HOSCN with thiol-containing proteins were also investigated for four proteins (creatine kinase, BSA, beta-lactoglobulin and beta-L-crystallins). The values obtained for cysteine residues on these proteins are in the range 1 x 10(4)- 7 x 10(4) M(-1).s(-1). These second-order rate constants indicate that HOSCN is a major mediator of thiol oxidation in biological systems exposed to peroxidase/H(2)O(2) systems at (patho)physiological concentrations of halide and SCN- ions, and that HOSCN may play an important role in inflammation-induced oxidative damage.}, }
@article {pmid19492307, year = {2009}, author = {Hur, JM and Hyun, MS and Lim, SY and Lee, WY and Kim, D}, title = {The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells.}, journal = {Journal of cellular biochemistry}, volume = {107}, number = {5}, pages = {955-964}, doi = {10.1002/jcb.22198}, pmid = {19492307}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects/radiation effects ; Berberine/chemistry/*pharmacology ; Carcinoma, Hepatocellular/*enzymology/*pathology ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects/radiation effects ; Drug Screening Assays, Antitumor ; Enzyme Activation/drug effects/radiation effects ; Humans ; Liver Neoplasms/*enzymology/*pathology ; Models, Biological ; Nitric Oxide/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Radiation, Ionizing ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Berberine, an isoquinoline plant alkaloid, has been known to generate a wide variety of biochemical and pharmacological effects. In order to elucidate the molecular mechanism for the berberine-induced enhancement of radio-sensitization, the human hepatoma HepG2 cells were treated with berberine combined with irradiation. The anti-tumor effect of gamma radiation was found to be significantly enhanced by berberine. The evidences of apoptosis, such as apoptotic DNA fragmentation and annexin V staining, were observed in the cells treated with the combination of berberine and irradiation. Additionally, the levels of reactive oxygen species (ROS) and nitric oxide (NO) were apparently elevated in the combination system. The activations of p38, Bax, and caspase-3 were also detected in the irradiated cells pretreated with berberine. The productions of ROS and annexin V staining in the cells treated with the combination of berberine and irradiation were significantly inhibited by the specific inhibitor of p38 MAPK, SB203580. The cell death induced by berberine alone or the combination of berberine and irradiation was suppressed by the anti-oxidant, N-acetyl cysteine (NAC). Taken together, the present results clearly indicate that the combination of berberine and gamma-radiation enhance the anti-cancer effects through the p38 MAPK pathway and ROS generation.}, }
@article {pmid19491006, year = {2009}, author = {Wu, ZM and Zhang, XG and Zheng, C and Li, CX and Zhang, SM and Dong, RN and Yu, DM}, title = {Disulfide-crosslinked chitosan hydrogel for cell viability and controlled protein release.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {37}, number = {3-4}, pages = {198-206}, doi = {10.1016/j.ejps.2009.01.010}, pmid = {19491006}, issn = {1879-0720}, mesh = {3T3 Cells ; Acetylcysteine/chemistry ; Animals ; Cell Adhesion/drug effects ; Cell Survival/*drug effects ; Chitosan/*chemistry ; Cross-Linking Reagents ; Delayed-Action Preparations ; Disulfides/*chemistry ; Drug Compounding ; Electrophoresis, Polyacrylamide Gel ; Hydrogels ; Magnetic Resonance Spectroscopy ; Mice ; Microscopy, Electron, Scanning ; Molecular Weight ; Proteins/*administration &amp; dosage/chemistry ; Rheology ; Serum Albumin, Bovine/chemistry ; Sulfhydryl Compounds/chemistry ; Thermogravimetry ; }, abstract = {Synthetic hydrogel mimics of the extracellular matrix (ECM) were prepared by cross-linking a thiol-modified chitosan (CS). CS was chemically modified using N-acetyl-l-cysteine (NAC). To minimize interference with biological function, the degree of substitution of thiol groups was kept below 50%. Solution of thiolated CS was prepared in pH 7.4 phosphate buffered saline (PBS) and crosslinked by disulfide bond formation in air. The gelation mainly depended on the content of thiol groups on thiolated CS, concentration of thiolated CS and the molecular weight of CS. Thermogravimetric analysis showed the thermal stabilities of CSS-S hydrogels. Results from SEM observation showed a porous 3D hydrogel structure with pores ranging from 5 to 30microm. In vitro release showed that insulin and BSA release could be controlled by choosing the composition, loading and disulfide bond contents. In vitro cell compatibility of the hydrogels on NIH 3T3 cells was evaluated, indicating that the hydrogels were biocompatible and the cells could migrate into the hydrogels. Moreover, cells were viable and preserved 3D cell morphology inside the hydrogels. These results demonstrate that disulfide-crosslinked CS hydrogels, a new type of macroporous, biocompatible, synthetic polymers, are promising applications in tissue engineering, drug delivery, and cell culture.}, }
@article {pmid19490753, year = {2009}, author = {Whillier, S and Raftos, JE and Chapman, B and Kuchel, PW}, title = {Role of N-acetylcysteine and cystine in glutathione synthesis in human erythrocytes.}, journal = {Redox report : communications in free radical research}, volume = {14}, number = {3}, pages = {115-124}, doi = {10.1179/135100009X392539}, pmid = {19490753}, issn = {1743-2928}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Cells, Cultured ; Cysteine/metabolism ; Cystine/*pharmacology ; Erythrocytes/*drug effects/*metabolism ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/*metabolism ; Humans ; Male ; Middle Aged ; }, abstract = {Glutathione is an intracellular antioxidant that often becomes depleted in pathologies with high oxidative loads. We investigated the provision of cysteine for glutathione synthesis to the human erythrocyte (red blood cell; RBC). Almost all plasma cysteine exists as cystine, its oxidized form. In vitro, extracellular cystine at 1.0 mM sustained glutathione synthesis in glutathione-depleted RBCs, at a rate of 0.206 +/- 0.036 micromol (L RBC)(-1)min(-1) only 20% of the maximum rate obtained with cysteine or N-acetylcysteine. In plasma-free solutions, N-acetylcysteine provides cysteine by intracellular deacetylation but to achieve maximum rates of glutathione synthesis by this process in vivo, plasma N-acetylcysteine concentrations would have to exceed 1.0 mM, which is therapeutically unattainable. (1)H-NMR experiments demonstrated that redox exchange reactions between NAC and cystine produce NAC-cysteine, NAC-NAC and cysteine. Calculations using a mathematical model based on these results showed that plasma concentrations of N-acetylcysteine as low as 100 microM, that are attainable therapeutically, could potentially react with plasma cystine to produce approximately 50 microM cysteine, that is sufficient to produce maximal rates of glutathione synthesis. We conclude that the mechanism of action of therapeutically administered N-acetylcysteine is to reduce plasma cystine to cysteine that then enters the RBC and sustains glutathione synthesis.}, }
@article {pmid19490595, year = {2009}, author = {Athuraliya, TN and Jones, AL}, title = {Prolonged N-acetylcysteine therapy in late acetaminophen poisoning associated with acute liver failure--a need to be more cautious?.}, journal = {Critical care (London, England)}, volume = {13}, number = {3}, pages = {144}, pmid = {19490595}, issn = {1466-609X}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/pharmacology ; Analgesics, Non-Narcotic/*poisoning ; Animals ; Antidotes/*administration &amp; dosage/pharmacology ; Drug Administration Schedule ; Drug Overdose/drug therapy ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Liver/drug effects ; Liver Failure, Acute/*chemically induced/*drug therapy ; Mice ; }, abstract = {Since the 1970s, N-acetylcysteine (NAC) has shown proven efficacy as an antidote for acetaminophen (APAP) poisoning and APAP-induced liver failure for early presenters. The current evidence of benefits of NAC for late presenters is controversial because of the poor understanding of the mechanism of late toxicity. In the previous issue of Critical Care, Yang and colleagues use a mouse model to demonstrate that NAC in doses similar to those used therapeutically to treat APAP poisoning in humans impairs liver regenerative capacity and that the effect is more pronounced when administered for a longer duration. Studies based on cell cultures support this evidence. Cytokine and growth factor signalling pathways are recognised to be involved in the process of liver regeneration and apoptosis. This research paper generates several issues related to the future management of APAP-induced liver failure and research into the mechanism of toxicity, especially of late toxicity.}, }
@article {pmid19490358, year = {2009}, author = {Staniloae, CS and Doucet, S and Sharma, SK and Katholi, RE and Mody, KR and Coppola, JT and Solomon, R}, title = {N-Acetylcysteine added to volume expansion with sodium bicarbonate does not further prevent contrast-induced nephropathy: results from the cardiac angiography in renally impaired patients study.}, journal = {Journal of interventional cardiology}, volume = {22}, number = {3}, pages = {261-265}, doi = {10.1111/j.1540-8183.2009.00456.x}, pmid = {19490358}, issn = {1540-8183}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Buffers ; *Coronary Angiography ; Creatinine/blood ; Female ; Free Radical Scavengers/*therapeutic use ; Glomerular Filtration Rate ; Humans ; Iopamidol ; Kidney Diseases/*chemically induced ; Male ; *Plasma Substitutes ; Retrospective Studies ; Risk Factors ; Sodium Bicarbonate/*therapeutic use ; Triiodobenzoic Acids ; }, abstract = {We reviewed data from the multicenter CARE (Cardiac Angiography in Renally Impaired Patients) study to see if benefit could be shown for N-acetylcysteine (NAC) in patients undergoing cardiac angiography who all received intravenous bicarbonate fluid expansion. Four hundred fourteen patients with moderate-to-severe chronic kidney disease were randomized to receive intra-arterial administration of iopamidol-370 or iodixanol-320. All patients were prehydrated with isotonic sodium bicarbonate solution. Each site chose whether or not to administer NAC 1,200 mg twice daily to all patients. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2-5 days after receiving contrast. The primary outcome was a postdose SCr increase 0.5 mg/dL (44.2 mumol/L) over baseline. Secondary outcomes were a postdose SCr increase 25% and the mean peak change in SCr. The NAC group received significantly less hydration (892 +/- 236 mL vs. 1016 +/- 328 mL; P < 0.001) and more contrast volume (146 +/- 74 mL vs. 127 +/- 71 mL; P = 0.009) compared with no-NAC group. SCr increases 0.5 mg/dL occurred in 4.2% (7 of 168 patients) in NAC group and 6.5% (16 of 246 patients) in no-NAC group (P = 0.38); rates of SCr increases 25% were 11.9% and 10.6%, respectively (P = 0.75); mean post-SCr increases were 0.07 mg/dL in NAC group versus 0.11 mg/dL in no-NAC group (P = 0.14). In conclusion, addition of NAC to fluid expansion with sodium bicarbonate failed to reduce the rate of contrast-induced nephropathy (CIN) after the intra-arterial administration of iopamidol or iodixanol to high-risk patients with chronic kidney disease.}, }
@article {pmid19486866, year = {2009}, author = {Tiwari, P and Kumar, A and Balakrishnan, S and Kushwaha, HS and Mishra, KP}, title = {Radiation-induced micronucleus formation and DNA damage in human lymphocytes and their prevention by antioxidant thiols.}, journal = {Mutation research}, volume = {676}, number = {1-2}, pages = {62-68}, doi = {10.1016/j.mrgentox.2009.03.007}, pmid = {19486866}, issn = {0027-5107}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cells, Cultured ; DNA/drug effects/radiation effects ; DNA Damage/*drug effects ; Dose-Response Relationship, Radiation ; Drug Interactions ; Free Radical Scavengers/pharmacology ; *Gamma Rays ; Glutathione/pharmacology ; Humans ; Leukocyte Count/statistics &amp; numerical data ; Lymphocytes/*drug effects ; Micronuclei, Chromosome-Defective/*chemically induced/statistics &amp; numerical data ; Micronucleus Tests ; Oxidative Stress ; Radiation ; Radiation-Protective Agents/*pharmacology ; Sulfhydryl Compounds/*pharmacology ; Ultraviolet Rays ; }, abstract = {Thiol family of antioxidants has been considered to be the most effective class of radio protective agents. Present study reports a comparative evaluation of antioxidant thiols, namely N-acetyl cysteine (NAC), glutathione (GSH) and thioproline (TP), on gamma radiation-induced damage to human lymphocytes DNA as assessed by micronucleus (MN) formation and comet assay parameters. Pretreatment of cells with NAC, GSH and TP showed significant protection against DNA damage and MN frequency in irradiated lymphocytes (2-4 Gy). The magnitude of DNA damage protection was found to be concentration dependent (100-300 microM) which followed the order GSH>NAC>TP. Further, antioxidant thiols mediated protection against DNA damage in irradiated lymphocyte showed significant correlation with their ability to decrease intracellular ROS but not to the increase in intracellular GSH. Experiments on the effect of antioxidant thiols on plasmid DNA irradiated under cell free aqueous conditions showed that NAC exerts greater protection than GSH against radiation damage. TP showed similar responses in cellular and plasmid DNA. Greater protection of plasmid DNA by NAC is ascribable to its more potential hydrogen donor ability as revealed by radical chromogen 2,2-diphenyl-1-picrylhydrazyl (DPPH) photometric assay. Thus, present study indicated that radioprotection of lymphocytes DNA by antioxidant thiols are closely correlated to the reduction of cellular oxidative stress, which seems to involve multiple mechanisms.}, }
@article {pmid19486862, year = {2009}, author = {Toyooka, T and Ibuki, Y}, title = {Cigarette sidestream smoke induces phosphorylated histone H2AX.}, journal = {Mutation research}, volume = {676}, number = {1-2}, pages = {34-40}, doi = {10.1016/j.mrgentox.2009.03.002}, pmid = {19486862}, issn = {0027-5107}, mesh = {Cell Survival/drug effects ; DNA/drug effects/metabolism ; Histones/*metabolism ; Humans ; Lung Neoplasms/*etiology/pathology ; Nicotine/*toxicity ; Phosphorylation/drug effects ; Smoke/*adverse effects ; Smoking/*adverse effects ; }, abstract = {Cigarette sidestream smoke (CSS) is a widespread environmental pollutant having highly genotoxic potency. In spite of the overwhelming evidence that CSS induces a wide range of DNA damage such as oxidative base damage and DNA adducts, evidence that CSS can result in DNA double strand breaks (DSBs) is little. In this study, we showed that CSS generated phosphorylated histone H2AX (gamma-H2AX), recently considered as a sensitive marker of the generation of DSBs, in a human pulmonary epithelial cell model, A549. Treatment with CSS drastically induced discrete foci of gamma-H2AX within the nucleus in a dose-dependent manner. CSS increased intracellular oxidation, and N-acetylcysteine (NAC), an antioxidant, significantly attenuated the formation of gamma-H2AX, suggesting that reactive oxygen species produced from CSS partially contributed to the phosphorylation. The generation of gamma-H2AX is considered to be accompanied the induction of DSBs. CSS in fact induced DSBs, which was also inhibited by NAC. DSBs are the worst type of DNA damage, related to genomic instability and carcinogenesis. Our results would increase the evidence of the strong genotoxicity of passive smoking.}, }
@article {pmid19485208, year = {2009}, author = {Nayak, S and Tanuja, P and Sashidhar, RB}, title = {Synthesis and characterization of mercapturic acid (N-acetyl-L-cysteine)-aflatoxin B1 adduct and its quantitation in rat urine by an enzyme immunoassay.}, journal = {Journal of AOAC International}, volume = {92}, number = {2}, pages = {487-495}, pmid = {19485208}, issn = {1060-3271}, mesh = {Acetylcysteine/chemical synthesis/*urine ; Aflatoxin B1/chemical synthesis/immunology/toxicity/*urine ; Animals ; Antibody Formation ; Cattle ; Chromatography, Thin Layer ; Food Contamination/analysis ; Glutathione/chemistry ; Humans ; Immunoenzyme Techniques/*methods/standards/statistics &amp; numerical data ; Male ; Ovalbumin/chemistry ; Rabbits ; Rats ; Rats, Inbred F344 ; Reference Standards ; Sensitivity and Specificity ; Serum Albumin, Bovine/chemistry ; Spectroscopy, Fourier Transform Infrared ; }, abstract = {A simple and sensitive indirect noncompetitive enzyme immunoassay to quantitate mercapturic acid-aflatoxin B1 (AFB1) adduct in rat urine is reported. A novel procedure was developed for in vitro synthesis of an immunogen, bovine serum albumen-glutathione-aflatoxin B1 (BSA-GSH-AFB1) using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. Sulphydryl group's analysis confirmed the conjugation of-SH groups to AFB1. Thin-layer chromatography and spectral analysis (absorption, fluorescence, and Fourier transform infrared) of the conjugates further confirmed the formation of the adducts. Polyclonal antibodies specific to mercapturic acid-AFB1 adduct were produced against BSA-GSH-AFB1. The assay was found to be linear in the range of 100 pg-100 ng of the analyte (y = a + bx). A 50% displacement of BSA-GSH-AFB1 antibodies was achieved at an inhibitory concentration (IC50) of 11.9 ng GSH-AFB1 (r2 = 0.98) and 1.22 ng N-acetyl-L-cysteine (NAC)-AFB1 (r2 = 0.98). Spiking 5 microg/mL of reference standard to the control rat urine showed a recovery of 98 +/- 2%. The immunoassay was validated in a rodent model exposed to a single oral dose of 1 mg/kg body mass of pure AFB1. The excretion of NAC-AFB1 adduct was quantitated at the end of 24 h. The concentration of the NAC-AFB1 adduct excreted in urine as determined by the immunoassay was found to be in the range of 3.22-5.97 microg/mg creatinine. The present method may find wide application as a biochemical tool in molecular epidemiological and intervention studies with respect to human exposure to dietary aflatoxins.}, }
@article {pmid19483385, year = {2009}, author = {Watanabe, J and Nakamachi, T and Ogawa, T and Naganuma, A and Nakamura, M and Shioda, S and Nakajo, S}, title = {Characterization of antioxidant protection of cultured neural progenitor cells (NPC) against methylmercury (MeHg) toxicity.}, journal = {The Journal of toxicological sciences}, volume = {34}, number = {3}, pages = {315-325}, doi = {10.2131/jts.34.315}, pmid = {19483385}, issn = {1880-3989}, mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Count ; Cell Survival/drug effects ; Cells, Cultured ; Diencephalon/drug effects/embryology/pathology ; Drug Interactions ; Environmental Pollutants/*toxicity ; Glutathione/antagonists &amp; inhibitors/biosynthesis ; Methylmercury Compounds/*toxicity ; Mice ; Mice, Inbred ICR ; Neurons/*drug effects/metabolism/pathology ; Oxidative Stress/*drug effects ; Stem Cells/*drug effects/metabolism/pathology ; Telencephalon/drug effects/embryology/pathology ; }, abstract = {Methylmercury (MeHg) is an environmental pollutant known to cause neurobehavioral defects and is especially toxic to the developing brain. With recent studies showing that fetal exposure to low-dose MeHg causes developmental abnormalities, it is therefore important to find ways to combat its effects as well as to clarify the mechanism(s) underlying MeHg toxicity. In the present study, the effects of MeHg on cultured neural progenitor cells (NPC) derived from mouse embryonic brain were investigated. We first confirmed the vulnerability of embryonic NPC to MeHg toxicity, NPC from the telencephalon were more sensitive to MeHg compared to those from the diencephalon. Buthionine sulfoximine (BSO) which is known to inhibit glutathione synthesis accelerated MeHg toxicity. Furthermore, antioxidants such as N-acetyl cysteine and alpha-tocopherol dramatically rescued the NPC from MeHg's toxic effects. Interestingly, a 12 hr delay in the addition of either antioxidant was still able to prevent the cells from undergoing cell death. Although it is now difficult to avoid MeHg exposure from our environment and contaminated foods, taking anti-oxidants from foods or supplements may prevent or diminish the toxicological effects of MeHg.}, }
@article {pmid19481559, year = {2009}, author = {Kim, BM and Choi, YJ and Han, Y and Yun, YS and Hong, SH}, title = {N,N-dimethyl phytosphingosine induces caspase-8-dependent cytochrome c release and apoptosis through ROS generation in human leukemia cells.}, journal = {Toxicology and applied pharmacology}, volume = {239}, number = {1}, pages = {87-97}, doi = {10.1016/j.taap.2009.05.020}, pmid = {19481559}, issn = {1096-0333}, mesh = {Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Caspase 8/*physiology ; Caspase Inhibitors ; Cell Survival/drug effects ; Cytochromes c/*metabolism ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Down-Regulation ; Flow Cytometry ; HL-60 Cells ; Humans ; Jurkat Cells ; K562 Cells ; Membrane Potential, Mitochondrial/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Reactive Oxygen Species/*metabolism ; Sphingosine/*analogs &amp; derivatives/pharmacology ; bcl-X Protein/biosynthesis ; }, abstract = {N,N-dimethyl phytosphingosine (DMPS) blocks the conversion of sphingosine to sphingosine-1-phosphate (S1P) by the enzyme sphingosine kinase (SK). In this study, we elucidated the apoptotic mechanisms of DMPS action on a human leukemia cell line using functional pharmacologic and genetic approaches. First, we demonstrated that DMPS-induced apoptosis is evidenced by nuclear morphological change, distinct internucleosomal DNA fragmentation, and an increased sub-G1 cell population. DMPS treatment led to the activation of caspase-9 and caspase-3, accompanied by the cleavage of poly(ADP-ribose) polymerase (PARP) and led to cytochrome c release, depolarization of the mitochondrial membrane potential, and downregulation of the anti-apoptotic members of the bcl-2 family. Ectopic expression of bcl-2 and bcl-xL conferred resistance of HL-60 cells to DMPS-induced cell death, suggesting that DMPS-induced apoptosis occurs predominantly through the activation of the intrinsic mitochondrial pathway. We also observed that DMPS activated the caspase-8-Bid-Bax pathway and that the inhibition of caspase-8 by z-IETD-fmk or small interfering RNA suppressed the cleavage of Bid, cytochrome c release, caspase-3 activation, and apoptotic cell death. In addition, cells subjected to DMPS exhibited significantly increased reactive oxygen species (ROS) generation, and ROS scavengers, such as quercetin and Tiron, but not N-acetylcysteine (NAC), inhibited DMPS-induced activations of caspase-8, -3 and subsequent apoptotic cell death, indicating the role of ROS in caspase-8-mediated apoptosis. Taken together, these results indicate that caspase-8 acts upstream of caspase-3, and that the caspase-8-mediated mitochondrial pathway is important in DMPS-induced apoptosis. Our results also suggest that ROS are critical regulators of caspase-8-mediated apoptosis in DMPS-treated leukemia cells.}, }
@article {pmid19478716, year = {2009}, author = {Pflueger, A and Abramowitz, D and Calvin, AD}, title = {Role of oxidative stress in contrast-induced acute kidney injury in diabetes mellitus.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {15}, number = {6}, pages = {RA125-36}, pmid = {19478716}, issn = {1643-3750}, mesh = {Contrast Media/*adverse effects ; Diabetic Nephropathies/*chemically induced/epidemiology/mortality/therapy ; Humans ; Kidney Diseases/*chemically induced/epidemiology/mortality/therapy ; Osmolar Concentration ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {Contrast-induced acute kidney injury (CIAKI) is the most-common form of in-hospital drug-induced acute kidney injury and occurs in 1 to over 50% of patients undergoing intravascular contrast media (CM) administration. Numerous risk factors for CIAKI have been described, the most prominent among them is pre-existing kidney disease such as diabetic nephropathy. The pathogenesis of CIAKI appears to be caused, at least in part, by renal vasoconstriction and renal ischemia leading to the generation of reactive oxygen species (ROS). Diabetes is associated with increased sensitivity to renal vasoconstrictors including CM agents and is also associated with dysfunctional renal handling of ROS, making diabetics particularly susceptible to CIAKI. At present, there are limited srtategies for the prevention of CIAKI among them the administration of the antioxidant N-acetylcysteine (NAC) and intravenous hydration. In light of the rising prevalence of diabetes worldwide and the high risk it represents for the development of CIAKI and CIAKI-associated cardiovascular mortality, a lucid understanding of the pathogenesis of CIAKI and diabetic nephropathy is indispensable. The current review addresses the role of ROS in the pathogenesis of CIAKI in the diabetic renal milieu and discusses current and potential novel treatment modalities for the prevention of CIAKI in diabetic patients.}, }
@article {pmid19477272, year = {2009}, author = {Liu, CY and Lee, CF and Wei, YH}, title = {Activation of PKCdelta and ERK1/2 in the sensitivity to UV-induced apoptosis of human cells harboring 4977 bp deletion of mitochondrial DNA.}, journal = {Biochimica et biophysica acta}, volume = {1792}, number = {8}, pages = {783-790}, doi = {10.1016/j.bbadis.2009.05.005}, pmid = {19477272}, issn = {0006-3002}, mesh = {Acetophenones/metabolism ; Acetylcysteine/metabolism ; Apoptosis/*radiation effects ; Benzopyrans/metabolism ; Cells, Cultured ; DNA, Mitochondrial/*genetics ; Enzyme Activation ; Enzyme Inhibitors/metabolism ; Fibroblasts/cytology/physiology ; *Gene Deletion ; Humans ; Mitogen-Activated Protein Kinase 1/genetics/*metabolism ; Mitogen-Activated Protein Kinase 3/genetics/*metabolism ; Ophthalmoplegia, Chronic Progressive External/genetics ; Protein Kinase C-delta/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; *Ultraviolet Rays ; }, abstract = {The 4977 bp deletion of mitochondrial DNA (mtDNA), often found in patients with chronic progressive external ophthalmoplegia (CPEO), has been demonstrated to increase the susceptibility to apoptosis of human cells. We investigated the mechanism underlying the apoptotic susceptibility of the Delta4977 cybrid harboring about 80% 4977 bp-deleted mtDNA. The production of hydrogen peroxide (H(2)O(2)) and phosphorylation of PKCdelta and ERK1/2 were increased in the Delta4977 cybrid, which was more susceptible to UV-induced apoptosis. Moreover, treatment with N-acetyl-l-cysteine (NAC) or blocking of activation of PKCdelta by rottlerin or PKCdelta-siRNA, and inhibition of ERK1/2 by PD98059 or ERK1/2-siRNA significantly attenuated the susceptibility of the Delta4977 cybrid to apoptosis. Furthermore, the increase of PKCdelta expression in the Delta4977 cybrid also amplified the apoptotic signal through caspase 3-mediated proteolytic activation of PKCdelta. In addition, PKCdelta and ERK1/2 were hyperphosphorylated in skin fibroblasts of CPEO patients harboring 4977 bp-deleted mtDNA. We suggest that the activation of PKCdelta and ERK1/2 elicited by 4977 bp-deleted mtDNA-induced oxidative stress plays a role in the susceptibility of the mutant cells to apoptosis. This may explain, at least in part, the degenerative manifestation of brain and muscle in patients with mitochondrial encephalomyopathies such as CPEO syndrome.}, }
@article {pmid19475715, year = {2009}, author = {Chatterjee, S and Kundu, S and Sengupta, S and Bhattacharyya, A}, title = {Divergence to apoptosis from ROS induced cell cycle arrest: effect of cadmium.}, journal = {Mutation research}, volume = {663}, number = {1-2}, pages = {22-31}, doi = {10.1016/j.mrfmmm.2008.12.011}, pmid = {19475715}, issn = {0027-5107}, mesh = {Animals ; Apoptosis/*drug effects ; Cadmium/*toxicity ; Caspase 3/metabolism ; Cell Cycle/*drug effects ; Cell Proliferation/drug effects ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cytochromes c/metabolism ; Enzyme Activation/drug effects ; Flow Cytometry ; Inhibitory Concentration 50 ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Models, Biological ; Reactive Oxygen Species/*metabolism ; Spectrophotometry ; Tumor Suppressor Protein p53/metabolism ; bcl-2-Associated X Protein/metabolism ; bcl-X Protein/metabolism ; }, abstract = {Recently, the role of cadmium (Cd) in immunosupression has gained importance. Nevertheless, the signaling pathways underlying cadmium-induced immune cell death remains largely unclear. In accordance to our previous in vivo report, and to evaluate the further details of the mechanism, we have investigated the effects of cadmium (CdCl(2), H(2)O) on cell cycle regulation and apoptosis in splenocytes in vitro. Our results have revealed that reactive oxygen species (ROS) and p21 are involved in cell cycle arrest in a p53 independent manner but late hour apoptotic response was accompanied by the p53 up-regulation, loss of mitochondrial transmembrane potential (MTP), down-regulation of Bcl-xl, activation of caspase-3 and release of cytochrome c (Cyt c). However, pifithrin alfa (PFT-alpha), an inhibitor of p53, fails to rescue the cells from the cadmium-induced cell cycle arrest but prevents Bcl-xl down-regulation and loss of Deltapsi(m), which indicates that there is an involvement of p53 in apoptosis. In contrast, treatment with N-acetyl cysteine (NAC) can prevent cell cycle arrest and p21 up-regulation at early hours. Although it is clear that, NAC has no effect on apoptosis, p53 expression and MPT changes at late stage events. Taken together, we have demonstrated that cadmium promotes ROS generation, which potently initiates the cell cycle arrest at early hours and finally induces p53-dependent apoptosis at later part of the event.}, }
@article {pmid19469519, year = {2009}, author = {Jenkinson, C and Jenkins, RE and Maggs, JL and Kitteringham, NR and Aleksic, M and Park, BK and Naisbitt, DJ}, title = {A mechanistic investigation into the irreversible protein binding and antigenicity of p-phenylenediamine.}, journal = {Chemical research in toxicology}, volume = {22}, number = {6}, pages = {1172-1180}, doi = {10.1021/tx900095r}, pmid = {19469519}, issn = {1520-5010}, support = {G0700654//Medical Research Council/United Kingdom ; //Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Amino Acid Sequence ; Antigens/immunology ; Cell Proliferation ; Coloring Agents/*chemistry ; Dermatitis, Allergic Contact/metabolism ; Glutathione S-Transferase pi/*chemistry/metabolism ; Haptens/immunology ; Humans ; Molecular Sequence Data ; Phenylenediamines/*chemistry/*immunology ; Protein Binding ; T-Lymphocytes/immunology ; }, abstract = {Exposure to the skin sensitizer p-phenylenediamine (PPD) is associated with allergic contact dermatitis; however, the ability of PPD to modify protein has not been fully investigated. The aims of this study were to characterize the reactions of PPD and the structurally related chemical 2,5-dimethyl-1,4-benzoquinonediamine with model nucleophiles, a synthetic peptide (DS3) containing each of the naturally occurring amino acids and His-tagged glutathione-S-transferase pi (GSTP), and to explore the effect of dimethyl substitution on PPD-specific T-cell responses using lymphocytes from allergic patients. The reductive soft nucleophiles N-acetyl cysteine and glutathione prevented PPD self-conjugation reactions and Bandrowski's base formation, but no adducts were detected. N-Acetyl lysine, a hard nucleophile, did not alter the rate of PPD degradation or form PPD adducts. With PPD and 2,5-dimethyl-1,4-benzoquinonediamine, only cysteine was targeted in the DS3 peptide. PPD and 2,5-dimethyl-1,4-benzoquinonediamine were also found to selectively modify the reactive Cys 47 residue of GSTP, which has a pK(a) of 3.5-4.2 and therefore exists in a largely protonated form. Glutathione formed mixed disulfides with the DS3 peptide, reducing levels of PPD binding. Lymphocytes from PPD allergic patients proliferated in the presence of PPD but not with 2,5-dimethyl-1,4-benzoquinonediamine. These results reveal that PPD and 2,5-dimethyl-1,4-benzoquinonediamine bind selectively to specific cysteine residues in peptides and proteins. Lymphocytes from PPD allergic patients were capable of discriminating between the different haptenic structures, suggesting that the hapten, but not the peptide moiety associated with MHC, is an important determinant for T-cell recognition.}, }
@article {pmid19468286, year = {2009}, author = {Chen, C and Liu, Y and Zheng, D}, title = {An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells.}, journal = {Cell research}, volume = {19}, number = {8}, pages = {984-995}, doi = {10.1038/cr.2009.60}, pmid = {19468286}, issn = {1748-7838}, mesh = {Acetylcysteine/pharmacology ; Antibodies, Monoclonal/*pharmacology ; Apoptosis ; Caspase 8/metabolism ; Cell Line, Tumor ; Endodeoxyribonucleases/*metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Jurkat Cells ; Leukemia/enzymology/*metabolism ; Membrane Potential, Mitochondrial ; Mitochondria/metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/agonists/*metabolism ; Signal Transduction ; }, abstract = {We have previously reported that AD5-10, a novel agonistic monoclonal antibody against DR5, possessed a strong cytotoxic activity in various tumor cells, via induction of caspase-dependent and -independent signaling pathways. The present study further demonstrates that reactive oxygen species (ROS) were generated in abundance in Jurkat leukemia cells upon AD5-10 stimulation and that ROS accumulation subsequently evoked sustained activation of c-Jun N-terminal kinase (JNK), loss of mitochondrial membrane potential, and release of endonuclease G (Endo G) from mitochondria into the cytosol. The reducing agent, N-acetylcysteine (NAC), effectively inhibited the sustained activation of JNK, release of Endo G, and cell death in Jurkat cells treated by AD5-10. Moreover, a dominant-negative form of JNK (but not of p38) enhanced NF-kappaB activation, suppressed caspase-8 recruitment in death-inducing signaling complexes (DISCs), and reduced adverse effects on mitochondria, thereby inhibiting AD5-10-induced cell death in Jurkat leukemia cells. These data provide novel information on the DR5-mediated cell death-signaling pathway and may shed new light on effective strategies for leukemia and solid tumor therapies.}, }
@article {pmid19467834, year = {2009}, author = {Prabhu, A and Sujatha, DI and Kanagarajan, N and Vijayalakshmi, MA and Ninan, B}, title = {Effect of N-acetylcysteine in attenuating ischemic reperfusion injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.}, journal = {Annals of vascular surgery}, volume = {23}, number = {5}, pages = {645-651}, doi = {10.1016/j.avsg.2008.12.005}, pmid = {19467834}, issn = {1615-5947}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/*therapeutic use ; Biomarkers/blood ; Cardiopulmonary Bypass/*adverse effects ; Cardiotonic Agents/*therapeutic use ; Catalase/blood ; Coronary Artery Bypass/*adverse effects ; Double-Blind Method ; Glutathione/blood ; Glutathione Peroxidase/blood ; Glutathione Reductase/blood ; Heart Arrest, Induced/*methods ; Hemodynamics/drug effects ; Humans ; Malondialdehyde/blood ; Middle Aged ; Myocardial Reperfusion Injury/etiology/metabolism/physiopathology/*prevention &amp; control ; Oxidative Stress/*drug effects ; Prospective Studies ; Stroke Volume/drug effects ; Superoxide Dismutase/blood ; Time Factors ; Treatment Outcome ; Troponin I/blood ; Ventricular Function, Left/drug effects ; }, abstract = {Ischemic reperfusion injury due to oxidative stress remains one of the challenging problems during cardiac surgeries. The imbalance in the production of free radicals and antioxidants in vivo determines the extent of oxidative stress. The use of antioxidants in cardioplegia has become an important strategy to salvage the myocardium from the attack of these radicals. The objective of this study was to analyze the cardioprotective effect of N-acetylcysteine (NAC) on early reperfusion injury in patients undergoing coronary artery bypass grafting using biochemical markers. Fifty-three patients with left ventricular ejection fraction >0.4 scheduled for coronary artery bypass grafting with cardiopulmonary bypass were selected and divided into two groups. The first group of patients (n=25) received isothermic cardioplegia alone, whereas the second group of patients (n=28) received cardioplegia enriched with NAC (50mg/kg body weight). The free radicals, antioxidants, cardiac troponin I, and hemodynamic and clinical properties of the patients were preoperatively and postoperatively evaluated at five different time intervals. Malondialdehyde level as a measure of free radicals was significantly lower in the NAC-enriched group during reperfusion (p<0.05) and after 12 hr (p<0.05) and 24hr (p<0.001) of surgery. All the antioxidants were elevated in the test group during the reperfusion period (p<0.01). A significant improvement (p=0.001) in the postoperative ejection fraction was noted in the test group. No significant differences were observed between the groups in the level of cardiac troponin I (p=not significant). The use of NAC in patients undergoing coronary artery bypass grafting using cardiopulmonary bypass decreased oxidative stress substantially. However, it did not lead to improvement in the level of cardiac troponin I, a marker of myocardial injury, in our study. Hence, the cardioprotective effect of NAC and the adaptation of the myocardium to oxidative stress should be extensively studied.}, }
@article {pmid19467570, year = {2009}, author = {Lee, WY and Liu, KW and Yeung, JH}, title = {Reactive oxygen species-mediated kinase activation by dihydrotanshinone in tanshinones-induced apoptosis in HepG2 cells.}, journal = {Cancer letters}, volume = {285}, number = {1}, pages = {46-57}, doi = {10.1016/j.canlet.2009.04.040}, pmid = {19467570}, issn = {1872-7980}, mesh = {Abietanes ; Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/enzymology/*pathology ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation ; Furans ; Humans ; Imidazoles/pharmacology ; Inhibitory Concentration 50 ; JNK Mitogen-Activated Protein Kinases/metabolism ; L-Lactate Dehydrogenase/metabolism ; Liver Neoplasms/enzymology/*pathology ; Oxidative Stress/*drug effects ; Phenanthrenes/*pharmacology ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Transport ; Pyridines/pharmacology ; Quinones ; Reactive Oxygen Species/*metabolism ; Time Factors ; bcl-2-Associated X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The role of reactive oxygen species (ROS) and p38 mitogen-activated protein kinases (MAPK) in tanshinones-induced apoptosis was investigated in HepG2 cells in this study. The major tanshinones (cryptotanshinone, dihydrotanshinone, tanshinone I, tanshinone IIA), isolated from Salvia miltiorrhiza, inhibit cell growth and induce caspase-dependent apoptosis concentration-dependently, with dihydrotanshinone being the most potent. All four tanshinones were found to induce ROS generation, but only dihydrotanshinone can induce activation of p38 MAPK. The p38 MAPK activation by dihydrotanshinone was inhibited by N-acetyl cysteine pretreatment. It is thus concluded that ROS-mediated p38 MAPK activation plays a vital role in dihydrotanshinone-induced apoptosis in HepG2 cells.}, }
@article {pmid19465435, year = {2009}, author = {Alipour, M and Suntres, ZE and Omri, A}, title = {Importance of DNase and alginate lyase for enhancing free and liposome encapsulated aminoglycoside activity against Pseudomonas aeruginosa.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {64}, number = {2}, pages = {317-325}, doi = {10.1093/jac/dkp165}, pmid = {19465435}, issn = {1460-2091}, mesh = {Acetylcysteine/*metabolism ; Aminoglycosides/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/drug effects ; Chemistry, Pharmaceutical ; Deoxyribonucleases/*metabolism ; Humans ; Liposomes/pharmacology ; Microbial Sensitivity Tests ; Mucins/metabolism ; Polysaccharide-Lyases/*metabolism ; Pseudomonas aeruginosa/*drug effects ; Sputum/microbiology ; }, abstract = {OBJECTIVES: This study evaluated the potential of DNase, alginate lyase (AlgL) and N-acetylcysteine (NAC) in enhancing the in vitro bactericidal activity of conventional (free) and vesicle-entrapped (liposomal) gentamicin, amikacin and tobramycin.<br><br>METHODS: The MICs and biofilm eradication for two clinical isolates of Pseudomonas aeruginosa (a mucoid strain and a non-mucoid strain) were determined in the presence and absence of AlgL. The co-activity of aminoglycosides with DNase and/or AlgL against endogenous P. aeruginosa in cystic fibrosis (CF) sputum was also measured. The inhibitory effects of mucin in the presence and absence of the mucolytic agent NAC on aminoglycosidic activity were also examined.<br><br>RESULTS: The MIC values of the liposomal aminoglycosides were similar to or lower than those of free aminoglycosides. Biofilm formation increased the bactericidal concentrations of these drugs by 8- to 256-fold and treatment with AlgL improved killing of the mucoid strain. The activity of some aminoglycosides against the sputum was increased by the addition of DNase or AlgL (P < 0.05), and was increasingly evident with concurrent DNase and AlgL administration. Addition of mucin inhibited liposomal aminoglycosidic activity (up to 32-fold) evidently more than the free aminoglycosides (up to 8-fold). The addition of NAC did not improve activity significantly (P > 0.05). Tobramycin was the most effective aminoglycoside to reduce biofilms and sputum.<br><br>CONCLUSIONS: Liposomal aminoglycosides do not fare better than conventional forms. The co-administration of DNase and AlgL is essential for enhanced activity in reducing biofilm growth and sputum bacterial counts. While mucin retards bactericidal activity, NAC does not improve aminoglycosidic activity.}, }
@article {pmid19464336, year = {2009}, author = {Mukhopadhyay, S and Mukherjee, S and Stone, WL and Smith, M and Das, SK}, title = {Role of MAPK/AP-1 signaling pathway in the protection of CEES-induced lung injury by antioxidant liposome.}, journal = {Toxicology}, volume = {261}, number = {3}, pages = {143-151}, doi = {10.1016/j.tox.2009.05.010}, pmid = {19464336}, issn = {1879-3185}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Activating Transcription Factors/metabolism ; Animals ; Antidotes/administration &amp; dosage/*pharmacology ; Antioxidants/administration &amp; dosage/*pharmacology ; Blood Proteins/metabolism ; Cell Proliferation/drug effects ; Cyclin D1/metabolism ; Disease Models, Animal ; Erythrocytes/drug effects ; Guinea Pigs ; Liposomes ; Lung/*drug effects/enzymology/pathology ; Lung Injury/chemically induced/enzymology/pathology/*prevention &amp; control ; Male ; Mitogen-Activated Protein Kinases/*metabolism ; Mustard Gas/analogs &amp; derivatives ; Neutrophil Infiltration/drug effects ; Phosphorylation ; Proliferating Cell Nuclear Antigen/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; Proto-Oncogene Proteins c-jun/metabolism ; Pulmonary Eosinophilia/chemically induced/prevention &amp; control ; Time Factors ; Tocopherols/administration &amp; dosage/*pharmacology ; Transcription Factor AP-1/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {We have recently reported that antioxidant liposomes can be used as antidotes for mustard gas induced lung injury in guinea pigs. The maximum protection was achieved with a liposome composed of tocopherols (alpha, gamma, delta) and N-acetylcysteine (NAC) when administered after 5 min of exposure of 2-chloroethyl ethyl sulfide (CEES), a half sulfur mustard gas. We also reported an association of mustard gas-induced lung injury with an activation of MAPK/AP-1 signaling pathway and cell proliferation. The objective of the present study was to investigate whether CEES-induced MAPKs/AP-1 signaling pathway is influenced by antioxidant liposome therapy. A single dose (200 microl) of the antioxidant liposome was administered intratracheally after 5 min of exposure of CEES (0.5 mg/kg). The animals were sacrificed after 1h and 30 days of CEES exposure. Although the liposome treatment did not have any significant effect on the activation of the MAPKs family (ERK1/2, p38 and JNK1/2), it significantly counteracted the CEES-induced activation of AP-1 transcription factors and corresponding increase in the protein levels of Fos, ATF and Jun family members. The liposome treatment significantly blocked the CEES-induced increase in the protein levels of cyclin D1, a cell cycle protein and PCNA, a cell differentiation marker. Furthermore, it protected lung against CEES-induced inflammation and infiltration of neutrophils, eosinophils and erythrocytes in the alveolar space. This suggests that the protective effect of antioxidant liposome against CEES-induced lung damage is mediated via control of AP-1 signaling.}, }
@article {pmid19463931, year = {2009}, author = {Wang, B and Navath, RS and Romero, R and Kannan, S and Kannan, R}, title = {Anti-inflammatory and anti-oxidant activity of anionic dendrimer-N-acetyl cysteine conjugates in activated microglial cells.}, journal = {International journal of pharmaceutics}, volume = {377}, number = {1-2}, pages = {159-168}, pmid = {19463931}, issn = {1873-3476}, support = {Z01 HD002401/ImNIH/Intramural NIH HHS/United States ; Z01 HD002400/ImNIH/Intramural NIH HHS/United States ; ZIA HD002401-17/ImNIH/Intramural NIH HHS/United States ; Z01 HD002400-17/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/chemistry/pharmacokinetics/pharmacology ; Animals ; Anions ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Cell Line ; Cell Survival/drug effects ; Dendrimers/chemical synthesis/chemistry/*pharmacology ; Drug Evaluation, Preclinical ; Free Radical Scavengers/administration &amp; dosage/chemistry/pharmacokinetics/pharmacology ; Mice ; Microglia/*drug effects/metabolism ; Molecular Structure ; Nitric Oxide/metabolism ; *Pharmaceutical Vehicles ; Polyamines/chemistry/pharmacokinetics/*pharmacology ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Dendrimers are emerging as potential intracellular drug delivery vehicles. Understanding and improving the cellular efficacy of dendrimer-drug conjugates, can lead to significant in vivo benefits. This study explores efficacy of anionic polyamidoamine (PAMAM-COOH) dendrimer-N-acetyl cysteine (NAC) conjugates for applications in neuroinflammation. The anti-oxidative and anti-inflammatory effects of PAMAM-(COOH)(46)-(NAC)(18) conjugate is evaluated on microglial cells in vitro. Cell entry and localization of PAMAM-(COOH)(62)-(FITC)(2) conjugate in BV-2 microglial cells were assessed using flow cytometry and confocal microscopy. ELISA assays were used to evaluate markers of oxidative stress (ROS, NO) and inflammation (TNF-alpha) after stimulation of microglial cells with lipopolysaccharides (LPS), following treatment with increasing doses of free N-acetyl-L-cysteine (NAC) or PAMAM-(COOH)(46)-(NAC)(18) conjugate containing an equivalent molar concentration of NAC. Flow cytometry and confocal microscopy demonstrated the PAMAM-(COOH)(62)-(FITC)(2) conjugate entered BV-2 cells rapidly with significant increase in fluorescence within 15 min and localized mostly in the cytoplasm. PAMAM-(COOH)(46)-(NAC)(18) conjugate was non-toxic, and significantly reduced ROS, NO and TNF-alpha release by activated microglial cells after 24 h and 72 h stimulation of LPS following 3h pre-treatment when compared to the same concentration of free NAC (P<0.05 or P<0.01). Anionic PAMAM dendrimer-NAC conjugate was synthesized with a glutathione sensitive linker for intracellular release. The non-toxic conjugate is a more effective anti-oxidant and anti-inflammatory agent when compared to free NAC in vitro. The conjugate showed significant efficacy even at the lowest dose (0.5mM NAC), where the activity was comparable or better than that of free drug at 8mM (16x higher dosage). The improved efficacy of the conjugate, when combined with the intrinsic neuroinflammation-targeting ability of the PAMAM dendrimers, may provide new opportunities for in vivo applications.}, }
@article {pmid19463428, year = {2009}, author = {Meyer, M and LeWinter, MM and Bell, SP and Chen, Z and Selby, DE and Singla, DK and Dauerman, HL}, title = {N-acetylcysteine-enhanced contrast provides cardiorenal protection.}, journal = {JACC. Cardiovascular interventions}, volume = {2}, number = {3}, pages = {215-221}, pmid = {19463428}, issn = {1876-7605}, support = {T32 HL007647/HL/NHLBI NIH HHS/United States ; T32 HL007647-20/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/*pharmacology ; *Angioplasty, Balloon, Coronary ; Animals ; Apoptosis ; Contrast Media/adverse effects/*pharmacology ; Creatinine/blood ; Disease Models, Animal ; Feasibility Studies ; Free Radical Scavengers/adverse effects/*pharmacology ; Iopamidol/adverse effects/*pharmacology ; Kidney/drug effects ; Kidney Diseases/*chemically induced/prevention &amp; control ; *Myocardial Infarction ; Myocardium ; Risk Factors ; Swine ; }, abstract = {OBJECTIVES: We sought to evaluate the cardiac and renal effects of an N-acetylcysteine (NAC)-enhanced intracoronary radiographic contrast agent.<br><br>BACKGROUND: Recent studies suggest that high-dose NAC provides better protection from contrast-induced nephropathy, and the antioxidant properties of NAC may also provide cardiac protection. The use of angiographic contrast agents as a drug delivery vehicle for cardiorenal protection effects has not been investigated.<br><br>METHODS: In a pig model of prolonged cardiac ischemia-reperfusion, NAC-enhanced contrast medium was tested and compared with iopamidol contrast only. Myocardium and renal function were assessed after 24 h.<br><br>RESULTS: There was no significant difference in the area-at-risk for myocardial infarction (MI) between contrast only and NAC-enhanced contrast medium. In contrast, MI size was about 40% smaller in NAC-enhanced contrast medium-treated animals. These findings were associated with a significant difference in MI morphology. MIs in the NAC-enhanced contrast medium group had a mottled appearance, whereas in the contrast only group they were homogeneous and had a discrete border zone. These differences could explain a higher incidence of periprocedural ventricular arrhythmias in the NAC-enhanced contrast medium group. Histopathological analysis of the myocardium revealed a reduction in programmed cell death by NAC-enhanced contrast medium that may explain the increase in ischemia tolerance. Last, NAC-enhanced contrast medium administration blunted the rise in serum creatinine levels by about 60% and protected from renotubular apotosis.<br><br>CONCLUSIONS: NAC-enhanced contrast medium reduces MI size and protects renal function in a pig model of ischemia and reperfusion.}, }
@article {pmid19463156, year = {2009}, author = {Pollicita, M and Muscoli, C and Sgura, A and Biasin, A and Granato, T and Masuelli, L and Mollace, V and Tanzarella, C and Del Duca, C and Rodinò, P and Perno, CF and Aquaro, S}, title = {Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line.}, journal = {BMC neuroscience}, volume = {10}, number = {}, pages = {51}, pmid = {19463156}, issn = {1471-2202}, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Antiviral Agents/pharmacology ; Apoptosis/drug effects/*physiology ; Astrocytoma/*pathology/ultrastructure ; Cell Line, Tumor ; Enzyme-Linked Immunosorbent Assay ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; HIV-1/*metabolism ; Humans ; Microscopy, Electron/methods ; Oxidative Stress/drug effects/*physiology ; Telomere/drug effects/*pathology ; Time Factors ; }, abstract = {BACKGROUND: Oxidative stress plays a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV-1) infection causing apoptosis of astroglia cells and neurons. Recent data have shown that oxidative stress is also responsible for the acceleration of human fibroblast telomere shortening in vitro. In the present study we analyzed the potential relations occurring between free radicals formation and telomere length during HIV-1 mediated astroglial death.<br><br>RESULTS: To this end, U373 human astrocytoma cells have been directly exposed to X4-using HIV-1IIIB strain, for 1, 3 or 5 days and treated (where requested) with N-acetylcysteine (NAC), a cysteine donor involved in the synthesis of glutathione (GSH, a cellular antioxidant) and apoptosis has been evaluated by FACS analysis. Quantitative-FISH (Q-FISH) has been employed for studying the telomere length while intracellular reduced/oxidized glutathione (GSH/GSSG) ratio has been determined by High-Performance Liquid Chromatography (HPLC). Incubation of U373 with HIV-1IIIB led to significant induction of cellular apoptosis that was reduced in the presence of 1 mM NAC. Moreover, NAC improved the GSH/GSSG, a sensitive indicator of oxidative stress, that significantly decreased after HIV-1IIIB exposure in U373. Analysis of telomere length in HIV-1 exposed U373 showed a statistically significant telomere shortening, that was completely reverted in NAC-treated U373.<br><br>CONCLUSION: Our results support the role of HIV-1-mediated oxidative stress in astrocytic death and the importance of antioxidant compounds in preventing these cellular damages. Moreover, these data indicate that the telomere structure, target for oxidative damage, could be the key sensor of cell apoptosis induced by oxidative stress after HIV infection.}, }
@article {pmid19462279, year = {2009}, author = {Oksuz, H and Bulbuloglu, E and Senoglu, N and Ciralik, H and Yuzbasioglu, MF and Kilinc, M and Dogan, Z and Goksu, M and Yildiz, H and Ozkan, OV and Atli, Y}, title = {Re-protective effects of pre- and post-laparoscopy conditioning, zinc, pentoxifylline, and N-acetylcysteine in an animal model of laparoscopy-induced ischemia/reperfusion injury of the kidney.}, journal = {Renal failure}, volume = {31}, number = {4}, pages = {297-302}, doi = {10.1080/08860220902780044}, pmid = {19462279}, issn = {1525-6049}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Disease Models, Animal ; Kidney/*blood supply ; *Laparoscopy ; Male ; Pentoxifylline/*therapeutic use ; Pneumoperitoneum, Artificial/*adverse effects ; *Postoperative Care ; *Preoperative Care ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*etiology/*prevention &amp; control ; Zinc/*therapeutic use ; }, abstract = {BACKGROUND: Pneumoperitoneum (P) created to facilitate laparoscopy (L) is associated with splanchnic hypoperfusion, ischemia/reperfusion (I/R) injury, and oxidative stress.<br><br>AIM: This study investigated the effects of pre- and post-laparoscopic conditioning, zinc, pentoxifylline (PTX), and N-acetylcysteine (NAC) on markers of I/R injury in an animal model.<br><br>METHODS: Sprague-Dawley male rats (n = 56, weight range 300-350 g) were randomly placed in one of seven treatment groups. Except for group C (control group who underwent a sham operation without pneumoperitoneum), pneumoperitoneum was created in all using CO(2) insufflation under a pressure of 15 mmHg. Group L (laparoscopy) was subjected to 60 min of pneumoperitoneum. Group Lpre (laparoscopic preconditioning plus laparoscopy) was subjected to 5 min of insufflation and 5 min of desufflation followed by 60 min of pneumoperitoneum. Group Lpost (laparoscopy plus laparoscopic post-conditioning) was subjected to 60 min of pneumoperitoneum and 60 min of desufflation followed by 5 min of insufflation and 5 min of desufflation. The laparoscopy plus zinc (LZ), PTX (LP), and NAC (LNAC) groups received a single intraperitoneal injection of zinc (50 mg/kg), pentoxifylline (50 mg/kg), or N-acetylcysteine (150 mg/kg) 5 min before the desufflation period. Animals were sacrificed at the end of the experiments, and kidney samples were tested for malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD).<br><br>RESULTS: MDA levels, as an indicator of oxidative stress in kidney tissue samples, were significantly higher in all pneumoperitoneum groups compared to Group C, except for Group Lpre. The pattern of change in tissue levels of SOD, GPX, and catalase was variable in the different treatment groups.<br><br>CONCLUSIONS: In this animal model of renal ischemia/reperfusion injury, laparoscopy caused renal ischemia as evidenced by elevated markers of tissue ischemia-reperfusion injury. This effect was significantly attenuated by post-laparoscopy conditioning, zinc, pentoxifylline, and N-acetylcysteine, but not by pre-laparoscopy conditioning.}, }
@article {pmid19461052, year = {2009}, author = {Bellis, A and Castaldo, D and Trimarco, V and Monti, MG and Chivasso, P and Sadoshima, J and Trimarco, B and Morisco, C}, title = {Cross-talk between PKA and Akt protects endothelial cells from apoptosis in the late ischemic preconditioning.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {29}, number = {8}, pages = {1207-1212}, doi = {10.1161/ATVBAHA.109.184135}, pmid = {19461052}, issn = {1524-4636}, mesh = {Animals ; Aorta/pathology ; Apoptosis/*physiology ; Cattle ; Cells, Cultured ; Cyclic AMP-Dependent Protein Kinases/*metabolism ; Disease Models, Animal ; Endothelium, Vascular/metabolism/*pathology ; Immunoblotting ; Ischemia/metabolism/*pathology ; Ischemic Preconditioning ; Nitric Oxide/biosynthesis ; Proto-Oncogene Proteins c-akt/*metabolism ; Receptor Cross-Talk/*physiology ; Time Factors ; }, abstract = {OBJECTIVE: The aim of this study was to explore the molecular mechanisms involved in late preconditioning-induced cell protection in endothelial cells.<br><br>METHODS AND RESULTS: Preconditioning (PC) was induced by exposing bovine aortic endothelial cells (BAECs) to 3 cycles of 15 minutes of hypoxia followed by 15 minutes of reoxygenation. A 12-hour period of hypoxia induced cell death in 60% of BAECs (48+/-5% apoptosis, 12+/-4% necrosis). Early and late PC decreased hypoxia-induced apoptotic (25+/-5% and 28+/-4%, respectively) and necrotic (6+/-3%, and 8+/-2%, respectively) cell death. Consistently, hypoxia-induced caspase-3 cleavage was reduced by PC. Pretreatment with H89 (protein kinase A [PKA] inhibitor), LY294002 (phosphatidyl-inositol-3-kinase [PI3K] inhibitor), and N-acetyl-cysteine (antioxidant) abrogated late PC-induced cell protection, whereas inhibition of protein kinase C by Go6983, and of nitric oxide synthesis by L-NAME,1400W and bovine eNOS siRNA did not. In addition, in early and late PC, PKA physically interacted with the phosphorylated form of Akt, suggesting that PKA is required for Akt phosphorylation. Expression of PKA and Akt dominant negative mutants inhibited ischemic late PC-induced protection, indicating that these kinases play a key role in late PC-mediated cell protection.<br><br>CONCLUSIONS: Late ischemic PC protects BAECs against hypoxia through PKA- and PI3K-dependent activation of Akt.}, }
@article {pmid19459771, year = {2009}, author = {Markkanen Penttinen, P and Pelkonen, J and Tapanainen, M and Mäki-Paakkanen, J and Jalava, PI and Hirvonen, MR}, title = {Co-cultivated damp building related microbes Streptomyces californicus and Stachybotrys chartarum induce immunotoxic and genotoxic responses via oxidative stress.}, journal = {Inhalation toxicology}, volume = {21}, number = {10}, pages = {857-867}, doi = {10.1080/08958370802526873}, pmid = {19459771}, issn = {1091-7691}, mesh = {Acetylcysteine/metabolism ; Animals ; Cell Cycle/drug effects ; Cell Line ; Cell Survival/drug effects ; Comet Assay ; Cytokines/biosynthesis ; DNA/biosynthesis/genetics ; Dogs ; Dose-Response Relationship, Drug ; Flow Cytometry ; Humans ; Immunotoxins/*toxicity ; Lipid Peroxidation/drug effects ; Macrophages/drug effects/immunology ; Mutagens/*toxicity ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Sick Building Syndrome/*microbiology ; Spores, Bacterial/chemistry/metabolism ; Stachybotrys/immunology/*metabolism ; Streptomyces/immunology/*metabolism ; }, abstract = {Oxidative stress has been proposed to be one mechanism behind the adverse health outcomes associated with living in a damp indoor environment. In the present study, the capability of damp building-related microbes Streptomyces californicus and Stachybotrys chartarum to induce oxidative stress was evaluated in vitro. In addition, the role of oxidative stress in provoking the detected cytotoxic, genotoxic, and inflammatory responses was studied by inhibiting the production of reactive oxygen species (ROS) using N-acetyl-l-cysteine (NAC). RAW264.7 macrophages were exposed in a dose- and time-dependent manner to the spores of co-cultivated S. californicus and S. chartarum, to their separately cultivated spore-mixture, or to the spores of these microbes alone. The intracellular peroxide production and cytotoxicity were measured by flow cytometric analysis, nitric oxide production was analyzed by the Griess method, DNA damage was determined by the comet assay, and cytokine production was measured by an immunochemical ELISA (enzyme-linked immunosorbent assay). All the studied microbial exposures triggered oxidative stress and subsequent cellular damage in RAW264.7 macrophages. The ROS scavenger, NAC, prevented growth arrest, apoptosis, DNA damage, and cytokine production induced by the co-culture since it reduced the intracellular level of ROS within macrophages. In contrast, the DNA damage and cell cycle arrest induced by the spores of S. californicus alone could not be prevented by NAC. Bioaerosol-induced oxidative stress in macrophages may be an important mechanism behind the frequent respiratory symptoms and diseases suffered by residents of moisture damaged buildings. Furthermore, microbial interactions during co-cultivation stimulate the production of highly toxic compound(s) which may significantly increase oxidative damage.}, }
@article {pmid19459161, year = {2009}, author = {Wang, CC and Fang, KM and Yang, CS and Tzeng, SF}, title = {Reactive oxygen species-induced cell death of rat primary astrocytes through mitochondria-mediated mechanism.}, journal = {Journal of cellular biochemistry}, volume = {107}, number = {5}, pages = {933-943}, doi = {10.1002/jcb.22196}, pmid = {19459161}, issn = {1097-4644}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis Inducing Factor/metabolism ; Astrocytes/*cytology/drug effects/enzymology ; Caspase 3 ; Cell Death/drug effects ; Cell Nucleus/drug effects/metabolism ; Cells, Cultured ; Chromium/toxicity ; Cytoprotection/drug effects ; DNA/metabolism ; Endodeoxyribonucleases/metabolism ; Enzyme Activation/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/enzymology/*metabolism ; NF-kappa B/metabolism ; Neurons/cytology/drug effects/metabolism ; Protein Binding/drug effects ; Protein Transport/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Transcription Factor AP-1/metabolism ; }, abstract = {Astrocytes, the most abundant glial cell population in the central nervous system (CNS), play physiological roles in neuronal activities. Oxidative insult induced by the injury to the CNS causes neural cell death through extrinsic and intrinsic pathways. This study reports that reactive oxygen species (ROS) generated by exposure to the strong oxidizing agent, hexavalent chromium (Cr(VI)) as a chemical-induced oxidative stress model, caused astrocytes to undergo an apoptosis-like cell death through a caspase-3-independent mechanism. Although activating protein-1 (AP-1) and NF-kappaB were activated in Cr(VI)-primed astrocytes, the inhibition of their activity failed to increase astrocytic cell survival. The results further indicated that the reduction in mitochondrial membrane potential (MMP) was accompanied by an increase in the levels of ROS in Cr(VI)-primed astrocytes. Moreover, pretreatment of astrocytes with N-acetylcysteine (NAC), the potent ROS scavenger, attenuated ROS production and MMP loss in Cr(VI)-primed astrocytes, and significantly increased the survival of astrocytes, implying that the elevated ROS disrupted the mitochondrial function to result in the reduction of astrocytic cell viability. In addition, the nuclear expression of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) was observed in Cr(VI)-primed astrocytes. Taken together, evidence shows that astrocytic cell death occurs by ROS-induced oxidative insult through a caspase-3-independent apoptotic mechanism involving the loss of MMP and an increase in the nuclear levels of mitochondrial pro-apoptosis proteins (AIF/EndoG). This mitochondria-mediated but caspase-3-independent apoptotic pathway may be involved in oxidative stress-induced astrocytic cell death in the injured CNS.}, }
@article {pmid19458036, year = {2009}, author = {Balansky, R and Ganchev, G and Iltcheva, M and Steele, VE and De Flora, S}, title = {Prenatal N-acetylcysteine prevents cigarette smoke-induced lung cancer in neonatal mice.}, journal = {Carcinogenesis}, volume = {30}, number = {8}, pages = {1398-1401}, pmid = {19458036}, issn = {1460-2180}, support = {N01-CN53301/CN/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adenocarcinoma, Bronchiolo-Alveolar/etiology/*prevention &amp; control ; Animals ; Animals, Newborn ; Body Weight/drug effects ; Female ; Free Radical Scavengers/*pharmacology ; Hyperplasia/etiology/prevention &amp; control ; Lung Neoplasms/etiology/*prevention &amp; control ; Mice ; Pregnancy ; *Prenatal Exposure Delayed Effects ; Smoking/*adverse effects ; }, abstract = {Certain adult diseases may have their origin early in life, and perinatal exposures may contribute to cancers both during childhood and later in life. We recently demonstrated that mainstream cigarette smoke (MCS) induces a potent carcinogenic response in mice when exposure starts soon after birth. We also showed that the antioxidant N-acetylcysteine (NAC) prevents the extensive nucleotide and gene expression alterations that occur 'physiologically' at birth in mouse lung. The present study was designed to evaluate whether administration of NAC during pregnancy may affect the yield of tumors in mice exposed to MCS, starting after birth and continuing for 120 days. The results obtained showed that 210 days after birth, one adenoma only was detectable in sham-exposed mice. In contrast, as much as the 61.1% (33/54) of MCS-exposed mice born from untreated dams had lung tumors, including both benign tumors and bronchoalveolar carcinomas. Treatment with NAC during pregnancy strikingly inhibited the formation of benign lung tumors and totally prevented occurrence of carcinomas. In addition, prenatal NAC inhibited the MCS-induced hyperplasia of the urinary bladder epithelium. These findings demonstrate for the first time that treatment during pregnancy with an antioxidant chemopreventive agent can affect the induction of tumors consequent to exposure to a carcinogen after birth.}, }
@article {pmid19456128, year = {2009}, author = {Lin, CC and Su, TH and Wang, TS}, title = {Protein carbonylation in THP-1 cells induced by cigarette smoke extract via a copper-catalyzed pathway.}, journal = {Chemical research in toxicology}, volume = {22}, number = {7}, pages = {1232-1238}, doi = {10.1021/tx900008h}, pmid = {19456128}, issn = {1520-5010}, mesh = {Antioxidants/pharmacology ; Catalysis ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Humans ; Immunoassay ; Penicillamine/chemistry/pharmacology ; *Protein Carbonylation ; *Smoke ; Nicotiana/chemistry/*toxicity ; }, abstract = {Cigarette smoke is a mixture of chemicals that cause direct or indirect oxidative stress in different cell lines. We investigated the effect of nonfractionated cigarette smoke extract (CSE) on protein carbonylation in human THP-1 cells. Cells were exposed to various concentrations (2.5-20%) of CSE for 30 min, and protein carbonylation was assessed by use of the sensitive 2,4-dinitrophenylhydrazine immuno-dot blot assay. CSE-induced protein carbonylation exhibited a dose-response relation with CSE concentrations. However, with prolonged exposure to CSE, significant decrements were observed when compared with the 30 min exposure. Cotreatment of THP-1 cells with antioxidants (N-acetyl-cysteine, S-allyl-cysteine, and alpha-tocopherol) and copper(II) ion chelators (d-penicillamine) during CSE exposure significantly reduced protein carbonylation, whereas cotreatment with antioxidants (vitamin C and trolox) and a metal chelator (EDTA), iron chelator (1,10-phenanthroline), or copper(I) chelator (neocuprin) did not decrease CSE-induced protein carbonylation in THP-1 cells. These results suggest that protein carbonylation is induced by CSE in THP-1 cells via a copper(II)-catalyzed reaction and not an iron-catalyzed reaction. Furthermore, the copper(II) ions involved in this CSE-induced protein carbonylation are derived from the intracellular pool, not via uptake from the extracellular medium. We speculate that natural copper(II) chelators may prevent some of the health problems caused by cigarette smoking, including lung disease, renal failure, and diabetes.}, }
@article {pmid19447919, year = {2009}, author = {Stav, D and Raz, M}, title = {Effect of N-acetylcysteine on air trapping in COPD: a randomized placebo-controlled study.}, journal = {Chest}, volume = {136}, number = {2}, pages = {381-386}, doi = {10.1378/chest.09-0421}, pmid = {19447919}, issn = {1931-3543}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Exercise Test ; Exercise Tolerance/*drug effects ; Female ; Follow-Up Studies ; Forced Expiratory Volume ; Humans ; Male ; Middle Aged ; Probability ; Pulmonary Disease, Chronic Obstructive/*diagnosis/*drug therapy ; Reference Values ; Respiratory Function Tests ; Risk Assessment ; Severity of Illness Index ; Total Lung Capacity/*drug effects ; Treatment Outcome ; }, abstract = {BACKGROUND: FEV(1) is used for the classification of disease severity and is a good predictor of COPD mortality. However, it is a poor predictor of clinical symptoms, exercise tolerance, and response to bronchodilators in COPD. Progressive reduction in inspiratory capacity (IC) during exercise reflects dynamic hyperinflation and is a good predictor of decreased exercise ability as well as increased exertional dyspnea. In animal models of COPD, N-acetylcysteine (NAC), an antioxidant/mucous modifier, has been shown to modify small airways, which mainly causes lung hyperinflation.<br><br>OBJECTIVE: Our goal was to examine the effect of 1,200 mg/d of NAC on lung hyperinflation at rest and after exercise in patients with moderate-to-severe COPD.<br><br>METHODS: This was a randomized, double-blind, cross-over study that included 24 eligible patients > 40 years of age with a diagnosis of COPD, a FEV(1) < 70% of predicted, FEV(1)/FVC ratio < 0.70, and a functional residual capacity > 120% of predicted normal. Patients were randomized to placebo treatment or NAC treatment twice daily for 6 weeks. This was followed by a 2-week washout period, and then patients were crossed over to alternate therapy for an additional 6 weeks. Evaluation was performed after each 6 weeks of each treatment.<br><br>RESULTS: IC and FVC were higher especially after exercise after NAC treatment compared with placebo treatment. In addition, the relationship of residual volume to total lung capacity was reduced in a similar pattern. Furthermore, endurance time was longer after NAC treatment compared with placebo treatment.<br><br>CONCLUSIONS: NAC treatment of patients with stable, moderate-to-severe COPD has a beneficial effect on physical performance, probably due to a reduction in air trapping.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00476736.}, }
@article {pmid19446573, year = {2009}, author = {Hill, DS and Wlodarczyk, BJ and Mitchell, LE and Finnell, RH}, title = {Arsenate-induced maternal glucose intolerance and neural tube defects in a mouse model.}, journal = {Toxicology and applied pharmacology}, volume = {239}, number = {1}, pages = {29-36}, pmid = {19446573}, issn = {1096-0333}, support = {P30 ES009106-049002/ES/NIEHS NIH HHS/United States ; P30ES09106/ES/NIEHS NIH HHS/United States ; P42 ES004917-160010/ES/NIEHS NIH HHS/United States ; P42 ES004917/ES/NIEHS NIH HHS/United States ; ES04917/ES/NIEHS NIH HHS/United States ; P30 ES009106/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Arsenates/*toxicity ; Blood Glucose/*analysis ; Disease Models, Animal ; Female ; Glucose Intolerance/blood/*chemically induced ; Glucose Tolerance Test ; Insulin/metabolism ; Maternal Exposure/*adverse effects ; Mice ; Mice, Inbred Strains ; Neural Tube Defects/*chemically induced/embryology/metabolism ; Pregnancy ; Pregnancy Outcome ; }, abstract = {BACKGROUND: Epidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals.<br><br>OBJECTIVES: We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic's teratogenicity in early neurodevelopment.<br><br>METHODS: We evaluated maternal intraperitoneal (IP) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selected compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), l-methionine (L-Met), N-tert-Butyl-alpha-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate's effects.<br><br>RESULTS: Arsenate caused significant glucose elevation during an IP glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p=0.0260). Arsenate caused NTDs (100%, p<0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%.<br><br>CONCLUSIONS: IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin's success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.}, }
@article {pmid19445591, year = {2009}, author = {Manning, VA and Chu, AL and Steeves, JE and Wolpert, TJ and Ciuffetti, LM}, title = {A host-selective toxin of Pyrenophora tritici-repentis, Ptr ToxA, induces photosystem changes and reactive oxygen species accumulation in sensitive wheat.}, journal = {Molecular plant-microbe interactions : MPMI}, volume = {22}, number = {6}, pages = {665-676}, doi = {10.1094/MPMI-22-6-0665}, pmid = {19445591}, issn = {0894-0282}, support = {//Howard Hughes Medical Institute/United States ; }, mesh = {Acetylcysteine/pharmacology ; Ascomycota/metabolism/*pathogenicity ; Cell Death/drug effects ; Chloroplasts/drug effects/metabolism/ultrastructure ; Free Radical Scavengers/pharmacology ; Mycotoxins/*pharmacology ; Photosystem I Protein Complex/metabolism ; Photosystem II Protein Complex/metabolism ; Plant Leaves/metabolism/ultrastructure ; Plant Proteins/metabolism ; Reactive Oxygen Species/*metabolism ; Triticum/drug effects/*microbiology ; }, abstract = {Ptr ToxA (ToxA) is a proteinaceous necrotizing host-selective toxin produced by Pyrenophora tritici-repentis, a fungal pathogen of wheat (Triticum aestivum). In this study, we have found that treatment of ToxA-sensitive wheat leaves with ToxA leads to a light-dependent accumulation of reactive oxygen species (ROS) that correlates with the onset of necrosis. Furthermore, the accumulation of ROS and necrosis could be inhibited by the antioxidant N-acetyl cysteine, providing further evidence that ROS production is required for necrosis. Microscopic evaluation of ToxA-treated whole-leaf tissue indicated that ROS accumulation occurs in the chloroplasts. Analysis of total protein extracts from ToxA-treated leaves showed a light-dependent reduction of the chloroplast protein RuBisCo. In addition, Blue native-gel electrophoresis followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis revealed that ToxA induces changes in photosystem I (PSI) and photosystem II (PSII) in the absence of light, and therefore, the absence of ROS. When ToxA-treated leaves were exposed to light, all proteins in both PSI and PSII were extremely reduced. We propose that ToxA induces alterations in PSI and PSII affecting photosynthetic electron transport, which subsequently leads to ROS accumulation and cell death when plants are exposed to light.}, }
@article {pmid19444991, year = {2009}, author = {Uner, N and Sevgiler, Y and Durmaz, H and Piner, P and Cinkiloğlu, E}, title = {N-Acetylcysteine provides dose-dependent protection against fenthion toxicity in the brain of Cyprinus carpio L.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {150}, number = {1}, pages = {33-38}, doi = {10.1016/j.cbpc.2009.02.001}, pmid = {19444991}, issn = {1532-0456}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Brain/*drug effects/*metabolism ; Carps/*metabolism ; Dose-Response Relationship, Drug ; Fenthion/*toxicity ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects/physiology ; }, abstract = {N-Acetyl-L-cysteine, a low-molecular weight thiol compound, with two different doses was used to prevent fenthion, an organophosphorus insecticide and acaricide, related oxidative stress in the brain of a model organism, Cyprinus carpio. Fish were exposed to sub-lethal and nominal concentration of fenthion after intraperitoneal injection of 0.5 or 400 mg/kg NAC. Brain tissues were then dissected and homogenized to analyse GSH, GSSG, TBARS, and protein contents. Enzymes that constitute the first line antioxidant defence, namely SOD and CAT, GSH-related enzymes, GR and GST, together with AChE activities were also determined spectrophotometrically. Fenthion did not cause any alteration in SOD and CAT activities while increasing GSH content, GSH/GSSG ratio and GST specific enzyme activity and decreasing GSSG, TBARS, and protein contents. Although, the highest induction in SOD and GST enzymes activities and the highest increase in GSH content were observed in the 0.5 mg/kg NAC-injected fish, their protein contents showed a decrease. 400 mg/kg NAC impeded the activation of the GST enzyme and a higher decrease in lipid peroxidation was observed. Fish were also protected against protein depletion by the higher dose NAC application. AChE activity was not influenced by fenthion exposure. Xenobiotic and GSH transporters may cause mild oxidative stress conditions in brain. Cellular redox status could trigger a series of reactions that result in an increase in SOD activity and a decrease in protein content. Based on the present results, it was suggested that the usefulness of NAC against fenthion depends on applied dose and tissue characteristics. Species-specifity and concentration selection should be taken into consideration in studies dealing with anticholinesterases.}, }
@article {pmid19444802, year = {2009}, author = {Krittaphol, W and McDowell, A and Thomson, CD and Tucker, IG and Fawcett, JP and Mikov, M}, title = {An improved HPLC method for the investigation of L-selenomethionine metabolism in rat gut contents.}, journal = {Biomedical chromatography : BMC}, volume = {23}, number = {11}, pages = {1169-1174}, doi = {10.1002/bmc.1239}, pmid = {19444802}, issn = {1099-0801}, mesh = {Acetylcysteine/chemistry ; Animals ; Benzenesulfonates ; Chromatography, High Pressure Liquid/*methods ; Gastrointestinal Contents/*chemistry ; Male ; Rats ; Rats, Wistar ; Reproducibility of Results ; Salicylates/chemistry ; Selenomethionine/analysis/*metabolism ; Sensitivity and Specificity ; o-Phthalaldehyde/chemistry ; }, abstract = {Selenomethionine (SeMet) is a widely used nutritional supplement that has potential benefit for people living in selenium-deficient areas. Previous research has shown that selenium administered as SeMet undergoes significant enterohepatic recycling which may involve the gut microflora. In order to investigate this we have developed a simple method for the quantitation of l-SeMet in rat gut content suspensions prepared from jejunum, ileum, caecum and colon. After incubation of l-SeMet with gut content suspensions, samples were deproteinized with sulfosalicylic acid and derivatized with o-phthaldialdehyde (OPA) and N-acetyl-l-cysteine (NAC). Mass spectrometry confirmed the formation of a 1:1:1 derivative of l-SeMet with OPA and NAC. Samples were analysed by reversed-phase high-performance liquid chromatography with fluorescence detection. The assay was linear in the concentration range 0.5-100 microg/mL (r(2) = 0.9992) with a limit of detection of 0.025 microg/mL (signal-to-noise ratio of 5). Intra-day and inter-day accuracies were 91.1-92.8 and 91.7-95.5%, respectively with corresponding precisions as relative standard deviation of <5%. Incubation of l-SeMet with gut content suspensions from different parts of the rat intestine showed that l-SeMet metabolism occurs mainly in the caecum.}, }
@article {pmid19442767, year = {2009}, author = {Yamada, M and Ogawa, T}, title = {Chemodynamics underlying N-acetyl cysteine-mediated bone cement monomer detoxification.}, journal = {Acta biomaterialia}, volume = {5}, number = {8}, pages = {2963-2973}, doi = {10.1016/j.actbio.2009.04.027}, pmid = {19442767}, issn = {1878-7568}, mesh = {Adhesiveness ; Animals ; Apoptosis/drug effects ; Bone Cements/*chemistry/*pharmacology ; Cell Adhesion/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Cysteine/*chemistry/*pharmacology ; Materials Testing ; Osteoblasts/cytology/*drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Methyl methacrylate (MMA)-based bone cement monomer is cytotoxic. N-Acetyl cysteine (NAC), a cysteine derivative, may alleviate this toxicity by inactivating the monomer components with its sulfhydryl moiety. This study examined the chemical interaction dynamics between bone cement monomer and NAC resulting in detoxification of the monomer. A monomer/NAC mixture was prepared by mixing and incubating a commercially available MMA-based bone cement monomer with NAC for various time periods of 1 min, 1h, 6h and 24h. Rat bone marrow-derived osteoblastic cells were cultured with either the monomer/NAC mixture or the monomer alone. Only 17% of the cells were viable 24h after seeding in the culture containing the monomer alone. The proliferation rate and alkaline phosphatase activity of the cells were substantially reduced under this condition. In contrast, when cultured with the monomer/NAC mixture, the viability and function of the cells were improved with increasing time of monomer/NAC incubation. For instance, the monomer/NAC mixture that was pre-reacted for 1 min increased cell viability from 17% to 55%. The monomer/NAC mixture that was pre-reacted for 24h nearly completely restored cell viability, proliferation and ALP activity to the level of an untreated control culture. The DPPH radical-scavenging capacity of monomer/NAC mixture decreased with an increase in their reaction time, indicating time-dependent depletion of the NAC anti-oxidant moiety. Within the limit of this experimental condition, these data demonstrate the immediate initiation and rapid completion of bone cement monomer/NAC interaction, resulting in abrogation of the monomer's cytotoxicity.}, }
@article {pmid19442679, year = {2009}, author = {Naranmandura, H and Ogra, Y and Iwata, K and Lee, J and Suzuki, KT and Weinfeld, M and Le, XC}, title = {Evidence for toxicity differences between inorganic arsenite and thioarsenicals in human bladder cancer cells.}, journal = {Toxicology and applied pharmacology}, volume = {238}, number = {2}, pages = {133-140}, doi = {10.1016/j.taap.2009.05.006}, pmid = {19442679}, issn = {1096-0333}, mesh = {Aquaporins/*drug effects/metabolism ; Arsenic Poisoning/*metabolism ; Arsenicals/pharmacokinetics ; Arsenites/pharmacokinetics/toxicity ; Cacodylic Acid/analogs &amp; derivatives/pharmacokinetics/toxicity ; Carcinogenicity Tests ; Carcinoma/*metabolism ; Carcinoma, Squamous Cell/metabolism ; Cell Line, Tumor ; Environmental Pollutants/pharmacokinetics/toxicity ; Female ; Humans ; Lethal Dose 50 ; Reactive Oxygen Species/*metabolism ; Urinary Bladder Neoplasms/*metabolism ; Vulvar Neoplasms/metabolism ; }, abstract = {Arsenic toxicity is dependent on its chemical species. In humans, the bladder is one of the primary target organs for arsenic-induced carcinogenicity. However, little is known about the mechanisms underlying arsenic-induced carcinogenicity, and what arsenic species are responsible for this carcinogenicity. The present study aimed at comparing the toxic effect of DMMTA(V) with that of inorganic arsenite (iAs(III)) on cell viability, uptake efficiency and production of reactive oxygen species (ROS) toward human bladder cancer EJ-1 cells. The results were compared with those of a previous study using human epidermoid carcinoma A431 cells. Although iAs(III) was known to be toxic to most cells, here we show that iAs(III) (LC(50)=112 microM) was much less cytotoxic than DMMTA(V) (LC(50)=16.7 microM) in human bladder EJ-1 cells. Interestingly, pentavalent sulfur-containing DMMTA(V) generated a high level of intracellular ROS in EJ-1 cells. However, this was not observed in the cells exposed to trivalent inorganic iAs(III) at their respective LC(50) dose. Furthermore, the presence of N-acetyl-cysteine completely inhibited the cytotoxicity of DMMTA(V) but not iAs(III), suggesting that production of ROS was the main cause of cell death from exposure to DMMTA(V), but not iAs(III). Because the cellular uptake of iAs(III) is mediated by aquaporin proteins, and because the resistance of cells to arsenite can be influenced by lower arsenic uptake due to lower expression of aquaporin proteins (AQP 3, 7 and 9), the expression of several members of the aquaporin family was also examined. In human bladder EJ-1 cells, mRNA/proteins of AQP3, 7 and 9 were not detected by reverse transcription polymerase chain reaction (RT-PCR)/western blotting. In A431 cells, only mRNA and protein of AQP3 were detected. The large difference in toxicity between the two cell lines could be related to their differences in uptake of arsenic species.}, }
@article {pmid19270218, year = {2009}, author = {Bozkurt, D and Hur, E and Ulkuden, B and Sezak, M and Nar, H and Purclutepe, O and Sen, S and Duman, S}, title = {Can N-acetylcysteine preserve peritoneal function and morphology in encapsulating peritoneal sclerosis?.}, journal = {Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis}, volume = {29 Suppl 2}, number = {}, pages = {S202-5}, pmid = {19270218}, issn = {0896-8608}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Disease Models, Animal ; Endothelial Cells/drug effects/metabolism/pathology ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Injections, Intraperitoneal ; Oxidative Stress/*drug effects ; Peritoneal Dialysis/*adverse effects ; Peritoneal Diseases/etiology/pathology/*prevention &amp; control ; Peritoneum/drug effects/metabolism/*pathology ; Rats ; Rats, Wistar ; Sclerosis ; Treatment Outcome ; }, abstract = {Long-term use of the peritoneum as a dialysis membrane results in progressive irreversible dysfunction, described as peritoneal fibrosis. Oxidative stress during peritoneal dialysis has been established in many studies. Generation of reactive oxygen species (ROS) by conventional peritoneal dialysis solutions, regardless of whether produced by high glucose, angiotensin II, or glucose degradation products may be responsible for progressive membrane dysfunction. The well-known antioxidant molecule N-acetylcysteine (NAC) is capable of direct scavenging of ROS. The aim of the present study was to investigate the effect of NAC therapy on both progression and regression of encapsulating peritoneal sclerosis (EPS). We divided 49 nonuremic Wistar albino rats into four groups: Control group-2 mL isotonic saline intraperitoneally (IP) daily for 3 weeks; CG group-2 mL/200 g 0.1% chlorhexidine gluconate (CG) and 15% ethanol dissolved in saline injected IP daily for a total of 3 weeks; Resting group-CG (weeks 1 - 3), plus peritoneal resting (weeks 4 - 6); NAC-R group-CG (weeks 1 - 3), plus 2 g/L NAC (weeks 4 - 6). At the end of the experiment, all rats underwent a 1-hour peritoneal equilibration test with 25 mL 3.86% PD solution. Dialysate-to-plasma ratio (D/P) urea, dialysate white blood cell count (per cubic milliliter), ultrafiltration (UF) volume, and morphology changes of parietal peritoneum were examined. The CG group progressed to encapsulating peritoneal sclerosis, characterized by loss of UF, increased peritoneal thickness, inflammation, and ultimately, development of fibrosis. Resting produced advantages only in dialysate cell count; with regard to vascularity and dialysate cell count, NAC was more effective than was peritoneal rest. Interestingly, we observed no beneficial effects of NAC on fibrosis. That finding may be a result of our experimental severe peritoneal injury model. However, decreased inflammation and vascularity with NAC therapy were promising results in regard to membrane protection.}, }
@article {pmid19438509, year = {2009}, author = {Lee, DH and Rhee, JG and Lee, YJ}, title = {Reactive oxygen species up-regulate p53 and Puma; a possible mechanism for apoptosis during combined treatment with TRAIL and wogonin.}, journal = {British journal of pharmacology}, volume = {157}, number = {7}, pages = {1189-1202}, pmid = {19438509}, issn = {1476-5381}, support = {CA96989/CA/NCI NIH HHS/United States ; R01 CA096989/CA/NCI NIH HHS/United States ; CA121395/CA/NCI NIH HHS/United States ; CA95191/CA/NCI NIH HHS/United States ; R03 CA121395/CA/NCI NIH HHS/United States ; R01 CA095191/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*physiology ; Apoptosis Regulatory Proteins/*biosynthesis/genetics ; Caspases/metabolism ; Cell Line, Tumor ; DNA Damage ; Drug Synergism ; Enzyme Activation ; Flavanones/*pharmacology ; Gene Knockdown Techniques ; Histones/metabolism ; Humans ; Male ; Phosphorylation ; Prostatic Neoplasms ; Proto-Oncogene Proteins/*biosynthesis/genetics ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Recombinant Proteins/pharmacology ; TNF-Related Apoptosis-Inducing Ligand/*pharmacology ; Tumor Suppressor Protein p53/*biosynthesis/genetics ; Up-Regulation ; bcl-2-Associated X Protein/physiology ; }, abstract = {BACKGROUND AND PURPOSE: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptotic death in a variety of cancer cells without marked toxicity to most normal cells. We previously reported that wogonin, a potent anticancer agent from a Chinese herb, up-regulates p53 in prostate cancer cells. In this study, the effects of combinations of TRAIL and wogonin on a human prostate cancer cell line LNCaP, resistant to TRAIL, was evaluated for evidence of synergy in triggering apoptosis.<br><br>EXPERIMENTAL APPROACH: Western blot assay and the 'comet' assay were used to study the underlying mechanisms of cell death and search for any mechanisms of enhancement of TRAIL-induced apoptosis in the presence of wogonin.<br><br>KEY RESULTS: During combined treatment with wogonin and TRAIL, cytotoxicity, poly(ADP-ribose) polymerase cleavage and caspase activation were associated with up-regulation of p53 through DNA damage and reactive oxygen species (ROS) generation. N-acetylcysteine (NAC), an antioxidant, inhibited ROS generation and synergistic interaction between TRAIL and wogonin. Experimental results in human colon cancer HCT116 cells demonstrated that p53-dependent Puma up-regulation played an important role; deficiency in either p53 or Puma prevented wogonin-enhanced TRAIL-induced apoptosis.<br><br>CONCLUSIONS AND IMPLICATIONS: The present studies suggest that wogonin enhances TRAIL-induced cytotoxicity through up-regulation of p53 and Puma, mediated by ROS.}, }
@article {pmid19437484, year = {2009}, author = {Gong, A and He, M and Krishna Vanaja, D and Yin, P and Karnes, RJ and Young, CY}, title = {Phenethyl isothiocyanate inhibits STAT3 activation in prostate cancer cells.}, journal = {Molecular nutrition &amp; food research}, volume = {53}, number = {7}, pages = {878-886}, pmid = {19437484}, issn = {1613-4133}, support = {R01 CA088900/CA/NCI NIH HHS/United States ; R01 CA088900-04/CA/NCI NIH HHS/United States ; 88900//PHS HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anticarcinogenic Agents/*pharmacology ; Cell Division/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; G2 Phase/drug effects ; Humans ; Interleukin-6/pharmacology ; Isothiocyanates/*pharmacology ; Janus Kinase 2/antagonists &amp; inhibitors/metabolism ; Male ; Phosphorylation ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Receptors, Androgen/genetics ; STAT3 Transcription Factor/*antagonists &amp; inhibitors/metabolism ; }, abstract = {This study was undertaken to investigate the mechanism by which phenethyl isothiocyanate (PEITC), a natural compound from cruciferous vegetables, exhibits antitumor effect on prostate cancer cells. Cell proliferation, cell cycle, Western blot, gene transfer, and reporter assays were used to test the effects of PEITC on the growth and IL6/JAK/STAT3 pathway in prostate cancer. The result showed that PEITC significantly inhibited DU145 cell proliferation in a dose-dependent manner and induced the cell arrest at G2-M phase. PEITC inhibited both constitutive and IL-6-induced STAT3 activity in DU145 cells. IL-6-stimulated phosphorylation of JAK2, an STAT3 upstream kinase, was also attenuated by PEITC. Moreover, an antioxidant reagent, N-acetyl-L-cysteine (NAC) which suppresses reactive oxygen species (ROS) generation, reversed the early inhibitory effects of PEITC on cell proliferation, constitutive or IL-6-mediated JAK-STAT3 phosphorylation in PCa cells. Taken together, our data demonstrated that PEITC can inhibit the activation of the JAK-STAT3 signal-cascade in prostate cancer cells and the underlying mechanism may be partially involved with blocking cellular ROS production during the early stage of the signaling activation by IL-6.}, }
@article {pmid19436334, year = {2009}, author = {Liu, M and Grigoryev, DN and Crow, MT and Haas, M and Yamamoto, M and Reddy, SP and Rabb, H}, title = {Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice.}, journal = {Kidney international}, volume = {76}, number = {3}, pages = {277-285}, doi = {10.1038/ki.2009.157}, pmid = {19436334}, issn = {1523-1755}, support = {R01 DK084445/DK/NIDDK NIH HHS/United States ; 2R01 DK54770/DK/NIDDK NIH HHS/United States ; P0 HL073944/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Acute Kidney Injury/chemically induced/*metabolism/pathology ; Animals ; Antineoplastic Agents/toxicity ; Capillary Permeability ; Cisplatin/toxicity ; Glutathione/pharmacology ; Inflammation Mediators/metabolism ; Kidney/pathology ; Kidney Function Tests ; Mice ; Mice, Inbred ICR ; Mice, Knockout ; NF-E2-Related Factor 2/genetics/*metabolism ; Oligonucleotide Array Sequence Analysis ; Reperfusion Injury/*metabolism ; Up-Regulation ; }, abstract = {Oxidative stress is involved in acute kidney injury due to ischemia-reperfusion and chemotherapy-induced nephrotoxicity. To investigate their basic mechanisms we studied the role of nuclear factor-erythroid 2-p45-related factor 2 (Nrf2), a redox-sensitive transcription factor that regulates expression of several antioxidant and cytoprotective genes. We compared the responses of Nrf2-knockout mice and their wild-type littermates in established mouse models of ischemia-reperfusion injury and cisplatin-induced nephrotoxicity. Several Nrf2-regulated genes encoding antioxidant enzymes/proteins were significantly upregulated in the kidneys of wild type but not Nrf2-knockout mice following renal ischemia. Renal function, histology, vascular permeability, and survival were each significantly worse in the Nrf2 knockout mice. Further, proinflammatory cytokine and chemokine expression tended to increase after ischemia in the knockout compared to the wild-type mice. Treatment of the knockout mice with the antioxidants N-acetyl-cysteine or glutathione improved renal function. The knockout mice were more susceptible to cisplatin-induced nephrotoxicity, and this was blunted by N-acetyl-cysteine pretreatment. Our study demonstrates that Nrf2-deficiency enhances susceptibility to both ischemic and nephrotoxic acute kidney injury, and identifies this transcription factor as a potential therapeutic target in these injuries.}, }
@article {pmid19436121, year = {2009}, author = {Shimada, K and Murayama, T and Yokode, M and Kita, T and Uzui, H and Ueda, T and Lee, JD and Kishimoto, C}, title = {N-acetylcysteine reduces the severity of atherosclerosis in apolipoprotein E-deficient mice by reducing superoxide production.}, journal = {Circulation journal : official journal of the Japanese Circulation Society}, volume = {73}, number = {7}, pages = {1337-1341}, doi = {10.1253/circj.cj-08-1148}, pmid = {19436121}, issn = {1346-9843}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Apolipoproteins E/*deficiency ; Atherosclerosis/*drug therapy/etiology/*metabolism ; Dietary Fats/adverse effects ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/*therapeutic use ; Intercellular Adhesion Molecule-1/metabolism ; Macrophages/drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Oxidative Stress/drug effects ; *Severity of Illness Index ; Superoxides/*metabolism ; }, abstract = {BACKGROUND: Oxidative stress may play an important role in the development of atherosclerosis. Because N-acetylcysteine (NAC) is able to reduce oxidative stress, the present study assessed the hypothesis that NAC may reduce the severity of atherosclerosis in apolipoprotein (apo) E-deficient mice.<br><br>METHODS AND RESULTS: Atherosclerosis was induced in apoE-deficient mice fed a high-fat diet containing 0.3% cholesterol. Mice were injected intraperitoneally with NAC (20 mg . kg(-1) . day(-1)) 3 times per week over 8 weeks. Fatty streak plaque developed in the apoE-deficient mice, but not in mice treated with NAC. In addition, NAC reduced superoxide production in the aortic walls, as detected by ethidium staining. NAC treatment did not significantly modify the serum lipid profiles.<br><br>CONCLUSIONS: In this animal model NAC may suppress atherosclerosis via reducing superoxide production.}, }
@article {pmid19436114, year = {2009}, author = {Hanczko, R and Fernandez, DR and Doherty, E and Qian, Y and Vas, G and Niland, B and Telarico, T and Garba, A and Banerjee, S and Middleton, FA and Barrett, D and Barcza, M and Banki, K and Landas, SK and Perl, A}, title = {Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.}, journal = {The Journal of clinical investigation}, volume = {119}, number = {6}, pages = {1546-1557}, pmid = {19436114}, issn = {1558-8238}, support = {R01 DK049221/DK/NIDDK NIH HHS/United States ; R01 DK 49221/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Biomarkers, Tumor/metabolism ; Carcinoma, Hepatocellular/*enzymology/genetics/pathology/*prevention &amp; control ; Cell Transformation, Neoplastic/genetics/*metabolism/pathology ; JNK Mitogen-Activated Protein Kinases/metabolism ; Liver Failure/*chemically induced ; Liver Neoplasms/*enzymology/genetics/pathology/prevention &amp; control ; Male ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; Phosphorylation ; Transaldolase/*deficiency/metabolism ; alpha-Fetoproteins/metabolism ; beta Catenin/metabolism ; fas Receptor/metabolism ; }, abstract = {Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.}, }
@article {pmid19434859, year = {2008}, author = {Knobloch, J and Reimann, K and Klotz, LO and Rüther, U}, title = {Thalidomide resistance is based on the capacity of the glutathione-dependent antioxidant defense.}, journal = {Molecular pharmaceutics}, volume = {5}, number = {6}, pages = {1138-1144}, doi = {10.1021/mp8001232}, pmid = {19434859}, issn = {1543-8384}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*metabolism ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Chickens ; Culture Media, Conditioned/pharmacology ; Dose-Response Relationship, Drug ; Drug Resistance/*drug effects ; Embryo, Mammalian ; Embryo, Nonmammalian ; Fibroblasts/metabolism ; Free Radical Scavengers/pharmacology ; Glutathione/analogs &amp; derivatives/analysis/*metabolism/pharmacology ; Humans ; Mice ; Superoxides/metabolism ; Teratogens/*pharmacology ; Thalidomide/*pharmacology ; Time Factors ; }, abstract = {Thalidomide as an effective treatment for multiple myeloma and leprosy has also caused birth defects in thousands of children five decades ago particularly in Europe. Thus its use in humans remains limited. The rapid and fatal approval of thalidomide at that time ultimately was a consequence of the sole use of thalidomide-insensitive species in animal toxicity tests. Here, we aimed at elucidating the molecular basis for the resistance of mice to thalidomide teratogenicity. By using hydroethidine staining we demonstrate that thalidomide induces the formation of superoxide in embryonic fibroblasts of thalidomide-sensitive species but not in those of mice. As determined by trypan blue staining, scavenging of superoxide prevents thalidomide-induced apoptosis, a marker for thalidomide teratogenicity. Mouse embryonic fibroblasts are found to have higher glutathione levels than those of sensitive species and can be sensitized for thalidomide by glutathione depletion with diethyl maleate or diamide. Accordingly, experimental increase of glutathione levels in human embryonic fibroblasts by adding N-acetyl cysteine or glutathione ethyl ester to the culture medium counteracts thalidomide-induced apoptosis. Finally, we show that thalidomide-induced molecular pathology downstream of superoxide is essentially identical in human and sensitized mouse embryonic fibroblasts. In conclusion, thalidomide-resistance is based on the capacity of the glutathione-dependent antioxidant defense. We provide a basis to pharmacologically overcome the limitations of thalidomide use at humans and describe substantial differences between human and mouse embryonic cells regarding the protection against oxidative stress.}, }
@article {pmid19429773, year = {2009}, author = {Teng, RJ and Eis, A and Bakhutashvili, I and Arul, N and Konduri, GG}, title = {Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {297}, number = {1}, pages = {L184-95}, pmid = {19429773}, issn = {1522-1504}, support = {R01-HL-57268/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects ; Biological Assay ; Blotting, Western ; Bromodeoxyuridine/metabolism ; Cell Proliferation/drug effects ; Endothelial Cells/drug effects/enzymology/pathology ; Female ; Fetus/*blood supply/drug effects/enzymology/pathology ; Gene Expression Regulation/drug effects ; Hypertension, Pulmonary/enzymology/genetics/*metabolism/*pathology ; NADPH Oxidases/genetics/metabolism ; *Neovascularization, Physiologic/drug effects ; Oxygen/pharmacology ; Pregnancy ; Pulmonary Artery/drug effects/enzymology/*metabolism/*pathology ; RNA, Messenger/genetics/metabolism ; Sheep ; Superoxide Dismutase/genetics/metabolism ; Superoxides/*metabolism ; Time Factors ; }, abstract = {Persistent pulmonary hypertension of newborn (PPHN) is associated with impaired pulmonary vasodilation at birth. Previous studies demonstrated that a decrease in angiogenesis contributes to this failure of postnatal adaptation. We investigated the hypothesis that oxidative stress from NADPH oxidase (Nox) contributes to impaired angiogenesis in PPHN. PPHN was induced in fetal lambs by ductus arteriosus ligation at 85% of term gestation. Pulmonary artery endothelial cells (PAEC) from fetal lambs with PPHN (HTFL-PAEC) or control lambs (NFL-PAEC) were compared for their angiogenic activities and superoxide production. HTFL-PAEC had decreased tube formation, cell proliferation, scratch recovery, and cell invasion and increased cell apoptosis. Superoxide (O(2)(-)) production, measured by dihydroethidium epifluorescence and HPLC, were increased in HTFL-PAEC compared with NFL-PAEC. The mRNA levels for Nox2, Rac1, p47(phox), and Nox4, protein levels of p67(phox) and Rac1, and NADPH oxidase activity were increased in HTFL-PAEC. NADPH oxidase inhibitor, apocynin (Apo), and antioxidant, N-acetyl-cysteine (NAC), improved angiogenic measures in HTFL-PAEC. Apo and NAC also reduced apoptosis in HTFL-PAEC. Our data suggest that PPHN is associated with increased O(2)(-) production from NADPH oxidase in PAEC. Increased oxidative stress from NADPH oxidase contributes to the impaired angiogenesis of PAEC in PPHN.}, }
@article {pmid19429708, year = {2009}, author = {Ma, Q and Cavallin, LE and Yan, B and Zhu, S and Duran, EM and Wang, H and Hale, LP and Dong, C and Cesarman, E and Mesri, EA and Goldschmidt-Clermont, PJ}, title = {Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {106}, number = {21}, pages = {8683-8688}, pmid = {19429708}, issn = {1091-6490}, support = {R01 HL071536/HL/NHLBI NIH HHS/United States ; P30 AI073961/AI/NIAID NIH HHS/United States ; R01 CA075918/CA/NCI NIH HHS/United States ; HL71536-08/HL/NHLBI NIH HHS/United States ; CA75918/CA/NCI NIH HHS/United States ; }, mesh = {Acquired Immunodeficiency Syndrome/complications/enzymology/genetics ; Animals ; Antioxidants/*metabolism ; Cell Transformation, Neoplastic/genetics/metabolism/pathology ; Disease Models, Animal ; Enzyme Activation ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neovascularization, Pathologic/genetics/metabolism/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Reactive Oxygen Species/metabolism ; Sarcoma, Kaposi/blood supply/etiology/*metabolism/*pathology ; Transcription, Genetic/genetics ; Tumor Cells, Cultured ; rac1 GTP-Binding Protein/genetics/*metabolism ; }, abstract = {Kaposi's sarcoma (KS) is the major AIDS-associated malignancy. It is characterized by the proliferation of spindle cells, inflammatory infiltrate, and aberrant angiogenesis caused by Kaposi's sarcoma herpesvirus (KSHV) infection. Small GTPase Rac1, an inflammatory signaling mediator triggering reactive oxygen species (ROS) production by NADPH-oxidases, is implicated in carcinogenesis and tumor angiogenesis. Here, we show that expression of a constitutively active Rac1 (RacCA) driven by the alpha-smooth muscle actin promoter in transgenic mice is sufficient to cause KS-like tumors through mechanisms involving ROS-driven proliferation, up-regulation of AKT signaling, and hypoxia-inducible factor 1-alpha-related angiogenesis. RacCA-induced tumors expressed KS phenotypic markers; displayed remarkable transcriptome overlap with KS lesions; and were, like KS, associated with male gender. The ROS scavenging agent N-acetyl-cysteine inhibited angiogenesis and completely abrogated transgenic RacCA tumor formation, indicating a causal role of ROS in tumorigenesis. Consistent with a pathogenic role in KS, immunohistochemical analysis revealed that Rac1 is overexpressed in KSHV(+) spindle cells of AIDS-KS biopsies. Our results demonstrate the direct oncogenicity of Rac1 and ROS and their contribution to a KS-like malignant phenotype, further underscoring the carcinogenic potential of oxidative stress in the context of chronic infection and inflammation. They define the RacCA transgenic mouse as a model suitable for studying the role of oxidative stress in the pathogenesis and therapy of KS, with relevance to other inflammation-related malignancies. Our findings suggest host and viral genes triggering Rac1 or ROS production as key determinants of KS onset and potential KS chemopreventive or therapeutic targets.}, }
@article {pmid19428790, year = {2009}, author = {Mishra, MK and Ghosh, D and Duseja, R and Basu, A}, title = {Antioxidant potential of Minocycline in Japanese Encephalitis Virus infection in murine neuroblastoma cells: correlation with membrane fluidity and cell death.}, journal = {Neurochemistry international}, volume = {54}, number = {7}, pages = {464-470}, doi = {10.1016/j.neuint.2009.01.022}, pmid = {19428790}, issn = {1872-9754}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anisotropy ; Anti-Bacterial Agents/*pharmacology ; *Antioxidants ; Blotting, Western ; Brain Neoplasms/*pathology ; Cell Death/*drug effects ; Cell Line, Tumor ; Encephalitis, Japanese/*pathology ; Enzyme Inhibitors/pharmacology ; Free Radicals/metabolism ; In Situ Nick-End Labeling ; L-Lactate Dehydrogenase/metabolism ; Membrane Fluidity/*drug effects ; Membrane Potentials/drug effects ; Mice ; Mice, Inbred BALB C ; Minocycline/*pharmacology ; Mitochondrial Membranes/drug effects ; Neuroblastoma/*pathology ; Onium Compounds/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Minocycline is neuroprotective in animal models of a number of acute CNS injuries, neurodegenerative diseases and CNS infection. While anti-inflammatory and anti-apoptotic effects of Minocycline have been characterized, the molecular basis for the neuroprotective effects of Minocycline remains unclear. We report here that Minocycline and two classical antioxidant compounds inhibit the Japanese Encephalitis Virus (JEV)-induced free radical generation in mouse neuroblastoma. In cultures of Neuro2a (N2a) cells infected with JEV for up to 24h, the number of cells undergoing cell death was also reduced by Minocycline (20 microM). JEV infection resulted in increased oxidative stress, as revealed by an increase in the fluorescence intensity for 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA), a reactive oxygen species (ROS) indicator. Minocycline at 20 microM inhibited this ROS production. Cells were moderately protected from JEV-induced death by diphenyleneiodonium (DPI), an inhibitor of flavon-containing enzyme inhibitor, whereas common antioxidants such as N-acetyl-cysteine (NAC) turned out to be ineffective. Direct antioxidant property of Minocycline and reference antioxidant compounds is evaluated by LDH assay, ROS measurement and mitochondrial membrane potential measurement. Our findings suggest that Minocycline reduces the neuronal damage seen in JEV infection in neuronal cell culture models at least in part through inhibition of oxidative stress.}, }
@article {pmid19428783, year = {2009}, author = {Pan, J and Xiao, Q and Sheng, CY and Hong, Z and Yang, HQ and Wang, G and Ding, JQ and Chen, SD}, title = {Blockade of the translocation and activation of c-Jun N-terminal kinase 3 (JNK3) attenuates dopaminergic neuronal damage in mouse model of Parkinson's disease.}, journal = {Neurochemistry international}, volume = {54}, number = {7}, pages = {418-425}, doi = {10.1016/j.neuint.2009.01.013}, pmid = {19428783}, issn = {1872-9754}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Blotting, Western ; Cell Nucleus/metabolism ; Dopamine/*physiology ; Dopamine Agents/pharmacology ; Enzyme Activation/drug effects ; Excitatory Amino Acid Antagonists/pharmacology ; Immunohistochemistry ; Immunoprecipitation ; Ketamine/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase 10/*antagonists &amp; inhibitors/physiology ; Neostriatum/pathology ; Neurons/*pathology ; Parkinson Disease/*pathology ; Protein Transport/drug effects ; Quinoxalines/pharmacology ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal death in Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). JNK3, the only neural-specific isoform, may play an important role in mediating the neurotoxic effects of MPTP in dopaminergic neuronal injury. To analyze the variation in JNK3 activation, the levels of phospho-JNK3 were measured at the various time points of occurrence of MPTP-induced lesions. In our study, we observed that during MPTP intoxication, two peaks of JNK3 activation appeared at 8 and 24h. To further define the mechanism of JNK3 activation and translocation, the antioxidant N-acetylcysteine (NAC), the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX) were administered to the mice 30 min after each of the four MPTP injections. The results revealed that NAC clearly inhibited JNK3 activation during the early intoxication, whereas ketamine preferably attenuated JNK3 activation during the latter intoxication. DNQX had no significant effects on JNK3 activation during intoxication. Consequently, reactive oxygen species (ROS) and the NMDA receptor were closely associated with JNK3 activation following MPTP intoxication. NAC and ketamine exerted a preventive effect against MPTP-induced loss of tyrosine hydroxylase-positive neurons and suppressed the nuclear translocation of JNK3, suggesting that NAC and ketamine can prevent MPTP-induced dopaminergic neuronal death by suppressing JNK3 activation.}, }
@article {pmid19428345, year = {2009}, author = {Lin, TH and Lu, FJ and Yin, YF and Tseng, TH}, title = {Enhancement of esculetin on arsenic trioxide-provoked apoptosis in human leukemia U937 cells.}, journal = {Chemico-biological interactions}, volume = {180}, number = {1}, pages = {61-68}, doi = {10.1016/j.cbi.2009.01.011}, pmid = {19428345}, issn = {1872-7786}, mesh = {Antineoplastic Agents/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Antioxidants/therapeutic use ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Blotting, Western ; Cell Survival ; Fluorescent Antibody Technique ; Humans ; *Leukemia ; Oxides/*pharmacology ; U937 Cells ; Umbelliferones/*pharmacology ; }, abstract = {In order to overcome chemotherapy resistance, many laboratories are searching for agents that increase the sensitivity of cancer cells to anticancer drugs. Arsenic trioxide (As(2)O(3)) is widely used in treating human acute polymyelocytic leukemia (APL). However, solid tumors and other leukemia cells such as U937 promonocytic leukemia cells are insensitive to As(2)O(3). Esculetin, a coumarin derivative, has previously induced cell cycle arrest and apoptosis of HL-60 cells as well as enhanced taxol-induced apoptosis in HepG2 cells, thereby displaying anticancer potential. In this study, esculetin inhibited proliferation and mitogen activated protein kinases (MAPKs) activation in human leukemia U937 cells. Since inhibitors of MAPKs have modulated the GSH-redox state and enhanced the sensitivity of leukemia cells to As(2)O(3)-provoked apoptosis, we monitored the effect of combining esculetin and As(2)O(3) (2.5 microM) on the GSH level. Our study showed that esculetin, PD98059 (MEK/ERK inhibitor), and SP600125 (JNK inhibitor) similarly enhanced the As(2)O(3)-induced GSH depletion. We found that the As(2)O(3) (2.5 microM) treatment slightly induced apoptosis and the pretreatment of esculetin enhanced the As(2)O(3)-provoked apoptosis significantly. In addition, esculetin enhanced the effect of As(2)O(3) on caspase activation in U937 cells. We compared the combined esculetin and As(2)O(3) treatment to the As(2)O(3) treated alone. The combined esculetin and As(2)O(3) treatment increased Bid cleavage, Bax conformation change and cytochrome C release. The study also indicated that esculetin enhanced the As(2)O(3)-induced lysosomal leakage and apoptosis. Furthermore, pretreatment with N-acetylcysteine (NAC) reduced these enhanced effects. Based on these studies, esculetin enhances the As(2)O(3)-provoked apoptosis by modulating the MEK/ERK and JNK pathways and reducing intracellular GSH levels. GSH depletion led to higher oxidative stress which activated lysosomal-mitochondrial pathway of apoptosis.}, }
@article {pmid19428344, year = {2009}, author = {Usta, J and Kreydiyyeh, S and Knio, K and Barnabe, P and Bou-Moughlabay, Y and Dagher, S}, title = {Linalool decreases HepG2 viability by inhibiting mitochondrial complexes I and II, increasing reactive oxygen species and decreasing ATP and GSH levels.}, journal = {Chemico-biological interactions}, volume = {180}, number = {1}, pages = {39-46}, doi = {10.1016/j.cbi.2009.02.012}, pmid = {19428344}, issn = {1872-7786}, mesh = {Acyclic Monoterpenes ; Adenosine Triphosphate/*metabolism ; Animals ; Cell Line ; Cell Survival ; Coriandrum/chemistry ; Down-Regulation ; Electron Transport Complex I/*antagonists &amp; inhibitors ; Electron Transport Complex II/*antagonists &amp; inhibitors ; Glutathione/*metabolism ; Insecticides/pharmacology ; Liver/*drug effects/pathology ; Mitochondria/enzymology/metabolism ; Molecular Structure ; Monoterpenes/*pharmacology ; Plant Preparations/chemistry/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Seeds/chemistry ; }, abstract = {Coriander is used as an appetizer, a common food seasoning in Mediterranean dishes, and a remedy for many ailments. In this study we tested the biochemical effect of its essential oil components, in particular linalool, its main component. The oil extract was prepared by hydro-distillation of coriander seeds. The various components were identified by gas chromatography coupled to mass spectroscopy. The effect of the various oil components on the viability of different cell lines (HepG2, Caco2, NIH3t3, MCF7 and Hek293) was examined using MTT assay. Linalool was the most potent and HepG2 cells the most sensitive. A 50% and 100% decrease in the viability of HepG2 was obtained at 0.4 microM and 2 microM linalool, respectively. Whereas none of the other components exerted a significant effect at concentrations lower than 50 microM, myrcene and nerolidol, the structural analogues of linalool, were more potent at 100 microM than the other components decreasing HepG2 viability to 26%. The biochemical effect of linalool on mitochondria isolated from HepG2 showed a concentration-dependent inhibition in complexes I and II activities of the respiratory chain, and a time-dependent decrease in ATP level. In addition, a time-dependent decrease in glutathione (GSH) level and in the reduction of nitroblue tetrazolium was obtained, indicating increase in reactive oxygen species (ROS) generation. Pretreatment with the antioxidants: N-acetyl cysteine (2mM), Trolox (100 microM) and different flavonoids (50 microM) was partially protective against the linalool-induced cell death; the most effective response was that of rutin and apigenin which restored 91% of HepG2 viability. We hereby report a decrease in cell viability of HepG2 cells by linalool and identify the mitochondria as one possible target for its site of action, inhibiting complexes I and II and decreasing ATP. In addition linalool increased ROS generation and decreased GSH level.}, }
@article {pmid19428083, year = {2009}, author = {Ciftci, H and Verit, A and Savas, M and Yeni, E and Erel, O}, title = {Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status.}, journal = {Urology}, volume = {74}, number = {1}, pages = {73-76}, doi = {10.1016/j.urology.2009.02.034}, pmid = {19428083}, issn = {1527-9995}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Humans ; Infertility, Male/*drug therapy/*metabolism ; Male ; Oxidation-Reduction ; Semen/*drug effects/*metabolism ; Spermatozoa/*drug effects ; }, abstract = {OBJECTIVES: To examine whether a beneficial effect of N-acetylcysteine (NAC) on semen parameters and oxidative/antioxidant status in idiopathic male infertility exists. The production of reactive oxygen species is a normal physiologic event in various organs. However, overproduction of reactive oxygen species can be detrimental to sperm and has been associated with male infertility.<br><br>METHODS: Our study included 120 patients who had attended our clinic and were diagnosed with idiopathic infertility according to medical history and physical and seminal examination findings, as initial evaluations. The patients were divided randomly into 2 groups. Those in the study group (60 men) were given NAC (600 mg/d orally) for 3 months; the control group (60 men) received a placebo. The oxidative status was determined by measuring the total antioxidant capacity, total peroxide and oxidative stress index in plasma samples. The sperm parameters were evaluated after NAC treatment and were compared with those in the control group.<br><br>RESULTS: NAC had significant improving effects on the volume, motility, and viscosity of semen. After NAC treatment, the serum total antioxidant capacity was greater and the total peroxide and oxidative stress index were lower in the NAC-treated group compared with the control group. These beneficial effects resulted from reduced reactive oxygen species in the serum and reduced viscosity of the semen. No significant differences were found in the number or morphology of the sperm between the 2 groups.<br><br>CONCLUSIONS: We believe that NAC could improve some semen parameters and the oxidative/antioxidant status in patients with male infertility.}, }
@article {pmid19427509, year = {2009}, author = {Reliene, R and Pollard, JM and Sobol, Z and Trouiller, B and Gatti, RA and Schiestl, RH}, title = {N-acetyl cysteine protects against ionizing radiation-induced DNA damage but not against cell killing in yeast and mammals.}, journal = {Mutation research}, volume = {665}, number = {1-2}, pages = {37-43}, doi = {10.1016/j.mrfmmm.2009.02.016}, pmid = {19427509}, issn = {0027-5107}, support = {1R03 CA133928-01/CA/NCI NIH HHS/United States ; U19 AI67769/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Death/*drug effects ; Cell Line ; Colony-Forming Units Assay ; Comet Assay ; DNA Breaks ; *DNA Damage ; Free Radical Scavengers/pharmacology ; Histones/metabolism ; Humans ; Lymphocytes/cytology/drug effects/metabolism/radiation effects ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Saccharomyces cerevisiae/cytology/*drug effects/genetics/*radiation effects ; }, abstract = {Ionizing radiation (IR) induces DNA strand breaks leading to cell death or deleterious genome rearrangements. In the present study, we examined the role of N-acetyl-L-cysteine (NAC), a clinically proven safe agent, for it's ability to protect against gamma-ray-induced DNA strand breaks and/or DNA deletions in yeast and mammals. In the yeast Saccharomyces cerevisiae, DNA deletions were scored by reversion to histidine prototrophy. Human lymphoblastoid cells were examined for the frequency of gamma-H2AX foci formation, indicative of DNA double strand break formation. DNA strand breaks were also measured in mouse peripheral blood by the alkaline comet assay. In yeast, NAC reduced the frequency of IR-induced DNA deletions. However, NAC did not protect against cell death. NAC also reduced gamma-H2AX foci formation in human lymphoblastoid cells but had no protective effect in the colony survival assay. NAC administration via drinking water fully protected against DNA strand breaks in mice whole-body irradiated with 1Gy but not with 4Gy. NAC treatment in the absence of irradiation was not genotoxic. These data suggest that, given the safety and efficacy of NAC in humans, NAC may be useful in radiation therapy to prevent radiation-mediated genotoxicity, but does not interfere with efficient cancer cell killing.}, }
@article {pmid19426784, year = {2009}, author = {Kamboj, SS and Chopra, K and Sandhir, R}, title = {Hyperglycemia-induced alterations in synaptosomal membrane fluidity and activity of membrane bound enzymes: beneficial effect of N-acetylcysteine supplementation.}, journal = {Neuroscience}, volume = {162}, number = {2}, pages = {349-358}, doi = {10.1016/j.neuroscience.2009.05.002}, pmid = {19426784}, issn = {1873-7544}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Blood Glucose/metabolism ; Calcium-Transporting ATPases/metabolism ; Cerebral Cortex/chemistry ; Diabetes Mellitus, Experimental/metabolism ; Hyperglycemia/*metabolism ; Intracellular Membranes/*drug effects/enzymology ; Lipid Peroxidation/drug effects ; Lipids/analysis ; Male ; Membrane Fluidity/*drug effects ; Neuroprotective Agents/*pharmacology ; Protein Binding ; Rats ; Rats, Wistar ; Sodium-Potassium-Exchanging ATPase/metabolism ; Synaptosomes/*drug effects/enzymology ; }, abstract = {Diabetic encephalopathy is characterized by impaired cognitive functions that appear to underlie neuronal damage triggered by glucose driven oxidative stress. Hyperglycemia-induced oxidative stress in diabetic brain may initiate structural and functional changes in synaptosomal membranes. The objective of the present study was to examine the neuroprotective role of N-acetylcysteine (NAC) in hyperglycemia-induced alterations in lipid composition and activity of membrane bound enzymes (Na(+),K(+)-ATPase and Ca(2+)-ATPase) in the rodent model of type 1 diabetes. Male Wistar rats weighing between 180 and 200 g were rendered diabetic by a single injection of streptozotocin (50 mg/kg body weight, i.p.). The diabetic animals were administered NAC (1.4-1.5 g/kg body weight) for eight weeks and lipid composition along with membrane fluidity were determined. A significant increase in lipid peroxidation was observed in cerebral cortex of diabetic rats. NAC administration on the other hand lowered the hyperglycemia-induced lipid peroxidation to near control levels. The increased lipid peroxidation following chronic hyperglycemia was accompanied by a significant increase in the total lipids which can be attributed to increase in the levels of cholesterol, triglycerides and glycolipids. On the contrary phospholipid and ganglioside levels were decreased. Hyperglycemia-induced increase in cholesterol to phospholipid ratio reflected decrease in membrane fluidity. Fluorescence polarization (p) with DPH also confirmed decrease in synaptosomal membrane fluidity that influenced the activity of membrane bound enzymes. An inverse correlation was found between fluorescence polarization with the activities of Na(+),K(+)-ATPase (r(2)=0.416, P<0.05) and Ca(2+) ATPase (r(2)=0.604, P<0.05). NAC was found to significantly improve lipid composition, restore membrane fluidity and activity of membrane bound enzymes. Our results clearly suggest perturbations in lipid composition and membrane fluidity as a major factor in the development of diabetic encephalopathy. Furthermore, NAC administration ameliorated the effect of hyperglycemia on oxidative stress and alterations in lipid composition thereby restoring membrane fluidity and activity of membrane bound enzymes.}, }
@article {pmid19419996, year = {2009}, author = {Zheng, MQ and Tang, K and Zimmerman, MC and Liu, L and Xie, B and Rozanski, GJ}, title = {Role of gamma-glutamyl transpeptidase in redox regulation of K+ channel remodeling in postmyocardial infarction rat hearts.}, journal = {American journal of physiology. Cell physiology}, volume = {297}, number = {2}, pages = {C253-62}, pmid = {19419996}, issn = {1522-1563}, support = {R01 HL066446/HL/NHLBI NIH HHS/United States ; 5 P20 RR017675/RR/NCRR NIH HHS/United States ; HL-66446/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Buthionine Sulfoximine/metabolism ; Cells, Cultured ; Enzyme Inhibitors/metabolism ; Glutathione/metabolism ; Heart Ventricles/metabolism/pathology/physiopathology ; Hydrogen Peroxide/metabolism ; Male ; Myocardial Infarction/pathology/*physiopathology ; Myocytes, Cardiac/cytology/metabolism ; Oxidants/metabolism ; Oxidation-Reduction ; Patch-Clamp Techniques ; Potassium Channels/*metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/physiology ; Thioredoxin-Disulfide Reductase/*metabolism ; Thioredoxins/metabolism ; Ventricular Remodeling/*physiology ; gamma-Glutamyltransferase/genetics/*metabolism ; }, abstract = {gamma-Glutamyl transpeptidase (gamma-GT) is a key enzyme in GSH metabolism that regulates intracellular GSH levels in response to extracellular GSH (GSH(o)). The objective of this study was to identify the role of gamma-GT in reversing pathogenic K(+) channel remodeling in the diseased heart. Chronic ventricular dysfunction was induced in rats by myocardial infarction (MI), and studies were done after 6-8 wk. Biochemical assays of tissue extracts from post-MI hearts revealed significant increases in gamma-GT activity in left ventricle (47%) and septum (28%) compared with sham hearts, which paralleled increases in protein abundance and mRNA. Voltage-clamp studies of isolated left ventricular myocytes from post-MI hearts showed that downregulation of transient outward K(+) current (I(to)) was reversed after 4-5 h by 10 mmol/l GSH(o) or N-acetylcysteine (NAC(o)), and that the effect of GSH(o) but not NAC(o) was blocked by the gamma-GT inhibitors, acivicin or S-hexyl-GSH. Inhibition of gamma-glutamylcysteine synthetase by buthionine sulfoximine did not prevent upregulation of I(to) by GSH(o), suggesting that intracellular synthesis of GSH was not directly involved. However, pretreatment of post-MI myocytes with an SOD mimetic [manganese (III) tetrapyridylporphyrin] and catalase completely blocked recovery of I(to) by GSH(o). Confocal microscopy using the fluorogenic dye 2',7'-dichlorodihydrofluorescein diacetate confirmed that GSH(o) increased reactive oxygen species (ROS) generation by post-MI myocytes and to a lesser extent in myocytes from sham hearts. Furthermore, GSH(o)-mediated upregulation of I(to) was blocked by inhibitors of tyrosine kinase (genistein, lavendustin A, and AG1024) and thioredoxin reductase (auranofin and 13-cis-retinoic acid). These data suggest that GSH(o) elicits gamma-GT- and ROS-dependent transactivation of tyrosine kinase signaling that upregulates K(+) channel activity or expression via redox-mediated mechanisms. The signaling events stimulated by gamma-GT catalysis of GSH(o) may be a therapeutic target to reverse pathogenic electrical remodeling of the failing heart.}, }
@article {pmid19414577, year = {2009}, author = {Odabasi, Z and Karaalp, A and Cermik, H and Mohr, J and Tigen, ET and Koc, M and Korten, V}, title = {Reduction of amphotericin B-induced renal tubular apoptosis by N-acetylcysteine.}, journal = {Antimicrobial agents and chemotherapy}, volume = {53}, number = {7}, pages = {3100-3102}, pmid = {19414577}, issn = {1098-6596}, mesh = {Acetylcysteine/*pharmacology ; Amphotericin B/*pharmacology ; Animals ; Anti-Bacterial Agents/*pharmacology ; Antiviral Agents/*pharmacology ; Apoptosis/*drug effects ; Kidney/cytology/*drug effects ; Kidney Tubules/cytology/*drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The reduction of amphotericin B (AmB)-induced renal tubular apoptosis and nephrotoxicity by N-acetylcysteine (NAC) in a murine model was evaluated. Four groups of rats were treated with AmB for 5 days, and each group concomitantly received two doses of 30, 60, or 120 mg of NAC/kg of body weight/day or sterile water for 5 days. Groups that received concomitant NAC at any dose had significantly decreased levels of apoptosis compared to that in animals receiving AmB only (48.8% versus 27.4, 23.6, or 23.5%, respectively; P < 0.001).}, }
@article {pmid19413603, year = {2009}, author = {Wang, Y and Jia, XM and Jia, JH and Li, MB and Cao, YY and Gao, PH and Liao, WQ and Cao, YB and Jiang, YY}, title = {Ascorbic acid decreases the antifungal effect of fluconazole in the treatment of candidiasis.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {36}, number = {10}, pages = {e40-6}, doi = {10.1111/j.1440-1681.2009.05187.x}, pmid = {19413603}, issn = {1440-1681}, mesh = {Animals ; Antifungal Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology ; Ascorbic Acid/*pharmacology ; Candida albicans/drug effects ; Candidiasis/*drug therapy/mortality ; Disease Models, Animal ; Drug Antagonism ; Drug Evaluation, Preclinical ; Drug Resistance, Fungal/drug effects ; Fluconazole/pharmacology/*therapeutic use ; Mice ; Microbial Sensitivity Tests ; }, abstract = {1. The aim of the present study was to investigate the effects of ascorbic acid (AA) on the antifungal activity of fluconazole (FCZ) in a systemic murine candidiasis model as well as in vitro. 2. The murine model was established by infusion of Candida albicans via the tail vein. Control mice received no further treatment. Other groups of mice were injected with FCZ (0.5 mg/kg, i.p.) and then treated or not with 50 or 500 mg/kg AA intragastrically (i.g.) or i.p. In all groups, FCZ was administered i.p. 2 h after fungal inoculation, whereas AA was administered 6 h after fungal inoculation. Survival rate, kidney fungal burden and renal pathological changes were evaluated. 3. The in vitro effects of AA (5, 1 and 0.2 mmol/L) on the growth of various Candida strains in the presence of FCZ (0.125-64 microg/mL) were also investigated. The in vitro effects of two anti-oxidants, namely N-acetylcysteine (NAC; 5, 1 and 0.2 mmol/L) and reduced glutathione (GSH; 5, 1 and 0.2 mmol/L), on FCZ activity were evaluated to determine the mechanism of action of AA. 4. Intragastric administration of AA (50 or 500 mg/kg) significantly decreased the antifungal effect of 0.5 mg/kg FCZ. Although i.p. administration of AA (50 or 500 mg/kg) had no significant effect on the survival of mice, it dose-dependently inhibited the activity of FCZ, with significant inhibition observed with 500 mg/kg AA. 5. In vitro, AA decreased the activity of FCZ against various Candida strains. Both NAC and GSH dose-dependently decreased the activity of FCZ. 6. The results of the present study indicate that AA inhibits the antifungal activity of FCZ, suggesting that the two should not be used together clinically for the treatment of candidiasis.}, }
@article {pmid19412010, year = {2009}, author = {Mitry, RR and Bansal, S and Hughes, RD and Mieli-Vergani, G and Dhawan, A}, title = {In vitro effects of sera from children with acute liver failure on metabolic and synthetic activity of cryopreserved human hepatocytes.}, journal = {Journal of pediatric gastroenterology and nutrition}, volume = {48}, number = {5}, pages = {604-607}, doi = {10.1097/MPG.0b013e31819114da}, pmid = {19412010}, issn = {1536-4801}, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Cells, Cultured ; Child ; Child, Preschool ; *Cryopreservation ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP1A2/metabolism ; Cytochrome P-450 Enzyme System/metabolism ; Female ; Free Radical Scavengers/*pharmacology ; Hepatocytes/*drug effects/metabolism/transplantation ; Humans ; Infant ; Liver Failure, Acute/*metabolism/therapy ; Male ; Proteins/metabolism ; Serum/*metabolism ; }, abstract = {OBJECTIVE: The aim of the study was to investigate the in vitro effects of sera from children with acute liver failure (ALF) who had received N-acetylcysteine (NAC) on the metabolic and synthetic activity of cryopreserved human hepatocytes.<br><br>MATERIALS AND METHODS: Cryopreserved human hepatocytes were plated on collagen-coated culture plates and incubated in cell culture medium containing pooled sera at 20% (v/v) obtained from children with ALF (ALF) who received treatment with NAC (ALF + NAC), no treatment with NAC and from normal controls (normal sera [NS]). The effects of the sera on cell metabolic functions were assessed using methylthiazolyldiphenyltetrazolium bromide, [14C]-leucine incorporation, and cytochrome P-450 (CYP1A1/2) activity assays.<br><br>RESULTS: The overall hepatocyte metabolic activity was lower with ALF sera than with NS and ALF + NAC sera. [14C]-leucine incorporation was higher with both ALF sera (ALF and ALF + NAC) than with NS sera. There was a slightly higher activity of cytochrome P450 (CYP1A1/2 activity) in cultures treated with ALF and ALF + NAC than with normal sera treated hepatocyte cultures.<br><br>CONCLUSIONS: Sera from children with ALF who received NAC did not impair the overall cell metabolic activity of cryopreserved human hepatocyte in vitro, which is encouraging for the use of hepatocytes transplantation in these patients.}, }
@article {pmid19411311, year = {2009}, author = {Bartling, TR and Drumm, ML}, title = {Loss of CFTR results in reduction of histone deacetylase 2 in airway epithelial cells.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {297}, number = {1}, pages = {L35-43}, pmid = {19411311}, issn = {1522-1504}, support = {HL-68883/HL/NHLBI NIH HHS/United States ; P30-DK-27651/DK/NIDDK NIH HHS/United States ; T32-GM-08613/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylation/drug effects ; Acetylcysteine/pharmacology ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Cystic Fibrosis/enzymology/pathology ; Cystic Fibrosis Transmembrane Conductance Regulator/*deficiency/metabolism ; Epithelial Cells/drug effects/*enzymology/pathology ; Gene Knockdown Techniques ; Histone Deacetylase 2 ; Histone Deacetylases/*metabolism ; Humans ; Interleukin-8/genetics/metabolism ; NF-kappa B/metabolism ; Promoter Regions, Genetic/genetics ; RNA Interference/drug effects ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/metabolism ; Repressor Proteins/*metabolism ; Respiratory System/*cytology ; p300-CBP Transcription Factors/metabolism ; }, abstract = {Inflammatory cytokines, particularly the neutrophil chemoattractant IL-8, are elevated in the cystic fibrosis (CF) airway, even in the absence of detectable infection. The transcriptional regulation of many inflammatory genes, including IL8 (CXCL8), involves chromatin remodeling through histone acetylation. NF-kappaB is known to facilitate histone acetylation of IL8 and other proinflammatory gene promoters, but we find that increased NF-kappaB activation cannot explain the elevated IL8 expression and promoter acetylation seen in CFTR-deficient cells. Recognized components of the NF-kappaB-coactivator complex, acetyltransferase CBP, p300, and the histone deacetylase HDAC1, are unchanged by CFTR activity. However, we find that the histone acetyltransferase (HAT)/HDAC balance is sensitive to CFTR function, as cells with reduced or absent CFTR function have decreased HDAC2 protein, resulting in hyperacetylation of the IL8 promoter and increased IL8 transcription. Reduced HDAC2 and HDAC2 activity, but not HDAC2 mRNA, is observed in cells deficient in CFTR. Suppressing HDAC2 expression with HDAC2 short hairpin RNA (shRNA) results in increased IL8 expression and promoter acetylation comparable with CFTR-deficient cells. Treating CFTR-deficient cells with N-acetyl-cysteine (NAC) increases HDAC2 expression to near control levels. Our data suggest that there is an intrinsic alteration in the HAT/HDAC balance in cells lacking CFTR function in vitro and in native CF tissue and that oxidative stress is likely contributing to this alteration. This mechanism, found in other inflammatory airway diseases, provides an explanation for the apparent dysregulation of inflammatory mediators seen in the CF airway, as reduced histone deacetylation would potentially influence many genes.}, }
@article {pmid19409980, year = {2009}, author = {Birch, CS and Brasch, NE and McCaddon, A and Williams, JH}, title = {A novel role for vitamin B(12): Cobalamins are intracellular antioxidants in vitro.}, journal = {Free radical biology &amp; medicine}, volume = {47}, number = {2}, pages = {184-188}, doi = {10.1016/j.freeradbiomed.2009.04.023}, pmid = {19409980}, issn = {1873-4596}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cell Line ; Cell Survival/drug effects/physiology ; Cysteine/analogs &amp; derivatives/pharmacology ; Glutathione/analogs &amp; derivatives/pharmacology ; Homocysteine/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/*pharmacology ; Vitamin B 12/analogs &amp; derivatives/*pharmacology ; Vitamin B Complex/*pharmacology ; }, abstract = {Oxidative stress is a feature of many chronic inflammatory diseases. Such diseases are associated with up-regulation of a vitamin B(12) (cobalamin) blood transport protein and its membrane receptor, suggesting a link between cobalamin and the cellular response to inflammation. The ability of cobalamin to regulate inflammatory cytokines suggests that it may have antioxidative properties. Here we show that cobalamins, including the novel thiolatocobalamins N-acetyl-l-cysteinylcobalamin and glutathionylcobalamin, are remarkably effective antioxidants in vitro. We also show that thiolatocobalamins have superior efficacy compared with other cobalamin forms, other cobalamins in combination with N-acetyl-l-cysteine (NAC) or glutathione (GSH), and NAC or GSH alone. Pretreatment of Sk-Hep-1 cells with thiolatocobalamins afforded robust protection (>90% cell survival) against exposure to 30 microM concentrations of the pro-oxidants homocysteine and hydrogen peroxide. The compounds inhibited intracellular peroxide production, maintained intracellular glutathione levels, and prevented apoptotic and necrotic cell death. Moreover, thiolatocobalamins are remarkably nontoxic in vitro at supraphysiological concentrations (>2 mM). Our results demonstrate that thiolatocobalamins act as powerful but benign antioxidants at pharmacological concentrations. Because inflammatory oxidative stress is a component of many conditions, including atherosclerosis, dementia, and trauma, their utility in treating such disorders merits further investigation.}, }
@article {pmid19407260, year = {2009}, author = {Ferreira, LF and Gilliam, LA and Reid, MB}, title = {L-2-Oxothiazolidine-4-carboxylate reverses glutathione oxidation and delays fatigue of skeletal muscle in vitro.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {107}, number = {1}, pages = {211-216}, pmid = {19407260}, issn = {8750-7587}, support = {T32 HL086341/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Diaphragm/*drug effects/metabolism/physiopathology ; Fatigue/*prevention &amp; control ; Free Radical Scavengers/pharmacology ; Glutathione Disulfide/*metabolism ; In Vitro Techniques ; Male ; Mice ; Mice, Inbred ICR ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Pyrrolidonecarboxylic Acid/*pharmacology ; Thiazolidines/*pharmacology ; }, abstract = {Fatiguing exercise promotes oxidation of intracellular thiols, notably glutathione. Interventions that oppose or reverse thiol oxidation can inhibit fatigue. The reduced cysteine donor l-2-oxothiazolidine-4-carboxylate (OTC) supports glutathione synthesis and is approved for use in humans but has not been evaluated for effects on skeletal muscle. We tested the hypotheses that OTC would 1) increase reduced glutathione (GSH) levels and decrease oxidized glutathione, and 2) inhibit functional indexes of fatigue. Diaphragm fiber bundles from adult male ICR mice were incubated for 1 or 2 h at 37 degrees C with buffer (control, C) or OTC (10 mM). N-acetylcysteine (NAC; 10 mM) was used as a positive control. We measured GSH metabolites and fatigue characteristics. We found that muscle GSH content was increased after 1-h incubation with OTC or NAC but was not altered after 2-h incubation. One-hour treatment with OTC or NAC slowed the decline in force with repetitive stimulation [mean (SD) fatigue index at 300 s: OTC = 34 +/- 6% vs. C = 50 +/- 8%, P < 0.05; NAC = 55 +/- 4% vs. C = 65 +/- 8%, P < 0.05] as did the 2-h OTC treatment (OTC = 38 +/- 9% vs. C = 51 +/- 9%, P < 0.05). These results demonstrate that OTC modulates the muscle GSH pool and opposes fatigue under the current experimental conditions.}, }
@article {pmid19401659, year = {2009}, author = {Erturk, E and Cekic, B and Geze, S and Kosucu, M and Coskun, I and Eroglu, A and Ulusoy, H and Mentese, A and Karahan, C and Kerimoglu, S}, title = {Comparison of the effect of propofol and N-acetyl cysteine in preventing ischaemia-reperfusion injury.}, journal = {European journal of anaesthesiology}, volume = {26}, number = {4}, pages = {279-284}, doi = {10.1097/EJA.0b013e32831c87c7}, pmid = {19401659}, issn = {1365-2346}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Anesthesia, Spinal/*methods ; Anesthetics, Intravenous/administration &amp; dosage/*pharmacology ; Blood Gas Analysis ; Double-Blind Method ; Female ; Humans ; Lactic Acid/blood ; Male ; Malondialdehyde/blood ; Middle Aged ; Propofol/administration &amp; dosage/*pharmacology ; Prospective Studies ; Reperfusion Injury/etiology/*prevention &amp; control ; Tourniquets ; Treatment Outcome ; Young Adult ; }, abstract = {BACKGROUND AND OBJECTIVE: The aim of this study was to compare the effects of propofol and N-acetyl cysteine (NAC) on tourniquet-induced ischaemia-reperfusion injury by determining malonyldialdehyde, ischaemia-modified albumin, lactate, blood gas and haemodynamic levels in arthroscopic knee surgery.<br><br>METHODS: Sixty ASA I or II patients were randomized into three groups. Intrathecal anaesthesia was administered using 0.5% heavy bupivacaine in all patients. In group P, propofol was administered in a 0.2 mg kg(-1) bolus, followed by infusion at a rate of 2 mg kg(-1) h(-1); in group NAC, NAC was administered as an infusion at a rate of 5 mg kg(-1) h(-1), and, in group C (the control group), an equal volume of isotonic saline was administered to patients until 30 min after reperfusion. Blood samplings were obtained immediately before intrathecal anaesthesia (t1), 1 min before tourniquet release (t2), 5 min after tourniquet release (t3) and 30 min after tourniquet release (t4).<br><br>RESULTS: Plasma malonyldialdehyde, ischaemia-modified albumin and lactate levels increased significantly in group C at t3 and t4 compared with the baseline values. Plasma concentrations of malonyldialdehyde, ischaemia-modified albumin and lactate in groups P and NAC were significantly lower than those in group C at t3 and t4. In blood gas analyses, pH, HCO3 and base excess were found to be significantly lower at t3 and t4 compared with t1 and t2 in group C. Comparisons between groups P and NAC revealed no significant differences.<br><br>CONCLUSION: Small-dose infusions of both propofol and NAC appear to provide similar protection against ischaemia-reperfusion injury in arthroscopic knee surgery.}, }
@article {pmid19399602, year = {2009}, author = {Ayaz, M and Guney, O and Erdi, F and Kucukbagriacik, Y}, title = {Electrophysiology of papillary muscle in SAH: changes and N-acetylcysteine protection.}, journal = {Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing}, volume = {26}, number = {2}, pages = {95-100}, pmid = {19399602}, issn = {1572-8595}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cardiotonic Agents/*administration &amp; dosage ; Free Radical Scavengers/administration &amp; dosage ; Male ; Muscle Contraction/*drug effects ; Papillary Muscles/*drug effects/*physiopathology ; Rabbits ; Subarachnoid Hemorrhage/*drug therapy/*physiopathology ; Treatment Outcome ; }, abstract = {BACKGROUND: Although subarachnoid hemorrhage (SAH) serves as a good model to study heart-brain interactions, neither the changes on the single ventricular action potential (SVAP) and contraction nor the effects of possible cardioprotective agents have been investigated.<br><br>MATERIALS AND METHODS: A total of 18 male rabbits were used for the three experimental groups. SAH was induced by replacing the cerebrospinal fluid (CSF) with fresh autologous blood at the ratio of 1 mL to the 1-kg body mass (N = 6). In the control (CON; N = 6) group, the CSF was replaced with serum physiologic at the same ratio. The treated SAH group (SAH+NAC) received daily intraperitoneal N-acetylcysteine (NAC; 150 mg/kg for 3 days) starting from just before SAH was induced by CSF replacement. On the fourth day, animals were examined for the single action potential and contraction recordings from the left ventricular papillary muscle.<br><br>RESULTS: At the end of 3 days, the overshoot decreased together with increased time to reach the peak potential. Additionally, the resting membrane potential was depressed and repolarization was slowed during SVAPs. On the other hand, peak tension depressed and time to peak increased. NAC treatment, which protects infarction in the brain, prevented these pathological changes in the cardiac muscle.<br><br>CONCLUSION: SAH-induced cardiac changes can be attributed to adenosine triphosphate depletion through mitochondrial dysfunction. Pretreatment of NAC to SAH on the other hand had a positive effect on these cardiac changes. But the exact mechanism by which NAC treatment protects the cardiac muscle needs further investigation.}, }
@article {pmid19398917, year = {2009}, author = {Galicia-Moreno, M and Rodríguez-Rivera, A and Reyes-Gordillo, K and Segovia, J and Shibayama, M and Tsutsumi, V and Vergara, P and Moreno, MG and Muriel, P}, title = {N-acetylcysteine prevents carbon tetrachloride-induced liver cirrhosis: role of liver transforming growth factor-beta and oxidative stress.}, journal = {European journal of gastroenterology &amp; hepatology}, volume = {21}, number = {8}, pages = {908-914}, doi = {10.1097/MEG.0b013e32831f1f3a}, pmid = {19398917}, issn = {1473-5687}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Carbon Tetrachloride ; Carbon Tetrachloride Poisoning/metabolism ; Liver Cirrhosis, Experimental/chemically induced/metabolism/*prevention &amp; control ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Transforming Growth Factor beta/*drug effects/metabolism ; }, abstract = {OBJECTIVES: N-acetylcysteine (NAC) is an antioxidant, a precursor of reduced glutathione, and an inhibitor of the profibrotic cytokine liver transforming growth factor-beta (TGF-beta). Carbon tetrachloride (CCl4) cirrhosis is characterized by oxidative stress and fibrosis. Therefore, the aim of this work was to study the effect of NAC on experimental cirrhosis.<br><br>METHODS: CCl4 was chronically administered for 8 weeks along with 300 mg/kg of NAC orally once a day. Alkaline phosphatase, alanine aminotransferase, and gamma-glutamyltranspeptidase were measured in plasma. Hydroxyproline, glycogen, lipid peroxidation, glutathione were determined in liver samples by colorimetric methods. TGF-beta was evaluated by western blotting, and a histopathological analysis was performed.<br><br>RESULTS: Serum markers of liver damage increased by CCl4 intoxication (P<0.05), whereas cotreatment with NAC prevented these increases (P<0.05); glycogen was depleted in the cirrhotic group (P<0.05), but preserved by NAC (P<0.05). Lipid peroxidation increased and glutathione decreased by the administration of CCl4 (P<0.05), again NAC prevented both effects (P<0.05). Importantly, collagen increased by about seven-fold in the CCl4 group (P<0.05); administration of NAC preserved the normal levels of collagen (P<0.05). Biochemical determinations were corroborated by hematoxylin and eosin, and trichromic stains. Western blots revealed a four-fold increase in TGF-beta in the group receiving CCl4, NAC cotreatment abolished TGF-beta signal (P<0.05).<br><br>CONCLUSION: Our results strongly suggest that NAC prevents experimental cirrhosis by two mechanisms: by preventing oxidative stress and by downregulating the profibrogenic cytokine TGF-beta. As NAC is currently used in humans intoxicated with paracetamol, it can be tested in fibrotic or cirrhotic patients under controlled trials.}, }
@article {pmid19396405, year = {2009}, author = {Bulucu, F and Ocal, R and Karadurmus, N and Sahin, M and Kenar, L and Aydin, A and Oktenli, C and Koc, B and Inal, V and Yamanel, L and Yaman, H}, title = {Effects of N-acetylcysteine, deferoxamine and selenium on doxorubicin-induced hepatotoxicity.}, journal = {Biological trace element research}, volume = {132}, number = {1-3}, pages = {184-196}, doi = {10.1007/s12011-009-8377-y}, pmid = {19396405}, issn = {1559-0720}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Catalase/metabolism ; Copper/metabolism ; Deferoxamine/*pharmacology ; Doxorubicin/*toxicity ; Glutathione Peroxidase/metabolism ; Iron/metabolism ; Lipid Peroxidation/drug effects ; Liver/*drug effects/*metabolism ; Male ; Malondialdehyde/metabolism ; Rats ; Rats, Sprague-Dawley ; Selenium/*pharmacology ; Superoxide Dismutase/metabolism ; Zinc/metabolism ; }, abstract = {The aims of our study were to evaluate the antioxidant defence mechanisms of liver tissue challenged by doxorubucin (DOX) and to compare the possible protective effects of N-acetylcysteine (NAC) (n=10), deferoxamine (DOF) (n=10), DOF+NAC (n= 10) and selenium (n=9) on doxorubicin-induced hepatotoxicity. Fifty-six male rats (Mean weight = 250 ± 50 g) randomly divided into five groups. Animals in study groups were pretreated with a single dose of Dox, which was administered intravenously. Control group (n=7) was treated with intravenous saline injection. Selenium was given intraperitoneally. Blood and urine samples were collected before sacrifice. Liver tissue samples were collected and tissue superoxide dismutase (SOD), glutathione peroxidase (GSH-px), CAT activity, MDA, Zn, iron and copper were determined. DFO decreased lipid peroxidation significantly. DFO and NAC decreased CAT activity significantly. Antioxidant regimes increase SOD activities significantly. DOF and NAC increase GSH-px activities and copper levels significantly. Beneficial effect of selenium seems to result from its stimulation of SOD but not to GSH-px. It has been found that DOF, NAC and selenium have protective effects on Dox-induced hepatocellular damage. DOF+NAC did not result additional benefit.}, }
@article {pmid19393651, year = {2009}, author = {Aoto, M and Shinzawa, K and Suzuki, Y and Ohkubo, N and Mitsuda, N and Tsujimoto, Y}, title = {Essential role of p38 MAPK in caspase-independent, iPLA(2)-dependent cell death under hypoxia/low glucose conditions.}, journal = {FEBS letters}, volume = {583}, number = {10}, pages = {1611-1618}, doi = {10.1016/j.febslet.2009.04.028}, pmid = {19393651}, issn = {1873-3468}, mesh = {Animals ; Caspases/*metabolism ; Cell Death/physiology ; Cell Hypoxia/physiology ; Cell Line, Tumor ; Glucose/metabolism ; Mice ; Phospholipases A2, Calcium-Independent/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The mechanisms of cell death induced by hypoxia or ischemia are not yet fully understood. We have previously demonstrated that cell death induced by hypoxia occurs independently of caspases, and is mediated by phospholipase A(2) (PLA(2)). Here, we show that p38 mitogen-activated protein kinase is activated under hypoxia. A selective inhibitor of p38 or decrease in the p38alpha protein level prevents hypoxia-induced cell death. The p38 inhibitor abolishes PLA(2) activation by hypoxia, indicating that p38 acts upstream of PLA(2). The antioxidant N-acetyl-cysteine inhibits activation of p38 and cell death induced by hypoxia, indicating that reactive oxygen species (ROS) are responsible for p38 activation. These results demonstrate that the ROS/p38/PLA(2) signaling axis has a crucial role in caspase-independent cell death induced by hypoxia.}, }
@article {pmid19393328, year = {2009}, author = {Sugiura, H and Ichikawa, T and Liu, X and Kobayashi, T and Wang, XQ and Kawasaki, S and Togo, S and Kamio, K and Mao, L and Ann, Y and Ichinose, M and Rennard, SI}, title = {N-acetyl-L-cysteine inhibits TGF-beta1-induced profibrotic responses in fibroblasts.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {22}, number = {6}, pages = {487-491}, doi = {10.1016/j.pupt.2009.04.002}, pmid = {19393328}, issn = {1522-9629}, mesh = {Acetylcysteine/*pharmacology ; Actins/biosynthesis/genetics ; Animals ; Blotting, Western ; Cells, Cultured ; Collagen Type I/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts/*drug effects/*pathology ; Fibronectins/biosynthesis/genetics ; Fibrosis ; Humans ; Rats ; Transforming Growth Factor beta1/*antagonists &amp; inhibitors/*toxicity ; Vascular Endothelial Growth Factor A/biosynthesis/genetics ; }, abstract = {BACKGROUND: Excessive production of TGF-beta(1) plays a key role in the tissue remodeling or fibrotic process observed in bronchial asthma, chronic pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). TGF-beta(1) has been reported to decrease the intracellular glutathione level and stimulate the production of reactive oxygen species.<br><br>OBJECTIVES: The aim of this study was to evaluate whether the antioxidant N-acetyl-l-cysteine (NAC) can affect TGF-beta(1)-mediated tissue remodeling in fibroblasts or modulate the production of fibronectin and vascular endothelial growth factor (VEGF) which are believed to be important mediators of tissue repair and remodeling.<br><br>METHODS: To accomplish this, human fetal lung fibroblasts (HFL-1) were used to assess the effect of NAC on the TGF-beta(1)-mediated contraction of floating gels and the TGF-beta(1)-induced mediator production. In addition, the effect of NAC on the TGF-beta(1)-induced differentiation to myofibroblasts was evaluated by assessing alpha-smooth muscle actin (alpha-SMA) expression.<br><br>RESULTS: NAC significantly abolished the TGF-beta(1)-augmented gel contraction (at 3mM, gel size 63.4+/-2.6% vs. 39.1+/-4.1%; p<0.01) compared with control in a concentration-dependent manner. NAC also significantly inhibited the TGF-beta(1)-augmented fibronectin (p<0.01) and VEGF (p<0.01) production in the media of both the three-dimensional gel and monolayer culture. Furthermore, NAC reversed the TGF-beta(1)-stimulated alpha-SMA expression (p<0.01).<br><br>CONCLUSION: These results suggest that NAC can affect the TGF-beta(1)-induced tissue remodeling or fibrotic process in vitro.}, }
@article {pmid19393240, year = {2009}, author = {Sarkar, A and Mandal, G and Singh, N and Sundar, S and Chatterjee, M}, title = {Flow cytometric determination of intracellular non-protein thiols in Leishmania promastigotes using 5-chloromethyl fluorescein diacetate.}, journal = {Experimental parasitology}, volume = {122}, number = {4}, pages = {299-305}, doi = {10.1016/j.exppara.2009.04.012}, pmid = {19393240}, issn = {1090-2449}, mesh = {Animals ; Antimony Sodium Gluconate/pharmacology ; Antiprotozoal Agents/pharmacology ; Culture Media, Serum-Free ; Flow Cytometry/*methods ; *Fluoresceins ; *Fluorescent Dyes ; Humans ; Leishmania donovani/*chemistry/drug effects ; Pentamidine/pharmacology ; Phosphorylcholine/analogs &amp; derivatives/pharmacology ; Sensitivity and Specificity ; Sulfhydryl Compounds/*analysis ; }, abstract = {Leishmania parasites lack catalase and therefore, their anti-oxidant system hinges primarily upon non-protein thiols; accordingly, depletion of thiols could potentially serve as an effective drug target. We have developed a flow cytometry based assay using 5-chloromethyl fluorescein diacetate based upon its selective staining of non-protein thiols. Its specificity was confirmed using buthionine sulphoximine (a gamma-glutamyl cysteine synthetase inhibitor), diamide (an oxidizing agent of intracellular thiols) and N-ethylmaleimide (a covalent modifier of cysteine residues) as evidenced by reduction in fluorescence; furthermore, restoration of fluorescence by N-acetyl cysteine corroborated specificity of 5-chloromethyl fluorescein diacetate to measure non-protein thiols. Differences in basal level of thiols in antimony sensitive and antimony resistant Leishmania field isolates were detected. The depletion of non-protein thiols by conventional anti-leishmanial drugs e.g. antimony and miltefosine was demonstrated. Furthermore, fluorescence was unaffected by depletion of ATP in majority of the strains studied, indicating that 5-chloromethyl fluorescein diacetate is not a substrate for the pump operative in most Leishmania donovani strains. Taken together, measurement of 5-chloromethyl fluorescein diacetate fluorescence is an effective method for monitoring non-protein thiols in Leishmania promastigotes.}, }
@article {pmid19390136, year = {2009}, author = {Güler, G and Türközer, Z and Ozgur, E and Tomruk, A and Seyhan, N and Karasu, C}, title = {Protein oxidation under extremely low frequency electric field in guinea pigs. Effect of N-acetyl-L-cysteine treatment.}, journal = {General physiology and biophysics}, volume = {28}, number = {1}, pages = {47-55}, doi = {10.4149/gpb_2009_01_47}, pmid = {19390136}, issn = {0231-5882}, mesh = {Acetylcysteine/*administration &amp; dosage ; Analysis of Variance ; Animals ; Electromagnetic Fields/*adverse effects ; Free Radical Scavengers/*administration &amp; dosage ; Guinea Pigs ; Hydroxyproline/metabolism ; Liver/drug effects/*metabolism/radiation effects ; Male ; Oxidation-Reduction ; Protein Carbonylation/drug effects/radiation effects ; Proteins/*metabolism/radiation effects ; Radiation-Protective Agents/administration &amp; dosage ; Random Allocation ; Tyrosine/analogs &amp; derivatives/blood ; }, abstract = {Modern age exposes humans to an increasing level of electromagnetic activity in their environment due to overhead power lines and transformers around residential areas. Studies have shown that treatment with antioxidants can suppress the oxidative damage induced by electromagnetic fields in various frequencies of the non-ionizing radiation band. In this study, we detected protein carbonyl content (PCO), advanced oxidation protein products (AOPP) in liver and 3-nitrotyrosine (3-NT) levels in plasma of guinea pigs in order to investigate the effects of N-acetyl-L-cysteine (NAC) administration on oxidative protein damage induced by power frequency electric (E) field (50 Hz, 12 kV/m, 7 days/8 h/day). We also analyzed hepatic hydroxyproline level to study protein synthesis. According to the findings of the present study, no statistically significant changes occurred in PCO, AOPP and 3-NT levels of the guinea pigs that were exposed to the E field with respect to the control group. However, liver hydroxyproline level was significantly diminished in the E field exposure group compared to the control and PCO, hydroxyproline and 3-NT levels changed significantly in the NAC-administrated groups.}, }
@article {pmid19389194, year = {2009}, author = {Tang, SM and Gabelaia, L and Gauthier, TW and Brown, LA}, title = {N-acetylcysteine improves group B streptococcus clearance in a rat model of chronic ethanol ingestion.}, journal = {Alcoholism, clinical and experimental research}, volume = {33}, number = {7}, pages = {1197-1201}, pmid = {19389194}, issn = {1530-0277}, support = {R01 AA012197/AA/NIAAA NIH HHS/United States ; P50 AA 13757/AA/NIAAA NIH HHS/United States ; F32 AA016873/AA/NIAAA NIH HHS/United States ; T32 AA13528/AA/NIAAA NIH HHS/United States ; P50 AA013757-050004/AA/NIAAA NIH HHS/United States ; R01 AA013979-03/AA/NIAAA NIH HHS/United States ; 1 R01 AA12197/AA/NIAAA NIH HHS/United States ; R01 AA013979-04/AA/NIAAA NIH HHS/United States ; P50 AA013757-059001/AA/NIAAA NIH HHS/United States ; P50 AA013757-040004/AA/NIAAA NIH HHS/United States ; T32 AA013528/AA/NIAAA NIH HHS/United States ; R01 AA012197-06/AA/NIAAA NIH HHS/United States ; P50 AA013757/AA/NIAAA NIH HHS/United States ; F32 AA016873-01/AA/NIAAA NIH HHS/United States ; R01 AA013979/AA/NIAAA NIH HHS/United States ; P50 AA013757-049001/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics ; Alcoholism/diet therapy/*metabolism/*microbiology ; Animals ; *Disease Models, Animal ; Ethanol/*administration &amp; dosage ; Pulmonary Alveoli/drug effects/metabolism/microbiology ; Rats ; Rats, Sprague-Dawley ; Streptococcus agalactiae/*drug effects/*physiology ; }, abstract = {BACKGROUND: Sepsis is the most common risk factor associated with acute respiratory distress syndrome (ARDS) and results in a 40-60% mortality rate due to respiratory failure. Furthermore, recent epidemiological studies have demonstrated that a history of alcohol abuse increases the risk of ARDS by 3.6-fold. More recently, group B streptococcus (GBS) infections in nonpregnant adults have been increasing, particularly in alcoholics where there is an increased risk of lobular invasion and mortality. We have shown in an established rat model that chronic ethanol ingestion impaired macrophage internalization of inactivated infectious particles in vitro and enhanced bidirectional protein flux across the alveolar epithelial-endothelial barriers, both of which were attenuated when glutathione precursors were added to the diet. We hypothesized that chronic ethanol ingestion would increase the risk of infection even though GBS is less pathogenic but that dietary N-acetylcysteine (NAC), a glutathione precursor, would improve in vivo clearance of infectious particles and reduce systemic infection.<br><br>METHODS: After 6 weeks of ethanol feeding, rats were given GBS intratracheally and sacrificed 24 hours later. GBS colony-forming units were counted in the lung, liver, spleen, and bronchoalveolar lavage fluid. Acute lung injury in response to GBS was also assessed.<br><br>RESULTS: Chronic ethanol exposure decreased GBS clearance from the lung indicating an active lung infection. In addition, increased colonies formed within the liver and spleen indicated that ethanol increased the risk of systemic infection. Ethanol also exacerbated the acute lung injury induced by GBS. NAC supplementation normalized GBS clearance by the lung, prevented the appearance of GBS systemically, and attenuated acute lung injury.<br><br>CONCLUSIONS: These data suggested that chronic alcohol ingestion increased the susceptibility of the lung to bacterial infections from GBS as well as systemic infections. Furthermore, dietary NAC improved in vivo clearance of GBS particles, attenuated acute lung injury, and disseminated infection.}, }
@article {pmid19389043, year = {2009}, author = {Prakash, A and Kumar, A}, title = {Effect of N-acetyl cysteine against aluminium-induced cognitive dysfunction and oxidative damage in rats.}, journal = {Basic &amp; clinical pharmacology &amp; toxicology}, volume = {105}, number = {2}, pages = {98-104}, doi = {10.1111/j.1742-7843.2009.00404.x}, pmid = {19389043}, issn = {1742-7843}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/*pharmacology ; Aluminum Chloride ; Aluminum Compounds/*toxicity ; Animals ; Brain/*drug effects/metabolism ; Catalase/metabolism ; Chlorides/*toxicity ; Cognition Disorders/chemically induced/*prevention &amp; control ; Glutathione/analysis ; Lipid Peroxidation/drug effects ; Male ; Maze Learning/drug effects ; Memory/drug effects ; Motor Activity/drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Aluminium is a potent neurotoxin involved in the initiation and progression of various cognitive disorders like Alzheimer's disease. Chronic aluminium exposure induces oxidative stress and increases amyloid beta levels in vivo. The role of oxidative stress has been well-suggested in these cognitive problems. Therefore, the present study was designed to explore the possible role of N-acetyl cysteine against aluminium mediating cognitive dysfunction and oxidative stress in rats. Aluminium chloride (100 mg/kg, p.o.) was given to rats daily for 6 weeks. N-acetyl cysteine (per se; 50 and 100 mg/kg, i.p.) pre-treatment was given 30 min. before aluminium daily for 6 weeks. On the third (21st day) and sixth week (42nd day) of the study, various behavioural tests (Morris water maze and elevated plus maze task paradigms) and locomotion (photoactometer) were done to evaluate cognitive tasks. The rats were killed on the 43rd day following the last behavioural test, and various biochemical tests were performed to assess the extent of oxidative damage. Chronic aluminium chloride administration resulted in poor retention of memory in Morris water maze, elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant increase in the acetylcholinesterase activity. Chronic administration of N-acetyl cysteine significantly improved memory retention in tasks, attenuated oxidative damage and acetylcholinesterase activity in aluminium-treated rats. The study suggests a neuroprotective effect of N-acetyl cysteine against aluminium-induced cognitive dysfunction and oxidative damage.}, }
@article {pmid19382502, year = {2009}, author = {de Gussem, EM and Snijder, RJ and Disch, FJ and Zanen, P and Westermann, CJ and Mager, JJ}, title = {The effect of N-acetylcysteine on epistaxis and quality of life in patients with HHT: a pilot study.}, journal = {Rhinology}, volume = {47}, number = {1}, pages = {85-88}, pmid = {19382502}, issn = {0300-0729}, mesh = {Acetylcysteine/*therapeutic use ; Epistaxis/*etiology/*prevention &amp; control ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Pilot Projects ; *Quality of Life ; Severity of Illness Index ; Sex Factors ; Telangiectasia, Hereditary Hemorrhagic/*complications/drug therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Free O2- radicals may cause precapillary sphincter abnormalities, resulting in epistaxis in hemizygous knockout mice for Endoglin. The objective of this study was to test if antioxidants, like N-acetylcysteine (NAC), are have a role in the treatment of epistaxis in hereditary hemorrhagic telangiectasia (HHT).<br><br>METHODS: Forty-three patients participated in this study taking NAC 600 mg t.i.d for 12 weeks. Patients registered frequency, severity and duration of epistaxis and private and work-related quality of life (QOL), using a diary for two 6 weeks periods. The first period was prior to starting treatment and the second started after 6 weeks using NAC.<br><br>RESULTS: There was a decrease infrequency (p < 0.01) and severity (p < 0.01) of epistaxis during the day. The improvement was most remarkable in male patients and patients with an ENDOGLIN mutation. In women and patients with an ALK-1 mutation, only a trend for improvement was found. Nocturnal epistaxis did not improve. The effect of epistaxis on the ability to work (p = 0.02) was reduced.<br><br>CONCLUSION: This pilot study was conducted to investigate whether animal experiments can be translated to humans with HHT regarding epistaxis. The positive results with NAC are promising and justify a randomised clinical trial.}, }
@article {pmid19381868, year = {2009}, author = {Galgóczy, L and Kovács, L and Krizsán, K and Papp, T and Vágvölgyi, C}, title = {Inhibitory effects of cysteine and cysteine derivatives on germination of sporangiospores and hyphal growth of different Zygomycetes.}, journal = {Mycopathologia}, volume = {168}, number = {3}, pages = {125-134}, pmid = {19381868}, issn = {1573-0832}, mesh = {Antifungal Agents/*pharmacology ; Cysteine/*analogs &amp; derivatives/*pharmacology ; Fungi/cytology/*drug effects/growth &amp; development ; Hyphae/drug effects ; Microbial Sensitivity Tests/methods ; Microscopy/methods ; Spores, Fungal/drug effects ; }, abstract = {The in vitro antifungal activity of cysteine (D- and L-cysteine) and its four derivatives (L-cysteine-methyl-ester, N-acetyl-cysteine, N-isobutyryl-D-cysteine, and N-isobutyryl-L-cysteine) were investigated on 20 fungal isolates representing 16 genera (Absidia, Actinomucor, Backusella, Gilbertella, Micromucor, Mortierella, Mucor, Mycotypha, Phycomyces, Rhizomucor, Rhizopus, Saksenaea, Syncephalastrum, Thamnostylum, Umbellopsis, and Zygorynchus). The inhibitory potential of different concentrations of these compounds, ranging from 0.625 to 10 mM, were investigated on the germination of sporangiospores as well as on hyphal extension, using broth microdilution method and agar plate test. Treatment with cysteine and its derivatives resulted in a strong inhibition in most studied strains. At 10 mM of compounds, complete blockage of growth was observed for some isolates. Sensitive species exhibited severe changes in colony morphology in the presence of 10 mM L-cysteine, N-acetyl-cysteine, and N-isobutyryl-L-cysteine. Microscopic observations revealed that 10 mM N-acetyl-cysteine induced dramatic modifications in the structural organization of the hyphae. Results suggest that cysteine and its derivatives have a therapeutic potential against fungal infections caused by Zygomycetes species.}, }
@article {pmid19376147, year = {2009}, author = {Jana, M and Rajaram, A and Rajaram, R}, title = {Chromium picolinate induced apoptosis of lymphocytes and the signaling mechanisms thereof.}, journal = {Toxicology and applied pharmacology}, volume = {237}, number = {3}, pages = {331-344}, doi = {10.1016/j.taap.2009.04.006}, pmid = {19376147}, issn = {1096-0333}, mesh = {Apoptosis/*drug effects/immunology ; Cell Survival/drug effects/immunology ; Cells, Cultured ; Humans ; Lymphocytes/*drug effects/metabolism/pathology ; Picolinic Acids/metabolism/*toxicity ; Reactive Oxygen Species/metabolism/toxicity ; Signal Transduction/*drug effects/immunology ; }, abstract = {Cr(III)(picolinate)(3) [Cr(III)(pic)(3)] is currently used as a nutritional supplement and for treating Type-2 diabetes. The effect of Cr(III)(pic)(3) uptake in peripheral blood lymphocytes is investigated in this study. From the cytotoxicity data, DNA fragmentation pattern, Annexin V staining, TUNEL positivity and the ultrastructural characteristics such as chromatin condensation and formation of apoptotic bodies, it is clear that Cr(III)(pic)(3) induces a concentration dependent apoptosis. It is shown that reactive oxygen species (ROS) produced by treatment with Cr(III)(pic)(3) leads to apoptosis, since we find that pretreatment with N-acetyl cysteine inhibits the process. Using Western blotting technique and fluorescence measurements, the downstream signaling molecules have also been identified. Cr(III)(pic)(3) treatment leads to collapse of the mitochondrial membrane potential, Bax expression, increase in cytosolic cytochrome c content and active caspase-3 and DNA fragmentation and all these manifestations are reduced by pretreating the lymphocytes with N-acetyl cysteine. Thus, it is shown that Cr(III)(pic)(3) is cytotoxic to lymphocytes with ROS and mitochondrial events playing a role in bringing about apoptosis.}, }
@article {pmid19374849, year = {2009}, author = {Tajima, M and Kurashima, Y and Sugiyama, K and Ogura, T and Sakagami, H}, title = {The redox state of glutathione regulates the hypoxic induction of HIF-1.}, journal = {European journal of pharmacology}, volume = {606}, number = {1-3}, pages = {45-49}, doi = {10.1016/j.ejphar.2009.01.026}, pmid = {19374849}, issn = {1879-0712}, mesh = {Acetylcysteine/pharmacology ; Animals ; Azoles/pharmacology ; Cell Line, Tumor ; Enzyme Inhibitors/pharmacology ; Glutathione/analogs &amp; derivatives/*metabolism/*pharmacology ; Glutathione Disulfide/pharmacology ; Glutathione Reductase/antagonists &amp; inhibitors/metabolism ; Humans ; Hypoxia/*metabolism ; Hypoxia-Inducible Factor 1/*metabolism ; Isoindoles ; Organoselenium Compounds/pharmacology ; Oxidation-Reduction ; RNA, Messenger/genetics ; Transcriptional Activation/*drug effects ; Vascular Endothelial Growth Factor A/genetics ; }, abstract = {Hypoxia inducible factor 1 (HIF-1) regulates the transcription of vascular endothelial growth factor (VEGF), which plays important roles in angiogenesis. We investigated the redox effect of glutathione (GSH) on the hypoxic induction of HIF-1 in a human oral squamous cell carcinoma (HSC-2) cell line. The maximal induction of HIF-1 in HSC-2 cells was observed 30 h after hypoxia, and VEGF mRNA was expressed after 36 h under hypoxia. GSH ethyl ester (GSHee, a membrane permeable analog of GSH) and N-acetyl-L-cysteine (NAC, a membrane permeable precursor of GSH) reduced HIF-1 binding activity in a dose-dependent manner. Further, HIF-1 dependent promoter activity was similarly reduced by GSHee and NAC. However, ebselen, which increases glutathione peroxidase activity and oxidizes GSH, negated the effect of GSHee on HIF-1 dependent promoter activity. The inhibitory effect of GSHee and NAC on HIF-1 binding activity was reversed by bis (2-chlorethyl)-nitrosourea, an oxidized glutathione (GSSG) reductase inhibitor which increases the concentration of GSSG. GSSG methyl ester (GSSGme), a membrane permeable analog of GSSG, enhanced HIF-1 dependent promoter activity and exhibited a bell-shaped concentration-dependant activity curve. The increasing effect of GSSGme on HIF-1 induction was also observed under chemically-induced hypoxia obtained using cobalt chloride. These results suggest that changes in the intracellular GSSG/GSH ratio may regulate HIF-1 induction during hypoxia.}, }
@article {pmid19373606, year = {2009}, author = {Odom, RY and Dansby, MY and Rollins-Hairston, AM and Jackson, KM and Kirlin, WG}, title = {Phytochemical induction of cell cycle arrest by glutathione oxidation and reversal by N-acetylcysteine in human colon carcinoma cells.}, journal = {Nutrition and cancer}, volume = {61}, number = {3}, pages = {332-339}, pmid = {19373606}, issn = {1532-7914}, support = {RR03032/RR/NCRR NIH HHS/United States ; S06 GM008248-120031/GM/NIGMS NIH HHS/United States ; G12 RR003032/RR/NCRR NIH HHS/United States ; G12 RR003032-150002/RR/NCRR NIH HHS/United States ; S06 GM008248/GM/NIGMS NIH HHS/United States ; U54 MD007593/MD/NIMHD NIH HHS/United States ; GM-028248/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Allyl Compounds/pharmacology ; Anticarcinogenic Agents/*pharmacology ; Butyrates/pharmacology ; Carotenoids/pharmacology ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Dimethyl Fumarate ; Disulfides/pharmacology ; Fumarates/pharmacology ; Glutathione/*metabolism ; HT29 Cells ; Humans ; Isothiocyanates/pharmacology ; Lycopene ; Oxidation-Reduction ; Plants/*chemistry ; }, abstract = {Cancer prevention by dietary phytochemicals has been shown to involve decreased cell proliferation and cell cycle arrest. However, there is limited understanding of the mechanisms involved. Previously, we have shown that a common effect of phytochemicals investigated is to oxidize the intracellular glutathione (GSH) pool. Therefore, the objective of this study was to evaluate whether changes in the glutathione redox potential in response to dietary phytochemicals was related to their induction of cell cycle arrest. Human colon carcinoma (HT29) cells were treated with benzyl isothiocyanate (BIT) (BIT), diallyl disulfide (DADS), dimethyl fumarate (DMF), lycopene (LYC) (LYC), sodium butyrate (NaB) or buthione sulfoxamine (BSO, a GSH synthesis inhibitor) at concentrations shown to cause oxidation of the GSH: glutathione disulfide pool. A decrease in cell proliferation, as measured by [(3)H]-thymidine incorporation, was observed that could be reversed by pretreatment with the GSH precursor and antioxidant N-acetylcysteine (NAC). Cell cycle analysis on cells isolated 16 h after treatment indicated an increase in the percentage (ranging from 75-30% for benzyl isothiocyanate and lycopene, respectively) of cells at G2/M arrest compared to control treatments (dimethylsulfoxide) in response to phytochemical concentrations that oxidized the GSH pool. Pretreatment for 6 h with N-acetylcysteine (NAC) resulted in a partial reversal of the G2/M arrest. As expected, the GSH oxidation from these phytochemical treatments was reversible by NAC. That both cell proliferation and G2/M arrest were also reversed by NAC leads to the conclusion that these phytochemical effects are also mediated, in part, by intracellular oxidation. Thus, one potential mechanism for cancer prevention by dietary phytochemicals is inhibition of the growth of cancer cells through modulation of their intracellular redox environment.}, }
@article {pmid19372642, year = {2009}, author = {Kuo, HT and Lee, JJ and Hsiao, HH and Chen, HW and Chen, HC}, title = {N-acetylcysteine prevents mitochondria from oxidative injury induced by conventional peritoneal dialysate in human peritoneal mesothelial cells.}, journal = {American journal of nephrology}, volume = {30}, number = {3}, pages = {179-185}, doi = {10.1159/000213502}, pmid = {19372642}, issn = {1421-9670}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Cells, Cultured ; Dialysis Solutions/*pharmacology ; Epithelium ; Humans ; Mitochondria/*drug effects/*metabolism ; *Oxidative Stress ; Peritoneum/*cytology ; }, abstract = {INTRODUCTION: Bioincompatible peritoneal dialysate fluids (PDFs) may lead to peritoneal injury. The present study investigated the possible effects of N-acetylcysteine (NAC) during conventional PDF exposure for human peritoneal mesothelial cells (HPMCs).<br><br>METHODS: Cultured HPMCs were incubated with conventional 1.5% dextrose PDF for different time periods, and NAC was utilized as the antioxidant. The cell survival, superoxide accumulation, mitochondrial membrane potential (Deltapsim), expression of heat shock protein 72(HSP72), catalase, superoxide dismutase (SOD), and glutathione content of HPMCs were evaluated.<br><br>RESULTS: HPMC exposed to PDF resulted in a significant decrease in cell survival in a time-dependent manner, which was reversed by NAC. PDF exposure resulted in intracellular accumulation of superoxide in a time-dependent manner, with collapse of Deltapsim as well. The activity of enzymatic antioxidant, SOD and catalase remained the same in all groups. However, the reduced glutathione was significantly suppressed after PDF exposure. NAC treatment preserved the content of intracellular reduced glutathione, and also attenuated the PDF-induced superoxide accumulation and Deltapsim collapse. Moreover, the enhanced expression of HSP72 induced by PDF exposure was also reversed by NAC.<br><br>CONCLUSION: Depletion of a nonenzymatic antioxidant, i.e. reduced glutathione, in HPMC is a crucial cause of PDF-induced oxidative stress. NAC protects HPMCs from PDF-induced cellular damage by preserving the reduced glutathione.}, }
@article {pmid19371603, year = {2009}, author = {O'Toole, TE and Zheng, YT and Hellmann, J and Conklin, DJ and Barski, O and Bhatnagar, A}, title = {Acrolein activates matrix metalloproteinases by increasing reactive oxygen species in macrophages.}, journal = {Toxicology and applied pharmacology}, volume = {236}, number = {2}, pages = {194-201}, pmid = {19371603}, issn = {1096-0333}, support = {P01 ES011860-05/ES/NIEHS NIH HHS/United States ; R01 HL059378/HL/NHLBI NIH HHS/United States ; R01 HL059378-09/HL/NHLBI NIH HHS/United States ; HL55477/HL/NHLBI NIH HHS/United States ; P01 ES011860/ES/NIEHS NIH HHS/United States ; R01 HL055477-13/HL/NHLBI NIH HHS/United States ; R01 HL055477/HL/NHLBI NIH HHS/United States ; HL59378/HL/NHLBI NIH HHS/United States ; ES11860/ES/NIEHS NIH HHS/United States ; }, mesh = {Acrolein/*toxicity ; Animals ; Apolipoproteins E/genetics/metabolism ; Atherosclerosis/enzymology/genetics ; Calcium/metabolism ; Cell Line ; Environmental Pollutants/toxicity ; Gene Expression Regulation/drug effects ; Macrophages/*drug effects/*metabolism ; Matrix Metalloproteinases/*metabolism ; Mice ; Mice, Knockout ; Reactive Oxygen Species/*metabolism ; Xanthine Oxidase/metabolism ; }, abstract = {Acrolein is a ubiquitous component of environmental pollutants such as automobile exhaust, cigarette, wood, and coal smoke. It is also a natural constituent of several foods and is generated endogenously during inflammation or oxidation of unsaturated lipids. Because increased inflammation and episodic exposure to acrolein-rich pollutants such as traffic emissions or cigarette smoke have been linked to acute myocardial infarction, we examined the effects of acrolein on matrix metalloproteinases (MMPs), which destabilize atherosclerotic plaques. Our studies show that exposure to acrolein resulted in the secretion of MMP-9 from differentiated THP-1 macrophages. Acrolein-treatment of macrophages also led to an increase in reactive oxygen species (ROS), free intracellular calcium ([Ca2+](i)), and xanthine oxidase (XO) activity. ROS production was prevented by allopurinol, but not by rotenone or apocynin and by buffering changes in [Ca2+](I) with BAPTA-AM. The increase in MMP production was abolished by pre-treatment with the antioxidants Tiron and N-acetyl cysteine (NAC) or with the xanthine oxidase inhibitors allopurinol or oxypurinol. Finally, MMP activity was significantly stimulated in aortic sections from apoE-null mice containing advanced atherosclerotic lesions after exposure to acrolein ex vivo. These observations suggest that acrolein exposure results in MMP secretion from macrophages via a mechanism that involves an increase in [Ca2+](I), leading to xanthine oxidase activation and an increase in ROS production. ROS-dependent activation of MMPs by acrolein could destabilize atherosclerotic lesions during brief episodes of inflammation or pollutant exposure.}, }
@article {pmid19369049, year = {2010}, author = {Gil-Longo, J and González-Vázquez, C}, title = {Vascular pro-oxidant effects secondary to the autoxidation of gallic acid in rat aorta.}, journal = {The Journal of nutritional biochemistry}, volume = {21}, number = {4}, pages = {304-309}, doi = {10.1016/j.jnutbio.2009.01.003}, pmid = {19369049}, issn = {1873-4847}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aorta, Thoracic/*drug effects/physiology ; Catalase/metabolism ; Cell Death/drug effects ; Cyclooxygenase Inhibitors/pharmacology ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*drug effects/physiopathology ; Female ; Free Radical Scavengers/pharmacology ; Gallic Acid/analogs &amp; derivatives/antagonists &amp; inhibitors/*chemistry/*pharmacology ; Hydrogen Peroxide/antagonists &amp; inhibitors/chemistry/pharmacology ; In Vitro Techniques ; Muscle Contraction/drug effects ; Muscle, Smooth, Vascular/drug effects/physiology ; Neuromuscular Agents/antagonists &amp; inhibitors/pharmacology ; Oxidation-Reduction ; *Oxidative Stress ; Quinones/antagonists &amp; inhibitors/chemistry/pharmacology ; Rats ; Rats, Inbred WKY ; Superoxides/antagonists &amp; inhibitors/chemistry/pharmacology ; }, abstract = {UNLABELLED: Gallic acid autoxidation was monitored by absorption spectroscopy and H(2)O(2) production; vascular effects related to the autoxidation process were studied on intact and rubbed aortic rings from WKY rats. Gallic acid autoxidation in an oxygenated physiological salt solution (37 degrees C, pH=7.4) mostly occurred in a 2-h time period. Superoxide anions, H(2)O(2) and gallic acid quinones were produced during gallic acid autoxidation. In rings partially precontracted with phenylephrine, 0.1-3 microM gallic acid induced marked and largely endothelium-dependent contractions, 10-30 microM gallic acid induced endothelium-independent contractions and 0.1-0.3 mM gallic acid induced complete, fast-developing, endothelium-independent relaxations. Superoxide dismutase (SOD) shifted the endothelium-dependent gallic acid contractions to the right, and N(G)-nitro-l-arginine abolished them. Indomethacin suppressed the endothelium-independent gallic acid contractions, and catalase abolished the endothelium-independent contractions and relaxations. Gallic acid (30 microM) inhibited the relaxant effects of acetylcholine and sodium nitroprusside. In rings maximally precontracted with KCl, 0.1-100 microM gallic acid did not modify the tone, whereas 0.3 mM induced complete, slow-developing, endothelium-independent relaxations. Moreover, 0.3 mM gallic acid induced an irreversible impairment of ring reactivity and the release of lactate dehydrogenase. Catalase and N-acetyl cysteine suppressed the deleterious effects induced by gallic acid in the rings.<br><br>IN CONCLUSION: (a) gallic acid is rapidly and nonenzymatically oxidized in physiological solutions, generating superoxide anions, H(2)O(2) and quinones; (b) superoxide anions (by destroying NO) and low H(2)O(2) levels (by activating cyclooxygenase) both increase vascular tone; (c) moderate H(2)O(2) levels decrease vascular tone; (d) high H(2)O(2) and quinone levels cause irreversible relaxations due to cellular damage.}, }
@article {pmid19367648, year = {2009}, author = {Mukherjee, S and Stone, WL and Yang, H and Smith, MG and Das, SK}, title = {Protection of half sulfur mustard gas-induced lung injury in guinea pigs by antioxidant liposomes.}, journal = {Journal of biochemical and molecular toxicology}, volume = {23}, number = {2}, pages = {143-153}, doi = {10.1002/jbt.20279}, pmid = {19367648}, issn = {1099-0461}, mesh = {Animals ; Antioxidants/*pharmacology ; Chemical Warfare Agents/*toxicity ; Guinea Pigs ; *Liposomes ; Lung/*drug effects ; Lung Injury/*chemically induced ; Male ; Mustard Gas/*toxicity ; }, abstract = {The purpose of this study was to develop antioxidant liposomes as an antidote for mustard gas-induced lung injury in a guinea pig model. Five liposomes (LIP-1, LIP-2, LIP-3, LIP-4, and LIP-5) were tested with differing levels of phospholipid, cholesterol, phosphatidic acid, tocopherol (alpha, gamma, delta), N-acetylcysteine (NAC), and glutathione (GSH). A single dose (200 microL) of liposome was administered intratracheally 5 min or 1 h after exposure to 2-chloroethyl ethyl sulfide (CEES). The animals were sacrificed either 2 h after exposure (for lung injury study) or 30 days after exposure (for histology study). The liposomes offered 9%-76% protection against lung injury. The maximum protection was with LIP-2 (71.5% protection) and LIP-4 (75.4%) when administered 5 min after CEES exposure. Delaying the liposome administration 1 h after CEES exposure decreased the efficacy. Both liposomes contained 11 mM alpha-tocopherol, 11 mM gamma-tocopherol, and 75 mM NAC. However, LIP-2 contained additionally 5 mM delta-tocopherol. Overall, LIP-2 and LIP-4 offered significant protection by controlling the recruitment of neutrophils, eosinophils, and the accumulation of septal and perivascular fibrin and collagen. However, LIP-2 showed better protection than LIP-4 against the accumulation of red blood cells in the bronchi, alveolar space, arterioles and veins, and fibrin and collagen deposition in the alveolar space. The antifibrotic effect of the liposomes, particularly LIP-2, was further evident by a decreased level of lipid peroxidation and hydroxyproline in the lung. Thus, antioxidant liposomes containing both NAC and vitamin E are an effective antidote against CEES-induced lung injury.}, }
@article {pmid19367112, year = {2009}, author = {Siems, W and Salerno, C and Crifò, C and Sommerburg, O and Wiswedel, I}, title = {Beta-carotene degradation products - formation, toxicity and prevention of toxicity.}, journal = {Forum of nutrition}, volume = {61}, number = {}, pages = {75-86}, doi = {10.1159/000212740}, pmid = {19367112}, issn = {1660-0347}, mesh = {Animals ; Cell Respiration/drug effects ; Cells, Cultured ; Chromatography, Gas ; Chromatography, High Pressure Liquid ; Humans ; Liver/drug effects/metabolism ; Male ; Mitochondria/drug effects/metabolism ; Neutrophils/drug effects/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Vitamins/*metabolism/*toxicity ; beta Carotene/*metabolism/*toxicity ; }, abstract = {Carotenoids are widely used as important micronutrients in food. Furthermore, carotenoid supplementation has been used in the treatment of diseases associated with oxidative stress such as various types of cancer, inflammatory diseases or cystic fibrosis. However, in some clinical studies harmful effects have been observed, e.g. a higher incidence of lung cancer in individuals exposed to extraordinary oxidative stress. The causal mechanisms of harmful effects are still unclear. Carotenoid breakdown products (CBPs) including highly reactive aldehydes and epoxides are formed during oxidative attacks in the course of antioxidative action. We investigated the formation of CBPs by stimulated neutrophils (and at further conditions), tested the hypothesis that CBPs may exert mitochondriotoxicity and tried to prevent toxicity in the presence of members of the antioxidative network. Stimulated neutrophils are able to degrade beta-carotene and to generate a number of CBPs. Concerning mitochondriotoxicity, we found that CBPs strongly inhibit state 3 respiration of rat liver mitochondria at concentrations between 0.5 and 20 microM. This was true for retinal, beta-ionone, and for mixtures of cleavage/breakdown products. The inhibition of mitochondrial respiration was accompanied by a reduction in protein sulfhydryl content, decreasing GSH levels and redox state, and elevated accumulation of malondialdehyde. Changes in mitochondrial membrane potential favor functional deterioration in the adenine nucleotide translocator as a sensitive target. The presence of additional antioxidants such as alpha-tocopherol, ascorbic acid, N-acetyl-cysteine or others could mitigate mitochondriotoxicity. The findings reflect a basic mechanism of increasing the risk of cancer induced by carotenoid degradation products.}, }
@article {pmid19365035, year = {2009}, author = {Hongyok, T and Chae, JJ and Shin, YJ and Na, D and Li, L and Chuck, RS}, title = {Effect of chitosan-N-acetylcysteine conjugate in a mouse model of botulinum toxin B-induced dry eye.}, journal = {Archives of ophthalmology (Chicago, Ill. : 1960)}, volume = {127}, number = {4}, pages = {525-532}, doi = {10.1001/archophthalmol.2009.52}, pmid = {19365035}, issn = {1538-3601}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Topical ; Animals ; Blinking/physiology ; Botulinum Toxins ; Botulinum Toxins, Type A ; Chitosan/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Conjunctiva/metabolism ; Cornea/metabolism ; Cytokines/genetics/metabolism ; *Disease Models, Animal ; Dry Eye Syndromes/chemically induced/*drug therapy/metabolism ; Female ; Fluorescent Antibody Technique, Indirect ; Fluorometholone/administration &amp; dosage/pharmacology ; Lacrimal Apparatus/metabolism ; Mice ; Mice, Inbred CBA ; Ophthalmic Solutions/administration &amp; dosage/pharmacology ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tears/metabolism ; }, abstract = {OBJECTIVE: To evaluate the effect of a thiolated polymer lubricant, chitosan-N-acetylcysteine conjugate (C-NAC), in a mouse model of dry eye.<br><br>METHODS: Eye drops containing 0.5% C-NAC, 0.3% C-NAC, a vehicle (control group), artificial tears, or fluorometholone were applied in a masked fashion in a mouse model of induced dry eye from 3 days to 4 weeks after botulinum toxin B injection. Corneal fluorescein staining was periodically recorded. Real-time reverse transcriptase-polymerase chain reaction and immunofluorescence staining were performed at the end of the study to evaluate inflammatory cytokine expressions.<br><br>RESULTS: Mice treated with C-NAC, 0.5%, and fluorometholone showed a downward trend that was not statistically significant in corneal staining compared with the other groups. Chitosan-NAC formulations, fluorometholone, and artificial tears significantly decreased IL-1beta (interleukin 1beta), IL-10, IL-12alpha, and tumor necrosis factor alpha expression in ocular surface tissues.<br><br>CONCLUSIONS: The botulinum toxin B-induced dry eye mouse model is potentially useful in evaluating new dry eye treatment. Evaluation of important molecular biomarkers suggests that C-NAC may impart some protective ocular surface properties. However, clinical data did not indicate statistically significant improvement of tear production and corneal staining in any of the groups tested.<br><br>CLINICAL RELEVANCE: Topically applied C-NAC might protect the ocular surface in dry eye syndrome, as evidenced by decreased inflammatory cytokine expression.}, }
@article {pmid19363327, year = {2009}, author = {Pearson, L and Bissinger, R and Romero, KR}, title = {Neonatal hemochromatosis: a case report.}, journal = {Advances in neonatal care : official journal of the National Association of Neonatal Nurses}, volume = {9}, number = {2}, pages = {72-76}, doi = {10.1097/ANC.0b013e31819ac020}, pmid = {19363327}, issn = {1536-0903}, mesh = {Adult ; Antioxidants/administration &amp; dosage ; Diagnosis, Differential ; Female ; Hemochromatosis/blood/*diagnosis/drug therapy/nursing ; Humans ; Immunoglobulins, Intravenous/administration &amp; dosage ; Infant, Newborn ; Intensive Care Units, Neonatal ; Liver Failure, Acute/blood/*complications/*diagnosis ; Male ; Pregnancy ; Pregnancy Complications/blood/diagnosis ; Treatment Outcome ; alpha-Fetoproteins/analysis ; }, abstract = {Neonatal hemochromatosis is a rare disease of iron metabolism, characterized by the excess accumulation of iron in the tissues. This occurs in utero and can lead to fetal demise or an infant who presents with advanced liver disease in the neonatal period. A case of neonatal hemochromatosis is reported in a 37-week infant who presented at birth with thrombocytopenia, coagulopathy, and abnormal liver imaging studies. The diagnoses of infection and metabolic errors were excluded before the confirmation of neonatal hemochromatosis was made. This diagnosis was confirmed by elevated ferritin levels and extrahepatic siderosis excluding the reticuloendothelial system. Anti-oxidant therapy was initiated with N-acetyl cysteine, selenium, vitamins C and E and intravenous immunoglobulin. The infant demonstrated a positive response and was discharged home with outpatient follow up. The clinical presentation of neonatal hemochromatosis is reviewed as well as diagnosis and treatment strategies.}, }
@article {pmid19360315, year = {2009}, author = {Hanayama, R and Shimizu, H and Nakagami, H and Osako, MK and Makino, H and Kunugiza, Y and Tomita, T and Tsukamoto, I and Yoshikawa, H and Rakugi, H and Morishita, R}, title = {Fluvastatin improves osteoporosis in fructose-fed insulin resistant model rats through blockade of the classical mevalonate pathway and antioxidant action.}, journal = {International journal of molecular medicine}, volume = {23}, number = {5}, pages = {581-588}, doi = {10.3892/ijmm_00000167}, pmid = {19360315}, issn = {1107-3756}, mesh = {Animals ; Animals, Newborn ; Antioxidants/pharmacology/therapeutic use ; Cell Differentiation/drug effects ; Cells, Cultured ; Diet ; Down-Regulation/drug effects ; Drug Evaluation, Preclinical ; Fatty Acids, Monounsaturated/pharmacology/*therapeutic use ; Female ; Fluvastatin ; *Fructose ; Indoles/pharmacology/*therapeutic use ; *Insulin Resistance/physiology ; Mevalonic Acid/*metabolism ; Osteoclasts/drug effects/physiology ; Osteoporosis/*chemically induced/*drug therapy/metabolism ; Rabbits ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; }, abstract = {Feeding rats with a high-fructose diet induced insulin resistance, leading to hypertension or metabolic disorders. Although hypertension is known to accelerate osteoporosis, it is not obvious whether insulin resistance would accelerate osteoporosis. In this study, we evaluated whether osteoporosis might accelerate in fructose-fed rats (FFR), and examined the effect of fluvastatin through a blockade of the mevalonate pathway and an antioxidant action. Stimulation of recombinant receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) expressed by osteoblasts/ stromal cells and macrophage-colony stimulating factor (M-CSF) significantly increased TRAP-positive multinuclear osteoclasts and pit formation, accompanied by an increase in reactive oxygen species as assessed by dichlorodihydrofluorescein (DCF) staining. Interestingly, it was completely abolished by treatment with fluvastatin, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), but not pravastatin. These actions of fluvastatin were partially abolished by co-treatment with geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP). In the estrogen-deficient model by ovariectomy, FFR exhibited a decrease in bone mineral density, activation of osteoclasts, and an increase in urinary deoxypyridinoline. Importantly, the treatment of fluvastatin, but not pravastatin, attenuated FFR-induced osteoporosis. The present study demonstrates that fructose fed to rats induced insulin resistance and accelerated osteoporosis, while fluvastatin, but not pravastatin, significantly attenuated osteoclast differentiation and activation through a blockade of the classical mevalonate pathway and an antioxidant action, leading to prevention of osteoporosis.}, }
@article {pmid19358737, year = {2009}, author = {Yang, R and Miki, K and He, X and Killeen, ME and Fink, MP}, title = {Prolonged treatment with N-acetylcystine delays liver recovery from acetaminophen hepatotoxicity.}, journal = {Critical care (London, England)}, volume = {13}, number = {2}, pages = {R55}, pmid = {19358737}, issn = {1466-609X}, mesh = {Acetaminophen/*poisoning ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/*poisoning ; Animals ; Antidotes/administration &amp; dosage/pharmacology/*therapeutic use ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/*drug therapy/enzymology ; Cystine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology/therapeutic use ; Disease Models, Animal ; Drug Overdose/*drug therapy ; Glutathione/blood ; Male ; Mice ; Mice, Inbred C57BL ; Time Factors ; Treatment Outcome ; }, abstract = {INTRODUCTION: Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in the US and Europe. Massive hepatocyte necrosis is the predominant feature of APAP-induced acute liver injury (ALI). Liver regeneration is a vital process for survival after a toxic insult, it occurs at a relative late time point after the injurious phase. Currently, N-acetylcysteine (NAC), a glutathione precursor, is the antidote for acetaminophen overdose. However, NAC is effective only for patients who present within hours of an acute overdose, and is less effective for late-presenting patients. It is possible that in delayed patients, previously reduced endogenous glutathione (GSH) level has restored and prolonged treatment with NAC might be toxic and impair liver regeneration. Therefore, we hypothesize that prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP.<br><br>METHODS: ALI was induced in C57BL/6 male mice by a single dose of APAP (350 mg/kg) by intraperitoneal injection. After two hours of APAP challenge, the mice were given 100 mg/kg NAC dissolved in 0.6 mL saline, or saline treatment every 12 hours for a total of 72 hours.<br><br>RESULTS: Seventy-two hours after APAP challenge, compared with saline treatment, NAC treatment significantly increased serum transaminases (alanine transaminase/aspartate aminotransferase), induced evident hepatocyte vacuolation in the periportal area and delayed liver regeneration seen in histopathology. This detrimental effect was associated with reduced hepatic nuclear factor (NF)-kappaB DNA binding and decreased expression of cell cycle protein cyclin D1, two important factors in liver regeneration.<br><br>CONCLUSIONS: Prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP.}, }
@article {pmid19351855, year = {2009}, author = {Deng, X and Ewton, DZ and Friedman, E}, title = {Mirk/Dyrk1B maintains the viability of quiescent pancreatic cancer cells by reducing levels of reactive oxygen species.}, journal = {Cancer research}, volume = {69}, number = {8}, pages = {3317-3324}, pmid = {19351855}, issn = {1538-7445}, support = {R01 CA067405/CA/NCI NIH HHS/United States ; R01 CA067405-09/CA/NCI NIH HHS/United States ; 2R01CA67405/CA/NCI NIH HHS/United States ; }, mesh = {Cell Survival/physiology ; Cyclin D ; Cyclins/metabolism ; G1 Phase/physiology ; Humans ; Pancreatic Neoplasms/enzymology/genetics/*metabolism/*pathology ; Protein Serine-Threonine Kinases/genetics/*metabolism ; Protein-Tyrosine Kinases/genetics/*metabolism ; RNA Interference ; Reactive Oxygen Species/*metabolism ; Resting Phase, Cell Cycle/physiology ; Superoxide Dismutase/biosynthesis/genetics/metabolism ; Transcription, Genetic ; Transfection ; Up-Regulation ; Dyrk Kinases ; }, abstract = {The kinase Mirk/dyrk1B mediated the clonogenic growth of pancreatic cancer cells in earlier studies. It is now shown that Mirk levels increased 7-fold in SU86.86 pancreatic cancer cells when over a third of the cells were accumulated in a quiescent G(0) state, defined by Hoechst/Pyronin Y staining. Depletion of Mirk by a doxycycline-inducible short hairpin RNA increased the G(0) fraction to approximately 50%, suggesting that Mirk provided some function in G(0). Mirk reduced the levels of reactive oxygen species (ROS) in quiescent cultures of SU86.86 cells and of Panc1 cells by increasing transcription of the antioxidant genes ferroxidase, superoxide dismutase (SOD)2, and SOD3. These genes were functional antioxidant genes in pancreatic cancer cells because ectopic expression of SOD2 and ferroxidase in Mirk-depleted cells lowered ROS levels. Quiescent pancreatic cancer cells quickly lost viability when depleted of Mirk because of elevated ROS levels, exhibiting up to 4-fold less colony-forming activity and 4-fold less capability for dye exclusion. As a result, reduction of ROS by N-acetyl cysteine led to more viable cells. Mirk also destabilizated cyclin D1 and D3 in quiescent cells. Thus, quiescent pancreatic cancer cells depleted of Mirk became less viable because they were damaged by ROS, and had increased levels of G(1) cyclins to prime cells to escape quiescence.}, }
@article {pmid19347580, year = {2009}, author = {Becker, A and Soliman, KF}, title = {The role of intracellular glutathione in inorganic mercury-induced toxicity in neuroblastoma cells.}, journal = {Neurochemical research}, volume = {34}, number = {9}, pages = {1677-1684}, pmid = {19347580}, issn = {1573-6903}, support = {G12 RR003020/RR/NCRR NIH HHS/United States ; G12 RR003020-255367/RR/NCRR NIH HHS/United States ; P20 MD006738/MD/NIMHD NIH HHS/United States ; RR 03020/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cytoprotection/drug effects ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors ; Glutathione/*physiology ; Mercuric Chloride/toxicity ; Mercury Poisoning/*physiopathology ; Mice ; Neuroblastoma ; Sulfhydryl Compounds/metabolism ; }, abstract = {It is well known that antioxidants containing sulfhydryl (-SH) groups are protective against the toxic effects of mercury. The current study was designed to elucidate the mechanism(s) of the cytoprotective effects of glutathione (GSH) and N-acetylcysteine (NAC) against the toxicity of inorganic mercury (HgCl(2)) in neuroblastoma cells (N-2A). The obtained results demonstrated the protective effects of these compounds in a dose dependant manner up to 95 and 74% cell viability, respectively as compared to the control of HgCl(2) of 10%. The administration of buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, increased the toxicity of HgCl(2) in a dose dependent manner. Moreover, BSO treatment attenuated the levels of the cellular free -SH concentrations at low concentrations (1-100 microM) of HgCl(2). The data also show that cellular thiol concentrations were augmented in the presence of GSH and NAC and these compounds were cytoprotective against HgCl(2) and this is due to up regulating of GSH synthesis. A reduction in intracellular levels of GSH was observed with treatment of HgCl(2). In addition, the ratio of GSH/GSSG increased from 16:1 to 50:1 from 1 to 10 microM concentration of HgCl(2.) The ratio of GSH/GSSG then decreased from 4:1 to 0.5:1 with the increase of concentration of HgCl(2) between 100 microM and 1 mM due to the collapse of the N-2A cells. It was of interest to note that the synthesis of GSH was stimulated in cells exposed to low concentration of HgCl(2) when extra GSH is available. These data support the idea that the loss of GSH plays a contributing role to the toxic effects of HgCl(2) and that inorganic mercury adversely affects viability, through altering intracellular -SH concentrations. The data further indicate that the availability of GSH to the cells may not be sufficient to provide protection against mercury toxicity and the de novo synthesis of intracellular GSH is required to prevent the damaging effects of mercury.}, }
@article {pmid19346747, year = {2009}, author = {Kabali, B and Girgin, S and Gedik, E and Ozturk, H and Kale, E and Buyukbayram, H}, title = {N-acetylcysteine prevents deleterious effects of ischemia/reperfusion injury on healing of colonic anastomosis in rats.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {43}, number = {1}, pages = {8-12}, doi = {10.1159/000210673}, pmid = {19346747}, issn = {1421-9921}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Anastomosis, Surgical/adverse effects ; Animals ; Colon/*surgery ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Infusions, Parenteral ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*prevention &amp; control ; Wound Healing/*drug effects ; }, abstract = {This study was designed to determine the effects of intraperitoneally or orally administered N-acetylcysteine (NAC) on wound healing following resection and anastomosis of a colon segment with ischemia/reperfusion injury. Forty female Sprague-Dawley rats were randomly allocated to one of four groups containing 10 rats each: (1) normal resection plus anastomosis; (2) ischemia/reperfusion plus resection plus anastomosis; (3) ischemia/reperfusion plus resection plus anastomosis plus intraperitoneal NAC; (4) ischemia/reperfusion plus resection plus anastomosis plus oral NAC. Group comparison showed that the anastomosis bursting pressure was significantly higher in group 3 than in the other groups. The mean tissue hydroxyproline concentration in the anastomotic tissue was significantly lower in group 2 than in the other groups. The collagen deposition was significantly increased on day 7 in groups 3 and 4 compared to the other groups. In conclusion, this study demonstrates that NAC significantly prevents the effects of reperfusion injury on colonic anastomoses in a rat model.}, }
@article {pmid19346170, year = {2009}, author = {Mitamura, K and Watanabe, S and Sakai, T and Okihara, R and Sogabe, M and Wakamiya, T and Hofmann, AF and Ikegawa, S}, title = {Chemical synthesis of N-acetylcysteine conjugates of bile acids and in vivo formation in cholestatic rats as shown by liquid chromatography/electrospray ionization-linear ion trap mass spectrometry.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {877}, number = {25}, pages = {2630-2638}, doi = {10.1016/j.jchromb.2009.03.029}, pmid = {19346170}, issn = {1873-376X}, mesh = {Acetylcysteine/chemical synthesis/chemistry/*metabolism ; Animals ; Bile Acids and Salts/chemical synthesis/chemistry/*metabolism ; Carboxylesterase/metabolism ; Cholestasis/*metabolism ; Chromatography, Liquid/*methods ; Disease Models, Animal ; Humans ; Liver/chemistry/metabolism ; Male ; Rabbits ; Rats ; Spectrometry, Mass, Electrospray Ionization/*methods ; }, abstract = {N-Acetylcysteine (NAC) conjugates of the five major bile acids occurring in man were synthesized in order to investigate the possible formation in vivo of these conjugates. Upon collision-induced dissociation, structurally informative daughter ions were observed. The transformation of cholyl-adenylate and cholyl-CoA thioester into a N-acetyl-S-(cholyl)cysteine by rat hepatic glutathione S-transferase was confirmed by liquid chromatography/electrospray ionization-linear ion trap mass spectrometry (LC/ESI-MS(2)). Lithocholic acid was administered orally to bile duct-ligated rats that also received NAC intraperitoneally. The NAC conjugate of lithocholic acid was identified in urine by means of LC/ESI-MS(2). Rapid hydrolysis of the BA-NAC conjugates by rabbit liver carboxylesterase was found, demonstrating the possible labile nature of the NAC conjugates formed in the liver.}, }
@article {pmid19344884, year = {2009}, author = {Beloosesky, R and Weiner, Z and Khativ, N and Maravi, N and Mandel, R and Boles, J and Ross, MG and Itskovitz-Eldor, J}, title = {Prophylactic maternal n-acetylcysteine before lipopolysaccharide suppresses fetal inflammatory cytokine responses.}, journal = {American journal of obstetrics and gynecology}, volume = {200}, number = {6}, pages = {665.e1-5}, doi = {10.1016/j.ajog.2009.01.032}, pmid = {19344884}, issn = {1097-6868}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cytokines/*biosynthesis ; Female ; Fetal Diseases/immunology/*prevention &amp; control ; Inflammation/immunology/*prevention &amp; control ; Interleukin-10/biosynthesis/*immunology ; Interleukin-1beta/biosynthesis/*immunology ; Interleukin-6/biosynthesis/*immunology ; Lipopolysaccharides/administration &amp; dosage ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: Maternal infection or inflammation may induce fetal inflammatory responses and potentially fetal brain injury. We sought to determine whether prophylactic n-acetylcysteine (NAC), a known antiinflammatory, may modulate the fetal cytokine response to maternal lipopolysaccharide (LPS).<br><br>STUDY DESIGN: Pregnant Sprague Dawley rats (20/21 days = 0.95 gestation; n = 35) received intraperitoneal NAC (300 mg/kg) or saline at time 0 and LPS (500 microg/kg) or saline at 30 minutes. An additional group received NAC following saline. At 6 hours, rats were killed and interleukin (IL)-6, IL-1 beta, and IL-10 levels were determined in fetal and maternal blood.<br><br>RESULTS: Following maternal LPS, fetal blood IL-6 (median [25th, 75th] 50 [27, 50] to 2072 [448, 4853] pg/mL) and IL-1 beta (74 [10, 139] to 391 [284, 797] pg/mL) significantly increased. NAC before LPS significantly reduced the fetal IL-6 and IL-1 beta response. Fetal IL-10 was not attenuated by any treatment. NAC attenuated both maternal pro- and antiinflammatory responses to LPS.<br><br>CONCLUSION: Maternal NAC suppressed fetal and maternal inflammatory responses to maternal LPS. These results suggest that prophylactic NAC may protect the fetus from maternal inflammation.}, }
@article {pmid19344704, year = {2009}, author = {Kunwar, A and Sandur, SK and Krishna, M and Priyadarsini, KI}, title = {Curcumin mediates time and concentration dependent regulation of redox homeostasis leading to cytotoxicity in macrophage cells.}, journal = {European journal of pharmacology}, volume = {611}, number = {1-3}, pages = {8-16}, doi = {10.1016/j.ejphar.2009.03.060}, pmid = {19344704}, issn = {1879-0712}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Biological Transport/drug effects ; Cell Line ; Cell Survival/drug effects ; Curcumin/metabolism/pharmacology/*toxicity ; Dose-Response Relationship, Drug ; Gamma Rays ; Gene Expression Regulation/drug effects ; Glutathione/pharmacology ; Homeostasis/*drug effects/radiation effects ; Macrophages/cytology/*drug effects/*metabolism/radiation effects ; Mice ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects/radiation effects ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; Time Factors ; }, abstract = {The present study was designed to test a hypothesis that curcumin may be modulating oxidative stress parameters including reactive oxygen species, non-protein thiols and expression of antioxidant genes in a concentration and time dependent manner in exhibiting cytotoxic effects in macrophage cell line RAW 264.7. The results have shown that curcumin elevated the reactive oxygen species levels accompanied by a decrease in levels of intracellular non-protein thiols at 2 h after its addition to cells. However, the levels of reactive oxygen species decreased and non-protein thiols content increased at 18 h after its addition. Whereas the expression of glutathione peroxidase (GPx), catalase, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and heme oxygenase-1 (HO-1) increased with curcumin concentration and also with increase in time of incubation, the expression of Mn- superoxide dismutase (Mn-SOD) showed concentration dependant repression upon treatment with curcumin. The cell viability was significantly reduced at high concentration (25 microM) of curcumin treatment but not at low concentration (5 microM). Curcumin at 5 microM scavenged gamma-radiation induced reactive oxygen species and inhibited cell death. On the contrary, at 25 microM, curcumin increased radiation induced reactive oxygen species production and augmented cell death. Interestingly pretreatment with reducing agents glutathione (GSH) or N-acetyl-cysteine (NAC), modified the curcumin mediated redox changes and cell death differentially, due to the inhibition of cellular uptake of curcumin by GSH but not by NAC. The important finding of the study is that the concentration and time dependent dual effect of curcumin may be attributed to changes in oxidative stress and antioxidant gene expression levels leading to inhibition or promotion of cell death.}, }
@article {pmid19341424, year = {2009}, author = {Cai, S and Chen, P and Zhang, C and Chen, JB and Wu, J}, title = {Oral N-acetylcysteine attenuates pulmonary emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats.}, journal = {Respirology (Carlton, Vic.)}, volume = {14}, number = {3}, pages = {354-359}, doi = {10.1111/j.1440-1843.2009.01511.x}, pmid = {19341424}, issn = {1440-1843}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Administration, Oral ; Animals ; Antioxidants/administration &amp; dosage/pharmacology/*therapeutic use ; *Apoptosis/drug effects ; Bronchoalveolar Lavage Fluid ; Disease Models, Animal ; Male ; Pulmonary Alveoli/drug effects/*pathology/physiopathology ; Pulmonary Disease, Chronic Obstructive/*drug therapy/pathology/physiopathology ; Pulmonary Emphysema/*drug therapy/pathology/physiopathology ; Rats ; Rats, Sprague-Dawley ; Smoking/*adverse effects ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {BACKGROUND AND OBJECTIVE: The role of apoptosis in lung destruction in emphysema/COPD is increasingly being recognized. The relationship between anti-oxidants and alveolar septal cell apoptosis in COPD lungs remains to be elucidated. The aim of this study was to investigate the effects of the anti-oxidant, N-acetylcysteine (NAC), on the development of emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats.<br><br>METHODS: Sprague-Dawley rats (n = 48) were randomly assigned to normal, COPD, sham and NAC groups. The effects of treatment were assessed by measuring the levels of vascular endothelial growth factor (VEGF) in BAL fluid by ELISA, VEGF and VEGF receptor-2 (VEGFR2) protein expression by western blotting, and the apoptotic index (AI) of alveolar septal cells by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. Histopathological evaluations (mean linear intercept (MLI), destructive index (DI)) and lung function measurements were performed.<br><br>RESULTS: FEV(0.3)/FVC and PEF were lower in the COPD group than in the normal group. MLI and DI were lower in the NAC-treated group than in the COPD or sham-treated groups. As confirmed by western blotting, the levels of VEGF in BAL fluid were higher in the NAC-treated group than in the COPD group. VEGFR2 protein expression was higher in the NAC-treated group than in the COPD group. The AI was significantly lower in the NAC-treated group than in the COPD group. There was an inverse correlation between levels of VEGF in BAL fluid and the AI of alveolar septal cells.<br><br>CONCLUSIONS: NAC attenuates lung damage, pulmonary emphysema and alveolar septal cell apoptosis by partly reversing the decrease in VEGF secretion and VEGFR2 protein expression in smoking-induced COPD in rats.}, }
@article {pmid19341122, year = {2009}, author = {Efrati, S and Gall, N and Bergan, J and Fishlev, G and Bass, A and Berman, S and Hamad-Abu, R and Feigenzon, M and Weissgarten, J}, title = {Hyperbaric oxygen, oxidative stress, NO bioavailability and ulcer oxygenation in diabetic patients.}, journal = {Undersea &amp; hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc}, volume = {36}, number = {1}, pages = {1-12}, pmid = {19341122}, issn = {1066-2936}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aged ; Analysis of Variance ; Benzothiazoles/metabolism ; Blood Gas Monitoring, Transcutaneous ; Clinical Protocols ; Cross-Over Studies ; Diabetes Mellitus, Type 2/complications ; Diabetic Foot/classification/metabolism/*therapy ; Female ; Humans ; Hyperbaric Oxygenation/*methods ; Injury Severity Score ; Male ; Malondialdehyde/analysis ; Middle Aged ; Nitric Oxide/*metabolism ; *Oxidative Stress ; Oxygen/*metabolism ; Prospective Studies ; Sulfonic Acids/metabolism ; }, abstract = {BACKGROUND: Hyperbaric oxygen therapy (HBO2) increases tissue oxygenation, thus serving as an adjunct therapy for diabetic wounds. However, in some patients there is insufficient increase in tissue O2.<br><br>AIMS: To investigate the pathophysiology of insufficient HBO2 and the possible role of N-acetylcysteine (NAC).<br><br>METHODS: Prospective, randomized, cross-over trial included 50 diabetic patients with non-healing ulcers. Each patient received two treatments with 100% oxygen/2ATA. NAC was administered i.v. at one of the two treatments. Basal and post-treatment peri-wound transcutaneous O2 (TcPO2) pressure, malondialdehyde (MDA), total anti-oxidant status (TAOS) and nitric oxide (NO) were assessed. An ulcer oxygenation increase above 200 mmHg was accepted as sufficient.<br><br>RESULTS: During HBO2, 17 patients (34%) demonstrated insufficient increase in TcPO2. Concomitantly, their TAOS and NO decreased, while MDA increased. NAC administration attenuated these parameters, thus improving the HBO2 outcome. In those affected by NAC, the cure rate was 75%. By contrast, in 66% of patients with sufficient increase in TcPO2 TAOS was increased and MDA decreased irrespective of NAC administration. The cure rate in this subgroup was 82%.<br><br>CONCLUSIONS: Insufficient increase of ulcer oxygenation during HBO2 results from exaggerated oxidative stress and decreased NO bioavailability. NAC administration-induced modulation of both parameters and may improve ulcer oxygenation during HBO2.}, }
@article {pmid19339682, year = {2009}, author = {Sethi, R and Adameova, A and Dhalla, KS and Khan, M and Elimban, V and Dhalla, NS}, title = {Modification of epinephrine-induced arrhythmias by N-acetyl-L-cysteine and vitamin E.}, journal = {Journal of cardiovascular pharmacology and therapeutics}, volume = {14}, number = {2}, pages = {134-142}, doi = {10.1177/1074248409333855}, pmid = {19339682}, issn = {1074-2484}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Arrhythmias, Cardiac/*prevention &amp; control ; Dose-Response Relationship, Drug ; Electrocardiography ; Epinephrine/blood/toxicity ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Norepinephrine/blood ; Rats ; Rats, Sprague-Dawley ; Vitamin E/administration &amp; dosage/*pharmacology ; }, abstract = {Sprague-Dawley rats were pretreated for 21 days with N-acetyl-L-cysteine (NAC) or vitamin E to investigate their influence on arrhythmias induced by a bolus injection or by cumulative doses of epinephrine. Electrocardiographic analysis revealed that both NAC and vitamin E decreased the duration and increased the time of onset of epinephrine-induced arrhythmias in a dose-dependent manner. The antiarrhythmic effects of NAC were comparable with those seen in the vitamin E-pretreated animals. The lipid peroxidation due to cumulative doses of epinephrine was reduced in both pretreated groups; however, NAC, unlike vitamin E, failed to decrease the basal level of malondialdehyde. Although the plasma concentrations of both norepinephrine and epinephrine were markedly increased, the level of aminochromes on epinephrine administration was decreased by both NAC and vitamin E pretreatments. The results support the view that antioxidants may prevent the catecholamine-induced heart rhythm disorders by reducing the formation of oxidized catecholamines.}, }
@article {pmid19336887, year = {2009}, author = {Zhang, X and Cao, J and Jiang, L and Zhong, L}, title = {Suppressive effects of hydroxytyrosol on oxidative stress and nuclear Factor-kappaB activation in THP-1 cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {32}, number = {4}, pages = {578-582}, doi = {10.1248/bpb.32.578}, pmid = {19336887}, issn = {0918-6158}, mesh = {Antioxidants/*pharmacology ; Blotting, Western ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Humans ; Lipopolysaccharides/pharmacology ; NF-kappa B/*metabolism ; Nitric Oxide/biosynthesis ; Oxidative Stress/*drug effects ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species/metabolism ; Stimulation, Chemical ; }, abstract = {This study was designed to investigate whether hydroxytyrosol (HT) may ameliorate oxidative stress and nuclear factor kappaB (NF-kappaB) activation in the lipopolysaccharide (LPS)-stimulated THP-1 cell line. We measured the intracellular reactive oxygen species (ROS) formation using 2,7-dichlorofluorescein diacetate (DCFH-DA) as a fluorescent probe. Intracellular glutathione (GSH) level was estimated by fluorometric methods. Nitric oxide (NO) production was measured as nitrite (a stable metabolite of NO) concentrations using the Griess reagent system following Jiancheng Institute of Biotechnology protocols. To study the effect of HT on LPS-induced NF-kappaB activation in THP-1 cells, Western blot analysis of the nuclear fraction of cell lysates was performed. The results showed that treatment of THP-1 cells with HT significantly reduced LPS-stimulated NO production and ROS formation in a concentration-dependent manner. HT at 50 and 100 microM concentrations increased the GSH level. The specific DNA-binding activities of NF-kappaB on nuclear extracts from 50 and 100 microM HT treatments were significantly suppressed. The antioxidant N-acetylcysteine (NAC) also showed the same effects as HT on LPS-induced ROS and NO generation, change of GSH level, and NF-kappaB activation. These findings suggest that HT has antioxidant activity to suppress intracellular oxidative stress and NF-kappaB activation in THP-1 cells.}, }
@article {pmid19335088, year = {2009}, author = {Toker, H and Ozdemir, H and Eren, K and Ozer, H and Sahin, G}, title = {N-acetylcysteine, a thiol antioxidant, decreases alveolar bone loss in experimental periodontitis in rats.}, journal = {Journal of periodontology}, volume = {80}, number = {4}, pages = {672-678}, doi = {10.1902/jop.2009.080509}, pmid = {19335088}, issn = {0022-3492}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Alveolar Bone Loss/etiology/*prevention &amp; control ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Dose-Response Relationship, Drug ; Male ; Osteoclasts/drug effects ; Periodontitis/complications ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: The purpose of this study was to analyze the morphometric and histopathologic changes associated with experimental periodontitis in rats in response to systemic administration of N-acetylcysteine (NAC).<br><br>METHODS: Forty-three Wistar rats were divided into five experimental groups: non-ligated (NL) group (n = 10), ligature only (LO) group (n = 10), and groups that were administered NAC systemically (7, 35, or 70 mg/kg body weight per day [NAC7, NAC35, and NAC70 groups, respectively]; n = 8, 9, and 6). Silk ligatures were placed at the gingival margin of the lower first molars in a mandibular quadrant. The study duration was 11 days, and the animals were sacrificed at the end of this period. Changes in alveolar bone levels were measured clinically and tissues were histopathologically examined to assess the differences among the study groups.<br><br>RESULTS: At the end of 11 days, the alveolar bone loss was significantly higher in the LO group compared to NL, NAC7, NAC35, and NAC70 groups (P <0.05). There was no statistically significant difference in the osteoclast numbers among the study groups (P >0.05), whereas the effect of NAC was dose-dependent.<br><br>CONCLUSION: NAC prevented alveolar bone loss in the rat model, in a dose-dependent manner, when administered systemically.}, }
@article {pmid19333788, year = {2009}, author = {Shenouda, SK and Varner, KJ and Carvalho, F and Lucchesi, PA}, title = {Metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes.}, journal = {Cardiovascular toxicology}, volume = {9}, number = {1}, pages = {30-38}, pmid = {19333788}, issn = {1559-0259}, support = {R01 HL063318/HL/NHLBI NIH HHS/United States ; R01 HL63318-05/HL/NHLBI NIH HHS/United States ; P20RR18766/RR/NCRR NIH HHS/United States ; R01 HL063318-05/HL/NHLBI NIH HHS/United States ; P20 RR018766-057610/RR/NCRR NIH HHS/United States ; P20 RR018766/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Calcium Signaling/drug effects ; Cells, Cultured ; Deoxyepinephrine/analogs &amp; derivatives/toxicity ; Dose-Response Relationship, Drug ; Glutathione/analogs &amp; derivatives/toxicity ; Heart Ventricles/drug effects/metabolism/physiopathology ; Male ; Myocardial Contraction/*drug effects ; Myocytes, Cardiac/*drug effects/metabolism ; N-Methyl-3,4-methylenedioxyamphetamine/metabolism/*toxicity ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Time Factors ; }, abstract = {Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) (ecstasy) produces eccentric left ventricular (LV) dilation and diastolic dysfunction. While the mechanism(s) underlying this toxicity are unknown, oxidative stress plays an important role. MDMA is metabolized into redox cycling metabolites that produce superoxide. In this study, we demonstrated that metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes. Metabolites of MDMA used in this study included alpha-methyl dopamine, N-methyl alpha-methyl dopamine and 2,5-bis(glutathion-S-yl)-alpha-MeDA. Dihydroethidium was used to detect drug-induced increases in reactive oxygen species (ROS) production in ventricular myocytes. Contractile function and changes in intracellular calcium transients were measured in paced (1 Hz), Fura-2 AM loaded, myocytes using the IonOptix system. Production of ROS in ventricular myocytes treated with MDMA was not different from control. In contrast, all three metabolites of MDMA exhibited time- and concentration-dependent increases in ROS that were prevented by N-acetyl-cysteine (NAC). The metabolites of MDMA, but not MDMA alone, significantly decreased contractility and impaired relaxation in myocytes stimulated at 1 Hz. These effects were prevented by NAC. Together, these data suggest that MDMA-induced oxidative stress in the left ventricle can be due, at least in part, to the metabolism of MDMA to redox active metabolites.}, }
@article {pmid19332996, year = {2009}, author = {Johnson, ST and Bigam, DL and Emara, M and Slack, G and Jewell, LD and Obaid, L and Korbutt, G and Van Aerde, J and Cheung, PY}, title = {Effects of N-acetylcysteine on intestinal reoxygenation injury in hypoxic newborn piglets resuscitated with 100% oxygen.}, journal = {Neonatology}, volume = {96}, number = {3}, pages = {162-170}, doi = {10.1159/000210089}, pmid = {19332996}, issn = {1661-7819}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Animals, Newborn ; Antioxidants/*therapeutic use ; Disease Models, Animal ; Enterocolitis/*drug therapy/metabolism/pathology ; Hypoxia/complications/*drug therapy/metabolism ; Ileum/drug effects/pathology ; Oxygen/*adverse effects ; Oxygen Inhalation Therapy ; Reperfusion Injury/*drug therapy/metabolism/pathology ; Splanchnic Circulation/drug effects ; Swine ; }, abstract = {BACKGROUND: Neonatal asphyxia may lead to the development of ischemia-reperfusion induced intestinal injury, which is related to oxygen-derived free radical production. N-Acetylcysteine (NAC) is a thiol-containing antioxidant which increases intracellular stores of glutathione.<br><br>OBJECTIVES: Using a swine model of neonatal hypoxia-reoxygenation, we examined whether administration of NAC after resuscitation improved intestinal perfusion and reduced intestinal damage.<br><br>METHODS: Twenty-four piglets (1-4 days old, 1.4-2.2 kg) were anesthetized and acutely instrumented for continuous monitoring of superior mesenteric arterial flow and oxygen delivery. Alveolar hypoxia was induced for 2 h, followed by resuscitation with 100% oxygen for 1 h and 21% oxygen for 3 h. Animals were randomized to sham-operated, hypoxic control and NAC treatment (150 mg/kg i.v. at 0 or 10 min of reoxygenation followed by infusion 100 mg/kg/h) groups. During hypoxia-reoxygenation, intestinal tissue glutathione content, caspase-3 activity and reoxygenation injury were examined.<br><br>RESULTS: After 2 h of hypoxia, piglets were acidotic and hypotensive, with significantly depressed blood flow and oxygen delivery to the small intestine. Upon reoxygenation, hemodynamics recovered as did oxygen supply to the small intestine. After 4 h of reoxygenation, the NAC treatment improved mesenteric flow and oxygen delivery. Despite reducing the increase in caspase-3 activities after hypoxia-reoxygenation by NAC treatment, no significant differences in the glutathione content and histological grading of ileal injury were found among the experimental groups.<br><br>CONCLUSIONS: In newborn piglets with hypoxia-reoxygenation, NAC may improve mesenteric blood flow and oxygen delivery without significant effect on tissue glutathione content. The protective role of NAC in the reoxygenated intestine after severe hypoxia warrants further investigation.}, }
@article {pmid19330623, year = {2009}, author = {Kim, D and Kim, YJ and Seo, JN and Kim, J and Lee, Y and Park, CS and Kim, DW and Kim, DS and Kwon, HJ}, title = {2,4-Dinitrofluorobenzene modifies cellular proteins and induces macrophage inflammatory protein-2 gene expression via reactive oxygen species production in RAW 264.7 cells.}, journal = {Immunological investigations}, volume = {38}, number = {2}, pages = {132-152}, doi = {10.1080/08820130802667499}, pmid = {19330623}, issn = {1532-4311}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/pharmacology ; Cell Line ; Cell Survival/drug effects/immunology ; Chemokine CXCL2/*genetics ; Dermatitis, Contact/*immunology ; Dinitrofluorobenzene/*toxicity ; Free Radical Scavengers/pharmacology ; Gene Expression/*drug effects ; Hypersensitivity, Delayed/*immunology ; Mice ; Mitogen-Activated Protein Kinases/biosynthesis ; Peroxidase/pharmacology ; Proteins/*drug effects/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Skin/*drug effects/immunology/metabolism ; Vitamins/pharmacology ; }, abstract = {The skin sensitizer 2,4-dinitrofluorobenzene (DNFB) provokes delayed hypersensitivity responses as a result of topical application to the skin. Here, we demonstrate that DNFB modifies proteins in RAW 264.7 cells and skin tissues in NC/Nga mice; we also show the functional involvement of DNFB-induced modification of cellular proteins in the DNFB-induced macrophage inflammatory protein (MIP)-2 gene expression in RAW 264.7 cells. In addition, we demonstrate that DNFB strongly induces reactive oxygen species (ROS) production. Our RT-PCR analysis and reporter gene assays reveal that the DNFB-induced intracellular ROS production is necessary for MIP-2 gene expression by DNFB. We observed that the vitamin C and chemical oxidant scavenger N-acetyl-cysteine have an inhibitory effect on the generation of ROS, the activation of MAP kinase pathways, and the MIP-2 gene expression in DNFB-treated RAW 264.7 cells. These results provide insight into the mechanisms involved in DNFB-induced contact hypersensitivity.}, }
@article {pmid19329757, year = {2009}, author = {Kowalczyk, MC and Walaszek, Z and Kowalczyk, P and Kinjo, T and Hanausek, M and Slaga, TJ}, title = {Differential effects of several phytochemicals and their derivatives on murine keratinocytes in vitro and in vivo: implications for skin cancer prevention.}, journal = {Carcinogenesis}, volume = {30}, number = {6}, pages = {1008-1015}, pmid = {19329757}, issn = {1460-2180}, support = {P30 CA 54174-1651/CA/NCI NIH HHS/United States ; R01 CA 102747/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Anticarcinogenic Agents/*pharmacology/therapeutic use ; Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use ; Aryl Hydrocarbon Hydroxylases/metabolism ; Carotenoids/pharmacology/therapeutic use ; Cell Line ; Cell Line, Tumor ; Cell Transformation, Neoplastic/drug effects/metabolism/pathology ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP1B1 ; Ellagic Acid/pharmacology/therapeutic use ; Female ; Free Radical Scavengers/*pharmacology/therapeutic use ; Free Radicals/metabolism ; Genes, ras ; Keratinocytes/*drug effects/metabolism ; Lycopene ; Mice ; Mutation ; Plant Extracts/*pharmacology/therapeutic use ; Proto-Oncogene Proteins p21(ras)/genetics ; Resveratrol ; Skin Neoplasms/metabolism/*prevention &amp; control ; Stilbenes/pharmacology/therapeutic use ; Triterpenes/pharmacology/therapeutic use ; Vitis/chemistry ; Ursolic Acid ; }, abstract = {The purpose of our study was to investigate in vitro the potential cancer preventive properties of several phytochemicals, i.e. grape seed extract (GSE), resveratrol (RES), ursolic acid (URA), ellagic acid (ELA), lycopene and N-acetyl-L-cysteine (NAC) to define the mechanisms by which these compounds may inhibit murine skin carcinogenesis. We measured quenching of peroxyl, superoxide and hydroxyl radicals by these phytochemicals. We also used adenosine triphosphate (ATP) bioluminescence, Caspase-Glo 3/7 and P450-Glo (CYP1A1 and CYP1B1) assays to study antiproliferative, proapoptotic and CYP-inhibiting effects of the phytochemicals. We next determined their effects on a 4 week inflammatory hyperplasia assay using 7,12-dimethylbenz[a]anthracene-induced murine skin carcinogenesis model to further understand their mechanism of action. Three murine keratinocyte cell lines, i.e. non-tumorigenic (3PC), papilloma-derived (MT1/2) and squamous cell carcinoma-derived (Ca3/7) cell lines, were used in in vitro assays. We have found that GSE, ELA and RES are potent scavengers of peroxyl and superoxide radicals. Statistically significant effects on activities of caspase-3 and -7 were observed only after GSE and URA treatments. All tested compounds protected cells from hydrogen peroxide-induced DNA damage. Using a short-term complete carcinogenesis assay, we have found that all selected compounds caused marked decreases of epidermal thickness and (except RES) reduced percentages of mice with mutation in codon 61 of Ha-ras oncogene. In conclusion, differential effects of tested phytochemicals on events and processes critical for the growth inhibition of keratinocytes in vitro and in vivo indicate that combinations of tested compounds may, in the future, better counteract both tumor initiation and tumor promotion/progression.}, }
@article {pmid19327972, year = {2010}, author = {Colbay, M and Yuksel, S and Uslan, I and Acarturk, G and Karaman, O and Bas, O and Mollaoglu, H and Yagmurca, M and Ozen, OA}, title = {Novel approach for the prevention of contrast nephropathy.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {62}, number = {1}, pages = {81-89}, doi = {10.1016/j.etp.2009.02.119}, pmid = {19327972}, issn = {1618-1433}, mesh = {Acetylcysteine/pharmacology ; Animals ; Caffeic Acids/*pharmacology ; Catalase/analysis ; Contrast Media/*adverse effects ; Creatinine/blood ; Glutathione Peroxidase/analysis ; Kidney/chemistry/*drug effects/pathology ; Male ; Malondialdehyde/analysis ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; Rats ; Rats, Sprague-Dawley ; Renal Insufficiency/chemically induced/pathology/prevention &amp; control ; Superoxide Dismutase/analysis ; }, abstract = {OBJECTIVE: To date, there is no effective treatment of contrast medium (CM)-induced nephropathy. Multiple studies documented a protective role of hydration and N-acetylcystein (NAC) as prophylactic agents against CM-induced nephropathy in a high-risk population. In the present study, we investigated a new antioxidant agent, caffeic acid phenethyl ester (CAPE), and compare with NAC against contrast nephropathy.<br><br>METHODS: Forty-two adult male rats were divided into six experimental groups, which were control, injected with intravenous (i.v.) CM, injected with i.p. CAPE, injected with i.p. NAC, injected with i.v. CM pretreated with i.p. CAPE, injected with i.v. CM pretreated with i.p. NAC. CAPE and NAC were given daily throughout the study. All rats were deprived of water for 24h at the third day of the study and then contrast medium was administered to CM, CAPECM and NACCM groups. The rats were sacrificed at the fifth day. Oxidant-antioxidant status was determined in renal tissues. The severity of injury was scored with a light microscope in renal tissue. Plasma creatinine levels were measured.<br><br>RESULTS: Renal injury scores were higher in CAPECM and NACCM groups than in control, CAPE and NAC groups, but lower than the CM group. Likewise, creatinine levels of CAPECM and NACCM groups were higher than the control groups but they were significantly lower than the level of the CM group. Creatinine levels of the NACCM group were significantly higher than the CAPECM group. Malondialdehyde levels were significantly lower in CAPECM and NACCM groups than the CM group.<br><br>CONCLUSION: CAPE might protect renal structure and functions as well as NAC against CM injury.}, }
@article {pmid19326266, year = {2009}, author = {Sue, YM and Chen, CH and Hsu, YH and Hou, CC and Cheng, CY and Chen, YC and Lin, SL and Chen, TW and Chen, TH}, title = {Urotensin II induces transactivation of the epidermal growth factor receptor via transient oxidation of SHP-2 in the rat renal tubular cell line NRK-52E.}, journal = {Growth factors (Chur, Switzerland)}, volume = {27}, number = {3}, pages = {155-162}, doi = {10.1080/08977190902879866}, pmid = {19326266}, issn = {1029-2292}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; ErbB Receptors/*metabolism ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/metabolism ; Flavonoids/pharmacology ; Humans ; Kidney Tubules, Proximal/cytology/drug effects/*metabolism ; Oxidation-Reduction ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/*metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Transcriptional Activation ; Urotensins/pharmacology/*physiology ; }, abstract = {Urotensin-II (UII) is a potent vasoactive peptide that has been implicated in cardiac fibrosis and renal diseases. However, the role played by UII in renal tissues is largely unknown. In this study, we investigated the effects of human UII (hUII) on rat renal proximal tubular cells of the NRK-52E line and the role of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) in the hUII-induced transactivation of the epidermal growth factor receptor (EGFR). Exposure to hUII at low concentrations significantly induced proliferation in NRK-52E cells; this effect was inhibited by treatment with an ERK1/2 inhibitor (PD98059). UII treatment increased the phosphorylation of EGFR and induced the generation of reactive oxygen species (ROS). Treatment of the ROS scavenger N-acetyl-cysteine (NAC) inhibited EGFR transactivation and ERK phosphorylation induced by hUII. SHP-2 was found to interact with EGFR and be transiently oxidized following the hUII treatment. In SHP-2 knockdown cells, UII-induced phosphorylation of EGFR was less influenced by NAC, and significantly suppressed by heparin binding (HB)-EGF neutralizing antibody. Our data suggest that the ROS-mediated oxidation of SHP-2 is essential for the hUII-induced mitogenic pathway in NRK-52E cells.}, }
@article {pmid19308849, year = {2009}, author = {Meszka-Jordan, A and Mahlapuu, R and Soomets, U and Carlson, GP}, title = {Oxidative stress due to (R)-styrene oxide exposure and the role of antioxidants in non-Swiss albino (NSA) mice.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {72}, number = {10}, pages = {642-650}, doi = {10.1080/15287390902769436}, pmid = {19308849}, issn = {1528-7394}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/*pharmacology ; Bronchoalveolar Lavage Fluid/cytology ; Cell Count ; Chemical and Drug Induced Liver Injury/pathology ; Epoxy Compounds/chemistry/*toxicity ; Glutathione/metabolism ; L-Iditol 2-Dehydrogenase/metabolism ; L-Lactate Dehydrogenase/metabolism ; Lung Diseases/chemically induced/pathology ; Male ; Mice ; Oxidative Stress/*drug effects ; Quinolines/pharmacology ; Reactive Oxygen Species/metabolism ; Stereoisomerism ; Trans-Activators/metabolism ; }, abstract = {Styrene produces lung and liver damage that may be related to oxidative stress. The purpose of this study was to investigate the toxicity of (R)-styrene oxide (R-SO), the more active enantiomeric metabolite of styrene, and the protective properties of the antioxidants glutathione (GSH), N-acetylcysteine (NAC), and 4-methoxy-L-tyrosinyl-gamma-L-glutamyl-L-cysteinyl-glycine (UPF1) against R-SO-induced toxicity in non-Swiss Albino (NSA) mice. UPF1 is a synthetic GSH analog that was shown to have 60 times the ability to scavenge reactive oxygen species (ROS) in comparison to GSH. R-SO toxicity to the lung was measured by elevations in the activity of lactate dehydrogenase (LDH), protein concentration, and number of cells in bronchoalveolar lavage fluid (BALF). Toxicity to the liver was measured by increases in serum sorbitol dehydrogenase (SDH) activity. Antioxidants were not able to decrease the adverse effects of R-SO on lung. However, NAC (200 mg/kg) ip and GSH (600 mg/kg), administered orally prior to R-SO (300 mg/kg) ip, showed significant protection against liver toxicity as measured by SDH activity. Unexpectedly, a synthetic GSH analog, UPF1 (0.8 mg/kg), administered intravenously (iv) prior to R-SO, produced a synergistic effect with regard to liver and lung toxicity. Treatment with UPF1 (0.8 mg/kg) iv every other day for 1 wk for preconditioning prior to R-SO ip did not result in any protection against liver and lung toxicity, but rather enhanced the toxicity when administered prior R-SO. The results of the present study demonstrated protection against R-SO toxicity in liver but not lung by the administration of the antioxidants NAC and GSH.}, }
@article {pmid19303139, year = {2009}, author = {Tsukimura, N and Yamada, M and Aita, H and Hori, N and Yoshino, F and Chang-Il Lee, M and Kimoto, K and Jewett, A and Ogawa, T}, title = {N-acetyl cysteine (NAC)-mediated detoxification and functionalization of poly(methyl methacrylate) bone cement.}, journal = {Biomaterials}, volume = {30}, number = {20}, pages = {3378-3389}, doi = {10.1016/j.biomaterials.2009.02.043}, pmid = {19303139}, issn = {1878-5905}, mesh = {Acetylcysteine/*chemistry/metabolism ; Animals ; Biocompatible Materials/*chemistry/metabolism ; Bone Cements/*chemistry/metabolism ; Bone Regeneration/physiology ; Bone and Bones/cytology/metabolism/pathology ; Calcification, Physiologic ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Humans ; Male ; Materials Testing ; Osteoblasts/cytology/metabolism ; Phenotype ; Polymethyl Methacrylate/*chemistry/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Currently used poly(methyl methacrylate) (PMMA)-based bone cement lacks osteoconductivity and induces osteolysis and implant loosening due to its cellular and tissue-toxicity. A high percentage of revision surgery following the use of bone cement has become a significant universal problem. This study determined whether incorporation of the amino acid derivative N-acetyl cysteine (NAC) in bone cement reduces its cytotoxicity and adds osteoconductivity to the material. Biocompatibility and bioactivity of PMMA-based bone cement with or without 25mm NAC incorporation was examined using rat bone marrow-derived osteoblastic cells. Osteoconductive potential of NAC-incorporated bone cement was determined by microCT bone morphometry and implant biomechanical test in the rat model. Generation of free radicals within the polymerizing bone cement was examined using electron spin resonance spectroscopy. Severely compromised viability and completely suppressed phenotypes of osteoblasts on untreated bone cement were restored to the normal level by NAC incorporation. Bone volume formed around 25mm NAC-incorporated bone cement was threefold greater than that around control bone cement. The strength of bone-bone cement integration was 2.2 times greater for NAC-incorporated bone cement. For NAC-incorporated bone cement, the spike of free radical generation ended within 12h, whereas for control bone cement, a peak level lasted for 6 days and a level greater than half the level of the peak was sustained for 20 days. NAC also increased the level of antioxidant glutathione in osteoblasts. These results suggest that incorporation of NAC in PMMA bone cement detoxifies the material by immediate and effective in situ scavenging of free radicals and increasing intracellular antioxidant reserves, and consequently adds osteoconductivity to the material.}, }
@article {pmid19302592, year = {2009}, author = {Yip, KH and Leung, FP and Huang, Y and Lau, HY}, title = {Inhibition of anti-IgE mediated human mast cell activation by NO donors is dependent on their NO release kinetics.}, journal = {British journal of pharmacology}, volume = {156}, number = {8}, pages = {1279-1286}, pmid = {19302592}, issn = {1476-5381}, mesh = {Acetylcysteine/pharmacology ; Anti-Allergic Agents/metabolism/*pharmacology ; Anti-Inflammatory Agents/metabolism/*pharmacology ; Antibodies ; Antioxidants/pharmacology ; Benzoates/pharmacology ; Cell Degranulation/*drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Histamine Release/*drug effects ; Humans ; Hydrazines/metabolism/pharmacology ; Imidazoles/pharmacology ; Immunoglobulin E/*immunology ; Kinetics ; Mast Cells/*drug effects/immunology/metabolism ; Nitric Oxide/*metabolism ; Nitric Oxide Donors/metabolism/*pharmacology ; Nitroprusside/metabolism/pharmacology ; S-Nitroso-N-Acetylpenicillamine/metabolism/pharmacology ; Superoxide Dismutase/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Although the mast cell is a source of nitric oxide (NO), the effect of NO on human mast cells has not been defined. This study investigated if exogenous NO could affect human mast cell activation.<br><br>EXPERIMENTAL APPROACH: Effects of different NO donors on immunoglobulin E (IgE)-dependent activation of human-cultured mast cells (HCMC) derived from precursors in buffy coat were investigated by measuring histamine release. Intracellular NO in HCMC was monitored with confocal microscopy using the fluorescent NO indicator 4-amino-5-methylamino-2', 7'-difluorofluorescein.<br><br>KEY RESULTS: Diethylamine NONOate (DEA/NO) and MAHMA NONOate (NOC-9), both have rapid NO release rates, only inhibited anti-IgE-induced histamine release when added to HCMC at the time of activation. NO donors with slower NO release kinetics were ineffective even after 30 min incubation. Confocal microscopy revealed that the effectiveness of NO donors was dependent on the availability of adequate NO inside HCMC during activation. The inhibitory action of DEA/NO was diminished by the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl but potentiated by the anti-oxidant, N-acetylcysteine (NAC). Furthermore, co-incubation with NAC allowed previously ineffective NO donors to suppress HCMC activation and thus suggested that NAC could increase the availability of NO from NO donors.<br><br>CONCLUSIONS AND IMPLICATIONS: Our results demonstrated that NO was able to modulate human mast cell activation but only when enough NO was present at the time of cell activation. Our findings explain the controversy over the effectiveness of NO on mast cell degranulation and supports the possibility that NO donors could be beneficial for treating allergic inflammation.}, }
@article {pmid19298701, year = {2009}, author = {Kinoshita, A and Kobayashi, D and Saitoh, Y and Komada, F}, title = {Effects of anticancer agents and scavengers on CMV-promoter-driven exogenous gene expression in genetically modified cells.}, journal = {The Journal of pharmacy and pharmacology}, volume = {61}, number = {4}, pages = {527-531}, doi = {10.1211/jpp/61.03.0016}, pmid = {19298701}, issn = {0022-3573}, mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage/*pharmacology ; Cell Line, Transformed ; Cytomegalovirus/*genetics ; Fibroblasts/*metabolism ; Fluorescence ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Gene Expression/drug effects ; *Gene Transfer Techniques ; Genetic Vectors ; Green Fluorescent Proteins/*genetics ; Promoter Regions, Genetic ; RNA, Messenger/metabolism ; Rats ; Transfection ; }, abstract = {OBJECTIVES: This study aimed to investigate whether the levels of rsGFP mRNA and the fluorescence levels of cytomegalovirus (CMV)-promoter-driven rsGFP (red-shifted green fluorescent protein) could be changed by using anticancer agents and also to examine the effects of co-treatment with anticancer agents and scavengers.<br><br>METHODS: The pQBI25 vector, which encodes the CMV promoter and the cDNA for rsGFP, was transfected into FR cells (rat skin fibroblast cell line). FR-pQBI25 cells were then exposed to doxorubicin, 5-fluorouracil, methotrexate or paraquat with or without scavengers such as N-acetyl cysteine (NAC) and edaravone for 48 h.<br><br>KEY FINDINGS: The levels of rsGFP mRNA were found to be significantly higher following doxorubicin, 5-fluorouracil and paraquat treatment but were not changed by methotrexate. These levels of rsGFP mRNA were found to be significantly lower after paraquat/edaravone co-treatment compared with paraquat alone. The fluorescence levels of rsGFP were found to be significantly higher following doxorubicin and paraquat treatment but were not changed by 5-fluorouracil and methotrexate. The levels were also found to be significantly lower after paraquat/edaravone co-treatment compared with paraquat alone and also after doxorubicin/NAC co-treatment compared with doxorubicin alone.<br><br>CONCLUSIONS: These findings suggest that CMV-promoter-driven exogenous gene expression may be partly regulated by reactive oxygen species.}, }
@article {pmid19298655, year = {2009}, author = {Kourtidis, A and Srinivasaiah, R and Carkner, RD and Brosnan, MJ and Conklin, DS}, title = {Peroxisome proliferator-activated receptor-gamma protects ERBB2-positive breast cancer cells from palmitate toxicity.}, journal = {Breast cancer research : BCR}, volume = {11}, number = {2}, pages = {R16}, pmid = {19298655}, issn = {1465-542X}, mesh = {Apoptosis/*drug effects ; Breast Neoplasms/*metabolism/*pathology ; Cell Proliferation/*drug effects ; Fluorescent Antibody Technique ; Humans ; PPAR gamma/*metabolism ; Palmitates/*pharmacology ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Receptor, ErbB-2/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured/drug effects ; }, abstract = {INTRODUCTION: Accumulation of fatty acids and neutral lipids in nonadipose tissues is cytotoxic. We recently showed that ERBB2-positive breast cancer cells produce significantly high amounts of fats, because of overexpression of the peroxisome proliferator-activated receptor (PPAR)gamma-binding protein and the nuclear receptor NR1D1 (nuclear receptor subfamily 1, group D, member 1; Rev-erbalpha). These genes upregulate de novo fatty acid synthesis, which is a critical pathway for the energy production and survival of these cells. NR1D1 and PPARgamma-binding protein are functionally related to PPARgamma, a well established positive regulator of adipogenesis and lipid storage.<br><br>METHODS: The effects of GW9662 and exogenously added palmitate on breast cells (BT474, MDA-MB-361, MCF-7, and human mammary epithelial cells) in monolayer culture were assessed. Mass spectrometric quantitation of fatty acids and fluorescence-based high content microscopy assays of cell growth, apoptosis, triglyceride storage and reactive oxygen species production were used.<br><br>RESULTS: ERBB2-positive breast cancer cells are more sensitive to inhibition of PPARgamma activity by the antagonist GW9662. PPARgamma inhibition results in increased levels of total fats in the cells, mostly because of increased amounts of palmitic and stearic unsaturated acids. Administration of exogenous palmitate is lethal to ERBB2-positive but not to ERBB2-negative cells. GW9662 exacerbates the effects of palmitate addition on BT474 and MDA-MB-361 cells, but it has no significant effect on MCF-7 and human mammary epithelial cells. Palmitate administration results in a fivefold to tenfold greater increase in fat stores in ERBB2-negative cells compared with ERBB2-positive cells, which suggests that the ERBB2-positive cells have maximized their ability to store fats and that additional palmitate is toxic to these cells. Both PPARgamma inhibition and palmitate administration result in increased reactive oxygen species production in BT474 cells. The cell death that results from this treatment can be counteracted by the antioxidant N-acetyl cysteine.<br><br>CONCLUSIONS: Our findings indicate that PPARgamma activity enables ERBB2-positive breast cancer cells, which produce high levels of fat, to convert fatty acids to triglycerides, allowing these cells to avert the cell death that results from lipotoxicity. Endogenous palmitate toxicity represents a genetically based property of ERBB2-positive breast cancer that can be exploited for therapeutic intervention.}, }
@article {pmid19291423, year = {2009}, author = {Banerjee Mustafi, S and Chakraborty, PK and Dey, RS and Raha, S}, title = {Heat stress upregulates chaperone heat shock protein 70 and antioxidant manganese superoxide dismutase through reactive oxygen species (ROS), p38MAPK, and Akt.}, journal = {Cell stress &amp; chaperones}, volume = {14}, number = {6}, pages = {579-589}, pmid = {19291423}, issn = {1466-1268}, mesh = {Acetylcysteine ; Animals ; Cell Line ; Cricetinae ; Cricetulus ; DNA-Binding Proteins/metabolism ; Fibroblasts/physiology ; Free Radical Scavengers/metabolism ; HSP70 Heat-Shock Proteins/*metabolism ; Heat Shock Transcription Factors ; Heat-Shock Response/*physiology ; Imidazoles ; Phosphorylation/physiology ; Proto-Oncogene Proteins c-akt/genetics/*metabolism ; Pyridines ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Superoxide Dismutase/*metabolism ; Transcription Factors/metabolism ; Up-Regulation/physiology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/*metabolism ; }, abstract = {Chinese hamster lung fibroblasts V79 cells were treated with heat stress for 4 weeks with short duration (15 min) heat shock every alternate day in culture. It was observed that Hsp 70 and the antioxidant enzyme MnSOD became overexpressed during the chronic heat stress period. Both p38 MAPK and Akt became phosphorylated by chronic heat stress exposure. Simultaneous exposure to SB203580, a potent and specific p38MAPK inhibitor drastically inhibited the phosphorylation of p38MAPK and Akt. Furthermore, exposure to SB203580 also blocked the increase in Hsp70 and MnSOD levels and the elevated SOD activity brought about by chronic heat stress. Heat shock factor 1 (HSF1) transcriptional activity and nuclear translocation of HSF1 were prominently augmented by chronic heat stress, and this amplification is markedly reduced by concomitant exposure to SB203580. Also, activations of p38MAPK and Akt and upregulations of Hsp70 and MnSOD were observed on exposure to heat shock for a single exposure of longer duration (40 min). siRNA against p38MAPK notably reduced Akt phosphorylation by single exposure to heat stress and drastically diminished the rise in Hsp70 and MnSOD levels. Similarly, siRNA against Akt also eliminated the augmentation in Hsp70 and MnSOD levels but p38MAPK levels remained unaffected. Heat stress produced reactive oxygen species (ROS) in V79 fibroblasts. N-acetyl cysteine blocked the increase in phosphorylation of p38MAPK, amplification of Hsp70, and MnSOD levels by heat stress. Therefore, we conclude that heat stress-activated p38MAPK which in turn activated Akt. Akt acted downstream of p38MAPK to increase Hsp70 and MnSOD levels.Concise summary: Thermal injury of the skin over a long period of time has been associated with development of cancerous lesions. Also, in many cancers, the cytoprotective genes Hsp70 and MnSOD have been found to be overexpressed. Therefore, we considered it important to identify the signaling elements upstream of the upregulated survival genes in heat stress. We conclude that heat stress activated p38MAPK which in turn activated Akt. Akt mediated an augmentation in Hsp70 and MnSOD levels working downstream of p38MAPK.}, }
@article {pmid19290682, year = {2009}, author = {Puerto, M and Prieto, AI and Pichardo, S and Moreno, I and Jos, A and Moyano, R and Cameán, AM}, title = {Effects of dietary N-acetylcysteine on the oxidative stress induced in tilapia (Oreochromis niloticus) exposed to a microcystin-producing cyanobacterial water bloom.}, journal = {Environmental toxicology and chemistry}, volume = {28}, number = {8}, pages = {1679-1686}, doi = {10.1897/08-520.1}, pmid = {19290682}, issn = {0730-7268}, mesh = {Acetylcysteine/*pharmacology ; Animal Feed ; Animals ; Antioxidants ; Cichlids/*metabolism ; Cyanobacteria/*metabolism ; Diet/veterinary ; Dietary Supplements ; Dose-Response Relationship, Drug ; Fish Diseases/chemically induced ; Glutathione ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Male ; Microcystins/*toxicity ; Oxidative Stress/*drug effects ; Water/chemistry ; }, abstract = {Fish can be exposed to toxic cyanobacterial cells in natural waters and fish farms and suffer from oxidative damage. The present study investigates the effects of N-acetylcysteine (NAC), a glutathione (GSH) precursor, on the oxidative stress induced by Microcystis cyanobacterial cells containing microcystins (MCs) in tilapia fish (Oreochromis niloticus). Variation in lipid peroxidation (LPO) levels, carbonyl group content, reduced glutathione to oxidized glutathione ratio (GSH:GSSG), and catalase (Enzyme Commission [EC] 1.11.1.6), superoxide dismutase (SOD; EC 1.15.1.1), glutathione reductase (GR; EC 1.8.1.7), glutathione peroxidase (GPx; EC 1.11.1.9), and glutathione S-transferase (EC 2.5.1.18) activities in liver and kidney of tilapia exposed to a single oral dose of 120 microg MC-LR (with leucine [L] and arginine [R])/fish and killed in 24 h were investigated in the absence and presence of 20.0, 44.0, and 96.8 mg NAC/fish/d. Results showed a protective role of NAC, depending on the dose and the biomarker considered. The increase in LPO (1.9- and 1.4-fold in liver and kidney, respectively) and the decreased protein content and GSH: GSSG in the liver induced by MCs were recovered mainly by the lower doses of NAC employed. Antioxidant enzyme activities increased (range, 1.4- to 1.7-fold) by MCs also were ameliorated by NAC, although the highest level used induced significant alteration of some enzymatic activities, such as SOD, GPx, and GR. Thus, NAC can be considered to be a useful chemoprotectant that reduces hepatic and renal oxidative stress in the prophylaxis and treatment of MC-related intoxications in fish when careful attention is given to its application dose because of its own pro-oxidant activity, as shown in the present study at 96.8 mg NAC/fish/d.}, }
@article {pmid19286926, year = {2009}, author = {Moretto, N and Facchinetti, F and Southworth, T and Civelli, M and Singh, D and Patacchini, R}, title = {alpha,beta-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {296}, number = {5}, pages = {L839-48}, doi = {10.1152/ajplung.90570.2008}, pmid = {19286926}, issn = {1040-0605}, mesh = {Acetylcysteine/pharmacology ; Aged ; Aldehydes/*pharmacology ; Cell Survival/drug effects ; Epithelial Cells/cytology/drug effects/*metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Fibroblasts/cytology/drug effects/enzymology/*metabolism ; Humans ; Interleukin-8/*metabolism ; Lung/*cytology ; Macrophages/cytology/drug effects/metabolism ; Male ; Mesna/pharmacology ; Middle Aged ; Mitogen-Activated Protein Kinases/*metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; *Smoking ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD), a syndrome characterized by pulmonary neutrophil infiltration, chronic inflammation, and progressive tissue destruction. We examined here the acute effect of aqueous cigarette smoke extract (CSE) and of two alpha,beta-unsaturated aldehydes (acrolein and crotonaldehyde) contained in CSE in cultured normal human lung fibroblasts and small airway epithelial cells. By examining a panel of 19 cytokines and chemokines, we found that IL-8 release was elevated by CSE as well as by acrolein, whereas other inflammatory mediators were mostly unaffected. CSE-evoked IL-8 release was mimicked by acrolein and crotonaldehyde at concentrations (3-60 microM each) found in CSE and fully prevented by 1 mM alpha,beta-unsaturated aldehydes scavengers N-acetylcysteine (NAC) or sodium 2-mercaptoethanesulfonate. Neither the saturated aldehyde acetaldehyde nor H(2)O(2) evoked IL-8 release. In addition, CSE or crotonaldehyde upregulated the release of IL-8 from alveolar macrophages from both COPD patients and healthy nonsmokers, indicating that this is a response common to cells involved in lung inflammation. CSE-evoked IL-8 release was accompanied by increased phosphorylation of p38 MAPK and ERK1/2. CSE-evoked p38 and ERK1/2 phosphorylation was mimicked by acrolein and inhibited by NAC. IL-8 release elicited by both acrolein and CSE was blocked by pharmacological inhibition of p38 and ERK1/2 phosphorylation. In summary, our data show that alpha,beta-unsaturated aldehydes-evoked phosphorylation of p38 and ERK1/2 underlies IL-8 release elicited by CSE, thus shedding light on the mechanisms through which cigarette smoke can initiate inflammation in the lung.}, }
@article {pmid19282300, year = {2009}, author = {Adabag, AS and Ishani, A and Bloomfield, HE and Ngo, AK and Wilt, TJ}, title = {Efficacy of N-acetylcysteine in preventing renal injury after heart surgery: a systematic review of randomized trials.}, journal = {European heart journal}, volume = {30}, number = {15}, pages = {1910-1917}, pmid = {19282300}, issn = {1522-9645}, support = {DK063300-01A2/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*prevention &amp; control ; Aged ; Antioxidants/*therapeutic use ; Female ; Humans ; Male ; Perioperative Care ; Randomized Controlled Trials as Topic ; Risk Factors ; Thoracic Surgical Procedures/*adverse effects ; Treatment Outcome ; }, abstract = {AIMS: The aim of this study was to assess whether perioperative N-acetylcysteine (NAC), an antioxidant, prevents acute renal injury (ARI) after cardiac surgery.<br><br>METHODS AND RESULTS: We performed a systematic review of randomized controlled trials (RCTs) of NAC in adult cardiac surgery patients. The RCTs were identified by searching MEDLINE (1960-2008), clinicaltrials.gov website, and hand-searching references of relevant publications. Primary outcome was ARI (absolute increase >0.5 mg/dL or relative increase >25%, in serum creatinine from baseline within 5 days after surgery). Random effects model was used to perform a meta-analysis. Forest plots and I(2) test were used to assess heterogeneity among studies. Ten RCTs (n = 1163 patients) were included. Mean age was 70 +/- 7.4 years, 71% were male, and 66% underwent coronary artery bypass surgery. N-Acetylcysteine did not reduce ARI incidence [35% NAC vs. 37% placebo; relative risk (RR) 0.91, 95% CI 0.79-1.06, P = 0.24]. Overall, 3.3% of patients required haemodialysis (NAC vs. placebo; RR = 1.13, 95% CI 0.59-2.17) and 3% died (RR = 1.10, 95% CI 0.56-2.16). There was a trend towards reduced ARI incidence among patients with baseline chronic kidney disease assigned to intravenous NAC (RR = 0.80, 95% CI 0.64-1.01, P = 0.06).<br><br>CONCLUSION: This meta-analysis of RCTs showed that prophylactic perioperative NAC in cardiac surgery does not reduce ARI, haemodialysis, or death.}, }
@article {pmid19282043, year = {2010}, author = {Ozaydin, M and Turker, Y and Peker, O and Erdogan, D and Varol, E and Dogan, A and Ibrisim, E}, title = {Association between the use of non-antiarrhythmic drugs and postoperative atrial fibrillation.}, journal = {International journal of cardiology}, volume = {144}, number = {2}, pages = {304-306}, doi = {10.1016/j.ijcard.2009.02.029}, pmid = {19282043}, issn = {1874-1754}, mesh = {Acetylcysteine/therapeutic use ; Angiotensin Receptor Antagonists/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Atrial Fibrillation/*drug therapy/*etiology ; Cardiac Surgical Procedures/*adverse effects ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Male ; Middle Aged ; }, abstract = {PURPOSE: To evaluate the association between statins, N-acetylcysteine (NAC) and angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) and postoperative atrial fibrillation (AF).<br><br>METHODS: A total of 590 patients undergoing coronary artery bypass and/or valve surgery were studied. An AF episode lasting >5 min during hospitalization was accepted as endpoint.<br><br>RESULTS: AF rate was 18% (n=106). Multivariable positive predictors of AF included age &#x2265; 65, left atrial diameter &#x2265; 45 mm, cross clamp time; negative predictors included use of left internal mammarian artery, NAC, and ACEIs or ARBs.<br><br>CONCLUSIONS: ACEIs or ARBs and NAC is associated with low incidence of postoperative AF, however, this association was not found with statin or combined use these agents.}, }
@article {pmid19277967, year = {2009}, author = {Gere-Pászti, E and Jakus, J}, title = {The effect of N-acetylcysteine on amphetamine-mediated dopamine release in rat brain striatal slices by ion-pair reversed-phase high performance liquid chromatography.}, journal = {Biomedical chromatography : BMC}, volume = {23}, number = {6}, pages = {658-664}, doi = {10.1002/bmc.1171}, pmid = {19277967}, issn = {1099-0801}, mesh = {Acetylcysteine/*pharmacology ; Amphetamine/*metabolism ; Animals ; Chromatography, High Pressure Liquid/instrumentation/*methods ; Corpus Striatum/cytology/*drug effects/metabolism ; Dopamine/*analysis/metabolism ; Female ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Reserpine/pharmacology ; }, abstract = {The amphetamine (AMPH)-induced alteration in rat brain dopamine levels modified by N-acetylcysteine (NAC) administration has been examined using isocratic ion-pair reversed-phase high-performance liquid chromatography with electrochemical detection. The aim of the development of a novel validated evaluation scheme implying a double AMPH challenge was to enhance the efficiency of AMPH-triggered dopamine release measurements in rat brain striatal slices by improving the reproducibility of the results. The proposed experimental protocol was tested in vivo and proved to be capable of fast and reliable drug screening for tracing the effect of NAC as a model compound in AMPH-mediated dopaminergic response. The subcellular localization of the dopamine mobilizing effect of NAC has been established indirectly by the use of an irreversible dopamine vesicular depletor, reserpine. The antioxidant NAC at 10 mM plays an important role in the complete suppression of acute AMPH-elicited dopamine release. The possible role of this quenching effect is discussed.}, }
@article {pmid19275668, year = {2009}, author = {Anuradha, CV}, title = {Aminoacid support in the prevention of diabetes and diabetic complications.}, journal = {Current protein &amp; peptide science}, volume = {10}, number = {1}, pages = {8-17}, doi = {10.2174/138920309787315194}, pmid = {19275668}, issn = {1389-2037}, mesh = {Amino Acids/metabolism/*pharmacology/therapeutic use ; Animals ; Diabetes Complications/drug therapy/metabolism/*prevention &amp; control ; Diabetes Mellitus/drug therapy/metabolism/*prevention &amp; control ; Humans ; Insulin Resistance ; }, abstract = {Emerging evidence suggests that amino acids may be potentially important in the prevention of diabetes and diabetes-associated complications. The pathways involved in the pathogenesis of diabetic complications include increased polyol pathway flux, increased advanced glycation end products formation, activation of protein kinase C and oxidative and carbonyl stress. This review will discuss the modulatory effects of amino acids on insulin secretion and their action in concert with insulin as signaling molecules. Evidences for the role of some amino acids in controlling glycemia and glucose-triggered pathological pathways are also included. Individual amino acids, especially the ones bestowed with antioxidant property like N-acetyl cysteine and taurine seem to have beneficial effects by their ability to reduce intracellular oxidative stress generation and glycooxidation. Other amino acids like glycine and lysine may be good candidates for the prevention of glycation. Nutritional intervention with taurine, phenyl alanine or branched chain amino acids can improve insulin sensitivity and post-prandial glucose disposal. Deficiency of one or more amino acids has been observed in diabetes and the beneficial effects of amino acids in some studies are positively correlated with the increase in plasma levels of these amino acids. Inclusion of individual amino acids/mixture, perhaps as a combinational therapy with conventional treatment protocols could be of therapeutic interest.}, }
@article {pmid19272177, year = {2009}, author = {Hsieh, CY and Hsiao, HY and Wu, WY and Liu, CA and Tsai, YC and Chao, YJ and Wang, DL and Hsieh, HJ}, title = {Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells.}, journal = {Journal of biomedical science}, volume = {16}, number = {1}, pages = {12}, pmid = {19272177}, issn = {1423-0127}, mesh = {Active Transport, Cell Nucleus/*physiology ; Cell Nucleus/metabolism ; Cells, Cultured ; Endothelial Cells/cytology/*metabolism ; Enzyme Inhibitors/metabolism ; Gene Expression Regulation ; Heme Oxygenase-1/genetics/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Nitric Oxide Synthase/antagonists &amp; inhibitors/metabolism ; Oxidants/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Shear Strength ; *Stress, Mechanical ; }, abstract = {BACKGROUND: Vascular endothelial cells (ECs) constantly experience fluid shear stresses generated by blood flow. Laminar flow is known to produce atheroprotective effects on ECs. Nrf2 is a transcription factor that is essential for the antioxidant response element (ARE)-mediated induction of genes such as heme-oxygenase 1 (HO-1). We previously showed that fluid shear stress increases intracellular reactive oxygen species (ROS) in ECs. Moreover, oxidants are known to stimulate Nrf2. We thus examined the regulation of Nrf2 in cultured human ECs by shear stress.<br><br>RESULTS: Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm2) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1.<br><br>CONCLUSION: Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.}, }
@article {pmid19269634, year = {2009}, author = {Tsai, CS and Loh, SH and Liu, JC and Lin, JW and Chen, YL and Chen, CH and Cheng, TH}, title = {Urotensin II-induced endothelin-1 expression and cell proliferation via epidermal growth factor receptor transactivation in rat aortic smooth muscle cells.}, journal = {Atherosclerosis}, volume = {206}, number = {1}, pages = {86-94}, doi = {10.1016/j.atherosclerosis.2009.02.013}, pmid = {19269634}, issn = {1879-1484}, mesh = {Animals ; Aorta/cytology ; Cell Proliferation/drug effects ; Cells, Cultured ; Endothelin-1/*genetics ; ErbB Receptors/*physiology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Myocytes, Smooth Muscle/*physiology ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism ; Rats ; Transcriptional Activation/drug effects ; Urotensins/*pharmacology ; }, abstract = {Urotensin II (U-II) is implicated in vascular smooth muscle cell proliferation, which results in vascular remodeling. We recently demonstrated that both reactive oxygen species (ROS) generation and epidermal growth factor receptor (EGFR) transactivation play critical roles in U-II signal transduction. However, the detailed intracellular mechanism of U-II in vascular smooth muscle cells remains unclear. In this study, we used rat aortic smooth muscle cells treated with U-II to investigate the connection between ROS generation and EGFR transactivation. U-II treatment was found to stimulate endothelin-1 (ET-1) expression and cell proliferation through the phosphorylation of EGFR and ROS generation. NAD(P)H oxidase inhibitor apocynin and ROS scavenger N-acetylcysteine (NAC) inhibited the EGFR transactivation induced by U-II. In contrast, AG-1478 (an EGFR inhibitor) failed to inhibit intracellular ROS generation induced by U-II. Src homology 2-containing tyrosine phosphatase (SHP-2) was shown to be associated with EGFR during U-II treatment by EGFR coimmunoprecipitation. ROS have been reported to oxidize the catalytic cysteine of SHP-2 and inhibit its activity. We examined the effect of U-II on SHP-2 in smooth muscle cells using a modified malachite green phosphatase assay. SHP-2 was oxidized during U-II treatment; and this oxidization could be repressed by NAC treatment. In SHP-2 knockdown cells, U-II-induced EGFR phosphorylation, ET-1 secretion, and cell proliferation were enhanced, and were not influenced by NAC. Our data suggest that U-II-mediated ROS generation can inhibit SHP-2 activity to facilitate the EGFR transactivation and mitogenic signal transduction in rat aortic smooth muscle cells.}, }
@article {pmid19268665, year = {2009}, author = {Zhang, P and Wong, TA and Lokuta, KM and Turner, DE and Vujisic, K and Liu, B}, title = {Microglia enhance manganese chloride-induced dopaminergic neurodegeneration: role of free radical generation.}, journal = {Experimental neurology}, volume = {217}, number = {1}, pages = {219-230}, pmid = {19268665}, issn = {1090-2430}, support = {R01 ES013265/ES/NIEHS NIH HHS/United States ; R01 ES013265-02/ES/NIEHS NIH HHS/United States ; ES013265/ES/NIEHS NIH HHS/United States ; }, mesh = {Analysis of Variance ; Animals ; Animals, Newborn ; CD11b Antigen/metabolism ; Cell Survival ; Cells, Cultured ; *Chlorides ; Coculture Techniques ; Dopamine/*metabolism ; Female ; Interleukin-1beta/metabolism ; *Manganese Compounds ; Mesencephalon/cytology ; Microglia/drug effects/*physiology ; Microtubule-Associated Proteins/metabolism ; Nerve Degeneration/*chemically induced/physiopathology ; Neurons/*drug effects ; Phosphopyruvate Hydratase/metabolism ; Pregnancy ; Rats ; Rats, Inbred F344 ; Reactive Oxygen Species/*metabolism ; Tritium/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Exposure to elevated levels of manganese has been shown to cause neuronal damage in the midbrain and the development of Parkinsonian symptoms. Activation of microglia and release of neurotoxic factors in particular free radicals are known to contribute to neurodegeneration. We have recently reported that manganese chloride (MnCl(2)) stimulates microglia to produce reactive oxygen species (ROS). The aim of this study is to determine the role of microglia in the MnCl(2)-induced degeneration of dopaminergic (DA) neurons that are particularly vulnerable to oxidative insult. MnCl(2) (10-300 microM; 7 days) was markedly more effective in damaging DA neurons in the rat mesencephalic neuron-glia cultures than the neuron-enriched (microglia-depleted) cultures. In addition, the microglia-enhanced MnCl(2) toxicity was found to be preferential to DA neurons. The microglial enhancement of DA neurotoxicity was further supported by the observation that replenishment of microglia to the neuron-enriched cultures significantly increased the susceptibility of DA neurons to the MnCl(2)-induced damage. Analysis of the temporal relationship between microglial activation and DA neurodegeneration revealed that MnCl(2)-stimulated microglial activation preceded DA neurodegeneration. Mechanistically, MnCl(2) (10-300 microM) stimulated a concentration- and time-dependent robust production of ROS and moderate production of nitric oxide but no detectable release of tumor necrosis factor-alpha and interleukin-1beta. Application of free radical scavengers including superoxide dismutase/catalase, glutathione, N-acetyl cysteine and an inhibitor of nitric oxide biosynthesis significantly protected DA neurons against the MnCl(2)-induced degeneration. These results demonstrate that microglial activation and the production of reactive nitrogen and oxygen free radicals promote the MnCl(2)-induced DA neurodegeneration.}, }
@article {pmid19268479, year = {2009}, author = {Han, WQ and Zhu, DL and Wu, LY and Chen, QZ and Guo, SJ and Gao, PJ}, title = {N-acetylcysteine-induced vasodilation involves voltage-gated potassium channels in rat aorta.}, journal = {Life sciences}, volume = {84}, number = {21-22}, pages = {732-737}, doi = {10.1016/j.lfs.2009.02.023}, pmid = {19268479}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/metabolism ; Cyclic AMP/physiology ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Guanylate Cyclase/antagonists &amp; inhibitors ; Muscle Contraction/drug effects ; Muscle, Smooth, Vascular/*drug effects ; Nitric Oxide/physiology ; Nitric Oxide Synthase Type III/antagonists &amp; inhibitors ; Oxadiazoles/pharmacology ; Phenylephrine/pharmacology ; Potassium Channel Blockers/pharmacology ; Potassium Channels, Voltage-Gated/*physiology ; Protein Kinase C/metabolism ; Quinoxalines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Vasoconstrictor Agents/pharmacology ; Vasodilation/*drug effects ; omega-N-Methylarginine/pharmacology ; }, abstract = {AIMS: N-acetylcysteine (NAC) has a protective effect against vascular dysfunction by decreasing the level of reactive oxygen species (ROS) in experimental and human hypertension. This study was designed to examine whether NAC would relax vascular rings in vitro via nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, extracellular Ca2+ and/or K+ channels.<br><br>MAIN METHODS: Rat aortic arteries were mounted in an organ bath, contracted with 0.1, 0.5 or 1 micromol/L phenylephrine to plateau, and the vasodilatory effect of NAC was examined in the absence or presence of ROS scavengers, inhibitors of NO-cGMP pathway or K+ channels. Vascular smooth muscle cells (VSMCs) were loaded with a calcium sensitive fluorescent dye fluo-3 AM, and [Ca2+](i) was determined with laser-scanning confocal microscopy.<br><br>KEY FINDINGS: NAC (0.1-4 mmol/L) dose-dependently relaxed rat aorta pre-contracted with phenylephrine. Endothelium removal, endothelial nitric oxide synthase inhibitor N(omega)-Nitro-l-arginine (L-NNA) (100 micromol/L) or soluble guanylyl cyclase (sGC) inhibitor (ODQ) (10 micromol/L) did not affect NAC-induced vasodilation. In contrast, NAC-induced vasodilation was blunted after extracellular calcium was removed and calcium imaging showed that 4 mmol/L NAC quickly decreased [Ca2+](i) in fluo-3 AM loaded VSMCs. NAC-induced vasodilation was significantly reduced in the presence of voltage-gated K+ channels (Kv) inhibitor 4-aminopyridine (4-AP).<br><br>SIGNIFICANCE: The vasodilatory effect of NAC may be explained at least partly by activation of voltage-gated K+ channels.}, }
@article {pmid19268006, year = {2009}, author = {Minder, EI and Schneider-Yin, X and Steurer, J and Bachmann, LM}, title = {A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {55}, number = {1}, pages = {84-97}, pmid = {19268006}, issn = {1165-158X}, mesh = {Ascorbic Acid/therapeutic use ; Clinical Trials as Topic ; Cysteine/therapeutic use ; Humans ; Protoporphyria, Erythropoietic/*drug therapy ; Treatment Outcome ; beta Carotene/therapeutic use ; }, abstract = {Erythropoietic protoporphyria (EPP) is a rare inherited disease characterized by dermal photosensitivity due to the accumulation of photosensitizer protoporphyrin IX. We performed a systematic database search on studies related to treatment of EPP. A total of 25 relevant studies were retrieved, 16 of them dealing with the application of beta-carotene. Two studies were found on each of the three substances, n-acetyl-cysteine (NAC), cysteine, and dihydroxyacetone/Lawson (henna). In addition, single studies on vitamin C, canthaxanthin and UVB treatment respectively, were located. The total number of patients in the 25 studies was 454, including 337 patients in the various beta-carotene trials. Most studies were published in the 1970's. Efficacy criteria were not standardized. Only 5 of the 25 studies were randomized and controlled trials; the rest were either open-label, uncontrolled studies or retrospective case reports. Four of the five well-designed studies suggested lack of efficacy of beta-carotene, NAC and vitamin C. The results of the beta-carotene studies were strongly contradictory and efficacy was inversely correlated with study quality. Our data confirm the opinion of experts in the field who are much more skeptical as to its efficacy than were early proponents of treatment with this agent. We conclude, that the available data are insufficient to prove efficacy of any treatments studied so far in EPP. We emphasize the necessity of high quality efficacy studies in porphyrias and in other rare diseases.}, }
@article {pmid19267363, year = {2009}, author = {Zira, A and Mikros, E and Giannioti, K and Galanopoulou, P and Papalois, A and Liapi, C and Theocharis, S}, title = {Acute liver acetaminophen toxicity in rabbits and the use of antidotes: a metabonomic approach in serum.}, journal = {Journal of applied toxicology : JAT}, volume = {29}, number = {5}, pages = {395-402}, doi = {10.1002/jat.1425}, pmid = {19267363}, issn = {1099-1263}, mesh = {Acetaminophen/pharmacokinetics/*toxicity ; Acetylcysteine/administration &amp; dosage/therapeutic use ; Acute Disease ; Alanine Transaminase/*blood ; Animals ; Antidotes/administration &amp; dosage/*therapeutic use ; Aspartate Aminotransferases/*blood ; Biomarkers/blood ; Chemical and Drug Induced Liver Injury/blood/etiology/*metabolism/pathology/prevention &amp; control ; Cimetidine/administration &amp; dosage/therapeutic use ; Disease Models, Animal ; Liver/*drug effects/enzymology/metabolism/pathology ; Magnetic Resonance Spectroscopy ; Male ; Rabbits ; Silybin ; Silymarin/administration &amp; dosage/therapeutic use ; }, abstract = {The metabonomic approach has been widely used in toxicology to investigate mechanisms of toxicity. In the present study alterations in the metabolic profiles, monitored by (1)H-NMR spectroscopy, on serum samples in acetaminophen (APAP)-induced liver injury in rabbits were examined. Furthermore, the effect of the established antidote N-acetylcysteine (NAC) and the proposed antidotes silybinin (SIL), cimetidine (CIM) and SIL/CIM was also investigated. A single dose of APAP (2 g kg(-1) b.w., i.g.) was administered to rabbits and APAP combined with the antidotes SIL, CIM and NAC. Animals were sacrificed at 24 h post-APAP treatment. Healthy untreated animals served as controls. (1)H-NMR spectra of serum samples were acquired and underwent principal component analysis (PCA). Acute liver injury was verified by histopathological examination and the alterations of serum biochemical enzymes AST and ALT. (1)H-NMR spectroscopy revealed variations in the serum metabolic profile of APAP-intoxicated rabbits compared with controls. Co-administration of APAP with NAC, CIM and SIL + CIM seems to ameliorate the metabolic profile of animals compared with simply APAP-treated ones. In this study, the model of APAPinduced liver injury was successfully described using the (1)H-NMR based metabonomic approach in serum. Furthermore, the use of antidotes that reduced the toxic insult was also recorded using this technique. The combination of NMR spectroscopy and PCA is a rapid methodology, capable of detecting alterations in the metabolic profile, and produces adequate models that could be used for the characterization of unknown samples, both experimental and clinical, reinforcing its future use in clinical settings.}, }
@article {pmid19264484, year = {2009}, author = {Lu, H and Zhang, DM and Chen, HL and Lin, YX and Hang, CH and Yin, HX and Shi, JX}, title = {N-acetylcysteine suppresses oxidative stress in experimental rats with subarachnoid hemorrhage.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {16}, number = {5}, pages = {684-688}, doi = {10.1016/j.jocn.2008.04.021}, pmid = {19264484}, issn = {0967-5868}, mesh = {Analysis of Variance ; Animals ; Brain Edema/drug therapy/etiology ; Carnosine/administration &amp; dosage/*analogs &amp; derivatives ; Cerebral Cortex/drug effects/metabolism ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Nervous System Diseases/drug therapy/etiology ; Neuroprotective Agents/*administration &amp; dosage ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage/*drug therapy/*physiopathology ; Superoxide Dismutase/metabolism ; }, abstract = {The neuroprotective effect of N-acetylcysteine (NAC), a sulfhydryl-containing antioxidant, on experimentally induced subarachnoid hemorrhage (SAH) in rats was assessed. NAC was administered to rats after the induction of SAH. Neurological deficits and brain edema were investigated. The activity of antioxidant defense enzymes, copper/zinc superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px), were measured in the brain cortex by spectrophotometer. The content of the lipid peroxidation product malondialdehyde (MDA) was also analyzed. We found that NAC markedly reversed the SAH-induced neurological deficit and brain edema. We further investigated the mechanism involved in the neuroprotective effects of NAC on rat brain tissue and found that NAC significantly increased CuZn-SOD and GSH-Px activity and decreased MDA content in the SAH brain. NAC has the potential to be a novel therapeutic strategy for the treatment of SAH, and its neuroprotective effect may be partly mediated via enhancing the activity of endogenous antioxidant enzymes and inhibiting free radical generation.}, }
@article {pmid19263279, year = {2009}, author = {Walther, UI and Mückter, H}, title = {Glutathione synthesis against oxidant injury by peroxides in two alveolar epithelial cell lines.}, journal = {Experimental lung research}, volume = {35}, number = {2}, pages = {89-103}, doi = {10.1080/01902140802441569}, pmid = {19263279}, issn = {1521-0499}, mesh = {Acetylcysteine/*pharmacology ; Antidotes/pharmacology ; Cell Line ; Epithelial Cells/*metabolism ; Glutathione/*biosynthesis/physiology ; Humans ; Hydrogen Peroxide/toxicity ; Oxidative Stress/*drug effects ; Peroxides/*toxicity ; Pulmonary Alveoli/*cytology ; tert-Butylhydroperoxide/toxicity ; }, abstract = {The D- and L-forms of N-acetylcysteine (NADC, NAC) were tested in antagonizing the toxicity mediated by hydrogen peroxide (H(2)O(2)) or tertiary butyl hydroperoxide (tBHP) in two lung cell lines to assess the effectivity of glutathione synthesis against peroxides. Toxicity was assessed by methionine incorporation, total glutathione content, and glutathione disulfide to glutathione ratio. NAC or NADC, at 2 mmol/L, increased cellular glutathione to about 1.5- or 3-fold (NAC) and 1.1- or 1.2-fold (NADC) in A549 or L2 cells, respectively, as compared to naive cells. H(2)O(2)-mediated toxicity was decreased by NADC (as compared to controls), but increased slightly with NAC, whereas tBHP-mediated toxicity was decreased both by NAC and NADC. However, when compared to controls, NADC was an effective antidote against tBHP in L2 cells only. Dexamethasone pretreatment increased toxicity of H(2)O(2) and tBHP in L2 cells, but did not affect the antioxidative efficacy of NAC/NADC. Antidotal properties of NAC/NADC were similar in both cell lines, despite significant differences of the glutathione redox system in both situations. Hence, it is concluded that direct antioxidative properties of NAC and NADC is a main antagonizing factor in H(2)O(2)-based toxicity but not in tBHP-mediated toxicity. Enhancement of glutathione biosynthesis decreased toxicity of tBHP, but not of H(2)O(2) in 2 pulmonary cell lines.}, }
@article {pmid19262475, year = {2009}, author = {Wang, H and Li, H and Hou, Z and Pan, L and Shen, X and Li, G}, title = {Role of oxidative stress in elevated blood pressure induced by high free fatty acids.}, journal = {Hypertension research : official journal of the Japanese Society of Hypertension}, volume = {32}, number = {2}, pages = {152-158}, doi = {10.1038/hr.2008.35}, pmid = {19262475}, issn = {1348-4214}, mesh = {Animals ; Blood Pressure/*drug effects ; Fatty Acids, Nonesterified/*pharmacology ; Glucose Clamp Technique ; Glutathione/metabolism ; Hypertension/chemically induced/metabolism/physiopathology ; In Vitro Techniques ; Male ; Nitrates/blood ; Nitric Oxide Synthase Type III/metabolism ; Nitrites/blood ; Oxidative Stress/*drug effects ; RNA/biosynthesis/genetics ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tyrosine/analogs &amp; derivatives/blood ; }, abstract = {The aim of the study is to investigate the possible mechanism of oxidative stress in the high free fatty acids (FFAs)-induced hypertension. Male Sprague-Dawley rat models were established and classified into three groups, namely the control group (NC group), the FFA group, and the N-acetylcysteine (NAC) group. Blood pressure (BP) was recorded. An organ chamber experiment was performed to determine endothelium-dependent/-independent vasodilation (EDV/EIV). Reactive oxygen species (ROS), nitrotyrosine, reduced glutathione hormone (GSH) and NO(2)(-)/NO(3)(-) levels were measured in plasma. Endothelial nitric oxide synthase (eNOS) mRNA expression in endothelial cells was evaluated by real-time PCR. The following results were observed: (1) In the FFA group, BP increased after 4 h infusion of Intralipid+heparin. In the NAC group, systolic and diastolic BP remained the same. (2) In the FFA group, the aortic rings tended to show impaired EDV in response to acetylcholine (ACh). There was no difference of EDV response in the NAC and NC groups. (3) In the FFA group, NO(2)(-)/NO(3)(-) levels were significantly reduced, and eNOS mRNA expression and activity were significantly decreased compared with the NC group. NAC administration increased eNOS mRNA expression and activity. (4) ROS and nitrotyrosine concentrations in the FFA group were higher than in the NC group, and GSH concentrations in the FFA group were lower than in the NC group. Elevated FFAs can induce elevated BP, potentially through FFA-induced impairment of EDV resulting from decreased eNOS mRNA expression and activity. Oxidative stress may also play an important role in potential mechanisms of this high FFA-induced elevated BP.}, }
@article {pmid19261913, year = {2009}, author = {Krüger, K and Frost, S and Most, E and Völker, K and Pallauf, J and Mooren, FC}, title = {Exercise affects tissue lymphocyte apoptosis via redox-sensitive and Fas-dependent signaling pathways.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {296}, number = {5}, pages = {R1518-27}, doi = {10.1152/ajpregu.90994.2008}, pmid = {19261913}, issn = {0363-6119}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*physiology ; Fas Ligand Protein/metabolism ; Free Radical Scavengers/pharmacology ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Inbred MRL lpr ; Models, Animal ; Oxidation-Reduction ; Oxidative Stress/physiology ; Physical Conditioning, Animal/*physiology ; Signal Transduction/*physiology ; T-Lymphocytes/drug effects/pathology/*physiology ; fas Receptor/deficiency/genetics/*physiology ; }, abstract = {Intensive and exhaustive exercise induces an activation of blood T-lymphocytes, which seems to be terminated by apoptotic processes in the postexercise period. Here, we report that exercise-induced T-lymphocyte apoptosis is a systemic phenomenon occurring in various lymphoid and nonlymphoid tissues. The apoptosis rate could be related to exercise intensity and type. Although in some tissues, such as the spleen and Peyer's patches, an early start of apoptosis (1-3 h postexercise) could be detected, a delayed apoptosis (24 h postexercise) was observed in lung, bone marrow, and lymph nodes. Further analysis showed a similar apoptosis distribution among lymphocyte subpopulations. We tested whether components of the extrinsic or the intrinsic apoptotic pathways or both were involved in these processes. Elevated levels of lipid peroxidation-product malondialdehyde (MDA), indicating an increased production of reactive oxygen species (ROS), were found after exercise in Peyer's patches, lung, and spleen, but not in lymph nodes. Application of N-acetyl-cysteine (NAC) prevented exercise-induced T-cell apoptosis completely in spleen and bone marrow, partially in lung and Peyer's patches, while it was ineffective in lymph nodes. Additionally, exercise addressed the Fas-mediated apoptosis. The percentage of Fas-receptor (Fas+) and Fas-ligand positive (FasL+) lymphocytes was enhanced in Peyer's patches after exercise. Moreover, FasL+ T cells were increased in the lung, while in lymph nodes Fas+ cells were increased. The critical role of Fas signaling in exercise-induced apoptosis was supported by using Fas-deficient MRL/lpr-mice. In Fas-deficient mice, exercise-induced T-lymphocyte apoptosis was prevented in spleen, lung, bone marrow, and lymph nodes, but not in Peyer's patches. These data demonstrate that exercise-induced lymphocyte apoptosis is a transient systemic process with tissue-type specific apoptosis-inducing mechanisms, whose relevance for the adaptive immune competence remains to be shown.}, }
@article {pmid19252136, year = {2009}, author = {Zherebitskaya, E and Akude, E and Smith, DR and Fernyhough, P}, title = {Development of selective axonopathy in adult sensory neurons isolated from diabetic rats: role of glucose-induced oxidative stress.}, journal = {Diabetes}, volume = {58}, number = {6}, pages = {1356-1364}, pmid = {19252136}, issn = {1939-327X}, support = {72893/CAPMC/CIHR/Canada ; 84214/CAPMC/CIHR/Canada ; }, mesh = {Aging/*physiology ; Animals ; Axons/metabolism/*pathology ; Caspases/metabolism ; Diabetes Mellitus, Experimental/metabolism/*pathology ; Glucose/*pharmacology ; Male ; Neurofilament Proteins/metabolism ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; Sensory Receptor Cells/metabolism/*pathology ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: Reactive oxygen species (ROS) are pro-oxidant factors in distal neurodegeneration in diabetes. We tested the hypothesis that sensory neurons exposed to type 1 diabetes would exhibit enhanced ROS and oxidative stress and determined whether this stress was associated with abnormal axon outgrowth.<br><br>RESEARCH DESIGN AND METHODS: Lumbar dorsal root ganglia sensory neurons from normal or 3- to 5-month streptozotocin (STZ)-diabetic rats were cultured with 10 or 25-50 mmol/l glucose. Cell survival and axon outgrowth were assessed. ROS were analyzed using confocal microscopy. Immunofluorescent staining detected expression of manganese superoxide dismutase (MnSOD) and adducts of 4-hydroxy-2-nonenal (4-HNE), and MitoFluor Green dye detected mitochondria.<br><br>RESULTS: Dorsal root ganglion neurons from normal rats exposed to 25-50 mmol/l glucose did not exhibit oxidative stress or cell death. Cultures from diabetic rats exhibited a twofold (P < 0.001) elevation of ROS in axons after 24 h in 25 mmol/l glucose compared with 10 mmol/l glucose or mannitol. Perikarya exhibited no change in ROS levels. Axonal outgrowth was reduced by approximately twofold (P < 0.001) in diabetic cultures compared with control, as was expression of MnSOD. The antioxidant N-acetyl-cysteine (1 mmol/l) lowered axonal ROS levels, normalized aberrant axonal structure, and prevented deficits in axonal outgrowth in diabetic neurons (P < 0.05).<br><br>CONCLUSIONS: Dorsal root ganglia neurons with a history of diabetes expressed low MnSOD and high ROS in axons. Oxidative stress was initiated by high glucose concentration in neurons with an STZ-induced diabetic phenotype. Induction of ROS was associated with impaired axonal outgrowth and aberrant dystrophic structures that may precede or predispose the axon to degeneration and dissolution in human diabetic neuropathy.}, }
@article {pmid19251114, year = {2009}, author = {Ferreira Seiva, FR and Amauchi, JF and Ribeiro Rocha, KK and Souza, GA and Ebaid, GX and Burneiko, RM and Novelli, EL}, title = {Effects of N-acetylcysteine on alcohol abstinence and alcohol-induced adverse effects in rats.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {43}, number = {2}, pages = {127-135}, doi = {10.1016/j.alcohol.2008.12.003}, pmid = {19251114}, issn = {1873-6823}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Alcohol Drinking ; Alcoholism/drug therapy ; Animals ; Glutathione/metabolism ; Lipids/blood ; Lipoproteins, LDL/blood ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; *Temperance ; }, abstract = {Alcoholism is rampant in modern society and some antioxidant compound could perhaps be useful to reduce the damage done by alcohol consumption and abstinence. The present study was undertaken to investigate the association of N-acetylcysteine (NAC) intake, alcoholism, and alcohol abstinence on lipid profile, in vivo low-density lipoprotein (LDL) oxidation, oxidative stress, and antioxidant status in serum and liver of rats. Initially, male Wistar 30 rats were divided into two groups: (C, N=6) given standard chow and water; (E, N=24) receiving standard chow and aqueous ethanol solution in semi-voluntary research. After 30 days of ethanol exposure, (E) group was divided into four subgroups (N=6/group): (E-E) continued drinking 30% ethanol solution; (E-NAC) drinking ethanol solution containing 2 g/L NAC; (AB) changed ethanol solution to water; (AB-NAC) changed ethanol to aqueous solution 2 g/L NAC. After 15 days of the E-group division, E-E rats had higher serum alanine transaminase, lower body weight, and surface area, despite higher energy intake than C. E-E rats had also lower feed efficiency, dyslipidemia with enhanced triacylglycerol, very low-density lipoprotein (VLDL), lipid hydroperoxide (LH) and in vivo oxidized-LDL (ox-LDL). AB, E-NAC, and AB-NAC rats ameliorated serum oxidative stress markers and normalized serum lipids. E-E rats had higher hepatic LH and lower reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio than C, indicating hepatic oxidative stress. AB and E-NAC rats normalized hepatic LH, GSSG, and the GSH/GSSG ratio, compared to E-E. AB-NAC rats had the lowest serum ox-LDL, hepatic LH levels, and the highest GSH reductase activity in hepatic tissue. In conclusion, the present study brought new insights into alcohol consumption, because ethanol exposure enhanced serum in vivo ox-LDL, as well as serum and hepatic oxidative stress. N-acetylcysteine offers promising therapeutic value to inhibit ethanol-induced adverse effects. Ethanol withdrawal had beneficial effects on serum lipids, but was more effective when coupled with NAC supplementation. Ethanol abstinence and NAC intake interact synergistically, improving serum lipids and hepatic antioxidant defenses.}, }
@article {pmid19249432, year = {2009}, author = {Jo, SH and Koo, BK and Park, JS and Kang, HJ and Kim, YJ and Kim, HL and Chae, IH and Choi, DJ and Sohn, DW and Oh, BH and Park, YB and Choi, YS and Kim, HS}, title = {N-acetylcysteine versus AScorbic acid for preventing contrast-Induced nephropathy in patients with renal insufficiency undergoing coronary angiography NASPI study-a prospective randomized controlled trial.}, journal = {American heart journal}, volume = {157}, number = {3}, pages = {576-583}, doi = {10.1016/j.ahj.2008.11.010}, pmid = {19249432}, issn = {1097-6744}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aged ; Antioxidants/administration &amp; dosage/*therapeutic use ; Ascorbic Acid/administration &amp; dosage/*therapeutic use ; Comorbidity ; Contrast Media/*adverse effects ; Coronary Angiography ; Creatinine/blood ; Diabetes Mellitus/epidemiology ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Male ; Middle Aged ; Prospective Studies ; Renal Insufficiency/blood/*chemically induced/epidemiology/*prevention &amp; control ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired renal failure and affects mortality and morbidity. There has been no study comparing the efficacy of N-acetylcysteine (NAC) and ascorbic acid that have potential for CIN prevention in patients with renal insufficiency.<br><br>METHODS: We conducted a prospective randomized controlled trial. A total of 212 patients who had pre-existing renal impairment with basal creatinine clearance < or =60 mL/min and/or serum creatinine (SCr) level of > or =1.1 mg/dL, were randomized to have either high-dose NAC (1,200 mg orally twice a day before and on the day of coronary catheterization, n = 106) or ascorbic acid (3 g and 2 g orally before, and 2 g twice after coronary catheterization with a 12-hour interval, n = 106). The primary end point was the maximum increase of SCr level, and the secondary end point was the incidence of CIN.<br><br>RESULTS: The maximum increase of SCr level was significantly lower in NAC group than in ascorbic acid group as follows: -0.03 +/- 0.18 mg/dL versus 0.04 +/- 0.20 mg/mL, respectively (P = .026). Patients with diabetes or who had received a high dose of contrast media experienced significantly less rise of SCr level with NAC than ascorbic acid; in diabetic subgroup, -0.05 +/- 0.22 mg/dL versus 0.09 +/- 0.29 mg/mL, respectively (P = .020); in patients with high dose of dye, -0.03 +/- 0.17 mg/dL versus 0.04 +/- 0.21 mg/mL, respectively (P = .032). The incidence of CIN, the secondary end point, tended to be in favor of NAC rather than ascorbic acid, 1.2% versus 4.4%, respectively (P = .370). Notably, among the diabetes patients, the NAC significantly lowered CIN rate than ascorbic acid, 0% (0/38) versus 12.5% (4/32), respectively (P = .039).<br><br>CONCLUSION: High-dose NAC seems more beneficial than ascorbic acid in preventing contrast-induced renal function deterioration in patients, especially diabetic patients, with renal insufficiency undergoing coronary angiography.}, }
@article {pmid19243635, year = {2009}, author = {Nakajima, Y and Tsuruma, K and Shimazawa, M and Mishima, S and Hara, H}, title = {Comparison of bee products based on assays of antioxidant capacities.}, journal = {BMC complementary and alternative medicine}, volume = {9}, number = {}, pages = {4}, pmid = {19243635}, issn = {1472-6882}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/pharmacology ; Bees ; Caffeic Acids/pharmacology ; Chromans/pharmacology ; Cinnamates/pharmacology ; Coumaric Acids/pharmacology ; Fatty Acids/*pharmacology ; Fatty Acids, Monounsaturated/pharmacology ; Free Radical Scavengers/*pharmacology ; Phenylpropionates/pharmacology ; Plant Extracts/pharmacology ; *Pollen ; Propolis/*pharmacology ; Quinic Acid/analogs &amp; derivatives/pharmacology ; Trichothecenes/pharmacology ; }, abstract = {BACKGROUND: Bee products (including propolis, royal jelly, and bee pollen) are popular, traditional health foods. We compared antioxidant effects among water and ethanol extracts of Brazilian green propolis (WEP or EEP), its main constituents, water-soluble royal jelly (RJ), and an ethanol extract of bee pollen.<br><br>METHODS: The hydrogen peroxide (H2O2)-, superoxide anion (O2.-)-, and hydroxyl radical (HO.)- scavenging capacities of bee products were measured using antioxidant capacity assays that employed the reactive oxygen species (ROS)-sensitive probe 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA) or aminophenyl fluorescein (APF).<br><br>RESULTS: The rank order of antioxidant potencies was as follows: WEP > EEP > pollen, but neither RJ nor 10-hydroxy-2-decenoic acid (10-HDA) had any effects. Concerning the main constituents of WEP, the rank order of antioxidant effects was: caffeic acid > artepillin C > drupanin, but neither baccharin nor coumaric acid had any effects. The scavenging effects of caffeic acid were as powerful as those of trolox, but stronger than those of N-acetyl cysteine (NAC) or vitamin C.<br><br>CONCLUSION: On the basis of the present assays, propolis is the most powerful antioxidant of all the bee product examined, and its effect may be partly due to the various caffeic acids it contains. Pollen, too, exhibited strong antioxidant effects.}, }
@article {pmid19243001, year = {2009}, author = {Sperl, J and Procházková, J and Martásek, P and Subhanová, I and Franková, S and Trunecka, P and Jirsa, M}, title = {N-acetyl cysteine averted liver transplantation in a patient with liver failure caused by erythropoietic protoporphyria.}, journal = {Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society}, volume = {15}, number = {3}, pages = {352-354}, doi = {10.1002/lt.21669}, pmid = {19243001}, issn = {1527-6473}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Exons ; Ferrochelatase/genetics ; Humans ; Liver Failure/drug therapy/*etiology/*surgery ; Liver Transplantation ; Male ; Mutation ; Polymorphism, Single Nucleotide ; Protoporphyria, Erythropoietic/*diagnosis/drug therapy ; }, }
@article {pmid19234301, year = {2009}, author = {Kim, JY and Cho, HJ and Sir, JJ and Kim, BK and Hur, J and Youn, SW and Yang, HM and Jun, SI and Park, KW and Hwang, SJ and Kwon, YW and Lee, HY and Kang, HJ and Oh, BH and Park, YB and Kim, HS}, title = {Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia.}, journal = {Cardiovascular research}, volume = {82}, number = {3}, pages = {550-560}, doi = {10.1093/cvr/cvp072}, pmid = {19234301}, issn = {1755-3245}, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/*therapeutic use ; Antioxidants/metabolism ; Apoptosis/drug effects ; Carotid Artery Diseases/prevention &amp; control ; Carotid Artery, Common/pathology ; Cell Proliferation/drug effects ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Gene Expression Regulation ; Graft Occlusion, Vascular/*prevention &amp; control ; Heme Oxygenase-1/*metabolism ; Hyperplasia/prevention &amp; control ; Muscle, Smooth, Vascular/drug effects ; Myocytes, Smooth Muscle/drug effects ; NF-E2-Related Factor 2/*metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sulfasalazine/pharmacology/*therapeutic use ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {AIMS: Inflammation, and the subsequent proliferative activity of vascular smooth muscle cells (VSMCs), is one of the major pathophysiological mechanisms associated with neointimal hyperplasia following vascular injury. Although sulfasalazine (SSZ) has been used as an anti-inflammatory and immune-modulatory agent in various inflammatory diseases, its primary targets and therapeutic effects on vascular disease have not yet been determined. We investigated whether SSZ could suppress VSMC growth and prevent neointimal hyperplasia.<br><br>METHODS AND RESULTS: SSZ was found to have pro-apoptotic and anti-proliferative activity in cultured VSMCs. Unexpectedly, these effects were not mediated by nuclear factor kappa B (NF-kappaB) inhibition, which has been suggested to be the anti-inflammatory mechanism associated with the effects of SSZ. Instead, cell-cycle arrest of the VSMCs was observed, which was mediated by induction of haem oxygenase-1 (HO-1) followed by an increased expression of p21(waf1/Cip1). The underlying mechanism for SSZ-induced HO-1 expression was by reactive oxygen species (ROS)-dependent nuclear translocation and activation of nuclear factor erythroid-2-related factor 2 (Nrf2). In a rat carotid artery balloon injury model, administration of SSZ significantly suppressed neointimal growth. In a series of reverse experiments, inhibition of HO-1 by shRNA, ROS by N-acetylcysteine (NAC) or Nrf2 by dominant-negative Nrf2 abrogated the beneficial effects of SSZ.<br><br>CONCLUSION: Our data demonstrate that SSZ inhibits VSMC proliferation in vitro and in vivo through a novel signalling pathway and may be a promising therapeutic option for the treatment of proliferative vascular disease.}, }
@article {pmid19233942, year = {2009}, author = {Timme-Laragy, AR and Van Tiem, LA and Linney, EA and Di Giulio, RT}, title = {Antioxidant responses and NRF2 in synergistic developmental toxicity of PAHs in zebrafish.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {109}, number = {2}, pages = {217-227}, pmid = {19233942}, issn = {1096-0929}, support = {P42 ES10356/ES/NIEHS NIH HHS/United States ; TS ES07031/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*metabolism ; Benzoflavones/toxicity ; Buthionine Sulfoximine/toxicity ; Drug Synergism ; Embryo, Nonmammalian/abnormalities/*drug effects ; Embryonic Development/drug effects ; Enzyme Inhibitors/toxicity ; Gene Expression Regulation/*drug effects ; Gene Knockdown Techniques ; Glutathione/analysis ; NF-E2-Related Factor 2/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Pericardial Effusion ; Polycyclic Aromatic Hydrocarbons/*toxicity ; Up-Regulation ; Zebrafish/*embryology ; Zebrafish Proteins/*metabolism ; beta-Naphthoflavone/toxicity ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {Early piscine life stages are sensitive to polycyclic aromatic hydrocarbon (PAH) exposure, which can cause pericardial effusion and craniofacial malformations. We previously reported that certain combinations of PAHs cause synergistic developmental toxicity, as observed with coexposure to the aryl hydrocarbon receptor agonist beta-naphthoflavone (BNF) and cytochrome P4501A inhibitor alpha-naphthoflavone (ANF). Herein, we hypothesized that oxidative stress is a component of this toxicity. We examined induction of antioxidant genes in zebrafish embryos (Danio rerio) exposed to BNF or ANF individually, a BNF + ANF combination, and a prooxidant positive control, tert-butylhydroperoxide (tBOOH). We measured total glutathione (GSH) and attempted to modulate deformities using the GSH synthesis inhibitor L-buthionine (S,R)-sulfoximine (BSO) and increase GSH pools with N-acetyl cysteine (NAC). In addition, we used a morpholino to knockdown expression of the antioxidant response element transcription factor NRF2 to determine if this would alter gene expression or increase deformity severity. BNF + ANF coexposure significantly increased expressions of superoxide dismutase 1 and 2, glutathione peroxidase 1, pi class glutathione-s-transferase, and glutamate cysteine-ligase to a greater extent than tBOOH, BNF, or ANF alone. BSO pretreatment decreased some GSH levels, but did not worsen deformities, nor did NAC diminish toxicity. Knockdown of NRF2 increased mortality following tBOOH challenge, prevented significant upregulation of antioxidant genes following both tBOOH and BNF + ANF exposures, and exacerbated BNF + ANF-related deformities. Collectively, these findings demonstrate that antioxidant responses are a component of PAH synergistic developmental toxicity and that NRF2 is protective against prooxidant and PAH challenges during development.}, }
@article {pmid19233765, year = {2009}, author = {Rodrigues, AJ and Evora, PR and Bassetto, S and Alves, L and Scorzoni Filho, A and Origuela, EA and Vicente, WV}, title = {Blood cardioplegia with N-acetylcysteine may reduce coronary endothelial activation and myocardial oxidative stress.}, journal = {The heart surgery forum}, volume = {12}, number = {1}, pages = {E44-8}, doi = {10.1532/HSF98.20081134}, pmid = {19233765}, issn = {1522-6662}, mesh = {Acetylcysteine/*administration &amp; dosage ; Combined Modality Therapy ; Coronary Artery Disease/*therapy ; Endothelium, Vascular/drug effects ; Female ; Free Radical Scavengers/administration &amp; dosage ; Heart Arrest, Induced/*methods ; Humans ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Treatment Outcome ; Vasoconstriction/drug effects ; }, abstract = {OBJECTIVES: The aim of this prospective study was to compare the efficacy of intermittent antegrade blood cardioplegia with or without n-acetylcysteine (NAC) in reducing myocardial oxidative stress and coronary endothelial activation.<br><br>METHODS: Twenty patients undergoing elective isolated coronary artery bypass graft surgery were randomly assigned to receive intermittent antegrade blood cardioplegia (32 degrees C-34 degrees C) with (NAC group) or without (control group) 300 mg of NAC. For these 2 groups we compared clinical outcome, hemodynamic evolution, systemic plasmatic levels of troponin I, and plasma concentrations of malondialdehyde (MDA) and soluble vascular adhesion molecule 1 (sVCAM-1) from coronary sinus blood samples.<br><br>RESULTS: Patient demographic characteristics and operative and postoperative data findings in both groups were similar. There was no hospital mortality. Comparing the plasma levels of MDA 10 min after the aortic cross-clamping and of sVCAM-1 30 min after the aortic cross-clamping period with the levels obtained before the aortic clamping period, we observed increases of both markers, but the increase was significant only in the control group (P= .039 and P= .064 for MDA; P= .004 and P= .064 for sVCAM-1). In both groups there was a significant increase of the systemic serum levels of troponin I compared with the levels observed before cardiopulmonary bypass (P< .001), but the differences between the groups were not significant (P= .570).<br><br>CONCLUSIONS: Our investigation showed that NAC as an additive to blood cardioplegia in patients undergoing on-pump coronary artery bypass graft surgery may reduce oxidative stress and the resultant coronary endothelial activation.}, }
@article {pmid19220795, year = {2010}, author = {Whitaker, BD and Knight, JW}, title = {Effects of N-acetyl-cysteine and N-acetyl-cysteine-amide supplementation on in vitro matured porcine oocytes.}, journal = {Reproduction in domestic animals = Zuchthygiene}, volume = {45}, number = {5}, pages = {755-759}, doi = {10.1111/j.1439-0531.2009.01344.x}, pmid = {19220795}, issn = {1439-0531}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacology ; Animals ; Culture Media/*chemistry ; Dose-Response Relationship, Drug ; Embryo Culture Techniques/veterinary ; Embryonic Development ; Female ; Fertilization in Vitro/veterinary ; Oocytes/*drug effects/*physiology ; Swine/*embryology ; }, abstract = {This study was conducted to evaluate the effects of different concentrations of the antioxidant N-acetyl-cysteine (NAC) supplemented to the maturation medium on porcine embryo development. Concentrations of NAC and its synthetic derivative, NAC-amide (NACA) were evaluated for effects on nuclear maturation, fertilization success and embryo development. Concentrations of NAC (0, 0.5, 1.0, 1.5, 2.0, 2.5 and 5.0 mm) were supplemented to maturing oocytes, and embryo development was analysed at 48 and 144 h post-fertilization. There were no differences among cleavage rates for any of the treatment groups. Blastocyst formation for 1.5 mm NAC (56.5 ± 9.2%) was higher (p < 0.05) than all other supplementations. There were no differences in nuclear maturation or fertilization or in cleavage rates when comparing 1.5 mm NAC and 1.5 mm NACA supplementation to the control. Blastocyst formation for 1.5 mm NAC (44.4 ± 4.7%) and 1.5 mm NACA (46.2 ± 3.4%) supplementation were higher (p < 0.05) than the control (32.1 ± 6.2%) oocytes. These results indicate that supplementing 1.5 mm of NAC or NACA to the oocyte maturation medium increased the percentage of viable embryos reaching the blastocyst stage of development.}, }
@article {pmid19218780, year = {2009}, author = {Demirel, C and Kilçiksiz, S and Ay, OI and Gürgül, S and Ay, ME and Erdal, N}, title = {Effect of N-acetylcysteine on radiation-induced genotoxicity and cytotoxicity in rat bone marrow.}, journal = {Journal of radiation research}, volume = {50}, number = {1}, pages = {43-50}, doi = {10.1269/jrr.08066}, pmid = {19218780}, issn = {0449-3060}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Apoptosis/*drug effects/*radiation effects ; Bone Marrow Cells/drug effects/*physiology/*radiation effects ; Cell Survival/*drug effects/*radiation effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Female ; Radiation Dosage ; Radiation-Protective Agents/administration &amp; dosage ; Rats ; Rats, Wistar ; *Whole-Body Irradiation ; }, abstract = {The aim of this study is to evaluate the potential radioprotective effects of N-acetylcysteine (NAC) against genotoxicity and cytotoxicity. The effect of WR-2721, as a representative of clinically used radioprotector, was compared with that of NAC, using the chromosomal aberration (CA) and micronucleus (MN) test systems in the irradiated rat's femoral bone marrow cells. We also investigated the mitotic index (MI), and the ratio of polychromatic erythrocytes (PCEs) to normochromatic erythrocytes (NCEs). The rats (n = 16) were divided randomly and equally into four groups: Control (C), Radiation (R), R+NAC (received irradiation and 1000 mg/kg NAC) and R+WR-2721 (received irradiation and 200 mg/kg WR-2721) rats. All the irradiated groups received whole-body gamma irradiation as a single dose of 6 Gy. Group R showed higher CA and MN formation when compared to C. Group R showed higher frequency of MN formation when compared to both R+NAC and R+WR-2721. The mean MI and PCE/NCE ratios were lower in Group R when compared to those of Group C. The mean MI and PCE/NCE ratios of both R+NAC and R+WR-2721 groups were lower when compared to those of Group C. The MI in Group R was lower when compared to that of both R+NAC and R+WR-2721 groups. In this study, the results give clues about the beneficial effects of NAC against radiation-induced genotoxicity and cytotoxicity in rat bone marrow and its effect may be comparable to that observed for WR-2721.}, }
@article {pmid19211687, year = {2009}, author = {Lee, YJ and Suh, HN and Han, HJ}, title = {Effect of BSA-induced ER stress on SGLT protein expression levels and alpha-MG uptake in renal proximal tubule cells.}, journal = {American journal of physiology. Renal physiology}, volume = {296}, number = {6}, pages = {F1405-16}, doi = {10.1152/ajprenal.90652.2008}, pmid = {19211687}, issn = {1931-857X}, mesh = {Animals ; Cells, Cultured ; Endoplasmic Reticulum/*drug effects ; Endoplasmic Reticulum Chaperone BiP ; Gene Expression Regulation/physiology ; Heat-Shock Proteins/genetics/metabolism ; Kidney Tubules, Proximal/*cytology/metabolism ; MAP Kinase Kinase 4/metabolism ; Male ; Methylglucosides/*metabolism ; Molecular Chaperones/genetics/metabolism ; NF-kappa B/metabolism ; PPAR gamma/metabolism ; Protein Serine-Threonine Kinases/genetics/metabolism ; Rabbits ; Reactive Oxygen Species ; Serum Albumin, Bovine/*toxicity ; Signal Transduction/drug effects ; Sodium-Glucose Transport Proteins/genetics/*metabolism ; }, abstract = {Recent studies demonstrated that endoplasmic reticulum (ER) stress regulates glucose homeostasis and that ER stress preconditioning which induces an adaptive, protective unfolded protein response (UPR) offers cytoprotection against nephrotoxins. Thus the aim of the present study was to use renal proximal tubule cells (PTCs) to further elucidate the link between the BSA-induced ER stress and alpha-methyl-d-glucopyranoside (alpha-MG) uptake and to identify related signaling pathways. Among ER stress inducers such as high glucose, BSA, H2O2, or tumicamycin, BSA pretreatment ameliorated the reduction of Na(+)-glucose cotransporter (SGLT) expression and alpha-MG uptake by gentamicin or cyclosporine A. Immunofluorescence studies revealed that BSA (10 mg/ml) stimulated the expression of glucose-regulated protein 78 (GRP78), an ER stress biomarker. In addition, BSA increased levels of GRP78 protein expression and eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation in a time-dependent manner. Furthermore, transfection with a GRP78-specific small interfering RNA (siRNA) inhibited BSA-stimulated SGLT expression and alpha-MG uptake. In experiments designed to unravel the mechanisms underlying BSA-induced ER stress, BSA stimulated the production of cellular reactive oxygen species (ROS), and antioxidants such as ascorbic acid or N-acetylcysteine (NAC) blocked BSA-induced increases in GRP78 activation, eIF2alpha phosphorylation, SGLT expression, and alpha-MG uptake. Moreover, the cells upregulated peroxisome proliferator-activated receptor-gamma (PPARgamma) mRNA levels in response to BSA or troglitazone (a PPARgamma agonist), but BSA was ineffective in the presence of GW9662 (a PPARgamma antagonist). In addition, both BSA and troglitazone stimulated GRP78 and eIF2alpha activation, SGLT expression, and alpha-MG uptake, whereas GW9662 inhibited the effects of BSA. BSA also stimulated phosphorylation of JNK and NF-kappaB, and GW9662 or GRP78 siRNA attenuated this response. Moreover, SP600125 or SN50 effectively blocked SGLT expression and alpha-MG uptake in BSA- or PPARgamma agonists (troglitazone or PGJ2)-treated PTCs. We conclude that BSA induces ER stress through ROS production and PPARgamma activation, which subsequently activates JNK/NF-kappaB signaling to enhance glucose uptake in renal PTCs.}, }
@article {pmid19210339, year = {2009}, author = {Gonzalez, R and Arancibia, R and Cáceres, M and Martínez, J and Smith, PC}, title = {Cigarette smoke condensate stimulates urokinase production through the generation of reactive oxygen species and activation of the mitogen activated protein kinase pathways in human gingival fibroblasts.}, journal = {Journal of periodontal research}, volume = {44}, number = {3}, pages = {386-394}, doi = {10.1111/j.1600-0765.2008.01114.x}, pmid = {19210339}, issn = {1600-0765}, mesh = {Blotting, Western ; Cells, Cultured ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibrinolysin/biosynthesis ; Fibroblasts/enzymology ; Gingiva/cytology/*enzymology ; Humans ; MAP Kinase Kinase 4/metabolism ; MAP Kinase Signaling System ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Smoke/*adverse effects ; Nicotiana ; Urokinase-Type Plasminogen Activator/*biosynthesis ; }, abstract = {BACKGROUND AND OBJECTIVE: Tobacco smoking is a significant risk factor for periodontal disease. It has been suggested that smoking may alter connective tissue remodeling in the periodontium. In the present study, we investigated whether cigarette smoke condensate modulates the production of the serine protease urokinase in human gingival fibroblasts.<br><br>MATERIAL AND METHODS: Primary cultures of human gingival fibroblasts were stimulated with cigarette smoke condensate. Urokinase production was evaluated through casein zymography and western blotting. Plasmin activation was assessed by means of a radial diffusion assay. The roles of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and reactive oxygen species in cigarette smoke condensate-stimulated urokinase production were studied using distinct selective inhibitors (SP600125, PD98059, N-acetyl cysteine). Reactive oxygen species production was determined using a fluorometric assay. Activation of ERK and JNK pathways were evaluated using western blots.<br><br>RESULTS: In gingival fibroblasts, cigarette smoke condensate potently stimulated urokinase production and plasmin activation. Cigarette smoke condensate-stimulated urokinase production was dependent on the activity of ERK/JNK pathways and was inhibited by the reactive oxygen species scavenger, N-acetyl cysteine. Cigarette smoke condensate strongly stimulated ERK and JNK phosphorylation and the generation of reactive oxygen species.<br><br>CONCLUSION: Cigarette smoke condensate stimulates urokinase production and plasmin activation in gingival fibroblasts. Moreover, cigarette smoke condensate-stimulated urokinase production depends on both the activation of ERK/JNK pathways and on the generation of intracellular reactive oxygen species. These results show that cigarette smoke may alter connective tissue remodeling by inducing production of the urokinase-type plasminogen activator through specific signaling pathways.}, }
@article {pmid19204016, year = {2009}, author = {Petronilho, F and Constantino, L and de Souza, B and Reinke, A and Martins, MR and Fraga, CM and Ritter, C and Dal-Pizzol, F}, title = {Efficacy of the combination of N-acetylcysteine and desferrioxamine in the prevention and treatment of gentamicin-induced acute renal failure in male Wistar rats.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {24}, number = {7}, pages = {2077-2082}, doi = {10.1093/ndt/gfn774}, pmid = {19204016}, issn = {1460-2385}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/chemically induced/*drug therapy/*prevention &amp; control ; Animals ; Deferoxamine/*administration &amp; dosage ; Drug Therapy, Combination ; Free Radical Scavengers/*administration &amp; dosage ; Gentamicins/administration &amp; dosage ; Male ; Rats ; Rats, Wistar ; Siderophores/*administration &amp; dosage ; }, abstract = {BACKGROUND: Oxidative stress and the formation of aminoglycoside-iron complexes through iron-dependent Fenton reaction have been proposed to be the major mechanisms in the development of GM-induced acute renal failure (ARF); however, the efficacy of the combination of N-acetylcysteine (NAC) and desferrioxamine (DFX) in the prevention and the treatment of GM-induced ARF has not previously been investigated.<br><br>METHODS: In the prevention protocol, adult male Wistar rats received gentamicin (GM) [70 mg/kg, intraperitoneally (i.p), each 12 h for 7 days], NAC (20 mg/kg, sc, each 8 h for 7 days) and/or DFX (20 mg/kg, sc, at first, fourth and seventh days). In the treatment protocol animals received GM for 7 days. Additionally, animals received NAC and or DFX starting in the fourth day after GM administration. Parameters of renal function had been evaluated 24 h, 4 and 8 days after the beginning of GM administration in the prevention protocol and in Days 5 and 8 in the treatment protocol. At the end of experiment, lipid peroxidation (TBARS assay) and protein oxidation (protein carbonyls levels) formation were evaluated in kidney tissue as oxidative damage parameters.<br><br>RESULTS: In the prevention protocol, GM-induced ARF was prevented by the NAC and DFX association. Lipid peroxidation was attenuated by both antioxidant treatments, but the effects of NAC plus DFX were of greater magnitude. In the treatment protocol, plasma markers of renal injury were improved only in the NAC group, despite the similar antioxidant effect of both NAC, DFX and NAC plus DFX.<br><br>CONCLUSION: Although the combination of NAC and DFX was more effective in the prevention protocol, the use of NAC alone seemed to be superior to NAC-DFX combination, in the treatment of GM-induced ARF in adult male Wistar rats.}, }
@article {pmid19202565, year = {2009}, author = {Song, JD and Lee, SK and Kim, KM and Park, SE and Park, SJ and Kim, KH and Ahn, SC and Park, YC}, title = {Molecular mechanism of diallyl disulfide in cell cycle arrest and apoptosis in HCT-116 colon cancer cells.}, journal = {Journal of biochemical and molecular toxicology}, volume = {23}, number = {1}, pages = {71-79}, doi = {10.1002/jbt.20266}, pmid = {19202565}, issn = {1099-0461}, mesh = {Allyl Compounds/*pharmacology ; Antioxidants/metabolism ; Apoptosis/*drug effects ; CDC2 Protein Kinase/metabolism ; Cell Cycle/*drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Colonic Neoplasms/*pathology ; Cyclin B/metabolism ; Cyclin B1 ; Disulfides/*pharmacology ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Flow Cytometry ; HCT116 Cells ; Humans ; Oligomycins/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Time Factors ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Diallyl disulfide (DADS) is the most prevalent oil-soluble sulfur compound in garlic and inhibits cell proliferation in many cancer cell lines. Here we examined DADS cytotoxicity in a redox-mediated process, involving reactive oxygen species (ROS) production. In the present study, p53-independent cell cycle arrest at G2/M phase was observed with DADS treatment, along with time-dependent increase of cyclin B1. In addition, apoptosis was also observed upon 24-h DADS treatment accompanied by activation of p53. In HCT-116 cells, DADS application induced a dose-dependent increase and time-dependent changes in ROS production. Scavenging of DADS-induced ROS by N-acetyl cysteine or reduced glutathione inhibited cell cycle arrest, apoptosis and p53 activation by DADS. These results suggest that ROS trigger the DADS-induced cell cycle arrest and apoptosis and that ROS are involved in stress-induced signaling upstream of p53 activation. Transfection of p53 small interfering RNA prevents the accumulation of cleaved poly(ADP-ribose) polymerase and sub-G1 cell population by 65% and 35%, respectively. Moreover, DADS-induced apoptosis was also prevented by treatment with oligomycin, which is known to prevent p53-dependent apoptosis by reducing ROS levels in mitochondria. These results suggest that mitochondrial ROS may serve as second messengers in DADS-induced apoptosis, which requires activation of p53.}, }
@article {pmid19199600, year = {2009}, author = {Beyer, M and Ferse, I and Mulac, D and Würthwein, EU and Humpf, HU}, title = {Structural elucidation of T-2 toxin thermal degradation products and investigations toward their occurrence in retail food.}, journal = {Journal of agricultural and food chemistry}, volume = {57}, number = {5}, pages = {1867-1875}, doi = {10.1021/jf803516s}, pmid = {19199600}, issn = {1520-5118}, mesh = {Cell Line ; Drug Stability ; *Food Analysis ; Humans ; Molecular Structure ; Spectrometry, Mass, Electrospray Ionization ; T-2 Toxin/*chemistry/toxicity ; }, abstract = {The stability of T-2 toxin under the conditions of baking or cooking was investigated using heating experiments with the model substances alpha-d-glucose, alpha-d-methyl-glucopyranosid, N-alpha-acetyl-l-lysine methyl ester, and N-alpha-acetyl-cysteine methyl ester. The reaction residue was screened for degradation products using gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography with evaporative light-scattering detection (HPLC-ELSD). Although T-2 toxin was degraded under all conditions, only heating of T-2 toxin with alpha-d-glucose produced a mixture of three degradation products, which were isolated and identified by MS and nuclear magnetic resonance (NMR) experiments. The reaction mechanism for the formation of the T-2 degradation products was elucidated by quantum chemical calculations. The relevance of these degradation products was investigated by baking experiments as well as the analysis of retail food samples. In cell-culture studies using immortalized human kidney epithelial (IHKE) cells, the T-2 degradation products were less cytotoxic (formazan dye cytotoxicity assay) compared to T-2 toxin.}, }
@article {pmid19191959, year = {2009}, author = {Yiannakopoulou, ECh and Tiligada, E}, title = {Protective effect of salicylates against hydrogen peroxide stress in yeast.}, journal = {Journal of applied microbiology}, volume = {106}, number = {3}, pages = {903-908}, doi = {10.1111/j.1365-2672.2008.04061.x}, pmid = {19191959}, issn = {1365-2672}, mesh = {Acetylcysteine/pharmacology ; Aspirin/*pharmacology ; Cell Proliferation/drug effects ; Cells, Cultured ; Glutathione/pharmacology ; Hydrogen Peroxide/*pharmacology ; Oxidative Stress/*drug effects ; Saccharomyces cerevisiae/drug effects/*physiology ; }, abstract = {AIMS: To investigate the effects of salicylates in Saccharomyces cerevisiae exposed to oxidative stress induced by hydrogen peroxide (H(2)O(2)).<br><br>METHODS AND RESULTS: Saccharomyces cerevisiae was cultured through to the postlogarithmic phase of growth. Stress was induced by the addition of 1.5 mmol l(-1) H(2)O(2) for 1 h, while N-acetyl-l-cysteine (NAC) and glutathione (GSSG) were used as control agents that affect the redox balance. Sodium salicylate, at 0.01-10 mmol l(-1)or acetylsalicylic acid, at 0.02-2.5 mmol l(-1) was administered at various times before hydrogen peroxide stress. Both agents conferred resistance to a subsequent hydrogen peroxide stress, similarly to the induction of the adaptive response observed upon pretreatment with NAC and GSSG. Sodium salicylate was more potent as a short-term, but not as a long-term pretreatment agent, compared to acetylsalicylic acid.<br><br>CONCLUSIONS: Pharmacological pretreatment with salicylates resulted in dose related increases in cell survival, indicating the induction of the protective response in yeast.<br><br>The possible role of salicylates in the modulation of the hydrogen peroxide stress response in eukaryotic cells address questions on the effects of these commonly used therapeutic agents in a number of disorders exhibiting an oxidative stress component.}, }
@article {pmid19191214, year = {2009}, author = {West, PL and Lindgren, J and Horowitz, BZ}, title = {Amanita smithiana mushroom ingestion: a case of delayed renal failure and literature review.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {5}, number = {1}, pages = {32-38}, pmid = {19191214}, issn = {1556-9039}, mesh = {Amanita ; Antidotes/therapeutic use ; Creatinine/blood ; Humans ; Liver Diseases/etiology ; Liver Function Tests ; Male ; Middle Aged ; Mushroom Poisoning/*complications/therapy ; Oregon ; Renal Dialysis ; Renal Insufficiency/diagnosis/*etiology/therapy ; Time Factors ; Treatment Outcome ; }, abstract = {INTRODUCTION: In the Pacific Northwest a new pattern of mushroom ingestion has emerged, attributed to Amanita smithiana, in which renal failure has been the predominant manifestation.<br><br>CASE REPORT: A 55-year-old male ate 3 raw wild mushrooms in a salad and had onset of severe nausea and vomiting within 6 hours. His vital signs were unremarkable. His labs were significant for a BUN of 14 mg/dL (5.0 mmol/L), and a creatinine of 1.0 mg/dL (88 umol/L), transaminases were elevated with an AST of 56 U/L (nl 9-40) and an ALT of 131 U/L (nl 14-72). Treatment was initiated with N-acetyl cysteine, penicillin, and milk thistle extract on the presumption that this was an amanitin-toxin containing mushroom. He developed acute renal failure that was not responsive to our treatment. Dialysis started on day 4 with a creatinine of 6.5 mg/dL, which peaked on day 7 at 10.2 mg/dL. We were able to obtain a positive mushroom identification by a mycologist as Amanita smithiana. The patient was discharged from the hospital for outpatient dialysis on day 10 and dialysis catheter was removed 39 days after ingestion with a creatinine of 1.4 mg/dL (123.8 umol/L).<br><br>DISCUSSION: Amanita smithiana mushroom poisoning presents within 6 hours of ingestion with GI toxicity, and develops delayed onset of renal insufficiency over the first 1 to 4 days. The early hospitalization of this case allowed a profile of the onset of liver and renal injury. Mild elevation of hepatic transaminases occurred on presentation and peaked 24 hours after the ingestion. Renal injury was detected 1 day after presentation, and progressed to require hemodialysis by 4 days postingestion. This pattern of delayed-onset renal toxic mushroom ingestion is emerging among mushroom ingestions in Western North America.}, }
@article {pmid19189384, year = {2010}, author = {Aita, H and Tsukimura, N and Yamada, M and Hori, N and Kubo, K and Sato, N and Maeda, H and Kimoto, K and Ogawa, T}, title = {N-acetyl cysteine prevents polymethyl methacrylate bone cement extract-induced cell death and functional suppression of rat primary osteoblasts.}, journal = {Journal of biomedical materials research. Part A}, volume = {92}, number = {1}, pages = {285-296}, doi = {10.1002/jbm.a.32336}, pmid = {19189384}, issn = {1552-4965}, support = {C06 RR014529/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Bone Cements/*pharmacology ; Calcification, Physiologic/drug effects ; Caspases/metabolism ; Cell Count ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Gene Expression Regulation/drug effects ; Glutathione/metabolism ; Male ; Membrane Potential, Mitochondrial/drug effects ; Osteoblasts/*cytology/*drug effects/enzymology ; Polymethyl Methacrylate/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; }, abstract = {This study examines the cytotoxicity of bone cement extract to osteoblasts and the potential detoxification and restoration of osteoblastic function by an antioxidant amino acid, N-acetyl cysteine (NAC). The osteoblastic cells derived from rat femurs were cultured with extract from polymethyl methacrylate (PMMA)-based bone cement. The calcein and ethidium homodimer staining of the cells after 24-h incubation showed that 23.0% of the cells were dead in the culture with bone cement extract, while the addition of 5 mM NAC into the culture reduced the percentage to 4.3%. Annexin V and propidium iodide-based flow cytometric analysis also revealed that the apoptotic cells present at 15.8% in the culture with bone cement extract was reduced to 2.4% in the culture cotreated with bone cement extract and NAC. Severely suppressed alkaline phosphatase activity and matrix mineralization in the culture with bone cement extract (reduced to 10% and 5%, respectively, compared with the control culture) were restored to a normal level when treated with 5 mM NAC. The bone cement extract-induced, downregulated expression of osteoblastic genes, such as alkaline phosphatase, collagen I, and osteocalcin, was also restored to the baseline level by cotreatment with NAC. The data indicated that the addition of NAC into acrylic bone cement extract remarkably ameliorated the cytotoxicity to osteoblasts and restored their phenotype and function to a biologically significant degree, suggesting the potential usefulness of NAC in developing more biocompatible acrylic bone cement.}, }
@article {pmid19188555, year = {2009}, author = {Osoata, GO and Hanazawa, T and Brindicci, C and Ito, M and Barnes, PJ and Kharitonov, S and Ito, K}, title = {Peroxynitrite elevation in exhaled breath condensate of COPD and its inhibition by fudosteine.}, journal = {Chest}, volume = {135}, number = {6}, pages = {1513-1520}, doi = {10.1378/chest.08-2105}, pmid = {19188555}, issn = {1931-3543}, mesh = {Adult ; Aged ; Breath Tests ; Case-Control Studies ; Cystine/*analogs &amp; derivatives/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Female ; Half-Life ; Humans ; Inflammation Mediators/metabolism ; Interleukin-8/metabolism ; Male ; Middle Aged ; Nitric Oxide/metabolism ; Oxidative Stress/drug effects/*physiology ; Peroxynitrous Acid/*metabolism ; Pilot Projects ; Probability ; Pulmonary Disease, Chronic Obstructive/*diagnosis/*drug therapy ; Reference Values ; Respiratory Function Tests ; Sensitivity and Specificity ; Severity of Illness Index ; Sputum/cytology/metabolism ; }, abstract = {BACKGROUND: Peroxynitrite (PN) formed by the reaction of nitric oxide and superoxide is a powerful oxidant/nitrosant. Nitrative stress is implicated in COPD pathogenesis, but PN has not been detected due to a short half-life (< 1 s) at physiologic condition. Instead, 3-nitrotyrosine has been measured as a footprint of PN release.<br><br>METHOD: PN was measured using oxidation of 2',7'-dichlorofluorescein (DCDHF) in exhaled breath condensate (EBC) collected in high pH and sputum cells. The PN scavenging effect was also evaluated by the same system as PN-induced bovine serum albumin (BSA) nitration.<br><br>RESULTS: The mean (+/- SD) PN levels in EBC of COPD patients (7.9 +/- 3.0 nmol/L; n = 10) were significantly higher than those of healthy volunteers (2.0 +/- 1.1 nmol/L; p < 0.0001; n = 8) and smokers (2.8 +/- 0.9 nmol/L; p = 0.0017; n = 6). There was a good correlation between PN level and disease severity (FEV(1)) in COPD (p = 0.0016). Fudosteine (FDS), a unique mucolytic antioxidant, showed a stronger scavenging effect of PN than N-acetyl-cysteine on DCDHF oxidation in vitro and in sputum macrophages, and also on PN-induced BSA nitration. FDS (0.1 mmol/L) reduced PN-enhanced interleukin (IL)-1beta-induced IL-8 release and restored corticosteroid sensitivity defected by PN more potently than those induced by H(2)O(2) in A549 airway epithelial cells.<br><br>CONCLUSION: This noninvasive PN measurement in EBC may be useful for monitoring airway nitrative stress in COPD. Furthermore, FDS has the potential to inhibit PN-induced events in lung by its scavenging effect.}, }
@article {pmid19187231, year = {2009}, author = {Cheng, Y and Qiu, F and Ye, YC and Guo, ZM and Tashiro, S and Onodera, S and Ikejima, T}, title = {Autophagy inhibits reactive oxygen species-mediated apoptosis via activating p38-nuclear factor-kappa B survival pathways in oridonin-treated murine fibrosarcoma L929 cells.}, journal = {The FEBS journal}, volume = {276}, number = {5}, pages = {1291-1306}, doi = {10.1111/j.1742-4658.2008.06864.x}, pmid = {19187231}, issn = {1742-4658}, mesh = {Animals ; *Autophagy ; Cell Line, Tumor ; Diterpenes, Kaurane/*pharmacology ; Fibrosarcoma ; Mice ; Microscopy, Electron, Transmission ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Autophagy and apoptosis have been known to be interconnected positively or negatively; however, the molecular mechanisms mediating these two cellular processes are not fully understood. In the present study, we demonstrated that the exposure of L929 cells to oridonin led to intracellular reactive oxygen species generation, followed by lipid peroxidation, as well as decreases in superoxide dismutase and glutathione activities. The reactive oxygen species scavenger N-acetyl-cysteine resulted in the complete inhibition of oridonin-induced apoptosis and mitochondrial membrane potential collapse. We showed that reactive oxygen species triggered apoptosis by Bax translocation, cytochrome c release and extracellular signal-regulated kinase activation. Further data confirmed that oridonin also induced L929 cell autophagy, as demonstrated by extensive autophagic vacuolization and the punctuate distribution of monodansylcadaverine staining and GFP-LC3, as well as the LC3-II/LC3-I proportion and Beclin 1 activation. Subsequently, we found that inhibition of autophagy by 3-methyladenine or small interfering RNA against LC3 and Beclin 1 promoted oridonin-induced cell apoptosis. The effects of p38 and nuclear factor-kappa B in oridonin-induced apoptosis and autophagy were further examined. Interruption of p38 and nuclear factor-kappa B activation by specific inhibitors or small interfering RNAs promoted apoptosis and reactive oxygen species generation, but decreased autophagy. Moreover, we showed that inhibition of autophagy reduced oridonin-induced activation of p38. Additionally, nuclear factor-kappa B activation was inhibited by blocking the p38 pathway. Consequently, these findings indicate that oridonin-induced L929 cell apoptosis is regulated by reactive oxygen species-mediated signaling pathways, and that oridonin-induced autophagy may block apoptosis by up-regulating p38 and nuclear factor-kappa B activation.}, }
@article {pmid19185564, year = {2009}, author = {Di, X and Shiu, RP and Newsham, IF and Gewirtz, DA}, title = {Apoptosis, autophagy, accelerated senescence and reactive oxygen in the response of human breast tumor cells to adriamycin.}, journal = {Biochemical pharmacology}, volume = {77}, number = {7}, pages = {1139-1150}, doi = {10.1016/j.bcp.2008.12.016}, pmid = {19185564}, issn = {1873-2968}, mesh = {Apoptosis/drug effects/*physiology ; Autophagy/drug effects/*physiology ; Breast Neoplasms/drug therapy/*metabolism ; Cell Line, Tumor ; Cellular Senescence/drug effects/*physiology ; Doxorubicin/*pharmacology ; Humans ; Reactive Oxygen Species/*metabolism ; }, abstract = {Although the primary response to Adriamycin (doxorubicin) in p53 mutant MDA-MB231 and p53 null MCF-7/E6 breast tumor cells is apoptotic cell death, the residual surviving population appears to be in a state of senescence, based on cell morphology, beta galactosidase staining, induction of p21(waf1/cip1) and down regulation of cdc2/cdk1. Suppression of apoptosis in MDA-MB231 and MCF-7/E6 cells treated with Adriamycin using the broad spectrum caspase inhibitor, zvad-Fmk, results in substantial induction of autophagy. Overall sensitivity to Adriamycin, measured by clonogenic survival, is not altered in the cells undergoing autophagy, consistent with autophagy contributing to cell death in response to Adriamycin. The free radical scavengers, glutathione and N-acetyl cysteine attenuate the accelerated senescence response to Adriamycin in MCF-7 cells as well as in MDA-MB231 and MCF-7/E6 cells, but protect primarily the MCF-7 cells, indicating that reactive oxygen is unlikely to be directly responsible for Adriamycin toxicity in breast tumor cells. Expression of caspase 3 or induced expression of c-myc in MCF-7 cells fails to abrogate accelerated senescence induced by Adriamycin. Taken together, these studies suggest that accelerated senescence induced by Adriamycin is similar in cells with wild type p53 and in cells lacking functional p53 with regard to the upregulation of p21(waf1/cip1), down regulation of cdc2 and the involvement of reactive oxygen species. Furthermore, accelerated senescence, autophagy and apoptosis all appear to be effective in suppressing self-renewal capacity in breast tumor cells exposed to Adriamycin.}, }
@article {pmid19182949, year = {2009}, author = {Tsay, JG and Chung, KT and Yeh, CH and Chen, WL and Chen, CH and Lin, MH and Lu, FJ and Chiou, JF and Chen, CH}, title = {Calvatia lilacina protein-extract induces apoptosis through glutathione depletion in human colorectal carcinoma cells.}, journal = {Journal of agricultural and food chemistry}, volume = {57}, number = {4}, pages = {1579-1588}, doi = {10.1021/jf8030265}, pmid = {19182949}, issn = {1520-5118}, mesh = {Agaricales/*chemistry ; Antineoplastic Agents ; Apoptosis/*drug effects ; Cell Line, Tumor ; Colorectal Neoplasms ; DNA Damage/drug effects ; Glutathione/*analysis ; Humans ; In Situ Nick-End Labeling ; Mitochondria/drug effects ; Proteins/*pharmacology ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/analysis ; }, abstract = {This paper reports that a novel protein extract isolated from Calvatia lilacina (CL) can induce cell death against four types of human colorectal cancer cells. Importantly, CL was shown to be free of apoptotic effects against normal rat liver cells. We have also identified that CL-induced glutathione (GSH) depletion is the major contributor responsible for the apoptotic cell death induction of SW 480 cells, as evidenced by the observation that exogenously added N-acetylcysteine (NAC), or GSH, but not vitamin C, could offer a near complete protection of CL-treated cells against apoptotic cell death. Furthermore, the participation of reactive oxygen species (ROS) evoked a drop in the transmembrane potential (Delta Psi(m)) in the CL-induced apoptotic cell death. This observation can only be deemed as a minor pathway due to the fact that cyclosporine A (CyA) could only partially rescue the CL-treated cells from apoptotic cell death. Likewise, despite the fact that CL could induce the upregulation of Bax, its knockdown via siRNA (48 h) failed to completely mitigate apoptotic cell death, indicating that its role in this apoptotic process was insignificant. To further explore the possible underlying mechanism associated with CL-induced GSH depletion, we proceeded to determine the effect of CL on the cellular gamma-glutamylcysteine synthetase (gamma-GCS), a rate-limiting enzyme responsible for GSH biosynthesis, and demonstrated that indeed gamma-GCS could be repressed by CL. Taken together, we report here for the first time that the anticancer effect of CL on human colorectal cancer cells is mediated through GSH depletion mechanism rather than a ROS-mediated killing process. This functional attribute of CL can thus provide the basis for the strategic design of a treatment of colorectal cancer.}, }
@article {pmid19177506, year = {2009}, author = {Harada, H and Endo, T and Momose, Y and Kusama, H}, title = {A liquid chromatography/tandem mass spectrometry method for detecting UGT-mediated bioactivation of drugs as their N-acetylcysteine adducts in human liver microsomes.}, journal = {Rapid communications in mass spectrometry : RCM}, volume = {23}, number = {5}, pages = {564-570}, doi = {10.1002/rcm.3912}, pmid = {19177506}, issn = {0951-4198}, mesh = {Acetylcysteine/*analysis ; Chromatography, High Pressure Liquid/*methods ; Cyclooxygenase Inhibitors/analysis ; Diclofenac/*analysis ; Glucuronosyltransferase/*analysis ; Humans ; Ketoprofen/*analysis ; Microsomes, Liver/*metabolism ; Spectrometry, Mass, Electrospray Ionization/*methods ; }, abstract = {The detection of the reactive metabolites of drugs has recently been gaining increasing importance. In vitro trapping studies using trapping agents such as glutathione are usually conducted for the detection of reactive metabolites, especially those of cytochrome P450-mediated metabolism. In order to detect the UDP-glucuronosyltransferase (UGT)-mediated bioactivation of drugs, an in vitro trapping method using N-acetylcysteine (NAC) as a trapping agent followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) was developed in this study. After the test compounds (diclofenac and ketoprofen) had been incubated in human liver microsomes with uridine diphosphoglucuronic acid (UDPGA) and NAC, the NAC adducts formed through their acyl glucuronides were analyzed using LC/MS/MS with electrospray ionization (ESI). The NAC adduct showed a mass shift of 145 units as compared to its parent, and the characteristic ion fragmentations reflected the parent. This is a concise and high-throughput method for evaluating reactive metabolites by UGT-mediated bioactivation.}, }
@article {pmid19176594, year = {2009}, author = {Paranjpe, A and Cacalano, NA and Hume, WR and Jewett, A}, title = {N-acetyl cysteine mediates protection from 2-hydroxyethyl methacrylate induced apoptosis via nuclear factor kappa B-dependent and independent pathways: potential involvement of JNK.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {108}, number = {2}, pages = {356-366}, pmid = {19176594}, issn = {1096-0929}, support = {R01-10331//PHS HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cell Line ; Cell Nucleus/drug effects ; Cytokines/biosynthesis ; Cytoplasm/drug effects/metabolism ; DNA/biosynthesis/genetics ; Dental Materials/*toxicity ; Enzyme Activation/drug effects ; Enzyme-Linked Immunosorbent Assay ; Free Radical Scavengers/*pharmacology ; Gene Transfer Techniques ; Humans ; JNK Mitogen-Activated Protein Kinases/*physiology ; Keratinocytes/drug effects ; Luciferases/metabolism ; Methacrylates/*toxicity ; NF-kappa B/*antagonists &amp; inhibitors/*physiology ; Retroviridae/genetics ; Signal Transduction/drug effects ; }, abstract = {The mechanisms by which resin based materials induce adverse effects in patients have not been completely elucidated. Here we show that 2-hydroxyethyl methacrylate (HEMA) induces apoptotic cell death in oral keratinocytes. Functional loss and cell death induced by HEMA was significantly inhibited in the presence of N-acetyl cysteine (NAC) treatment. NAC also prevented HEMA mediated decrease in vascular endothelial growth factor secretion. The protective effect of NAC was partly related to its ability to induce NF-kappaB in the cells, since HEMA mediated inhibition of nuclear NF-kappaB expression and function was significantly blocked in the presence of NAC treatment. Moreover, blocking of nuclear translocation of NF-kappaB in oral keratinocytes sensitized these cells to HEMA mediated apoptosis. In addition, since NAC was capable of rescuing close to 50% of NF-kappaB knockdown cells from HEMA mediated cell death, there is, therefore, an NF-kappaB independent pathway of protection from HEMA mediated cell death by NAC. NAC mediated prevention of HEMA induced cell death in NF-kappaB knockdown cells was correlated with a decreased induction of c-Jun N-terminal kinase (JNK) activity since NAC inhibited HEMA mediated increase in JNK levels. Furthermore, the addition of a pharmacologic JNK inhibitor to HEMA treated cells prevented cell death and restored NF-kappaB knockdown cell function significantly. Therefore, NAC protects oral keratinocytes from the toxic effects of HEMA through NF-kappaB dependent and independent pathways. Moreover, our data suggest the potential involvement of JNK pathway in NAC mediated protection.}, }
@article {pmid19176390, year = {2009}, author = {Kim, DK and Yang, JS and Maiti, K and Hwang, JI and Kim, K and Seen, D and Ahn, Y and Lee, C and Kang, BC and Kwon, HB and Cheon, J and Seong, JY}, title = {A gonadotropin-releasing hormone-II antagonist induces autophagy of prostate cancer cells.}, journal = {Cancer research}, volume = {69}, number = {3}, pages = {923-931}, doi = {10.1158/0008-5472.CAN-08-2115}, pmid = {19176390}, issn = {1538-7445}, mesh = {Animals ; Autophagy/*drug effects/physiology ; Caspase 3/metabolism ; Cell Growth Processes/drug effects ; Cell Line, Tumor ; Cytochromes c/metabolism ; Female ; Gonadotropin-Releasing Hormone/*analogs &amp; derivatives/antagonists &amp; inhibitors ; HeLa Cells ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitochondria/drug effects/metabolism ; Oligopeptides/*pharmacology ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Gonadotropin-releasing hormone-I (GnRH-I) is known to directly regulate prostate cancer cell proliferation. However, the role of GnRH-II in prostate cancer is unclear. Here, we investigated the effect of the GnRH-II antagonist trptorelix-1 (Trp-1) on growth of PC3 prostate cancer cells. Trp-1 induced growth inhibition of PC3 cells in vitro and inhibited growth of PC3 cells xenografted into nude mice. FITC-N3, an FITC-conjugated Trp-1 analogue, was largely present in the mitochondria of prostate cancer cells, but not in other cells that are not derived from the prostate. Trp-1-induced PC3 growth inhibition was associated with decreased mitochondrial membrane potential and increased levels of mitochondrial and cytosolic reactive oxygen species (ROS). Growth inhibition was partially prevented by cotreating cells with N-acetyl cysteine, an antioxidant. Cytochrome c release and caspase-3 activation were not detected in Trp-1-treated cells. However, Trp-1 induced autophagosome formation, as seen by increased LysoTracker staining and recruitment of microtubule-associated protein 1 light chain 3 to these new lysosomal compartments. Trp-1-induced autophagy was accompanied by decreased AKT phosphorylation and increased c-Jun NH(2) terminal kinase phosphorylation, two events known to be linked to autophagy. Taken together, these data suggest that Trp-1 directly induces mitochondrial dysfunction and ROS increase, leading to autophagy of prostate cancer cells. GnRH-II antagonists may hold promise in the treatment of prostate cancer.}, }
@article {pmid19171376, year = {2009}, author = {Kurtoglu, YE and Navath, RS and Wang, B and Kannan, S and Romero, R and Kannan, RM}, title = {Poly(amidoamine) dendrimer-drug conjugates with disulfide linkages for intracellular drug delivery.}, journal = {Biomaterials}, volume = {30}, number = {11}, pages = {2112-2121}, pmid = {19171376}, issn = {1878-5905}, support = {N01 HD023342/HD/NICHD NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cattle ; Cell Line ; Chromatography, High Pressure Liquid ; Cysteine/chemistry ; Dendrimers/*chemistry ; Drug Delivery Systems/*methods ; Flow Cytometry ; Glutathione/chemistry ; Hydrogen-Ion Concentration ; Mice ; Polyamines/*chemistry ; Reactive Oxygen Species/metabolism ; Serum Albumin, Bovine/chemistry ; }, abstract = {Understanding and improving drug release kinetics from dendrimer-drug conjugates are key steps to improve their in vivo efficacy. N-Acetyl cysteine (NAC) is an anti-inflammatory agent with significant potential for clinical use in the treatment of neuroinflammation, stroke and cerebral palsy. There is a need for delivery of NAC which can enhance its efficacy, reduce dosage and prevent it from binding plasma proteins. For this purpose, a poly(amidoamine) dendrimer-NAC conjugate that contains a disulfide linkage was synthesized and evaluated for its release kinetics in the presence of glutathione (GSH), cysteine (Cys), and bovine serum albumin (BSA) at both physiological and lysosomal pH. The results indicate that the prepared conjugate can deliver approximately 60% of its NAC payload within 1h at intracellular GSH concentrations at physiological pH, whereas the conjugate did not release any drug at plasma GSH levels. The stability of the conjugate in the presence of bovine serum albumin at plasma concentrations was also demonstrated. The efficacy of the dendrimer-NAC conjugate was measured in activated microglial cells (target cells in vivo) using the reactive oxygen species (ROS) assay. The conjugates showed an order of magnitude increase in antioxidant activity compared to free drug. When combined with intrinsic and ligand-based targeting with dendrimers, these types of GSH sensitive nanodevices can lead to improved drug release profiles and in vivo efficacy.}, }
@article {pmid19168506, year = {2009}, author = {Poncin, S and Colin, IM and Gérard, AC}, title = {Minimal oxidative load: a prerequisite for thyroid cell function.}, journal = {The Journal of endocrinology}, volume = {201}, number = {1}, pages = {161-167}, doi = {10.1677/JOE-08-0470}, pmid = {19168506}, issn = {1479-6805}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Dual Oxidases ; Humans ; Mice ; NADPH Oxidases/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects/*physiology ; Peroxiredoxins/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Thyroid Gland/drug effects/metabolism/*physiology ; }, abstract = {In addition to reactive oxygen species (ROS) produced by mitochondria during aerobic respiration, thyrocytes are continuously producing H(2)O(2), a key element for hormonogenesis. Because nothing is known about ROS implication in normal non-stimulated cells, we studied their possible involvement in thyrocytes incubated with a potent antioxidant, N-acetylcysteine (NAC). NAC, which blocked the production of intracellular ROS, also decreased dual oxidases, thyroperoxidase, pendrin, and thyroglobulin protein and/or gene expression. By contrast, Na(+)/I(-) symporter mRNA expression was unaffected. Among antioxidant systems, peroxiredoxin (PRDX) five expression was reduced by NAC, whereas peroxiredoxin three increased and catalase remained unchanged. In vivo, the expression of both dual oxidases and peroxiredoxin five proteins was also decreased by NAC. In conclusion, when intracellular ROS levels drop below a basal threshold, the expression of proteins involved in thyroid cell function is hampered. This suggests that keeping ROS at a minimal level is required for safeguarding thyrocyte function.}, }
@article {pmid19161674, year = {2009}, author = {Yamada, M and Kojima, N and Att, W and Hori, N and Suzuki, T and Ogawa, T}, title = {N-Acetyl cysteine restores viability and function of rat odontoblast-like cells impaired by polymethylmethacrylate dental resin extract.}, journal = {Redox report : communications in free radical research}, volume = {14}, number = {1}, pages = {13-22}, doi = {10.1179/135100009X392430}, pmid = {19161674}, issn = {1743-2928}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 7/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Dental Pulp/cytology ; Dose-Response Relationship, Drug ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Male ; Membrane Potential, Mitochondrial/drug effects ; Odontoblasts/cytology/*drug effects/metabolism ; Polymethyl Methacrylate/*toxicity ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Resins, Synthetic/*toxicity ; }, abstract = {There is concern that dental-resin materials directly loaded on a prepared tooth adversely affect dental pulp tissue by releasing the resin chemicals through dentinal tubes. This study determined whether self-curing polymethyl methacrylate (PMMA)-based dental resin extract adversely affected the viability and function of odontoblast-like cells and whether the cytotoxicity of this resin, if any, could be eliminated by N-acetyl cysteine, an antioxidant amino acid derivative. Odontoblast-like cells isolated from rat maxillary incisor dental pulp tissue were exposed to a PMMA resin extract with or without N-acetyl cysteine for 1 h and then cultured in osteoblastic media. The percentage of viable cells 24 h after seeding was 20% in cells exposed to the resin extract without N-acetyl cysteine, whereas 45% of cells were viable after exposure to the N-acetyl cysteine-supplemented extract. The cells that had been exposed to the extract showed a strong tendency for apoptosis associated with the increased reactive oxygen species production and decreased intracellular glutathione level, which was improved by the addition of N-acetyl cysteine. N-Acetyl cysteine supplementation almost completely restored the significantly reduced alkaline phosphatase activity and matrix mineralization by the resin extract. These results conclusively demonstrated that exposure of odontoblast-like cells to the resin extract impaired the cell viability and function and, more intriguingly, N-acetyl cysteine supplementation to the extract significantly prevented these toxic effects.}, }
@article {pmid19160131, year = {2008}, author = {Senoglu, N and Yuzbasioglu, MF and Aral, M and Ezberci, M and Kurutas, EB and Bulbuloglu, E and Ezberci, F and Oksuz, H and Ciragil, P}, title = {Protective effects of N-acetylcysteine and beta-glucan pretreatment on oxidative stress in cecal ligation and puncture model of sepsis.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {21}, number = {5}, pages = {237-243}, doi = {10.1080/08941930802180136}, pmid = {19160131}, issn = {1521-0553}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism/*pharmacology ; Cecum ; Cytokines/blood ; Disease Models, Animal ; Female ; Inflammation Mediators/metabolism ; Ligation ; Lipid Peroxidation/drug effects ; Male ; Oxidative Stress/drug effects ; Punctures ; Rats ; Rats, Wistar ; Sepsis/etiology/metabolism/*prevention &amp; control ; beta-Glucans/*pharmacology ; }, abstract = {This study was designed to compare the effect of pretreatment with N-acetylcysteine (NAC) and beta -glucan (beta GLU) on inflammatory response in a rat model of sepsis. The study was performed in the animal laboratory of the Kahramanmaras Sutcu Imam University, School of Medicine. Forty rats were randomized into four groups (control, sham, NAC, and beta GLU). Control and Sham groups received saline or NAC (200 mg/kg, po) in the NAC group and beta GLU (50 mg/kg, po) in the betaGLU group via intragastric gavage once a day for 10 days and 30 min prior to surgery. Sepsis was induced by cecal ligation and puncture (CLP) in rats. In the NAC, beta GLU, and control groups, a laparotomy was performed with the CLP procedure. In the sham group, laparotomy was performed and cecum was manipulated but not ligated or perforated. TNF-alpha and IL-6 levels were significantly elevated in the control group and decreased in the NAC and beta GLU groups. IL-10 levels were significantly increased in the beta GLU group (p < .05). Superoxide dismutase and catalase levels in the liver tissue were significantly increased in the NAC and beta GLU groups, whereas superoxide dismutase levels were higher in the beta GLU pretreatment group than the NAC pretreatment group (p < 0.05). Malondialdehyde levels in the liver tissue were significantly elevated in the control group and decreased in the NAC and beta GLU groups (p < .05). Prophylactic administration of NAC or beta GLU similarly ameliorated sepsis syndrome by reduction of the proinflammatory cytokines and increase of the anti-inflammatory cytokine levels and accession of cellular antioxidants, which protect cells from oxidative stress, thereby recruiting inflammatory cells into tissue.}, }
@article {pmid19159629, year = {2009}, author = {Kumar, S and Sitasawad, SL}, title = {N-acetylcysteine prevents glucose/glucose oxidase-induced oxidative stress, mitochondrial damage and apoptosis in H9c2 cells.}, journal = {Life sciences}, volume = {84}, number = {11-12}, pages = {328-336}, doi = {10.1016/j.lfs.2008.12.016}, pmid = {19159629}, issn = {1879-0631}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Blotting, Western ; Cell Line ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Glucose/metabolism/*pharmacology ; Glucose Oxidase/metabolism/*pharmacology ; Hyperglycemia/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Heart/*drug effects/metabolism ; Myocytes, Cardiac/*drug effects/metabolism ; Oxidative Stress/*drug effects ; Peroxynitrous Acid/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {AIMS: High blood glucose may auto-oxidize and generate free radicals, which are proposed to induce apoptosis in cardiac cells. The aim of the present study was to investigate the cell damage induced by glucose/glucose oxidase-dependent oxidative stress and the protective effect of N-acetylcysteine (NAC) on H9c2 cardiac muscle cells.<br><br>MAIN METHODS: H9c2 cells were exposed to 33 mM glucose (G)+1.6 milliunits (mU) of glucose oxidase (GO) and termed G/GO. Cell apoptosis, generation of reactive oxygen species (ROS-super oxide anion and hydrogen peroxide) and reactive nitrogen species (RNS-peroxinitrite), and the change in mitochondrial membrane potential (DeltaPsim) was studied using flow cytometry and confocal microscopy, and cytochrome c release was measured using confocal microscopy. The expression of Bcl-2, Bax and the activation of procaspase-9 was studied by western blot.<br><br>KEY FINDINGS: Exposure of H9c2 cells to G/GO resulted in a significant increase in cellular apoptosis (P<0.05) and the generation of ROS and RNS (P<0.001). Further, G/GO treatment led to a decrease in DeltaPsim, release of cytochrome c, decrease in Bcl-2, increase in Bax expression and the activation of procaspase-9. Treatment with NAC significantly decreased apoptosis (P<0.05) and reduced the levels of ROS and RNS (P<0.001). NAC was also able to normalize DeltaPsim, inhibit cytochrome c release, increase Bcl-2 and decrease Bax expression and procaspase-9 activation.<br><br>SIGNIFICANCE: Our studies suggest that NAC has antioxidative and antiapoptotic activity against G/GO-induced oxidative stress through the inhibition of mitochondrial damage in H9c2 cells.}, }
@article {pmid19153832, year = {2009}, author = {Rakshit, S and Bagchi, J and Mandal, L and Paul, K and Ganguly, D and Bhattacharjee, S and Ghosh, M and Biswas, N and Chaudhuri, U and Bandyopadhyay, S}, title = {N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl+ cells by endothelial nitric oxide synthase-mediated production of nitric oxide.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {14}, number = {3}, pages = {298-308}, doi = {10.1007/s10495-008-0305-7}, pmid = {19153832}, issn = {1573-675X}, mesh = {Acetylcysteine/*pharmacology ; Annexin A5/pharmacology ; Apoptosis/drug effects/*physiology ; Benzamides ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Free Radical Scavengers/*pharmacology ; Fusion Proteins, bcr-abl/metabolism ; Hematologic Neoplasms/metabolism ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology ; Membrane Potential, Mitochondrial/physiology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/drug effects/*metabolism ; Piperazines/*pharmacology ; Protein Kinase Inhibitors/*pharmacology ; Protein-Tyrosine Kinases/*antagonists &amp; inhibitors ; Pyrimidines/*pharmacology ; Reactive Oxygen Species/analysis ; Up-Regulation/drug effects/physiology ; }, abstract = {INTRODUCTION: Imatinib, a small-molecule inhibitor of the Bcr-Abl kinase, is a successful drug for treating chronic myeloid leukemia (CML). Bcr-Abl kinase stimulates the production of H(2)O(2), which in turn activates Abl kinase. We therefore evaluated whether N-acetyl cysteine (NAC), a ROS scavenger improves imatinib efficacy.<br><br>MATERIALS AND METHODS: Effects of imatinib and NAC either alone or in combination were assessed on Bcr-Abl(+) cells to measure apoptosis. Role of nitric oxide (NO) in NAC-induced enhanced cytotoxicity was assessed using pharmacological inhibitors and siRNAs of nitric oxide synthase isoforms. We report that imatinib-induced apoptosis of imatinib-resistant and imatinib-sensitive Bcr-Abl(+) CML cell lines and primary cells from CML patients is significantly enhanced by co-treatment with NAC compared to imatinib treatment alone. In contrast, another ROS scavenger glutathione reversed imatinib-mediated killing. NAC-mediated enhanced killing correlated with cleavage of caspases, PARP and up-regulation and down regulation of pro- and anti-apoptotic family of proteins, respectively. Co-treatment with NAC leads to enhanced production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS). Involvement of eNOS dependent NO in NAC-mediated enhancement of imatinib-induced cell death was confirmed by nitric oxide synthase (NOS) specific pharmacological inhibitors and siRNAs. Indeed, NO donor sodium nitroprusside (SNP) also enhanced imatinib-mediated apoptosis of Bcr-Abl(+) cells.<br><br>CONCLUSION: NAC enhances imatinib-induced apoptosis of Bcr-Abl(+) cells by endothelial nitric oxide synthase-mediated production of nitric oxide.}, }
@article {pmid19151335, year = {2009}, author = {Wilson, SJ and Cavanagh, CC and Lesher, AM and Frey, AJ and Russell, SE and Smyth, EM}, title = {Activation-dependent stabilization of the human thromboxane receptor: role of reactive oxygen species.}, journal = {Journal of lipid research}, volume = {50}, number = {6}, pages = {1047-1056}, pmid = {19151335}, issn = {0022-2275}, support = {HL-066233/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Biological Transport, Active ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cell Line ; Cells, Cultured ; Endoplasmic Reticulum/metabolism ; Fatty Acids, Unsaturated/pharmacology ; Golgi Apparatus/metabolism ; Humans ; Mice ; Mice, Knockout ; Myocytes, Smooth Muscle/drug effects/metabolism ; NADPH Oxidases/deficiency/genetics ; RNA Processing, Post-Transcriptional ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Thromboxane A2, Prostaglandin H2/agonists/genetics/*metabolism ; Recombinant Proteins/genetics/metabolism ; Thromboxane A2/metabolism ; Transfection ; Up-Regulation/drug effects ; }, abstract = {Thromboxane A(2) (TxA(2)), the principle product of platelet COX-1-dependent arachidonic acid metabolism, directs multiple pro-atherogenic processes via its receptor, TP. Oxidative challenge offsets TP degradation, a key component in limiting TxA(2)'s actions. Following TP activation, we observed cellular reactive oxygen species (ROS) generation coincident with increased TP expression. We examined the link between TP-evoked ROS and TP regulation. TP expression was augmented in TPalpha-transfected cells treated with a TxA(2) analog [1S-1alpha,2beta(5Z),3alpha(1E,3R*),4alpha]]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid (IBOP). This was reduced with a cellular antioxidant, N-acetyl cysteine, or two distinct NADPH oxidase inhibitors, diphenyleneiodonium and apocynin. Homologous upregulation of the native TP was also reduced in apocynin-treated aortic smooth muscle cells (ASMCs) and was absent in ASMCs lacking an NADPH oxidase subunit (p47(-/-)). TP transcription was not increased in IBOP-treated cells, indicating a posttranscriptional mechanism. IBOP induced translocation of TPalpha to the Golgi and reduced degradation of the immature form of the receptor. These data are consistent with a ROS-dependent mechanism whereby TP activation enhanced TP stability early in posttranscriptional biogenesis. Given the significant role played by TP and ROS in perturbed cardiovascular function, the convergence of TP on ROS-generating pathways for regulation of TxA(2)-dependent events may be critical for cardiovascular disease.}, }
@article {pmid19150383, year = {2009}, author = {Zhang, SP and Zhou, YJ and Liu, Y and Cai, YQ}, title = {Effect of liquiritigenin, a flavanone existed from Radix glycyrrhizae on pro-apoptotic in SMMC-7721 cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {47}, number = {4}, pages = {693-701}, doi = {10.1016/j.fct.2008.12.015}, pmid = {19150383}, issn = {1873-6351}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Flavanones/*pharmacology ; Flow Cytometry ; Glutathione Peroxidase/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Proto-Oncogene Proteins c-bcl-2/analysis ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Tumor Suppressor Protein p53/analysis ; }, abstract = {Liquiritigenin is a flavanone existed in Radix glycyrrhizae. The objective of this study is to explore the effects of liquiritigenin on SMMC-7721 cells and its possible mechanism. The viability of liquiritigenin treat cells was decreased in a dose-dependent manner assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazolium bromide (MTT), and apoptotic morphological changes also be observed, such as chromatin condensation and nuclear fragmentation. Assessment of apoptotic cells by flow cytometry indicated that cells fell into apoptosis after 0.4mM liquiritigenin treatment. In addition, a concomitant time-dependent increase in caspase-3 activity was also observed. The level of p53 protein increased and Bcl-2 protein decreased time-dependently. Further studies found the induction of apoptosis by liquiritigenin was accompanied with the production of reactive oxygen species (ROS), disruption of mitochondrial membrane potential and depletion of antioxidant enzymes. The significant ROS generation was firstly found at 3h and being time-dependent until 9h. A time-dependent decrease in membrane potential occurred, and significant loss appeared at 9h and 12h. Furthermore, pretreatment of N-acetyl-cysteine (NAC), ROS production and apoptosis induced by liquiritigenin were both suppressed. In sum, this paper indicated the cytotoxicity of liquiritigenin on SMMC-7721 cells may via effect on generation of ROS, later lead to cell apoptosis.}, }
@article {pmid19147369, year = {2009}, author = {Baker, WL and Anglade, MW and Baker, EL and White, CM and Kluger, J and Coleman, CI}, title = {Use of N-acetylcysteine to reduce post-cardiothoracic surgery complications: a meta-analysis.}, journal = {European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery}, volume = {35}, number = {3}, pages = {521-527}, doi = {10.1016/j.ejcts.2008.11.027}, pmid = {19147369}, issn = {1873-734X}, mesh = {Acetylcysteine/*therapeutic use ; Cardiopulmonary Bypass/*adverse effects ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Oxidative Stress/*drug effects ; Postoperative Complications/*prevention &amp; control ; }, abstract = {Post-cardiothoracic surgery (CTS) complications (e.g. myocardial injury, renal dysfunction, atrial fibrillation) may occur as a result of enhanced systemic inflammation, perhaps provoked by an oxidative stress response. N-acetylcysteine (NAC) is a free radical scavenger antioxidant agent that may attenuate this physiologic response and reduce post-CTS complications. Thus, a meta-analysis was performed to help characterize the potential beneficial effects of perioperative NAC administration in patients undergoing CTS. A systematic literature search in MEDLINE, EMBASE and the Cochrane Library was conducted through April 2008. A search strategy using medical subject headings and text keywords was performed. Results are reported as odds ratios or weighted mean differences with accompanying 95% confidence intervals (CIs). Studies were pooled using a fixed-effect model. The primary outcomes included atrial fibrillation (AF), myocardial infarction (MI), stroke, acute kidney injury (AKI), need for renal replacement therapy (RRT), mortality and total hospital length-of-stay (LOS). Upon meta-analysis of 13 trials (n=1338 subjects), the use of NAC appeared to statistically significantly lower the odds of developing post-CTS AF by 36% (95%CI 2-58%) (n=6 studies). This corresponded to an 8% (1-15%) pooled risk difference and a number-needed-to-treat of 13. NAC did not appear to significantly alter any of the other meta-analysis endpoints. The exclusion of the study utilizing only oral NAC therapy and the study with lower internal validity did not affect the overall conclusions of our meta-analysis. Currently, the most compelling data for using NAC in CTS patients is in post-CTS AF prevention. However, additional, larger randomized controlled trials evaluating this and other postoperative complication endpoints are needed.}, }
@article {pmid19139768, year = {2009}, author = {Ayvaz, S and Aksu, B and Inan, M and Uzun, H and Aydin, S and Bilgi, S and Umit, HC and Pul, M}, title = {The effects of N-acetylcysteine on intestinal ischemia/reperfusion injury in rats.}, journal = {Saudi medical journal}, volume = {30}, number = {1}, pages = {24-29}, pmid = {19139768}, issn = {1658-3175}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Intestines/blood supply/*drug effects ; Rats ; Rats, Wistar ; Reperfusion Injury/*drug therapy/pathology ; }, abstract = {OBJECTIVE: To evaluate the effects of N-acetylcysteine NAC on the injury of intestinal ischemia-reperfusion.<br><br>METHODS: Forty-eight Wistar-Albino rats were divided into 6 groups: as control, ischemia, ischemia-reperfusion, ischemia + N-acetylcysteine, ischemia-reperfusion + N-acetylcysteine (IRN), and reperfusion + N-acetylcysteine (RN). Histopathologic examination was performed to all groups. In the tissue and plasma, and erythrocyte samples, malondialdehyde, superoxide dismutase, glutathione, and nitric oxide NO levels were evaluated. The present study was carried out in Trakya and Istanbul University, Edirne, Turkey between December 2002 and July 2003.<br><br>RESULTS: The most severe histopathological damage was seen in the intestinal ischemia-reperfusion group, and this damage was observed to be reduced by NAC administration. Lowest plasma malondialdehyde levels were observed in RN group. The tissue glutathione levels were found to be higher in RN group than those in IRN group.<br><br>CONCLUSION: It was found that administration of NAC has important effects on the injury of intestinal ischemia, as well as, reperfusion in rats. N-acetylcysteine administration causes an improvement in the histopathologic findings of ischemia/reperfusion damages. The N-acetylcysteine treatment protects the antioxidant enzymes in the tissue, plasma, and the erythrocytes, which are crucially important in the intestinal ischemia/reperfusion injury in rats.}, }
@article {pmid19138796, year = {2009}, author = {Eckhardt, A and Gerstmayr, N and Hiller, KA and Bolay, C and Waha, C and Spagnuolo, G and Camargo, C and Schmalz, G and Schweikl, H}, title = {TEGDMA-induced oxidative DNA damage and activation of ATM and MAP kinases.}, journal = {Biomaterials}, volume = {30}, number = {11}, pages = {2006-2014}, doi = {10.1016/j.biomaterials.2008.12.045}, pmid = {19138796}, issn = {1878-5905}, mesh = {Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line ; Cell Survival/drug effects ; DNA Damage/*drug effects ; DNA-Binding Proteins/*metabolism ; Enzyme Activation/*drug effects ; Guanine/analogs &amp; derivatives/metabolism ; Humans ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Oxidative Stress/drug effects ; Polyethylene Glycols/*toxicity ; Polymethacrylic Acids/*toxicity ; Protein Serine-Threonine Kinases/*metabolism ; Tumor Suppressor Proteins/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The development of strategies for the protection of oral tissues against the adverse effects of resin monomers is primarily based on the elucidation of underlying molecular mechanisms. The generation of reactive oxygen species beyond the capacity of a balanced redox regulation in cells is probably a cause of cell damage. This study was designed to investigate oxidative DNA damage, the activation of ATM, a reporter of DNA damage, and redox-sensitive signal transduction through mitogen-activated protein kinases (MAPKs) by the monomer triethylene glycol dimethacrylate (TEGDMA). TEGDMA concentrations as high as 3-5 mM decreased THP-1 cell viability after a 24h and 48h exposure, and levels of 8-oxoguanine (8-oxoG) increased about 3- to 5-fold. The cells were partially protected from toxicity in the presence of N-acetylcysteine (NAC). TEGDMA also induced a delay in the cell cycle. The number of THP-1 cells increased about 2-fold in G1 phase and 5-fold in G2 phase in cultures treated with 3-5 mM TEGDMA. ATM was activated in THP-1 cells by TEGDMA. Likewise, the amounts of phospho-p38 were increased about 3-fold by 3 mM TEGDMA compared to untreated controls after a 24h and 48h exposure period, and phospho-ERK1/2 was induced in a very similar way. The activation of both MAPKs was inhibited by NAC. Our findings suggest that the activation of various signal transduction pathways is related to oxidative stress caused by a resin monomer. Signaling through ATM indicates oxidative DNA damage and the activation of MAPK pathways indicates oxidative stress-induced regulation of cell survival and apoptosis.}, }
@article {pmid19138505, year = {2009}, author = {Schermer, T and Chavannes, N and Dekhuijzen, R and Wouters, E and Muris, J and Akkermans, R and van Schayck, O and van Weel, C}, title = {Fluticasone and N-acetylcysteine in primary care patients with COPD or chronic bronchitis.}, journal = {Respiratory medicine}, volume = {103}, number = {4}, pages = {542-551}, doi = {10.1016/j.rmed.2008.11.003}, pmid = {19138505}, issn = {1532-3064}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Androstadienes/*therapeutic use ; Bronchitis, Chronic/drug therapy ; Bronchodilator Agents/*therapeutic use ; Expectorants/*therapeutic use ; Female ; Fluticasone ; Forced Expiratory Volume ; Humans ; Male ; Middle Aged ; Netherlands ; Primary Health Care ; Pulmonary Disease, Chronic Obstructive/*drug therapy ; Quality of Life ; Smoking ; Treatment Outcome ; }, abstract = {BACKGROUND: Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD.<br><br>AIM: To investigate whether treatment with the inhaled corticosteroid fluticasone propionate (FP) or the anti-oxidative agent N-acetylcysteine (NAC) are effective in primary care patients.<br><br>METHODS: The study was a 3-year placebo-controlled randomised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment. Patients were (ex-)smokers with chronic bronchitis or COPD. Interventions were inhaled FP 500microg b.i.d., oral NAC 600mg o.d., or placebo. Exacerbation rate and quality of life measured with the Chronic Respiratory Questionnaire (CRQ) were the primary outcomes, FEV(1) decline and respiratory symptoms secondary outcomes.<br><br>RESULTS: 286 patients recruited from 44 general practices were randomised. Exacerbation rate was 1.35 times higher for NAC (p=0.054) and 1.30 times higher for FP (p=0.095) compared with placebo. CRQ total scores did not differ between NAC (p=0.306) or FP (p=0.581) treatment compared to placebo. Annual postbronchodilator FEV(1) decline was 64mL [SD 5.4] for NAC [p=0.569 versus placebo], 59mL [SD 5.7] for FP [p=0.935], and 60mL [SD 5.4] for placebo.<br><br>CONCLUSION: No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis.}, }
@article {pmid19136971, year = {2009}, author = {Moussawi, K and Pacchioni, A and Moran, M and Olive, MF and Gass, JT and Lavin, A and Kalivas, PW}, title = {N-Acetylcysteine reverses cocaine-induced metaplasticity.}, journal = {Nature neuroscience}, volume = {12}, number = {2}, pages = {182-189}, pmid = {19136971}, issn = {1546-1726}, support = {P50 DA015369-06/DA/NIDA NIH HHS/United States ; P50 DA015369/DA/NIDA NIH HHS/United States ; DA12513/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; DA015369/DA/NIDA NIH HHS/United States ; R01 DA012513/DA/NIDA NIH HHS/United States ; DA024355/DA/NIDA NIH HHS/United States ; R37 DA003906-25/DA/NIDA NIH HHS/United States ; R37 DA003906/DA/NIDA NIH HHS/United States ; R01 DA024355/DA/NIDA NIH HHS/United States ; DA03906/DA/NIDA NIH HHS/United States ; R01 DA012513-09/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Behavior, Animal/drug effects ; Cocaine-Related Disorders/*drug therapy/*physiopathology ; Disease Models, Animal ; Excitatory Amino Acid Antagonists/pharmacology ; Excitatory Postsynaptic Potentials/drug effects ; Free Radical Scavengers/*pharmacology ; Long-Term Potentiation/drug effects ; Long-Term Synaptic Depression/drug effects ; Male ; Neuronal Plasticity/*drug effects ; Nucleus Accumbens/drug effects/physiology ; Prefrontal Cortex/drug effects/physiology ; Pyridines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/antagonists &amp; inhibitors/physiology ; Secondary Prevention ; Self Administration ; Substance Withdrawal Syndrome/drug therapy/physiopathology ; }, abstract = {Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.}, }
@article {pmid19136474, year = {2009}, author = {Zhao, W and Mackenzie, GG and Murray, OT and Zhang, Z and Rigas, B}, title = {Phosphoaspirin (MDC-43), a novel benzyl ester of aspirin, inhibits the growth of human cancer cell lines more potently than aspirin: a redox-dependent effect.}, journal = {Carcinogenesis}, volume = {30}, number = {3}, pages = {512-519}, pmid = {19136474}, issn = {1460-2180}, support = {R01 CA092423/CA/NCI NIH HHS/United States ; R01 CA101019/CA/NCI NIH HHS/United States ; 2R01 CA92423/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/physiology ; Aspirin/*analogs &amp; derivatives/chemistry/*pharmacology ; Cell Cycle/*drug effects/physiology ; Cell Death/*drug effects/physiology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Humans ; Isomerism ; Membrane Potential, Mitochondrial/drug effects/physiology ; Organophosphates/chemistry/*pharmacology ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Aspirin is chemopreventive against colon and probably other cancers, but this effect is relatively weak and its chronic administration to humans is associated with significant side effects. Because of these limitations, extensive effort has been exerted to improve the pharmacological properties of aspirin. We have determined the anticancer activity and mechanisms of action of the novel para positional isomer of phosphoaspirin [P-ASA; MDC-43; 4-((diethoxyphosphoryloxy)methyl)phenyl 2-acetoxybenzoate]. P-ASA inhibited the growth of 10 human cancer cell lines originating from colon, lung, liver, pancreas and breast, at least 18- to 144-fold more potently than conventional aspirin. P-ASA achieved this effect by modulating cell kinetics; compared with controls, P-ASA reduced cell proliferation by up to 68%, increased apoptosis 5.5-fold and blocked cell cycle progression in the G(2)/M phase. P-ASA increased intracellular levels of reactive oxygen species (ROS), depleted glutathione levels and modulated cell signaling predominantly through the mitogen-activated protein kinase (p38 and c-jun N-terminal kinase), cyclooxygenase (COX) and nuclear factor-kappa B pathways. P-ASA targeted the mitochondria, increasing mitochondrial superoxide anion levels; this effect on ROS led to collapsed mitochondrial membrane potential and triggered the intrinsic apoptotic pathway. The antioxidant N-acetyl cysteine abrogated the cell growth inhibitory and signaling effects of P-ASA, underscoring the centrality of ROS in its mechanism of action. Our results, establishing P-ASA as a potent inhibitor of the growth of several human cancer cell lines, suggest that it may possess broad anticancer properties. We conclude that the novel P-ASA is a promising anticancer agent, which merits further evaluation.}, }
@article {pmid19136048, year = {2009}, author = {Hariharakrishnan, J and Satpute, RM and Prasad, GB and Bhattacharya, R}, title = {Oxidative stress mediated cytotoxicity of cyanide in LLC-MK2 cells and its attenuation by alpha-ketoglutarate and N-acetyl cysteine.}, journal = {Toxicology letters}, volume = {185}, number = {2}, pages = {132-141}, doi = {10.1016/j.toxlet.2008.12.011}, pmid = {19136048}, issn = {0378-4274}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cell Line ; Cell Survival/drug effects ; Energy Metabolism/drug effects ; Epithelial Cells/*drug effects/enzymology/metabolism ; Ketoglutaric Acids/*pharmacology ; Lipid Peroxidation/drug effects ; Macaca mulatta ; Oxidative Stress/*drug effects ; Potassium Cyanide/*toxicity ; }, abstract = {Cyanide is a rapidly acting mitochondrial poison that inhibits cellular respiration and energy metabolism leading to histotoxic hypoxia followed by cell death. Cyanide is predominantly a neurotoxin but its toxic manifestations in non-neuronal cells are also documented. This study addresses the oxidative stress mediated cytotoxicity of cyanide in Rhesus monkey kidney epithelial cells (LLC-MK2). Cells were treated with various concentrations of potassium cyanide (KCN) for different time intervals and cytotoxicity was evidenced by increased leakage of intracellular lactate dehydrogenase, mitochondrial dysfunction (MTT assay) and depleted energy status of cells (ATP assay). Cytotoxicity was accompanied by lipid peroxidation indicated by elevated levels of malondialdehyde (MDA), reactive oxygen species (ROS) and reactive nitrogen species (RNS) (DCF-DA staining), diminished cellular antioxidant status (reduced glutathione (GSH), glutathione peroxidase, superoxide dismutase and catalase). These cascading events triggered an apoptotic kind of cell death characterized by oligonucleosomal DNA fragmentation and nuclear fragmentation (Hoechst 33342 staining). Apoptosis was further confirmed by increased caspase-3 activity. Cyanide-induced cytotoxicity, oxidative stress, and DNA fragmentation were prevented by alpha-ketoglutarate (A-KG) and N-acetyl cysteine (NAC). A-KG is a potential cyanide antidote that confers protection by interacting with cyanide to form cyanohydrin complex while NAC is a free radical scavenger and enhances the cellular GSH levels. The study reveals cytotoxicity of cyanide in cells of renal origin and the protective efficacy of A-KG and NAC.}, }
@article {pmid19135143, year = {2009}, author = {Papaefthimiou, C and Antonopoulou, E and Theophilidis, G}, title = {Inhibitory vs. protective effects of N-acetyl-l-cysteine (NAC) on the electromechanical properties of the spontaneously beating atria of the frog (Rana ridibunda): an ex vivo study.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {23}, number = {2}, pages = {272-280}, doi = {10.1016/j.tiv.2008.12.012}, pmid = {19135143}, issn = {0887-2333}, mesh = {Acetylcysteine/*pharmacology ; Action Potentials/drug effects ; Animals ; Atrial Function/*drug effects ; Cadmium/toxicity ; Dose-Response Relationship, Drug ; Drug Antagonism ; Drug Combinations ; Female ; Free Radical Scavengers/*pharmacology ; Heart Atria/*drug effects/pathology/physiopathology ; In Vitro Techniques ; Male ; Myocytes, Cardiac/drug effects/pathology ; No-Observed-Adverse-Effect Level ; *Rana ridibunda ; Rotenone/toxicity ; }, abstract = {The results of this study have shown that N-acetyl-l-cysteine (NAC), a compound used for protection of tissues or cell cultures against the deleterious effects of various environmental pollutants, has certain unusual effects on the contraction of the spontaneously beating atria of the frog isolated in saline (ex vivo): (1) NAC, 6.0 and 10.0mM, eliminated, in a concentration-dependent manner, the contractile properties of the atria (force and frequency) within minutes, without affecting its electrical properties; (2) the IC(50) of NAC for the force was 5.09+/-1.01 mM (n=6) [4.98-5.19 mM, 95% confidence interval (CI)], significantly lower than the IC(50) for the frequency, 6.15+/-1.01 mM, (6.02-6.29 mM, 95% CI), indicating that working atria cells are more sensitive to NAC than autorhythmic cells. The no-observed-effect concentration (NOEC) was 1-2mM; (3) the pattern of NAC-induced inhibition of electromechanical activity was similar to that of verapamil, an indication that NAC possibly affects L-type voltage-gated calcium channels; (4) NAC at 2mM protected against cadmium-induced inhibition of atria contraction. The IC(50) for cadmium was 17.9+/-1.1 microM (n=6) (16.9-19.0 microM, 95% CI), while in the presence of 2mM NAC, it became 123.3+/-1.0 microM (n=6) (114.8-132.4 microM, 95% CI). The same concentration of NAC failed to exert any protective effects against rotenone (5 microM)-induced inhibition of atria contraction. The protective effects of NAC are probably due to chelation of cadmium, rather than scavenging of oxidants.}, }
@article {pmid19135140, year = {2009}, author = {Zhou, YJ and Zhang, SP and Liu, CW and Cai, YQ}, title = {The protection of selenium on ROS mediated-apoptosis by mitochondria dysfunction in cadmium-induced LLC-PK(1) cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {23}, number = {2}, pages = {288-294}, doi = {10.1016/j.tiv.2008.12.009}, pmid = {19135140}, issn = {0887-2333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cadmium Chloride/*toxicity ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Enzyme Activation/drug effects ; LLC-PK1 Cells/*drug effects/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/physiology ; Necrosis/chemically induced ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Sodium Selenite/*pharmacology ; Swine ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Selenium, an essential trace element, showed the significant protective effects against liver and kidney damage induced by some heavy metals. However, the mechanism how selenium suppresses cadmium (Cd)-induced cytotoxicity remains unclear. In this study, we investigated the protective mechanism of selenium on Cd-induced apoptosis in LLC-PK(1) cells via reactive oxygen species (ROS) and mitochondria linked signal pathway. Studies of PI and Annexin V dual staining analysis demonstrated that 20 microM Cd-induced apoptosis as early as 18 h. A concomitant by the generation of ROS, the loss of mitochondrial membrane potential, cytochrome c (cyt c) release, activation of caspase-9, -3 and regulation of Bcl-2 and Bax were observed. N-acetylcysteine (NAC, 500 microM), a free radical scavenger, was used to determine the involvement of ROS in Cd-induced apoptosis. During the process, selenium played the same role as NAC. The anti-apoptosis exerted by selenium involved the blocking of Cd-induced ROS generation, the inhibition of Cd-induced mitochondrial membrane potential collapse, the prevention of cyt c release, subsequent inhibition of caspase activation and the changed level of Bcl-2 and Bax. Taken together, we concluded that Cd-induced apoptosis was mediated by oxidative stress and selenium produced a significant protection against Cd-induced apoptosis in LLC-PK(1) via ameliorating the mitochondrial dysfunction.}, }
@article {pmid19130331, year = {2009}, author = {Gürer, A and Ozdoğan, M and Gökakin, AK and Gömceli, I and Gülbahar, O and Arikök, AT and Kulaçoğlu, H and Aydin, R}, title = {Tissue oxidative stress level and remote organ injury in two-hit trauma model of sequential burn injury and peritoneal sepsis are attenuated with N-acetylcysteine treatment in rats.}, journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma &amp; emergency surgery : TJTES}, volume = {15}, number = {1}, pages = {1-6}, pmid = {19130331}, issn = {1306-696X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Burns ; Cecum/injuries ; Disease Models, Animal ; Glutathione/*analysis ; Intestinal Perforation/complications ; Ligation ; Liver/metabolism ; Lung/metabolism ; Male ; Malondialdehyde/*analysis ; Oxidative Stress/*drug effects ; Random Allocation ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: The second hit in trauma leads to an exaggerated inflammatory response and multiple organ failure. Infection following burn injury is a useful model for two-hit trauma studies. The aim of this study was to investigate the effect of N-acetylcysteine (NAC) treatment as an antioxidant in a two-hit trauma model.<br><br>METHODS: 30% scalding burn injury was performed in 45 rats and cecal ligation-puncture (CLP) was performed 72 hours later. Groups were allocated as follows: Group I: No treatment was performed; Group II: Rats were treated with 150 mg/kg/day i.p. NAC for 72 h following CLP; Group III: Rats were treated with 150 mg/kg/day i.p. NAC for 6 days following thermal injury. Tissue samples were collected to study the tissue malonyldialdehyde (MDA) and glutathione (GSH) levels, and for histopathological examination on day 7.<br><br>RESULTS: No difference in mortality between groups was detected. Tissue MDA levels significantly decreased in the liver (p=0.01, p=0.02) and ileum (p=0.01, p=0.02) in the treatment groups. Lung tissue GSH levels were found to be significantly increased in Group II (p=0.02). Lung injury scores were decreased in Group II (p=0.005) compared to the control group.<br><br>CONCLUSION: NAC attenuated tissue oxidative stress level and remote organ injury in two-hit trauma. Further experimental and clinical studies on this subject are necessary.}, }
@article {pmid19126599, year = {2009}, author = {Wang, SH and Shih, YL and Kuo, TC and Ko, WC and Shih, CM}, title = {Cadmium toxicity toward autophagy through ROS-activated GSK-3beta in mesangial cells.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {108}, number = {1}, pages = {124-131}, doi = {10.1093/toxsci/kfn266}, pmid = {19126599}, issn = {1096-0929}, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Autophagy/*drug effects ; Cadmium/*toxicity ; Cell Line ; Gene Expression ; Gene Knockdown Techniques ; Glycogen Synthase Kinase 3/*metabolism ; Glycogen Synthase Kinase 3 beta ; Indoles/pharmacology ; Maleimides/pharmacology ; Mesangial Cells/*metabolism/ultrastructure ; Mice ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; }, abstract = {We previously demonstrated that cadmium (Cd) is able to induce autophagic cell death through a calcium-extracellular signal-regulated kinase pathway. Here, the object of this study is to investigate the role of glycogen synthase kinase-3beta (GSK-3beta) in the induction of autophagy. After treatment with Cd, MES-13 mesangial cells were determined to have undergone autophagy based on the formation of acidic vesicular organelles and autophagosomes as well as on the processing of microtubule-associated protein 1 light chain 3, using flow cytometry with acridine orange staining, electron microscopy, and immunoblot, respectively. Use of the GSK-3beta inhibitor SB 216763 or the small interfering RNA technique to knockdown the expression of GSK-3beta resulted in a decrease of Cd-induced autophagy. In contrast, overexpression of GSK-3beta by transient transfection potentiated Cd toxicity toward the mesangial cells, suggesting that GSK-3beta plays a crucial role in regulating Cd-induced autophagy. Moreover, a decrease of the phosphorylated level at Ser9 of GSK-3beta was observed by immunoblot after treatment with Cd, indicating GSK-3beta was activated by Cd. This phenomenon was reversed by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC), demonstrated that ROS might activate GSK-3beta. In fact, intracellular hydrogen peroxide (H(2)O(2)) was 2.6-fold elevated after 3 h of exposure to Cd. Both Cd-induced ROS bursts and autophagy were reduced by NAC and vitamin E. In summary, this study demonstrated that, in MES-13 mesangial cells, Cd-induced autophagy was mediated through the ROS-GSK-3beta signaling pathway.}, }
@article {pmid19124377, year = {2008}, author = {Dal Negro, R and Visconti, M and Trevisan, F and Bertacco, S and Micheletto, C and Tognella, S}, title = {Erdosteine enhances airway response to salbutamol in patients with mild-to-moderate COPD.}, journal = {Therapeutic advances in respiratory disease}, volume = {2}, number = {5}, pages = {271-277}, doi = {10.1177/1753465808096109}, pmid = {19124377}, issn = {1753-4658}, mesh = {Adrenergic beta-Agonists/*therapeutic use ; Aged ; Albuterol/*therapeutic use ; Bronchi/drug effects ; Drug Synergism ; Expectorants/*pharmacology ; Female ; Forced Expiratory Volume ; Humans ; Lipid Peroxidation/drug effects ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy ; Reactive Oxygen Species/analysis ; Thioglycolates/*pharmacology ; Thiophenes/*pharmacology ; }, abstract = {BACKGROUND: Oxidative stress is presumed to impair beta-adenoceptor function and airway patency. Erdosteine (E), a mucomodulatory compound, has shown important antioxidant properties.<br><br>METHODS: The objective was to assess the effect of antioxidant interventions on short-term airway response to salbutamol in non-reversible mild-to-moderate COPD patients. Thirty COPD patients (GOLD class 1-2), current smoker (>or=10 pack/year), randomly received E 300 mg, N-acetylcysteine (NAC) 600 mg, or placebo, twice daily for ten days. Reversibility to salbutamol 200 microg was tested in baseline, after four and ten days of each treatment. ROS and 8-isoprostane blood levels were measured on the same days. Between-treatment comparison was performed by ANOVA and t-test or Wilcoxon test, and p<0.05 assumed. E enhanced FEV1 reversibility after four and ten days significantly (+5.1% and +5.0%; both p<0.01 vs. placebo), while NAC only showed a transient effect at day 4 (+3.0%, p<0.05), but not at day 10 (+1.3%, p = ns).<br><br>RESULTS: E and NAC caused significant drops in ROS blood levels after four and ten days (p<0.001 and p<0.0001 vs. placebo). In contrast to NAC, E lowered 8-isoprostane levels substantially for ten days (p = 0.017 and p = 0.0004 vs. placebo, respectively). Only E restored significantly short-term reversibility in COPD patients previously unresponsive to beta(2)-adrenergics.<br><br>CONCLUSIONS: This effect seems more related to the peculiar protection against lipid peroxidation rather than to the scavenging activity, which proves equal to that of NAC. E provides a sort of indirect bronchodilation through 're-sensitisation' of beta(2)-adrenoceptors. Once confirmed in further controlled studies, it may be useful in long-term treatment of COPD.}, }
@article {pmid19122744, year = {2008}, author = {Glauert, HP and Tharappel, JC and Lu, Z and Stemm, D and Banerjee, S and Chan, LS and Lee, EY and Lehmler, HJ and Robertson, LW and Spear, BT}, title = {Role of oxidative stress in the promoting activities of pcbs.}, journal = {Environmental toxicology and pharmacology}, volume = {25}, number = {2}, pages = {247-250}, pmid = {19122744}, issn = {1382-6689}, support = {P42 ES013661-02/ES/NIEHS NIH HHS/United States ; P42 ES007380/ES/NIEHS NIH HHS/United States ; P42 ES013661-01A1/ES/NIEHS NIH HHS/United States ; P42 ES013661-030001/ES/NIEHS NIH HHS/United States ; P42 ES013661-01A10001/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; P42 ES013661-03/ES/NIEHS NIH HHS/United States ; P42 ES013661-020001/ES/NIEHS NIH HHS/United States ; }, abstract = {PCBs are organic pollutants that persist and bioaccumulate in the environment. These chemicals induce and promote liver tumors in rodents. Previous studies have shown that they increase oxidative stress in the liver, including lipid peroxidation, oxidative DNA damage, and NF-κB activation. The objective of these studies was to determine if the promoting activities of PCBs could be inhibited by dietary antioxidants (vitamin E, selenium, or phytochemicals) or by knocking out the p50 subunit of NF-κB. In the antioxidant studies, female rats were first injected with DEN (150 mg/kg) and then administered 4 biweekly i.p. injections (300 μmol/kg/injection) of PCB-77, PCB-153, or vehicle; the number and volume of placental glutathione S-transferase (PGST)-positive foci were then quantified. Vitamin E did not influence the promoting activities of PCBs. Increasing dietary selenium above the recommended intake increased the number of foci induced but decreased their volume. Most of the phytochemicals examined (N-acetyl cysteine, β-carotene, resveratrol, EGCG) had no significant effect on the promoting activity of PCB-77. Ellagic acid increased and lycopene decreased the number of foci; ellagic acid, CoQ(10), and curcumin decreased the volume of foci. In the NF-κB knockout study, male mice were first injected with DEN (90 mg/kg); controls not receiving DEN were also studied. Both p50 -/- and wild-type mice were then injected biweekly 20 times with PCB-153 (300 (μmol/kg). In DEN-treated and DEN + PCB-treated mice, the incidence of tumors was lower in the p50 -/- mice than in wild-type mice. In mice receiving PCB-153, the tumor incidence and tumor volume were higher. The volume of tumors that were positive for glutamine synthetase was increased in mice administered PCB-153. This study shows that the promotion of hepatocarcinogenesis by PCBs is largely unaffected by dietary antioxidants but is diminished when NF-κB activation is impaired by the absence of the p50 subunit.}, }
@article {pmid19122686, year = {2008}, author = {Kilciksiz, S and Demirel, C and Erdal, N and Gürgül, S and Tamer, L and Ayaz, L and Ors, Y}, title = {The effect of N-acetylcysteine on biomarkers for radiation-induced oxidative damage in a rat model.}, journal = {Acta medica Okayama}, volume = {62}, number = {6}, pages = {403-409}, doi = {10.18926/AMO/30946}, pmid = {19122686}, issn = {0386-300X}, mesh = {Acetylcysteine/*pharmacology ; Amifostine/pharmacology ; Animals ; Biomarkers/blood ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/blood ; Liver/metabolism/radiation effects ; Malondialdehyde/blood ; Oxidative Stress/drug effects/radiation effects ; Peroxidase/blood ; Radiation Dosage ; Radiation Injuries, Experimental/*drug therapy/*metabolism ; Radiation-Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {Our study aimed to investigate the potential radioprotective effects of N-acetylcysteine (NAC) by comparing its biochemical effects with those of WR-2721, as a representative of clinically used radioprotectors, in preventing oxidative damage caused by gamma irradiation (single dose, 6Gy) in normal rat tissue. The rats (n=40) were divided randomly and equally into 4 groups:Control (C), Radiation (R), R+NAC (received irradiation and 1,000 mg/kg NAC) and R+WR-2721 (received irradiation and 200 mg/kg WR-2721) rats. Liver tissues and blood samples were harvested and utilized for reduced glutathione (GSH), malondialdehyde (MDA) and myeloperoxidase (MPO) detection. Serum and tissue GSH levels of R rats decreased compared to those of other groups (p<0.01). Tissue MDA levels of R+NAC and R+WR-2721 rats decreased compared to R rats (p<0.01; p<0.05, respectively). Tissue MPO activities of R+NAC and R+WR-2721 rats were higher than those of R rats (p<0.001). Serum MPO levels of R+WR-2721 rats were lower than those of C rats and R rats (p<0.01, p<0.001, respectively). In conclusion, the study suggests that the radioprotective effect against radiation-induced oxidative damage of NAC may be similar to that of WR-2721.}, }
@article {pmid19122538, year = {2009}, author = {Leung, KS and Cottler, LB}, title = {Treatment of pathological gambling.}, journal = {Current opinion in psychiatry}, volume = {22}, number = {1}, pages = {69-74}, doi = {10.1097/YCO.0b013e32831575d9}, pmid = {19122538}, issn = {1473-6578}, mesh = {Disruptive, Impulse Control, and Conduct Disorders/drug therapy/rehabilitation ; *Gambling ; Humans ; Narcotic Antagonists/*therapeutic use ; Psychotherapy/*methods ; Psychotropic Drugs/*therapeutic use ; }, abstract = {PURPOSE OF REVIEW: This paper highlights the development of pharmacological and nonpharmacological treatments for pathological gambling and is based on a review of the literature published in the past 12 months.<br><br>RECENT FINDINGS: The efficacy of naltrexone treatment for pathological gambling has been replicated in a double-blind, placebo-controlled, confirmatory study. For mood stabilizers, whereas carbamazepine and topiramate continued to produce positive results, olanzapine failed to show superior outcomes compared with placebo control. Two new pharmacological agents for pathological gambling, N-acetyl cysteine and modafinil, produced significant improvement for pathological gamblers. Several studies examined the outcomes of nonpharmacological treatments. Recent studies showed that cognitive-behavioral therapy failed to produce superior outcomes compared with other less costly methods such as brief interventions. Two new nonpharmacological treatment methods have been reported, including the use of videoconferencing in delivering ongoing supervisions after exposure therapy and the congruence couple therapy, which aims to heal the person as a system whole.<br><br>SUMMARY: Recent treatment outcomes studies address not only the effectiveness, but also the efficacy of different treatment approaches. Results of two meta-analysis studies showed that nonpharmacological treatments have a larger overall effect size than pharmacological treatments; however, owing to the diversity in study designs, it is unclear whether nonpharmacological treatments are more effective than pharmacological treatments at this point.}, }
@article {pmid19117669, year = {2009}, author = {Ogura, A and Oowada, S and Kon, Y and Hirayama, A and Yasui, H and Meike, S and Kobayashi, S and Kuwabara, M and Inanami, O}, title = {Redox regulation in radiation-induced cytochrome c release from mitochondria of human lung carcinoma A549 cells.}, journal = {Cancer letters}, volume = {277}, number = {1}, pages = {64-71}, doi = {10.1016/j.canlet.2008.11.021}, pmid = {19117669}, issn = {1872-7980}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/radiation effects ; Caspases/metabolism ; Cell Line, Tumor ; Cytochromes c/*metabolism ; Electron Spin Resonance Spectroscopy ; Humans ; Lung Neoplasms/enzymology/pathology/*radiotherapy ; Membrane Potential, Mitochondrial/radiation effects ; Mitochondria/enzymology/*radiation effects ; Oxidation-Reduction ; Proto-Oncogene Proteins c-bcl-2/analysis ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; bcl-2-Associated X Protein/analysis ; bcl-X Protein/analysis ; }, abstract = {Mitochondria in mammalian cells are well-known to play an important role in the intrinsic pathway of genotoxic-agent-induced apoptosis by releasing cytochrome c into cytosol and to be a major source of reactive oxygen species (ROS). The aim of this study was to examine whether mitochondrial ROS are involved in radiation-induced apoptotic signaling in A549 cells. Post-irradiation treatment with N-acetyl-L-cysteine (NAC) inhibited cytochrome c release from mitochondria but did not affect expression levels of Bcl-2, Bcl-X(L) and Bax, suggesting that late production of ROS triggered cytochrome c release. Experiments using DCFDA (a classical ROS fluorescence probe) and MitoAR (a novel mitochondrial ROS probe) demonstrated that intracellular and mitochondrial ROS were enhanced 6h after X irradiation. Furthermore, the O(2)(-*) production ability of mitochondria isolated from A549 cells was evaluated by ESR spectroscopy combined with a spin-trapping reagent (CYPMPO). When isolated mitochondria were incubated with NADH, succinate and CYPMPO, an ESR spectrum due to CYPMPO-OOH was detected. This NADH/succinate-dependent O(2)(-*) production from mitochondria of irradiated cells was significantly increased in comparison with that of unirradiated cells. These results indicate that ionizing radiation enhances O(2)(-*) production from mitochondria to trigger cytochrome c release in A549 cells.}, }
@article {pmid19117608, year = {2009}, author = {Rivadeneira, J and Barrio, DA and Arrambide, G and Gambino, D and Bruzzone, L and Etcheverry, SB}, title = {Biological effects of a complex of vanadium(V) with salicylaldehyde semicarbazone in osteoblasts in culture: mechanism of action.}, journal = {Journal of inorganic biochemistry}, volume = {103}, number = {4}, pages = {633-642}, doi = {10.1016/j.jinorgbio.2008.11.009}, pmid = {19117608}, issn = {1873-3344}, mesh = {Aldehydes/*chemistry/pharmacology ; Animals ; Apoptosis ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Mice ; Organometallic Compounds/*chemistry/pharmacology ; Osteoblasts/cytology/*drug effects/metabolism ; Oxidative Stress ; Rats ; Semicarbazones/*chemistry/pharmacology ; Vanadium/*chemistry/*pharmacology ; }, abstract = {Vanadium compounds display important pharmacological actions in vivo and in vitro systems. Semicarbazones are versatile ligands with therapeutic effects. Herein, we report the effects of V(V)O(2)(salicylaldehydesemicarbazone) (V(V)-Salsem) on two osteoblast cell lines in culture (MC3T3-E1 and UMR106). V(V)-Salsem inhibited cell proliferation in a dose response manner. At 100muM, the complex caused an inhibition of ca. 48% and 38% for the normal and the tumoral osteoblasts, respectively (p<0.001). This inhibition could be partially reversed to 35% and 28% by NAC (N-acetylcysteine) and a mixture of vitamins E and C. Changes in cell proliferation correlated with morphological alterations and the disruption of actin cytoskeleton fibers. The complex also enhanced the level of ROS (reactive oxygen species) up to ca. 100% over basal in both cell lines. Activation of ERK signalling cascade was also observed. These events led to apoptosis (up to 44% in MC3T3-E1 and 33% in UMR106 cells). Scavengers of ROS and inhibitors of ERK cascade allowed to elucidate the mechanisms involved in the cytotoxicity. In conclusion, V(V)-Salsem displayed cytotoxic effects on osteoblasts in culture through the production of free radicals and the activation of ERK cascade. These mechanisms triggered the apoptotic events that conveyed to cell death.}, }
@article {pmid20535236, year = {2009}, author = {Wangpaichitr, M and Wu, C and You, M and Maher, JC and Dinh, V and Feun, LG and Savaraj, N}, title = {N',N'-Dimethyl-N',N'-bis(phenylcarbonothioyl) Propanedihydrazide (Elesclomol) Selectively Kills Cisplatin Resistant Lung Cancer Cells through Reactive Oxygen Species (ROS).}, journal = {Cancers}, volume = {1}, number = {1}, pages = {23-38}, pmid = {20535236}, issn = {2072-6694}, support = {R01 CA109578-01/CA/NCI NIH HHS/United States ; R01 CA109578-02/CA/NCI NIH HHS/United States ; R01 CA109578-03/CA/NCI NIH HHS/United States ; }, abstract = {Cisplatin is an important chemotherapeutic agent in lung cancer treatment. The mechanism of drug resistance to cisplatin is complex and historically has been difficult to overcome. We report here that cisplatin resistant lung cancer cell lines possess high basal levels of reactive oxygen species (ROS) when compared to normal cells and their parental cell counterparts. These resistant cells also have low thioredoxin (TRX) levels which may be one of the contributory factors to high ROS. N'(1),N'(3)-dimethyl-N'(1),N'(3)-bis(phenylcarbonothioyl) propanedihydrazide (elesclomol), an agent known to increase ROS is selectively toxic to cisplatin-resistant cells, while sparing normal cells and the parental counterpart. The cytotoxic effect of elesclomol in resistant cells is accompanied by further decreases in TRX and glutathione (GSH) antioxidant systems, while opposite results were found in parental cells. The ID(50) of elesclomol in cisplatin-resistant cells ranged from 5-10 nM, which is well within clinically achievable ranges. N-Acetylcysteine (NAC), which is known to neutralize ROS, can abolish the cytotoxic effect of elesclomol, suggesting that the cytotoxic effect results from increased ROS. Overall, our data suggest that elesclomol selectively kills cisplatin-resistant tumor cells through increased ROS. This agent may hold potential to overcome cisplatin resistance and should be further explored to treat patients who have failed cisplatin therapy.}, }
@article {pmid20408504, year = {2009}, author = {Babizhayev, MA}, title = {Potentiation of intraocular absorption and drug metabolism of N-acetylcarnosine lubricant eye drops: drug interaction with sight threatening lipid peroxides in the treatment for age-related eye diseases.}, journal = {Drug metabolism and drug interactions}, volume = {24}, number = {2-4}, pages = {275-323}, doi = {10.1515/dmdi.2009.24.2-4.275}, pmid = {20408504}, issn = {0792-5077}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Antioxidants/metabolism ; Aqueous Humor/metabolism ; Carnosine/*analogs &amp; derivatives/pharmacokinetics ; Cataract/*metabolism/pathology ; Delayed-Action Preparations ; Drug Synergism ; Eye/*metabolism ; Female ; Humans ; Lens, Crystalline/metabolism/ultrastructure ; Lipid Peroxidation/drug effects/physiology ; Lipid Peroxides/*metabolism ; Liposomes ; Male ; Microscopy, Electron ; Middle Aged ; Ophthalmic Solutions ; Rabbits ; Tissue Culture Techniques ; Young Adult ; }, abstract = {Cataract is the dominant cause of blindness worldwide. Studies of the morphological structure and biophysical changes of the lens in human senile cataracts have demonstrated the disappearance of normal fiber structure in the opaque region of the lens and the disintegration of the lens fiber plasma membrane in the lens tissue. Morphological and biochemical techniques have revealed the regions in human cataractous lenses in which the plasma membrane derangement occurs as the primary light scattering centers which cause the observed lens opacity. Human cataract formation is mostly considered to be a multifactorial disease; however, oxidative stress might be one of the leading causes for both nuclear and cortical cataract. Phospholipid molecules modified with oxygen, accumulating in the lipid bilayer, change its geometry and impair lipid-lipid and protein-lipid interactions in lenticular fiber membranes. Electron microscopy data of human lenses at various stages of age-related cataract document that these disruptions were globules, vacuoles, multilamellar membranes, and clusters of highly undulating membranes. The opaque shades of cortical cataracts represent cohorts of locally affected fibres segregated from unaffected neighbouring fibres by plasma membranes. Other potential scattering centers found throughout the mature cataract nucleus included variations in staining density between adjacent cells, enlarged extracellular spaces between undulating membrane pairs, and protein-like deposits in the extracellular space. These affected parts had membranes with a fine globular aspect and in cross-section proved to be filled with medium to large globular elements. Lipid peroxidation (LPO) is a pathogenetic and causative factor of cataract. Increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides, fatty acid oxy-derivatives) and end fluorescent LPO products were detected in the lipid moieties of the aqueous humor samples and human lenses obtained from patients with senile and complicated cataracts as compared to normal donors. Utilizing the pharmacokinetic studies and the specific purity N-acetylcarnosine (NAC) ingredient as a source of pharmacological principal L-carnosine, we have created an ophthalmic time-release prodrug form combined with a muco-adhesive lubricant compound carboxymethylcellulose and other essential corneal absorption promoter excipients tailoring the increased intraocular absorption of L-carnosine in the aqueous humor and optimizing its specific effect in producing the basic antioxidant activity in vivo and reducing toxic effects of lipid peroxides to the crystalline lens. L-Carnosine that finds its way into the aqueous humor can accumulate in the lens tissue for a reasonable period of time. However, administration of pure L-carnosine (1% solution) to the rabbit eye (instillation, subconjunctival injection) does not lead to accumulation of this natural compound in the aqueous humor over 30 min in concentration exceeding that in the placebo-treated matched eyes, and its effective concentration is exhausted more rapidly. The NAC prodrug eye drops optimize the clinical effects for the treatment of ophthalmic disorders (such as prevention and reversal of cataracts in human and animal [canine] eyes). The data provided predict a particular NAC ophthalmic prodrug's clinical effect; the suitable magnitude and duration of this effect suggest dose-related bioavailability of L-camosine released from NAC in the aqueous humor of the anterior eye segment. The ophthalmic NAC drug shows promise in the treatment of a range of ophthalmic disorders which have a component of oxidative stress in their genesis (including cataract and after-cataract, glaucoma, dry eye, vitreous floaters, inflammatory disorders, corneal, retinal and systemic diseases [such as diabetes mellitus and its ophthalmic complications]). The clinical efficacy of N-acetylcarnosine lubricant eye drops in ripe cataracts and retinal disorders can be enhanced in combined treatment with a patented oral formulation (Can-C Plus) of non-hydrolyzed carnosine including synergistic compounds (histidine, D-panthethine) with chaperone activity towards lens crystallins and oral supplementation with N-acetylcysteine providing an alternate means of boosting reduced glutathione (GSH) synthesis in the lens.}, }
@article {pmid20230768, year = {2009}, author = {Scriabine, A and Rabin, DU}, title = {New developments in the therapy of pulmonary fibrosis.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {57}, number = {}, pages = {419-464}, doi = {10.1016/S1054-3589(08)57011-6}, pmid = {20230768}, issn = {1557-8925}, mesh = {Animals ; Clinical Trials as Topic ; *Drug Discovery ; Humans ; Pulmonary Fibrosis/*drug therapy ; Pyridones/chemistry/therapeutic use ; }, abstract = {Fibrosis is a normal response to injury. When it becomes excessive, however, it can interfere with the normal function of various organs. In the lungs fibrosis can lead to interstitial pneumonias. Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia of unknown cause and poor prognosis. It is characterized by clinical, radiologic, and histologic criteria. The frequently used therapy of steroids (e.g. prednisolone) and immunosuppressants (e.g. azathioprine) has not been shown to be effective. No drugs for the therapy of IPF are approved in the United States. Bosentan, pirfenidone, and N-acetyl cysteine are currently in clinical trials with preliminary results suggesting they may prolong the life expectancy of patients with IPF. New approaches to the treatment of IPF have been proposed. They include endothelial and cytokine antagonists, and antioxidants. Preclinical and clinical studies with these drugs in IPF are reviewed in this chapter. Their antifibrotic activity has been demonstrated in cell culture as well as in vivo in bleomycin-induced fibrosis in mice or rats. Better translation of preclinical findings to clinical medicine will help in the discovery and development of new drugs for the treatment of IPF.}, }
@article {pmid19117019, year = {2009}, author = {Ali, BH and Al-Salam, S and Al-Husseini, I and Nemmar, A}, title = {Comparative protective effect of N-acetyl cysteine and tetramethylpyrazine in rats with gentamicin nephrotoxicity.}, journal = {Journal of applied toxicology : JAT}, volume = {29}, number = {4}, pages = {302-307}, doi = {10.1002/jat.1409}, pmid = {19117019}, issn = {1099-1263}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Animals ; Antioxidants/*pharmacology ; Body Weight/drug effects ; Creatinine/metabolism ; *Gentamicins ; Kidney Cortex/drug effects/metabolism ; Male ; *Protective Agents ; *Protein Synthesis Inhibitors ; Pyrazines/*pharmacology ; Rats ; Rats, Wistar ; Urea/metabolism ; Urodynamics/drug effects ; }, abstract = {Gentamicin (GM) is used against serious and life-threatening infections, but its use is limited by the occurrence of nephrotoxicity, which involves the generation of free radicals. In this work we tested the effect of a compound with antioxidant properties, tertamethylpyrazine (TMP), a major constituent of the Chinese medicinal plant Lingusticum wallichi, on GM-induced nephrotoxicity, and compared it with an established anti-oxidant compound N-acetyl cysteine (NAC). Six groups of rats were studied: (1) control, treated orally (p.o.) and intraperitoneally (i.p.) with saline; (2) treated i.p. with GM (80 mg kg(-1) per day for 6 days); (3) TMP, given p.o. (100 mg kg(-1) per day for 10 days) + GM (same dose as above during the last 6 days); (4) NAC, given i.p. (500 mg kg(-1) per day for 10 days) + GM as above; (5) TMP (100 mg kg(-1) per day for 10 days) + saline; (6) NAC (500 mg kg(-1) per day for 10 days) + saline. GM nephrotoxicity was characterized by reduced creatinine clearance, increased creatinine and urea concentrations in plasma, increased urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG) and total protein. These functional and structural alterations were prevented or ameliorated by NAC treatment, while TMP had only a slight mitigating effect that was less marked than that produced by NAC. The concentration of GM in the renal cortex of the rats given GM + NAC (but not TMP) was lower than that found in rats treated with GM alone by about 25%. The mechanism by which NAC and, to a lesser extent TMP, protected against GM-induced nephrotoxicity may be related, at least in part, to the decrease in oxidative stress in renal cortex.}, }
@article {pmid19114891, year = {2009}, author = {Charunwatthana, P and Abul Faiz, M and Ruangveerayut, R and Maude, RJ and Rahman, MR and Roberts, LJ and Moore, K and Bin Yunus, E and Hoque, MG and Hasan, MU and Lee, SJ and Pukrittayakamee, S and Newton, PN and White, NJ and Day, NP and Dondorp, AM}, title = {N-acetylcysteine as adjunctive treatment in severe malaria: a randomized, double-blinded placebo-controlled clinical trial.}, journal = {Critical care medicine}, volume = {37}, number = {2}, pages = {516-522}, pmid = {19114891}, issn = {1530-0293}, support = {R01 GM042056/GM/NIGMS NIH HHS/United States ; R37 GM042056/GM/NIGMS NIH HHS/United States ; GM42056/GM/NIGMS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 GM042056-11/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Antimalarials/administration &amp; dosage/*therapeutic use ; Artemisinins/administration &amp; dosage/*therapeutic use ; Artesunate ; Bangladesh ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Malaria, Falciparum/*drug therapy/physiopathology ; Male ; Placebos/therapeutic use ; Thailand ; Treatment Outcome ; }, abstract = {OBJECTIVE: Markers of oxidative stress are reported to be increased in severe malaria. It has been suggested that the antioxidant N-acetylcysteine (NAC) may be beneficial in treatment. We studied the efficacy and safety of parenteral NAC as an adjunct to artesunate treatment of severe falciparum malaria.<br><br>DESIGN: A randomized, double-blind, placebo-controlled trial on the use of high-dose intravenous NAC as adjunctive treatment to artesunate.<br><br>SETTING: A provincial hospital in Western Thailand and a tertiary referral hospital in Chittagong, Bangladesh.<br><br>PATIENTS: One hundred eight adult patients with severe falciparum malaria.<br><br>INTERVENTIONS: Patients were randomized to receive NAC or placebo as an adjunctive treatment to intravenous artesunate.<br><br>MEASUREMENTS AND MAIN RESULTS: A total of 56 patients were treated with NAC and 52 received placebo. NAC had no significant effect on mortality, lactate clearance times (p = 0.74), or coma recovery times (p = 0.46). Parasite clearance time was increased from 30 hours (range, 6-144 hours) to 36 hours (range, 6-120 hours) (p = 0.03), but this could be explained by differences in admission parasitemia. Urinary F2-isoprostane metabolites, measured as a marker of oxidative stress, were increased in severe malaria compared with patients with uncomplicated malaria and healthy volunteers. Admission red cell rigidity correlated with mortality, but did not improve with NAC.<br><br>CONCLUSION: Systemic oxidative stress is increased in severe malaria. Treatment with NAC had no effect on outcome in patients with severe falciparum malaria in this setting.}, }
@article {pmid19112401, year = {2008}, author = {Maes, M and Leunis, JC}, title = {Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria.}, journal = {Neuro endocrinology letters}, volume = {29}, number = {6}, pages = {902-910}, pmid = {19112401}, issn = {0172-780X}, mesh = {Adult ; Age Factors ; Analysis of Variance ; Anti-Inflammatory Agents/therapeutic use ; Antibodies, Bacterial/*blood ; Antioxidants/therapeutic use ; Bacterial Translocation/immunology ; Diet Therapy ; Enterobacteriaceae/*immunology/metabolism ; Fatigue Syndrome, Chronic/blood/*immunology/microbiology/therapy ; Female ; Humans ; Immunoglobulin A/blood ; Immunoglobulin M/blood ; Intestines/*immunology/microbiology ; Lipopolysaccharides/immunology/metabolism ; Male ; Middle Aged ; Oxidative Stress/immunology ; Time Factors ; Treatment Outcome ; }, abstract = {BACKGROUND: There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative &amp; nitrosative stress (IO&amp;NS), is a new pathway in chronic fatigue syndrome (CFS).<br><br>METHODS: The present study examines the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in CFS patients both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet during 10-14 months. We measured the above immune variables as well as the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and 10-14 months after intake of NAIOSs.<br><br>RESULTS: Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).<br><br>DISCUSSION: The results show that normalization of the IgA and IgM responses to translocated LPS may predict clinical outcome in CFS. The results support the view that a weakened tight junction barrier with subsequent gut-derived inflammation is a novel pathway in CFS and that it is a new target for drug development in CFS. Meanwhile, CFS patients with leaky gut can be treated with specific NAIOSs and a leaky gut diet.}, }
@article {pmid19111613, year = {2009}, author = {Yubero, S and Ramudo, L and Manso, MA and De Dios, I}, title = {The role of redox status on chemokine expression in acute pancreatitis.}, journal = {Biochimica et biophysica acta}, volume = {1792}, number = {2}, pages = {148-154}, doi = {10.1016/j.bbadis.2008.12.002}, pmid = {19111613}, issn = {0006-3002}, mesh = {Animals ; Chemokines/genetics/*metabolism ; Gene Expression Regulation ; Interleukin-6/blood ; Male ; NF-kappa B/metabolism ; Oxidation-Reduction ; Pancreatitis/genetics/*metabolism ; Phosphorylation ; RNA, Messenger/genetics ; Rats ; Rats, Wistar ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {This study focused on the involvement of oxidative stress in the mechanisms mediating chemokine production in different cell sources during mild and severe acute pancreatitis (AP) induced by bile-pancreatic duct obstruction (BPDO) and 3.5% NaTc, respectively. N-Acetylcysteine (NAC) was used as antioxidant treatment. Pancreatic glutathione depletion, acinar overexpression of monocyte chemoattractant protein-1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC), and activation of p38MAPK, NF-kappaB and STAT3 were found in both AP models. NAC reduced the depletion of glutathione in BPDO- but not in NaTc-induced AP, in which oxidative stress overwhelmed the antioxidant capability of NAC. As a result, inhibition of the acinar chemokine expression and signalling pathways occurs in mild, but not in severe AP. However, MCP-1 and CINC expressions in whole pancreas and plasma chemokine levels were not reduced by NAC, even in BPDO-induced AP, suggesting that in addition to acini, other pancreatic cells produced chemokines by antioxidant resistant mechanisms. The high Il-6 plasma levels found during AP, both in NAC-treated and non-treated rats, pointed out cytokines as activating factors of chemokine expression in non-acinar cells. In conclusion, from early AP oxidant-mediated MAPK, NF-kappaB and STAT3 activation triggers the chemokine expression in acini but not in non-acinar cells.}, }
@article {pmid19109388, year = {2009}, author = {Kuroki, M and Ariumi, Y and Ikeda, M and Dansako, H and Wakita, T and Kato, N}, title = {Arsenic trioxide inhibits hepatitis C virus RNA replication through modulation of the glutathione redox system and oxidative stress.}, journal = {Journal of virology}, volume = {83}, number = {5}, pages = {2338-2348}, pmid = {19109388}, issn = {1098-5514}, mesh = {Arsenic Trioxide ; Arsenicals/*pharmacology ; Cell Line ; Glutathione/*metabolism ; Hepacivirus/*drug effects/genetics/physiology ; Humans ; Oxidation-Reduction ; *Oxidative Stress ; Oxides/*pharmacology ; RNA, Viral/drug effects ; Superoxides/metabolism ; Virus Replication/*drug effects ; }, abstract = {Arsenic trioxide (ATO), a therapeutic reagent used for the treatment of acute promyelocytic leukemia, has recently been reported to increase human immunodeficiency virus type 1 infectivity. However, in this study, we have demonstrated that replication of genome-length hepatitis C virus (HCV) RNA (O strain of genotype 1b) was notably inhibited by ATO at submicromolar concentrations without cell toxicity. RNA replication of HCV-JFH1 (genotype 2a) and the release of core protein into the culture supernatants were also inhibited by ATO after the HCV infection. To clarify the mechanism of the anti-HCV activity of ATO, we examined whether or not PML is associated with this anti-HCV activity, since PML is known to be a target of ATO. Interestingly, we observed the cytoplasmic translocation of PML after treatment with ATO. However, ATO still inhibited the HCV RNA replication even in the PML knockdown cells, suggesting that PML is dispensable for the anti-HCV activity of ATO. In contrast, we found that N-acetyl-cysteine, an antioxidant and glutathione precursor, completely and partially eliminated the anti-HCV activity of ATO after 24 h and 72 h of treatment, respectively. In this context, it is worth noting that we found an elevation of intracellular superoxide anion radical, but not hydrogen peroxide, and the depletion of intracellular glutathione in the ATO-treated cells. Taken together, these findings suggest that ATO inhibits the HCV RNA replication through modulation of the glutathione redox system and oxidative stress.}, }
@article {pmid19105616, year = {2009}, author = {Agashi, K and Chau, DY and Shakesheff, KM}, title = {The effect of delivery via narrow-bore needles on mesenchymal cells.}, journal = {Regenerative medicine}, volume = {4}, number = {1}, pages = {49-64}, doi = {10.2217/17460751.4.1.49}, pmid = {19105616}, issn = {1746-076X}, support = {//Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Apoptosis ; Caspase 3/metabolism ; Cell Count ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; Flow Cytometry ; Mesenchymal Stem Cell Transplantation/*instrumentation/methods ; Mesenchymal Stem Cells/*cytology/metabolism ; Mice ; Mice, Inbred Strains ; }, abstract = {AIMS: Recently, there have been numerous preclinical and human studies investigating the regenerative capacity of cell suspensions following their direct injection into a target organ: the fundamental parameters for successful (clinical) cell therapy. At present, limited data exist in the identification of factors important for the survival of these cells (i.e., morphology, viability and proliferation rates) during and following their ejection via narrow-bore needles.<br><br>MATERIALS &amp; METHODS: Primary murine mesenchymal stem cells (mMSCs) were isolated, expanded and processed into a concentrated cell suspension consisting of either HBSS or HBSS supplemented with the antioxidant n-acetyl-cysteine. This suspension was then ejected from a 10 microl Hamilton syringe, via a variety of bore-sized needles, at different ejection rates. Cell characteristics including viability, spreading and attachment, apoptosis and proliferative ability were then assessed.<br><br>RESULTS: Following manipulation within a syringe, a decrease in the viability and cell spreading of mMSCs and a concurrent increase in the production of the caspase-3 protein, an early regulatory event in apoptosis, occurs. These detrimental effects were found to be increased when the cells were left in the syringe chamber for increased periods of time, and were similar at 5 microl/min and 1 microl/min ejection rates. However, on increasing the needle bore diameter, a significant reduction in these characteristics was observed. By comparison, mMSCs that were left to stand at room temperature (18-20 degrees C), but were not manipulated within a syringe, showed a significantly greater viability compared with manipulated cells. However, cells kept at 4 degrees C demonstrated a decreased viability compared with manipulated cells. When the mMSC were incubated with n-acetyl-cysteine, a known antioxidant, no significant change in caspase-3 production or cell spreading was observed.<br><br>CONCLUSIONS: This study highlights potential parameters, such as minimizing the time period the cells are within the syringe and the use of wider-bore needles, involved in maintaining the high viable cell density required for the delivery of cell suspensions for cell therapy applications.}, }
@article {pmid19105592, year = {2009}, author = {Wangpradit, O and Teesch, LM and Mariappan, SV and Duffel, MW and Norstrom, K and Robertson, LW and Luthe, G}, title = {Oxidation of 4-chlorobiphenyl metabolites to electrophilic species by prostaglandin H synthase.}, journal = {Chemical research in toxicology}, volume = {22}, number = {1}, pages = {64-71}, pmid = {19105592}, issn = {1520-5010}, support = {P42 ES013661-02/ES/NIEHS NIH HHS/United States ; P30 ES005605-170006/ES/NIEHS NIH HHS/United States ; ES013661/ES/NIEHS NIH HHS/United States ; P30 ES005605/ES/NIEHS NIH HHS/United States ; P30 ES005605-180006/ES/NIEHS NIH HHS/United States ; P42 ES013661-01A1/ES/NIEHS NIH HHS/United States ; P42 ES013661-030001/ES/NIEHS NIH HHS/United States ; P42 ES013661-01A10001/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; P42 ES013661-020001/ES/NIEHS NIH HHS/United States ; ES05605/ES/NIEHS NIH HHS/United States ; P42 ES013661-03/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemistry ; Biphenyl Compounds/*chemistry/toxicity ; Chromatography, Liquid ; DNA Damage ; Environmental Pollutants/*chemistry/toxicity ; Mass Spectrometry ; Oxidation-Reduction ; Polychlorinated Biphenyls/chemistry/toxicity ; Prostaglandin-Endoperoxide Synthases/*metabolism ; Quinones/chemistry ; }, abstract = {Hormonally sensitive tissues, like the prostate, ovary, and breast, increasingly studied as targets of environmental chemicals, are sources of an enzyme potentially capable of transforming and activating xenobiotics to highly reactive metabolites. Our study specifically addresses the question of whether prostaglandin H synthase (PGHS) can activate phenolic metabolites of polychlorinated biphenyls (PCBs). We found that human recombinant PGHS-2 catalyzed the oxidation of ortho (2',3'- and 3',4'-) and para (2',5'-) dihydroxy 4-chlorobiphenyl metabolites to their corresponding quinones. These were trapped in situ with N-acetyl cysteine, and the reaction products were isolated and characterized by liquid chromatography coupled mass spectrometry and (1)H and heteronuclear ((1)H-(13)C) nuclear magnetic resonance spectroscopy. Both mono- and di-N-acetyl cysteine Michael addition adducts were identified, with the 2',3'- and 2',5'-dihydroxy metabolites predominantly forming mono-N-acetyl cysteine adducts, while the 3',4'-dihydroxy predominantly formed disubstituted N-acetyl cysteine adducts. These studies clearly demonstrate that the phenolic metabolites of these environmental pollutants are activated by PGHS, as cosubstrates, to highly reactive electrophilic PCB quinones, with a potential for protein and DNA damage, especially in nonhepatic tissues where the enzyme is found.}, }
@article {pmid19103540, year = {2008}, author = {Köksal, H and Rahman, A and Burma, O and Halifeoğlu, I and Bayar, MK}, title = {The effects of low dose N-acetylcysteine (NAC) as an adjunct to cardioplegia in coronary artery bypass surgery.}, journal = {Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of cardiology}, volume = {8}, number = {6}, pages = {437-443}, pmid = {19103540}, issn = {1308-0032}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Cardiopulmonary Bypass/*methods ; Coronary Artery Bypass/*methods ; Coronary Artery Disease/surgery ; Creatine Kinase, MB Form/blood/drug effects ; Female ; Free Radical Scavengers/therapeutic use ; Heart Arrest, Induced/*methods ; Humans ; Inflammation Mediators/blood ; Male ; Middle Aged ; Myocardial Reperfusion Injury/blood/*prevention &amp; control ; Oxidative Stress/drug effects ; Prospective Studies ; Reactive Oxygen Species/blood ; Treatment Outcome ; }, abstract = {OBJECTIVE: We aimed to evaluate the efficacy of low dose N-acetylcysteine (NAC) against myocardial ischemia-reperfusion damage in coronary artery bypass surgery accompanied by cardiopulmonary bypass (CPB).<br><br>METHODS: Thirty patients operated due to triple coronary artery disease were enrolled into this prospective randomized study (control group -n=15 and NAC group - n=15). N-acetylcysteine was added to induction cardioplegia solution in dose of 4 mmol/l and in dose of 2 mmol/l to maintenance cardioplegia solution in the NAC group. Hemodynamic measurements were performed before and after anesthesia with different intervals. Creatine kinase-MB (CK-MB) levels were analyzed during 24 hours postoperatively. Blood samples were obtained from coronary sinus before CPB (T1), just before the cross-clamp removed (T2) and 30 minutes later (T3). Malondialdehyde (MDA), glutathione peroxidase (GSH-Px), nitric oxide (NO) levels and neutrophil percentage were determined. Statistical analysis was performed using student's t test, Chi-square and two-way ANOVA tests.<br><br>RESULTS: There were no significant differences between the two groups with regard to the hemodynamic parameters, and CK-MB levels. The MDA levels were significantly lower in NAC group than in control group during reperfusion period (0.75 nmol/l vs 0.88 nmol/l, p<0.05). Neutrophil percentage in coronary sinus blood was significantly lower in NAC group than in control group during the reperfusion period (77.6% vs 82.7%, p<0.05). The GSH-Px and NO levels were also not statistically different between groups.<br><br>CONCLUSION: Low dose NAC as an adjunct to cardioplegic solutions effectively reduces myocardial oxidative stress in coronary bypass surgery with cardiopulmonary bypass, but may not restore the myocardial injury.}, }
@article {pmid19101287, year = {2009}, author = {Nigwekar, SU and Kandula, P}, title = {N-acetylcysteine in cardiovascular-surgery-associated renal failure: a meta-analysis.}, journal = {The Annals of thoracic surgery}, volume = {87}, number = {1}, pages = {139-147}, doi = {10.1016/j.athoracsur.2008.09.026}, pmid = {19101287}, issn = {1552-6259}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*mortality/*prevention &amp; control/therapy ; Cardiovascular Surgical Procedures/*adverse effects/methods ; Confidence Intervals ; Education, Medical, Continuing ; Female ; Hospital Mortality/trends ; Humans ; Length of Stay ; Male ; Odds Ratio ; Postoperative Complications/prevention &amp; control ; Premedication/*methods ; Primary Prevention/methods ; Prognosis ; Randomized Controlled Trials as Topic ; Renal Dialysis ; Risk Assessment ; Survival Analysis ; Treatment Failure ; }, abstract = {BACKGROUND: Clinical trials with N-acetylcysteine (NAC) in perioperative cardiovascular settings have shown inconsistent effects for renal endpoints. We aimed to systematically review these trials to ascertain its role in prevention of post-cardiovascular surgery acute renal failure.<br><br>METHODS: We searched MEDLINE, EMBASE, Cochrane Renal Health Library, and Google Scholar for randomized controlled studies that evaluated NAC in adult patients undergoing cardiovascular surgery. Acute renal failure, acute renal failure requiring dialysis, and mortality were the primary outcomes. Additional outcomes studied were length of intensive care unit stay, postoperative serum creatinine, creatinine clearance, renal biomarkers, and adverse effects of NAC.<br><br>RESULTS: Twelve studies comprising 1,324 patients were found to be eligible. Meta-analytic estimates showed that NAC was not associated with reduction in acute renal failure (odds ratio [OR]: 0.89, 95% confidence interval [CI]: 0.68 to 1.15), acute renal failure requiring dialysis (OR: 1.09, 95% CI: 0.57 to 2.09) or mortality (OR: 0.95, 95% CI: 0.53 to 1.71). N-acetylcysteine was well tolerated but was not associated with any reduction in the length of intensive care unit stay. It had inconsistent effects on postoperative serum creatinine, creatinine clearance, and renal biomarkers. Subgroup analysis restricted to studies using intravenous NAC preparation showed a nonsignificant trend toward reduction in acute renal failure (OR: 0.81, 95% CI: 0.61 to 1.08) without any significant change in other outcomes.<br><br>CONCLUSIONS: Overall analysis of the existent literature shows that NAC is not beneficial in the prevention of post-cardiovascular surgery renal dysfunction. Routine use of NAC for this indication should be avoided.}, }
@article {pmid19101011, year = {2009}, author = {Iriti, M and Castorina, G and Picchi, V and Faoro, F and Gomarasca, S}, title = {Acute exposure of the aquatic macrophyte Callitriche obtusangula to the herbicide oxadiazon: the protective role of N-acetylcysteine.}, journal = {Chemosphere}, volume = {74}, number = {9}, pages = {1231-1237}, doi = {10.1016/j.chemosphere.2008.11.025}, pmid = {19101011}, issn = {1879-1298}, mesh = {Acetylcysteine/*metabolism ; Analysis of Variance ; Herbicides/chemistry/*toxicity ; Histocytochemistry ; Hydrogen Peroxide/metabolism ; Molecular Structure ; Oxadiazoles/chemistry/*toxicity ; Oxidative Stress/drug effects ; Plant Leaves/drug effects ; Plants/*drug effects/metabolism ; Toxicity Tests, Acute ; }, abstract = {In this study we investigated the acute exposure of the aquatic macrophyte Callitriche obtusangula to the herbicide oxadiazon (Ronstar). The toxic effects on C. obtusangula were evaluated, 24h after exposure, by assessing visible necrotic leaf lesions and, 12 h after exposure, via analyses of dead cells and hydrogen peroxide (H2O2) deposits localized by histocytochemical analysis with Trypan blue and 3,3'-diaminobenzidine (DAB), respectively. As a result, we found that 0.1275 microg L(-1) a.i. (active ingredient) oxadiazon was the maximum concentration that produced no observable adverse effects (NOAEC) both at leaf and tissue levels, at any considered exposure time. Additionally, we assayed the protective effect of pre-treatment with 0.25 mM N-acetylcysteine (NAC), a cysteine donor, on the damage caused by the toxic herbicidal dose of 6.37 microg L(-1) a.i to C. obtusangula, correlating the NAC observed protection to the direct H2O2-scavenging and to the enhancement of glutathione parameters. NAC-treated plants showed a fourfold increase in the GSH (reduced glutathione)+GSSG (oxidised glutathione) content (149.2 nmol g(-1) FW) compared to controls (36.1 nmol g(-1) FW); in the NAC+oxadiazon treatments, the GSH+GSSG content was more than fivefold higher (202.1 nmol g(-1) FW). GSH showed a similar trend in NAC and NAC+oxadiazon treatments, being six- (130.0 nmol g(-1) FW) and eightfold (185.0 nmol g(-1) FW) higher, respectively, compared to controls (20.7 nmol g(-1) FW). Accordingly, the GSH/GSSG ratio in NAC- and NAC+oxadiazon-treated plants was significantly increased compared to controls, indicating alleviation of oxidative stress.}, }
@article {pmid19099954, year = {2008}, author = {Zhang, FX and Chen, ML and Yang, B and Chen, HW and Cao, KJ}, title = {[N-acetylcysteine promoted aging through adjusting expression of cell cycle related protein in neonatal SD rat cardiomyocytes].}, journal = {Zhonghua xin xue guan bing za zhi}, volume = {36}, number = {2}, pages = {146-150}, pmid = {19099954}, issn = {0253-3758}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Cycle ; Cells, Cultured ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Myocytes, Cardiac/metabolism ; RNA, Messenger/genetics ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: To observe the effects of N-acetylcysteine (NAC) on aging in neonatal SD rat cardiomyocytes and explore related mechanisms.<br><br>METHODS: Cultured cardiomyocytes were randomized assigned to 6 groups: 1-day, 5-day, 10-day, 1-day + NAC (1 mmol/L), 5-day + NAC (1 mmol/L) and 10-day + NAC (1 mmol/L). Flow cytometry was used to examine cell cycle. Real-time quantitative PCR and Western blot were used to determine mRNA and protein expression of p16INK4a, p21WAF1 and Rb gene. beta-galactosidase staining kit was used to investigate beta-galactosidase activity.<br><br>RESULTS: Numbers of cardiomyocytes resided in G(0)/G(1) phase were significantly higher in the group of 5-day + NAC and 10-day + NAC compared with 5-day, 10-day, respectively (P < 0.05). The mRNA and protein expression of p16INK4a and p21WAF1 were also significantly higher in the group of 5-day + NAC and 10-day + NAC compared with 5-day, 10-day, respectively (P < 0.05 or P < 0.01). The mRNA and protein expression of Rb was significantly lower in the group of 5-day + NAC and 10-day + NAC compared with 5-day, 10-day, respectively (P < 0.01). beta-galactosidase activity was not affected by NAC in the 1-day + NAC group but was significantly higher in 5-day + NAC and 10-day + NAC groups compared with the 5-day, 10-day groups (all P < 0.05).<br><br>CONCLUSION: NAC could promote aging through upregulating the expression of p16INK4a and p21WAF1 and inhibiting Rb phosphorylation in neonatal SD rat cardiomyocytes.}, }
@article {pmid19098111, year = {2009}, author = {Yuan, H and Perry, CN and Huang, C and Iwai-Kanai, E and Carreira, RS and Glembotski, CC and Gottlieb, RA}, title = {LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and is associated with cytoprotection.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {296}, number = {2}, pages = {H470-9}, pmid = {19098111}, issn = {0363-6135}, support = {R01-AG033283/AG/NIA NIH HHS/United States ; R01 HL071091/HL/NHLBI NIH HHS/United States ; R01 HL060590/HL/NHLBI NIH HHS/United States ; R01 AG033283/AG/NIA NIH HHS/United States ; P01-HL085577/HL/NHLBI NIH HHS/United States ; P01 HL085577/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Autophagy/*drug effects ; Cells, Cultured ; *Cytoprotection ; Enzyme Inhibitors/pharmacology ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Imidazoles/pharmacology ; Lipopolysaccharides/*pharmacology ; Mice ; Mice, Transgenic ; Mitochondria, Heart/drug effects/metabolism/pathology ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; Nitric Oxide/metabolism ; Nitric Oxide Donors/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors/metabolism ; Nitroprusside/pharmacology ; Oxidative Stress/*drug effects ; Pyridines/pharmacology ; Rats ; Signal Transduction/*drug effects ; Sirolimus/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Tyrphostins/pharmacology ; omega-N-Methylarginine/pharmacology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Bacterial endotoxin lipopolysaccharide (LPS) is responsible for the multiorgan dysfunction that characterizes septic shock and is causal in the myocardial depression that is a common feature of endotoxemia in patients. In this setting the myocardial dysfunction appears to be due, in part, to the production of proinflammatory cytokines. A line of evidence also indicates that LPS stimulates autophagy in cardiomyocytes. However, the signal transduction pathway leading to autophagy and its role in the heart are incompletely characterized. In this work, we wished to determine the effect of LPS on autophagy and the physiological significance of the autophagic response. Autophagy was monitored morphologically and biochemically in HL-1 cardiomyocytes, neonatal rat cardiomyocytes, and transgenic mouse hearts after the administration of bacterial LPS or TNF-alpha. We observed that autophagy was increased after exposure to LPS or TNF-alpha, which is induced by LPS. The inhibition of TNF-alpha production by AG126 significantly reduced the accumulation of autophagosomes both in cell culture and in vivo. The inhibition of p38 MAPK or nitric oxide synthase by pharmacological inhibitors also reduced autophagy. Nitric oxide or H(2)O(2) induced autophagy in cardiomyocytes, whereas N-acetyl-cysteine, a potent antioxidant, suppressed autophagy. LPS resulted in increased reactive oxygen species (ROS) production and decreased total glutathione. To test the hypothesis that autophagy might serve as a damage control mechanism to limit further ROS production, we induced autophagy with rapamycin before LPS exposure. The activation of autophagy by rapamycin suppressed LPS-mediated ROS production and protected cells against LPS toxicity. These findings support the notion that autophagy is a cytoprotective response to LPS-induced cardiomyocyte injury; additional studies are needed to determine the therapeutic implications.}, }
@article {pmid19097988, year = {2009}, author = {Nemec, AA and Leikauf, GD and Pitt, BR and Wasserloos, KJ and Barchowsky, A}, title = {Nickel mobilizes intracellular zinc to induce metallothionein in human airway epithelial cells.}, journal = {American journal of respiratory cell and molecular biology}, volume = {41}, number = {1}, pages = {69-75}, pmid = {19097988}, issn = {1535-4989}, support = {HL085655/HL/NHLBI NIH HHS/United States ; HL065697/HL/NHLBI NIH HHS/United States ; ES10638/ES/NIEHS NIH HHS/United States ; HL077763/HL/NHLBI NIH HHS/United States ; U01 ES015675/ES/NIEHS NIH HHS/United States ; ES015675/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Bronchi/*metabolism ; Cell Separation/methods ; Cells, Cultured ; Chelating Agents/pharmacology ; Chlorides/metabolism/*toxicity ; DNA-Binding Proteins/genetics/metabolism ; Epithelial Cells/*drug effects/metabolism ; Ethylamines/pharmacology ; Flow Cytometry ; Fluorescent Dyes ; Humans ; Metallothionein/genetics/*metabolism ; Mice ; Mice, Knockout ; Nickel/*toxicity ; Polycyclic Compounds ; Pyridines ; Pyrimidines/pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Time Factors ; Transcription Factors/genetics/metabolism ; Transcriptional Activation/drug effects ; Transfection ; Up-Regulation ; Zinc Compounds/metabolism/*toxicity ; Transcription Factor MTF-1 ; }, abstract = {We recently reported that induction of metallothionein (MT) was critical in limiting nickel (Ni)-induced lung injury in intact mice. Nonetheless, the mechanism by which Ni induces MT expression is unclear. We hypothesized that the ability of Ni to mobilize zinc (Zn) may contribute to such regulation and therefore, we examined the mechanism for Ni-induced MT2A expression in human airway epithelial (BEAS-2B) cells. Ni induced MT2A transcript levels and protein expression by 4 hours. Ni also increased the activity of a metal response element (MRE) promoter luciferase reporter construct, suggesting that Ni induces MRE binding of the metal transcription factor (MTF-1). Exposure to Ni resulted in the nuclear translocation of MTF-1, and Ni failed to induce MT in mouse embryonic fibroblasts lacking MTF-1. As Zn is the only metal known to directly bind MTF-1, we then showed that Ni increased a labile pool of intracellular Zn in cells as revealed by fluorescence-activated cell sorter using the Zn-sensitive fluorophore, FluoZin-3. Ni-induced increases in MT2A mRNA and MRE-luciferase activity were sensitive to the Zn chelator, TPEN, supporting an important role for Zn in mediating the effect of Ni. Although neither the source of labile Zn nor the mechanism by which Ni liberates labile Zn was apparent, it was noteworthy that Ni increased intracellular reactive oxygen species (ROS). Although both N-acetyl cysteine (NAC) and ascorbic acid (AA) decreased Ni-induced increases in ROS, only NAC prevented Ni-induced increases in MT2A mRNA, suggesting a special role for interactions of Ni, thiols, and Zn release.}, }
@article {pmid19095747, year = {2009}, author = {Ramos, G and Limon-Flores, AY and Ullrich, SE}, title = {JP-8 induces immune suppression via a reactive oxygen species NF-kappabeta-dependent mechanism.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {108}, number = {1}, pages = {100-109}, pmid = {19095747}, issn = {1096-0929}, support = {CA131207/CA/NCI NIH HHS/United States ; CA112660/CA/NCI NIH HHS/United States ; CA 16672/CA/NCI NIH HHS/United States ; R01 CA131207/CA/NCI NIH HHS/United States ; R01 CA131207-04/CA/NCI NIH HHS/United States ; }, mesh = {Administration, Cutaneous ; Analysis of Variance ; Animals ; Carrier Proteins/genetics/metabolism ; Cell Line ; Cyclooxygenase 2/genetics/metabolism ; Female ; Gene Expression/drug effects ; Hydrocarbons/pharmacology/*toxicity ; Immune Tolerance/*drug effects ; Mice ; NF-kappa B/genetics/*metabolism ; Neoplasm Proteins/genetics/metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Sesquiterpenes/pharmacology ; Superoxide Dismutase/genetics/metabolism ; Transcription Factor RelA ; }, abstract = {Applying jet fuel (JP-8) to the skin of mice induces immune suppression. JP-8-treated keratinocytes secrete prostaglandin E(2), which is essential for activating immune suppressive pathways. The molecular pathway leading to the upregulation of the enzyme that controls prostaglandin synthesis, cyclooxygenase (COX)-2, is unclear. Because JP-8 activates oxidative stress and because reactive oxygen species (ROS) turn on nuclear factor kappa B (NF-kappabeta), which regulates the activity of COX-2, we asked if JP-8-induced ROS and NF-kappabeta contributes to COX-2 upregulation and immune suppression in vivo. JP-8 induced the production of ROS in keratinocytes as measured with the ROS indicator dye, aminophenyl fluorescein. Fluorescence was diminished in JP-8-treated keratinocytes overexpressing catalase or superoxide dismutase (SOD) genes. JP-8-induced COX-2 expression was also reduced to background in the catalase and SOD transfected cells, or in cultures treated with N-acetylcysteine (NAC). When NAC was injected into JP-8-treated mice, dermal COX-2 expression, and JP-8-induced immune suppression was inhibited. Because ROS activates NF-kappabeta, we asked if this transcriptional activator played a role in the enhanced COX-2 expression and JP-8-induced immune suppression. When JP-8-treated mice, or JP-8-treated keratinocytes were treated with a selective NF-kappabeta inhibitor, parthenolide, COX-2 expression, and immune suppression were abrogated. Similarly, when JP-8-treated keratinocytes were treated with small interfering RNA specific for the p65 subunit of NF-kappabeta, COX-2 upregulation was blocked. These data indicate that ROS and NF-kappabeta are activated by JP-8, and these pathways are involved in COX-2 expression and the induction of immune suppression by jet fuel.}, }
@article {pmid19093882, year = {2009}, author = {Pinnen, F and Cacciatore, I and Cornacchia, C and Sozio, P and Cerasa, LS and Iannitelli, A and Nasuti, C and Cantalamessa, F and Sekar, D and Gabbianelli, R and Falcioni, ML and Di Stefano, A}, title = {Codrugs linking L-dopa and sulfur-containing antioxidants: new pharmacological tools against Parkinson's disease.}, journal = {Journal of medicinal chemistry}, volume = {52}, number = {2}, pages = {559-563}, doi = {10.1021/jm801266x}, pmid = {19093882}, issn = {1520-4804}, mesh = {Analysis of Variance ; Animals ; Antioxidants/chemistry/pharmacokinetics/*therapeutic use ; Antiparkinson Agents/chemistry/pharmacokinetics/*therapeutic use ; Area Under Curve ; Chromatography, High Pressure Liquid ; Corpus Striatum/metabolism ; Half-Life ; Humans ; Injections, Intraventricular ; Levodopa/*analysis ; Parkinson Disease/*drug therapy ; Rats ; Spectrophotometry, Ultraviolet ; Sulfur/*analysis ; }, abstract = {A series of multifunctional codrugs (1-6) were synthesized to overcome the pro-oxidant effect associated with L-dopa (LD) therapy. Target compounds release LD and dopamine (DA) in human plasma after enzymatic hydrolysis, displaying an antioxidant effect superior to that of N-acetylcysteine (NAC). After intracerebroventricular injection of codrug 4, the levels of DA in the striatum were higher than those in LD-treated groups, indicating that this compound has a longer half-life in brain than LD.}, }
@article {pmid19093729, year = {2009}, author = {Zembron-Lacny, A and Slowinska-Lisowska, M and Szygula, Z and Witkowski, K and Szyszka, K}, title = {The comparison of antioxidant and hematological properties of N-acetylcysteine and alpha-lipoic acid in physically active males.}, journal = {Physiological research}, volume = {58}, number = {6}, pages = {855-861}, doi = {10.33549/physiolres.931590}, pmid = {19093729}, issn = {0862-8408}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adolescent ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; Cross-Over Studies ; Double-Blind Method ; Erythrocyte Indices ; Erythrocytes/*drug effects/metabolism ; Erythropoietin/blood ; *Exercise ; Glutathione/blood ; Hematocrit ; Hemoglobins/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Male ; Protein Carbonylation/drug effects ; Thiobarbituric Acid Reactive Substances/metabolism ; Thioctic Acid/*administration &amp; dosage ; Time Factors ; Young Adult ; }, abstract = {The aim of this study was to follow up whether the modification of pro-antioxidant status by oral thiol administration such as N-acetylcysteine and alpha-lipoic acid affects the hematological response. Twenty-eight healthy men participated in two independent experiments. Subjects were randomly assigned to one of four groups: controls (C(NAC) and C(ALA)), N-acetylcysteine (NAC) and alpha-lipoic acid (ALA). 1200 mg of N-acetylcysteine, 600 mg of alpha-lipoic acid or placebo were administered for 8 days in two doses. NAC or ALA administration significantly elevated plasma total antioxidant status (TAS) and reduced protein carbonylation (PC) and lipid peroxidation (TBARS) by more than 30 %. The reduced glutathione (GSH) and hematological parameters changed only in response to NAC administration. NAC significantly elevated the level of GSH (+33%), EPO (+26%), Hb (+9%) and Hct (+9%) compared with C(NAC). The mean corpuscular volume (MCV) and the mean corpuscular hemoglobin (MCH) also increased by more than 12% after NAC. The numerous negative or positive correlations between the measures of TAS, PC, TBARS and hematological parameters were found, which suggest the NAC-induced interaction between pro-antioxidant and hematological values. Our study has shown that both N-acetylcysteine and alpha-lipoic acid intake reveal an antioxidant action, but only N-acetylcysteine improves the haematological response.}, }
@article {pmid19093139, year = {2009}, author = {Huh, KH and Ahn, HJ and Park, J and Ju, MK and Song, JS and Kim, MS and Kim, SI and Kim, YS}, title = {Mycophenolic acid inhibits oleic acid-induced mesangial cell activation through both cellular reactive oxygen species and inosine monophosphate dehydrogenase 2 pathways.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {24}, number = {4}, pages = {737-745}, pmid = {19093139}, issn = {0931-041X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies, Blocking/pharmacology ; Cells, Cultured ; Culture Media, Conditioned/chemistry/metabolism ; Drug Antagonism ; Enzyme Inhibitors/*pharmacology ; Fibronectins/*drug effects/genetics/metabolism ; Guanosine/pharmacology ; IMP Dehydrogenase/*antagonists &amp; inhibitors/genetics/metabolism ; Mesangial Cells/*drug effects/metabolism ; Mice ; Mice, Transgenic ; Mycophenolic Acid/*pharmacology ; Oleic Acid/*pharmacology ; RNA Interference/drug effects ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta/immunology ; }, abstract = {The synthesis of extracellular matrix (ECM) in mesangial cells (MCs) plays important roles in the development and progression of renal diseases, including chronic allograft nephropathy. Mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase 2 (IMPDH2), suppresses MC proliferation and ECM synthesis. However, the exact inhibitory mechanism of MPA on MCs has not been clearly elucidated. In this study we compared the inhibitory effects of MPA and IMPDH2 reduction [by using small interfering RNA (siRNA)] on oleic acid (OA)-induced fibronectin secretion and cellular reactive oxygen species (ROS) in mouse MCs. Growth-arrested MCs were stimulated with OA in the presence or absence of MPA, IMPDH2 siRNA, N-acetylcysteine (NAC), transforming growth factor beta (TGF-beta) antibody or exogenous guanosine. Fibronectin secretion into the medium was examined by Western blot, dichlorodihydrofluorescein (DCF)-sensitive cellular ROS by fluorescence-activated cell scanning (FACS), TGF-beta levels in the media by enzyme-linked immunosorbent assay (ELISA). OA increased fibronectin secretion, TGF-beta and cellular ROS levels. A TGF-beta neutralizing antibody effectively suppressed OA-induced fibronectin secretion. NAC and MPA completely suppressed OA-induced fibronectin secretion and decreased the levels of TGF-beta and cellular ROS. However, IMPDH2 siRNA partly inhibited OA-induced MC activation. Exogenous guanosine successfully reversed the inhibitory effects of IMPDH2 siRNA on OA-induced MC activation. Pleiotropic inhibitory effect of MPA on OA-induced mouse MC activation was mediated via its antioxidant effect on cellular ROS production and partly via inhibition of IMPDH2 itself. Our results implicate ROS as an alternative therapeutic target for the prevention of hyperlipidemia-related glomerulopathy, chronic allograft nephropathy, and subsequent graft loss.}, }
@article {pmid19092257, year = {2008}, author = {Renke, M and Tylicki, L and Rutkowski, P and Larczyński, W and Aleksandrowicz, E and Lysiak-Szydłowska, W and Rutkowski, B}, title = {The effect of N-acetylcysteine on proteinuria and markers of tubular injury in non-diabetic patients with chronic kidney disease. A placebo-controlled, randomized, open, cross-over study.}, journal = {Kidney &amp; blood pressure research}, volume = {31}, number = {6}, pages = {404-410}, doi = {10.1159/000185828}, pmid = {19092257}, issn = {1423-0143}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology/therapeutic use ; Adult ; Angiotensin-Converting Enzyme Inhibitors ; Antioxidants/therapeutic use ; Biomarkers/analysis ; Chronic Disease ; Cross-Over Studies ; Drug Therapy, Combination ; Female ; Fibrosis/drug therapy ; Humans ; Kidney Diseases/*drug therapy ; Kidney Tubules/drug effects/*pathology ; Male ; Proteinuria/*drug therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin II subtype 1 receptor antagonists (ARB) constitutes a strategy in the management of patients with chronic kidney disease. There is still no optimal therapy which can stop the progression of chronic kidney disease. Antioxidants such as N-acetylcysteine (NAC) have been reported as a promising strategy in this field.<br><br>METHODS: In a placebo-controlled, randomized, open, 2-period cross-over study, we evaluated the influence of NAC (1,200 mg/day) added to renin-angiotensin-aldosterone system blockade on proteinuria and surrogate markers of tubular injury and renal fibrosis in 20 non-diabetic patients with proteinuria (0.4-6.36 g/24 h) with normal or decreased kidney function (estimated glomerular filtration rate 61-163 ml/min). Subjects entered the 8-week run-in period during which the therapy using ACEI and/or ARB was established with blood pressure below 130/80 mm Hg. Next, patients were randomly assigned to 1 of 2 treatment sequences: NAC/washout/placebo or placebo/washout/NAC. Clinical evaluation and laboratory tests were performed at the randomization point and after each period of the study.<br><br>RESULTS: No significant changes in laboratory tests were observed.<br><br>CONCLUSION: NAC had no effect on proteinuria, surrogate markers of tubular injury or renal fibrosis in non-diabetic patients with chronic kidney disease.}, }
@article {pmid19091331, year = {2009}, author = {Safarinejad, MR and Safarinejad, S}, title = {Efficacy of selenium and/or N-acetyl-cysteine for improving semen parameters in infertile men: a double-blind, placebo controlled, randomized study.}, journal = {The Journal of urology}, volume = {181}, number = {2}, pages = {741-751}, doi = {10.1016/j.juro.2008.10.015}, pmid = {19091331}, issn = {1527-3792}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Analysis of Variance ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Drug Therapy, Combination ; Follow-Up Studies ; Humans ; Infertility, Male/*blood/diagnosis/*drug therapy ; Male ; Middle Aged ; Multivariate Analysis ; Prospective Studies ; Reference Values ; Risk Assessment ; Selenium/*administration &amp; dosage ; Semen Analysis ; Sperm Count ; Sperm Motility/drug effects ; Statistics, Nonparametric ; Treatment Outcome ; }, abstract = {PURPOSE: We explored the efficacy of selenium and/or or N-acetyl-cysteine for improving semen parameters in infertile men, and the associations among semen quality and the concentrations of selenium and N-acetyl-cysteine in seminal plasma.<br><br>MATERIALS AND METHODS: The study included 468 infertile men with idiopathic oligo-asthenoteratospermia who were randomized to receive 200 microg selenium orally daily (selenium group of 116), 600 mg N-acetyl-cysteine orally daily (N-acetyl-cysteine group of 118), 200 microg selenium plus 600 mg N-acetyl-cysteine orally daily (selenium plus N-acetyl-cysteine group of 116) or similar regimen of placebo (control group of 118) for 26 weeks, followed by a 30-week treatment-free period. These patients provided blood samples for the measurement of serum testosterone, estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, inhibin B, selenium and N-acetyl-cysteine. Semen samples were also obtained for routine semen analysis, and the measurement of seminal plasma selenium and N-acetyl-cysteine.<br><br>RESULTS: In response to selenium and N-acetyl-cysteine treatment serum follicle-stimulating hormone decreased but serum testosterone and inhibin B increased. All semen parameters significantly improved with selenium and N-acetyl-cysteine treatment. Administering selenium plus N-acetyl-cysteine resulted in additive beneficial effects. A significant positive correlation existed between the seminal plasma concentrations of selenium and N-acetyl-cysteine, and semen parameters. A strong correlation was observed between the sum of the selenium and N-acetyl-cysteine concentrations, and mean sperm concentration (r = 0.67, p = 0.01), sperm motility (r = 0.64, p = 0.01) and percent normal morphology (r = 0.66, p = 0.01).<br><br>CONCLUSIONS: These results indicate that supplemental selenium and N-acetyl-cysteine improve semen quality. We advocate their use for male infertility treatment.}, }
@article {pmid19090771, year = {2009}, author = {Hernandez, MD and Mansouri, MD and Aslam, S and Zeluff, B and Darouiche, RO}, title = {Efficacy of combination of N-acetylcysteine, gentamicin, and amphotericin B for prevention of microbial colonization of ventricular assist devices.}, journal = {Infection control and hospital epidemiology}, volume = {30}, number = {2}, pages = {190-192}, doi = {10.1086/593205}, pmid = {19090771}, issn = {1559-6834}, mesh = {Acetylcysteine/pharmacology ; Amphotericin B/pharmacology ; Animals ; Anti-Bacterial Agents/*pharmacology ; Coated Materials, Biocompatible ; *Disease Models, Animal ; Equipment Contamination/*prevention &amp; control ; Gentamicins/pharmacology ; Heart-Assist Devices/*microbiology ; Humans ; Prosthesis-Related Infections/microbiology/prevention &amp; control ; Rabbits ; Staphylococcal Infections/microbiology/prevention &amp; control ; Staphylococcus aureus/*drug effects/*growth &amp; development ; }, abstract = {We assessed the in vitro antimicrobial activity and the in vivo efficacy of dipping ventricular assist devices in a combination of N-acetylcysteine, gentamicin, and amphotericin B (NAC/G/A). Ventricular assist devices dipped in NAC/G/A exhibited broad-spectrum antimicrobial activity in vitro and were less likely than undipped devices to become colonized with Staphylococcus aureus in a rabbit model.}, }
@article {pmid19090673, year = {2009}, author = {Hu, W and Xie, J and Zhao, J and Xu, Y and Yang, S and Ni, W}, title = {Involvement of Bcl-2 family in apoptosis and signal pathways induced by cigarette smoke extract in the human airway smooth muscle cells.}, journal = {DNA and cell biology}, volume = {28}, number = {1}, pages = {13-22}, doi = {10.1089/dna.2008.0782}, pmid = {19090673}, issn = {1557-7430}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Cell Cycle/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Fas Ligand Protein/metabolism ; Gene Expression/drug effects/genetics ; Humans ; Lung/*cytology ; Myocytes, Smooth Muscle/cytology/drug effects/*metabolism ; NF-kappa B p50 Subunit/genetics/metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/*physiology ; Smoke/*adverse effects ; Thiocarbamates/pharmacology ; Nicotiana/*chemistry ; Transcription Factor RelA/genetics/metabolism ; bcl-2-Associated X Protein/genetics/metabolism ; bcl-Associated Death Protein/genetics/metabolism ; fas Receptor/genetics/metabolism ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a highly prevalent airway disease characterized by an abnormal inflammatory response of the lungs to noxious particles and gases. Cigarette smoking remains a major risk factor for COPD development; however, little is known about its effect on human airway smooth muscle cells (HASMCs). The aim of this study is to examine whether apoptosis is involved in cigarette smoke extract (CSE)-induced HASMC death and the molecular mechanisms underlying it. Our studies have shown that CSE increased the level of reactive oxygen species (ROS) and cell apoptosis of HASMCs in a dose- and time-dependent manner, and the ROS scavenger N-acetyl-cysteine abrogated the effect of ROS level and apoptosis on HASMCs. Further, the expression of Bax, Bad, and Fas was increased but Bcl-2 and nuclear factor-kappaB (NF-kappaB) was decreased in a dose- and time-dependent fashion in CSE-induced apoptosis in HASMCs. Taken together, CSE could inhibit the cell growth and induce apoptosis of HASMCs through both the mitochondrial pathway and death receptor pathway. Oxidative stress and inhibition of NF-kappaB expression caused by CSE may play important roles in apoptosis and inhibition of cell growth in HASMCs.}, }
@article {pmid19079974, year = {2008}, author = {Hart, AM and Terenghi, G and Wiberg, M}, title = {Neuronal death after peripheral nerve injury and experimental strategies for neuroprotection.}, journal = {Neurological research}, volume = {30}, number = {10}, pages = {999-1011}, doi = {10.1179/174313208X362479}, pmid = {19079974}, issn = {0161-6412}, mesh = {Animals ; Axotomy/methods ; Cell Death/drug effects/physiology ; Humans ; Nerve Regeneration/drug effects ; Neurons/drug effects/*physiology ; Neuroprotective Agents/pharmacology/therapeutic use ; *Peripheral Nervous System Diseases/pathology/physiopathology/therapy ; }, abstract = {OBJECTIVE: Despite considerable microsurgical innovation in peripheral nerve repair, the outcome has improved little since the 1940s, reflecting surgical inability to adequately address the complex neurobiology of nerve injury and regeneration. Axotomy-induced neuronal death is potentially the most fundamental problem, and given recently published data, a review is timely.<br><br>METHODS: Initial review of relevant doctoral theses from the University of Ume&#xe5;, and Blond-McIndoe Research Laboratories, the University of Manchester, plus initial PubMed search including terms 'neuron death' and 'neuroprotection', subsequently expanded to relevant quoted articles.<br><br>RESULTS: Various factors related to patient (principally age) and injury (Sunderland grade, proximity to cell body and mechanism) determine the extent of neuronal death, the mechanism of which is reviewed. A considerable proportion of sensory neurons (particularly small cutaneous afferents) die after distal injury and death is more widespread after proximal injury. Motor neurons are susceptible to post-ganglionic plexus and spinal root level injury. Root avulsion causes the greatest cell death. The time course of neuronal death is fortuitously slow and mainly occurs by a process akin to apoptosis. A therapeutic window therefore exists, as do potential neuroprotective targets. Nerve repair is partly neuroprotective, but must be performed early. Exogenous neurotrophic factor administration (e.g. in tissue engineered conduits) is beneficial, but not practical for various reasons. In contrast, adjuvant neuroprotective pharmacotherapy is practical, and two clinically safe agents are reviewed. Acetyl-L-carnitine arrests sensory neuronal death and speeds up regeneration. N-acetyl-cysteine provides comparable sensory neuronal protection via mitochondrial preservation and protects motor neurons. Both agents are well characterized experimentally and highly effective even after clinically relevant delays between injury and treatment. Barriers to translational research are being addressed.<br><br>DISCUSSION: The future of peripheral nerve repair lies in modulating neurobiology at the time of injury, repair and during regeneration. Neuroprotection may be an essential component of that therapeutic package.}, }
@article {pmid19078915, year = {2008}, author = {Cerqueira, NF and Hussni, CA and Yoshida, WB and Sequeira, JL and Padovani, CR}, title = {Effects of pentoxifylline and n-acetylcysteine on injuries caused by ischemia and reperfusion of splanchnic organs in rats.}, journal = {International angiology : a journal of the International Union of Angiology}, volume = {27}, number = {6}, pages = {512-521}, pmid = {19078915}, issn = {0392-9590}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Hemodynamics/*drug effects ; Intestinal Mucosa/drug effects/pathology ; Intestine, Small/blood supply/*drug effects/metabolism/pathology ; Male ; Mesenteric Vascular Occlusion/*drug therapy/metabolism/pathology/physiopathology ; Oxidative Stress/drug effects ; Pentoxifylline/*pharmacology ; Rats ; Rats, Wistar ; Reperfusion Injury/metabolism/pathology/physiopathology/*prevention &amp; control ; Severity of Illness Index ; Shock/physiopathology/prevention &amp; control ; Splanchnic Circulation/*drug effects ; Time Factors ; }, abstract = {AIM: Occlusion and reperfusion of splanchnic arteries cause local and systemic changes due to the release of cytotoxic substances and the interaction between neutrophils and endothelial cells. This study evaluated the role of pentoxifylline (PTX) and n-acetylcysteine (NAC) in the reduction of ischemia, reperfusion shock and associated intestinal injury.<br><br>METHODS: Sixty rats were divided into 6 groups of 10 animals. Rats in three groups underwent mesenteric ischemia for 30 minutes followed by 120 minutes of reperfusion, and were treated with saline (SAL-5 mL/kg/h), pentoxifylline (PTX-50 mg/kg) or n-acetylcysteine (NAC-430 mg/kg/h). The other 3 groups underwent sham ischemia and reperfusion (I/R) and received the same treatments. Hemodynamic, biochemical and histological parameters were evaluated.<br><br>RESULTS: No significant hemodynamic or intestinal histological changes were seen in any sham group. No histological changes were found in the lung or liver of animals in the different groups. There was a progressive decrease in mean arterial blood pressure, from mean of 111.53 mmHg (30 minutes of ischemia) to 44.30+/-19.91 mmHg in SAL-I/R, 34.52+/-17.22 mmHg in PTX-I/R and 33.81+/-8.39 mmHg in NAC-I/R (P<0.05). In all I/R groups, there was a progressive decrease in: aortic blood flow, from median baseline of 19.00 mL/min to 2.50+/-5.25 mL/min in SAL-I/R; 2.95+/-6.40 mL/min in PTX-I/R and 3.35+/-3.40 mL/min in NAC-I/R (P<0.05); in the heart rate, from mean baseline of 311.74 bpm to 233.33+/-83.88 bpm in SAL-I/R, 243.20+/-73.25 bpm in PTX-I/R and 244.92+/-76.05 bpm in NAC-I/R (P<0.05); and esophageal temperature, from mean baseline of 33.68 degrees C to 30.53+/-2.05 degrees C in SAL-I/R, 30.69+/-2.21 degrees C in PTX-I/R and 31.43+/-1.03 degrees C in NAC-I/R (P<0.05). In the other hand, there was an attenuation of mucosal damage in the small intestine of the animals receiving PTX, and only in the ileum of the animals receiving NAC. No changes were found in ileum or plasma malondialdehyde levels in any group.<br><br>CONCLUSIONS: PTX was more efficient in reducing histological lesions than NAC, but neither treatment prevented hemodynamic changes during splanchnic organs I/R.}, }
@article {pmid19074972, year = {2009}, author = {Johansson, T and Jurva, U and Grönberg, G and Weidolf, L and Masimirembwa, C}, title = {Novel metabolites of amodiaquine formed by CYP1A1 and CYP1B1: structure elucidation using electrochemistry, mass spectrometry, and NMR.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {37}, number = {3}, pages = {571-579}, doi = {10.1124/dmd.108.025171}, pmid = {19074972}, issn = {1521-009X}, mesh = {Amodiaquine/chemistry/*metabolism ; Animals ; Aryl Hydrocarbon Hydroxylases/*metabolism ; Chromatography, Liquid ; Cytochrome P-450 CYP1A1/*metabolism ; Cytochrome P-450 CYP1B1 ; Electrochemistry/*methods ; Magnetic Resonance Spectroscopy/*methods ; Microsomes, Liver/metabolism ; Molecular Structure ; Rats ; Spectrometry, Mass, Electrospray Ionization/*methods ; }, abstract = {An aldehyde metabolite of amodiaquine and desethylamodiaquine has been identified. The aldehyde was the major metabolite formed in incubations with two recombinantly expressed human cytochromes P450 (rP450s), namely, CYP1A1 and CYP1B1. The aldehyde metabolite was also formed, to a lesser extent, in both human and rat liver microsomes. When comparing results from incubations with liver microsomes from 3-methylcholanthrene-treated rats (inducing CYP1A1 and CYP1B1) with those from noninduced rats, a 6-fold increase of the aldehyde metabolite was observed in the rat liver microsomes after 3-methylcholanthrene treatment. The metabolic oxidation was mimicked by the electrochemical system, and the electrochemical oxidation product was matched with the metabolite from the in vitro incubations. The electrochemical generation of the aldehyde metabolite was repeated on a preparative scale, and the proposed structure was confirmed by NMR. Trapping of the aldehyde metabolite was done with methoxyl amine. Trapping experiments with N-acetyl cysteine revealed that the aldehyde was further oxidized to an aldehyde quinoneimine species, both in the rP450 incubations and in the electrochemical system. Three additional new metabolites of amodiaquine and desethylamodiaquine were formed via rCYP1A1 and rCYP1B1. Trace amounts of these metabolites were also observed in incubations with liver microsomes from 3-methylcholanthrene-treated rats. Tentative structures of the metabolites and adducts were assigned based on liquid chromatography/tandem mass spectrometry in combination with accurate mass measurements.}, }
@article {pmid19070306, year = {2008}, author = {Vats, P and Singh, VK and Singh, SN and Singh, SB}, title = {Glutathione metabolism under high-altitude stress and effect of antioxidant supplementation.}, journal = {Aviation, space, and environmental medicine}, volume = {79}, number = {12}, pages = {1106-1111}, doi = {10.3357/asem.2305.2008}, pmid = {19070306}, issn = {0095-6562}, mesh = {Acetylcysteine/therapeutic use ; Adaptation, Physiological/*drug effects ; Adult ; *Altitude ; Antioxidants/*therapeutic use ; Ascorbic Acid/therapeutic use ; *Dietary Supplements ; Erythrocytes/drug effects ; Free Radical Scavengers/therapeutic use ; Free Radicals ; Glutathione/*metabolism ; Glutathione Peroxidase/drug effects ; Glutathione Reductase/drug effects ; Humans ; Male ; Oxidative Stress/*drug effects ; Prospective Studies ; Reactive Oxygen Species ; Stress, Physiological/drug effects ; Tocopherols/therapeutic use ; }, abstract = {INTRODUCTION: Humans have a number of mechanisms for protection against reactive oxygen species, but under stressful conditions these defenses are not completely successful. Glutathione plays an important role in protection against free radicals and reactive oxygen species induced damages. The present study was undertaken to understand the effect of high-altitude (HA) exposure on glutathione metabolism and antioxidant status along with the effects of N-acetyl cysteine (NAC) and vitamin E supplementation in humans.<br><br>METHODS: The study was conducted on 30 healthy male volunteers (age 22.9 +/- 2.6, mean +/- SD) divided into three groups. Group 1 was placebo control and 2 and 3 were supplemented with 400 mg of NAC or vitamin E, respectively, per day. The study was conducted initially at sea level (Phase I, 320 m); then the subjects were taken to high altitude (Phase II, 3600 m) by air. After a week at this altitude, subjects ascended on foot to an altitude of 4580 m (Phase III).<br><br>RESULTS: Significant decreases in reduced glutathione and increases in oxidized glutathione levels were observed on HA exposure. Increase in glutathione peroxidase and glutathione reductase levels were also observed on HA exposure. Lower levels of plasma vitamin C and total antioxidant status were observed during HA exposure. The changes observed were less in the supplemented groups as compared to placebo control.<br><br>DISCUSSION: Results indicate that HA exposure adversely affects glutathione metabolism and antioxidant defense mechanisms and these changes can be ameliorated through supplementation of NAC and vitamin E.}, }
@article {pmid19069643, year = {2008}, author = {Gao, P and He, W and He, P and Xu, B}, title = {[Effects of PCB153 on DNA damage and DNA repair-related genes expressions induced by PBDE-47 in human neuroblastoma cells in vitro].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {37}, number = {5}, pages = {525-528}, pmid = {19069643}, issn = {1000-8020}, mesh = {Cell Line, Tumor ; DNA Damage/*genetics ; DNA Repair/*genetics ; DNA-Binding Proteins/genetics/metabolism ; Halogenated Diphenyl Ethers/*toxicity ; Humans ; Neuroblastoma/*genetics/pathology ; Oxidative Stress/drug effects ; Polychlorinated Biphenyls/*toxicity ; }, abstract = {OBJECTIVE: To explore the effects of PCB153 on DNA damage and DNA repair-related gene expressions induced by PBDE-47 in SH-SY5Y cells.<br><br>METHODS: SH-SY5Y cells were incubated with different concentrations of 1,5 and 10 micromol/L PBDE-47 or/and 5 micromol/L PCB153 and antioxidant n-acetyl cysteine (NAC 100 micromol/L) for 24h in vitro, percentage of DNA in the tail, olive tail moment, the mRNA expression levels of XRCC1 and XRCC3 were measured respectively.<br><br>RESULTS: PBDE-47 increased percentage of DNA in the tail and olive tail moment significantly at doses of 5 micromol/L and above in a concentration-dependent manner compared to the control (P < 0.05). The percentage of DNA in the tail and olive tail moment were significantly higher in cells treated by 5 micromol/L PBDE-47 + 5 micromol/L PCB153 and 10 micromol/L PBDE-47 + 5 micromol/L PCB153 groups compared to the corresponding doses of PBDE-47 groups or PCB153 group (P < 0.05). The percentage of DNA in the tail and olive tail moment of cells treated by the groups added NAC were obviously lower than that of their corresponding groups not added it (P < 0.05). The interactive action was observed between PBDE-47 and PCB153 at concentrations of 10 micromol/L PBDE-47 (F = 23.74, P < 0.01). Significant decreased XRCC1 mRNA expression were observed at 10 micromol/L PBDE-47, 5 micromol/L PBDE-47 + 5 micromol/L PCB153, and 10 micromol/L PBDE-47 + 5 micromol/L PCB153 groups while significant increased XRCC3 mRNA expression were observed at 10 micromol/L PBDE-47 and 10 micromol/L PBDE-47 + 5 micromol/L PCB153 compared to the control group (P < 0.05). XRCC1 mRNA expression in cells treated by 100 micromol/L NAC + 10 micromol/L PBDE-47 + 5 micromol/L PCB153 group was significantly higher than that in 10 micromol/L PBDE-47 + 5 micromol/L PCB153 group (P < 0.05). XRCC3 mRNA expression in cells treated by PBDE-47 antioxidant groups were significantly lower than that in their corresponding non-antioxidant groups (P < 0.05). Correlation analysis showed there was a negative relationship between DNA damage and XRCC1 mRNA expression while a positive relationship between DNA damage and XRCC3 mRNA expression (r1 = 0.74, r2 = 0.76, P < 0.05).<br><br>CONCLUSION: PBDE-47 can induce DNA damage, PBDE-47 combined with PCB153 may increase the effects on DNA damage in SH-SY5Y cells in vitro, oxidative stress may play a important role in DNA damage induced by PBDE-47.}, }
@article {pmid19067892, year = {2008}, author = {Darmaun, D and Smith, SD and Sweeten, S and Hartman, BK and Welch, S and Mauras, N}, title = {Poorly controlled type 1 diabetes is associated with altered glutathione homeostasis in adolescents: apparent resistance to N-acetylcysteine supplementation.}, journal = {Pediatric diabetes}, volume = {9}, number = {6}, pages = {577-582}, doi = {10.1111/j.1399-5448.2008.00436.x}, pmid = {19067892}, issn = {1399-5448}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Deuterium ; Diabetes Mellitus, Type 1/blood/*diet therapy/*physiopathology ; Female ; Glutathione/*blood ; Glycated Hemoglobin/metabolism ; Homeostasis ; Humans ; Male ; }, abstract = {Blood glutathione concentrations represent a measure of protection against oxidative damage. In earlier studies, we observed that, in adolescents with poorly controlled type 1 diabetes mellitus (T1DM), blood glutathione is significantly depleted because of increased rates of glutathione utilization. To determine whether increased availability of cysteine - one of the three constitutive amino acids of glutathione - would attenuate the alterations in glutathione metabolism, ten 16 +/- 1 yr-old adolescents with poorly controlled T1DM [hemoglobin A1c (HbA1c): 9.9 +/- 1.3%] received 5-h infusions of l-[3,3-(2)H(2)] cysteine and d-[6,6-(2)H(2)]glucose on two occasions, 3 wk apart, after a 10-d oral supplementation with (i) N-acetylcysteine (NAC, 30-45 mg/kg/d) or (ii) L-alanine, in randomized order, and with a 3-wk 'washout' interim period. Blood glucose was maintained in the same hyperglycemic range on both infusion study days, using intravenous insulin. Glutathione fractional synthesis rate (FSR) was determined from (2)H(2)-cysteine incorporation into blood glutathione. NAC supplementation failed to raise erythrocyte cysteine concentrations (23 +/- 6 vs. 17 +/- 1 micromol/L, p = 0.853) and did not alter erythrocyte glutathione concentrations (838 +/- 106 vs. 793 +/- 111 micromol/L, p = 0.220) or glutathione FSR (96 +/- 20 vs. 89 +/- 19%/d, p = 0.974). We conclude that in adolescents with poorly controlled T1DM, dietary cysteine supplementation alone cannot correct glutathione status. In the presence of relative insulinopenia, either higher amino acid doses or aggressive insulin therapy may be needed to achieve this goal. This would require further study.}, }
@article {pmid19063961, year = {2009}, author = {Wu, D and Xu, C and Cederbaum, A}, title = {Role of nitric oxide and nuclear factor-kappaB in the CYP2E1 potentiation of tumor necrosis factor alpha hepatotoxicity in mice.}, journal = {Free radical biology &amp; medicine}, volume = {46}, number = {4}, pages = {480-491}, doi = {10.1016/j.freeradbiomed.2008.11.001}, pmid = {19063961}, issn = {1873-4596}, support = {033312//PHS HHS/United States ; AA017425/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Amidines/administration &amp; dosage ; Animals ; Benzylamines/administration &amp; dosage ; Cytochrome P-450 CYP2E1/*physiology ; Cytotoxicity, Immunologic/drug effects/*physiology ; Hepatocytes/pathology/*physiology ; Liver/pathology/physiology ; MAP Kinase Signaling System/drug effects/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria, Liver/drug effects/physiology ; Mitochondrial Swelling/drug effects/physiology ; NF-kappa B/immunology/*metabolism ; Nitric Oxide/genetics/immunology/*metabolism ; Nitric Oxide Synthase Type II/genetics/metabolism ; Oxidative Stress/drug effects/physiology ; Pyrazoles/administration &amp; dosage/metabolism ; Transcriptional Activation/drug effects/physiology ; Tumor Necrosis Factor-alpha/administration &amp; dosage/*metabolism ; }, abstract = {Induction of CYP2E1 by pyrazole (PY) potentiated the hepatotoxicity induced by TNFalpha in mice. We evaluated the role of nitrosative and oxidative stress and the NF-kappaB activation pathway in this liver injury. The iNOS inhibitor N-(3-aminomethyl)benzylacetamindine (1400W) or the antioxidant N-acetyl-l-cysteine (NAC) prevented this liver injury. TNFalpha plus PY treatment triggered radical stress in the liver with increased lipid peroxidation and decreased glutathione and caused mitochondrial damage as reflected by elevated membrane swelling and cytochrome c release. The radical stress and mitochondrial damage were prevented by 1400W and NAC. TNFalpha plus PY treatment elevated 3-nitrotyrosine adduct formation and induced NOS2 in the liver; 1400W and NAC blocked these changes. A lower extent of liver injury and oxidative stress was found in NOS2(-/-) mice treated with TNFalpha plus PY compared with wild-type controls. Neither 1400W nor NAC modified CYP2E1 activity or protein. Activation of JNK and p38MAPK was weaker in TNFalpha plus PY-treated NOS2(-/-) mice and 1400W and NAC blocked the activation of JNK and p38MAPK in wild-type mice. IKKalpha/beta protein levels were decreased by TNFalpha plus PY treatment, whereas IkappaBalpha and IkappaBbeta protein levels were elevated compared with saline, PY, or TNFalpha alone. NF-kappaB DNA binding activity was increased by TNFalpha alone but lowered by TNFalpha plus PY. All these changes were blocked by 1400W and NAC. NF-kappaB activation products such as Bcl-2, Bcl-X(L), cFLIP(S), cFLIP(L), and Mn-SOD were reduced by TNFalpha plus PY and restored by 1400W or NAC. We conclude that TNFalpha plus CYP2E1 induces oxidative/nitrosative stress, which plays a role in the activation of JNK or p38MAPK and mitochondrial damage. These effects combine with the blunting of the NF-kappaB activation pathways and the synthesis of protective factors to cause liver injury.}, }
@article {pmid19063590, year = {2009}, author = {Kang, P and Dalvie, D and Smith, E and Renner, M}, title = {Bioactivation of lumiracoxib by peroxidases and human liver microsomes: identification of multiple quinone imine intermediates and GSH adducts.}, journal = {Chemical research in toxicology}, volume = {22}, number = {1}, pages = {106-117}, doi = {10.1021/tx8002356}, pmid = {19063590}, issn = {1520-5010}, mesh = {Benzoquinones/chemistry/toxicity ; Cyclooxygenase 2 Inhibitors/*chemistry/pharmacology/toxicity ; Diclofenac/*analogs &amp; derivatives/chemistry/pharmacology/toxicity ; Glutathione/*chemistry/metabolism ; Humans ; Imines/chemistry/toxicity ; Microsomes, Liver/*metabolism ; Peroxidases/*metabolism ; Spectrophotometry, Ultraviolet ; }, abstract = {Lumiracoxib (Prexige; 2-[(2-fluoro-6-chlorophenyl)amino]-5-methyl-benzeneacetic acid) is a cyclooxygenase-2 selective inhibitor for the symptomatic treatment of osteoarthritis. Recently, the drug has been withdrawn in several countries due to serious liver side effects. Li et al. recently have shown that lumiracoxib is bioactivated to a proposed quinone imine that is trapped by N-acetylcysteine (NAC) to form two NAC adducts in human and rat liver microsomal incubations. The current study demonstrated that the lumiracoxib metabolite 4'-hydroxylumiracoxib (M5) can also be bioactivated by peroxidases such as horseradish peroxidase, myeloperoxidase, and prostaglandin H synthases. Efforts were also made to identify GSH adducts formed by P450s in human liver microsomal incubations of lumiracoxib. We herein report the detection and characterization of mono-, di-, tri-, and tetra-GSH adducts in these oxidizing systems. Most of the conjugates were generated as a result of bioactivation of M5 by both peroxidases and P450s. Quinone imine (M15) and two GSH-conjugated quinone imines (M17 and M18) were identified as intermediates in the formation of these conjugates. The latter two were formed through sequential elimination of the fluorine and chlorine groups of GSH-conjugated M15. An additional GSH adduct, which appeared to be formed directly from parent, was only observed in human liver microsomal incubations. A mechanism was proposed for the bioactivation of lumiracoxib and the formation of the observed GSH adducts. These results suggest that bioactivation of lumiracoxib and M5 may result in GSH depletion, covalent binding to proteins, and oxidative stress and may potentially lead to hepatotoxicity.}, }
@article {pmid19062520, year = {2008}, author = {Voronkina, IV and Kirpichnikova, KM and Smagina, LV and Gamaliĭ, IA}, title = {[Changes in matrix metalloproteinases activities in normal and transformed mouse fibroblasts under effect of antioxidants].}, journal = {Tsitologiia}, volume = {50}, number = {10}, pages = {877-881}, pmid = {19062520}, issn = {0041-3771}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Line, Transformed ; Cell Transformation, Viral/drug effects ; Enzyme Inhibitors/*pharmacology ; Fibroblasts/drug effects/enzymology ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; *Matrix Metalloproteinase Inhibitors ; Mice ; Thioctic Acid/*pharmacology ; }, abstract = {The effect of two antioxidants on the activities of matrix metalloproteinases (MMP) secreted by normal (3T3) and transformed (3T3-SV40) mouse fibroblasts was examined. We compared the effect of N-acetylcystein (NAC) and alpha-lipoic acid (ALA) on two gelatinases, MMP-2 and MMP-9. Gel zymography demonstrated that activity of MMP-2 was higher in normal 3T3 cells, and MMP-9 activity was higher in transformed 3T3-SV40 cells. NAC action for 2-6 hours completely inhibited MMP-2 and MMP-9 activity in both cell lines. The inhibitory effect almost did not depend on NAC concentration at the range of 1-10 mM. ALA (1.2 mM) affected the cells not so dramatically. ALA decreased the MMP-2 activity in both cellular types. As to MMP-9 activity, it decreased in 3T3 cells and slightly increased in 3T3-SV40 cells in the presence of ALA. The activity of membrane bound and intracellular MMP was not changed under the same conditions. In conclusion, an altered activity of MMP in the presence of an antioxidant may influence the intracellular signalling and cell functions.}, }
@article {pmid19060765, year = {2009}, author = {Cartotto, R and Walia, G and Ellis, S and Fowler, R}, title = {Oscillation after inhalation: high frequency oscillatory ventilation in burn patients with the acute respiratory distress syndrome and co-existing smoke inhalation injury.}, journal = {Journal of burn care &amp; research : official publication of the American Burn Association}, volume = {30}, number = {1}, pages = {119-127}, doi = {10.1097/BCR.0b013e3181920fe6}, pmid = {19060765}, issn = {1559-047X}, mesh = {Adult ; Analysis of Variance ; Burn Units ; Burns/*complications/physiopathology ; Chi-Square Distribution ; Female ; *High-Frequency Ventilation/adverse effects ; Humans ; Male ; Middle Aged ; Respiratory Distress Syndrome/physiopathology/*therapy ; Retrospective Studies ; Smoke Inhalation Injury/physiopathology/*therapy ; Treatment Outcome ; }, abstract = {The purpose of this study was to evaluate the effectiveness of, and complications associated with High Frequency Oscillatory Ventilation (HFOV) in burn patients with the Acute Respiratory Distress Syndrome (ARDS) who have had a smoke inhalation injury, and to compare with those without an inhalation injury. Burn patients with progressive oxygenation failure from ARDS while on conventional mechanical ventilation were placed on HFOV as a "rescue" ventilation modality. There were 19 patients with burn + inhalation injury and 30 patients with burn only. Burned patients with ARDS but without inhalation injury had significant temporal improvement in the oxygenation index from 27 +/- 8 on conventional mechanical ventilation to 17 +/- 6 within 48 hours of initiating HFOV. However, burned patients with ARDS and smoke inhalation injury did not achieve significant or even eventual improvements in oxygenation index with HFOV. There was also a trend towards higher rates of early HFOV failure and severe hypercapnia while on HFOV among the patients with inhalation injury. Delivery of nebulized bronchodilators, heparin and n-acetyl cysteine, normally mainstays of smoke inhalation therapy, was impossible during HFOV. The presence of a smoke inhalation injury appears to impair the response to HFOV when this ventilation modality is instituted for ARDS-related oxygenation failure. Severe hypercapnia tended to be more frequent during HFOV among patients with smoke inhalation. These findings, combined with the difficulties in delivery of nebulized medications during HFOV suggest that HFOV may not be the optimal "rescue" ventilation modality in cases of ARDS if there has been an inhalation injury.}, }
@article {pmid19059111, year = {2008}, author = {Oroszlán, M and Bieri, M and Ligeti, N and Farkas, A and Koestner, SC and Meier, B and Mohacsi, PJ}, title = {Proliferation signal inhibitor-induced decrease of vascular endothelial cadherin expression and increase of endothelial permeability in vitro are prevented by an anti-oxidant.}, journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}, volume = {27}, number = {12}, pages = {1311-1318}, doi = {10.1016/j.healun.2008.08.013}, pmid = {19059111}, issn = {1557-3117}, mesh = {Acetylcysteine/*pharmacology ; Cadherins/*genetics ; Cell Division/drug effects ; Cell Membrane Permeability/drug effects/*physiology ; Endothelium, Vascular/cytology/drug effects/*physiology ; Everolimus ; Free Radical Scavengers/pharmacology ; Humans ; Oxidative Stress/*drug effects ; Permeability ; Signal Transduction/drug effects/physiology ; Sirolimus/*analogs &amp; derivatives/*pharmacology ; Umbilical Veins ; }, abstract = {BACKGROUND: Rapamycines, sirolimus (SRL) and everolimus (ERL), are proliferation signal inhibitors (PSIs). PSI therapy often leads to edema. We hypothesized that increased oxidative stress in response to PSIs may modulate the expression of vascular endothelial (VE)-cadherin on endothelial cells (ECs) and, subsequently, vascular permeability, which in turn may be involved in the development of edema.<br><br>METHODS: Experiments were performed on human umbilical vein ECs (HUVECs). Oxidative stress was measured by dichlorofluorescein-diacetate. Expression of VE-cadherin was evaluated by immunofluorescent staining and western blot analysis. Endothelial "permeability" was assessed using a transwell model.<br><br>RESULTS: SRL and ERL, at concentrations of 1, 10 and 100 nmol/liter, enhanced oxidative stress (SRL: 24 +/- 12%, 29 +/- 9%, 41 +/- 13% [p < 0.05, in all three cases]; ERL: 13 +/- 10%, 27 +/- 2%, 40 +/- 12% [p < 0.05, in the latter two cases], respectively) on HUVECs, which was inhibited by the anti-oxidant, N-acetyl-cysteine (NAC) and, to a lesser extent, by the specific inhibitor of nitric oxide synthase, N-Omega-nitro-L-arginine methylester. By the use of NAC, VE-cadherin expression remained comparable with control, according to both immunocytochemistry and western blot analysis. Permeability was significantly increased by SRL and ERL at 100 nmol/liter (29.5 +/- 6.4% and 33.8 +/- 4.2%, respectively); however, co-treatment with NAC abrogated the increased permeability.<br><br>CONCLUSIONS: EC homeostasis, as indicated by VE-cadherin expression, may be damaged by SRL and ERL, but resolved by the anti-oxidant NAC.}, }
@article {pmid19058177, year = {2009}, author = {Hao, J and Zhang, B and Liu, B and Lee, M and Hao, X and Reuhl, KR and Chen, X and Yang, CS}, title = {Effect of alpha-tocopherol, N-acetylcysteine and omeprazole on esophageal adenocarcinoma formation in a rat surgical model.}, journal = {International journal of cancer}, volume = {124}, number = {6}, pages = {1270-1275}, pmid = {19058177}, issn = {1097-0215}, support = {P30CA72720/CA/NCI NIH HHS/United States ; P30 ES005022/ES/NIEHS NIH HHS/United States ; N01-CN-43309/CN/NCI NIH HHS/United States ; R01 CA075683/CA/NCI NIH HHS/United States ; R01 CA075683-09/CA/NCI NIH HHS/United States ; CA75683/CA/NCI NIH HHS/United States ; N01CN43309/CA/NCI NIH HHS/United States ; P30 CA072720/CA/NCI NIH HHS/United States ; ES05022/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adenocarcinoma/etiology/pathology/*prevention &amp; control/surgery ; Animals ; Disease Models, Animal ; Esophageal Neoplasms/etiology/pathology/*prevention &amp; control/surgery ; Gastroesophageal Reflux/complications ; Hydrogen-Ion Concentration ; Male ; Omeprazole/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Vitamin A/blood ; alpha-Tocopherol/blood/*therapeutic use ; }, abstract = {We previously demonstrated that oxidative stress subsequent to gastroesophageal reflux is an important driving force of esophageal adenocarcinoma (EAC) formation in the esophagogastroduodenal anastomosis (EGDA) rat model. This study investigated the possible tumor inhibitory effects of 2 antioxidants, alpha-tocopherol (389 and 778 ppm), N-acetylcysteine (NAC, 500 and 1,000 ppm), and their combination (389 and 500 ppm, respectively), as well as an antacid therapeutic agent, omeprazole (1,400 ppm). The rats were fed experimental diets 2 weeks after EGDA. All the animals were sacrificed 40 weeks after EGDA and the esophagi were harvested for histopathological examination. alpha-Tocopherol dose-dependently decreased the incidence of EAC (p = 0.03), with 778 ppm alpha-tocopherol reducing the incidence of EAC to 59% (16/27) in comparison with 84% (26/31) in the control group (p = 0.04). Supplementation of alpha-tocopherol also increased the serum concentration of alpha-tocopherol. NAC at 500 and 1,000 ppm did not significantly decrease EAC incidence; however, the combination of alpha-tocopherol 389 ppm and NAC 500 ppm significantly reduced the incidence of EAC to 55% (15/27) (p = 0.02). alpha-Tocopherol alone or in combination with NAC significantly reduced the number of infiltrating cells positively stained for 4-hydroxynonenal. Omeprazole showed only a slight nonsignificant inhibitory effect at the dose given. Our results suggest that supplementation with alpha-tocopherol inhibits the development of EAC in the rat EGDA model and similar inhibitory effect can be achieved when a lower dose of alpha-tocopherol is used in combination with NAC.}, }
@article {pmid19056706, year = {2009}, author = {Remington, R and Chan, A and Paskavitz, J and Shea, TB}, title = {Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer's disease: a placebo-controlled pilot study.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {24}, number = {1}, pages = {27-33}, pmid = {19056706}, issn = {1533-3175}, mesh = {Activities of Daily Living/psychology ; Affect/drug effects ; Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis/*drug therapy/physiopathology ; *Chemistry, Pharmaceutical ; Cognition/*drug effects ; Cohort Studies ; *Dietary Supplements ; Drug Therapy, Combination ; Humans ; Pilot Projects ; Severity of Illness Index ; Treatment Outcome ; Vitamins/*therapeutic use ; }, abstract = {Recent studies demonstrated efficacy of a vitamin/ nutriceutical formulation (folate, vitamin B12, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine) for mild to moderate Alzheimer's disease. Herein, we tested the efficacy of this formulation in a small cohort of 12 institutionalized patients diagnosed with moderate-stage to later-stage Alzheimer's disease. Participants were randomly separated into treatment of placebo groups. Participants receiving the formulation demonstrated a clinically significant delay in decline in the Dementia Rating Scale and clock-drawing test as compared to those receiving placebo. Institutional caregivers reported approximately 30% improvement in the Neuropyschiatric Inventory and maintenance of performance in the Alzheimer's Disease Cooperative Study-Activities of Daily Living for more than 9 months. This formulation holds promise for delaying the decline in cognition, mood, and daily function that accompanies the progression of Alzheimer's disease, and may be particularly useful as a supplement for pharmacological approaches during later stages of this disorder. A larger trial is warranted.}, }
@article {pmid19054265, year = {2009}, author = {Tunc, T and Oter, S and Güven, A and Topal, T and Kul, M and Korkmaz, A and Ongürü, O and Sarici, U}, title = {Protective effect of sulfhydryl-containing antioxidants against ischemia/reperfusion injury of prepubertal rat intestine.}, journal = {Journal of gastroenterology and hepatology}, volume = {24}, number = {4}, pages = {681-687}, doi = {10.1111/j.1440-1746.2008.05673.x}, pmid = {19054265}, issn = {1440-1746}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Constriction ; Disease Models, Animal ; Glutathione Peroxidase/metabolism ; Ileum/blood supply/*drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Mesenteric Artery, Superior/surgery ; Oxidative Stress/*drug effects ; Protein Carbonylation/drug effects ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/metabolism/pathology/*prevention &amp; control ; *Sexual Development ; Sulfhydryl Compounds/*pharmacology ; Superoxide Dismutase/metabolism ; Thioctic Acid/pharmacology ; Thioglycolates/pharmacology ; Thiophenes/pharmacology ; }, abstract = {BACKGROUND AND AIM: Reactive oxygen species generated during reperfusion of the tissue are known to play an important role in the basic pathophysiology of ischemia/reperfusion (I/R) injury. The aim of this study was to investigate and compare the protective effects of three sulfide-based antioxidants, N-acetylcysteine (NAC), erdosteine (ERD), and alpha-lipoic acid (LA), on I/R injury of the small intestine tissue.<br><br>METHODS: Forty male Sprague-Dawley rats weighing between 100-150 g were divided into five groups (n = 8 for each): control (sham operated), I/R, I/R + NAC, I/R + ERD, and I/R + LA. Intestinal ischemia was provided by occluding the superior mesenteric artery via a special microvascular clamp; ischemia for 30 min and reperfusion for 3 days were carried out. Ileal specimens were obtained to determine the tissue levels of malondialdehyde (MDA), protein carbonyl contents (PCO), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities and histological changes.<br><br>RESULTS: The rats subjected to intestinal I/R exhibited an increase in tissue MDA and PCO; the levels could hardly be ameliorated in the treatment groups. SOD and GPx activities were significantly decreased in the I/R group, whereas their reduction was less expressed in the treatment groups. Additionally, the histopathological injury scores of the disulfide-treated groups were lower than those of the I/R group.<br><br>CONCLUSION: All of the sulfhydryl-containing antioxidants used in this study exhibited a significant role in attenuating intestinal I/R injury; however, the outcome of the LA-treated group was significantly marked than that of the others.}, }
@article {pmid19053299, year = {2008}, author = {Navath, RS and Kurtoglu, YE and Wang, B and Kannan, S and Romero, R and Kannan, RM}, title = {Dendrimer-drug conjugates for tailored intracellular drug release based on glutathione levels.}, journal = {Bioconjugate chemistry}, volume = {19}, number = {12}, pages = {2446-2455}, pmid = {19053299}, issn = {1520-4812}, support = {N01 HD023342/HD/NICHD NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/*chemistry/*metabolism/pharmacology ; Animals ; Cell Line ; Cytoplasm/metabolism ; Dendrimers ; Disulfides/chemistry ; Drug Carriers/*chemistry ; Glutathione/chemistry/*metabolism ; Intracellular Space/*metabolism ; Mice ; Microglia/cytology/drug effects ; Oxidation-Reduction ; Polyamines/chemical synthesis/*chemistry ; }, abstract = {N-Acetyl-L-cysteine (NAC) is an antioxidant and anti-inflammatory agent with significant potential in clinical applications including stroke and neuroinflammation. The drug shows high plasma binding upon IV administration, requiring high doses and associated side effects. Through the use of an appropriate delivery vehicle, the stability and efficacy of NAC can be significantly improved. Dendrimers are an emerging class of nanoscale drug delivery vehicles, which enable high drug payloads and intracellular delivery. Poly(amidoamine) (PAMAM) dendrimer-NAC conjugates having cleavable disulfide linkages are designed for intracellular delivery based on glutathione levels. We have successfully synthesized two conjugates with a cationic G4-NH(2) and an anionic G3.5-COOH PAMAM dendrimer with NAC payloads of 16 and 18 per dendrimer, respectively, as confirmed by (1)H NMR and MALDI-TOF analysis. NAC release from the conjugates at intracellular and extracellular glutathione (GSH) concentrations were evaluated by reverse phase HPLC (RP-HPLC) analysis, and approximately 70% of NAC payload was released within one hour at intracellular GSH concentrations (approximately 10 mM), whereas negligible NAC release was observed at extracellular GSH levels (2 microM). FITC-labeled conjugates showed that they enter cells rapidly and localize in the cytoplasm of lipopolysaccharide (LPS)-activated microglial cells (the target cells in vivo). The significantly improved efficacies of dendrimer-NAC conjugates in activated microglial cells was confirmed by measuring the nitrite inhibition in the cell culture medium, which is an indication of the antioxidative property of the drug. Both G4-NH(2) and G3.5-COOH conjugates showed significantly better nitrite inhibition both at 24 and 72 h compared to free NAC, by as much as a factor of 16. The results indicate that PAMAM dendrimer conjugates produce higher local NAC concentration inside the cells, with GSH-sensitive disulfide linker enabling efficient and rapid cellular release of the drug.}, }
@article {pmid19053182, year = {2009}, author = {Li, F and Chordia, MD and Huang, T and Macdonald, TL}, title = {In vitro nimesulide studies toward understanding idiosyncratic hepatotoxicity: diiminoquinone formation and conjugation.}, journal = {Chemical research in toxicology}, volume = {22}, number = {1}, pages = {72-80}, doi = {10.1021/tx800152r}, pmid = {19053182}, issn = {1520-5010}, mesh = {Anilides/toxicity/urine ; Anti-Inflammatory Agents, Non-Steroidal/*chemistry/toxicity ; Benzene Derivatives/chemistry ; *Chemical and Drug Induced Liver Injury/etiology ; Chromatography, Liquid ; Cytochrome P-450 Enzyme System/metabolism ; Humans ; Imines/*chemistry/toxicity ; Mass Spectrometry ; Sulfonamides/*chemistry/toxicity ; }, abstract = {Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) marketed in more than 50 countries. This drug has caused rare and idiosyncratic but severe hepatotoxicity. The mechanisms associated with and factors responsible for this toxicity remain unknown. One of the nimesulide metabolites identified in human urine is 4-amino-2-phenoxy-methanesulfonanilide (M1). In the current study, we demonstrate that M1 is a stable metabolite that is highly susceptible to facile oxidation by cytochrome P450 enzymes (P450s) to form a reactive diiminoquinone intermediate (M2). Direct detection of M2 was difficult by LC-MS. However, its formation was confirmed indirectly by identification of N-acetyl-cysteine (NAC) adducts of M2. The formation of diiminoquinone M2 was P450 mediated with 2C19 and 1A2 as the two principal P450 enzymes catalyzing M1 oxidation. M1 metabolism irreversibly inhibited 2C19 but activated 1A2 in a time-dependent manner. P450 2C19 exclusively mediated further metabolism of M1 to the amino hydroxynimesulide M3 and its diiminoquinone M4. Similar to M2, M4 is also reactive and can be observed indirectly as its NAC adduct. Nucleophilic addition to diiminoquinone M2 occurs with low regioselectivity, yielding three adducts (the peak area ratio 1:0.08:12). The three regioisomers have the same m/z for [M + H](+), presumably due to nucleophilic addition at the three possible electrophilic sites (C-3, -5, and -6 positions of the sulfonaniline ring). The primary adduct, R, was derived from the attack of the nucleophile at the C-5 position of the sulfonaniline ring and was determined by MS/MS and (1)H and (13)C NMR analyses. The structural assignments were confirmed by chemical synthesis of the adduct R. M2 demonstrated its electrophilic reactivity by selectively alkylating human serum albumin (HSA) at the only free thiol, Cys-34. This suggests the possibility that other proteins may undergo a similar conjugation to form irreversible adducts. Under oxidizing conditions in the presence of cumene hydroperoxide (CHP), the formation of M2 was enhanced, indicating that oxidative stress may accelerate the production of reactive diiminoquinone species (M2 and M4).}, }
@article {pmid19051069, year = {2009}, author = {Yang, WP and Hu, BH and Chen, GD and Bielefeld, EC and Henderson, D}, title = {Protective effect of N-acetyl-L-cysteine (L-NAC) against styrene-induced cochlear injuries.}, journal = {Acta oto-laryngologica}, volume = {129}, number = {10}, pages = {1036-1043}, pmid = {19051069}, issn = {1651-2251}, support = {R01 DC006862/DC/NIDCD NIH HHS/United States ; 1 R 01 OH 008113-01A1/OH/NIOSH CDC HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Free Radical Scavengers/pharmacology/*therapeutic use ; Glutathione/metabolism ; Hair Cells, Auditory, Outer/*drug effects ; Hearing Loss/chemically induced/metabolism/*prevention &amp; control ; Rats ; Rats, Long-Evans ; Styrene/*toxicity ; }, abstract = {CONCLUSION: Styrene exposure causes hair cell death through both apoptotic and necrotic pathways and treatment with N-acetyl-L-cysteine (L-NAC) reduces styrene ototoxicity.<br><br>OBJECTIVE: Exposure to styrene causes hearing loss and hair cell death in the middle frequency region in the cochlea. The current study was designed to examine the cell death pathways and the protective effect of L-NAC against styrene-induced cochlear injuries.<br><br>MATERIALS AND METHODS: Seventeen rats were exposed to styrene by gavage at 400 mg/kg 5 days per week for 3 weeks. Nine of the styrene-treated rats received L-NAC by intraperitoneal injection (325 mg/kg), and the remaining eight rats received saline injections as controls. The styrene-induced hearing loss was assessed by auditory brainstem responses (ABRs). Apoptotic, necrotic, and missing hair cells were quantified using combined methods, including nuclear staining with propidium iodide, F-actin staining with FITC-phalloidin, and the TUNEL assay.<br><br>RESULTS: The styrene exposure caused a threshold shift of 15&#xb1;4.3 dB. Both apoptosis and necrosis were involved in the pathogenesis of the cochlear lesion, but apoptosis appeared to be the major cell death pathway leading to the styrene ototoxicity. Treatment with L-NAC reduced the number of missing and dying outer hair cells (OHCs) and reduced the styrene-induced hearing loss.}, }
@article {pmid19050604, year = {2009}, author = {Yubero, S and Ramudo, L and Manso, MA and De Dios, I}, title = {Targeting peripheral immune response reduces the severity of necrotizing acute pancreatitis.}, journal = {Critical care medicine}, volume = {37}, number = {1}, pages = {240-245}, doi = {10.1097/CCM.0b013e31819320fc}, pmid = {19050604}, issn = {1530-0293}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Dexamethasone/*therapeutic use ; Leukocytes, Mononuclear/*drug effects/*immunology ; Male ; Pancreatitis, Acute Necrotizing/*immunology/*prevention &amp; control ; Rats ; Rats, Wistar ; Severity of Illness Index ; }, abstract = {OBJECTIVE: A complex cascade of immunologic events leads to the development of systemic inflammatory response in acute pancreatitis (AP). Our aim was to evaluate the effects of two different immunomodulating treatments: Dexamethasone (Dx) and N-acetylcysteine (NAC), on the progression of necrotizing AP.<br><br>DESIGN: Prospective, random, and control study. Laboratory animals.<br><br>SETTING: University-based research laboratory.<br><br>SUBJECTS: Male Wistar rats.<br><br>INTERVENTIONS: Retrograde infusion of 3.5% of sodium taurocholate into pancreatic-biliary duct was used to induce AP in rats. Dx (1 mg/kg) was administered 30 mins before or 1 hr after AP, and NAC (50 mg/kg) was given 1 hr before and 1 hr after inducing AP.<br><br>MEASUREMENTS AND MAIN RESULTS: Dx and NAC treatments reduced the severity of AP in terms of amylasemia, pancreatic edema, and pancreatic and liver necrosis. Dx, administered before or after AP, and NAC reduced the leukocytosis induced by AP and blocked the ability of circulating monocytes to produce tumor necrosis factor-alpha and monocyte chemoattractant protein-1; however none of them significantly reduced the overexpression of intercellular cell adhesion molecule-1 found in monocytes 6 hrs after inducing AP. Leukocyte infiltration in the pancreas was attenuated in Dx-pretreated rats and significantly reduced 6 hrs after inducing AP in rats treated with NAC. However, neither Dx nor NAC were able to significantly reduce interleukin-6 in plasma or mitigate leukocyte infiltration in the lung.<br><br>CONCLUSIONS: Our data demonstrated that treatments targeting the peripheral immune response reduced the severity of sodium taurocholate -induced AP attenuating pancreatic and liver injury, but they were not effective for limiting the spread of the inflammatory damage to the lung.}, }
@article {pmid19050086, year = {2008}, author = {Naughton, F and Wijeysundera, D and Karkouti, K and Tait, G and Beattie, WS}, title = {N-acetylcysteine to reduce renal failure after cardiac surgery: a systematic review and meta-analysis.}, journal = {Canadian journal of anaesthesia = Journal canadien d'anesthesie}, volume = {55}, number = {12}, pages = {827-835}, doi = {10.1007/BF03034054}, pmid = {19050086}, issn = {0832-610X}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Cardiac Surgical Procedures/*adverse effects ; Cardiopulmonary Bypass/adverse effects ; Free Radical Scavengers/*therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; Renal Insufficiency/*etiology/*prevention &amp; control ; Risk ; Treatment Outcome ; }, abstract = {PURPOSE: To assess the effect of N-acetylcysteine (NAC) on acute renal failure and important clinical outcomes after cardiac surgery.<br><br>METHODS: Two reviewers performed literature searches, using EMBASE and PubMed, of randomized controlled trials investigating the renoprotective effect of N-acetylcysteine in cardiac surgery. Treatment effects were calculated as relative risks (RR) with 95% confidence intervals (CI). Heterogeneity and publication bias were assessed using the I(2) test and funnel plots, respectively. Meta regression was performed to assess the effect of baseline renal function and the use of aprotinin on renal function.<br><br>RESULTS: Seven randomized controlled trials (RCTs) (n = 1000) were identified. No study could demonstrate, either independently or meta-analytically, an improvement in the postoperative increase in creatinine, mortality (RR 0.93, 95% CI 0.4 to 2.07), renal failure requiring renal replacement therapy (RR 1.01, 95% CI 0.49 to 2.12), myocardial infarction (RR 0.88, 95% CI 0.36 to 1.88), atrial fibrillation (RR 0.88, 95% CI 0.70 to 1.10), or stroke (RR 0.69, 95% CI 0.27 to 1.69). There was a small, though significant increase in postoperative blood loss among patients treated with NAC (weighted mean difference 119 mL 95% CI 51, 187). After meta regression neither increase in postoperative creatinine (r(2) = 0.33) nor renal replacement therapy (r(2) = 0.04) was associated with the baseline creatinine or with NAC dose (r(2) =0.04).<br><br>CONCLUSION: This analysis did not find that treatment with NAC was associated with clinical renal protection during cardiac surgery, or improvement in other clinical outcomes.}, }
@article {pmid19049703, year = {2008}, author = {Heng, AE and Cellarier, E and Aublet-Cuvelier, B and Decalf, V and Motreff, P and Marcaggi, X and Deteix, P and Souweine, B}, title = {Is treatment with N-acetylcysteine to prevent contrast-induced nephropathy when using bicarbonate hydration out of date?.}, journal = {Clinical nephrology}, volume = {70}, number = {6}, pages = {475-484}, doi = {10.5414/cnp70475}, pmid = {19049703}, issn = {0301-0430}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aged ; Contrast Media/*adverse effects ; Coronary Angiography/adverse effects/methods ; Coronary Disease/diagnostic imaging ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Free Radical Scavengers/administration &amp; dosage ; Glomerular Filtration Rate/drug effects/physiology ; Humans ; Injections, Intravenous ; Iopamidol/administration &amp; dosage/adverse effects/*analogs &amp; derivatives ; Kidney Diseases/chemically induced/physiopathology/*prevention &amp; control ; Male ; Prospective Studies ; Sodium Bicarbonate/administration &amp; dosage/*therapeutic use ; Treatment Outcome ; Triiodobenzoic Acids/administration &amp; dosage/*adverse effects ; }, abstract = {AIMS: Chronic renal failure (CRF) is a major risk factor for contrast-induced nephropathy (CIN) and could be prevented by bicarbonate hydration. The effect of N-acetylcysteine (NAC) in preventing CIN in patients treated by bicarbonate hydration has never been investigated.<br><br>METHODS: Patients admitted for cardiac angiography from January 2002 to November 2004, with stable CRF (glomerular filtration rate (GFR) < 56 ml/min, Cockcroft-Gault formula) were included in a prospective, randomized, double-blind study comparing the efficacy of oral NAC + bicarbonate hydration vs oral placebo + bicarbonate hydration to prevent CIN. NAC 1,200 mg twice daily or placebo was given on Day -1 and Day 0 (Day 0 = cardiac angiography). A 1.4% bicarbonate solution (1 ml/ kg/h) was administered 12 hours before and after cardiac angiography. The overall CIN incidence on Day 2 was defined by one or more of the following criteria: increase in serum creatinine > 44.2 micromol/l, increase in serum creatinine > 25% or decrease in GFR > 5 ml/ min.<br><br>RESULTS: Between NAC group (n = 28) and placebo group (n = 32) there was no difference in baseline demographics (age, sex ratio, weight, arterial hypertension, diabetes), in Day 0 characteristics (serum creatinine, GFR, hematocrit, protidemia) and in Day 0 cardiac angiography procedure (diagnostic or interventional, number of stents, type and volume of contrast media infused). The overall incidence of CIN in the NAC and placebo groups was 7.1 vs 9.3% (p = 1), respectively, and the rates of the observed criteria a, b, and c were 0 vs 6.3% (p = 0.49), 3.5 vs 6.3% (p = 1), and 7.1 vs 9.3% (p = 1).<br><br>CONCLUSION: In CRF patients undergoing cardiac angiography, the use of bicarbonate hydration is associated with a very low incidence of CIN. In these conditions, on the basis of our results, we cannot draw any meaningful conclusion on the effect of NAC on the prevention of CIN.}, }
@article {pmid19047474, year = {2008}, author = {Chan, A and Paskavitz, J and Remington, R and Rasmussen, S and Shea, TB}, title = {Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer's disease: a 1-year, open-label pilot study with an 16-month caregiver extension.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {23}, number = {6}, pages = {571-585}, pmid = {19047474}, issn = {1533-3175}, mesh = {Activities of Daily Living ; Alzheimer Disease/*drug therapy/psychology/rehabilitation ; Caregivers ; Cognition/*drug effects ; *Dietary Supplements ; Follow-Up Studies ; Humans ; Pilot Projects ; Tablets ; Treatment Outcome ; Vitamins/administration &amp; dosage/*therapeutic use ; }, abstract = {We examined the efficacy of a vitamin/nutriceutical formulation (folate, vitamin B6, alpha-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine) in a 12-month, open-label trial with 14 community-dwelling individuals with early-stage Alzheimer's disease. Participants improved in the Dementia Rating Scale and Clock-drawing tests (Clox 1 and 2). Family caregivers reported improvement in multiple domains of the Neuropsychiatric Inventory (NPI) and maintenance of performance in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADL). Sustained performance was reported by caregivers for those participants who continued in an 16-month extension. Performance on the NPI was equivalent to published findings at 3 to 6 months for donepezil and exceeded that of galantamine and their historical placebos. Participants demonstrated superior performance for more than 12 months in NPI and ADL versus those receiving naproxen and rofecoxib or their placebo group. This formulation holds promise for treatment of early-stage Alzheimer's disease prior to and/or as a supplement for pharmacological approaches. A larger, placebo-controlled trial is warranted.}, }
@article {pmid19046408, year = {2009}, author = {Zhou, ZD and Kerk, SY and Xiong, GG and Lim, TM}, title = {Dopamine auto-oxidation aggravates non-apoptotic cell death induced by over-expression of human A53T mutant alpha-synuclein in dopaminergic PC12 cells.}, journal = {Journal of neurochemistry}, volume = {108}, number = {3}, pages = {601-610}, doi = {10.1111/j.1471-4159.2008.05795.x}, pmid = {19046408}, issn = {1471-4159}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzimidazoles ; Cell Death/*physiology ; Chromatography, High Pressure Liquid ; Cysteine/pharmacology ; Dopamine/*metabolism ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Fluorescent Dyes ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Humans ; Monophenol Monooxygenase/antagonists &amp; inhibitors ; Mutation ; Nerve Growth Factor/pharmacology ; Oxidation-Reduction ; PC12 Cells ; Rats ; Tetrazolium Salts ; Thiazoles ; Transfection ; alpha-Synuclein/*biosynthesis/*genetics ; }, abstract = {In this study, we demonstrated that transient transfection and over-expression of human mutant A53T alpha-synuclein (alpha-syn) could induce expression level- and time-dependent, non-apoptotic cell death in PC12 cells, while wild-type and mutant A30P alpha-syn could not. The non-apoptotic cell death induced by over-expression of A53T alpha-syn in PC12 cells was found to be dopamine (DA) related. It could be alleviated by nerve growth factor but not by chemicals that abrogate endoplasmic reticulum stress. Furthermore, PC12 cell death could be alleviated by N-acetyl-cysteine (NAC) as well as by L-cysteine; but not by cell permeable tyrosinase inhibitors. NAC could prevent DA auto-oxidation and tyrosinase-catalyzed DA oxidation, whereas L-cysteine could potently abrogate DA auto-oxidation but could not prevent tyrosinase-catalyzed DA oxidation. Both NAC and L-cysteine could increase the reduced and total GSH levels, and concurrently decrease the oxidized GSH level in PC12 cells. On the other hand, over-expression of human mutant A53T alpha-syn could decrease the reduced and total GSH levels, and increase the oxidized GSH level in the cells. Taken together, we concluded that auto-oxidation of endogenous DA aggravates non-apoptotic cell death induced by over-expression of human mutant A53T alpha-syn in PC12 cells.}, }
@article {pmid19043054, year = {2008}, author = {Ortega, JA and Ortega, JM and Julian, D}, title = {Hypotaurine and sulfhydryl-containing antioxidants reduce H2S toxicity in erythrocytes from a marine invertebrate.}, journal = {The Journal of experimental biology}, volume = {211}, number = {Pt 24}, pages = {3816-3825}, doi = {10.1242/jeb.021303}, pmid = {19043054}, issn = {0022-0949}, mesh = {Animals ; Antioxidants/*chemistry/*pharmacology ; Cell Survival/drug effects ; Erythrocytes/*drug effects ; Free Radical Scavengers/chemistry/pharmacology ; Polychaeta/*cytology ; Sulfhydryl Compounds/chemistry/pharmacology ; Sulfides/*toxicity ; Taurine/*analogs &amp; derivatives/pharmacology ; }, abstract = {Hypotaurine (HT) has been proposed to reduce sulfide toxicity in some deep-sea invertebrates by scavenging free radicals produced from sulfide oxidation or by scavenging sulfide via the reaction of HT with sulfide, forming thiotaurine (ThT). We tested whether HT or several antioxidants could reduce the total dissolved sulfide concentration in buffered seawater exposed to H(2)S, and whether HT, ThT or antioxidants could increase the viability of Glycera dibranchiata erythrocytes exposed to H(2)S in vitro. We found that 5 and 50 mmol l(-1) HT reduced the dissolved sulfide in cell-free buffer exposed to H(2)S by up to 80% whereas the antioxidants glutathione ethyl ester (GEE), N-acetylcysteine (NAC), L-ascorbic acid (ASC), Tempol and Trolox had no consistent effect. Exposure of erythrocytes to 0.10%-3.2% H(2)S (producing 0.18-4.8 mmol l(-1) sulfide) decreased the fraction of viable cells, as evidenced by loss of plasma membrane integrity, with virtually no cells remaining viable at 1.0% or more H(2)S. Addition of HT (0.5-50 mmol l(-1)) significantly increased the fraction of viable cells (e.g. from 0.01 to 0.84 at 0.32% H(2)S) whereas ThT (0.5 and 5 mmol l(-1)) decreased cell viability. GEE (0.03-3 mmol l(-1)) and NAC (0.001-1 mmol l(-1)), which contain sulfhydryl groups, increased cell viability during H(2)S exposure but to a lesser extent than HT whereas ASC, Tempol and Trolox, which do not contain sulfhydryl groups, decreased viability or had no effect. These data show that HT can protect cells from sulfide in vitro and suggest that sulfide scavenging, rather than free radical scavenging, is the most important mechanism of protection.}, }
@article {pmid19041939, year = {2009}, author = {Park, YJ and Ahn, HJ and Chang, HK and Kim, JY and Huh, KH and Kim, MS and Kim, YS}, title = {The RhoGDI-alpha/JNK signaling pathway plays a significant role in mycophenolic acid-induced apoptosis in an insulin-secreting cell line.}, journal = {Cellular signalling}, volume = {21}, number = {2}, pages = {356-364}, doi = {10.1016/j.cellsig.2008.11.009}, pmid = {19041939}, issn = {1873-3913}, mesh = {Analysis of Variance ; Animals ; *Apoptosis/drug effects ; Base Sequence ; Caspase 3/metabolism ; Cell Line ; Electrophoresis, Gel, Two-Dimensional ; Guanine Nucleotide Dissociation Inhibitors/*metabolism ; Insulin-Secreting Cells/drug effects/enzymology/*metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mycophenolic Acid/*pharmacology ; Proteomics ; Rats ; Signal Transduction/drug effects ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; rho-Specific Guanine Nucleotide Dissociation Inhibitors ; }, abstract = {Mycophenolic acid (MPA)-induced beta-cell toxicity is an important factor for islet graft function. The signal transduction mechanisms underlying this process have not been fully explored. Using a proteomics approach, we examined protein expression patterns in MPA-treated RIN-5 cells and found that RhoGDI-alpha expression is altered by MPA-treatment. We examined the relationship between RhoGDI-alpha expression and activated JNK during MPA-induced apoptosis. Cells were treated with N-acetyl-cysteine (NAC), caspase inhibitor, JNK inhibitor, guanosine or GTP for 1 h before being treated with MPA. To investigate the regulatory effects of RhoGDI-alpha on JNK activity, we examined cells showing either elevated or reduced expression of RhoGDI-alpha as a result of transfection with cDNA or siRNA constructs, respectively. MPA significantly increased cell death, caspase-3 expression and JNK activation, but it decreased the expression of a protein spot 25 observed by two-dimensional electrophoresis. This protein 25 was identified as RhoGDI-alpha by mass spectrometry. MPA-induced cell death and down-regulation of RhoGDI-alpha were prevented by guanosine, GTP or a JNK inhibitor. However, MPA-induced cell death was partially restored by treatment with a caspase inhibitor, but not by NAC treatment. RhoGDI-alpha expression was not affected by treatment with NAC or caspase inhibitor. Over-expression of RhoGDI-alpha increased cell viability and decreased activated JNK expression following exposure to MPA, whereas knockdown of RhoGDI-alpha enhanced MPA-induced cell death and increased the activation of JNK. In conclusion, MPA induces significant apoptosis in insulin-secreting cells via down-regulation of RhoGDI-alpha linked with increased JNK expression. This RhoGDI-alpha/JNK pathway might be the focus of therapeutic target for the prevention of MPA-induced islet apoptosis.}, }
@article {pmid19041272, year = {2009}, author = {Ogawa, R and Lee, SI and Izumi, H and Kagiya, G and Yohsida, T and Watanabe, A and Morii, A and Kakutani, S and Kondo, T and Feril, LB and Ishimoto, T}, title = {Enhancement of artificial promoter activity by ultrasound-induced oxidative stress.}, journal = {Ultrasonics sonochemistry}, volume = {16}, number = {3}, pages = {379-386}, doi = {10.1016/j.ultsonch.2008.10.007}, pmid = {19041272}, issn = {1350-4177}, mesh = {Animals ; Cell Line ; Cloning, Molecular ; Female ; HeLa Cells ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; *Oxidative Stress ; Promoter Regions, Genetic/*genetics ; *Sonication ; Time Factors ; *Up-Regulation ; X-Rays ; }, abstract = {We previously developed artificial promoters that were activated in response to X-ray irradiation. Sonication with 1.0MHz ultrasound that causes intracellular oxidative stress was found to activate some of these promoters though to lesser degrees. The most sensitive one among these promoters showed intensity- and duration-dependent activations by sonication. In addition, its activation by sonication was attenuated when N-acetyl cysteine was present, suggesting the involvement of intracellular oxidative stress in the activation mechanism. Improved promoters for sensitivity to X-ray irradiation were also found more sensitive to sonication. The most improved one showed 6.0 fold enhancement after sonication with 1.0MHz ultrasound at 1.0W/cm2 for 60s. This enhancement was also attenuated with the presence of N-acetyl cysteine. When stably transfected HeLa cells with the most sensitive promoter were transplanted on to mice and sonicated, luciferase activity by the promoter increased to 1.35 fold in average though it was not statistically significant compared to control. Although gene regulation in vivo by sonication was not clear, this is the first report on artificially constructed promoters responsive to ultrasound.}, }
@article {pmid19040079, year = {2008}, author = {Zhang, L and Wang, NL and Zhang, W and Chang, ZJ}, title = {[Suppression of cell proliferation by inhibitors to redox signaling in human lens epithelial cells].}, journal = {[Zhonghua yan ke za zhi] Chinese journal of ophthalmology}, volume = {44}, number = {7}, pages = {622-628}, pmid = {19040079}, issn = {0412-4081}, mesh = {Acetylcysteine/metabolism ; Arachidonic Acids/pharmacology ; Catalase/metabolism ; Cell Proliferation/*drug effects ; Cells, Cultured ; Enzyme Inhibitors/*pharmacology ; Epidermal Growth Factor/pharmacology ; Epithelial Cells/cytology/*drug effects/metabolism ; Fibroblast Growth Factor 2/pharmacology ; Humans ; Lens, Crystalline/*drug effects/metabolism ; Male ; NADP/antagonists &amp; inhibitors ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; }, abstract = {OBJECTIVE: Physiological level of reactive oxygen species (ROS) has been shown to play an important role in mitogen-stimulated cell signaling in many cell types. Both EGF and bFGF can induce ROS generation in human lens epithelial cells. But the role of ROS and Redox signaling on EGF and bFGF-stimulated cell proliferation is not clear. This study was to investigate the control of EGF and bFGF-induced cell proliferation by Redox signaling in human lens epithelial cells (SRA 01/04), using specific inhibitors to Redox signaling.<br><br>METHODS: EGF and bFGF-induced cell proliferation was measured by [methyl-3H] thymidine incorporation assay. In some experiments, cell proliferation was also measured by trypan blue negative cell counting parallel with 3H-thymidine incorporation assay. The inhibitors used in this study include: catalase (specific enzyme to detoxify hydrogen peroxide), N-acetyl-L-cysteine (free radical scavenger), DPI (inhibitor for NADPH oxidase) and AACOCF3 (specific inhibitor for cytosolic phospholipase A2, which had been shown to play important role in ROS generation in our previous study). Serum starved SRA 01/04 cells were pretreated with these inhibitors for 30 minutes before exposure to EGF or bFGF (20 microg/L). In short term study, all these inhibitors were removed before adding growth factor, while in long term study, inhibitors were maintained in the medium along with growth factor. Cells were kept growing in the medium with 20 microg/L EGF or 20 microg/L bFGF for 48 hours. Then cell proliferation was quantified by [methyl-3H] thymidine incorporation assay or by cell counting.<br><br>RESULTS: We found that catalase, NAC, DPI and AACOCF3 were able to suppress EGF and bFGF-induced cell proliferation in both short term and long term study. In EGF study, 20 microg/L EGF produced about 26% (t = 7.093, P <0.01) increase in DNA synthesis after 48 hours. Pretreatment of the cells for 30 minutes with 1 x 10(5) U/L catalase, 0.5 mmol/L NAC, 0.1 micromol/L DPI or 0.5 micromol/L AACOCF3 inhibited EGF-stimulated DNA synthesis by 18.0% (t=6.132, P<0.01), 24.6% (t=6.188, P<0.01), 28.5% (t=6.386, P<0.01) and 16.4% (t =3.705, P =0.001) respectively. The inhibition was dose-dependent and was proved by trypan-blue negative cell counting. If the cells were treated with inhibitors for 48.5 hours (long term study), the lowest concentrations to inhibit cell proliferation were much lower than those used in short term study. Treatment of the cells with 0.5 x 10(5) U/L catalase, 0.2 mmol/L NAC, 0.01 micromol/L DPI and 0.1 micromol/L AACOCF3 led to suppression on DNA synthesis significantly. Similar results were detected in bFGF study. 48 hours treatment with 20 microg/L bFGF induced about 28.8% (t =9.523, P <0.01) increase in cell proliferation. If the cells were pretreated with 1 x 10(5) U/L catalase, 0.5 mmol/L NAC, 0.1 micromol/L DPI or 0.5 micromol/L AACOCF3 for 30 minutes, bFGF-stimulated cell proliferation was suppressed by 24.5% (t = 6.697, P < 0.01), 22.2% (t = 6.693, P<0.01), 23.9% (t =6.661, P<0.01) and 30.5% (t =8.959, P <0.01) respectively. If cells were treated with inhibitors for 48.5 hours, the lowest concentration of catalase, NAC, DPI and AACOCF3 to inhibit cell proliferation significantly was 0.5 x 10(5) U/L(t =21.641, P <0.01), 0.2 mmol/L (t =11.218, P < 0.01), 0.01 micromol/L (t = 4.570, P <0.01) and 0.1 micromol/L (t = 5.426, P < 0.01) respectively, lower than those used in short term study.<br><br>CONCLUSIONS: We conclude that mitogenic stimulus function of EGF and bFGF in human lens epithelial cells appears to be mediated via ROS to activate cell proliferation. Inhibition of Redox signaling, either by removal of ROS (the role of catalase and NAC) or blocking ROS generation (the role of DPI and AACOCF3), eradicate EGF and bFGF-stimulated cell proliferation. It is proposed that Redox signaling may play an important role in cell proliferation in human lens epithelial cells.}, }
@article {pmid19034653, year = {2009}, author = {You, Y and Fu, JJ and Meng, J and Huang, GD and Liu, YH}, title = {Effect of N-acetylcysteine on the murine model of colitis induced by dextran sodium sulfate through up-regulating PON1 activity.}, journal = {Digestive diseases and sciences}, volume = {54}, number = {8}, pages = {1643-1650}, pmid = {19034653}, issn = {1573-2568}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Aryldialkylphosphatase/*metabolism ; Colitis/*chemically induced/*metabolism/prevention &amp; control ; Colon/drug effects/metabolism/pathology ; Dextran Sulfate/*adverse effects ; Disease Models, Animal ; Down-Regulation/drug effects ; Glutathione/metabolism ; Interleukin-1beta/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/drug effects ; Peroxidase/metabolism ; Reactive Oxygen Species/metabolism ; Severity of Illness Index ; Tumor Necrosis Factor-alpha/metabolism ; Up-Regulation/*drug effects ; }, abstract = {Reactive oxygen species (ROS) are increased in inflammatory bowel disease (IBD) and have been implicated as mediators of intestinal inflammation. We investigated the hypothesis that N-acetylcysteine (NAC) as a glutathione (GSH) precursor attenuates disease progression in a murine dextran sodium sulfate (DSS)-induced colitis model. A colitis model was induced by adding 5% DSS into the drinking water for 7 days. BALB/c mice were injiciatur enema with saline, 5-ASA, N-acetylcysteine, respectively, and free drinking water as control group. DSS-treated mice developed severe colitis as shown by bloody diarrhea, weight loss, and pathologic involvement. Colon lengths were significantly decreased in DSS-treated mice with decreased GSH activity too (P < 0.01). ROS in the colon, the level of interleukin 1 beta (IL-1 beta) in colonic mucosa, serum tumor necrosis factor a (TNF-alpha), MPO, and MDA were significantly increased in DSS-treated animals (P < 0.01), with decreased PON1 activity (P < 0.01). However, NAC significantly decreased colonic MPO activity, ROS, TNF-alpha and IL-1 beta levels and increased PON1 activity and GSH concentration. Moreover, NAC attenuated the macroscopic colonic damage and the histopathologic changes-induced by DSS while similar to 5-ASA group. These results suggest that NAC may be effective in the treatment of colitis through its up-regulating PON1 and scavenging oxygen-derived free radicals.}, }
@article {pmid19033392, year = {2009}, author = {Ade, N and Leon, F and Pallardy, M and Peiffer, JL and Kerdine-Romer, S and Tissier, MH and Bonnet, PA and Fabre, I and Ourlin, JC}, title = {HMOX1 and NQO1 genes are upregulated in response to contact sensitizers in dendritic cells and THP-1 cell line: role of the Keap1/Nrf2 pathway.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {107}, number = {2}, pages = {451-460}, doi = {10.1093/toxsci/kfn243}, pmid = {19033392}, issn = {1096-0929}, mesh = {Antigens, CD34/genetics ; B7-2 Antigen/biosynthesis/genetics ; Blotting, Western ; Cell Line ; Cystine/analogs &amp; derivatives/pharmacology ; Dendritic Cells/*drug effects/*metabolism ; Dermatitis, Contact/*genetics ; Fetal Blood/cytology ; Flow Cytometry ; Heme Oxygenase-1/*genetics ; Humans ; Intracellular Signaling Peptides and Proteins/*genetics ; Irritants/*toxicity ; Kelch-Like ECH-Associated Protein 1 ; NAD(P)H Dehydrogenase (Quinone)/*genetics ; NF-E2-Related Factor 2/*genetics ; RNA, Messenger/biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects/genetics ; Skin/metabolism ; Up-Regulation/drug effects ; }, abstract = {Electrophilicity is one of the most common features of skin contact sensitizers and is necessary for protein haptenation. The Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 -signaling pathway is dedicated to the detection of electrophilic stress in cells leading to the upregulation of genes involved in protection or neutralization of chemical reactive species. Signals provided by chemical stress could play an important role in dendritic cell activation and the aim of this work was to test whether contact sensitizers were specific activators of the Keap1/Nrf2 pathway. CD34-derived dendritic cells (CD34-DC) and the THP-1 myeloid cell line were treated by a panel of sensitizers (Ni, 1-chloro 2,4-dinitrobenzene, cinnamaldehyde, 7-hydroxycitronellal, 1,4-dihydroquinone, alpha-methyl-trans-cinnamaldehyde, 2-4-tert-(butylbenzyl)propionaldehyde or Lilial, and 1,4-phenylenediamine), irritants (sodium dodecyl sulfate, benzalkonium chloride), and a nonsensitizer molecule (chlorobenzene). Three well-known Nrf2 activators (tert-butylhydroquinone, lipoic acid, sulforaphane) were also tested. Expression of hmox1 and nqo1 was measured using real-time PCR and cellular accumulation of Nrf2 was assessed by Western blot. Our results showed an increased expression at early time points of hmox1 and nqo1 mRNAs in response to sensitizers but not to irritants. Accumulation of the Nrf2 protein was also observed only with chemical sensitizers. A significant inhibition of the expression of hmox1 and nqo1 mRNAs and CD86 expression was found in 1-chloro 2,4-dinitrobenzene-treated THP-1 cells preincubated with N-acetyl cysteine, a glutathione precursor. Altogether, these data suggested that the Keap1/Nrf2-signaling pathway was activated by electrophilic molecules including sensitizers in dendritic cells and in the THP-1 cell line. Monitoring of this pathway may provide new biomarkers (e.g., Nrf2, hmox1) for the detection of the sensitization potential of chemicals.}, }
@article {pmid19029642, year = {2008}, author = {Birnbaum, J and Klotz, E and Spies, CD and Hein, OV and Mallin, K and Kawka, R and Ziemer, S and Lehmann, C}, title = {The combinations C1 esterase inhibitor with coagulation factor XIII and N-acetylcysteine with tirilazad mesylate reduce the leukocyte adherence in an experimental endotoxemia in rats.}, journal = {Clinical hemorheology and microcirculation}, volume = {40}, number = {3}, pages = {167-176}, pmid = {19029642}, issn = {1386-0291}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Adhesion/drug effects ; Complement C1 Inhibitor Protein/*pharmacology ; Endotoxemia/chemically induced/drug therapy/*metabolism ; Factor XIII/*pharmacology ; Free Radical Scavengers/*pharmacology ; Leukocytes/*metabolism/pathology ; Lipopolysaccharides/toxicity ; Male ; Pregnatrienes/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {The study's objective was to determine the effects of the administration of combinations of C1 esterase inhibitor (C1-INH) with coagulation factor XIII (F XIII) and N-acetylcysteine (NAC) with tirilazad mesylate (TM) on leukocyte adherence and on intestinal functional capillary density during experimental endotoxemia in rats. In a prospective, randomized, controlled animal study, 40 male Wistar rats were divided into 4 groups. Group 1 (CON group) served as control group. Group 2 (LPS group), group 3 (C1-INH+F XIII group) and group 4 (NAC+TM group) received endotoxin infusions (10 mg/kg/h for 2 h). In C1-INH+F XIII group, 100 U/kg b.w. C1-INH and 50 U/kg b.w. F XIII were administered after the first 30 min of endotoxemia. In the NAC+TM group, 150 mg/kg b.w. N-acetylcysteine and 10 mg/kg b.w. Tirilazad mesylate were administered after 30 min of endotoxemia. Leukocyte adherence at venules of the intestinal submucosal layer and functional capillary density in the villi intestinales and in the longitudinal and circular muscle layers were estimated by intravital fluorescence microscopy (IVM). C1-INH+F XIII reduced the count of firmly adherent leukocytes that was increased after LPS administration in the V3 venules (CON group 69 (17-160)/mm2; LPS group 635 (556-814)/mm2; C1-INH+F XIII group 503 (337-646)/mm2). NAC+TM reduced the firmly adherent leukocytes in the V3 venules (NAC+TM group 403 (309-572)/mm2) and in the V1 venules (CON group 55 (16-131)/mm2; LPS group 368 (306-475)/mm2; NAC+TM group 270 (216-308)/mm2) as well. FCD was not impaired after LPS challenge and there was no influence of both combinations on the FCD. We conclude that both drug combinations can reduce the leukocyte adherence in a sepsis model in rats.}, }
@article {pmid19027931, year = {2009}, author = {Güler, G and Türközer, Z and Ozgur, E and Seyhan, N}, title = {Antioxidants alleviate electric field-induced effects on lung tissue based on assays of heme oxygenase-1, protein carbonyl content, malondialdehyde, nitric oxide, and hydroxyproline.}, journal = {The Science of the total environment}, volume = {407}, number = {4}, pages = {1326-1332}, doi = {10.1016/j.scitotenv.2008.10.050}, pmid = {19027931}, issn = {0048-9697}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Biodiversity ; Catechin/analogs &amp; derivatives/pharmacology ; Electromagnetic Fields/*adverse effects ; Guinea Pigs ; Heme Oxygenase-1/metabolism ; Hydroxyproline/metabolism ; Lung Diseases/*drug therapy/etiology/*metabolism ; Male ; Malondialdehyde/metabolism ; Nitric Oxide/metabolism ; Protein Carbonylation ; Random Allocation ; }, abstract = {In order to test whether antioxidants have beneficiary effects on electric field induced damage, we determined the pulmonary levels of heme oxygenase-1 (HO-1), protein carbonyl content (PCO), malondialdehyde (MDA), nitric oxide (NO) and hydroxyproline (HP) under extremely low frequency (ELF) electric (E) field exposure (50 Hz, 12 kV/m, 7 days/for 8 h/day). While PCO levels significantly increased (p<0.05), insignificant changes (p>0.05) were observed in HO-1, MDA, NO and HP levels for electric field exposure groups compared to the control group. We have not observed any significant change in these parameters on the electric field group compared to the group where NAC and EGCG were separately applied along with electric field. However, during our previous studies, we have concluded that NAC and EGCG are potent antioxidants and we believe that new studies should be established by way of setting up different experimental conditions.}, }
@article {pmid19027737, year = {2009}, author = {Leite, MS and Thomaz, R and Oliveira, JH and Oliveira, PL and Meyer-Fernandes, JR}, title = {Trypanosoma brucei brucei: effects of ferrous iron and heme on ecto-nucleoside triphosphate diphosphohydrolase activity.}, journal = {Experimental parasitology}, volume = {121}, number = {2}, pages = {137-143}, doi = {10.1016/j.exppara.2008.10.018}, pmid = {19027737}, issn = {1090-2449}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase/pharmacology ; Ferrous Compounds/*pharmacology ; Heme/*pharmacology ; Lipid Peroxidation/drug effects ; Magnesium/metabolism ; Polyethylene Glycols/pharmacology ; Pyrophosphatases/*antagonists &amp; inhibitors/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Trypanosoma brucei brucei/*drug effects/enzymology ; Xanthurenates/pharmacology ; }, abstract = {Trypanosoma brucei brucei is the causative agent of animal African trypanosomiasis, also called nagana. Procyclic vector form resides in the midgut of the tsetse fly, which feeds exclusively on blood. Hemoglobin digestion occurs in the midgut resulting in an intense release of free heme. In the present study we show that the magnesium-dependent ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) activity of procyclic T. brucei brucei is inhibited by ferrous iron and heme. The inhibition of E-NTPDase activity by ferrous iron, but not by heme, was prevented by pre-incubation of cells with catalase. However, antioxidants that permeate cells, such as PEG-catalase and N-acetyl-cysteine prevented the inhibition of E-NTPDase by heme. Ferrous iron was able to induce an increase in lipid peroxidation, while heme did not. Therefore, both ferrous iron and heme can inhibit E-NTPDase activity of T. brucei brucei by means of formation of reactive oxygen species, but apparently acting through distinct mechanisms.}, }
@article {pmid19023021, year = {2009}, author = {Milovanova, TN and Bhopale, VM and Sorokina, EM and Moore, JS and Hunt, TK and Hauer-Jensen, M and Velazquez, OC and Thom, SR}, title = {Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {106}, number = {2}, pages = {711-728}, pmid = {19023021}, issn = {8750-7587}, support = {R01 GM081570/GM/NIGMS NIH HHS/United States ; R21 DK080376/DK/NIDDK NIH HHS/United States ; DK080376/DK/NIDDK NIH HHS/United States ; GM081570/GM/NIGMS NIH HHS/United States ; }, mesh = {Angiogenesis Modulating Agents/pharmacology ; Angiogenic Proteins/metabolism ; Animals ; Antioxidants/metabolism ; Autocrine Communication ; Biomarkers/metabolism ; Blood Vessels/cytology/metabolism ; Bone Marrow Cells/drug effects/*metabolism ; Cell Cycle ; *Cell Differentiation/drug effects ; Cell Movement ; *Cell Proliferation/drug effects ; Collagen/metabolism ; Drug Combinations ; Glutathione/metabolism ; *Hyperbaric Oxygenation ; Hypoxia-Inducible Factor 1/deficiency/genetics ; Lactic Acid/metabolism ; Laminin/metabolism ; Mice ; Mice, Knockout ; *Neovascularization, Physiologic/drug effects ; *Oxidative Stress/drug effects ; Proteoglycans/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Stem Cells/drug effects/*metabolism ; Subcutaneous Tissue/*blood supply ; Thioredoxins/metabolism ; Time Factors ; }, abstract = {We hypothesized that oxidative stress from hyperbaric oxygen (HBO(2), 2.8 ATA for 90 min daily) exerts a trophic effect on vasculogenic stem cells. In a mouse model, circulating stem/progenitor cell (SPC) recruitment and differentiation in subcutaneous Matrigel were stimulated by HBO(2) and by a physiological oxidative stressor, lactate. In combination, HBO(2) and lactate had additive effects. Vascular channels lined by CD34(+) SPCs were identified. HBO(2) and lactate accelerated channel development, cell differentiation based on surface marker expression, and cell cycle entry. CD34(+) SPCs exhibited increases in thioredoxin-1 (Trx1), Trx reductase, hypoxia-inducible factors (HIF)-1, -2, and -3, phosphorylated mitogen-activated protein kinases, vascular endothelial growth factor, and stromal cell-derived factor-1. Cell recruitment to Matrigel and protein synthesis responses were abrogated by N-acetyl cysteine, dithioerythritol, oxamate, apocynin, U-0126, neutralizing anti-vascular endothelial growth factor, or anti-stromal cell-derived factor-1 antibodies, and small inhibitory RNA to Trx reductase, lactate dehydrogenase, gp91(phox), HIF-1 or -2, and in mice conditionally null for HIF-1 in myeloid cells. By causing an oxidative stress, HBO(2) activates a physiological redox-active autocrine loop in SPCs that stimulates vasculogenesis. Thioredoxin system activation leads to elevations in HIF-1 and -2, followed by synthesis of HIF-dependent growth factors. HIF-3 has a negative impact on SPCs.}, }
@article {pmid19022608, year = {2010}, author = {Whyte, AJ and Kehrl, T and Brooks, DE and Katz, KD and Sokolowski, D}, title = {Safety and effectiveness of acetadote for acetaminophen toxicity.}, journal = {The Journal of emergency medicine}, volume = {39}, number = {5}, pages = {607-611}, doi = {10.1016/j.jemermed.2008.05.007}, pmid = {19022608}, issn = {0736-4679}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Antidotes/*administration &amp; dosage ; Female ; Humans ; Infusions, Intravenous ; Length of Stay ; Male ; Middle Aged ; Retrospective Studies ; Transaminases/blood ; Young Adult ; }, abstract = {BACKGROUND: Acetaminophen (APAP) toxicity is commonly encountered in the Emergency Department. Until 2004, treatment consisted of either oral N-acetylcysteine (NAC) or filtered oral NAC administered intravenously (i.v.). Intravenous acetylcysteine (Acetadote) is a new Food and Drug Administration-approved i.v. formulation of acetylcysteine manufactured by Cumberland Pharmaceuticals in Nashville, Tennessee. Little post-marketing data exists on the effectiveness and safety of i.v. acetylcysteine.<br><br>OBJECTIVES: We evaluated the clinical presentations and outcomes of patients treated with i.v. acetylcysteine for APAP toxicity.<br><br>METHODS: We performed a retrospective chart review of patients treated with i.v. acetylcysteine for APAP ingestion. The primary outcome measures were: adverse reactions to and effectiveness of i.v. acetylcysteine, as defined by elevation of transaminases, liver failure, renal failure, death, and hospital length of stay (LOS). Data collected included: comorbidities, allergies, intentionality, timing and dosing of i.v. acetylcysteine, hospital LOS, transaminases > 1000 IU/L, development of liver failure requiring transplant, development of renal failure requiring hemodialysis, death, and anaphylactoid reactions.<br><br>RESULTS: Sixty-four patients met our study criteria. Overall, 16 (25%) patients developed transaminases > 1000 IU/L, 4 (6%) of them died and 2 (3%) received liver transplants. Of the 15 patients (23%) treated within 8 h, none died or developed liver or renal failure, and only 1 developed transient transaminase elevation > 1000 IU/L. In the patients treated outside of 8 h, the median LOS was 3 days, whereas the group treated within 8 h had a median LOS of only 1 day. Six (9%) patients developed anaphylactoid reactions, 2 of whom received the i.v. acetylcysteine bolus over 15 min. Five of these patients were treated pharmacologically and completed treatment, and one had treatment discontinued for undocumented reasons.<br><br>CONCLUSION: Intravenous acetylcysteine seemed to be a safe and effective formulation of N-acetylcysteine.}, }
@article {pmid19020758, year = {2008}, author = {Lee, KB and Kim, KR and Huh, TL and Lee, YM}, title = {Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways.}, journal = {International journal of oncology}, volume = {33}, number = {6}, pages = {1247-1256}, pmid = {19020758}, issn = {1019-6439}, mesh = {Animals ; Apoptosis/*radiation effects ; Apoptosis Regulatory Proteins/metabolism ; Carcinoma, Lewis Lung ; Caspases/metabolism ; Cell Cycle/radiation effects ; Cell Hypoxia ; Dose-Response Relationship, Radiation ; *Gamma Rays ; HCT116 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mice ; Neoplasms/enzymology/*pathology ; Oxidative Stress/radiation effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/*radiation effects ; Tumor Suppressor Protein p53/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Tumor hypoxia is a main obstacle for radiation therapy. To investigate whether exposure to a proton beam can overcome radioresistance in hypoxic tumor cells, three kinds of cancer cells, Lewis lung carcinoma (LLC) cells, hepatoma HepG2 and Molt-4 leukemia cells, were treated with a proton beam (35 MeV, 1, 2, 5, 10 Gy) in the presence or absence of hypoxia. Cell death rates were determined 72 h after irradiation. Hypoxic cells exposed to the proton beam underwent a typical apoptotic program, showing condensed nuclei, fragmented DNA ladders, and poly-ADP-ribose polymerase (PARP) cleavage. Fluorescence-activated cell sorter analysis revealed a significant increase in Annexin-V-positive cells. Cells treated with the proton beam and hypoxia displayed increased expression of p53, p21 and Bax, but decreased levels of phospho-Rb, Bcl-2 and XIAP, as well as activated caspase-9 and -3. The proton beam with hypoxia induced cell death in wild-type HCT116 cells, but not in a p53 knockout cell line, demonstrating a requirement for p53. As reactive oxygen species (ROS) were also significantly increased, apoptosis could also be abolished by treatment with the anti-oxidant N-acetyl cysteine (NAC). P38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) were activated by the treatment, and their respective DN mutants restored the cell death induced by either proton therapy alone or with hypoxia. In conclusion, proton beam treatment did not differently regulate cancer cell apoptosis either in normoxic or hypoxic conditions via a p53-dependent mechanism and by the activation of p38/JNK MAPK pathways through ROS.}, }
@article {pmid19017541, year = {2009}, author = {Smith, SS and Reyes, JR and Arbon, KS and Harvey, WA and Hunt, LM and Heggland, SJ}, title = {Cadmium-induced decrease in RUNX2 mRNA expression and recovery by the antioxidant N-acetylcysteine (NAC) in the human osteoblast-like cell line, Saos-2.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {23}, number = {1}, pages = {60-66}, pmid = {19017541}, issn = {0887-2333}, support = {P20 RR016454-076942/RR/NCRR NIH HHS/United States ; P20RR016454/RR/NCRR NIH HHS/United States ; P20 RR016454-086150/RR/NCRR NIH HHS/United States ; P20 RR016454-066708/RR/NCRR NIH HHS/United States ; P20 RR016454/RR/NCRR NIH HHS/United States ; R15ES015866/ES/NIEHS NIH HHS/United States ; R15 ES015866/ES/NIEHS NIH HHS/United States ; R15 ES015866-01A1/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/drug effects ; Cadmium Chloride/*toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; Core Binding Factor Alpha 1 Subunit/genetics/*metabolism ; Dose-Response Relationship, Drug ; Drug Antagonism ; Environmental Pollutants/*toxicity ; Free Radical Scavengers/*pharmacology ; Gene Expression/*drug effects ; Glutathione/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Osteoblasts/*drug effects/metabolism/pathology ; Osteosarcoma/pathology ; Oxidative Stress/drug effects ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Exposure to cadmium poses a threat to human health, including increased susceptibility to developing the bone disease osteoporosis. Despite its recognized importance as an environmental toxin, little is known about how cadmium directly impacts bone-forming osteoblasts. We previously reported that cadmium induces apoptosis in human osteoblast-like Saos-2 cells. In this work, we hypothesize that cadmium exposure induces oxidative stress which leads to decreased RUNX2 mRNA expression and increased apoptotic death, and predict that the antioxidant NAC mitigates the damaging effects of cadmium. Oxidative stress is implicated in osteoporosis; furthermore the osteoblast transcriptional factor RUNX2 is reported to play a protective role against osteoporosis in postmenopausal women. Cells treated with 10 microM CdCl2 exhibited signs of oxidative damage including depletion in glutathione, increased reactive oxygen species formation, and enhanced lipid peroxidation. RUNX2 mRNA expression, by RT-PCR, was significantly reduced after exposure to 10 microM CdCl2. Pretreatment with the antioxidant NAC (1mM) prevented cadmium-induced decrease in RUNX2 mRNA and protected cells from apoptotic death. This study provides insight into the mechanisms underlying cadmium-induced osteotoxicity. In addition, this study distinguishes itself by identifying RUNX2 as a target for heavy metal-induced osteotoxicity.}, }
@article {pmid19012644, year = {2008}, author = {Cooke, A and Deshpande, AV and Wong, CK and Cohen, R}, title = {Hepatic derangement following N-Acetylcysteine enemas in an infant with cystic fibrosis.}, journal = {Journal of paediatrics and child health}, volume = {44}, number = {11}, pages = {673-675}, doi = {10.1111/j.1440-1754.2008.01399.x}, pmid = {19012644}, issn = {1440-1754}, mesh = {Acetylcysteine/administration &amp; dosage/*adverse effects ; *Chemical and Drug Induced Liver Injury ; *Cystic Fibrosis ; *Enema ; Fecal Impaction/drug therapy ; Free Radical Scavengers/administration &amp; dosage/*adverse effects ; Humans ; Ileus/drug therapy ; Infant, Newborn ; Meconium/drug effects ; }, abstract = {We discuss an infant with MI secondary to cystic fibrosis, who was managed surgically by a double barrel ileostomy for mid - small bowel atresia and developed severe faecal impaction in the post - operative period. The faecal impaction was treated successfully with oral NAC and 0.2% NAC contrast enemas. The patient's liver function tests revealed a dramatic increase in transaminases and bilirubin contemporaneous with the administration of the enemas. The levels showed a spontaneous improvement after discontinuation. This is only the second reported case of hepatotoxicity secondary to NAC enemas in the literature. While our experience offers modest support for the use of NAC, its efficacy is not yet proven and paediatric surgeons using NAC in the enema form need to closely monitor liver function contemporaneous with this agent's administration and adjust their treatment accordingly.}, }
@article {pmid19011670, year = {2008}, author = {El Midaoui, A and Ismael, MA and Lu, H and Fantus, IG and de Champlain, J and Couture, R}, title = {Comparative effects of N-acetyl-L-cysteine and ramipril on arterial hypertension, insulin resistance, and oxidative stress in chronically glucose-fed rats.}, journal = {Canadian journal of physiology and pharmacology}, volume = {86}, number = {11}, pages = {752-760}, doi = {10.1139/Y08-090}, pmid = {19011670}, issn = {0008-4212}, mesh = {Acetylcysteine/*pharmacology ; Aldehydes/metabolism ; Angiotensin-Converting Enzyme Inhibitors/*pharmacology ; Animals ; Aorta, Thoracic/enzymology ; Blood Pressure/*drug effects ; Diet ; Free Radical Scavengers/*pharmacology ; Glucose/*pharmacology ; Hypertension/drug therapy/*physiopathology ; Insulin Receptor Substrate Proteins/metabolism ; Insulin Resistance/*physiology ; Lipid Peroxidation/drug effects ; Liver/drug effects/enzymology ; Male ; Malondialdehyde/metabolism ; Muscle, Skeletal/drug effects/metabolism ; NADPH Oxidases/metabolism ; Oxidative Stress/*drug effects ; Oxygen Consumption/drug effects ; Ramipril/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {Beneficial effects of an antioxidant (N-acetyl-L-cysteine, NAC) and an angiotensin I-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. Treatments with NAC (2 g/kg per day) and ramipril (1 mg/kg per day) were initiated at 16 weeks in the drinking fluid. Systolic blood pressure, plasma levels of insulin and glucose, and insulin resistance were significantly higher in rats treated with glucose for 20 weeks. This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. NAC prevented all these alterations. Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. Ramipril, in contrast to NAC, did not reduce NADPH oxidase activity in aorta and liver or plasma levels of 4-hydroxynonenal and malondialdehyde. Results suggest that the inhibition of the oxidative stress in hypertensive and insulin-resistant states contributes to the therapeutic effects of NAC and ramipril. Whereas NAC exerts effective antioxidant activity in multiple tissues, ramipril appears to preferentially target the vasculature.}, }
@article {pmid19010381, year = {2009}, author = {Hsiao, CJ and Stapleton, SR}, title = {Early sensing and gene expression profiling under a low dose of cadmium exposure.}, journal = {Biochimie}, volume = {91}, number = {3}, pages = {329-343}, doi = {10.1016/j.biochi.2008.10.006}, pmid = {19010381}, issn = {1638-6183}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cadmium/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Gene Expression/*drug effects ; *Gene Expression Profiling ; Hepatocytes/drug effects/metabolism ; Male ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; Time Factors ; }, abstract = {Cadmium (Cd) has been shown to have various detrimental effects on health. In recent years progress has been made in dissecting apart the molecular mechanisms underlying the effects of exposure to this toxic metal. In this paper we investigated changes in gene expression using a global transcript profiling approach to better understand the early molecular events that occur in primary rat hepatocytes when exposed to Cd at a concentration (4 microM) and time (3 h) that is prior to any significant increase in cytotoxic parameters. Gene expression changes were most dramatically noticed for proteins involved in transcriptional regulation, zinc finger protein production, and heat shock protein expression. Other genes whose expression changed significantly were those associated with maintaining cellular redox homeostasis such as increasing glutathione synthesis and antioxidant capacity, facilitating the survival or death response, and repairing damage or stimulating degradation. Expression changes were confirmed for selected genes in various groups utilizing qRT-PCR. Various times of Cd incubation were also used to assess the extent of the impact. To define whether or not any of these changes were associated with cadmium's ability to disturb the redox balance, we also tested the effects of Cd in the presence of a blocker of glutathione synthesis, D,L-buthionine-(S,R)-sulfoximine (BSO), and an antioxidant, N-acetylcysteine (NAC). The results show that the Cd induction of some genes can be categorized as occurring primarily in response to changes in the redox state as measured by attenuation of the response by the addition of NAC or to the availability of reduced glutathione as measured by the increase in response in the presence of BSO.}, }
@article {pmid19010314, year = {2009}, author = {Mehta, R and Wong, L and O'Brien, PJ}, title = {Cytoprotective mechanisms of carbonyl scavenging drugs in isolated rat hepatocytes.}, journal = {Chemico-biological interactions}, volume = {178}, number = {1-3}, pages = {317-323}, doi = {10.1016/j.cbi.2008.10.026}, pmid = {19010314}, issn = {1872-7786}, mesh = {Animals ; Cell-Free System ; Cytoprotection/*drug effects ; Glycation End Products, Advanced/metabolism ; Hepatocytes/*drug effects/metabolism ; Lipid Peroxidation ; Male ; Membrane Potentials ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Diabetes is a disease among several others that has been linked with the accumulation of carbonylated proteins in tissues. Carbonylation is an irreversible, non-enzymatic modification of proteins by carbonyls. In Diabetes, dicarbonyls are thought to be generated by the autoxidation of reducing sugars which react with proteins and eventually lead to the formation of advanced glycation end-products (AGEs). Carbonyl scavenging drugs containing thiol or amine functional groups have been suggested to act therapeutically in preventing protein carbonylation by trapping the dicarbonyls glyoxal and methylglyoxal to form non-toxic adducts. This study seeks to determine the mechanism by which carbonyl scavenging drugs prevent glyoxal toxicity in a cell-free system as well as in isolated rat hepatocytes. In a cell free system, the glyoxal trapping ability of the drugs was measured by following glyoxal disappearance using Girard's Reagent T. For the thiol-containing drugs, the order of effectiveness for glyoxal trapping was penicillamine>cysteine>N-acetyl-cysteine, whereas for the amine-containing drugs, the order of effectiveness for glyoxal trapping was aminoguanidine>>pyridoxamine>metformin. Furthermore, aminoguanidine, penicillamine and cysteine at concentrations equimolar to glyoxal prevented protein carbonylation. Other scavenging drugs such as pyridoxamine, hydralazine or metformin did not prevent glyoxal-induced cytotoxicity by trapping glyoxal, but instead prevented cytotoxicity by acting as a mitochondrial vitamin, lipid antioxidant or reactive oxygen species scavenger, respectively.}, }
@article {pmid19010165, year = {2008}, author = {Santiago, FM and Bueno, P and Olmedo, C and Muffak-Granero, K and Comino, A and Serradilla, M and Mansilla, A and Villar, JM and Garrote, D and Ferrón, JA}, title = {Effect of N-acetylcysteine administration on intraoperative plasma levels of interleukin-4 and interleukin-10 in liver transplant recipients.}, journal = {Transplantation proceedings}, volume = {40}, number = {9}, pages = {2978-2980}, doi = {10.1016/j.transproceed.2008.08.103}, pmid = {19010165}, issn = {0041-1345}, mesh = {Acetylcysteine/*therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Double-Blind Method ; Humans ; Interleukin-10/*blood ; Interleukin-4/*blood ; Liver Transplantation/*physiology ; Monitoring, Intraoperative ; Placebos ; Prospective Studies ; }, abstract = {We investigated whether intraoperative administration of N-acetylcysteine (NAC) in liver transplant recipients ameliorated their inflammatory responses by increasing intraoperative plasma levels of interleukin (IL)-4 and IL-10. This prospective, randomized, double-blind clinical trial included liver transplant recipients randomly assigned to the NAC-treated (n = 25) or the placebo (n = 25) group. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose over the next 24 hours, whereas the placebo group received equal amounts of 5% dextrose solution during the same time. Peripheral blood samples were drawn in EDTA-containing tubes after induction of anesthesia (I-1); at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo; at 5 minutes before reperfusion (I-3); at 10 minutes after reperfusion (I-4); at 20 minutes after reperfusion (I-5); at 60 minutes after reperfusion (I-6); and at 1 hour after completion of the liver transplantation (I-7). Cytokine levels were determined using a technique which combined enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Plasma IL-4 levels were significantly higher among the NAC-treated group than the placebo group at I-3 (P = .046) and I-4 (P = .041). Plasma IL-10 levels showed significant enhancement in the NAC-treated group at 5 minutes before reperfusion (I-3; P = .007). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly increased recipient IL-4 plasma levels before and after reperfusion, and IL-10 plasma values before reperfusion (I-3). These enhancements seemed to be associated with a protective effect against reperfusion injury.}, }
@article {pmid19010140, year = {2008}, author = {Ruiz Fuentes, MC and Moreno Ayuso, JM and Ruiz Fuentes, N and Vargas Palomares, JF and Asensio Peinado, C and Osuna Ortega, A}, title = {Treatment with N-acetylcysteine in stable renal transplantation.}, journal = {Transplantation proceedings}, volume = {40}, number = {9}, pages = {2897-2899}, doi = {10.1016/j.transproceed.2008.08.109}, pmid = {19010140}, issn = {0041-1345}, mesh = {Acetylcysteine/*therapeutic use ; Catalase/blood ; Cholesterol/blood ; Free Radical Scavengers/*therapeutic use ; Glutathione Peroxidase/blood ; Humans ; Kidney Function Tests ; Kidney Transplantation/*physiology ; Lipids/blood ; Lipoproteins, HDL/blood ; Malondialdehyde/blood ; }, abstract = {The primary cause of morbidity and mortality in renal transplantation is cardiovascular disease. Increased oxidative stress implies a greater degree of atherogenesis in these patients. N-acetylcysteine (NAC) which has a thiol group that is the source of l-cysteine and reduced glutathione, acts against atherosclerosis via a decrease in apoptosis, vasoconstriction, and endothelial dysfunction. Experimental models have examined the antioxidant effects of NAC during and after ischemia-reperfusion, but few studies have shown an effect in renal transplantation in human beings. In 8 months, we studied the effect of NAC treatment on oxidative stress, lipids, and renal function in 25 patients with stable renal function and no diabetes after transplantation. Data were collected on oxidative parameters: malondialdehyde, glutathione peroxidase, catalase, superoxide dismutase, glutathione reductase, lipid profile, and renal function (creatinine concentration, Cockroft-Gault formula, and Modified Diet in Renal Disease study). There were no significant differences in oxidative profile before and after treatment with NAC. The mean serum high-density lipoprotein cholesterol fraction increased after treatment and showed a significant positive correlation with glutathione peroxidase (r = 0.495). Serum creatinine concentration decreased, and Cockroft-Gault and Modified Diet in Renal Disease study estimates of renal function increased in the treatment period. In conclusion, NAC treatment in patients with stable renal function after transplantation increased high-density lipoprotein cholesterol and antioxidant molecules in relation to glutathione peroxidase, with a positive influence on renal function.}, }
@article {pmid19007345, year = {2009}, author = {Doyon, S and Klein-Schwartz, W}, title = {Hepatotoxicity despite early administration of intravenous N-acetylcysteine for acute acetaminophen overdose.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {16}, number = {1}, pages = {34-39}, doi = {10.1111/j.1553-2712.2008.00296.x}, pmid = {19007345}, issn = {1553-2712}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Acute Disease ; Adult ; Aged ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*administration &amp; dosage ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/blood/epidemiology/*prevention &amp; control ; Drug Administration Schedule ; Drug Overdose/drug therapy ; Female ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Observation ; Retrospective Studies ; }, abstract = {OBJECTIVES: The objective was to evaluate the effectiveness of intravenous N-acetylcysteine (IV NAC; 300 mg/kg over 21 hours) in early acute acetaminophen (APAP) overdose patients.<br><br>METHODS: This observational case series included patients hospitalized between 2004 and 2007 for acute APAP overdoses and who were reported to a regional poison center. Inclusion criteria were plasma APAP concentrations on or above the treatment line on the Rumack-Matthew nomogram, administration of IV NAC within 8 hours of ingestion, and follow-up to known outcome. The hospital chart of each patient who received IV NAC for longer than the standard 21 hours was reviewed. Hepatotoxicity was defined as hepatic aminotransferase levels greater than 1,000 IU/L.<br><br>RESULTS: Seventy-seven patients met inclusion criteria and received at least 21 hours of IV NAC for an acute APAP overdose. Seven patients received antidotal therapy for greater than 21 hours. These patients tended to have ingested combination preparations, have very high initial plasma APAP concentrations, and had persistently elevated plasma concentrations during their hospital stay. Hepatotoxicity occurred in 4 patients (5.2%, 95% confidence interval [CI] = 0.2% to 10.1%), including 1 death and 1 liver transplantation.<br><br>CONCLUSIONS: Hepatotoxicity developed in 5.2% of cases, suggesting that the 21-hour IV NAC regimen is suboptimal in some patients. In addition to high initial plasma APAP concentrations, APAP product formulation and persistently elevated plasma APAP concentrations were identified as factors possibly associated with developing hepatotoxicity. The authors propose a tailored approach to the discontinuation of IV NAC and point out the need for reevaluation of optimal doses and duration of therapy.}, }
@article {pmid19004747, year = {2008}, author = {Ghosh, S and Baumann, J and Falusi, B and Bogár, L and Roth, E and Gál, J}, title = {[Hemodynamic effects of N-acetylcysteine and ischemic preconditioning in a liver ischemia-reperfusion model].}, journal = {Orvosi hetilap}, volume = {149}, number = {47}, pages = {2245-2249}, doi = {10.1556/OH.2008.28495}, pmid = {19004747}, issn = {0030-6002}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cardiovascular Agents/*pharmacology ; Disease Models, Animal ; Dogs ; Hemodynamics/*drug effects ; *Ischemic Preconditioning ; Liver/blood supply/*drug effects/physiopathology ; Reperfusion Injury/physiopathology/*prevention &amp; control ; }, abstract = {UNLABELLED: The aim of the study was to investigate whether repeated ischemic preconditioning or N-acetylcysteine (NAC) prevents ischemic-reperfusion injury as determined by having favourable hemodynamic effects during reperfusion in canine livers.<br><br>METHODS: The control group (n = 10) underwent 60 minutes of hepatic ischemia followed by 180 minutes reperfusion. In the NAC group (n = 5) 150 mg kg -1 of NAC was administered intravenously before inducing ischemia. In the preconditioned group (n = 5) animals received ischemic preconditioning (10 minutes of ischemia followed by 10 minutes of reperfusion repeated three times) before clamping the portal triad.<br><br>RESULTS: 18 dogs survived the study period. One dog in the NAC group died due to circulatory failure unresponsive to inotropic drugs. The cardiac index and the intrathoracic blood volume index were significantly higher in the preconditioning group compared to the controls throughout the study period.<br><br>CONCLUSIONS: Repeated ischemic preconditioning might improve hemodynamic parameters, whereas we were unable to find any significant differences between the groups regarding N-acetylcysteine.}, }
@article {pmid19002586, year = {2008}, author = {Zhang, R and Humphreys, I and Sahu, RP and Shi, Y and Srivastava, SK}, title = {In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {13}, number = {12}, pages = {1465-1478}, doi = {10.1007/s10495-008-0278-6}, pmid = {19002586}, issn = {1573-675X}, support = {R01 CA129038/CA/NCI NIH HHS/United States ; R01 CA106953/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Anthracenes/metabolism ; Apoptosis/*drug effects ; Capsaicin/*pharmacology ; Cell Line, Tumor/drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Enzyme Activation ; Female ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mice ; Mice, Nude ; Mitochondria/*drug effects ; Neoplasm Transplantation ; Pancreatic Neoplasms/drug therapy/*metabolism/pathology ; Reactive Oxygen Species/*metabolism ; Sensory System Agents/*pharmacology ; Transplantation, Heterologous ; }, abstract = {Pancreatic cancer is one of the most common invasive malignancies and the fourth leading cause of cancer related mortality in U.S., thus developing new strategies to control pancreatic cancer is an important mission. We investigated the mechanism of capsaicin, the major pungent ingredient of red-chili pepper, in inducing apoptosis in pancreatic cancer cells. Treatment of AsPC-1 and BxPC-3 cells with capsaicin resulted in a dose-dependent inhibition of cell-viability and induction of apoptosis which was associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. These effects were significantly blocked when the cells were pretreated with a general antioxidant N-acetyl cysteine (NAC). Exposure of AsPC-1 and BxPC-3 cells to capsaicin was also associated with increased expression of Bax, down-regulation of bcl-2, survivin and significant release of cytochrome c and AIF in the cytosol. On the contrary, above-mentioned effects were not observed in the normal acinar cells in response to capsaicin-treatment. Capsaicin-treatment resulted in the activation of JNK and JNK inhibitor SP600125 afforded protection against capsaicin-induced apoptosis. Furthermore, capsaicin when given orally markedly suppressed the growth of AsPC-1 pancreatic tumor xenografts in athymic nude mice, without side effects. Tumors from capsaicin treated mice demonstrated increased apoptosis, which was related to the activation of JNK and increased cytosolic protein expression of Bax, cytochrome c, AIF and cleaved caspase-3, as compared with controls. Taken together, these results show that capsaicin is an effective inhibitor of in vitro and in vivo growth of pancreatic cancer cells. These findings provide the rationale for further clinical investigation of capsaicin against pancreatic cancer.}, }
@article {pmid19001480, year = {2011}, author = {Souza, GA and Ebaid, GX and Seiva, FR and Rocha, KH and Galhardi, CM and Mani, F and Novelli, EL}, title = {N-acetylcysteine an allium plant compound improves high-sucrose diet-induced obesity and related effects.}, journal = {Evidence-based complementary and alternative medicine : eCAM}, volume = {2011}, number = {}, pages = {643269}, pmid = {19001480}, issn = {1741-4288}, abstract = {This study was designed to determine whether N-acetylcysteine (NAC, C(5)H(9)-NO(3)S), a compound from Allium species may be used as a complementary therapeutic agent, to inhibit high-sucrose induced-obesity and its effects on glucose tolerance, in vivo low-density lipoprotein (LDL)-oxidation and serum oxidative stress in rats. Initially, 24 male Wistar rats were divided into two groups: controls receiving standard chow (C, n = 6) and those receiving high-sucrose diet (HS, n = 18). After 22 days, (HS) group was divided into three groups (n = 6/group); (HS-HS) continued to eat high-sucrose diet and water; (HS-N) continued to eat high-sucrose diet and received 2 mg l(-1)-NAC in its drinking water; (HS-CN) changing high-sucrose to standard chow and receiving 2 mg l(-1)-NAC in its drinking water. After 22 days of the HS-group division (44 days of experimental period) body weight, body mass index and surface area were enhanced in HS-HS rats (P < .001). HS-HS rats had glucose intolerance, increased serum triacylglycerol (TG), very low-density lipoprotein (VLDL), oxidized-LDL (ox-LDL) and lipid-hydroperoxide (LH) than the others (P < .01). NAC in HS-N and HS-CN rats reduced the obesity markers, feed efficiency, LH and ox-LDL, as well normalized glucose response, TG and VLDL (P < .01) in these groups compared with HS-HS. Total antioxidant substances, GSH/GSSG ratio and glutathione-reductase, were higher in HS-N than in HS-HS (P < .01). In conclusion, NAC improved high-sucrose diet-induced obesity and its effects on glucose tolerance, lipid profile, in vivo LDL-oxidation and serum oxidative stress, enhancing antioxidant defences. The application of this agent may be feasible and beneficial for high-sucrose diet-induced obesity, which certainly would bring new insights on obesity-related adverse effects control.}, }
@article {pmid18998004, year = {2008}, author = {Ozturk, H and Terzi, EH and Ozturk, H and Kukner, A}, title = {The effects of N-acetylcysteine and vitamin C on liver and pulmonary tissue damage in rats following bile duct ligation.}, journal = {Saudi medical journal}, volume = {29}, number = {11}, pages = {1580-1584}, pmid = {18998004}, issn = {0379-5284}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ascorbic Acid/*pharmacology ; Bile Ducts/*pathology ; Liver/*drug effects/pathology ; Lung/*drug effects/pathology ; Male ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: To evaluate the effects of N-acetylcysteine NAC and vitamin C on pulmonary histological alterations in bile duct-ligated (BDL) rats.<br><br>METHODS: The current study was conducted in the Department of Pediatric Surgery, Medical School of Abant Izzet Baysal University, Bolu, Turkey between May 2007 and July 2007. Thirty-five males Sprague-Dawley rats, weighing 210-240 grams, were used. Group 1 rats (n=7) underwent only laparotomy. Group 2 rats (n=7) were subjected to BDL. Group 3 rats (n=7) were subjected to BDL and given vitamin C. Group 4 rats (n=7) were subjected to BDL and given NAC. Group 5 rats (n=7) were subjected to BDL and received NAC plus vitamin C. At the end of the 3 week period, biochemical and histological evaluations were processed.<br><br>RESULTS: Total bilirubin values were decreased in group 5 compared to group 2, 3, and 4. Group 2 showed massive interstitial infiltration with inflammatory cells. Interstitial edema, focal cuboidal metaplasias of alveolar lining cells, and severely damaged pulmonary architecture were noted. Treatment of rats with NAC and vitamin C produced a significant reduction in the histopathological score compared to groups 2, 3, and 4.<br><br>CONCLUSION: The combination of NAC and vitamin C reduced lung histological alterations in BDL rats with afforded by each drug individually.}, }
@article {pmid18996500, year = {2009}, author = {Gomez-Niño, A and Agapito, MT and Obeso, A and Gonzalez, C}, title = {Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {165}, number = {1}, pages = {104-111}, doi = {10.1016/j.resp.2008.10.020}, pmid = {18996500}, issn = {1569-9048}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/pharmacology ; Carotid Body/*cytology ; Catecholamines/metabolism ; Chemoreceptor Cells/*drug effects/physiology ; Diaphragm/drug effects ; Dose-Response Relationship, Drug ; Drug Interactions ; Female ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; In Vitro Techniques ; Male ; Mitochondria/*drug effects ; Oxidation-Reduction/*drug effects ; Poisons/*toxicity ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; }, abstract = {Low oxygen sensing in chemoreceptor cells involves the inhibition of specific plasma membrane K(+) channels, suggesting that mitochondria-derived reactive oxygen species (ROS) link hypoxia to K(+) channel inhibition, subsequent cell depolarization and activation of neurotransmitter release. We have used several mitochondrial poisons, alone and in combination with the antioxidant N-acetylcysteine (NAC), and quantify their capacity to alter GSH/GSSG levels and glutathione redox potential (E(GSH)) in rat diaphragm. Selected concentrations of mitochondrial poisons with or without NAC were tested for their capacity to activate neurotransmitter release in chemoreceptor cells and to alter ATP levels in intact rat carotid body (CB). We found that rotenone (1 microM), antimycin A (0.2 microg/ml) and sodium azide (5mM) decreased E(GSH); NAC restored E(GSH) to control values. At those concentrations mitochondrial poisons activated neurotransmitter release from CB chemoreceptor cells and decreased CB ATP levels, NAC being ineffective to modify these responses. Additional experiments with 3-nitroprionate (5mM), lower concentrations of rotenone and dinitrophenol revealed variable relationships between E(GSH) and chemoreceptor cell neurotransmitter release responses and ATP levels. These findings indicate a lack of correlation between mitochondrial-generated modifications of E(GSH) and chemoreceptor cells activity. This lack of correlation renders unlikely that alteration of mitochondrial production of ROS is the physiological pathway chemoreceptor cells use to signal hypoxia.}, }
@article {pmid18996201, year = {2009}, author = {Novelli, EL and Santos, PP and Assalin, HB and Souza, G and Rocha, K and Ebaid, GX and Seiva, FR and Mani, F and Fernandes, AA}, title = {N-acetylcysteine in high-sucrose diet-induced obesity: energy expenditure and metabolic shifting for cardiac health.}, journal = {Pharmacological research}, volume = {59}, number = {1}, pages = {74-79}, doi = {10.1016/j.phrs.2008.10.004}, pmid = {18996201}, issn = {1043-6618}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Energy Metabolism/*drug effects ; Heart/*drug effects ; Male ; Myocardium/metabolism ; Obesity/metabolism/*prevention &amp; control ; Oxygen Consumption/drug effects ; Rats ; Rats, Wistar ; Sucrose/administration &amp; dosage ; Triglycerides/metabolism ; }, abstract = {To study the effects of N-acetylcysteine (NAC, C(5)H(9)-NO(3)S) on high-sucrose diet-induced obesity and its effects on energy metabolism and cardiac oxidative stress, male Wistar 24 rats were divided into four groups (n=6): (C) given standard chow and water; (N) receiving standard chow and 2g/l N-acetylcysteine in its drinking water; (HS) given standard chow and 30% sucrose in its drinking water, and (HS-N) receiving standard chow, 30% sucrose and N-acetylcysteine in its drinking water. After 30 days of the treatment, obesity was evidenced in HS rats from enhanced body weight, respiratory quotient, hypertriglyceridemia. As well depressed resting metabolic rate, and oxygen consumption per surface area. HS rats had triacylglycerol accumulation, oxidative stress and metabolic shifting in cardiac tissue. NAC enhanced fat oxidation and energy expenditure, normalizing these adverse effects, comparing HS-N and HS rats. The beta-hydroxyacyl coenzymne-A dehydrogenase activity was higher in HS-N animals, indicating higher heart fatty acid degradation than in HS. NAC normalized myocardial glycogen and lactate dehydrogenase activity, comparing HS-N and HS rats, but had no effects on calorimetric and biochemical parameters in standard-fed rats, comparing N and C groups. In conclusion, N-acetylcysteine offers promising therapeutic value in prevention of high-sucrose induced-obesity and its effect on cardiac tissue. N-acetylcysteine reduced the oxidative stress and prevented the metabolic shifting in cardiac tissue, enhancing fatty acid oxidation and reducing anaerobic metabolism in high-sucrose-fed conditions. The application of this agent in food system via exogenous addition may be feasible and beneficial for antioxidant protection and energy metabolism in cardiac tissue.}, }
@article {pmid18993042, year = {2009}, author = {Moradi, M and Mojtahedzadeh, M and Mandegari, A and Soltan-Sharifi, MS and Najafi, A and Khajavi, MR and Hajibabayee, M and Ghahremani, MH}, title = {The role of glutathione-S-transferase polymorphisms on clinical outcome of ALI/ARDS patient treated with N-acetylcysteine.}, journal = {Respiratory medicine}, volume = {103}, number = {3}, pages = {434-441}, doi = {10.1016/j.rmed.2008.09.013}, pmid = {18993042}, issn = {1532-3064}, mesh = {Acetylcysteine/*administration &amp; dosage/therapeutic use ; Acute Lung Injury/*drug therapy/genetics/mortality ; Adult ; Antioxidants/*administration &amp; dosage/therapeutic use ; Case-Control Studies ; Chi-Square Distribution ; Drug Administration Schedule ; Female ; Gene Frequency ; Genotype ; Glutathione Transferase/*genetics ; Humans ; Male ; Middle Aged ; Oxidative Stress ; *Polymorphism, Genetic ; Respiratory Distress Syndrome/*drug therapy/genetics/mortality ; Single-Blind Method ; Treatment Outcome ; }, abstract = {Oxidative stress has a proven role in pathophysiology of acute respiratory distress syndrome. The antioxidant drugs, especially N-acetylcysteine (NAC) have been used for years to overcome oxidative stress effects in patients. In the present study we have investigated the effects of NAC treatment (IV NAC in 150mg/kg at the first day followed by 50mg/kg/day for three days) on 27 ICU patients with ALI/ARDS considering the glutathione-S-transferase genetic variations, as an important enzyme contributing in oxidative stress pathways. The results indicated that NAC improved oxygenation (increase in PaO(2)/FiO(2)) and decreased mortality rate in treated patients compared to control group (p<0.05). Evaluation of three isoforms of glutathione-S-transferase (GST M1, P1 and T1), in these patients have showed an association between GST M1 null, and GST M1 and T1 double null polymorphisms with increased mortality in control group, suggesting antioxidant therapy critical for this group of patients.}, }
@article {pmid18992854, year = {2009}, author = {Kelly, MK and Wicker, RJ and Barstow, TJ and Harms, CA}, title = {Effects of N-acetylcysteine on respiratory muscle fatigue during heavy exercise.}, journal = {Respiratory physiology &amp; neurobiology}, volume = {165}, number = {1}, pages = {67-72}, doi = {10.1016/j.resp.2008.10.008}, pmid = {18992854}, issn = {1569-9048}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Analysis of Variance ; Cross-Over Studies ; Double-Blind Method ; Exercise/*physiology ; Free Radical Scavengers/*pharmacology ; Glutathione/blood ; Humans ; Male ; Muscle Fatigue/*drug effects/physiology ; Oxygen Consumption/drug effects/physiology ; Physical Endurance/drug effects/physiology ; Respiration/drug effects ; Respiratory Function Tests/methods ; Respiratory Muscles/*drug effects ; Young Adult ; }, abstract = {Respiratory muscle fatigue (RMF) occurs during heavy exercise in humans. N-acetylcysteine (NAC) infusion has been shown to reduce RMF, suggesting that oxidative stress is a contributing factor. The purpose of the present study was to determine the effect of an acute oral dose of NAC on RMF during heavy exercise. Subjects (n=8) were given either placebo (PLA) or NAC (1,800 mg) 45 min prior to a 30 min constant load (85V(O)(2peak)), discontinuous exercise test. Maximum respiratory pressures (inspiratory, PI(max); expiratory, PE(max)) and venous blood samples were made prior to and following each 5 min of exercise. There was no difference (p>0.05) in PI(max) between NAC (127.9+/-34.1 cm H(2)O) or PLA (134.1+/-28.1cm H(2)O) at rest. During exercise, PI(max) was significantly lower with PLA (approximately 14%) compared to NAC at 25 and 30 min suggesting less RMF with NAC. There were no differences (p>0.05) between groups in PE(max), V(O)(2), V(E), or heart rate at rest or throughout exercise. These results suggest that an acute dose of NAC reduces RMF during heavy exercise.}, }
@article {pmid18992754, year = {2009}, author = {Omiya, S and Hikoso, S and Imanishi, Y and Saito, A and Yamaguchi, O and Takeda, T and Mizote, I and Oka, T and Taneike, M and Nakano, Y and Matsumura, Y and Nishida, K and Sawa, Y and Hori, M and Otsu, K}, title = {Downregulation of ferritin heavy chain increases labile iron pool, oxidative stress and cell death in cardiomyocytes.}, journal = {Journal of molecular and cellular cardiology}, volume = {46}, number = {1}, pages = {59-66}, doi = {10.1016/j.yjmcc.2008.09.714}, pmid = {18992754}, issn = {1095-8584}, mesh = {Animals ; Antioxidants/chemistry/metabolism ; Aorta/pathology ; Apoferritins/chemistry/*metabolism ; Chelating Agents/pharmacology ; Deferoxamine/pharmacology ; *Down-Regulation ; Ferrocyanides/pharmacology ; Heart Failure/metabolism ; Iron/chemistry/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Myocytes, Cardiac/*metabolism ; *Oxidative Stress ; RNA Interference ; }, abstract = {Ferritin heavy chain (FHC) protein was significantly reduced in murine failing hearts following left coronary ligation or thoracic transverse aortic constriction. The mRNA expression of FHC was not significantly altered in failing hearts, compared to that in control sham-operated hearts. Prussian blue staining revealed spotty iron depositions in myocardial infarct failing hearts. Oxidative stress was enhanced in the myocardial infarct failing hearts, as evidenced by increases in 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine immunoreactivity. To clarify the functional significance of FHC downregulation in hearts, we infected rat neonatal cardiomyocytes with adenoviral vector expressing short hairpin RNA targeted to FHC (Ad-FHC-RNAi). The downregulation of FHC induced a reduction in the viability of cardiomyocytes. The relative number of iron deposition-, 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cardiomyocytes was significantly higher in Ad-FHC-RNAi-infected cardiomyocytes than in control vector-infected cardiomyocytes. Treatment of Ad-FHC-RNAi-infected cardiomyocytes with desferrioxamine, an iron chelator, significantly reduced the number of iron, 4-hydroxy-2-nonenal or 8-hydroxy-2'-deoxyguanosine-positive cells, and increased viability. In addition, treatment with N-acetyl cysteine, an antioxidant, significantly reduced the number of 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cells. Reduced viability in Ad-FHC-RNAi-infected cardiomyocytes was significantly improved with N-acetyl cysteine treatment. These findings indicate that excessive free iron and the resultant enhanced oxidative stress caused by downregulation of FHC lead to cardiomyocyte death. The decrease in FHC expression in failing hearts may play an important role in the pathogenesis of heart failure.}, }
@article {pmid18991735, year = {2008}, author = {Fiore, G and Capasso, A}, title = {Effects of vitamin E and C on placental oxidative stress: an in vitro evidence for the potential therapeutic or prophylactic treatment of preeclampsia.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {4}, number = {6}, pages = {526-530}, doi = {10.2174/157340608786242124}, pmid = {18991735}, issn = {1573-4064}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Endothelin-1/pharmacology ; Female ; Glutathione/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Placenta/drug effects/*metabolism ; Pre-Eclampsia/*drug therapy/*prevention &amp; control ; Pregnancy ; Vitamin E/*pharmacology ; Young Adult ; }, abstract = {Preeclampsia (PE) is a multisystem disorder that remains a major cause of maternal and foetal morbidity and death. To date, no treatment has been found that prevents the development of the disease. Endothelial dysfunction is considered to underlie its clinical manifestations, such as maternal hypertension, proteinuria and edema; and oxidative stress has been increasingly postulated as a major contributor to endothelial dysfunction in PE. A large body of research has investigated the potential role of antioxidant nutrients in the prevention of PE in women at high increased risk of the disease. Therefore, the present study was primary designed to assess the potential benefit of antioxidant supplementation on markers of placental oxidative stress in an in vitro model of PE, since we previously found that endothelin-1 (ET-1) is able to trigger the placental secretion of stress molecules. In this regard, we evaluated the effects of vitamin C, vitamin E and N-acetylcysteine (NAC), alone or in combination, in placental villi culture after exposure to ET-1. The effect of antioxidant nutrients on trophoblast cells proliferation and vitality was also evaluated. The results obtained suggest that in a pathophysiological condition, such as PE, the deleterious effect of reactive oxygen species may be counteract by an antioxidant therapy, and there is the need to investigate the optimum dosing and timing of antioxidants administration, since an inappropriate antioxidant treatment in pregnant women may have deleterious consequences, reducing placental cells proliferation until to cell death.}, }
@article {pmid18990976, year = {2008}, author = {van der Deen, M and Homan, S and Timmer-Bosscha, H and Scheper, RJ and Timens, W and Postma, DS and de Vries, EG}, title = {Effect of COPD treatments on MRP1-mediated transport in bronchial epithelial cells.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {3}, number = {3}, pages = {469-475}, pmid = {18990976}, issn = {1176-9106}, mesh = {Acetylcysteine/metabolism/therapeutic use ; Biological Transport/drug effects ; Bronchi/*cytology ; Bronchodilator Agents/*metabolism/therapeutic use ; Budesonide/metabolism/therapeutic use ; Cholinergic Antagonists/metabolism/therapeutic use ; Drug Resistance, Multiple/*physiology ; Epithelial Cells/drug effects/*physiology ; Ethanolamines/metabolism/therapeutic use ; Expectorants/metabolism/therapeutic use ; Flow Cytometry ; Formoterol Fumarate ; Humans ; In Vitro Techniques ; Ipratropium/metabolism/therapeutic use ; Multidrug Resistance-Associated Proteins/*drug effects/*physiology ; Oxidative Stress/*drug effects/physiology ; Pulmonary Disease, Chronic Obstructive/drug therapy/*metabolism ; }, abstract = {BACKGROUND: Smoking is the principle risk factor for development of chronic obstructive pulmonary disease (COPD). Multidrug resistance-associated protein 1 (MRP1) is known to protect against toxic compounds and oxidative stress, and might play a role in protection against smoke-induced disease progression. We questioned whether MRP1-mediated transport is influenced by pulmonary drugs that are commonly prescribed in COPD.<br><br>METHODS: The immortalized human bronchial epithelial cell line 16HBE14o- was used to analyze direct in vitro effects of budesonide, formoterol, ipratropium bromide and N-acetylcysteine (NAC) on MRP1-mediated transport. Carboxyfluorescein (CF) was used as a model MRP1 substrate and was measured with functional flow cytometry.<br><br>RESULTS: Formoterol had a minor effect, whereas budesonide concentration-dependently decreased CF transport by MRP1. Remarkably, addition of formoterol to the highest concentration of budesonide increased CF transport. Ipratropium bromide inhibited CF transport at low concentrations and tended to increase CF transport at higher levels. NAC increased CF transport by MRP1 in a concentration-dependent manner.<br><br>CONCLUSIONS: Our data suggest that, besides their positive effects on respiratory symptoms, budesonide, formoterol, ipratropium bromide, and NAC modulate MRP1 activity in bronchial epithelial cells. Further studies are required to assess whether stimulation of MRP1 activity is beneficial for long-term treatment of COPD.}, }
@article {pmid18990082, year = {2008}, author = {Dodd, S and Dean, O and Copolov, DL and Malhi, GS and Berk, M}, title = {N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility.}, journal = {Expert opinion on biological therapy}, volume = {8}, number = {12}, pages = {1955-1962}, doi = {10.1517/14728220802517901}, pmid = {18990082}, issn = {1744-7682}, mesh = {Acetylcysteine/adverse effects/*pharmacology/*therapeutic use ; Antioxidants/adverse effects/*pharmacology/*therapeutic use ; Drug Administration Routes ; Humans ; }, abstract = {BACKGROUND: Glutathione is an endogenous antioxidant and has a ubiquitous role in many of the body's defences. Treatment with N-acetylcysteine (NAC) has been shown to increase levels of glutathione. NAC has been proposed as a treatment for several illnesses.<br><br>OBJECTIVES: The efficacy and tolerability of NAC was examined across a range of conditions to evaluate the evidence supporting the use of NAC for each indication.<br><br>METHODS: A literature search was conducted using PubMed. Information was also collected from other online sources including the websites of the Therapeutic Goods Administration of Australia and the FDA.<br><br>RESULTS: Reports ranged from case studies to clinical trials. There is strong evidence to support the use of NAC for the treatment of paracetamol overdose and emerging evidence suggesting it has utility in psychiatric disorders, particularly schizophrenia and bipolar disorder. NAC is safe and well tolerated when administered orally but has documented risks with intravenous administration.}, }
@article {pmid18983911, year = {2009}, author = {Mattson, DM and Ahmad, IM and Dayal, D and Parsons, AD and Aykin-Burns, N and Li, L and Orcutt, KP and Spitz, DR and Dornfeld, KJ and Simons, AL}, title = {Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism.}, journal = {Free radical biology &amp; medicine}, volume = {46}, number = {2}, pages = {232-237}, pmid = {18983911}, issn = {1873-4596}, support = {R01 CA133114-01A1/CA/NCI NIH HHS/United States ; T32 CA078586-09/CA/NCI NIH HHS/United States ; R01 CA133114/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; R01-CA100045/CA/NCI NIH HHS/United States ; P30 CA086862-069012/CA/NCI NIH HHS/United States ; T32-CA078586-08/CA/NCI NIH HHS/United States ; T32 CA078586/CA/NCI NIH HHS/United States ; R01 CA100045/CA/NCI NIH HHS/United States ; R01 CA100045-05/CA/NCI NIH HHS/United States ; P30-CA086862/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cisplatin/*pharmacology ; Drug Therapy, Combination ; Glutathione/analogs &amp; derivatives/antagonists &amp; inhibitors/*metabolism ; Head and Neck Neoplasms/*drug therapy/enzymology/pathology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/enzymology ; Oxidative Stress/*drug effects ; Sulfhydryl Compounds/metabolism ; Zidovudine/*pharmacology ; }, abstract = {Oxidative stress and mitochondrial dysfunction in cancer cells represent features that may be exploited therapeutically. We determined whether agents that induce mitochondrial dysfunction, such as zidovudine (AZT) and cisplatin (CIS), could enhance killing of human head and neck cancer cells via oxidative stress. AZT- and/or CIS-induced cytotoxicity was determined using clonogenic survival, mitochondrial membrane potential was analyzed to investigate mitochondrial function, and glutathione was measured to determine thiol metabolism perturbations. AZT+CIS significantly increased toxicity and reduced mitochondrial membrane potential in FaDu, Cal-27, and SQ20B head and neck cancer cells while increasing the percentage of glutathione disulfide (%GSSG). Treatment with the thiol antioxidant N-acetylcysteine (NAC) reversed the loss of mitochondrial membrane potential and the increase in %GSSG and partially protected FaDu and Cal-27 cells from AZT+CIS. Finally, an inhibitor of glutathione synthesis, l-buthionine-[S,R]-sulfoximine, sensitized the cells to AZT+CIS-induced cytotoxicity, which was partially reversed by NAC. These results suggest that exposure of cancer cells to agents that induce mitochondrial dysfunction, such as AZT, causes significant sensitization to CIS-induced toxicity via disruptions in thiol metabolism and oxidative stress. These findings provide a biochemical rationale for evaluating agents that induce mitochondrial dysfunction in combination with chemotherapy and inhibitors of glutathione metabolism in head and neck cancer.}, }
@article {pmid18983759, year = {2008}, author = {Amin, AF and Shaaban, OM and Bediawy, MA}, title = {N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss.}, journal = {Reproductive biomedicine online}, volume = {17}, number = {5}, pages = {722-726}, doi = {10.1016/s1472-6483(10)60322-7}, pmid = {18983759}, issn = {1472-6491}, mesh = {Abortion, Habitual/*drug therapy/etiology/metabolism ; Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Female ; Humans ; Infant, Newborn ; Oxidative Stress/drug effects ; Pregnancy ; Pregnancy Outcome ; Prospective Studies ; Young Adult ; }, abstract = {Pregnancy could be associated with a state of oxidative stress that could initiate and propagate a cascade of changes that may lead to pregnancy wastage. This process of oxidative stress may be suppressed by the antioxidant effect of N-acetyl cysteine (NAC). The current study aimed to evaluate the effect of NAC therapy in patients diagnosed with unexplained recurrent pregnancy loss (RPL). The study was a prospective controlled study performed in the Women's Health Centre, Assiut University, Egypt. A group of 80 patients with history of recurrent unexplained pregnancy loss were treated with NAC 0.6 g + folic acid 500 microg/day and compared with an aged-matched group of 86 patients treated with folic acid 500 microg/day alone. NAC + folic acid compared with folic acid alone caused a significantly increased rate of continuation of a living pregnancy up to and beyond 20 weeks [P < 0.002, relative risk (RR) 2.9, 95% confidence interval (CI) 1.5-5.6]. NAC + folic acid was associated with a significant increase in the take-home baby rate as compared with folic acid alone (P < 0.047, RR 1.98, 95% CI 1.3-4.0). In conclusion, NAC is a well-tolerated drug that could be a potentially effective treatment in patients with unexplained RPL.}, }
@article {pmid18972393, year = {2008}, author = {Ahmed, T and Tripathi, AK and Ahmed, RS and Das, S and Suke, SG and Pathak, R and Chakraboti, A and Banerjee, BD}, title = {Endosulfan-induced apoptosis and glutathione depletion in human peripheral blood mononuclear cells: Attenuation by N-acetylcysteine.}, journal = {Journal of biochemical and molecular toxicology}, volume = {22}, number = {5}, pages = {299-304}, doi = {10.1002/jbt.20240}, pmid = {18972393}, issn = {1099-0461}, mesh = {Acetylcysteine/*pharmacology ; Annexin A5/metabolism ; Apoptosis/*drug effects ; DNA Fragmentation/drug effects ; Endosulfan/*toxicity ; Glutathione/*deficiency ; Humans ; Leukocytes, Mononuclear/*cytology/*drug effects ; Microscopy, Fluorescence ; Necrosis ; }, abstract = {Present study investigated whether endosulfan, an organochlorine pesticide is able to deplete glutathione (GSH) and induce apoptosis in human peripheral blood mononuclear cells (PBMC) in vitro. The role of oxidative stress in the induction of apoptosis was also evaluated by the measurement of the GSH level in cell lysate. The protective role of N-acetylcysteine (NAC) on endosulfan-induced apoptosis was also studied. Isolated human PBMC were exposed to increasing concentrations (0-100 microM) of endosulfan (alpha/beta at 70:30 mixture) alone and in combination with NAC (20 microM) up to 24 h. Apoptotic cell death was determined by Annexin-V Cy3.18 binding and DNA fragmentation assays. Cellular GSH level was measured using dithionitrobenzene. Endosulfan at low concentrations, i.e., 5 and 10 microM, did not cause significant death during 6 h/12 h incubation, whereas a concentration-dependent cell death was observed at 24 h. DNA fragmentation analysis revealed no appreciable difference between control cells and 5 microM/10 microM endosulfan treated cells, where only high molecular weight DNA band was observed. Significant ladder formation was observed at higher concentration, which is indicative of apoptotic cell death. Intracellular GSH levels decreased significantly in endosulfan-treated cells in a dose-dependent manner, showing a close correlation between oxidative stress and degree of apoptosis of PBMC. Cotreatment with NAC attenuated GSH depletion as well as apoptosis. Our results provide experimental evidence of involvement of oxidative stress in endosulfan-mediated apoptosis in human PBMC in vitro.}, }
@article {pmid18970401, year = {2006}, author = {Pinto, PC and Saraiva, ML and Santos, JL and Lima, JL}, title = {Fluorimetric determination of aminocaproic acid in pharmaceutical formulations using a sequential injection analysis system.}, journal = {Talanta}, volume = {68}, number = {3}, pages = {857-862}, doi = {10.1016/j.talanta.2005.06.008}, pmid = {18970401}, issn = {1873-3573}, abstract = {A sequential injection analysis (SIA) methodology for the fluorimetric determination of aminocaproic acid in pharmaceutical formulations is proposed. The developed analytical procedure is based on the derivatisation reaction of the aminocaproic primary amine with o-phthalaldehyde (OPA) and N-acetylcysteine (NAC) and fluorimetric detection of the formed product (lambda(ex)=350 nm; lambda(em)=450 nm). The implementation of a SIA flow system allowed for the development of a simple, fast and versatile automated methodology, which exhibits evident advantages regarding the US Pharmacopoeia 24 (USP 24) reference procedure. By combining the SIA time-based sample insertion with a subsequent zone sampling approach, which permitted to select for detection of a well-defined sample zone, it was possible to implement an on-line dilution strategy that enabled the expansion of the analytical working range of the methodology, and thus its application in dissolution studies, without manifold re-configuration. Linear calibration plots were obtained for aminocaproic acid concentrations up to 6 x 10(-5)mol l(-1). The developed methodology exhibit a good precision, with a R.S.D.<2.0% (n=15) and the detection limit was 2.5 x 10(-7)mol l(-1). The obtained results complied with those furnished by the reference procedure with a relative deviation lower than 1.2%. No interference was found.}, }
@article {pmid18969305, year = {2004}, author = {Moliner Martinez, Y and Molins Legua, C and Campíns Falcó, P}, title = {Analysis of primary aliphatic short-chain monoamines by LC in water samples.}, journal = {Talanta}, volume = {62}, number = {2}, pages = {373-382}, doi = {10.1016/j.talanta.2003.08.013}, pmid = {18969305}, issn = {1873-3573}, abstract = {Several derivatization procedures with o-phthaldialdehyde-N-acetylcysteine (OPA-NAC) were compared for a rapid analysis of primary aliphatic short-chain monoamines in water samples by HPLC using a LiChorospher analytical separation column (100RP(18)125 mm x4 mm i.d., 5mum). Both the solution and the solid-support assisted off-line derivatization on C(18) SPE cartridges were inadequate options because of beginning degradation processes of the instable isoindol derivatives during their transfer to the analytical column. This problem was precluded with the on-column or solid-support assisted on-line derivatization. In the last mentioned procedure, the derivatization took place in a Hypersil C(18) precolumn (20 mm x2.1 mm i.d., 30mum) connected with an additional preconcentration step resulting in better detection limits (0.002-0.040mugml(-1) requiring only 150mul of water sample) than in the on-column procedure (0.08-0.16mugml(-1)). The improved sample handling, the better control of parameters affecting reaction rates, the fully automation of this method with only 10min analysis time for each sample are further advantageous. The potential of the solid-support assisted on-line derivatization was outlined and applied to water samples from several sources. Recovery values near 100% were obtained.}, }
@article {pmid18957327, year = {2009}, author = {Yin, P and Kawamura, T and He, M and Vanaja, DK and Young, CY}, title = {Phenethyl isothiocyanate induces cell cycle arrest and reduction of alpha- and beta-tubulin isotypes in human prostate cancer cells.}, journal = {Cell biology international}, volume = {33}, number = {1}, pages = {57-64}, pmid = {18957327}, issn = {1095-8355}, support = {R01 CA088900/CA/NCI NIH HHS/United States ; R01 CA088900-04/CA/NCI NIH HHS/United States ; 91956//PHS HHS/United States ; CA88900/CA/NCI NIH HHS/United States ; }, mesh = {Anticarcinogenic Agents/*pharmacology ; Antioxidants/pharmacology ; Blotting, Western ; Cell Cycle/*drug effects ; Cell Line, Tumor ; Cysteine/pharmacology ; Flow Cytometry ; G2 Phase/drug effects ; Humans ; Isothiocyanates/*pharmacology ; Leupeptins/pharmacology ; Male ; Prostatic Neoplasms/*metabolism ; Protein Isoforms/metabolism ; Tubulin/*metabolism ; }, abstract = {This study was to investigate the effect of phenethyl isothiocyanate (PEITC), a constituent of many edible cruciferous vegetables, on the expression of alpha- and beta-tubulins, which are the main components of microtubules in prostate cancer cells. Flow cytometry, light microscopy and western blot were used to study the cell cycle distribution, morphology changes and the expression of alpha- and beta-tubulins in prostate cancer cells treated with PEITC. The results showed that PEITC-induced G2-M cell phase arrest and inhibited the expression of alpha- and beta-tubulin proteins in a number of human prostatic carcinoma cell lines. Further, it is showed that this inhibitory effect could be reversed by antioxidant N-acetyl cysteine and proteasome inhibitor MG132. Finally, it is concluded that PEITC inhibited the expression of alpha- and beta-tubulins in prostate cancer cells, which is at least related to the oxygen reaction species and protein degradation.}, }
@article {pmid18951497, year = {2009}, author = {Xu, Y and Hou, XY and Liu, Y and Zong, YY}, title = {Different protection of K252a and N-acetyl-L-cysteine against amyloid-beta peptide-induced cortical neuron apoptosis involving inhibition of MLK3-MKK7-JNK3 signal cascades.}, journal = {Journal of neuroscience research}, volume = {87}, number = {4}, pages = {918-927}, doi = {10.1002/jnr.21909}, pmid = {18951497}, issn = {1097-4547}, mesh = {Acetylcysteine/*pharmacology ; Amyloid beta-Peptides/*metabolism ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects/physiology ; Carbazoles/*pharmacology ; Cells, Cultured ; Cerebral Cortex/drug effects/physiology ; Indole Alkaloids/*pharmacology ; MAP Kinase Kinase 7/metabolism ; MAP Kinase Kinase Kinases/metabolism ; MAP Kinase Signaling System/*drug effects ; Mitogen-Activated Protein Kinase 10/metabolism ; Neurons/*drug effects/physiology ; Neuroprotective Agents/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Sprague-Dawley ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; }, abstract = {Amyloid-beta peptide (Abeta) has been implicated in the etiopathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms underlying Abeta neurotoxicity remain to be elucidated. This study showed that Abeta treatment resulted in the increased phosphorylation (activation) of MLK3, MKK7, and JNK3 in cultured cortical neurons, which characterized as biphasic activation (first peaked at 1 hr and second peaked at 12 hr after Abeta treatment). K252a blocked Abeta-induced neuronal apoptosis, both early and late phases of MLK3-MKK7-JNK3 activation, as well as downstream signal events involving p-JNKs nuclear translocation, c-Jun phosphorylation, and Bad translocation to the mitochondria. The neuroprotective effect of K252a on Abeta-induced apoptosis was partially dependent on Akt activation. In contrast, antioxidant N-acetyl-L-cysteine (NAC) reduced early, but not late, MLK3-MKK7-JNK3 activation by Abeta treatment and provided a weak neuroprotective ability in Abeta-induced apoptosis. Taken together, Abeta neurotoxicity is mainly due to MLK3-MKK7-JNK3 signal cascades. The late signal events of MLK3 activation after Abeta treatment may play an important role in AD neuronal loss and will be a promising pharmacological target for AD therapeutic intervention.}, }
@article {pmid18949735, year = {2008}, author = {Pinto, CF and Watanabe, M and Vattimo, Mde F}, title = {Hydration and N-acetylcysteine in acute renal failure caused by iodinated contrast medium: an experiment with rats.}, journal = {Journal of nephrology}, volume = {21}, number = {5}, pages = {783-788}, pmid = {18949735}, issn = {1121-8428}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/*chemically induced/metabolism/pathology/prevention &amp; control ; Animals ; Contrast Media/*toxicity ; Creatinine/metabolism ; *Fluid Therapy ; Free Radical Scavengers/*pharmacology ; Iothalamate Meglumine/*toxicity ; Kidney/drug effects/pathology ; Male ; Peroxides/urine ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: The involvement of nephrotoxic agents in acute renal failure (ARF) has increased over the last few decades. Among the drugs associated with nephrotoxic ARF are the radiologic contrast media whose nephrotoxic effects have grown, following the increasing diagnostic use of these agents.<br><br>METHODS: We evaluated the effect of iodinated contrast (IC) medium, administered in combination, or not, with hyperhydration or N-acetylcysteine (NAC), on creatinine clearance, production of urinary peroxides and renal histology of rats. Adult Wistar rats treated for 5 days were divided into the following groups: control (saline, 3 ml/kg/day, intraperitoneally [i.p.]), IC (sodium iothalamate meglumine, 3 ml/kg/day i.p.), IC + water (12 mL water, orally + IC, 3 ml/kg/day i.p. after 1 hour), IC + NAC (NAC, 150 mg/kg/day, orally + IC, 3 ml/kg/day i.p. after 1 hour) and IC + water + NAC.<br><br>RESULTS: IC medium reduced renal function, with maintenance of urinary flow. Hyperhydration did not reduce the nephrotoxic effect of the IC agent, which was observed in the group IC + NAC. The combination of hyperhydration and NAC had no superior protective effect compared with NAC alone. An increase in urinary peroxides was observed in the IC group, with NAC or water or the combination of both reducing this parameter. Histopathologic analysis revealed no significant alterations.<br><br>CONCLUSIONS: In summary, given 5 days previously, NAC was found to be more effective than hyperhydration alone in the prevention of contrast-induced acute renal failure.}, }
@article {pmid18948301, year = {2009}, author = {Gao, P and He, P and Wang, A and Xia, T and Xu, B and Xu, Z and Niu, Q and Guo, L and Chen, X}, title = {Influence of PCB153 on oxidative DNA damage and DNA repair-related gene expression induced by PBDE-47 in human neuroblastoma cells in vitro.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {107}, number = {1}, pages = {165-170}, doi = {10.1093/toxsci/kfn224}, pmid = {18948301}, issn = {1096-0929}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/metabolism ; Cell Line, Tumor ; DNA Breaks/drug effects ; DNA Damage/*drug effects ; DNA Repair/*drug effects ; DNA-Binding Proteins/genetics/metabolism ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Gene Expression/*drug effects ; Halogenated Diphenyl Ethers/*pharmacology ; Humans ; Neuroblastoma/metabolism ; Oxidative Stress/drug effects ; Polychlorinated Biphenyls/*pharmacology ; Reactive Oxygen Species/metabolism ; X-ray Repair Cross Complementing Protein 1 ; }, abstract = {We studied the relationship between 2,2,4,4-tetrabromodiphenyl ether (PBDE-47) and oxidative DNA damage as well as the mode of interaction between PBDE-47 and 2,2,4,4,5,5-hexachlorobiphenyl (PCB153) by incubating SH-SY5Y cells in four doses of PBDE-47 (0, 1, 5, 10 microM) and/or 5 microM PCB153 and 100 microM NAC (N-acetylcysteine) for 24 h. Results showed that reactive oxygen species (ROS) production in the 5 microM PBDE-47 + PCB153 and 10 microM PBDE-47 + PCB153 groups were significantly higher than that of the control group (p < 0.05). DNA strand breakage and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were significantly increased in the 10 microM PBDE-47, 5 microM PBDE-47 + PCB153, and 10 microM PBDE-47 + PCB153 groups compared with the control (p < 0.05). Furthermore, ROS formation and DNA strand breakage were dramatically increased in the 5 microM PBDE-47 + PCB153 and 10 microM PBDE-47 + PCB153 groups compared with the corresponding PBDE-47 only group and the PCB153 group (p< 0.05). The level of 8-OHdG was significantly increased in the 10 microM PBDE-47 + PCB153 group compared with the corresponding PBDE-47 only group and the PCB153 group (p < 0.05). The PBDE-47 group coincubated with NAC decreased the ROS level and ameliorated PBDE-47-mediated DNA damage. The mRNA expression levels of X-ray repair cross-complementing gene 1 (Xrcc1) were significantly decreased in the 10 microM PBDE-47, 5 microM PBDE-47 + PCB153, and 10 microM PBDE-47 + PCB153 groups, whereas X-ray repair cross-complementing gene 3 (Xrcc3) were significantly increased in the 10 microM PBDE-47 and 10 microM PBDE-47 + PCB153 groups compared with the control (p < 0.05). The PBDE-47 groups coincubated with NAC, however, considerably increased Xrcc1 while decreasing Xrcc3 mRNA expression (p < 0.05). These results indicate that PBDE-47 induced oxidative DNA damage and that PBDE-47 combined with PCB153 may increase such effects in SH-SY5Y cells in vitro. Furthermore, our results suggest that oxidative stress is responsible for DNA damage induced by PBDE-47.}, }
@article {pmid18941206, year = {2008}, author = {Kim, YS and Park, GB and Lee, HK and Song, H and Choi, IH and Lee, WJ and Hur, DY}, title = {Cross-linking of B7-H1 on EBV-transformed B cells induces apoptosis through reactive oxygen species production, JNK signaling activation, and fasL expression.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {181}, number = {9}, pages = {6158-6169}, doi = {10.4049/jimmunol.181.9.6158}, pmid = {18941206}, issn = {1550-6606}, mesh = {Animals ; Antibodies, Monoclonal/metabolism ; Apoptosis/*immunology ; B-Lymphocyte Subsets/enzymology/*immunology/metabolism/virology ; B7-1 Antigen/*metabolism ; Callithrix ; Cell Line, Transformed ; Cross-Linking Reagents/metabolism ; Enzyme Activation/immunology ; Fas Ligand Protein/*biosynthesis/genetics ; Herpesvirus 4, Human/*immunology ; Humans ; Inducible T-Cell Co-Stimulator Ligand ; JNK Mitogen-Activated Protein Kinases/*metabolism/physiology ; MAP Kinase Signaling System/*immunology ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; Phosphorylation/immunology ; Proto-Oncogene Proteins c-akt/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {B7-H1 is a newly identified member of the B7 family with important regulatory functions in cell-mediated immune responses, and it is expressed in human immune cells and several tumors. We first observed that expression of surface B7-H1 on B cells was increased during the immortalization process by EBV, which is strongly related to both inflammation and tumorigenesis. Cross-linking of B7-H1 on EBV-transformed B cells using anti-B7-H1 Ab (clone 130002) induced reactive oxygen species (ROS) generation, mitochondrial disruption, release of apoptotic proteins from mitochondria, and subsequent apoptosis. Inhibition of caspases and ROS generation recovered B7-H1-mediated apoptosis and proteolytic activities of caspase-8, -9, and -3. We observed that B7-H1 stimulation induced both transcription and translation of fasL. ZB4, an antagonistic anti-fas Ab, and NOK-1, an antagonistic anti-fasL Ab, effectively blocked apoptosis without exerting any influence on ROS generation. N-acetylcysteine (NAC) completely blocked the induction of fasL mRNA and protein. We found that B7-H1 stimulation activated the phosphorylation of JNK and c-jun and down-regulated ERK1/2 and p-Akt. NAC blocked the activation of JNK and down-regulation of ERK, but both z-VAD-fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone) and ZB4 did not inhibit JNK activation of B7-H1 stimulation. SP600125 blocked fasL induction and apoptosis but did not affect ROS generation after B7-H1 stimulation. Taken together, we concluded that B7-H1-mediated apoptosis on EBV-transformed B cells may be involved in the induction of fasL, which is evoked by ROS generation and JNK activation after cross-linking of B7-H1. These results provide a new concept for understanding reverse signaling through B7-H1 and another mechanism of tumor immunotherapy using anti-B7-H1.}, }
@article {pmid18940247, year = {2009}, author = {Lee, JW and Kim, WH and Lim, JH and Song, EH and Song, J and Choi, KY and Jung, MH}, title = {Mitochondrial dysfunction: glucokinase downregulation lowers interaction of glucokinase with mitochondria, resulting in apoptosis of pancreatic beta-cells.}, journal = {Cellular signalling}, volume = {21}, number = {1}, pages = {69-78}, doi = {10.1016/j.cellsig.2008.09.015}, pmid = {18940247}, issn = {1873-3913}, mesh = {Analysis of Variance ; Animals ; Anti-Bacterial Agents/pharmacology ; Antimycin A/pharmacology ; *Apoptosis ; Cells, Cultured ; Down-Regulation ; Glucokinase/*metabolism ; Immunoprecipitation ; Insulin/metabolism ; Insulin-Secreting Cells/enzymology/*metabolism ; Membrane Potentials/physiology ; Mice ; Mitochondria/drug effects/*metabolism ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Time Factors ; bcl-Associated Death Protein/metabolism ; }, abstract = {Mitochondrial dysfunction has been considered a critical component in the development of diabetes. In pancreatic beta-cells especially, mitochondrial dysfunction impairs insulin secretion and the eventual apoptosis of beta-cells. The aim of this study was to elucidate the molecular mechanism underlying these events. Metabolic stress induced by antimycin or oligomycin was used to impair mitochondrial function in MIN6N8 cells, a mouse pancreatic beta-cells, and the effects of glucokinase (GCK) and mitochondria were investigated. Concurrent with reduction in mitochondrial membrane potential (DeltaPsim) and cellular ATP content, impaired mitochondrial function reduced GCK expression and resulted in decreased insulin secretion and beta-cell apoptosis. Specifically, lowered GCK expression led to decreased interactions between GCK and mitochondria, which increased Bax binding to mitochondria and cytochrome C release into cytoplasm. However, these events were blocked by treatment with the antioxidant, N-acetyl-cysteine (NAC), as well as GCK overexpression. Moreover, examination of the GCK promoter in antimycin-treated cells demonstrated that the promoter region within -287 bases from transcription site is involved in the transcriptional repression of GCK by mitochondrial stress, whose region contains a putative binding site for pancreatic duodenal homeobox-1 (PDX-1). Mitochondrial stress reduced PDX-1 expression, and increased ATF3 expression dependent on reactive oxygen species (ROS). Collectively, these data demonstrate that mitochondrial dysfunction by metabolic stress reduces GCK expression through PDX-1 downregulation via production of ROS, which then decreases the association of GCK with mitochondria, resulting in pancreatic beta-cell apoptosis and reduction of insulin secretion.}, }
@article {pmid18923390, year = {2008}, author = {James, LP and Capparelli, EV and Simpson, PM and Letzig, L and Roberts, D and Hinson, JA and Kearns, GL and Blumer, JL and Sullivan, JE and , }, title = {Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose.}, journal = {Clinical pharmacology and therapeutics}, volume = {84}, number = {6}, pages = {684-690}, pmid = {18923390}, issn = {1532-6535}, support = {DK06799/DK/NIDDK NIH HHS/United States ; U10 HD031324/HD/NICHD NIH HHS/United States ; HD031324/HD/NICHD NIH HHS/United States ; U01 HD031324/HD/NICHD NIH HHS/United States ; U10 HD031324-15/HD/NICHD NIH HHS/United States ; }, mesh = {Acetaminophen/*pharmacokinetics/*poisoning ; Adolescent ; Alanine Transaminase/drug effects/*metabolism ; Aspartate Aminotransferases/drug effects/*metabolism ; Bayes Theorem ; Biomarkers/metabolism ; Blood Chemical Analysis ; Chemical and Drug Induced Liver Injury/*enzymology/*etiology ; Child ; Child, Preschool ; Cohort Studies ; Drug Compounding/adverse effects ; Drug Overdose ; Female ; Half-Life ; Humans ; Male ; Predictive Value of Tests ; Probability ; Risk Assessment ; Statistics, Nonparametric ; }, abstract = {Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack-Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k(e)), elimination half-lives (t(1/2)), and maximum concentration of adducts (C(max)) of the subjects. The mean (+/-SD)k(e) and half-life were 0.486 +/- 0.084 days(-1) and 1.47+/- 0.30 days, respectively, and the C(max) was 1.2 (+/-2.92) nmol/ml serum. The model-derived, predicted adduct value at 48 h (Adduct 48) correlated with adductC(max), adduct T(max), Rumack-Matthews risk determination, peak aspartate aminotransferase (AST), and peak alanine aminotransferase (ALT). The pharmacokinetics and clinical correlates of APAP adducts in pediatric and adolescent patients with APAP overdose support the need for a further examination of the role of APAP adducts as clinically relevant and specific biomarkers of APAP toxicity.}, }
@article {pmid18922898, year = {2008}, author = {Sun, Y and Rigas, B}, title = {The thioredoxin system mediates redox-induced cell death in human colon cancer cells: implications for the mechanism of action of anticancer agents.}, journal = {Cancer research}, volume = {68}, number = {20}, pages = {8269-8277}, pmid = {18922898}, issn = {1538-7445}, support = {R01 CA092423/CA/NCI NIH HHS/United States ; R01 CA101019/CA/NCI NIH HHS/United States ; R01 CA10101902/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/pharmacology ; Aspirin/analogs &amp; derivatives/pharmacology ; Gold Sodium Thiomalate/pharmacology ; HT29 Cells ; Humans ; MAP Kinase Kinase Kinase 5/physiology ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Nitric Oxide Donors/pharmacology ; Organophosphates/pharmacology ; Oxidation-Reduction ; Oxidative Stress ; Oxides/pharmacology ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Thioredoxin-Disulfide Reductase/antagonists &amp; inhibitors ; Thioredoxins/*physiology ; }, abstract = {Anticancer agents act, at least in part, by inducing reactive oxygen and nitrogen species (RONS). We examined the redox effect on SW480 and HT-29 colon cancer cells of four anticancer compounds, arsenic trioxide, phosphoaspirin, phosphosulindac, and nitric oxide-donating aspirin (NO-ASA). All compounds inhibited the growth of both cell lines (IC(50), 10-90 micromol/L) and induced RONS detected by a general RONS molecular probe. NO-ASA, which induced at least four individual RONS (NO, H(2)O(2), superoxide anion, and peroxynitirte), induced apoptotic and necrotic cell death that was RONS-mediated (cell death paralleled RONS levels and was abrogated by N-acetyl cysteine but not by diphenylene iodonium, which displayed prooxidant activity and enhanced cell death). Nuclear factor-kappaB and mitogen-activated protein kinases were modulated by RONS. Thioredoxin-1 (Trx-1), an oxidoreductase involved in redox regulation, was heavily oxidized in response to RONS and mediated the growth inhibitory effect of the anticancer agents; knocking-down trx-1 expression by small interfering RNA abrogated cell death induced by them. These compounds also inhibited the activity of Trx reductase that reduces oxidized Trx-1, whereas the Trx reductase inhibitor aurothiomalate synergized with NO-ASA in the induction of cell death. Our findings indicate that the Trx system mediates to a large extent redox-induced cell death in response to anticancer agents. This mechanism of action may be shared by more anticancer agents and deserves further assessment as a candidate mechanism for the pharmacologic control of cancer.}, }
@article {pmid18851855, year = {2009}, author = {Shahin, AY and Hassanin, IM and Ismail, AM and Kruessel, JS and Hirchenhain, J}, title = {Effect of oral N-acetyl cysteine on recurrent preterm labor following treatment for bacterial vaginosis.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {104}, number = {1}, pages = {44-48}, doi = {10.1016/j.ijgo.2008.08.026}, pmid = {18851855}, issn = {0020-7292}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Anti-Infective Agents/therapeutic use ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Metronidazole/therapeutic use ; Obstetric Labor, Premature/*prevention &amp; control ; Pregnancy ; Pregnancy Complications, Infectious/*drug therapy/microbiology ; Vaginosis, Bacterial/*drug therapy ; Young Adult ; }, abstract = {OBJECTIVE: To evaluate the effect of N-acetyl cysteine (NAC) on gestational age at delivery in women with previous preterm labor and bacterial vaginosis.<br><br>METHODS: A randomized, double-blind, placebo-controlled trial with 280 women between 16 and 18 weeks of pregnancy who had 1 previous preterm birth and had just been successfully treated for bacterial vaginosis with metronidazole for 1 week. The women were randomized to receive 0.6 g of NAC per day plus 17-hydroxyprogesterone caproate (17-OHPC) or placebo plus 17-OHPC until 36 completed weeks of pregnancy or active labor. A vaginal swab was taken during labor.<br><br>RESULTS: Reaching 36 weeks of pregnancy was more frequent (P<0.05) and gestational age at delivery was significantly higher in the NAC than in the placebo group (37.4 weeks+/-0.4 weeks vs 34.1 weeks+/-1.2 weeks, P<0.05). The discontinuation rate was 11.4% in the NAC group.<br><br>CONCLUSIONS: Oral NAC was found to reduce the recurrence of preterm birth in patients with bacterial vaginosis.}, }
@article {pmid18848847, year = {2008}, author = {Marra, M and Lombardi, A and Agostinelli, E and Giuberti, G and Zappavigna, S and Tempera, G and Vitale, G and Bifulco, M and Abbruzzese, A and Caraglia, M}, title = {Bovine serum amine oxidase and spm potentiate docetaxel and interferon-alpha effects in inducing apoptosis on human cancer cells through the generation of oxidative stress.}, journal = {Biochimica et biophysica acta}, volume = {1783}, number = {12}, pages = {2269-2278}, doi = {10.1016/j.bbamcr.2008.09.002}, pmid = {18848847}, issn = {0006-3002}, mesh = {Amine Oxidase (Copper-Containing)/blood/*pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3/metabolism ; Cattle ; Cell Proliferation/drug effects ; Docetaxel ; Drug Synergism ; Enzyme Activation/drug effects ; Flow Cytometry ; Humans ; Interferon alpha-2 ; Interferon-alpha/*pharmacology ; Lipid Peroxidation ; Nitric Oxide/metabolism ; Oncogene Protein v-akt/metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Recombinant Proteins ; Signal Transduction/drug effects ; Spermine/*pharmacology ; Superoxide Dismutase ; Taxoids/*pharmacology ; Tumor Cells, Cultured/pathology ; ras Proteins ; }, abstract = {It was previously demonstrated that bovine serum amine-oxidase (BSAO) and SPM (SPM) addition to cancer cells induces cell growth inhibition and over-run the multi-drug resistance (MDR) phenotype through the oxidative stress caused by polyamine metabolites. In this study, it is reported that BSAO/SPM enzymatic system antagonizes the survival pathway induced by either docetaxel (DTX) or interferon alpha (IFNalpha) in human epidermoid cancer KB cells. The combination of BSAO/SPM with either DTX or IFNalpha had a synergistic effect on cell growth inhibition through apoptosis in both human epidermoid KB and breast cancer MCF-7 cell lines. The effects of the BSAO/SPM-DTX combination on apoptosis were caspase 3 and 9-dependent and were paralleled by the enhancement of intracellular O(2-), nitric oxide levels and of lipo-oxidation. The scavenger moiety N-acetyl-cysteine antagonized the effects on apoptosis and cell growth inhibition induced by the combination suggesting a role of the oxidative products of SPM. These effects occurred together with a decrease of the physiological scavenger MnSOD and an increase of both p38 kinase activity and DNA damage. The results suggest that DTX and IFNalpha could sensitize tumour cells to the oxidative stress and apoptosis induced by BSAO/SPM through the induction of a survival ras-dependent pathway and the consequent elevation of the intracellular polyamine pool. These data allow the design of new therapeutic strategy based on the use of this combination in human neoplasms.}, }
@article {pmid18847491, year = {2008}, author = {Shi, Y and Sahu, RP and Srivastava, SK}, title = {Triphala inhibits both in vitro and in vivo xenograft growth of pancreatic tumor cells by inducing apoptosis.}, journal = {BMC cancer}, volume = {8}, number = {}, pages = {294}, pmid = {18847491}, issn = {1471-2407}, support = {R01 CA106953/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Damage ; Enzyme Activation ; Enzyme-Linked Immunosorbent Assay ; Extracellular Signal-Regulated MAP Kinases/genetics/metabolism ; Humans ; Immunohistochemistry ; Mice ; Neoplasm Transplantation ; Pancreas/metabolism/pathology ; Pancreatic Neoplasms/drug therapy/metabolism/*pathology ; Plant Extracts/*pharmacology/therapeutic use ; Reactive Oxygen Species/metabolism ; Transplantation, Heterologous ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {BACKGROUND: Triphala is commonly used in Ayurvedic medicine to treat variety of diseases; however its mechanism of action remains unexplored. This study elucidates the molecular mechanism of Triphala against human pancreatic cancer in the cellular and in vivo model.<br><br>METHODS: Growth-inhibitory effects of Triphala were evaluated in Capan-2, BxPC-3 and HPDE-6 cells by Sulphoradamine-B assay. Apoptosis was determined by cell death assay and western blotting. Triphala was administered orally to nude mice implanted with Capan-2 xenograft. Tumors were analyzed by immunohistochemistry and western blotting.<br><br>RESULTS: Exposure of Capan-2 cells to the aqueous extract of Triphala for 24 h resulted in the significant decrease in the survival of cells in a dose-dependent manner with an IC50 of about 50 microg/ml. Triphala-mediated reduced cell survival correlated with induction of apoptosis, which was associated with reactive oxygen species (ROS) generation. Triphala-induced apoptosis was linked with phosphorylation of p53 at Ser-15 and ERK at Thr-202/Tyr-204 in Capan-2 cells. Above mentioned effects were significantly blocked when the cells were pretreated with an antioxidant N-acetylcysteine (NAC), suggesting the involvement of ROS generation. Pretreatment of cells with pifithrin-alpha or U0126, specific inhibitors of p53 or MEK-1/2, significantly attenuated Triphala-induced apoptosis. Moreover, NAC or U0126 pretreatment significantly attenuated Triphala-induced p53 transcriptional activity. Similarly, Triphala induced apoptosis in another pancreatic cancer cell line BxPC-3 by activating ERK. On the other hand, Triphala failed to induce apoptosis or activate ERK or p53 in normal human pancreatic ductal epithelial (HPDE-6) cells. Further, oral administration of 50 mg/kg or 100 mg/kg Triphala in PBS, 5 days/week significantly suppressed the growth of Capan-2 pancreatic tumor-xenograft. Reduced tumor-growth in Triphala fed mice was due to increased apoptosis in the tumors cells, which was associated with increased activation of p53 and ERK.<br><br>CONCLUSION: Our preclinical studies demonstrate that Triphala is effective in inhibiting the growth of human pancreatic cancer cells in both cellular and in vivo model. Our data also suggests that the growth inhibitory effects of Triphala is mediated by the activation of ERK and p53 and shows potential for the treatment and/or prevention of human pancreatic cancer.}, }
@article {pmid18846238, year = {2008}, author = {Chen, J and Kinter, M and Shank, S and Cotton, C and Kelley, TJ and Ziady, AG}, title = {Dysfunction of Nrf-2 in CF epithelia leads to excess intracellular H2O2 and inflammatory cytokine production.}, journal = {PloS one}, volume = {3}, number = {10}, pages = {e3367}, pmid = {18846238}, issn = {1932-6203}, mesh = {Animals ; Antioxidants/metabolism ; Cells, Cultured ; Cystic Fibrosis/*metabolism/pathology ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Epithelial Cells/cytology/*metabolism ; Humans ; Hydrogen Peroxide/*metabolism ; Interleukin-1beta/immunology ; Interleukin-6/*immunology ; Interleukin-8/*immunology ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/genetics/*metabolism ; Oxidants/*metabolism ; Oxidation-Reduction ; Tumor Necrosis Factor-alpha/immunology ; }, abstract = {Cystic fibrosis is characterized by recurring pulmonary exacerbations that lead to the deterioration of lung function and eventual lung failure. Excessive inflammatory responses by airway epithelia have been linked to the overproduction of the inflammatory cytokine IL-6 and IL-8. The mechanism by which this occurs is not fully understood, but normal IL-1beta mediated activation of the production of these cytokines occurs via H2O2 dependent signaling. Therefore, we speculated that CFTR dysfunction causes alterations in the regulation of steady state H2O2. We found significantly elevated levels of H2O2 in three cultured epithelial cell models of CF, one primary and two immortalized. Increases in H2O2 heavily contributed to the excessive IL-6 and IL-8 production in CF epithelia. Proteomic analysis of three in vitro and two in vivo models revealed a decrease in antioxidant proteins that regulate H2O2 processing, by > or =2 fold in CF vs. matched normal controls. When cells are stimulated, differential expression in CF versus normal is enhanced; corresponding to an increase in H2O2 mediated production of IL-6 and IL-8. The cause of this redox imbalance is a decrease by approximately 70% in CF cells versus normal in the expression and activity of the transcription factor Nrf-2. Inhibition of CFTR function in normal cells produced this phenotype, while N-acetyl cysteine, selenium, an activator of Nrf-2, and the overexpression of Nrf-2 all normalized H2O2 processing and decreased IL-6 and IL-8 to normal levels, in CF cells. We conclude that a paradoxical decrease in Nrf-2 driven antioxidant responses in CF epithelia results in an increase in steady state H2O2, which in turn contributes to the overproduction of the pro-inflammatory cytokines IL-6 and IL-8. Treatment with antioxidants can ameliorate exaggerated cytokine production without affecting normal responses.}, }
@article {pmid18845245, year = {2008}, author = {Krasnowska, EK and Pittaluga, E and Brunati, AM and Brunelli, R and Costa, G and De Spirito, M and Serafino, A and Ursini, F and Parasassi, T}, title = {N-acetyl-l-cysteine fosters inactivation and transfer to endolysosomes of c-Src.}, journal = {Free radical biology &amp; medicine}, volume = {45}, number = {11}, pages = {1566-1572}, doi = {10.1016/j.freeradbiomed.2008.09.012}, pmid = {18845245}, issn = {0891-5849}, mesh = {Acetylcysteine/*chemistry/*pharmacology ; Amino Acid Sequence ; Animals ; Blotting, Western ; CSK Tyrosine-Protein Kinase ; Caco-2 Cells ; Cell Line, Tumor ; Cell Membrane/drug effects/metabolism ; Fluorescent Antibody Technique ; Free Radical Scavengers/chemistry/pharmacology ; Humans ; Immunoprecipitation ; Kinetics ; Lysosomes/drug effects/*metabolism ; Microscopy, Confocal ; Oxidation-Reduction/drug effects ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/chemistry/isolation &amp; purification/*metabolism ; Rats ; src-Family Kinases ; }, abstract = {The non-receptor-protein tyrosine kinase c-Src is overexpressed and activated in a large number of human cancers, in which it is associated with tumor development and progression. Canonical regulation takes place by means of an alternative phosphorylation of tyrosine residues -- Tyr419 for activation and Tyr530 for inactivation. An independent redox regulation mechanism, involving cysteine residues, has also been proposed, in which oxidation activates the enzyme. Here we present a kinetic analysis of the effect of N-acetyl-l-cysteine (NAC) on c-Src, demonstrating that reduction reverts the oxidation-driven activation. In cancer cells, we show that NAC treatment produces an increase in specifically labeled reduced thiols of c-Src cysteines, thus confirming a redox transition. In addition to a decrease in Tyr419 phosphorylation, this leads to a massive shift of c-Src from plasma membranes -- where its active form is located -- to endolysosomal compartments. With the objective of deciphering the complex issue of c-Src regulation and of devising new strategies to revert its activation in cancers, redox regulation thus emerges as a promising area for study.}, }
@article {pmid18842737, year = {2008}, author = {Yen, YT and Chen, HC and Lin, YD and Shieh, CC and Wu-Hsieh, BA}, title = {Enhancement by tumor necrosis factor alpha of dengue virus-induced endothelial cell production of reactive nitrogen and oxygen species is key to hemorrhage development.}, journal = {Journal of virology}, volume = {82}, number = {24}, pages = {12312-12324}, pmid = {18842737}, issn = {1098-5514}, mesh = {Animals ; Apoptosis ; Cells, Cultured ; Dengue Virus/*physiology ; Endothelial Cells/cytology/*metabolism ; Gene Expression Regulation, Enzymologic ; Hemorrhage/genetics/*metabolism/*pathology ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nitric Oxide Synthase Type II/genetics/metabolism ; Reactive Nitrogen Species/*biosynthesis ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/*biosynthesis ; Up-Regulation ; Virus Replication ; }, abstract = {Hemorrhage is a severe manifestation of dengue disease. Virus strain and host immune response have been implicated as the risk factors for hemorrhage development. To delineate the complex interplay between the virus and the host, we established a dengue hemorrhage model in immune-competent mice. Mice inoculated intradermally with dengue virus develop hemorrhage within 3 days. In the present study, we showed by the presence of NS1 antigen and viral nuclei acid that dengue virus actively infects the endothelium at 12 h and 24 h after inoculation. Temporal studies showed that beginning at day 2, there was macrophage infiltration into the vicinity of the endothelium, increased tumor necrosis factor alpha (TNF-alpha) production, and endothelial cell apoptosis in the tissues. In the meantime, endothelial cells in the hemorrhage tissues expressed inducible nitric oxide synthase (iNOS) and nitrotyrosine. In vitro studies showed that primary mouse and human endothelial cells were productively infected by dengue virus. Infection by dengue virus induced endothelial cell production of reactive nitrogen and oxygen species and apoptotic cell death, which was greatly enhanced by TNF-alpha. N(G)-nitro-L-arginine methyl ester and N-acetyl cysteine reversed the effects of dengue virus and TNF-alpha on endothelial cells. Importantly, hemorrhage development and the severity of hemorrhage were greatly reduced in mice lacking iNOS or p47(phox) or treatment with oxidase inhibitor, pointing to the critical roles of reactive nitrogen and oxygen species in dengue hemorrhage.}, }
@article {pmid18837652, year = {2009}, author = {Tyagi, N and Moshal, KS and Sen, U and Vacek, TP and Kumar, M and Hughes, WM and Kundu, S and Tyagi, SC}, title = {H2S protects against methionine-induced oxidative stress in brain endothelial cells.}, journal = {Antioxidants &amp; redox signaling}, volume = {11}, number = {1}, pages = {25-33}, pmid = {18837652}, issn = {1557-7716}, support = {R01 HL088012-03/HL/NHLBI NIH HHS/United States ; R01 NS051568/NS/NINDS NIH HHS/United States ; R01 HL088012/HL/NHLBI NIH HHS/United States ; NS-51568/NS/NINDS NIH HHS/United States ; HL-75185/HL/NHLBI NIH HHS/United States ; R01 NS051568-02/NS/NINDS NIH HHS/United States ; HL-71010/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/metabolism ; Acetylcysteine/metabolism ; Animals ; Brain/*cytology ; Catalase/metabolism ; Cell Line, Transformed ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects/*metabolism ; Formazans/metabolism ; Glutathione/metabolism ; Homocysteine/biosynthesis ; Hydrogen Sulfide/metabolism/pharmacology/*therapeutic use ; Methionine/*toxicity ; Mice ; Models, Biological ; NG-Nitroarginine Methyl Ester/metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Tetrazolium Salts/metabolism ; Time Factors ; }, abstract = {Homocysteine (Hcy) causes cerebrovascular dysfunction by inducing oxidative stress. However, to date, there are no strategies to prevent Hcy-induced oxidative damage. Hcy is an H2S precursor formed from methionine (Met) metabolism. We aimed to investigate whether H2S ameliorated Met-induced oxidative stress in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to Met treatment in the presence or absence of NaHS (donor of H2S). Met-induced cell toxicity increased the levels of free radicals in a concentration-dependent manner. Met increased NADPH-oxidase-4 (NOX-4) expression and mitigated thioredxion-1(Trx-1) expression. Pretreatment of bEnd3 with NaHS (0.05 mM) attenuated the production of free radicals in the presence of Met and protected the cells from oxidative damage. Furthermore, NaHS enhanced inhibitory effects of apocynin, N-acetyl-l-cysteine (NAC), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), Nomega-nitro-l-arginine methyl ester (L-NAME) on ROS production and redox enzymes levels induced by Met. In conclusion, the administration of H2S protected the cells from oxidative stress induced by hyperhomocysteinemia (HHcy), which suggested that NaHS/H2S may have therapeutic potential against Met-induced oxidative stress.}, }
@article {pmid18837519, year = {2008}, author = {Teffera, Y and Colletti, AE and Harmange, JC and Hollis, LS and Albrecht, BK and Boezio, AA and Liu, J and Zhao, Z}, title = {Chemical reactivity of methoxy 4-o-aryl quinolines: identification of glutathione displacement products in vitro and in vivo.}, journal = {Chemical research in toxicology}, volume = {21}, number = {11}, pages = {2216-2222}, doi = {10.1021/tx800307n}, pmid = {18837519}, issn = {1520-5010}, mesh = {Aminopyridines/chemistry/*metabolism ; Animals ; Glutathione/chemistry/*metabolism ; Humans ; Magnetic Resonance Spectroscopy ; Male ; Microsomes, Liver/metabolism ; Protein Binding ; Proto-Oncogene Proteins c-met/*antagonists &amp; inhibitors ; Pyrazoles/chemistry/*metabolism ; Quinolines/chemistry/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AMG 458 {1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide} is a potent, selective inhibitor of c-Met, a receptor tyrosine kinase that is often deregulated in cancer. AMG 458 was observed to bind covalently to liver microsomal proteins from rats and humans in the absence of NADPH. When [(14)C]AMG 458 was incubated with liver microsomes in the presence of glutathione and N-acetyl cysteine, thioether adducts were detected by radiochromatography and LC/MS/MS analysis. These adducts were also formed upon incubation of AMG 458 with glutathione and N-acetyl cysteine in buffers at pH 7.4. In vivo, the thioether adducts were detected in bile and urine of bile duct-cannulated rats dosed with [(14)C]AMG 458. The two adducts were isolated, and their structures were determined by MS/MS and NMR analysis. The identified structures resulted from a thiol displacement reaction to yield a quinoline thioether structure and the corresponding hydroxyaryl moiety. The insights gained from elucidating the mechanism of adduct formation led to the design of AMG 458 analogues that exhibited eliminated or reduced glutathione adduct formation in vitro and in vivo.}, }
@article {pmid18836818, year = {2009}, author = {Kumar, B and Kumar, A and Pandey, BN and Mishra, KP and Hazra, B}, title = {Role of mitochondrial oxidative stress in the apoptosis induced by diospyrin diethylether in human breast carcinoma (MCF-7) cells.}, journal = {Molecular and cellular biochemistry}, volume = {320}, number = {1-2}, pages = {185-195}, pmid = {18836818}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Animals ; Antimycin A/pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms/*metabolism ; Cardiolipins/metabolism ; *Cell Line, Tumor/drug effects/metabolism ; Cyclosporine/pharmacology ; Cytochromes c/metabolism ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mitochondria/*drug effects/metabolism/ultrastructure ; Naphthoquinones/*pharmacology ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Rotenone/pharmacology ; Uncoupling Agents/pharmacology ; Vitamin K 3/pharmacology ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Mitochondria and associated oxidative stress have been shown to play critical roles in apoptotic death induced by various stress agents. Previously, we reported the antitumor property of diospyrin (D1), a plant-derived bisnaphthoquinonoid, and its diethylether derivative (D7), which was found to cause apoptotic death in human cancer cell lines. The present study aims to explore the relevant mechanism of apoptosis involving generation of cellular reactive oxygen species (ROS) by D7 in human breast carcinoma (MCF-7) cells. It was found that while D7 inhibited the proliferation of tumor cells, the associated apoptosis induced by D7 was prevented by treating the cells with N-acetyl-L-cysteine (NAC), an antioxidant, and cyclosporine A (CsA), an inhibitor of mitochondrial permeability transition (MPT). Experiments using suitable inhibitors also demonstrated that D7 could alter the electron flow in mitochondrial electron transport chain by affecting target(s) between complex I and complex III, and indicated the probable site of D7-induced generation of ROS. These results were further supported by confocal microscopic observation on changes in mitochondrial organization and shape in cells treated with D7. Taken together, the results of our study clearly suggested that the apoptosis induced by D7 would involve alteration of MPT, cardiolipin peroxidation, migration of Bax from cytosol to mitochondria, decreased expression of Bcl-2, and release of cytochrome c, indicating oxidative mechanism at the mitochondrial level in the tumor cells.}, }
@article {pmid18830972, year = {2009}, author = {Zhang, D and Shen, J and Wang, C and Zhang, X and Chen, J}, title = {GSH-dependent iNOS and HO-1 mediated apoptosis of human Jurkat cells induced by nickel(II).}, journal = {Environmental toxicology}, volume = {24}, number = {4}, pages = {404-414}, doi = {10.1002/tox.20440}, pmid = {18830972}, issn = {1522-7278}, mesh = {Acetylcysteine/metabolism/pharmacology ; Antioxidants/metabolism/pharmacology ; Apoptosis/*drug effects ; Cells, Cultured ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Heme Oxygenase-1/*metabolism ; Humans ; Jurkat Cells ; Nickel/*toxicity ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/*metabolism ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/drug effects/metabolism ; }, abstract = {The molecular mechanisms by which nickel compounds cause immune cytotoxicity are far from understood. Our preliminary data suggested that nickel(II) induced apoptosis in Jurkat cells by mitochondrial pathway, specifically via mitochondrial membrane potential dissipation and antiapoptotic gene bcl-2 down-regulation. The main goal of this study was to further investigate the toxicity of nickel, especially the induction of reactive oxygen species (ROS) on immune cells, which finally induced apoptosis. Nickel was found to induce glutathione (GSH) depletion in a dose- and time-dependent manner. When Jurkat cells were preincubated with antioxidant N-acetylcysteine (NAC), apoptosis was inhibited distinctly, which suggested that ROS played an initial role in nickel immune toxicity. Heme oxygenase-1 (HO-1) and Nitric oxide (NO) which may play an important role in regulatory and protective processes in cells were assayed upon nickel treatment. A significant increase in HO-1 mRNA levels was detected in nickel treated cells. We confirmed that reduction of Nitrate levels in Jurkat cells was due to down-regulation of inducible nitric oxide synthase (iNOS), not endothelial nitric oxide synthase (eNOS). Expression changes of HO-1 and iNOS were markedly blocked when Jurkat cells were preincubated with NAC, suggesting that ROS resulted in HO-1 and iNOS dysfunction in Jurkat cells. We supposed that the immune toxicity of nickel(II) was mainly due to GSH depletion and finally led to apoptosis, probably via changing the expression levels of HO-1 and iNOS in human T lymphocytes.}, }
@article {pmid18823668, year = {2008}, author = {Tilton, F and La Du, JK and Tanguay, RL}, title = {Sulfhydryl systems are a critical factor in the zebrafish developmental toxicity of the dithiocarbamate sodium metam (NaM).}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {90}, number = {2}, pages = {121-127}, pmid = {18823668}, issn = {1879-1514}, support = {P30 ES000210/ES/NIEHS NIH HHS/United States ; P30 ES000210-36/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology/toxicity ; Embryo, Nonmammalian/*drug effects ; Glutathione/pharmacology ; Sulfhydryl Compounds/pharmacology/toxicity ; Thiocarbamates/*toxicity ; Toxicity Tests ; Water Pollutants, Chemical/*toxicity ; Zebrafish/*embryology ; }, abstract = {Dithiocarbamates (DTCs) are sulfhydryls (thiol)-containing compounds, often associated with metals, and have both antioxidant and pro-oxidant abilities depending on the compound, experimental system and condition. In this study we investigated whether cell death plays a role in the manifestation of DTC-induced notochord distortions in the developing zebrafish and if thiol-containing compounds or antioxidants could modify this developmental toxicity. Sodium metam (NaM) induced notochord distortions could not be protected with the antioxidants ascorbic acid, trolox (synthetic vitamin E) or lipoic acid. However, NaM-induced distortions could be protected with co-exposure to glutathione or N-Acetyl Cysteine. Staggering the NaM and glutathione exposures in consecutive 10h developmental windows also resulted in protection. There were no discernable changes in TUNEL positive cells, a marker of apoptotic cells, at 24h post-fertilization (hpf) in NaM, dimethyl-dithiocarbamate, carbon disulfide, or neocuproine exposed embryos. Live NaM-exposed embryos incubated with acridine orange, a general stain for cell death, for 1h beginning at 11, 18 and 24hpf showed clusters of stained nuclei near the somitogenic front but not in the cells making up the notochord. Overall, induction of apoptotic pathways and widespread cell death are not involved in the manifestation of the adverse developmental outcomes following NaM exposure. However, cellular thiol status or critical sulfhydryl moieties are important considerations in the mechanisms of DTC developmental toxicity.}, }
@article {pmid18822012, year = {2008}, author = {Wang, FM and Hu, T and Cheng, R and Tan, H and Zhou, XD}, title = {Substance P influenced gelatinolytic activity via reactive oxygen species in human pulp cells.}, journal = {International endodontic journal}, volume = {41}, number = {10}, pages = {856-862}, doi = {10.1111/j.1365-2591.2008.01437.x}, pmid = {18822012}, issn = {1365-2591}, mesh = {Acetylcysteine/pharmacology ; Cells, Cultured ; Culture Media, Conditioned ; Dental Pulp/*drug effects/enzymology ; Dose-Response Relationship, Drug ; Electrophoresis, Polyacrylamide Gel ; Free Radical Scavengers/pharmacology ; Gelatinases/administration &amp; dosage/antagonists &amp; inhibitors/*pharmacology ; Humans ; Matrix Metalloproteinase 2/drug effects ; Matrix Metalloproteinase Inhibitors ; Microscopy, Confocal ; Reactive Oxygen Species/antagonists &amp; inhibitors/*pharmacology ; Substance P/administration &amp; dosage/*pharmacology ; }, abstract = {AIM: To investigate the effects of substance P (SP) on gelatinolytic activity of matrix metalloproteinases (MMPs) in human pulp cells.<br><br>METHODOLOGY: Human dental pulp cells were isolated and cultured. Subconfluent cells, between the third and sixth passages, were maintained under serum deprivation for 18 h followed by the treatment of varying doses of SP (1 pmol L(-1), 100 pmol L(-1), 10 nmol L(-1), 1 micromol L(-1) and 100 micromol L(-1)). Conditioned media were then subjected to gelatin zymography using 8% sodium dodecyl sulphate polyacrylamide gel electrophoresis minigels containing 1.5 g L(-1) gelatin. The effect of SP on intracellular reactive oxygen species (ROS) was also examined by confocal microscopy. ROS scavenger N-Acetyl-L-cysteine (NAC, 5 mmol L(-1)) was utilized to evaluate the roles of ROS pathway in mediating the impact of SP on cellular gelatinolytic activity. Data were analysed using analysis of variance with Bonferroni correction for multiple comparisons or an unpaired Student's t-test.<br><br>RESULTS: Substance P, at levels above 1 micromol L(-1), remarkably enhanced MMP-2 activity reflected by the band migrating at 66 kDa (P < 0.05). A gelatinolytic band at approximately 44 kDa appeared to be intensified in a SP dose-dependent manner. In addition, it was demonstrated that SP could induce ROS production in pulp cells and ROS scavenger NAC was further found to significantly reduce MMP-2 activity (P < 0.05), as well as other bands of gelatinolytic proteinases.<br><br>CONCLUSION: Substance P can influence gelatinolytic activity in human pulp cells via ROS pathway.}, }
@article {pmid18818479, year = {2008}, author = {Wu, JN and Huang, J and Yang, J and Tashiro, S and Onodera, S and Ikejima, T}, title = {Caspase inhibition augmented oridonin-induced cell death in murine fibrosarcoma l929 by enhancing reactive oxygen species generation.}, journal = {Journal of pharmacological sciences}, volume = {108}, number = {1}, pages = {32-39}, doi = {10.1254/jphs.fp0072079}, pmid = {18818479}, issn = {1347-8613}, mesh = {Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/drug effects ; *Caspase Inhibitors ; Cell Death/drug effects ; Cell Line ; Diterpenes, Kaurane/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Fibroblasts/drug effects ; Genes, bcl-2/drug effects ; Indicators and Reagents ; L-Lactate Dehydrogenase/metabolism ; Membrane Potentials/drug effects ; Mice ; Mitochondrial Membranes/drug effects ; Reactive Oxygen Species/*metabolism ; Tumor Suppressor Protein p53/physiology ; bcl-2-Associated X Protein/physiology ; }, abstract = {Oridonin, a diterpenoid isolated from Rabdosia rubescences, has been reported to have antitumor effects. In this study, the growth-inhibitory activity of oridonin for L929 cells was exerted in a time-and dose-dependent manner. After treatment with oridonin for 24 h, L929 cells underwent both apoptosis and necrosis as measured by an lactate dehydrogenase (LDH) activity-based assay. A rapid generation of reactive oxygen species (ROS) was triggered by oridonin, and subsequently up-regulation of phospho-p53 (ser 15) expression and an increased expression ratio of Bax/Bcl-2 was observed. Furthermore, there was a significant fall in mitochondrial membrane potential (MMP) and increase in caspase-3 activity after exposure to oridonin for 24 h. Surprisingly, the pan-caspase inhibitor z-VAD-fmk and caspase3 inhibitor z-DEVD-fmk rendered L929 cells more sensitive to oridonin, rather than preventing oridonin-induced cell death. Oridonin and z-VAD-fmk co-treatment not only resulted in an even higher ROS production, but also made a more significant reduction in the MMP. Pretreatment of ROS scavenger N-acetylcysteine (NAC) led to a complete inhibition of oridonin-induced cell death, intracellular ROS generation, and MMP collapse. NAC treatment also reversed the potentiation of cell death by the pan-caspase inhibitor z-VAD-fmk. Taken together, these observations showed that oridonin-induced cell death in L929 cells involved intracellular ROS generation, activation of phospho-p53 (ser 15), and up-regulation of the Bax/Bcl-2 ratio; and the augmented cell death by z-VAD-fmk was dependent on an increased ROS production.}, }
@article {pmid18817839, year = {2008}, author = {Song, Y and Liang, X and Hu, Y and Wang, Y and Yu, H and Yang, K}, title = {p,p'-DDE induces mitochondria-mediated apoptosis of cultured rat Sertoli cells.}, journal = {Toxicology}, volume = {253}, number = {1-3}, pages = {53-61}, doi = {10.1016/j.tox.2008.08.013}, pmid = {18817839}, issn = {0300-483X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cells, Cultured ; Dichlorodiphenyl Dichloroethylene/*toxicity ; Dose-Response Relationship, Drug ; Flow Cytometry ; Insecticides/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Male ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects/metabolism ; Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sertoli Cells/*drug effects/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1 ; bcl-2 Homologous Antagonist-Killer Protein/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {p,p'-Dichlorodiphenoxydichloroethylene (p,p'-DDE), the major metabolite of dichlorodiphenoxytrichloroethane (DDT), is a known persistent organic pollutant and male reproductive toxicant. However, the mechanism underlying male reproductive toxicity of p,p'-DDE remains limited. In the present study, Sertoli cells were used to investigate the molecular mechanism involved in p,p'-DDE's male reproductive toxicity. Results showed that p,p'-DDE exposure at over 30 microM showed induction of apoptotic cell death. p,p'-DDE could induce mitochondria-mediated apoptotic changes including elevation in reactive oxygen species (ROS) generation, decrease in mitochondrial membrane potential (DeltaPsi(m)), and release of cytochrome c into the cytosol, which could be blocked by antioxidant agent N-acetyl-l-cysteine (NAC). In addition, elevated ratios of Bax/Bcl-w and Bak/Bcl-w and cleavages of procaspase-3 and -9 were induced by p,p'-DDE treatment. All of the results suggested that ROS generation may play a critical role in the initiation of p,p'-DDE-induced apoptosis by mediation of the disruption of DeltaPsi(m), the release of cytochrome c into the cytosol and further the activation of caspase cascade.}, }
@article {pmid18813787, year = {2008}, author = {Wang, X and Li, H and Chen, Y and Fu, J and Ren, Y and Dong, L and Tang, S and Liu, S and Wu, M and Wang, H}, title = {p28GANK knockdown-derived reactive oxygen species induces apoptosis through mitochondrial dysfunction mediated by p38 in HepG2 cells.}, journal = {International journal of oncology}, volume = {33}, number = {4}, pages = {743-750}, pmid = {18813787}, issn = {1019-6439}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Cell Line, Tumor ; Cytochromes c/metabolism ; Enzyme Inhibitors/pharmacology ; *Gene Expression Regulation, Neoplastic ; Humans ; Mitochondria/*metabolism ; Models, Biological ; Proteasome Endopeptidase Complex/metabolism/*physiology ; Protein Transport ; Proto-Oncogene Proteins/metabolism/*physiology ; RNA Interference ; *Reactive Oxygen Species ; Subcellular Fractions/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Oncoprotein p28GANK knockdown by RNA interference (RNAi) can induce hepatoma cells apoptosis. However, the mechanisms have not been well defined yet. In the present study the p28GANK knockdown-induced apoptosis in HepG2 cells was prevented by caspase-9 inhibitor (Z-LEHD-FMK). During the knockdown of p28GANK, mitochondrial translocation of Bax, loss of mitochondrial transmembrane potential (DeltaPsim) and release of cytochrome c were observed. In this study, the activation of p38 was found to be critical for the p28GANK knockdown-induced apoptosis, as suggested by the finding that pharmacological inhibition of p38 with SB203580 suppressed the redistribution of Bax, the loss of DeltaPsim and the apoptosis. Moreover, generation of reactive oxygen species (ROS) contributed to the cell death because N-acetyl-L-cystenine (NAC), a ROS scavenger, suppressed the phosphorylation of p38 and the apoptosis. Our studies established the signaling pathway of p28GANK knockdown-induced apoptosis in HepG2 cells, namely, mitochondrial dysfunction mediated by p38 downstream of intracellular ROS generation.}, }
@article {pmid18812223, year = {2008}, author = {Chakraborty, PK and Mustafi, SB and Raha, S}, title = {Pro-survival effects of repetitive low-grade oxidative stress are inhibited by simultaneous exposure to Resveratrol.}, journal = {Pharmacological research}, volume = {58}, number = {5-6}, pages = {281-289}, doi = {10.1016/j.phrs.2008.08.007}, pmid = {18812223}, issn = {1043-6618}, mesh = {Animals ; Anticarcinogenic Agents/*pharmacology ; Antioxidants/*pharmacology ; Blotting, Western ; Cell Line ; Cell Survival/*drug effects/*physiology ; Cricetinae ; DNA Fragmentation ; Electrophoretic Mobility Shift Assay ; Fibroblasts/drug effects/physiology ; Flow Cytometry ; Gene Expression/drug effects ; Lung/cytology/drug effects ; Microscopy, Confocal ; NF-kappa B/genetics ; Oxidative Stress/drug effects/*physiology ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/metabolism ; Resveratrol ; Signal Transduction/drug effects/physiology ; Stilbenes/*pharmacology ; Transcription Factors/drug effects/physiology ; Transfection ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {V79 lung fibroblasts were subjected to repetitive oxidative stress in culture through exposures to 30 microM H(2)O(2) for 4 weeks. Repetitively stressed cells were found to be significantly resistant to apoptosis-inducing agent such as ultraviolet radiation (UVR). Concurrent treatment with Resveratrol completely restored the normal apoptotic response after UVR. p38MAPK became dually phosphorylated during the stress period. Akt also became phosphorylated on Ser(473) in cells subjected to repetitive oxidative stress. In these cells, NFkappaB p65 became phosphorylated and appreciable nuclear localization of p65 was observed. NFkappaB transcriptional activity also became augmented during repetitive stress. Treatment of the repetitively stressed cells concurrently with Resveratrol or SB203580, a p38MAPK inhibitor, robustly blocked activation of p38MAPK, NFkappaB transcriptional activity, phosphorylation and nuclear localization of p65, and Akt phosphorylation. Pre-exposure to short interfering RNA (si RNA) to p38MAPK, resulted in a blockage of the Akt and NFkappaB p65 phosphorylation. However, inhibition of Akt activity through PI3 kinase inhibitor LY294002 did not result in obstruction of p38MAPK phosphorylation by H(2)O(2). Also, Resveratrol was effective as an antioxidant in counteracting a rise in reactive oxygen species (ROS) and p38MAPK activation by H(2)O(2) was completely blocked by antioxidant N-acetyl cysteine (NAC). We conclude that Resveratrol acts as an antioxidant and completely reverses the anti-apoptotic effects of repetitive stress by blocking oxidative stress-induced p38MAPK activation which is the key regulatory step for the activation of down-stream survival elements Akt and NFkappaB.}, }
@article {pmid18810589, year = {2008}, author = {Keles, MS and Demirci, N and Yildirim, A and Atamanalp, SS and Altinkaynak, K}, title = {Protective effects of N-acetylcysteine and Ginkgo biloba extract on ischaemia-reperfusion-induced hepatic DNA damage in rats.}, journal = {Clinical and experimental medicine}, volume = {8}, number = {4}, pages = {193-198}, pmid = {18810589}, issn = {1591-8890}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Chromatography, High Pressure Liquid ; DNA Damage/*drug effects ; Electrochemistry ; Ginkgo biloba/*chemistry ; L-Lactate Dehydrogenase/blood ; Liver/*drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Plant Extracts/*pharmacology ; Rats ; Rats, Wistar ; Reperfusion Injury/enzymology/genetics/*prevention &amp; control ; }, abstract = {Hepatic ischaemia-reperfusion injury is a serious problem that occurs during various surgical operations such as liver transplantation, surgical revascularization, and partial organ resection. Different pharmacological agents have been used for the protection of organ function and for extending the tolerable ischaemic interval after the ischaemic insult. We aimed to determine the presence of 8-hydroxydeoxyguanosine (8-OHdG) in the DNA from liver undergoing ischaemia-reperfusion, and also to evaluate the protective effects of N-acetylcysteine (NAC) and EGb761 (Ginkgo biloba extract) against hepatic oxidative DNA damage. A total of 40 rats were divided into four groups of 10 animals each (sham-operation group, control group, NAC group, and EGb761 group). Oxidative damage to DNA was evaluated by measuring the increase in 8-OHdG formation in liver tissue and also the effects of NAC and EGb761 pretreatment. Hepatic ischaemia for 90 min followed by reperfusion caused a marked increase in tissue levels of 8-OHdG, thiobarbituric acid-reactive substance, serum ALT, AST and LDH activities compared to sham-operated group. Pretreatment with both NAC and EGb761 clearly diminished 8-OHdG formation and lipid peroxidation. These findings suggest that antioxidant molecules such as NAC and EGb761 may be useful in preventing postischaemic reperfusion injury in hepatic tissue.}, }
@article {pmid18809463, year = {2008}, author = {González-Correa, JA and Navas, MD and Lopez-Villodres, JA and Trujillo, M and Espartero, JL and De La Cruz, JP}, title = {Neuroprotective effect of hydroxytyrosol and hydroxytyrosol acetate in rat brain slices subjected to hypoxia-reoxygenation.}, journal = {Neuroscience letters}, volume = {446}, number = {2-3}, pages = {143-146}, doi = {10.1016/j.neulet.2008.09.022}, pmid = {18809463}, issn = {0304-3940}, mesh = {Acetates/*pharmacology/therapeutic use ; Animals ; Antioxidants/pharmacology ; Brain/*drug effects/metabolism/physiopathology ; Catechols/*pharmacology/therapeutic use ; Diet, Mediterranean ; Dose-Response Relationship, Drug ; Energy Metabolism/drug effects/physiology ; Hypoxia-Ischemia, Brain/*drug therapy/metabolism/physiopathology ; L-Lactate Dehydrogenase/drug effects/metabolism ; Male ; Nerve Degeneration/drug therapy/metabolism/physiopathology ; Neuroprotective Agents/*pharmacology ; Olive Oil ; Organ Culture Techniques ; Oxidative Stress/drug effects/physiology ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology/therapeutic use ; Plant Oils/therapeutic use ; Rats ; Rats, Wistar ; Reperfusion Injury/*drug therapy/metabolism/physiopathology ; }, abstract = {Hydroxytyrosol (HT) and hydroxytyrosol acetate (HT-AC) are two well-known phenolic compounds with antioxidant properties that are present in virgin olive oil (VOO). Because VOO has shown neuroprotective effects in rats, the purpose of the present study was to investigate the possible neuroprotective effect of HT and HT-AC in a model of hypoxia-reoxygenation in rat brain slices after in vitro incubation of these compounds or after 7 days of oral treatment with 5 or 10 mg/kg per day. Lactate dehydrogenase (LDH) efflux to the incubation medium was measured as a marker of brain cell death. HT and HT-AC inhibited LDH efflux in a concentration-dependent manner, with 50% inhibitory concentrations of 77.78 and 28.18 microM, respectively. Other well-known antioxidants such as vitamin E and N-acetyl-cysteine had no neuroprotective effect in this experimental model. After 1 week of treatment, HT (5 and 10 mg/kg per day p.o.) reduced LDH efflux by 37.8% and 52.7%, respectively, and HT-AC reduced LDH efflux by 45.4% and 67.8%. These data are additional evidence of the cytoprotective effect of VOO administration, and provide a preliminary basis for further study of these polyphenols as potential neuroprotective compounds.}, }
@article {pmid18806307, year = {2007}, author = {Schmelzer, C and Lorenz, G and Lindner, I and Rimbach, G and Niklowitz, P and Menke, T and Döring, F}, title = {Effects of Coenzyme Q10 on TNF-alpha secretion in human and murine monocytic cell lines.}, journal = {BioFactors (Oxford, England)}, volume = {31}, number = {1}, pages = {35-41}, doi = {10.1002/biof.5520310104}, pmid = {18806307}, issn = {0951-6433}, mesh = {Animals ; Anti-Inflammatory Agents/*pharmacology ; Apolipoprotein E3/physiology ; Apolipoprotein E4/physiology ; Cell Line ; Cell Survival/drug effects ; Humans ; Mice ; Monocytes/drug effects/*metabolism ; Tumor Necrosis Factor-alpha/*metabolism ; Ubiquinone/*analogs &amp; derivatives/pharmacology ; }, abstract = {Studies in humans and cell culture as well as bioinformatics suggested that Coenzyme Q(10) (CoQ10) functions as an anti-inflammatory molecule. Here we studied the influence of CoQ10 (Kaneka Q10) on secretion of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) by using the human and murine monocytic cell lines THP-1 and RAW264.7 expressing human apolipoprotein E3 (apoE3) or pro-inflammatory apoE4. Incubation of cells with physiological (0.1-10 microM) and supra-physiological (> 10 to < 100 microM) concentrations of CoQ10 led to an intracellular accumulation of its reduced form without any cytotoxic effects. Stimulation of cell models with lipopolysaccharide (LPS) resulted in a substantially release of TNF-alpha. When THP-1 cells were pre-incubated with 10 microM CoQ10, the LPS-induced TNF-alpha release was significantly decreased to 72 +/- 32%. This effect is similar to those obtained by 10 microM N-Acetyl-Cysteine, a well known reference antioxidant. In RAW264.7-apoE3 and -apoE4 cells, significant reductions of LPS-induced TNF-alpha secretion to 73.3 +/- 2.8% and 74.7 +/- 8.9% were found with 2.5 microM and 75 microM CoQ10, respectively. In conclusion, CoQ10 has moderate anti-inflammatory effects in two monocytic cell lines which could be mediated by its antioxidant activity.}, }
@article {pmid18806304, year = {2007}, author = {Jariwalla, RJ and Roomi, MW and Gangapurkar, B and Kalinovsky, T and Niedzwiecki, A and Rath, M}, title = {Suppression of influenza A virus nuclear antigen production and neuraminidase activity by a nutrient mixture containing ascorbic acid, green tea extract and amino acids.}, journal = {BioFactors (Oxford, England)}, volume = {31}, number = {1}, pages = {1-15}, doi = {10.1002/biof.5520310101}, pmid = {18806304}, issn = {0951-6433}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antigens, Viral/biosynthesis ; Ascorbic Acid/*pharmacology ; Cell Line ; Cell Survival/drug effects ; Chlorocebus aethiops ; Culture Media/pharmacology ; Dogs ; Flavonoids/pharmacology ; Influenza A virus/drug effects/enzymology/*immunology ; Lysine/*pharmacology ; Neuraminidase/*antagonists &amp; inhibitors ; Nucleocapsid Proteins ; Phenols/pharmacology ; Polyphenols ; Proline/*pharmacology ; RNA-Binding Proteins/*biosynthesis/drug effects ; *Tea ; Vero Cells ; Viral Core Proteins/*biosynthesis/drug effects ; }, abstract = {Influenza, one of the oldest and most common infections, poses a serious health problem causing significant morbidity and mortality, and imposing substantial economic costs. The efficacy of current drugs is limited and improved therapies are needed. A unique nutrient mixture (NM), containing ascorbic acid, green tea extract, lysine, proline, N-acetyl cysteine, selenium among other micronutrients, has been shown to exert anti-carcinogenic and anti-atherogenic activity both in vitro and in vivo. Many of the constituents of NM have been shown to have an inhibitory effect on replication of influenza virus and HIV. This prompted us to study the effect of NM on influenza A virus multiplication in infected cells and neuraminidase activity (NA) in virus particles. Addition of NM to Vero or MDCK cells post infection resulted in dose-dependent inhibition of viral nucleoprotein (NP) production in infected cells. NM-mediated inhibition of viral NP was selective and not due to cytotoxicity towards host cells. This antiviral effect was enhanced by pretreatment of virus with the nutrient mixture. Individual components of NM, namely ascorbic acid and green tea extract, also blocked viral NP production, conferring enhanced inhibition when tested in combination. Incubation of cell-free virus with NM resulted in dose-dependent inhibition of associated NA enzyme activity. In conclusion, the nutrient mixture exerts an antiviral effect against influenza A virus by lowering viral protein production in infected cells and diminishing viral enzymatic activity in cell-free particles.}, }
@article {pmid18806095, year = {2008}, author = {Baumgardner, JN and Shankar, K and Hennings, L and Albano, E and Badger, TM and Ronis, MJ}, title = {N-acetylcysteine attenuates progression of liver pathology in a rat model of nonalcoholic steatohepatitis.}, journal = {The Journal of nutrition}, volume = {138}, number = {10}, pages = {1872-1879}, pmid = {18806095}, issn = {1541-6100}, support = {R01 AA012819/AA/NIAAA NIH HHS/United States ; R01 AA012819-05/AA/NIAAA NIH HHS/United States ; R01 AA018282/AA/NIAAA NIH HHS/United States ; R01 AA 12819/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Autoantibodies/blood ; Disease Models, Animal ; Energy Intake ; Fatty Liver/immunology/*pathology/physiopathology/*prevention &amp; control ; Glutathione/metabolism ; Inflammation ; Liver/drug effects/metabolism/*pathology ; Liver Function Tests ; Male ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Triglycerides/blood ; }, abstract = {A "2-hit" model for nonalcoholic steatohepatitis (NASH) has been proposed in which steatosis constitutes the "first hit" and sensitizes the liver to potential "second hits" resulting in NASH. Oxidative stress is considered a candidate for the second hit. N-acetylcysteine (NAC), an antioxidant, has been suggested as a dietary therapy for NASH. We examined the effects of NAC in a rat total enteral nutrition (TEN) model where NASH develops as the result of overfeeding dietary polyunsaturated fat. Male Sprague-Dawley rats consumed pelleted AIN-93G diets ad libitum or were overfed a 9200 kJ.kg(-0.75).d(-1) liquid diet containing 70% corn oil with or without 2 g.kg(-1).d(-1) NAC i.g. for 65 d. Hepatic steatosis was not influenced by dietary supplementation with NAC; however, the liver pathology score was lower (P </= 0.05) and NAC provided partial protection against alanine aminotransferase release (P </= 0.05). NAC attenuated increased hepatic oxidative stress (TBARS; P </= 0.05) and prevented increases in cytochrome P450 2E1 apoprotein and mRNA and in tumor necrosis factor-alpha (TNFalpha) mRNA. Titers of auto-antibodies against proteins adducted to lipid peroxidation products were lower in serum of the NAC group than in the 70% corn oil group (P </= 0.05). NAC also decreased Picosirius red staining of collagen, a marker of fibrosis. However, markers of hepatic stellate cell activation were unaffected. Using NAC in a TEN model of NASH, we have demonstrated that NAC prevents many aspects of NASH progression by decreasing development of oxidative stress and subsequent increases in TNFalpha but does not block development of steatosis.}, }
@article {pmid18803085, year = {2008}, author = {Pakravan, N and Waring, WS and Sharma, S and Ludlam, C and Megson, I and Bateman, DN}, title = {Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {46}, number = {8}, pages = {697-702}, doi = {10.1080/15563650802245497}, pmid = {18803085}, issn = {1556-3650}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*adverse effects ; Adult ; Analgesics, Non-Narcotic/blood/*poisoning ; Anaphylaxis/blood/*chemically induced/immunology ; Antidotes/*adverse effects ; Blood Coagulation Factors/metabolism ; Drug Overdose/drug therapy ; Female ; Histamine Release/drug effects ; Humans ; Inflammation Mediators/blood ; Logistic Models ; Male ; Odds Ratio ; Pedigree ; Prospective Studies ; Risk Assessment ; Risk Factors ; Severity of Illness Index ; Sex Factors ; Time Factors ; }, abstract = {BACKGROUND: Adverse effects to N-acetylcysteine (NAC) are well recognized, but their etiology and incidence are unclear.<br><br>METHODS: The nature and severity of adverse effects were prospectively studied in 169 patients and potential reaction mediators studied in 22 patients.<br><br>RESULTS: Adverse effects were minimal in 101 (59.8%), moderate in 51 (30.2%), and severe in 17 (10.1%). Features were nausea (70.4%), vomiting (60.4%), flushing (24.9%), pruritus (20.1%), dyspnea (13.6%), chest pain (7.1%), dizziness (7.7%), fever (4.7%), wheeze and bronchospasm (7.1%), and rash and urticaria (3.6%). Serum acetaminophen concentration was lower in patients with severe adverse effects: median (IQR) 46 mg/L (0 to 101 mg/L), moderate 108 mg/L (54 to 178 mg/L), and minimal 119 mg/L (77 to 174 mg/L), p = 0.002. Family history of allergy and female gender were independent risk factors for adverse effects. Severity of adverse effects was associated with histamine release: AUC for change from baseline histamine was -6 ng/mL min (-60 to 11 ng/mL min) in the minimal group, 26 ng/mL min (3-129 ng/mL min) in the moderate group, and 49 ng/mL min (21-68 ng/mL min) in the severe group (p = 0.01). There was no increase in tryptase and no differences between groups for NAC concentrations or hemostatic and inflammatory variables (factors II, VII, IX, X, vWF, tPA, IL6, and CRP).<br><br>CONCLUSION: Severity of adverse effects correlates with the extent of histamine release. Histamine release appears independent of tryptase suggesting a non-mast cell source. Acetaminophen is protective against adverse effects of NAC, and mechanisms by which acetaminophen might lessen histamine release require further attention.}, }
@article {pmid18802743, year = {2008}, author = {Kamboj, SS and Chopra, K and Sandhir, R}, title = {Neuroprotective effect of N-acetylcysteine in the development of diabetic encephalopathy in streptozotocin-induced diabetes.}, journal = {Metabolic brain disease}, volume = {23}, number = {4}, pages = {427-443}, pmid = {18802743}, issn = {0885-7490}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/*metabolism ; Animals ; Brain/enzymology ; Brain Diseases/etiology/prevention &amp; control ; Cognition Disorders/etiology/*prevention &amp; control ; Diabetes Mellitus, Experimental/*complications ; Hyperglycemia/complications ; Lipid Peroxidation/physiology ; Male ; Maze Learning/*physiology ; Neuroprotective Agents/metabolism ; Oxidative Stress/*physiology ; Random Allocation ; Rats ; Rats, Wistar ; }, abstract = {Diabetic encephalopathy is characterized by impaired cognitive functions that involve neuronal damage triggered by glucose driven oxidative stress. The objective of the present study was to determine whether N-acetylcysteine (NAC) supplementation ameliorates learning and memory deficits caused by hyperglycemia-induced oxidative stress in experimental diabetes. Male Wistar rats (200-250 g) were rendered diabetic by a single intraperitoneal injection of streptozotocin (50 mg/kg). Cognitive deficits were observed in diabetic animals assessed using elevated plus maze test after 8 weeks of induction of diabetes. Acetylcholinesterase activity, a marker of cholinergic function, was decreased by 15.6% in the cerebral cortex, 20.9% in cerebellum and 14.9% in brain stem of diabetic rats compared to control rats. There was an increase in lipid peroxidation in cerebral cortex (21.97%), cerebellum (20.4%) and brain stem (25.5%) of diabetic rats. This was accompanied by decrease in glutathione and total thiol content along with decrease in the activities of superoxide dismutase, catalase and glutathione reductase. However, glutathione peroxidase activity increased by 11.2%, 13.6% and 23.1% in cerebral cortex, cerebellum and brain stem respectively, while the activity of glutathione-s-transferase decreased only in cerebral cortex (21.7%). Supplementation with NAC (1.4 g/kg/day in drinking water) significantly attenuated cognitive deficits and oxidative stress in diabetic rats. Our results emphasize the involvement of increased oxidative stress in cognitive impairment in diabetic animals and point towards the potential beneficial role of NAC as an adjuvant therapy to conventional anti-hyperglycemic regimens for the prevention and treatment of diabetic encephalopathy.}, }
@article {pmid18802057, year = {2008}, author = {Williams, MA and Rangasamy, T and Bauer, SM and Killedar, S and Karp, M and Kensler, TW and Yamamoto, M and Breysse, P and Biswal, S and Georas, SN}, title = {Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {181}, number = {7}, pages = {4545-4559}, pmid = {18802057}, issn = {1550-6606}, support = {R01 HL073952/HL/NHLBI NIH HHS/United States ; P01 ES009606/ES/NIEHS NIH HHS/United States ; P30 ES001247/ES/NIEHS NIH HHS/United States ; CA 94076/CA/NCI NIH HHS/United States ; R01 CA094076/CA/NCI NIH HHS/United States ; P50 HL084945/HL/NHLBI NIH HHS/United States ; R01 CA094076-03/CA/NCI NIH HHS/United States ; P01ES09606/ES/NIEHS NIH HHS/United States ; R01 HL071933-02/HL/NHLBI NIH HHS/United States ; HL071933/HL/NHLBI NIH HHS/United States ; R01 HL071933/HL/NHLBI NIH HHS/United States ; P30 ES03819/ES/NIEHS NIH HHS/United States ; R01 HL073952-01/HL/NHLBI NIH HHS/United States ; P30 ES003819-18/ES/NIEHS NIH HHS/United States ; P30 ES001247-35/ES/NIEHS NIH HHS/United States ; P30 ES003819/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Baltimore ; Bone Marrow Cells/drug effects/immunology/metabolism ; Cell Differentiation/drug effects/genetics/*immunology ; Cells, Cultured ; Coculture Techniques ; Dendritic Cells/drug effects/*immunology/metabolism ; Lung/cytology/drug effects/immunology/metabolism ; Lymphocyte Activation/drug effects/genetics/*immunology ; Male ; Mice ; Mice, Inbred ICR ; Mice, Knockout ; Mice, Transgenic ; NF-E2-Related Factor 2/biosynthesis/*deficiency/*genetics ; Oxidative Stress/drug effects/*immunology ; Particulate Matter/*toxicity ; Th2 Cells/drug effects/*immunology/metabolism ; }, abstract = {Oxidative stress is important in dendritic cell (DC) activation. Environmental particulate matter (PM) directs pro-oxidant activities that may alter DC function. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates expression of antioxidant and detoxification genes. Oxidative stress and defective antioxidant responses may contribute to the exacerbations of asthma. We hypothesized that PM would impart differential responses by Nrf2 wild-type DCs as compared with Nrf2(-/-) DCs. We found that the deletion of Nrf2 affected important constitutive functions of both bone marrow-derived and highly purified myeloid lung DCs such as the secretion of inflammatory cytokines and their ability to take up exogenous Ag. Stimulation of Nrf2(-/-) DCs with PM augmented oxidative stress and cytokine production as compared with resting or Nrf2(+/+) DCs. This was associated with the enhanced induction of Nrf2-regulated antioxidant genes. In contrast to Nrf2(+/+) DCs, coincubation of Nrf2(-/-) DCs with PM and the antioxidant N-acetyl cysteine attenuated PM-induced up-regulation of CD80 and CD86. Our studies indicate a previously underappreciated role of Nrf2 in innate immunity and suggest that deficiency in Nrf2-dependent pathways may be involved in susceptibility to the adverse health effects of air pollution in part by promoting Th2 cytokine responses in the absence of functional Nrf2. Moreover, our studies have uncovered a hierarchal response to oxidative stress in terms of costimulatory molecule expression and cytokine secretion in DCs and suggest an important role of heightened oxidative stress in proallergic Th2-mediated immune responses orchestrated by DCs.}, }
@article {pmid18797686, year = {2008}, author = {Azeredo, MA and Azeredo, LA and Eleuthério, EC and Schanaider, A}, title = {Propofol and N-Acetylcysteine attenuate oxidative stress induced by intestinal ischemia/reperfusion in rats: protein carbonyl detection by immunoblotting.}, journal = {Acta cirurgica brasileira}, volume = {23}, number = {5}, pages = {425-428}, doi = {10.1590/s0102-86502008000500006}, pmid = {18797686}, issn = {1678-2674}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers/metabolism ; Free Radical Scavengers/*pharmacology ; Intestines/*blood supply ; Male ; Oxidative Stress/*drug effects/physiology ; Propofol/*pharmacology ; Protein Carbonylation/*physiology ; Rats ; Rats, Wistar ; Reperfusion Injury/*metabolism/physiopathology ; }, abstract = {PURPOSE: To evaluate the antioxidant effect of Propofol and N-Acetylcysteine (NAC) on intestinal ischemia/reperfusion (I/R) in rats by determining carbonyl protein level.<br><br>METHODS: Forty Wistar rats were randomly assigned into the following groups: Control; Sham; I/R with Propofol; I/R with Propofol and NAC; I/R with Ketamine and Xylazine. The I/R groups underwent 60 minutes of ischemia and an equal period of reperfusion. Blood samples, collected by cardiac punction, were centrifuged for plasma obtainment. Protein carbonyl level in plasma samples was determined by immunoblotting.<br><br>RESULTS: No significant difference in protein carbonyl level was found between Control and Sham groups (P>0.05). The highest reduction in protein carbonyl level (P<0.05) was obtained with the administration of Propofol and NAC (Group 4) in intestinal I/R procedure.<br><br>CONCLUSION: The administration of Propofol and NAC showed the best antioxidant effect on oxidative stress in rats that underwent intestinal I/R procedure, suggesting a synergistic interaction.}, }
@article {pmid18797252, year = {2008}, author = {Ferreira, FR and Biojone, C and Joca, SR and Guimarães, FS}, title = {Antidepressant-like effects of N-acetyl-L-cysteine in rats.}, journal = {Behavioural pharmacology}, volume = {19}, number = {7}, pages = {747-750}, doi = {10.1097/FBP.0b013e3283123c98}, pmid = {18797252}, issn = {0955-8810}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antidepressive Agents/*pharmacology ; Antidepressive Agents, Tricyclic/pharmacology ; Dose-Response Relationship, Drug ; Escape Reaction/*drug effects ; Exploratory Behavior/drug effects ; Free Radical Scavengers/*pharmacology ; Imipramine/pharmacology ; Injections, Intraperitoneal ; Male ; *Motivation ; Motor Activity/*drug effects ; Rats ; Rats, Wistar ; Swimming ; }, abstract = {Oxidative stress disturbances have been reported in depressed patients and in animals submitted to stress. Recent evidence suggests that antidepressants may have antioxidant properties. However, the therapeutic potential of antioxidants as antidepressant drugs has not been systematically investigated. Therefore, this study tested the hypothesis that N-acetyl-L-cysteine (NAC), a cysteine prodrug with powerful antioxidant activity, would possess antidepressant-like properties in the forced swimming test. Male Wistar rats were subjected to 15 min of forced swimming and immediately afterward, 5, and 23 h later received intraperitoneal injections of NAC (5, 15, 50, 150, and 250 mg/kg), imipramine, (15 mg/kg) or vehicle. One hour later they were submitted to the 5 min test swimming session, where immobility time was recorded. Independent groups of animals received the same treatments and their exploratory activity was measured in an open arena for 5 min. NAC (at the doses of 15, 50, and 150 mg/kg) and imipramine induced a significant decrease in immobility time without changing exploratory behavior measured in an open arena. These results suggest that antioxidants such as NAC may have antidepressant effects.}, }
@article {pmid18796454, year = {2009}, author = {Sharif, MA and Bayraktutan, U and Arya, N and Badger, SA and O'Donnell, ME and Young, IS and Soong, CV}, title = {Effects of antioxidants on endothelial function in human saphenous vein in an ex vivo model.}, journal = {Angiology}, volume = {60}, number = {4}, pages = {448-454}, doi = {10.1177/0003319708321186}, pmid = {18796454}, issn = {1940-1574}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/*pharmacology ; Aged ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Dose-Response Relationship, Drug ; Female ; Humans ; In Vitro Techniques ; Male ; Metalloporphyrins/*pharmacology ; Middle Aged ; Saphenous Vein/*drug effects/surgery ; Vasodilation/*drug effects ; Vasodilator Agents/*pharmacology ; }, abstract = {This ex vivo study is aimed at determining the beneficial effects of antioxidant agents on human saphenous vein endothelial function. Vein rings harvested during infrainguinal bypass surgery were assessed in an organ bath for endothelium-dependent relaxation, initially without and then with the addition of 10 microM manganese tetrakis benzoic acid porphyrin (MnTBAP), 0.01% N-acetylcysteine (NAC), 0.02% NAC, 10 microM vitamin C, and 100 microM vitamin C. Fifty-five vein rings from 22 patients were analyzed. MnTBAP improved the endothelium-dependent relaxation when compared with control (57.0% vs 37.8%, P < .01). Addition of 0.01% or 0.02% NAC did not improve the endothelium-dependent vasorelaxation (28.2% vs 18.6%, P = ns and 37.8% vs 29.8%, P = ns, respectively). Although 10-microM vitamin C failed to improve endothelial function (50.6% vs 37.2%, P = ns), 100-microM vitamin C significantly enhanced endothelium-dependent relaxation (66.5% vs 38.3%, P < .001). These results suggest that the addition of MnTBAP and high-dose vitamin C can improve the endothelial function of harvested saphenous vein segments in an ex vivo model.}, }
@article {pmid18796325, year = {2008}, author = {Tharappel, JC and Lehmler, HJ and Srinivasan, C and Robertson, LW and Spear, BT and Glauert, HP}, title = {Effect of antioxidant phytochemicals on the hepatic tumor promoting activity of 3,3',4,4'-tetrachlorobiphenyl (PCB-77).}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {46}, number = {11}, pages = {3467-3474}, pmid = {18796325}, issn = {0278-6915}, support = {K25 ES012475-01A1/ES/NIEHS NIH HHS/United States ; ES013661/ES/NIEHS NIH HHS/United States ; P42 ES007380-050003/ES/NIEHS NIH HHS/United States ; P42 ES013661-01A10001/ES/NIEHS NIH HHS/United States ; P42 ES013661/ES/NIEHS NIH HHS/United States ; P42 ES013661-03/ES/NIEHS NIH HHS/United States ; P42 ES013661-020001/ES/NIEHS NIH HHS/United States ; P42 ES013661-02S2/ES/NIEHS NIH HHS/United States ; P42 ES013661-02/ES/NIEHS NIH HHS/United States ; P42 ES013661-02S1/ES/NIEHS NIH HHS/United States ; P42 ES007380/ES/NIEHS NIH HHS/United States ; ES07380/ES/NIEHS NIH HHS/United States ; P42 ES013661-01A1/ES/NIEHS NIH HHS/United States ; P42 ES007380-070003/ES/NIEHS NIH HHS/United States ; P42 ES013661-03S1/ES/NIEHS NIH HHS/United States ; K25 ES012475/ES/NIEHS NIH HHS/United States ; P42 ES007380-060003/ES/NIEHS NIH HHS/United States ; P42 ES013661-030001/ES/NIEHS NIH HHS/United States ; P42 ES007380-040003/ES/NIEHS NIH HHS/United States ; ES012475/ES/NIEHS NIH HHS/United States ; P42 ES007380-080003/ES/NIEHS NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Carcinogens, Environmental/toxicity ; Carotenoids/administration &amp; dosage/pharmacology ; Cell Proliferation/*drug effects ; Curcumin/administration &amp; dosage/pharmacology ; *Diet ; Ellagic Acid/administration &amp; dosage/pharmacology ; Female ; Glutathione Transferase/metabolism ; Hepatocytes/drug effects/metabolism/pathology ; Immunohistochemistry ; Injections, Intraperitoneal ; Liver/*drug effects/metabolism/pathology ; Liver Neoplasms, Experimental/chemically induced/*drug therapy ; Lycopene ; Organ Size/drug effects ; Oxidative Stress/*drug effects/physiology ; Polychlorinated Biphenyls/toxicity ; Rats ; Rats, Sprague-Dawley ; Ubiquinone/administration &amp; dosage/analogs &amp; derivatives/pharmacology ; }, abstract = {Polychlorinated biphenyls (PCBs) have promoting activity in the liver, which may be brought about in part by the induction of oxidative stress. In this study we examined the effects of several antioxidant phytochemicals on the tumor promoting activity of 3,3',4'4-tetrachlorobiphenyl (PCB-77). Female Sprague Dawley rats were first injected with diethylnitrosamine (DEN, 150 mg/kg) and one week later the rats were fed an AIN-93 based purified diet or the same diet containing ellagic acid (0.4%), beta-carotene (0.5%), curcumin (0.5%), N-acetyl cysteine (NAC, 1.0%), coenzyme CoQ10 (CoQ10, 0.4%), resveratrol (0.005%), lycopene (10% as Lycovit, which contains 10% lycopene), or a tea extract (1%, containing 16.5% epigallocatechin-3-gallate [EGCG] and 33.4% total catechins). Rats were fed the diets for the remainder of the study. After three weeks, 2/3 of the control rats and all of the antioxidant diet-fed rats were injected i.p. with PCB-77 (300 micromol/kg) every other week for four injections. All rats were euthanized ten days after the last PCB injection. The rats that received PCB-77 alone showed an increase in the number and size of placental glutathione S-transferase (PGST)-positive foci in the liver. Lycopene significantly decreased the number of foci, while curcumin and CoQ10 decreased the size of the foci. In contrast, ellagic acid increased the number but decreased the size of the foci. All of the other phytochemicals showed only slight or no effects. Compared with the PCB-77 group, CoQ10 increased cell proliferation in normal hepatocytes, whereas the other antioxidants had no effect in either normal or PGST-positive hepatocytes. These findings show that none of the antioxidant phytochemicals produced a clear decrease in the promoting activity of PCB-77.}, }
@article {pmid18796241, year = {2008}, author = {Muthukumaran, S and Sudheer, AR and Nalini, N and Menon, VP}, title = {Effect of quercetin on nicotine-induced biochemical changes and DNA damage in rat peripheral blood lymphocytes.}, journal = {Redox report : communications in free radical research}, volume = {13}, number = {5}, pages = {217-224}, doi = {10.1179/135100008X308948}, pmid = {18796241}, issn = {1743-2928}, mesh = {Acetylcysteine/pharmacology ; Animals ; Catalase/metabolism ; Cells, Cultured ; Comet Assay ; DNA Damage/*drug effects ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation/drug effects ; Lymphocytes/*drug effects/metabolism ; Male ; Micronucleus Tests ; Nicotine/*toxicity ; Quercetin/*pharmacology ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {We elucidated the protective effect of quercetin, a polyphenolic flavonoid, on lipid peroxidation, endogenous antioxidant status and DNA damage during nicotine-induced toxicity in cultured rat peripheral blood lymphocytes as compared to N-acetylcysteine (NAC), a well-known antioxidant. Lymphocytes were exposed to nicotine (3 mM) with and without quercetin and NAC (1 mM) in RPMI-1640 medium for 1 h. In preliminary experiments to fix the effective dose of quercetin, different doses of quercetin (25, 50, 75, 100 and 200 microM) were administered to lymphocytes with nicotine, and lipid peroxidation markers (thiobarbituric acid reactive substances and hydroperoxides) were analysed. A 75 microM dose of quercetin was found to be effective as evidenced by decreased lipid peroxidation. To evaluate the protective potential of quercetin against genotoxic effects of nicotine we used comet and micronucleus assays, which are valid parameters to assess genetic damage. In addition, biochemical changes including lipid peroxidation and antioxidant status were assessed. There were significant increases in the levels of lipid peroxidation, comet parameters and micronuclei frequencies, followed by decrease in the endogenous antioxidant status, in nicotine-treated lymphocytes, which were brought back to near normal by quercetin or NAC treatment. The protective effect of quercetin against nicotine toxicity was comparable to that of NAC. These findings suggest that quercetin can be as effective as NAC in protecting rat peripheral lymphocytes against nicotine-induced cellular and DNA damage.}, }
@article {pmid18793918, year = {2008}, author = {Paranjpe, A and Cacalano, NA and Hume, WR and Jewett, A}, title = {Mechanisms of N-acetyl cysteine-mediated protection from 2-hydroxyethyl methacrylate-induced apoptosis.}, journal = {Journal of endodontics}, volume = {34}, number = {10}, pages = {1191-1197}, doi = {10.1016/j.joen.2008.06.011}, pmid = {18793918}, issn = {1878-3554}, support = {R01-10331//PHS HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Caspase Inhibitors ; Cell Line, Tumor ; Cell Survival/drug effects ; Cells, Cultured ; Dental Materials/*toxicity ; Dental Pulp/drug effects/pathology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/*pharmacology ; Humans ; Jurkat Cells ; Keratinocytes/drug effects ; Male ; Materials Testing ; Membrane Potential, Mitochondrial/drug effects ; Methacrylates/*toxicity ; Osteoblasts/drug effects ; Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Stromal Cells/drug effects ; Time Factors ; }, abstract = {Resin-based materials are now commonly used in dentistry in restorative materials as well as in endodontic sealers. These materials have been shown to be cytotoxic. The mechanisms by which resin-based materials mediate their adverse effects have not been completely elucidated. Here we show that 2-hydroxyethyl methacrylate (HEMA) induces apoptotic cell death in oral keratinocytes and immune cells through the intrinsic cell death pathway. Functional loss and cell death induced by HEMA was significantly inhibited in the presence of N-acetyl cysteine (NAC) treatment. In addition, HEMA induced a decrease in mitochondrial membrane potential, and an increase in cleaved caspases was potently inhibited in the presence of NAC treatment. Overall, the results reported in this article indicate that NAC is an effective chemoprotectant that can safely be used to protect the pulp and the surrounding tissues from adverse effects of dental restorative and endodontic materials.}, }
@article {pmid18793617, year = {2008}, author = {Simerabet, M and Robin, E and Aristi, I and Adamczyk, S and Tavernier, B and Vallet, B and Bordet, R and Lebuffe, G}, title = {Preconditioning by an in situ administration of hydrogen peroxide: involvement of reactive oxygen species and mitochondrial ATP-dependent potassium channel in a cerebral ischemia-reperfusion model.}, journal = {Brain research}, volume = {1240}, number = {}, pages = {177-184}, doi = {10.1016/j.brainres.2008.08.070}, pmid = {18793617}, issn = {1872-6240}, mesh = {Animals ; Hydrogen Peroxide/*administration &amp; dosage ; Hypoxia-Ischemia, Brain/complications/*drug therapy/pathology ; Injections, Intraventricular ; Ischemic Preconditioning/methods ; Male ; Oxidants/*administration &amp; dosage ; Potassium Channels/drug effects/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/etiology/*prevention &amp; control ; }, abstract = {Reactive oxygen species (ROS) and the mitochondrial ATP-dependent potassium channel (mitoK(+)(-)(ATP)) play a major role in myocardial preconditioning. The same pathways seem to be involved in cerebral preconditioning. The aim of this study was to evaluate ROS involvement during the initial phase of delayed preconditioning and its relationship with mitoK(+)(-ATP) opening in a rat model of cerebral ischemia-reperfusion. Ischemia was induced by a 1-h occlusion of middle cerebral artery followed by a 24-h reperfusion period. A delayed preconditioning was induced by a 3-min ischemia (IPC), an in situ infusion of hydrogen peroxide (H(2)O(2)), or an administration of mitoK(+)(-ATP) agonist diazoxide, 72 h before the ischemia-reperfusion (I/R). IPC was performed in the presence or not of N-acetyl-cysteine (NAC) or 5-hydroxydecanoate (5-HD). A neuroprotection was induced by IPC and administration of H(2)O(2) or diazoxide. The decrease in infarct size was respectively 24.5%, 45.7% and 24.6%. IPC was abolished by 5-HD and NAC, indicating that mitoK(+)(-ATP) and ROS are involved. The protection induced by H(2)O(2) was blocked by 5-HD and diazoxide triggering was abolished by NAC. This strong relationship between ROS and mitoK(+)(-ATP) needs to be clarified as ROS might be involved both upstream and downstream of mitoK(+)(-ATP) opening.}, }
@article {pmid18791325, year = {2009}, author = {Hung, KY and Liu, SY and Kao, SH and Huang, JW and Chiang, CK and Tsai, TJ}, title = {N-acetylcysteine-mediated antioxidation prevents hyperglycemia-induced apoptosis and collagen synthesis in rat mesangial cells.}, journal = {American journal of nephrology}, volume = {29}, number = {3}, pages = {192-202}, doi = {10.1159/000155657}, pmid = {18791325}, issn = {1421-9670}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Adenosine Triphosphate/biosynthesis ; Animals ; Apoptosis/*drug effects ; Caspases/metabolism ; Cells, Cultured ; Collagen/*biosynthesis ; Cytochromes c/metabolism ; Enzyme Activation/drug effects ; Extracellular Matrix/drug effects ; Free Radical Scavengers/*pharmacology/therapeutic use ; Gene Expression/drug effects ; Hyperglycemia/*drug therapy ; Malondialdehyde/metabolism ; Mesangial Cells/*drug effects/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Transforming Growth Factor beta1/biosynthesis ; }, abstract = {BACKGROUND/AIMS: High-glucose (HG)-induced mesangial apoptosis and fibrogenesis possibly involves reactive oxygen species (ROS) formation and activated mitochondrial stress. We investigated the therapeutic effect of the antioxidant N-acetylcysteine (NAC) on cellular apoptosis and matrix accumulation in HG-treated rat mesangial cells (RMCs).<br><br>METHODS: RMCs were cultured in media containing 5 (control) or 35 mM (HG) glucose. Cellular apoptosis was assayed by TdT-mediated dUTP nick-end labeling staining. Collagen and transforming growth factor-1 gene expression were measured by reverse transcriptase-polymerase chain reaction or Northern blotting. Mitochondrial capacity and intracellular ROS generation was assayed by fluorescence microscopy and flow cytometry, respectively. Cellular ATP production and malondialdehyde (MDA) formation were determined by a luciferin-luciferase reaction and high-performance liquid chromatography, respectively. Cytochrome c release, caspase activation and poly(ADP)ribose polymerase cleavage were assayed by Western blotting.<br><br>RESULTS: HG-treated RMCs displayed enhanced cellular apoptosis (65%) and collagen gene expression (1.8-fold increase); these reactions could be significantly suppressed by 1 mM NAC (p < 0.05). Intracellular ROS generation, production of ATP and MDA, and caspase-3, -8 and -9 activities were significantly increased in HG-treated RMCs, and were effectively attenuated by addition of NAC.<br><br>CONCLUSION: It is concluded that NAC prevents HG-induced mesangial apoptosis and fibrogenesis pathways by the reduction of oxidative stress.}, }
@article {pmid18788931, year = {2008}, author = {Kim, HK and Kim, YJ and Kim, JT and Kwon, CH and Kim, YK and Bae, YC and Kim, DH and Jung, JS}, title = {Alterations in the proangiogenic functions of adipose tissue-derived stromal cells isolated from diabetic rats.}, journal = {Stem cells and development}, volume = {17}, number = {4}, pages = {669-680}, doi = {10.1089/scd.2007.0141}, pmid = {18788931}, issn = {1557-8534}, mesh = {Acetylcysteine/pharmacology ; Adipose Tissue/pathology/*physiopathology ; Animals ; Catalase/pharmacology ; *Cell Proliferation/drug effects ; Diabetes Mellitus, Experimental/metabolism/pathology/*physiopathology ; Free Radical Scavengers/pharmacology ; Glucose/pharmacology ; Hindlimb/blood supply/metabolism/pathology/physiopathology ; Humans ; Ischemia/metabolism/pathology/physiopathology ; Male ; Mice ; Mice, Nude ; *Neovascularization, Physiologic/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Stromal Cells/pathology/transplantation ; Time Factors ; }, abstract = {Cardiovascular complications in diabetic patients have been reported to be related to the impaired proangiogenic actions of endothelial progenitor cells. In this study, we investigated the functions of adipose tissue-derived stromal cells (ASCs) in diabetes. We induced type I diabetes in rats by a intraperitoneal injection of 60 mg/kg of streptozotocin (STZ) and type II diabetes by the combined treatment of high fat diet and 45 mg/kg of STZ. Rat ASCs (rASCs) isolated from the adipose tissues in the interscapular and abdominal region of type I or type II diabetic rats showed lower proliferating ability than those of control rats. Diabetic rASCs showed lower blood flow recovery than those of control rats in a hindlimb ischemia model of nude mouse. When ASCs isolated from rat and human were exposed to high glucose concentrations, their proliferating abilities and improved blood flow in a hindlimb ischemia model were compromised, compared with ASCs that were maintained at control glucose concentrations. However, the same concentrations of mannitol did not affect these characteristics. Exposure of human ASCs (hASCs) to high glucose concentrations increased reactive oxygen species (ROS) production, and the addition of ROS scavengers [N-acetylcysteine (NAC) or catalase] to high glucose media partially decreased the high glucose-induced inhibitory effect on proliferating ability in hASCs. However, hASCs treated with high glucose medium for 6 days showed lower proliferation in control culture medium, which was not recovered by the addition of NAC or catalase. These data indicate that ASCs isolated from diabetic rats and exposed at high concentration of glucose have an impaired proangiogenic action and that the functional impairment is partly due to ROS generated by chronic exposure to high glucose concentrations.}, }
@article {pmid18788755, year = {2008}, author = {Madsen, KG and Grönberg, G and Skonberg, C and Jurva, U and Hansen, SH and Olsen, J}, title = {Electrochemical oxidation of troglitazone: identification and characterization of the major reactive metabolite in liver microsomes.}, journal = {Chemical research in toxicology}, volume = {21}, number = {10}, pages = {2035-2041}, doi = {10.1021/tx8002214}, pmid = {18788755}, issn = {1520-5010}, mesh = {Acetylcysteine/chemistry ; Animals ; Chromans/*chemistry/*metabolism ; Electrochemistry ; Humans ; Magnetic Resonance Spectroscopy ; Microsomes, Liver/*metabolism ; Molecular Structure ; Oxidation-Reduction ; Pioglitazone ; Rats ; Rosiglitazone ; Thiazolidinediones/*chemistry/*metabolism ; Troglitazone ; }, abstract = {Troglitazone (TGZ) was developed for the treatment of type 2 diabetes but was withdrawn from the market due to hepatotoxicity. The formation of reactive metabolites has been associated with the observed hepatotoxicity. Such reactive metabolites have been proposed to be formed via three different mechanisms. One of the proposed mechanisms involves the oxidation of the chromane moiety of TGZ to a reactive o-quinone methide. The two other mechanisms involve metabolic activation of the thiazolidinedione moiety of TGZ. In the present study, it is shown that electrochemical oxidations can be used to generate a reactive metabolite of TGZ, which can be trapped by GSH or N-acetylcysteine. From incubations of TGZ with rat and human liver microsomes in the presence of either GSH or N-acetylcysteine, it was shown that similar conjugates were formed in vitro as formed from electrochemical oxidations of TGZ. One- and two-dimensional NMR studies of the troglitazone- S-(N-acetyl)cysteine conjugate revealed that N-acetylcysteine was attached to a benzylic carbon in the chromane moiety, showing that the conjugate was formed via a reaction between the o-quinone methide of TGZ and N-acetylcysteine. From electrochemical oxidations of rosiglitazone, pioglitazone, and ciglitazone in the presence of GSH, no GSH conjugates could be identified. These three compounds all contain a thiazolidinedione moiety. In conclusion, it has been shown that the primary reactive metabolite of TGZ formed from electrochemical oxidation was the o-quinone methide, and this metabolite was similar to what was observed to be the primary reaction product in human and rat liver microsomes.}, }
@article {pmid18784907, year = {2008}, author = {Preziosi, P and Di Primio, M and Erdembileg, T and Mancino, R and D'Este, G and Cerulli, L and Simonetti, G}, title = {Treatment of lacrimal stenoses obstructions with interventional radiology: immediate and 5-year follow-up results.}, journal = {La Radiologia medica}, volume = {113}, number = {8}, pages = {1211-1218}, pmid = {18784907}, issn = {0033-8362}, mesh = {Adult ; Aged ; Aged, 80 and over ; *Dacryocystorhinostomy ; Female ; Follow-Up Studies ; Humans ; Lacrimal Duct Obstruction/*diagnostic imaging ; Male ; Middle Aged ; *Nasolacrimal Duct ; *Radiography, Interventional ; *Stents ; Time Factors ; Young Adult ; }, abstract = {PURPOSE: This study was undertaken to evaluate the effectiveness of the Song stent in patients with nasolacrimal duct obstruction.<br><br>MATERIALS AND METHODS: Between 2003 and 2007, we treated 76 consecutive nasolacrimal obstructions in 73 patients (mean age 56 years; range 19-81) with implantation of polyurethane stents. Indications were epiphora in 46 patients, dacryocystitis in 18 and recurrent conjunctivitis in three. Average follow-up was 1 year (3 months to 5 years).<br><br>RESULTS: Technical success was achieved in 73 procedures (96%). Complications included pain in three cases, eyelid inflammation in four cases and severe bleeding in one case. Postprocedural mucocele was observed in five patients. Mean time without symptoms was 31 weeks. There were 24 cases of stent obstruction: 15 were treated with high-pressure 5% N-acetyl-cysteine and saline flush, achieving resolution in two cases; in three cases, attempts to recanalise the obstruction with a guidewire failed. The occluded stents were rsemoved in 22 patients: seven remained asymptomatic, 15 had recurrence of epiphora, nine received a new stent after dacryocystography and six underwent dacryocystorhinostomy.<br><br>CONCLUSIONS: Advantages of the procedure include the lack of anatomical alterations to the lacrimal ducts and a low short-term complication rate, whereas limitations include restricted duration of stent patency. The pathophysiological causes of stent obstruction should be clarified in order to relate them to stent morphology.}, }
@article {pmid18784309, year = {2008}, author = {Nicolakakis, N and Aboulkassim, T and Ongali, B and Lecrux, C and Fernandes, P and Rosa-Neto, P and Tong, XK and Hamel, E}, title = {Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {28}, number = {37}, pages = {9287-9296}, pmid = {18784309}, issn = {1529-2401}, mesh = {Acetylcholine/metabolism ; Acetylcysteine/*therapeutic use ; *Aging ; Alzheimer Disease/complications/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Animals ; Antioxidants/*therapeutic use ; Behavior, Animal/drug effects ; Cerebrovascular Disorders/*drug therapy/etiology/genetics ; Disease Models, Animal ; Gene Expression Regulation/drug effects ; Humans ; Hypoglycemic Agents/*therapeutic use ; Memory/drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation/genetics ; Nerve Tissue Proteins/metabolism ; Nitric Oxide Synthase/metabolism ; PPAR gamma/agonists ; Peptide Fragments/metabolism ; Pioglitazone ; Superoxide Dismutase/metabolism ; Thiazolidinediones/*therapeutic use ; }, abstract = {Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged (approximately 16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-beta (Abeta) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor gamma agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Abeta levels or Abeta plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.}, }
@article {pmid18782442, year = {2008}, author = {Vaillancourt, F and Fahmi, H and Shi, Q and Lavigne, P and Ranger, P and Fernandes, JC and Benderdour, M}, title = {4-Hydroxynonenal induces apoptosis in human osteoarthritic chondrocytes: the protective role of glutathione-S-transferase.}, journal = {Arthritis research &amp; therapy}, volume = {10}, number = {5}, pages = {R107}, pmid = {18782442}, issn = {1478-6362}, mesh = {Aged ; Aldehydes/*toxicity ; Apoptosis/physiology ; Blotting, Western ; Caspases/metabolism ; Cell Survival ; Chondrocytes/metabolism/*pathology ; Cysteine Proteinase Inhibitors/*toxicity ; Glutathione Transferase/*metabolism ; Humans ; Microscopy, Fluorescence ; Middle Aged ; Osteoarthritis/metabolism/*pathology ; Signal Transduction/physiology ; Transfection ; }, abstract = {INTRODUCTION: 4-Hydroxynonenal (HNE) is one of the most abundant and reactive aldehydes of lipid peroxidation products and exerts various effects on intracellular and extracellular signalling cascades. We have previously shown that HNE at low concentrations could be considered as an important mediator of catabolic and inflammatory processes in osteoarthritis (OA). In the present study, we focused on characterizing the signalling cascade induced by high HNE concentration involved in cell death in human OA chondrocytes.<br><br>METHODS: Markers of apoptosis were quantified with commercial kits. Protein levels were evaluated by Western blotting. Glutathione (GSH) and ATP levels were measured with commercial kits. Glucose uptake was assessed by 2-deoxy-D-[3H]-glucose. The role of GSH-S-transferase A4-4 (GSTA4-4) in controlling HNE-induced chondrocyte apoptosis was investigated by chondrocyte transfection with small interfering RNA (siRNA) or with the expression vector of GSTA4-4.<br><br>RESULTS: Our data showed that HNE at concentrations of up to 10 microM did not alter cell viability but was cytotoxic at concentrations of greater than or equal to 20 microM. HNE-induced chondrocyte death exhibited several classical hallmarks of apoptosis, including caspase activation, cytochrome c and apoptosis-induced factor release from mitochondria, poly (ADP-ribose) polymerase cleavage, Bcl-2 downregulation, Bax upregulation, and DNA fragmentation. Our study of signalling pathways revealed that HNE suppressed pro-survival Akt kinase activity but, in contrast, induced Fas/CD95 and p53 expression in chondrocytes. All of these effects were inhibited by an antioxidant, N-acetyl-cysteine. Analysis of cellular energy and redox status showed that HNE induced ATP, NADPH, and GSH depletion and inhibited glucose uptake and citric acid cycle activity. GSTA4-4 ablation by the siRNA method augmented HNE cytotoxicity, but, conversely, its overexpression efficiently protected chondrocytes from HNE-induced cell death.<br><br>CONCLUSION: Our study provides novel insights into the potential mechanisms of cell death in OA cartilage and suggests the potential role of HNE in OA pathophysiology. GSTA4-4 expression is critically important for cellular defence against oxidative stress-induced cell death in OA cartilage, possibly by HNE elimination.}, }
@article {pmid18781062, year = {2009}, author = {Efrati, S and Berman, S and Ilgiyeav, I and Siman-Tov, Y and Averbukh, Z and Weissgarten, J}, title = {Differential effects of N-acetylcysteine, theophylline or bicarbonate on contrast-induced rat renal vasoconstriction.}, journal = {American journal of nephrology}, volume = {29}, number = {3}, pages = {181-191}, doi = {10.1159/000154471}, pmid = {18781062}, issn = {1421-9670}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Contrast Media/adverse effects ; Dinoprostone/biosynthesis ; Free Radical Scavengers/pharmacology/therapeutic use ; Hypoxia/drug therapy/metabolism ; Iothalamic Acid/adverse effects/analogs &amp; derivatives ; Isoprostanes/biosynthesis ; Kidney/blood supply/*drug effects/metabolism ; Microcirculation/drug effects ; Nitric Oxide/metabolism ; Rats ; Rats, Sprague-Dawley ; Renal Insufficiency/chemically induced/*drug therapy/metabolism ; Sodium Bicarbonate/*pharmacology/therapeutic use ; Theophylline/*pharmacology/therapeutic use ; Vasoconstriction/*drug effects ; Vasodilator Agents/pharmacology/therapeutic use ; }, abstract = {BACKGROUND: Vasoconstriction and reactive oxygen species (ROS) accumulation following contrast media (CM) injection are the key factors triggering CM-induced nephropathy. We compared the effects of N-acetylcysteine (NAC), theophylline or sodium bicarbonate on intrarenal vasoconstriction and ROS generation in a rat model of CM-induced nephropathy.<br><br>METHODS: Following a 3-day dehydration, Sprague-Dawley rats received CM (Telebrix) or sham 'CM' injection of 0.9% saline. Part of them received NAC, theophylline or bicarbonate prior to CM. Medullar renal blood flow was estimated by laser Doppler. The animals were sacrificed 1, 15 or 30 min after the respective treatments, their kidneys allocated and intrarenal STAT-8 isoprostane, PGE(2) and NO assessed.<br><br>RESULTS: Vasoconstriction was significantly attenuated by NAC. Theophylline only mildly attenuated the perfusion drop at 15 min, and was ineffective following 30 min. Unlike theophylline or bicarbonate, NAC significantly augmented intrarenal PGE(2). NAC, theophylline but not bicarbonate, gradually increased intrarenal NO. In all experimental variables, CM-induced ROS accumulation, represented by STAT-8 isoprostane estimation, progressed undisturbed.<br><br>CONCLUSIONS: (1) CM-induced intrarenal vasoconstriction was efficiently prohibited by NAC but not bicarbonate or theophylline; (2) the vasodilatory effect of NAC was mediated via increased PGE(2) synthesis, and (3) ROS accumulation was a primary renal response to CM-induced injury, not affected by any pharmacologic manipulations.}, }
@article {pmid18771720, year = {2008}, author = {Mittal, R and Sharma, S and Chhibber, S and Harjai, K}, title = {Contribution of free radicals to Pseudomonas aeruginosa induced acute pyelonephritis.}, journal = {Microbial pathogenesis}, volume = {45}, number = {5-6}, pages = {323-330}, doi = {10.1016/j.micpath.2008.08.003}, pmid = {18771720}, issn = {0882-4010}, mesh = {Acute Disease ; Animals ; Biofilms ; Female ; Free Radicals/*immunology ; Humans ; Kidney/immunology/microbiology ; Malondialdehyde/immunology ; Mice ; Neutrophil Infiltration ; Oxidative Stress ; Pseudomonas Infections/*immunology/microbiology ; Pseudomonas aeruginosa/*immunology/pathogenicity/physiology ; Pyelonephritis/immunology/*microbiology ; Reactive Nitrogen Species/immunology ; Urinary Bladder/immunology/microbiology ; }, abstract = {Pyelonephritis induces an inflammatory process in the renal parenchyma, which may occur as a result of excessive reactive nitrogen intermediates (RNI) and reactive oxygen species (ROS) and/or impaired antioxidant capacity. In the present investigation, contribution of free radicals to the development of acute pyelonephritis induced by planktonic and biofilm cells of Pseudomonas aeruginosa was studied. Increase in production of RNI and ROS in urine, bladder and renal tissue following infection with P. aeruginosa was observed which correlated with bacterial load, neutrophil recruitment and malondialdehyde (MDA). Evaluation of the data revealed that excessive production of free radicals causes tissue damage leading to bacterial persistence in host's tissues. Treatment of mice with N-acetylcysteine (NAC), a potent antioxidant, lead to significant amelioration of oxidative stress and subsequent decrease in bacterial titer, neutrophil influx, MDA as well as tissue pathology highlighting important role of free radicals in P. aeruginosa induced pyelonephritis. Results of the present study bring out that production of RNI and ROS contributes to the pathophysiology of pyelonephritis. These findings may be relevant for the better understanding of host-parasite interactions and may be of clinical importance in the development of preventive intervention against P. aeruginosa induced pyelonephritis.}, }
@article {pmid18768219, year = {2008}, author = {Zhang, J and Skardal, A and Prestwich, GD}, title = {Engineered extracellular matrices with cleavable crosslinkers for cell expansion and easy cell recovery.}, journal = {Biomaterials}, volume = {29}, number = {34}, pages = {4521-4531}, pmid = {18768219}, issn = {1878-5905}, support = {R01 DC004336/DC/NIDCD NIH HHS/United States ; R01 DC004336-09/DC/NIDCD NIH HHS/United States ; R01 DC004336-10/DC/NIDCD NIH HHS/United States ; 2 R01 DC04336/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Biocompatible Materials/*chemical synthesis/chemistry ; Cell Culture Techniques/*methods ; Cell Line ; Cell Proliferation ; Cell Survival ; *Cross-Linking Reagents ; Extracellular Matrix/*chemistry/*metabolism ; Fibroblasts/cytology ; Hepatocytes/cytology ; Humans ; Hydrogels/chemical synthesis/chemistry ; Mesenchymal Stem Cells/cytology ; Mice ; Polymers/chemical synthesis ; }, abstract = {An unmet need for expansion of primary cells and progenitor cells in three dimensions (3-D) is a synthetic mimic of the extracellular matrix (ECM) with user-controllable composition that would permit rapid recovery of viable cells under mild, non-enzymatic conditions. Three block copolymers based on disulfide-containing polyethylene glycol diacrylate crosslinkers were synthesized, and were used to crosslink thiol-modified hyaluronan and gelatin macromonomers in the presence of cells. The triblock PEGSSDA contained a single disulfide-containing block, the pentablock PEG(SS)(2)DA contained two disulfide blocks, and the heptablock PEG(SS)(3)DA contained three disulfide blocks. For each hydrogel composition, four cell types were encapsulated in 3-D, and growth and proliferation were evaluated. Murine NIH 3T3 fibroblasts, human HepG2 C3A hepatocytes, human bone marrow-derived mesenchymal stem cells (MSCs), and human umbilical vein endothelial cells (HUVECs) all showed excellent viability and growth during expansion in 3-D in the three disulfide block copolymer crosslinkers. After cell expansion, the hydrogels were dissociated using the thiol-disulfide exchange reaction in the presence of N-acetyl-cysteine or glutathione, which dissolved the hydrogel network. After dissolution, cells were recovered in high yield and with high viability by gentle centrifugation.}, }
@article {pmid18762247, year = {2008}, author = {Thayyullathil, F and Chathoth, S and Hago, A and Patel, M and Galadari, S}, title = {Rapid reactive oxygen species (ROS) generation induced by curcumin leads to caspase-dependent and -independent apoptosis in L929 cells.}, journal = {Free radical biology &amp; medicine}, volume = {45}, number = {10}, pages = {1403-1412}, doi = {10.1016/j.freeradbiomed.2008.08.014}, pmid = {18762247}, issn = {0891-5849}, mesh = {Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/*metabolism ; Caspase Inhibitors ; Cell Cycle Proteins/biosynthesis/drug effects ; Cell Line ; Cell Survival/drug effects ; Curcumin/*pharmacology ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cytochromes c/drug effects/metabolism ; Dose-Response Relationship, Drug ; Mice ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; Time Factors ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {Evidence that curcumin may have anticancer activities has renewed interest in its potential to prevent and treat disease. In this study, we show that curcumin-mediated rapid generation of reactive oxygen species (ROS) leads to apoptosis by modulating different apoptotic pathways in mouse fibroblast L929 cells. We show for the first time that curcumin-induced rapid ROS generation causes the release of apoptosis inducing factor (AIF) from the mitochondria to the cytosol and nucleus, hence, leading to caspase 3-independent apoptosis. However, our studies also show that curcumin induces the release of cytochrome c from mitochondria, causing activation of caspase 3, and concomitant PARP cleavage, which is the hallmark of caspase-dependent apoptosis. Furthermore, curcumin-induced ROS generation leads to the induction of the proapoptotic protein p53 and its effector protein p21 and down-regulation of cell cycle regulatory proteins such as Rb and cyclin D1 and D3. Both glutathione (GSH) and N-acetylcysteine (NAC) pretreatment resulted in the complete inhibition of curcumin-induced ROS generation, AIF release from mitochondria, and caspase activation. Additionally, pretreatment of L929 cells with these antioxidants completely blocked the induction of p53-dependent p21 accumulation. In conclusion, our data show that in addition to caspase 3 activation, curcumin-induced rapid ROS generation leads to AIF release, and the activation of the caspase-independent apoptotic pathway.}, }
@article {pmid18759864, year = {2008}, author = {Li, L and Gao, PJ and Xi, R and Wu, CF and Zhu, DL and Yan, J and Lu, GP}, title = {Pioglitazone inhibits homocysteine-induced migration of vascular smooth muscle cells through a peroxisome proliferator-activated receptor gamma-independent mechanism.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {35}, number = {12}, pages = {1471-1476}, doi = {10.1111/j.1440-1681.2008.05025.x}, pmid = {18759864}, issn = {1440-1681}, mesh = {Animals ; Cell Movement/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Homocysteine/*antagonists &amp; inhibitors/*pharmacology ; Male ; Muscle, Smooth, Vascular/*drug effects/physiology ; Myocytes, Smooth Muscle/*drug effects/physiology ; PPAR gamma/*physiology ; Pioglitazone ; Rats ; Rats, Sprague-Dawley ; Thiazolidinediones/*pharmacology ; }, abstract = {1. Peroxisome proliferator-activated receptor (PPAR)-gamma agonists have been demonstrated to exert protective effects against homocysteine (Hcy)-induced pathogenesis. However, the effects of PPAR-gamma agonists on Hcy-induced migration are unknown. In the present study, we examined the effect of pioglitazone on the migration of vascular smooth muscle cells (VSMC) induced by Hcy and the possible mechanism involved. 2. Vascular smooth muscle cells were isolated from the thoracic aortas of male Sprague-Dawley rats. The migration of VSMC was examined using a transwell technique. The generation of intracellular reactive oxygen species (ROS) was measured using the ROS-sensitive fluoroprobe 2',7'-dichlorodihydrofluorescein diacetate. The activity of NAD(P)H oxidase was assessed by lucigenin enhanced chemiluminescence. Activation of p38 mitogen-activated protein kinase (MAPK) was determined by western blotting. 3. The results showed that pioglitazone dose-dependently inhibited the migration of VSMC induced by Hcy. This was not reversed by the PPAR-gamma antagonist GW9662. In addition, pretreatment with the NAD(P)H oxidase inhibitor diphenylene iodonium (DPI), the free radical scavenger N-acetylcysteine and the p38 MAPK inhibitor SB202190 blocked Hcy-induced VSMC migration. Furthermore, we observed that pioglitazone suppressed Hcy-induced intracellular ROS production; similar effects were observed with DPI and NAC. Pioglitazone attenuated Hcy-induced activation of NAD(P)H oxidase. Moreover, pioglitazone blocked Hcy-induced p38 MAPK phosphorylation; similar effects were observed for DPI, NAC and SB202190. 4. The data demonstrate that pioglitazone inhibits Hcy-induced VSMC migration that is independent of PPAR-gamma. Furthermore, part of the biological effect of pioglitazone involves a decrease in the levels of NAD(P)H oxidase derived-ROS and p38 MAPK activation.}, }
@article {pmid18759863, year = {2008}, author = {Heili Frades, S and Del Puerto-Nevado, L and Pérez-Rial, S and Martin-Mosquero, C and Ortega,  and Martinez-Galán, L and Rubio, ML and Rodriguez Nieto, MJ and González-Mangado, N and Peces-Barba Romero, G}, title = {Improving the cadmium-induced centriacinar emphysema model in rats by concomitant anti-oxidant treatment.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {35}, number = {11}, pages = {1337-1342}, doi = {10.1111/j.1440-1681.2008.05026.x}, pmid = {18759863}, issn = {1440-1681}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antioxidants/*therapeutic use ; Cadmium Chloride/*toxicity ; *Disease Models, Animal ; Lung Compliance/drug effects/physiology ; Male ; Pulmonary Emphysema/*chemically induced/*drug therapy/pathology ; Rats ; Rats, Wistar ; }, abstract = {1. The aim of the present study was to perform an evolutionary analysis of the morphometrical, biochemical and functional parameters of centriacinar emphysema induced by cadmium chloride (CdCl2) in rats and to determine the effects of concomitant N-acetylcysteine (NAC) administration. 2. Male Wistar rats were instilled orotracheally with either CdCl2 (n = 24) or saline (n = 24). One group of rats, consisting of both CdCl2- and saline-treated rats, was fed a normal diet (n = 24), whereas the other group received NAC (n = 24). 3. Changes in inspiratory capacity (IC), lung compliance (CL), expiratory flow at 75% (F75), forced vital capacity (FVC) and hydroxyproline content were assessed 2, 8, 21 and 45 days after instillation. Polymorphonuclear cells were evaluated 2 and 8 days after instillation and the mean linear intercept (Lm) was determined at 21 and 45 days. 4. Over time, CdCl2 instillation causes several changes that are bound up with centriacinar emphysema. The concomitant administration of NAC to CdCl2-treated rats partially reversed Lm at 21 days compared with CdCl2 alone (115 +/- 2 vs 127 +/- 2, respectively; P < 0.05). However, 45 days after instillation, NAC improved lung function in CdCl2-treated rats compared with that in the saline-treated control group (IC 14.64 vs 15.25, respectively (P = 0.054); FVC 16.94 vs 16.28, respectively (P = 0.052), F75 31.41 vs 32.48, respectively (P = 0.062)). In addition, 45 days after instillation, NAC reduced lung collagen content in both the saline-treated control (100 vs 81% alone and in the presence of NAC, respectively) and CdCL2-treated groups (213 vs 161% alone and in the presence of NAC, respectively). In addition, although the results were not significant, NAC tended to reduce Lm and enhance CL in NAC + CdCl2-treated rats. 5. In conclusion, NAC partially improved emphysematous changes and reduced collagen deposition, which diminished the CdCl2-induced fibrotic component of centriacinar emphysema.}, }
@article {pmid18758148, year = {2008}, author = {Kamiyama, N and Ogawa, R and Hamada, H and Ohno, T and Asano, R and Umemura, J and Yoshida, H}, title = {Preventive effect of N-acetylcysteine on contrast-induced nephropathy following coronary angiography and angioplasty.}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {128}, number = {9}, pages = {1333-1339}, doi = {10.1248/yakushi.128.1333}, pmid = {18758148}, issn = {0031-6903}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Angioplasty ; Biomarkers/blood ; Contrast Media/*adverse effects ; Coronary Angiography ; Creatinine/blood ; Dose-Response Relationship, Drug ; Female ; Humans ; Kidney Diseases/*chemically induced/diagnosis/*prevention &amp; control ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {Contrast-induced nephropathy (CIN) is one of the serious side effects of contrast media. A few studies have suggested that N-acetylcysteine (NAC) is effective to prevent CIN, but the efficacy remains unclear in Japanese. Therefore, we retrospectively studied the preventive effect of NAC on CIN in Sakakibara Heart Institute. Patients who had been administered NAC for the purpose of preventing CIN before coronary intervention between February 2005 and November 2006 were included in the NAC group. In addition, age- and rate of diabetes mellitus-matched controls were randomly extracted. We retrieved and analyzed patient data including demographics, NAC dosage, and serum creatinine concentrations (Scr). NAC group (n=16) showed significantly higher baseline Scr (p<0.01) and a tendency toward a lower dose of contrast media (p=0.068) compared with controls (n=48). Since the occurrence of CIN was low, there was no significant difference in the proportion of CIN between the groups (NAC: 6%, controls: 4%). NAC group trended toward a decrease in Scr after the use of contrast media, while controls increased (-0.04+/-0.25 versus +0.03+/-0.36 mg/dl, p=0.096). The multivariate analysis showed that the dosage of NAC is inversely correlated with Scr independent of baseline Scr and dosage of contrast media. Despite higher baseline Scr (i.e., high-risk with CIN) in the NAC group, the real Scr value reflected a lower trend on average. In addition, this finding suggests that a larger dose of NAC results in a lower Scr value, we consider that the NAC dosage more likely prevented CIN.}, }
@article {pmid18755987, year = {2008}, author = {O'Brien, JJ and Spinelli, SL and Tober, J and Blumberg, N and Francis, CW and Taubman, MB and Palis, J and Seweryniak, KE and Gertz, JM and Phipps, RP}, title = {15-deoxy-delta12,14-PGJ2 enhances platelet production from megakaryocytes.}, journal = {Blood}, volume = {112}, number = {10}, pages = {4051-4060}, pmid = {18755987}, issn = {1528-0020}, support = {R21 HL086367/HL/NHLBI NIH HHS/United States ; HL086367/HL/NHLBI NIH HHS/United States ; P30 ES001247/ES/NIEHS NIH HHS/United States ; R01 DE011390/DE/NIDCR NIH HHS/United States ; R01 HL078603/HL/NHLBI NIH HHS/United States ; HL078603/HL/NHLBI NIH HHS/United States ; T32ES07026/ES/NIEHS NIH HHS/United States ; T32 ES007026/ES/NIEHS NIH HHS/United States ; DK09361/DK/NIDDK NIH HHS/United States ; EY017123/EY/NEI NIH HHS/United States ; DE011390/DE/NIDCR NIH HHS/United States ; R01 EY017123/EY/NEI NIH HHS/United States ; ES01247/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Antioxidants/pharmacology ; Blood Platelets/*metabolism ; Bone Marrow/metabolism ; Cell Line ; Female ; Glutathione/analogs &amp; derivatives/pharmacology ; Humans ; Male ; Megakaryocytes/*metabolism ; Mice ; PPAR gamma/metabolism ; Platelet Transfusion ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology/therapeutic use ; Radiation Injuries, Experimental/metabolism/therapy ; Reactive Oxygen Species/metabolism ; Thrombocytopenia/*metabolism/therapy ; }, abstract = {Thrombocytopenia is a critical problem that occurs in many hematologic diseases, as well as after cancer therapy and radiation exposure. Platelet transfusion is the most commonly used therapy but has limitations of alloimmunization, availability, and expense. Thus, the development of safe, small, molecules to enhance platelet production would be advantageous for the treatment of thrombocytopenia. Herein, we report that an important lipid mediator and a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand called 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), increases Meg-01 maturation and platelet production. 15d-PGJ(2) also promotes platelet formation from culture-derived mouse and human megakaryocytes and accelerates platelet recovery after in vivo radiation-induced bone marrow injury. Interestingly, the platelet-enhancing effects of 15d-PGJ(2) in Meg-01 cells are independent of PPARgamma, but dependent on reactive oxygen species (ROS) accumulation; treatment with antioxidants such as glutathione ethyl ester (GSH-EE); or N-acetylcysteine (NAC) attenuate 15d-PGJ(2)-induced platelet production. Collectively, these data support the concept that megakaryocyte redox status plays an important role in platelet generation and that small electrophilic molecules may have clinical efficacy for improving platelet numbers in thrombocytopenic patients.}, }
@article {pmid18755394, year = {2008}, author = {Cao, J and Jiang, L and Zhang, X and Yao, X and Geng, C and Xue, X and Zhong, L}, title = {Boric acid inhibits LPS-induced TNF-alpha formation through a thiol-dependent mechanism in THP-1 cells.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {22}, number = {3}, pages = {189-195}, doi = {10.1016/j.jtemb.2008.03.005}, pmid = {18755394}, issn = {0946-672X}, mesh = {Acetylcysteine/pharmacology ; Boric Acids/*pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Gene Expression Regulation/drug effects ; Glutathione/metabolism ; Humans ; Lipopolysaccharides/*pharmacology ; Monocytes/drug effects/metabolism ; RNA, Messenger/genetics ; Sulfhydryl Compounds/*metabolism ; Tumor Necrosis Factor-alpha/*biosynthesis/genetics/metabolism ; }, abstract = {Oxidative stress plays an important role during inflammatory diseases and antioxidant administration to diminish oxidative stress may arrest inflammatory processes. Boron has been implicated to modulate certain inflammatory mediators and regulate inflammatory processes. Here we investigated the role of the tripeptide glutathione (GSH) in modulating the effects of boric acid (BA) on lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) formation in THP-1 monocytes. Interestingly, we found that BA had no significant effects on both TNF-alpha production and intracellular GSH contents, whereas it could inhibit LPS-induced TNF-alpha formation and ameliorated the d,l-buthionine-S,R-sulfoximine (BSO)-induced GSH depletion. Twenty-four hour incubation with BSO induced a decrease of the intracellular GSH and an increase of TNF-alpha. Treatment with N-acetyl-l-cysteine (NAC) did not significantly increase intracellular content of GSH but significantly reduced the secretion of TNF-alpha. BSO-pretreatment for 24h enhanced the LPS-induced secretion and mRNA expression of TNF-alpha further. BA inhibited LPS-stimulated TNF-alpha formation was also seen after GSH depletion by BSO. These results indicate that BA may have anti-inflammatory effect in the LPS-stimulated inflammation and the effect of BA on TNF-alpha secretion may be induced via a thiol-dependent mechanism.}, }
@article {pmid18729331, year = {2008}, author = {Sartori, A and Garay-Malpartida, HM and Forni, MF and Schumacher, RI and Dutra, F and Sogayar, MC and Bechara, EJ}, title = {Aminoacetone, a putative endogenous source of methylglyoxal, causes oxidative stress and death to insulin-producing RINm5f cells.}, journal = {Chemical research in toxicology}, volume = {21}, number = {9}, pages = {1841-1850}, doi = {10.1021/tx8001753}, pmid = {18729331}, issn = {1520-5010}, mesh = {Acetone/*analogs &amp; derivatives/chemistry/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase/pharmacology ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Copper/pharmacology ; Dose-Response Relationship, Drug ; Insulin/*metabolism ; Insulin Secretion ; Mice ; Molecular Structure ; NIH 3T3 Cells ; Oxidative Stress/*drug effects ; RNA, Messenger/metabolism ; Superoxide Dismutase/pharmacology ; Trioses/pharmacology ; }, abstract = {Aminoacetone (AA), triose phosphates, and acetone are putative endogenous sources of potentially cytotoxic and genotoxic methylglyoxal (MG), which has been reported to be augmented in the plasma of diabetic patients. In these patients, accumulation of MG derived from aminoacetone, a threonine and glycine catabolite, is inferred from the observed concomitant endothelial overexpression of circulating semicarbazide-sensitive amine oxidases. These copper-dependent enzymes catalyze the oxidation of primary amines, such as AA and methylamine, by molecular oxygen, to the corresponding aldehydes, NH4(+) ion and H2O2. We recently reported that AA aerobic oxidation to MG also takes place immediately upon addition of catalytic amounts of copper and iron ions. Taking into account that (i) MG and H2O2 are reportedly cytotoxic to insulin-producing cell lineages such as RINm5f and that (ii) the metal-catalyzed oxidation of AA is propagated by O2(*-) radical anion, we decided to investigate the possible pro-oxidant action of AA on these cells taken here as a reliable model system for pancreatic beta-cells. Indeed, we show that AA (0.10-5.0 mM) administration to RINm5f cultures induces cell death. Ferrous (50-300 microM) and Fe(3+) ion (100 microM) addition to the cell cultures had no effect, whereas Cu(2+) (5.0-100 microM) significantly increased cell death. Supplementation of the AA- and Cu(2+)-containing culture medium with antioxidants, such as catalase (5.0 microM), superoxide dismutase (SOD, 50 U/mL), and N-acetylcysteine (NAC, 5.0 mM) led to partial protection. mRNA expression of MnSOD, CuZnSOD, glutathione peroxidase, and glutathione reductase, but not of catalase, is higher in cells treated with AA (0.50-1.0 mM) plus Cu(2+) ions (10-50 microM) relative to control cultures. This may imply higher activity of antioxidant enzymes in RINm5f AA-treated cells. In addition, we have found that AA (0.50-1.0 mM) plus Cu(2+) (100 microM) (i) increase RINm5f cytosolic calcium; (ii) promote DNA fragmentation; and (iii) increase the pro-apoptotic (Bax)/antiapoptotic (Bcl-2) ratio at the level of mRNA expression. In conclusion, although both normal and pathological concentrations of AA are probably much lower than those used here, it is tempting to propose that excess AA in diabetic patients may drive oxidative damage and eventually the death of pancreatic beta-cells.}, }
@article {pmid18728404, year = {2008}, author = {Zou, Y and Niu, P and Yang, J and Yuan, J and Wu, T and Chen, X}, title = {The JNK signaling pathway is involved in sodium-selenite-induced apoptosis mediated by reactive oxygen in HepG2 cells.}, journal = {Cancer biology &amp; therapy}, volume = {7}, number = {5}, pages = {689-696}, doi = {10.4161/cbt.7.5.5688}, pmid = {18728404}, issn = {1555-8576}, mesh = {*Apoptosis ; Cell Line, Tumor ; Cell Survival ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; MAP Kinase Kinase 4/*metabolism ; MAP Kinase Signaling System ; Models, Biological ; Oxygen/metabolism ; *Reactive Oxygen Species ; Signal Transduction/drug effects ; Sodium Selenite/*pharmacology ; Time Factors ; }, abstract = {Selenium compounds as effective chemopreventive agents can induce apoptosis in tumor cells, and reactive oxygen species (ROS) are important mediators in apoptosis induced by various stimuli including chemopreventive agents. The major mitogen-activated protein kinases (MAPKs), c-JUN N-terminal kinase (JNK), p38 and extracelluar signal-regulated kinase (ERK) are three kinases that have been shown to regulate apoptosis. In this study, we showed that selenite-induced apoptosis in HepG2 cells was mediated by ROS that activated JNK to regulate apoptosis. The selenite-treated HepG2 cells showed a dose- and time-dependent decrease in cell viability that was coincident with increased the levels of the apoptosis rate. The levels of selenite-induced ROS as measured by 2', 7'-dichlorofluorescein diacetate (DCFH-DA) fluorescence also showed a dose- and time-dependent increase in HepG2 cells. The kinase activity of JNK was induced by selenite in a dose-dependent manner and HepG2 cells exposed to selenite (10 microM) for 4 h showed increased levels of phosphorylated JNK, which decreased when exposed for additional 4 h. In contrast, Sp600125, a specific inhibitor of JNK, remarkably blocked the apoptosis of HepG2 exposed to selenite. Furthermore, N-acetylcysteine (NAC), a known antioxidant, increased cell viability and decreased ROS generation. Moreover, NAC effectively blocked apoptosis and decreased the levels of phosphorylated JNK induced by selenite. These results revealed that JNK might be involved in selenite-induced ROS-mediated apoptosis in HepG2 cells.}, }
@article {pmid18725324, year = {2008}, author = {Piao, HZ and Choi, IY and Park, JS and Kim, HS and Cheong, JH and Son, KH and Jeon, SJ and Ko, KH and Kim, WK}, title = {Wogonin inhibits microglial cell migration via suppression of nuclear factor-kappa B activity.}, journal = {International immunopharmacology}, volume = {8}, number = {12}, pages = {1658-1662}, doi = {10.1016/j.intimp.2008.07.018}, pmid = {18725324}, issn = {1567-5769}, mesh = {Animals ; Cell Movement/drug effects ; Chemokine CCL2/antagonists &amp; inhibitors ; Chemokine CCL5/antagonists &amp; inhibitors ; Cyclic AMP/biosynthesis ; Drugs, Chinese Herbal/*pharmacology ; Flavanones/*pharmacology ; Microglia/*drug effects/physiology ; NF-kappa B/*antagonists &amp; inhibitors ; Rats ; Rats, Sprague-Dawley ; Scutellaria/*chemistry ; }, abstract = {Previously, we and others have demonstrated that wogonin, an active component from the root of Scutellaria baicalensis Georgi, has a neuroprotective effect in cerebral ischemic insult. The neuroprotective effect of wogonin may at least in part be due to its anti-inflammatory properties. Microglial cells, well-known residential macrophages in the central nervous system, migrate to the ischemic lesion and play a pivotal role in the development of chronic inflammation. In the present study, we observed that wogonin potently inhibited microglial migration toward a chemokine, monocyte chemoattractant protein-1 (MCP-1). The anti-migratory effect of wogonin was provoked at nanomolar concentrations, at which wogonin did not significantly inhibit the production of cytokines and chemokines. NF-kappaB has previously shown to regulate microglial cell migration, and activation of cAMP-signaling pathway has also been associated with inhibition of microglial cell motility. In the present study, wogonin at low micromolar concentrations completely suppressed the activity of NF-kappaB in MCP-1-stimulated microglia, and NF-kappaB inhibitors such as N-acetyl cysteine and pyrrolidinedithiocarbamate inhibited the MCP-1-induced migration of microglial cells. However, wogonin did not stimulate the production of cAMP in microglial cells. Our results indicate that the anti-inflammatory activity of wogonin is exerted at least in part by suppressing microglial cell motility via inhibition of NF-kappaB activity.}, }
@article {pmid18725210, year = {2008}, author = {Marreilha dos Santos, AP and Santos, D and Au, C and Milatovic, D and Aschner, M and Batoréu, MC}, title = {Antioxidants prevent the cytotoxicity of manganese in RBE4 cells.}, journal = {Brain research}, volume = {1236}, number = {}, pages = {200-205}, doi = {10.1016/j.brainres.2008.07.125}, pmid = {18725210}, issn = {0006-8993}, support = {NIEHS 10563//PHS HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Antioxidants/*pharmacology ; Cell Line, Transformed ; Cell Survival/drug effects ; Chlorides/*toxicity ; Chromans/*pharmacology ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Glutathione/metabolism ; L-Lactate Dehydrogenase/metabolism ; Manganese Compounds ; Rats ; Sulfates/*toxicity ; Tetrazolium Salts ; Thiazoles ; }, abstract = {Manganese (Mn) is an essential trace element required for ubiquitous enzymatic reactions. Chronic overexposure to this metal may, however, promote potent neurotoxic effects. The mechanism of Mn toxicity is not well established, but several studies indicate that oxidative stress and mitochondria play major roles in the Mn-induced neurodegenerative processes that lead to dysfunction in the basal ganglia. The aim of this study was to address the toxic effects of MnCl2 and MnSO4 on the immortalized rat brain microvessel endothelial cell line (RBE4) and to characterize toxic mechanism associated with exposure to Mn. The cytotoxicity of Mn in RBE4 cells was evaluated using the LDH and the MTT assays. A significant increase was noted in LDH release from RBE4 cells exposed for 24 h to MnCl2 at concentrations of 800 microM and MnSO4 at concentrations > or = 400 microM (p < 0.05) when compared with control unexposed cells. The MTT assay established significant decrease in cellular viability upon exposure to MnCl2 at concentrations > or = 100 microM and to MnSO4 at concentrations > or = 50 microM (p < 0.05). Thus, the cytotoxicity assays showed that the MTT assay was more sensitive than the LDH assay, suggesting that mitochondrial changes precede other toxic effects of Mn. In addition, upon exposure to MnCl2 (200 and 800 microM), intracellular reduced glutathione (GSH) levels in RBE4 cells decreased as Mn exposure concentrations increased (p < 0.05). To confirm the oxidative hypothesis of Mn cytotoxicity, co-exposure of MnCl2 with antioxidant agents (N-acetylcysteine [NAC] or Trolox) were carried out. The cellular viability was evaluated using the MTT assay. A significant decrease in Mn cytotoxicity was observed in co-exposed cells confirming that (1) oxidative stress plays a critical role in the mechanism of Mn toxicity, and (2) antioxidants may offer a useful therapeutic modality to reverse the aberrant effects of Mn.}, }
@article {pmid18721209, year = {2008}, author = {Tozawa, K and Yasui, T and Okada, A and Hirose, M and Hamamoto, S and Itoh, Y and Kohri, K}, title = {NF-kappaB activation in renal tubular epithelial cells by oxalate stimulation.}, journal = {International journal of urology : official journal of the Japanese Urological Association}, volume = {15}, number = {10}, pages = {924-928}, doi = {10.1111/j.1442-2042.2008.02131.x}, pmid = {18721209}, issn = {1442-2042}, mesh = {Acetylcysteine/pharmacology ; Cells, Cultured ; Epithelial Cells/*drug effects/*physiology ; Humans ; Kidney Tubules/*cytology/*physiology ; NF-kappa B/antagonists &amp; inhibitors/*drug effects/*physiology ; Osteopontin/*biosynthesis ; Oxalates/*pharmacology ; }, abstract = {OBJECTIVES: The transcription factor nuclear factor-kappaB (NF-kappaB) is involved in inflammatory and immune responses through the induction of various cytokines and growth factors. Recently, the coordinated action of NF-kappaB and activator protein-1 was reported in osteopontin (OPN) expression. In the present study, we demonstrated that oxalate induces OPN expression by activating NF-kappaB in renal tubular cells. Furthermore, we investigated the inhibitory effect of N-acetyl-L-cysteine (NAC) on NF-kappaB activation in the human renal tubular cell line.<br><br>METHODS: All of the experiments were carried out using human kidney-2 cells, which are human proximal tubular epithelial cells immortalized by transduction with the human papillomavirus 16E6/E7 gene. The time-dependent extraction of total protein was performed after the uptake of 0.5 mM oxalate by the cells. The NF-kappaB activation and OPN expression were examined by western blotting and immunocytochemistry.<br><br>RESULTS: As a result of oxalate stimulation, the amount of p65 subunit in the nucleus increased significantly (P < 0.05), and NAC significantly inhibited the translocation of p65 into the nucleus (P < 0.05).<br><br>CONCLUSION: These observations indicate that NAC can be used as a drug to prevent stone formation.}, }
@article {pmid18719315, year = {2008}, author = {Huang, J and Wu, L and Tashiro, S and Onodera, S and Ikejima, T}, title = {Reactive oxygen species mediate oridonin-induced HepG2 apoptosis through p53, MAPK, and mitochondrial signaling pathways.}, journal = {Journal of pharmacological sciences}, volume = {107}, number = {4}, pages = {370-379}, doi = {10.1254/jphs.08044fp}, pmid = {18719315}, issn = {1347-8613}, mesh = {Apoptosis/*drug effects ; Carcinoma, Hepatocellular/drug therapy/pathology ; Caspase 3/drug effects/metabolism ; Caspase 9/drug effects/metabolism ; Cell Line, Tumor ; Cytochromes c/drug effects/metabolism ; Diterpenes, Kaurane/*pharmacology ; Humans ; Isodon/chemistry ; Liver Neoplasms/drug therapy/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinases/drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tumor Suppressor Protein p53/drug effects/metabolism ; p38 Mitogen-Activated Protein Kinases/drug effects/metabolism ; }, abstract = {Oridonin, a diterpenoid isolated from Rabdosia rubescences, could induce apoptosis through the generation of reactive oxygen species (ROS) in human hepatoma HepG2 cells. p53, a specific inhibitor of pifithrin alpha (PFT alpha), markedly inhibited ROS generation and apoptosis, showing that p53 was responsible for the cytotoxity of oridonin through mediation by ROS. Moreover, the ROS activated the p38 kinase, which in turn promoted the activation of p53, as verified by evidence showing that the ROS scavenger N-acetyl-cysteine (NAC) not only blocked the phosphorylation of p38 but also partially inhibited the activation of p53, and the p38 inhibitor SB203580 reduced the activation of p53 as well. Mitochondria were either the sources or the targets of ROS. This study showed that oridonin stimulated mitochondrial transmembrane permeabilization in a ROS-dependent manner because NAC almost thoroughly reversed the drop of mitochondrial transmembrane potential (Deltapsim) and the release of cytochrome c from the mitochondrial inter-membrane space into cytosol. Furthermore, as a result of mitochondrial permeability transition, procaspases-9 and -3 were cleaved into 37- and 17-kDa proteolytic products, respectively, which acted as executors of oridonin-induced apoptosis.}, }
@article {pmid18718574, year = {2008}, author = {Hashimoto, K}, title = {Regarding "N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial".}, journal = {Biological psychiatry}, volume = {64}, number = {9}, pages = {e1}, doi = {10.1016/j.biopsych.2008.06.025}, pmid = {18718574}, issn = {1873-2402}, mesh = {Acetylcysteine/*therapeutic use ; Double-Blind Method ; Free Radical Scavengers/*therapeutic use ; Glutathione/*metabolism ; Humans ; Randomized Controlled Trials as Topic ; Schizophrenia/*drug therapy ; }, }
@article {pmid18716872, year = {2009}, author = {Ancha, HR and Kurella, RR and McKimmey, CC and Lightfoot, S and Harty, RF}, title = {Effects of N-acetylcysteine plus mesalamine on prostaglandin synthesis and nitric oxide generation in TNBS-induced colitis in rats.}, journal = {Digestive diseases and sciences}, volume = {54}, number = {4}, pages = {758-766}, pmid = {18716872}, issn = {1573-2568}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Colitis/chemically induced/*drug therapy/metabolism/pathology ; Colon/enzymology/pathology ; Cyclooxygenase 1/metabolism ; Cyclooxygenase 2/metabolism ; Dinoprostone/*biosynthesis ; Drug Therapy, Combination ; Free Radical Scavengers/pharmacology/therapeutic use ; Intestinal Mucosa/pathology ; Male ; Membrane Proteins/metabolism ; Mesalamine/pharmacology/*therapeutic use ; Nitric Oxide/*biosynthesis ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Trinitrobenzenesulfonic Acid ; }, abstract = {The aim of the present studies was to examine mechanisms by which the rectally administered combination of N-acetylcysteine (NAC) plus mesalamine (5-ASA) affects inducers of inflammation to promote mucosal healing and reduce tissue inflammation in chemically (trinitrobenzene sulfonic acid, TNBS) induced colitis in rats. Experimental findings demonstrate that dual therapy with NAC plus 5-ASA was superior to individual agents in reducing histological measures of colitis. NAC alone and in combination with 5-ASA suppressed COX2 gene expression and prostaglandin E(2) (PGE(2)) levels to control values. Furthermore, NAC plus 5-ASA reduced nitrate generation, an expression of inducible nitric oxide synthase (iNOS) activity, to basal levels and these results were significantly lower than those observed with either NAC or 5-ASA alone. In conclusion, these results indicate that NAC plus 5-ASA exerts therapeutic benefit, in part by countering the actions of PGE(2) and the deleterious effects of oxidative and nitrosative stress induced by TNBS colitis.}, }
@article {pmid18715889, year = {2008}, author = {Yalçin, S and Bilgili, A and Onbasilar, I and Eraslan, G and Ozdemir, M}, title = {Synergistic action of sodium selenite and N-acetylcysteine in acetaminophen-induced liver damage.}, journal = {Human &amp; experimental toxicology}, volume = {27}, number = {5}, pages = {425-429}, doi = {10.1177/0960327108094612}, pmid = {18715889}, issn = {0960-3271}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Analgesics/*toxicity ; Animals ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/blood/pathology/*prevention &amp; control ; Disease Models, Animal ; Drug Combinations ; Drug Synergism ; Free Radical Scavengers/*therapeutic use ; L-Lactate Dehydrogenase/blood ; Male ; Mice ; Sodium Selenite/*therapeutic use ; }, abstract = {Acetaminophen (AAP) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis in both humans and experimental animals. In this study, we investigated whether selenium (Se) and N-acetylcysteine (NAC), alone or in combination, are protective against AAP toxicity in mice. At the beginning of the experiment, blood samples were taken from 10 of 350 mice. Then, the remaining mice were randomly allocated into four groups, each consisting of 35 animals. The 1st group received a single administration of AAP by gavage at a dose of 600 mg/kg-bw, p.o. The 2nd group (AAP-Se) was treated with sodium selenite (0.5 mg Se/kg-bw, p.o.) one hour after ingestion of AAP. The 3rd group (AAP-NAC) ingested AAP, 1.5 h later followed by NAC (500 mg/kg-bw, p.o.). The 4th group (AAP-Se-NAC) was given sodium selenite and NAC, 1 and 1.5 h after administration of AAP, respectively. From each group, blood samples of seven mice for each time point were taken at 4, 8, 24, and 48 h after AAP toxicity. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) levels were measured. Compared with AAP group, the levels of ALT were lower after AAP ingestion in AAP-NAC, AAP-Se, and AAP-Se-NAC groups at the 8th hour. ALT, AST, and LDH levels in AAP-Se-NAC group were 50% of the levels of other groups starting form the 4th hour of toxicity. It is concluded that protection against AAP hepatotoxicity using a combination of Se and NAC is better than that found with either agent alone.}, }
@article {pmid18715270, year = {2009}, author = {Lin, AM and Feng, SF and Chao, PL and Yang, CH}, title = {Melatonin inhibits arsenite-induced peripheral neurotoxicity.}, journal = {Journal of pineal research}, volume = {46}, number = {1}, pages = {64-70}, doi = {10.1111/j.1600-079X.2008.00629.x}, pmid = {18715270}, issn = {1600-079X}, mesh = {Analysis of Variance ; Animals ; Arsenites/*antagonists &amp; inhibitors/*toxicity ; Ganglia, Spinal/drug effects/metabolism ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/metabolism ; Heme Oxygenase-1/metabolism ; Male ; Melatonin/metabolism/*pharmacology ; Neuroprotective Agents/metabolism/*pharmacology ; Neurotoxicity Syndromes/metabolism ; Peripheral Nervous System Diseases/*chemically induced/metabolism/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; }, abstract = {In this study, the effect of melatonin on sodium arsenite (arsenite)-induced peripheral neurotoxicity was investigated using dorsal root ganglion (DRG) explants. After 24-hr incubation, arsenite (30 microm) consistently elevated the expression of heat shock protein 70 and haeme oxygenase-1, two well-known stress proteins, in the treated DRG explants. Co-incubation with melatonin (4 and 20 mm) concentration-dependently attenuated arsenite-induced elevation in stress proteins. Furthermore, melatonin inhibited arsenite-induced phosphorylation of p38 and DNA fragmentation. Inhibition by melatonin of arsenite-induced apoptosis was mediated via inactivating both endoplasmic reticulum (ER) and mitochondrial pathways. In the ER pathway, melatonin suppressed arsenite-induced elevation in activating transcription factor-6 and CCAAT/enhancer-binding protein homologous protein in the nuclear fraction of the treated DRG explants. Moreover, melatonin attenuated arsenite-induced activation of caspase 12, an ER-specific enzyme. In the mitochondrial pathway, arsenite-induced increases in Bcl-2 levels and cytosolic cytochrome c were reduced by melatonin. At the same time, melatonin inhibited arsenite-induced activation of caspase 3 in the treated DRG explants. Compared with glutathione and N-acetyl cysteine, melatonin was more potent than either in inhibiting arsenite-induced elevation in stress proteins. Taken together, our study demonstrates that melatonin is protective against arsenite-induced neurotoxicity in DRG explants. In addition, melatonin prevented arsenite-induced apoptosis via suppression of ER and mitochondrial activation. Our data suggest that melatonin is potentially a therapy for arsenite-induced peripheral neuropathy.}, }
@article {pmid18709443, year = {2008}, author = {Cort, JR and Ramelot, TA and Murray, D and Acton, TB and Ma, LC and Xiao, R and Montelione, GT and Kennedy, MA}, title = {Structure of an acetyl-CoA binding protein from Staphylococcus aureus representing a novel subfamily of GCN5-related N-acetyltransferase-like proteins.}, journal = {Journal of structural and functional genomics}, volume = {9}, number = {1-4}, pages = {7-20}, pmid = {18709443}, issn = {1345-711X}, support = {U54 GM074958/GM/NIGMS NIH HHS/United States ; U54 GM094597/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetyl Coenzyme A/metabolism ; Acetyl-CoA C-Acetyltransferase/chemistry/*genetics/*metabolism ; Amino Acid Sequence ; Bacterial Proteins/chemistry/genetics/*metabolism ; Coenzyme A/metabolism ; Conserved Sequence ; Kinetics ; Ligands ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Sequence Alignment ; Sequence Homology, Amino Acid ; Staphylococcus aureus/*enzymology/*genetics ; }, abstract = {We have determined the solution NMR structure of SACOL2532, a putative GCN5-like N-acetyltransferase (GNAT) from Staphylococcus aureus. SACOL2532 was shown to bind both CoA and acetyl-CoA, and structures with and without bound CoA were determined. Based on analysis of the structure and sequence, a subfamily of small GCN5-related N-acetyltransferase (GNAT)-like proteins can be defined. Proteins from this subfamily, which is largely congruent with COG2388, are characterized by a cysteine residue in the acetyl-CoA binding site near the acetyl group, by their small size in relation to other GNATs, by a lack of obvious substrate binding site, and by a distinct conformation of bound CoA in relation to other GNATs. Subfamily members are found in many bacterial and eukaryotic genomes, and in some archaeal genomes. Whereas other GNATs transfer the acetyl group of acetyl-CoA directly to an aliphatic amine, the presence of the conserved cysteine residue suggests that proteins in the COG2388 GNAT-subfamily transfer an acetyl group from acetyl-CoA to one or more presently unidentified aliphatic amines via an acetyl (cysteine) enzyme intermediate. The apparent absence of a substrate-binding region suggests that the substrate is a macromolecule, such as another protein, or that a second protein subunit providing a substrate-binding region must combine with SACOL2532 to make a fully functional N-acetyl transferase.}, }
@article {pmid18708687, year = {2008}, author = {Silva, LA and Silveira, PC and Pinho, CA and Tuon, T and Dal Pizzol, F and Pinho, RA}, title = {N-acetylcysteine supplementation and oxidative damage and inflammatory response after eccentric exercise.}, journal = {International journal of sport nutrition and exercise metabolism}, volume = {18}, number = {4}, pages = {379-388}, doi = {10.1123/ijsnem.18.4.379}, pmid = {18708687}, issn = {1526-484X}, mesh = {Acetylcysteine/*pharmacology ; Creatine Kinase/blood ; Dietary Supplements ; Double-Blind Method ; Elbow Joint ; Exercise/*physiology ; Humans ; Inflammation/*blood ; Interleukin-10/blood ; Lipid Peroxidation/*drug effects ; Lipid Peroxides/blood ; Male ; Malondialdehyde/blood ; Muscle, Skeletal/*injuries/pathology ; Myoglobin/blood ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Tumor Necrosis Factor-alpha/metabolism ; Young Adult ; }, abstract = {The objective of the study was to verify the effect of N-acetylcysteine (NAC) supplementation on parameters of oxidative damage and inflammatory response after high-intensity eccentric exercise (EE). 29 participants with a mean age of 21.3+/-4 yr, weight of 74.5+/-7.7 kg, and height of 177.2+/-6.9 cm were selected and divided randomly into 3 groups: placebo (21 days; n=8), NAC (21 days; n=9), and NAC plus placebo (14 days; n=8). Four participants withdrew from the study for personal reasons. 14 days after starting supplementation, the participants performed EE: 3 sets until exhaustion (elbow flexion and extension on the Scott bench, 80% 1RM). Blood samples were collected before and on the 2nd, 4th, and 7th day after EE. Muscle soreness (MS), lipoperoxidation, protein carbonylation, tumor-necrosis factor- (TNF-), and interleukin 10 (IL-10) were determined. Results showed a significant increase in MS in all the groups on the 2nd day after EE and a decrease in the following days. A significant increase was observed in malondialdehyde and carbonyl levels on the 4th and 7th days after EE in all groups. TNF- increased significantly on the 2nd day after eccentric exercise and decreased in the following days irrespective of NAC supplementation; concentration of IL-10 increased significantly on the 4th day in all groups. Only the supplemented groups maintained high levels of IL-10 on the 7th day after EE. The results suggest that treatment with NAC represents an important factor in the defense against muscle soreness and has different effects on oxidative damage and pro- and anti-inflammatory cytokines.}, }
@article {pmid18707685, year = {2009}, author = {Türüt, H and Ciralik, H and Kilinc, M and Ozbag, D and Imrek, SS}, title = {Effects of early administration of dexamethasone, N-acetylcysteine and aprotinin on inflammatory and oxidant-antioxidant status after lung contusion in rats.}, journal = {Injury}, volume = {40}, number = {5}, pages = {521-527}, doi = {10.1016/j.injury.2008.05.001}, pmid = {18707685}, issn = {1879-0267}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Acute Lung Injury/drug therapy/*metabolism/physiopathology ; Animals ; Aprotinin/administration &amp; dosage/*pharmacology ; Blood Gas Analysis ; Bronchoalveolar Lavage Fluid/cytology ; Catalase/metabolism ; Dexamethasone/administration &amp; dosage/*pharmacology ; Disease Models, Animal ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Male ; Malondialdehyde/metabolism ; Neutrophils/drug effects ; Nitric Oxide/blood ; Oxidants/pharmacology ; Pulmonary Alveoli/drug effects/physiopathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Wounds, Nonpenetrating/*metabolism ; }, abstract = {INTRODUCTION: This experimental setting was undertaken to elucidate and confirm the role of inflammatory and oxidant-antioxidant mechanisms on blunt injury induced moderate pulmonary contusion (PC). We intended to determine the effects of dexamethasone (DXM), N-acetylcysteine (NAC) and aprotinin (APR) in terms of their ability to diminish the consequences of acute lung injury due to PC.<br><br>METHODS: Rats were allocated to five subgroups. Except for the control, all subgroups had a moderate pulmonary contusion. Following 45 min of observation, animals in groups I and II received intraperitoneal saline, group III 10 mg/kg DXM, group IV 500 mg/kg NAC and group V 30,000 kIU/ml APR. After the procedure, 6 h after contusion, blood gas analysis, lung tissue nitric oxide (NO) and malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activity, bronchoalveolar lavage (BAL) fluid and histopathological examination were performed.<br><br>RESULTS: All PaO(2) values decreased significantly in contused rats as compared with the control group (p<0.05). DXM, NAC and APR resulted in a slight increase in PaO(2) values compared with group II (p<0.05). Lung tissue levels of MDA and NO were higher in the contusion group than in the control (p<0.05). DXM, NAC and APR all decreased the levels of MDA and NO (p<0.05), however the decrease in NO was not found to be significant with APR (p>0.05). SOD and CAT activities increased significantly after contusion compared to control group (p<0.05). There was no significant difference even though SOD levels were elevated in groups III, IV and V compared with contused animals (p>0.05). Neutrophils in BAL fluid significantly increased in contused animals (p<0.05). Only DXM significantly decreased neutrophil population in BAL fluid (p<0.05). Scores for alveolar haemorrhage/oedema were higher in all contusion-performed rats than those in the control (p<0.05). Compared with the other drugs, only APR significantly improved the haemorrhage/oedema scores compared to sham animals (p=0.024).<br><br>CONCLUSIONS: Our findings demonstrate that moderate bilateral PC induced by blunt chest trauma leads to an early inflammatory process which is clearly associated with activation of the oxidant-antioxidant cascade. On this basis, early supportive treatment with DXM, NAC and APR may yield favourable results on pulmonary pathophysiological parameters which are adversely affected due to PC.}, }
@article {pmid18706875, year = {2009}, author = {Att, W and Yamada, M and Kojima, N and Ogawa, T}, title = {N-Acetyl cysteine prevents suppression of oral fibroblast function on poly(methylmethacrylate) resin.}, journal = {Acta biomaterialia}, volume = {5}, number = {1}, pages = {391-398}, doi = {10.1016/j.actbio.2008.07.021}, pmid = {18706875}, issn = {1878-7568}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Cells, Cultured ; Collagen/metabolism ; Collagen Type I/metabolism ; Fibroblasts/*metabolism ; Humans ; Mouth/*metabolism ; Polymers/chemistry ; Polymethyl Methacrylate/chemistry/*metabolism ; Polystyrenes/chemistry ; Rats ; Time Factors ; }, abstract = {Despite the proven cytotoxicity, poly(methylmethacrylate) (PMMA) resin is one of the most frequently and extensively used materials in medical and dental fields. The study examined the potential detoxification of the resin material and restoration of the resin-induced suppression of cellular function using an antioxidant amino acid derivative, N-acetyl cysteine (NAC). Oral fibroblasts extracted from rat oral mucosa were cultured on the resin material with or without incorporation of NAC into the material. Twenty-four hour after incubation, less than 2% of the cells were viable on the untreated control resin, while up to 35% of the cells were viable on the resin with incorporation of NAC. At day 7 of culture, the expression of collagen I and III genes was downregulated on the untreated resin, while the cells on NAC-supplemented resin showed the expression levels similar to those in polystyrene culture. The cells produced three times greater amount of collagen on the NAC-supplemented resin than on the untreated resin. The data demonstrated that the cytotoxicity of PMMA resin was substantially lower when the material contains NAC. The potential usefulness of this principle should be explored with a view of developing biocompatible polymer-based materials in a broad range of dental and medical resin materials and tissue engineering scaffolds.}, }
@article {pmid18703135, year = {2008}, author = {Chen, L and Liu, L and Huang, S}, title = {Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5.}, journal = {Free radical biology &amp; medicine}, volume = {45}, number = {7}, pages = {1035-1044}, doi = {10.1016/j.freeradbiomed.2008.07.011}, pmid = {18703135}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Blotting, Western ; Cadmium/*toxicity ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Humans ; Mitogen-Activated Protein Kinases/*drug effects ; Nuclear Proteins/*drug effects ; Phosphoprotein Phosphatases/*drug effects ; Protein Phosphatase 2/*drug effects ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd may induce neuronal apoptosis in part through activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (Erk1/2) pathways. However, the underlying mechanism remains enigmatic. Here we show that Cd induced generation of reactive oxygen species (ROS), leading to apoptosis of PC12 and SH-SY5Y cells. Pretreatment with N-acetyl-L-cysteine (NAC) scavenged Cd-induced ROS, and prevented cell death, suggesting that Cd-induced apoptosis is attributed to its induction of ROS. Furthermore, we found that Cd-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), leading to activation of Erk1/2 and JNK, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented Cd-induced activation of Erk1/2 and JNK, as well as cell death. Cd-induced ROS was also linked to the activation of caspase-3. Pretreatment with inhibitors of JNK (SP600125) and Erk1/2 (U0126) partially blocked Cd-induced cleavage of caspase-3 and prevented cell death. However, zVAD-fmk, a pan caspase inhibitor, only partially prevented Cd-induced apoptosis. The results indicate that Cd induction of ROS inhibits PP2A and PP5, leading to activation of JNK and Erk1/2 pathways, and consequently resulting in caspase-dependent and -independent apoptosis of neuronal cells. The findings strongly suggest that the inhibitors of JNK, Erk1/2, or antioxidants may be exploited for prevention of Cd-induced neurodegenerative diseases.}, }
@article {pmid18702961, year = {2008}, author = {Maioli, M and Toso, A and Leoncini, M and Gallopin, M and Tedeschi, D and Micheletti, C and Bellandi, F}, title = {Sodium bicarbonate versus saline for the prevention of contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention.}, journal = {Journal of the American College of Cardiology}, volume = {52}, number = {8}, pages = {599-604}, doi = {10.1016/j.jacc.2008.05.026}, pmid = {18702961}, issn = {1558-3597}, mesh = {Aged ; Angioplasty, Balloon, Coronary ; *Coronary Angiography ; Coronary Disease/epidemiology/therapy ; Creatinine/blood ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Prospective Studies ; Renal Insufficiency/epidemiology ; Risk Factors ; Sodium Bicarbonate/*administration &amp; dosage ; Sodium Chloride/*administration &amp; dosage ; }, abstract = {OBJECTIVES: The purpose of this study was to compare the efficacy of sodium bicarbonate versus isotonic saline in addition to N-acetylcysteine (NAC) to prevent contrast-induced nephropathy (CIN) in a larger population of patients with renal dysfunction undergoing coronary angiography or intervention.<br><br>BACKGROUND: Contrast-induced nephropathy accounts for more than 10% of hospital-acquired renal failure. Recent studies suggest that hydration with sodium bicarbonate is more protective than isotonic saline in the prevention of CIN.<br><br>METHODS: The prospective, single center study included 502 patients with estimated creatinine clearance <60 ml/min, randomized to receive infusion of either saline or sodium bicarbonate before and after iso-osmolar contrast medium administration. All patients received oral NAC 600 mg twice a day. Contrast-induced nephropathy was defined as an absolute increase of serum creatinine > or =0.5 mg/dl measured within 5 days.<br><br>RESULTS: Contrast-induced nephropathy occurred in 54 patients (10.8%); 25 (10%) were treated with sodium bicarbonate and 29 (11.5%) with saline (p = 0.60). In patients with CIN, the mean increase in creatinine was not significantly different in the 2 study groups (0.9 +/- 0.6 mg/dl vs. 0.7 +/- 0.2 mg/dl, respectively; p = 0.15). Only 2 patients needed temporary hemofiltration.<br><br>CONCLUSIONS: Hydration with sodium bicarbonate plus NAC before contrast medium exposure is not more effective than hydration with isotonic saline plus NAC for prophylaxis of CIN in patients with moderate-to-severe renal dysfunction. (Sodium Bicarbonate Versus Saline for the Prevention of Contrast-Induced Nephropathy; NCT00606827).}, }
@article {pmid18695935, year = {2009}, author = {Zinellu, A and Sotgia, S and Scanu, B and Usai, MF and Fois, AG and Spada, V and Deledda, A and Deiana, L and Pirina, P and Carru, C}, title = {Simultaneous detection of N-acetyl-L-cysteine and physiological low molecular mass thiols in plasma by capillary electrophoresis.}, journal = {Amino acids}, volume = {37}, number = {2}, pages = {395-400}, doi = {10.1007/s00726-008-0167-x}, pmid = {18695935}, issn = {1438-2199}, mesh = {Acetylcysteine/*blood/therapeutic use ; Electrophoresis, Capillary/*methods ; Expectorants/metabolism/therapeutic use ; Humans ; Molecular Weight ; Pulmonary Disease, Chronic Obstructive/blood ; *Sulfhydryl Compounds/blood/chemistry ; }, abstract = {N-acetyl-L-cysteine (NAC) is a therapeutic drug widely used as mucolytic agent in the treatment of respiratory diseases. Recently it has been proposed that NAC administration may modify the plasma levels of low molecular weight thiols (LMW) like cysteine, homocysteine and glutathione, though it has been still debated if their plasma concentration increases or decreases during the therapy. Therefore research calls for methods able to analyze simultaneously NAC and the other plasma LMW thiols in order to evaluate if NAC is able to modify plasma thiols concentration and in particular to reduce homocysteine levels in hyperhomocysteinemia. In this paper we present a new capillary electrophoresis method that allows a baseline separation of plasma NAC from the physiological thiols. The proposed method has been utilized to measure the drug and the physiological LMW thiols in NAC administered chronic obstructive broncho-pneumopathy (COPB) disease patients.}, }
@article {pmid18694818, year = {2008}, author = {Arranz, L and Fernández, C and Rodríguez, A and Ribera, JM and De la Fuente, M}, title = {The glutathione precursor N-acetylcysteine improves immune function in postmenopausal women.}, journal = {Free radical biology &amp; medicine}, volume = {45}, number = {9}, pages = {1252-1262}, doi = {10.1016/j.freeradbiomed.2008.07.014}, pmid = {18694818}, issn = {0891-5849}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Adult ; Aged ; Case-Control Studies ; Female ; Glutathione/*metabolism ; Humans ; *Immune System ; Interleukin-2/metabolism ; Interleukin-8/metabolism ; Leukocytes/metabolism ; Middle Aged ; Models, Biological ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Aging is a chronic oxidation process in which the immune system is involved. Because leukocyte functions is a good health marker and longevity predictor, the effects of daily oral administration of N-acetylcysteine (NAC, 600 mg) on several lymphocyte (adherence, chemotaxis, proliferation, natural killer activity) and neutrophil (adherence, chemotaxis, phagocytosis, superoxide) functions, as well as cytokine levels (interleukin-2, tumor necrosis factor alpha, interleukin-8), were studied in 36 healthy postmenopausal women: 18 aged 50-69 years and 18 aged > 69 years. In addition, plasma and leukocyte oxidative stress markers (glutathione, superoxide, malondialdehyde) were evaluated. These parameters were analyzed within 2 and 4 months of of NAC intake and 3 months after the end of the supplementation. In parallel, samples from 18 healthy adult women aged 30-49 years were used as a control age group. the results showed general impairment of immune function and increased oxidation markers in postmenopausal women as compared with the control group; however, NAC administration significantly improved the parameters studied, bringing their values closer to those of younger women and thus exerting a modulatory, rather than a merely stimulatory, action on the immune system. These effects were also observed 3 months after the end of supplementation. The present finding suggest that a short period of NAC supply (i.e., 2-4 months) at the dose used may lead to prolonged strengthening of immune defence in postmenopausal women, likely by increasing the leukocyte glutathione pool. Thus, NAC could contribute to maintenance of good health and quality of life in postmenopausal women by decreasing the probability of immune system-related diseases, such as infections, in aging.}, }
@article {pmid18694812, year = {2008}, author = {Mitsopoulos, P and Omri, A and Alipour, M and Vermeulen, N and Smith, MG and Suntres, ZE}, title = {Effectiveness of liposomal-N-acetylcysteine against LPS-induced lung injuries in rodents.}, journal = {International journal of pharmaceutics}, volume = {363}, number = {1-2}, pages = {106-111}, doi = {10.1016/j.ijpharm.2008.07.015}, pmid = {18694812}, issn = {0378-5173}, mesh = {Acetylcysteine/*administration &amp; dosage/chemistry ; Acute Lung Injury/chemically induced/metabolism/pathology/*prevention &amp; control ; Animals ; Antioxidants/*administration &amp; dosage/chemistry ; Bronchoalveolar Lavage Fluid/chemistry ; Chemistry, Pharmaceutical ; Chloramines/metabolism ; Disease Models, Animal ; Drug Compounding ; Injections, Intravenous ; Leukotriene B4/metabolism ; Lipid Peroxidation/drug effects ; Lipopolysaccharides ; Liposomes ; Lung/*drug effects/enzymology/pathology ; Male ; Organ Size/drug effects ; Peptidyl-Dipeptidase A/metabolism ; Peroxidase/metabolism ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/metabolism ; Thromboxane B2/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS) are frequent complications in critically ill patients and are responsible for significant morbidity and mortality. So far, experimental evidence supports the role of oxidants and oxidative injury in the pathogenesis of ALI/ARDS. In this study, the antioxidant effects of conventional N-acetylcysteine (NAC) and liposomally entrapped N-acetylcysteine (L-NAC) were evaluated in experimental animals challenged with lipopolysaccharide (LPS). Rats were pretreated with empty liposomes, NAC, or L-NAC (25mg/kg body weight, iv); 4h later were challenged with LPS (E. coli, LPS 0111:B4) and sacrificed 20h later. Challenge of saline (SAL)-pretreated animals with LPS resulted in lung injury as evidenced by increases in wet lung weight (edema), increases in lipid peroxidation (marker of oxidative stress), decreases of lung angiotensin-converting enzyme (ACE) (injury marker for pulmonary endothelial cells) and increases in the pro-inflammatory eicosanoids, thromboxane B(2) and leukotriene B(4). The LPS challenge also increased pulmonary myeloperoxidase activity and chloramine concentrations indicative of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with L-NAC resulted in significant increases in the levels of non-protein thiols and NAC levels in lung homogenates (p<0.05) and bronchoalveolar lavage fluids (p<0.001), respectively. L-NAC was significantly (p<0.05) more effective than NAC or empty liposomes in attenuating the LPS-induced lung injuries as indicated by the aforementioned injury markers. Our results suggested that the delivery of NAC as a liposomal formulation improved its prophylactic effectiveness against LPS-induced lung injuries.}, }
@article {pmid18692031, year = {2008}, author = {Rogalska, A and Koceva-Chyła, A and Jóźwiak, Z}, title = {Aclarubicin-induced ROS generation and collapse of mitochondrial membrane potential in human cancer cell lines.}, journal = {Chemico-biological interactions}, volume = {176}, number = {1}, pages = {58-70}, doi = {10.1016/j.cbi.2008.07.002}, pmid = {18692031}, issn = {0009-2797}, mesh = {Aclarubicin/*pharmacology ; Antibiotics, Antineoplastic/*pharmacology ; Cell Count ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Shape/drug effects ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Membrane Potential, Mitochondrial/*drug effects ; Microscopy, Fluorescence ; Reactive Oxygen Species/*metabolism ; }, abstract = {The cytotoxicity of aclarubicin (ACL) in A549 (human non-small lung), HepG2 (human hepatoma) and MCF-7 (human breast adenocarcinoma) cancer cell lines was evaluated and compared with that of doxorubicin (DOX). Changes in mitochondrial transmembrane potential (DeltaPsim), and production of reactive oxygen species (ROS) of drug-treated cells were monitored. Moreover, morphological changes associated with apoptosis were examined using double staining with Hoechst 33258-propidium iodide (PI). The results showed that ACL was much more cytotoxic than DOX in all investigated cell lines. Furthermore, ACL induced a concentration- and time-dependent increase in ROS production and decrease in mitochondrial membrane potential. The drugs, especially ACL, also induced ROS mediated apoptosis and necrosis pathways in all cell lines depending on the length of the post-treatment time. All these processes were partially inhibited by the antioxidants: N-acetylcysteine (NAC) and alpha-tocopherol. Of both drugs, DOX caused considerably weaker depolarization of the mitochondrial membrane. Its 10-fold higher concentration, as compared to ACL, was required to induce a similar effect, in accordance with the highly distinct cytotoxicity of these drugs towards investigated cells. In conclusion, ROS production preceded a decrease in mitochondrial membrane potential, but only changes in DeltaPsim were correlated with drug cytotoxicity in particular cell line. These results suggest that the impairment of DeltaPsim and an increase in ROS level might be important mechanisms of ACL cytotoxicity in cancer cells in solid tumors.}, }
@article {pmid18690526, year = {2008}, author = {Konat, GW and Kraszpulski, M and James, I and Zhang, HT and Abraham, J}, title = {Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats.}, journal = {Metabolic brain disease}, volume = {23}, number = {3}, pages = {325-333}, pmid = {18690526}, issn = {0885-7490}, mesh = {Animals ; Antibiotics, Antineoplastic/toxicity ; Antineoplastic Agents/*toxicity ; Antineoplastic Agents, Alkylating/toxicity ; Antioxidants/therapeutic use ; Avoidance Learning/drug effects ; Cognition Disorders/*chemically induced/prevention &amp; control/*psychology ; Cyclophosphamide/toxicity ; Doxorubicin/toxicity ; Female ; Memory, Short-Term/drug effects ; Motor Activity/drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Although cognitive dysfunction manifested by severe memory and attention deficits has been reported in up to 70% of cancer patients undergoing chemotherapy, the mechanisms of this serious side effect have not been defined. In particular, it has not been decisively resolved whether the dysfunction is attributable to the chemotherapy or to the malignancy itself. In the present study we tested whether cognitive dysfunction can be induced in an experimental setting by the administration of commonly used chemotherapeutics to rats. Female 10 month old Sprague-Dawley rats were injected intraperitoneally with a combination of 2.5 mg/kg of adriamycin (ADR) and 25 mg/kg of cytoxan (CTX). A total of four doses were given at weekly intervals. The control group was treated with saline only. No mortality and no apparent morbidity were observed in either group. However, the chemotherapeutic treatment severely impaired memory function of rats as measured by a passive avoidance test. This memory deficiency was fully prevented by the administration of an antioxidant, N-acetyl cysteine (NAC) injected subcutaneously three times a week at 200 mg/kg in the course of chemotherapeutic treatment. These results indicate that chemotherapeutic agents alone, i.e., in the absence of malignancy, damage the brain resulting in memory dysfunction. Moreover, the results strongly indicate that the damaging effect is mediated by oxidative stress, as memory dysfunction is preventable by the co-administration of NAC.}, }
@article {pmid18690414, year = {2008}, author = {Bełtowski, J and Jamroz-Wiśniewska, A and Wójcicka, G and Lowicka, E and Wojtak, A}, title = {Renal antioxidant enzymes and glutathione redox status in leptin-induced hypertension.}, journal = {Molecular and cellular biochemistry}, volume = {319}, number = {1-2}, pages = {163-174}, pmid = {18690414}, issn = {1573-4919}, mesh = {Animals ; Antioxidants/*metabolism/pharmacology ; Enzyme Inhibitors/pharmacology ; Hydrogen Peroxide/metabolism ; Hypertension/chemically induced/*enzymology ; Kidney/*enzymology ; Leptin/*adverse effects/pharmacology ; Male ; Oxidation-Reduction/drug effects ; Rats ; Rats, Wistar ; Sodium/urine ; Superoxides/metabolism ; Time Factors ; }, abstract = {Previously, we have demonstrated that leptin increases blood pressure (BP) in the rats through two oxidative stress-dependent mechanisms: stimulation of extracellular signal-regulated kinases (ERK) by H(2)O(2) and scavenging of nitric oxide (NO) by superoxide (O(2-.)). Herein, we examined if renal glutathione system and antioxidant enzymes determine the mechanism of prohypertensive effect of leptin. Leptin administered at 0.5 mg/kg/day for 4 or 8 days increased BP and renal Na(+),K(+)-ATPase activity and reduced fractional sodium excretion; these effects were prevented by NADPH oxidase inhibitor, apocynin. Superoxide scavenger, tempol, abolished the effect of leptin on BP and renal Na(+) pump in rats receiving leptin for 8 days, whereas ERK inhibitor, PD98059, was effective in animals treated with leptin for 4 days. Leptin administered for 4 days decreased glutathione (GSH) and increased glutathione disulfide (GSSG) in the kidney. In animals receiving leptin for 8 days GSH returned to normal level, which was accompanied by up-regulation of gamma-glutamylcysteine synthetase (gamma-GCS), a rate-limiting enzyme of the GSH biosynthetic pathway. In addition, superoxide dismutase (SOD) activity was decreased, whereas glutathione peroxidase (GPx) was increased in rats receiving leptin for 8 days. Cotreatment with gamma-GCS inhibitor, buthionine sulfoximine (BSO), accelerated, whereas GSH precursor, N-acetylcysteine (NAC), attenuated leptin-induced changes in gamma-GCS, SOD, and GPx. In addition, coadministration of BSO changed the mechanism of BP elevation from H(2)O(2)-ERK to (O(2-.))-NO dependent in animals receiving leptin for 4 days, whereas NAC had the opposite effect in rats treated with leptin for 8 days. These results suggest that initial change in GSH redox status induces decrease in SOD/GPx ratio, which results in greater amount of (O)2-.)) versus H(2)O(2) in later phase of leptin treatment, thus shifting the mechanism of BP elevation from H(2)O(2)-ERK to (O(2-.))-NO dependent.}, }
@article {pmid18687213, year = {2008}, author = {Fan, JL and Cai, HB and Tan, WS}, title = {[Effect of regulating intracellular ROS with antioxidants on the ex vivo expansion of cord blood CD34+ cells].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {24}, number = {8}, pages = {767-770}, pmid = {18687213}, issn = {1007-8738}, mesh = {Acetylcysteine/pharmacology ; Antigens, CD34/*metabolism ; Antioxidants/*pharmacology ; Catalase/pharmacology ; Cell Proliferation/drug effects ; Cells, Cultured ; Fetal Blood/cytology/*metabolism ; Humans ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/pharmacology ; }, abstract = {AIM: To investigate the effect of regulating intracellular ROS with antioxidants on the ex vivo expansion of cord blood CD34(+) cells.<br><br>METHODS: The levels of reactive oxygen species (ROS) in cord blood CD34(+) cells were reduced by superoxide dismutase (SOD), catalase (CAT) or N-acetylcysteine (NAC) in ex vivo expansion. The expansion of CD34(+) cells reducing ROS levels with antioxidant was studied.<br><br>RESULTS: It was observed that the generation of ROS was increased markedly by the cytokine combination. ROS was eliminated by antioxidant effectively. With the addition of antioxidant at different concentration, ROS was reduced to different levels. The percentage of CD34(+) cells and CD34(+)CD38(-) cells, the colony growth of colony-forming cells (CFC) and the re-expansion capability of CD34(+) cells were enhanced by 2 000 U/mL SOD, 200 U/mL CAT or 2 mmol/L NAC. However, its effect on fold expansion of CD34(+) cells was not significant. The expansion of the cells was inhibited by 8 000 U/mL SOD, 1 000 U/mL CAT or 5 mmol/L NAC.<br><br>CONCLUSION: The proportion of hematopoietic stem and progenitor cells in the culture substance was increased markedly with the addition of low dose antioxidants in ex vivo expansion.}, }
@article {pmid18684975, year = {2008}, author = {Akool, el-S and Doller, A and Babelova, A and Tsalastra, W and Moreth, K and Schaefer, L and Pfeilschifter, J and Eberhardt, W}, title = {Molecular mechanisms of TGF beta receptor-triggered signaling cascades rapidly induced by the calcineurin inhibitors cyclosporin A and FK506.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {181}, number = {4}, pages = {2831-2845}, doi = {10.4049/jimmunol.181.4.2831}, pmid = {18684975}, issn = {1550-6606}, mesh = {Animals ; *Calcineurin Inhibitors ; Cells, Cultured ; Cyclosporine/*pharmacology ; Fibrosis ; Humans ; Injections, Intraperitoneal ; Male ; Mesangial Cells/drug effects/enzymology/pathology ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/*physiology ; Rats ; Rats, Wistar ; Receptor, Transforming Growth Factor-beta Type I ; Receptor, Transforming Growth Factor-beta Type II ; Receptors, Transforming Growth Factor beta/antagonists &amp; inhibitors/*physiology ; Signal Transduction/*drug effects/immunology ; Smad2 Protein/metabolism/physiology ; Tacrolimus/*administration &amp; dosage/pharmacology ; Transforming Growth Factor beta1/biosynthesis/metabolism ; }, abstract = {The calcineurin inhibitor (CNI)-induced renal fibrosis is attributed to an exaggerated deposition of extracellular matrix, which is mainly due to an increased expression of TGFbeta. Herein we demonstrate that the CNI cyclosporin A and tacrolimus (FK506), independent of TGFbeta synthesis, rapidly activate TGFbeta/Smad signaling in cultured mesangial cells and in whole kidney samples from CNI-treated rats. By EMSA, we demonstrate increased DNA binding of Smad-2, -3, and -4 to a cognate Smad-binding promoter element (SBE) accompanied by CNI-triggered activation of Smad-dependent expression of tissue inhibitor of metalloprotease-1 (TIMP-1) and connective tissue growth factor. Using an activin receptor-like kinase-5 (ALK-5) inhibitor and by small interfering RNA we depict a critical involvement of both types of TGFbeta receptors in CNI-triggered Smad signaling and fibrogenic gene expression, respectively. Mechanistically, CNI cause a rapid activation of latent TGFbeta, which is prevented in the presence of the antioxidant N-acetyl cysteine. A convergent activation of p38 MAPK is indicated by the partial blockade of CNI-induced Smad-2 activation by SB203580; conversely, both TGFbeta-RII and TGFbeta are critically involved in p38 MAPK activation by CNI. Activation of both signaling pathways is similarly triggered by reactive oxygen species. Finally, we show that neutralization of TGFbeta markedly reduced the CNI-dependent Smad activation in vitro and in vivo. Collectively, this study demonstrates that CNI via reactive oxygen species generation activate latent TGFbeta and thereby initiate the canonical Smad pathway by simultaneously activating p38 MAPK, which both synergistically induce Smad-driven gene expression.}, }
@article {pmid18679584, year = {2008}, author = {Kwok, SC and Daskal, I}, title = {Brefeldin A activates CHOP promoter at the AARE, ERSE and AP-1 elements.}, journal = {Molecular and cellular biochemistry}, volume = {319}, number = {1-2}, pages = {203-208}, pmid = {18679584}, issn = {1573-4919}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Apoptosis/drug effects ; Brefeldin A/*pharmacology ; Buthionine Sulfoximine/pharmacology ; DNA-Binding Proteins/biosynthesis ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors ; Protein Synthesis Inhibitors/*pharmacology ; Regulatory Factor X Transcription Factors ; *Response Elements ; Transcription Factor CHOP/*biosynthesis ; Transcription Factors/biosynthesis ; Up-Regulation/*drug effects ; X-Box Binding Protein 1 ; }, abstract = {Brefeldin A induces apoptosis in PC-3 and MCF-7 cells at a concentration of 30 ng/ml. RT-PCR analyses showed up-regulation of CHOP/GADD153 and splicing of XBP-1 mRNA in brefeldin A-treated cells. CHOP promoter-luciferase reporter assays demonstrated activation of AARE, ERSE, and AP-1 elements of CHOP promoter by brefeldin A treatment. The activation of these elements was not affected by preincubation of cells with N-acetyl-cysteine (NAC), L: -buthionine-(S,R)-sulfoximine (BSO), and c-Jun N-terminal kinase (JNK) inhibitor (SP600125), suggesting that activation of CHOP promoter by brefeldin A may not involve oxidative stress or JNK signaling pathway. On the other hand, brefeldin A-induced apoptosis was not affected by NAC and BSO pretreatment, but was completely suppressed by JNK inhibitor pretreatment. Our results suggest that although CHOP is up-regulated by brefeldin A, it is not a major mediator of brefeldin A-induced apoptosis.}, }
@article {pmid18676857, year = {2008}, author = {Fukuyo, Y and Inoue, M and Nakajima, T and Higashikubo, R and Horikoshi, NT and Hunt, C and Usheva, A and Freeman, ML and Horikoshi, N}, title = {Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives.}, journal = {Cancer research}, volume = {68}, number = {15}, pages = {6324-6330}, pmid = {18676857}, issn = {1538-7445}, support = {R01 HL062458/HL/NHLBI NIH HHS/United States ; R01CA98666/CA/NCI NIH HHS/United States ; P01CA104457/CA/NCI NIH HHS/United States ; R01 CA098666-03/CA/NCI NIH HHS/United States ; R01 CA098666-02/CA/NCI NIH HHS/United States ; R01 CA098666-05/CA/NCI NIH HHS/United States ; P01 CA104457/CA/NCI NIH HHS/United States ; R01 CA098666-04/CA/NCI NIH HHS/United States ; R01 CA098666/CA/NCI NIH HHS/United States ; R01 CA098666-01A1/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antibiotics, Antineoplastic/*pharmacology ; Benzoquinones/*pharmacology ; Cell Line, Tumor ; Enzyme Activation ; HSP90 Heat-Shock Proteins/antagonists &amp; inhibitors ; Humans ; Lactams, Macrocyclic/*pharmacology ; Mitogen-Activated Protein Kinases/metabolism ; *Mutation ; *Oxidative Stress ; Proto-Oncogene Proteins B-raf/*antagonists &amp; inhibitors/genetics ; }, abstract = {The geldanamycin derivatives 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) are promising chemotherapeutic drugs that inhibit heat shock protein 90 (HSP90) function. Previous studies have shown that 17-AAG/DMAG treatment induces the degradation of mutant BRAF (V600E) and inhibits the activation of mitogen-activated protein/extracellular signal-regulated kinase 1/2 (MEK1/2). We have found, however, that HSP90 inhibition alone is not sufficient for efficient BRAF(V600E) degradation in some cells. HSP90 inhibitors structurally unrelated to geldanamycin, radicicol and novobiocin, while inducing the degradation of the HSP90 client protein RAF-1 fail to induce BRAF(V600E) degradation or inhibit MEK1/2 activation in HT29 human colon cancer cells. Moreover, after treatment with 17-DMAG, the kinase activity of residual, undegraded BRAF(V600E) was also lost. Incubation of cells with a reactive oxygen species (ROS) scavenger, N-acetyl cysteine, partially restored kinase activity and also partially prevented BRAF(V600E) degradation due to 17-DMAG treatment. Conversely, treatment with the ROS producing drug menadione clearly inhibited MEK1/2 and reduced BRAF(V600E). These results suggest that in addition to direct inhibition of HSP90, the antitumor effect of geldanamycin and its derivatives is also mediated though the production of ROS, which may directly inactivate tumorigenic mutant BRAF(V600E).}, }
@article {pmid18671917, year = {2008}, author = {Whitaker, BD and Knight, JW}, title = {Mechanisms of oxidative stress in porcine oocytes and the role of anti-oxidants.}, journal = {Reproduction, fertility, and development}, volume = {20}, number = {6}, pages = {694-702}, doi = {10.1071/rd08037}, pmid = {18671917}, issn = {1031-3613}, mesh = {Animals ; Antioxidants/*pharmacology ; Catalase/antagonists &amp; inhibitors/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Ditiocarb/pharmacology ; Embryo Culture Techniques ; Enzyme Inhibitors/pharmacology ; Female ; Glutathione/metabolism ; Glutathione Peroxidase/antagonists &amp; inhibitors/metabolism ; Iodoacetic Acid/pharmacology ; Male ; Models, Biological ; Oocytes/*drug effects/growth &amp; development/physiology ; Oogenesis/drug effects ; Oxidative Stress/*physiology ; Pregnancy ; Swine/*physiology ; }, abstract = {The mechanisms of oxidative stress in in vitro maturing porcine oocytes and the effects of anti-oxidant supplementation of the medium in ameliorating these effects were investigated in the present study. In addition to intracellular reduced glutathione (GSH) concentrations and DNA fragmentation, the present study focused on superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase activity. The anti-oxidants used were N-acetylcysteine (NAC) and its derivative NAC-amide (NACA). The results indicate that when SOD is inhibited, supplementation of the maturarion medium with 1.5 mm NAC or NACA compensates for the decrease in SOD activity by reducing the degree of DNA fragmentation (P < 0.05). When GPx is inhibited, supplementation of the maturarion medium with 1.5 mm NAC alleviates the effects of no GPx activity, as indicated by a decrease in the degree of DNA fragmentation (P < 0.05). When the maturarion medium was supplemented with 1.5 mm NACA, intracellular GSH concentrations decreased (P < 0.05) and SOD and catalase activities increased (P < 0.05) along with the degree of DNA fragmentation. These results indicate that the mechanisms of alleviating oxidative stress in porcine oocytes are very complex and supplementing maturing oocytes with anti-oxidants may enhance enzyme activities and eliminate free radicals.}, }
@article {pmid18670083, year = {2008}, author = {Wu, YL and Piao, DM and Han, XH and Nan, JX}, title = {Protective effects of salidroside against acetaminophen-induced toxicity in mice.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {31}, number = {8}, pages = {1523-1529}, doi = {10.1248/bpb.31.1523}, pmid = {18670083}, issn = {0918-6158}, mesh = {Acetaminophen/*antagonists &amp; inhibitors/*toxicity ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/*antagonists &amp; inhibitors/*toxicity ; Animals ; Aspartate Aminotransferases/blood ; Caspase 3/metabolism ; Chemical and Drug Induced Liver Injury/enzymology/pathology/*prevention &amp; control ; Glucosides/*pharmacology ; Glutathione/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/genetics ; Immunohistochemistry ; Lipid Peroxidation/drug effects ; Liver/drug effects/enzymology ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/physiology ; Phenols/*pharmacology ; Rhodiola/chemistry ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {The protective effect of salidroside (SDS) isolated from Rhodiola sachalinensis A. BOR. (Crassulaceae), was investigated in acetaminophen (APAP)-induced hepatic toxicity mouse model in comparison to N-acetylcysteine (NAC). Drug-induced hepatotoxicity was induced by an intraperitoneal (i.p.) injection of 300 mg/kg (sub-lethal dose) of APAP. SDS was given orally to mice at a dose of 50 or 100 mg/kg 2 h before the APAP administration in parallel with NAC. Mice were sacrificed 12 h after the APAP injection to determine aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-alpha (TNF-alpha) levels in serum and glutathione (GSH) depletion, malondialdehyde (MDA) accumulation, and caspase-3 expression in liver tissues. SDS significantly protected APAP-induced hepatotoxicity for SDS improved mouse survival rates better than NAC against a lethal dose of APAP and significantly blocked not only APAP-induced increases of AST, ALT, and TNF-alpha but also APAP-induced GSH depletion and MDA accumulation. Histopathological and immunohistochemical analyses also demonstrated that SDS could reduce the appearance of necrosis regions as well as caspase-3 and hypoxia inducible factor-1alpha (HIF-1alpha) expression in liver tissue. Our results indicated that SDS protected liver tissue from the APAP-induced oxidative damage via preventing or alleviating intracellular GSH depletion and oxidation damage, which suggested that SDS would be a potential antidote against APAP-induced hepatotoxicity.}, }
@article {pmid18669924, year = {2008}, author = {Sayed, N and Kim, DD and Fioramonti, X and Iwahashi, T and Durán, WN and Beuve, A}, title = {Nitroglycerin-induced S-nitrosylation and desensitization of soluble guanylyl cyclase contribute to nitrate tolerance.}, journal = {Circulation research}, volume = {103}, number = {6}, pages = {606-614}, pmid = {18669924}, issn = {1524-4571}, support = {R01 GM067640/GM/NIGMS NIH HHS/United States ; HL089771/HL/NHLBI NIH HHS/United States ; R01 GM067640-05/GM/NIGMS NIH HHS/United States ; GM067640/GM/NIGMS NIH HHS/United States ; R21 HL089771/HL/NHLBI NIH HHS/United States ; R01 HL070634/HL/NHLBI NIH HHS/United States ; HL070634/HL/NHLBI NIH HHS/United States ; R21 HL089771-01A1/HL/NHLBI NIH HHS/United States ; R01 HL070634-04/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Arterioles/drug effects/physiology ; Cricetinae ; Cysteine/analogs &amp; derivatives/pharmacology ; Drug Tolerance/*physiology ; Enzyme Activation/drug effects/physiology ; Guanylate Cyclase/genetics/*metabolism ; Mouth Mucosa/blood supply/drug effects/enzymology ; Nitrates/*metabolism/physiology ; Nitroglycerin/*pharmacology ; Receptors, Cytoplasmic and Nuclear/genetics/*metabolism ; S-Nitrosothiols/pharmacology ; Soluble Guanylyl Cyclase ; Vasodilation/*drug effects/*physiology ; }, abstract = {Nitrates such as nitroglycerin (GTN) and nitric oxide donors such as S-nitrosothiols are clinically vasoactive through stimulation of soluble guanylyl cyclase (sGC), which produces the second messenger cGMP. Development of nitrate tolerance, after exposure to GTN for several hours, is a major drawback to a widely used cardiovascular therapy. We recently showed that exposure to nitric oxide and to S-nitrosothiols causes S-nitrosylation of sGC, which directly desensitizes sGC to stimulation by nitric oxide. We tested the hypothesis that desensitization of sGC by S-nitrosylation is a mechanism of nitrate tolerance. Our results established that vascular tolerance to nitrates can be recapitulated in vivo by S-nitrosylation through exposure to cell membrane-permeable S-nitrosothiols and that sGC is S-nitrosylated and desensitized in the tolerant, treated tissues. We next determined that (1) GTN treatment of primary aortic smooth muscle cells induces S-nitrosylation of sGC and its desensitization as a function of GTN concentration; (2) S-nitrosylation and desensitization are prevented by treatment with N-acetyl-cysteine, a precursor of glutathione, used clinically to prevent development of nitrate tolerance; and (3) S-nitrosylation and desensitization are reversed by cessation of GTN treatment. Finally, we demonstrated that in vivo development of nitrate tolerance and crosstolerance by 3-day chronic GTN treatment correlates with S-nitrosylation and desensitization of sGC in tolerant tissues. These results suggest that in vivo nitrate tolerance is mediated, in part, by desensitization of sGC through GTN-dependent S-nitrosylation.}, }
@article {pmid18667992, year = {2008}, author = {Lorito, G and Giordano, P and Petruccelli, J and Martini, A and Hatzopoulos, S}, title = {Different strategies in treating noiseinduced hearing loss with N-acetylcysteine.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {14}, number = {8}, pages = {BR159-64}, pmid = {18667992}, issn = {1643-3750}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Auditory Threshold/drug effects ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Hearing Loss, Noise-Induced/chemically induced/*drug therapy/physiopathology ; Male ; Otoacoustic Emissions, Spontaneous/drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: The cellular mechanisms leading to noise-induced hearing loss (NIHL) involve the generation of reactive oxygen species (ROS). Recent studies on glutathione (GSH) and N-acetylcysteine (NAC) show that they can protect the cochlea from ROS-derived damage, increasing the levels of endogenous cellular defences. The purpose of this study was to verify NAC's oto-protective efficacy and determine if drug administration timing influences the degree of oto-protection.<br><br>MATERIAL/METHODS: Forty male Sprague Dawley albino rats were divided in four groups exposed to 8-kHz 105-dB SPL continuous noise. The groups were treated with diverse NAC administration modalities: group A received 4 injections during 48 hours (pre- and post-noise exposure), group B 1 injection prior to exposure, group C 1 injection 24 h after exposure, and group D served as untreated controls. The single injection dosage was 375 mg/kg; the controls received an equal volume of saline solution. Cochlear function was assessed by pre- and post-noise (after 168 hours) recordings of distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABR). DPOAEs were obtained by three different asymmetric protocols (P1=60-50, P2=50-40, P3=40-30 dB SPL) for frequencies of 4-16 kHz. ABR responses were elicited by tone-bursts at 8 and 16 kHz.<br><br>RESULTS: The most important outcome of the study was that the administration of NAC significantly reduced the threshold shifts in the treated animals. NAC provided different degrees of threshold reduction according to the timing of the drug injection.<br><br>CONCLUSIONS: The role played by the timing of NAC injection was important for the OHC protection index. From a DPOAE perspective, the best protection scheme was observed in the group receiving NAC after noise exposure, but full recovery of cochlear function was not observed in any of the tested groups.}, }
@article {pmid18667743, year = {2008}, author = {Rehman, T and Fought, J and Solomon, R}, title = {N-acetylcysteine effect on serum creatinine and cystatin C levels in CKD patients.}, journal = {Clinical journal of the American Society of Nephrology : CJASN}, volume = {3}, number = {6}, pages = {1610-1614}, pmid = {18667743}, issn = {1555-905X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; Chronic Disease ; Contrast Media/adverse effects ; Creatinine/*blood ; Cystatin C/*blood ; Female ; Humans ; Kidney Diseases/diagnostic imaging/*drug therapy/metabolism ; Male ; Middle Aged ; Prospective Studies ; Radiography ; Severity of Illness Index ; Time Factors ; }, abstract = {BACKGROUND AND OBJECTIVES: N-acetylcysteine (NAC) has been widely used as a prophylactic therapy for contrast-induced nephropathy (CIN). Its efficacy is controversial because of heterogeneity in study results and because of evidence that NAC can alter serum creatinine levels without affecting glomerular filtration rate. This confounding effect of N-acetylcysteine on serum creatinine has not been rigorously tested, however, in a population at risk for CIN and following doses of NAC currently recommended for prophylaxis of CIN.<br><br>"Double-dose" NAC was administered in the absence of iodinated contrast media to 29 stage 3 to 5 stable chronic kidney disease patients. Serum creatinine and cystatin C were measured before and 4 h and 48 h after the last dose of NAC.<br><br>RESULTS: There was no effect of NAC on either serum creatinine or cystatin C levels.<br><br>CONCLUSION: NAC, in doses currently recommended for prophylaxis of CIN, has no effect on serum creatinine or cystatin C levels. It is therefore unlikely that the heterogeneity seen in clinical trials of NAC prophylaxis for CIN is related to a confounding effect on serum creatinine.}, }
@article {pmid18665799, year = {2008}, author = {Matsuhisa, S and Otani, H and Okazaki, T and Yamashita, K and Akita, Y and Sato, D and Moriguchi, A and Iwasaka, T}, title = {N-acetylcysteine abolishes the protective effect of losartan against left ventricular remodeling in cardiomyopathy hamster.}, journal = {Antioxidants &amp; redox signaling}, volume = {10}, number = {12}, pages = {1999-2008}, doi = {10.1089/ars.2008.2069}, pmid = {18665799}, issn = {1557-7716}, mesh = {Acetylcysteine/*pharmacology ; Amidines/pharmacology ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Benzylamines/pharmacology ; Cardiomyopathies/pathology/physiopathology/*prevention &amp; control ; Cricetinae ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Fibrosis ; Free Radical Scavengers/pharmacology ; Heart/drug effects/physiopathology ; Heart Ventricles/drug effects/pathology/physiopathology ; Losartan/*pharmacology ; Male ; Myocardium/metabolism/pathology ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Organ Size/drug effects ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Ventricular Function, Left/drug effects/physiology ; Ventricular Remodeling/*drug effects/physiology ; }, abstract = {Oxidative stress mediated by activation of angiotensin II type-1 receptor (AT(1)R) plays a crucial role in the progression of heart failure. We investigated the effect of N-acetylcysteine (NAC) and an AT(1)R blocker on oxidative stress and left ventricular (LV) remodeling in BIO14.6 cardiomyopathy hamsters. The cardiomyopathy hamsters were treated with NAC or the AT(1)R blocker losartan for 20 weeks. Although NAC and losartan inhibited oxidative stress and upregulation of iNOS in the cardiomyopathy hamster heart, only losartan inhibited LV chamber dilation, myocardial fibrosis, and LV dysfunction in the cardiomyopathy hamster. Co-treatment with NAC abolished the protective effect of losartan against LV remodeling associated with inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt and eNOS activation. An iNOS inhibitor 1400W or a nonselective NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) exacerbated LV remodeling in the cardiomyopathy hamster. However, L-NAME but not 1400W abrogated losartan-mediated inhibition of LV remodeling. These results suggest that redox-sensitive upregulation of iNOS plays a crucial role in preventing LV remodeling in the BIO14.6 cardiomyopathy hamster. Losartan inhibits LV remodeling by switching the cardioprotective mechanism from iNOS- to eNOS-dependence, but NAC abolishes the protective effect of losartan by inhibiting redox-sensitive activation of PI3K/Akt and eNOS in the cardiomyopathy hamster.}, }
@article {pmid18665117, year = {2008}, author = {Peker, O and Peker, T and Erdogan, D and Ozaydin, M and Kapan, S and Sutcu, R and Ibrisim, E}, title = {Effects of intravenous N-acetylcysteine on periprocedural myocardial injury after on-pump coronary artery by-pass grafting.}, journal = {The Journal of cardiovascular surgery}, volume = {49}, number = {4}, pages = {527-531}, pmid = {18665117}, issn = {0021-9509}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Antioxidants/*administration &amp; dosage ; Biomarkers/blood ; Coronary Artery Bypass/*adverse effects ; Creatine Kinase, MB Form/blood ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Myocardial Reperfusion Injury/etiology/pathology/*prevention &amp; control ; Myocardium/metabolism/*pathology ; Prospective Studies ; Time Factors ; Treatment Failure ; Troponin T/blood ; }, abstract = {AIM: Myocardial ischemia/reperfusion injury in patients undergoing coronary artery by-pass grafting (CABG) involves the reperfusion-induced conversion of reversible injured myocardial and endothelial cells. N-acetylcysteine (NAC) has a potential being the minimization of the impact of reperfusion injury. The aim of this study was to evaluate the effects of intravenous NAC on periprocedural myocardial injury after CABG.<br><br>METHODS: The population of this prospective-randomized, double blind, placebo controlled study consisted of 40 patients undergoing on-pump CABG. All the patients were treated with standard medical therapy and eligible patients were randomized to NAC group (N.=19; intravenous infusion for 1 hour before the procedure at a dose of 50 mg/kg, followed by intravenous infusion for 48 hours after the operation at a dose of 50 mg/kg/day) and placebo (saline) group (N.=21). The study drug and placebo infusions were set to infuse at the same rate.<br><br>RESULTS: Demographic and procedural variables were similar in the both groups (All P>0.05). Creatine kinase MB isoform (CK-MB) mass levels did not significantly differ between the groups at both preoperative and postoperative periods. Similarly, cTnT levels were similar in the groups at all periods. Eight patients in the NAC group and 7 in the placebo group had increased CK-MB >3 times normal value. However, only 3 patients in the NAC group experienced CK-MB>5 times normal value.<br><br>CONCLUSION: Results of this study indicated that periprocedural use of NAC as intravenously did not attenuate myocardial damage after on-pump CABG surgery.}, }
@article {pmid18664129, year = {2008}, author = {Filatova, NA and Kirpichnikova, KM and Gamaleĭ, IA}, title = {[Reorganization of actin cytoskeleton in 3T3-SV40 cells and their sensitivity to lysis by natural killer cells].}, journal = {Tsitologiia}, volume = {50}, number = {3}, pages = {261-267}, pmid = {18664129}, issn = {0041-3771}, mesh = {3T3 Cells ; Actins/*physiology ; Animals ; Cell Line, Transformed/*immunology/*metabolism ; Cytotoxicity, Immunologic ; Killer Cells, Natural/*immunology ; Mice ; Simian virus 40 ; }, abstract = {The present work was aimed to examine whether the actin reorganization of 3T3-SV40 cells influences their sensitivity to natural killer (NK) cells activity. The effects of N-acetylcystein (NAC) and latrunculin B, actin depolimerizator, on both cellular parameters were studied. Experiments with NAC demonstrated that 3T3-SV40 sensitivity to NK cells activity remained unchanged under the disordered microfilaments but decreased upon the appearance of structured stress-fibres. The data on latrunculin B action resulted in the opposite conclusion: the more microfilaments disorganization in the presence of latrunculin B the lesser 3T3-SV40 sensitivity to lysis by NK cells. These facts suggest that relations between microfilament integrity in 3T3-SV40 cells and their sensitivity to NK cells are rather independent. The latter confirms our previous conclusion (Gamaley et al., 2006). Decrease in 3T3-SV40 sensitivity to NK cells activity accompanied by actin reorganization resulted from both latrunculin B and NAC action suggests changes in cellular surface, which ultimately lead to inactivation (or loss) of the molecules being activating signals to NK cells.}, }
@article {pmid18662630, year = {2008}, author = {Pagel, PS and Krolikowski, JG and Pratt, PF and Shim, YH and Amour, J and Warltier, DC and Weihrauch, D}, title = {Reactive oxygen species and mitochondrial adenosine triphosphate-regulated potassium channels mediate helium-induced preconditioning against myocardial infarction in vivo.}, journal = {Journal of cardiothoracic and vascular anesthesia}, volume = {22}, number = {4}, pages = {554-559}, pmid = {18662630}, issn = {1532-8422}, support = {R01 HL054820-11/HL/NHLBI NIH HHS/United States ; HL 054820/HL/NHLBI NIH HHS/United States ; R01 HL054820/HL/NHLBI NIH HHS/United States ; P01 GM066730-040001/GM/NIGMS NIH HHS/United States ; GM 066730/GM/NIGMS NIH HHS/United States ; P01 GM066730/GM/NIGMS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/*physiology ; Animals ; Helium/pharmacology/*therapeutic use ; Ischemic Preconditioning, Myocardial/*methods ; Male ; Mitochondria, Heart/drug effects/physiology ; Myocardial Infarction/metabolism/*prevention &amp; control ; Potassium Channels/*physiology ; Rabbits ; Reactive Oxygen Species/*metabolism ; }, abstract = {OBJECTIVES: Helium produces preconditioning by activating prosurvival kinases, but the roles of reactive oxygen species (ROS) or mitochondrial adenosine triphosphate-regulated potassium (K(ATP)) channels in this process are unknown. The authors tested the hypothesis that ROS and mitochondrial K(ATP) channels mediate helium-induced preconditioning in vivo.<br><br>DESIGN: A randomized, prospective study.<br><br>SETTING: A university research laboratory.<br><br>PARTICIPANTS: Male New Zealand white rabbits.<br><br>INTERVENTIONS: Rabbits (n = 64) were instrumented for the measurement of systemic hemodynamics and subjected to a 30-minute left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. In separate experimental groups, rabbits (n = 7 or 8 per group) were randomly assigned to receive 0.9% saline (control) or 3 cycles of 70% helium-30% oxygen administered for 5 minutes interspersed with 5 minutes of an air-oxygen mixture before LAD occlusion with or without the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2 mercaptoproprionyl glycine (2-MPG; 75 mg/kg), or the mitochondrial K(ATP) antagonist 5-hydroxydecanoate (5-HD; 5 mg/kg). Statistical analysis of data was performed with analysis of variance for repeated measures followed by Bonferroni's modification of a Student t test.<br><br>MEASUREMENTS AND MAIN RESULTS: The myocardial infarct size was determined by using triphenyltetrazolium chloride staining and presented as a percentage of the left ventricular area at risk. Helium significantly (p < 0.05) reduced infarct size (23 +/- 4% of the area at risk; mean +/- standard deviation) compared with control (46 +/- 3%). NAC, 2-MPG, and 5-HD did not affect irreversible ischemic injury when administered alone (49 +/- 5%, 45 +/- 6%, and 45 +/- 3%), but these drugs blocked reductions in infarct size produced by helium (45 +/- 4%, 45 +/- 2%, and 44 +/- 3%).<br><br>CONCLUSIONS: The results suggest that ROS and mitochondrial K(ATP) channels mediate helium-induced preconditioning in vivo.}, }
@article {pmid18661381, year = {2008}, author = {Guler, G and Turkozer, Z and Tomruk, A and Seyhan, N}, title = {The protective effects of N-acetyl-L-cysteine and epigallocatechin-3-gallate on electric field-induced hepatic oxidative stress.}, journal = {International journal of radiation biology}, volume = {84}, number = {8}, pages = {669-680}, doi = {10.1080/09553000802241747}, pmid = {18661381}, issn = {0955-3002}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Catechin/*analogs &amp; derivatives/pharmacology ; Electromagnetic Fields/*adverse effects ; Glutathione Peroxidase/metabolism ; Guinea Pigs ; Lipid Peroxidation ; Liver/metabolism/*radiation effects ; Male ; Nitric Oxide/biosynthesis ; Oxidative Stress/*radiation effects ; Peroxidase/metabolism ; Radiation-Protective Agents/*pharmacology ; }, abstract = {PURPOSE: To investigate the effects of 12 kV/m electric (E) field sourced by power lines on oxidative and nitrosative stress, and antioxidant status. Furthermore, the study aimed to examine the protective effects of N-Acetyl-L-cysteine (NAC) and epigallocatechin-gallate (EGCG) in the liver tissues of guinea pigs against the possible detriments of electromagnetic field exposure.<br><br>MATERIALS AND METHODS: Guinea pigs were exposed to 50 Hz 12 kV/m E-field. NAC and EGCG were administered intraperitoneally. Malonedialdehyde (MDA), a product of lipid peroxidation (LPO), and nitric oxide derivatives (nitrate (NO(3)), nitrite (NO(2)), total level of nitric oxide (NO(x)) were estimated as biomarkers of oxidative and nitrosative stress, respectively. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and myeloperoxidase (MPO) were evaluated as endogenous antioxidant enzymes in liver tissues of the guinea pigs.<br><br>RESULTS: The results of our study indicated a significant increase in the levels of oxidant products (MDA, NO(3), NO(2), NO(x)), and a significant decrease in antioxidant enzyme (SOD, GSH-Px and MPO) activities. We also found that the individual or plus application of NAC and EGCG resulted in the reduction of oxidative stress prior to E field application.<br><br>CONCLUSION: To conclude, extremely low frequency (ELF) electric field has potential harmful effects on the living organisms by enhancing the free radical production. NAC and EGCG might have hepatoprotective effects in ELF-E field induced oxidative and nitrosative stress.}, }
@article {pmid18657320, year = {2008}, author = {Liu, J and Yoshida, Y and Yamashita, U}, title = {DNA-binding activity of NF-kappaB and phosphorylation of p65 are induced by N-acetylcysteine through phosphatidylinositol (PI) 3-kinase.}, journal = {Molecular immunology}, volume = {45}, number = {15}, pages = {3984-3989}, doi = {10.1016/j.molimm.2008.06.012}, pmid = {18657320}, issn = {0161-5890}, mesh = {Acetylcysteine/*pharmacology ; Active Transport, Cell Nucleus ; Agammaglobulinaemia Tyrosine Kinase ; Antioxidants/*pharmacology ; Ascorbic Acid/metabolism/pharmacology ; Cell Line ; Cell Nucleus/metabolism ; DNA/*metabolism ; Humans ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Phosphatidylinositol 3-Kinases/*physiology ; Phosphorylation ; Protein Binding ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Thiourea/analogs &amp; derivatives/pharmacology ; Transcription Factor RelA/antagonists &amp; inhibitors/metabolism ; }, abstract = {N-Acetylcysteine (NAC) has been widely used as an antioxidant in research, however, it has also been found to reduce the binding of TNF to its receptor independent of its antioxidative role. In this study, we investigated the effect of NAC on NF-kappaB activation. In HeLa cells, Hep3B cells, and A549 cells, DNA-binding activity of NF-kappaB was induced by NAC without any other stimulation but not by tetramethylthiourea (TMTU) or vitamin C, suggesting that ROS is not involved in the effect of NAC. The degradation of IkappaBalpha and nuclear translocation of NF-kappaB were not induced by NAC. The phosphorylation of p65 at serine 536 was induced by NAC, which is known to contribute to the enhancement of DNA-binding activity of NF-kappaB, however, NAC did not directly phosphorylate p65. The NAC-induced DNA-binding activity of NF-kappaB and phosphorylation of p65 were sensitive to a phosphatidylinositol (PI) 3-kinase inhibitor, partially sensitive to an IkappaB kinase (IKK) inhibitor, but not sensitive to a Bruton's tyrosine kinase (Btk) inhibitor. Moreover, both the DNA-binding activity and phosphorylation induced by NAC were reduced by the overexpression of a dominant negative Akt in HeLa cells. These results suggest that NAC activates mainly PI3K to phosphorylate p65 and subsequently induces DNA-binding activity of NF-kappaB, independent of its antioxidative function.}, }
@article {pmid18652771, year = {2008}, author = {Birnbaum, J and Klotz, E and Spies, CD and Mueller, J and Vargas Hein, O and Feller, J and Lehmann, C}, title = {Impact of combined C1 esterase inhibitor/coagulation factor XIII or N-acetylcysteine/tirilazad mesylate administration on leucocyte adherence and cytokine release in experimental endotoxaemia.}, journal = {The Journal of international medical research}, volume = {36}, number = {4}, pages = {748-759}, doi = {10.1177/147323000803600417}, pmid = {18652771}, issn = {0300-0605}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/therapeutic use ; Cell Adhesion/physiology ; Complement C1 Inhibitor Protein/*therapeutic use ; Cytokines/*blood/immunology ; Drug Therapy, Combination ; Endothelium, Vascular/cytology/metabolism ; *Endotoxemia/drug therapy/immunology ; Factor XIII/*therapeutic use ; Humans ; Leukocytes/cytology/*metabolism ; Male ; Pregnatrienes/*therapeutic use ; Random Allocation ; Rats ; Rats, Wistar ; }, abstract = {We determined the effects of combinations of C1 esterase inhibitor (C1-INH) with factor XIII and of N-acetylcysteine (NAC) with tirilazad mesylate (TM) during lipo-polysaccharide (LPS)-induced endotoxaemia in rats. Forty Wistar rats were divided into four groups: the control (CON) group received no LPS; the LPS, C1-INH + factor XIII and NAC + TM groups received endotoxin infusions (5 mg/kg per h). After 30 min of endotoxaemia, 100 U/kg C1-INH + 50 U/kg factor XIII was administered to the C1-INH + factor XIII group, and 150 mg/kg NAC + 10 mg/kg TM was administered in the NAC + TM group. Administration of C1-INH + factor XIII and NAC + TM both resulted in reduced leucocyte adherence and reduced levels of interleukin-1beta (IL-1beta). The LPS-induced increase in IL-6 levels was amplified by both drug combinations. There was no significant effect on mesenteric plasma extravasation. In conclusion, the administration of C1-INH + factor XIII and NAC + TM reduced endothelial leucocyte adherence and IL-1beta plasma levels, but increased IL-6 levels.}, }
@article {pmid18651549, year = {2008}, author = {Bulucu, F and Oktenli, C and Kenar, L and Ocal, R and Koc, B and Inal, V and Yamanel, L and Yaman, H and Sanisoglu, YS and Aydin, A}, title = {Efficacy of deferoxamine, N-acetylcysteine and selenium treatments in rats with Adriamycin-induced nephrotic syndrome.}, journal = {Journal of nephrology}, volume = {21}, number = {4}, pages = {576-583}, pmid = {18651549}, issn = {1121-8428}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antibiotics, Antineoplastic/toxicity ; Colorimetry ; Creatinine/blood/urine ; Deferoxamine/*therapeutic use ; Disease Models, Animal ; Doxorubicin/toxicity ; Drug Therapy, Combination ; Erythrocytes/drug effects/metabolism ; Free Radical Scavengers/therapeutic use ; Kidney/drug effects/metabolism ; Male ; Nephrotic Syndrome/chemically induced/*drug therapy/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Selenium/*therapeutic use ; Siderophores/therapeutic use ; Treatment Outcome ; }, abstract = {BACKGROUND: Various experimental models related to Adriamycin (ADR)-induced nephropathy have been reported. The purpose of the present study was to evaluate the efficacy of N-acetylcysteine (NAC), deferoxamine (DFO) and selenium in protection against renal injury in ADR nephropathy.<br><br>METHODS: The study included 53 Sprague Dawley male rats. Nephrotic syndrome was induced by injection of ADR 5 mg/kg intravenously (n=46). Control rats (n=7) were injected with an equal volume of isotonic saline. After ADR administration, they were divided into a group given only ADR (n=17) and 3 antioxidant treatment groups: (i) NAC (n=10), (ii) DFO (n=10) and (iii) selenium (n=9). In both renal tissue and erythrocytes, oxidative system parameters and trace elements were determined.<br><br>RESULTS: Nephrotic syndrome was proven in ADR-injected rats 4 weeks after injections, with proteinuria, higher blood lipids and hypoalbuminemia. All of the antioxidant agents used in the present study to prevent the development of nephrotic syndrome provided benefits for the nephrotic state. Of them, selenium seemed to offer relatively lower and statistically insignificant efficacy for preventing proteinuria compared with the others.<br><br>CONCLUSIONS: Our results showed that concomitant administration of some antioxidants with ADR injections seems to have beneficial effects on clinical parameters even if antioxidants were given in a single dose. NAC and DFO are more effective than selenium to prevent renal injury.}, }
@article {pmid18650254, year = {2008}, author = {Roomi, MW and Kalinovsky, T and Ivanov, V and Rath, M and Niedzwiecki, A}, title = {A nutrient mixture prevents acetaminophen hepatic and renal toxicity in ICR mice.}, journal = {Human &amp; experimental toxicology}, volume = {27}, number = {3}, pages = {223-230}, doi = {10.1177/0960327108090276}, pmid = {18650254}, issn = {0960-3271}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Ascorbic Acid/pharmacology ; Aspartate Aminotransferases/blood ; Blood Urea Nitrogen ; Creatinine/blood ; Kidney/*drug effects/pathology ; Liver/*drug effects/pathology ; Lysine/pharmacology ; Male ; Mice ; Mice, Inbred ICR ; Organ Size/drug effects ; Proline/pharmacology ; Tea ; }, abstract = {Acetaminophen (APAP) overdose is often fatal, leading to fulminant hepatic and renal tubular necrosis in humans and animals. We studied the effect of a nutrient mixture (NM) containing, among other nutrients, lysine, proline, ascorbic acid, N-acetyl cysteine, and green tea extract, which has previously been demonstrated to exhibit a broad spectrum of therapeutic properties on APAP-induced hepatic and renal damage in ICR (Imprinting Control Region) mice. Seven-week-old male ICR mice were divided into four groups (A-D) of five animals each. Groups A and C mice were fed a regular diet for 2 weeks, while groups B and D mice were supplemented with 0.5% NM (w/w) during that period. Groups A and B received saline i.p., while groups C and D received APAP (600 mg/kg) i.p. All animals were killed 24 h after APAP administration, serum was collected to assess the liver and kidney functions, and the livers and kidneys were excised for histology. Mean serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, BUN (Blood Urea Nitrogen), creatinine, and BUN/creatinine ratios were comparable in groups A and B, increased markedly in group C and significantly lower in group D compared with group C. APAP caused significant centrilobular necrosis and glomerular damage in unsupplemented animals, while NM prevented these alterations. The results indicate that NM has potential to protect against APAP-induced liver and kidney damage.}, }
@article {pmid18647532, year = {2008}, author = {Liu, YY and Xie, Q and Wang, H and Lin, LY and Jiang, S and Zhou, XQ and Yu, H and Guo, Q}, title = {[The effect of N-acetyl-L-cysteine on endoplasmic reticulum stress mediated apoptosis of HepG2 cells].}, journal = {Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology}, volume = {16}, number = {7}, pages = {524-527}, pmid = {18647532}, issn = {1007-3418}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Chaperone BiP ; Hep G2 Cells ; Humans ; Hydrogen Peroxide ; *Oxidative Stress ; Reactive Oxygen Species/adverse effects ; }, abstract = {OBJECTIVE: To analyze the mechanisms of NAC on endoplasmic reticulum (ER) stress mediated cells apoptosis of HepG2 cells and to evaluate the potential role of NAC in the treatment of liver injury.<br><br>METHODS: HepG2 cells were treated with H2O2 to make a model of oxidative ER stress mediated apoptosis. To evaluate the apoptosis, various methods such as MTT, DNA ladder, Western blot and flow cytometry were used. Then the optimal dosage and incubation time of NAC intervention in apoptosis were ascertained, and the differences between induction and intervention of apoptosis, including the percentage of apoptosis, the expression of apoptotic protein (GRP78, Caspase-12, PARP) and the production of reactive oxygen species (ROS) were compared.<br><br>RESULTS: The activity of the cells decreased by H2O2 (0, 1, 3, 5 mmol/L) treatments in a dose-dependent manner. The ratio of apoptotic cells increased (0.7%+/-0.5%, 26.4%+/-1.8%, 29.7%+/-1.2% and 51.2%+/-9.4%, respectively) as did the production of ROS (14.0%+/-0.5%, 95.2%+/-0.1%, 97.5%+/-0.2% and 98.3%+/-0.2%, respectively). The HepG2 cells showed typical morphologic change of ER stress 6 hr after they were treated with 3 mmol/L H2O2. ER stress mediated-apoptosis was confirmed by Western blot. NAC (10 mmol/L and 20 mmol/L) protected cells from apoptosis. Typical features of ER stress apoptosis were seen accompanied by diminishing the ratio of apoptotic cells from 29.7%+/-1.2% to 23.3%+/-4.7% and 14.3%+/-1.2%. The production of ROS also decreased from 97.5%+/-0.2% to 52.2%+/-0.8% and 51.2%+/-2.9%. The effect was related to the concentration: 20 mmol/L NAC was more effective than 10 mmol/L.<br><br>CONCLUSIONS: As an oxidizing agent, H2O2 may induce ROS in cells and induce oxidative stress, causing ER stress and apoptosis. NAC can inhibit the procession of ROS directly and prevent injuries to the hepatocytes.}, }
@article {pmid18647523, year = {2008}, author = {Wang, N and Shi, XF and Guo, SH and Zhang, DZ and Ren, H}, title = {[A clinical study of N-acetylcysteine treatment in chronic hepatitis B patients].}, journal = {Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology}, volume = {16}, number = {7}, pages = {487-489}, pmid = {18647523}, issn = {1007-3418}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Bilirubin/blood ; Female ; Glutathione/therapeutic use ; Hepatitis B, Chronic/blood/*drug therapy ; Humans ; Male ; Middle Aged ; Treatment Outcome ; }, abstract = {OBJECTIVE: To evaluate the efficacy and safety of N-acetylcysteine (NAC) and glutathione (GSH) in treating chronic hepatitis B patients.<br><br>METHODS: Seventy-five patients with chronic hepatitis B were treated daily with an injection containing the same basic therapeutic drugs and randomly divided into a NAC group (50 patients) and a GSH group (25 patients). A daily dose of 8 grams of NAC and 1.2 grams of GSH was added to the injections of the two groups respectively. The trial lasted 28 days. Hepatic function and other biochemistry parameters (TBil, PTA, ALB et al) were tested on experimental day 0 and on days 7, 14, 21 and 28. The evaluation on the total effective rates of the NAC and GSH groups was based on the decreases of serum TBil and the increases of PTA.<br><br>RESULTS: Both NAC and GSH have therapeutic effects. The total effective rate was 84% in the NAC group and 72% in the GSH group. The rate of side effects was 13% in the NAC group.<br><br>CONCLUSION: NAC and GSH can decrease the level of serum TBil and increase PTA, but NAC was more effective in decreasing TBil than GSH. Serious adverse effects of NAC were not observed during the period of our treatment.}, }
@article {pmid18645718, year = {2008}, author = {Zanchi, AC and Venturini, CD and Saiki, M and Nascimento Saldiva, PH and Tannhauser Barros, HM and Rhoden, CR}, title = {Chronic nasal instillation of residual-oil fly ash (ROFA) induces brain lipid peroxidation and behavioral changes in rats.}, journal = {Inhalation toxicology}, volume = {20}, number = {9}, pages = {795-800}, doi = {10.1080/08958370802009060}, pmid = {18645718}, issn = {1091-7691}, mesh = {Acetylcysteine/pharmacology ; Administration, Intranasal ; Air Pollutants/*toxicity ; Animals ; Behavior, Animal/*drug effects ; Brain/*drug effects/metabolism ; Carbon/*toxicity ; Coal Ash ; Disease Models, Animal ; Exploratory Behavior/drug effects ; Free Radical Scavengers/pharmacology ; Lipid Peroxidation/*drug effects ; Male ; Motor Activity/drug effects ; Oxidative Stress/*drug effects ; Particulate Matter/*toxicity ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Several epidemiological studies have linked particulate matter exposure to numerous adverse health effects on the respiratory, cardiovascular, and reproductive systems (Braga et al., 1999; Zanobetti et al., 2000; Anderson et al., 2001; Farhat et al., 2005). More recently, ambient levels of black carbon were associated to impaired cognitive function in children (Suglia et al., 2008), suggesting that the central nervous system (CNS) may be a target of air pollutants. The present study was conducted to (a) determine whether chronic residual oil fly ash (ROFA) exposure promotes behavioral changes and lipid peroxidation in rat brain areas, and (b) determine whether N-acetylcysteine (NAC), a general antioxidant, prevents these effects. Forty-five-day-old male Wistar rats were exposed or not to ROFA by intranasal instillation and were treated or not with NAC (150 mg/kg) ip for 30 days. One day later, rats were submitted to the open field test to evaluate the motor/exploratory activities and emotionality followed by decapitation. Striatum and cerebellum were dissected to determine lipid peroxidation by the accumulation of thiobarbituric acid-reactive substances (TBARS). ROFA instillation induced an increase in lipid peroxidation level in striatum (p = .033) and cerebellum (p = .030), as compared with the control group. NAC treatment blocked these changes. ROFA promoted a decrease in the frequency of peripheral walking (p = .006) and a decrease in exploration (p = .001), which were not blocked by N-acetylcysteine. The present study provides evidence that toxic particles, administered by the respiratory route, induce oxidative stress in structures of the central nervous system, as well as behavioral alterations. The administration of NAC reduces lipid peroxidation at the striatum and cerebellum levels, but does not influence behavioral disturbances.}, }
@article {pmid18642776, year = {2008}, author = {Xu, CF and Wu, AR and Shen, YZ}, title = {[Effects of N-acetylcysteine on mRNA expression of monocyte chemotactic protein and macrophage inflammatory protein 2 in acute necrotizing pancreatitis: experiment with rats].}, journal = {Zhonghua yi xue za zhi}, volume = {88}, number = {10}, pages = {711-715}, pmid = {18642776}, issn = {0376-2491}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chemokine CCL2/*genetics ; Chemokine CXCL2/*genetics ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Male ; Pancreas/*drug effects/metabolism/pathology ; Pancreatitis, Acute Necrotizing/*physiopathology ; RNA, Messenger/genetics/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {OBJECTIVE: To explore the potential role of monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 2 (MIP-2) in the pathogenesis of acute necrotizing pancreatitis (ANP), and to study the effect of N-acetylcysteine (NAC) on the mRNA expression of MCP-1 and MIP-2.<br><br>METHODS: Thirty-five SD rats were randomly divided into 3 groups: sham-operation (SO) group (n = 5), acute necrotizing pancreatitis (ANP) group (n = 15), and NAC-pretreated group (n = 15), ANP were induced by retrograde injection of 4% sodium taurocholate into the biliopancreatic duct. The NAC- groups underwent intraperitoneal injection of NAC 500 mg/kg 30 minutes before the induction of sodium taurocholate. The ANP and NAC groups were re-divided into 3 equal subgroups respectively: 3 h, 6 h, and 12 h subgroups. 3, 6, and 12 hours after the establishment of models heart blood samples were collected from 5 rats from each model group to detect the serum amylase. Then the rats were killed by blood letting with their pancreases taken out. HE staining and microscopy were used to observe the pathological changes of the pancreas. The wet/dry ratio of pancreas was determined. Enzyme histochemical method was used to detect the activity of myeloperoxidase (MPO) in the pancreas. RT-PCR was used to examine the mRNA expression of MCP-1 and MIP-2.<br><br>RESULTS: The levels of serum amylase, wet/dry ratio of pancreas, pancreatic MPO activity, and histological score of pancreas of the ANP group increased time-dependently, all the levels at different time-points were significantly higher than those of the SO group (all P < 0.01). The expression levels of MCP-1 mRNA at the time points 3, 6, and 12 h of the ANP group were 0.3653 +/- 0.0213, 0.5890 +/- 0.0225, and 0.7164 +/- 0.0275 respectively, all significantly higher than that of the SO group (0.1492 +/- 0.0036, all P < 0.01). The expression levels of MIP-2 mRNA at different time points of the ANP group were 0.3871 +/- 0.0286, 0.6040 +/- 0.0448, and 0.7692 +/- 0.0620 respectively, all significantly higher than that of the SO group (0.1593 +/- 0.0117, all P < 0.01). The intrapancreatic MPO levels at the time points 3 h, 6 h, and 12 h of the NAC group were 0.63 +/- 0.03, 0.88 +/- 0.05, and 1.31 +/- 0.09 respectively, all significantly lower than those of the ANP groups (0.89 +/- 0.03, 1.42 +/- 0.14, and 1.94 +/- 0.07, all P < 0.05). The MCP-1 mRNA expression levels at different time points the NAC group were 0.2497 +/- 0.0168, 0.4457 +/- 0.0097, and 0.6306 +/- 0.0423 respectively, and the MIP-2 mRNA expression levels at the time points 3 h, 6 h, and 12 h of the NAC group were 0.2436 +/- 0.0099, 0.4312 +/- 0.0221, and 0.6302 +/- 0.0288 respectively, all significantly lower than those of the ANP group (all P < 0.05). The pancreatic histological scores at different time points of the NAC group were 3.50 +/- 0.61, 5.60 +/- 0.65, and 7.50 +/- 0.79, all significantly lower than those of the ANP group (5.10 +/- 0.42, 7.50 +/- 0.50, and 9.90 +/- 0.96, all P < 0.05). The MCP-1 mRNA expression and MIP-2 mRNA expression were both correlated with the severity of pancreatic injury (r = 0.76 and 0.82, both P < 0.05).<br><br>CONCLUSION: The chemokines of MCP-1 and MIP-2 are overexpressed at the early stage of acute pancreatitis. Both of them may play an important role in the pathogenesis of AP. NAC may have beneficial effects on AP through downregulation of the expression of MCP-1 and MIP-2.}, }
@article {pmid18637830, year = {2008}, author = {Cumbo-Nacheli, G and Weinberger, J and Alkhalil, M and Thati, N and Baptist, AP}, title = {Anticonvulsant hypersensitivity syndrome: is there a role for immunomodulation?.}, journal = {Epilepsia}, volume = {49}, number = {12}, pages = {2108-2112}, doi = {10.1111/j.1528-1167.2008.01720.x}, pmid = {18637830}, issn = {1528-1167}, mesh = {Anticonvulsants/*adverse effects/*immunology ; Drug Hypersensitivity/drug therapy/*etiology ; Epilepsy/drug therapy ; Erythema/chemically induced/drug therapy ; Exanthema/chemically induced/drug therapy ; Female ; Glucocorticoids/therapeutic use ; Humans ; Immunoglobulins, Intravenous/therapeutic use ; Methylprednisolone/therapeutic use ; Middle Aged ; }, abstract = {The anticonvulsant hypersensitivity syndrome (AHS) is an idiosyncratic immunologic reaction to certain anticonvulsant medications, in which internal organ involvement may lead to fatal multisystemic failure. This syndrome has been associated with the use of aromatic ring-containing agents such as phenytoin, carbamazepine, or phenobarbitone. Clinically, this condition presents with the classic triad of fever, rash, and lymphadenopathy. We review the existing literature on AHS pathogenesis and illustrate a case complicated by liver dysfunction where the use of N-acetylcysteine (N-AC) and intravenous immunoglobulin (IVIG) may have altered the course of the disease. The rationale of suggesting N-AC and IVIG for the treatment of this syndrome relies on the theoretical synergistic effects of the two agents. Although treatment for this syndrome remains controversial and relies heavily on anecdotal evidence, the progression of hepatic injury may be prevented by the addition of N-AC. The scavenging properties of N-AC may palliate and possibly prevent free radical-mediated liver damage. In addition, IVIG may effectively modulate the overreactive immune system in AHS. We discuss the possible role of using immunomodulating agents for the treatment of this syndrome and suggest that alternative regimens should be given special consideration especially in those critical clinical situations where supportive measures appear to be unsuccessful.}, }
@article {pmid18635816, year = {2009}, author = {Bartling, TR and Drumm, ML}, title = {Oxidative stress causes IL8 promoter hyperacetylation in cystic fibrosis airway cell models.}, journal = {American journal of respiratory cell and molecular biology}, volume = {40}, number = {1}, pages = {58-65}, pmid = {18635816}, issn = {1535-4989}, support = {HL68883/HL/NHLBI NIH HHS/United States ; P30 DK027651/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylation ; Acetylcysteine/metabolism ; Animals ; Cell Line ; *Cystic Fibrosis/genetics/metabolism ; Cytokines/genetics/metabolism ; Epithelial Cells/cytology/*metabolism ; Free Radical Scavengers/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; *Interleukin-8/genetics/metabolism ; Oxidants/metabolism ; Oxidative Stress/*physiology ; *Promoter Regions, Genetic ; Respiratory Mucosa/*cytology ; Transcription, Genetic ; }, abstract = {Dysregulated inflammation has been implicated in cystic fibrosis (CF) airway pathophysiology. The expression of inflammatory genes, like interleukin 8 (IL8), involves chromatin remodeling through histone acetylation. Inflammatory gene hyperacetylation could explain inflammatory mediator dysregulation seen in CF airways. CF airways are exposed to high levels of oxidative stress, and oxidative stress increases histone acetylation and inflammatory gene transcription. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) may even reduce protection against oxidative stress. Consequently, increasing oxidative stress would likely lead to an imbalance of histone acetyl-transferase (HAT) and deacetylase (HDAC) stoichiometry and contribute to the heightened inflammatory response seen in the CF airway. We hypothesize that oxidative stress in CF airways causes increased acetylation of inflammatory gene promoters, contributing to transcriptional activity of these loci. Messenger RNA levels of IL8, IL6, CXCL1, CXCL2, CXCL3, and IL1 are significantly elevated in CF epithelial cell models. Histone H4 acetylation is lower at the IL8 promoter of the non-CF cell lines than the CF models. The reducing agent N-acetyl-cysteine decreases IL8 message and promoter H4 acetylation to non-CF levels, suggesting that oxidative stress contributes to IL8 expression in these models. H(2)O(2) treatment causes increased IL-8 acetylation and mRNA in all cells, but less in the CF-model cells. Together these data suggest a model in which cells without functional CFTR are under increased oxidative stress. Our data suggest intrinsic alterations in the HAT/HDAC balance in CFTR-deficient cells, and that oxidative stress contributes to this alteration.}, }
@article {pmid18630824, year = {2008}, author = {Saviuc, P and Danel, V}, title = {[Acute acetaminophen overdose].}, journal = {La Revue du praticien}, volume = {58}, number = {8}, pages = {861-865}, pmid = {18630824}, issn = {0035-2640}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/therapeutic use ; Analgesics, Non-Narcotic/*adverse effects ; Antidotes/therapeutic use ; Chemical and Drug Induced Liver Injury/prevention &amp; control ; Drug Overdose/drug therapy ; Humans ; }, abstract = {Acute ingestion of acetaminophen can induce a dose-dependent hepatotoxicity and lead to death. The management of acute acetaminophen poisoning at the early stage is well codified. A reported amount of ingestion > 200 mg/kg in a child, > 150 mg/kg in an adult (125 mg/kg if risk factors are present) require hospitalisation. Activated charcoal is administered within 1-2 hours of ingestion. AST/ALT levels are measured on admission, 12 hours after, and according to outcome every 12-24 h. N-acetylcysteine (NAC) administration within 8-10 hours protects against acetaminophen-induced hepatotoxicity. The two protocols of NAC administration, intravenous and oral, have a comparable effectiveness. NAC is indicated if the serum acetaminophen level drawn 4 hours after ingestion and plotted on the nomograme falls above the "200 mg/L-4 hours" line. Nomograme is not usable with repeated acute ingestion or repeated supratherapeutic doses; presence of risk factors (enzymatic induction, malnutrition, chronic alcoholism) must be taken into account ("100 mg/L - 4 hours" line). Outcome is favorable with respect to these conditions.}, }
@article {pmid18630691, year = {2008}, author = {Jiang, XF and Zeng, WY and Pu, J and Liu, YM}, title = {[Effect of N-acetylcysteine on lipopolysaccharide stimulating IL-8 expression of human uterine smooth cell].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {39}, number = {2}, pages = {235-238}, pmid = {18630691}, issn = {1672-173X}, mesh = {Acetylcysteine/*pharmacology ; Blotting, Western ; Cells, Cultured ; Female ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Humans ; Interleukin-8/biosynthesis/*genetics ; Lipopolysaccharides/*pharmacology ; Myocytes, Smooth Muscle/cytology/*drug effects/metabolism ; RNA, Messenger/biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factor RelA/biosynthesis/genetics ; Uterus/*cytology ; }, abstract = {OBJECTIVE: To investigate the effects of N-acetylcysteine (NAC)on the expression of IL-8 and the activity of NF-kappaB, which are induced by lipopolysaccharide (LPS) in human uterine smooth cell.<br><br>METHODS: Human uterine smooth cells were primarily cultured and stimulated by LPS after pretreated by 5,10,15 mmol/L NAC and normal saline (NS). ELISA was performed to measure the expression of IL-8 protein in supernatants and RT-PCR was used to detect the IL-8 mRNA expression. The expression of NF-kappaB P65 protein was detected by Western Blotting. Furthermore, the expression of IL-8 mRNA and protein were detected at 0, 3, 6, 12, 24 and 48 h after LPS challenge in human smooth cell pretreated by 10 mmol/L NAC.<br><br>RESULTS: (1) NAC significantly inhibited IL-8 mRNA expression and production in human uterine smooth cells with a concentration-dependent way (5-15 mmol/L). (2) The decreasing expression of NF-kappaB P65 protein was accompanied with increasing concentration of NAC in accordance with IL-8 mRNA (P < 0.01).<br><br>CONCLUSION: NAC may inhibit the induction IL-8 gene and protein by LPS inhibiting NF-kappaB activation in human uterine smooth cell.}, }
@article {pmid18628444, year = {2008}, author = {Smith, SW and Howland, MA and Hoffman, RS and Nelson, LS}, title = {Acetaminophen overdose with altered acetaminophen pharmacokinetics and hepatotoxicity associated with premature cessation of intravenous N-acetylcysteine therapy.}, journal = {The Annals of pharmacotherapy}, volume = {42}, number = {9}, pages = {1333-1339}, doi = {10.1345/aph.1K680}, pmid = {18628444}, issn = {1542-6270}, mesh = {Acetaminophen/blood/*pharmacokinetics/*poisoning ; Acetylcysteine/*administration &amp; dosage/*therapeutic use ; Aged ; *Chemical and Drug Induced Liver Injury ; Drug Overdose ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Half-Life ; Humans ; Male ; Time Factors ; }, abstract = {OBJECTIVE: To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous N-acetylcysteine (NAC) treatment in the setting of a massive acetaminophen overdose.<br><br>CASE SUMMARY: A 78-year-old man reportedly ingested approximately 96 immediate-release acetaminophen 500-mg tablets (48 g) over a one-hour period in an apparent suicide attempt. The acetaminophen concentration at 2.25 hours was 264 microg/mL. Intravenous NAC was initiated 5 hours postingestion. At 6.25 hours postingestion, the acetaminophen concentration was 281 microg/mL. Following administration of intravenous NAC for 21 hours, therapy was discontinued despite a residual acetaminophen concentration of 116 microg/mL. The patient experienced hepatotoxicity, coagulopathy, and renal injury. Pharmacokinetic analysis revealed significantly prolonged acetaminophen absorption and a second peak acetaminophen concentration of 228 microg/mL approximately 48 hours postingestion. Direct in-hospital monitoring of the patient made a second ingestion unlikely.<br><br>DISCUSSION: Acetaminophen overdose is usually effectively managed with NAC. Patients with massive ingestions may have altered absorption kinetics due to acetaminophen's solubility being exceeded, physiologically or chemically altered gastrointestinal emptying or motility, or other factors. These patients may benefit from gastrointestinal decontamination and prolonged NAC therapy.<br><br>CONCLUSIONS: In patients with massive acetaminophen ingestion, erratic absorption may occur, and toxic serum concentrations may persist beyond a standard 21-hour course of intravenous NAC therapy. Acetaminophen concentrations and aminotransferase levels should be evaluated at the completion of the intravenous NAC infusion to ensure complete elimination of acetaminophen and absence of hepatotoxicity and to exclude the need for prolonged treatment.}, }
@article {pmid18625331, year = {2008}, author = {Fan, J and Cai, H and Yang, S and Yan, L and Tan, W}, title = {Comparison between the effects of normoxia and hypoxia on antioxidant enzymes and glutathione redox state in ex vivo culture of CD34(+) cells.}, journal = {Comparative biochemistry and physiology. Part B, Biochemistry &amp; molecular biology}, volume = {151}, number = {2}, pages = {153-158}, doi = {10.1016/j.cbpb.2008.06.008}, pmid = {18625331}, issn = {1096-4959}, mesh = {Antigens, CD34/metabolism ; Base Sequence ; Catalase/genetics ; Cell Hypoxia/genetics/*physiology ; DNA Primers/genetics ; Fetal Blood/cytology/metabolism ; Flow Cytometry ; Gene Expression ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Glutathione Peroxidase/genetics ; Hematopoietic Stem Cells/immunology/*metabolism ; Humans ; In Vitro Techniques ; Infant, Newborn ; Oxidation-Reduction ; Preservation, Biological ; RNA, Messenger/genetics/metabolism ; Superoxide Dismutase/genetics ; Superoxides/metabolism ; }, abstract = {Hypoxia maintained biological characteristics of CD34(+) cells through keeping lower intracellular reactive oxygen specials (ROS) levels. The effects of normoxia and hypoxia on antioxidant enzymes and glutathione redox state were compared in this study. Hypoxia decreased the mRNA expression of both catalase (CAT) and glutathione peroxidase (GPX), but not affected mRNAs expression of superoxide dismutase (SOD). While the cellular GPX activities under hypoxia were apparently less than those under normoxia, neither SOD activities nor CAT activities were affected by hypoxia. The analysis of glutathione redox status and ROS products showed the lower oxidized glutathione (GSSG) levels, the higher reduced glutathione (GSH) levels, the higher GSH/GSSG ratios, and the less O(2)- and H(2)O(2) generation under hypoxia (versus normoxia). Meanwhile more primary CD34(+)CD38(-) cells were obtained when cultivation was performed under hypoxia or with N-acetyl cysteine (the precursor of GSH) under normoxia. These results demonstrated the different responses of anti-oxidative mechanism between normoxia and hypoxia. Additionally, the present study suggested that the GSH-GPX antioxidant system played an important role in HSPCs preservation by reducing peroxidation.}, }
@article {pmid18622472, year = {2008}, author = {Pereira-Filho, G and Ferreira, C and Schwengber, A and Marroni, C and Zettler, C and Marroni, N}, title = {Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats.}, journal = {Arquivos de gastroenterologia}, volume = {45}, number = {2}, pages = {156-162}, doi = {10.1590/s0004-28032008000200013}, pmid = {18622472}, issn = {0004-2803}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Carbon Tetrachloride ; Collagen/drug effects ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation/drug effects ; Liver Cirrhosis, Experimental/*drug therapy/enzymology/pathology ; Male ; Nitric Oxide/physiology ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress/*drug effects ; Random Allocation ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis which is the main response to the liver injury. The inhalatory carbon tetrachloride is an effective experimental model that triggers cirrhosis and allows to obtain histological and physiological modifications similar to the one seen in humans.<br><br>AIM: To investigate the effects of N-acetylcysteine (NAC) on the fibrosis and oxidative stress in the liver of cirrhotic rats, analyzing liver function tests, lipoperoxidation, activity of glutathione peroxidase enzyme, collagen quantification, histopathology, as well as the nitric oxide role.<br><br>METHODS: The animals were randomly in three experimental groups: control (CO); cirrhotic (CCl4) and CCl4 + NAC. Evaluate the lipid peroxidation, the glutathione peroxidase enzyme, the collagen and the expression of inducible nitric oxide synthase (iNOS).<br><br>RESULTS: The cirrhotic group treated with N-acetylcysteine showed trough the histological analysis and collagen quantification lower degrees of fibrosis. This group has also shown less damage to the cellular membranes, less decrease on the glutathione peroxidase levels and less expression of inducible nitric oxide synthase when matched with the cirrhotic group without treatment.<br><br>CONCLUSION: N-acetylcysteine seams to offer protection against hepatic fibrosis and oxidative stress in cirrhotic rat livers.}, }
@article {pmid18621018, year = {2008}, author = {Freikman, I and Amer, J and Cohen, JS and Ringel, I and Fibach, E}, title = {Oxidative stress causes membrane phospholipid rearrangement and shedding from RBC membranes--an NMR study.}, journal = {Biochimica et biophysica acta}, volume = {1778}, number = {10}, pages = {2388-2394}, doi = {10.1016/j.bbamem.2008.06.008}, pmid = {18621018}, issn = {0006-3002}, mesh = {Antioxidants/pharmacology ; Erythrocyte Membrane/*chemistry/drug effects/*metabolism ; Humans ; Membrane Lipids/*metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Oxidants/pharmacology ; *Oxidative Stress ; Phosphatidylcholines/metabolism ; Phosphatidylserines/metabolism ; Phospholipids/*metabolism ; beta-Thalassemia/blood ; }, abstract = {Nuclear Magnetic Resonance (NMR) spectroscopy was used to investigate the relationship between oxidative stress experienced by RBCs and their phospholipid content and shedding. Using 1H-NMR, we demonstrated a higher lactate/pyruvate ratio, an indicator of oxidative stress, in normal RBCs treated with oxidants (t-butylhydroxyperoxide and H2O2) as well as in beta-thalassemic RBCs. Using 31P-NMR, we found 30% more phosphatidylcholine (PC), and unexpectedly, 35% less phosphatidylserine (PS) in the thalassemic RBCs. PS was decreased by treatment with oxidants and increased by anti-oxidants (vitamin C and N-acetyl cysteine); PC showed the opposite behavior. Thalassemic RBCs incubated in phosphate buffered saline produced more PS in the supernatant than normal RBCs. Anti-oxidants reduced the PS in the supernatant while oxidants increased it. Plasma of thalassemic patients contained 2.6-fold and 1.8-fold more PS and PC, respectively, than normal plasma. These results indicate that the decreased PS in RBCs resulted from increased shedding. The nature of the shed PS was studied by purifying and analyzing membranous microparticles from the plasma and RBC supernatants. More PS was found in microparticles purified from thalassemic plasma and RBC supernatants (5.6- and 4.8-fold, respectively) than in their normal counterparts. However, the bulk (80-90%) of the shed PS was not associated with microparticles. The significance of PS shedding for RBC survival needs further clarification.}, }
@article {pmid18619603, year = {2008}, author = {Oguri, S and Okuya, Y and Yanase, Y and Suzuki, S}, title = {Post-column derivatization capillary electrochromatography for detection of biogenic amines in tuna-meat.}, journal = {Journal of chromatography. A}, volume = {1202}, number = {1}, pages = {96-101}, doi = {10.1016/j.chroma.2008.06.034}, pmid = {18619603}, issn = {0021-9673}, mesh = {Animals ; Biogenic Amines/*analysis ; Capillary Electrochromatography/*methods ; Histamine/analysis ; Reproducibility of Results ; Seafood/*analysis ; Tuna/*metabolism ; }, abstract = {A system to perform post-column derivatization capillary electrochromatography (CEC) was developed for the first time. The system mainly included a 4-microm (O.D.) silica packed column (200 mm effective length x 0.1 mm inner diameter I.D.) with micro-magnetic particles (MMPs) frits, a T-junction connector, an in-line fluorescence detector and a high-voltage power supply. The system was evaluated by using histamine (HA) as a standard biogenic amine for this study. A 5 microM HA solution was loaded at the anodic site of the capillary column by applying 3 kV for 5s. Then, HA was electrophoretically eluted with a 20mM phosphate buffer (pH 7) by applying 3 kV, and was derivatized with 3mM o-phthalaldehyde (OPA)/N-acetylcysteine (NAC) in 100 mM borate (pH 10), which was continuously delivered through the reagent-loading capillary tube by gravity into the T-junction connector. HA derivative was finally detected with the in-line fluorescence detector (lambda(Ex)=340 nm, lambda(Em)=450 nm) at 9.7 min after sample loading. To test the utility of this system, it was next employed for its ability to detect the presence of HA and other kinds of biogenic amines, including cadaverine (Cad), spermidine (Spm) and tyramine (Tyr) in tuna-meat, once the validity of the method had been confirmed.}, }
@article {pmid18618466, year = {2009}, author = {Wang, X and Zheng, C and Wu, Z and Teng, D and Zhang, X and Wang, Z and Li, C}, title = {Chitosan-NAC nanoparticles as a vehicle for nasal absorption enhancement of insulin.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {88}, number = {1}, pages = {150-161}, doi = {10.1002/jbm.b.31161}, pmid = {18618466}, issn = {1552-4981}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Intranasal ; Animals ; Cell Adhesion ; Chitosan/*chemistry ; Insulin/*administration &amp; dosage/*chemistry ; Magnetic Resonance Spectroscopy ; Models, Chemical ; Mucins/chemistry ; Nanoparticles/*chemistry ; Polyphosphates/chemistry ; Rats ; Spectrophotometry, Infrared ; Sulfhydryl Compounds/chemistry ; Surface Properties ; }, abstract = {The purpose of this work was to investigate chitosan-N-acetyl-L-cysteine (chitosan-NAC) nanoparticles as a potential carrier system for the nasal delivery of insulin. For the study, we used insulin-loaded chitosan-NAC nanoparticles (140-210 nm in diameter) prepared by in situ gelation with tripolyphosphate (TPP), with positive zeta potential values of +19.5-31.7 mV and insulin loading capacities of 13-42%. The physicochemical properties of the nanoparticles were affected by the number of thiol groups present. Mucoadhesive properties, which were evaluated by measuring the in vitro absorbed mass of mucin, of chitosan-NAC nanoparticles were >1.8-fold that of unmodified chitosan nanoparticles. In aqueous solution, chitosan-NAC nanoparticles exhibited fast swelling behavior. Insulin was released from chitosan-NAC nanoparticles in vitro in an initial burst followed by slow release. Intranasal administration of chitosan-NAC nanoparticles in rats enhanced the absorption of insulin by the nasal mucosa compared with unmodified chitosan nanoparticles and control insulin solution. In light of these observations, the novel thiolated chitosan nanoparticles represent a promising vehicle for nasal insulin administration.}, }
@article {pmid18617679, year = {2009}, author = {Zhao, Y and Usatyuk, PV and Gorshkova, IA and He, D and Wang, T and Moreno-Vinasco, L and Geyh, AS and Breysse, PN and Samet, JM and Spannhake, EW and Garcia, JG and Natarajan, V}, title = {Regulation of COX-2 expression and IL-6 release by particulate matter in airway epithelial cells.}, journal = {American journal of respiratory cell and molecular biology}, volume = {40}, number = {1}, pages = {19-30}, pmid = {18617679}, issn = {1535-4989}, support = {R01 HL071152/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Baltimore ; CCAAT-Enhancer-Binding Protein-beta/genetics/metabolism ; Cyclooxygenase 2/genetics/*metabolism ; Cytokines/metabolism ; Dinoprostone/genetics/metabolism ; Epithelial Cells/cytology/*metabolism ; Humans ; Interleukin-6/*metabolism ; Mitochondria/metabolism ; NF-kappa B/metabolism ; Organometallic Compounds/metabolism ; Particulate Matter/*metabolism ; RNA, Small Interfering/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Respiratory Mucosa/*cytology/metabolism ; Salicylates/metabolism ; }, abstract = {Particulate matter (PM) in ambient air is a risk factor for human respiratory and cardiovascular diseases. The delivery of PM to airway epithelial cells has been linked to release of proinflammatory cytokines; however, the mechanisms of PM-induced inflammatory responses are not well-characterized. This study demonstrates that PM induces cyclooxygenase (COX)-2 expression and IL-6 release through both a reactive oxygen species (ROS)-dependent NF-kappaB pathway and an ROS-independent C/EBPbeta pathway in human bronchial epithelial cells (HBEpCs) in culture. Treatment of HBEpCs with Baltimore PM induced ROS production, COX-2 expression, and IL-6 release. Pretreatment with N-acetylcysteine (NAC) or EUK-134, in a dose-dependent manner, attenuated PM-induced ROS production, COX-2 expression, and IL-6 release. The PM-induced ROS was significantly of mitochondrial origin, as evidenced by increased oxidation of the mitochondrially targeted hydroethidine to hydroxyethidium by reaction with superoxide. Exposure of HBEpCs to PM stimulated phosphorylation of NF-kappaB and C/EBPbeta, while the NF-kappaB inhibitor, Bay11-7082, or C/EBPbeta siRNA attenuated PM-induced COX-2 expression and IL-6 release. Furthermore, NAC or EUK-134 attenuated PM-induced activation of NF-kappaB; however, NAC or EUK-134 had no effect on phosphorylation of C/EBPbeta. In addition, inhibition of COX-2 partly attenuated PM-induced Prostaglandin E2 and IL-6 release.}, }
@article {pmid18615317, year = {2008}, author = {Chen, C and Jeon, H and Johnston, TD and Gedaly, R and McHugh, PP and Ranjan, D}, title = {Cyclosporin A-induced lipid and protein oxidation in human B-cells and in Epstein-Barr virus-infected B-cells is prevented by antioxidants.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {21}, number = {4}, pages = {201-208}, doi = {10.1080/08941930802262223}, pmid = {18615317}, issn = {1521-0553}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*therapeutic use ; B-Lymphocytes/drug effects/*metabolism/virology ; Cells, Cultured ; Cyclosporine/*adverse effects ; Epstein-Barr Virus Infections/complications/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Lipid Peroxidation/*drug effects ; Lymphoproliferative Disorders/*chemically induced ; Malondialdehyde/metabolism ; Organ Transplantation/adverse effects ; Oxidation-Reduction ; Postoperative Complications/virology ; Protein Carbonylation/*drug effects ; Pyrrolidines/pharmacology ; Thiocarbamates/pharmacology ; Vitamin E/pharmacology ; }, abstract = {The incidence of post-transplant lymphoproliferative disorder (PTLD) has increased since cyclosporin A (CsA) became the mainstay of transplant immunosuppression. We have previously shown that, in addition to its potent immunosuppressive property, CsA-induced oxidative stress plays an important role in Epstein-Barr virus (EBV)-related PTLD. Using lipid hydroperoxide and malondialdehyde as markers of lipid oxidation, and protein carbonyls as markers of protein oxidation, we further investigated the in vitro effect of CsA on human B cells and EBV-infected human B cells. We found that CsA at 500 ng/ml, a relatively safe and effective blood concentration in organ transplant recipients, induced the highest lipid hydroperoxide and malondialdehyde after 10 min of treatment in time- and concentration-related kinetic studies. We also found that treatment with CsA at 500 ng/ml for 10 min increased the EBV-infected B cell protein carbonyl formation as assayed by immunoblot method. CsA-induced lipid and protein oxidation could be inhibited by vitamin E, N-acetyl cysteine, and pyrollidine dithiocarbamate. CsA significantly promoted the EBV-B cell transformation as assayed by colony counting, cell counting, and (3)H-thymidine incorporation. Our recent study provides further evidence to support the hypothesis that CsA exerts direct oxidative stress in EBV-infected as well as non-EBV-infected human B cells. A greater understanding of these cellular and molecular mechanisms may benefit the clinical practice and prevention of PTLD.}, }
@article {pmid18608208, year = {2008}, author = {Sánchez, CA and Rodríguez, E and Varela, E and Zapata, E and Páez, A and Massó, FA and Montaño, LF and Lóopez-Marure, R}, title = {Statin-induced inhibition of MCF-7 breast cancer cell proliferation is related to cell cycle arrest and apoptotic and necrotic cell death mediated by an enhanced oxidative stress.}, journal = {Cancer investigation}, volume = {26}, number = {7}, pages = {698-707}, doi = {10.1080/07357900701874658}, pmid = {18608208}, issn = {1532-4192}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Atorvastatin ; Breast Neoplasms/metabolism/*pathology ; Cell Cycle/*drug effects ; Cell Line, Tumor ; Cell Membrane/drug effects ; Cell Proliferation/drug effects ; DNA Replication/drug effects ; Dose-Response Relationship, Drug ; Fatty Acids, Monounsaturated/pharmacology ; Female ; Fluvastatin ; Heptanoic Acids/pharmacology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology ; Indoles/pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Necrosis ; Oxidative Stress/*drug effects ; Pyrroles/pharmacology ; Reactive Oxygen Species/metabolism ; Simvastatin/pharmacology ; }, abstract = {Statins have antiproliferative and anti-tumoral effects in MCF-7 cells. We determined the effect of statins upon MCF-7 cell cycle, toxicity, cell death, reactive oxygen species (ROS) production and mitochondrial membrane potential. Fluvastatin, simvastatin and atorvastatin inhibited cell proliferation. Antiproliferation was associated with a decrease in the DNA synthesis and a cell cycle arrest in the G1 and G2/M phases. A loss in the mitochondrial membrane potential was observed with fluvastatin. Statins induced increase in ROS production that was associated with cell death, which was abrogated by the antioxidant NAC. Our results suggest that the cytotoxic effect observed is mediated by an oxidative stress.}, }
@article {pmid18605229, year = {2007}, author = {Chan, E and Obaid, L and Johnson, ST and Bigam, DL and Cheung, PY}, title = {N-acetylcysteine administration improves platelet aggregation in hypoxia-reoxygenation injury.}, journal = {Proceedings of the Western Pharmacology Society}, volume = {50}, number = {}, pages = {53-57}, pmid = {18605229}, issn = {0083-8969}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Hypoxia/*blood ; Matrix Metalloproteinase 2/blood ; Matrix Metalloproteinase 9/blood ; Oxygen/blood ; Platelet Aggregation/*drug effects ; Platelet Count ; Swine ; }, abstract = {Platelet activation and dysfunction occurs upon hypoxia and reoxygenation and is associated with oxygen free radical generation and matrix metalloproteinase (MMP) -2 and -9 activation. The effect of NAC on platelet function in newborn piglets after asphyxia was studied along with plasma MMP-2 and MMP-9 activities. Piglets (1-4 day, 1.4-2.2 kg) were acutely instrumented for the induction of normocapnic hypoxia (10-15% O2) for 2hr followed by reoxygenation for 1hr with 100% O2 and then 3hr with 21% O2. Animals were randomized to 3 groups (n = 6 each); sham, control and treatment with NAC upon reoxygenation (150 mg/kg i.v. bolus and 100 mg/kg/hr i.v. infusion). Platelet count and collagen (2, 5 and 10 microg/mL)-stimulated whole blood aggregation were studied at baseline and after 4hr reoxygenation. Plasma MMP -2 and -9 activities were analyzed by gelatin zymography. Piglets had severe hypoxia (PaO2 32 +/- 2 vs. 65 +/- 2 mmHg sham; p < 0.05) and metabolic acidosis (pH 6.96 +/- 0.04 vs. 7.33 +/- 0.01 sham; p < 0.05). At 4hr of reoxygenation, platelet counts decreased similarly in all experimental groups, and no animal had a platelet count < 100 x 10(9)/L. Platelet aggregation was significantly reduced with a rightward shift of concentration-response curve. NAC treatment improved platelet aggregatory function at 4hr of reoxygenation (p < 0.05). Plasma MMP-9, but not MMP-2, activities were increased with NAC treatment (147 +/- 19 vs. 51 +/- 20 and 42 +/- 11 AU of control and sham, respectively, p < 0.001). In a newborn piglet model of asphyxia and reoxygenation, NAC treatment effectively improves platelet aggregation when given upon resuscitation.}, }
@article {pmid18603603, year = {2008}, author = {Murphy, KT and Medved, I and Brown, MJ and Cameron-Smith, D and McKenna, MJ}, title = {Antioxidant treatment with N-acetylcysteine regulates mammalian skeletal muscle Na+-K+-ATPase alpha gene expression during repeated contractions.}, journal = {Experimental physiology}, volume = {93}, number = {12}, pages = {1239-1248}, doi = {10.1113/expphysiol.2008.042796}, pmid = {18603603}, issn = {0958-0670}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Cross-Over Studies ; Double-Blind Method ; Electric Stimulation ; *Exercise ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Infusions, Intravenous ; Male ; *Muscle Contraction ; Protein Isoforms ; Quadriceps Muscle/*drug effects/enzymology ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Sodium-Potassium-Exchanging ATPase/genetics/*metabolism ; Young Adult ; }, abstract = {Exercise increases Na(+)-K(+) pump isoform gene expression and elevates muscle reactive oxygen species (ROS). We investigated whether enhanced ROS scavenging induced with the antioxidant N-acetylcysteine (NAC) blunted the increase in Na(+)-K(+) pump mRNA during repeated contractions in human and rat muscle. In experiment 1, well-trained subjects received saline or NAC intravenously prior to and during 45 min cycling. Vastus lateralis muscle biopsies were taken pre-infusion and following exercise. In experiment 2, isolated rat extensor digitorum longus muscles were pre-incubated without or with 10 mm NAC and then rested or stimulated electrically at 60 Hz for 90 s. After 3 h recovery, muscles were frozen. In both experiments, the muscles were analysed for Na(+)-K(+) pump alpha(1), alpha(2), alpha(3), beta(1), beta(2) and beta(3) mRNA. In experiment 1, exercise increased alpha(2) mRNA by 1.0-fold (P = 0.03), but alpha(2) mRNA was reduced by 0.40-fold with NAC (P = 0.03). Exercise increased alpha(3), beta(1) and beta(2) mRNA by 2.0- to 3.4-fold (P < 0.05), but these were not affected by NAC (P > 0.32). Neither exercise nor NAC altered alpha(1) or beta(3) mRNA (P > 0.31). In experiment 2, electrical stimulation increased alpha(1), alpha(2) and alpha(3) mRNA by 2.3- to 17.4-fold (P < 0.05), but these changes were abolished by NAC (P > 0.07). Electrical stimulation almost completely reduced beta(1) mRNA but only in the presence of NAC (P < 0.01). Neither electrical stimulation nor NAC altered beta(2) or beta(3) mRNA (P > 0.09). In conclusion, NAC attenuated the increase in Na(+)-K(+) pump alpha(2) mRNA with exercise in human muscle and all alpha isoforms with electrical stimulation in rat muscle. This indicates a regulatory role for ROS in Na(+)-K(+) pump alpha isoform mRNA in mammalian muscle during repeated contractions.}, }
@article {pmid18596559, year = {2008}, author = {Hauber, HP and Steffen, A and Goldmann, T and Vollmer, E and Hung, HL and Wollenberg, B and Zabel, P}, title = {Effect of steroids, acetyl-cysteine and calcium-activated chloride channel inhibitors on allergic mucin expression in sinus mucosa.}, journal = {The Laryngoscope}, volume = {118}, number = {9}, pages = {1528-1533}, doi = {10.1097/MLG.0b013e31817b0732}, pmid = {18596559}, issn = {1531-4995}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Cells, Cultured ; Chloride Channels/*antagonists &amp; inhibitors ; Cytokines/immunology ; Dexamethasone/pharmacology ; Female ; Follow-Up Studies ; Glucocorticoids/*pharmacology ; Humans ; Hypersensitivity/complications/drug therapy/*metabolism ; Immunohistochemistry ; Male ; Mucins/*biosynthesis/drug effects ; Niflumic Acid/pharmacology ; Prospective Studies ; Respiratory Mucosa/drug effects/*metabolism/pathology ; Sinusitis/complications/drug therapy/*metabolism ; Th2 Cells/drug effects/immunology ; }, abstract = {OBJECTIVES/HYPOTHESIS: Allergic inflammation of the upper airways is commonly associated with mucus hypersecretion. At present, there is no specific mucus regulating drug available. Our goal was to investigate the effect of glucocorticosteroids, acetyl-cysteine (ACC), and calcium-activated chloride channel (CLCA) inhibitors in a model of Th2 type cytokine induced mucin expression in human airway mucosa.<br><br>STUDY DESIGN: Prospective.<br><br>METHODS: Explanted tissue from human sinus mucosa was stimulated with interleukin (IL)-4, IL-9, or IL-13. Different concentrations of dexamethasone, ACC, or CLCA inhibitors [niflumic acid (NFA) or MSI-2216] were added to stimulated tissue. Epithelial mucin expression was quantified using periodic acid-Schiff staining.<br><br>RESULTS: IL-4, IL-9, and IL-13 significantly increased epithelial mucin expression (P < .05). Dexamethasone reduced Th2 type cytokine induced mucin expression in a dose-dependent manner being statistically significant at concentrations >or=4.0 micromol/L (IL-4) and >or=40.0 micromol/L (IL-9 and IL-13) (P < .05). ACC had no significant effect on IL-4 and IL-13 induced mucin expression, whereas IL-9 induced mucin expression was significantly decreased at concentrations >or=3.0 mmol/L (P < .05). NFA and MSI-2216 decreased Th2 type cytokine induced mucin expression in a dose-dependent manner. This effect was statistically significant at concentrations >or=100 micromol/L (NFA) and >or=50 micromol/L (MSI-2216) (P < .05).<br><br>CONCLUSIONS: Th2 type cytokines can induce mucin expression in a model of explanted human airway mucosa. Th2 type cytokine induced mucin expression can be effectively reduced by either glucocorticosteroids or CLCA inhibitors ex vivo. Besides glucocorticosteroids CLCA inhibitors may offer an alternative therapeutic approach to treat allergic mucus hypersecretion.}, }
@article {pmid18592146, year = {2008}, author = {Kuleci, S and Hanta, I and Kocabas, A and Canacankatan, N}, title = {The effect of different treatment modalities on oxidative stress in COPD.}, journal = {Advances in therapy}, volume = {25}, number = {7}, pages = {710-717}, doi = {10.1007/s12325-008-0064-4}, pmid = {18592146}, issn = {0741-238X}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Adrenergic beta-Antagonists/therapeutic use ; Aged ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*pharmacology/therapeutic use ; Glucocorticoids/*pharmacology/therapeutic use ; Humans ; Ipratropium/therapeutic use ; Male ; Malondialdehyde/blood ; Methylprednisolone/therapeutic use ; Middle Aged ; Oxidative Stress/*drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy/metabolism ; Respiratory Function Tests ; Superoxide Dismutase/blood ; }, abstract = {INTRODUCTION: Oxidant/antioxidant interactions are known to be important processes in the pathogenesis of chronic obstructive pulmonary disease (COPD). We aimed to evaluate the effects of corticosteroids (CS), and N-acetylcysteine (NAC) on plasma oxidant/antioxidant levels in patients with COPD.<br><br>METHODS: This study utilised a single-blind, randomised, placebo-controlled, parallel-group methodology. We enrolled 58 patients with stable COPD and 30 healthy controls with similar demographic profiles. The patients with COPD were randomly divided into three treatment groups. Group 1 received basal treatment (regular ipratropium bromide and beta-2 agonist as needed), placebo CS and placebo NAC. In addition to basal treatment, group 2 received oral CS (methylprednisolone 40 mg/day) and placebo NAC. Group 3 received basal treatment plus NAC (600 mg/day) and placebo CS. Each group received treatment for 15 days. We measured plasma malondialdehyde (MDA) and superoxide dismutase (SOD) at the start and the end of study.<br><br>RESULTS: Post-treatment plasma MDA levels were significantly lowered only in group 2 (P=0.004). No significant differences were found with respect to erythrocyte SOD levels.<br><br>CONCLUSION: This study demonstrates that oral CS, by aiding the oxidant/antioxidant system, may offer a new therapeutic option in COPD treatment.}, }
@article {pmid18591773, year = {2008}, author = {Guedes, MM and Carvalho, AC and Lima, AF and Lira, SR and de Queiroz, SS and Silveira, ER and Santos, FA and Rao, VS}, title = {Gastroprotective mechanisms of centipedic acid, a natural diterpene from Egletes viscosa LESS.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {31}, number = {7}, pages = {1351-1355}, doi = {10.1248/bpb.31.1351}, pmid = {18591773}, issn = {0918-6158}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; *Anti-Ulcer Agents ; Asteraceae/*chemistry ; Capsaicin/pharmacology ; Central Nervous System Depressants ; Diterpenes/*pharmacology ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Ethanol ; Fatty Acids, Unsaturated/*pharmacology ; Free Radical Scavengers/pharmacology ; Furans/*pharmacology ; Gastric Mucosa/pathology ; Glyburide/pharmacology ; Hypoglycemic Agents/pharmacology ; Indomethacin/pharmacology ; Male ; Mice ; NG-Nitroarginine Methyl Ester/pharmacology ; Neurons, Afferent/drug effects ; Oxidative Stress/drug effects ; Pylorus/physiology ; Stomach Ulcer/chemically induced/pathology/prevention &amp; control ; Sulfhydryl Compounds/pharmacology ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {This study was aimed to clarify the mechanisms of gastroprotection by centipedic acid (CPA), a natural diterpene from Egletes viscosa LESS. (Asteraceae) using ethanol-induced gastric mucosal damage in mice and gastric secretion in 4-h pylorus-ligated rats as model systems. In mice, intragastrically administered CPA (25, 50, 100 mg/kg) greatly reduced the mucosal lesions induced by 96% ethanol (0.2 ml, p.o.) by 18, 53, and 79%, respectively, whereas N-acetylcysteine (NAC, 300 mg/kg, i.p.), the reference compound produced a 50% inhibition. In 4-h pylorus-ligated rats, CPA (50 mg/kg) applied intraduodenally decreased both gastric secretory volume and total acidity. Similar to NAC, the plant diterpene effectively prevented the ethanol associated decrease in non-proteic sulfhydryls (NP-SH) and the elevated thiobarbituric acid-reactive substances (TBARS) in gastric tissue, suggesting that these compounds exert an antioxidant effect. Pretreatment of mice with indomethacin, the cyclooxygenase inhibitor but not with capsazepine, the transient receptor potential vanilloid-1 (TRPV1)-receptor antagonist greatly suppressed the gastroprotective effect of CPA. Furthermore, CPA gastroprotection was significantly attenuated in mice pretreated with L-NAME or glibenclamide the respective inhibitors of nitric oxide synthase and K(+)(ATP) channel activation. These data suggest that CPA affords gastroprotection by different and complementary mechanisms, which include a sparing effect on NP-SH reserve, and roles for endogenous prostaglandins, nitric oxide, and TRPV1-receptor and K(+)(ATP) channel activation.}, }
@article {pmid18590811, year = {2008}, author = {Roy, A and Jana, A and Yatish, K and Freidt, MB and Fung, YK and Martinson, JA and Pahan, K}, title = {Reactive oxygen species up-regulate CD11b in microglia via nitric oxide: Implications for neurodegenerative diseases.}, journal = {Free radical biology &amp; medicine}, volume = {45}, number = {5}, pages = {686-699}, pmid = {18590811}, issn = {0891-5849}, support = {R21 NS048923-03/NS/NINDS NIH HHS/United States ; R01 NS039940-09/NS/NINDS NIH HHS/United States ; R01 NS039940/NS/NINDS NIH HHS/United States ; NS48923/NS/NINDS NIH HHS/United States ; NS39940/NS/NINDS NIH HHS/United States ; R21 NS048923/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; CD11b Antigen/genetics/*metabolism ; Cell Line ; Cells, Cultured ; HIV Envelope Protein gp120/genetics/metabolism ; HIV-1/genetics/metabolism ; Hydrogen Peroxide/metabolism ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/*metabolism ; Neurodegenerative Diseases/genetics/*metabolism ; Nitric Oxide/*metabolism ; RNA, Double-Stranded/genetics ; RNA, Messenger/genetics ; Reactive Oxygen Species/*metabolism ; *Up-Regulation/drug effects ; }, abstract = {Microglial activation is considered as a hallmark of several neurodegenerative disorders. During microglial activation, the expression of CD11b, the beta-integrin marker of microglia, is increased. However, the molecular mechanism behind increased microglial CD11b expression is poorly understood. The present study was undertaken to explore the role of reactive oxygen species (ROS) in the expression of CD11b in microglial cells. Bacterial lipopolysaccharide (LPS) stimulated the expression of CD11b in mouse BV-2 microglial cells and primary microglia, the effect that was blocked by antioxidants such as N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). Furthermore, comicroinjection of either NAC or PDTC with LPS was also able to suppress LPS-stimulated expression of CD11b in striatum in vivo. Similarly, other neurotoxic molecules, such as interleukin-1beta (IL-1beta), IL-12 p40(2), fibrillar amyloid-beta (Abeta) peptides, HIV-1 gp120, and double-stranded RNA (poly(IC)), also stimulated the expression of CD11b in microglia through the involvement of ROS. Complete inhibition of LPS-stimulated expression of CD11b by catalase, induction of CD11b expression by H2O2 alone, and inhibition of superoxide-stimulated CD11b expression by catalase suggest that H2O2, but not superoxide, is in fact involved in the expression of CD11b. Interestingly, we also demonstrate that ROS stimulated the expression of CD11b after the induction of nitric oxide (NO) production and failed to stimulate CD11b when NO production was inhibited by either 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) or L-N6-(1-iminoethyl)-L-lysine (L-NIL). Taken together, these studies suggest that the up-regulation of CD11b in microglia is redox sensitive and that ROS up-regulates CD11b via NO.}, }
@article {pmid18584360, year = {2008}, author = {Waring, WS and Stephen, AF and Robinson, OD and Dow, MA and Pettie, JM}, title = {Lower incidence of anaphylactoid reactions to N-acetylcysteine in patients with high acetaminophen concentrations after overdose.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {46}, number = {6}, pages = {496-500}, doi = {10.1080/15563650701864760}, pmid = {18584360}, issn = {1556-9519}, mesh = {Acetaminophen/*pharmacokinetics/poisoning ; Acetylcysteine/*adverse effects/therapeutic use ; Adult ; Analgesics, Non-Narcotic/*pharmacokinetics/poisoning ; Anaphylaxis/*chemically induced/epidemiology ; Antidotes/*adverse effects/therapeutic use ; Drug Interactions ; Drug Overdose ; Female ; Humans ; Male ; Prospective Studies ; }, abstract = {BACKGROUND: Mechanisms responsible for anaphylactoid reactions to N-acetylcysteine (NAC) are poorly understood, and acetaminophen itself may play an important role. The present study examined the relationship between serum acetaminophen concentrations and risk of anaphylactoid reactions.<br><br>METHODS: Prospective study of adverse reactions to NAC administered according to standardized clinical protocols in patients who present to hospital after acute acetaminophen overdose. Subgroups were defined by serum acetaminophen concentrations 0 to 100 mg/L, 101 to 150 mg/L, 151 to 200 mg/L, 201 to 300 mg/L, and >300 mg/L.<br><br>RESULTS: There were 362 patients, and anaphylactoid reactions occurred in 14.9%. Anaphylactoid reactions occurred less commonly in patients with high serum acetaminophen concentrations (p = 0.046 by Cochran-Armitage trend test) and high equivalent 4 h acetaminophen concentrations (p = 0.004).<br><br>DISCUSSION: High serum acetaminophen concentrations were associated with fewer anaphylactoid reactions, suggesting that these might in some way be protective. The biological basis needs further exploration so as to allow a better understanding of the mechanisms responsible for adverse reactions to NAC treatment.}, }
@article {pmid18583239, year = {2008}, author = {Li, X and Meng, Y and Huang, ML and Zhang, XL and Zhang, ZS}, title = {[Angiotensin II stimulates platelet-derived growth factor-B expression in hepatic stellate cells by activating EGR-1].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {28}, number = {6}, pages = {963-967}, pmid = {18583239}, issn = {1673-4254}, mesh = {Angiotensin II/*pharmacology ; Becaplermin ; Blotting, Western ; Cells, Cultured ; Early Growth Response Protein 1/*metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Hepatic Stellate Cells/cytology/*drug effects/metabolism ; Humans ; Immunohistochemistry ; Platelet-Derived Growth Factor/*biosynthesis ; Proto-Oncogene Proteins c-sis ; Signal Transduction/drug effects ; }, abstract = {OBJECTIVE: To investigate the signal transduction mechanism underlying the effects of angiotensin II (AngII) on extracellular signal-regulated kinase 1/2 (ERK1/2), early growth response-1 (EGR-1) and platelet-derived growth factor-B (PDGF-B) in hepatic stellate cells (HSCs).<br><br>METHODS: HSC-T6 cells treated with AngII for 10 or 30 min were examined for phospho-P42/44 protein expression using Western blotting. In another experiment, the cells were preincubated for 1 h in the presence of U0126 (an inhibitor of the MAPK/ERK kinase), irbesartan (an AT-1 receptor blocker), or antioxidant-N-acetylcysteine (NAC) prior to AngII exposure, and the protein expression of phospho-P42/44 and PDGF-B were measured with Western blotting. The DNA binding activity of EGR-1 was analyzed using electrophoretic gel mobility shift assay (EMSA), and the expression of PDGF-B was detected immunohistochemically.<br><br>RESULTS: AngII induced phospho-P42/44 expression in HSC-T6, which was abrogated by U0126 or irbesartan. NAC did not inhibit phospho-P42/44 expression. EMSA showed that AngII exposure of the HSC cells markedly increased EGR-1 DNA binding activity, reaching the maximum after 60 min of exposure followed by progressive declination; irbesartan and U0126 significantly suppressed AngII-induced EGR-1 activity enhancement. ACEI at 1 micromol/L and 10 nmol/L inhibited EGR-1 activity, but ACEI at the concentration of 0.1 nmol/L resulted in enhanced EGR-1 activity. NAC showed no obvious effect in suppressing EGR-1 activity. AngII increased PDGF-B protein level in the HSCs, the effect of which was inhibited by irbesartan. U0126, NAC and ACEI did not attenuate PDGF-BB protein level in the HSCs.<br><br>CONCLUSION: Stimulation of the HSCs with AngII results in EGR-1 activation via the ERK1/2 pathway, leading to up-regulation of PDGF-B expression.}, }
@article {pmid18570648, year = {2008}, author = {Paromov, V and Qui, M and Yang, H and Smith, M and Stone, WL}, title = {The influence of N-acetyl-L-cysteine on oxidative stress and nitric oxide synthesis in stimulated macrophages treated with a mustard gas analogue.}, journal = {BMC cell biology}, volume = {9}, number = {}, pages = {33}, pmid = {18570648}, issn = {1471-2121}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Survival ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects/*metabolism ; Mice ; Microscopy, Fluorescence ; Mustard Gas/*analogs &amp; derivatives/toxicity ; Nitric Oxide/*biosynthesis ; *Oxidative Stress ; Polymyxin B/pharmacology ; }, abstract = {BACKGROUND: Sulphur mustard gas, 2, 2'-dichlorodiethyl sulphide (HD), is a chemical warfare agent. Both mustard gas and its monofunctional analogue, 2-chloroethyl ethyl sulphide (CEES), are alkylating agents that react with and diminish cellular thiols and are highly toxic. Previously, we reported that lipopolysaccharide (LPS) significantly enhances the cytotoxicity of CEES in murine RAW 264.7 macrophages and that CEES transiently inhibits nitric oxide (NO) production via suppression of inducible NO synthase (iNOS) protein expression. NO generation is an important factor in wound healing. In this paper, we explored the hypotheses that LPS increases CEES toxicity by increasing oxidative stress and that treatment with N-acetyl-L-cysteine (NAC) would block LPS induced oxidative stress and protect against loss of NO production. NAC stimulates glutathione (GSH) synthesis and also acts directly as a free radical scavenger. The potential therapeutic use of the antibiotic, polymyxin B, was also evaluated since it binds to LPS and could thereby block the enhancement of CEES toxicity by LPS and also inhibit the secondary infections characteristic of HD/CEES wounds.<br><br>RESULTS: We found that 10 mM NAC, when administered simultaneously or prior to treatment with 500 muM CEES, increased the viability of LPS stimulated macrophages. Surprisingly, NAC failed to protect LPS stimulated macrophages from CEES induced loss of NO production. Macrophages treated with both LPS and CEES show increased oxidative stress parameters (cellular thiol depletion and increased protein carbonyl levels). NAC effectively protected RAW 264.7 cells simultaneously treated with CEES and LPS from GSH loss and oxidative stress. Polymyxin B was found to partially block nitric oxide production and diminish CEES toxicity in LPS-treated macrophages.<br><br>CONCLUSION: The present study shows that oxidative stress is an important mechanism contributing to CEES toxicity in LPS stimulated macrophages and supports the notion that antioxidants could play a therapeutic role in preventing mustard gas toxicity. Although NAC reduced oxidative stress in LPS stimulated macrophages treated with CEES, it did not reverse CEES-induced loss of NO production. NAC and polymyxin B were found to help prevent CEES toxicity in LPS-treated macrophages.}, }
@article {pmid18570390, year = {2008}, author = {Annangudi, SP and Deng, Y and Gu, X and Zhang, W and Crabb, JW and Salomon, RG}, title = {Low-density lipoprotein has an enormous capacity to bind (E)-4-hydroxynon-2-enal (HNE): detection and characterization of lysyl and histidyl adducts containing multiple molecules of HNE.}, journal = {Chemical research in toxicology}, volume = {21}, number = {7}, pages = {1384-1395}, pmid = {18570390}, issn = {1520-5010}, support = {R01 GM021249/GM/NIGMS NIH HHS/United States ; R01 HL053315/HL/NHLBI NIH HHS/United States ; R01 EY014239/EY/NEI NIH HHS/United States ; GM 21249/GM/NIGMS NIH HHS/United States ; EY 014239/EY/NEI NIH HHS/United States ; HL53315/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/metabolism ; Aldehydes/chemistry/*metabolism ; Cross-Linking Reagents/chemistry/*metabolism ; Histidine/analogs &amp; derivatives/chemistry/*metabolism ; Lipoproteins, LDL/chemistry/*metabolism ; Lysine/analogs &amp; derivatives/chemistry/*metabolism ; Protein Binding ; Spectrometry, Mass, Electrospray Ionization/methods ; Tandem Mass Spectrometry/methods ; Time Factors ; }, abstract = {(E)-4-Hydroxynon-2-enal (HNE), an electrophilic bifunctional cytotoxic lipid peroxidation product, forms covalent adducts with nucleophilic side chains of amino acid residues. HNE-derived adducts have been implicated in many pathophysiological processes including atherosclerosis, diabetes, and Alzheimer's disease. Tritium- and deuterium-labeled HNE (d 4-HNE) were used orthogonally to study adduction with proteins and individual nucleophilic groups of histidyl, lysyl, and cysteine residues. Using tritium-labeled HNE, we detected the binding of 486 molecules of HNE per low-density lipoprotein (LDL) particle, significantly more than the total number of all reactive nucleophiles in the LDL particle. This suggests the formation of adducts that incorporate multiple molecules of HNE with some nucleophilic amino acid side chains. We also found that the reaction of a 1:1 mixture of d 4-HNE and d 0-HNE with N-acetylhistidine, N-acetyl-Gly-Lys-OMe, or N-acetyl cysteine generates 1:1, 2:1, and 3:1 adducts, which exhibit unique mass spectral signatures that aid in structural characterization. A domino-like reaction of initial 1:1 HNE Michael adducts of histidyl or lysyl nucleophiles with multiple additional HNE molecules forms 2:1 and 3:1 adducts that were structurally characterized by tandem mass spectrometry.}, }
@article {pmid18569934, year = {2008}, author = {Wang, JH and Subeq, YM and Tsai, WC and Lee, RP and Hsu, BG}, title = {Intravenous N-acetylcysteine with saline hydration improves renal function and ameliorates plasma total homocysteine in patients undergoing cardiac angiography.}, journal = {Renal failure}, volume = {30}, number = {5}, pages = {527-533}, doi = {10.1080/08860220802064754}, pmid = {18569934}, issn = {1525-6049}, mesh = {Acetylcysteine/*administration &amp; dosage ; C-Reactive Protein/analysis ; *Coronary Angiography ; Creatinine/blood ; Glomerular Filtration Rate ; Homocysteine/*blood ; Humans ; Injections, Intravenous ; Interleukin-10/blood ; Kidney/*physiology ; Osmotic Fragility ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {Proinflammatory cytokines and hyperhomocysteinemia are associated with clinically relevant restenosis in coronary artery disease. N-acetylcysteine (NAC) can decrease proinflammatory cytokines and plasma homocystine as well as reduce contrast-induced nephropathy. The aim of this study, therefore, was to compare normal saline hydration with and without intravenous NAC in terms of changes in renal function, proinflammatory cytokines, inflammatory markers, and plasma total homocysteine during coronary angiography. Forty-six patients who underwent coronary angiography and/or stent implantation for unstable angina were enrolled and assigned to NAC or NS treatment groups based on normal saline hydration with or without intravenous NAC, respectively. The NS group had lower serum creatinine (Cre: p = 0.02) and plasma total homocysteine (tHcy; p < 0.001) and increased glomerular filtration rate (GFR; p = 0.003) after angiography. In the NAC group, the serum blood urea nitrogen (BUN; p = 0.001), Cre (p < 0.001), and plasma tHcy (p < 0.001) were lower, and the GFR (P = 0.013) was increased after angiography. There were no statistically significant differences in serum high-sensitivity C reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-alpha), or interleukin-10 (IL-10) before and after angiography in the NS and NAC groups. Intergroup comparison revealed that plasma tHcy level was lower for the NAC-treated patients (p = 0.002), with lower plasma tHcy level before and after treatment in this group (p < 0.001). Normal saline hydration can improve renal function and decrease plasma tHcy after coronary angiography with or without NAC; however, the combination of the two decreases plasma tHcy more than normal saline hydration alone.}, }
@article {pmid18569921, year = {2008}, author = {Duru, M and Nacar, A and Yönden, Z and Kuvandik, G and Helvaci, MR and Koç, A and Akaydin, Y and Oksüz, H and Söğüt, S}, title = {Protective effects of N-acetylcysteine on cyclosporine-A-induced nephrotoxicity.}, journal = {Renal failure}, volume = {30}, number = {4}, pages = {453-459}, doi = {10.1080/08860220801985942}, pmid = {18569921}, issn = {1525-6049}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/chemically induced/pathology/*prevention &amp; control ; Analysis of Variance ; Animals ; Biopsy, Needle ; Blood Urea Nitrogen ; Creatinine/blood ; Cyclosporine/pharmacology ; Disease Models, Animal ; Immunohistochemistry ; Kidney/*drug effects/ultrastructure ; Male ; Malondialdehyde/*blood ; Microscopy/methods ; Nitric Oxide/*blood ; Probability ; Random Allocation ; Rats ; Rats, Wistar ; }, abstract = {OBJECTIVES: Cyclosporine A (CsA) is used for the treatment of autoimmune and inflammatory disorders. However, CsA-induced nephrotoxicity remains an important clinical problem, and oxidative stress has been implicated as a possible responsible mechanism. We assessed the protective ability of N-acetylcysteine (NAC), an antioxidant, against CsA-induced nephrotoxicity.<br><br>MATERIALS AND METHODS: Wistar albino rats were randomly assigned into four groups. Group 1 rats were treated with sodium chloride as control, group 2 with CsA, group 3 with CsA and NAC, and group 4 with NAC alone. Animals were sacrificed and blood samples were analyzed for blood urea nitrogen (BUN), serum creatinine (Cr), malondialdehyde (MDA) and nitric oxide (NO) levels, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Kidney sections were analyzed for MDA and NO levels and SOD and GSH-Px activities, as well as histopathological changes.<br><br>RESULTS: Overall, the treatment of rats with CsA alone produced significant increases in NO and MDA levels and significant decreases in SOD and GSH-Px activities in serum and renal samples. Morphological changes, including tubular epithelial atrophy, vacuolizations, and cellular desquamations, were clearly observed in the rats treated with CsA alone. Concurrent NAC administration with CsA improved renal function, as indicated by lower BUN and Cr values. Moreover, NAC significantly reduced MAD and NO levels and increased SOD and GSH-Px activities in serum and renal tissue, as well as provided a histologically proven protection against CsA-induced nephrotoxicity.<br><br>CONCLUSION: These results indicate that NAC produces a protective mechanism against CsA-induced nephrotoxicity and suggest a role for oxidative stress in pathogenesis.}, }
@article {pmid18564794, year = {2008}, author = {Peter, JV and Moran, JL and Pichamuthu, K and Chacko, B}, title = {Adjuncts and alternatives to oxime therapy in organophosphate poisoning--is there evidence of benefit in human poisoning? A review.}, journal = {Anaesthesia and intensive care}, volume = {36}, number = {3}, pages = {339-350}, doi = {10.1177/0310057X0803600305}, pmid = {18564794}, issn = {0310-057X}, mesh = {Animals ; Antidotes/*therapeutic use ; Cholinergic Antagonists/therapeutic use ; Cholinesterase Reactivators/therapeutic use ; Humans ; *Organophosphate Poisoning ; Organophosphorus Compounds/antagonists &amp; inhibitors/pharmacokinetics ; Oximes/*therapeutic use ; Poisoning/*drug therapy ; }, abstract = {Organophosphate poisoning is common in developing countries. The morbidity and mortality with organophosphate poisoning is relatively high despite the use of atropine as specific antidotal therapy and oximes to reactivate acetylcholinesterase. Several adjunct and alternative therapies have been explored in animal and human studies. We reviewed the literature to ascertain if there was evidence of benefit of such therapies. Adjunct and alternative therapies included treatments to reduce poison absorption by topical application of creams, enhance toxin elimination by haemoperfusion or bioremediation and neutralise the poison by scavenging free organophosphate with cholinesterase-rich human plasma. In addition, magnesium, clonidine, diazepam, N-acetyl cysteine and adenosine receptor agonists have also been used to counteract poison effects. Detailed assessment was limited by the paucity of trials on adjunct/alternative therapies. The limited evidence from the review process suggested potential benefit from the use of human plasma infusion, early initiation of haemoperfusion and intravenous magnesium, in addition to standard therapy with atropine and pralidoxime. There appeared to be no additional benefit with alkalinisation or use of glycopyrrolate instead of atropine in human trials. Diazepam administration has been advocated by military authorities if symptoms developed following exposure to organophosphate. Bioremediation, clonidine, N-acetyl cysteine and adenosine receptor agonists have been evaluated only in animal models. The impact of adjunct and alternate therapies on outcomes in human poisoning needs to be further explored before implementation as standard treatment.}, }
@article {pmid18563361, year = {2008}, author = {Jang, GH and Ha, JH and Huh, TL and Lee, YM}, title = {Effect of proton beam on blood vessel formation in early developing zebrafish (Danio rerio) embryos.}, journal = {Archives of pharmacal research}, volume = {31}, number = {6}, pages = {779-785}, doi = {10.1007/s12272-001-1226-1}, pmid = {18563361}, issn = {0253-6269}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Genetically Modified ; Antioxidants/pharmacology ; Blood Vessels/drug effects/embryology/metabolism/*radiation effects ; Cell Death/radiation effects ; Cells, Cultured ; DNA Damage ; Dose-Response Relationship, Radiation ; Endothelial Cells/metabolism/pathology/radiation effects ; Green Fluorescent Proteins/metabolism ; Humans ; Neovascularization, Physiologic/drug effects/*radiation effects ; *Protons ; Reactive Oxygen Species/metabolism ; Recombinant Fusion Proteins/metabolism ; Vascular Endothelial Growth Factor Receptor-2/genetics/metabolism ; Zebrafish/*embryology/genetics/metabolism ; }, abstract = {Proton beam therapy can kill tumor cells while saving normal cells because of its specific energy delivery properties and so is used to various tumor patients. However, the effect of proton beam on angiogenesis in the development of blood vessels has not been determined. Here we used the zebrafish model to determine in vivo whether proton beam inhibits angiogenesis. Flk-1-GFP transgenic embryos irradiated with protons (35 MeV, spread out Bragg peak, SOBP) demonstrated a marked inhibition of embryonic growth and an altered fluorescent blood vessel development in the trunk region. When cells were stained with acridine orange to evaluate DNA damage, the number of green fluorescent cell death spots was increased in trunk regions of irradiated embryos compared to non-irradiated control embryos. Proton beam also significantly increased the cell death rate in human umbilical vein endothelial cells (HUVEC), but pretreatment with N-acetyl cystein (NAC), an antioxidant, reduced the proton-induced cell death rate (p<0.01). Moreover, pretreatment with NAC abrogated the inhibition of trunk vessel development and prevented the trunk malformation caused by proton irradiation. In conclusion, proton irradiation significantly inhibited in vivo vascular development possibly due to increased vascular cell death via reactive oxygen species formation.}, }
@article {pmid18562625, year = {2008}, author = {Lee, YS and Kim, AY and Choi, JW and Kim, M and Yasue, S and Son, HJ and Masuzaki, H and Park, KS and Kim, JB}, title = {Dysregulation of adipose glutathione peroxidase 3 in obesity contributes to local and systemic oxidative stress.}, journal = {Molecular endocrinology (Baltimore, Md.)}, volume = {22}, number = {9}, pages = {2176-2189}, pmid = {18562625}, issn = {0888-8809}, mesh = {3T3-L1 Cells ; Acetylcysteine/pharmacology ; Adipose Tissue/drug effects/*enzymology ; Animals ; Antioxidants/pharmacology ; Base Sequence ; Gene Expression Regulation, Enzymologic/genetics ; Glutathione Peroxidase/blood/*genetics/*metabolism ; Humans ; Hypoxia/enzymology/genetics ; Kidney/enzymology ; Lipopolysaccharides/pharmacology ; Lung/enzymology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity/blood/*enzymology/*genetics ; Oxidative Stress ; PPAR gamma/metabolism ; RNA, Messenger/genetics/metabolism ; Rosiglitazone ; Thiazolidinediones/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Glutathione peroxidase 3 (GPx3) accounts for the major antioxidant activity in the plasma. Here, we demonstrate that down-regulation of GPx3 in the plasma of obese subjects is associated with adipose GPx3 dysregulation, resulting from the increase of inflammatory signals and oxidative stress. Although GPx3 was abundantly expressed in kidney, lung, and adipose tissue, we observed that GPx3 expression was reduced selectively in the adipose tissue of several obese animal models as decreasing plasma GPx3 level. Adipose GPx3 expression was greatly suppressed by prooxidative conditions such as high levels of TNFalpha and hypoxia. In contrast, the antioxidant N-acetyl cysteine and the antidiabetic drug rosiglitazone increased adipose GPx3 expression in obese and diabetic db/db mice. Moreover, GPx3 overexpression in adipocytes improved high glucose-induced insulin resistance and attenuated inflammatory gene expression whereas GPx3 neutralization in adipocytes promoted expression of proinflammatory genes. Taken together, these data suggest that suppression of GPx3 expression in the adipose tissue of obese subjects might constitute a vicious cycle to expand local reactive oxygen species accumulation in adipose tissue potentially into systemic oxidative stress and obesity-related metabolic complications.}, }
@article {pmid18558355, year = {2008}, author = {Guilpain, P and Servettaz, A and Batteux, F and Guillevin, L and Mouthon, L}, title = {Natural and disease associated anti-myeloperoxidase (MPO) autoantibodies.}, journal = {Autoimmunity reviews}, volume = {7}, number = {6}, pages = {421-425}, doi = {10.1016/j.autrev.2008.03.009}, pmid = {18558355}, issn = {1568-9972}, mesh = {Animals ; Autoantibodies/immunology/toxicity ; Autoimmune Diseases/*immunology ; Humans ; Mice ; Neutrophils/drug effects ; Peroxidase/antagonists &amp; inhibitors/*immunology/physiology ; Respiratory Burst ; Vasculitis/*immunology ; }, abstract = {Myeloperoxidase (MPO) is a cationic protein present in primary azurophilic granules of neutrophils and monocytes. MPO produces a highly deleterious reactive oxygen species, the hypochlorous acid (HOCl), using hydrogen peroxide (H(2)O(2)) and chloride ions as substrate. Anti-MPO antibodies (Abs) are present in 70% of the cases in patients with microscopic polyangiitis (MPA), a small-sized vessel vasculitis. Anti-MPO Abs from patients with MPA can trigger the release of MPO by neutrophils and monocytes. Anti-MPO Abs can activate MPO to generate an oxidative stress deleterious for the endothelium. Thus, we recently demonstrated that MPA sera with anti-MPO Abs activated MPO in vitro, and generated hypochlorous acid, whereas sera from MPA patients with no anti-MPO Abs or healthy individuals did not. Both hypochlorous acid production and endothelial lysis were abrogated by N-acetylcysteine (NAC), an antioxidant molecule. Thus, anti-MPO Abs could play a pathogenic role in vivo by triggering an oxidative burst leading to severe endothelial damages.}, }
@article {pmid18557424, year = {2008}, author = {Jia, J and Chen, J}, title = {Histone hyperacetylation is involved in the quercetin-induced human leukemia cell death.}, journal = {Die Pharmazie}, volume = {63}, number = {5}, pages = {379-383}, pmid = {18557424}, issn = {0031-7144}, mesh = {Acetylation ; Acetylcysteine/pharmacology ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Free Radical Scavengers/pharmacology ; HL-60 Cells ; Histones/isolation &amp; purification/*metabolism ; Humans ; Hydroxamic Acids/pharmacology ; Leukemia/*drug therapy/pathology ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Quercetin/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Quercetin (QU) is recognized as a promising anticancer drug, but its mechanism remains elusive. Here we found that QU induced human leukemia cell death in a dose-dependent manner. However, it did not show a dose-dependent inhibition on ROS generation (indicated by the level of malondialdehyde, MDA) in the same cells. QU showed similar antioxidant activity at concentrations of 50, 75 and 100 microM. Consistent with that, the antioxidant, N-acetyl-cysteine (NAC) could only further decrease the ROS generation and enhance the cell death triggered by QU at the concentrations less than 50 microM. These results indicate that an additional mechanism is involved in the anticancer activity of high concentrations of QU. When the effect of QU on histone acetylation was studied, QU induced significant histone hyperacetylation at 75 and 100 microM, indicating the possible involvement of histone hyperacetylation in the anticancer activity of high concentrations of QU. This conclusion was supported by the findings that when histone acetylation in the cells treated by QU was increased by different concentrations of TSA, the cell death was significantly enhanced. Our results thus provide the first evidence that QU can induce histone hyperacetylation and this induction of histone hyperacetylation may represent an unrevealed mechanism in its anticancer activity.}, }
@article {pmid18554678, year = {2008}, author = {Röder-Stolinski, C and Fischäder, G and Oostingh, GJ and Feltens, R and Kohse, F and von Bergen, M and Mörbt, N and Eder, K and Duschl, A and Lehmann, I}, title = {Styrene induces an inflammatory response in human lung epithelial cells via oxidative stress and NF-kappaB activation.}, journal = {Toxicology and applied pharmacology}, volume = {231}, number = {2}, pages = {241-247}, doi = {10.1016/j.taap.2008.04.010}, pmid = {18554678}, issn = {1096-0333}, mesh = {Cell Line ; Chemokine CCL2/drug effects/metabolism ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects ; Gene Expression Regulation/drug effects ; Glutathione Transferase/drug effects/metabolism ; Humans ; Lung/*drug effects/metabolism ; NF-kappa B/*drug effects/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Signal Transduction/drug effects ; Solvents/administration &amp; dosage/*toxicity ; Styrene/administration &amp; dosage/*toxicity ; }, abstract = {Styrene is a volatile organic compound (VOC) that is widely used as a solvent in many industrial settings. Chronic exposure to styrene can result in irritation of the mucosa of the upper respiratory tract. Contact of styrene with epithelial cells stimulates the expression of a variety of inflammatory mediators, including the chemotactic cytokine monocyte chemoattractant protein-1 (MCP-1). To characterise the underlying mechanisms of the induction of inflammatory signals by styrene, we investigated the influence of this compound on the induction of oxidative stress and the activation of the nuclear factor-kappa B (NF-kappaB) signalling pathway in human lung epithelial cells (A549). The results demonstrate that styrene-induced MCP-1 expression, as well as the expression of the oxidative stress marker glutathione S-transferase (GST), is associated with a concentration dependent pattern of NF-kappaB activity. An inhibitor of NF-kappaB, IKK-NBD, and the anti-inflammatory antioxidant N-acetylcysteine (NAC) were both effective in suppressing styrene-induced MCP-1 secretion. In addition, NAC was capable of inhibiting the upregulation of GST expression. Our findings suggest that the activation of the NF-kappaB signalling pathway by styrene is mediated via a redox-sensitive mechanism.}, }
@article {pmid18552708, year = {2008}, author = {Paintlia, MK and Paintlia, AS and Singh, AK and Singh, I}, title = {Attenuation of lipopolysaccharide-induced inflammatory response and phospholipids metabolism at the feto-maternal interface by N-acetyl cysteine.}, journal = {Pediatric research}, volume = {64}, number = {4}, pages = {334-339}, pmid = {18552708}, issn = {1530-0447}, support = {R37 NS022576-24/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; R01 NS022576/NS/NINDS NIH HHS/United States ; R01 NS022576-16/NS/NINDS NIH HHS/United States ; R01 NS034741/NS/NINDS NIH HHS/United States ; R01 NS034741-11/NS/NINDS NIH HHS/United States ; R37 NS022576/NS/NINDS NIH HHS/United States ; C06 RR018823/RR/NCRR NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; R01 NS034741-08/NS/NINDS NIH HHS/United States ; NS-22576/NS/NINDS NIH HHS/United States ; R37 NS022576-23/NS/NINDS NIH HHS/United States ; R01 NS037766-06A2/NS/NINDS NIH HHS/United States ; R01 NS040810/NS/NINDS NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; R01 NS037766-10/NS/NINDS NIH HHS/United States ; R01 NS022576-17/NS/NINDS NIH HHS/United States ; R01 NS037766/NS/NINDS NIH HHS/United States ; R01 NS034741-12/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Cyclooxygenase 2/metabolism ; DNA Primers/genetics ; Female ; Immunoblotting ; Immunoenzyme Techniques ; Inflammation/*drug therapy/*immunology/microbiology ; Lipid Peroxidation/physiology ; Lipopolysaccharides/toxicity ; Malondialdehyde/metabolism ; Maternal-Fetal Exchange/*physiology ; Phospholipids/*metabolism ; Placenta/immunology/metabolism/pathology ; Pregnancy ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Maternal microbial infections cause adverse fetal developmental outcomes including embryonic resorption, intrauterine fetal death, and preterm labor. Recent studies demonstrated that oxidative-stress plays an important role in chorioamniotitis pathogenesis. Herein we investigated the effect of N-acetyl cysteine (NAC) on lipopolysaccharide (LPS)-induced preterm labor and fetal demise in murine model. Lipopolysaccharide exposure at embryonic day 18 demonstrated an increase in the abortion rate and fetal demise in pregnant rats. This was associated with increase in an inflammatory response (cytokines, chemokines, and iNOS expression) and infiltration of leukocytes (monocytes and polymorphonuclear cells) in the placenta. There was increased expression of cytosolic and secretary phospholipase A2 with increased secretion of prostaglandin-2 and leukotriene B4 in the placenta, suggestive of increased metabolism of phospholipids. In addition, expression of cycloxygenase-2 and malondialdehyde production (oxidative-stress marker) was increased in the placenta. Conversely, NAC pretreatment abolished these effects of LPS in the placenta. Collectively, these data provide evidence that LPS-induced increased inflammation and metabolism of phospholipids at the feto-maternal interface (placenta) is critical for preterm labor and fetal demise during maternal microbial infections which could be blocked by antioxidant-based therapies.}, }
@article {pmid18547707, year = {2008}, author = {Quinteros, FA and Machiavelli, LI and Miler, EA and Cabilla, JP and Duvilanski, BH}, title = {Mechanisms of chromium (VI)-induced apoptosis in anterior pituitary cells.}, journal = {Toxicology}, volume = {249}, number = {2-3}, pages = {109-115}, doi = {10.1016/j.tox.2008.04.012}, pmid = {18547707}, issn = {0300-483X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Catalase/metabolism ; Cells, Cultured ; Chromium/*toxicity ; DNA Primers ; Male ; Oxidative Stress/drug effects ; Pituitary Gland, Anterior/*cytology/*drug effects ; Proto-Oncogene Proteins c-bcl-2/metabolism ; RNA/biosynthesis/isolation &amp; purification ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tetrazolium Salts ; Thiazoles ; Tumor Suppressor Protein p53/metabolism ; bcl-2-Associated X Protein/biosynthesis/genetics ; }, abstract = {Hexavalent chromium (Cr (VI)) is a highly toxic metal. Exposure to Cr (VI) compounds may affect reproductive functions. Due to the importance of anterior pituitary hormones on reproductive physiology we have studied the effects of Cr (VI) on anterior pituitary. We previously demonstrated that, after in vivo Cr (VI) administration, Cr accumulates in the pituitary gland and affects prolactin secretion. In vitro, Cr (VI) causes apoptosis in anterior pituitary cells due to oxidative stress generation. To better understand the mechanisms involved in Cr (VI)-induced apoptosis we studied: (a) whether Cr (VI) affects the intracellular antioxidant response and (b) which of the apoptotic factors participates in Cr (VI) effect. Our results show that Cr (VI) treatment induces a decrease in catalase and glutathione peroxidase (GPx) activity but does not modify glutathione reductase (GR) activity. Cr (VI) exposure causes an increase of GSH levels. p53 and Bax mRNA are also upregulated by the metal. Pifithrin alpha, a p53 transcriptional inhibitor, increases Cr (VI) cytotoxicity, suggesting a role of p53 as a survival molecule. The antioxidant N-acetyl-cysteine (NAC) could prevent Bax mRNA increase and caspase 3 activation, confirming that Cr (VI)-induced apoptosis involves oxidative stress generation.}, }
@article {pmid18541003, year = {2008}, author = {Poitevin, S and Garnotel, R and Antonicelli, F and Gillery, P and Nguyen, P}, title = {Type I collagen induces tissue factor expression and matrix metalloproteinase 9 production in human primary monocytes through a redox-sensitive pathway.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {6}, number = {9}, pages = {1586-1594}, doi = {10.1111/j.1538-7836.2008.03051.x}, pmid = {18541003}, issn = {1538-7836}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Base Sequence ; Blotting, Western ; Cells, Cultured ; Collagen Type I/*physiology ; Cytokines/physiology ; DNA Primers ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; Matrix Metalloproteinase 9/*biosynthesis ; Monocytes/enzymology/*metabolism ; NF-kappa B/metabolism ; Oxidation-Reduction ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Thiocarbamates/pharmacology ; Thromboplastin/*metabolism ; }, abstract = {BACKGROUND: Tissue factor (TF), the main trigger of coagulation cascade, is a major component of the atherosclerotic plaque. Matrix metalloproteinases (MMPs) are recognized as key mediators of extracellular matrix remodeling during inflammation. It was recently emphasized that both TF and MMP-9 were overexpressed in atherosclerotic plaques, suggesting a role of both molecules in plaque instability and thrombogenicity.<br><br>OBJECTIVE: The present study was designed to determine whether human monocytes could co-express TF and MMP-9 when the cells interact with type I collagen, a major component of the extracellular matrix and atherosclerotic plaque.<br><br>METHODS: Human monocytes were isolated by elutriation and incubated in collagen I-coated plates. Tissue factor and MMP-9 expression were examined using real-time reverse transcription-polymerase chain reaction, flow cytometry, western blot and zymography. The activation of nuclear factor-kappa B (NF-kappaB) and the role of reactive oxygen species (ROS) in TF and MMP-9 production was studied using gel shift experiments, antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetyl-cysteine (NAC), and apocynin (a specific inhibitor of the NADPH oxidase).<br><br>RESULTS: Type I collagen induced TF expression and increased MMP-9 production. In addition, the pro-inflammatory tumor necrosis factor-alpha (TNF-alpha), produced in response to collagen I, increased MMP-9 production. PDTC and NAC inhibited NF-kappaB activation during monocyte interaction with collagen I. Finally, both antioxidants and apocynin decreased the expression of TF, TNF-alpha, and MMP-9.<br><br>CONCLUSIONS: These results indicate a new mechanism in the monocyte expression of TF and MMP-9 in response to collagen I involving a ROS-dependent pathway linked to the activation of the NADPH oxidase.}, }
@article {pmid18539323, year = {2008}, author = {Kojima, N and Yamada, M and Paranjpe, A and Tsukimura, N and Kubo, K and Jewett, A and Ogawa, T}, title = {Restored viability and function of dental pulp cells on poly-methylmethacrylate (PMMA)-based dental resin supplemented with N-acetyl cysteine (NAC).}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {24}, number = {12}, pages = {1686-1693}, doi = {10.1016/j.dental.2008.04.008}, pmid = {18539323}, issn = {0109-5641}, support = {C06RR014529/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Collagen Type I/biosynthesis ; Composite Resins/chemistry/*toxicity ; Cytoprotection ; Dental Pulp/cytology/*drug effects/metabolism ; Dental Restoration, Temporary ; Extracellular Matrix Proteins ; Gene Expression ; Male ; Odontoblasts/metabolism ; Phosphoproteins ; Polymethyl Methacrylate/*toxicity ; Protein Precursors/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Sialoglycoproteins ; }, abstract = {This study examines cytotoxicity of poly-methylmethacrylate (PMMA)-based dental temporary filling resin to dental pulp cells, and the potential amelioration of the toxicity with an anti-oxidant amino-acid, N-acetyl cysteine (NAC). Dental pulp cells extracted from rat maxillary incisors were cultured on the resin material with or without NAC incorporation, or on the polystyrene. The cultures were supplied with osteoblastic media, containing dexamethasone. Forty five percent of cells on the PMMA dental resin were necrotic at 24h after seeding. However, this percentage was reduced to 27% by incorporating NAC in the resin, which was the level equivalent to that in the culture on polystyrene. The culture on the untreated resin was found to be negative for alkaline phosphate (ALP) activity at days 5 and 10 or von Kossa mineralized nodule formation at day 20. In contrast, some areas of the cultures on NAC-incorporated resin substrates were ALP and von Kossa positive. Collagen I and dentin sialoprotein genes were barely expressed in day 7 culture on the untreated resin. However, those genes were expressed in the culture on the resin with NAC. These results suggest that the decreased cell viability and the nearly completely suppressed odontoblast-like cell phenotype of dental pulp cells cultured on PMMA dental resin can be salvaged to a biologically significant degree by the incorporation of NAC in the resin.}, }
@article {pmid18538675, year = {2008}, author = {Briganti, S and Wlaschek, M and Hinrichs, C and Bellei, B and Flori, E and Treiber, N and Iben, S and Picardo, M and Scharffetter-Kochanek, K}, title = {Small molecular antioxidants effectively protect from PUVA-induced oxidative stress responses underlying fibroblast senescence and photoaging.}, journal = {Free radical biology &amp; medicine}, volume = {45}, number = {5}, pages = {636-644}, doi = {10.1016/j.freeradbiomed.2008.05.006}, pmid = {18538675}, issn = {0891-5849}, mesh = {Antioxidants/*pharmacology ; Cells, Cultured ; Cellular Senescence/*drug effects/*radiation effects ; Child ; Child, Preschool ; Fibroblasts ; Glutathione/metabolism ; Humans ; Male ; Oxidative Stress/*drug effects/*radiation effects ; Phenotype ; Reactive Oxygen Species/metabolism ; }, abstract = {Exposure of human fibroblasts to 8-methoxypsoralen plus ultraviolet-A irradiation (PUVA) results in stress-induced cellular senescence in fibroblasts. We here studied the role of the antioxidant defense system in the accumulation of reactive oxygen species (ROS) and the effect of the antioxidants alpha-tocopherol, N-acetylcysteine, and alpha-lipoic acid on PUVA-induced cellular senescence. PUVA treatment induced an immediate and increasing generation of intracellular ROS. Supplementation of PUVA-treated fibroblasts with alpha-tocopherol (alpha-Toc), N-acetylcysteine (NAC), or alpha-lipoic acid (alpha-LA) abrogated the increased ROS generation and rescued fibroblasts from the ROS-dependent changes into the cellular senescence phenotype, such as cytoplasmic enlargement, enhanced expression of senescence-associated-beta-galactosidase and matrix-metalloproteinase-1, hallmarks of photoaging and intrinsic aging. PUVA treatment disrupted the integrity of cellular membranes and impaired homeostasis and function of the cellular antioxidant system with a significant decrease in glutathione and hydrogen peroxide-detoxifying enzymes activities. Supplementation with NAC, alpha-LA, and alpha-Toc counteracted these changes. Our data provide causal evidence that (i) oxidative stress due to an imbalance in the overall cellular antioxidant capacity contributes to the induction and maintenance of the PUVA-induced fibroblast senescence and that (ii) low molecular antioxidants protect effectively against these deleterious alterations.}, }
@article {pmid18534556, year = {2008}, author = {Berk, M and Copolov, DL and Dean, O and Lu, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Bush, AI}, title = {N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial.}, journal = {Biological psychiatry}, volume = {64}, number = {6}, pages = {468-475}, doi = {10.1016/j.biopsych.2008.04.022}, pmid = {18534556}, issn = {1873-2402}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antidepressive Agents/*therapeutic use ; Bipolar Disorder/*drug therapy/*epidemiology ; Depression/diagnosis/*drug therapy/*epidemiology ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorder are complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder.<br><br>METHODS: A randomized, double-blind, multicenter, placebo-controlled study of individuals (n = 75) with bipolar disorder in the maintenance phase treated with NAC (1 g twice daily) adjunctive to usual medication over 24 weeks, with a 4-week washout. The two primary outcomes were the Montgomery Asberg Depression Rating Scale (MADRS) and time to a mood episode. Secondary outcomes included the Bipolar Depression Rating Scale and 11 other ratings of clinical status, quality of life, and functioning.<br><br>RESULTS: NAC treatment caused a significant improvement on the MADRS (least squares mean difference [95% confidence interval]: -8.05 [-13.16, -2.95], p = .002) and most secondary scales at end point. Benefit was evident by 8 weeks on the Global Assessment of Functioning Scale and Social and Occupational Functioning Assessment Scale and at 20 weeks on the MADRS. Improvements were lost after washout. There was no effect of NAC on time to a mood episode (log-rank test: p = .968) and no significant between-group differences in adverse events. Effect sizes at end point were medium to high for improvements in MADRS and 9 of the 12 secondary readouts.<br><br>CONCLUSIONS: NAC appears a safe and effective augmentation strategy for depressive symptoms in bipolar disorder.}, }
@article {pmid18533267, year = {2008}, author = {Vassallo, R and Kroening, PR and Parambil, J and Kita, H}, title = {Nicotine and oxidative cigarette smoke constituents induce immune-modulatory and pro-inflammatory dendritic cell responses.}, journal = {Molecular immunology}, volume = {45}, number = {12}, pages = {3321-3329}, pmid = {18533267}, issn = {0161-5890}, support = {R01 AI071106/AI/NIAID NIH HHS/United States ; R01 AI071106-01A2/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Animals ; Antioxidants/pharmacology ; Cell Differentiation/drug effects ; Cyclooxygenase 2/metabolism ; Dendritic Cells/cytology/*drug effects/enzymology/*immunology ; Dinoprostone/biosynthesis ; Humans ; Inflammation/*immunology ; Interleukin-8 ; Intracellular Space/drug effects/enzymology ; Lung/cytology ; Mice ; Neutrophils/drug effects ; Nicotine/*pharmacology ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Smoking/*immunology ; }, abstract = {Chronic airway inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD), a destructive cigarette smoke-induced lung disease. Although it is apparent that dendritic cells (DCs) are an important constituent of the chronic inflammatory cell influx found in airways of COPD patients, the functional roles of DCs in the pathogenesis of smoking-induced emphysema are unknown. We postulated that DCs activated by cigarette smoke constituents directly participate in the chronic inflammation that characterizes COPD airways. Concordant with this hypothesis, we observed that incubation of DCs with cigarette smoke extract (CSE), and chronic exposure of mice to cigarette smoke, both augmented the generation of neutrophilic chemokines by immature and lipopolysaccharide (LPS) or CD40L-matured DCs. The generation of interleukin-8 (CXCL8/IL-8) by human DCs conditioned with CSE was suppressed by the anti-oxidant n-acetyl cysteine (NAC), implying the involvement of oxidant sensitive pathways as a primary mechanism involved in the enhanced CXCL8/IL-8 generation. Cigarette smoke extract and nicotine also augment the production of secreted prostaglandin-E2 and intra-cellular cyclo-oxygenase-2 (COX-2) in maturing DCs. Whereas NAC suppressed production of CXCL8 by CSE-conditioned DCs, it augmented production of PGE2 and cellular COX-2 levels in maturing DCs. These studies indicate that the stimulation of DCs by cigarette smoke-induced oxidative stress and nicotine promote the generation of pro-inflammatory responses that promote chronic inflammation in smokers. Certain pharmacologic strategies such as anti-oxidant therapy may be only partially effective in mitigating cigarette smoke-induced pro-inflammatory DC-mediated responses in smokers.}, }
@article {pmid18524611, year = {2008}, author = {Ohlsson, AB and Landberg, T and Berglund, T and Greger, M}, title = {Increased metal tolerance in Salix by nicotinamide and nicotinic acid.}, journal = {Plant physiology and biochemistry : PPB}, volume = {46}, number = {7}, pages = {655-664}, doi = {10.1016/j.plaphy.2008.04.004}, pmid = {18524611}, issn = {0981-9428}, mesh = {Acetylcysteine/pharmacology ; Adaptation, Physiological ; Analysis of Variance ; Buthionine Sulfoximine/pharmacology ; Cadmium/pharmacology ; Chromatography, High Pressure Liquid ; Copper/pharmacology ; Enzyme Inhibitors/pharmacology ; Glutathione/metabolism ; Metals/*pharmacology ; Niacin/*pharmacology ; Niacinamide/*pharmacology ; Pyrrolidonecarboxylic Acid/pharmacology ; Salix/*drug effects/metabolism ; Thiazolidines/pharmacology ; Zinc/pharmacology ; }, abstract = {We have earlier shown that nicotinamide (NIC) and nicotinic acid (NiA) can induce defence-related metabolism in plant cells; e.g. increase the level of glutathione. Here we investigated if NIC and NiA could increase the metal tolerance in metal sensitive clones of Salix viminalis and whether this would be mediated via increased glutathione level. Salix clones, sensitive or tolerant to zinc (Zn), copper (Cu) and cadmium (Cd) were grown in the presence of heavy metals (Cd, Cu or Zn) or NIC and NiA as well as in combination. In addition, the influence of N-acetyl-cystein (NAC) and l-2-oxothiazolidine 4-carboxylate (OTC), stimulators of reduced glutathione (GSH) biosynthesis, and the glutathione biosynthesis inhibitor buthionine sulfoximine (BSO) was analysed. Tolerance was measured as effects on root and shoot dry weight, and the glutathione and metal concentrations in the tissues were analysed. Results showed that NIC and NiA decreased the toxic effects of Cd, Cu and Zn on growth significantly in sensitive clones, but also to some extent in tolerant clones. However, the glutathione level and metal concentration did not change by NIC or NiA addition. Treatment with NAC, OTC or BSO did not per se influence the sensitivity to Cd, although the glutathione level increased in the presence of NAC and OTC and decreased in response to BSO. The results suggest that NIC and NiA increased the defence against heavy metals but not via glutathione formation per se.}, }
@article {pmid18524328, year = {2008}, author = {Calderón-Cabrera, L and Durán-Galetta, MG and Garcia, I and Galetta, D and Lacruz, L and Naranjo, R and Pérez, B and Ferreira, E}, title = {[Determination of the N-acetylcysteine and methionine effects in the cerebellum of rats intoxicated with lead].}, journal = {Investigacion clinica}, volume = {49}, number = {1}, pages = {17-28}, pmid = {18524328}, issn = {0535-5133}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Cerebellum/*drug effects ; Lead/blood ; Lead Poisoning/blood/*drug therapy ; Male ; Methionine/pharmacology/*therapeutic use ; Rats ; Rats, Wistar ; }, abstract = {A therapeutic essay was done to determine the effects of N-Acetylcysteine (NAC), Methionine (MET) and the NAC + MET combination on the lead (Pb) blood levels, the malondialdehide (MDA) and catalase activity (CAT) in cerebellum of rats treated with 0.5 and 2 microg/g of Pb acetate. One hundred ninety eight male Wistar rats with an average weight of 240 g were subjected to a test, divided into five groups. Group 1 was the control group where basal levels were determined; Group 2 was the treated group; the rest of the groups once treated received the following: Group 3 NAC, Group 4 MET, Group 5 NAC + MET. The results showed that NAC lowers blood lead levels by 35% and 38% with intoxication doses of 0.5 microg/g and 2 microg/g of Pb acetate respectively. This decrease was not statistically significant; however, there was a 56% decrease of MDA in the cerebellum with a dose of 0.5 microg/g of Pb and of 75% with 2 microg/g; CAT activity increased in the cerebellum by 62% and 71% with the studied Pb doses, making this a statistically significant difference (p < 0.0001) in relation to the intoxication group. MET has a similar effect to NAC, even though it was less strong; anyhow, when NAC + MET are combined a quelant effect is shown, with a statistically significant 45% and 51% reduction in the Pb levels with the doses administered (p < 0.001); MDA decreased and CAT activity increased in the cerebellum. In this research we can conclude that NAC+MET when combined, have a beneficial effect on the studied parameters during acute Pb treatment.}, }
@article {pmid18523380, year = {2008}, author = {Hu, X and Zhang, Y and Cheng, D and Ding, Y and Yang, D and Jiang, F and Zhou, C and Ying, B and Wen, F}, title = {Mechanical stress upregulates intercellular adhesion molecule-1 in pulmonary epithelial cells.}, journal = {Respiration; international review of thoracic diseases}, volume = {76}, number = {3}, pages = {344-350}, doi = {10.1159/000137509}, pmid = {18523380}, issn = {1423-0356}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cell Survival ; Cells, Cultured ; Epithelial Cells/*metabolism ; Flavonoids/pharmacology ; Humans ; Intercellular Adhesion Molecule-1/*metabolism ; Pulmonary Alveoli/cytology ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; *Stress, Mechanical ; Time Factors ; Up-Regulation/*physiology ; }, abstract = {BACKGROUND: Mechanical ventilation can affect the lung, causing edema and alveolar inflammation. Intercellular adhesion molecule-1 (ICAM-1) plays an important role in this inflammatory response.<br><br>OBJECTIVE: The aims of this study were to investigate whether cyclic cell stretch upregulates the production of ICAM-1 by human alveolar epithelium and to explore possible mechanisms of upregulation.<br><br>METHODS: Human type 2-like alveolar epithelial cells (A549 cells) were exposed to cyclic tensile strain via a four-point bending system, with strains of varying frequency (0.2, 0.5, and 1 Hz), duration (0, 1, 3, and 6 h), and magnitude (500, 1,000, and 2,000 microstrain). Strain was applied at varying frequency (0.2, 0.5, 1 Hz) but at constant time (3 h) and magnitude (1,000 microstrain), at varying duration (0, 1, 3, and 6 h) but at constant frequency (0.5 Hz) and magnitude (1,000 microstrain), or at varying magnitude (500, 1,000, and 2,000 microstrain) but at constant time (3 h) and frequency (0.5 Hz).<br><br>RESULTS: Mechanical loading induced ICAM-1 protein and mRNA production in a frequency- and duration-dependent manner. At the 3-hour time point, large loadings (1,000 or 2,000 microstrain) upregulated ICAM-1 protein production, but there was no statistically significant difference between these two groups (p > 0.05). PD98059, a specific inhibitor of extracellular signal-regulated kinase (ERK), and N-acetylcysteine (NAC), an antioxidant, partially abrogated the stretch-induced ICAM-1 protein upregulation at the 3-hour loading.<br><br>CONCLUSION: Mechanical strain can upregulate ICAM-1 production. The response is frequency and duration dependent, which may involve both ERK pathways and reactive oxidant species production.}, }
@article {pmid18520151, year = {2008}, author = {Baumann, J and Ghosh, S and Szakmany, T and Jancso, G and Ferencz, A and Roth, E and Bogar, L}, title = {Short-term effects of N-acetylcysteine and ischemic preconditioning in a canine model of hepatic ischemia-reperfusion injury.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {41}, number = {2}, pages = {226-230}, doi = {10.1159/000135707}, pmid = {18520151}, issn = {1421-9921}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Coloring Agents/pharmacokinetics ; Disease Models, Animal ; Dogs ; Indocyanine Green/pharmacokinetics ; Ischemic Preconditioning/*methods ; Liver Diseases/*metabolism/*prevention &amp; control ; Reperfusion Injury/*metabolism/*prevention &amp; control ; }, abstract = {AIMS: We evaluated the possibility that repeated ischemic preconditioning or N-acetylcysteine (NAC) could prevent ischemia-reperfusion injury as determined by indocyanine green plasma disappearance rate (ICG-PDR) or has favorable hemodynamic effects during reperfusion in an in vivo canine liver model.<br><br>METHODS: Under general anesthesia, 3 groups of mongrel dogs (n = 5 per group) were subjected to (1) 60-min hepatic ischemia, (2) same ischemia preceded by intravenous administration of 150 mg kg(-1) NAC, and (3) three episodes of IPC (10-min ischemia followed by 10-min reperfusion) prior to same ischemia. Hepatic reperfusion was maintained for a further 180 min, with hemodynamic and hepatic function parameters monitored throughout.<br><br>RESULTS: Plasma disappearance rate of indocyanine green and serum levels of aspartate transferase and alanine transferase showed no significant differences between groups. Although liver injury was obvious, reflected by hemodynamic, blood gas, and liver function tests, NAC and IPC failed to prevent decay in hepatic function in this canine model.<br><br>CONCLUSION: The results do not support the hypothesis that short-term use of NAC and IPC is beneficial in hepatic surgery.}, }
@article {pmid18513531, year = {2008}, author = {Adabag, AS and Ishani, A and Koneswaran, S and Johnson, DJ and Kelly, RF and Ward, HB and McFalls, EO and Bloomfield, HE and Chandrashekhar, Y}, title = {Utility of N-acetylcysteine to prevent acute kidney injury after cardiac surgery: a randomized controlled trial.}, journal = {American heart journal}, volume = {155}, number = {6}, pages = {1143-1149}, doi = {10.1016/j.ahj.2008.01.013}, pmid = {18513531}, issn = {1097-6744}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/blood/*etiology/*prevention &amp; control ; Aged ; Cardiac Surgical Procedures/*adverse effects ; Cardiovascular Diseases/*surgery ; Creatinine/blood ; Double-Blind Method ; Female ; Humans ; Male ; Perioperative Care ; Treatment Outcome ; }, abstract = {BACKGROUND: Acute kidney injury (AKI) after heart surgery is associated with increased mortality. We sought to determine whether prophylactic perioperative administration of N-acetylcysteine (NAC) prevents postoperative AKI in patients with chronic kidney disease undergoing cardiac surgery (clinical trials.gov identifier NCT00211653).<br><br>METHODS: In this prospective, randomized, placebo-controlled, double-blinded clinical trial, 102 patients with chronic kidney disease who underwent heart surgery at the Minneapolis Veterans Affairs Medical Center were randomized to either NAC (n = 50) 600 mg PO twice daily or placebo (n = 52) for a total of 14 doses (3 preoperative). The primary outcome was maximum change in creatinine from baseline within 7 days after surgery. Secondary outcome was AKI (ie, >0.5 mg/dL or >or=25% increase in creatinine from baseline).<br><br>RESULTS: Creatinine increased in both groups (0.45 +/- 0.7 mg/dL in NAC vs 0.55 +/- 0.9 mg/dL in placebo, P = .53) and peaked on postoperative day 5. Acute kidney injury occurred in 41 patients (22 NAC vs 19 placebo, P = .44) by postoperative day 5, but persisted in only 14 (7 NAC vs 7 placebo, P = .94) by day 30. In multivariable analysis, perioperative NAC was unassociated with AKI (relative risk 1.2, 95% CI, 0.8-1.9, P = .34). Five patients (3 NAC vs 2 placebo, P = .68) underwent hemodialysis, and 5 (2 NAC vs 3 placebo, P = 1.0) died perioperatively. There was no difference in lengths of stay in the intensive care unit (4.9 +/- 7 days in NAC vs 6.5 +/- 9 days in placebo, P = .06) and the hospital (13.2 +/- 13 days in NAC vs 16.7 +/- 17 days in placebo, P = .12).<br><br>CONCLUSION: Prophylactic perioperative NAC administration does not prevent AKI after cardiac surgery.}, }
@article {pmid18512759, year = {2008}, author = {Hsiao, YH and Chen, PS and Yeh, SH and Lin, CH and Gean, PW}, title = {N-acetylcysteine prevents beta-amyloid toxicity by a stimulatory effect on p35/cyclin-dependent kinase 5 activity in cultured cortical neurons.}, journal = {Journal of neuroscience research}, volume = {86}, number = {12}, pages = {2685-2695}, doi = {10.1002/jnr.21710}, pmid = {18512759}, issn = {1097-4547}, mesh = {Acetylcysteine/*pharmacology ; Amyloid beta-Peptides/antagonists &amp; inhibitors/*toxicity ; Animals ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Cerebral Cortex/cytology/drug effects/*enzymology ; Cyclin-Dependent Kinase 5/genetics/metabolism ; Enzyme Activation/drug effects/physiology ; Neurons/drug effects/*enzymology ; Phosphotransferases/genetics/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Although previous studies have indicated that the neuroprotective effect of N-acetylcysteine (NAC) required activation of the Ras-extracellular-signal-regulated kinase (ERK) pathway, the detailed mechanisms and signal cascades leading to activation ERK are not clear. In the present study, we investigated the effect of NAC on A beta(25-35)-induced neuronal death. Pretreatment of neurons with NAC 1 hr before application of A beta prevented A beta-mediated cell death. NAC increased cyclin-dependent kinase 5 (Cdk5) phosphorylation, an effect that was blocked by Cdk5 inhibitor. The neuroprotective effect of NAC was significantly attenuated by Cdk5 inhibitors or in neurons transfected with Cdk5 or p35 small interfering RNA (siRNA). Conversely, pretreatment of neurons with the calpain inhibitors calpeptin or MDL28170 enhanced the neuroprotective effect of NAC. A beta(25-35) caused a significant decrease in the level of p35, with a concomitant increase in p25, which was completely prevented by NAC. This effect of NAC was blocked by the Cdk5 inhibitors roscovitine and butyrolactone. In addition, NAC increased Cdk5/p35 kinase activity but reduced Cdk5 kinase activity. A beta(25-35) treatment decreased phosphorylated levels of ERK, which could be reversed by NAC. The effect of NAC was completely blocked by Cdk5 inhibitors. NAC reversed the A beta(25-35)-induced decrease in the expression of Bcl-2, which could be blocked by the MAPK kinase (MEK) inhibitor or Cdk5 inhibitors. These results suggest that NAC-mediated neuroprotection against A beta toxicity is likely mediated by the p35/Cdk5-ERKs-Bcl-2 signal pathway.}, }
@article {pmid18511884, year = {2008}, author = {Han, YH and Kim, SZ and Kim, SH and Park, WH}, title = {Suppression of arsenic trioxide-induced apoptosis in HeLa cells by N-acetylcysteine.}, journal = {Molecules and cells}, volume = {26}, number = {1}, pages = {18-25}, pmid = {18511884}, issn = {1016-8478}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Catalase/metabolism ; Cell Cycle/drug effects ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Growth Inhibitors/pharmacology ; HeLa Cells/pathology ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Oxides/*pharmacology ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; }, abstract = {Arsenic trioxide (ATO) can affect many biological functions such as apoptosis and differentiation in various cells. We investigated the involvement of ROS and GSH in ATO-induced HeLa cell death using ROS scavengers, especially N-acetylcysteine (NAC). ATO increased intracellular O(2)(*-) levels and reduced intracellular GSH content. The ROS scavengers, Tempol, Tiron and Trimetazidine, did not significantly reduce levels of ROS or GSH depletion in ATO-treated HeLa cells. Nor did they reduce the apoptosis induced by ATO. In contrast, treatment with NAC reduced ROS levels and GSH depletion in the ATO-treated HeLa cells and prevented ATO-induced apoptosis. Treatment with exogenous SOD and catalase reduced the depletion of GSH content in ATO-treated cells. Catalase strongly protected the cells from ATO-induced apoptosis. In addition, treatment with SOD, catalase and NAC slightly inhibited the G1 phase accumulation induced by ATO. In conclusion, NAC protects HeLa cells from apoptosis induced by ATO by up-regulating intracellular GSH content and partially reducing the production of O(2)(*-).}, }
@article {pmid18507034, year = {2008}, author = {Tencer, L and Burgermeister, E and Ebert, MP and Liscovitch, M}, title = {Rosiglitazone induces caveolin-1 by PPARgamma-dependent and PPRE-independent mechanisms: the role of EGF receptor signaling and its effect on cancer cell drug resistance.}, journal = {Anticancer research}, volume = {28}, number = {2A}, pages = {895-906}, pmid = {18507034}, issn = {0250-7005}, mesh = {Caveolin 1/*metabolism ; Cell Survival ; Drug Resistance, Neoplasm ; Epidermal Growth Factor/pharmacology ; ErbB Receptors/*physiology ; HT29 Cells ; Humans ; PPAR gamma/antagonists &amp; inhibitors/*pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism ; Rosiglitazone ; Signal Transduction ; Superoxides/metabolism ; Thiazolidinediones/*pharmacology ; }, abstract = {BACKGROUND: Caveolin-1, a key component of plasma membrane caveolae, has been implicated in the regulation of cancer cell growth and survival. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-activated nuclear receptor which plays a pivotal role in many cellular processes. Activation of PPARgamma by its ligand rosiglitazone upregulates caveolin-1 mRNA and protein in human carcinoma cells.<br><br>MATERIALS AND METHODS: We have used specific signaling inhibitors to dissect the mechanisms of caveolin-1 mRNA and protein induction by rosiglitazone, determined by RT-PCR and Western blotting, respectively. ROS generation was measured by flow cytometry and cell survival was determined by the MTT assay.<br><br>RESULTS: We show that in HT-29 human colon cancer cells the induction ofcaveolin-1 by rosiglitazone is inhibited by the EGF receptor (EGFR) blocker AG1478. Moreover, rosiglitazone stimulates EGFR phosphorylation, while direct activation of EGFR by EGF up-regulates caveolin-1 mRNA. Inhibitors of Src and the Mek1-Erk1/2 and p38 MAP kinase pathways also inhibit up-regulation of caveolin-1 by rosiglitazone. Furthermore, rosiglitazone stimulates formation of superoxide anions, whereas induction of caveolin-1 expression by rosiglitazone is attenuated by the antioxidant N-acetyl-cysteine. Finally, rosiglitazone increases the resistance of HT-29 cells to doxorubicin and to hydrogen peroxide. The caveolin-1 gene promoter lacks a canonical PPARgamma response element (PPRE) and a PPRE-reporter construct is not sensitive to EGF or EGFR inhibition.<br><br>CONCLUSION: Our findings indicate that up-regulation of caveolin-1 by rosiglitazone requires superoxide formation and the activation of Src, EGFR, and the Mek1-Erk1/2 and p38 MAP kinase pathways. We suggest a novel mode of action of PPARgamma ligands in the regulation of caveolin-1, and possibly other genes devoid of a PPRE in their promoters, which involves the coordinate activation of PPARgamma and intracellular signaling pathways.}, }
@article {pmid18507007, year = {2008}, author = {Cory, AH and Chen, J and Cory, JG}, title = {Implications of the involvement of the endoplasmic reticulum stress pathway in drug-induced apoptosis.}, journal = {Anticancer research}, volume = {28}, number = {2A}, pages = {681-686}, pmid = {18507007}, issn = {0250-7005}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Deoxyadenosines/pharmacology ; Drug Resistance, Neoplasm ; Endoplasmic Reticulum/*metabolism ; Endoplasmic Reticulum Chaperone BiP ; Heat-Shock Proteins/*metabolism ; Leukemia L1210 ; Molecular Chaperones/metabolism ; NF-kappa B/metabolism ; Nitriles/*pharmacology ; Sesquiterpenes/*pharmacology ; Signal Transduction ; Sulfones/*pharmacology ; Transcription Factor CHOP/metabolism ; }, abstract = {Apoptosis occurs by distinct pathways that involve the cell surface, mitochondria or the endoplasmic reticulum. Previous studies had shown that deoxyadenosine-resistant L1210 cells (Y8) proceeded to apoptosis under conditions in which the parental L1210 cell line (WT) did not undergo an apoptotic response. Combinations of drugs, acting at different molecular targets, markedly potentiated the apoptotic response in the Y8 cells without inducing apoptosis in the WT cells. In the present study, induction of apoptosis by parthenolide and BAY 11-7085, drugs that targeted nuclear factor kappa B activation, was blocked by the presence of N-acetylcysteine (NAC). On the other hand, the levels of apoptosis induced by parthenolide or BAY 11-7085 were increased by pre-treatment of the cells with glutathione lowering L-buthionine-(S,R)-sulfoximine (BSO). Western blot analyses showed that the levels of the stress proteins, Grp 78 and Gadd 153 were reduced in the parthenolide-treated Y8 cells, but not in those co-treated with NAC. Protection of the cells from apoptosis induced by parthenolide or BAY 11-7085 by NAC was relatively specific as the induction of apoptosis in the Y8 cells by MG-132, flavopiridol, Gemcitabine or PRIMA-1 was not decreased by NAC. These data suggest that multiple pathways, one of which is ER-stress induced, may ultimately be involved and interactive in the induction of apoptosis in specific cell lines.}, }
@article {pmid18506790, year = {2008}, author = {Liu, Y and Templeton, DM}, title = {Initiation of caspase-independent death in mouse mesangial cells by Cd2+: involvement of p38 kinase and CaMK-II.}, journal = {Journal of cellular physiology}, volume = {217}, number = {2}, pages = {307-318}, doi = {10.1002/jcp.21499}, pmid = {18506790}, issn = {1097-4652}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor/metabolism ; Cadmium Chloride/*toxicity ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism ; Caspases/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Culture Media, Serum-Free ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mesangial Cells/*drug effects/enzymology/pathology ; Mice ; Mitochondria/drug effects/metabolism ; Phosphorylation ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Time Factors ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Cadmium (Cd) is a toxic metal with multiple effects on cell signaling and cell death. We studied the effects of Cd(2+) on quiescent mouse mesangial cells in serum-free conditions. Cadmium induces cell death over 6 h through annexin V+ states without or with causing uptake of propidium iodide, termed apoptotic and apoptosis-like death, respectively. Little or no necrosis is observed, and cell death is caspase-independent and associated with nuclear translocation of the apoptosis-inducing factor, AIF. We previously showed that Cd(2+) increased phosphorylation of Erk and CaMK-II, and CaMK-II activation increased cell death in an Erk-independent manner. Here we demonstrate that Cd(2+) increases Jnk and p38 kinase phosphorylation, and inhibition of p38-but not of Jnk-increases cell viability by suppressing apoptosis in preference to apoptosis-like death. Neither p38 kinase nor CaMK-II inhibition protects against a decrease in mitochondrial membrane potential, psi, indicating that kinase-mediated death is either independent of, or involves events downstream of a mitochondrial pathway. However, both the antioxidant N-acetyl cysteine (NAC) and the mitochondrial membrane-stabilizing agent cyclosporine A (CsA) partially preserve psi, suppress activation of p38 kinase, and partially protect the cells from Cd(2+)-induced death. Whereas the effect of CsA is on apoptosis, NAC acts on apoptosis-like death. Inhibition of glutathione synthesis exacerbates a Cd(2+)-dependent increase in cellular peroxides and favors apoptosis-like death over apoptosis. The caspase-independence of these modes of cell death is not due to an absence of this machinery in the mesangial cells: when they are exposed to Cd(2+) for longer periods in the presence of serum, procaspase-3 and PARP are cleaved and caspase inhibition is protective. We conclude that Cd(2+) can kill mesangial cells by multiple pathways, including caspase-dependent and -independent apoptotic and apoptosis-like death. Necrosis is not prominent. Activation of p38 kinase and of CaMK-II by Cd(2+) are associated with caspase-independent apoptosis that is not dependent on mitochondrial destabilization.}, }
@article {pmid18506365, year = {2008}, author = {Han, YH and Kim, SZ and Kim, SH and Park, WH}, title = {Pyrogallol as a glutathione depletor induces apoptosis in HeLa cells.}, journal = {International journal of molecular medicine}, volume = {21}, number = {6}, pages = {721-730}, pmid = {18506365}, issn = {1107-3756}, mesh = {Acetylcysteine/metabolism/pharmacology ; Annexin A5/chemistry ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Catalase/metabolism/pharmacology ; Dose-Response Relationship, Drug ; Flow Cytometry ; Fluorescein-5-isothiocyanate/chemistry ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism/pharmacology ; HeLa Cells ; Humans ; Hydrogen Peroxide/metabolism ; Hydroxyl Radical/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/physiology ; Models, Biological ; Pyrogallol/*pharmacology ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism/pharmacology ; Superoxides/metabolism ; }, abstract = {Pyrogallol, a polyphenol, is known to be a superoxide anion (O2(.-)) generator. We investigated the involvement of glutathione (GSH) and reactive oxygen species (ROS) in pyrogallol-induced HeLa cell death. We measured the changes of ROS levels, GSH levels, sub-G1 cells, annexin V/PI staining cells and mitochondria membrane potential (DeltaPsi m) in HeLa cells treated with pyrogallol and/or ROS scavenger. The intracellular ROS levels were decreased or increased depending on the concentration of pyrogallol. The level of O2(.-) was significantly increased and superoxide dismutase (SOD) activity was down-regulated by pyrogallol. Pyrogallol reduced intracellular GSH content in HeLa cells. The ROS scavengers, Tempol, Tiron, Trimetazidine and N-acetylcysteine (NAC), did not down-regulate the production of O2(.-). However, treatment with NAC showed the recovery of GSH depletion and significantly rescued cells from pyrogallol-induced apoptosis. In addition, the recovery of GSH depletion by SOD and catalase was accompanied by the decrease of apoptosis levels. Furthermore, NAC and SOD significantly inhibited CMF-negative (GSH-depleted) and PI-positive cells induced by pyrogallol. Taken together, pyrogallol potently increased intracellular O2(.-) levels and decreased GSH content in HeLa cells, and NAC, SOD and catalase significantly rescued HeLa cells from pyrogallol-induced apoptosis accompanied by the recovery of GSH depletion.}, }
@article {pmid18504181, year = {2008}, author = {Fu, L and Cai, SX and Zhao, HJ and Li, WJ and Tong, WC}, title = {[Effect of N-acetylcysteine on HMGB1 and RAGE expression in the lungs of asthmatic mice].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {28}, number = {5}, pages = {692-695}, pmid = {18504181}, issn = {1673-4254}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Asthma/*physiopathology ; Female ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; HMGB1 Protein/biosynthesis/*genetics ; Immunohistochemistry ; Lung/*drug effects/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; Mitogen-Activated Protein Kinases/biosynthesis/*genetics ; RNA, Messenger/biosynthesis/genetics ; Random Allocation ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {OBJECTIVE: To investigate the expression of HMGB1 and RAGE mRNA in the lungs of asthmatic mice and the effect of N-acetylcysteine (NAC) on their expression.<br><br>METHODS: Twenty-one female BALB/c mice were randomly divided into control group, asthma group and NAC group (n=7). The expressions of HMGB1 and RAGE mRNA and their distributions in the lungs were detected by RT-PCR and immunohistochemical method.<br><br>RESULTS: The expression levels of HMGB1 and RAGE mRNA were not significantly different between the control group (0.88-/+0.02 and 1.20-/+0.20, respectively) and the asthma model group (0.86-/+0.05 and 1.21-/+0.08, P>0.05). After NAC treatment, both of HMGB1 and RAGE mRNA levels (0.98-/+0.05 and 1.58-/+0.21) were significantly higher than those in the other two groups (P<0.05). HMGB1 was found in the nuclei and membrane of the bronchial and alveolar epithelial cells, and RAGE was located on the membrane of the alveolar epithelial cells.<br><br>CONCLUSION: HMGB1 and RAGE may play a role in the oxidative stress during asthma, but the exact mechanism needs further investigation.}, }
@article {pmid18503116, year = {2008}, author = {Birnbaum, J and Lehmann, Ch and Klotz, E and Hein, OV and Blume, A and Jubin, F and Polze, N and Luther, D and Spies, CD}, title = {Effects of N-acetylcysteine and tirilazad mesylate on intestinal functional capillary density, leukocyte adherence, mesenteric plasma extravasation and cytokine levels in experimental endotoxemia in rats.}, journal = {Clinical hemorheology and microcirculation}, volume = {39}, number = {1-4}, pages = {99-111}, pmid = {18503116}, issn = {1386-0291}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Capillaries/*drug effects/metabolism ; Cell Adhesion ; Cytokines/*metabolism ; Endotoxemia/*blood ; Endotoxins/metabolism ; Heart Rate ; Intestines/*blood supply ; Leukocytes/*cytology/drug effects/metabolism ; Male ; Pregnatrienes/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {INTRODUCTION: The study's objective was to determine the effects of the administration of N-acetylcysteine (NAC) and of tirilazad mesylate (TM) on intestinal functional capillary density, mesenteric plasma extravasation, leukocyte adherence and on cytokine release during experimental endotoxemia in rats.<br><br>METHODS: In a prospective, randomized, controlled animal study, 80 male Wistar rats were examined in 2 test series. Both series were divided into 4 groups. Group 1 served as control group (CON group). Group 2 (LPS group), group 3 (NAC group) and group 4 (TM group) received endotoxin infusions (10 mg/kg over 2 h). In NAC group 150 mg/kg body weight NAC was administered after the first 30 minutes of endotoxemia intravenously. In TM group, 10 mg/kg body weight TM was administered after the first 30 minutes of endotoxemia intravenously. Animals of the series 1 underwent studies of leukocyte adherence on submucosal venular endothelium of the small bowel wall and intestinal functional capillary density (FCD) in the intestinal mucosa and the circular as well as the longitudinal muscle layer by intravital fluorescence microscopy (IVM). Plasma levels of interleukin 1beta (IL-1beta), interferone gamma (IFN-gamma) and soluble intercellular adhesion molecule1 (s-ICAM 1) as well as white blood cell count (WBC) were estimated. In the animals of the series 2 mesenteric plasma extravasation was determined by IVM and plasma levels of tumor necrosis factor alpha (TNF-alpha), IL-4, IL-6, IL-10 and malondialdehyde (MDA) were estimated.<br><br>RESULTS: After LPS administration, FCD in the villi intestinales was unchanged and in the longitudinal muscularis layer it was increased. There was no effect of NAC or TM administration on FCD.Although the plasma extravasation was not significantly influenced by LPS administration, TM administration resulted in a lower plasma extravasation in the TM group compared to the other groups. After endotoxin challenge, the firmly adherence of leukocytes to vascular endothelium as a parameter of leukocyte activation in endotoxemia was increased but NAC or TM administration had no influence on leukocyte adherence. The plasma levels of IL-1beta, IL-6, IL-10, TNF-alpha, IFN-gamma and sICAM-1 were increased in the endotoxemic groups (LPS group, NAC group and TM group) and the WBC was decreased compared to controls. IL-4 levels were unchanged during observation period. Plasma MDA levels were not influenced by LPS administration compared to controls. The administration of NAC resulted in lower sICAM-1 and MDA levels compared to the LPS group. The IL-1beta, IL-6, IL-10, TNF-alpha and IFN-gamma plasma levels were not influenced by NAC or TM administration.<br><br>CONCLUSIONS: In this posttreatment sepsis model in rats, NAC administration resulted in lower sICAM-1 and MDA levels compared to the LPS treated animals. TM administration reduced the plasma extravasation in this model.}, }
@article {pmid18502961, year = {2008}, author = {Paranjpe, A and Sung, EC and Cacalano, NA and Hume, WR and Jewett, A}, title = {N-acetyl cysteine protects pulp cells from resin toxins in vivo.}, journal = {Journal of dental research}, volume = {87}, number = {6}, pages = {537-541}, doi = {10.1177/154405910808700603}, pmid = {18502961}, issn = {0022-0345}, support = {R01 DE 10331/DE/NIDCR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Death/*drug effects ; Composite Resins/*toxicity ; Dental Pulp/cytology/*drug effects ; Dental Restoration, Permanent/adverse effects ; Humans ; Male ; Methacrylates/toxicity ; Molar, Third ; Rats ; Rats, Sprague-Dawley ; Resin Cements/toxicity ; Stromal Cells/drug effects ; }, abstract = {Potential risks of the use of resin-based restorative materials include direct damage to the pulp cells and the induction of hypersensitivity reactions in patients. In this study, we tested the hypothesis that N-acetyl cysteine (NAC) inhibits resin toxicity and restores the function of pulp cells. Analysis of our data demonstrates toxicity of composite resins on pulp cells in both an in vivo rat and an ex vivo human model system. Moreover, cells that survive after the placement of composites are weaker, and they are induced to undergo cell death when exposed to 2-hydroxyethyl methacrylate (HEMA). The toxic effect of composites on pulp cells is neutralized by NAC. Therefore, NAC protects the cells from damage induced by clinically relevant levels of restorative materials, in both rat and human model systems. The addition of N-acetyl cysteine prior to or concomitant with the application of restorative materials may be beneficial for the health and safety of dental patients.}, }
@article {pmid18500954, year = {2005}, author = {Kerksick, C and Willoughby, D}, title = {The antioxidant role of glutathione and N-acetyl-cysteine supplements and exercise-induced oxidative stress.}, journal = {Journal of the International Society of Sports Nutrition}, volume = {2}, number = {2}, pages = {38-44}, pmid = {18500954}, issn = {1550-2783}, abstract = {An increase in exercise intensity is one of the many ways in which oxidative stress and free radical production has been shown to increase inside our cells. Effective regulation of the cellular balance between oxidation and antioxidation is important when considering cellular function and DNA integrity as well as the signal transduction of gene expression. Many pathological states, such as cancer, Parkinson's disease, and Alzheimer's disease have been shown to be related to the redox state of cells. In an attempt to minimize the onset of oxidative stress, supplementation with various known antioxidants has been suggested. Glutathione and N-acetyl-cysteine (NAC) are antioxidants which are quite popular for their ability to minimize oxidative stress and the downstream negative effects thought to be associated with oxidative stress. Glutathione is largely known to minimize the lipid peroxidation of cellular membranes and other such targets that is known to occur with oxidative stress. N-acetyl-cysteine is a by-product of glutathione and is popular due to its cysteine residues and the role it has on glutathione maintenance and metabolism. The process of oxidative stress is a complicated, inter-twined series of events which quite possibly is related to many other cellular processes. Exercise enthusiasts and researchers have become interested in recent years to identify any means to help minimize the detrimental effects of oxidative stress that are commonly associated with intense and unaccustomed exercise. It is possible that a decrease in the amount of oxidative stress a cell is exposed to could increase health and performance.}, }
@article {pmid18496137, year = {2008}, author = {Kin, H and Wang, NP and Mykytenko, J and Reeves, J and Deneve, J and Jiang, R and Zatta, AJ and Guyton, RA and Vinten-Johansen, J and Zhao, ZQ}, title = {Inhibition of myocardial apoptosis by postconditioning is associated with attenuation of oxidative stress-mediated nuclear factor-kappa B translocation and TNF alpha release.}, journal = {Shock (Augusta, Ga.)}, volume = {29}, number = {6}, pages = {761-768}, doi = {10.1097/SHK.0b013e31815cfd5a}, pmid = {18496137}, issn = {1073-2322}, support = {HL64886/HL/NHLBI NIH HHS/United States ; HL69487/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus/drug effects ; Animals ; *Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Nucleus/*metabolism/pathology ; DNA Fragmentation/drug effects ; Free Radical Scavengers/pharmacology ; *Ischemic Preconditioning ; Male ; Myocardium/*metabolism/pathology ; NF-kappa B/*metabolism ; *Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Superoxides/metabolism ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Oxidative stress-stimulated nuclear factor-kappa B (NF-kappa B) activation has been associated with rapid transcription of TNF-alpha and induction of apoptosis. This study tested the hypothesis that postconditioning (Postcon) reduces myocardial apoptosis and inhibits translocation of NF-kappa B and release of TNF-alpha secondary to an attenuation of oxidant generation during reperfusion. Anesthetized rats were subjected to 30 min of ischemia and 3 h of reperfusion and divided randomly to Control or Postcon (three cycles of 10-s reperfusion and 10-s reocclusion applied at the onset of reperfusion) group, respectively. Relative to Control, Postcon reduced the plasma malondialdehyde (1.21 +/- 0.08 vs. 0.8 +/- 0.06* microM/mL) and decreased the generation of superoxide radical in area at risk myocardium (dihydroethidium staining). Compared with Control, Postcon also inhibited translocation of NF-kappa B to nuclei (167% +/- 21% vs. 142% +/- 18%*), decreased the level of plasma TNF-alpha (1,994 +/- 447 vs. 667 +/- 130* pg/mL), and inhibited caspase-3 activity (0.57% +/- 0.1% vs. 0.21% +/- 0.1%*). The number of apoptotic cells (percent total nuclei) in ischemic myocardium was reduced (20% +/- 1% vs. 11% +/- 2%*), consistent with reduced appearance of DNA fragmentation. To support whether oxidant generation is important in the triggering of cytokine release and apoptosis, N-acetylcysteine (NAC), a potent antioxidant agent, was administered before ischemia and at reperfusion. Treatment with NAC inhibited superoxide radical generation and decreased plasma malondialdehyde to a comparable level to that in Postcon, concomitant with an inhibition of NF-kappa B expression (42% +/- 8%*) and reduction of release of TNF-alpha (231 +/- 72* pg/mL). Caspase-3 activity (0.33% +/- 0.1%*) and apoptotic cells (12% +/- 1%*) were also comparably reduced by NAC. These data suggest that Postcon attenuates myocardial apoptosis, reduces caspase-3 activity, and is potentially mediated by inhibiting oxidant-activated NF-kappa B-TNF-alpha signaling pathway. *P < 0.05 Postcon and NAC vs. Control.}, }
@article {pmid18490958, year = {2008}, author = {Zhang, S and Chai, FY and Yan, H and Guo, Y and Harding, JJ}, title = {Effects of N-acetylcysteine and glutathione ethyl ester drops on streptozotocin-induced diabetic cataract in rats.}, journal = {Molecular vision}, volume = {14}, number = {}, pages = {862-870}, pmid = {18490958}, issn = {1090-0535}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Glucose/metabolism ; Body Weight/drug effects ; Catalase/metabolism ; Cataract/*complications/enzymology ; Diabetes Mellitus, Experimental/chemically induced/*complications/enzymology ; Eye Proteins/metabolism ; Glutathione/*analogs &amp; derivatives/pharmacology ; Glutathione Reductase/metabolism ; Glycosylation/drug effects ; Injections ; Lens, Crystalline/drug effects/enzymology ; Ophthalmic Solutions/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Solubility/drug effects ; Streptozocin ; Sulfhydryl Compounds/metabolism ; Water/metabolism ; }, abstract = {PURPOSE: To evaluate the effect of N-acetylcysteine (NAC) and glutathione ethyl ester (GSH-EE) eye drops on the progression of diabetic cataract formation induced by streptozotocin (STZ).<br><br>METHODS: One hundred and thirty Sprague-Dawley (SD) rats were selected, and diabetes was induced by streptozotocin (65 mg/kg bodyweight) in a single intraperitoneal injection. The control group (group I) received only vehicle. Then, 78 rats with random blood glucose above 14 mmol/l were divided into four groups (group II-V). The drug-treated rats received NAC and GSH-EE eye drops five days before STZ injection. Group I and V animals received sodium phosphate buffer drops (pH 7.4), and those in groups II, III, and IV received 0.01% NAC, 0.05% NAC, and 0.1% GSH-EE drops, respectively. Lens transparency was monitored with a slit lamp biomicroscope and classified into six stages. At the end of four weeks, eight weeks, and 13 weeks, animals were killed and components involved in the pathogenesis of diabetic cataract including thiols (from glutathione and protein), glutathione reductase (GR), catalase (CAT), and glycated proteins were investigated in the lens extracts. Blood glucose, urine glucose, and bodyweight were also determined.<br><br>RESULTS: The progression in lens opacity induced by diabetes showed a biphasic pattern in which an initial slow increase in the first seven weeks after STZ injection was followed by a rapid increase in the next six weeks. The progression of lens opacity in the treated groups (group II-IV) was slower than that of the untreated group (group V) in the earlier period and especially in the fourth week. There were statistically significant differences between the treated groups and the untreated group (p<0.05). However, these differences became insignificant after the sixth week, and the progression of lens opacification in all diabetic groups became aggravated. The content of thiol (from glutathione and protein), glutathione reductase (GR), and catalase (CAT) were lower in the lens extracts of the diabetic rats four weeks, eight weeks, and 13 weeks after the STZ injection while the levels of thiol and CAT activity were both higher in the treated groups (group II-IV) than in the untreated group (group V) at every stage. However, there was no statistically significant difference (p>0.05). Moreover, the diabetes resulted in an increased level of glycated proteins in both the treated groups and the untreated group, but there was no statistically significant difference between all the diabetic groups (p>0.05).<br><br>CONCLUSIONS: NAC and GSH-EE can slightly inhibit the progression of the diabetic cataract at the earlier stage. They may maintain lens transparency and function by serving as a precursor for glutathione biosynthesis and by protecting sulfhydryl groups from oxidation.}, }
@article {pmid18490076, year = {2008}, author = {Yang, YY and Lee, KC and Huang, YT and Wang, YW and Hou, MC and Lee, FY and Lin, HC and Lee, SD}, title = {Effects of N-acetylcysteine administration in hepatic microcirculation of rats with biliary cirrhosis.}, journal = {Journal of hepatology}, volume = {49}, number = {1}, pages = {25-33}, doi = {10.1016/j.jhep.2008.02.012}, pmid = {18490076}, issn = {0168-8278}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Bile Ducts ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Ligation ; Liver Circulation/*drug effects ; Liver Cirrhosis, Biliary/*drug therapy/*metabolism/physiopathology ; Liver Function Tests ; Male ; Microcirculation/drug effects ; Oxidants/metabolism ; Peptide Fragments/genetics/metabolism ; Procollagen/genetics/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Thromboxane-A Synthase/metabolism ; Tyrosine/analogs &amp; derivatives/metabolism ; Vascular Resistance/drug effects ; }, abstract = {BACKGROUND/AIMS: Increased intrahepatic resistance (IHR) in cirrhosis is due to fibrosis and hepatic endothelial dysfunction (HED). Besides producing fibrosis, increased reactive oxygen species (ROS) promotes ROS-related nitration of anti-oxidative enzymes in cirrhotic livers. Tyrosine nitration (nitrotyrosilation)-related inactivation of anti-oxidative enzymes is increased in cirrhotic livers. This study investigates effects of N-acetylcysteine (NAC) administrations in bile-duct-ligation (BDL) rats.<br><br>METHODS: This study measured portal venous pressure (PVP), IHR, hepatic endothelial function, hepatic levels of anti-oxidants and oxidants, type III procollagen (PIIIP), proteins expression of thromboxane synthase (TXS), nitrotyrosine, manganese superoxide dismutase (MnSOD), and hepatic NOx and thromboxane A(2) (TXA(2)) production in perfusates.<br><br>RESULTS: The improvement of HED was associated with decreased PVP and IHR, hepatic protein and mRNA levels of PIIIP, protein expression of TXS and nitrotyrosine, oxidants and production of TXA(2) in NAC-treated BDL rat livers. Conversely, hepatic NOx production, anti-oxidants, and protein expression of MnSOD were increased in NAC-treated BDL rat livers.<br><br>CONCLUSIONS: In NAC-treated cirrhotic rats, the decrease in IHR was mainly caused by its anti-oxidative effect-related prevention of hepatic fibrogenesis associated with the decrease of oxidants-related nitrotyrosilation and improvement of HED.}, }
@article {pmid18483565, year = {2008}, author = {Chen, G and Shi, J and Hu, Z and Hang, C}, title = {Inhibitory effect on cerebral inflammatory response following traumatic brain injury in rats: a potential neuroprotective mechanism of N-acetylcysteine.}, journal = {Mediators of inflammation}, volume = {2008}, number = {}, pages = {716458}, pmid = {18483565}, issn = {1466-1861}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Apoptosis/drug effects ; Blood-Brain Barrier/drug effects ; Brain Injuries/*drug therapy/immunology ; DNA/metabolism ; Intercellular Adhesion Molecule-1/blood ; Interleukin-1beta/analysis ; Interleukin-6/analysis ; Male ; NF-kappa B/metabolism ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/analysis ; }, abstract = {Although N-acetylcysteine (NAC) has been shown to be neuroprotective for traumatic brain injury (TBI), the mechanisms for this beneficial effect are still poorly understood. Cerebral inflammation plays an important role in the pathogenesis of secondary brain injury after TBI. However, it has not been investigated whether NAC modulates TBI-induced cerebral inflammatory response. In this work, we investigated the effect of NAC administration on cortical expressions of nuclear factor kappa B (NF-kappaB) and inflammatory proteins such as interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and intercellular adhesion molecule-1 (ICAM-1) after TBI. As a result, we found that NF-kappaB, proinflammatory cytokines, and ICAM-1 were increased in all injured animals. In animals given NAC post-TBI, NF-kappaB, IL-1beta, TNF-alpha, and ICAM-1 were decreased in comparison to vehicle-treated animals. Measures of IL-6 showed no change after NAC treatment. NAC administration reduced brain edema, BBB permeability, and apoptotic index in the injured brain. The results suggest that post-TBI NAC administration may attenuate inflammatory response in the injured rat brain, and this may be one mechanism by which NAC ameliorates secondary brain damage following TBI.}, }
@article {pmid18482805, year = {2008}, author = {Huang, D and Zhang, Y and Qi, Y and Chen, C and Ji, W}, title = {Global DNA hypomethylation, rather than reactive oxygen species (ROS), a potential facilitator of cadmium-stimulated K562 cell proliferation.}, journal = {Toxicology letters}, volume = {179}, number = {1}, pages = {43-47}, doi = {10.1016/j.toxlet.2008.03.018}, pmid = {18482805}, issn = {0378-4274}, mesh = {Acetylcysteine/pharmacology ; Cadmium Chloride/*toxicity ; Carcinogens/*toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Comet Assay ; DNA Damage ; DNA Methylation/*drug effects ; DNA, Neoplasm/chemistry/*drug effects ; Drug Combinations ; Epigenesis, Genetic/drug effects ; Free Radical Scavengers/pharmacology ; Gene Silencing/drug effects ; Humans ; K562 Cells/*drug effects/metabolism/pathology ; Methionine/pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cell proliferation plays a critical role in the process of cadmium (Cd) carcinogenesis. Although both induction of reactive oxygen species (ROS) and alteration of DNA methylation are involved in Cd-stimulated cell proliferation, the detailed mechanism of Cd-stimulated cell proliferation remains poorly understood. In this study, K562 cells pre-treated with N-acetylcysteine (NAC) or methionine (Meth) were exposed to Cd to investigate the potential contribution of ROS and global DNA methylation pathways in Cd-induced cell proliferation. The results showed that Cd-stimulated cell proliferation, increased ROS and DNA damage levels, and induced global DNA hypomethylation. The increases of ROS and DNA damage levels were attenuated by pre-treatment with NAC. Cd-stimulated cell proliferation did not appear to be suppressed through eliminating ROS by NAC. However, methionine was shown to prevent Cd-induced global DNA hypomethylation and Cd-stimulated cell proliferation. Our results suggest that global DNA hypomethylation, rather than ROS, is a potential facilitator of Cd-stimulated K562 cell proliferation.}, }
@article {pmid18480072, year = {2008}, author = {Ho, CC and Ling, YC and Chang, LW and Tsai, HT and Tsai, MH and Lin, P}, title = {17-Beta estradiol and hydroxyestradiols interact via the NF-kappa B pathway to elevate cyclooxygenase 2 expression and prostaglandin E2 secretion in human bronchial epithelial cells.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {104}, number = {2}, pages = {294-302}, doi = {10.1093/toxsci/kfn096}, pmid = {18480072}, issn = {1096-0929}, mesh = {Acetylcysteine/pharmacology ; Animals ; Bronchi/*drug effects/metabolism ; Cyclooxygenase 2/genetics/*metabolism ; Dinoprostone/*metabolism ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Synergism ; Epigenesis, Genetic/drug effects ; Estradiol/*analogs &amp; derivatives/*pharmacology ; Estrogens/pharmacology ; Estrogens, Catechol/pharmacology ; Female ; Humans ; Lung/drug effects/metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Nitriles/pharmacology ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Respiratory Mucosa/drug effects/metabolism ; Sulfones/pharmacology ; }, abstract = {Some epidemiological studies suggest women may be at greater risk for lung cancer than men. Hydroxyestradiols (OHE(2)) are genotoxic and considered as carcinogenic metabolites of estrogens. In this study, we demonstrate that treatment with 0.1 or 1 nM 2/4 OHE(2) significantly increased intracellular oxidative stress, nuclear factor kappa B (NF-kappaB) activity, and cyclooxygenase-2 (COX-2) expression within 24 h in human bronchial epithelial cells BEAS-2B. Cotreatment with the NF-kappaB inhibitor, Bay 117085, prevented OHE(2)-induced COX-2 mRNA accumulation, suggesting that OHE(2) induced COX-2 expression via the NF-kappaB dependent pathway. Furthermore, cotreatment with 10nM 17-beta estradiol (E(2)) significantly enhanced OHE(2)-increased intracellular oxidative stress and significantly increased not only NF-kappaB activity but also COX-2 levels. As COX-2 participates in biosynthesis of prostaglandin E2 (PGE2), PGE2 secretion was enhanced by the cotreatment of 1 nM OHE(2) and 10nM E(2). To understand the enhancement mechanism between OHE(2) and E(2), cells were cotreated with an antioxidant, N-acetylcysteine (NAC), or NF-kB inhibitor, Bay 117085. Both NAC and Bay 117085 prevented the enhancement in COX-2 expression and PGE2 secretion by the cotreatment of E(2) and OHE(2) in BEAS-2B cells. Similarly, Bay 117085 prevented PGE2 secretion induced by the cotreatment of E(2) and OHE(2) in rat lung slice cultures. These results suggest that E(2) enhanced OHE(2)-increased intracellular oxidative stress which increased NF-kappaB activity, COX-2 expression, and PGE2 secretion. Elevated COX-2 expression and PGE2 secretion has been shown to increase the risk of cancer development. Our present data suggest a pathway that contributes an epigenetic mechanism to the overall mechanism of carcinogenesis.}, }
@article {pmid18477646, year = {2008}, author = {Hecht, SS and Villalta, PW and Hochalter, JB}, title = {Analysis of phenanthrene diol epoxide mercapturic acid detoxification products in human urine: relevance to molecular epidemiology studies of glutathione S-transferase polymorphisms.}, journal = {Carcinogenesis}, volume = {29}, number = {5}, pages = {937-943}, pmid = {18477646}, issn = {1460-2180}, support = {P50 DA013333/DA/NIDA NIH HHS/United States ; R01 CA092025/CA/NCI NIH HHS/United States ; CA-92025/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*pharmacokinetics/*urine ; Biotransformation ; Carcinogens/*pharmacokinetics ; Chromatography, High Pressure Liquid ; Glutathione Transferase/*genetics ; Humans ; *Inactivation, Metabolic ; Models, Molecular ; Neoplasms/*epidemiology/*genetics ; Phenanthrenes/chemistry/*pharmacokinetics/urine ; *Polymorphism, Genetic ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {Many studies have investigated the effects of glutathione S-transferase (GST) polymorphisms on cancer incidence in people exposed to carcinogenic polycyclic aromatic hydrocarbons (PAHs). The basis for this is that the carcinogenic bay region diol epoxide metabolites of several PAH are detoxified by GSTs in in vitro studies. However, there are no reports in the literature on the identification in urine of the mercapturic acid metabolites that would result from this process in humans. We addressed this by developing a method for quantitation in human urine of mercapturic acids which would be formed from angular ring diol epoxides of phenanthrene (Phe), the simplest PAH with a bay region, and a common environmental pollutant. We prepared standard mercapturic acids by reactions of syn- or anti-Phe-1,2-diol-3,4-epoxide and syn- or anti-Phe-3,4-diol-1,2-epoxide with N-acetylcysteine. Analysis of human urine conclusively demonstrated that the only detectable mercapturic acid of this type--N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c/t-1-phenanthryl)-L-cysteine (anti-PheDE-1-NAC)--was derived from the 'reverse diol epoxide', anti-Phe-3,4-diol-1,2-epoxide, and not from the bay region diol epoxides, syn- or anti-Phe-1,2-diol-3,4-epoxide. Levels of anti-PheDE-1-NAC in the urine of 36 smokers were (mean +/- SD) 728 +/- 859 fmol/ml urine. The results of this study provide the first evidence for a mercapturic acid of a PAH diol epoxide in human urine, but it was not derived from a bay region diol epoxide as molecular epidemiologic studies have presumed, but rather from a reverse diol epoxide, representative of metabolites with little if any carcinogenic activity. These results demonstrate the need for integration of genotyping and phenotyping information in molecular epidemiology studies.}, }
@article {pmid18473409, year = {2008}, author = {Guijarro, LG and Mate, J and Gisbert, JP and Perez-Calle, JL and Marin-Jimenez, I and Arriaza, E and Olleros, T and Delgado, M and Castillejo, MS and Prieto-Merino, D and Gonzalez Lara, V and Pena, AS}, title = {N-acetyl-L-cysteine combined with mesalamine in the treatment of ulcerative colitis: randomized, placebo-controlled pilot study.}, journal = {World journal of gastroenterology}, volume = {14}, number = {18}, pages = {2851-2857}, pmid = {18473409}, issn = {1007-9327}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adult ; Aged ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects/*therapeutic use ; Chemokine CCL2/blood ; Colitis, Ulcerative/blood/*drug therapy ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/adverse effects/*therapeutic use ; Glutathione/blood ; Humans ; Interleukin-6/blood ; Interleukin-8/blood ; Male ; Mesalamine/adverse effects/*therapeutic use ; Middle Aged ; Pilot Projects ; Severity of Illness Index ; Treatment Outcome ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {AIM: To evaluate the effectiveness and safety of oral N-acetyl-L-cysteine (NAC) co-administration with mesalamine in ulcerative colitis (UC) patients.<br><br>METHODS: Thirty seven patients with mild to moderate UC were randomized to receive a four-wk course of oral mesalamine (2.4 g/d) plus N-acetyl-L-cysteine (0.8 g/d) (group A) or mesalamine plus placebo (group B). Patients were monitored using the Modified Truelove-Witts Severity Index (MTWSI). The primary endpoint was clinical remission (MTWSI < or = 2) at 4 wk. Secondary endpoints were clinical response (defined as a reduction from baseline in the MTWSI of > or = 2 points) and drug safety. The serum TNF-alpha, interleukin-6, interleukin-8 and MCP-1 were evaluated at baseline and at 4 wk of treatment.<br><br>RESULTS: Analysis per-protocol criteria showed clinical remission rates of 63% and 50% after 4 wk treatment with mesalamine plus N-acetyl-L-cysteine (group A) and mesalamine plus placebo (group B) respectively (OR = 1.71; 95% CI: 0.46 to 6.36; P = 0.19; NNT = 7.7). Analysis of variance (ANOVA) of data indicated a significant reduction of MTWSI in group A (P = 0.046) with respect to basal condition without significant changes in the group B (P = 0.735) during treatment. Clinical responses were 66% (group A) vs 44% (group B) after 4 wk of treatment (OR = 2.5; 95% CI: 0.64 to 9.65; P = 0.11; NNT = 4.5). Clinical improvement in group A correlated with a decrease of IL-8 and MCP-1. Rates of adverse events did not differ significantly between both groups.<br><br>CONCLUSION: In group A (oral NAC combined with mesalamine) contrarily to group B (mesalamine alone), the clinical improvement correlates with a decrease of chemokines such as MCP-1 and IL-8. NAC addition not produced any side effects.}, }
@article {pmid18469310, year = {2008}, author = {Shimizu, MH and Danilovic, A and Andrade, L and Volpini, RA and Libório, AB and Sanches, TR and Seguro, AC}, title = {N-acetylcysteine protects against renal injury following bilateral ureteral obstruction.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {23}, number = {10}, pages = {3067-3073}, pmid = {18469310}, issn = {1460-2385}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aquaporin 2/metabolism ; Glomerular Filtration Rate/drug effects ; Kidney/drug effects/pathology/physiopathology ; Kidney Diseases/etiology/pathology/physiopathology/*prevention &amp; control ; Lipid Peroxidation/drug effects ; Male ; Nitric Oxide Synthase Type III/metabolism ; Osmolar Concentration ; Rats ; Rats, Wistar ; Renal Circulation/drug effects ; Thiobarbituric Acid Reactive Substances/metabolism ; Ureteral Obstruction/*complications/*drug therapy/physiopathology ; Urine/chemistry ; }, abstract = {BACKGROUND: Obstructive nephropathy decreases renal blood flow (RBF) and glomerular filtration rate (GFR), causing tubular abnormalities, such as urinary concentrating defect, as well as increasing oxidative stress. This study aimed to evaluate the effects of N-acetylcysteine (NAC) on renal function, as well as on the protein expression of aquaporin 2 (AQP2) and endothelial nitric oxide synthase (eNOS), after the relief of bilateral ureteral obstruction (BUO).<br><br>METHODS: Adult male Wistar rats were divided into four groups: sham (sham operated); sham operated + 440 mg/kg body weight (BW) of NAC daily in drinking water, started 2 days before and maintained until 48 h after the surgery; BUO (24-h BUO only); BUO + NAC-pre (24-h BUO plus 440 mg/kg BW of NAC daily in drinking water started 2 days before BUO); and BUO + NAC-post (24-h BUO plus 440 mg/kg BW of NAC daily in drinking water started on the day of BUO relief). Experiments were conducted 48 h after BUO relief.<br><br>RESULTS: Serum levels of thiobarbituric reactive substances, which are markers of lipid peroxidation, were significantly lower in NAC-treated rats than in the BUO group rats. The administration of NAC provided significant protection against post-BUO GFR drops and reductions in RBF. Renal cortices and BUO rats presented decreased eNOS protein expression of eNOS in the renal cortex of BUO group rats, whereas it was partially recovered in BUO + NAC-pre group rats. Urine osmolality was significantly lower in BUO rats than in sham group rats or NAC-treated rats, the last also presenting less interstitial fibrosis. Post-BUO downregulation of AQP2 protein expression was averted in the BUO + NAC-pre group rats.<br><br>CONCLUSIONS: This study demonstrates that NAC administration ameliorates the renal function impairment observed 48 h after the relief of 24-h BUO. Oxidative stress is important for the suppression of GFR, RBF, tissue AQP2 and eNOS in the polyuric phase after the release of BUO.}, }
@article {pmid18468994, year = {2008}, author = {Romano, G and Briguori, C and Quintavalle, C and Zanca, C and Rivera, NV and Colombo, A and Condorelli, G}, title = {Contrast agents and renal cell apoptosis.}, journal = {European heart journal}, volume = {29}, number = {20}, pages = {2569-2576}, doi = {10.1093/eurheartj/ehn197}, pmid = {18468994}, issn = {1522-9645}, mesh = {Animals ; Apoptosis/*drug effects ; Ascorbic Acid/administration &amp; dosage ; Caspases/drug effects/metabolism ; Cell Death/drug effects ; Cell Line ; Contrast Media/*adverse effects ; Dogs ; Epithelial Cells/metabolism ; Flow Cytometry ; Humans ; Iohexol/adverse effects/*analogs &amp; derivatives ; Kidney Tubules/*drug effects/metabolism ; Osmolar Concentration ; Swine ; Triiodobenzoic Acids/*adverse effects ; }, abstract = {AIMS: Contrast media (CM) induce a direct toxic effect on renal tubular cells. This toxic effect may have a role in the pathophysiology of contrast nephropathy.<br><br>METHODS AND RESULTS: We evaluated (i) the cytotoxicity of CM [both low-osmolality (LOCM) and iso-osmolality (IOCM)], of iodine alone, and of an hyperosmolar solution (mannitol 8%) on human embryonic kidney (HEK 293), porcine proximal renal tubular (LLC-PK1), and canine Madin-Darby distal tubular renal (MDCK) cells; and (ii) the effectiveness of various antioxidant compounds [n-acetylcysteine (NAC), ascorbic acid and sodium bicarbonate] in preventing CM cytotoxicity. The cytotoxicity of CM was assessed at different time points, with different methods: cell viability, DNA laddering, flow cytometry, and caspase activation. Both LOCM and IOCM produced a concentration- and time-dependent increase in cell death as assessed by the different methods. On the contrary, iodine alone and hyperosmolar solution did not induce any significant cytotoxic effect. There was not any significant difference in the cytotoxic effect between LOCM and IOCM. Furthermore, both LOCM and IOCM caused a marked increase in caspase-3 and -9 activities and poly(ADP-ribose) fragmentation, while no effect on caspase-8/-10 was observed, thus indicating that the CM activated apoptosis mainly through the intrinsic pathway. Both CM induced an increase in protein expression levels of pro-apoptotic members of the Bcl2 family (Bim and Bad). NAC and ascorbic acid but not sodium bicarbonate had a dose-dependent protective effect on renal cells after 3 h incubation with high dose (200 mg iodine/mL) of both LOCM and IOCM.<br><br>CONCLUSION: Both LOCM and IOCM induce a dose-dependent renal cell apoptosis. NAC and ascorbic acid but not sodium bicarbonate prevent this contrast-induced apoptosis.}, }
@article {pmid18466778, year = {2008}, author = {Jay, DB and Papaharalambus, CA and Seidel-Rogol, B and Dikalova, AE and Lassègue, B and Griendling, KK}, title = {Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells.}, journal = {Free radical biology &amp; medicine}, volume = {45}, number = {3}, pages = {329-335}, pmid = {18466778}, issn = {0891-5849}, support = {HL074604/HL/NHLBI NIH HHS/United States ; F32 HL074604/HL/NHLBI NIH HHS/United States ; F32 HL074604-02/HL/NHLBI NIH HHS/United States ; R01 HL058863/HL/NHLBI NIH HHS/United States ; R01 HL058863-10/HL/NHLBI NIH HHS/United States ; HL058863/HL/NHLBI NIH HHS/United States ; }, mesh = {Aorta/drug effects/*metabolism ; Blotting, Western ; Cell Proliferation/drug effects ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Humans ; Janus Kinase 2/drug effects/metabolism ; Membrane Proteins/drug effects/*metabolism ; Muscle, Smooth, Vascular/*metabolism ; Myocytes, Smooth Muscle/drug effects/*metabolism ; NADPH Oxidase 5 ; NADPH Oxidases/drug effects/*metabolism ; Phosphorylation ; Platelet-Derived Growth Factor/drug effects/*metabolism ; Protein Isoforms/metabolism ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/drug effects/metabolism ; Transfection ; }, abstract = {The proliferation of vascular smooth muscle cells is important in the pathogenesis of many vascular diseases. Reactive oxygen species (ROS) produced by NADPH oxidases in smooth muscle cells have been shown to participate in signaling cascades regulating proliferation induced by platelet-derived growth factor (PDGF), a powerful smooth muscle mitogen. We sought to determine the role of Nox5 in the regulation of PDGF-stimulated human aortic smooth muscle cell (HASMC) proliferation. Cultured HASMC were found to express four isoforms of Nox5. When HASMC stimulated with PDGF were pretreated with N-acetyl cysteine (NAC), proliferation was significantly reduced. Proliferation induced by PDGF was also heavily dependent on JAK/STAT activation, as the JAK inhibitor, AG490, was able to completely abolish PDGF-stimulated HASMC growth. Specific knockdown of Nox5 with a siRNA strategy reduced PDGF-induced HASMC ROS production and proliferation. Additionally, siRNA to Nox5 inhibited PDGF-stimulated JAK2 and STAT3 phosphorylation. ROS produced by Nox5 play an important role in PDGF-induced JAK/STAT activation and HASMC proliferation.}, }
@article {pmid18463678, year = {2008}, author = {Young, CN and Koepke, JI and Terlecky, LJ and Borkin, MS and Boyd, SL and Terlecky, SR}, title = {Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease.}, journal = {The Journal of investigative dermatology}, volume = {128}, number = {11}, pages = {2606-2614}, pmid = {18463678}, issn = {1523-1747}, support = {P30 ES006639/ES/NIEHS NIH HHS/United States ; P30 ES06639/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/therapeutic use ; Catalase/therapeutic use ; Cells, Cultured ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen Peroxide/metabolism/pharmacology ; I-kappa B Proteins/metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Keratinocytes/cytology/*drug effects/*metabolism ; Male ; Protein Kinases/metabolism ; Psoriasis/drug therapy/*metabolism/physiopathology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/physiology ; Sirolimus/pharmacology ; Skin Diseases/drug therapy/*metabolism/physiopathology ; TOR Serine-Threonine Kinases ; Taurine/pharmacology ; Transcription Factor RelA/metabolism ; Tumor Necrosis Factor-alpha/metabolism/*pharmacology ; }, abstract = {The multifunctional cytokine tumor necrosis factor-alpha (TNF-alpha) is known to play an important role in inflammatory and immunological responses in human skin. Although it has been documented that reactive oxygen species (ROS) are involved in TNF-alpha-induced signaling pathways associated with certain inflammatory diseases, their role in TNF-alpha signaling cascades has not been examined in primary human keratinocytes used as a model of inflammatory skin disease and psoriasis. Employing a series of in vitro and in cellulo approaches, we have demonstrated that in primary human keratinocytes (i) TNF-alpha rapidly induces ROS generation, IkappaB degradation, NF-kappaB p65 nuclear translocation, and ultimately production of inflammatory cytokines; (ii) TNF-alpha-induced cytokine production is mediated both by the mammalian target of rapamycin signaling pathway via NF-kappaB activation and by ROS; (iii) TNF-alpha-dependent NF-kappaB activation (that is, IkappaB degradation and NF-kappaB p65 nuclear translocation) is not mediated by ROS; and (iv) a cell-penetrating derivative of the antioxidant enzyme, catalase, as well as taurine and N-acetyl-cysteine attenuate the TNF-alpha-induced production of cytokines. These latter results suggest that catalase and perhaps other antioxidants should be considered as part of a more specific and effective therapy for the treatment of inflammatory skin diseases, including psoriasis.}, }
@article {pmid18456507, year = {2008}, author = {Reyes-Martin, P and Ramirez-Rubio, S and Parra-Cid, T and Bienes-Martínez, R and Lucio-Cazana, J}, title = {15-Deoxy-delta12,14-prostaglandin-J(2) up-regulates cyclooxygenase-2 but inhibits prostaglandin-E(2) production through a thiol antioxidant-sensitive mechanism.}, journal = {Pharmacological research}, volume = {57}, number = {5}, pages = {344-350}, doi = {10.1016/j.phrs.2008.03.007}, pmid = {18456507}, issn = {1043-6618}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/metabolism ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Cyclooxygenase 2/*metabolism ; Dinoprostone/*biosynthesis ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Humans ; Mesangial Cells/drug effects/metabolism ; PPAR gamma/metabolism ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology ; Prostaglandins A/pharmacology ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; Up-Regulation/drug effects ; }, abstract = {15-Deoxy-delta12,14-prostaglandin-J(2) (15d-PGJ(2)) has potent anti-inflammatory effects including the inhibition of interleukin-1beta (IL-1beta)-induced expression of cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) production in several cell types. 15d-PGJ(2) contains an alpha,beta-unsaturated electrophilic ketone and several evidences suggest that thiol reducing agents prevent or revert the cellular effects of 15d-PGJ(2). The present study was devoted to analyze the effect of 15d-PGJ(2) on COX-2 expression in cultured human mesangial cells (HMC). 15d-PGJ(2) induced an increase in the reduced glutathione (GSH) content and up-regulated COX-2 protein expression, but not COX-1, in a manner which was unaffected by selective peroxisome proliferator-activated receptor gamma (PPARgamma) blockade nor mimicked by ciglitazone, a PPARgamma agonist. N-acetylcysteine (NAC), a thiol reducing agent, but not reactive oxygen species scavengers, prevented 15d-PGJ(2)-induced COX-2 up-regulation. Depletion of GSH by buthionine sulfoximine, which diminishes thiol antioxidant activity, cooperated with 15d-PGJ(2) to accumulate COX-2. Therefore, 15d-PGJ(2) up-regulated COX-2 through a thiol antioxidant-sensitive mechanism. Interestingly, NAC did not inhibit the COX-2 expression induced by the electrophilic alpha,beta-unsaturated compound PGA(2). Up-regulation of COX-2 by 15d-PGJ(2) did not result in increased PGE(2) production. Furthermore, preincubation with 15d-PGJ(2) inhibited IL-1beta-induced PGE(2) production although IL-1beta-induced COX-2 expression remained unaffected by the treatment with 15d-PGJ(2). On the contrary, PGA(2) elicited an increase in PGE(2) production and it acted synergistically with IL-1beta to enhance PGE(2) production. These results indicate for the first time that 15d-PGJ(2) inhibits PGE(2) production independently of its effect on COX-2 expression.}, }
@article {pmid18451565, year = {2008}, author = {Yamaguchi, H and Noshita, T and Kidachi, Y and Umetsu, H and Fuke, Y and Ryoyama, K}, title = {Detection of 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) and its conjugate with N-acetyl-L-cysteine (NAC) by high performance liquid chromatograpy-atmospheric pressure chemical ionization mass spectrometry (HPLC-MS/APCI).}, journal = {Chemical &amp; pharmaceutical bulletin}, volume = {56}, number = {5}, pages = {715-719}, doi = {10.1248/cpb.56.715}, pmid = {18451565}, issn = {0009-2363}, mesh = {Acetylcysteine/*analysis ; Calibration ; Chromatography, High Pressure Liquid ; Indicators and Reagents ; Isothiocyanates/*analysis ; Mass Spectrometry ; Reproducibility of Results ; Spectrophotometry, Ultraviolet ; }, abstract = {A method using high-performance liquid chromatography (HPLC) and atmospheric pressure chemical ionization (APCI) mass spectrometry (MS) was established for the detection of 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) and its conjugate with N-acetyl-L-cysteine (NAC). The optimal chromatographic conditions were obtained on an ODS column (150 x 4.6 mm, 3 microm) with the column temperature at 37 degrees C. The mobile phase consisted of a methanol-0.1% trifluoroacetic acid (TFA) mixture (50 : 50, v/v), and the flow rate was 0.3 ml/min. The detection wavelength was set at 220 nm. The identities of the peaks were accomplished by comparing retention times (tR), UV and mass data. All calibration curves showed good linear regression (correlation coefficients for 6-MITC and NAC>0.999) within test ranges. The developed method provided satisfactory precision calculated as percent coefficient of variation with overall intra-day and inter-day variations of less than 5% (4.1 and 4.9% for 6-MITC; 4.2 and 4.9% for NAC). Both 6-MITC and NAC had good responses in the positive APCI and formed strong [M+H]+ ions in the full scan spectra at an m/z of 206 and 164, respectively. The presence of the [M+H]+ ion for the 6-MITC/NAC conjugate was also observed at an m/z of 369. To our best knowledge, this is the first report that describes the formation of the 6-MITC/NAC conjugate and its detection method by HPLC-MS.}, }
@article {pmid18450357, year = {2008}, author = {Lee, SJ and Kim, MS and Park, JY and Woo, JS and Kim, YK}, title = {15-Deoxy-delta 12,14-prostaglandin J2 induces apoptosis via JNK-mediated mitochondrial pathway in osteoblastic cells.}, journal = {Toxicology}, volume = {248}, number = {2-3}, pages = {121-129}, doi = {10.1016/j.tox.2008.03.014}, pmid = {18450357}, issn = {0300-483X}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Immunologic Factors/*toxicity ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/*drug effects/metabolism ; Osteoblasts/*drug effects/metabolism/pathology ; PPAR gamma/metabolism ; Prostaglandin D2/*analogs &amp; derivatives/toxicity ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {The cyclopentenone prostaglandin 15-deoxy-delta 12,14-prostaglandin J2 (15d-PGJ2) induces apoptosis in various cell types. However, the underlying mechanism of 15d-PGJ2-induced apoptosis is not fully understood. The present study was undertaken to determine the molecular mechanism by which 15d-PGJ2 induces apoptosis in MC3T3-E1 mouse osteoblastic cells. 15d-PGJ2 caused a concentration- and time-dependent apoptotic cell death. 15d-PGJ2 induced a transient activation of ERK1/2 and sustained activation of JNK. 15d-PGJ2-induced cell death was prevented by the JNK inhibitor SP6001, but not by inhibitors of ERK1/2 and p38. JNK activation by 15d-PGJ2 was blocked by antioxidants N-acetylcysteine (NAC) and GSH. 15d-PGJ2 caused ROS generation and 15d-PGJ2-induced cell death was prevented by antioxidants, suggesting involvement of ROS generation in 15d-PGJ2-induced cell death. 15d-PGJ2 triggered the mitochondrial apoptotic pathway indicated by enhanced Bax expression, loss of mitochondrial membrane potential, cytochrome c release, and caspase-3 activation. The JNK inhibitor blocked these events induced by 15d-PGJ2. Taken together, these results suggest that the 15d-PGJ2 induces cell death through the mitochondrial apoptotic pathway dependent of ROS and JNK activation in osteoblastic cells.}, }
@article {pmid18448127, year = {2008}, author = {Wu, W and Abraham, L and Ogony, J and Matthews, R and Goldstein, G and Ercal, N}, title = {Effects of N-acetylcysteine amide (NACA), a thiol antioxidant on radiation-induced cytotoxicity in Chinese hamster ovary cells.}, journal = {Life sciences}, volume = {82}, number = {21-22}, pages = {1122-1130}, doi = {10.1016/j.lfs.2008.03.016}, pmid = {18448127}, issn = {0024-3205}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology/toxicity ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/radiation effects ; CHO Cells ; Caspase 3/metabolism ; Catalase/metabolism ; Cell Proliferation/drug effects/radiation effects ; Cell Survival/*drug effects/*radiation effects ; Cricetinae ; Cricetulus ; Cysteine/metabolism ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects/radiation effects ; *Radiation-Protective Agents ; }, abstract = {Ionizing radiation is known to cause tissue damage in biological systems, mainly due to its ability to produce reactive oxygen species (ROS) in cells. Many thiol antioxidants have been used previously as radioprotectors, but their application has been limited by their toxicity. In this investigation, we have explored the possible radioprotective effects of a newly synthesized thiol antioxidant, N-acetylcysteine amide (NACA), in comparison with N-acetylcysteine (NAC), a commonly used antioxidant. Protective effects of NACA and NAC were assessed using Chinese hamster ovary (CHO) cells, irradiated with 6 gray (Gy) radiation. Oxidative stress parameters, including levels of reduced glutathione (GSH), cysteine, malondialdehyde (MDA), and activities of antioxidant enzymes like glutathione peroxidase, glutathione reductase, and catalase, were measured. Results indicate that NACA was capable of restoring GSH levels in irradiated cells in a dose dependent manner. In addition, NACA prevented radiation-induced loss in cell viability. NACA further restored levels of malondialdehyde, caspase-3 activity, and antioxidant enzyme activities to control levels. Although NAC affected cells in a similar manner to NACA, its effects were not as significant. Further, NAC was also found to be cytotoxic to cells at higher concentrations, whereas NACA was non-toxic at similar concentrations. These results suggest that NACA may be able to attenuate radiation-induced cytotoxicity, possibly by its ability to provide thiols to cells.}, }
@article {pmid18446840, year = {2008}, author = {Gawande, S and Kale, A and Kotwal, S}, title = {Effect of nutrient mixture and black grapes on the pharmacokinetics of orally administered (-)epigallocatechin-3-gallate from green tea extract: a human study.}, journal = {Phytotherapy research : PTR}, volume = {22}, number = {6}, pages = {802-808}, doi = {10.1002/ptr.2372}, pmid = {18446840}, issn = {1099-1573}, mesh = {Administration, Oral ; Adult ; Antioxidants/administration &amp; dosage/pharmacokinetics ; Biological Availability ; Catechin/administration &amp; dosage/*analogs &amp; derivatives/pharmacokinetics ; Female ; *Food ; Humans ; Male ; Plant Extracts/chemistry/*pharmacology ; Tea/*chemistry ; Vitis/*chemistry ; }, abstract = {(-)Epigallocatechin-3-gallate (EGCG), a green tea component, has been attributed with anticarcinogenic and antioxidant activities. The extent and rate of absorption of EGCG by the small intestine depends on various factors such as molecular size, lipophilicity, solubility, pKa, gastric and intestinal transit time, lumen pH, membrane permeability and first pass metabolism. The bioavailability of EGCG can be increased by decreasing the presystemic elimination by stabilizing EGCG in the lumen, helping its transfer across the intestinal apical membrane and its accumulation and thus its availability by inhibiting phase I and II enzymes and phase III transporters. In a crossover study, five human volunteers were given a single oral dose of GTE (A), nutrient mixture (NM) containing GTE (B) and formulation B along with black grapes 250 g (C). Blood samples were drawn at 0, 2, 4, 6 and 8 h. The pharmacokinetic parameters were analysed by WinNonLin (Vs 5.0.1.) using a non-compartmental approach. Supplementation with nutrient mixture normally prescribed to cancer patients containing ascorbic acid, selenium, N-acetyl cysteine and other nutrients (formulation B) resulted in an increase of the systemic availability of EGCG by 14% and formulation C further increased it by 13%, thus leading to a total increase of 27%.}, }
@article {pmid18446570, year = {2008}, author = {Schmitz, T and Hombach, J and Bernkop-Schnürch, A}, title = {Chitosan-N-acetyl cysteine conjugates: in vitro evaluation of permeation enhancing and P-glycoprotein inhibiting properties.}, journal = {Drug delivery}, volume = {15}, number = {4}, pages = {245-252}, doi = {10.1080/10717540802006708}, pmid = {18446570}, issn = {1521-0464}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*antagonists &amp; inhibitors ; Acetylcysteine/*chemistry/pharmacology ; Animals ; Caco-2 Cells ; Chitosan/*chemistry/pharmacology ; Dextrans/pharmacokinetics ; Drug Carriers/chemistry ; Fluoresceins/pharmacokinetics ; Humans ; In Vitro Techniques ; L-Lactate Dehydrogenase/metabolism ; Molecular Weight ; Permeability/drug effects ; Rats ; Rhodamine 123/pharmacokinetics ; Toxicity Tests ; }, abstract = {This study evaluated three chitosan-N-acetyl cysteine (CAC) conjugates of increasing molecular mass as a valuable tool to improve the absorption of drugs by assessing its permeation enhancing effect regarding the active P-gp substrate rhodamine-123 in comparison to the trans- and paracellular marker FD 4 both in rat intestine and Caco 2 monolayers. Additional LDH and MTT cytotoxicity tests have attested a non-toxic profile to CAC, which can consequently be seen as a safe and promising novel drug carrier with the ability to enhance drug absorption and to inhibit P-gp efflux transporters.}, }
@article {pmid18445488, year = {2008}, author = {Malakar, D and Dey, A and Basu, A and Ghosh, AK}, title = {Antiapoptotic role of S-adenosyl-l-methionine against hydrochloric acid induced cell death in Saccharomyces cerevisiae.}, journal = {Biochimica et biophysica acta}, volume = {1780}, number = {7-8}, pages = {937-947}, doi = {10.1016/j.bbagen.2008.03.014}, pmid = {18445488}, issn = {0006-3002}, mesh = {Apoptosis/*drug effects ; Catalase/metabolism ; Glutathione/analysis ; Hydrochloric Acid/*pharmacology ; Hydrogen-Ion Concentration ; Lipid Peroxidation/drug effects ; Membrane Potentials/drug effects ; Mitochondria/physiology ; Reactive Oxygen Species/metabolism ; S-Adenosylmethionine/*pharmacology ; Saccharomyces cerevisiae/*drug effects/ultrastructure ; Superoxide Dismutase/metabolism ; Time Factors ; }, abstract = {Exposure of stationary phase cells of Saccharomyces cerevisiae to 10 mM HCl (pH approximately 2) resulted in cell death as a function of time (up to 6 h) with most (about 40%-65%) of the cells showing apoptotic features including chromatin condensation along the nuclear envelope, exposure of phosphatidylserine on the outer leaflet of cytoplasmic membrane, and DNA fragmentation. During the first 2 h of acid exposure there was an increase in reactive oxygen species (ROS) level inside cells, with subsequent elevation in the level of lipid peroxidation and decrease in reducing equivalents culminating in loss of mitochondrial membrane potential (DeltaPsi(m)). An initial (1 h) event of mitochondrial hyper-polarization with subsequent elevation of ROS level of the acid treated cells was also observed. S-adenosyl-l-methionine (AdoMet; 1 mM) treatment increased the cell survival of the acid stressed cells. It partially scavenged the increased intracellular ROS level by supplementing glutathione through the transsulfuration pathway. It also inhibited acid mediated lipid peroxidation, partially recovered acid evoked loss of DeltaPsi(m) and protected the cells from apoptotic cell death. S-adenosyl di-aldehyde, an indirect inhibitor of the AdoMet metabolic pathway, increased mortality of the acid treated cells. Incubation of acid stressed cells with the antioxidant, N-acetyl-cysteine (1 mM), decreased the cellular mortality, but the same concentration of AdoMet offered more protection by scavenging the free radicals. The ability of AdoMet to scavenge ROS mediated apoptosis may be an important function of this molecule in responding to cellular stress. The study could open a new avenue for detailed investigation on the curative potential of AdoMet against gastric ulcer.}, }
@article {pmid18443432, year = {2008}, author = {Kim, BW and Lee, ER and Min, HM and Jeong, HS and Ahn, JY and Kim, JH and Choi, HY and Choi, H and Kim, EY and Park, SP and Cho, SG}, title = {Sustained ERK activation is involved in the kaempferol-induced apoptosis of breast cancer cells and is more evident under 3-D culture condition.}, journal = {Cancer biology &amp; therapy}, volume = {7}, number = {7}, pages = {1080-1089}, doi = {10.4161/cbt.7.7.6164}, pmid = {18443432}, issn = {1555-8576}, mesh = {*Apoptosis ; Cell Culture Techniques/*methods ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Cell Survival ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/pharmacology ; *Extracellular Signal-Regulated MAP Kinases ; Flow Cytometry ; Humans ; Kaempferols/*pharmacology ; MAP Kinase Signaling System ; Microscopy, Confocal/methods ; Reactive Oxygen Species ; }, abstract = {In order to determine the effects of a variety of flavonoids, we applied differing amounts of several flavonoids to human breast cancer cells. Kaempferol treatment resulted in significant reduction of cell viability in the MCF-7 cells, although it exerted only minor effect on the cell viability of MDA-MB-231 or mammary epithelial HC-11 cells. Kaempferol was demonstrated to induce sustained ERK activation concomitantly with MEK1 and ELK1 activation, and this kaempferol-induced apoptosis was suppressed by treatment with PD98059, the overexpression of a kinase-inactive ERK mutant, or ERK siRNA. Kaempferol treatment was shown to profoundly induce the generation of fluorescent DCF in the MCF-7 cells, and treatment with N-acetyl cysteine suppressed kaempferol-induced PARP cleavage. Moreover, because breast cancer is associated with increased collagen synthesis and accumulation, we utilized a collagen-based 3D culture method. Under the 3-dimensional culture condition employed herein, kaempferol treatment was shown to result in a significant reduction in cell viability, an effect which occurred in a dose-dependent manner. Compared with what was observed under conventional 2D culture condition, we observed more evident apoptotic cell death and ERK activation as the result of kaempferol treatment in a collagen-based 3D culture environment. Similar to the case of conventional 2D cultured cells, the addition of PD98059 significantly suppressed intracellular ROS production. Collectively, these results show that the sustained activation of the ERK signaling pathway is markedly involved in kaempferol-induced apoptosis of breast cancer MCF-7 cells, and that this effect is more evident under 3D culture condition.}, }
@article {pmid18437097, year = {2008}, author = {Lee, TF and Tymafichuk, CN and Bigam, DL and Cheung, PY}, title = {Effects of postresuscitation N-acetylcysteine on cerebral free radical production and perfusion during reoxygenation of hypoxic newborn piglets.}, journal = {Pediatric research}, volume = {64}, number = {3}, pages = {256-261}, doi = {10.1203/PDR.0b013e31817cfcc0}, pmid = {18437097}, issn = {1530-0447}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Animals, Newborn ; Carotid Arteries/physiology ; Cerebral Cortex/blood supply/drug effects/metabolism ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology/therapeutic use ; Free Radicals/*metabolism ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Hypoxia-Ischemia, Brain/*metabolism ; Lactates/metabolism ; Nitric Oxide/metabolism ; Oxidative Stress/*drug effects ; Oxygen/*pharmacology/therapeutic use ; Random Allocation ; Regional Blood Flow/drug effects ; Swine ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Hydrogen peroxide (H2O2) and nitric oxide (NO) contribute to the pathogenesis of cerebral hypoxic-ischemic injury. We evaluated the neuroprotective effect of N-acetyl-l-cysteine (NAC, a free radical scavenger) against oxidative stress and perfusion in a model of neonatal hypoxia-reoxygenation (H-R). Piglets (1-3 d, 1.6-2.3 kg) were randomized into a sham-operated group (without H-R) (n = 5) and two H-R experimental groups (2 h normocapnic alveolar hypoxia followed by 4 h reoxygenation) (n = 7/group). Five minutes after reoxygenation, piglets were given either i.v. saline (H-R controls) or NAC (30 mg/kg bolus then 20 mg/kg/h infusion) in a blinded-randomized fashion. Heart rate, mean arterial pressure, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H2O2 and NO production (electrochemical sensor), cerebral tissue glutathione and nitrotyrosine levels (enzyme-linked immunosorbent assay) were examined. Hypoxic piglets were acidotic (pH 6.88-6.90), which recovered similarly in the H-R groups (p > 0.05 versus shams). Postresuscitation NAC treatment significantly attenuated the increase in cortical H2O2, but not NO, concentration during reoxygenation, with lower cerebral oxidized glutathione levels. NAC-treated piglets had significantly higher carotid oxygen delivery and lower cerebral lactate levels than that of H-R controls with corresponding changes in carotid arterial flow and vascular resistance. In newborn piglets with H-R, postresuscitation administration of NAC reduced cerebral oxidative stress and improved cerebral perfusion.}, }
@article {pmid18436195, year = {2008}, author = {Berk, M and Copolov, D and Dean, O and Lu, K and Jeavons, S and Schapkaitz, I and Anderson-Hunt, M and Judd, F and Katz, F and Katz, P and Ording-Jespersen, S and Little, J and Conus, P and Cuenod, M and Do, KQ and Bush, AI}, title = {N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial.}, journal = {Biological psychiatry}, volume = {64}, number = {5}, pages = {361-368}, doi = {10.1016/j.biopsych.2008.03.004}, pmid = {18436195}, issn = {1873-2402}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Analysis of Variance ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Movement Disorders/drug therapy/etiology ; Outcome Assessment, Health Care/methods ; Psychiatric Status Rating Scales ; Schizophrenia/complications/*drug therapy ; }, abstract = {BACKGROUND: Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period.<br><br>METHODS: A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment.<br><br>RESULTS: Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [-5.97 (-10.44, -1.51), p = .009], PANSS negative [mean difference -1.83 (95% confidence interval: -3.33, -.32), p = .018], and PANSS general [-2.79 (-5.38, -.20), p = .035], CGI-Severity (CGI-S) [-.26 (-.44, -.08), p = .004], and CGI-Improvement (CGI-I) [-.22 (-.41, -.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits.<br><br>CONCLUSIONS: These data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.}, }
@article {pmid18430051, year = {2008}, author = {Krug, S and Zhang, Y and Mori, TA and Croft, KD and Vickers, JJ and Langton, LK and Whitworth, JA}, title = {N-Acetylcysteine prevents but does not reverse dexamethasone-induced hypertension.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {35}, number = {8}, pages = {979-981}, doi = {10.1111/j.1440-1681.2008.04947.x}, pmid = {18430051}, issn = {1440-1681}, mesh = {Acetylcysteine/*administration &amp; dosage/*pharmacology ; Animals ; Blood Pressure/drug effects ; Dexamethasone/*toxicity ; Energy Metabolism ; F2-Isoprostanes/blood ; Hypertension/*chemically induced ; Male ; Nitric Oxide/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {1. We have shown previously that N-acetylcysteine (NAC) prevents the increase in blood pressure induced by adrenocorticotropin treatment. The present study investigated the effect of NAC on dexamethasone (Dex)-induced hypertension. 2. Male Sprague-Dawley rats were randomly divided into six groups (n = 10 in each). In a prevention study, NAC (10 g/L in the drinking water) was given for 4 days prior to and 11 days during concurrent treatment with saline (0.1 mL/rat per day) or with Dex (10 mg/rat per day). In a reversal study, daily injections of Dex or saline began 8 days before NAC and cotreatment continued for 5 days. Systolic blood pressure (SBP) was measured on alternate days using a tail-cuff system. 3. Dexamethasone significantly increased SBP from 113 +/- 4 to 139 +/- 6 mmHg (n = 10; P < 0.01). N-Acetylcysteine alone had no effect on SBP. In NAC + Dex-treated rats, SBP was significantly lower than that of Dex-treated rats (P cent < 0.01). In fully established Dex-hypertension NAC was ineffective and SBP remained high. 4. Both Dex and NAC treatments decreased bodyweight gain. N-Acetylcysteine reduced food and water consumption. Dexamethasone reduced thymus weight (P cent < 0.01) but NAC treatment did not alter this marker of glucocorticoid activity. 5. Dexamethasone tended to decrease plasma NO(x), whereas NAC restored plasma NO(x) concentrations to control levels. N-Acetylcysteine had no effect on Dex-induced increased plasma F(2)-isoprostane concentrations. 6. In conclusion, NAC partially prevented, but did not reverse, Dex-induced hypertension.}, }
@article {pmid18423961, year = {2008}, author = {Bijarnia, RK and Kaur, T and Aggarwal, K and Singla, SK and Tandon, C}, title = {Modulatory effects of N-acetylcysteine on hyperoxaluric manifestations in rat kidney.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {46}, number = {6}, pages = {2274-2278}, doi = {10.1016/j.fct.2008.03.007}, pmid = {18423961}, issn = {0278-6915}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Catalase/metabolism ; Creatinine/metabolism ; Free Radical Scavengers/*pharmacology ; Hyperoxaluria/*metabolism/pathology/*prevention &amp; control ; Kidney/drug effects/*metabolism/pathology ; Kidney Calculi/urine ; Male ; Oxalic Acid/metabolism ; Oxidative Stress/drug effects ; Phospholipids/metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Urea/blood ; Urodynamics/drug effects ; }, abstract = {Hyperoxaluria is a condition where excessive oxalate is present in the urine. Many reports have documented free radical generation followed by hyperoxaluria as a consequence of which calcium oxalate deposition occurs in the kidney tissue. The present invivo study was designed to investigate the potential of N-acetylcysteine in modulating hyperoxaluric manifestation induced by sodium oxalate in the rat kidneys. Male wistar rats in one group were administered single dose of sodium oxalate (70mg/kg body weight) intraperitoneally to induce hyperoxaluric conditions and in the other group, rats were injected N-acetylcysteine (NAC) (200mg/kg body weight) intraperitoneally, half an hour after sodium oxalate dose. The treatment is for a period of 24h. N-acetylcysteine significantly reduced hyperoxaluria caused oxidative stress by reducing lipid peroxidation, restoring antioxidant enzymes activity in kidney tissue, followed by reduction in impairment of renal functioning. In addition, NAC administration reduced the number of calcium oxalate monohydrate (COM) crystals in the urine as observed under polarization microscope. Histological analysis depicted that NAC treatment decreased renal epithelial damage, inflammation and restored normal glomeruli morphology. Thus, it shows that use of an extraneous antioxidant may prove beneficial for combating the conditions of oxidative stress produced by hyperoxaluria.}, }
@article {pmid18421302, year = {2008}, author = {Jin, SM and Cho, HJ and Jung, ES and Shim, MY and Mook-Jung, I}, title = {DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress.}, journal = {Cell death and differentiation}, volume = {15}, number = {9}, pages = {1375-1384}, doi = {10.1038/cdd.2008.49}, pmid = {18421302}, issn = {1350-9047}, mesh = {Amyloid Precursor Protein Secretases/*metabolism ; Amyloid beta-Peptides/*metabolism/pharmacology ; Animals ; *Apoptosis ; CHO Cells ; Camptothecin/toxicity ; Cricetinae ; Cricetulus ; Cytochromes c/metabolism ; *DNA Damage ; Enzyme Activation ; Etoposide/toxicity ; Glutathione/metabolism ; Humans ; Mice ; Mitochondria/metabolism ; Mitochondrial Membrane Transport Proteins/antagonists &amp; inhibitors ; Mitochondrial Permeability Transition Pore ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {According to the amyloid cascade hypothesis, Alzheimer's disease is the consequence of neuronal cell death induced by beta-amyloid (Abeta), which accumulates by abnormal clearance or production. On the other hand, recent studies have shown cell death-induced alteration in amyloid precursor protein (APP) processing, suggesting potential mutual interactions between APP processing and cell death. We have shown previously that the cell death caused by DNA damage-inducing agents (DDIAs) facilitated gamma-secretase activity and Abeta generation in a Bax/Bcl-2-dependent, but caspase-independent manner. Here, we attempted to elucidate the downstream mechanism that modulates gamma-secretase activity in DDIA-treated cells. N-acetyl cysteine, a potent antioxidant, attenuated DDIA-induced enhancement of gamma-secretase activity but failed to rescue cell death. Overexpression of heat shock protein 70, which blocks cytochrome c release from mitochondria, also reduced gamma-secretase activity. Moreover, glutathione depletion significantly facilitated gamma-secretase activity and Abeta generation by enhancing the formation of higher molecular weight gamma-secretase complex before signs of cell death developed. Finally, Abeta treatment, a known inducer of oxidative stress, also increased gamma-secretase activity. Taken together, these results indicate that DDIA-induced gamma-secretase activation is dependent on augmented oxidative stress, and that Abeta and gamma-secretase may activate each other. On the basis of these results, we propose a feed-back loop between oxidative stress and Abeta generation mediated by gamma-secretase activation.}, }
@article {pmid18420745, year = {2008}, author = {Lamirand, A and Pallud-Mothré, S and Ramaugé, M and Pierre, M and Courtin, F}, title = {Oxidative stress regulates type 3 deiodinase and type 2 deiodinase in cultured rat astrocytes.}, journal = {Endocrinology}, volume = {149}, number = {7}, pages = {3713-3721}, doi = {10.1210/en.2007-1462}, pmid = {18420745}, issn = {0013-7227}, mesh = {Animals ; Astrocytes/cytology/*drug effects/metabolism ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Cyclic AMP/metabolism ; Enzyme Activation/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Hydrogen Peroxide/*pharmacology ; Iodide Peroxidase/genetics/*metabolism ; Isoenzymes/genetics/metabolism ; Oxidants/pharmacology ; *Oxidative Stress ; Phorbol Esters/metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Selenium/metabolism ; Thyroxine/metabolism ; Triiodothyronine/metabolism ; }, abstract = {Type 2 deiodinase (D2) and type 3 deiodinase (D3) locally achieve the determination of the concentration of T3, which binds to the thyroid hormone receptor with high affinity. D2 converts T4 into T3, and D3 degrades T4 and T3. Neurons take up T3 released by astrocytes, the main cerebral site for the D2 expression. Because oxidative stress is believed to be involved in several neurological disorders, we explored the effects of oxidative stress on D3 and D2 in primary culture of rat astrocytes. H2O2 (250 microm) increased D3 activity with maximal effects around 8 h. Stimulation of D3 activity by H2O2 was synergistic with T4, phorbol ester, and also cAMP. H2O2 (250 microm) did not affect basal D2 activity but inhibited the stimulation of D2 activity by cAMP and factors implicating cAMP-independent pathways in astrocytes, TSH, and phorbol ester. N-Acetyl cysteine and selenium repletion, which respectively increase intracellular glutathione and glutathione peroxidase, inhibited D2 and D3 regulation by H2O2, whereas L-buthionine sulfoximine, which decreases intracellular glutathione, mimicked H2O2 effects. Oxidative stress up-regulated D3 and inhibited cAMP-stimulated D2 by transcriptional mechanisms. A decrease in cAMP by oxidative stress could contribute to the inhibition of cAMP-stimulated D2. Using specific inhibitors of signaling pathways, we show that the ERK pathway was required in D2 and D3 regulation by oxidative stress and that the p38 MAPK pathway was implicated in H2O2-induced D3. We suggest that the expected decrease in T3 might modulate the cellular injury of oxidative stress in some pathological brain conditions.}, }
@article {pmid18419763, year = {2008}, author = {Woo, MS and Park, JS and Choi, IY and Kim, WK and Kim, HS}, title = {Inhibition of MMP-3 or -9 suppresses lipopolysaccharide-induced expression of proinflammatory cytokines and iNOS in microglia.}, journal = {Journal of neurochemistry}, volume = {106}, number = {2}, pages = {770-780}, doi = {10.1111/j.1471-4159.2008.05430.x}, pmid = {18419763}, issn = {1471-4159}, mesh = {Animals ; Animals, Newborn ; Cells, Cultured ; Cerebral Cortex/cytology ; Cytokines/genetics/*metabolism ; Electrophoretic Mobility Shift Assay/methods ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic/*drug effects ; Lipopolysaccharides/*pharmacology ; Matrix Metalloproteinase 3/*metabolism ; Matrix Metalloproteinase 9/*metabolism ; Mice ; Microglia/*drug effects ; Nitric Oxide Synthase Type II/genetics/*metabolism ; Nitrites/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tetradecanoylphorbol Acetate/pharmacology ; Transfection/methods ; }, abstract = {Recently, matrix metalloproteinases (MMPs) are emerging as important molecules in neuroinflammation as well as neuronal cell death. However, the role of MMPs in activated microglia remains unclear. In the present study, we found that expressions of MMP-1, -3, -8 and -9 were significantly induced by single or combined treatment of immunostimulants lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) in primary cultured microglia and BV2 microglial cells. Inhibition of MMP-3 or -9 significantly suppressed the expression of iNOS and pro-inflammatory cytokines and the activities of NF-kappaB, AP-1, and MAPK in LPS-stimulated microglia. The results suggest that MMP-3 and -9 both mediate LPS-induced inflammatory reactions. Inhibition of reactive oxygen species (ROS) by N-acetyl-cysteine or diphenylene iodonium significantly suppressed the expression of MMP-3, MMP-9, NO and TNF-alpha in LPS-stimulated microglia, suggesting that ROS is an early signaling inducer in LPS-stimulated microglial cells. MMP inhibitors also suppressed ROS production, suggesting a cross-talk between ROS and MMPs. Collectively, the present study demonstrates that MMP-3 and MMP-9 play a role as inflammatory mediators in activated microglia. Pharmacological intervention of MMPs especially MMP-3 and -9 would be a therapeutic strategy for the treatment of inflammatory diseases in the CNS caused by over-activation of microglial cells.}, }
@article {pmid18418892, year = {2008}, author = {Yedjou, CG and Rogers, C and Brown, E and Tchounwou, PB}, title = {Differential effect of ascorbic acid and n-acetyl-L-cysteine on arsenic trioxide-mediated oxidative stress in human leukemia (HL-60) cells.}, journal = {Journal of biochemical and molecular toxicology}, volume = {22}, number = {2}, pages = {85-92}, pmid = {18418892}, issn = {1099-0461}, support = {G12 RR013459/RR/NCRR NIH HHS/United States ; G12 RR013459-11/RR/NCRR NIH HHS/United States ; 1G12RR13459/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/antagonists &amp; inhibitors/*pharmacology ; Arsenic Trioxide ; Arsenicals ; Ascorbic Acid/*pharmacology ; Cell Survival/drug effects ; HL-60 Cells ; Humans ; Lipid Peroxidation ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Oxides/*toxicity ; }, abstract = {Arsenic trioxide (ATO) has been recommended for the treatment of refractory cases of acute promyelocytic leukemia (APL). Recent studies in our laboratory indicated that oxidative stress plays a key role in ATO-induced cytotoxicity in human leukemia (HL-60) cells. In the present investigation, we performed the MTT assay and trypan blue exclusion test for cell viability. We also performed the thiobarbituric acid test to determine the levels of malondialdehyde (MDA) production in HL-60 cells coexposed to either ascorbic acid (AA) and ATO or to n-acetyl-L-cysteine (NAC) and ATO. The results of MTT assay indicated that AA exposure potentiates the cytotoxicity of ATO in HL-60 cells, as evidenced by a gradual increase in MDA levels with increasing doses of AA. In contrary, the addition of NAC to ATO-treated HL-60 cells resulted in a dose-dependent decrease of MDA production. From these results, we conclude that the addition of the AA to ATO-treated HL-60 cells enhances the formation of reactive oxygen species (ROS), whereas the addition of NAC under the same experimental condition significantly (p < .05) decreases the level of ROS formation. On the basis of these direct in vitro findings, our studies provide evidence that AA may extend the therapeutic spectrum of ATO. The coadministration of NAC with ATO shows a potential specificity for tumor cells, indicating that it may not enhance the clinical outcome associated with ATO monotherapy in vivo.}, }
@article {pmid18418868, year = {2008}, author = {Kang, SJ and Kim, BM and Lee, YJ and Chung, HW}, title = {Titanium dioxide nanoparticles trigger p53-mediated damage response in peripheral blood lymphocytes.}, journal = {Environmental and molecular mutagenesis}, volume = {49}, number = {5}, pages = {399-405}, doi = {10.1002/em.20399}, pmid = {18418868}, issn = {1098-2280}, mesh = {Adult ; Blotting, Western ; Cell Survival/drug effects ; Cells, Cultured ; Comet Assay ; *DNA Damage ; Female ; Humans ; Lymphocytes/cytology/*drug effects/metabolism ; Micronuclei, Chromosome-Defective/chemically induced ; Micronucleus Tests ; Mutagens/*toxicity ; *Nanoparticles ; Particle Size ; Reactive Oxygen Species/metabolism ; Titanium/*toxicity ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Titanium dioxide nanoparticles (nano-TiO2) are widely used as a photocatalyst in air and water remediation. These nanoparticles are known to induce toxicity; however, their cytotoxic mechanism is not fully understood. In this study, we investigated the underlying mechanism of nano-TiO2-induced cytotoxicity in peripheral blood lymphocytes. We examined the genotoxic effects of nano-TiO2 in lymphocytes using alkaline single-cell gel electrophoresis (Comet) and cytokinesis-block micronucleus (CBMN) assays. Lymphocytes treated with nano-TiO2 showed significantly increased micronucleus formation and DNA breakage. Western-blot analysis to identify proteins involved in the p53-mediated response to DNA damage revealed the accumulation of p53 and activation of DNA damage checkpoint kinases in nano-TiO2-treated lymphocytes. However, p21 and bax, downstream targets of p53, were not affected, indicating that nano-TiO2 does not stimulate transactivational activity of p53. The generation of reactive oxygen species (ROS) in nano-TiO2-treated cells was also observed, andN-acetylcysteine (NAC) supplementation inhibited the level of nano-TiO2-induced DNA damage. Given that ROS-induced DNA damage leads to p53 activation in the DNA damage response, our results suggest that nano-TiO2 induces ROS generation in lymphocytes, thereby activating p53-mediated DNA damage checkpoint signals.}, }
@article {pmid18417530, year = {2008}, author = {Abidi, P and Zhang, H and Zaidi, SM and Shen, WJ and Leers-Sucheta, S and Cortez, Y and Han, J and Azhar, S}, title = {Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway.}, journal = {The Journal of endocrinology}, volume = {198}, number = {1}, pages = {193-207}, doi = {10.1677/JOE-07-0570}, pmid = {18417530}, issn = {1479-6805}, support = {DK56339/DK/NIDDK NIH HHS/United States ; }, mesh = {20-alpha-Dihydroprogesterone/*biosynthesis ; Adrenal Glands/*metabolism ; Adrenocorticotropic Hormone/pharmacology ; Animals ; Cell Line, Tumor ; Cyclic CMP/analogs &amp; derivatives/pharmacology ; MAP Kinase Kinase 3/physiology ; MAP Kinase Kinase 6/physiology ; *MAP Kinase Signaling System ; Mice ; *Oxidative Stress ; Phosphoproteins/genetics ; Phosphorylation ; Superoxides/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*physiology ; }, abstract = {Previous studies from this laboratory identified excessive oxidative stress as an important mediator of age-related decline in steroid hormone production. Here, we investigated whether oxidative stress exerts its antisteroidogenic action through modulation of oxidant-sensitive mitogen-activated protein kinase (MAPK) signaling pathways. To accomplish these studies, we employed a highly responsive mouse adrenocortical cell line, Y1-BS1 cells that secrete large quantities of steroids when stimulated with lipoprotein plus hormone. Treatment of these cells with superoxide, H(2)O(2) or 4-hydroxy-2-nonenal (HNE) significantly inhibited steroid production and increased phosphorylation and activation of p38 MAPK. None of the treatments altered the phosphorylation of either extracellular signal-regulated kinases or c-Jun N-terminal kinases (JNKs). Pretreatment of Y1-BS1 cells with MnTMPyP, a cell-permeable superoxide-dismutase/catalase mimetic reactive oxygen species (ROS scavenger), completely prevented the superoxide- and H(2)O(2)-mediated inhibition of steroid production. Likewise, antioxidant N-acetylcysteine completely blocked the HNE-induced loss of steroidogenic response. Incubation of Y1-BS1 cells with either MnTMPyP or NAC also upregulated Bt(2)cAMP and Bt(2)cAMP+hHDL(3)-stimulated steroid synthesis, indicating that endogenously produced ROS can inhibit steroidogenesis. Inhibition of p38 MAPK with SB203580 or SB202190 upregulated the basal steroid production and also prevented the oxidant-mediated inhibition of steroid production. mRNA measurements by qPCR indicated that Y1-BS1 adrenal cells predominantly express p38 MAPKalpha isoform, along with relatively low-level expression of p38 MAPKgamma. By contrast, little or no expression was detected for p38 MAPKbeta and p38 MAPKdelta isoforms in these cells. Transfection of Y1-BS1 cells with either caMKK3 or caMMK6 construct, the upstream p38 MAPK activators, decreased steroidogenesis, whereas transfection with dnMKK3 or dnMKK6 plasmid DNA increased steroidogenesis. Similarly, transfection of cells with a dnp38 MAPKalpha or dnp38 MAPKbeta construct also increased steroid hormone production; however, the effect was less pronounced after expression of either dnp38 MAPKgamma or dnp38 MAPKdelta construct. These results indicate that activated p38 MAPK mediates oxidant (excessive oxidative stress)-induced inhibition of adrenal steroidogenesis.}, }
@article {pmid18410527, year = {2009}, author = {Scharstuhl, A and Mutsaers, HA and Pennings, SW and Szarek, WA and Russel, FG and Wagener, FA}, title = {Curcumin-induced fibroblast apoptosis and in vitro wound contraction are regulated by antioxidants and heme oxygenase: implications for scar formation.}, journal = {Journal of cellular and molecular medicine}, volume = {13}, number = {4}, pages = {712-725}, pmid = {18410527}, issn = {1582-4934}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Bilirubin/pharmacology ; Cicatrix/*enzymology ; Collagen/metabolism ; Curcumin/*pharmacology ; Dermis/cytology ; Dose-Response Relationship, Drug ; Fibroblasts/*cytology/drug effects/*enzymology ; Gels ; Glutathione/pharmacology ; Heme Oxygenase (Decyclizing)/*metabolism ; Humans ; Reactive Oxygen Species/metabolism ; Wound Healing/*drug effects ; }, abstract = {Fibroblast apoptosis plays a crucial role in normal and pathological scar formation and therefore we studied whether the putative apoptosis-inducing factor curcumin affects fibroblast apoptosis and may function as a novel therapeutic. We show that 25-microM curcumin causes fibroblast apoptosis and that this could be inhibited by co-administration of antioxidants N-acetyl-l-cysteine (NAC), biliverdin or bilirubin, suggesting that reactive oxygen species (ROS) are involved. This is supported by our observation that 25-microM curcumin caused the generation of ROS, which could be completely blocked by addition of NAC or bilirubin. Since biliverdin and bilirubin are downstream products of heme degradation by heme oxygenase (HO), it has been suggested that HO-activity protects against curcumin-induced apoptosis. Interestingly, exposure to curcumin maximally induced HO-1 protein and HO-activity at 10-15 microM, whereas, at a concentration of >20-microM curcumin HO-1-expression and HO-activity was negligible. NAC-mediated inhibition of 25-microM curcumin-induced apoptosis was demonstrated to act in part via restored HO-1-induction, since the rescuing effect of NAC could be reduced by inhibiting HO-activity. Moreover pre-induction of HO-1 using 5-microM curcumin protected fibroblasts against 25-microM curcumin-induced apoptosis. On a functional level, fibroblast-mediated collagen gel contraction, an in vitro wound contraction model, was completely prevented by 25-microM curcumin, while this could be reversed by co-incubation with NAC, an effect that was also partially HO-mediated. In conclusion, curcumin treatment in high doses (>25 microM) may provide a novel way to modulate pathological scar formation through the induction of fibroblast apoptosis, while antioxidants, HO-activity and its effector molecules act as a possible fine-tuning regulator.}, }
@article {pmid18407480, year = {2008}, author = {Caylak, E and Aytekin, M and Halifeoglu, I}, title = {Antioxidant effects of methionine, alpha-lipoic acid, N-acetylcysteine and homocysteine on lead-induced oxidative stress to erythrocytes in rats.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {60}, number = {4-5}, pages = {289-294}, doi = {10.1016/j.etp.2007.11.004}, pmid = {18407480}, issn = {0940-2993}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Chromatography, High Pressure Liquid ; Erythrocytes/*drug effects ; Glutathione Peroxidase/drug effects/metabolism ; Hemoglobins/analysis/drug effects ; Homocystine/pharmacology ; Lead/*toxicity ; Male ; Malondialdehyde/blood ; Methionine/pharmacology ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Superoxide Dismutase/drug effects/metabolism ; Thioctic Acid/pharmacology ; Vitamin A/blood ; Vitamin E/blood ; }, abstract = {Lead, widely used in industry, is a great environmental health problem. Many studies have examined its effects on the health of both humans and animals. Experimental studies have shown that sulphur-containing antioxidants have beneficial effects against the detrimental properties of lead. The present study was designed to investigate markers of oxidative stress (hemoglobin (Hb) in whole blood, malondialdehyde (MDA) in sera; superoxidase dismutase (SOD) and glutathione peroxidise (GSH-Px) in erythrocyte hemolysate and vitamins A and E in plasma) in rats given lead (2000ppm) with or without sulphur-containing antioxidants (l-methionine (Met) (100mg/kg/day), N-acetylcysteine (NAC) (800mg/kg/day), l-homocysteine (Hcy) (25mg/kg/day), lipoic acid (LA) (50mg/kg/day)) in their water for 5 weeks. In the lead group, Hb and plasma vitamin E levels were significantly lower whereas MDA levels were significantly higher compared to controls (p<0.05). Hb levels in lead-methionine and lead-LA groups were significantly higher than the lead group (p<0.01). MDA levels were reduced in all groups compared to the lead group (p<0.01). There was a decrease below control values in erythrocyte SOD (p<0.01) and GSH-Px (p<0.05) levels in the lead-LA group. Plasma vitamin A levels were significantly high in lead-methionine group compared to lead group (p<0.01). In conclusion, the data suggests that oxidative stress induced by lead is reduced by sulphur-containing compounds.}, }
@article {pmid18406588, year = {2008}, author = {Farombi, EO and Ugwuezunmba, MC and Ezenwadu, TT and Oyeyemi, MO and Ekor, M}, title = {Tetracycline-induced reproductive toxicity in male rats: effects of vitamin C and N-acetylcysteine.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {60}, number = {1}, pages = {77-85}, doi = {10.1016/j.etp.2008.02.002}, pmid = {18406588}, issn = {0940-2993}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Anti-Bacterial Agents/*toxicity ; Ascorbic Acid/*pharmacology ; Catalase/metabolism ; Drug Therapy, Combination ; Free Radical Scavengers/*pharmacology ; Glucosephosphate Dehydrogenase/metabolism ; Glutathione/blood ; Glutathione Transferase/metabolism ; Male ; Organ Size/drug effects ; Oxidative Stress/drug effects ; Rats ; Sperm Count ; Sperm Motility/drug effects ; Spermatozoa/drug effects/physiology ; Superoxide Dismutase/metabolism ; Testicular Diseases/*chemically induced/metabolism/pathology ; Testis/*drug effects/metabolism/pathology ; Testosterone/blood ; Tetracycline/*toxicity ; }, abstract = {Tetracycline, a broad-spectrum antibiotic employed clinically in the treatment of bacteria infections, is known to cause a number of biochemical dysfunctions and suspected to induce testicular damage to animals and humans, but there is paucity of data on its effect and mechanism of action on the male reproductive system. The present study therefore evaluates its spermatotoxic and testicular toxicity in male rats and the chemoprotective effects of Vitamin C (Vit C) and N-acetylcysteine (NAC). Tetracycline was administered orally at the dose level of 28.6 mg/kg body weight per day in two equal divided doses (12h interval). Vit C and NAC were also administered orally to the rats at doses of 200 and 50 mg/kg body weight per day, respectively, for the 14 days of the experiment. While there was no change in the body weights of rats, tetracycline administration caused significant decrease in the relative weights of testis, epididymis and seminal vesicles (P<0.05). Administration of tetracycline caused a reduction in the epididymal sperm motility, percentage of live spermatozoa, sperm count, and an increase in abnormal sperm morphology, as well as induction of adverse histopathologic changes in the testes. While Vit C and NAC significantly mitigated the toxic effect of tetracycline on sperm parameters, the antioxidants did not improve the adverse histopathologic changes induced by antibiotic. Treatment of rats with tetracycline significantly decreased the activities of superoxide dismutase, catalase (CAT), glucose-6-phosphate dehydrogenase, glutathione-S-transferase (GST) and the levels of GSH and serum testosterone, while the activity of gamma-glutamyltranspeptidase and the formation of malondialdehyde (MDA) increased. Both Vit C and NAC significantly attenuated the toxic effects of tetracycline to the antioxidant and testicular marker enzymes as well as markers of oxidative stress. Collectively, the results suggest that therapeutic dose of tetracycline elicits spermatotoxic and testicular toxicity in male rats through induction of oxidative stress. The chemoprotective effects of Vit C and NAC during tetracycline treatment suggest that these antioxidants may find clinical application in cellular damage involving reactive oxygen species (ROS).}, }
@article {pmid18405900, year = {2008}, author = {Henderson, B and Csordas, A and Backovic, A and Kind, M and Bernhard, D and Wick, G}, title = {Cigarette smoke is an endothelial stressor and leads to cell cycle arrest.}, journal = {Atherosclerosis}, volume = {201}, number = {2}, pages = {298-305}, doi = {10.1016/j.atherosclerosis.2008.02.022}, pmid = {18405900}, issn = {1879-1484}, mesh = {Cell Cycle ; Cell Separation ; Endothelial Cells/*metabolism ; Endothelium, Vascular/metabolism ; Flow Cytometry ; Heat-Shock Proteins/metabolism ; Humans ; Inflammation ; Metals ; Mitochondria/metabolism ; Nicotine/*adverse effects ; Oligonucleotide Array Sequence Analysis ; Reactive Oxygen Species ; *Smoking ; Time Factors ; }, abstract = {The molecular mechanisms underlying the atherogenic activity of cigarette smoke have yet to be fully elucidated. In the present study, genome-wide microarray analysis was performed on endothelial cells exposed to an aqueous cigarette smoke extract (CSE) for 3, 7, and 24 h, to obtain a better insight into how smoking may lead to endothelial damage. Microarray analysis showed the transcriptional response to CSE was dominated by heat shock, stress responsive, and inflammatory genes, along with genes encoding for anti-oxidant and metal detoxification proteins. The heat shock response was shown to be a result of short lived reactive species of CSE, with the abrogation of the effect by the addition of old CSE, the anti-oxidant N-acetyl cysteine, or the removal of metals from CSE implying that reactive oxygen species are the main culprit. This was further supported by a strong decline in the level of intracellular protein oxidation levels seen under these conditions compared to freshly prepared CSE. Mitochondrial integrity was also found to be significantly compromised after CSE treatment, resulting in a threefold increase in depolarised mitochondria after 6 h. Finally, cell cycle analysis showed the induction of G1 cell cycle arrest. An increased stress and inflammation response indicates that endothelial damage from smoking could contribute to immune cell infiltration, while decreased growth rates reduce endothelial layer repair, promoting atherogenesis.}, }
@article {pmid18404536, year = {2008}, author = {Ates, B and Abraham, L and Ercal, N}, title = {Antioxidant and free radical scavenging properties of N-acetylcysteine amide (NACA) and comparison with N-acetylcysteine (NAC).}, journal = {Free radical research}, volume = {42}, number = {4}, pages = {372-377}, doi = {10.1080/10715760801998638}, pmid = {18404536}, issn = {1029-2470}, support = {1 R15DA023409-01A2/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/*chemistry/pharmacology ; Antioxidants/chemistry/*metabolism ; Biphenyl Compounds/chemistry ; Chelating Agents/pharmacology ; Dose-Response Relationship, Drug ; Edetic Acid/chemistry ; Free Radical Scavengers/*metabolism ; *Free Radicals ; Humans ; Hydrazines/chemistry ; Hydrogen Peroxide/pharmacology ; Linoleic Acid/chemistry ; Metals/chemistry ; Picrates ; Sulfhydryl Compounds/chemistry ; beta Carotene/chemistry ; }, abstract = {The antioxidant potential of N-acetylcysteine amide (NACA), also known as AD4, was assessed by employing different in vitro assays. These included reducing power, free radical scavenging capacities, peroxidation inhibiting activity through linoleic acid emulsion system and metal chelating capacity, as compared to NAC and three widely used antioxidants, alpha-tocopherol, ascorbic acid and butylated hydroxytoluene (BHT). Of the antioxidant properties that were investigated, NACA was shown to possess higher 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging ability and reducing power than NAC, at all the concentrations, whereas the scavenging ability of H(2)O(2) differed with concentration. While NACA had greater H(2)O(2) scavenging capacity at the highest concentration, NAC was better than NACA at lower concentrations. NAC and NACA had a 60% and 55% higher ability to prevent beta-carotene bleaching, respectively, as compared to control. The chelating activity of NACA was more than 50% that of the metal chelating capacity of EDTA and four and nine times that of BHT and alpha-tocopherol, respectively. When compared to NACA and NAC; alpha-tocopherol had higher DPPH scavenging abilities and BHT and alpha-tocopherol had better beta-carotene bleaching power. These findings provide evidence that the novel antioxidant, NACA, has indeed enhanced the antioxidant properties of NAC.}, }
@article {pmid18404532, year = {2008}, author = {García-Román, R and Salazar-González, D and Rosas, S and Arellanes-Robledo, J and Beltrán-Ramírez, O and Fattel-Fazenda, S and Villa-Treviño, S}, title = {The differential NF-kB modulation by S-adenosyl-L-methionine, N-acetylcysteine and quercetin on the promotion stage of chemical hepatocarcinogenesis.}, journal = {Free radical research}, volume = {42}, number = {4}, pages = {331-343}, doi = {10.1080/10715760802005169}, pmid = {18404532}, issn = {1029-2470}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/chemistry/metabolism ; Biomarkers, Tumor/metabolism ; *Gene Expression Regulation ; Lipid Peroxidation ; Liver Neoplasms/chemically induced/*etiology ; Male ; NF-kappa B/*metabolism ; Oxidative Stress ; Quercetin/*pharmacology ; Rats ; Rats, Inbred F344 ; S-Adenosylmethionine/*pharmacology ; Signal Transduction ; }, abstract = {S-adenosylmethionine (SAM), N-acetylcysteine (NAC) and quercetin exhibit a chemoprotective effect. Likely this effect is mediated by counteracting, oxidative stress and NF-kB activation. To test this hypothesis F344 rats were subjected to hepatocarcinogenesis with or without antioxidants. NAC decreased foci in number and area, SAM and quercetin decreased area. Lipid-peroxidation was decreased by antioxidants, but only SAM increased glutathione. SAM, in its regulation from IKK downwards, abolished the NF-kB activation. NAC decreased IKK and IkB-a phosphorylation, and Rel-A/p65 and NF-kB binding, though the last two were affected with less intensity compared to the NF-kB inhibitor. Quercetin decreased Rel-A/p65, without modifying upstream signalling. Although all antioxidants inhibited oxidative stress as shown by reduction of lipid peroxidation, not all exerted the same effect on NF-kB signalling pathway and only SAM increased GSH. The mechanisms exerted by SAM in the reduction of foci makes this compound a potential liver cancer therapeutic agent.}, }
@article {pmid18403082, year = {2008}, author = {Valvassori, SS and Petronilho, FC and Réus, GZ and Steckert, AV and Oliveira, VB and Boeck, CR and Kapczinski, F and Dal-Pizzol, F and Quevedo, J}, title = {Effect of N-acetylcysteine and/or deferoxamine on oxidative stress and hyperactivity in an animal model of mania.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {32}, number = {4}, pages = {1064-1068}, doi = {10.1016/j.pnpbp.2008.02.012}, pmid = {18403082}, issn = {0278-5846}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bipolar Disorder/*chemically induced/*psychology ; Central Nervous System Stimulants/pharmacology ; Deferoxamine/*pharmacology ; Dextroamphetamine/pharmacology ; Free Radical Scavengers/*pharmacology ; Hyperkinesis/*chemically induced/prevention &amp; control/*psychology ; Male ; Oxidative Stress/*drug effects ; Protein Carbonylation/drug effects ; Rats ; Rats, Wistar ; }, abstract = {Studies have consistently reported the participation of free radicals in Bipolar Disorder. Administration of d-amphetamine (d-AMPH) is a relevant animal model of mania and it increases oxidative stress in rat brain. Evidences indicate that the antioxidants N-acetylcysteine (NAC) and Deferoxamine (DFX) exert protective effects in the brain. The present study was designed to evaluate the effects of NAC, DFX or their combination on AMPH-induced hyperactivity. The protein oxidation levels were analyzed in prefrontal cortex and hippocampus. In the first animal model (reversal treatment), adult male Wistar rats received saline or d-AMPH for 14 days, and from the 8th to the 14th day, they were treated with saline, NAC, DFX, or NAC plus DFX. In the second animal model (prevention treatment), rats were pretreated with saline or antioxidant regime, and from the 8th to the 14th day, they also received saline or d-AMPH. In the prefrontal cortex, the protein carbonyls were not affected by the treatment with antioxidants alone but it was increased by treatment with NAC plus DFX. At the same model, NAC plus DFX reversed the protein damage in the hippocampus, but NAC alone increased this damage. In the prevention treatment, it was observed that the protein damage in the prefrontal cortex was prevented by DFX or NAC plus DFX. In the hippocampus, the pretreatment with all antioxidant regime prevented protein damage induced by d-AMPH. At both treatments (reversal or prevention) the antioxidants did not present any effect against d-AMPH-induced hyperactivity. In conclusion, NAC or DFX and the combination of NAC plus DFX reverse and protect against d-AMPH-induced oxidative protein damage. Using these protocols we could not observe affects on locomotion, however this effect varies depending on the brain region and the treatment regime.}, }
@article {pmid18399853, year = {2008}, author = {Syrkina, O and Jafari, B and Hales, CA and Quinn, DA}, title = {Oxidant stress mediates inflammation and apoptosis in ventilator-induced lung injury.}, journal = {Respirology (Carlton, Vic.)}, volume = {13}, number = {3}, pages = {333-340}, doi = {10.1111/j.1440-1843.2008.01279.x}, pmid = {18399853}, issn = {1440-1843}, support = {HL 3915/HL/NHLBI NIH HHS/United States ; HL03920/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*physiology ; Bronchoalveolar Lavage Fluid ; Chemokine CXCL2/metabolism ; Disease Models, Animal ; Epithelial Cells/metabolism/pathology ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Interleukin-6/metabolism ; Lung/drug effects/metabolism/physiopathology ; Oxidative Stress/*physiology ; Pneumonia/metabolism/pathology/*physiopathology ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome/*etiology/metabolism/*physiopathology ; Tumor Necrosis Factor-alpha/metabolism ; Ventilators, Mechanical/*adverse effects ; }, abstract = {BACKGROUND AND OBJECTIVE: Ventilator-induced lung injury (VILI) leads to airway epithelial cell apoptosis and lung inflammation. High tidal volume ventilation in vivo has been shown to induce MIP-2 production, lung neutrophil sequestration and apoptotic airway cell death. This study aimed to determine the effect of N-acetylcysteine (NAC), a scavenger of oxygen radicals, on lung inflammation and apoptosis in an in vivo model of VILI.<br><br>METHODS: Sprague-Dawley rats (n = 5 per group) were ventilated at low tidal volume (V(T) 7 mL/kg) or high tidal volume (V(T) 20 mL/kg) with or without administration of 140 mg/kg of intravenous NAC. Animals were ventilated for 30 min, 1 or 2 h, then allowed to recover for 2 h, at which time neutrophil infiltration, MIP-2, TNF-alpha and IL-6 in BAL fluid, as well as the percentage of apoptotic airway epithelial cells, were measured.<br><br>RESULTS: Ventilation at V(T) 20 mL/kg increased oxidant release, as measured by serum isoprostane, and decreased lung glutathione, the major antioxidant in the lung. NAC treatment during ventilation at V(T) 20 mL/kg prevented the decrease in lung glutathione and significantly lowered serum isoprostane levels, neutrophil infiltration, cytokines in the BAL and apoptosis in the airways as compared with animals ventilated at V(T) 20 mL/kg without NAC (P < 0.05).<br><br>CONCLUSIONS: These data point to an early role of oxidant-induced inflammation and apoptosis in VILI.}, }
@article {pmid18398338, year = {2008}, author = {Xu, H and Duan, J and Wang, W and Dai, S and Wu, Y and Sun, R and Ren, J}, title = {Reactive oxygen species mediate oxidized low-density lipoprotein-induced endothelin-1 gene expression via extracellular signal-regulated kinase in vascular endothelial cells.}, journal = {Journal of hypertension}, volume = {26}, number = {5}, pages = {956-963}, doi = {10.1097/HJH.0b013e3282f56bb7}, pmid = {18398338}, issn = {0263-6352}, mesh = {Cells, Cultured ; Endothelial Cells/*metabolism ; Endothelin-1/genetics/*metabolism ; Extracellular Signal-Regulated MAP Kinases/*physiology ; Gene Expression Regulation ; Humans ; Lipoproteins, LDL/*physiology ; Phosphorylation ; *Reactive Oxygen Species ; Signal Transduction ; Umbilical Veins/metabolism ; }, abstract = {BACKGROUND: Oxidized low-density lipoprotein (oxLDL) promotes expression and secretion of endothelin-1 (ET-1), however, the precise mechanism involved is unclear. This study was designed to identify the regulatory mechanism of oxLDL-induced ET-1 expression in endothelial cells.<br><br>METHODS: ET-1 mRNA expression, secretion and promoter activity were evaluated by reverse transcriptase-PCR (RT-PCR), enzyme immunometric and luciferase assays, respectively.<br><br>RESULTS: oxLDL (35 microg/ml) significantly enhanced reactive oxygen species (ROS), mRNA expression, secretion and promoter activity of ET-1 in human umbilical vein endothelial cells (HUVECs), all of which were nullified by the antioxidant N-acetyl cysteine (NAC). oxLDL stimulated the extracellular signal-regulated kinase (ERK) phosphorylation in HUVECs, which was blocked by NAC and the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD98059. NAC and PD98059 stopped oxLDL-elicited increase in mRNA expression, secretion and promoter activity of ET-1. Fusion plasmids with decreasing length of 5'-flanking sequence of ET-1 from -566 bpLuc to -250 bpLuc displayed increased luciferase activity after 24 h of oxLDL treatment. Interestingly, fusion plasmid from -233 and -185 bpLuc significantly reduced the luciferase activity in control and oxLDL-treated HUVECs. In addition, transfection of the reporter construct -250Luc, which contains a 2 bp mutation at activator protein-1 site, abolished both basal and oxLDL-stimulated ET-1 promoter activities.<br><br>CONCLUSION: Collectively, our data favor the notion that oxLDL stimulates ERK phosphorylation via ROS accumulation, which in turn stimulates vascular endothelial transcriptional factor activator protein-1 and ET-1 expression as well as secretion.}, }
@article {pmid18389381, year = {2009}, author = {Liu, B and Li, W and Li, Y and Wang, Z and Li, H and Liu, P and Fu, J}, title = {Protective effects of N-acetylcysteine in isoproterenol-induced myocardium injury in rats.}, journal = {Molecular biology reports}, volume = {36}, number = {4}, pages = {761-765}, pmid = {18389381}, issn = {0301-4851}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Creatine Kinase, MB Form/metabolism ; Cytokines/biosynthesis/genetics ; Gene Expression Regulation/drug effects ; Isoproterenol/*pharmacology ; L-Lactate Dehydrogenase/metabolism ; Male ; Myocardial Infarction/*chemically induced/metabolism/pathology/*prevention &amp; control ; Rats ; Rats, Wistar ; }, abstract = {Isoproterenol (ISO) has been found to cause severe injury in the myocardium. The aim of this study was to investigate the protective effects of N-acetylcysteine (NAC) on ISO-induced myocardial injury in rats and its underlying mechanisms. Fouty male Wistar rats were randomly divided into four groups: control, ISO, NAC, and ISO + NAC group. Myocardial histopathological observation were performed; The activities of creatine kinase isoenzyme-MB (CK-MB) and lactate dehydrogenase (LDH) were examined; Myocardium TNF-alphaand IL-1beta gene expressions were examined by RT-PCR analysis; Myocardial expressions of TNF-alphaand IL-1betaproteins were observed by immunohistochemical assay and western blotting analysis. The myocardial injury induced by ISO was significantly reduced by the treatment of NAC as judged by the reduction of myocardial necrosis. Compared with ISO group, rats pre-injected with NAC showed a significant decrease in the activities of cardiac marker enzymes such as CK-MB and LDH in serum. NAC inhibits the pro-inflammatory factors expressions (TNF-alphaand IL-1beta) stimulated by ISO. In conclusion, NAC exerts significant cardio-protective effects against ISO-induced myocardial injury in rats, likely regulating pro-inflammatory factors expressions.}, }
@article {pmid18387516, year = {2008}, author = {Lee, CY and Wey, SP and Liao, MH and Hsu, WL and Wu, HY and Jan, TR}, title = {A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells.}, journal = {International immunopharmacology}, volume = {8}, number = {5}, pages = {732-740}, doi = {10.1016/j.intimp.2008.01.018}, pmid = {18387516}, issn = {1567-5769}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cannabidiol/*pharmacology ; Cell Cycle/drug effects ; Cell Line, Tumor ; Flow Cytometry ; Fluorescent Dyes ; In Situ Nick-End Labeling ; Male ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; T-Lymphocytes/*drug effects/metabolism ; Thymoma/metabolism/*pathology ; Thymus Neoplasms/metabolism/*pathology ; }, abstract = {It has been shown that leukemia and glioma cells are sensitive to cannabidiol (CBD)-induced apoptosis, whereas primary monocytes and glia cells are relatively insensitive. In the current study, the cellular events and sensitivity to CBD-induced apoptosis between murine thymocytes and EL-4 thymoma cells were compared. Cannabidiol markedly induced apoptosis in a time- and concentration-related manner in both cells. The efficacy of CBD to induce apoptosis was comparable between the 2 types of T cells, whereas CBD induced apoptosis in thymocytes with a slightly greater potency than in EL4 cells. Time-course analyses revealed CBD-mediated apoptosis occurred earlier in EL-4 cells than that in thymocytes. An increased level of cellular reactive oxygen species (ROS) was detected in both cells with the peak response at 2 h post CBD treatment. Concordantly, CBD triggered a gradual diminishment in the cellular thiols. The presence of N-acetyl-L-cysteine (NAC), a precursor of glutathione, markedly attenuated the induction of apoptosis, and restored the diminished levels of cellular thiols. The results demonstrated that both thymocytes and EL-4 thymoma cells were susceptible to CBD-induced apoptosis and that ROS played a critical role in the apoptosis induction.}, }
@article {pmid18385540, year = {2008}, author = {Abe, M and Takiguchi, Y and Ichimaru, S and Tsuchiya, K and Wada, K}, title = {Comparison of the protective effect of N-acetylcysteine by different treatments on rat myocardial ischemia-reperfusion injury.}, journal = {Journal of pharmacological sciences}, volume = {106}, number = {4}, pages = {571-577}, doi = {10.1254/jphs.fp0071664}, pmid = {18385540}, issn = {1347-8613}, mesh = {Acetylcysteine/*administration &amp; dosage/blood ; Animals ; Antioxidants/*administration &amp; dosage/metabolism ; Disease Models, Animal ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; I-kappa B Proteins/metabolism ; Infusions, Intravenous ; Injections, Intravenous ; L-Lactate Dehydrogenase/metabolism ; Male ; Myocardial Reperfusion Injury/metabolism/pathology/*prevention &amp; control ; Myocardium/enzymology/metabolism/*pathology ; Peroxidase/metabolism ; Phosphorylation ; Rats ; Rats, Wistar ; }, abstract = {Reactive oxygen species have been known as important contributors to ischemia/reperfusion (I/R) injury. Studies on the beneficial effect of N-acetylcysteine (NAC), a potent antioxidant, on limiting infarct size induced by I/R yielded contrasting results. The present study was undertaken to compare the effect of NAC by different administration methods on infarct size in a rat myocardial I/R model. Rats underwent 30 min of left coronary occlusion followed by 4 h of reperfusion. Treatment with continuous infusion of NAC (150 mg/kg per hour) from 30 min before occlusion for 2 h (until 1 h after the start of reperfusion) produced a significant limitation of the infarct size as a percentage of the ischemic area (8%) compared to the non-treated control (60%). However, bolus injection of 150 mg/kg at 30 min prior to occlusion and 5 min prior to reperfusion failed to reduce it (56%) although the total dose is the same. The decreased total glutathione content and glutathione peroxidase activity in the ischemic region were recovered in the continuous infusion group, but not in the bolus injection group. The increased myeloperoxidase activity and phosphorylation of inhibitor kappaB after I/R were inhibited by the continuous treatment. These results indicate that the protective effect of NAC on myocardial infarction induced by I/R was different depending on the administration method. It is necessary to maintain blood concentration during the early period of reperfusion to obtain the beneficial effect of NAC.}, }
@article {pmid18385389, year = {2008}, author = {Luo, J and Tsuji, T and Yasuda, H and Sun, Y and Fujigaki, Y and Hishida, A}, title = {The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {23}, number = {7}, pages = {2198-2205}, doi = {10.1093/ndt/gfn090}, pmid = {18385389}, issn = {1460-2385}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Acute Kidney Injury/chemically induced/*drug therapy/*metabolism ; Animals ; Antineoplastic Agents/*toxicity ; Antioxidants/pharmacology ; Cisplatin/*toxicity ; Cross-Linking Reagents ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/*therapeutic use ; Male ; Melatonin/pharmacology ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Proline/analogs &amp; derivatives/pharmacology ; Rats ; Rats, Sprague-Dawley ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND: The clinical use of cisplatin (cis-diamminedichloro-platinum II, CDDP) is highly limited by its nephrotoxicity. Although N-acetylcysteine (NAC), a thiol-containing antioxidant, has been documented to be effective in attenuating renal injury induced by CDDP, the precise mechanisms involved in its renoprotection have not been completely clarified.<br><br>METHODS: We investigated the effects of NAC on oxidative stress and oxidation-associated signals, such as p38 mitogen-activated protein kinase (MAPK), NF-kappaB and TNF-alpha, in CDDP-induced acute renal failure (ARF) rats, in comparison to the effects of melatonin (MT), one of the physiological TNF-alpha inhibitors, and pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor.<br><br>RESULTS: NAC blocked oxidative stress, p38 MAPK activation, caspase-3 cleavage, tissue apoptosis, renal dysfunction and morphological damage induced by CDDP. CDDP-triggered NF-kappaB translocation into the nucleus and TNF-alpha mRNA increase in the kidney were also inhibited in NAC-treated rats. MT downregulated the TNF-alpha mRNA level, and PDTC inhibited the increases in both NF-kappaB translocation and TNF-alpha mRNA. Neither MT nor PDTC were capable of interfering with oxidative stress, p38 MAPK phosphorylation, caspase-3 cleavage, tissue apoptosis and kidney injury induced by CDDP.<br><br>CONCLUSIONS: These data suggest that oxidative stress and p38 MAPK-mediated apoptotic cell death pathways are involved, at least in part, in the pathogenesis of CDDP-induced ARF, and negative regulation of p38 MAPK activation through inhibition of oxidative stress appears to play a central role in the beneficial effects of NAC.}, }
@article {pmid18385062, year = {2008}, author = {He, Y and Leung, KW and Zhang, YH and Duan, S and Zhong, XF and Jiang, RZ and Peng, Z and Tombran-Tink, J and Ge, J}, title = {Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {49}, number = {4}, pages = {1447-1458}, doi = {10.1167/iovs.07-1361}, pmid = {18385062}, issn = {0146-0404}, mesh = {Acetylcysteine/therapeutic use ; Adenosine Triphosphate/metabolism ; Adolescent ; Adult ; Annexin A5/metabolism ; Antioxidants/*therapeutic use ; Apoptosis/*drug effects ; Cells, Cultured ; Cyclosporine/therapeutic use ; Cytochromes c/metabolism ; Electron Transport Complex I/*antagonists &amp; inhibitors ; Glaucoma, Open-Angle/metabolism/pathology/*prevention &amp; control ; Humans ; L-Lactate Dehydrogenase/metabolism ; Membrane Potential, Mitochondrial ; Middle Aged ; Mitochondrial Membrane Transport Proteins/antagonists &amp; inhibitors ; Mitochondrial Permeability Transition Pore ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Rotenone/pharmacology ; Trabecular Meshwork/*drug effects/metabolism/pathology ; Uncoupling Agents/*pharmacology ; Vitamin E/therapeutic use ; }, abstract = {PURPOSE: There is growing evidence that oxidative stress contributes to the progression of primary open-angle glaucoma (POAG), a leading cause of irreversible blindness worldwide. The authors provide evidence that mitochondrial dysfunction is a possible mechanism for the loss of trabecular meshwork (TM) cells in persons with POAG.<br><br>METHODS: TM from patients with POAG (GTM) and age-matched subjects without disease (NTM) were obtained by standard surgical trabeculectomy. Primary TM cultures were treated with one of the following mitochondrial respiratory chain inhibitors: rotenone (ROT, complex I inhibitor), thenoyltrifluoroacetone (TTFA, complex II inhibitor), myxothiazol or antimycin A (MYX, AM-complex III inhibitors); mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA); and antioxidants vitamin E (Vit E) or N-acetylcysteine (NAC). Mitochondrial function was determined by changes in mitochondrial membrane potential (DeltaPsim) and adenosine triphosphate (ATP) production with the fluorescent probes 5,5',6,6'-tetrachloro-1,1'3,3'-tetraethylbenzimid azolocarbocyanine iodide (JC-1) and a luciferin/luciferase-based ATP assay, respectively. Reactive oxygen species (ROS) level, determined by H(2)-DCF-DA, and cell death, measured by lactate dehydrogenase activity and Annexin V-FITC labeling, were also examined.<br><br>RESULTS: GTM cells have higher endogenous ROS levels, lower ATP levels, and decreased Delta Psi m and they are more sensitive to mitochondrial complex I inhibition than their normal counterparts. ROT induces a further increase in ROS production, the release of cytochrome c, and decreases in ATP level and Delta Psi m in GTM cells, eventually leading to apoptosis. Complex II and III inhibition had little effect on the cells. Antioxidants protect against ROT-induced death by inhibiting ROS generation and cytochrome c release.<br><br>CONCLUSIONS: The authors propose that a mitochondrial complex I defect is associated with the degeneration of TM cells in patients with POAG, and antioxidants and MPT inhibitors can reduce the progression of this condition.}, }
@article {pmid18384088, year = {2008}, author = {Pan, MH and Hsieh, MC and Kuo, JM and Lai, CS and Wu, H and Sang, S and Ho, CT}, title = {6-Shogaol induces apoptosis in human colorectal carcinoma cells via ROS production, caspase activation, and GADD 153 expression.}, journal = {Molecular nutrition &amp; food research}, volume = {52}, number = {5}, pages = {527-537}, doi = {10.1002/mnfr.200700157}, pmid = {18384088}, issn = {1613-4133}, mesh = {Adenocarcinoma/pathology ; Apoptosis/*drug effects ; Caspases/metabolism ; Catechols/isolation &amp; purification/*pharmacology ; Cell Line, Tumor ; Colonic Neoplasms/pathology ; Colorectal Neoplasms/*pathology ; Fatty Alcohols/isolation &amp; purification/pharmacology ; Zingiber officinale ; Humans ; Membrane Potentials/drug effects ; Mitochondrial Membranes/drug effects/physiology ; Plant Extracts/chemistry/*pharmacology ; RNA, Neoplasm/drug effects/isolation &amp; purification ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factor CHOP/drug effects/genetics ; }, abstract = {Ginger, the rhizome of Zingiber officinale, is a traditional medicine with anti-inflammatory and anticarcinogenic properties. This study examined the growth inhibitory effects of the structurally related compounds 6-gingerol and 6-shogaol on human cancer cells. 6-Shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one] inhibits the growth of human cancer cells and induces apoptosis in COLO 205 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of 6-shogaol-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. Up-regulation of Bax, Fas, and FasL, as well as down-regulation of Bcl-2 and Bcl-X(L)were observed in 6-shogaol-treated COLO 205 cells. N-acetylcysteine (NAC), but not by other antioxidants, suppress 6-shogaol-induced apoptosis. The growth arrest and DNA damage (GADD)-inducible transcription factor 153 (GADD153) mRNA and protein is markedly induced in a time- and concentration-dependent manner in response to 6-shogaol.}, }
@article {pmid19565955, year = {2008}, author = {Mills, MO and Lee, MG}, title = {Acetaminophen overdose in Jamaica.}, journal = {The West Indian medical journal}, volume = {57}, number = {2}, pages = {132-134}, pmid = {19565955}, issn = {0043-3144}, mesh = {Acetaminophen/*poisoning ; Adolescent ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Drug Overdose ; Female ; Humans ; Jamaica/epidemiology ; Liver Failure, Acute/*chemically induced/diagnosis/epidemiology ; Liver Function Tests ; Male ; Retrospective Studies ; Suicide, Attempted/*statistics &amp; numerical data ; Young Adult ; }, abstract = {Acetaminophen is a dose dependent hepatotoxin which is frequently associated with intentional self-harm. Forty-nine cases of parasuicide attempts involving paracetamol only or in combination with another drug were treated at the UHWI, Jamaica, between 1994-2004. The majority were women (84%) and the mean age was 23 years. Acetaminophen was the only agent ingested in 71% of cases; 29% involved an additional drug. Patients presented an average of 6.5 hours after ingestion (range 1-45 hours). Serum transaminases were elevated in 18% of cases and N-acetylcysteine (NAC) therapy given in 55%. The mean duration of hospitalization was three days. One patient developed liver failure and there were no deaths. Education of the public and medical profession is needed to increase awareness of the potential toxic effects of acetaminophen overdose. N-acetylcysteine therapy should be given early in suspected cases.}, }
@article {pmid20020933, year = {2008}, author = {Akdur, O and Sozuer, EM and Ikizceli, I and Avsarogullari, L and Ozturk, F and Muhtaroglu, S and Ozkan, S and Durukan, P}, title = {Experimental inhalation of chlorine gas produced with a different method; effects of N-acetyl cysteine on acute pulmonary damage.}, journal = {Toxicology mechanisms and methods}, volume = {18}, number = {9}, pages = {739-743}, doi = {10.1080/15376510802354912}, pmid = {20020933}, issn = {1537-6524}, abstract = {The two most common gas inhalation injuries encountered in emergency departments are carbon monoxide and chlorine inhalations. In this study, chlorine was produced through a method different to the previous experimental models. Rats were subjected to inhale chlorine, after which the effects of N-acetylcysteine on pulmonary damage were evaluated. A total of 50 rats were equally divided into five groups. Group 1 received nothing. Groups 2 and 3 were taken as 6 h, groups 4 and 5 as 24 h control and N-acetylcysteine groups, respectively. Firstly, 200 ppm chlorine gas was given for 20 min. Then, 40 mg/kg N-acetylcysteine was given intraperitoneally. The same procedure with the same dose was repeated 3 h later. The same procedures were applied to the control group but this time saline was used. Tissue samples of lungs were taken. Glutathione levels of the rats in the N-acetylcysteine group sacrificed at 24 h were significantly higher than those of the control group. Histopathological evaluation of the pulmonary tissues of the rats sacrificed at 6 and 24 h revealed mild-to-moderate degrees of tissue damage. The degree of tissue damage at 6 h and 24 h N-acetylcysteine group rats was lower than that in the control group. As a result, tissue damage resulting from experimental chlorine inhalation can be alleviated by N-acetylcysteine. This is mainly the result of the antioxidant effects of the N-acetylcysteine.}, }
@article {pmid19346584, year = {2008}, author = {Deryabin, PG and Lvov, DK and Botikov, AG and Ivanov, V and Kalinovsky, T and Niedzwiecki, A and Rath, M}, title = {Effects of a nutrient mixture on infectious properties of the highly pathogenic strain of avian influenza virus A/H5N1.}, journal = {BioFactors (Oxford, England)}, volume = {33}, number = {2}, pages = {85-97}, doi = {10.1002/biof.5520330201}, pmid = {19346584}, issn = {0951-6433}, mesh = {Animals ; Antiviral Agents/*pharmacology ; Ascorbic Acid/pharmacology ; Cells, Cultured ; Chlorocebus aethiops ; Humans ; Influenza A Virus, H5N1 Subtype/*drug effects/*pathogenicity ; Lysine/pharmacology ; Micronutrients/*pharmacology ; Plant Extracts/pharmacology ; Proline/pharmacology ; Selenium/pharmacology ; Tea ; Vero Cells ; }, abstract = {Numerous outbreaks of avian influenza virus infection (A/H5N1) have occurred recently, infecting domestic birds, chicken and ducks. The possibility of the emergence of a new strain of influenza virus capable of causing a pandemic in humans is high and no vaccine effective against such a strain currently exists. A unique nutrient mixture (NM), containing lysine, proline, ascorbic acid, green tea extract, N-acetyl cysteine, selenium among other micro nutrients, has been shown to exert a wide range of biochemical and pharmacological effects, including an inhibitory effect on replication of influenza virus and HIV. This prompted us to investigate the potential anti-viral activity of a nutrient mixture (NM) and its components on avian influenza virus A/H5N1at viral dosages of 1.0, 0.1 and 0.01 TCID(50). Antiviral activity was studied in cultured cell lines PK, BHK-21, and Vero-E6. Virus lysing activity was determined by co-incubation of virus A/H5N1 with NM for 0-60 min, followed residual virulence titration in cultured SPEV or BHK-21 cells. NM demonstrated high antiviral activity evident even at prolonged periods after infection. NM antiviral properties were comparable to those of conventional drugs (amantadine and oseltamivir); however, NM had the advantage of affecting viral replication at the late stages of the infection process.}, }
@article {pmid19276537, year = {2008}, author = {Roomi, MW and Jariwalla, RJ and Kalinovsky, T and Roomi, N and Niedzwiecki, A and Rath, M}, title = {Inhibition of cellular invasive parameters in influenza A virus-infected MDCK and Vero cells by a nutrient mixture.}, journal = {BioFactors (Oxford, England)}, volume = {33}, number = {1}, pages = {61-75}, doi = {10.1002/biof.5520330106}, pmid = {19276537}, issn = {0951-6433}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Arginine/pharmacology ; Ascorbic Acid/pharmacology ; Cell Line ; Cell Movement/*drug effects ; Cell Survival/drug effects ; Chlorocebus aethiops ; Dogs ; *Influenza A virus ; Lysine/pharmacology ; Matrix Metalloproteinase 9/*metabolism ; Orthomyxoviridae Infections/*drug therapy/*physiopathology ; Plant Extracts/pharmacology ; Tea/chemistry ; Vero Cells ; }, abstract = {Influenza, a long-standing common infection, poses a serious health problem causing significant morbidity and mortality, and imposing substantial economic costs. To date there are no effective antiviral therapies. A unique nutrient mixture (NM), containing lysine, proline, ascorbic acid, green tea extract, N-acetyl cysteine and selenium among other micro nutrients, has been shown to exert a wide range of biochemical and pharmacological effects, among them anti-carcinogenic and anti-atherogenic activity both in vitro and in vivo. In a previous study, NM was found to significantly inhibit influenza virus A associated neuraminidase enzyme as well as production of NP antigen in a dose-dependent manner. Influenza virus A not only infects pulmonary areas, but also manifests in extrapulmonary areas, which require basement membrane disruption by matrix metalloproteinases capable of degrading collagen type IV. This prompted us to study the effect of NM on cellular invasive parameters of virus-infected and non-infected MDCK and Vero cells. NM inhibited extracellular invasive parameters such as MMP-2 and MMP-9 secretion and Matrigel invasion. Results indicated that the relatively non-toxic nutrient mixture tested in this investigation has potential in influenza treatment by not only decreasing viral multiplication in infected cells but also by blocking the enzymatic degradation of the extracellular matrix.}, }
@article {pmid20020979, year = {2007}, author = {Shadnia, S and Dasgar, M and Taghikhani, S and Mohammadirad, A and Khorasani, R and Abdollahi, M}, title = {Protective Effects of alpha-Tocopherol and N-Acetyl-Cysteine on Diazinon-Induced Oxidative Stress and Acetylcholinesterase Inhibition in Rats.}, journal = {Toxicology mechanisms and methods}, volume = {17}, number = {2}, pages = {109-115}, doi = {10.1080/15376510600860318}, pmid = {20020979}, issn = {1537-6524}, abstract = {Diazinon, an organophosphate (OP) insecticide, is widely used in agriculture and domestically. Reactive oxygen species (ROS) caused by OPs are involved in the toxicity of various pesticides. The aim of the present study was to analyze the role of diazinon in inducing oxidative stress in adult male Wistar rats and to evaluate the possible protective effects of alpha-tocopherol (TPH) and the glutathione prodrug N-acetyl-cysteine (NAC) after 4 weeks of exposure to a sublethal dose of diazinon. TPH (10 mg/kg/day), NAC (160 mg/kg/day), diazinon (25 mg/kg/day), a combination of NAC (160 mg/kg/day) and diazinon (25 mg/kg/day), and a combination of TPH (10 mg/kg/day) and diazinon (25 mg/kg/day) were given to rats orally via gavage for 4 weeks. The thiobarbituric acid reactive substances (TBARS) marker of lipid peroxides levels, total thiol molecules, and total antioxidant capacity of plasma were all analyzed as biomarkers of oxidative stress. In addition, the acetylcholinesterase (AChE) activity was measured as a biomarker of toxicity. The results from this study well indicate diazinon-induced oxidative stress demonstrated by enhanced TBARS, decreased total thiol molecules, and total antioxidant capacity. In addition, AChE activity was inhibited as a marker of OP toxicity. Data show the protective roles of TPH and NAC in reducing the diazinon-induced oxidative stress. Interestingly, both TPH and NAC recovered diazinon-induced AChE inhibition. It is concluded that supplementation with TPH and NAC can reduce toxicity of OP in human exposure.}, }
@article {pmid20020952, year = {2007}, author = {Nehru, B and Kanwar, SS}, title = {Modulation by N-acetylcysteine of lead-induced alterations in rat brain: reduced glutathione levels and morphology.}, journal = {Toxicology mechanisms and methods}, volume = {17}, number = {5}, pages = {289-293}, doi = {10.1080/15376510601017769}, pmid = {20020952}, issn = {1537-6524}, abstract = {The present study pertains to the modulator action of N-acetylcysteine (NAC) on glutathione (GSH) status in lead-exposed brain regions of the rat. The effect of lead at a dose of 20 mg/kg body weight/day was studied on the cerebral cortex and cerebellum region of rat brain. The results showed a significant decline in the reduced glutathione level in the cerebellar and cerebral tissue homogenates. Histological analysis of the different brain regions also revealed a marked deterioration in the organization of the pyramidal cellular layer of the cerebrum and the Purkinje's cellular layer of the cerebellum. The animals that underwent lead treatment when administrated with N-acetylcysteine at a dose of 160 mg/kg body weight/day showed a significant recovery of the GSH level in the brain region, while it reached almost the normal level in the cerebellum. NAC treatment also brought about appreciable improvement in the histoarchitecture of the cellular layers, which showed clearly that NAC may play a very useful role in arresting the neurotoxicological damage of lead in cerebral and cerebellar brain regions.}, }
@article {pmid19537988, year = {2006}, author = {Shelby, KS and Popham, HJ}, title = {Plasma phenoloxidase of the larval tobacco budworm, Heliothis virescens, is virucidal.}, journal = {Journal of insect science (Online)}, volume = {6}, number = {}, pages = {1-12}, pmid = {19537988}, issn = {1536-2442}, mesh = {Animals ; Antiviral Agents/metabolism/pharmacology ; Baculoviridae/drug effects/*physiology ; Larva/enzymology/virology ; Monophenol Monooxygenase/*metabolism/pharmacology ; Moths/*enzymology/*virology ; }, abstract = {Heliothis virescens larval plasma contains high levels of an antiviral activity against the budded form of the Helicoverpa zea single nucleopolyhedrovirus (HzSNPV) in vitro. Preliminary results indicated that phenoloxidase is primarily responsible for this virucidal effect. However it is known that other enzymes that generate antimicrobial reactive oxygen intermediates and reactive nitrogen intermediates are present in hemolymph that could contribute to the observed virucidal activity. To elucidate the contributions of phenoloxidase and other candidate activities to plasma innate immune response against baculovirus infection specific metabolic inhibitors were used. In vitro the general inhibitors of melanization (N-acetyl cysteine, ascorbate and glutathione), and specific inhibitors of phenoloxidase (phenylthiourea and Kojic acid), completely blocked virucidal activity up to the level seen in controls. Addition of the enzyme superoxide dismutase to plasma did not affect virucidal activity; however addition of catalase had an inhibitory effect. Inhibitors of nitric oxide synthase activity did not affect virucidal activity. Our results confirm that phenoloxidase is the predominate activity in larval plasma accounting for inactivation of HzSNPV in vitro, and that phenoloxidase-dependent H(2)O(2) production may contribute to this virucidal activity.}, }
@article {pmid20650139, year = {1995}, author = {Menegola, E and Broccia, ML and Prati, M and Ricolfi, R and Giavini, E}, title = {Glutathione and N-acetylcysteine protection against acetaldehyde embryotoxicity in rat embryos developing in vitro.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {9}, number = {5}, pages = {633-641}, doi = {10.1016/0887-2333(95)00066-h}, pmid = {20650139}, issn = {0887-2333}, abstract = {Previous in vitro studies demonstrated that acetaldehyde (ACHO) is able to produce specific morphological alterations related to the foetal alcohol syndrome. Intracellular reduced glutathione (GSH) has been shown to modulate the embryotoxicity elicited by various chemicals in vivo and in vitro. The present study evaluates the role played by endogenous and exogenous GSH and its precursor N-acetylcysteine (NAC) on the embryotoxicity induced by ACHO using the rat whole embryo culture system. In the first experiment embryos at gestation day (GD) 9.5 were cultured in rat serum medium for 18 hr in the presence of 1 mm l-buthionine-S,R-solfoximine (BSO), a specific inhibitor of GSH synthesis. Following pretreatment, conceptuses were cultured for a further 30 hr in the presence of 30 mug ACHO/ml. Pretreatment with BSO significantly enhanced the embryotoxic effects of ACHO and markedly reduced the GSH level only in the yolk sac. In the second experiment GSH or NAC (8 mum) were added to the medium by two different procedures in an attempt to reduce ACHO-induced embryotoxicity. In one case the embryos were exposed to ACHO for 8 hr and then transferred to media containing NAC or GSH for the remaining time of culture (22 hr); in another, the embryos were maintained for the entire culture period (30 hr) in a medium containing ACHO plus NAC or GSH. Only in the first case did exposure to NAC significantly reduce the frequency of abnormal embryos; in the second case the concurrent exposure to ACHO and thiols only marginally reduced ACHO-induced effects. Significant variations in the GSH content were recorded only at the level of the yolk sac. This result suggests that the yolk sac GSH can play a major role in the protection of the embryo against the toxic effects produced by xenobiotics.}, }
@article {pmid18966221, year = {1995}, author = {Banica, FG and Fogg, AG and Moreira, JC}, title = {Catalytic cathodic stripping voltammetry of oxidized glutathione at a hanging mercury drop electrode in the presence of nickel ion.}, journal = {Talanta}, volume = {42}, number = {2}, pages = {227-234}, doi = {10.1016/0039-9140(94)00232-h}, pmid = {18966221}, issn = {0039-9140}, abstract = {Oxidized glutathione (GSSG) can be determined after previous accumulation on the HMDE at E > -0.2 V (vs. the Ag AgCl reference electrode). GSH is formed during the accumulation, possibly by a mercury-ion-assisted hydrolytic disproportionation of GSSG. In the subsequent cathodic scan GSH is released and catalyses the reduction of nickel ion, giving a peak located at -0.6 V. This enables the determination of GSSG by differential-pulse cathodic stripping voltammetry at pH 7.0 in the phosphate acetate or MOPS buffer containing 0.5-1.0 mM Ni(II). The detection limit is 10 nM. The calibration graph is linear even in the presence of small amounts of human serum albumin, HSA. However, HSA increases the detection limit (20 nM for 3 x 10(-4)% HSA). Acetyl-cysteine in small excess or Cu(II) present as reagent impurity do not interfere. Glutathione, cysteine and similar compounds, which accumulate as mercury salts and form stable nickel complexes, will interfere. The method is put forward as a novel alternative stripping voltammetric method to those involving accumulation and determination as mercury or copper salts and complexes, in the knowledge that it may have advantages in particular analytical situations. In particular the method discriminates against compounds which accumulate as mercury salts but which do not form stable nickel complexes.}, }
@article {pmid20702212, year = {1990}, author = {Wormser, U and Ben-Zakine, S}, title = {The liver slice system: An in vitro acute toxicity test for assessment of hepatotoxins and their antidotes.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {4}, number = {4-5}, pages = {449-451}, doi = {10.1016/0887-2333(90)90098-e}, pmid = {20702212}, issn = {0887-2333}, abstract = {A simple method for rapid and reliable assessment of hepatotoxic agents is described. Liver slices from rats and mice of two age groups were incubated with the test hepatotoxins. Exposure of liver slices from 3-month-old mice to acetaminophen (6.8 mg/ml) resulted in 80% leakage of lactate dehydrogenase into the incubation medium, whereas liver slices from one-day-old mice showed only 12% leakage. Similar results were obtained with rat liver slices. The relative lack of response by livers of newborn rats was also demonstrated with carbon tetrachloride. The in vitro liver slice system has also been used to test the potency of N-acetylcysteine (NAC) as an antidote to acetaminophen toxicity. NAC protected mouse liver slices against acetaminophen toxicity in a dose-dependent manner. Addition of the antidote (10 mm) 20 min following hepatotoxin application reduced enzyme leakage by 75% as compared with the system with acetaminophen only. These findings demonstrate that the liver slice system provides the same type of information about hepatotoxins that is usually obtained by the use of acute in vivo tests on a large number of animals. It can be used for testing potential antidotes against hepatotoxins as well as for demonstration of species and age differences in the toxicity of various substances.}, }
@article {pmid18376141, year = {2008}, author = {Sikora, MJ and Bauer, JA and Verhaegen, M and Belbin, TJ and Prystowsky, MB and Taylor, JC and Brenner, JC and Wang, S and Soengas, MS and Bradford, CR and Carey, TE}, title = {Anti-oxidant treatment enhances anti-tumor cytotoxicity of (-)-gossypol.}, journal = {Cancer biology &amp; therapy}, volume = {7}, number = {5}, pages = {767-776}, pmid = {18376141}, issn = {1555-8576}, support = {P50 CA097248/CA/NCI NIH HHS/United States ; R01 DE013346/DE/NIDCR NIH HHS/United States ; R01 CA083087/CA/NCI NIH HHS/United States ; P30 CA046592/CA/NCI NIH HHS/United States ; P30 DC005188/DC/NIDCD NIH HHS/United States ; P30 CA046592-19/CA/NCI NIH HHS/United States ; P30 DC005188-07/DC/NIDCD NIH HHS/United States ; P50 CA097248-08/CA/NCI NIH HHS/United States ; R01 DE013346-04/DE/NIDCR NIH HHS/United States ; R01 DE13346/DE/NIDCR NIH HHS/United States ; R01 CA083087-05/CA/NCI NIH HHS/United States ; P50 CA97248/CA/NCI NIH HHS/United States ; P30 DC 05188/DC/NIDCD NIH HHS/United States ; P30 CA46592/CA/NCI NIH HHS/United States ; R01 CA83087/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/*pharmacology ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Drug Synergism ; *Gene Expression Regulation, Neoplastic ; Gossypol/*pharmacology ; Humans ; Models, Biological ; Neoplasms/*drug therapy ; Oligonucleotide Array Sequence Analysis ; Oxidants/metabolism ; Reactive Oxygen Species ; }, abstract = {We showed that tumor cells with wild-type p53 and high levels of Bcl-x(L) are cisplatin resistant but are induced to undergo apoptosis by (-)-gossypol, making this a promising agent for overcoming cisplatin resistance. However, some cells in a population with this phenotype are not killed and continue to survive. Conversely, tumor cells with low Bcl-x(L) expression and either wild type or mutant p53 are relatively cisplatin sensitive and do not exhibit such high levels of apoptosis. However, these do undergo progressive loss of viability after (-)-gossypol that may not be tumor specific. We sought to elucidate the basis for these observations using cDNA microarray analysis of (-)-gossypol treated cisplatin sensitive and resistant cells. Genes in the reactive oxygen species (ROS) pathway were highly upregulated in response to (-)-gossypol. The upregulation was of much greater magnitude in cisplatin sensitive than resistant cells. Staining with an oxidation reporter dye confirmed differential induction of ROS in tumor cells with low Bcl-x(L). As (-)-gossypol is known to undergo oxidative metabolism in vivo, ROS generation may be responsible for both off-target cytotoxicity and inactivation of the drug. In agreement with this hypothesis, oxidation of (-)-gossypol by pre-treatment with hydrogen peroxide eliminated its activity. Combined treatment with the antioxidant N-acetyl-cysteine (NAC) to block ROS increased (-)-gossypol-induced cytotoxicity to tumor but not normal cells. Furthermore, NAC increased the induction of apoptosis as measured by the sub-G(1) population, in both cisplatin sensitive and resistant cells. We postulate that concurrent treatment with antioxidant to block ROS prevents oxidative inactivation of (-)-gossypol and limits off-target toxicity allowing more potent (-)-gossypol-induced anti-tumor activity.}, }
@article {pmid18374104, year = {2008}, author = {Park, J and Ju, MK and Song, JS and Huh, KH and Kim, MS and Kim, YS}, title = {Effects of mycophenolic Acid on high glucose-induced fibronectin secretion and cellular reactive oxygen species in rat vascular smooth muscle cells.}, journal = {Transplantation proceedings}, volume = {40}, number = {2}, pages = {467-469}, doi = {10.1016/j.transproceed.2008.01.015}, pmid = {18374104}, issn = {0041-1345}, mesh = {Animals ; Cell Culture Techniques ; Cell Division ; Fibronectins/*metabolism ; Flow Cytometry ; Glucose/*pharmacology ; Muscle, Smooth, Vascular/cytology/drug effects/*physiology ; Mycophenolic Acid/*pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {Vascular smooth muscle cell (VSMC) proliferation, migration, and matrix protein accumulation play important roles in the development and progression of vascular disease including diabetic vascular complications and chronic allograft vasculopathy. Mycophenolic acid (MPA) inhibits various mesenchymal cell proliferation and matrix protein accumulation and reactive oxygen species (ROS). In this study, we investigated the effects of MPA on high glucose (HG)-induced fibronectin secretion and the role of ROS in rat VSMCs. Primary cultured rat VSMCs from Sprague-Dawley rats were exposed for 1 hour before stimulation with media containing 5.6 mmol/L glucose (low glucose [LG]), 30 mmol/L mannitol (M), or 30 mmol/L glucose (HG) with or without MPA (0.1-10 micromol/L) or N-acetylcysteine (NAC; 5 mmol/L). Fibronectin secretion was measured by Western blot analysis and dichlorofluorescein (DCF)-sensitive cellular ROS by flow cytometry. HG significantly increased fibronectin secretion by 1.7-fold. The increment of DCF-sensitive cellular ROS was 1.5-fold at 1 hour by HG. MPA at concentrations above 1 micromol/L effectively inhibited HG-induced fibronectin secretion and cellular ROS in a dose-dependent manner. NAC at 5 mmol/L also inhibited HG-induced rat VSMC activation. These results suggested that MPA inhibits HG-induced VSMC activation partially through inhibiting cellular ROS.}, }
@article {pmid18373392, year = {2008}, author = {Matejíková, J and Kucharská, J and Pancza, D and Ravingerová, T}, title = {The effect of antioxidant treatment and NOS inhibition on the incidence of ischemia-induced arrhythmias in the diabetic rat heart.}, journal = {Physiological research}, volume = {57 Suppl 2}, number = {}, pages = {S55-S60}, doi = {10.33549/physiolres.931552}, pmid = {18373392}, issn = {0862-8408}, mesh = {Acetylcysteine/*pharmacology ; Adaptation, Physiological ; Animals ; Antioxidants/*pharmacology ; Diabetes Mellitus, Experimental/complications/*drug therapy/enzymology/physiopathology ; Enzyme Inhibitors/*pharmacology ; Male ; Myocardial Ischemia/complications/*drug therapy/enzymology/physiopathology ; Myocardium/*enzymology ; NG-Nitroarginine Methyl Ester/*pharmacology ; Nitric Oxide Synthase/*antagonists &amp; inhibitors/metabolism ; Rats ; Rats, Wistar ; Tachycardia, Ventricular/enzymology/etiology/physiopathology/*prevention &amp; control ; Ubiquinone/analogs &amp; derivatives/metabolism ; Up-Regulation ; Ventricular Function, Left ; alpha-Tocopherol/metabolism ; }, abstract = {Contrary to clinical trials, experimental studies revealed that diabetes mellitus (DM) may initiate, besides increased myocardial vulnerability to ischemia-reperfusion injury (I/R) and pro/antioxidant dysbalance, development of adaptation leading to an enhanced tolerance to I/R. The aims were to characterize 1) susceptibility to ischemia-induced ventricular arrhythmias in the diabetic rat heart 2) its response to antioxidant N-acetylcysteine (NAC) and a NOS inhibitor L-NAME, and 3) the effect of DM on endogenous antioxidant systems. Seven days after streptozotocin injection (65 mg/kg, i.p.), Langendorff-perfused control (C) and DM hearts were subjected to 30-min occlusion of the LAD coronary artery with or without prior 15-min treatment with L-NAME (100 microM) or NAC (4 mM). Total number of ventricular premature beats (VPB), as well the total duration of ventricular tachycardia (VT) were reduced in the DM group (from 533+/-58 and 37.9+/-10.2 s to 224.3+/-52.6 and 19+/-13.5 s; P<0.05). In contrast to the antiarrhythmic effects of L-NAME and NAC in controls group (VPB 290+/-56 and 74+/-36, respectively; P<0.01 vs. control hearts), application of both drugs in the diabetics did not modify arrhythmogenesis (L-NAME: VPB 345+/-136, VT 25+/-13 s; NAC: VPB 207+/-50, VT 12+/-3.9 s; P>0.05 vs non-treated diabetic hearts). Diabetic state was associated with significantly elevated levels of CoQ10 and CoQ9 (19.6+/-0.8 and 217.3+/-9.5 vs. 17.4+/- 0.5 and 185.0+/-5.0 nmol/g, respectively, in controls; P<0.05), as well as alpha-tocopherol (38.6+/-0.7 vs. 31.5+/-2.1 nmol/g in controls; P<0.01) in the myocardial tissue. It is concluded that early period of DM is associated with enhanced resistance to ischemia-induced arrhythmias. Diabetes mellitus might induce adaptive processes in the myocardium leading to lower susceptibility to antioxidant and L-NAME treatment.}, }
@article {pmid18371657, year = {2007}, author = {Agüí, L and Peña-Farfal, C and Yáñez-Sedeño, P and Pingarrón, JM}, title = {Electrochemical determination of homocysteine at a gold nanoparticle-modified electrode.}, journal = {Talanta}, volume = {74}, number = {3}, pages = {412-420}, doi = {10.1016/j.talanta.2007.05.035}, pmid = {18371657}, issn = {1873-3573}, mesh = {Carbon/chemistry ; Chemistry Techniques, Analytical/*instrumentation ; Chromatography, High Pressure Liquid ; Electrochemistry ; Electrodes ; Gold Colloid/*chemistry ; Homocysteine/*analysis/blood/chemistry ; Humans ; Metal Nanoparticles/*chemistry ; Oxidation-Reduction ; Serum/chemistry ; Sulfhydryl Compounds/analysis/chemistry ; }, abstract = {The construction of a colloidal gold-cysteamine-carbon paste electrode, Au(coll)-Cyst-CPE, for the electrochemical determination of homocysteine is reported. The improved voltammetric behaviour of homocysteine at Au(coll)-Cyst-CPE with respect to that observed at a gold disk electrode is attributed to an enhanced electron transfer kinetics as a consequence of the array distribution of gold nanoparticles immobilized onto the Cyst SAM. Cyclic voltammetry of homocysteine showed an adsorption-controlled current for scan rates between 500 and 5000 mV s(-1). The hydrodynamic voltammogram constructed for homocysteine allowed the selection of a potential value of +600 mV, where the background current is negligible, for the amperometric detection of the analyte at the Au(coll)-Cyst-CPE. Using a flow rate of 0.8 ml min(-1), the R.S.D. value for i(p) after 25 repetitive injections of homocysteine was of 4.3%, and one single electrode could be used for more than 15 days without any treatment or regeneration procedure of the modified electrode surface. An HPLC method for the separation and quantification of homocysteine and related thiols, using amperometric detection at the modified electrode has been developed. A mobile phase consisting of 2:98% (v/v) acetonitrile:0.05 mol l(-1) buffer solution of pH 2.0, and a detection potential of +0.80 V were selected. Separation with baseline resolution and retention times of 3.00, 3.60, 4.52, 5.71 and 7.79 min were obtained for cysteine, homocysteine, glutathione, penicillamine and N-acetyl-cysteine, respectively. Calibration graphs were constructed for all the separated compounds. Detection limits ranged between 20 nM for cysteine and 120 nM for penicillamine, with a value for homocysteine of 30 nM. These values compare advantageously with those achieved with previously reported HPLC methods using electrochemical, UV, fluorescence and MS detection modes. The developed method was applied to the determination of cysteine and homocysteine serum samples with good results.}, }
@article {pmid18371156, year = {2008}, author = {Wentzel, P and Eriksson, UJ}, title = {Genetic influence on dysmorphogenesis in embryos from different rat strains exposed to ethanol in vivo and in vitro.}, journal = {Alcoholism, clinical and experimental research}, volume = {32}, number = {5}, pages = {874-887}, doi = {10.1111/j.1530-0277.2008.00647.x}, pmid = {18371156}, issn = {1530-0277}, mesh = {Abnormalities, Drug-Induced/*genetics ; Animals ; Embryo, Mammalian/*drug effects ; Ethanol/*pharmacology ; Female ; Morphogenesis/*drug effects ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: The aim was to investigate the susceptibility of embryos from 2 rat strains (U and H) to a 48 hours ethanol exposure in early pregnancy, both in vivo and in vitro.<br><br>METHODS: The embryos were studied on gestational days 9 to 11. We used 1 ethanol dose in vivo (6 g/kg x 2), 3 different ethanol concentrations in vitro (88 mM, 132 mM, 176 mM) and also attempted to diminish the teratogenic effect in vitro by supplying the antioxidant N-acetylcysteine (NAC, 0.5 mM) to the culture medium.<br><br>RESULTS: The U embryos were more damaged by ethanol than the H embryos, both in vivo and in vitro. NAC addition diminished, but failed to completely normalize, the embryonic maldevelopment. Ethanol increased the Bax/Bcl-2 ratio in the U embryos both in vivo and in vitro, but not in the H embryos. Furthermore, ethanol caused increased Caspase-3 immunostaining in U embryos, but not in H embryos. Ethanol exposure in vivo did not alter CuZnSOD and MnSOD mRNA levels in U and H embryos. In vitro, however, the ethanol-exposed U embryos increased their CuZnSOD and MnSOD mRNA levels, whereas the CuZnSOD mRNA was unchanged and MnSOD mRNA decreased in the H embryos, in neither strain did NAC exert any effect. The U embryos increased catalase gene expression in response to ethanol in vivo, but decreased catalase mRNA levels in vitro, changes normalized by NAC. The H embryos did not alter catalase mRNA levels in vivo, but increased gene expression in vitro, with no NAC effect. Ethanol affected the gene expression of the other ROS scavenging enzymes and the developmental genes studied - Bmp-4, Ret, Shh, Pax-6 - similarly in the 2 strains.<br><br>CONCLUSIONS: The findings support a role for genetic predisposition, oxidative stress, and apoptosis in ethanol teratogenicity, and suggest that the teratogenic predisposition of the more susceptible U rats may reside, at least in part, in the regulation of the ROS scavenging enzymes in the U embryos.}, }
@article {pmid18368580, year = {2008}, author = {Low, WK and Sun, L and Tan, MG and Chua, AW and Wang, DY}, title = {L-N-Acetylcysteine protects against radiation-induced apoptosis in a cochlear cell line.}, journal = {Acta oto-laryngologica}, volume = {128}, number = {4}, pages = {440-445}, doi = {10.1080/00016480701762490}, pmid = {18368580}, issn = {0001-6489}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Apoptosis/*drug effects/radiation effects ; Cell Line ; Cochlea/drug effects/metabolism/*pathology ; Flow Cytometry ; Free Radical Scavengers/*therapeutic use ; Hearing Loss, Sensorineural/etiology/pathology/*prevention &amp; control ; In Situ Nick-End Labeling ; Mice ; Mice, Transgenic ; Radiation Injuries, Experimental/metabolism/pathology/*prevention &amp; control ; Reactive Oxygen Species/metabolism ; }, abstract = {CONCLUSION: L-N-Acetylcysteine (L-NAC) significantly reduced reactive oxygen species (ROS) generation and cochlear cell apoptosis after irradiation. The safe and effective use of L-NAC in reducing radiation-induced sensorineural hearing loss (SNHL) should be verified by further in vivo studies.<br><br>OBJECTIVES: Radiation-induced SNHL is a common complication after radiotherapy of head and neck tumours. There is growing evidence to suggest that ROS play an important role in apoptotic cochlear cell death from ototoxicity, resulting in SNHL. The aim of this study was to evaluate the effectiveness of L-NAC, an antioxidant, on radiation-induced apoptosis in cochlear cells.<br><br>MATERIALS AND METHODS: The OC-k3 cochlear cell line was studied after 0 and 20 Gy of gamma-irradiation. Cell viability assay was performed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. Flow cytometry and TUNEL assay were done with and without the addition of 10 mmol/L of L-NAC. Intracellular generation of ROS was detected by 2',7'-dichlorofluorescein diacetate, with comparisons made using fluorescence intensity.<br><br>RESULTS: L-NAC increased the viability of cells after irradiation. Generation of ROS was demonstrated at 1 h post-irradiation and was significantly reduced by L-NAC (p<0.0001). Flow cytometry and TUNEL assay showed cell apoptosis at 72 h post-irradiation, which was diminished by the addition of L-NAC.}, }
@article {pmid18363638, year = {2008}, author = {Healy, CF and McMorrow, C and O'Herlihy, C and O'Connell, PR and Jones, JF}, title = {External anal sphincter fatigue is not improved by N-acetylcysteine in an animal model.}, journal = {Neurogastroenterology and motility}, volume = {20}, number = {6}, pages = {719-724}, doi = {10.1111/j.1365-2982.2008.01101.x}, pmid = {18363638}, issn = {1365-2982}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Anal Canal/*drug effects/*physiology ; Animals ; Antioxidants/pharmacology/therapeutic use ; Fecal Incontinence/physiopathology/prevention &amp; control ; Female ; In Vitro Techniques ; *Models, Animal ; Muscle Fatigue/*drug effects/*physiology ; Rats ; Rats, Wistar ; }, abstract = {Oxidative stress is associated with skeletal muscle fatigue. This study tests the hypotheses that N-acetylcysteine (NAC) reduces fatigue and accelerates recovery of the rat external anal sphincter (EAS). Fifteen female Wistar rats were killed humanely. The EAS was mounted as a ring preparation and electrically stimulated with 50 Hz trains of 200 ms in duration every 4 s for three and a half minutes. Three groups were analysed: a control group (n = 5), a group pretreated with NAC (10(-4) mol L(-1); n = 5) and a group pretreated with NAC (10(-3) mol L(-1); n = 5). A novel fatigue index was formulated and was compared to a conventional method of expressing fatigue. There was no significant difference at concentrations of NAC (10(-4) mol L(-1); P > 0.05). At high concentrations of NAC (10(-3) mol L(-1)) there was a significant depression in peak twitch amplitude before fatigue (P = 0.04). N-acetylcysteine in both concentrations used, did not alter fatigue or recovery of the rat EAS. There was a significant positive correlation between the two methods of expressing fatigue but the conventional method produced a higher fatigue index (22.4% on average). N-acetylcysteine does not ameliorate fatigue or accelerate recovery of the EAS and may not be a useful medical therapy for faecal incontinence.}, }
@article {pmid18363435, year = {2008}, author = {Hafer, K and Iwamoto, KS and Schiestl, RH}, title = {Refinement of the dichlorofluorescein assay for flow cytometric measurement of reactive oxygen species in irradiated and bystander cell populations.}, journal = {Radiation research}, volume = {169}, number = {4}, pages = {460-468}, doi = {10.1667/RR1212.1}, pmid = {18363435}, issn = {0033-7587}, support = {1 U19 AI 67769-01/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/pharmacology ; *Bystander Effect ; CHO Cells ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Radiation ; Flow Cytometry/*methods ; Fluoresceins/*metabolism ; Reactive Oxygen Species/*analysis/*radiation effects ; }, abstract = {Reactive oxygen species (ROS) have been implicated in many ionizing radiation-related phenomena, including bystander effects. The oxidation of 2'7'-dichlorofluorescin (DCFH) to fluorescent 2'7'-dichlorofluorescein (DCF) is commonly used for the detection of radiation-induced ROS. The DCF assay was adapted for efficient, systematic flow cytometry quantification of low-linear energy transfer (LET) gamma-radiation-induced ROS in vitro in Chinese hamster ovary (CHO) cells. This method is optimized for increased sensitivity to radiation-induced ROS and to discriminate against measurement of extracellular ROS. This method can detect a significant increase in ROS in cells exposed to gamma radiation at doses as low as 10 cGy. The antioxidants N-acetyl-cysteine and ascorbic acid (vitamin C) significantly reduced the amount of ROS measured in cells exposed to 5 Gy ionizing radiation. This method was used to measure the intracellular ROS in unirradiated CHO bystander cells co-cultured with low-LET-irradiated cells. No increase in ROS was measured in bystander cell populations co-cultured with the irradiated cells beginning 9 s after radiation exposure.}, }
@article {pmid18363433, year = {2008}, author = {Wambi, C and Sanzari, J and Wan, XS and Nuth, M and Davis, J and Ko, YH and Sayers, CM and Baran, M and Ware, JH and Kennedy, AR}, title = {Dietary antioxidants protect hematopoietic cells and improve animal survival after total-body irradiation.}, journal = {Radiation research}, volume = {169}, number = {4}, pages = {384-396}, pmid = {18363433}, issn = {0033-7587}, support = {T32 CA009677/CA/NCI NIH HHS/United States ; T32 CA009677-07/CA/NCI NIH HHS/United States ; 2T32CA009677/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*administration &amp; dosage ; Bone Marrow Cells/metabolism/radiation effects ; Diet ; Hematopoietic Stem Cells/*radiation effects ; Leukocyte Count ; Male ; Mice ; Mice, Inbred ICR ; Neutrophils/radiation effects ; Radiation-Protective Agents/*administration &amp; dosage ; Transforming Growth Factor beta1/genetics ; *Whole-Body Irradiation ; }, abstract = {The purpose of this study was to determine whether a dietary supplement consisting of L-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve the survival of mice after total-body irradiation. Antioxidants significantly increased the 30-day survival of mice after exposure to a potentially lethal dose of X rays when given prior to or after animal irradiation. Pretreatment of animals with antioxidants resulted in significantly higher total white blood cell and neutrophil counts in peripheral blood at 4 and 24 h after 1 Gy and 8 Gy. Antioxidants were effective in preventing peripheral lymphopenia only after low-dose irradiation. Antioxidant supplementation was also associated with increased bone marrow cell counts after irradiation. Supplementation with antioxidants was associated with increased Bcl2 and decreased Bax, caspase 9 and TGF-beta1 mRNA expression in the bone marrow after irradiation. Maintenance of the antioxidant diet was associated with improved recovery of the bone marrow after sublethal or potentially lethal irradiation. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival, and modulation of apoptosis is implicated as a mechanism for the radioprotection of the hematopoietic system by antioxidants.}, }
@article {pmid18204118, year = {2007}, author = {Brozmanova, M and Plevkova, J and Bartos, V and Plank, L and Javorka, M and Masar, J and Tatar, M}, title = {Oral N-acetylcysteine reverses hyperoxia-related cough suppression in guinea pigs.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {58 Suppl 5}, number = {Pt 1}, pages = {75-84}, pmid = {18204118}, issn = {0867-5910}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Animals ; Antioxidants/*administration &amp; dosage ; Citric Acid ; Cough/etiology/metabolism/physiopathology/*prevention &amp; control ; Disease Models, Animal ; Guinea Pigs ; Hyperoxia/complications/*drug therapy/metabolism/physiopathology ; Lung/*drug effects/innervation/metabolism/physiopathology ; Lung Diseases/*drug therapy/etiology/metabolism/physiopathology ; Male ; Oxidative Stress/*drug effects ; Physical Stimulation ; Reflex/*drug effects ; }, abstract = {Hyperoxia-induced lung injury is well known in animal and human studies. We have previously shown that hyperoxic exposure of guinea pigs is associated with suppression of cough reflex. The goal of this study was to determine the effects of oral N-acetylcysteine (NAC) on hyperoxia-induced oxidative stress in lung tissue directed on cough reflex. The experimental group was pretreated with NAC daily for 7 days and subsequently exposed to 100% O2 for 60 h. Hyperoxic group inhaled 100% O2 only. The control group was exposed to normoxia. Cough was induced by inhalation of citric acid aerosol before and after exposure to oxygen. Cough was also induced by mechanical stimulation of airways in anesthetized animals just after the end of oxygen exposure. Our results showed a significant decrease (P=0.002) in citric acid-induced cough in hyperoxic animals and reversal of that effect in animals pretreated with NAC. In addition, there was a significant interaction between antioxidant therapy and hyperoxia (P=0.005). NAC also reversed the hyperoxia-induced inhibition of mechanically-induced cough. In conclusion, our results indicate that NAC attenuated hyperoxia-induced down-regulation of chemically and mechanically-induced cough.}, }
@article {pmid18362322, year = {2008}, author = {Yamada, M and Kojima, N and Paranjpe, A and Att, W and Aita, H and Jewett, A and Ogawa, T}, title = {N-acetyl cysteine (NAC)-assisted detoxification of PMMA resin.}, journal = {Journal of dental research}, volume = {87}, number = {4}, pages = {372-377}, doi = {10.1177/154405910808700417}, pmid = {18362322}, issn = {0022-0345}, support = {C06RR014529/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Alkaline Phosphatase/antagonists &amp; inhibitors/drug effects ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Apoptosis/drug effects ; Biotransformation ; Calcification, Physiologic/drug effects ; Calcium/analysis ; Cell Survival/drug effects ; Cells, Cultured ; Collagen Type I/antagonists &amp; inhibitors/drug effects ; Dental Pulp/cytology/*drug effects ; Dose-Response Relationship, Drug ; Extracellular Matrix/chemistry/drug effects ; Extracellular Matrix Proteins ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Male ; Odontoblasts/drug effects ; Phosphoproteins/antagonists &amp; inhibitors/drug effects ; Phosphorus/analysis ; Polymethyl Methacrylate/*toxicity ; Protein Precursors/antagonists &amp; inhibitors/drug effects ; Rats ; Rats, Sprague-Dawley ; Sialoglycoproteins ; }, abstract = {Despite its proven cytotoxicity, poly-methyl methacrylate (PMMA) resin is one of the most frequently and extensively used materials in dental practice. This study hypothesized that an anti-oxidant amino acid, N-acetyl cysteine (NAC), has the potential to detoxify this material. Ten percent of the rat dental pulp cells were viable when cultured on the PMMA resin for 24 hours, while over 70% of the cells were viable on the NAC-added resin. Nearly all suppressed alkaline phosphatase activity, matrix mineralizing capability, and odontoblastic gene expression, such as dentin sialoprotein, on the untreated control resin was recovered by NAC in a concentration-dependent manner. A Ca/P ratio of 1.65 was found in the extracellular matrix of cultures on NAC-added resin, while that in the untreated resin culture was 0.70. The addition of NAC to PMMA resin significantly ameliorated its cytotoxicity to the dental pulp cells and restored their odontoblast-like cell phenotype to a biologically significant degree.}, }
@article {pmid18362060, year = {2008}, author = {Ardestani, A and Yazdanparast, R and Nejad, AS}, title = {2-Deoxy-D-ribose-induced oxidative stress causes apoptosis in human monocytic cells: prevention by pyridoxal-5'-phosphate.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {22}, number = {4}, pages = {968-979}, doi = {10.1016/j.tiv.2008.02.010}, pmid = {18362060}, issn = {0887-2333}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line ; Cell Survival/drug effects ; Deoxyribose/*toxicity ; Glutathione/drug effects/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Monocytes/metabolism ; Oxidative Stress/*drug effects ; Pyridoxal Phosphate/*pharmacology ; Reactive Oxygen Species/metabolism ; Vitamin B Complex/*pharmacology ; }, abstract = {Hyperglycemia-induced oxidative stress plays a crucial role in the pathogenesis of diabetic complications. Although some clinical evidences suggest the use of pyridoxal-5'-phosphate (PLP) in diabetes with nephropathy, the exact mechanism of PLP has not been fully understood. In the present study, the effect of PLP on 2-deoxy-D-ribose (dRib)-induced oxidative damages and apoptosis on human monocytic cells (U937) was investigated. U937 cells exposed to dRib (30 mM) exhibited abnormal properties, including loss pf cell viability, overproduction of reactive oxygen species (ROS), glutathione depletion and some biochemical features of apoptosis. Treatment with PLP at two effective concentrations (100 and 250 microM) strongly inhibited ROS production and glutathione depletion in dRib-treated U937 cells. The extent of Lipid peroxidation and protein oxidation was also decreased in the presence of PLP. In addition, PLP suppressed dRib-induced apoptotic criteria such as sub-G1 apoptotic population and annexin-V staining. The use of N-acetylcysteine (NAC), a thiol antioxidant and GSH precursor, prevented the extent of apoptosis. The results demonstrate that dRib induces the generation of ROS leading to dRib-mediated apoptosis which can be attenuated by PLP through antioxidant mechanisms.}, }
@article {pmid18359172, year = {2008}, author = {Park, BC and Park, SH and Paek, SH and Park, SY and Kwak, MK and Choi, HG and Yong, CS and Yoo, BK and Kim, JA}, title = {Chloroquine-induced nitric oxide increase and cell death is dependent on cellular GSH depletion in A172 human glioblastoma cells.}, journal = {Toxicology letters}, volume = {178}, number = {1}, pages = {52-60}, doi = {10.1016/j.toxlet.2008.02.003}, pmid = {18359172}, issn = {0378-4274}, mesh = {Antimalarials/*toxicity ; Antirheumatic Agents/*toxicity ; *Apoptosis ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Chloroquine/*toxicity ; Glioblastoma ; Glutathione/*metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Glutathione Transferase/metabolism ; Humans ; Nitric Oxide/*metabolism ; Nitrites/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {Chloroquine (CQ) is used to treat malaria and a variety of inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis. However, CQ is known to cause cytotoxicity of which mechanism is still uncertain. This study investigated the molecular mechanism responsible for the cell death in CQ-treated A172 human glioblastoma cells. CQ-induced apoptotic cell death of the cells in a time- and concentration-dependent manner. CQ also increased the production of nitric oxide in the cells. However, the pretreatment with aminoguanidine (AG) and N-Omega-nitro-l-arginine methyl ester (NAME), nitric oxide synthase inhibitors, did not block the CQ-induced cell death. In contrast to NO level increase, the level of intracellular reactive oxygen species (ROS) and their extracellular release were transiently and mildly increased by CQ. In addition, CQ depleted cellular GSH content, which was accompanied with time-dependent increase in GSH peroxidase without any significant change in GSH reductase activity. Glutathione (GSH) S-transferase activity was only transiently increased at 15 min treatment with CQ. Furthermore, the CQ-induced cell death was significantly suppressed when intracellular GSH decrease was prevented by the pretreatment with N-acetylcysteine (NAC) or glutathione ethylester (GSH-EE). At the same time, the pretreatment of the cells with NAC and GSH-EE significantly blocked the CQ-induced NO increase, representing that CQ-induced NO increase was resulted from the depletion of GSH. CQ also induced time-dependent increase in Bax level and caspase-3 activity with no change in Bcl-2 level. Overall, these results suggest that CQ-induced NO increase and cell death are dependent on GSH depletion, the cellular redox changes.}, }
@article {pmid18358339, year = {2008}, author = {Wolf, SJ and Heard, K and Sloan, EP and Jagoda, AS and , }, title = {Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose.}, journal = {Journal of emergency nursing}, volume = {34}, number = {2}, pages = {e1-18}, doi = {10.1016/j.jen.2008.02.004}, pmid = {18358339}, issn = {1527-2966}, abstract = {This clinical policy focuses on critical issues concerning the management of patients presenting to the emergency department (ED) with acetaminophen overdose. The subcommittee reviewed the medical literature relevant to the questions posed. The critical questions are: 1. What are the indications for N-acetylcysteine (NAC) in the acetaminophen overdose patient with a known time of acute ingestion who can be risk stratified by th Rumack-Matthew nomogram? 2. What are the indications for NAC in the acetaminophen overdose patient who cannot be risk stratified by the Rumack-Matthew nomogram? Recommendations are provided on the basis of the strength of evidence of the literature. Level A recommendations represent patient management principles that reflect a high degree of clinical certainty; Level B recommendations represent patient management principles that reflect moderate clinical certainty; and Level C recommendations represent other patient management strategies that are based on preliminary, inconclusive, or conflicting evidence, or based on committee consensus. This guideline is intended for physicians working in EDs.}, }
@article {pmid18357790, year = {2007}, author = {Hubs'kyĭ, IuI and Belenichev, IF and Levyts'kyĭ, IeL and Halytsia, VV and Bukhtiiarova, NV and Kovalenko, SI and Babenko, LP and Zadoryna, OV}, title = {[Antioxidant activity of condensed [1,2,4]-triazinone derivatives in nitrosative stress].}, journal = {Ukrains'kyi biokhimichnyi zhurnal (1999)}, volume = {79}, number = {5}, pages = {159-164}, pmid = {18357790}, mesh = {Animals ; Antioxidants/chemistry/*pharmacology ; Brain/*drug effects/enzymology/metabolism ; In Vitro Techniques ; Male ; Models, Chemical ; Molecular Structure ; Nitric Oxide/*chemistry ; Nitric Oxide Donors/chemistry ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; Superoxide Dismutase/metabolism ; Triazines/chemistry/*pharmacology ; }, abstract = {Antioxidant activity of nine [1,2,4]-triazinone derivatives was studied in the work. Our data show that [1,2,4]-triazinone derivatives with benzyl alcohol, propyl alcohol, me-thyl alcohol and tolyl residues in their structure have antioxidant activity in condition of in vitro NO formation. KO-17 compound proved to have the greatest antioxidant activity which exceeded N-acetyl cysteine's one.}, }
@article {pmid18357459, year = {2008}, author = {Usta, U and Inan, M and Erbas, H and Aydogdu, N and Oz Puyan, F and Altaner, S}, title = {Tissue damage in rat ovaries subjected to torsion and detorsion: effects of L-carnitine and N-acetyl cysteine.}, journal = {Pediatric surgery international}, volume = {24}, number = {5}, pages = {567-573}, pmid = {18357459}, issn = {0179-0358}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Carnitine/*therapeutic use ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Female ; Free Radical Scavengers/therapeutic use ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Immunohistochemistry ; Interleukin-6/blood ; Malondialdehyde/metabolism ; Ovarian Diseases/drug therapy/metabolism/*pathology ; Ovary/blood supply/metabolism/pathology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/drug therapy/etiology/*pathology ; Severity of Illness Index ; Torsion Abnormality/complications/drug therapy/*pathology ; Torsion, Mechanical ; Vitamin B Complex/therapeutic use ; }, abstract = {We aimed to evaluate histopathological changes, to detect HIF-1alpha staining intensities and to determine MDA levels in rat ovaries, which were subjected to torsion and detorsion and treated with L -carnitine or N-acetyl cysteine (NAC). Forty-eight prepubertal female Sprague-Dawley rats were divided into five groups (n = 8): 1, control; 2, ischemia; 3, reperfusion; 4, L -carnitine; and 5, NAC groups. In groups 3, 4 and 5, an ischemic period of 3 h was followed by reperfusion for 24 h. In groups 4 and 5, ischemia was performed and either L -carnitine or NAC was infused intraperitoneally 30 min before reperfusion. Ovarian tissues were examined histopathologically; tissue MDA levels and serum IL-6 levels were determined biochemically. HIF-1alpha was applied to all ovaries immunohistochemically. Total tissue damage scores, tissue MDA levels and HIF-1alpha scores, were significantly higher in group 2 (all P < 0.001) than group 4, and group 3 than group 4 (P < 0.001, P = 0.05 and P < 0.001, respectively). They were also significantly higher in group 2 (all P < 0.001) than group 5. When group 3 is compared to group 5, total tissue damage scores and tissue MDA levels were significantly higher in the former (P < 0.01 and P < 0.001, respectively). Serum IL-6 levels were significantly higher in group 2 when compared to groups 1, 4 and 5 (all P < 0.01). The degree of tissue damage of the torsioned ovaries decreased after a reperfusion period of 24 h in the torsioned ovaries. However, ovaries of both L -carnitine and NAC groups showed better recovery than the reperfusion group.}, }
@article {pmid18356775, year = {2007}, author = {Ivanovski, O and Nikolov, IG and Drueke, BT and Massy, AZ}, title = {Atherosclerosis and vascular calcification in uraemia - a new experimental model.}, journal = {Prilozi}, volume = {28}, number = {2}, pages = {11-24}, pmid = {18356775}, issn = {0351-3254}, mesh = {Animals ; Aorta, Thoracic/*pathology ; Atherosclerosis/complications/*pathology/prevention &amp; control ; Calcinosis/*complications/pathology ; Humans ; Kidney Failure, Chronic/complications/pathology ; Mice ; Mice, Knockout ; Uremia/*complications/pathology ; }, abstract = {Cardiovascular disease (CVD) is the most frequent cause of morbidity and mortality in chronic renal failure (CRF) patients. Accelerated calcifying atherosclerosis, medial calcification, and valvular calcification are hallmarks of CVD in the dialysis population. The mechanisms by which uraemia promotes vascular calcification and the relationship between arterial wall calcification and atherosclerosis are poorly understood. We surgically induced CRF in apolipoprotein E knockout (apoE-/-) mice to study a possible acceleration of aortic atherosclerosis, the degree and type of vascular calcification as well as factors involved in the calcification process. Finally we investigated appropriate treatment measures. Atherosclerotic lesions in the thoracic aorta were significantly larger in uraemic apoE-/- mice than in non-uraemic controls. The relative proportion of the calcified area to the total surface area of both atherosclerotic lesions and lesion-free vascular tissue was increased in the aortic root of uraemic apoE-/- mice when compared with controls. The accelerated atherosclerosis was associated with an increase in aortic nitrotyrosine expression, indicating enhanced oxidative stress, and an increase in plaque collagen content, indicating changes in plaque composition. N-acetylcysteine (NAC) treatment slowed the rapid progression of atherosclerotic lesions and reversed the increase in plaque collagen content compared with placebo treatment. NAC-treatment also reduced nitrotyrosine expression in uremic apoE-/- mice whereas the degree of macrophage infiltration was unchanged. Sevelamer treatment delayed not only vascular calcification but also atherosclerotic lesion progression in uraemic apoE-/- mice. These treatment effects also were associated with diminished oxidative stress and were independent of cholesterol lowering. We anticipate that this experimental model will prove to be useful to test other treatment strategies aimed at decreasing the accelerated atherosclerosis and arterial calcification of the uraemic state.}, }
@article {pmid18356557, year = {2008}, author = {Shahid, M and Tauseef, M and Sharma, KK and Fahim, M}, title = {Brief femoral artery ischaemia provides protection against myocardial ischaemia-reperfusion injury in rats: the possible mechanisms.}, journal = {Experimental physiology}, volume = {93}, number = {8}, pages = {954-968}, doi = {10.1113/expphysiol.2007.041442}, pmid = {18356557}, issn = {0958-0670}, mesh = {Animals ; Arginine/pharmacology ; Blood Pressure/physiology ; Creatine Kinase, MB Form/blood ; Diazoxide/pharmacology ; Disease Models, Animal ; Femoral Artery/*physiopathology ; Heart Rate/physiology ; Hindlimb/blood supply ; Ischemia/metabolism/*physiopathology ; Ischemic Preconditioning, Myocardial ; KATP Channels/*metabolism ; L-Lactate Dehydrogenase/blood ; Male ; Myocardial Infarction/pathology ; Myocardial Reperfusion Injury/metabolism/*prevention &amp; control ; Nitric Oxide/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Vasodilator Agents ; }, abstract = {The present study was conducted to examine the role of nitric oxide (NO), mitochondrial ATP-sensitive K(+) channels (mito K(+)(ATP) channels) and reactive oxygen species (ROS) and their interdependence in brief femoral artery ischaemia-induced myocardial preconditioning. To assess myocardial injury, myocardial infarction was induced by occlusion followed by reperfusion of the left anterior descending (LAD) coronary artery in anaesthetized rats and was assessed by triphenyl tetrazolium chloride (TTC) staining. Left ventricular function was assessed by left ventricular end-diastolic pressure (LVEDP) and the maximal rate of rise of left ventricular pressure [LV(dP/dt)(max)]. Serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were determined by colorimetric kits. Remote preconditioning (RPC) was induced by 15 min occlusion of femoral arteries followed by 10 min of reperfusion just before LAD coronary artery occlusion. Brief femoral artery ischaemia led to a 61% reduction in myocardial infarct size, 57% reduction in elevated serum LDH and 72% reduction in elevated CK-MB activities, and a significant improvement in LVEDP and LV(dP/dt)(max) compared with control animals. Pretreatment with 5-hydroxydecanoate (5-HD) or l-NAME or N-acetylcystein (NAC) blocked this protective effect of femoral artery ischaemia. Moreover, infusion of l-arginine or diazoxide before coronary artery occlusion markedly reduced the myocardial infarction and improved the left ventricular function. This effect of l-arginine was found to be abolished by the blockade of mito K(+)(ATP) channels with 5-HD and, similarly, the effect of diazoxide was blocked in the presence of a ROS scavenger, NAC. The results suggest that brief femoral artery ischaemia-induced RPC is mediated by a combination of increased NO synthesis, opening of mito K(+)(ATP) channels and increased ROS production. Moreover, it appears that NO is working upstream and acts via activation of mito K(+)(ATP) channels, which subsequently increases the production of ROS.}, }
@article {pmid18348255, year = {2008}, author = {Demiralay, R and Gürsan, N and Erdem, H}, title = {The effects of erdosteine, N-acetylcysteine, and vitamin E on nicotine-induced apoptosis of hippocampal neural cells.}, journal = {Journal of cellular biochemistry}, volume = {104}, number = {5}, pages = {1740-1746}, doi = {10.1002/jcb.21739}, pmid = {18348255}, issn = {1097-4644}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Hippocampus/*cytology/enzymology ; Neurons/*cytology/drug effects/enzymology ; Nicotine/*pharmacology ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Thioglycolates/*pharmacology ; Thiophenes/*pharmacology ; Tocopherols/*pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {This study investigated the frequency of apoptosis in rat hippocampal neural cells after intraperitoneal nicotine injection, examining the roles of the inflammatory markers myeloperoxidase (MPO) and tumor necrosis factor alpha (TNF-alpha) in nicotine-induced brain damage and the protective effects of three known antioxidant agents, N-acetylcysteine (NAC), erdosteine, and vitamin E. Female Wistar rats were divided into seven groups, each composed of nine rats: 2 negative control groups, 2 positive control groups, one erdosteine-treated group (500 mg/kg), one NAC-treated group (500 mg/kg), and one vitamin E-treated group (500 mg/kg). Nicotine was intraperitoneally injected at a dosage of 0.6 mg/kg for 21 days. Following nicotine injection, the antioxidants were administered orally; treatment was continued until the rats were killed. Apoptosis level in hippocampal neural cells was determined by using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling) method. Staining of cytoplasmic TNF-alpha in hippocampal neural cells and hippocampus MPO activity were evaluated by immunohistochemistry. Nicotine administration had no effect on local TNF-alpha production, or hippocampal MPO activity. The treatments with erdosteine, NAC and vitamin E significantly reduced the rate of nicotine-induced hippocampal neural cell apoptosis. This findings suggest that erdosteine and NAC can be as effective as vitamin E in protecting against nicotine-induced hippocampal neural cell apoptosis.}, }
@article {pmid18343507, year = {2008}, author = {Bergamo, P and Maurano, F and D'Arienzo, R and David, C and Rossi, M}, title = {Association between activation of phase 2 enzymes and down-regulation of dendritic cell maturation by c9,t11-conjugated linoleic acid.}, journal = {Immunology letters}, volume = {117}, number = {2}, pages = {181-190}, doi = {10.1016/j.imlet.2008.02.001}, pmid = {18343507}, issn = {0165-2478}, mesh = {Animals ; Antioxidants/metabolism/*pharmacology ; Celiac Disease/drug therapy/enzymology/immunology ; Cell Differentiation/drug effects ; Cytoprotection/*drug effects/immunology ; Dendritic Cells/*cytology/drug effects/*enzymology ; Disease Models, Animal ; Down-Regulation/drug effects ; Enzyme Activation/drug effects ; Glutamate-Cysteine Ligase/metabolism ; Heme Oxygenase-1/metabolism ; Linoleic Acids, Conjugated/metabolism/*pharmacology ; Lymphocyte Activation/drug effects ; Mice ; NADPH Dehydrogenase/metabolism ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/antagonists &amp; inhibitors ; Subcellular Fractions/chemistry/drug effects/enzymology ; }, abstract = {Antioxidant and cytoprotective enzymes (phase 2) exert protective activity against reactive oxygen species (ROS)-induced injury. We have recently shown how the beneficial effects of conjugated linoleic acid (CLA) in a mouse model of an autoimmune disease are parallel with the activation of phase 2 enzymes. In the present study we found that c9,t11-CLA isomer activates cytoprotective enzymes and down-regulates LPS- or gliadin-induced maturation in dendritic cells (DCs) obtained from a murine model of celiac disease. As expected, the enhancement of LPS-induced maturation (increased NFkappaB p65 nuclear translocation, CD86 expression and decreased CD11c+ cell number) was exacerbated by specific glutathione (GSH) inhibitor (buthionine sulphoximine; BSO). Conversely, the down-regulation of DC maturation by antioxidant N-acetylcysteine (NAC) was associated with the marked increase of intracellular thiol concentration. c9,t11-CLA activation of phase 2 enzymes in mouse DCs was observed first. Next, we found that the significant reduction of LPS- and gliadin-induced DC maturation in cultures pre-treated with c9,t11-CLA improved cellular redox status (decreased ROS and higher antioxidant defenses). Finally, the process of DC maturation triggered by gliadin, in contrast with that exhibited by LPS, was not associated with enhanced NFkappaB nuclear translocation and pro-inflammatory cytokines synthesis. These results demonstrate that c9,t11-CLA renders DCs more resistant to gliadin- or LPS-induced maturation, thus indicating that a cytoprotective mechanism elicited by c9,t11-CLA may modulate DC responsiveness.}, }
@article {pmid18338302, year = {2008}, author = {Mazer, M and Perrone, J}, title = {Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {4}, number = {1}, pages = {2-6}, pmid = {18338302}, issn = {1556-9039}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/pharmacology ; Analgesics, Non-Narcotic/*toxicity ; Female ; Humans ; Kidney/*drug effects ; Liver/drug effects ; Middle Aged ; }, abstract = {UNLABELLED: Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1-2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the role of prostaglandin synthetase and N-deacetylase enzymes. Paradoxically, glutathione is considered an important element in the detoxification of acetaminophen and its metabolites; however, its conjugates have been implicated in the formation of nephrotoxic compounds. Acetaminophen-induced renal failure becomes evident after hepatotoxicity in most cases, but can be differentiated from the hepatorenal syndrome, which may complicate fulminant hepatic failure. The role of N-acetylcysteine therapy in the setting of acetaminophen-induced renal failure is unclear. This review will focus on the pathophysiology, clinical features, and management of renal insufficiency in the setting of acute acetaminophen toxicity.<br><br>CASE: A 47-year-old female was found lethargic at home and brought by ambulance to an emergency department. History from family members suggested an inadvertent acetaminophen overdose, and she had last been seen a few hours earlier. She reportedly ingested 18 tablets of 500 mg acetaminophen (APAP) over the previous two days because she had run out of her prescription pain medication. Her past medical history was significant for fibromyalgia, arthritis, and a prior gastric bypass procedure. She had no history of alcohol abuse or renal insufficiency. She was lethargic. Vital signs: BP 128/96 mmHg, pulse 112/min, respirations 32/min; pulse oximetry 98% on 2L nasal cannula oxygen. Laboratory studies: BUN 9 mg/dL, creatinine 0.9 mg/dl, acetaminophen 12 mcg/mL, AST 5409 u/L and ALT 1085 u/L. A urinalysis was negative for blood with trace protein and ketones. A urine drug screen was positive for marijuana and opioid metabolites. At the initial hospital, she was treated with N-acetylcysteine (NAC) orally. Subsequently, she developed fulminant hepatic failure with elevated transaminases, hypoglycemia, and coagulopathy (Tables 1A and 1B). She was transferred to our facility two days after initial presentation for liver transplant evaluation. At that time, her APAP level was 2.0 mg/L. Oral NAC therapy was continued after transfer. The patient's liver function subsequently improved and she ultimately did not require transplantation. She did develop acute renal failure during the course of her hospitalization, with a creatinine of 2.3 mg/dL on transfer, which increased to 8.1 mg/dL nine days later (approximately 11-13 days post-ingestion). Medical toxicology was consulted by the intensive care unit team to address whether this was acetaminophen-induced renal failure and if there was a role for NAC in this setting.}, }
@article {pmid18337831, year = {2008}, author = {Zhang, Q and Chang, Q and Cox, RA and Gong, X and Gould, LJ}, title = {Hyperbaric oxygen attenuates apoptosis and decreases inflammation in an ischemic wound model.}, journal = {The Journal of investigative dermatology}, volume = {128}, number = {8}, pages = {2102-2112}, doi = {10.1038/jid.2008.53}, pmid = {18337831}, issn = {1523-1747}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Apoptosis/*physiology ; Caspase 3/genetics/metabolism ; Cyclooxygenase 2/metabolism ; Free Radical Scavengers/pharmacology/therapeutic use ; *Hyperbaric Oxygenation ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism ; Inflammation/*physiopathology/therapy ; Ischemia/metabolism/*physiopathology/therapy ; Male ; Membrane Proteins/genetics/metabolism ; Mitochondrial Proteins ; Models, Animal ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/physiology ; Tumor Suppressor Protein p53/genetics/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Wound Healing/drug effects/physiology ; Wounds and Injuries/metabolism/*physiopathology/therapy ; bcl-2-Associated X Protein/metabolism ; }, abstract = {The molecular mechanisms whereby hyperbaric oxygen (HBO) improves ischemic wound healing remain elusive. In this study, a rat model of wound ischemia was used to test the hypothesis that HBO enhances wound healing by modulating hypoxia-inducible factor-1alpha (HIF-1alpha) signaling. Male Sprague-Dawley rats underwent creation of a previously validated ischemic flap. Three groups underwent daily treatment: HBO (90 minutes, 2.4 atm); systemic administration of the free radical scavenger, N-acetylcysteine (NAC 150 mg kg(-1) intraperitoneal); control (neither HBO nor NAC). HBO treatment improved healing of the ischemic wounds. Analysis of ischemic wound tissue extracts demonstrated significantly reduced expression of HIF-1alpha, p53, and BNip3. Additionally, HBO increased expression of Bcl-2 while decreasing cleaved caspase-3. DNA fragmentation was abolished and the number of TUNEL-positive cells was reduced compared to the other groups. Vascular endothelial growth factor, cyclooxygenase-2, and neutrophil infiltration were reduced in ischemic wounds treated with HBO. These results indicate that HBO improves ischemic wound healing by downregulation of HIF-1alpha and subsequent target gene expression with attenuation of cell apoptosis and reduction of inflammation.}, }
@article {pmid18332044, year = {2008}, author = {Joseph, P and He, Q and Umbright, C}, title = {Heme-oxygenase 1 gene expression is a marker for hexavalent chromium-induced stress and toxicity in human dermal fibroblasts.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {103}, number = {2}, pages = {325-334}, doi = {10.1093/toxsci/kfn048}, pmid = {18332044}, issn = {1096-0929}, mesh = {Acetylcysteine/pharmacology ; Antimetabolites/pharmacology ; Biomarkers/*metabolism ; Buthionine Sulfoximine/pharmacology ; Carcinogens, Environmental/*toxicity ; Chromium/*toxicity ; Dactinomycin/pharmacology ; Enzyme Inhibitors/pharmacology ; Fibroblasts/drug effects/metabolism/pathology ; Gene Expression Regulation, Enzymologic/*drug effects ; Glutathione/deficiency/metabolism ; Heme Oxygenase-1/antagonists &amp; inhibitors/genetics/*metabolism ; Humans ; Microarray Analysis ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Oxidative Stress/drug effects ; Skin/*drug effects/metabolism/pathology ; }, abstract = {Several adverse health effects, including irritant and allergic contact dermatitis, have been reported among workers who are occupationally exposed to chromium-containing compounds. Human dermal fibroblasts were used as an in vitro experimental model to study the potential mechanisms underlying hexavalent chromium [Cr(VI)]-induced dermal toxicity. Exposure of the fibroblasts to 5 microM Cr(VI) (LC50 for a 24-h exposure period) followed by microarray analysis of the gene expression profile revealed overexpression of several genes including those involved in cell stress response. The cellular level of glutathione, the major antioxidant molecule present in the cells, was significantly lower in the Cr(VI)-treated cells compared to the corresponding control cells. The Cr(VI)-induced overexpression of heme-oxygenase 1 messenger RNA (HO-1) in the fibroblasts was significantly blocked by actinomycin D and by inhibitors of MAP kinase pathways. The Cr(VI)-induced cytotoxicity and the overexpression of the HO-1 gene were dependent on the glutathione level of the fibroblasts. Buthionine sulfoximine-mediated GSH depletion resulted in enhanced Cr(VI) cytotoxicity and further overexpression of the HO-1 gene. On the other hand, elevated cellular levels of glutathione resulting from pretreating the cells with GSH significantly protected the cells against the Cr(VI)-induced cytotoxicity and blocked the HO-1 gene's overexpression. Pretreating the fibroblasts with N-acetyl cysteine also significantly reduced the Cr(VI)-induced cytotoxicity and overexpression of the HO-1 gene. In conclusion, depletion of GSH leading to cellular stress is a major mechanism responsible for Cr(VI)-induced cytotoxicity. Furthermore, the expression level of HO-1 gene is a marker for Cr(VI)-induced cell stress leading to cytotoxicity.}, }
@article {pmid18329204, year = {2008}, author = {Hamernik, RP and Qiu, W and Davis, B}, title = {The effectiveness of N-acetyl-L-cysteine (L-NAC) in the prevention of severe noise-induced hearing loss.}, journal = {Hearing research}, volume = {239}, number = {1-2}, pages = {99-106}, doi = {10.1016/j.heares.2008.02.001}, pmid = {18329204}, issn = {0378-5955}, support = {1-R01-OH02317/OH/NIOSH CDC HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Acoustics ; Animals ; Antioxidants/pharmacology ; Auditory Threshold/drug effects ; Chinchilla ; Cochlea/drug effects ; Evoked Potentials, Auditory ; Free Radical Scavengers/pharmacology ; Hair Cells, Auditory/drug effects ; Hearing Loss, Noise-Induced/*prevention &amp; control ; Male ; Models, Statistical ; Noise ; Normal Distribution ; }, abstract = {Three groups of chinchillas were exposed to a nonGaussian continuous broadband noise at an Leq=10 5dB SPL, 8h/d for 5d. One group (N=6) received only the noise. A second group (N=6) received the noise and was additionally treated with L-NAC (325 mg/kg, i.p.). Treatment was administered twice daily for 2d prior to exposure and for 2d following the exposure. During exposure the animals received the L-NAC just prior to and immediately after each daily exposure. The third group (N=4) was exposed to the noise and received saline injections on the same schedule as the L-NAC treated animals. Auditory evoked potential recordings from the inferior colliculus were used to estimate pure tone thresholds and surface preparations of the organ of Corti quantified the sensory cell population. In all three groups PTS exceeded 50 dB at 2.0k Hz and above with severe sensory cell loss in the basal half of the cochlea. There was no statistically significant difference among the three groups in all measures of noise-induced trauma. Treatment with L-NAC did not reduce the trauma produced by a high-level, long duration, broadband noise exposure.}, }
@article {pmid18325696, year = {2008}, author = {Kaminskyy, V and Kulachkovskyy, O and Stoika, R}, title = {A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids.}, journal = {Toxicology letters}, volume = {177}, number = {3}, pages = {168-181}, doi = {10.1016/j.toxlet.2008.01.009}, pmid = {18325696}, issn = {0378-4274}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Benzophenanthridines/*pharmacology ; Cells, Cultured ; Chelidonium/chemistry ; Cyclosporine/pharmacology ; DNA Damage ; Dose-Response Relationship, Drug ; Humans ; Isoquinolines/*pharmacology ; Mitochondria/*drug effects/physiology ; Proto-Oncogene Proteins c-bcl-2/analysis ; Reactive Oxygen Species ; }, abstract = {Sanguinarine, chelerythrine and chelidonine possess prominent apoptotic effects towards cancer cells. In this study, we found that sanguinarine and chelerythrine induce apoptosis in human CEM T-leukemia cells, and that is accompanied by an early increase in cytosolic cytochrome c that precedes caspases-8, -9 and -3 processing. During apoptosis induction by sanguinarine and chelerythrine, reactive oxygen species (ROS) was rapidly generated and DeltaPsi(mt) dissipated, while Bax, Bcl-2 and Bcl-X((L/S)) proteins' content in the mitochondrial fraction did not change significantly. Caspase-3 activation and DNA fragmentation were considerably inhibited by N-acetyl-cysteine (NAC). Chelidonine induced only a slight release of cytochrome c (12h), parallel to caspase-3 activation. Effect of sanguinarine or chelerythrine towards mitochondria was confirmed by marked changes in morphology of this organelle (3h), while chelidonine did not affect mitochondria intactness. Sanguinarine or chelerythrine also caused an intensive DNA damage in cells in 1h, however a massive increase in number of such impaired cells occurred in 6h, while chelidonine induced intensive DNA damage in 15-20% cells only in 24h. Thus, our results demonstrated that rapid cytochrome c release in CEM T-leukemia cells exposed to sanguinarine or chelerythrine was not accompanied by changes in Bax, Bcl-2 and Bcl-X((L/S)) proteins in the mitochondrial fraction, and preceded activation of the initiator caspase-8.}, }
@article {pmid18325578, year = {2008}, author = {Kim, HJ and Barajas, B and Wang, M and Nel, AE}, title = {Nrf2 activation by sulforaphane restores the age-related decrease of T(H)1 immunity: role of dendritic cells.}, journal = {The Journal of allergy and clinical immunology}, volume = {121}, number = {5}, pages = {1255-1261.e7}, pmid = {18325578}, issn = {1097-6825}, support = {R01 AG014992/AG/NIA NIH HHS/United States ; U19 AI070453/AI/NIAID NIH HHS/United States ; P30 AG028748/AG/NIA NIH HHS/United States ; 5P30 AG028748/AG/NIA NIH HHS/United States ; R01 AG14992/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adoptive Transfer ; Aging/*physiology ; Animals ; Dendritic Cells/cytology/*immunology ; Dermatitis, Contact/immunology ; Female ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Interferon-gamma/metabolism ; Interleukin-4/metabolism ; Isothiocyanates ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/agonists/*metabolism ; Oxidation-Reduction ; RNA, Messenger/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Sulfoxides ; Th1 Cells/cytology/*immunology ; Thiocyanates/*pharmacology ; }, abstract = {BACKGROUND: The decrease in cellular immunity with aging is of considerable public health importance. Recent studies suggest that the redox equilibrium of dendritic cells (DCs) is a key factor in maintaining protective cellular immunity and that a disturbance of this homeostatic mechanism could contribute to immune senescence.<br><br>OBJECTIVES: We sought (1) to elucidate the role of DC redox equilibrium in the decrease of contact hypersensitivity (CHS) and T(H)1 immunity during aging and (2) to determine how restoration of glutathione (GSH) levels by the Nrf2-mediated antioxidant defense pathway affects this decrease.<br><br>METHODS: We assessed the effect of Nrf2 deficiency and boosting of GSH levels by the Nrf2 agonist sulforaphane or the thiol precursor N-acetyl cysteine (NAC) on the CHS response to contact antigens in old mice. We studied the effect of SFN and NAC on restoring T(H)1 immunity by treating DCs ex vivo before adoptive transfer and in vivo challenge.<br><br>RESULTS: Aging was associated with a decreased CHS response that was accentuated by Nrf2 deficiency. Systemic SFN treatment reversed this decrease through Nrf2-mediated antioxidant enzyme expression and GSH synthesis. Adoptive transfer of DCs from old animals induced a weakened CHS response in recipient animals. Treatment of DCs from old animals with SFN or NAC ex vivo restored the in vivo challenge response.<br><br>CONCLUSION: SFN and NAC upregulate T(H)1 immunity in aging through a restoration of redox equilibrium.}, }
@article {pmid18324519, year = {2008}, author = {Xing, YX and Li, P and Miao, YX and Du, W and Wang, CB}, title = {Involvement of ROS/ASMase/JNK signalling pathway in inhibiting UVA-induced apoptosis of HaCaT cells by polypeptide from Chlamys farreri.}, journal = {Free radical research}, volume = {42}, number = {1}, pages = {12-19}, doi = {10.1080/10715760701762415}, pmid = {18324519}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Antioxidants/isolation &amp; purification/*pharmacology ; Apoptosis/*drug effects ; Cell Line ; Desipramine/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation ; Free Radical Scavengers/pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Keratinocytes/*drug effects/enzymology/metabolism/pathology/radiation effects ; *Pectinidae/chemistry ; Peptides/isolation &amp; purification/*pharmacology ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/radiation effects ; Sphingomyelin Phosphodiesterase/antagonists &amp; inhibitors/*metabolism ; *Ultraviolet Rays ; }, abstract = {Polypeptide from Chlamys farreri (PCF), a novel marine active material isolated from gonochoric Chinese scallop C. farreri, has potential antioxidant activity and protective effect against ultraviolet (UV) irradiation. The aim was to investigate whether PCF protects HaCaT cells from apoptosis induced by UVA and explore related molecular mechanisms. The results showed that PCF significantly prevented UVA-induced apoptosis of HaCaT cells. PCF not only strongly reduced the intracellular reactive oxygen species (ROS) production, but also diminished expression of acid sphingomyelinase (ASMase) and phosphorylated JNK in HaCaT cells radiated by UVA in a dose-dependent manner. Pre-treatment with ROS scavenger NAC, ASMase inhibitor desipramine or JNK inhibitor SP600125 was found to effectively prohibit UVA-induced apoptosis and desipramine markedly blocked phosphorylation of JNK. So it is concluded that PCF obviously protects HaCaT cells from apoptosis induced by UVA and protective effects may attribute to decreasing intracellular ROS level and blocking ASMase/JNK apoptotic signalling pathway.}, }
@article {pmid18311734, year = {2008}, author = {Schetz, M and Bove, T and Morelli, A and Mankad, S and Ronco, C and Kellum, JA}, title = {Prevention of cardiac surgery-associated acute kidney injury.}, journal = {The International journal of artificial organs}, volume = {31}, number = {2}, pages = {179-189}, doi = {10.1177/039139880803100211}, pmid = {18311734}, issn = {0391-3988}, mesh = {Acute Kidney Injury/epidemiology/etiology/physiopathology/*prevention &amp; control ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Aortic Diseases/epidemiology ; Atherosclerosis/epidemiology ; Blood Volume ; Cardiac Surgical Procedures/*adverse effects ; Cardiopulmonary Bypass ; Hemodynamics ; Humans ; Kidney/drug effects/physiopathology ; }, abstract = {Numerous strategies have been evaluated to prevent early CSA-AKI. Although correction of hemodynamic problems is paramount, there are no clinical studies that compare different hemodynamic management or monitoring strategies with regard to their effect on kidney function. Pharmacologic strategies including diuretics, different classes of vasodilators and drugs with anti-inflammatory effects such as N-acetyl-cysteine, do not appear to be effective. Most of the studies are underpowered and use physiological rather than clinical endpoints. Further trials are warranted with fenoldopam and nesiritide (rhBNP). Observational and underpowered randomized studies show beneficial renal effects of off-pump technique and avoidance of aortic manipulation. There is very limited evidence for preoperative fluid loading and preemptive RRT. Potentially nephrotoxic agents should be used with caution in patients at risk of CSA-AKI. Tranexamic acid or aminocaproic acid should be preferred over aprotinin. No pharmacologic intervention has been adequately tested in the prevention of late CSA-AKI. A singlecenter study, including a predominance of patients after cardiac surgery, showed a decrease of kidney injury with tight glycemic control.}, }
@article {pmid18311068, year = {2008}, author = {Khanna, G and Diwan, V and Singh, M and Singh, N and Jaggi, AS}, title = {Reduction of ischemic, pharmacological and remote preconditioning effects by an antioxidant N-acetyl cysteine pretreatment in isolated rat heart.}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {128}, number = {3}, pages = {469-477}, doi = {10.1248/yakushi.128.469}, pmid = {18311068}, issn = {0031-6903}, mesh = {Acetylcysteine/*pharmacology ; Angiotensin II ; Animals ; Cardiotonic Agents/antagonists &amp; inhibitors/*pharmacology ; Female ; Free Radical Scavengers/*pharmacology ; Hydrogen Peroxide ; In Vitro Techniques ; *Ischemic Preconditioning ; Male ; Myocardial Infarction/prevention &amp; control ; Oxidation-Reduction/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/antagonists &amp; inhibitors/*pharmacology ; }, abstract = {The present study was designed to investigate the possible role of free radicals in cardioprotective effects of ischemic, pharmacological and remote preconditioning. Isolated rat heart was perfused on Langendorff apparatus with Kreb's Henseleit solution and subjected to 30 min global ischemia followed by 120 min reperfusion. To assess myocardial injury, coronary effluent was analyzed for lactate dehydrogenase and creatine kinase activity. Myocardial infarct size was estimated using triphenyl tetrazolium chloride staining. Ischemic preconditioning, pharmacological preconditioning (angiotensin II; H2O2), remote aortic preconditioning markedly attenuated I/R induced increase in lactate dehydrogenase and creatine kinase release and myocardial infarct size. Administration of N-Acetyl Cysteine (NAC), in vitro, during ischemic and pharmacological, and in vivo during remote preconditioning attenuated the cardioprotective effects of preconditioning. On the basis of these results, it may be concluded that sub threshold generation of Reactive Oxygen Species (ROS) may activate redox signaling which may be responsible for preconditioning induced cardioprotection.}, }
@article {pmid18306297, year = {2008}, author = {Lanté, F and Meunier, J and Guiramand, J and De Jesus Ferreira, MC and Cambonie, G and Aimar, R and Cohen-Solal, C and Maurice, T and Vignes, M and Barbanel, G}, title = {Late N-acetylcysteine treatment prevents the deficits induced in the offspring of dams exposed to an immune stress during gestation.}, journal = {Hippocampus}, volume = {18}, number = {6}, pages = {602-609}, doi = {10.1002/hipo.20421}, pmid = {18306297}, issn = {1098-1063}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology/therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/pharmacology/therapeutic use ; Drug Administration Schedule ; Drug Evaluation, Preclinical ; Endotoxemia/*drug therapy/immunology/physiopathology ; Female ; Glutathione/analysis/deficiency ; Hippocampus/chemistry/embryology/pathology ; Lipopolysaccharides/toxicity ; *Long-Term Potentiation/drug effects/physiology ; Male ; *Maternal Exposure ; Maze Learning/drug effects/physiology ; Memory Disorders/etiology/physiopathology/*prevention &amp; control ; Neuroprotective Agents/*administration &amp; dosage/pharmacology/therapeutic use ; Pregnancy ; Pregnancy Complications/*drug therapy/immunology ; Prenatal Exposure Delayed Effects/physiopathology/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; alpha-Tocopherol/administration &amp; dosage/analysis/therapeutic use ; }, abstract = {Prenatal infection is a major stressful experience leading to enhanced susceptibility for mental illnesses in humans. We recently reported in rats, that oxidative stress and glutathione (GSH) shortage occurred in fetal male brain after lipopolysaccharide (LPS) to the dams and that these responses might be involved in the neurodevelopmental deficits observed in adolescent offspring. Furthermore, pretreatment with N-acetylcysteine (NAC) before LPS avoided both delayed synaptic plasticity and mnesic performance deficits. Since NAC is one of the few medications permitted in pregnant women, this study evaluated the ability of NAC to serve as a protective therapy even after the LPS challenge. Pregnant rats received a single ip injection of E. coli LPS, two days before delivery, and were given NAC in their tap water after the LPS. GSH was evaluated at the time of its expected drop in the hippocampus of male fetuses, whereas long-term potentiation (LTP) in the CA1 area of the hippocampus and spatial memory in the water-maze were recorded in 28-day-old male offspring. Post-treatment with NAC, four hours after the LPS challenge fully prevented the drop in the GSH hippocampal content. LTP, as well as spatial learning were completely protected. NAC administration at delivery also partially restored the LTP whereas post-treatment two days later was inefficient. Another set of dams were supplemented with alpha-tocopherol prior to LPS exposure, enhancing the alpha-tocopherol levels in fetal hippocampus. This treatment did not prevent the LPS-induced synaptic plasticity impairment. These results point to fetal hippocampal GSH as a major target of the detrimental effects of in utero LPS challenge. The therapeutic window of NAC extends up to birth, suggesting that this drug might be clinically useful even after an immuno-inflammatory episode.}, }
@article {pmid18306112, year = {2008}, author = {Krakauer, T and Buckley, M}, title = {The potency of anti-oxidants in attenuating superantigen-induced proinflammatory cytokines correlates with inactivation of NF-kappaB.}, journal = {Immunopharmacology and immunotoxicology}, volume = {30}, number = {1}, pages = {163-179}, doi = {10.1080/08923970701692577}, pmid = {18306112}, issn = {1532-2513}, mesh = {Acetylcysteine/*pharmacology ; Antigens, CD/metabolism ; Antigens, Differentiation, T-Lymphocyte/metabolism ; Antioxidants/*pharmacology ; Cells, Cultured ; Cytokines/*antagonists &amp; inhibitors ; Enterotoxins/immunology ; Glutathione/metabolism ; Humans ; Interleukin-2 Receptor alpha Subunit/antagonists &amp; inhibitors ; Lectins, C-Type ; Lymphocyte Activation/drug effects ; Monocytes/drug effects/immunology ; NF-kappa B/*antagonists &amp; inhibitors ; Pyrrolidines/*pharmacology ; Superantigens/immunology ; T-Lymphocytes/*drug effects/immunology ; Thiocarbamates/*pharmacology ; }, abstract = {Excessive release of proinflammatory cytokines and chemokines mediates the toxic effects of superantigenic staphylococcal exotoxins (SE). We evaluated the potency of two anti-oxidants, N-acetyl-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) in inhibiting the staphylococcal enterotoxin B and staphylococcal toxic shock syndrome-1-induced activation of human peripheral blood mononuclear cells (PBMC). Both NAC and PDTC dose-dependently inhibited SE-stimulated T-cell proliferation (by 98%), production of cytokines and chemokines by PBMC and expression of SE-induced cell surface activation markers. The potency of both NAC and PDTC corresponded to their ability to inhibit NF-kappaB activation. Our results suggest that anti-oxidants might be useful to mitigate the pathogenic effects of SE by blocking transcriptional signaling activated by superantigens.}, }
@article {pmid18305405, year = {2008}, author = {Lee, KB and Lee, JS and Park, JW and Huh, TL and Lee, YM}, title = {Low energy proton beam induces tumor cell apoptosis through reactive oxygen species and activation of caspases.}, journal = {Experimental &amp; molecular medicine}, volume = {40}, number = {1}, pages = {118-129}, pmid = {18305405}, issn = {1226-3613}, mesh = {Apoptosis/*radiation effects ; Caspases/*metabolism ; Cell Line, Tumor ; DNA Fragmentation/radiation effects ; Dose-Response Relationship, Radiation ; Enzyme Activation/radiation effects ; Flow Cytometry ; Gamma Rays ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Neoplasms/*enzymology/*pathology ; *Protons ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Proton beam is useful to target tumor tissue sparing normal cells by allowing precise dose only into tumor cells. However, the cellular and molecular mechanisms by which proton beam induces tumor cell death are still undefined. We irradiated three different tumor cells (LLC, HepG2, and Molt-4) with low energy proton beam (35 MeV) with spread out Bragg peak (SOBP) in vitro, and investigated cell death by MTT or CCK-8 assay at 24 h after irradiation. LLC and HepG2 cells were sensitive to proton beam at over 10 Gy to induce apoptosis whereas Molt-4 showed rather low sensitivity. Relative biological effectiveness (RBE) values for the death rate relative to gamma-ray were ranged from 1.1 to 2.3 in LLC and HepG2 but from 0.3 to 0.7 in Molt-4 at 11 d after irradiation by colony formation assay. The typical apoptotic nuclear DNA morphological pattern was observed by staining with 4'-6-diamidino-2-phenylindole (DAPI). Tiny fragmented DNA was observed in HepG2 but not in Molt-4 by the treatment of proton in apoptotic DNA fragment assay. By FACS analysis after stained with FITC-Annexin-V, early as well as median apoptotic fractions were clearly increased by proton treatment. Proton beam-irradiated tumor cells induced a cleavage of poly (ADP-ribose) polymerase-1 (PARP-1) and procaspases-3 and -9. Activity of caspases was highly enhanced after proton beam irradiation. Reactive oxygen species (ROS) were significantly increased and N-acetyl cysteine pretreatment restored the apoptotic cell death induced by proton beam. Furthermore, p38 and JNK but not ERK were activated by proton and dominant negative mutants of p38 and JNK revived proton-induced apoptosis, suggesting that p38 and JNK pathway may be activated through ROS to activate apoptosis. In conclusion, our data clearly showed that single treatment of low energy proton beam with SOBP increased ROS and induced cell death of solid tumor cells (LLC and HepG2) in an apoptotic cell death program by the induction of caspases activities.}, }
@article {pmid18304734, year = {2008}, author = {Di-Pietro, PB and Dias, ML and Scaini, G and Burigo, M and Constantino, L and Machado, RA and Dal-Pizzol, F and Streck, EL}, title = {Inhibition of brain creatine kinase activity after renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration.}, journal = {Neuroscience letters}, volume = {434}, number = {1}, pages = {139-143}, doi = {10.1016/j.neulet.2008.01.051}, pmid = {18304734}, issn = {0304-3940}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Brain/*drug effects/enzymology/physiopathology ; Brain Diseases, Metabolic/*drug therapy/enzymology/physiopathology ; Creatine Kinase/*antagonists &amp; inhibitors/metabolism ; Deferoxamine/pharmacology/therapeutic use ; Down-Regulation/drug effects/physiology ; Ischemia/complications ; Kidney Diseases/complications ; Male ; Nerve Degeneration/drug therapy/enzymology/physiopathology ; Oxidative Stress/*drug effects/physiology ; Rats ; Rats, Wistar ; Subcellular Fractions ; Time Factors ; Treatment Outcome ; Uremia/*drug therapy/enzymology/physiopathology ; }, abstract = {Encephalopathy may accompany acute or chronic renal failure, and the mechanisms responsible for neurological complications in patients with renal failure are poorly known. Considering that creatine kinase (CK) is important for brain energy homeostasis and is inhibited by free radicals, and that oxidative stress is probably involved in the pathogenesis of uremic encephalopathy, we measured CK activity (hippocampus, striatum, cerebellum, cerebral cortex and prefrontal cortex) in brain if rats submitted to renal ischemia and the effect of administration of antioxidants (N-acetylcysteine, NAC and deferoxamine, DFX) on this enzyme. We verified that CK activity was not altered in cerebellum and striatum of rats. CK activity was inhibited in prefrontal cortex and hippocampus of rats 12h after renal ischemia. The treatment with antioxidants prevented such effect. Cerebral cortex was also affected, but in this area CK activity was inhibited 6 and 12h after renal ischemia. Moreover, only NAC or NAC plus DFX were able to prevent the inhibition on the enzyme. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity after renal failure may be associated to neuronal loss and may be involved in the pathogenesis of uremic encephalopathy.}, }
@article {pmid18303122, year = {2008}, author = {Takahashi, K and Yamaguchi, S and Shimoyama, T and Seki, H and Miyokawa, K and Katsuta, H and Tanaka, T and Yoshimoto, K and Ohno, H and Nagamatsu, S and Ishida, H}, title = {JNK- and IkappaB-dependent pathways regulate MCP-1 but not adiponectin release from artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate in vitro.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {294}, number = {5}, pages = {E898-909}, doi = {10.1152/ajpendo.00131.2007}, pmid = {18303122}, issn = {0193-1849}, mesh = {3T3 Cells ; Adipocytes/drug effects/*metabolism/ultrastructure ; Adiponectin/*metabolism ; Animals ; Blotting, Western ; Cell Size/drug effects ; Chemokine CCL2/*metabolism ; Hydrogen Peroxide/metabolism ; I-kappa B Kinase/*physiology ; Interleukin-1beta/pharmacology ; JNK Mitogen-Activated Protein Kinases/*physiology ; Mice ; PPAR gamma/metabolism/physiology ; Palmitates/*pharmacology ; Signal Transduction/*physiology ; Triglycerides/biosynthesis ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Obese conditions increase the expression of adipocytokine monocyte chemoattractant protein-1 (MCP-1) in adipose tissue as well as MCP-1 plasma levels. To investigate the mechanism behind increased MCP-1, we used a model in which 3T3-L1 adipocytes were artificially hypertrophied by preloading with palmitate in vitro. As observed in obesity, under our model conditions, palmitate-preloaded cells showed significantly increased oxidative stress and increased MCP-1 expression relative to control cells. This increased MCP-1 expression was enhanced by adding exogenous tumor necrosis factor-alpha (TNF-alpha; 17.8-fold vs. control cells, P < 0.01) rather than interleukin-1beta (IL-1beta; 2.6-fold vs. control cells, P < 0.01). However, endogenous TNF-alpha and IL-1beta release was not affected in hypertrophied cells, suggesting that these endogenous cytokines do not mediate hypertrophy-induced increase in MCP-1. MCP-1 secretion from hypertrophied cells was significantly decreased by treatment with antioxidant N-acetyl-cysteine, JNK inhibitors SP600125 and JIP-1 peptide, and IkappaB phosphorylation inhibitors BAY 11-7085 and BMS-345541 (P < 0.01). MCP-1 secretion was not affected by peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonists assayed. Adiponectin, another adipocytokine studied in parallel, also showed increased release in hypertrophy relative to control cells. But in contrast to MCP-1, adiponectin release was significantly suppressed by both exogenous TNF-alpha and IL-1beta as well as by PPARgamma antagonists bisphenol A diglycidyl ether and T0070907 (P < 0.01). JNK inhibitors and IkappaB phosphorylation inhibitors showed no significant effect on adiponectin. We conclude that adipocyte hypertrophy through palmitate loading causes oxidative stress, which in turn increases MCP-1 expression and secretion through JNK and IkappaB signaling. In contrast, the parallel increase in adiponectin expression appears to be related to the PPARgamma ligand properties of palmitate.}, }
@article {pmid18302967, year = {2008}, author = {Voghel, G and Thorin-Trescases, N and Farhat, N and Mamarbachi, AM and Villeneuve, L and Fortier, A and Perrault, LP and Carrier, M and Thorin, E}, title = {Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients.}, journal = {Mechanisms of ageing and development}, volume = {129}, number = {5}, pages = {261-270}, pmid = {18302967}, issn = {0047-6374}, support = {14496-3/CAPMC/CIHR/Canada ; 14496-4/CAPMC/CIHR/Canada ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Aged ; Antioxidants/administration &amp; dosage/*pharmacology ; Atherosclerosis/metabolism/*pathology ; Cells, Cultured ; Cellular Senescence/*drug effects ; Endothelial Cells/*drug effects/enzymology/metabolism/*pathology ; Endothelium, Vascular/cytology ; Female ; Humans ; Lipid Peroxidation/drug effects ; Male ; Mammary Arteries/surgery ; Middle Aged ; Organ Culture Techniques ; Oxidative Stress/drug effects ; Telomerase/metabolism ; }, abstract = {Endothelial senescence may contribute to the pathogenesis of age-related vascular disorders. Furthermore, chronic exposure to risk factors for cardiovascular disease (CVD) accelerates the effects of chronological aging by generating stress-dependent damages, including oxidative stress, therefore promoting stress-induced premature senescence. Our objective was to determine whether a chronic treatment with an antioxidant (N-acetyl-cystein, NAC) could delay senescence of endothelial cells (EC) isolated and cultured from arterial segments of patients with severe coronary artery disease. If EC were considered as one population (n=26), chronic NAC treatment slightly shortened telomere attrition rate associated with senescence but did not significantly delay the onset of endothelial senescence. However, in a subgroup of NAC-treated EC (n=15) cellular senescence was significantly delayed, NAC decreased lipid peroxidation (HNE), activated the catalytic subunit of telomerase (hTERT) and inhibited telomere attrition. In contrast, in another subgroup of EC (n=11) characterized by initial short telomeres, no effect of NAC on HNE and high levels of DNA damages, the antioxidant was not beneficial on senescence, suggesting an irreversible stress-dependent damage. In conclusion, chronic exposure to NAC can delay senescence of diseased EC via hTERT activation and transient telomere stabilization, unless oxidative stress-associated cell damage has become irreversible.}, }
@article {pmid18299995, year = {2008}, author = {Papa, L and Rockwell, P}, title = {Persistent mitochondrial dysfunction and oxidative stress hinder neuronal cell recovery from reversible proteasome inhibition.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {13}, number = {4}, pages = {588-599}, doi = {10.1007/s10495-008-0182-0}, pmid = {18299995}, issn = {1573-675X}, support = {RR03037/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspases/metabolism ; Cell Death/physiology ; Cell Survival/*physiology ; Cells, Cultured ; Hippocampus/cytology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mitochondria/*drug effects/physiology ; Models, Biological ; Neurons/*drug effects/physiology ; Oligopeptides/*pharmacology ; Oxidative Stress/*physiology ; Proteasome Endopeptidase Complex/metabolism ; *Proteasome Inhibitors ; Reactive Oxygen Species/metabolism ; bcl-X Protein/biosynthesis/pharmacology ; }, abstract = {Oxidative stress, proteasome impairment and mitochondrial dysfunction are implicated as contributors to ageing and neurodegeneration. Using mouse neuronal cells, we showed previously that the reversible proteasome inhibitor, [N-benzyloxycarbonyl-Ile-Glu (O-t-bytul)-Ala-leucinal; (PSI)] induced excessive reactive oxygen species (ROS) that mediated mitochondrial damage and a caspase-independent cell death. Herein, we examined whether this insult persists in neuronal cells recovering from inhibitor removal over time. Recovery from proteasome inhibition showed a time and dose-dependent cell death that was accompanied by ROS overproduction, caspase activation and mitochondrial membrane permeabilization with the subcellular relocalizations of the proapoptotic proteins, Bax, cytochrome c and the apoptosis inducing factor (AIF). Caspase inhibition failed to promote survival indicating that cell death was caspase-independent. Treatments with the antioxidant N-acetyl-cysteine (NAC) were needed to promote survival in cell recovering from mild proteasome inhibition while overexpression of the antiapoptotic protein Bcl-xL together with NAC attenuated cell death during recovery from potent inhibition. Whereas inhibitor removal increased proteasome function, cells recovering from potent proteasome inhibition showed excessive levels of ubiquitinated proteins that required the presence of NAC for their removal. Collectively, these results suggest that the oxidative stress and mitochondrial inhibition induced by proteasome inhibition persists to influence neuronal cell survival when proteasome function is restored.}, }
@article {pmid18299140, year = {2008}, author = {Usenko, CY and Harper, SL and Tanguay, RL}, title = {Fullerene C60 exposure elicits an oxidative stress response in embryonic zebrafish.}, journal = {Toxicology and applied pharmacology}, volume = {229}, number = {1}, pages = {44-55}, pmid = {18299140}, issn = {0041-008X}, support = {ES 07060/ES/NIEHS NIH HHS/United States ; T32 ES007060-29/ES/NIEHS NIH HHS/United States ; P30 ES003850/ES/NIEHS NIH HHS/United States ; P30 ES000210-39A19017/ES/NIEHS NIH HHS/United States ; ES 03850/ES/NIEHS NIH HHS/United States ; T32 ES007060/ES/NIEHS NIH HHS/United States ; P30 ES000210/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Carrier Proteins/drug effects/metabolism ; Embryo, Nonmammalian/drug effects/metabolism ; Ferritins/drug effects/metabolism ; Fullerenes/*toxicity ; Gene Expression Regulation/*drug effects ; Glutamate-Cysteine Ligase/drug effects/metabolism ; Glutathione Transferase/drug effects/metabolism ; HSP70 Heat-Shock Proteins/drug effects/metabolism ; Hydrogen Peroxide/metabolism ; Light ; Maleates/pharmacology ; Microarray Analysis ; Models, Animal ; Oxidative Stress/*drug effects ; Pericardial Effusion/chemically induced ; Time Factors ; Zebrafish ; }, abstract = {Due to its unique physicochemical and optical properties, C60 has raised interest in commercialization for a variety of products. While several reports have determined this nanomaterial to act as a powerful antioxidant, many other studies have demonstrated a strong oxidative potential through photoactivation. To directly address the oxidative potential of C60, the effects of light and chemical supplementation and depletion of glutathione (GSH) on C60-induced toxicity were evaluated. Embryonic zebrafish were used as a model organism to examine the potential of C60 to elicit oxidative stress responses. Reduced light during C60 exposure significantly decreased mortality and the incidence of fin malformations and pericardial edema at 200 and 300 ppb C60. Embryos co-exposed to the glutathione precursor, N-acetylcysteine (NAC), also showed reduced mortality and pericardial edema; however, fin malformations were not reduced. Conversely, co-exposure to the GSH synthesis inhibitors, buthionine sulfoximine (BSO) and diethyl maleate (DEM), increased the sensitivity of zebrafish to C60 exposure. Co-exposure of C60 or its hydroxylated derivative, C60(OH)(24), with H2O2 resulted in increased mortality along the concentration gradient of H2O2 for both materials. Microarrays were used to examine the effects of C60 on the global gene expression at two time points, 36 and 48 h post fertilization (hpf). At both life stages there were alterations in the expression of several key stress response genes including glutathione-S-transferase, glutamate cysteine ligase, ferritin, alpha-tocopherol transport protein and heat shock protein 70. These results support the hypothesis that C60 induces oxidative stress in this model system.}, }
@article {pmid18295335, year = {2008}, author = {Hoefer, MM and Aichem, A and Knight, AM and Illges, H}, title = {Modulation of murine complement receptor type 2 (CR2/CD21) ectodomain shedding by its cytoplasmic domain.}, journal = {Molecular immunology}, volume = {45}, number = {8}, pages = {2127-2137}, doi = {10.1016/j.molimm.2007.12.015}, pmid = {18295335}, issn = {0161-5890}, mesh = {Amino Acid Sequence ; Animals ; Antioxidants/pharmacology ; B-Lymphocytes/cytology/drug effects/metabolism ; Cytoplasm/drug effects/*metabolism ; Fluorescence ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Structure, Tertiary ; Receptors, Complement 3d/*chemistry/*metabolism ; Sequence Deletion ; Sulfhydryl Compounds/pharmacology ; Time Factors ; Vanadates/pharmacology ; }, abstract = {Ectodomain shedding is a mechanism that regulates numerous functions of cell surface proteins. The extracellular domain of the human complement receptor 2 (CR2/CD21) is released by proteolytic cleavage as a soluble protein through a variety of stimuli including the thiol antioxidants N-acetylcysteine (NAC) and glutathione (GSH), and the oxidant pervanadate (PV). In addition, PV mimics B cell antigen receptor (BCR) signaling. Here, we show that murine CD21 is shed upon those stimuli and that the cytoplasmic domain is an important modulator for CD21-shedding. B cells expressing a mutant CD21 cytoplasmic domain with only three amino acids (KHR) showed increased CD21-shedding and required lower stimuli concentrations. At lower PV concentrations, wildtype CD21 was up-regulated on the cell surface, whereas at higher PV concentrations the ectodomain was shed. These findings further indicate that GSH and NAC utilize different pathways than PV to activate CD21-shedding. Altogether, as pre-activated B cells express higher CD21 levels than resting mature B cells or fully activated and antigen-experienced B cells, we suggest CD21-shedding to be a mechanism to fine-tune B cell activation.}, }
@article {pmid18291369, year = {2008}, author = {Paintlia, MK and Paintlia, AS and Contreras, MA and Singh, I and Singh, AK}, title = {Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: attenuation by N-acetyl cysteine.}, journal = {Experimental neurology}, volume = {210}, number = {2}, pages = {560-576}, pmid = {18291369}, issn = {0014-4886}, support = {NS-40810/NS/NINDS NIH HHS/United States ; R01 NS022576/NS/NINDS NIH HHS/United States ; R01 NS034741/NS/NINDS NIH HHS/United States ; R37 NS022576/NS/NINDS NIH HHS/United States ; R01 NS037766-08/NS/NINDS NIH HHS/United States ; NS-22576/NS/NINDS NIH HHS/United States ; C06 RR018823/RR/NCRR NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; R01 NS034741-08/NS/NINDS NIH HHS/United States ; R01 NS037766/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; R01 NS040810/NS/NINDS NIH HHS/United States ; R37 NS022576-22/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Acyltransferases/metabolism ; Analysis of Variance ; Animals ; Brain Injuries/chemically induced/pathology ; Case-Control Studies ; Cells, Cultured ; Child, Preschool ; Drug Interactions ; Female ; Fetus ; Flow Cytometry/methods ; Free Radical Scavengers/*therapeutic use ; Humans ; In Vitro Techniques ; Infant ; Lipopolysaccharides/*toxicity ; Neuroglia/*drug effects/pathology ; Peroxisomal Disorders/*chemically induced/drug therapy ; Peroxisomes/drug effects/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species ; Time Factors ; Transfection/methods ; }, abstract = {Cerebral white matter injury during prenatal maternal infection characterized as periventricular leukomalacia is the main substrate for cerebral palsy (CP) in premature infants. Previously, we reported that maternal LPS exposure causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by an antioxidant agent, N-acetyl cysteine (NAC). Herein, we elucidated the role of peroxisomes in LPS-induced neuroinflammation and cerebral white matter injury. Peroxisomes are important for detoxification of reactive oxidative species (ROS) and metabolism of myelin-lipids in OLs. Maternal LPS exposure induced selective depletion of developing OLs in the fetal brain which was associated with ROS generation, glutathione depletion and peroxisomal dysfunction. Likewise, hypomyelination in the postnatal brain was associated with decrease in peroxisomes and OLs after maternal LPS exposure. Conversely, NAC abolished these LPS-induced effects in the developing brain. CP brains imitated these observed changes in peroxisomal/myelin proteins in the postnatal brain after maternal LPS exposure. In vitro studies revealed that pro-inflammatory cytokines cause OL-injury via peroxisomal dysfunction and ROS generation. NAC or WY14643 (peroxisome proliferators activated receptor (PPAR)-alpha agonist) reverses these effects of pro-inflammatory cytokines in the wild-type OLs, but not in PPAR-alpha(-/-) OLs. Similarly treated B12 oligodenroglial cells co-transfected with PPAR-alpha siRNAs/pTK-PPREx3-Luc, and LPS exposed PPAR-alpha(-/-) pregnant mice treated with NAC or WY14643 further suggested that PPAR-alpha activity mediates NAC-induced protective effects. Collectively, these data provide unprecedented evidence that LPS-induced peroxisomal dysfunction exacerbates cerebral white matter injury and its attenuation by NAC via a PPAR-alpha dependent mechanism expands therapeutic avenues for CP and related demyelinating diseases.}, }
@article {pmid18291118, year = {2008}, author = {Fernández, V and Tapia, G and Varela, P and Gaete, L and Vera, G and Mora, C and Vial, MT and Videla, LA}, title = {Causal role of oxidative stress in liver preconditioning by thyroid hormone in rats.}, journal = {Free radical biology &amp; medicine}, volume = {44}, number = {9}, pages = {1724-1731}, doi = {10.1016/j.freeradbiomed.2008.01.010}, pmid = {18291118}, issn = {0891-5849}, mesh = {Acetylcysteine/blood/metabolism ; Animals ; Aspartate Aminotransferases/metabolism ; Glutathione/metabolism ; Ischemic Preconditioning ; Liver/*pathology ; Male ; Models, Biological ; NF-kappa B/metabolism ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; Thyroid Hormones/*metabolism ; Triiodothyronine/metabolism ; }, abstract = {Hepatic ischemia-reperfusion (IR) injury, a major clinical drawback during surgery, is abolished by L-3,3',5-triiodothyronine (T(3)) administration. Considering that the triggering mechanisms are unknown, the aim of this study is to assess the role of oxidative stress in T(3) preconditioning using N-acetylcysteine (NAC) before T(3) administration. Male Sprague-Dawley rats given a single dose of 0.1 mg of T(3)/kg were subjected to 1 h ischemia followed by 20 h reperfusion, in groups of animals pretreated with 0.5 g of NAC/kg 0.5 h before T(3) or with the respective control vehicles. At the end of the reperfusion period, blood and liver samples were taken for analysis of serum aspartate aminotransferase (AST) and hepatic histology, glutathione (GSH) and protein carbonyl contents, and nuclear factor-kappaB (NF-kappaB) and activating protein 1 (AP-1) DNA binding. The IR protocol used led to a 4.5-fold increase in serum AST levels and drastic changes in liver histology, with significant GSH depletion and enhancement of protein carbonyl levels and of the protein carbonyl/GSH content ratio, whereas NF-kappaB and AP-1 DNA binding was decreased and enhanced, respectively. In a time window of 48 h, T(3) exerted protection against hepatic IR injury, with 88% reduction in the protein carbonyl/GSH ratio and normalization of NF-kappaB and AP-1 DNA binding, changes that were suppressed by NAC administration before T(3). Data presented suggest that a transient increase in the oxidative stress status of the liver is an important trigger for T(3) preconditioning, evidenced in a warm IR injury model through antioxidant intervention.}, }
@article {pmid18289923, year = {2008}, author = {Hu, C and Jiang, L and Geng, C and Zhang, X and Cao, J and Zhong, L}, title = {Possible involvement of oxidative stress in trichloroethylene-induced genotoxicity in human HepG2 cells.}, journal = {Mutation research}, volume = {652}, number = {1}, pages = {88-94}, doi = {10.1016/j.mrgentox.2008.01.002}, pmid = {18289923}, issn = {0027-5107}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Carcinoma, Hepatocellular/metabolism/*pathology ; *DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Drug Evaluation, Preclinical ; Glutathione/pharmacology ; Humans ; Lipid Peroxidation/drug effects ; Liver Neoplasms/metabolism/*pathology ; Micronuclei, Chromosome-Defective/chemically induced ; Mutagenicity Tests ; Oxidative Stress/*physiology ; Solvents/toxicity ; Trichloroethylene/*toxicity ; Tumor Cells, Cultured ; }, abstract = {Trichloroethylene (TCE) is an environmental and industrial pollutant whose hepatotoxicity has been demonstrated in experimental animals. However, the mechanisms of the effects, in particular those related to its genotoxicity in humans, are not well understood. The aim of this study was to assess the genotoxic effects of TCE and to identify and clarify the mechanisms, using human hepatoma HepG2 cells. Exposure of the cells to TCE caused significant increase of DNA migration in comet assay and of micronuclei (MN) frequencies at all tested concentrations (0.5-4mM), respectively, which suggests that TCE caused DNA strand breaks and chromosome damage. The involvement of lipid peroxidation in the genotoxic properties of TCE was confirmed by using immunoperoxidase staining for 8-hydroxydeoxyguanosine (8-OHdG) and by measuring levels of thiobarbituric acid-reactive substances (TBARS). To elucidate the role of glutathione (GSH) in these effects, the intracellular GSH level was modulated by pre-treatment with buthionine-(S,R)-sulfoximine (BSO), a specific GSH synthesis inhibitor, and by co-treatment with N-acetylcysteine (NAC), a GSH precursor. It was found that depletion of GSH in HepG2 cells with BSO dramatically increased the susceptibility of HepG2 cells to TCE-induced cytotoxicity and DNA damage, while when the intracellular GSH content was elevated by NAC, the DNA damage induced by TCE was almost completely prevented. These results indicate that TCE exerts genotoxic effects in HepG2 cells, probably through DNA damage by oxidative stress; GSH, as a main intracellular antioxidant, is responsible for cellular defense against TCE-induced DNA damage.}, }
@article {pmid18284032, year = {2007}, author = {Vats, P and Singh, VK and Singh, SN and Singh, SB}, title = {High altitude induced anorexia: effect of changes in leptin and oxidative stress levels.}, journal = {Nutritional neuroscience}, volume = {10}, number = {5-6}, pages = {243-249}, doi = {10.1080/10284150701722299}, pmid = {18284032}, issn = {1028-415X}, mesh = {Acetylcysteine/administration &amp; dosage ; Adult ; *Altitude ; Anorexia/*etiology/physiopathology ; Antioxidants/administration &amp; dosage ; Body Mass Index ; Energy Intake ; Humans ; Leptin/*blood ; Male ; Malondialdehyde/blood ; Neuropeptide Y/blood ; Oxidative Stress/*physiology ; Placebos ; Vitamin E/administration &amp; dosage ; Weight Loss ; }, abstract = {High altitude (HA) exposure usually leads to a significant weight loss in non-acclimatized humans. Anorexia is believed to be the main cause of this body weight loss. Appetite regulatory peptides, i.e. leptin and neuropeptide Y play a key role in food intake and energy homeostasis. Recent studies suggests increased oxidative stress during HA exposure. In present study effect of HA exposure on levels of leptin and NPY was evaluated along with N-acetyl cysteine (NAC) and vitamin E supplementation in relation to food intake and body weight changes. The study was conducted on 30 healthy male volunteers (age 19-29 years). Subjects were divided randomly into three groups of 10 each. Group 1 (placebo) supplemented with 400 mg of calcium gluconate, group 2 and 3 were supplemented with 400 mg of NAC and 400 mg vitamin E, respectively per day. The study was conducted at low altitude (320 m, Phase I), at HA 3600 m (Phase II) and at an altitude of 4580 m (Phase III). On HA exposure significant reduction in plasma leptin levels was observed in all the groups on day 2 (Phase II) along with decrease in food intake and reduction in body weight. Statistically significant increase in blood malondialdehyde (MDA) levels was seen in all the groups on HA exposure (Phase II, Day 2), but the maximum increase was in case of placebo group (65.1%) on day 2 (Phase II) in comparison to low altitude values. The decrease in energy intake was almost same in all the groups indicating that antioxidant supplementation did not provide any protection against HA anorexia. From the study, it may be concluded that leptin and oxidative stress possibly are not the key players for HA anorexia.}, }
@article {pmid18283998, year = {2007}, author = {Joannidis, M}, title = {Medical therapy of acute kidney injury.}, journal = {Acta clinica Belgica}, volume = {62 Suppl 2}, number = {}, pages = {353-356}, doi = {10.1179/acb.2007.079}, pmid = {18283998}, issn = {1784-3286}, mesh = {Acute Kidney Injury/*drug therapy/mortality/physiopathology ; Antioxidants/therapeutic use ; Contrast Media/adverse effects ; Diuretics/therapeutic use ; Diuretics, Osmotic/therapeutic use ; Erythropoietin/therapeutic use ; Humans ; Kidney Diseases/chemically induced/drug therapy ; Mannitol/therapeutic use ; Multicenter Studies as Topic ; Prospective Studies ; Randomized Controlled Trials as Topic ; Reactive Oxygen Species ; Regeneration/physiology ; Renal Circulation ; Theophylline/therapeutic use ; Vasoconstrictor Agents/therapeutic use ; Vasodilator Agents/therapeutic use ; }, abstract = {Pharmacologic interventions for the prevention and therapy of acute kidney injury (AKI) can be roughly divided into 2 main strategies: Optimising renal perfusion and modulation of intrarenal pathophysiological mechanisms, i.e. formation of free oxygen radicals, inflammation, tubular cast formation and renal (tubular) regeneration. Improvement of impaired renal perfusion can be achieved by optimising systemic haemodynamics by volume expansion and the appropriate use of inotropes and/or vasopressors. Up to now prospective randomised controlled trials on selective renal vasodilatation have turned out rather unsuccessful, with the exception of the adenosine antagonist theophylline, in certain indications like drug-induced renal failure or contrast nephropathy. Studies in humans on pharmacological interventions interfering with intrarenal pathophysiological mechanisms of AKI are also sparse. Investigated compounds comprise N-acetyl-cysteine, mannitol and antioxidants like selenium or vitamin C. The results are heterogeneous and a significant beneficial effect of either substance could not yet be convincingly demonstrated.}, }
@article {pmid18282716, year = {2008}, author = {Liao, Y and Lu, X and Lu, C and Li, G and Jin, Y and Tang, H}, title = {Selection of agents for prevention of cisplatin-induced hepatotoxicity.}, journal = {Pharmacological research}, volume = {57}, number = {2}, pages = {125-131}, doi = {10.1016/j.phrs.2008.01.001}, pmid = {18282716}, issn = {1043-6618}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Alanine Transaminase/blood ; Animals ; Antineoplastic Agents/administration &amp; dosage/*adverse effects ; Antioxidants/administration &amp; dosage/*therapeutic use ; Chemical and Drug Induced Liver Injury/etiology/*prevention &amp; control ; Cisplatin/administration &amp; dosage/*adverse effects ; Drug Therapy, Combination ; Fosfomycin/administration &amp; dosage/therapeutic use ; Glutathione/metabolism ; Injections, Intraperitoneal ; Male ; Malondialdehyde/metabolism ; Methionine/administration &amp; dosage/therapeutic use ; Mice ; Pilot Projects ; Selenium/administration &amp; dosage/therapeutic use ; Taurine/administration &amp; dosage/therapeutic use ; Thiosulfates/administration &amp; dosage/therapeutic use ; Zinc/administration &amp; dosage/therapeutic use ; }, abstract = {The objective of this study was to explore the optimal combination of agents used along with cisplatin for protection of hepatotoxicity. Animal experiment was carried out based on the orthogonal design L(8) (2(7)) setting seven factors with two different levels of each, and eight groups of mice were needed. The agents tested in this study were zinc, selenium, fosfomycin, sodium thiosulfate (STS), N-acetyl-cysteine (NAC), methionine and taurine. Mice were supplemented by gavage with various combinations of agents as designed in the orthogonal table once a day for nine days beginning two days before cisplatin administration. 3.5mg/kg body weight of cisplatin was given intraperitoneally once a day for five days simultaneously. After cessation of cisplatin administration, the agents were supplemented continuously for two days. Activities of alanine aminotransferase (ALT) in serum, levels of glutathione (GSH) and malondialdehyde (MDA) in liver were analyzed after cessation of supplementation. Results showed zinc, fosfomycin and methionine were the effective factors for protection of weight loss; fosfomycin and methionine were the effective factors for prevention of decreased liver ratio; selenium, fosfomycin and STS were the effective factors for prevention of increased ALT activities in serum. On the other hand, methionine was the only effective factor for prevention of decreased GSH levels in liver; zinc, selenium and fosfomycin were the effective factors for prevention of increased MDA levels in liver. Based on the data observed in this study, the optimum combinations of agents were selenium, fosfomycin, methionine and taurine, and zinc, selenium, STS and methionine. In conclusion, each agent used in this study could play a beneficial role for prevention of cisplatin hepatotoxicity, however, none could play the crucial role. The potentiated actions for prevention of cisplatin hepatotoxicity could be achieved via combined use of these agents.}, }
@article {pmid18278066, year = {2008}, author = {Chen, N and Aleksa, K and Woodland, C and Rieder, M and Koren, G}, title = {N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats.}, journal = {British journal of pharmacology}, volume = {153}, number = {7}, pages = {1364-1372}, pmid = {18278066}, issn = {0007-1188}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents, Alkylating/*adverse effects ; Creatinine/blood ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Glutathione/drug effects/metabolism ; Glutathione Transferase/drug effects/metabolism ; Ifosfamide/*adverse effects ; Kidney Diseases/*chemically induced/prevention &amp; control ; Lipid Peroxides/metabolism ; Magnesium/metabolism ; Male ; Rats ; Rats, Wistar ; Severity of Illness Index ; beta 2-Microglobulin/drug effects/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Ifosfamide nephrotoxicity is a serious adverse effect for children undergoing cancer chemotherapy. Our recent in vitro studies have shown that the antioxidant N-acetylcysteine (NAC), which is used extensively as an antidote for paracetamol (acetaminophen) poisoning in children, protects renal tubular cells from ifosfamide-induced toxicity at a clinically relevant concentration. To further validate this observation, an animal model of ifosfamide-induced nephrotoxicity was used to determine the protective effect of NAC.<br><br>EXPERIMENTAL APPROACH: Male Wistar albino rats were injected intraperitoneally with saline, ifosfamide (50 or 80 mg kg(-1) daily for 5 days), NAC (1.2 g kg(-1) daily for 6 days) or ifosfamide+NAC (for 6 days). Twenty-four hours after the last injection, rats were killed and serum and urine were collected for biochemical analysis. Kidney tissues were obtained for analysis of glutathione, glutathione S-transferase and lipid peroxide levels as well as histology analysis.<br><br>KEY RESULTS: NAC markedly reduces the severity of renal dysfunction induced by ifosfamide with a significant decrease in elevations of serum creatinine (57.8+/-2.3 vs 45.25+/-2.1 micromol l(-1)) as well as a reduced elevation of beta2-microglobulin excretion (25.44+/-3.3 vs 8.83+/-1.3 nmol l(-1)) and magnesium excretion (19.5+/-1.5 vs 11.16+/-1.5 mmol l(-1)). Moreover, NAC significantly improved the ifosfamide-induced glutathione depletion and the decrease of glutathione S-transferase activity, lowered the elevation of lipid peroxides and prevented typical morphological damages in renal tubules and glomeruli.<br><br>CONCLUSIONS AND IMPLICATIONS: Our results suggest a potential therapeutic role for NAC in paediatric patients in preventing ifosfamide nephrotoxicity.}, }
@article {pmid18270969, year = {2008}, author = {Traore, K and Sharma, R and Thimmulappa, RK and Watson, WH and Biswal, S and Trush, MA}, title = {Redox-regulation of Erk1/2-directed phosphatase by reactive oxygen species: role in signaling TPA-induced growth arrest in ML-1 cells.}, journal = {Journal of cellular physiology}, volume = {216}, number = {1}, pages = {276-285}, pmid = {18270969}, issn = {1097-4652}, support = {R01 HL081205-03/HL/NHLBI NIH HHS/United States ; R01 GM079239/GM/NIGMS NIH HHS/United States ; R01 HL081205/HL/NHLBI NIH HHS/United States ; HL081205/HL/NHLBI NIH HHS/United States ; R01 ES 03760/ES/NIEHS NIH HHS/United States ; P30 ES 03819/ES/NIEHS NIH HHS/United States ; P30 ES003819/ES/NIEHS NIH HHS/United States ; T32 ES007141/ES/NIEHS NIH HHS/United States ; T32 ES 07141/ES/NIEHS NIH HHS/United States ; }, mesh = {Carcinogens/metabolism ; Cell Line ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism ; Enzyme Activation ; Enzyme Induction ; Enzyme Inhibitors/metabolism ; Fluorescent Dyes/metabolism ; Gene Expression Profiling ; Humans ; Hydrogen Peroxide/metabolism ; Mitogen-Activated Protein Kinase 1/genetics/*metabolism ; Mitogen-Activated Protein Kinase 3/genetics/*metabolism ; Oligonucleotide Array Sequence Analysis ; Oxidants/metabolism ; Oxidation-Reduction ; Phenanthridines/metabolism ; Phosphoprotein Phosphatases/*metabolism ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Kinase C/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*physiology ; Superoxide Dismutase/genetics/metabolism ; Tetradecanoylphorbol Acetate/*metabolism ; }, abstract = {Extracellular signal-regulated kinase (Erk)1/2 activity signals myeloid cell differentiation induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Previously, we reported that Erk1/2 activation (phosphorylation) induced by TPA required reactive oxygen species (ROS) as a second messenger. Here, we hypothesized that ROS generated in response to TPA inhibit Erk1/2-directed phosphatase activity, which leads to an increase phosphorylation of Erk1/2 to signal p21(WAF1/Cip1)-mediated growth arrest in ML-1 cells. Incubation of ML-1 cells with TPA resulted in a marked accumulation of phosphorylated Erk1/2, and is subsequent to H2O2 generation. Interestingly, post-TPA-treatment with N-acetylcysteine (NAC) stimulated a marked and a rapid dephosphorylation of Erk1/2, suggesting a regeneration of Erk1/2-directed phospahatase activity by NAC. ROS generation in ML-1 cells induced by TPA was suggested to occur in the mitochondrial electron transport chain (METC) based on the following observations: (i) undifferentiated ML-1 cells not only lack p67-phox and but also express a low level of p47-phox key components required for NADPH oxidase enzymatic activity, (ii) pretreatment with DPI, an inhibitor of NADH- and NADPH-dependent enzymes, or rhein, an inhibitor of complex I, blocked the ROS generation, and (iii) examination of the microarray analysis data and Western blot analysis data revealed an induction of MnSOD expression at both mRNA and protein levels in response to TPA. MnSOD is a key member of the mitochondrial defense system against mitochondrial-derived superoxide. Together, this study suggested that TPA stimulated ROS generation as a second messenger to activate Erk1/2 via a redox-mediated inhibition of Erk1/2-directed phosphatase in ML-1 cells.}, }
@article {pmid18268065, year = {2008}, author = {Martina, V and Masha, A and Gigliardi, VR and Brocato, L and Manzato, E and Berchio, A and Massarenti, P and Settanni, F and Della Casa, L and Bergamini, S and Iannone, A}, title = {Long-term N-acetylcysteine and L-arginine administration reduces endothelial activation and systolic blood pressure in hypertensive patients with type 2 diabetes.}, journal = {Diabetes care}, volume = {31}, number = {5}, pages = {940-944}, doi = {10.2337/dc07-2251}, pmid = {18268065}, issn = {1935-5548}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Aged ; Arginine/*therapeutic use ; Blood Pressure/*drug effects ; Diabetes Mellitus, Type 2/*blood ; Diabetic Angiopathies/*drug therapy ; Double-Blind Method ; Endothelium, Vascular/drug effects/*physiopathology ; Humans ; Hypertension/*drug therapy ; Hypoglycemic Agents/administration &amp; dosage/therapeutic use ; Male ; Middle Aged ; Placebos ; Systole/drug effects ; }, abstract = {OBJECTIVE: Reactive oxygen and nitric oxide (NO) have recently been considered to be involved in the cardiovascular complications of patients with type 2 diabetes, as NO is thought to lose its beneficial physiological effects in the presence of oxygen radicals. For this reason, we tested the effects of l-arginine (ARG) and N-acetylcysteine (NAC) administration in increasing NO bioavailability by reducing free radical formation.<br><br>RESEARCH DESIGN AND METHODS: A double-blind study was performed on 24 male patients with type 2 diabetes and hypertension divided into two groups of 12 patients that randomly received either an oral supplementation of placebo or NAC + ARG for 6 months.<br><br>RESULTS: The NAC + ARG treatment caused a reduction of both systolic (P < 0.05) and diastolic (P < 0.05) mean arterial blood pressure, total cholesterol (P < 0.01), LDL cholesterol (P < 0.005), oxidized LDL (P < 0.05), high-sensitive C-reactive protein (P < 0.05), intracellular adhesion molecule (P < 0.05), vascular cell adhesion molecule (P < 0.01), nitrotyrosine (P < 0.01), fibrinogen (P < 0.01), and plasminogen activator inhibitor-1 (P < 0.05), and an improvement of the intima-media thickness during endothelial postischemic vasodilation (P < 0.02). HDL cholesterol increased (P < 0.05). No changes in other parameters studied were observed.<br><br>CONCLUSIONS: NAC + ARG administration seems to be a potential well-tolerated antiatherogenic therapy because it improves endothelial function in hypertensive patients with type 2 diabetes by improving NO bioavailability via reduction of oxidative stress and increase of NO production. Our study's results give prominence to its potential use in primary and secondary cardiovascular prevention in these patients.}, }
@article {pmid18267208, year = {2008}, author = {Circu, ML and Rodriguez, C and Maloney, R and Moyer, MP and Aw, TY}, title = {Contribution of mitochondrial GSH transport to matrix GSH status and colonic epithelial cell apoptosis.}, journal = {Free radical biology &amp; medicine}, volume = {44}, number = {5}, pages = {768-778}, pmid = {18267208}, issn = {0891-5849}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-13A1/DK/NIDDK NIH HHS/United States ; R01 DK044510-14/DK/NIDDK NIH HHS/United States ; DK 44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antifibrinolytic Agents/pharmacology ; Apoptosis/*physiology ; Biological Transport ; Blotting, Western ; Caspases/metabolism ; Cell Membrane/*metabolism ; Cells, Cultured ; Colon/drug effects/*metabolism ; Cytochromes c/metabolism ; Cytosol/metabolism ; Dicumarol/pharmacology ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/drug effects/metabolism ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/*metabolism ; Oxidation-Reduction ; Oxygen Consumption ; Protein Transport ; Vitamin K 3/pharmacology ; }, abstract = {Previously, we showed that cellular glutathione/glutathione disulfide (GSH/GSSG) play an important role in apoptotic signaling, and early studies linked mitochondrial GSH (mtGSH) loss to enhanced cytotoxicity. The current study focuses on the contribution of mitochondrial GSH transport and mitochondrial GSH/GSSG status to apoptosis initiation in a nontransformed colonic epithelial cell line, NCM460, using menadione (MQ), a quinone with redox cycling bioreactivity, as a model of oxidative challenge. Our results implicate the semiquinone radical in MQ-mediated apoptosis, which was associated with marked oxidation of the mitochondrial soluble GSH and protein-bound thiol pools, mitochondria-to-cytosol translocation of cytochrome c, and activation of caspase-9. MQ-induced apoptosis was potentiated by inhibition of mtGSH uptake in accordance with exacerbated mitochondrial GSSG (mtGSSG) and protein-SSG and compromised mitochondrial respiratory activity. Moreover, cell apoptosis was prevented by N-acetyl-L-cysteine (NAC) pretreatment, which restored cellular redox homeostasis. Importantly, mtGSH transport inhibition effectively blocked NAC-mediated protection in accordance with its failure to attenuate mtGSSG. These results support the importance of mitochondrial GSH transport and the mtGSH status in oxidative cell killing.}, }
@article {pmid18266932, year = {2008}, author = {Guo, S and Bragina, O and Xu, Y and Cao, Z and Chen, H and Zhou, B and Morgan, M and Lin, Y and Jiang, BH and Liu, KJ and Shi, H}, title = {Glucose up-regulates HIF-1 alpha expression in primary cortical neurons in response to hypoxia through maintaining cellular redox status.}, journal = {Journal of neurochemistry}, volume = {105}, number = {5}, pages = {1849-1860}, doi = {10.1111/j.1471-4159.2008.05287.x}, pmid = {18266932}, issn = {1471-4159}, support = {P20 RR15636/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Cell Hypoxia/drug effects/physiology ; Cells, Cultured ; Cerebral Cortex/cytology/*metabolism/physiology ; Female ; Gene Expression Regulation/*physiology ; Glucose/*physiology ; Hypoxia-Inducible Factor 1, alpha Subunit/*biosynthesis/genetics ; Male ; Neurons/cytology/*metabolism/physiology ; Oxidation-Reduction ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Up-Regulation/*physiology ; }, abstract = {It has been suggested that hypoxia-inducible factor 1 (HIF-1), a key regulator in cell's adaptation to hypoxia, plays an important role in the fate of neurons during ischemia. However, the mechanism of HIF-1 regulation is still not fully understood in neurons subjected to ischemia. In this study, we demonstrated that glucose up-regulated the expression of HIF-1alpha, the oxygen-dependent subunit of HIF-1, in rat primary cortical neurons exposed to hypoxia. To understand the mechanism of glucose-regulated HIF-1alpha expression, we investigated the relationships between HIF-1alpha expression, reactive oxygen species (ROS), and redox status. Low levels of HIF-1alpha protein expression were observed in the neurons exposed to in vitro ischemic conditions that had high levels of ROS (oxidizing environments), and vice versa. The glutathione (GSH) precursor, N-acetyl cysteine, induced HIF-1alpha protein expression in hypoxic neurons while the GSH synthesis inhibitor, l-buthionine sulfoximine, inhibited the expression. Moreover, (-)-epicatechin gallate, a ROS scavenger, elevated HIF-1alpha expression in the neurons subjected to in vitro ischemia. Furthermore, results from a systemic hypoxia model showed that a reducing environment increased HIF-1alpha expression in rat brains. Taken together, these data presented the first evidence that glucose promoted HIF-1alpha stabilization through regulating redox status in primary neurons exposed to hypoxia. The results imply that hypoxia only may not be sufficient to stabilize HIF-1alpha and that a reducing environment is required to stabilize HIF-1alpha in neurons exposed to hypoxia.}, }
@article {pmid18263874, year = {2008}, author = {Ozaydin, M and Peker, O and Erdogan, D and Kapan, S and Turker, Y and Varol, E and Ozguner, F and Dogan, A and Ibrisim, E}, title = {N-acetylcysteine for the prevention of postoperative atrial fibrillation: a prospective, randomized, placebo-controlled pilot study.}, journal = {European heart journal}, volume = {29}, number = {5}, pages = {625-631}, doi = {10.1093/eurheartj/ehn011}, pmid = {18263874}, issn = {0195-668X}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Anti-Arrhythmia Agents/*therapeutic use ; Atrial Fibrillation/*prevention &amp; control ; Cardiac Surgical Procedures/*adverse effects ; Epidemiologic Methods ; Female ; Humans ; Male ; Middle Aged ; Postoperative Complications/*prevention &amp; control ; }, abstract = {AIMS: Oxidative stress has recently been implicated in the pathophysiology of atrial fibrillation (AF). The aim of the present study was to evaluate the effects of antioxidant agent N-acetylcysteine (NAC) on postoperative AF.<br><br>METHODS AND RESULTS: The population of this prospective, randomized, double-blind, placebo-controlled study consisted of 115 patients undergoing coronary artery bypass and/or valve surgery. All the patients were treated with standard medical therapy and were randomized to NAC group (n = 58) or placebo (saline, n = 57). An AF episode >5 min during hospitalization was accepted as endpoint. During follow-up period, 15 patients (15/115, 13%) had AF. The rate of AF was lower in NAC group compared with placebo group (three patients in NAC group [5.2%] and 12 patients in placebo group [21.1%] had postoperative AF; odds ratio [OR] 0.20; 95% confidence interval [CI] 0.05 to 0.77; P = 0.019). In the multivariable logistic regression analysis, independent predictors of postoperative AF were left atrial diameter (OR, 1.18; 95% CI, 1.06-1.31; P = 0.002) and the use of NAC (OR, 0.20; 95% CI, 0.04-0.91; P = 0.038).<br><br>CONCLUSION: The result of this study indicates that NAC treatment decreases the incidence of postoperative AF.}, }
@article {pmid18262302, year = {2008}, author = {Gu, JM and Lim, SO and Oh, SJ and Yoon, SM and Seong, JK and Jung, G}, title = {HBx modulates iron regulatory protein 1-mediated iron metabolism via reactive oxygen species.}, journal = {Virus research}, volume = {133}, number = {2}, pages = {167-177}, doi = {10.1016/j.virusres.2007.12.014}, pmid = {18262302}, issn = {0168-1702}, mesh = {Animals ; Antigens, CD/metabolism ; Apoferritins/metabolism ; Cells, Cultured ; Ferritins ; *Gene Expression Regulation, Viral ; Hepatocytes ; Humans ; Iron/metabolism ; Iron Regulatory Protein 1/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Reactive Oxygen Species/*metabolism ; Receptors, Transferrin/metabolism ; Trans-Activators/*metabolism ; Viral Regulatory and Accessory Proteins ; }, abstract = {Hepatitis B virus X protein (HBx) is involved in viral metabolism and progression of liver disease. Iron metabolism plays a significant role in liver disease. In this report, to elucidate the relationship between iron metabolism and HBx, we established the Huh7 cell lines in which HBx was stably expressed (Huh7-HBx). In Huh7-HBx, we observed that transferrin receptor 1 (TfR1) expression decreased and ferritin heavy chain (FtH) expression increased as well as reactive oxygen species (ROS) level increased. We also found that these modulations were caused by the downregulation of iron regulatory protein 1 (IRP1). Furthermore, the levels of total iron and labile iron pool (LIP) were altered in Huh7-HBx. In addition, antioxidant N-acetylcystein (NaC) increased IRP1 expression by depleting HBx-induced ROS. We also confirmed these alterations of TfR1 and FtH in the primary hepatocytes of HBx transgenic mice and in HepG2.2.15 cells that constitutively replicate the intact HBV genome. In conclusion, these results suggest that HBx modulates iron metabolism via ROS leading to pathological status in liver diseases.}, }
@article {pmid18262273, year = {2008}, author = {Lyng, GD and Seegal, RF}, title = {Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: experimental dopamine depletion prevents reductions in GABA.}, journal = {Neurotoxicology}, volume = {29}, number = {2}, pages = {301-308}, pmid = {18262273}, issn = {0161-813X}, support = {P01 ES011263/ES/NIEHS NIH HHS/United States ; P01 ES011263-050003/ES/NIEHS NIH HHS/United States ; ES829390/ES/NIEHS NIH HHS/United States ; ES11263/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Basal Ganglia/*drug effects/embryology/enzymology/metabolism ; Coculture Techniques ; Dopamine/*metabolism ; Down-Regulation ; Environmental Pollutants/*toxicity ; Enzyme Inhibitors/pharmacology ; Fluorescent Dyes ; Glutathione/metabolism ; Mesencephalon/*drug effects/embryology/enzymology/metabolism ; Microscopy, Fluorescence/methods ; Organ Culture Techniques ; Oxidative Stress/*drug effects ; Polychlorinated Biphenyls/*toxicity ; Rats ; Rats, Sprague-Dawley ; Rhodamine 123 ; Synaptic Vesicles/drug effects/metabolism ; Tyrosine 3-Monooxygenase/antagonists &amp; inhibitors/metabolism ; alpha-Methyltyrosine/pharmacology ; gamma-Aminobutyric Acid/*metabolism ; }, abstract = {Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been demonstrated to be toxic to the dopamine (DA) systems of the central nervous system. One proposed mechanism for PCB-induced DA neurotoxicity is inhibition of the vesicular monoamine transporter (VMAT); such inhibition results in increased levels of unsequestered DA and DA metabolism leading to oxidative stress. We have used an organotypic co-culture system of developing rat striatum and ventral mesencephalon (VM) to determine whether alterations in the vesicular storage of DA, resulting from PCB exposure and consequent induction of oxidative stress, leads to GABA and DA neuronal dysfunction. Twenty-four-hour exposure to an environmentally relevant mixture of PCBs reduced tissue DA and GABA concentrations, increased medium levels of DA and measures of oxidative stress in both the striatum and VM. Alterations in neurochemistry and increases in measures of oxidative stress were blocked in the presence of n-acetylcysteine (NAC). Although NAC treatment did not alter PCB-induced changes in DA neurochemistry, it did protect against reductions in GABA concentration. To determine whether alterations in the vesicular storage of DA were responsible for PCB-induced oxidative stress and consequent reductions in GABA levels, we depleted DA from the co-cultures using alpha-methyl-p-tyrosine (AMPT). AMPT reduced striatal and VM DA levels by 90% and 70%, respectively. PCB exposure, following DA depletion, neither increased levels of oxidative stress nor resulted in GABA depletion. These results suggest that PCB-induced alterations in the vesicular storage of DA, resulting in increased levels of unsequestered DA, leads to increased oxidative stress, depletion of tissue glutathione, and consequent reductions in tissue GABA concentrations.}, }
@article {pmid18258657, year = {2008}, author = {Whitehead, NP and Pham, C and Gervasio, OL and Allen, DG}, title = {N-Acetylcysteine ameliorates skeletal muscle pathophysiology in mdx mice.}, journal = {The Journal of physiology}, volume = {586}, number = {7}, pages = {2003-2014}, pmid = {18258657}, issn = {1469-7793}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Caveolin 3/metabolism ; Disease Models, Animal ; Dystroglycans/metabolism ; Dystrophin/genetics/metabolism ; Free Radical Scavengers/pharmacology/*therapeutic use ; Mice ; Mice, Inbred mdx ; Muscle Contraction/drug effects/physiology ; Muscle, Skeletal/drug effects/metabolism/*physiopathology ; Muscular Dystrophy, Animal/etiology/physiopathology/*prevention &amp; control ; Muscular Dystrophy, Duchenne/physiopathology/prevention &amp; control ; Mutation/genetics ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by a mutation in the gene encoding dystrophin, a protein linking the cytoskeleton to the extracellular matrix. In this study we investigated whether the antioxidant N-acetylcysteine (NAC) provided protection against dystrophic muscle damage in the mdx mouse, an animal model of DMD. In isolated mdx muscles, NAC prevented the increased membrane permeability and reduced the force deficit associated with stretch-induced muscle damage. Three-week-old mdx mice were treated with NAC in the drinking water for 6 weeks. Dihydroethidium staining showed that NAC treatment reduced the concentration of reactive oxygen species (ROS) in mdx muscles. This was accompanied by a significant decrease in centrally nucleated fibres in muscles from NAC-treated mdx mice. Immunoblotting showed that NAC treatment decreased the nuclear protein expression of NF-kappaB, a transcription factor involved in pro-inflammatory cytokine expression. Finally, we show that NAC treatment reduced caveolin-3 protein levels and increased the sarcolemmal expression of beta-dystroglycan and the dystrophin homologue, utrophin. Taken together, our findings suggest that ROS play an important role in the dystrophic pathogenesis, both in terms of activating damage pathways and in regulating the expression of some dystrophin-associated membrane proteins. These results offer the prospect that antioxidants such as NAC could have therapeutic potential for DMD patients.}, }
@article {pmid18257742, year = {2008}, author = {Hoesel, LM and Flierl, MA and Niederbichler, AD and Rittirsch, D and McClintock, SD and Reuben, JS and Pianko, MJ and Stone, W and Yang, H and Smith, M and Sarma, JV and Ward, PA}, title = {Ability of antioxidant liposomes to prevent acute and progressive pulmonary injury.}, journal = {Antioxidants &amp; redox signaling}, volume = {10}, number = {5}, pages = {973-981}, doi = {10.1089/ars.2007.1878}, pmid = {18257742}, issn = {1523-0864}, support = {P01 HL031963/HL/NHLBI NIH HHS/United States ; R01 GM029507/GM/NIGMS NIH HHS/United States ; HL 31963/HL/NHLBI NIH HHS/United States ; GM 029507/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/metabolism/therapeutic use ; Animals ; *Antioxidants/chemistry/metabolism/therapeutic use ; Bronchoalveolar Lavage Fluid/chemistry ; Chemokines/metabolism ; Cytokines/metabolism ; Free Radical Scavengers/administration &amp; dosage/metabolism/therapeutic use ; Humans ; *Liposomes/administration &amp; dosage/chemistry/metabolism/therapeutic use ; Lung/cytology/drug effects/metabolism/pathology ; Macrophages, Alveolar/metabolism ; Male ; Mustard Gas/analogs &amp; derivatives/pharmacology ; Rats ; Rats, Long-Evans ; Respiratory Distress Syndrome/chemically induced/*drug therapy/pathology/*prevention &amp; control ; Tocopherols/administration &amp; dosage/metabolism/therapeutic use ; }, abstract = {We recently showed that acute oxidant-related lung injury (ALI) in rats after application of 2-chloroethyl ethyl sulfide (CEES) is attenuated by the airway instillation of antioxidants. We investigated whether intratracheal administration of antioxidant-containing liposomes immediately after instillation of CEES would attenuate short-term as well as long-term (fibrotic) effects of CEES-induced lung injury. In the acute injury model (4 h after injury), N-acetylcysteine (NAC)-containing liposomes were protective and reduced to baseline levels both the lung permeability index and the appearance of proinflammatory mediators in bronchoalveolar lavage fluids from CEES-exposed lungs. Similar results were obtained when rat alveolar macrophages were incubated in vitro with either CEES or lipopolysaccharide in the presence of NAC-liposomes. When lung fibrosis 3 weeks after CEES was quantitated by using hydroxyproline content, liposomes containing NAC or NAC + glutathione had no effects, but liposomes containing alpha/gamma-tocopherol alone or with NAC significantly suppressed the increase in lung hydroxyproline. The data demonstrate that delivery of antioxidants via liposomes to CEES-injured lungs is, depending on liposomal content, protective against ALI, prevents the appearance of proinflammatory mediators in bronchoalveolar fluids, and suppresses progressive fibrosis. Accordingly, the liposomal strategy may be therapeutically useful in CEES-induced lung injury in humans.}, }
@article {pmid18254209, year = {2007}, author = {Singh, V and Joshi, D and Shrivastava, S and Shukla, S}, title = {Effect of monothiol along with antioxidant against mercury-induced oxidative stress in rat.}, journal = {Indian journal of experimental biology}, volume = {45}, number = {12}, pages = {1037-1044}, pmid = {18254209}, issn = {0019-5189}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/*pharmacology ; Chelating Agents/*therapeutic use ; Chemical and Drug Induced Liver Injury ; Dietary Supplements ; Drug Therapy, Combination ; Liver Diseases/*drug therapy/pathology ; Magnesium/*pharmacology ; Male ; Mercury Poisoning/*drug therapy/pathology ; Oxidative Stress/drug effects ; Penicillamine/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Sodium Selenite/*pharmacology ; Treatment Outcome ; Zinc/pharmacology ; }, abstract = {Efficacy of thiol chelators viz. N-acetyl cysteine and D-penicillamine (NAC and DPA) along with nutritional supplements viz. zinc acetate, sodium selenite and magnesium sulphate (Zn, Se and Mg) in the treatment of mercury intoxication was investigated in rats. This is of particular interest since high bonding affinity between mercuric ion and the thiol group exits. The mutual antagonism of mercury and selenium is one of the strongest examples of the interaction in the trace element field. Adult rats of Sprague-Dawley strain were administered a bolus dose of dimethyl mercury (10 mg/kg) orally. A significant rise in the aspartate aminotransferase, alanine aminotransferase, serum alkaline phosphatase, lactate dehydrogenase, gamma glutamyltranspeptidase, bilirubin and creatinine were observed. Single mercury exposure also resulted in a significant increase in lipid peroxides with a concomitant decrease in reduced glutathione level in liver, kidney and brain. A decrease in the enzymatic activities of acetyl cholinesterase in different regions of the brain was observed. These parameters were restored considerably with chelating agents along with nutritional supplementation, but NAC+Se and DPA+Mg offered significant protection in comparison with other combinations.}, }
@article {pmid18246115, year = {2008}, author = {Thompson, JS and Asmis, R and Chu, Y and Glass, J and Nelson, B and Brown, SA}, title = {Amifostine prior to lethal irradiation prevents allogeneic bone marrow engraftment in mice.}, journal = {Bone marrow transplantation}, volume = {41}, number = {11}, pages = {927-934}, doi = {10.1038/sj.bmt.1705995}, pmid = {18246115}, issn = {0268-3369}, mesh = {Amifostine/*adverse effects ; Animals ; Bone Marrow Transplantation/*methods ; Disease Models, Animal ; *Graft Rejection ; Graft Survival/*drug effects ; Graft vs Host Disease/prevention &amp; control ; Mice ; Mice, Inbred BALB C ; Radiation-Protective Agents/*adverse effects ; Transplantation Conditioning/*methods ; Transplantation, Homologous/methods ; Whole-Body Irradiation ; }, abstract = {We and others have demonstrated that the milieu created by ionizing radiation (IR) used for conditioning plays a major role in the development of acute graft-versus-host disease (aGVHD). We reasoned that antioxidants that could inhibit IR induction of inflammatory cytokines and/or apoptosis might reduce the incidence or severity of aGVHD. Therefore, BALB/c mice were treated with amifostine, n-acetyl cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC) prior to transplantation with allogeneic C57Bl/6 bone marrow and spleen cells. None of 30 amifostine-pretreated mice developed weight loss or other signs of aGVHD and they rejected their allogeneic transplants. However, pretreatment to groups of five mice each with molar equivalent doses of NAC or PDTC accelerated death, and lower doses did not prevent aGVHD. In vitro tests demonstrated that PDTC and NAC acted as pro-oxidants when incubated with isolated normal mouse lymphocytes, whereas amifostine and its active metabolite WR-1065 did not. The conclusion that amifostine protected immune function from IR in vivo was further supported by the fact that amifostine and WR-1065 preserved the response of radiated normal lymphocytes to respond to PHA and both stimulated growth of non-radiated, non-PHA-treated normal lymphocytes in vitro. Taken together, these data caution the use of amifostine in allogeneic transplantation.}, }
@article {pmid18241324, year = {2008}, author = {Abidi, P and Leers-Sucheta, S and Cortez, Y and Han, J and Azhar, S}, title = {Evidence that age-related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats.}, journal = {Aging cell}, volume = {7}, number = {2}, pages = {168-178}, doi = {10.1111/j.1474-9726.2007.00364.x}, pmid = {18241324}, issn = {1474-9726}, support = {DK56339/DK/NIDDK NIH HHS/United States ; }, mesh = {Adrenal Cortex/enzymology ; Adrenal Cortex Hormones/biosynthesis/*deficiency ; Age Factors ; Aging/*metabolism ; Animals ; Enzyme Activation ; Enzyme Inhibitors ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Free Radical Scavengers ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lipid Peroxidation ; MAP Kinase Signaling System ; Male ; Metalloporphyrins ; Oxidants ; Oxidative Stress/*physiology ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Thiobarbituric Acid Reactive Substances/analysis ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The current studies were initiated to investigate whether excessive oxidative stress exerts its antisteroidogenic action through modulation of oxidant-sensitive mitogen-activated protein kinase (MAPK) signaling pathways. Western blot analysis indicated that aging caused increased phosphorylation and activation of rat adrenal p38 MAPK, but not the ERK1/2 or JNK1/2. Lipid peroxidation measurements (an index of cellular oxidative stress) indicated that adrenal membranes from young animals contained only minimal levels of endogenous thiobarbituric acid-reactive substances (TBARS), and exposure of membranes to enzymatic and non-enzymatic pro-oxidants enhanced TBARS formation approximately 12- and 20-fold, respectively. The adrenal membranes from old animals showed much more susceptibility to lipid peroxidation and exhibited roughly 4- to 6-fold higher TBARS formation than young controls both under basal conditions and in response to pro-oxidants. Qualitatively similar results were obtained when lipid peroxide formation was measured using a sensitive FOXRS (ferrous oxidation-xylenol orange-reactive substances) technique. We next tested whether aging-induced excessive oxidative insult alters steroidogenesis through modulation of MAPK signaling pathway. Treatment of adrenocortical cells from old rats with specific p38 MAPK inhibitors restored Bt(2)cAMP-stimulated steroidogenesis approximately 60-70% of the value seen in cells of young animals. Likewise, pretreatment of cells with reactive oxygen species (ROS) scavengers MnTMPyP and N-acetyl cysteine also partially rescued age-induced loss of steroid production. In contrast, simultaneous treatment of cells with ROS scavengers and p38 MAPK inhibitor did not produce any additional effect suggesting that both types of inhibitors exert their stimulatory action through inhibition of p38 MAPK activation. Collectively, these results indicate that p38 MAPK functions as a signaling effector in oxidative stress-induced inhibition of steroidogenesis during aging.}, }
@article {pmid18234258, year = {2008}, author = {Roberts, JE and Wielgus, AR and Boyes, WK and Andley, U and Chignell, CF}, title = {Phototoxicity and cytotoxicity of fullerol in human lens epithelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {228}, number = {1}, pages = {49-58}, pmid = {18234258}, issn = {0041-008X}, support = {NIH0010085416/ImNIH/Intramural NIH HHS/United States ; Z01 ES050046-29/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Line ; Cell Survival/*drug effects ; Dermatitis, Phototoxic/*pathology ; Epithelial Cells/*pathology/radiation effects ; Fullerenes/*toxicity ; Humans ; Indicators and Reagents ; L-Lactate Dehydrogenase/metabolism ; Lens, Crystalline/*pathology/radiation effects ; Light ; Lutein/toxicity ; Necrosis/pathology ; Particle Size ; Rats ; Rats, Sprague-Dawley ; Ultraviolet Rays ; alpha-Crystallins/chemistry/drug effects ; }, abstract = {The water-soluble, hydroxylated fullerene [fullerol, nano-C60(OH)22-26] has several clinical applications including use as a drug carrier to bypass the blood ocular barriers. We have assessed fullerol's potential ocular toxicity by measuring its cytotoxicity and phototoxicity induced by UVA and visible light in vitro with human lens epithelial cells (HLE B-3). Accumulation of nano-C60(OH)22-26 in the cells was confirmed spectrophotometrically at 405 nm and cell viability estimated using MTS and LDH assays. Fullerol was cytotoxic to HLE B-3 cells maintained in the dark at concentrations higher than 20 microM. Exposure to either UVA or visible light in the presence of >5 microM fullerol-induced phototoxic damage. When cells were pretreated with non-toxic antioxidants: 20 microM lutein, 1 mM N-acetyl cysteine, or 1 mM l-ascorbic acid prior to irradiation, only the singlet oxygen quencher-lutein significantly protected against fullerol photodamage. Apoptosis was observed in lens cells treated with fullerol whether or not the cells were irradiated, in the order UVA>visible light>dark. Dynamic light scattering (DLS) showed that in the presence of the endogenous lens protein alpha-crystallin, large aggregates of fullerol were reduced. In conclusion, fullerol is both cytotoxic and phototoxic to human lens epithelial cells. Although the acute toxicity of water-soluble nano-C60(OH)22-26 is low, these compounds are retained in the body for long periods, raising concern for their chronic toxic effect. Before fullerols are used to deliver drugs to the eye, they should be tested for photo- and cytotoxicity in vivo.}, }
@article {pmid18231637, year = {2008}, author = {Cai, J and Niu, X and Chen, Y and Hu, Q and Shi, G and Wu, H and Wang, J and Yi, J}, title = {Emodin-induced generation of reactive oxygen species inhibits RhoA activation to sensitize gastric carcinoma cells to anoikis.}, journal = {Neoplasia (New York, N.Y.)}, volume = {10}, number = {1}, pages = {41-51}, pmid = {18231637}, issn = {1476-5586}, mesh = {Acetylcysteine/pharmacology ; Actins/metabolism ; *Anoikis/genetics ; Arsenic Trioxide ; Arsenicals/pharmacology ; Carcinoma/*enzymology/pathology ; Cell Line, Tumor ; Emodin/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Oxidative Stress ; Oxides/pharmacology ; Protein Kinase Inhibitors/*pharmacology ; Reactive Oxygen Species/*metabolism ; Stomach Neoplasms/*enzymology/pathology ; Transfection ; rhoA GTP-Binding Protein/*antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {RhoA is a critical signaling molecule regulating a variety of cellular processes, such as cytoskeletal organization, adhesion, and apoptosis. It is recently considered responsive to reactive oxygen species (ROS). Nevertheless, how RhoA regulates anoikis, a detachment-initiated apoptosis, and how this regulation is affected by ROS are not clear. The present study investigated the role of RhoA in apoptosis/anoikis in gastric cancer cells and the changes of RhoA and anoikis under oxidative stress. Immunohistochemistry showed that RhoA expression was upregulated in the primary gastric carcinoma compared with normal gastric mucosa. Overactivation of RhoA by transfection with the V14RhoA mutant prevented gastric cancer line SGC-7901 cells from arsenic-induced apoptosis and conferred anoikis resistance through, at least in part, promoting formations of F-actin fibers and focal adhesion. Oxidative stress caused by emodin, an ROS producer, in combination with arsenic trioxide (ATO) led to RhoA inactivation that triggered structural disruption of focal adhesion complex and eventually resulted in anoikis, and these effects could be partially reversed by antioxidant N-acetylcysteine (NAC). In conclusion, activation of RhoA is required for the maintenance of anoikis resistance phenotype of gastric cancer cells, and oxidative stress might be a therapeutic strategy for the inhibition of RhoA in cancer cells.}, }
@article {pmid18226399, year = {2008}, author = {Thaha, M and Widodo,  and Pranawa, W and Yogiantoro, M and Tomino, Y}, title = {Intravenous N-acetylcysteine during hemodialysis reduces asymmetric dimethylarginine level in end-stage renal disease patients.}, journal = {Clinical nephrology}, volume = {69}, number = {1}, pages = {24-32}, doi = {10.5414/cnp69024}, pmid = {18226399}, issn = {0301-0430}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Arginine/*analogs &amp; derivatives/blood ; Biomarkers/blood ; Double-Blind Method ; Enzyme-Linked Immunosorbent Assay ; Female ; Follow-Up Studies ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Infusions, Intravenous ; Kidney Failure, Chronic/blood/*therapy ; Male ; Middle Aged ; Renal Dialysis/*methods ; Treatment Outcome ; }, abstract = {AIM: Cardiovascular disease is the main cause of mortality in chronic kidney disease patients. Moreover, uremic patients are in a pro-oxidant state and show an increase in asymmetric dimethylarginine (ADMA) levels due to inhibition of the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Asymmetric dimethylarginine per se seems responsible for a 52% increase in the risk of death and for a 34% increase in the risk of cardiovascular events in dialysis patients. N-acetylcysteine (NAC) is a thiol molecule that has direct and indirect antioxidant effects which decrease reactive oxidant species and increase the bioavailability of the DDAH enzyme. The aim of the current study was to determine the effect of intravenous NAC on plasma ADMA level when administered during hemodialysis in end-stage renal disease (ESRD) patients.<br><br>MATERIALS AND METHODS: 40 patients with ESRD were randomized to receive a 4-hour intravenous infusion of NAC or placebo during a 4-hour hemodialysis session. There were 3 diabetic patients (15%) in the treatment group and 6 patients in the control group. Plasma ADMA levels were measured before and immediately after hemodialysis. Hemodynamic parameters, including pulse pressure, were also measured. The paired t-test was used to compare the difference of ADMA levels before and after hemodialysis in each group, while the independent t-test was used to compare the difference of ADMA levels between the groups.<br><br>RESULTS: Compared with the pre-dialysis condition, there was a decrease of ADMA level in the control group (1.1253 +/- 0.1797 microM to 0.8676 +/- 0.1449 microM) (p < 0.001), and in the NAC group (1.1522 +/- 0.1737 microM to 0.7844 +/- 0.1586 microM) (p < 0.001). Compared with hemodialysis alone, NAC had a greater lowering effect on the ADMA level (21.3 vs. 31.9%, p < 0.05).<br><br>CONCLUSION: N-acetylcysteine (NAC) administered intravenously during hemodialysis reduced asymmetric dimethylarginine (ADMA) levels more significantly than hemodialysis alone.}, }
@article {pmid18225474, year = {2007}, author = {Kuntscher, V and Treska, V and Racek, J and Kobr, J and Trefil, L and Hes, O}, title = {Does the administration of antioxidants as scavengers of reactive oxygen species in kidney transplantation really have sense?.}, journal = {Bratislavske lekarske listy}, volume = {108}, number = {9}, pages = {385-387}, pmid = {18225474}, issn = {0006-9248}, mesh = {Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Infusions, Intravenous ; *Kidney Transplantation ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/metabolism/*prevention &amp; control ; Sus scrofa ; }, abstract = {BACKGROUND: The aim of the study was to evaluate the degree of ischemia reperfusion syndrome (IRS) in serious ischemic insult of a kidney transplant and to try to mitigate the production of reactive oxygen substances (ROS) and inflammatory response.<br><br>METHODS: The study was performed on 14 white pigs (20 kg). The pigs were divided in couples using a negative cross-matching and the couples were divided into the two groups. Each animal from the compatible couple was a donor/recipient of a kidney to/from the counterpart. Group II (TxII) received the intravenous antioxidants. Group I (TxI) was a control group. L-ascorbic acid 125 mg, selenium 4.4 mg, tocoferol 50 mg and N-acetyl-cysteine 200 mg were used as the antioxidants. They were applied intravenously to the TxII animals for 20 minutes before reperfusion of a kidney transplant. A serious ischemic insult was created by the left kidney hilum's cross-clamping for 30 min before donation. After the kidneys' removal, the left ones were flushed with Histidine Tryptophan Ketoglutarate (HTK) preservation solution and transplanted after the 1.5 hour (in the meantime stored in melted ice). Venous blood samples were taken for the assessment of malondialdehyde (MDA), reduced glutathione (GSH), glutathioneperoxidase (GSHPx), antioxidative capacity of plasma (AOC), interleukin 6 (IL-6), and tumor-necrosis factor alfa (TNFalfa) prior to the nefrectomy, before application of ROS scavengers (TxII), and during the 120-minute period after the transplantation (TxL+TxII).<br><br>RESULTS: There wasn't a significant difference neither in production of MDA, nor in the levels of GSH, GSHPx, AOC, IL6 and TNFalfa between the TxI and TxII groups.<br><br>CONCLUSIONS: Based on our results, we cannot conclude that the intravenous application of ROS scavengers in given combination and amount, administered to the recipient in the period just before transplantation, is a useful protective mechanism against kidney damage during IRS (Fig. 3, Ref. 17). Full Text (Free, PDF) www.bmj.sk.}, }
@article {pmid18223385, year = {2008}, author = {Mager, DR and Marcon, M and Wales, P and Pencharz, PB}, title = {Use of N-acetyl cysteine for the treatment of parenteral nutrition-induced liver disease in children receiving home parenteral nutrition.}, journal = {Journal of pediatric gastroenterology and nutrition}, volume = {46}, number = {2}, pages = {220-223}, doi = {10.1097/MPG.0b013e3180653ce6}, pmid = {18223385}, issn = {1536-4801}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Cholestasis/*chemically induced/*prevention &amp; control ; Dose-Response Relationship, Drug ; Female ; Humans ; Infant ; Male ; Parenteral Nutrition, Home/*adverse effects ; Treatment Outcome ; }, }
@article {pmid18220832, year = {2008}, author = {Vannini, N and Pfeffer, U and Lorusso, G and Noonan, DM and Albini, A}, title = {Endothelial cell aging and apoptosis in prevention and disease: E-selectin expression and modulation as a model.}, journal = {Current pharmaceutical design}, volume = {14}, number = {3}, pages = {221-225}, doi = {10.2174/138161208783413248}, pmid = {18220832}, issn = {1873-4286}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/physiology ; Cellular Senescence/physiology ; E-Selectin/drug effects/genetics/*metabolism ; Endothelial Cells/*metabolism/pathology ; Gene Expression Regulation/*drug effects/physiology ; Humans ; NF-kappa B/drug effects/metabolism ; Oligonucleotide Array Sequence Analysis ; RNA, Messenger/drug effects/metabolism ; }, abstract = {Endothelial cell senescence and apoptosis are features of numerous human pathologies including atherosclerosis, allograft vasculopathy, heart failure, diabetic retinopathy and scleroderma. In contrast, endothelial cell activation and replication associated with vessel proliferation and angiogenesis are now therapeutic targets in other diseases such as cancer and macular dystrophy. Finally, preventive medicine, in particular cardiovascular and cancer chemoprevention, commonly involve the endothelium. Here we discuss several aspects of the interplay between endothelial cell aging, apoptosis and senescence. Further, we show novel microarray data on endothelial cells "aged" in culture, and note that many genes regulated by the aging process are also modulated by a chemopreventive anti-angiogenic and anti-apoptotic drug, N-acetyl-cysteine (NAC). Focusing on one of these genes, the leukocyte adhesion protein E-selectin, we show that E-selectin is down-modulated with time in culture and upon treatment with NAC at mRNA and protein levels. This correlates with reduced adhesion of breast cancer cells and NF-kB activation in NAC treated endothelial cells. These data underscore the effects of a chemoprevention agent in modulating parameters associated with endothelial cell aging.}, }
@article {pmid18219322, year = {2008}, author = {Li, X and Luo, Y and Yu, L and Lin, Y and Luo, D and Zhang, H and He, Y and Kim, YO and Kim, Y and Tang, S and Min, W}, title = {SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis.}, journal = {Cell death and differentiation}, volume = {15}, number = {4}, pages = {739-750}, doi = {10.1038/sj.cdd.4402303}, pmid = {18219322}, issn = {1350-9047}, support = {P01HL070295-6/HL/NHLBI NIH HHS/United States ; R01 HL-65978-5/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; *Apoptosis/drug effects ; Carrier Proteins/genetics/*metabolism ; Cattle ; Cells, Cultured ; Cysteine Endopeptidases ; Cytoplasm/metabolism ; Endopeptidases/genetics/*metabolism ; Endothelial Cells/drug effects/enzymology/*metabolism/pathology ; Fibroblasts/metabolism/pathology ; Humans ; MAP Kinase Kinase Kinase 5/*metabolism ; Mice ; Mice, Knockout ; Mutation ; Protein Kinases/genetics/*metabolism ; *Protein Processing, Post-Translational ; Protein Serine-Threonine Kinases ; Protein Transport ; RNA Interference ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/metabolism ; Signal Transduction ; Small Ubiquitin-Related Modifier Proteins/*metabolism ; Thioredoxins/metabolism ; Time Factors ; Transfection ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {We have previously shown that tumor necrosis factor (TNF)-induced desumoylation and subsequent cytoplasmic translocation of HIPK1 are critical for ASK1-JNK activation. However, the mechanism by which TNF induces desumoylation of HIPK1 is unclear. Here, we show that SENP1, a SUMO-specific protease, specifically deconjugates SUMO from HIPK1 in vitro and in vivo. In resting endothelial cells (ECs), SENP1 is localized in the cytoplasm where it is complexed with an antioxidant protein thioredoxin. TNF induces the release of SENP1 from thioredoxin as well as nuclear translocation of SENP1. TNF-induced SENP1 nuclear translocation is specifically blocked by antioxidants such as N-acetyl-cysteine, suggesting that TNF-induced translocation of SENP1 is ROS dependent. TNF-induced nuclear import of SENP1 kinetically correlates with HIPK1 desumoylation and cytoplasmic translocation. Furthermore, the wild-type form of SENP1 enhances, whereas the catalytic-inactive mutant form or siRNA of SENP1 blocks, TNF-induced desumoylation and cytoplasmic translocation of HIPK1 as well as TNF-induced ASK1-JNK activation. More importantly, these critical functions of SENP1 in TNF signaling were further confirmed in mouse embryonic fibroblast cells derived from SENP1-knockout mice. We conclude that SENP1 mediates TNF-induced desumoylation and translocation of HIPK1, leading to an enhanced ASK1-dependent apoptosis.}, }
@article {pmid18218673, year = {2008}, author = {Jin, S and Ray, RM and Johnson, LR}, title = {TNF-alpha/cycloheximide-induced apoptosis in intestinal epithelial cells requires Rac1-regulated reactive oxygen species.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {294}, number = {4}, pages = {G928-37}, doi = {10.1152/ajpgi.00219.2007}, pmid = {18218673}, issn = {0193-1857}, support = {DK-16505/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aminoquinolines/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cell Line ; Cycloheximide/*pharmacology ; Cytosol/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/*drug effects/enzymology/metabolism/pathology ; Hydrogen Peroxide/pharmacology ; Intestinal Mucosa/*drug effects/enzymology/metabolism/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/drug effects/metabolism ; Mitogen-Activated Protein Kinase 8/metabolism ; Mitogen-Activated Protein Kinase 9/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Onium Compounds/pharmacology ; Oxidants/pharmacology ; Oxidative Stress/*drug effects ; Pyrimidines/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Rotenone/pharmacology ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/*metabolism ; Uncoupling Agents/pharmacology ; rac1 GTP-Binding Protein/antagonists &amp; inhibitors/genetics/*metabolism ; }, abstract = {Previously we have shown that both Rac1 and c-Jun NH(2)-terminal kinase (JNK1/2) are key proapoptotic molecules in tumor necrosis factor (TNF)-alpha/cycloheximide (CHX)-induced apoptosis in intestinal epithelial cells, whereas the role of reactive oxygen species (ROS) in apoptosis is unclear. The present studies tested the hypothesis that Rac1-mediated ROS production is involved in TNF-alpha-induced apoptosis. In this study, we showed that TNF-alpha/CHX-induced ROS production and hydrogen peroxide (H(2)O(2))-induced oxidative stress increased apoptosis. Inhibition of Rac1 by a specific inhibitor NSC23766 prevented TNF-alpha-induced ROS production. The antioxidant, N-acetylcysteine (NAC), or rotenone (Rot), the mitochondrial electron transport chain inhibitor, attenuated mitochondrial ROS production and apoptosis. Rot also prevented JNK1/2 activation during apoptosis. Inhibition of Rac1 by expression of dominant negative Rac1 decreased TNF-alpha-induced mitochondrial ROS production. Moreover, TNF-alpha-induced cytosolic ROS production was inhibited by Rac1 inhibition, diphenyleneiodonium (DPI, an inhibitor of NADPH oxidase), and NAC. In addition, DPI inhibited TNF-alpha-induced apoptosis as judged by morphological changes, DNA fragmentation, and JNK1/2 activation. Mitochondrial membrane potential change is Rac1 or cytosolic ROS dependent. Lastly, all ROS inhibitors inhibited caspase-3 activity. Thus these results indicate that TNF-alpha-induced apoptosis requires Rac1-dependent ROS production in intestinal epithelial cells.}, }
@article {pmid18216605, year = {2008}, author = {Liu, DD and Kao, SJ and Chen, HI}, title = {N-acetylcysteine attenuates acute lung injury induced by fat embolism.}, journal = {Critical care medicine}, volume = {36}, number = {2}, pages = {565-571}, doi = {10.1097/01.CCM.0000299737.24338.5C}, pmid = {18216605}, issn = {1530-0293}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Embolism, Fat/complications/*drug therapy/enzymology ; Expectorants/*therapeutic use ; Leukocyte Elastase/metabolism ; Male ; Nitric Oxide Synthase Type II/metabolism ; Peroxidase/metabolism ; Pulmonary Embolism/complications/*drug therapy/enzymology ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome/enzymology/etiology/*prevention &amp; control ; }, abstract = {OBJECTIVES: Fat embolism syndrome is a clinical issue in subjects with long-bone fracture. It may lead to acute lung injury. The mechanisms and therapeutic regimen remain unclear. The present study was designed to investigate the pathologic and biochemical changes after fat embolization in isolated rat lungs, and to test the effects of posttreatment with N-acetylcysteine (NAC).<br><br>DESIGN: Prospective, randomized, controlled animal study.<br><br>SETTING: University research laboratory.<br><br>SUBJECTS: A total of 36 perfused lungs isolated from Sprague-Dawley rats.<br><br>INTERVENTIONS: The isolated lungs were randomly assigned to receive physiologic saline solution (vehicle group), fat embolism (FE group), or FE with NAC posttreatment (FE + NAC group). There were 12 isolated lungs in each group. FE was produced by introduction of corn oil micelles. NAC at a dose 150 mg/kg was given 10 mins after FE.<br><br>MEASUREMENTS AND MAIN RESULTS: The extent of acute lung injury was evaluated by lung weight change, protein concentration in bronchoalveolar lavage, and exhaled nitric oxide. We also measured the pulmonary arterial pressure and capillary filtration coefficient and determined the nitrate/nitrite, methylguanidine, tumor necrosis factor-alpha, and interleukin-1beta in lung perfusate. Histopathologic changes of the lung were examined and quantified. The levels of neutrophil elastase and myeloperoxidase were determined. The expression of inducible nitric oxide synthase was detected. FE caused acute lung injury as evidenced by the lung weight changes, increases in exhaled nitric oxide and protein concentration in bronchoalveolar lavage, pulmonary hypertension, increased capillary filtration coefficient, and lung pathology. The insult also increased nitrate/nitrite, methylguanidine, tumor necrosis factor-alpha, and interleukin-1beta in lung perfusate, increased neutrophil elastase and myeloperoxidase levels, and upregulated inducible nitric oxide synthase expression. Posttreatment with NAC abrogated these changes induced by FE.<br><br>CONCLUSION: FE caused acute lung injury and associated biochemical changes. Posttreatment with NAC was effective to alleviate the pathologic and biochemical changes caused by FE.}, }
@article {pmid18214889, year = {2008}, author = {Jia, J and Chen, J}, title = {Chronic nickel-induced DNA damage and cell death: the protection role of ascorbic acid.}, journal = {Environmental toxicology}, volume = {23}, number = {3}, pages = {401-406}, doi = {10.1002/tox.20346}, pmid = {18214889}, issn = {1520-4081}, mesh = {Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cell Death ; *DNA Fragmentation ; HL-60 Cells ; Humans ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred C57BL ; Nickel/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {High consumption of nickel-containing products leads to more exposure of humans to nickel and its by-products. Except the lethal effect of acute nickel poison, chronic nickel exposure is also harmful to humans, but the mechanism of chronic nickel-induced cytotoxicity remains unclear. Here, we found that long-term exposure of Ni(2+) led to significant DNA fragmentation, cell death, and reactive oxygen species (ROS) generation in human leukemia HL-60 cells. Induction of Ni(2+) on DNA fragmentation and cell death could be prevented by the antioxidants ascorbic acid (ASA) or N-acetyl-cysteine (NAC), or enhanced by H(2)O(2), indicating the involvement of ROS generation in the chronic nickel cytotoxicity in cells. Long-term exposure of mice to low Ni(2+) also led to a significant increase in both the ROS generation in the serum and the DNA fragmentation in the peripheral blood mononuclear cells (PBMC), while coadministration of ASA with Ni(2+) together significantly decreased both the DNA fragmentation and the ROS generation. Collectively, these results proved that ROS generation is at least one mechanism of the cytotoxicity of chronic nickel exposure, while ASA is probably useful for people to prevent the chronic nickel cytotoxicity, especially for those who work or live near a mining area or a factory related with nickel.}, }
@article {pmid18214123, year = {2007}, author = {Yilmaz, H and Sahin, S and Sayar, N and Tangurek, B and Yilmaz, M and Nurkalem, Z and Onturk, E and Cakmak, N and Bolca, O}, title = {Effects of folic acid and N-acetylcysteine on plasma homocysteine levels and endothelial function in patients with coronary artery disease.}, journal = {Acta cardiologica}, volume = {62}, number = {6}, pages = {579-585}, doi = {10.2143/AC.62.6.2024017}, pmid = {18214123}, issn = {0001-5385}, mesh = {Acetylcysteine/*administration &amp; dosage/therapeutic use ; Administration, Oral ; Aged ; Coronary Artery Disease/*blood/drug therapy/*physiopathology ; Double-Blind Method ; Endothelium, Vascular/drug effects/*physiopathology ; Female ; Folic Acid/*administration &amp; dosage/therapeutic use ; Homocysteine/*blood ; Humans ; Hyperhomocysteinemia/blood/drug therapy/physiopathology ; Male ; Middle Aged ; }, abstract = {OBJECTIVE: Hyperhomocysteinaemia is related with premature coronary artery disease and adverse cardiac events in patients with coronary artery disease (CAD). It is assumed that hyper-homocysteinaemia causes endothelial dysfunction. In this study, the effect of folic acid and oral N-acetylcysteine (NAC) therapies on plasma homocysteine levels and endothelial function were evaluated in hyperhomocysteinaemic patients with CAD.<br><br>METHODS AND RESULTS: 60 patients were randomized to either folic acid 5 mg or NAC 600 mg or placebo daily for eight weeks. Brachial artery endothelial functions were studied by using high-resolution ultrasound and assessed by measuring endothelium-dependent dilation (EDD) and endothelium-independent dilation (NEDD). Folic acid and NAC therapies decreased plasma homocysteine (from 21.7 +/- 8.7 micromol/l to 12.5 +/- 2.5 micromol/l, P < 0.001; from 20.9 +/- 7.6 micromol/l to 15.6 +/- 4.3 micromol/l, P = 0.03, respectively), and increased EDD (6.7 +/- 6.1% P = 0.002, 4.4 +/- 2.6% P < 0.001, respectively) compared with placebo. There was no significant difference in improving EDD between the folic acid and the NAC group (6.7 +/- 6.1%, 4.4 +/- 2.6%, P = 0. 168). In the univariate analyses there was an inverse correlation between the post-treatment homocysteine level and the percent change in EDD with folic acid therapy (r= -0.490, P = 0.028), but there was no correlation with the NAC therapy (r = 0.259, P = 0.333)<br><br>CONCLUSION: In patients with hyperhomocysteinaemic CAD, folic acid and NAC lowered plasma homocysteine levels and improved endothelial function. The effects of both treatments in improvement of EDD were similar.}, }
@article {pmid18211314, year = {2008}, author = {Waring, WS and Stephen, AF and Malkowska, AM and Robinson, OD}, title = {Acute ethanol coingestion confers a lower risk of hepatotoxicity after deliberate acetaminophen overdose.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {15}, number = {1}, pages = {54-58}, doi = {10.1111/j.1553-2712.2007.00019.x}, pmid = {18211314}, issn = {1553-2712}, mesh = {Acetaminophen/*poisoning ; Analgesics, Non-Narcotic/*poisoning ; Chemical and Drug Induced Liver Injury/*epidemiology ; Drug Overdose ; Ethanol/*pharmacology ; Female ; Humans ; Male ; Prospective Studies ; Risk Factors ; Scotland/epidemiology ; Self-Injurious Behavior/epidemiology ; }, abstract = {OBJECTIVES: Little is known about the clinical significance of acute ethanol coingestion around the time of acetaminophen (paracetamol) overdose. This study prospectively examined the effect of acute ethanol coingestion on risk of hepatotoxicity among patients admitted to hospital for N-acetylcysteine (NAC) therapy after deliberate acetaminophen overdose.<br><br>METHODS: This was a prospective observational study and included sequential patients who presented within 24 hours of acute acetaminophen ingestion and required NAC therapy. Significant hepatotoxicity was defined by alanine transaminase > 1,000 U/L or the international normalized ratio > 1.3 after a standardized intravenous administration of 300 mg/kg NAC.<br><br>RESULTS: There were 362 patients, including 178 (49.2%) who coingested ethanol acutely. The prevalence of hepatotoxicity was 5.1% (95% CI = 2.6% to 9.5%) in those who ingested ethanol, compared to 15.2% (95% CI = 10.7% to 21.2%) in those who did not (p = 0.0027 by chi-square proportional test). Acute ethanol intake conferred a lower risk of hepatotoxicity in patients who had acetaminophen concentrations above or below the "200-line" and was independent of the interval between ingestion and assessment.<br><br>CONCLUSIONS: Acute ethanol intake is associated with a lower risk of hepatotoxicity after acetaminophen overdose. This apparent protective effect cannot be explained solely by lower exposure to acetaminophen in this group, nor differences in the interval between ingestion and initiation of treatment. Further work is required to establish mechanisms by which ethanol might confer protection against hepatotoxicity, so as to identify novel strategies for reducing risk after acute acetaminophen ingestion.}, }
@article {pmid18210232, year = {2007}, author = {Lima-Júnior, RC and Sousa, DI and Brito, GA and Cunha, GM and Chaves, MH and Rao, VS and Santos, FA}, title = {Modulation of acute visceral nociception and bladder inflammation by plant triterpene, alpha, beta-amyrin in a mouse model of cystitis: role of tachykinin NK(1)-receptors, and K(+)(ATP) channels.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {56}, number = {12}, pages = {487-494}, doi = {10.1007/s00011-007-7023-4}, pmid = {18210232}, issn = {1023-3830}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use ; Capsaicin/pharmacology ; Cyclophosphamide ; Cystitis/chemically induced/*drug therapy ; Edema/chemically induced/drug therapy ; Glyburide/pharmacology ; KATP Channels/*physiology ; Male ; Mice ; Oleanolic Acid/*analogs &amp; derivatives/pharmacology/therapeutic use ; Pain/drug therapy/*physiopathology ; Receptors, Neurokinin-1/*physiology ; TRPV Cation Channels/*physiology ; Urinary Bladder/drug effects/physiopathology ; }, abstract = {OBJECTIVE AND DESIGN: We previously described the visceral antinociceptive property of alpha, beta-amyrin in a mouse model of cystitis induced by cyclophosphamide (CPM). This study examined the contribution of vanilloid-1 (TRPV1), peripheral NK1 receptors to CPM-evoked nociceptive behaviors and bladder edema, and its possible modulation by alpha, beta-amyrin.<br><br>METHODS: The effect of alpha, beta-amyrin (10, 30, and 100 mg/kg, p. o.) and N-acetylcysteine (NAC) on CPM (400 mg/kg, i. p.)-induced cystitis was studied in mice. Sensory deafferentation was done by a high dose capsaicin. The parameters analysed were: CPM-evoked noxious behaviors, bladder edema, vascular permeability, and NK(1) immunoreactivity. To assess the role of K(+) (ATP) channels in alpha, beta-amyrin effect, animals were pretreated with glibenclamide.<br><br>RESULTS: alpha, beta-amyrin (30 and 100 mg/kg) and NAC significantly (p < 0.01) suppressed the visceral pain-related behaviors and NK(1) immunoreactivity, but bladder edema was reduced weakly. Glibenclamide reversed the effects of alpha, beta-amyrin. Sensory deafferentation by capsaicin significantly reduced the nociceptive responses and the NK(1) immunoreactivity to noxious stimulation by CPM.<br><br>CONCLUSIONS: alpha, beta-amyrin attenuates CPM-induced visceral pain and bladder edema by mechanisms that involve, at least in part, a block either of Substance P release or its receptor function, and partly by opening K(+) (ATP) channels.}, }
@article {pmid18206665, year = {2008}, author = {Lambert, JD and Sang, S and Yang, CS}, title = {N-Acetylcysteine enhances the lung cancer inhibitory effect of epigallocatechin-3-gallate and forms a new adduct.}, journal = {Free radical biology &amp; medicine}, volume = {44}, number = {6}, pages = {1069-1074}, pmid = {18206665}, issn = {0891-5849}, support = {R03 CA125780/CA/NCI NIH HHS/United States ; R03 CA125780-02/CA/NCI NIH HHS/United States ; P30 ES005022/ES/NIEHS NIH HHS/United States ; R01 AT004678/AT/NCCIH NIH HHS/United States ; CA121390/CA/NCI NIH HHS/United States ; R03 CA121390/CA/NCI NIH HHS/United States ; CA125780/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/chemistry ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Antioxidants/chemistry/*pharmacology ; Apoptosis/drug effects ; Catechin/administration &amp; dosage/analogs &amp; derivatives/chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chromatography, High Pressure Liquid ; Flow Cytometry ; Humans ; Lung Neoplasms/*metabolism ; Mice ; Radiation-Protective Agents/administration &amp; dosage/chemistry ; }, abstract = {The major tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), inhibits carcinogenesis in many in vivo models. Many potential mechanisms of action have been proposed based on cell line studies, including prooxidant activity. In the present study, we studied the effect of N-acetylcysteine (NAC) on the inhibitory effects of EGCG on lung cancer cell growth. We found that NAC (0-2 mM) dose dependently enhanced the growth inhibitory activity of EGCG against murine and human lung cancer cells. The combination of NAC and EGCG caused an 8.8-fold increase in apoptosis in CL13 mouse lung cancer cells compared to treatment with either agent alone. Addition of 2 mM NAC increased the stability of EGCG in the presence of CL13 cells (t 1/2=8.5 h vs 22.7 h). Intracellular levels of EGCG were increased 5.5-fold by the addition of 2 mM NAC. HPLC and LC-MS analyses of cell culture medium from CL13 cells treated with EGCG and NAC for 24 h revealed that EGCG-2'-NAC was time dependently formed. This adduct was not formed in the absence of NAC. The present results show that under cell culture conditions, EGCG and NAC interact to form a previously unreported adduct, EGCG-2'-NAC, which may contribute to enhancement of EGCG-mediated cell killing.}, }
@article {pmid18205750, year = {2008}, author = {Paintlia, MK and Paintlia, AS and Khan, M and Singh, I and Singh, AK}, title = {Modulation of peroxisome proliferator-activated receptor-alpha activity by N-acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial cultures.}, journal = {Journal of neurochemistry}, volume = {105}, number = {3}, pages = {956-970}, pmid = {18205750}, issn = {1471-4159}, support = {R37 NS022576-24/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; R01 NS022576/NS/NINDS NIH HHS/United States ; R01 NS034741/NS/NINDS NIH HHS/United States ; R37 NS022576/NS/NINDS NIH HHS/United States ; NS-22576/NS/NINDS NIH HHS/United States ; R01 NS040810/NS/NINDS NIH HHS/United States ; C06 RR018823/RR/NCRR NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; C06 RR015455/RR/NCRR NIH HHS/United States ; R01 NS037766-10/NS/NINDS NIH HHS/United States ; R01 NS022576-17/NS/NINDS NIH HHS/United States ; R01 NS037766/NS/NINDS NIH HHS/United States ; R01 NS034741-12/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Brain/*growth &amp; development/*metabolism ; Cell Differentiation/drug effects/*physiology ; Cell Line ; Cells, Cultured ; Coculture Techniques ; Down-Regulation/genetics ; Encephalitis/drug therapy/metabolism/physiopathology ; Free Radical Scavengers/pharmacology ; Infectious Disease Transmission, Vertical ; Inflammation Mediators/pharmacology ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Knockout ; Oligodendroglia/drug effects/*metabolism ; Oxidative Stress/drug effects/physiology ; PPAR alpha/drug effects/genetics/*metabolism ; Peroxisomes/*metabolism ; RNA, Small Interfering/genetics ; Rats ; Rats, Sprague-Dawley ; Stem Cells/drug effects/metabolism ; }, abstract = {Glial cells secrete proinflammatory mediators in the brain in response to exogenous stimuli such as infection and injury. Previously, we documented that systemic maternal lipopolysaccharide (LPS)-exposure at embryonic gestation day 18 causes oligodendrocyte (OL)-injury/hypomyelination in the developing brain which can be attenuated by N-acetyl cysteine (NAC; precursor of glutathione). The present study delineates the underlying mechanism of NAC-mediated attenuation of inhibition of OL development in LPS-stimulated mixed glial cultures. Factors released by LPS-stimulated mixed glial cultures inhibited OL development as shown by decrease in both proliferation 3bromo-deoxyuridine+/chondroitin sulfate proteoglycan-NG2+, hereafter BrdU+/NG+ and differentiation (O4+ and myelin basic protein+) of OL-progenitors. Correspondingly, an impairment of peroxisomal proliferation was shown by a decrease in the level of peroxisomal proteins in the developing OLs following exposure to LPS-conditioned media (LCM). Both NAC and WY14643, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist attenuated these LCM-induced effects in OL-progenitors. Similar to WY14643, NAC attenuated LCM-induced inhibition of PPAR-alpha activity in developing OLs. Studies conducted with cytokines and diamide (a thiol-depleting agent) confirmed that cytokines are active agents in LCM which may be responsible for inhibition of OL development via peroxisomal dysfunction and induction of oxidative stress. These findings were further corroborated by similar treatment of developing OLs generated from PPAR-alpha(-/-) and wild-type mice or B12 oligodendroglial cells co-transfected with PPAR-alpha small interfering RNAs/pTK-PPREx3-Luc plasmids. Collectively, these data provide evidence that the modulation of PPAR-alpha activity, thus peroxisomal function by NAC attenuates LPS-induced glial factors-mediated inhibition of OL development suggesting new therapeutic interventions to prevent the devastating effects of maternal infections.}, }
@article {pmid18202091, year = {2008}, author = {Haase, M and Haase-Fielitz, A and Ratnaike, S and Reade, MC and Bagshaw, SM and Morgera, S and Dragun, D and Bellomo, R}, title = {N-Acetylcysteine does not artifactually lower plasma creatinine concentration.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {23}, number = {5}, pages = {1581-1587}, doi = {10.1093/ndt/gfm818}, pmid = {18202091}, issn = {1460-2385}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Aged ; Cardiac Surgical Procedures ; Contrast Media/adverse effects ; Creatinine/*blood ; Cystatin C ; Cystatins/blood ; Double-Blind Method ; Female ; Glomerular Filtration Rate/drug effects ; Humans ; Infusions, Intravenous ; Intraoperative Care ; Kidney Diseases/etiology/physiopathology/prevention &amp; control ; Male ; Middle Aged ; Urea/blood ; }, abstract = {BACKGROUND: All randomized controlled trials of N-acetylcysteine (NAC) in contrast media-induced nephropathy used creatinine as a marker of renal function. However, it has been suggested that NAC may lower plasma creatinine levels independent of any effects on glomerular filtration rate (GFR).<br><br>METHODS: At a tertiary hospital 110 cardiac surgical patients were randomly allocated to peri-operative infusion of NAC (300 mg/kg over 24 h, N = 30) or placebo (N = 80). We compared the plasma concentrations of creatinine, cystatin C and urea, the plasma creatinine/plasma cystatin C ratio and the estimated GFR at baseline and at 24 and 72 h after commencement of the infusion. We measured urinary creatinine concentration at 24 h.<br><br>RESULTS: At baseline, the plasma creatinine/plasma cystatin C ratio did not differ between the NAC and placebo group (0.90 versus 0.92; P = 0.94). There was no significant difference in the plasma creatinine/plasma cystatin C ratio for the NAC and placebo group either during or after NAC infusion at 24 h (1.03 versus 1.00; P = 0.78) and 72 h (0.94 versus 0.89; P = 0.09). Those allocated to NAC showed no difference in urinary creatinine excretion when compared to placebo (P = 0.24).<br><br>CONCLUSIONS: The results of our study do not demonstrate that NAC artifactually lowers creatinine measured using the Jaff&#xe9; method. (ClinicalTrials.gov, NCT00332631, NCT00334191).}, }
@article {pmid18198991, year = {2009}, author = {Matejíková, J and Kucharská, J and Pintérová, M and Pancza, D and Ravingerová, T}, title = {Protection against ischemia-induced ventricular arrhythmias and myocardial dysfunction conferred by preconditioning in the rat heart: involvement of mitochondrial K(ATP) channels and reactive oxygen species.}, journal = {Physiological research}, volume = {58}, number = {1}, pages = {9-19}, doi = {10.33549/physiolres.931317}, pmid = {18198991}, issn = {0862-8408}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Arrhythmia Agents/pharmacology ; Antioxidants/pharmacology ; Decanoic Acids/pharmacology ; Diazoxide/pharmacology ; Hydroxy Acids/pharmacology ; In Vitro Techniques ; *Ischemic Preconditioning, Myocardial ; Lipid Peroxidation ; Male ; *Myocardial Contraction/drug effects ; Myocardial Reperfusion Injury/metabolism/physiopathology/*prevention &amp; control ; Myocardium/*metabolism ; Oxidative Stress ; Perfusion ; Potassium Channel Blockers/pharmacology ; Potassium Channels/drug effects/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Recovery of Function ; Thiobarbituric Acid Reactive Substances/metabolism ; Time Factors ; *Ventricular Function, Left/drug effects ; Ventricular Premature Complexes/metabolism/physiopathology/*prevention &amp; control ; }, abstract = {Ischemic preconditioning (I-PC) induced by brief episodes of ischemia and reperfusion (I/R) protects the heart against sustained I/R. Although activation of mitochondrial K(ATP) channels (mitoK(ATP)) interacting with reactive oxygen species (ROS) has been proposed as a key event in this process, their role in the antiarrhythmic effect is not clear. This study was designed: 1) to investigate the involvement of mito K(ATP) opening in the effect of I-PC (1 cycle of I/R, 5 min each) on ventricular arrhythmias during test ischemia (TI, 30-min LAD coronary artery occlusion) in Langendorff-perfused rat hearts and subsequent postischemic contractile dysfunction, and 2) to characterize potential mechanisms of protection conferred by I-PC and pharmacological PC induced by mito K(ATP) opener diazoxide (DZX), with particular regards to the modulation of ROS generation. Lipid peroxidation (an indicator of increased ROS production) was determined by measurement of myocardial concentration of conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS) in non-ischemic controls, non-preconditioned and preconditioned hearts exposed to TI, I-PC alone, as well as after pretreatment with DZX, mito K(ATP) blocker 5-hydroxydecanoate (5-HD) and antioxidant N-acetylcysteine (NAC). Total number of ventricular premature beats (VPB) that occurred in the control hearts (518+/-71) was significantly (P<0.05) reduced by I-PC (195+/-40), NAC (290+/-56) and DZX (168+/-22). I-PC and NAC suppressed an increase in CD and TBARS caused by ischemia indicating lower production of ROS. On the other hand, I-PC and DZX themselves moderately enhanced ROS generation, prior to TI. Bracketing of I-PC with 5-HD suppressed both, ROS production during PC and its cardioprotective effect. In conclusion, potential mechanisms of protection conferred by mito K(ATP) opening in the rat heart might involve a temporal increase in ROS production in the preconditioning phase triggering changes in the pro/antioxidant balance in the myocardium and attenuating ROS production during subsequent prolonged ischemia.}, }
@article {pmid18197877, year = {2008}, author = {de Oliveira, CP and Stefano, JT and de Siqueira, ER and Silva, LS and de Campos Mazo, DF and Lima, VM and Furuya, CK and Mello, ES and Souza, FG and Rabello, F and Santos, TE and Nogueira, MA and Caldwell, SH and Alves, VA and Carrilho, FJ}, title = {Combination of N-acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non-alcoholic steatohepatitis.}, journal = {Hepatology research : the official journal of the Japan Society of Hepatology}, volume = {38}, number = {2}, pages = {159-165}, doi = {10.1111/j.1872-034X.2007.00215.x}, pmid = {18197877}, issn = {1386-6346}, abstract = {AIM: There is no proven medical therapy for the treatment of non-alcoholic steatohepatitis (NASH). Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis. The aim of our study was to evaluate the efficacy of N-acetylcysteine (NAC) in combination with metformin (MTF) in improving the aminotransferases and histological parameters (steatosis, inflammation, hepatocellular ballooning, and fibrosis) after 12 months of treatment.<br><br>METHODS: Twenty consecutive patients (mean age 53 +/- 2 years [36-68] and body mass index [BMI] 29 [25-35]) with biopsy-proven NASH were enrolled in the study. NAC (1.2 g/day) and MTF (850-1000 mg/day) were given orally for 12 months. All patients underwent evaluation of serum aminotransferases, fasting lipid profile and serum glucose, anthropometric parameters, and nutritional status at 0 and 12 months. A low calorie diet was prescribed for all patients.<br><br>RESULTS: Serum alanine aminotransferase, high-density lipoprotein, insulin, and glucose concentrations and thehomeostasis model assessment-insulin resistance (HOMA-IR) index were reduced significantly at the end of study (P < 0.05). The BMI declined, but without statistical significance. Aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, cholesterol, and triglycerides levels were not altered with the treatment. Liver steatosis and fibrosis decreased (P < 0.05), but no improvement was noted in lobular inflammation or hepatocellular ballooning. The NASH activity score was significantly improved after treatment.<br><br>CONCLUSION: Based on the biochemical and histological evidence in this pilot study, NAC in combination with MTF appears to ameliorate several aspects of NASH, including fibrosis. Further studies of this form of combination therapy are warranted to assess its potential efficacy.}, }
@article {pmid18197295, year = {2008}, author = {Aremu, DA and Madejczyk, MS and Ballatori, N}, title = {N-acetylcysteine as a potential antidote and biomonitoring agent of methylmercury exposure.}, journal = {Environmental health perspectives}, volume = {116}, number = {1}, pages = {26-31}, pmid = {18197295}, issn = {0091-6765}, support = {R01 DK048823/DK/NIDDK NIH HHS/United States ; F32 ES015965/ES/NIEHS NIH HHS/United States ; ES01247/ES/NIEHS NIH HHS/United States ; P30 ES001247/ES/NIEHS NIH HHS/United States ; ES07026/ES/NIEHS NIH HHS/United States ; R01 ES007026/ES/NIEHS NIH HHS/United States ; DK48823/DK/NIDDK NIH HHS/United States ; ES06484/ES/NIEHS NIH HHS/United States ; ES015965/ES/NIEHS NIH HHS/United States ; T32 ES007026/ES/NIEHS NIH HHS/United States ; R01 ES006484/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Antidotes/*pharmacology ; Environmental Monitoring ; Female ; Kidney/metabolism ; Liver/metabolism ; Male ; Methylmercury Compounds/blood/pharmacokinetics/*urine ; Pregnancy ; Rats ; Rats, Wistar ; Spleen/metabolism ; }, abstract = {BACKGROUND: Many people, by means of consumption of seafood or other anthropogenic sources, are exposed to levels of methylmercury (MeHg) that are generally considered to be quite low, but that may nevertheless produce irreversible brain damage, particularly in unborn babies. The only way to prevent or ameliorate MeHg toxicity is to enhance its elimination from the body.<br><br>OBJECTIVES: Using N-acetylcysteine (NAC), we aimed to devise a monitoring protocol for early detection of acute exposure or relatively low MeHg levels in a rodent model, and to test whether NAC reduces MeHg levels in the developing embryo.<br><br>RESULTS: NAC produced a transient, dose-dependent acceleration of urinary MeHg excretion in rats of both sexes. Approximately 5% of various MeHg doses was excreted in urine 2 hr after injection of 1 mmol/kg NAC. In pregnant rats, NAC markedly reduced the body burden of MeHg, particularly in target tissues such as brain, placenta, and fetus. In contrast, NAC had no significant effect on urinary MeHg excretion in preweanling rats.<br><br>CONCLUSIONS: Because NAC causes a transient increase in urinary excretion of MeHg that is proportional to the body burden, it is promising as a biomonitoring agent for MeHg in adult animals. In view of this and because NAC is effective at enhancing MeHg excretion when given either orally or intravenously, can decrease brain and fetal levels of MeHg, has minimal side effects, and is widely available in clinical settings, NAC should be evaluated as a potential antidote and biomonitoring agent in humans.}, }
@article {pmid18193173, year = {2008}, author = {Walther, UI and Walther, SC and Mückter, H and Fichtl, B}, title = {Enhancing glutathione synthesis can decrease zinc-mediated toxicity.}, journal = {Biological trace element research}, volume = {122}, number = {3}, pages = {216-228}, doi = {10.1007/s12011-007-8072-9}, pmid = {18193173}, issn = {0163-4984}, mesh = {Acetylcysteine/*pharmacology ; Cell Line ; Cell Line, Tumor ; Cysteine/pharmacology ; Glutathione/biosynthesis/*metabolism ; Humans ; Hydrocortisone/pharmacology ; Methionine/metabolism ; Reducing Agents/pharmacology ; Stereoisomerism ; Up-Regulation/drug effects ; Zinc Compounds/metabolism/*toxicity ; }, abstract = {Zinc toxicity has been linked to cellular glutathione: A decrease in glutathione is followed by an increase in zinc-mediated toxicity. The question arises whether an increase in glutathione synthesis might decrease zinc-mediated cytotoxicity. We incubated five cell lines (hepatoma and lung-derived) with zinc chloride and 2 mmol/l N-acetyl-L-cysteine (NAC) to support glutathione synthesis. In all but one hepatic cell line, the glutathione content was increased by NAC as compared to the D-enantiomere NADC, whereas NADC did not increase GSH content as compared to not treated controls. In both alveolar epithelial cell lines, an increase in zinc tolerance was observed due to NAC as compared to NADC. In native fibroblast-like and the hepatoma cell lines, no changes in zinc tolerance were found due to NAC. In the fibroblast-like cells, zinc tolerance was increased due to NAC only after cellular glutathione had been previously decreased (by lowered cysteine concentrations in the medium). Enhancing glutathione synthesis can antagonize zinc-mediated toxicity in the alveolar epithelial cell lines, whereas some other characteristics than glutathione synthesis might be more important in other cell types. Furthermore, NAC acted as a GSH precursor only at cysteine medium concentrations of 10 micromol/l or below and therefore might be described as a poor cysteine repletor for glutathione synthesis.}, }
@article {pmid18191753, year = {2008}, author = {Reid, MB}, title = {Free radicals and muscle fatigue: Of ROS, canaries, and the IOC.}, journal = {Free radical biology &amp; medicine}, volume = {44}, number = {2}, pages = {169-179}, doi = {10.1016/j.freeradbiomed.2007.03.002}, pmid = {18191753}, issn = {0891-5849}, support = {HL45721/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/physiology ; Athletic Performance/physiology ; Bicycling/physiology ; Biomedical Enhancement ; Cell Respiration ; Electric Stimulation ; Free Radicals/*metabolism/*pharmacology ; Humans ; Models, Biological ; Muscle Fatigue/drug effects/*physiology ; Muscle, Skeletal/physiology ; Oxidation-Reduction ; Oxidative Stress/physiology ; Physical Exertion/physiology ; Reactive Oxygen Species/*metabolism/*pharmacology ; }, abstract = {Skeletal muscle fibers continually generate reactive oxygen species (ROS) at a slow rate that increases during muscle contraction. This activity-dependent increase in ROS production contributes to fatigue of skeletal muscle during strenuous exercise. Existing data suggest that muscle-derived ROS primarily act on myofibrillar proteins to inhibit calcium sensitivity and depress force. Decrements in calcium sensitivity and force are acutely reversible by dithiothreitol, a thiol-selective reducing agent. These observations suggest that thiol modifications on one or more regulatory proteins are responsible for oxidant-induced losses during fatigue. More intense ROS exposure leads to losses in calcium regulation that mimic pathologic changes and are not reversible. Studies in humans, quadrupeds, and isolated muscle preparations indicate that antioxidant pretreatment can delay muscle fatigue. In humans, this phenomenon is best defined for N-acetylcysteine (NAC), a reduced thiol donor that supports glutathione resynthesis. NAC has been shown to inhibit fatigue in healthy adults during electrical muscle activation, inspiratory resistive loading, handgrip exercise, and intense cycling. These findings identify ROS as endogenous mediators of muscle fatigue and highlight the importance of future research to (a) define the cellular mechanism of ROS action and (b) develop antioxidants as novel therapeutic interventions for treating fatigue.}, }
@article {pmid18187174, year = {2008}, author = {Chang, YC and Lin, P}, title = {Trans, trans-2,4-decadienal induced cell proliferation via p27 pathway in human bronchial epithelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {228}, number = {1}, pages = {76-83}, doi = {10.1016/j.taap.2007.11.028}, pmid = {18187174}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/antagonists &amp; inhibitors/*toxicity ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Blotting, Western ; Bronchi/*cytology/drug effects ; Cell Cycle/drug effects ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/antagonists &amp; inhibitors/*physiology ; DNA, Complementary/biosynthesis/genetics ; Epithelial Cells/*drug effects ; Gene Expression Regulation/drug effects ; Humans ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; Retinoblastoma Protein/biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*drug effects ; }, abstract = {Lung cancer is the leading cause of cancer deaths worldwide. Epidemiological studies have shown that exposure to cooking oil fumes (COF) is a risk factor for lung cancer. Trans, trans-2,4-decadienal (tt-DDE), a dienaldehyde, is abundant in heated oils and COF. Previously, we found that long-term exposure (45 days) to a sub-lethal dose (1 microM) of tt-DDE significantly increased growth of human bronchial epithelial cells (BEAS-2B). Aims of this study are to understand the mechanism of tt-DDE-induced cell proliferation and possible protective effects of antioxidant, vitamin C and N-acetylcysteine (NAC) in BEAS-2B cells. Utilizing the real-time RT-PCR and Western immunoblotting, we found that p27 mRNA and protein levels were significantly increased by 1 microM tt-DDE treatment. Co-treatment with vitamin C or NAC partially prevented tt-DDE-induced cell proliferation. In addition, the downstream targets of p27, including CDK4, cyclin D1 and phosphorylated-Rb proteins, increased in 1 microM tt-DDE-treated cells and these changes were prevented by NAC co-treatment. Therefore, these results suggest that tt-DDE increased cell proliferation via inhibition of p27 expression, increase in CDK4/cyclin D1 protein accumulation and enhancement of Rb phosphorylation. Increased cell proliferation is considered as the early stages of lung carcinogenesis. Administration of antioxidants may prevent COF-associated lung carcinogenesis.}, }
@article {pmid18179781, year = {2008}, author = {Guo, H and Ling, W and Wang, Q and Liu, C and Hu, Y and Xia, M}, title = {Cyanidin 3-glucoside protects 3T3-L1 adipocytes against H2O2- or TNF-alpha-induced insulin resistance by inhibiting c-Jun NH2-terminal kinase activation.}, journal = {Biochemical pharmacology}, volume = {75}, number = {6}, pages = {1393-1401}, doi = {10.1016/j.bcp.2007.11.016}, pmid = {18179781}, issn = {1873-2968}, mesh = {3T3-L1 Cells ; Adipocytes/*drug effects/metabolism ; Animals ; Anthocyanins/*pharmacology ; Glucose/metabolism ; Glucosides/*pharmacology ; Hydrogen Peroxide ; Insulin/metabolism ; *Insulin Resistance ; Mice ; Mitogen-Activated Protein Kinase 8/genetics/*metabolism ; Protective Agents/*pharmacology ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha ; }, abstract = {Anthocyanins are naturally occurring plant pigments and exhibit an array of pharmacological properties. Our previous study showed that black rice pigment extract rich in anthocyanin prevents and ameliorates high-fructose-induced insulin resistance in rats. In present study, cyanidin 3-glucoside (Cy-3-G), a typical anthocyanin most abundant in black rice was used to examine its protective effect on insulin sensitivity in 3T3-L1 adipocytes exposed to H(2)O(2) (generated by adding glucose oxidase to the medium) or tumor necrosis factor alpha (TNF-alpha). Twelve-hour exposure of 3T3-L1 adipocytes to H(2)O(2) or TNF-alpha resulted in the increase of c-Jun NH(2)-terminal kinase (JNK) activation and insulin receptor substrate 1 (IRS1) serine 307 phosphorylation, concomitantly with the decrease in insulin-stimulated IRS1 tyrosine phosphorylation and cellular glucose uptake. Blocking JNK expression using RNA interference efficiently prevented the H(2)O(2)- or TNF-alpha-induced defects in insulin action. Pretreatment of cells with Cy-3-G reduced the intracellular production of reactive oxygen species, the activation of JNK, and attenuated H(2)O(2)- or TNF-alpha-induced insulin resistance in a dose-dependent manner. In parallel, N-acetyl-cysteine, an antioxidant compound, did not exhibit an attenuation of TNF-alpha-induced insulin resistance. Taken together, these results indicated that Cy-3-G exerts a protective role against H(2)O(2)- or TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes by inhibiting the JNK signal pathway.}, }
@article {pmid18176610, year = {2008}, author = {Barkholt, L and Remberger, M and Hassan, Z and Fransson, K and Omazic, B and Svahn, BM and Karlsson, H and Brune, M and Hassan, M and Mattsson, J and Ringdén, O}, title = {A prospective randomized study using N-acetyl-L-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation.}, journal = {Bone marrow transplantation}, volume = {41}, number = {9}, pages = {785-790}, doi = {10.1038/sj.bmt.1705969}, pmid = {18176610}, issn = {0268-3369}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Aged ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Child ; Child, Preschool ; Female ; Free Radical Scavengers/*administration &amp; dosage ; *Hematopoietic Stem Cell Transplantation ; Hepatic Veno-Occlusive Disease/*prevention &amp; control ; Humans ; Male ; Middle Aged ; Neoplasms/blood/*therapy ; Prospective Studies ; Time Factors ; Transplantation, Homologous ; }, abstract = {Allogeneic hematopoietic stem cell transplantation (ASCT) and its conditioning with chemoradiotherapy often results in liver toxicity, the most severe form being veno-occlusive liver disease (VOD). N-acetyl-L-cysteine (NAC), an antioxidant glutathione precursor, may provide protection from liver toxicity. Patients with elevated bilirubin (>26 mmol/l) and/or elevated (ALT) (>1.4 microkat/l) and/or aspartate aminotransferase (AST) (>1.4 microkat/l) levels were randomized to treatment with NAC or no treatment. Among 522 transplanted patients, 160 were included in the trial. NAC was given, 100 mg/kg per day, as a 6-h i.v. infusion until normalization of bilirubin, ALT and AST values. Maximum bilirubin level was the same in patients randomized to NAC (n=72) or controls (n=88). Increase and recovery of ALT and AST were the same in patients randomized to NAC or controls. There were two patients in the NAC group who developed VOD, as compared to three of the controls. To conclude, NAC does not improve liver toxicity after ASCT.}, }
@article {pmid18176068, year = {2008}, author = {Takayama, M and Fujisawa, M and Hori, Y and Oda, A and Katsuyama, S and Hirose, Y and Yamazaki, K and Wakabayashi, H}, title = {[Clinical usefulness of the acetaminophen detection kit in treating acute poisoning--data from a survey of 28 cases treated at Niigata City general hospital].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {128}, number = {1}, pages = {159-163}, doi = {10.1248/yakushi.128.159}, pmid = {18176068}, issn = {0031-6903}, mesh = {Acetaminophen/*blood/*poisoning ; Acute Disease ; *Hospitals, Urban ; Humans ; Japan ; Poisoning/*diagnosis ; *Reagent Kits, Diagnostic ; }, abstract = {In acute poisoning caused by acetaminophen (N-acetyl-p-aminophenol, APAP), it is critical to predict the onset of delayed liver injury based on the prompt measurement of serum APAP level and to administer the antidote N-acetylcysteine (NAC) without delay as needed. However, all emergency medical facilities are not necessarily equipped with an expensive analytical instrument that allows prompt determination of APAP. Here, we tested the clinical usefulness of the Acetaminophen Detection Kit (Kanto Chemical Co., Ltd.), which claims to rapidly detect APAP in serum using a simple procedure, by spectrophotometrically measuring the APAP concentration in 34 serum samples collected from 28 patients with acute APAP poisoning. The results showed that the correlation coefficient between the APAP value measured by the Acetaminophen Detection Kit and that determined by the HPLC method was, at 0.888, not very high, but that the decision on whether to administer NAC based on the measured APAP level was consistent between the two analytical methods in 23 out of 25 patients. Also, the value obtained by the Acetaminophen Detection Kit was equal to, or larger than, that obtained by the HPLC method, suggesting that it is unlikely that patients requiring NAC would be left untreated. These results indicate that the Acetaminophen Detection Kit, with its ease and simplicity of use, is clinically useful in emergency medical facilities for which an expensive analytical instrument is not affordable.}, }
@article {pmid18174269, year = {2008}, author = {Kimmel, M and Butscheid, M and Brenner, S and Kuhlmann, U and Klotz, U and Alscher, DM}, title = {Improved estimation of glomerular filtration rate by serum cystatin C in preventing contrast induced nephropathy by N-acetylcysteine or zinc--preliminary results.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {23}, number = {4}, pages = {1241-1245}, doi = {10.1093/ndt/gfm785}, pmid = {18174269}, issn = {1460-2385}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Aged ; Contrast Media/administration &amp; dosage/*adverse effects ; Coronary Angiography/adverse effects/methods ; Coronary Disease/diagnostic imaging ; Creatinine/blood ; Cystatin C ; Cystatins/*blood ; Dose-Response Relationship, Drug ; Double-Blind Method ; Female ; Follow-Up Studies ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Glomerular Filtration Rate/*physiology ; Humans ; Injections, Intravenous ; Iopamidol/administration &amp; dosage/adverse effects/analogs &amp; derivatives ; Male ; Protease Inhibitors ; Renal Insufficiency/blood/chemically induced/*prevention &amp; control ; Retrospective Studies ; Severity of Illness Index ; Treatment Outcome ; Zinc Compounds/administration &amp; dosage/*therapeutic use ; }, abstract = {BACKGROUND: Prevention of contrast media (CM) induced nephropathy (CIN) by prophylaxis (e.g. N-acetylcysteine; NAC) is controversially discussed. Up to now, assessment of kidney function has been based on measurements of serum creatinine, although this biomarker has several limitations. We investigated NAC and zinc (Zn) for the prevention of CIN by monitoring creatinine and cystatin C.<br><br>METHODS: In a prospective, placebo-controlled, double blind trial, patients with moderately impaired kidney function receiving low-osmolar, non-ionic CM were randomly assigned to an oral treatment for 2 days with 1.2 g/day of NAC (n = 19), for 1 day with 60 mg/day of Zn (n = 18) or placebo (n = 17). All patients received peri-procedurally 1 ml/kg/h of 0.45% saline for 24 h. At baseline, prior to exposure of CM, 2 and 6 days after CM, creatinine and cystatin C were measured.<br><br>RESULTS: There was no difference in the incidence of CIN, but a significant drop in creatinine (P < 0.05) was observed in all patients during volume expansion. Creatinine showed no increase after CM and it was normalized to the baseline values in all groups at the study end. In contrast, 2 days after CM there was a significant rise in cystatin C in the Zn (P = 0.012) and the placebo (P = 0.041) group, whereas NAC prevented this deterioration of kidney function.<br><br>CONCLUSIONS: Cystatin C seems to reflect CM-induced changes in kidney function better than creatinine. NAC and Zn have no effect in preventing CIN by the standard definition, but based on cystatin C we can confirm a preventive effect of NAC. It appears mandatory to assess kidney function by cystatin C in CIN intervention trials, because relying on creatinine can be misleading.}, }
@article {pmid18170962, year = {2007}, author = {Araki, S and Dobashi, K and Kubo, K and Kawagoe, R and Yamamoto, Y and Shirahata, A}, title = {N-acetylcysteine inhibits induction of nitric oxide synthase in 3T3-L1 adipocytes.}, journal = {Journal of UOEH}, volume = {29}, number = {4}, pages = {417-429}, doi = {10.7888/juoeh.29.417}, pmid = {18170962}, issn = {0387-821X}, mesh = {3T3-L1 Cells/*enzymology/metabolism ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cells, Cultured ; Depression, Chemical ; Dose-Response Relationship, Drug ; Enzyme Induction/drug effects ; Interleukin-6/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase/*biosynthesis ; Oxidative Stress ; Pyrrolidines/pharmacology ; Stimulation, Chemical ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The present study was designed to determine whether N-acetylcysteine (NAC), a potent antioxidant, modulates nitric oxide (NO) production stimulated by lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) in adipocytes. Stimulation by the combination of 5 microg/ml of LPS and 100 ng/ml of TNF-alpha (LT) significantly enhanced NO production in 3T3-L1 adipocytes. Preincubation of the cells with NAC (5-20 mM) for 24 h suppressed the increased NO production in a dose-dependent manner. The production of NO was decreased by 49% at the concentration of 20 mM of NAC. The decrease in NO production by NAC was accompanied by a decrease in inducible nitric oxide synthase (iNOS) protein, detected by immunoblot analysis, and iNOS mRNA, determined by real-time reverse-transcriptase coupled polymerase chain reaction analysis. Nuclear factor-kappa B (NF-kappa B) was significantly activated by LT-treatment, while the pretreatment with 20 mM of NAC prevented the activity by 42%. Pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, also inhibited the LT-mediated NO production dose-dependently. One hundred microM of PDTC inhibited the NO production by 46%. We also investigated the effect of NAC and PDTC on the production of interleukein-6 (IL-6), which is regulated transcriptionally by NF-kappa B in 3T3-L1 adipocytes. IL-6 production was markedly increased by LT stimulus, and the enhanced secretion of IL-6 was suppressed in a dose-dependent manner by pretreatment with NAC or PDTC. These results suggest that NAC regulates iNOS expression and NO production in adipocytes through the modulating activation of NF-kappa B.}, }
@article {pmid18165532, year = {2007}, author = {Spichler, A and Ko, AI and Silva, EF and De Brito, T and Silva, AM and Athanazio, D and Silva, C and Seguro, A}, title = {Reversal of renal tubule transporter downregulation during severe leptospirosis with antimicrobial therapy.}, journal = {The American journal of tropical medicine and hygiene}, volume = {77}, number = {6}, pages = {1111-1119}, pmid = {18165532}, issn = {0002-9637}, support = {300861/96-11//PHS HHS/United States ; 420067/2005-1//PHS HHS/United States ; AI052473/AI/NIAID NIH HHS/United States ; TW00919/TW/FIC NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Ampicillin/administration &amp; dosage/*pharmacology ; Animals ; Anti-Bacterial Agents/administration &amp; dosage/*pharmacology ; Antigens, Bacterial/analysis ; Cricetinae ; Down-Regulation ; Female ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation/*drug effects ; Kidney/pathology/physiopathology ; Liver/pathology ; Mesocricetus ; Sodium-Hydrogen Exchanger 3 ; Sodium-Hydrogen Exchangers/analysis/*biosynthesis/drug effects ; Sodium-Potassium-Chloride Symporters/analysis/*biosynthesis/drug effects ; Solute Carrier Family 12, Member 1 ; Thiobarbiturates/blood ; Weil Disease/*drug therapy/pathology/physiopathology ; }, abstract = {Tubular dysfunction is a hallmark of severe leptospirosis. Antimicrobial therapy is thought to interfere on renal involvement. We evaluated the expression of a proximal tubule type-3 Na+/H+ exchanger (NHE3) and a thick ascending limb Na+-K+-2Cl(-) cotransporter (NKCC2) in controls and treated hamsters. Animals infected by a serovar Copenhageni isolate, were treated or not with ampicillin (AMP) and/or N-acetylcysteine (NAC). Leptospiral antigen(s) and expression of renal transporters were evaluated by immunohistochemistry, and serum thiobarbituric acid (TBARS) was quantified. Infected hamsters had high amounts of detectable leptospiral antigen(s) in target tissues while renal expression of NHE3 and NKCC2 decreased. Ampicillin treatment was associated with minimal or no detection of leptospiral antigens, normal expression of NHE3 and NKCC2 transporters, and reduced levels of TBARS. NAC effect was restricted to lowering TBARS. Early and late AMP treatment rescued tubular defects in severe leptospirosis disease, and there was no evidence of benefit from antioxidant therapy.}, }
@article {pmid18165129, year = {2008}, author = {Aronis, A and Madar, Z and Tirosh, O}, title = {Lipotoxic effects of triacylglycerols in J774.2 macrophages.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {24}, number = {2}, pages = {167-176}, doi = {10.1016/j.nut.2007.10.017}, pmid = {18165129}, issn = {0899-9007}, mesh = {Animals ; Cell Cycle/*drug effects ; Cell Death ; Cell Line ; DNA/drug effects/metabolism ; Linoleic Acid/pharmacology ; Macrophages/*drug effects/metabolism ; Mice ; *Necrosis ; Oleic Acid/pharmacology ; Olive Oil ; *Oxidative Stress ; Palmitic Acid/pharmacology ; Paraoxon/pharmacology ; Plant Oils ; Reactive Oxygen Species ; Serum Albumin, Bovine/pharmacology ; Soybean Oil ; Time Factors ; Triglycerides/*pharmacology ; }, abstract = {OBJECTIVE: Triacylglycerols (TGs) are being considered as an independent risk factor in atherosclerosis and metabolic syndrome, acting by dysregulation of the TG/high-density lipoprotein axis. Accumulation of lipids in subendothelial space attracts macrophages, leading to atherosclerotic plaque formation and increased plaque instability due to formation of foam cells and macrophage death. The aim of this study was to evaluate lipotoxic effects in macrophages caused by TG uptake.<br><br>METHODS: J774.2 macrophages were exposed to soybean or olive oil-based lipid emulsions as a source of TGs (1 mg/mL) in a presence or absence of lipase inhibitor paraoxon (20 microM) or to bovine serum albumin-complexed palmitic (150 microM), linoleic (600 microM), and oleic (600 microM) fatty acids.<br><br>RESULTS: The results demonstrated accumulation of TGs, G1/S arrest, and cell death with necrotic morphologic features after exposure to TG emulsions. These effects were prevented by treatment with an antioxidant N-acetyl-cysteine (0.5 mM). Paraoxon inhibited intracellular TG degradation but did not prevent lipotoxicity and cell death. Olive oil TG triggered macrophage death in a manner similar to soybean oil. Treatment of the macrophages with free fatty acid, mainly with palmitic acid, showed a reactive oxygen species-independent cell death pathway, which was different from that of TG and was not prevented by N-acetyl-cysteine.<br><br>CONCLUSION: This study shows a direct lipotoxic pathway for TG molecules in macrophages, which is not associated with degradation of TG molecule to free fatty acids. This study for the first time can explain at a cellular level how TGs as an independent risk factor aggravate atherosclerotic outcomes.}, }
@article {pmid18164382, year = {2008}, author = {Taoufik, K and Mavrogonatou, E and Eliades, T and Papagiannoulis, L and Eliades, G and Kletsas, D}, title = {Effect of blue light on the proliferation of human gingival fibroblasts.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {24}, number = {7}, pages = {895-900}, doi = {10.1016/j.dental.2007.10.006}, pmid = {18164382}, issn = {0109-5641}, mesh = {Acetylcysteine/pharmacology ; Cell Count ; Cell Proliferation/radiation effects ; Cells, Cultured ; Color ; DNA/radiation effects ; DNA Damage ; Fibroblasts/*radiation effects ; Fluorescent Antibody Technique ; Free Radical Scavengers/pharmacology ; Gingiva/*radiation effects ; Histones ; Humans ; Light ; Lighting/instrumentation ; Materials Testing ; Oxidative Stress/physiology ; Radiopharmaceuticals ; Thymidine ; Time Factors ; Tritium ; }, abstract = {OBJECTIVES: Previous studies have reported that blue light, under conditions similar to those used for orthodontic bonding, influences several aspects of cellular physiology. The purpose of this study was to investigate the effect of the exposure to blue light curing sources, i.e. halogen, light emitting diode (LED) and plasma arc irradiation, on the proliferation of human gingival fibroblasts.<br><br>METHODS: Primary cultures of human gingival fibroblasts were exposed to halogen, LED and plasma arc irradiation for 240, 180 and 120 s, respectively. The effect of blue light on DNA synthesis and cell proliferation was estimated by tritiated thymidine incorporation and direct cell counting, respectively. The possible involvement of an oxidative stress on the effect of blue light irradiation was studied by using N-acetyl-cysteine. Finally the formation of DNA double-strand breaks after irradiation was studied by immunofluorescence with an antibody against histone H2A.x phosphorylated in Ser139.<br><br>RESULTS: Blue light showed no immediate effect on the regulation of DNA synthesis. However, exposure of cells to these light sources inhibits cell proliferation measured one week after irradiation. This phenomenon is not attributed to the formation of DNA double strand breaks and cannot be annulled by N-acetyl-cysteine.<br><br>SIGNIFICANCE: The results presented here indicate a mild inhibition of gingival fibroblasts' proliferation after exposure to blue light and necessitate further study to clarify the exact mechanism underlying this effect.}, }
@article {pmid18161828, year = {2008}, author = {Kortsalioudaki, C and Taylor, RM and Cheeseman, P and Bansal, S and Mieli-Vergani, G and Dhawan, A}, title = {Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure.}, journal = {Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society}, volume = {14}, number = {1}, pages = {25-30}, doi = {10.1002/lt.21246}, pmid = {18161828}, issn = {1527-6465}, mesh = {Acetaminophen ; Acetylcysteine/*administration &amp; dosage ; Adolescent ; Analgesics, Non-Narcotic ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Infant ; Infant, Newborn ; Infusions, Intravenous ; Liver Failure, Acute/*drug therapy/etiology/mortality ; Male ; Retrospective Studies ; Survival Rate ; Treatment Outcome ; United Kingdom/epidemiology ; }, abstract = {Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminophen-induced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) > 2 and abnormal liver function or INR >1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989-1994), standard care (n = 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995-2004), standard care and NAC administration (n = 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR < 1.4, death, or liver transplantation (LT). The median duration of NAC administration in Group 2 was 5 (range, 1-77) days. Complications were noted in 8 (10.8%) children: rash in 3, arrhythmia in 3, and dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P = not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P = ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P = 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P = 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P = 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P = ns; and LT was performed in 32 (54%) vs. 42 (38%), P = ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8 (16%) in Group 2, P = 0.02. In conclusion, NAC is safe in non-acetaminophen-induced ALF. In this retrospective study NAC was associated with a shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation.}, }
@article {pmid18161797, year = {2008}, author = {Leonis, MA and Balistreri, WF}, title = {Is there a "NAC" to treating acute liver failure in children?.}, journal = {Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society}, volume = {14}, number = {1}, pages = {7-8}, doi = {10.1002/lt.21228}, pmid = {18161797}, issn = {1527-6465}, mesh = {Acetaminophen/adverse effects ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Analgesics, Non-Narcotic/adverse effects ; Child ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Injections, Intravenous ; Liver Failure, Acute/chemically induced/*drug therapy ; }, }
@article {pmid18155508, year = {2008}, author = {Miron, T and Wilchek, M and Sharp, A and Nakagawa, Y and Naoi, M and Nozawa, Y and Akao, Y}, title = {Allicin inhibits cell growth and induces apoptosis through the mitochondrial pathway in HL60 and U937 cells.}, journal = {The Journal of nutritional biochemistry}, volume = {19}, number = {8}, pages = {524-535}, doi = {10.1016/j.jnutbio.2007.06.009}, pmid = {18155508}, issn = {0955-2863}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Caspases/metabolism ; Cell Division/*drug effects ; Cytochromes c/metabolism ; DNA Fragmentation/drug effects ; Disulfides ; Enzyme Inhibitors/pharmacology ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors ; Glutathione/analysis ; HL-60 Cells ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Oxidation-Reduction ; Sulfinic Acids/*pharmacology ; U937 Cells ; }, abstract = {In this article, the effects of allicin, a biological active compound of garlic, on HL60 and U937 cell lines were examined. Allicin induced growth inhibition and elicited apoptotic events such as blebbing, mitochondrial membrane depolarization, cytochrome c release into the cytosol, activation of caspase 9 and caspase 3 and DNA fragmentation. Pretreatment of HL60 cells with cyclosporine A, an inhibitor of the mitochondrial permeability transition pore (mPTP), inhibited allicin-treated cell death. HL60 cell survival after 1 h pretreatment with cyclosporine A, followed by 16 h in presence of allicin (5 microM) was approximately 80% compared to allicin treatment alone (approximately 50%). Also N-acetyl cysteine, a reduced glutathione (GSH) precursor, prevented cell death. The effects of cyclosporine A and N-acetyl cysteine suggest the involvement of mPTP and intracellular GSH level in the cytotoxicity. Indeed, allicin depleted GSH in the cytosol and mitochondria, and buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly augmented allicin-induced apoptosis. In HL60 cells treated with allicin (5 microM, 30 min) the redox state for 2GSH/oxidized glutathione shifted from EGSH -240 to -170 mV. The same shift was observed in U937 cells treated with allicin at a higher concentration for a longer period of incubation (20 microM, 2 h). The apoptotic events induced by various concentrations of allicin correlate to intracellular GSH levels in the two cell types tested (HL60: 3.7 nmol/10(6) cells; U937: 7.7 nmol/10(6) cells). The emerging mechanistic basis for the antiproliferative function of allicin, therefore, involves the activation of the mitochondrial apoptotic pathway by GSH depletion and by changes in the intracellular redox status.}, }
@article {pmid18097876, year = {2007}, author = {Klass, O and Fischer, UM and Antonyan, A and Bosse, M and Fischer, JH and Bloch, W and Mehlhorn, U}, title = {Pneumocyte apoptosis induction during cardiopulmonary bypass: effective prevention by radical scavenging using N-acetylcysteine.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {20}, number = {6}, pages = {349-356}, doi = {10.1080/08941930701772165}, pmid = {18097876}, issn = {0894-1939}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cardiopulmonary Bypass/*adverse effects ; Caspase 3/analysis ; Female ; Free Radical Scavengers/*pharmacology ; Lung/*pathology ; Male ; Reactive Oxygen Species/toxicity ; Swine ; Tyrosine/analogs &amp; derivatives/analysis ; }, abstract = {Cardiopulmonary bypass (CPB) and cardioplegic arrest are associated with pulmonary dysfunction. We sought to investigate whether pulmonary ischemia/reperfusion during standard CPB and cardioplegic arrest is associated with reactive oxygen species (ROS)-mediated pulmonary tissue injury and pneumocyte apoptosis induction, and whether ROS scavenging using N-acetylcysteine (NAC) attenuates these alterations. Twelve pigs (41 +/- 8 kg) were randomized to receive either NAC (100 mg/kg prior to CPB; n = 7) or placebo (n = 5) and subjected to CPB and 60 min of cold (4 degrees C) crystalloid cardioplegic arrest. We collected lung biopsies prior to CPB, at 60 min CPB, as well as at 30, 60, and 120 min post CPB. Lung specimens were immunocytochemically stained against nitrotyrosine, 8-isoprostaglandin-F(2)alpha, and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) as indicators for ROS-mediated tissue injury and active caspase-3, an apoptosis signal pathway key enzyme. Oxidative stress markers were judged using a scale from 1 to 4 (low to intensive staining), and caspase-3-positive pneumocytes were counted per view field. In placebo, the number of caspase-3-positive pneumocytes significantly increased over time to reach a maximum at 120 min post CPB (p = .03 vs baseline). NAC significantly prevented caspase-3 activation in pneumocytes (p = .001 vs Placebo). Pneumocyte nitrotyrosine and 8-OH-dG staining significantly increased over time (p = .003) in the placebo group, but decreased in the NAC group (p = .004). In both groups staining for 8-isoprostaglandin-F(2)alpha showed no significant changes. This yields the conclusion that standard CPB and cardioplegic arrest initiate ROS-mediated tissue injury and apoptosis in pneumocytes that can be reduced by NAC. Thus, ROS scavenging using NAC may represent a novel approach to minimize lung injury associated with CPB.}, }
@article {pmid18096486, year = {2007}, author = {Geudens, N and Van De Wauwer, C and Neyrinck, AP and Timmermans, L and Vanhooren, HM and Vanaudenaerde, BM and Verleden, GM and Verbeken, E and Lerut, T and Van Raemdonck, DE}, title = {N-acetyl cysteine pre-treatment attenuates inflammatory changes in the warm ischemic murine lung.}, journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}, volume = {26}, number = {12}, pages = {1326-1332}, doi = {10.1016/j.healun.2007.09.008}, pmid = {18096486}, issn = {1557-3117}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Biopsy ; Bronchoalveolar Lavage ; Cell Count ; Chemokines/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Free Radical Scavengers/*therapeutic use ; Intercellular Signaling Peptides and Proteins/metabolism ; Leukocytes/pathology ; Lung/metabolism/*pathology ; Lung Transplantation/methods/*pathology ; Lymphocytes/pathology ; Macrophages/pathology ; Mice ; Reperfusion Injury/etiology/metabolism/*prevention &amp; control ; Warm Ischemia/*adverse effects ; }, abstract = {BACKGROUND: The warm ischemic period in non-heart-beating donor lungs may contribute to a higher degree of ischemia-reperfusion injury after lung transplantation. We investigated the impact and timing of administration of N-acetyl cysteine (NAC) on inflammatory parameters.<br><br>METHODS: Ischemia (I) was induced by clamping the hilum of the left lung for 90 minutes, and some protocols were followed by reperfusion (R) for 4 hours. Mice were divided into nine groups (n = 6/group): three control groups ([sham] (thoracotomy only), [I] and [I+R]); two groups with saline instillation only ([saline+I] and [saline+I+R]); and four experimental groups with NAC (50 mg/kg), administered by instillation ([NAC+I], [NAC+I+R] and [I+NAC+R]) or by aerosol ([NACaero+I+R]). Cell counts and protein levels in bronchoalveolar lavage (BAL) were determined.<br><br>RESULTS: NAC administered prior to hilar clamping led to a significant decrease in macrophages and lymphocytes and interleukin (IL)-1 beta levels after ischemia. NAC also resulted in significantly fewer macrophages, lymphocytes and neutrophils as well as IL-1 beta, keratinocyte cytokine (KC), monocyte chemoattractant protein (MCP)-1 and IL-6 levels in BAL taken after reperfusion.<br><br>CONCLUSIONS: NAC treatment prior to warm ischemia attenuates inflammatory changes after both the ischemic and reperfusion periods.}, }
@article {pmid18094999, year = {2008}, author = {Monteiro, MC and Marques, FC and Blazius, RD and Santos da Silva, O and de Queiroz Cunha, F and Bento, DB and Torres Romão, PR}, title = {N-acetyl-L: -cysteine reduces the parasitism of BALB/c mice infected with Leishmania amazonensis.}, journal = {Parasitology research}, volume = {102}, number = {4}, pages = {801-803}, pmid = {18094999}, issn = {0932-0113}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Female ; Foot/parasitology/pathology ; Glutathione/*metabolism ; Leishmania/classification/*drug effects/isolation &amp; purification/pathogenicity ; Leishmaniasis, Cutaneous/*drug therapy/*parasitology/pathology ; Lymph Nodes/metabolism/parasitology ; Mice ; Mice, Inbred BALB C ; Spleen/metabolism ; Treatment Outcome ; }, abstract = {Leishmania amazonensis infection leads to progressive diseases in a majority of inbred strains of mice. Glutathione (GSH) participates in a large number of cellular phenomena and seems to be essential for several immune functions, including host defense during leishmaniasis. In this study, we evaluated the effects of N-acetyl-L: -cysteine (NAC), as GSH supplement, on the course of L. amazonensis infection in susceptible BALB/c mice. The treatment with NAC (200 mg/kg daily) was effective in raising GSH levels in both lymph node and spleen cells. Although this treatment did not change the footpad swelling development in L. amazonensis-infected mice, it caused a significant decrease in the number of parasites recovered from the footpad lesion and draining popliteal lymph node. Our data suggest that intracellular Leishmania killing in vivo was improved by the augment of GSH levels through NAC administration.}, }
@article {pmid18093171, year = {2008}, author = {Aoyama, K and Matsumura, N and Watabe, M and Nakaki, T}, title = {Oxidative stress on EAAC1 is involved in MPTP-induced glutathione depletion and motor dysfunction.}, journal = {The European journal of neuroscience}, volume = {27}, number = {1}, pages = {20-30}, doi = {10.1111/j.1460-9568.2007.05979.x}, pmid = {18093171}, issn = {1460-9568}, mesh = {1-Methyl-4-phenylpyridinium/pharmacology ; Acetylcysteine/administration &amp; dosage ; Animals ; Aspartic Acid/pharmacology ; Behavior, Animal/drug effects ; Cysteine/metabolism ; Disease Models, Animal ; Drug Interactions ; Excitatory Amino Acid Transporter 1/*metabolism ; Free Radical Scavengers/administration &amp; dosage ; Glutathione/*deficiency ; Humans ; Hydrogen Peroxide/pharmacology ; Hydroxamic Acids/pharmacology ; In Vitro Techniques ; Indazoles/administration &amp; dosage ; MPTP Poisoning/*complications/*metabolism/pathology/prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Movement Disorders/*etiology ; Neuroprotective Agents/administration &amp; dosage ; Oxidative Stress/drug effects/*physiology ; Substantia Nigra/drug effects/metabolism ; }, abstract = {Excitatory amino acid carrier 1 (EAAC1) is a glutamate transporter expressed on mature neurons in the CNS, and is the primary route for uptake of the neuronal cysteine needed to produce glutathione (GSH). Parkinson's disease (PD) is a neurodegenerative disorder pathogenically related to oxidative stress and shows GSH depletion in the substantia nigra (SN). Herein, we report that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, an experimental model of PD, showed reduced motor activity, reduced GSH contents, EAAC1 translocation to the membrane and increased levels of nitrated EAAC1. These changes were reversed by pre-administration of n-acetylcysteine (NAC), a membrane-permeable cysteine precursor. Pretreatment with 7-nitroindazole, a specific neuronal nitric oxide synthase inhibitor, also prevented both GSH depletion and nitrotyrosine formation induced by MPTP. Pretreatment with hydrogen peroxide, L-aspartic acid beta-hydroxamate or 1-methyl-4-phenylpyridinium reduced the subsequent cysteine increase in midbrain slice cultures. Studies with chloromethylfluorescein diacetate, a GSH marker, demonstrated dopaminergic neurons in the SN to have increased GSH levels after NAC treatment. These findings suggest that oxidative stress induced by MPTP may reduce neuronal cysteine uptake, via EAAC1 dysfunction, leading to impaired GSH synthesis, and that NAC would exert a protective effect against MPTP neurotoxicity by maintaining GSH levels in dopaminergic neurons.}, }
@article {pmid18088059, year = {2008}, author = {Sfara, V and Zerba, EN and Alzogaray, RA}, title = {Decrease in DEET repellency caused by nitric oxide in Rhodnius prolixus.}, journal = {Archives of insect biochemistry and physiology}, volume = {67}, number = {1}, pages = {1-8}, doi = {10.1002/arch.20210}, pmid = {18088059}, issn = {0739-4462}, mesh = {Animals ; Cyclic GMP/metabolism ; DEET/*pharmacology ; Dose-Response Relationship, Drug ; Insect Repellents/*pharmacology ; Nitric Oxide/*pharmacology ; Smell ; Triatominae/*drug effects ; }, abstract = {N,N-diethyl-3-methylbenzamide (DEET) is widely used as an insect repellent; however, little is known about its mode of action. On the other hand, nitric oxide (NO) participates in the olfaction transduction pathway of insects. In this work, nitroso-acetyl-cysteine (SNAC), a nitric oxide donor, or dibutyril-cyclic-GMP (db-cGMP), the cyclic nucleotide analog, were applied on fifth instar nymphs of Rhodnius prolixus before exposing them to DEET, to obtain information about the possible role of NO/cGMP system in the olfaction process. In the first place, we exposed the nymphs to several DEET concentrations (70, 700, 1,750, and 3,500 microg/cm2). All these concentrations produced a repellent effect. A decrease in repellency during the course of the experiment was observed when the nymphs were exposed to high concentrations of DEET (700 and 1,750 microg/cm2), suggesting an adaptation phenomenon. The pre-treatment of the insects with 15 microg /insect of SNAC or 2 microg/insect of db-cGMP produced a reduction of the repellency. An increase in locomotor activity was observed in insects exposed to 350 or 700 microg/cm2 DEET. Although exposure to 70 microg/cm2 DEET produced a high repellency response, it did not modify the insects' locomotor activity. Insects treated with two doses of SNAC before being exposed to 350 microg/cm2 of DEET showed no differences in locomotor activity compared to controls.}, }
@article {pmid18085317, year = {2008}, author = {Dunleavy, M and Bradford, A and O'Halloran, KD}, title = {Oxidative stress impairs upper airway muscle endurance in an animal model of sleep-disordered breathing.}, journal = {Advances in experimental medicine and biology}, volume = {605}, number = {}, pages = {458-462}, doi = {10.1007/978-0-387-73693-8_80}, pmid = {18085317}, issn = {0065-2598}, mesh = {Animals ; Disease Models, Animal ; Electric Stimulation ; Hypoxia/*physiopathology ; Male ; Muscle Fatigue/*physiology ; Oxidative Stress/*physiology ; Physical Endurance/*physiology ; Rats ; Rats, Wistar ; Respiration Disorders/*etiology/physiopathology ; Respiratory Muscles/*physiopathology ; Sleep Wake Disorders/*physiopathology ; }, abstract = {Obstructive sleep apnoea is characterised by intermittent hypoxia due to recurrent obstructions of the pharyngeal airway during sleep. We have shown that chronic intermittent hypoxia impairs respiratory muscle function and CNS control of upper airway patency. In this study, we tested the hypothesis that disruption of an endogenous antioxidant defence system exacerbates the effects of intermittent hypoxia on upper airway muscle contractile function. Thirty-two male Wistar rats were placed in restrainers with their heads in hoods in which the ambient oxygen concentration could be modified by controlling the gas supply to the hoods. Sixteen rats were exposed to alternating equal periods of hypoxia and normoxia, twice per minute, 8 hours per day for 1 week. The remaining 16 animals were exposed to normoxia continuously under identical experimental conditions. In both groups, half the animals received daily injections of buthionine sulfoxamine (BSO), an inhibitor of the rate-limiting enzyme in glutathione synthesis. The other half received daily vehicle injections. At the end of the 1-week treatment period, the sternohyoid muscles were removed and fatigue characteristics were determined in vitro. Intermittent hypoxia was associated with a decrease in sternohyoid muscle endurance, an effect that was exacerbated by treatment with BSO. In separate experiments, daily treatment with the antioxidant N-acetyl cysteine blocked the deleterious effects of intermittent hypoxia on respiratory muscle function. We suggest that oxidative stress contributes to impaired upper airway muscle endurance in our animal model and that endogenous glutathione may be especially important in limiting free radical-induced muscle dysfunction. Our results may have particular relevance to respiratory disorders associated with recurrent hypoxia, such as the sleep apnoea/hypopnoea syndrome.}, }
@article {pmid18084618, year = {2007}, author = {Campos, AC and Molognoni, F and Melo, FH and Galdieri, LC and Carneiro, CR and D'Almeida, V and Correa, M and Jasiulionis, MG}, title = {Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation.}, journal = {Neoplasia (New York, N.Y.)}, volume = {9}, number = {12}, pages = {1111-1121}, pmid = {18084618}, issn = {1476-5586}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anoikis/genetics ; Cell Adhesion/drug effects ; Cell Culture Techniques/methods ; Cell Transformation, Neoplastic/drug effects/*genetics/metabolism ; Cells, Cultured/cytology/drug effects/metabolism ; Cysteine/metabolism ; *DNA Methylation/drug effects ; Gene Expression Regulation ; Glutathione/metabolism ; Homocysteine/metabolism ; Lipid Peroxidation ; Melanocytes/drug effects/*metabolism/pathology ; Mice ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide/metabolism ; *Oxidative Stress ; Sepharose/pharmacology ; Superoxides/metabolism ; Trypsin/pharmacology ; }, abstract = {Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenicmelanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hcy), an element in the methionine (universal methyl donor) cycle. This alteration was accompanied by increase in glutathione (GSH) levels and methylated DNA content. Furthermore, a significant increase in dnmt1 and 3b expression was identified along melan-a anchorage blockade. L(G)-Nitro-L-arginine methyl esther (L-NAME), known as a nitric oxide synthase (NOS) inhibitor, and N-acetyl-L-cysteine (NAC) prevented the increase in global DNA methylation, as well as the increase in dnmt1 and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit nitric oxide (NO) production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism.}, }
@article {pmid18083000, year = {2008}, author = {Gelain, DP and Moreira, JC}, title = {Evidence of increased reactive species formation by retinol, but not retinoic acid, in PC12 cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {22}, number = {3}, pages = {553-558}, doi = {10.1016/j.tiv.2007.11.007}, pmid = {18083000}, issn = {0887-2333}, mesh = {Animals ; Antioxidants/pharmacology ; Calcium/metabolism ; Cell Survival/drug effects ; Chelating Agents/pharmacology ; Egtazic Acid/pharmacology ; Fluorescent Dyes ; Iron Chelating Agents/pharmacology ; Kinetics ; PC12 Cells ; Phenanthrolines/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Tetrazolium Salts ; Thiazoles ; Tretinoin/*pharmacology/toxicity ; Vitamin A/*pharmacology/toxicity ; }, abstract = {The biological effects of vitamin A (retinol) are generally ascribed to the activation of nuclear retinoid receptors by retinoic acid (RA), considered the most biologically active retinoid. However, it is not established whether the cytotoxic effects of vitamin A are due to retinoid receptors activation by RA. Vitamin A-related toxicity is associated with cellular redox modifications, often leading to severe oxidative damage, but the role of RA in this effect is also uncertain. We therefore studied the formation of intracellular reactive species induced by retinol and retinoic acid in PC12 cells, using an in vitro dichlorofluorescein (DCFH) fluorescence real-time assay. We observed that retinol, but not retinoic acid, induced a steady increase in DCF-based fluorescence over 60 min of incubation, and this increase was reversed by antioxidant (N-acetyl-cysteine and alpha-tocopherol) pre-treatment. This effect was also inhibited by the iron chelator 1,10-phenantroline and the impermeable calcium chelator EGTA. These results suggest that vitamin A-associated cytotoxicity is probably related to an oxidant mechanism dependent on iron and calcium, and the formation of intracellular reactive species is related to retinol, but not to RA.}, }
@article {pmid18082636, year = {2008}, author = {Amer, J and Atlas, D and Fibach, E}, title = {N-acetylcysteine amide (AD4) attenuates oxidative stress in beta-thalassemia blood cells.}, journal = {Biochimica et biophysica acta}, volume = {1780}, number = {2}, pages = {249-255}, doi = {10.1016/j.bbagen.2007.11.009}, pmid = {18082636}, issn = {0006-3002}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Blood Cells/chemistry/*drug effects ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/analysis ; Hemolysis/drug effects ; Humans ; Male ; Mice ; Oxidative Stress/*drug effects ; Phagocytosis/drug effects ; beta-Thalassemia/*metabolism ; }, abstract = {Many aspects of the pathology in beta-hemoglobinopathies (beta-thalassemia and sickle cell anemia) are mediated by oxidative stress. In the present study we tested a novel thiol compound, N-acetylcysteine amide (AD4), the amide form of N-acetyl cysteine (NAC) for its antioxidant effects. Using flow-cytometry, we showed that in vitro treatment of blood cells from beta-thalassemic patients with AD4 elevated the reduced glutathione (GSH) content of red blood cells (RBC), platelets and polymorphonuclear (PMN) leukocytes, and reduced their ROS. These effects resulted in a significant reduced sensitivity of thalassemic RBC to hemolysis and phagocytosis by macrophages. Intra-peritoneal injection of AD4 to beta-thalassemic mice (150 mg/kg) reduced the parameters of oxidative stress (p<0.001). Our results show the superiority of AD4, compared to NAC, in reducing oxidative stress markers in thalassemic cells both in vitro and in vivo.}, }
@article {pmid18078828, year = {2008}, author = {Kajimoto, S and Horie, M and Manabe, H and Masuda, Y and Shibayama-Imazu, T and Nakajo, S and Gong, XF and Obama, T and Itabe, H and Nakaya, K}, title = {A tyrosine kinase inhibitor, beta-hydroxyisovalerylshikonin, induced apoptosis in human lung cancer DMS114 cells through reduction of dUTP nucleotidohydrolase activity.}, journal = {Biochimica et biophysica acta}, volume = {1782}, number = {1}, pages = {41-50}, doi = {10.1016/j.bbadis.2007.11.004}, pmid = {18078828}, issn = {0006-3002}, mesh = {Amino Acid Sequence ; Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Deoxyuracil Nucleotides/genetics/*metabolism ; Enzyme Activation/drug effects ; Fluorouracil/pharmacology ; Humans ; Lung Neoplasms/*enzymology/pathology ; Molecular Sequence Data ; Naphthoquinones/*pharmacology ; Phosphoproteins/metabolism ; Protein Kinase Inhibitors/*pharmacology ; Protein-Tyrosine Kinases/*antagonists &amp; inhibitors/metabolism ; Pyrophosphatases/chemistry/*metabolism ; RNA, Small Interfering/genetics ; }, abstract = {Apoptotic cell death was induced in human lung cancer DMS114 cells by treatment with beta-hydroxyisovalerylshikonin (beta-HIVS), an ATP-noncompetitive inhibitor of protein tyrosine kinases. Changes in phosphoprotein profiles were analyzed by two-dimensional-polyacrylamide gel electrophoresis (2D-PAGE) after the cells were treated with beta-HIVS. One spot on the 2D gel showed a marked decrease in intensity and the corresponding protein was identified by mass spectrometry as dUTP nucleotidohydrolase (dUTPase). The beta-HIVS-induced decrease of dUTPase in the phosphoprotein fraction of DMS114 cells was confirmed using immunoblotting. Treatment of the cells with beta-HIVS-induced rapid reduction of dUTPase activity. An antioxidant N-acetyl-cysteine inhibited both the reduction of phosphorylated dUTPase and the induction of apoptosis by beta-HIVS treatment of DMS114 cells. Introduction of siRNA directed against dUTPase mRNA into DMS114 cells enhanced the susceptibility of beta-HIVS-induced apoptosis. Treatment of DMS114 cells with beta-HIVS and 5-fluorouracil, a specific inhibitor of thymidylate synthase used as a chemotherapeutic drug, revealed the synergistic effects of these drugs on the inhibition of cell growth. These results suggest that dUTPase activity is one of the crucial factors involved in apoptotic cell death in lung cancer cells.}, }
@article {pmid18078672, year = {2008}, author = {Satpute, RM and Hariharakrishnan, J and Bhattacharya, R}, title = {Alpha-ketoglutarate and N-acetyl cysteine protect PC12 cells from cyanide-induced cytotoxicity and altered energy metabolism.}, journal = {Neurotoxicology}, volume = {29}, number = {1}, pages = {170-178}, doi = {10.1016/j.neuro.2007.10.009}, pmid = {18078672}, issn = {0161-813X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/metabolism ; Cell Survival/drug effects ; Cyanates/*toxicity ; Dose-Response Relationship, Drug ; Drug Interactions ; Energy Metabolism/*drug effects ; Free Radical Scavengers/*pharmacology ; Ketoglutaric Acids/*pharmacology ; Lactic Acid/metabolism ; PC12 Cells/*drug effects ; Peroxides/metabolism ; Rats ; Time Factors ; }, abstract = {Cyanide is a rapidly acting neurotoxin that inhibits cellular respiration and energy metabolism leading to histotoxic hypoxia. This results in the dissipation of mitochondrial membrane potential (MMP) accompanied by decreased cellular ATP content which in turn is responsible for increased levels of intracellular calcium ions ([Ca(2+)](i)) and total lactic acid content of the cells. Rat pheochromocytoma (PC12) cells possess much of the biochemical machinery associated with synaptic neurons. In the present study, we evaluated the cytoprotective effects of alpha-ketoglutarate (A-KG) and N-acetylcysteine (NAC) against cyanide-induced cytotoxicity and altered energy metabolism in PC12 cells. Cyanide-antagonism by A-KG is attributed to cyanohydrin formation whereas NAC is known for its antioxidant properties. Data on leakage of intracellular lactate dehydrogenase and mitochondrial function (MTT assay) revealed that simultaneous treatment of A-KG (0.5 mM) and NAC (0.25 mM) significantly prevented the cytotoxicity of cyanide. Also, cellular ATP content was found to improve, followed by restoration of MMP, intracellular calcium [Ca(2+)](i) and lactic acid levels. Treatment with A-KG and NAC also attenuated the levels of peroxides generated by cyanide. The study indicates that combined administration of A-KG and NAC protected the cyanide-challenged PC12 cells by resolving the altered energy metabolism. The results have implications in the development of new treatment regimen for cyanide poisoning.}, }
@article {pmid18077580, year = {2007}, author = {Chao, PL and Fan, SF and Chou, YH and Lin, AM}, title = {N-acetylcysteine attenuates arsenite-induced oxidative injury in dorsal root ganglion explants.}, journal = {Annals of the New York Academy of Sciences}, volume = {1122}, number = {}, pages = {276-288}, doi = {10.1196/annals.1403.020}, pmid = {18077580}, issn = {0077-8923}, mesh = {Acetylcysteine/*pharmacology ; Activating Transcription Factor 6 ; Animals ; Arsenites/*adverse effects ; Caspases/metabolism ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Ganglia, Spinal/*drug effects/*injuries/pathology ; Glutathione ; HSP70 Heat-Shock Proteins ; Male ; Organ Culture Techniques ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Chronic exposure to arsenic causes health problems, including peripheral neuropathy. Oxidative stress is one of the mechanisms underlying arsenic-induced neurotoxicity. For this report, we studied the protective effect of N-acetylcysteine (NAC) on arsenic-induced oxidative injury in dorsal root ganglion (DRG) explants. After 24-h incubation, NAC concentration-dependently attenuated arsenite-induced depletion in glutathione (GSH) content and increases in the ratio of oxidized GSH/reduced GSH (GSSG/GSH ratio) in DRG explants. Furthermore, NAC inhibited arsenite-induced elevation in the expression of stress proteins, such as heat shock protein 70 and heme oxygenase 1, as well as arsenite-induced phosphorylation of p38 mitogen-activated protein kinase. Incubation with NAC ameliorated arsenite-induced apoptosis by abolishing both mitochondrial and endoplasmic reticulum (ER) pathways. In the mitochondrial pathway, NAC attenuated arsenite-induced elevation in Bcl-2 level and cytosolic cytochrome c, as well as arsenite-induced reduction in procaspase-3 levels. In the ER pathway, NAC suppressed arsenite-induced increases in activating transcription factor 6 and C/EBP homologous protein in the nuclear fraction. Furthermore, arsenite-induced reductions in procaspase-12 and elevation in BIP and caspase-12, an ER-specific enzyme, were prevented after NAC incubation. Taken together, our results demonstrate that NAC is neuroprotective against arsenite-induced oxidative injury in DRG explants. Furthermore, NAC inhibits arsenite-induced toxicity by inhibiting ER and mitochondrion activation. Our data indicate that NAC is potentially therapeutic for arsenite-induced peripheral neuropathy.}, }
@article {pmid18072168, year = {2007}, author = {Miller, MA and Navarro, M and Bird, SB and Donovan, JL}, title = {Antiemetic use in acetaminophen poisoning: how does the route of N-acetylcysteine administration affect utilization?.}, journal = {Journal of medical toxicology : official journal of the American College of Medical Toxicology}, volume = {3}, number = {4}, pages = {152-156}, pmid = {18072168}, issn = {1556-9039}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*administration &amp; dosage ; Antiemetics/economics/*therapeutic use ; Cost-Benefit Analysis ; Dose-Response Relationship, Drug ; Drug Administration Routes ; Drug Therapy, Combination ; Female ; Humans ; Injections, Intravenous/economics ; Male ; Metoclopramide/therapeutic use ; Ondansetron/therapeutic use ; Poisoning/*drug therapy ; Retrospective Studies ; Treatment Outcome ; }, abstract = {INTRODUCTION: We sought to compare antiemetic use after acetaminophen poisoning in patients treated with oral or intravenous (IV) N-acetylcysteine (NAC).<br><br>METHODS: Our retrospective chart review identified 20 orally treated patients and 17 IV-treated patients. For both groups, we calculated the total number of antiemetic doses given, their associated cost, and also determined parameters that correlated with antiemetic use.<br><br>RESULTS: IV-treated patients received fewer total antiemetic doses than those receiving oral NAC (1.1 0.2 vs. 2.8 0.7; P 0.04). Antiemetic cost correlated with doses received for both groups; however, because the regression lines differed (P 0.02), antiemetic therapy cost was less in IV-treated patients. In addition, serum acetaminophen concentration correlated with total antiemetic doses in oral NAC patients (P 0.002) but not with IV treatment patients (P 0.78).<br><br>CONCLUSIONS: Intravenous NAC reduced antiemetic utilization, and it costs less than oral therapy. Furthermore, antiemetic use appeared to be determined by a combination of acetaminophen concentration and NAC administration route.}, }
@article {pmid18070748, year = {2007}, author = {Moon, HS and Chung, CS and Lee, HG and Kim, TG and Choi, YJ and Cho, CS}, title = {Inhibitory effect of (-)-epigallocatechin-3-gallate on lipid accumulation of 3T3-L1 cells.}, journal = {Obesity (Silver Spring, Md.)}, volume = {15}, number = {11}, pages = {2571-2582}, doi = {10.1038/oby.2007.309}, pmid = {18070748}, issn = {1930-7381}, mesh = {3T3-L1 Cells/*drug effects/*metabolism/pathology ; AMP-Activated Protein Kinase Kinases ; Adaptor Proteins, Signal Transducing/metabolism ; Adipocytes/drug effects/*metabolism/pathology ; Animals ; Antioxidants/*pharmacology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; DNA-Binding Proteins/metabolism ; Enzyme Activation/drug effects ; Glyceraldehyde-3-Phosphate Dehydrogenases/antagonists &amp; inhibitors/metabolism ; Insulin Receptor Substrate Proteins ; Lipid Metabolism/*drug effects ; Liver X Receptors ; Mice ; Orphan Nuclear Receptors ; PPAR gamma/metabolism ; Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Time Factors ; }, abstract = {OBJECTIVE: The objective of this study was to investigate the molecular mechanisms underlying the attenuating effect of (-)-epigallocatechin-3-gallate (EGCG) on proliferation and lipid accumulation of 3T3-L1 cells, with a focus on the duration of EGCG treatment.<br><br>Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay and diamidino-2-phenylindole staining. The anti-adipogenic effect of EGCG on 3T3-L1 cells was analyzed by glycerol-3-phosphate dehydrogenase activity and Oil red O staining. Western blot analysis was used to detect adenosine monophosphate-activated protein kinase (AMPK) activation and phosphorylation of its substrate, acetyl-CoA carboxylase (ACC), and expression of insulin (INS) receptor, INS receptor substrate-1 (IRS-1), and adipocyte marker proteins.<br><br>RESULTS: Exposure to EGCG during the early period of adipogenesis (7 days) was sufficient to prevent lipid accumulation. During this period, EGCG greatly decreased expression of the adipocyte marker proteins peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and liver X receptor (LXR)-alpha. Furthermore, EGCG significantly induced generation of reactive oxygen species (ROS), which led to AMPK activation, and these effects were eliminated by N-acetylcysteine (NAC) treatment. Also, EGCG increased the tyrosine phosphorylation of INS receptor and INS-1 with increasing incubation time. In contrast, EGCG treatment did not alter glycerol release in the presence or absence of 2',5'-dideoxyadenosine (DDA), indicating that EGCG had no effect on lipolysis.<br><br>DISCUSSION: Our data demonstrate that EGCG decreased cell viability and inhibited differentiation of 3T3-L1 cells in a manner dependent on the duration of treatment. Also, we showed that inhibition of adipocyte differentiation by EGCG was associated with decreased glycerol-3-phosphate dehydrogenase (GPDH) activity accompanied by a strong inhibition of PPARgamma2-induced transcriptional activity. Furthermore, the inhibition of adipocyte differentiation by EGCG involved generation of ROS and activation of AMPK.}, }
@article {pmid18068290, year = {2008}, author = {Terneus, MV and Brown, JM and Carpenter, AB and Valentovic, MA}, title = {Comparison of S-adenosyl-L-methionine (SAMe) and N-acetylcysteine (NAC) protective effects on hepatic damage when administered after acetaminophen overdose.}, journal = {Toxicology}, volume = {244}, number = {1}, pages = {25-34}, pmid = {18068290}, issn = {0300-483X}, support = {P20 RR016477/RR/NCRR NIH HHS/United States ; P20 RR016477-07/RR/NCRR NIH HHS/United States ; 5P20RR016477/RR/NCRR NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood/metabolism ; Aldehydes/metabolism ; Analysis of Variance ; Animals ; Blotting, Western ; Drug Overdose ; Glutathione/metabolism ; Injections, Intraperitoneal ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism/pathology ; Liver Failure, Acute/chemically induced/pathology/*prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Polarization/methods ; Organ Size/drug effects ; Protein Carbonylation/drug effects ; S-Adenosylmethionine/*analogs &amp; derivatives/therapeutic use ; Time Factors ; }, abstract = {In the clinical setting, antidotes are generally administered after the occurrence of a drug overdose. Therefore, the most pertinent evaluation of any new agent should model human exposure. This study tested whether acetaminophen (APAP) hepatotoxicity was reversed when S-adenosyl-L-methionine (SAMe) was administered after APAP exposure, similar to what occurs in clinical situations. Comparisons were made for potency between SAMe and N-acetylcysteine (NAC), the current treatment for APAP toxicity. Male C57BL/6 mice were fasted overnight and divided into groups: control (VEH), SAMe treated (SAMe), APAP treated (APAP), N-acetylcysteine treated (NAC), SAMe or NAC administered 1h after APAP (SAMe+APAP) and (NAC+APAP), respectively. Mice were injected intraperitoneal (i.p.) with water (VEH) or 250 mg/kg APAP (15 ml/kg). One hour later, mice were injected (i.p.) with 1.25 mmol/kg SAMe (SAMe+APAP) or NAC (NAC+APAP). Hepatotoxicity was evaluated 4h after APAP or VEH treatment. APAP induced centrilobular necrosis, increased liver weight and alanine transaminase (ALT) levels, depressed total hepatic glutathione (GSH), increased protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins. Treatment with SAMe 1h after APAP overdose (SAMe+APAP) was hepatoprotective and was comparable to NAC+APAP. Treatment with SAMe or NAC 1h after APAP was sufficient to return total hepatic glutathione (GSH) to levels comparable to the VEH group. Western blot showed reversal of APAP mediated effects in the SAMe+APAP and NAC+APAP groups. In summary, SAMe was protective when given 1h after APAP and was comparable to NAC.}, }
@article {pmid18068289, year = {2008}, author = {Sudheer, AR and Muthukumaran, S and Devipriya, N and Devaraj, H and Menon, VP}, title = {Influence of ferulic acid on nicotine-induced lipid peroxidation, DNA damage and inflammation in experimental rats as compared to N-acetylcysteine.}, journal = {Toxicology}, volume = {243}, number = {3}, pages = {317-329}, doi = {10.1016/j.tox.2007.10.016}, pmid = {18068289}, issn = {0300-483X}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Alkaline Phosphatase/blood ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Blotting, Western ; Catalase/metabolism ; Comet Assay ; Coumaric Acids/administration &amp; dosage/chemistry/*pharmacology ; Cyclooxygenase 2/metabolism ; DNA Damage/*drug effects ; Glutathione/blood/metabolism ; Glutathione Peroxidase/blood/metabolism ; Inflammation/chemically induced/metabolism/*prevention &amp; control ; Injections, Subcutaneous ; Intubation, Gastrointestinal ; L-Lactate Dehydrogenase/blood ; Lipid Peroxidation/*drug effects ; Male ; Molecular Structure ; NF-kappa B/metabolism ; Nicotine/administration &amp; dosage/*toxicity ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {We examined the effect of ferulic acid (FA), a naturally occurring phenolic compound on lipid peroxidation and endogenous antioxidant status, DNA damage and inflammation in nicotine-administered Wistar rats. The effect of FA against nicotine toxicity was compared with N-acetylcysteine (NAC), a well-known antioxidant. Lung toxicity was induced by subcutaneous injection of nicotine at a dose of 2.5mg/kg body weight (5 days a week, for 22 weeks) and FA and NAC were given simultaneously by intragastric intubation for 22 weeks. Seventy two Wistar rats were divided into six groups: (i) control, (ii) nicotine, (iii) nicotine+FA (iv), nicotine+NAC, (v) FA and (vi) NAC. At the end of the experimental period, cellular damage was assessed by measuring the activities of lactate dehydrogenase and alkaline phosphatase in plasma, which were significantly elevated in nicotine-administered rats when compared with control group. Enhanced lipid peroxidation (evaluated by measuring the thiobarbituric acid reactive substances and hydroperoxides) was accompanied by a significant decrease in the endogenous antioxidant status viz., superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione in circulation, lung and liver of nicotine-treated rats when compared with control group. DNA single strand breaks (evaluated by comet assay) and frequency of micronuclei were significantly increased in peripheral blood of nicotine-treated rats when compared with control. Our Western blot analysis showed a significant increase in the expression of cyclooxygenase-2 and NF-kappaB in lung and liver of nicotine-treated rats. FA and NAC co-treated rats showed a significant decrease in the activities of circulatory lactate dehydrogenase and alkaline phosphatase, the levels of lipid peroxidative markers (in circulation, lung and liver), DNA single stranded breaks (comet parameters), micronuclei frequency (in the whole blood) and expression of cyclooxygenase-2 and Nf-kappaB (in lung and liver tissues), and significant increase in antioxidant status (in circulation, lung and liver). The protection of FA against nicotine-induced toxicity was merely equal to the effect of NAC. FA and NAC treatment alone did not produce any damage to control rats. Thus, we propose that FA exerts protective effect against nicotine toxicity by modulating the lipid peroxidation, inflammation, DNA damage and endogenous antioxidant status.}, }
@article {pmid18067231, year = {2007}, author = {Wang, B and Li, HL and Yang, WY}, title = {[N-acetyl-l-cysteine improves function of islet beta cell in hyperlipidemic rats and its mechanism].}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {36}, number = {6}, pages = {575-580}, doi = {10.3785/j.issn.1008-9292.2007.06.010}, pmid = {18067231}, issn = {1008-9292}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dietary Fats/administration &amp; dosage ; Free Radical Scavengers/pharmacology ; Hyperlipidemias/metabolism/*physiopathology ; *Insulin Resistance ; Islets of Langerhans/drug effects/*metabolism ; Male ; Oxidative Stress/drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; }, abstract = {OBJECTIVE: To investigate the effect of N-acetyl-l-cysteine (NAC) on islet beta cell function in hyperlipidemic rats and its mechanism.<br><br>METHODS: Fifty-nine male SD rats of 8 week old were randomly divided into 3 groups: normal diet group(NC, n=20), high fat diet group (HF, n=20) and NAC treated group (NAC, n=19, NAC 300 mg x kg(-1) x d(-1) and high fat diet). At the end of 20 weeks, fasting serum insulin (Ins), glucose(Glu), malonaldehyde (MDA) and reduced glutathione (GSH) were determined in plasma and pancreas tissue. The glucose infusion rate (GIR) was measured by euglycemic hyperinsulinemia clamp to evaluate the peripheral insulin resistance.Pancreatic islets were isolated and subjected to a perifusion medium containing 3.3 mmol/L glucose for 15 min, followed by 16.7 mmol/L glucose for 30 min, insulin content of perifusion medium was measured by RIA. The expressions of IRS-1, IRS-2, Glut-2 gene in islets were detected by real time PCR.<br><br>RESULTS: (1)The insulin, glucose and MDA concentration in HF group were higher than those in NC group, but GSH levels in plasma and pancreas were lower. NAC intervention could reverse these effects. (2)The GIR was decreased significantly in HF group compared with NC group [(5.25 +/-1.2) Compared with (13.56 +/-1.7) mg x min(-1) x kg(-1), P<0.01], NAC intervention reversed these effect: GIR[(9.28 +/-1.50) Compared with (5.25 +/-1.2)mg x min(-1) x kg(-1), P<0.01]. (3) 16.7 mmol/L glucose increased the insulin secretion in the islet cells of the three groups, but the peak was lower in HF group. NAC intervention reversed these effects. (4) The gene expression of IRS-1 was significantly decreased by 42.3 % in HF group (P<0.05), and the expressions of IRS-2 and Glut-2 were decreased by 28.1% and 22.9% (P<0.05) compared with NC group. In contrast, the expressions of IRS-1, IRS-2, Glut-2 in NAC group increased by 40.2%, 30.2% and 19.1%, respectively than those in HF group.<br><br>CONCLUSION: NAC can reverse functional disorder of islet beta cells induced by high-fat-diet feeding. This antioxidant effect might be associated with upgrading gene expression of insulin signal transduction molecules in islet beta cells.}, }
@article {pmid18066968, year = {2007}, author = {Bulucu, F and Oktenli, C and Kenar, L and Koc, B and Ocal, R and Karadurmus, N and Inal, V and Yamanel, L and Sanisoglu, YS and Aydin, A}, title = {Detrimental effects of N-acetylcysteine plus desferoxamine combination in an experimental nephrotic syndrome model.}, journal = {International journal of toxicology}, volume = {26}, number = {6}, pages = {525-532}, doi = {10.1080/10915810701707403}, pmid = {18066968}, issn = {1091-5818}, mesh = {Acetylcysteine/*adverse effects/therapeutic use ; Animals ; Antioxidants/*adverse effects/therapeutic use ; Catalase/blood/metabolism ; Copper/blood ; Deferoxamine/*adverse effects/therapeutic use ; Doxorubicin ; Drug Therapy, Combination ; Glutathione Peroxidase/blood/metabolism ; Kidney/drug effects/metabolism ; Male ; Nephrotic Syndrome/chemically induced/*drug therapy/metabolism ; Rats ; Rats, Sprague-Dawley ; Selenium/blood ; Superoxide Dismutase/blood/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Zinc/blood/metabolism ; }, abstract = {The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) and desferoxamine (DFO) administered alone or in combination together in rats with doxorubicin (DOX)-induced nephrotic syndrome, by monitoring oxidative stress parameters and trace elements in renal tissue and erythrocytes. Fifty-four male Sprague-Dawley rats were included the study. Equal volume of isotonic saline was injected to control rats. After DOX administration, the animals were divided into four experimental groups: (a) rats given only DOX; (b) rats treated with NAC; (c) rats treated with DFO; (d) rats treated with NAC plus DFO. The combination of N-acetylcysteine and DFO has no beneficial effect on reducing proteinuria in experimentally nephrotic rats, although both of these agents ameliorate the condition when administered separately. It seems likely that detrimental effects of NAC plus DFO could be secondary to its effects on erythrocyte selenium levels demonstrated here. Consequently, the results may propose caution to the use of antioxidant therapeutic strategies such as NAC plus DFO against nephropathy.}, }
@article {pmid18066108, year = {2007}, author = {Neuman, MG and Jia, AY and Steenkamp, V}, title = {Senecio latifolius induces in vitro hepatocytotoxicity in a human cell line.}, journal = {Canadian journal of physiology and pharmacology}, volume = {85}, number = {11}, pages = {1063-1075}, doi = {10.1139/Y07-107}, pmid = {18066108}, issn = {0008-4212}, mesh = {Acetylcysteine/pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Glutathione/analysis ; Humans ; In Situ Nick-End Labeling ; Liver/*drug effects/metabolism ; Pyrrolizidine Alkaloids/pharmacology ; Senecio/*toxicity ; }, abstract = {The objectives of this study were twofold: (i) to determine the mechanism(s) of Senecio-induced toxicity in human hepatoblastoma cells (HepG2) in vitro and whether such toxicity could be prevented using N-acetyl-cysteine (NAC), and (ii) to evaluate whether caspases are involved in Senecio-induced apoptosis. Cells were treated with aqueous extracts of Senecio (10 mg x mL-1) with and without NAC. Cytotoxicity was determined by using the MTT assay. Total glutathione (GSH) was measured by using the Tietze assay. Cells were also treated with aqueous extracts of Senecio in the presence or absence of 50 micromol/L caspase-3 inhibitor (IDN) for 24 h. Apoptosis was determined by transmission electron microscopy, and DNA fragmentation was determined by ELISA and terminal dUTP nick-end labelling (TUNEL). Senecio produced cytotoxicity and depleted GSH in a concentration- and time-dependent manner. A significant depletion in GSH was observed after 15 min (p < 0.001 vs. control), whereas significant cytotoxicity was only observed after 3 h (p < 0.001 vs. control). Treatment with NAC prevented Senecio-induced GSH depletion and resulted in a significant decrease in Senecio-induced cytotoxicity (p < 0.001 vs. NAC-untreated cells). Treatment with Senecio for 24 h resulted in 22% +/- 2.5% (p < 0.001) apoptosis (vs. control). Pretreatment with 50 mumol caspase inhibitor reduced Senecio-induced apoptosis significantly (vs. non-exposed to IDN) (12% +/- 1.5%; p < 0.05). Our results suggest the mechanism of Senecio-induced cytotoxicity in HepG2 cells in vitro involves depletion of cellular GSH. Cytotoxicity is reduced by supplementation with NAC, which thus prevents GSH depletion. Caspase activation is involved in Senecio-induced apoptosis.}, }
@article {pmid18064629, year = {2008}, author = {Cao, C and Wan, S and Jiang, Q and Amaral, A and Lu, S and Hu, G and Bi, Z and Kouttab, N and Chu, W and Wan, Y}, title = {All-trans retinoic acid attenuates ultraviolet radiation-induced down-regulation of aquaporin-3 and water permeability in human keratinocytes.}, journal = {Journal of cellular physiology}, volume = {215}, number = {2}, pages = {506-516}, doi = {10.1002/jcp.21336}, pmid = {18064629}, issn = {1097-4652}, support = {P20 RR016457/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Aquaporin 3/*metabolism ; Cell Membrane Permeability/drug effects/radiation effects ; Cell Movement/physiology ; Cells, Cultured ; Down-Regulation/drug effects ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors ; Genes, erbB-1 ; Humans ; Hydrogen Peroxide/pharmacology ; Keratinocytes/*metabolism/*radiation effects ; Mitogen-Activated Protein Kinase Kinases/antagonists &amp; inhibitors ; Oxidants/pharmacology ; Time Factors ; Transcriptional Activation/physiology ; Tretinoin/*pharmacology ; Ultraviolet Rays ; Water/*metabolism ; Wound Healing/physiology ; }, abstract = {One of the major characteristics of human skin photoaging induced by ultraviolet (UV) radiation is the dehydration of the skin. Water movement across plasma membrane occurs via diffusion through lipid bilayer and via aquaporins (AQPs). We find that UV induces aquaporin-3 (AQP3) down-regulation in human skin keratinocytes. MEK/ERK inhibitors PD98059 and U0126 inhibit UV-induced down-regulation of AQP3. Antioxidant N-acetyl-L-cysteine or NAC blocks UV-induced MEK/ERK activation and down-regulation of AQP3. All-trans retinoic acid or atRA, while alone inducing AQP3 expression, attenuates UV-induced down-regulation of AQP3 and water permeability. Using special inhibitors, we find that activation of EGFR and inhibition on ERK activation are involved in atRA's protective effects against UV-induced AQP3 down-regulation. Using specific AQP3's water transport inhibitors and siRNA knockdown, we observe that AQP3 is involved in cell migration and in vitro wound healing. UV-induced AQP3 down-regulation results in reduced water permeability, decreased cell migration, and delayed wound healing, which are attenuated by atRA pretreatment. We conclude that atRA protects against UV-induced down-regulation AQP3 and decrease in water permeability, reduction in cell migration and delayed in vitro wound healing via trans-activation of EGFR and inhibition on ROS-mediated MEK/ERK pathway. This novel finding provides evidence to support possible involvement of AQP3 in UV induced skin dehydration.}, }
@article {pmid18064495, year = {2008}, author = {Kaplan, M and Atakan, IH and Aydoğdu, N and Aktoz, T and Ozpuyan, F and Seren, G and Tokuç, B and Inci, O}, title = {Influence of N-acetylcysteine on renal toxicity of cadmium in rats.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {23}, number = {2}, pages = {233-241}, pmid = {18064495}, issn = {0931-041X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Cadmium Chloride/metabolism/*toxicity ; Catalase/metabolism ; Chemoprevention ; Creatine/blood/urine ; Disease Models, Animal ; Drug Antagonism ; Free Radical Scavengers/*therapeutic use ; Glomerular Filtration Rate/drug effects ; Glutathione/metabolism ; Kidney/*drug effects/metabolism/pathology ; Kidney Diseases/chemically induced/metabolism/*prevention &amp; control ; Kidney Tubules, Proximal/drug effects/pathology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Urea/blood/urine ; }, abstract = {The aim of this study was to investigate the ability of N-acetylcysteine (NAC) to prevent cadmium (Cd)-induced renal damage and whether NAC would reverse cadmium damage to the kidney. Fifty adult male rats were divided into five experimental groups: group 1 received tap water for 3 months and 7 days, group 2 received cadmium chloride (CdCl(2)) for 3 months, group 3 (NAC cotreatment group) received CdCl(2) and 0.5% NAC in tap water for 3 months, group 4 received CdCl(2) in tap water for 3 months and 3 months later received only tap water for 7 days, and group 5 (NAC posttreatment group) received CdCl(2) in tap water for 3 months and 3 months later received 2% NAC in tap water for 7 days. NAC significantly decreased the elevated kidney malondialdehyde levels, as a marker of lipid peroxidation, in both cotreatment and posttreatment modalities. Cotreatment and posttreatment with NAC significantly increased kidney superoxide dismutase enzyme activity and glutathione level but did not change kidney catalase enzyme activity. NAC decreased fractional excretion of sodium in posttreatment group. Neither Cd nor NAC affected the glomerular filtration rate (GFR). Cotreatment and posttreatment with NAC reduced the effects of Cd on proximal tubules. It was found that NAC showed these effects without changing kidney accumulation of cadmium. Exogenously administrated NAC might reduce toxic effects of Cd on the kidney without any reduction in tissue Cd level.}, }
@article {pmid18063464, year = {2008}, author = {Kim, MS and Kim, MK and Kim, KS and Chung, JH and Kim, SJ and Kim, JH and Kim, JR and Lee, J and Yu, BP and Chung, HY}, title = {Cytotoxicity of 1,2-diacetylbenzene in human neuroblastoma SHSY5Y cells is mediated by oxidative stress.}, journal = {Toxicology}, volume = {243}, number = {1-2}, pages = {216-223}, doi = {10.1016/j.tox.2007.10.012}, pmid = {18063464}, issn = {0300-483X}, mesh = {Acetophenones/*toxicity ; Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Environmental Pollutants/*toxicity ; Flow Cytometry ; Glutathione/pharmacology ; Humans ; Microscopy, Electron, Scanning ; Microscopy, Fluorescence ; Neuroblastoma ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Environmental substances or metabolites induce neuronal damage through oxidative stress. Environmental organic solvent metabolite, 1,2-diacetylbenzene (1,2-DAB), treated rats develop limb weakness with neuropathological damage in both the central and peripheral nervous systems. In this experiment, we examined the relevance of 1,2-DAB-induced toxicity to increased oxidative stress using human dopaminergic neuroblastoma SHSY5Y cells. 1,2-DAB (4, 16, and 32 microM) disrupted cytoskeletal integrity and caused morphological changes. 1,2-DAB significantly decreased cell viability and induced cell cycle arrest in the G(1) phase in a concentration-dependent manner. At higher concentration, it produced apoptosis. Pre-treatment of cells with the antioxidants, GSH or N-acetylcysteine (NAC), effectively blocked 1,2-DAB-mediated cytotoxicity including cell viability, and morphological changes. These results therefore suggest that oxidative stress is involved in environmental metabolite 1,2-DAB-mediated neurotoxicity and that antioxidant treatment can effectively protect the nervous system from environmental hazards.}, }
@article {pmid18062993, year = {2008}, author = {Elmes, MJ and McMullen, S and Gardner, DS and Langley-Evans, SC}, title = {Prenatal diet determines susceptibility to cardiac ischaemia-reperfusion injury following treatment with diethylmaleic acid and N-acetylcysteine.}, journal = {Life sciences}, volume = {82}, number = {3-4}, pages = {149-155}, doi = {10.1016/j.lfs.2007.10.022}, pmid = {18062993}, issn = {0024-3205}, support = {//British Heart Foundation/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Diet, Protein-Restricted/*adverse effects ; Disease Models, Animal ; Female ; Glutathione/metabolism ; Heart/*drug effects/physiopathology ; Hemodynamics/drug effects ; Maleates/*pharmacology ; Maternal Exposure ; Myocardial Reperfusion Injury/*etiology/physiopathology ; Myocardium/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects/*etiology/physiopathology ; *Prenatal Nutritional Physiological Phenomena ; Rats ; Ventricular Dysfunction, Left/etiology/physiopathology ; }, abstract = {Fetal undernutrition programmes increased risk of developing cardiovascular disease in adult life. We hypothesized that prenatal protein restriction would impair recovery in post-ischaemic cardiac function in adult offspring through antioxidant-mediated processes. Pregnant Wistar rats were fed control or maternal low protein diets (MLP) throughout gestation. The offspring of these rats were treated with either saline, N-acetylcysteine (NAC), diethylmaleate (DEM), or both NAC and DEM to manipulate glutathione status at 6 months of age. Hearts were rapidly excised and retro-perfused (Langendorff) to assess isolated cardiac function before (baseline), and during 30 min global ischaemia and 60 min reperfusion. Hearts from adult rats exposed to a MLP diet in utero suffered greater cardiac dysfunction than those from controls following 30 min ischaemia. Left ventricular developed pressure (LVDP) was significantly reduced upon early reperfusion (p<0.042) in MLP rats compared to controls. NAC pre-treatment had no effect on LVDP of hearts from control animal hearts but improved the revival of MLP hearts to the same level as controls. DEM treatment did not affect control hearts but significantly reduced recovery of LVDP of MLP hearts during early (p<0.008) and late reperfusion (0.035). Combined NAC and DEM treatment had no effect on LVDP between control and MLP fed offspring. Prenatal protein restriction throughout pregnancy increases the susceptibility of the adult rat heart to suffer a functional deficit following ischaemia-reperfusion injury. Pharmacologically improving antioxidant status prevented this injury. A nutritionally-imbalanced developmental environment may increase susceptibility to coronary heart disease through the programming of myocardial glutathione metabolism.}, }
@article {pmid18062818, year = {2007}, author = {Visalli, V and Muscoli, C and Sacco, I and Sculco, F and Palma, E and Costa, N and Colica, C and Rotiroti, D and Mollace, V}, title = {N-acetylcysteine prevents HIV gp 120-related damage of human cultured astrocytes: correlation with glutamine synthase dysfunction.}, journal = {BMC neuroscience}, volume = {8}, number = {}, pages = {106}, pmid = {18062818}, issn = {1471-2202}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Astrocytes/*drug effects ; Astrocytoma/pathology ; Brain Neoplasms/pathology ; Cell Death/drug effects ; Cell Line, Tumor ; Drug Interactions ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; Glutamate-Ammonia Ligase/*physiology ; Glutamine/metabolism ; HIV Envelope Protein gp120/*toxicity ; Humans ; In Situ Nick-End Labeling/methods ; Male ; Malondialdehyde/metabolism ; Middle Aged ; }, abstract = {BACKGROUND: HIV envelope gp 120 glycoprotein is released during active HIV infection of brain macrophages thereby generating inflammation and oxidative stress which contribute to the development of the AIDS-Dementia Complex (ADC). Gp120 has also been found capable to generate excitotoxic effect on brain tissue via enhancement of glutamatergic neurotransmission, leading to neuronal and astroglial damage, though the mechanism is still to be better understood. Here we investigated on the effect of N-acetylcysteine (NAC), on gp120-induced damage in human cultured astroglial cells and the possible contribution of gp120-related reacting oxygen species (ROS) in the imbalanced activity of glutamine synthase (GS), the enzyme that metabolizes glutamate into glutamine within astroglial cells playing a neuroprotective role in brain disorders.<br><br>RESULTS: Incubation of Lipari human cultured astroglial cells with gp 120 (0.1-10 nM) produced a significant reduction of astroglial cell viability and apoptosis as evaluated by TUNEL reaction and flow cytometric analysis (FACS). This effect was accompanied by lipid peroxidation as detected by means of malondialdehyde assay (MDA). In addition, gp 120 reduced both glutamine concentration in astroglial cell supernatants and GS expression as detected by immunocytochemistry and western blotting analysis. Pre-treatment of cells with NAC (0.5-5 mM), dose-dependently antagonised astroglial apoptotic cell death induced by gp 120, an effect accompanied by significant attenuation of MDA accumulation. Furthermore, both effects were closely associated with a significant recovery of glutamine levels in cell supernatants and by GS expression, thus suggesting that overproduction of free radicals might contribute in gp 120-related dysfunction of GS in astroglial cells.<br><br>CONCLUSION: In conclusion, the present experiments demonstrate that gp 120 is toxic to astroglial cells, an effect accompanied by lipid peroxidation and by altered glutamine release. All the effects of gp120 on astroglial cells were counteracted by NAC thus suggesting a novel and potentially useful approach in the treatment of glutammatergic disorders found in HAD patients.}, }
@article {pmid18059323, year = {2008}, author = {McMaster, SK and Paul-Clark, MJ and Walters, M and Fleet, M and Anandarajah, J and Sriskandan, S and Mitchell, JA}, title = {Cigarette smoke inhibits macrophage sensing of Gram-negative bacteria and lipopolysaccharide: relative roles of nicotine and oxidant stress.}, journal = {British journal of pharmacology}, volume = {153}, number = {3}, pages = {536-543}, pmid = {18059323}, issn = {0007-1188}, support = {//British Heart Foundation/United Kingdom ; //Medical Research Council/United Kingdom ; }, mesh = {Animals ; Blotting, Western ; Gene Expression Regulation, Enzymologic/drug effects ; Gram-Negative Bacteria/*metabolism ; In Vitro Techniques ; Lipopolysaccharides/metabolism ; Macrophages/*drug effects/metabolism ; Mice ; Nicotine/adverse effects ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Oxidants/metabolism ; Oxidative Stress/drug effects ; Receptors, Nicotinic/drug effects/metabolism ; Smoke/*adverse effects ; Nicotiana/*adverse effects ; Tumor Necrosis Factor-alpha/drug effects/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: Smoking cigarettes is a major risk factor for the development of cardiovascular and respiratory disease. Moreover, smokers are more prone to infections. This has been associated with a suppression of the immune system by smoke. However, it is not clear how cigarette smoke affects the ability of immune cells to sense pathogens. Cigarette smoke contains a large number of molecules which may mediate responses on immune cells and of these, nicotine and oxidants have both been identified as inhibitory for the sensing of bacterial lipopolysaccharide (LPS). Nitric oxide synthase (NOS) and tumour necrosis factor (TNF)-alpha are both induced in macrophages on stimulation with Gram negative bacteria or LPS.<br><br>EXPERIMENTAL APPROACH: We used murine macrophages stimulated with whole heat-killed bacteria or LPS. We measured output of NO (as nitrite) and TNFalpha, NOS protein by Western blotting and cellular oxidant stress.<br><br>KEY RESULTS: Cigarette smoke extract suppressed the ability of murine macrophages to release NO, but not TNFalpha in response to whole bacteria. Cigarette smoke extract also inhibited nitric oxide synthase II protein expression in response to LPS. The effects of cigarette smoke extract on nitrite formation stimulated by LPS were unaffected by inhibition of nicotinic receptors with alpha-bungarotoxin (100 units ml(-1)). However, the effects of cigarette smoke extract on LPS-induced nitrite formation were mimicked by hydrogen peroxide and reversed by the anti-oxidants N-acetyl cysteine and glutathione.<br><br>CONCLUSIONS AND IMPLICATIONS: We suggest that cigarette smoke exerts its immunosuppressive effects through an oxidant-dependent and not a nicotine-dependent mechanism.}, }
@article {pmid18059023, year = {2008}, author = {McLean, L and Soto, U and Agama, K and Francis, J and Jimenez, R and Pommier, Y and Sowers, L and Brantley, E}, title = {Aminoflavone induces oxidative DNA damage and reactive oxidative species-mediated apoptosis in breast cancer cells.}, journal = {International journal of cancer}, volume = {122}, number = {7}, pages = {1665-1674}, pmid = {18059023}, issn = {1097-0215}, support = {R25 GM060507/GM/NIGMS NIH HHS/United States ; R25 GM060507-02/GM/NIGMS NIH HHS/United States ; 5R01GM41336/GM/NIGMS NIH HHS/United States ; R01 GM041336/GM/NIGMS NIH HHS/United States ; P20 MD001632/MD/NIMHD NIH HHS/United States ; P20 MD001632-01/MD/NIMHD NIH HHS/United States ; P20 MD006988/MD/NIMHD NIH HHS/United States ; R01 GM041336-16/GM/NIGMS NIH HHS/United States ; 5P20 MD001632/MD/NIMHD NIH HHS/United States ; R25 GM060507-01A1/GM/NIGMS NIH HHS/United States ; /ImNIH/Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/antagonists &amp; inhibitors/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Breast Neoplasms/chemistry/*drug therapy/genetics/*pathology ; Caspases/metabolism ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP1A2/metabolism ; DNA Damage/*drug effects ; DNA, Neoplasm/*drug effects ; Enzyme Activation/drug effects ; Female ; Flavonoids/antagonists &amp; inhibitors/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Reactive Oxygen Species/*metabolism ; Receptors, Estrogen/analysis ; S Phase/drug effects ; }, abstract = {Aminoflavone (5-amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methylchromen-4-one; AF; NSC 686288), a novel anticancer candidate agent, is undergoing clinical evaluation. AF induces DNA-protein cross-links (DPCs), Gamma-H2AX phosphorylation, aryl hydrocarbon receptor (AhR) signaling, apoptosis and its own metabolism via cytochrome P4501A1 and 1A2 (CYP1A1/1A2) activation in sensitive estrogen receptor positive (ER+) MCF7 breast cancer cells. Estrogen receptor negative (ER-) breast cancer is typically more aggressive with a poorer prognosis. In this investigation, we evaluated the ability of AF to induce reactive oxygen species (ROS) formation, oxidative DNA damage and apoptosis in ER- MDA-MB-468 breast cancer cells. The antioxidant, N-acetyl-L-cysteine (NAC), attenuated the cytotoxic effects of AF in MDA-MB-468 cells; an effect is also observed in ER+ T47D breast cancer cells. Nonmalignant MCF10A breast epithelial cells were resistant to the cytotoxic effects of AF. AF increased intracellular ROS, an effect blocked by NAC and the CYP1A1/1A2 inhibitor, alpha-Naphthoflavone (alpha-NF). AF induced oxidative DNA damage as evidenced by increased 8-oxo-7,8-dihydroguanine (8-oxodG) levels and DPC formation in these cells. AF caused S-phase arrest corresponding to an increase in p21((waf1/cip1)) protein expression. AF induced caspase 3, 8 and 9 activation, caspase-dependent apoptotic body formation and poly [ADP-ribose] polymerase (PARP) cleavage. Pretreatment with the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-DL-Asp(OMe)-fluoromethylketone inhibited apoptosis and partially inhibited ROS formation and oxidative DNA damage. Pretreatment with NAC attenuated AF-induced apoptotic body formation and caspase 3 activation. These studies suggest AF inhibits the growth of breast cancer cells in part, by inducing ROS production, oxidative DNA damage and apoptosis and has the potential to treat hormone-independent breast cancer.}, }
@article {pmid18057552, year = {2007}, author = {Adachi, Y and Yoshikawa, Y and Sakurai, H}, title = {Antidiabetic zinc(II)-N-acetyl-L-cysteine complex: evaluations of in vitro insulinomimetic and in vivo blood glucose-lowering activities.}, journal = {BioFactors (Oxford, England)}, volume = {29}, number = {4}, pages = {213-223}, doi = {10.1002/biof.5520290405}, pmid = {18057552}, issn = {0951-6433}, mesh = {Acetylcysteine/*chemistry/*pharmacology ; Adipocytes/drug effects/metabolism ; Animals ; Antioxidants/pharmacology ; Blood Glucose/*drug effects ; Blood Urea Nitrogen ; Cholesterol/blood ; Diabetes Mellitus, Type 2/blood/*drug therapy ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Glucose Tolerance Test ; Hemoglobins/drug effects ; Hyperglycemia/drug therapy ; Hyperinsulinism/drug therapy ; Hypoglycemic Agents/chemistry/*pharmacology ; *Insulin/blood ; Insulin Resistance ; Male ; Mice ; Mice, Knockout ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Zinc ; }, abstract = {The diabetic state is known to induce oxidative stress in its mechanism, which in turn is responsible for the complications of diabetes mellitus (DM). Recently, we found that Zn(II) complexes have in vitro insulinomimetic and in vivo blood glucose-lowering activities. During our study on the development of new Zn(II) complexes with antioxidative ligands involving L-cysteine, L-cysteine-methylester, and N-acetyl-L-cysteine (nac), we found a new (N-acetyl-L-cysteinato)Zn(II) (Zn(nac)) complex by evaluating of both its in vitro insulinomimetic and in vivo potencies. The insulinomimetic activity of Zn(nac) with respect to the inhibition of free fatty acid release in isolated rat adipocytes treated with epinephrine was higher than that of a well-known insulinomimetic VOSO4, being equivalent to that of ZnSO4. The blood glucose level of hyperglycemic KK-Ay mice with type 2 DM was reduced by daily intraperitoneal injections of Zn(nac) for 28 days. Their serum insulin, HbA1c, TCHO, and UN levels were remarkably decreased, indicating that Zn(nac) improved the insulin resistance of the mice. The improvement of DM by Zn(nac) was also confirmed by the oral glucose tolerance test. In conclusion, Zn(nac) complex is proposed to attenuate both hyperglycemia and hyperinsulinemia in KK-Ay mice by decreasing serum insulin, HbA1c, UN, and TCHO levels.}, }
@article {pmid18049032, year = {2007}, author = {Fujii, S and Zhang, L and Kosaka, H}, title = {Albuminuria, expression of nicotinamide adenine dinucleotide phosphate oxidase and monocyte chemoattractant protein-1 in the renal tubules of hypertensive Dahl salt-sensitive rats.}, journal = {Hypertension research : official journal of the Japanese Society of Hypertension}, volume = {30}, number = {10}, pages = {991-998}, doi = {10.1291/hypres.30.991}, pmid = {18049032}, issn = {0916-9636}, mesh = {Albuminuria/*metabolism ; Animals ; Chemokine CCL2/*metabolism ; Gene Expression ; Hypertension/*metabolism ; Immunohistochemistry ; Kidney Tubules/*metabolism ; Male ; NADPH Oxidases/*metabolism ; Rats ; Rats, Inbred Dahl ; }, abstract = {In chronic renal diseases, experimental and human data suggest that excess albumin filtered through the glomerular capillary barrier is over-reabsorbed by proximal tubular cells, thereby activating these cells and upregulating the expression of chemokines. On the other hand, a high-salt diet has been shown to induce proteinuria in hypertensive Dahl salt-sensitive (DSS) rats, accompanied with the expression of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the kidney. In the current study, we therefore examined albuminuria and the expressions of NADPH oxidase and monocyte chemoattractant protein-1 (MCP-1) in the renal tubular cells in hypertensive DSS rats, as well as the effects of the antioxidant N-acetylcysteine (NAC) on each of these parameters. DSS rats were fed a normal-salt diet (0.24% NaCl), a high-salt diet (8% NaCl), or a high-salt diet plus NAC supplementation (15 mg/mL drinking water) for 4 weeks. The high-salt diet provoked an increase in glomerular injuries accompanied with albuminuria and in urinary H2O2 and MCP-1 excretion. Immunohistochemical analysis showed the prominent expression of MCP-1 in the dilated tubular cells, where the NADPH oxidase subunit p47phox was also expressed. The current results suggest that albuminuria caused expression of NADPH oxidase and MCP-1 in the dilated renal tubules, resulting in interstitial inflammation and migration of mononuclear cells in DSS rats, because blockade of albuminuria by NAC counteracted the p47phox and MCP-1 expression.}, }
@article {pmid18047630, year = {2008}, author = {Colantuono, G and Tiravanti, EA and Di Venosa, N and Cazzato, A and Rastaldo, R and Cagiano, R and D'Agostino, D and Federici, A and Fiore, T}, title = {Hyperoxia confers myocardial protection in mechanically ventilated rats through the generation of free radicals and opening of mitochondrial ATP-sensitive potassium channels.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {35}, number = {1}, pages = {64-71}, doi = {10.1111/j.1440-1681.2007.04745.x}, pmid = {18047630}, issn = {1440-1681}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood Pressure ; Coronary Circulation ; Decanoic Acids/pharmacology ; Disease Models, Animal ; Free Radical Scavengers/pharmacology ; Glyburide/pharmacology ; Heart Rate ; Hydroxy Acids/pharmacology ; Hypoxia/*metabolism/physiopathology ; Male ; Myocardial Infarction/metabolism/physiopathology/*prevention &amp; control ; Myocardial Reperfusion Injury/metabolism/physiopathology/*prevention &amp; control ; Myocardium/*metabolism ; *Oxidative Stress/drug effects ; Potassium Channel Blockers/pharmacology ; Potassium Channels/drug effects/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; *Respiration, Artificial ; Time Factors ; Ventricular Function, Left ; Ventricular Pressure ; }, abstract = {1. One hour exposure to hyperoxia has been shown previously to limit a subsequent ischaemia-reperfusion injury in spontaneously breathing rats. We tested the cardioprotective effect of a shorter period of hyperoxia during mechanical ventilation and the possible contribution of reactive oxygen species (ROS) and mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels. 2. Mechanically ventilated rats were exposed to normoxia (Fi O2 = 0.3) or hyperoxia (Fi O2 = 1.0) for 30 min and pH, P CO2, PO2, heart rate, airway and blood pressure were measured at baseline and after 30 min mechanical ventilation. Isolated hearts were subsequently subjected to 30 min ischaemia and 120 min reperfusion. Infarct size and left ventricular end-diastolic pressure (LVEDP), developed pressure (LVDP) and coronary flow (CF) were measured. In order to investigate the role of ROS and KATP channels within the mechanism leading to cardioprotection, the free radical scavenger N-acetylcysteine (NAC; 150 mg/kg) was infused in mechanically ventilated rats and the KATP channel blockers glibenclamide (200 mmol/L) or 5-hydroxydecanoate (10 mmol/L) were infused in isolated hearts immediately before ischaemia. 3. No differences were detected in P CO2, pH, heart rate, airway and blood pressure between the groups. However, the PO2 in hyperoxic groups was significantly higher compared with that in normoxic groups (P < 0.01). After 30 min ischaemia, we found that hyperoxic preconditioning significantly improved CF (P < 0.01), LVDP (P < 0.01) and LVEDP (P < 0.01) and reduced the extent of infarct size in the reperfused heart compared with the normoxic group (P < 0.01). When rats were pretreated either with NAC before hyperoxic ventilation or with K(ATP) channel blockers before ischaemia, myocardial protection was abolished. 4. Hyperoxic mechanical ventilation, prior to ischaemia, reduces myocardial reperfusion injury. This is likely to occur through the induction of oxidative stress, which leads to myocyte mitoKATP channel opening.}, }
@article {pmid18046886, year = {2006}, author = {Dekhuijzen, PN and van Beurden, WJ}, title = {The role for N-acetylcysteine in the management of COPD.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {1}, number = {2}, pages = {99-106}, pmid = {18046886}, issn = {1176-9106}, mesh = {Acetylcysteine/*therapeutic use ; Biomarkers/metabolism ; Exhalation ; Free Radical Scavengers/*therapeutic use ; Humans ; Oxidative Stress ; Pulmonary Disease, Chronic Obstructive/*drug therapy/metabolism/physiopathology ; }, abstract = {Oxidative stress has been implicated in the pathogenesis and progression of COPD. Both reactive oxidant species from inhaled cigarette smoke and those endogenously formed by inflammatory cells constitute an increased intrapulmonary oxidant burden. Structural changes to essential components of the lung are caused by oxidative stress, contributing to irreversible damage of both parenchyma and airway walls. The antioxidant N-acetylcysteine (NAC), a glutathione precursor, has been applied in these patients to reduce symptoms, exacerbations, and the accelerated lung function decline. This article reviews the available experimental and clinical data on the antioxidative effects of NAC in COPD, with emphasis on the role of exhaled biomarkers.}, }
@article {pmid18045763, year = {2008}, author = {Muthukumaran, S and Sudheer, AR and Menon, VP and Nalini, N}, title = {Protective effect of quercetin on nicotine-induced prooxidant and antioxidant imbalance and DNA damage in Wistar rats.}, journal = {Toxicology}, volume = {243}, number = {1-2}, pages = {207-215}, doi = {10.1016/j.tox.2007.10.006}, pmid = {18045763}, issn = {0300-483X}, mesh = {Acetylcysteine/pharmacology ; Alkaline Phosphatase/blood ; Animals ; *Antioxidants/metabolism/pharmacology ; Body Weight/drug effects ; *DNA Damage ; Kidney/drug effects/enzymology/metabolism ; L-Lactate Dehydrogenase/blood ; Liver/drug effects/enzymology/metabolism ; Lung/drug effects/enzymology/metabolism ; Male ; Nicotine/*toxicity ; Oxidants/*metabolism ; Quercetin/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {We have investigated the protective effect of quercetin (QN) against nicotine-induced prooxidant and antioxidant imbalance in circulation, lung, liver and kidney of experimental rats. The protective effect of QN was compared with N-acetylcysteine (NAC), a well-known antioxidant. Male albino rats of Wistar stain were used for the experimental study. Lung toxicity was induced by subcutaneous injection of nicotine at a dose of 2.5mg/kg body weight (5 days a week, for 22 weeks) and QN was given simultaneously by intragastric intubations for 22 weeks. The body weight gain of rats during experimental period was significantly decreased in nicotine treated group, whereas QN co-treated rats significantly increased in their body weight. The levels of lipid peroxidative indices viz., thiobarbituric acid reactive substances and hydroperoxides, and nitric oxide in circulation, lung, liver and kidney of nicotine-treated rats were increased significantly when compared to normal, which were brought down to near normal in QN co-treated group. Endogenous antioxidant status viz., superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione were found to be significantly decreased in circulation, lung, liver and kidney of nicotine-treated group, which were significantly increased in QN-administered groups. The extent of DNA damage (evaluated by comet assay) was significantly increased in circulatory blood of nicotine-treated rats, which was effectively brought down by QN treatment. The protective effect of QN against nicotine toxicity was comparable to that of NAC. Our data suggest that QN exerts its protective effect by modulating the extent of lipid peroxidation and augmenting antioxidant defense system and thus protects the DNA in experimental animals.}, }
@article {pmid18044098, year = {2006}, author = {Sadowska, AM and Verbraecken, J and Darquennes, K and De Backer, WA}, title = {Role of N-acetylcysteine in the management of COPD.}, journal = {International journal of chronic obstructive pulmonary disease}, volume = {1}, number = {4}, pages = {425-434}, pmid = {18044098}, issn = {1176-9106}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Cost-Benefit Analysis ; Dyspnea/drug therapy ; Expectorants/pharmacology/*therapeutic use ; Humans ; Lung/drug effects/*physiopathology ; Pulmonary Disease, Chronic Obstructive/*drug therapy ; Quality of Life ; Respiratory Function Tests ; Treatment Outcome ; }, abstract = {The importance of the underlying local and systemic oxidative stress and inflammation in chronic obstructive pulmonary disease (COPD) has long been established. In view of the lack of therapy that might inhibit the progress of the disease, there is an urgent need for a successful therapeutic approach that, through affecting the pathological processes, will influence the subsequent issues in COPD management such as lung function, airway clearance, dyspnoea, exacerbation, and quality of life. N-acetylcysteine (NAC) is a mucolytic and antioxidant drug that may also influence several inflammatory pathways. It provides the sulfhydryl groups and acts both as a precursor of reduced glutathione and as a direct reactive oxygen species (ROS) scavenger, hence regulating the redox status in the cells. The changed redox status may, in turn, influence the inflammation-controlling pathways. Moreover, as a mucolytic drug, it may, by means of decreasing viscosity of the sputum, clean the bronchi leading to a decrease in dyspnoea and improved lung function. Nevertheless, as successful as it is in the in vitro studies and in vivo studies with high dosage, its actions at the dosages used in COPD management are debatable. It seems to influence exacerbation rate and limit the number of hospitalization days, however, with little or no influence on the lung function parameters. Despite these considerations and in view of the present lack of effective therapies to inhibit disease progression in COPD, NAC and its derivatives with their multiple molecular modes of action remain promising medication once doses and route of administration are optimized.}, }
@article {pmid18042957, year = {2007}, author = {Sansevero, MR and Houser, R and Phelan, G and Wanke, C and Tang, A and Hendricks, K}, title = {Nonvitamin, nonmineral dietary supplementation in HIV-positive people.}, journal = {Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition}, volume = {22}, number = {6}, pages = {679-687}, doi = {10.1177/0115426507022006679}, pmid = {18042957}, issn = {0884-5336}, support = {P01 DK045734/DK/NIDDK NIH HHS/United States ; }, mesh = {Adult ; Cohort Studies ; Cross-Sectional Studies ; Diet ; Diet Records ; Dietary Supplements/adverse effects/*economics/*statistics &amp; numerical data ; Dietetics ; *Drug Interactions ; Female ; *Food-Drug Interactions ; HIV Infections/drug therapy/*psychology ; Health Knowledge, Attitudes, Practice ; Humans ; Male ; Middle Aged ; Risk Factors ; }, abstract = {BACKGROUND: Many consumers with chronic diseases attempt to take control of their health by using dietary supplements. The objective of this study was to describe current nonvitamin, nonmineral (NVNM) supplement use of HIV-infected persons in the Nutrition for Healthy Living (NFHL) cohort, the financial burden that buying these supplements might pose to this population, and to review current literature on potential interactions between NVNM supplements.<br><br>METHODS: At baseline visit, participants were educated by a registered dietitian on keeping a complete 3-day food record (including all supplements) for 2 weekdays and 1 weekend day. Seventy-two subjects reported consumption of NVNM supplements, and their food records were reviewed in detail.<br><br>RESULTS: Each of the 72 subjects in this study used a mean of 6 NVNM supplements, which may have been in the form of a pill, powder, bar, or liquid. The 6 most common were glutamine (51%), N-acetyl-cysteine (36%), fish oil (33%), alpha-lipoic acid (32%), acetyl-l-carnitine (28%), and coenzyme Q10 (28%). Participants were also taking an average of 4 vitamin/mineral supplements; the 6 most common were multivitamin/multimineral (83%), vitamin E (51%), vitamin C (47%), vitamin B complex (43%), calcium (29%), and selenium (28%).<br><br>CONCLUSIONS: With a total of 107 different types of NVNM supplements, our estimated cost examples indicated a weekly supplement regimen cost of between $25 and $40 dollars. According to literature review, taking an NVNM supplement may involve some risk because many components have not been studied and these products are not tightly regulated.}, }
@article {pmid18038907, year = {2007}, author = {Kim, DY and Jun, JH and Lee, HL and Woo, KM and Ryoo, HM and Kim, GS and Baek, JH and Han, SB}, title = {N-acetylcysteine prevents LPS-induced pro-inflammatory cytokines and MMP2 production in gingival fibroblasts.}, journal = {Archives of pharmacal research}, volume = {30}, number = {10}, pages = {1283-1292}, doi = {10.1007/BF02980269}, pmid = {18038907}, issn = {0253-6269}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Aggregatibacter actinomycetemcomitans ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Antioxidants/*pharmacology/therapeutic use ; Cells, Cultured ; Cytokines/*metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation ; Fibroblasts/drug effects/enzymology/metabolism/microbiology ; Gingiva/*blood supply/enzymology/metabolism/microbiology ; Humans ; Inflammation Mediators/*metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Lipopolysaccharides/*pharmacology ; Matrix Metalloproteinase 2/*metabolism ; Periodontitis/drug therapy/metabolism/microbiology ; Porphyromonas gingivalis ; Reactive Oxygen Species/metabolism ; Time Factors ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Periodontitis is an inflammatory process that ultimately results in tooth loss. Although the primary etiologic agent for periodontitis is bacteria, the majority of periodontal tissue destruction is thought to be caused by an inappropriate host response. Reactive oxygen species (ROS) have been known to be involved in periodontal tissue destruction. We treated human gingival fibroblasts with lipopolysaccharide (LPS) obtained from E. coli and the periodontopathogens Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis, and examined their inflammatory responses in the presence and absence of the antioxidant N-acetylcysteine (NAC). LPS enhanced ROS production, as well as, expression of pro-inflammatory cytokines such as interleukin-1beta, interleukin-6, interleukin-8 and tumor necrosis factor-alpha, and the production and activation of MMP2. NAC suppressed all LPS-induced inflammatory responses examined, suggesting that LPS-induced ROS may play a major regulatory role in these responses in gingival fibroblasts. In addition, NAC prevented LPS-induced activation of p38 MAPK and JNK but not phosphorylation and subsequent degradation of IkB. These results indicate that NAC exerts anti-inflammatory effects in LPS-stimulated gingival fibroblasts, functioning at least in part via down-regulation of JNK and p38 MAPK activation. Furthermore, this work suggests that antioxidants may be useful in adjunctive therapies that complement conventional periodontal treatments.}, }
@article {pmid18037553, year = {2008}, author = {Reliene, R and Fleming, SM and Chesselet, MF and Schiestl, RH}, title = {Effects of antioxidants on cancer prevention and neuromotor performance in Atm deficient mice.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {46}, number = {4}, pages = {1371-1377}, pmid = {18037553}, issn = {0278-6915}, support = {U54 ES012078/ES/NIEHS NIH HHS/United States ; T32 NS007449/NS/NINDS NIH HHS/United States ; P50NS38367/NS/NINDS NIH HHS/United States ; U54ES12078/ES/NIEHS NIH HHS/United States ; T32 NS07449-05/NS/NINDS NIH HHS/United States ; R01 ES009519-07A2/ES/NIEHS NIH HHS/United States ; R01 ES009519/ES/NIEHS NIH HHS/United States ; R01 ES09519/ES/NIEHS NIH HHS/United States ; P50 NS038367/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*genetics ; DNA-Binding Proteins/*genetics ; Free Radical Scavengers/pharmacology ; Mice ; Mice, Knockout ; Neoplasms/*prevention &amp; control ; Protein Serine-Threonine Kinases/*genetics ; Psychomotor Performance/*drug effects ; Tumor Suppressor Proteins/*genetics ; }, abstract = {Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by immunodeficiency, neurodegeneration and cancer. The disease results from bi-allelic mutations in the AT mutated (ATM) gene involved in cell cycle checkpoint control and repair of DNA double-strand breaks. Evidence has been accumulating that oxidative stress is associated with AT and may be involved in the pathogenesis of the disease. This led to a hypothesis that antioxidants may alleviate the symptoms of AT. Consequently, several studies were conducted in Atm deficient mice to examine the role of antioxidants in cancer prevention and/or correction of neuromotor performance. N-acetyl-l-cysteine (NAC), EUK-189, tempol, and 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) have been tested in Atm deficient mice. In contrast to other antioxidants, NAC has been used in the clinical practice for many decades and is available as a dietary supplement. In this article, we review chemoprevention studies in Atm deficient mice and, in more detail, our findings on the effect of NAC. Our short-term study showed that NAC suppressed genome rearrangements linked to cancer. The long-term study demonstrated that NAC reduced the incidence and multiplicity of lymphoma and improved some aspects of motor performance.}, }
@article {pmid18036807, year = {2008}, author = {Shohrati, M and Aslani, J and Eshraghi, M and Alaedini, F and Ghanei, M}, title = {Therapeutics effect of N-acetyl cysteine on mustard gas exposed patients: evaluating clinical aspect in patients with impaired pulmonary function test.}, journal = {Respiratory medicine}, volume = {102}, number = {3}, pages = {443-448}, doi = {10.1016/j.rmed.2007.10.004}, pmid = {18036807}, issn = {0954-6111}, mesh = {Acetylcysteine/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Bronchiolitis Obliterans/*chemically induced/drug therapy ; Chemical Warfare Agents/*toxicity ; Double-Blind Method ; Female ; Forced Expiratory Volume/drug effects ; Free Radical Scavengers/*therapeutic use ; Free Radicals/adverse effects ; Humans ; Male ; Middle Aged ; Mustard Gas/*toxicity ; Treatment Outcome ; Vital Capacity/drug effects ; }, abstract = {AIMS: Long-term prescription of N-acetyl cysteine (NAC) may be effective in diseases caused by active radicals of oxygen species. The aim of this study was to determine the effect of 2- and 4-month administration of NAC (1800 mg daily) on mustard induced bronchiolitis obliterans.<br><br>METHODS AND MATERIALS: In a double blind clinical trial, 144 patients with bronchiolitis obliterans due to sulfur mustard in bronchiolitis obliterans syndrome (BOS) classes 1 and 2, randomly entered Group 1 (n=72, NAC) and Group 2 (n=72, placebo). Dyspnea, wake-up dyspnea, cough, and sputum were measured after 4 months. Spirometric findings were measured at the beginning of the trial, 2 months after and after 4 months of prescription of 1800 mg/day in three doses of NAC or placebo.<br><br>RESULTS: Dyspnea, cough, sputum, and wake-up dyspnea improved after 4 months of NAC compared to the control group. After 4 months, spirometric components were significantly improved in NAC group compared to placebo group.<br><br>CONCLUSION: Fourth months administration of NAC (1800 mg daily) can improve clinical conditions and spirometric findings in mustard exposed in BOS class 1 or 2.}, }
@article {pmid18036352, year = {2008}, author = {Shin, MH and Moon, YJ and Seo, JE and Lee, Y and Kim, KH and Chung, JH}, title = {Reactive oxygen species produced by NADPH oxidase, xanthine oxidase, and mitochondrial electron transport system mediate heat shock-induced MMP-1 and MMP-9 expression.}, journal = {Free radical biology &amp; medicine}, volume = {44}, number = {4}, pages = {635-645}, doi = {10.1016/j.freeradbiomed.2007.10.053}, pmid = {18036352}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Catalase/pharmacology ; Cells, Cultured ; *Electron Transport ; *Hot Temperature ; Humans ; Matrix Metalloproteinase 1/*genetics ; Matrix Metalloproteinase 9/*genetics ; Mitochondria/*metabolism ; Mitogen-Activated Protein Kinases/physiology ; NADPH Oxidases/*physiology ; RNA, Messenger/analysis ; Reactive Oxygen Species/*metabolism ; Superoxides/metabolism ; Xanthine Oxidase/*physiology ; }, abstract = {In addition to ultraviolet radiation, human skin is also exposed to infrared radiation (IR) from natural sunlight. IR typically increases the skin temperature. This study examined whether or not heat shock-induced ROS stimulates MMPs in keratinocyte HaCaT cells. In HaCaT cells, heat shock was found to increase the intracellular ROS levels, including hydrogen peroxide and superoxide. The heat shock treatment induced MMP-1 and MMP-9, but not MMP-2, at the mRNA and protein levels. Moreover, heat shock caused the rapid activation of the three distinct MAPKs, ERK, JNK, and p38 kinase. The heat shock-induced expression of MMP-1 and MMP-9 was significantly suppressed by a pretreatment with the antioxidant NAC or catalase. On the other hand, SOD inhibited heat shock-induced activity of MMP-9 induction, but not MMP-1. A pretreatment with NAC or catalase, but not SOD, attenuated the phosphorylation of ERK, JNK, and p38 kinase by heat shock. The potential sites of ROS generation by heat shock along with its role in the heat shock-induced expression of MMP-1 and MMP-9 were next analyzed. These results indicate that heat shock-induced ROS is promoted via NADPH oxidase, xanthine oxidase, and mitochondria. Indeed, the NADPH oxidase and xanthine oxidase activities were increased by heat shock. Overall, the ROS produced by heat shock may play an important role in the heat shock-induced activation of MAPKs, which can induce MMP-1 and-9 expressions.}, }
@article {pmid18035855, year = {2008}, author = {Van Berkel, GJ and Kertesz, V and Koeplinger, KA and Vavrek, M and Kong, AN}, title = {Liquid microjunction surface sampling probe electrospray mass spectrometry for detection of drugs and metabolites in thin tissue sections.}, journal = {Journal of mass spectrometry : JMS}, volume = {43}, number = {4}, pages = {500-508}, doi = {10.1002/jms.1340}, pmid = {18035855}, issn = {1076-5174}, support = {P30 ES005022/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Anticarcinogenic Agents/*analysis/pharmacokinetics ; Antipsychotic Agents/*analysis/pharmacokinetics ; Frozen Sections ; Isothiocyanates ; Liver/cytology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Microtomy ; Rats ; Rats, Sprague-Dawley ; Reserpine/*analysis/pharmacokinetics ; Spectrometry, Mass, Electrospray Ionization/instrumentation/*methods ; Sulfoxides ; Thiocyanates/*analysis/pharmacokinetics ; }, abstract = {A self-aspirating, liquid microjunction surface sampling probe/electrospray emitter mass spectrometry system was demonstrated for use in the direct analysis of spotted and dosed drugs and their metabolites in thin tissue sections. Proof-of-principle sampling and analysis directly from tissue without the need for sample preparation was demonstrated first by raster scanning a region on a section of rat liver onto which reserpine was spotted. The mass spectral signal from selected reaction monitoring was used to develop a chemical image of the spotted drug on the tissue. The probe was also used to selectively spot sample areas of sagittal whole-body tissue from a mouse that had been dosed orally (90 mg/kg) with R,S-sulforaphane 3 h prior to sacrifice. Sulforaphane and its glutathione and N-acetyl cysteine conjugates were monitored with selected reaction monitoring and detected in the stomach and various other tissues from the dosed mouse. No signal for these species was observed in the tissue from a control mouse. The same dosed-tissue section was used to illustrate the possibility of obtaining a lane scan across the whole-body section. In total, these results illustrate the potential for rapid screening of the distribution of drugs and metabolites in thin tissue sections with the liquid micro-junction surface sampling probe/electrospray mass spectrometry approach. Published in 2007 by John Wiley &amp; Sons, Ltd.}, }
@article {pmid18032928, year = {2007}, author = {Cai, Y and Lu, J and Miao, Z and Lin, L and Ding, J}, title = {Reactive oxygen species contribute to cell killing and P-glycoprotein downregulation by salvicine in multidrug resistant K562/A02 cells.}, journal = {Cancer biology &amp; therapy}, volume = {6}, number = {11}, pages = {1794-1799}, doi = {10.4161/cbt.6.11.4860}, pmid = {18032928}, issn = {1555-8576}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*antagonists &amp; inhibitors ; Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Ascorbic Acid/pharmacology ; DNA Breaks, Double-Stranded ; Drug Resistance, Multiple ; Etoposide/pharmacology ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; K562 Cells ; Naphthoquinones/*pharmacology ; *Reactive Oxygen Species/metabolism ; }, abstract = {Salvicine, a novel diterpenoid quinone compound, displays potent antitumor activities in vitro and in vivo, which is under Phase II clinical trials for cancer therapy. Our previous studies have shown that salvicine effectively kills multidrug-resistant (MDR) cells and downregulates mdr-1 and P-glycoprotein (P-gp) levels by activation of transcription factor c-Jun in MDR K562/A02 cells. Recent studies have further demonstrated that salvicine-formed reactive oxygen species (ROS) contribute to its induction of cytotoxicity, DNA double strand breaks and apoptosis. In this study, we showed that salvicine induced equal ROS generation and glutathione depletion in both sensitive K562 and MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine (NAC, precursor of intracellular glutathione) almost abolished the cytotoxicity of salvicine, which also could be attenuated by the H(2)O(2)-specific scavenger catalase. Moreover, NAC abrogated salvicine-induced DNA double strand breaks and apoptosis. Notably, both H(2)O(2) and vitamin C potentiated the cytotoxicity and apoptotic induction of salvicine in parental K562 and MDR K562/A02 cells, and catalase could remove such potentiation. Furthermore, pretreatment of K562/A02 cells with NAC eliminated P-gp downregulation, JNK phosphorylation and c-Jun activation induced by salvicine. Our data collectively indicate that salvicine-generated ROS contribute to both cell killing and P-gp downregulation in MDR K562/A02 cells, thus extending our prior related studies. This study also opens the possibility of the combination therapy of salvicine and vitamin C in the future.}, }
@article {pmid18031542, year = {2008}, author = {Shi, B and Grahn, JC and Reilly, DA and Dizon, TC and Isseroff, RR}, title = {Responses of the 27-kDa heat shock protein to UVB irradiation in human epidermal melanocytes.}, journal = {Experimental dermatology}, volume = {17}, number = {2}, pages = {108-114}, doi = {10.1111/j.1600-0625.2007.00641.x}, pmid = {18031542}, issn = {1600-0625}, mesh = {Cells, Cultured ; Epidermal Cells ; Epidermis/metabolism/radiation effects ; Gene Expression Regulation/radiation effects ; HSP27 Heat-Shock Proteins ; Heat-Shock Proteins/genetics/*metabolism ; Humans ; Melanocytes/cytology/*metabolism/*radiation effects ; Molecular Chaperones ; Neoplasm Proteins/genetics/*metabolism ; Phosphorylation/radiation effects ; Protein Isoforms/genetics/metabolism ; Protein Transport/radiation effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; *Ultraviolet Rays ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Solar ultraviolet radiation (UVR) is a major environmental hazard for the skin, and UVB (280-320 nm) has been proposed to be a main factor for melanoma development. In response to sunlight exposure, the skin has adapted a number of innate resistance mechanisms. Among them is the small heat shock protein of 27 kDa (HSP27) known to play a role in the protection of cells from variety of environmental insults including UV irradiation. In this study, we demonstrated that UVB irradiation of cultured normal epidermal melanocytes initiates changes in HSP27 phosphorylation and localization. In unstressed melanocytes, HSP27 was present as the non-phosphorylated isoform. UVB irradiation with a physiological dose (7-25 mJ/cm(2)) resulted in the formation of a mono-phosphorylated isoform and sometimes a bi-phosphorylated isoform. The UVB-induced HSP27 phosphorylation was inhibited when melanocytes were treated with the antioxidant N-acetyl cysteine or inhibitor of p38 MAP kinase prior to UVB exposure, suggesting that UVB induced HSP27 phosphorylation through reactive oxygen species/p38 MAP kinase pathway. In response to UBV irradiation, HSP27 in melanocytes translocated from the cytoplasm to the nucleus. The HSP27 responses may provide some protective role against UVB-induced cell damage in the skin.}, }
@article {pmid18028880, year = {2008}, author = {Mansour, HH and Hafez, HF and Fahmy, NM and Hanafi, N}, title = {Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats.}, journal = {Biochemical pharmacology}, volume = {75}, number = {3}, pages = {773-780}, doi = {10.1016/j.bcp.2007.09.018}, pmid = {18028880}, issn = {0006-2952}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/radiation effects ; *DNA Damage ; Gamma Rays ; Lipid Peroxidation/radiation effects ; Liver/*radiation effects ; Male ; Radiation-Protective Agents/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {The present study was designed to evaluate the radioprotective effect of N- acetylcysteine (NAC) on gamma-radiation induced toxicity in hepatic tissue in rat. The cellular changes were estimated using malondialdehyde (MDA, an index of lipid peroxidation), superoxide dismutase (SOD), glutathione peroxidase (GSHPx), reduced glutathione (GSH), and total nitrate/nitrite (NO(x)) as markers of hepatic oxidative stress in rats following gamma-irradiation. The DNA damage was determined by agarose gel electrophoresis. To achieve the ultimate goal of this study, 40 adult rats were randomly divided into 4 groups of 10 animals each. Group I was injected intraperitoneally with saline solution for 7 consecutive days and served as control group. Group II was irradiated with a single dose of 6Gy gamma-radiation. Group III was daily injected with NAC (1g/kg, i.p.) for 7 consecutive days. Group IV received a daily i.p. injection of NAC (1g/kg, i.p.) for 7 consecutive days and 1h after the last dose, rats were irradiated with a single dose (6Gy) gamma-radiation. The animals were sacrificed after 24h. DNA damage was observed in tissue after total body irradiation with a single dose of 6Gy. Malondialdehyde and total nitrate/nitrite were increased significantly whereas the levels of GSH and antioxidant enzymes were significantly decreased in gamma-irradiated group. Pretreatment with NAC showed a significant decrease in the levels of MDA, NO(x) and DNA damage. The antioxidant enzymes increased significantly along with the levels of GSH. Moreover, histopathological examination of liver tissues confirmed the biochemical data. Thus, our results show that pretreatment with N-acetylcysteine offers protection against gamma-radiation induced cellular damage.}, }
@article {pmid18028373, year = {2008}, author = {Song, JD and Lee, SK and Kim, KM and Kim, JW and Kim, JM and Yoo, YH and Park, YC}, title = {Redox factor-1 mediates NF-kappaB nuclear translocation for LPS-induced iNOS expression in murine macrophage cell line RAW 264.7.}, journal = {Immunology}, volume = {124}, number = {1}, pages = {58-67}, pmid = {18028373}, issn = {1365-2567}, mesh = {Animals ; Cell Line ; Cell Nucleus/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics/*physiology ; Lipopolysaccharides/immunology ; Macrophage Activation/physiology ; Macrophages/*metabolism ; Mice ; NADPH Oxidases/metabolism ; NF-kappa B/*metabolism ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase Type II/*biosynthesis ; RNA, Small Interfering/genetics ; Signal Transduction/physiology ; Translocation, Genetic ; Up-Regulation ; }, abstract = {Redox-sensitive transcriptional regulator redox factor-1 (Ref-1) is induced by oxidative stress and protects cells against it. However, the function of Ref-1 in regulating nitric oxide (NO) synthesis in macrophages has not been defined. We investigated the role of Ref-1 related to the regulation of NO synthesis in lipopolysaccharide (LPS)-stimulated macrophage RAW 264.7 cells. LPS stimulates the up-regulation and nuclear translocation of Ref-1 in macrophages. Importantly, Ref-1-deficient macrophages using a small interfering RNA did not stimulate inducible NO synthase (iNOS) expression as well as nuclear factor-kappaB nuclear translocation by stimulation with LPS. When the cells were pretreated with diphenyleneiodonium or p47(phox) small interfering RNA for inhibition of NADPH oxidase activity, LPS did not stimulate the nuclear translocation of Ref-1. We next asked whether reactive oxygen species are sufficient for the nuclear translocation of Ref-1 in macrophages. The direct use of H2O2 stimulated the translocation to the nucleus of nuclear factor-kappaB, but not Ref-1 and antioxidant N-acetyl cysteine did not inhibit the LPS-stimulated nuclear translocation of Ref-1. These data suggest that Ref-1 nuclear translocation in LPS-stimulated macrophages requires the activation of other signalling molecules aside from reactive oxygen species followed by the activation of NADPH oxidase.}, }
@article {pmid18027092, year = {2008}, author = {Fu, J and Liang, X and Chen, Y and Tang, L and Zhang, QH and Dong, Q}, title = {Oxidative stress as a component of chromium-induced cytotoxicity in rat calvarial osteoblasts.}, journal = {Cell biology and toxicology}, volume = {24}, number = {3}, pages = {201-212}, doi = {10.1007/s10565-007-9029-7}, pmid = {18027092}, issn = {0742-2091}, mesh = {Acetylcysteine/pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Chromium/*toxicity ; Male ; Microscopy, Electron, Transmission ; Osteoblasts/cytology/*drug effects/enzymology/metabolism ; *Oxidative Stress ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {It has been documented that medical prosthetic alloys release metal ions into surrounding tissues and cause cytotoxicity, but the mechanisms remain undefined. In that regard the cellular oxidative stress may be a common pathway in cellular responses to metal ions. The objective of this study was to approach the hypothesis that oxidative stress mediates chromium-induced cytotoxicity in rat calvarial osteoblasts. Osteoblasts were exposed to different concentrations of Cr6+ or Cr3+ (5-20 microM) in the presence or absence of the antioxidant N-acetyl-cysteine (NAC; 1-5 mM). Cellular viability, differentiation, and intracellular ultrastructural alterations were evaluated by MTT assay, alkaline phosphatase (ALP) activity assay, and transmission electron microscopy. Cellular oxidative stress was evaluated by intracellular reactive oxygen species (ROS) production. ROS production was monitored by the oxidation-sensitive fluorescent probe 2'7'-dichlorofluorescin diacetate (DCFH-DA). A time- and concentration- dependent increased cytotoxicity, time-dependent increased intracellular ROS production were indicated on exposure to Cr6+. Pretreatment of osteoblasts with 1-5 mM NAC afforded dose-dependent cytoprotective effects against Cr6+-induced cytotoxicity in osteoblasts. NAC decreased the level of intracellular ROS induced by Cr6+, too. While Cr3+ and NAC did not have any significant effects on osteoblasts (5-20 microM). These results suggest that oxidative stress is involved in Cr6+-induced cytotoxicity in osteoblasts, and NAC can provide protection for osteoblasts against Cr6+-induced oxidative stress. Cr3+ (5-20 microM) have no significant cytotoxicity in osteoblasts based on the results of this study.}, }
@article {pmid18026714, year = {2008}, author = {Xiao, C and Giacca, A and Lewis, GF}, title = {Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men.}, journal = {Diabetologia}, volume = {51}, number = {1}, pages = {139-146}, pmid = {18026714}, issn = {0012-186X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Diabetes Mellitus/metabolism ; Fatty Acids, Nonesterified/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Insulin/*metabolism ; Insulin-Secreting Cells/*metabolism ; Lipids/chemistry ; Male ; Middle Aged ; Obesity/*metabolism ; *Overweight ; Taurine/*administration &amp; dosage ; }, abstract = {AIMS/HYPOTHESIS: Antioxidants have been shown to ameliorate lipid-induced impairment of insulin action and beta cell function, both in vitro and in animal studies. The aim of the present study was to examine the effects of two orally administered antioxidants, N-acetylcysteine (NAC) and taurine (TAU), on lipotoxicity in humans.<br><br>METHODS: Nine non-diabetic men, who were either overweight or obese, underwent three studies each, 4-6 weeks apart, in random order: (1) i.v. infusion of saline for 48 h (SAL); (2) i.v. infusion of Intralipid and heparin for 48 h to mimic chronic elevation of plasma NEFA (IH); and (3) IH infusion for 48 h with concurrent oral NAC (IH+NAC). Six men underwent similar studies except for study 3, where instead of NAC they received a 2 week pretreatment with oral TAU (IH+TAU).<br><br>RESULTS: For both the NAC and TAU studies, a 48 h IH infusion alone without antioxidant impaired insulin sensitivity (S(I), 63% and 62% of SAL in NAC and TAU studies, respectively) and beta cell function, as evidenced by a reduction in disposition index (DI, 55% and 54% of SAL in NAC and TAU studies, respectively). NAC failed to prevent the lipid-induced increase in levels of the plasma oxidative stress marker malondialdehyde and did not prevent the lipid-induced reduction in S(I) or DI, whereas TAU completely prevented the rise in malondialdehyde and decreased 4-hydroxynonenal, and significantly improved S(I) (91% of SAL) and DI (81% of SAL).<br><br>CONCLUSIONS/INTERPRETATION: Oral TAU ameliorates lipid-induced functional beta cell decompensation and insulin resistance in humans, possibly by reducing oxidative stress.}, }
@article {pmid18025839, year = {2008}, author = {Sarchahi, AA and Maimandi, A and Tafti, AK and Amani, M}, title = {Effects of acetylcysteine and dexamethasone on experimental corneal wounds in rabbits.}, journal = {Ophthalmic research}, volume = {40}, number = {1}, pages = {41-48}, doi = {10.1159/000111158}, pmid = {18025839}, issn = {1423-0259}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Cornea/pathology/physiopathology ; *Corneal Injuries ; Dexamethasone/administration &amp; dosage/*therapeutic use ; Drug Administration Schedule ; Drug Therapy, Combination ; Glucocorticoids/administration &amp; dosage/*therapeutic use ; Ophthalmic Solutions ; Rabbits ; Time Factors ; Wound Healing/*drug effects ; Wounds, Penetrating/*drug therapy/pathology/physiopathology ; }, abstract = {Corneal wound healing often leads to the development of scar tissue with loss of transparency. Reconstitution of transparent corneal stroma depends on the regulation of the biosynthetic activities of post-lesional keratocytes as well as to a large extent on the limitation of matrix degradation. It has been shown that 3% concentration of N-acetylcysteine (NAC) improves the healing time of corneal wounds but some corneal haze remains. On the other hand, topical corticosteroids may retard the corneal wound healing but decrease the haze. Thus, the aim of the study was to evaluate whether adding dexamethasone to NAC could reduce the side effects of the two drugs. In this study, experimental corneal wounds were created surgically, up to the depth of one half of the stroma in the center of both eyes of all rabbits. The left eyes were treated topically with 0.9% NaCl as controls and the right eyes were treated with a combination of one drop of 3% NAC and one drop of 0.1% dexamethasone, 6 times per day. Corneal wounds were measured by fluorescein staining every day. The results indicated that the combination of acetylcysteine and dexamethasone significantly increased the mean healing time compared to the control group (p < 0.05). Clinical and histopathologic examinations revealed that the corneal haze in the treatment group was greater than in the control group. It is concluded that treatment of the eyes by a combination of 3% acetylcysteine and 0.1% dexamethasone (if used from the first day of ulceration) may retard the corneal wound healing in rabbits.}, }
@article {pmid18023956, year = {2008}, author = {Szadkowski, A and Myers, CR}, title = {Acrolein oxidizes the cytosolic and mitochondrial thioredoxins in human endothelial cells.}, journal = {Toxicology}, volume = {243}, number = {1-2}, pages = {164-176}, pmid = {18023956}, issn = {0300-483X}, support = {R01 ES012707/ES/NIEHS NIH HHS/United States ; R01 ES012707-03/ES/NIEHS NIH HHS/United States ; R56 ES012707/ES/NIEHS NIH HHS/United States ; ES012707/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Acrolein/*toxicity ; Cell Line ; Cytosol/*drug effects/metabolism/pathology ; Endothelial Cells/*drug effects/metabolism/pathology ; Endothelium, Vascular/*drug effects/metabolism/pathology ; Environmental Pollutants/*toxicity ; Humans ; Mitochondria/*drug effects/metabolism/pathology ; Oxidation-Reduction ; Thioredoxins/*metabolism ; }, abstract = {Acrolein is a reactive aldehyde that is a widespread environmental pollutant and can be generated endogenously from lipid peroxidation. The thioredoxin (Trx) system in endothelial cells plays a major role in the maintenance of cellular thiol redox balance, and is critical for cell survival. Normally, cells maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. In human microvascular endothelial cells, Trx1 was more sensitive than Trx2 to oxidation by acrolein. A 30-min exposure to 2.5 microM acrolein caused partial oxidation of Trx1 but not Trx2. The active site dithiol of Trx1 was essentially completely oxidized by 5 microM acrolein whereas 12.5 microM was required for complete oxidation of Trx2. Partial recovery of the Trx1 redox status was observed over a 4h acrolein-free recovery period, with increases in the reduced form and decreases in the fully oxidized form. For cells treated with 2.5 or 5 microM acrolein the recovery did not require protein synthesis, whereas protein synthesis was required for the return of reduced Trx1 in cells treated with 12.5 microM acrolein. Pretreatment of cells with N-acetylcysteine (NAC) resulted in partial protection of Trx1 from oxidation by acrolein. In cells treated with acrolein for 30 min, followed by a 14- to 16-h acrolein-free period, small but significant cytotoxic effects were observed with 2.5 microM acrolein whereas all cells were adversely affected by >or= 12.5 microM. NAC pretreatment significantly decreased the percentage of stressed cells subsequently exposed to 5 or 12.5 microM acrolein. Given the critical role of the thioredoxins in cell survival, the ability of acrolein to oxidize both thioredoxins should be taken into account for a thorough understanding of its cytotoxic effects.}, }
@article {pmid18022818, year = {2008}, author = {Pang, PH and Lin, YH and Lee, YH and Hou, HH and Hsu, SP and Juan, SH}, title = {Molecular mechanisms of p21 and p27 induction by 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, involved in antiproliferation of human umbilical vascular endothelial cells.}, journal = {Journal of cellular physiology}, volume = {215}, number = {1}, pages = {161-171}, doi = {10.1002/jcp.21299}, pmid = {18022818}, issn = {1097-4652}, mesh = {Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21/genetics/*metabolism ; Cyclin-Dependent Kinase Inhibitor p27/genetics/*metabolism ; Dose-Response Relationship, Drug ; Endothelial Cells/*cytology/*drug effects ; Enzyme Activation/drug effects ; Gene Expression Regulation/drug effects ; Humans ; Luciferases/metabolism ; Methylcholanthrene/*pharmacology ; Phosphorylation/drug effects ; Protein Binding/drug effects ; Receptors, Aryl Hydrocarbon/*agonists ; Response Elements ; Resveratrol ; Sequence Deletion ; Stilbenes/pharmacology ; Time Factors ; Tritium/metabolism ; Umbilical Cord/*cytology/drug effects ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors ; }, abstract = {We previously reported that 3-methylcholanthrene (3MC), an aryl-hydrocarbon receptor (AhR) agonist, inhibits the proliferation of human umbilical vascular endothelial cells (HUVECs; Juan et al., 2006, Eur J Pharmacol 530: 1-8). Herein, pretreatment of HUVECs with p21 or p27 small interfering (si)RNA reduced 3MC-induced elimination of [(3)H]thymidine incorporation, demonstrating their essential roles in the antiproliferation of HUVECs. The molecular mechanisms of p21 and p27 involved in the antiproliferative effects of 3MC were elucidated in this study. 3MC time- and concentration-dependently increased p21 and p27 levels, and decreased the protein level of CDK2 with no apparent alteration of p53. Interestingly, 3MC-mediated p21 and p27 inductions were eliminated by resveratrol, an AhR antagonist, suggesting their AhR dependency, further confirmed by AhR siRNA. Among the relevant pathways, p38MAPK activation sustained the levels of p21 and p27 induced by 3MC, which was eliminated by AhR antagonists and N-acetylcysteine (NAC), an antioxidant. 3MC concentration-dependently enhanced not only the consensus dioxin-responsive element (DRE)-driven luciferase activity, but also the binding activity of the AhR to the putative DRE derived from the p21 and p27 promoters. A deletion of the DRE (-285/-270) in p21 (-2,300/+8) only partially alleviated the 3MC-induced luciferase activity unless NAC was added, suggesting that there may be a DRE-independent mechanism associated with oxidative stress. However, a deletion of the DRE (-660/-645) in p27 (-1,358/-100) almost completely abrogated the activation. Our study demonstrated that both the functional DRE and the phosphorylation of p38MAPK are essential for the induction of p21 and p27, resulting in the antiproliferative action of 3MC in HUVECs.}, }
@article {pmid18022000, year = {2007}, author = {Barańska-Kosakowska, A and Zakliczyński, M and Przybylski, R and Zembala, M}, title = {Role of N-acetylcysteine on renal function in patients after orthotopic heart transplantation undergoing coronary angiography.}, journal = {Transplantation proceedings}, volume = {39}, number = {9}, pages = {2853-2855}, doi = {10.1016/j.transproceed.2007.08.057}, pmid = {18022000}, issn = {0041-1345}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; *Cardiac Catheterization ; Contrast Media/*adverse effects ; *Coronary Angiography ; Coronary Disease/diagnostic imaging/prevention &amp; control ; Creatinine/blood ; Female ; Heart Transplantation/*physiology ; Humans ; Kidney/drug effects/physiopathology ; Male ; Middle Aged ; Postoperative Complications/prevention &amp; control ; Prospective Studies ; }, abstract = {INTRODUCTION: The aim of this study was to assess nephroprotective influence of intravenous N-acetylcysteine (NAC) on renal function after radiocontrast use in calcineurin inhibitor-treated patients after orthotopic heart transplantation (OHT).<br><br>MATERIALS AND METHODS: We analyzed the results of 112 consecutive coronary angiography examinations (CAG). All patients received intravenous 500 mL multielectrolyte fluid (PWE) before catheterization. Group I of 55 randomly selected cases in addition were treated with 300 mg of NAC. The other 57 cases (group II) received only hydration. After catheterization, we administered 500 mL 0.9% saline with 20 mg furosemide. A nonionic, low-osmolality contrast agent (OPTIRAY) was used for all catheterizations. All patients underwent measurements of serum creatinine and creatinine clearance levels before and after the procedure (CREA0, CREA1, CC0, and CC1, respectively). We assessed the influence of NAC on CREA1 and the relative change of CREA1/CREA0 and CC1/CC0 ratios.<br><br>RESULTS: In groups I and II we noticed decreased CC0 in 17 versus 22 cases (31% vs 39%), a relative change of CREA1/CREA0 ratio of 0% versus -3.95% and of CC1/CC0 ratio 0% versus 4, 11%, respectively. CIN was not recognized in any patient. None of the differences was significant.<br><br>CONCLUSION: Intravenous NAC (300 mg) along with hydration before radiocontrast use had no impact on renal function in OHT patients undergoing CAG. It seems that there is no need for an additional preventive strategy apart from hydration and a small volume of low osmolar contrast in the majority of patients.}, }
@article {pmid18006866, year = {2008}, author = {Ferreira, LF and Reid, MB}, title = {Muscle-derived ROS and thiol regulation in muscle fatigue.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {104}, number = {3}, pages = {853-860}, doi = {10.1152/japplphysiol.00953.2007}, pmid = {18006866}, issn = {8750-7587}, mesh = {Animals ; Antioxidants/metabolism/pharmacology ; *Exercise ; Glutathione/metabolism ; Humans ; *Muscle Contraction/drug effects ; *Muscle Fatigue/drug effects ; Muscle, Skeletal/drug effects/*metabolism ; Oxidation-Reduction ; Oxidative Stress ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/*metabolism ; Research Design ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Muscles produce oxidants, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), from a variety of intracellular sources. Oxidants are detectable in muscle at low levels during rest and at higher levels during contractions. RNS depress force production but do not appear to cause fatigue of healthy muscle. In contrast, muscle-derived ROS contribute to fatigue because loss of function can be delayed by ROS-specific antioxidants. Thiol regulation appears to be important in this biology. Fatigue causes oxidation of glutathione, a thiol antioxidant in muscle fibers, and is reversed by thiol-specific reducing agents. N-acetylcysteine (NAC), a drug that supports glutathione synthesis, has been shown to lessen oxidation of cellular constituents and delay muscle fatigue. In humans, NAC pretreatment improves performance of limb and respiratory muscles during fatigue protocols and extends time to task failure during volitional exercise. These findings highlight the importance of ROS and thiol chemistry in fatigue, show the feasibility of thiol-based countermeasures, and identify new directions for mechanistic and translational research.}, }
@article {pmid18004285, year = {2008}, author = {Lavoie, S and Murray, MM and Deppen, P and Knyazeva, MG and Berk, M and Boulat, O and Bovet, P and Bush, AI and Conus, P and Copolov, D and Fornari, E and Meuli, R and Solida, A and Vianin, P and Cuénod, M and Buclin, T and Do, KQ}, title = {Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {33}, number = {9}, pages = {2187-2199}, doi = {10.1038/sj.npp.1301624}, pmid = {18004285}, issn = {0893-133X}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Acoustic Stimulation/methods ; Adult ; Brain Mapping ; Cerebral Cortex/drug effects/physiopathology ; Contingent Negative Variation/*drug effects ; Cross-Over Studies ; Discrimination, Psychological/drug effects ; Double-Blind Method ; Electroencephalography ; Evoked Potentials, Auditory/*drug effects ; Female ; Free Radical Scavengers/*pharmacology/therapeutic use ; Glutathione/blood ; Humans ; Male ; Middle Aged ; Neuropsychological Tests ; Reaction Time/drug effects ; Retrospective Studies ; Schizophrenia/blood/drug therapy/pathology/*physiopathology ; Time Factors ; }, abstract = {In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.}, }
@article {pmid18003766, year = {2008}, author = {Fishbane, S}, title = {N-acetylcysteine in the prevention of contrast-induced nephropathy.}, journal = {Clinical journal of the American Society of Nephrology : CJASN}, volume = {3}, number = {1}, pages = {281-287}, doi = {10.2215/CJN.02590607}, pmid = {18003766}, issn = {1555-905X}, mesh = {Acetylcysteine/chemistry/*therapeutic use ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Contrast Media/*adverse effects ; Free Radical Scavengers/chemistry/*therapeutic use ; Humans ; }, abstract = {BACKGROUND AND OBJECTIVES: Contrast-induced nephropathy (CIN) is a common clinical problem that is growing in importance as an increasing number of tests and procedures that utilize contrast media are performed.<br><br>The biological and pharmacological properties of n-acetylcysteine (NAC) are reviewed, as well as the current literature relevant to the ability of NAC to prevent CIN.<br><br>RESULTS: After publication of a seminal study by Tepel et al. in 2000, there has been a surge in interest regarding the ability of NAC to reduce the risk for CIN. Since then a large number of studies, mostly with relatively small sample sizes, have been published.<br><br>CONCLUSIONS: The results have been remarkably varied with some studies finding great efficacy with NAC but most finding no significant benefit.}, }
@article {pmid18001477, year = {2007}, author = {Gonzales, DA and Norsworthy, KJ and Kern, SJ and Banks, S and Sieving, PC and Star, RA and Natanson, C and Danner, RL}, title = {A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity.}, journal = {BMC medicine}, volume = {5}, number = {}, pages = {32}, pmid = {18001477}, issn = {1741-7015}, support = {//Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aged ; Cluster Analysis ; Contrast Media/*adverse effects ; Creatinine/metabolism ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Models, Biological ; Publication Bias ; Randomized Controlled Trials as Topic ; Regression Analysis ; Renal Dialysis ; Risk Factors ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: Meta-analyses of N-acetylcysteine (NAC) for preventing contrast-induced nephrotoxicity (CIN) have led to disparate conclusions. Here we examine and attempt to resolve the heterogeneity evident among these trials.<br><br>METHODS: Two reviewers independently extracted and graded the data. Limiting studies to randomized, controlled trials with adequate outcome data yielded 22 reports with 2746 patients.<br><br>RESULTS: Significant heterogeneity was detected among these trials (I2 = 37%; p = 0.04). Meta-regression analysis failed to identify significant sources of heterogeneity. A modified L'Abb&#xe9; plot that substituted groupwise changes in serum creatinine for nephrotoxicity rates, followed by model-based, unsupervised clustering resolved trials into two distinct, significantly different (p < 0.0001) and homogeneous populations (I2 = 0 and p > 0.5, for both). Cluster 1 studies (n = 18; 2445 patients) showed no benefit (relative risk (RR) = 0.87; 95% confidence interval (CI) 0.68-1.12, p = 0.28), while cluster 2 studies (n = 4; 301 patients) indicated that NAC was highly beneficial (RR = 0.15; 95% CI 0.07-0.33, p < 0.0001). Benefit in cluster 2 was unexpectedly associated with NAC-induced decreases in creatinine from baseline (p = 0.07). Cluster 2 studies were relatively early, small and of lower quality compared with cluster 1 studies (p = 0.01 for the three factors combined). Dialysis use across all studies (five control, eight treatment; p = 0.42) did not suggest that NAC is beneficial.<br><br>CONCLUSION: This meta-analysis does not support the efficacy of NAC to prevent CIN.}, }
@article {pmid18000850, year = {2007}, author = {Piner, P and Sevgiler, Y and Uner, N}, title = {In vivo effects of fenthion on oxidative processes by the modulation of glutathione metabolism in the brain of Oreochromis niloticus.}, journal = {Environmental toxicology}, volume = {22}, number = {6}, pages = {605-612}, doi = {10.1002/tox.20286}, pmid = {18000850}, issn = {1520-4081}, mesh = {Animals ; Brain/*drug effects/enzymology/metabolism ; Cichlids ; Fenthion/*toxicity ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Lipid Peroxidation ; Oxidation-Reduction ; Pesticides/*toxicity ; Proteins/metabolism ; }, abstract = {The present study was designed to understand the oxidative stress potential of fenthion, an organophosphate (OP) pesticide and its involvement in glutathione metabolism modulated buthionine sulfoximine (BSO, 50 mg/kg) and N-acetylcysteine (NAC, 100 mg/kg) in the brain of fish, Oreochromis niloticus. A sublethal fenthion concentration (0.45 mg/L) was applied for 24, 48, and 96 h together with injection with BSO or NAC; following treatment, recovery periods for 24, 48, and 96 h were allowed. Total glutathione (tGSH), oxidized glutathione (GSSG), lipid peroxidation, protein level, and GSH-related enzyme activities were analyzed by using spectrophotometric methods. Fenthion in applied concentration did not change GSH levels, but increased GSSG levels. BSO application in fenthion exposure caused a depletion in GSH, while increasing the GSSG levels. Glutathione peroxidase (GPx; EC 1.11.1.9) specific activity increased in fenthion-applied groups at 24-h treatment. gamma-Glutamylcysteinyl synthetase (gamma-GCS; EC 6.3.2.2) was not detected in the brain. NAC injection in fenthion treatment decreased GSH and increased GSSG levels and GST activity. In conclusion, fenthion in sublethal concentration induced an oxidative stress processes in brain. BSO application provided an evidence for the involvement of fenthion in GSH metabolism. NAC elevated the fenthion-induced effects in spite of its antioxidant properties. Recovery period for 96 h was not adequate to eliminate the fenthion-induced changes.}, }
@article {pmid17999779, year = {2007}, author = {Zembron-Lacny, A and Szyszka, K and Szygula, Z}, title = {Effect of cysteine derivatives administration in healthy men exposed to intense resistance exercise by evaluation of pro-antioxidant ratio.}, journal = {The journal of physiological sciences : JPS}, volume = {57}, number = {6}, pages = {343-348}, doi = {10.2170/physiolsci.RP009307}, pmid = {17999779}, issn = {1880-6546}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Adult ; Antioxidants/administration &amp; dosage/*metabolism/*pharmacology ; Catalase/blood/metabolism ; Exercise/*physiology ; Glutathione Peroxidase/metabolism ; Health ; Humans ; Male ; Oxidative Stress/drug effects ; Superoxide Dismutase/metabolism ; Taurine/administration &amp; dosage/*pharmacology ; Thiobarbituric Acid Reactive Substances/metabolism ; Thioctic Acid/administration &amp; dosage/*pharmacology ; Time Factors ; }, abstract = {The aim of this study was to ascertain the influence of cysteine derivatives on pro-antioxidant equilibrium and to compare the antioxidant effectiveness of N-acetylcysteine, alpha-lipoic acid, and taurine by using Loverro's coefficient (pro-antioxidant ratio) in healthy men exposed to intensity-resistance exercise. Fifty-five men were randomly assigned to one of four groups: control (CON, placebo), N-acetylcysteine (NAC 1.8 g.day(-1), 3 days), alpha-lipoic acid (LIP 1.2 g.day(-1), 3 days), or taurine (TAU 3 g.day(-1), 3 days). The erythrocyte superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities, lipid peroxidation products (TBARS), and plasma protein thiol concentrations were evaluated. The P/A ratio was determined from the mean values of TBARS, SOD, GPx, and CAT. The applied exercise at maximal intensity induced the significant changes in pro-antioxidant equilibrium toward peroxidation, which was proved by a 25% increase in TBARS concentration in the CON group. The peroxidation was significantly diminished by NAC (-14%) and LIP (-16%), whereas TAU had no effect on the TBARS concentration. Cysteine derivatives administration prevented exercise-induced decline in SOD activity and increased in GPx activity during exercise. CAT activity changed only in the LIP group. The estimation of P/A ratio showed the lowest level of pro-antioxidant equilibrium after LIP administration. In the CON group, P/A ratio was directly correlated with the protein thiols level (r = 0.495, p < 0.001). These data confirm the antioxidant action of tested cysteine derivatives, particularly lipoic acid, and demonstrate the practical application of P/A ratio to evaluate the effectiveness of antioxidants in athletes.}, }
@article {pmid17998295, year = {2008}, author = {Li, Y and Slatter, JG and Zhang, Z and Li, Y and Doss, GA and Braun, MP and Stearns, RA and Dean, DC and Baillie, TA and Tang, W}, title = {In vitro metabolic activation of lumiracoxib in rat and human liver preparations.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {36}, number = {2}, pages = {469-473}, doi = {10.1124/dmd.107.019018}, pmid = {17998295}, issn = {1521-009X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Chromatography, Liquid ; Cyclooxygenase 2 Inhibitors/*metabolism ; Diclofenac/*analogs &amp; derivatives/metabolism ; Hepatocytes/*metabolism ; Humans ; Microsomes, Liver/*metabolism ; Rats ; Tandem Mass Spectrometry ; }, abstract = {Recent clinical reports have suggested that the cyclooxygenase-2 inhibitor, lumiracoxib (Prexige), may cause a rare but serious hepatotoxicity in patients. In view of the close structural resemblance between lumiracoxib and diclofenac, a widely used nonsteroidal anti-inflammatory drug whose use also has been associated with rare cases of liver injury, it is possible that the toxicity of the two agents may share a common mechanism. Because it is believed that chemically reactive metabolites may play a role as mediators of diclofenac-mediated hepatotoxicity, the present in vitro study was carried out to test the hypothesis that lumiracoxib also undergoes metabolic activation when incubated with liver microsomal preparations and hepatocytes from rats and humans. By means of liquid chromatography tandem mass spectrometry and nuclear magnetic resonance spectrometry techniques, two previously unknown N-acetylcysteine (NAC) conjugates were identified, namely, 3'-NAC-4'-hydroxy lumiracoxib (M1) and 4'-hydroxy-6'-NAC-desfluoro lumiracoxib (M2), the structures of which reveal the intermediacy of an electrophilic quinone imine species. Based on the results of studies with immunoinhibitory antibodies, it was demonstrated that the formation of M1 and M2 in human liver microsomes was catalyzed by cytochrome P450 (P450) 2C9. These findings demonstrate that lumiracoxib is subject to P450-mediated bioactivation in both rat and human liver preparations, leading to the formation of a reactive intermediate analogous to species generated during the metabolism of diclofenac.}, }
@article {pmid17992120, year = {2007}, author = {Vartanian, AA and Burova, OS and Stepanova, EV and Baryshnikov, AY and Lichinitser, MR}, title = {Melanoma vasculogenic mimicry is strongly related to reactive oxygen species level.}, journal = {Melanoma research}, volume = {17}, number = {6}, pages = {370-379}, doi = {10.1097/CMR.0b013e3282f1d2ec}, pmid = {17992120}, issn = {0960-8931}, mesh = {Angiogenesis Inhibitors/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis ; Capillaries/metabolism ; Caspase 3/*metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Female ; Humans ; Melanoma/*blood supply/*metabolism/pathology ; Mice ; Mice, Inbred C57BL ; *Neovascularization, Pathologic ; Reactive Oxygen Species/*metabolism ; Resveratrol ; Stilbenes/pharmacology ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {The concept of 'vasculogenic mimicry' (VM) was introduced to describe the unique ability of highly invasive tumor cells to form capillary-like structures (CLS) and matrix-rich patterned network in three-dimensional culture that mimic embryonic vasculogenic network. Recently, we have shown that CLS formation requires apoptotic cell death through activation of caspase-3-dependent mechanism. In this study, to identify some molecular determinants driving aggressive melanoma cells to express a latent 'angiogenic program' that recapitulates the early events of CLS formation, we focused on the involvement of antioxidants (AOs) in the process of melanoma VM. We have studied the effects of resveratrol, (-)-epigallocathechin gallate, N-acetyl-cysteine (NAC) and Trolox on the ability of melanoma cells to form/destroy CLS. We observed that the formation of CLS was strongly related to reactive oxygen species level. In vivo animal experiments confirmed the involvement of reactive oxygen species level in melanoma VM. To understand the molecular mechanisms of this phenomenon, we specifically looked for induction of apoptosis and vascular endothelial growth factor (VEGF) release. Western blot analysis revealed that the level of VEGF, VEGF receptors (VEGF-Rs) and active caspase-3 dramatically decreased in cells treated with AOs. Here, we also report further experiments designed to determine whether the crosstalk between AOs and apoptosis exists in melanoma VM.}, }
@article {pmid17991881, year = {2008}, author = {Farrow, KN and Groh, BS and Schumacker, PT and Lakshminrusimha, S and Czech, L and Gugino, SF and Russell, JA and Steinhorn, RH}, title = {Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells.}, journal = {Circulation research}, volume = {102}, number = {2}, pages = {226-233}, pmid = {17991881}, issn = {1524-4571}, support = {R01 HL079650-03/HL/NHLBI NIH HHS/United States ; K12 HD052902-01/HD/NICHD NIH HHS/United States ; R01 HL054705-11/HL/NHLBI NIH HHS/United States ; R01 HL035440/HL/NHLBI NIH HHS/United States ; R01 HL54705/HL/NHLBI NIH HHS/United States ; K12 HD052902/HD/NICHD NIH HHS/United States ; L40 HD045314/HD/NICHD NIH HHS/United States ; L40 HD045314-03/HD/NICHD NIH HHS/United States ; K08 HL086715/HL/NHLBI NIH HHS/United States ; K08 HL086715-01/HL/NHLBI NIH HHS/United States ; R01 HL035440-21/HL/NHLBI NIH HHS/United States ; R01 HL079650/HL/NHLBI NIH HHS/United States ; R01 HL054705/HL/NHLBI NIH HHS/United States ; R01 HL35440/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; Cells, Cultured ; Cyclic GMP/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5/analysis/*genetics ; *Gene Expression Regulation, Enzymologic ; Hyperoxia/*enzymology ; Hypertension, Pulmonary ; Myocytes, Smooth Muscle/*enzymology/metabolism ; Nitric Oxide/pharmacology ; Pulmonary Artery/cytology/*embryology ; RNA, Messenger/analysis ; Sheep, Domestic ; }, abstract = {In the pulmonary vasculature, cGMP concentrations are regulated in part by a cGMP-dependent phosphodiesterase (PDE), PDE5. Infants with persistent pulmonary hypertension of the newborn (PPHN) are often mechanically ventilated with high oxygen concentrations. The effects of hyperoxia on the developing pulmonary vasculature and PDE5 are largely unknown. Here, we demonstrate that exposure of fetal pulmonary artery smooth muscle cells (FPASMCs) to high levels of oxygen for 24 hours leads to decreased responsiveness to exogenous NO, as determined by a decreased intracellular cGMP response, increased PDE5 mRNA and protein expression, as well as increased PDE5 cGMP hydrolytic activity. We demonstrate that inhibition of PDE5 activity with sildenafil partially rescues cGMP responsiveness to exogenous NO. In FPASMCs, hyperoxia leads to increased oxidative stress without increasing cell death. Treatment of normoxic FPASMCs with H2O2 is sufficient to induce PDE5 expression and activity, suggesting that reactive oxygen species mediate the effects of hyperoxia in FPASMCs. In support of this mechanism, a chemical antioxidant, N-acetyl-cysteine, is sufficient to block the hyperoxia-mediated increase in PDE5 expression and activity and rescue cGMP responsiveness to exogenous NO. Finally, ventilation of healthy neonatal sheep with 100% O2 for 24 hours leads to increased PDE5 protein expression in the resistance pulmonary arteries and increased PDE5 activity in whole lung extracts. These data suggest that PDE5 expression and activity play a critical role in modulating neonatal pulmonary vascular tone in response to common clinical treatments for PPHN, such as oxygen and inhaled NO.}, }
@article {pmid17991199, year = {2007}, author = {Zoccali, C and Mallamaci, F and Tripepi, G}, title = {It is important to lower homocysteine in dialysis patients.}, journal = {Seminars in dialysis}, volume = {20}, number = {6}, pages = {530-533}, doi = {10.1111/j.1525-139X.2007.00345.x}, pmid = {17991199}, issn = {0894-0959}, mesh = {Acetylcysteine/therapeutic use ; Clinical Trials as Topic ; Homocysteine/*blood ; Humans ; Hyperhomocysteinemia/blood/complications/drug therapy/genetics ; Kidney Failure, Chronic/blood/complications/therapy ; *Renal Dialysis ; }, abstract = {Homocysteine has been implicated in atherosclerotic and thrombotic vascular disease in the general and in the end-stage renal disease (ESRD) population as well. Although not strong, the risk associated with raised homocysteine (25% risk excess for a 5 mum increase) is quite consistent across studies in the general population. Likewise, individuals harboring a polymorphism leading to higher homocysteine levels coherently display an increased risk for cardiovascular events in comparison with individuals without such a polymorphism. Randomized controlled trials of homocysteine-lowering therapy performed so far failed to prove causality but the size effect of these interventions is still compatible with the hypothesis that reducing the plasma levels of this aminoacid may be beneficial. In ESRD, high homocysteine is a coherent predictor of death and adverse cardiovascular events in patients without malnutrition and inflammation. In the sole randomized placebo-controlled study performed in this population folic acid produced a small beneficial effect which, because of the lack of power, failed to achieve statistical significance. In another randomized study testing the effect of a well established homocysteine-lowering agent, N-acetyl-cysteine, a 40% reduction in cardiovascular events was observed. There is still insufficient knowledge to draw definitive conclusions on the causal implication of homocysteine in the high risk of ESRD. The contention that the homocysteine pathway cannot be used for interventions aimed at curbing cardiovascular risk in this population is, at least by now, unwarranted.}, }
@article {pmid17988378, year = {2007}, author = {Ramani, S and Chelliah, J}, title = {UV-B-induced signaling events leading to enhanced-production of catharanthine in Catharanthus roseus cell suspension cultures.}, journal = {BMC plant biology}, volume = {7}, number = {}, pages = {61}, pmid = {17988378}, issn = {1471-2229}, mesh = {Antineoplastic Agents/pharmacology ; Aromatic-L-Amino-Acid Decarboxylases/genetics/metabolism ; Calcium/metabolism ; Calcium-Binding Proteins/antagonists &amp; inhibitors/metabolism ; Carbon-Nitrogen Lyases/genetics/metabolism ; Catharanthus/genetics/*metabolism/*radiation effects ; Cells, Cultured ; Culture Media/radiation effects ; Gene Expression/drug effects ; Hydrogen Peroxide/antagonists &amp; inhibitors/metabolism ; Hydrogen-Ion Concentration/drug effects ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Phosphorylation ; Plant Proteins/antagonists &amp; inhibitors/metabolism ; Protein Kinases/metabolism ; Signal Transduction/*radiation effects ; Suramin/pharmacology ; Transcription, Genetic/radiation effects ; *Ultraviolet Rays ; Vinca Alkaloids/*biosynthesis ; }, abstract = {BACKGROUND: Elicitations are considered to be an important strategy towards improved in vitro production of secondary metabolites. In cell cultures, biotic and abiotic elicitors have effectively stimulated the production of plant secondary metabolites. However, molecular basis of elicitor-signaling cascades leading to increased production of secondary metabolites of plant cell is largely unknown. Exposure of Catharanthus roseus cell suspension culture to low dose of UV-B irradiation was found to increase the amount of catharanthine and transcription of genes encoding tryptophan decarboxylase (Tdc) and strictosidine synthase (Str). In the present study, the signaling pathway mediating UV-B-induced catharanthine accumulation in C. roseus suspension cultures were investigated.<br><br>RESULTS: Here, we investigate whether cell surface receptors, medium alkalinization, Ca2+ influx, H2O2, CDPK and MAPK play required roles in UV-B signaling leading to enhanced production of catharanthine in C. roseus cell suspension cultures. C. roseus cells were pretreated with various agonists and inhibitors of known signaling components and their effects on the accumulation of Tdc and Str transcripts as well as amount of catharanthine production were investigated by various molecular biology techniques. It has been found that the catharanthine accumulation and transcription of Tdc and Str were inhibited by 3-4 fold upon pretreatment of various inhibitors like suramin, N-acetyl cysteine, inhibitors of calcium fluxes, staurosporine etc.<br><br>CONCLUSION: Our results demonstrate that cell surface receptor(s), Ca2+ influx, medium alkalinization, CDPK, H2O2 and MAPK play significant roles in UV-B signaling leading to stimulation of Tdc and Str genes and the accumulation of catharanthine in C. roseus cell suspension cultures. Based on these findings, a model for signal transduction cascade has been proposed.}, }
@article {pmid17986488, year = {2007}, author = {Alipour, M and Omri, A and Smith, MG and Suntres, ZE}, title = {Prophylactic effect of liposomal N-acetylcysteine against LPS-induced liver injuries.}, journal = {Journal of endotoxin research}, volume = {13}, number = {5}, pages = {297-304}, doi = {10.1177/0968051907085062}, pmid = {17986488}, issn = {0968-0519}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Body Weight ; Chloramines/analysis ; Disease Models, Animal ; Lipid Peroxidation/drug effects/immunology ; *Lipopolysaccharides/administration &amp; dosage/antagonists &amp; inhibitors ; Liver/*drug effects/enzymology/*injuries ; Lysine/*analogs &amp; derivatives/pharmacology ; Male ; Organ Size ; Peroxidase/analysis ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/immunology ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {The aim of this study was to evaluate and compare the effectiveness of N-acetylcysteine (NAC) and liposomally-encapsulated NAC (L-NAC) in ameliorating the hepatotoxic effects of lipopolysaccharide (LPS). LPS, a major cell wall molecule of Gram-negative bacteria and the principal initiator of septic shock, causes liver injury in vivo that is dependent on neutrophils, platelets, and several inflammatory mediators, including tumour necrosis factor-alpha (TNF-alpha). Male Sprague-Dawley rats were pretreated intravenously with saline, plain liposomes (dipalmitoylphosphatidylcholine [DPPC]), NAC (25 mg/kg body weight), or L-NAC (25 mg/kg NAC body weight) and 4 h later were challenged intravenously with LPS (Escherichia coli O111:B4, 1.0 mg/kg body weight); animals were killed 20 h post-LPS challenge. Hepatic cell injury was evaluated by measuring the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in plasma. LPS-induced activation of the inflammatory response was evaluated by measuring the levels of myeloperoxidase activity and chloramine concentration in liver homogenates as well as TNF-alpha levels in plasma. The hepatic levels of lipid peroxidation products and non-protein thiols (NPSH) were used to assess the extent of involvement of oxidative stress mechanisms. In general, challenge of animals with LPS resulted in hepatic injuries, activation of the inflammatory response, decreases in NPSH levels and increases in the levels of lipid peroxidation products (malondialdehyde and 4-hydroxyalkenals). Pretreatment of animals with NAC or empty liposomes did not have any significant protective effect against LPS-induced hepatotoxicity. On the other hand, pretreatment of animals with an equivalent dose of L-NAC conferred protection against the liver injuries induced following LPS challenge. These data suggest that NAC when delivered as a liposomal formulation is a potentially more effective prophylactic pharmacological agent in alleviating LPS-induced liver injuries.}, }
@article {pmid17985540, year = {2007}, author = {West, CA and Hart, AM and Terenghi, G and Wiberg, M}, title = {Analysis of the dose-response of N-acetylcysteine in the prevention of sensory neuronal loss after peripheral nerve injury.}, journal = {Acta neurochirurgica. Supplement}, volume = {100}, number = {}, pages = {29-31}, doi = {10.1007/978-3-211-72958-8_6}, pmid = {17985540}, issn = {0065-1419}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Cell Count ; Dose-Response Relationship, Drug ; Ganglia, Spinal/drug effects/pathology ; Neurons, Afferent/*drug effects/*pathology ; Rats ; Sciatic Nerve/drug effects/*injuries/*pathology ; Wounds and Injuries/pathology ; }, abstract = {BACKGROUND: N-Acetylcysteine (NAC) is a safe pharmaceutical agent known to protect cells from oxidative damage. Following peripheral nerve transection, NAC has been found to eliminate sensory neuronal loss. This study examines the dose-response relationship of NAC in preventing neuronal death.<br><br>METHODS AND FINDINGS: The rat sciatic nerve transection model was used, and stereological quantification of sensory neuron survival carried out at two weeks post-axotomy. NAC was administered systemically as an intraperitoneal injection to five groups of rats at a range of doses (1-300 mg/kg/day). Significant neuronal loss was observed in the 1 mg/kg/day dosage group (18.5% loss, p = 0.067 vs. sham treatment). A degree of neuroprotection occurred with 10 mg/kg/day (9.1% loss, p < 0.005 vs. control), whilst there was no significant loss with either 150 or 300 mg/kg/day.<br><br>CONCLUSIONS: The prevention of sensory neuronal loss with NAC is dose dependent and effective over a wide therapeutic range. This analysis confirms the efficacy of systemic administration and provides a dose framework with which NAC has clinical potential to improve outcome after peripheral nerve trauma.}, }
@article {pmid17984140, year = {2007}, author = {Soltan-Sharifi, MS and Mojtahedzadeh, M and Najafi, A and Reza Khajavi, M and Reza Rouini, M and Moradi, M and Mohammadirad, A and Abdollahi, M}, title = {Improvement by N-acetylcysteine of acute respiratory distress syndrome through increasing intracellular glutathione, and extracellular thiol molecules and anti-oxidant power: evidence for underlying toxicological mechanisms.}, journal = {Human &amp; experimental toxicology}, volume = {26}, number = {9}, pages = {697-703}, doi = {10.1177/0960327107083452}, pmid = {17984140}, issn = {0960-3271}, mesh = {APACHE ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Antioxidants/administration &amp; dosage/metabolism/*therapeutic use ; Biomarkers/blood ; Blood Platelets/*drug effects/metabolism ; Female ; Glutathione/*blood ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Respiratory Distress Syndrome/blood/*drug therapy/metabolism ; Sulfhydryl Compounds/*blood ; Treatment Outcome ; Up-Regulation ; }, abstract = {In acute respiratory distress syndrome (ARDS), there is extensive overproduction of free radicals to the extent that endogenous anti-oxidants are overwhelmed, permitting oxidative cell damage. The present study examined the benefit of the anti-oxidant compound N-acetylcysteine (NAC) in the management of ARDS by measuring patient's intracellular glutathione (inside red blood cells) and extracellular (plasma) anti-oxidant defense biomarkers and outcome. Twenty-seven ARDS patients were recruited from the intensive care unit of a teaching Hospital and randomly divided into two groups. Both groups were managed similarly by regular treatments but 17 patients received NAC 150 mg/kg at the first day that followed by 50 mg/kg/day for three days and 10 patients did not receive NAC. Treatment by NAC increased extracellular total anti-oxidant power and total thiol molecules and also improved intracellular glutathione and the outcome of the patients. In conclusion, patients with ARDS are in a deficient oxidant-anti-oxidant balance that can get a significant benefit if supplemented with NAC.}, }
@article {pmid17982638, year = {2007}, author = {Bondza-Kibangou, P and Millot, C and El Khoury, V and Millot, JM}, title = {Antioxidants and doxorubicin supplementation to modulate CD14 expression and oxidative stress induced by vitamin D3 and seocalcitol in HL60 cells.}, journal = {Oncology reports}, volume = {18}, number = {6}, pages = {1513-1519}, pmid = {17982638}, issn = {1021-335X}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Antioxidants/*pharmacology ; Calcitriol/analogs &amp; derivatives/pharmacology ; Catalase/pharmacology ; Cell Differentiation/*drug effects ; Doxorubicin/*pharmacology ; HL-60 Cells ; Humans ; Leukemia, Promyelocytic, Acute ; Lipopolysaccharide Receptors/drug effects/*genetics ; *Oxidative Stress ; RNA, Neoplasm/genetics ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/pharmacology ; }, abstract = {1alpha,25-dihydroxyvitamin D3 (VD3) and the EB1089 analog are well known for their roles in the modulation of proliferation and the differentiation of several malignant cells. In addition, VD3 or EB1089 displayed a high disposal of oxidant features and the ability to cause release of reactive oxygen species (ROS). We attempted to enhance HL60 cell differentiation and to limit ROS generation, by the association of deltanoids with doxorubicin and the antioxidants catalase (CAT), superoxide dismutase (SOD) and N-acetyl cystein (NAC). Differentiation of HL60 cells into monocytic lineage was studied by expression of mRNA, protein CD14 and functional differentiation by the nitroblue tetrazolium assay. The 2',7'-dichlorodihydrofluorescein diacetate (H2-DCFDA) dye allowed to evaluate in situ ROS generation. When associated with 0.1 nM EB1089, 15 nM doxorubicin induced an increase of differentiated cell percentage from 29% to 87% and did not affect VD3-treated cells. The association with doxorubicin also induced a significant increase of ROS release (p<0.05) versus VD3 and EB1089-treated cells. These results correspond to additivity of individual effects of doxorubicin and deltanoids. Antioxidant agents (10 nM NAC, 50 U/ml SOD or 2000 U/ml CAT) were associated with 10 nM VD3 or 1 nM EB1089 for 72 h. Compared to VD3 and EB1089 treatments, associations with antioxidants induced a slight increase of differentiated cells and a significant increase of CD14 mRNA. The highest differentiation effect occurred in the case of the EB1089-NAC association. Antioxidants induced a decrease (p<0.05) in ROS release generated by VD3 or EB1089 near the level of untreated cells. Thus, antioxidant agents demonstrated a protective effect against VD3 and EB1089 oxidative cytotoxicity and an enhancement of the monocyte differentiation. Combinations of antioxidants with deltanoids could dissociate the oxidative stress and differentiation.}, }
@article {pmid17980561, year = {2008}, author = {Hombach, J and Hoyer, H and Bernkop-Schnürch, A}, title = {Thiolated chitosans: development and in vitro evaluation of an oral tobramycin sulphate delivery system.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {33}, number = {1}, pages = {1-8}, doi = {10.1016/j.ejps.2007.09.001}, pmid = {17980561}, issn = {0928-0987}, mesh = {Acetylcysteine/administration &amp; dosage/chemistry/pharmacokinetics ; Administration, Oral ; Animals ; Biological Transport ; Caco-2 Cells ; Chitosan/chemical synthesis/*chemistry ; Chromatography, High Pressure Liquid ; Delayed-Action Preparations/administration &amp; dosage/chemistry/pharmacokinetics ; Epithelial Cells/metabolism ; Glutathione/chemistry ; Humans ; In Vitro Techniques ; Intestinal Mucosa/*metabolism ; Intestine, Small/metabolism ; Male ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/chemical synthesis/*chemistry ; Tablets ; Technology, Pharmaceutical/methods ; Tobramycin/administration &amp; dosage/chemistry/*pharmacokinetics ; Verapamil/administration &amp; dosage/pharmacokinetics ; }, abstract = {The aim of the present study was to develop and evaluate an oral delivery system for tobramycin sulphate intended to improve the oral bioavailability. Chitosan was thiolated by the immobilisation of N-acetylcysteine (NAC) to the amino groups of the polymer. The permeation enhancing effect of the resulting chitosan-NAC conjugate in combination with the permeation mediator glutathione (GSH) was evaluated both in Ussing-type chambers across freshly excised rat intestinal mucosa and Caco-2 cells using the poorly orally absorbed aminoglycoside tobramycin sulphate as model drug. Additionally, the release profile from tablets containing tobramycin sulphate, chitosan-NAC and glutathione was determined. The obtained thiomer chitosan-NAC displayed 962.2+/-53.2 micromol thiol groups per gram polymer of which 35.5+/-5.0% were oxidised. In comparison to buffer only, tobramycin sulphate uptake in presence of 0.5% (w/v) unmodified chitosan, 0.5% (w/v) chitosan-NAC, 0.5% (w/v) glutathione and the combination of 0.5% (w/v) glutathione and 0.5% (w/v) chitosan-NAC was improved 1.2-fold, 1.3-fold, 1.5-fold and 2.0-fold, respectively, across rat small intestine and 2.6-fold, 2.7-fold, 1.6-fold and 3.3-fold, respectively, across Caco-2 cell monolayer. Almost 90% of the tobramycin sulphate was released from tablets within 4h. The developed drug delivery system containing chitosan-NAC and glutathione is a promising tool for oral tobramycin sulphate administration showing improved gastrointestinal uptake and a sustained release.}, }
@article {pmid17979115, year = {2008}, author = {Jun, JH and Lee, SH and Kwak, HB and Lee, ZH and Seo, SB and Woo, KM and Ryoo, HM and Kim, GS and Baek, JH}, title = {N-acetylcysteine stimulates osteoblastic differentiation of mouse calvarial cells.}, journal = {Journal of cellular biochemistry}, volume = {103}, number = {4}, pages = {1246-1255}, doi = {10.1002/jcb.21508}, pmid = {17979115}, issn = {1097-4644}, mesh = {Acetylcysteine/*pharmacology ; Alkaline Phosphatase/metabolism ; Animals ; Antioxidants/*pharmacology ; Bacterial Proteins/pharmacology ; Bacterial Toxins/pharmacology ; Bone Morphogenetic Proteins/metabolism ; Caffeic Acids/pharmacology ; Cell Differentiation ; Cells, Cultured ; Glutathione/metabolism ; Mice ; Osteoblasts/*cytology ; Osteogenesis ; Phenylethyl Alcohol/analogs &amp; derivatives/pharmacology ; Skull/*cytology ; rho GTP-Binding Proteins/metabolism ; rhoA GTP-Binding Protein ; }, abstract = {Estrogen deficiency causes osteoporosis via increased generation of reactive oxygen species (ROS), and thus, antioxidants may prove to be the effective therapeutic candidates. We examined the effects of the antioxidant N-acetylcysteine (NAC) on osteoblastic differentiation in mouse calvarial cells. NAC (10-30 mM) enhanced alkaline phosphatase activity, mRNA expression of osteoblast differentiation-associated genes and mineralized nodule formation. It also increased expression of bone morphogenetic proteins-2, -4, and -7. The osteogenic activity of NAC was partially reduced by inhibition of glutathione synthesis. Since caffeic acid phenethyl ester did not stimulate osteoblast differentiation, it is unlikely that ROS scavenging activity of NAC is sufficient for osteogenic activity. We observed that NAC suppressed small GTPase RhoA activity and activation of RhoA by Pasteurella multocida toxin suppressed the osteogenic activity of NAC. These results suggest that NAC might exert its osteogenic activity via increased glutathione synthesis and inhibition of RhoA activation.}, }
@article {pmid17978497, year = {2007}, author = {Sommani, P and Yamashita, K and Miyoshi, T and Tsunemine, H and Kodaki, T and Mori, H and Hirota, K and Arai, T and Sasada, M and Makino, K}, title = {Inhibitory effect of 6-formylpterin on HIF-1alpha protein accumulation.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {30}, number = {11}, pages = {2181-2184}, doi = {10.1248/bpb.30.2181}, pmid = {17978497}, issn = {0918-6158}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Carcinoma, Hepatocellular/pathology ; Cell Hypoxia/physiology ; Cell Line, Tumor ; Deferoxamine/toxicity ; Dose-Response Relationship, Drug ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists &amp; inhibitors/biosynthesis ; Liver Neoplasms/pathology ; Pterins/*pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; }, abstract = {Hypoxia-inducible factor-1 (HIF-1) is a main regulator of metabolic adaptation to hypoxia. HIF-1alpha is induced by hypoxia, or by hypoxia-mimicking reagents, such as desferrioxamine (DFX), under a normoxic condition. A xanthine oxidase inhibitor, 6-formylpterin (6FP), is reported to exert its functions on reactive oxygen species (ROS) modulation. In this study, we investigated the effect of 6FP on HIF-1alpha expression under a DFX-treated or hypoxic condition. 6FP decreased HIF-1alpha expression at the protein level, but not at the mRNA level, in a dose-dependent manner, and this suppressive effect was reversed by the antioxidant, N-acetyl-L-cysteine (NAC). Furthermore, the ROS generated by 6FP was reversed with NAC coincubation. These findings suggest that intracellular ROS generated by 6FP decreased the HIF-1alpha protein accumulation under a DFX-treated or hypoxic condition.}, }
@article {pmid17978059, year = {2007}, author = {Nuchsongsin, F and Chotivanich, K and Charunwatthana, P and Omodeo-Salè, F and Taramelli, D and Day, NP and White, NJ and Dondorp, AM}, title = {Effects of malaria heme products on red blood cell deformability.}, journal = {The American journal of tropical medicine and hygiene}, volume = {77}, number = {4}, pages = {617-622}, pmid = {17978059}, issn = {0002-9637}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Albumins/metabolism/*pharmacology ; Anemia/blood/parasitology ; Antioxidants/pharmacology ; Erythrocyte Deformability/*drug effects ; Erythrocytes/*drug effects/*parasitology/pathology ; Glutathione/metabolism/pharmacology ; Hemeproteins/metabolism/*pharmacology ; Hemin/metabolism/pharmacology ; Hemoglobins/metabolism/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Malaria, Falciparum/*blood ; }, abstract = {In falciparum malaria, the deformability of the entire erythrocyte population is reduced in proportion to disease severity, and this compromises microcirculatory blood flow through vessels partially obstructed by cytoadherent parasitized erythrocytes. The cause of rigidity of uninfected erythrocytes in not known but could be mediated by malaria heme products. In this study, we show that red blood cell deformability (RBC-D), measured by laser-assisted optical rotational cell analyzer, decreased in a dose-dependent manner after incubation with hemin and hydrogen peroxide but not with hemoglobin or beta-hematin. Hemin also reduced mean red cell volume. Albumin decreased and N-acetylcysteine (NAC) both prevented and reversed rigidity induced by hemin. Hemin-induced oxidative damage of the membrane seems to be a more important contributor to pathology than cell shrinkage because the antioxidant NAC restored RBC-D but not red blood cell volume. The findings suggest novel approaches to the treatment of potentially lethal malaria.}, }
@article {pmid17977619, year = {2008}, author = {Ishimura, A and Ishige, K and Taira, T and Shimba, S and Ono, S and Ariga, H and Tezuka, M and Ito, Y}, title = {Comparative study of hydrogen peroxide- and 4-hydroxy-2-nonenal-induced cell death in HT22 cells.}, journal = {Neurochemistry international}, volume = {52}, number = {4-5}, pages = {776-785}, doi = {10.1016/j.neuint.2007.09.008}, pmid = {17977619}, issn = {0197-0186}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/*toxicity ; Blotting, Western ; Calcium/metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; Cobalt/pharmacology ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen Peroxide/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; NF-kappa B/physiology ; Neurons/drug effects ; Neuroprotective Agents/pharmacology ; Oxidants/*toxicity ; Oxidative Stress/drug effects ; Propidium ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tetrazolium Salts ; Thiazoles ; }, abstract = {Several studies have indicated that lipid peroxidation often occurs in response to oxidative stress, and that many aldehydic products including 4-hydroxy-2-nonenal (HNE) are formed when lipid hydroperoxides break down. In order to clarify the mechanism of oxidative stress-induced neuronal death in the nervous system, we investigated H(2)O(2)- and HNE-induced cell death pathways in HT22 cells, a mouse hippocampal cell line, under the same experimental conditions. Treatment with H(2)O(2) and HNE decreased the viability of these cells in a time- and concentration-dependent manner. In the cells treated with H(2)O(2), significant increases in the immunoreactivities of DJ-1 and nuclear factor-kappaB (NF-kappaB) subunits (p65 and p50) were observed in the nuclear fraction. H(2)O(2) also induced an increase in the intracellular concentration of Ca(2+), and cobalt chloride (CoCl(2)), a Ca(2+) channel inhibitor, suppressed the H(2)O(2)-induced cell death. In HNE-treated cells, none of these phenomena were observed; however, HNE adduct proteins were formed after exposure to HNE, but not to H(2)O(2). N-Acetyl-L-cysteine (NAC) suppressed both HNE-induced cell death and HNE-induced expression of HNE adduct proteins, whereas H(2)O(2)-induced cell death was not affected. These findings suggest that the mechanisms of cell death induced by H(2)O(2) different from those induced by HNE in HT22 cells, and that HNE adduct proteins play an important role in HNE-induced cell death. It is also suggested that the pathway for H(2)O(2)-induced cell death in HT22 cells does not involve HNE production.}, }
@article {pmid17977529, year = {2008}, author = {Kalariya, NM and Ramana, KV and Srivastava, SK and van Kuijk, FJ}, title = {Carotenoid derived aldehydes-induced oxidative stress causes apoptotic cell death in human retinal pigment epithelial cells.}, journal = {Experimental eye research}, volume = {86}, number = {1}, pages = {70-80}, pmid = {17977529}, issn = {0014-4835}, support = {Z01 DK036118/ImNIH/Intramural NIH HHS/United States ; GM71036/GM/NIGMS NIH HHS/United States ; R01 DK036118/DK/NIDDK NIH HHS/United States ; R01 GM071036/GM/NIGMS NIH HHS/United States ; R37 DK036118/DK/NIDDK NIH HHS/United States ; R01 GM071036-05/GM/NIGMS NIH HHS/United States ; R37 DK036118-20/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aldehydes/antagonists &amp; inhibitors/*pharmacology ; Apoptosis/*drug effects ; Carotenoids/*chemistry ; Cells, Cultured ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Humans ; Membrane Potential, Mitochondrial/drug effects/physiology ; NF-kappa B/metabolism ; Oxidative Stress/*drug effects/physiology ; Pigment Epithelium of Eye/cytology/*drug effects ; Reactive Oxygen Species/metabolism ; Retina/cytology/*drug effects ; Transcription Factor AP-1/metabolism ; }, abstract = {Carotenoids have been advocated as potential therapeutic agents in treating age-related macular degeneration (AMD). In ocular tissues carotenoids may undergo oxidation and form carotenoid-derived aldehydes (CDA), which would be toxic to tissues. We have investigated the cytotoxic effects of CDA from beta-carotene, Lutein and Zeaxanthin on human retinal pigment epithelial cells (ARPE-19). The serum-starved ARPE-19 cells were treated with CDA without or with antioxidant, N-acetylcysteine (NAC) and cell viability, apoptosis, reactive oxygen species (ROS) levels, nuclear chromatin condensation as well as fragmentation, change in mitochondrial membrane potential (MMP) and activation of transcription factors NF-kappaB and AP-1 were determined. We observed a dose and time-dependent decline in cell viability upon incubation of ARPE-19 cells with CDA. The CDA treatment also led to elevation in ROS levels in a dose-dependent manner. Upon CDA treatment a significant number of apoptotic cells were observed. Also early apoptotic changes in ARPE-19 cells induced by CDA were associated with change in MMP. Increased nuclear chromatin condensation and fragmentation were also observed in cells treated with CDA. The cytotoxicity of CDA in ARPE-19 cells was significantly ameliorated by the antioxidant, NAC. Furthermore, CDA induced the activation of NF-kappaB and AP-1 which was significantly inhibited by NAC. Thus our results demonstrate that CDA could increase the oxidative stress in ARPE-19 cells by elevating ROS levels that would cause imbalance in cellular redox status, which could lead to cell death. This would suggest that high carotenoid supplementation for treatment of AMD should be used cautiously.}, }
@article {pmid17969299, year = {2007}, author = {Shavit, L and Lifschitz, M and Lachish, T and Rosenmann, D and Balkin, J and Slotki, I}, title = {[Use of N-acetylcysteine prior to cardiac catheterization to prevent acute renal injury in patients with stage III chronic kidney disease].}, journal = {Harefuah}, volume = {146}, number = {9}, pages = {655-9, 736}, pmid = {17969299}, issn = {0017-7768}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/epidemiology/prevention &amp; control ; Aged ; Aged, 80 and over ; Cardiac Catheterization/*adverse effects ; Contrast Media/*adverse effects ; Female ; Glomerular Filtration Rate ; Humans ; Kidney Failure, Chronic/*physiopathology ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {BACKGROUND: The role of N-acetylcysteine (NAC) to protect against contrast-induced nephropathy (CN) in patients with pre-existing renal insufficiency remains controversial despite several randomized controlled trials and meta-analyses. The potential reasons of inconsistency may be due to differences in definition, type and dose of contrast medium, imaging procedures, and the frequency of other potential causes of acute renal injury. Renal function before contrast administration is a major determinant of deterioration in function after administration.<br><br>METHODS: We conducted a retrospective review of patients with Stage III Chronic Kidney Disease (CKD) who underwent cardiac catheterization from January 2000 through January 2004 in our hospital. The incidence of CN was examined in patients pretreated and not pretreated with NAC.<br><br>RESULTS: From January 2000 to January 2004, 189 patients with Stage III CKD underwent cardiac catheterization. All patients received 0.45% or 0.9% saline hydration prior to catheterization. NAC was given prior to 83 catheterizations and not given prior to 57. Eleven of 57 patients (19.3%) not pretreated with NAC developed acute renal injury (ARI) while 6 of 83 who received NAC (7.2%) developed ARI (p<0.05). Nineteen patients underwent more than one cardiac catheterization, but there was no pattern to their potential for multiple episodes of ARI irrespective of prophylactic NAC administration.<br><br>CONCLUSION: In our study NAC offered significant protection against ARI in patients with Stage III CKD. No overt risk factor for multiple episodes of ARI was observed, nor was the occurrence of ARI after first cardiac catheterization predictive of ARI after a subsequent catheterization.}, }
@article {pmid17967787, year = {2008}, author = {Hasan, RN and Schafer, AI}, title = {Hemin upregulates Egr-1 expression in vascular smooth muscle cells via reactive oxygen species ERK-1/2-Elk-1 and NF-kappaB.}, journal = {Circulation research}, volume = {102}, number = {1}, pages = {42-50}, doi = {10.1161/CIRCRESAHA.107.155143}, pmid = {17967787}, issn = {1524-4571}, support = {R01-HL36045/HL/NHLBI NIH HHS/United States ; }, mesh = {Cells, Cultured ; Early Growth Response Protein 1/drug effects/*genetics ; Hemin/*pharmacology ; Humans ; Mitogen-Activated Protein Kinase 3/*metabolism ; Muscle, Smooth, Vascular/cytology ; Myocytes, Smooth Muscle/drug effects/*metabolism ; NF-kappa B/*metabolism ; Oxidative Stress/drug effects ; Promoter Regions, Genetic ; Reactive Oxygen Species ; Up-Regulation/*drug effects/genetics ; ets-Domain Protein Elk-1/*metabolism ; }, abstract = {Reactive oxygen species (ROS) and oxidant stress are important mediators of cardiovascular pathologies including atherosclerosis. One source of ROS in the vasculature is free heme released from hemoglobin. Because Egr-1, the regulator of cell proliferation and apoptosis, is also induced by oxidant stress and is likewise implicated in atherosclerosis, we examined the regulation of Egr-1 by heme in vascular smooth muscle cells (SMCs). Hemin increased Egr-1 expression (mRNA, protein) within 30 minutes and ERK-1/2 phosphorylation and nuclear translocation within 5 minutes. Inhibiting hemin-induced ERK-1/2 activation by U0126 (MAPK-inhibitor), the antioxidant N-acetyl cysteine, the NADPH oxidase inhibitors apocynin and diphenyleneiodonium chloride, the superoxide scavenger tiron, or tricarbonyldichlororuthenium(II)-dimer (carbon-monoxide donor; CORM-2) blocked hemin-induced Egr-1 expression. Hemin activated Elk-1, SRF, and NF-kappaB and promoted their interaction with the Egr-1 promoter. Downregulating Elk-1 (via siRNA) or blocking NF-kappaB activation (via BAY-11-7082) abolished hemin induction of Egr-1. Finally, hemin-induced Egr-1 bound the promoters of tissue factor (TF), Plasminogen Activator Inhibitor (PAI)-1, and NGF-1A Binding (NAB)-2, upregulating their expression, and increased the biochemical activity of TF and PAI-1. Upregulation of Egr-1 and its target genes by heme-induced oxidant stress may be an important event in the initiation and progression of inflammatory vascular diseases such as atherosclerosis.}, }
@article {pmid17967216, year = {2008}, author = {Rungapamestry, V and Rabot, S and Fuller, Z and Ratcliffe, B and Duncan, AJ}, title = {Influence of cooking duration of cabbage and presence of colonic microbiota on the excretion of N-acetylcysteine conjugates of allyl isothiocyanate and bioactivity of phase 2 enzymes in F344 rats.}, journal = {The British journal of nutrition}, volume = {99}, number = {4}, pages = {773-781}, doi = {10.1017/S0007114507841134}, pmid = {17967216}, issn = {0007-1145}, mesh = {Acetylcysteine/*urine ; Animals ; Bacteria/*metabolism ; *Brassica ; Colon/*metabolism/microbiology ; *Cooking ; Diet ; Female ; Germ-Free Life ; Glucosinolates/metabolism ; Glucuronosyltransferase/metabolism ; Glutathione Transferase/metabolism ; Glycoside Hydrolases/*metabolism ; Humans ; Isothiocyanates/metabolism ; Liver/metabolism ; Male ; Models, Animal ; Rats ; Rats, Inbred F344 ; Time Factors ; }, abstract = {Isothiocyanates have been implicated in the cancer-protective effects of brassica vegetables. When cabbage is consumed, sinigrin is hydrolysed by plant or microbial myrosinase partly to allyl isothiocyanate (AITC), which is mainly excreted as N-acetylcysteine conjugates (NAC) of AITC in urine. The effect of cooking cabbage on the excretion of NAC of AITC, and glutathione-S-transferase (GST) and uridine 5'-diphospho-glucuronosyl transferase (UGT) activity in rat liver and colon was investigated. Germ-free (GF) and human faecal microbiota-associated (HFM) rats were fed a control diet containing 20 % raw, lightly cooked, or fully cooked cabbage for 14 d. When plant myrosinase was present, excretion of NAC of AITC/24 h was increased by 1.4 and 2.5 times by the additional presence of microbial myrosinase after consumption of raw and lightly cooked cabbage respectively. When plant myrosinase was absent, as after consumption of fully cooked cabbage, excretion of the AITC conjugate was almost zero in GF and HFM rats. None of the cabbage diets modified hepatic GST activity. When microbiota was absent, colonic GST was 1.3-fold higher after fully cooked cabbage, and hepatic UGT was increased by 1.4-1.8-fold after all cabbage diets, compared with the control feed. There were no differences in GST or UGT following cabbage consumption when microbiota was present. It is possible that other constituents of cabbage, rather than metabolites of glucosinolates per se, may be responsible for changes in phase 2 enzyme activity. The main effect of cooking cabbage and altering colonic microbiota was on excretion of NAC of AITC.}, }
@article {pmid17967133, year = {2008}, author = {Shankar, K and Hidestrand, M and Liu, X and Chen, JR and Haley, R and Perrien, DS and Skinner, RA and Lumpkin, CK and Badger, TM and Ronis, MJ}, title = {Chronic ethanol consumption inhibits postlactational anabolic bone rebuilding in female rats.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {23}, number = {3}, pages = {338-349}, doi = {10.1359/jbmr.071023}, pmid = {17967133}, issn = {1523-4681}, support = {R01 AA12928/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adipocytes/metabolism/pathology ; Alcoholism/*metabolism/pathology ; Animals ; Bone Density/drug effects ; Bone Diseases, Metabolic/chemically induced/metabolism/pathology ; Bone Resorption/chemically induced/*metabolism/pathology ; Central Nervous System Depressants/*toxicity ; Ethanol/*toxicity ; Female ; Free Radical Scavengers/pharmacology ; Lactation/*metabolism ; Osteogenesis/*drug effects ; Oxidative Stress/drug effects ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Risk Factors ; Signal Transduction/drug effects ; Tibia/metabolism/pathology ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {UNLABELLED: EtOH consumption significantly impaired anabolic rebuilding of bone after lactation. Lower BMD and BMC in EtOH-fed rats were associated with decreased bone formation in the proximal tibia, increased proportion of adipocytes, and increased expression of TNF-alpha. EtOH-induced skeletal deficits were prevented by treatment with either NAC or sTNFR1. These data suggest that postlactational anabolic rebuilding is influenced by EtOH consumption and may affect the long-term risk of osteopenia.<br><br>INTRODUCTION: Despite significant loss of bone during lactation, BMD is restored by a powerful anabolic rebuilding process after weaning. A significant number of women resume alcohol consumption after weaning their offspring from breast feeding. The objectives of this study were to examine the consequences of chronic ethanol (EtOH) consumption on the postlactational rebuilding process and to investigate the underlying mechanisms by which EtOH mediates its detrimental effects.<br><br>MATERIALS AND METHODS: Female Sprague-Dawley rats (n = 7-9 per group) were fed EtOH-containing diets (13 g/kg/d) for 1, 2, or 4 wk after weaning of their offspring. Skeletal parameters in the proximal tibia were examined using pQCT, microCT, and histomorphometric techniques, and interventional studies were performed on the mechanistic roles of EtOH-induced oxidative stress and TNF-alpha.<br><br>RESULTS AND CONCLUSIONS: EtOH consumption completely abolished the anabolic bone rebuilding that occurred after lactation. Decreased BMD and BMC were associated with decreased bone formation and not with increased osteoclast activity. Furthermore, EtOH-fed rats showed greater proportion of fat volume/bone volume and expression of adipocyte-specific genes. EtOH-induced skeletal effects were mitigated by the dietary antioxidant, N-acetyl cysteine or by blocking TNF-alpha signaling. These data suggest EtOH consumption in the period immediately postweaning may significantly impair the mother's skeletal health and lead to long-term osteopenia.}, }
@article {pmid17966065, year = {2007}, author = {Burke, AS and Redeker, K and Kurten, RC and James, LP and Hinson, JA}, title = {Mechanisms of chloroform-induced hepatotoxicity: oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {70}, number = {22}, pages = {1936-1945}, doi = {10.1080/15287390701551399}, pmid = {17966065}, issn = {1528-7394}, support = {2 P20 RR 16460/RR/NCRR NIH HHS/United States ; T-32 ES010952/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Alanine Transaminase/metabolism ; Animals ; Antioxidants/pharmacology ; Cells, Cultured ; Chloroform/*toxicity ; Cyclosporine/pharmacology ; Female ; Glutathione/metabolism ; Hepatocytes/*drug effects/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Mice, Inbred Strains ; Mitochondria, Liver/*drug effects/physiology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; *Oxidative Stress/drug effects ; Peroxynitrous Acid/metabolism ; Reactive Oxygen Species/metabolism ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {The role of mitochondrial permeability transition (MPT) and oxidative stress in chloroform toxicity was determined in freshly isolated female B6C3F1 mouse hepatocytes. Incubation of chloroform (12 mM) with hepatocytes resulted in cell death (alanine aminotransferase release and propidium iodide fluorescence). Chloroform had volatilized from the incubation and glutathione was depleted by 1 h; however, toxicity was not significantly different between control and chloroform-incubated cells. Hepatocytes were washed and reincubated in fresh media at 1 h. Subsequent reincubation of chloroform-treated hepatocytes resulted in significant toxicity at 3-5 h. Inclusion of the MPT inhibitor cyclosporine A or the antioxidant N-acetylcysteine (NAC) in the reincubation media at 1 h prevented toxicity. Confocal microscopy studies with the dye calcein AM indicated MPT that was blocked by cyclosporine A or NAC. Fluorescence microscopy studies utilizing JC-1 indicated loss of mitochondrial membrane potential, which was also blocked by cyclosporine A or NAC. Dichlorofluorescein fluorescence increased during the reincubation phase, indicating increased oxidative stress, and the increase was blocked by cyclosporine A. Since oxidative stress may occur by peroxynitrite, its role in toxicity was examined. Either of the nitric oxide synthase inhibitors N(G)-methyl-L-arginine (L-NMMA) and 7-nitroindazole (7-NI) at 1 h blocked toxicity. Western blot analysis of hepatocytes for 3-nitrotyrosine in proteins, a biomarker of peroxynitrite, indicated one major nitrated protein at 81 kD. Nitration of this protein was inhibited by cyclosporine A, L-NMMA, 7-NI, or NAC. The data indicate that chloroform-induced cell death occurs in two phases: a metabolic phase characterized by glutathione depletion, and an oxidative phase characterized by MPT and protein nitration.}, }
@article {pmid17965288, year = {2007}, author = {Saitoh, S and Kiyooka, T and Rocic, P and Rogers, PA and Zhang, C and Swafford, A and Dick, GM and Viswanathan, C and Park, Y and Chilian, WM}, title = {Redox-dependent coronary metabolic dilation.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {293}, number = {6}, pages = {H3720-5}, doi = {10.1152/ajpheart.00436.2007}, pmid = {17965288}, issn = {0363-6135}, support = {HL 32788/HL/NHLBI NIH HHS/United States ; HL 73755/HL/NHLBI NIH HHS/United States ; HL 77566/HL/NHLBI NIH HHS/United States ; HL 85119/HL/NHLBI NIH HHS/United States ; RR 018766/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Coronary Vessels/drug effects/enzymology/*metabolism ; Culture Media, Conditioned/metabolism ; Dithiothreitol/pharmacology ; Enzyme Activation ; Hydrogen Peroxide/metabolism ; Imidazoles/pharmacology ; In Vitro Techniques ; Microscopy, Fluorescence ; Myocytes, Cardiac/drug effects/*metabolism ; Nitroprusside/pharmacology ; Oxidation-Reduction ; *Paracrine Communication ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Pyridines/pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Reducing Agents/pharmacology ; Sulfhydryl Compounds/*metabolism ; *Vasodilation/drug effects ; Vasodilator Agents/pharmacology ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {We have observed that hydrogen peroxide (H2O2), the dismutated product of superoxide, is a coronary metabolic dilator and couples myocardial oxygen consumption to coronary blood flow. Because the chemical activity of H2O2 favors its role as an oxidant, and thiol groups are susceptible to oxidation, we hypothesized that coronary metabolic dilation occurs via a redox mechanism involving thiol oxidation. To test this hypothesis, we studied the mechanisms of dilation of isolated coronary arterioles to metabolites released by metabolically active (paced at 400 min) isolated cardiac myocytes and directly compared these responses with authentic H2O2. Studies were performed under control conditions and using interventions designed to reduce oxidized thiols [0.1 microM dithiothreitol (DTT) and 10 mM N-acetyl-L-cysteine (NAC)]. Aliquots of the conditioned buffer from paced myocytes produced vasodilation of isolated arterioles (peak response, 71% +/- 6% of maximal dilation), whereas H2O2 produced complete dilation (92% +/- 7%). Dilation to either the conditioned buffer or to H2O2 was significantly reduced by the administration of either NAC or DTT. The location of the thiols oxidized by the conditioned buffer or of H2O2 was determined by the administration of the fluorochromes monochlorobimane (20 microM) or monobromotrimethylammoniobimane (20 microM), which covalently label the reduced total or extracellular-reduced thiols, respectively. H2O2 or the conditioned buffer predominantly oxidized intracellular thiols since the fluorescent signal from monochlorobimane was reduced more than that of monobromotrimethylammoniobimane. To determine whether one of the intracellular targets of thiol oxidation that leads to dilation is the redox-sensitive kinase p38 mitogen-activated protein (MAP) kinase, we evaluated dilation following the administration of the p38 inhibitor SB-203580 (10 microM). The inhibition of p38 attenuated dilation to either H2O2 or to the conditioned buffer from stimulated myocytes by a similar degree, but SB-203580 did not attenuate dilation to nitroprusside. Western blot analysis for the activated form of p38 (phospho-p38) in the isolated aortae revealed robust activation of this enzyme by H2O2. Taken together, our results show that an active component of cardiac metabolic dilation, like that of H2O2, produces dilation by the oxidation of thiols, which are predominantly intracellular and dependent activation on the p38 MAP kinase. Thus coronary metabolic dilation appears to be mediated by redox-dependent signals.}, }
@article {pmid17963796, year = {2008}, author = {Sobol, Z and Cook, NM and Schiestl, RH}, title = {HNO induces DNA deletions in the yeast S. cerevisiae.}, journal = {Mutation research}, volume = {638}, number = {1-2}, pages = {83-89}, doi = {10.1016/j.mrfmmm.2007.08.018}, pmid = {17963796}, issn = {0027-5107}, mesh = {Acetylcysteine/pharmacology ; Anaerobiosis ; DNA, Fungal/drug effects ; Mutagenicity Tests/methods ; Nitrites/*toxicity ; Nitrogen Oxides/*toxicity ; Recombination, Genetic ; Saccharomyces cerevisiae/drug effects/*genetics ; *Sequence Deletion ; }, abstract = {HNO is genotoxic but its mechanism is not well understood. There are many possible mechanisms by which HNO can attack DNA. Since HNO is electrophilic, it may react with exocyclic amine groups on DNA bases and through a series of subsequent reactions form a deaminated product. Alternatively, HNO may induce radical chemistry through O(2)-dependent (or possibly O(2)-independent) chemistry. In cell free systems, experiments have shown that HNO does react with DNA, resulting in base oxidation and strand cleavage. In this study, we used a whole-cell system in the yeast Saccharomyces cerevisiae to study the mechanism of HNO induced DNA damage with Angeli's salt as HNO donor. The yeast DEL assay provided a measure of intrachromosomal recombination leading to DNA deletions. We also examined interchromosomal recombination leading to genomic rearrangements and used the canavanine (CAN) assay to study induction of forward point mutations. HNO was a potent inducer of DNA deletions and recombination but it was negative for induction of point mutations. This suggests that HNO causes DNA strand breaks rather than base damage. Genotoxicity was observed under aerobic and anaerobic conditions and NAC protected against HNO induced DNA deletions. Since HNO is genotoxic under anaerobic conditions, NAC probably protected against radicals generated by HNO independent of oxygen.}, }
@article {pmid17960877, year = {2007}, author = {Wu, TF and Hsu, CY and Huang, HS and Chou, SP and Wu, H}, title = {Proteomic analysis of pycnogenol effects in RAW 264.7 macrophage reveals induction of cathepsin D expression and enhancement of phagocytosis.}, journal = {Journal of agricultural and food chemistry}, volume = {55}, number = {24}, pages = {9784-9791}, doi = {10.1021/jf070453o}, pmid = {17960877}, issn = {0021-8561}, mesh = {Animals ; Annexin A4 ; Cathepsin D/*metabolism ; Dose-Response Relationship, Drug ; Electrophoresis, Gel, Two-Dimensional/methods ; Fatty Acid-Binding Proteins ; Flavonoids/*pharmacology ; Gene Expression ; Macrophages ; Mass Spectrometry ; Mice ; Neoplasm Proteins ; Phagocytosis/*drug effects/physiology ; Plant Extracts ; Protein Subunits ; *Proteomics ; Time Factors ; }, abstract = {Pycnogenol, polyphenolic compounds extracted from the pine bark, is beneficial for human health. To understand more of its effects, the present study is to explore the protein expression pattern induced by pycnogenol in RAW 264.7 cells. Global analysis using two-dimensional gel electrophoresis indicated that treatment with pycnogenol induces upregulation of four proteins, whose identities were revealed by mass spectrometry as cathepsin D, keratinocyte lipid-binding protein, proteasome subunit alpha type 1, and annexin IV. The pycnogenol effect displayed a time- and concentration-dependent manner. Unlike pycnogenol, N-acetyl cysteine and vitamin C had no effect on cathepsin D expression. Further studies showed that cathepsin D induction is correlated with an increase of lysosomal staining and enhancement of phagocytosis. These results reveal the novel effects of pycnogenol on protein expression and phagocytic functions and illustrate the advantage of proteomics-based strategy in unveiling the molecular basis of phytochemicals.}, }
@article {pmid17959349, year = {2008}, author = {Moschou, M and Kosmidis, EK and Kaloyianni, M and Geronikaki, A and Dabarakis, N and Theophilidis, G}, title = {In vitro assessment of the neurotoxic and neuroprotective effects of N-acetyl-L-cysteine (NAC) on the rat sciatic nerve fibers.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {22}, number = {1}, pages = {267-274}, doi = {10.1016/j.tiv.2007.09.005}, pmid = {17959349}, issn = {0887-2333}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/toxicity ; Action Potentials/drug effects ; Animals ; Cadmium/toxicity ; Dose-Response Relationship, Drug ; Free Radical Scavengers/administration &amp; dosage/pharmacology/toxicity ; In Vitro Techniques ; Male ; Neuroprotective Agents/administration &amp; dosage/*pharmacology/toxicity ; Neurotoxicity Syndromes/etiology/prevention &amp; control ; Neurotoxins/administration &amp; dosage/*pharmacology/toxicity ; Potassium Channels, Voltage-Gated/drug effects/metabolism ; Rats ; Rats, Wistar ; Sciatic Nerve/*drug effects/metabolism ; Sodium Channels/drug effects/metabolism ; Time Factors ; }, abstract = {N-acetyl-L-cysteine (NAC), at a concentration of 1-60mM, has been previously used extensively for protection in a variety of cell cultures against the deleterious effects of various compounds. The results of this in vitro study show that NAC has certain unusual effects on the evoked compound action potential (CAP) of the rat sciatic nerve fibers. Firstly, at concentrations of 5.0, 3.5 and 2.5mM, concentrations used by others as a protectant for cell cultures, NAC inhibits the action potentials of the sciatic nerve fibers completely in a concentration-dependent manner within a few minutes or hours (2.5mM). Secondly, the acute inhibitory action of NAC on the CAP of the nerve fibers was not spontaneously reversible, but as soon as NAC was replaced with saline there was a partial (approximately 75%) recovery in the function of the nerve fibers. Thirdly, the no observed effect concentration for NAC was estimated to be 1mM. The paradox is that NAC at 1 mM not only had no effect on the nerve fibers, but it became an excellent neuroprotective compound, giving almost 100% neuroprotection against cadmium-induced neurotoxicity. The results show a possible effect of NAC on voltage-gated sodium and potassium channels. The observed neuroprotective-neurotoxic properties of NAC require careful reconsideration of its use in either in vitro studies or in vivo pharmaceutical applications.}, }
@article {pmid17959342, year = {2008}, author = {Venketaraman, V and Millman, A and Salman, M and Swaminathan, S and Goetz, M and Lardizabal, A and David Hom,  and Connell, ND}, title = {Glutathione levels and immune responses in tuberculosis patients.}, journal = {Microbial pathogenesis}, volume = {44}, number = {3}, pages = {255-261}, doi = {10.1016/j.micpath.2007.09.002}, pmid = {17959342}, issn = {0882-4010}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Antigens, Bacterial/immunology ; Glutathione/*blood/metabolism ; Humans ; Leukocytes, Mononuclear/*immunology ; Lymphocyte Activation/*immunology ; Mycobacterium tuberculosis/drug effects/immunology ; Pilot Projects ; Tuberculosis/*blood/immunology ; }, abstract = {Glutathione levels are significantly reduced in peripheral blood mononuclear cells and red blood cells isolated from tuberculosis patients. Treatment of blood cultures from tuberculosis patients with N-acetyl cysteine, a glutathione precursor, was associated with improved control of intracellular M. tuberculosis infection. N-acetyl-cysteine treatment decreased the levels of IL-10, IL-6, TNF-alpha and IL-1, in blood cultures derived from tuberculosis patients, favoring the host immune cells to successfully control M. tuberculosis replication.}, }
@article {pmid17959236, year = {2008}, author = {Wataha, JC and Lewis, JB and McCloud, VV and Shaw, M and Omata, Y and Lockwood, PE and Messer, RL and Hansen, JM}, title = {Effect of mercury(II) on Nrf2, thioredoxin reductase-1 and thioredoxin-1 in human monocytes.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {24}, number = {6}, pages = {765-772}, doi = {10.1016/j.dental.2007.09.002}, pmid = {17959236}, issn = {0109-5641}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cells, Cultured ; Dental Materials/*pharmacology ; Electrophoresis ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Immunoblotting ; Lipopolysaccharides/pharmacology ; Materials Testing ; Mercury/*pharmacology ; Monocytes/*drug effects/enzymology/metabolism ; NF-E2-Related Factor 2/*drug effects ; Oxidation-Reduction ; Selenium Compounds/pharmacology ; Thioredoxin Reductase 1/antagonists &amp; inhibitors/*drug effects ; Thioredoxins/*drug effects ; }, abstract = {OBJECTIVES: Human blood levels of mercury are commonly 10nM, but may transiently reach 50-75nM after dental amalgam placement or removal. Controversy persists about the use of mercury because the effects of these 'trace' levels of mercury are not clear. Concentrations of mercury > or =5000nM unequivocally alter redox balance in blood cells including monocytes. In the current study, we tested a hypothesis that concentrations of mercury <100nM altered levels and activities of key proteins that maintain monocytic redox balance.<br><br>METHODS: Human THP1 monocytes were exposed to 10-75nM of Hg(II) for 6-72h, with or without activation by lipopolysaccharide (LPS). The redox management proteins Nrf2 and thioredoxin-1 (Trx1) were separated by electrophoresis, then quantified by immunoblotting. The activity of the seleno-enzyme thioredoxin reductase (TrxR1), important in maintaining Trx1 redox balance, was measured by cell-free and cell-dependent assays.<br><br>RESULTS: Concentrations of Hg(II) between 10-75nM increased Nrf2 levels (3.5-4.5 fold) and decreased Trx1 levels (2-3 fold), but these changes persisted <24h. Hg(II) potently inhibited (at concentrations of 5-50nM) TrxR1 activity in both cell-free and intracellular assays. Furthermore, Hg(II) transiently amplified LPS-induced Nrf2 levels by 2-3 fold and limited LPS-induced decreases in Trx1. All effects of Hg(II) were mitigated by pre-adding N-acetyl-cysteine (NAC) or sodium selenide (Na2SeO3), supplements of cellular thiols and selenols, respectively.<br><br>SIGNIFICANCE: Our results suggest that nanomolar concentrations of Hg(II) transiently alter cellular redox balance in monocytes that trigger changes in Nrf2 and Trx1 levels. These changes indicate that monocytes have a capacity to adapt to trace concentrations of Hg(II) that are introduced into the bloodstream after dental amalgam procedures or fish consumption. The ability of monocytes to adapt suggests that low levels of mercury exposure from dental amalgam may not overtly compromise monocyte function.}, }
@article {pmid17959032, year = {2007}, author = {Wang, H and Xu, DX and Lu, JW and Zhao, L and Zhang, C and Wei, W}, title = {N-acetylcysteine attenuates lipopolysaccharide-induced apoptotic liver damage in D-galactosamine-sensitized mice.}, journal = {Acta pharmacologica Sinica}, volume = {28}, number = {11}, pages = {1803-1809}, pmid = {17959032}, issn = {1671-4083}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Chemical and Drug Induced Liver Injury/*drug therapy/pathology ; Disease Models, Animal ; Female ; Galactosamine/administration &amp; dosage/*pharmacology ; Lipopolysaccharides/administration &amp; dosage ; Mice ; Mice, Inbred Strains ; Nitric Oxide/biosynthesis ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {AIM: To investigate the effects of N-acetylcysteine on D-galactosamine (GalN)/ lipopolysaccharide (LPS)-induced apoptotic liver injury in mice.<br><br>METHODS: When given together with a low dose of LPS, GalN highly sensitizes animals to produce apoptotic liver injury with severe hepatic congestion, resulting in rapid death. In the GalN/LPS model, TNF-alpha is the major mediator leading to apoptotic liver injury. Reactive oxygen species (ROS) are involved in GalN-induced sensitization to TNF-alpha-evoked hepatocyte apoptosis. N-acetylcysteine (NAC) is an antioxidant and a glutathione (GSH) precursor. In this study, we investigated the effects of NAC on LPS-induced apoptotic liver injury in GalN-sensitized mice.<br><br>RESULTS: Pretreatment with NAC significantly reduced GalN/LPS-induced elevation of serum alanine aminotransferase levels. In parallel, GalN/LPS-induced hepatic necrosis and congestion were obviously improved by NAC. Furthermore, NAC pretreatment significantly alleviated GalN/LPS-induced hepatic apoptosis, measured by the inhibition of hepatic caspase-3 activity and attenuation of DNA laddering. NAC pretreatment had no effect on LPS-evoked nitric oxide production in GalN-sensitized mice. Increases in serum TNF-alpha concentration, which were observed in GalN/LPS-treated mice, were not significantly reduced by NAC. Although NAC pretreatment significantly alleviated LPS-induced hepatic GSH depletion, DL-buthionine-(SR)-sulfoximine, an inhibitor of GSH synthesis, did not influence the protective effect of NAC on GalN/LPS-induced apoptotic liver injury.<br><br>CONCLUSION: NAC attenuates GalN/LPS-induced apoptotic liver injury via its strong ROS scavenging and anti-apoptotic effects.}, }
@article {pmid17952457, year = {2008}, author = {Wang, X and Ma, Y and Huang, C and Wan, Q and Li, N and Bi, Y}, title = {Glucose-6-phosphate dehydrogenase plays a central role in modulating reduced glutathione levels in reed callus under salt stress.}, journal = {Planta}, volume = {227}, number = {3}, pages = {611-623}, pmid = {17952457}, issn = {0032-0935}, mesh = {Acetylcysteine/metabolism ; *Adaptation, Physiological ; Blotting, Western ; Buthionine Sulfoximine/metabolism ; Glucosephosphate Dehydrogenase/*metabolism ; Glutathione/*metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Hydrogen Peroxide/metabolism ; Intracellular Space/metabolism ; Ions/metabolism ; Poaceae/*enzymology/growth &amp; development/metabolism ; *Salinity ; Sodium Chloride/metabolism ; Wetlands ; }, abstract = {In the present study, we investigated the role of glucose-6-phosphate dehydrogenase (G6PDH) in regulating the levels of reduced form of glutathione (GSH) to the tolerance of calli from two reed ecotypes, Phragmites communis Trin. dune reed (DR) and swamp reed (SR), in a long-term salt stress. G6PDH activity was higher in SR callus than that of DR callus under 50-150 mM NaCl treatments. In contrast, at higher NaCl concentrations (300-600 mM), G6PDH activity was lower in SR callus. A similar profile was observed in GSH contents, glutathione reductase (GR) and glutathione peroxidase (GPX) activities in both salt-stressed calli. After G6PDH activity and expression were reduced in glycerol treatments, GSH contents and GR and GPX activity decreased strongly in both calli. Simultaneously, NaCl-induced hydrogen peroxide (H2O2) accumulation was also abolished. Exogenous application of H2O2 increased G6PDH, GR, and GPX activities and GSH contents in the control conditions and glycerol treatment. Diphenylene iodonium (DPI), a plasma membrane (PM) NADPH oxidase inhibitor, which counteracted NaCl-induced H(2)O(2) accumulation, decreased these enzymes activities and GSH contents. Furthermore, exogenous application of H2O2 abolished the N-acetyl-L: -cysteine (NAC)-induced decrease in G6PDH activity, and DPI suppressed the effect of buthionine sulfoximine (BSO) on induction of G6PDH activity. Western-blot analyses showed that G6PDH expression was stimulated by NaCl and H2O2, and blocked by DPI in DR callus. Taken together, G6PDH activity involved in GSH maintenance and H2O2 accumulation under salt stress. And H2O2 regulated G6PDH, GR, and GPX activities to maintain GSH levels. In the process, G6PDH plays a central role.}, }
@article {pmid17951366, year = {2008}, author = {Li, D and Yang, C and Chen, Y and Tian, J and Liu, L and Dai, Q and Wan, X and Xie, Z}, title = {Identification of a PKCepsilon-dependent regulation of myocardial contraction by epicatechin-3-gallate.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {294}, number = {1}, pages = {H345-53}, doi = {10.1152/ajpheart.00785.2007}, pmid = {17951366}, issn = {0363-6135}, support = {HL 36573/HL/NHLBI NIH HHS/United States ; HL 67963/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Alkaloids/pharmacology ; Animals ; Antioxidants/pharmacology ; Benzophenanthridines/pharmacology ; Biflavonoids/pharmacology ; Calcium/metabolism ; Cardiotonic Agents/*pharmacology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Activation ; Gallic Acid/analogs &amp; derivatives/pharmacology ; In Vitro Techniques ; Myocardial Contraction/*drug effects ; Myocardium/*enzymology ; Myocytes, Cardiac/*drug effects/enzymology ; Peptides/pharmacology ; Plant Extracts/pharmacology ; Protein Kinase C-epsilon/antagonists &amp; inhibitors/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; *Tea/chemistry ; Type C Phospholipases/metabolism ; }, abstract = {In this study, the effects of tea catechins and tea theaflavins on myocardial contraction were examined in isolated rat hearts using a Langendorff-perfusion system. We found that both tea catechins and theaflavins had positive inotropic effects on the myocardium. Of the tested chemicals, epicatechin-3-gallate (ECG) and theaflavin-3,3'-digallate (TF(4)) appear to be the most effective tea catechin and theaflavin, respectively. Further studies of ECG-induced positive inotropy revealed the following insights. First, unlike digitalis drugs, ECG had no effect on intracellular Ca(2+) level in cultured adult cardiac myocytes. Second, it activated PKCepsilon, but not PKCalpha, in the isolated hearts as well as in cultured cells. Neither a phospholipase C (PLC) inhibitor (U73122) nor the antioxidant N-acetyl cysteine (NAC) affected the ECG-induced activation of PKCepsilon. Third, inhibition of PKCepsilon by either chelerythrine chloride (CHE) or PKCepsilon translocation inhibitor peptide (TIP) caused a partial reduction of ECG-induced increases in myocardial contraction. Moreover, NAC was also effective in reducing the effects of ECG on myocardial contraction. Finally, pretreatment of the heart with both CHE and NAC completely abolished ECG-induced inotropic effects on the heart. Together, these findings indicate that ECG can regulate myocardial contractility via a novel PKCepsilon-dependent signaling pathway.}, }
@article {pmid17950515, year = {2008}, author = {Lin, S and Fujii, M and Hou, DX}, title = {Molecular mechanism of apoptosis induced by schizandrae-derived lignans in human leukemia HL-60 cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {46}, number = {2}, pages = {590-597}, doi = {10.1016/j.fct.2007.08.048}, pmid = {17950515}, issn = {0278-6915}, mesh = {Apoptosis/*drug effects ; Caspase 3/drug effects/metabolism ; Cell Survival/*drug effects ; Cyclooctanes/isolation &amp; purification/*pharmacology ; DNA Fragmentation/drug effects ; HL-60 Cells ; Humans ; Lignans/isolation &amp; purification/*pharmacology ; Molecular Biology ; Phytotherapy/*methods ; Plant Preparations/isolation &amp; purification/*pharmacology ; Polycyclic Compounds/isolation &amp; purification/*pharmacology ; *Schisandra ; Structure-Activity Relationship ; }, abstract = {Schizandrae chinensis, a traditional Chinese medicine herb, has been used to treat hepatitis B disease in Chinese hospital clinic. We have isolated two bioactive compounds, deoxyschizandrin and gamma-schizandrin, from S. chinensis. In the present, we reported that deoxyschizandrin and gamma-schizandrin could induce apoptosis in human promyelocytic leukemia cells (HL-60), as characterized by DNA fragmentation and poly (ADP) ribose polymerase (PARP) cleavage. Further molecular analysis showed that deoxyschizandrin and gamma-schizandrin caused the loss of mitochondrial membrane potential (DeltaPsim), cytochrome c release from mitochondrion to cytosol, truncation of Bid protein, and activation of caspase-3 and -9. However, they did not increase the intracellular level of reactive oxygen species (ROS). Antioxidants such as N-acetyl cysteine (NAC) and catalase did not block the apoptosis induced by deoxyschizandrin or gamma-schizandrin. These findings suggest that deoxyschizandrin and gamma-schizandrin-induced apoptosis in HL-60 cells involved ROS-independent mitochondrial dysfunction pathway.}, }
@article {pmid17950393, year = {2008}, author = {Wu, HY and Chu, RM and Wang, CC and Lee, CY and Lin, SH and Jan, TR}, title = {Cannabidiol-induced apoptosis in primary lymphocytes is associated with oxidative stress-dependent activation of caspase-8.}, journal = {Toxicology and applied pharmacology}, volume = {226}, number = {3}, pages = {260-270}, doi = {10.1016/j.taap.2007.09.012}, pmid = {17950393}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cannabidiol/*pharmacology ; Caspase 8/*biosynthesis ; Caspase Inhibitors ; Cell Nucleus/drug effects/pathology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Immunologic Factors/*pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Spleen/*drug effects/metabolism/pathology ; }, abstract = {We recently reported that cannabidiol (CBD) exhibited a generalized suppressive effect on T-cell functional activities in splenocytes directly exposed to CBD in vitro or isolated from CBD-administered mice. To investigate the potential mechanisms of CBD effects on T cells, we characterized the pro-apoptotic effect of CBD on primary lymphocytes. The apoptosis of splenocytes was markedly enhanced following CBD exposure in a time- and concentration-dependent manner, as evidenced by nuclear hypodiploidity and DNA strand breaks. Exposure of splenocytes to CBD elicited an early production of reactive oxygen species (ROS) with the peak response at 1 h post CBD treatment. In parallel with the ROS production, a gradual diminishment in the cellular glutathione (GSH) content was detected in CBD-treated splenocytes. Both CBD-mediated ROS production and GSH diminishment were remarkably attenuated by the presence of N-acetyl-L-cysteine (NAC), a thiol antioxidant. In addition, CBD treatment significantly stimulated the activation of caspase-8, which was abrogated in the presence of NAC or GSH. Pretreatment of splenocytes with a cell-permeable inhibitor for caspase-8 significantly attenuated, in a concentration-dependent manner, CBD-mediated apoptosis, but not ROS production. Collectively, the present study demonstrated that the apoptotic effect of CBD in primary lymphocytes is closely associated with oxidative stress-dependent activation of caspase-8.}, }
@article {pmid17950327, year = {2008}, author = {Toklu, HZ and Tunali Akbay, T and Velioglu-Ogunc, A and Ercan, F and Gedik, N and Keyer-Uysal, M and Sener, G}, title = {Silymarin, the antioxidant component of Silybum marianum, prevents sepsis-induced acute lung and brain injury.}, journal = {The Journal of surgical research}, volume = {145}, number = {2}, pages = {214-222}, doi = {10.1016/j.jss.2007.03.072}, pmid = {17950327}, issn = {0022-4804}, mesh = {Acridines ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/*pharmacology ; Brain/metabolism/pathology ; Brain Diseases/etiology/pathology/*prevention &amp; control ; Female ; Glutathione/metabolism ; L-Lactate Dehydrogenase/blood ; Luminescent Agents ; Luminol ; Male ; *Silybum marianum ; Peroxidase/metabolism ; Pulmonary Alveoli/metabolism/pathology ; Rats ; Rats, Wistar ; Respiratory Distress Syndrome/etiology/pathology/*prevention &amp; control ; Sepsis/complications/*drug therapy/pathology ; Silymarin/*pharmacology ; Survival Rate ; Thromboplastin/metabolism ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: Sepsis is associated with enhanced generation of reactive oxygen species, which leads to multiple organ dysfunctions. Based on the potent antioxidant effects of silymarin, we investigated the putative protective role of silymarin against sepsis-induced oxidative damage in lung and brain tissues.<br><br>MATERIALS AND METHODS: Sepsis was induced by cecal ligation and perforation (CLP). Sham and CLP groups received either vehicle or silymarin (50 mg/kg, p.o.) or 150 mg/kg i.p. N-acetylcysteine (NAC) for 10 days prior and immediately after the operation. Six hours after the surgery, rats were decapitated and blood was collected for the measurement of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta [IL-1 beta], and IL-6) levels, lactate dehydrogenase activity, and total antioxidant capacity. Lung and brain samples were taken for the measurement of malondialdehyde and glutathione levels, myeloperoxidase activity, thromboplastic activity, and also for histological assessment. Formation of reactive oxygen species in tissue samples was monitored by using chemiluminescence technique with luminol and lusigenin probe.<br><br>RESULTS: Sepsis increased serum TNF-alpha, IL-1 beta, IL-6 levels, and lactate dehydrogenase activity and decreased total antioxidant capacity. On the other hand, tissue glutathione levels were decreased while malondialdehyde levels and myeloperoxidase activity were increased in both the lung and the brain tissues due to CLP. Furthermore, luminol and lucigenin chemiluminescence were significantly increased in the CLP group, indicating the presence of the oxidative damage. Silymarine and NAC treatment reversed these biochemical parameters and preserved tissue morphology as evidenced by histological evaluation.<br><br>CONCLUSIONS: Silymarin, like NAC, reduced sepsis-induced remote organ injury, at least in part, through its ability to balance oxidant-antioxidant status, to inhibit neutrophil infiltration, and to regulate the release of inflammatory mediators.}, }
@article {pmid17941913, year = {2007}, author = {Springer, J and Groneberg, DA and Dinh, QT and Quarcoo, D and Hamelmann, E and Braun-Dullaeus, RC and Geppetti, P and Anker, SD and Fischer, A}, title = {Neurokinin-1 receptor activation induces reactive oxygen species and epithelial damage in allergic airway inflammation.}, journal = {Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology}, volume = {37}, number = {12}, pages = {1788-1797}, doi = {10.1111/j.1365-2222.2007.02851.x}, pmid = {17941913}, issn = {1365-2222}, mesh = {Animals ; Cell Cycle Proteins/metabolism ; Epithelial Cells/*metabolism ; Hypersensitivity/*metabolism/*pathology ; Immunohistochemistry ; Mice ; Mice, Inbred BALB C ; Pneumonia/*metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Receptors, Neurokinin-1/*metabolism ; }, abstract = {BACKGROUND: An induction of reactive oxygen species (ROS) is characteristic for inflammation but the exact pathways have not been identified for allergic airway diseases so far.<br><br>OBJECTIVE: The aim of this study was to characterize the role of the tachykinin NK-1 receptor on ROS production during allergen challenge and subsequent inflammation and remodelling.<br><br>METHODS: Precision-cut lung slices of ovalbumin (OVA)-sensitized mice were cultivated and ROS-generation in response to OVA challenge (10 microg/mL) was examined by the 2',7'-dichloroflourescein-diacetate method. Long-term ROS effects on epithelial proliferation were investigated by 5-bromo-2'-deoxyuridine incorporation (72 h). In vivo, the results were validated in OVA-sensitized animals which were treated intra-nasally with either placebo, the tachykinin neurokinin 1 (NK-1) receptor antagonist SR 140333 or the anti-oxidant N-acetylcystein (NAC) before allergen challenge. Inflammatory infiltration and remodelling were assessed 48 h after allergen challenge.<br><br>RESULTS: ROS generation was increased by 3.7-fold, which was inhibited by SR 140333. [Sar(9),Met(11)(O(2))]-Substance P (5 nM) caused a tachykinin NK-1 receptor-dependent fourfold increase in ROS generation. Epithelial proliferation was decreased by 68% by incubation with [Sar(9),Met(11)(O(2))]-SP over 72 h. In-vivo, treatment with SR 140333 and NAC reduced epithelial damage (91.4% and 76.8% vs. placebo, respectively, P<0.01) and goblet cell hyperplasia (67.4% and 50.1% vs. placebo, respectively, P<0.05), and decreased inflammatory cell influx (65.3% and 45.3% vs. placebo, respectively, P<0.01).<br><br>CONCLUSION: Allergen challenge induces ROS in a tachykinin NK-1 receptor-dependent manner. Inhibition of the tachykinin NK-1 receptor reduces epithelial damage and subsequent remodelling in vivo. Therefore, patients may possibly benefit from treatment regime that includes radical scavengers or tachykinin NK-1 receptor antagonists.}, }
@article {pmid17941088, year = {2008}, author = {Choudhary, R and Baker, KM and Pan, J}, title = {All-trans retinoic acid prevents angiotensin II- and mechanical stretch-induced reactive oxygen species generation and cardiomyocyte apoptosis.}, journal = {Journal of cellular physiology}, volume = {215}, number = {1}, pages = {172-181}, doi = {10.1002/jcp.21297}, pmid = {17941088}, issn = {1097-4652}, mesh = {Angiotensin II/*antagonists &amp; inhibitors/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cells, Cultured ; Cytoprotection/drug effects ; Hydrogen Peroxide/pharmacology ; Mitochondria/drug effects/metabolism ; Myocytes, Cardiac/*cytology/*drug effects ; NADPH Oxidases/antagonists &amp; inhibitors ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Retinoid X Receptors/metabolism ; Stress, Mechanical ; Tretinoin/*pharmacology ; }, abstract = {Cardiomyocyte apoptosis has an important role in the transition from compensatory cardiac remodeling to heart failure. All-trans retinoic acid (RA), a bioactive vitamin A derivative, prevents stretch- and angiotensin II (Ang II)-induced cardiac hypertrophy. However, the anti-apoptotic potential of RA in the heart remains unexplored. Here, we demonstrate that stretch- and Ang II-induced apoptosis is prevented by RA in neonatal cardiomyocytes. RA improved mitochondrial function by inhibiting the stretch- and Ang II-induced reduction in mitochondrial membrane potential, cytochrome c release and by increasing the Bcl2/Bax ratio. RA inhibited stretch- and Ang II-induced intracellular reactive oxygen species (ROS) generation and upregulated the SOD2 level. Hydrogen peroxide-induced increases in the number of TUNEL-positive cells and percentage of Annexin V positive cells, were dose-dependently inhibited by RA. The thiol antioxidant, N-acetyl cysteine (NAC), completely inhibited stretch- and Ang II-induced apoptosis. Using diazoxide (mitochondrial ATP-sensitive K(+) channel opener) and SDS (NADPH oxidase activator), we confirmed that RA suppressed both mitochondrial- and NADPH oxidase-derived ROS. We also observed that both RAR and RXR were involved in preventing Ang II- and stretch-induced ROS production and apoptosis, by using selective retinoid receptor agonists and antagonists. Our data provide the first evidence that RA prevents Ang II and stretch induced apoptosis, by inhibiting ROS generation and increasing the anti-oxidant defense system, suggesting that RA-mediated signaling may provide a new therapeutic target for the prevention of the cardiac remodeling process.}, }
@article {pmid17940892, year = {2008}, author = {Aguiar, AS and Tuon, T and Soares, FS and da Rocha, LG and Silveira, PC and Pinho, RA}, title = {The effect of n-acetylcysteine and deferoxamine on exercise-induced oxidative damage in striatum and hippocampus of mice.}, journal = {Neurochemical research}, volume = {33}, number = {5}, pages = {729-736}, pmid = {17940892}, issn = {0364-3190}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Catalase/metabolism ; Corpus Striatum/*drug effects/enzymology ; Deferoxamine/*pharmacology ; Hippocampus/*drug effects/enzymology ; Lipid Peroxidation ; Male ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; *Physical Conditioning, Animal ; Superoxide Dismutase/metabolism ; }, abstract = {The aim of this study was to analyze the effects of intense exercise on brain redox status, associated with antioxidant supplementation of N-acetylcysteine (NAC), deferoxamine (DFX) or a combination of both. Seventy-two C57BL-6 adult male mice were randomly assigned to 8 groups: control, NAC, DFX, NAC plus DFX, exercise, exercise with NAC, exercise with DFX, and exercise with NAC plus DFX. They were given antioxidant supplementation, exercise training on a treadmill for 12 weeks, and sacrificed 48 h after the last exercise session. Training significantly increased (P < 0.05) soleus citrate synthase (CS) activity when compared to control. Blood lactate levels classified the exercise as intense. Exercise significantly increased (P < 0.05) oxidation of biomolecules and superoxide dismutase activity in striatum and hippocampus. Training significantly increased (P < 0.05) catalase activity in striatum. NAC and DFX supplementation significantly protected (P < 0.05) against oxidative damage. These results indicate intense exercise as oxidant and NAC and DFX as antioxidant to the hippocampus and the striatum.}, }
@article {pmid17940358, year = {2007}, author = {Payabvash, S and Salmasi, AH and Kiumehr, S and Tavangar, SM and Nourbakhsh, B and Faghihi, SH and Dehpour, AR}, title = {Salutary effects of N-acetylcysteine on apoptotic damage in a rat model of testicular torsion.}, journal = {Urologia internationalis}, volume = {79}, number = {3}, pages = {248-254}, doi = {10.1159/000107958}, pmid = {17940358}, issn = {1423-0399}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Catalase/metabolism ; Disease Models, Animal ; Drug Administration Schedule ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation/drug effects ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/etiology/metabolism/pathology/*prevention &amp; control ; Spermatic Cord Torsion/complications/*drug therapy/metabolism/pathology ; Spermatozoa/*drug effects/pathology ; Superoxide Dismutase/metabolism ; Testis/*drug effects/enzymology/metabolism/pathology ; }, abstract = {INTRODUCTION: Numerous studies performed in recent years have shown protective effects of N-acetylcysteine (NAC) on cardiac and renal tissue damage following ischemia/reperfusion injury. We assessed the effectiveness of systemic administration of NAC, at a therapeutic dose, in a rat model of a 1-hour 720-degree testicular torsion/detorsion.<br><br>MATERIALS AND METHODS: Sprague-Dawley rats were divided into five groups, 14 animals in each: group 1 animals underwent sham operation as the control group; group 2 rats underwent torsion/detorsion and received saline injection, and the animals in groups 3, 4, and 5 received intraperitoneal injections of 150 mg/kg NAC 30 min before torsion, after torsion, and after detorsion, respectively. Markers of oxidative stress as well as germ cell apoptosis indices were assessed 4 and 24 h after detorsion, respectively.<br><br>RESULTS: The apoptosis indices were significantly higher in group 2 as compared with the control group. Four hours after detorsion, the testicular level of lipid peroxidation was significantly increased, and antioxidant enzyme activities were significantly decreased in group 2 as compared with the controls. Administration of NAC either 30 min before or after torsion (groups 3 and 4) significantly improved the germ cell apoptosis indices and oxidant/antioxidant balance. Administration of NAC after detorsion had no significant effect on biochemical markers or germ cell apoptosis.<br><br>CONCLUSION: Administration of NAC prior to torsion or detorsion, but not after detorsion, induces protective effects against ischemia/reperfusion injury in a rat model of testicular torsion.}, }
@article {pmid17936751, year = {2007}, author = {Boudreau, RT and Conrad, DM and Hoskin, DW}, title = {Differential involvement of reactive oxygen species in apoptosis caused by the inhibition of protein phosphatase 2A in Jurkat and CCRF-CEM human T-leukemia cells.}, journal = {Experimental and molecular pathology}, volume = {83}, number = {3}, pages = {347-356}, doi = {10.1016/j.yexmp.2007.09.003}, pmid = {17936751}, issn = {0014-4800}, mesh = {Animals ; Antioxidants/metabolism ; Apoptosis/*physiology ; Caspase 3/metabolism ; DNA Fragmentation ; Enzyme Activation ; Enzyme Inhibitors/metabolism ; Humans ; Jurkat Cells ; Leukemia/*metabolism ; Leukemia, T-Cell/*metabolism ; Membrane Potentials/physiology ; Okadaic Acid/metabolism ; Protein Phosphatase 2/antagonists &amp; inhibitors/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {A better understanding of dysregulated signaling pathways in cancer cells may suggest novel strategies to prevent tumor development and/or progression. Here we show that Jurkat and CCRF-CEM human T-leukemia cell lines were more sensitive than normal human T cells to the cytotoxic effect of inhibiting protein phosphatase 2A (PP2A). Inhibition of PP2A by okadaic acid (OA) caused T-leukemia cells to die by apoptosis, as indicated by DNA fragmentation, caspase-3 activation, loss of mitochondrial membrane potential (DeltaPsi(m)), and changes in nuclear morphology that were consistent with apoptosis. PP2A might therefore be a useful intracellular target for the treatment of T cell-derived leukemias. We also observed that reactive oxygen species (ROS) were generated in response to PP2A inhibition in T-leukemia cells. However, loss of DeltaPsi(m) that resulted from PP2A inhibition was not prevented by exogenous antioxidants (glutathione and N-acetyl-cysteine), indicating that OA-induced changes in mitochondrial membrane permeability were not a consequence of ROS production. Moreover, exogenous antioxidants protected CCRF-CEM T-leukemia cells from apoptosis caused by PP2A inhibition but failed to prevent OA-induced apoptosis in Jurkat T-leukemia cells, indicating a differential role for ROS in apoptosis caused by PP2A inhibition in two different human T-leukemia cell lines.}, }
@article {pmid17936662, year = {2008}, author = {Conover, CA and Harrington, SC and Bale, LK}, title = {Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells.}, journal = {Growth hormone &amp; IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society}, volume = {18}, number = {3}, pages = {213-220}, pmid = {17936662}, issn = {1096-6374}, support = {R01 HL074871/HL/NHLBI NIH HHS/United States ; HL074871/HL/NHLBI NIH HHS/United States ; R01 HL074871-04/HL/NHLBI NIH HHS/United States ; R01 AG028141/AG/NIA NIH HHS/United States ; R01 HL074871-01/HL/NHLBI NIH HHS/United States ; R01 HL074871-02/HL/NHLBI NIH HHS/United States ; R01 HL074871-03/HL/NHLBI NIH HHS/United States ; }, mesh = {Cells, Cultured ; Coronary Vessels/*cytology ; Cytokines/pharmacology ; Endothelial Cells/drug effects/*enzymology ; *Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Intercellular Signaling Peptides and Proteins/pharmacology ; Lipoproteins, LDL/pharmacology ; Myocytes, Smooth Muscle/drug effects/*enzymology ; Pregnancy-Associated Plasma Protein-A/genetics/*metabolism ; }, abstract = {BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A), a metalloproteinase that serves to modulate local insulin-like growth factor (IGF) action, is upregulated in atherosclerotic plaque. However, little is known about the cellular mechanisms underlying this elevated PAPP-A.<br><br>OBJECTIVE: To continue study of PAPP-A expression and its regulation in human vascular cells, with a focus on endothelial cells.<br><br>DESIGN: Primary cultures of human coronary artery endothelial cells (ECs) were treated without and with cytokines, growth factors, or low density lipoprotein (LDL). PAPP-A mRNA, protein, and protease activity were assessed using real-time PCR, ultra-sensitive PAPP-A ELISA and cell-free proteolysis of IGF binding protein (IGFBP-4), respectively. In addition, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), monocyte chemotactic protein (MCP-1), IGF-I, IGF-I receptor, and IGFBP-4 and -5 mRNA expression levels were determined.<br><br>RESULTS: ECs in culture show little basal PAPP-A expression. The pro-inflammatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-beta, stimulated PAPP-A expression (TNF-alpha>>IL-1beta), whereas there was no effect of IL-6, transforming growth factor-beta, IGF-I, insulin, fibroblast growth factor or epidermal growth factor in these cells. Stimulation of PAPP-A expression by TNF-alpha was associated with significantly increased VCAM, ICAM, and MCP-1 expression but without major changes in other IGF system components. TNF-alpha-induced VCAM, ICAM, and MCP-1 expression (4h) preceded PAPP-A expression (24h). The anti-oxidant, N-acetyl cysteine, inhibited TNF-alpha-induced PAPP-A expression without altering the induction in VCAM, ICAM, and MCP-1. Treatment with native or oxidized LDL had no effect on PAPP-A expression in ECs. Comparative results in human coronary smooth muscle cells indicated qualitative and quantitative differences in PAPP-A expression and regulation between the two vascular cell types.<br><br>CONCLUSIONS: Human coronary artery ECs express PAPP-A mRNA and functional protein when activated by the pro-inflammatory cytokine, TNF-alpha. This study complements work on PAPP-A expression in human coronary artery SMCs and human monocyte-derived macrophages and suggests an interactive model of PAPP-A regulation and action in human atherosclerotic plaque.}, }
@article {pmid17936186, year = {2007}, author = {Paranjpe, A and Cacalano, NA and Hume, WR and Jewett, A}, title = {N-acetylcysteine protects dental pulp stromal cells from HEMA-induced apoptosis by inducing differentiation of the cells.}, journal = {Free radical biology &amp; medicine}, volume = {43}, number = {10}, pages = {1394-1408}, pmid = {17936186}, issn = {0891-5849}, support = {R01 DE010331-08/DE/NIDCR NIH HHS/United States ; R01-10331//PHS HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Alkaline Phosphatase/analysis ; Apoptosis/*drug effects ; Ascorbic Acid/pharmacology ; Cell Differentiation/*drug effects/genetics ; Cell Proliferation ; Cytoprotection ; Dental Pulp/cytology/*drug effects/metabolism ; Free Radical Scavengers/*pharmacology ; Gene Expression/drug effects ; Humans ; Methacrylates/*toxicity ; NF-kappa B/metabolism ; Stromal Cells/cytology/drug effects ; Vascular Endothelial Growth Factor A/metabolism ; Vitamin E/pharmacology ; }, abstract = {Resin-based materials are now widely used in dental restorations. Although the use of these materials is aesthetically appealing to patients, it carries the risk of local and systemic adverse effects. The potential risks are direct damage to the cells and induction of immune-based hypersensitivity reactions. Dental pulp stromal cells (DPSCs) and oral keratinocytes are the major cell types which may come in contact with dental resins such as 2-hydroxyethyl methacrylate (HEMA) after dental restorations. Here we show that N-acetylcysteine (NAC) inhibits HEMA-induced apoptotic cell death and restores the function of DPSCs and oral epithelial cells. NAC inhibits HEMA-mediated toxicity through induction of differentiation in DPSCs, because the genes for dentin sialoprotein, osteopontin (OPN), osteocalcin, and alkaline phosphatase, which are induced during differentiation, are also induced by NAC. Unlike NAC, vitamins E and C, which are known antioxidant compounds, failed to prevent either HEMA-mediated cell death or the decrease in VEGF secretion by human DPSCs. More importantly, when added either alone or in combination with HEMA, vitamin E and vitamin C did not increase the gene expression for OPN, and in addition vitamin E inhibited the protective effect of NAC on DPSCs. NAC inhibited the HEMA-mediated decrease in NF-kappaB activity, thus providing a survival mechanism for the cells. Overall, the studies reported in this paper indicate that undifferentiated DPSCs have exquisite sensitivity to HEMA-induced cell death, and their differentiation in response to NAC resulted in an increased NF-kappaB activity, which might have provided the basis for their increased protection from HEMA-mediated functional loss and cell death.}, }
@article {pmid17935707, year = {2008}, author = {Han, YH and Kim, SH and Kim, SZ and Park, WH}, title = {Intracellular GSH levels rather than ROS levels are tightly related to AMA-induced HeLa cell death.}, journal = {Chemico-biological interactions}, volume = {171}, number = {1}, pages = {67-78}, doi = {10.1016/j.cbi.2007.08.011}, pmid = {17935707}, issn = {0009-2797}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Antimycin A/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Caspase 8/metabolism ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chelating Agents/pharmacology ; Cyclic N-Oxides/pharmacology ; Cysteine Proteinase Inhibitors/pharmacology ; Dipeptides/pharmacology ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Glutathione/*metabolism ; HeLa Cells ; Humans ; Hydrogen Peroxide/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Propyl Gallate/pharmacology ; Reactive Oxygen Species/*metabolism ; Spin Labels ; Superoxides/metabolism ; Trimetazidine/pharmacology ; }, abstract = {Antimycin A (AMA) inhibits succinate oxidase and NADH oxidase, and also inhibits mitochondrial electron transport between cytochromes b and c. We investigated the involvement of ROS and GSH in AMA-induced HeLa cell death. AMA increased the intracellular H(2)O(2) and O(2)(*-) levels and reduced the intracellular GSH content. ROS scavengers (Tempol, Tiron, Trimetazidine and NAC) did not down-regulate the production of ROS and inhibit apoptosis in AMA-treated cells. Treatment with NAC and N-propylgallate showing the enhancement of GSH depletion in AMA-treated cells significantly intensified the levels of apoptosis. Calpain inhibitors I and II (calpain inhibitor III) and Ca(2+)-chelating agent (EGTA/AM) significantly reduced H(2)O(2) levels in AMA-treated HeLa cells. However, treatment with calpain inhibitor III intensified the levels of O(2)(*-) in AMA-treated cells. In addition, calpain inhibitor III strongly depleted GSH content with an enhancement of apoptosis in AMA-treated cells. Conclusively, the changes of ROS by AMA were not tightly correlated with apoptosis in HeLa cells. However, intracellular GSH levels are tightly related to AMA-induced cell death.}, }
@article {pmid17934852, year = {2008}, author = {Eşrefoğlu, M and Gül, M and Turan, F}, title = {Comparative effects of several therapatic agents on hepatic damage induced by acute experimental pancreatitis.}, journal = {Digestive diseases and sciences}, volume = {53}, number = {5}, pages = {1303-1310}, pmid = {17934852}, issn = {0163-2116}, mesh = {Acetylcysteine/pharmacology ; Acute Disease ; Animals ; Antioxidants/*pharmacology ; Arginine/pharmacology ; Ascorbic Acid/pharmacology ; Ceruletide ; Female ; Liver Diseases/*drug therapy/*etiology ; Melatonin/pharmacology ; Pancreatitis/*complications/*drug therapy ; Pentoxifylline/pharmacology ; Rats ; Rats, Wistar ; Statistics, Nonparametric ; }, abstract = {PURPOSE: The prognosis of acute pancreatitis (AP) depends upon the degree of pancreatic necrosis and the intensity of multisystem organ failure. The liver contributes to the systemic manifestations of AP by releasing some cytokines. This study was undertaken to examine comparative effects of melatonin, antioxidant mixture containing L(+)-ascorbic acid and N-acetyl cysteine, pentoxifylline and L-arginine on hepatic damage induced by caerulein-pancreatitis.<br><br>RESULTS: The liver specimens of all groups showed histopathological alterations such as hepatocyte necrosis, intracellular vacuolization, vascular congestion, sinusoidal dilatation and inflammatory infiltration. TEM studies revealed vacuole formation, mitochondrial degeneration, lysosome accumulation and necrosis. The mean histopathological score of the caerulein group was significantly different from that of each treatment group.<br><br>CONCLUSION: L-Arginine and antioxidant administration be important for reducing hepatic damage induced by AP. Improvement of hepatic damage, in turn, might be beneficial for the prognosis of AP.}, }
@article {pmid17932440, year = {2007}, author = {Ying-fang, S and Jing-fang, H and Huan-zhang, L and Hao-wen, Q}, title = {Effect of platelet-activating factor on cell proliferation &amp; NF-kappaB activation in airway smooth muscle cells in rats.}, journal = {The Indian journal of medical research}, volume = {126}, number = {2}, pages = {139-145}, pmid = {17932440}, issn = {0971-5916}, mesh = {Animals ; Cell Proliferation/*drug effects ; Cells, Cultured ; Male ; Myocytes, Smooth Muscle/*cytology ; NF-kappa B/*physiology ; Platelet Activating Factor/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Respiratory System/*cytology ; }, abstract = {BACKGROUND &amp; OBJECTIVE: Despite the established pro-inflammatory actions of platelet activating factor (PAF) observed on chronic obstructive pulmonary disease (COPD), its action on airway remodeling has been still unclear. It has been reported that nuclear factor-kappa B (NF-kappaB) activity is necessary for ASMC proliferation. Further, PAF has been identified as the proximal inducer of NF-kappaB. The present study was thus aimed to investigate the effect of PAF on airway smooth muscle cells (ASMC) proliferation and to evaluate the potential role of NF-kappaB in this regulation.<br><br>METHODS: Healthy male Sprague-Dowley rats of 6-8 wk age were used for obtaining ASMCs. 3-(4,5- dimethylthiazole-2-yl)-2,5-diphenyltetrazolium-bromide (MTT) assay was to investigate the effects of PAF on ASMC proliferation and to confirm its optimum concentration for action. Additionally, cell proliferation was also examined using cell cycle assay by flow cytometry and immunocytochemical staining for proliferating cell nuclear antigen (PCNA). And NF-kappaB DNA-binding activity was assayed by electrophoretic mobility shift assay (EMSA).<br><br>RESULTS: PAF stimulated ASMC proliferation with its peak at 100 nM. At this optimum concentration, PAF significantly increased the cell proliferation index (PI) and the PCNA-positive rate in the ASMCs, as well as NF-kappaB DNA- binding activity. Whereas, 20 mM N-acetylcysteine (NAC) pre-treatment effectively blocked all of these events.<br><br>The present findings demonstrated that PAF could promote ASMC proliferation, suggesting its potential involvement in airway remodeling. Our study also suggested the promising action of 20 mM NAC on the alleviation of airway remodeling due to direct inhibition of ASMC proliferation. The involved mechanism would be relevant to the change of NF-kappaB activation in ASMCs.}, }
@article {pmid17929238, year = {2008}, author = {García, A and Morales, P and Arranz, N and Delgado, E and Rafter, J and Haza, AI}, title = {Induction of apoptosis and reactive oxygen species production by N-nitrosopiperidine and N-nitrosodibutylamine in human leukemia cells.}, journal = {Journal of applied toxicology : JAT}, volume = {28}, number = {4}, pages = {455-465}, doi = {10.1002/jat.1295}, pmid = {17929238}, issn = {0260-437X}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Carcinogens/*toxicity ; Cell Shape/drug effects ; Cell Survival/drug effects ; Chromatin Assembly and Disassembly/drug effects ; Dose-Response Relationship, Drug ; Flow Cytometry ; HL-60 Cells ; Humans ; In Situ Nick-End Labeling ; Leukemia/metabolism/*pathology ; Nitrosamines/*toxicity ; Oxidative Stress/*drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; Time Factors ; }, abstract = {N-nitrosopiperidine (NPIP) and N-nitrosodibutylamine (NDBA) belong to a group of N-nitrosamines that are widely distributed in foodstuffs and the occupational environment. In the present study, the human promyelocytic leukemia cell line HL-60, was used to characterize the apoptotic effects of N-nitrosamines, and to examine the production of reactive oxygen species (ROS). Apoptotic cells were identified by (i) chromatin condensation (ii) flow cytometry analysis and (iii) poly(ADP-ribose) polymerase (PARP) cleavage. NPIP and NDBA induced morphological changes consistent with apoptotic events in HL-60 cells. Flow cytometry analysis showed that both N-nitrosamines induced apoptotic cell death in a concentration and time dependent-manner. It was observed that NDBA was stronger than NPIP, since it induced a significant apoptotic cell death after 18 h starting from a concentration of 2 mm, whereas NPIP was effective at 10 mm. Furthermore, PARP was markedly cleaved with 0.5 mm of NDBA and 5 mm of NPIP after treatments for 3 and 18 h, respectively. Finally, the ROS level was found to be elevated after 0.5 h of treatment with both N-nitrosamines. Antioxidant N-acetylcysteine (NAC) completely inhibited the ROS production induced by NPIP and NDBA. However, this action seems not to be associated with the apoptosis because NAC did not block N-nitrosamines-induced apoptosis. The data demonstrate that NPIP and NDBA induce apoptosis and ROS production in HL-60 cells.}, }
@article {pmid17928719, year = {2007}, author = {Kim, M and Murakami, A and Ohigashi, H}, title = {Modifying effects of dietary factors on (-)-epigallocatechin-3-gallate-induced pro-matrix metalloproteinase-7 production in HT-29 human colorectal cancer cells.}, journal = {Bioscience, biotechnology, and biochemistry}, volume = {71}, number = {10}, pages = {2442-2450}, doi = {10.1271/bbb.70213}, pmid = {17928719}, issn = {0916-8451}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Catechin/*analogs &amp; derivatives/pharmacology ; Colorectal Neoplasms/diet therapy/*drug therapy ; Culture Media/analysis/chemistry ; Curcumin/pharmacology ; Gallic Acid/pharmacology ; Genes, Reporter ; HT29 Cells ; Humans ; Hydrogen Peroxide/analysis ; Isothiocyanates/pharmacology ; Luciferases/metabolism ; Matrix Metalloproteinase 7/*biosynthesis ; RNA, Messenger/metabolism ; Transcription Factor AP-1/metabolism ; }, abstract = {(-)-Epigallocatechin-3-gallate (EGCG), one of the main constituents of green tea, has been reported to function as an antioxidant with chemopreventive potential. In contrast, we have recently reported that EGCG enhanced pro-matrix metalloproteinase (MMP)-7 in HT-29 human colon cancer cells via spontaneous superoxide generation. In the present study, we examined the effects of dietary antioxidants on both spontaneous and EGCG-upregulated proMMP-7 production in HT-29 cells. Benzyl isothiocyanate (BITC), curcumin (CUR), gallic acid (GA), and N-acetyl-L-cysteine (NAC) reduced that production, while each alone did not have any effect on spontaneous production. None of the dietary factors suppressed EGCG-induced hydrogen peroxide generation in the media tested, whereas BITC, GA, and NAC inhibited the EGCG-enhanced activator protein (AP)-1 transcription activity by 126%, 77%, and 97%, respectively. Although CUR abolished the EGCG-upregulated MMP-7 mRNA expression, it unexpectedly enhanced the AP-1 activity by 502%, suggesting that this factor may disrupt the MMP-7 mRNA stabilization process. Together, our results indicate that dietary antioxidants modulate EGCG-induced MMP-7 production through different mechanisms.}, }
@article {pmid17922515, year = {2007}, author = {Jung, EJ and Avliyakulov, NK and Boontheung, P and Loo, JA and Nel, AE}, title = {Pro-oxidative DEP chemicals induce heat shock proteins and an unfolding protein response in a bronchial epithelial cell line as determined by DIGE analysis.}, journal = {Proteomics}, volume = {7}, number = {21}, pages = {3906-3918}, doi = {10.1002/pmic.200700377}, pmid = {17922515}, issn = {1615-9853}, support = {R01 ES012053/ES/NIEHS NIH HHS/United States ; R01 ES013432/ES/NIEHS NIH HHS/United States ; U19 AI070453/AI/NIAID NIH HHS/United States ; }, mesh = {Activating Transcription Factor 4/biosynthesis/drug effects ; Base Sequence ; Bronchi/cytology/drug effects/metabolism ; Cell Line ; DNA Primers/genetics ; Electrophoresis, Gel, Two-Dimensional ; Epithelial Cells/drug effects/metabolism ; HSP70 Heat-Shock Proteins/biosynthesis/chemistry/drug effects/genetics ; Heat-Shock Proteins/*biosynthesis/chemistry/*drug effects/genetics ; Humans ; Inflammation Mediators/metabolism ; Oxidants/toxicity ; Oxidative Stress/drug effects ; Protein Array Analysis ; Protein Denaturation/drug effects ; Proteomics ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Vehicle Emissions/*toxicity ; }, abstract = {Ambient particulate matter (PM) induces adverse health effects through the ability of pro-oxidative chemicals to induce the production of oxygen radicals and oxidant injury. Utilizing a proteomics strategy involving 2-D DIGE, immunoblotting, and real-time PCR, we demonstrate that organic diesel exhaust particle (DEP) chemicals induce an unfolding protein response (UPR) and proinflammatory effects in the human bronchial epithelial cell line, BEAS-2B. DIGE and MS showed the induction of at least 14 proteins, among which heat shock protein 70 (HSP70), HSP40, TPR2, and T-complex protein 1 (zeta-subunit) are known to play a role in the UPR. Demonstrating increased HSP70 mRNA expression and nuclear translocation of HSF1, the key transcription factor responsible for HSP expression, further strengthened this notion. Immunoblotting demonstrated increased expression of ATF4, an ER stress-associated transcriptional enhancer responsible for differential protein translation under conditions of ER stress. Finally, the DEP extract induced the expression of IL-6 and IL-8 in the culture supernatant. The role of oxidative stress was demonstrated further by response subtraction in the presence of the thiol antioxidant, N-acetyl cysteine. Our data suggest that pro-oxidative DEP chemicals induce protein unfolding/misfolding that lead to UPR and proinflammatory effects in a cell type that is targeted by PM in the lung.}, }
@article {pmid17920721, year = {2008}, author = {Han, YH and Kim, SZ and Kim, SH and Park, WH}, title = {Apoptosis in pyrogallol-treated Calu-6 cells is correlated with the changes of intracellular GSH levels rather than ROS levels.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {59}, number = {3}, pages = {301-314}, doi = {10.1016/j.lungcan.2007.08.034}, pmid = {17920721}, issn = {0169-5002}, mesh = {Adenocarcinoma/*metabolism ; Analysis of Variance ; Antioxidants/*toxicity ; Apoptosis/*drug effects ; Blotting, Western ; Catalase/metabolism ; Cyclic N-Oxides ; Glutathione/*metabolism ; Humans ; Lung Neoplasms/*metabolism ; Membrane Potentials ; Pyrogallol/*toxicity ; Reactive Oxygen Species/metabolism ; Spin Labels ; Superoxide Dismutase/metabolism ; Tumor Cells, Cultured ; }, abstract = {We investigated the involvement of glutathione (GSH) and reactive oxygen species (ROS) such as H2O2 and O2-* in the deaths of pyrogallol-treated Calu-6 cells. Pyrogallol inhibited the growth of Calu-6 cells with an IC50 of approximately 50 microM. Levels of intracellular H2O2 were not altered or were decreased in pyrogallol-treated Calu-6 cells at 72 h. However, levels of O2*- were increased. Treatment with pyrogallol also reduced the intracellular GSH content. The activity of SOD was down-regulated, but the activity of catalase was up-regulated by pyrogallol at 72 h. ROS scavengers, including Tempol, Tiron, Trimetazidine, and N-acetylcysteine (NAC), did not reduce the levels of the intracellular O2*-. Tempol showing the recovery of GSH depletion in pyrogallol-treated cells significantly prevented apoptosis, while Tiron prevented the loss of mitochondrial transmembrane potential (DeltaPsi(m)). In contrast, treatment with NAC showing an increased effect on O2*- levels and depletion of GSH intensified pyrogallol-induced apoptosis. In addition, treatment with SOD and catalase significantly prevented the loss of mitochondrial transmembrane potential (DeltaPsi(m)) in pyrogallol-treated Calu-6 cells. However, only catalase showing a decreased effect on O2*- levels and depletion of GSH prevented pyrogallol-induced apoptosis. Taken together, apoptosis in pyrogallol-treated Calu-6 cells is correlated with the changes of intracellular GSH levels rather than ROS levels.}, }
@article {pmid17920077, year = {2007}, author = {Noutsopoulos, D and Markopoulos, G and Koliou, M and Dova, L and Vartholomatos, G and Kolettas, E and Tzavaras, T}, title = {Vanadium induces VL30 retrotransposition at an unusually high level: a possible carcinogenesis mechanism.}, journal = {Journal of molecular biology}, volume = {374}, number = {1}, pages = {80-90}, doi = {10.1016/j.jmb.2007.09.012}, pmid = {17920077}, issn = {1089-8638}, mesh = {Animals ; Blotting, Northern ; Blotting, Western ; Cell Line, Transformed ; *Cell Transformation, Viral ; Comet Assay ; Genome, Viral ; Green Fluorescent Proteins/genetics/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; NIH 3T3 Cells ; Oxidative Stress ; Plasmids ; Polymerase Chain Reaction ; RNA-Directed DNA Polymerase/genetics ; Retroelements/genetics/*physiology ; Simian virus 40/*physiology ; Trace Elements/*pharmacology ; Transfection ; *Up-Regulation ; Vanadium/*pharmacology ; }, abstract = {Carcinogenesis by vanadium is thought to occur through induction of DNA-double-strand breaks (DSBs) but its mechanism is not fully understood. We investigated the effect of vanadium on induction of viral-like 30 element (VL30) retrotransposition using a NIH3T3 cell-retrotransposition assay based on a recombinant VL30/EGFP element. Incubation of assay cells with vanadyl sulphate (VOSO(4)) induced retrotransposition frequency in a dose and time-dependent manner, measured by fluorescence-activated cell scanning (FACS) and retrotransposition events were confirmed by UV microscopy and PCR analysis. Among vanadium salts with different valence tested, vanadyl (4+) ions were the most potent retrotransposition inducers. VOSO(4), at 50 muM induced retrotranspositions at an unusually high frequency of up to 0.185 events per cell per generation. VOSO(4), acting at the transcription level, strongly induced VL30 and endogenous reverse transcriptase (enRT) transcripts with maxima at 50 muM and 100 muM of 22 and 18-fold, respectively. VOSO(4)-induced retrotransposition frequency was inhibited by 42% with efavirenz, an inhibitor of enRTs, while paraquat, a DNA-DSBs inducer, had no effect. Furthermore, it was completely abolished with deferoxamine, a metal chelator, while reduced by 75% with N-acetyl-cysteine, a general antioxidant. Remarkably, H(2)O(2) reproduced inducible retrotransposition linking for the first time oxidative stress to induction of retrotransposition. We propose that VOSO(4)-induced VL30 retrotransposition through H(2)O(2) generation may be an alternative mutagenic, DNA-DSBs independent, mechanism leading to carcinogenesis.}, }
@article {pmid17919749, year = {2008}, author = {Chang, Q and Petrash, JM}, title = {Disruption of aldo-keto reductase genes leads to elevated markers of oxidative stress and inositol auxotrophy in Saccharomyces cerevisiae.}, journal = {Biochimica et biophysica acta}, volume = {1783}, number = {2}, pages = {237-245}, pmid = {17919749}, issn = {0006-3002}, support = {P30 EY002687/EY/NEI NIH HHS/United States ; P30 EY002687-29/EY/NEI NIH HHS/United States ; R01 EY005856-22/EY/NEI NIH HHS/United States ; R01 EY005856/EY/NEI NIH HHS/United States ; EY05856/EY/NEI NIH HHS/United States ; EY02687/EY/NEI NIH HHS/United States ; P30 EY002687-28/EY/NEI NIH HHS/United States ; R01 EY005856-23/EY/NEI NIH HHS/United States ; }, mesh = {Alcohol Oxidoreductases/deficiency/*genetics/metabolism ; Aldehyde Reductase ; Aldo-Keto Reductases ; *Autotrophic Processes ; Biomarkers/metabolism ; Cell Nucleus/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; *Gene Deletion ; Gene Expression Regulation, Fungal ; Genes, Fungal ; Glycogen/metabolism ; Inositol/*metabolism ; *Oxidative Stress ; Phenotype ; Protein Transport ; Saccharomyces cerevisiae/cytology/*enzymology/*genetics/growth &amp; development ; Saccharomyces cerevisiae Proteins/metabolism ; Signal Transduction ; Transcription Factors/metabolism ; Transcription, Genetic ; ras Proteins/metabolism ; }, abstract = {A large family of aldo-keto reductases with similar kinetic and structural properties but unknown physiological roles is expressed in the yeast Saccharomyces cerevisiae. Strains with one or two AKR genes disrupted have apparently normal phenotypes, but disruption of at least three AKR genes results in a heat shock phenotype and slow growth in inositol-deficient culture medium (Ino(-)). The present study was carried out to identify metabolic or signaling defects that may underlie phenotypes that emerge in AKR deficient strains. Here we demonstrate that pretreatment of a pentuple AKR null mutant with the anti-oxidative agent N-acetyl-cysteine rescues the heat shock phenotype. This indicates that AKR gene disruption may be associated with defects in oxidative stress response. We observed additional markers of oxidative stress in AKR-deficient strains, including reduced glutathione levels, constitutive nuclear localization of the oxidation-sensitive transcription factor Yap1 and upregulation of a set of Yap1 target genes whose function as a group is primarily involved in response to oxidative stress and redox balance. Genetic analysis of the Ino(-) phenotype of the null mutants showed that defects in transcriptional regulation of the INO1, which encodes for inositol-1-phosphate synthase, can be rescued through ectopic expression of a functional INO1. Taken together, these results suggest potential roles for AKRs in oxidative defense and transcriptional regulation.}, }
@article {pmid17919343, year = {2007}, author = {Storozhevykh, TP and Senilova, YE and Persiyantseva, NA and Pinelis, VG and Pomytkin, IA}, title = {Mitochondrial respiratory chain is involved in insulin-stimulated hydrogen peroxide production and plays an integral role in insulin receptor autophosphorylation in neurons.}, journal = {BMC neuroscience}, volume = {8}, number = {}, pages = {84}, pmid = {17919343}, issn = {1471-2202}, mesh = {Animals ; Cell Respiration/physiology ; Cells, Cultured ; Electron Transport/*physiology ; Hydrogen Peroxide/*metabolism ; Insulin/metabolism/*pharmacology/physiology ; Mitochondria/metabolism ; Neurons/*metabolism/physiology ; Phosphorylation ; Rats ; Rats, Wistar ; Receptor, Insulin/*metabolism ; }, abstract = {BACKGROUND: Accumulated evidence suggests that hydrogen peroxide (H2O2) generated in cells during insulin stimulation plays an integral role in insulin receptor signal transduction. The role of insulin-induced H2O2 in neuronal insulin receptor activation and the origin of insulin-induced H2O2 in neurons remain unclear. The aim of the present study is to test the following hypotheses (1) whether insulin-induced H2O2 is required for insulin receptor autophosphorylation in neurons, and (2) whether mitochondrial respiratory chain is involved in insulin-stimulated H2O2 production, thus playing an integral role in insulin receptor autophosphorylation in neurons.<br><br>RESULTS: Insulin stimulation elicited rapid insulin receptor autophosphorylation accompanied by an increase in H2O2 release from cultured cerebellar granule neurons (CGN). N-acetylcysteine (NAC), a H2O2 scavenger, inhibited both insulin-stimulated H2O2 release and insulin-stimulated autophosphorylation of insulin receptor. Inhibitors of respiratory chain-mediated H2O2 production, malonate and carbonyl cyanide-4-(trifluoromethoxy)-phenylhydrazone (FCCP), inhibited both insulin-stimulated H2O2 release from neurons and insulin-stimulated autophosphorylation of insulin receptor. Dicholine salt of succinic acid, a respiratory substrate, significantly enhanced the effect of suboptimal insulin concentration on the insulin receptor autophosphorylation in CGN.<br><br>CONCLUSION: Results of the present study suggest that insulin-induced H2O2 is required for the enhancement of insulin receptor autophosphorylation in neurons. The mitochondrial respiratory chain is involved in insulin-stimulated H2O2 production, thus playing an integral role in the insulin receptor autophosphorylation in neurons.}, }
@article {pmid17917164, year = {2007}, author = {Moreira, PI and Harris, PL and Zhu, X and Santos, MS and Oliveira, CR and Smith, MA and Perry, G}, title = {Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {12}, number = {2}, pages = {195-206}, doi = {10.3233/jad-2007-12210}, pmid = {17917164}, issn = {1387-2877}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Alzheimer Disease/*drug therapy ; Fibroblasts/*drug effects ; Humans ; Immunohistochemistry ; Mitochondria/*drug effects ; Oxidative Stress/*drug effects ; Thioctic Acid/administration &amp; dosage/*pharmacology ; }, abstract = {In this study, we evaluated the effect of lipoic acid (LA) and N-acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal, N(epsilon)-(carboxymethyl)lysine and heme oxygenase-1] and apoptotic (caspase 9 and Bax) markers in fibroblasts from patients with Alzheimer disease (AD) and age-matched and young controls. AD fibroblasts showed the highest levels of oxidative stress, and the antioxidants, lipoic acid (1 mM) and/or N-acetyl cysteine (100 microM) exerted a protective effect as evidenced by decreases in oxidative stress and apoptotic markers. Furthermore, we observed that the protective effect of LA and NAC was more pronounced when both agents were present simultaneously. AD-type changes could be generated in control fibroblasts using N-methylprotoporphyrin to inhibit cytochrome oxidase assembly indicating that the the oxidative damage observed was associated with mitochondrial dysfunction. The effects of N-methylprotoporphyrine were reversed or attenuated by both lipoic acid and N-acetyl cysteine. These data suggest mitochondria are important in oxidative damage that occurs in AD. As such, antioxidant therapies based on lipoic acid and N-acetyl cysteine supplementation may be promising.}, }
@article {pmid17916759, year = {2008}, author = {Chen, JR and Shankar, K and Nagarajan, S and Badger, TM and Ronis, MJ}, title = {Protective effects of estradiol on ethanol-induced bone loss involve inhibition of reactive oxygen species generation in osteoblasts and downstream activation of the extracellular signal-regulated kinase/signal transducer and activator of transcription 3/receptor activator of nuclear factor-kappaB ligand signaling cascade.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {324}, number = {1}, pages = {50-59}, doi = {10.1124/jpet.107.130351}, pmid = {17916759}, issn = {1521-0103}, support = {R01 AA12928/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Bone Resorption/chemically induced/metabolism/*prevention &amp; control ; Cell Differentiation/drug effects ; Cell Line ; Cells, Cultured ; Estradiol/*pharmacology ; Ethanol/*adverse effects ; Female ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; NADPH Oxidases/metabolism ; Osteoblasts/cytology/*drug effects/metabolism ; Oxidative Stress/drug effects ; RANK Ligand/genetics ; RNA, Messenger/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Skull/cytology ; }, abstract = {Bone loss occurs following chronic ethanol (EtOH) consumption in males and cycling females in part as a result of increased bone resorption. We have demonstrated in vivo that estradiol treatment can reverse this effect. Using osteoclast precursors from bone marrow and osteoblast/preosteoclast coculture, we found that EtOH-induced receptor activator of nuclear factor-kappaB ligand (RANKL) expression in osteoblasts was able to promote osteoclastogenesis. These effects were blocked by pretreatment of cells with either 17beta-estradiol (E(2)) or the anti-oxidant N-acetyl cysteine (NAC). EtOH treatment of stromal osteoblasts increased the intracellular level of reactive oxygen species (ROS). This was associated with induction of NADPH oxidase (NOX) and a downstream signaling cascade involving sustained activation of extracellular signal-regulated kinase (ERK) and activation of signal transducer and activator of transcription 3, resulting in increased gene expression of RANKL. In the presence of EtOH, sustained nuclear ERK translocation >24 h was observed in calvarial osteoblasts and UMR-106 cells transfected with green fluorescent protein-ERK2 plasmid. This was abolished by pretreatment with either E(2) or NAC. NOX subtypes 1, 2, and 4, but not 3, were expressed in stromal osteoblasts. Chemical inhibition of NOX by diphenylene iodonium also reversed the ability of EtOH to phosphorylate ERK and induce RANKL mRNA expression. Down-regulation of EtOH-induced ROS generation in osteoblasts was also observed after treatment with E(2) or NAC. These data suggest that the molecular mechanisms whereby E(2) prevents EtOH-induced bone loss involve interference with ROS generation and cytoplasmic kinase activation.}, }
@article {pmid17914184, year = {2007}, author = {Chan, A and Shea, TB}, title = {Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine on cognitive performance and aggression in normal mice and mice expressing human ApoE4.}, journal = {Neuromolecular medicine}, volume = {9}, number = {3}, pages = {264-269}, pmid = {17914184}, issn = {1535-1084}, mesh = {Acetylcarnitine/*pharmacology ; Acetylcysteine/*pharmacology ; Aggression/*drug effects ; Animals ; Apolipoprotein E4/genetics/*metabolism ; Cognition/*drug effects ; *Dietary Supplements ; Humans ; Mice ; Mice, Transgenic ; Oxidation-Reduction ; S-Adenosylmethionine/*pharmacology ; }, abstract = {In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer's Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels, protects mitochondria, and buffers A beta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents.}, }
@article {pmid17913704, year = {2007}, author = {Defer, N and Azroyan, A and Pecker, F and Pavoine, C}, title = {TNFR1 and TNFR2 signaling interplay in cardiac myocytes.}, journal = {The Journal of biological chemistry}, volume = {282}, number = {49}, pages = {35564-35573}, doi = {10.1074/jbc.M704003200}, pmid = {17913704}, issn = {0021-9258}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies/pharmacology ; Calcium/metabolism ; Calcium Signaling/*drug effects ; Calcium-Binding Proteins/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Chronic Disease ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Free Radical Scavengers/pharmacology ; Heart Failure/metabolism/pathology ; Male ; Myocytes, Cardiac/*metabolism/pathology ; Phospholipases A2, Cytosolic/metabolism ; Phosphorylation/drug effects ; Protein Kinase C/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptors, Tumor Necrosis Factor, Type I/antagonists &amp; inhibitors/*metabolism ; Receptors, Tumor Necrosis Factor, Type II/antagonists &amp; inhibitors/*metabolism ; Ribosomal Protein S6 Kinases, 90-kDa/metabolism ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism/*pharmacology ; }, abstract = {Tumor necrosis factor alpha (TNFalpha) plays a major role in chronic heart failure, signaling through two different receptor subtypes, TNFR1 and TNFR2. Our aim was to further delineate the functional role and signaling pathways related to TNFR1 and TNFR2 in cardiac myocytes. In cardiac myocytes isolated from control rats, TNFalpha induced ROS production, exerted a dual positive and negative action on [Ca(2+)] transient and cell fractional shortening, and altered cell survival. Neutralizing anti-TNFR2 antibodies exacerbated TNFalpha responses on ROS production and cell death, arguing for a major protective role of the TNFR2 pathway. Treatment with either neutralizing anti-TNFR1 antibodies or the glutathione precursor, N-acetylcysteine (NAC), favored the emergence of TNFR2 signaling that mediated a positive effect of TNFalpha on [Ca(2+)] transient and cell fractional shortening. The positive effect of TNFalpha relied on TNFR2-dependent activation of the cPLA(2) activity, independently of serine 505 phosphorylation of the enzyme. Together with cPLA(2) redistribution and AA release, TNFalpha induced a time-dependent phosphorylation of ERK, MSK1, PKCzeta, CaMKII, and phospholamban on the threonine 17 residue. Taken together, our results characterized a TNFR2-dependent signaling and illustrated the close interplay between TNFR1 and TNFR2 pathways in cardiac myocytes. Although apparently predominant, TNFR1-dependent responses were under the yoke of TNFR2, acting as a critical limiting factor. In vivo NAC treatment proved to be a unique tool to selectively neutralize TNFR1-mediated effects of TNFalpha while releasing TNFR2 pathways.}, }
@article {pmid17909806, year = {2008}, author = {Dickey, DT and Muldoon, LL and Doolittle, ND and Peterson, DR and Kraemer, DF and Neuwelt, EA}, title = {Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models.}, journal = {Cancer chemotherapy and pharmacology}, volume = {62}, number = {2}, pages = {235-241}, pmid = {17909806}, issn = {0344-5704}, support = {R01 NS053468/NS/NINDS NIH HHS/United States ; R01 CA137488-15/CA/NCI NIH HHS/United States ; R01 NS034608/NS/NINDS NIH HHS/United States ; R01 NS053468-03/NS/NINDS NIH HHS/United States ; R01 NS044687/NS/NINDS NIH HHS/United States ; R01 CA137488/CA/NCI NIH HHS/United States ; R37 NS044687-26/NS/NINDS NIH HHS/United States ; R01 NS033618/NS/NINDS NIH HHS/United States ; R37 NS044687/NS/NINDS NIH HHS/United States ; }, mesh = {*Acetylcysteine/administration &amp; dosage/pharmacology/therapeutic use ; Administration, Oral ; Animals ; Antineoplastic Agents/*toxicity ; Cisplatin/*toxicity ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; *Free Radical Scavengers/administration &amp; dosage/pharmacology/therapeutic use ; Injections, Intra-Arterial ; Injections, Intraperitoneal ; Injections, Intravenous ; Kidney Diseases/chemically induced/*prevention &amp; control ; Kidney Function Tests ; Rats ; Rats, Long-Evans ; }, abstract = {Dosing and route of administration of N-acetylcysteine (NAC) for protection against cisplatin (CDDP) nephrotoxicity was investigated in rats. Two models of toxicity were tested: a single high dose of CDDP (10 mg/kg intraperitoneally (IP)), and multiple low dose treatments (1 mg/kg IP twice a day for 4 days, 10 days rest, then repeated). NAC (50-1,200 mg/kg) was given to the rats by IP, oral (PO), intravenous (IV) and intra-arterial (IA) routes. Renal toxicity was determined by blood urea nitrogen (BUN) and creatinine (CR) levels 3 days after treatment. Blood collected 15 min after NAC was analyzed for total NAC. Both models of CDDP administration produced renal toxicity. In the single dose CDDP model, NAC 400 mg/kg given IP and PO produced no renal protection as measured by BUN (131.8 +/- 8.2 and 123.3 +/- 8.2, respectively) or CR (2.3 +/- 0.38 and 1.77 +/- 0.21, respectively). IV NAC reduced nephrotoxicity, (BUN 26.3 +/- 6.8, CR 0.47 +/- 0.15). NAC 50 mg/kg IA gave better protection than IV. In the repeated-dose CDDP model, nephrotoxicity was blocked by 800 mg/kg NAC given IV but not IP. Blood concentrations of total NAC showed a dose response after IV NAC, but high dose NAC (1,200 mg/kg) by the PO route gave very low levels of NAC. Thus the protective properties of NAC are affected by the dose and route of administration.}, }
@article {pmid17909563, year = {2008}, author = {Ganguly, N and Giang, PH and Gupta, C and Basu, SK and Siddiqui, I and Salunke, DM and Sharma, P}, title = {Mycobacterium tuberculosis secretory proteins CFP-10, ESAT-6 and the CFP10:ESAT6 complex inhibit lipopolysaccharide-induced NF-kappaB transactivation by downregulation of reactive oxidative species (ROS) production.}, journal = {Immunology and cell biology}, volume = {86}, number = {1}, pages = {98-106}, doi = {10.1038/sj.icb.7100117}, pmid = {17909563}, issn = {0818-9641}, mesh = {Animals ; Antigens, Bacterial/genetics/*metabolism ; Bacterial Proteins/genetics/*metabolism ; Cell Line ; DNA-Binding Proteins/genetics ; Electrophoretic Mobility Shift Assay ; Genes, Reporter ; Lipopolysaccharides/pharmacology ; Macrophages, Peritoneal/immunology/*metabolism/microbiology ; Mice ; Mycobacterium tuberculosis/genetics/*metabolism ; NF-kappa B/antagonists &amp; inhibitors/genetics/*metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Recombinant Fusion Proteins/genetics/*metabolism ; Recombinant Proteins/genetics/metabolism ; Signal Transduction/genetics ; *Transcriptional Activation/drug effects ; Tuberculosis/immunology/*metabolism/pathology ; }, abstract = {Mycobacterium tuberculosis (Mtb) causes death of 2-3 million people annually and is considered one of the most successful intracellular pathogens to persist inside the host macrophage. Recent studies have implicated the role of RD-1 region of Mtb genome in the mycobacterial pathogenesis. The role of RD-1-encoded secretory proteins of Mtb in modulation of macrophage function has not been investigated in detail. Here we show that RD-1 encoded two major secretory proteins, namely, culture filtrate protein-10 kDa (CFP-10) and early secreted antigenic target-6 kDa (ESAT-6), and their 1:1 CFP-10:ESAT6 complex inhibit production of reactive oxidative species (ROS) in RAW264.7 cells. These proteins also downregulated the bacterial lipopolysaccharide (LPS)-induced ROS production, which, in turn, downregulated LPS-induced nuclear factor-kappaB (NF-kappaB) p65 DNA-binding activity, as well as inhibited the NF-kappaB-dependent reporter gene (chloramphenicol acetyl transferase) expression in the treated macrophages. Moreover, addition of N-acetyl cysteine, which is a scavenger of ROS, also inhibited LPS-induced reporter gene expression by scavenging the ROS, thereby preventing NF-kappaB transactivation. These studies indicate that the secretory proteins CFP-10, ESAT-6 and the CFP10:ESAT6 complex of Mtb can inhibit LPS-induced NF-kappaB-dependent gene expression via downregulation of ROS production.}, }
@article {pmid17909450, year = {2007}, author = {Okur, E and Kilinc, M and Yildirim, I and Kilic, MA and Tolun, FI}, title = {Effect of N-acetylcysteine on carboplatin-induced ototoxicity and nitric oxide levels in a rat model.}, journal = {The Laryngoscope}, volume = {117}, number = {12}, pages = {2183-2186}, doi = {10.1097/MLG.0b013e31813e6041}, pmid = {17909450}, issn = {0023-852X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antineoplastic Agents/toxicity ; Biomarkers/metabolism ; Carboplatin/toxicity ; Cochlea/drug effects/*metabolism ; Disease Models, Animal ; Evoked Potentials, Auditory, Brain Stem ; Follow-Up Studies ; Free Radical Scavengers/*therapeutic use ; Glutathione Peroxidase/metabolism ; Hearing Loss, Sensorineural/chemically induced/*metabolism ; Male ; Nitric Oxide/*metabolism ; Rats ; Rats, Sprague-Dawley ; Spectrophotometry ; Treatment Outcome ; }, abstract = {OBJECTIVE: The aim of the present study is to investigate the effect of N-acetylcysteine (NAC) given 30 minutes before carboplatin administration on carboplatin-induced ototoxicity and nitric oxide (NO) levels in a rat model.<br><br>STUDY DESIGN: Animal study.<br><br>METHODS: Eighteen Sprague-Dawley rats were divided into three groups that each contained six animals. Intraperitoneal injection of physiologic saline was performed in group 1 twice with an interval of 30 minutes. Group 2 was treated with a single bolus administration of carboplatin at a dose of 256 mg/kg 30 minutes after the intraperitoneal injection of physiologic saline. Group 3 was treated with a single bolus administration of carboplatin at a dose of 256 mg/kg 30 minutes after the intraperitoneal injection of NAC at a dose of 400 mg/kg. Pretreatment and posttreatment distortion product otoacoustic emissions (DPOAE) were performed in rats from all groups. Then, the animals were sacrificed on the fourth day, and cochlear tissue NO and glutathione peroxidase (GSH-Px) levels were measured.<br><br>RESULTS: The comparison of pre- and posttreatment DPOAE responses did not demonstrate any significant changes for groups 1 and 3. Results of group 2 showed a decrease of the DPOAE amplitude. Cochlear NO levels were significantly higher in rats treated with carboplatin than in controls and in those treated with carboplatin plus NAC (P < .05). Cochlear GSH-Px levels were higher in rats treated with carboplatin plus NAC than in those treated with carboplatin, but the difference did not reach statistical significance (P = .079).<br><br>CONCLUSIONS: The present study showed that carboplatin at higher doses induced hearing loss and increased NO levels in the cochlea of rats. NAC appears to have a protective effect against carboplatin-induced ototoxicity, which may be related to its inhibitory effect on NO production.}, }
@article {pmid17908992, year = {2007}, author = {Cotter, MA and Thomas, J and Cassidy, P and Robinette, K and Jenkins, N and Florell, SR and Leachman, S and Samlowski, WE and Grossman, D}, title = {N-acetylcysteine protects melanocytes against oxidative stress/damage and delays onset of ultraviolet-induced melanoma in mice.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {13}, number = {19}, pages = {5952-5958}, pmid = {17908992}, issn = {1078-0432}, support = {AR050102/AR/NIAMS NIH HHS/United States ; RR17525/RR/NCRR NIH HHS/United States ; R01 AR050102/AR/NIAMS NIH HHS/United States ; R03 CA125761/CA/NCI NIH HHS/United States ; R03 CA125761-02/CA/NCI NIH HHS/United States ; T32 CA093247/CA/NCI NIH HHS/United States ; K23 RR017525/RR/NCRR NIH HHS/United States ; R01 AR050102-04/AR/NIAMS NIH HHS/United States ; CA093247/CA/NCI NIH HHS/United States ; CA125761/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anticarcinogenic Agents/pharmacology ; Humans ; Male ; Melanocytes/*metabolism/*radiation effects ; Melanoma/*drug therapy/*etiology ; Mice ; Mice, Inbred C57BL ; Neoplasms, Radiation-Induced/*drug therapy ; *Oxidative Stress ; Pyrimidine Dimers/chemistry ; Reactive Oxygen Species ; Skin/drug effects/metabolism/radiation effects ; Ultraviolet Rays ; }, abstract = {PURPOSE: UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies. We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UV-induced oxidative stress/damage in vitro and from UV-induced melanoma in vivo.<br><br>EXPERIMENTAL DESIGN: In vitro experiments used the mouse melanocyte line melan-a. For in vivo experiments, mice transgenic for hepatocyte growth factor and survivin, shown previously to develop melanoma following a single neonatal dose of UV irradiation, were given NAC (7 mg/mL; mother's drinking water) transplacentally and through nursing until 2 weeks after birth.<br><br>RESULTS: NAC (1-10 mmol/L) protected melan-a cells from several UV-induced oxidative sequelae, including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine, and depletion of free reduced thiols (primarily glutathione). Delivery of NAC reduced thiol depletion and blocked formation of 8-oxoguanine in mouse skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared with control mice (21 versus 14 weeks; P = 0.0003).<br><br>CONCLUSIONS: Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma and suggest that NAC may be useful as a chemopreventive agent.}, }
@article {pmid17907423, year = {2007}, author = {Beecher, BR and Martin, JA and Pedersen, DR and Heiner, AD and Buckwalter, JA}, title = {Antioxidants block cyclic loading induced chondrocyte death.}, journal = {The Iowa orthopaedic journal}, volume = {27}, number = {}, pages = {1-8}, pmid = {17907423}, issn = {1541-5457}, support = {P50 AR048939/AR/NIAMS NIH HHS/United States ; P50 AR48939/AR/NIAMS NIH HHS/United States ; }, mesh = {Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cartilage, Articular/*cytology/*pathology ; Chondrocytes/*pathology ; Humans ; In Situ Nick-End Labeling ; Lactic Acid/analysis ; Osteoarthritis/physiopathology/prevention &amp; control ; Stress, Mechanical ; Tissue Culture Techniques ; }, abstract = {Articular cartilage in congruous joints benefits from the moderate stresses and strains associated with normal cyclic loading. However, loading of joints with surface incongruities can lead to local stress and strain elevation at "step-off' sites where cartilage is not fully buttressed b ysurrounding matrix. Excessive stresses and strains predicted to occur at such sites may induce apoptosis, a process thought to promote cartilage degeneration and osteoarthritis (OA) through chondrocyte attrition. We hypothesized that the induction of apoptosis is mediated by oxidants, and that antioxidants can reduce elevated stress-induced chondrocyte attrition. To test this we exposed cylindrical cartilage explants from human articular cartilage to radially unconfined cyclic axial compression (3600 cycles, 1 Hz, 50% duty cycle) using two different physiologic loads (2MPa and 5 MPa). We found that 30% of chondrocytes in the superficial zone died within 24 hours of exposure to loading with 5 MPa axial compression, whereas mortality was limited to less than 15% with 2 MPa axial compression. Similarly, lactate accumulation in the medium was suppressed by compression with 5 MPa, but not 2 MPa. Approximately 80% of cell death induced by 5 MPa compression was blocked by pre-incubation of the explants in a variety of anti-oxidants including vitamin E, n-acetyl cysteine (NAC), and a superoxide dismutase mimetic (SOD). SOD and NAC also prevented the suppression of lactate secretion after 5 MPa compression. These observations support the hypothesis that the harmful effects of abnormal cyclic loading are mediated by oxidants and suggest that treatments to prevent OA may include methods of minimizing oxidative damage to chondrocytes.}, }
@article {pmid17907002, year = {2007}, author = {Li, BH and Zhou, YB and Guo, SB and Wang, CB}, title = {Polypeptide from Chlamys farreri inhibits UVB-induced HaCaT cells apoptosis via inhibition CD95 pathway and reactive oxygen species.}, journal = {Free radical research}, volume = {41}, number = {11}, pages = {1224-1232}, doi = {10.1080/10715760701636858}, pmid = {17907002}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/radiation effects ; Cells, Cultured ; Drug Evaluation, Preclinical ; Fas-Associated Death Domain Protein/genetics ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects/radiation effects ; Humans ; Keratinocytes/*drug effects/metabolism/physiology/*radiation effects ; Pectinidae/*chemistry ; Peptides/isolation &amp; purification/*pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects ; Ultraviolet Rays ; fas Receptor/*antagonists &amp; inhibitors/genetics ; }, abstract = {Polypeptide from Chlamys farreri (PCF) is a novel marine active product isolated from gonochoric Chinese scallop Chlamys farreri which has recently been found to be an effective antioxidant. In this study, we assessed the effect of PCF on UVB-induced intracellular signalling of apoptosis in HaCaT cells. Pre-treatment with PCF significantly inhibited UVB-induced apoptosis in HaCaT cells. PCF strongly reduced the intracellular reactive oxygen species (ROS) level followed by inhibiting the release of cytochrome c. The expression of CD95 and Fas-associating protein with death domain (FADD) was eliminated in a dose-dependent manner by PCF pre-treatment in UVB-irradiated HaCaT cells, followed by inhibition of cleavage of procaspase-8, whose activation induced cell apoptosis. Furthermore, pre-treatment with the ROS scavenger N-acetylcysteine (NAC) and the caspase-8 inhibitor z-IETD-fmk was found to effectively prevent UVB-induced apoptosis, suggesting that UVB-induced HaCaT cell apoptosis was partially due to generation of ROS and activation of the caspase-8 pathway. Consequently, the protective effect of PCF against UVB irradiation in HaCaT cells is exerted by suppression of generation of ROS followed by inhibition of cytochrome c release and inactivation of Fas-FADD-caspase-8 pathway, resulting in blockage of UVB-induced apoptosis.}, }
@article {pmid17905400, year = {2007}, author = {Seok, SH and Baek, MW and Lee, HY and Kim, DJ and Na, YR and Noh, KJ and Park, SH and Lee, HK and Lee, BH and Ryu, DY and Park, JH}, title = {Quantitative GFP fluorescence as an indicator of arsenite developmental toxicity in mosaic heat shock protein 70 transgenic zebrafish.}, journal = {Toxicology and applied pharmacology}, volume = {225}, number = {2}, pages = {154-161}, doi = {10.1016/j.taap.2007.07.011}, pmid = {17905400}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Genetically Modified ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Arsenites/administration &amp; dosage/*toxicity ; Biomarkers ; Dose-Response Relationship, Drug ; Embryo, Nonmammalian/drug effects/metabolism ; Environmental Pollutants/administration &amp; dosage/*toxicity ; Fluorescent Dyes/*metabolism ; Gene Expression Regulation, Developmental/drug effects ; Genes, Reporter/drug effects ; Green Fluorescent Proteins/*metabolism ; HSP70 Heat-Shock Proteins/genetics/metabolism ; In Situ Nick-End Labeling ; Mosaicism ; Zebrafish/genetics ; }, abstract = {In transgenic zebrafish (Danio rerio), green fluorescent protein (GFP) is a promising marker for environmental pollutants. In using GFP, one of the obstacles which we faced was how to compare toxicity among different toxicants or among a specific toxicant in different model species with the intensity of GFP expression. Using a fluorescence detection method, we first validated our method for estimating the amount of GFP fluorescence present in transgenic fish, which we used as an indicator of developmental toxicity caused by the well-known toxicant, arsenite. To this end, we developed mosaic transgenic zebrafish with the human heat shock response element (HSE) fused to the enhanced GFP (EGFP) reporter gene to indicate exposure to arsenite. We confirmed that EGFP expression sites correlate with gross morphological disruption caused by arsenite exposure. Arsenite (300.0 microM) caused stronger EGFP fluorescence intensity and quantity than 50.0 microM and 10.0 microM arsenite in our transgenic zebrafish. Furthermore, arsenite-induced apoptosis was demonstrated by TUNEL assay. Apoptosis was inhibited by the antioxidant, N-acetyl-cystein (NAC) in this transgenic zebrafish. The distribution of TUNEL-positive cells in embryonic tissues was correlated with the sites of arsenite toxicity and EGFP expression. The EGFP values quantified using the standard curve equation from the known GFP quantity were consistent with the arsenite-induced EGFP expression pattern and arsenite concentration, indicating that this technique can be a reliable and applicable measurement. In conclusion, we propose that fluorescence-based EGFP quantification in transgenic fish containing the hsp70 promoter-EGFP reporter-gene construct is a useful indicator of development toxicity caused by arsenite.}, }
@article {pmid17904883, year = {2008}, author = {Teixeira, KC and Soares, FS and Rocha, LG and Silveira, PC and Silva, LA and Valença, SS and Dal Pizzol, F and Streck, EL and Pinho, RA}, title = {Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {21}, number = {2}, pages = {309-316}, doi = {10.1016/j.pupt.2007.07.006}, pmid = {17904883}, issn = {1094-5539}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antineoplastic Agents/administration &amp; dosage/*adverse effects ; Antioxidants/pharmacology/*therapeutic use ; Bleomycin/administration &amp; dosage/*adverse effects ; Catalase/metabolism ; Deferoxamine/pharmacology/*therapeutic use ; Drug Therapy, Combination ; Fibrosis ; Iron Chelating Agents/pharmacology/*therapeutic use ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; Lung/drug effects/metabolism/pathology ; Lung Diseases/chemically induced/metabolism/pathology/*prevention &amp; control ; Male ; Mice ; Mice, Inbred Strains ; Oxidative Stress/*drug effects ; Superoxide Dismutase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Reactive oxygen species (ROS) play an important role in the pathogenesis of pulmonary injury and antioxidant therapy may be useful with impaired oxidative defense mechanism. This study examines the effect of N-acetylcysteine (NAC) and deferoxamine (DFX) on inflammatory indicators and oxidative stress in the lungs of mice exposed to bleomycin (BLM). The animals received endotracheally a single dose of BLM (2.5 U/kg body weight dissolved in 0.25 ml of 0.9% NaCl) or saline (0.9% NaCl) and were divided into eight groups (n=8): saline; BLM; saline+NAC; BLM+NAC; saline+DFX; BLM+DFX; saline+NAC+DFX; BLM+NAC+DFX. Treatments with NAC (20mg/kg) or DFX (30 mg/kg) were administered for 60 days after BLM exposure. Lactate dehydrogenase (LDH) activity and total cell count, neutrophil and protein concentration were determined in the bronchoalveolar lavage fluid (BALF). Lipid peroxidation thiobarbituric acid-reactive species (TBARS), oxidative protein damage (carbonyl contents), and catalase and superoxide dismutase activities were determined in the lung tissue. BLM administration resulted in lung lesion as determinated lung histology, which is almost completely prevented by NAC plus DFX. The results of total cell counts and neutrophils and LDH increased after BLM exposure and were reduced with NAC. DFX and NAC plus DFX also caused a significant decrease of LDH activity. The increased malondialdehyde equivalents and carbonyl contents in lung tissue produced by BLM were also prevented by NAC plus DFX. However, the isolated use of NAC increased lipid peroxidation. SOD activity increased after BLM exposure only in the group treated with DFX and catalase activity not was altered in the presence of BLM. Data presented here indicates that the isolated use of NAC had limited effects on BLM-induced pulmonary oxidative stress in mice. The use of DFX improves the defense response and in association with NAC may be a good alternative in the treatment or prevention of diseases that have ROS and iron involved in their pathogenesis.}, }
@article {pmid17904098, year = {2007}, author = {Kim, BM and Chung, HW}, title = {Hypoxia/reoxygenation induces apoptosis through a ROS-mediated caspase-8/Bid/Bax pathway in human lymphocytes.}, journal = {Biochemical and biophysical research communications}, volume = {363}, number = {3}, pages = {745-750}, doi = {10.1016/j.bbrc.2007.09.024}, pmid = {17904098}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis/*drug effects/physiology ; Apoptosis Regulatory Proteins/*metabolism ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Blotting, Western ; Caspase 3/metabolism ; Caspase 8/metabolism ; Caspase 9/metabolism ; Caspase Inhibitors ; Cell Hypoxia/physiology ; Cells, Cultured ; Cysteine Proteinase Inhibitors/pharmacology ; Enzyme Activation/drug effects ; Humans ; Lymphocytes/cytology/*drug effects/metabolism ; Mitochondria/metabolism ; Oxygen/*pharmacology ; Protein Conformation/drug effects ; Protein Transport/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects/physiology ; Time Factors ; bcl-2-Associated X Protein/chemistry/metabolism ; }, abstract = {Recently, we showed that hypoxia/reoxygenation (H/R) induced apoptosis in human lymphocytes via reactive oxygen species (ROS) generation and disruption of the mitochondrial membrane; however, the signaling mechanisms responsible for these events are unclear. Here, we investigated the mechanism of H/R-induced apoptosis in human cultured lymphocytes. H/R increased the proportion of apoptotic cells, while z-IETD-fmk, z-VAD-fmk, and z-DEVD-fmk inhibited H/R-induced apoptosis. H/R also enhanced caspase-3 and caspase-8 activity. Time-sequence analysis of the induction of apoptosis by H/R revealed that H/R triggers apoptosis through a mitochondrial pathway involving caspase-8, Bid cleavage, and Bax activation. Furthermore, suppression of caspase-8 activity with z-IETD-fmk prevented Bid cleavage and Bax activation during apoptosis. N-acetylcysteine (NAC), a well-known ROS scavenger, suppressed caspase-8 activation and the subsequent cleavage of caspase-9 and caspase-3, indicating the role of ROS in caspase-8-mediated apoptosis. Overall, our results indicate that H/R induces apoptosis via a mitochondrial pathway involving caspase-8/Bid/Bax activation in human lymphocytes. Our results also suggest that ROS are critical regulators of caspase-8-mediated apoptosis in H/R-treated human lymphocytes.}, }
@article {pmid17902149, year = {2007}, author = {Boogaard, R and de Jongste, JC and Merkus, PJ}, title = {Pharmacotherapy of impaired mucociliary clearance in non-CF pediatric lung disease. A review of the literature.}, journal = {Pediatric pulmonology}, volume = {42}, number = {11}, pages = {989-1001}, doi = {10.1002/ppul.20693}, pmid = {17902149}, issn = {8755-6863}, mesh = {Acetylcysteine/therapeutic use ; Adolescent ; Child ; Child, Preschool ; Deoxyribonuclease I/therapeutic use ; Expectorants/*therapeutic use ; Humans ; Infant ; Lung Diseases/complications/*drug therapy ; Mucociliary Clearance/*drug effects/physiology ; Physical Therapy Modalities ; Randomized Controlled Trials as Topic ; Saline Solution, Hypertonic/therapeutic use ; }, abstract = {Mucoactive agents are used to treat a variety of lung diseases involving impaired mucociliary clearance or mucus hypersecretion. The mucoactive agents studied most frequently are N-acetylcysteine (NAC), recombinant human DNase (rhDNase), and hypertonic saline. Studies on the efficacy of these have been mainly conducted in adults, and in patients with cystic fibrosis (CF). The exact role of mucoactive agents in children with non-CF lung disease is not well established. We present an overview of the current literature reporting clinical outcome measures of treatment with NAC, rhDNase, and hypertonic saline in children.}, }
@article {pmid17900531, year = {2007}, author = {Bogani, P and Canavesi, M and Hagen, TM and Visioli, F and Bellosta, S}, title = {Thiol supplementation inhibits metalloproteinase activity independent of glutathione status.}, journal = {Biochemical and biophysical research communications}, volume = {363}, number = {3}, pages = {651-655}, doi = {10.1016/j.bbrc.2007.09.018}, pmid = {17900531}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; CHO Cells ; Cricetinae ; Cricetulus ; Electrophoresis, Polyacrylamide Gel ; Glutathione/*metabolism/pharmacology ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Matrix Metalloproteinase Inhibitors ; Metalloproteases/*antagonists &amp; inhibitors/metabolism ; Sulfhydryl Compounds/*pharmacology ; Thioctic Acid/pharmacology ; }, abstract = {Matrix metalloproteinases (MMPs) are proteolytic enzymes that regulate both integrity and composition of the extracellular matrix (ECM). Excessive ECM breakdown by MMPs is implicated in many physiological and pathological conditions, such as atherosclerosis. Activated macrophages, especially in the atherosclerotic lesion, are a major source of reactive oxygen species (ROS). Antioxidants protect against ROS-induced MMPs activation and inhibit gelatinolytic activity. We sought to determine whether the antioxidants glutathione (GSH), N-acetylcysteine (NAC), or lipoic acid (LA) affect gelatinase production and secretion. The results show that thiol compounds affect MMPs expression and activity in different ways. MMP-2 activity is directly inhibited by NAC and GSH, while LA is ineffective. On the contrary, MMP-9 expression is inhibited by LA at a pretrascriptional level, and MMP-9 activity is stimulated by GSH through a direct interaction with the gelatinase itself. Although all thiols, these compounds have different properties and different cellular uptakes and metabolic characteristics, and this could explain, at least in part, their differential effects on MMPs.}, }
@article {pmid17898673, year = {2007}, author = {Choe, WT and Murray, MT and Stidham, KR and Roberson, JB}, title = {N-Acetylcysteine as an adjunct for refractory ear infections.}, journal = {Otology &amp; neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology}, volume = {28}, number = {8}, pages = {1022-1025}, doi = {10.1097/MAO.0b013e318155a4d3}, pmid = {17898673}, issn = {1531-7129}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Aged ; Aged, 80 and over ; Anti-Infective Agents/administration &amp; dosage/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; Antiviral Agents/*therapeutic use ; Audiometry ; Audiometry, Pure-Tone ; Child ; Ciprofloxacin/administration &amp; dosage/therapeutic use ; Dexamethasone/therapeutic use ; Drug Combinations ; Drug Resistance ; Ear Diseases/*drug therapy ; Female ; Humans ; Infections/*drug therapy ; Male ; Middle Aged ; Pharmaceutical Solutions ; Pilot Projects ; }, abstract = {OBJECTIVE: To analyze the efficacy of Ciprodex otic augmented with N-acetylcysteine (NAC) against difficult ear infections.<br><br>SUBJECTS: Subjects were selected with at least 1 month of continuous otorrhea despite at least 3 distinct medical or surgical treatments.<br><br>INTERVENTIONS: Subjects received Ciprodex otic augmented with 0.5 or 2% NAC using standard dosing schemes.<br><br>MAIN OUTCOME MEASURES: Serial audiometry and cessation of otorrhea by both history and binocular microscopy.<br><br>RESULTS: Seven subjects were included with an average of 18.4 months of continuous otorrhea despite aggressive therapy. Cessation of otorrhea was achieved in 6 of 7 subjects generally within 4 weeks of treatment. One of these 6 subjects remains on chronic suppressive therapy. The remaining subject failed because of persistent noncompliance. No subjects demonstrated ototoxicity via pretreatment and posttreatment audiometry.<br><br>CONCLUSION: Ciprodex otic augmented with NAC seems to have considerable efficacy against otherwise refractory ear infections. This technique may prove to be a simple and powerful option for the treatment of difficult ear infections.}, }
@article {pmid17897629, year = {2007}, author = {Hosokawa, K and Arai, F and Yoshihara, H and Nakamura, Y and Gomei, Y and Iwasaki, H and Miyamoto, K and Shima, H and Ito, K and Suda, T}, title = {Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction.}, journal = {Biochemical and biophysical research communications}, volume = {363}, number = {3}, pages = {578-583}, doi = {10.1016/j.bbrc.2007.09.014}, pmid = {17897629}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Bone Marrow Cells/cytology/drug effects/metabolism ; Cadherins/genetics/metabolism ; Cell Count ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Fluorouracil/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Hematopoietic Stem Cells/cytology/drug effects/*metabolism ; Imidazoles/pharmacology ; Immunohistochemistry ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/*physiology ; Pyridines/pharmacology ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {During postnatal life, the bone marrow (BM) supports both self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized niches, such as osteoblastic niche and vascular niche. A cell adhesion molecule, N-cadherin expressed in the HSCs and osteoblasts, suggesting that homophylic binding of N-cadherin induce the adhesion of HSCs to the niche cells. Here we demonstrate that an anti-cancer drug, 5-fuluorouracil induces reactive oxygen species (ROS) in HSCs, which suppressed N-cadherin expression. These events result in the shift of side population (SP) cells to non-SP cells, indicating that quiescent HSCs are detached from the niche. Administration of a potent anti-oxidant, N-acetyl cystein (NAC) suppressed the shift from SP cells. These data suggest that ROS suppressed the N-cadherin-mediated cell adhesion, and induce the exit of HSCs from the niche.}, }
@article {pmid17892265, year = {2007}, author = {Barshteyn, N and Elfarra, AA}, title = {Formation of three N-acetyl-L-cysteine monoadducts and one diadduct by the reaction of S-(1,2-dichlorovinyl)-L-cysteine sulfoxide with N-acetyl-L-cysteine at physiological conditions: chemical mechanisms and toxicological implications.}, journal = {Chemical research in toxicology}, volume = {20}, number = {10}, pages = {1563-1569}, doi = {10.1021/tx700263w}, pmid = {17892265}, issn = {0893-228X}, support = {DK44295/DK/NIDDK NIH HHS/United States ; T32-ES-007015/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*chemistry/metabolism/toxicity ; Cross-Linking Reagents/chemistry/metabolism/toxicity ; Cysteine/*analogs &amp; derivatives/chemistry/metabolism/toxicity ; Free Radical Scavengers/*chemistry/metabolism/toxicity ; Kidney/drug effects ; Kidney Diseases/chemically induced/metabolism ; Sulfoxides/*chemistry/metabolism/toxicity ; }, abstract = {Previously, our laboratory has shown that S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS), a Michael acceptor produced by a flavin-containing monooxygenase 3 (FMO3)-mediated oxidation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), is a more potent nephrotoxicant than DCVC. In the present study, we characterized reactions of DCVCS with nucleophilic amino acids. DCVCS incubations with N-acetyl-L-cysteine (NAC) at pH 7.4 and 37 degrees C for 1 h resulted in the formation of three monoadducts and one diadduct characterized by LC/MS, 1H NMR, and 1H-detected heteronuclear single quantum correlation. The formation of all adducts (with relative ratios of 29, 31, 24, and 12%, respectively) was rapid and time-dependent; the half-lives of the two DCVCS diastereomers in the presence of NAC were 13.8 (diastereomer I) and 9.4 min (diastereomer II). Adducts 1 and 2 were determined to be diastereomers of S-[1-chloro-2-(N-acetyl-L-cystein- S-yl)vinyl]-L-cysteine sulfoxide formed by Michael addition of NAC to the terminal vinylic carbon of DCVCS followed by loss of HCl. Adduct 4 was determined to be S-[2-chloro-2-(N-acetyl-L-cystein- S-yl)vinyl]-L-cysteine sulfoxide formed from the initial Michael addition product followed by a less favorable loss of HCl and/or by a rearrangement of adduct 2 through the formation of a cyclic chloronium ion. The addition of another molecule of NAC to monoadducts 1, 2, or 4 resulted in the formation of the novel diadduct, S-[2,2-(N-acetyl-L-cystein-S-yl)vinyl]-L-cysteine sulfoxide (adduct 3), whose detection in relatively large amount suggests that DCVCS could act as a cross-linking agent. DCVCS was not reactive with N-acetyl-L-lysine or L-valinamide at similar incubation conditions. Collectively, the results suggest selective reactivity of DCVCS toward protein sulfhydryl groups. Furthermore, the cross-linking properties of DCVCS may in part explain its high nephrotoxic potency.}, }
@article {pmid17891553, year = {2008}, author = {Desai, KG and Mallery, SR and Schwendeman, SP}, title = {Formulation and characterization of injectable poly(DL-lactide-co-glycolide) implants loaded with N-acetylcysteine, a MMP inhibitor.}, journal = {Pharmaceutical research}, volume = {25}, number = {3}, pages = {586-597}, pmid = {17891553}, issn = {0724-8741}, support = {R01 HL068345/HL/NHLBI NIH HHS/United States ; R01 CA129609/CA/NCI NIH HHS/United States ; R01 CA095901/CA/NCI NIH HHS/United States ; R01 CA095901-01A1/CA/NCI NIH HHS/United States ; R01 HL68345/HL/NHLBI NIH HHS/United States ; R01 CA95901/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*chemistry/pharmacology ; Animals ; Antineoplastic Agents/administration &amp; dosage/*chemistry/pharmacology ; Calcium Compounds/chemistry ; Calorimetry, Differential Scanning ; Catalysis ; Chemistry, Pharmaceutical ; *Drug Carriers ; Drug Compounding ; Drug Implants ; Drug Stability ; Head and Neck Neoplasms/drug therapy/enzymology/surgery ; Humans ; Injections ; Kinetics ; Lactic Acid/*chemistry ; Magnesium Compounds/chemistry ; *Matrix Metalloproteinase Inhibitors ; Microscopy, Electron, Scanning ; Polyglycolic Acid/*chemistry ; Polylactic Acid-Polyglycolic Acid Copolymer ; Polymers/*chemistry ; Protease Inhibitors/administration &amp; dosage/*chemistry/pharmacology ; Solubility ; Technology, Pharmaceutical ; X-Ray Diffraction ; }, abstract = {PURPOSE: The objective of this study was to develop poly(lactic-co-glycolic acid) (PLGA) injectable implants (i.e., millicylinders) with microencapsulated N-acetylcysteine (NAC) for site-specific controlled NAC release, for potential chemopreventive applications in persons with previously excised head and neck cancers.<br><br>METHODS: PLGA 50:50 (i.v.=0.57 dl/g) implants with 1-10 wt% NAC free acid or 10 wt% NAC salts (NAC-Na+, NAC-Mg2+ and NAC-Ca2+) were prepared by solvent extrusion and/or fluid energy micronization (FEM) methods. X-ray diffraction (XRD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) studies were performed to evaluate the physical mixing of NAC with PLGA. PLGA implant degradation was studied by kinetics of polymer molecular weight decline (gel permeation chromatography) and mass loss. Release studies were conducted in N2 purged PBS (pH 7.4) at 37 degrees C in evacuated and sealed ampoules. NAC was quantified by HPLC at 210 nm.<br><br>RESULTS: XRD, SEM and DSC studies indicated that NAC had dissolved in the polymer phase at 1-3.5% w/w loading, but became discretely suspended in the polymer at 6-10% w/w. Initial burst and long-term release rate increased with increased drug loading, and release was uncharacteristically rapid at higher loading (6-10% w/w). The cause of the rapid release was linked to extensive plasticization, matrix porosity and general acid catalysis of PLGA degradation caused by the NAC free acid. PLGA millicylinders loaded with 10% w/w NAC-Ca2+ and NAC-Mg2+salts exhibited reduced burst (34 vs 13-22% release within a day of incubation for NAC free acid vs NAC-Ca2+ and NAC-Mg2+salts, respectively) and slow and continuous complete release over 4 weeks without significant NAC-catalyzed degradation of PLGA. Release of NAC from NAC-Ca2+/PLGA implant was slower than that of NAC-Mg2+/PLGA consistent with the lower solubility of the former salt. NAC with its free thiol was rapidly converted to its cystine dimer in the presence of molecular oxygen. PLGA released samples in sealed and evacuated ampoules indicated>80% parent NAC remaining after the 1 month release analysis irrespective of initial NAC free acid and salt forms.<br><br>CONCLUSION: By encapsulating the NAC-Mg2+ and NAC-Ca2+ salts in PLGA implants, the high initial burst, short release duration, and the general acid catalysis caused by the NAC free acid were each prevented and 1-month slow and continuous release was attained with minimal instability of the free thiol group.}, }
@article {pmid17888874, year = {2007}, author = {Lu, C and Armstrong, JS}, title = {Role of calcium and cyclophilin D in the regulation of mitochondrial permeabilization induced by glutathione depletion.}, journal = {Biochemical and biophysical research communications}, volume = {363}, number = {3}, pages = {572-577}, doi = {10.1016/j.bbrc.2007.08.196}, pmid = {17888874}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Blotting, Western ; Calcium/metabolism/*physiology ; Cell Line, Tumor ; Cell Survival/drug effects ; Chelating Agents/pharmacology ; Peptidyl-Prolyl Isomerase F ; Cyclophilins/genetics/metabolism/*physiology ; Cyclosporine/pharmacology ; Cytosol/drug effects/metabolism ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism ; Humans ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/metabolism/*physiology ; Organophosphorus Compounds/pharmacology ; Permeability ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/metabolism ; Transfection ; Ubiquinone/analogs &amp; derivatives/pharmacology ; }, abstract = {The mitochondrial permeability transition (MPT) is a calcium and oxidative stress sensitive transition in the permeability of the mitochondrial inner membrane that plays a crucial role in cell death. However, the mechanism regulating the MPT remains controversial. To study the role of oxidative stress in the regulation of the MPT, we used diethyl maleate (DEM) to deplete glutathione (GSH) in human leukemic CEM cells. GSH depletion increased mitochondrial calcium and reactive oxygen species (ROS) levels in a co-dependent manner causing loss of mitochondrial membrane potential (deltapsi(m)) and cell death. These events were inhibited by the calcium chelator BAPTA-AM and the antioxidants N-acetylcysteine (NAC) and the triphenyl phosphonium-linked ubiquinone derivative MitoQ. In contrast, the MPT inhibitor cyclosporine A (CsA) and small interference RNA (siRNA) knockdown of cyclophilin D (Cyp-D) were not protective. These results indicate that mitochondrial permeabilization induced by GSH depletion is not regulated by the classical MPT.}, }
@article {pmid17884964, year = {2007}, author = {Demiralay, R and Gürsan, N and Erdem, H}, title = {Regulation of nicotine-induced apoptosis of pulmonary artery endothelial cells by treatment of N-acetylcysteine and vitamin E.}, journal = {Human &amp; experimental toxicology}, volume = {26}, number = {7}, pages = {595-602}, doi = {10.1177/0960327106070079551}, pmid = {17884964}, issn = {0960-3271}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Apoptosis/*drug effects ; Endothelial Cells/*drug effects/metabolism/pathology ; Female ; Injections, Intraperitoneal ; Nicotine/administration &amp; dosage/*toxicity ; Nicotinic Agonists/administration &amp; dosage/*toxicity ; Peroxidase/metabolism ; Pulmonary Artery/*drug effects/enzymology/metabolism/pathology ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Vitamin E/administration &amp; dosage/*pharmacology ; }, abstract = {This study investigated the frequency of apoptosis in rat pulmonary artery endothelial cells after intraperitoneal nicotine injection, examining the roles of the inflammatory markers myeloperoxidase (MPO), tumour necrosis factor alpha (TNF-alpha), and vascular endothelial growth factor (VEGF) in nicotine-induced vascular damage and the protective effects of two known antioxidant agents, N-acetylcysteine (NAC) and vitamin E. Female Wistar rats were divided into four groups, each composed of nine rats: negative control group, positive control group, NAC-treated group (500 mg/kg), and vitamin E-treated group (500 mg/kg). Nicotine was intraperitoneally injected at a dosage of 0.6 mg/kg for 21 days. Following nicotine injection, the antioxidants were administered orally; treatment was continued until the rats were killed. Lung tissue samples were stained with hematoxylin-eosin (H&amp;E) for histopathological assessments. Apoptosis level in endothelial cells was determined by using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling) method. Staining of cytoplasmic TNF-alpha and VEGF in endothelial cells, and perivascular MPO activity were evaluated by immunohistochemistry. The treatments with NAC and vitamin E significantly reduced the rate of nicotine-induced endothelial cell apoptosis. NAC and vitamin E significantly reduced the increases in the local production of TNF-alpha and VEGF, and perivascular MPO activity. This findings suggest that NAC can be as effective as vitamin E in protecting against nicotine-induced endothelial cell apoptosis.}, }
@article {pmid17877536, year = {2007}, author = {Manso, MA and Ramudo, L and De Dios, I}, title = {Extrapancreatic organ impairment during acute pancreatitis induced by bile-pancreatic duct obstruction. Effect of N-acetylcysteine.}, journal = {International journal of experimental pathology}, volume = {88}, number = {5}, pages = {343-349}, pmid = {17877536}, issn = {0959-9673}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Alanine Transaminase/blood ; Amylases/blood ; Animals ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Biomarkers/blood ; Cholestasis ; Creatinine/blood ; L-Lactate Dehydrogenase/blood ; Ligation ; Liver/pathology ; Lung/pathology ; Male ; Models, Animal ; Multiple Organ Failure/blood/drug therapy/*pathology ; Pancreas/pathology ; Pancreatitis/blood/drug therapy/*pathology ; Peroxidase/blood ; Rats ; Rats, Wistar ; Time Factors ; Treatment Outcome ; }, abstract = {Multiple organ failure is frequently associated with acute pancreatitis (AP). Our aim was to study pulmonary, hepatic and renal complications developed in the course of AP experimentally induced in rats by bile-pancreatic duct obstruction (BPDO), differentiating the complications caused by AP itself, from those directly caused by bile duct obstruction (BDO), after ligating the choledocus. N-acetylcysteine (NAC) was administered as a therapeutic approach. Myeloperoxidase activity revealed neutrophil infiltration in lungs from 12 h after BDO, even if AP was not triggered. Lactate dehydrogenase (LDH) activity indicated hepatocyte death from 48 h after BDO, and from 24 h following BPDO-induced AP onwards, an effect delayed until 48 h by NAC treatment. Rats with single cholestasis (BDO) and rats with BPDO-induced AP showed a significant increase in plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin concentration from 12 h onwards, whose values were reduced by NAC treatment at early BPDO. No renal failure was found during 120 h of bile-pancreatic obstruction. Our results showed lung and liver impairment as a result of BDO, even if AP does not develop. Pancreatic damage and extrapancreatic complications during AP induced by BPDO were palliated by NAC treatment.}, }
@article {pmid17876880, year = {2007}, author = {Thong-Ngam, D and Samuhasaneeto, S and Kulaputana, O and Klaikeaw, N}, title = {N-acetylcysteine attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis.}, journal = {World journal of gastroenterology}, volume = {13}, number = {38}, pages = {5127-5132}, pmid = {17876880}, issn = {1007-9327}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Fatty Liver/metabolism/*pathology ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Hepatocytes/drug effects/metabolism/pathology ; Liver/drug effects/metabolism/*pathology ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIM: To evaluate attenuating properties of N-acetylcysteine (NAC) on oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis (NASH).<br><br>METHODS: Male Sprague-Dawley rats were randomly divided into three groups. Group 1 (control, n=8) was free accessed to regular dry rat chow (RC) for 6 wk. Group 2 (NASH, n=8) was fed with 100% fat diet for 6 wk. Group 3 (NASH+NAC(20), n=9) was fed with 100% fat diet plus 20 mg/kg per day of NAC orally for 6 wk. All rats were sacrificed to collect blood and liver samples at the end of the study.<br><br>RESULTS: The levels of total glutathione (GSH) and hepatic malondialdehyde (MDA) were increased significantly in the NASH group as compared with the control group (GSH; 2066.7+/-93.2 vs 1337.5+/-31.5 micromol/L and MDA; 209.9+/-43.9 vs 3.8+/-1.7 micromol/g protein, respectively, P<0.05). Liver histopathology from group 2 showed moderate to severe macrovesicular steatosis, hepatocyte ballooning, and necroinflammation. NAC treatment improved the level of GSH (1394.8+/-81.2 micromol/L, P<0.05), it did not affect MDA (150.1+/-27.0 micromol/g protein), but led to a decrease in fat deposition and necroinflammation.<br><br>CONCLUSION: NAC treatment could attenuate oxidative stress and improve liver histology in rats with NASH.}, }
@article {pmid17876277, year = {2007}, author = {Ahn, HJ and Park, J and Song, JS and Ju, MK and Kim, MS and Ha, H and Song, KH and Kim, YS}, title = {Mycophenolic acid inhibits oleic acid-induced vascular smooth muscle cell activation by inhibiting cellular reactive oxygen species.}, journal = {Transplantation}, volume = {84}, number = {5}, pages = {634-638}, doi = {10.1097/01.tp.0000278729.96633.6d}, pmid = {17876277}, issn = {0041-1337}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; Cytoprotection/drug effects ; Fibronectins/metabolism ; Muscle, Smooth, Vascular/cytology/*drug effects/*metabolism ; Mycophenolic Acid/*pharmacology ; Oleic Acid/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation and matrix protein accumulation play important roles in the development and progression of chronic allograft vasculopathy. Mycophenolic acid (MPA) inhibits various types of mesenchymal cell proliferation and cellular reactive oxygen species (ROS) are involved in the anti-proliferative effect of MPA. In this study, we investigated the effects of MPA on oleic acid (OA)-induced VSMC proliferation and the role of ROS in this process.<br><br>METHODS: Primary VSMCs from Sprague-Dawley rats were stimulated with 100 microM OA, with or without MPA (0.1- 10 microM) or 5 mM N-acetylcysteine (NAC) for one hour prior to the addition of OA. Cell proliferation was measured by methylthiazoletetrazolium (MTT) assays, proliferating cell nuclear antigen (PCNA) expression, and fibronectin secretion by Western blot analysis, and dichlorofluorescein (DCF)-sensitive cellular ROS by fluorescence-activated cell scanning (FACS).<br><br>RESULTS: OA (100 microM) increased cell proliferation, as measured by MTT (by 1.6-fold), PCNA expression, fibronectin secretion, and cellular ROS (by 1.6-fold). Treatment with MPA dose-dependently inhibited OA-induced VSMC proliferation, fibronectin secretion, and cellular ROS. Treatment with 5 mM NAC also inhibited OA-induced rat VSMC activation.<br><br>CONCLUSIONS: These results suggest that MPA inhibits OA-induced VSMC proliferation and matrix protein synthesis partially by inhibiting cellular ROS.}, }
@article {pmid17875717, year = {2007}, author = {Rassool, FV and Gaymes, TJ and Omidvar, N and Brady, N and Beurlet, S and Pla, M and Reboul, M and Lea, N and Chomienne, C and Thomas, NS and Mufti, GJ and Padua, RA}, title = {Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia?.}, journal = {Cancer research}, volume = {67}, number = {18}, pages = {8762-8771}, doi = {10.1158/0008-5472.CAN-06-4807}, pmid = {17875717}, issn = {0008-5472}, mesh = {Animals ; *DNA Damage ; *DNA Repair ; Disease Models, Animal ; Disease Progression ; Genes, bcl-2 ; Genes, ras ; *Genomic Instability ; Leukemia, Myeloid/*genetics/metabolism/pathology ; Mice ; Mice, Transgenic ; Reactive Oxygen Species/*metabolism ; }, abstract = {Myelodysplastic syndromes (MDS) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis, with an increased propensity to develop acute myelogenous leukemia (AML). The molecular basis for MDS progression is unknown, but a key element in MDS disease progression is loss of chromosomal material (genomic instability). Using our two-step mouse model for myeloid leukemic disease progression involving overexpression of human mutant NRAS and BCL2 genes, we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error-prone repair of double-strand breaks (DSB) by nonhomologous end-joining. There is a concomitant increase in reactive oxygen species (ROS) in these transgenic mice with disease progression. Importantly, RAC1, an essential component of the ROS-producing NADPH oxidase, is downstream of RAS, and we show that ROS production in NRAS/BCL2 mice is in part dependent on RAC1 activity. DNA damage and error-prone repair can be decreased or reversed in vivo by N-acetyl cysteine antioxidant treatment. Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with MDS disease progression. These data suggest treatment strategies that target RAS/RAC pathways and ROS production in human MDS/AML.}, }
@article {pmid17874299, year = {2007}, author = {Malik, F and Kumar, A and Bhushan, S and Khan, S and Bhatia, A and Suri, KA and Qazi, GN and Singh, J}, title = {Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic cell death of human myeloid leukemia HL-60 cells by a dietary compound withaferin A with concomitant protection by N-acetyl cysteine.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {12}, number = {11}, pages = {2115-2133}, doi = {10.1007/s10495-007-0129-x}, pmid = {17874299}, issn = {1360-8185}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/*drug effects ; Ergosterol/*analogs &amp; derivatives/pharmacology ; HL-60 Cells ; HeLa Cells ; Humans ; Leukemia, Myeloid/drug therapy/metabolism/*pathology ; Mitochondria/drug effects/*pathology ; Reactive Oxygen Species/*metabolism ; Withania ; Withanolides ; }, abstract = {Induction of apoptosis in cancer cells has become the major focus of anti-cancer therapeutics development. WithaferinA, a major chemical constituent of Withania somnifera, reportedly shows cytotoxicity in a variety of tumor cell lines while its molecular mechanisms of action are not fully understood. We observed that withaferinA primarily induces oxidative stress in human leukemia HL-60 cells and in several other cancer cell lines. The withanolide induced early ROS generation and mitochondrial membrane potential (Deltapsi(mt)) loss, which preceded release of cytochrome c, translocation of Bax to mitochondria and apoptosis inducing factor to cell nuclei. These events paralleled activation of caspases -9, -3 and PARP cleavage. WA also activated extrinsic pathway significantly as evidenced by time dependent increase in caspase-8 activity vis-à-vis TNFR-1 over expression. WA mediated decreased expression of Bid may be an important event for cross talk between intrinsic and extrinsic signaling. Furthermore, withaferinA inhibited DNA binding of NF-kappaB and caused nuclear cleavage of p65/Rel by activated caspase-3. N-acetyl-cysteine rescued all these events suggesting thereby a pro-oxidant effect of withaferinA. The results of our studies demonstrate that withaferinA induced early ROS generation and mitochondrial dysfunction in cancer cells trigger events responsible for mitochondrial -dependent and -independent apoptosis pathways.}, }
@article {pmid17873392, year = {2007}, author = {Ustundag, A and Duydu, Y}, title = {The influence of melatonin and N-acetylcysteine in delta-aminolevulinic acid and lead induced genotoxicity in lymphocytes in vitro.}, journal = {Biological trace element research}, volume = {117}, number = {1-3}, pages = {53-64}, doi = {10.1007/BF02698083}, pmid = {17873392}, issn = {0163-4984}, mesh = {Acetylcysteine/*chemistry/pharmacology ; Aminolevulinic Acid/antagonists &amp; inhibitors/*toxicity ; Cell Death/drug effects/genetics ; Female ; Free Radical Scavengers/*pharmacology ; Humans ; Lead/antagonists &amp; inhibitors/*toxicity ; Lymphocytes/drug effects/*metabolism/*pathology ; Melatonin/*chemistry/physiology ; Middle Aged ; Sister Chromatid Exchange/drug effects/physiology ; }, abstract = {As is well known from earlier studies, the genotoxic effect of lead exposure was partly attributed to the formation of the highly reactive oxygen metabolites (ROMs) in the blood. However, lead ions have no ability to generate ROMs. Therefore, the recently published studies paid more attention to the role of delta-aminolevulinic acid (ALA) accumulation in lead-induced DNA damage. If the above-mentioned assumptions were taken into consideration, it seemed a reasonable approach to study the possible protective effects of antioxidants against genotoxic effects of lead. According to our results, N-acetylcysteine (NAC) and melatonin (MEL) were able to reduce significantly (p<0.05) the lead- and ALA-induced sister chromatid exchange frequencies in human lymphocytes in vitro. In spite of a relative reduction in the lead- and ALA-induced micronucleus formation in human lymphocytes, the reduction was not statistically significant (p>0.05). These results could be evaluated as supportive evidence for the hypothesis that increased antioxidant capacity of cells might fortify the efficiency of protective pathways against cytogenetic damage in lead exposure.}, }
@article {pmid17869641, year = {2007}, author = {Moon, EY and Park, H}, title = {B cell activating factor (BAFF) gene promoter activity depends upon co-activator, p300.}, journal = {Immunobiology}, volume = {212}, number = {8}, pages = {637-645}, doi = {10.1016/j.imbio.2007.06.002}, pmid = {17869641}, issn = {0171-2985}, mesh = {Acetylcysteine/metabolism ; Animals ; B-Cell Activating Factor/*metabolism ; Base Sequence ; Cells, Cultured ; E1A-Associated p300 Protein/*metabolism ; Gene Expression Regulation, Enzymologic ; Genes, Reporter ; Hydrogen Peroxide/metabolism ; Luciferases/drug effects ; Macrophages ; Mice ; NF-kappa B/metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Transcription Factor RelA/*metabolism ; Transcription, Genetic ; Transcriptional Activation ; Transfection ; }, abstract = {B-cell activating factor (BAFF) plays a critical role for mature B cell generation and maintenance. We have previously described that mouse BAFF (mBAFF) transcript expression was increased by toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS), through reactive oxygen species (ROS) production and NF-kappaB activation. Here, we investigated whether mBAFF expression could be regulated by promoter activation through the cooperation of NF-kappaB and p300, co-activator to various transcription factors. We cloned mBAFF promoter into luciferase-expressing pGL3-basic vector and computer-analyzed its NF-kappaB binding motif. Due to the existence of NF-kappaB binding motifs, activity in 2.0 kb mBAFF promoter was higher than that in 1.0 or 0.5 kb mBAFF promoter. When Raw 264.7 murine macrophages were stimulated with LPS, 2.0 kb mBAFF promoter activity was increased time dependently. Serum deprivation (0.5% FBS) producing ROS and exogenous H(2)O(2) treatment also enhanced mBAFF promoter activity, which was reduced by N-acetyl-l-cysteine (NAC), a well-known ROS scavenger. LPS and serum-starved ROS production increased NF-kappaB activation. mBAFF promoter activity was augmented by co-transfection with p65 and/or co-activator, p300. It was inhibited by dominant negative (DN) p300. Binding of p300 to BAFF promoter was detected by chromatin immunoprecipitation (ChIP) assay. Data suggest that mBAFF expression could be regulated by promoter activation through NF-kappaB activation, which might be dependent on the cooperation with co-activator, p300.}, }
@article {pmid17869034, year = {2008}, author = {Takatsuka, S and Morita, T and Horikiri, Y and Yamahara, H and Saji, H}, title = {Influence of various combinations of mucolytic agent and non-ionic surfactant on intestinal absorption of poorly absorbed hydrophilic compounds.}, journal = {International journal of pharmaceutics}, volume = {349}, number = {1-2}, pages = {94-100}, doi = {10.1016/j.ijpharm.2007.07.031}, pmid = {17869034}, issn = {0378-5173}, mesh = {Acetylcysteine/chemistry ; Animals ; Area Under Curve ; Chemical Phenomena ; Chemistry, Physical ; Dextrans/chemistry/pharmacokinetics ; Expectorants/chemistry/*pharmacology ; Fluorescein-5-isothiocyanate/analogs &amp; derivatives/chemistry/pharmacokinetics ; Intestinal Absorption/*drug effects ; Kinetics ; Male ; Pharmaceutical Preparations/*metabolism ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; Surface-Active Agents/chemistry/*pharmacology ; }, abstract = {The absorption enhancing effects of various combinations of a mucolytic agent and a non-ionic surfactant on the intestinal absorption of poorly absorbed hydrophilic compounds were examined. Fluorescein isothiocyanate-labeled dextran with an average molecular weight of ca. 4.4 kDa (FD-4) was used as a model compound. Cysteine derivatives such as N-acetylcysteine (NAC), S-carboxymethylcysteine (SCMC), S-ethylcysteine (SEC), and S-methylcysteine (SMC) were selected as mucolytic agents. A homogeneous series of single chain polyoxyethylene alkyl ethers were employed as non-ionic surfactants. Various dosing solutions were administered into rat jejunum, and the bioavailability of FD-4 was determined. Unlike NAC, the agents such as SCMC, SEC, and SMC, which do not possess a free thiol group, did not show any apparent enhancement of intestinal FD-4 absorption, when they were co-administered with p-t-octyl phenol polyoxyethylene-9.5 (Triton X-100, TX-100). In addition, the absorption enhancement was dependent on the kinds of polyoxyethylene alkyl ethers used, when used in combination with NAC. For a constant alkyl chain of 12 with a varying polyoxyethylene (POE) chain length, the surfactant with a short to medium POE chain length such as lauryl poly (4.2) oxyethylene ether (BL-4.2) and lauryl poly (9) oxyethylene ether (BL-9) were effective. In addition, for a constant alkyl chain of 18 with a varying POE chain length, the surfactants with a longer POE chain length such as oleyl poly (15) oxyethylene ether (BO-15) and stearyl poly (20) oxyethylene ether (BS-20) showed the effective enhancement. All these results suggest that a mucolytic agent not possessing a free thiol group is not effective for enhancing the intestinal absorption of poorly absorbed hydrophilic compounds. Also, they indicate that the combination of a mucolytic agent possessing a free thiol group and a non-ionic surfactant either with a short to medium POE chain length and a medium alkyl chain length, or with a longer POE chain length and a longer alkyl chain length shows the effective enhancement. This fundamental information might be useful for finding the optimal combination.}, }
@article {pmid17853088, year = {2007}, author = {Arakawa, M and Ito, Y}, title = {N-acetylcysteine and neurodegenerative diseases: basic and clinical pharmacology.}, journal = {Cerebellum (London, England)}, volume = {6}, number = {4}, pages = {308-314}, pmid = {17853088}, issn = {1473-4230}, mesh = {Acetylcysteine/pharmacokinetics/*pharmacology/*therapeutic use ; Aldehydes/pharmacology/therapeutic use ; Central Nervous System Diseases/drug therapy/pathology ; Cerebellum/cytology/drug effects/pathology ; Free Radical Scavengers/pharmacokinetics/*pharmacology/*therapeutic use ; Humans ; Neurodegenerative Diseases/*drug therapy/pathology ; Neurons/drug effects/pathology ; Reactive Oxygen Species/metabolism ; }, abstract = {Increasing lines of evidence suggest a key role of oxidative stress in neurodegenerative diseases. Alzheimer's disease, Parkinson's disease, myoclonus epilepsy of the Unverricht-Lundborg type, spinocerebellar degeneration, tardive dyskinesia and Down's syndrome have been associated with several mitochondrial alterations. Oxidative stress can decrease cellular bioenergetic capacity, which will then increase the generation of reactive oxygen species resulting in cellular damage and programmed cell death. First, this review examines the mechanisms of action of N-acetylcysteine (NAC), an antioxidant and a free radical-scavenging agent that increases intracellular GSH, at the cellular level. NAC can act as a precursor for glutathione synthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration. The chemical properties of NAC include redox interactions, particularly with other members of the group XIV elements (selenium, etc.) and ebselen, a lipid-soluble seleno-organic compound. Second, NAC has been shown to protect against oxidative stress-induced neuronal death in cultured granule neurons. Recent findings on the protective effect of NAC against 4-hydroxynonenal (HNE)-induced toxicity in cerebellar granule neurons are summarized. Finally, the protective pharmacokinetics of NAC in humans and the possible usefulness of NAC for the treatment of neurodegenerative diseases are discussed with reference to basic and clinical studies.}, }
@article {pmid17851176, year = {2007}, author = {Sathishkumar, K and Xi, X and Martin, R and Uppu, RM}, title = {Cholesterol secoaldehyde, an ozonation product of cholesterol, induces amyloid aggregation and apoptosis in murine GT1-7 hypothalamic neurons.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {11}, number = {3}, pages = {261-274}, doi = {10.3233/jad-2007-11302}, pmid = {17851176}, issn = {1387-2877}, support = {ES10018/ES/NIEHS NIH HHS/United States ; P20 RR16456/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Amyloid beta-Peptides/*metabolism ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Apoptosis/*drug effects ; Cell Aggregation/*physiology ; Cholestanones/antagonists &amp; inhibitors/*metabolism ; Cholesterol/*metabolism ; Cholesterol, HDL/drug effects/metabolism ; Chromans/administration &amp; dosage/pharmacology ; DNA Fragmentation/drug effects ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Hypothalamus/drug effects/*metabolism/*pathology ; Lipid Peroxidation ; Mice ; Myoblasts, Cardiac/drug effects/pathology/*physiology ; Neurons/*metabolism/*pathology ; Ozone/*metabolism ; Reactive Oxygen Species/metabolism ; Secosteroids/antagonists &amp; inhibitors/*metabolism ; Trinucleotide Repeat Expansion/*physiology ; }, abstract = {Aldehydic products from ozonation of cholesterol and peroxidation of phospholipids have been shown to accelerate aggregation of amyloid-beta (Abeta) in vitro. Here, we show that 3beta-hydroxy-5-oxo-5,6-secocholestan-6-al (ChSeco), an ozonation product of cholesterol, induces Abeta aggregation, generation of reactive oxygen species (ROS), and cytotoxicity in murine GT1-7 hypothalamic neurons. The formation of Abeta aggregates in situ was dose-dependent at ChSeco concentrations ranging from 1 to 20 microM. The increase in insoluble Abeta aggregates at increasing concentrations of ChSeco was accompanied by a decrease in soluble Abeta as evidenced by Western blot analysis. The formation of ROS in neuronal cells was found to be dose- and time-dependent with the magnitude being higher at 20 microM compared to 10 microM ChSeco or untreated controls. The increase in ROS was associated with depletion of GSH. The cytotoxicity induced by ChSeco involved changes in phosphatidylserine translocation, DNA fragmentation, and caspase 3/7 activity that are characteristic of apoptosis. Pretreatment of neuronal cells with Trolox, a water-soluble analog of alpha-tocopherol offered partial, but significant protection against ChSeco-induced cell death, whereas, N-acetyl-L-cysteine (NAC) completely prevented the cytotoxic effects of ChSeco. NAC and Trolox were without any effects on ChSeco-induced Abeta aggregation. Fibrillogenesis inhibitors, which inhibited Abeta aggregation, did not inhibit cell death induced by ChSeco, implying that ROS generation, and not Abeta aggregation, plays a major role in the observed cytotoxicity. However, since Alzheimer's and other neurodegenerative diseases are slow and progressive, the formation of Abeta aggregates in vivo by ChSeco may have long-term pathological consequences.}, }
@article {pmid17846503, year = {2007}, author = {Shim, HY and Park, JH and Paik, HD and Nah, SY and Kim, DS and Han, YS}, title = {Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondria-mediated death signaling and SAPK/JNK1/2-c-Jun activation.}, journal = {Molecules and cells}, volume = {24}, number = {1}, pages = {95-104}, pmid = {17846503}, issn = {1016-8478}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms/pathology/*physiopathology ; Caspase 3/physiology ; Caspase Inhibitors ; Caspases/*physiology ; Cell Line, Tumor ; Female ; Flavones/*pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/*physiology ; MAP Kinase Kinase 4/*physiology ; Membrane Potential, Mitochondrial/drug effects ; Mitogen-Activated Protein Kinase 1/physiology ; Mitogen-Activated Protein Kinase 3/physiology ; Oligopeptides/pharmacology ; Proto-Oncogene Proteins c-bcl-2/physiology ; Reactive Oxygen Species/metabolism ; bcl-2-Associated X Protein/physiology ; }, abstract = {The mechanism of acacetin-induced apoptosis of human breast cancer MCF-7 cells was investigated. Acacetin caused 50% growth inhibition (IC50) of MCF-7 cells at 26.4% 0.7% M over 24 h in the MTT assay. Apoptosis was characterized by DNA fragmentation and an increase of sub-G1 cells and involved activation of caspase-7 and PARP (poly-ADP-ribose polymerase). Maximum caspase 7 activity was observed with 100 microM acacetin for 24 h. Caspase 8 and 9 activation cascades mediated the activation of caspase 7. Acacetin caused a reduction of Bcl-2 expression leading to an increase of the Bax:Bcl-2 ratio. It also caused a loss of mitochondrial membrane potential that induced release of cytochrome c and apoptosis inducing factor (AIF) into the cytoplasm, enhancing ROS generation and subsequently resulting in apoptosis. Pretreatment of cells with N-acetylcysteine (NAC) reduced ROS generation and cell growth inhibition, and pretreatment with NAC or a caspase 8 inhibitor (Z-IETD-FMK) inhibited the acacetin-induced loss of mitochondrial membrane potential and release of cytochrome c and AIF. Stress-activated protein kinase/c-Jun NH4-terminal kinase 1/2 (SAPK/ JNK1/2) and c-Jun were activated by acacetin but extracellular-regulated kinase 1/2 (Erk1/2) nor p38 mitogen-activated protein kinase (MAPK) were not. Our results show that acacetin-induced apoptosis of MCF-7 cells is mediated by caspase activation cascades, ROS generation, mitochondria-mediated cell death signaling and the SAPK/JNK1/2-c-Jun signaling pathway, activated by acacetin-induced ROS generation.}, }
@article {pmid17844698, year = {2007}, author = {Balamugesh, T and Behera, D}, title = {Idiopathic pulmonary fibrosis.}, journal = {The Journal of the Association of Physicians of India}, volume = {55}, number = {}, pages = {363-370}, pmid = {17844698}, issn = {0004-5772}, mesh = {Adrenal Cortex Hormones/therapeutic use ; Bronchoscopy ; Cytotoxins/therapeutic use ; Humans ; Immunosuppressive Agents/therapeutic use ; India/epidemiology ; Prognosis ; Pulmonary Fibrosis/*diagnosis/drug therapy/epidemiology ; Risk Factors ; Tomography, X-Ray Computed ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) is being more frequently diagnosed in India, due to its increased awareness, better availability of computed tomography (CT) and fiberoptic bronchoscopy. IPF has the histological appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy. Recent research has given a new insight into the etiology of the disease. Clinical criteria have been specified for presumptive diagnosis of IPF and distinguishing IPF from other conditions. The conventional therapy has been steroids and immunosuppressive agents. But only a minority of patients respond to such a therapy. Immunomodulators (interferon Y1b), antioxidants (Acetyl cysteine) and antifibrotic agents (like pirfenidone) are being studied as novel therapies in this, otherwise, fatal condition. Lung transplantation is the only hope for those patients who show progressive deterioration on medical treatment. Living-donor lobar lung transplantation has been developed as a procedure for patients considered too ill to await cadaveric lung transplantation.}, }
@article {pmid17825281, year = {2007}, author = {Liu, Y and Zhang, H and Zhang, L and Zhou, Q and Wang, X and Long, J and Dong, T and Zhao, W}, title = {Antioxidant N-acetylcysteine attenuates the acute liver injury caused by X-ray in mice.}, journal = {European journal of pharmacology}, volume = {575}, number = {1-3}, pages = {142-148}, doi = {10.1016/j.ejphar.2007.07.026}, pmid = {17825281}, issn = {0014-2999}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Animals ; Antioxidants/*therapeutic use ; Apoptosis/drug effects/physiology ; Colorimetry ; Comet Assay ; DNA Damage/drug effects/physiology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/therapeutic use ; Glutathione/metabolism ; Lipid Peroxidation/drug effects/physiology ; Liver Diseases/*prevention &amp; control ; Malondialdehyde/metabolism ; Mice ; Superoxide Dismutase/metabolism ; *X-Rays ; }, abstract = {The aim of this study was to evaluate the protective effects of different doses and administration modes of N-acetylcysteine (NAC) against X-ray -induced liver damage in mice. Kun-Ming mice were divided into four groups, each composed of six animals: two control groups and two NAC-treated groups. An acute study was carried out to determine alterations in lipid peroxidation (determined by measuring malondiadehyde (MDA) level), glutathione (GSH) content and superoxide dismutase (SOD) activity (assayed by colorimetric method), and DNA damage (characterized by DNA-single strand break using with comet assay) as well as cell apoptosis (measured by flow cytometry) at 12 h after irradiation. The results showed that there were dose-related decreases in MDA level, DNA damage and cell apoptosis, and dose-dependent increases in GSH content and SOD activity in all NAC-treated groups compared to control groups, indicating that pre-treatment or post-treatment with NAC significantly attenuates the acute liver damage caused by X-ray. In addition, significant positive correlations were observed between MDA level and DNA damage or cell apoptosis, implying that lipid peroxidation plays a major role in X-ray-induced liver injury. The data suggest that NAC exerts its radioprotective effect by counteracting accumulated reactive oxygen species in the liver through its properties as a direct antioxidant and a GSH precursor, when administered before or after X-ray irradiation.}, }
@article {pmid17824617, year = {2007}, author = {Fisher, AA and Labenski, MT and Malladi, S and Gokhale, V and Bowen, ME and Milleron, RS and Bratton, SB and Monks, TJ and Lau, SS}, title = {Quinone electrophiles selectively adduct "electrophile binding motifs" within cytochrome c.}, journal = {Biochemistry}, volume = {46}, number = {39}, pages = {11090-11100}, doi = {10.1021/bi700613w}, pmid = {17824617}, issn = {0006-2960}, support = {CA09480/CA/NCI NIH HHS/United States ; T32 ES007091/ES/NIEHS NIH HHS/United States ; ES06694/ES/NIEHS NIH HHS/United States ; P30 ES006694/ES/NIEHS NIH HHS/United States ; R01 GM070890/GM/NIGMS NIH HHS/United States ; GM070890/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Apoptosomes/drug effects/*metabolism ; Benzoquinones/*chemistry/pharmacology ; Caspase 3/chemistry/metabolism ; Caspase 9/chemistry/metabolism ; Cell Line, Tumor ; Chromatography, Liquid ; Circular Dichroism ; Cytochromes c/*chemistry/metabolism ; Horses ; Humans ; Hydrogen-Ion Concentration ; Models, Molecular ; Molecular Sequence Data ; Molecular Structure ; Protein Binding/drug effects ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Tandem Mass Spectrometry ; }, abstract = {Electrophiles generated endogenously, or via the metabolic bioactivation of drugs and other environmental chemicals, are capable of binding to a variety of nucleophilic sites within proteins. Factors that determine site selective susceptibility to electrophile-mediated post-translational modifications, and the consequences of such alterations, remain largely unknown. To identify and characterize chemical-mediated protein adducts, electrophiles with known toxicity were utilized. Hydroquinone, and its mercapturic acid pathway metabolites, cause renal proximal tubular cell necrosis and nephrocarcinogenicity in rats. The adverse effects of HQ and its thioether metabolites are in part a consequence of their oxidation to the corresponding electrophilic 1,4-benzoquinones (BQ). We now report that BQ and 2-(N-acetylcystein-S-yl)benzoquinone (NAC-BQ) preferentially bind to solvent-exposed lysine-rich regions within cytochrome c. Furthermore, we have identified specific glutamic acid residues within cytochrome c as novel sites of NAC-BQ adduction. The microenvironment at the site of adduction governs both the initial specificity and the structure of the final adduct. The solvent accessibility and local pKa of the adducted and neighboring amino acids contribute to the selectivity of adduction. Postadduction chemistry subsequently alters the nature of the final adduct. Using molecular modeling, the impact of BQ and NAC-BQ adduction on cytochrome c was visualized, revealing the spatial rearrangement of critical residues necessary for protein-protein interactions. Consequently, BQ-adducted cytochrome c fails to initiate caspase-3 activation in native lysates and also inhibits Apaf-1 oligomerization into an apoptosome complex in a purely reconstituted system. In summary, a combination of mass spectroscopic, molecular modeling, and biochemical approaches confirms that electrophile-protein adducts produce structural alterations that influence biological function.}, }
@article {pmid17823784, year = {2007}, author = {Erley, C}, title = {[Iodinated contrast agent-induced nephropathy].}, journal = {Der Radiologe}, volume = {47}, number = {9}, pages = {761-767}, pmid = {17823784}, issn = {0033-832X}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Acute Kidney Injury/chemically induced/prevention &amp; control/therapy ; Age Factors ; Angiography/adverse effects ; Clinical Trials as Topic ; Contrast Media/*adverse effects ; Diabetes Complications ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Glomerular Filtration Rate/drug effects/physiology ; Heart Failure/complications ; Humans ; Kidney Diseases/*chemically induced/complications/physiopathology/*prevention &amp; control/therapy ; Renal Replacement Therapy ; Risk Factors ; Theophylline/administration &amp; dosage/therapeutic use ; Tomography, X-Ray Computed/adverse effects ; Vasodilator Agents/administration &amp; dosage/therapeutic use ; }, abstract = {Contrast-induced nephropathy (CIN) is a well-known complication of therapeutic and diagnostic procedures requiring contrast administration and accounts for 10% of acute renal failure in hospitalized patients. Although the incidence of this complication is relatively low, its consequences can be catastrophic. The development of CIN is associated with increased length of hospital stay, an increased requirement for acute dialysis, and an increased risk of death. Preexisting renal dysfunction, age, diabetes, congestive heart failure, and volume of administered contrast are all associated with a risk of developing CIN. Despite a large number of clinical trials that have evaluated prophylaxis strategies for CIN, no uniform strategies have been developed so far. The use of N-acetyl-L-cysteine (NAC) or theophylline in specific subgroups of patients has been shown to reduce dialysis requirement and mortality in patients undergoing angiographic procedures. Hemofiltration has also shown positive results. In this review we will discuss the epidemiology and the risk factors for CIN and the evidence for commonly employed prophylaxis strategies, and we will provide general recommendations with respect to CIN prevention and management.A practicable strategy to prevent CIN includes: correct identification of individuals at greatest risk, thorough evaluation of whether other diagnostic maneuvers could be employed instead (i.e., sonography), application of low-osmolar contrast media at the minimum acceptable dose, stopping potential nephrotoxic drugs (NSAID), hydration with sodium chloride 0.9% 1 ml/kg per h i.v. 12 h before and after CM application, administration of acetylcysteine 600 mg twice the day before and after (in cases of emergency investigation and high-risk patients 1200 mg i.v.), and theophylline (250-350 mg) the day before and the day after CM application (in cases of emergency investigation 5 mg/kg i.v.).}, }
@article {pmid17803476, year = {2007}, author = {Mainra, R and Gallo, K and Moist, L}, title = {Effect of N-acetylcysteine on renal function in patients with chronic kidney disease.}, journal = {Nephrology (Carlton, Vic.)}, volume = {12}, number = {5}, pages = {510-513}, doi = {10.1111/j.1440-1797.2007.00833.x}, pmid = {17803476}, issn = {1320-5358}, mesh = {Acetylcysteine/*pharmacology/*therapeutic use ; Aged ; Chronic Disease ; Cimetidine/pharmacology ; Creatinine/blood ; Cystatin C ; Cystatins/blood ; Drug Synergism ; Female ; Free Radical Scavengers/*pharmacology ; Humans ; Kidney/*drug effects/*physiopathology ; Kidney Diseases/blood/*physiopathology ; Male ; Middle Aged ; Time Factors ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is commonly administered to high-risk individuals to attenuate the risk of contrast-induced nephropathy in spite of the debate regarding its efficacy. In several studies serum creatinine decreased after exposure to NAC and contrast dye. The mechanism by which NAC attenuates the decline in renal function is not known. Studies in subjects with normal renal function suggest NAC may have an effect on tubular secretion.<br><br>AIM: The aim of this study was to determine the effect of NAC on renal function, measured by serum creatinine and Cystatin C, in patients with stage 3 chronic kidney disease.<br><br>METHOD: Serum creatinine and Cystatin C were measured prior to, 4, 24 and 48 h after the administration of 600 mg oral NAC in 30 patients. The protocol was repeated with the addition of 1200 mg oral cimetidine administered 3 h before NAC.<br><br>RESULTS: Serum creatinine was not significantly different from baseline (186 +/- 65 micromol/L) to 4 h (185 +/- 62 micromol/L), 24 h (187 +/- 64 micromol/L) or 48 h (184 +/- 61 micromol/L) post NAC, nor were Cystatin C levels. Co-administration of cimetidine resulted in a significant rise in serum creatinine with no change in Cystatin C levels.<br><br>CONCLUSION: This study failed to detect a change in serum creatinine or Cystatin C after a single dose of NAC in participants with stage 3 chronic kidney disease. Further randomized trials of multiple doses and longer follow up are needed to confirm these results.}, }
@article {pmid17786977, year = {2008}, author = {Wartenberg, M and Wirtz, N and Grob, A and Niedermeier, W and Hescheler, J and Peters, SC and Sauer, H}, title = {Direct current electrical fields induce apoptosis in oral mucosa cancer cells by NADPH oxidase-derived reactive oxygen species.}, journal = {Bioelectromagnetics}, volume = {29}, number = {1}, pages = {47-54}, doi = {10.1002/bem.20361}, pmid = {17786977}, issn = {1521-186X}, mesh = {*Apoptosis ; Cell Line, Tumor ; *Electricity ; Humans ; Mouth Mucosa/enzymology/metabolism/*pathology ; Mouth Neoplasms/enzymology/metabolism/*pathology ; NADPH Oxidases/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {The presence of more than one dental alloy in the oral cavity often causes pathological galvanic currents and voltage resulting in superficial erosions of the oral mucosa and eventually in the emergence of oral cancer. In the present study the mechanisms of apoptosis of oral mucosa cancer cells in response to electromagnetic fields was investigated. Direct current (DC) electrical fields with field strengths between 2 and 16 V/m, applied for 24 h to UM-SCC-14-C oral mucosa cancer cells, dose-dependently resulted in decreased cell proliferation as evaluated by Ki-67 immunohistochemistry and upregulation of the cyclin-dependent kinase (CDK) inhibitors p21(cip1/waf1) and p27(kip1), which are associated with cell cycle arrest. Electrical field treatment (4 V/m, 24 h) increased apoptosis as evaluated by immunohistochemical analysis of cleaved caspase-3 and poly-(ADP-ribose)-polymerase-1 (PARP-1). Furthermore, robust reactive oxygen species (ROS) generation, increased expression of NADPH oxidase subunits as well as Hsp70 was observed. Electrical field treatment (4 V/m, 24 h) resulted in increased expression of Cu/Zn superoxide dismutase and decreased intracellular concentration of reduced glutathione (GSH), whereas the expression of catalase remained unchanged. Pre-treatment with the free radical scavenger N-acetyl cysteine (NAC) and the superoxide dismutase mimetic EUK-8 abolished caspase-3 and PARP-1 induction, suggesting that apoptosis in oral mucosa cancer cells is initated by ROS generation in response to DC electrical field treatment.}, }
@article {pmid17786826, year = {2007}, author = {Fabbri, R and Pasquinelli, G and Montanaro, L and Mozzanega, B and Magnani, V and Tamburini, F and Venturoli, S and Keane, D}, title = {Healthy early preantral follicle can be obtained in a culture of frozen-thawed human ovarian tissue of 32 weeks.}, journal = {Ultrastructural pathology}, volume = {31}, number = {4}, pages = {257-262}, doi = {10.1080/01913120701515496}, pmid = {17786826}, issn = {1521-0758}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Bone Morphogenetic Protein 15 ; Cell Culture Techniques/*methods ; *Cryopreservation ; Culture Media/chemistry ; Female ; Growth Differentiation Factor 9 ; Humans ; Intercellular Signaling Peptides and Proteins/biosynthesis ; Microscopy, Electron, Transmission ; Ovarian Follicle/drug effects/*metabolism/*ultrastructure ; *Ovary ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; }, abstract = {The objective of this study was to report morphological and functional evidence of a well-preserved preantral follicle recovered from human frozen-thawed ovarian tissue in a long-term culture. The tissue was originally obtained from a 26-year-old woman with breast cancer. The ovarian cortex was collected by laparoscopy and frozen/thawed and cultured for 32 weeks in minimum essential medium alpha-MEM, supplemented with insulin transferrine selenite (ITS), human serum (HS), antibiotics, follicle-stimulating hormone (FSH). and N-acetyl cysteine (NAC). Thawed tissue samples were examined by light microscopy (LM), transmission electron microscopy (TEM), and real-time RT-PCR. LM examination of cortical pieces after 32 weeks of culture showed a healthy early preantral follicle; TEM and real-time PCR confirmed its good state of preservation. The synergy in action of NAC and FSH plays an important role in follicle growth of ovarian tissue cultures. For the first time a well-preserved preantral follicle was found in a culture of frozen-thawed human ovarian tissue.}, }
@article {pmid17786245, year = {2007}, author = {Palmer, LA and Doctor, A and Chhabra, P and Sheram, ML and Laubach, VE and Karlinsey, MZ and Forbes, MS and Macdonald, T and Gaston, B}, title = {S-nitrosothiols signal hypoxia-mimetic vascular pathology.}, journal = {The Journal of clinical investigation}, volume = {117}, number = {9}, pages = {2592-2601}, pmid = {17786245}, issn = {0021-9738}, support = {HL059337/HL/NHLBI NIH HHS/United States ; R01 HL068173/HL/NHLBI NIH HHS/United States ; R56 HL059337/HL/NHLBI NIH HHS/United States ; 1K08GM069977/GM/NIGMS NIH HHS/United States ; HL068173/HL/NHLBI NIH HHS/United States ; K08 GM069977/GM/NIGMS NIH HHS/United States ; R01 HL059337/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Animals ; Erythrocytes/drug effects/metabolism ; Glutathione/analogs &amp; derivatives/pharmacology ; Hypertension/physiopathology ; Hypoxia/chemically induced/*metabolism/*pathology ; Mice ; Mice, Knockout ; Nitric Oxide Synthase Type III/deficiency/genetics/metabolism ; Nitro Compounds/pharmacology ; Nitroso Compounds/chemistry/pharmacology ; Oxygen/metabolism ; Pulmonary Artery/*pathology/physiopathology ; S-Nitrosothiols/*metabolism ; *Signal Transduction ; }, abstract = {NO transfer reactions between protein and peptide cysteines have been proposed to represent regulated signaling processes. We used the pharmaceutical antioxidant N-acetylcysteine (NAC) as a bait reactant to measure NO transfer reactions in blood and to study the vascular effects of these reactions in vivo. NAC was converted to S-nitroso-N-acetylcysteine (SNOAC), decreasing erythrocytic S-nitrosothiol content, both during whole-blood deoxygenation ex vivo and during a 3-week protocol in which mice received high-dose NAC in vivo. Strikingly, the NAC-treated mice developed pulmonary arterial hypertension (PAH) that mimicked the effects of chronic hypoxia. Moreover, systemic SNOAC administration recapitulated effects of both NAC and hypoxia. eNOS-deficient mice were protected from the effects of NAC but not SNOAC, suggesting that conversion of NAC to SNOAC was necessary for the development of PAH. These data reveal an unanticipated adverse effect of chronic NAC administration and introduce a new animal model of PAH. Moreover, evidence that conversion of NAC to SNOAC during blood deoxygenation is necessary for the development of PAH in this model challenges conventional views of oxygen sensing and of NO signaling.}, }
@article {pmid17786231, year = {2007}, author = {Marsden, PA}, title = {Low-molecular-weight S-nitrosothiols and blood vessel injury.}, journal = {The Journal of clinical investigation}, volume = {117}, number = {9}, pages = {2377-2380}, pmid = {17786231}, issn = {0021-9738}, mesh = {Acetylcysteine/pharmacology ; Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Blood Vessels/*injuries ; Humans ; Hypertension, Pulmonary/chemically induced/metabolism/pathology ; Molecular Weight ; Nitric Oxide/metabolism ; S-Nitrosothiols/chemistry/*metabolism ; Vascular Diseases/*metabolism/pathology ; }, abstract = {S-nitrosothiol signaling reactions are argued to play key modulatory roles in mediating the actions of NOS in health and disease. A report by Palmer et al. in this issue of the JCI provides new insight into the in vivo biology of S-nitrosothiols (see the related article beginning on page 2592). The authors examine the chronic effects of exogenous nitrosothiol therapy and demonstrate that the commonly used antioxidant N-acetylcysteine (NAC) induces pulmonary arterial hypertension in mice. Importantly, the authors argue that the vascular pathology they observe in the lungs of these animals is functionally and morphologically equivalent to that observed in chronic hypoxia. These findings raise the concern that chronic NAC therapy may induce similar vascular pathology in patients.}, }
@article {pmid17765224, year = {2007}, author = {Yang, D and Elner, SG and Bian, ZM and Till, GO and Petty, HR and Elner, VM}, title = {Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells.}, journal = {Experimental eye research}, volume = {85}, number = {4}, pages = {462-472}, pmid = {17765224}, issn = {0014-4835}, support = {EY09441/EY/NEI NIH HHS/United States ; R01 EY009441-12/EY/NEI NIH HHS/United States ; EY07003/EY/NEI NIH HHS/United States ; R01 EY009441/EY/NEI NIH HHS/United States ; P30 EY007003/EY/NEI NIH HHS/United States ; F31 EY007003/EY/NEI NIH HHS/United States ; }, mesh = {Cells, Cultured ; Cytokines/*pharmacology ; Dose-Response Relationship, Drug ; Electron Transport/drug effects/physiology ; Enzyme Inhibitors/pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Inflammation Mediators/*pharmacology ; Interferon-gamma/pharmacology ; Interleukin-1beta/pharmacology ; Mitochondria/physiology ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Onium Compounds/pharmacology ; Pigment Epithelium of Eye/cytology/*drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Recombinant Proteins/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Reactive oxygen species (ROS) generated during inflammation are believed to play critical roles in various ocular diseases. However, the underlying mechanisms remain poorly understood. We investigated if pro-inflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin-1 beta (IL-1 beta), and interferon-gamma (IFN-gamma), induce ROS in human retinal pigment epithelial (RPE) cells. TNF-alpha, IL-1 beta and IFN-gamma increased both intracellular and extracellular ROS production in a time- and dose-dependent manner. Thenoyltrifluoroacetone (TTFA), an inhibitor of mitochondrial respiratory chain, blocked TNF-alpha- and IFN-gamma-, but not IL-1 beta-induced ROS, whereas other two mitochondrial respiratory chain inhibitors, rotenone and antimycin A, had no effect. NADPH oxidase inhibitor (diphenylene iodinium) abolished the ROS production induced by IL-1 beta or IFN-gamma, but not by TNF-alpha, whereas 6-aminonicotinamide (6AN), an inhibitor of the hexose monophosphate shunt (HMS), had no significant effects on the ROS induced by all three cytokines. ROS scavengers, pyrrolidinedithiocarbamate (PDTC) and N-acetyl-cysteine (NAC), reduced the levels of ROS induced by TNF-alpha, IL-1 beta and IFN-gamma (P<0.05). Collectively, these results demonstrate that TNF-alpha, IL-1 beta and IFN-gamma increase mitochondrial- and NADPH oxidase-generated ROS in human RPE cells.}, }
@article {pmid17763945, year = {2008}, author = {Harvey, BH and Joubert, C and du Preez, JL and Berk, M}, title = {Effect of chronic N-acetyl cysteine administration on oxidative status in the presence and absence of induced oxidative stress in rat striatum.}, journal = {Neurochemical research}, volume = {33}, number = {3}, pages = {508-517}, pmid = {17763945}, issn = {0364-3190}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antipsychotic Agents/toxicity ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Haloperidol/toxicity ; Lipid Peroxidation/drug effects ; Male ; Neostriatum/drug effects/*metabolism/pathology ; Neurodegenerative Diseases/chemically induced/prevention &amp; control ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Superoxides/metabolism ; }, abstract = {Antioxidants have possible therapeutic value in neurodegenerative disorders, although they may have pro-oxidant effects under certain conditions. Glutathione (GSH) is a key free radical scavenger. N-acetylcysteine (NAC) bolsters GSH and intracellular cysteine and also has effective free radical scavenger properties. The effects of chronic NAC administration (50 mg/kg/day, 500 mg/kg/day, 1500 mg/kg/day x 21 days) on cellular markers of oxidative status was studied in striatum of healthy male Sprague-Dawley rats as well as in animals with apparent striatal oxidative stress following chronic haloperidol treatment (1.5 mg/kg/day x 3 weeks). In non-haloperidol treated animals, NAC 50 and 500 mg/kg did not affect oxidative status, although NAC 1,500 mg/kg significantly increased striatal superoxide levels, decreased lipid peroxidation and increased consumption of reduced glutathione (GSH). Haloperidol alone evoked a significant increase in superoxide and lipid peroxidation. All NAC doses blocked haloperidol induced increases in superoxide levels, while NAC 500 mg/kg and 1,500 mg/kg prevented haloperidol-associated lipid peroxidation levels and also increased the GSSG/GSH ratio. NAC may protect against conditions of striatal oxidative stress, although possible pro-oxidative actions at high doses in otherwise healthy individuals, e.g. to offset worsening of neurodegenerative illness, should be viewed with caution.}, }
@article {pmid17761838, year = {2007}, author = {Asaumi, H and Watanabe, S and Taguchi, M and Tashiro, M and Otsuki, M}, title = {Externally applied pressure activates pancreatic stellate cells through the generation of intracellular reactive oxygen species.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {293}, number = {5}, pages = {G972-8}, doi = {10.1152/ajpgi.00018.2007}, pmid = {17761838}, issn = {0193-1857}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Catechin/analogs &amp; derivatives/pharmacology ; Kinetics ; Models, Animal ; Pancreas/*cytology/drug effects/*physiology ; Pancreatitis/pathology/physiopathology ; *Pressure ; Rats ; Reactive Oxygen Species/*metabolism ; Reference Values ; Superoxide Dismutase/metabolism ; }, abstract = {Local tissue pressure is higher in chronic pancreatitis than in the normal pancreas. We reported recently that pressure application induces synthesis of extracellular matrix (ECM) and cytokines in pancreatic stellate cells (PSCs) and that epigallocatechin gallate (EGCG), a potent antioxidant, inhibits the transformation of PSCs from quiescent to activated phenotype and ethanol-induced synthesis of ECM and cytokines in PSCs. These results suggest that oxidative stress and reactive oxygen species (ROS) are important in PSC activation. The aim of this study was to clarify the effects of ROS on activation and functions of pressure-stimulated PSCs. We used freshly isolated rat PSCs and culture-activated PSCs. Pressure was applied on rat cultured PSCs by adding compressed helium gas into a pressure-loading apparatus. PSCs were cultured with or without antioxidants (EGCG and N-acetyl cysteine) under normal or elevated pressure. Externally applied high pressure (80 mmHg) resulted in a gradual decrease of superoxide dismutase activity in PSCs and increased intracellular ROS generation as early as 30 s, reaching a peak level at 1 h. Antioxidants significantly inhibited ROS generation. Pressure increased the expression levels of alpha-smooth muscle actin, alpha(1)(I)-procollagen, and TGF-beta1 in PSCs. EGCG suppressed these alterations, abolished pressure-induced phosphorylation of p38 MAPK, and suppressed pressure-induced PSC transformation to activated phenotype. Our results indicated that ROS is a key player in pressure-induced PSC activation and ECM synthesis. Antioxidants could be potentially effective against the development of pancreatic fibrosis in patients with chronic pancreatitis.}, }
@article {pmid17760840, year = {2007}, author = {Das, M and Das, S and Das, DK}, title = {Caveolin and MAP kinase interaction in angiotensin II preconditioning of the myocardium.}, journal = {Journal of cellular and molecular medicine}, volume = {11}, number = {4}, pages = {788-797}, pmid = {17760840}, issn = {1582-1838}, support = {R01 HL034360/HL/NHLBI NIH HHS/United States ; HL 34360/HL/NHLBI NIH HHS/United States ; R01 HL022559/HL/NHLBI NIH HHS/United States ; HL 33889/HL/NHLBI NIH HHS/United States ; HL 22559/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Angiotensin II/*pharmacology ; Animals ; Apoptosis/drug effects ; Caveolins/*metabolism ; In Vitro Techniques ; *Ischemic Preconditioning, Myocardial ; Mitogen-Activated Protein Kinases/*metabolism ; Myocytes, Cardiac/cytology/drug effects/enzymology ; Phosphoproteins/metabolism ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; }, abstract = {Angiotensin II (Ang II) has been found to exert preconditioning (PC)-like effect in mammalian hearts. The present investigation reported for the first time a unique mitogen activated protein (MAP) kinase signalling in Ang II PC of the heart involving lipid rafts, which generated a survival signal by differentially associating MAP kinases with caveolin. A group of rat hearts was treated with Ang II in the absence or presence of NADPH oxidase inhibitor, apocynin or a cell permeable reactive oxygen species (ROS) scavenger, N-acetyl-cysteine (NAC). Ang II pre-treatment improved post-ischaemic ventricular recovery, myocardial infraction and decreased the number of cardiomyocyte apoptosis indicating PC effect of Ang II. Both apocynin and NAC abolished the PC ability of Ang II. In Ang II treated heart, there was a decreased association of p38MAPKbeta &amp; extracellular-signal regulated kinase (ERK) 1/ 2 (anti-death signalling component) with caveolin while there was an increased association of p38MAPKalpha &amp; Jun N-terminal kinase (JNK) (death signalling component) indicating reduced amount of death signal components and increased amount of anti-death signalling components being available to the Ang II treated heart to generate a survival signal, which was reversed with NAC or apocynin. The survival signal was also demonstrated by increased phosphorylation of serine/threonine-protein kinase B (AKT) and enhanced induction of expression of Bcl-2 during Ang II PC and its reversal with NAC &amp; apocynin treated heart.}, }
@article {pmid17760653, year = {2007}, author = {Zingg, U and Hofer, CK and Seifert, B and Metzger, U and Zollinger, A}, title = {High dose N-acetylcysteine to prevent pulmonary complications in partial or total transthoracic esophagectomy: results of a prospective observational study.}, journal = {Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus}, volume = {20}, number = {5}, pages = {399-405}, doi = {10.1111/j.1442-2050.2007.00690.x}, pmid = {17760653}, issn = {1120-8694}, mesh = {Acetylcysteine/*administration &amp; dosage ; Dose-Response Relationship, Drug ; Esophageal Neoplasms/mortality/surgery ; Esophagectomy/*adverse effects/methods ; Female ; Follow-Up Studies ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Length of Stay ; Lung Diseases/etiology/*prevention &amp; control ; Male ; Middle Aged ; Oxygen/blood ; Postoperative Period ; Prospective Studies ; Retrospective Studies ; Treatment Outcome ; }, abstract = {Cancer of the esophagus has a poor long-term prognosis and a high peri-operative morbidity in which pulmonary complications play a major role. The combination of the surgical approach, pre-existing pulmonary disorders, poor nutritional status and the release of pro-inflammatory cytokines may be contributing factors. N-acetylcysteine ((NAC) has been shown to have oxygen scavenging abilities. In severe sepsis and acute respiratory distress syndrome, positive effects of NAC on morbidity and mortality were discovered. In this observational study peri-operative high dose NAC was administered in 22 patients. The effects of this treatment on respiratory function, morbidity and survival were studied. These prospectively collected data were compared with data of a matched, retrospective group without NAC treatment. There were no significant differences between the groups in terms of socio-demographic data, preoperative pulmonary function, intra-operative course and oncologic characteristics. The oxygenation indices at the postoperative hours 2 (P = 0.019), 4 (P < 0.001), 8 (P = 0.035), 12 (P = 0.035) and 24 (P = 0.046) were significantly higher in the NAC group. After 36 h, the difference between groups was no longer significant (P = 0.064). NAC-treated patients showed significant lower overall pulmonary morbidity, 45.5% versus 81.8% (P = 0.027). Surgical morbidity, intensive care unit and hospital stay were not significantly different between groups, mortality was zero. Kaplan-Meier curves showed no significant difference in survival 12 months postoperatively. These data indicate that postoperative oxygenation can be improved and rate of overall pulmonary complications is reduced using peri-operative high dose NAC in transthoracic esophagectomy.}, }
@article {pmid17728093, year = {2008}, author = {Grosicka-Maciag, E and Kurpios, D and Czeczot, H and Szumiło, M and Skrzycki, M and Suchocki, P and Rahden-Staroń, I}, title = {Changes in antioxidant defense systems induced by thiram in V79 Chinese hamster fibroblasts.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {22}, number = {1}, pages = {28-35}, doi = {10.1016/j.tiv.2007.07.006}, pmid = {17728093}, issn = {0887-2333}, mesh = {Animals ; Antioxidants/*metabolism ; Catalase/drug effects/metabolism ; Cell Line ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Drug ; Fibroblasts/*drug effects/metabolism ; Free Radicals/metabolism ; Fungicides, Industrial/administration &amp; dosage/*toxicity ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Glutathione Peroxidase/drug effects/metabolism ; Glutathione Reductase/drug effects/metabolism ; In Vitro Techniques ; Superoxide Dismutase/drug effects/metabolism ; Superoxide Dismutase-1 ; Thiram/administration &amp; dosage/*toxicity ; }, abstract = {The role of antioxidant defence systems in protection against oxidative damage of lipids and proteins induced by fungicide thiram during in vitro exposure was investigated in cultured Chinese hamster V79 cells with normal, depleted, and elevated glutathione (GSH) levels. We analyzed the catalytic activities of superoxide dismutases (SOD1 and SOD2), Se-dependent and Se-independent glutathione peroxidases (GSH-Px), glutathione reductase (GR), and catalase (CAT), as well as total glutathione/glutathione disulfide ratio (GSH(total)/GSSG). Thiram treatment resulted in an increase in activities of SOD1, Se-dependent GSH-Px, and GR at the highest tested dose (150 microM). On the contrary, inhibition of CAT and Se-independent GSH-Px activities, and no significant changes in the level of SOD2 activity was observed at any tested doses (100-150 microM). GSH(total)/GSSG ratio in the 100 microM thiram treated cells was not significantly changed comparing to the control, despite significant decrease of GSH total (50%). In 150 microM thiram treated cells the ratio falls to 43% of control value. Pretreatment with l-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, significantly enhanced decrease in CAT and Se-independent GSH-Px activities, as well as GSH(total)/GSSG ratio, and reduced Se-dependent GSH-Px activity, following exposure to thiram. Simultaneously, L-BSO pretreatment enhanced increase in SOD1 activity, and had no effect on SOD2, following thiram exposure. Pretreatment with N-acetyl cysteine (NAC), a GSH precursor, prevented enzymatic changes in CAT, Se-dependent GSH-Px, GR, SOD1 activities, and significantly decreased SOD2 activity following exposure to thiram. GSH(total)/GSSG ratio was restored to the control value. This study suggests that following the changes in antioxidant defense systems thiram can act through the production of free radicals.}, }
@article {pmid17727829, year = {2007}, author = {Ahmed, K and Zhao, QL and Matsuya, Y and Yu, DY and Feril, LB and Nemoto, H and Kondo, T}, title = {Rapid and transient intracellular oxidative stress due to novel macrosphelides trigger apoptosis via Fas/caspase-8-dependent pathway in human lymphoma U937 cells.}, journal = {Chemico-biological interactions}, volume = {170}, number = {2}, pages = {86-99}, doi = {10.1016/j.cbi.2007.07.007}, pmid = {17727829}, issn = {0009-2797}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Blotting, Western ; Caspase 8/*metabolism ; Cytochromes c/metabolism ; Flow Cytometry ; Glutathione/metabolism ; Heterocyclic Compounds/*pharmacology ; Humans ; Lipid Peroxidation ; Membrane Potentials ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; U937 Cells ; fas Receptor/*metabolism ; }, abstract = {The ability of the derivatives of macrosphelides (MS) core (simplified 16-membered core structure of natural MS) to induce apoptosis in human lymphoma U937 cells was investigated. Of the five compounds examined, MS core with ketones at 8 and 14 positions (MS5) showed the highest potency to induce apoptosis, while another, MS3 with one ketone, was minimal potent. MS5 was found to induce apoptosis in the U937 cells in a time- and dose-dependent fashion, as confirmed by DNA fragmentation analysis. MS5 treated cells showed increase in intracellular reactive oxygen species (ROS), glutathione depletion, Bid activation and lipid peroxidation. Pretreatment of cells with pancaspase inhibitor resulted in the complete inhibition of MS5-induced apoptosis. N-Acetyl-l-cysteine (NAC) pretreatment resulted in the increase in glutathione concentration, reduction of intracellular ROS, complete inhibition of DNA fragmentation, mitochondrial membrane potential (MMP) collapse, Fas externalization and caspase-8 activation. Furthermore, MS5-induced oxidative stress also triggered transient increase in intracellular calcium ion ([Ca2+]i) concentration which was completely inhibited by NAC. Pretreatment with an intracellular Ca2+ chelator, BAPTA-AM reduced MS5-induced DNA fragmentation and caspase-8 activation while it has marginal effects on MMP collapse. Taken together our present data showed that a rapid increase in intracellular ROS by MS5 triggers apoptosis via the Fas/caspase-8-mediated mitochondrial pathway suggesting that the presence of diketone makes the compound more potent to induce apoptosis. These characteristics of MS5 will make it useful for therapeutic applications of targeted apoptosis.}, }
@article {pmid17724027, year = {2007}, author = {Franco, R and Panayiotidis, MI and Cidlowski, JA}, title = {Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation.}, journal = {The Journal of biological chemistry}, volume = {282}, number = {42}, pages = {30452-30465}, pmid = {17724027}, issn = {0021-9258}, support = {NIH0011756287//Intramural NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; *Apoptosis/drug effects ; Cell Death/drug effects ; Free Radical Scavengers/pharmacology ; Glutathione/*deficiency/pharmacology ; Humans ; Jurkat Cells ; Lipid Peroxidation/drug effects ; Lymphocytes/*metabolism ; Membrane Transport Proteins/*metabolism ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/*metabolism ; Receptors, Death Domain/metabolism ; *Signal Transduction/drug effects ; }, abstract = {Changes in the intracellular redox environment of cells have been reported to be critical for the activation of apoptotic enzymes and the progression of programmed cell death. Glutathione (GSH) depletion is an early hallmark observed in apoptosis, and we have demonstrated that GSH efflux during death receptor-mediated apoptosis occurs via a GSH transporter. We now evaluate the relationship between GSH depletion, the generation of reactive oxygen species (ROS), and the progression of apoptosis. Simultaneous single cell analysis of changes in GSH content and ROS formation by multiparametric FACS revealed that loss of intracellular GSH was paralleled by the generation of different ROS including hydrogen peroxide, superoxide anion, hydroxyl radical, and lipid peroxides. However, inhibition of ROS formation by a variety of antioxidants showed that GSH loss was independent from the generation of ROS. Furthermore, GSH depletion was observed to be necessary for ROS generation. Interestingly, high extracellular thiol concentration (GSH and N-acetyl-cysteine) inhibited apoptosis, whereas, inhibition of ROS generation by other non-thiol antioxidants was ineffective in preventing cell death. Finally, GSH depletion was shown to be a necessary for the progression of apoptosis activated by both extrinsic and intrinsic signaling pathways. These results document a necessary and critical role for GSH loss in apoptosis and clearly uncouple for the first time GSH depletion from ROS formation.}, }
@article {pmid17721603, year = {2007}, author = {Ai, X and Xu, Q and Jones, M and Song, Q and Ding, SY and Ellingson, RJ and Himmel, M and Rumbles, G}, title = {Photophysics of (CdSe)ZnS colloidal quantum dots in an aqueous environment stabilized with amino acids and genetically-modified proteins.}, journal = {Photochemical &amp; photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology}, volume = {6}, number = {9}, pages = {1027-1033}, doi = {10.1039/b706471c}, pmid = {17721603}, issn = {1474-905X}, mesh = {Amino Acids/genetics/*metabolism ; Cadmium Compounds/*chemistry ; Cellulase/genetics/*metabolism ; Colloids ; Microscopy, Electron, Transmission ; Molecular Structure ; Photochemistry ; *Quantum Dots ; Recombinant Proteins/genetics/metabolism ; Selenium Compounds/*chemistry ; Zinc Compounds/*chemistry ; }, abstract = {Using a combination of two amino acids, histidine and N-acetyl-cysteine, to replace the original organic capping groups of (CdSe)ZnS quantum dots, water-soluble and highly luminescent (CdSe)ZnS quantum dots have been successfully prepared at pH 8. Characterization by steady-state and time-resolved photoluminescence spectroscopy, and transient absorption spectroscopy, demonstrate that the electronic properties of these quantum dots exceed those of the original as-synthesized samples dissolved in a more-conventional organic solvent. Furthermore, these amino acid-stabilized quantum dots have been assembled onto a cellulose substrate via cellulose binding proteins that specifically bind to cellulose and was genetically engineered to harbor dual hexahistidine tags at the N- and C-termini to confer binding with the zinc(II) on the quantum dot surface. The spectroscopic measurements show that the protein-bound quantum dots continue to retain their desirable electronic properties when bound on the substrate. Meanwhile, the specific and very selective binding properties of the proteins have remained effective.}, }
@article {pmid17719565, year = {2008}, author = {Zhou, W and Kalivas, PW}, title = {N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking.}, journal = {Biological psychiatry}, volume = {63}, number = {3}, pages = {338-340}, pmid = {17719565}, issn = {1873-2402}, support = {P50 DA015369-06/DA/NIDA NIH HHS/United States ; P50 DA015369/DA/NIDA NIH HHS/United States ; DA-15369/DA/NIDA NIH HHS/United States ; R37 DA003906-25/DA/NIDA NIH HHS/United States ; R01 DA003906/DA/NIDA NIH HHS/United States ; DA-12513/DA/NIDA NIH HHS/United States ; R01 DA012513-09/DA/NIDA NIH HHS/United States ; R01 DA012513/DA/NIDA NIH HHS/United States ; R37 DA003906/DA/NIDA NIH HHS/United States ; P50 DA015369-060005/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Behavior, Animal/drug effects ; *Cues ; Disease Models, Animal ; Drug Interactions ; Extinction, Psychological/*drug effects ; Free Radical Scavengers/*pharmacology ; Heroin/*administration &amp; dosage ; Heroin Dependence/*drug therapy/psychology ; Male ; Narcotics/*administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; Time Factors ; }, abstract = {BACKGROUND: Previous studies show that the acute administration of N-acetylcysteine (NAC) inhibits the desire for cocaine in addicts and cocaine-seeking in animals.<br><br>METHODS: Rats were trained to self-administer heroin, and the reinstatement model of drug seeking was used to determine whether chronic NAC treatment inhibited heroin-seeking.<br><br>RESULTS: Daily NAC administration inhibited cue- and heroin-induced seeking. Moreover, repeated NAC administration during extinction training reduced extinction-responding and inhibited cue- and heroin-induced reinstatement for up to 40 days after discontinuing daily NAC injection.<br><br>CONCLUSIONS: These data show that daily NAC inhibits heroin-induced reinstatement and produces an enduring reduction in cue- and heroin-induced drug seeking for over 1 month after the last injection of NAC. Both the inhibitory effect of NAC on the reinstatement of heroin-seeking and the ability of NAC to reduce extinction-responding support clinical evaluation of repeated NAC administration to decrease in drug-seeking in heroin addicts.}, }
@article {pmid17719303, year = {2007}, author = {Ozcan, EE and Guneri, S and Akdeniz, B and Akyildiz, IZ and Senaslan, O and Baris, N and Aslan, O and Badak, O}, title = {Sodium bicarbonate, N-acetylcysteine, and saline for prevention of radiocontrast-induced nephropathy. A comparison of 3 regimens for protecting contrast-induced nephropathy in patients undergoing coronary procedures. A single-center prospective controlled trial.}, journal = {American heart journal}, volume = {154}, number = {3}, pages = {539-544}, doi = {10.1016/j.ahj.2007.05.012}, pmid = {17719303}, issn = {1097-6744}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; *Angioplasty, Balloon, Coronary ; Contrast Media/*adverse effects ; *Coronary Angiography ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Prospective Studies ; Sodium Bicarbonate/*therapeutic use ; Sodium Chloride/*therapeutic use ; }, abstract = {BACKGROUND: Several protective therapies have been developed to prevent contrast-induced nephropathy (CIN). We aimed to investigate the efficacy of sodium bicarbonate by comparing 2 other regimens, including combination of N-acetylcysteine (NAC) plus sodium chloride and sodium chloride alone, to prevent CIN in patients undergoing cardiovascular procedures.<br><br>METHODS: We prospectively enrolled 264 patients who were scheduled for cardiovascular procedures and had a baseline creatinine level >1.2 mg/dL. The patients were assigned 1 of 3 prophylactic regimens: infusion of sodium bicarbonate, sodium chloride, sodium chloride plus oral NAC (600 mg bid). Contrast-induced nephropathy was defined as an increase in serum creatinine level >25% or 0.5 mg/dL after 48 hours.<br><br>RESULTS: There were no significant differences among groups regarding baseline demographic properties and nephropathy risk factors. The change in creatinine clearance was significantly better in the sodium bicarbonate group than other 2 groups (P = .007). The incidence of CIN was significantly lower in the sodium bicarbonate group (4.5%) compared with sodium chloride alone (13.6%, P = .036) and tended to be lower than in the combination group (12.5%, P = .059). After adjusting the Mehran nephropathy risk score, the risk of CIN significantly reduced with sodium bicarbonate compared with sodium chloride alone (adjusted risk ratio 0.29, P = .043).<br><br>CONCLUSIONS: Hydration with sodium bicarbonate provides better protection against CIN than the sodium chloride infusion does alone. Combination therapy of NAC plus sodium chloride did not offer additional benefit over hydration with sodium chloride alone.}, }
@article {pmid17718901, year = {2007}, author = {Shankar, S and Chen, Q and Siddiqui, I and Sarva, K and Srivastava, RK}, title = {Sensitization of TRAIL-resistant LNCaP cells by resveratrol (3, 4', 5 tri-hydroxystilbene): molecular mechanisms and therapeutic potential.}, journal = {Journal of molecular signaling}, volume = {2}, number = {}, pages = {7}, pmid = {17718901}, issn = {1750-2187}, support = {R01 CA114469/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: We have previously shown that prostate cancer LNCaP cells are resistant to TRAIL, and downregulation of PI-3K/Akt pathway by molecular and pharmacological means sensitizes cells to undergo apoptosis by TRAIL and curcumin. The purpose of this study was to examine the molecular mechanisms by which resveratrol sensitized TRAIL-resistant LNCaP cells.<br><br>RESULTS: Resveratrol inhibited growth and induced apoptosis in androgen-dependent LNCaP cells, but had no effect on normal human prostate epithelial cells. Resveratrol upregulated the expression of Bax, Bak, PUMA, Noxa, Bim, TRAIL-R1/DR4 and TRAIL-R2/DR5, and downregulated the expression of Bcl-2, Bcl-XL, survivin and XIAP. Treatment of LNCaP cells with resveratrol resulted in generation of reactive oxygen species, translocation of Bax and p53 to mitochondria, subsequent drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, AIF, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and caspase-9 and induction of apoptosis. The ability of resveratrol to sensitize TRAIL-resistant LNCaP cells was inhibited by dominant negative FADD, caspase-8 siRNA or N-acetyl cysteine. Smac siRNA inhibited resveratrol-induced apoptosis, whereas Smac N7 peptide induced apoptosis and enhanced the effectiveness of resveratrol.<br><br>CONCLUSION: Resveratrol either alone or in combination with TRAIL or Smac can be used for the prevention and/or treatment of human prostate cancer.}, }
@article {pmid17718197, year = {2007}, author = {Jiao, Z and Qu, Z and Ge, X and Ao, Q and Xiong, M}, title = {Protective role of tretinoin and N-acetyl-L-cysteine from antiproliferative action of cigarette smoke extract on alveolar epithelial cells.}, journal = {Die Pharmazie}, volume = {62}, number = {7}, pages = {539-543}, pmid = {17718197}, issn = {0031-7144}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/*pharmacology ; Blotting, Western ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Down-Regulation/drug effects ; Epithelial Cells/drug effects ; Free Radical Scavengers/*pharmacology ; Humans ; Indicators and Reagents ; Insulin-Like Growth Factor Binding Protein 2/antagonists &amp; inhibitors/biosynthesis ; Pulmonary Alveoli/*cytology/drug effects ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Smoke/*adverse effects ; Nicotiana/*chemistry ; Tretinoin/*pharmacology ; }, abstract = {To investigate the mechanisms by which tretinoin and N-acetyl-L-cysteine (NAC) reverse the growth inhibition of alveolar epithelial cells induced by cigarette smoke extract (CSE), MTT assay was used to evaluate cell viability. It was observed that both tretinoin and NAC could restore the viability of CSE-inhibited A549 cells. By incubation with fluorescent indicator H2DCFDA, it was documented that CSE-stimulated accumulation of intracellular reactive oxygen species (ROS) was obviously decreased by tretinoin or NAC. Furthermore, using semi-quantitative and real-time quantitative RT-PCR as well as western blot methods, high expression of insulin-like growth factor binding protein-2 (IGFBP-2) in A549 cells treated with CSE was found at both transcriptional and protein levels, and concomitant with the restoration of cell growth after treatment with tretinoin or NAC, down regulation of IGFBP-2 was observed. From the present study, it is concluded that both RA and NAC can antagonize CSE-induced growth arrest of alveolar epithelial cells and that down regulation of IGFBP-2 may play an important role in the process.}, }
@article {pmid17717282, year = {2007}, author = {Oprescu, AI and Bikopoulos, G and Naassan, A and Allister, EM and Tang, C and Park, E and Uchino, H and Lewis, GF and Fantus, IG and Rozakis-Adcock, M and Wheeler, MB and Giacca, A}, title = {Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo.}, journal = {Diabetes}, volume = {56}, number = {12}, pages = {2927-2937}, doi = {10.2337/db07-0075}, pmid = {17717282}, issn = {1939-327X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Blood Glucose/drug effects/metabolism ; C-Peptide/blood ; Diabetes Mellitus, Type 2/blood/complications ; Fatty Acids, Nonesterified/*pharmacology ; Female ; Glucose/*pharmacology ; Infusions, Intravenous ; Insulin/blood/*metabolism ; Insulin Secretion ; Obesity/blood ; Oleic Acid/*pharmacology ; Oxidative Stress/drug effects/*physiology ; RNA, Messenger/genetics ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Taurine/pharmacology ; }, abstract = {OBJECTIVE: An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease beta-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in beta-cell function.<br><br>RESEARCH DESIGN AND METHODS: We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells.<br><br>RESULTS: Forty-eight-hour infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp (P < 0.01), an effect prevented by coinfusion of the antioxidants N-acetylcysteine (NAC) and taurine. Similar to the findings in vivo, 48-h infusion of oleate decreased glucose-stimulated insulin secretion ex vivo (P < 0.01) and induced oxidative stress (P < 0.001) in isolated islets, effects prevented by coinfusion of the antioxidants NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight-hour infusion of olive oil induced oxidative stress (P < 0.001) and decreased the insulin response of isolated islets similar to oleate (P < 0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both P < 0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells after oleate exposure, an effect partially prevented by taurine.<br><br>CONCLUSIONS: Our data are the first demonstration that oxidative stress plays a role in the decrease in beta-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo.}, }
@article {pmid17715118, year = {2007}, author = {Poletti, PA and Saudan, P and Platon, A and Mermillod, B and Sautter, AM and Vermeulen, B and Sarasin, FP and Becker, CD and Martin, PY}, title = {I.v. N-acetylcysteine and emergency CT: use of serum creatinine and cystatin C as markers of radiocontrast nephrotoxicity.}, journal = {AJR. American journal of roentgenology}, volume = {189}, number = {3}, pages = {687-692}, doi = {10.2214/AJR.07.2356}, pmid = {17715118}, issn = {1546-3141}, mesh = {Acetylcysteine/*administration &amp; dosage ; *Acute Kidney Injury/blood/chemically induced/prevention &amp; control ; Adult ; Biomarkers/blood ; Contrast Media/adverse effects ; Creatinine/*blood ; Cystatin C ; Cystatins/*blood ; Emergency Medical Services/methods ; Female ; Humans ; Injections, Intravenous/adverse effects ; Iohexol/adverse effects/*analogs &amp; derivatives ; Male ; Tomography, X-Ray Computed/*adverse effects ; Treatment Outcome ; }, abstract = {OBJECTIVE: The purpose of this study was to assess the effect of i.v. administration of N-acetylcysteine (NAC) on serum levels of creatinine and cystatin C, two markers of renal function, in patients with renal insufficiency who undergo emergency contrast-enhanced CT.<br><br>SUBJECTS AND METHODS: Eighty-seven adult patients with renal insufficiency who underwent emergency CT were randomized to two groups. In the first group, in addition to hydration, patients received a 900-mg injection of NAC 1 hour before and another immediately after injection of iodine contrast medium. Patients in the second group received hydration only. Serum levels of creatinine and cystatin C were measured at admission and on days 2 and 4 after CT. Nephrotoxicity was defined as a 25% or greater increase in serum creatinine or cystatin C concentration from baseline value.<br><br>RESULTS: A 25% or greater increase in serum creatinine concentration was found in nine (21%) of 43 patients in the control group and in two (5%) of 44 patients in the NAC group (p = 0.026). A 25% or greater increase in serum cystatin C concentration was found in nine (22%) of 40 patients in the control group and in seven (17%) of 41 patients in the NAC group (p = 0.59).<br><br>CONCLUSION: On the basis of serum creatinine concentration only, i.v. administration of NAC appears protective against the nephrotoxicity of contrast medium. No effect is found when serum cystatin C concentration is used to assess renal function. The effect of NAC on serum creatinine level remains unclear and may not be related to a renoprotective action.}, }
@article {pmid17714694, year = {2007}, author = {Omodeo-Salè, F and Cortelezzi, L and Riva, E and Vanzulli, E and Taramelli, D}, title = {Modulation of glyceraldehyde 3 phosphate dehydrogenase activity and tyr-phosphorylation of Band 3 in human erythrocytes treated with ferriprotoporphyrin IX.}, journal = {Biochemical pharmacology}, volume = {74}, number = {9}, pages = {1383-1389}, doi = {10.1016/j.bcp.2007.07.012}, pmid = {17714694}, issn = {0006-2952}, mesh = {Anion Exchange Protein 1, Erythrocyte/*metabolism ; Blotting, Western ; Cells, Cultured ; Electrophoresis, Polyacrylamide Gel ; Erythrocyte Membrane/*drug effects/enzymology/metabolism ; Erythrocytes/cytology/*drug effects/enzymology/metabolism ; Glyceraldehyde-3-Phosphate Dehydrogenases/*metabolism ; Hemin/*pharmacology ; Humans ; Phosphorylation ; Tyrosine/*metabolism ; }, abstract = {Erythrocyte glyceraldehyde-3-phosphate dehydrogenase (G3PD), is a glycolytic enzyme normally inhibited upon binding to the anion transporter Band 3 and activated when free in the cytosol. We have previously reported that ferric protoporphyrin IX (FP) enhances G3PD activity in human erythrocytes (RBC). This could be due to two mechanisms considered in this work: Band 3 tyrosine phosphorylation or oxidative damage of specific G3PD binding sites in the membrane. In both cases binding of G3PD to the membrane would be prevented, leading to the enhancement of G3PD activity. Here, we show that FP induces a dose- and time-dependent phosphorylation of tyrosine 8 and 21 of Band 3, as confirmed by the recruitment of SHP2 phosphatase to the membrane. It appears that Band 3 phosphorylation is due to the oxidation of critical sulfydryl groups of a membrane phosphatase (PTP). Data on membrane localization, Mg2+ dependence, sensitivity to thiol oxidizing agents and protection by N-acetylcysteine (NAC) and DTT strongly suggest the involvement of PTP1B, the major PTP of human RBC associated to and acting on Band 3. However, FP activates G3PD even when Band 3 phosphorylation is inhibited, therefore phosphorylation is not the mechanism underlying G3PD activation by FP. The capacity of NAC of counteracting the stimulatory activity of FP, supports the hypothesis that FP might induce the oxidative damage of specific G3PD binding sites in the membrane, causing the displacement of the enzyme into the cytosol and/or the release from its binding site and therefore its activation.}, }
@article {pmid17712668, year = {2007}, author = {Bielefeld, EC and Kopke, RD and Jackson, RL and Coleman, JK and Liu, J and Henderson, D}, title = {Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration.}, journal = {Acta oto-laryngologica}, volume = {127}, number = {9}, pages = {914-919}, doi = {10.1080/00016480601110188}, pmid = {17712668}, issn = {0001-6489}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Auditory Threshold ; Chinchilla ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Evoked Potentials, Auditory, Brain Stem ; Free Radical Scavengers/*administration &amp; dosage ; Hearing Loss, Noise-Induced/*prevention &amp; control ; Models, Animal ; Noise/adverse effects ; }, abstract = {CONCLUSION: These studies extend previous work on N-acetyl-l-cysteine (NAC) and noise, showing protection with NAC against a high-kurtosis noise, showing protection with NAC at low doses, as well as protection by oral gavage. The studies further reveal the potential for the use of NAC in a clinical population exposed to noise.<br><br>OBJECTIVE: To extend previous work on NAC protection from noise, the current study examined the effectiveness of NAC against a high-kurtosis noise that combined continuous and impact noise, tested the effectiveness of NAC at varying doses, and tested NAC when administered by gavage.<br><br>MATERIALS AND METHODS: Chinchillas were tested for auditory brainstem responses (ABRs) at five frequencies before and at three time points after one of three noise exposures: high-kurtosis (2 h, 108 dB L(eq)), impulse (75 pairs of 155 dB pSPL impulses), or continuous (4 kHz octave band, 105 dB SPL for 6 h). Animals were treated with NAC or saline vehicle before and after noise.<br><br>RESULTS: The NAC was protective against the high-kurtosis noise both at low doses and when given orally by gavage.}, }
@article {pmid17709050, year = {2007}, author = {Wolf, SJ and Heard, K and Sloan, EP and Jagoda, AS and , }, title = {Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose.}, journal = {Annals of emergency medicine}, volume = {50}, number = {3}, pages = {292-313}, doi = {10.1016/j.annemergmed.2007.06.014}, pmid = {17709050}, issn = {1097-6760}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Emergency Service, Hospital ; Humans ; Poisoning/*drug therapy ; }, abstract = {This clinical policy focuses on critical issues concerning the management of patients presenting to the emergency department (ED) with acetaminophen overdose. The subcommittee reviewed the medical literature relevant to the questions posed. The critical questions are: 1. What are the indications for N-acetylcysteine (NAC) in the acetaminophen overdose patient with a known time of acute ingestion who can be risk stratified by the Rumack-Matthew nomogram? 2. What are the indications for NAC in the acetaminophen overdose patient who cannot be risk stratified by the Rumack-Matthew nomogram? Recommendations are provided on the basis of the strength of evidence of the literature. Level A recommendations represent patient management principles that reflect a high degree of clinical certainty; Level B recommendations represent patient management principles that reflect moderate clinical certainty; and Level C recommendations represent other patient management strategies that are based on preliminary, inconclusive, or conflicting evidence, or based on committee consensus. This guideline is intended for physicians working in EDs.}, }
@article {pmid17707397, year = {2007}, author = {Adamy, C and Mulder, P and Khouzami, L and Andrieu-abadie, N and Defer, N and Candiani, G and Pavoine, C and Caramelle, P and Souktani, R and Le Corvoisier, P and Perier, M and Kirsch, M and Damy, T and Berdeaux, A and Levade, T and Thuillez, C and Hittinger, L and Pecker, F}, title = {Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats.}, journal = {Journal of molecular and cellular cardiology}, volume = {43}, number = {3}, pages = {344-353}, doi = {10.1016/j.yjmcc.2007.06.010}, pmid = {17707397}, issn = {0022-2828}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Cardiotonic Agents/*therapeutic use ; Case-Control Studies ; Disease Models, Animal ; Echocardiography, Doppler ; Glutathione/deficiency/metabolism ; Heart Failure/*drug therapy ; Male ; Myocardial Infarction/*drug therapy/etiology/pathology ; Oxidative Stress/drug effects ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Sphingomyelin Phosphodiesterase/*antagonists &amp; inhibitors/metabolism ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Deficiency in cellular thiol tripeptide glutathione (L-gamma glutamyl-cysteinyl-glycine) determines the severity of several chronic and inflammatory human diseases that may be relieved by oral treatment with the glutathione precursor N-acetylcysteine (NAC). Here, we showed that the left ventricle (LV) of human failing heart was depleted in total glutathione by 54%. Similarly, 2-month post-myocardial infarction (MI) rats, with established chronic heart failure (CHF), displayed deficiency in LV glutathione. One-month oral NAC treatment normalized LV glutathione, improved LV contractile function and lessened adverse LV remodelling in 3-month post-MI rats. Biochemical studies at two time-points of NAC treatment, 3 days and 1 month, showed that inhibition of the neutral sphingomyelinase (N-SMase), Bcl-2 depletion and caspase-3 activation, were key, early and lasting events associated with glutathione repletion. Attenuation of oxidative stress, downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and its TNF-R1 receptor were significant after 1-month NAC treatment. These data indicate that, besides glutathione deficiency, N-SMase activation is associated with post-MI CHF progression, and that blockade of N-SMase activation participates to post-infarction failing heart recovery achieved by NAC treatment. NAC treatment in post-MI rats is a way to disrupt the vicious sTNF-alpha/TNF-R1/N-SMase cycle.}, }
@article {pmid17706441, year = {2007}, author = {Lee, DH and Lim, BS and Lee, YK and Yang, HC}, title = {Mechanisms of root canal sealers cytotoxicity on osteoblastic cell line MC3T3-E1.}, journal = {Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics}, volume = {104}, number = {5}, pages = {717-721}, doi = {10.1016/j.tripleo.2007.05.018}, pmid = {17706441}, issn = {1528-395X}, mesh = {Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cattle ; Cell Line ; Chromans/*pharmacology ; Cystine/*analogs &amp; derivatives/pharmacology ; DNA Fragmentation/drug effects ; Glutathione/analysis ; Mice ; Osteoblasts/*drug effects ; Reactive Oxygen Species/analysis ; Root Canal Filling Materials/*toxicity ; }, abstract = {OBJECTIVE: The cytotoxic mechanisms of root canal sealers (Sealapex, AH26, and N2 Universal) were studied in vitro with MC3T3-E1 osteoblastic cells.<br><br>STUDY DESIGN: MC3T3-E1 cells were cotreated with root canal sealers and antioxidants, and concentrations of intracellular glutathione (GSH) and reactive oxygen species (ROS) were measured. DNA fragmentation was observed after treatment with the sealers.<br><br>RESULTS: N-Acetylcysteine (NAC) prevented N2 Universal- and AH26-induced cytotoxicities. However, ascorbic acid and Trolox did not affect the cytotoxicity of the sealers. N2 Universal and AH26 significantly decreased the GSH pool within a 3-hour treatment period. Unlike GSH levels, the ROS levels were not altered by the sealers. Cytotoxicity of Sealapex was not affected by NAC, and there were no changes of GSH/glutathione disulfide levels in cells treated with Sealapex.<br><br>CONCLUSION: Cytotoxicities of N2 Universal and AH26 are caused by an intracellular GSH depletion without a burst of ROS. Sealapex may cause cytotoxicity in a way different from N2 Universal and AH26.}, }
@article {pmid17706314, year = {2007}, author = {Liu, D and Wang, L and Zhong, R and Li, B and Ye, N and Liu, X and Lin, B}, title = {Parallel microfluidic networks for studying cellular response to chemical modulation.}, journal = {Journal of biotechnology}, volume = {131}, number = {3}, pages = {286-292}, doi = {10.1016/j.jbiotec.2007.06.014}, pmid = {17706314}, issn = {0168-1656}, mesh = {Antineoplastic Agents/*administration &amp; dosage ; Biological Assay/*instrumentation/methods ; Breast Neoplasms/*metabolism ; Cell Culture Techniques/instrumentation/methods ; Drug Evaluation, Preclinical/*instrumentation/methods ; Equipment Design ; Equipment Failure Analysis ; Flow Injection Analysis/*instrumentation/methods ; Glutathione/*metabolism ; Humans ; Microfluidic Analytical Techniques/*instrumentation/methods ; }, abstract = {A microfluidic chip featuring parallel gradient-generating networks etched on glass plate was designed and fabricated. The dam and weir structures were fabricated to facilitate cell positioning and seeding, respectively. The microchip contains five gradient generators and 30 cell chambers where the resulted concentration gradients of drugs are delivered to stimulate the on-chip cultured cells. This microfluidics exploits the advantage of lab-on-a-chip technology by integrating the generation of drug concentration gradients and a series of cell operations including seeding, culture, stimulation and staining into a chip. Steady parallel concentration gradients were generated by flowing two fluids in each network. The microchip described above was applied in studying the role of reduced glutathione (GSH) in MCF-7 cells' chemotherapy sensitivity. The parental breast cancer cell line, MCF-7 and the derived adriamycin resistant cell line MCF-7(adm) were treated with concentration gradients of arsenic trioxide (ATO) and N-acetyl cysteine (NAC) for GSH modulation, followed by exposure to adriamycin. The intracellular GSH level and cell viability were assessed by fluorescence image analysis. GSH levels of both cell lines were down-regulated upon ATO treatment and up-regulated upon NAC treatment. For both cell lines, suppression of intracellular GSH by treatment with ATO has been shown to increase chemotherapy sensitivity; conversely, elevation of intracellular GSH by treatment with NAC leads to increased drug resistance. The results indicated that high intracellular GSH level has negative effect on chemotherapy sensitivity, while depletion of cellular GSH may serve as an effective way to improve chemotherapy sensitivity. The integrated microfluidic chip is able to perform multiparametric pharmacological profiling with easy operation, thus, holds great potential for extrapolation to the high-content drug screening.}, }
@article {pmid17705945, year = {2007}, author = {Whyte, IM and Francis, B and Dawson, AH}, title = {Safety and efficacy of intravenous N-acetylcysteine for acetaminophen overdose: analysis of the Hunter Area Toxicology Service (HATS) database.}, journal = {Current medical research and opinion}, volume = {23}, number = {10}, pages = {2359-2368}, doi = {10.1185/030079907X219715}, pmid = {17705945}, issn = {1473-4877}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Child ; Child, Preschool ; *Database Management Systems ; Drug Overdose/*drug therapy ; Humans ; Infant ; Infusions, Intravenous ; Retrospective Studies ; }, abstract = {BACKGROUND: Acetaminophen (N-acetyl-p-aminophenyl; APAP) is the leading drug used in self-poisoning and frequently causes hepatotoxicity, including acute liver failure.<br><br>OBJECTIVE: To provide descriptive data on the safety and efficacy of intravenous N-acetylcysteine (IV-NAC) in the treatment of APAP toxicity, based on information in the Hunter Area Toxicology Service (HATS) database involving residents of the Greater Newcastle Area of New South Wales, Australia.<br><br>METHODS: This was a retrospective analysis of all APAP overdoses from January 1987 to January 2003. Data were collected prospectively according to a published protocol and included patient characteristics, exposures to APAP and other potential toxins, treatments, and outcomes. Primary safety/tolerability endpoints included the mortality rate and incidence of adverse drug reactions, while efficacy endpoints included alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.<br><br>RESULTS: Of 1749 patients, 399 (22.8%) were treated with IV-NAC. Of these, 37 (9.3%) had an adverse drug reaction to IV-NAC, of which seven (1.8% of total) were anaphylactoid. There were five deaths in hospital (mortality rate = 0.3%), including two attributed to APAP (0.1%) and none to IV-NAC. Of 64 patients who were treated with IV-NAC within 8 hours after APAP ingestion and had available ALT/AST data, two (3.1%) developed hepatotoxicity (AST/ALT > 1000 IU/L) compared with 32 (25%) of 128 patients receiving IV-NAC > 8 hours after APAP ingestion (p = 0.0002). A total of 26 patients (15.6%) receiving IV-NAC treatment within 8 hours after APAP ingestion had hospitalization stays > 48 hours compared with 70 (33.3%) receiving IV-NAC > 8 hours after ingestion (p < 0.0001).<br><br>CONCLUSIONS: For patients with APAP overdose seen in the HATS database of New South Wales, Australia, in-hospital death was infrequent (< 1%) and hepatotoxicity was significantly less likely when IV-NAC was administered within 8 hours after APAP ingestion compared with longer intervals (p < 0.01). As a descriptive retrospective database analysis, this study could not exclude certain sources of bias, including temporal changes over the 16-year course of data collection in the use of IV-NAC and low ascertainment of mild, self-limiting reactions to IV-NAC.}, }
@article {pmid17703737, year = {2007}, author = {Li, HB and Gao, JM and Ying, XX and Wang, SP and Li, JC}, title = {Protective effect of magnolol on TBHP-induced injury in H460 cells partially via a p53 dependent mechanism.}, journal = {Archives of pharmacal research}, volume = {30}, number = {7}, pages = {850-857}, doi = {10.1007/BF02978836}, pmid = {17703737}, issn = {0253-6269}, mesh = {Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Biphenyl Compounds/*pharmacology ; Blotting, Western ; Cell Culture Techniques ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; Humans ; Lignans/*pharmacology ; Lipid Peroxidation/drug effects ; Oxidants/*toxicity ; PTEN Phosphohydrolase/biosynthesis ; Proto-Oncogene Proteins c-akt/biosynthesis ; Tumor Suppressor Protein p53/*biosynthesis ; tert-Butylhydroperoxide/*toxicity ; }, abstract = {The aim is to investigate the effect of Magnolol preserved H460 cells from an oxidative agent tert-butylhydroperoxide (TBHP)-induced cell death. Magnolol augmented cell survival ratio after TBHP challenged. The protective action of this drug was more efficacious than that of N-acetylcysteine (NAC) which is a putative antioxidant. DNA damage, detected by the comet assay, was diminished after treatment of Magnolol. The cells viability decreased after treatment with 0.15 mM TBHP for 24 h, accompanied by inducing apoptotic death of the cells. Cytotoxicity and apoptosis induced by TBHP were significantly inhibited or attenuated after pretreatment with 20 microM Magnolol. Magnolol contributes to the cells survival through downregulated the p53 phosphorylation and PTEN expression, and upregulated Akt phosphorylation. Taken together, Magnolol was effective against DNA single strand breaks (SSB) formation, cytotoxicity and lipid peroxidation induced by TBHP, and its effects on p53 phosphorylation, PTEN and Akt phosphorylation were due to its antioxidative function, and partially via a p53 dependent mechanism in this protective effects.}, }
@article {pmid17698947, year = {2007}, author = {Gokcimen, A and Cim, A and Tola, HT and Bayram, D and Kocak, A and Ozgüner, F and Ayata, A}, title = {Protective effect of N-acetylcysteine, caffeic acid and vitamin E on doxorubicin hepatotoxicity.}, journal = {Human &amp; experimental toxicology}, volume = {26}, number = {6}, pages = {519-525}, doi = {10.1177/0960327107076885}, pmid = {17698947}, issn = {0960-3271}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Animals ; Antibiotics, Antineoplastic/administration &amp; dosage/toxicity ; Caffeic Acids/administration &amp; dosage/*therapeutic use ; Chemical and Drug Induced Liver Injury ; Doxorubicin/administration &amp; dosage/*toxicity ; Drug Therapy, Combination ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Hepatocytes/drug effects/metabolism/pathology ; Injections, Intraperitoneal ; Leukocytes, Mononuclear/drug effects/metabolism/pathology ; Liver Diseases/*prevention &amp; control ; Male ; Microscopy, Polarization/methods ; Protective Agents/administration &amp; dosage/therapeutic use ; Random Allocation ; Rats ; Rats, Wistar ; Vitamin E/administration &amp; dosage/*therapeutic use ; Vitamins/administration &amp; dosage/therapeutic use ; }, abstract = {The aim of this study was to compare the possible protective effects of N-acetylcysteine (NAC), caffeic acid (CAPE) and vitamin E (Vit-E) on doxorubicin-induced hepatotoxicity. Thirty-two male Wistar albino rats, weighing between 250 and 350 g were supplied and randomly divided into five groups. Animals in study groups were pretreated with a single dose of doxorubicin (Dox), which was administered intraperitoneally (i.p.). Control group (Group I) was treated with intraperitoneal saline injection. Group II did not received any antioxidant agent after the injection. Group III and Group IV were given CAPE and intraperitoneal vitamin E injection for eight days, respectively. Group V received NAC for eight days. The study was finished after 10 days. Tissue samples were collected from all animals and histopathological examination was performed. There was statistically significant difference between the experiment groups and controls by means of mononuclear cell infiltration and diameters of hepatic sinusoid, terminal hepatic venule (central vein) and portal area (portal canal). Changes related with hepatocellular damage were more prominent, whereas there was no significant difference between Dox and NAC given groups histopathologically. It was observed that structural changes were regressed after CAPE administration. However, this recovery was more prominent in vitamin E given group. These findings suggest that Dox induced liver damage could be efficiently reversed by vitamin E administration. It has been found that CAPE, but not NAC has protective effects on Dox-induced hepatocellular damage.}, }
@article {pmid17702197, year = {2007}, author = {Popovic, M and Kolarovic, J and Mikov, M and Trivic, S and Kaurinovic, B}, title = {Anthracycline-based combined chemotherapy in the mouse model.}, journal = {European journal of drug metabolism and pharmacokinetics}, volume = {32}, number = {2}, pages = {101-108}, pmid = {17702197}, issn = {0378-7966}, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Anthracyclines/administration &amp; dosage/*adverse effects ; Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/*adverse effects/*therapeutic use ; Antioxidants/pharmacology ; Catalase/drug effects ; Cholic Acids/pharmacology ; Doxorubicin/administration &amp; dosage/*adverse effects ; Drug Interactions ; Free Radical Scavengers/pharmacology ; Glutathione Peroxidase/drug effects ; Heart/drug effects ; Lipid Peroxidation/drug effects ; Liver/drug effects ; Mice ; Mice, Inbred BALB C ; Peroxidase/drug effects ; Prednisolone/administration &amp; dosage/adverse effects ; Selenium/pharmacology ; Superoxide Dismutase/pharmacology ; Vincristine/administration &amp; dosage/adverse effects ; Xanthine Oxidase/drug effects ; }, abstract = {Our research was aimed at establishing if and how selenium (Se) ion, N-acetylcysteine (NAC), sodium salt of monoketocholic acid (MKH) and superoxide-dismutase (SOD), administered in the experimental animal model, could affect the possible cytotoxicity associated with anthracycline-based combined chemotherapy with doxorubicin, vincristine and prednisolone (DVP). The following biochemical parameters were investigated: the extent of lipid peroxidation (LPx), and the activity of peroxidase (Px), catalase (CAT), glutathione-peroxidase (GSHPx), and xanthine-oxidase (XOD). A statistical increase in LPx activity was obtained by SOD, MKH, DVPSe and DVPMKH. All chemotherapeutic agents reduced Px activity in a statistically significant manner. There was no statistical significance for the results regarding the effects of the administered substances on GSHPx activity. The results for DVP, SOD, MKH, DVPSOD, DVPSe and DVPMKH showed reduced XOD activity which was statistically significant, which was lowest in the case of MKH, while NAC and Se reduced the activity of this enzyme but statistically non significant. NAC, Se, DVP, MKH and DVPMKH caused a reduction in CAT activity, while DVPSOD and DVPSe caused an increase of the latter.}, }
@article {pmid17700262, year = {2007}, author = {Li, J and Tu, HJ and Li, J and Dai, G and Dai, YC and Wu, Q and Shi, QZ and Cao, Q and Li, ZJ}, title = {N-acetyl cysteine inhibits human signet ring cell gastric cancer cell line (SJ-89) cell growth by inducing apoptosis and DNA synthesis arrest.}, journal = {European journal of gastroenterology &amp; hepatology}, volume = {19}, number = {9}, pages = {769-774}, doi = {10.1097/MEG.0b013e3282202bda}, pmid = {17700262}, issn = {0954-691X}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Signet Ring Cell/*pathology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; DNA Replication/*drug effects ; DNA, Neoplasm/analysis/biosynthesis ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Humans ; In Situ Nick-End Labeling ; Stomach Neoplasms/genetics/*pathology ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND AND AIMS: In this study, we investigated the inhibitory effects of N-acetyl cysteine (NAC) on the growth of the human signet ring cell from the gastric-cancer cell line SJ-89 , via the induction of apoptosis and the arrest of DNA synthesis.<br><br>MATERIALS AND METHODS: SJ-89 cells were regularly incubated in the presence of NAC at 5, 10 and 20 mmol/l, and with IMDM as untreated control. Trypan blue-dye exclusion analysis and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay were applied to detect cell proliferation. Apoptotic morphology was observed by electron microscopy. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay were performed to detect NAC-triggered apoptosis.<br><br>RESULTS: NAC could inhibit proliferation of human gastric cancer SJ-89 cells in a dose-dependent and time-dependent manner. The growth curve showed suppression by 15.8, 37.6 and 66.3% following 72 h of NAC treatment at 5, 10 and 20 mmol/l, respectively, similar to the findings of 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay. DNA synthesis was evidently reduced by 25, 39 and 91% after 24 h NAC treated at 20 mmol/l and 5 days at 10 and 20 mmol/l, respectively. Cell growth was inhibited by 100% with the treatment of 20 mmol/l NAC on day 6. NAC-treated SJ-89 cells were characterized by typical apoptotic alterations, including morphological changes by electron microscopy, typical apoptotic sub-G1 peaking observed by flow cytometry and increase of apoptotic cells with the elevation of the concentration of NAC in a clearly dose-dependent manner by TUNEL assay. Electrophoresis analysis showed typical 'DNA ladder'.<br><br>CONCLUSION: The data above implicated that NAC inhibits human gastric-cancer SJ-89 cell growth by inducing apoptosis and DNA synthesis arrest. Although the exact mechanisms involved in NAC-induced apoptosis have not been known up to now, the ability to induce apoptosis in a tumor-cell population within 48 h is worth noting. It is also noteworthy that NAC can selectively inhibit the growth of tumor cells. Further studies are needed to elucidate the mechanisms.}, }
@article {pmid17697939, year = {2007}, author = {Stöckl, P and Zankl, C and Hütter, E and Unterluggauer, H and Laun, P and Heeren, G and Bogengruber, E and Herndler-Brandstetter, D and Breitenbach, M and Jansen-Dürr, P}, title = {Partial uncoupling of oxidative phosphorylation induces premature senescence in human fibroblasts and yeast mother cells.}, journal = {Free radical biology &amp; medicine}, volume = {43}, number = {6}, pages = {947-958}, doi = {10.1016/j.freeradbiomed.2007.06.005}, pmid = {17697939}, issn = {0891-5849}, support = {S 9302/FWF_/Austrian Science Fund FWF/Austria ; }, mesh = {Acetylcysteine/metabolism ; Aging, Premature/chemically induced/*etiology/metabolism ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology ; Cell Proliferation ; Cell Respiration ; Cells, Cultured ; *Cellular Senescence ; Fibroblasts/drug effects/metabolism ; Humans ; *Oxidative Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; Saccharomyces cerevisiae/drug effects/metabolism ; Uncoupling Agents/pharmacology ; }, abstract = {The mitochondrial theory of aging predicts that functional alterations in mitochondria leading to reactive oxygen species (ROS) production contribute to the aging process in most if not all species. Using cellular senescence as a model for human aging, we have recently reported partial uncoupling of the respiratory chain in senescent human fibroblasts. In the present communication, we address a potential cause-effect relationship between impaired mitochondrial coupling and premature senescence. Chronic exposure of human fibroblasts to the chemical uncoupler carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) led to a temporary, reversible uncoupling of oxidative phosphorylation. FCCP inhibited cell proliferation in a dose-dependent manner, and a significant proportion of the cells entered premature senescence within 12 days. Unexpectedly, chronic exposure of cells to FCCP led to a significant increase in ROS production, and the inhibitory effect of FCCP on cell proliferation was eliminated by the antioxidant N-acetyl-cysteine. However, antioxidant treatment did not prevent premature senescence, suggesting that a reduction in the level of oxidative phosphorylation contributes to phenotypical changes characteristic of senescent human fibroblasts. To assess whether this mechanism might be conserved in evolution, the influence of mitochondrial uncoupling on replicative life span of yeast cells was also addressed. Similar to our findings in human fibroblasts, partial uncoupling of oxidative phsophorylation in yeast cells led to a substantial decrease in the mother-cell-specific life span and a concomitant incrase in ROS, indicating that life span shortening by mild mitochondrial uncoupling may represent a "public" mechanism of aging.}, }
@article {pmid17696279, year = {2007}, author = {Oliver, SJ and Firestein, GS and Arsenault, L and Cruz, TF and Cheng, TP and Banquerigo, ML and Boyle, DL and Brahn, E}, title = {Vanadate, an inhibitor of stromelysin and collagenase expression, suppresses collagen induced arthritis.}, journal = {The Journal of rheumatology}, volume = {34}, number = {9}, pages = {1802-1809}, pmid = {17696279}, issn = {0315-162X}, support = {AR-42200/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; *Ankle Joint/drug effects/pathology ; Arthritis, Experimental/*drug therapy/pathology ; Arthritis, Rheumatoid/*drug therapy ; Collagenases/drug effects/metabolism ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/*pharmacology ; Female ; Injections, Subcutaneous ; Interleukin-1/metabolism ; Matrix Metalloproteinase 3/drug effects/metabolism ; Pyrones/*administration &amp; dosage ; Random Allocation ; Rats ; Vanadates/administration &amp; dosage/*pharmacology ; }, abstract = {OBJECTIVE: Collagen induced arthritis (CIA) is a model of chronic inflammatory synovitis with pannus, neovascularization, and joint destruction similar to rheumatoid arthritis (RA). Matrix metalloproteinases (MMP) are involved in degradation of the extracellular matrix and joint destruction in RA. c-fos and c-jun are protooncogenes whose products combine to form activating protein (AP-1), a regulatory protein that is required for cell proliferation and the transcription of a variety of genes, including MMP such as collagenase and stromelysin. Administration of vanadium compounds suppresses c-fos/c-jun expression and AP-1 activity, resulting in inhibition of MMP expression in response to factors such as interleukin 1 (IL-1). We evaluated whether a vanadium AP-1 inhibitor could reduce MMP expression and subsequent joint damage in CIA.<br><br>METHODS: Vanadate [bis (maltolato) oxovanadium (IV) (BMOV; 10 mg/kg/day)] and the reducing agent N-acetyl cysteine (NAC; 100 mg/kg/day) were given subcutaneously daily in an attempt to suppress established CIA in rats. NAC in combination with vanadate appeared to increase the efficacy of c-fos/c-jun inhibition, while decreasing toxicity. Controls were given NAC alone. Clinical, radiographic, and histologic measures were evaluated as well as synovial MMP and IL-1a expression.<br><br>RESULTS: BMOV therapy, initiated on the day of onset of clinical arthritis, significantly reduced clinical arthritis within 2 days (p <0.05) compared to controls. Significance was maintained to the termination of the study on Day 18 post-arthritis onset (p < 0.005), with a maximum difference seen on Day 5 (p < 0.00001). Blinded radiographic scores at the completion of the protocols indicated less joint destruction in the experimental group compared to the control group (p < 0.005). Scanning and transmission electron microscopy confirmed the preservation of articular cartilage with therapy. In BMOV-treated rats, synovial mRNA expression of collagenase, stromelysin, and IL-la were reduced by 78%, 58%, and 85%, respectively, compared to controls.<br><br>CONCLUSION: This is the first study of vanadate as a potential antirheumatic agent. Further study of this AP-1 and MMP inhibitor may lead to new treatment options in RA.}, }
@article {pmid17693979, year = {2007}, author = {Maes, M and Mihaylova, I and Bosmans, E}, title = {Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta.}, journal = {Neuro endocrinology letters}, volume = {28}, number = {4}, pages = {456-462}, pmid = {17693979}, issn = {0172-780X}, mesh = {Adult ; Case-Control Studies ; Cell Nucleus/*physiology ; Fatigue Syndrome, Chronic/*metabolism/physiopathology/psychology ; Female ; Humans ; Inflammation/metabolism/physiopathology ; Lymphocytes/drug effects/*metabolism ; Male ; Middle Aged ; NF-kappa B/*metabolism ; Neurasthenia/*physiopathology ; Oxidative Stress/physiology ; Severity of Illness Index ; Tetradecanoylphorbol Acetate/analogs &amp; derivatives/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {There is now some evidence that chronic fatigue syndrome is accompanied by an activation of the inflammatory response system and by increased oxidative and nitrosative stress. Nuclear factor kappa beta (NFkappabeta) is the major upstream, intracellular mechanism which regulates inflammatory and oxidative stress mediators. In order to examine the role of NFkappabeta in the pathophysiology of CFS, this study examines the production of NFkappabeta p50 in unstimulated, 10 ng/mL TNF-alpha (tumor necrosis factor alpha) and 50 ng/mL PMA (phorbolmyristate acetate) stimulated peripheral blood lymphocytes of 18 unmedicated patients with CFS and 18 age-sex matched controls. The unstimulated (F=19.4, df=1/34, p=0.0002), TNF-alpha-(F=14.0, df=1/34, p=0.0009) and PMA-(F=7.9, df=1/34, p=0.008) stimulated production of NFkappabeta were significantly higher in CFS patients than in controls. There were significant and positive correlations between the production of NFkappabeta and the severity of illness as measured with the FibroFatigue scale and with symptoms, such as aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection. The results show that an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS and that previous findings on increased oxidative stress and inflammation in CFS may be attributed to an increased production of NFkappabeta. The results suggest that the symptoms of CFS, such as fatigue, muscular tension, depressive symptoms and the feeling of infection reflect a genuine inflammatory response in those patients. It is suggested that CFS patients should be treated with antioxidants, which inhibit the production of NFkappabeta, such as curcumin, N-Acetyl-Cysteine, quercitin, silimarin, lipoic acid and omega-3 fatty acids.}, }
@article {pmid17693944, year = {2008}, author = {Qin, X and Caputo, FJ and Xu, DZ and Deitch, EA}, title = {Hydrophobicity of mucosal surface and its relationship to gut barrier function.}, journal = {Shock (Augusta, Ga.)}, volume = {29}, number = {3}, pages = {372-376}, doi = {10.1097/shk.0b013e3181453f4e}, pmid = {17693944}, issn = {1073-2322}, support = {GM59841/GM/NIGMS NIH HHS/United States ; T32 069330//PHS HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Expectorants/pharmacology ; Hydrophobic and Hydrophilic Interactions ; Intestinal Mucosa/blood supply/drug effects/*physiology/physiopathology ; Ischemia/physiopathology ; Male ; Mucus/drug effects/physiology ; Permeability ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Loss of the gut barrier has been implicated in the pathogenesis of the multiple organ dysfunction syndrome, and, thus, understanding the intestinal barrier is of potential clinical importance. An important, but relatively neglected, component of the gut barrier is the unstirred mucus layer, which through its hydrophobic and other properties serves as an important barrier to bacterial and other factors within the gut lumen. Thus, the goal of this study was to establish a reproducible method of measuring mucosal hydrophobicity and test the hypothesis that conditions that decrease mucosal hydrophobicity are associated with increased gut permeability. Hydrophobicity was measured in various segments of normal gut by measuring the contact angle of an aqueous droplet placed on the mucosal surface using a commercial goniometer. Second, the effect of the mucolytic agent N-acetyl cysteine on mucosal hydrophobicity and gut permeability was measured, as was the effects of increasing periods of in vivo gut ischemia on these parameters. Gut ischemia was induced by superior mesenteric artery occlusion, and gut permeability was measured by the mucosal-to-serosal passage of fluoresceine isothiocyanate-dextran (4.3 kDa) (FD4) across the everted sacs of ileum. Intestinal mucosal hydrophobicity showed a gradual increase from the duodenum to the end of the ileum and remained at high level in the cecum, colon, and rectum. Both N-acetyl cysteine treatment and ischemia caused a dose-dependent decrease in mucosal hydrophobicity, which significantly correlated increased gut permeability. Mucosal hydrophobicity of the intestine can be reproducibly measured, and decreases in mucosal hydrophobicity closely correlate with increased gut permeability. These results suggest that mucosal hydrophobicity can be a reliable method of measuring the barrier function of the unstirred mucus layer and a useful parameter in evaluating the pathogenesis of gut barrier dysfunction.}, }
@article {pmid17692765, year = {2007}, author = {Spiller, HA and Sawyer, TS}, title = {Impact of activated charcoal after acute acetaminophen overdoses treated with N-acetylcysteine.}, journal = {The Journal of emergency medicine}, volume = {33}, number = {2}, pages = {141-144}, doi = {10.1016/j.jemermed.2007.02.016}, pmid = {17692765}, issn = {0736-4679}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/therapeutic use ; Charcoal/*therapeutic use ; Chemical and Drug Induced Liver Injury ; Drug Overdose ; Humans ; Liver Diseases/*prevention &amp; control ; Registries ; Retrospective Studies ; }, abstract = {Previous studies have suggested that patients receiving both activated charcoal (AC) and N-acetylcysteine (NAC) after acute acetaminophen (APAP) overdoses may have improved outcomes. We evaluated all acute acetaminophen overdoses that received NAC therapy reported to US poison centers for the years 1993 through 2004. Groups were separated based on therapy received: 1) both AC and NAC and 2) NAC alone. There were 97,960 acetaminophen overdoses reported, with 49,427 patients (50%) receiving NAC and AC. Reports of AST/ALT > 1000, a major effect, and death were 1301 (2.9%), 2957 (6.6%), and 232 (0.5%), respectively, for patients receiving NAC plus AC, vs. 5273 (12%), 4534 (10.3%), and 369 (0.8%), respectively, for patients receiving NAC alone (p < 0.01). Use of Toxic Exposure Surveillance System data in the present study has a number of limitations, including its retrospective nature and no documentation of when NAC therapy was initiated. It is possible that those patients who did not receive AC presented to the Emergency Department later in their overdose and had NAC therapy initiated later, and therefore they were predisposed to a greater risk of hepatic injury. Evaluation of 12 years of acute APAP overdoses suggests that the use of AC, in addition to NAC therapy, may provide improved patient outcomes.}, }
@article {pmid17692455, year = {2007}, author = {Choi, K and Han, YH and Choi, C}, title = {N-acetyl cysteine and caffeic acid phenethyl ester sensitize astrocytoma cells to Fas-mediated cell death in a redox-dependent manner.}, journal = {Cancer letters}, volume = {257}, number = {1}, pages = {79-86}, doi = {10.1016/j.canlet.2007.07.006}, pmid = {17692455}, issn = {0304-3835}, mesh = {Acetylcysteine/*pharmacology ; Astrocytoma/*drug therapy/pathology ; Caffeic Acids/*pharmacology ; Caspase Inhibitors ; Caspases/metabolism ; Cell Death ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Humans ; Membrane Potentials ; Mitochondrial Membranes/metabolism ; Models, Biological ; *Oxidation-Reduction ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species ; Time Factors ; fas Receptor/*metabolism ; }, abstract = {In this study, we investigated the role of reactive oxygen species (ROS) in Fas-induced cell death in human astrocytoma cells. Fas activation increased intracellular ROS levels in a NADPH oxidase- and caspase-dependent manner. ROS inhibitors such as N-acetyl cysteine (NAC) and caffeic acid phenethyl ester (CAPE) dramatically sensitized astocytoma cells to Fas-induced loss of mitochondrial transmembrane potential and subsequent cell death, which were abrogated by pretreatment with z-VAD-fmk, a broad-spectrum caspase inhibitor. These results collectively indicate that NAC and CAPE sensitize astrocytoma cells to Fas-induced apoptosis in a redox-dependent manner, suggesting a potential use in the treatment of malignant brain tumors.}, }
@article {pmid17687726, year = {2007}, author = {Hu, S and Zhao, H and Yin, XJ and Ma, JK}, title = {Role of mitochondria in silica-induced apoptosis of alveolar macrophages: inhibition of apoptosis by rhodamine 6G and N-acetyl-L-cysteine.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {70}, number = {17}, pages = {1403-1415}, doi = {10.1080/15287390701251990}, pmid = {17687726}, issn = {1528-7394}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects/immunology ; Caspase 9/drug effects/metabolism ; Cells, Cultured ; Cytokines/metabolism ; Macrophages, Alveolar/*drug effects ; Male ; Mitochondria/*drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Rhodamines/*pharmacology ; Silicon Dioxide/*toxicity ; }, abstract = {Induction of apoptosis by silica in alveolar macrophages (AM) may be a critical step in silica-induced lung injury and pulmonary fibrosis. This study investigated the mechanism(s) through which silica induces apoptosis in AM and their production of proinflammatory cytokines. Using N-acetyl-L-cysteine (NAC) for glutathione (GSH) synthesis and removal of reactive oxygen species (ROS), and rhodamine 6G (R6G) to inhibit the mitochondrial-dependent function, this study found that silica-induced apoptosis of rat AM in primary culture is mitochondria dependent and exhibits a mechanism involving ROS generation, increased mitochondrial release of cytochrome c, and the activation of caspase 9, but not caspase 8, activity. Silica-induced apoptosis was accompanied by a lowering of intracellular and mitochondrial GSH (mGSH) and was blocked by pretreatment of cells with NAC or R6G. When cells were exposed to silica and then treated with either NAC or R6G, silica-induced apoptosis was not affected by the blocking agent. In addition, R6G, which inhibited cellular ATP production and mitochondrial ROS generation, had no effect on apoptosis induced by exogenous hydrogen peroxide or superoxide. Pretreatment of cells with NAC or R6G also inhibited silica-induced production of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, but the inhibition of these cytokines with agents known to block their secretion did not protect cells from silica-induced apoptosis. Data indicate that silica-induced apoptosis is mediated through mitochondrial generation of ROS, which may be inhibited by pretreatment of cells with R6G that prevents ROS generation, or with NAC that maintains a high level of mGSH. The secretion of IL-1beta and TNF-alpha by silica-exposed AM was markedly inhibited by NAC and R6G, suggesting that the production of these cytokines is also ROS dependent.}, }
@article {pmid17682092, year = {2007}, author = {Tang, C and Han, P and Oprescu, AI and Lee, SC and Gyulkhandanyan, AV and Chan, GN and Wheeler, MB and Giacca, A}, title = {Evidence for a role of superoxide generation in glucose-induced beta-cell dysfunction in vivo.}, journal = {Diabetes}, volume = {56}, number = {11}, pages = {2722-2731}, doi = {10.2337/db07-0279}, pmid = {17682092}, issn = {1939-327X}, mesh = {Animals ; Glucose/administration &amp; dosage/*pharmacology ; Hyperglycemia/metabolism ; Infusions, Intravenous ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/drug effects/*metabolism/physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxides/*metabolism ; }, abstract = {OBJECTIVE: Prolonged elevation of glucose can adversely affect beta-cell function. In vitro studies have linked glucose-induced beta-cell dysfunction to oxidative stress; however, whether oxidative stress plays a role in vivo is unclear. Therefore, our objective was to investigate the role of oxidative stress in an in vivo model of glucose-induced beta-cell dysfunction.<br><br>RESEARCH DESIGN AND METHODS: Wistar rats were infused intravenously with glucose for 48 h to achieve 20 mmol/l hyperglycemia with/without co-infusion of one of the following antioxidants: taurine (2-amino ethanesulfonic acid) (TAU), an aldehyde scavenger; N-acetylcysteine (NAC), a precursor of glutathione; or tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) (TPO), a superoxide dismutase mimetic. This was followed by islet isolation or hyperglycemic clamp.<br><br>RESULTS: A 48-h glucose infusion decreased glucose-stimulated insulin secretion (GSIS) and elevated reactive oxygen species (ROS), total superoxide, and mitochondrial superoxide in freshly isolated islets. TPO prevented the increase in total and mitochondrial superoxide and the beta-cell dysfunction induced by high glucose. However, TAU and NAC, despite completely normalizing H(2)DCF-DA (dihydro-dichlorofluorescein diacetate)-measured ROS, did not prevent the increase in superoxide and the decrease in beta-cell function induced by high glucose. TPO but not TAU also prevented beta-cell dysfunction induced by less extreme hyperglycemia (15 mmol/l) for a longer period of time (96 h). To further investigate whether TPO is effective in vivo, a hyperglycemic clamp was performed. Similar to the findings in isolated islets, prolonged glucose elevation (20 mmol/l for 48 h) decreased beta-cell function as assessed by the disposition index (insulin secretion adjusted for insulin sensitivity), and co-infusion of TPO with glucose completely restored beta-cell function.<br><br>CONCLUSIONS: These findings implicate superoxide generation in beta-cell dysfunction induced by prolonged hyperglycemia.}, }
@article {pmid17681439, year = {2008}, author = {Schmitz, T and Grabovac, V and Palmberger, TF and Hoffer, MH and Bernkop-Schnürch, A}, title = {Synthesis and characterization of a chitosan-N-acetyl cysteine conjugate.}, journal = {International journal of pharmaceutics}, volume = {347}, number = {1-2}, pages = {79-85}, doi = {10.1016/j.ijpharm.2007.06.040}, pmid = {17681439}, issn = {0378-5173}, mesh = {Acetylcysteine/*chemistry ; Adsorption ; Animals ; Chitosan/analogs &amp; derivatives/*chemistry/metabolism ; Hydrogen-Ion Concentration ; Intestinal Mucosa/metabolism ; Molecular Structure ; Muramidase/chemistry ; Oxidation-Reduction ; Rheology ; Sulfhydryl Compounds/analysis ; Swine ; Tensile Strength ; Viscosity ; Water/chemistry ; }, abstract = {The aim of the present study was to synthesize and characterize a novel thiolated polymer by covalent attachment of N-acetyl cysteine to chitosan. The obtained conjugate was characterized in vitro by quantification of immobilized thiol groups and their pH dependent oxidation, swelling behaviour in artificial intestinal fluid at pH 6.8, rheological properties and evaluation of its mucoadhesive properties on freshly excised porcine mucosa. The chitosan-N-acetyl cysteine conjugate was synthesized via a carbodiimide mediated coupling reaction displaying up to 325.5+/-41.8 micromol of immobilized thiol groups per gram polymer. 79% of the total amount of thiol groups was oxidized to disulfide groups during the coupling reaction. Adhesion studies on the mucosa indicate that the resulting polymer shows a 50-fold longer residence time on the mucosa and 8.3-fold higher total work of adhesion necessary to detach a flat-faced polymeric tablet from the mucosa in comparison to unmodified chitosan. Swelling properties at pH 6.8 were rather limited displaying only 5% of increment in weight after 2h of experiment. Within 1h the viscosity of an aqueous chitosan-N-acetyl cysteine conjugate mixture at 37 degrees C, pH 5.0 decreased by 35% after addition of hen white egg lysozyme demonstrating its biodegradability. Because of these features chitosan-N-acetyl cysteine seems to represent a promising novel tool, which might be useful in particular for the development of mucoadhesive and biodegradable formulations.}, }
@article {pmid17679146, year = {2007}, author = {Viola-Rhenals, M and Rieber, MS and Rieber, M}, title = {Role of peroxidases, thiols and Bak/Bax in tumor cell susceptibility to Cu[DEDTC]2.}, journal = {Biochemical pharmacology}, volume = {74}, number = {6}, pages = {841-850}, doi = {10.1016/j.bcp.2007.06.048}, pmid = {17679146}, issn = {0006-2952}, mesh = {Antineoplastic Agents/*pharmacology ; Carcinoma/pathology ; Cell Death/drug effects ; Cell Line, Tumor ; Copper ; Ditiocarb/*pharmacology ; *Drug Resistance, Neoplasm ; Humans ; Melanoma/pathology ; Peroxidases/*analysis ; Sulfhydryl Compounds/*analysis ; bcl-2 Homologous Antagonist-Killer Protein/*analysis ; bcl-2-Associated X Protein/*analysis ; }, abstract = {Copper and two molecules of diethyl dithiocarbamate [DEDTC] form the Cu[DEDTC](2) complex, which shows cytotoxicity against melanoma and carcinoma cells, making it a potentially useful anti-cancer agent. The differential response to Cu[DEDTC](2) in susceptible human SKBR3 carcinoma and C8161 melanoma cell variants of moderate and high resistance to this organometallic complex was evaluated in this study. Both cell lines underwent apoptosis-associated PARP cleavage, changes in expression of nuclear NFkB p65, p21WAF1 and cyclin A, with loss of clonogenicity in response to this agent. However, a threefold greater concentration [IC(50) 0.6 microM DEDTC: 0.3 microM Cu] was required to kill moderately resistant C8161 melanoma compared to highly susceptible SKBR3 cells. Decreased susceptibility to Cu[DEDTC](2) in C8161 melanoma correlated with greater levels of glutathione peroxidase and catalase, and a fourfold lower requirement for N-acetyl cysteine (1mM) to overcome toxicity. Whereas melanoma cells selected for resistance to [0.8 microM DEDTC: 0.4 microM Cu] showed persistent catalase and GPx activity, melanoma cells with moderate susceptibility showed decreased catalase and Gpx when responding to treatment. Cytotoxic response in moderately susceptible C8161 melanoma cells involved an early accumulation of pro-apoptotic Bax in the G2 cell cycle phase, followed by an increased ratio of pro-apoptotic Bak to anti-apoptotic Mcl-1 in mitochondria. Our data suggests that Cu[DEDTC](2) toxicity is mediated through an increase in pro-apoptotic Bak/Bax via disruption of the peroxide and thiol metabolism.}, }
@article {pmid17676198, year = {2007}, author = {Koc, E and Yavuzer, SA and Can, B and Ocakcioglu, B and Ergun, A and Saran, Y}, title = {Does N-acetylcysteine have an effect on acetylcholine-induced contractions and histopathological changes on isolated rat ileum?.}, journal = {Saudi medical journal}, volume = {28}, number = {8}, pages = {1180-1184}, pmid = {17676198}, issn = {0379-5284}, mesh = {Acetylcholine ; Acetylcysteine/*pharmacology ; Animals ; Female ; Free Radical Scavengers/*pharmacology ; Gastrointestinal Motility/drug effects ; Ileum/*drug effects/pathology/physiopathology ; Male ; Muscle Contraction/drug effects ; Muscle, Smooth/drug effects ; Rats ; Rats, Wistar ; }, abstract = {OBJECTIVE: To investigate the action of N-acetylcysteine (NAC) on rat isolated ileal contractility, and to determine the effects of NAC on histopathological changes on ileal tissue.<br><br>METHODS: The study took place at the Faculty of Medicine, Ankara University, Ankara, Turkey, in January 2003. Adult Wistar rats were used in all experiments. Two groups were designed. The experimental group, to which NAC 0.5 g/Kg/day was administered orally by adding to their water for 7 days, and the control group to which only saline was administered. At the end of the experimental periods, one cm pieces of terminal ileum segments were removed for testing ileal contractility, and one cm pieces of ileum segments were removed for histopathological experiments. The acetylcholine (ACh)-induced contraction was recorded, and the ileal tissue examined using light and electron microscopic technics for histopathological changes.<br><br>RESULTS: The average peak amplitude of ACh-induced contraction recorded in standard tyrode solution of the experimental group was decreased significantly when compared to the control group in standard and calcium-Free tyrode solution. On histopathological findings, there were swollen mitochondria with disturbed cristae in the ileal muscle.<br><br>CONCLUSION: Our data suggest that the NAC in the present experiment decreased the ACh-induced contractility on rat-isolated ileum.}, }
@article {pmid17670639, year = {2006}, author = {Fischer, UM and Antonyan, A and Bloch, W and Mehlhorn, U}, title = {Impact of antioxidative treatment on nuclear factor kappa-B regulation during myocardial ischemia-reperfusion.}, journal = {Interactive cardiovascular and thoracic surgery}, volume = {5}, number = {5}, pages = {531-535}, doi = {10.1510/icvts.2006.130765}, pmid = {17670639}, issn = {1569-9285}, abstract = {Nuclear factor kappa-B (NFkappaB), a transcription factor, plays a role in numerous pathological states such as myocardial ischemia-reperfusion (I/R), apoptosis, and ischemic preconditioning. As both myocardial ischemia and reperfusion (by reactive oxygen intermediates) can activate NFkappaB, we investigated the impact of the antioxidant N-acetylcysteine (NAC) on NFkappaB-regulation in patients subjected to cardioplegic arrest (CA) on cardiopulmonary bypass (CPB). Seventeen coronary artery surgery patients (66+/-9[S.D.] years) subjected to cardiopulmonary bypass (CPB) and cardioplegic arrest were randomized in a double-blind fashion to receive either NAC (100 mg/kg into CPB prime followed by infusion at 20 mg/kg/h; n=9) or placebo (n=8). Transmural LV biopsies were collected prior to CPB (baseline) and at CPB-end and immuno-cytochemically stained against active NFkappaB and phosphorylated IkappaB alpha (activates NFkappaB). At the end of CPB both NFkappaB and IkappaB alpha were unchanged in endothelial cells of controls compared to baseline (45.6+/-7.6 vs. 49.9+/-7.1 and 36.8+/-6.1 vs. 47.5+/-8.6 counts per viewfield (cpv), P>0.05, respectively). In NAC, NFkappaB and IkappaB alpha in endothelial cells were significantly decreased at CPB-end (19.8+/-1.7 vs. 39.1+/-4.1 cpv, P<0.001, and 22.1+/-1.9 vs. 38.3+/-4.4 cpv, P=0.006). In cardiomyocytes, however, there were no changes observed in either group. Antioxidative treatment with NAC decreases NFkappaB-activity following I/R in endothelial cells. We conclude that NFkappaB-activity post I/R is mediated by free radicals rather than ischemia alone.}, }
@article {pmid17668070, year = {2007}, author = {Efferth, T and Giaisi, M and Merling, A and Krammer, PH and Li-Weber, M}, title = {Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells.}, journal = {PloS one}, volume = {2}, number = {8}, pages = {e693}, pmid = {17668070}, issn = {1932-6203}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/*pharmacology ; Antimalarials/*pharmacology ; Apoptosis/*drug effects ; Artemisinins/*pharmacology ; Artesunate ; Cell Line, Tumor/drug effects ; Doxorubicin/*pharmacology ; Drug Resistance, Neoplasm/*physiology ; Drug Screening Assays, Antitumor ; Free Radical Scavengers/pharmacology ; Humans ; Leukemia/drug therapy/metabolism/pathology ; Mice ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: A major obstacle for successful cancer treatment often is the development of drug resistance in cancer cells during chemotherapy. Therefore, there is an urgent need for novel drugs with improved efficacy against tumor cells and with less toxicity on normal cells. Artesunate (ART), a powerful anti-malarial herbal compound, has been shown to inhibit growth of various tumor cell lines in vitro and of xenografted Kaposi's sarcoma in mice in vivo. However, the molecular mechanisms by which ART exerts its cytotoxicity have not been elucidated. The ART-class of anti-malarial compounds is attractive due to their activity against multidrug-resistant Plasmodium falciparum and Plasmodium vivax strains. Another salient feature of these compounds is the lack of severe side effects in malaria patients.<br><br>In this study, we used T-cell leukemias as a model system to study the molecular mechanisms of ART-induced apoptosis. The most typical anticancer drugs are DNA intercalators such as Doxorubicin. To investigate drug sensitivity and resistance, we chose a Doxorubicin-resistant leukemia cell line and investigated the killing effect of ART on these cells. We show that ART induces apoptosis in leukemic T cells mainly through the mitochondrial pathway via generation of reactive oxygen species (ROS), a mechanism different from Doxorubicin. This is confirmed by the fact that the antioxidant N-Acetyle-Cysteine (NAC) could completely block ROS generation and, consequently, inhibited ART-induced apoptosis. Therefore, ART can overcome the Doxorubicin-resistance and induce the Doxorubicin-resistant leukemia cells to undergo apoptosis. We also show that ART can synergize with Doxorubicin to enhance apoptotic cell death in leukemic T cells. This synergistic effect can be largely explained by the fact that ART and Doxorubicin use different killing mechanisms.<br><br>CONCLUSIONS: Our studies raise the possibility to develop ART in combination with other established anticancer drugs which induce apoptosis through the pathways or mechanisms different from ART.}, }
@article {pmid17665241, year = {2007}, author = {Assimakopoulos, SF and Maroulis, I and Patsoukis, N and Vagenas, K and Scopa, CD and Georgiou, CD and Vagianos, CE}, title = {Effect of antioxidant treatments on the gut-liver axis oxidative status and function in bile duct-ligated rats.}, journal = {World journal of surgery}, volume = {31}, number = {10}, pages = {2023-2032}, pmid = {17665241}, issn = {0364-2313}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Alanine Transaminase/blood ; Allopurinol/therapeutic use ; Animals ; Bilirubin/blood ; Biomarkers/analysis ; Free Radical Scavengers/*pharmacology/therapeutic use ; Intestines/drug effects ; Jaundice, Obstructive/drug therapy/*physiopathology ; Lipid Peroxidation ; Liver/drug effects/metabolism ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; alpha-Tocopherol/therapeutic use ; }, abstract = {BACKGROUND: Experimental and clinical studies have demonstrated the pivotal role of oxidative stress in the promotion of hepatic and intestinal injury in obstructive jaundice. The present study was undertaken to investigate the effect of well known antioxidant treatments on the gut-liver axis oxidative status and function in bile duct-ligated rats.<br><br>METHODS: A total of 60 male Wistar rats were randomly divided into six groups of 10 animals each: controls, sham operated, bile duct ligated (BDL), and BDL treated with either N-acetylcysteine (NAC), allopurinol, or alpha-tocopherol (alpha-TC). Ten days after treatment, the hepatic and intestinal oxidative status was estimated by measuring lipid peroxidation and a battery of biochemical markers comprising the organ's thiol redox state (i.e., glutathione, cysteine, protein thiols, oxidized glutathione, nonprotein mixed disulfides, oxidized cysteine derivatives, protein symmetrical disulfides, and protein mixed disulfides). Portal and aortic endotoxin concentrations and alanine aminotransferase (ALT) levels were also determined.<br><br>RESULTS: All antioxidant treatments significantly improved intestinal barrier function and protected from cholestatic liver injury, as evidenced by reduction of the portal and aortic endotoxin concentration and ALT levels, respectively. This effect accompanied their significant antioxidant action in both organs, mediated by a certain influence profile on the thiol redox state by each treatment.<br><br>CONCLUSION: NAC, allopurinol, and alpha-TC, exerting a potent combined antioxidant effect on the intestine and liver in experimental obstructive jaundice, significantly prevented intestinal barrier dysfunction and liver injury. The variety of results depending on the antioxidant agent that was administered and the marker of oxidative stress that was estimated, indicates that a battery of biomarkers would be more appropriate in assessing pharmacologic responses to therapeutic interventions.}, }
@article {pmid17665043, year = {2007}, author = {Dong, R and Wang, Q and He, XL and Chu, YK and Lu, JG and Ma, QJ}, title = {Role of nuclear factor kappa B and reactive oxygen species in the tumor necrosis factor-alpha-induced epithelial-mesenchymal transition of MCF-7 cells.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {40}, number = {8}, pages = {1071-1078}, doi = {10.1590/s0100-879x2007000800007}, pmid = {17665043}, issn = {0100-879X}, mesh = {Blotting, Western ; Cadherins/metabolism ; Case-Control Studies ; Cell Line, Tumor ; Cell Movement/drug effects ; Epithelial Cells/*metabolism/pathology ; Humans ; Mesoderm/*cytology/metabolism ; NF-kappa B/metabolism/*physiology ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Snail Family Transcription Factors ; Transcription Factors/*metabolism ; Tumor Necrosis Factor-alpha/*pharmacology/physiology ; Vimentin/metabolism ; }, abstract = {The microenvironment of the tumor plays an important role in facilitating cancer progression and activating dormant cancer cells. Most tumors are infiltrated with inflammatory cells which secrete cytokines such as tumor necrosis factor-alpha (TNF-alpha). To evaluate the role of TNF-alpha in the development of cancer we studied its effects on cell migration with a migration assay. The migrating cell number in TNF-alpha-treated group is about 2-fold of that of the control group. Accordingly, the expression of E-cadherin was decreased and the expression of vimentin was increased upon TNF-alpha treatment. These results showed that TNF-alpha can promote epithelial-mesenchymal transition (EMT) of MCF-7 cells. Further, we found that the expression of Snail, an important transcription factor in EMT, was increased in this process, which is inhibited by the nuclear factor kappa B (NFkappaB) inhibitor aspirin while not affected by the reactive oxygen species (ROS) scavenger N-acetyl cysteine. Consistently, specific inhibition of NFkappaB by the mutant IkappaBalpha also blocked the TNF-alpha-induced upregulation of Snail promoter activity. Thus, the activation of NFkappaB, which causes an increase in the expression of the transcription factor Snail is essential in the TNF-alpha-induced EMT. ROS caused by TNF-alpha seemed to play a minor role in the TNF-alpha-induced EMT of MCF-7 cells, though ROS per se can promote EMT. These findings suggest that different mechanisms might be responsible for TNF-alpha- and ROS-induced EMT, indicating the need for different strategies for the prevention of tumor metastasis induced by different stimuli.}, }
@article {pmid17663721, year = {2007}, author = {Kani, S and Nakayama, E and Yoda, A and Onishi, N and Sougawa, N and Hazaka, Y and Umeda, T and Takeda, K and Ichijo, H and Hamada, Y and Minami, Y}, title = {Chk2 kinase is required for methylglyoxal-induced G2/M cell-cycle checkpoint arrest: implication of cell-cycle checkpoint regulation in diabetic oxidative stress signaling.}, journal = {Genes to cells : devoted to molecular &amp; cellular mechanisms}, volume = {12}, number = {8}, pages = {919-928}, doi = {10.1111/j.1365-2443.2007.01100.x}, pmid = {17663721}, issn = {1356-9597}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Cell Line ; Checkpoint Kinase 1 ; Checkpoint Kinase 2 ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Diabetes Mellitus/enzymology/*metabolism ; Enzyme Activation/drug effects ; G2 Phase/*drug effects ; Guanidines/pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Kinetics ; MAP Kinase Kinase Kinase 5/metabolism ; Mesangial Cells/drug effects/enzymology ; Mitosis/*drug effects ; Oxidative Stress/*drug effects ; Phosphorylation/drug effects ; Protein Kinases/metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Pyruvaldehyde/*pharmacology ; RNA, Small Interfering/metabolism ; Signal Transduction/*drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Methylglyoxal (MG) is a reactive endogenous metabolite that is produced from the process of degradation of triose-phosphates. Under hyperglycemic conditions the rate of MG formation increases as a result of elevated concentrations of precursors. It has been established that MG elicits oxidative stress signaling, leading to the activation of MAP kinases, p38 MAPK and JNK, yet it remains largely unknown about a role of cell-cycle checkpoint regulation in MG-induced signaling. Here, we show that checkpoint kinases, Chk1 and Chk2, as well as their upstream ATM kinase are phosphorylated and activated following MG treatment of cultured cells. This MG-induced activation of Chk1 and Chk2 were inhibited by either aminoguanidine (AG), an inhibitor of production of advanced glycation end products (AGEs) or N-acetyl-l-cysteine (NAC), an anti-oxidant in dose dependent manners, indicating that oxidative stress via AGEs is involved critically in the activation of Chk1 and Chk2 by MG. Furthermore, it was found that cell-cycle synchronized cells exhibited G(2)/M checkpoint arrest following MG treatment, and that siRNA-mediated knock-down of Chk2, but not Chk1, results in a failure of MG-induced G(2)/M arrest. Thus, the results indicate a critical role for Chk2 in MG-induced G(2)/M cell-cycle checkpoint arrest.}, }
@article {pmid17663482, year = {2007}, author = {Im, JY and Han, PL}, title = {Nordihydroguaiaretic acid induces astroglial death via glutathione depletion.}, journal = {Journal of neuroscience research}, volume = {85}, number = {14}, pages = {3127-3134}, doi = {10.1002/jnr.21431}, pmid = {17663482}, issn = {0360-4012}, mesh = {Analysis of Variance ; Animals ; Antioxidants/*pharmacology ; Astrocytes/*drug effects ; Cell Death/drug effects ; Cerebral Cortex/*cytology ; Dose-Response Relationship, Drug ; Drug Interactions ; Embryo, Mammalian ; Enzyme Inhibitors/pharmacology ; Glutathione/*metabolism ; Masoprocol/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mice ; Neurons/drug effects ; Reactive Oxygen Species/metabolism ; Time Factors ; }, abstract = {Nordihydroguaiaretic acid (NDGA) is known to cause cell death in certain cell types that is independent of its activity as a lipoxygenase inhibitor; however, the underlying mechanisms are not fully understood. In the present study, we examined the cellular responses of cultured primary astroglia to NDGA treatment. Continuous treatment of primary astroglia with 30 microM NDGA caused >85% cell death within 24 hr. Cotreatment with the lipoxygenase products 5-HETE, 12-HETE, and 15-HETE did not override the cytotoxic effects of NDGA. In assays employing the mitochondrial membrane potential-sensitive dye JC-1, NDGA was found to induce a rapid and almost complete loss of mitochondrial membrane potential. However, the mitochondrial permeability transition pore inhibitors cyclosporin A and bongkrekic acid did not block NDGA-induced astroglial death. We found that treatment with N-acetyl cysteine (NAC), glutathione (GSH), and GSH ethyl ester (GSH-EE) did inhibit NDGA-induced astroglial death. Consistently, NDGA-induced astroglial death proceeded in parallel with intracellular GSH depletion. Pretreatment with GSH-EE and NAC did not block NDGA-induced mitochondrial membrane potential loss, and there was no evidence that reactive oxygen species (ROS) production was involved in NDGA-induced astroglial death. Together, these results suggest that NDGA-induced astroglial death occurs via a mechanism that involves GSH depletion independent of lipoxygenase activity inhibition and ROS stress.}, }
@article {pmid17663266, year = {2007}, author = {Sharma, CS and Sarkar, S and Periyakaruppan, A and Barr, J and Wise, K and Thomas, R and Wilson, BL and Ramesh, GT}, title = {Single-walled carbon nanotubes induces oxidative stress in rat lung epithelial cells.}, journal = {Journal of nanoscience and nanotechnology}, volume = {7}, number = {7}, pages = {2466-2472}, pmid = {17663266}, issn = {1533-4880}, support = {G12 RR003045/RR/NCRR NIH HHS/United States ; G12 RR003045-180001/RR/NCRR NIH HHS/United States ; RR03045-18/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; Epithelial Cells/drug effects/*physiology ; Lung/cytology/drug effects/*physiology ; Nanotubes, Carbon/*toxicity ; Oxidative Stress/drug effects/*physiology ; Rats ; Reactive Oxygen Species/*metabolism ; Respiratory Mucosa/drug effects/*physiology ; }, abstract = {Single-walled carbon nanotubes (SWCNT) show unique properties find applications in micro devices; electronics to biological systems specially drug delivery and gene therapy. However the manufacture and extensive use of nanotubes raises concern about its safe use and human health. Very few studies have been carried out on toxicity of carbon nanotubes in experimental animals and humans, thus resulted in limiting their use. The extensive toxicological studies using in vitro and in vivo models are necessary and are required to establish safe manufacturing guidelines and also the use of SWCNT. These studies also help the chemists to prepare derivative of SWCNT with less or no toxicity. The present study was undertaken to determine the toxicity exhibited by SWCNT in rat lung epithelial cells as a model system. Lung epithelial cells (LE cells) were cultured with or without SWCNT and reactive oxygen species (ROS) produced were measured by change in fluorescence using dichloro fluorescein (DCF). The results show increased ROS on exposure to SWCNT in a dose and time dependent manner. The decrease in glutathione content suggested the depletion and loss of protective mechanism against ROS in SWCNT treated cells. Use of rotenone, the inhibitor of mitochondrial function have no effect on ROS levels suggested that mitochondria is not involved in SWCNT induced ROS production. Studies carried out on the effect of SWCNT on superoxide dismutase (SOD-1 and SOD-2) levels in LE cells, indicates that these enzyme levels decreased by 24 hours. The increased ROS induced by SWCNT on LE cells decreased by treating the cells with 1 mM of glutathione, N-Acetyl Cysteine, and Vitamin C. These results further prove that SWCNT induces oxidative stress in LE cells and shows loss of antioxidants.}, }
@article {pmid17660951, year = {2007}, author = {Jia, X and Wu, L}, title = {Accumulation of endogenous methylglyoxal impaired insulin signaling in adipose tissue of fructose-fed rats.}, journal = {Molecular and cellular biochemistry}, volume = {306}, number = {1-2}, pages = {133-139}, pmid = {17660951}, issn = {0300-8177}, mesh = {3T3-L1 Cells/drug effects ; Acetylcysteine/pharmacology ; Adipocytes/drug effects/metabolism ; Adipose Tissue/*metabolism ; Animals ; Diet ; Fluorescent Antibody Technique ; Fructose/*administration &amp; dosage ; Glucose/metabolism ; Glucose Tolerance Test ; Immunoblotting ; Insulin/pharmacology ; Insulin Receptor Substrate Proteins ; *Insulin Resistance ; Male ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoproteins/metabolism ; Phosphorylation ; Pyruvaldehyde/*metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/*drug effects ; }, abstract = {Increased accumulation of methylglyoxal (MG) has been linked to different insulin resistance states including diabetes and hypertension. In this study, the effects of MG on insulin signaling pathway were investigated. Following 9 weeks of fructose treatment, an insulin resistance state was developed in Sprague-Dawley (SD) rats, demonstrated as increased triglyceride and insulin levels, high blood pressure, and decreased insulin-stimulated glucose uptake by adipose tissue. More importantly, we observed a close correlation between the development of insulin resistance and elevated MG level in serum and adipose tissue. Both insulin resistance state and the elevated MG level were reversed by the MG scavenger, N-acetyl cysteine (NAC). When 3T3-L1 adipocytes were treated directly with MG, the impaired insulin signaling was also observed, indicated by decreased insulin-induced insulin-receptor substrate-1 (IRS-1) tyrosine phosphorylation and the decreased kinase activity of phosphatidylinositol (PI) 3-kinase (PI3K). The ability of NAC to block MG-impairment of PI3K activity and IRS-1 phosphorylation further confirmed the role of MG in the development of insulin resistance. In conclusion, the increase in endogenous MG accumulation impairs insulin-signaling pathway and decreases insulin-stimulated glucose uptake in adipose tissue, which may contribute to the development of insulin resistance.}, }
@article {pmid17660234, year = {2007}, author = {Lobascio, AM and Klinger, FG and Scaldaferri, ML and Farini, D and De Felici, M}, title = {Analysis of programmed cell death in mouse fetal oocytes.}, journal = {Reproduction (Cambridge, England)}, volume = {134}, number = {2}, pages = {241-252}, doi = {10.1530/REP-07-0141}, pmid = {17660234}, issn = {1470-1626}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Autophagy ; Caspase Inhibitors ; Cell Culture Techniques ; Cells, Cultured ; Cysteine Proteinase Inhibitors/pharmacology ; DNA Fragmentation ; Female ; Fetus/*physiology ; Glycoproteins/pharmacology ; Immunosuppressive Agents/pharmacology ; In Situ Nick-End Labeling ; Insulin-Like Growth Factor I/pharmacology ; Meiotic Prophase I/*physiology ; Mice ; Mice, Inbred Strains ; Microscopy, Electron, Transmission ; Necrosis ; Oligopeptides/pharmacology ; Oocytes/*cytology/drug effects/ultrastructure ; Ovary/*cytology ; Sirolimus/pharmacology ; Stem Cell Factor/pharmacology ; }, abstract = {We report a short-term culture system that allows to define novel characteristic of programmed cell death (PCD) in fetal oocytes and to underscore new aspects of this process. Mouse fetal oocytes cultured in conditions allowing meiotic prophase I progression underwent apoptotic degeneration waves as revealed by TUNEL staining. TEM observations revealed recurrent atypical apoptotic morphologies characterized by the absence of chromatin margination and nuclear fragmentation; oocytes with autophagic and necrotic features were also observed. Further characterization of oocyte death evidenced DNA ladder, Annexin V binding, PARP cleavage, and usually caspase activation (namely caspase-2). In the aim to modulate the oocyte death process, we found that the addition to the culture medium of the pan-caspase inhibitors Z-VAD or caspase-2-specific inhibitor Z-VDVAD resulted in a partial and transient prevention of this process. Oocyte death was significantly reduced by the antioxidant agent NAC and partly prevented by KL and IGF-I growth factors. Finally, oocyte apoptosis was reduced by calpain inhibitor I and increased by rapamycin after prolonged culture. These results support the notion that fetal oocytes undergo degeneration mostly by apoptosis. This process is, however, often morphologically atypical and encompasses other forms of cell death including caspase-independent apoptosis and autophagia. The observation that oocyte death occurs mainly at certain stages of meiosis and can only be attenuated by typical anti-apoptotic treatments favors the notion that it is controlled at least in part by stage-specific oocyte-autonomous meiotic checkpoints and when activated is little amenable to inhibition being the oocyte able to switch back and forth among different death pathways.}, }
@article {pmid17657622, year = {1998}, author = {Al-Ali, AK and Al-Mustafa, ZH and Qaw, FS and Fayz, M}, title = {Paracetamol-induced hepatotoxicity: lack of enhancement of the hepatoprotective effect of N-acetylcysteine by sodium sulphate.}, journal = {Inflammopharmacology}, volume = {6}, number = {3}, pages = {235-241}, pmid = {17657622}, issn = {0925-4692}, abstract = {The potential role of sodium sulphate in possible enhancement of the hepatoprotective action of N-acetylcysteine (NAC) in paracetamol (PCM) overdose was examined. The effects of sodium sulphate (200 mg/kg) in combination with NAC (400 mg/kg) administered intraperitoneally 2 h post-PCM dose, on mortality rate and plasma activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were investigated in mice 24 h after receiving a single oral dose of 400 mg/kg PCM. In addition, the effect on the mortality rate of PCM-treated animals of co-administering 400 mg/kg sodium sulphate with NAC (200 or 400 mg/kg) was also studied. NAC alone caused a marked reduction in the mortality rate of PCM-treated mice and a sharp drop in their plasma AST and ALT activities to near normal values. However, no additional reduction in plasma levels of AST and ALT was observed when sodium sulphate was co-administered with NAC. Similarly, sodium sulphate (200 mg/kg) administered alone to PCM-treated mice had no effect on the high mortality rate or the elevation in plasma AST and ALT activities observed in these animals. Furthermore, increasing the dose of sodium sulphate to 400 mg/kg did not influence the mortality rate. It is therefore concluded that sodium sulphate neither protects against paracetamol-induced hepatotoxicity nor enhances the hepatoprotective action of N-acetylcysteine.}, }
@article {pmid17654252, year = {2007}, author = {Kim, MK and Kim, KS and Chung, JH and Kim, JH and Kim, JR and Chung, HY and Kim, MS}, title = {Environmental metabolite, 1,2-diacetylbenzene, produces cytotoxicity through ROS generation in HUVEC cells.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {70}, number = {15-16}, pages = {1336-1343}, doi = {10.1080/15287390701428895}, pmid = {17654252}, issn = {1528-7394}, mesh = {Acetophenones/*toxicity ; Apoptosis/*drug effects ; Cells, Cultured ; Endothelial Cells/*drug effects ; Humans ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Solvents/*toxicity ; Umbilical Veins/drug effects ; }, abstract = {Organic solvents are ubiquitous in industrial and household surroundings, and thus individuals are easily exposed. 1,2-Diethylbenzene (DEB) is one of organic solvents contained in gasoline or jet fuels. DEB is absorbed by dermal or inhalation routes, metabolized by cytochrome P-450 in the liver, and ultimately affects mammalian functions. 1,2-Diacetylbenzene (1,2-DAB), which is a putative metabolite of 1,2-DEB, resulted in neuropathological effects on rodent central and peripheral nervous systems. To elucidate the possibility of 1,2-DAB effects on the vascular system, studies were undertaken to examine whether 1,2-DAB induces endothelial cytotoxicity through reactive oxygen species (ROS) generation. Incubation of human umbilical vein endothelial cells (HUVEC) with lower concentrations (4 or 8 microM) of 1,2-DAB induced inhibition of cellular growth and at higher amounts (16 or 32 microM) produced apoptosis. Endothelial cells cultured with 1,2-DAB also showed increased intracellular ROS production and morphological alterations indicative of senescence. Pretreatment with the well-known antioxidant glutathione or N-acetylcysteine (NAC) reduced cytotoxicity induced by 1,2-DAB. Taken together, the results provide evidence that cytotoxicity induced by 1,2-DAB in endothelial cells may be mediated by ROS generation.}, }
@article {pmid17652768, year = {2007}, author = {Chen, N and Aleksa, K and Woodland, C and Rieder, M and Koren, G}, title = {Prevention of ifosfamide nephrotoxicity by N-acetylcysteine: clinical pharmacokinetic considerations.}, journal = {The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique}, volume = {14}, number = {2}, pages = {e246-50}, pmid = {17652768}, issn = {1710-6222}, mesh = {Acetylcysteine/*pharmacokinetics/therapeutic use ; Humans ; Ifosfamide/*adverse effects/*pharmacokinetics/toxicity ; Kidney Diseases/chemically induced/metabolism/*prevention &amp; control ; }, abstract = {BACKGROUND: Ifosfamide, which is routinely given to treat a variety of solid tumours in children, causes serious nephrotoxicity in treated children. Previous in vitro studies have shown that depletion of intracellular glutathione can enhance ifosfamide nephrotoxicity. Presently, there is no therapeutic agent that can prevent ifosfamide nephrotoxicity. We have recently shown that N-acetylcysteine (NAC) at 0.4 mM prevents ifosfamide-induced nephrotoxicity in vitro. However, this in vitro concentration of NAC needed to be compared to those used in human pharmacokinetic studies since the in vitro pharmacological effect of a compound is achieved at concentrations exceeding those used in clinical.<br><br>OBJECTIVE: The aim of the present study was to verify whether the in vitro concentration of NAC, which was found to protect renal cells from ifosfamide-induced damages, is comparable to the currently used clinical concentrations.<br><br>METHODS: A systematic literature review of all published papers reporting on the pharmacokinetics of NAC in humans was conducted.<br><br>RESULTS: The steady state concentrations of NAC administered intravenously to humans ranged from 0.04 mM to 0.9 mM and the urine concentration of NAC was 2 mM.<br><br>CONCLUSION: This suggests that the concentration chosen for in vitro studies is well within the range of clinical levels.}, }
@article {pmid17652361, year = {2007}, author = {Chen, P and Guo, AM and Edwards, PA and Trick, G and Scicli, AG}, title = {Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {293}, number = {4}, pages = {R1619-29}, doi = {10.1152/ajpregu.00290.2007}, pmid = {17652361}, issn = {0363-6119}, support = {14385//PHS HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Angiogenesis Inhibitors/pharmacology ; Angiotensin II/administration &amp; dosage/*pharmacology ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Antioxidants/pharmacology ; *Diabetes Mellitus, Experimental ; Dose-Response Relationship, Drug ; Imidazoles/pharmacology ; Indoles/pharmacology ; Leukostasis/*metabolism ; Losartan/pharmacology ; Male ; NADPH Oxidases/antagonists &amp; inhibitors/*metabolism ; Pyridines/pharmacology ; Pyrroles/pharmacology ; Rats ; Reactive Oxygen Species ; Receptor, Angiotensin, Type 1/metabolism ; Receptor, Angiotensin, Type 2/metabolism ; Retinal Diseases/*metabolism ; Vascular Endothelial Growth Factor A/antagonists &amp; inhibitors/metabolism ; Vasoconstrictor Agents/pharmacology ; }, abstract = {We studied whether angiotensin II (ANG II) via superoxide may contribute to retinal leukostasis and thus to the pathogenesis of retinopathies. We studied: 1) whether intravitreal ANG II induces retinal leukostasis that is altered by antioxidants or by apocynin, a NAD(P)H oxidase inhibitor and 2) whether retinal leukostasis induced by diabetes in rats is also altered by these treatments. Rats were injected intravitreally with ANG II (20 microg in 2 microl), and divided into the following three groups: 1) untreated; 2) treated with tempol doses (approximately 3 mM/day) and N-acetylcysteine (NAC; approximately 1 g.kg(-1).day(-1)); and 3) treated with apocynin (approximately 2 mM/day), both in the drinking water. Rats with streptozotocin-induced diabetes were similarly treated. Leukostasis was evaluated 48 h after ANG II or 2 wk after diabetes induction. ANG II increased retinal leukostasis from 0.3 +/- 0.5 to 3.7 +/- 0.4 leukocytes/ mm(2) (P < 0.01), and these changes were markedly decreased by treatment with tempol + NAC or apocynin, and also by a blocking antibody against vascular endothelial growth factor given intravitreally (P < 0.01). In addition, incubation of dihydroethidium-loaded retina sections with ANG II caused marked increase in superoxide formation. Compared with normal controls, retinal leukostasis in diabetic rats markedly increased from 0.2 +/- 0.3 to 3.8 +/- 0.1 leukocytes/mm(2) (P < 0.01). Diabetic retinal leukostasis was also decreased by treatment with tempol-NAC and normalized by apocynin. Thus increases in intravitreal ANG II can induce retinal leukostasis, which appears to be mediated via increasing superoxide generation by NAD(P)H oxidase, and by VEGF. The activity of NAD(P)H oxidase is required for leukostasis to occur in the diabetic retina.}, }
@article {pmid17651528, year = {2008}, author = {Lin, CC and Yin, MC}, title = {Effects of cysteine-containing compounds on biosynthesis of triacylglycerol and cholesterol and anti-oxidative protection in liver from mice consuming a high-fat diet.}, journal = {The British journal of nutrition}, volume = {99}, number = {1}, pages = {37-43}, doi = {10.1017/S0007114507793881}, pmid = {17651528}, issn = {0007-1145}, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/*metabolism ; Catalase/metabolism ; Cholesterol/analysis/*biosynthesis ; Cysteine/analogs &amp; derivatives/*metabolism/pharmacology ; Dietary Fats/*administration &amp; dosage/metabolism ; Fatty Acid Synthases/genetics/metabolism ; Glutathione/analysis/metabolism ; Glutathione Peroxidase/metabolism ; Hydroxymethylglutaryl CoA Reductases/genetics/metabolism ; Lipid Metabolism ; Liver/*metabolism ; Malate Dehydrogenase/genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; RNA, Messenger/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Sterol Regulatory Element Binding Protein 1/metabolism ; Sterol Regulatory Element Binding Protein 2/metabolism ; Sterol Regulatory Element Binding Proteins/genetics/metabolism ; Triglycerides/analysis/*biosynthesis ; }, abstract = {Effects of n-acetyl cysteine (NAC), s-ethyl cysteine (SEC), s-propyl cysteine (SPC) and cysteine on enzymes participating in biosynthesis of TAG and cholesterol, and antioxidant protection in liver from mice consuming a high-saturated fat diet was examined. The high-fat diet provided 70 % fat energy, in which saturated fat was 55 % of total fat. NAC, SEC, SPC or cysteine, each agent at 1 g/l, was directly added into the drinking water as a supplement for 4 weeks. Results showed high saturated fat significantly increased hepatic TAG and total cholesterol contents (P < 0.05) via enhancing the activity and mRNA expression of malic enzyme, fatty acid synthase and 3-hydroxy-3-methylglutaryl coenzyme A reductase (P < 0.05). The intake of NAC, SEC or SPC significantly decreased TAG and total cholesterol levels (P < 0.05) via lowering the activity and mRNA expression of these three lipogenic-related enzymes (P < 0.05). NAC, SEC or SPC treatment also significantly suppressed high saturated fat-induced hepatic mRNA expression of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2 (P < 0.05). High saturated fat decreased hepatic content of glutathione, and the activity of catalase and glutathione peroxidase (P < 0.05). The intake of NAC, SEC or SPC significantly increased hepatic glutathione content (P < 0.05), restored the activity and mRNA expression of glutathione peroxidase, and alleviated the high saturated fat-induced oxidative stress (P < 0.05). These results support that NAC, SEC and SPC are potent agents for affecting hepatic biosynthesis of TAG and cholesterol, and protecting liver against high saturated fat-associated oxidative damage.}, }
@article {pmid17645304, year = {2007}, author = {Tzeng, HP and Yang, RS and Ueng, TH and Liu, SH}, title = {Upregulation of cyclooxygenase-2 by motorcycle exhaust particulate-induced reactive oxygen species enhances rat vascular smooth muscle cell proliferation.}, journal = {Chemical research in toxicology}, volume = {20}, number = {8}, pages = {1170-1176}, doi = {10.1021/tx700084z}, pmid = {17645304}, issn = {0893-228X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Proliferation/*drug effects ; Cells, Cultured ; Cyclooxygenase 1/analysis/*metabolism ; Cyclooxygenase 2/analysis/*metabolism ; Dose-Response Relationship, Drug ; Extracellular Signal-Regulated MAP Kinases/metabolism ; *Motorcycles ; Muscle, Smooth, Vascular/*drug effects/enzymology/metabolism ; NF-kappa B/metabolism ; Prostaglandins E, Synthetic/metabolism ; Pyrrolidines/pharmacology ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/analysis/*metabolism ; Thiocarbamates/pharmacology ; Up-Regulation ; Vehicle Emissions/*toxicity ; }, abstract = {Long-term exposure to particulate air pollution has been implicated as a risk factor for cardiovascular disease and mortality. Short-term exposure has also been suggested to contribute to complications of atherosclerosis. Aberrant regulation of smooth muscle cell proliferation is thought to associate with the pathophysiology of vascular disorders such as atherosclerosis. In this study, we investigate the influence of organic extracts of motorcycle exhaust particulates (MEPE) on rat vascular smooth muscle cell (VSMC) proliferation and related regulation signaling. Exposure of VSMCs to MEPE (10-100 microg/mL) enhanced serum-induced VSMC proliferation. The expression of proliferating cell nuclear antigen (PCNA) was also enhanced in the presence of MEPE. VSMCs treated with MEPE induced the increase in the extent of cyclooxygenase (COX)-2 mRNA and protein expression and prostaglandin E 2 production, whereas the level of COX-1 protein was unchanged. Moreover, MEPE increased the production of reactive oxygen species (ROS) in VSMCs in a dose-dependent manner. MEPE could also trigger time-dependently extracellular signal-regulated kinase (ERK)1/2 phosphorylation in VSMCs, which was attenuated by antioxidants N-acetylcysteine (NAC) and pyrrolidinedithiocarbamate (PDTC). The level of translocation of nuclear factor (NF)-kappaB-p65 in the nuclei of VSMCs was also increased under MEPE exposure. The potentiating effect of MEPE on serum-induced VSMC proliferation could be abolished by COX-2 selective inhibitor NS-398, specific ERK inhibitor PD98059, and antioxidants NAC and PDTC. Taken together, these findings suggest that MEPE may contribute to the enhancement of the pathogenesis of cardiovascular diseases by augmenting proliferation of VSMCs through a ROS-regulated ERK1/2-activated COX-2 signaling pathway.}, }
@article {pmid17644109, year = {2008}, author = {Geudens, N and Wuyts, WA and Rega, FR and Vanaudenaerde, BM and Neyrinck, AP and Verleden, GM and Lerut, TE and Van Raemdonck, DE}, title = {N-acetyl cysteine attenuates the inflammatory response in warm ischemic pig lungs.}, journal = {The Journal of surgical research}, volume = {146}, number = {2}, pages = {177-183}, doi = {10.1016/j.jss.2007.05.018}, pmid = {17644109}, issn = {0022-4804}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Disease Models, Animal ; Inflammation/drug therapy ; Ischemia ; Lung/blood supply/*drug effects ; Lung Transplantation ; Organ Preservation/*methods ; Reperfusion Injury/*drug therapy ; Swine ; Temperature ; }, abstract = {BACKGROUND: Lungs donated after cardiac death (DCD) may significantly reduce current organ shortage. However, the warm ischemic period following circulatory arrest may enhance ischemia-reperfusion injury (IRI). We investigated the possible therapeutic effect of N-acetyl cysteine (NAC), a potent anti-oxidative agent on IRI in a porcine ex vivo lung reperfusion model.<br><br>MATERIALS AND METHODS: NAC (50 mg/kg) was nebulized to pigs (n = 6/group) prior to sacrifice (NAC-DCD). In DCD-NAC, animals received NAC 15 min after death. Control animals did not receive an aerosol (DCD). Interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-8, lactate dehydrogenase activity and thiobarbituric acid reactive substances were measured and cells were counted in broncho-alveolar lavage from the right lung after a 3-h warm plus 1-h cold ischemic interval.<br><br>RESULTS: There were no differences in cells between groups, however cell death was lower in NAC-DCD (10.3 +/- 1.5%) and DCD-NAC (7.83 +/- 1.8%) compared to DCD (18.0 +/- 3.8%). IL-1beta levels (111.5 +/- 28.8 pg/mL and 92.2 +/- 51.0 pg/mL versus 250.3 +/- 56.6 pg/mL) and lactate dehydrogenase activity (1258.0 +/- 440.9 U/L and 1606.0 +/- 289.0 U/L versus 2848.0 +/- 760.9 U/L) were significantly lower in NAC-DCD and DCD-NAC compared with DCD, respectively. These postischemic inflammatory markers correlated with functional parameters upon reperfusion of the left lung, reported in a previous study.<br><br>CONCLUSIONS: Administration of NAC prior to or shortly after circulatory arrest results in a marked reduction of inflammation during the warm ischemic phase.}, }
@article {pmid17643057, year = {2007}, author = {Sahin, G and Yalcin, AU and Akcar, N}, title = {Effect of N-acetylcysteine on endothelial dysfunction in dialysis patients.}, journal = {Blood purification}, volume = {25}, number = {4}, pages = {309-315}, doi = {10.1159/000106103}, pmid = {17643057}, issn = {1421-9735}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Antioxidants/pharmacology/*therapeutic use ; Brachial Artery/diagnostic imaging/drug effects/physiopathology ; Cardiovascular Diseases/etiology/*prevention &amp; control ; Endothelium, Vascular/*drug effects/physiopathology ; Female ; Hemorheology ; Humans ; Male ; Middle Aged ; Nitric Oxide/physiology ; Nitroglycerin ; Oxidative Stress/drug effects ; *Renal Dialysis ; Ultrasonography ; Uremia/blood/*therapy ; Vasodilation/drug effects ; }, abstract = {BACKGROUND/AIMS: Patients with K/DOQI stage 5 chronic kidney disease (CKD) have higher incidence of cardiovascular events due to the oxidative stress and endothelial dysfunction (ED). The aim of this study is to evaluate the effects of N-acetylcysteine (NAC), which might prevent cardiovascular events by improving oxidative stress on endothelial cells in patients with CKD.<br><br>METHODS: Thirty uremic patients (age 40 +/- 12 years, 6 males) on hemodialysis (HD) were evaluated for ED by using high-resolution Doppler ultrasound of brachial artery before and after 6 weeks of oral NAC (2 x 600 mg) medication. Also, 13 healthy controls (35 +/- 9 years, 5 males) were included in the study. Reactive hyperemia following 5 min forearm ischemia was accepted as endothelium-dependent vasodilatation (flow-mediated dilatation; FMD) and compared to endothelium-independent vasodilatation in response to sublingual glyceril trinitrate (GTN).<br><br>RESULTS: Patients on HD had lower DeltaFMD (0.28 +/- 0.17 vs. 0.41 +/- 0.11, p < 0.05) and FMD% (7.5 +/- 5.05 vs. 11.33 +/- 2.95, p < 0.05) than the controls. Baseline DeltaGTN and GTN% were similar in two groups. NAC treatment significantly increased the DeltaFMD (0.41 +/- 0.11, p < 0.001 vs. baseline) and FMD% (10.59 +/- 3.22, p < 0.01 vs. baseline) of patients on HD, while it had no effect on DeltaGTN and GTN%.<br><br>CONCLUSION: These results suggest that NAC treatment could improve the ED by preventing the reduction of FMD in patients on HD.}, }
@article {pmid17635921, year = {2007}, author = {An, Z and Wang, H and Song, P and Zhang, M and Geng, X and Zou, MH}, title = {Nicotine-induced activation of AMP-activated protein kinase inhibits fatty acid synthase in 3T3L1 adipocytes: a role for oxidant stress.}, journal = {The Journal of biological chemistry}, volume = {282}, number = {37}, pages = {26793-26801}, doi = {10.1074/jbc.M703701200}, pmid = {17635921}, issn = {0021-9258}, support = {HL 074399/HL/NHLBI NIH HHS/United States ; HL 079584/HL/NHLBI NIH HHS/United States ; HL 080499/HL/NHLBI NIH HHS/United States ; }, mesh = {3T3-L1 Cells ; AMP-Activated Protein Kinases ; Acetyl-CoA Carboxylase/metabolism ; Adipocytes/*enzymology ; Animals ; Fatty Acid Synthases/*antagonists &amp; inhibitors ; Lipolysis/drug effects ; Mice ; Multienzyme Complexes/*physiology ; Nicotine/*pharmacology ; *Oxidative Stress ; Phosphorylation ; Protein Serine-Threonine Kinases/*physiology ; Triglycerides/analysis ; }, abstract = {Recent studies suggest that the AMP-activated protein kinase (AMPK) acts as a major energy sensor and regulator in adipose tissues. The objective of this study was to investigate the role of AMPK in nicotine-induced lipogenesis and lipolysis in 3T3L1 adipocytes. Exposure of 3T3L1 adipocytes to smoking-related concentrations of nicotine increased lipolysis and inhibited fatty acid synthase (FAS) activity in a time- and dose-dependent manner. The effects of nicotine on FAS activity were accompanied by phosphorylation of both AMPK (Thr(172)) and acetyl-CoA carboxylase (ACC; Ser(79)). Nicotine-induced AMPK phosphorylation appeared to be mediated by reactive oxygen species based on the finding that nicotine significantly increased superoxide anions and 3-nitrotyrosine-positive proteins, exogenous peroxynitrite (ONOO(-)) mimicked the effects of nicotine on AMPK, and N-acetylcysteine (NAC) abolished nicotine-enhanced AMPK phosphorylation. Inhibition of AMPK using either pharmacologic (insulin, compound C) or genetic means (overexpression of dominant negative AMPK; AMPK-DN) abolished FAS inhibition induced by nicotine or ONOO(-). Conversely, activation of AMPK by pharmacologic (nicotine, ONOO(-), metformin, and AICAR) or genetic (overexpression of constitutively active AMPK) means inhibited FAS activity. Notably, AMPK activation increased threonine phosphorylation of FAS, and this effect was blocked by adenovirus encoding dominant negative AMPK. Finally, AMPK-dependent FAS phosphorylation was confirmed by (32)P incorporation into FAS in adipocytes. Taken together, our results strongly suggest that nicotine, via ONOO(-) activates AMPK, resulting in enhanced threonine phosphorylation and consequent inhibition of FAS.}, }
@article {pmid17633826, year = {2007}, author = {Fan, ZG and Zhang, LM and Li, KJ and Li, W and Zhu, PX and Yang, G}, title = {[Effect of N-acetylcysteine on the egg granuloma in hepatic tissue of mice with Schistosomosis japonica].}, journal = {Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology &amp; parasitic diseases}, volume = {25}, number = {2}, pages = {137-140}, pmid = {17633826}, issn = {1000-7423}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Female ; Free Radical Scavengers/pharmacology ; Glutathione/blood/metabolism ; Glutathione Peroxidase/blood/metabolism ; Granuloma/classification/drug therapy/parasitology/pathology ; Liver/*drug effects/metabolism/parasitology ; Mice ; Mice, Inbred Strains ; Nitric Oxide/blood/metabolism ; Nitric Oxide Synthase Type II/blood/metabolism ; Random Allocation ; Schistosoma japonicum/*drug effects ; Schistosomiasis japonica/classification/*drug therapy/parasitology ; Treatment Outcome ; }, abstract = {OBJECTIVE: To study the effect of N-acetylcysteine (NAC) on the egg granuloma in hepatic tissue of mice infected with Schistosoma japonicum.<br><br>METHODS: 36 mice were randomly divided into normal group, infected group and NAC group, each with 12 mice. The mice in the latter two groups were each infected with 25+/-2 cercariae of S. japonicum through the skin of abdomen. NAC solution was orally given to the mice of NAC group, 200 mg/kg, 2 times/d from the day of infection through to the 42nd day. Mice in the other 2 groups were given 2 ml normal saline daily. The mice were all sacrificed at the end of the 42nd day and their livers were collected for pathologic observation. Area of the egg granuloma was measured with computer image analysis software. Concentration of nitric oxide (NO) and reduced glutathione hormone (GSH), and the activity of glutathione peroxidase (GSH-PX) in serum and hepatic tissue, and the activity of inducible nitric oxide synthase (iNOS) in the hepatic tissue were all detected.<br><br>RESULTS: Number of the single egg granuloma of "+,++,+++" grade were 1.80+/-0.25, 1.37+/-0.23 and 0.53+/-0.15 respectively in NAC treated group, which were less than those of infected group (3.70+/-0.28, 2.77+/-0.25 and 2.00+/-0.14 respectively) (P<0.05). The serum NO and GSH concentration was 0.53+/-0.17 and 229.66+/-9.47 respectively in NAC group, lower than those of infected group (2.64+/-0.31 and 312.47+/-18.55 respectively) (P<0.05), but its GSH-PX activity was 1101.99+/-140.81, higher than that of infected group (663.66+/-25.59) (P<0.05). The concentration of NO and GSH, and the activity of iNOS and GSH-PX in hepatic tissue of NAC group were 6.85+/-0.30, 13.44+/-0.40, 358.40+/-19.15 and 110.84+/-10.93 respectively, lower than those in infected group (8.26+/-1.69, 28.40+/-0.56, 1132.44+/-52.82 and 226.26+/-16.25 respectively) (P<0.05).<br><br>CONCLUSION: NAC may have the effect of retarding pathological change of the liver, which may associate with the decrease of NO and GSH in serum and hepatic tissue and iNOS activity in the tissue.}, }
@article {pmid17631703, year = {2007}, author = {Wu, HS and Jin, X and Tian, Y and Zhang, JH and Wang, CY}, title = {[Protective effect of N-acetyl-L-cysteine on liver and lung injury in mice after partial hepatic ischemia/reperfusion].}, journal = {Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue}, volume = {19}, number = {7}, pages = {394-397}, pmid = {17631703}, issn = {1003-0603}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Antioxidants/pharmacology ; Disease Models, Animal ; Liver/*blood supply/metabolism ; Lung/metabolism ; Lung Injury/metabolism/*prevention &amp; control ; Mice ; Mice, Inbred BALB C ; RNA, Messenger/genetics ; Random Allocation ; Reperfusion Injury/metabolism/*prevention &amp; control ; Toll-Like Receptor 2/genetics/metabolism ; Toll-Like Receptor 4/genetics/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVE: To investigate the changes in Toll-like receptor 2/4(TLR2/4) gene expression in liver and lung in ischemia/reperfusion (I/R) injury with or without preconditioning of N-acetyl-L-cysteine (NAC).<br><br>METHODS: BALB/c mice were used in a model of partial hepatic I/R injury and randomly divided into sham-injury control group (SH group), hepatic I/R group and hepatic I/R with NAC pretreatment group (NAC group), each n=10. The level of tumor necrosis factor-alpha (TNF-alpha) in portal vein and plasma alanine aminotransferase (ALT) were measured at 1 hour and 3 hours respectively after reperfusion, the expressions of TLR2/4 mRNA and protein in liver and lung were observed with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting at the same time points.<br><br>RESULTS: Compared with I/R group, the expressions of TLR2/4 mRNA and protein in liver and lung in NAC group were decreased at same time points (P<0.05 or P<0.01). The level of TNF-alpha in portal vein and plasma ALT increased continually in I/R group at 1 hour and 3 hours after reperfusion compared with SH group, however, they were significantly lowered in the group pretreated by NAC (P<0.05 or P<0.01).<br><br>CONCLUSION: TLR2/4 is activated in liver and lung in the process of partial hepatic I/R injury. NAC can inhibit the activation of TLR2/4 and the induction of TNF-alpha resulted from I/R injury via modulating the state of redox process; thus it might mitigate liver and lung injury following partial hepatic I/R in mice.}, }
@article {pmid17628600, year = {2007}, author = {Huang, H and Yin, R and Zhu, J and Feng, X and Wang, C and Sheng, Y and Dong, G and Li, D and Jing, H}, title = {Protective effects of melatonin and N-acetylcysteine on hepatic injury in a rat cardiopulmonary bypass model.}, journal = {The Journal of surgical research}, volume = {142}, number = {1}, pages = {153-161}, doi = {10.1016/j.jss.2006.12.553}, pmid = {17628600}, issn = {0022-4804}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Apoptosis/drug effects ; Cardiopulmonary Bypass/*adverse effects ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/*therapeutic use ; Glutathione/metabolism ; Liver/drug effects/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Melatonin/pharmacology/*therapeutic use ; Nitric Oxide Synthase/metabolism ; Oxidative Stress/physiology ; Peroxidase/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/metabolism/pathology/*prevention &amp; control ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: An increasing number of patients were undergoing cardiac surgery with cardiopulmonary bypass (CPB) and more attention had been paid to hepatic injury after CPB. This study was designed to test the hypothesis that melatonin and N-acetylcysteine (NAC) could attenuate hepatic injury induced by CPB in rats.<br><br>MATERIALS AND METHODS: Male Sprague Dawley rats were randomly divided into four groups: sham, control (CPB + placebo), NAC (CPB + 250 mg/kg N-acetylcysteine), and melatonin (CPB + 20 mg/kg melatonin). Blood samples were collected at the beginning, at the end of CPB, and at 0.5, 1, 2, 3, and 24 h postoperation. Liver samples were harvested at 24 h after the operation.<br><br>RESULTS: In the control group, the levels of serum liver enzymes and tumor necrosis factor-alpha, activities of inducible nitric oxide synthase, malondialdehyde, and myeloperoxidase in liver tissue were significantly increased. In addition, swollen hepatocytes, vacuolization, and congestion in sinusoids were observed. These changes were markedly reversed in both NAC and melatonin groups. Furthermore, the glutathione content and liver antioxidative enzymes activities were significantly decreased in the control group compared with the sham group. However, the levels of these antioxidants were markedly elevated after NAC or melatonin treatment compared with placebo treatment.<br><br>CONCLUSIONS: Our findings showed that NAC and melatonin had acceptably beneficial effects against the CPB-induced hepatic injury.}, }
@article {pmid17626009, year = {2007}, author = {Heiss, EH and Schilder, YDC and Dirsch, VM}, title = {Chronic treatment with resveratrol induces redox stress- and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells.}, journal = {The Journal of biological chemistry}, volume = {282}, number = {37}, pages = {26759-26766}, doi = {10.1074/jbc.M703229200}, pmid = {17626009}, issn = {0021-9258}, mesh = {Anticarcinogenic Agents/*pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*physiology ; Cellular Senescence/*drug effects ; Cyclin-Dependent Kinase Inhibitor p21/physiology ; DNA-Binding Proteins/*physiology ; HCT116 Cells ; Humans ; Mitochondria/drug effects/metabolism ; Neoplasms/*pathology ; Oxidation-Reduction ; Protein Serine-Threonine Kinases/*physiology ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/*pharmacology ; Tumor Suppressor Protein p53/*physiology ; Tumor Suppressor Proteins/*physiology ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {The induction of senescence, an irreversible growth arrest, in cancer cells is regarded as a mean to halt tumor progression. The phytoalexin resveratrol (RV) is known to possess a variety of cancer-preventive, -therapeutic, and -chemosensitizing properties. We report here that chronic treatment with RV in a subapoptotic concentration induces senescence-like growth arrest in tumor cells. In contrast to the widely accepted antioxidant property of RV, we demonstrate that one causative stimulus for senescence induction by chronic RV is an increased level of reactive oxygen species (ROS). The ROS formed upon RV exposure include hydrogen peroxide and superoxide and originate largely from mitochondria. Consistently, co-incubation with the antioxidant N-acetyl cysteine interfered with RV-mediated reactivation of the senescence program. Molecular mediators on the way from increased ROS levels to the observed growth arrest include p38 MAPK, p53, and p21. Moreover, we provide evidence that RV-initiated replication stress, apparent by activation of the ataxia telangiectasia-mutated kinase pathway, is associated with increased ROS levels and senescence induction. This is the first report linking cell cycle effects with a pro-oxidant and pro-senescent effect of RV in cancer cells.}, }
@article {pmid17624247, year = {2007}, author = {Garozzo, A and Tempera, G and Ungheri, D and Timpanaro, R and Castro, A}, title = {N-acetylcysteine synergizes with oseltamivir in protecting mice from lethal influenza infection.}, journal = {International journal of immunopathology and pharmacology}, volume = {20}, number = {2}, pages = {349-354}, doi = {10.1177/039463200702000215}, pmid = {17624247}, issn = {0394-6320}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antiviral Agents/*pharmacology ; Disease Models, Animal ; Drug Synergism ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections/*drug therapy/*mortality ; Oseltamivir/*pharmacology ; }, abstract = {Many studies have shown that oxidative stress is important in the pathogenesis of pulmonary damage during influenza virus infections. Antioxidant molecules are therefore potentially useful against viral infection. Our previous studies show that N-acetylcysteine (NAC) has a protective effect in a model of lethal influenza infection in mice. NAC administration significantly decreased the mortality in infected mice. Further studies have demonstrated that NAC enhanced survival in combination with the antiviral agent ribavirin. In the present study, we report the effect of combined treatment with NAC and Oseltamivir, clinically used in the treatment and prevention of influenza virus infection, in a murine model of lethal influenza infection. NAC was given as a single daily dose of 1000 mg/kg starting from 4 h before infection and until day 4 after infection; Oseltamivir was given twice daily at dose of 1 mg/kg/die for 5 days, starting from 4 h before infection. End-point evaluation was 21-days survival. NAC alone was slightly effective (20%), since a suboptimal treatment was used. Survival increased to 60% with Oseltamivir and to 100% with Oseltamivir and NAC used in combination. Since NAC alone does not show any antiviral action, the present findings suggest that antioxidant therapy increase survival by an improvement in host defense mechanisms, and/or by a direct antioxidant effect against oxidative stress associated with viral infection. Our studies demonstrate the effectiveness of combining agents acting through different mechanisms, such as antiviral drugs oseltamivir and the antioxidant NAC, indicating a possible advantage of combining the two treatments.}, }
@article {pmid17623874, year = {2007}, author = {Hamilton, D and Loignon, M and Alaoui-Jamali, MA and Batist, G}, title = {Novel use of the fluorescent dye 5-(and-6)-chloromethyl SNARF-1 acetate for the measurement of intracellular glutathione in leukemic cells and primary lymphocytes.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {71}, number = {9}, pages = {709-715}, doi = {10.1002/cyto.a.20433}, pmid = {17623874}, issn = {1552-4922}, mesh = {Acetylcysteine/pharmacology ; *Benzopyrans ; Buthionine Sulfoximine/pharmacology ; Cell Line, Tumor ; Diamide/pharmacology ; Flow Cytometry/*methods ; Fluorescent Dyes ; Glutathione/*metabolism ; Humans ; Jurkat Cells ; Lymphocytes/*metabolism ; *Naphthols ; *Rhodamines ; }, abstract = {Glutathione (GSH) plays an important role in protecting cells against injury, particularly during oxidative stress. Alterations in GSH metabolism are becoming the focus of attention in many diseases such as cancer, neurodegeneration, and AIDS. As such, a rapid assessment of GSH levels in a clinical setting is of increasing importance. We tested the efficacy of the thiol-labeling fluorescent dye CM-SNARF in its ability to measure variations in GSH concentration using a visible-light flow cytometer. GSH levels in I83, Jurkat, and primary lymphocytes were depleted with buthionine sulfoximine (BSO) or diamide, or increased with N-acetylcysteine (NAC). Following each treatment, cells were divided and either labeled with CM-SNARF followed by flow cytometry analysis, or assayed for GSH using a biochemical method. BSO treatment caused a maximal 87-90% decrease in GSH and 68-76% decrease in fluorescence units. Diamide depleted GSH 91-95%, corresponding to a fluorescence decrease of 85-88%. NAC treatment increased GSH levels 27% and fluorescence 12-19%. The overall correlation (R2) between mean GSH concentration and mean fluorescence was 0.80-0.88. CM-SNARF can be used to semi-quantitatively and rapidly determine intracellular variations in GSH concentration in the range of 10-150 nmoles GSH/mg protein.}, }
@article {pmid17620185, year = {2007}, author = {Li, YJ and Kawada, T and Matsumoto, A and Azuma, A and Kudoh, S and Takizawa, H and Sugawara, I}, title = {Airway inflammatory responses to oxidative stress induced by low-dose diesel exhaust particle exposure differ between mouse strains.}, journal = {Experimental lung research}, volume = {33}, number = {5}, pages = {227-244}, doi = {10.1080/01902140701481062}, pmid = {17620185}, issn = {0190-2148}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Bronchial Hyperreactivity/*etiology/*metabolism/pathology ; Bronchoalveolar Lavage Fluid/cytology ; Cytokines/genetics/*metabolism ; Female ; Gene Expression Regulation, Enzymologic ; Heme Oxygenase-1/genetics/*metabolism ; Lung/drug effects/metabolism/pathology ; Macrophages, Alveolar/metabolism/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Oxidative Stress/*drug effects ; RNA, Messenger/genetics/metabolism ; Reproducibility of Results ; Species Specificity ; Vehicle Emissions/*toxicity ; }, abstract = {Low-dose diesel exhaust particle (DEP) exposure induces airway inflammation and exaggerates asthmatic responses in mice, but it is unclear whether strains differ in their susceptibility to adverse effects from low-dose DEP exposure. The authors used BALB/c and C57BL/6 mouse strains to search for genetically based differences in response to low-dose DEP (100 microg/m(3)) exposure in terms of airway inflammatory response. The macrophage count in bronchoalveolar lavage (BAL) fluid soon after DE exposure began was significantly greater in C57BL/6 mice (P < .05) than that in BALB/c mice. The count did not increase significantly in BALB/c mice until later. Heme oxygenase-1 (HO-1) mRNA expression and protein production in lung tissues soon after exposure began were more marked in BALB/c mice than in C57BL/6 mice, but the reverse was true later on. The increases in interleukin (IL)-1beta and interferon (IFN)-gamma levels in BAL fluid after DE exposure were significant only in BALB/c mice; there were significantly increases in monocyte chemoattractant protein (MCP)-1, IL-12, IL-10, IL-4, and IL-13 in both strains, but these were more marked in C57BL/6 mice. These interstrain differences in airway inflammatory response after DE exposure were significantly attenuated by antioxidant N-acetylcysteine (NAC) treatment. Changes in airway hyperresponsiveness were independent of the airway inflammation induced by low-dose DEP. Thus, in BALB/c mice, innate immunity may play a central role in DE exposure response, whereas in C57BL/6 mice Th2-dominant responses play a central role. Low-dose DEP exposure induces airway inflammatory responses that differ among strains, and these differences may be caused by differences in sensitivity to oxidative stress.}, }
@article {pmid17618663, year = {2007}, author = {Kawiak, A and Piosik, J and Stasilojc, G and Gwizdek-Wisniewska, A and Marczak, L and Stobiecki, M and Bigda, J and Lojkowska, E}, title = {Induction of apoptosis by plumbagin through reactive oxygen species-mediated inhibition of topoisomerase II.}, journal = {Toxicology and applied pharmacology}, volume = {223}, number = {3}, pages = {267-276}, doi = {10.1016/j.taap.2007.05.018}, pmid = {17618663}, issn = {0041-008X}, mesh = {Apoptosis/*drug effects ; Comet Assay ; *DNA Damage ; Dose-Response Relationship, Drug ; Drosera/chemistry ; Enzyme Inhibitors/isolation &amp; purification/*pharmacology ; Flow Cytometry ; Gas Chromatography-Mass Spectrometry ; HL-60 Cells ; Humans ; Naphthoquinones/isolation &amp; purification/*pharmacology ; Reactive Oxygen Species/*metabolism ; *Topoisomerase II Inhibitors ; }, abstract = {Reactive oxygen species (ROS) have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis. Plumbagin, a naphthoquinone exhibiting antitumor activity, is known to generate ROS and has been found to inhibit the activity of topoisomerase II (Topo II) through the stabilization of the Topo II-DNA cleavable complex. The objective of this research was to clarify the role of ROS and Topo II inhibition in the induction of apoptosis mediated by plumbagin. As determined by the comet assay, plumbagin induced DNA cleavage in HL-60 cells, whereas in a cell line with reduced Topo II activity-HL-60/MX2, the level of DNA damage was significantly decreased. The onset of DNA strand break formation in HL-60 cells was delayed in comparison with the generation of intracellular ROS. In HL-60/MX2 cells, ROS were generated at a similar rate, whereas a significant reduction in the level of DNA damage was detected. The pretreatment of cells with N-acetylcysteine (NAC) attenuated plumbagin-induced DNA damage, pointing out to the involvement of ROS generation in cleavable complex formation. These results suggest that plumbagin-induced ROS does not directly damage DNA but requires the involvement of Topo II. Furthermore, experiments carried out using light spectroscopy indicated no direct interactions between plumbagin and DNA. The induction of apoptosis was significantly delayed in HL-60/MX2 cells indicating the involvement of Topo II inhibition in plumbagin-mediated apoptosis. Thus, these findings strongly suggest ROS-mediated inhibition of Topo II as an important mechanism contributing to the apoptosis-inducing properties of plumbagin.}, }
@article {pmid17617676, year = {2007}, author = {Yedjou, CG and Tchounwou, PB}, title = {N-acetyl-l-cysteine affords protection against lead-induced cytotoxicity and oxidative stress in human liver carcinoma (HepG2) cells.}, journal = {International journal of environmental research and public health}, volume = {4}, number = {2}, pages = {132-137}, pmid = {17617676}, issn = {1661-7827}, support = {G12 RR013459/RR/NCRR NIH HHS/United States ; 1G12RR13459/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Cell Proliferation ; Cell Survival ; Chelating Agents ; Free Radicals ; Humans ; Lead/*toxicity ; Lipid Peroxidation/drug effects ; Liver Neoplasms/*pathology ; Mutation ; Nitrates/*toxicity ; Oxidative Stress/*drug effects ; Thiobarbiturates ; }, abstract = {Although lead exposure has declined in recent years as a result of change to lead-free gasoline, several epidemiological have pointed out that it represents a medical and public health emergency, especially in young children consuming high amounts of lead-contaminated flake paints. A previous study in our laboratory indicated that lead exposure induces cytotoxicity in human liver carcinoma cells. In the present study, we evaluated the role of oxidative stress in lead-induced toxicity, and the protective effect of the anti-oxidant n-acetyl-l-cysteine (NAC). We hypothesized that oxidative stress plays a role in lead-induced cytotoxicity, and that NAC affords protection against this adverse effect. To test this hypothesis, we performed the MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay and the trypan blue exclusion test for cell viability. We also performed the thiobarbituric acid test for lipid peroxidation. Data obtained from the MTT assay indicated that NAC significantly increased the viability of HepG2 cells in a dose-dependent manner upon 48 hours of exposure. Similar trend was obtained with the trypan blue exclusion test. Data generated from the thiobarbituric acid test showed a significant (p <or= 0.05) increase of MDA levels in lead nitrate-treated HepG2 cells compared to control cells. Interestingly, the addition of NAC to lead nitrate-treated HepG2 cells significantly decreased cellular content of reactive oxygen species (ROS), as evidenced by the decrease in lipid peroxidation byproducts. Overall, findings from this study suggest that NAC inhibits lead nitrate-induced cytotoxicity and oxidative stress in HepG2 cells. Hence, NAC may be used as a salvage therapy for lead-induced toxicity in exposed persons.}, }
@article {pmid17616699, year = {2007}, author = {Menon, SG and Sarsour, EH and Kalen, AL and Venkataraman, S and Hitchler, MJ and Domann, FE and Oberley, LW and Goswami, PC}, title = {Superoxide signaling mediates N-acetyl-L-cysteine-induced G1 arrest: regulatory role of cyclin D1 and manganese superoxide dismutase.}, journal = {Cancer research}, volume = {67}, number = {13}, pages = {6392-6399}, doi = {10.1158/0008-5472.CAN-07-0225}, pmid = {17616699}, issn = {0008-5472}, support = {CA111365/CA/NCI NIH HHS/United States ; CA66081/CA/NCI NIH HHS/United States ; CA73612/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cyclin D1/*metabolism ; Dicarbethoxydihydrocollidine/analogs &amp; derivatives/pharmacology ; Electron Spin Resonance Spectroscopy ; Fibroblasts/metabolism ; G1 Phase ; Humans ; Mice ; NIH 3T3 Cells ; Oxidation-Reduction ; Reactive Oxygen Species ; Signal Transduction ; Superoxide Dismutase/*metabolism ; Superoxides/*metabolism ; }, abstract = {Thiol antioxidants, including N-acetyl-L-cysteine (NAC), are widely used as modulators of the intracellular redox state. We investigated the hypothesis that NAC-induced reactive oxygen species (ROS) signaling perturbs cellular proliferation by regulating the cell cycle regulatory protein cyclin D1 and the ROS scavenging enzyme Mn-superoxide dismutase (MnSOD). When cultured in media containing NAC, mouse fibroblasts showed G(1) arrest with decreased cyclin D1 protein levels. The absence of a NAC-induced G(1) arrest in fibroblasts overexpressing cyclin D1 (or a nondegradable mutant of cyclin D1-T286A) indicates that cyclin D1 regulates this G(1) arrest. A delayed response to NAC exposure was an increase in both MnSOD protein and activity. NAC-induced G(1) arrest is exacerbated in MnSOD heterozygous fibroblasts. Results from electron spin resonance spectroscopy and flow cytometry measurements of dihydroethidine fluorescence showed an approximately 2-fold to 3-fold increase in the steady-state levels of superoxide (O(2)(*-)) in NAC-treated cells compared with control. Scavenging of O(2)(*-) with Tiron reversed the NAC-induced G(1) arrest. These results show that an O(2)(*-) signaling pathway regulates NAC-induced G(1) arrest by decreasing cyclin D1 protein levels and increasing MnSOD activity.}, }
@article {pmid17616649, year = {2007}, author = {Negash, S and Gao, Y and Zhou, W and Liu, J and Chinta, S and Raj, JU}, title = {Regulation of cGMP-dependent protein kinase-mediated vasodilation by hypoxia-induced reactive species in ovine fetal pulmonary veins.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {293}, number = {4}, pages = {L1012-20}, doi = {10.1152/ajplung.00061.2007}, pmid = {17616649}, issn = {1040-0605}, support = {R01 HL-075187/HL/NHLBI NIH HHS/United States ; R01 HL-59435-05/HL/NHLBI NIH HHS/United States ; R01/MIRS HL-75187-01/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cyclic GMP-Dependent Protein Kinase Type I ; Cyclic GMP-Dependent Protein Kinases/*metabolism ; Dose-Response Relationship, Drug ; Fetus/metabolism/physiology ; Hypoxia/metabolism/*physiopathology ; Isoenzymes/metabolism ; Muscle, Smooth, Vascular/embryology ; Myocytes, Smooth Muscle/metabolism ; Nitrates/metabolism ; Nitrites/metabolism ; Peroxynitrous Acid/administration &amp; dosage/pharmacology ; Pulmonary Veins/*embryology ; Reactive Nitrogen Species/*metabolism ; Reactive Oxygen Species/*metabolism ; Sheep ; Time Factors ; Tyrosine/analogs &amp; derivatives/biosynthesis ; *Vasodilation ; }, abstract = {We previously reported that hypoxia attenuates cGMP-dependent protein kinase (PKG)-mediated relaxation in pulmonary vessels (Am J Physiol Lung Cell Mol Physiol 279: L611-L618, 2003). To determine whether hypoxia-induced reactive oxygen and nitrogen species (ROS and RNS, respectively) may be involved in the downregulation of PKG-mediated relaxation, ovine fetal intrapulmonary veins were exposed to 4 h of normoxia or hypoxia, with or without scavengers of ROS [N-acetylcysteine (NAC)] or peroxynitrite (quercetin and Trolox) and preconstricted with endothelin-1. Hypoxia decreased the relaxation response to 8-bromo-cGMP, PKG protein expression, and kinase activity and increased tyrosine nitration in PKG. However, ROS and RNS scavengers prevented these changes. To determine whether increased PKG nitration diminishes PKG activity, pulmonary vein smooth muscle cells (PVSMC) were exposed to shorter-term (30 min) hypoxia, which increased PKG nitration and decreased PKG activity but did not alter PKG protein expression. Increased dihydro-2,7-dichlorofluorescein diacetate (DCFH(2)-DA) fluorescence in PVSMC after 4 h or 30 min of hypoxia was not observed in the presence of NAC, quercetin, or Trolox, suggesting increased ROS and RNS production. Increased PKG nitration and the associated decrease in PKG activity in PVSMC after 30 min of hypoxia were also reversed on reoxygenation. The consequences of PKG nitration were assessed by exposure of purified PKG-Ialpha to peroxynitrite, which caused increased 3-nitrotyrosine immunoreactivity and inhibition of kinase activity. Our data suggest that, after 30 min of hypoxia, reversible covalent modification of PKG by hypoxia-induced reactive species may be an important mechanism by which the relaxation response to cGMP is regulated. However, after 4 h of hypoxia, PKG nitration and decreased PKG expression are involved.}, }
@article {pmid17615545, year = {2007}, author = {Saito, Y and Geisen, P and Uppal, A and Hartnett, ME}, title = {Inhibition of NAD(P)H oxidase reduces apoptosis and avascular retina in an animal model of retinopathy of prematurity.}, journal = {Molecular vision}, volume = {13}, number = {}, pages = {840-853}, pmid = {17615545}, issn = {1090-0535}, support = {R01 EY015130/EY/NEI NIH HHS/United States ; R01 EY015130-03/EY/NEI NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cryoultramicrotomy ; *Disease Models, Animal ; Endothelial Cells/drug effects/enzymology/pathology ; Injections, Intraperitoneal ; Lipid Peroxides/metabolism ; Membrane Glycoproteins/*antagonists &amp; inhibitors ; NADPH Oxidase 2 ; NADPH Oxidases/*antagonists &amp; inhibitors ; Neuroglia/drug effects/pathology ; Oxygen ; Pericytes/drug effects/pathology ; Rats ; Rats, Sprague-Dawley ; Retina/drug effects/*enzymology/*pathology ; Retinal Diseases/*enzymology/*pathology ; Retinal Neovascularization/enzymology/pathology ; Retinal Vessels/pathology ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {PURPOSE: To study the mechanisms of action of the antioxidants, n-acetylcysteine (NAC), and the nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase oxidase inhibitor, apocynin, on intravitreous neovascularization (IVNV), and retinal avascularity in a rat model of retinopathy of prematurity (ROP).<br><br>METHODS: Newborn rats exposed to oxygen-induced retinopathy underwent intraperitoneal (IP) injections of NAC (150 mg/kg) at post-natal day (p)2, p6, p10 (early NAC-treated), or p12 through p17 (late NAC-treated), apocynin (10 mg/kg) from p12 through p17, or phosphate buffered saline (PBS; controls). Lipid hydroperoxide (LHP) was measured in early NAC-treated oxygen-induced retinopathy (OIR) at p7, p14 and p18. Pups were placed in room air at p14. At p18, retinal flat mounts were scored for IVNV and avascular/total retinal area, or retinas were assayed for cleaved caspase-3 and vascular endothelial growth factor (VEGF) protein. In non-injected OIR pups, retinas were assayed for gp91(phox). Cryosections were stained with isolectin B4, cleaved caspase-3, CD68, CD31, gp91(phox), neuron-glial antigen 2 (NG-2), or anti-glial fibrillary acidic protein (GFAP) and visualized with confocal microscopy.<br><br>RESULTS: LHP increased over time in retinas from OIR exposed pups in association with IVNV. Early NAC-treated retinas had significantly reduced LHP compared to PBS-control at p18 (p<0.012). However, neither early nor late treatment with NAC had an effect on IVNV or retinal avascularity. Although apocynin had no effect on IVNV, it reduced both avascular retina (p=0.017) and retinal cleaved caspase-3 determined by western blot (p=0.021). In cryosections from OIR eyes, cleaved caspase-3 positive cells co-labeled with some lectin-stained vessels, NG2 labeled cells, and with GFAP positive cells in the inner nuclear layer. We found that the intravascular expression of gp91(phox) co-localized mostly with CD31 and some CD68 positive cells.<br><br>CONCLUSIONS: Our results do not support the antioxidant properties of NAC as effective in reducing IVNV or avascular retina in the 50/10 OIR rat model. Apocynin reduced avascularity and apoptosis in the OIR model perhaps through pathways triggered by ROS generation but upstream from LHP production. Further study and consideration may be given to apocynin or NAD(P)H oxidase inhibitors as adjunctive therapy for ROP to reduce the avascular retina.}, }
@article {pmid17615175, year = {2007}, author = {De Lisle, RC and Roach, E and Jansson, K}, title = {Effects of laxative and N-acetylcysteine on mucus accumulation, bacterial load, transit, and inflammation in the cystic fibrosis mouse small intestine.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {293}, number = {3}, pages = {G577-84}, doi = {10.1152/ajpgi.00195.2007}, pmid = {17615175}, issn = {0193-1857}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Bacteria/*drug effects/genetics/growth &amp; development ; Body Weight/drug effects ; Cathartics/*pharmacology/therapeutic use ; Cystic Fibrosis/*drug therapy/metabolism/microbiology/physiopathology ; Disease Models, Animal ; Expectorants/*pharmacology/therapeutic use ; Gastric Emptying/drug effects ; Gastrointestinal Transit/*drug effects ; Gene Expression Regulation/drug effects ; Immunity, Innate/drug effects/genetics ; Inflammation/*drug therapy/metabolism/microbiology/physiopathology ; Intestine, Small/*drug effects/metabolism/microbiology/physiopathology ; Mice ; Mice, Inbred CFTR ; Mucus/*metabolism ; Polyethylene Glycols/*pharmacology/therapeutic use ; RNA, Bacterial/metabolism ; RNA, Ribosomal, 16S/metabolism ; }, abstract = {The accumulation of mucus in affected organs is characteristic of cystic fibrosis (CF). The CF mouse small intestine has dramatic mucus accumulation and exhibits slower interdigestive intestinal transit. These factors are proposed to play cooperative roles that foster small intestinal bacterial overgrowth (SIBO) and contribute to the innate immune response of the CF intestine. It was hypothesized that decreasing the mucus accumulation would reduce SIBO and might improve other aspects of the CF intestinal phenotype. To test this, solid chow-fed CF mice were treated with an osmotic laxative to improve gut hydration or liquid-fed mice were treated orally with N-acetylcysteine (NAC) to break mucin disulfide bonds. Treatment with laxative or NAC reduced mucus accumulation by 43% and 50%, respectively, as measured histologically as dilation of the intestinal crypts. Laxative and NAC also reduced bacterial overgrowth in the CF intestine by 92% and 63%, respectively. Treatment with laxative normalized small intestinal transit in CF mice, whereas NAC did not. The expression of innate immune response-related genes was significantly reduced in laxative-treated CF mice, whereas there was no significant effect in NAC-treated CF mice. In summary, laxative and NAC treatments of CF mice reduced mucus accumulation to a similar extent, but laxative was more effective than NAC at reducing bacterial load. Eradication of bacterial overgrowth by laxative treatment was associated with normalized intestinal transit and a reduction in the innate immune response. These results suggest that both mucus accumulation and slowed interdigestive small intestinal transit contribute to SIBO in the CF intestine.}, }
@article {pmid17613008, year = {2007}, author = {Bijarnia, RK and Kaur, T and Singla, SK and Tandon, C}, title = {Reversal of hyperoxaluria-induced alteration in rat liver by administration of N-acetylcysteine.}, journal = {Drug and chemical toxicology}, volume = {30}, number = {3}, pages = {229-240}, doi = {10.1080/01480540701375125}, pmid = {17613008}, issn = {0148-0545}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/therapeutic use ; Animals ; Catalase/metabolism ; Disease Models, Animal ; Free Radical Scavengers/administration &amp; dosage/*pharmacology/therapeutic use ; Hyperoxaluria/chemically induced/*complications/drug therapy ; Lipid Metabolism/drug effects ; Lipid Peroxidation/drug effects ; Liver/*drug effects/enzymology/metabolism/pathology ; Liver Diseases/etiology/metabolism/pathology/*prevention &amp; control ; Male ; Membrane Fluidity/drug effects ; Oxalates ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {The current work was designed to study the potential of N-acetylcysteine (NAC) in modulating hyperoxaluric manifestations induced by acute oxalate dose in rat liver. Hyperoxaluric conditions were induced by giving a single dose of sodium oxalate (70 mg/kg body weight) in one group, and in the other group, hyperoxaluric rats were administered NAC (200 mg/kg body weight) after 30 min of the oxalate dose. After 12 h of the above treatment, blood was taken from the orbital sinus for testing serum oxalate, and animals were sacrificed. To exploit the potential of NAC, various oxidative stress parameters [lipid peroxidation (LP) and activity of antioxidant enzymes], lipid content, and histologic analysis of rat liver were performed. The increased level of LP and activities of superoxide dismutase and catalase in hyperoxaluric rats were restored after NAC treatment. Not only the decreased amount of total lipids and phospholipids but also the increased ratio of cholesterol/phospholipid (showing decreased membrane fluidity) in hyperoxaluric rats were balanced by NAC treatment. Further restored histologic changes of liver tissue confirmed the protective antioxidant effects of the given drug. Thus, N-acetylcysteine being an extraneous antioxidant showed curative properties toward hyperoxaluric manifestations in liver.}, }
@article {pmid17612979, year = {2007}, author = {Arfsten, DP and Johnson, EW and Wilfong, ER and Jung, AE and Bobb, AJ}, title = {Distribution of radio-labeled N-Acetyl-L-Cysteine in Sprague-Dawley rats and its effect on glutathione metabolism following single and repeat dosing by oral gavage.}, journal = {Cutaneous and ocular toxicology}, volume = {26}, number = {2}, pages = {113-134}, doi = {10.1080/15569520701212233}, pmid = {17612979}, issn = {1556-9527}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacokinetics/*pharmacology ; Animals ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacokinetics/*pharmacology ; Glutathione/blood/*metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Glutathione Transferase/metabolism ; Intubation, Gastrointestinal ; Male ; Rats ; Rats, Sprague-Dawley ; Skin/enzymology/metabolism ; Tissue Distribution ; }, abstract = {The distribution of radio-labeled N-Acetyl-L-Cysteine (NAC) and its impact on glutathione (GSH) metabolism was studied in Sprague-Dawley rats following single and multiple dosing with NAC by oral gavage. Radioactivity associated with administration of (14)C-NAC distributed to most tissues examined within 1 hour of administration with peak radioactivity levels occurring within 1 hour to 4 hours and for a majority of the tissues examined, radioactivity remained elevated for up to 12 hours or more. Administration of a second dose of 1,200 mg/kg NAC + (14)C-NAC 4 hours after the first increased liver, kidney, skin, thymus, spleen, eye, and serum radioactivity significantly beyond levels achieved following 1 dose. Administration of a third dose of 1,200 mg/kg NAC + (14)C-NAC 4 hours after the second dose did not significantly increase tissue radioactivity further except in the skin. GSH concentrations were increased 20% in the skin and 50% in the liver after one dose of 1,200 mg/kg NAC whereas lung and kidney GSH were unaffected. Administration of a second and third dose of 1,200 mg/kg NAC at 4 hours and 8 hours after the first did not increase tissue GSH concentrations above background with the exception that skin GSH levels were elevated to levels similar to those obtained after a single dose of NAC. Glutathione-S-transferase (GST) activity was increased 150% in the kidney and 10% in the liver, decreased 60% in the skin, and had no effect on lung GST activity following a single dose of 1,200 mg/kg NAC. Administration of a second dose of 1,200 mg/kg NAC 4 hours after the first decreased skin GST activity a further 20% whereas kidney GST activity remained elevated at levels similar to those obtained after 1 dose of NAC. Administration of a third dose of NAC 4 hours after the second dose increased liver GST activity significantly as compared to background but did not affect skin, kidney, or lung GST activity. Transient decreases in glutathione reductase (GR) activity were measured in the skin and kidney in association with repeat administration of 1,200 mg/kg NAC. Glutathione peroxidase (GxP) activity was increased in the skin, kidney, and liver suggesting that oxidative stress was occurring in these tissues in response to repeat dosing with NAC. Overall, the results of this study present the possibility that NAC could provide some benefit in preventing or reducing toxicity related to exposure to chemical irritants (particularly sulfur mustard) in some tissues by increasing tissue NAC and/or cysteine levels, GSH concentrations, and GST activity. However, follow-on studies in animals are needed to confirm that oral administration of single and multiple doses of NAC can significantly reduce skin, eye, and lung toxicity associated with sulfur mustard exposure. The finding that GxP activity is elevated, albeit transiently, following repeat administration of NAC suggests that repeat administration of NAC may induce oxidative stress in some tissues and further studies are needed to confirm this finding.}, }
@article {pmid17610195, year = {2007}, author = {Gawenda, M and Möller, A and Wassmer, G and Brunkwall, J}, title = {[Prophylaxis of contrast-induced nephropathy with N-acetylcysteine].}, journal = {Zentralblatt fur Chirurgie}, volume = {132}, number = {3}, pages = {227-231}, doi = {10.1055/s-2007-960756}, pmid = {17610195}, issn = {0044-409X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*chemically induced/prevention &amp; control ; Contrast Media/*toxicity ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Premedication ; Prospective Studies ; *Radiography, Interventional ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {PURPOSE: Clinical trials evaluating N-acetylcysteine (NAC) for the prevention of radiocontrast-induced nephropathy (RCN) have reported mixed results. Despite formerly published meta-analyses and due to currently published RCTs, time has come to re-evaluate the current evidence of preventing RCN by administering NAC.<br><br>METHODS: We performed a computerized search without restricted to a language to identify relevant published randomized clinical trials that evaluated N-acetylcysteine for the prevention of radiocontrast-induced nephropathy. Abstracted data from each trial included assessments of clinical outcomes, trial quality, and additional characteristics. The primary outcome of interest was the incidence of nephropathy after contrast administration. Data were combined using random effects models with the performance of standard tests to assess for heterogeneity and publication bias. Subgroup analyses were also performed.<br><br>RESULTS: Twenty-eight trials involving 3 604 patients met our inclusion criteria. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The summary risk ratio for contrast-related nephropathy was 0.69 (95 % confidence interval: 0.57 to 0.82; P = 0.02), a statistically significant trend towards benefit in patients treated with N-acetylcysteine. This effect varied, however, across the 28 trials, and only eight of the 28 trials demonstrated significant results although higher-quality trials demonstrated a stronger benefit for N-acetylcysteine in general, few reported important elements of study design, such as concealment of allocation, placebo-controls, or double-blinding. Heterogenity was unexplained by subgroup analyses.<br><br>SUMMARY AND CONCLUSIONS: N-acetylcysteine (NAC) may reduce the incidence of contrast-related nephropathy, but this finding is reported inconsistently across currently available trials. Large high-quality, clinical trials are needed before the application of N-acetylcysteine can be recommended in general for this indication.}, }
@article {pmid17607690, year = {2007}, author = {Gorina, R and Sanfeliu, C and Galitó, A and Messeguer, A and Planas, AM}, title = {Exposure of glia to pro-oxidant agents revealed selective Stat1 activation by H2O2 and Jak2-independent antioxidant features of the Jak2 inhibitor AG490.}, journal = {Glia}, volume = {55}, number = {13}, pages = {1313-1324}, doi = {10.1002/glia.20542}, pmid = {17607690}, issn = {0894-1491}, mesh = {Animals ; Antioxidants/*pharmacology ; Astrocytes/drug effects/metabolism ; Cells, Cultured ; Hydrogen Peroxide/*pharmacology ; Janus Kinase 2/*antagonists &amp; inhibitors/metabolism ; Microglia/drug effects/metabolism ; Neuroglia/*drug effects/metabolism ; Oxidants/*pharmacology ; Oxidative Stress ; Peroxides/pharmacology ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; STAT1 Transcription Factor/drug effects/metabolism/*physiology ; Tyrphostins/*pharmacology ; }, abstract = {The JAK/STAT pathway is activated in response to cytokines and growth factors. In addition, oxidative stress can activate this pathway, but the causative pro-oxidant forms are not well identified. We exposed cultures of rat glia to H2O2, FeSO4, nitroprussiate, or paraquat. We assessed oxidative stress by measuring reactive oxygen species (ROS) and oxidated proteins, we determined phosphorylated Stat1 (pStat1), and we evaluated the effect of antioxidants (trolox, propyl gallate, and N-acetylcysteine) and of Jak2 (Janus tyrosine kinases) inhibitors (AG490 and Jak2-Inhibitor-II). Pro-oxidant agents induced ROS and protein oxidation, excluding nitroprussiate that induced protein nitrosylation. H2O2, and to a lesser extent FeSO4, increased the level of pStat1, whereas nitroprussiate and paraquat did not. Trolox and propyl gallate strongly prevented ROS formation but they did not abolish H2O2-induced pStat1. In contrast, NAC did not reduce the level of ROS but it prevented the increase of pStat1 induced by H2O2, evidencing a differential effect on ROS formation and on Stat1 phosphorylation. H2O2 induced pStat1 in mixed glia cultures and, to a lesser extent, in purified astroglia, but not in microglia. Jak2 inhibitors reduced H2O2-induced pStat1, suggesting the involvement of this kinase in the increased phosphorylation of Stat1 by peroxide. Unexpectedly, AG490, but not Jak2-Inhibitor-II, reduced ROS formation, and it abrogated lipid peroxidation in microsomal preparations. Furthermore, AG490 reduced ROS in glial cells that were transfected with siRNA to silence Jak2 expression. These findings reveal previously unrecognized Jak2-independent antioxidant properties of AG490, and show that Jak2-dependent Stat1 activation by peroxide is dissociated from ROS generation.}, }
@article {pmid17606339, year = {2007}, author = {Esmat, A and El-Demerdash, E and El-Mesallamy, H and Abdel-Naim, AB}, title = {Toxicity and oxidative stress of acrylonitrile in rat primary glial cells: preventive effects of N-acetylcysteine.}, journal = {Toxicology letters}, volume = {171}, number = {3}, pages = {111-118}, doi = {10.1016/j.toxlet.2007.05.001}, pmid = {17606339}, issn = {0378-4274}, mesh = {Acetylcysteine/*pharmacology ; Acrylonitrile/*toxicity ; Adenosine Triphosphate/metabolism ; Animals ; Cell Survival/drug effects ; Cyanides/metabolism ; Free Radical Scavengers/*pharmacology ; Glial Fibrillary Acidic Protein/metabolism ; Glutathione/metabolism ; Immunohistochemistry ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; Neuroglia/*drug effects ; Oxidative Stress/*drug effects ; Rats ; }, abstract = {Brain is a target organ for acrylonitrile (ACN) toxicity. The objective of the current work was to investigate ACN cytotoxicity in rat primary glial cells, using N-acetyl-l-cysteine (NAC) as a potential protective agent. Cells were exposed in vitro to different concentrations of ACN for different time intervals. Cell membrane integrity was assessed by trypan blue exclusion and lactate dehydrogenase (LDH) leakage. Approximately 50% membrane damage was observed in the incubations containing 1.0mM ACN for 3h. Therefore, these experimental conditions were used in subsequent studies. ACN enhanced lipid peroxidation, as indicated by malondialdehyde (MDA) accumulation, and depleted reduced glutathione (GSH) level with no change in total glutathione. Also, ACN was activated to cyanide (CN(-)) with dramatic decrease in ATP level. Cell treatment with NAC prior to exposure to ACN afforded some protection; as indicated by reducing MDA level and elevating level of both reduced and total glutathione. Further, pretreatment with NAC inhibited CN(-) formation and caused an increase in ATP level. Our results indicate that ACN is toxic to rat primary glial cells as evidenced by induction of oxidative stress and generation of CN(-) with subsequent energy depletion. NAC can play an important role against ACN-induced oxidative damage.}, }
@article {pmid17603285, year = {2007}, author = {Park, BC and Lee, YS and Park, HJ and Kwak, MK and Yoo, BK and Kim, JY and Kim, JA}, title = {Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death.}, journal = {Experimental &amp; molecular medicine}, volume = {39}, number = {3}, pages = {316-326}, doi = {10.1038/emm.2007.35}, pmid = {17603285}, issn = {1226-3613}, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Calcium/metabolism ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Cytoprotection ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Enzyme Activation ; Flavonoids/*pharmacology ; Humans ; Imidazoles/pharmacology ; Neurons/cytology/*drug effects ; Oxidopamine/*toxicity ; Phosphorylation ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Rhus/*chemistry ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {6-Hydroxydopamine (6-OHDA) is a neurotoxin and is commonly used to generate experimental models of Parkinson's disease (PD). In this study, we investigated the signaling molecules involved in the 6-OHDA-induced cell death using a neuronal catecholaminergic cell line (SK-N-SH cells), and the protective effect of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-OHDA-induced neuronal death. 6-OHDA significantly increased levels of reactive oxygen species (ROS), intracellular Ca(2+) ([Ca(2+)](i)), and p38 phosphorylation. In addition, this ROS increase by 6-OHDA was reduced by pretreatment with N-acetylcysteine (NAC), a free radical scavenger, but not by bis-(o-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid (BAPTA), a Ca(2+) chelator. However, the [Ca(2+)](i) increase induced by 6-OHDA was suppressed by NAC. Moreover, pretreatment with NAC or BAPTA significantly prevented the 6-OHDA-induced increases in p38 phosphorylation, Bax/Bcl-2 ratio, and caspase-3 activity. Although 6-OHDA-increased phosphorylation of p38 was prevented by NAC or BAPTA, inhibition of p38 by SB203580 did not suppress ROS, Bax/Bcl-2 ratio, or caspase-3 activity increases, and only partially prevented 6-OHDA-induced cell death, thus demonstrating that p38 activation is a component of a signaling pathway leading to the initiation of 6-OHDA-induced cell death, which acts in parallel with an ROS-Ca(2+)-Bcl-2-caspase-3 pathway. Moreover, fustin not only suppressed 6-OHDA-induced cell death in a concentration-dependent manner but also blocked 6-OHDA-induced increases in ROS, [Ca(2+)](i), Bax/Bcl-2 ratio, caspase-3 activity, and p38 phosphorylation. These results suggest that fustin exerts neuroprotection against 6-OHDA-induced cell death.}, }
@article {pmid17603091, year = {2007}, author = {Liu, JB and Wang, YM and Peng, SQ and Han, G and Dong, YS and Yang, HY and Yan, CH and Wang, GQ}, title = {Toxic effects of Fusarium mycotoxin butenolide on rat myocardium and primary culture of cardiac myocytes.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {50}, number = {3}, pages = {357-364}, doi = {10.1016/j.toxicon.2007.04.014}, pmid = {17603091}, issn = {0041-0101}, mesh = {4-Butyrolactone/*analogs &amp; derivatives/chemistry/toxicity ; Animals ; Cell Survival ; Cells, Cultured ; Dose-Response Relationship, Drug ; Fusarium/*metabolism ; Heart/*drug effects ; Lipid Peroxidation ; Molecular Structure ; Mycotoxins/chemistry/toxicity ; Myocytes, Cardiac/*drug effects ; Rats ; Time Factors ; }, abstract = {Mycotoxin toxicosis has been implicated in the etiopathogenesis of Keshan disease (KD), an endemic cardiomyopathy prevailing in some regions of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone, CAS No. 16275-44-8), a mycotoxin produced by several Fusarium species such as Fusarium tricinctum and Fusarium graminearum, is frequently detected from the cereals in the endemic areas of KD. The present study is undertaken to investigate whether this mycotoxin can induce myocardial damage. Exposure of primary culture of cardiac myocytes to butenolide resulted in significant cytotoxicity, manifested by changes in cell morphology and decreases in cell viability. Consistent with the in vitro findings, distinct myocardial toxicity in vivo was observed after administration of rats by gavage with butenolide (10 and 20 mg/kg/day) for 2 months, and the myocardial injuries were characterized by focal necrosis of myocardium and fragmentation of myofiber. Butenolide also induced significant oxidative damage to the myocardium in vitro evidenced by a concentration-dependent lipid peroxidation in the myocardial homogenates, whereas antioxidants superoxide dismutase (SOD), N-acetylcysteine (NAC) and glutathione (GSH) provided significant protections against this oxidative effect. Taken together, these results clearly reveal that butenolide possesses the potential to induce myocardial toxicity. The present findings may reinforce the hypothesis that toxicosis by mycotoxins is one of the etiological factors for KD.}, }
@article {pmid17602868, year = {2007}, author = {Atkuri, KR and Mantovani, JJ and Herzenberg, LA and Herzenberg, LA}, title = {N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency.}, journal = {Current opinion in pharmacology}, volume = {7}, number = {4}, pages = {355-359}, pmid = {17602868}, issn = {1471-4892}, support = {R01 AI077395/AI/NIAID NIH HHS/United States ; R01 AI098519/AI/NIAID NIH HHS/United States ; AI566223/AI/NIAID NIH HHS/United States ; }, mesh = {Acetaminophen/poisoning ; Acetylcysteine/*administration &amp; dosage/adverse effects/pharmacokinetics ; Antidotes/*administration &amp; dosage/adverse effects/pharmacokinetics ; Controlled Clinical Trials as Topic ; Cysteine/*deficiency ; Cystic Fibrosis/drug therapy ; Free Radical Scavengers/*administration &amp; dosage/adverse effects/pharmacokinetics ; Glutathione/*deficiency ; HIV Infections/drug therapy ; Humans ; Prodrugs ; Quality of Life ; }, abstract = {Glutathione (GSH) deficiency is associated with numerous pathological conditions. Administration of N-acetylcysteine (NAC), a cysteine prodrug, replenishes intracellular GSH levels. NAC, best known for its ability to counter acetaminophen toxicity, is a safe, well-tolerated antidote for cysteine/GSH deficiency. NAC has been used successfully to treat GSH deficiency in a wide range of infections, genetic defects and metabolic disorders, including HIV infection and COPD. Over two-thirds of 46 placebo-controlled clinical trials with orally administered NAC have indicated beneficial effects of NAC measured either as trial endpoints or as general measures of improvement in quality of life and well-being of the patients.}, }
@article {pmid17602713, year = {2007}, author = {Jayalakshmi, K and Singh, SB and Kalpana, B and Sairam, M and Muthuraju, S and Ilavazhagan, G}, title = {N-acetyl cysteine supplementation prevents impairment of spatial working memory functions in rats following exposure to hypobaric hypoxia.}, journal = {Physiology &amp; behavior}, volume = {92}, number = {4}, pages = {643-650}, doi = {10.1016/j.physbeh.2007.05.051}, pmid = {17602713}, issn = {0031-9384}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Altitude Sickness/*drug therapy/metabolism/physiopathology ; Analysis of Variance ; Animals ; Atmospheric Pressure ; Dietary Supplements ; Free Radicals/metabolism ; Hippocampus/drug effects/metabolism ; Hypoxia/drug therapy/metabolism ; Male ; Maze Learning/*drug effects/physiology ; Memory, Short-Term/*drug effects/physiology ; Neuroprotective Agents/metabolism/*pharmacology ; Oxidative Stress/drug effects ; Oxygen Consumption ; Rats ; Rats, Sprague-Dawley ; Space Perception/drug effects/physiology ; }, abstract = {Exposure to high altitude (HA), especially extreme altitude, is associated with impairment of cognitive functions including memory and increased oxidative stress. However, the underlying mechanisms involved are not well understood. It is hypothesized that HA induced oxidative stress may be one of the factors underlying hypoxia induced memory impairment. The aim of the present study was to investigate the effect of hypobaric hypoxia (HH) on spatial working and reference memory functions, oxidative stress markers in rats and effect of supplementation of N-acetyl cysteine (NAC). The rats were divided into four groups. Group I served as normoxic (n=6), Group II served as hypoxic (n=6), Group III as hypoxia group treated with NAC (n=6) and Group IV served as normoxic group treated with NAC (n=6). Group II &amp; III were exposed to HH for 3 days equivalent to 6100 m and received oral NAC supplementation (750 mg/kg) daily. Rats from all the groups were trained in Morris Water Maze (MWM) task for 8 consecutive days. Spatial working and reference memory were tested immediately after the termination of HH and then the rats were sacrificed for estimation of oxidative stress markers in hippocampus. Rats displayed significant deficits in spatial working memory, and increased oxidative stress along with decrease in antioxidant status on hypoxic exposure. Supplementation with NAC in hypoxia-exposed group improved spatial memory performance, and decreased oxidative stress. These findings indicate that hypoxic exposure is associated with increased oxidative stress, which may have caused memory deficit in rats exposed to simulated HA.}, }
@article {pmid17600317, year = {2007}, author = {Hauber, HP and Goldmann, T and Vollmer, E and Wollenberg, B and Zabel, P}, title = {Effect of dexamethasone and ACC on bacteria-induced mucin expression in human airway mucosa.}, journal = {American journal of respiratory cell and molecular biology}, volume = {37}, number = {5}, pages = {606-616}, doi = {10.1165/rcmb.2006-0404OC}, pmid = {17600317}, issn = {1535-4989}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Anti-Inflammatory Agents/*pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Cell Line ; Dexamethasone/*pharmacology ; Female ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation/drug effects ; Humans ; Lipopolysaccharides/immunology ; Lipoproteins/immunology ; Male ; Mucins/*biosynthesis/genetics ; Respiratory Mucosa/*drug effects/immunology/metabolism ; Salmonella/*immunology ; }, abstract = {Gram-negative bacteria can stimulate mucin production, but excessive mucus supports bacterial infection and consequently leads to airway obstruction. Therefore, the effect of dexamethasone (DEX) and the antioxidant acetyl-cysteine (ACC) on bacteria-induced mucus expression was investigated. Explanted human airway mucosa and mucoepidermoid cells (Calu-3) were stimulated with lipopolysaccharide (LPS) or PAM3 (a synthetic lipoprotein). DEX or ACC were added to either LPS- or PAM3-stimulated airway mucosa or Calu-3 cells. Mucin mRNA expression (MUC5AC) and total mucus glycoconjugates (mucin protein) were quantified using real-time PCR and periodic acid Schiff staining. LPS and PAM3 significantly increased mucin expression in airway mucosa and Calu-3 cells (P < 0.05). DEX alone had no significant effect on mucin expression in airway mucosa or Calu-3 cells (P > 0.05). In contrast, DEX significantly reduced LPS- and PAM3-induced mucin expression in explanted mucosal tissue and mucin expression in Calu-3 cells (P < 0.05). In explanted human airway mucosa ACC alone significantly increased mucin expression (P < 0.05). In contrast, ACC significantly decreased LPS- and PAM3-induced mucin expression (P < 0.05). In Calu-3 cells ACC alone had no significant effect on mucin expression (P > 0.05). ACC decreased LPS- and PAM3-induced mucin expression, but this effect was not significant (P > 0.05). These data suggest that DEX can effectively reduce bacteria-induced mucin expression in the airways. ACC alone may increase mucin expression in noninfected mucosa, but it decreased bacteria-induced mucin expression. Further studies are warranted to evaluate whether the effect of DEX or ACC is clinically relevant.}, }
@article {pmid17600310, year = {2007}, author = {Facchinetti, F and Amadei, F and Geppetti, P and Tarantini, F and Di Serio, C and Dragotto, A and Gigli, PM and Catinella, S and Civelli, M and Patacchini, R}, title = {Alpha,beta-unsaturated aldehydes in cigarette smoke release inflammatory mediators from human macrophages.}, journal = {American journal of respiratory cell and molecular biology}, volume = {37}, number = {5}, pages = {617-623}, doi = {10.1165/rcmb.2007-0130OC}, pmid = {17600310}, issn = {1535-4989}, mesh = {Aldehydes/*adverse effects ; Humans ; Inflammation Mediators/*metabolism ; Interleukin-8/*metabolism ; Macrophages/*metabolism ; Pulmonary Disease, Chronic Obstructive/etiology/metabolism ; Smoking/*adverse effects ; Tumor Necrosis Factor-alpha/*metabolism ; U937 Cells ; }, abstract = {Smoking cigarettes is the major risk factor for chronic obstructive pulmonary disease (COPD). COPD is a condition associated with chronic pulmonary inflammation, characterized by macrophage activation, neutrophil recruitment, and cell injury. Many substances contained in cigarette smoke, including reactive oxygen species (ROS), have been proposed to be responsible for the inflammatory process of COPD. However, this issue remains unsettled. By gas chromatography/mass spectrometry (GC/MS) we show that acrolein and crotonaldehyde, two alpha,beta-unsaturated aldehydes, are contained in aqueous cigarette smoke extract (CSE) at micromolar concentrations and mimic CSE in evoking the release of the neutrophil chemoattractant IL-8 and of the pleiotropic inflammatory cytokine TNF-alpha from the human macrophagic cell line U937. In addition, acrolein (10-30 microM) released IL-8 also from cultured human alveolar macrophages and THP-1 macrophagic cells. 4-hydroxy-2-nonenal (30-100 microM), an endogenous alpha,beta-unsaturated aldehyde that is abundant in lungs of patients with COPD, stimulated the release of IL-8 from U937 cells, whereas the saturated aldehyde, acetaldehyde, was ineffective. CSE-evoked IL-8 release was remarkably (> 80%) inhibited by N-acetyl-cysteine (0.1-3 mM) or glutathione monoethyl ester (1-3 mM). Both compounds, by forming covalent adducts (Michael adducts), completely removed unsaturated aldehydes from CSE. Our data demonstrate that alpha,beta-unsaturated aldehydes are major mediators of cigarette smoke-induced macrophage activation, and suggest that they might contribute to pulmonary inflammation associated with cigarette smoke.}, }
@article {pmid17599755, year = {2007}, author = {Guilpain, P and Servettaz, A and Goulvestre, C and Barrieu, S and Borderie, D and Chéreau, C and Kavian, N and Pagnoux, C and Guillevin, L and Weill, B and Mouthon, L and Batteux, F}, title = {Pathogenic effects of antimyeloperoxidase antibodies in patients with microscopic polyangiitis.}, journal = {Arthritis and rheumatism}, volume = {56}, number = {7}, pages = {2455-2463}, doi = {10.1002/art.22741}, pmid = {17599755}, issn = {0004-3591}, mesh = {Adult ; Aged ; Antibodies, Antineutrophil Cytoplasmic/*blood ; Female ; Humans ; Male ; Middle Aged ; Peroxidase/blood/*immunology ; Reference Values ; Vasculitis/blood/enzymology/*immunology ; }, abstract = {OBJECTIVE: Microscopic polyangiitis (MPA) is a small-vessel vasculitis associated with antimyeloperoxidase (MPO) antibodies in 70% of patients. Anti-MPO antibodies can trigger the release of MPO by neutrophils and monocytes, but their involvement in the pathogenesis of MPA is still questioned. The aim of this study was to investigate whether anti-MPO antibodies can activate MPO to generate an oxidative stress that is potentially deleterious to the endothelium.<br><br>METHODS: MPA sera, purified IgG from MPA sera, normal control sera, and purified IgG from normal sera were incubated with MPO coated onto microtitration plates. The peroxidase activity of MPO was evaluated by adding o-phenylenediamine. Production of hypochlorous acid (HOCl) was determined by chemiluminescence. The cytotoxic properties of byproducts of MPO activation were tested on endothelial cells in culture.<br><br>RESULTS: MPA sera with anti-MPO antibodies were found to activate MPO in vitro (P < 0.0001 versus normal sera) and to generate HOCl (P < 0.001), as did IgG purified from MPA sera (P < 0.05). MPA sera without anti-MPO antibodies and MPA IgG absorbed on MPO did not show these activities. The byproducts of MPO activation by MPA sera exerted a strong cytolytic activity on endothelial cells in culture (P < 0.01). Both HOCl production and endothelial lysis were abrogated by N-acetylcysteine (NAC), an antioxidant molecule (P < 0.05 and P < 0.0001, respectively).<br><br>CONCLUSION: Anti-MPO antibodies could play a pathogenic role in vivo by triggering an oxidative burst, leading to severe endothelial damage. Treatment of MPA patients with NAC might be proposed in an attempt to abrogate these deleterious phenomena.}, }
@article {pmid17596533, year = {2007}, author = {Huang, JS and Chuang, LY and Guh, JY and Huang, YJ and Hsu, MS}, title = {Antioxidants attenuate high glucose-induced hypertrophic growth in renal tubular epithelial cells.}, journal = {American journal of physiology. Renal physiology}, volume = {293}, number = {4}, pages = {F1072-82}, doi = {10.1152/ajprenal.00020.2007}, pmid = {17596533}, issn = {1931-857X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects/physiology ; Cell Line ; Epithelial Cells/drug effects/metabolism/*pathology ; Extracellular Matrix/drug effects/metabolism ; Glucose/*adverse effects ; Hyperglycemia/complications ; Hypertrophy/etiology/pathology/prevention &amp; control ; Janus Kinases/metabolism ; Kidney Tubules, Proximal/drug effects/metabolism/*pathology ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Proto-Oncogene Proteins c-raf/metabolism ; STAT Transcription Factors/metabolism ; Signal Transduction/drug effects ; Swine ; Taurine/pharmacology ; }, abstract = {Hyperglycemia-induced oxidative stress is a key mediator of renal tubular hypertrophy in diabetic nephropathy (DN). The molecular mechanisms of antioxidants responsible for inhibition of renal tubular hypertrophy in DN are incompletely characterized. We now aim at verifying the effects of N-acetylcysteine (NAC) and taurine on cellular hypertrophy in renal tubular epithelial cells under high ambient glucose. We found that NAC and taurine treatments significantly attenuated high glucose (HG)-inhibited cellular growth and HG-induced hypertrophy. HG-induced Raf-1, p42/p44 mitogen-activated protein kinase (MAPK), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 1 (STAT1) and STAT3 (but not STAT5) activation was markedly blocked by NAC and taurine. Moreover, NAC and taurine increased cyclin D1/cdk4 activation and suppressed p21(Waf1/Cip1) and p27(Kip1) expression in HG-treated cells. It seems that apoptosis was not observed in these treatments. There were no changes in bcl-2 and poly(ADP-ribose) polymerase expression, and mitochondrial cytochrome c release. However, NAC or taurine markedly inhibited the stimulation by HG of fibronectin and type IV collagen protein levels. It is concluded that both NAC and taurine significantly attenuated HG-induced activation of the Raf-1/MAPK and the JAK2-STAT1/STAT3 signaling pathways and hypertrophic growth in renal tubular epithelial cells.}, }
@article {pmid17595391, year = {2007}, author = {Sharif, MA and Bayraktutan, U and Young, IS and Soong, CV}, title = {N-acetylcysteine does not improve the endothelial and smooth muscle function in the human saphenous vein.}, journal = {Vascular and endovascular surgery}, volume = {41}, number = {3}, pages = {239-245}, doi = {10.1177/1538574407299618}, pmid = {17595391}, issn = {1538-5744}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Aged, 80 and over ; Endothelium, Vascular/*drug effects ; Female ; Free Radical Scavengers/*pharmacology ; Humans ; Male ; Middle Aged ; Muscle, Smooth/*drug effects ; Nitroprusside/pharmacology ; *Saphenous Vein ; }, abstract = {Oxidative stress can lead to vein graft dysfunction in the saphenous vein. This ex vivo study is aimed to compare the effects of increasing concentrations of the antioxidant N-acetylcysteine (NAC) with heparinized saline (HS) on endothelial and smooth muscle function in the human saphenous vein. Long saphenous vein segment obtained during infrainguinal bypass surgery was divided into 7 rings; 1 immersed in HS and the remaining 6 in increasing NAC concentrations (0.0025%, 0.005%, 0.01%, 0.02%, 0.03%, and 0.04%). Rings were mounted in an organ bath, and relaxant responses to acetylcholine and sodium nitroprusside were assessed through isometric tension studies. Endothelium-dependent relaxations were observed in 77 vein segments from 11 patients. No significant difference was seen in veins treated with either lower NAC concentrations (0.0025%, 0.005%, 0.01%, 0.02%, and 0.03%) or HS. However, HS-treated veins showed significantly better relaxation compared to those treated with maximum (0.04%) NAC (P < .05). Endothelium-independent relaxations were observed in 91 segments from 13 patients. No difference in relaxation was observed between veins treated with HS or any of the NAC concentrations. In conclusion, lower NAC concentrations do not offer better endothelial protection than HS, whereas the highest NAC concentration has a detrimental effect on endothelium-dependent relaxation. Moreover, NAC did not show beneficial effect on direct smooth muscle relaxation.}, }
@article {pmid17593831, year = {2007}, author = {Fu, J and Liang, X and Chen, Y and Zhang, QH and Tang, L and Zhang, N}, title = {[Effect of chromium ion and antioxidant N-acetyl-cysteine on morphology of human osteoblast-like MG63 cell line].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {38}, number = {3}, pages = {459-462}, pmid = {17593831}, issn = {1672-173X}, mesh = {Acetylcysteine/*pharmacology ; Alloys/chemistry ; Animals ; Antioxidants/*pharmacology ; Cell Line ; Chromium/chemistry/*toxicity ; Cytotoxins/*antagonists &amp; inhibitors ; Humans ; Osteoblasts/*cytology/*drug effects ; Salts/chemistry ; Solutions ; }, abstract = {OBJECTIVE: The objective of this study was to evaluate the cellular morphology and ultrastructural changes of MG63 cell line exposed to salt solutions of hexavalent chromium ions which may be released from the alloys used in biomedicine, and to determine if antioxidant N-acetyl-cysteine (NAC) could reduce the cytotoxicity induced by chromium ion.<br><br>METHODS: MG63 cell lines were exposed respectively to 5 micromol/L Cr6+ , 10 micromol/L Cr6+ 20 micromol/L Cr6+ or 2 mmol/L NAC F12 medium in vitro for 24 h. And also, in order to assess the ability of antioxidant NAC to protect MG63 against chromium ion-induced cellular morphology and ultrastructural changes, MG63 were preincubated with 2 mmol/L NAC for 30 min, and then cultured with 10 micromol/L Cr6+ F12 medium for further 24 h. The cellular morphology and ultrastructural features were examined by optical microscopy and transmission electron microscopy (TEM).<br><br>RESULTS: Under optical microscopy, we found that MG63 cells became round and detached from the culture dishes when exposed to chromium ions. The TEM examination confirmed these optical microscopic findings. MG63 cells treated with Cr6+ had the irregular shaped nuclei, swollen mitochondria, dilation of rER and numerous large vacuoles in the cytoplasm. These cellular morphology and ultrastructural changes of MG63 cell line were noticeably reduced by the NAC (2 mmol/L) pretreatment.<br><br>CONCLUSION: Cr6+ significantly destroyed the cellular morphology and ultrastructure of MG63 cell line. Antioxidant N-acetyl-cysteine can play a critical role against Cr6+-induced cell changes.}, }
@article {pmid17590522, year = {2008}, author = {Foster, HD}, title = {Host-pathogen evolution: Implications for the prevention and treatment of malaria, myocardial infarction and AIDS.}, journal = {Medical hypotheses}, volume = {70}, number = {1}, pages = {21-25}, doi = {10.1016/j.mehy.2007.05.008}, pmid = {17590522}, issn = {0306-9877}, mesh = {Acquired Immunodeficiency Syndrome/*prevention &amp; control ; Animals ; Child ; Coxsackievirus Infections ; Enterovirus B, Human ; Host-Pathogen Interactions/*physiology ; Humans ; Malaria/*prevention &amp; control ; Models, Biological ; Myocardial Infarction/*prevention &amp; control/virology ; Plasmodium falciparum/growth &amp; development/physiology ; }, abstract = {Humans have evolved complex immune systems to protect against infection by pathogens. However, pathogens possess a remarkable genetic versatility that allows them to gain new vigour and so escape such population immunity. Conflicting pathogen-host objectives, therefore, lead to the evolutionary equivalent of an "arms race". Typically, in this struggle, pathogens attempt to deplete their host of specific nutrients that are essential for immune system function. After infection, the resulting deficiency of nutrient(s) may cause many of the disease symptoms and sequela. In malaria, Plasmodium falciparum, for example, depletes its host of Vitamin A, possibly resulting in blindness in some cases. However, 200,000 International Units of Vitamin A, given to children every three months can reduce significantly their susceptibility to malaria. This would seem to be a minimum child dosage for the treatment of the disease. In contrast, the Coxsackie B virus causes a selenium deficiency that may result in myocardial infarction or Keshan disease. However, table salt fortified with 15ppm anhydrous sodium selenite can cause dramatic drops in the incidence of Keshan disease, while selenium supplementation also reduces re-infarction rates. HIV-1 depletes its host of four nutrients: selenium, cysteine, glutamine and tryptophan, resulting in symptoms known as AIDS. Open and closed clinical trials in South Africa, Zambia and Uganda, involving daily adult doses of 600mcg l-selenomethione, and some 500mg l-glutamine, hydroxytryptophan and N-acetyl cysteine, however, have shown that such supplementation can reverse the symptoms of AIDS and prevent HIV-1 infected patients declining into this disease. It is obvious, therefore, that supplementation of diet with specific nutrients can reduce infection by particular pathogens. In addition, if infection still occurs, their use as a treatment may prevent many of the symptoms and sequela commonly associated with diseases such as malaria, myocardial infarction and AIDS.}, }
@article {pmid17590383, year = {2007}, author = {Rosa, RM and Hoch, NC and Furtado, GV and Saffi, J and Henriques, JA}, title = {DNA damage in tissues and organs of mice treated with diphenyl diselenide.}, journal = {Mutation research}, volume = {633}, number = {1}, pages = {35-45}, doi = {10.1016/j.mrgentox.2007.05.006}, pmid = {17590383}, issn = {0027-5107}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Benzene Derivatives/*toxicity ; Cell Survival/drug effects ; Cells, Cultured/drug effects ; Comet Assay ; DNA Damage/*drug effects ; Dose-Response Relationship, Drug ; Free Radical Scavengers/therapeutic use ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Lymphocytes/*drug effects ; Male ; Mice ; Mutagenicity Tests ; Organ Culture Techniques ; Organoselenium Compounds/*toxicity ; Oxidants/*toxicity ; Tissue Distribution ; }, abstract = {Diphenyl diselenide (DPDS) is an organoselenium compound with interesting pharmacological activities and various toxic effects. In previous reports, we demonstrated the pro-oxidant action and the mutagenic properties of this molecule in bacteria, yeast and cultured mammalian cells. This study investigated the genotoxic effects of DPDS in multiple organs (brain, kidney, liver, spleen, testes and urinary bladder) and tissues (bone marrow, lymphocytes) of mice using in vivo comet assay, in order to determine the threshold of dose at which it has beneficial or toxic effects. We assessed the mechanism underlying the genotoxicity through the measurement of GSH content and thiobarbituric acid reactive species, two oxidative stress biomarkers. Male CF-1 mice were given 0.2-200 micromol/kg BW DPDS intraperitonially. DPDS induced DNA damage in brain, liver, kidney and testes in a dose response manner, in a broad dose range at 75-200 micromol/kg with the brain showing the highest level of damage. Overall, our analysis demonstrated a high correlation among decreased levels of GSH content and an increase in lipid peroxidation and DNA damage. This finding establishes an interrelationship between pro-oxidant and genotoxic effects. In addition, DPDS was not genotoxic and did not increase lipid peroxidation levels in any organs at doses < 50 micromol/kg. Finally, pre-treatment with N-acetyl-cysteine completely prevented DPDS-induced oxidative damage by the maintenance of cellular GSH levels, reinforcing the positive relationship of DPDS-induced GSH depletion and DNA damage. In summary, DPDS induces systemic genotoxicity in mammals as it causes DNA damage in vital organs like brain, liver, kidney and testes.}, }
@article {pmid17588422, year = {2007}, author = {Inci, I and Zhai, W and Arni, S and Hillinger, S and Vogt, P and Weder, W}, title = {N-acetylcysteine attenuates lung ischemia-reperfusion injury after lung transplantation.}, journal = {The Annals of thoracic surgery}, volume = {84}, number = {1}, pages = {240-6; discussion 246}, doi = {10.1016/j.athoracsur.2007.03.082}, pmid = {17588422}, issn = {1552-6259}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Glutathione/analysis ; Lipid Peroxidation ; Lung/metabolism/pathology ; Lung Transplantation/*adverse effects ; Male ; Peroxidase/metabolism ; Rats ; Rats, Inbred F344 ; Reperfusion Injury/*prevention &amp; control ; Superoxides/metabolism ; Thiobarbituric Acid Reactive Substances/analysis ; }, abstract = {BACKGROUND: Early acute graft dysfunction continues to be a problem after lung transplantation and results in significant postoperative morbidity and mortality. This study assessed the protective effect of N-acetylcysteine (NAC) on posttransplant lung ischemia-reperfusion injury.<br><br>METHODS: Rat single-lung transplantation was performed in two experimental groups (n = 5) after 18 hours of cold (4 degrees C) ischemia. Group I was the ischemic control (IC) group. In group II (NAC), donor and recipient animals were treated with an intraperitoneal injection of 150 mg/kg NAC 15 minutes before harvest, and recipient animals were treated again before reperfusion. After 2 hours of reperfusion, oxygenation was measured. Lung tissue was assessed for lipid peroxidation, neutrophil infiltration, and reduced glutathione level. Peak airway pressure was recorded throughout the reperfusion period.<br><br>RESULTS: Rats treated with NAC showed significantly better oxygenation (184.5 +/- 83.3 mm Hg versus 67.3 +/- 16.4 mm Hg, p = 0.016) and reduced lipid peroxidation (7.34 +/- 1.9 micromol/g versus 17.46 +/- 10.6 micromol/g, p = 0.016). Lung tissue reduced glutathione levels were 6.8 +/- 0.9 microM in the IC group and 20.6 +/- 2.4 microM in the NAC group (p = 0.004). Peak airway pressure at the end of the reperfusion period was 14.4 +/- 1.6 cm H2O in the NAC group, and 19.2 +/- 2.2 cm H2O in the IC group (p = 0.008). Myeloperoxidase activity and the ratio of wet-to-dry weight did not differ between the groups.<br><br>CONCLUSIONS: In this model, exogenously administered NAC effectively protected the lungs from reperfusion injury after prolonged ischemia.}, }
@article {pmid17586520, year = {2007}, author = {Mehta, SK and Kaur, K and Sharma, S and Bhasin, KK}, title = {Behavior of acetyl modified amino acids in reverse micelles: a non-invasive and physiochemical approach.}, journal = {Journal of colloid and interface science}, volume = {314}, number = {2}, pages = {689-698}, doi = {10.1016/j.jcis.2007.05.084}, pmid = {17586520}, issn = {0021-9797}, mesh = {Acetylcysteine/chemistry ; Amino Acids/*chemistry ; Aspartic Acid/*analogs &amp; derivatives/chemistry ; Chemistry, Physical/*methods ; Electric Conductivity ; Glycine/analogs &amp; derivatives/chemistry ; Kinetics ; *Micelles ; Spectrophotometry/methods ; Spectrophotometry, Ultraviolet ; Spectroscopy, Fourier Transform Infrared ; Surface-Active Agents/chemistry ; Temperature ; Thermodynamics ; Water/chemistry ; }, abstract = {The well-characterized, monodisperse nature of reverse micelles formed by sodium bis-(2-ethylhexyl)sulfosuccinate/water/isooctane and their usefulness in assimilating compounds of varied interests have been exploited to investigate the effect of acetyl modified amino acids (MAA) viz., N-acetyl-L-glycine (NAG), N-acetyl-L-aspartic acid (NAA) and N-acetyl-L-cysteine (NAC), on the water pool and physiochemical properties. Non-invasive techniques such as FTIR and UV-vis absorption spectroscopy have been employed to analyze the interactions of MAA with core water and the AOT headgroup. The micropolarities on both sides of AOT interface have further been investigated by UV-vis absorption probes, methyl orange (MO) and methylene blue (MB). The dynamics of water and temperature induced percolation process have also been studied. The MAA molecules have been found to assist the process with the increase in water content where as a contrary behavior has been observed with the increase in temperature. Conductivity results have been further rationalized in terms of scaling equations, which delineate the dynamic nature of the percolation process. The results have also been analyzed in the light of activation energy of the percolation process and thermodynamics of droplet clustering.}, }
@article {pmid17585863, year = {2007}, author = {Chen, N and Aleksa, K and Woodland, C and Rieder, M and Koren, G}, title = {The effect of N-acetylcysteine on ifosfamide-induced nephrotoxicity: in vitro studies in renal tubular cells.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {150}, number = {1}, pages = {51-57}, doi = {10.1016/j.trsl.2007.02.001}, pmid = {17585863}, issn = {1931-5244}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents, Alkylating/*toxicity ; Cell Line ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Ifosfamide/*toxicity ; In Vitro Techniques ; Kidney Tubules, Proximal/cytology/*drug effects/metabolism ; Swine ; }, abstract = {Ifosfamide (IF) nephrotoxicity is a serious adverse effect in children undergoing chemotherapy. Previous studies have shown that, in addition to the renal production of chloroacetaldehyde, a toxic metabolite of IF, lower levels of glutathione (GSH) may predispose the kidney to damage. The antioxidant N-acetylcysteine (NAC) is used extensively as an antidote for acetaminophen poisoning in children by replenishing GSH levels. As it has been safely and effectively used clinically, the objective of this study was to test whether the reversal of ifosfamide-induced nephrotoxicity can be achieved by administering NAC. Supplementation with NAC may reduce or prevent the degree of cellular cytotoxicity induced by IF. Porcine renal proximal tubular (LLCPK-1) cells were treated with NAC (0.4 mM or 2.5 mM) concurrently with 1 mM IF and 50 microM L-buthionine sulfoximine (BSO). Cellular viability was assessed by alamarBlue assay at 96 h. Intracellular GSH and oxidized GSH (GSSG) levels were determined using a GSH/GSSG colorimetric detection kit. A significant 60% decrease in cellular viability occurred when cells were treated daily with BSO and IF for 96 h. This decrease was significantly reduced when cells were concurrently treated with NAC in a concentration-dependent manner. Intracellular and total GSH levels in cells receiving concurrent treatment of NAC were significantly higher than those without NAC treatment. NAC protects renal tubular cells from IF-induced cytotoxicity. It is likely that NAC is protecting the cells by partially acting as a precursor for GSH synthesis. This mode of therapy may allow for protecting children from life-threatening nephrotoxicity induced by IF.}, }
@article {pmid17584759, year = {2007}, author = {McConnachie, LA and Mohar, I and Hudson, FN and Ware, CB and Ladiges, WC and Fernandez, C and Chatterton-Kirchmeier, S and White, CC and Pierce, RH and Kavanagh, TJ}, title = {Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {99}, number = {2}, pages = {628-636}, doi = {10.1093/toxsci/kfm165}, pmid = {17584759}, issn = {1096-6080}, support = {T32AG000057/AG/NIA NIH HHS/United States ; R01ES10849/ES/NIEHS NIH HHS/United States ; P30ES07033/ES/NIEHS NIH HHS/United States ; T32 ES007032/ES/NIEHS NIH HHS/United States ; P42ES004696/ES/NIEHS NIH HHS/United States ; T32ES007032/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Female ; Glutamate-Cysteine Ligase/deficiency/*physiology ; Glutathione/analysis ; Liver/*drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Protein Subunits ; Sex Characteristics ; }, abstract = {The analgesic and antipyretic drug acetaminophen (APAP) is bioactivated to the reactive intermediate N-acetyl-p-benzoquinoneimine, which is scavenged by glutathione (GSH). APAP overdose can deplete GSH leading to the accumulation of APAP-protein adducts and centrilobular necrosis in the liver. N-acetylcysteine (NAC), a cysteine prodrug and GSH precursor, is often given as a treatment for APAP overdose. The rate-limiting step in GSH biosynthesis is catalyzed by glutamate cysteine ligase (GCL) a heterodimer composed of catalytic and modifier (GCLM) subunits. Previous studies have indicated that GCL activity is likely to be an important determinant of APAP toxicity. In this study, we investigated APAP toxicity, and NAC or GSH ethyl ester (GSHee)-mediated rescue in mice with normal or compromised GCLM expression. Gclm wild-type, heterozygous, and null mice were administered APAP (500 mg/kg) alone, or immediately following NAC (800 mg/kg) or GSHee (168 mg/kg), and assessed for hepatotoxicity 6 h later. APAP caused GSH depletion in all mice. Gclm null and heterozygous mice exhibited more extensive hepatic damage compared to wild-type mice as assessed by serum alanine aminotransferase activity and histopathology. Additionally, male Gclm wild-type mice demonstrated greater APAP-induced hepatotoxicity than female wild-type mice. Cotreatment with either NAC or GSHee mitigated the effects of APAP in Gclm wild-type and heterozygous mice, but not in Gclm null mice. Collectively, these data reassert the importance of GSH in protection against APAP-induced hepatotoxicity, and indicate critical roles for GCL activity and gender in APAP-induced liver damage in mice.}, }
@article {pmid17582039, year = {2007}, author = {Selvan, VA and Calvert, SH and Cavell, G and Glucksman, E and Kerins, M and Gonzalez, J}, title = {Weight-based N-acetylcysteine dosing chart to minimise the risk of calculation errors in prescribing and preparing N-acetylcysteine infusions for adults presenting with paracetamol overdose in the emergency department.}, journal = {Emergency medicine journal : EMJ}, volume = {24}, number = {7}, pages = {482-484}, pmid = {17582039}, issn = {1472-0213}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Clinical Competence ; Drug Administration Schedule ; Drug Overdose ; Emergencies ; Expectorants/*administration &amp; dosage ; Humans ; Infusions, Parenteral ; Medical Staff, Hospital ; Medication Errors/prevention &amp; control ; Nursing Staff, Hospital ; }, abstract = {Management of paracetamol overdose (POD) is common in the emergency department (ED) and forms part of the clinical effectiveness audit programme of the British Association for Emergency Medicine. N-acetylcysteine (NAC) infusion regimens for the treatment of POD are complicated and prescribing and administration errors have been well documented. This study assessed the ability of doctors and nurses to calculate correct doses using manual calculation skills and a weight-based NAC dosing chart when prescribing and preparing NAC infusions. With manual calculations, errors were made by doctors and nurses in 26% of cases collectively. No errors were made using the dosing chart. The dosing chart ensured 100% accuracy in dose calculations, which may translate into improved patient safety.}, }
@article {pmid17577140, year = {2007}, author = {Johnson, ST and Bigam, DL and Emara, M and Obaid, L and Slack, G and Korbutt, G and Jewell, LD and Van Aerde, J and Cheung, PY}, title = {N-acetylcysteine improves the hemodynamics and oxidative stress in hypoxic newborn pigs reoxygenated with 100% oxygen.}, journal = {Shock (Augusta, Ga.)}, volume = {28}, number = {4}, pages = {484-490}, doi = {10.1097/shk.0b013e31804f775d}, pmid = {17577140}, issn = {1073-2322}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Animals, Newborn ; Blood Flow Velocity/drug effects ; Blood Pressure/drug effects ; Female ; Glutathione/metabolism ; Hypoxia/*drug therapy/physiopathology ; Kidney/blood supply/drug effects/metabolism ; Lipid Peroxides/metabolism ; Male ; Myocardium/metabolism ; Oxidative Stress/*drug effects ; Oxygen/metabolism/*pharmacology/therapeutic use ; Oxygen Inhalation Therapy/methods ; Stroke Volume/drug effects ; Swine ; Time Factors ; }, abstract = {Neonatal asphyxia may lead to cardiac and renal complications perhaps mediated by oxygen free radicals. Using a model of neonatal hypoxia-reoxygenation, we tested the hypothesis that N-acetylcysteine (NAC) would improve cardiac function and renal blood flow. Eighteen piglets (aged 1-4 days old, weighing 1.4-2.2 kg) were anesthetized and acutely instrumented for continuous monitoring of pulmonary and renal artery flow (cardiac index [CI] and renal artery flow index [RAFI], respectively) and mean blood pressure. Alveolar hypoxia was induced for 2 h, followed by resuscitation with 100% oxygen for 1 h and 21% oxygen for 3 h. Animals were randomized to sham-operated, hypoxic control, and NAC treatment (i.v. bolus of 150 mg/kg given at 10 min of reoxygenation followed by 100 mg/kg per h infusion) groups. Myocardial and renal tissue glutathione content and lipid hydroperoxide levels were assayed, and histology was examined. After 2 h of hypoxia, all animals were acidotic (pH 6.96 +/- 0.04) and in cardiogenic shock with depressed renal blood flow. Upon reoxygenation, CI and RAFI increased but gradually deteriorated later. The NAC treatment prevented the decreased CI, stroke volume, mean blood pressure, systemic oxygen delivery, RAFI, and renal oxygen delivery at 2 to 4 h of reoxygenation observed in hypoxic controls (versus shams, all P < 0.05). The myocardial and renal tissue glutathione content was significantly higher in the NAC treatment group (versus controls). The CI and RAFI at 4 h of reoxygenation correlated with the tissue glutathione redox ratio (r = 0.5 and 0.6, respectively, P < 0.05). There were no significant differences in heart rate, pulmonary artery pressure, systemic oxygen uptake, and tissue lipid hydroperoxide levels between groups. No histologic injury was found in the heart or kidney. In this porcine model of neonatal hypoxia and 100% reoxygenation, NAC improved cardiac function and renal perfusion, with improved tissue glutathione content.}, }
@article {pmid17576777, year = {2007}, author = {Morita, K and Miyamoto, T and Fujita, N and Kubota, Y and Ito, K and Takubo, K and Miyamoto, K and Ninomiya, K and Suzuki, T and Iwasaki, R and Yagi, M and Takaishi, H and Toyama, Y and Suda, T}, title = {Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification.}, journal = {The Journal of experimental medicine}, volume = {204}, number = {7}, pages = {1613-1623}, pmid = {17576777}, issn = {0022-1007}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Calcification, Physiologic/drug effects/*physiology ; Cell Cycle Proteins/genetics ; Cell Differentiation/drug effects/physiology ; Cell Division ; Cell Line ; Chondrocytes/*cytology/drug effects/pathology ; DNA-Binding Proteins/deficiency/genetics ; Hypertrophy ; Mice ; Mice, Knockout ; Neovascularization, Physiologic/drug effects ; Protein Serine-Threonine Kinases/deficiency/genetics ; Reactive Oxygen Species/metabolism/*pharmacology ; Tumor Suppressor Proteins/deficiency/genetics ; }, abstract = {Chondrocyte hypertrophy during endochondral ossification is a well-controlled process in which proliferating chondrocytes stop proliferating and differentiate into hypertrophic chondrocytes, which then undergo apoptosis. Chondrocyte hypertrophy induces angiogenesis and mineralization. This step is crucial for the longitudinal growth and development of long bones, but what triggers the process is unknown. Reactive oxygen species (ROS) have been implicated in cellular damage; however, the physiological role of ROS in chondrogenesis is not well characterized. We demonstrate that increasing ROS levels induce chondrocyte hypertrophy. Elevated ROS levels are detected in hypertrophic chondrocytes. In vivo and in vitro treatment with N-acetyl cysteine, which enhances endogenous antioxidant levels and protects cells from oxidative stress, inhibits chondrocyte hypertrophy. In ataxia telangiectasia mutated (Atm)-deficient (Atm(-/-)) mice, ROS levels were elevated in chondrocytes of growth plates, accompanied by a proliferation defect and stimulation of chondrocyte hypertrophy. Decreased proliferation and excessive hypertrophy in Atm(-/-) mice were also rescued by antioxidant treatment. These findings indicate that ROS levels regulate inhibition of proliferation and modulate initiation of the hypertrophic changes in chondrocytes.}, }
@article {pmid17574387, year = {2007}, author = {Chen, CM and Yin, MC and Hsu, CC and Liu, TC}, title = {Antioxidative and anti-inflammatory effects of four cysteine-containing agents in striatum of MPTP-treated mice.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {23}, number = {7-8}, pages = {589-597}, doi = {10.1016/j.nut.2007.05.004}, pmid = {17574387}, issn = {0899-9007}, mesh = {Acetylcysteine/pharmacology ; Animals ; Catalase/metabolism ; Corpus Striatum/*drug effects/metabolism ; Cysteine/analogs &amp; derivatives/*pharmacology ; Disease Models, Animal ; Glutathione/*metabolism ; Glutathione Peroxidase/metabolism ; Interleukin-6/blood/metabolism ; Lipid Peroxidation/drug effects ; *MPTP Poisoning ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred C57BL ; Neuroprotective Agents/*pharmacology ; Neurotoxins/toxicity ; Parkinson Disease/prevention &amp; control ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {OBJECTIVES: Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used to examine the neuroprotective effects of n-acetyl cysteine (NAC), s-ethyl cysteine (SEC), s-methyl cysteine (SMC), and s-propyl cysteine (SPC).<br><br>METHODS: Each agent at 1 g/L was directly added to the drinking water for 3 wk. Mice were treated by subcutaneous injection of MPTP (24 mg/kg body weight) for 6 consecutive days. The brain from each mouse was quickly removed and the striatum was collected for analyses.<br><br>RESULTS: The MPTP treatment significantly depleted striatal glutathione content, reduced the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase, increased malondialdehyde level, and elevated interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) levels in striatum (P < 0.05). The pre-intake of NAC, SEC, SMC, and SPC significantly attenuated MPTP-induced glutathione loss, retained the activity of GPX and SOD, diminished oxidative stress, and suppressed MPTP-induced elevation of IL-6 and TNF-alpha (P < 0.05). MPTP treatment significantly suppressed GPX mRNA expression and enhanced TNF-alpha mRNA expression (P < 0.05). Compared with MPTP treatment alone, the pre-intake of NAC, SEC, SMC, and SPC significantly elevated GPX mRNA expression and diminished TNF-alpha mRNA expression (P < 0.05), in which SPC showed the greatest suppressive effect against MPTP-induced TNF-alpha mRNA expression (P < 0.05). Dopamine and 3,4-dihydroxyphenylacetic acid contents in the striatum were significantly decreased by MPTP treatment (P < 0.05). The pre-intake of four test agents significantly improved MPTP-induced dopamine depletion and increased dopamine/3,4-dihydroxyphenylacetic acid content (P < 0.05).<br><br>CONCLUSION: These results suggest that these cysteine-containing compounds could provide antioxidative and anti-inflammatory protection for the striatum against the development of Parkinson's disease.}, }
@article {pmid17574268, year = {2007}, author = {Staniszewska, M and Nagaraj, RH}, title = {Detection of kynurenine modifications in proteins using a monoclonal antibody.}, journal = {Journal of immunological methods}, volume = {324}, number = {1-2}, pages = {63-73}, doi = {10.1016/j.jim.2007.05.002}, pmid = {17574268}, issn = {0022-1759}, support = {P30EY-11373/EY/NEI NIH HHS/United States ; R01EY-016219/EY/NEI NIH HHS/United States ; R01EY-09912/EY/NEI NIH HHS/United States ; }, mesh = {Aged ; Animals ; Antibodies, Monoclonal/biosynthesis/*metabolism ; Cattle ; Cell Line ; Child, Preschool ; Chromatography, High Pressure Liquid ; Eye Proteins/*immunology/*metabolism ; Humans ; Kynurenine/analogs &amp; derivatives/*immunology/*metabolism/pharmacology ; Lens, Crystalline/chemistry/cytology/immunology ; Magnetic Resonance Spectroscopy ; Mice ; Mice, Inbred BALB C ; }, abstract = {N-formylkynurenine and kynurenine are oxidation products of tryptophan formed from the reaction catalyzed by indoleamine 2,3-dioxygenase. These kynurenines react with proteins to produce chemical modifications in the lens. We developed a novel monoclonal antibody that detects a kynurenine modification in proteins. The antibody recognized proteins (human lens proteins, RNase A and BSA) that were modified by either kynurenine or N-formylkynurenine. The antibody also reacted strongly with N-formylkynurenine-modified N(alpha)-acetyl histidine and weakly with N-formylkynurenine-modified N(alpha)-acetyl lysine, N(alpha)-acetyl cysteine and N(alpha)-acetyl arginine. The antibody recognized kynurenine and N-formylkynurenine but not other tryptophan oxidation products. We isolated and purified a major antigen from the reaction mixture of N(alpha)-acetyl histidine and N-formylkynurenine and identified the product as N-acetyl-1-[3-(2-aminophenyl)-1-carboxy-3-oxopropyl]-histidine. We then used our purified antibody to detect kynurenine modifications in kynurenine-treated human lens epithelial cells and human lens. We found epithelial immunoreactivity in a lens from an aged donor but not in one from a very young donor. This would suggest that the antibody detects age-related changes in lens proteins altered by kynurenines. We believe that our antibody could be used to establish the importance of kynurenine modifications in diseases where tryptophan oxidation is enhanced.}, }
@article {pmid17573457, year = {2007}, author = {Williams, IA and Allen, DG}, title = {The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {293}, number = {3}, pages = {H1969-77}, doi = {10.1152/ajpheart.00489.2007}, pmid = {17573457}, issn = {0363-6135}, mesh = {Acetylcysteine/pharmacology ; Actin Cytoskeleton/physiology ; Animals ; Antioxidants/therapeutic use ; Calcium/metabolism ; Disease Models, Animal ; Dystrophin/genetics/*metabolism ; Fibrosis ; Free Radical Scavengers/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscular Dystrophy, Duchenne/drug therapy/metabolism ; Myocardium/*metabolism/pathology ; Myocytes, Cardiac/*metabolism/pathology ; NADPH Oxidases/metabolism ; Oxidative Stress/physiology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Duchenne muscular dystrophy (DMD) is caused by deficiency of the cytoskeletal protein dystrophin. Oxidative stress is thought to contribute to the skeletal muscle damage in DMD; however, little is known about the role of oxidative damage in the pathogenesis of the heart failure that occurs in DMD patients. The dystrophin-deficient (mdx) mouse is an animal model of DMD that also lacks dystrophin. The current study investigates the role of the antioxidant N-acetylcysteine (NAC) on mdx cardiomyocyte function, Ca(2+) handling, and the cardiac inflammatory response. Treated mice received 1% NAC in their drinking water for 6 wk. NAC had no effect on wild-type (WT) mice. Immunohistochemistry experiments revealed that mdx mice had increased dihydroethidine (DHE) staining, an indicator of superoxide production; NAC-treatment reduced DHE staining in mdx hearts. NAC treatment attenuated abnormalities in mdx cardiomyocyte Ca(2+) handling. Mdx cardiomyocytes had decreased fractional shortening and decreased Ca(2+) sensitivity; NAC treatment returned mdx fractional shortening to WT values but did not affect the Ca(2+) sensitivity. Immunohistochemistry experiments revealed that mdx hearts had increased levels of collagen type III and the macrophage-specific protein, CD68; NAC-treatment returned collagen type III and CD68 expression close to WT values. Finally, mdx hearts had increased NADPH oxidase activity, suggesting it could be a possible source of increased reactive oxygen species in mdx mice. This study is the first to demonstrate that oxidative damage may be involved in the pathogenesis of the heart failure that occurs in mdx mice. Therapies designed to reduce oxidative damage might be beneficial to DMD patients with heart failure.}, }
@article {pmid17566772, year = {2007}, author = {Sarr, M and Chataigneau, M and Etienne-Selloum, N and Diallo, AS and Schott, C and Geffard, M and Stoclet, JC and Schini-Kerth, VB and Muller, B}, title = {Targeted and persistent effects of NO mediated by S-nitrosation of tissue thiols in arteries with endothelial dysfunction.}, journal = {Nitric oxide : biology and chemistry}, volume = {17}, number = {1}, pages = {1-9}, doi = {10.1016/j.niox.2007.04.003}, pmid = {17566772}, issn = {1089-8603}, mesh = {Angiotensin II/metabolism ; Animals ; Anions ; Cysteine/chemistry/metabolism ; Endothelium, Vascular/*metabolism/pathology ; Male ; Models, Biological ; NG-Nitroarginine Methyl Ester/metabolism ; Nitric Oxide/*metabolism ; Nitrogen/*chemistry ; Oxidative Stress ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; Sulfhydryl Compounds/*chemistry ; }, abstract = {We have previously demonstrated that in endothelium-denuded arteries, S-nitrosation of cysteine residues is a mechanism of formation of releasable nitric oxide (NO) stores, accounting for the long-lasting relaxation induced by S-nitrosating agents like S-nitrosoglutathione (GSNO). Here, we have investigated whether such effects could also be obtained in arteries exhibiting oxidative stress-associated endothelial dysfunction. Rats were implanted or not with a minipump delivering saline or angiotensin II for 14 days. As expected, aorta from angiotensin II-infused rats exhibited increased level of superoxide anions (as evaluated with dihydroethidine as fluorescent probe) and a reduced relaxation to acetylcholine in comparison to saline group. Unlike aortic rings with endothelium from controls, those from angiotensin II-infused rats exhibited persistent hyporesponsiveness to phenylephrine after pre-exposure to GSNO, as well as relaxation upon addition of N-acetylcysteine (NAC, which can displace NO from cysteine-NO residues) or HgCl(2) (which cleaves S-NO bonds). In aorta from angiotensin II-infused rats, GSNO also induced a persistent increase in cysteine-NO residues (as determined using anti-cysteine-NO antiserum), which was blunted by NAC and HgCl(2). These data indicate that (i) the vasorelaxant influence of releasable NO stores is unmasked by endothelial dysfunction (ii) S-nitrosation of cysteine residues remains an effective mechanism of formation of releasable NO stores in arteries exhibited oxidative stress-associated endothelial dysfunction. Thus, formation of releasable NO stores by S-nitrosating agents allows targeted vasculoprotective effects of NO at sites of endothelial dysfunction.}, }
@article {pmid17562874, year = {2007}, author = {Reimann, M and Loddenkemper, C and Rudolph, C and Schildhauer, I and Teichmann, B and Stein, H and Schlegelberger, B and Dörken, B and Schmitt, CA}, title = {The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo.}, journal = {Blood}, volume = {110}, number = {8}, pages = {2996-3004}, doi = {10.1182/blood-2007-02-075614}, pmid = {17562874}, issn = {0006-4971}, mesh = {Animals ; Apoptosis/physiology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*genetics/metabolism ; Cyclin-Dependent Kinase Inhibitor p16/metabolism ; *DNA Damage ; DNA-Binding Proteins/*genetics/metabolism ; Drug Resistance, Neoplasm/*genetics ; Flow Cytometry ; Gene Transfer Techniques ; *Genes, myc ; Immunoblotting ; Lymphoma, B-Cell/drug therapy/*genetics ; Mice ; Mice, Transgenic ; Protein Serine-Threonine Kinases/*genetics/metabolism ; RNA, Small Interfering ; Reactive Oxygen Species/pharmacology ; Transduction, Genetic ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/*genetics/metabolism ; }, abstract = {In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogene-provoked anticancer barrier in early human tumorigenesis leading to apoptosis or cellular senescence. DDR mutations may promote tumor formation, but their impact on treatment outcome remains unclear. In this study, we generated ataxia telangiectasia mutated (Atm)-proficient and -deficient B-cell lymphomas in Emu-myc transgenic mice to examine the role of DDR defects in lymphomagenesis and treatment sensitivity. Atm inactivation accelerated development of lymphomas, and their DNA damage checkpoint defects were virtually indistinguishable from those observed in Atm+/+-derived lymphomas that spontaneously inactivated the proapoptotic Atm/p53 cascade in response to Myc-evoked reactive oxygen species (ROS). Importantly, acquisition of DDR defects, but not selection against the ARF pathway, could be prevented by lifelong exposure to the ROS scavenger N-acetylcysteine (NAC) in vivo. Following anticancer therapy, DDR-compromised lymphomas displayed apoptotic but, surprisingly, no senescence defects and achieved a much poorer long-term outcome when compared with DDR-competent lymphomas treated in vivo. Hence, Atm eliminates preneoplastic lesions by converting oncogenic signaling into apoptosis, and selection against an Atm-dependent response promotes formation of lymphomas with predetermined treatment insensitivity.}, }
@article {pmid17560018, year = {2007}, author = {Zhang, W and Zhang, C and Narayani, N and Du, C and Balaji, KC}, title = {Nuclear translocation of apoptosis inducing factor is associated with cisplatin induced apoptosis in LNCaP prostate cancer cells.}, journal = {Cancer letters}, volume = {255}, number = {1}, pages = {127-134}, doi = {10.1016/j.canlet.2007.04.006}, pmid = {17560018}, issn = {0304-3835}, mesh = {Acetylcysteine/pharmacology ; *Active Transport, Cell Nucleus ; Amino Acid Chloromethyl Ketones/pharmacology ; Antineoplastic Agents/pharmacology ; *Apoptosis ; Apoptosis Inducing Factor/*metabolism ; Cell Line, Tumor ; Cell Survival ; Cisplatin/*pharmacology ; DNA Fragmentation ; Enzyme Inhibitors/pharmacology ; *Gene Expression Regulation, Neoplastic ; Humans ; Male ; Prostatic Neoplasms/*drug therapy/*pathology ; }, abstract = {Prostate cancer (PC) is considered resistant to cisplatin chemotherapy. In order to identify novel causes of resistance to cisplatin, we explored the role of Apoptosis Inducing Factor (AIF) that mediates caspase independent apoptosis in cisplatin induced cell death in PC. Similar to treatment with pancaspase inhibitor Z-VAD-fmk, cisplatin induced apoptosis in LNCaP cells was inhibited by AIF inhibitor N-acetyl-L-cysteine (NAC), treatment of LNCaP cells with NAC prevented AIF translocation to the nucleus and over-expression of recombinant AIF gene increased apoptosis. Our results suggest that AIF is associated with cisplatin induced apoptosis in PC.}, }
@article {pmid17557777, year = {2007}, author = {Levin, A and Pate, GE and Shalansky, S and Al-Shamari, A and Webb, JG and Buller, CE and Humphries, KH}, title = {N-acetylcysteine reduces urinary albumin excretion following contrast administration: evidence of biological effect.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {22}, number = {9}, pages = {2520-2524}, doi = {10.1093/ndt/gfl707}, pmid = {17557777}, issn = {0931-0509}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Albumins/metabolism ; Albuminuria/*chemically induced ; Catheterization ; Contrast Media/*administration &amp; dosage/*adverse effects/pharmacology ; Creatinine/metabolism ; Female ; Humans ; Kidney Function Tests ; Male ; }, abstract = {BACKGROUND: There are conflicting results regarding the effectiveness of N-acetylcysteine (NAC) in attenuating contrast-induced nephropathy (CIN). NAC administration independently reduces serum creatinine, potentially confounding studies utilizing creatinine-based endpoints. Albuminuria is a marker of renal injury and spot urine albumin: creatinine ratios (ACR) reflect 24-h urine albumin excretion. We performed a pre-specified secondary analysis from our published negative randomized control trial of NAC for prevention of CIN, to determine if NAC administration reduces albuminuria after contrast exposure following cardiac catheterization.<br><br>METHODS: We included study patients who had paired urine specimens obtained pre- and post-cardiac catheterization. Baseline characteristics were compared using the chi square test or Mann-Whitney U-test, as appropriate. Changes in ACR were evaluated using binomial exact test. The effect of NAC on post-cardiac catheterization changes in ACR ratio was evaluated by ordinal logistic regression.<br><br>RESULTS: A total of 125 patients met inclusion criteria (pre- and post-catheterization urinalysis within 7 days). Baseline characteristics neither differ between NAC and placebo groups, nor were they different from those who were excluded. Among the patients receiving NAC, 10.7% improved their ACR ratio and 7.1% worsened; in contrast, in patients on placebo only 4.3% improved, while 21.7% worsened (P=0.015). Change in ACR ratio was not associated with change in kidney function as measured by calculated creatinine clearance or GFR.<br><br>CONCLUSIONS: The results of this analysis suggest NAC may attenuate contrast-induced glomerular or tubular injury, as defined by albumin excretion, and appears to be independent of any effect on creatinine-derived measures of kidney function. Larger studies are required to confirm this observation.}, }
@article {pmid17553538, year = {2007}, author = {Shenoy, S and Vasania, VS and Gopal, M and Mehta, A}, title = {8-Methyl-4-(3-diethylaminopropylamino) pyrimido [4',5';4,5] thieno (2,3-b) quinoline (MDPTQ), a quinoline derivate that causes ROS-mediated apoptosis in leukemia cell lines.}, journal = {Toxicology and applied pharmacology}, volume = {222}, number = {1}, pages = {80-88}, doi = {10.1016/j.taap.2007.04.005}, pmid = {17553538}, issn = {0041-008X}, mesh = {Annexin A5/metabolism ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase 3/biosynthesis ; Cell Cycle/drug effects ; Cell Line, Tumor ; DNA Damage ; Ellipticines/pharmacology ; Flow Cytometry ; Humans ; Leukemia/*pathology ; Membrane Potentials/drug effects ; Mitochondrial Membranes/drug effects ; Phosphatidylserines/pharmacology ; Quinolines/*pharmacology ; Reactive Oxygen Species/*metabolism ; Thiophenes/*pharmacology ; Tumor Stem Cell Assay ; }, abstract = {The present study reports the biological activity of 8-methyl-4-(3-diethylamino-propylamino) pyrimido [4';5';4,5] thieno (2,3-b) quinoline (MDPTQ), a quinoline derivative structurally related to ellipticine and suggests a possible mechanism through which the compound induces apoptosis in carcinoma cell lines. Out of the 8 cell lines used in the study as representatives of different types of cancer, MDPTQ was found to be effective only against leukemia cell lines (HL-60 and K-562) whereas it had no effect on normal human bone marrow cells (BMC) which were used as controls. Fall mitochondrial membrane potential and increased reactive oxygen species (ROS) were mainly responsible for inducing apoptosis in the two cell lines. Cell death was demonstrated by increase in caspase 3 activity as well as phosphatidyl serine exposure. Pre-incubation with N-acetylcysteine (NAC) reduced the increased ROS and caspase 3 activity as well as phosphatidyl serine exposure. MDPTQ also caused cell cycle arrest in these cell lines. The above study for the first time reports the mode of action of a quinoline derivative, which could be a possible future candidate for leukemia therapy. However, there are lot of questions that need to be answered in terms of signalling pathways and its effects on animal models.}, }
@article {pmid17552491, year = {2007}, author = {Loretz, B and Thaler, M and Bernkop-Schnürch, A}, title = {Role of sulfhydryl groups in transfection? A case study with chitosan-NAC nanoparticles.}, journal = {Bioconjugate chemistry}, volume = {18}, number = {4}, pages = {1028-1035}, doi = {10.1021/bc0603079}, pmid = {17552491}, issn = {1043-1802}, mesh = {Acetylcysteine/administration &amp; dosage/*chemistry ; Caco-2 Cells ; Cell Survival/drug effects ; Chitosan/administration &amp; dosage/*chemistry ; Dithionitrobenzoic Acid/pharmacology ; Humans ; L-Lactate Dehydrogenase/metabolism ; Microscopy, Electron, Transmission ; Nanoparticles/administration &amp; dosage/*chemistry/ultrastructure ; Papain/chemistry ; Sulfhydryl Compounds/*analysis ; Sulfhydryl Reagents/pharmacology ; Transfection/*methods ; }, abstract = {This study investigated the use of chitosan-N-acetylcysteine (NAC) as a non-viral gene carrier. In particular, we aimed to elucidate whether the advantage of thiolation was more pronounced in the stabilization of particles or in the effect of nonspecific sulfhydryl reduction of the target cells. Low-viscosity chitosan was modified by covalent binding of NAC. The resulting conjugate displayed 1.35 mM SH/g polymer. Particles produced via self-assembly of chitosan conjugate and pDNA had a mean particle size of 113.7 nm and a positive zeta-potential. Sulfhydryl group content on the particle surface was investigated by Ellman's test and papain reactivation assay, with the result of about 100 nM SH groups/mL nanoparticle suspension. An oxidation step was performed to stabilize polyplexes via disulfide bonds. The enhanced stability of oxidized particles against both polyanion heparin and alkaline pH was proven by a gel retardation assay. The stabilization was demonstrated to be reversible by treatment with glutathione. Further, the effect of immobilized SH groups and of supplementation with free NAC on transfection efficacy on Caco-2 cells was investigated. The expression of the transgene was raised 2.5-fold and 10-fold with nonoxidized thiomer polyplexes in comparison to polyplexes of unmodified chitosan and oxidized chitosan-NAC, respectively. The impact of sulfhydryl reduction on transfection was assessed via thiol group inactivation with 5,5'-dithiobis-(2-nitrobenzoic acid) (DNTB). This inactivation resulted in a decrease of transfection efficacy. In conclusion, chitosan-NAC conjugate was demonstrated to be beneficial for transfection, either for stabilization via disulfide bonds or for raising the expression of transgene via shifting the redox potential of the target cells.}, }
@article {pmid17548252, year = {2007}, author = {Jin, X and Wang, L and Wu, HS and Zhang, L and Wang, CY and Tian, Y and Zhang, JH}, title = {N-acetylcysteine inhibits activation of toll-like receptor 2 and 4 gene expression in the liver and lung after partial hepatic ischemia-reperfusion injury in mice.}, journal = {Hepatobiliary &amp; pancreatic diseases international : HBPD INT}, volume = {6}, number = {3}, pages = {284-289}, pmid = {17548252}, issn = {1499-3872}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Gene Expression Regulation/*drug effects ; Liver/*blood supply/*metabolism ; Lung/*metabolism ; Male ; Mice ; Mice, Inbred BALB C ; RNA, Messenger/analysis ; Reactive Oxygen Species/metabolism ; Reperfusion Injury/*metabolism ; Toll-Like Receptor 2/analysis/*genetics/physiology ; Toll-Like Receptor 4/analysis/*genetics/physiology ; Tumor Necrosis Factor-alpha/blood ; }, abstract = {BACKGROUND: Toll-like receptor 2 and 4 (TLR2/4) may play important roles in ischemia-reperfusion (I/R) injury, and N-acetylcysteine (NAC) can prevent the generation of reactive oxygen species (ROS) induced by I/R injury. This study aimed to investigate the changes in TLR2/4 gene expression in the liver and lung after I/R injury with or without NAC pretreatment.<br><br>METHODS: BALB/c mice were used in a model of partial hepatic I/R injury and randomly assigned to a sham-operated control group (SH), a hepatic ischemia/reperfusion group (I/R) or a NAC pretreated, hepatic I/R group (I/R-NAC). The levels of TNF-alpha in the portal vein and plasma alanine aminotransferase (ALT) were measured at 1 and 3 hours after reperfusion. The lung wet-to-dry ratio was measured, and the expression of TLR2/4 mRNA and protein in the liver and lung were assessed with RT-PCR and Western blotting at the same time points.<br><br>RESULTS: Compared with the I/R group, the expression of TLR2/4 mRNA and protein in the liver and lung in the I/R-NAC group was decreased at the same time point (P<0.05). The levels of portal vein TNF-alpha and plasma ALT increased continuously in the I/R group at 1 and 3 hours of reperfusion compared with the SH group; however, they declined significantly in the group pretreated with NAC (P<0.05). The extent of lung edema was relieved in the I/R-NAC group compared with the I/R group (P<0.05).<br><br>CONCLUSIONS: TLR2/4 was activated in the liver and lung in the process of partial hepatic I/R injury. NAC inhibited the activation of TLR2/4 and the induction of TNF-alpha resulting from I/R injury via modulating the redox state, thus it may mitigate liver and lung injury following partial hepatic I/R in mice.}, }
@article {pmid17545941, year = {2007}, author = {Mollen, KP and McCloskey, CA and Tanaka, H and Prince, JM and Levy, RM and Zuckerbraun, BS and Billiar, TR}, title = {Hypoxia activates c-Jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes.}, journal = {Shock (Augusta, Ga.)}, volume = {28}, number = {3}, pages = {270-277}, doi = {10.1097/shk.0b013e3180485acd}, pmid = {17545941}, issn = {1073-2322}, support = {GM-53789-08/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Enzyme Activation ; Fluoresceins ; Hepatocytes/*metabolism ; Hypoxia/*physiopathology ; Isotonic Solutions/pharmacology ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Male ; Membrane Glycoproteins/antagonists &amp; inhibitors/deficiency ; Mice ; Mice, Inbred C57BL ; NADPH Oxidase 2 ; NADPH Oxidases/antagonists &amp; inhibitors/deficiency ; Onium Compounds/pharmacology ; Reactive Oxygen Species/*metabolism ; Shock, Hemorrhagic/*physiopathology ; Specific Pathogen-Free Organisms ; rac1 GTP-Binding Protein/*physiology ; }, abstract = {The earliest events after the induction of hemorrhagic shock (HS) are complex and poorly understood. We have recently demonstrated that decreased tissue perfusion and hypoxia during HS lead to an increased phosphorylation of c-Jun N-terminal kinase (JNK) in vivo. The purpose of these investigations was to test the hypothesis that hypoxia activates JNK via Rac1-dependent reactive oxygen species (ROS) signaling. Mice subjected to HS and resuscitated with Ringer's ethyl pyruvate solution (REPS) or N-acetylcysteine (NAC), two scavengers of ROS, demonstrated decreased levels of phosphorylated JNK. Exposure of primary mouse hepatocytes in culture to 1% oxygen led to increased production of ROS and phosphorylation of JNK. The duration of hypoxia correlated with the level of generation of ROS and JNK activation. The phosphorylation of JNK was attenuated in the presence of ROS scavengers or the nicotinamide adenosine dinucleotide phosphate [NDA(P)H] oxidase inhibitor, diphenyleneiodonium (DPI). In addition, hypoxia increased activation of Rac1. Inhibition of Rac1 activation by adenoviral gene transfer of dominant-negative Rac1 (AdRac1) attenuated both ROS formation and JNK activation. Together, these data suggest that ROS generation during hypoxia in the liver directly leads to JNK activation in a Rac1-dependent process.}, }
@article {pmid17544319, year = {2007}, author = {Arreesrisom, P and Dondorp, AM and Looareesuwan, S and Udomsangpetch, R}, title = {Suppressive effects of the anti-oxidant N-acetylcysteine on the anti-malarial activity of artesunate.}, journal = {Parasitology international}, volume = {56}, number = {3}, pages = {221-226}, doi = {10.1016/j.parint.2007.04.004}, pmid = {17544319}, issn = {1383-5769}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antimalarials/*antagonists &amp; inhibitors/pharmacology ; Antioxidants/*pharmacology ; Artemisinins/*antagonists &amp; inhibitors/pharmacology ; Artesunate ; Drug Interactions ; Humans ; Parasitic Sensitivity Tests ; Plasmodium falciparum/*drug effects ; Quinine/pharmacology ; Sesquiterpenes/*antagonists &amp; inhibitors/pharmacology ; }, abstract = {The anti-oxidant drug N-acetylcysteine (NAC) has been proposed as adjunctive treatment in severe falciparum malaria. However, this might inhibit the anti-malarial drug action of the artemisinins, which are thought to exert their parasitocidal action through oxidative damage. We studied the interaction between NAC and artesunate as well as quinine in an in vitro drug sensitivity assay. Combination with NAC reduced the parasitocidal effect of artesunate only within the first 6 h of incubation, whereas no interaction was observed with quinine. Pre-incubation of P. falciparum with NAC resulted in a similar inhibitory effect on the anti-malarial activity of artesunate, whereas no inhibition was observed when NAC was added 2 h after parasite exposure to artesunate. Assessment of parasite maturation inhibition by the standard Giemsa's staining was in accordance with the use of a vital staining. The results herein caution the use of adjunctive treatment for malaria infection. Combination of antagonistic drugs may lead to adverse effects.}, }
@article {pmid17542780, year = {2007}, author = {Lin, X and Li, Q and Wang, YJ and Ju, YW and Chi, ZQ and Wang, MW and Liu, JG}, title = {Morphine inhibits doxorubicin-induced reactive oxygen species generation and nuclear factor kappaB transcriptional activation in neuroblastoma SH-SY5Y cells.}, journal = {The Biochemical journal}, volume = {406}, number = {2}, pages = {215-221}, pmid = {17542780}, issn = {1470-8728}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Cytoprotection/drug effects ; Doxorubicin/*antagonists &amp; inhibitors/pharmacology ; Enzyme Activation/drug effects ; Humans ; I-kappa B Kinase/metabolism ; Morphine/*pharmacology ; NF-kappa B/*metabolism ; Neuroblastoma/*genetics/*metabolism/pathology ; Protein Transport ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Transcriptional Activation/*drug effects/genetics ; }, abstract = {Morphine is recommended as a first-line opioid analgesic in the pain management of cancer patients. Accumulating evidence shows that morphine has anti-apoptotic activity, but its impact on the therapeutic applications of antineoplastic drugs is not well known. The present study was undertaken to test the hypothesis that morphine might antagonize the pro-apoptotic activity of DOX (doxorubicin), a commonly used antitumour drug for the treatment of neuroblastoma, in cultured SH-SY5Y cells. In the present study we demonstrated that morphine suppressed DOX-induced inhibition of cell proliferation and programmed cell death in a concentration-dependent, and naloxone as well as pertussis toxin-irreversible, manner. Further studies showed that morphine inhibited ROS (reactive oxygen species) generation, and prevented DOX-mediated caspase-3 activation, cytochrome c release and changes of Bax and Bcl-2 protein expression. The antioxidant NAC (N-acetylcysteine) also showed the same effects as morphine on DOX-induced ROS generation, caspase-3 activation and cytochrome c release and changes in Bax (Bcl-2-associated X protein) and Bcl-2 protein expression. Additionally, morphine was found to suppress DOX-induced NF-kappaB (nuclear factor kappaB) transcriptional activation via a reduction of IkappaBalpha (inhibitor of nuclear factor kappaB) degradation. These present findings support the hypothesis that morphine can inhibit DOX-induced neuroblastoma cell apoptosis by the inhibition of ROS generation and mitochondrial cytochrome c release, as well as by blockade of NF-kappaB transcriptional activation, and suggests that morphine might have an impact on the antitumour efficiency of DOX.}, }
@article {pmid17540521, year = {2007}, author = {Li, HY and Wu, SY and Shi, N}, title = {Transcription factor Nrf2 activation by deltamethrin in PC12 cells: Involvement of ROS.}, journal = {Toxicology letters}, volume = {171}, number = {1-2}, pages = {87-98}, doi = {10.1016/j.toxlet.2007.04.007}, pmid = {17540521}, issn = {0378-4274}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Nucleus/drug effects/metabolism ; Fluorescent Antibody Technique ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Glutamate-Cysteine Ligase/genetics/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Immunoblotting ; Immunohistochemistry ; NF-E2-Related Factor 2/*genetics/metabolism ; Nitriles/*pharmacology ; PC12 Cells ; Pyrethrins/*pharmacology ; RNA, Messenger/genetics/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Activation of transcription factor NF-E2-related factor 2 (Nrf2) is a key initiation step in the cellular protection against a broad range of chemical oxidative stresses. To gain insights into dopaminergic cell responses to pesticides, the present study was conducted to examine the effects of deltamethrin (DM), a prototype of widely used pyrithroid pesticides, on the activation and expression of Nrf2 in PC12 rat adrenal pheochromocytoma cells as a dopaminergic cell model. We found, for the first time, that DM enhanced cellular expression of Nrf2 at the transcriptional and protein levels and activated expression of Nrf2-regulated genes in these cells. In addition, DM exposure caused nuclear accumulation of Nrf2 in association with downstream activation of Nrf2-mediated oxidative response genes, such as heme oxygenase-l (HO-1) and gamma-glutamylcysteine synthetase catalytic heavy subunit (GCSh). Furthermore, when cells were pretreated with N-acetyl cysteine (NAC), a scavenger of reactive oxygen species (ROS), DM-induced Nrf2 signaling was suppressed. These results indicate that ROS is the mediator of nuclear Nrf2 accumulation. Taken together, these data clearly show that DM increases Nrf2 expression and activity and that ROS is one of the mediators of this process.}, }
@article {pmid17540441, year = {2007}, author = {Michael, A and Alexopoulos, C and Pontiki, E and Hadjipavlou-Litina, D and Saratsis, P and Boscos, C}, title = {Effect of antioxidant supplementation on semen quality and reactive oxygen species of frozen-thawed canine spermatozoa.}, journal = {Theriogenology}, volume = {68}, number = {2}, pages = {204-212}, doi = {10.1016/j.theriogenology.2007.04.053}, pmid = {17540441}, issn = {0093-691X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Catalase/pharmacology ; *Cryopreservation ; *Dogs ; Male ; Reactive Oxygen Species/metabolism ; Semen/*drug effects ; Sperm Motility/drug effects ; Spermatozoa/*drug effects ; Taurine/pharmacology ; Vitamin E/pharmacology ; }, abstract = {The objective of this study was to evaluate post-thaw quality of frozen dog semen processed with diluents containing different antioxidants. Ejaculates were collected, pooled and evaluated for concentration, motility, rapid steady forward movement (RSF movement), viability, acrosomal integrity and by the hypo-osmotic swelling test. Also, superoxide production, hydroxyl radicals and total reactive oxygen species (tROS) were determined. The pool was divided in seven aliquots, for control and test conditions, which were processed for cryopreservation. The sperm pellets were diluted to a final concentration of 200x10(6)sperm/ml with TRIS-glucose-egg yolk extender containing one of the following supplements: vitamin C (1.5mM), NAC (N-acetyl-l-cysteine; 1.5mM), taurine (0.6mM), catalase (300U/ml), vitamin E (0.3mM) and B16 [5-(4-dimethylamino-phenyl)-2-phenyl-penta-2,4-dienoic acid; 0.3mM]. Post-thaw semen evaluation showed that mean (+/-S.E.M.) motility was increased (p<0.001) after addition of catalase (49.75+/-3.63 versus 39.00+/-2.90 in controls), whereas more spermatozoa with RSF movement were observed (p<0.001) after the catalase, NAC and vitamin E treatments (31.75+/-3.46, 28.00+/-3.27, 26.75+/-3.15, respectively, versus 17.00+/-2.26 in controls). Viability was increased (p<0.001) after addition of catalase, taurine, NAC and tocopherol (66.00+/-3.03, 61.90+/-2.48, 60.60+/-1.93 and 60.50+/-4.12, respectively, versus 51.70+/-2.81 in controls). The percentage of swollen spermatozoa was increased after addition of catalase and taurine (61.75+/-1.61 and 61.25+/-1.49, respectively, versus 55.65+/-1.64 in controls). Acrosomal integrity was not influenced in any case. B16 addition had adverse effects on all parameters evaluated. None of the reactive oxygen species were significantly reduced post-thaw in antioxidant treated semen. The results suggest that catalase had the most pronounced effect in improving post-thaw quality of canine spermatozoa.}, }
@article {pmid17536822, year = {2007}, author = {Pan, MH and Lai, YS and Lai, CS and Wang, YJ and Li, S and Lo, CY and Dushenkov, S and Ho, CT}, title = {5-Hydroxy-3,6,7,8,3',4'-hexamethoxyflavone induces apoptosis through reactive oxygen species production, growth arrest and DNA damage-inducible gene 153 expression, and caspase activation in human leukemia cells.}, journal = {Journal of agricultural and food chemistry}, volume = {55}, number = {13}, pages = {5081-5091}, doi = {10.1021/jf070068z}, pmid = {17536822}, issn = {0021-8561}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspases/*metabolism ; Cell Division/*drug effects ; DNA Damage/*genetics ; Enzyme Activation/drug effects ; Flavones/*pharmacology ; Gene Expression/drug effects ; HL-60 Cells ; Humans ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/*genetics ; }, abstract = {This study examined the growth inhibitory effects of structurally related polymethoxylated flavones in human cancer cells. Here, we report that 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-OH-HxMF) induces growth inhibition of human cancer cells and induction of apoptosis in HL-60 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of 5-OH-HxMF-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. The changes occurred after single breaks in DNA were detected, suggesting that 5-OH-HxMF induced irreparable DNA damage, which in turn triggered the process of apoptosis. Up-regulation of Bax was found in 5-OH-HxMF-treated HL-60 cells. In addition, a caspase-independent pathway indicated by endonuclease G also contributed to apoptosis caused by 5-OH-HxMF. Antioxidants suppress 5-OH-HxMF-induced apoptosis. 5-OH-HxMF markedly enhanced growth arrest DNA damage-inducible gene 153 (GADD153) protein in a time-dependent manner. N-acetylcysteine (NAC) and catalase prevented up-regulation of GADD153 expression caused by 5-OH-HxMF. These findings suggest that 5-OH-HxMF creates an oxidative cellular environment that induces DNA damage and GADD153 gene activation, which in turn helps trigger apoptosis in HL-60 cells. Meanwhile, ROS were proven an important inducer in this apoptotic process. The C-5 hydroxyl on the ring of 5-OH-HxMF was found to be essential for the antiproliferative and apoptosis-inducing activity. Our study identified the novel mechanisms of 5-OH-HxMF-induced apoptosis and indicated that these results have significant applications as potential chemopreventive and chemotherapeutic agents.}, }
@article {pmid17532680, year = {2005}, author = {Zuin, R and Palamidese, A and Negrin, R and Catozzo, L and Scarda, A and Balbinot, M}, title = {High-dose N-acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease.}, journal = {Clinical drug investigation}, volume = {25}, number = {6}, pages = {401-408}, pmid = {17532680}, issn = {1173-2563}, abstract = {OBJECTIVE: To investigate the efficacy and tolerability of high-dose N-acetylcysteine (NAC) in the treatment of patients with exacerbations of chronic obstructive pulmonary disease (COPD).<br><br>DESIGN AND PATIENTS: Randomised, double-blind, double-dummy, placebo-controlled study in 123 patients experiencing an acute exacerbation of COPD.<br><br>INTERVENTIONS: NAC 1200 mg/day, 600 mg/day or placebo administered once daily for 10 days.<br><br>MAIN OUTCOME MEASURES: The primary objective was to assess the proportion of patients with normalised C-reactive protein (CRP) levels. Also assessed were effects on interleukin (IL)-8 levels, lung function and symptoms.<br><br>RESULTS: Both NAC 600 and 1200 mg/day were associated with a significantly higher proportion of patients achieving normalised CRP levels compared with placebo (52% and 90% vs 19% of patients; p </= 0.01); however, NAC 1200 mg/day was superior to NAC 600 mg/day (p = 0.002). Furthermore, treatment with NAC 1200 mg/day was more efficacious than NAC 600 mg/day in reducing IL-8 levels and difficulty of expectoration, while the two active regimens had similar beneficial effects on lung function and other clinical outcomes (cough intensity and frequency, and lung auscultation). Treatments were well tolerated with one adverse event reported in NAC 1200 mg/day recipients and two reported in placebo recipients.<br><br>CONCLUSION: Treatment with NAC 1200 mg/day improved biological markers and clinical outcomes in patients with COPD exacerbations. It is speculated that the effect of NAC on inflammatory markers may be due to both mucolytic and antioxidant properties.}, }
@article {pmid17532486, year = {2007}, author = {Lin, HY and Shen, SC and Lin, CW and Yang, LY and Chen, YC}, title = {Baicalein inhibition of hydrogen peroxide-induced apoptosis via ROS-dependent heme oxygenase 1 gene expression.}, journal = {Biochimica et biophysica acta}, volume = {1773}, number = {7}, pages = {1073-1086}, doi = {10.1016/j.bbamcr.2007.04.008}, pmid = {17532486}, issn = {0006-3002}, mesh = {Animals ; Antioxidants/chemistry/*metabolism ; Apoptosis/*physiology ; Carbon Monoxide/metabolism ; Cell Line ; Enzyme Activation ; Enzyme Inhibitors/chemistry/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Flavanones/chemistry/*metabolism ; Flavonoids/chemistry/metabolism ; *Gene Expression Regulation, Enzymologic ; Heme Oxygenase-1/genetics/*metabolism ; Hydrogen Peroxide/*metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Membrane Potentials/physiology ; Metalloporphyrins/metabolism ; Mice ; Mitochondria/metabolism ; Molecular Structure ; Oligonucleotides, Antisense/genetics/metabolism ; Oxidants/metabolism ; Protoporphyrins/metabolism ; Reactive Oxygen Species/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {In the present study, baicalein (BE) but not its glycoside, baicalin (BI), induced heme oxygenase-1 (HO-1) gene expression at both the mRNA and protein levels, and the BE-induced HO-1 protein was blocked by adding cycloheximide (CHX) or actinomycin D (Act D). Activation of ERK, but not JNK or p38, proteins via induction of phosphorylation in accordance with increasing intracellular peroxide levels was detected in BE-treated RAW264.7 macrophages. The addition of the ERK inhibitor, PD98059, (but not the p38 inhibitor, SB203580, or the JNK inhibitor, SP600125) and the chemical antioxidant, N-acetyl cysteine (NAC), significantly reduced BE-induced HO-1 protein expression by respectively blocking ERK protein phosphorylation and intracellular peroxide production. Additionally, BE but not BI effectively protected RAW264.7 cells from hydrogen peroxide (H(2)O(2))-induced cytotoxicity, and the preventive effect was attenuated by the addition of the HO inhibitor, SnPP, and the ERK inhibitor, PD98059. H(2)O(2)-induced apoptotic events including hypodiploid cells, DNA fragmentation, activation of caspase 3 enzyme activity, and a loss in the mitochondrial membrane potential with the concomitant release of cytochrome c from mitochondria to the cytosol were suppressed by the addition of BE but not BI. Blocking HO-1 protein expression by the HO-1 antisense oligonucleotide attenuated the protective effect of BE against H(2)O(2)-induced apoptosis by suppressing HO-1 gene expression in macrophages. Overexpression of the HO-1 protein inhibited H(2)O(2)-induced apoptotic events such as DNA fragmentation and hypodiploid cells by reducing intracellular peroxide production induced by H(2)O(2), compared with those events in neo-control (neo-RAW264.7) cells. In addition, CO, but not bilirubin and biliverdin, addition inhibits H(2)O(2)-induced cytotoxicity in macrophages. It suggests that CO can be responsible for the protective effect associated with HO-1 overexpression. The notion of induction of HO-1 gene expression through a ROS-dependent manner suppressing H(2)O(2)-induced cell death is identified in the present study.}, }
@article {pmid17529908, year = {2007}, author = {Xing, L and Remick, DG}, title = {Mechanisms of oxidant regulation of monocyte chemotactic protein 1 production in human whole blood and isolated mononuclear cells.}, journal = {Shock (Augusta, Ga.)}, volume = {28}, number = {2}, pages = {178-185}, doi = {10.1097/shk.0b013e3180311cf4}, pmid = {17529908}, issn = {1073-2322}, support = {R01 GM050401/GM/NIGMS NIH HHS/United States ; R01 GM050401-13/GM/NIGMS NIH HHS/United States ; ES 09589/ES/NIEHS NIH HHS/United States ; GM 50403/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/physiology ; Cells, Cultured ; Chemokine CCL2/*biosynthesis ; Female ; Humans ; Leukocytes, Mononuclear/*metabolism ; Mice ; Mice, Inbred ICR ; Oxidants/*physiology ; }, abstract = {Previous work has demonstrated that reactive oxygen intermediates (ROIs) play an important regulatory role in the induction of monocyte chemotactic protein 1 (MCP-1) in certain cells. This study investigated the mechanisms of ROI regulation of MCP-1 gene expression in whole blood and isolated peripheral blood mononuclear cells (PBMCs). The antioxidants dimethyl sulfoxide (DMSO), N-acetyl cysteine, and dimethyl thiourea significantly inhibited lipopolysaccharide (LPS)-induced MCP-1 production in either whole blood or isolated blood cells. In contrast, interleukin 6 and tumor necrosis factor production were not affected and interleukin-1beta levels were actually increased with DMSO treatment. Exogenous ROI (either hydrogen peroxide or O2 generated by xanthine/xanthine oxidase) stimulated MCP-1 production, which was also inhibited by DMSO. To confirm the biological relevance of these findings in vivo, mice treated with DMSO before LPS challenge had significantly lower plasma levels of MCP-1. The level of inhibition was addressed in experiments which demonstrated that DMSO significantly decreased MCP-1 mRNA induced by LPS in whole blood and PBMCs. Cycloheximide treatment did not abolish the DMSO inhibition of MCP-1 mRNA, demonstrating that de novo protein synthesis is not required. Treatment with actinomycin D showed that DMSO did not increase the decay rate of MCP-1 mRNA, indicating that ROI did not change the stability of MCP-1 mRNA. These results provide evidence that in whole blood and PBMCs, DMSO regulates MCP-1 gene expression by decreasing the induction of MCP-1 mRNA.}, }
@article {pmid17526765, year = {2007}, author = {Ramudo, L and De Dios, I and Yubero, S and Vicente, S and Manso, MA}, title = {ICAM-1 and CD11b/CD18 expression during acute pancreatitis induced by bile-pancreatic duct obstruction: effect of N-acetylcysteine.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {232}, number = {6}, pages = {737-743}, pmid = {17526765}, issn = {1535-3702}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; CD11b Antigen/*metabolism ; CD18 Antigens/*metabolism ; Cholestasis ; Disease Models, Animal ; Intercellular Adhesion Molecule-1/*blood/genetics ; Male ; Monocytes/drug effects/metabolism ; Neutrophils/drug effects/metabolism ; Pancreas/cytology/drug effects/metabolism/pathology ; Pancreatitis/*metabolism/pathology ; Peroxidase/metabolism ; RNA, Messenger/biosynthesis ; Rats ; Rats, Wistar ; Up-Regulation ; }, abstract = {Different molecules are involved in the recruitment of leukocytes during inflammation. The aim was to investigate (i) the contribution of acinar cells to the overall production of ICAM-1 and (ii) the kinetics of leukocyte CD11b/CD18 expression during acute pancreatitis (AP) induced by bile-pancreatic duct obstruction (BPDO) to evaluate the contribution of both molecules to leukocyte homing. The role of reactive oxygen species (ROS) as mediators in the expression of ICAM-1 and CD11b/CD18 was examined by using N-acetylcysteine (NAC) as an antioxidant treatment. By mechanisms resistant to NAC treatment, acinar cells were able to produce ICAM-1 at first onset of AP; other cell sources contribute to maintaining increased ICAM-1 plasma levels during AP. By contrast, CD11b/CD18 was overexpressed in leukocytes in the course of AP by oxidant-dependent mechanisms. Since NAC treatment reduced neutrophil infiltration in the pancreas, we conclude that CD11b/CD18 over-expression is required for leukocyte recruitment; however, other adhesion molecules in addition to ICAM-1 seem to contribute to leukocyte homing during BPDO-induced AP.}, }
@article {pmid17526490, year = {2007}, author = {Peng, Z and Peng, L and Fan, Y and Zandi, E and Shertzer, HG and Xia, Y}, title = {A critical role for IkappaB kinase beta in metallothionein-1 expression and protection against arsenic toxicity.}, journal = {The Journal of biological chemistry}, volume = {282}, number = {29}, pages = {21487-21496}, doi = {10.1074/jbc.M702510200}, pmid = {17526490}, issn = {0021-9258}, support = {R01 EY015227/EY/NEI NIH HHS/United States ; ES11798/ES/NIEHS NIH HHS/United States ; }, mesh = {3T3 Cells ; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Arsenic/*pharmacology/toxicity ; Arsenites/pharmacology ; *Gene Expression Regulation, Enzymologic ; I-kappa B Kinase/metabolism/*physiology ; MAP Kinase Kinase 4/metabolism ; Metallothionein/*chemistry ; Mice ; NF-kappa B/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; }, abstract = {Arsenic is a widespread environmental toxic agent that has been shown to cause diverse tissue and cell damage and at the same time to be an effective anti-cancer therapeutic agent. The objective of this study is to explore the signaling mechanisms involved in arsenic toxicity. We show that the IkappaB kinase beta (IKKbeta) plays a crucial role in protecting cells from arsenic toxicity. Ikkbeta(-)(/)(-) mouse 3T3 fibroblasts have decreased expression of antioxidant genes, such as metallothionein 1 (Mt1). In contrast to wild type and IKKbeta-reconstituted Ikkbeta(-)(/)(-) cells, IKKbeta-null cells display a marked increase in arsenic-induced reactive oxygen species (ROS) accumulation, which leads to activation of the MKK4-c-Jun NH(2)-terminal kinase (JNK) pathway, c-Jun phosphorylation, and apoptosis. Pretreatment with the antioxidant N-acetylcysteine (NAC) and expression of MT1 in the Ikkbeta(-)(/)(-) cells prevented JNK activation; moreover, NAC pretreatment, MT1 expression, MKK4 ablation, and JNK inhibition all protected cells from death induced by arsenic. Our data show that two signaling pathways appear to be important for modulating arsenic toxicity. First, the IKK-NF-kappaB pathway is crucial for maintaining cellular metallothionein-1 levels to counteract ROS accumulation, and second, when this pathway fails, excessive ROS leads to activation of the MKK4-JNK pathway, resulting in apoptosis.}, }
@article {pmid17525826, year = {2007}, author = {Sen, U and Moshal, KS and Singh, M and Tyagi, N and Tyagi, SC}, title = {Homocysteine-induced biochemical stress predisposes to cytoskeletal remodeling in stretched endothelial cells.}, journal = {Molecular and cellular biochemistry}, volume = {302}, number = {1-2}, pages = {133-143}, pmid = {17525826}, issn = {0300-8177}, support = {HL-71010/HL/NHLBI NIH HHS/United States ; HL-74185/HL/NHLBI NIH HHS/United States ; }, mesh = {Actins/metabolism ; Androstadienes/pharmacology ; Animals ; Biomechanical Phenomena ; Cells, Cultured ; Cytochalasin D/pharmacology ; Cytoskeleton/*drug effects/*metabolism ; Endothelial Cells/*cytology/*drug effects/enzymology ; Enzyme Activation/drug effects ; Focal Adhesion Protein-Tyrosine Kinases/metabolism ; Homocysteine/*pharmacology ; Hyperhomocysteinemia/enzymology ; Mice ; Oxidative Stress/*drug effects ; Paxillin/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Protein Transport/drug effects ; Wortmannin ; rac GTP-Binding Proteins/metabolism ; rhoA GTP-Binding Protein/metabolism ; }, abstract = {Cellular cytoskeletal remodeling reflects alterations in local biochemical and mechanical changes in terms of stress that manifests relocation of signaling molecules within and across the cell. Although stretching due to load and chemical changes by high homocysteine (HHcy) causes cytoskeletal re-arrangement, the synergism between stretch and HHcy is unclear. We investigated the contribution of HHcy in cyclic stretch-induced focal adhesion (FA) protein redistribution leading to cytoskeletal re-arrangement in mouse aortic endothelial cells (MAEC). MAEC were subjected to cyclic stretch (CS) and HHcy alone or in combination. The redistribution of FA protein, and small GTPases were determined by Confocal microscopy and Western blot techniques in membrane and cytosolic compartments. We found that each treatment induces focal adhesion kinase (FAK) phosphorylation and cytoskeletal actin polymerization. In addition, CS activates and membrane translocates small GTPases RhoA with minimal effect on Rac1, whereas HHcy alone is ineffective in both GTPases translocation. However, the combined effect of CS and HHcy activates and membrane translocates both GTPases. Free radical scavenger NAC (N-Acetyl-Cysteine) inhibits CS and HHcy-mediated FAK phosphorylation and actin stress fiber formation. Interestingly, CS also activates and membrane translocates another FA protein, paxillin in HHcy condition. Cytochalasin D, an actin polymerization blocker and PI3-kinase inhibitor Wortmannin inhibited FAK phosphorylation and membrane translocation of paxillin suggesting the involvement of PI3K pathway. Together our results suggest that CS- and HHcy-induced oxidative stress synergistically contribute to small GTPase membrane translocation and focal adhesion protein redistribution leading to endothelial remodeling.}, }
@article {pmid17524832, year = {2007}, author = {Chen, CF and Hsueh, CW and Tang, TS and Wang, D and Shen, CY and Pei, JS}, title = {Reperfusion liver injury-induced superoxide dismutase and catalase expressions and the protective effects of N-acetyl cysteine.}, journal = {Transplantation proceedings}, volume = {39}, number = {4}, pages = {858-860}, doi = {10.1016/j.transproceed.2007.02.018}, pmid = {17524832}, issn = {0041-1345}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Alanine Transaminase/blood ; Animals ; Catalase/*genetics ; Gene Expression Regulation, Enzymologic/drug effects ; Liver/*injuries ; Male ; RNA, Messenger/genetics ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*enzymology/*prevention &amp; control ; Superoxide Dismutase/*genetics ; }, abstract = {AIM: Reperfusion of the ischemic liver results in the generation of oxygen radicals. In this study, we analyzed if the mRNA and protein expressions of superoxide dismutase (SOD) and catalase increased after ischemia (I) and reperfusion (R) of the rat liver.<br><br>MATERIALS AND METHODS: Ischemia was induced by clamping off the common hepatic artery and portal vein of rats for 40 minutes, which were then reperfused for 90 minutes. Blood samples collected prior to I and after R were analyzed for hydroxyl radical (.OH), nitric oxide (NO), and alanine transferase (ALT). Liver tissues were used to analyze the SOD and catalase mRNA and protein expressions by real-time polymerase chain reaction and Western blot.<br><br>RESULTS: The results showed that this protocol resulted in elevation of the blood ALT, NO, and .OH levels (P<.001). mRNA (P<.01) and protein expressions (P<.05) of SOD and catalase were all increased. Pretreatment with antioxidant, N-acetyl cysteine, attenuated the liver injury.<br><br>CONCLUSION: These results indicate that reperfusion of the ischemic liver induced antioxidant enzymes expressions so that oxygen radicals are scavenged. Oxygen radical scavenger could further attenuate the I/R-induced liver injury.}, }
@article {pmid17519112, year = {2007}, author = {Yang, MS and Yu, LC and Pat, SW}, title = {Manipulation of energy and redox states in the C6 glioma cells by buthionine sulfoxamine and N-acetylcysteine and the effect on cell survival to cadmium toxicity.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {53}, number = {1}, pages = {56-61}, pmid = {17519112}, issn = {1165-158X}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Antimetabolites, Antineoplastic/metabolism/*pharmacology ; Buthionine Sulfoximine/metabolism/*pharmacology ; Cadmium/*toxicity ; Cell Line, Tumor/drug effects/metabolism ; Cell Survival/*drug effects ; Energy Metabolism ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Humans ; Oxidation-Reduction ; Rats ; }, abstract = {Changes in cellular energy and redox states were studied in the C6 glioma cells following exposure to chemicals that affect glutathione metabolism. It was demonstrated that treatment with sublethal concentrations (25, 50 and 100 microM) of buthionine sulfoxamine (BSO) did not affect cellular energy state as measured by total adenosine nucleotides (TAN=ATP+ADP+ AMP), ATP:ADP:AMP and energy charge potential (ECP=[ATP + 0.5 (ADP)]/TAN). However, there was a significantly decrease in cellular GSH/GSSG and total glutathione (TG=[GSH+GSSG]/ TAN). The change was due to a significant decrease in intracellular GSH level without significant change in [GSSG]. Cells exposed to BSO for 24 hr were much more sensitive to subsequent injuries caused by Cd (0.6 mM for 3 hr). The results indicated that while a significant reduction of intracellular redox state did not affect cell viability, it could increase the susceptibility of cells to subsequent chemical stress. N-acetylcysteine (NAC), on the other hand, caused a dose (1, 5 and 10 mM)-dependent increase in GSH/GSSG without significant changes in intracellular energy state. Improvement of intracellular GSH/GSSG offered no protection against subsequent Cd induced cell death unless NAC was present at the time Cd was added. The pattern of cell death also correlated with the increase in intracellular free radial generation as measured by the fluorescence labeling with 27- dichlorofluorescin. Results of the present study demonstrated that intracellular redox states could be manipulated by addition of chemicals that affect glutathione metabolism. While the redox state may not be the sufficient condition to cause cell death, it could modulate the response of cells to subsequent Cd treatment. Furthermore, the action of NAC against Cd cytotoxicity may not be related to intracellular redox status.}, }
@article {pmid17519111, year = {2007}, author = {Sharma, A and Kaur, P and Kumar, V and Gill, KD}, title = {Attenuation of 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine induced nigrostriatal toxicity in mice by N-acetyl cysteine.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {53}, number = {1}, pages = {48-55}, pmid = {17519111}, issn = {1165-158X}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/*metabolism ; Acetylcysteine/*metabolism/therapeutic use ; Animals ; Antioxidants/*metabolism/therapeutic use ; Corpus Striatum/chemistry/*drug effects/metabolism ; Dopamine/metabolism ; *Dopamine Agents/metabolism/toxicity ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Humans ; Lipid Peroxidation ; *MPTP Poisoning/drug therapy/metabolism ; Mice ; Mice, Inbred C57BL ; Middle Aged ; *Neurotoxins/metabolism/toxicity ; Substantia Nigra/chemistry/*drug effects/metabolism ; Sulfhydryl Compounds/metabolism ; Superoxide Dismutase/metabolism ; gamma-Glutamyltransferase/metabolism ; }, abstract = {The present study was designed to investigate the effects of N-acetyl cysteine (NAC), an antioxidant on 1-methyl 4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induced neurotoxicity in the nigrostriatal dopaminergic system of mice. MPTP treatment caused 80% decrease of the dopamine levels in the striatum of C57BL/ 6J mice. A marked increase in the extent of lipid peroxidation, superoxide dismutase (SOD) and g-glutamyl transpeptidase (g-GTP) was seen, while a significant decrease in the levels of glutathione (GSH), total thiols and glutathione peroxidase (GPx) activity was observed in the substantia nigra pars compacta (SNpc) of MPTP treated animals. As compared to control animals, Co-administration of NAC with MPTP restored the depleted dopamine, GSH, total tissue thiol levels and GPx activity in SNpc of treated mice brain. Moreover, NAC treatment also provided protection against lipid peroxidation and superoxide dismutase activity. The results of present study suggested that NAC attenuates MPTP neurotoxicity in mice brain and this protection by the NAC might be contributing to the regeneration of GSH, a major antioxidant.}, }
@article {pmid17517376, year = {2007}, author = {Mahipal, SV and Subhashini, J and Reddy, MC and Reddy, MM and Anilkumar, K and Roy, KR and Reddy, GV and Reddanna, P}, title = {Effect of 15-lipoxygenase metabolites, 15-(S)-HPETE and 15-(S)-HETE on chronic myelogenous leukemia cell line K-562: reactive oxygen species (ROS) mediate caspase-dependent apoptosis.}, journal = {Biochemical pharmacology}, volume = {74}, number = {2}, pages = {202-214}, doi = {10.1016/j.bcp.2007.04.005}, pmid = {17517376}, issn = {0006-2952}, mesh = {Apoptosis/*drug effects ; Arachidonate 15-Lipoxygenase/physiology ; Caspase 3/*physiology ; Catalase/physiology ; Cell Proliferation/drug effects ; Cytochromes c/metabolism ; Flow Cytometry ; Glutathione Peroxidase/physiology ; Humans ; Hydroxyeicosatetraenoic Acids/*pharmacology ; K562 Cells ; Leukotrienes/*pharmacology ; Lipid Peroxides/*pharmacology ; NADPH Oxidases/physiology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Growth inhibitory effects of 15-lipoxygenase-1 [13-(S)-HPODE and 13-(S)-HODE] and 15-lipoxygenase-2 [15-(S)-HPETE and 15-(S)-HETE] (15-LOX-1 and LOX-2) metabolites and the underlying mechanisms were studied on chronic myeloid leukemia cell line (K-562). The hydroperoxy metabolites, 15-(S)-HPETE and 13-(S)-HPODE rapidly inhibited the growth of K-562 cells by 3h with IC(50) values, 10 and 15microM, respectively. In contrast, the hydroxy metabolite of 15-LOX-2, 15-(S)-HETE, showed 50% inhibition only at 40microM by 6h and 13-(S)-HODE, hydroxy metabolite of 15-LOX-1, showed no significant effect up to 160microM. The cells exposed to 10microM of 15-(S)-HPETE and 40microM of 15-(S)-HETE showed typical apoptotic features like release of cytochrome c, caspase-3 activation and PARP-1 (poly(ADP) ribose polymerase-1) cleavage. A flow cytometry based DCFH-DA analysis and inhibitory studies with DPI, a pharmacological inhibitor of NADPH oxidase, NAC (N-acetyl cysteine) and GSH revealed that NADPH oxidase-mediated generation of ROS is responsible for caspase-3 activation and subsequent induction of apoptosis in the K-562 cell line.}, }
@article {pmid17516861, year = {2007}, author = {Upham, BL and Guzvić, M and Scott, J and Carbone, JM and Blaha, L and Coe, C and Li, LL and Rummel, AM and Trosko, JE}, title = {Inhibition of gap junctional intercellular communication and activation of mitogen-activated protein kinase by tumor-promoting organic peroxides and protection by resveratrol.}, journal = {Nutrition and cancer}, volume = {57}, number = {1}, pages = {38-47}, doi = {10.1080/01635580701268188}, pmid = {17516861}, issn = {0163-5581}, support = {5D43 TW00641/TW/FIC NIH HHS/United States ; P42 ES04911-17/ES/NIEHS NIH HHS/United States ; R01 ES013268-01A2/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Anticarcinogenic Agents/*pharmacology ; Blotting, Western ; Cell Communication/*drug effects ; Dose-Response Relationship, Drug ; Epithelial Cells/enzymology ; Gap Junctions/*drug effects ; Glutathione/metabolism ; Humans ; Liver/cytology ; Mitogen-Activated Protein Kinases/*metabolism ; Oxidants/*pharmacology ; Peroxides/*pharmacology ; Rats ; Rats, Inbred F344 ; Resveratrol ; Stilbenes/*pharmacology ; Time Factors ; }, abstract = {Dicumyl peroxide (di-CuOOH) and benzoyl peroxide (BzOOH) act as tumor promoters in SENCAR mice, whereas di-tert-butylhydroperoxide does not. Tumor promotion requires the removal of growth suppression by inhibition of gap junctional intercellular communication (GJIC) and the induction of mitogenic intracellular pathways. We showed that di-CuOOH and BzOOH both reversibly inhibited GJIC and transiently activated mitogen-activated protein kinase, specifically, the extracellular receptor kinase at noncytotoxic conditions in WB-F344 rat liver epithelial cells, whereas the non-tumor-promoting di-tert-butylhydroperoxide did not inhibit GJIC or activate extracellular receptor kinase. di-CuOOH but not BzOOH inhibited GJIC through a phosphatidylcholine-specific phospholipase C-dependent mechanism. N-acetylcysteine (NAC) was needed to prevent a cytotoxic, glutathione-depleting effect of BzOOH, whereas di-CuOOH was noncytotoxic and did not alter glutathione levels at all doses and times tested. Pretreatment of WB-F344 cells with resveratrol, a polyphenolic antioxidant present in red wine, prevented at physiological doses the inhibition of GJIC by di-CuOOH but not from BzOOH and was effective in significantly preventing extracellular receptor kinase activation by both peroxides. NAC did not prevent any of the peroxide effects on either GJIC or extracellular receptor kinase, suggesting a specific antioxidant effect of resveratrol.}, }
@article {pmid17513449, year = {2007}, author = {Grimble, GK}, title = {Adverse gastrointestinal effects of arginine and related amino acids.}, journal = {The Journal of nutrition}, volume = {137}, number = {6 Suppl 2}, pages = {1693S-1701S}, doi = {10.1093/jn/137.6.1693S}, pmid = {17513449}, issn = {0022-3166}, mesh = {Animals ; Arginine/*adverse effects/pharmacokinetics ; Citrulline/adverse effects/pharmacokinetics ; Gastrointestinal Diseases/*chemically induced/*metabolism ; Humans ; Nitric Oxide/metabolism ; }, abstract = {Oral supplements of arginine and citrulline increase local nitric oxide (NO) production in the small intestine and this may be harmful under certain circumstances. Gastrointestinal toxicity was therefore reviewed with respect to the intestinal physiology of arginine, citrulline, ornithine, and cystine (which shares the same transporter) and the many clinical trials of supplements of the dibasic amino acids or N-acetylcysteine (NAC). The human intestinal dibasic amino acid transport system has high affinity and low capacity. L-arginine (but not lysine, ornithine, or D-arginine) induces water and electrolyte secretion that is mediated by NO, which acts as an absorbagogue at low levels and as a secretagogue at high levels. The action of many laxatives is NO mediated and there are reports of diarrhea following oral administration of arginine or ornithine. The clinical data cover a wide span of arginine intakes from 3 g/d to>100 g/d, but the standard of reporting adverse effects (e.g. nausea, vomiting, and diarrhea) was variable. Single doses of 3-6 g rarely provoked side effects and healthy athletes appeared to be more susceptible than diabetic patients to gastrointestinal symptoms at individual doses>9 g. This may relate to an effect of disease on gastrointestinal motility and pharmacokinetics. Most side effects of arginine and NAC occurred at single doses of >9 g in adults (>140 mg/kg) often when part of a daily regime of approximately>30 g/d (>174 mmol/d). In the case of arginine, this compares with the laxative threshold of the nonabsorbed disaccharide alcohol, lactitol (74 g or 194 mmol). Adverse effects seemed dependent on the dosage regime and disappeared if divided doses were ingested (unlike lactitol). Large single doses of poorly absorbed amino acids seem to provoke diarrhea. More research is needed to refine dosage strategies that reduce this phenomenon. It is suggested that dipeptide forms of arginine may meet this criterion.}, }
@article {pmid17512465, year = {2007}, author = {Probin, V and Wang, Y and Zhou, D}, title = {Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway.}, journal = {Free radical biology &amp; medicine}, volume = {42}, number = {12}, pages = {1858-1865}, pmid = {17512465}, issn = {0891-5849}, support = {C06 RR014516/RR/NCRR NIH HHS/United States ; R01CA102558/CA/NCI NIH HHS/United States ; R01 CA086860/CA/NCI NIH HHS/United States ; R01 CA086860-05A2/CA/NCI NIH HHS/United States ; R01 CA102558/CA/NCI NIH HHS/United States ; C06RR014516/RR/NCRR NIH HHS/United States ; //Intramural NIH HHS/United States ; C06 RR014516-01/RR/NCRR NIH HHS/United States ; R01CA86688/CA/NCI NIH HHS/United States ; R01 CA102558-04/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Alkylating/*pharmacology ; Blotting, Western ; Bromodeoxyuridine ; Busulfan/*pharmacology ; Cell Proliferation/drug effects ; Cells, Cultured ; Cellular Senescence/*drug effects ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibroblasts/drug effects/metabolism ; Glutathione/metabolism ; Humans ; Lung/drug effects/embryology/metabolism ; Mitogen-Activated Protein Kinases/*physiology ; NADPH Oxidases/metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; Tumor Suppressor Protein p53/genetics/metabolism ; beta-Galactosidase/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Induction of cellular senescence is a common response of a normal cell to a DNA-damaging agent, which may contribute to cancer chemotherapy- and ionizing radiation-induced normal tissue injury. The induction has been largely attributed to the activation of p53. However, the results from the present study suggest that busulfan (BU), an alkylating agent that causes DNA damage by cross-linking DNAs and DNA and proteins, induces senescence in normal human diploid WI38 fibroblasts through the extracellular signal-regulated kinase (Erk) and p38 mitogen-activated protein kinase (p38 MAPK) cascade independent of the p53-DNA damage pathway. The induction of WI38 cell senescence is initiated by a transient depletion of intracellular glutathione (GSH) and followed by a continuous increase in reactive oxygen species (ROS) production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which leads to the activation of the Erk and p38 MAPK pathway. Incubation of WI38 cells with N-acetylcysteine (NAC) replenishes intracellular GSH, abrogates the increased production of ROS, ameliorates Erk and p38 MAPK activation, and attenuates senescence induction by BU. Thus, inhibition of senescence induction using a potent antioxidant or specific inhibitor of the Erk and p38 MAPK pathway has the potential to be developed as a mechanism-based strategy to ameliorate cancer therapy-induced normal tissue damage.}, }
@article {pmid17512076, year = {2007}, author = {Matsuyama, T and Morita, T and Horikiri, Y and Yamahara, H and Yoshino, H}, title = {Influence of fillers in powder formulations containing N-acetyl-L-cysteine on nasal peptide absorption.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {120}, number = {1-2}, pages = {88-94}, doi = {10.1016/j.jconrel.2007.04.006}, pmid = {17512076}, issn = {1873-4995}, mesh = {Acetylcysteine/*chemistry ; Administration, Intranasal ; Animals ; Biological Availability ; Calcitonin/administration &amp; dosage/chemistry/pharmacokinetics ; Cellulose/analogs &amp; derivatives/chemistry ; Chemistry, Pharmaceutical ; Excipients/*chemistry ; Expectorants/*chemistry ; Insulin/administration &amp; dosage/chemistry/pharmacokinetics ; Lactose/chemistry ; Male ; Nasal Mucosa/*metabolism ; Parathyroid Hormone/administration &amp; dosage/chemistry/pharmacokinetics ; Particle Size ; Peptides/*administration &amp; dosage/chemistry/*pharmacokinetics ; Powders ; Rats ; Rats, Wistar ; Solubility ; Water/chemistry ; Wettability ; }, abstract = {We examined the influence of filler species on the nasal absorbability of peptide drugs via a newly developed powdery formulation system containing N-acetyl-l-cysteine (NAC) as an absorption enhancer. Using salmon calcitonin (SCT) as the principal model drug, we tested the effects of various formulations with different powder materials as fillers on the nasal absorption of SCT in rats. An intranasal administration experiment revealed that the use of less wettable powders provided better nasal absorbability, and the highest absolute bioavailability (30.0% +/- 8.6%) was obtained when ethylcellulose was used as a filler. All these results were readily explicable in terms of our hypothetical enhancing mechanism. Furthermore, human parathyroid hormone and insulin were applied to this ethylcellulose formulation system, giving nasal bioavailabilities of 28.2% +/- 6.5% and 23.4% +/- 10.6%, respectively, thus suggesting that this formulation system is widely applicable to peptide drugs.}, }
@article {pmid17509548, year = {2007}, author = {Slättegård, R and Gammon, DW and Oscarson, S}, title = {Synthesis of fused bicyclic thioglycosides of N-acylated glucosamine as analogues of mycothiol.}, journal = {Carbohydrate research}, volume = {342}, number = {12-13}, pages = {1943-1946}, doi = {10.1016/j.carres.2007.04.019}, pmid = {17509548}, issn = {0008-6215}, mesh = {Acetylglucosamine ; Bridged Bicyclo Compounds/*chemical synthesis/chemistry ; Carbohydrate Conformation ; Cysteine/*chemistry ; Glucosamine/*chemistry ; Glycopeptides/*chemistry ; Inositol/*chemistry ; Models, Molecular ; Molecular Conformation ; Thioglycosides/*chemical synthesis/chemistry ; }, abstract = {The synthesis of a fused bicyclic thioglycoside analogue of mycothiol, (3R)-3-acetylamino-4-one-6,7-dihydro-(1',2'-dideoxy-beta-D-glucopyranoso)[2',1'-f]-1,5-thiazepane (5), is reported. Treatment of phthalimido-protected peracetylated glucosamine with N-acetyl-cysteine and boron trifluoride-etherate gave the beta-linked thioglycoside, which was deprotected and cyclized, using HOBt and EDCl to form the lactam and giving the target structure. This mycothiol mimic and its tri-O-acetate will be investigated as potential inhibitors of enzymes involved in the biosynthesis of mycothiol. The protected derivative also has the potential to be an alpha-selective N-cysteinyl glucosamine donor; however, initial glycosylation attempts failed due to the apparent stability of the fused bicyclic system.}, }
@article {pmid17507140, year = {2007}, author = {Shin, JS and Lee, SW and Kim, NH and Park, JS and Kim, KJ and Choi, SH and Hong, YS}, title = {Successful extracorporeal life support after potentially fatal pulmonary oedema caused by inhalation of nitric and hydrofluoric acid fumes.}, journal = {Resuscitation}, volume = {75}, number = {1}, pages = {184-188}, doi = {10.1016/j.resuscitation.2007.04.004}, pmid = {17507140}, issn = {0300-9572}, mesh = {Adult ; Air Pollutants, Occupational/adverse effects ; Electroplating ; Explosive Agents/administration &amp; dosage/*adverse effects ; Extracorporeal Membrane Oxygenation/*methods ; Fatal Outcome ; Humans ; Hydrofluoric Acid/administration &amp; dosage/*adverse effects ; Male ; Nitric Acid/administration &amp; dosage/*adverse effects ; Occupational Exposure/adverse effects ; Pulmonary Edema/*chemically induced/*therapy ; }, abstract = {Two patients presented with potentially fatal pulmonary oedema after accidental exposure to nitric and hydrofluoric acid fumes during electroplating. Despite aggressive respiratory support, one succumbed to respiratory failure 3.5h after inhalation. The other patient also rapidly progressed to respiratory failure. Extracorporeal life support (ECLS) was started 5h after exposure at the ED. During ECLS, hypoxia improved, but pulmonary oedema shown by chest radiography became aggravated. N-Acetyl cysteine and calcium gluconate were given i.v. on the first day of admission and nebulised for 48 h after exposure. Pulmonary secretions were significantly reduced 24 h after the nebulising therapy began. Ultimately, the patient was discharged without serious pulmonary or neurological complications after 28 days of hospitalisation. In this case, early ECLS, nebulised antioxidant and antidote were available to treat potentially fatal pulmonary oedema after exposure to nitric and hydrofluoric acid fumes.}, }
@article {pmid17506000, year = {2007}, author = {Andersson, E and Axelsson, J and Pedersen, LC and Elm, T and Andersson, R}, title = {Treatment with anti-factor VIIa in acute pancreatitis in rats: blocking both coagulation and inflammation?.}, journal = {Scandinavian journal of gastroenterology}, volume = {42}, number = {6}, pages = {765-770}, doi = {10.1080/00365520701295632}, pmid = {17506000}, issn = {0036-5521}, mesh = {Acute Disease ; Animals ; Blood Coagulation/*drug effects ; Chemokine CXCL2 ; Enzyme-Linked Immunosorbent Assay ; Factor VIIa/*antagonists &amp; inhibitors ; Inflammation/*drug therapy ; Interleukin-6/blood ; Male ; Monokines/blood ; Oxidative Stress ; Pancreatitis/*drug therapy ; Peroxidase/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: Acute pancreatitis starts as an autodigestive process restricted to the pancreas and progresses to a systemic inflammation via cytokine release into the blood stream. Several inhibitors of the coagulation cascade, including active-site-inactivated factor VIIa, have shown anti-inflammatory properties in other inflammatory models than acute pancreatitis. Free radical scavengers have proven useful in reducing the oxidative damage during hyperinflammatory conditions. The aim of this study was to investigate whether pretreatment with FVIIai would have any effect on the multiple organ dysfunction syndrome (MODS) in severe acute pancreatitis.<br><br>MATERIAL AND METHODS: Experimental acute pancreatitis was induced by intraductal infusion of taurodeoxycholate in the pancreatic duct. The animals were pretreated with N-acetyl-cysteine and active-site-inactivated factor VIIa. Neutrophil infiltration in the lungs, ileum and colon was quantified by myeloperoxidase activity. Inflammatory markers, IL-6 and MIP-2, were measured using ELISA.<br><br>RESULTS: Tissue infiltration of neutrophils in the lungs, ileum and colon significantly increased during acute pancreatitis as compared to sham operation. These levels were reduced by pretreatment with N-acetylcysteine and active-site-inactivated factor VIIa. Levels of interleukin-6 and macrophage inflammatory protein-2 increased significantly during acute pancreatitis. Pretreatment with NAC and FVIIai reduced these levels.<br><br>CONCLUSIONS: Both N-acetylcysteine and active-site-inactivated factor VIIa showed powerful anti-inflammatory properties in experimental acute pancreatitis. As they exert their effects through different physiological mechanisms, they represent potential candidates for future multimodal treatment of acute pancreatitis.}, }
@article {pmid17504796, year = {2007}, author = {Martinez-Losa, M and Cortijo, J and Juan, G and Ramón, M and Sanz, MJ and Morcillo, EJ}, title = {Modulatory effects of N-acetyl-L-cysteine on human eosinophil apoptosis.}, journal = {The European respiratory journal}, volume = {30}, number = {3}, pages = {436-442}, doi = {10.1183/09031936.00073706}, pmid = {17504796}, issn = {0903-1936}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Annexin A5/metabolism ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Drug Synergism ; Eosinophils/*drug effects ; Flow Cytometry ; Glutathione/metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; In Vitro Techniques ; Interleukin-5/pharmacology ; NF-kappa B/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Eosinophils are oxidant-sensitive cells considered relevant in allergic inflammation. The present study aimed to examine the effects of the antioxidant N-acetyl-L-cysteine (NAC) on constitutive and cytokine-delayed apoptosis in human isolated eosinophils. Human eosinophils were purified from the blood of healthy donors by a magnetic separation system. Apoptosis and cellular glutathione were assessed by cytofluorometric analysis and nuclear factor (NF)-kappaB binding activity assessed by electrophoresis mobility shift assay. The rate of spontaneous apoptosis of human eosinophils after 24 h culture, as assessed by annexin-V-positive staining, was mean+/-sem 48.2+/-1.4%, n = 5. Granulocyte-macrophage colony-stimulating factor (GM-CSF; 10 ng.mL(-1)) decreased apoptosis to 19.4+/-1.8%, n = 5. NAC (5 mM) inhibited spontaneous apoptosis (33.6+/-2.7%, n = 5) but augmented apoptosis in the presence of GM-CSF (30.9+/-1.5%, n = 5). NAC (5 mM) also increased the rate of apoptosis in the presence of tumour necrosis factor (TNF)-alpha (10 ng.mL(-1)) and interleukin-5 (5 ng.mL(-1)). NAC (5 mM) increased eosinophil glutathione content. The increase in eosinophil NF-kappaB binding activity induced by GM-CSF and TNF-alpha was suppressed by NAC. In conclusion, N-acetylcysteine modulates eosinophil apoptosis by inhibiting constitutive apoptosis but reversing the survival effect produced by inflammatory cytokines in human eosinophils.}, }
@article {pmid17504267, year = {2007}, author = {Zafar, KS and Inayat-Hussain, SH and Ross, D}, title = {A comparative study of proteasomal inhibition and apoptosis induced in N27 mesencephalic cells by dopamine and MG132.}, journal = {Journal of neurochemistry}, volume = {102}, number = {3}, pages = {913-921}, doi = {10.1111/j.1471-4159.2007.04637.x}, pmid = {17504267}, issn = {0022-3042}, support = {R01 NS44613/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*physiology ; Caspases/drug effects/metabolism ; Cell Line, Transformed ; Cysteine Proteinase Inhibitors/pharmacology ; Dopamine/*metabolism/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects/physiology ; Leupeptins/pharmacology ; Mesencephalon/cytology/drug effects/metabolism ; Nerve Degeneration/metabolism/physiopathology ; Neurons/drug effects/*metabolism ; Oxidative Stress/drug effects/physiology ; Parkinson Disease/*metabolism/physiopathology ; Proteasome Endopeptidase Complex/drug effects/*metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Substantia Nigra/*metabolism/physiopathology ; }, abstract = {Dopamine (DA) and its metabolites have been implicated in the pathogenesis of Parkinson's disease. DA can produce reactive-oxygen species and DA-derived quinones such as aminochrome can induce proteasomal inhibition. We therefore examined the ability of DA and MG132 to induce apoptosis and proteasomal inhibition in N27 rat dopaminergic cells. DA (0-500 micromol/L, 0-24 h) and MG132 (0-5 micromol/L, 0-24 h) treated N27 cells resulted in time- and concentration-dependent apoptosis. To better define DA and MG132-induced apoptosis, the activation of initiator caspases 2 and caspase 9 and the executioner caspase 3 was investigated. Activation of caspase 2, caspase 9, and caspase 3 occurred early and prior to cell death. In addition, N-acetylcysteine (NAC) blocked DA but not MG132-induced apoptosis and mitochondrial membrane potential loss. NAC can react with both reactive-oxygen and quinoid metabolites and its inhibitory activity suggests a role for reactive species in DA-induced apoptosis. Proteasomal inhibition was detected after DA treatment in N27 cells which occurred prior to cell death and was abrogated by NAC. Our results implicate DA-derived reactive species in proteasomal inhibition and caspase-dependent apoptosis in N27 cells. The ability of endogenous DA-derived metabolites to induce proteasomal inhibition and apoptosis may contribute to the selective loss of dopaminergic neurons in Parkinson's disease.}, }
@article {pmid17503877, year = {2007}, author = {Bloomer, RJ}, title = {The role of nutritional supplements in the prevention and treatment of resistance exercise-induced skeletal muscle injury.}, journal = {Sports medicine (Auckland, N.Z.)}, volume = {37}, number = {6}, pages = {519-532}, pmid = {17503877}, issn = {0112-1642}, mesh = {Humans ; Musculoskeletal System/*injuries ; *Nutritional Support ; United States ; Weight Lifting/*injuries ; Wounds and Injuries/etiology/*prevention &amp; control/*therapy ; }, abstract = {The topic of exercise-induced skeletal muscle injury has received considerable attention in recent years. Likewise, strategies to minimise the injury resulting from heavy resistance exercise have been studied. Over the past 15 years, several investigations have been performed focused on the role of nutritional supplements to attenuate signs and symptoms of muscle injury. Of these, some have reported favourable results, while many others have reported no benefit of the selected nutrient. Despite these mixed findings, recommendations for the use of nutritional supplements for the purposes of attenuating muscle injury are rampant within the popular fitness media and athletic world, largely without scientific support. Those nutrients include the antioxidant vitamin C (ascorbic acid) and vitamin E (tocopherol), N-acetyl-cysteine, flavonoids, L-carnitine, astaxanthin, beta-hydroxy-beta-methylbutyrate, creatine monohydrate, essential fatty acids, branched-chain amino acids, bromelain, proteins and carbohydrates. A discussion of all published peer-reviewed articles in reference to these nutrients and their impact on resistance exercise-induced skeletal muscle injury is presented, in addition to a brief view into the potential mechanism of action for each nutrient.Based on the current state of knowledge, the following conclusions can be made with regard to nutritional supplements and their role in attenuating signs and symptoms of skeletal muscle injury occurring as a consequence of heavy resistance exercise: (i) there appears to be a potential role for certain supplements (vitamin C, vitamin E, flavonoids, and L-carnitine); (ii) these supplements cannot effectively eliminate muscle injury, only attenuate certain signs and symptoms; (iii) it is presently unclear what the optimal dosage of these nutrients is (whether used alone or in combination); (iv) it is unclear what the optimal pretreatment period is; and (v) the effectiveness is largely specific to non-resistance trained individuals.Ultimately, because so few studies have been conducted in this area, it is difficult to recommend with confidence the use of selected nutrients for the sole purpose of minimising signs and symptoms of resistance exercise-induced muscle injury, in particular with regard to resistance-trained individuals.}, }
@article {pmid17503468, year = {2007}, author = {Antherieu, S and Ledirac, N and Luzy, AP and Lenormand, P and Caron, JC and Rahmani, R}, title = {Endosulfan decreases cell growth and apoptosis in human HaCaT keratinocytes: partial ROS-dependent ERK1/2 mechanism.}, journal = {Journal of cellular physiology}, volume = {213}, number = {1}, pages = {177-186}, doi = {10.1002/jcp.21108}, pmid = {17503468}, issn = {0021-9541}, mesh = {Apoptosis/drug effects ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Cell Proliferation/drug effects ; Cyclin A/metabolism ; Cyclin B/metabolism ; Cyclin B1 ; Cyclin D ; Cyclins/metabolism ; Endosulfan/*toxicity ; Humans ; Insecticides/toxicity ; Keratinocytes/cytology/*drug effects/metabolism ; MAP Kinase Signaling System/drug effects ; Mutagens/toxicity ; Oxidative Stress ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Staurosporine/pharmacology ; }, abstract = {Endosulfan is an organochlorine insecticide described as a potential carcinogen in humans. This insecticide was recently reported to alter the mitogen-activated protein (MAP) kinase signaling pathways and is suspected to affect cell growth and differentiation in human keratinocytes. This study was designed to assess the mitogenic, apoptogenic, and genotoxic effects of endosulfan on the HaCaT cell line. We first found that 25 microM endosulfan led to persistent extracellular signal-regulated kinase (ERK)1/2 phosphorylation with an accumulation of the phosphorylated form in the nucleus, probably caused by MAP kinase phosphatase (MKP) inhibition. As previously described under sustained ERK1/2 activation, cell growth was decreased: delayed confluency and 35% decrease of BrdU incorporation was demonstrated in endosulfan-treated keratinocytes. In addition, endosulfan has been shown to generate transient reactive oxygen species (ROS), and blocking this oxidative stress by N-acetyl cysteine (NAC) strongly prevented both persistent nuclear ERK1/2 phosphorylation and cell growth decrease. Additional experiments demonstrated that unchanged endosulfan rather than its metabolites has mutagenic effects (Ames positive without S9) and increased DNA strand breaks (Comet assay) in HaCaT cells, via a ROS-dependent mechanism. Therefore, to assess the putative pro-apoptotic response of damaged cells, caspases 3/7 activity and poly(ADP-ribose)-polymerase (PARP) cleavage were measured. The results clearly indicated that endosulfan inhibited both spontaneous and staurosporine-induced apoptosis. Taken together, these findings strongly support that endosulfan induces ROS generation leading to sustained ERK1/2 phosphorylation and decrease in cell growth. Moreover, endosulfan was found to inhibit apoptosis and this could contribute to mutant cell survival and therefore have possible carcinogenic effects.}, }
@article {pmid17499213, year = {2007}, author = {Lambert, D and Padfield, PJ and McLaughlin, J and Cannell, S and O'Neill, CA}, title = {Ochratoxin A displaces claudins from detergent resistant membrane microdomains.}, journal = {Biochemical and biophysical research communications}, volume = {358}, number = {2}, pages = {632-636}, doi = {10.1016/j.bbrc.2007.04.180}, pmid = {17499213}, issn = {0006-291X}, support = {D17799/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Caco-2 Cells ; Detergents/*administration &amp; dosage ; Dose-Response Relationship, Drug ; Drug Resistance ; Humans ; Membrane Microdomains/*drug effects/*metabolism ; Membrane Proteins/*metabolism ; Ochratoxins/*administration &amp; dosage ; Tight Junctions/*drug effects/*metabolism ; }, abstract = {Ochratoxin A (OchA) is a food-borne mycotoxin with multiple effects in vivo. Previously, we have demonstrated that the toxin can significantly impair the barrier function of the gut epithelial cell line, Caco-2. Barrier disruption involved loss of claudins 3 and 4, but not claudin 1 from the tight junction complex. In this study, we demonstrate for the first time, that OchA is able to remove claudins 3 and 4 from the detergent insoluble membrane microdomains associated with the tight junctions. However, cholesterol distribution within the microdomain was unaffected by the toxin. In addition, the thiol antioxidant, N-acetyl cysteine, preserved the microdomain localisation of claudins and also the barrier function of Caco-2 cells. This work suggests that OchA-mediated barrier toxicity is due to removal of claudins from detergent insoluble membrane microdomains. Moreover, loss of microdomain association may be due to oxidative events.}, }
@article {pmid17498688, year = {2007}, author = {Murata, K and Ota, S and Niki, T and Goto, A and Li, CP and Ruriko, UM and Ishikawa, S and Aburatani, H and Kuriyama, T and Fukayama, M}, title = {p63 - Key molecule in the early phase of epithelial abnormality in idiopathic pulmonary fibrosis.}, journal = {Experimental and molecular pathology}, volume = {83}, number = {3}, pages = {367-376}, doi = {10.1016/j.yexmp.2007.03.006}, pmid = {17498688}, issn = {0014-4800}, mesh = {Acetylcysteine/metabolism ; Biomarkers/metabolism ; Calcium-Binding Proteins/genetics/metabolism ; Cell Line, Tumor ; Cluster Analysis ; DNA-Binding Proteins/genetics/*metabolism ; Epithelial Cells/metabolism/*pathology ; Gene Expression Profiling ; Humans ; Intercellular Signaling Peptides and Proteins/genetics/metabolism ; Jagged-1 Protein ; Keratin-14/genetics/metabolism ; Keratin-6/genetics/metabolism ; Membrane Proteins/genetics/metabolism ; Metaplasia/metabolism/pathology ; Oligonucleotide Array Sequence Analysis ; Protein Isoforms/genetics/metabolism ; Protein Precursors/genetics/metabolism ; *Pulmonary Fibrosis/metabolism/pathology ; RNA, Small Interfering/genetics/metabolism ; Respiratory Mucosa/*cytology ; Serrate-Jagged Proteins ; Trans-Activators/genetics/*metabolism ; Transcription Factors ; Transforming Growth Factor beta1/metabolism ; Tumor Suppressor Proteins/genetics/*metabolism ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) is the most common lung disease predisposing lung cancer. To clarify the early phase of epithelial abnormalities in IPF, we used an in vitro squamous metaplasia model, transforming growth factor beta1 (TGF beta1)-treated airway epithelial cells (BEAS-2B). The model repeated the expression of squamous epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in TGF beta1-treated airway epithelial cells, 20 specifically up-regulated genes including p63, jagged 1 (jag1) and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaNp63alpha was the dominant isoform of p63 in our experimental model. Immunohistochemical analysis demonstrated the expression of p63 and jag1 in lung tissues of IPF. Inhibition of p63 with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of p63 was totally suppressed by N-acetyl-l-cysteine (NAC), but not by dexamethasone or pirfenidone. Thus, the p63-jag1 pathway may be up-regulated at an early phase of epithelial abnormalities in IPF, which can be overcome by NAC even in the TGF beta1-rich milieu.}, }
@article {pmid17489966, year = {2007}, author = {Damiani, CR and Benetton, CA and Stoffel, C and Bardini, KC and Cardoso, VH and Di Giunta, G and Pinho, RA and Dal-Pizzol, F and Streck, EL}, title = {Oxidative stress and metabolism in animal model of colitis induced by dextran sulfate sodium.}, journal = {Journal of gastroenterology and hepatology}, volume = {22}, number = {11}, pages = {1846-1851}, doi = {10.1111/j.1440-1746.2007.04890.x}, pmid = {17489966}, issn = {0815-9319}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents/*pharmacology/therapeutic use ; Antioxidants/*pharmacology/therapeutic use ; Colitis, Ulcerative/chemically induced/*drug therapy/metabolism/pathology ; Colon/*drug effects/enzymology/metabolism/pathology ; Deferoxamine/*pharmacology/therapeutic use ; Dextran Sulfate ; Disease Models, Animal ; Electron Transport Complex II/metabolism ; Electron Transport Complex IV/metabolism ; Gastrointestinal Agents/*pharmacology/therapeutic use ; Leukocyte Count ; Lipid Peroxidation/drug effects ; Male ; Mitochondria/drug effects/enzymology/metabolism ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Succinate Dehydrogenase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {BACKGROUND AND AIM: Ulcerative colitis is a chronic inflammatory disease of the gastrointestinal tract. Its etiology remains unclear, but it appears to result from a dysregulated immune response, with infiltration of phagocytic leukocytes into the mucosal interstitium. The production and release of reactive oxygen species by immune cells seems to play a crucial role in physiopathology of colitis. The aim of this work was to evaluate the effects of N-acetylcysteine (NAC) and deferoxamine (DFX) in the treatment of colitis induced by dextran sulfate sodium (DSS).<br><br>METHODS: The effects of NAC and DRX on rats with DSS-induced colitis were determined by measuring intestinal parameters of oxidative stress and mitochondrial function, inflammatory response and bowel histopathological alterations.<br><br>RESULTS: DSS increased white blood cells count and NAC and DFX did not prevent this effect. However, DSS increased mitochondrial respiratory chain complex IV in colon of rats and NAC and DFX prevented this alteration. In addition, thiobarbituric acid reactive substances were increased in colon of DSS-treated rats. NAC and DFX, when taken together, prevented this effect. Complex II and succinate dehydrogenase were not affected by DSS, as protein carbonyl content.<br><br>CONCLUSIONS: It is speculated that NAC and DFX might be useful for treatment of colitis, but further research is necessary to clarify these effects.}, }
@article {pmid17487501, year = {2007}, author = {Li, JL and Liu, N and Chen, XH and Sun, M and Wang, CB}, title = {Inhibition of UVA-induced apoptotic signaling pathway by polypeptide from Chlamys farreri in human HaCaT keratinocytes.}, journal = {Radiation and environmental biophysics}, volume = {46}, number = {3}, pages = {263-268}, pmid = {17487501}, issn = {0301-634X}, mesh = {Animals ; Apoptosis/drug effects/*radiation effects ; Caspase 3/metabolism/radiation effects ; Cell Culture Techniques ; Cell Line ; Coloring Agents ; DNA Fragmentation ; Flow Cytometry ; Humans ; Keratinocytes/cytology/drug effects/physiology/*radiation effects ; Pectinidae ; Peptides/isolation &amp; purification/*pharmacology ; Signal Transduction/drug effects/radiation effects ; *Ultraviolet Rays ; }, abstract = {Chronic UVA irradiation has been reported to induce photoaging and photocarcinogenesis. UVA is a potent inducer of reactive oxygen species (ROS), which can induce various biological processes, including apoptosis. Polypeptide from Chlamys farreri (PCF) is a novel marine active material isolated from the gonochoric Chinese scallop C. farreri. In our previous studies, PCF was found to be an effective antioxidant inhibiting UVA-induced ROS production and a potential inhibitory agent for UVA-induced apoptosis in the human keratinocyte cell line HaCaT. The intracellular mechanisms of how PCF protects HaCaT cells from UVA-induced apoptosis are not understood. Thus, we here investigate the effect of PCF on UVA-induced intracellular signaling of apoptosis. Pretreatment with the ROS scavenger N-acetylcysteine (NAC), the p38 MAPK inhibitor SB203580 or the caspase-3 inhibitor Ac-DEVD-CHO was found to effectively prevent UVA-induced apoptosis, indicating that ROS, p38 MAPK and caspase-3 play important roles in apoptosis. H(2)O(2)-induced apoptosis was attenuated by PCF, suggesting that PCF plays its anti-apoptotic role through its antioxidant activity. In addition, PCF treatment inhibited UVA-induced p38 MAPK activation and caspase-3 activation, as assayed by Western blot analysis and flow cytometry, respectively. Our results suggest that PCF attenuates UVA-induced apoptosis through a reduction of ROS generation and diminished p38 MAPK and caspase-3 activation.}, }
@article {pmid17487136, year = {2007}, author = {Samuhasaneeto, S and Thong-Ngam, D and Kulaputana, O and Patumraj, S and Klaikeaw, N}, title = {Effects of N-acetylcysteine on oxidative stress in rats with non-alcoholic steatohepatitis.}, journal = {Journal of the Medical Association of Thailand = Chotmaihet thangphaet}, volume = {90}, number = {4}, pages = {788-797}, pmid = {17487136}, issn = {0125-2208}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Dietary Fats/administration &amp; dosage ; Disease Models, Animal ; Fatty Liver/*drug therapy/pathology ; Free Radical Scavengers/*administration &amp; dosage ; Hepatitis/*drug therapy/pathology ; Liver/*drug effects/pathology ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: Prove the attenuated effects of N-acetylcysteine (NAC) on oxidative stress in rats with nonalcoholic steatohepatitis (NASH).<br><br>MATERIAL AND METHOD: Male Sprague-Dawley rats were randomly divided into five groups. Group I (normal control) was fed regular dry rat chow (RC) for 6 weeks. Group 2 (NASH) was fed 100% fat diet for 6 weeks. Group 3-5 were fed 100% fat diet for 6 weeks, and then switched to RC alone (NASH + diet ; group 3), to RC + 20 mg/kg/day of NAC orally (NASH + diet + NAC20; group 4) or to RC + 500 mg/kg/day of NAC orally (NASH + diet + NAC500; group 5) for 4 weeks, respectively. They were sacrificed to collect blood and liver samples at the end of the present study.<br><br>RESULTS: Levels of total glutathione (GSH), serum cholesterol, and hepatic malondialdehyde (MDA) were increased significantly in the NASH group compared with normal control. Liver histopathology from group 2 showed moderate to severe macrovesicular steatosis, hepatocyte ballooning, and necroinflammation. Treatment with diet or diet plus NAC reduced the levels of GSH, cholesterol, and hepatic MDA back to normal. Liver sections from group 3-5 showed a decrease in fat deposition and necroinflammation in hepatocytes. However, no differences on all variables existed between diet alone and diet plus NAC groups.<br><br>CONCLUSION: Our data indicate that diet or diet plus NAC treatment could attenuate oxidative stress and improve liver histopathology of NASH. However the addition of NAC is not better than diet treatment alone.}, }
@article {pmid17483607, year = {2007}, author = {Sanli, A and Eken, M and Evren, C and Ateş, G and Paksoy, M}, title = {Does topical N-acetylcysteine application after myringotomy cause severe otorrhea?.}, journal = {Kulak burun bogaz ihtisas dergisi : KBB = Journal of ear, nose, and throat}, volume = {17}, number = {1}, pages = {22-25}, pmid = {17483607}, issn = {1300-7475}, mesh = {Acetylcysteine/administration &amp; dosage/*adverse effects ; Administration, Topical ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/*adverse effects ; Guinea Pigs ; Otitis Media, Suppurative/*chemically induced/pathology ; Severity of Illness Index ; Tympanic Membrane Perforation/*drug therapy/pathology ; }, abstract = {OBJECTIVES: The effect of topical N-acetylcysteine (NAC) application was investigated on the healing of acute experimental tympanic membrane perforations.<br><br>MATERIALS AND METHODS: Twenty guinea pigs were used in this study. Under intraperitoneal ketamine anesthesia, incisional myringotomies were performed in the posterosuperior quadrant of the tympanic membranes with a straight otologic hook. The diameter of the perforations was approximately 2 mm. Perforations in both ears were treated with freshly prepared sponges soaked in either 0.1 ml 0.9% NaCl solution (10 control animals) or 0.6 mg/0.1 ml NAC (10 animals) for three consecutive days. All the tympanic membranes were examined by otomicroscopy on the third, fifth, seventh, and ninth days.<br><br>RESULTS: In the control group, all the perforations were completely closed at the end of nine days. During the same period, only 40% of the perforations were completely closed in the NAC group. The remaining ears exhibited otorrhea by the third day.<br><br>CONCLUSION: N-acetylcysteine may cause severe otorrhea in the healing process of tympanic membrane perforations. Further studies including histopathological examinations are required to elucidate this condition.}, }
@article {pmid17482099, year = {2006}, author = {Al-Ghonaim, M and Pannu, N}, title = {Prevention and treatment of contrast-induced nephropathy.}, journal = {Techniques in vascular and interventional radiology}, volume = {9}, number = {2}, pages = {42-49}, doi = {10.1053/j.tvir.2006.12.002}, pmid = {17482099}, issn = {1089-2516}, mesh = {Acute Kidney Injury/*chemically induced/prevention &amp; control/*therapy ; Contrast Media/*adverse effects ; Humans ; Risk Factors ; }, abstract = {Contrast-induced nephropathy (CIN) is a well-known complication of therapeutic and diagnostic procedures requiring contrast administration and accounts for 10 to 12% of acute renal failure in hospitalized patients. Although the incidence of this complication is relatively low, its consequences can be catastrophic. The development of CIN is associated with increased hospital length of stay, an increased requirement for acute dialysis, and an increased risk of death. Preexisting renal dysfunction, age, diabetes, congestive heart failure, and volume of administered contrast are all associated with a risk of developing CIN. Despite a large number of clinical trials that have evaluated prophylaxis strategies for CIN, only the use of hemofiltration and N-acetylcysteine (NAC) in specific subgroups of patients have been shown to reduce dialysis requirement and mortality in patients undergoing angiographic procedures. In this review we will discuss the epidemiology and the risk factors for CIN and the evidence for commonly employed prophylaxis strategies, and we will provide general recommendations with respect to CIN prevention and management.}, }
@article {pmid17481927, year = {2007}, author = {Bağriaçik, E&#xdc; and Uslu, K and Yurtçu, E and Stefek, M and Karasu, C}, title = {Stobadine inhibits doxorubicin-induced apoptosis through a caspase-9 dependent pathway in P815 mastocytoma cells.}, journal = {Cell biology international}, volume = {31}, number = {9}, pages = {979-984}, doi = {10.1016/j.cellbi.2007.03.008}, pmid = {17481927}, issn = {1065-6995}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Carbolines/*pharmacology ; Caspase 9/*metabolism ; Caspase Inhibitors ; Doxorubicin/*pharmacology ; Mastocytoma/*enzymology/*pathology ; Mice ; Necrosis ; }, abstract = {Doxorubicin (DOXO), a widely used chemotherapeutic agent, induces apoptosis in transformed and non-transformed cells. The apoptotic effect of DOXO has been linked to the generation of reactive oxygen species (ROS). Antioxidants may be effective in the prevention of DOX-induced apoptosis. In the present study we investigated the effects of stobadine, a pyridoindole antioxidant in a DOXO-induced apoptosis model of P815 cells by flow cytometric analyses and by measuring caspase-3 and caspase-9 activities. Pretreating cells with stobadine significantly increased cell viability and decreased apoptosis rate. Inhibition in apoptosis was observed at maximum levels following treatment of cells with 10(-7)M stobadine as evident from flow cytometric analyses. The antiapoptotic effect of stobadine was further confirmed by inhibition of caspase-3 and caspase-9 activities. We found that the antioxidative effects of stobadine were comparable to the effects of a well known antioxidant, N-acetyl l-cysteine (NAC).}, }
@article {pmid17481858, year = {2007}, author = {Park, ES and Kim, SY and Na, JI and Ryu, HS and Youn, SW and Kim, DS and Yun, HY and Park, KC}, title = {Glutathione prevented dopamine-induced apoptosis of melanocytes and its signaling.}, journal = {Journal of dermatological science}, volume = {47}, number = {2}, pages = {141-149}, doi = {10.1016/j.jdermsci.2007.03.009}, pmid = {17481858}, issn = {0923-1811}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/physiology ; Blotting, Western ; Cell Line, Transformed ; Dopamine/*toxicity ; Dopamine Agents/*toxicity ; Glutathione/*metabolism ; Melanocytes/cytology/*drug effects/*metabolism ; Mice ; Oxidative Stress/drug effects/physiology ; Signal Transduction/drug effects/physiology ; Vitiligo/metabolism/pathology ; }, abstract = {BACKGROUND: Dopamine (DA), a monoamine neurotransmitter, is a well-known neurotoxin and plays an etiologic role in neurodegenerative disorders such as Parkinson's disease. DA exerts its toxic effect by generation of reactive oxygen species and quinone product. Vitiligo, a depigmentary disorder of the skin and hair characterized by selective destruction of melanocytes, has been reported to show increased levels of DA with onset and progression of the disease.<br><br>OBJECTIVE: The aim of this study is to investigate the cytotoxic effect of DA on melanocytes and to search for protective antioxidants against DA-induced toxicity. In addition, molecular mechanism of cell death was also investigated.<br><br>METHODS: Cells were treated with DA and cell viabilities were measured by crystal violet staining method. To investigate the cytoprotective activity of various antioxidants, vitamin C, vitamin E, Trolox, quercetin, N-acetylcysteine (NAC) and l-glutathione (GSH) were used. To study cytoprotective effects of NAC and GSH, Mel-Ab cells and cultured normal human melanocytes were pretreated with NAC or GSH, then DA solution was added. DA-induced apoptosis and activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) were also observed by flow cytometric analysis and Western blotting.<br><br>RESULTS: The viability of DA-treated Mel-Ab cells significantly decreased in a dose-dependent manner while keratinocytes were much more resistant to DA-toxicity, which was a consistent finding with the selective melanocyte loss observed in vitiligo. Among various antioxidants used in this study, only thiol-containing antioxidants such as NAC or GSH inhibited both JNK and p38 MAPK activation and apoptosis, indicating the unique protective capacity of thiol compounds. Cultured normal human melanocytes were also susceptible to DA and thiol compounds were very efficiently protective against DA-induced cytotoxicity.<br><br>CONCLUSION: DA-induced apoptosis and cytoprotective effect of thiol compounds shown in this study could be a clue to understand pathogenesis of viltigo and provide a new therapeutic strategy.}, }
@article {pmid17479278, year = {2007}, author = {Wiesenhütter, B and Selinski, S and Golka, K and Brüning, T and Bolt, HM}, title = {Re-assessment of the influence of polymorphisms of phase-II metabolic enzymes on renal cell cancer risk of trichloroethylene-exposed workers.}, journal = {International archives of occupational and environmental health}, volume = {81}, number = {2}, pages = {247-251}, pmid = {17479278}, issn = {0340-0131}, mesh = {*Genetic Predisposition to Disease ; Germany ; Glutathione Transferase/*genetics ; Humans ; Kidney Neoplasms/*chemically induced/enzymology/genetics ; *Occupational Exposure ; Polymorphism, Genetic/*genetics ; Risk Assessment ; Trichloroethylene/adverse effects/*pharmacology ; }, abstract = {PROBLEM: Individual differences in susceptibility to trichloroethylene-induced nephrocarcinogenicity may be conferred by genetic polymorphisms of glutathione S-transferases (GST), because enzymes of this group are pivotal for the metabolic activation of trichloroethylene. Because of a potential involvement of N-acetylation in the detoxication of reactive trichloroethylene metabolite(s) to N-acetyl-cysteine derivatives, polymorphisms of the NAT2 gene may also be relevant.<br><br>METHODS: The primary collective used for a re-investigation of these questions was that of a hospital-based case-control study by Br&#xfc;ning et al. (Am J Ind Med 43:274-285, 2003) of 134 renal cell cancer cases (20 cases exposed to trichloroethylene) and 401 matched controls. Genetic polymorphisms of GSTT1, GSTM1, GSTP1 and NAT2 were studied. Additional control collectives of non-diseased persons were used for comparison of allele frequencies.<br><br>RESULTS: No genetic influences on the development of renal cancer due to trichloroethylene were apparent, related to the deletion polymorphisms of GSTT1 and GSTM1, as well as to the NAT2 rapid/slow acetylator states. However, renal cell cancer cases displayed a somewhat higher proportion of the homozygous GSTP1 313A wild type (GSTP1*A), although this was not statistically significant (chi(2) test: P=0.1071, when using only the original controls of Br&#xfc;ning et al. (2003); P=0.0781 with inclusion of the additional controls).<br><br>CONCLUSION: The re-investigation does not confirm the working hypothesis of an influence of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 on renal cell cancer development due to high occupational exposures to trichloroethylene.}, }
@article {pmid17478966, year = {2005}, author = {Bielefeld, EC and Hynes, S and Pryznosch, D and Liu, J and Coleman, JK and Henderson, D}, title = {A comparison of the protective effects of systemic administration of a pro-glutathione drug and a Src-PTK inhibitor against noise-induced hearing loss.}, journal = {Noise &amp; health}, volume = {7}, number = {29}, pages = {24-30}, doi = {10.4103/1463-1741.31875}, pmid = {17478966}, issn = {1463-1741}, support = {1 P01 DC03600-01A1/DC/NIDCD NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Apoptosis/drug effects ; Auditory Threshold/drug effects ; Chinchilla ; Disease Models, Animal ; Electrodes ; Environmental Exposure/adverse effects ; Evoked Potentials, Auditory/*drug effects ; Glutathione/*administration &amp; dosage/pharmacology ; Hearing Loss, Noise-Induced/drug therapy/*prevention &amp; control ; Inferior Colliculi/physiology ; Injections, Intraperitoneal ; Noise/*adverse effects ; Protein Kinase Inhibitors/*administration &amp; dosage/pharmacology ; Reactive Oxygen Species/*adverse effects ; Time Factors ; src-Family Kinases/administration &amp; dosage/*antagonists &amp; inhibitors/pharmacology ; }, abstract = {Both the antioxidant, n-l-acetyl cysteine (L-NAC) and the Src inhibitor, KX1-004, have been used to protect the cochlea from hazardous noise. To date, KX1-004 has only been used locally on the round window. In the current study, the two drugs were administered systemically. LNAC was delivered intraperitoneally at a dose of 325 mg/kg while KX1-004 was administered subcutaneously at a dose of 50 mg/kg. The noise exposure consisted of a 4 kHz octave band of noise at 100 dB SPL for 6 hours/day for 4 days. The drugs were administered once each day, 30 minutes prior to the onset of the noise exposure. The animals' hearing was estimated using the evoked response records from surgically-implanted chronic electrodes in the inferior colliculi. Animals treated with LNAC and KX1-004 had from 10 to 20 dB less temporary threshold shift at day 1 and an average 10 dB less permanent threshold shift by day 21 when compared to control saline treated animals. There were no significant side effects (i.e.: appetite loss, weight loss, lethargy, etc.) related to either of the drug treatments. KX1-004 produced at least as much protection as L-NAC, but at a significantly lower concentration.}, }
@article {pmid17478559, year = {2007}, author = {Aoki, N and Jin-no, S and Nakagawa, Y and Asai, N and Arakawa, E and Tamura, N and Tamura, T and Matsuda, T}, title = {Identification and characterization of microvesicles secreted by 3T3-L1 adipocytes: redox- and hormone-dependent induction of milk fat globule-epidermal growth factor 8-associated microvesicles.}, journal = {Endocrinology}, volume = {148}, number = {8}, pages = {3850-3862}, doi = {10.1210/en.2006-1479}, pmid = {17478559}, issn = {0013-7227}, mesh = {3T3-L1 Cells ; Adipocytes/*metabolism/ultrastructure ; Animals ; Antigens, Surface/isolation &amp; purification/*metabolism ; Apoptosis ; Cell Fractionation ; Cell Membrane/metabolism/ultrastructure ; Chromatography, High Pressure Liquid ; Culture Media, Conditioned/metabolism ; Exocytosis/*physiology ; Hormones/metabolism ; Humans ; Jurkat Cells ; Male ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Microscopy, Electron, Transmission ; Milk Proteins/isolation &amp; purification/*metabolism ; NIH 3T3 Cells ; Obesity/*metabolism/pathology ; Oxidation-Reduction ; Phospholipids/metabolism ; Proteomics ; Secretory Vesicles/*metabolism/ultrastructure ; Sucrose ; Ultracentrifugation ; }, abstract = {Adipocytes are now recognized as endocrine cells secreting adipocytokines, regulating multiple metabolic pathways. In this study, we addressed secretion of microvesicles by 3T3-L1 adipocytes. We found that MFG-E8, one of the exosomal proteins, was present in the microvesicles and was distributed in the sucrose density fractions with 1.13-1.20 g/ml, which has been reported for exosomes. Several integral, cytosolic, and nuclear proteins such as caveolin-1, c-Src kinase, and heat shock protein 70 were also found to be microvesicle components. Unexpectedly, adiponectin was also substantially distributed in the microvesicle fractions. Furthermore, proteomic analysis of the microvesicles revealed that many other proteins such as extracellular matrix-related proteins were also present. Microvesicles secreted by 3T3-L1 adipocytes exhibited heterogeneity in size and comprised both smaller exosome-like and larger membrane vesicles as revealed by electron microscopy. Milk fat globule-epidermal growth factor 8 (MFG-E8)-associated adiposomes exhibited binding activity toward phosphatidylserine and apoptotic cells. MFG-E8 in the microvesicles was reduced when cultured in the low-glucose medium or cultured in the high-glucose medium with antioxidant N-acetyl cysteine. Insulin and TNF-alpha also up-regulated MFG-E8 in the microvesicles. Moreover, MFG-E8 was strongly up-regulated in the hypertrophic adipose tissue, predominantly in adipocyte fractions, of diet-induced obese C57BL/6 mice, where increased oxidative stress is induced. Thus, it is suggested that microvesicles, especially MFG-E8-associated ones, modulate adipose functions under redox- and hormone-dependent regulation. Based on the above findings, the adipocyte-derived microvesicles were named adiposomes.}, }
@article {pmid17477423, year = {2007}, author = {Galhardo, MA and Júnior, CQ and Riboli Navarro, PG and Morello, RJ and Simões, Mde J and Montero, EF}, title = {Liver and lung late alterations following hepatic reperfusion associated to ischemic preconditioning or N-acetylcysteine.}, journal = {Microsurgery}, volume = {27}, number = {4}, pages = {295-299}, doi = {10.1002/micr.20359}, pmid = {17477423}, issn = {0738-1085}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Aspartate Aminotransferases/blood ; Free Radical Scavengers/*therapeutic use ; *Ischemic Preconditioning/methods ; Liver/blood supply/*pathology ; Liver Circulation/physiology ; Lung/blood supply/*pathology ; Male ; Random Allocation ; Rats ; Rats, Wistar ; Reperfusion Injury/*pathology/prevention &amp; control ; Time Factors ; }, abstract = {This study aimed the effect of n-acetylcysteine or ischemic preconditioning in hepatic and pulmonary damage after liver ischemia-reperfusion injury. Twenty-four male Wistar-EPM rats were assigned into four groups: (IR) Hepatic ischemia-reperfusion; (IPC) IPC achieved before hepatic ischemia; (NAC) Animals received NAC pretreatment; and Sham operated group. After 24 h of hepatic reperfusion, blood, liver, and pulmonary samples were evaluated. Nonparametric tests were used (P <or= 0.05). Aspartate aminotransferase levels were similar among experimental groups. Lower alanine aminotrasnferase levels were observed in sham group (P = 0.04). IPC and NAC groups prevented from necrosis (P = 0.027), apoptosis (P = 0.003), and microvesicular steatosis (P = 0.0007), but not from neutrophil infiltration in liver tissue. IPC and NAC treatment reduced alveolar septal edema (P = 0.014), but did not prevent from neutrophil infiltration or vascular congestion. In conclusion, IPC and NAC attenuated hepatic and pulmonary damage after hepatic ischemia-reperfusion injury.}, }
@article {pmid17475277, year = {2007}, author = {Lee, HJ and Oh, YK and Rhee, M and Lim, JY and Hwang, JY and Park, YS and Kwon, Y and Choi, KH and Jo, I and Park, SI and Gao, B and Kim, WH}, title = {The role of STAT1/IRF-1 on synergistic ROS production and loss of mitochondrial transmembrane potential during hepatic cell death induced by LPS/d-GalN.}, journal = {Journal of molecular biology}, volume = {369}, number = {4}, pages = {967-984}, doi = {10.1016/j.jmb.2007.03.072}, pmid = {17475277}, issn = {0022-2836}, mesh = {Acetylcysteine/metabolism ; Animals ; Apoptosis/physiology ; Cells, Cultured ; Enzyme Inhibitors/metabolism ; Free Radical Scavengers/metabolism ; Galactosamine/*pharmacology ; *Hepatocytes/drug effects/physiology ; Humans ; Interferon Regulatory Factor-1/genetics/*metabolism ; Interferon-gamma/genetics/metabolism ; Lipid Peroxidation ; Lipopolysaccharides/*pharmacology ; Male ; Membrane Potentials/drug effects/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/drug effects/*metabolism ; NF-kappa B/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; STAT1 Transcription Factor/genetics/*metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism ; omega-N-Methylarginine/metabolism ; }, abstract = {Previously, we demonstrated that signal transducer and activator of transcription factor 1 (STAT1) plays an essential role in liver injury induced by lipopolysaccharide (LPS)/D-galactosamine (D-GalN); however, the underlying mechanism involved remains unclear. Here, we showed that LPS/D-GalN administration induced secretion of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma), which mediated apoptosis synergistically. Moreover, LPS/D-GalN-induced apoptosis was associated with increased inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production, as well as elevated reactive oxygen species (ROS) production, which were all strongly inhibited by treatment with the antioxidant N-acetyl-L-cysteine (NAC) and an iNOS/NO inhibitor, L-NMMA. Although STAT1 activation and expression did not change significantly in TNF-alpha/IFN-gamma-cotreated cells compared with cells treated with IFN-gamma alone, the absence of STAT1 or interferon regulatory factor 1 (IRF-1) in genetic knockout mice strongly abrogated the observed effects of TNF-alpha/IFN-gamma on iNOS/NO induction, ROS production, loss of mitochondrial transmembrane potential (DeltaPsim), and apoptosis compared with STAT1(+/+) and IRF-1(+/+) mice. Additionally, the synergistic effects of TNF-alpha/IFN-gamma on iNOS/NO induction, ROS production, and apoptosis were significantly inhibited by overexpression of dominant negative STAT1 in contrast to overexpression of wild-type STAT1. In STAT1-deficient mice, nuclear factor kappaB (NF-kappaB) activation by TNF-alpha/IFN-gamma was attenuated and strongly inhibited by both NAC and L-NMMA. Moreover, the proteasome inhibitor, MG132, inhibited NF-kappaB activation and strongly inhibited iNOS/NO induction, ROS production, and loss of DeltaPsim induced by TNF-alpha/IFN-gamma, thereby inhibiting apoptosis. Interestingly, it appears peroxynitrite, which is produced by TNF-alpha/IFN-gamma, may interfere with STAT1 phosphorylation by inducing STAT1 nitration. Collectively, these findings demonstrate that TNF-alpha/IFN-gamma synergistically potentiates iNOS/NO induction, ROS production, and loss of DeltaPsim via STAT1 overexpression, playing an important role in promoting apoptosis and liver injury induced by LPS/D-GalN.}, }
@article {pmid17467761, year = {2007}, author = {Bridges, CC and Battle, JR and Zalups, RK}, title = {Transport of thiol-conjugates of inorganic mercury in human retinal pigment epithelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {221}, number = {2}, pages = {251-260}, pmid = {17467761}, issn = {0041-008X}, support = {ES11288/ES/NIEHS NIH HHS/United States ; R01 ES011288-05/ES/NIEHS NIH HHS/United States ; R01 ES005980-12/ES/NIEHS NIH HHS/United States ; F32 ES012556/ES/NIEHS NIH HHS/United States ; R01 ES005980/ES/NIEHS NIH HHS/United States ; R01 ES011288/ES/NIEHS NIH HHS/United States ; ES05980/ES/NIEHS NIH HHS/United States ; ES012556/ES/NIEHS NIH HHS/United States ; F32 ES012556-03/ES/NIEHS NIH HHS/United States ; }, mesh = {Base Sequence ; Cell Line ; DNA Primers ; Humans ; Mercury/*metabolism ; Pigment Epithelium of Eye/cytology/*metabolism ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Inorganic mercury (Hg(2+)) is a prevalent environmental contaminant to which exposure to can damage rod photoreceptor cells and compromise scotopic vision. The retinal pigment epithelium (RPE) likely plays a role in the ocular toxicity associated with Hg(2+) exposure in that it mediates transport of substances to the photoreceptor cells. In order for Hg(2+) to access photoreceptor cells, it must first be taken up by the RPE, possibly by mechanisms involving transporters of essential nutrients. In other epithelia, Hg(2+), when conjugated to cysteine (Cys) or homocysteine (Hcy), gains access to the intracellular compartment of the target cells via amino acid and organic anion transporters. Accordingly, the purpose of the current study was to test the hypothesis that Cys and Hcy S-conjugates of Hg(2+) utilize amino acid transporters to gain access into RPE cells. Time- and temperature-dependence, saturation kinetics, and substrate-specificity of the transport of Hg(2+), was assessed in ARPE-19 cells exposed to the following S-conjugates of Hg(2+): Cys (Cys-S-Hg-S-Cys), Hcy (Hcy-S-Hg-S-Hcy), N-acetylcysteine (NAC-S-Hg-S-NAC) or glutathione (GSH-S-Hg-S-GSH). We discovered that only Cys-S-Hg-S-Cys and Hcy-S-Hg-S-Hcy were taken up by these cells. This transport was Na(+)-dependent and was inhibited by neutral and cationic amino acids. RT-PCR analyses identified systems B(0,+) and ASC in ARPE-19 cells. Overall, our data suggest that Cys-S-Hg-S-Cys and Hcy-S-Hg-S-Hcy are taken up into ARPE-19 cells by Na-dependent amino acid transporters, possibly systems B(0,+) and ASC. These amino acid transporters may play a role in the retinal toxicity observed following exposure to mercury.}, }
@article {pmid17467183, year = {2007}, author = {Capela, JP and Macedo, C and Branco, PS and Ferreira, LM and Lobo, AM and Fernandes, E and Remião, F and Bastos, ML and Dirnagl, U and Meisel, A and Carvalho, F}, title = {Neurotoxicity mechanisms of thioether ecstasy metabolites.}, journal = {Neuroscience}, volume = {146}, number = {4}, pages = {1743-1757}, doi = {10.1016/j.neuroscience.2007.03.028}, pmid = {17467183}, issn = {0306-4522}, mesh = {3,4-Methylenedioxyamphetamine/administration &amp; dosage ; Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Caspase 3/metabolism ; Cell Death/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology ; Deoxyepinephrine/administration &amp; dosage/analogs &amp; derivatives ; Dose-Response Relationship, Drug ; Drug Interactions ; Embryo, Mammalian ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Hallucinogens/chemistry/*metabolism/*toxicity ; N-Methyl-3,4-methylenedioxyamphetamine/administration &amp; dosage/chemistry/*metabolism/*toxicity ; Neurons/*drug effects ; Rats ; Rats, Wistar ; Temperature ; Time Factors ; }, abstract = {3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy"), is a widely abused, psychoactive recreational drug that is known to induce neurotoxic effects. Human and rat hepatic metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, which are both catechols that can undergo oxidation to the corresponding ortho-quinones. Ortho-quinones may be conjugated with glutathione (GSH) to form glutathionyl adducts, which can be transported into the brain and metabolized to the correspondent N-acetylcysteine (NAC) adducts. In this study we evaluated the neurotoxicity of nine MDMA metabolites, obtained by synthesis: N-Me-alpha-MeDA, alpha-MeDA and their correspondent GSH and NAC adducts. The studies were conducted in rat cortical neuronal cultures, for a 6 h of exposure period, under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings show that thioether MDMA metabolites are strong neurotoxins, significantly more than their correspondent parent catechols. On the other hand, N-Me-alpha-MeDA and alpha-MeDA are more neurotoxic than MDMA. GSH and NAC conjugates of N-Me-alpha-MeDA and alpha-MeDA induced a concentration dependent delayed neuronal death, accompanied by activation of caspase 3, which occurred earlier in hyperthermic conditions. Furthermore, thioether MDMA metabolites time-dependently increased the production of reactive species, concentration-dependently depleted intracellular GSH and increased protein bound quinones. Finally, thioether MDMA metabolites induced neuronal death and oxidative stress was prevented by NAC, an antioxidant and GSH precursor. This study provides new insights into the neurotoxicity mechanisms of thioether MDMA metabolites and highlights their importance in "ecstasy" neurotoxicity.}, }
@article {pmid17462539, year = {2007}, author = {Martín, V and Herrera, F and García-Santos, G and Antolín, I and Rodriguez-Blanco, J and Rodriguez, C}, title = {Signaling pathways involved in antioxidant control of glioma cell proliferation.}, journal = {Free radical biology &amp; medicine}, volume = {42}, number = {11}, pages = {1715-1722}, doi = {10.1016/j.freeradbiomed.2007.02.028}, pmid = {17462539}, issn = {0891-5849}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain Neoplasms/*metabolism ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cyclin-Dependent Kinase Inhibitor p21 ; Glioma/*metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; NF-kappa B/metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Up-Regulation ; }, abstract = {Tumor cells are able to survive and proliferate despite the higher-than-average level of reactive oxygen species (ROS) they exhibit. This is generally taken as a clue as to the implications of ROS in cell proliferation. In fact many mitogenic intracellular signaling pathways could be redox regulated, more particularly those involving tyrosine kinase receptors (RTK). In the present work we use N-acetylcysteine (NAC)-a well-known antioxidant molecule-to study the implications of cellular redox state on rat C6 glioma cell proliferation. NAC is shown to decrease glioma cell proliferation, inducing a cell cycle arrest in the G(0)/G(1) phase and markedly up-regulating p21 expression. A rapid, and glutathione-independent, decrease in intracellular oxidants was observed as well. NAC also lowers Akt activity, extracellular signal-regulated kinase 1/2, and the redox-sensitive transcription factor NF-kappaB, all of which are ROS related and seem to be in close connection with cell proliferation. NAC effects apparently relate to protein kinase C (PKC) activity because 100 nM TPA-a PKC activator-induces a partial blockage of the NAC antiproliferative effect. Bringing our results together, it seems that intracellular reduction of oxidants in C6 glioma cells can induce inhibition of cell proliferation by modulating RTK-related intracellular signaling pathways.}, }
@article {pmid17461432, year = {2008}, author = {Kaya, H and Koc, A and Sogut, S and Duru, M and Yilmaz, HR and Uz, E and Durgut, R}, title = {The protective effect of N-acetylcysteine against cyclosporine A-induced hepatotoxicity in rats.}, journal = {Journal of applied toxicology : JAT}, volume = {28}, number = {1}, pages = {15-20}, doi = {10.1002/jat.1245}, pmid = {17461432}, issn = {0260-437X}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Antioxidants/*therapeutic use ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury ; *Cyclosporine ; Glutathione Peroxidase/metabolism ; Liver/drug effects/metabolism/pathology ; Liver Diseases/*drug therapy/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Nitric Oxide/metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {The immunosuppressive agent cyclosporine A (CsA) has been reported to exert measurable hepatotoxic effects. One of the causes leading to hepatotoxicity is thought to be reactive oxygen radical formation. The aim of this study was to investigate the effects of N-acetylcysteine (NAC) treatment on CsA-induced hepatic damage by both analysing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), aspartate aminotransferase (AST) and alanine transaminase (ALT) activities with malondialdehyde (MDA) and nitric oxide (NO) levels, and using an histological approach. CsA administration produced a decrease in hepatic SOD activity, and co-administration of NAC with CsA resulted in an increase in SOD activity. MDA and NO levels increased in the CsA group and NAC treatment prevented those increases. A significant elevation in serum AST and ALT activities was observed in the CsA group, and when NAC and CsA were co-administered, the activities of AST and ALT were close to the control levels. CsA treatment caused evident morphological alterations. Control rats showed no abnormality in the cytoarchitecture of the hepatic parenchyma. The co-administration of NAC with CsA showed no signs of alteration and the morphological pattern was almost similar to the control group. In conclusion, CsA induced liver injury and NAC treatment prevented the toxic side effects induced by CsA administration through the antioxidant and radical scavenging effects of NAC.}, }
@article {pmid17458902, year = {2007}, author = {Lin, CW and Yang, LY and Shen, SC and Chen, YC}, title = {IGF-I plus E2 induces proliferation via activation of ROS-dependent ERKs and JNKs in human breast carcinoma cells.}, journal = {Journal of cellular physiology}, volume = {212}, number = {3}, pages = {666-674}, doi = {10.1002/jcp.21061}, pmid = {17458902}, issn = {0021-9541}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Antineoplastic Agents/chemistry/*pharmacology ; Antioxidants/pharmacology ; Breast Neoplasms/enzymology/*metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Estradiol/*metabolism ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/*metabolism ; Female ; Flavanones/pharmacology ; Flavonoids/chemistry/*pharmacology ; Glycosides/pharmacology ; Humans ; Insulin Receptor Substrate Proteins ; Insulin-Like Growth Factor I/*metabolism ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/genetics/*metabolism ; MAP Kinase Kinase Kinases/genetics/metabolism ; Molecular Structure ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-jun/metabolism ; Quercetin/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Structure-Activity Relationship ; Transfection ; }, abstract = {Induction of 17beta-estradiol (E2) and insulin-like growth factor-I (IGF-I) has been detected in breast carcinoma, however the interaction between E2 and IGF-I in the proliferation of breast carcinoma cells is still unclear. In the present study, we found that IGF-I enhances the E2-induced proliferation in MCF-7 human breast carcinoma cells in accordance with stimulation of colony formation via a soft agar assay. Activation of insulin receptor substrate-1 (IRS-1) protein and extracellular signal-related kinases (ERKs) and c-Jun N-terminal kinases (JNKs), but not p38 mitogen-activated protein kinase (MAPK), via phosphorylation induction was detected in MCF-7 cells treated with IGF-I plus E2 (E2/IGF-I). E2/IGF-I-induced proliferation was blocked by chemical inhibitors of ERKs (PD98059) and JNKs (SP600125). An increase in the expression of c-Jun protein was detected in E2/IGF-I-treated MCF-7 cells, and this was inhibited by PD98059 and SP600125. Transfection of the dominant negative MEKK and JNK plasmids significantly reduced E2/IGF-I-induced proliferation with suppression of c-Jun protein expression. An increase in peroxide production was detected in E2/IGF-I-treated cells, and N-acetyl-L-cysteine (NAC) and Tiron (TIR) addition significantly inhibited E2/IGF-I-induced cell proliferation with blocking of the phosphorylation of ERKs and JNKs, and the expression of c-Jun protein. Additionally, 3-OH flavone, baicalein, and quercetin showed effective inhibitory activities against E2/IGF-I-induced proliferation through suppressing proliferative events such as phosphorylation of IRS-1, ERKs, and JNKs proteins, and induction of c-Jun protein and colony formation. These results indicate that IGF-I interacts with E2 to promote the proliferation of breast carcinoma cells via ROS-dependent MAPK activation and c-Jun protein expression. The structure-related inhibition of E2/IGF-I-induced proliferative events by flavonoids is elucidated.}, }
@article {pmid17457375, year = {2007}, author = {Feldman, L and Efrati, S and Eviatar, E and Abramsohn, R and Yarovoy, I and Gersch, E and Averbukh, Z and Weissgarten, J}, title = {Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine.}, journal = {Kidney international}, volume = {72}, number = {3}, pages = {359-363}, doi = {10.1038/sj.ki.5002295}, pmid = {17457375}, issn = {0085-2538}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Administration, Oral ; Aged ; Aminoglycosides/adverse effects/therapeutic use ; Anti-Bacterial Agents/*adverse effects/therapeutic use ; Antioxidants/administration &amp; dosage/adverse effects/*therapeutic use ; Bacteremia/prevention &amp; control ; Cysteine/blood ; Female ; Gentamicins/*adverse effects/therapeutic use ; Glutathione/blood ; Hearing Loss/*chemically induced/physiopathology/*prevention &amp; control ; Humans ; Kidney Failure, Chronic/therapy ; Male ; Middle Aged ; Oxidative Stress/physiology ; Prospective Studies ; Renal Dialysis ; }, abstract = {Aminoglycoside (AG) antibiotics are associated with several side effects, including a reversible nephrotoxicity and a permanent ototoxicity. Oxidative stress is thought to contribute to the pathophysiology of both conditions. We studied the possible protective effect of the antioxidant N-acetylcysteine (NAC) in gentamicin-induced hearing loss in hemodialysis patients. This study includes 53 hemodialysis patients scheduled to receive gentamicin for dialysis catheter-related bacteremia that were randomized to receive the antibiotic with or without NAC. Hearing function was assessed by the standard technique of pure-tone audiograms over a range of frequencies. Audiometric evaluations were performed at baseline, 1 week and at 6 weeks after the completion of gentamicin therapy. A total of 40 patients completed the study protocol with a mean duration of therapy of almost 15 days. At both 1 and 6 weeks after the completion of antibiotic therapy, there were significantly more patients exhibiting ototoxicity in the control group compared with the group receiving NAC. Additionally, significantly more patients in the control group had bilateral ototoxicity. The greatest otoprotective effect of NAC was noticed in the high audiometric tone frequencies. Taken together, our study suggests that NAC treatment may ameliorate gentamicin-induced ototoxicity in hemodialysis patients.}, }
@article {pmid17456219, year = {2007}, author = {Martinez-Losa, M and Cortijo, J and Juan, G and O'Connor, JE and Sanz, MJ and Santangelo, F and Morcillo, EJ}, title = {Inhibitory effects of N-acetylcysteine on the functional responses of human eosinophils in vitro.}, journal = {Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology}, volume = {37}, number = {5}, pages = {714-722}, doi = {10.1111/j.1365-2222.2007.02694.x}, pmid = {17456219}, issn = {0954-7894}, mesh = {Acetylcysteine/*pharmacology ; Calcium/blood ; Cell Death/drug effects ; Chemokine CCL11 ; Chemokines, CC/antagonists &amp; inhibitors/pharmacology ; Eosinophil Cationic Protein/blood ; Eosinophils/*drug effects/metabolism/physiology ; Free Radical Scavengers/*pharmacology ; Glutathione/blood ; Humans ; Luminescence ; N-Formylmethionine Leucyl-Phenylalanine/antagonists &amp; inhibitors/pharmacology ; NADPH Oxidases/blood ; Phosphoproteins/blood ; Reactive Oxygen Species/metabolism ; Translocation, Genetic/drug effects ; }, abstract = {BACKGROUND: Oxidative stress appears to be relevant in the pathogenesis of inflammation in allergic diseases like bronchial asthma. Eosinophils are oxidant-sensitive cells considered as key effectors in allergic inflammation.<br><br>OBJECTIVE: The aim of this work was to study the effects of the clinically used antioxidant N-acetyl-L-cysteine (NAC) on the functional responses of human-isolated eosinophils.<br><br>METHODS: Human eosinophils were purified from the blood of healthy donors by a magnetic bead separation system. The effects of NAC were investigated on the generation of reactive oxygen species (chemiluminescence and flow cytometry), Ca(2+) signal (fluorimetry), intracellular glutathione (GSH; flow cytometry), p47(phox)-p67(phox) translocation (Western blot) and eosinophil cationic protein (ECP) release (radioimmunoassay).<br><br>RESULTS: NAC (0.1-1 mm) inhibited the extracellular generation of oxygen species induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) and eotaxin (in the presence of IL-5) with -logIC(50) values of 3.61+/-0.03 and 3.36+/-0.09, respectively. Also, the intracellular generation of hydrogen peroxide was virtually abolished by NAC (0.5-1 mm). NAC (1 mm) did not alter the fMLP-induced Ca(2+) signal but augmented the eosinophil content of reduced GSH and inhibited p47(phox)-p67(phox) translocation. NAC inhibited the release of ECP (approximately 90% inhibition at 1 mm) from fMLP-activated eosinophils.<br><br>CONCLUSION: Inhibition by NAC of human eosinophil functions in vitro is potentially useful in the treatment of allergic inflammation.}, }
@article {pmid17455275, year = {2008}, author = {Li, YC and Huang, FM and Lee, SS and Lin, RH and Chou, MY and Chang, YC}, title = {Protective effects of antioxidants on micronuclei induced by irradiated 9-fluorenone/N,N-dimethyl-p-toluidine in CHO cells.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {84}, number = {1}, pages = {58-63}, doi = {10.1002/jbm.b.30843}, pmid = {17455275}, issn = {1552-4973}, mesh = {Acetylcysteine/pharmacology ; Algorithms ; Animals ; Antioxidants/*pharmacology ; CHO Cells ; Cell Cycle/drug effects/radiation effects ; Cell Survival/drug effects ; Cricetinae ; Cricetulus ; Fluorenes/chemistry/radiation effects/*toxicity ; Light ; *Micronucleus Tests ; Mutagens/toxicity ; Toluidines/chemistry/radiation effects/*toxicity ; }, abstract = {9-Fluorenone (9F), the aromatic photosensitizer, is widely used as an initiator in visible-light (VL) cured resin systems. There is growing concern that 9F may produce genetic damage by inducing mutation. In this study, 9F in the presence or absence of reducing agent N,N-dimethyl-p-toluidine (DMT) with or without VL irradiation was analyzed for the induction of chromosomal aberrations indicated by micronuclei (MN) induced in CHO cells. Our data demonstrated that a dose-related increase in the frequency of MN and prolonged cell cycles in 9F with or without DMT in the presence or absence of VL irradiation (p < 0.05). The rank orders with respect to genotoxicity and cytotoxicity were found to be as follows: 9F/DMT +VL > 9F/DMT = 9F + VL > 9F. To determine whether oxidative stress could modulate MN induced by 9F/DMT with or without VL irradiation in CHO cells, cells were pretreated with N-acetyl-L-cysteine (NAC), ascorbic acid, and alpha-tocopherol. The pretreatment with antioxidants could diminish not only the prolonged cell cycle but also the decreased frequency of MN which is induced by 9F with or without DMT in the presence or absence of VL irradiation in CHO cells (p < 0.05). Our findings provide the evidences for the induction of MN by 9F in the presence or absence of DMT with or without VL irradiation in CHO cells, indicating clastogenic activity of 9F/DMT in vitro. These antioxidants act as the antagonists against the genotoxicity and cytotoxicity of 9F/DMT. Thus, leaching photoinitiator and reducing agent might be contributing the sources of oxidative stress.}, }
@article {pmid17453873, year = {2007}, author = {Good, AM and Kelly, CA and Bateman, DN}, title = {Differences in treatment advice for common poisons by poisons centres--an international comparison.}, journal = {Clinical toxicology (Philadelphia, Pa.)}, volume = {45}, number = {3}, pages = {234-239}, doi = {10.1080/15563650601031601}, pmid = {17453873}, issn = {1556-3650}, mesh = {Acetaminophen/poisoning ; Antidotes/administration &amp; dosage ; Charcoal/administration &amp; dosage ; Decontamination/methods ; Emergency Treatment/*methods ; Gastric Lavage ; Humans ; *International Cooperation ; Ipecac/administration &amp; dosage ; *Poison Control Centers ; Poisoning/*therapy ; Surveys and Questionnaires ; }, abstract = {OBJECTIVE: To investigate how poisons centres advise on management of common drug poisonings and compare advice on gut decontamination with the EAPCCT/AACT Position Statements.<br><br>METHODS: An interactive questionnaire was sent to 14 poisons centres asking about working practices, "top 20" enquiries in 2002, and management of 4 specific drug poisonings.<br><br>RESULTS: Replies were received from centres in 11 countries. Annual telephone enquiry numbers varied from 620 (Sri Lanka) to over 50,000 (Germany for 2000). Recommendations for gut decontamination for acetaminophen poisoning were: activated charcoal (AC) alone (5 centres); gastric lavage (GL) alone (1); AC and/or GL (3); AC, GL and/or ipecac (2). Only 40% (4/10) recommended AC and 50% (3/6) GL within 1 hour. Intervention doses for gut decontamination ranged from 100-200 mg/kg (nine centres) and for "high-risk" groups 75-100 mg/kg (3). Plasma concentration for N-acetylcysteine (NAC) treatment ranged from 150 mg/L (four centres) to 200 mg/L (6) at 4 hours. Results were similarly varied for three other common drug poisons (benzodiazepines, amitriptyline, and paroxetine).<br><br>CONCLUSIONS: Most poisons centres have protocols that differ in terms of gut decontamination, timing, and intervention doses. Many centres recommend charcoal or gastric lavage after the 1-hour limit proposed in the Position Statements. There is scope for rationalization of approaches to the management of common poisons.}, }
@article {pmid17452691, year = {2007}, author = {Bourdeaux, C and Bewley, J}, title = {Death from paracetamol overdose despite appropriate treatment with N-acetylcysteine.}, journal = {Emergency medicine journal : EMJ}, volume = {24}, number = {5}, pages = {e31}, pmid = {17452691}, issn = {1472-0213}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Drug Overdose/complications/drug therapy ; Fatal Outcome ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Multiple Organ Failure/chemically induced ; }, abstract = {A case of death from severe paracetamol poisoning which presented early and received appropriate treatment according to evidence-based guidelines is presented here. It is very rare for patients to die from paracetamol poisoning when they receive N-acetylcysteine (NAC) within 8 h of ingestion. The patient had a marked lactic acidosis on presentation to hospital. This case demonstrates that a patient can die from paracetamol poisoning despite early and appropriate treatment, and raises the question whether lactic acidosis in a patient following paracetamol overdose should prompt the initiation of NAC treatment while awaiting paracetamol levels.}, }
@article {pmid17450321, year = {2008}, author = {Jurkowska, H and Wróbel, M}, title = {N-acetyl-L-cysteine as a source of sulfane sulfur in astrocytoma and astrocyte cultures: correlations with cell proliferation.}, journal = {Amino acids}, volume = {34}, number = {2}, pages = {231-237}, doi = {10.1007/s00726-007-0471-2}, pmid = {17450321}, issn = {1438-2199}, mesh = {Acetylcysteine/*metabolism ; Animals ; Astrocytes/*metabolism ; Astrocytoma/*metabolism ; Cell Line, Tumor ; Cell Proliferation/*drug effects ; Cell Survival ; Cells, Cultured ; Disulfides/*metabolism ; Glutathione/metabolism ; Humans ; Mice ; Sulfhydryl Compounds/*metabolism ; Sulfurtransferases/antagonists &amp; inhibitors/metabolism ; Thiosulfate Sulfurtransferase/antagonists &amp; inhibitors/metabolism ; }, abstract = {N-acetyl-L-cysteine (NAC), a precursor of L-cysteine, not only elevates the level of glutathione in both astrocytoma and astrocyte cultures, but also affects the cellular level of sulfane sulfur. Astrocytoma cells were investigated using the stable U373 human cell line. In the U373 cells, N-acetyl-L-cysteine, depending on the concentration in the culture medium and culture duration, either elevated or diminished the level of sulfane sulfur, and this was respectively accompanied by decreased or increased cellular proliferation. In murine astrocytes, in turn, NAC was capable of lowering the level of sulfane sulfur and in this way decreased cellular proliferation. It seems that normal (astrocyte) and transformed (astrocytoma) cells differed in their reaction to NAC in the culture medium. The effect of N-acetyl-L-cysteine on astrocytoma cells was advantageous in that it inhibited their proliferation through the elevation of the level of sulfane sulfur.}, }
@article {pmid17448280, year = {2007}, author = {Lu, ZQ and Qiu, QM and Miao, XJ and Hu, GX}, title = {[Experimental study on detoxication effect of sulfhydryl compounds in acute poisoning of dimethylformamide].}, journal = {Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue}, volume = {19}, number = {4}, pages = {233-235}, pmid = {17448280}, issn = {1003-0603}, mesh = {Animals ; Antidotes/*therapeutic use ; Dimethylformamide/*poisoning ; Disease Models, Animal ; Female ; Liver/enzymology ; Male ; Mice ; Mice, Inbred ICR ; Poisoning/drug therapy/enzymology ; Random Allocation ; Sulfhydryl Compounds/*therapeutic use ; Superoxide Dismutase/metabolism ; Xanthine Oxidase/metabolism ; }, abstract = {OBJECTIVE: To study the change in oxidase and anti-oxidase in liver of the mice poisoned by dimethylformamide (DMF), and the effects of the treatment with sulfhydryl compounds in acute poisoning of DMF.<br><br>METHODS: The sulfhydryl compounds included sodium dimercaptopropane (Na-DMPS), N-acetylcysteine (NAC), glutathione (GSH) and dimercaptosuccinic acid (DMSA). The model of acute poisoning with DMF in mice was reproduced, and the left hepatic lobes were harvested at 6, 12, 24, 48 and 72 hours after DMF to detect the dynamic changes in the activities of superoxide dismutase (SOD) and xanthine oxidase (XOD) in liver homogenate. Treatment groups included intraperitoneal injection of Na-DMPS, NAC, GSH, DMSA respectively. In the control groups, the activities of XOD and SOD in liver were determined 24 hours after intragastric administration of DMF.<br><br>RESULTS: The activities of XOD, SOD in liver were elevated at 24 hours after intragastric administration of DMF (both P<0.01), and returned to the normal levels at 48-72 hours. Compared to the poisoning group, the activities of XOD, SOD in liver homogenate were significantly lowered after the treatment of Na-DMPS, NAC and DMSA (P<0.05 or P<0.01). The activity of XOD in liver homogenate was reduced 24 hours after treating with GSH (P<0.05), and no obvious change was observed in SOD (P>0.05). As far as the activity of SOD was concentrated, Na-DMPS, NAC, DMSA showed better effects than GSH (all P<0.05), and Na-DMPS was the best. There was no significant differences in XOD among the four sulfhydryl compounds.<br><br>CONCLUSION: The balance of oxidase and anti-oxidase is interrupted by DMF, which might be one of the mechanisms of damage to the liver. Na-DMPS, NAC and DMSA could protect liver function by restoring the balance.}, }
@article {pmid17445781, year = {2007}, author = {Grant, JE and Kim, SW and Odlaug, BL}, title = {N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study.}, journal = {Biological psychiatry}, volume = {62}, number = {6}, pages = {652-657}, doi = {10.1016/j.biopsych.2006.11.021}, pmid = {17445781}, issn = {0006-3223}, support = {K23 MH 069754-01A1/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Aged ; Behavior, Addictive/diagnosis/drug therapy/psychology ; Dopamine/metabolism ; Double-Blind Method ; Drug Administration Schedule ; Female ; Gambling/*psychology ; Glutamates/drug effects/metabolism ; Humans ; Male ; Middle Aged ; Nucleus Accumbens/drug effects/metabolism ; Personality Inventory ; Pilot Projects ; Placebos ; Psychiatric Status Rating Scales ; Treatment Outcome ; }, abstract = {BACKGROUND: Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. N-acetyl cysteine (NAC), an amino acid, seems to restore extracellular glutamate concentration in the nucleus accumbens and therefore offers promise in reducing addictive behavior.<br><br>METHODS: Twenty-seven subjects (12 women) with DSM-IV PG were treated in an 8-week open-label trial of NAC with responders (defined as a > or = 30% reduction in Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling [PG-YBOCS] total score at end point) randomized to 6 weeks of double-blind NAC or placebo.<br><br>RESULTS: The PG-YBOCS scores decreased from a mean of 20.3 +/- 4.1 at baseline to 11.8 +/- 9.8 at the end of the open-label phase (p < .001). Sixteen of 27 subjects (59.3%) met responder criteria. The mean effective dose of NAC was 1476.9 +/- 311.3 mg/day. Of 16 responders, 13 entered the double-blind phase. Of those assigned to NAC, 83.3% still met responder criteria at the end of the double-blind phase, compared with only 28.6% of those assigned to placebo.<br><br>CONCLUSIONS: The efficacy of NAC lends support to the hypothesis that pharmacological manipulation of the glutamate system might target core symptoms of reward-seeking addictive behaviors such as gambling. Larger, longer, placebo-controlled double-blind studies are warranted.}, }
@article {pmid17445339, year = {2007}, author = {Elmes, MJ and Gardner, DS and Langley-Evans, SC}, title = {Fetal exposure to a maternal low-protein diet is associated with altered left ventricular pressure response to ischaemia-reperfusion injury.}, journal = {The British journal of nutrition}, volume = {98}, number = {1}, pages = {93-100}, doi = {10.1017/S000711450769182X}, pmid = {17445339}, issn = {0007-1145}, mesh = {Animals ; Blood Pressure/physiology ; Diet, Protein-Restricted/*adverse effects ; Dietary Proteins/administration &amp; dosage ; Disease Models, Animal ; Female ; Heart Rate/physiology ; Male ; Myocardial Infarction/etiology/physiopathology ; Myocardial Reperfusion Injury/*etiology/physiopathology ; Pregnancy ; Prenatal Exposure Delayed Effects/*physiopathology ; Rats ; Rats, Wistar ; Sex Factors ; Ventricular Dysfunction, Left/*etiology/physiopathology ; }, abstract = {Rats exposed to protein restriction as fetuses develop hypertension as adults. Hypertension increases the risk of myocardial ischaemia and infarction. We investigated whether rats exposed to low-protein diets in utero are more susceptible to myocardial ischaemia-reperfusion (IR) injury. Pregnant Wistar rats were fed control or low-protein (MLP) diets throughout pregnancy. At 4 and 8 weeks postnatal age systolic blood pressure was determined in the offspring using tail-cuff plethysmography. At 6 months of age, rats were treated with saline or N-acetylcysteine (NAC) for 48 h. Rapidly excised hearts were retro-perfused (Langendorff) to assess isolated cardiac function before (baseline), during 30 min ischaemia (no coronary perfusion) and for 60 min after reinstating coronary perfusion (reperfusion). Hearts were then harvested and treated appropriately for analysis of infarct size. Exposure to the MLP diet in utero significantly increased systolic blood pressure at 4 and 8 weeks of age (6-13 mmHg increase; P < 0.001) and significantly impaired recovery of left ventricular developed pressure after ischaemia at 6 months of age in male offspring only (P < 0.003). Pre-treatment with NAC prevented this impairment of recovery in MLP male offspring and improved recovery in all females. Myocardial infarct size was not different between dietary groups after IR, but NAC pre-treatment significantly reduced the degree of infarction (P < 0.001). In conclusion, an MLP diet throughout gestation significantly impairs recovery of the 6-month-old adult rat heart to IR-induced injury in a sex-specific manner. Undernutrition during development may increase susceptibility to CHD by impairing recovery from coronary events.}, }
@article {pmid17443666, year = {2007}, author = {Lee, S and Pagoria, D and Raigrodski, A and Geurtsen, W}, title = {Effects of combinations of ROS scavengers on oxidative DNA damage caused by visible-light-activated camphorquinone/N,N-dimethyl-p-toluidine.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {83}, number = {2}, pages = {391-399}, doi = {10.1002/jbm.b.30808}, pmid = {17443666}, issn = {1552-4973}, mesh = {Acetylcysteine/chemistry/pharmacology ; Ascorbic Acid/chemistry/pharmacology ; DNA/*drug effects ; DNA Damage/*drug effects ; Free Radical Scavengers/chemistry/*pharmacology ; Glutathione/chemistry/*pharmacology ; Light ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/chemistry ; Terpenes/chemistry/radiation effects ; Toluidines/chemistry/radiation effects ; Vitamin E/chemistry/pharmacology ; }, abstract = {The objective of this investigation was to analyze whether various combinations of the ROS scavengers glutathione (GSH), N-acetyl-cysteine (NAC), and vitamins C and E decrease DNA damage due to visible-light-irradiated (VL-irradiated) camphorquinone/N,N-dimethyl-p-toluidine (CQ/DMT) compared with individual vitamin C or E. PhiX-174 RF plasmid DNA was used to determine single and double strand breaks as parameters of DNA damage. Individual ROS scavengers and combinations of the antioxidants were added to plasmid DNA treated with VL-irradiated CQ/DMT/Cu (II). After incubation, DNA was loaded into a 1% agarose gel. Following electrophoresis, gels stained with 0.5 microg/mL ethidium bromide were photographed under ultraviolet illumination and analyzed with NIH ImageJ software. Results were evaluated between groups for statistical significance using Student's paired t-test (p < 0.05). Glutathione significantly reduced oxidative DNA damage at all test concentrations when combined with vitamin C or vitamin E. The concentration of damaged DNA observed in the presence of combinations of GSH with vitamin C or vitamin E was significantly lower compared with all other combinations of antioxidants investigated in our study (p < 0.05). In contrast to GSH, NAC was not able to compensate the pro-oxidative effects of vitamin C and vitamin E. Only at a concentration of 2 mM, NAC combined with vitamin C efficiently prevented CQ/DMT/Cu (II)-associated DNA damage. Our data indicate that solely the combinations of GSH with vitamin C or vitamin E significantly reduce the severity of oxidative DNA damage caused by CQ/DMT, whereas NAC may even increase the pro-oxidant activity of vitamin C and vitamin E.}, }
@article {pmid17441349, year = {2007}, author = {Jiang, XF and Zeng, WY and Yang, KX and Xu, ZH and Xu, AQ}, title = {[Effect of N-acetylcysteine on lipopolysaccharide induced preterm labor in mice].}, journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition}, volume = {38}, number = {2}, pages = {279-283}, pmid = {17441349}, issn = {1672-173X}, mesh = {Acetylcysteine/*pharmacology/therapeutic use/toxicity ; Animals ; Female ; Fetus/drug effects ; Gene Expression Regulation/drug effects ; Infections/complications ; Interleukin-8/genetics/metabolism ; Lipopolysaccharides/*pharmacology ; Mice ; Obstetric Labor, Premature/*chemically induced/drug therapy/metabolism/prevention &amp; control ; Oxidation-Reduction/drug effects ; Pregnancy ; RNA, Messenger ; Transcription Factor RelA/metabolism ; }, abstract = {OBJECTIVE: To test the effect of N-acetylcysteine (NAC) on the mice with infection associated preterm labor.<br><br>METHODS: The pregnant C57BL/6 mice were randomly distributed into five groups, each with 20 mice and were given lipopolysaccharide (LPS), saline solution (NS), NAC, LPS+NAC (therapy), and NAC+ LPS (prevention) respectively. The LPS (20 microg) was injected intraperitoneally to the mice every 12 hours since day 16 of gestation to induce preterm labor. The NAC was orally administered (0.5 g/kg) every 12 hours since day 15 or day 16 for the prevention and therapy groups respectively. The latency interval (from LPS injection to delivery of the first pup) and fetal survival rates were recorded in eight mice from each group. The remaining mice were killed at 4, 8, 12, and 24 hours after the LPS injection (three for a group each time). The NF-kappaB activity and IL-8 mRNA in uterine and maternal and fetal hepatic GSH-PX and serum IL-8, MDA, and SOD were examined.<br><br>RESULTS: The average latency interval of LPS-treated mice was (15.1 +/- 1.9) hours, with a fetal survival rate of 4.3%. The NAC therapy extended the latency interval of LPS-treated mice to (35.4 +/- 2.1) hours, with a fetal survival rate of 69.0%. The NAC prevention extended the latency interval of LPS-treated mice to (44.8 +/- 2.6) hours, with a fetal survival rate of 84.3%. The expression of NF-KB P65 was activated and reached the peak 4 hours after the LPS injection. The uterine IL-8 mRNA and serum IL-8 and MDA reached the peak whereas the maternal and fetal hepatic GSH and SOD declined to the lowest 8 hours after the LPS injection. The NAC significantly inhibited the effect induced by the LPS (P < 0.01).<br><br>CONCLUSION: The NAC has a therapeutic effect on the LPS-induced preterm labor in mice. It is even better to be used in preventing preterm labor. The mechanism of the protective effect of NAC may include the deactivation of the NF-kappaB/IL-8 and the reduce of the production of ROS.}, }
@article {pmid17436097, year = {2007}, author = {Tahan, G and Tarcin, O and Tahan, V and Eren, F and Gedik, N and Sahan, E and Biberoglu, N and Guzel, S and Bozbas, A and Tozun, N and Yucel, O}, title = {The effects of N-acetylcysteine on bile duct ligation-induced liver fibrosis in rats.}, journal = {Digestive diseases and sciences}, volume = {52}, number = {12}, pages = {3348-3354}, pmid = {17436097}, issn = {0163-2116}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bile Ducts/*surgery ; Collagen/metabolism ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Ligation/adverse effects ; Liver Cirrhosis/*drug therapy/etiology/metabolism ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Spectrophotometry ; }, abstract = {Stellate cells are activated by free radicals, and synthesize collagen. N-acetylcysteine (NAC) is a precursor of reduced glutathione and a potent scavenger of hydroxyl radicals and has potential antifibrotic effects. We aimed to test the effects of NAC on bile duct ligation (BDL) induced liver damage in rats. Forty-seven Wistar rats were divided into 5 groups: group 1, BDL+NAC (n=10); group 2, BDL (n=10); group 3, sham+NAC (n=10); group 4, sham (n=10); and group 5, control group (n=10). NAC (50 micromol/kg per day) or saline of single doses were administered intraperitoneally for 28 days. Serum biochemical and liver oxidative stress parameters were studied. Liver collagen level was determined by the method of Lopez de Leon and Rojkind. Liver slides were stained by hematoxylin and eosin and Masson trichrome\Gomory reticulum staining. Aspartate aminotransferase (AST) and alkaline phosphatase levels in the BDL+NAC group were lower than the BDL group and were higher than the control groups (all P< .001). Malondialdehyde, luminal, and glutathione levels in group 1 were lower than the BDL group (P= .01, P= .002, and P< .001) and higher than the control groups (all P< .001). NAC had no effect on alanine aminotransferase (ALT), gammaglutamyl transferase, bilirubin, albumin, or lucigenin levels. Liver collagen levels were higher in the BDL groups (P< .001); however, NAC had no effect on the collagen levels. The BDL groups showed stage 3 fibrosis; all the control groups were normal. NAC improved some biochemical parameters (AST, alkaline phosphatase) and oxidative stress parameters (malondialdehyde, luminol, glutathione) in the BDL model. NAC was found to be effective on cholestasis-induced hepatotoxicity. However, NAC was inefficient as an antifibrotic agent within a 1-month period of administration in the BDL model.}, }
@article {pmid17434230, year = {2007}, author = {Hanada, S and Harada, M and Kumemura, H and Bishr Omary, M and Koga, H and Kawaguchi, T and Taniguchi, E and Yoshida, T and Hisamoto, T and Yanagimoto, C and Maeyama, M and Ueno, T and Sata, M}, title = {Oxidative stress induces the endoplasmic reticulum stress and facilitates inclusion formation in cultured cells.}, journal = {Journal of hepatology}, volume = {47}, number = {1}, pages = {93-102}, doi = {10.1016/j.jhep.2007.01.039}, pmid = {17434230}, issn = {0168-8278}, support = {DK52951/DK/NIDDK NIH HHS/United States ; }, mesh = {Cysteine Proteinase Inhibitors/pharmacology ; Endoplasmic Reticulum/*metabolism/ultrastructure ; Fluoresceins/pharmacology ; Glucose Oxidase/pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Inclusion Bodies/chemistry/*metabolism/ultrastructure ; Keratin-18/analysis ; Keratin-8/analysis ; Leupeptins/pharmacology ; Liver Diseases/*metabolism/pathology ; *Oxidative Stress ; Phenylbutyrates/metabolism ; Proteasome Inhibitors ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND/AIMS: The precise mechanism of formation and significance of Mallory bodies (MBs) are poorly understood. The endoplasmic reticulum (ER) is the organelle responsible for proper folding and elimination of unfolded proteins. Therefore, failure of this function increases defective proteins in the cell.<br><br>METHODS: We examined the effects of oxidative stress on induction of ER stress and keratin 8 and 18 (K8/18)-containing inclusion formation in cultured human hepatoma cells and hepatocytes by immunofluorescence and immunoblot analyses.<br><br>RESULTS: Generation of H(2)O(2) was detected in glucose oxidase (GO)-treated cells by 2',7'-dichlorodihydrofluorescein diacetate and co-treatment with GO and acetyl-leucyl-leucyl-norleucinal (ALLN), a proteasome inhibitor, induced formation of extensive keratin inclusions that were inhibited by pre-treatment with N-acetyl-cysteine. These inclusions shared similar features with MBs by immunofluorescence analysis. Electron microscopy showed that these structures appeared near the nuclei, surrounded by filamentous structures. GO and ALLN upregulated the expression of ER stress markers, however, 4-phenylbutyrate, a chemical chaperone, reduced formation of inclusions and expression of the ER stress markers.<br><br>CONCLUSIONS: The oxidative stress coupled with limited inhibition of the proteasome induces dysfunction of the ER and results in inclusion formation in cultured cells. This suggests that ER stress plays a role in MB formation in liver disease.}, }
@article {pmid17432610, year = {2007}, author = {Solov'eva, ME and Solov'ev, VV and Faskhutdinova, AA and Kudriavtsev, AA and Akatov, VS}, title = {[Prooxidant and cytotoxic action of N-acetylcysteine and glutathione combined with vitamin Bl2b].}, journal = {Tsitologiia}, volume = {49}, number = {1}, pages = {70-78}, pmid = {17432610}, issn = {0041-3771}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; *Apoptosis/drug effects ; Catalase/pharmacology ; Cell Line, Tumor ; Cell Physiological Phenomena/*drug effects ; Deferoxamine/pharmacology ; Drug Synergism ; Free Radical Scavengers/*pharmacology ; Glutathione/*pharmacology ; Humans ; Iron Compounds/pharmacology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Phenanthrolines/pharmacology ; Pyruvic Acid/pharmacology ; Siderophores/pharmacology ; Vitamin B 12/*pharmacology ; }, abstract = {We studied the prooxidant and cytotoxic action of thiols N-acetylcystein (NAC) and glutathione (GSH) combined with vitamin Bl2b. The synergism of action of the thiols and Bl2b resulted in human carcinoma cell damage was found. It was shown that GSH and NAC in physiological doses combined with Bl2b caused the initiation of apoptosis. It was established that prooxidant action of the thiols combined with vitamin Bl2b, i. e. generation and accumulation of hydrogen peroxide in culture medium, led to intracellular oxidative stress and injury of cell redox system. These effects were completely abolished by nonthiol antioxidants catalase and pyruvate. The chelators of iron phenanthroline and deferoxamine did not suppress the H2O2 accumulation in culture medium but significantly inhibited the cell death induced by the thiols combined with Bl2b. Therefore, the thiols GSH and NAC widely used as antioxidants, in combination with vitamin Bl2b show prooxidant characteristics and induce, with the participation of intracellular iron, apoptotic HEp-2 cell death.}, }
@article {pmid17429612, year = {2007}, author = {Patsoukis, N and Georgiou, CD}, title = {Effect of thiol redox state modulators on oxidative stress and sclerotial differentiation of the phytopathogenic fungus Rhizoctonia solani.}, journal = {Archives of microbiology}, volume = {188}, number = {3}, pages = {225-233}, doi = {10.1007/s00203-007-0237-6}, pmid = {17429612}, issn = {0302-8933}, mesh = {Oxidation-Reduction ; Oxidative Stress/physiology ; Rhizoctonia/*growth &amp; development/*metabolism ; Spores, Fungal/physiology ; Sulfhydryl Compounds/*metabolism ; }, abstract = {This study showed that sclerotial differentiation in the filamentous phytopathogenic fungus Rhizoctonia solani is directly related to oxidative stress and thiol redox state (TRS). Sclerotial differentiation is modulated by the availability of non-cytotoxic -SH groups as was shown by the inhibition of sclerorial differentiation by the TRS modulator N-acetyl cysteine (AcCSH), and not necessarily with those of the TRS reduced components glutathione (GSH) and its precursor cysteine (CSH) as indicated by the GSH-biosynthesis inducer and inhibitor L-2-oxo-thiazolidine-4-carboxylate and L-buthionine-S,R-sulfoximine, respectively. Moreover, inhibition of sclerotial differentiation was accompanied by decrease of the high oxidative stress indicators, lipid peroxidation and DNA damage in the mycelial substrate where sclerotia initials are formed, which suggests that this phenomenon is related to oxidative stress as it is predicted by our theory on sclerotial differentiation.}, }
@article {pmid17429056, year = {2007}, author = {Madejczyk, MS and Aremu, DA and Simmons-Willis, TA and Clarkson, TW and Ballatori, N}, title = {Accelerated urinary excretion of methylmercury following administration of its antidote N-acetylcysteine requires Mrp2/Abcc2, the apical multidrug resistance-associated protein.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {322}, number = {1}, pages = {378-384}, doi = {10.1124/jpet.107.122812}, pmid = {17429056}, issn = {0022-3565}, support = {DK48823/DK/NIDDK NIH HHS/United States ; ES01247/ES/NIEHS NIH HHS/United States ; ES06484/ES/NIEHS NIH HHS/United States ; ES07026/ES/NIEHS NIH HHS/United States ; }, mesh = {ATP-Binding Cassette Transporters/*physiology ; Acetylcysteine/metabolism/*pharmacology ; Adenosine Triphosphate/pharmacology ; Animals ; Antidotes/*pharmacology ; Cell Membrane/metabolism ; Female ; Liver/metabolism ; Male ; Methylmercury Compounds/metabolism/*urine ; Rats ; Rats, Wistar ; }, abstract = {N-Acetylcysteine (NAC) is a sulfhydryl-containing compound that produces a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned mice, but the molecular mechanism for this effect is poorly defined. MeHg readily binds to NAC to form the MeHg-NAC complex, and recent studies indicate that this complex is an excellent substrate for the basolateral organic anion transporter (Oat)-1, Oat1/Slc22a6, thus potentially explaining the uptake from blood into the renal tubular cells. The present study tested the hypothesis that intracellular MeHg is subsequently transported across the apical membrane of the cells into the tubular fluid as a MeHg-NAC complex using the multidrug resistance-associated protein-2 (Mrp2/Abcc2). NAC markedly stimulated urinary [(14)C]MeHg excretion in wild-type Wistar rats, and a second dose of NAC was as effective as the first dose in stimulating MeHg excretion. In contrast with the normal Wistar rats, NAC was much less effective at stimulating urinary MeHg excretion in the Mrp2-deficient (TR-) Wistar rats. The TR- rats excreted only approximately 30% of the MeHg excreted by the wild-type animals. To directly test whether MeHg-NAC is a substrate for Mrp2, studies were carried out in plasma membrane vesicles isolated from livers of TR- and control Wistar rats. Transport of MeHg-NAC was lower in vesicles prepared from TR- rats, whereas transport of MeHg-cysteine was similar in control and TR- rats. These results indicate that Mrp2 is involved in urinary MeHg excretion after NAC administration and suggest that the transported molecule is most likely the MeHg-NAC complex.}, }
@article {pmid17428624, year = {2007}, author = {Bai, P and Hegedus, C and Erdélyi, K and Szabó, E and Bakondi, E and Gergely, S and Szabó, C and Virág, L}, title = {Protein tyrosine nitration and poly(ADP-ribose) polymerase activation in N-methyl-N-nitro-N-nitrosoguanidine-treated thymocytes: implication for cytotoxicity.}, journal = {Toxicology letters}, volume = {170}, number = {3}, pages = {203-213}, doi = {10.1016/j.toxlet.2007.03.007}, pmid = {17428624}, issn = {0378-4274}, support = {HL71254/HL/NHLBI NIH HHS/United States ; R01 GM060915/GM/NIGMS NIH HHS/United States ; }, mesh = {Alkylating Agents/pharmacology ; Animals ; Apoptosis/drug effects ; Blotting, Western ; Caspases/metabolism ; Cell Death/drug effects ; Cell Survival/drug effects ; Comet Assay ; DNA Damage ; DNA Fragmentation ; Fluorescent Antibody Technique ; Male ; Methylnitronitrosoguanidine/*toxicity ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/metabolism ; Nitrates/*metabolism ; Nitric Oxide/metabolism ; Peroxynitrous Acid/metabolism ; Poly(ADP-ribose) Polymerases/*metabolism ; Superoxides/metabolism ; T-Lymphocytes/*drug effects/enzymology/*metabolism ; Tyrosine/*metabolism ; }, abstract = {1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) is a DNA alkylating agent. DNA alkylation by MNNG is known to trigger accelerated poly(ADP-ribose) metabolism. Various nitroso compounds release nitric oxide (NO). Therefore, we set out to investigate whether MNNG functions as NO donor and whether MNNG-derived NO or secondary NO metabolites such as peroxynitrite contribute to MNNG-induced cytotoxicity. MNNG in aqueous solutions resulted in time- and concentration-dependent NO release and nitrite/nitrate formation. Moreover, various proteins in MNNG-treated thymocytes were found to be nitrated, indicating that MNNG-derived NO may combine with cellular superoxide to form peroxynitrite, a nitrating agent. MNNG also caused DNA breakage and increased poly(ADP-ribose) polymerase activity and cytotoxicity in thymocytes. MNNG-induced DNA damage (measured by the comet assay) and thymocyte death (measured by propidium iodide uptake) was prevented by the PARP inhibitor PJ-34 and by glutathione (GSH) or N-acetylcysteine (NAC). The cytoprotection provided by PJ-34 against necrotic parameters was paralleled by increased outputs in apoptotic parameters (caspase activity, DNA laddering) indicating that PARP activation diverts apoptotic death toward necrosis. As MNNG-induced cytotoxicity showed many similarities to peroxynitrite-induced cell death, we tested whether peroxynitrite was responsible for at least part of the cytotoxicity induced by MNNG. Cell-permeable enzymic antioxidants (superoxide dismutase and catalase), the NO scavenger cPTIO or the peroxynitrite decomposition catalyst FP15 failed to inhibit MNNG-induced DNA breakage and cytotoxicity. In conclusion, MNNG induces tyrosine nitration in thymocytes. Furthermore, MNNG damages DNA by a radical mechanism that does not involve NO or peroxynitrite.}, }
@article {pmid17416483, year = {2007}, author = {Seok, SH and Baek, MW and Lee, HY and Kim, DJ and Na, YR and Noh, KJ and Park, SH and Lee, HK and Lee, BH and Ryu, DY and Park, JH}, title = {Arsenite-induced apoptosis is prevented by antioxidants in zebrafish liver cell line.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {21}, number = {5}, pages = {870-877}, doi = {10.1016/j.tiv.2007.02.011}, pmid = {17416483}, issn = {0887-2333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Arsenites/*antagonists &amp; inhibitors/*toxicity ; Cell Line ; Cell Survival/drug effects ; Chemical and Drug Induced Liver Injury/*pathology/*prevention &amp; control ; Dithiothreitol/pharmacology ; Dose-Response Relationship, Drug ; Genes, Reporter/drug effects ; Green Fluorescent Proteins/metabolism ; HSP70 Heat-Shock Proteins/biosynthesis/genetics/physiology ; Humans ; Liver/*pathology ; Oxidative Stress/drug effects ; Plasmids/genetics ; Transfection ; Trypan Blue ; Zebrafish ; }, abstract = {This study evaluated oxidative stress-induced apoptosis as a possible mechanism of arsenite toxicity in zebrafish liver cell line (ZFL cells). The heat shock protein 70 (HSP70), a chaperone protein, appears to provide protection against oxidative stress and apoptosis. Using the MTT assay, we demonstrated that survival of ZFL cells treated with arsenite for 24h decreased in a dose-dependent manner. The possible mechanisms that promote the cytotoxicity of arsenite were addressed. Cell viability assays revealed that arsenite caused a dose-dependent increase in cell death, and pretreatment of the ZFL cells with antioxidants blunted these effects. Antioxidants such as N-acetyl-cysteine (NAC, 5 mM) and dithiothreitol (DTT, 80 microM) significantly prevented ZFL cells from arsenite-induced death. Nuclear staining was performed using 1 microg/ml Hoechst, and cells were analyzed with a fluorescent microscope. Arsenite (30 microM) induced massive apoptosis that was identified by morphology and condensation and fragmentation of the nuclei of the ZFL cells. Pretreatment with NAC or DTT before arsenite insult effectively protected the cells against oxidative stress-induced apoptosis from the arsenite. Using a transfected human hsp 70 promoter-enhanced green fluorescent protein (EGFP) reporter, pHhsp70-EGFP, the induction of HSP70 against oxidative stress-induced apoptosis by arsenite was observed. The induction of HSP70 by arsenite increased in a dose-dependent manner, and pretreatment of transfected ZFL cells with NAC or DTT before arsenite insult reduced EGFP expression. Taken together, our results provide evidence that stimulation of the heat shock response is a sensitive biomarker of arsenic exposure and that arsenite causes oxidative stress-induced apoptosis in ZFL cells.}, }
@article {pmid17415663, year = {2007}, author = {Papa, L and Gomes, E and Rockwell, P}, title = {Reactive oxygen species induced by proteasome inhibition in neuronal cells mediate mitochondrial dysfunction and a caspase-independent cell death.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {12}, number = {8}, pages = {1389-1405}, doi = {10.1007/s10495-007-0069-5}, pmid = {17415663}, issn = {1360-8185}, support = {RR03037/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Caspases/*metabolism ; Cell Death/drug effects ; Cell Survival/drug effects/genetics ; Cells, Cultured ; Glutathione/metabolism ; Mice ; Mitochondria/*drug effects/physiology ; Models, Biological ; Neurons/*drug effects/enzymology ; Oligopeptides/pharmacology ; *Proteasome Inhibitors ; Reactive Oxygen Species/*metabolism/*pharmacology ; Transfection ; bcl-2-Associated X Protein/metabolism ; bcl-X Protein/genetics/metabolism ; }, abstract = {While increasing evidence shows that proteasome inhibition triggers oxidative damage, mitochondrial dysfunction and death in neuronal cells, the regulatory relationship among these events is unclear. Using mouse neuronal cells we show that the cytotoxicity induced by mild (0.25 microM) and potent (5.0 microM) doses of the proteasome inhibitor, N-Benzyloxycarbonyl-Ile-Glu (O-t-butyl)-Ala-leucinal, (PSI) involved a dose-dependent increase in caspase activation, overproduction of reactive oxygen species (ROS) and a mitochondrial dysfunction manifested by the translocation of the proapoptotic protein, Bax, from the cytoplasm to the mitochondria, membrane depolarization and the release of cytochrome c and the apoptosis inducing factor (AIF) from mitochondria to the cytoplasm and nucleus, respectively. Whereas caspase or Bax inhibition failed to prevent mitochondrial membrane depolarization and neuronal cell death, pretreatments with the antioxidant N-acetyl-L-cysteine (NAC) or overexpression of the antiapoptotic protein Bcl-xL abrogated these events in cells exposed to mild levels of PSI. These findings implicated ROS as a mediator of PSI-induced cytotoxicity. However, depletions in glutathione and Bcl-xL with potent proteasome inhibition exacerbated this response whereupon survival required the cooperative protection of NAC with Bcl-xL overexpression. Collectively, ROS induced by proteasome inhibition mediates a mitochondrial dysfunction in neuronal cells that culminates in death through caspase- and Bax-independent mechanisms.}, }
@article {pmid17414623, year = {2007}, author = {Takahashi, K and Sakurai, K and Takahashi, K and Tanaka, H and Fujimoto, Y}, title = {Necrotic pathway in human osteosarcoma Saos-2 cell death induced by chloroacetaldehyde.}, journal = {Anti-cancer drugs}, volume = {18}, number = {5}, pages = {543-553}, doi = {10.1097/CAD.0b013e328026240f}, pmid = {17414623}, issn = {0959-4973}, mesh = {Acetaldehyde/*analogs &amp; derivatives/pharmacology ; Adenosine Triphosphate/physiology ; Annexin A5/metabolism ; Antineoplastic Agents, Alkylating/pharmacology ; Blotting, Western ; Bone Neoplasms/*drug therapy/pathology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Flow Cytometry ; Humans ; Ifosfamide/pharmacology ; Membrane Potentials/drug effects ; Mitochondrial Membranes/drug effects ; Necrosis ; Osteosarcoma/*drug therapy/pathology ; Propidium/metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {Chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, may be responsible for serious adverse effects like encephalopathy in ifosfamide chemotherapy. In this study, we demonstrate that chloroacetaldehyde, but not ifosfamide, induces cell death in human osteosarcoma Saos-2 cells and we investigated the mechanism by which this occurs. Chloroacetaldehyde above 30 micromol/l induced significant cell death in a time-dependent manner. Thiol compounds such as N-acetyl cysteine, glutathione and dithiothreitol protected the cells against chloroacetaldehyde-induced cell death, although other nonthiol compounds and the antioxidative enzymes superoxide dismutase and catalase did not, suggesting that reactive oxygen species might not mediate cell death. In cells exposed to chloroacetaldehyde, levels of both total thiols and glutathione were significantly reduced. Chloroacetaldehyde also collapsed the mitochondrial membrane potential of these cells, induced the release of cytochrome c from mitochondria to the cytosol and significantly reduced cellular ATP levels during the course of death. The mitochondrial potential collapse was also prevented by thiol compounds. Flow cytometric analyses by means of annexin-V and propidium iodide double staining and immunofluorescence staining of active caspase-3 revealed that cells subjected to a lethal dose of chloroacetaldehyde displayed features characteristic of necrosis and that caspase-3 was not activated in response to chloroacetaldehyde. Taken together, these findings suggest that Saos-2 cells exposed to chloroacetaldehyde die by necrosis resulting from a decrease in intracellular thiols, disruption of the mitochondrial membrane potential and the depletion of cellular ATP.}, }
@article {pmid17414258, year = {2007}, author = {Odlaug, BL and Grant, JE}, title = {N-acetyl cysteine in the treatment of grooming disorders.}, journal = {Journal of clinical psychopharmacology}, volume = {27}, number = {2}, pages = {227-229}, doi = {10.1097/01.jcp.0000264976.86990.00}, pmid = {17414258}, issn = {0271-0749}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Bulimia/drug therapy ; Compulsive Behavior/*drug therapy/psychology ; Diagnostic and Statistical Manual of Mental Disorders ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Nail Biting/psychology/therapy ; Self-Injurious Behavior/drug therapy/psychology ; Treatment Outcome ; Trichotillomania/drug therapy/psychology ; }, }
@article {pmid17414225, year = {2007}, author = {Ivanov, V and Roomi, MW and Kalinovsky, T and Niedzwiecki, A and Rath, M}, title = {Anti-atherogenic effects of a mixture of ascorbic acid, lysine, proline, arginine, cysteine, and green tea phenolics in human aortic smooth muscle cells.}, journal = {Journal of cardiovascular pharmacology}, volume = {49}, number = {3}, pages = {140-145}, doi = {10.1097/FJC.0b013e3180308489}, pmid = {17414225}, issn = {0160-2446}, mesh = {Amino Acids/*pharmacology ; Animals ; Aorta/cytology/drug effects ; Ascorbic Acid/*pharmacology ; Atherosclerosis/*drug therapy/prevention &amp; control ; Catechin/analogs &amp; derivatives/pharmacology ; Cattle ; Cell Proliferation/drug effects ; Cells, Cultured ; Chemokine CCL2/drug effects/metabolism ; Dose-Response Relationship, Drug ; Humans ; Immunochemistry ; Interleukin-6/metabolism ; Matrix Metalloproteinase 2/drug effects/metabolism ; Myocytes, Smooth Muscle ; Phenols/isolation &amp; purification/pharmacology ; Plant Extracts/*pharmacology ; Tea/*chemistry ; }, abstract = {Certain drastic behavioral modifications by arterial wall smooth muscle cells (SMC) have been considered key steps in the formation of atherosclerotic lesions: massive migration of SMC from the media to the intima layer of the vessel, dedifferentiation of SMC to proliferating phenotype, and increased secretion of inflammatory cytokines as a response to inflammatory stimuli. We investigated the anti-atherogenic effects of naturally occurring compounds (ascorbic acid, green tea extract, lysine, proline, arginine, and N-acetyl cysteine) using the model of cultured aortic SMC. Cell growth was measured by DNA synthesis, cell invasiveness was measured through Matrigel, matrix metalloproteinase-2 (MMP-2) secretion was measured by zymography, and SMC secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) was measured by immunochemistry. Fetal bovine serum-stimulated SMC growth was inhibited by the nutrient mixture (NM) with 85% inhibition at 100 microg/mL. A corresponding concentration of epigallocatechin gallate (EGCG; 15 microM), the most active tea phenolic, produced a significant effect but one lower than NM. NM inhibited aortic SMC Matrigel invasion in a dose-dependent manner and significantly decreased MMP-2 expression. Stimulation of SMC with tumor necrosis factor-alpha significantly increased production and secretion of such mediators of inflammation as IL-6 and MCP-1; addition of 100 microg/mL NM inhibited secretion of MCP-1 and IL-6 by 65% and 47%, respectively. These data suggest that the NM of ascorbic acid, tea phenolics, and selected amino acids has potential in blocking the development of atherosclerotic lesions by inhibiting atherogenic responses of vascular SMC to pathologic stimuli and warrants in vivo studies.}, }
@article {pmid17413030, year = {2007}, author = {Reddy, NM and Kleeberger, SR and Cho, HY and Yamamoto, M and Kensler, TW and Biswal, S and Reddy, SP}, title = {Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants.}, journal = {American journal of respiratory cell and molecular biology}, volume = {37}, number = {1}, pages = {3-8}, pmid = {17413030}, issn = {1044-1549}, support = {HL 66109/HL/NHLBI NIH HHS/United States ; P50 HL 073994/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/metabolism/pharmacology ; Cell Proliferation ; Epithelial Cells/cytology ; Glutathione/*physiology ; Lung/*cytology/metabolism ; Mice ; Mice, Transgenic ; Models, Biological ; NF-E2-Related Factor 2/*genetics/*physiology ; Oxidants/*metabolism ; Oxidation-Reduction ; Phenotype ; Reactive Oxygen Species ; *Signal Transduction ; }, abstract = {Redox imbalance has been implicated in the pathogenesis of many acute and chronic lung diseases. The b-Zip transcription factor Nrf2 acts via an antioxidant/electrophilic response element to regulate antioxidants and maintain cellular redox homeostasis. Our previous studies have shown that Nrf2-deficient mice (Nrf2(-/-)) show reduced pulmonary expression of several antioxidant enzymes, which renders them highly susceptible to hyperoxia-induced lung injury. To better understand the physiologic significance of Nrf2-induced redox signaling, we have used primary cells isolated from the lungs of Nrf2(+/+) and Nrf2(-/-) mice. Our studies were focused on type II cells because these cells are constantly exposed to the oxidant environment and play key roles in host defense, injury, and repair processes. Using this system, we now report that an Nrf2 deficiency leads to defects in type II cell proliferation and greatly enhances the cells' sensitivity to oxidant-induced cell death. These defects were closely associated with high levels of reactive oxygen species (ROS) and redox imbalance in Nrf2(-/-) cells. Glutathione (GSH) supplementation rescued these phenotypic defects associated with the Nrf2 deficiency. Intriguingly, although the antioxidant N-acetyl-cysteine drastically squelched ROS levels, it was unable to counteract growth arrest in Nrf2(-/-) cells. Moreover, despite their elevated levels of ROS, Nrf2(-/-) type II cells were viable and, like their wild-type counterparts, exhibited normal differentiation characteristics. Our data suggest that dysfunctional Nrf2-regulated GSH-induced signaling is associated with deregulation of type II cell proliferation, which contributes to abnormal injury and repair and leads to respiratory impairment.}, }
@article {pmid17410531, year = {2008}, author = {el-Saadany, MA and Rawel, HM and Raila, J and el-Dashloty, MS and Schweigert, FJ}, title = {Antioxidants modulate the IL-6 induced inhibition of negative acute-phase protein secretion in HepG2 cells.}, journal = {Cell biochemistry and function}, volume = {26}, number = {1}, pages = {95-101}, doi = {10.1002/cbf.1405}, pmid = {17410531}, issn = {1099-0844}, mesh = {Acute-Phase Proteins/*antagonists &amp; inhibitors/*metabolism ; Antioxidants/*physiology ; Carcinoma, Hepatocellular/metabolism ; Cell Line, Tumor ; Humans ; Interleukin-6/antagonists &amp; inhibitors/*physiology ; Liver/*metabolism ; Prealbumin/metabolism ; Retinol-Binding Proteins/metabolism ; Thioctic Acid/physiology ; }, abstract = {Despite increasing evidence on the potential of dietary antioxidants in modulating the etiology of certain chronic diseases such as cancer and cardiovascular diseases, little is known about their beneficial role in acute-phase responses and inflammatory diseases. From this viewpoint the aim of this study was to investigate the effect of selected dietary antioxidants in modulating the secretion of negative acute-phase proteins caused by interleukin-6 (IL-6) in HepG2 cells. Cells were first stimulated with a fixed dose of IL-6 for 24 h then incubated for a further 8 h with varying concentrations of eight antioxidants, alpha-lipoic acid (LA), (-)-epicatechin (EC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC), (-)-epigallocatechin gallate (EGCG), alpha-tocopherol (TOC), ascorbic acid (AA) and N-acetylcysteine (NAC). The culture supernatants were assayed for transthyretin (TTR) and retinol binding protein (RBP) using ELISA. The data revealed that IL-6 significantly reduced TTR and RBP secretion compared with the basal production. All tested antioxidants attenuate the reduction in TTR and RPB levels. The strongest effects were achieved with the highest concentration of each antioxidant. The order of effect were LA > EGCG > ECG > TOC > EGC > EC > NAC > AA. In conclusion, these results provide evidence that the dietary antioxidants can play a fundamental role in inflammatory processes.}, }
@article {pmid17409498, year = {2007}, author = {Kukongviriyapan, U and Luangaram, S and Leekhaosoong, K and Kukongviriyapan, V and Preeprame, S}, title = {Antioxidant and vascular protective activities of Cratoxylum formosum, Syzygium gratum and Limnophila aromatica.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {30}, number = {4}, pages = {661-666}, doi = {10.1248/bpb.30.661}, pmid = {17409498}, issn = {0918-6158}, mesh = {Animals ; Antioxidants/administration &amp; dosage/*pharmacology/therapeutic use ; Blood Pressure/drug effects ; Blood Vessels/*drug effects ; Cell Line ; Clusiaceae/*chemistry ; Inhibitory Concentration 50 ; Macrophages/*drug effects ; Male ; Mice ; Plant Extracts/pharmacology ; Plant Leaves/chemistry ; Plants, Medicinal ; Protective Agents/administration &amp; dosage/*pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Regional Blood Flow/drug effects ; Scrophulariaceae/*chemistry ; Syzygium/*chemistry ; Vascular Resistance/drug effects ; Water/chemistry ; }, abstract = {Phytochemicals contained in dietary plants provide a variety of health benefits and may reduce the risk of cardiovascular diseases. The aqueous extracts from three popular Thai dietary and herbal plants, Cratoxylum formosum, Syzygium gratum, and Limnophila aromatica, were investigated for the antioxidant and vascular protective activities in the in vitro and in vivo models. The free radical scavenging and antioxidant activities of plant extracts were evaluated in vitro by the 1,1-diphenyl-2-picrylhydrazyl assay, the ferric reducing antioxidant power assay, the intracellular antioxidant activity in rat peritoneal macrophages by dihydrofluorescein assay, and the inhibition of nitric oxide (NO) production in RAW 264.7 macrophages. In an animal model of oxidative stress and vascular dysfunction, male Sprague-Dawley rats were orally administered with aqueous plant extracts (1 g/kg/d) or N-acetylcysteine (NAC; 300 mg/kg/d) as a control for 6 d. On day four, all animals except the normal control group, were administered with phenylhydrazine (PHZ) intraperitoneally. It was demonstrated that the plant extracts possessed high free radical scavenging and antioxidant activities. PHZ induced severe hemolysis and hemodynamic disturbances and treatment with the extracts and NAC significantly improved the hemodynamic status. Vascular responsiveness to bradykinin, acetylcholine, and phenylephrine in PHZ-control rats was markedly impaired, and the plant extracts or NAC largely restored the vascular responses. Moreover, the plant extracts prevented loss of blood reduced glutathione and suppressed formation of plasma malondialdehyde, plasma NO metabolites and blood superoxide anion. It was concluded that the plant extracts possess antioxidants and have potential roles in protection of vascular dysfunction.}, }
@article {pmid17409446, year = {2007}, author = {Simons, AL and Ahmad, IM and Mattson, DM and Dornfeld, KJ and Spitz, DR}, title = {2-Deoxy-D-glucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells.}, journal = {Cancer research}, volume = {67}, number = {7}, pages = {3364-3370}, pmid = {17409446}, issn = {0008-5472}, support = {P30 CA086862/CA/NCI NIH HHS/United States ; R01-CA100045/CA/NCI NIH HHS/United States ; P01-CA66081/CA/NCI NIH HHS/United States ; P01 CA066081/CA/NCI NIH HHS/United States ; R01 CA100045/CA/NCI NIH HHS/United States ; P30-CA086862/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Buthionine Sulfoximine/pharmacology ; Carcinoma, Squamous Cell/*drug therapy/metabolism ; Catalase/pharmacology ; Cell Growth Processes/drug effects ; Cisplatin/*pharmacology ; Deoxyglucose/antagonists &amp; inhibitors/*pharmacology ; Drug Synergism ; Glutathione/metabolism ; Head and Neck Neoplasms/*drug therapy/metabolism ; Humans ; Oxidative Stress ; Polyethylene Glycols/pharmacology ; Superoxide Dismutase/pharmacology ; }, abstract = {Glucose deprivation has been hypothesized to cause cytotoxicity by inducing metabolic oxidative stress in human cancer cells. The current work tests the hypothesis that 2-deoxy-d-glucose (2DG) combined with cisplatin [cis-diamminedichloroplatinum(II)] can enhance cytotoxicity in human head and neck cancer cells (FaDu) by mechanisms involving oxidative stress. Exposure of FaDu cells to the combination of 2DG and cisplatin resulted in a significant decrease in cell survival when compared with 2DG or cisplatin alone. Treatment with 2DG and cisplatin also caused perturbations in parameters indicative of oxidative stress, including decreased intracellular total glutathione and increased percentage of glutathione disulfide. Simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC) inhibited parameters indicative of oxidative stress, as well as protected FaDu cells from the cytotoxic effects of cisplatin alone and the combination of 2DG and cisplatin. In addition, polyethylene glycol-conjugated antioxidant enzymes (PEG-superoxide dismutase and PEG-catalase) also protected FaDu cells from 2DG toxicity. An inhibitor of glutathione synthesis, l-buthionine-[S,R]-sulfoximine (BSO), sensitized FaDu cells to the cytotoxic effects of 2DG and cisplatin, and these effects were inhibited by NAC. Furthermore, the combination of 2DG, cisplatin, and BSO significantly increased the percentage of glutathione disulfide, which was also inhibited by NAC. These results support the hypothesis that exposure of human head and neck cancer cells to 2DG combined with cisplatin enhances cytotoxicity via metabolic oxidative stress. These findings provide a strong biochemical rationale for evaluating inhibitors of glucose and hydroperoxide metabolism in combination with cisplatin for the treatment of head and neck cancer.}, }
@article {pmid17408840, year = {2007}, author = {Rooney, JP}, title = {The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury.}, journal = {Toxicology}, volume = {234}, number = {3}, pages = {145-156}, doi = {10.1016/j.tox.2007.02.016}, pmid = {17408840}, issn = {0300-483X}, mesh = {*Animal Nutritional Physiological Phenomena ; Animals ; Chelating Agents/therapeutic use ; Half-Life ; Humans ; Ligands ; Mercury/chemistry/pharmacokinetics/*toxicity ; Mercury Poisoning/diagnosis/drug therapy ; *Nutritional Physiological Phenomena ; Sulfhydryl Compounds/*physiology ; Thioctic Acid/therapeutic use ; }, abstract = {Mercury has been a known as a toxic substance for centuries. Whilst the clinical features of acute mercury poisoning have been well described, chronic low dose exposure to mercury remains poorly characterised and its potential role in various chronic disease states remains controversial. Low molecular weight thiols, i.e. sulfhydryl containing molecules such as cysteine, are emerging as important factors in the transport and distribution of mercury throughout the body due to the phenomenon of "Molecular Mimicry" and its role in the molecular transport of mercury. Chelation agents such as the dithiols sodium 2,3-dimercaptopropanesulfate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are the treatments of choice for mercury toxicity. Alpha-lipoic acid (ALA), a disulfide, and its metabolite dihydrolipoic acid (DHLA), a dithiol, have also been shown to have chelation properties when used in an appropriate manner. Whilst N-acetyl-cysteine (NAC) and glutathione (GSH) have been recommended in the treatment of mercury toxicity in the past, an examination of available evidence suggests these agents may in fact be counterproductive. Zinc and selenium have also been shown to exert protective effects against mercury toxicity, most likely mediated by induction of the metal binding proteins metallothionein and selenoprotein-P. Evidence suggests however that the co-administration of selenium and dithiol chelation agents during treatment may also be counter-productive. Finally, the issue of diagnostic testing for chronic, historical or low dose mercury poisoning is considered including an analysis of the influence of ligand interactions and nutritional factors upon the accuracy of "chelation challenge" tests.}, }
@article {pmid17405573, year = {2007}, author = {Ambrosi, P and Drici, MD and Herpin, D and Pathak, A}, title = {[The best of clinical pharmacology in 2006].}, journal = {Archives des maladies du coeur et des vaisseaux}, volume = {100 Spec No 1}, number = {}, pages = {99-102}, pmid = {17405573}, issn = {0003-9683}, mesh = {Angioplasty, Balloon, Coronary/adverse effects ; Cardiovascular Diseases/*drug therapy/epidemiology ; Drug Therapy/trends ; Fatty Acids, Omega-3/therapeutic use ; France ; Humans ; Risk Factors ; }, abstract = {The clinical pharmacological and therapeutic working group was particularly impressed by twelve recent publications relative to its various themes of interest. Two studies were made of the prognostic impact of non-observance of treatment which seems to be associated with an extra-mortality even when the treatment is placebo: the probable explanation is that the non-observance of drug therapy is also associated with the non observance of dietary/life style measures and with cognitive dysfunction associated with more severe cardiac disease. A recent study on n-acetyl-cysteine has rekindled the debate on this substance for preventing nephrotoxicity of radiological contrast used during angioplasty in high risk patients. The risks of AINS drug therapy has been reassessed. The increased risk of myocardial infarction is confirmed with celecoxib but not with "classical" AINS drugs if not prescribed for more than one year and without aspirin. With respect to lipid-lowering drugs, should statins be prescribed to attain a target value of LDL-cholesterol or to attain a given reduction in LDL-cholesterol? The death knell of fibrates has more or less been rung by the results of the FIELD study and the real value of OMEGA-3 drugs should be reassessed by good quality prospective studies. In the domain of hypertension, the recent arrival of aliskiren, the first of the antirenin drugs, is noteworthy although its role in the therapeutic strategy, remains to be defined. Finally, a comment is made on the results of the TROPHY study which suggest value in the possible prevention of hypertension with angiotensin II inhibitors in patients at risk of developing hypertension.}, }
@article {pmid17404061, year = {2007}, author = {Kim, MJ and Kim, DH and Lee, KW and Yoon, DY and Surh, YJ}, title = {Jaceosidin induces apoptosis in ras-transformed human breast epithelial cells through generation of reactive oxygen species.}, journal = {Annals of the New York Academy of Sciences}, volume = {1095}, number = {}, pages = {483-495}, doi = {10.1196/annals.1397.052}, pmid = {17404061}, issn = {0077-8923}, mesh = {Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects/physiology ; Cell Line, Transformed ; Cell Proliferation/drug effects ; Epithelial Cells/*drug effects/metabolism ; Female ; Flavonoids/*pharmacology ; Growth Inhibitors/pharmacology ; Humans ; Mammary Glands, Human/cytology/*drug effects/*metabolism ; Reactive Oxygen Species/*metabolism ; ras Proteins/*physiology ; }, abstract = {Extracts of Artemisia plants possess anti-inflammatory and antioxidative activities. Eupatilin (5,7-dihydroxy-3',4',6-tri-methoxy-flavone), a pharmacologically active flavone derived from Artemisia asiatica, was shown to inhibit phorbol ester-induced cyclooxygenase-2 expression and NF-kappaB activation in mouse skin, and also to induce cell cycle arrest in ras-transformed human mammary epithelial (MCF10A-ras) cells. In this article, we examined the ability of jaceosidin (4',5,7-trihydroxy-3',6-dimethoxyflavone) isolated from Artemisia argyi to inhibit the proliferation of MCF10A-ras cells. Jaceosidin reduced the viability of MCF10A-ras cells to a greater extent than eupatilin. Jaceosidin treatment resulted in increased intracellular accumulation of reactive oxygen species (ROS) in MCF10A-ras cells, which was blocked by the antioxidant N-acetylcysteine (NAC). NAC attenuated jaceosidin-induced cytotoxicity. To better assess the proapoptotic effects of jaceosidin, we analyzed the treated cells by the flow cytometry. MCF10A-ras cells treated with jaceosidin (100 microM) exhibited the increased proportion of hypodiploid or apoptotic cells (48.72% as composed to 7.78% in control cells). Jaceosidin treatment also increased the ratio of proapoptotic Bax to the antiapoptotic Bcl-2 and induced the cleavage of caspase-3 and poly(ADP-ribose)polymerase (PARP). Moreover, jaceosidin elevated the expression of p53 and p21, while the compound inhibited the activation of ERK1/2 that is an important component of cell survival signaling.}, }
@article {pmid17400565, year = {2007}, author = {Efrati, S and Berman, S and Siman-Tov, Y and Lotan, R and Averbukh, Z and Weissgarten, J and Golik, A}, title = {N-acetylcysteine attenuates NSAID-induced rat renal failure by restoring intrarenal prostaglandin synthesis.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {22}, number = {7}, pages = {1873-1881}, doi = {10.1093/ndt/gfm113}, pmid = {17400565}, issn = {0931-0509}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Anti-Inflammatory Agents, Non-Steroidal ; *Cytoprotection ; Diclofenac ; Dinoprostone/*biosynthesis ; Hydrogen Peroxide/antagonists &amp; inhibitors ; Kidney/*drug effects/*metabolism/physiopathology ; Kidney Cortex/metabolism ; Kidney Medulla/blood supply/metabolism ; Male ; Microcirculation/drug effects ; Rats ; Rats, Sprague-Dawley ; Renal Circulation/drug effects ; Renal Insufficiency/*chemically induced/metabolism/*physiopathology ; Tissue Distribution ; }, abstract = {BACKGROUND: Renal failure is a threatening side-effect of NSAID administration, consequent to NSAID-mediated abrogation of prostaglandin synthesis and resultant renal ischaemia. N-acetylcysteine (NAC) has renoprotective properties. We examined effects of NAC in a rat model of NSAID-induced renal failure.<br><br>METHODS: Renal failure was generated in 80 rats by 6-day water deprivation and 3-day 15 mg/kg/day diclofenac injection. The rats were concomitantly treated, or not, by NAC, 40 mg/kg/day. Renal function was evaluated by cystatin C, creatinine and urea. Intrarenal blood flow was measured by laser Doppler. The kidneys were subjected to pathological examination or evaluation of intrarenal NO, H2O2 and PGE2.<br><br>RESULTS: NAC significantly attenuated deterioration of renal function in diclofenac-treated rats: cystatin C dropped from 2.8+/-0.35 to 2.2+/-0.67 mg/l, P=0.016; creatinine from 1.2+/-0.97 to 0.96+/-0.19 mg/dl, P=0.02; urea from 208.4+/-57.9 to 157.6+/-33.7 mg/dl, P=0.028. Diclofenac-inflicted hystopathological damage was significantly reduced following NAC treatment. Intrarenal medullar blood flow dropped by 51+/-12.4% in diclofenac-treated rats, but only by 14+/-3.39% in those receiving NAC after diclofenac injection (P<0.001). H2O2 was elevated in renal tissues of diclofenac-receiving rats, while decreased in NAC-treated animals. PGE2 release by diclofenac-treated rats dropped significantly, but was restored after NAC administration both in renal cortices (144.7+/-10.4 vs 19.7+/-1.5 pmol/ml, P<0.001) and medullae (148.5+/-7.3 vs 66.6+/-7.3 pmol/ml, P<0.001).<br><br>CONCLUSIONS: In this model of renal failure induced by NSAID administration combined with water deprivation, NAC treatment successfully attenuated the deterioration of renal function by inducing renal vasodilatation, decreasing oxidative stress via inhibition of intrarenal ROS content and restoration of intrarenal PGE2 release back to the basal levels.}, }
@article {pmid17397890, year = {2007}, author = {Cheng, Y and Chang, LW and Cheng, LC and Tsai, MH and Lin, P}, title = {4-Methoxyestradiol-induced oxidative injuries in human lung epithelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {220}, number = {3}, pages = {271-277}, doi = {10.1016/j.taap.2007.01.024}, pmid = {17397890}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cell Proliferation/drug effects ; Comet Assay ; DNA Damage ; Dose-Response Relationship, Drug ; Epithelial Cells/*drug effects/metabolism/pathology ; Estradiol/*analogs &amp; derivatives/metabolism/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Glutathione Disulfide/metabolism ; Humans ; Lung/drug effects/metabolism/pathology ; Mitotic Index ; Models, Biological ; Oxidative Stress/*drug effects ; Polychlorinated Dibenzodioxins/pharmacology ; Reactive Oxygen Species/metabolism ; Spindle Apparatus/drug effects ; Superoxide Dismutase/metabolism ; Tubulin/drug effects ; }, abstract = {Epidemiological studies indicated that people exposed to dioxins were prone to the development of lung diseases including lung cancer. Animal studies demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increased liver tumors and promoted lung metaplasia in females. Metabolic changes in 17beta-estradiol (E(2)) resulted from an interaction between TCDD and E(2) could be associated with gender difference. Previously, we reported that methoxylestradiols (MeOE(2)), especially 4-MeOE(2), accumulated in human lung cells (BEAS-2B) co-treated with TCDD and E(2). In the present study, we demonstrate unique accumulation of 4-MeOE(2), as a result of TCDD/E(2) interaction and revealed its bioactivity in human lung epithelial cell line (H1355). 4-Methoxyestradiol treatment significantly decreased cell growth and increased mitotic index. Elevation of ROS and SOD activity, with a concomitant decrease in the intracellular GSH/GSSG ratio, was also detected in 4-MeOE(2)-treated cells. Quantitative comet assay showed increased oxidative DNA damage in the 4-MeOE(2)-treated H1355 cells, which could be significantly reduced by the anti-oxidant N-acetylcysteine (NAC). However, inhibition of cell growth and increase in mitotic arrest induced by 4-MeOE(2) were unaffected by NAC. We concluded that 4-MeOE(2) accumulation resulting from TCDD and E(2) interaction would contribute to the higher vulnerability on lung pathogenesis in females when exposed to TCDD.}, }
@article {pmid17395740, year = {2007}, author = {Kaniuk, NA and Kiraly, M and Bates, H and Vranic, M and Volchuk, A and Brumell, JH}, title = {Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy.}, journal = {Diabetes}, volume = {56}, number = {4}, pages = {930-939}, doi = {10.2337/db06-1160}, pmid = {17395740}, issn = {0012-1797}, mesh = {Animals ; Autophagy ; Cell Line ; Diabetes Mellitus/*physiopathology ; Genes, Reporter ; Insulin/*genetics ; Insulin-Secreting Cells/*physiology ; Insulinoma ; Oxidative Stress/*physiology ; Proteins/*metabolism ; Rats ; Ubiquitin/*metabolism ; }, abstract = {Diabetes-induced oxidative stress can lead to protein misfolding and degradation by the ubiquitin-proteasome system. This study examined protein ubiquitination in pancreatic sections from Zucker diabetic fatty rats. We observed large aggregates of ubiquitinated proteins (Ub-proteins) in insulin-expressing beta-cells and surrounding acinar cells. The formation of these aggregates was also observed in INS1 832/13 beta-cells after exposure to high glucose (30 mmol/l) for 8-72 h, allowing us to further characterize this phenotype. Oxidative stress induced by aminotriazole (ATZ) was sufficient to stimulate Ub-protein aggregate formation. Furthermore, the addition of the antioxidants N-acetyl cysteine (NAC) and taurine resulted in a significant decrease in formation of Ub-protein aggregates in high glucose. Puromycin, which induces defective ribosomal product (DRiP) formation was sufficient to induce Ub-protein aggregates in INS1 832/13 cells. However, cycloheximide (which blocks translation) did not impair Ub-protein aggregate formation at high glucose levels, suggesting that long-lived proteins are targeted to these structures. Clearance of Ub-protein aggregates was observed during recovery in normal medium (11 mmol/l glucose). Despite the fact that 20S proteasome was localized to Ub-protein aggregates, epoxomicin treatment did not affect clearance, indicating that the proteasome does not degrade proteins localized to these structures. The autophagy inhibitor 3MA blocked aggregate clearance during recovery and was sufficient to induce their formation in normal medium. Together, these findings demonstrate that diabetes-induced oxidative stress induces ubiquitination and storage of proteins into cytoplasmic aggregates that do not colocalize with insulin. Autophagy, not the proteasome, plays a key role in regulating their formation and degradation. To our knowledge, this is the first demonstration that autophagy acts as a defense to cellular damage incurred during diabetes.}, }
@article {pmid17395153, year = {2007}, author = {Lai, KP and Law, AY and Yeung, HY and Lee, LS and Wagner, GF and Wong, CK}, title = {Induction of stanniocalcin-1 expression in apoptotic human nasopharyngeal cancer cells by p53.}, journal = {Biochemical and biophysical research communications}, volume = {356}, number = {4}, pages = {968-975}, doi = {10.1016/j.bbrc.2007.03.074}, pmid = {17395153}, issn = {0006-291X}, mesh = {*Apoptosis ; Cell Line, Tumor ; *Gene Expression Regulation, Neoplastic ; Glycoproteins/*metabolism ; Humans ; Nasopharyngeal Neoplasms/*metabolism/*pathology ; Signal Transduction ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {There is growing evidence to suggest that altered patterns of STC1 gene expression relate to the process of human cancer development. Our previous study has demonstrated the involvement of HIF-1 in the regulation of STC1 expression in human cancer cells. Recently, STC1 has been implicated as a putative pro-apoptotic factor in regulating the cell-death mechanism. Thus it would be of interest to know if STC1 is regulated by a tumor suppressor protein, p53. In this study, we provide evidence to demonstrate that the induction of STC1 expression in apoptotic human nasopharyngeal cancer cells (CNE2) is mediated by the activation of p53. Our study indicated that the activation of STC1 and heat-shock protein (hsp70) accompanied iodoacetamide (IDAM)-induced apoptosis in CNE-2. In addition, cellular events such as GSH depletion, mitochondrial membrane depolarization, reduction of pAkt and procaspase-3, and the induction of total p53 protein, acetylated p53, and annexin V positive cells were observed. The activation of STC1 was found to be at the transcriptional level and was independent of prior protein synthesis. Co-treatment of IDAM exposed cells with N-acetyl cysteine (NAC) prevented cell death by restoring mitochondrial membrane potential and cellular levels of GSH. NAC co-treatment also suppressed STC1 expression but had no effect on IDAM-induced hsp70 expression. RNA interference studies demonstrated that endogenous p53 was involved in activating STC1 gene expression. Collectively, the present findings provide the first evidence of p53 regulation of STC1 expression in human cancer cells.}, }
@article {pmid17395010, year = {2007}, author = {Yang, J and Su, Y and Richmond, A}, title = {Antioxidants tiron and N-acetyl-L-cysteine differentially mediate apoptosis in melanoma cells via a reactive oxygen species-independent NF-kappaB pathway.}, journal = {Free radical biology &amp; medicine}, volume = {42}, number = {9}, pages = {1369-1380}, pmid = {17395010}, issn = {0891-5849}, support = {IK6 BX005225/BX/BLRD VA/United States ; T32 HL007751/HL/NHLBI NIH HHS/United States ; R01 CA116021-01/CA/NCI NIH HHS/United States ; R01 CA116021-02/CA/NCI NIH HHS/United States ; I01 BX000196/BX/BLRD VA/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; R01 CA116021/CA/NCI NIH HHS/United States ; CA116021/CA/NCI NIH HHS/United States ; T32 CA119925/CA/NCI NIH HHS/United States ; K12 CA090625/CA/NCI NIH HHS/United States ; K12 GM068543/GM/NIGMS NIH HHS/United States ; CA68485/CA/NCI NIH HHS/United States ; 5P30 AR41943/AR/NIAMS NIH HHS/United States ; P30 AR041943/AR/NIAMS NIH HHS/United States ; }, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/*pharmacology ; Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Humans ; Melanoma ; Membrane Potentials/drug effects/physiology ; Mitochondria/drug effects/physiology ; NF-kappa B/*physiology ; Necrosis ; Reactive Oxygen Species/*metabolism ; }, abstract = {Tiron and N-acetyl-L-cysteine (NAC) have been recognized as potential antioxidants capable of inhibiting apoptosis induced by reactive oxygen species (ROS). Although the ROS-scavenging function of tiron and NAC is clear, the mechanism for their regulation of apoptosis is still elusive. Here we demonstrate that tiron increases nuclear factor-kappaB (NF-kappaB)/DNA binding and as a result enhances NF-kappaB transcriptional activity. In contrast, NAC inhibits NF-kappaB activation by reducing inhibitor of kappaB kinase (IKK) activity. Moreover, the expression of an NF-kappaB target gene, the chemokine CXCL1, is promoted by tiron and suppressed by NAC. Finally, tiron confers an antiapoptotic function, while NAC imparts a proapoptotic function in melanoma cells. These functions correlate with the alteration of mitochondrial membrane potential but not ROS production or induction of activating protein-1 (AP-1). This study underscores the potential benefits of regulating NF-kappaB activity in melanoma cells as a therapeutic approach.}, }
@article {pmid17394959, year = {2007}, author = {Recio-Mayoral, A and Chaparro, M and Prado, B and Cózar, R and Méndez, I and Banerjee, D and Kaski, JC and Cubero, J and Cruz, JM}, title = {The reno-protective effect of hydration with sodium bicarbonate plus N-acetylcysteine in patients undergoing emergency percutaneous coronary intervention: the RENO Study.}, journal = {Journal of the American College of Cardiology}, volume = {49}, number = {12}, pages = {1283-1288}, doi = {10.1016/j.jacc.2006.11.034}, pmid = {17394959}, issn = {1558-3597}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; *Angioplasty, Balloon, Coronary/methods ; Coronary Disease/physiopathology/therapy ; *Emergency Medical Services/methods ; Female ; *Fluid Therapy/methods ; Humans ; Male ; Middle Aged ; Prospective Studies ; Single-Blind Method ; Sodium Bicarbonate/*administration &amp; dosage ; }, abstract = {OBJECTIVES: This study was designed to determine the effectiveness of a protocol for rapid intravenous hydration to prevent contrast-induced nephropathy (CIN) in patients undergoing emergency percutaneous coronary intervention (PCI).<br><br>BACKGROUND: Contrast-induced nephropathy frequently complicates PCI, resulting in prolonged hospitalization and increased in-hospital and long-term morbidity and mortality. Little is known regarding prevention of CIN in patients undergoing urgent PCI.<br><br>METHODS: We conducted a prospective, controlled, randomized, single-center trial in 111 consecutive patients with acute coronary syndrome undergoing emergency PCI. As part of the hydration therapy, 56 patients (group A) received an infusion of sodium bicarbonate plus N-acetylcysteine (N-AC) started just before contrast injection and continued for 12 h after PCI. The remaining 55 patients (group B) received the standard hydration protocol consisting of intravenous isotonic saline for 12 h after PCI. In both groups, 2 doses of oral N-AC were administered the next day.<br><br>RESULTS: The 2 groups were similar with respect to age, gender, diabetes mellitus, and baseline serum creatinine. A serum creatinine concentration >0.5 mg/dl from baseline after emergency PCI was observed in 1 patient in group A (1.8%) and in 12 patients in group B (21.8%; p < 0.001). Acute anuric renal failure was observed in 1 patient (1.8%) in group A and in 7 patients (12.7%) in group B (p = 0.032).<br><br>CONCLUSIONS: Rapid intravenous hydration with sodium bicarbonate plus N-AC before contrast injection is effective and safe in the prevention of CIN in patients undergoing emergency PCI.}, }
@article {pmid17394767, year = {2007}, author = {Yuan, J and Jia, R and Bao, Y}, title = {Aldosterone up-regulates production of plasminogen activator inhibitor-1 by renal mesangial cells.}, journal = {Journal of biochemistry and molecular biology}, volume = {40}, number = {2}, pages = {180-188}, doi = {10.5483/bmbrep.2007.40.2.180}, pmid = {17394767}, issn = {1225-8687}, mesh = {Acetylcysteine/pharmacology ; Aldosterone/*pharmacology ; Angiotensin II/pharmacology ; Animals ; Antibodies/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Mesangial Cells/cytology/*drug effects/*metabolism ; Neutralization Tests ; Plasminogen Activator Inhibitor 1/*genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Spironolactone/pharmacology ; Time Factors ; Transforming Growth Factor beta1/immunology/metabolism ; Up-Regulation/*drug effects ; }, abstract = {In vivo studies have demonstrated that aldosterone is an independent contributor to glomerulosclerosis. In the present study, we have investigated whether aldosterone itself mediated glomerulosclerosis, as angiotensin II (Ang II) did, by inducing cultured renal mesangial cells to produce plasminogen activator inhibitor-1 (PAI-1), and whether these effects were mediated by aldosterone-induced increase in transforming growth factor beta(1) (TGF-beta(1)) expression and cellular reactive oxygen species (ROS) activity. Quiescent rat mesangial cells were treated by aldosterone alone or by combination of aldosterone and spironolactone, Ang II, neutralizing antibody to TGF-beta(1) or antioxidant Nacetylcysteme (NAC). This study indicate that aldosterone can increase PAI-1 mRNA and protein expression by cultured mesangial cells alone, which is independent of aldosterone-induced increases in TGF-beta(1) expression and cellular ROS. The effects on PAI-1, TGF-beta(1) and ROS generation were markedly attenuated by spironolactone, a mineralocorticoid receptor antagonist, which demonstrate that mineralocorticoid receptor (MR) may play a role in mediating these effects of aldosterone.}, }
@article {pmid17383050, year = {2007}, author = {Opitz, I and Sigrist, B and Hillinger, S and Lardinois, D and Stahel, R and Weder, W and Hopkins-Donaldson, S}, title = {Taurolidine and povidone-iodine induce different types of cell death in malignant pleural mesothelioma.}, journal = {Lung cancer (Amsterdam, Netherlands)}, volume = {56}, number = {3}, pages = {327-336}, doi = {10.1016/j.lungcan.2007.01.024}, pmid = {17383050}, issn = {0169-5002}, mesh = {Anti-Infective Agents, Local ; Antineoplastic Agents/*therapeutic use ; Biopsy ; Blotting, Western ; Caspase 3/drug effects/metabolism ; Cell Death/*drug effects ; Cell Line, Tumor ; Cell Membrane Permeability/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cisplatin/therapeutic use ; Drug Therapy, Combination ; Enzyme Activation/drug effects ; Flow Cytometry ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, p53/drug effects/genetics ; Humans ; Mesothelioma/drug therapy/*pathology ; Mitochondrial Membranes/drug effects/metabolism ; Pleural Neoplasms/drug therapy/*pathology ; Povidone-Iodine/*therapeutic use ; Reactive Oxygen Species/agonists/metabolism ; Taurine/*analogs &amp; derivatives/therapeutic use ; Thiadiazines/*therapeutic use ; }, abstract = {Taurolidine and povidone-iodine (PVP-I) are used in every day clinical practice, taurolidine as a broad spectrum antibiotic, and PVP-I as an antiseptic. The type of cell death induced in malignant pleural mesothelioma (MPM) cell lines by these agents was compared, and their ability to sensitize to chemotherapy assessed. Both taurolidine and PVP-I inhibited MPM cell growth after 7.5min incubation, but taurolidine was more effective at later time points and was more specific towards tumour cells than PVP-I. Taurolidine induced death by caspase-dependent and independent mechanisms, whereas in contrast, PVP-I induced a necrotic phenotype that was not caspase-dependent. Interestingly, both taurolidine and PVP-I induced the production of reactive oxygen intermediates and decreased mitochondrial membrane permeability, and cell death was inhibited by the oxygen scavenger N-acetyl cysteine. Taurolidine but not PVP-I treatment resulted in p53 activation in 2/3 MPM cell lines and a decrease in the protein levels of survivin, Bcl-2 and Mcl-1. Survivin also decreased in response to PVP-I whereas Bcl-xL remained unaffected by both treatments. Targeting of Bcl-xL with siRNA sensitized MPM cells to taurolidine and taurolidine treatment sensitized MPM cells to cisplatin-induced apoptosis. In conclusion, taurolidine and PVP-I are both cytotoxic to human MPM cells at early and late time points and induce reactive oxygen intermediate production. Taurolidine induces apoptosis and necrosis, activates p53 and sensitizes cells to cisplatin, whereas PVP-I inhibits cell growth via necrosis. Both agents are promising candidates for use in local treatment within multimodality concepts for MPM.}, }
@article {pmid17382202, year = {2007}, author = {Hong, J and Kwon, SJ and Sang, S and Ju, J and Zhou, JN and Ho, CT and Huang, MT and Yang, CS}, title = {Effects of garcinol and its derivatives on intestinal cell growth: Inhibitory effects and autoxidation-dependent growth-stimulatory effects.}, journal = {Free radical biology &amp; medicine}, volume = {42}, number = {8}, pages = {1211-1221}, doi = {10.1016/j.freeradbiomed.2007.01.016}, pmid = {17382202}, issn = {0891-5849}, mesh = {Apoptosis/drug effects ; Cell Cycle/*drug effects ; Cell Division/*drug effects ; Cell Line ; Cell Line, Tumor ; Colonic Neoplasms ; Humans ; Intestines/*cytology/drug effects ; Kinetics ; Plant Extracts/pharmacology ; Terpenes/*pharmacology ; }, abstract = {Garcinol, a polyisoprenylated benzophenone, from the Garcinia indica fruit rind, has been suggested to be an anti-inflammatory and anti-cancer agent. To explore the possible use of this redox-sensitive compound as a colon cancer preventive agent, we investigated the effects of garcinol and its oxidative derivatives, cambogin, garcim-1, and garcim-2, on the growth of HT-29 and HCT-116 colon cancer cells, as well as IEC-6 and INT-407 normal immortalized intestinal cells. Garcinol and its derivatives showed potent growth-inhibitory effects on all intestinal cells, showing IC50 of 3.2-21.4 microM after a 3-day treatment. Garcim-1 exhibited the strongest effect with IC50 of 3.2-5.9 microM. Garcinol was more effective in inhibiting growth of cancer cells than that of normal immortalized cells. Flow-cytometric analysis showed increased sub-G1 cells by treatment with garcinol and cambogin. Induction of apoptosis by garcinol and cambogin (2-10 microM) was also observed based on caspase-3 activation and enhanced annexin V staining. The inhibitory effect of garcinol on cell growth was much more pronounced in the absence of fetal bovine serum (FBS), decreasing IC50 to 1.5 from 11.8 microM in 72-h incubations and to 3 from 38 microM in 24-h incubations, possibly due to the binding of garcinol to FBS, which markedly reduced cellular levels of garcinol. Under these conditions, redox reactions seem not to be involved in the inhibition. In contrast to the inhibitory effect, low concentrations (<1 microM) of garcinol and cambogin stimulated the growth of both normal and cancer cells by 10-100%, and the activity seemed to be mediated by reactive oxygen species. In the presence of superoxide dismutase/catalase or N-acetyl cysteine, low concentrations of garcinol (<1 microM) decreased cell growth. Garcinol (0.5-1 microM) also increased the phosphorylation of extracellular signal-related kinase 1/2 and AKT and the level of survivin, and the effects were abolished in the presence of superoxide dismutase/catalase. Our results indicate that garcinol and its derivatives can inhibit intestinal cell growth, but low concentrations of garcinol can stimulate cell growth. It remains to be determined whether the currently observed stimulatory and inhibitory effects of garcinol on colon cell growth occur in vivo.}, }
@article {pmid17382198, year = {2007}, author = {Millar, TM and Phan, V and Tibbles, LA}, title = {ROS generation in endothelial hypoxia and reoxygenation stimulates MAP kinase signaling and kinase-dependent neutrophil recruitment.}, journal = {Free radical biology &amp; medicine}, volume = {42}, number = {8}, pages = {1165-1177}, doi = {10.1016/j.freeradbiomed.2007.01.015}, pmid = {17382198}, issn = {0891-5849}, mesh = {Antimycin A/pharmacology ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology ; Cell Hypoxia/drug effects/*physiology ; Endothelium, Vascular/drug effects/*physiology ; Extracellular Signal-Regulated MAP Kinases/*blood ; Glutathione Transferase/metabolism ; Humans ; MAP Kinase Signaling System/*physiology ; Membrane Potentials/drug effects ; Mitochondrial Membranes/drug effects/physiology ; Neutrophils/drug effects/*physiology ; Oxygen Consumption/drug effects/*physiology ; Reactive Oxygen Species/*metabolism ; Rotenone/pharmacology ; Umbilical Veins ; }, abstract = {Reactive oxygen species (ROS)-induced injury has been shown to occur during the reperfusion phase of ischemia-reperfusion and ROS are known to induce signaling events. We hypothesized that oxygen sensing in endothelial cells is also dependent on internal redox changes during hypoxia and that endothelial cells respond to changing oxygen environments via signaling, switching to an inflammatory phenotype. Endothelial cells exposed to relative hypoxia or the mitochondrial inhibitors rotenone, antimycin A, or FCCP show loss of mitochondrial membrane potential. During hypoxia, an increase in cytoplasmic ROS and glutathione S-transferase activity occurred, suggesting changes in intracellular redox state, mimicked with rotenone or FCCP but inhibited by antimycin A. Phosphorylation of stress-responsive mitogen-activated protein kinases occurred in hypoxia and was rapid and prolonged. Phosphorylation was inhibited by vitamin C, N-acetyl cysteine, or antimycin A. Chelation of intracellular calcium inhibits phosphorylation but the mitochondrial transition pore inhibitor cyclosporin A had no effect. Reoxygenation caused a further round of signaling, which was rapid but transient. Functionally, adhesion of neutrophils after hypoxia-reoxygenation under flow is ROS, P-selectin, and MAPK dependent. Therefore, changes in cellular signaling and phenotype are abrogated by ROS scavengers and suggest their use as therapeutic agents in ischemia-reperfusion.}, }
@article {pmid17382001, year = {2004}, author = {Chong, E and Zed, PJ}, title = {N-acetylcysteine for radiocontrast-induced nephropathy: potential role in the emergency department?.}, journal = {CJEM}, volume = {6}, number = {4}, pages = {253-258}, doi = {10.1017/s1481803500009210}, pmid = {17382001}, issn = {1481-8035}, abstract = {OBJECTIVE: To systematically review the efficacy and safety of N-acetylcysteine (NAC) for the prevention of radiocontrast-induced nephropathy (RIN), and to discuss its potential role in the emergency department.<br><br>METHODOLOGY: We conducted a search of MEDLINE (from 1966 to December 2003), PubMed (1966 to December 2003) and EMBASE (1988 to December 2003) for English-language, prospective, randomized, controlled trials in humans using the search terms N-acetylcysteine, acetylcysteine, radiopharmaceuticals, contrast media, and kidney failure (acute).<br><br>RESULTS: Five trials support and 4 trials refute the hypothesis that NAC helps prevent RIN. In 7 of 9 trials, oral NAC was administered twice daily for 2 days, on the day before and on the day of the radiocontrast study--a regime not feasible for emergent situations. More recent trials suggest that adequate hydration and lower volumes of radiocontrast, rather than NAC, are more effective ways to prevent RIN.<br><br>CONCLUSION: Although further study may be indicated, current evidence does not suggest that NAC has a role in the emergency prevention of RIN.}, }
@article {pmid17378375, year = {2006}, author = {Zicha, J and Dobesová, Z and Kunes, J}, title = {Antihypertensive mechanisms of chronic captopril or N-acetylcysteine treatment in L-NAME hypertensive rats.}, journal = {Hypertension research : official journal of the Japanese Society of Hypertension}, volume = {29}, number = {12}, pages = {1021-1027}, doi = {10.1291/hypres.29.1021}, pmid = {17378375}, issn = {0916-9636}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antihypertensive Agents/pharmacology/*therapeutic use ; Blood Pressure/drug effects ; Captopril/pharmacology/*therapeutic use ; Hypertension/chemically induced/*prevention &amp; control ; Male ; NG-Nitroarginine Methyl Ester/antagonists &amp; inhibitors/pharmacology ; Nitroprusside/pharmacology/therapeutic use ; Pentolinium Tartrate/pharmacology/therapeutic use ; Rats ; Rats, Wistar ; Tetraethylammonium/pharmacology/therapeutic use ; }, abstract = {Hypertension due to chronic inhibition of NO synthase (NOS) by Nomega-nitro-L-arginine methyl ester (L-NAME) administration is characterized by both impaired NO-dependent vasodilation and enhanced sympathetic vasoconstriction. The aim of our study was to evaluate changes in the participation of major vasoactive systems in L-NAME-treated rats which were subjected to simultaneous antihypertensive (captopril) or antioxidant (N-acetylcysteine, NAC) treatment. Three-month-old Wistar males treated with L-NAME (60 mg/kg/day) for 5 weeks were compared to rats in which L-NAME treatment was combined with simultaneous chronic administration of captopril or NAC. Basal blood pressure (BP) and its acute responses to consecutive i.v. injections of captopril (10 mg/kg), pentolinium (5 mg/kg), L-NAME (30 mg/kg), tetraethylammonium (TEA, 16 mg/kg) and nitroprusside (NP, 20 microg/kg) were determined in conscious rats at the end of the study. The development of L-NAME hypertension was prevented by captopril treatment, whereas NAC treatment caused only a moderate BP reduction. Captopril treatment normalized the sympathetic BP component and significantly reduced residual BP (measured at full NP-induced vasodilation). In contrast, chronic NAC treatment did not modify the sympathetic BP component or residual BP, but significantly enhanced NO-dependent vasodilation. Neither captopril nor NAC treatment influenced the compensatory increase of TEA-sensitive vasodilation mediated by endothelium-derived hyperpolarizing factor in L-NAME-treated rats. Chronic captopril treatment prevented L-NAME hypertension by lowering of sympathetic tone, whereas chronic NAC treatment attenuated L-NAME hypertension by reduction in the vasodilator deficit due to enhanced NO-dependent vasodilation.}, }
@article {pmid17374475, year = {2007}, author = {D'Agostini, F and Fiallo, P and Pennisi, TM and De Flora, S}, title = {Chemoprevention of smoke-induced alopecia in mice by oral administration of L-cystine and vitamin B6.}, journal = {Journal of dermatological science}, volume = {46}, number = {3}, pages = {189-198}, doi = {10.1016/j.jdermsci.2007.02.005}, pmid = {17374475}, issn = {0923-1811}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Administration, Oral ; Alopecia/*etiology/pathology/*prevention &amp; control ; Animals ; Apoptosis ; Body Weight ; Chemoprevention/*methods ; Cystine/administration &amp; dosage/metabolism/*pharmacology ; Dose-Response Relationship, Drug ; Female ; Hair Follicle/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Tobacco Smoke Pollution/*adverse effects ; Vitamin B 6/administration &amp; dosage/*pharmacology ; }, abstract = {BACKGROUND: We previously demonstrated that high doses of environmental cigarette smoke (ECS) induce alopecia in mice. This effect was prevented by the oral administration of N-acetylcysteine (NAC), an analogue and precursor of L-cysteine and reduced glutathione.<br><br>OBJECTIVES: The present study aimed at assessing whether L-cystine, the oxidized form of L-cysteine, which is a key hair component, may behave like NAC in inhibiting ECS-induced alopecia and modulating the mechanisms responsible for this condition.<br><br>METHODS: C57BL/6 mice were exposed whole-body to ECS in a smoking machine. Groups of mice received in the diet, at three dose levels, a mixture of L-cystine with vitamin B6, which plays a role in L-cystine incorporation in hair cells. Occurrence of alopecia areas and apoptosis of hair bulb cells were evaluated for up to 6 months of exposure, and the time course induction of micronucleated erythrocytes in peripheral blood was investigated.<br><br>RESULTS: The frequency of micronucleated erythrocytes was increased by ECS, irrespective of treatment with L-cystine/vitamin B6. ECS-induced alopecia and apoptosis of hair bulb cells in all exposed mice. L-Cystine/vitamin B6 inhibited alopecia in a dose-dependent fashion.<br><br>CONCLUSIONS: High-dose ECS induces apoptosis-related alopecia in mice, and oral administration of L-cystine/vitamin B6 is an effective preventive treatment.}, }
@article {pmid17371946, year = {2007}, author = {Chiu, JJ and Chen, LJ and Lee, CI and Lee, PL and Lee, DY and Tsai, MC and Lin, CW and Usami, S and Chien, S}, title = {Mechanisms of induction of endothelial cell E-selectin expression by smooth muscle cells and its inhibition by shear stress.}, journal = {Blood}, volume = {110}, number = {2}, pages = {519-528}, pmid = {17371946}, issn = {0006-4971}, support = {R01 HL064382/HL/NHLBI NIH HHS/United States ; R01 HL080518/HL/NHLBI NIH HHS/United States ; HL064382/HL/NHLBI NIH HHS/United States ; HL080518/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Coculture Techniques ; E-Selectin/*genetics ; Endothelium, Vascular/cytology/*physiology ; Gene Expression Regulation ; Humans ; Interleukin-1/genetics ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Muscle, Smooth, Vascular/cytology/*physiology ; Signal Transduction ; Stress, Mechanical ; Umbilical Veins ; }, abstract = {E-selectin is a major adhesion molecule expressed by endothelial cells (ECs), which are exposed to shear stress and neighboring smooth muscle cells (SMCs). We investigated the mechanisms underlying the modulation of EC E-selectin expression by SMCs and shear stress. SMC coculture induced rapid and sustained increases in expression of E-selectin and phosphorylation of interleukin-1 (IL-1) receptor-associated kinase glycoprotein-130, as well as the downstream mitogen-activated protein kinases (MAPKs) and Akt. By using specific inhibitors, dominant-negative mutants, and small interfering RNA, we demonstrated that activations of c-Jun-NH(2)-terminal kinase (JNK) and p38 of the MAPK pathways are critical for the coculture-induced E-selectin expression. Gel shifting and chromatin immunoprecipitation assays showed that SMC coculture increased the nuclear factor-kappaB (NF-kappaB)-promoter binding activity in ECs; inhibition of NF-kappaB activation by p65-antisense, lactacystin, and N-acetyl-cysteine blocked the coculture-induced E-selectin promoter activity. Protein arrays and blocking assays using neutralizing antibodies demonstrated that IL-1beta and IL-6 produced by EC/SMC cocultures are major contributors to the coculture induction of EC signaling and E-selectin expression. Preshearing of ECs at 12 dynes/cm(2) inhibited the coculture-induced EC signaling and E-selectin expression. Our findings have elucidated the molecular mechanisms underlying the SMC induction of EC E-selectin expression and the shear stress protection against this SMC induction.}, }
@article {pmid17371789, year = {2007}, author = {Dilger, RN and Baker, DH}, title = {Oral N-acetyl-L-cysteine is a safe and effective precursor of cysteine.}, journal = {Journal of animal science}, volume = {85}, number = {7}, pages = {1712-1718}, doi = {10.2527/jas.2006-835}, pmid = {17371789}, issn = {1525-3163}, mesh = {Acetylcysteine/*pharmacokinetics/*toxicity ; Administration, Oral ; Animal Feed ; Animal Nutritional Physiological Phenomena/*physiology ; Animals ; Biological Availability ; Chickens/*growth &amp; development/metabolism ; Cysteine/*metabolism ; Dose-Response Relationship, Drug ; Male ; Nutritional Requirements ; Random Allocation ; Weight Gain/*drug effects ; }, abstract = {Relative bioavailability and toxicity of N-acetyl-l-Cys (NAC) were evaluated in 9-d chick growth assays. The bioavailability of NAC relative to Cys was determined by feeding young chicks a highly purified crystalline AA diet singly deficient in Cys. Bio-availability estimates were obtained using standard slope-ratio methodology. N-Acetyl-l-cysteine was shown to be as effective as Cys in supporting chick growth, and was assigned a relative bioavailability value of 100%. To assess toxicity, a nutritionally adequate corn-soybean meal diet was supplemented with graded concentrations of NAC (isomolar to 10, 20, 30, or 40 g/kg of Cys, as-fed). When NAC supplied 10 or 20 g/kg of Cys, chick growth performance was unaffected, but NAC supplying 30 or 40 g/kg of Cys reduced (P < 0.05) BW gain by 13 and 34%, respectively, relative to the unsupplemented control diet. Only plasma-free NAC was substantially increased (P < 0.05) because of excess dietary NAC; plasma-free Cys was unaltered. We concluded that dietary NAC is efficacious in supplying Cys in support of chick growth, and only large excesses of NAC are growth depressing. Hence, the human clinical benefits of oral NAC likely result from its ability to deliver Cys safely and effectively to the portal circulation.}, }
@article {pmid17370867, year = {2007}, author = {Basyigit, I and Tugay, M and Dilioglugil, MO and Yildiz, F and Maral, H and Sozubir, S}, title = {Protective effects of N-acetylcysteine on peroxidative changes of the fetal rat lungs whose mothers were exposed to cigarette smoke.}, journal = {Human &amp; experimental toxicology}, volume = {26}, number = {2}, pages = {99-103}, doi = {10.1177/0960327107071917}, pmid = {17370867}, issn = {0960-3271}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Female ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Lung/drug effects/embryology/metabolism ; Malondialdehyde/metabolism ; Maternal-Fetal Exchange ; Oxidative Stress/drug effects ; Pregnancy ; Rats ; Rats, Wistar ; Smoke/*adverse effects ; }, abstract = {BACKGROUND: This experimental study investigated the protective effects of N-acetylcysteine (NAC) on peroxidative changes in fetal lungs in the offspring of rats exposed to cigarette smoke.<br><br>METHODS: Thirty fetal rats used for analysis, were divided into three groups as follows: control group (n = 10), whose mothers were exposed to fresh air; group I (n =10), whose mothers were exposed to cigarette smoke; and group II (n =10), whose mothers were exposed to cigarette smoke and given 10 mg/kg per day NAC. In groups I and II, smoke exposure was started 4 weeks before the pregnancy, and continued to the 14th day of pregnancy, and in Group II, NAC was administered intraperitoneally for 14 days. The mothers and their fetuses were decapitated on the 14th day of pregnancy. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in the lung tissues of fetuses to determine the oxidant-antioxidant balance.<br><br>RESULTS: While tissue MDA levels in Group I were found significantly higher than the control group (129.7+/-65.4 versus 63.4 +/-15.4 nmol/100 mg protein, P <0.05), GSH levels were significantly lower (17.1+/-7.3 versus 45.4 + 8.1 nmol/mg protein, P <0.01). Furthermore, in Group II, MDA levels were significantly lower (56.9+/-20.6 versus 129.7+/-65.4 nmol/100 mg protein, P <0.05), and GSH levels were significantly higher (34.57+/-10.7 versus 17.1+/-7.3 nmol/mg protein, P <0.0001) when compared with Group I. No statistically significant difference was found in tissue MDA and GSH levels between Group II and the control group (P >0.05).<br><br>CONCLUSIONS: These results suggest that smoke exposure during pregnancy causes oxidative damage in fetal lungs. This smoke-induced damage might be prevented by NAC.}, }
@article {pmid17367161, year = {2007}, author = {Bheemreddy, RM and Jeffery, EH}, title = {The metabolic fate of purified glucoraphanin in F344 rats.}, journal = {Journal of agricultural and food chemistry}, volume = {55}, number = {8}, pages = {2861-2866}, doi = {10.1021/jf0633544}, pmid = {17367161}, issn = {0021-8561}, mesh = {Animals ; Bile/chemistry ; Brassica/*chemistry ; Glucose/administration &amp; dosage/*analogs &amp; derivatives/analysis/pharmacokinetics ; Glucosinolates ; Imidoesters/administration &amp; dosage/analysis/*pharmacokinetics ; Male ; Oximes ; Rats ; Rats, Inbred F344 ; Seeds/*chemistry ; Sulfoxides ; }, abstract = {Dietary broccoli is commonly eaten cooked, exposing individuals to intact glucoraphanin rather than to its hydrolysis product, the anticarcinogenic isothiocyanate sulforaphane, since cooking destroys the hydrolyzing enzyme myrosinase. There is little information on the absorption and metabolism of glucoraphanin, due partly to the lack of purified compound. In this study, glucoraphanin was purified from broccoli seed and 150 mumol/kg was administered to male F344 rats. Glucoraphanin (5% of an oral dose) was recovered intact in urine, showing that it is absorbed intact, and no glucoraphanin or metabolites were found in feces. Total urinary products accounted for 20 and 45% of oral and intraperitonneal doses, respectively, including sulforaphane N-acetyl cysteine conjugate (12.5 and 2%), free sulforaphane (0.65 and 0.77%), sulforaphane nitrile (2 and 1.4%), and erucin (0.1 and 0.1%), respectively. Both glucoraphanin and its reduced form glucoerucin were identified in bile following intravenous glucoraphanin administration. We conclude that orally administered glucoraphanin is absorbed intact, undergoes enterohepatic circulation, and is hydrolyzed in the gut in F344 rats.}, }
@article {pmid17365925, year = {2007}, author = {Garofalo, AS and Borges, FT and Dalboni, MA and Pavão dos Santos, OF}, title = {Reactive oxygen species independent cytotoxicity induced by radiocontrast agents in tubular cells (LLC-PK1 and MDCK).}, journal = {Renal failure}, volume = {29}, number = {2}, pages = {121-131}, doi = {10.1080/08860220601095892}, pmid = {17365925}, issn = {0886-022X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Hypoxia ; Cell Line ; Cell Line, Tumor ; Cell Survival/*drug effects/radiation effects ; Contrast Media ; Dogs ; Kidney ; L-Lactate Dehydrogenase/analysis ; Lung Neoplasms ; Necrosis ; Radioisotopes/pharmacology ; Reactive Oxygen Species/*metabolism ; Swine ; }, abstract = {PURPOSE: Radiocontrast agents (RAs) cause renal tubular damage by hemodynamic imbalance, which could cause hypoxic stimulus and direct cytotoxicity. However, reactive oxygen species (ROS) could be an important factor in RAs' direct cytotoxicity. This study investigated the involvement of ROS in deleterious effects produced by RAs on normoxic and hypoxic renal tubular cells.<br><br>MATERIALS AND METHODS: LLC-PK1 and MDCK were exposed to diatrizoate and ioxaglate in normoxic and hypoxic conditions. Apoptotic and necrotic cell death were assessed by acridine orange/ethidium bromide and annexin V methods. Hydrogen peroxide, superoxide anion, and malondialdehyde levels were analyzed by, respectively, 2',7'-dichlorofluorescein, luminal, and thiobarbituric acid. Antioxidant agents were used to prevent cellular RAs damage.<br><br>RESULTS: Diatrizoate and ioxaglate decreased cellular viability in both cells, and this effect was enhanced by hypoxic conditions. Diatrizoate induced more injury than ioxaglate to both cell lines. LLC-PK1 underwent necrosis, while MDCK cells underwent apoptosis when exposed to diatrizoate. These results could not be attributed to an increase in osmolality. RAs did not increase hydrogen peroxide, superoxide anion or malondialdehyde levels in both cells. Additionally, N-acetyl-L-cysteine (NAC), ascorbic acid, alpha-tocopherol, glutathione, beta-carotene, allopurinol, cimetidine, and citric acid did not protect cells against RAs damage. Surprising, NAC increased the cellular damage induced by ioxaglate in the both cell lines.<br><br>CONCLUSION: The present study shows that RAs induce damage in cultured tubular cells, especially in hypoxic conditions. ROS were not involved in the observed RAs' cytotoxicity, and NAC increased ioxaglate-induced tubular damage.}, }
@article {pmid17364960, year = {2007}, author = {Celedón, G and González, G and Pino, J and Lissi, EA}, title = {Peroxynitrite oxidizes erythrocyte membrane band 3 protein and diminishes its anion transport capacity.}, journal = {Free radical research}, volume = {41}, number = {3}, pages = {316-323}, doi = {10.1080/10715760601090305}, pmid = {17364960}, issn = {1071-5762}, mesh = {Acetylcysteine/chemistry ; Anion Exchange Protein 1, Erythrocyte/*antagonists &amp; inhibitors ; Anions/metabolism ; Catechin/pharmacology ; Erythrocytes/*drug effects/metabolism ; Hemoglobins/chemistry ; Humans ; Ion Transport/drug effects ; Nitrates/chemistry ; Oxidants/*pharmacology ; Oxidation-Reduction ; Peroxynitrous Acid/*physiology ; Tyrosine/chemistry ; }, abstract = {We describe an altered membrane band 3 protein-mediated anion transport in erythrocytes exposed to peroxynitrite, and relate the loss of anion transport to cell damage and to band 3 oxidative modifications. We found that peroxynitrite down-regulate anion transport in a dose dependent relation (100-300 micromoles/l). Hemoglobin oxidation was found at all peroxynitrite concentrations studied. A dose-dependent band 3 protein crosslinking and tyrosine nitration were also observed. Band 3 protein modifications were concomitant with a decrease in transport activity. (-)-Epicatechin avoids band 3 protein nitration but barely affects its transport capacity, suggesting that both processes are unrelated. N-acetyl cysteine partially reverted the loss of band 3 transport capacity. It is concluded that peroxynitrite promotes a decrease in anion transport that is partially due to the reversible oxidation of band 3 cysteine residues. Additionally, band 3 tyrosine nitration seems not to be relevant for the loss of its anion transport capacity.}, }
@article {pmid17364286, year = {2007}, author = {Badawy, A and State, O and Abdelgawad, S}, title = {N-Acetyl cysteine and clomiphene citrate for induction of ovulation in polycystic ovary syndrome: a cross-over trial.}, journal = {Acta obstetricia et gynecologica Scandinavica}, volume = {86}, number = {2}, pages = {218-222}, doi = {10.1080/00016340601090337}, pmid = {17364286}, issn = {0001-6349}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Chorionic Gonadotropin/*administration &amp; dosage ; Clomiphene/*administration &amp; dosage ; Cross-Over Studies ; Drug Therapy, Combination ; Endometrium/*drug effects ; Estrogens/blood ; Female ; Fertility Agents, Female/*administration &amp; dosage ; Follicle Stimulating Hormone/blood ; Humans ; Infertility, Female/*drug therapy/etiology ; Luteinizing Hormone/blood ; Ovary/diagnostic imaging ; Ovulation Induction/*methods ; Polycystic Ovary Syndrome/blood/*drug therapy ; Pregnancy ; Progesterone/blood ; Prospective Studies ; Testosterone/blood ; Ultrasonography ; }, abstract = {OBJECTIVE: To compare clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for inducing ovulation in patients with polycystic ovary syndrome.<br><br>DESIGN: Prospective cross-over trial.<br><br>SETTING: University teaching hospital and a private practice setting.<br><br>PATIENTS: Five hundred and seventy-three patients were treated with clomiphene citrate for one menstrual cycle among which 470 patients were treated with clomiphene citrate plus N-acetyl cysteine for another cycle. All women suffered from polycystic ovary syndrome.<br><br>INTERVENTIONS: Patients had clomiphene citrate 50-mg tablets twice daily alone or with N-acetyl cysteine 1,200 mg/day orally for 5 days starting on day 3 of the menstrual cycle.<br><br>OUTCOME MEASURES: Primary outcomes were number of mature follicles, serum E2, serum progesterone, and endometrial thickness. Secondary outcome was the occurrence of pregnancy.<br><br>RESULTS: Ovulation rate improved significantly after the addition of N-acetyl cysteine (17.9% versus 52.1%). Although the number of mature follicles was more in the N-acetyl cysteine group (2.1+/-0.88 versus 3.2+/-0.93), the difference was not statistically significant. The mean E2 levels (pg/ml) at the time of human chorionic gonadotropine injection, serum progesterone levels (ng/ml) on days 21-23 of the cycle, and the endometrial thickness were significantly improved in the N-acetyl cysteine group. The overall pregnancy rate was 11.5% in the N-acetyl cysteine group. Insulin resistance occurred in 260 patients (55.4%). There was no significant difference between the insulin resistance group (n = 260) and non-insulin resistance group (n = 210) as regards ovulation rate, number of follicles, serum E2 (pg/ml), serum progesterone (ng/ml), endometrial thickness (mm), or pregnancy rate.<br><br>CONCLUSION: N-Acetyl cysteine is proved effective in inducing or augmenting ovulation in polycystic ovary patients.}, }
@article {pmid17356134, year = {2007}, author = {Miller, CP and Ban, K and Dujka, ME and McConkey, DJ and Munsell, M and Palladino, M and Chandra, J}, title = {NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells.}, journal = {Blood}, volume = {110}, number = {1}, pages = {267-277}, pmid = {17356134}, issn = {0006-4971}, support = {F31 CA123645/CA/NCI NIH HHS/United States ; P50 CA100632/CA/NCI NIH HHS/United States ; F31CA123645-01/CA/NCI NIH HHS/United States ; P50 CA100632-04/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Caspase 8/metabolism ; Cell Line, Tumor ; *Histone Deacetylase Inhibitors ; Humans ; Lactones/administration &amp; dosage/*pharmacology ; Leukemia/*drug therapy/pathology ; Mice ; Oxidative Stress ; Protease Inhibitors/administration &amp; dosage/pharmacology ; *Proteasome Inhibitors ; Pyrroles/administration &amp; dosage/*pharmacology ; Reactive Oxygen Species/metabolism ; Tumor Burden/drug effects ; Tumor Cells, Cultured ; }, abstract = {The proteasome has been successfully targeted for the treatment of multiple myeloma and mantle cell lymphoma; however, in other hematologic malignancies, bortezomib has been less effective as a single agent. Here, we describe effects of NPI-0052, a novel proteasome inhibitor, in leukemia model systems. In cell lines, NPI-0052 inhibits all 3 proteolytic activities associated with the proteasome: chymotrypsin-, trypsin-, and caspase-like. NPI-0052 also induces DNA fragmentation in leukemia lines and in mononuclear cells from a Ph + acute lymphoblastic leukemia (ALL) patient. Caspase-3 activation by NPI-0052 was seen in wild-type Jurkat cells, but was significantly lessened in Fas-associated death domain (FADD)-deficient or caspase-8-deficient counterparts. NPI-0052-induced apoptosis was further probed using caspase-8 inhibitors, which were more protective than caspase-9 inhibitors. N-acetyl cysteine (NAC) also conferred protection against NPI-0052-induced apoptosis, indicating a role for oxidative stress by NPI-0052. In support of the drug's in vitro activities, biweekly treatment with NPI-0052 lessened total white blood cell (WBC) burden over 35 days in leukemic mice. Interestingly, combining NPI-0052 with either MS-275 or valproic acid (VPA) induced greater levels of cell death than the combination of bortezomib with these histone deacetylase inhibitors (HDACi). These effects of NPI-0052, alone and in combination with HDACi, warrant further testing to determine the compound's clinical efficacy in leukemia.}, }
@article {pmid17349922, year = {2007}, author = {Lu, SP and Lin Feng, MH and Huang, HL and Huang, YC and Tsou, WI and Lai, MZ}, title = {Reactive oxygen species promote raft formation in T lymphocytes.}, journal = {Free radical biology &amp; medicine}, volume = {42}, number = {7}, pages = {936-944}, doi = {10.1016/j.freeradbiomed.2006.11.027}, pmid = {17349922}, issn = {0891-5849}, mesh = {Humans ; Lymphocyte Activation ; Reactive Oxygen Species/*metabolism ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes/*metabolism ; }, abstract = {Lipid rafts are involved in many cell biology events, yet the molecular mechanisms on how rafts are formed are poorly understood. In this study we probed the possible requirement of reactive oxygen species (ROS) for T-cell receptor (TCR)-induced lipid raft formation. Microscopy and biochemical analyses illustrated that blockage of ROS production, by superoxide dismutase-mimic MnTBAP, significantly reduced partitioning of LAT, phospho-LAT, and PLC-gamma in lipid rafts. Another antioxidant N-acetylcysteine (NAC) displayed a similar suppressive effect on the entry of phospho-LAT into raft microdomains. The involvement of ROS in TCR-mediated raft assembly was observed in T-cell hybridomas, T leukemia cells, and normal T cells. Removal of ROS was accompanied by an attenuated activation of LAT and PKCtheta, with reduced production of IL-2. Consistently, treating T cells with the ROS-producer tert-butyl hydrogen peroxide (TBHP) greatly enhanced membrane raft formation, distribution of phospho-LAT into lipid rafts, and increased IL-2 production. Our results indicate for the first time that ROS contribute to TCR-induced membrane raft formation.}, }
@article {pmid17349145, year = {2007}, author = {Wang, L and Xu, JB and Tian, Y and Wu, HS and Liu, YL}, title = {[Protective effect of N-acetylcysteine against lipopolysaccharide injury in hepatocytes of neonatal mice].}, journal = {Zhonghua er ke za zhi = Chinese journal of pediatrics}, volume = {45}, number = {1}, pages = {30-33}, pmid = {17349145}, issn = {0578-1310}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/metabolism ; Animals ; Animals, Newborn ; Anti-Inflammatory Agents/*pharmacology ; Cells, Cultured ; Hepatocytes/*drug effects ; Lipopolysaccharides ; Mice ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; }, abstract = {OBJECTIVE: N-Acetylcysteine (NAC) is a sulfhydryl donor molecule with antioxidant and antiinflammatory effects. A major role has been described for inducible nitric oxide (NO) synthase in several inflammatory liver diseases. NAC attenuates NO generation following lipopolysaccharide injection in rats. The purpose of this study was to investigate the effect of NAC against lipopolysaccharide injury in hepatocytes of neonatal mice and the molecular mechanisms by which NAC influences inflammatory responses of the hepatocytes.<br><br>METHODS: The liver of neonatal mouse was digested by collagenase to dissociate the hepatocytes. The hepatocytes were cultured and isolated. After 7 days of culture the normal hepatocytes were divided into two groups: LPS group and NAC group. In LPS group, 10 microg/ml LPS was added into the culture medium. In NAC group, 5 mmol/L NAC was added into the culture medium firstly, 10 microg/ml LPS was added after 1 h of culture. There were 12 mice in each group. The cell supernatants and the hepatocytes were collected at 0, 6 and 12 hours after adding LPS. The cell supernatants were taken to measure the alanine aminotransferase (ALT) level and nitric oxide (NO) production by the biochemical methods. The cells were taken to analyze the gene expression of induced nitric oxide synthase (iNOS) by the RT-PCR.<br><br>RESULTS: In LPS group, the levels of ALT, NO and iNOS mRNA increased significantly at the time points 6 h and 12 h compared with the time point 0, (P < 0.01). Compared with the LPS group, the levels of ALT, NO and iNOS mRNA of NAC group were lower at the time points 6 h and 12 h (P < 0.01).<br><br>CONCLUSIONS: NAC may play a protective role in the hepatocytes injury caused by LPS in the neonatal mice. The protective mechanism works partially through the inhibition of iNOS activation by LPS.}, }
@article {pmid17343919, year = {2007}, author = {Estany, S and Palacio, JR and Barnadas, R and Sabes, M and Iborra, A and Martínez, P}, title = {Antioxidant activity of N-acetylcysteine, flavonoids and alpha-tocopherol on endometrial cells in culture.}, journal = {Journal of reproductive immunology}, volume = {75}, number = {1}, pages = {1-10}, doi = {10.1016/j.jri.2007.01.007}, pmid = {17343919}, issn = {0165-0378}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antioxidants/metabolism/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Endometrial Neoplasms/metabolism ; Endometrium/*cytology/drug effects/*metabolism ; Female ; Flavonoids/metabolism/*pharmacology ; Humans ; Hydrogen Peroxide/metabolism/toxicity ; Liposomes ; Oxidants/metabolism ; Oxidative Stress/drug effects ; alpha-Tocopherol/metabolism/*pharmacology ; }, abstract = {An appropriate local environment is necessary for successful implantation. Oxidative stress is implicated in the pathogenesis of several pathologies, and may contribute to early pregnancy failure. Antioxidant therapies have been studied in infertility. In this study, we have assessed the antioxidant activity of N-acetylcysteine (NAC), flavonoids (quercetin, catechin) and alpha-tocopherol in an oxidative model of endometrial cells (RL95). Endometrial cells were incubated at several hydrogen peroxide concentrations. Antioxidant effects of NAC (15 mM), quercetin (150 microM), catechin (150 microM) and alpha-tocopherol included in liposomes (1.6 microg) were assessed by measuring cell viability by the MTT assay. Alpha-tocopherol-liposomes taken up by endometrial cells were assessed by HPLC. All liposomes used were able to introduce alpha-tocopherol into cells. The antioxidant effect of NAC and quercetin improved the viability of oxidised cells, and this effect was observed when the oxidant and antioxidant were coincubated. No viability change occurred when the antioxidant was added before or after the oxidant. The antioxidant effect of NAC was better than that of quercetin. When catechin or alpha-tocopherol were used in the same conditions, no antioxidant effect was detected in cells in culture. These results demonstrate that NAC and quercetin are good H2O2 scavengers.}, }
@article {pmid17340120, year = {2007}, author = {Gonsebatt, ME and Del Razo, LM and Cerbon, MA and Zúñiga, O and Sanchez-Peña, LC and Ramírez, P}, title = {Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression.}, journal = {Archives of toxicology}, volume = {81}, number = {9}, pages = {619-626}, doi = {10.1007/s00204-007-0192-7}, pmid = {17340120}, issn = {0340-5761}, mesh = {Animals ; Arsenites/*toxicity ; Keratin-18/*biosynthesis/genetics ; Liver/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Oxidative Stress ; RNA, Messenger/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 microM of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise liver function.}, }
@article {pmid17338280, year = {2006}, author = {Ozkilic, AC and Cengiz, M and Ozaydin, A and Cobanoglu, A and Kanigur, G}, title = {The role of N-acetylcysteine treatment on anti-oxidative status in patients with type II diabetes mellitus.}, journal = {Journal of basic and clinical physiology and pharmacology}, volume = {17}, number = {4}, pages = {245-254}, doi = {10.1515/jbcpp.2006.17.4.245}, pmid = {17338280}, issn = {0792-6855}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Antioxidants/*metabolism ; Blood Glucose/metabolism ; Catalase/blood ; Diabetes Mellitus, Type 2/*blood ; Enzymes/blood ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/blood ; Glutathione Peroxidase/blood ; Glutathione Transferase/blood ; Humans ; Male ; Middle Aged ; }, abstract = {The development of diabetic complications has usually been attributed to the nonenzymic glycation of tissue proteins. Only recently, however, have researchers examined the possible role on free radicals in the pathogenesis of diabetes. In the present study, glutathione (GSH) and major antioxidant enzyme levels in plasma of patients with type II diabetes mellitus were assessed both before and after 3 months of N-acetylcysteine (NAC) therapy. Thirty-two diabetic patients were examined as well as fifteen healthy controls. Before treatment with NAC, glutathione peroxidase (GPx), catalase (CAT), and (GSH) levels of diabetic patients and control subjects showed no significant differences, whereas glutathione S-transferase (GST) levels were higher in type II diabetic patients. Following 3 months of Following NAC supplementation, GSH, GST, and CAT levels were found to be similar to the levels before treatment. On the other hand, GPx activity was significantly lower compared with the values before treatment. According to this finding, NAC treatment could have a positive effect on GPx values in type II diabetic patients showing abnormally high values.}, }
@article {pmid17337135, year = {2007}, author = {Carrera, MP and Antolín, I and Martín, V and Sainz, RM and Mayo, JC and Herrera, F and García-Santos, G and Rodríguez, C}, title = {Antioxidants do not prevent acrylonitrile-induced toxicity.}, journal = {Toxicology letters}, volume = {169}, number = {3}, pages = {236-244}, doi = {10.1016/j.toxlet.2007.01.011}, pmid = {17337135}, issn = {0378-4274}, mesh = {Acrylonitrile/*toxicity ; Animals ; Antioxidants/*pharmacology ; Astrocytes/*drug effects/enzymology/metabolism ; Body Weight/drug effects ; Catalase/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Several reports have recently described that acrylonitrile (ACN) toxicity resides in its capacity for inducing oxidative stress. ACN can be conjugated with glutathione (GSH), diminishing its cellular content, or being metabolized to cyanide. In the present report, we determine the effect of ACN on the viability of primary-cultured astrocytes as well as the oxidative damage generated by ACN by measuring GSH levels in primary cultured astrocytes. We also analyzed whether the ACN (2.5mM) toxicity could be avoided by using antioxidants such as taurine (5mM), N-acetylcysteine (20 mM), trolox (100 microM), estradiol (10 microM) and melatonin (100 nM-1mM). In this cell culture model, antioxidants were not able to prevent ACN-induced cell damage, with the exception of NAC, confirming that only GSH seems to play a key role in ACN-derived toxicity. Additionally, we measured different parameters of oxidative stress such as catalase activity, lipid peroxidation and GSH concentration, as indicators of the potential oxidative stress mediated by the toxicity of ACN, after exposure of Wistar rats to a concentration of 200 ppm ACN for 14 days. At the concentration assayed, we did not find any evidence of oxidative damage in the brain of ACN-treated rats.}, }
@article {pmid17336614, year = {2007}, author = {Dharajiya, N and Choudhury, BK and Bacsi, A and Boldogh, I and Alam, R and Sur, S}, title = {Inhibiting pollen reduced nicotinamide adenine dinucleotide phosphate oxidase-induced signal by intrapulmonary administration of antioxidants blocks allergic airway inflammation.}, journal = {The Journal of allergy and clinical immunology}, volume = {119}, number = {3}, pages = {646-653}, pmid = {17336614}, issn = {0091-6749}, support = {N01HV28184/HL/NHLBI NIH HHS/United States ; P01 AI062885/AI/NIAID NIH HHS/United States ; P01 AI062885-03/AI/NIAID NIH HHS/United States ; R01 CA084461/CA/NCI NIH HHS/United States ; CA84461/CA/NCI NIH HHS/United States ; R01 HL071163/HL/NHLBI NIH HHS/United States ; P01 AI062885-02/AI/NIAID NIH HHS/United States ; R01 HL071163-01A2/HL/NHLBI NIH HHS/United States ; N01-HV28184/HV/NHLBI NIH HHS/United States ; P30 ES006676-10/ES/NIEHS NIH HHS/United States ; P01 AI062885-01/AI/NIAID NIH HHS/United States ; P30 ES006676-09/ES/NIEHS NIH HHS/United States ; N01 HV028184-13/HV/NHLBI NIH HHS/United States ; P30 ES006676-11/ES/NIEHS NIH HHS/United States ; P30 ES006676/ES/NIEHS NIH HHS/United States ; R01 HL071163-02/HL/NHLBI NIH HHS/United States ; ES06676/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Administration, Inhalation ; Animals ; Antioxidants/*administration &amp; dosage ; Ascorbic Acid/administration &amp; dosage ; Bronchitis/*prevention &amp; control ; Chloride Channels/analysis/metabolism ; Hypersensitivity/*prevention &amp; control ; Interleukin-13/analysis/metabolism ; Interleukin-4/analysis/metabolism ; Lung/chemistry/immunology ; Mice ; Mucins/analysis/metabolism ; Nitrate Reductase (NAD(P)H)/antagonists &amp; inhibitors/*toxicity ; Plant Extracts/toxicity ; Pollen/enzymology/*immunology ; Reactive Oxygen Species/antagonists &amp; inhibitors ; Tocopherols/administration &amp; dosage ; }, abstract = {BACKGROUND: Ragweed extract (RWE) contains NADPH oxidases that induce oxidative stress in the airways independent of adaptive immunity (signal 1) and augment antigen (signal 2)-induced allergic airway inflammation.<br><br>OBJECTIVE: To test whether inhibiting signal 1 by administering antioxidants inhibits allergic airway inflammation in mice.<br><br>METHODS: The ability of ascorbic acid (AA), N-acetyl cystenine (NAC), and tocopherol to scavenge pollen NADPH oxidase-generated reactive oxygen species (ROS) was measured. These antioxidants were administered locally to inhibit signal 1 in the airways of RWE-sensitized mice. Recruitment of inflammatory cells, mucin production, calcium-activated chloride channel 3, IL-4, and IL-13 mRNA expression was quantified in the lungs.<br><br>RESULTS: Antioxidants inhibited ROS generation by pollen NADPH oxidases and intracellular ROS generation in cultured epithelial cells. AA in combination with NAC or Tocopherol decreased RWE-induced ROS levels in cultured bronchial epithelial cells. Coadministration of antioxidants with RWE challenge inhibited 4-hydroxynonenal adduct formation, upregulation of Clca3 and IL-4 in lungs, mucin production, recruitment of eosinophils, and total inflammatory cells into the airways. Administration of antioxidants with a second RWE challenge also inhibited airway inflammation. However, administration of AA+NAC 4 or 24 hours after RWE challenge failed to inhibit allergic inflammation.<br><br>CONCLUSION: Signal 1 plays a proinflammatory role during repeated exposure to pollen extract. We propose that inhibiting signal 1 by increasing antioxidant potential in the airways may be a novel therapeutic strategy to attenuate pollen-induced allergic airway inflammation.<br><br>CLINICAL IMPLICATIONS: Administration of antioxidants in the airways may constitute a novel therapeutic strategy to prevent pollen induced allergic airway inflammation.}, }
@article {pmid17335885, year = {2007}, author = {Kim, HJ and Barajas, B and Chan, RC and Nel, AE}, title = {Glutathione depletion inhibits dendritic cell maturation and delayed-type hypersensitivity: implications for systemic disease and immunosenescence.}, journal = {The Journal of allergy and clinical immunology}, volume = {119}, number = {5}, pages = {1225-1233}, doi = {10.1016/j.jaci.2007.01.016}, pmid = {17335885}, issn = {0091-6749}, support = {R01 AG14992/AG/NIA NIH HHS/United States ; U19 AI070453/AI/NIAID NIH HHS/United States ; }, mesh = {Adoptive Transfer ; Animals ; Cell Differentiation/immunology ; Dendritic Cells/cytology/*immunology/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; Glutathione/*antagonists &amp; inhibitors/immunology ; Hypersensitivity, Delayed/*immunology/metabolism ; Interferon-gamma/metabolism ; Interleukin-12/metabolism ; Lymphocyte Activation/*immunology ; Lymphocyte Culture Test, Mixed ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Reactive Oxygen Species/antagonists &amp; inhibitors/immunology ; Reverse Transcriptase Polymerase Chain Reaction ; Skin/cytology/immunology ; Th1 Cells/immunology ; }, abstract = {BACKGROUND: Dendritic cells (DCs) play a key role as antigen-presenting cells in the immune system. There is growing evidence that the redox equilibrium of these cells influences their ability to induce T-cell activation and to regulate the polarity of the immune response. This could affect the outcome of the immune response during systemic diseases and aging.<br><br>OBJECTIVE: Our aim was to elucidate the mechanism by which the redox equilibrium of antigen-presenting DCs affects the delayed-type hypersensitivity (DTH) response during experimental modification of glutathione levels, as well as during aging.<br><br>METHODS: We looked at the effect of glutathione depletion by diethyl maleate in DCs as well as during systemic administration on the DTH response to the contact-sensitizing antigens, oxazolone, and 2,4-dinitro-1-fluorobenzene. We also determined whether glutathione repletion with N-acetyl cysteine could influence the decline of the DTH response in aged mice.<br><br>RESULTS: Glutathione depletion in bone marrow-derived DCs interfered in their ability to mount a DTH response on adoptive transfer into recipient mice. Glutathione depletion interfered in IL-12 production and costimulatory receptor expression in DCs, leading to decreased IFN-gamma production in the skin of recipient mice. Systemic diethyl maleate treatment exerted similar effects on the DTH response and IFN-gamma production, whereas N-acetyl cysteine administration reversed the decline of the DTH response in aged animals.<br><br>CONCLUSION: Glutathione depletion downregulates T(H)1 immunity through a perturbation of DC maturation and IL-12 production.<br><br>CLINICAL IMPLICATIONS: These data show that the induction of oxidative stress in the immune system, under disease conditions and aging, interferes in T(H)1 immunity.}, }
@article {pmid17335818, year = {2007}, author = {Elnashar, A and Fahmy, M and Mansour, A and Ibrahim, K}, title = {N-acetyl cysteine vs. metformin in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective randomized controlled study.}, journal = {Fertility and sterility}, volume = {88}, number = {2}, pages = {406-409}, doi = {10.1016/j.fertnstert.2006.11.173}, pmid = {17335818}, issn = {1556-5653}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Blood Glucose/analysis ; Clomiphene/*therapeutic use ; Drug Resistance/drug effects ; Female ; Humans ; Insulin/blood ; Metformin/*therapeutic use ; Ovulation/drug effects ; Polycystic Ovary Syndrome/blood/*drug therapy ; Selective Estrogen Receptor Modulators/therapeutic use ; Testosterone/blood ; Treatment Failure ; }, abstract = {OBJECTIVE: To compare the effect of N-acetyl cysteine and metformin on hormonal profile (insulin and T) and ovulation rate in women with clomiphene citrate-resistant polycystic ovary syndrome.<br><br>DESIGN: Prospective randomized controlled study.<br><br>SETTING: Department of obstetrics and gynecology in a university hospital in Egypt.<br><br>PATIENT(S): Sixty-one infertile women with clomiphene citrate-resistant polycystic ovary syndrome were assigned randomly to receive either metformin (1,500 mg/d) or N-acetyl cysteine (1.8 g/d) for 6 weeks.<br><br>INTERVENTION(S): Hormonal profile was determined before and after the course of treatment. Folliculometry was performed to assess ovulation.<br><br>MAIN OUTCOME MEASURE(S): Ovulation rate and insulin and T changes.<br><br>RESULT(S): In the metformin group, there was a significant decrease in the fasting glucose, fasting insulin, and total T. In the N-acetyl cysteine group, there was no significant difference in the fasting glucose or fasting insulin and there was a significant decrease in total T. There was no significant difference in the fasting glucose-fasting insulin ratio in both groups. In the metformin group, the rate of ovulation was 51.6% (16/31), vs. 6.7% (2/30) in the N-acetyl cysteine group, which was statistically significant.<br><br>CONCLUSION(S): Metformin alone is an effective drug in inducing ovulation in clomiphene citrate-resistant polycystic ovary syndrome, whereas N-acetyl cysteine alone is not. Further large studies are required to confirm our results.}, }
@article {pmid17334646, year = {2007}, author = {Kim, MH and Yoo, HS and Kim, MY and Jang, HJ and Baek, MK and Kim, HR and Kim, KK and Shin, BA and Ahn, BW and Jung, YD}, title = {Helicobacter pylori stimulates urokinase plasminogen activator receptor expression and cell invasiveness through reactive oxygen species and NF-kappaB signaling in human gastric carcinoma cells.}, journal = {International journal of molecular medicine}, volume = {19}, number = {4}, pages = {689-697}, pmid = {17334646}, issn = {1107-3756}, mesh = {Acetylcysteine/pharmacology ; Carcinoma/enzymology/microbiology/*pathology ; Free Radical Scavengers/pharmacology ; *Helicobacter pylori ; Humans ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Neoplasm Invasiveness ; Nitriles/pharmacology ; Reactive Oxygen Species/*metabolism ; Receptors, Cell Surface/*agonists ; Receptors, Urokinase Plasminogen Activator ; Signal Transduction ; Stomach Neoplasms/enzymology/microbiology/*pathology ; Sulfones/pharmacology ; Tumor Cells, Cultured ; }, abstract = {The gastric pathogen, helicobacter pylori (H. pylori), has been associated with the progression of gastric cancer. It was previously reported that H. pylori induced urokinase plasminogen activator receptor (uPAR) expression and stimulated cell invasiveness in human gastric cancer AGS cells. However, the precise mechanisms for how H. pylori upregulates uPAR are unclear. This study investigated the underlying signal pathways in H. pylori-induced uPAR in human gastric cancer AGS cells. The intracellular H2O2 content, as determined using H2O2-sensitive probe 2',7'-dichlorodihydrofluorescein, increased after the H. pylori treatment. N-acetyl cysteine (NAC), an antioxidant, prevented the H. pylori-induced production of H2O2 and uPAR expression. In addition, exogenous H2O2 was found to increase uPAR mRNA expression and its promoter activity. Site-directed mutagenesis of the potential NF-kappaB element in the uPAR promoter showed that the redox-sensitive transcription factor NF-kappaB was essential for H. pylori-induced uPAR expression. The expression of vectors encoding a mutated-type NF-kappaB-inducing kinase and I-kappaB, and a specific inhibitor of NF-kappaB (BAY11-7082) decreased the H. pylori-induced uPAR promoter activity. Chromatin immunoprecipitation and the electrophoretic mobility shift assay confirmed that H. pylori increased the DNA binding activity of NF-kappaB. With the aid of NAC and H2O2, it was determined that reactive oxygen species (ROS) is an upstream signaling molecule for activating the NF-kappaB induced by H. pylori. The enhanced AGS cell invasiveness by H. pylori was partially abrogated by an NAC and BAY11-7082 treatment. These results suggest that the ROS and NF-kappaB signaling pathway is important in H. pylori-induced uPAR expression and the increased cell invasiveness of human gastric cancer AGS cells.}, }
@article {pmid17334226, year = {2007}, author = {Song, HY and Ryu, J and Ju, SM and Park, LJ and Lee, JA and Choi, SY and Park, J}, title = {Extracellular HIV-1 Tat enhances monocyte adhesion by up-regulation of ICAM-1 and VCAM-1 gene expression via ROS-dependent NF-kappaB activation in astrocytes.}, journal = {Experimental &amp; molecular medicine}, volume = {39}, number = {1}, pages = {27-37}, doi = {10.1038/emm.2007.4}, pmid = {17334226}, issn = {1226-3613}, mesh = {Astrocytes/cytology/metabolism ; Cell Adhesion/drug effects ; Cell Line ; Gene Products, tat/*pharmacology ; *HIV-1 ; Humans ; Intercellular Adhesion Molecule-1/genetics/*metabolism ; Monocytes/cytology/*drug effects/metabolism ; NF-kappa B/*metabolism ; Reactive Oxygen Species/*metabolism ; Transcription, Genetic/genetics ; Up-Regulation/*drug effects ; Vascular Cell Adhesion Molecule-1/genetics/*metabolism ; tat Gene Products, Human Immunodeficiency Virus ; }, abstract = {One of characteristic features of AIDS-related encephalitis and dementia is the infiltration of monocytes into the CNS. HIV-1 Tat was demonstrated to facilitate monocyte entry into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of adhesion molecules, generation of reactive oxygen species (ROS) and NF-kappaB activation in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein and mRNA levels of ICAM-1 and VCAM-1, as measured by Western blot analysis and RT-PCR, indicating that Tat increases these protein levels at an mRNA level. In addition, Tat induced the activation of NF-kappaB in astrocytes. Treatment of CRT-MG with NF-kappaB inhibitors led to decrease in Tat-induced protein and mRNA expression of ICAM-1 and VCAM-1. Furthermore, HIV-1 Tat protein increased ROS generation. Inhibition of Tat-induced ROS generation by N-acetyl cysteine, vitamin C and diphenyl iodonium suppressed Tat-induced NF-kappaB activation, ICAM-1 and VCAM-1 expression, and monocyte adhesion in CRT-MG. These data indicate that HIV-1 Tat can modulate monocyte adhesiveness by increasing expression of adhesion molecules such as ICAM-1 and VCAM-1 via ROS- and NF-kappaB-dependent mechanisms in astrocytes.}, }
@article {pmid17331847, year = {2007}, author = {Weiss, L and Reich, S and Zeira, M and Or, R and Resnick, IB and Slavin, S and Shapira, MY}, title = {N-acetylcysteine mildly inhibits the graft-vs.-leukemia effect but not the lymphokine activated cells (LAK) activity.}, journal = {Transplant immunology}, volume = {17}, number = {3}, pages = {198-202}, doi = {10.1016/j.trim.2006.10.005}, pmid = {17331847}, issn = {0966-3274}, mesh = {Acetylcysteine/*pharmacology ; Adoptive Transfer ; Animals ; Antioxidants/*pharmacology ; Female ; Graft vs Host Disease/*prevention &amp; control ; Graft vs Leukemia Effect/*immunology ; Killer Cells, Lymphokine-Activated/*drug effects ; Male ; Mice ; Stem Cell Transplantation ; }, abstract = {N-acetylcysteine (NAC) is a known antioxidant and induces modulation of glutathione cellular content effects. It has been suggested that in the context of stem cell transplantation (SCT), NAC can prevent and treat graft-vs.-host disease, veno-occlusive disease and idiopathic pneumonia syndrome. We investigated the possible effect of NAC on graft-vs.-leukemia effect (GVL) and lymphokine activated cells (LAK) activity in murine models. After 10 days of NAC treatment, the cytotoxic activity of the LAK cells did not significantly differ from LAK activity generated from spleen cells obtained from untreated controls. However, NAC mildly suppressed GVL (appearance of leukemia in 8/36 animals treated with NAC as compared to 0/20 in the SCT control group, p=0.023). In spite of this mild suppression of GVL, no negative effect on achievement of donor chimerism was seen. We conclude that NAC usage in SCT may be relatively safe with regard to the GVL effect, yet further clinical studies are warranted.}, }
@article {pmid17331500, year = {2007}, author = {Bian, ZM and Elner, SG and Elner, VM}, title = {Regulation of VEGF mRNA expression and protein secretion by TGF-beta2 in human retinal pigment epithelial cells.}, journal = {Experimental eye research}, volume = {84}, number = {5}, pages = {812-822}, pmid = {17331500}, issn = {0014-4835}, support = {EY007003/EY/NEI NIH HHS/United States ; EY-09441/EY/NEI NIH HHS/United States ; R01 EY009441-12/EY/NEI NIH HHS/United States ; R01 EY009441/EY/NEI NIH HHS/United States ; P30 EY007003/EY/NEI NIH HHS/United States ; F31 EY007003/EY/NEI NIH HHS/United States ; P30 EY007003-20/EY/NEI NIH HHS/United States ; }, mesh = {Anti-Inflammatory Agents/pharmacology ; Blotting, Western ; Cells, Cultured ; Cyclosporine/pharmacology ; Dexamethasone/pharmacology ; Drug Synergism ; Epithelial Cells/drug effects/metabolism ; Fibroblast Growth Factor 2/pharmacology ; Gene Expression Regulation/*drug effects ; Humans ; Immunosuppressive Agents/pharmacology ; Pigment Epithelium of Eye/cytology/*drug effects/metabolism ; RNA, Messenger/genetics ; Recombinant Proteins/pharmacology ; Signal Transduction/physiology ; Transforming Growth Factor beta2/*pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; Vascular Endothelial Growth Factor A/*biosynthesis/genetics ; }, abstract = {VEGF secretion by the human retinal pigment epithelium (hRPE) plays an important role in retinal and choroidal neovascularization. In this study, transforming growth factor-beta2 (TGF-beta2)-induced vascular endothelial growth factor (VEGF) gene expression was investigated in hRPE cells. Treatment of hRPE cells with TGF-beta2 for 24 and 48h as compared to 8h resulted in markedly increased VEGF secretion by fivefold and nine-fold, respectively. Induced VEGF mRNA peaked within 3h of stimulation and remained above the basal at 36h. Stimulation of VEGF expression by TGF-beta2 was blocked by cycloheximide, suggesting that de novo protein synthesis is required. Induced VEGF production was strongly inhibited by anti-inflammatory agents, dexamethasone and cyclosporin A. Despite of the weak stimulation of VEGF expression by TNF-alpha or bFGF alone, co-administration of either of these two cytokines synergized the effect of TGF-beta2 on VEGF mRNA expression and protein production. Quantitative RT-PCR revealed that the synergy was predominantly at the level of VEGF transcription. Moreover, TGF-beta2-induced RPE VEGF secretion was significantly reduced by inhibitors of mitogen-activated protein (MAP) kinase (MEK) (U0126), p38 (SB202190), c-Jun NH2-terminal kinase (JNK), Sp600125, protein tyrosine kinase (PTK) (Genistein), and phosphatidylinositol 3-kinase (PI3K) (Ly294002). Induced VEGF expression was completely abrogated by inhibitors of protein kinase C (PKC) (Ro318220), nuclear factor-kappaB (NF-kappaB) [caffeic acid phenethyl ester (CAPE)], and reactive oxygen species (ROS) [N-acetyl-cysteine (Nac) and diphenyleneiodonium (DPI)]. These results suggest that MEK, p38, JNK, PI3K, and NF-kappaB as well as multiple essential signaling intermediates, including PKC, PTK and ROS, are involved in hRPE VEGF up regulation by TGF-beta2.}, }
@article {pmid17329844, year = {2007}, author = {Yurumez, Y and Cemek, M and Yavuz, Y and Birdane, YO and Buyukokuroglu, ME}, title = {Beneficial effect of N-acetylcysteine against organophosphate toxicity in mice.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {30}, number = {3}, pages = {490-494}, doi = {10.1248/bpb.30.490}, pmid = {17329844}, issn = {0918-6158}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Atropine/administration &amp; dosage/therapeutic use ; Cholinesterase Inhibitors/administration &amp; dosage/toxicity ; Drug Therapy, Combination ; Fenthion/administration &amp; dosage/*toxicity ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Glutathione/blood ; Injections, Intraperitoneal ; Injections, Subcutaneous ; Insecticides/administration &amp; dosage/toxicity ; Kaplan-Meier Estimate ; Male ; Malondialdehyde/blood ; Mice ; Nitrates/blood ; Nitrites/blood ; Oxidative Stress/*drug effects/physiology ; Time Factors ; }, abstract = {Recent studies showed that oxidative stress could be an important component of the mechanism of organophosphate (OP) compounds toxicity. The aim of present study was to investigate either prophylactic and therapeutic effects of N-acetylcysteine (NAC) against fenthion-induced oxidative stress in mice. Additionally, the effects on survival rates were investigated. Therefore, we determined the changes of the blood levels of glutathione (GSH), malondialdehyde (MDA), nitrite, and nitrate in blood or serum. Additionally, all animals were observed for 6 h and the survival rates were recorded. It was found that fenthion administration increased the levels of MDA, and decreased the levels of GSH, nitrite and nitrate. On the other hand, both prophylactic and therapeutic NAC treatment decreased the levels of MDA, and increased the levels of GSH, nitrite, and nitrate. The results showed that NAC is able to attenuate the fenthion-induced oxidative stress whereby NAC has not only prophylactic but also therapeutic activity in fenthion poisoning. On the other hand, we found that NAC can clearly improve survival rates in mice administered with an acute high dose of fenthion poisoning. In conclusion, NAC can decrease OP-induced oxidative stress and mortality rate, but the exact mechanism of its NAC protective effect needs to be explored further.}, }
@article {pmid17329835, year = {2007}, author = {Yasui, Y and Sasao, E and Sakata, M and Matsui, N and Fukuishi, N and Akagi, R and Akagi, M}, title = {Upregulation of heme oxygenase-1 by degranulation in rat basophilic leukemia cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {30}, number = {3}, pages = {443-446}, doi = {10.1248/bpb.30.443}, pmid = {17329835}, issn = {0918-6158}, mesh = {Acetylcysteine/pharmacology ; Animals ; Azo Compounds/metabolism ; Blotting, Northern ; Blotting, Western ; *Cell Degranulation ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Fluoresceins/metabolism ; Fluorescence ; Free Radical Scavengers/pharmacology ; Heme Oxygenase-1/antagonists &amp; inhibitors/genetics/*metabolism ; Leukemia, Basophilic, Acute/*metabolism/pathology/physiopathology ; Metalloporphyrins/pharmacology ; Ovalbumin/immunology/pharmacology ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Inbred BN ; Reactive Oxygen Species/metabolism ; Up-Regulation ; }, abstract = {Heme oxygenase (HO)-1, which is a rate-limiting enzyme involved in the catabolism of heme, is upregulated by a variety of stresses including oxidative stresses and inflammatory cytokines, in many cell types. Recent studies have suggested that upregulation of HO-1 might provide cytoprotection and immunomodulatory functions in addition to its obvious role in heme metabolism. In this study, we examined whether HO-1 was upregulated following degranulation in mast cells that initiate vigorous immunity reactions. To trigger degranulation, rat basophilic leukemia (RBL)-2H3 cells were passively sensitized using an antiserum collected from ovalbumin (OA) immunized-Brown Norway rats, and the cells were stimulated by treatment with OA. Degranulation was confirmed by measuring the release of beta-hexosaminidase. HO-1 mRNA and presence of HO-1 protein were detected using Northern blot and Western blot analyses, respectively. The effect of the antioxidant N-acetyl-L-cysteine (NAC) on HO-1 expression was also tested. HO-1 mRNA transiently increased at 1--2 h after RBL-2H3 cells were stimulated to degranulate. Its mRNA increases were dependent on the extent of degranulation. Following the upregulation of HO-1 mRNA, HO-1 protein was also increased. We also detected intracellular production of reactive oxygen species following degranulation in RBL-2H3 cells. NAC attenuated the HO-1 expression in a dose-dependent manner. This is the first report to reveal induction of both HO-1 mRNA and protein by degranulation in RBL-2H3 cells. We showed that NAC inhibited HO-1 upregulation. These results suggest that oxidative stress in activated RBL-2H3 cells results in the upregulation of HO-1.}, }
@article {pmid17320770, year = {2007}, author = {Glantzounis, GK and Rocks, SA and Sheth, H and Knight, I and Salacinski, HJ and Davidson, BR and Winyard, PG and Seifalian, AM}, title = {Formation and role of plasma S-nitrosothiols in liver ischemia-reperfusion injury.}, journal = {Free radical biology &amp; medicine}, volume = {42}, number = {6}, pages = {882-892}, doi = {10.1016/j.freeradbiomed.2006.12.020}, pmid = {17320770}, issn = {0891-5849}, mesh = {Acetylcysteine/metabolism ; Animals ; Electron Spin Resonance Spectroscopy ; Electron Transport Complex IV/metabolism ; Electrophoresis, Capillary ; Liver/metabolism/*pathology ; Nitrates/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitrites/metabolism ; RNA, Messenger/metabolism ; Rabbits ; Reactive Nitrogen Species ; *Reperfusion Injury ; S-Nitrosothiols/*blood ; }, abstract = {Plasma S-nitrosothiols (RSNOs) may act as a circulating form of nitric oxide that affects vascular function and platelet aggregation. Their role in liver ischemia/reperfusion (I/R) injury is largely unknown. The aim of the present study was to investigate the changes in plasma RSNOs following liver I/R injury. Two groups of New Zealand white rabbits were used (n=6, each): the I/R group underwent 60 min lobar liver ischemia and 7 h reperfusion, while the sham group underwent laparotomy but no liver ischemia. Serial RSNO levels were measured in plasma by electron paramagnetic resonance (EPR) spectrometry, nitrite/nitrates by capillary electrophoresis, hepatic microcirculation by laser Doppler flowmetry, redox state of hepatic cytochrome oxidase by near-infrared spectroscopy, liver iNOS mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR) and the oxidation of dihydrorhodamine to rhodamine by fluorescence. The effect of the antioxidant N-acetylcysteine (NAC) on RSNOs formation and DHR oxidation was tested in a third group of animals (n=6) undergoing lobar liver I/R. Hepatic I/R was associated with a significant increase in plasma RSNOs, plasma nitrites, hepatic iNOS mRNA expression, impairment in hepatic microcirculation, decrease in the redox state of cytochrome oxidase, and significant production of rhodamine. The changes were more obvious during the late phase of reperfusion (>4 h). NAC administration decreased plasma RSNOs and oxidation of DHR to RH (P<0.05, 5 and 7 h postreperfusion, respectively). These results suggest that significant upregulation of nitric oxide synthesis during the late phase of reperfusion is associated with impairment in microcirculation and mitochondrial dysfunction. Plasma S-nitrosothiols are a good marker of this nitric oxide-mediated hepatotoxicity.}, }
@article {pmid17317052, year = {2007}, author = {Takatsuka, S and Morita, T and Horikiri, Y and Yamahara, H and Saji, H}, title = {Absorption enhancement of poorly absorbed hydrophilic compounds from various mucosal sites by combination of mucolytic agent and non-ionic surfactant.}, journal = {International journal of pharmaceutics}, volume = {338}, number = {1-2}, pages = {87-93}, doi = {10.1016/j.ijpharm.2007.01.027}, pmid = {17317052}, issn = {0378-5173}, mesh = {Absorption ; Acetylcysteine/*administration &amp; dosage ; Animals ; Intestinal Absorption ; Lung/metabolism ; Male ; Mucous Membrane/*metabolism ; Nasal Mucosa/metabolism ; Octoxynol/*administration &amp; dosage ; Rats ; Rats, Wistar ; }, abstract = {Absorption enhancement of poorly absorbed hydrophilic compounds from various mucosal sites by co-administration of a mucolytic agent and a non-ionic surfactant was examined in rats. Fluorescein isothiocyanate-labeled dextran with average molecular weight of ca. 4.4kDa (FD-4), and salmon calcitonin (SCT) were used as model compounds. N-acetylcysteine (NAC) and p-t-octyl phenol polyoxyethylene-9.5 (Triton X-100, TX-100) were selected as a mucolytic agent and a non-ionic surfactant, respectively. Dosing solutions containing these agents were administered into various mucosal sites including the nose, the lung and the large intestine, and the bioavailabilities were determined. The combination of 5% NAC and 5% TX-100 significantly enhanced the nasal, the pulmonary and the large intestinal absorption of FD-4 compared to the control, and the enhancement ratios relative to the control were 7.2-, 2.8- and 4.5-fold, respectively. The different enhancement ratio among the administration sites explored indicates that the absorption enhancing effect of the combination of NAC and TX-100 is site-dependent. This combination also improved the nasal and the pulmonary absorption of SCT, and the enhancement ratios relative to the control were 6.1- and 8.1-fold, respectively. All these results suggest that the combination strategy of a mucolytic agent and a non-ionic surfactant may be widely applicable to various mucosal deliveries of poorly absorbed hydrophilic compounds.}, }
@article {pmid17309916, year = {2007}, author = {Briguori, C and Airoldi, F and D'Andrea, D and Bonizzoni, E and Morici, N and Focaccio, A and Michev, I and Montorfano, M and Carlino, M and Cosgrave, J and Ricciardelli, B and Colombo, A}, title = {Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies.}, journal = {Circulation}, volume = {115}, number = {10}, pages = {1211-1217}, doi = {10.1161/CIRCULATIONAHA.106.687152}, pmid = {17309916}, issn = {1524-4539}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Aged ; Ascorbic Acid/administration &amp; dosage ; Cardiovascular Diseases/complications/diagnosis ; Contrast Media/administration &amp; dosage/*adverse effects ; Creatinine/blood ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Glomerular Filtration Rate/drug effects ; Humans ; Infusions, Intravenous ; Kidney Diseases/complications/*physiopathology ; Male ; Renal Insufficiency/blood/*chemically induced/*prevention &amp; control ; Risk Factors ; Sodium Bicarbonate/administration &amp; dosage ; Sodium Chloride/administration &amp; dosage ; Treatment Outcome ; Triiodobenzoic Acids/administration &amp; dosage/*adverse effects ; }, abstract = {BACKGROUND: Volume supplementation by saline infusion combined with N-acetylcysteine (NAC) represents an effective strategy to prevent contrast agent-induced nephrotoxicity (CIN). Preliminary data support the concept that sodium bicarbonate and ascorbic acid also may be effective in preventing CIN.<br><br>METHODS AND RESULTS: Three hundred twenty-six consecutive patients with chronic kidney disease, referred to our institutions for coronary and/or peripheral procedures, were randomly assigned to prophylactic administration of 0.9% saline infusion plus NAC (n=111), sodium bicarbonate infusion plus NAC (n=108), and 0.9% saline plus ascorbic acid plus NAC (n=107). All enrolled patients had serum creatinine > or = 2.0 mg/dL and/or estimated glomerular filtration rate < 40 mL x min(-1) x 1.73 m(-2). Contrast nephropathy risk score was calculated in each patient. In all cases, iodixanol (an iso-osmolar, nonionic contrast agent) was administered. The primary end point was an increase of > or = 25% in the creatinine concentration 48 hours after the procedure (CIN). The amount of contrast media administered (179+/-102, 169+/-92, and 169+/-94 mL, respectively; P=0.69) and risk scores (9.1+/-3.4, 9.5+/-3.6, and 9.3+/-3.6; P=0.21) were similar in the 3 groups. CIN occurred in 11 of 111 patients (9.9%) in the saline plus NAC group, in 2 of 108 (1.9%) in the bicarbonate plus NAC group (P=0.019 by Fisher exact test versus saline plus NAC group), and in 11 of 107 (10.3%) in the saline plus ascorbic acid plus NAC group (P=1.00 versus saline plus NAC group).<br><br>CONCLUSIONS: The strategy of volume supplementation by sodium bicarbonate plus NAC seems to be superior to the combination of normal saline with NAC alone or with the addition of ascorbic acid in preventing CIN in patients at medium to high risk.}, }
@article {pmid17306056, year = {2007}, author = {MacLeod, ET and Maudlin, I and Darby, AC and Welburn, SC}, title = {Antioxidants promote establishment of trypanosome infections in tsetse.}, journal = {Parasitology}, volume = {134}, number = {Pt 6}, pages = {827-831}, doi = {10.1017/S0031182007002247}, pmid = {17306056}, issn = {0031-1820}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Antioxidants/*pharmacology ; Female ; Gastrointestinal Tract/parasitology ; Host-Parasite Interactions/*drug effects ; Insect Vectors/*drug effects/*parasitology ; Male ; Trypanosoma brucei brucei/*physiology ; Tsetse Flies/*drug effects/*parasitology ; }, abstract = {Efficient, cyclical transmission of trypanosomes through tsetse flies is central to maintenance of human sleeping sickness and nagana across sub-Saharan Africa. Infection rates in tsetse are normally very low as most parasites ingested with the fly bloodmeal die in the fly gut, displaying the characteristics of apoptotic cells. Here we show that a range of antioxidants (glutathione, cysteine, N-acetyl-cysteine, ascorbic acid and uric acid), when added to the insect bloodmeal, can dramatically inhibit cell death of Trypanosoma brucei brucei in tsetse. Both L- and D-cysteine invoked similar effects suggesting that inhibition of trypanosome death is not dependent on protein synthesis. The present work suggests that antioxidants reduce the midgut environment protecting trypanosomes from cell death induced by reactive oxygen species.}, }
@article {pmid17305994, year = {2007}, author = {Oz, S and Okay, E and Karadenizli, A and Cekmen, MB and Ozdogan, HK}, title = {N-acetylcysteine improves intestinal barrier in partially hepatectomized rats.}, journal = {ANZ journal of surgery}, volume = {77}, number = {3}, pages = {173-176}, doi = {10.1111/j.1445-2197.2006.04001.x}, pmid = {17305994}, issn = {1445-1433}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bacterial Translocation/*drug effects ; Escherichia coli/*physiology ; Gastrointestinal Agents/*pharmacology ; Hepatectomy ; Intestines/*drug effects/physiology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Translocating enteric bacteria play an important role in the development of infections following partial hepatectomy. The intestine itself is the first line of defence against bacterial translocation (BT). We investigated the effect of N-acetylcysteine (NAC) on BT and the intestinal wall.<br><br>METHODS: We compared four groups of Sprague-Dawley male rats (eight in each group): sham, sham plus preoperative single dose of NAC, partial hepatectomy and partial hepatectomy plus preoperative single dose of NAC. Microorganism count in the tissues and the glutathione and malondialdehyte contents of the intestinal wall were studied at the end of the 24th hour.<br><br>RESULTS: Bacterial growth was observed in the spleen and mesenteric lymph nodes in the sham group. There was bacterial growth in all the samples of the partial hepatectomy group. Differences were significant except in atrial and portal blood counts. In the partial hepatectomy plus NAC treatment group, counts were significantly low in all, except atrial and portal blood samples. The malondialdehyte level in the intestinal wall was 35.38 +/- 10.27 in the sham group, increasing significantly in the partial hepatectomy group (69.50 +/- 21.48), and decreasing in the partial hepatectomy plus NAC treatment group (35.63 +/- 14.12). Glutathione levels decreased significantly in the partial hepatectomy group and increased with preoperative single-dose NAC.<br><br>CONCLUSION: Partial hepatectomy resulted in oxidative disturbances in intestinal wall, which in turn gave rise to BT. Parenteral NAC protects the intestinal wall from oxidative injury and attenuates BT.}, }
@article {pmid17303202, year = {2007}, author = {Santra, A and Chowdhury, A and Ghatak, S and Biswas, A and Dhali, GK}, title = {Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine.}, journal = {Toxicology and applied pharmacology}, volume = {220}, number = {2}, pages = {146-155}, doi = {10.1016/j.taap.2006.12.029}, pmid = {17303202}, issn = {0041-008X}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Apoptosis/*drug effects ; Arsenic/metabolism/*toxicity ; Chemical and Drug Induced Liver Injury/*pathology/*prevention &amp; control ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Hepatocytes/pathology ; In Situ Nick-End Labeling ; Liver/drug effects/metabolism/*pathology ; Liver Function Tests ; Male ; Mice ; Mice, Inbred BALB C ; Mitochondria, Liver/drug effects/*physiology ; Oxidative Stress/drug effects/physiology ; Poly(ADP-ribose) Polymerases/metabolism ; Triglycerides/blood ; }, abstract = {Arsenicosis, caused by arsenic contamination of drinking water supplies, is a major public health problem in India and Bangladesh. Chronic liver disease, often with portal hypertension occurs in chronic arsenicosis, contributes to the morbidity and mortality. The early cellular events that initiate liver cell injury due to arsenicosis have not been studied. Our aim was to identify the possible mechanisms related to arsenic-induced liver injury in mice. Liver injury was induced in mice by arsenic treatment. The liver was used for mitochondrial oxidative stress, mitochondrial permeability transition (MPT). Evidence of apoptosis was sought by TUNEL test, caspase assay and histology. Pretreatment with N-acetyl-L-cysteine (NAC) was done to modulate hepatic GSH level. Arsenic treatment in mice caused liver injury associated with increased oxidative stress in liver mitochondria and alteration of MPT. Altered MPT facilitated cytochrome c release in the cytosol, activation of caspase 9 and caspase 3 activities and apoptotic cell death. Pretreatment of NAC to arsenic-treated mice abrogated all these alteration suggesting a glutathione (GSH)-dependent mechanism. Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury. The phenomenon is GSH dependent and supplementation of NAC might have beneficial effects.}, }
@article {pmid17302199, year = {2007}, author = {Noonan, DM and Benelli, R and Albini, A}, title = {Angiogenesis and cancer prevention: a vision.}, journal = {Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer}, volume = {174}, number = {}, pages = {219-224}, doi = {10.1007/978-3-540-37696-5_19}, pmid = {17302199}, issn = {0080-0015}, mesh = {Angiogenesis Inhibitors/*therapeutic use ; Animals ; Antineoplastic Agents/therapeutic use ; Cell Transformation, Neoplastic/*drug effects ; Humans ; Inflammation/complications/drug therapy ; Neoplasms/etiology/*prevention &amp; control ; Neovascularization, Pathologic/*prevention &amp; control ; }, abstract = {Angiogenesis is necessary for solid tumor growth and dissemination. In addition to angiogenesis, it has become increasingly clear that inflammation is a key component in cancer insurgence that can promote tumor angiogenesis. We noted that angiogenesis is a common and key target of most chemopreventive molecules, where they most likely suppress the angiogenic switch in premalignant tumors, a concept we termed angioprevention. We have shown that various molecules, such as flavonoids, antioxidants, and retinoids, act in the tumor microenvironment, inhibiting the recruitment and/or activation of endothelial cells and phagocytes of the innate immunity. N-acetyl-cysteine, and the green tea flavonoid epigallocatechin-3-gallate (EGCG) and the beer/ hops-derived chalcone Xanthohumol all prevent angiogenesis in the Matrigel sponge angiogenic assay in vivo and inhibit the growth of the highly angiogenic Kaposi's sarcoma tumor cells (KS-Imm) in nude mice. The synthetic retinoid 4-hydroxyfenretinide (4HPR) also shows anti-angiogenic effects. We analyzed the regulation of gene expression they exert in primary human umbilical endothelial cells (HUVEC) in culture with functional genomics. Expression profiles obtained through Affymetrix GeneChip arrays identified overlapping sets of genes regulated by anti-oxidants. In contrast, the ROS-producing 4HPR induced members of the TGFbeta-ligand superfamily, which, at least in part, explains its anti-angiogenic activity. NAC and the flavonoids all suppressed the IkB/NF-kappaB signaling pathway even in the presence of NF-kappaB stimulation by TNFalpha, and showed reduced expression of many NF-kappaB target genes. A selective apoptotic effect on transformed cells, but not on endothelial cells, of the anti-oxidants may be related to the reduced expression of the NF-kappaB-dependent survival factors Bcl2 and Birc5/surviving, which are selectively overexpressed in transformed cells by these factors. The repression of the NF-kappaB pathway suggests anti-inflammatory effects for the antioxidant compounds that may also represent an indirect role in angiogenesis inhibition. The green tea flavonoid EGCG does target inflammatory cells, mostly neutrophils, and inhibits inflammation-associated angiogenesis. The other angiopreventive molecules are turning out to be effective modulators of phagocyte recruitment and activation, further linking inflammation and vascularization to tumor onset and progression and providing a key target for cancer prevention.}, }
@article {pmid17300844, year = {2007}, author = {Alzate, JF and Arias, AA and Moreno-Mateos, D and Alvarez-Barrientos, A and Jiménez-Ruiz, A}, title = {Mitochondrial superoxide mediates heat-induced apoptotic-like death in Leishmania infantum.}, journal = {Molecular and biochemical parasitology}, volume = {152}, number = {2}, pages = {192-202}, doi = {10.1016/j.molbiopara.2007.01.006}, pmid = {17300844}, issn = {0166-6851}, mesh = {Animals ; Antioxidants/pharmacology ; *Apoptosis ; Flow Cytometry ; *Heat-Shock Response ; Leishmania infantum/drug effects/*metabolism ; Membrane Potential, Mitochondrial ; Mitochondria/*metabolism ; Oxidative Stress ; Oxygen/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Superoxides/*metabolism ; Time Factors ; }, abstract = {Previous studies have shown that heat stress triggers a process of programmed cell death in Leishmania infantum promastigotes that resembles apoptosis in higher eukaryotes. Even though this cell death process takes about 40 h to be completed, several early changes in the heat-stressed cells can be observed. Hyperpolarization of the parasite mitochondrion is the earliest event detected, which correlates with an increase in respiration rates and a concomitant increase in superoxide radical production. Induction of oxidative stress seems to mediate the heat-induced cell death process, as indicated by the partial prevention of parasite death observed when cell cultures are supplemented with N-acetyl-cysteine or glutathione. These antioxidants are able to diminish the concentration of superoxide radical but they do not prevent mitochondrial hyperpolarization. Treatment of the heat stressed parasites with the inhibitors of the mitochondrial respiration TTFA, antimycin A and KCN significantly decreases the production of superoxide radicals, which confirms the mitochondrial origin of this reactive oxygen species.}, }
@article {pmid17297310, year = {2007}, author = {Tanaka, T and Halicka, HD and Traganos, F and Seiter, K and Darzynkiewicz, Z}, title = {Induction of ATM activation, histone H2AX phosphorylation and apoptosis by etoposide: relation to cell cycle phase.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {6}, number = {3}, pages = {371-376}, doi = {10.4161/cc.6.3.3835}, pmid = {17297310}, issn = {1551-4005}, support = {R01 CA028704/CA/NCI NIH HHS/United States ; R01 CA028704-28/CA/NCI NIH HHS/United States ; CA R01 28 704/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anthraquinones/pharmacology ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/*drug effects ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/drug effects ; Cell Cycle Proteins/*metabolism ; Cell Line ; DNA Damage/drug effects ; DNA Replication/drug effects/genetics ; DNA-Binding Proteins/*metabolism ; Etoposide/*pharmacology ; Flow Cytometry/methods ; Free Radical Scavengers/pharmacology ; G1 Phase/drug effects ; Histones/*metabolism ; Humans ; Immunohistochemistry ; Mitoxantrone/pharmacology ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/*metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {Etoposide (VP-16) belongs to the family of DNA topoisomerase II (topo2) inhibitors, drugs widely used in cancer chemotherapy. Their presumed mode of action is stabilization of "cleavable complexes" between topo2 and DNA; collisions of DNA replication forks with these complexes convert them into DNA double-strand breaks (DSBs), potentially lethal lesions that may trigger apoptosis. Immunocytochemical detection of activation of ATM (ATM-S1981P) and histone H2AX phosphorylation (gammaH2AX) provides a sensitive probe of the induction of DSBs in individual cells. Using multiparameter cytometry we measured the expression of ATM-S1981P and gammaH2AX as well as initiation of apoptosis (caspase-3 activation) in relation to the cell cycle phase in etoposide-treated human lymphoblastoid TK6 cells. The induction of ATM-S1981P and gammaH2AX was seen in all phases of the cell cycle. The G(1)-phase cells, however, preferentially underwent apoptosis. The extent of etoposide-induced H2AX phosphorylation was partially reduced by N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS). The maximal reduction of H2AX phosphorylation by NAC, seen in G(1)-phase cells, was nearly 50%. NAC also protected a fraction of G(1) cells from etoposide-induced apoptosis, but had no such effect on S or G(2)M cells. However, no significant rise in the intracellular level of ROS upon treatment with etoposide was detected. The effects of etoposide were compared with the previously investigated effects of another topo2 inhibitor, mitoxantrone. The latter was seen to induce a maximal level of ATM-S1981P and gammaH2AX (partially abrogated by NAC) in G(1)-phase cells, but unlike etoposide, triggered apoptosis exclusively of S-phase cells. The data suggest that in addition to the generally accepted mechanism involving collisions of replication forks with the "cleavable complexes", other mechanisms which appear to be different for etoposide vs. mitoxantrone, may contribute to formation of DSBs and to triggering of apoptosis.}, }
@article {pmid17295922, year = {2007}, author = {Choi, AO and Cho, SJ and Desbarats, J and Lovrić, J and Maysinger, D}, title = {Quantum dot-induced cell death involves Fas upregulation and lipid peroxidation in human neuroblastoma cells.}, journal = {Journal of nanobiotechnology}, volume = {5}, number = {}, pages = {1}, pmid = {17295922}, issn = {1477-3155}, abstract = {BACKGROUND: Neuroblastoma, a frequently occurring solid tumour in children, remains a therapeutic challenge as existing imaging tools are inadequate for proper and accurate diagnosis, resulting in treatment failures. Nanoparticles have recently been introduced to the field of cancer research and promise remarkable improvements in diagnostics, targeting and drug delivery. Among these nanoparticles, quantum dots (QDs) are highly appealing due to their manipulatable surfaces, yielding multifunctional QDs applicable in different biological models. The biocompatibility of these QDs, however, remains questionable.<br><br>RESULTS: We show here that QD surface modifications with N-acetylcysteine (NAC) alter QD physical and biological properties. In human neuroblastoma (SH-SY5Y) cells, NAC modified QDs were internalized to a lesser extent and were less cytotoxic than unmodified QDs. Cytotoxicity was correlated with Fas upregulation on the surface of treated cells. Alongside the increased expression of Fas, QD treated cells had increased membrane lipid peroxidation, as measured by the fluorescent BODIPY-C11 dye. Moreover, peroxidized lipids were detected at the mitochondrial level, contributing to the impairment of mitochondrial functions as shown by the MTT reduction assay and imaged with confocal microscopy using the fluorescent JC-1 dye.<br><br>CONCLUSION: QD core and surface compositions, as well as QD stability, all influence nanoparticle internalization and the consequent cytotoxicity. Cadmium telluride QD-induced toxicity involves the upregulation of the Fas receptor and lipid peroxidation, leading to impaired neuroblastoma cell functions. Further improvements of nanoparticles and our understanding of the underlying mechanisms of QD-toxicity are critical for the development of new nanotherapeutics or diagnostics in nano-oncology.}, }
@article {pmid17295135, year = {2007}, author = {Zhang, XY and Hayasaka, S and Hayasaka, Y and Cui, HS and Chi, ZL}, title = {Effect of N-acetylcysteine on lipopolysaccharide-induced uveitis in rats.}, journal = {Japanese journal of ophthalmology}, volume = {51}, number = {1}, pages = {14-20}, pmid = {17295135}, issn = {0021-5155}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Aqueous Humor/metabolism ; Ciliary Body/metabolism ; *Disease Models, Animal ; Dose-Response Relationship, Drug ; E-Selectin/genetics ; *Escherichia coli ; *Injections, Subcutaneous ; Intercellular Adhesion Molecule-1/genetics ; Interleukin-6/genetics ; Iris/metabolism ; Lipopolysaccharides ; Male ; Nitric Oxide Synthase Type II/genetics ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha/genetics ; Uveitis, Anterior/*drug therapy/metabolism ; }, abstract = {PURPOSE: In this study we investigated the in vivo effect of N-acetylcysteine (NAC) on lipopolysaccharide (LPS)-induced uveitis in rats.<br><br>METHODS: To induce uveitis, LPS (100 microg) was injected into subcutaneous tissue of Wistar rats (170-190 g). NAC was injected intraperitoneally. Intracameral levels of protein, cells, nitrite, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 were determined by spectrophotometry, hemocytometry, and enzyme-linked immunosorbent assay. Expression of TNF-alpha, IL-6, endothelial leukocyte adhesion molecule-1 (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and inducible nitric oxide synthase (iNOS) mRNA was examined by real-time polymerase chain reaction.<br><br>RESULTS: LPS injection elevated intracameral protein and cells, and the elevation was inhibited by NAC. LPS injection induced expression of TNF-alpha, IL-6, E-selectin, and ICAM-1 mRNA in the iris/ciliary body at 3 h, and iNOS mRNA at 6 h. The LPS-induced elevation of the mRNA levels was inhibited by NAC. NAC inhibited LPS-induced intracameral elevation of TNF-alpha, IL-6, and nitrite.<br><br>CONCLUSION: NAC decreased LPS-induced uveitis in vivo by reducing the expression of proinflammatory cytokines and adhesion molecules.}, }
@article {pmid17294035, year = {2007}, author = {He, R and Qu, AJ and Mao, JM and Wang, X and Sun, W}, title = {Synergistic proliferation induced by insulin and glycated serum albumin in rat vascular smooth muscle cells.}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {59}, number = {1}, pages = {1-7}, pmid = {17294035}, issn = {0371-0874}, mesh = {Animals ; Aorta, Thoracic/cytology ; Cell Proliferation/*drug effects ; Cells, Cultured ; Drug Synergism ; Glycation End Products, Advanced ; Insulin/pharmacology/*physiology ; Male ; Muscle, Smooth, Vascular/*cytology ; Myocytes, Smooth Muscle/*cytology/drug effects ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Serum Albumin/pharmacology/*physiology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; Glycated Serum Albumin ; }, abstract = {Hyperglycemia, advanced glycation end products (AGEs), hyperinsulinemia and dyslipidemia may play roles in the development of diabetes-associated atherosclerosis and post-angioplasty restenosis. Clinically, their effects seem to be synergic. However, few studies have focused on the synergistic action of these factors. In the present study, we investigated whether glycated serum albumin (GSA) has a synergistic effect with insulin on the proliferation of vascular smooth muscle cells (VSMCs). VSMCs were isolated from rat thoracic aortas and cultured in fetal bovine serum (FBS)-free medium for 24 h, then exposed to GSA, insulin or GSA + insulin for 48 h with or without pretreatment of mitogen-activated protein kinase (MAPK) inhibitors or the antioxidant N-acetylcysteine (NAC). Cell growth rate was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or cell counting. The changes of phosphorylated-p38 MAPK and phosphorylated-C-Jun N-terminal kinase 1/2 (JNK1/2) were measured by Western blot analysis. The results showed that only p38 MAPK, but not JNK was activated by GSA and insulin co-incubation. VSMC proliferation was increased by insulin (10-1000 nmol/L) or GSA (10, 100 microg/mL). Co-incubation of insulin (100 nmol/L) and GSA (100 mug/mL) caused a more potent increase in VSMC proliferation than insulin or GSA incubation alone. p38 MAPK inhibitor, SB203580, as well as NAC, could inhibit the VSMC proliferation induced by co-incubation of GSA and insulin. The results show that insulin enhances GSA-induced VSMC proliferation, which may be mediated through a reactive oxygen species (ROS)-p38 MAPK pathway. The synergism of AGEs and insulin may play a detrimental role in the pathogenesis of diabetic atherosclerosis and post-angioplasty restenosis.}, }
@article {pmid17291459, year = {2007}, author = {Jiang, M and Wei, Q and Pabla, N and Dong, G and Wang, CY and Yang, T and Smith, SB and Dong, Z}, title = {Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity.}, journal = {Biochemical pharmacology}, volume = {73}, number = {9}, pages = {1499-1510}, pmid = {17291459}, issn = {0006-2952}, support = {R01 DK058831/DK/NIDDK NIH HHS/United States ; R01 DK067388/DK/NIDDK NIH HHS/United States ; R01 DK067388-02/DK/NIDDK NIH HHS/United States ; R01 DK087843/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects/physiology ; Cells, Cultured ; Cisplatin/pharmacology ; Free Radical Scavengers/*pharmacology ; Genes, p53/physiology ; Hydroxyl Radical/*metabolism ; Kidney/*drug effects/pathology ; Kidney Tubules/*drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Rats ; Reactive Oxygen Species ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {Nephrotoxicity is a major side effect of cisplatin, a widely used cancer therapy drug. Recent work has suggested a role of p53 in renal cell injury by cisplatin. However, the mechanism of p53 activation by cisplatin is unclear. This study determined the possible involvement of oxidative stress in p53 activation under the pathological condition using in vitro and in vivo models. In cultured renal proximal tubular cells, cisplatin at 20 microM induced an early p53 phosphorylation followed by protein accumulation. Cisplatin also induced reactive oxygen species (ROS), among which hydroxyl radicals showed a rapid and drastic accumulation. Dimethylthiourea (DMTU) and N-acetyl-cysteine (NAC) attenuated hydroxyl radical accumulation, and importantly, diminished p53 activation during cisplatin treatment. This was accompanied by the suppression of PUMA-alpha, a p53-regulated apoptotic gene. Concomitantly, mitochondrial cytochrome c release and apoptosis were ameliorated. Notably, DMTU and NAC, when added post-cisplatin treatment, were also inhibitory to p53 activation and apoptosis. In C57BL/6 mice, cisplatin at 30 mg/kg induced p53 phosphorylation and protein accumulation, which was also abrogated by DMTU. DMTU also ameliorated tissue damage, tubular cell apoptosis and cisplatin-induced renal failure. Collectively, this study has suggested a role of oxidative stress, particularly hydroxyl radicals, in cisplatin-induced p53 activation, tubular cell apoptosis and nephrotoxicity.}, }
@article {pmid17290278, year = {2007}, author = {Tolar, J and Orchard, PJ and Bjoraker, KJ and Ziegler, RS and Shapiro, EG and Charnas, L}, title = {N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy.}, journal = {Bone marrow transplantation}, volume = {39}, number = {4}, pages = {211-215}, doi = {10.1038/sj.bmt.1705571}, pmid = {17290278}, issn = {0268-3369}, mesh = {Acetylcysteine/*therapeutic use ; Adrenoleukodystrophy/*complications/*drug therapy ; Antioxidants/*therapeutic use ; Brain Diseases/etiology ; Child ; Combined Modality Therapy ; *Hematopoietic Stem Cell Transplantation ; Humans ; Kaplan-Meier Estimate ; Magnetic Resonance Imaging ; Male ; Pilot Projects ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {Hematopoietic stem cell transplantation as a treatment for childhood cerebral adrenoleukodystrophy (ALD) has historically only been successful in early disease. As ALD is associated with oxidative damage, we reasoned that adjunctive therapy with an antioxidant agent, N-acetyl-L-cysteine (NAC), may provide protection from rapid neurologic decline in boys with advanced cerebral disease. We report three boys with advanced ALD, whose neurologic status and brain radiographic findings were stabilized by treatment including NAC 8-11 months after hematopoietic stem cell transplantation. These results contrast with previous survival data in cerebral ALD patients who had a similar degree of brain involvement, all of whom died within 1 year of stem cell infusion despite a full donor engraftment. Thus, NAC merits investigation as a therapeutic strategy for patients with advanced ALD as an intervention that could change this lethal disease to a condition amendable to treatment with hematopoietic stem cell transplantation.}, }
@article {pmid17289842, year = {2007}, author = {Cheng, J and Cui, R and Chen, CH and Du, J}, title = {Oxidized low-density lipoprotein stimulates p53-dependent activation of proapoptotic Bax leading to apoptosis of differentiated endothelial progenitor cells.}, journal = {Endocrinology}, volume = {148}, number = {5}, pages = {2085-2094}, doi = {10.1210/en.2006-1709}, pmid = {17289842}, issn = {0013-7227}, support = {R01 DK095867/DK/NIDDK NIH HHS/United States ; P50-DK064233/DK/NIDDK NIH HHS/United States ; R01 HL 70762/HL/NHLBI NIH HHS/United States ; }, mesh = {AC133 Antigen ; Animals ; Antigens, CD ; Apoptosis/drug effects/*physiology ; Calcimycin/pharmacology ; Carotid Arteries/physiology ; Cell Differentiation/physiology ; Cells, Cultured ; Endothelium, Vascular/*cytology/metabolism ; Fetal Blood/cytology ; Glycoproteins ; Humans ; Hypercholesterolemia/metabolism/*pathology ; Ionophores/pharmacology ; Lipoproteins, LDL/*metabolism/pharmacology ; Mitochondria/metabolism ; Peptides ; Protein Conformation ; RNA, Small Interfering ; Reactive Oxygen Species/metabolism ; Sheep ; Stem Cells/*cytology/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; Vasodilation/drug effects/physiology ; bcl-2-Associated X Protein/chemistry/genetics/*metabolism ; }, abstract = {Dyslipidemia increases the risks for atherosclerosis in part by impairing endothelial integrity; endothelial progenitor cells (EPCs) play a pivotal role in reendothelialization. In this study, we investigated the mechanism whereby oxidized low-density lipoprotein (oxLDL) affects the function of differentiated EPCs (EDCs). In EDCs expanded in vitro from EPCs isolated from human cord blood, we measured EDC responses to both copper-oxidized LDL and L5, an electronegative LDL minimally oxidized in vivo in patients with hypercholesterolemia. OxLDL induced apoptosis of EDCs and impaired their response to nitric oxide. We found that the key to oxLDL-induced apoptosis in both EDCs and endothelial cells is the induction of a conformational change of Bax, leading to Bax activation without altering its expression. The conformationally changed Bax translocated to the mitochondria and stimulated apoptosis, as Bax knockdown prevented oxLDL-induced apoptosis in EDCs. The activation of Bax is mediated by an increase in p53 and knockdown of p53 abolished oxLDL-induced activation of Bax and apoptosis. OxLDL activated p53 through production of mitochondria-derived reactive oxygen species. In EDCs treated with a recombinant adenovirus expressing superoxide dismutase or N-acetyl-cysteine (but not catalase), the p53-Bax pathway activated by oxLDL was blocked, and apoptosis was prevented. Of importance, treatment of EDC with low-concentration L5 stimulated superoxide dismutase expression, which significantly attenuated apoptosis in EDCs exposed to high-concentration L5. These findings suggest that exposure of EDCs and endothelial cells to either experimentally prepared or naturally occurring modified LDL results in an increased transfer of mitochondria-derived superoxide anion to p53, which stimulates a conformational change in Bax favoring its translocation to the mitochondria with resultant apoptosis of these cells.}, }
@article {pmid17285200, year = {2006}, author = {Ciralik, H and Bulbuloglu, E and Cetinkaya, A and Kurutas, EB and Celik, M and Polat, A}, title = {Effects of N-acetylcysteine on methotrexate-induced small intestinal damage in rats.}, journal = {The Mount Sinai journal of medicine, New York}, volume = {73}, number = {8}, pages = {1086-1092}, pmid = {17285200}, issn = {0027-2507}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antimetabolites, Antineoplastic/pharmacology/*therapeutic use ; Intestinal Mucosa/*drug effects/pathology ; Intestine, Small/*drug effects/pathology ; Male ; Methotrexate/*adverse effects ; Models, Animal ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; }, abstract = {Methotrexate (MTX) is known to cause damage to the small intestine, leading to its dysfunction. The aim of the present study was to examine whether the administration of N-acetylcysteine (NAC) provides protection against the MTX-induced damage to small intestinal epithelium in rats. A single dose of MTX (20 mg/kg, intraperitoneal) was followed by intraperitoneal saline or NAC administration (150 mg/kg, MTX+NAC group) for the next 5 days. Afterward, the rats were sacrificed and small intestinal segments were fixed for light microscopic examinations. Glutathione and malondialdehyde levels, myeloperoxidase, superoxide dismutase and catalase activities were measured in the other intestinal segments. MTX caused an increase in the levels of glutathione and malondialdehyde and in the activities of myeloperoxidase, superoxide dismutase and catalase. These changes were significantly reversed in MTX+NAC-treated rats. Light microscopy in the MTX group revealed mucosal damage, which decreased with NAC treatment. Our results confirmed that administration of NAC decreased the MTX-induced damage to the small intestine. This protective effect of NAC may have clinical applications in chemotherapy.}, }
@article {pmid17279683, year = {2007}, author = {Cho, SJ and Maysinger, D and Jain, M and Röder, B and Hackbarth, S and Winnik, FM}, title = {Long-term exposure to CdTe quantum dots causes functional impairments in live cells.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {23}, number = {4}, pages = {1974-1980}, doi = {10.1021/la060093j}, pmid = {17279683}, issn = {0743-7463}, mesh = {Cadmium/chemistry/pharmacology ; Cadmium Compounds/*chemistry/toxicity ; Cations, Divalent/chemistry ; Cell Survival/drug effects ; Humans ; Nanoparticles/chemistry ; *Quantum Dots ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Tellurium/*chemistry/toxicity ; Time Factors ; }, abstract = {Several studies suggested that the cytotoxic effects of quantum dots (QDs) may be mediated by cadmium ions (Cd2+) released from the QDs cores. The objective of this work was to assess the intracellular Cd2+ concentration in human breast cancer MCF-7 cells treated with cadmium telluride (CdTe) and core/shell cadmium selenide/zinc sulfide (CdSe/ZnS) nanoparticles capped with mercaptopropionic acid (MPA), cysteamine (Cys), or N-acetylcysteine (NAC) conjugated to cysteamine. The Cd2+ concentration determined by a Cd2+-specific cellular assay was below the assay detection limit (<5 nM) in cells treated with CdSe/ZnS QDs, while in cells incubated with CdTe QDs, it ranged from approximately 30 to 150 nM, depending on the capping molecule. A cell viability assay revealed that CdSe/ZnS QDs were nontoxic, whereas the CdTe QDs were cytotoxic. However, for the various CdTe QD samples, there was no dose-dependent correlation between cell viability and intracellular [Cd2+], implying that their cytotoxicity cannot be attributed solely to the toxic effect of free Cd2+. Confocal laser scanning microscopy of CdTe QDs-treated cells imaged with organelle-specific dyes revealed significant lysosomal damage attributable to the presence of Cd2+ and of reactive oxygen species (ROS), which can be formed via Cd2+-specific cellular pathways and/or via CdTe-triggered photoxidative processes involving singlet oxygen or electron transfer from excited QDs to oxygen. In summary, CdTe QDs induce cell death via mechanisms involving both Cd2+ and ROS accompanied by lysosomal enlargement and intracellular redistribution.}, }
@article {pmid17268844, year = {2007}, author = {Kamboj, A and Sandhir, R}, title = {Perturbed synaptosomal calcium homeostasis and behavioral deficits following carbofuran exposure: neuroprotection by N-acetylcysteine.}, journal = {Neurochemical research}, volume = {32}, number = {3}, pages = {507-516}, pmid = {17268844}, issn = {0364-3190}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/*metabolism ; Calcium-Transporting ATPases/metabolism ; Carbofuran/*pharmacology ; Cholinesterase Inhibitors/*pharmacology ; Disease Models, Animal ; Homeostasis/drug effects ; Lipid Peroxidation/drug effects ; Male ; Neuroprotective Agents/*pharmacology ; Potassium/pharmacology ; Rats ; Rats, Wistar ; Synaptosomes/*metabolism ; }, abstract = {The protective effects of N-acetylcysteine (NAC) on carbofuran-induced alterations in calcium homeostasis and neurobehavioral functions were investigated in rats. Rats were exposed to carbofuran at a dose of 1 mg/kg body weight, orally for a period of 28 days. A significant decrease in Ca2+ATPase activity was observed following carbofuran exposure with a concomitant increase in K+ -induced (45)Ca2+ uptake through voltage operated calcium channels. This was accompanied with a marked accumulation of intracellular free calcium in synaptosomes. The increase in intracellular calcium levels were associated with an increased lipid peroxidation and decreased glutathione content in carbofuran exposed animals. NAC administration (200 mg/kg body weight, orally) to the carbofuran exposed animals had a beneficial effect on carbofuran-induced alterations in calcium homeostasis and resulted in repletion in glutathione levels and resulted in lowering the extent of lipid peroxidation. Marked impairment in the motor functions were seen following carbofuran exposure, which were evident by the significant decrease in the locomotor activity and reduction in the retention time of the rats on rotating rods. Cognitive deficits were also seen as indicated by the significant decrease in active and passive avoidance response. NAC treatment, on the other hand, protected the animals against carbofuran-induced neurobehavioral deficits. The results support the hypothesis that carbofuran exerts its toxic effects by disrupting calcium homeostasis, which may have serious consequences on neuronal functioning, and clearly show the potential beneficial effects of N-acetylcysteine on carbofuran induced alterations in synaptosomal calcium homeostasis.}, }
@article {pmid17267348, year = {2006}, author = {Coleman, MD and Aerry, R and Wanogho, E and Khan, NB and Lambert, PA and Rathbone, DL}, title = {Effects of glutathione and N-acetyl cysteine on the antimycobacterial efficacy of isoniazid on Mycobacterium fortuitum in vitro.}, journal = {Journal of chemotherapy (Florence, Italy)}, volume = {18}, number = {6}, pages = {665-666}, doi = {10.1179/joc.2006.18.6.665}, pmid = {17267348}, issn = {1120-009X}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Drug Interactions ; Glutathione/*pharmacology ; Isoniazid/*pharmacology ; Microbial Sensitivity Tests ; Mycobacterium fortuitum/*drug effects ; Sulfhydryl Compounds/pharmacology ; Thioctic Acid/analogs &amp; derivatives/pharmacology ; }, }
@article {pmid17266944, year = {2007}, author = {Szotowski, B and Antoniak, S and Goldin-Lang, P and Tran, QV and Pels, K and Rosenthal, P and Bogdanov, VY and Borchert, HH and Schultheiss, HP and Rauch, U}, title = {Antioxidative treatment inhibits the release of thrombogenic tissue factor from irradiation- and cytokine-induced endothelial cells.}, journal = {Cardiovascular research}, volume = {73}, number = {4}, pages = {806-812}, doi = {10.1016/j.cardiores.2006.12.018}, pmid = {17266944}, issn = {0008-6363}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Antioxidants/*pharmacology ; Apoptosis ; Caspase 3/analysis ; Cells, Cultured ; Endothelial Cells/drug effects/*metabolism/radiation effects ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; Luminescent Measurements ; Pyrrolidines/*pharmacology ; Radiation, Ionizing ; Reactive Oxygen Species/analysis/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Thiocarbamates/*pharmacology ; Thromboplastin/analysis/*metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; Umbilical Veins ; }, abstract = {OBJECTIVES: The aim of this study was to investigate the effect of the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC) on the ionizing radiation (IR)- and tumor necrosis factor-alpha (TNF-alpha) induced tissue factor (TF) expression and its release from human umbilical vein endothelial cells (HUVECs).<br><br>METHODS: HUVECs were irradiated with a single dose of either 5 Gy or 10 Gy and stimulated with TNF-alpha (10 ng/mL) in the presence or absence of PDTC and NAC, respectively. Quantitative real-time PCR, ELISA, and TF activity measurements were performed, including TF activity in the supernatant. Apoptosis was detected by flow cytometric active caspase-3 measurement and formation of reactive oxygen species (ROS) by chemiluminescence.<br><br>RESULTS: We demonstrated a thus far uninvestigated persistent induction of TF expression in HUVECs after treatment with IR and TNF-alpha. Combined stimulation with IR and TNF-alpha led to an immense shedding of microparticle-associated TF which was positively correlated with apoptosis and ROS formation. Antioxidative pre-treatment reduced not only apoptosis and ROS formation, but also the release of thrombogenic microparticles.<br><br>CONCLUSIONS: Antioxidative treatment inhibited apoptosis and shedding of microparticles, thereby reducing thrombogenicity. Thus, antioxidants may help to prevent late thrombosis after antiproliferative treatment when used in combination with anticoagulants.}, }
@article {pmid17266938, year = {2007}, author = {Maiti, S and Zhang, J and Chen, G}, title = {Redox regulation of human estrogen sulfotransferase (hSULT1E1).}, journal = {Biochemical pharmacology}, volume = {73}, number = {9}, pages = {1474-1481}, pmid = {17266938}, issn = {0006-2952}, support = {R01 GM078606-01/GM/NIGMS NIH HHS/United States ; R01 GM059873-05/GM/NIGMS NIH HHS/United States ; R01 GM078606-02/GM/NIGMS NIH HHS/United States ; R01 GM059873/GM/NIGMS NIH HHS/United States ; GM59873/GM/NIGMS NIH HHS/United States ; R01 GM078606/GM/NIGMS NIH HHS/United States ; }, mesh = {Amino Acid Substitution ; Humans ; Mutagenesis, Site-Directed ; *Oxidation-Reduction ; Sulfotransferases/genetics/*metabolism ; }, abstract = {Sulfotransferases (SULTs) are enzymes that catalyze the sulfation of hydroxyl-containing compounds. Sulfation regulates hormone activities and detoxifies xenobiotics. Human estrogen sulfotransferase (hSULT1E1) catalyzes the sulfation of estrogens and regulates estrogen bioactivities. Oxidative regulation provides a biological mechanism for regulating enzyme activities in vivo. The oxidative regulation of human SULTs has not been reported. In this study, we used amino acid modification, manipulation of intracellular redox state, and site-directed mutagenesis to study the redox regulation of human SULTs and specifically the mechanism of hSULT1E1 inhibitory regulation by oxidized glutathione (GSSG). Of the four major human SULTs, hSULT1A1, hSULT1A3, and hSULT2A1 do not undergo redox regulation; hSULT1E1, on the other hand, can be redox regulated. GSSG inactivated hSULT1E1 activity in an efficient, time- and concentration-dependant manner. The co-enzyme adenosine 3'-phosphate 5'-phosphosulfate protected hSULT1E1 from GSSG-associated inactivation. A reduced glutathione (GSH) inducer (N-acetyl cysteine) significantly increased while a GSH depletor (buthionine sulfoxamine) significantly decreased hSULT1E1 activity, but both failed to affect the amount of hSULT1E1 protein in human hepatocyte carcinoma Hep G2 cells. Crystal structure suggested that no Cys residues exist near the active sites of hSULT1A1, hSULT1A3, and hSULT2A1, but Cys residues do exist within the active site of hSULT1E1. Site-directed mutagenesis demonstrated that Cys83 is critical for the redox regulation of hSULT1E1. This first report on the redox regulation of human SULTs suggests that the redox regulation of hSULT1E1 may interrupt the regulation and function of estrogens under various physiological and pathological conditions.}, }
@article {pmid17266621, year = {2007}, author = {Carbonell, LF and Díaz, J and Hernández, I and Cuevas, S and Valero, F and Quesada, T and Fenoy, F and Salom, MG}, title = {N-acetylcysteine exerts protective effects and prevents lung redox imbalance and peroxynitrite generation in endotoxemic rats.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {3}, number = {1}, pages = {29-34}, doi = {10.2174/157340607779317580}, pmid = {17266621}, issn = {1573-4064}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Coloring Agents ; Endotoxemia/blood/metabolism/*prevention &amp; control ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/*pharmacology ; Lactic Acid/blood ; Lipopolysaccharides/pharmacology ; Lung/drug effects/*metabolism ; Male ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Oxidation-Reduction/drug effects ; Peroxynitrous Acid/blood/*metabolism ; Platelet Count ; Rats ; Rats, Wistar ; Rhodamines ; Sulfhydryl Compounds/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The aim of this study was to determine in endotoxemic rats the effects of N-acetylcysteine on lung redox imbalance and plasma peroxynitrite generation. Eighty male Wistar rats were divided in two sets of five experimental groups. Six hours after vehicle (Control group: isotonic NaCl sterile solution i.p.; n=7), lipopolysaccharide (LPS group: 1 mg/Kg i.p.; n=8), N-acetylcysteine plus LPS (NAC+LPS group, n=8), NAC plus the nitric oxide synthesis inhibitor N(w)-nitro-L-arginine methyl ester plus LPS (NAC+NAME+LPS group; n=8), or NAME plus LPS (NAME+LPS group; n=9), arterial blood and lung samples were taken from each animal under sodium pentobarbital anesthesia. In five additional groups treated as described above, in vivo plasma oxidation of dihydrorhodamine (DRH) 123 to rhodamine (RH)123 was measured as index of peroxynitrite formation. LPS treated rats presented increased plasma lactate, thrombocytopenia and both, decreased reduced thiols and increased lipid peroxidation in lung tissue. Moreover, LPS produced increments in plasma concentration of nitrites/nitrates and DRH 123 oxidation. Pretreatment with NAC prevented all these changes induced by LPS except the increment in plasma concentration of nitrites/nitrates. The protective effects seen in LPS rats pretreated with NAC were not observed in the NAC+NAME+LPS group. In conclusion, the results of this study show that in endotoxemia induced by LPS in rats, NAC produces protective effects on lung redox balance and prevents peroxynitrite anion generation.}, }
@article {pmid17263498, year = {2007}, author = {Chen, CY and Liu, TZ and Liu, YW and Tseng, WC and Liu, RH and Lu, FJ and Lin, YS and Kuo, SH and Chen, CH}, title = {6-shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism.}, journal = {Journal of agricultural and food chemistry}, volume = {55}, number = {3}, pages = {948-954}, doi = {10.1021/jf0624594}, pmid = {17263498}, issn = {0021-8561}, mesh = {Apoptosis/*drug effects ; Carcinoma, Hepatocellular/*pathology ; Caspases/*metabolism ; Catechols/*pharmacology ; Cell Line, Tumor ; DNA Damage/drug effects ; Zingiber officinale/chemistry ; Humans ; Liver Neoplasms/*pathology ; Mutation ; *Oxidative Stress ; Plant Extracts ; Plant Roots/chemistry ; Reactive Oxygen Species/metabolism ; }, abstract = {Mahlavu cells, poorly differentiated and p53 mutants of a human hepatoma subline, are known to be highly refractory to a number of chemotherapeutic agents and radiotherapy due to their high expressions of multidrug resistance gene-1 (MDR-1) and Bcl-2 proteins. Thus, it is desirable to search for an alternative strategy for effective eradication of this type of cancer cells. We present evidence here for the first time that 6-shogaol (6-SG), an alkanone isolated from the rhizomes of ginger, can effectively induce apoptotic cell death of Mahlavu cells via an oxidative stress-mediated caspase-dependent mechanism. The cascade of events in 6-SG-induced apoptosis of these cells involved an initial overproduction of reactive oxygen species (ROS) followed by a severe depletion of intracellular glutathione (GSH) contents. Both events consequently entailed a significant drop in mitochondrial transmembrane potential (DeltaPsim), which ultimately activated the activities of caspases 3/7 resulting in the DNA fragmentation. Interestingly, we also found that N-acetylcysteine (NAC), an antioxidant and a precursor of GSH biosynthesis, could offer a near complete protection of apoptotic cell death exerted by 6-SG. Similarly, exogenously added GSH could also provide protection with an equal efficacy. However, it was paradoxical that both Boc-Asp(OMe)-fmk (a broad caspases inhibitor) and cyclosporin A (an mitochondrial permeability transition opening inhibitor) could only partially protect these cells from 6-SG-induced apoptosis. Taking these data into consideration, it is obvious that GSH depletion is the major contributing factor in arbitrating 6-SG-induced apoptosis of Mahlavu cells. In conclusion, we provide here a novel modality that can help to eradicate a p53 mutant of human hepatoma cells by using a natural consistent isolated form of ginger. These data also provide evidence to reaffirm the notion that consumption of certain foodstuffs can be beneficial to health because some of the constituents contained in them may be anticarcinogenic.}, }
@article {pmid17260537, year = {2007}, author = {Kanwar, SS and Nehru, B}, title = {Modulatory effects of N-acetylcysteine on cerebral cortex and cerebellum regions of ageing rat brain.}, journal = {Nutricion hospitalaria}, volume = {22}, number = {1}, pages = {95-100}, pmid = {17260537}, issn = {0212-1611}, mesh = {Acetylcysteine/*pharmacology ; Aging/*drug effects/*metabolism ; Animals ; Cerebellum/*drug effects/*metabolism ; Cerebral Cortex/*drug effects/*metabolism ; Female ; Lipid Peroxidation/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Oxidative stress has been implicated in brain ageing and in age-related neurodegenerative disorders. Since N-acetylcysteine (NAC) has recently been shown to prevent oxidative damage in ageing brain, we have examined the effects of this thiolic antioxidant on the age associated oxidative stress related parameters in rat brain regions. The lipid peroxide formation, reduced glutathione (GSH) content along with the activities of superoxide dismutase (SOD) and catalase were determined in the cerebral cortex and cerebellum brain regions of the young (4 months) and older (14 months) female rats. The lipid peroxidation was observed to be increased in the cerebral cortex regions accompanied by simultaneous decrease in the GSH content in both the regions of older rats. The SOD activity was reduced in both the regions while catalase was reduced only in cerebellum region of the older rats. Following NAC supplementation (160 mg/kg. b. wt./ day), lipid peroxidation was observed to be reduced which was accompanied by enhanced GSH levels, along with enhanced SOD and catalase in both the brain regions of older age rats. Further, in the younger age rats the NAC treatment resulted in the decrease of lipid peroxidation in both the regions that was accompanied by the increase catalase activity in cerebral cortex region along with increase in GSH content and SOD in cerebellum regions. Our result suggests that the normal brain ageing is associated with the decrease in antioxidative defense status and the supplementation of thiol antioxidants like NAC may prove helpful in managing the age related brain disorders characterized by compromised antioxidative defense systems.}, }
@article {pmid17259074, year = {2007}, author = {Mishra, DP and Dhali, A}, title = {Endotoxin induces luteal cell apoptosis through the mitochondrial pathway.}, journal = {Prostaglandins &amp; other lipid mediators}, volume = {83}, number = {1-2}, pages = {75-88}, doi = {10.1016/j.prostaglandins.2006.10.002}, pmid = {17259074}, issn = {1098-8823}, mesh = {Animals ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins/metabolism ; Caspase 3/metabolism ; Cattle ; Cell Survival/drug effects ; Cells, Cultured ; Cyclosporine/pharmacology ; DNA Fragmentation/drug effects ; Endotoxins/*pharmacology ; Female ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Lipopolysaccharides/pharmacology ; Luteal Cells/*cytology/*drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase Type II/metabolism ; Progesterone/metabolism ; Superoxides/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Time Factors ; }, abstract = {The effect of endotoxin (lipopolysacharide, LPS) exposure on luteal cells was studied using an in vitro cell culture system. Buffalo luteal cells were isolated from corpora lutea of the late luteal phase (days 14-16 post estrus) and exposed to various LPS doses (5, 10 and 100 microg/ml) for different time periods (6, 12, 18 or 24 h). The cultured cells were subsequently evaluated for oxidative stress (super oxide, nitric oxide, inducible nitric oxide synthase activity, reduced glutathione depletion and lipid peroxidation) and apoptotic markers (mitochondrial membrane potential, DNA fragmentation, apoptotic cells and cell viability). LPS exposure significantly increased the production of super oxide (P<0.05) and nitric oxide (P<0.01) and increased inducible nitric oxide synthase activity (P<0.01). LPS exposure further depleted reduced glutathione (P<0.05) levels and induced lipid peroxidation (P<0.05). LPS exposure also induced the loss of mitochondrial membrane potential (P<0.05), increased DNA fragmentation (P<0.01) and apoptosis (P<0.01) and decreased cell viability (P<0.01). LPS mediated apoptotic pathway in luteal cells was further characterized using a selected LPS dose (10 microg/ml). It was observed that LPS exposure induced mitochondrial translocation of proapoptotic protein Bax, increased the total Bad expression and down regulated the expression of antiapoptotic proteins Bcl2 and BclXL. LPS exposure further induced cytochrome c release and increased Caspase-9 (P<0.01) and Caspase-3 (P<0.01) activities. LPS exposure also inhibited luteal progesterone secretion (P<0.01). It was evident that the LPS mediated apoptotic effects could be prevented by the coincubation of luteal cells with mitochondrial permeability transition pore blocker Cyclosporine A, inducible nitric oxide synthase inhibitor N-[3-(aminomethyl)benzyl]acetamidine and oxidative stress scavenger N-acetyl cysteine. Our study clearly indicates that LPS induces oxidative stress mediated apoptosis in luteal cells through the mitochondrial pathway.}, }
@article {pmid17253623, year = {2007}, author = {Wang, X and Svedin, P and Nie, C and Lapatto, R and Zhu, C and Gustavsson, M and Sandberg, M and Karlsson, JO and Romero, R and Hagberg, H and Mallard, C}, title = {N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury.}, journal = {Annals of neurology}, volume = {61}, number = {3}, pages = {263-271}, doi = {10.1002/ana.21066}, pmid = {17253623}, issn = {0364-5134}, support = {GM 44842/GM/NIGMS NIH HHS/United States ; N01-HD-2-3342/HD/NICHD NIH HHS/United States ; //Intramural NIH HHS/United States ; }, mesh = {Animals ; Animals, Newborn ; Apoptosis/drug effects ; Calpain/drug effects ; Caspases/drug effects ; Cystine/*analogs &amp; derivatives/pharmacology ; Enzyme Activation/drug effects ; Glutathione/drug effects ; Hypoxia-Ischemia, Brain/chemically induced/*prevention &amp; control ; Isoprostanes/metabolism ; Lipopolysaccharides/toxicity ; Membrane Proteins/drug effects ; Neuroprotective Agents/*pharmacology ; Oxidation-Reduction/*drug effects ; Rats ; Rats, Wistar ; Thioredoxins/drug effects ; Tyrosine/analogs &amp; derivatives/drug effects ; }, abstract = {OBJECTIVE: Maternal inflammation/infection alone or in combination with birth asphyxia increases the risk for perinatal brain injury. Free radicals are implicated as major mediators of inflammation and hypoxia-ischemia (HI)-induced perinatal brain injury. This study evaluated the neuroprotective efficacy of a scavenging agent, N-acetylcysteine (NAC), in a clinically relevant model.<br><br>METHODS: Lipopolysaccharide (LPS)-sensitized HI brain injury was induced in 8-day-old neonatal rats. NAC was administered in multiple doses, and brain injury was evaluated at 7 days after HI.<br><br>RESULTS: NAC (200mg/kg) provided marked neuroprotection with up to 78% reduction of brain injury in the pre+post-HI treatment group and 41% in the early (0 hour) post-HI treatment group, which was much more pronounced protection than another free radical scavenger, melatonin. Protection by NAC was associated with the following factors: (1) reduced isoprostane activation and nitrotyrosine formation; (2) increased levels of the antioxidants glutathione, thioredoxin-2, and (3) inhibition of caspase-3, calpain, and caspase-1 activation.<br><br>INTERPRETATION: NAC provides substantial neuroprotection against brain injury in a model that combines infection/inflammation and HI. Protection by NAC was associated with improvement of the redox state and inhibition of apoptosis, suggesting that these events play critical roles in the development of lipopolysaccharide-sensitized HI brain injury.}, }
@article {pmid17250813, year = {2007}, author = {Xia, Z and Kuo, KH and Nagareddy, PR and Wang, F and Guo, Z and Guo, T and Jiang, J and McNeill, JH}, title = {N-acetylcysteine attenuates PKCbeta2 overexpression and myocardial hypertrophy in streptozotocin-induced diabetic rats.}, journal = {Cardiovascular research}, volume = {73}, number = {4}, pages = {770-782}, doi = {10.1016/j.cardiores.2006.11.033}, pmid = {17250813}, issn = {0008-6363}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Cardiomegaly/enzymology/pathology/*prevention &amp; control ; Cell Size/drug effects ; Cells, Cultured ; Collagen Type I/analysis ; Collagen Type II/analysis ; Connective Tissue Growth Factor ; Diabetes Mellitus, Experimental/*enzymology/pathology ; Dinoprost/analogs &amp; derivatives/analysis/blood ; Glucose/pharmacology ; Immediate-Early Proteins/metabolism ; Immunohistochemistry ; Intercellular Signaling Peptides and Proteins/metabolism ; Male ; Myocardium/chemistry/*enzymology ; Myocytes, Cardiac/drug effects/pathology ; Oxidative Stress ; Protein Kinase C/*metabolism ; Protein Kinase C beta ; Rats ; Rats, Wistar ; Superoxides/analysis ; }, abstract = {OBJECTIVE: Oxidative stress-mediated activation of protein kinase C (PKC) beta(2) in the myocardium has been implicated in the development of cardiomyopathy. Overexpression of PKCbeta(2) is associated with increased expression of connective tissue growth factor (CTGF) in myocardium, resulting in myocardial hypertrophy. We hypothesized that chronic treatment with the antioxidant N-acetylcysteine (NAC) would normalize oxidative stress-mediated overexpression of myocardial PKCbeta(2) and CTGF and attenuate the development of myocardial hypertrophy.<br><br>METHODS: Control and streptozotocin-induced diabetic rats were treated with NAC in drinking water for 8 weeks. At termination rats were surgically prepared for hemodynamic measurement, subsequent to which their hearts were removed to evaluate cardiac performance and histological and biochemical changes. Further, the role of PKCbeta(2) in hyperglycemia-induced cardiomyocyte hypertrophy was tested in cultured neonatal cardiomyocytes.<br><br>RESULTS: Myocardial hypertrophy, characterized by an increased ratio of ventricle weight to body weight and cardiomyocyte cross-sectional area was found to be higher in untreated diabetic rats. Further, in myocardium, increased levels of 15-F(2t)-isoprostane were accompanied by an increased expression of membrane-bound PKCbeta(2) and CTGF. N-acetylcysteine treatment not only attenuated these changes but also prevented hyperglycemia-induced hypertrophy in cultured neonatal rat cardiomyocytes.<br><br>CONCLUSIONS: The results suggest that PKCbeta(2) overexpression represents a mechanism causing hyperglycemia-mediated myocardial hypertrophy, which can be prevented by the antioxidant N-acetylcysteine.}, }
@article {pmid17237434, year = {2007}, author = {Mukherjee, TK and Mishra, AK and Mukhopadhyay, S and Hoidal, JR}, title = {High concentration of antioxidants N-acetylcysteine and mitoquinone-Q induces intercellular adhesion molecule 1 and oxidative stress by increasing intracellular glutathione.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {178}, number = {3}, pages = {1835-1844}, doi = {10.4049/jimmunol.178.3.1835}, pmid = {17237434}, issn = {0022-1767}, support = {HL67281/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Aorta ; Cells, Cultured ; Endothelial Cells/drug effects/pathology ; Endothelium, Vascular/*drug effects/pathology ; Glutathione/*biosynthesis ; Humans ; I-kappa B Kinase/*antagonists &amp; inhibitors ; Intercellular Adhesion Molecule-1/*genetics ; Organophosphorus Compounds/*pharmacology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; Ubiquinone/*pharmacology ; Up-Regulation ; }, abstract = {In endothelial cells, the intracellular level of glutathione is depleted during offering protection against proinflammatory cytokine TNF-alpha-induced oxidative stress. Administration of anti-inflammatory drugs, i.e., N-acetylcysteine (NAC) or mitoquinone-Q (mito-Q) in low concentrations in the human pulmonary aortic endothelial cells offered protection against depletion of reduced glutathione and oxidative stress mediated by TNF-alpha. However, this study addressed that administration of NAC or mito-Q in high concentrations resulted in a biphasic response by initiating an enhanced generation of both reduced glutathione and oxidized glutathione and enhanced production of reactive oxygen species, along with carbonylation and glutathionylation of the cellular proteins. This study further addressed that IkappaB kinase (IKK), a phosphorylation-dependent regulator of NF-kappaB, plays an important regulatory role in the TNF-alpha-mediated induction of the inflammatory cell surface molecule ICAM-1. Of the two catalytic subunits of IKK (IKKalpha and IKKbeta), low concentrations of NAC and mito-Q activated IKKalpha activity, thereby inhibiting the downstream NF-kappaB and ICAM-1 induction by TNF-alpha. High concentrations of NAC and mito-Q instead caused glutathionylation of IKKalpha, thereby inhibiting its activity that in turn enhanced the downstream NF-kappaB activation and ICAM-1 expression by TNF-alpha. Thus, establishing IKKalpha as an anti-inflammatory molecule in endothelial cells is another focus of this study. This is the first report that describes a stressful situation in the endothelial cells created by excess of antioxidative and anti-inflammatory agents NAC and mito-Q, resulting in the generation of reactive oxygen species, carbonylation and glutathionylation of cellular proteins, inhibition of IKKalpha activity, and up-regulation of ICAM-1expression.}, }
@article {pmid17235423, year = {2007}, author = {Klein, M and Koedel, U and Pfister, HW}, title = {[N-acetyl-L-cysteine as a therapeutic option in bacterial meningitis].}, journal = {Der Nervenarzt}, volume = {78}, number = {2}, pages = {202-205}, pmid = {17235423}, issn = {0028-2804}, mesh = {Acetylcysteine/*therapeutic use ; Anti-Bacterial Agents/therapeutic use ; Chemotherapy, Adjuvant ; Free Radical Scavengers/*therapeutic use ; Humans ; Meningitis, Bacterial/*drug therapy/*prevention &amp; control ; Practice Guidelines as Topic ; Practice Patterns, Physicians' ; Treatment Outcome ; }, abstract = {Despite antibiotic therapy, supportive intensive care, and adjunctive treatment with dexamethasone, the mortality and morbidity remain high in patients with bacterial meningitis. The intracranial complications that mainly contribute to the poor outcome are in part a result of the production of reactive oxygen and nitrogen species. Experimental studies have shown that the prognosis for bacterial meningitis can be improved by the administration of antioxidants. Especially adjunctive therapy with N-acetyl-L-cystein (NAC) was shown to have mainly positive effects. Since NAC is already in clinical use in high doses for treating other diseases (e.g., acetaminophen intoxication) and only minor side effects have been observed, there is justified hope that adjunctive therapy with NAC could improve the prognosis of patients with bacterial meningitis.}, }
@article {pmid17230616, year = {2007}, author = {Chang, CC and Chen, SH and Lin, CP and Hsieh, CR and Lou, HY and Suk, FM and Pan, S and Wu, MS and Chen, JN and Chen, YF}, title = {Premedication with pronase or N-acetylcysteine improves visibility during gastroendoscopy: an endoscopist-blinded, prospective, randomized study.}, journal = {World journal of gastroenterology}, volume = {13}, number = {3}, pages = {444-447}, pmid = {17230616}, issn = {1007-9327}, mesh = {*Acetylcysteine ; Adult ; Aged ; Dimethylpolysiloxanes ; *Expectorants ; Female ; Gastroscopy/*methods ; Helicobacter Infections/diagnosis ; Helicobacter pylori ; Humans ; Male ; Middle Aged ; *Premedication ; *Pronase ; Prospective Studies ; Single-Blind Method ; Urease ; }, abstract = {AIM: To assess the efficacy of premedicaton with pronase or N-acetylcysteine (NAC) at 20 min before upper gastrointestinal (UGI) endoscopy and to determine whether pronase or NAC pretreatment influences the reliability of the rapid urease test.<br><br>METHODS: A total of 146 patients were prospectively and randomly assigned into the study groups according to different premedications before endoscopy. One endoscopist assessed mucosal visibility (MV) with scores ranged from 1 to 4 at four sites in the stomach. The sum of the MV scores from these four locations was defined as the total mucosal visibility (TMV) score. Identification of H pylori was performed using CLO test, histology, and serology.<br><br>RESULTS: The Group with pronase premedication had a significantly lower TMV score than did the groups with gascon and gascon water (P < 0.001 and P < 0.01, respectively). The group with NAC had a significantly lower TMV score than the group with gascon (P < 0.01) and a trend of a lower MV score than the group with gascon water (P = 0.06). The TMV score did not significantly differ between the group with pronase and the group with NAC (P = 0.39 and P = 0.14, respectively). The sensitivity and specificity of the CLO test were 92.5% and 93.9%, respectively, in groups premedicated with pronase and NAC together.<br><br>CONCLUSION: Premedication with pronase or NAC at 20 min before UGI endoscopy improves the mucosal visibility of the stomach. Neither pronase nor NAC produces any obvious interference with the CLO test for the identification of H pylori infection.}, }
@article {pmid17225996, year = {2007}, author = {Costa, D and Fernandes, E and Santos, JL and Pinto, DC and Silva, AM and Lima, JL}, title = {New noncellular fluorescence microplate screening assay for scavenging activity against singlet oxygen.}, journal = {Analytical and bioanalytical chemistry}, volume = {387}, number = {6}, pages = {2071-2081}, doi = {10.1007/s00216-006-0998-9}, pmid = {17225996}, issn = {1618-2642}, mesh = {Antioxidants/chemistry ; Buffers ; Histidine ; Hydrogen-Ion Concentration ; Molecular Structure ; Oxidation-Reduction ; Rhodamine 123 ; Singlet Oxygen/*analysis/chemistry ; Solutions ; Spectrometry, Fluorescence/*methods ; Temperature ; Water ; }, abstract = {In the present study, a new fluorescence microplate screening assay for evaluating scavenging activity against singlet oxygen (1O2) was implemented. The chemical generation of 1O2 was promoted using the thermodissociable endoperoxide of disodium 3,3'-(1,4-naphthalene)bispropionate (NDPO2). The detection of 1O2 was achieved using dihydrorhodamine 123 (DHR), a nonfluorescent molecule that is oxidizable to the fluorescent form rhodamine 123 (RH). The combined use of a 1O2-selective generator and a highly sensitive probe (DHR) was then successfully applied to perform a screening assay of the 1O2 scavenging activities of ascorbic acid, penicillamine, cysteine, N-acetylcysteine (NAC), methionine, reduced glutathione (GSH), dihydrolipoic acid, lipoic acid, and sodium azide. All of these antioxidants exhibited concentration-dependent 1O2 scavenging capacities. They could be ranked according to observed activity: ascorbic acid>cysteine>penicillamine>dihydrolipoic acid>GSH>NAC>sodium azide>lipoic acid (IC50 values of 3.0+/-0.2, 8.0+/-0.7, 10.9+/-0.8, 25.2+/-4.5, 57.4+/-5.9, 138+/-13, 1124+/-128, 2775+/-359 microM, mean+/-SEM, respectively)>methionine (35% of scavenging effect at 10 mM). In conclusion, the use of NDPO2 as a selective generator for 1O2 and its fluorescence detection by the highly sensitive probe DHR is shown to be a reliable and resourceful analytical alternative means to implement a microplate screening assay for scavenging activity against 1O2.}, }
@article {pmid17223684, year = {2007}, author = {Berndsen, CE and Albaugh, BN and Tan, S and Denu, JM}, title = {Catalytic mechanism of a MYST family histone acetyltransferase.}, journal = {Biochemistry}, volume = {46}, number = {3}, pages = {623-629}, pmid = {17223684}, issn = {0006-2960}, support = {R01 GM059785-08/GM/NIGMS NIH HHS/United States ; GM064089/GM/NIGMS NIH HHS/United States ; GM059785/GM/NIGMS NIH HHS/United States ; R37 GM059785/GM/NIGMS NIH HHS/United States ; R01 GM059785/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetyltransferases ; Catalysis ; Histone Acetyltransferases/*metabolism ; Kinetics ; Multienzyme Complexes/metabolism ; Saccharomyces cerevisiae Proteins/*metabolism ; }, abstract = {Distinct catalytic mechanisms have been proposed for the Gcn5 and MYST histone acetyltransferase (HAT) families. Gcn5-like HATs utilize an ordered sequential mechanism involving direct nucleophilic attack of the N-epsilon-lysine on the enzyme-bound acetyl-CoA. Recently, MYST enzymes were reported to employ a ping-pong route of catalysis via an acetyl-cysteine intermediate. Here, using the prototypical MYST family member Esa1, and its physiological complex (piccolo NuA4), steady-state kinetic analyses revealed a kinetic mechanism that requires the formation of a ternary complex prior to catalysis, where acetyl-CoA binds first and CoA is the last product released. In the absence of histone acceptor, slow rates of enzyme auto-acetylation (7 x 10(-4) s(-1), or approximately 2500-fold slower than histone acetylation; kcat = 1.6 s(-1)) and of CoA formation (0.0021 s(-1)) were inconsistent with a kinetically competent acetyl-enzyme intermediate. Previously, Cys-304 of Esa1 was the proposed nucleophile that forms an acetyl-cysteine intermediate. Here, mutation of this cysteine (C304A) in Esa1 or within the piccolo NuA4 complex yielded an enzyme that was catalytically indistinguishable from the wild type. Similarly, a pH rate (kcat) analysis of the wild type and C304A revealed an ionization (pKa = 7.6-7.8) that must be unprotonated. Mutation of a conserved active-site glutamate (E338Q) reduced kcat approximately 200-fold at pH 7.5; however, at higher pH, E338Q exhibited nearly wild-type activity. These data are consistent with Glu-338 (general base) activating the N-epsilon-lysine by deprotonation. Together, the results suggest that MYST family HATs utilize a direct-attack mechanism within an Esa1 x acetyl-CoA x histone ternary complex.}, }
@article {pmid17222527, year = {2007}, author = {Sudheer, AR and Muthukumaran, S and Kalpana, C and Srinivasan, M and Menon, VP}, title = {Protective effect of ferulic acid on nicotine-induced DNA damage and cellular changes in cultured rat peripheral blood lymphocytes: a comparison with N-acetylcysteine.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {21}, number = {4}, pages = {576-585}, doi = {10.1016/j.tiv.2006.11.006}, pmid = {17222527}, issn = {0887-2333}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Cells, Cultured ; Comet Assay ; Coumaric Acids/*pharmacology ; *DNA Damage ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Lipid Peroxidation/drug effects ; Lymphocytes/drug effects/*metabolism ; Nicotine/*antagonists &amp; inhibitors/*toxicity ; Nicotinic Agonists/*toxicity ; Rats ; }, abstract = {Nicotine is the major pharmacologically active substance in cigarette smoke and plays an important etiological role in the development of lung cancer. Incidence of cancer may be related to oxidative damage to host genome by nicotine. These oxidative actions may be modified by the phytochemicals present in food. The present study describes the protective effect of ferulic acid (FA), a naturally occurring nutritional compound on nicotine-induced DNA damage and cellular changes in cultured rat peripheral blood lymphocytes in comparison with N-acetylcysteine (NAC), a well-known antioxidant. One-hour exposure of lymphocytes to nicotine at the doses of 0.125, 0.25, 0.5, 1, 2, 3 and 4 mM induced a statistically significant dose-dependent increase in the levels of thiobarbituric acid reactive substances (TBARS), a lipid peroxidative marker and decrease in the levels of reduced glutathione (GSH), an important endogenous antioxidant. The lowest concentration eliciting significant damage was 1 mM nicotine and maximum damage was observed with 3 mM concentration. Hence, the test concentration was fixed at 3 mM nicotine. We have used 5 different doses of FA (10, 50, 100, 150 and 300 microM) and NAC (0.25, 0.5, 1, 2 and 4 mM) to test their protective effects. In all the groups, FA and NAC showed a dose-dependent inhibitory effect. Maximum protection was observed at the dose of 150 microM FA and 1mM NAC. So, 150 microM FA and 1mM NAC were used for further studies. There was a significant increase in the levels of lipid peroxidative index (TBARS and hydroperoxides (HP)), severity of DNA damage (evaluated by comet assay) in nicotine-treated group, which were significantly decreased in FA and NAC-treated groups. Nicotine treatment significantly decreased the endogenous antioxidant status viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), GSH, vitamin A, E and C. Co-administration of FA and NAC to nicotine-treated lymphocytes showed a significant increase in the antioxidant status. The protective effect of FA was merely equal to that of NAC effect. FA and NAC treatment alone did not produce any toxicity to the normal lymphocytes at their effective doses. On the whole, there is overwhelming evidence that FA has the ability to modulate DNA damage and a variety of cellular changes that occur during nicotine-induced toxicity in rat peripheral blood lymphocytes.}, }
@article {pmid17222524, year = {2007}, author = {Pouyatos, B and Gearhart, C and Nelson-Miller, A and Fulton, S and Fechter, L}, title = {Oxidative stress pathways in the potentiation of noise-induced hearing loss by acrylonitrile.}, journal = {Hearing research}, volume = {224}, number = {1-2}, pages = {61-74}, doi = {10.1016/j.heares.2006.11.009}, pmid = {17222524}, issn = {0378-5955}, support = {OH-03481/OH/NIOSH CDC HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Acrylonitrile/metabolism/*toxicity ; Action Potentials ; Animals ; Antioxidants/metabolism ; Cochlea/drug effects/metabolism/pathology/physiopathology ; Cyanides/metabolism ; Fomepizole ; Glutathione/metabolism ; Hearing Loss, Noise-Induced/*etiology/*metabolism/pathology/physiopathology ; Liver/drug effects/metabolism ; Male ; Otoacoustic Emissions, Spontaneous ; Oxidative Stress/*drug effects ; Pyrazoles/pharmacology ; Rats ; Rats, Long-Evans ; Reactive Oxygen Species/metabolism ; Thiosulfates/pharmacology ; }, abstract = {We hypothesize that the disruption of antioxidant defenses is a key mechanism whereby chemical contaminants can potentiate noise-induced hearing loss (NIHL). This hypothesis was tested using acrylonitrile (ACN), a widely used industrial chemical whose metabolism is associated with glutathione (GSH) depletion and cyanide (CN) generation. CN, in turn, can inhibit Cu/Zn superoxide dismutase (SOD). We have shown previously that ACN potentiates NIHL, even with noise exposure approaching permissible occupational levels. However, the relative involvement of GSH depletion and/or CN production in this potentiation is still unknown. In this study, we altered these metabolic pathways pharmacologically in order to further delineate the role of specific antioxidants in the protection of the cochlea. We investigated the effects of sodium thiosulfate (STS), a CN inhibitor, 4-methylpyrazole (4MP), a drug that blocks CN generation by competing with CYP2E1, and l-N-acetylcysteine (l-NAC), a pro-GSH drug, in order to distinguish between GSH depletion and CN production as the mechanism responsible for potentiation of NIHL by ACN. Long-Evans rats were exposed to an octave-band noise (97 dB SPL, 4h/day, 5 days) and ACN (50 mg/kg). Separate pre-treatments with STS (150 mg/kg), 4MP (100 mg/kg) and l-NAC (4 x 400 mg/kg) all dramatically reduced blood CN levels, but only l-NAC significantly protected GSH levels in both the liver and the cochlea. Concurrently, only l-NAC treatment decreased the auditory loss and hair cell loss resulting from ACN + noise, suggesting that GSH is involved in the protection of the cochlea against reactive oxygen species generated by moderate noise levels. On the other hand, CN does not seem to be involved in this potentiation.}, }
@article {pmid17216608, year = {2007}, author = {Demiralay, R and Gürsan, N and Erdem, H}, title = {The effects of erdosteine, N-acetylcysteine and vitamin E on nicotine-induced apoptosis of cardiac cells.}, journal = {Journal of applied toxicology : JAT}, volume = {27}, number = {3}, pages = {247-254}, doi = {10.1002/jat.1196}, pmid = {17216608}, issn = {0260-437X}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Apoptosis/*drug effects ; DNA Fragmentation/drug effects ; Female ; Immunochemistry/methods ; In Situ Nick-End Labeling ; Injections, Intraperitoneal ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; Necrosis ; Nicotine/administration &amp; dosage/*toxicity ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Thioglycolates/administration &amp; dosage/*pharmacology ; Thiophenes/administration &amp; dosage/*pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Vitamin E/administration &amp; dosage/*pharmacology ; }, abstract = {This study was conducted to investigate the frequency of apoptosis in rat cardiomyocytes after intratraperitoneal nicotine injection, in order to examine the roles of inflammatory markers [myeloperoxidase (MPO) and tumor necrosis factor alpha (TNF-alpha)] in nicotine-induced cardiac damage and to determine the protective effects of three known antioxidant agents (N-acetylcysteine (NAC), erdosteine and vitamin E) on nicotine toxicity in the heart. Female Wistar rats were divided into seven groups, each composed of nine rats: two negative control groups, two positive control groups, one erdosteine-treated group (500 mg kg(-1)), one NAC-treated group (500 mg kg(-1)) and one vitamin E-treated group (500 mg kg(-1)). Nicotine was intraperitoneally injected at a dosage of 0.6 mg kg(-1) for 21 days. Following nicotine injection, the antioxidants were administered orally; treatment was continued until the rats were killed. Heart tissue samples were stained with hematoxylin-eosin for histopathological assessments. Apoptosis level in cardiomyocytes was determined by using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling) method. Staining of cytoplasmic TNF-alpha in cardiomyocytes and heart MPO activity were evaluated by immunohistochemistry. The treatments with erdosteine, NAC and vitamin E significantly reduced the rate of nicotine-induced cardiomyocyte apoptosis. The effect of vitamin E on apoptosis regulation was weaker than the effects of erdosteine and NAC. Erdosteine, NAC and vitamin E significantly reduced the increases in the local production of TNF-alpha and heart MPO activity. This findings suggest that the effects of erdosteine and NAC on apoptosis regulation are stronger than that of vitamin E.}, }
@article {pmid17210758, year = {2007}, author = {Gäreskog, M and Wentzel, P}, title = {N-Acetylcysteine and alpha-cyano-4-hydroxycinnamic acid alter protein kinase C (PKC)-delta and PKC-zeta and diminish dysmorphogenesis in rat embryos cultured with high glucose in vitro.}, journal = {The Journal of endocrinology}, volume = {192}, number = {1}, pages = {207-214}, doi = {10.1677/joe.1.06966}, pmid = {17210758}, issn = {0022-0795}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Benzopyrans/pharmacology ; Biological Transport/drug effects ; Congenital Abnormalities/enzymology/*prevention &amp; control ; Coumaric Acids/*pharmacology ; Culture Media ; Culture Techniques ; Diabetes, Gestational/*enzymology ; Female ; Free Radical Scavengers/*pharmacology ; Glucose/pharmacology ; Immunoblotting/methods ; Mitochondria/metabolism ; Models, Animal ; Oligopeptides/pharmacology ; Pregnancy ; Protein Kinase C/analysis/antagonists &amp; inhibitors/*metabolism ; Protein Kinase C-delta/analysis/antagonists &amp; inhibitors/metabolism ; Pyruvates/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/analysis ; }, abstract = {Malformations and growth disturbances are two- to threefold more common in infants of diabetic mothers than in offspring of non-diabetic pregnancy. Several suggestions have emerged to explain the reasons for diabetic embryopathy, including enhanced mitochondrial production of reactive oxygen species leading to altered activation of protein kinase C. This study aimed to evaluate the effect of alpha-cyano-4-hydroxycinnamic acid (CHC) and N-acetylcysteine (NAC) addition on morphology and activity of protein kinase C-delta and protein kinase C-zeta in rat embryos exposed to a high glucose concentration in vitro. Day 9 embryos from normal rats were cultured in 10 or 30 mM glucose concentrations with or without supplementation of CHC, NAC, or protein kinase C inhibitors specific for protein kinase C-delta and protein kinase C-zeta. Embryos were evaluated for malformations, crown rump length, and somite number. Protein kinase C-delta and protein kinase C-zeta activities were estimated by western blot by separating membranous and cytosolic fractions of the embryo. We found increased malformations and growth retardation in embryos cultured in high versus low glucose concentrations. These abnormalities were diminished when CHC and NAC or specific protein kinase C-inhibitors were added to the culture medium. The activities of embryonic protein kinase C-delta and protein kinase C-zeta were increased in the high glucose environment after 24-h culture, but were normalized by the addition of CHC and NAC as well as respective inhibitor to the culture medium. These findings suggest that mitochondrial overproduction of reactive oxygen species is involved in diabetic embryopathy. Furthermore, such overproduction may affect embryonic development, at least partly, by enhancing the activities of protein kinase C-delta and protein kinase C-zeta.}, }
@article {pmid17210452, year = {2007}, author = {Navarro-Antolín, J and Redondo-Horcajo, M and Zaragoza, C and Alvarez-Barrientos, A and Fernández, AP and León-Gómez, E and Rodrigo, J and Lamas, S}, title = {Role of peroxynitrite in endothelial damage mediated by Cyclosporine A.}, journal = {Free radical biology &amp; medicine}, volume = {42}, number = {3}, pages = {394-403}, doi = {10.1016/j.freeradbiomed.2006.11.008}, pmid = {17210452}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Aorta/cytology ; Cattle ; Cell Membrane/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cyclosporine/*adverse effects ; Endothelial Cells/cytology/*drug effects/metabolism ; Immunosuppressive Agents/*adverse effects ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/metabolism ; Peroxynitrous Acid/*metabolism ; Superoxide Dismutase/metabolism ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Although Cyclosporine A (CsA) is an effective therapy for immunosuppression, its use encompasses serious side effects that have been associated with oxidative stress. We previously reported the intracellular formation of both peroxynitrite and 3-nitrotyrosine in cultured bovine aortic endothelial cells (BAEC) when exposed to CsA. Here we show that re-addition of CsA to BAEC increases peroxynitrite formation in a concentration-dependent manner. This effect is inhibited by the glutathione donor and antioxidant, N-acetylcysteine (NAC). BAEC exposed to CsA showed impaired integrity of plasma membranes and increased cytolysis, a phenomenon prevented by NAC. When CsA was administered to mice, the increased presence of 3-nitrotyrosine was detected in the aortic endothelium, an effect also abrogated by the concomitant administration of NAC. An increase in nitrated MnSOD was detected in BAEC treated with CsA and the peroxynitrite donor SIN-1 and recapitulated in recombinant MnSOD, exposed to the conditioned media from BAEC. We propose that CsA promotes nitration of specific molecular targets, such as MnSOD, within vascular endothelial cells. This may represent a pathogenetic mechanism of vascular injury. Inhibition of this process by clinically applicable antioxidants, such as NAC, lends a basis for the exploration of therapeutic alternatives in patients treated with CsA.}, }
@article {pmid17207576, year = {2007}, author = {Thompson, RJ and Buttigieg, J and Zhang, M and Nurse, CA}, title = {A rotenone-sensitive site and H2O2 are key components of hypoxia-sensing in neonatal rat adrenomedullary chromaffin cells.}, journal = {Neuroscience}, volume = {145}, number = {1}, pages = {130-141}, doi = {10.1016/j.neuroscience.2006.11.040}, pmid = {17207576}, issn = {0306-4522}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Adrenal Medulla/*cytology ; Age Factors ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Cell Hypoxia/*drug effects ; Cells, Cultured ; Chromaffin Cells/*drug effects ; Electric Stimulation/methods ; Hydrogen Peroxide/*pharmacology ; Luminescent Measurements/methods ; Membrane Potentials/drug effects/physiology/radiation effects ; Oxidants/*pharmacology ; Patch-Clamp Techniques/methods ; Potassium/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Rotenone/*analogs &amp; derivatives/pharmacology ; }, abstract = {In the perinatal period, adrenomedullary chromaffin cells (AMC) directly sense PO2 and secrete catecholamines during hypoxic stress, and this response is lost in juvenile (approximately 2 week-old) chromaffin cells following postnatal innervation. Here we tested the hypothesis that a rotenone-sensitive O2-sensor and ROS are involved in the hypoxic response of AMC cultured from neonatal and juvenile rats. In whole-cell recordings, hypoxia (PO2=5-15 mm Hg) inhibited outward current in neonatal AMC; this response was reversed by exogenous H2O2 and mimicked and occluded by intracellular catalase (1000 units/ml), as well as the antioxidants, N-acetyl-L-cysteine (NAC; 50 microM) and Trolox (200 microM). Acute hypoxia decreased ROS levels and stimulated ATP secretion in these cells, as measured by luminol and luciferin-luciferase chemiluminescence, respectively. Of several mitochondrial electron transport chain (ETC) inhibitors tested, only rotenone, a complex I blocker, mimicked and occluded the effects of hypoxia on outward current, cellular ROS, and ATP secretion. Succinate donors, which act as complex II substrates, reversed the effects of hypoxia and rotenone in neonatal AMC. In contrast, in hypoxia-insensitive juvenile AMC, neither NAC nor rotenone stimulated ATP secretion though they both caused a decrease in ROS levels. We propose that O2-sensing by neonatal AMC is mediated by decreased ROS generation via a rotenone-sensitive site that is coupled to outward current inhibition and secretion. Interestingly, juvenile AMC display at least two modifications, i.e. an uncoupling of the O2-sensor from ROS regulation, and an apparent insensitivity of outward current to decreased ROS.}, }
@article {pmid17204747, year = {2007}, author = {Tanel, A and Averill-Bates, DA}, title = {Inhibition of acrolein-induced apoptosis by the antioxidant N-acetylcysteine.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {321}, number = {1}, pages = {73-83}, doi = {10.1124/jpet.106.114678}, pmid = {17204747}, issn = {0022-3565}, mesh = {Acetylcysteine/*pharmacology ; Acrolein/*antagonists &amp; inhibitors/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; CHO Cells ; Caspases/metabolism ; Cell Survival/drug effects ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Flow Cytometry ; Glutathione/pharmacology ; Membrane Potentials/drug effects/physiology ; Microscopy, Fluorescence ; Mitochondria/drug effects ; Signal Transduction/drug effects ; Subcellular Fractions/metabolism ; }, abstract = {Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde to which humans are exposed in many situations. It is an environmental pollutant that is responsible for multiple respiratory diseases and has been implicated in neurodegenerative diseases such as Alzheimer's disease. The hypothesis of the study is that the antioxidant N-acetylcysteine (NAC), a precursor of glutathione, could protect cells against acrolein-induced apoptosis. Exposure of Chinese hamster ovary cells to a noncytotoxic dose of acrolein (4 fmol/cell) depleted intracellular glutathione to 45% of initial levels. NAC, which increased intracellular glutathione levels by 30%, afforded protection against acrolein-induced cytotoxicity (loss of cell proliferation) and apoptosis. NAC protected against apoptosis by diminishing acrolein-induced activation of the mitochondrial death pathway. NAC inhibited acrolein-induced Bad translocation from the cytosol to the mitochondria, as well as Bcl-2 translocation from mitochondria to the cytosol, as evaluated by Western blot analysis. However, NAC had no effect on acrolein-induced Bax translocation to mitochondria and cytochrome c liberation into the cytosol. Meanwhile, NAC inhibited depolarization of mitochondrial membrane potential, as evaluated by rhodamine fluorescence using flow cytometry. NAC also inhibited procaspase-9 processing, activation of enzymatic activity of caspase-9, -7, and -8, and poly(ADP-ribose) polymerase cleavage induced by acrolein. Inhibition of acrolein-induced apoptosis using NAC was confirmed morphologically by diminished condensation of nuclear chromatin, as evaluated by fluorescence microscopy. These findings suggest that NAC could be potentially useful as a protective agent for people exposed to acrolein.}, }
@article {pmid17200984, year = {2008}, author = {Maksimchik, YZ and Lapshina, EA and Sudnikovich, EY and Zabrodskaya, SV and Zavodnik, IB}, title = {Protective effects of N-acetyl-L-cysteine against acute carbon tetrachloride hepatotoxicity in rats.}, journal = {Cell biochemistry and function}, volume = {26}, number = {1}, pages = {11-18}, doi = {10.1002/cbf.1382}, pmid = {17200984}, issn = {1099-0844}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Animals ; Carbon Tetrachloride/*metabolism ; Carbon Tetrachloride Poisoning/*drug therapy/metabolism/*prevention &amp; control ; Free Radical Scavengers/*pharmacology ; Humans ; Liver/*drug effects/metabolism/*pathology ; Male ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; }, abstract = {In recent years, N-acetyl-L-cysteine (NAC) has been widely investigated as a potentially useful protective and antioxidative agent to be applied in many pathological states. The aim of the present work was further evaluation of the mechanisms of the NAC protective effect under carbon tetrachloride-induced acute liver injuries in rats. The rat treatment with CCl4 (4 g/kg, intragastrically) caused pronounced hepatolysis observed as an increase in blood plasma bilirubin levels and hepatic enzyme activities, which agreed with numerous previous observations. The rat intoxication was accompanied by an enhancement of membrane lipid peroxidation (1.4-fold) and protein oxidative damage (protein carbonyl group and mixed protein-glutathione disulphide formations) in the rat liver. The levels of nitric oxide in blood plasma and liver tissue significantly increased (5.3- and 1.5-fold, respectively) as blood plasma triacylglycerols decreased (1.6-fold). The NAC administration to control and intoxicated animals (three times at doses of 150 mg/kg) elevated low-molecular-weight thiols in the liver. The NAC administration under CCl4-induced intoxication prevented oxidative damage of liver cells, decreased membrane lipid peroxidation, protein carbonyls and mixed protein-glutathione disulphides formation, and partially normalized plasma triacylglycerols. At the same time the NAC treatment of intoxicated animals did not produce a marked decrease of the elevated levels of blood plasma ALT and AST activities and bilirubin. The in vitro exposure of human red blood cells to NAC increased the cellular low-molecular-weight thiol levels and retarded tert-butylhydroperoxide-induced cellular thiol depletion and membrane lipid peroxidation as well as effectively inhibited hypochlorous acid-induced erythrocyte lysis. Thus, NAC can replenish non-protein cellular thiols and protect membrane lipids and proteins due to its direct radical-scavenging properties, but it did not attenuate hepatotoxicity in the acute rat CCl4-intoxication model.}, }
@article {pmid17196629, year = {2007}, author = {Chang, MC and Chan, CP and Wang, YJ and Lee, PH and Chen, LI and Tsai, YL and Lin, BR and Wang, YL and Jeng, JH}, title = {Induction of necrosis and apoptosis to KB cancer cells by sanguinarine is associated with reactive oxygen species production and mitochondrial membrane depolarization.}, journal = {Toxicology and applied pharmacology}, volume = {218}, number = {2}, pages = {143-151}, doi = {10.1016/j.taap.2006.10.025}, pmid = {17196629}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Alkaloids/*pharmacology ; Annexin A5/metabolism ; *Anticarcinogenic Agents ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Benzophenanthridines/*pharmacology ; Catalase/pharmacology ; Cell Adhesion/drug effects ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Collagen/pharmacology ; DNA Fragmentation/drug effects ; Fibronectins/pharmacology ; Flow Cytometry ; Humans ; Isoquinolines/*pharmacology ; KB Cells ; Membrane Potentials/drug effects ; Mitochondrial Membranes/chemistry/drug effects/*metabolism ; Necrosis ; Reactive Oxygen Species/*metabolism ; Thiourea/analogs &amp; derivatives/pharmacology ; Tumor Stem Cell Assay ; }, abstract = {Sanguinarine is a benzopheanthridine alkaloid present in the root of Sanguinaria canadensis L. and Chellidonium majus L. In this study, sanguinarine (2 and 3 microM) exhibited cytotoxicity to KB cancer cells by decreasing MTT reduction to 83% and 52% of control after 24-h of exposure. Sanguinarine also inhibited the colony forming capacity (>52-58%) and growth of KB cancer cells at concentrations higher than 0.5-1 microM. Short-term exposure to sanguinarine (>0.5 microM) effectively suppressed the adhesion of KB cells to collagen and fibronectin (FN). Sanguinarine (2 and 3 microM) induced evident apoptosis as indicated by an increase in sub-G0/G1 populations, which was detected after 6-h of exposure. Only a slight increase in cells arresting in S-phase and G2/M was noted. Induction of KB cell apoptosis and necrosis by sanguinarine (2 and 3 microM) was further confirmed by Annexin V-PI dual staining flow cytometry and the presence of DNA fragmentation. The cytotoxicity by sanguinarine was accompanied by an increase in production of reactive oxygen species (ROS) and depolarization of mitochondrial membrane potential as indicated by single cell flow cytometric analysis of DCF and rhodamine fluorescence. NAC (1 and 3 mM) and catalase (2000 U/ml) prevented the sanguinarine-induced ROS production and cytotoxicity, whereas dimethylthiourea (DMT) showed no marked preventive effect. These results suggest that sanguinarine has anticarcinogenic properties with induction of ROS production and mitochondrial membrane depolarization, which mediate cancer cell death.}, }
@article {pmid17196077, year = {2006}, author = {Berlinski, A and Waldrep, JC}, title = {Nebulized drug admixtures: effect on aerosol characteristics and albuterol output.}, journal = {Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine}, volume = {19}, number = {4}, pages = {484-490}, doi = {10.1089/jam.2006.19.484}, pmid = {17196077}, issn = {0894-2684}, mesh = {Adrenergic beta-Agonists/*administration &amp; dosage ; Aerosols ; Albuterol/*administration &amp; dosage ; Anti-Bacterial Agents/administration &amp; dosage ; Cromolyn Sodium/administration &amp; dosage ; Drug Combinations ; Equipment Design ; Fluocinolone Acetonide/administration &amp; dosage/analogs &amp; derivatives ; Humans ; Nebulizers and Vaporizers ; Particle Size ; Tobramycin/administration &amp; dosage ; }, abstract = {Although not recommended, co-administration of drugs separately prescribed for nebulization is done in real life. The impact of this practice on drug output and aerosol characteristics is poorly understood. We studied the effect of drug admixtures (DA) on aerosol characteristics and drug output of nebulized albuterol delivered by a continuous output (CONT) and a breath enhanced nebulizer (BEN). Albuterol was nebulized alone (ALB) and combined with cromolyn sodium (A+CRO), ipratropium bromide (A+IB), tobramycin (A+TOB), flunisolide (A+FLU), and n-acetylcysteine (A+NAC). A BEN (PARI LC Plus) and a CONT (Hudson T UP-DRAFT II) were tested at 8 liters per minute (Lpm) for 2 and 5 min, respectively. Albuterol output and aerosol characteristics were determined by impaction and chemical analysis. Mass median aerodynamic diameter (MMAD; microm) A+CRO reduced MMAD from 2.57 (ALB) to 1.29 with CONT. A+FLU increased MMAD from 2.71 (ALB) to 3.40 with BEN. Geometric standard deviation (GSD) A+CRO increased GSD from 2.66 (ALB) to 3.36 with CONT. GSD was 2.33 for ALB and was not changed by DA with BEN. BEN generated a smaller and less heterodisperse aerosol than CONT. Respirable fraction (RF%) was 74% for ALB and was not changed by DA with CON. A+TOB and A+FLU decreased RF% from 75%, to 70% and 67% (respectively) with BEN. Respirable mass (RM; microg) for ALB was 935 and was not changed by DA with CONT. A+IB and A+FLU increased RM from 917 (ALB) to 1172 and 1240, respectively, with BEN. Co-nebulization of albuterol with other drugs can affect its output and aerosol characteristics. In vivo data is needed to asses the clinical implications of our findings.}, }
@article {pmid17192422, year = {2007}, author = {Li, R and Chen, W and Yanes, R and Lee, S and Berliner, JA}, title = {OKL38 is an oxidative stress response gene stimulated by oxidized phospholipids.}, journal = {Journal of lipid research}, volume = {48}, number = {3}, pages = {709-715}, doi = {10.1194/jlr.M600501-JLR200}, pmid = {17192422}, issn = {0022-2275}, support = {P01 HL030568/HL/NHLBI NIH HHS/United States ; HL-30568/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Apoptosis Regulatory Proteins ; Blotting, Western ; Cells, Cultured ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; Humans ; Hydroquinones/pharmacology ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Phosphatidylcholines/*pharmacology ; Phospholipids/metabolism/*pharmacology ; Proteins/*genetics/metabolism ; RNA, Small Interfering/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxides/metabolism ; }, abstract = {Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) is present in oxidative modified LDL and accumulates in lesions of many chronic inflammatory diseases, such as atherosclerosis. In a microarray study, OxPAPC has been demonstrated to modulate the expression of >700 genes in human aortic endothelial cells. We found that the levels of mRNA for OKL38 [also named Bone marrow Derived Growth Factor (BDGI)], a tumor growth inhibitor, were strongly increased by OxPAPC. Here, we report that OKL38 is regulated by an oxidative signal induced by OxPAPC and its component lipid 1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine. The stimulation of OKL38 by OxPAPC depends on superoxide production, because the NADPH oxidase (Nox) inhibitor apocynin and the superoxide scavenger N-acetyl cysteine block this stimulation. Oxidative stress by tert-butylhydroquinone treatment also induced the expression of OKL38. The stimulation of OKL38 expression by OxPAPC is mediated via transcription factor nuclear factor E2-related factor (Nrf2), a common factor involved in the regulation of oxidative stress-stimulated genes. Activation of Nrf2 induces the expression of OKL38, whereas small interfering RNA knockdown of Nrf2 blocks the stimulation of OKL38 by OxPAPC. Our results suggest that OKL38 is regulated via the Nox/Nrf2 pathway in response to oxidative stress stimuli.}, }
@article {pmid17190844, year = {2007}, author = {Schmidt, P and Pang, D and Nykamp, D and Knowlton, G and Jia, H}, title = {N-acetylcysteine and sodium bicarbonate versus N-acetylcysteine and standard hydration for the prevention of radiocontrast-induced nephropathy following coronary angiography.}, journal = {The Annals of pharmacotherapy}, volume = {41}, number = {1}, pages = {46-50}, doi = {10.1345/aph.1H354}, pmid = {17190844}, issn = {1542-6270}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Contrast Media/*adverse effects ; Coronary Angiography/*methods ; Drug Therapy, Combination ; Female ; Fluid Therapy/*methods ; Humans ; Kidney Diseases/chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Retrospective Studies ; Sodium Bicarbonate/*administration &amp; dosage ; }, abstract = {BACKGROUND: Radiocontrast-induced nephropathy (RCIN) is thought to be caused by renal ischemia and direct toxic effects on renal tubular cells brought on by contrast media. The combination of N-acetylcysteine (NAC) and hydration fluids (NaCl 0.9% or 0.45%) has been shown to reduce these deleterious effects and is commonly given prior to coronary angiography. The use of bicarbonate as the hydration anion has been shown to confer additional RCIN protection compared with that of saline. However, limited data are available regarding whether sodium bicarbonate hydration, proven to be beneficial alone, can further improve outcomes when given with NAC.<br><br>OBJECTIVE: To compare the incidence of RCIN in patients undergoing coronary angiography after pretreatment with NAC plus sodium bicarbonate hydration or NAC plus standard hydration (NaCl 0.9% or 0.45%).<br><br>METHODS: A retrospective, single-center study evaluated 96 patients who underwent coronary angiography from January 2002 to December 2005. Data were collected through electronic chart reviews.<br><br>RESULTS: Forty-seven patients received NAC and sodium bicarbonate for hydration and 49 received NAC and standard hydration. Baseline characteristics between the 2 groups were similar. All patients received at least one 600 mg oral dose of NAC before angiography was performed. RCIN was defined as impairment of renal function occurring within 72 hours of administering contrast media, indicated by an absolute increase in the serum creatinine level of 0.5 mg/dL or more. A total of 12.2% of the patients receiving NAC and standard hydration developed RCIN, versus 14.9% of the patients in the NAC and sodium bicarbonate group (p = 0.713).<br><br>CONCLUSIONS: The addition of sodium bicarbonate to NAC does not appear to confer additional protection against the development of RCIN. Prospective, randomized, placebo-controlled trials are warranted to definitively determine how this combination compares with NAC and standard hydration in preventing RCIN.}, }
@article {pmid17188792, year = {2007}, author = {Moffit, JS and Aleksunes, LM and Kardas, MJ and Slitt, AL and Klaassen, CD and Manautou, JE}, title = {Role of NAD(P)H:quinone oxidoreductase 1 in clofibrate-mediated hepatoprotection from acetaminophen.}, journal = {Toxicology}, volume = {230}, number = {2-3}, pages = {197-206}, pmid = {17188792}, issn = {0300-483X}, support = {R01 DK069557/DK/NIDDK NIH HHS/United States ; F32 ES011239/ES/NIEHS NIH HHS/United States ; F32 ES011239-01/ES/NIEHS NIH HHS/United States ; F32 ES011239-02/ES/NIEHS NIH HHS/United States ; ES10093/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Benzoquinones/metabolism ; Blotting, Western ; Chemical and Drug Induced Liver Injury/*enzymology/etiology/prevention &amp; control ; Clofibrate/*pharmacology ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Hepatocytes/drug effects/enzymology ; Imines/metabolism ; Indolequinones/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Male ; Mice ; Microsomes, Liver/drug effects/enzymology ; NAD(P)H Dehydrogenase (Quinone)/antagonists &amp; inhibitors/*metabolism ; Peroxisome Proliferators/*pharmacology ; }, abstract = {Mice pretreated with the peroxisome proliferator clofibrate (CFB) are resistant to acetaminophen (APAP) hepatotoxicity. Whereas the mechanism of protection is not entirely known, CFB decreases protein adducts formed by the reactive metabolite of APAP, N-acetyl-p-benzoquinone imine (NAPQI). NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme with antioxidant properties that is responsible for the reduction of cellular quinones. We hypothesized that CFB increases NQO1 activity, which in turn enhances the conversion of NAPQI back to the parent APAP. This could explain the decreases in APAP covalent binding and glutathione depletion produced by CFB without affecting APAP bioactivation to NAPQI. Administration of CFB (500mg/kg, i.p.) to male CD-1 mice for 5 or 10 days increased NQO1 protein and activity levels. To evaluate the capacity of NQO1 to reduce NAPQI back to APAP, we utilized a microsomal activating system. Cytochrome P450 enzymes present in microsomes bioactivate APAP to NAPQI, which binds the electrophile trapping agent, N-acetyl cysteine (NAC). We analyzed the formation of APAP-NAC metabolite in the presence of human recombinant NQO1. Results indicate that NQO1 is capable of reducing NAPQI. The capacity of NQO1 to amelioriate APAP toxicity was then evaluated in primary hepatocytes. Primary hepatocytes isolated from mice dosed with CFB are resistant to APAP toxicity. These hepatocytes were also exposed to ES936, a high affinity, and irreversible inhibitor of NQO1 in the presence of APAP. Concentrations of ES936 that resulted in over 94% inhibition of NQO1 activity did not increase the susceptibility of hepatocytes from CFB treated mice to APAP. Whereas NQO1 is mechanistically capable of reducing NAPQI, CFB-mediated hepatoprotection does not appear to be dependent upon enhanced expression of NQO1.}, }
@article {pmid17188416, year = {2007}, author = {Sudheer, AR and Muthukumaran, S and Devipriya, N and Menon, VP}, title = {Ellagic acid, a natural polyphenol protects rat peripheral blood lymphocytes against nicotine-induced cellular and DNA damage in vitro: with the comparison of N-acetylcysteine.}, journal = {Toxicology}, volume = {230}, number = {1}, pages = {11-21}, doi = {10.1016/j.tox.2006.10.010}, pmid = {17188416}, issn = {0300-483X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Cell Separation ; Comet Assay ; DNA Damage/*drug effects ; Dose-Response Relationship, Drug ; Ellagic Acid/*pharmacology ; Flavonoids/*pharmacology ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; In Vitro Techniques ; Lipid Peroxidation/drug effects ; Lymphocytes/*drug effects ; Male ; Micronucleus Tests ; Nicotine/*antagonists &amp; inhibitors/*toxicity ; Nicotinic Agonists/*toxicity ; Phenols/*pharmacology ; Polyphenols ; Rats ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The present work is aimed at evaluating the protective effect of ellagic acid (EA), a natural polyphenolic compound that is widely distributed in fruits and nuts against nicotine-induced toxicity in rat peripheral blood lymphocytes. The effect of EA against nicotine toxicity was compared with N-acetylcysteine (NAC), a well-known antioxidant. Lymphocytes were exposed to nicotine at the doses of 0.125, 0.25, 0.5, 1, 2, 3 and 4 mM for 1h in culture media. Thiobarbituric acid reactive substances (TBARS), a lipid peroxidative marker and reduced glutathione (GSH), as indicative of endogenous antioxidant status were analyzed to fix the optimum dose. The lowest concentration eliciting significant damage was 1 mM nicotine and maximum damage was observed with 3 mM concentration, as evidenced by increased levels of TBARS and decreased levels of GSH. Hence, the test concentration was fixed at 3 mM nicotine. To establish most effective protective support we used five different concentrations of EA (10, 50, 100, 150 and 300 microM) against 3 mM nicotine. A dose-dependent inhibitory effect was observed with all doses of EA. Maximum protection was observed at the dose of 100 microM EA. So, 100 microM dose was used for further studies. We have tested five different concentrations of NAC-0.25, 0.5, 1, 2 and 4 mM to elucidate the optimum protective dose against nicotine toxicity. One millimolar NAC showed a significant protection against nicotine toxicity. Protective effect of EA against nicotine toxicity was elucidated by analyzing the lipid peroxidative index, viz., TBARS, hydroperoxides (HP) and endogenous antioxidant status, viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), Vitamins A, E and C. DNA damage and repair were assessed by using alkaline single-cell microgel electrophoresis (Comet assay) and micronucleus assay. There was a significant increase in the levels of lipid peroxidative index, severity in DNA damage and micronuclei number in nicotine-treated group, which was positively modulated by EA treatment. Antioxidant status was significantly depleted in nicotine-treated group, which was effectively restored by EA treatment. The protection of EA against nicotine toxicity was equally effective to that of NAC. EA and NAC treatment alone did not produce any damage to the normal lymphocytes at their effective doses. These findings suggest the potential use and benefit of EA as a modifier of nicotine-induced genotoxicity.}, }
@article {pmid17188240, year = {2007}, author = {Kinoshita, M and Eguchi, Y and Hynynen, K}, title = {Activation of Bak in ultrasound-induced, JNK- and p38-independent apoptosis and its inhibition by Bcl-2.}, journal = {Biochemical and biophysical research communications}, volume = {353}, number = {2}, pages = {515-521}, pmid = {17188240}, issn = {0006-291X}, support = {R01 EB003268/EB/NIBIB NIH HHS/United States ; EB 003268/EB/NIBIB NIH HHS/United States ; }, mesh = {Apoptosis/*physiology/*radiation effects ; Dose-Response Relationship, Radiation ; Humans ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Jurkat Cells ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Radiation Dosage ; *Sonication ; bcl-2 Homologous Antagonist-Killer Protein/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {The molecular mechanisms underlying ultrasound-induced apoptosis remain poorly understood. We have demonstrated that in Jurkat cells, the over-expression of the anti-apoptotic protein Bcl-2 inhibited ultrasound-induced apoptosis, but not necrosis. Inhibition of caspase activity also protected the cells from apoptosis, but not from necrosis, showing the involvement of different mechanisms in ultrasound-induced apoptosis and necrosis. Bak, a pro-apoptotic member of the Bcl-2 family proteins, was activated by ultrasound and its activation was completely inhibited by Bcl-2 over-expression, but not by caspase inhibition. Antioxidant N-acetyl cysteine did not protect the cells from ultrasound-induced apoptosis or necrosis, nor did the inhibition of either c-Jun N-terminal kinase or p38, key factors in the radical oxygen species (ROS)-mediated cell stress response, suggesting that ROS do not play a crucial role in ultrasound-induced apoptosis. Our results confirm that ultrasound induces apoptosis via a pathway that involves Bak, Bcl-2, and caspases, but not ROS.}, }
@article {pmid17187767, year = {2007}, author = {Luchese, C and Zeni, G and Rocha, JB and Nogueira, CW and Santos, FW}, title = {Cadmium inhibits delta-aminolevulinate dehydratase from rat lung in vitro: interaction with chelating and antioxidant agents.}, journal = {Chemico-biological interactions}, volume = {165}, number = {2}, pages = {127-137}, doi = {10.1016/j.cbi.2006.11.007}, pmid = {17187767}, issn = {0009-2797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Benzene Derivatives/pharmacology ; Cadmium Chloride/*pharmacology ; Chelating Agents/*pharmacology ; Chlorides/pharmacology ; Dithiothreitol/pharmacology ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Interactions ; Environmental Pollutants/pharmacology ; Enzyme Inhibitors/*pharmacology ; Lung/*drug effects/enzymology ; Male ; Organoselenium Compounds/pharmacology ; Porphobilinogen Synthase/*antagonists &amp; inhibitors/metabolism ; Rats ; Rats, Wistar ; Succimer/pharmacology ; Unithiol/pharmacology ; Zinc Compounds/pharmacology ; }, abstract = {The effect of cadmium (Cd(2+)) on delta-aminolevulinate dehydratase (delta-ALA-D) activity from rat lung in vitro was investigated. delta-ALA-D activity, a parameter for metal intoxication, has been reported as a target of Cd(2+) in different tissues. The protective effect of monotherapies with dithiol chelating (meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid (DMPS)) or antioxidant agents (ascorbic acid, diphenyl diselenide (PhSe)(2), and N-acetylcysteine (NAC)) was evaluated. The effect of a combined therapy (dithiol chelatingxantioxidant agent) was also studied. Zinc chloride (ZnCl(2)) and dithiothreitol (DTT) were used to investigate the mechanisms involved in cadmium, chelating and antioxidant effects on delta-ALA-D activity. Cadmium inhibited rat lung delta-ALA-D activity at low concentrations. DTT (3mM), but not ZnCl(2) (100microM), protected the inhibition of enzyme activity caused by Cd(2+). Chelating agents were not effective in restoring the enzyme activity. DMPS and DMSA presented inhibitory effect on enzyme activity. DTT restored the inhibition caused by both chelating agents, but ZnCl(2) restored only the inhibitory effect induced by DMSA. These compounds caused a marked potentiation of delta-ALA-D inhibition induced by Cd(2+). ZnCl(2) did not restore inhibition of enzyme activity caused by Cd(2+) plus chelating agents. Conversely, DTT restored the inhibition induced by Cd(2+)/DMSA, but not by Cd(2+)/DMPS. Antioxidants were not effective in ameliorating delta-ALA-D inhibition induced by Cd(2+), whereas ascorbic acid potentiated the enzyme inhibition induced by this metal. A combined effect of Cd(2+)xDMPSx(PhSe)(2) and Cd(2+)xDMPSxNAC was observed. There was no combined effect of Cd(2+)xchelatorxantioxidants when DMSA was used. This study demonstrated that Cd(2+)inhibited delta-ALA-D activity and chelating and antioxidant agents, alone or combined, did not restore the enzyme activity. In contrast, these compounds potentiated the inhibition induced by Cd(2+) in rat lung.}, }
@article {pmid17184943, year = {2007}, author = {Kopke, RD and Jackson, RL and Coleman, JK and Liu, J and Bielefeld, EC and Balough, BJ}, title = {NAC for noise: from the bench top to the clinic.}, journal = {Hearing research}, volume = {226}, number = {1-2}, pages = {114-125}, doi = {10.1016/j.heares.2006.10.008}, pmid = {17184943}, issn = {0378-5955}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/therapeutic use ; Clinical Trials as Topic ; Cochlea/drug effects/injuries/metabolism/pathology ; Hearing Loss, Noise-Induced/*drug therapy/metabolism/pathology ; Humans ; Safety ; }, abstract = {Noise-induced hearing loss (NIHL) is an important etiology of deafness worldwide. Hearing conservation programs are in place and have reduced the prevalence of NIHL, but this disorder is still far too common. Occupational and recreational pursuits expose people to loud noise and ten million persons in the US have some degree of noise-induced hearing impairment. It is estimated that 50 million in the US and 600 million people worldwide are exposed to noise hazards occupationally. Noise deafness is still an important and frequent cause of battlefield injury in the US military. A mainstay of hearing conservation programs is personal mechanical hearing protection devices which are helpful but have inherent limitations. Research has shown that oxidative stress plays an important role in noise-induced cochlear injury resulting in the discovery that a number of antioxidant and cell death inhibiting compounds can ameliorate deafness associated with acoustic trauma. This article reviews one such compound, N-acetylcysteine (NAC), in terms of its efficacy in reducing hearing loss in a variety of animal models of acute acoustic trauma and hypothesizes what its therapeutic mechanisms of action might be based on the known actions of NAC. Early clinical trials with NAC are mentioned.}, }
@article {pmid17182831, year = {2007}, author = {Reliene, R and Schiestl, RH}, title = {Antioxidants suppress lymphoma and increase longevity in Atm-deficient mice.}, journal = {The Journal of nutrition}, volume = {137}, number = {1 Suppl}, pages = {229S-232S}, doi = {10.1093/jn/137.1.229S}, pmid = {17182831}, issn = {0022-3166}, support = {ES09519/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; DNA Damage ; DNA-Binding Proteins/*deficiency/genetics/*metabolism ; Humans ; Longevity/*drug effects/physiology ; Lymphoma/drug therapy/genetics/*metabolism/*pathology ; Mice ; Protein Serine-Threonine Kinases/*deficiency/genetics/*metabolism ; Tumor Suppressor Proteins/*deficiency/genetics/*metabolism ; }, abstract = {Ataxia telangiectasia (AT), a human hereditary disorder resulting from mutations in the ATM gene, is characterized by a high incidence of lymphoid malignancies, neurodegeneration, immunodeficiency, premature aging, elevated radiosensitivity, and genomic instability. Evidence has been accumulating that ATM-deficient cells are in a continuous state of oxidative stress. A variety of markers of oxidative stress were detected in AT patients as well as Atm-deficient mice, used as an animal model of AT. Since then, it has been proposed that oxidative stress contributes to the clinical phenotype of AT, especially carcinogenesis and neurodegeneration, and several animal studies were conducted to determine whether exogenous antioxidants mitigate the symptoms of AT. Tempol, EUK-189, and N-acetyl cysteine have been tested as chemopreventive antioxidants in Atm-deficient mice. We review these findings, mainly focusing on the effect of N-acetyl cysteine, which is known as a safe and efficient drug and nutritional supplement.}, }
@article {pmid17182545, year = {2007}, author = {Ito, K and Takubo, K and Arai, F and Satoh, H and Matsuoka, S and Ohmura, M and Naka, K and Azuma, M and Miyamoto, K and Hosokawa, K and Ikeda, Y and Mak, TW and Suda, T and Hirao, A}, title = {Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {178}, number = {1}, pages = {103-110}, doi = {10.4049/jimmunol.178.1.103}, pmid = {17182545}, issn = {0022-1767}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Ataxia Telangiectasia Mutated Proteins ; B-Lymphocytes/drug effects/metabolism ; Cell Cycle Proteins/genetics/*physiology ; Cellular Senescence/drug effects/genetics/immunology ; *DNA Breaks, Double-Stranded ; DNA-Binding Proteins/genetics/*physiology ; *Gene Rearrangement, beta-Chain T-Cell Antigen Receptor/drug effects ; *Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor/drug effects ; Immunoglobulin Class Switching/drug effects/genetics ; Lymphoma/*genetics/immunology/prevention &amp; control ; Mice ; Mice, Mutant Strains ; Protein Serine-Threonine Kinases/genetics/*physiology ; Radiation Tolerance/drug effects ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; T-Lymphocytes/drug effects/immunology ; Tumor Suppressor Proteins/genetics/*physiology ; }, abstract = {The ataxia telangiectasia-mutated (ATM) gene plays a pivotal role in the maintenance of genomic stability. Although it has been recently shown that antioxidative agents inhibited lymphomagenesis in Atm(-/-) mice, the mechanisms remain unclear. In this study, we intensively investigated the roles of reactive oxygen species (ROS) in phenotypes of Atm(-/-) mice. Reduction of ROS by the antioxidant N-acetyl-l-cysteine (NAC) prevented the emergence of senescent phenotypes in Atm(-/-) mouse embryonic fibroblasts, hypersensitivity to total body irradiation, and thymic lymphomagenesis in Atm(-/-) mice. To understand the mechanisms for prevention of lymphomagenesis, we analyzed development of pretumor lymphocytes in Atm(-/-) mice. Impairment of Ig class switch recombination seen in Atm(-/-) mice was mitigated by NAC, indicating that ROS elevation leads to abnormal response to programmed double-strand breaks in vivo. Significantly, in vivo administration of NAC to Atm(-/-) mice restored normal T cell development and inhibited aberrant V(D)J recombination. We conclude that Atm-mediated ROS regulation is essential for proper DNA recombination, preventing immunodeficiency, and lymphomagenesis.}, }
@article {pmid17174578, year = {2007}, author = {Nagata, M and Arimitsu, N and Ito, T and Sekimizu, K}, title = {Antioxidant N-acetyl-L-cysteine inhibits erythropoietin-induced differentiation of erythroid progenitors derived from mouse fetal liver.}, journal = {Cell biology international}, volume = {31}, number = {3}, pages = {252-256}, doi = {10.1016/j.cellbi.2006.11.001}, pmid = {17174578}, issn = {1065-6995}, mesh = {Acetylcysteine/*metabolism/pharmacology ; Animals ; Antigens, Differentiation/analysis ; Blood Group Antigens/analysis ; Erythroid Precursor Cells/cytology/drug effects/*metabolism ; Erythropoiesis/drug effects/physiology ; Erythropoietin/*metabolism/pharmacology ; Female ; GATA1 Transcription Factor/analysis ; Liver/*cytology/*embryology/physiology ; MafK Transcription Factor/analysis ; Male ; Mice ; Mice, Inbred C57BL ; Reactive Oxygen Species/*metabolism/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {To determine the role of reactive oxygen species in erythroid differentiation, we investigated the effects of an antioxidant, N-acetyl-L-cysteine (NAC), on the differentiation of erythroid progenitors derived from mouse fetal liver. In response to erythropoietin (Epo), erythroid progenitors undergo differentiation in vitro and express erythroid-specific genes such as betamajor-globin, Alas2, MafK, p45, Eklf, and Gata1. Expression of these genes was decreased in the presence of NAC, whereas the expression of c-myb, which is downregulated during erythroid differentiation, remained constant. Moreover, NAC treatment inhibited an increase in the number of cells expressing high levels of erythroid-specific antigen TER119. Treatment with another antioxidant, pyrrolidine dithiocarbamate, also caused the attenuation of TER119 expression. These results suggest that reactive oxygen species are involved in Epo-mediated erythroid differentiation.}, }
@article {pmid17171638, year = {2007}, author = {Scott, DW and Loo, G}, title = {Curcumin-induced GADD153 upregulation: modulation by glutathione.}, journal = {Journal of cellular biochemistry}, volume = {101}, number = {2}, pages = {307-320}, doi = {10.1002/jcb.21179}, pmid = {17171638}, issn = {0730-2312}, mesh = {Animals ; *Antineoplastic Agents/metabolism/pharmacology ; Cell Line, Tumor ; *Curcumin/metabolism/pharmacology ; Enzyme Activation ; Gene Expression Regulation/*drug effects ; Glutathione/*metabolism ; Humans ; Oxidation-Reduction ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Protein Kinase C-delta/metabolism ; Protein Kinase Inhibitors/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Transcription Factor CHOP/genetics/*metabolism ; }, abstract = {As we reported previously, GADD153 is upregulated in colon cancer cells exposed to curcumin. In the present study, we ascertained the involvement of glutathione and certain sulfhydryl enzymes associated with signal transduction in mediating the effect of curcumin on GADD153. Curcumin-induced GADD153 gene upregulation was attenuated by reduced glutathione (GSH) or N-acetylcysteine (NAC) and potentiated by the glutathione synthesis inhibitor, L-buthionine-(S,R)-sulfoximine (BSO). Additionally, GSH and NAC decreased the intracellular content of curcumin. Conversely, curcumin decreased intracellular glutathione and also increased the formation of reactive oxygen species (ROS) in cells, but either GSH or NAC prevented both of these effects of curcumin. In affecting the thiol redox status, curcumin caused activation of certain sulfhydryl enzymes involved in signal transduction linked to GADD153 expression. Curcumin increased the expression of the phosphorylated forms of PTK, PDK1, and PKC-delta, which was attenuated by either GSH or NAC and potentiated by BSO. Furthermore, selective inhibitors of PI3K and PKC-delta attenuated curcumin-induced GADD153 upregulation. Collectively, these findings suggest that a regulatory thiol redox-sensitive signaling cascade exists in the molecular pathway leading to induction of GADD153 expression as caused by curcumin.}, }
@article {pmid17163414, year = {2007}, author = {Verrax, J and Vanbever, S and Stockis, J and Taper, H and Calderon, PB}, title = {Role of glycolysis inhibition and poly(ADP-ribose) polymerase activation in necrotic-like cell death caused by ascorbate/menadione-induced oxidative stress in K562 human chronic myelogenous leukemic cells.}, journal = {International journal of cancer}, volume = {120}, number = {6}, pages = {1192-1197}, doi = {10.1002/ijc.22439}, pmid = {17163414}, issn = {0020-7136}, mesh = {Antioxidants/*pharmacology ; *Apoptosis ; Ascorbic Acid/*pharmacology ; Enzyme Activation ; Glycolysis/drug effects ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*enzymology/metabolism ; NAD/deficiency ; Necrosis ; Oxidative Stress ; Poly(ADP-ribose) Polymerases/*metabolism ; Tumor Cells, Cultured ; Vitamin K 3/*pharmacology ; }, abstract = {Among different features of cancer cells, two of them have retained our interest: their nearly universal glycolytic phenotype and their sensitivity towards an oxidative stress. Therefore, we took advantage of these features to develop an experimental approach by selectively exposing cancer cells to an oxidant insult induced by the combination of menadione (vitamin K(3)) and ascorbate (vitamin C). Ascorbate enhances the menadione redox cycling, increases the formation of reactive oxygen species and kills K562 cells as shown by more than 65% of LDH leakage after 24 hr of incubation. Since both lactate formation and ATP content are depressed by about 80% following ascorbate/menadione exposure, we suggest that the major intracellular event involved in such a cytotoxicity is related to the impairment of glycolysis. Indeed, NAD(+) is rapidly and severely depleted, a fact most probably related to a strong Poly(ADP-ribose) polymerase (PARP) activation, as shown by the high amount of poly-ADP-ribosylated proteins. The addition of N-acetylcysteine (NAC) restores most of the ATP content and the production of lactate as well. The PARP inhibitor dihydroxyisoquinoline (DiQ) was able to partially restore both parameters as well as cell death induced by ascorbate/menadione. These results suggest that the PARP activation induced by the oxidative stress is a major but not the only intracellular event involved in cell death by ascorbate/menadione. Due to the high energetic dependence of cancer cells on glycolysis, the impairment of such an essential pathway may explain the effectiveness of this combination to kill cancer cells.}, }
@article {pmid17149372, year = {2007}, author = {Shastry, S and Ingram, AJ and Scholey, JW and James, LR}, title = {Homocysteine induces mesangial cell apoptosis via activation of p38-mitogen-activated protein kinase.}, journal = {Kidney international}, volume = {71}, number = {4}, pages = {304-311}, doi = {10.1038/sj.ki.5002031}, pmid = {17149372}, issn = {0085-2538}, support = {DK062799/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*physiology ; Caspase 3/metabolism ; Cells, Cultured ; Homocysteine/*physiology ; Mesangial Cells/*physiology ; Oxidative Stress/physiology ; Rats ; Reactive Oxygen Species/metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Hyperhomocysteinemia is prevalent among patients with chronic kidney disease (CKD) and has been linked to progressive kidney and vascular diseases. Increased glomerular mesangial cell (MC) turnover, including proliferation and apoptosis, is a hallmark of CKD. Activation of p38-mitogen-activated protein kinase (p38-MAPK) has been linked to apoptosis in many cell lines. Accordingly, we studied the effect of homocysteine (Hcy) on MC p38-MAPK signalling and apoptosis. Hcy (50 microM/24 h) increased MC apoptosis as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) and single-stranded DNA (ssDNA) analysis. In addition to increases in pro-caspase-3 protein and caspase-3 activity, cells exposed to Hcy manifested enhanced reactive oxygen species content. Hcy increased p38-MAPK activity (fivefold), with maximal effect at 50 microM and 20 min; p38-MAPK activation was attenuated by N-acetylcysteine (Nac) and catalase (Cat), further indicating that the effect was via oxidative stress. Confocal microscopy revealed activation and nuclear translocation of p38-MAPK that was attenuated by Cat. In addition, Hcy-induced apoptosis as determined by TUNEL and ssDNA assay was abrogated by Nac, Cat, and SB203580 (p38-MAPK inhibitor). We conclude that in MC, Hcy (i) activates p38-MAPK and increases p38MAPK nuclear translocation via an oxidative stress dependent mechanism and (ii) induces DNA damage and apoptosis that is dependent on oxidative stress and p38-MAPK activation.}, }
@article {pmid17145984, year = {2007}, author = {Elkareh, J and Kennedy, DJ and Yashaswi, B and Vetteth, S and Shidyak, A and Kim, EG and Smaili, S and Periyasamy, SM and Hariri, IM and Fedorova, L and Liu, J and Wu, L and Kahaleh, MB and Xie, Z and Malhotra, D and Fedorova, OV and Kashkin, VA and Bagrov, AY and Shapiro, JI}, title = {Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {49}, number = {1}, pages = {215-224}, doi = {10.1161/01.HYP.0000252409.36927.05}, pmid = {17145984}, issn = {1524-4563}, support = {HL67963/HL/NHLBI NIH HHS/United States ; //Intramural NIH HHS/United States ; }, mesh = {Animals ; Blood Pressure/drug effects ; Bufanolides/*pharmacology ; Cardiomyopathies/*chemically induced/*pathology ; Cells, Cultured ; Collagen/*biosynthesis ; Fibroblasts/drug effects/*metabolism ; Fibrosis ; Heart/physiopathology ; Male ; Myocardium/cytology/*metabolism ; Rats ; Rats, Sprague-Dawley ; Renal Insufficiency/physiopathology ; Signal Transduction ; Sodium-Potassium-Exchanging ATPase/metabolism ; Transforming Growth Factor beta/metabolism ; Uremia/*complications ; }, abstract = {We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased MBG levels, blood pressure, heart size, impaired diastolic function, and caused cardiac fibrosis. PNx after immunization against MBG and concomitant PNx and adrenalectomy had similar blood pressure as PNx but less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis. MBG induced increases in procollagen-1 expression by cultured cardiac fibroblasts at 1 nM concentration. These increases in procollagen expression were accompanied by increases in collagen translation and increases in procollagen-1 mRNA without any demonstrable increase in procollagen-1 protein stability. The stimulation of fibroblasts with MBG could be prevented by administration of inhibitors of tyrosine phosphorylation, Src activation, epidermal growth factor receptor transactivation, and N-acetyl cysteine. Based on these findings, we propose that MBG directly induces increases in collagen expression by fibroblasts, and we suggest that this may be important in the cardiac fibrosis seen with experimental renal failure.}, }
@article {pmid17142968, year = {2006}, author = {Suzuki, S and Tomita, M and Hyodo, M and Horikawa, M and Tsunoda, T and Sato, M}, title = {Pigments from Uroleucon nigrotuberculatum induce apoptosis in HL60 human leukemia cells, implicating intracellular oxidative stress and activation of caspases.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {29}, number = {12}, pages = {2383-2387}, doi = {10.1248/bpb.29.2383}, pmid = {17142968}, issn = {0918-6158}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aphids/*chemistry ; Apoptosis/*drug effects ; Caspases/*metabolism ; Enzyme Activation ; HL-60 Cells ; Humans ; In Situ Nick-End Labeling ; *Oxidative Stress ; Pigments, Biological/*pharmacology ; alpha-Tocopherol/pharmacology ; }, abstract = {Two pigmented compounds from Uroleucon nigrotuberculatum, uroleuconaphin-B(1) [corrected] (H427) and uroleuconaphin-A(1) [corrected] (H373), significantly diminished the cell viability of HL60 cells with IC50 of 10 microM and 30 microM, respectively, in an 18 h-dye uptake assay. Both H427 and H373 augmented the levels of intracellular reactive oxygen species (ROS) and induced apoptosis as demonstrated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis. ROS augmentation by both H427 and H373 was inhibited by N-acetylcysteine (NAC) and alpha-tocopherol. The apoptosis induced by H427 was inhibited efficiently with NAC and caspase-8 inhibitor but less efficiently with alpha-tocopherol and caspase-9 inhibitor. These findings suggested that these pigments have pro-apoptotic activities via oxidative stress.}, }
@article {pmid17142801, year = {2006}, author = {Leonard, MO and Kieran, NE and Howell, K and Burne, MJ and Varadarajan, R and Dhakshinamoorthy, S and Porter, AG and O'Farrelly, C and Rabb, H and Taylor, CT}, title = {Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {20}, number = {14}, pages = {2624-2626}, doi = {10.1096/fj.06-5097fje}, pmid = {17142801}, issn = {1530-6860}, support = {R01 N100K//PHS HHS/United States ; //Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Gene Expression Regulation ; Humans ; Kidney Diseases/*metabolism ; Liver/metabolism ; Liver Transplantation ; Mice ; NAD(P)H Dehydrogenase (Quinone) ; NADPH Dehydrogenase/genetics/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Promoter Regions, Genetic ; Reperfusion Injury/*metabolism ; Signal Transduction ; Up-Regulation ; }, abstract = {Tissue reoxygenation following hypoxia is associated with ischemia-reperfusion injury (IRI) and may signal the development of ischemic preconditioning, an adaptive state that is protective against subsequent IRI. Here we used microarray RNA analysis of in vivo and in vitro models of IRI to delineate the underlying molecular mechanisms. Microarray analysis of renal tissue after ischemia-reperfusion revealed a number of highly up-regulated antioxidant genes including aldehyde dehydrogenases (ALDH1A1 and ALDH1A7), glutathione S-transferases (GSTM5, GSTA2 and GSTP1), and NAD(P)H quinone oxidoreductase (NQO1). The transcription factor NF-E2-related factor-2 (Nrf2), a master regulator of this antioxidant response, is also elevated in IRI. Furthermore, microarray analysis of renal epithelial cells exposed to hypoxia/reoxygenation identified Nrf2 to be up-regulated on reoxygenation. We also reveal a reoxygenation-specific nuclear accumulation of Nrf2 protein and subsequent activation of a NQO1 promoter reporter construct. Attenuating reactive oxygen species (ROS) in reoxygenation using the antioxidant N-acetyl cysteine results in inhibition of Nrf-2 activation. mRNA levels for Nrf2-dependent genes were detected in human liver biopsy 1 h after transplantation. These results indicate that reoxygenation-dependent Nrf-2 activity facilitates ischemic preconditioning through the induction of antioxidant gene expression and that ROS may be critical in signaling this event.}, }
@article {pmid17142027, year = {2007}, author = {Blouet, C and Mariotti, F and Mikogami, T and Tome, D and Huneau, JF}, title = {Meal cysteine improves postprandial glucose control in rats fed a high-sucrose meal.}, journal = {The Journal of nutritional biochemistry}, volume = {18}, number = {8}, pages = {519-524}, doi = {10.1016/j.jnutbio.2006.10.002}, pmid = {17142027}, issn = {0955-2863}, mesh = {Animals ; Area Under Curve ; Blood Glucose/drug effects/*metabolism ; Buthionine Sulfoximine/blood/pharmacology ; Cysteine/administration &amp; dosage/*pharmacology ; *Dietary Carbohydrates ; Insulin/blood ; Kinetics ; Liver/metabolism ; Male ; Postprandial Period ; Rats ; Rats, Wistar ; Sucrose/*pharmacology ; }, abstract = {Whey protein, particularly the alpha-lactalbumin fraction, are rich in cysteine (cys) and could therefore favor postprandial glucose homeostasis by a glutathione-mediated effect. This work investigates the effects of the ingestion of an alpha-lactalbumin-rich whey concentrate (alpha-LAC) during a high-sucrose (HS) meal on postprandial glucose homeostasis in healthy rats. In the first experiment, rats received an HS meal containing 14% protein, in which the protein source was either alpha-LAC (HS(a)) or total milk proteins, alone (HS(0)) or supplemented with 17 mg (HS(1)) or 59 mg (HS(2)) of N-acetylcysteine (NAC). This resulted in a total cys content 3.6-fold higher in the HS(1) and HS(a) meals and 12-fold higher in the HS(2) meal, when compared to the HS(0) meal. Postprandial parameters were monitored for 3 h after ingestion of the meal. The same measurements were performed on rats injected with 4 mmol/kg of buthionine sulfoximine (BSO), a specific inhibitor of glutathione synthesis. Increasing the meal's cys content dose-dependently reduced both postprandial glucose and insulin (P<.05). The inhibition of glutathione synthesis with BSO injection abrogated the beneficial effects of NAC supplementation on postprandial glucose response but did not affect those of alpha-LAC. These results show that (1) the substitution of alpha-LAC for total milk protein reduces glucose response, as does the addition of a cys donor to the meal, (2) but contrary to those of a simple cys donor, the beneficial effects of alpha-LAC are not entirely mediated by glutathione synthesis, suggesting additional mechanisms.}, }
@article {pmid17141508, year = {2007}, author = {Woltjer, RL and McMahan, W and Milatovic, D and Kjerulf, JD and Shie, FS and Rung, LG and Montine, KS and Montine, TJ}, title = {Effects of chemical chaperones on oxidative stress and detergent-insoluble species formation following conditional expression of amyloid precursor protein carboxy-terminal fragment.}, journal = {Neurobiology of disease}, volume = {25}, number = {2}, pages = {427-437}, doi = {10.1016/j.nbd.2006.10.003}, pmid = {17141508}, issn = {0969-9961}, support = {AG05144/AG/NIA NIH HHS/United States ; AG22040/AG/NIA NIH HHS/United States ; AG23801/AG/NIA NIH HHS/United States ; AG24011/AG/NIA NIH HHS/United States ; }, mesh = {Amyloid beta-Peptides/biosynthesis/chemistry ; Amyloid beta-Protein Precursor/chemistry/*metabolism ; Antioxidants/pharmacology ; Cell Line ; Detergents/chemistry/pharmacology ; Humans ; Molecular Chaperones/*metabolism/pharmacology ; Neurodegenerative Diseases/metabolism/physiopathology ; Oxidative Stress/drug effects/*physiology ; Peptide Fragments/*metabolism/toxicity ; Plaque, Amyloid/chemistry/*drug effects/metabolism ; Protein Folding ; Solubility/drug effects ; }, abstract = {Oxidative stress, protein misfolding, protein complex formation, and detergent insolubility are biochemical features of Alzheimer's disease (AD). We tested the cause-and-effect relationships among these using MC65 human neuroblastoma cells that exhibit toxicity upon conditional expression of carboxy-terminal fragments (CTFs) of the human amyloid precursor protein (APP). Treatments with three different antioxidants (alpha-tocopherol, N-acetyl cysteine, and alpha-lipoic acid) or three different compounds (glycerol, trimethylamine-N-oxide, and 4-phenylbutyric acid) that have been described to have a "chemical chaperone" function in promoting protein folding all had a protective effect on MC65 cells and decreased markers of oxidative damage and accumulation of high molecular weight amyloid (A) beta-immunoreactive (IR) species. However, chaperones partially reduced detergent insolubility of the remaining Abeta-IR species, while antioxidants did not. These results suggest that protein misfolding associated with overexpression of APP CTFs promotes oxidative stress and cytotoxicity and contributes to formation of detergent-insoluble species that appear unrelated to cytotoxicity.}, }
@article {pmid17127716, year = {2007}, author = {Larghero, P and Venè, R and Minghelli, S and Travaini, G and Morini, M and Ferrari, N and Pfeffer, U and Noonan, DM and Albini, A and Benelli, R}, title = {Biological assays and genomic analysis reveal lipoic acid modulation of endothelial cell behavior and gene expression.}, journal = {Carcinogenesis}, volume = {28}, number = {5}, pages = {1008-1020}, doi = {10.1093/carcin/bgl233}, pmid = {17127716}, issn = {0143-3334}, mesh = {Anti-Inflammatory Agents/pharmacology ; Apoptosis ; Biological Assay ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Endothelium, Vascular/*drug effects ; Gene Expression Regulation, Neoplastic ; Neovascularization, Pathologic/drug therapy ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress/drug effects ; Phosphorylation ; Polymerase Chain Reaction ; Sarcoma, Kaposi/*blood supply/drug therapy ; Thioctic Acid/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {Lipoic acid (LA) is a sulfated antioxidant produced physiologically as a coenzyme of the pyruvate dehydrogenase complex; it is currently used for treatment of non-insulin-dependent diabetes to favor the cellular uptake of glucose. We have previously described the angiopreventive potential of molecules sharing common features with LA: N-acetyl cysteine, epigallocatechin-3-gallate and xanthohumol. To expand these studies, we have tested the capacity of LA to modulate angiogenesis in tumor growth using a Kaposi's sarcoma model. Endothelial cells exposed to LA displayed a dose-dependent reduction of cell migration and a time-dependent modulation of the phosphorylation of key signaling molecules. In vivo, LA efficiently repressed angiogenesis in matrigel plugs and KS-Imm tumor growth. We analyzed modulation of gene expression in endothelial cells treated with LA for 5 h (early response), finding a mild anti-apoptotic, antioxidant and anti-inflammatory response. A group of LA-targeted genes was selected to perform real-time polymerase chain reaction time-lapse experiments. The long-term gene regulation (48 h and 4 days) shows higher rates of modulation as compared with the array data, confirming that LA is able to switch the regulation of several genes linked to cell survival, inflammation and oxidative stress. LA induced the production of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) in KS-Imm and activin-A in KS-Imm and endothelial cells; these factors show anti-angiogenic activity in vivo contributing to explain the inhibitory effect of LA on neovascularization. According to our data, LA has promising anti-angiogenic properties, though its influence on central metabolic pathways should suggest more caution about its widespread and not prescribed use at pharmacological doses.}, }
@article {pmid17127228, year = {2006}, author = {Macchi, A and Ardito, F and Marchese, A and Schito, GC and Fadda, G}, title = {Efficacy of N-acetyl-cysteine in combination with thiamphenicol in sequential (intramuscular/aerosol) therapy of upper respiratory tract infections even when sustained by bacterial biofilms.}, journal = {Journal of chemotherapy (Florence, Italy)}, volume = {18}, number = {5}, pages = {507-513}, doi = {10.1179/joc.2006.18.5.507}, pmid = {17127228}, issn = {1120-009X}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Adolescent ; Adult ; Aerosols/therapeutic use ; Aged ; Anti-Bacterial Agents/administration &amp; dosage/adverse effects ; Bacterial Physiological Phenomena/*drug effects ; Biofilms/*drug effects ; Drug Administration Routes ; Drug Combinations ; Expectorants/administration &amp; dosage/adverse effects ; Female ; Humans ; Injections, Intramuscular ; Male ; Middle Aged ; Respiratory Tract Infections/*drug therapy/microbiology ; Thiamphenicol/administration &amp; dosage/adverse effects/*analogs &amp; derivatives ; Treatment Outcome ; }, abstract = {A total of 102 patients with recurrent upper respiratory tract infections underwent microbiological exploration with appropriate sampling and direct biopsies of the infected sites. Therapy was then started and on day 1 each patient received two intramuscular injections of thiamphenicol glycinate acetylcysteinate (TGA). From day 2 to 10 sequential therapy with the same drug was continued employing TGA administered by aerosol. All putative etiologic agents recovered were susceptible to thiamphenicol and only 24 demonstrated the ability to produce in vitro biofilms. The organisms comprised 10 Staphylococcus aureus, 6 Streptococcus pyogenes, 4 Streptococcus pneumoniae and 3 Haemophilus influenzae. Of the 24 subjects in whom biofilms were demonstrated to be present in vivo by Scanning Electron Microscopy, clinical and bacteriological cure was obtained in 21 cases (87.5%) following sequential therapy with TGA. Failures were considered to be persistent signs and symptoms at day 15 after initiation of treatment and lack of eradication of 3 S. aureus strains, despite their in vitro susceptibility to thiamphenicol. Very few adverse events attributable to TGA were reported in this cohort of patients. In no case was discontinuation of treatment deemed necessary by the attending physician.}, }
@article {pmid17125867, year = {2007}, author = {Arakawa, M and Ishimura, A and Arai, Y and Kawabe, K and Suzuki, S and Ishige, K and Ito, Y}, title = {N-Acetylcysteine and ebselen but not nifedipine protected cerebellar granule neurons against 4-hydroxynonenal-induced neuronal death.}, journal = {Neuroscience research}, volume = {57}, number = {2}, pages = {220-229}, doi = {10.1016/j.neures.2006.10.011}, pmid = {17125867}, issn = {0168-0102}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/*toxicity ; Animals ; Animals, Newborn ; Azoles/pharmacology ; Calcium/metabolism ; Cell Death/drug effects ; Cells, Cultured ; Cerebellum/*cytology ; Cysteine Proteinase Inhibitors/*toxicity ; Dose-Response Relationship, Drug ; Drug Interactions ; Glutathione/metabolism ; Isoindoles ; Membrane Potential, Mitochondrial/drug effects ; Neurons/*drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Nifedipine/pharmacology ; Organoselenium Compounds/pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Time Factors ; }, abstract = {4-Hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, has been shown to induce neurotoxicity in various types of neurons. To clarify the mechanisms underlying HNE-induced neurotoxicity, the effects of antioxidants (N-acetylcysteine (NAC) and ebselen with or without NAC pretreatment) and Ca(2+)-related reagents were examined in cerebellar granule neurons. The decreases in neuronal survival and mitochondrial membrane potential induced by HNE were suppressed by pretreatment with NAC at concentrations of 500 and 1000 microM. HNE-induced protein modification and reactive oxygen species generation were also suppressed by pretreatment with NAC at 1000 microM. Although simultaneous application of ebselen (10 microM) did not protect against HNE-induced neurotoxicity, it completely suppressed HNE-induced injury after pretreatment with NAC at 300 microM. HNE increased [Ca(2+)](i) levels, and this increase was significantly attenuated by simultaneous application of nifedipine (10 microM) or EGTA (1000 microM), but not by MK-801 or CNQX. However, none of these Ca(2+)-related reagents was able to prevent HNE-induced neuronal death or mitochondrial injury. These results suggest that pretreatment with a low concentration of NAC dramatically potentiates the neuroprotective activity of ebselen, and that HNE-induced increase in [Ca(2+)](i) is not involved in HNE-induced neuronal death in cerebellar granule neurons.}, }
@article {pmid17125620, year = {2006}, author = {Jin, X and Wu, HS and Tian, Y and Zhang, JH and Wang, CY}, title = {[Effect of NAC on LPS-induced toll-like receptor 2 and 4 expressions in murine macrophages].}, journal = {Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology}, volume = {14}, number = {11}, pages = {852-854}, pmid = {17125620}, issn = {1007-3418}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Gene Expression ; Lipopolysaccharides/pharmacology ; Macrophages/*drug effects ; Mice ; Toll-Like Receptor 2/*genetics ; Toll-Like Receptor 4/*genetics ; }, }
@article {pmid17123753, year = {2007}, author = {Naisbitt, DJ and Sanderson, LS and Meng, X and Stachulski, AV and Clarke, SE and Park, BK}, title = {Investigation of the immunogenicity of diclofenac and diclofenac metabolites.}, journal = {Toxicology letters}, volume = {168}, number = {1}, pages = {45-50}, doi = {10.1016/j.toxlet.2006.10.014}, pmid = {17123753}, issn = {0378-4274}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Antigens/*toxicity ; Cell Proliferation/drug effects ; Diclofenac/*analogs &amp; derivatives/*toxicity ; Female ; Glucuronides/toxicity ; Local Lymph Node Assay ; Lymph Nodes/cytology ; Mice ; Mice, Inbred BALB C ; }, abstract = {Oral administration of the non-steroidal anti-inflammatory drug diclofenac (DCF) is associated with a high incidence of adverse drug reactions, some of which are thought to be mediated by the immune system. It has been proposed that metabolic activation of DCF and covalent binding to protein generates an antigenic determinant that stimulates immune cells; however, the nature of the metabolite remains ill-defined. The aim of this study was to synthesize and evaluate the antigenic potential of DCF metabolites in the mouse. DCF and DCF metabolites were administered via subcutaneous injection over a 5-day period to BALB/C strain mice to induce immune activation. Proliferation was measured by the addition of [(3)H] thymidine to ex vivo isolated draining auricular lymph node cells. Results were compared with those provoked by exposure to 2,4-dinitrochlorobenzene. Lymph node activation was observed following treatment with 2,4-dinitrochlorobenzene, 5-hydroxy DCF quinoneimine and 4'-hydroxy DCF quinoneimine, but not DCF acyl glucuronide or DCF itself. Interestingly, lymph node cells from 5-hydroxy DCF treated mice were also found to proliferate, when compared with cells from vehicle-treated mice, while 4'-hydroxy DCF did not stimulate lymph node cell activation. The reactivity of 5-hydroxy DCF quinoneimine was confirmed by synthesis and characterization of an N-acetyl cysteine adduct. These data show that formation of 5-hydroxy DCF and subsequent autoxidation provides an antigenic determinant for immune cell activation in the mouse.}, }
@article {pmid17122355, year = {2007}, author = {Brown, LA and Ping, XD and Harris, FL and Gauthier, TW}, title = {Glutathione availability modulates alveolar macrophage function in the chronic ethanol-fed rat.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {292}, number = {4}, pages = {L824-32}, doi = {10.1152/ajplung.00346.2006}, pmid = {17122355}, issn = {1040-0605}, support = {P50 AA-135757/AA/NIAAA NIH HHS/United States ; R01 AA-12197/AA/NIAAA NIH HHS/United States ; R01 AA-139879/AA/NIAAA NIH HHS/United States ; R01 HL-67399/HL/NHLBI NIH HHS/United States ; R03 HD-39651/HD/NICHD NIH HHS/United States ; }, mesh = {Alcoholism/*physiopathology ; Animals ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Glutathione/*physiology ; Homeostasis ; In Situ Nick-End Labeling ; Macrophages, Alveolar/*physiology ; Male ; Microscopy, Confocal ; Oxidative Stress/physiology ; Phagocytosis/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {We have previously demonstrated that chronic alcohol exposure decreases glutathione in the alveolar space. Although alcohol use is associated with decreased alveolar macrophage function, the mechanism by which alcohol impairs macrophage phagocytosis is unknown. In the current study, we examined the possibility that ethanol-induced alveolar macrophage dysfunction was secondary to decreased glutathione and subsequent chronic oxidative stress in the alveolar space. After 6 wk of ethanol ingestion, oxidant stress in the alveolar macrophages was evidenced by a 30-mV oxidation of the GSH/GSSG redox potential (P <or= 0.05). For control macrophages, approximately 80% internalized fluorescent Staphylococcus aureus were added in vitro. In contrast, only 20% of the macrophages from the ethanol-fed rats were able to bind and internalize fluorescent S. aureus. This ethanol-induced decreased capacity for phagocytosis was paralleled by increased apoptosis. When added to the ethanol diet, the glutathione precursors procysteine or N-acetyl cysteine normalized glutathione and oxidant stress in the epithelial lining fluid as well as the alveolar macrophages to control values. This attenuation of oxidant stress was associated with normalization of macrophage phagocytosis and viability. These results suggested that decreased glutathione availability in the alcoholic lung contribute to alveolar macrophage dysfunction via oxidative stress, resulting in not only decreased function but decreased viability.}, }
@article {pmid17122328, year = {2007}, author = {Brault, S and Gobeil, F and Fortier, A and Honoré, JC and Joyal, JS and Sapieha, PS and Kooli, A and Martin, E and Hardy, P and Ribeiro-da-Silva, A and Peri, K and Lachapelle, P and Varma, D and Chemtob, S}, title = {Lysophosphatidic acid induces endothelial cell death by modulating the redox environment.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {292}, number = {3}, pages = {R1174-83}, doi = {10.1152/ajpregu.00619.2006}, pmid = {17122328}, issn = {0363-6119}, mesh = {Animals ; Animals, Newborn ; Astrocytes/cytology/*drug effects ; Brain/blood supply/cytology ; Cell Death ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/*drug effects/ultrastructure ; Endothelium, Vascular/cytology ; Kinetics ; Lysophospholipids/*pharmacology ; Models, Biological ; Oxidation-Reduction/*drug effects ; Rats ; Rats, Sprague-Dawley ; Sus scrofa ; }, abstract = {Oxidant stress plays a significant role in hypoxic-ischemic injury to the susceptible microvascular endothelial cells. During oxidant stress, lysophosphatidic acid (LPA) concentrations increase. We explored whether LPA caused cytotoxicity to neuromicrovascular cells and the potential mechanisms thereof. LPA caused a dose-dependent death of porcine cerebral microvascular as well as human umbilical vein endothelial cells; cell death appeared oncotic rather than apoptotic. LPA-induced cell death was mediated via LPA(1) receptor, because the specific LPA(1) receptor antagonist THG1603 fully abrogated LPA's effects. LPA decreased intracellular GSH levels and induced a p38 MAPK/JNK-dependent inducible nitric oxide synthase (NOS) expression. Pretreatment with the antioxidant GSH precursor N-acetyl-cysteine (NAC), as well as with inhibitors of NOS [N(omega)-nitro-l-arginine (l-NNA); 1400W], significantly prevented LPA-induced endothelial cell death (in vitro) to comparable extents; as expected, p38 MAPK (SB203580) and JNK (SP-600125) inhibitors also diminished cell death. LPA did not increase indexes of oxidation (isoprostanes, hydroperoxides, and protein nitration) but did augment protein nitrosylation. Endothelial cytotoxicity by LPA in vitro was reproduced ex vivo in brain and in vivo in retina; THG1603, NAC, l-NNA, and combined SB-203580 and SP600125 prevented the microvascular rarefaction. Data implicate novel properties for LPA as a modulator of the cell redox environment, which partakes in endothelial cell death and ensued neuromicrovascular rarefaction.}, }
@article {pmid17122189, year = {2007}, author = {Guo, Z and Xia, Z and Jiang, J and McNeill, JH}, title = {Downregulation of NADPH oxidase, antioxidant enzymes, and inflammatory markers in the heart of streptozotocin-induced diabetic rats by N-acetyl-L-cysteine.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {292}, number = {4}, pages = {H1728-36}, doi = {10.1152/ajpheart.01328.2005}, pmid = {17122189}, issn = {0363-6135}, mesh = {Acetylcysteine/pharmacology ; Animals ; Biomarkers/metabolism ; Blood Glucose ; Cyclooxygenase 2/metabolism ; Diabetes Mellitus, Experimental/immunology/*metabolism ; Diastole/drug effects/physiology ; Dinoprost/analogs &amp; derivatives/metabolism ; Down-Regulation/drug effects/physiology ; Free Radical Scavengers/pharmacology ; Heart Ventricles/enzymology/immunology/pathology ; Heme Oxygenase (Decyclizing)/*metabolism ; Insulin/blood ; Interleukin-6/metabolism ; Male ; Myocardium/*enzymology/immunology/pathology ; NADPH Oxidases/*metabolism ; Organ Size ; Oxidative Stress/drug effects/physiology ; Phosphoproteins/*metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/*metabolism ; }, abstract = {We investigated the effect of N-acetyl-l-cysteine (NAC) on the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, antioxidant enzymes, and inflammatory markers in diabetic rat hearts. Metabolic parameters, free 15-F(2t)-isoprostane level, protein expression of NADPH oxidase, superoxide dismutase (SOD), heme oxygenase (HO-1), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) were analyzed in control and streptozotocin-induced diabetic rats treated with or without NAC in drinking water for 8 wk. The cardiac protein expression of p67(phox) and p22(phox) was increased in diabetic rats, accompanied by increased NADPH-dependent superoxide production. As a compensatory response to the increased NADPH oxidase, the protein expression of Cu-Zn-SOD and HO-1 and the total SOD activity were also increased in diabetic rat hearts. Consequently, cardiac free 15-F(2t)-isoprostane, an index of oxidative stress, was increased in diabetic rats, indicating that the production of reactive oxygen species becomes excessive in diabetic rat hearts. Cardiac inflammatory markers IL-6 and COX-2 were also increased in diabetic rats. NAC treatment prevented the increased expression of p22(phox) and translocation of p67(phox) to the membrane in diabetic rat hearts. Subsequently, the levels of cardiac free 15-F(2t)-isoprostane, HO-1, Cu-Zn-SOD, total SOD, IL-6, and COX-2 in diabetic rats were decreased by NAC. Consequently, cardiac hypertrophy was attenuated in diabetic rats treated with NAC. The protective effects of NAC on diabetic rat hearts may be attributable to its protection of hearts against oxidative damage induced by the increased NADPH oxidase and to its reduction in cardiac inflammatory mediators IL-6 and COX-2.}, }
@article {pmid17113207, year = {2007}, author = {Mardikian, PN and LaRowe, SD and Hedden, S and Kalivas, PW and Malcolm, RJ}, title = {An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study.}, journal = {Progress in neuro-psychopharmacology &amp; biological psychiatry}, volume = {31}, number = {2}, pages = {389-394}, doi = {10.1016/j.pnpbp.2006.10.001}, pmid = {17113207}, issn = {0278-5846}, support = {DA07288/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adolescent ; Adult ; Cocaine-Related Disorders/*drug therapy ; Dose-Response Relationship, Drug ; Female ; Free Radical Scavengers/adverse effects/*therapeutic use ; Humans ; Male ; Middle Aged ; Pilot Projects ; Treatment Outcome ; }, abstract = {Recent preclinical studies implicate N-acetylcysteine (NAC), a cysteine prodrug, as a potential medication for preventing relapse to cocaine use; however, little is known about the safety and tolerability of NAC in cocaine-dependent subjects in an outpatient setting. This pilot study examines the safety and tolerability of 3 doses of NAC for the treatment of cocaine dependence. Twenty three treatment-seeking cocaine-dependent patients participated in a 4-week medication trial and received NAC at doses of 1200 mg/day, 2400 mg/day or 3600 mg/day. Results suggested that the three doses were well tolerated. Overall, the retention rates appeared to favor higher doses of NAC (2400 mg/day and 3600 mg/day). The majority of subjects who completed the study (n=16) either terminated use of cocaine completely or significantly reduced their use of cocaine during treatment. Overall the findings suggest that it is feasible to treat cocaine-dependent treatment seekers with N-acetylcysteine on an outpatient basis.}, }
@article {pmid17112826, year = {2006}, author = {Di Giorno, C and Pinheiro, HS and Heinke, T and Franco, MF and Galante, NZ and Pacheco-Silva, A and Camara, NO}, title = {Beneficial effect of N-acetyl-cysteine on renal injury triggered by ischemia and reperfusion.}, journal = {Transplantation proceedings}, volume = {38}, number = {9}, pages = {2774-2776}, doi = {10.1016/j.transproceed.2006.08.178}, pmid = {17112826}, issn = {0041-1345}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Dendritic Cells/immunology ; Disease Models, Animal ; Kidney Function Tests ; Lymphocyte Activation ; Male ; Mice ; Mice, Inbred C57BL ; *Renal Circulation ; Reperfusion Injury/immunology/pathology/*prevention &amp; control ; T-Lymphocytes/immunology ; Transplantation, Isogeneic ; }, abstract = {Reactive oxygen species are critical mediators of the early phase of ischemic (IR) injury. The contribution of antioxidants, such as N-acetyl-cysteine (NAC), in ameliorating the parenchymal lesions, inflammatory parameters, and functional variables in renal IR is still controversial. We studied the effect of NAC administration on renal injury induced by IR. Mice were subjected to renal pedicle occlusion and subsequent reperfusion for 24 or 120 hours. NAC was administered prior to surgery at two concentrations (40 or 300 mg/kg, i.p.). Renal function and acute tubular necrosis were assessed, as well as immune phenotyping of infiltrating cells, by flow cytometry. At 40 mg/dL of NAC, we did not observe any significant improvement in renal function (1.85 +/- 0.43 md/dL, P = .367) or tissue architecture (% of ATN: 2.51 +/- 0.27 mm, P = .852) compared to the controls (1.87 +/- 0.43 mg/dL and 3.12 +/- 0.34 mm, respectively). However, animals that received 300 mg/dL of NAC showed lower serum creatinine values (24 hours: 1.25 +/- 0.54 mg/dL) compared to controls (P = .009) and less extensive acute tubular necrosis (1.54 +/- 0.12 vs, P < .05). Treatment with 300 mg/dL of NAC decreased renal dendritic cell infiltration. The protective effect of NAC was better observed at high concentrations and early times.}, }
@article {pmid17108112, year = {2006}, author = {van Gorp, AG and Pomeranz, KM and Birkenkamp, KU and Hui, RC and Lam, EW and Coffer, PJ}, title = {Chronic protein kinase B (PKB/c-akt) activation leads to apoptosis induced by oxidative stress-mediated Foxo3a transcriptional up-regulation.}, journal = {Cancer research}, volume = {66}, number = {22}, pages = {10760-10769}, doi = {10.1158/0008-5472.CAN-06-1111}, pmid = {17108112}, issn = {0008-5472}, support = {BBS/B/03785/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Animals ; Apoptosis/*physiology ; Apoptosis Regulatory Proteins/biosynthesis/genetics ; Bcl-2-Like Protein 11 ; Cyclin-Dependent Kinase Inhibitor p27/biosynthesis/genetics ; Enzyme Activation ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/*biosynthesis/genetics ; Membrane Proteins/biosynthesis/genetics ; Mice ; Oxidative Stress/physiology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins/biosynthesis/genetics ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/metabolism ; Transcription, Genetic ; Up-Regulation ; }, abstract = {Increased protein kinase B (PKB; c-Akt) activation is a hallmark of diverse neoplasias providing both proliferative and antiapoptotic survival signals. In this study, we investigated the effect of chronic PKB activation on cellular survival and proliferation using cytokine-dependent bone marrow-derived Ba/F3 cells, in which PKBalpha activation can be directly, and specifically, induced by addition of 4-hydroxytamoxifen (4-OHT). Direct activation of PKB rescued Ba/F3 cells from cytokine withdrawal-induced apoptosis; however, surprisingly, these antiapoptotic effects were short lived, cells only being protected for up to 48 hours. We observed that activation of PKB in survival factor-deprived cells led to a dramatic increase of Foxo3a on both the transcriptional and protein level leading to expression of its transcriptional targets Bim and p27(kip1). High levels of PKB activity result in increased aerobic glycolysis and mitochondrial activity resulting in overproduction of reactive oxygen species. To determine whether oxidative stress might itself be responsible for Foxo3a up-regulation, we utilized hydrogen peroxide (H(2)O(2)) as an artificial inducer of oxidative stress and N-acetylcysteine (NAC), a thiol-containing radical oxygen scavenger. Addition of NAC to the culture medium prolonged the life span of cells treated with 4-OHT and prevented the up-regulation of Foxo3a protein levels caused by PKB activation. Conversely, treatment of Ba/F3 cells with H(2)O(2) caused an increase of Foxo3a on both transcriptional and protein levels, suggesting that deregulated PKB activation leads to oxidative stress resulting in Foxo3a up-regulation and subsequently cell death. Taken together, our data provide novel insights into the molecular consequences of uncontrolled PKB activation.}, }
@article {pmid17103249, year = {2006}, author = {Zborek, A and Malusecka, E and Rusin, A and Krzyzowska-Gruca, S and Krawczyk, Z}, title = {Influx of macrophages into livers of rats treated with hepatotoxicants (thioacetamide, allyl alcohol, D-galactosamine) induces expression of HSP25.}, journal = {Journal of molecular histology}, volume = {37}, number = {8-9}, pages = {381-389}, pmid = {17103249}, issn = {1567-2379}, mesh = {Animals ; Galactosamine/*pharmacology ; Heat-Shock Proteins/*metabolism ; Hepatocytes/drug effects/metabolism ; Inflammation/chemically induced ; Liver/drug effects/*metabolism ; Macrophages/drug effects/*metabolism/physiology ; Male ; Molecular Chaperones ; Neoplasm Proteins/*metabolism ; Propanols/*pharmacology ; Rats ; Thioacetamide/*pharmacology ; }, abstract = {Treatment of rats with a single dose of thioacetamide (TAA) provokes centrilobular inflammation and a significant expression of heat shock protein HSP25 in hepatocytes surrounding the area of inflammation. The HSP25 accumulation in hepatocytes adjacent to inflammatory regions was confirmed by identification of positive hepatocytes concentrated at periportal areas after treatment of rats with allyl alcohol (AA) or distributed diffusely throughout liver lobule after treatment with D-galactosamine (D-gal). In our model of TAA-treated rats the use of the anti-inflammatory drug-indomethacin, and the redox-regulating drug-N-acetylcysteine (NAC), significantly attenuated TAA-induced HSP25 expression and evoked morphological changes of recruited ED1+ macrophages. Treatment of rats with gadolinium chloride (GdCl(3)) decreased considerably the number of Kupffer cells (ED2+ macrophages) without affecting significantly the number and morphology of ED1+ macrophages as well as the expression pattern of TAA-induced HSP25. Our data shows for the first time that ED1+ macrophages recruited into the liver by treatment with TAA play a significant role in HSP25 induction in hepatocytes.}, }
@article {pmid17095404, year = {2006}, author = {Yang, R and Le, G and Li, A and Zheng, J and Shi, Y}, title = {Effect of antioxidant capacity on blood lipid metabolism and lipoprotein lipase activity of rats fed a high-fat diet.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {22}, number = {11-12}, pages = {1185-1191}, doi = {10.1016/j.nut.2006.08.018}, pmid = {17095404}, issn = {0899-9007}, mesh = {Acetylcysteine/administration &amp; dosage/metabolism ; Animals ; Antioxidants/administration &amp; dosage/metabolism/*pharmacology ; Atherosclerosis/blood/metabolism ; Cholesterol/blood ; Dietary Fats/*administration &amp; dosage ; Lipid Metabolism/*drug effects ; Lipid Peroxidation/*drug effects ; Lipoprotein Lipase/*metabolism ; Male ; Malondialdehyde/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Thioctic Acid/administration &amp; dosage/metabolism ; Triglycerides/blood ; }, abstract = {OBJECTIVE: The present study explored the effect of antioxidant capacity on blood lipid metabolism and lipoprotein lipase (LPL) activity of rats fed with a high-fat diet (HFD). Furthermore, the relation of the atherosclerotic index (AI) and LPL activity to total antioxidant capacity (TAC) was studied.<br><br>METHODS: Thirty-two Sprague-Dawley rats were randomly assigned to one of four groups (n = 8). The control group consumed an ordinary diet (5.1% fat, w/w). The other three experimental groups were fed with an HFD (14.1% fat, w/w), an HFD plus 0.1% lipoic acid (LA), or an HFD plus 0.1% N-acetylcysteine (NAC). After 4 wk, serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol and LPL activity were examined. To evaluate rats' antioxidant status, TAC and superoxide dismutase activities and malondialdehyde level were measured.<br><br>RESULTS: The HFD induced abnormal increases in lipid peroxidation, serum concentrations of total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol, and a decrease in high-density lipoprotein cholesterol concentration. Decreased activity of LPL, accompanied by a depressed antioxidant defense system, was observed in HFD-fed rats. These changes were partially restored in the NAC- and LA-treated groups. There was a negative correlation between AI and TAC (r = -0.969, P < 0.05). In addition, a significant positive correlation between LPL activity and TAC was found (r = 0.979, P < 0.05).<br><br>CONCLUSION: Oxidative injury and lipid abnormalities were induced by an HFD. Administration of LA and NAC can improve the antioxidant capacity and activity of LPL and reduce blood lipid significantly. Antioxidant capacity is correlated with AI and LPL activity.}, }
@article {pmid17094462, year = {2006}, author = {Watanabe, M and Akiyama, N and Sekine, H and Mori, M and Manome, Y}, title = {Inhibition of poly (ADP-ribose) polymerase as a protective effect of nicaraven in ionizing radiation- and ara-C-induced cell death.}, journal = {Anticancer research}, volume = {26}, number = {5A}, pages = {3421-3427}, pmid = {17094462}, issn = {0250-7005}, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/metabolism/pathology ; Adenoviridae/genetics ; Antimetabolites, Antineoplastic/*toxicity ; Antioxidants/pharmacology ; Apoptosis/drug effects/radiation effects ; Benzamides/pharmacology ; Cell Proliferation/drug effects/radiation effects ; Cytarabine/*toxicity ; Early Growth Response Protein 1/pharmacology ; Free Radical Scavengers/pharmacology ; Genes, Reporter/physiology ; Humans ; Hydrogen Peroxide/pharmacology ; Leukemia, Myeloid/metabolism/pathology ; Niacinamide/*analogs &amp; derivatives/pharmacology ; *Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Promoter Regions, Genetic/genetics ; Protective Agents/*pharmacology ; *Radiation, Ionizing ; Stomach Neoplasms/metabolism/pathology ; Thymidine/metabolism ; Transfection ; Tumor Cells, Cultured/drug effects/radiation effects ; }, abstract = {BACKGROUND: Nicaraven is a drug used for patients with a subarachnoid hemorrhage. It crosses the blood-brain barrier and has potent antivasospastic and brain-protective effects. While nicaraven scavenges the hydroxyl radical, the mechanism of its protection remains obscure. In addition to the hydroxyl radical scavenging effect, nicaraven also exhibits inhibitory action on poly (ADP-ribose) polymerase (PARP). The mechanism of the pharmacological action of nicaraven has not yet been clarified.<br><br>MATERIALS AND METHODS: Human myeloid HL-525 cells were exposed to ionizing radiation or hydrogen peroxide and the effect of nicaraven on the activation of the Egr-1 promoter was measured. Next, the action of the drug on DNA fragmentation and inhibition of thymidine uptake caused by the genotoxic stimulation of ionizing radiation or cytosine B-D-arabinofuranoside (ara-C) were assessed. Finally, direct inhibition of the PARP enzyme by nicaraven was measured.<br><br>RESULTS: Nicaraven did not inhibit the activation of the Egr-1 promoter caused by H2O2 and the activation caused by ionizing radiation. However, the drug repressed DNA fragmentation and increased thymidine uptake dose-dependently. Nicaraven had a direct inhibitory effect on PARP.<br><br>DISCUSSION: The effect of nicaraven on the Egr-1 promoter was different from that of another free-radical scavenger, N-acetyl cysteine. Nicaraven demonstrated similar protection of the PARP inhibitors including 3-aminobenzamide. Since nicaraven directly inhibits the PARP enzyme, the drug might be useful in oncology as well as in studying tissue-damaging conditions characterized by increased PARP activity.}, }
@article {pmid17084062, year = {2007}, author = {Walther, UI and Walther, SC and Temrück, O}, title = {Effect of enlarged glutathione on zinc-mediated toxicity in lung-derived cell lines.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {21}, number = {3}, pages = {380-386}, doi = {10.1016/j.tiv.2006.09.014}, pmid = {17084062}, issn = {0887-2333}, mesh = {Acetylcysteine/*toxicity ; Animals ; Cell Line, Tumor ; Cell Survival/drug effects ; Chlorides/metabolism/*toxicity ; Dose-Response Relationship, Drug ; Drug Combinations ; Epithelial Cells/drug effects/*metabolism ; Free Radical Scavengers/*toxicity ; Glutathione/*biosynthesis ; Humans ; Hydrocortisone/pharmacology ; Isomerism ; Pulmonary Alveoli/drug effects/*metabolism ; Rats ; Zinc Compounds/metabolism/*toxicity ; }, abstract = {Zinc-mediated toxicity has been linked to cellular glutathione content in isolated cells. In addition, treatment of alveolar epithelial type II cells with glucocorticoids diminishes cellular glutathione content, and this is followed by an increase in zinc-mediated toxicity. The question arises whether an increase in glutathione synthesis might decrease zinc-mediated toxicity. For this purpose an administration of 200 micromol/l N-acetyl-L-cysteine (NAC) was given to the cells, while cysteine was used up to 100 micromol/l. Zinc-mediated toxicity was assessed by measuring protein synthesis inhibition and glutathione dependent parameters. De novo synthesis of glutathione was assessed as compared to controls by N-acetyl-D-cysteine (NADC) treatment. Comparing NAC and NADC treatment no differences in zinc-mediated toxicity were found. Furthermore only in one (of three) cell line tested a significant increase in GSH content by NAC as compared to NADC treatment was achieved. But even in this cell line no changes by zinc-mediated toxicity were found. It is concluded that the cell lines tested can use other sources of cys for glutathione synthesis. Furthermore the increased zinc-mediated toxicity due to hydrocortisone was abolished in the alveolar epithelial cell lines by the NADC/NAC treatment. It is therefore discussed that additionally to glutathione some other antioxidative defence mechanisms can influence zinc-mediated toxicity as well.}, }
@article {pmid17082565, year = {2007}, author = {Chung, SW and Chung, HY and Toriba, A and Kameda, T and Tang, N and Kizu, R and Hayakawa, K}, title = {An environmental quinoid polycyclic aromatic hydrocarbon, acenaphthenequinone, modulates cyclooxygenase-2 expression through reactive oxygen species generation and nuclear factor kappa B activation in A549 cells.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {95}, number = {2}, pages = {348-355}, doi = {10.1093/toxsci/kfl150}, pmid = {17082565}, issn = {1096-6080}, mesh = {Acenaphthenes/chemistry/*toxicity ; Cell Line, Tumor ; Cyclooxygenase 2/*biosynthesis ; Dose-Response Relationship, Drug ; Environmental Pollutants/chemistry/*toxicity ; Humans ; Isomerism ; Molecular Structure ; NF-kappa B/*metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/*metabolism ; }, abstract = {Diesel exhaust particles (DEPs) contain oxygen-containing polycyclic aromatic hydrocarbons (PAHs) called quinoid PAHs. Some quinoid PAHs generate free radicals as they undergo enzymatic and nonenzymatic redox cycling with their corresponding semiquinone radicals. Reactive oxygen species (ROS) produced by these reactions can cause severe oxidative stress connected with inflammatory processing. Although humans and animals are continuously exposed to these chemicals in the environment, little is known about which quinoid PAHs are active. In this study, we estimated the intracellular ROS production and nuclear factor kappa B (NF-kappaB) translocation in A549 cells exposed to isomers of quinoid PAHs having two to four rings. We found that both acenaphthenequinone (AcQ) and 9,10-phenanthrenequinone (PQ) enhanced ROS generation and that AcQ translocated NF-kappaB from the cytosol to the nucleus. However, PQ, which has been reported to induce apoptosis, did not influence NF-kappaB activation. In addition, AcQ induced cyclooxygenase-2 (COX-2) expression which is a key enzyme in the inflammatory processing involved in the activation of NF-kappaB. Upregulation of NF-kappaB and COX-2 expression by AcQ treatment was suppressed by the antioxidant N-acetylcysteine (NAC). These results provide that AcQ might play an important role in human lung inflammatory diseases as an air pollutant.}, }
@article {pmid17072061, year = {2006}, author = {Radomska-Leśniewska, DM and Sadowska, AM and Van Overveld, FJ and Demkow, U and Zieliński, J and De Backer, WA}, title = {Influence of N-acetylcysteine on ICAM-1 expression and IL-8 release from endothelial and epithelial cells.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {57 Suppl 4}, number = {}, pages = {325-334}, pmid = {17072061}, issn = {1899-1505}, mesh = {Acetylcysteine/*pharmacology ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/pharmacology ; Cell Line ; Endothelial Cells/*drug effects/metabolism ; Epithelial Cells/*drug effects/metabolism ; Humans ; Intercellular Adhesion Molecule-1/*metabolism ; Interleukin-8/*antagonists &amp; inhibitors/metabolism ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation. The initial step in the inflammatory process is overexpression of adhesion molecules, which leads to excessive transmigration of neutrophils. One of these adhesion molecules is ICAM-1 which is elevated in COPD patients. In this study we evaluated the influence of N-acetylcysteine (NAC) (0.01 mM-30 mM) on the cytokine-induced (TNF-alpha/IL-1 beta) expression of the ICAM-1 adhesion molecule and on IL-8 release in endothelial (ECV-304) and bronchial epithelial (H292) cell lines. The methodology used consisted of immunochemistry for the assessment of surface ICAM-1 and ELISA method for that of soluble ICAM-1 and IL-8. NAC inhibited the TNF-alpha/IL-1 beta-stimulated ICAM-1 expression and IL-8 release from both cell lines in a concentration dependent manner. The most effective concentrations were 30 mM and 20 mM (99 and 90% inhibition respectively, P<0.01). We conclude that NAC is an effective inhibitor of TNF-alpha/IL-1 beta- stimulated ICAM-1 and IL-8 release in endothelial and epithelial cells. This fact highlights the anti-inflammatory potential of NAC in COPD.}, }
@article {pmid17071120, year = {2007}, author = {Chuang, IC and Liu, DD and Kao, SJ and Chen, HI}, title = {N-acetylcysteine attenuates the acute lung injury caused by phorbol myristate acetate in isolated rat lungs.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {20}, number = {6}, pages = {726-733}, doi = {10.1016/j.pupt.2006.08.010}, pmid = {17071120}, issn = {1094-5539}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Animals ; Blood Pressure/drug effects ; Body Weight/drug effects ; Bronchoalveolar Lavage Fluid ; Capillary Permeability ; Expectorants/*pharmacology ; Free Radical Scavengers/*pharmacology ; In Vitro Techniques ; Inflammation Mediators/metabolism ; Lung/*drug effects/pathology ; Lung Diseases/chemically induced/*drug therapy ; Male ; Nitric Oxide/metabolism ; Organ Size/drug effects ; Pulmonary Artery/drug effects/pathology ; Pulmonary Edema/chemically induced/*drug therapy ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Tetradecanoylphorbol Acetate ; }, abstract = {Acute lung injury (ALI) caused by phorbol myristate acetate (PMA) is characterized by pulmonary edema and inflammatory cells infiltration. PMA-activated neutrophils in vivo and in vitro to release free radicals, pro-inflammatory cytokines, nitric oxide (NO) and other mediators. These mediators may be the causes of pulmonary hypertension and increased microvascular permeability. In the present study, we used isolated perfused rat lungs from Sprague-Dawley (SD) rats. The purpose was to evaluate the effects of pretreatment of N-acetylcysteine (NAC) on the PMA-induced ALI and associated changes. PMA (2 microg kg(-1)) was introduced into the lung perfusate. NAC (150 mg kg(-1)) was administered 10 min before PMA. Thirty isolated lungs were randomly assigned to receive vehicle (dimethyl sulfoxide, DMSO, the solvent for PMA, 100 microg g(-1)), PMA alone and PMA with NAC pretreatment. There were 10 lungs in each group. We measured the lung weight (LW) to body weight (BW) ratio (LW/BW), LW gain (LWG), exhaled nitric oxide (NO) and protein concentration in bronchoalveolar lavage (PCBAL). The pulmonary arterial pressure (PAP) and microvascular permeability (K(fc)) were assessed. The concentration of nitrate/nitrite, methyl guanidine (MG), tumor necrosis factor(alpha) (TNF(alpha)) and interleukin-1(beta) (IL-1(beta)) in lung perfusate were determined. In addition, we also evaluate the lung injury by histopathological examination and by grading system for the lung injury score (LIS). PMA caused severe ALI as evidenced by the marked increases in LW changes, exhaled NO, PCBAL, histopathological changes, and LIS. It also increased the nitrate/nitrite, MG, TNF(alpha), and IL-1(beta) in lung perfusate. Pretreatment with NAC significantly attenuated these changes and abrogated the extent of ALI. Our results suggest that NAC exerts strong protective effects on the PMA-induced ALI and associated alterations. The mechanisms are possibly attributable to its antioxidant actions, inhibition of pro-inflammatory cytokines, and restoration of glutathione enzymes.}, }
@article {pmid17069760, year = {2006}, author = {Yan, SK and Chang, T and Wang, H and Wu, L and Wang, R and Meng, QH}, title = {Effects of hydrogen sulfide on homocysteine-induced oxidative stress in vascular smooth muscle cells.}, journal = {Biochemical and biophysical research communications}, volume = {351}, number = {2}, pages = {485-491}, doi = {10.1016/j.bbrc.2006.10.058}, pmid = {17069760}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase/metabolism ; Cell Line ; Glutathione/pharmacology ; Homocysteine/pharmacology/*physiology ; Hydrogen Sulfide/*metabolism/pharmacology ; Muscle, Smooth, Vascular/drug effects/*metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Onium Compounds/pharmacology ; *Oxidative Stress ; Rats ; Reactive Nitrogen Species/*metabolism ; Reactive Oxygen Species/metabolism ; Sulfides/metabolism ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; }, abstract = {Hydrogen sulfide (H(2)S) is an important gasotransmitter that generated in mammalian cells from l-cysteine metabolism. Little is known about its protective role in oxidative stress. In the present study, we investigated whether H(2)S could affect homocysteine (HCY)-induced cytotoxicity and oxidative stress in vascular smooth muscle cells. Cultured A-10 cells were exposed to HCY treatment in the presence or absence of NaHS (donor of H(2)S). HCY induced cytotoxicity, increased levels of H(2)O(2), ONOO(-), and O2- in a time- and concentration-dependent manner. Low levels of NaHS (30 or 50microM) protected A-10 cells from cytotoxicity, decreased the production of H(2)O(2), ONOO(-), and O2- in the presence of HCY. Furthermore, NaHS enhanced inhibitory effects of NAC, GSH, DPI, SOD, L-NAME, or vitamin C on oxidized DCF or O2- formation induced by HCY. In conclusion, our findings provide the first evidence that low levels of H(2)S decrease reactive oxygen species and improve cell viability and by doing so limit cellular damage induced by HCY.}, }
@article {pmid17065366, year = {2007}, author = {Terneus, MV and Kiningham, KK and Carpenter, AB and Sullivan, SB and Valentovic, MA}, title = {Comparison of S-Adenosyl-L-methionine and N-acetylcysteine protective effects on acetaminophen hepatic toxicity.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {320}, number = {1}, pages = {99-107}, doi = {10.1124/jpet.106.111872}, pmid = {17065366}, issn = {0022-3565}, mesh = {Acetaminophen/poisoning/*toxicity ; Acetylcysteine/*pharmacology ; Aldehydes/analysis ; Animals ; Antidotes/*pharmacology ; Blotting, Western ; Glutathione/analysis ; Liver/*drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Organ Size/drug effects ; Protein Carbonylation/drug effects ; S-Adenosylmethionine/*pharmacology ; }, abstract = {Nutraceuticals are widely used by the general public, but very little information is available regarding the effects of nutritional agents on drug toxicity. Excessive doses of acetaminophen (APAP, 4-hydroxyacetanilide) induce hepatic centrilobular necrosis. The naturally occurring substance S-adenosyl-l-methionine (SAMe) has been reported to reduce the hepatic toxicity of APAP. The present study was designed to investigate the hepatoprotective effects of SAMe in comparison to the clinically used antidote N-acetylcysteine (NAC). Male C57BL/6 mice were injected intraperitoneally (i.p.) with an equimolar dose (1.25 mmol/kg) of either SAMe or NAC just before APAP, and the groups were denoted SAMe+APAP and NAC+APAP, respectively. Mice were immediately injected i.p. with 300 mg/kg APAP, and hepatotoxicity was evaluated after 4 h. SAMe was more hepatoprotective than NAC at a dose of 1.25 mmol/kg as liver weight was unchanged by APAP injection in the SAMe+APAP group, whereas liver weight was increased in the NAC+APAP group. SAMe was more hepatoprotective for APAP toxicity than NAC, because alanine aminotransferase levels were lower in the SAMe+APAP. Pretreatment with SAMe maintained total hepatic glutathione (GSH) levels higher than NAC pretreatment before APAP, although total hepatic GSH levels were lower in the SAMe+APAP and NAC+APAP groups than the vehicle control values. Oxidative stress was less extensive in the SAMe+APAP group compared with the APAP-treated mice as indicated by Western blots for protein carbonyls and 4-hydroxynonenal-adducted proteins. In summary, SAMe reduced APAP toxicity and was more potent than NAC in reducing APAP hepatotoxicity.}, }
@article {pmid17063982, year = {2006}, author = {Lorito, G and Giordano, P and Prosser, S and Martini, A and Hatzopoulos, S}, title = {Noise-induced hearing loss: a study on the pharmacological protection in the Sprague Dawley rat with N-acetyl-cysteine.}, journal = {Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale}, volume = {26}, number = {3}, pages = {133-139}, pmid = {17063982}, issn = {0392-100X}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/*therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology/*therapeutic use ; Cochlea/drug effects ; Evoked Potentials, Auditory, Brain Stem ; Hair Cells, Auditory/drug effects/pathology ; Hearing Loss, Noise-Induced/*diagnosis/pathology/*prevention &amp; control ; Male ; Otoacoustic Emissions, Spontaneous/drug effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Noise-induced hearing loss is one of the most common causes of deafness and, at present, there is no treatment for the recovery of the normal hearing threshold after prolonged exposure to loud acoustic stimuli and the generation of acoustic trauma. Prolonged exposure to noise can cause oxidative stress in the cochlea which results in the loss (via apoptotic pathways) of the outer hair cells of the organ of Corti. It has been demonstrated that some antioxidant molecules, for example L-N-acetyl-cysteine, can prevent oxidative stress in the inner ear. Aim of the study was to evaluate whether L-N-acetyl-cysteine, given at various dosages, can preserve the fine structures of the cochlea from the insult of continuous noise. A series of 18 Sprague Dawley male albino rats were exposed to continuous noise (8 kHz octave band noise, 105 dB SPL, 4 hours), and cochlear functionality was evaluated by recordings of transient evoked otoacoustic emissions and distortion products otoacoustic emissions). The group which showed the best protection was that which received a total dosage of 1500 mg/kg of L-N-acetyl-cysteine. These data suggest that while L-Nacetyl-cysteine can partially protect the cochlea from continuous noise, the protection effect is strongly dose-dependent: lower dosages do not fully protect the cochlea and higher dosages can damage the rat systemically (e.g. pulmonary toxicity).}, }
@article {pmid17054487, year = {2006}, author = {Pagl, R and Aurich, C and Kankofer, M}, title = {Anti-oxidative status and semen quality during cooled storage in stallions.}, journal = {Journal of veterinary medicine. A, Physiology, pathology, clinical medicine}, volume = {53}, number = {9}, pages = {486-489}, doi = {10.1111/j.1439-0442.2006.00879.x}, pmid = {17054487}, issn = {0931-184X}, mesh = {Animals ; Antioxidants/*metabolism ; Cold Temperature ; Glutathione Peroxidase/metabolism ; Horses/*physiology ; *Lipid Peroxidation ; Male ; Oxidative Stress ; Semen/enzymology/*physiology ; Semen Preservation/methods/*veterinary ; Superoxide Dismutase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Activity of the anti-oxidative enzymes glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT), content of thiobarbituric acid reactive substances (TBARS) and SH-groups were determined in native stallion semen (n = 8 stallions). Semen was then diluted in Kenney extender, EquiPro((R)) extender either with or without addition of N-acetyl cysteine or phosphate-buffered saline (PBS) and stored for 72 h at 5 degrees C. Correlations between initial activity of enzymes and development of semen motility and membrane integrity were calculated. Activities of GSH-Px, SOD and CAT immediately after semen collections were 10.0 +/- 0.6 picokatals, 0.40 +/- 0.03 SOD units and 0.70 +/- 0.05 nanokatals/10(6) spermatozoa respectively. TBARS content was 0.06 +/- 0.01 nmol and SH-group content 1.7 +/- 0.5 mmol/10(6) spermatozoa. The loss of motile spermatozoa during storage did not differ between extenders. N-acetyl cysteine had no effect on semen motility and membrane integrity. The loss in membrane-intact spermatozoa was highest (P < 0.05) in semen diluted in PBS. Motility and membrane integrity after addition of extender were positively correlated with GSH-Px and CAT, indicating that anti-oxidative mechanisms contribute to the initial high percentage of motile and membrane-intact spermatozoa. However, in these samples the decrease in semen quality was most pronounced. No correlations existed between initial activity of anti-oxidative enzymes, peroxidation products and semen quality during storage. This indicates that once extender has been added, peroxidative damage to sperm membranes is not the predominant cause of losses in semen quality.}, }
@article {pmid17051330, year = {2006}, author = {Wang, W and Adachi, M and Kawamura, R and Sakamoto, H and Hayashi, T and Ishida, T and Imai, K and Shinomura, Y}, title = {Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {11}, number = {12}, pages = {2225-2235}, doi = {10.1007/s10495-006-0287-2}, pmid = {17051330}, issn = {1360-8185}, mesh = {Acetylcysteine/pharmacology ; Aged, 80 and over ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antioxidants/metabolism ; Apoptosis/*drug effects ; Catalase/antagonists &amp; inhibitors/*metabolism ; Cell Survival/drug effects ; Enzyme Inhibitors/pharmacology ; Humans ; Multiple Myeloma/*pathology ; Onium Compounds/pharmacology ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; }, abstract = {The sesquiterpene lactone, parthenolide (PTL), possesses strong anticancer activity against various cancer cells. We report that PTL strongly induced apoptosis in 4 multiple myeloma (MM) cell lines and primary MM cells (CD38(+) high), but barely induced death in normal lymphocytes (CD38(-/+)low). PTL-mediated apoptosis correlated well with ROS generation and was almost completely inhibited by L-N-acetylcysteine (L-NAC), indicating the crucial role of oxidative stress in the mechanism. Among 4 MM cell lines, there is considerable difference in susceptibility to PTL. KMM-1 and MM1S cells sensitive to PTL possess less catalase activity than the less sensitive KMS-5 and NCI-H929 cells as well as normal lymphocytes. A catalase inhibitor 3-amino-1,2,4-triazole enhanced their PTL-mediated ROS generation and cell death. The siRNA-mediated knockdown of catalase in KMS-5 cells decreased its activity and sensitized them to PTL. Our findings indicate that PTL induced apoptosis in MM cells depends on increased ROS and intracellular catalase activity is a crucial determinant of their sensitivity to PTL.}, }
@article {pmid17046137, year = {2006}, author = {Demiralay, R and Gürsan, N and Erdem, H}, title = {Regulation of sepsis-induced apoptosis of pulmonary cells by posttreatment of erdosteine and N-aceylcysteine.}, journal = {Toxicology}, volume = {228}, number = {2-3}, pages = {151-161}, doi = {10.1016/j.tox.2006.08.027}, pmid = {17046137}, issn = {0300-483X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Bronchoalveolar Lavage Fluid/cytology ; Epithelial Cells/drug effects ; Free Radical Scavengers/*pharmacology ; Immunohistochemistry ; In Situ Nick-End Labeling ; Lipopolysaccharides ; Lung/*cytology/*drug effects ; Peroxidase/metabolism ; Pneumonia/chemically induced/pathology ; Rats ; Rats, Wistar ; Sepsis/*pathology ; Thioglycolates/*pharmacology ; Thiophenes/*pharmacology ; Tissue Embedding ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {This study investigated the frequency of apoptosis in rat pulmonary epithelial cells after intraperitoneal endotoxin (LPS) injection, the effects of LPS on inflammatory markers [myeloperoxidase (MPO), tumor necrosis factor alpha (TNF-alpha), and vascular endothelial growth factor (VEGF)] in lung damage and the protective effects of two known antioxidant agents, erdosteine and N-acetylcysteine (NAC). Male Wistar rats were divided into six groups, each composed of nine rats: two control groups, two LPS-treated groups, one erdosteine-treated group (150 mg/kg), and one NAC-treated group. LPS was intraperitoneally injected at a dosage of 20mg/kg. Following LPS injection, the antioxidants were administered orally. The rats were killed 24h after LPS administration. Lung tissue samples were stained with hematoxylin-eosin (H&amp;E) for histopathological assessments. Apoptosis level in epithelial cells was determined by using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling) method. Staining of cytoplasmic TNF-alpha in epithelial cells and VEGF in endothelial cells, and epithelial MPO activity were evaluated by immunohistochemistry. Posttreatment with erdosteine and NAC significantly reduced the rate of LPS-induced epithelial cell apoptosis. Posttreatment with erdosteine and NAC significantly reduced the increases in the local production of TNF-alpha and VEGF, and epithelial MPO activity. The effects of NAC on apoptosis, the increases in the local production of TNF-alpha and VEGF, were weaker than the effects of erdosteine. This finding suggests that the effects of erdosteine at the administered dose on apoptosis regulation are stronger than that of NAC.}, }
@article {pmid17044076, year = {2007}, author = {Mackenzie, GG and Oteiza, PI}, title = {Zinc and the cytoskeleton in the neuronal modulation of transcription factor NFAT.}, journal = {Journal of cellular physiology}, volume = {210}, number = {1}, pages = {246-256}, doi = {10.1002/jcp.20861}, pmid = {17044076}, issn = {0021-9541}, support = {HD01743/HD/NICHD NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/drug effects ; Animals ; Antioxidants/pharmacology ; Calcineurin/metabolism ; Calcineurin Inhibitors ; Calcium/metabolism ; Cell Nucleus/drug effects/*metabolism ; Cell Survival/drug effects ; Cerebellum/cytology/drug effects/metabolism ; Chelating Agents/pharmacology ; Cyclosporine/pharmacology ; Cytoskeleton/*drug effects/metabolism ; DNA/metabolism ; Dose-Response Relationship, Drug ; Humans ; NFATC Transcription Factors/genetics/*metabolism ; Neurons/drug effects/*metabolism ; Oxidants/metabolism ; PC12 Cells ; Promoter Regions, Genetic/drug effects ; Rats ; Rats, Wistar ; Time Factors ; Transcriptional Activation/drug effects ; Transfection ; Tubulin Modulators/pharmacology ; Zinc/deficiency/*metabolism ; }, abstract = {Transcription factor NFAT is crucial in the development of the nervous system due to its role in neuronal plasticity and survival. In this study we characterized the role of zinc and the cytoskeleton in the modulation of NFAT in neuronal cells. The incubation of cells in zinc deficient media led to NFAT activation that was inhibited by the calcium chelator BAPTA and the antioxidants (+/-)-alpha-lipoic acid and N-acetyl cysteine, suggesting the involvement of calcium and oxidants in the initial steps of NFAT activation associated with zinc deficiency. At a second step of regulation, a decrease in cellular zinc led to an impaired transport of the active NFAT from the cytosol into the nucleus due to alterations in tubulin polymerization secondary to a decrease in neuronal zinc. Furthermore, disruption of the cytoskeleton structure by cold and chemical agents (colchicine (Col), vinblastine (VB), cytochalasin D (Cyt)) also inhibited NFAT transport into the nucleus. The altered nuclear transport caused a decrease in NFAT-dependent gene expression. This study demonstrates for the first time that zinc can modulate transcription factor NFAT in neuronal cells, and that microtubules are involved in NFAT nuclear translocation, crucial event in the regulation of NFAT transcriptional activity.}, }
@article {pmid17042662, year = {2006}, author = {Moore, NN and Lapsley, M and Norden, AG and Firth, JD and Gaunt, ME and Varty, K and Boyle, JR}, title = {Does N-acetylcysteine prevent contrast-induced nephropathy during endovascular AAA repair? A randomized controlled pilot study.}, journal = {Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists}, volume = {13}, number = {5}, pages = {660-666}, doi = {10.1583/06-1833.1}, pmid = {17042662}, issn = {1526-6028}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/blood/*chemically induced/*prevention &amp; control/urine ; Aged ; Aortic Aneurysm, Abdominal/blood/*surgery/urine ; Biomarkers/blood/urine ; Contrast Media/*adverse effects ; Creatinine/blood ; Free Radical Scavengers/*therapeutic use ; Humans ; Intraoperative Complications/blood/chemically induced/prevention &amp; control/urine ; Male ; Pilot Projects ; Prospective Studies ; Research Design ; Retinol-Binding Proteins/urine ; Serum Albumin/metabolism ; Stents ; Time Factors ; Treatment Failure ; *Vascular Surgical Procedures/instrumentation ; }, abstract = {PURPOSE: To examine if N-acetylcysteine (NAC) reduces the incidence of contrast nephropathy during endovascular abdominal aortic aneurysm repair (EVAR) as evidenced by changes in markers of renal function.<br><br>METHODS: Twenty consecutive men (mean age 72 years, range 65-79) undergoing EVAR were randomized to receive standard intravenous fluid hydration or standard fluid hydration and NAC (600 mg BID orally, 4 doses). Venous blood and urine were collected prior to the procedure and for 5 postoperative days and analyzed blindly for serum creatinine, urinary retinol-binding protein (RBP), and albumin/creatinine ratio (ACR).<br><br>RESULTS: There were no significant differences in baseline demographics between the groups. No patient developed acute renal failure. In both groups, urinary RBP rose significantly from baseline (median 15 microg/mmol to peak 699 microg/mmol in controls versus 17 to 648 microg/mmol in the treatment group, p<0.003). There were similar significant rises in ACR (p<0.02). There was, however, no significant difference in the postoperative RBP or ACR between the groups at any time point.<br><br>CONCLUSION: EVAR causes significant acute renal injury in most patients. This was not attenuated by N-acetylcysteine. The causes of renal injury are probably multifactorial, the long-term clinical significance of which is unclear.}, }
@article {pmid17041759, year = {2006}, author = {Fu, YC and Yin, SC and Chi, CS and Hwang, B and Hsu, SL}, title = {Norepinephrine induces apoptosis in neonatal rat endothelial cells via a ROS-dependent JNK activation pathway.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {11}, number = {11}, pages = {2053-2063}, doi = {10.1007/s10495-006-0192-8}, pmid = {17041759}, issn = {1360-8185}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Ascorbic Acid/pharmacology ; Down-Regulation ; Endothelial Cells/*cytology/metabolism ; Enzyme Activation ; Hydrogen Peroxide/metabolism ; JNK Mitogen-Activated Protein Kinases/*metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Myocardium/cytology ; NADPH Oxidases/metabolism ; Norepinephrine/pharmacology/*physiology ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Receptors, Adrenergic/metabolism ; Signal Transduction ; }, abstract = {Our previous study demonstrated that norepinephrine (NE) induces endothelial apoptosis mainly through down-regulation of Bcl-2 protein and activation of the beta-adrenergic and caspase-2 pathways. However, whether reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) are involved in this signal transduction remains unknown. Endothelial cells cultured from neonatal rat heart were treated with 100 microM NE. Proteins of MAPKs and Bcl-2 family were assayed by Western blotting. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling assay. ROS was analyzed with flow cytometry. Caspase activity was measured using specific fluorogenic substrates. Treatment with NE increased intracellular ROS level and extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 phosphorylation. Whereas the phosphorylated form of Akt was decreased. The NE-induced apoptosis was abrogated by SP600125 (a specific inhibitor of JNK). Antioxidants such as vitamin C and N-acetyl cysteine inhibited NE-induced ROS production, JNK phosphorylation, caspase activation and apoptosis. Exogenously added superoxide dismutase or catalase markedly diminished NE-induced ROS production and cell death. In conclusions, our study is the first report documenting that NE induces apoptosis in neonatal rat endothelial cells via a ROS-dependent JNK activation pathway. Antioxidants may be useful in the prevention and management of NE-mediated endothelial apoptosis during heart failure.}, }
@article {pmid17040102, year = {2006}, author = {Druckova, A and Marnett, LJ}, title = {Characterization of the amino acid adducts of the enedial derivative of teucrin A.}, journal = {Chemical research in toxicology}, volume = {19}, number = {10}, pages = {1330-1340}, doi = {10.1021/tx060143k}, pmid = {17040102}, issn = {0893-228X}, support = {CA87819/CA/NCI NIH HHS/United States ; }, mesh = {Amino Acids/*chemistry ; Chromatography, High Pressure Liquid ; Diterpenes/chemical synthesis/*chemistry ; Diterpenes, Clerodane ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Spiro Compounds/chemical synthesis/*chemistry ; }, abstract = {The toxicity of germander, a herb used to treat obesity, is attributed to cytochrome P450 activation of the furan ring of its major diterpenoid component (teucrin A) into a reactive metabolite capable of adducting proteins. 1,4-Enedials have been proposed to be the reactive products of metabolism, possibly arising from a rearrangement of putative epoxide intermediates. We synthesized the enedial derivative of teucrin A as well as the enedial derived from a model furan, 3-(4-methoxy-benzyloxymethyl)-furan, by dimethyldioxirane oxidation and characterized the products of their reactions with amino acids and peptides. The reactions of the model enedial, 2-(4-methoxy-benzyloxymethyl)-but-2-enedial, with N-acetyl lysine (NAL) afforded regioisomeric N-alkyl-3-pyrrolin-2-ones, differing in the substitution on the double bond of the heterocyclic ring. Novel products formed in the reactions of the model enedial with N-acetyl cysteine (NAC) and both NAC/NAL uncovered the existence of tautomerization between the enedial and a hydroxyenal, which was manifest by the loss of 4-methoxybenzylalcohol and the incorporation of a second molecule of NAC. The reactions of teucrin A-enedial with NAC and NAL afforded analogues of the products observed with the model enedial, and the existence of the tautomeric equilibrium resulted in epimerization of the proton (H12) adjacent to the former furan ring. This work further illuminates the complex chemical behavior of unsaturated dialdehydes as an important class of toxic metabolites and lays the foundation for studies of the protein targets of teucrin A-enedial.}, }
@article {pmid17034719, year = {2006}, author = {Wang, HT and Gao, JL and Tian, YX and Kan, Q}, title = {[Inhibition of N-acetyl-L-cysteine on expressions of matrix metalloproteinases increased by exposure to silicon dioxide in lung fibroblasts in rats].}, journal = {Zhonghua lao dong wei sheng zhi ye bing za zhi = Zhonghua laodong weisheng zhiyebing zazhi = Chinese journal of industrial hygiene and occupational diseases}, volume = {24}, number = {9}, pages = {514-517}, pmid = {17034719}, issn = {1001-9391}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cells, Cultured ; Fibroblasts/drug effects/*metabolism ; Gene Expression Regulation, Enzymologic/*drug effects ; Lung/cytology ; Male ; Matrix Metalloproteinase 2/*biosynthesis/genetics ; Matrix Metalloproteinase 9/*biosynthesis/genetics ; RNA, Messenger/genetics ; Random Allocation ; Rats ; Rats, Wistar ; Silicon Dioxide/*toxicity ; }, abstract = {OBJECTIVE: To explore the effect of N-acetyl L-cysteine (NAC) on expressions of matrix metalloproteinases-2, 9 (MMP-2, MMP-9) in lung fibroblasts of SiO(2) exposed rats.<br><br>METHODS: Seventy-five Wistar rats were divided randomly into three groups. The control group was administered with normal Saline. The model group and the interventional group were administered with SiO(2), and the interventional group was administered with NAC before SiO(2) was administered. Lung fibroblasts were isolated on day 1, 3, 7, 14, 28 after exposure to SiO(2). The expressions of MMP-2 and MMP-9 were evaluated by Immunocytochemistry and RT-PCR.<br><br>RESULTS: (1) The expressions of protein and mRNA of MMP-2 in the model group were higher than that in the control group on all days after exposure to SiO(2) (P < 0.01). The expression of protein of MMP-9 was higher than the control group on day 1, 3, 7, and mRNA was higher on day 1, 3 (P < 0.01). (2) The expression of protein of MMP-2 in the interventional group was lower than the model group on all days, higher than the control group on day 3, 7, 14, 28, and the expression of mRNA was higher than the control group, lower than the model group, on all days (P < 0.05 or P < 0.01). The expression of protein of MMP-9 in the interventional group was lower than the model group on day 1, 3, 7, but higher than the control group on day 3, 7, and mRNA was lower than the model group on days 1, 3, higher than the control group (P < 0.05).<br><br>CONCLUSION: NAC inhibits the expressions of MMP-2, MMP-9 in lung fibroblasts.}, }
@article {pmid17033604, year = {2006}, author = {Ege, T and Eskiocak, S and Edis, M and Duran, E}, title = {The role of N-acetylcysteine in lower extremity ischemia/reperfusions.}, journal = {The Journal of cardiovascular surgery}, volume = {47}, number = {5}, pages = {563-568}, pmid = {17033604}, issn = {0021-9509}, mesh = {Acetylcysteine/*therapeutic use ; Biomarkers/blood ; Blood Gas Analysis ; Catalase/blood ; Embolectomy ; Embolism/*complications/diagnostic imaging/surgery ; Female ; *Femoral Artery ; Free Radical Scavengers/*therapeutic use ; Humans ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/blood ; Middle Aged ; Reperfusion Injury/blood/etiology/*prevention &amp; control ; Spectrophotometry ; Thiobarbiturates/blood ; Treatment Outcome ; Ultrasonography, Doppler, Color ; }, abstract = {AIM: To evaluate the efficacy of N-acetyl cysteine (NAC) in lower extremity ischemia/reperfusion.<br><br>METHODS: A total of 23 patients who underwent surgical intervention due to acute femoral artery occlusion were assigned into 2 groups: control group (group 1, n=12); and NAC group (group 2, n=11). Patients in NAC group received NAC before reperfusion, and 8 and 16 h after reperfusion (3x300 mg), while patients in control group received only NaCl 0.9% (3x100 mL). Catalase, malondialdehyde (MDA) and thiol concentrations were determined in femoral vein samples collected at 6 different time points: before reperfusion (t1), and 30 min (t2), 2 h (t3), 6 h (t4), 12 h (t5) and 24 h (t6) after reperfusion. Alveolar-arterial oxygen gradient (A-aO2) was calculated in radial artery blood samples simultaneously collected at the same time points.<br><br>RESULTS: No significant differences between the two groups with regard to age (control group 61+/-13 and NAC group 64+/-11 years), gender (control group M/F: 7/5, NAC 6/5) and the average time from onset of symptoms (control group 9.6+/-3.5 h, and NAC group 10.2+/-3.1 h) were present. Catalase enzyme activity increased with reperfusion in both groups and there were no differences between the two groups. MDA levels did not change significantly with reperfusion in NAC group, whereas they were significantly higher in control group at t2 and t3 compared to NAC group (P<0.05). Thiol concentrations decreased with reperfusion in control group, and in NAC group increases that started with reperfusion returned back to baseline levels after 24 hours. Although the A-aO2 gradient increased in both groups with the beginning of reperfusion, the most prominent increase occurred in control group (P<0.05).<br><br>CONCLUSIONS: In control group, the significant increase in MDA levels and A-aO2 gradient in reperfusion phase were considered a sign of local and end organ injury. We did not observe these changes in NAC performed group thus showing the efficacy of NAC.}, }
@article {pmid17031475, year = {2007}, author = {Unahara, Y and Kojima-Yuasa, A and Higashida, M and Kennedy, DO and Murakami, A and Ohigashi, H and Matsui-Yuasa, I}, title = {Cellular thiol status-dependent inhibition of tumor cell growth via modulation of p27(kip1) translocation and retinoblastoma protein phosphorylation by 1'-acetoxychavicol acetate.}, journal = {Amino acids}, volume = {33}, number = {3}, pages = {469-476}, doi = {10.1007/s00726-006-0437-4}, pmid = {17031475}, issn = {1438-2199}, mesh = {Acetylcysteine/metabolism ; Animals ; Benzyl Alcohols ; Carcinoma, Ehrlich Tumor ; Cell Cycle/*physiology ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p27/*metabolism ; DNA/biosynthesis ; Glutathione/analogs &amp; derivatives/metabolism ; Humans ; Phosphorylation ; Plant Extracts/chemistry/metabolism ; Retinoblastoma Protein/*metabolism ; Sulfhydryl Compounds/chemistry/*metabolism ; Terpenes/chemistry/*metabolism ; }, abstract = {1'-Acetoxychavicol acetate (ACA) has been shown to inhibit tumor cell growth, but there is limited information on its effects on cell signaling and the cell cycle control pathway. In this study, we sought to determine how ACA alters cell cycle and its related control factors in its growth inhibitory effect in Ehrlich ascites tumor cells (EATC). ACA caused an accumulation of cells in the G1 phase and an inhibition of DNA synthesis, which were reversed by supplementation with N-acetylcysteine (NAC) or glutathione ethyl ester (GEE). Furthermore, ACA decreased hyperphosphorylated Rb levels and increased hypophosphorylated Rb levels. NAC and GEE also abolished the decease in Rb phosphorylation by ACA. As Rb phosphorylation is regulated by G1 cyclin dependent kinase and CDK inhibitor p27(kip1), which is an important regulator of the mammalian cell cycle, we estimated the amount of p27(kip1) levels by western blotting. Treatment with ACA had virtually no effect on the amount of p27(kip1) levels, but caused a decrease in phosphorylated p27(kip1) and an increase in unphosphorylated p27(kip1) as well as an increase in the nuclear localization of p27(kip1). These events were abolished in the presence of NAC or GEE. These results suggest that in EATC, cell growth inhibition elicited by ACA involves decreases in Rb and p27(kip1) phosphorylation and an increase in nuclear localization of p27(kip1), and these events are dependent on the cellular thiol status.}, }
@article {pmid17031004, year = {2006}, author = {Martin, H and Abadie, C and Heyd, B and Mantion, G and Richert, L and Berthelot, A}, title = {N-acetylcysteine partially reverses oxidative stress and apoptosis exacerbated by Mg-deficiency culturing conditions in primary cultures of rat and human hepatocytes.}, journal = {Journal of the American College of Nutrition}, volume = {25}, number = {5}, pages = {363-369}, doi = {10.1080/07315724.2006.10719547}, pmid = {17031004}, issn = {0731-5724}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Caspase 3/metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Hepatocytes/cytology/*physiology ; Humans ; Lipid Peroxidation/drug effects ; Magnesium/metabolism/*pharmacology ; Magnesium Deficiency/*physiopathology ; Oxidative Stress/*drug effects ; Rats ; }, abstract = {OBJECTIVE: The effects of magnesium (Mg) deficiency on the rate of oxidative stress and apoptosis in primary cultures of human hepatocytes were compared to cultured rat hepatocytes. The possible reversion by N-acetylcysteine (NAC) in Mg-deficient culturing conditions was evaluated.<br><br>METHODS: Incubations were conducted for up to 72 h in media containing a deficient (0-0.4 mM) or a physiological (0.8 mM) Mg concentration, and in the presence or absence of NAC after 24 h of culture in these Mg concentration conditions.<br><br>RESULTS: We obtained similar profiles in terms of apoptosis and oxidative stress in primary cultures of human hepatocytes, as compared to rat hepatocytes, i.e. a Mg concentration-dependent effect on the caspase-3 activity and GSH levels after 72 h of culture, caspase-3 activity being highest and GSH levels being lowest in Mg-free cultures. The addition of NAC to culture media after the first 24 h of culture increased GSH concentrations. This was accompanied in Mg-deficient cultures by a decrease in both the caspase-3 activity and the lipid peroxidation. However, when culturing hepatocytes with physiological Mg concentrations, an increase in both caspase-3 activity and lipid peroxidation was observed.<br><br>CONCLUSIONS: Our results indicate that Mg deficiency exacerbates the rate of apoptosis in cultured hepatocytes, associated with an increase in oxidative stress, the sensitivity of human hepatocytes being equivalent to that of rat hepatocytes. They also indicate a dual role of NAC and/or GSH, i.e. protective for hepatocytes placed in a Mg-deficient environment, while deleterious for hepatocytes placed in a Mg-physiological environment.}, }
@article {pmid17030433, year = {2006}, author = {Zhang, QG and Tian, H and Li, HC and Zhang, GY}, title = {Antioxidant N-acetylcysteine inhibits the activation of JNK3 mediated by the GluR6-PSD95-MLK3 signaling module during cerebral ischemia in rat hippocampus.}, journal = {Neuroscience letters}, volume = {408}, number = {3}, pages = {159-164}, doi = {10.1016/j.neulet.2006.07.007}, pmid = {17030433}, issn = {0304-3940}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Blotting, Western ; Brain Ischemia/drug therapy/*pathology ; Disease Models, Animal ; Disks Large Homolog 4 Protein ; Enzyme Activation/drug effects ; Gene Expression Regulation/drug effects ; Hippocampus/*drug effects ; Humans ; Immunoprecipitation/methods ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Kinase Kinases/metabolism ; Male ; Membrane Proteins/metabolism ; Mitogen-Activated Protein Kinase 10/*metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Kainic Acid/metabolism ; Signal Transduction/*drug effects ; Time Factors ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; GluK2 Kainate Receptor ; }, abstract = {Cerebral ischemia induces kainate receptor glutamate receptor 6 (GluR6) binding to the postsynaptic density protein 95 (PSD95), which in turn anchors mixed lineage kinase 3 (MLK3) via SH3 domain in rat brain. MLK3 subsequently activates c-Jun NH(2)-terminal kinase (JNK) via MAP kinase kinases (MKKs). In this study, we investigated the association of PSD95 with GluR6 and MLK3, the autophosphorylation of MLK3, the combination of MLK3 with JNK3, and the phosphorylation of JNK3 during cerebral ischemia in rat hippocampus CA1. Our results indicate that the GluR6-PSD95-MLK3 complex quickly enhanced at 5 min of ischemia and peaked at 10 min of ischemia, and then gradually reduced with the prolonged time of ischemia. Interestingly, the combination of MLK3 and JNK3 gradually increased from 5 min to 30 min of ischemia. JNK3 phosphorylation first increased and then attenuated in cytosol, suggesting the translocation of activated JNK3 to nucleus during ischemia. To further investigate the possible mechanism of JNK3 activation, antioxidant N-acetylcysteine (NAC) was given to the rats 20 min prior to ischemia. Results indicate that NAC distinctly inhibited the association of PSD95 with GluR6 and MLK3, the autophosphorylation of MLK3, the combination of MLK3 with JNK3 and JNK3 activation. Taken together, these finding indicate that ischemic stimulation results in JNK3 activation through the GluR6-PSD95-MLK3 signaling module, and that the activation of JNK3 is closely related to oxidative stress.}, }
@article {pmid17030102, year = {2006}, author = {Shen, C and Zhang, H and Zhang, G and Meng, Q}, title = {Isoniazid-induced hepatotoxicity in rat hepatocytes of gel entrapment culture.}, journal = {Toxicology letters}, volume = {167}, number = {1}, pages = {66-74}, doi = {10.1016/j.toxlet.2006.08.010}, pmid = {17030102}, issn = {0378-4274}, mesh = {Acetylcysteine/metabolism ; Animals ; Antidotes/pharmacology ; Antitubercular Agents/antagonists &amp; inhibitors/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/*pathology/prevention &amp; control ; Cytochrome P-450 CYP2E1/metabolism ; Ditiocarb/pharmacology ; Female ; Glutathione/metabolism ; Glycyrrhiza ; Glycyrrhizic Acid/pharmacology ; Hepatocytes/*drug effects ; Isoniazid/antagonists &amp; inhibitors/*toxicity ; Plant Extracts/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Serum Albumin/metabolism ; }, abstract = {Gel entrapment culture of rat hepatocytes in hollow fibers were evaluated as a potential in vitro model for studies on isoniazid-induced hepatotoxicity. After exposure to isoniazid (0.11 mM and 1.1 mM) for 24-96 h, gel entrapped hepatocytes were more severely damaged than hepatocyte monolayers according to the assays on methyl thiazolyl tetrazolium (MTT) reduction, intracellular glutathione (GSH) content, reactive oxygen species (ROS) levels, and albumin secretion. Furthermore, CYP 2E1 activity detected by 4-nitrocatechol (4-NC) formation maintained at least 7 days in gel entrapped hepatocytes but decreased to an undetectable level within 2 days in hepatocyte monolayer. And the addition of CYP 2E1 inhibitor, diethyl-dithiocarbamate (DDC), significantly reduced isoniazid-induced GSH depletion in gel entrapped hepatocytes. In addition, the protective effects of N-acetylcysteine (NAC), GSH, liquorice extract and glycyrrhizic acid (GA), a purified compound from liquorice extract, against isoniazid hepatotoxicity were clearly observed in gel entrapped hepatocytes at 72 h incubation. Overall, gel entrapped hepatocytes were more susceptible to isoniazid-induced hepatotoxicity than hepatocyte monolayers by a possible mechanism that higher CYP 2E1 activity in gel entrapped hepatocytes could enhance isoniazid toxicity. This indicates that gel entrapped hepatocytes in hollow fibers could be a more effective model than hepatocyte monolayer for hepatotoxicity research in vitro.}, }
@article {pmid17026986, year = {2006}, author = {Xia, Z and Liu, M and Wu, Y and Sharma, V and Luo, T and Ouyang, J and McNeill, JH}, title = {N-acetylcysteine attenuates TNF-alpha-induced human vascular endothelial cell apoptosis and restores eNOS expression.}, journal = {European journal of pharmacology}, volume = {550}, number = {1-3}, pages = {134-142}, doi = {10.1016/j.ejphar.2006.08.044}, pmid = {17026986}, issn = {0014-2999}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cells, Cultured ; Endothelial Cells/*drug effects/enzymology ; Endothelium, Vascular/*cytology/*drug effects/enzymology ; Flow Cytometry ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Humans ; In Situ Nick-End Labeling ; L-Lactate Dehydrogenase/metabolism ; Malondialdehyde/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/*biosynthesis ; Superoxide Dismutase/metabolism ; Tetrazolium Salts ; Thiazoles ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/*pharmacology ; }, abstract = {The circulatory inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is increased in pathological conditions, such as diabetes, which initiate or exacerbate vascular endothelial injury. Both nitric oxide (NO) and reactive oxygen species may play a dual role (i.e., inhibiting or promoting) in TNF-alpha-induced endothelial cell apoptosis. We investigated the effects of the antioxidant N-acetylcysteine on TNF-alpha-induced apoptosis in human vascular endothelial cell (cell line ECV304) apoptosis, NO production and lipid peroxidation. Cultured vascular endothelial cell (ECV304) were either not treated (control), or treated with TNF-alpha (40 ng/ml) alone or TNF-alpha in the presence of N-acetylcysteine at 30 mmol/l or 1 mmol/l, respectively, for 24 h. Cell viability was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Cell apoptosis was assessed by flow cytometry. TNF-alpha-induced endothelial cell apoptosis was associated with increased inducible NO synthase but reduced endothelial NO synthase (eNOS) protein expression. NO production and the levels of the lipid peroxidation product malondialdehyde were concomitantly increased. Treatment with NAC at 30 mmol/l restored eNOS expression and further increased NO production as compared to TNF-alpha alone, resulting in improved cell viability and reduced apoptosis. This was accompanied by increased superoxide dismutase activity, increased glutathione peroxidase production and reduced malondialdehyde levels. N-acetylcysteine at 1 mmol/l, however, did not have significant effects on TNF-alpha-induced endothelial cell apoptosis and cell viability despite it slightly enhanced glutathione peroxidase production. N-acetylcysteine attenuation of TNF-alpha-induced human vascular endothelial cell apoptosis is associated with the restoration of eNOS expression.}, }
@article {pmid17023529, year = {2007}, author = {Rachek, LI and Musiyenko, SI and LeDoux, SP and Wilson, GL}, title = {Palmitate induced mitochondrial deoxyribonucleic acid damage and apoptosis in l6 rat skeletal muscle cells.}, journal = {Endocrinology}, volume = {148}, number = {1}, pages = {293-299}, doi = {10.1210/en.2006-0998}, pmid = {17023529}, issn = {0013-7227}, support = {AG19602/AG/NIA NIH HHS/United States ; ES03456/ES/NIEHS NIH HHS/United States ; ES05865/ES/NIEHS NIH HHS/United States ; NS041208/NS/NINDS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Apoptosis/*drug effects/physiology ; Caspase 3/metabolism ; Cell Nucleus ; Cells, Cultured ; Cytochromes c/metabolism ; DNA Damage/physiology ; DNA Fragmentation/drug effects ; DNA, Mitochondrial/*metabolism ; Diabetes Mellitus, Type 2/*metabolism/pathology/physiopathology ; Free Radical Scavengers/pharmacology ; Mitochondria/drug effects/metabolism ; Muscle, Skeletal/*cytology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Oxidative Stress/*physiology ; Palmitates/*pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {A major characteristic of type 2 diabetes mellitus (T2DM) is insulin resistance in skeletal muscle. A growing body of evidence indicates that oxidative stress that results from increased production of reactive oxygen species and/or reactive nitrogen species leads to insulin resistance, tissue damage, and other complications observed in T2DM. It has been suggested that muscular free fatty acid accumulation might be responsible for the mitochondrial dysfunction and insulin resistance seen in T2DM, although the mechanisms by which increased levels of free fatty acid lead to insulin resistance are not well understood. To help resolve this situation, we report that saturated fatty acid palmitate stimulated the expression of inducible nitric oxide (NO) synthase and the production of reactive oxygen species and NO in L6 myotubes. Additionally, palmitate caused a significant dose-dependent increase in mitochondrial DNA (mtDNA) damage and a subsequent decrease in L6 myotube viability and ATP levels at concentrations as low as 0.5 mM. Furthermore, palmitate induced apoptosis, which was detected by DNA fragmentation, caspase-3 cleavage, and cytochrome c release. N-acetyl cysteine, a precursor compound for glutathione formation, aminoguanidine, an inducible NO synthase inhibitor, and 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III), a peroxynitrite inhibitor, all prevented palmitate-induced mtDNA damage and diminished palmitate-induced cytotoxicity. We conclude that exposure of L6 myotubes to palmitate induced mtDNA damage and triggered mitochondrial dysfunction, which caused apoptosis. Additionally, our findings indicate that palmitate-induced mtDNA damage and cytotoxicity in skeletal muscle cells were caused by overproduction of peroxynitrite.}, }
@article {pmid17023264, year = {2006}, author = {Sury, MD and Frese-Schaper, M and Mühlemann, MK and Schulthess, FT and Blasig, IE and Täuber, MG and Shaw, SG and Christen, S}, title = {Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase.}, journal = {Free radical biology &amp; medicine}, volume = {41}, number = {9}, pages = {1372-1383}, doi = {10.1016/j.freeradbiomed.2006.07.016}, pmid = {17023264}, issn = {0891-5849}, support = {R01 NS33997/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/cytology/*metabolism ; Cell Line ; Endothelin-1/genetics/*metabolism ; Endothelium, Vascular/cytology/*metabolism ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/*pharmacology ; MAP Kinase Signaling System/physiology ; NF-kappa B/metabolism ; Nitrates/metabolism ; Nitric Oxide Synthase Type II/metabolism ; Nitrites/metabolism ; Phosphorylation ; Protein Transport ; Rats ; Ribosomal Protein S6 Kinases, 90-kDa/*metabolism ; Tumor Necrosis Factor-alpha/*pharmacology ; Up-Regulation ; }, abstract = {N-acetylcysteine (NAC) is neuroprotective in animal models of acute brain injury such as caused by bacterial meningitis. However, the mechanism(s) by which NAC exerts neuroprotection is unclear. Gene expression of endothelin-1 (ET-1), which contributes to cerebral blood flow decline in acute brain injury, is partially regulated by reactive oxygen species, and thus a potential target of NAC. We therefore examined the effect of NAC on tumor necrosis factor (TNF)-alpha-induced ET-1 production in cerebrovascular endothelial cells. NAC dose dependently inhibited TNF-alpha-induced preproET-1 mRNA upregulation and ET-1 protein secretion, while upregulation of inducible nitric oxide synthase (iNOS) was unaffected. Intriguingly, NAC had no effect on the initial activation (i.e., IkappaB degradation, nuclear p65 translocation, and Ser536 phosphorylation) of NF-kappaB by TNF-alpha. However, transient inhibition of NF-kappaB DNA binding suggested that NAC may inhibit ET-1 upregulation by inhibiting (a) parallel pathway(s) necessary for full transcriptional activation of NF-kappaB-mediated ET-1 gene expression. Similar to NAC, the MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and the protein kinase inhibitor H-89 selectively inhibited ET-1 upregulation without affecting nuclear p65 translocation, suggesting that NAC inhibits ET-1 upregulation via inhibition of mitogen- and stress-activated protein kinase (MSK). Supporting this notion, cotreatment with NAC inhibited the TNF-alpha-induced rise in MSK1 and MSK2 kinase activity, while siRNA knock-down experiments showed that MSK2 is the predominant isoform involved in TNF-alpha-induced ET-1 upregulation.}, }
@article {pmid17021698, year = {2006}, author = {San-Miguel, B and Alvarez, M and Culebras, JM and González-Gallego, J and Tuñón, MJ}, title = {N-acetyl-cysteine protects liver from apoptotic death in an animal model of fulminant hepatic failure.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {11}, number = {11}, pages = {1945-1957}, doi = {10.1007/s10495-006-0090-0}, pmid = {17021698}, issn = {1360-8185}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Animals, Inbred Strains ; Antioxidants/metabolism/*pharmacology ; *Apoptosis ; Caliciviridae Infections/metabolism/pathology ; Disease Models, Animal ; Hemorrhagic Disease Virus, Rabbit/physiology ; Hepatocytes/*pathology/virology ; Liver/metabolism/*pathology/virology ; Liver Failure, Acute/*metabolism/pathology ; Oxidative Stress/*drug effects ; Rabbits ; }, abstract = {BACKGROUND: This work was undertaken to investigate whether treatment with N-acetyl-cysteine (NAC) prevents oxidative stress and inhibits the apoptotic pathways in an animal model of fulminant hepatic failure.<br><br>METHODS: Rabbits were experimentally infected with 2x10(4) hemagglutination units of a rabbit hemorrhagic disease virus isolate.<br><br>RESULTS: The spontaneous mortality rate of infected animals was 67% at 36 h post infection (pi) and 90% at 48 h pi. This percentage decreased significantly in animals receiving an i.p. injection of NAC (150 mg/kg body way/daily), for 7 days prior to infection. From 36 h pi marked increases were detected in blood levels of transaminases, lactate dehydrogenase, bilirubin and the oxidised/reduced glutathione ratio. All these effects were significantly prevented by NAC treatment. The Bax to Bcl-2 relative expression, the expression of FasL, cytochrome c and PARP-1, and the activity of caspase 3 were significantly increased at 36 and 48 h pi in infected animals. These changes were markedly reduced in animals treated with NAC, with the exception of FasL.<br><br>CONCLUSION: Our results suggest a potential hepatoprotective role of NAC in fulminant hepatic failure, mediated partially through the modulation of the intrinsic pathway of apoptosis.}, }
@article {pmid17017911, year = {2006}, author = {Schultz, MJ and Baas, MC and van der Sluijs, HP and Stamkot, GA and Smit, W}, title = {N-acetylcysteine and other preventive measures for contrast-induced nephropathy in the intensive care unit.}, journal = {Current medicinal chemistry}, volume = {13}, number = {21}, pages = {2565-2570}, doi = {10.2174/092986706778201684}, pmid = {17017911}, issn = {0929-8673}, mesh = {Acetylcysteine/*therapeutic use ; Contrast Media/*adverse effects ; Free Radical Scavengers/*therapeutic use ; Humans ; Intensive Care Units ; Kidney Diseases/*chemically induced/*prevention &amp; control ; }, abstract = {The increase in diagnostic imaging procedures that require infusion of intravenous radiographic contrast has led to a parallel increase in the incidence of contrast-induced nephropathy (CIN). Since CIN accounts for a significant increase of hospital-acquired renal failure, length of stay and mortality, several additive strategies to prevent CIN are presently advocated, including N-acetylcysteine (NAC), sodium bicarbonate, theophylline or fenoldopam, and peri-procedural hemofiltration/hemodialysis. As only one (non-randomized) study has been performed in the intensive care setting, at present it is hard to give firm recommendations on preventive measures for CIN in intensive care patients. Indeed, future studies are needed to determine the true role of the above-mentioned preventive measures in critically ill patients at risk for CIN. Since NAC has only few side-effects, we presently advise NAC as an additive preventive measure in the intensive care setting. Theophylline or sodium bicarbonate hydration are viable options, either in conjunction NAC or as alternatives.}, }
@article {pmid17015178, year = {2006}, author = {Pei, P and Horan, MP and Hille, R and Hemann, CF and Schwendeman, SP and Mallery, SR}, title = {Reduced nonprotein thiols inhibit activation and function of MMP-9: implications for chemoprevention.}, journal = {Free radical biology &amp; medicine}, volume = {41}, number = {8}, pages = {1315-1324}, pmid = {17015178}, issn = {0891-5849}, support = {R01 CA095901/CA/NCI NIH HHS/United States ; R01 CA095901-01A1/CA/NCI NIH HHS/United States ; R21 CA111210/CA/NCI NIH HHS/United States ; R01 CA95901/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Anticarcinogenic Agents/pharmacology ; Catalytic Domain ; Cell Line, Tumor ; Chemoprevention ; Enzyme Activation/drug effects ; Glutathione/*pharmacology ; Humans ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/chemistry ; *Matrix Metalloproteinase Inhibitors ; Models, Molecular ; Neoplasms/drug therapy/enzymology/prevention &amp; control ; Oxidation-Reduction ; Phenylmercuric Acetate/analogs &amp; derivatives/pharmacology ; Protein Conformation ; Zinc/metabolism ; }, abstract = {Clinical studies demonstrate a positive correlation between the extent of matrix metalloproteinase (MMP) activation and malignant progression of precancerous lesions. Therefore, identification of effective, well-tolerated MMP inhibitors represents a rational chemopreventive strategy. A variety of agents, including proteinases and thiol-oxidizing compounds, activate MMPs by initiating release of the propeptide's cysteine sulfur "blockage" of the MMP active site. Despite the importance of the propeptide's cysteine thiol in preserving MMP latency, limited studies have evaluated the effects of reduced thiols on MMP function. This study investigated the effects of two naturally occurring nonprotein thiols, i.e., glutathione (GSH) and N-acetylcysteine (NAC), on activation, function, and cellular-extracellular matrix interactions of the basement-membrane-degrading gelatinase, MMP-9. Our results reveal that NAC and GSH employ protein S-thiolation to inhibit organomercurial activation of pro-MMP-9. Gelatinase activity assays showed that GSH and NAC significantly inhibited MMP-9 but not MMP-2 function, implying isoform structural specificity. Immunoblot analyses, which suggested GSH interacts with MMP-9's active-site Zn, were corroborated by computational molecular modeling. Cell invasion assays revealed that NAC enhanced endostatin's ability to inhibit human cancer cell invasion. Collectively, these data demonstrate that nonprotein thiols suppress MMP-9 activation and function and introduce the prospect for their use in chemopreventive applications.}, }
@article {pmid17014914, year = {2006}, author = {Jung, MK and Song, HK and Kim, KE and Hur, DY and Kim, T and Bang, S and Park, H and Cho, DH}, title = {IL-18 enhances the migration ability of murine melanoma cells through the generation of ROI and the MAPK pathway.}, journal = {Immunology letters}, volume = {107}, number = {2}, pages = {125-130}, doi = {10.1016/j.imlet.2006.08.004}, pmid = {17014914}, issn = {0165-2478}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Cell Movement/drug effects ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; Interleukin-18/genetics/pharmacology/*physiology ; Melanoma, Experimental/immunology/*pathology ; Mice ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/analysis/antagonists &amp; inhibitors/*metabolism ; Transfection ; }, abstract = {Interleukin-18 (IL-18) has multiple effects on various cells that are involved in immune escape of murine melanoma cells and in the inflammatory responses. This study investigated the effect of IL-18 on the ability of murine melanoma cells to migrate by using B16F10 cells and the IL-18 antisense transfectants of B16F10 cells (the B16F10/IL-18 antisense transfectant). The B16F10 cells were more able to migrate than were the B16F10/IL-18 antisense transfectants. An exogenous IL-18 treatment improved the ability of the B16F10/IL-18 antisense transfectant cells to migrate, indicating that IL-18 enhanced the migration ability of melanoma cells. To determine the signaling mechanisms involved in IL-18-enhanced migration, we measured the ROI levels. It was found that the ROI levels were increased by IL-18, and an antioxidant, N-acetyl-l-cystein (NAC), blocked the effect of IL-18 on migration, suggesting the involvement of ROI in the signal transduction of IL-18-enhanced cell migration. IL-18-enhanced cell migration was also reduced by PD98059. In addition, the level of ERK1/2 phosphorylation was markedly increased by treating with exogenous IL-18 at 20 min. These results suggest that IL-18 enhances the ability of melanoma cells to migrate via the generation of ROI and the MAPK pathway.}, }
@article {pmid17010595, year = {2007}, author = {Nagata, K and Iwasaki, Y and Yamada, T and Yuba, T and Kono, K and Hosogi, S and Ohsugi, S and Kuwahara, H and Marunaka, Y}, title = {Overexpression of manganese superoxide dismutase by N-acetylcysteine in hyperoxic lung injury.}, journal = {Respiratory medicine}, volume = {101}, number = {4}, pages = {800-807}, doi = {10.1016/j.rmed.2006.07.017}, pmid = {17010595}, issn = {0954-6111}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Aerosols/administration &amp; dosage ; Animals ; Blotting, Western/methods ; Bronchoalveolar Lavage Fluid/chemistry ; Cell Count ; Free Radical Scavengers/*administration &amp; dosage ; Glutathione/analysis ; Hyperoxia/*enzymology ; Lipid Peroxidation/physiology ; Lung/metabolism/pathology ; Lung Diseases/*enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; RNA, Messenger/analysis ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Superoxide Dismutase/*analysis ; }, abstract = {BACKGROUND: Exposure of animals to hyperoxia causes lung injury, characterized by diffuse alveolar damage and exudation of plasma into the alveolar space. Reactive oxygen species (ROS) play an important role in the development of hyperoxic lung injury. Mitochondrial oxidative phosphorylation is one of the major sources of ROS. N-acetylcysteine (NAC) is a precursor of glutathione (GSH), which functions as an antioxidant by reducing hydrogen peroxide to water and alcohols. NAC has been shown to diminish lung injury in a large variety of animal models.<br><br>AIM: We elucidated the mechanism underlying the protective effects of NAC in hyperoxia-induced lung injury.<br><br>METHODS: Male BALB/c mice were exposed to 98% oxygen for 72 h. The mice inhaled NAC or saline twice a day from 72 h before oxygen exposure to the end of experiment.<br><br>RESULTS: Inhaled NAC increased the GSH level in lung homogenate. NAC also attenuated cellular infiltrations in both bronchoalveolar lavage fluid (BALF) and lung tissue. The total protein level in BALF and the level of 8-isoprostane, a marker of lipid peroxidation, in lung homogenate were decreased by inhalation of NAC. Inhaled NAC induced the overexpression of Mn superoxide dismutase (MnSOD) mRNA and protein, but did not alter the expressions of other antioxidant enzymes, including CuZnSOD, extracellular SOD, and glutathione peroxydase 1.<br><br>CONCLUSION: These findings suggest that the antioxidant properties of NAC in hyperoxic lung injury involve a decrease in mitochondrial ROS in association with the induction of MnSOD, in addition to its role as a precursor of GSH.}, }
@article {pmid17008589, year = {2006}, author = {Lin, FY and Chen, YH and Tasi, JS and Chen, JW and Yang, TL and Wang, HJ and Li, CY and Chen, YL and Lin, SJ}, title = {Endotoxin induces toll-like receptor 4 expression in vascular smooth muscle cells via NADPH oxidase activation and mitogen-activated protein kinase signaling pathways.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {26}, number = {12}, pages = {2630-2637}, doi = {10.1161/01.ATV.0000247259.01257.b3}, pmid = {17008589}, issn = {1524-4636}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Aorta/metabolism/pathology ; Atherosclerosis/genetics/metabolism/pathology ; Cells, Cultured ; Endotoxins/*pharmacology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/*drug effects/genetics ; Humans ; Inflammation/genetics/metabolism/physiopathology ; Lipopolysaccharides/pharmacology ; Mitogen-Activated Protein Kinase Kinases/genetics/*metabolism ; Muscle, Smooth, Vascular/drug effects/*metabolism/pathology ; NADPH Oxidases/genetics/*metabolism ; Onium Compounds/pharmacology ; RNA, Messenger/genetics/metabolism ; Rabbits ; Signal Transduction/*genetics ; Toll-Like Receptor 4/genetics/*metabolism ; }, abstract = {OBJECTIVE: Toll-like receptor 4 (TLR4) plays a major role mediating endotoxin-induced cellular inflammation and regulates vascular smooth muscle cell (VSMC) proliferation, which is related to atherogenesis and restenosis. This study was conducted to investigate the mechanisms involved in lipopolysaccharide (LPS)-induced TLR4 expression in VSMCs.<br><br>METHODS AND RESULTS: Stimulation of human aortic smooth muscle cells (HASMCs) with LPS significantly increased TLR4 expression. The increase was regulated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (including the activation of subunits p47(phox) and Rac1), which mediates the production of reactive oxygen species and the activation of intracellular mitogen-activated protein kinase signaling pathways. Treatment with polyethylene-glycol-conjugated superoxide dismutase, N-acetylcysteine (NAC), diphenylene iodonium (DPI), or apocynin significantly decreased LPS-induced TLR4 expression. An actinomycin D chase experiment showed that LPS increased the half-life of TLR4 mRNA. Inhibition of NADPH oxidase activity by DPI, apocynin, or NAC significantly decreased TLR4 mRNA stability, as did the knock-down of RAC1 gene expression by RNA interference. We also demonstrated in an animal model that LPS administration led to a significant elevation of balloon-injury-induced neointimal hyperplasia, and of TLR4 expression, in rabbit aorta.<br><br>CONCLUSIONS: These findings suggest that NADPH oxidase activation, mRNA stabilization, and MAPK signaling pathways play critical roles in LPS-enhanced TLR4 expression in HASMCs, which contributes to vascular inflammation and cardiovascular disorders.}, }
@article {pmid17005195, year = {2006}, author = {Timolati, F and Ott, D and Pentassuglia, L and Giraud, MN and Perriard, JC and Suter, TM and Zuppinger, C}, title = {Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes.}, journal = {Journal of molecular and cellular cardiology}, volume = {41}, number = {5}, pages = {845-854}, doi = {10.1016/j.yjmcc.2006.08.002}, pmid = {17005195}, issn = {0022-2828}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/pharmacology ; Calcium/metabolism ; Doxorubicin/antagonists &amp; inhibitors/*pharmacology ; Hydrogen Peroxide/pharmacology ; Male ; Myocardial Contraction/*drug effects ; Myocytes, Cardiac/*drug effects/physiology ; Neuregulin-1/*pharmacology ; *Oxidative Stress ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Wistar ; Receptor, ErbB-2/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; Signal Transduction ; Ventricular Function ; }, abstract = {Treatment of metastatic breast cancer with doxorubicin (Doxo) in combination with trastuzumab, an antibody targeting the ErbB2 receptor, results in an increased incidence of heart failure. Doxo therapy induces reactive oxygen species (ROS) and alterations of calcium homeostasis. Therefore, we hypothesized that neuregulin-1 beta (NRG), a ligand of the cardiac ErbB receptors, reduces Doxo-induced alterations of EC coupling by triggering antioxidant mechanisms. Adult rat ventricular cardiomyocytes (ARVM) were isolated and treated for 18-48 h. SERCA protein was analyzed by Western blot, EC coupling parameters by fura-2 and video edge detection, gene expression by RT-PCR, and ROS by DCF-fluorescence microscopy. At clinically relevant doses Doxo reduced cardiomyocytes contractility, SERCA protein and SR calcium content. NRG, similarly as the antioxidant N-acetylcystein (NAC), did not affect EC coupling alone, but protected against Doxo-induced damage. NRG and Doxo showed an opposite modulation of glutathione reductase gene expression. NRG, similarly as NAC, reduced peroxide- or Doxo-induced oxidative stress. Specific inhibitors showed, that the antioxidant action of NRG depended on signaling via the ErbB2 receptor and on the Akt- and not on the MAPK-pathway. Therefore, NRG attenuates Doxo-induced alterations of EC coupling and reduces oxidative stress in ARVM. Inhibition of the ErbB2/NRG signaling pathway by trastuzumab in patients concomitantly treated with Doxo might prevent beneficial effects of NRG in the myocardium.}, }
@article {pmid17003133, year = {2006}, author = {Perl, A and Qian, Y and Chohan, KR and Shirley, CR and Amidon, W and Banerjee, S and Middleton, FA and Conkrite, KL and Barcza, M and Gonchoroff, N and Suarez, SS and Banki, K}, title = {Transaldolase is essential for maintenance of the mitochondrial transmembrane potential and fertility of spermatozoa.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {103}, number = {40}, pages = {14813-14818}, pmid = {17003133}, issn = {0027-8424}, support = {R01 DK049221/DK/NIDDK NIH HHS/United States ; R01 DK 49221/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Calcium Signaling/physiology ; Epididymis/enzymology/ultrastructure ; Fertility/*physiology ; Gene Expression ; Gene Silencing ; Heterozygote ; Homozygote ; Infertility, Male ; Male ; Membrane Potentials/physiology ; Mice ; Mice, Knockout ; Mitochondria/pathology/ultrastructure ; Mitochondrial Membranes/*enzymology ; Molecular Sequence Data ; NAD/metabolism ; Reactive Oxygen Species/metabolism ; Recombination, Genetic ; Sperm Motility/physiology ; Spermatozoa/cytology/*enzymology/*physiology/ultrastructure ; Sugar Phosphates/metabolism ; Transaldolase/deficiency/*metabolism ; }, abstract = {Fertility of spermatozoa depends on maintenance of the mitochondrial transmembrane potential (Deltapsi(m)), which is generated by the electron-transport chain and regulated by an oxidation-reduction equilibrium of reactive oxygen intermediates, pyridine nucleotides, and glutathione (GSH). Here, we report that male mice lacking transaldolase (TAL)(-/-) are sterile because of defective forward motility. TAL(-/-) spermatozoa show loss of Deltapsi(m) and mitochondrial membrane integrity because of diminished NADPH, NADH, and GSH. Mitochondria constitute major Ca(2+) stores; thus, diminished mitochondrial mass accounts for reduced Ca(2+) fluxing, defective forward motility, and infertility. Reduced forward progression of TAL-deficient spermatozoa is associated with diminished mitochondrial reactive oxygen intermediate production and Ca(2+) levels, intracellular acidosis, and compensatory down-regulation of carbonic anhydrase IV and overexpression of CD38 and gamma-glutamyl transferase. Microarray analyses of gene expression in the testis, caput, and cauda epididymidis of TAL(+/+), TAL(+/-), and TAL(-/-) littermates confirmed a dominant impact of TAL deficiency on late stages of sperm-cell development, affecting the electron-transport chain and GSH metabolism. Stimulation of de novo GSH synthesis by oral N-acetyl-cysteine normalized the low fertility rate of TAL(+/-) males without affecting the sterility of TAL(-/-) males. Whereas TAL(-/-) sperm failed to fertilize TAL(+/+) oocytes in vitro, sterility of TAL(-/-) sperm was circumvented by intracytoplasmic sperm injection, indicating that TAL deficiency influenced the structure and function of mitochondria without compromising the nucleus and DNA integrity. Collectively, these data reveal an essential role of TAL in sperm-cell mitochondrial function and, thus, male fertility.}, }
@article {pmid17002920, year = {2006}, author = {Datta, PK and Lianos, EA}, title = {Nitric oxide induces metallothionein-I gene expression in mesangial cells.}, journal = {Translational research : the journal of laboratory and clinical medicine}, volume = {148}, number = {4}, pages = {180-187}, doi = {10.1016/j.trsl.2006.04.002}, pmid = {17002920}, issn = {1931-5244}, support = {R01 DK51357/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Dose-Response Relationship, Drug ; Fluorescent Antibody Technique, Indirect ; Gene Expression Regulation, Enzymologic/*drug effects ; Glomerular Mesangium/cytology/drug effects/*metabolism ; Metallothionein/biosynthesis/*genetics ; Nitric Oxide/*metabolism ; Nitric Oxide Donors/*pharmacology ; Nitroprusside/pharmacology ; Oxidative Stress/drug effects/physiology ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; S-Nitroso-N-Acetylpenicillamine/pharmacology ; Up-Regulation/drug effects/*genetics ; }, abstract = {In various forms of injury involving the renal glomerulus, mesangial cells are exposed to potentially toxic concentrations of nitric oxide (NO) caused by activation of the inducible isoform of nitric oxide synthase (NOS). Whether mesangial cells possess systems that can defend against NO mediated oxidative injury is unknown. One putative system is Metallothionein (MT). Metallothioneins constitute a family of cysteine proteins and play a significant role as anti-oxidants. The authors assessed whether NO upregulates MT-I expression in cultured glomerular mesangial cells. Northern blot analysis revealed that steady state MT-I mRNA levels were increased by three different NO donors: sodium nitroprusside (SNP), S-nitroso-N-acetyl-DL-penicillamine (SNAP), and Spermine-NONOate (Sper/NO). The increase in MT-I mRNA levels induced by SNAP-derived NO was attenuated by the antioxidant N-acetylcysteine (NAC), a glutathione (GSH) precursor, which indicates that the mechanism of NO-mediated MT-I expression may involve an oxidative stress response. These observations identify MT-I as a putative antioxidant system in NO-mediated mesangial cell injury.}, }
@article {pmid17002883, year = {2006}, author = {Park, LJ and Ju, SM and Song, HY and Lee, JA and Yang, MY and Kang, YH and Kwon, HJ and Kim, TY and Choi, SY and Park, J}, title = {The enhanced monocyte adhesiveness after UVB exposure requires ROS and NF-kappaB signaling in human keratinocyte.}, journal = {Journal of biochemistry and molecular biology}, volume = {39}, number = {5}, pages = {618-625}, doi = {10.5483/bmbrep.2006.39.5.618}, pmid = {17002883}, issn = {1225-8687}, mesh = {Cell Adhesion/radiation effects ; Cell Line, Tumor ; Gene Expression/*radiation effects ; Humans ; Inflammation ; Intercellular Adhesion Molecule-1/genetics/metabolism ; Keratinocytes/immunology/metabolism/*physiology ; Monocytes/immunology/*physiology ; NF-kappa B/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Skin/immunology ; T-Lymphocytes/physiology ; *Ultraviolet Rays ; }, abstract = {The infiltration of both monocyte and activated T cells in the skin is one of critical steps in the development of UVB-induced inflammation. Upregulation of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) on the surface of keratinocytes plays an important role in this process. In this study, we examined the molecular mechanism responsible for UVB-induced expression of ICAM-1 and subsequent monocyte adhesion by keratinocyte. We observed that (1) UVB induced protein and mRNA expression of ICAM-1 in a dose- and time-dependent manner in human keratinocyte cell HaCaT; (2) UVB induced the translocation of NF-kappaB and inhibition of NF-kappaB by NF-kappaB inhibitors suppressed UVB-induced mRNA and protein expression of ICAM-1; (3) UVB increased the intracellular level of reactive oxygen species (ROS) by HaCaT cells; (4) UVB-induced increase of intracellular ROS level was suppressed by pretreatment with diphenyl iodonium (DPI) and N-acetyl cysteine (NAC); and (5) inhibition of UVB-induced ROS production by DPI or NAC suppressed UVB-mediated translocation of NF-kappaB, expression of ICAM-1 and subsequent monocyte adhesion in HaCaT cells. These results suggest that UVB-induced ROS is involved in the translocation of NF-kappaB which is responsible for expression of ICAM-1 and subsequent increased monocyte adhesion in human keratinocyte.}, }
@article {pmid17000131, year = {2006}, author = {Onaran, I and Guven, GS and Ozdaş, SB and Kanigur, G and Vehid, S}, title = {Metformin does not prevent DNA damage in lymphocytes despite its antioxidant properties against cumene hydroperoxide-induced oxidative stress.}, journal = {Mutation research}, volume = {611}, number = {1-2}, pages = {1-8}, doi = {10.1016/j.mrgentox.2006.06.036}, pmid = {17000131}, issn = {0027-5107}, mesh = {Acetylcysteine/pharmacology ; Adult ; Aged ; Aged, 80 and over ; Antioxidants/*pharmacology ; Benzene Derivatives/pharmacology ; Cells, Cultured ; Comet Assay ; DNA Damage/*drug effects ; DNA Fragmentation/drug effects ; Female ; Humans ; Hypoglycemic Agents/pharmacology ; Lipid Peroxidation/drug effects ; Lymphocytes/*drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Metformin/*pharmacology ; Oxidative Stress/*drug effects ; }, abstract = {Metformin (1-(diaminomethylidene)-3,3-dimethyl-guanidine), which is the most commonly prescribed oral antihyperglycaemic drug in the world, was reported to have several antioxidant properties such as the inhibition of advanced glycation end-products. In addition to its use in the treatment of diabetes, it has been suggested that metformin may be a promising anti-aging agent. The present work was aimed at assessing the possible protective effects of metformin against DNA-damage induction by oxidative stress in vitro. The effects of metformin were compared with those of N-acetylcysteine (NAC). For this purpose, peripheral blood lymphocytes from aged (n=10) and young (n=10) individuals were pre-incubated with various concentrations of metformin (10-50microM), followed by incubation with 15microM cumene hydroperoxide (CumOOH) for 48h, under conditions of low oxidant level, which do not induce cell death. Protection against oxidative DNA damage was evaluated by use of the Comet assay and the cytokinesis-block micronucleus technique. Changes in the levels of malondialdehyde+4-hydroxy-alkenals, an index of oxidative stress, were also measured in lymphocytes. At concentrations ranging from 10microM to 50microM, metformin did not protect the lymphocytes from DNA damage, while 50microM NAC possessed an effective protective effect against CumOOH-induced DNA damage. Furthermore, NAC, but not metformin, inhibited DNA fragmentation induced by CumOOH. In contrast to the lack of protection against oxidative damage in lymphocyte cultures, metformin significantly protected the cells from lipid peroxidation in both age groups, although not as effective as NAC in preventing the peroxidative damage at the highest doses. Within the limitations of this study, the results indicate that pharmacological concentrations of metformin are unable to protect against DNA damage induced by a pro-oxidant stimulus in cultured human lymphocytes, despite its antioxidant properties.}, }
@article {pmid16998124, year = {2006}, author = {Schweikl, H and Spagnuolo, G and Schmalz, G}, title = {Genetic and cellular toxicology of dental resin monomers.}, journal = {Journal of dental research}, volume = {85}, number = {10}, pages = {870-877}, doi = {10.1177/154405910608501001}, pmid = {16998124}, issn = {0022-0345}, mesh = {Animals ; Apoptosis/drug effects ; Biological Availability ; Cell Cycle/drug effects ; Cell Line ; *Chromosome Breakage ; Composite Resins/pharmacokinetics/*toxicity ; Humans ; Mammals ; Micronuclei, Chromosome-Defective/*chemically induced ; Mutation/drug effects ; Oxidative Stress/*drug effects ; Polyethylene Glycols/pharmacokinetics/*toxicity ; Polymethacrylic Acids/pharmacokinetics/*toxicity ; Signal Transduction/drug effects ; }, abstract = {Monomers are released from dental resin materials, and thus cause adverse biological effects in mammalian cells. Cytotoxicity and genotoxicity of some of these methacrylates have been identified in a vast number of investigations during the last decade. It has been well-established that the co-monomer triethylene glycol dimethacrylate (TEGDMA) causes gene mutations in vitro. The formation of micronuclei is indicative of chromosomal damage and the induction of DNA strand breaks detected with monomers like TEGDMA and 2-hydroxyethyl methacrylate (HEMA). As a consequence of DNA damage, the mammalian cell cycle was delayed in both G1 and G2/M phases, depending on the concentrations of the monomers. Yet, the mechanisms underlying the genetic and cellular toxicology of resin monomers have remained obscure until recently. New findings indicate that increased oxidative stress results in an impairment of the cellular pro- and anti-oxidant redox balance caused by monomers. It has been demonstrated that monomers reduced the levels of the natural radical scavenger glutathione (GSH), which protects cell structures from damage caused by reactive oxygen species (ROS). Depletion of the intracellular GSH pool may then significantly contribute to cytotoxicity, because a related increase in ROS levels can activate pathways leading to apoptosis. Complementary, cytotoxic, and genotoxic effects of TEGDMA and HEMA are inhibited in the presence of ROS scavengers like N-acetylcysteine (NAC), ascorbate, and Trolox (vitamin E). Elevated intracellular levels of ROS can also activate a complex network of redox-responsive macromolecules, including redox-sensitive transcription factors like nuclear factor kappaB (NF-kappaB). It has been shown that NF-kappaB is activated probably to counteract HEMA-induced apoptosis. The induction of apoptosis by TEGDMA in human pulp cells has been associated with an inhibition of the phosphatidylinositol 3-kinase (PI3-K) cell-survival signaling pathway. Although the details of the mechanisms leading to cell death, genotoxicity, and cell-cycle delay are not completely understood, resin monomers may be able to alter the functions of the cells of the oral cavity. Pathways regulating cellular homeostasis, dentinogenesis, or tissue repair may be modified by monomers at concentrations well below those which cause acute cytotoxicity.}, }
@article {pmid16996755, year = {2007}, author = {Machiavelli, LI and Poliandri, AH and Quinteros, FA and Cabilla, JP and Duvilanski, BH}, title = {Reactive oxygen species are key mediators of the nitric oxide apoptotic pathway in anterior pituitary cells.}, journal = {Nitric oxide : biology and chemistry}, volume = {16}, number = {2}, pages = {237-246}, doi = {10.1016/j.niox.2006.08.002}, pmid = {16996755}, issn = {1089-8603}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/*physiology ; Caspase 3/metabolism ; Enzyme Activation ; Female ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Membrane Potentials ; Mitochondria/physiology ; Nitric Oxide/*physiology ; Pituitary Gland, Anterior/cytology/enzymology/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; }, abstract = {We previously showed that long-term exposure of anterior pituitary cells to nitric oxide (NO) induces apoptosis. The intracellular signals underlying this effect remained unclear. In this study, we searched for possible mechanisms involved in the early stages of the NO apoptotic cascade. Caspase 3 was activated by NO with no apparent disruption of mitochondrial membrane potential. NO caused a rapid increase of reactive oxygen species (ROS), and this increase seems to be dependent of mitochondrial electron transport chain. The antioxidant N-acetyl-cysteine avoided ROS increase, prevented the NO-induced caspase 3 activation, and reduced the NO apoptotic effect. Catalase was inactivated by NO, while glutathione peroxidase (GPx) activity and reduced glutathione (GSH) were not modified at first, but increased at later times of NO exposure. The increase of GSH level is important for the scavenging of the NO-induced ROS overproduction. Our results indicate that ROS have an essential role as a trigger of the NO apoptotic cascade in anterior pituitary cells. The permanent inhibition of catalase may strengthen the oxidative damage induced by NO. GPx activity and GSH level augment in response to the oxidative damage, though this increase seems not to be enough to rescue the cells from the NO effect.}, }
@article {pmid16996296, year = {2006}, author = {Zegura, B and Lah, TT and Filipic, M}, title = {Alteration of intracellular GSH levels and its role in microcystin-LR-induced DNA damage in human hepatoma HepG2 cells.}, journal = {Mutation research}, volume = {611}, number = {1-2}, pages = {25-33}, doi = {10.1016/j.mrgentox.2006.06.038}, pmid = {16996296}, issn = {0027-5107}, mesh = {Carcinoma, Hepatocellular/genetics/metabolism/pathology ; Cell Line, Tumor ; Comet Assay ; *DNA Damage ; DNA, Neoplasm/drug effects/genetics ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Glutamate-Cysteine Ligase/genetics ; Glutathione/*metabolism/physiology ; Glutathione Reductase/metabolism ; Humans ; Intracellular Fluid/drug effects/metabolism ; Liver Neoplasms/genetics/metabolism/pathology ; Marine Toxins ; Microcystins/*pharmacology ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Microcystin-LR (MCLR) is a liver-specific toxin known as a tumour promoter in experimental animals. Its mechanisms of hepatotoxicity have been well documented; however, the mechanisms of other effects, in particular those related to its genotoxicity, are not well understood. In our previous studies, we showed that MCLR-induced DNA strand breaks are transiently present and that the damage is mediated by reactive oxygen species (ROS). In this study, we show that exposure of HepG2 cells to non-cytotoxic doses of MCLR-induced time-dependent alterations in the level of intracellular reduced glutathione (GSH). These comprised a rapid initial decrease followed by a gradual increase, reaching a maximum after 6h of exposure, before returning to the control level after 8h. During the first 4h, expression of glutamate-cysteine ligase (GCL), the rate-limiting enzyme of GSH synthesis, increased, indicating an increased rate of de novo synthesis of GSH. The most important observation of this study, combined with the results of our previous studies is the correlation between the time course of alterations of intracellular GSH content and the formation and disappearance of MCLR-induced DNA damage. When the intracellular GSH level was reduced, MCLR-induced DNA damage was observed to increase. Later, when the level of intracellular GSH was normal or elevated, new DNA damage was not induced and existing damage was repaired. To confirm the role of GSH system in MCLR-induced genotoxicity, the intracellular GSH level was moderated by pre-treatment with buthionine-(S,R)-sulfoximine (BSO), a specific GSH synthesis inhibitor, and with N-acetylcysteine (NAC), a GSH precursor. Pre-treatment with BSO dramatically increased the susceptibility of HepG2 cells to MCLR-induced DNA damage, while pre-treatment with NAC almost completely prevented MCLR-induced DNA damage. Thus, intracellular GSH is shown to play a critical role in the cellular defence against MCLR-induced DNA damage in HepG2 cells.}, }
@article {pmid16990553, year = {2006}, author = {Kappert, K and Sparwel, J and Sandin, A and Seiler, A and Siebolts, U and Leppänen, O and Rosenkranz, S and Ostman, A}, title = {Antioxidants relieve phosphatase inhibition and reduce PDGF signaling in cultured VSMCs and in restenosis.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {26}, number = {12}, pages = {2644-2651}, doi = {10.1161/01.ATV.0000246777.30819.85}, pmid = {16990553}, issn = {1524-4636}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Movement/drug effects/physiology ; Cell Proliferation/drug effects ; Cells, Cultured ; Coronary Restenosis/genetics/*metabolism ; Cyclic N-Oxides/pharmacology ; Gene Expression Regulation/drug effects/genetics/physiology ; Gene Expression Regulation, Enzymologic/drug effects/genetics/physiology ; Hydrogen Peroxide/pharmacology ; Male ; Muscle, Smooth, Vascular/cytology/drug effects/*metabolism ; Platelet-Derived Growth Factor/genetics/*metabolism ; Protein Tyrosine Phosphatases/genetics/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Receptors, Platelet-Derived Growth Factor/genetics/metabolism ; Signal Transduction/*drug effects/genetics/physiology ; Spin Labels ; }, abstract = {OBJECTIVE: Growth factor- and reactive oxygen species (ROS)-induced activation of VSMCs is involved in vascular disease. This study investigates whether inhibitory oxidation of protein tyrosine phosphatases (PTPs) contributes to signaling in VSMCs in vitro and in vivo, and analyzes whether ROS- and growth factor-dependent vascular smooth muscle cell (VSMC) signaling is blunted by antioxidants that are able to activate oxidized PTPs.<br><br>METHODS AND RESULTS: Signaling induced by H2O2 and platelet-derived growth factor (PDGF) was analyzed in VSMCs with or without the antioxidants N-acetyl-cysteine (NAC) and tempol. Effects of antioxidants on PDGF-stimulated chemotaxis and proliferation were determined. In vivo effects of antioxidants were analyzed in the rat carotid balloon-injury model, by analyzing neointima formation, cell proliferation, PDGF beta-receptor status, and PTP expression and activity. NAC treatment prevented H2O2-induced PTP inhibition, and reduced H2O2- and ligand-induced PDGF beta-receptor phosphorylation, PDGF-induced proliferation, and chemotaxis of VSMCs. Antioxidants inhibited neointima formation and reduced PDGF receptor phosphorylation in the neointima and also increased PTP activity.<br><br>CONCLUSIONS: PTP-inhibition was identified as an intrinsic component of H2O2- and PDGF-induced signaling in cultured VSMCs. The reduction in PDGF beta-receptor phosphorylation in vivo, and the increase in PTP activity, by antioxidants indicate activation of oxidized PTPs as a previously unrecognized mechanism for the antirestenotic effects of antioxidants. The findings thus suggest, in general terms, reactivation of oxidized PTPs as a novel antirestenotic strategy.}, }
@article {pmid16989920, year = {2006}, author = {Matsuyama, T and Morita, T and Horikiri, Y and Yamahara, H and Yoshino, H}, title = {Improved nasal absorption of salmon calcitonin by powdery formulation with N-acetyl-L-cysteine as a mucolytic agent.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {115}, number = {2}, pages = {183-188}, doi = {10.1016/j.jconrel.2006.08.004}, pmid = {16989920}, issn = {0168-3659}, mesh = {Absorption ; Acetylcysteine/*administration &amp; dosage/*pharmacokinetics ; Administration, Inhalation ; Animals ; Area Under Curve ; Biological Availability ; Calcitonin/*administration &amp; dosage/*pharmacokinetics ; Cellulose/analogs &amp; derivatives ; Chemistry, Pharmaceutical ; Data Interpretation, Statistical ; Dogs ; Expectorants/*administration &amp; dosage/*pharmacokinetics ; Eye Diseases/chemically induced ; Irritants ; Male ; Nasal Mucosa/*metabolism ; Powders ; Rabbits ; Rats ; Rats, Wistar ; }, abstract = {To establish a new formulation technology for the nasal delivery of peptide and protein drugs, we examined whether a mucolytic agent, N-acetyl-L-cysteine (NAC), could enhance the nasal absorption of a powder form of salmon calcitonin, a model peptide drug. We used ethylcellulose as an inert water-insoluble excipient. Various test formulations were prepared, and the effects on nasal absorbability were evaluated in rats and dogs. The powder formulation with NAC gave significant nasal absorption of SCT in both animal models, with absolute bioavailabilities of 30.0% in rats and 24.9% in dogs. Also, nasal administration of this formulation gave a quicker absorption rate than subcutaneous administration of SCT. NAC may reduce nasal fluid viscocity and improve accessibility of the drug to the epithelial membrane. The powder SCT/NAC/ethylcellulose formulation did not induce irritation or histological damage to the nasal membrane in rabbits. These results suggest that this formulation technology may be widely applicable for the nasal delivery of peptide or protein drugs.}, }
@article {pmid16984740, year = {2006}, author = {Li, L and Xu, J and Min, T and Huang, W}, title = {Up-regulation of P-glycoprotein expression by catalase via JNK activation in HepG2 cells.}, journal = {Redox report : communications in free radical research}, volume = {11}, number = {4}, pages = {173-178}, doi = {10.1179/135100006X116682}, pmid = {16984740}, issn = {1743-2928}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics/*metabolism ; Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Biological Transport/drug effects ; Blotting, Western ; Catalase/*pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Gene Expression/*drug effects ; Humans ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Rhodamines/metabolism/pharmacokinetics ; Time Factors ; Up-Regulation/drug effects ; }, abstract = {Overexpression of the MDR1 gene is one of the reasons for multidrug resistance (MDR). Some studies suggested that antioxidants could down-regulate MDR1 expression as a possible cancer treatment. In this report, we try to determine the effects of antioxidants (catalase or N-acetylcysteine [NAC]) on the regulation of intrinsic MDR1 overexpression in HepG2 cells. Adding catalase or N-acetylcysteine to the HepG2 culture led to a significant increase of MDR1 mRNA and P-glycoprotein drug transporter activity. After catalase or NAC treatment, a reduced intracellular reactive oxygen species (ROS) was observed. The JNK inhibitor SP600125 abolished the positive effects of catalase on drug transporter activity in a dose-dependent manner. Furthermore, the up-regulation of P-glycoprotein functions by catalase was only observed in HepG2 cells but not in other cell lines tested (MCF-7, A549, A431). These data suggested that catalase can up-regulate P-glycoprotein expression in HepG2 cells via reducing intracellular ROS, and JNK may mediate this process.}, }
@article {pmid16983658, year = {2006}, author = {Lin, CH and Kuo, SC and Huang, LJ and Gean, PW}, title = {Neuroprotective effect of N-acetylcysteine on neuronal apoptosis induced by a synthetic gingerdione compound: involvement of ERK and p38 phosphorylation.}, journal = {Journal of neuroscience research}, volume = {84}, number = {7}, pages = {1485-1494}, doi = {10.1002/jnr.21047}, pmid = {16983658}, issn = {0360-4012}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Apoptosis/*drug effects ; Blotting, Western/methods ; Cell Count/methods ; Cells, Cultured ; Cerebral Cortex/cytology ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Guaiacol/*analogs &amp; derivatives/pharmacology ; In Situ Nick-End Labeling ; Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Tetrazolium Salts ; Thiazoles ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Besides being used as a spice, ginger has been applied in oriental medicine to ameliorate symptoms such as inflammatory, rheumatic disorders, and gastrointestinal discomforts. The effects of ginger on neuronal cells, however, have not been explored. We investigate the effect of 1-(3,4-dimethoxyphenyl)-3,5-dodecenedione (I(6)), a derivative of gingerdione, on cultured cortical neurons. After a 5-day maturation period in vitro, cortical neurons were treated with I(6) for 24 hr and cell viability was assessed using MTT assay. I(6) induced neuronal death in a concentration-dependent manner. Hoechst 33342, propidium iodide (PI), and TUNEL staining confirmed that the reduced cell viability by I(6) was due to apoptosis. Pre-treatment of cell with N-acetylcysteine (NAC) prevented cell death in a concentration-dependent manner. N-acetylcysteine increased phosphorylated levels of p42 and p44 extracellular signal-regulated kinases (ERKs). In parallel, farnesyltransferase and MEK inhibitors blocked ERK phosphorylation and neuroprotective effect of NAC. Unexpectedly, NAC also increased phosphorylated level of p38 mitogen-activated protein kinase (MAPK) and p38 specific inhibitors dose-dependently attenuated the effect of NAC. Farnesyltransferase and MEK inhibitors completely abolished NAC-induced p38 phosphorylation whereas p38 inhibitor did not influence NAC-induced ERK phosphorylation. These results show that NAC serially activates ERKs and p38 MAPK, and ERKs and p38 work together to mediate the neuroprotective effect of NAC.}, }
@article {pmid16983401, year = {2006}, author = {Zhang, X and Wu, XQ and Lu, S and Guo, YL and Ma, X}, title = {Deficit of mitochondria-derived ATP during oxidative stress impairs mouse MII oocyte spindles.}, journal = {Cell research}, volume = {16}, number = {10}, pages = {841-850}, doi = {10.1038/sj.cr.7310095}, pmid = {16983401}, issn = {1748-7838}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/*metabolism ; Animals ; Calcium/metabolism ; Chromosomes, Mammalian ; Cyclosporine/pharmacology ; Female ; Hydrogen Peroxide/pharmacology ; Membrane Potentials/drug effects ; Metaphase/*physiology ; Mice ; Mitochondria/*metabolism ; Mitochondrial Membranes/drug effects ; Oocytes/*cytology/drug effects ; Oxidative Stress/*physiology ; Radiography ; Spindle Apparatus/diagnostic imaging/drug effects/*metabolism ; }, abstract = {Although the role of oxidative stress in maternal aging and infertility has been suggested, the underlying mechanisms are not fully understood. The present study is designed to determine the relationship between mitochondrial function and spindle stability in metaphase II (MII) oocytes under oxidative stress. MII mouse oocytes were treated with H2O2 in the presence or absence of permeability transition pores (PTPs) blockers cyclosporin A (CsA). In addition, antioxidant N-acetylcysteine (NAC), F0/F1 synthase inhibitor oligomycin A, the mitochondria uncoupler carbonyl cyanide 4-trifluoro-methoxyphenylhydrazone (FCCP) or thapsigargin plus 2.5 mM Ca2+ (Th+2.5 mM Ca2+) were used in mechanistic studies. Morphologic analyses of oocyte spindles and chromosomes were performed and mitochondrial membrane potential (DeltaPsim), cytoplasmic free calcium concentration ([Ca2+]c) and cytoplasmic ATP content within oocytes were also assayed. In a time- and H2O2 dose-dependent manner, disruption of meiotic spindles was found after oocytes were treated with H2O2, which was prevented by pre-treatment with NAC. Administration of H2O2 led to a dissipation of DeltaPsim, an increase in [Ca2+]c and a decrease in cytoplasmic ATP levels. These detrimental responses of oocytes to H2O2 treatment could be blocked by pre-incubation with CsA. Similar to H2O2, both oligomycin A and FCCP dissipated DeltaPsim, decreased cytoplasmic ATP contents and disassembled MII oocyte spindles, while high [Ca2+]c alone had no effects on spindle morphology. In conclusion, the decrease in mitochondria-derived ATP during oxidative stress may cause a disassembly of mouse MII oocyte spindles, presumably due to the opening of the mitochondrial PTPs.}, }
@article {pmid16982484, year = {2006}, author = {Kozer, E and Greenberg, R and Zimmerman, DR and Berkovitch, M}, title = {Repeated supratherapeutic doses of paracetamol in children--a literature review and suggested clinical approach.}, journal = {Acta paediatrica (Oslo, Norway : 1992)}, volume = {95}, number = {10}, pages = {1165-1171}, doi = {10.1080/08035250600580503}, pmid = {16982484}, issn = {0803-5253}, mesh = {Acetaminophen/*administration &amp; dosage/*adverse effects/therapeutic use ; Algorithms ; Analgesics, Non-Narcotic/*administration &amp; dosage/*adverse effects/therapeutic use ; Child ; Drug Overdose ; Humans ; Liver/*drug effects/*injuries ; Risk Factors ; Wounds and Injuries/chemically induced ; }, abstract = {UNLABELLED: The safety of paracetamol when given in the recommended dosage is well documented. However, in recent years there have been many reports of liver failure associated with repeated exposure to supratherapeutic doses of paracetamol. This paper reviews the literature on chronic supratherapeutic paracetamol exposure in children and the different dosing guidelines. Based on which, we suggest the following approach: liver injury secondary to repeated dosing of paracetamol should be considered when a child has received more than 75 mg/kg/d for at least 2 d, or if risk factors for paracetamol toxicity have been identified. Liver transaminases, coagulation factors, and paracetamol serum concentrations should be measured in these children and in symptomatic children with vomiting, right upper quadrant abdominal pain, and jaundice who have taken paracetamol. Treatment with N-acetyl cysteine should be started regardless of paracetamol concentrations if transaminases or INR are elevated.<br><br>CONCLUSION: Liver injury secondary to repeated dosing of paracetamol is rare but may result in severe morbidity and mortality. The cumulative dose of paracetamol should not exceed 75 mg/kg/d. Children treated with higher doses for more than 2 d should be evaluated for possible liver injury and treated with N-acetyl cysteine if evidence of liver injury is found.}, }
@article {pmid16973330, year = {2006}, author = {Hill, EV and Sheppard, CL and Cheung, YF and Gall, I and Krause, E and Houslay, MD}, title = {Oxidative stress employs phosphatidyl inositol 3-kinase and ERK signalling pathways to activate cAMP phosphodiesterase-4D3 (PDE4D3) through multi-site phosphorylation at Ser239 and Ser579.}, journal = {Cellular signalling}, volume = {18}, number = {11}, pages = {2056-2069}, doi = {10.1016/j.cellsig.2006.07.018}, pmid = {16973330}, issn = {0898-6568}, support = {G8604010/MRC_/Medical Research Council/United Kingdom ; }, mesh = {3',5'-Cyclic-AMP Phosphodiesterases/antagonists &amp; inhibitors/*metabolism ; Animals ; Binding Sites ; COS Cells ; Cell Line ; Cells, Cultured ; Chlorocebus aethiops ; Cyclic Nucleotide Phosphodiesterases, Type 4 ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects/enzymology/metabolism ; Mice ; Oxidants/pharmacology ; *Oxidative Stress ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphodiesterase Inhibitors/pharmacology ; Phosphorylation/drug effects ; Serine/*chemistry/metabolism ; *Signal Transduction ; }, abstract = {RAW macrophages, which express the PDE4D3 and PDE4D5 cAMP phosphodiesterase isoforms, exhibited increased PDE4 activity when challenged with H2O2 in a fashion that was negated by treatment with the cell permeant antioxidant, N-acetyl cysteine and by diphenyleneiodonium chloride, an inhibitor of NADPH oxidase. In Cos1 cells transfected to express PDE4D3, challenge with H2O2 caused a rapid increase in both the activity and phosphorylation of PDE4D3. Lysates from H2O2-treated COS cells caused the phosphorylation of purified, recombinant PDE4D3 at two sites. One was the established ERK phosphorylation site at Ser579, located at the extreme C-terminus of the catalytic unit, and the other was a novel site at Ser239, located at the extreme N-terminus of the catalytic unit. Double Ser239Ala:Ser579Ala mutation of PDE4D3 prevented its H2O2-dependent phosphorylation both in vitro and in intact COS cells. Phosphorylation of PDE4D3 at Ser579 was ablated by treating COS cells with the MEK inhibitor, PD98059, which also negated activation. The activity of the Ser239Ala:Ser579Ala double mutant, and the Ser579Ala single PDE4D3 mutant was unaffected by H2O2 challenge of COS cells, whilst the Ser239Ala mutant was inhibited. Wortmannin inhibited the H2O2-dependent phosphorylation of PDE4D3 in COS cells by around 50%, whilst it fully ablated phosphorylation at Ser239 as well as ablating activation of PDE4D3. Neither immunodepletion of p70S6 kinase nor siRNA-mediated knockdown of mTor inhibited the H2O2-dependent phosphorylation of PDE4D3 at Ser239. Activation of PDE4D3 by challenge with H2O2 was not additive with activation through protein kinase A (PKA)-mediated phosphorylation of PDE4D3. Challenge with H2O2 did not alter PKA-mediated phosphorylation of PDE4D3 at Ser54. H2O2 dependent phosphorylation of PDE4D3, at Ser239 and Ser579, did not alter the sensitivity of PDE4D3 to inhibition by the selective PDE4 inhibitor, rolipram. An unknown protein kinase acting downstream of phosphatidyl inositol 3-kinase phosphorylates PDE4D3 at Ser239. This switches the effect of phosphorylation by ERK at Ser579 from inhibition to activation. We propose that phosphorylation at Ser239 attenuates interaction between either UCR2 or the UCR1/UCR2 module and the PDE4 catalytic unit so as to re-programme the functional outcome effect of phosphorylation by ERK. We identify a novel process through which reactive oxygen species activate long PDE4 isoforms so as to reduce cAMP levels and thereby promote inflammatory responses.}, }
@article {pmid16973216, year = {2007}, author = {Koros, C and Papalexi, E and Anastasopoulos, D and Kittas, C and Kitraki, E}, title = {Effects of AraC treatment on motor coordination and cerebellar cytoarchitecture in the adult rat. A possible protective role of NAC.}, journal = {Neurotoxicology}, volume = {28}, number = {1}, pages = {83-92}, doi = {10.1016/j.neuro.2006.07.016}, pmid = {16973216}, issn = {0161-813X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antimetabolites, Antineoplastic/*toxicity ; Calcium/metabolism ; Cerebellum/*cytology/drug effects ; Cognition/drug effects ; Cytarabine/*antagonists &amp; inhibitors/*toxicity ; Cytoskeleton/drug effects/pathology ; Dose-Response Relationship, Drug ; Immunohistochemistry ; Male ; Maze Learning/drug effects ; Mice ; Neurofilament Proteins/metabolism ; *Neuroprotective Agents ; Postural Balance/drug effects ; Psychomotor Performance/*drug effects ; Rats ; Rats, Wistar ; Space Perception/drug effects ; Walking ; }, abstract = {Intact cerebellum cytoarchitecture and cellular communication are indispensable for successful motor coordination and certain forms of memory. Cytosine arabinoside (AraC), often used as an anti-neoplastic agent in humans, can have cerebellum-targeting adverse effects. In order to characterize the nature of AraC-induced cerebellar lesions in an adult rodent model, we have administered AraC (400 mg/kg b.w., i.p.) in adult male Wistar rats for 5 days. The animals' walking pattern, motor coordination, locomotion, spatial navigation and cognition were evaluated, along with neurofilament- and calbindin-like distribution in the cerebellum. AraC-treated rats demonstrated a disturbed walking pattern and a reduced ability of motor learning and coordination, indicative of a mild cerebellar deficit. Although the general locomotion and spatial cognition of AraC-treated rats was not significantly altered, their navigation into the water, in terms of swimming velocity, was irregular, compared to vehicle-treated animals. Neurofilament-like immunostaining was reduced in the molecular cerebellar layer, while calbindin D 28 kDa levels were increased in Purkinje neurons, following AraC treatment. Administration of the antioxidant N-acetylcysteine (NAC) (200 mg/kg b.w., p.o.), for 14 days (prior to and during AraC treatment) largely prevented the AraC-induced behavioral deficits. Our in vivo model of neurotoxicity provides data on the AraC-induced behavioral and cellular alterations concerning the adult rat cerebellum. Furthermore, it provides evidence of a possible neuroprophylactic role of the antioxidant N-acetylcysteine in this model of chemotherapy-induced toxicity.}, }
@article {pmid16969233, year = {2006}, author = {Alkan, A and Eroğlu, F and Eroğlu, E and Ergin, C and Cerçi, C and Alsancak, G}, title = {Protective effects of N-acetylcysteine and erdosteine on hemorrhagic shock-induced acute lung injury.}, journal = {European journal of emergency medicine : official journal of the European Society for Emergency Medicine}, volume = {13}, number = {5}, pages = {281-285}, doi = {10.1097/00063110-200610000-00007}, pmid = {16969233}, issn = {0969-9546}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Blood Pressure ; Bronchoalveolar Lavage Fluid/chemistry ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology/therapeutic use ; Glutathione/blood/metabolism ; Lung/drug effects ; Macrophages, Alveolar ; Male ; Malondialdehyde/blood/metabolism ; Neutrophils ; Premedication ; Random Allocation ; Rats ; Rats, Wistar ; Respiratory Distress Syndrome/*prevention &amp; control ; Shock, Hemorrhagic/drug therapy/*metabolism ; Thioglycolates/*pharmacology/therapeutic use ; Thiophenes/*pharmacology/therapeutic use ; }, abstract = {BACKGROUND: The drugs N-acetylcysteine and erdosteine were used to evaluate their protective effects in hemorrhagic shock-induced acute lung injury in an animal model.<br><br>METHODS: Forty rats were used and randomly allocated into four groups (n=10). Animals in group III were fed with water containing 1 mg/dl erdosteine, and those in group IV were given 0.5 mg/dl N-acetylcysteine 3 days before the experiment. Group I was taken as the control and group II was taken as the hemorrhagic shock group. Hemorrhagic shock was initiated by blood withdrawal and reduction of the mean arterial pressure to 40 mmHg within 10 min via the right carotid artery. After a hypotensive period of 2 h, animals were resuscitated by transfusion of the shed blood and Ringer lactate in a volume equal to the shed blood. After a period of 1 h, blood samples were taken via the carotid artery. Bronchoalveolar lavage was performed to recover cells from the alveolar space with 40 ml of bronchoalveolar lavage fluid. Lung tissues were also resected to measure tissue malondialdehyde and L-gamma-glutamyl-L-cysteinyl-glycine levels with high performance liquid chromatography. The numbers of neutrophils and alveolar macrophages in bronchoalveolar lavage fluid were counted.<br><br>RESULTS: Serum malondialdehyde levels were significantly higher in the shock groups (P<0.05), but there was no significant difference (P>0.05). Lung malondialdehyde levels were also significantly increased in the shock groups (P<0.05). In the erdosteine-applied group, tissue malondialdehyde levels were lower than in group II and the NAC-applied group (P<0.05). In the analyses of serum and lung tissue L-gamma-glutamyl-L-cysteinyl-glycine, the values of groups I, II and IV were found to be below the calibration graphics. The alveolar macrophage count was found to be the highest and the neutrophil count the lowest in group III when compared with the other groups in bronchoalveolar lavage fluid analyses (P<0.05).<br><br>CONCLUSION: We may say that in the model of hemorrhagic shock-induced acute lung injury, it was found that erdosteine has a protective effect on lung tissue.}, }
@article {pmid16964587, year = {2006}, author = {Brandão, R and Santos, FW and Farina, M and Zeni, G and Bohrer, D and Rocha, JB and Nogueira, CW}, title = {Antioxidants and metallothionein levels in mercury-treated mice.}, journal = {Cell biology and toxicology}, volume = {22}, number = {6}, pages = {429-438}, doi = {10.1007/s10565-006-0119-8}, pmid = {16964587}, issn = {0742-2091}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Benzene Derivatives/therapeutic use ; Body Weight/drug effects ; Chelating Agents/therapeutic use ; Drug Therapy, Combination ; Free Radical Scavengers/*therapeutic use ; Injections, Subcutaneous ; Kidney/drug effects/metabolism ; Liver/drug effects/enzymology ; Male ; Mercuric Chloride/*toxicity ; Mercury Poisoning/etiology/*metabolism/prevention &amp; control ; Metallothionein/*biosynthesis ; Mice ; Organoselenium Compounds/therapeutic use ; Porphobilinogen Synthase/antagonists &amp; inhibitors/metabolism ; Sulfhydryl Compounds/metabolism ; Unithiol/therapeutic use ; Urea/blood ; }, abstract = {Acute effects of mercury on mouse blood, kidneys, and liver were evaluated. Mice received a single dose of mercuric chloride (HgCl2, 4.6 mg/kg, subcutaneously) for three consecutive days. We investigated the possible beneficial effects of antioxidant therapy (N-acetylcysteine (NAC) and diphenyl diselenide (PhSe)2) compared with the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS), an effective chelating agent in HgCl2 exposure in mice. We also verified whether metallothionein (MT) induction might be involved in a possible mechanism of protection against HgCl2 poisoning and whether different treatments would modify MT levels and other toxicological parameters. The results demonstrated that HgCl2 exposure significantly inhibited delta-aminolevulinate dehydratase (delta-ALA-D) activity in liver and only DMPS treatment prevented the inhibitory effect. Mercuric chloride caused an increase in renal non-protein thiol groups (NPSH) and none of the treatments modified renal NPSH levels. Urea concentration was increased after HgCl2 exposure. NAC plus (PhSe)2 was partially effective in protecting against the effects of mercury. DMPS and (PhSe)2 were effective in restoring the increment in urea concentration caused by mercury. Thiobarbituric acid-reactive substances (TBARS), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) activities and ascorbic acid levels were not modified after mercury exposure. Mercuric chloride poisoning caused an increase in hepatic and renal MT levels and antioxidant treatments did not modify this parameter. Our data indicated a lack of therapeutic effect of the antioxidants tested.}, }
@article {pmid16959797, year = {2006}, author = {Andoh, Y and Mizutani, A and Ohashi, T and Kojo, S and Ishii, T and Adachi, Y and Ikehara, S and Taketani, S}, title = {The antioxidant role of a reagent, 2',7'-dichlorodihydrofluorescin diacetate, detecting reactive-oxygen species and blocking the induction of heme oxygenase-1 and preventing cytotoxicity.}, journal = {Journal of biochemistry}, volume = {140}, number = {4}, pages = {483-489}, doi = {10.1093/jb/mvj187}, pmid = {16959797}, issn = {0021-924X}, mesh = {Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus ; Antioxidants/*pharmacology ; Arsenites/pharmacology ; Cadmium/pharmacology ; Cell Nucleus/metabolism ; Cell Survival/drug effects ; Cytoprotection ; Enzyme Induction ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fluoresceins/metabolism/*pharmacology ; HeLa Cells ; Heme Oxygenase-1/*biosynthesis/genetics ; Hemin/pharmacology ; Humans ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress ; Phosphorylation ; Promoter Regions, Genetic ; Reactive Oxygen Species/*metabolism ; }, abstract = {Heme oxygenase-1 (HO-1) degrades heme into biliverdin, iron and CO. The enzyme participates in adaptive and protective responses to oxidative stress and various inflammatory stimuli, and is induced in response to reactive oxygen species (ROS). 2',7'-Dichlorodihydrofluorescin diacetate (DCFH-DA) is a common reagent used to detect ROS by the oxidation of 2',7'-dichlorodihydrofluorescin (DCFH) to fluorescent dichlorodihydrofluorescein. We previously found that rapid oxidation of DCFH occurred with heme-compounds as well as ROS [Ohashi, T. et al. (2002) FEBS Lett. 511, 21-27], and then examined the effect of DCFH-DA on the induction of HO-1 expression by arsenite, cadmium and hemin, which induce oxidative stress and cytotoxicity. We found suppression of the arsenite-, cadmium- and hemin-dependent induction of HO-1 with DCFH-DA. The suppression occurred at the transcriptional level since the promoter activity of the Maf-recognition site of the HO-1 gene decreased with the DCFH-DA treatment. DCFH abolished the phosphorylation of extracellular signal-regulated kinase, the nuclear translocation of a transcriptional activator Nrf2, and cell death. An antioxidant, N-acetylcysteine (NAC), also suppressed the induction by arsenite and cadmium, but not that by hemin, indicating that DCFH blocked a different site in the stress signal pathway from NAC. Considering that the oxidation of DCFH diminishes ROS generated by various stressors, our findings provide a potential strategy for protection of cells from toxic insults using DCFH-like molecules.}, }
@article {pmid16959597, year = {2006}, author = {Modi, M and Kaul, RK and Kannan, GM and Flora, SJ}, title = {Co-administration of zinc and n-acetylcysteine prevents arsenic-induced tissue oxidative stress in male rats.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {20}, number = {3}, pages = {197-204}, doi = {10.1016/j.jtemb.2006.02.002}, pmid = {16959597}, issn = {0946-672X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Alanine Transaminase/blood ; Animals ; Arsenic/antagonists &amp; inhibitors/pharmacokinetics/*toxicity ; Arsenites/toxicity ; Aspartate Aminotransferases/blood ; Drug Synergism ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Male ; Oxidative Stress/*drug effects ; Porphobilinogen Synthase/blood ; Rats ; Rats, Wistar ; Sodium Compounds/toxicity ; Tissue Distribution ; Zinc/*administration &amp; dosage/blood ; }, abstract = {Arsenic is a widespread environmental toxicant that may cause neuropathy, skin lesions, vascular lesions and cancer upon prolonged exposure. Improving nourishment like supplementation of micronutrients, antioxidants, vitamins and amino acids could be able to halve the risk in those who were previously the poor nourished. The present study was planned to investigate the preventive effects of zinc and n-acetylcysteine (NAC) supplementation either alone or in combination with arsenic on selected biochemical variables indicative of oxidative stress and liver injury in male rats. For 3 weeks 25 male wistar rats were exposed to arsenic as sodium arsenite (2 mg/kg, orally through gastric intubation) either alone or in combination with NAC (10 mg/kg, intraperitoneally), zinc (5 mg/kg, orally) or zinc plus NAC. Animals were sacrificed 24h after the last dosing for various biochemical parameters. Concomitant administration of zinc with arsenic showed remarkable protection against blood delta-aminolevulinic acid dehydratase (ALAD) activity as well as providing protection to hepatic biochemical variables indicative of oxidative stress (like thiobarbituric acid reactive substances (TBARS) level, catalase) and tissue injury. NAC supplementation on the other hand, was moderately effective in protecting animals from the toxic effects of arsenic. Interestingly, concomitant administration of zinc and NAC was most effective compared to zinc or NAC in eliciting above-mentioned protective effects. The above results suggest significant protective value of combined zinc and NAC administration in acute arsenic exposure.}, }
@article {pmid16956375, year = {2006}, author = {Leak, RK and Liou, AK and Zigmond, MJ}, title = {Effect of sublethal 6-hydroxydopamine on the response to subsequent oxidative stress in dopaminergic cells: evidence for preconditioning.}, journal = {Journal of neurochemistry}, volume = {99}, number = {4}, pages = {1151-1163}, doi = {10.1111/j.1471-4159.2006.04149.x}, pmid = {16956375}, issn = {0022-3042}, support = {NS19608/NS/NINDS NIH HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/pharmacology ; Cell Death/drug effects/physiology ; Cell Line ; Cytoprotection/drug effects/*physiology ; Dopamine/*metabolism ; Drug Resistance/*physiology ; L-Lactate Dehydrogenase/metabolism ; MAP Kinase Signaling System/drug effects/physiology ; Mice ; Neurons/drug effects/*metabolism ; Oxidative Stress/drug effects/*physiology ; Oxidopamine/toxicity ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors ; Protein Processing, Post-Translational/drug effects/physiology ; Protein Synthesis Inhibitors/pharmacology ; Substantia Nigra/drug effects/*metabolism/physiopathology ; Sympatholytics/toxicity ; }, abstract = {Exposure to sublethal stress can trigger endogenous protection against subsequent, higher levels of stress. We tested for this preconditioning phenomenon in a model of Parkinson's disease by applying 6-hydroxydopamine to the dopaminergic MN9D cell line. Exposure to sublethal concentrations of 6-hydroxydopamine (5-10 microM) protected against the toxic effects of a subsequent exposure to a higher concentration (50 microM), as measured by the Hoechst assay for nuclear viability. This was accompanied by little or no protection against 6-hydroxydopamine-induced lactate dehydrogenase release, decline in ATP, or reduction in (3)H-dopamine uptake. The antioxidant, N-acetyl cysteine (20 mM), when applied during preconditioning, abolished protection, as did the protein synthesis inhibitor, cycloheximide (0.2 microM). Preconditioning did not affect superoxide dismutase or glutathione peroxidase enzymes, or levels of heat shock protein-72. However, Bcl-2 protein levels rose with preconditioning. Preconditioning rapidly increased phosphorylation of kinases ERK1/2, Akt and JNK, and was abolished by pharmacological inhibitors of their activity. Finally, sublethal 6-hydroxydopamine preconditioned against the toxicity of proteasome inhibitor, MG-132 (1 microM). Thus, exposure of a dopaminergic cell line to sublethal oxidative stress can protect against additional oxidative stress due to translational and post-translational modifications, as well as confer 'cross-tolerance' against a different insult, proteasome inhibition.}, }
@article {pmid16953164, year = {2006}, author = {Koksal, C and Bozkurt, AK and Ustundag, N and Konukoglu, D and Musellim, B and Sirin, G and Cortelekoglu, T and Sayin, AG}, title = {Attenuation of acute lung injury following lower limb ischemia/reperfusion: the pharmacological approach.}, journal = {The Journal of cardiovascular surgery}, volume = {47}, number = {4}, pages = {445-449}, pmid = {16953164}, issn = {0021-9509}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Aprotinin/*therapeutic use ; Biomarkers/metabolism ; Calcium Dobesilate/*therapeutic use ; Creatine Kinase/blood ; Disease Models, Animal ; Drug Therapy, Combination ; Free Radical Scavengers/therapeutic use ; Hemostatics/therapeutic use ; L-Lactate Dehydrogenase/blood ; Lower Extremity/*blood supply ; Male ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*complications ; Respiratory Distress Syndrome/*drug therapy/etiology/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Treatment Outcome ; }, abstract = {AIM: The purpose of this study was to examine the effects of N-acetylcysteine (NAC), calcium dobesilate (DOBE) and aprotinin on the amelioration of lung damage following ischemia/reperfusion injury in a rat hind limb model. A well known antioxidant dimethyl-sulfoxide (DMSO) was also tested for comparison.<br><br>METHODS: Ischemia was induced in the lower limb for 4 h by vascular clamping and followed by 1 h of reperfusion. Lung injury was evaluated in 5 groups as a saline (control), DMSO, NAC, DOBE and aprotinin group. Plasma creatine kinase, lactate dehydrogenase, thiobarbituric acid reactive substances (TBARS) as well as lung tissue TBARS levels were measured. Lung tissue samples were taken for histological examination. P<0.005 was considered statistically significant.<br><br>RESULTS: Plasma TBARS values were found to be significantly lower in the DMSO (P<0.005), NAC (P<0.005) and aprotinin (P<0.005) groups compared to the control group. Lung TBARS values were significantly lower in the DMSO, NAC, DOBE and aprotinin groups compared to the control group (P<0.001, P<0.001, P<0.001). Also in the aprotinin group lung TBARS values were found to be significantly lower compared to DMSO (P<0.001), NAC (P<0.001) and DOBE (P<0.001) groups. Histological examination showed less prominent peribronchial leukostasis (P<0.005) and interstitial leukostasis (P<0.005) in all drug groups compared to the control group.<br><br>CONCLUSION: These observations indicate that DOBE and NAC, which are known to have antioxidant properties and aprotinin, a serine proteinase inhibitor, acted effectively on the prevention of lung injury in a rat hind limb ischemia/reperfusion model. The reason why aprotinin exerts a more protective effect than the other drugs is not clear, however, its clinical use may have the dual advantage of hemostasis and lung protection in surgical practice.}, }
@article {pmid16952378, year = {2006}, author = {Araki, S and Dobashi, K and Kubo, K and Yamamoto, Y and Asayama, K and Shirahata, A}, title = {N-acetylcysteine attenuates TNF-alpha induced changes in secretion of interleukin-6, plasminogen activator inhibitor-1 and adiponectin from 3T3-L1 adipocytes.}, journal = {Life sciences}, volume = {79}, number = {25}, pages = {2405-2412}, doi = {10.1016/j.lfs.2006.08.004}, pmid = {16952378}, issn = {0024-3205}, mesh = {3T3-L1 Cells/drug effects ; Acetylcysteine/*pharmacology ; Adipocytes/cytology/*drug effects/metabolism ; Adiponectin/genetics/*metabolism ; Animals ; Antioxidants/*pharmacology ; Catalase/metabolism ; Cell Differentiation ; Cell Nucleus/metabolism ; Enzyme-Linked Immunosorbent Assay ; Glutathione/metabolism ; Interleukin-6/genetics/*metabolism ; Mice ; NF-kappa B/genetics/metabolism ; Plasminogen Activator Inhibitor 1/genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {TNF-alpha is a key molecule in obesity-related metabolic disturbances. This study was designed to determine whether N-acetylcysteine (NAC), an antioxidant, prevents the activation of nuclear factor-kappaB (NF-kappaB) by exogenously administered TNF-alpha in adipocytes, and whether such change affects the production of adipocytokines. The treatment of well-differentiated 3T3-L1 cells with 20 mM of NAC significantly increased the reduced glutathione concentration up to 150% of control. The treatment with 10 ng/ml of TNF-alpha decreased antioxidant enzyme levels such as CuZn-superoxide dismutase (SOD), MnSOD and catalase, and activated NF-kappaB in 3T3-L1 adipocytes. The activation of NF-kappaB was significantly prevented by the pretreatment with 20 mM of NAC. TNF-alpha (1-10 ng/ml) dose-dependently increased interleukin (IL)-6 and plasminogen activator inhibitor-1 (PAI-1) secretion from 3T3-L1 adipocytes, while decreased adiponectin secretion. NAC (5-20 mM) attenuated the TNF-alpha-induced changes in these adipocytokine secretions in a dose-dependent manner. The effect of TNF-alpha and NAC on the adipocytokine productions was exerted at the m-RNA level, judging from results of the real time RT-PCR analysis. The present study revealed that NAC inhibited the TNF-alpha-mediated activation of NF-kappaB and improved the adverse changes in the levels of IL-6, PAI-1 and adiponectin in 3T3-L1 adipocytes. NAC may have the potential to improve the obesity-related abnormal adipocytokine metabolism by attenuating the TNF-alpha-induced oxidant-antioxidant imbalance in adipocytes.}, }
@article {pmid16950796, year = {2007}, author = {Niture, SK and Velu, CS and Smith, QR and Bhat, GJ and Srivenugopal, KS}, title = {Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines.}, journal = {Carcinogenesis}, volume = {28}, number = {2}, pages = {378-389}, doi = {10.1093/carcin/bgl155}, pmid = {16950796}, issn = {0143-3334}, support = {R01 CA97343/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anticarcinogenic Agents/*pharmacology ; Antioxidants/pharmacology ; Base Sequence ; Biological Products/*pharmacology ; Blotting, Western ; Cell Line, Tumor ; Curcumin/pharmacology ; Cysteine/*chemistry ; DNA Modification Methylases ; DNA Primers ; DNA Repair Enzymes ; Dose-Response Relationship, Drug ; Fenretinide/pharmacology ; Glutathione/metabolism ; Glutathione S-Transferase pi/metabolism ; Humans ; Lymphocytes/*metabolism ; Prodrugs/chemistry/*pharmacology ; Pyrazines/pharmacology ; RNA, Messenger/genetics ; Silymarin/pharmacology ; Thiones ; Thiophenes ; Tumor Suppressor Protein p14ARF/*genetics/metabolism ; Tumor Suppressor Proteins ; }, abstract = {O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein which protects the cellular genome and critical oncogenic genes from the mutagenic action of endogenous and exogenous alkylating agents. An expedited elimination of O6-alkylguanines by increasing MGMT activity levels is likely to be a successful chemoprevention strategy. Here, we report for the first time that cysteine/glutathione enhancing drugs and certain plant antioxidants possess the ability to increase human MGMT expression beyond its steady-state levels that may afford protection. The non-toxic cysteine prodrugs, 2-oxothiazolidine-4-carboxylic acid (OTC) and N-acetyl-L-cysteine (NAC), metabolized, respectively by 5-oxoprolinase and acylases, increased the MGMT protein and its repair activity levels in a dose- and time-dependent manner in several cancer cell lines and peripheral blood lymphocytes with a maximum of 3-fold increase by 72 h. The natural antioxidants, namely, curcumin, silymarin, sulforaphane and resveratrol were also effective in raising the MGMT levels to different extents. Among the synthetic agents, oltipraz and N-(4-hydroxyphenyl) retinamide (4-HPR) also increased MGMT expression, albeit to a lesser extent. Augmented mRNA levels accounted at least, in part, for the increased activity of MGMT in this setting. However, evidence from cysteine/methionine deprivation, acivicin treatment, and protein synthesis measurements in OTC-treated cells suggested that an increased cysteine flux also contributed significantly to enhanced MGMT expression. Many of these treatments increased the glutathione S-transferase-P1 (GSTP1) levels as well. These findings raise the possibility of MGMT-targeted chemoprevention strategies through dietary supplementation of OTC and herbal antioxidants. Further, the studies reveal the antioxidant responsiveness of the human MGMT gene.}, }
@article {pmid16950237, year = {2006}, author = {Brennan, JP and Southworth, R and Medina, RA and Davidson, SM and Duchen, MR and Shattock, MJ}, title = {Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation.}, journal = {Cardiovascular research}, volume = {72}, number = {2}, pages = {313-321}, doi = {10.1016/j.cardiores.2006.07.019}, pmid = {16950237}, issn = {0008-6363}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/antagonists &amp; inhibitors/metabolism ; Animals ; Anti-Arrhythmia Agents/pharmacology ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/*pharmacology ; Decanoic Acids/pharmacology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Glyburide/pharmacology ; Hydroxy Acids/pharmacology ; Ischemic Preconditioning, Myocardial ; Magnetic Resonance Spectroscopy ; Male ; Microscopy, Fluorescence ; Mitochondria, Heart/*metabolism ; Myocardial Ischemia/*metabolism ; Perfusion ; Potassium Channels/drug effects/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/analysis/*metabolism ; Tiopronin/pharmacology ; Uncoupling Agents/*pharmacology ; }, abstract = {OBJECTIVE: Both K(ATP) channel opening drugs and ischaemic preconditioning have been suggested to protect the ischaemic heart by acting on K(ATP) channels in the inner mitochondrial membrane, uncoupling the proton gradient and partially dissipating the mitochondrial membrane potential. The aim of these studies was to use low concentrations of FCCP, a mitochondrial protonophore, to bypass the mitochondrial K(ATP) channel and partially uncouple the mitochondria and establish whether this activates protective pathways within the rat heart analogous to K(ATP) channel openers or preconditioning.<br><br>METHODS: Isolated, Langendorff-perfused rat hearts were subjected to 25 min global zero-flow ischaemia and functional recovery assessed. Hearts were pretreated with FCCP (30-300 nM) in the presence or absence of glibenclamide (1 microM), 5-hydroxydecanoate (5-HD: 100 microM), N-acetyl cysteine (4 mM), or N-2-mercaptopropionyl glycine (1 mM). The metabolic consequences of FCCP perfusion in isolated hearts were studied using (31)P NMR, and reactive oxygen species (ROS) production was measured using DCF fluorescence in isolated rat ventricular myocytes.<br><br>RESULTS: FCCP exerted a dose-dependent cardioprotective effect, with 100 nM FCCP being the optimal concentration. This effect could not be blocked by glibenclamide or 5-HD, but was completely attenuated by N-acetyl cysteine and N-2-mercaptopropionyl glycine. Perfusion with FCCP (100 nM) did not deplete bulk ATP during the pretreatment period but significantly depleted phosphocreatine. In ventricular myocytes, FCCP caused an antioxidant-sensitive increase in ROS production but diazoxide was without effect.<br><br>CONCLUSIONS: In the isolated rat heart, partial mitochondrial uncoupling with low-dose FCCP significantly improves post-ischaemic functional recovery via a ROS-dependent pathway. This cardioprotection is not mediated via the depletion of cellular ATP or mitochondrial K(ATP) channel activation.}, }
@article {pmid16948472, year = {2006}, author = {Yamagishi, S and Kikuchi, S and Nakamura, K and Matsui, T and Takeuchi, M and Inoue, H}, title = {Pigment epithelium-derived factor (PEDF) blocks angiotensin II-induced T cell proliferation by suppressing autocrine production of interleukin-2.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {2}, number = {3}, pages = {265-269}, doi = {10.2174/157340606776930826}, pmid = {16948472}, issn = {1573-4064}, mesh = {Angiotensin II/*antagonists &amp; inhibitors ; Base Sequence ; Cell Line ; Cell Proliferation/*drug effects ; DNA Primers ; Eye Proteins/*pharmacology ; Humans ; Interleukin-2/*biosynthesis/genetics ; NADPH Oxidases/metabolism ; Nerve Growth Factors/*pharmacology ; RNA, Messenger/genetics ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/pharmacology ; Serpins/*pharmacology ; T-Lymphocytes/cytology/*drug effects/metabolism ; Thymidine/metabolism ; }, abstract = {Angiotensin II (Ang II) elicits numerous inflammatory-proliferative responses in vascular cells, thereby being involved in atherosclerosis. We have previously shown that pigment epithelium-derived factor (PEDF) blocks the Ang II-induced endothelial cell activation, thus suggesting that PEDF may play a role in atherosclerosis. However, effects of PEDF on T cell activation, another key steps of atherosclerosis, remain to be elucidated. In this study, we examined whether PEDF could inhibit the Ang II-induced MOLT-3 T cell proliferation in vitro and the way that it might achieve this effect. Ang II significantly stimulated DNA synthesis in MOLT-3 T cells, which was inhibited by PEDF, olmesartan, an Ang II type I receptor blocker, an anti-oxidant N-acetylcysteine (NAC), or antibodies directed against IL-2. PEDF or NAC suppressed gene expression of interleukin-2 (IL-2) in Ang II-exposed MOLT-3 T cells. Furthermore, PEDF blocked the Ang II-induced reactive oxygen species (ROS) generation and NADPH oxidase activity in MOLT-3 T cells. These results demonstrate that PEDF inhibits the Ang II-induced T cell proliferation by blocking autocrine production of IL-2 via suppression of NADPH oxidase-mediated ROS generation. Blockade by PEDF of T cell activation may become a novel therapeutic target for atherosclerosis.}, }
@article {pmid16942797, year = {2007}, author = {Piga, R and Saito, Y and Yoshida, Y and Niki, E}, title = {Cytotoxic effects of various stressors on PC12 cells: involvement of oxidative stress and effect of antioxidants.}, journal = {Neurotoxicology}, volume = {28}, number = {1}, pages = {67-75}, doi = {10.1016/j.neuro.2006.07.006}, pmid = {16942797}, issn = {0161-813X}, mesh = {Aldehydes/toxicity ; Animals ; Annexin A5/metabolism ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Arsenic Trioxide ; Arsenicals ; Caspases/metabolism ; Cell Survival/drug effects ; Free Radicals/metabolism ; Ketocholesterols/toxicity ; Kinetics ; Oxidants/*toxicity ; Oxidative Stress/*physiology ; Oxides/toxicity ; PC12 Cells ; Propidium ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {In order to specifically elucidate the involvement of oxidative stress, the effects of various types of stressors and antioxidants on PC12 cells were examined. In this study, the following four stressors were studied in detail: free radicals generated from 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), 4-hydroxynonenal (HNE), 7-ketocholesterol (KC), and arsenic trioxide (As2O3). Undifferentiated PC12 cells were treated with 50% lethal concentration (LC50) of these stressors, and subsequently the viability, apoptosis/necrosis ratio, reactive oxygen species (ROS) production, caspase-3 activity, and protection by antioxidants were measured to elucidate the underlying mechanisms that determine the action of these stressors on PC12 cells. The cytotoxicity did not correlate directly with the intracellular formation of ROS. For example, as compared to AAPH, As2O3 produced considerably smaller amounts of ROS at LC50. As observed in the cells incubated with As2O3, KC and HNE exerted cell toxicity, but with a moderate production of ROS. With the exception of HNE, the apoptosis/necrosis ratio of all the stressors evaluated by annexin V and propidium iodide assays increased with an increase in the incubation time at the LC50 values of these stressors. In accordance with apoptosis ratio, caspase activity was detected in the cells incubated with AAPH, As2O3, and KC, but not HNE at LC50 for 24 h. The protective effect of alpha-tocopherol, 17beta-estradiol, 2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran (BO653), glutathione, and N-acetylcysteine (NAC) against cytotoxicity depended on the type of stressors. These antioxidants were found to be effective against the abovementioned stressors, except As2O3 against which only NAC was effective. These results suggest that the involvement of ROS and the protective effect of antioxidants depend on the type of stressors.}, }
@article {pmid16940754, year = {2006}, author = {Tanaka, T and Halicka, HD and Huang, X and Traganos, F and Darzynkiewicz, Z}, title = {Constitutive histone H2AX phosphorylation and ATM activation, the reporters of DNA damage by endogenous oxidants.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {5}, number = {17}, pages = {1940-1945}, pmid = {16940754}, issn = {1551-4005}, support = {R01 CA028704/CA/NCI NIH HHS/United States ; R01 CA028704-28/CA/NCI NIH HHS/United States ; R01 CA 28 704/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; *DNA Damage ; DNA-Binding Proteins/*metabolism ; Enzyme Activation ; Free Radical Scavengers/pharmacology ; Histones/*metabolism ; Humans ; Oxidants/metabolism ; *Oxidative Stress ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {DNA in live cells undergoes continuous oxidative damage caused by metabolically generated endogenous as well as external oxidants and oxidant-inducers. The cumulative oxidative DNA damage is considered the key factor in aging and senescence while the effectiveness of anti-aging agents is often assessed by their ability to reduce such damage. Oxidative DNA damage also preconditions cells to neoplastic transformation. Sensitive reporters of DNA damage, particularly the induction of DNA double-strand breaks (DSBs), are activation of ATM, through its phosphorylation on Ser 1981, and phosphorylation of histone H2AX on Ser 139; the phosphorylated form of H2AX has been named gammaH2AX. We review the observations that constitutive ATM activation (CAA) and H2AX phosphorylation (CHP) take place in normal cells as well in the cells of tumor lines untreated by exogenous genotoxic agents. We postulate that CAA and CHP, which have been measured by multiparameter cytometry in relation to the cell cycle phase, are triggered by oxidative DNA damage. This review also presents the findings on differences in CAA and CHP in various cell lines as well as on the effects of several agents and growth conditions that modulate the extent of these histone and ATM modifications. Specifically, described are effects of the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC), and the glutathione synthetase inhibitor buthionine sulfoximine (BSO) as well as suppression of cell metabolism by growth at higher cell density or in the presence of the glucose antimetabolite 2-deoxy-D-glucose. Collectively, the reviewed data indicate that multiparameter cytometric measurement of the level of CHP and/or CAA allows one to estimate the extent of ongoing oxidative DNA damage and to measure the DNA protective-effects of antioxidants or agents that reduce or amplify generation of endogenous ROS.}, }
@article {pmid16940233, year = {2006}, author = {Kwak, DJ and Kwak, SD and Gauda, EB}, title = {The effect of hyperoxia on reactive oxygen species (ROS) in rat petrosal ganglion neurons during development using organotypic slices.}, journal = {Pediatric research}, volume = {60}, number = {4}, pages = {371-376}, doi = {10.1203/01.pdr.0000239817.39407.61}, pmid = {16940233}, issn = {0031-3998}, support = {DA 013940-03/DA/NIDA NIH HHS/United States ; HL 072748/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Culture Techniques ; Cyclic N-Oxides/pharmacology ; Dissection ; Female ; Fluoresceins ; Ganglia, Sensory/*growth &amp; development/*metabolism/ultrastructure ; Hyperoxia/*metabolism/pathology ; Neurons, Afferent/*metabolism/ultrastructure ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/analysis/*metabolism ; }, abstract = {Hyperoxia, during development in rats, results in hypoxic chemosensitivity ablation, carotid body hypoplasia, and reduced chemoafferents. We hypothesized that hyperoxia increases reactive oxygen species (ROS) in cell bodies of chemoafferents. Organotypic slices of petrosal-nodose ganglia from rats at day of life (DOL) 5-6 and 17-18 were exposed to 8%, 21%, or 95% O(2) for 4 h in the presence or absence of the ROS-sensitive fluorescent indicator, CM-H(2)DCFDA, and propidium iodide was used to determine the relationship between cell death and oxygen tension. In tissue slices from DOL 5-6 rats, fluorescence intensity was 182.5 +/- 2.9 for hypoxia, 217.5 +/- 3.3 for normoxia, and 336.6 +/- 3.8 for hyperoxia, (mean +/- SEM, p < 0.001, ANOVA). Normoxia increased ROS levels by 19.2% from hypoxia (p < 0.01) with a further increase of 54.8% from normoxia to hyperoxia (p < 0.001). In tissue slices from DOL 17-18 rats, ROS levels increased with increasing oxygen tension but were less than in younger animals (p < 0.01, ANOVA). The antioxidants, NAC and TEMPO-9-AC, attenuated ROS levels and cell death. Electron microscopy demonstrated that hyperoxia damages the ultrastructure within petrosal ganglion neurons. Hyperoxic-induced increased levels of ROS in petrosal ganglion neurons may contribute to loss of hypoxic chemosensitivity during early postnatal development.}, }
@article {pmid16939684, year = {2006}, author = {Lu, FJ and Tseng, TH and Lee, WJ and Yen, CC and Yin, YF and Liao, CW and Liu, KM}, title = {Promoting neoplastic transformation of humic acid in mouse epidermal JB6 Cl41 cells.}, journal = {Chemico-biological interactions}, volume = {162}, number = {3}, pages = {249-258}, doi = {10.1016/j.cbi.2006.07.007}, pmid = {16939684}, issn = {0009-2797}, mesh = {Animals ; Cell Death/drug effects ; Cell Line ; Cell Movement/drug effects ; Cell Transformation, Neoplastic/*chemically induced/pathology ; Epidermal Cells ; Epidermis/*drug effects/*pathology ; Humic Substances/*toxicity ; Mice ; Oxidation-Reduction ; }, abstract = {Humic acid (HA), a group of high-molecular weight polymer, resulting from the decomposition of organic matter has been implicated as a possible etiological factor for Blackfoot disease and cancer. In this study, we evaluate the promotion effect of HA on the transformation in mouse epidermal JB6 clone 41 (JB6 Cl41) cells that have been used to identify the tumor promoting activity of various compounds. Our preliminary assay demonstrated that JB6 Cl41 cells with the treatment of HA at the concentration of 100 microg/ml for 72 and 96 h significantly increased reactive oxygen species (ROS) as compared to the untreated control. In addition, the 48 h cultured cells with HA pretreatment for 48 h also increased ROS as compared to the untreated control. HA-pretreated cells develop highly scattered and spindle-shaped cells with few observable cell-cell contacts, and contain more filopodia. In vitro wound-healing assay showed that JB6 Cl41 cells with HA pretreatment increased the migrating growth. Furthermore, transformed foci of JB6 Cl41 cells following the HA pretreatment were observed after 6 weeks culture. In anchorage-independent growth assay, we found that HA promoted the colony formation and that colonies were inhibited by antioxidant N-acetyl cysteine (NAC). Our results suggest that HA may promote the transformation of epidermal cells and that this process is mediated by the generation of ROS.}, }
@article {pmid16936002, year = {2007}, author = {Kolár, F and Jezková, J and Balková, P and Breh, J and Neckár, J and Novák, F and Nováková, O and Tomásová, H and Srbová, M and Ost'ádal, B and Wilhelm, J and Herget, J}, title = {Role of oxidative stress in PKC-delta upregulation and cardioprotection induced by chronic intermittent hypoxia.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {292}, number = {1}, pages = {H224-30}, doi = {10.1152/ajpheart.00689.2006}, pmid = {16936002}, issn = {0363-6135}, mesh = {Animals ; Chronic Disease ; Hypoxia/complications/*physiopathology/*prevention &amp; control ; Ischemic Preconditioning, Myocardial/*methods ; Male ; Myocardial Infarction/*physiopathology/prevention &amp; control ; *Oxidative Stress ; Protein Kinase C-delta/*metabolism ; Rats ; Rats, Wistar ; Secondary Prevention ; Up-Regulation ; }, abstract = {The aim was to determine whether increased oxidative stress during the adaptation to chronic intermittent hypoxia (CIH) plays a role in the induction of improved cardiac ischemic tolerance. Adult male Wistar rats were exposed to CIH in a hypobaric chamber (7,000 m, 8 h/day, 5 days/wk, 24-30 exposures). Half of the animals received antioxidant N-acetylcysteine (NAC; 100 mg/kg) daily before the exposure; the remaining rats received saline. Control rats were kept under normoxia and treated in a corresponding manner. One day after the last exposure (and/or NAC injection), anesthetized animals were subject to 20 min of coronary artery occlusion and 3 h of reperfusion for determination of infarct size. In parallel subgroups, biochemical analyses of the left ventricular myocardium were performed. Adaptation to CIH reduced infarct size from 56.7 +/- 4.5% of the area at risk in the normoxic controls to 27.7 +/- 4.9%. NAC treatment decreased the infarct size in the controls to 42.0 +/- 3.4%, but it abolished the protection provided by CIH (to 41.1 +/- 4.9%). CIH decreased the reduced-to-oxidized glutathione ratio and increased the relative amount of PKC isoform-delta in the particulate fraction; NAC prevented these effects. The expression of PKC-epsilon was decreased by CIH and not affected by NAC. Activities of superoxide dismutase, catalase, and glutathione peroxidase were affected by neither CIH nor NAC treatment. It is concluded that oxidative stress associated with CIH plays a role in the development of increased cardiac ischemic tolerance. The infarct size-limiting mechanism of CIH seems to involve the PKC-delta-dependent pathway but apparently not the increased capacity of major antioxidant enzymes.}, }
@article {pmid16931792, year = {2006}, author = {Fujii, H and Li, SH and Szmitko, PE and Fedak, PW and Verma, S}, title = {C-reactive protein alters antioxidant defenses and promotes apoptosis in endothelial progenitor cells.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {26}, number = {11}, pages = {2476-2482}, doi = {10.1161/01.ATV.0000242794.65541.02}, pmid = {16931792}, issn = {1524-4636}, mesh = {Acetylcysteine/pharmacology ; Antibodies/pharmacology ; Apoptosis/*drug effects ; C-Reactive Protein/administration &amp; dosage/immunology/*pharmacology ; Cells, Cultured ; Cytoprotection ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects/metabolism/pathology/*physiology ; Enzyme Activation/drug effects ; Glutathione Peroxidase/antagonists &amp; inhibitors ; Humans ; Necrosis ; Osmolar Concentration ; Oxidoreductases/*metabolism ; RNA Interference/physiology ; Reactive Oxygen Species/metabolism ; Stem Cells/drug effects/metabolism/*physiology ; Superoxide Dismutase/genetics/metabolism ; Telomerase/metabolism ; Transfection ; }, abstract = {OBJECTIVE: C-reactive protein (CRP) has been suggested to participate in the development of atherosclerosis, in part, by promoting endothelial dysfunction and impairing endothelial progenitor cell (EPC) survival and differentiation. In the present study, we evaluated the effects of CRP on antioxidative enzymes, reactive oxygen species production, telomerase activity, and apoptosis in human circulating EPCs.<br><br>METHODS AND RESULTS: EPCs, isolated from peripheral venous blood, were cultured in the absence or presence of native pentameric azide and lipopolysaccharide (LPS)-free CRP (0, 5, 15, and 20 microg/mL), N-acetylcysteine (NAC), hydrogen peroxide (H2O2) or monoclonal anti-CRP antibodies. Fluorescence-activated cell sorter (FACS) analysis was used for the measurement of intracellular H2O2 and superoxide (O2(-)) by loading cells with 2',7'-dichlorodihydrofluorescein diacetate (H2DCF-DA). Apoptosis was evaluated with Annexin V immunostaining and cytosolic cytochrome c expression. Western blot analysis was used for the determination of manganese superoxide dismutase (MnSOD) and glutathione peroxidase expression, and polymerase chain reaction enzyme-linked immunosorbent assay was used to assess telomerase activity. Incubation of EPCs with CRP caused a concentration dependent increase in reactive oxygen species (ROS) production and apoptosis, with an effect quantitatively similar to H2O2. This effect was attenuated during coincubation with NAC or anti-CRP antibodies. Furthermore, CRP altered EPC antioxidative enzyme levels, demonstrating a reduced expression of glutathione peroxidase and a significant increase in MnSOD expression. Transfection of EPCs with MnSOD-RNAi resulted in a reduction in CRP-induced ROS production, apoptosis, and telomerase inactivation.<br><br>CONCLUSIONS: CRP, at concentrations known to predict cardiovascular events, may serve to impair EPC antioxidant defenses, and promote EPC sensitivity toward oxidant-mediated apoptosis and telomerase inactivation. These data further support a direct role of CRP in the development and/or progression of atherothrombosis.}, }
@article {pmid16930891, year = {2007}, author = {Davis, RR and Kuo, MW and Stanton, SG and Canlon, B and Krieg, E and Alagramam, KN}, title = {N-Acetyl L-cysteine does not protect against premature age-related hearing loss in C57BL/6J mice: a pilot study.}, journal = {Hearing research}, volume = {226}, number = {1-2}, pages = {203-208}, doi = {10.1016/j.heares.2006.07.003}, pmid = {16930891}, issn = {0378-5955}, support = {DC05385/DC/NIDCD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aging/pathology/physiology ; Animals ; Antioxidants/pharmacology ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Female ; Hair Cells, Auditory, Inner/drug effects/pathology ; Hair Cells, Auditory, Outer/drug effects/pathology ; Mice ; Mice, Inbred C57BL ; Pilot Projects ; Presbycusis/pathology/physiopathology/*prevention &amp; control ; }, abstract = {A compound capable of preventing age-related hearing loss would be very useful in an aging population. N-acetyl-L-cysteine (L-NAC) has been shown to be protective against noise exposure, a condition that leads to increased oxidative stress. Not withstanding environmental factors, there is evidence that age-related hearing loss (AHL) in the mouse is linked to more than one genetic loci and, by extension, in humans. Our hypothesis is that AHL defect results in increased sensitivity to oxidative stress and L-NAC would be able to protect the hearing of a mouse model of pre-mature AHL, the C57BL/6J (B6) mouse strain. L-NAC was added to the regular water bottle of B6 mice (experimental group) and available ad lib. The other group received normal tap water. Hearing was tested monthly by the ability to generate the auditory brainstem response (ABR). After the final ABR test, mice were sacrificed by an overdose of Avertin, ears were harvested and hair cell loss was quantified. There was no difference in ABR thresholds or in histopathology between the control group and the group receiving L-NAC in their drinking water. In contrast to the protective effects of L-NAC against noise-induced hearing loss, the lack of protective effect in this study may be due to (i) the dosage level; (ii) the duration of treatment; (iii) the biochemical mechanisms underlying age-induced hearing loss; or (iv) how the mouse metabolizes L-NAC.}, }
@article {pmid16925458, year = {2007}, author = {Gao, X and Xu, X and Pang, J and Zhang, C and Ding, JM and Peng, X and Liu, Y and Cao, JM}, title = {NMDA receptor activation induces mitochondrial dysfunction, oxidative stress and apoptosis in cultured neonatal rat cardiomyocytes.}, journal = {Physiological research}, volume = {56}, number = {5}, pages = {559-569}, doi = {10.33549/physiolres.931053}, pmid = {16925458}, issn = {0862-8408}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Calcium/metabolism ; Caspase 3/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cytochromes c/metabolism ; Dizocilpine Maleate/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation ; Excitatory Amino Acid Agonists/*pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Glutathione/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Heart/*drug effects/metabolism/pathology ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; N-Methylaspartate/*pharmacology ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptors, N-Methyl-D-Aspartate/*agonists/antagonists &amp; inhibitors/metabolism ; Time Factors ; bcl-2-Associated X Protein/genetics/metabolism ; }, abstract = {Glutamate is a well-characterized excitatory neurotransmitter in the central nervous system (CNS). Recently, glutamate receptors (GluRs) were also found in peripheral tissues, including the heart. However, the function of GluRs in peripheral organs remains poorly understood. In the present study, we found that N-methyl-D-aspartate (NMDA) could increase intracellular calcium ([Ca(2+)]i) level in a dose-dependent manner in cultured neonatal rat cardiomyocytes. NMDA at 10(-4) M increased the levels of reactive oxygen species (ROS), cytosolic cytochrome c (cyto c), and 17-kDa caspase-3, but depolarized mitochondrial membrane potential, leading to cardiomyocyte apoptosis. In addition, NMDA treatment induced an increase in bax mRNA but a decrease in bcl-2 mRNA expression in the cardiomyocytes. The above effects of NMDA were blocked by the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), and by ROS scavengers glutathione (GSH) and N-acetylcystein (NAC). These results suggest that stimulation of NMDA receptor in the cardiomyocyte may lead to apoptosis via a Ca(2+), ROS, and caspase-3 mediated pathway. These findings suggest that NMDA receptor may play an important role in myocardial pathogenesis.}, }
@article {pmid16924570, year = {2006}, author = {Sezer, M and Fidan, F and Unlü, M and Sahin, O and Esme, H and Köken, T}, title = {Effects of N-acetylcysteine on the lung histopathology and oxidant-antioxidant status in rabbits exposed to cigarette smoke.}, journal = {Tuberkuloz ve toraks}, volume = {54}, number = {2}, pages = {144-151}, pmid = {16924570}, issn = {0494-1373}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/*metabolism ; Disease Models, Animal ; Expectorants/administration &amp; dosage/*pharmacology ; Injections, Intraperitoneal ; Lung/*drug effects/pathology ; Lung Diseases, Obstructive/blood/*metabolism/pathology ; Male ; Rabbits ; *Smoking ; }, abstract = {We aimed to evaluate the effects of smoking on the histopathology and the oxidant-antioxidant status of lungs and to test the effects of N-acetylcysteine (NAC) on the induced changes. Rabbits were exposed to cigarette smoke (CS) in a glass chamber for one hour daily for one month. An NAC control group was given intraperitoneal NAC only. CS + NAC rats were exposed to smoke and given intraperitoneal NAC. A control group was exposed to clean air only. At the end of one month, animals were sacrificed and lung tissues were examined histopathologically. Blood levels of protein sulfhydryls, carbonyls, prostaglandin F(2alpha) (PGF(2alpha)) and malondialdehyde (MDA) were measured. Intraparenchymal vascular congestion and thrombosis, intraparenchymal hemorrhage, respiratory epithelial proliferation, number of macrophages in the alveolar and bronchial lumen, alveolar destruction, emphysematous changes and bronchoalveolar hemorrhage scores were significantly increased in rabbits exposed to CS compared with the control group. Protein sulfhydryls were significantly decreased; carbonyls, PGF(2alpha) and MDA levels were significantly increased in the smoke exposed rabbits. Administration of NAC to rabbits exposed to CS caused a reduction in the bronchoalveolar hemorrhage score and blood PGF(2alpha) levels. Other parameters were unaffected by NAC. Exposure to CS causes severe histopathological changes and negatively effects the oxidant-antioxidant status in the lungs of rabbits. A low daily dose of NAC has some ameliorative effects on histopathological changes and oxidant-antioxidant status of the lungs in smoke exposed rabbits.}, }
@article {pmid16924499, year = {2007}, author = {Long, J and Manchandia, T and Ban, K and Gao, S and Miller, C and Chandra, J}, title = {Adaphostin cytoxicity in glioblastoma cells is ROS-dependent and is accompanied by upregulation of heme oxygenase-1.}, journal = {Cancer chemotherapy and pharmacology}, volume = {59}, number = {4}, pages = {527-535}, doi = {10.1007/s00280-006-0295-5}, pmid = {16924499}, issn = {0344-5704}, mesh = {Adamantane/*analogs &amp; derivatives/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; DNA Fragmentation/drug effects ; Fusion Proteins, bcr-abl/antagonists &amp; inhibitors ; Glioblastoma/*drug therapy/metabolism ; Glutathione/analysis ; Heme Oxygenase-1/*genetics ; Humans ; Hydroquinones/*pharmacology ; RNA, Messenger/analysis ; Reactive Oxygen Species/*metabolism ; Up-Regulation ; }, abstract = {PURPOSE: To delineate a role for reactive oxygen species (ROS) induction in adaphostin-induced apoptosis in glioblastoma cells.<br><br>METHODS: Three glioblastoma cell lines with different sensitivities to adaphostin were characterized for sensitivity to an oxidant, tert-butyl hydroperoxide. The degree and duration of the ROS levels was assessed in the three cell lines after adaphostin exposure. Antioxidant protein levels were evaluated by Western blotting.<br><br>RESULTS: Of the three glioblastoma cell lines, the U87 cells were least sensitive to adaphostin. These cells were also least sensitive to tert-butyl hydroperoxide, indicating that sensitivity to a direct oxidant stress mirrors the cells' adaphostin sensitivities. In addition, the antioxidant N-acetylcysteine, (NAC) was protective against adaphostin-induced apoptosis. Direct measurement of intracellular peroxides showed a transient increase in the two less sensitive cell lines (U87 and LN18) which diminishes by 24 h. In contrast, U251 cells, which are most sensitive to adaphostin, display a sustained increase in the ROS levels. After the initial increase in intracellular peroxides, the heat shock protein and antioxidant heme oxygenase-1 (HO-1) was upregulated. Levels of other antioxidant proteins, such as catalase and thioredoxin, however, were not altered by adaphostin in glioblastoma cell lines. NAC attenuated HO-1 upregulation, confirming the time course analysis.<br><br>CONCLUSIONS: These results suggest a primary role for ROS in adaphostin-induced apoptosis in glioblastoma. Our data indicate that the duration of intracellular ROS levels is a key factor in mediating sensitivity to adaphostin. Furthermore, upregulation of HO-1 is a novel molecular marker of adaphostin's action. The kinetics with which adaphostin upregulates HO-1 correlates with sensitivity to the drug. Taken together, our data indicate that a cell's ability to cope with ROS dictates sensitivity to adaphostin and conceivably other chemotherapies that cause redox perturbations.}, }
@article {pmid16922458, year = {2006}, author = {Inoue, S and Yamamoto, I and Akieda, K and Sekiguchi, H and Otuka, H and Morita, S and Nakagawa, Y and Inokuchi, S}, title = {[Alcohol abuse case of severe liver dysfunction induced by acetaminophen poisoning which was diagnosed as non-hepatic toxicity on admission].}, journal = {Chudoku kenkyu : Chudoku Kenkyukai jun kikanshi = The Japanese journal of toxicology}, volume = {19}, number = {3}, pages = {265-271}, pmid = {16922458}, issn = {0914-3777}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage ; Administration, Rectal ; Adult ; Alcoholism/*complications ; Analgesics, Non-Narcotic/*poisoning ; Drug Overdose ; Female ; Humans ; Liver Diseases/diagnosis/*etiology ; Plasma Exchange ; Severity of Illness Index ; *Suicide, Attempted ; Therapeutics ; }, abstract = {A 41-year-old female attempted suicide by taking 7.8g acetaminophen and was transferred to our hospital four hours after ingestion. The patient was diagnosed as non-hepatic toxicity (below the line set by the Rumack Matthew nomogram). Laboratory data showed an elevation in serum liver enzymes and coagulation defects at 3 days after ingestion, therefore, the patient was treated with plasma exchange and an oral administration of N-acetylcysteine (NAC). The elevation of liver enzymes was maximal at 4 days after ingestion, and the laboratory data became normalized at approximately 9 days after ingestion. In this case, habitual alcohol intake may have exacerbated the severe liver injury. We should consider an exacerbation of hepatotoxicity and administer NAC in any case having a history of habitual alcohol intake, even if the case was diagnosed as non-hepatic toxicity by the nomogram.}, }
@article {pmid16919916, year = {2006}, author = {Mitra, S and Abraham, E}, title = {Participation of superoxide in neutrophil activation and cytokine production.}, journal = {Biochimica et biophysica acta}, volume = {1762}, number = {8}, pages = {732-741}, doi = {10.1016/j.bbadis.2006.06.011}, pmid = {16919916}, issn = {0006-3002}, support = {HL62221/HL/NHLBI NIH HHS/United States ; P01HL68743/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cell Nucleus/drug effects ; Cells, Cultured ; Cytokines/*biosynthesis/metabolism ; Drug Synergism ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; I-kappa B Kinase/metabolism ; Lipopolysaccharides/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Neutrophil Activation/drug effects/*immunology ; Neutrophils/drug effects/metabolism ; Paraquat/pharmacology ; Phosphoserine/metabolism ; Protein Transport/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Superoxides/*metabolism ; Transcription Factor RelA/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Reactive oxygen species (ROS) can participate in cellular signaling and have been shown to modulate activation of the transcriptional regulatory factor NF-kappaB. However, the effects of ROS can differ in various cell populations. To examine the role of superoxide in neutrophil activation, we exposed resting neutrophils and neutrophils stimulated with LPS to paraquat, an agent that specifically increases intracellular superoxide concentrations. Culture of resting neutrophils with paraquat resulted in increased production of the proinflammatory cytokines TNF-alpha and MIP-2, enhanced degradation of IkappaB-alpha, and increased nuclear accumulation of NF-kappaB. Such effects of paraquat were due to intracellular superoxide (O2-) since they were blocked by the non-specific antioxidant N-acetyl cysteine and the cell permeable superoxide scavenger Tiron, but not by catalase, which facilitates the conversion of H2O2 to H2O and O2. Similar potentiating effects of paraquat were found in LPS-stimulated neutrophils. Exposure of neutrophils to paraquat also enhanced phosphorylation of Ser536 in the p65 subunit of NF-kappaB an event associated with increased transcriptional activity. Examination of kinases critical for LPS-stimulated gene expression showed that addition of paraquat to resting or LPS exposed neutrophils enhanced activation of p38 MAPK, but not that of Akt or ERK1/2. The potentiation of NF-kappaB translocation and proinflammatory cytokine production, but not of Ser536 p65 phosphorylation, by paraquat was dependent on activation of p38 MAPK. These results demonstrate that increased intracellular superoxide concentrations are proinflammatory in neutrophils, acting through a p38 MAPK dependent mechanism that results in enhanced nuclear accumulation of NF-kappaB and increased expression of NF-kappaB dependent proinflammatory cytokines.}, }
@article {pmid16919894, year = {2006}, author = {Peterszegi, G and Molinari, J and Ravelojaona, V and Robert, L}, title = {Effect of advanced glycation end-products on cell proliferation and cell death.}, journal = {Pathologie-biologie}, volume = {54}, number = {7}, pages = {396-404}, doi = {10.1016/j.patbio.2006.07.003}, pmid = {16919894}, issn = {0369-8114}, mesh = {Antibody Formation ; Cell Culture Techniques ; Cell Death/*drug effects ; Cell Division/*drug effects ; Free Radical Scavengers/pharmacology ; Glycation End Products, Advanced/*pharmacology ; Humans ; Skin/*cytology/drug effects/immunology ; }, abstract = {The effect of advanced glycation end products (AGE-s) was studied on the proliferation and cell death of human skin fibroblasts in culture. Several AGE-products were prepared from proteins, a peptide and amino acids, using Glucose or Fructose, with or without Fe2+. The AGE preparations increased cell death at the 7th day, after only 72 hours of incubation. Some of these glycation products modified also proliferation. This effect of AGE-s was even maintained without these products in fresh medium for a second period of incubation up to 10 days from the start of the experiment. In order to explore the role of AGE-receptors, especially of AGE-receptor and of growth factor receptors (fibroblast and epidermal growth factors receptors), antibodies to these receptors were added to cell cultures and their effect on both cell death and proliferation were determined as for the AGE-s. These anti-receptor antibodies imitated to some extent the results obtained with AGE-s, producing increase of cell death and proliferation, followed above a certain concentration of antibodies by a decrease and a new increase or plateau. This might correspond to the internalization of the receptors followed by a re-expression on the cell membrane. The role of receptor-mediated Reactive Oxygen Species-production was also explored using scavengers: N-acetyl-cysteine (NAC), L-Carnosine, superoxide dismutase (SOD) and Catalase. Several of these scavengers decreased cell death, suggesting that Reactive Oxygen Species-production is partially involved in the observed phenomena.}, }
@article {pmid16919817, year = {2006}, author = {Hacimuftuoglu, A and Handy, CR and Goettl, VM and Lin, CG and Dane, S and Stephens, RL}, title = {Antioxidants attenuate multiple phases of formalin-induced nociceptive response in mice.}, journal = {Behavioural brain research}, volume = {173}, number = {2}, pages = {211-216}, doi = {10.1016/j.bbr.2006.06.030}, pmid = {16919817}, issn = {0166-4328}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Behavior, Animal/drug effects ; Cyclic N-Oxides/therapeutic use ; Female ; Formaldehyde ; Injections, Spinal/methods ; Male ; Mice ; Nitrogen Oxides/therapeutic use ; Pain/chemically induced/*prevention &amp; control ; Pain Measurement/methods ; Spin Labels ; Time Factors ; }, abstract = {An emerging theme in the study of the pathophysiology of chronic and persistent pain is the role of pro-oxidant substances. Reactive oxygen species (ROS) have been implicated in contributing to and/or maintaining conditions of chronic pain. Recent pre-clinical reports suggest that antioxidants are effective analgesics in neuropathic and inflammatory pain models. The present study extends this work by examining the effect of three antioxidants on tissue injury-induced nociception. C57BL6 mice (20-25 g) were pretreated with either phenyl-N-tert-butylnitrone (PBN; 50 mg/kg, i.p.), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxy (TEMPOL; 200 or 50 mg/kg, i.p.), N-acetyl-L-cysteine (NAC; 200 or 100mg/kg, i.p.), or vehicle (0.5 ml/100 g), 5 min before intraplantar formalin (10%, 20 microl) injection. Nociceptive responding, indicated by licking or biting the affected hindlimb, was quantified for 30 min after formalin injection. Each drug was effective in attenuating two or more phases (acute, quiescent, and tonic) of the formalin response. To assess putative site of action, intrathecal TEMPOL (380 nmol/5 microl, i.t.) was given 5 min before intraplantar formalin. Intrathecal TEMPOL produced a 83% reduction in nociceptive responding in the tonic phase, but no significant attenuation of the acute phase response. To confirm that the antioxidant property of intrathecal TEMPOL was responsible for its analgesic effect on the formalin-induced pain response, intrathecal TEMPOL was coadministered with the free radical donor tert-butylhydroperoxide (tert-BuOOH). Tert-BuOOH coadminstration reversed the TEMPOL-induced analgesia in the tonic intraplantar formalin response reduction. The data suggest that pro-oxidant species may be important mediators of tissue injury-induced algesia in rodents, and that a spinal site of action is implicated in the tonic response.}, }
@article {pmid16916625, year = {2006}, author = {Reliene, R and Goad, ME and Schiestl, RH}, title = {Developmental cell death in the liver and newborn lethality of Ku86 deficient mice suppressed by antioxidant N-acetyl-cysteine.}, journal = {DNA repair}, volume = {5}, number = {11}, pages = {1392-1397}, doi = {10.1016/j.dnarep.2006.06.007}, pmid = {16916625}, issn = {1568-7864}, support = {R01 ES09519/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Antigens, Nuclear/genetics ; Apoptosis/*drug effects/genetics ; DNA Degradation, Necrotic/drug effects ; *DNA Repair/genetics ; DNA-Binding Proteins/*deficiency/genetics ; Free Radical Scavengers/*pharmacology ; Genes, Lethal ; Ku Autoantigen ; Liver/*drug effects/embryology/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mortality ; Oxidative Stress/drug effects/physiology ; }, abstract = {Repair of DNA double-strand breaks (DSBs) is essential for genome integrity and cell survival. Ku86 is involved in the repair of DNA DSBs by non-homologous end joining (NHEJ). Mice deficient in Ku86 show growth retardation, dwarfism, premature aging, and immunodeficiency. In this study, we observed severely compromised survival of Ku86(-/-) mice, such that most Ku86(-/-) mice died within the first postnatal weeks and only 1.5% of the expected 25% from heterozygous crosses survived for 1 month. Since post-mortem analysis was not possible due to parental cannibalism, histopathological examination was performed on Ku86(-/-) fetuses to assess possible causes of newborn death. Eighty percent and 75% of Ku86(-/-) fetuses exhibited apoptosis and necrosis in the liver, while only 20% and 10% of Ku86(+/+) littermates had apoptosis and necrosis, respectively. In addition, the severity of liver damage was significantly higher in Ku86(-/-) fetuses. Developmental liver damage may have led to postnatal lethality because the fetal liver with pre-existing injury may not be able to undergo transformation from a lymphohematopoietic to an indispensable metabolic organ. Free radicals can cause chromosomal breaks and lead to cell death. We postulated that endogenous oxidative stress might be involved in the resulting liver damage and animal lethality in Ku86(-/-) mice deficient in DNA DSB repair. This hypothesis was tested by treating Ku86(-/-) mice with the well known free radical scavenger, thiol antioxidant N-acetyl-cysteine (NAC), during embryonic development. We found that a significantly higher percentage, 7.7% of NAC treated Ku86(-/-) offspring versus 1.5% untreated Ku86(-/-) mice were alive at 1 month of age. In addition, the incidence of liver necrosis decreased by 21% and the severity of necrosis significantly reduced. Thus, Ku86 deficiency results in severe developmental liver damage and newborn lethality associated with oxidative stress.}, }
@article {pmid16914459, year = {2006}, author = {Ristikankare, A and Kuitunen, T and Kuitunen, A and Uotila, L and Vento, A and Suojaranta-Ylinen, R and Salmenperä, M and Pöyhiä, R}, title = {Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure undergoing cardiac surgery.}, journal = {British journal of anaesthesia}, volume = {97}, number = {5}, pages = {611-616}, doi = {10.1093/bja/ael224}, pmid = {16914459}, issn = {0007-0912}, mesh = {Acetylcysteine/*therapeutic use ; Acetylglucosaminidase/urine ; Acute Kidney Injury/*prevention &amp; control ; Adult ; Aged ; Aged, 80 and over ; Biomarkers/blood/urine ; *Cardiac Surgical Procedures ; Cardiopulmonary Bypass ; Creatinine/blood/urine ; Cystatin C ; Cystatins/blood ; Double-Blind Method ; Female ; Free Radical Scavengers/therapeutic use ; Humans ; Kidney Failure, Chronic/*complications ; Male ; Middle Aged ; Postoperative Complications/*prevention &amp; control ; Preanesthetic Medication ; Prospective Studies ; Treatment Failure ; Water-Electrolyte Balance ; }, abstract = {BACKGROUND: Pre-existing chronic renal failure is a significant risk factor for acute renal failure (ARF) after cardiac surgery. N-acetylcysteine (NAC) has been shown to prevent contrast media-induced ARF. Our objective was to evaluate whether i.v. NAC has renoprotective effects in patients with mild renal failure undergoing cardiac surgery.<br><br>METHODS: In this prospective, randomized, double-blind study, 80 patients with mild to moderate renal failure undergoing elective heart surgery with cardiopulmonary bypass were recruited. All received either i.v. NAC (n=38) or placebo (n=39) at induction of anaesthesia and then up to 20 h. Urine N-acetyl-beta-D-glucosaminidase (NAG) and urine creatinine ratio, plasma creatinine, and serum cystatin C levels indicated renal function.<br><br>RESULTS: Levels of urinary NAG/creatinine ratio, plasma creatinine and serum cystatin C did not significantly differ between NAC and placebo groups during five postoperative days. Urine NAG/creatinine ratio increased over 30% in 100% of patients in the NAC group vs 92.3% in the placebo group (P=0.081). Plasma creatinine increased by 25% from baseline or over 44 mumol litre(-1) in 42.1% in NAC group vs 48.7% in placebo group (P=0.560). Serum cystatin C exceeded 1.4 mg litre(-1) in 78.9% in NAC group vs 61.5% in placebo group (P=0.096).<br><br>CONCLUSIONS: Prophylactic treatment with i.v. N-acetylcysteine had no renoprotective effect in patients with pre-existing renal failure undergoing cardiac surgery.}, }
@article {pmid16911944, year = {2006}, author = {Zhang, SJ and Ma, TW and Ma, XX and Gou, JJ and Shi, JH and Guo, WZ}, title = {Protective effects of N-acetylcysteine on brain-dead rat liver.}, journal = {Hepatobiliary &amp; pancreatic diseases international : HBPD INT}, volume = {5}, number = {3}, pages = {428-431}, pmid = {16911944}, issn = {1499-3872}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; *Brain Death ; Liver/*drug effects/pathology/ultrastructure ; Microscopy, Electron ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Brain-dead donors have been the main sources in organ transplantation. But many studies show that brain-death affects the organ's function after transplantation. This study was undertaken to investigate liver injury after brain-death in rats and the protective effects of N-acetyleysteine (NAC) on liver injury.<br><br>METHODS: A total of 30 Wistar rats were randomized into 3 groups: normal control group (C), brain-dead group (B), and NAC pretreatment group (N). At 4 hours after the establishment of a brain-dead model, serum was collected to determine the levels of ALT, AST, TNF-alpha and hyaluronic acid (HA). Hepatic tissue was obtained for electron microscopic examination.<br><br>RESULTS: At 4 hours, the levels of ALT, AST, TNF-alpha, and HA in group N were significantly higher than those in group C, but these parameters were significantly lower than those in group B. Electron microscopy showed activated Kupffer cells, denuded sinusoidal endothelial cells (SECs), and widened fenestration in group B, but eliminated activation of Kupffer cells and intact SECs in group N.<br><br>CONCLUSION: Brain death can cause liver injury, and N-acetyleysteine can protect the liver from the injury.}, }
@article {pmid16910765, year = {2006}, author = {Lucantoni, G and Pietraforte, D and Matarrese, P and Gambardella, L and Metere, A and Paone, G and Bianchi, EL and Straface, E}, title = {The red blood cell as a biosensor for monitoring oxidative imbalance in chronic obstructive pulmonary disease: an ex vivo and in vitro study.}, journal = {Antioxidants &amp; redox signaling}, volume = {8}, number = {7-8}, pages = {1171-1182}, doi = {10.1089/ars.2006.8.1171}, pmid = {16910765}, issn = {1523-0864}, support = {0F14//PHS HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Aged ; Anion Exchange Protein 1, Erythrocyte/metabolism ; Biosensing Techniques/*methods ; Case-Control Studies ; Cell Shape/drug effects/physiology ; Dose-Response Relationship, Drug ; Erythrocytes/drug effects/enzymology/*physiology/ultrastructure ; Female ; Glycophorins/metabolism ; Humans ; In Vitro Techniques ; Male ; Methemoglobin/analysis ; Oxidants/administration &amp; dosage/pharmacology ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Peroxynitrous Acid/administration &amp; dosage/pharmacology ; Protein Tyrosine Phosphatases/analysis ; Pulmonary Disease, Chronic Obstructive/*blood/*metabolism ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity in Western countries. The increased oxidative stress, caused by the release of reactive oxygen and nitrogen species (ROS/RNS) from inflammatory airways cells, contributes to the pathogenesis of the disease. The aim of the present study was to evaluate (a) whether the oxidative imbalance can lead to specific alterations of red blood cells (RBCs) from stable COPD patients; (b) whether treatment with N-acetyl-cysteine (NAC), in widespread use as mucolytic agent in clinical practice, can counteract these effects; and (c) whether an in vitro model represented by the exposure of RBC to ROS/RNS could mimic the in vivo situation. The results obtained clearly indicated that the RBC integrity and function are similarly altered in COPD patients and in ROS/RNS in vitro-treated samples and that NAC administration was capable of counteracting RBC oxidative modifications both in vivo, as detected by clinical and laboratory evaluations, and in vitro. Altogether these results point to RBC oxidative modifications as valuable bioindicators in the clinical management of COPD and indicate that in vitro RBC exposure to ROS/RNS as a useful tool in experimental studies aimed at the comprehension of the pathogenic mechanisms of the redox-associated diseases.}, }
@article {pmid16909692, year = {2006}, author = {Ramesh, N and Pillai, RK and Abraham, T and Padmaja, NP and Hameed, S and Vijayaraghavan, G}, title = {Reno-protective effect of N-acetyl cysteine in patients with impaired renal function undergoing coronary angiography and interventions.}, journal = {The Journal of the Association of Physicians of India}, volume = {54}, number = {}, pages = {449-452}, pmid = {16909692}, issn = {0004-5772}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Aged ; Contrast Media/*adverse effects ; *Coronary Angiography ; Creatinine/*blood ; Female ; Free Radical Scavengers/*pharmacology/therapeutic use ; Humans ; Kidney/*drug effects ; Kidney Diseases/*physiopathology ; Male ; Middle Aged ; Protective Agents/*pharmacology/therapeutic use ; Retrospective Studies ; }, abstract = {BACKGROUND: The increasingly frequent use of contrast enhanced imaging for diagnosis or interventions in patients with CAD has generated concern about avoidance of contrast induced nephropathy (CIN). Reactive oxygen species have been shown to cause CIN.<br><br>OBJECTIVES: Angiographic contrasts worsen the renal function in patients with renal failure. We studied the reno-protective action of the antioxidant N-Acetyl cysteine (NAC) in patients undergoing coronary procedures.<br><br>METHODS: Retrospective analysis of 51 patients with elevated serum creatinine levels (> or = 15mg%) was done, 24 of whom received NAC prior to the procedure(NAC group) and 27 who did not (Non NAC group). NAC was administered in a dose of 400 mg twice daily for four doses starting on the day prior to the procedure. Both groups of patients were hydrated with 0.45% saline at 1 ml/kg/hr for 12 hours prior to and 12 hours following the procedure. Both groups were comparable with regard to age, sex, coronary risk profile, myocardial infarction history, left ventricular function and the drugs received. Serum urea and creatinine were measured on the day prior to and the day following the angiographic procedure.<br><br>RESULTS: Nine out of 51 patients developed more than 0.5mg% rise in serum creatinine level; 1 in the NAC group and 8 in the non NAC group (p<0.05), 24 hours after injection of the contrast medium. In the NAC group mean serum creatinine level decreased from 1.94 +/- 0.56 to 1.67 +/- 0.56 and blood urea from 47.58 +/- 20 to 41.58 +/- 15.1. In the non NAC group serum creatinine increased from 1.75 +/- 0.31 to 1.98 +/- 0.56 and blood urea from 44.96 +/- 15.5 to 52.85 +/- 20.1 (p<0.05). This corresponds to an increase in creatinine clearance from 30ml/min to 35.92ml/min in the NAC group and a decrease from 34.42ml/min to 29.87ml/min in the non NAC group. There was no significant difference in the levels of sodium and potassium before and after the procedure in both the groups.<br><br>CONCLUSION: We conclude that prophylactit administration of N-Acetyl Cysteine along with hydration diminishes the incidence of deterioration of renal function induced by contrast agents in patients with renal insufficiency during coronary angiographic procedures.}, }
@article {pmid16904205, year = {2006}, author = {Donadelli, M and Dalla Pozza, E and Costanzo, C and Scupoli, MT and Piacentini, P and Scarpa, A and Palmieri, M}, title = {Increased stability of P21(WAF1/CIP1) mRNA is required for ROS/ERK-dependent pancreatic adenocarcinoma cell growth inhibition by pyrrolidine dithiocarbamate.}, journal = {Biochimica et biophysica acta}, volume = {1763}, number = {9}, pages = {917-926}, doi = {10.1016/j.bbamcr.2006.05.015}, pmid = {16904205}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/*drug therapy ; Animals ; Cell Cycle/*drug effects ; Cell Line, Tumor/cytology ; Cell Proliferation/*drug effects ; Cyclin-Dependent Kinase Inhibitor p21/genetics/*metabolism ; DNA Primers ; Fibroblasts ; Flavonoids/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Silencing ; Humans ; Immunoblotting ; Mice ; Oligonucleotides, Antisense ; Pancreatic Neoplasms/*drug therapy ; Pyrrolidines/*pharmacology/therapeutic use ; *RNA Stability ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Thiocarbamates/*pharmacology/therapeutic use ; }, abstract = {We present evidence that pyrrolidine dithiocarbamate (PDTC) inhibits growth of p53-negative pancreatic adenocarcinoma cell lines via cell cycle arrest in the S-phase, while it has no effect on primary fibroblast proliferation. Growth inhibition of cancer cells is dependent on ROS and ERK1/2 induction as indicated by a significantly reduced PDTC-associated growth inhibition by the free radical scavenger N-acetyl-L-cysteine (NAC) or the MEK/ERK1/2 inhibitor (PD98059). Moreover, ERK1/2 induction is dependent on ROS production as demonstrated by a complete removal of PDTC-mediated ERK1/2 phosphorylation by NAC. p21(WAF1/CIP1) activation has a central role in growth inhibition by PDTC, as revealed by P21(WAF1/CIP1) silencing experiments with antisense oligonucleotide, and occurs via increased mRNA stability largely mediated by ROS/ERK induction. Conversely, PDTC does not affect P21(WAF1/CIP1) gene expression in primary fibroblasts, although it is able to activate p53 and the p53-regulated antioxidant SESN2. These results suggest that the resistance of fibroblasts to the cytotoxic action of PDTC may be related to the up-regulation of p53-dependent antioxidant genes. Finally, in vivo studies on PaCa44 cells subcutaneously xenografted in nude mice show that treatment with 100 or 200 mg/kg PDTC reduces of 30% or 60% the tumour volume, respectively, and does not cause any apparent form of toxicity.}, }
@article {pmid16901114, year = {2006}, author = {Hartman, RF and Rose, SD}, title = {Kinetics and mechanism of the addition of nucleophiles to alpha,beta-unsaturated thiol esters.}, journal = {The Journal of organic chemistry}, volume = {71}, number = {17}, pages = {6342-6350}, doi = {10.1021/jo060191+}, pmid = {16901114}, issn = {0022-3263}, mesh = {Acetylcysteine/chemistry ; Esters/*chemistry ; Hydrogen-Ion Concentration ; Kinetics ; Molecular Structure ; Sulfhydryl Compounds/*chemistry ; }, abstract = {Compounds containing the UV-absorbing chromophores p-methoxycinnamate, p-methoxycinnamide, or anthranilate and an alpha,beta- or alpha,beta,gamma,delta-unsaturated thiol ester (crotonyl or sorboyl) have been prepared. These compounds are subject to nucleophilic attack at the C=C conjugated to the thiol ester carbonyl group. The kinetics of the reactions of these thiol esters with N-acetyl-l-cysteine (NAC), N-acetylcysteamine, and N(2)-acetyl-L-lysine (NAL) have been studied, and the thiol addition products have been identified. The reaction rates increased at higher pH, and the reaction of NAC thiolate with a crotonyl thiol ester in 1:1 (v/v) acetonitrile/aqueous HEPES exhibited buffer catalysis as a result of protonation of the enolate intermediate. At the same concentration, NAC underwent approximately 300-fold more reaction than NAL with a crotonyl thiol ester at pH 9.8. Additionally, a crotonyl thiol ester was found to be 7.9 times more reactive than a sorboyl thiol ester toward NAC addition. These unsaturated thiol esters may serve as a means of covalently binding UVA and UVB sunscreens to the outer layer of skin to provide long-lasting protection.}, }
@article {pmid16899047, year = {2006}, author = {Novitskiy, G and Traore, K and Wang, L and Trush, MA and Mezey, E}, title = {Effects of ethanol and acetaldehyde on reactive oxygen species production in rat hepatic stellate cells.}, journal = {Alcoholism, clinical and experimental research}, volume = {30}, number = {8}, pages = {1429-1435}, doi = {10.1111/j.1530-0277.2006.00171.x}, pmid = {16899047}, issn = {0145-6008}, support = {AA000626/AA/NIAAA NIH HHS/United States ; ES 07141/ES/NIEHS NIH HHS/United States ; ES03819/ES/NIEHS NIH HHS/United States ; R 2464388//PHS HHS/United States ; }, mesh = {Acetaldehyde/*pharmacology ; Animals ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Combinations ; Ethanol/*administration &amp; dosage ; Hepatocytes/*drug effects/*metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {BACKGROUND: Alcoholism is a common cause of cirrhosis. Hepatic stellate cells are the main source of collagen that ultimately leads to hepatic fibrosis and cirrhosis. Reactive oxygen species (ROS) enhance stellate cell activation and stimulate fibrogenesis. In this study, the acute effects of ethanol (ET) and acetaldehyde (AC) were determined on the production of ROS in isolated rat hepatic stellate cells.<br><br>METHODS: Rat stellate cells were isolated in situ by perfusion of the portal vein and cultured. Hydrogen peroxide (H(2)O(2)) was determined by luminol-derived chemiluminescence (CL), while superoxide anion (O(2*-)) production was assessed by the fluorescent probe hydroethidine.<br><br>RESULTS: AC increased the formation of H(2)O(2) and O(2*-), and these effects were first detectable at AC concentrations of 5 and 10 microM, respectively, reaching a maximum at 50 to 75 microM. Reduction of glutathione (GSH) synthesis by 1-buthionine sulfoximide (BSO) or by GSH conjugation with dimethylmaleate (DEM) further enhanced the effects of AC on H(2)O(2) and O(2*-) formation, while N-acetylcysteine (NAC) decreased H(2)O(2) and eliminated the enhanced generation of O(2*-) caused by AC. Raloxifene, which inhibits O(2*-) production by NAD(P)H oxidase, reduced the effects of AC on H(2)O(2) and O(2*-) production. ET increased H(2)O(2) or O(2*-) only in the presence of BSO or DEM.<br><br>CONCLUSION: This study shows that concentrations of AC, which occur in vivo after the ingestion of alcoholic beverages, result in the formation of ROS in rat hepatic stellate cells. The increases in ROS are known to activate stellate cells promoting fibrogenesis.}, }
@article {pmid16898491, year = {2006}, author = {Zaniew, M and Zachwieja, J and Lewandowska-Stachowiak, M and Sobczyk, D and Siwińska, A}, title = {[The antioxidant therapy modulates intracellular lymphokine expression in children on dialysis].}, journal = {Przeglad lekarski}, volume = {63 Suppl 3}, number = {}, pages = {63-67}, pmid = {16898491}, issn = {0033-2240}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adolescent ; Adult ; Antioxidants/pharmacology/*therapeutic use ; Child ; Child, Preschool ; Humans ; Infant ; Interferon-gamma/metabolism ; Interleukin-4/biosynthesis ; Interleukin-6/biosynthesis ; Kidney Failure, Chronic/*metabolism/*therapy ; Lymphokines/blood/*drug effects ; Male ; Oxidative Stress/drug effects ; Peritoneal Dialysis/adverse effects ; Poland ; Renal Dialysis/adverse effects ; T-Lymphocytes/*metabolism ; Treatment Outcome ; Vitamin E/pharmacology/*therapeutic use ; }, abstract = {UNLABELLED: Oxidative stress (SOX) is believed to be responsible for functional disabilities of lymphocytes in end-stage renal disease (ESRD). Therefore, we investigated the effect of antioxidant therapy with vitamin E and N-acetylcysteine (NAC) on SOX and cytokine synthesis in T cells in dialyzed children. Eighteen children (aged 2-20, mean 10.9 yr) treated with hemodialysis (n=5) and peritoneal dialysis (n=13) were enrolled into the study. Vitamin E and NAC were given orally for six months. Throughout the study, intracellular lymphokines [interleukin (IL)-2, interferon (IFN)-gamma, IL-4, IL-6] and SOX in T cells were measured by means of flow cytometry. In dialyzed children, mean fluorescence intensity (MFI), which reflected intracellular SOX, was significantly higher than in the controls in both CD3+ and CD3+CD4+ cells (p<0.05). We also found a cytokine dysregulation with a trend toward a predominant T helper (Th)-1 response compared to the controls. After 6 months of treatment with antioxidants, a significant reduction in MFI was noted compared to baseline values in CD3+ and CD3+CD4- cells (p<0.001). Interestingly, the therapy led to a decrease in IFN-gamma as well as an increase in IL-4 and IL-6 production. In addition, a gradual decline in IFN-gamma/IL-4 ratio in Th cells was noted.<br><br>CONCLUSIONS: Vitamin E and NAC used in combination are effective in reducing the intracellular SOX, and besides their action on cellular redox state, they modulate the cytokine profile in children on dialysis.}, }
@article {pmid16892853, year = {2006}, author = {Filatova, NA and Kirpichnikova, KM and Gamaleĭ, IA}, title = {[N-acetylcysteine reduces transformed 3T3-SV40 fibroblast sensitivity to lysis by natural killer cells].}, journal = {Tsitologiia}, volume = {48}, number = {5}, pages = {438-442}, pmid = {16892853}, issn = {0041-3771}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; Cell Line, Transformed ; Cell Transformation, Viral ; Cytotoxicity, Immunologic/*drug effects ; Free Radical Scavengers/*pharmacology ; Humans ; K562 Cells ; Killer Cells, Natural/*immunology ; Mice ; Simian virus 40 ; Spleen/immunology ; }, abstract = {We have shown that 18-20 h cultivation of transformed mouse fibroblasts 3T3-SV40 in the presence of antioxidant, N-acetylcysteine (NAC, 10 mM), did not change their sensitivity to lysis by natural killer (NK) mouse splenocytes. However, in 18-20 h after NAC removal 3T3-SV40 cells demonstrated resistance to NK cell activity. The cytotoxicity index (CI) was reduced up to 4.6 +/- 2.4 % (in comparison with the control value 31.8 +/- 2.4 %) approximating to the value in non-transformed 3T3 mouse fibroblasts. Normal 3T3 cells were resistant to NK action in all experimental conditions (CI varied within 0.7-5.3 %). These results show that NAC can induce partial reversion of transformed phenotype. We suggest that this effect may be due to the NAC-induced modifications of the cell surface and extracellular matrix proteins.}, }
@article {pmid16890983, year = {2007}, author = {Schweikl, H and Hartmann, A and Hiller, KA and Spagnuolo, G and Bolay, C and Brockhoff, G and Schmalz, G}, title = {Inhibition of TEGDMA and HEMA-induced genotoxicity and cell cycle arrest by N-acetylcysteine.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {23}, number = {6}, pages = {688-695}, doi = {10.1016/j.dental.2006.06.021}, pmid = {16890983}, issn = {0109-5641}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Cycle/*drug effects ; Cell Line ; Composite Resins/*toxicity ; Cricetinae ; Cricetulus ; DNA Damage/*drug effects ; Fibroblasts/drug effects ; Free Radical Scavengers/*pharmacology ; Methacrylates/*toxicity ; Micronucleus Tests ; Oxidative Stress/drug effects ; Polyethylene Glycols/*toxicity ; Polymethacrylic Acids/*toxicity ; Reactive Oxygen Species/toxicity ; }, abstract = {OBJECTIVES: Dental resin monomers like triethylene glycol dimethacrylate (TEGDMA) and 2-hydroxyethyl methacrylate (HEMA) are able to cause an imbalance of the redox state in mammalian cells. The resulting oxidative stress originating from reactive oxygen species (ROS) has been associated with cytotoxicity. We hypothesized that ROS might contribute to the generation of genotoxicity by TEGDMA and HEMA as well. Therefore, we examined the formation of micronuclei in V79 cells by both resin monomers in the presence of the antioxidant N-acetylcysteine (NAC), which scavenges ROS. In addition, we analyzed the effects of TEGDMA and HEMA on the normal cell cycle in the presence of NAC.<br><br>METHODS: V79 fibroblasts were exposed to increasing concentrations of TEGDMA and HEMA in the presence and absence of NAC for 24h. Genotoxicity was indicated by the formation of micronuclei. The modification of the normal cell cycle was analyzed by flow cytometry (FACS).<br><br>RESULTS: A dose-related increase in the number of micronuclei in V79 cells-induced by TEGDMA and HEMA indicated genotoxicity of both chemicals. However, the formation of micronuclei was reduced in the presence of 10 mmol/L NAC, indicating its protective role. A cell cycle delay in G2 phase caused by TEGDMA was absent when cells were co-treated with NAC. Similarly, the presence of NAC led to a reversion of the cell cycle delay in HEMA-treated cell cultures.<br><br>SIGNIFICANCE: Our results suggest that genotoxic effects and the modification of the cell cycle caused by TEGDMA and HEMA are mediated, at least in part, by oxidative stress.}, }
@article {pmid16889929, year = {2006}, author = {de Carvalho, DD and Costa, FT and Duran, N and Haun, M}, title = {Cytotoxic activity of violacein in human colon cancer cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {20}, number = {8}, pages = {1514-1521}, doi = {10.1016/j.tiv.2006.06.007}, pmid = {16889929}, issn = {0887-2333}, mesh = {Apoptosis/drug effects ; Caco-2 Cells ; Calcium/metabolism ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Survival/drug effects ; Colonic Neoplasms/*pathology ; Cytochromes c/metabolism ; Enzyme Activation/drug effects ; HT29 Cells ; Humans ; Indicators and Reagents ; Indoles/*toxicity ; Reactive Oxygen Species/metabolism ; Tetrazolium Salts ; Thiazoles ; }, abstract = {Several studies have shown that violacein, a purple pigment extracted from Chromobacterium violaceum, is capable to induce apoptosis in a variety of cancer cells, including those leukemia cell lines. Herein, we examined the effects of violacein on reactive oxygen species (ROS) production during the apoptotic colon cancer cell death. We demonstrate that violacein mediates ROS production followed by activation of Caspase-3, release of cytochrome c, and calcium release to citosol in Caco-2 cells. Moreover, presence of ROS scavengers such as N-acetyl-cysteine (NAC) diminishes ROS cytotoxicity induced by violacein in Caco-2 cells, indicating that violacein mediates cellular critical mechanisms in the triggering of apoptotic tumor cell death. These data also imply that violacein-induced ROS are collectively key mediators of mitochondrial membrane collapse, leading to cytochrome c release, and culminating in tumor apoptosis. Unlike in Caco-2 cells, violacein was incapable of increasing ROS levels in HT29 cells, suggesting the existence of violacein cell-type specific mechanisms. Those findings bring light to the violacein cytotoxic mechanism studies, indicating that oxidative stress play a role in the violacein-induced cytotoxicity.}, }
@article {pmid16887872, year = {2006}, author = {Peng, YJ and Yuan, G and Jacono, FJ and Kumar, GK and Prabhakar, NR}, title = {5-HT evokes sensory long-term facilitation of rodent carotid body via activation of NADPH oxidase.}, journal = {The Journal of physiology}, volume = {576}, number = {Pt 1}, pages = {289-295}, pmid = {16887872}, issn = {0022-3751}, support = {P01 HL025830/HL/NHLBI NIH HHS/United States ; HL-25830/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Action Potentials/physiology ; Animals ; Carotid Body/*physiology ; Electrophysiology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Ketanserin/pharmacology ; Male ; NADPH Oxidases/*physiology ; Neuronal Plasticity/physiology ; Neurons, Afferent/*physiology ; Phosphorylation ; Protein Kinase C/physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Serotonin/physiology ; Serotonin/*physiology ; Serotonin Antagonists/pharmacology ; Signal Transduction/physiology ; }, abstract = {5-Hydroxytryptamine (5-HT) evokes long-term activation of neuronal activity in the nervous system. Carotid bodies, the sensory organs for detecting arterial oxygen, express 5-HT. In the present study we examined whether 5-HT evokes sensory long-term facilitation (LTF) of the carotid body, and if so by what mechanism(s). Experiments were performed on anaesthetized adult rats and mice. Sensory activity was recorded from carotid bodies ex vivo. Spaced (3 x 15 s of 100 nm at 5 min intervals) but not mass (300 nm, 45 s) application of 5-HT elicited LTF, whereas both modes of 5-HT application evoked initial sensory excitation of the carotid bodies in rats. Ketanserin, a 5-HT(2) receptor antagonist prevented sensory LTF but not the initial sensory excitation. Spaced application of 5-HT activated protein kinase C (PKC) as evidenced by increased phosphorylations of PKC at Thr(514) and myristoylated alanine-rich C kinase substrate (MARCKS) and these effects were abolished by ketanserin as well as bisindolylmaleimide (Bis-1), an inhibitor of PKC. Bis-1 prevented 5-HT-evoked sensory LTF. 5-HT increased NADPH oxidase activity and PKC-dependent phosphorylation of p47(phox) subunit of the oxidase complex. NADPH oxidase inhibitors (apocynin and diphenyl iodinium), as well as an anti-oxidant (N-acetyl cysteine), prevented 5-HT-evoked sensory LTF. Mice deficient in gp91(phox), the membrane subunit of the NADPH oxidase complex, showed no sensory LTF, although responding to 5-HT with initial afferent nerve activation, whereas both LTF and initial excitation by 5-HT were seen in wild-type mice. These results demonstrate that spaced but not mass application of 5-HT elicits sensory LTF of the carotid body via activation of 5-HT(2) receptors, which involves a novel signalling mechanism coupled to PKC-dependent activation of NADPH oxidase.}, }
@article {pmid16872586, year = {2006}, author = {Fu, AL and Dong, ZH and Sun, MJ}, title = {Protective effect of N-acetyl-L-cysteine on amyloid beta-peptide-induced learning and memory deficits in mice.}, journal = {Brain research}, volume = {1109}, number = {1}, pages = {201-206}, doi = {10.1016/j.brainres.2006.06.042}, pmid = {16872586}, issn = {0006-8993}, mesh = {Acetylcholine/metabolism ; Acetylcholinesterase/metabolism ; Acetylcysteine/*administration &amp; dosage ; *Amyloid beta-Peptides ; Analysis of Variance ; Animals ; Behavior, Animal/drug effects ; Brain Chemistry/drug effects ; Choline O-Acetyltransferase/metabolism ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Drug Interactions ; Expectorants/*administration &amp; dosage ; Glutathione/metabolism ; Hippocampus/drug effects/pathology ; Injections, Intraventricular/methods ; Learning Disabilities/chemically induced/*prevention &amp; control ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred Strains ; }, abstract = {This study aimed to examine the effects of N-acetyl-L-cysteine (NAC) on protecting neurons function and improving learning and memory deficits in mice. Mice were intracerebroventricularly (icv) injected with the aggregated amyloid beta-peptide (Abeta) to produce Alzheimer's disease (AD). Learning and memory functions in mice were examined by the step through test and the water maze performance. The results showed that the mice pretreated with NAC had significantly greater retention in the step through test and shorter latencies in the water maze performance. Biochemical studies showed the potential role of free radical toxicity and the damage of cholinergic neurons in the Abeta-treated mice. There was an increased lipid peroxidation as indicated by elevated malondehyde (MDA) and decrease of glutathione (GSH) levels. There was also an increase in acetylcholinesterase (AChE) activity and a reduction in the choline acetyltransferase (ChAT) activity and acetylcholine (ACh) levels. NAC pretreatment significantly reversed the elevated MDA, AChE and the reduced GSH, ChAT and ACh in the Abeta-model mice. The results of the present study suggest the potential usage of the neuroprotective action of NAC on AD.}, }
@article {pmid16870182, year = {2006}, author = {Eisner, V and Criollo, A and Quiroga, C and Olea-Azar, C and Santibañez, JF and Troncoso, R and Chiong, M and Díaz-Araya, G and Foncea, R and Lavandero, S}, title = {Hyperosmotic stress-dependent NFkappaB activation is regulated by reactive oxygen species and IGF-1 in cultured cardiomyocytes.}, journal = {FEBS letters}, volume = {580}, number = {18}, pages = {4495-4500}, doi = {10.1016/j.febslet.2006.07.029}, pmid = {16870182}, issn = {0014-5793}, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspases/metabolism ; Cells, Cultured ; Insulin-Like Growth Factor I/*pharmacology ; Myocytes, Cardiac/drug effects/*metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Osmotic Pressure ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {We have recently shown that hyperosmotic stress activates p65/RelB NFkappaB in cultured cardiomyocytes with dichotomic actions on caspase activation and cell death. It remains unexplored how NFkappaB is regulated in cultured rat cardiomyocytes exposed to hyperosmotic stress. We study here: (a) if hyperosmotic stress triggers reactive oxygen species (ROS) generation and in turn whether they regulate NFkappaB and (b) if insulin-like growth factor-1 (IGF-1) modulates ROS production and NFkappaB activation in hyperosmotically-stressed cardiomyocytes. The results showed that hyperosmotic stress generated ROS in cultured cardiac myocytes, in particular the hydroxyl and superoxide species, which were inhibited by N-acetylcysteine (NAC). Hyperosmotic stress-induced NFkappaB activation as determined by IkappaBalpha degradation and NFkappaB DNA binding. NFkappaB activation and procaspase-3 and -9 fragmentation were prevented by NAC and IGF-1. However, this growth factor did not decrease ROS generation induced by hyperosmotic stress, suggesting that its actions over NFkappaB and caspase activation may be due to modulation of events downstream of ROS generation. We conclude that hyperosmotic stress induces ROS, which in turn activates NFkappaB and caspases. IGF-1 prevents NFkappaB activation by a ROS-independent mechanism.}, }
@article {pmid16868182, year = {2007}, author = {Hsu, HY and Wu, HL and Tan, SK and Li, VP and Wang, WT and Hsu, J and Cheng, CH}, title = {Geldanamycin interferes with the 90-kDa heat shock protein, affecting lipopolysaccharide-mediated interleukin-1 expression and apoptosis within macrophages.}, journal = {Molecular pharmacology}, volume = {71}, number = {1}, pages = {344-356}, doi = {10.1124/mol.106.024240}, pmid = {16868182}, issn = {0026-895X}, mesh = {Animals ; Apoptosis/*drug effects ; Benzoquinones/*pharmacology ; Cell Line ; HSP90 Heat-Shock Proteins/drug effects/*metabolism ; Interleukin-1beta/*metabolism ; Lactams, Macrocyclic/*pharmacology ; Lipopolysaccharides/*pharmacology ; Macrophages/*cytology/drug effects/*physiology ; Mice ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors ; }, abstract = {We have demonstrated that lipopolysaccharide (LPS)-mediated reactive oxygen species (ROS) and signal transduction are involved in the regulation of interleukin-1 (IL-1) beta gene expression within macrophages. Because the 90-kDa heat shock protein (Hsp90) plays an important role in the LPS mediation of macrophage activation, using Hsp90 inhibitor geldanamycin A (GA), we analyzed the mechanism of Hsp90 upon LPS-transduced signaling in the regulation of IL-1 expression and determined the function of Hsp90 regarding the viability of human primary macrophages and murine macrophages cell line. In essence, GA decreased LPS-induced Hsp90/pp60Src heterocomplex formation. In addition, Hsp90 is important for IL-1 protein translation, plays a minor role in IL-1 mRNA transcription, and is involved in nuclear factor-kappaB activation and the phosphorylation and activation of p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase; however, Hsp90 plays a more important role in LPS-stimulated p38 activation. In analyzing the function of Hsp90 regarding the cytotoxicity/viability of macrophages, we found that the combination of LPS and GA increases apoptosis, as evidenced by the increased caspase-3 activity and the proportion of nuclear/chromatin condensation. In contrast, N-acetyl-cysteine dramatically blocked GA/LPS-induced ROS production, simultaneously decreasing caspase-3 activity and the presence of apoptotic nuclei. We concluded that Hsp90 plays an indispensable role in the process of LPS-induced IL-1 secretion. Furthermore, we established the mechanism of GA interference with Hsp90 function for LPS-stimulated macrophages, resulting in increased ROS production and caspase-3 activation, and consequently leading to synergistic enhancement of macrophage apoptosis.}, }
@article {pmid16865267, year = {2006}, author = {De Flora, S and Scarfì, S and Izzotti, A and D'Agostini, F and Chang, CC and Bagnasco, M and De Flora, A and Trosko, JE}, title = {Induction by 7,12-dimethylbenz(a)anthracene of molecular and biochemical alterations in transformed human mammary epithelial stem cells, and protection by N-acetylcysteine.}, journal = {International journal of oncology}, volume = {29}, number = {3}, pages = {521-529}, pmid = {16865267}, issn = {1019-6439}, support = {PA42 ES049111/ES/NIEHS NIH HHS/United States ; }, mesh = {9,10-Dimethyl-1,2-benzanthracene/*toxicity ; Acetylcysteine/*pharmacology ; Acid Anhydride Hydrolases/metabolism ; Apoptosis/drug effects ; Carcinogens/*toxicity ; Cell Line, Transformed ; Cell Nucleus ; Cells, Cultured ; Connexin 43/metabolism ; Epithelial Cells/*drug effects/metabolism ; Free Radical Scavengers/*pharmacology ; Humans ; Mammary Glands, Human/*drug effects/metabolism ; NF-kappa B/genetics/metabolism ; Neoplasm Proteins/metabolism ; Protein Transport ; Receptor, ErbB-2/metabolism ; Stem Cells/*drug effects/metabolism ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {Several lines of evidence suggest that stem cells are major targets for carcinogens. A normal human breast epithelial cell type was previously shown to possess stem cell characteristics. Further cell lines were derived following sequential transfection with SV40 large T-antigen (immortal, non-tumorigenic M13SV1 cells), exposure to X-rays (weakly tumorigenic M13SV1R2 cells), and ectopic expression of c-erbB2/neu (highly tumorigenic M13SV1R2N1 cells). We evaluated some characteristics of these cells and their susceptibility to the breast carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Compared to M13SV1 cells, the two untreated tumorigenic cell lines displayed higher levels of connexin 43 expression and NF-kappaB nuclear translocation, and a higher frequency of fhit loss. The baseline nuclear translocation of AP-1 and pCREB was particularly evident in M13SV1R2N1 cells and was further enhanced by DMBA treatment, indicating an interaction between c-erbB2/neu and DMBA-induced signalling. Treatment with DMBA did neither affect the baseline fhit loss nor p53 mutation, whereas it increased NF-kappaB nuclear translocation, the proportion of apoptotic cells, and the levels of connexin 43, common 4977-bp mitochondrial DNA deletion, and bulky adducts to nuclear DNA. DMBA-treated M13SV1 cells underwent significant oxidative DNA damage and exhibited the highest DNA adduct levels, while they had the lowest apoptotic rate. Co-treatment of cells with N-acetylcysteine (NAC) attenuated DMBA-induced toxicity and DNA alterations, particularly in M13SV1 cells. Thus, the immortal cell line derived from the normal human adult breast stem cell without further tumorigenic progression is the most susceptible both to DMBA-related alterations and to the protective effects of NAC.}, }
@article {pmid16865238, year = {2006}, author = {Previati, M and Lanzoni, I and Corbacella, E and Magosso, S and Guaran, V and Martini, A and Capitani, S}, title = {Cisplatin-induced apoptosis in human promyelocytic leukemia cells.}, journal = {International journal of molecular medicine}, volume = {18}, number = {3}, pages = {511-516}, pmid = {16865238}, issn = {1107-3756}, mesh = {Apoptosis/*drug effects ; Cell Cycle/drug effects ; Cell Survival/drug effects ; Cisplatin/*pharmacology ; Dose-Response Relationship, Drug ; HL-60 Cells ; Humans ; Leukemia, Promyelocytic, Acute/*drug therapy ; Malondialdehyde/metabolism ; Protein Carbonylation/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Cis-diamminedichloroplatinum (II) cisplatin (CDDP) is an organometallic compound frequently used in anti-cancer therapy, in particular ovarian, testicular, and head and neck tumors. We found cisplatin was effective against human promyelocytic leukemia cell line HL-60, inhibiting cell cycle progression and inducing time- and concentration- dependent cell death. Presence of nuclear fragmentation, caspase-3 cleavage and annexin V positivity suggests cell death occurred by apoptosis, although DNA internucleosomal fragmentation was not detected. In addition, analysis of malondialdehyde (MDA) production and protein carbonylation indicated that cisplatin increased lipid peroxidation and oxidation of cell proteins. This occurrence was prevented by antioxidants such as N-acetylcysteine (N-aC) and glutathione (GSH), which, consistently, were also able to prevent CDDP-induced cell death. Collectively, these findings indicate that, besides growth inhibition, an increase of oxygen radicals and lipid degradation can account for a significant part of CDDP-induced apoptosis.}, }
@article {pmid16865059, year = {2006}, author = {Cetinkaya, A and Bulbuloglu, E and Kurutas, EB and Kantarceken, B}, title = {N-acetylcysteine ameliorates methotrexate-induced oxidative liver damage in rats.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {12}, number = {8}, pages = {BR274-8}, pmid = {16865059}, issn = {1234-1010}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Chemical and Drug Induced Liver Injury ; Glutathione/metabolism ; Liver/drug effects/metabolism ; Methotrexate/*toxicity ; Oxidants/metabolism ; *Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Methotrexate (MTX), a folic acid antagonist, is widely used as a cytotoxic chemotherapeutic agent for malignancies as well as in the treatment of various inflammatory diseases. The efficacy of this agent is often limited by severe side effects and toxic conditions. The present study was undertaken to determine whether N-acetylcysteine (NAC), as a potent antioxidant compound, could ameliorate MTX-induced oxidative liver damage.<br><br>MATERIAL/METHODS: A single dose of MTX (20 mg/kg, intraperitoneal) to rats was followed by intraperitoneal saline or NAC administration (150 mg/kg, MTX + NAC group) for the next 5 days. On the fifth day the rats were sacrificed and liver tissue samples were obtained and stored to measure reduced glutathione (GSH) and malondialdehyde (MDA) levels and myeloperoxidase (MPO), superoxide dismutase (SOD), and catalase (CAT) activity.<br><br>RESULTS: MTX caused decreased GSH level and SOD and CAT activity and increased MDA level and MPO activity in the liver homogenates. These changes were significantly reversed by NAC treatment.<br><br>CONCLUSIONS: These results confirm that administration of NAC decreases MTX-induced oxidative damage to the liver. These data indicate that NAC may be of therapeutic use in preventing hepatotoxicity in patients receiving MTX treatment.}, }
@article {pmid16864970, year = {2006}, author = {Eşrefoğlu, M and Gül, M and Ateş, B and Yilmaz, I}, title = {Ultrastructural clues for the protective effect of ascorbic acid and N-acetylcysteine against oxidative damage on caerulein-induced pancreatitis.}, journal = {Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]}, volume = {6}, number = {5}, pages = {477-485}, doi = {10.1159/000094665}, pmid = {16864970}, issn = {1424-3903}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/therapeutic use ; Ascorbic Acid/*therapeutic use ; Ceruletide/*toxicity ; Female ; Gastrointestinal Agents/toxicity ; Oxidative Stress ; Pancreas/drug effects/pathology/ultrastructure ; Pancreatitis/*chemically induced/*drug therapy/pathology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Oxygen free radicals (OFR) have been implicated in the induction of acute pancreatitis (AP).<br><br>AIMS: The aim of this study was to determine the effect of ascorbic acid and N-acetylcysteine (NAC), potent antioxidants, against oxidative stress in AP.<br><br>METHODS: AP was induced by two i.p. injections of caerulein at 2-hour intervals (50 microg/kg BW). One group received additionally an antioxidant mixture composed of L(+)-ascorbic acid (14.3 mg/kg BW) and NAC (181 mg/kg BW) i.p. The rats were sacrificed 12 h after the last injection. Oxidative stress markers were evaluated. Light-microscopic and ultrastructural examination was performed.<br><br>RESULTS: Formation of vacuoles, mitochondrial damage, and dilatation of rough endoplasmic reticulum, margination and clumping of chromatin were major ultrastructural alterations in AP group. Ascorbic acid + NAC prevented these changes. Small vacuoles were present within the cytoplasm of some of the acinar cells. Pancreas damage was accompanied by an increase in tissue malondialdehyde (MDA) levels (p < 0.05), whereas a decrease was seen in catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities and total glutathione (GSH) levels (p < 0.005). Ascorbic acid + NAC decreased MDA levels but increased CAT, SOD, GPx activities and GSH levels (p < 0.005).<br><br>CONCLUSION: These results suggest that ascorbic acid + NAC is potentially capable of limiting pancreatic damage produced during AP via protecting fine structure of acinar cells and tissue antioxidant enzyme activities.}, }
@article {pmid16860347, year = {2006}, author = {Hsu, BG and Lee, RP and Yang, FL and Harn, HJ and Chen, HI}, title = {Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats.}, journal = {Life sciences}, volume = {79}, number = {21}, pages = {2010-2016}, doi = {10.1016/j.lfs.2006.06.040}, pmid = {16860347}, issn = {0024-3205}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Blood Pressure/drug effects ; Cytokines/metabolism ; Drug Administration Schedule ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Heart/drug effects ; Heart Rate/drug effects ; Kidney/drug effects/pathology ; Kidney Function Tests ; Lipopolysaccharides ; Liver/drug effects/pathology ; Liver Function Tests ; Male ; Multiple Organ Failure/*drug therapy/etiology/pathology/physiopathology ; Myocardium/pathology ; Rats ; Rats, Inbred WKY ; Shock, Septic/chemically induced/complications/pathology/physiopathology ; }, abstract = {N-acetylcysteine (NAC) is an antioxidant and cytoprotective agent with scavenging action against reactive oxygen species and inhibitory effects on pro-inflammatory cytokines. In a previous study, we found that pretreatment with NAC attenuated organ dysfunction and damage, reduced the production of free radicals, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) following endotoxemia elicited by administration of lipopolysaccharide (LPS). In the present study, we tested the effects of post-treatment with NAC on the sepsis-induced change. Post-treatment imitates clinical therapeutic regimen with administration of drug after endotoxemia. Endotoxin shock was induced by intravenous injection of Klebsiella pneumoniae LPS (10 mg/kg) in conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored for 48 h after LPS administration. NAC was given 20 min after LPS. Measurements of biochemical substances were taken to reflect organ functions. Biochemical factors included blood urea nitrogen (BUN), creatinine (Cre), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate transferase (GOT), alanine transferase (GPT), TNF-alpha, interleukin-6 (IL-6), and interleukin-10 (IL-10). LPS significantly increased blood BUN, Cre, LDH, CPK, GOT, GPT, TNF-alpha, IL-6, IL-10 levels and HR, and decreased MAP. Post-treatment with NAC diminished the decrease in MAP, increased the HR, and decreased the markers of organ injury (BUN, Cre, LDH, CPK, GOT, GPT) and inflammatory biomarkers (TNF-alpha, IL-6, IL-10) after LPS. We conclude that post-treatment with NAC suppresses the release of plasma TNF-alpha, IL-6, and IL-10 in endotoxin shock, and decreases the markers of organ injury. These beneficial effects protect against LPS-induced kidney, heart and liver damage in conscious rats. The beneficial effects may suggest a potential chemopreventive effect of this compound after sepsis.}, }
@article {pmid16859674, year = {2006}, author = {Emara, M and Cheung, PY}, title = {Inhibition of sulfur compounds and antioxidants on MMP-2 and -9 at the activity level found during neonatal hypoxia-reoxygenation.}, journal = {European journal of pharmacology}, volume = {544}, number = {1-3}, pages = {168-173}, doi = {10.1016/j.ejphar.2006.06.044}, pmid = {16859674}, issn = {0014-2999}, mesh = {Animals ; Animals, Newborn ; Antioxidants/*metabolism ; Brain/metabolism ; Enzyme Activation ; Heart Ventricles/metabolism ; Hypoxia/*pathology ; Inhibitory Concentration 50 ; Liver/metabolism ; Lung/metabolism ; Matrix Metalloproteinase 2/*metabolism ; Matrix Metalloproteinase 9/*metabolism ; Oxygen/metabolism ; Recombinant Proteins/chemistry ; Reperfusion Injury/*metabolism ; Sulfur Compounds/chemistry/*pharmacology ; Swine ; }, abstract = {The inhibitory effect of different sulfur compounds and antioxidants at the activity level of matrix metalloproteinase (MMP)-2 and -9 during neonatal hypoxia-reoxygenation is unknown. The tissue activity of MMP-2 and -9 was first determined by gelatin zymography in different tissues of 6 newborn piglets that underwent alveolar hypoxia and reoxygenation. The in vitro inhibitory effects of sulfur compounds and antioxidants with or without the thiol group were compared at the highest concentrations of MMP-2 and -9 found. These compounds included: amino acids containing sulfur [cysteine, DL-homocysteine, L-methionine] and not containing sulfur [L-histidine], antioxidants containing sulfur [L-glutathione and N-acetyl-cysteine] and not containing sulfur [ascorbic acid], and oxidized glutathione. Lung had the highest activity of MMP-2 and -9 among the tissues studied. The compounds showed differential effects on the activity of MMP-2 and -9. The order of the potency of inhibition of these compounds for MMP-2 was cysteine> or =histidine> or =ascorbic acid> or =glutathione> or =oxidized glutathione> or =homocysteine> or =N-acetyl-cysteine>methionine, whereas for MMP-9, it was cysteine> or =ascorbic acid> or =histidine>glutathione>homocysteine>N-acetyl-cysteine>oxidized glutathione>methionine. The IC50 values of these compounds on MMP-2 were significantly lower than the corresponding IC50 values on MMP-9. In conclusions, at the activity level of MMP-2 and -9 measured after neonatal hypoxia-reoxygenation, cysteine showed the highest potency of inhibition. The compounds showed different potencies of inhibition, regardless of the presence or absence of the thiol group or the antioxidant property of the compound.}, }
@article {pmid16854635, year = {2006}, author = {Oguri, S and Nomura, M and Fujita, Y}, title = {Site-specific sampling of taurine from rat brain followed by on-line sample pre-concentration, throughout in-capillary derivatization and capillary electrophoresis.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {843}, number = {2}, pages = {194-201}, doi = {10.1016/j.jchromb.2006.06.008}, pmid = {16854635}, issn = {1570-0232}, mesh = {Analytic Sample Preparation Methods/methods ; Animals ; *Brain Chemistry ; Electrophoresis, Capillary/*methods ; Online Systems ; Rats ; Taurine/*analysis/isolation &amp; purification ; Telencephalon/chemistry ; Tissue Distribution ; }, abstract = {A method of pinpoint-sampling followed by on-line pre-concentration of the sample, throughout in-capillary derivatization and capillary electrophoretic separation was evaluated by demonstrating the detection of taurine, 2-aminoethanesulfonic acid at a specific location of a rat brain. The direct sampling of taurine from the rat brain was accomplished by using voltage injection associated with two kinds of driving forces, electrophoretic flow and electroosmotic flow (EOF). The capillary tube (75 microm of inner diameter x 375 microm of outer diameter) of the capillary electrophoresis (CE) apparatus was already filled with a CE run buffer, viz., 40 mM phosphate-borate buffer (pH 10) containing 2mM o-phthalaldehyde (OPA)/N-acetylcysteine (NAC) as the derivatization reagent. One end of a platinum wire (0.5mm o.d.), used as the anode, and the inlet end of capillary tube (from which a 1.0 cm long polyimide coating was removed), were pricked down onto the surface of either the cerebrum or cerebellum of a rat brain at a location of very small dimension. When a low voltage (5 kV, 30s) was applied, taurine began to move from the rat brain into the capillary tube, and, simultaneously, electric focusing of taurine occurred by the action of "the pH-junction effect" at the inlet end of the capillary tube. After completing the injection, both the platinum wire and capillary tube were detached from the brain and dipped into the run buffer in an anode reservoir filed with the same solution as that in the capillary tube for the CE apparatus. Then, by applying a high voltage (20 kV) between the ends of the capillary tube, taurine was automatically derivatized to yield the fluorescent derivative, separated and detected with fluorescence (E(x)=340 nm, E(m)=455 nm) during migration throughout the capillary tube. The migration profiles obtained from cerebrum and cerebellum appeared to be different, but the peak corresponding to taurine was identified on both electropherograms. The efficacy of the present method including sample on-line pre-concentration prior to throughout in-capillary derivatization CE was first verified with several preliminary experiments by using samples of taurine in water, saline and a piece of 1.5% agar-gel block, as an alternate standard for the rat brain used in this study.}, }
@article {pmid16849722, year = {2006}, author = {Andersson, H and Hartmanová, B and Rydén, P and Noppa, L and Näslund, L and Sjöstedt, A}, title = {A microarray analysis of the murine macrophage response to infection with Francisella tularensis LVS.}, journal = {Journal of medical microbiology}, volume = {55}, number = {Pt 8}, pages = {1023-1033}, doi = {10.1099/jmm.0.46553-0}, pmid = {16849722}, issn = {0022-2615}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Clone Cells/metabolism ; *Francisella tularensis/growth &amp; development ; Free Radical Scavengers/pharmacology ; Gene Expression Profiling ; Glutathione/genetics/metabolism ; Inflammation/pathology ; Macrophages/drug effects/metabolism/microbiology ; Mice ; Nitric Oxide Synthase Type II/pharmacology ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress ; Time Factors ; Tularemia/*microbiology/pathology ; Tumor Necrosis Factor-alpha/genetics/metabolism ; }, abstract = {The response of cells of the mouse macrophage cell line J774 to infection with Francisella tularensis LVS was analysed by means of a DNA microarray representing approximately 18,500 genes (20,600 clones). The adaptive response was modest at all time points, and at most, 81 clones were differentially regulated from the time point of uptake of bacteria (0 min) up to 240 min later. For all five time points, 229 clones fulfilled the criteria of being differentially regulated, i.e. the ratio between infected versus non-infected cells was at least 1.7-fold up- or down-regulated and P <0.05. It was found that many of the differentially regulated genes are known to respond to stress in general and to oxidative stress specifically. However, at 120 min it was observed that genes that lead to depletion of glutathione were upregulated. Possibly, this was a result of mechanisms induced by F. tularensis. Generally, there was a conspicuous lack of inflammatory responses and, for example, although tumour necrosis factor alpha (TNF-alpha) was upregulated at 0 min, a significant down-regulation was noted at all subsequent time points. When cells were treated with an inhibitor of inducible nitric oxide synthase (iNOS) or the antioxidant N-acetylcysteine (NAC), the infection-induced cytopathogenic effect was significantly inhibited. Together, the results suggest that F. tularensis LVS infection confers an oxidative stress upon the target cells and that many of the host-defence mechanisms appear to be intended to counteract this stress. The infection is characterized by a very modest inflammatory response.}, }
@article {pmid16843502, year = {2006}, author = {Fimognari, C and Nüsse, M and Lenzi, M and Sciuscio, D and Cantelli-Forti, G and Hrelia, P}, title = {Sulforaphane increases the efficacy of doxorubicin in mouse fibroblasts characterized by p53 mutations.}, journal = {Mutation research}, volume = {601}, number = {1-2}, pages = {92-101}, doi = {10.1016/j.mrfmmm.2006.06.001}, pmid = {16843502}, issn = {0027-5107}, mesh = {Animals ; Antibiotics, Antineoplastic/pharmacology ; Anticarcinogenic Agents/pharmacology ; Apoptosis/drug effects ; Caspases/metabolism ; Cell Line ; Cell Membrane Permeability/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Doxorubicin/*pharmacology ; Drug Resistance, Neoplasm/drug effects/genetics ; Drug Synergism ; Enzyme Activation/drug effects ; Fibroblasts/cytology/*drug effects/metabolism ; Isothiocyanates ; Mice ; Mutation/*genetics ; Sulfoxides ; Thiocyanates/*pharmacology ; Tumor Suppressor Protein p53/*genetics ; }, abstract = {One novel strategy for increasing cancer chemotherapy efficacy and reversing chemoresistance involves co-administration of natural chemopreventive compounds alongside standard chemotherapeutic protocols. Sulforaphane is a particularly promising chemopreventive agent, which has been shown to exert proapoptotic effects on tumor cells containing p53 mutations. The p53(Ser220) mutation has been implicated in reduced efficacy and drug resistance in the context of osteosarcomas and breast tumors treated with doxorubicin-based protocols. We investigated the effects of a combination of doxorubicin and sulforaphane on cell viability and apoptosis induction in fibroblasts characterized by different p53 status (p53 wild-type, p53 knock-out, and p53(Ser220) mutation), and identified some of the molecular pathways triggered by the drug combination. Very high concentrations of doxorubicin were necessary to decrease the viability of p53(Ser220) and p53 knock-out (but not wild-type) cells. Treatment of p53(Ser220) and p53 knock-out cells with doxorubicin did not induce apoptosis, also at very high concentrations (10muM). Sulforaphane restored chemosensitivity and induced apoptosis in doxorubicin-resistant p53(Ser220) and p53 knock-out cells, irrespective of p53 status. The induction of apoptosis was caspase-3 dependent and caspase-8 independent. Bongkrekic acid, a mitochondrial membrane stabilizer, partially prevented the effects of doxorubicin plus sulforaphane on mitochondrial permeability but was unable to prevent the induction of apoptosis. N-acetyl-cysteine, a glutathione precursor, blocked the induction of apoptosis by doxorubicin plus sulforaphane. Considering the negligible safety profile of sulforaphane, our findings could prompt innovative clinical studies designed to investigate whether its coadministration can enhance the efficacy of doxorubicin-based regimens.}, }
@article {pmid16842099, year = {2006}, author = {Tucker, S and Ahl, M and Cho, HH and Bandyopadhyay, S and Cuny, GD and Bush, AI and Goldstein, LE and Westaway, D and Huang, X and Rogers, JT}, title = {RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl cysteine.}, journal = {Current Alzheimer research}, volume = {3}, number = {3}, pages = {221-227}, doi = {10.2174/156720506777632835}, pmid = {16842099}, issn = {1567-2050}, support = {5K01MH002001/MH/NIMH NIH HHS/United States ; AG21081/AG/NIA NIH HHS/United States ; }, mesh = {5' Untranslated Regions/drug effects/genetics ; Acetylcysteine/*pharmacology/therapeutic use ; Alzheimer Disease/*drug therapy/genetics/metabolism ; Amyloid beta-Protein Precursor/drug effects/*genetics/metabolism ; Animals ; Brain/drug effects/metabolism ; Drug Evaluation, Preclinical ; Drugs, Investigational/*pharmacology/therapeutic use ; Erythromycin/*pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; Paroxetine/*pharmacology/therapeutic use ; Peptide Fragments/drug effects/genetics/metabolism ; Pilot Projects ; Protein Biosynthesis/drug effects ; Protein Synthesis Inhibitors/pharmacology/therapeutic use ; RNA, Messenger/*drug effects ; }, abstract = {Lead compounds directed to the 5' leader of the Amyloid Precursor Protein transcript (i.e., paroxetine (SSRI), N-acetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic)) were employed in a pilot study to evaluate their anti-amyloid efficacy in the TgCRND8 transgenic mouse model for Alzheimer's Disease (AD). The relative levels of Abeta peptide were reduced after exposure of mice to paroxetine (N=5), NAC (N=7), and erythromycin (N=7) relative to matched placebo counterparts. Paroxetine limited the levels of APP holoprotein and total Abeta peptide levels (measurements of Abeta were performed at two separate sites by quantitative western blotting and ELISA assay). The paroxetine data provided proof-of-concept for our strategy for further screening the APP 5'UTR target to identify novel drugs that exhibit anti-amyloid efficacy in vivo. Erythromycin and azithromycin were macrolide antibiotics that markedly changed the cleavage of the APP C-Terminal Fragment (CTF) in SH-SY5Y cells. Erythromycin provided orally to TgCRND8 mice consistently (100%) reduced brain Abeta(1-42) levels. These data demonstrated a highly statistically significant anti-amyloid trend for paroxetine, NAC and erythromycin. The potential for conducting further studies with these compounds using larger cohorts of TgCRND8 mice is discussed, particularly since erythromycin has recently been exposed to mice for a further 6 months (N=6). It will be possible to employ the chemical structures of paroxetine and erythromycin as starting points for drug design and development for AD therapeutics.}, }
@article {pmid16841248, year = {2006}, author = {Brandão, R and Santos, FW and Zeni, G and Rocha, JB and Nogueira, CW}, title = {DMPS and N-acetylcysteine induced renal toxicity in mice exposed to mercury.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {19}, number = {4}, pages = {389-398}, doi = {10.1007/s10534-005-4020-3}, pmid = {16841248}, issn = {0966-0844}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/metabolism ; Animals ; Antidotes/pharmacology ; Aspartate Aminotransferases/metabolism ; Benzene Derivatives/pharmacology ; Body Weight/drug effects ; Creatine/metabolism ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; Kidney/*drug effects/metabolism/pathology ; Lipid Metabolism/drug effects ; Liver/drug effects/metabolism ; Male ; Mercuric Chloride/toxicity ; Mercury/*toxicity ; Mercury Poisoning/metabolism/mortality/prevention &amp; control ; Mice ; Organoselenium Compounds/pharmacology ; Porphobilinogen Synthase/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; Unithiol/*pharmacology ; Urea/metabolism ; }, abstract = {Acute effects of mercuric chloride (HgCl2) were evaluated on mice. Mice received a single dose of HgCl2 (4.6 mg/kg, subcutaneously) for three consecutive days. Thirty minutes after the last injection with HgCl2, mice received one single injection of 2,3-dimercapto-1-propanesulfonic acid (DMPS) or N-acetylcysteine (NAC) or diphenyl diselenide (PhSe)2. DMPS, NAC and (PhSe)2 were utilized as therapy against mercury exposure. At 24 h after the last HgCl2 injection, blood, liver and kidney samples were collected. delta-Aminolevulinate dehydratase (delta-ALA-D) and Na+, K- (+) ATPase activities, thiobarbituric acid-reactive substances (TBARS), non-protein thiols (NPSH) and ascorbic acid concentrations were evaluated. Plasma aspartate (AST) and alanine (ALT) aminotransferase activities, as well as urea and creatinine levels were determined. The group of mice exposed to Hg + (PhSe)2 presented 100% of lethality. Exposure with HgCl2 caused a decrease on the body weight gain and treatments did not modify this parameter. delta-ALA-D, AST and ALT activities, TBARS, ascorbic acid levels and NPSH (hepatic and erythrocytic) levels were not changed after HgCl2 exposure. HgCl2 caused an increase in renal NPSH content and therapies did not modify these levels. Mice treated with (PhSe)2, Hg + NAC and Hg + DMPS presented a reduction in plasma NPSH levels. Creatinine and urea levels were increased in mice exposed to Hg + NAC, while Hg + DMPS group presented an increase only in urea level. Na+, K- (+) ATPase activity was inhibited in mice exposed to Hg + DMPS and Hg + NAC. In conclusion, therapies with (PhSe)2, DMPS and NAC following mercury exposure must be better studied because the formation of more toxic complexes with mercury, which can mainly damage renal tissue.}, }
@article {pmid16840514, year = {2006}, author = {McKenna, MJ and Medved, I and Goodman, CA and Brown, MJ and Bjorksten, AR and Murphy, KT and Petersen, AC and Sostaric, S and Gong, X}, title = {N-acetylcysteine attenuates the decline in muscle Na+,K+-pump activity and delays fatigue during prolonged exercise in humans.}, journal = {The Journal of physiology}, volume = {576}, number = {Pt 1}, pages = {279-288}, pmid = {16840514}, issn = {0022-3751}, mesh = {Acetylcysteine/*pharmacology ; Acid-Base Equilibrium/physiology ; Adult ; Cross-Over Studies ; Double-Blind Method ; Exercise Test ; Free Radical Scavengers/*pharmacology ; Humans ; Male ; Muscle Contraction/drug effects/physiology ; Muscle Fatigue/*drug effects/physiology ; Muscle, Skeletal/drug effects/enzymology/physiology ; Physical Endurance/*physiology ; Potassium/blood ; *Reactive Oxygen Species ; Sodium-Potassium-Exchanging ATPase/*drug effects/physiology ; }, abstract = {Reactive oxygen species (ROS) have been linked with both depressed Na(+),K(+)-pump activity and skeletal muscle fatigue. This study investigated N-acetylcysteine (NAC) effects on muscle Na(+),K(+)-pump activity and potassium (K(+)) regulation during prolonged, submaximal endurance exercise. Eight well-trained subjects participated in a double-blind, randomised, crossover design, receiving either NAC or saline (CON) intravenous infusion at 125 mg kg(-1) h(-1) for 15 min, then 25 mg kg(-1) h(-1) for 20 min prior to and throughout exercise. Subjects cycled for 45 min at 71% , then continued at 92% until fatigue. Vastus lateralis muscle biopsies were taken before exercise, at 45 min and fatigue and analysed for maximal in vitro Na(+),K(+)-pump activity (K(+)-stimulated 3-O-methyfluorescein phosphatase; 3-O-MFPase). Arterialized venous blood was sampled throughout exercise and analysed for plasma K(+) and other electrolytes. Time to fatigue at 92% was reproducible in preliminary trials (c.v. 5.6 +/- 0.6%) and was prolonged with NAC by 23.8 +/- 8.3% (NAC 6.3 +/- 0.5 versus CON 5.2 +/- 0.6 min, P < 0.05). Maximal 3-O-MFPase activity decreased from rest by 21.6 +/- 2.8% at 45 min and by 23.9 +/- 2.3% at fatigue (P < 0.05). NAC attenuated the percentage decline in maximal 3-O-MFPase activity (%Deltaactivity) at 45 min (P < 0.05) but not at fatigue. When expressed relative to work done, the %Deltaactivity-to-work ratio was attenuated by NAC at 45 min and fatigue (P < 0.005). The rise in plasma [K(+)] during exercise and the Delta[K(+)]-to-work ratio at fatigue were attenuated by NAC (P < 0.05). These results confirm that the antioxidant NAC attenuates muscle fatigue, in part via improved K(+) regulation, and point to a role for ROS in muscle fatigue.}, }
@article {pmid16831439, year = {2006}, author = {Badawy, A and Baker El Nashar, A and El Totongy, M}, title = {Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial.}, journal = {Fertility and sterility}, volume = {86}, number = {3}, pages = {647-650}, doi = {10.1016/j.fertnstert.2006.02.097}, pmid = {16831439}, issn = {1556-5653}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Clomiphene/*administration &amp; dosage ; Double-Blind Method ; Drug Combinations ; Egypt/epidemiology ; Female ; Fertility Agents, Female/administration &amp; dosage ; Humans ; Infertility, Female/*epidemiology/pathology/*therapy ; Ovulation Induction/methods/*statistics &amp; numerical data ; Pregnancy ; Pregnancy Outcome/*epidemiology ; Treatment Outcome ; }, abstract = {OBJECTIVE: To compare clomiphene citrate with N-acetyl cysteine vs. clomiphene citrate alone for augmenting ovulation in management of unexplained infertility.<br><br>DESIGN: Prospective randomized double-blind controlled trial.<br><br>SETTING: Department of obstetrics and gynecology in a university medical faculty in Egypt.<br><br>PATIENT(S): Four hundred four patients as a study group (clomiphene citrate plus N-acetyl cysteine group) and 400 patients as a control group (clomiphene citrate-alone group). All women had unexplained infertility.<br><br>INTERVENTION(S): Patients in the study group were treated with clomiphene citrate (50-mg tablets) twice per day and with N-acetyl cysteine (1,200 mg/d orally) for 5 days starting on day 2 of the cycle. Patients in the control group were treated with clomiphene citrate with sugar powder.<br><br>MAIN OUTCOME MEASURE(S): The primary outcomes were number and size of growing follicles, serum E(2), serum P, and endometrial thickness. The secondary outcome was the occurrence of pregnancy.<br><br>RESULT(S): There were no statistically significant differences between the two groups in the number of follicles sized >18 mm, mean E(2) levels, serum P, or endometrial thickness. Pregnancy rate was comparable in both groups (22.2% vs. 27%). Miscarriage rate was comparable in both groups (6.7% in the study group vs. 7.4% in the control group).<br><br>CONCLUSION(S): N-Acetyl cysteine is ineffective in inducing or augmenting ovulation in patients with unexplained infertility and cannot be recommended as an adjuvant to clomiphene citrate in such patients.}, }
@article {pmid16828758, year = {2006}, author = {Su, M and Yang, Y and Yang, G}, title = {Quantitative measurement of hydroxyl radical induced DNA double-strand breaks and the effect of N-acetyl-L-cysteine.}, journal = {FEBS letters}, volume = {580}, number = {17}, pages = {4136-4142}, doi = {10.1016/j.febslet.2006.06.060}, pmid = {16828758}, issn = {0014-5793}, support = {GM 071793/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*chemistry ; Animals ; *DNA Damage ; Humans ; Hydroxyl Radical/*chemistry ; Microscopy, Atomic Force ; Nucleic Acid Conformation ; Plasmids/*chemistry ; }, abstract = {Reactive oxygen species, such as hydroxyl or superoxide radicals, can be generated by exogenous agents as well as from normal cellular metabolism. Those radicals are known to induce various lesions in DNA, including strand breaks and base modifications. These lesions have been implicated in a variety of diseases such as cancer, arteriosclerosis, arthritis, neurodegenerative disorders and others. To assess these oxidative DNA damages and to evaluate the effects of the antioxidant N-acetyl-L-cysteine (NAC), atomic force microscopy (AFM) was used to image DNA molecules exposed to hydroxyl radicals generated via Fenton chemistry. AFM images showed that the circular DNA molecules became linear after incubation with hydroxyl radicals, indicating the development of double-strand breaks. The occurrence of the double-strand breaks was found to depend on the concentration of the hydroxyl radicals and the duration of the reaction. Under the conditions of the experiments, NAC was found to exacerbate the free radical-induced DNA damage.}, }
@article {pmid16819733, year = {2006}, author = {Li, WW and Hellwig, P and Ritter, M and Haehnel, W}, title = {De novo design, synthesis, and characterization of quinoproteins.}, journal = {Chemistry (Weinheim an der Bergstrasse, Germany)}, volume = {12}, number = {27}, pages = {7236-7245}, doi = {10.1002/chem.200501212}, pmid = {16819733}, issn = {0947-6539}, mesh = {Amino Acid Sequence ; Chromatography, Gel ; Circular Dichroism ; Electrochemistry ; Models, Molecular ; Molecular Sequence Data ; Oxidation-Reduction ; Peptides, Cyclic/chemical synthesis/chemistry ; Protein Structure, Secondary ; Proteins/chemical synthesis/*chemistry ; Quinones/chemical synthesis/*chemistry ; Spectrometry, Mass, Electrospray Ionization ; Spectrophotometry, Ultraviolet ; Spectroscopy, Fourier Transform Infrared ; }, abstract = {Quinones and quinoproteins are essential redox components and enzymes in biological systems. Here, we report the de novo design, synthesis, and properties of model four-alpha-helix bundle quinoproteins. The proteins were designed and constructed from three different helices with 21 or 22 amino acid residues by chemoselective ligation to a cyclic decapeptide template. A free cysteine unit is placed at the hydrophobic core of the protein for binding of ubiquinone-0 and menaquinone-0 through a thioether bond. The quinoproteins with molecular weights of 11-12 kDa were characterized by electrospray ionization mass spectrometry, UV/Vis spectroscopy, size-exclusion chromatography, circular dichroism measurements, (1)H NMR spectroscopy, cyclic voltammetry, and redox-induced FTIR difference spectroscopy. The midpoint redox potentials at pH 8 in aqueous solution E(m,8) of thioether conjugates with N-acetyl cysteine methyl ester were 89 mV and -63 mV and with a synthetic protein 229 mV and 249 mV versus standard hydrogen electrode (SHE) for ubiquinone-0 and menaquinone-0, respectively. Detailed redox-induced FTIR difference spectroscopic studies of the model compounds and quinoproteins show the special resonance features for C=O bands at 1656-1660 and 1655-1665 cm(-1) due to the sulfur substitution to ubiquinone-0 and menaquinone-0, respectively. The construction of model quinoproteins represents a significant step toward more complex artificial redox systems.}, }
@article {pmid16817014, year = {2006}, author = {Deshpande, VS and Kehrer, JP}, title = {Mechanisms of N-acetylcysteine-driven enhancement of MK886-induced apoptosis.}, journal = {Cell biology and toxicology}, volume = {22}, number = {4}, pages = {303-311}, doi = {10.1007/s10565-006-0072-6}, pmid = {16817014}, issn = {0742-2091}, support = {CA83701/CA/NCI NIH HHS/United States ; ES07784/ES/NIEHS NIH HHS/United States ; }, mesh = {5-Lipoxygenase-Activating Proteins ; Acetylcysteine/*pharmacology ; Annexin A5/pharmacology ; *Apoptosis ; Carrier Proteins/metabolism ; Caspase 3/metabolism ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation ; Fluorescein-5-isothiocyanate/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Hydrogen-Ion Concentration ; Indoles/*pharmacology ; Jurkat Cells ; Membrane Proteins/metabolism ; Propidium/pharmacology ; }, abstract = {N-Acetylcysteine (NAC), besides being a precursor of glutathione, has an array of other effects including an ability to scavenge free radicals, modulate gene expression and signal transduction pathways, and regulate cell survival and apoptosis. At concentrations lower than 20 mmol/L, NAC is nontoxic to cultured cells and can protect against apoptosis induced by a number of agents. A few recent reports, however, have indicated that NAC can also increase apoptosis. MK886, a 5-lipoxygenase activating protein (FLAP) inhibitor, induces apoptosis in many cell lines by an unknown mechanism that is independent of FLAP and lipoxygenase activity but is possibly related to effects on kinases such as Akt. In Jurkat T lymphocytes, NAC pretreatment (10 mmol/L) enhanced MK886-induced apoptosis by 2.4-fold. Following NAC-MK886 treatment, there was a significant increase in caspase-3 activity, and a decrease in mitochondrial transmembrane potential compared to MK886 alone. However, the extent of cytochrome c release was comparable between MK886 alone and MK886-NAC treatments. The enhancement of MK886-induced apoptosis by 10 mmol/L NAC appears to be partly related to a decrease in pH caused by this concentration of NAC, because an acidic environment favors activation of effector caspases and triggering of mitochondrial apoptosis. However, because neutralized NAC also enhanced apoptosis (1.6-fold), a direct role for NAC in augmenting the apoptotic pathways initiated by MK886 is suggested.}, }
@article {pmid16814277, year = {2006}, author = {Diniz, YS and Rocha, KK and Souza, GA and Galhardi, CM and Ebaid, GM and Rodrigues, HG and Novelli Filho, JL and Cicogna, AC and Novelli, EL}, title = {Effects of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia, dyslipidemia and oxidative stress in rats.}, journal = {European journal of pharmacology}, volume = {543}, number = {1-3}, pages = {151-157}, doi = {10.1016/j.ejphar.2006.05.039}, pmid = {16814277}, issn = {0014-2999}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Blood Glucose/drug effects ; Body Weight/drug effects ; *Dietary Sucrose/administration &amp; dosage ; Dyslipidemias/blood/metabolism/*prevention &amp; control ; Glutathione/blood/metabolism ; Glutathione Peroxidase/blood/metabolism ; Hyperglycemia/blood/metabolism/*prevention &amp; control ; Lipid Metabolism/drug effects ; Lipid Peroxides/blood/metabolism ; Lipids/blood ; Liver/*drug effects/metabolism ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Superoxide Dismutase/blood/metabolism ; }, abstract = {This study examined whether sucrose-rich diet (SRD)-induced hyperglycaemia, dyslipidemia and oxidative stress may be inhibited by N-acetylcysteine (C(5)H(9)-NO(3)S), an organosulfur from Allium plants. Male Wistar 40 rats were divided into four groups (n=10): (C) given standard chow and water; (N) receiving standard chow and 2 mg/l N-acetylcysteine in its drinking water; (SRD) given standard chow and 30% sucrose in its drinking water; and (SRD-N) receiving standard chow, 30% sucrose and N-acetylcysteine in its drinking water. After 30 days of treatment, SRD rats had obesity with increased abdominal circumference, hyperglycaemia, dyslipidemia and hepatic triacylglycerol accumulation. These adverse effects were associated with oxidative stress and depressed lipid degradation in hepatic tissue. The SRD adverse effects were not observed in SDR-N rats. N-Acetylcysteine reduced the oxidative stress, enhancing glutathione-peroxidase activity, and normalizing lipid hydroperoxyde, reduced glutathione and superoxide dismutase in hepatic tissue of SRD-N rats. The beta-hydroxyacyl coenzyme-A dehydrogenase and citrate-synthase activities were increased in SRD-N rats, indicating enhanced lipid degradation in hepatic tissue as compared to SRD. SRD-N rats had reduced serum oxidative stress and diminished glucose, triacylglycerol, very-low-density lipoprotein (VLDL), oxidized low-density lipoprotein (ox-LDL) and cholesterol/high-density lipoprotein (HDL) ratio in relation to SRD. In conclusion, NAC offers promising therapeutic values in prevention of dyslipidemic profile and alleviation of hyperglycaemia in high-sucrose intake condition by improving antioxidant defences. N-Acetylcysteine had also effects preventing metabolic shifting in hepatic tissue, thus enhancing fat degradation and reducing body weight gain in conditions of excess sucrose intake. The application of this agent in food system via exogenous addition may be feasible and beneficial for antioxidant protection.}, }
@article {pmid16813521, year = {2006}, author = {Koh, JM and Lee, YS and Kim, YS and Kim, DJ and Kim, HH and Park, JY and Lee, KU and Kim, GS}, title = {Homocysteine enhances bone resorption by stimulation of osteoclast formation and activity through increased intracellular ROS generation.}, journal = {Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research}, volume = {21}, number = {7}, pages = {1003-1011}, doi = {10.1359/jbmr.060406}, pmid = {16813521}, issn = {0884-0431}, mesh = {Acid Phosphatase/metabolism ; Animals ; Bone Marrow Cells/*metabolism ; Bone Resorption/*drug therapy ; Cell Differentiation/*drug effects ; Cells, Cultured ; Fractures, Bone/metabolism ; Homocysteine/metabolism/*pharmacology ; Hyperhomocysteinemia/complications/metabolism ; Isoenzymes/metabolism ; MAP Kinase Signaling System/drug effects ; Mice ; Mice, Inbred ICR ; Osteoclasts/*metabolism ; Osteoporosis/etiology/metabolism ; Protein Kinases/metabolism ; Reactive Oxygen Species/*metabolism ; Risk Factors ; Tartrate-Resistant Acid Phosphatase ; }, abstract = {UNLABELLED: Hyperhomocystinemia is a modifiable risk factor for osteoporosis and fracture. Physiologic concentrations of Hcy directly activate osteoclast formation and activity through stimulation of p38 MAPK and integrin beta3. The effects of Hcy were mediated by generation of intracellular ROS.<br><br>INTRODUCTION: Hyperhomocysteinemia is a modifiable risk factor for osteoporosis and its related bone fractures. It has been reported that bone resorption and turnover rate were increased in hyperhomocystinemia. Using mouse bone marrow cells, we examined the direct effects of homocysteine (Hcy) on osteoclast formation and activity.<br><br>MATERIALS AND METHODS: Osteoclast formation was determined by TRACP staining and TRACP activity. Intracellular reactive oxygen species (ROS) generation was measured using a fluorescent probe, dichlorodihydrofluorescein diacetate. Intracellular signaling cascades of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-kappaB were measured by Western blotting. Integrin beta3 mRNA levels were measured by RT-PCR. Actin ring formation and bone resorption assays were also performed.<br><br>RESULTS: Physiologic concentrations of Hcy upregulated TRACP+ multinucleated cells and TRACP activity, stimulated actin ring formation, and increased the number of nuclei per cell and the level of expression of integrin beta3 mRNA. In addition, Hcy increased bone resorption and stimulated p38 MAPK activity and intracellular reactive oxygen species (ROS) generation. All of these Hcy-induced changes were blocked by pretreatment with the antioxidant, N-acetyl cysteine.<br><br>CONCLUSIONS: Hcy directly activates osteoclast formation and activity through increased generation of intracellular ROS. These findings suggest that, in individuals with mild to moderate hyperhomocystinemia, increased bone resorption by osteoclasts may contribute to osteoporosis and that an antioxidant may attenuate bone loss in these individuals.}, }
@article {pmid16810570, year = {2006}, author = {Sochman, J and Krizova, B}, title = {Prevention of contrast agent-induced renal impairment in patients with chronic renal insufficiency and heart disease by high-dose intravenous N-acetylcysteine: a pilot-ministudy.}, journal = {Kardiologia polska}, volume = {64}, number = {6}, pages = {559-64; discussion 565-6}, pmid = {16810570}, issn = {0022-9032}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Contrast Media/*adverse effects ; *Coronary Angiography ; Creatinine/blood ; Heart Diseases/complications/*diagnostic imaging ; Humans ; Infusions, Intravenous ; Pilot Projects ; Poland ; *Premedication ; Renal Insufficiency, Chronic/complications ; Safety ; Treatment Outcome ; }, abstract = {BACKGROUND: Contrast-induced nephropathy is a relatively common complication occurring after various procedures requiring contrast agent injection, especially in patients with pre-existing renal failure.<br><br>AIM: This pilot study was designed to assess the effects of a high intravenous dose of N-acetylcysteine (NAC) on plasma creatinine concentration.<br><br>METHODS: Twenty patients with pre-existing renal insufficiency were given NAC at a dose of 100 mg/kg. No contrast agent was given to 10 patients (Group A), whereas 10 patients received contrast at the time of coronary angiography (Group B). Changes in plasma creatinine were assessed at 3 hours and one day following NAC administration.<br><br>RESULTS: In Group B, NAC prevented creatinine increase: baseline levels were 210.98+/-77.33 micromol/L, 200.26+/-71.94 micromol/L (NS) after 3 hours, and 203.80+/-83.94 micromol/L 24 hours later (NS). The following was seen in Group A patients: 201.21+/-42.28 micromol/L, 190.31+/-42.74 micromol/L (p<0.01), and 170.08+/-45.53 micromol/L (p<0.01), respectively.<br><br>CONCLUSION: The results of this study confirm the effectiveness of NAC in prevention of contrast agent-induced renal impairment. In addition, we demonstrated the beneficial effects of NAC on renal function in patients who were not exposed to contrast agent. This pilot study should provide the basis for more comprehensive research and, also, for safe clinical practice.}, }
@article {pmid16809227, year = {2006}, author = {Caglikulekci, M and Dirlik, M and Pata, C and Plasse, M and Tamer, L and Ogetman, Z and Ercan, B}, title = {Effect of N-acetylcysteine on blood and tissue lipid peroxidation in lipopolysaccharide-induced obstructive jaundice.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {19}, number = {3}, pages = {175-184}, doi = {10.1080/08941930600674702}, pmid = {16809227}, issn = {0894-1939}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ascorbic Acid/blood ; Bile Ducts ; Erythrocytes/metabolism ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Jaundice, Obstructive/chemically induced/*drug therapy/*metabolism ; Kidney/metabolism ; Ligation ; Lipid Peroxidation/*drug effects ; Lipopolysaccharides/*pharmacology ; Liver/metabolism ; Male ; Malondialdehyde/blood ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Sodium-Potassium-Exchanging ATPase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {In obstructive jaundice, free radical production is increased and antioxidative activity is reduced. N-Acetylcysteine (NAC) has a beneficial effect with anti-inflammatory and antioxidant activity, acting as a free radical scavenger. NAC inhibits inducible nitric oxide synthase, suppresses cytokine expression/release, and inhibits adhesion molecule expression and nuclear factor kappa B. The aim of this study was to investigate the effects of NAC on liver/renal tissue and serum lipid peroxidation in lipopolysaccharide (LPS)-induced obstructive jaundice. We randomized 60 rats into 6 groups: group 1, Sham; group 2, obstructive jaundice (OJ) induced after bile-duct ligation; group 3, OJ + NAC (100 mg kg- 1 subcutaneously); group 4, OJ + LPS (10 mg kg-1); group 5, OJ + NAC + LPS; and group 6, OJ + LPS + NAC. For each group, the biochemical markers of lipid peroxidation and the antioxidant products were measured in serum and liver/renal tissue after sacrifice. Almost all lipid peroxidation products levels were increased and antioxidant products levels were decreased in groups who received LPS (groups 4, 5, and 6), but the effect was less remarkable when NAC was administered before LPS (group 5). The same trend was seen for groups with OJ +/- LPS who did not received NAC or received it after induced toxemia (groups 2, 4, and 6) as compared to groups 1 and 3. Moreover, in the case of OJ + LPS, rats treated with NAC before LPS (group 5) had lower lipid peroxidation products levels and higher antioxidant products levels as compared to those who did not received NAC (group 4). This phenomenon was not reproducible with NAC administered after LPS (group 6). Thus, results of this study showed that NAC prevents the deleterious effects of LPS in obstructive jaundice by reducing lipid peroxidation in serum and liver/renal tissue if administered before LPS. Nonetheless, NAC failed to prevent the lipid peroxidation in the case of established endotoxemia in obstructive jaundice.}, }
@article {pmid16807286, year = {2006}, author = {Gupta, RK and Miller, KP and Babus, JK and Flaws, JA}, title = {Methoxychlor inhibits growth and induces atresia of antral follicles through an oxidative stress pathway.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {93}, number = {2}, pages = {382-389}, doi = {10.1093/toxsci/kfl052}, pmid = {16807286}, issn = {1096-6080}, support = {R01 ES012893-01A2/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Catalase/genetics ; Female ; Follicular Atresia/*drug effects/physiology ; Glutathione Peroxidase/genetics ; Insecticides/*toxicity ; Methoxychlor/*toxicity ; Mice ; Ovarian Follicle/drug effects/growth &amp; development ; *Oxidative Stress ; RNA, Messenger/analysis ; Superoxide Dismutase/genetics ; }, abstract = {The mammalian ovary contains antral follicles, which are responsible for the synthesis and secretion of hormones that regulate estrous cyclicity and fertility. The organochlorine pesticide methoxychlor (MXC) causes atresia (follicle death via apoptosis) of antral follicles, but little is known about the mechanisms by which MXC does so. Oxidative stress is known to cause apoptosis in nonreproductive and reproductive tissues. Thus, we tested the hypothesis that MXC inhibits growth and induces atresia of antral follicles through an oxidative stress pathway. To test this hypothesis, antral follicles isolated from 39-day-old CD-1 mice were cultured with vehicle control (dimethylsulfoxide [DMSO]), MXC (1-100 microg/ml), or MXC + the antioxidant N-acetyl cysteine (NAC) (0.1-10 mM). During culture, growth was monitored daily. At the end of culture, follicles were processed for quantitative real-time polymerase chain reaction of Cu/Zn superoxide dismutase (SOD1), glutathione peroxidase (GPX), and catalase (CAT) mRNA expression or for histological evaluation of atresia. The results indicate that exposure to MXC (1-100 microg/ml) inhibited growth of follicles compared to DMSO controls and that NAC (1-10 mM) blocked the ability of MXC to inhibit growth. MXC induced follicular atresia, whereas NAC (1-10 mM) blocked the ability of MXC to induce atresia. In addition, MXC reduced the expression of SOD1, GPX, and CAT, whereas NAC reduced the effects of MXC on their expression. Collectively, these data indicate MXC causes slow growth and increased atresia by inducing oxidative stress.}, }
@article {pmid16804527, year = {2006}, author = {Bach, SP and Williamson, SE and O'Dwyer, ST and Potten, CS and Watson, AJ}, title = {Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut.}, journal = {British journal of cancer}, volume = {95}, number = {1}, pages = {35-41}, pmid = {16804527}, issn = {0007-0920}, mesh = {Animals ; Antioxidants/*toxicity ; Apoptosis/*drug effects ; Colorectal Neoplasms/*drug therapy/pathology ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Antagonism ; Drug Synergism ; Fluorouracil/*toxicity ; Intestinal Mucosa/*drug effects/metabolism/pathology ; Intestine, Large/drug effects/metabolism/pathology ; Intestine, Small/drug effects/metabolism/pathology ; Mice ; Mice, Knockout ; Mitosis/drug effects ; Organ Specificity ; Pyrrolidines/*toxicity ; Thiocarbamates/*toxicity ; Time Factors ; Tumor Suppressor Protein p53/deficiency/drug effects/genetics/*metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Pyrrolidinedithiocarbamate (PDTC) enhanced the activity of 5-fluorouracil (5-FU) in a colorectal cancer xenograft model. Pyrrolidinedithiocarbamate also reduced gastrointestinal toxicity associated with 5-FU therapy in large but not small bowel. We sought to clarify the basis of this differential enteric toxicity. Apoptosis and mitosis were assessed on a cell positional basis in small and large intestinal crypts of p53 wild-type (+/+) and p53 null (-/-) mice 6, 12, 24, 36, 48 and 72 h after the administration of high (200 mg kg(-1)) or low (40 mg kg(-1)) dose 5-FU+/-250 mg kg(-1) PDTC. Regimens were chosen to model a single human dose and a weekly schedule. The effects of another antioxidant N-acetylcysteine (NAC) were also investigated. Large intestinal crypts affect apoptosis purely by p53-dependent mechanisms, whereas small intestinal crypts are able to initiate both p53-dependent and -independent pathways following treatment with 5-FU. Pyrrolidinedithiocarbamate and NAC antagonised p53-dependent but potentiated p53-independent apoptotic activity. Consequently, the proportion of surviving clonogens increased in the large but not in the small intestine. Regional availability of p53-dependent and -independent apoptotic pathways in small and large intestine together with separate modulation of these pathways by antioxidants explains the different regional enterotoxicity following 5-FU therapy.}, }
@article {pmid16803874, year = {2006}, author = {Aichem, A and Masilamani, M and Illges, H}, title = {Redox regulation of CD21 shedding involves signaling via PKC and indicates the formation of a juxtamembrane stalk.}, journal = {Journal of cell science}, volume = {119}, number = {Pt 14}, pages = {2892-2902}, doi = {10.1242/jcs.02984}, pmid = {16803874}, issn = {0021-9533}, mesh = {Amino Acid Sequence ; Antioxidants/pharmacology ; Cell Membrane/*metabolism ; Cells, Cultured ; Cysteine/metabolism ; Disulfides/metabolism ; Epithelial Cells/cytology/drug effects ; Humans ; Ionomycin/pharmacology ; Metalloproteases/metabolism ; Models, Biological ; Molecular Sequence Data ; Oxidation-Reduction/drug effects ; Protein Kinase C/*metabolism ; *Protein Processing, Post-Translational/drug effects ; Receptors, Complement 3d/chemistry/*immunology ; Serine Endopeptidases/metabolism ; *Signal Transduction ; Sulfhydryl Compounds/metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Vanadates/pharmacology ; }, abstract = {Soluble CD21 (sCD21), released from the plasma membrane by proteolytic cleavage (shedding) of its extracellular domain (ectodomain) blocks B cell/follicular dendritic cell interaction and activates monocytes. We show here that both serine- and metalloproteases are involved in CD21 shedding. Using the oxidant pervanadate to mimic B cell receptor activation and thiol antioxidants such as N-acetylcysteine (NAC) and glutathione (GSH) we show that CD21 shedding is a redox-regulated process inducible by oxidation presumably through activation of a tyrosine kinase-mediated signal pathway involving protein kinase C (PKC), and by reducing agents that either directly activate the metalloprotease and/or modify intramolecular disulfide bridges within CD21 and thereby facilitate access to the cleavage site. Lack of short consensus repeat 16 (SCR16) abolishes CD21 shedding, and opening of the disulfide bridge between cys-2 (Cys941) and cys-4 (Cys968) of SCR16 is a prerequisite for CD21 shedding. Replacing these cysteines with selenocysteines (thereby changing the redox potential from -180 to -381 mV) results in a loss of inducible CD21 shedding, and removing this bridge by exchanging these cysteines with methionines increases CD21 shedding.}, }
@article {pmid16799053, year = {2006}, author = {Denton, ML and Foltz, MS and Estlack, LE and Stolarski, DJ and Noojin, GD and Thomas, RJ and Eikum, D and Rockwell, BA}, title = {Damage Thresholds for Exposure to NIR and Blue Lasers in an In Vitro RPE Cell System.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {47}, number = {7}, pages = {3065-3073}, doi = {10.1167/iovs.05-1066}, pmid = {16799053}, issn = {0146-0404}, mesh = {Acetylcysteine/pharmacology ; Ascorbic Acid/pharmacology ; Cell Line ; Cell Survival ; Coculture Techniques ; Computer Simulation ; DNA-Binding Proteins/genetics ; Humans ; *Lasers ; Melanosomes/metabolism ; Phagocytosis/physiology ; Pigment Epithelium of Eye/drug effects/metabolism/*radiation effects ; Radiation Tolerance ; Telomerase/genetics ; Transfection ; }, abstract = {PURPOSE: Until reliable nonanimal systems of analysis are available, animal models will be necessary for ocular laser hazard analysis and for evaluating clinical applications. The purpose of this work was to demonstrate the utility of an in vitro system for laser bioeffects by identifying photothermal and photochemical cytotoxicity thresholds for continuous-wave (cw) and mode-locked (ml) laser exposures.<br><br>METHODS: Exogenous melanosomes were added to hTERT-RPE1 cells in exposure wells 1 day before laser exposure. Thermal or photochemical laser exposures were delivered to artificially pigmented retinal pigment epithelial (RPE) cultures, with subsequent assay for viability 1 hour after exposure. Beam delivery for the 1-hour photochemical exposures was via a modified culture incubator. The cytoprotective effect of pretreatment with two antioxidants was investigated.<br><br>RESULTS: Phagocytosis of melanosomes by the RPE cells was efficient, yielding cultures of uniform pigmentation. The damage threshold for the thermal exposure was consistent with published in vivo results. Thresholds for both blue exposures (cw and ml) were identical. Overnight treatment of cells with ascorbic acid (AA) minimized cell death from both cw and ml blue laser exposure, whereas similar treatment with N-acetyl-L-cysteine (NAC) was less effective.<br><br>CONCLUSIONS: The in vitro system described is suitable for measuring meaningful thermal and photochemical laser damage thresholds. The system is also useful in comparative laser bioeffects studies, such as comparisons between cw and ml laser exposures, cells with various degrees of pigmentation, and studies determining the efficacy and mechanisms of treatments altering the response of cells to lasers.}, }
@article {pmid16795014, year = {2006}, author = {Urquhart, BL and House, AA and Cutler, MJ and Spence, JD and Freeman, DJ}, title = {Thiol exchange: an in vitro assay that predicts the efficacy of novel homocysteine lowering therapies.}, journal = {Journal of pharmaceutical sciences}, volume = {95}, number = {8}, pages = {1742-1750}, doi = {10.1002/jps.20680}, pmid = {16795014}, issn = {0022-3549}, mesh = {Chemistry, Pharmaceutical/*methods ; Homocysteine/*blood ; Humans ; Predictive Value of Tests ; Sulfhydryl Compounds/*blood/*therapeutic use ; }, abstract = {Elevated plasma total homocysteine (tHcy) is a risk factor for atherosclerosis. Hcy is 70-80% bound to albumin as a disulfide. Recent trials have evaluated ability of thiol-containing drugs to exchange with protein bound Hcy and consequently increase its renal clearance. The objective of this study was to develop an in vitro assay to predict the efficacy of thiol-containing drugs to lower tHcy in the clinical setting. The assay was used to test the effects of N-acetylcysteine (NAC), mesna, captopril, dimercaptosuccinic acid (DMSA), and penicillamine. Hcy was added in vitro to plasma of healthy subjects (n = 6) and equilibrated. Concentrations of thiol exchange agent were added and incubated at 37 degrees C. Aliquots were removed at selected intervals and free Hcy determined. Mesna, captopril, and NAC caused a concentration-dependent increase in free Hcy. Three-hundred micromolar mesna and captopril had a greater effect than equimolar NAC, increasing free Hcy by 33.9 +/- 5.0% and 32.0 +/- 2.6%, respectively compared to 22.3 +/- 2.4% for NAC, p < 0.001. Our in vitro results indicate that mesna, captopril, and NAC effectively exchange with covalently bound Hcy. This assay can act as screening tool for novel tHcy lowering therapies and should spare the expense of negative trials.}, }
@article {pmid16794664, year = {2006}, author = {Aakvik, R and Jacobsen, D}, title = {[Paracetamol poisoning--occurrence and treatment].}, journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke}, volume = {126}, number = {13}, pages = {1731-1733}, pmid = {16794664}, issn = {0807-7096}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/administration &amp; dosage/adverse effects ; Adult ; Analgesics, Non-Narcotic/blood/*poisoning ; Antidotes/administration &amp; dosage/adverse effects ; Drug Overdose ; Female ; Humans ; Liver/drug effects/enzymology ; Male ; Middle Aged ; Patient Admission ; Retrospective Studies ; Time Factors ; }, abstract = {BACKGROUND: Poisoning with paracetamol is common and potentially serious. We have assessed the incidence of paracetamol poisoning and the hospital's use of serum analyses to monitor the antidotal treatment N-acetyl cysteine.<br><br>MATERIAL AND METHODS: All hospital records of ICD-10 diagnoses T4n and T50.9 at the Department of Acute Medicine from July 2001 to July 2004, were retrospectively reviewed. All cases with possible or confirmed paracetamol poisoning were recorded. Liver damage was defined as ALT above 1,000 U/l. Standard European treatment nomogram was used.<br><br>RESULTS: Of 869 admissions with acute poisoning, 158 (21%) were caused by paracetamol; of these 120 (76%) were women and 38 (24%) were men. 107 (68%) of the patients were treated with N-acetyl cysteine at admission due to suspected ingestion of more than 10 grams of paracetamol. Treatment was abrupted in 84 (79%) of the patients, as levels of serum paracetamol were below the treatment line in the nomogram. The median time from admission to sampling was 5 hours. Nine patients (6%), who all arrived later than 15 hours after ingesting paracetamol, developed liver damage. One woman died after a sub-acute overdose of paracetamol.<br><br>INTERPRETATION: Few patients needed treatment with antidote. The treatment seemed to protect all against liver damage if started early. Liver damage and death was associated with admission later than 15 hours after intake.}, }
@article {pmid16787924, year = {2006}, author = {Safiulina, VF and Afzalov, R and Khiroug, L and Cherubini, E and Giniatullin, R}, title = {Reactive oxygen species mediate the potentiating effects of ATP on GABAergic synaptic transmission in the immature hippocampus.}, journal = {The Journal of biological chemistry}, volume = {281}, number = {33}, pages = {23464-23470}, doi = {10.1074/jbc.M601627200}, pmid = {16787924}, issn = {0021-9258}, support = {GGP04037/TI_/Telethon/Italy ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/antagonists &amp; inhibitors/metabolism/*physiology ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Astrocytes/drug effects/physiology ; Calcium Signaling/physiology ; Drug Synergism ; Excitatory Postsynaptic Potentials/drug effects/physiology ; Hippocampus/drug effects/growth &amp; development/*physiology ; Hydrogen Peroxide/pharmacology ; Interneurons/metabolism/physiology ; Organ Culture Techniques ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*pharmacology ; Synaptic Transmission/drug effects/*physiology ; gamma-Aminobutyric Acid/*physiology ; }, abstract = {Reactive oxygen species (ROS) constitute important signaling molecules in the central nervous system. They regulate a number of different functions both under physiological conditions and under pathological conditions. Here we tested the hypothesis that in the immature hippocampus ATP, the most diffuse neurotransmitter in the brain, modulates synaptic transmission via ROS. We show that ATP, acting on metabotropic P2Y1 receptors, increased the frequency of GABA(A)-mediated spontaneous postsynaptic currents (SPSCs) in CA3 principal cells, an effect that was prevented by the antioxidant N-acetyl-cysteine or by catalase, an enzyme that breaks down H2O2. The effect of ATP on SPSCs was mimicked by H2O2 or by the pro-oxidant, Fe2+, which, through the Fentol reaction, catalyzes the conversion of H2O2 into highly reactive hydroxyl radicals. MRS-2179, a P2Y1 receptor antagonist, removed the facilitatory action of Fe2+ on SPSCs, suggesting that endogenous ATP acting on P2Y1 receptors is involved in Fe2+-induced modulation of synaptic transmission. Imaging ROS with the H2O2-sensitive dye DCF revealed that ATP induces generation of peroxide in astrocytes via activation of P2Y1 receptors coupled to intracellular calcium rise. Neither N-acetyl-cysteine nor catalase prevented Ca2+ transients induced by ATP in astrocytes. Since a single hippocampal astrocyte can contact many neurons, ATP-induced ROS signaling may control thousands of synapses. This may be crucial for information processing in the immature brain when GABAergic activity is essential for the proper wiring of the hippocampal network.}, }
@article {pmid16787314, year = {2005}, author = {Zheng, J and Liu, G and Tozkoparan, B and Wen, D}, title = {Mechanistic studies of inactivation of glutathione S-transferase Pi isozyme by a haloenol lactone derivative.}, journal = {Medicinal chemistry (Shariqah (United Arab Emirates))}, volume = {1}, number = {2}, pages = {191-198}, doi = {10.2174/1573406053175300}, pmid = {16787314}, issn = {1573-4064}, mesh = {Enzyme Activation/drug effects ; Enzyme Inhibitors/chemical synthesis/*chemistry/*pharmacology ; Glutathione S-Transferase pi/*antagonists &amp; inhibitors ; Humans ; Isoenzymes/antagonists &amp; inhibitors ; Lactones/chemical synthesis/*chemistry/*pharmacology ; Molecular Structure ; Peptides/chemistry ; Structure-Activity Relationship ; Time Factors ; }, abstract = {Cancer chemotherapy often fails due to acquired drug resistance. One of the most critical biochemical changes observed in drug-resistant tumor cells is over-expression of glutathione S-transferase Pi isozyme (GSTP1). Glutathione S-transferase inhibitors have been used as potentiating agents of chemotherapeutic drugs. Earlier we reported haloenol lactone 1 as a site-directed GSTP1 inactivator. We proposed that enzymatic hydrolysis of the haloenol lactone may be the initial step of GSTP1 chemical modification, resulting in the inactivation of the enzyme. Enzyme inactivation is initiated through addition of Cys-47 to the lactone ring, which is opened in the process to form an alpha-bromoketone adduct. The acidity of Cys-47 confers good leaving group properties, and rapid hydrolysis occurs to generate an alpha-bromoketoacid intermediate. The reaction may proceed via alkylation of the transient thioester to form a six-membered ring episulfonium ion intermediate which would be yet more reactive toward hydrolysis, with either process leading to the observed mass increase of 230 Da. To probe the importance of the bromine of the lactone in GST inactivation, we designed and synthesized compound 2. Unlike lactone 1, lactone 2 did not show time-dependent inhibitory effect on GSTP1. Incubation of compounds 1 and 2 with excess of N-acetyl cysteine produced the corresponding di-N-acetyl cysteine conjugate and mono-N-acetyl cysteine conjugate, respectively. To probe the role of Cys-47 in the inactivation of GSTP1 by compound 1, we prepared mutant C47A GSTP1. The mutant GSTP1 still showed good activity toward CDNB, but it lost susceptibility to the inactivation by compound 1. In addition, LC-MS/MS technique allowed us to identify the modified Cys-47 after the enzyme was exposed to compound 1.}, }
@article {pmid16787218, year = {2006}, author = {Fraternale, A and Paoletti, MF and Casabianca, A and Oiry, J and Clayette, P and Vogel, JU and Cinatl, J and Palamara, AT and Sgarbanti, R and Garaci, E and Millo, E and Benatti, U and Magnani, M}, title = {Antiviral and immunomodulatory properties of new pro-glutathione (GSH) molecules.}, journal = {Current medicinal chemistry}, volume = {13}, number = {15}, pages = {1749-1755}, doi = {10.2174/092986706777452542}, pmid = {16787218}, issn = {0929-8673}, mesh = {Adjuvants, Immunologic/*pharmacology ; Animals ; Antiviral Agents/*pharmacology ; Glutathione/*pharmacology/physiology ; Humans ; Mice ; Th1 Cells/immunology ; Th2 Cells/immunology ; Virus Diseases/physiopathology ; }, abstract = {Reduced glutathione (GSH) is present in millimolar concentrations in mammalian cells. It is involved in many cellular functions such as detoxification, amino acid transport, production of coenzymes, and the recycling of vitamins E and C. GSH acts as a redox buffer to preserve the reduced intracellular environment. Decreased glutathione levels have been found in numerous diseases such as cancer, viral infections, and immune dysfunctions. Many antioxidant molecules, such as GSH and N-acetylcysteine (NAC), have been demonstrated to inhibit in vitro and in vivo viral replication through different mechanisms of action. Accumulating evidence suggests that intracellular GSH levels in antigen-presenting cells such as macrophages, influence the Th1/Th2 cytokine response pattern, and more precisely, GSH depletion inhibits Th1-associated cytokine production and/or favours Th2 associated responses. It is known that GSH is not transported to most cells and tissues in a free form. Therefore, a number of different approaches have been developed in the last years to circumvent this problem. This review discusses the capacity of some new molecules with potent pro-GSH effects either to exert significant antiviral activity or to augment GSH intracellular content in macrophages to generate and maintain the appropriate Th1/Th2 balance. The observations reported herein show that pro-GSH molecules represent new therapeutic agents to treat antiviral infections and Th2-mediated diseases such as allergic disorders and AIDS.}, }
@article {pmid16781710, year = {2006}, author = {Kropotov, A and Gogvadze, V and Shupliakov, O and Tomilin, N and Serikov, VB and Tomilin, NV and Zhivotovsky, B}, title = {Peroxiredoxin V is essential for protection against apoptosis in human lung carcinoma cells.}, journal = {Experimental cell research}, volume = {312}, number = {15}, pages = {2806-2815}, doi = {10.1016/j.yexcr.2006.05.006}, pmid = {16781710}, issn = {0014-4827}, mesh = {*Apoptosis/drug effects/radiation effects ; Calcium/metabolism ; Carcinoma/*enzymology/metabolism ; Carcinoma, Non-Small-Cell Lung/enzymology/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Down-Regulation ; Humans ; Lung Neoplasms/*enzymology/metabolism ; Membrane Potentials ; Mitochondria/metabolism/ultrastructure ; Peroxidases/*metabolism/physiology ; Peroxiredoxins ; }, abstract = {Sensitivity of tumor cells to treatment with anticancer drugs depends on expression and function of antiapoptotic and antioxidant proteins. The goal of our study was to determine the functional role of the novel antioxidant protein Peroxiredoxin V (PrxV), in protection of human lung carcinoma cell lines against apoptosis. Analysis of expression of PrxV in multiple lung carcinoma cell lines revealed a positive correlation between the expression of PrxV and radioresistance in vitro. Clones of the lung carcinoma cells U1810 with down-regulated expression of PrxV, or with its impaired enzymatic function (expression of redox-negative PrxV), demonstrated increased sensitivity to treatment with anticancer drugs etoposide and adriamycin. Pre-treatment of these clones with antioxidant N-acetyl-cysteine did not change their sensitivity to adriamycin, suggesting the involvement of a non-redox activity of PrxV. Expression of the redox-negative PrxV mainly affected the mitochondrial pathway of apoptosis, as assessed by cytochrome c release assay. Impairment of the PrxV enzymatic function also affected transmembrane potential and calcium loading capacity of mitochondria, as well as mitochondrial morphology. Altogether, these findings suggest that PrxV is a multifunctional protein, which is essential for protection against apoptosis induced by anticancer drugs.}, }
@article {pmid16781197, year = {2006}, author = {Reliene, R and Schiestl, RH}, title = {Antioxidant N-acetyl cysteine reduces incidence and multiplicity of lymphoma in Atm deficient mice.}, journal = {DNA repair}, volume = {5}, number = {7}, pages = {852-859}, doi = {10.1016/j.dnarep.2006.05.003}, pmid = {16781197}, issn = {1568-7864}, support = {R01 ES09519/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ataxia Telangiectasia/complications/drug therapy ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*genetics ; DNA Damage/drug effects ; DNA Repair ; DNA-Binding Proteins/*deficiency/*genetics ; Female ; Humans ; Lymphoma/etiology/*genetics/pathology/*prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Biological ; Pregnancy ; Protein Serine-Threonine Kinases/*deficiency/*genetics ; Tumor Suppressor Proteins/*deficiency/*genetics ; }, abstract = {Hereditary human disorder ataxia telangiectasia (AT) is characterized by an extremely high incidence of lymphoid malignancies, neuromotor dysfunction, immunodeficiency and radiosensitivity. Cells from AT patients show genetic instability and a continuous state of oxidative stress. We examined the effect of long-term dietary supplementation with the thiol-containing antioxidant, N-acetyl-L-cysteine (NAC), on survival and cancer formation in Atm (AT-mutated) deficient mice, used as an animal model of AT. NAC was chosen because it is well-tolerated in animals and humans. It can be used by the oral route and for long-term at high concentrations. In addition, NAC suppresses carcinogenesis-associated biological markers in Atm deficient mice, such as DNA deletions and oxidative DNA damage (R. Reliene, E. Fischer, R.H. Schiestl, Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice, Cancer Res. 64 (2004) 5148-5153). In this study, NAC significantly increased the lifespan and reduced both the incidence and multiplicity of lymphoma in Atm deficient mice. The life span increased from 50 to 68 weeks and the incidence of lymphoma decreased by two-fold (76.5% versus 37.5%). Moreover, in mice with lymphoma, multiplicity of tumors decreased from 4.6 to 2.8 tumors per mouse. Thus, dietary supplementation with NAC may turn out to be protective against lymphomagenesis in AT patients.}, }
@article {pmid16780821, year = {2006}, author = {Heinzel, FR and Luo, Y and Dodoni, G and Boengler, K and Petrat, F and Di Lisa, F and de Groot, H and Schulz, R and Heusch, G}, title = {Formation of reactive oxygen species at increased contraction frequency in rat cardiomyocytes.}, journal = {Cardiovascular research}, volume = {71}, number = {2}, pages = {374-382}, doi = {10.1016/j.cardiores.2006.05.014}, pmid = {16780821}, issn = {0008-6363}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cells, Cultured ; Diacetyl/analogs &amp; derivatives/pharmacology ; Electric Stimulation ; Enzyme Inhibitors/pharmacology ; Microscopy, Fluorescence ; Mitochondria, Heart/metabolism ; Myocardial Contraction/*physiology ; Myocytes, Cardiac/*metabolism ; Myosins/antagonists &amp; inhibitors/metabolism ; NADPH Oxidases/metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Oxidation-Reduction ; Oxygen Consumption ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Superoxides/metabolism ; }, abstract = {OBJECTIVE: Reactive oxygen species (ROS) play an ambivalent role in cardiomyocytes: low concentrations are involved in cellular signaling, while higher concentrations contribute to cellular injury. We studied ROS formation during increases in contraction frequency in isolated cardiomyocytes.<br><br>METHODS: Rat ventricular cardiomyocytes were loaded with dichlorodihydrofluorescein and electrically stimulated (37 degrees C). ROS formation was assessed by the rate of oxidation-dependent fluorescence increase (OxR). Oxygen consumption (VO(2)) and NAD(P)H autofluorescence were measured in parallel experiments.<br><br>RESULTS: Increases in contraction frequency were accompanied by an increase in VO(2) and a decrease in NAD(P)H fluorescence. OxR increased to 124+/-4%, 146+/-8%, 204+/-25% and 256+/-29% of OxR at baseline during 1, 2, 3 and 4 Hz stimulation, and subsequently returned to baseline values with 0.2 Hz. The OxR increase was dose-dependently inhibited by the antioxidant NAC (10 and 100 mM), but unaffected by the NO synthase inhibitor l-NAME (200 microM and 10 mM). The OxR increase was attenuated when myosin ATPase activity was inhibited by butanedione monoxime (BDM; 5 mM).<br><br>CONCLUSION: Increased contraction frequency induces ROS formation in rat cardiomyocytes.}, }
@article {pmid16778450, year = {2006}, author = {Wu, Y and Guo, SW}, title = {Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780.}, journal = {Gynecologic and obstetric investigation}, volume = {62}, number = {4}, pages = {193-205}, doi = {10.1159/000093975}, pmid = {16778450}, issn = {0378-7346}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cell Proliferation/*drug effects ; Dose-Response Relationship, Drug ; Endometriosis/drug therapy ; Endometrium/cytology/*drug effects ; Enzyme Inhibitors/*pharmacology ; Estradiol/analogs &amp; derivatives/pharmacology ; Fas Ligand Protein/metabolism ; Female ; Fulvestrant ; Humans ; Hydrogen Peroxide/pharmacology ; Hydroxamic Acids/pharmacology ; Mifepristone/pharmacology ; Norpregnadienes/pharmacology ; RNA, Messenger/analysis ; Receptors, Androgen/metabolism ; Receptors, Estrogen/*antagonists &amp; inhibitors/metabolism ; Receptors, Progesterone/metabolism ; Stromal Cells/drug effects ; fas Receptor/metabolism ; }, abstract = {BACKGROUND: All current major medications in treating endometriosis are effective in treating pain, most likely through suppression of proliferation of the implants, yet their effectiveness is relatively short term and they all have many undesirable, and sometimes severe, side effects. There is pressing need for novel, more effective medications in treating endometriosis with less and/or milder side effects.<br><br>METHODS: Using a recently established immortalized endometrial stromal cell line, we carried out cell proliferation assays for cells treated with trichostatin A (TSA), RU486, CDB-2914, and N-acetylcysteine, and ICI 182780. Gene expression levels for PR-A, PR-B, AR, Fas and FasL were measured. Protein expression levels for ERalpha, ERbeta, and AR were also measured.<br><br>RESULTS: Cell proliferation assay results for NAC, H2O2, CDB, and RU486 were nearly identical or similar to what have been reported based on primary cell cultures or in vivo studies. TSA, CDB, RU486 and NAC all had various antiproliferative effects. TSA had a more potent and longer lasting antiproliferative effect than CDB and NAC, even in the presence of an oxidant, H2O2. Its antiproliferative effect was concentration-dependent. ICI did not have a significant antiproliferative effect. PR-A, PR-B, AR, and FasL expression were all increased as compared with untreated cells.<br><br>CONCLUSIONS: The cell line appears to be an adequate model for stromal components of endometriotic implants. That ICI has no inhibitory effect on endometrial proliferation may explain why a phase II clinical trial on its use to treat endometriosis did not advance to later stages. The upregulation of PR-B and AR may be responsible for antiproliferative effects induced by TSA, a histone deacetylase inhibitor (HDACI). HDACIs may be promising therapeutics in treating endometriosis due to their antiproliferative effects as well as the potential to restore gene dysregulation through chromatin remodeling.}, }
@article {pmid16777943, year = {2006}, author = {Sandström, ME and Zhang, SJ and Bruton, J and Silva, JP and Reid, MB and Westerblad, H and Katz, A}, title = {Role of reactive oxygen species in contraction-mediated glucose transport in mouse skeletal muscle.}, journal = {The Journal of physiology}, volume = {575}, number = {Pt 1}, pages = {251-262}, pmid = {16777943}, issn = {0022-3751}, support = {R21 DK066232/DK/NIDDK NIH HHS/United States ; DK066232/DK/NIDDK NIH HHS/United States ; }, mesh = {AMP-Activated Protein Kinases ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Deoxyglucose/metabolism ; Glucose/*metabolism ; Glutathione/metabolism ; Hydrogen Peroxide/pharmacology ; In Vitro Techniques ; Male ; Mice ; Mice, Transgenic ; Multienzyme Complexes/metabolism ; *Muscle Contraction ; Muscle, Skeletal/drug effects/*enzymology/physiology ; Oxidative Stress ; Protein Serine-Threonine Kinases/metabolism ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {Exercise increases glucose transport into skeletal muscle via a pathway that is poorly understood. We investigated the role of endogenously produced reactive oxygen species (ROS) in contraction-mediated glucose transport. Repeated contractions increased 2-deoxyglucose (2-DG) uptake roughly threefold in isolated, mouse extensor digitorum longus (fast-twitch) muscle. N-Acetylcysteine (NAC), a non-specific antioxidant, inhibited contraction-mediated 2-DG uptake by approximately 50% (P < 0.05 versus control values), but did not significantly affect basal 2-DG uptake or the uptake induced by insulin, hypoxia or 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR, which mimics AMP-mediated activation of AMP-activated protein kinase, AMPK). Ebselen, a glutathione peroxidase mimetic, also inhibited contraction-mediated 2-DG uptake (by almost 60%, P < 0.001 versus control values). Muscles from mice overexpressing Mn2+-dependent superoxide dismutase, which catalyses H2O2 production from superoxide anions, exhibited a approximately 25% higher rate of contraction-mediated 2-DG uptake versus muscles from wild-type control mice (P < 0.05). Exogenous H2O2 induced oxidative stress, as judged by an increase in the [GSSG]/[GSH + GSSG] (reduced glutathione + oxidized glutathione) ratio to 2.5 times control values, and this increase was substantially blocked by NAC. Similarly, NAC significantly attenuated contraction-mediated oxidative stress as judged by measurements of glutathione status and the intracellular ROS level with the fluorescent indicator 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein (P < 0.05). Finally, contraction increased AMPK activity and phosphorylation approximately 10-fold, and NAC blocked approximately 50% of these changes. These data indicate that endogenously produced ROS, possibly H2O2 or its derivatives, play an important role in contraction-mediated activation of glucose transport in fast-twitch muscle.}, }
@article {pmid16766973, year = {2006}, author = {Weinbroum, AA}, title = {Concomitant administration of mannitol and N-acetylcysteine for the prevention of lung reperfusion injury.}, journal = {The Journal of trauma}, volume = {60}, number = {6}, pages = {1290-1296}, doi = {10.1097/01.ta.0000220382.91449.4a}, pmid = {16766973}, issn = {0022-5282}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Synergism ; Free Radical Scavengers/*administration &amp; dosage/pharmacology ; Ischemia/*therapy ; Liver/*blood supply ; Lung/*blood supply ; Male ; Mannitol/*administration &amp; dosage/pharmacology ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {BACKGROUND: Mannitol (MN) and N- acetylcysteine (NAC) are partially successful in preventing lung reperfusion injury after liver ischemia reperfusion (IR). Their concomitant administration might enhance the individual effects of each.<br><br>METHODS: Rat isolated livers were perfused with Krebs-Henseleit solution (controls) or made globally ischemic (IR) for 2 hours. Separately isolated lungs were paired with livers and each pair was reperfused in-series for 15 minutes. During reperfusion, eight groups were treated with Krebs containing two low and two high doses of MN and/or NAC; one group received no treatment.<br><br>RESULTS: The tested lung parameters were unchanged in all control groups. Pulmonary perfusion or ventilatory pressures, weight gain and bronchoalveolar lavage volume increased by 30 to 70% of baseline in the nontreated IR-paired lungs and in the only IR-MN 0.44- and the IR-NAC 0.25 mmol (weight/body weight) treated lungs but remained preserved by the two higher monotherapies (MN 0.55 mmol and NAC 0.37 mmol) and by the four bitherapies. The reduced glutathione content in all lung tissue subgroups treated by the bitherapies was higher by 63 to 124% of the corresponding monotherapy values. Xanthine oxidase activity in the bitherapies-treated IR-lungs decreased 1.5 to twofold compared with the corresponding monotherapies.<br><br>CONCLUSIONS: Co-administration of MN and NAC augments the amount of lung protection afforded by each drug individually and enhances their antioxidant potentials.}, }
@article {pmid16766235, year = {2006}, author = {Agrawal, S and Winnik, B and Buckley, B and Mi, L and Chung, FL and Cook, TJ}, title = {Simultaneous determination of sulforaphane and its major metabolites from biological matrices with liquid chromatography-tandem mass spectroscopy.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {840}, number = {2}, pages = {99-107}, doi = {10.1016/j.jchromb.2006.04.046}, pmid = {16766235}, issn = {1570-0232}, support = {P30 ES005022/ES/NIEHS NIH HHS/United States ; R01 CA100853/CA/NCI NIH HHS/United States ; R03 CA105465/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Calibration ; Chromatography, High Pressure Liquid/*methods ; Intestinal Mucosa/*metabolism ; Isothiocyanates ; Mass Spectrometry/*methods ; Permeability ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Sensitivity and Specificity ; Sulfoxides ; Thiocyanates/blood/*metabolism ; }, abstract = {A simple, sensitive and specific LC-MS/MS method for the simultaneous determination of sulforaphane (SFN) and its major metabolites, the glutathione (SFN-GSH) and N-acetyl cysteine conjugates (SFN-NAC) from biological matrices was developed and validated. The assay procedure involved solid-phase extratcion of all three analytes from rat intestinal perfusate using C2 extraction cartridges, whereas from rat plasma, metabolites were extracted by solid-phase extraction and SFN was extracted by liquid-liquid extraction with ethyl acetate. Chromatographic separation of SFN, SFN-GSH and SFN-NAC was achieved on a C8 reverse phase column with a mobile phase gradient (Mobile Phase A: 10mM ammonium acetate buffer, pH: 4.5 and Mobile Phase B: acetonitrile with 0.1% formic acid) at a flow rate of 0.3 mL/min. The Finnigan LCQ LC-MS/MS was operated under the selective reaction monitoring mode using the electrospray ionization technique in positive mode. The nominal retention times for SFN-GSH, SFN-NAC and SFN were 8.4, 11.0, and 28.2 min,, respectively. The method was linear for SFN and its metabolites with correlation coefficients >0.998 for all analytes. The limit of quantification was 0.01-0.1 microm depending on analyte and matrix, whereas the mean recoveries from spiked plasma and perfusate samples were approximately 90%. The method was further validated according to U.S. Food and Drug Administration guidance in terms of accuracy and precision. Stability of compounds was established in a battery of stability studies, i.e., bench top, auto-sampler and long-term storage stability as well as freeze/thaw cycles. The utility of the assay was confirmed by the analysis of intestinal perfusate and plasma samples from single-pass intestinal perfusion studies with mesenteric vein cannulation in rats.}, }
@article {pmid16763728, year = {2006}, author = {Shibayama-Imazu, T and Sonoda, I and Sakairi, S and Aiuchi, T and Ann, WW and Nakajo, S and Itabe, H and Nakaya, K}, title = {Production of superoxide and dissipation of mitochondrial transmembrane potential by vitamin K2 trigger apoptosis in human ovarian cancer TYK-nu cells.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {11}, number = {9}, pages = {1535-1543}, doi = {10.1007/s10495-006-7979-5}, pmid = {16763728}, issn = {1360-8185}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cycloheximide/pharmacology ; Diterpenes/pharmacology ; Female ; Humans ; Membrane Potentials/drug effects/*physiology ; Mitochondria/*drug effects/metabolism ; Ovarian Neoplasms/*drug therapy/metabolism ; Reactive Oxygen Species/pharmacology ; Superoxides/metabolism/*pharmacology ; Tumor Cells, Cultured ; Vitamin K 2/*pharmacology/therapeutic use ; alpha-Tocopherol/pharmacology ; }, abstract = {We reported previously that vitamin K(2) selectively induces apoptosis in human ovary cancer cells (TYK-nu cells) and pancreatic cancer cells (MIA PaCa-2 cells) through a mitochondrion-dependent pathway. In the present study, we examined the details of the mechanism of vitamin K(2)-induced apoptosis in TYK-nu cells. We found that superoxide (O(2)(*-)) was produced by TYK-nu cells between 2 and 3 days after the start of treatment with vitamin K(2), whereas it was produced within 30 min after the start of treatment with geranylgeraniol. The vitamin K(2)-induced apoptosis was inhibited by anti-oxidants, such as alpha-tocopherol, Tiron and N-acetyl-L-cysteine (NAC). Furthermore, both the production of superoxide and the induction of apoptosis by vitamin K(2) were inhibited almost completely by cycloheximide, an inhibitor of protein synthesis, suggesting that the synthesis of enzymes for the production of superoxide might be required for these processes. In parallel with the production of superoxide, the mitochondrial transmembrane potential, as measured by staining with Mitotracker Red CMXRos, dissipated during treatment of TYK-nu cells with vitamin K(2) for 3 days. The vitamin K(2)-induced depolarization of mitochondrial membranes was completely inhibited by alpha-tocopherol and, to a lesser extent, by Tiron and NAC. Since alpha-tocopherol reacts with oxygen radicals, such as superoxide, within the hydrophobic environment of the mitochondrial membrane, we postulate that vitamin K(2)-induced oxidative stress in mitochondria might damage mitochondrial membranes, with subsequent release of cytochrome c, the activation of procaspase 3 and, eventually, apoptosis.}, }
@article {pmid16761701, year = {2006}, author = {Kramer, S and Dreisbach, L and Lockwood, J and Baldwin, K and Kopke, R and Scranton, S and O'Leary, M}, title = {Efficacy of the antioxidant N-acetylcysteine (NAC) in protecting ears exposed to loud music.}, journal = {Journal of the American Academy of Audiology}, volume = {17}, number = {4}, pages = {265-278}, doi = {10.3766/jaaa.17.4.5}, pmid = {16761701}, issn = {1050-0545}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Antioxidants/administration &amp; dosage/*pharmacology ; Audiometry, Pure-Tone ; Auditory Threshold/*drug effects ; Double-Blind Method ; Female ; Hearing Loss, Noise-Induced/*prevention &amp; control ; Humans ; Male ; Noise/adverse effects ; Otoacoustic Emissions, Spontaneous/physiology ; }, abstract = {Antioxidants have been reported to be effective in reducing acoustic trauma in animal models but have not been studied in humans. In this study, the antioxidant N-acetylcysteine (NAC) was evaluated to determine if it would reduce temporary changes in auditory function as a result of exposure to loud music in humans. Pure-tone thresholds and distortion product otoacoustic emissions (DPOAEs) were collected in 31 normal-hearing participants, using a randomized, double-blind, placebo-controlled design, before and after two hours of live music in a nightclub. Using repeated measures analysis of variance, no statistically significant differences were found between participants who received NAC versus a placebo for any of the outcome measures. Across all subjects, the largest pure-tone threshold shift occurred at 4 kHz. DPOAE measures were characterized by reductions in amplitude and a trend for shorter group delay values. When the 3 and 4 kHz data were examined by imposing specific criteria of greater than 2 dB DPOAE amplitude reductions and 10 dB or greater pure-tone threshold shifts, DPOAE reductions occurred more often at 3 kHz, and pure-tone shifts occurred more often at 4 kHz.}, }
@article {pmid16760923, year = {2007}, author = {Achat-Mendes, C and Anderson, KL and Itzhak, Y}, title = {Impairment in consolidation of learned place preference following dopaminergic neurotoxicity in mice is ameliorated by N-acetylcysteine but not D1 and D2 dopamine receptor agonists.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {32}, number = {3}, pages = {531-541}, doi = {10.1038/sj.npp.1301119}, pmid = {16760923}, issn = {0893-133X}, support = {R01DA012867/DA/NIDA NIH HHS/United States ; R01DA019107/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Behavior, Animal/drug effects ; Brain Chemistry/drug effects ; Cocaine/administration &amp; dosage ; Conditioning, Operant/*drug effects ; Disease Models, Animal ; Dopamine/*metabolism ; Dopamine Agents/toxicity ; Dopamine Agonists/therapeutic use ; Dopamine Uptake Inhibitors/administration &amp; dosage ; Dose-Response Relationship, Drug ; Drug Interactions ; Free Radical Scavengers/*therapeutic use ; Gene Expression Regulation/drug effects ; Glial Fibrillary Acidic Protein/metabolism ; Glutathione/metabolism ; Learning Disabilities/*drug therapy/etiology ; Male ; Methamphetamine/toxicity ; Mice ; Neurotoxicity Syndromes/complications/drug therapy/etiology/*metabolism ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Some of the major concerns related to methamphetamine (METH) abuse are the neuronal damage inflicted at dopamine (DA) nerve terminals and the cognitive deficits observed in human METH abusers. We have shown that a high dose of METH selectively depleted dopaminergic markers in striatum, frontal cortex and amygdala of Swiss Webster mice, and impaired learned place preference. In this study, we investigated whether deficits in consolidation of place learning, as a consequence of METH neurotoxicity, underlie the underperformance of cocaine conditioned place preference (CPP). Administration of METH (5 mg/kg x 3) to Swiss Webster mice decreased striatal tyrosine hydroxylase (TH) immunoreactive neurons and significantly increased glial fibrillary acidic protein (GFAP) expression, confirming the neurotoxic potential of METH in mice. This treatment significantly attenuated the establishment of cocaine (15 mg/kg) CPP compared to control. To investigate whether manipulation of the consolidation phase improves learned place preference, mice were trained by cocaine and received daily post-training injections of DA receptor agonists or N-acetylcysteine (NAC). As memory consolidation occurs shortly after training, drugs were administered either immediately or 2 h post-training. Immediate post-training administration of the D1 DA receptor agonist SKF38393 (5, 10, and 20 mg/kg) or the D2 DA receptor agonist quinpirole (0.25, 0.5, and 1.0 mg/kg) did not improve the establishment of CPP following METH neurotoxicity. However, immediate but not delayed NAC administration (50 and 100 mg/kg) enhanced cocaine CPP following METH neurotoxicity and had no effect on control CPP. The levels of the reduced form of glutathione (GSH) in striatum, amygdala, hippocampus and frontal cortex were significantly lower in METH-treated mice compared to control during the period of CPP training. Acute and repeated administration of NAC to METH-treated mice restored the decreased brain GSH but had no effect on controls. Results suggest that METH-induced dopaminergic neurotoxicity is associated with impairment of consolidation of learned place preference, and that this impairment is improved by immediate post-training administration of the glutathione precursor NAC and not by D1 or D2 DA receptor agonists. Restoration of brain glutathione levels immediately post-training may facilitate the consolidation process.}, }
@article {pmid16760673, year = {2006}, author = {Huang, X and Kurose, A and Tanaka, T and Traganos, F and Dai, W and Darzynkiewicz, Z}, title = {Activation of ATM and histone H2AX phosphorylation induced by mitoxantrone but not by topotecan is prevented by the antioxidant N-acetyl-L-cysteine.}, journal = {Cancer biology &amp; therapy}, volume = {5}, number = {8}, pages = {959-964}, doi = {10.4161/cbt.5.8.2878}, pmid = {16760673}, issn = {1538-4047}, support = {R01 CA028704/CA/NCI NIH HHS/United States ; R01 CA028704-27/CA/NCI NIH HHS/United States ; CA R01 28704/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/therapeutic use ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/drug effects ; Cell Cycle Proteins/*metabolism ; DNA Damage/drug effects ; DNA-Binding Proteins/*metabolism ; Flow Cytometry ; Fluorescent Antibody Technique ; HL-60 Cells/drug effects/metabolism ; Histones/*metabolism ; Humans ; Lung Neoplasms/drug therapy/metabolism ; Mitoxantrone/*therapeutic use ; Phosphorylation/drug effects ; Protein Serine-Threonine Kinases/*metabolism ; Topotecan/*therapeutic use ; Tumor Cells, Cultured ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {The DNA topoisomerase II (topo2) inhibitor mitoxantrone (MXT) and topo1 inhibitor topotecan (TP) are antitumor drugs widely used to treat different types of cancer. Their mechanism of action is thought to stabilize otherwise transient ("cleavable") complexes between topo2 or topo1 and DNA; the collisions of the DNA replication fork during replication, or RNA polymerase during transcription, with these complexes convert them into double-strand DNA breaks (DSBs), potentially lethal lesions that may trigger apoptosis. In the present study we observed that treatment of human lung carcinoma A549 or promyelocytic leukemic HL-60 cells with MXT led to ATM activation and phosphorylation of histone H2AX on Ser-139, the reporters of induction of DSBs, in all phases of the cell-cycle. Only S-phase cells, however, underwent apoptosis after treatment with MXT, which implied that DSBs in the cells replicating DNA were more effective in triggering apoptosis than DSBs in G(1) or G(2)M phase cells. Unlike MXT, the treatment with TP induced ATM activation and H2AX phosphorylation almost exclusively in S-phase cells and only S phase cells underwent apoptosis. The induction of both ATM activation and H2AX phosphorylation by MXT was prevented to a large extent by N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS). The protective effect of NAC was observed for cells in all phases of the cell cycle. NAC offered no protection at all against TP. The induction of DSBs by MXT, thus, appears to be predominantly mediated through ROS, while DSBs generated during treatment with TP most likely are a consequence of collisions of replication forks with the "cleavable" complexes.}, }
@article {pmid16759702, year = {2008}, author = {Wang, G and Chen, K and Chen, L and Hu, C and Zhang, D and Liu, Y}, title = {The involvement of the antioxidant system in protection of desert cyanobacterium Nostoc sp. against UV-B radiation and the effects of exogenous antioxidants.}, journal = {Ecotoxicology and environmental safety}, volume = {69}, number = {1}, pages = {150-157}, doi = {10.1016/j.ecoenv.2006.03.014}, pmid = {16759702}, issn = {0147-6513}, mesh = {Antioxidants/*metabolism/*pharmacology ; Desert Climate ; Nostoc/drug effects/*metabolism/*radiation effects ; Photosynthesis/radiation effects ; *Ultraviolet Rays ; }, abstract = {In this study, we found that UV-B radiation decreased photosynthetic activity and boosted lipid peroxidation of desert Nostoc sp., and exogenous chemicals (ascorbate acid (ASC), N-acetylcysteine (NAC), and sodium nitroprusside (SNP)) had obvious protective effects on photosynthesis and membranes under UV-B radiation. High-concentration SNP boosted the activities of antioxidant enzymes, but low-concentration SNP reduced the activities of antioxidant enzymes. Both NAC and ASC treatments of cells decreased activities of antioxidant enzymes. The results suggested that those chemicals possibly had different mechanisms of protection of algae cells against UV-B radiation. SNP might play double roles as a signal molecule in the formation of algae cell protection of Photosystem II under UV-B radiation and as a (reactive oxygen species) scavenger, while NAC and ASC might function as antioxidant reagents or precursors of other antioxidant molecules, which could protect cells directly against ROS initiated by UV-B radiation.}, }
@article {pmid16758355, year = {2006}, author = {Hicdonmez, T and Kanter, M and Tiryaki, M and Parsak, T and Cobanoglu, S}, title = {Neuroprotective effects of N-acetylcysteine on experimental closed head trauma in rats.}, journal = {Neurochemical research}, volume = {31}, number = {4}, pages = {473-481}, pmid = {16758355}, issn = {0364-3190}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Apoptosis/physiology ; Brain/cytology/metabolism/pathology ; Caspase 3/metabolism ; Catalase/metabolism ; Free Radical Scavengers/*therapeutic use ; Glutathione Peroxidase/metabolism ; Head Injuries, Closed/*drug therapy/pathology ; Male ; Malondialdehyde/metabolism ; Neuroprotective Agents/*therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; }, abstract = {N-acetylcysteine (NAC) is a precursor of glutathione, a potent antioxidant, and a free radical scavenger. The beneficial effect of NAC on nervous system ischemia and ischemia/reperfusion models has been well documented. However, the effect of NAC on nervous system trauma remains less understood. Therefore, we aimed to investigate the therapeutic efficacy of NAC with an experimental closed head trauma model in rats. Thirty-six adult male Sprague-Dawley rats were randomly divided into three groups of 12 rats each: Group I (control), Group II (trauma-alone), and Group III (trauma+NAC treatment). In Groups II and III, a cranial impact was delivered to the skull from a height of 7 cm at a point just in front of the coronal suture and over the right hemisphere. Rats were sacrificed at 2 h (Subgroups I-A, II-A, and III-A) and 12 h (Subgroups I-B, II-B, and III-B) after the onset of injury. Brain tissues were removed for biochemical and histopathological investigation. The closed head trauma significantly increased tissue malondialdehyde (MDA) levels (P < 0.05), and significantly decreased tissue superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities (P < 0.05), but not tissue catalase (CAT) activity, when compared with controls. The administration of a single dose of NAC (150 mg/kg) 15 min after the trauma has shown protective effect via decreasing significantly the elevated MDA levels (P < 0.05) and also significantly (P < 0.05) increasing the reduced antioxidant enzyme (SOD and GPx) activities, except CAT activity. In the trauma-alone group, the neurons became extensively dark and degenerated into picnotic nuclei. The morphology of neurons in the NAC treatment group was well protected. The number of neurons in the trauma-alone group was significantly less than that of both the control and trauma+NAC treatment groups. In conclusion, the NAC treatment might be beneficial in preventing trauma-induced oxidative brain tissue damage, thus showing potential for clinical implications.}, }
@article {pmid16754540, year = {2006}, author = {Hu, S and Zhao, H and Al-Humadi, NH and Yin, XJ and Ma, JK}, title = {Silica-induced apoptosis in alveolar macrophages: evidence of in vivo thiol depletion and the activation of mitochondrial pathway.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {69}, number = {13}, pages = {1261-1284}, doi = {10.1080/15287390500361875}, pmid = {16754540}, issn = {1528-7394}, mesh = {Acetylcysteine/pharmacology ; Alkaloids/pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; *Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Benzylisoquinolines/pharmacology ; Caspase 3 ; Caspases/metabolism ; Cysteine/biosynthesis ; Cytochromes c/biosynthesis ; Disease Models, Animal ; Glutathione/biosynthesis ; Inflammation Mediators/immunology ; Macrophages, Alveolar/drug effects/*immunology ; Male ; Membrane Potentials/physiology ; Microscopy, Confocal ; Mitochondria/drug effects/*physiology ; Oxidative Stress ; Paclitaxel/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/analysis/immunology ; Silicon Dioxide/*adverse effects ; Sulfhydryl Compounds/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {Studies have shown that silica induces apoptosis through mechanisms that also regulate the inflammatory responses of lung cells to silica exposure. Although implicated in cell culture studies, the major in vivo pathway through which silica induces apoptosis has not been characterized. The present study is to study the role of mitochondria in silica-induced oxidative stress and apoptosis in vivo. Rats were intratracheally instilled with saline or silica (20 mg/kg) and sacrificed at 3 days post-exposure unless otherwise specified. Alveolar macrophages (AM) were harvested by bronchoalveolar lavage and measured for apoptosis and secretion of inflammatory mediators in the presence or absence of appropriate inhibitors. Concurrent studies were carried out to determine the presence of intracellular reactive oxygen species (ROS) via confocal microscopy, mitochondrial trans-membrane potential by flow cytometry, mitochondrial release of cytochrome c, and the activation of caspase activities in AM by Western blot analysis. Silica was shown to induce elevated levels of intracellular ROS, resulting in a marked decrease in intracellular glutathione (GSH) and cysteine and a sustained presence of apoptotic AM in silica-exposed rats up to two weeks post-exposure. The apoptotic AM were characterized by decreased mitochondrial trans-membrane potential, increased mitochondrial release of cytochrome c, activated caspase 9 (but not caspase 8) and caspase 3 activities, and PARP degradation, comparing to cells from the saline control. Silica induced AM production of IL-1 and TNF-alpha, which may be inhibited by ex vivo treatment of cells with N-acetylcysteine (NAC) or microtubule modifiers such as tetrandrine and taxol. NAC was shown to prevent intracellular GSH depletion and silica-induced production of IL-1beta and TNF-alpha but not apoptosis in AM from silica-exposed rats. These results show that silica-induced apoptosis is mediated through the mitochondrial pathway but not through cellular production of inflammatory cytokines, ROS generation, however, induces both apoptosis and cellular secretion of inflammatory mediators.}, }
@article {pmid16753318, year = {2007}, author = {Rysz, J and Stolarek, RA and Luczynski, R and Sarniak, A and Wlodarczyk, A and Kasielski, M and Nowak, D}, title = {Increased hydrogen peroxide concentration in the exhaled breath condensate of stable COPD patients after nebulized N-acetylcysteine.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {20}, number = {3}, pages = {281-289}, doi = {10.1016/j.pupt.2006.03.011}, pmid = {16753318}, issn = {1094-5539}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aged ; Analysis of Variance ; Breath Tests/methods ; Cross-Over Studies ; Double-Blind Method ; Exhalation ; Expectorants/administration &amp; dosage/therapeutic use ; Expiratory Reserve Volume/*drug effects ; Female ; Forced Expiratory Flow Rates/drug effects ; Forced Expiratory Volume/drug effects ; Humans ; Hydrogen Peroxide/analysis/*metabolism ; Male ; Middle Aged ; Nebulizers and Vaporizers ; Nitrates/analysis/metabolism ; Nitrites/analysis/metabolism ; Prospective Studies ; Pulmonary Disease, Chronic Obstructive/*drug therapy/metabolism/physiopathology ; Sulfhydryl Compounds/analysis/metabolism ; }, abstract = {BACKGROUND: The oxidative burden in the airways is a hallmark of chronic obstructive pulmonary disease (COPD).<br><br>AIMS: This prospective, cross-over, placebo (PL)-controlled study was designed to investigate the effect of N-acetyl-l-cysteine (NAC) on hydrogen peroxide (H(2)O(2)), nitrites and nitrates (NO(2)(-)+NO(3)(-)), and thiol (RSH) concentrations in exhaled breath condensate (EBC) in stable COPD patients (n=19, aged 52.6+/-15.6 years, 10 females, mean FEV(1) 95.2+/-23.8%, FEV(1)/FVC 69.1+/-11.4%).<br><br>METHODS: H(2)O(2), NO(2)(-)+NO(3)(-) and RSH concentrations in EBC were determined with homovanillic acid, NADPH-nitrite reductase assays and Ellman's reaction, respectively.<br><br>RESULTS: Thirty minutes after nebulization, H(2)O(2) concentration increased if levels after NAC (0.45+/-0.25microM) and PL (0.17+/-0.17microM) were compared in COPD patients (p=0.002). This increased H(2)O(2) level in EBC was no longer observed either after 90min: 0.16+/-0.09microM (PL 0.17+/-0.15microM) or 3h: 0.12+/-0.07microM (PL 0.21+/-0.23microM) (p=0.5 and 0.2, respectively). The levels of NO(2)(-) and NO(3)(-) did not differ between NAC and PL. There was no significant difference in RSH levels between nebulized NAC and PL. After nebulized NAC, however, exhaled RSH increased from 1.42+/-1.69microM (0min) to 2.49+/-2.00microM (30min), and 1.71+/-1.83microM (180min) (p=0.009 and 0.03, respectively, compared with 0min).<br><br>CONCLUSIONS: These data demonstrate that nebulized NAC transiently increases exhaled H(2)O(2) level, whereas it has no effect on other oxidative parameters.}, }
@article {pmid16753142, year = {2006}, author = {Arimochi, H and Morita, K}, title = {Characterization of cytotoxic actions of tricyclic antidepressants on human HT29 colon carcinoma cells.}, journal = {European journal of pharmacology}, volume = {541}, number = {1-2}, pages = {17-23}, doi = {10.1016/j.ejphar.2006.04.053}, pmid = {16753142}, issn = {0014-2999}, mesh = {Amitriptyline/pharmacology ; Antidepressive Agents, Tricyclic/*pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Proliferation/*drug effects ; Cell Survival/drug effects ; Colonic Neoplasms/pathology/physiopathology ; DNA Fragmentation/drug effects ; Desipramine/pharmacology ; HT29 Cells ; Humans ; Imipramine/pharmacology ; Membrane Potentials/drug effects ; Mitochondrial Membranes/drug effects/physiology ; Time Factors ; }, abstract = {Preclinical studies have suggested that the long-term use of antidepressants may result in the initiation and/or promotion of tumor in the gastrointestinal tract. However, a possible relationship between the use of antidepressants and the production of colon cancer has not yet been confirmed, and hence requires to be further investigated. To address this issue, the effects of antidepressants on the proliferation of colorectal tumor cells were examined using human HT29 colon carcinoma cells, and tricyclic antidepressant, such as imipramine, desipramine and amitriptyline, were shown to reduce the cell viability in a manner dependent on the time exposing to these drugs. In addition to these drugs, a selective serotonin reuptake inhibitor fluoxetine, but not a monoamine oxidase inhibitor tranylcypromine, caused the reduction of cell viability, similar in extent to that caused by imipramine. Further studies showed that desipramine caused the apoptotic cell death, which could be prevented by neither catalase, reduced-form glutathione (GSH), nor N-acetylcysteine (NAC), without accompanying the disruption of mitochondrial membrane potential within the cells and the release of cytochrome c into the cell cytoplasm. Moreover, desipramine caused the arrest of cell-cycle progression at either G0/G1-phase or G2/M-phase, which might be depending upon the drug concentration. Thus, these results suggest that tricyclic antidepressants may be cytotoxic, and induce the non-oxidative apoptotic death of human HT29 colon carcinoma cells probably through a non-mitochondrial pathway associated with the cell-cycle progression.}, }
@article {pmid16753129, year = {2006}, author = {Ptolemy, AS and Tran, L and Britz-McKibbin, P}, title = {Single-step enantioselective amino acid flux analysis by capillary electrophoresis using on-line sample preconcentration with chemical derivatization.}, journal = {Analytical biochemistry}, volume = {354}, number = {2}, pages = {192-204}, doi = {10.1016/j.ab.2006.04.016}, pmid = {16753129}, issn = {0003-2697}, mesh = {Acetylcysteine ; Alanine/analysis/chemistry/metabolism ; Amino Acids/*analysis/*chemistry ; Chromatography, Micellar Electrokinetic Capillary/methods ; Culture Media/analysis ; Electrophoresis, Capillary/*methods ; Escherichia coli/growth &amp; development/metabolism ; Extracellular Matrix/metabolism ; Hydrogen-Ion Concentration ; Spectrophotometry, Ultraviolet ; Stereoisomerism ; o-Phthalaldehyde ; }, abstract = {Capillary electrophoresis (CE) represents a versatile platform for integrating sample pretreatment with chemical analysis because of its ability to tune analyte electromigration and band dispersion properties in discontinuous electrolyte systems. In this article, a single-step method that combines on-line sample preconcentration with in-capillary chemical derivatization is developed for rapid, sensitive, and enantioselective analysis of micromolar levels of amino acids that lack intrinsic chromophores by CE with UV detection. Time-resolved electrophoretic studies revealed two distinct stages of amino acid band narrowing within the original long sample injection plug occurring both prior to and after in-capillary labeling via zone passing by ortho-phthalaldehyde/N-acetyl l-cysteine (OPA/NAC). This technique enabled direct analysis of d-amino acids in a 95% enantiomeric excess mixture with sub-micromolar detection limits and minimal sample handling, where the capillary functions as a preconcentrator, microreactor, and chiral selector. On-line sample preconcentration with chemical derivatization CE (SPCD-CE) was applied to study the enantioselective amino acid flux in Escherichia coli bacteria cultures, which demonstrated a unique l-Ala efflux into the extracellular medium. New strategies for high-throughput analyses of low-abundance metabolites are important for understanding fundamental physiological processes in bacteria required for screening the efficacy of new classes of antibiotics as well as altered metabolism in genetically modified mutant strains.}, }
@article {pmid16753063, year = {2006}, author = {de Groot-Besseling, RR and Ruers, TJ and Lamers-Elemans, IL and Maass, CN and de Waal, RM and Westphal, JR}, title = {Angiostatin generating capacity and anti-tumour effects of D-penicillamine and plasminogen activators.}, journal = {BMC cancer}, volume = {6}, number = {}, pages = {149}, pmid = {16753063}, issn = {1471-2407}, mesh = {Angiostatins/*biosynthesis/blood ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Humans ; In Vitro Techniques ; Melanoma/blood supply ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Penicillamine/administration &amp; dosage/*pharmacology ; Plasminogen Activators/administration &amp; dosage/*pharmacology ; Xenograft Model Antitumor Assays ; }, abstract = {BACKGROUND: Upregulation of endogenous angiostatin levels may constitute a novel anti-angiogenic, and therefore anti-tumor therapy. In vitro, angiostatin generation is a two-step process, starting with the conversion of plasminogen to plasmin by plasminogen activators (PAs). Next, plasmin excises angiostatin from other plasmin molecules, a process requiring a donor of a free sulfhydryl group. In previous studies, it has been demonstrated that administration of PA in combination with the free sulfhydryl donor (FSD) agents captopril or N-acetyl cysteine, resulted in angiostatin generation, and anti-angiogenic and anti-tumour activity in murine models.<br><br>METHODS: In this study we have investigated the angiostatin generating capacities of several FSDs. D-penicillamine proved to be most efficient in supporting the conversion of plasminogen to angiostatin in vitro. Next, from the optimal concentrations of tPA and D-penicillamine in vitro, equivalent dosages were administered to healthy Balb/c mice to explore upregulation of circulating angiostatin levels. Finally, anti-tumor effects of treatment with tPA and D-penicillamine were determined in a human melanoma xenograft model.<br><br>RESULTS: Surprisingly, we found that despite the superior angiostatin generating capacity of D-penicillamine in vitro, both in vivo angiostatin generation and anti-tumour effects of tPA/D-penicillamine treatment were impaired compared to our previous studies with tPA and captopril.<br><br>CONCLUSION: Our results indicate that selecting the most appropriate free sulfhydryl donor for anti-angiogenic therapy in a (pre)clinical setting should be performed by in vivo rather than by in vitro studies. We conclude that D-penicillamine is not suitable for this type of therapy.}, }
@article {pmid16737744, year = {2006}, author = {Koutsogiannaki, S and Evangelinos, N and Koliakos, G and Kaloyianni, M}, title = {Cytotoxic mechanisms of Zn2+ and Cd2+ involve Na+/H+ exchanger (NHE) activation by ROS.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {78}, number = {4}, pages = {315-324}, doi = {10.1016/j.aquatox.2006.04.004}, pmid = {16737744}, issn = {0166-445X}, mesh = {Acetylcysteine/pharmacology ; Amiloride/analogs &amp; derivatives/pharmacology ; Animals ; Antimycin A/pharmacology ; Antioxidants/pharmacology ; Cadmium/metabolism ; Cadmium Poisoning/metabolism/*veterinary ; Cell Survival ; Gills/metabolism ; Hydrogen-Ion Concentration ; Mytilus/*drug effects/*metabolism ; Naphthalenes/pharmacology ; Oxidants/pharmacology ; PPAR gamma/agonists/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyruvic Acid/pharmacology ; Reactive Oxygen Species/*metabolism ; Receptors, Adrenergic/metabolism ; Rosiglitazone ; Rotenone/pharmacology ; Sodium-Hydrogen Exchangers/antagonists &amp; inhibitors/*metabolism ; Thiazolidinediones/pharmacology ; Water Pollutants, Chemical/metabolism/*poisoning ; Zinc/metabolism/*poisoning ; }, abstract = {The signaling mechanism induced by cadmium (Cd) and zinc (Zn) in gill cells of Mytilus galloprovincialis was investigated. Both metals cause an increase in *O2- production, with Cd to be more potent (216 +/- 15%) than Zn (150 +/- 9.5%), in relation to control value (100%). The metals effect was reversed after incubation with the amiloride analogue, EIPA, a selective Na+/H+ exchanger (NHE) inhibitor as well as in the presence of calphostin C, a protein kinase C (PKC) inhibitor. The heavy metals effect on *O2- production was mediated via the interaction of metal ions with alpha1- and beta-adrenergic receptors, as shown after incubation with their respective agonists and antagonists. In addition, both metals caused an increase in intracellular pH (pHi) of gill cells. EIPA together with either metal significantly reduced the effect of each metal treatment on pHi. Incubation of gill cells with the oxidants rotenone, antimycin A and pyruvate caused a significant increase in pHi (delta pHi 0.830, 0.272 and 0.610, respectively), while in the presence of the anti-oxidant N-acetyl cysteine (NAC) a decrease in pHi (delta pHi -0.090) was measured, indicating that change in reactive oxygen species (ROS) production by heavy metals affects NHE activity. When rosiglitazone was incubated together with either heavy metal a decrease in O2- production was observed. Our results show a key role of NHE in the signal transduction pathway induced by Zn and Cd in gill cells, with the involvement of ROS, PKC, adrenergic and PPAR-gamma receptors. In addition, differences between the two metals concerning NHE activation, O2- production and interaction with adrenergic receptors were observed.}, }
@article {pmid16731823, year = {2006}, author = {Chen, YW and Huang, CF and Tsai, KS and Yang, RS and Yen, CC and Yang, CY and Lin-Shiau, SY and Liu, SH}, title = {The role of phosphoinositide 3-kinase/Akt signaling in low-dose mercury-induced mouse pancreatic beta-cell dysfunction in vitro and in vivo.}, journal = {Diabetes}, volume = {55}, number = {6}, pages = {1614-1624}, doi = {10.2337/db06-0029}, pmid = {16731823}, issn = {0012-1797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood Glucose/metabolism ; Blotting, Western ; Cell Line, Tumor ; Cell Survival/drug effects ; Chromones/pharmacology ; Cricetinae ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Glucose Tolerance Test ; Insulin/metabolism ; Insulin-Secreting Cells/drug effects/metabolism/*physiology ; Islets of Langerhans/drug effects/metabolism/physiopathology ; Lipid Peroxidation/drug effects ; Male ; Mercury/blood/*toxicity ; Mercury Compounds/blood/toxicity ; Mice ; Mice, Inbred ICR ; Morpholines/pharmacology ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-akt/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/*physiology ; }, abstract = {The relationship between oxidation stress and phosphoinositide 3-kinase (PI3K) signaling in pancreatic beta-cell dysfunction remains unclear. Mercury is a well-known toxic metal that induces oxidative stress. Submicromolar-concentration HgCl(2) or methylmercury triggered reactive oxygen species (ROS) production and decreased insulin secretion in beta-cell-derived HIT-T15 cells and isolated mouse islets. Mercury increased PI3K activity and its downstream effector Akt phosphorylation. Antioxidant N-acetyl-l-cysteine (NAC) prevented mercury-induced insulin secretion inhibition and Akt phosphorylation but not increased PI3K activity. Inhibition of PI3K/Akt activity with PI3K inhibitor or by expressing the dominant-negative p85 or Akt prevented mercury-induced insulin secretion inhibition but not ROS production. These results indicate that both PI3K and ROS independently regulated Akt signaling-related, mercury-induced insulin secretion inhibition. We next observed that 2- or 4-week oral exposure to low-dose mercury to mice significantly caused the decrease in plasma insulin and displayed the elevation of blood glucose and plasma lipid peroxidation and glucose intolerance. Akt phosphorylation was shown in islets isolated from mercury-exposed mice. NAC effectively antagonized mercury-induced responses. Mercury-induced in vivo effects and increased blood mercury were reversed after mercury exposure was terminated. These results demonstrate that low-dose mercury-induced oxidative stress and PI3K activation cause Akt signaling-related pancreatic beta-cell dysfunction.}, }
@article {pmid16728380, year = {2006}, author = {Kim, J and Sharma, RP}, title = {Cadmium-induced apoptosis in murine macrophages is antagonized by antioxidants and caspase inhibitors.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {69}, number = {12}, pages = {1181-1201}, doi = {10.1080/15287390600631144}, pmid = {16728380}, issn = {1528-7394}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cadmium/*toxicity ; Caspase 3 ; Caspase Inhibitors ; Caspases/*metabolism ; Cell Line ; Environmental Pollutants/*toxicity ; Enzyme Inhibitors/pharmacology ; Macrophages/*drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Oxidative Stress/*drug effects ; Reactive Oxygen Species ; }, abstract = {Cadmium is a toxic heavy metal that accumulates in the environment and is commonly found in cigarette smoke and industrial effluents. This study was designed to determine the role of reactive oxygen species (ROS) generation, and its antagonism by antioxidants, in cadmium-mediated cell signaling and apoptosis in murine macrophage cultures. Cadmium-generated ROS production was observed in J774A.1 cells at 6 h, reverting to control levels at 16 and 24 h. The ROS production was concentration related between 20 and 500 microM cadmium. Activation of caspase-3 was observed at 8 h and DNA fragmentation at 16 h in the presence of 20 microM cadmium, suggesting that caspase-3 activation is a prior step to DNA fragmentation in cadmium-induced apoptosis. Inhibitors of caspase-3, -8, -9, and a general caspase inhibitor suppressed cadmium-induced caspase-3 activation and apoptosis indicating the importance of caspase-3 in cadmium-induced toxicity in these cells. Protection against the oxidative stress with N-acetylcysteine (NAC) and silymarin (an antioxidant flavonoid) blocked cadmium-induced apoptosis. Pretreatment of cells with NAC and silymarin prevented cadmium-induced cell injury, including growth arrest, mitochondrial impairment, and necrosis, and reduced the cadmium-elevated intracellular calcium ([Ca2+]i), suggesting that the oxidative stress is a source of increased [Ca2+]i. NAC inhibited cadmium-induced activation of mitogen-activated protein kinases, the c-Jun NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK). However, silymarin provided only a partial protection for JNK activation, and only at the low concentration did it inhibit cadmium-induced ERK activation. Inhibition of caspase-3 protected oxidative stress produced by cadmium, suggesting that the activation of caspase-3 also contributes to generation of reactive oxygen species (ROS). Results emphasized the role of ROS, Ca2+ and mitogen-activated protein kinases in cadmium-induced cytotoxicity in murine macrophages.}, }
@article {pmid16719839, year = {2006}, author = {Pecora, F and Gualeni, B and Forlino, A and Superti-Furga, A and Tenni, R and Cetta, G and Rossi, A}, title = {In vivo contribution of amino acid sulfur to cartilage proteoglycan sulfation.}, journal = {The Biochemical journal}, volume = {398}, number = {3}, pages = {509-514}, pmid = {16719839}, issn = {1470-8728}, support = {GGP06076/TI_/Telethon/Italy ; }, mesh = {Acetylcysteine ; Amino Acid Substitution ; Amino Acids/*metabolism ; Animals ; Anion Transport Proteins ; CHO Cells ; Carrier Proteins/genetics/*metabolism ; Cartilage/*chemistry ; Cricetinae ; Gene Expression Regulation ; Membrane Transport Proteins/genetics/*metabolism ; Mice ; Mice, Transgenic ; Mutation ; Proteoglycans/chemistry/*metabolism ; Sulfate Transporters ; Sulfates/metabolism ; Sulfhydryl Compounds/metabolism ; Sulfur/*metabolism ; }, abstract = {Cytoplasmic sulfate for sulfation reactions may be derived either from extracellular fluids or from catabolism of sulfur-containing amino acids and other thiols. In vitro studies have pointed out the potential relevance of sulfur-containing amino acids as sources for sulfation when extracellular sulfate concentration is low or when its transport is impaired such as in DTDST [DTD (diastrophic dysplasia) sulfate transporter] chondrodysplasias. In the present study, we have considered the contribution of cysteine and cysteine derivatives to in vivo macromolecular sulfation of cartilage by using the mouse model of DTD we have recently generated [Forlino, Piazza, Tiveron, Della Torre, Tatangelo, Bonafe, Gualeni, Romano, Pecora, Superti-Furga et al. (2005) Hum. Mol. Genet. 14, 859-871]. By intraperitoneal injection of [35S]cysteine in wild-type and mutant mice and determination of the specific activity of the chondroitin 4-sulfated disaccharide in cartilage, we demonstrated that the pathway by which sulfate is recruited from the intracellular oxidation of thiols is active in vivo. To check whether cysteine derivatives play a role, sulfation of cartilage proteoglycans was measured after treatment for 1 week of newborn mutant and wild-type mice with hypodermic NAC (N-acetyl-L-cysteine). The relative amount of sulfated disaccharides increased in mutant mice treated with NAC compared with the placebo group, indicating an increase in proteoglycan sulfation due to NAC catabolism, although pharmacokinetic studies demonstrated that the drug was rapidly removed from the bloodstream. In conclusion, cysteine contribution to cartilage proteoglycan sulfation in vivo is minimal under physiological conditions even if extracellular sulfate availability is low; however, the contribution of thiols to sulfation becomes significant by increasing their plasma concentration.}, }
@article {pmid16718735, year = {2006}, author = {Wu, YT and Shen, C and Yin, J and Yu, JP and Meng, Q}, title = {Azathioprine hepatotoxicity and the protective effect of liquorice and glycyrrhizic acid.}, journal = {Phytotherapy research : PTR}, volume = {20}, number = {8}, pages = {640-645}, doi = {10.1002/ptr.1920}, pmid = {16718735}, issn = {0951-418X}, mesh = {Acetylcysteine/metabolism ; Animals ; Azathioprine/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/etiology/pathology/prevention &amp; control ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Interactions ; Glutathione/metabolism ; *Glycyrrhiza/chemistry ; Glycyrrhizic Acid/*pharmacology ; Hepatocytes/*drug effects/metabolism/pathology ; Humans ; Immunosuppressive Agents/*toxicity ; Male ; Plant Extracts/pharmacology ; Plant Roots/chemistry ; Rats ; Rats, Sprague-Dawley ; Species Specificity ; }, abstract = {This study aimed to evaluate the responses of human hepatocytes to azathioprine hepatotoxicity in comparison with the well-studied azathioprine hepatotoxicity in rat hepatocytes and the effects of protective agents to suppress azathioprine hepatotoxicity. Azathioprine presented its hepatotoxicity at clinically relevant concentrations (lower than 10 microm) in primary rat hepatocytes after 48 h of treatment as shown by a severe decrease in cell viability as well as intracellular GSH depletion. However, primary human hepatocytes exhibited only significant intracellular GSH depletion after treatment with azathioprine at these clinically relevant concentrations, while a reduction in cell viability by 29% was only evidenced after 48 h of treatment with azathioprine at the high concentration of 50 microm. In addition, a monolayer culture of primary rat hepatocytes was used as an in vitro model to examine the protective effects of antihepatotoxic drugs including glutathione (GSH), N-acetylcysteine (NAC, a GSH precursor), liquorice and glycyrrhizic acid (GA), a major bioactive component of liquorice, against hepatotoxicity of 1 microm azathioprine. It was found that both liquorice and GA showed substantial protection according to assays of cell viability and intracellular GSH, while neither GSH nor NAC had such a protective function. Similarly, GA protected human hepatocytes from intracellular GSH depletion on exposure to 1 microm azathioprine. These results implied that GA or liquorice could be considered as potent protection agents against azathioprine hepatotoxicity.}, }
@article {pmid16713667, year = {2006}, author = {Yeh, ST and Guo, HR and Su, YS and Lin, HJ and Hou, CC and Chen, HM and Chang, MC and Wang, YJ}, title = {Protective effects of N-acetylcysteine treatment post acute paraquat intoxication in rats and in human lung epithelial cells.}, journal = {Toxicology}, volume = {223}, number = {3}, pages = {181-190}, doi = {10.1016/j.tox.2006.03.019}, pmid = {16713667}, issn = {0300-483X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Epithelial Cells/*drug effects/metabolism/pathology ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Humans ; Insecticides/*toxicity ; Lung/*drug effects/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/drug effects ; Paraquat/*toxicity ; Rats ; Respiratory Mucosa/cytology ; Superoxides/metabolism ; }, abstract = {An animal study in rats and a cell culture study in normal human lung epithelial cells were conducted to evaluate the efficacy of N-acetyl-l-cysteine (NAC) in paraquat intoxication and associated inflammatory and oxidative stress. The effectiveness of post treatment was measured by the change of mortality rates and markers of oxidative stress, including glutathione, malondialdehyde and superoxide anion production. In addition, the levels of nitric oxide were also examined in both animal and cell culture system. NAC treatment does significantly increase the probability of survival in paraquat-intoxicated rats. It can suppress the serum malondialdehyde levels and production of superoxide anions, and conversely, augment total glutathione concentrations in all studying tissues significantly. Moreover, NAC treatment post in paraquat intoxication could reduce destruction of lung tissue, showing less inflammatory cell infiltration in interstitial stroma and mild vascular congestion. The levels of nitrite in serum and BALF were lower than those of the PQ-treated rats. Similarly, levels of iNOS expression and nitrite formation were significantly lower in normal human lung epithelial cells treated with PQ and NAC than PQ-treated alone cells.}, }
@article {pmid16713603, year = {2006}, author = {Zhang, HS and Wang, SQ}, title = {Salvianolic acid B from Salvia miltiorrhiza inhibits tumor necrosis factor-alpha (TNF-alpha)-induced MMP-2 upregulation in human aortic smooth muscle cells via suppression of NAD(P)H oxidase-derived reactive oxygen species.}, journal = {Journal of molecular and cellular cardiology}, volume = {41}, number = {1}, pages = {138-148}, doi = {10.1016/j.yjmcc.2006.03.007}, pmid = {16713603}, issn = {0022-2828}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Angiotensin II/metabolism/pharmacology ; Aorta/cytology ; Benzofurans/*pharmacology ; Cells, Cultured ; Humans ; Hydrogen Peroxide/metabolism ; Matrix Metalloproteinase 2/drug effects/genetics/*metabolism ; Muscle, Smooth, Vascular/*drug effects/metabolism ; NADPH Oxidases/drug effects/metabolism ; Onium Compounds/pharmacology ; Reactive Oxygen Species/*metabolism ; Salvia miltiorrhiza/chemistry ; Tumor Necrosis Factor-alpha/metabolism/*pharmacology ; Up-Regulation ; }, abstract = {Activated matrix metalloproteinases (MMPs) in patients with acute coronary syndromes may contribute to plaque destabilization. Tumor necrosis factor-alpha (TNF-alpha) enhances NAD (P) H oxidase-dependent reactive oxygen species (ROS) formation and ROS induce MMP-2. In the present study, the effects of a potent water-soluble antioxidant, salvianolic acid B (SalB), derived from a Chinese herb, Salvia miltiorrhiza, on the expression of MMP-2 by TNF-alpha-treated human aortic smooth muscle cells (HASMCs) were investigated. In this study, salvianolic acid B scavenged H2O2 in a dose-dependent manner in test tube. We found that SalB, as well as NADPH oxidase inhibitors, DPI or apocynin, and antioxidant NAC, inhibited TNF-alpha-induced MMP-2 mRNA, protein expression, and gelatinolytic activity in HASMCs in a concentration-dependent manner. We also observed a dose-dependent decrease in ROS production and NADPH oxidase activity induced by TNF-alpha in the presence of SalB. SalB also significantly inhibited angiotensin II or H2O2-induced MMP-2 mRNA and protein expression and gelatinolytic activity in HASMCs. Our data point out that the importance of NADPH oxidase-dependent ROS generation in the control of SalB inhibition of TNF-alpha-induced MMP-2 expression and activity.}, }
@article {pmid16713429, year = {2006}, author = {Shimoyama, T and Yamaguchi, S and Takahashi, K and Katsuta, H and Ito, E and Seki, H and Ushikawa, K and Katahira, H and Yoshimoto, K and Ohno, H and Nagamatsu, S and Ishida, H}, title = {Gliclazide protects 3T3L1 adipocytes against insulin resistance induced by hydrogen peroxide with restoration of GLUT4 translocation.}, journal = {Metabolism: clinical and experimental}, volume = {55}, number = {6}, pages = {722-730}, doi = {10.1016/j.metabol.2006.01.019}, pmid = {16713429}, issn = {0026-0495}, mesh = {3T3-L1 Cells ; Adipocytes/*drug effects ; Animals ; Gliclazide/*pharmacology ; Glucose/metabolism ; Glucose Transporter Type 4/genetics/*metabolism ; Hydrogen Peroxide/pharmacology ; Hypoglycemic Agents/pharmacology ; Insulin/pharmacology ; *Insulin Resistance ; Mice ; Oxidative Stress ; Protein Transport ; }, abstract = {Increased oxidative stress under hyperglycemia may contribute to progressive deterioration of peripheral insulin sensitivity. In this study, we investigated whether gliclazide, a second-generation sulfonylurea, can protect 3T3L1 adipocytes from insulin resistance induced by oxidative stress, and whether gliclazide can restore insulin-stimulated glucose transporter 4 (GLUT4) translocation under oxidative stress. We incubated 3T3L1 adipocytes in hydrogen peroxide to produce oxidative stress, then administered various concentrations of gliclazide, N-acetylcystein (NAC), or glibenclamide. Cells treated with these drugs were next exposed to insulin, subsequent glucose uptake was measured, and the insulin-stimulated GLUT4 translocation was monitored in living cells. We found that hydrogen peroxide treatment alone suppressed glucose uptake by insulin stimulation to 65.9%+/-7.8% of the corresponding controls (P<.01). However, addition of 0.1 to 10 micromol/L gliclazide to hydrogen peroxide-treated cells dose-dependently restored glucose uptake, with 5 micromol/L gliclazide significantly restoring glucose uptake to 93.3+/-6.6% (P<.01) even under hydrogen peroxide. Treatment with the known anti-oxidant NAC also dose-dependently (0.1-10 mmol/L) restored insulin-induced glucose uptake in the presence of hydrogen peroxide. However, glibenclamide (0.1-10 micromol/L), another second-generation sulfonylurea, failed to improve glucose uptake. Similarly, treatment with 5 micromol/L gliclazide or 10 mmol/L NAC significantly overcome the reduction in insulin-stimulated GLUT4 translocation by hydrogen peroxide (P<.01), whereas 5 micromol/L glibenclamide did not. Therefore our data regarding gliclazide further characterize its mechanism of hypoglycemic effect: the observed improvements in insulin sensitivity and in GLUT4 translocation indicate that gliclazide counters the hydrogen peroxide-induced insulin resistance in 3T3L1 adipocytes and also would further augment the hypoglycemic effect of this drug as insulinotropic sulfonylurea.}, }
@article {pmid16708641, year = {2006}, author = {Jacek, Z and Marcin, Z and Maria, LS and Ewa, S and Alfred, W and Aldona, S}, title = {[In vitro modification of antioxidant response and its influence on cytokine synthesis in children with renal failure].}, journal = {Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego}, volume = {20}, number = {116}, pages = {203-206}, pmid = {16708641}, issn = {1426-9686}, mesh = {Adolescent ; Antioxidants/*pharmacology/*therapeutic use ; Child ; Child, Preschool ; Cytokines/*biosynthesis/metabolism ; Female ; Flow Cytometry ; Humans ; In Vitro Techniques ; Interferon-gamma/biosynthesis ; Interleukin-2/biosynthesis ; Interleukin-4/biosynthesis ; Interleukin-6/biosynthesis ; Kidney Failure, Chronic/*drug therapy ; Male ; }, abstract = {Recently it was shown that oxidative stress has a negative influence on immunological response. The aim of the study was to investigate the influence of N-acetylcysteine on intracellular oxidative stress and cytokine synthesis in peripheral blood lymphocytes in children with end stage renal disease (ESRD). MATERIAL AND METHODS. We examined 25 children (age 2-16 ys.) with ESRD. To determine oxidative stress we used dihydrorhodamine 123 (DHR). Intracellular oxidation of DHR in T. lymphocytes reflected intracellular oxidative stress within cells. The intracellular synthesis of cytokines (IL-2, IFN-r, IL-4, IL-6) was detected with flow cytometty RESULTS. We found lower intracellular stress and higher cytokines synthesis after incubation with N-acetylcysteine (NA C) in all subpopulations of lymphocytes. CONCLUSIONS. Our results shows that patients with ESRD present increased oxidative stress in T lymphocytes which may lead to decreased cytokines synthesis and abnormal immune response. NAC has favorable influence on these abnormalities.}, }
@article {pmid16704636, year = {2006}, author = {Chu, CY and Liu, YL and Chiu, HC and Jee, SH}, title = {Dopamine-induced apoptosis in human melanocytes involves generation of reactive oxygen species.}, journal = {The British journal of dermatology}, volume = {154}, number = {6}, pages = {1071-1079}, doi = {10.1111/j.1365-2133.2006.07293.x}, pmid = {16704636}, issn = {0007-0963}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dopamine/*pharmacology ; Dopamine Antagonists/pharmacology ; Dose-Response Relationship, Drug ; Epinephrine/pharmacology ; Humans ; Male ; Melanocytes/cytology/*drug effects/metabolism ; Norepinephrine/pharmacology ; Reactive Oxygen Species/*metabolism ; Serotonin/pharmacology ; }, abstract = {BACKGROUND: Previous studies have shown that significant increases in urinary and plasma levels of several monoamines and their metabolites characterize the onset of vitiligo and its progression. Recently, both epidermal keratinocytes and melanocytes were found to have the capacity for the biosynthesis of several catecholamines and serotonin. Some monoamines and their metabolites can induce apoptosis and cytotoxicity in neural cells. However, no previous report has investigated the potential role of these monoamines in inducing apoptosis or cytotoxicity in melanocytes.<br><br>OBJECTIVES: To study the effects of dopamine (DA), norepinephrine (NE), epinephrine (EP), and serotonin (5-HT) on melanocyte cytotoxicity and apoptosis.<br><br>METHODS: Primary cultures of normal human melanocytes established from the foreskins of normal individuals were treated with different concentrations of DA, NE, EP and 5-HT for 5 and 7 days. Cell viability was measured by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Melanocyte apoptosis was evaluated by morphological examination and flow cytometric analysis. We also measured the generation of reactive oxygen species (ROS) after DA treatment.<br><br>RESULTS: Among the four monoamines used in this study, only DA had an effect, dose-dependently decreasing the melanocyte viability at concentrations ranging from 0.01 to 100 micromol L(-1) (0.1 and 1 micromol L(-1), P < 0.05; 10 micromol L(-1), P < 0.01). In addition, DA-induced melanocyte apoptosis was evidenced by the increased percentage of sub-G1 cells from 7.71 +/- 0.28% (control) to 12.22 +/- 1.05% (0.1 micromol L(-1) DA) (P < 0.005), and treatment with the antioxidant N-acetylcysteine (NAC) reversed this apoptotic effect. DA treatment led to the generation of ROS, which could be prevented by pretreatment with NAC.<br><br>CONCLUSIONS: DA can induce melanocyte apoptosis, which might be related to the generation of ROS. This novel effect might play an important role in the development or progression of vitiligo, which is currently viewed as a disease process closely related to melanocyte apoptosis.}, }
@article {pmid16697003, year = {2006}, author = {Das, S and Otani, H and Maulik, N and Das, DK}, title = {Redox regulation of angiotensin II preconditioning of the myocardium requires MAP kinase signaling.}, journal = {Journal of molecular and cellular cardiology}, volume = {41}, number = {2}, pages = {248-255}, doi = {10.1016/j.yjmcc.2006.03.009}, pmid = {16697003}, issn = {0022-2828}, support = {HL 22559/HL/NHLBI NIH HHS/United States ; HL 33889/HL/NHLBI NIH HHS/United States ; HL 34360/HL/NHLBI NIH HHS/United States ; HL 56803/HL/NHLBI NIH HHS/United States ; }, mesh = {Angiotensin II/*pharmacology ; Animals ; Apoptosis/drug effects ; *Ischemic Preconditioning, Myocardial ; MAP Kinase Signaling System/*drug effects ; Male ; Multienzyme Complexes/metabolism ; Myocardial Reperfusion Injury/*enzymology/pathology ; Myocardium/*enzymology/pathology ; Myocytes, Cardiac/enzymology/pathology ; NADH, NADPH Oxidoreductases/metabolism ; Oxidation-Reduction/drug effects ; Perfusion ; Protein Kinases/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {A recent study documented reactive oxygen species (ROS), generated through NADPH oxidase by angiotensin II (Ang II) with the activation of NADPH oxidase subunits, p22phox and gp91phox, to be responsible for the preconditioning effect of Ang II. The present study was designed to determine if similar to ischemic preconditioning (PC), mitogen-activated protein (MAP) kinases are also involved in Ang II PC of the heart. Isolated working rat hearts were perfused for 15 min with KHB (Krebs-Henseleit bicarbonate) buffer containing Ang II in the absence or presence of an Erk (1/2) inhibitor, PD 098059, a p38MAPK inhibitor, SB 202190, a JNK inhibitor, SP 600125 or a ROS scavenger, N-acetyl cysteine (NAC). All hearts were subsequently subjected to 30 min global ischemia followed by 2 h reperfusion with KHB buffer only. Cardioprotection was examined by determining infarct size, cardiomyocyte apoptosis and ventricular recovery. Redox and MAP kinase regulation were studied by determining the survival signaling mediated by Akt and Bcl-2. In consistent with previous results, Ang II preconditioned the heart as evidenced by improved postischemic ventricular recovery and reduced infarct size and decreases cardiomyocyte apoptosis. Ang II phosphorylated both Akt, Bcl-2 and Bad, which was blocked by NAC, PD 098059 or SP 600125, but not by SB 202190. NAC, PD 098059 and SP600125, but not SB202190, also abolished the cardioprotective effect of Ang II preconditioning. The results indicate that Ang II preconditioning is potentiated through MAP kinases that are regulated by redox signaling.}, }
@article {pmid16696567, year = {2006}, author = {Shi, H and Liu, S and Miyake, M and Liu, KJ}, title = {Ebselen induced C6 glioma cell death in oxygen and glucose deprivation.}, journal = {Chemical research in toxicology}, volume = {19}, number = {5}, pages = {655-660}, pmid = {16696567}, issn = {0893-228X}, support = {R01 ES012938-01/ES/NIEHS NIH HHS/United States ; R01 ES012938/ES/NIEHS NIH HHS/United States ; P30 ES012072/ES/NIEHS NIH HHS/United States ; P20 RR015636/RR/NCRR NIH HHS/United States ; P20 RR015636-060006/RR/NCRR NIH HHS/United States ; P20 RR15636/RR/NCRR NIH HHS/United States ; P30 ES-012072/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/toxicity ; Antioxidants/toxicity ; Azoles/*toxicity ; Brain Ischemia/metabolism/*pathology ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Glioma ; Glucose/deficiency ; Glutathione/metabolism ; Hypoxia ; Isoindoles ; L-Lactate Dehydrogenase/metabolism ; Organoselenium Compounds/*toxicity ; Rats ; }, abstract = {Studies have shown that ebselen is an antiinflammatory and antioxidative agent. Its protective effect has been investigated in oxidative stress related diseases such as cerebral ischemia in recent years. However, experimental evidence also shows that ebselen causes cell death in several different cell types. Whether ebselen will have a beneficial or detrimental effect on cells under ischemic condition is not known. Herein, we studied the effect of ebselen on C6 glioma cells under oxygen and glucose deprivation (OGD), an in vitro ischemic model. We found that ebselen significantly enhanced cell death after 3 h of OGD as observed by lactase dehydrogenase (LDH) release and cellular morphological changes. Further studies revealed that depletion of cellular glutathione level by the combined action of ebselen and OGD played a role in enhanced cell death as demonstrated by the following evidence: (1) cellular GSH was significantly depleted by the combined effort of ebselen and OGD, compared to that of ebselen or OGD insult alone; (2) exogenous addition of N-acetyl cysteine completely diminished the cell damage induced by ebselen and OGD; (3) supplement of glucose, which provides cellular reducing agents and thus maintains cellular GSH level, to the OGD medium diminished C6 cell damage induced by ebselen. We conclude that depleting cellular glutathione plays an important role in ebselen-induced cell death with OGD. Our results suggest that ebselen can have a beneficial or toxic effect, depending on the availability of GSH.}, }
@article {pmid16680064, year = {2006}, author = {Nagareddy, PR and Xia, Z and MacLeod, KM and McNeill, JH}, title = {N-acetylcysteine prevents nitrosative stress-associated depression of blood pressure and heart rate in streptozotocin diabetic rats.}, journal = {Journal of cardiovascular pharmacology}, volume = {47}, number = {4}, pages = {513-520}, doi = {10.1097/01.fjc.0000211744.93701.25}, pmid = {16680064}, issn = {0160-2446}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Glucose/metabolism ; Blood Pressure/*drug effects ; Blotting, Western ; Cholesterol/blood ; Diabetes Mellitus, Experimental/*physiopathology ; Free Radical Scavengers/*pharmacology ; Heart Rate/*drug effects ; Immunohistochemistry ; Insulin/blood ; Isoprostanes/metabolism ; Male ; Nitrates/blood/metabolism/*physiology ; Nitric Oxide Synthase Type II/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Nitrites/blood ; Oxidative Stress/physiology ; Rats ; Rats, Wistar ; Stress, Physiological/physiopathology ; Triglycerides/blood ; Tyrosine/analogs &amp; derivatives/biosynthesis ; }, abstract = {Previous studies have indicated that cardiovascular abnormalities such as depressed blood pressure and heart rate occur in streptozotocin (STZ) diabetic rats. Chronic diabetes, which is associated with increased expression of inducible nitric oxide synthase (iNOS) and oxidative stress, may produce peroxynitrite/nitrotyrosine and cause nitrosative stress. We hypothesized that nitrosative stress causes cardiovascular depression in STZ diabetic rats and therefore can be corrected by reducing its formation. Control and STZ diabetic rats were treated orally for 9 weeks with N-acetylcysteine (NAC), an antioxidant and inhibitor of iNOS. At termination, the mean arterial blood pressure (MABP) and heart rate (HR) were measured in conscious rats. Nitrotyrosine and endothelial nitric oxide synthase (eNOS) and iNOS expression were assessed in the heart and mesenteric arteries by immunohistochemistry and Western blot experiments. Untreated diabetic rats showed depressed MABP and HR that was prevented by treatment with NAC. In untreated diabetic rats, levels of 15-F(2t)-isoprostane, an indicator of lipid peroxidation increased, whereas plasma nitric oxide and antioxidant concentrations decreased. Furthermore, decreased eNOS and increased iNOS expression were associated with elevated nitrosative stress in blood vessel and heart tissue of untreated diabetic rats. N-acetylcysteine treatment of diabetic rats not only restored the antioxidant capacity but also reduced the expression of iNOS and nitrotyrosine and normalized the expression of eNOS to that of control rats in heart and superior mesenteric arteries. The results suggest that nitrosative stress depress MABP and HR following diabetes. Further studies are required to elucidate the mechanisms involved in nitrosative stress mediated depression of blood pressure and heart rate.}, }
@article {pmid16679547, year = {2006}, author = {Kannan, GM and Flora, SJ}, title = {Combined administration of N-acetylcysteine and monoisoamyl DMSA on tissue oxidative stress during arsenic chelation therapy.}, journal = {Biological trace element research}, volume = {110}, number = {1}, pages = {43-59}, doi = {10.1385/BTER:110:1:43}, pmid = {16679547}, issn = {0163-4984}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Arsenic/*therapeutic use ; *Chelation Therapy ; Guinea Pigs ; Male ; Oxidative Stress/*drug effects ; Succimer/*analogs &amp; derivatives/pharmacology ; }, abstract = {The present study deals with the therapeutic potential of combined administration of N-acetylcysteine (NAC) along with monoisoamyl DMSA (MiADMSA) against chronic arsenic poisoning in guinea pigs. Animal were exposed to 50 ppm arsenic in drinking water for 8 mo and subsequently treated for 5 consecutive days with 100 mg/kg NAC (orally) and MiADMSA (intraperitoneally), individually or in combination (50 mg/kg each). Arsenic exposure produced a significant depletion of blood delta- aminolevulinic acid dehydrate (ALAD) activity, increased the blood zinc protoporphyrin (ZPP) level, and reduced blood and liver glutathione (GSH) levels in guinea pigs. Hepatic oxidized glutathione (GSSG) and thiobarbituric acid reactive substance (TBARS) levels showed a marked increase, whereas hepatic alkaline phosphatase (ALP) activity decreased and acid phosphatase (ACP) activity increased on arsenic exposure. Significant depletion of liver transaminase activities on arsenic exposure suggests organ injury. Administration of MiADMSA, alone and in combination with NAC after arsenic exposure, was able to significantly enhance hepatic GSH and to reduce GSSG and TBARS levels compared to the arsenic control. Biochemical variables indicative of liver injury generally remained insensitive to any of these treatments. The recoveries in parameters indicative of oxidative stress were more marked in guinea pigs treated with combined administration of NAC and MiADMSA than monotherapy. Interestingly, there was a more pronounced depletion of arsenic from blood and tissues after combined treatment with NAC plus MiADMSA than MiADMSA. Blood and tissues copper, zinc, iron, and calcium concentrations showed a significant increase after arsenic exposure, which showed improvement, particularly after combined administration of MiADMSA and NAC. Based on these data, a proposal can be made that greater effectiveness in chelation treatment against chronic arsenic poisoning (i.e., turnover in the oxidative stress and removed of arsenic from the system) could be achieved by combined administration of an antioxidant (preferably having a thiol moiety) with MiADMSA.}, }
@article {pmid16678324, year = {2006}, author = {Wong, CH and Liu, TZ and Chye, SM and Lu, FJ and Liu, YC and Lin, ZC and Chen, CH}, title = {Sevoflurane-induced oxidative stress and cellular injury in human peripheral polymorphonuclear neutrophils.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {44}, number = {8}, pages = {1399-1407}, doi = {10.1016/j.fct.2006.03.004}, pmid = {16678324}, issn = {0278-6915}, mesh = {Adult ; Anesthetics, Inhalation/*pharmacology ; Apoptosis/drug effects ; Caspase 3 ; Caspase 7 ; Caspases/metabolism ; Cell Survival/drug effects ; Comet Assay ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Glutathione/blood ; Humans ; Hydrogen Peroxide/blood ; Membrane Potentials/drug effects ; Methyl Ethers/*pharmacology ; Mitochondrial Membranes/drug effects ; Neutrophils/*drug effects/metabolism ; Nitric Oxide/blood ; Oxidative Stress ; Sevoflurane ; Superoxides/blood ; }, abstract = {Sevoflurane is an inhalation anesthetic used for general anesthesia. Several studies have demonstrated that reactive oxygen species (ROS) exist in cardioprotection when preconditioned with sevoflurane. Moreover, sevoflurane can also directly trigger the formation of peroxynitrite. Up to now, information pertinent to the effect of sevoflurane on cellular injuries in human polymorphonuclear neutrophils (PMN) is scant. In this study, we demonstrated that sevoflurane significantly increases intracellular H2O2 and/or peroxide, superoxide, and nitric oxide (NO) in PMN within 1h treatment. Intensification of intracellular glutathione (GSH) depletion in PMN has been demonstrated with the presence of sevoflurane. Inhibition of sevoflurane-mediated intracellular H2O2 and/or peroxide in PMN by catalase, mannitol, dexamethasone, N-acetylcysteine (NAC) and trolox, but not superoxide dismutase (SOD) pretreatment, was observed. Among them, catalase has the best effect scavenging intracellular H2O2 and/or peroxide, suggesting that H2O2 is the major ROS during sevoflurane treatment. Two apoptotic critical factors-lowering of the mitochondrial transmembrane potential (DeltaPsim) and activation of caspase 3/7-were significantly increased after 1h of sevoflurane treatment. Apoptosis of PMN were determined by comet assay and flow cytometric analysis of annexin V-FITV protein binding to the cell surface. Exposure of PMN to sevoflurane markedly increased apoptosis in a dose-dependent manner. In summary, these results are important for demonstrating the oxidative stress and cellular injury on sevoflurane-treated human PMN.}, }
@article {pmid16675054, year = {2006}, author = {Arakawa, M and Ushimaru, N and Osada, N and Oda, T and Ishige, K and Ito, Y}, title = {N-acetylcysteine selectively protects cerebellar granule cells from 4-hydroxynonenal-induced cell death.}, journal = {Neuroscience research}, volume = {55}, number = {3}, pages = {255-263}, doi = {10.1016/j.neures.2006.03.008}, pmid = {16675054}, issn = {0168-0102}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Aldehydes/*antagonists &amp; inhibitors/toxicity ; Animals ; Animals, Newborn ; Antioxidants/pharmacology/therapeutic use ; Brain/drug effects/*metabolism/physiopathology ; Cell Death/drug effects/physiology ; Cells, Cultured ; Cerebellum/cytology/drug effects/metabolism ; Free Radical Scavengers/pharmacology/therapeutic use ; Glutathione/drug effects/metabolism ; L-Lactate Dehydrogenase/drug effects/metabolism ; Mitochondrial Membranes/drug effects/metabolism ; Nerve Degeneration/drug therapy/metabolism/prevention &amp; control ; Neurodegenerative Diseases/drug therapy/metabolism/physiopathology ; Neurons/drug effects/*metabolism ; Neuroprotective Agents/*pharmacology/therapeutic use ; Neurotoxins/antagonists &amp; inhibitors/toxicity ; Oxidative Stress/drug effects/*physiology ; Plant Extracts/pharmacology/therapeutic use ; Rats ; Rats, Wistar ; }, abstract = {4-hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, has been shown to induce neurotoxicity accompanied by multiple events. To clarify mechanisms of neuroprotective compounds on HNE-induced toxicity, the protective effects of N-acetylcysteine (NAC), alpha-tocopherol (TOC), ebselen and S-allyl-L-cysteine (SAC) were compared in cerebellar granule neurons. The decrease in MTT reduction induced by HNE was significantly suppressed by pretreatment of the neurons with 1000 microM NAC or 10 and 100 microM TOC; however, lactate dehydrogenase (LDH) release and propidium iodide (PI) fluorescence studies revealed that neuronal death was suppressed by NAC but not by TOC. Treatment of these neurons with HNE resulted in a drastic reduction of mitochondrial membrane potential, and this reduction was also prevented by NAC but not by TOC. Ebselen and SAC, a garlic compound, were unable to protect these neurons against HNE-induced toxicity. Pretreatment with NAC also prevented HNE-induced depletion of intracellular glutathione (GSH) levels in these neurons. These results suggest that NAC, but not other antioxidants such as TOC, SAC and ebselen, exerts significant protective effects against HNE-induced neuronal death in cerebellar granule neurons, and that this neuroprotective effect is due, at least in part, to preservation of mitochondrial membrane potential and intracellular GSH levels.}, }
@article {pmid16672770, year = {2006}, author = {Kim, JR and Ryu, HH and Chung, HJ and Lee, JH and Kim, SW and Kwun, WH and Baek, SH and Kim, JH}, title = {Association of anti-obesity activity of N-acetylcysteine with metallothionein-II down-regulation.}, journal = {Experimental &amp; molecular medicine}, volume = {38}, number = {2}, pages = {162-172}, doi = {10.1038/emm.2006.20}, pmid = {16672770}, issn = {1226-3613}, mesh = {3T3-L1 Cells ; Acetylcysteine/*pharmacology ; Adipocytes/cytology/drug effects/metabolism ; Adipose Tissue/cytology/drug effects/metabolism ; Aged ; Animals ; Anti-Obesity Agents/*pharmacology ; Body Weight/drug effects ; Cell Differentiation/drug effects ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects/genetics ; Female ; Humans ; Male ; Metallothionein/*genetics/metabolism/physiology ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Rats ; Rats, Sprague-Dawley ; Subcutaneous Fat/drug effects ; Time Factors ; Viscera/drug effects/metabolism ; }, abstract = {People with upper body or visceral obesity have a much higher risk of morbidity and mortality from obesity-related metabolic disorders than those with lower body obesity. In an attempt to develop therapeutic strategies targeting visceral obesity, depot- specific differences in the expression of genes in omental and subcutaneous adipose tissues were investigated by DNA array technology, and their roles in adipocyte differentiation were further examined. We found that levels of metallothionein-II (MT-II) mRNA and protein expression were higher in omental than in subcutaneous adipose tissues. The study demonstrates that MT-II may play an important role in adipocyte differentiation of 3T3L1 preadipocytes, and that N-acetylcysteine (NAC) inhibits the adipocyte differentiation of 3T3L1 cells by repressing MT-II in a time- and dose-dependent manner. Furthermore, the intraperitoneal administration of NAC to rats and mice resulted in a reduction of body weights, and a marked reduction in visceral fat tissues. These results suggest that MT-II plays important roles in adipogenesis, and that NAC may be useful as an anti-obesity drug or supplement.}, }
@article {pmid16672643, year = {2006}, author = {Gao, N and Kramer, L and Rahmani, M and Dent, P and Grant, S}, title = {The three-substituted indolinone cyclin-dependent kinase 2 inhibitor 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) kills human leukemia cells via down-regulation of Mcl-1 through a transcriptional mechanism.}, journal = {Molecular pharmacology}, volume = {70}, number = {2}, pages = {645-655}, doi = {10.1124/mol.106.024505}, pmid = {16672643}, issn = {0026-895X}, support = {CA100866/CA/NCI NIH HHS/United States ; CA63753, CA93738/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis/drug effects ; Caspases/physiology ; Cyclin-Dependent Kinase 2/*antagonists &amp; inhibitors ; Down-Regulation ; Gene Expression Regulation/*drug effects ; Humans ; Imidazoles/*pharmacology ; Indoles/*pharmacology ; Mitochondria/drug effects ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins/antagonists &amp; inhibitors/*genetics ; Phosphorylation ; Protein Kinase Inhibitors/*pharmacology ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-bcl-2/antagonists &amp; inhibitors/*genetics ; RNA Polymerase II/metabolism ; Reactive Oxygen Species/metabolism ; Transcription, Genetic/drug effects ; U937 Cells ; }, abstract = {Mechanisms of lethality of the three-substituted indolinone and putatively selective cyclin-dependent kinase (CDK)2 inhibitor 3-[1-(3H-imidazol-4-yl)-meth-(Z)-ylidene]-5-methoxy-1,3-dihydro-indol-2-one (SU9516) were examined in human leukemia cells. Exposure of U937 and other leukemia cells to SU9516 concentrations > or =5 microM rapidly (i.e., within 4 h) induced cytochrome c release, Bax mitochondrial translocation, and apoptosis in association with pronounced down-regulation of the antiapoptotic protein Mcl-1. These effects were associated with inhibition of phosphorylation of the carboxyl-terminal domain (CTD) of RNA polymerase (Pol) II on serine 2 but not serine 5. Reverse transcription-polymerase chain reaction analysis revealed pronounced down-regulation of Mcl-1 mRNA levels in SU9516-treated cells. Similar results were obtained in Jurkat and HL-60 leukemia cells. Furthermore, cotreatment with the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) blocked SU9516-mediated Mcl-1 down-regulation, implicating proteasomal degradation in diminished expression of this protein. Ectopic expression of Mcl-1 largely blocked SU9516-induced cytochrome c release, Bax translocation, and apoptosis, whereas knockdown of Mcl-1 by small interfering RNA potentiated SU9516 lethality, confirming the functional contribution of Mcl-1 down-regulation to SU9516-induced cell death. It is noteworthy that SU9516 treatment resulted in a marked increase in reactive oxygen species production, which was diminished, along with cell death, by the free radical scavenger N-acetylcysteine (NAC). We were surprised to find that NAC blocked SU9516-mediated inhibition of RNA Pol II CTD phosphorylation on serine 2, reductions in Mcl-1 mRNA levels, and Mcl-1 down-regulation. Together, these findings suggest that SU9516 kills leukemic cells through inhibition of RNA Pol II CTD phosphorylation in association with oxidative damage and down-regulation of Mcl-1 at the transcriptional level, culminating in mitochondrial injury and cell death.}, }
@article {pmid16672365, year = {2006}, author = {Balansky, R and D'Agostini, F and Ganchev, G and Izzotti, A and Di Marco, B and Lubet, RA and Zanesi, N and Croce, CM and De Flora, S}, title = {Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: chemoprevention by budesonide and N-acetylcysteine.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {103}, number = {20}, pages = {7823-7828}, pmid = {16672365}, issn = {0027-8424}, mesh = {Acetylcysteine/*metabolism/therapeutic use ; Acid Anhydride Hydrolases/genetics/*metabolism ; *Alopecia Areata/chemically induced/prevention &amp; control ; Animals ; Anti-Inflammatory Agents/metabolism/therapeutic use ; Benzo(a)pyrene/administration &amp; dosage/metabolism/*toxicity ; Budesonide/*metabolism/therapeutic use ; Female ; Genes, Tumor Suppressor ; Lung/pathology ; Mice ; Mice, Inbred Strains ; Neoplasm Proteins/genetics/*metabolism ; *Neoplasms/chemically induced/prevention &amp; control ; Stomach/pathology ; }, abstract = {The FHIT gene has many hallmarks of a tumor-suppressor gene and is involved in a large variety of cancers. We treated A/J mice and (C57BL/6J x 129/SvJ)F1 (B6/129 F1) mice, either wild-type or FHIT+/-, with multiple doses of benzo[a]pyrene (B[a]P) by gavage. B[a]P caused a time-related increase of micronuclei in peripheral blood erythrocytes. Both A/J and B6/129 F1 mice, irrespective of their FHIT status, were sensitive to induction of forestomach tumors, whereas B[a]P induced glandular stomach hyperplasia and a high multiplicity of lung tumors in A/J mice only. Preneoplastic lesions of the uterus were more frequent in FHIT+/- mice. B6/129 F1 mice underwent spontaneous alopecia areata and hair bulb cell apoptosis, which were greatly accelerated either by FHIT heterozygosity or by B[a]P treatment, thus suggesting that FHIT plays a role in the pathogenesis of alopecia areata. The oral administration of either budesonide or N-acetyl-L-cysteine (NAC) inhibited the occurrence of this inflammatory skin disease. In addition, these agents prevented B[a]P-induced glandular stomach hyperplasia and decreased the size of both forestomach tumors and lung tumors in A/J mice. Budesonide also attenuated lung tumor multiplicity. In B6/129 F1 mice, NAC significantly decreased the proliferating cell nuclear antigen in lung tumors. Both budesonide and NAC inhibited B[a]P-induced forestomach tumors and preneoplastic lesions of the respiratory tract in B6/129 F1 mice. In conclusion, heterozygosity for FHIT affects susceptibility of mice to spontaneous alopecia areata and B[a]P-induced preneoplastic lesions of the uterus and does not alter responsiveness to budesonide and NAC.}, }
@article {pmid16671959, year = {2006}, author = {Uma Devi, P and Pillai, KK and Vohora, D}, title = {Modulation of pentylenetetrazole-induced seizures and oxidative stress parameters by sodium valproate in the absence and presence of N-acetylcysteine.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {20}, number = {3}, pages = {247-253}, doi = {10.1111/j.1472-8206.2006.00401.x}, pmid = {16671959}, issn = {0767-3981}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Alanine Transaminase/blood ; Animals ; Anticonvulsants/*pharmacology/therapeutic use ; Antioxidants/*pharmacology/therapeutic use ; Aspartate Aminotransferases/blood ; Brain/drug effects/metabolism ; Disease Models, Animal ; Drug Therapy, Combination ; Glutathione/metabolism ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Mice ; *Oxidative Stress ; Pentylenetetrazole ; Seizures/blood/chemically induced/metabolism/*prevention &amp; control ; Thiobarbituric Acid Reactive Substances/metabolism ; Valproic Acid/*pharmacology/therapeutic use ; }, abstract = {In view of a role of oxidative stress in epilepsy and the evidence for the involvement of peroxidative injury in sodium valproate (SVP)-induced adverse effects on liver and kidneys, we investigated whether the combination of SVP with N-acetylcysteine (NAC), an antioxidant, may help us to achieve maximal efficacy in terms of seizure control, with minimal toxicity on liver and kidneys. Pentylenetetrazole (PTZ)-induced seizures were used to evaluate the anticonvulsant effect of drugs. Biochemical estimations included the determination of oxidative stress markers like thiobarbituric acid-reactive substances in brain tissue and glutathione (GSH) levels in liver and kidney tissues. Aspartate aminotransferase and alanine aminotransferase concentrations in the serum were also determined to assess liver function. In our study, NAC exhibited a nondose-dependent anticonvulsant effect. The concurrent administration of NAC with SVP significantly prolonged the latency to jerks, myoclonus and clonic generalized seizures. No significant oxidative stress was evident in brain tissue following PTZ-induced seizures, though an elevation of serum transaminase enzymes was seen. SVP at the dose studied did not produce any significant oxidative stress on the liver and kidneys, while treatment with NAC elevated liver and kidney GSH levels. The concurrent administration of NAC with SVP had beneficial effects on liver and kidney cells.}, }
@article {pmid16645287, year = {2006}, author = {Melzer, J and Saller, R and Schapowal, A and Brignoli, R}, title = {Systematic review of clinical data with BNO-101 (Sinupret) in the treatment of sinusitis.}, journal = {Forschende Komplementarmedizin (2006)}, volume = {13}, number = {2}, pages = {78-87}, doi = {10.1159/000091969}, pmid = {16645287}, issn = {1661-4119}, mesh = {Attitude to Health ; *Complementary Therapies ; Controlled Clinical Trials as Topic ; Cross-Sectional Studies ; Family Practice ; Humans ; Physicians, Family ; Phytotherapy ; Plant Extracts/*therapeutic use ; Sinusitis/*therapy ; Surveys and Questionnaires ; Switzerland ; }, abstract = {BACKGROUND: The herbal formula BNO-101 (containing Gentianae radix, Primulae flos, Rumicis herba, Sambuci flos and Verbenae herba; ratio 1:3:3:3:3) has been widely employed as a 'mucoactive' agent in Germany for 70 years for the symptoms of respiratory infections. This paper reviews the clinical evidence of BNO-101 in sinusitis.<br><br>METHODS: The systematic search identified 22 studies with BNO-101. Out of these, 6 controlled trials on sinusitis were reassessed according to predefined criteria. 4 trials had almost identical designs and could be examined by meta-analysis.<br><br>RESULTS: The database comprised approximately 900 patients, mostly young adult males. After 2 weeks of treatment, verum was significantly superior to placebo (2 RCTs, 159 vs. 160 patients, both add-on to antibacterial treatment). The benefit regards the patients' assessment ('cured': verum = 61.1%, placebo = 34.5%), reduction of drain obstruction, headache and radiological signs (all p < 0.05). Comparing BNO-101 to ambroxol (2 RCTs, 151 vs. 150 patients, add-on to antibacterials in 13% of the cases) the patients' assessment after 2 weeks showed no difference, although it favoured BNO-101 in chronic cases ('cured' BNO-101 = 37.1%, ambroxol = 12.5%; p < 0.05). It also favoured BNO-101 concerning pyorrhoea and headache (p < 0.05). No significant differences were reported in 2 open randomised trials vs. N-acetyl-cysteine and vs. the herbal product Myrtol std.<br><br>CONCLUSIONS: BNO-101, combined with standard antibacterial therapy, significantly reduces the acute symptoms and signs of sinusitis. The effects are of the same order of magnitude as observed with other mucoactive agents. In the trials investigated BNO-101 had a favourable risk/benefit ratio, with an incidence of adverse events similar to placebo.}, }
@article {pmid16644332, year = {2006}, author = {Coyle, LC and Rodriguez, A and Jeschke, RE and Simon-Lee, A and Abbott, KC and Taylor, AJ}, title = {Acetylcysteine In Diabetes (AID): a randomized study of acetylcysteine for the prevention of contrast nephropathy in diabetics.}, journal = {American heart journal}, volume = {151}, number = {5}, pages = {1032.e9-12}, doi = {10.1016/j.ahj.2006.02.002}, pmid = {16644332}, issn = {1097-6744}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Aged ; Contrast Media/*adverse effects ; Coronary Angiography ; Creatinine/blood ; Diabetes Mellitus/blood/*drug therapy ; Drug Administration Schedule ; Female ; Humans ; Incidence ; Injections, Intravenous ; Kidney Diseases/*chemically induced/epidemiology/*prevention &amp; control ; Male ; Middle Aged ; Sodium Chloride/administration &amp; dosage/therapeutic use ; Treatment Failure ; }, abstract = {BACKGROUND: Patients with diabetes mellitus (DM) are at increased risk of contrast-associated nephropathy irrespective of their baseline creatinine (Cr). We tested the efficacy of N-acetylcysteine (NAC) relative to hydration in unselected patients (irrespective of baseline Cr) with DM.<br><br>METHODS: We conducted a randomized open-label study comparing hydration alone (combined oral and rapid intravenous hydration, n = 69) to NAC plus hydration (similar hydration protocol plus NAC 600 mg BID x 4 doses, n = 68) in diabetic patients (mean age 65 +/- 10 years, 65% men) undergoing elective coronary angiography. The primary end point was the mean change in serum Cr measured up to 96 hours postangiography.<br><br>RESULTS: Baseline Cr was 1.14 +/- 0.43 mg/dL (Cr > or = 1.3 mg/dL in 37 subjects). Baseline characteristics including blood urea nitrogen, Cr, and contrast volume were similar between the 2 groups. The mean Cr change in the NAC group was 0.14 +/- 0.47 versus 0.08 +/- 0.11 mg/dL in the hydration only group (P = NS). Contrast-associated nephropathy, defined as a > or = 0.5 mg/dL increase in Cr, was significantly more common in the NAC group, 9.2% versus 1.4%, P = .043. Similar results were found in the subgroup of participants with either an increased baseline serum Cr (> or = 1.3 mg/dL) or in those receiving high contrast volumes (> 100 mL).<br><br>CONCLUSIONS: N-Acetylcysteine provides no benefit over an aggressive hydration protocol in patients with DM undergoing coronary angiography.}, }
@article {pmid16644300, year = {2006}, author = {Kim, DJ and Koh, JM and Lee, O and Kim, NJ and Lee, YS and Kim, YS and Park, JY and Lee, KU and Kim, GS}, title = {Homocysteine enhances apoptosis in human bone marrow stromal cells.}, journal = {Bone}, volume = {39}, number = {3}, pages = {582-590}, doi = {10.1016/j.bone.2006.03.004}, pmid = {16644300}, issn = {8756-3282}, mesh = {Apoptosis/*drug effects ; Bone Marrow/*drug effects/metabolism ; Caspases/metabolism ; Cell Differentiation/drug effects ; Cell Line ; Cytochromes c/metabolism ; Cytosol/drug effects/metabolism ; Homocysteine/*pharmacology ; Humans ; Mitochondria/drug effects/metabolism ; NF-kappa B/metabolism ; Osteoblasts/cytology/drug effects ; Reactive Oxygen Species/metabolism ; Stromal Cells/*cytology/*drug effects/metabolism ; }, abstract = {INTRODUCTION: High plasma homocysteine (Hcy) levels have been associated with increased risk of fracture. Since Hcy has been shown to induce apoptosis in many cell types, including vascular endothelial cells, we hypothesized that Hcy would have a similar apoptotic effect on osteoblasts, leading to osteoporosis by reducing bone formation.<br><br>MATERIALS AND METHODS: Using primary human bone marrow stromal cells (hBMSC) and HS-5 cell line (human bone marrow stromal cell line), we investigated the effects of Hcy on these cells by cell viability assay and analysis of cytoplasmic histone-associated DNA fragments. Caspase activity assay, Western blots, and electrophoresis mobility shift assay (EMSA) were performed to find the mechanism of apoptosis. Intracellular reactive oxygen species (ROS) were measured by spectrometry using dichlorofluorescein diacetate, and cellular total glutathione level was determined by a commercially available kit. N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) were used as tools for investigating the role of ROS and nuclear factor-kappaB (NF-kappaB), respectively.<br><br>RESULTS: Hcy induced apoptosis in primary human bone marrow stromal cells and the HS-5 cell line, and this apoptotic effect was caspase-dependent. In addition, Hcy increased cytochrome c release into the cytosol, and activated caspase-9 and caspase-3, but not caspase-8, indicating that Hcy induces apoptosis via the mitochondria pathway. Hcy increased ROS, and NAC inhibited the apoptotic effect of Hcy. Western blot and EMSA showed that Hcy activated the NF-kappaB pathway. PDTC blocked Hcy-induced caspase-3 activation and apoptosis.<br><br>CONCLUSION: These results suggest that Hcy induces apoptosis via the ROS-mediated mitochondrial pathway and NF-kappaB activation in hBMSCs, and that Hcy may contribute to the development of osteoporosis by reducing bone formation. Antioxidants may have a role in preventing bone loss in individuals with hyperhomocysteinemia.}, }
@article {pmid16641917, year = {2006}, author = {Noh, H and Kim, JS and Han, KH and Lee, GT and Song, JS and Chung, SH and Jeon, JS and Ha, H and Lee, HB}, title = {Oxidative stress during peritoneal dialysis: implications in functional and structural changes in the membrane.}, journal = {Kidney international}, volume = {69}, number = {11}, pages = {2022-2028}, doi = {10.1038/sj.ki.5001506}, pmid = {16641917}, issn = {0085-2538}, mesh = {Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Male ; *Oxidative Stress/drug effects ; *Peritoneal Dialysis ; Peritoneum/drug effects/*metabolism/*pathology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Progressive peritoneal fibrosis, membrane hyperpermeability, and ultrafiltration failure have been observed in patients on long-term peritoneal dialysis (PD). The present study tested the hypothesis that reactive oxygen species (ROS) generated by conventional PD solution (PDS) mediate functional and structural alterations of peritoneal membrane in vivo. Sprague-Dawley rats were randomized to control, PDS, PDS with an antioxidant, and PDS with an angiotensin II (Ang II) receptor blocker. Commercial PDS containing 3.86% glucose (20-30 ml) with or without N-acetylcystein (NAC) 10 mM or losartan 5 mg/kg was administered intraperitoneally twice a day for 12 weeks. Control rats received sham injection. Rats treated with PDS had significantly lower drain volume and D(4)/D(0) glucose, but higher D(4)/P(4) creatinine and increased membrane thickness and endothelial NOS (eNOS) expression compared to control rats. Omental transforming growth factor (TGF)-beta1, vascular endothelial growth factor (VEGF), collagen I, and heat-shock protein (hsp) 47 expression and lipid peroxide levels and dialysate VEGF and Ang II concentrations were significantly increased in rats treated with PDS compared to control. All of these changes were prevented by both NAC and losartan. In conclusion, the present study demonstrates that ROS generated by conventional PDS are, in large part, responsible for peritoneal fibrosis and membrane hyperpermeability. We suggest that antioxidants or Ang II receptor blockers may allow better preservation of the structural and functional integrity of the peritoneal membrane during long-term PD.}, }
@article {pmid16640638, year = {2006}, author = {Ho, YC and Huang, FM and Chang, YC}, title = {Mechanisms of cytotoxicity of eugenol in human osteoblastic cells in vitro.}, journal = {International endodontic journal}, volume = {39}, number = {5}, pages = {389-393}, doi = {10.1111/j.1365-2591.2006.01091.x}, pmid = {16640638}, issn = {0143-2885}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Catalase/pharmacology ; Cell Death/drug effects ; Cell Line ; Cell Proliferation/drug effects ; Dental Materials/*toxicity ; Dose-Response Relationship, Drug ; Eugenol/*toxicity ; Free Radical Scavengers/pharmacology ; Humans ; Materials Testing ; Osteoblasts/*drug effects ; Protective Agents/pharmacology ; Superoxide Dismutase/pharmacology ; Time Factors ; }, abstract = {AIM: To evaluate the mechanisms of cytotoxicity of eugenol in human osteoblastic cells in vitro.<br><br>METHODOLOGY: Cytotoxicity and cell proliferation assays were performed to elucidate the toxic effects of eugenol on the human osteoblastic cell line U2OS. Furthermore, the effects of antioxidants catalase (scavenger of H2O2), superoxide dismutase (SOD, an extracellular superoxide free radical scavenger) and N-acetyl-L-cysteine (NAC, a cell-permeable glutathione precursor) were added to discover the possible mechanisms of eugenol-induced cytotoxicity. Paired Student's t-test was applied for the statistical analysis of the results.<br><br>RESULTS: Eugenol demonstrated a cytotoxic effect to U2OS cells in a dose-dependent manner (P < 0.05). The 50% inhibition concentration of eugenol was approximately 0.75 mmol L(-1). Eugenol also inhibited cell proliferation during a 4-day culture period (P < 0.05). Addition of NAC extracellularly protected the cells from eugenol-induced cytotoxicity (P < 0.05). Neither, SOD nor catalase provided any protective effects on eugenol-induced cytotoxicity (P > 0.05).<br><br>CONCLUSIONS: The levels of eugenol tested inhibited growth and proliferation of U2OS cells. Eugenol has significant potential for periapical toxicity. These inhibitory effects were associated with glutathione levels.}, }
@article {pmid16635917, year = {2006}, author = {Shi, C and Zhao, X and Lagergren, A and Sigvardsson, M and Wang, X and Andersson, R}, title = {Immune status and inflammatory response differ locally and systemically in severe acute pancreatitis.}, journal = {Scandinavian journal of gastroenterology}, volume = {41}, number = {4}, pages = {472-480}, doi = {10.1080/00365520500318965}, pmid = {16635917}, issn = {0036-5521}, mesh = {Acetylcysteine/pharmacology ; Acute Disease ; Animals ; CD11b Antigen/blood ; Chemokines/analysis ; Cytokines/analysis ; Leukocyte Common Antigens/blood ; Male ; Monocytes/chemistry ; NF-kappa B/metabolism ; Pancreas/chemistry ; Pancreatitis/*immunology/*physiopathology ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {OBJECTIVE: Acute pancreatitis (AP) is an inflammatory disorder that develops a complex cascade of immunological events. The local and systemic immune status and inflammatory response might contribute to the understanding of underlying pathophysiological mechanisms and potential treatment.<br><br>MATERIAL AND METHODS: Severe AP was induced by intraductal perfusion of 5% sodium taurodeoxycholate in rats. mRNA expression of cytokines and chemokines was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and NF-kappaB activation was assessed by electrophoretic mobility shift assay in fresh pancreatic acini and circulating monocytes 1, 3, 6 or 9 h after sham operation, induction of AP or N-acetylcysteine (NAC) pretreatment. Flow cytometry was performed on cells obtained from the peripheral blood.<br><br>RESULTS: An inverse relationship in pancreatic and circulating monocytic NF-kappaB activation was detected 6 and 9 h after induction of AP. NAC further suppressed monocytic NF-kappaB activation induced by AP as seen 9 h after induction of AP. A marked constitutive increase in the expression of IL-6, CINC and MCP-1 was seen in pancreatic acini, whereas no change in mRNA expression of inflammatory mediators was observed in circulating monocytes 6 h after induction of AP. Flow cytometry further confirmed the altered function of circulating monocytes.<br><br>CONCLUSIONS: The different immune status and inflammatory response in the pancreas and circulating monocytes improve the understanding of the mechanisms by which systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) develop in severe AP. A potential therapeutic approach could be to restore the functional capacity of the immune system in AP. The use of an NF-kappaB inhibitor, preferentially reaching the local inflammatory foci, could be a potential future way of intervention.}, }
@article {pmid16632126, year = {2006}, author = {Zhang, HS and Wang, SQ}, title = {Notoginsenoside R1 inhibits TNF-alpha-induced fibronectin production in smooth muscle cells via the ROS/ERK pathway.}, journal = {Free radical biology &amp; medicine}, volume = {40}, number = {9}, pages = {1664-1674}, doi = {10.1016/j.freeradbiomed.2006.01.003}, pmid = {16632126}, issn = {0891-5849}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Arteries/drug effects/metabolism ; Blotting, Western ; Cell Movement/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/*drug effects/metabolism ; Fibronectins/biosynthesis/*drug effects ; Ginsenosides/*pharmacology ; Humans ; Myocytes, Smooth Muscle/*drug effects/metabolism ; Onium Compounds/pharmacology ; RNA, Messenger/analysis ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {The matrix fibronectin protein plays an important role in vascular remodeling. Notoginsenoside R1 is the main ingredient with cardiovascular activity in Panax notoginseng; however, its molecular mechanisms are poorly understood. We report that notoginsenoside R1 significantly decreased TNF-alpha-induced activation of fibronectin mRNA, protein levels, and secretion in human arterial smooth muscle cells (HASMCs) in a dose-dependent manner. Notoginsenoside R1 scavenged hydrogen peroxide (H2O2) in a dose-dependent manner in the test tube. TNF-alpha significantly increased intracellular ROS generation and then ERK activation, which was blocked by notoginsenoside R1 or DPI and apocynin, inhibitors of NADPH oxidase, or the antioxidant NAC. Our data demonstrated that TNF-alpha-induced upregulation of fibronectin mRNA and protein levels occurs via activation of ROS/ERK, which was prevented by treatment with notoginsenoside R1, DPI, apocynin, NAC, or MAPK/ERK inhibitors PD098059 and U0126. Notoginsenoside R1 significantly inhibited H2O2-induced upregulation of fibronectin mRNA and protein levels and secretion; it also significantly inhibited TNF-alpha and H2O2-induced migration. These results suggest that notoginsenoside R1 inhibits TNF-alpha-induced ERK activation and subsequent fibronectin overexpression and migration in HASMCs by suppressing NADPH oxidase-mediated ROS generation and directly scavenging ROS.}, }
@article {pmid16632117, year = {2006}, author = {Mishima, K and Baba, A and Matsuo, M and Itoh, Y and Oishi, R}, title = {Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity.}, journal = {Free radical biology &amp; medicine}, volume = {40}, number = {9}, pages = {1564-1577}, doi = {10.1016/j.freeradbiomed.2005.12.025}, pmid = {16632117}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*toxicity ; Antioxidants/pharmacology ; Apoptosis/drug effects/physiology ; Chemical and Drug Induced Liver Injury ; Cisplatin/*toxicity ; Cyclic AMP/analogs &amp; derivatives/*metabolism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Epoprostenol/analogs &amp; derivatives/pharmacology ; Fluorescent Antibody Technique ; In Situ Nick-End Labeling ; Lipid Peroxidation/drug effects/physiology ; Liver Diseases/*prevention &amp; control ; Male ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/drug effects ; Tumor Necrosis Factor-alpha/drug effects ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {We reported earlier that reactive oxygen species are implicated in necrotic injury induced by a transient exposure of cultured renal tubular cells to a high concentration of cisplatin but not in apoptosis occurring after continuous exposure to a low concentration of cisplatin. We report here the protective effect of cyclic AMP against cisplatin-induced necrosis in cultured renal tubular cells as well as cisplatin-induced acute renal failure in rats. Several pharmacological agents that stimulate cyclic AMP signaling, including the nonhydrolyzable cyclic AMP analogue dibutyryl cyclic AMP, forskolin, 3-isobutyl-1-methylxanthine, and a prostacyclin analogue, beraprost, prevented cisplatin-induced cell injury in a protein kinase A-dependent manner. Cisplatin enhanced lipid peroxidation, decreased CuZn superoxide dismutase (SOD) while enhancing MnSOD activity, and increased cellular tumor necrosis factor-alpha (TNF-alpha) content. The elevation of TNF-alpha content and cell injury induced by cisplatin were attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors including SB203580 and PD169316. Indeed, cisplatin increased the number of phosphorylated p38 MAPK-like immunoreactive cells. These intracellular events were all reversed by antioxidants such as N-acetylcysteine (NAC) and glutathione or cyclic AMP analogues. The in vivo acute renal injury after cisplatin injection was associated with the elevation of renal TNF-alpha content. The cisplatin-induced renal injury and the increase in TNF-alpha content were reversed by NAC or beraprost. These findings suggest that cyclic AMP protects renal tubular cells against cisplatin-induced oxidative injury by obliterating reactive oxygen species and subsequent inhibition of TNF-alpha synthesis through blockade of p38 MAPK activation.}, }
@article {pmid16632111, year = {2006}, author = {Seo, GS and Lee, SH and Choi, SC and Choi, EY and Oh, HM and Choi, EJ and Park, DS and Kim, SW and Kim, TH and Nah, YH and Kim, S and Kim, SH and You, SH and Jun, CD}, title = {Iron chelator induces THP-1 cell differentiation potentially by modulating intracellular glutathione levels.}, journal = {Free radical biology &amp; medicine}, volume = {40}, number = {9}, pages = {1502-1512}, doi = {10.1016/j.freeradbiomed.2005.12.020}, pmid = {16632111}, issn = {0891-5849}, mesh = {Blotting, Western ; Cell Adhesion/drug effects ; Cell Differentiation/*drug effects ; Cell Line, Tumor ; Deferoxamine/*pharmacology ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/drug effects/metabolism ; Flow Cytometry ; Glutathione/*drug effects/metabolism ; Humans ; Iron Chelating Agents/*pharmacology ; Leukocytes, Mononuclear/cytology/*drug effects ; Oxidative Stress/drug effects/physiology ; Phagocytosis/drug effects ; Reverse Transcriptase Polymerase Chain Reaction ; Scavenger Receptors, Class A/drug effects ; Transfection ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {Iron chelators have been implicated to modulate certain inflammatory mediators and regulate inflammatory processes. Here we report that iron chelator deferoxamine (DFO) induces differentiation of monocytic THP-1 cells into functional macrophages. DFO rapidly phosphorylated both extracellular signal-regulated kinase (ERK) and p38 kinase. Blockade of ERK signaling by the MEK1/2 inhibitor PD098059 abolished DFO-induced class A scavenger receptor (SR-A) expression and phagocytic activity, indicating that ERK cascades mediate the induction of THP-1 differentiation. In contrast, in cells treated with the p38 inhibitor SB203580 or transfected with the dominant-negative variant of p38 kinase, DFO-mediated ERK activation became more prominent, and the induction of SR-A expression and phagocytic activity were significantly increased. Interestingly, differentiation by DFO was associated with decrease in cellular glutathione (GSH) level. Both MAPK inhibitors did not influence the GSH level; however, treatment with ferric citrate (Fe3+) or N-acetyl-cysteine, a major precursor of GSH, markedly recovered GSH level to a normal extent, along with the significant decrease of differentiation. Collectively, these results indicate that oxidative stress by DFO and the resulting activation of ERK cascade play dominant roles in the process of THP-1 differentiation, while p38 acts as a negative signal transmitter.}, }
@article {pmid16631521, year = {2006}, author = {Cheng, PY and Lee, YM and Shih, NL and Chen, YC and Yen, MH}, title = {Heme oxygenase-1 contributes to the cytoprotection of alpha-lipoic acid via activation of p44/42 mitogen-activated protein kinase in vascular smooth muscle cells.}, journal = {Free radical biology &amp; medicine}, volume = {40}, number = {8}, pages = {1313-1322}, doi = {10.1016/j.freeradbiomed.2005.11.024}, pmid = {16631521}, issn = {0891-5849}, mesh = {Animals ; Cells, Cultured ; DNA/metabolism ; Enzyme Activation/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Heme Oxygenase-1/*metabolism ; Hydrogen Peroxide/pharmacology ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3/*metabolism ; Muscle, Smooth, Vascular/*drug effects/*enzymology ; Myocytes, Smooth Muscle/drug effects/*enzymology ; Phosphorylation/drug effects ; Promoter Regions, Genetic/genetics ; Rats ; Reactive Oxygen Species/metabolism ; Thioctic Acid/*pharmacology ; Transcription Factor AP-1/genetics/metabolism ; }, abstract = {Alpha-lipoic acid (ALA) is a natural antioxidant that scavenges reactive oxygen species (ROS) and regenerates or recycles endogenous antioxidants. ALA has recently been reported to protect against oxidative injury in various disease processes. The aim of this study was to investigate whether the antioxidant effect of ALA is mediated by the induction of heme oxygenase (HO)-1 in rat aortic smooth muscle cells (A10 cells). ALA significantly induced HO-1 expression accompanied by an increase in HO activity in A10 cells. Pretreatment with ALA increased the resistance of A10 cells to hydrogen-peroxide-induced oxidant stress. This protection of ALA was abrogated in the presence of the HO inhibitor zinc protoporphyrin IX. ALA significantly increased ROS, and this effect was blocked by N-acetyl-cysteine, which also inhibited ALA-induced activation of p44/42 mitogen-activated protein kinase (MAPK) and AP-1, HO-1 expression, and HO activity. These results suggest that ALA induces HO-1 expression through the production of ROS and subsequent activation of the p44/42 MAPK pathway and AP-1 in vascular smooth muscle cells. This study demonstrated that ALA increases the expression of HO-1, a critical cytoprotective molecule, and identified a novel pleiotropic effect of ALA on cardiovascular protection.}, }
@article {pmid16628006, year = {2006}, author = {Tanaka, T and Kurose, A and Halicka, HD and Traganos, F and Darzynkiewicz, Z}, title = {2-deoxy-D-glucose reduces the level of constitutive activation of ATM and phosphorylation of histone H2AX.}, journal = {Cell cycle (Georgetown, Tex.)}, volume = {5}, number = {8}, pages = {878-882}, doi = {10.4161/cc.5.8.2681}, pmid = {16628006}, issn = {1551-4005}, support = {R01 CA028704/CA/NCI NIH HHS/United States ; R01 CA028704-28/CA/NCI NIH HHS/United States ; CA 28 704/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line, Tumor ; Cell Proliferation ; DNA/chemistry ; DNA Damage ; DNA-Binding Proteins/*metabolism ; Deoxyglucose/*metabolism ; Histones/*metabolism ; Humans ; Oxygen/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; Reactive Oxygen Species ; Recombination, Genetic ; Tumor Suppressor Proteins/*metabolism ; }, abstract = {Histone H2AX phosphorylated on Ser-139, defined as gammaH2AX, is a reporter of DNA double-strand breaks (DSBs). While H2AX undergoes phosphorylation after induction of DNA damage by genotoxic agents or during physiological events that involve DNA recombination, it also is phosphorylated in untreated normal and tumor cells. We recently reported that this constitutive H2AX phosphorylation (CHP) is markedly reduced by the antioxidant N-acetyl-L-cysteine (NAC), and postulated that it reflects the oxidative DNA damage ("endogenous DSBs") induced by reactive oxygen species (ROS) generated by metabolic activity during progression through the cell cycle. In the present study, we provide evidence that growth of cells from three human lymphoblastoid cell lines TK6, NH32 and WTK1 in the presence of the glucose antimetabolite 2-deoxy-D-glucose (2-DG) led to a distinct reduction in the level of CHP. The reduction of CHP was more pronounced in S and G(2)M than in G(1) phase cells. Constitutive activation of ATM was also reduced. The data suggest that a decrease in a cell's metabolic activity as a result of inhibition of glycolysis by 2-DG reduces generation of ROS which leads to the reduction of oxidative DNA damage. The data also point out that ATM may play a role in CHP induced by oxidative DNA damage. Therefore, the assay of CHP by multiparameter cytometry provides the means to measure effects of antioxidants and metabolic inhibitors on endogenous oxidative DNA damage in relation to cell cycle phase.}, }
@article {pmid16627882, year = {2006}, author = {Jatana, M and Singh, I and Singh, AK and Jenkins, D}, title = {Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic-ischemic brain injury in neonatal rats.}, journal = {Pediatric research}, volume = {59}, number = {5}, pages = {684-689}, doi = {10.1203/01.pdr.0000215045.91122.44}, pmid = {16627882}, issn = {0031-3998}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; NS-40144/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Animals, Newborn ; Combined Modality Therapy ; *Hypothermia, Induced ; Hypoxia-Ischemia, Brain/*drug therapy/pathology/physiopathology/*therapy ; Myelin Basic Protein/metabolism ; Myelin Proteolipid Protein/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Hypoxic ischemic (HI) injury in neonates may have devastating, long-term consequences. Recently completed clinical trials in HI neonates indicate that hypothermia within 6 h of birth results in modest improvement in the combined outcome of death or severe disability. The aim of this study was to investigate the effects of combining hypothermia and N-acetylcysteine (NAC) on brain injury, neonatal reflexes and myelination after neonatal HI. Seven-day-old rats were subjected to right common carotid artery ligation and hypoxia (8% oxygen) for 2 h. Systemic hypothermia (30 + 0.5 degrees C) was induced immediately after the period of HI and was maintained for 2 h. NAC (50 mg/kg) was administered by intraperitoneal injection daily until sacrifice. Brain infarct volumes were significantly reduced at 48 h post-HI in the hypothermia plus NAC group (21.5 +/- 3.84 mm3) compared with vehicle (240.85 +/- 4.08 mm3). Neonatal reflexes were also significantly improved by combination therapy at days 1 and 7. There was a significant loss of right hemispheric brain volume in the untreated group at 2 and 4 wk after HI insult. Brain volumes were preserved in hypothermia plus NAC group and were not significantly different when compared with the sham group. Similarly, increased myelin expression was seen in brain sections from hypothermia plus NAC group, when stained for Luxol Fast Blue (LFB), Myelin Basic Protein (MBP) and Proteolipid protein (PLP). These results indicate that hypothermia plus NAC combination therapy improves infarct volume, myelin expression and functional outcomes after focal HI injury.}, }
@article {pmid16626552, year = {2006}, author = {Yao, K and Ge, JB and Sun, AJ and Hong, XW and Shi, HY and Huang, RC and Jia, QZ and Wang, KQ and Zhong, CP and Cao, XT and Zou, YZ}, title = {[Effects and mechanism of hyperglycemia on development and maturation and immune function of human monocyte derived dendritic cells].}, journal = {Zhonghua xin xue guan bing za zhi}, volume = {34}, number = {1}, pages = {60-64}, pmid = {16626552}, issn = {0253-3758}, mesh = {Cell Differentiation/*drug effects ; Cell Proliferation/*drug effects ; Cells, Cultured ; Culture Media ; Cytokines/biosynthesis ; *Dendritic Cells/drug effects/immunology/metabolism ; Glucose/*adverse effects/pharmacology ; Humans ; Immunophenotyping ; Monocytes/cytology ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/cytology ; }, abstract = {OBJECTIVE: Dendritic cells play an important role in the pathogenesis of atherosclerosis. To explore the effects of hyperglycemia on the maturation and immune function of human monocyte derived dendritic cells (MDCs).<br><br>METHODS: Immature MDCs were cultured in RPMI1640 medium with either 5.5 mmol/L D-glucose (NG), 25 mmol/L D-glucose (HG) or 5.5 mmol/L D-glucose + 19.5 mmol/L mannitol (HM) in the absence or presence of 30 mmol/L N-acetylcysteine [NAC, a reactive oxygen species inhibitor (ROS)] for 48 hours. FACS was used to investigate the MDCs immunophenotypic expression. Immune function was evaluated by allogeneic mixed T lymphocyte reaction and measurement of cytokine levels from culture supernatants. Intracellular ROS production in MDCs was also measured by 2', 7'-dichlorodihydrofluorescein (DCF, 10 micromol/L) fluorescence using confocal laser-scanning microscopy techniques.<br><br>RESULTS: Compared with NG and HM treated MDCs, the expression of maturation markers such as CD1a, HLA-DR, CD83, CD86 were significantly upregulated, allogeneic T cells proliferation as well as the cytokines secretions (IL-2, IL-12, IL-10 and IFN-gamma) significantly increased in HG treated MDCs. Intracellular ROS production in MDCs was also significantly increased and all these stimulatory effects of HG could be partially attenuated by NAC.<br><br>CONCLUSION: High glucose promote the maturation of MDCs and augment their capacity to stimulate T-cell proliferation and cytokine secretions at least in part through enhancing intracellular ROS generation. These stimulating effects of high glucose on MDCs maturation may be one of the mechanisms of accelerated atherosclerosis found in patients with diabetes.}, }
@article {pmid16624749, year = {2006}, author = {Lin, YX and Xu, RX and Jiang, XD and Kang, DZ and Ke, YQ and Du, MX and Cai, YQ and Qin, LS}, title = {[Effect of N-acetyl-cysteine and depakine pretreatment on ferrous chloride-induced membrane potential and peroxidate changes in rat cortex neurons].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {26}, number = {4}, pages = {448-451}, pmid = {16624749}, issn = {1673-4254}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Cells, Cultured ; Cerebral Cortex/cytology/metabolism/*physiopathology ; Female ; Ferrous Compounds/pharmacology ; Male ; Membrane Potentials/*drug effects ; Neurons/cytology/metabolism/physiology ; Neuroprotective Agents/pharmacology ; Peroxides/*metabolism ; Rats ; Rats, Sprague-Dawley ; Valproic Acid/*pharmacology ; }, abstract = {OBJECTIVE: To investigate the effect of N-acetyl-cysteine (NAC) and depakine (DP) on the changes of membrane potential and peroxidate in rat cortex neurons exposed to ferrous chloride (FeCl(2)).<br><br>METHODS: Cultured cortex neurons of newly born SD rats were randomly divided into control group (PBS group), model group (FeCl(2) group), NAC pretreatment group (NAC group), DP pretreatment group (DP group) and NAC+DP pretreatment group (NAC+DP group). In the latter three groups, NAC (0.08 mg/ml) and DP (0.1 mg/ml) were added in the cell culture 2 and 3 h before FeCl(2) (1 mmol/L) exposure, respectively. After exposure to FeCl(2), the membrane potential of the neurons was detected with fluorescent dye DiBAC4(3) (bis-(1,3-dibutylbarbituric acid) trimethine oxonol), and the peroxidate level with 2,7-dichlorofluorescin diacetate (H(2)DCF) by laser confocal scanning microscope (LCSM) and nuclear factor-KappaB (NF-KappaB) level with immunocytochemistry.<br><br>RESULTS: Compared with FeCl(2) group, the expression of NF-KappaB and peroxidate level in the neurons were decreased significantly in NAC and NAC+DP groups (P<0.01), but not in DP group (P>0.05). FeCl(2) depolarized the membrane potential and increased the expression of NF-KappaB in the neurons. Compared with FeCl(2) group, significant changes in the membrane potential were observed in DP and NAC+DP groups (P<0.01) but not in NAC or PBS group (P>0.05).<br><br>CONCLUSION: Both NAC and DP can protect the neurons from FeCl(2)-induced damage but through different pathways, and their combined use can significantly alleviate neuronal damages due to FeCl(2) exposure. Antioxidants such as NAC in combination with antiepileptic drugs may produce favorable effect in prevention and treatment of posttraumatic epilepsy.}, }
@article {pmid16624471, year = {2006}, author = {Chan, WH and Wu, HY and Chang, WH}, title = {Dosage effects of curcumin on cell death types in a human osteoblast cell line.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {44}, number = {8}, pages = {1362-1371}, doi = {10.1016/j.fct.2006.03.001}, pmid = {16624471}, issn = {0278-6915}, mesh = {Adenosine Triphosphate/metabolism ; Apoptosis/*drug effects ; Caspase 3 ; Caspases/metabolism ; Cell Line ; Cell Survival/drug effects ; Curcumin/*pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; Humans ; MAP Kinase Kinase 4/metabolism ; Membrane Potentials/drug effects ; Microscopy, Confocal ; Mitochondrial Membranes/drug effects ; Necrosis ; Osteoblasts/cytology/*drug effects/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Reactive Oxygen Species/metabolism ; p21-Activated Kinases ; }, abstract = {Curcumin, the yellow pigment of Curcuma longa, is known to have antioxidant and anti-inflammatory properties, as well as their ability to either induce or prevent cell apoptosis. However, the precise molecular mechanisms of these effects are unknown. Here, we demonstrate that curcumin can induce apoptotic changes, including JNK activation, caspase-3 activation, and cleavage of PARP and PAK2, at treatment concentrations lower than 25 microM in human osteoblast cells. In contrast, treatment with 50-200 microM of curcumin does not induce apoptosis, but rather triggers necrotic cell death in human osteoblasts. Using the cell permeable dye 2',7'-dichlorofluorescin diacetate (DCF-DA) as an indicator of reactive oxygen species (ROS) generation, we found that while treatment with 12.5-25 microM curcumin directly increased intracellular oxidative stress, 50-200 microM curcumin had far less effect. Pretreatment of cells with N-acetyl cysteine or alpha-tocopherol, two well known ROS scavengers, attenuated the intracellular ROS levels increases and converted the apoptosis to necrosis induced by 12.5-25 microM curcumin. Moreover, we observed a dose-dependent decrease in intracellular ATP levels after treatment of osteoblast cells with curcumin and pretreatment of cells with antimycin or 2-deoxyglucose to cause ATP depletion significantly converted 12.5-25 microM curcumin-induced apoptosis to necrosis, indicating that ATP (a known mediator of apoptotic versus necrotic death) is most likely involved in the switching mechanism. Overall, our results signify that curcumin dosage treatment determines the possible effect on ROS generation, intracellular ATP levels, and cell apoptosis or necrosis in osteoblast cells.}, }
@article {pmid16620943, year = {2006}, author = {Pagl, R and Aurich, JE and Müller-Schlösser, F and Kankofer, M and Aurich, C}, title = {Comparison of an extender containing defined milk protein fractions with a skim milk-based extender for storage of equine semen at 5 degrees C.}, journal = {Theriogenology}, volume = {66}, number = {5}, pages = {1115-1122}, doi = {10.1016/j.theriogenology.2006.03.006}, pmid = {16620943}, issn = {0093-691X}, mesh = {Animals ; *Cold Temperature ; Cysteine/pharmacology ; Horses/*physiology ; Image Processing, Computer-Assisted/methods ; Male ; Milk Proteins/*pharmacology ; Semen Preservation/methods/*veterinary ; Sperm Motility ; Spermatozoa/*physiology ; Temperature ; Time Factors ; }, abstract = {A problem of semen extenders based on milk or egg yolk is the fact that these biological products consist of a variety of substances. Extenders containing only components with clearly protective effects on spermatozoa would thus be an advantage. In this study, we have compared the effects of an extender containing defined caseinates and whey proteins only (EquiPro, defined milk protein extender) with skim milk extender on equine spermatozoa during cooled storage. The defined milk protein extender was used with and without the antioxidant N-acetyl cysteine (NAC). In a second experiment, semen was diluted with PBS or defined milk protein extender and was either stored directly or 90% of seminal plasma was removed by centrifugation and replaced by defined milk protein extender before storage. In both experiments, eight stallions were available for semen collections. Motility, velocity and membrane integrity of spermatozoa were determined by CASA immediately after semen processing and after 24, 48 and 72 h of storage at 5 degrees C. Total motility after 24 h of storage was lowest in semen diluted with PBS (p<0.05 versus all extenders). At 48 and 72 h, motility of spermatozoa in defined milk protein extender was significantly (p<0.05) higher than in PBS or skim milk extender. Velocity of spermatozoa after storage was highest in defined milk protein extender. Membrane integrity after storage was significantly (p<0.05) lower in semen diluted with PBS than in semen diluted with both extenders. Addition of NAC was without effect on the examined parameters. Centrifugation further increased the percentage of motile and membrane-intact spermatozoa in the defined milk protein extender (p<0.05). Velocity of spermatozoa in this extender was not negatively affected by centrifugation.}, }
@article {pmid16617125, year = {2006}, author = {Korge, P and Weiss, JN}, title = {Redox regulation of endogenous substrate oxidation by cardiac mitochondria.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {291}, number = {3}, pages = {H1436-45}, doi = {10.1152/ajpheart.01292.2005}, pmid = {16617125}, issn = {0363-6135}, support = {P50 HL-080111/HL/NHLBI NIH HHS/United States ; R01 HL-071870/HL/NHLBI NIH HHS/United States ; }, mesh = {3-Mercaptopropionic Acid/pharmacology ; Acetylcysteine/*pharmacology ; Adenosine Diphosphate/*metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Catalase/*pharmacology ; Cell Respiration/physiology ; Electron Transport/physiology ; Enzyme Inhibitors/pharmacology ; Fatty Acids/metabolism ; Hydrogen Peroxide ; Mitochondria, Heart/drug effects/*metabolism ; Oxidants ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Oxygen Consumption/drug effects/physiology ; Phosphorylation/*drug effects ; Rabbits ; Reactive Oxygen Species ; Tiopronin/pharmacology ; }, abstract = {Reactive oxygen species (ROS) play important roles in regulating mitochondrial function, as well as in ischemia-reperfusion injury and cardioprotection. Here we show that, in the absence of exogenous substrates, cardiac mitochondria have a surprisingly large capacity to phosphorylate ADP by oxidizing endogenous substrates, provided that H2O2 is removed from the extramitochondrial environment and a reduced environment is maintained in the matrix. In isolated mitochondria without exogenous substrates, addition of catalase and the membrane-permeant reducing agent N-acetylcysteine (Nac) or the ROS scavenger mercaptopropionyl glycine significantly increased the ability to phosphorylate added ADP, as demonstrated by 1) full recovery of membrane potential (Deltapsi) and matrix volume from ADP-induced dissipation and shrinkage, 2) ADP-dependent increase in O2 consumption, and 3) enhanced rate of ATP synthesis. Removal of extramitochondrial H2O2 by catalase was required to stimulate endogenous substrate oxidation, as shown by the increase in O2 consumption and Deltapsi. This effect was greatly enhanced by addition of Nac or mercaptopropionyl glycine to suppress oxidation-induced ROS increases in the matrix. Theoretical considerations, as well as reversible inhibition of O2 consumption with 3-mercaptopropionic acid and pyruvate in state 3, indicate that these substrates are fatty acids. Under in vivo conditions in which powerful antioxidant conditions are maintained, this mechanism may be important in stimulation of beta-oxidation and ATP production at low levels of extramitochondrial fatty acids. Incapacitation of this mechanism may potentially contribute to mitochondrial dysfunction during oxidative stress.}, }
@article {pmid16616762, year = {2006}, author = {Kin, H and Wang, NP and Halkos, ME and Kerendi, F and Guyton, RA and Zhao, ZQ}, title = {Neutrophil depletion reduces myocardial apoptosis and attenuates NFkappaB activation/TNFalpha release after ischemia and reperfusion.}, journal = {The Journal of surgical research}, volume = {135}, number = {1}, pages = {170-178}, doi = {10.1016/j.jss.2006.02.019}, pmid = {16616762}, issn = {0022-4804}, support = {HL64886/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Blood Pressure ; Caspase 3 ; Caspases/metabolism ; Cell Nucleus/metabolism ; DNA Fragmentation/*immunology ; Heart Rate ; Immune Sera/pharmacology ; Interleukin-6/blood ; Leukocyte Count ; Male ; Myocardium/immunology/*pathology ; NF-kappa B/*metabolism ; Neutrophils/*cytology/immunology/metabolism ; Oxidants/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/immunology/metabolism/*pathology ; Signal Transduction/physiology ; Tumor Necrosis Factor-alpha/*metabolism ; bcl-2-Associated X Protein/metabolism ; }, abstract = {BACKGROUND: This study tested the hypothesis that depletion of neutrophils (PMNs) reduces myocardial apoptosis via reducing oxidant generation and inhibiting NFkappaB-mediated signaling pathways after ischemia/reperfusion.<br><br>METHODS: Anesthetized rats were randomly divided into one of four groups:<br><br>CONTROL: 30 min ischemia and 3 h of reperfusion; PMN depletion: anti-PMN serum was injected 6 h before ischemia; N-acetylcysteine (NAC): NAC was given twice before ischemia and at reperfusion. Sham: the ligature was placed without coronary occlusion. Apoptosis was detected by TUNEL staining and DNA fragmentation. PMN accumulation was studied by immunohistochemical staining. Levels of TNF-alpha, IL-6, and caspase-3 were detected by Elisa kits. Expression in NFkappaB, Bcl-2, and Bax was assessed by Western blotting analysis.<br><br>RESULTS: Relative to CONTROL, depletion of PMNs or NAC treatment reduced levels of plasma TNFalpha (567 +/- 130* and 231 +/- 72* versus 1994 +/- 447 pg/ml) and IL-6 (791 +/- 473* and 666 +/- 300* versus 3724 +/- 1233, pg/ml), accompanying a reduction in PMN accumulation (12 +/- 1* and 13 +/- 0.6* versus 20 +/- 1 mm2 myocardium) in ischemic myocardium. Both groups showed a reduction in expression of nuclear NFkappaB relative to CONTROL (62 +/- 9* and 67 +/- 8* versus 124 +/- 16 arb.u), consistent with reduced NFkappaB binding activity. The number of apoptotic cells (%) in area at risk myocardium was comparably reduced in anti-PMN and NAC groups relative to CONTROL (12 +/- 1* and 14 +/- 0.9* versus 20 +/- 1), consistent with reduced appearance of DNA ladders. Furthermore, activated caspase-3 was significantly reduced and Bcl-2 was increased relative to CONTROL. No difference in all parameters measured was detected during the course of experiment in the Sham group.<br><br>CONCLUSION: These data suggest that the oxidants generated from activated PMNs after ischemia/reperfusion trigger myocardial apoptosis, which is further supported by an anti-oxidant therapy with NAC, potentially mediated by enhanced NFkappaB-TNFalpha signaling pathway, activated caspase-3 and down-regulated Bcl-2. *P < 0.05 versus CONTROL.}, }
@article {pmid16614991, year = {2006}, author = {Siddiqui, A and Ancha, H and Tedesco, D and Lightfoot, S and Stewart, CA and Harty, RF}, title = {Antioxidant therapy with N-acetylcysteine plus mesalamine accelerates mucosal healing in a rodent model of colitis.}, journal = {Digestive diseases and sciences}, volume = {51}, number = {4}, pages = {698-705}, pmid = {16614991}, issn = {0163-2116}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antioxidants/pharmacology ; Biopsy, Needle ; Colitis/*drug therapy/pathology ; Cytokines/analysis/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Immunohistochemistry ; Inflammation Mediators/analysis ; Male ; Mesalamine/*pharmacology ; Peroxidase/drug effects/metabolism ; Probability ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reference Values ; Sensitivity and Specificity ; }, abstract = {The aims of this study were to examine the ability of the antioxidant N-acetylcysteine (NAC) and mesalamine (5-ASA) alone and in combination to affect TNBS-induced colitis in rat. Three days following induction of TNBS colitis rats were randomized to receive daily intracolonic treatment with NAC, 5-ASA, and NAC plus 5-ASA for 5 or 8 days. At the end of the treatment period macroscopic and microscopic colonic injuries were scored. Myeloperoxidase (MPO) activity and cytokine gene expression were measured in colonic tissues. Results indicated that treatment with NAC plus 5-ASA caused a significantly greater reduction in colonic injury than either agent alone. Furthermore, combination therapy inhibited significantly MPO activity and inflammatory cytokine gene expression in the distal colon of TNBS-treated animals. The beneficial effects of NAC plus 5-ASA on reduction of colonic injury and promotion of healing were most evident after 8 days of treatment.}, }
@article {pmid16614485, year = {2006}, author = {Mizuguchi, S and Takemura, S and Minamiyama, Y and Kodai, S and Tsukioka, T and Inoue, K and Okada, S and Suehiro, S}, title = {S-allyl cysteine attenuated CCl4-induced oxidative stress and pulmonary fibrosis in rats.}, journal = {BioFactors (Oxford, England)}, volume = {26}, number = {1}, pages = {81-92}, doi = {10.1002/biof.5520260108}, pmid = {16614485}, issn = {0951-6433}, mesh = {Animals ; Bronchoalveolar Lavage Fluid/cytology ; Carbon Tetrachloride/*pharmacology ; Cysteine/*analogs &amp; derivatives/pharmacology ; Enzyme Precursors/analysis ; Glutathione/analysis ; Hydroxyproline/analysis ; Liver/pathology ; Lung/chemistry ; Male ; Matrix Metalloproteinase 9/analysis ; Nitric Oxide/urine ; Nitric Oxide Synthase Type II/analysis ; Oxidative Stress/*drug effects ; Pulmonary Fibrosis/*chemically induced/*prevention &amp; control ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/blood ; Transforming Growth Factor beta ; Transforming Growth Factor beta1 ; }, abstract = {This study examined effects of S-allyl cysteine (SAC) on carbon tetrachloride (CCl4)-induced interstitial pulmonary fibrosis in Wistar rats. CCl4 (0.5 ml/kg) was intraperitoneally injected into rats twice a week for 8 weeks, and SAC (50, 100, or 200 mg/kg), N-acetyl cysteine (NAC, 200 or 600 mg/kg), or L-cysteine (CYS, 600 mg/kg) were orally administrated to rats everyday for 8 weeks. SAC significantly reduced the increases of transforming growth factor beta, lipid peroxides, AST, and ALT in plasma, induced by CCl4. Although CCl4 is mainly metabolized by hepatic cytochrome P450, CCl4 induced systemic inflammation and some organ fibrosis. SAC dose-dependently and significantly attenuated CCl4-induced systemic inflammation and fibrosis of lung. SAC also inhibited the decrease of thiol levels, the increase of inducible nitric oxide synthase expression, the infiltration of leukocytes, and the generation of reactive oxygen species in lungs. Although NAC and CYS attenuated CCl4-induced pulmonary inflammation and fibrosis, the order of preventive potency was SAC > NAC > CYS according to their applied doses. These results indicate that SAC is more effective than other cysteine compounds in reducing CCl4-induced lung injury, and might be useful in prevention of interstitial pulmonary fibrosis.}, }
@article {pmid16614479, year = {2006}, author = {Hwang, ES and Lee, HJ}, title = {Induction of quinone reductase by allylisothiocyanate (AITC) and the N-acetylcysteine conjugate of AITC in Hepa1c1c7 mouse hepatoma cells.}, journal = {BioFactors (Oxford, England)}, volume = {26}, number = {1}, pages = {7-15}, doi = {10.1002/biof.5520260102}, pmid = {16614479}, issn = {0951-6433}, mesh = {Acetylcysteine/*chemistry/*pharmacology ; Animals ; Anticarcinogenic Agents ; Cell Division/drug effects ; Cell Line, Tumor ; Enzyme Induction/drug effects ; Gene Expression/drug effects ; Glucosinolates/metabolism ; Isothiocyanates/*chemistry/*pharmacology ; Liver Neoplasms, Experimental ; Mice ; NAD(P)H Dehydrogenase (Quinone)/*biosynthesis/genetics/metabolism ; RNA, Messenger/analysis ; Vegetables/chemistry ; }, abstract = {Cruciferous vegetables contain a series of relatively unique secondary metabolites of amino acids, called glucosinolates, from which isothiocyanates (ITC) can be generated. While glucosinolates are not thought to be bioactive directly, ITC appear to have anticarcinogenic activity. Sinigrin, the predominant aliphatic glucosinolate in cruciferous vegetables, is hydrolyzed to yield allylisothiocyanate (AITC), which, following absorption and metabolism in humans, is excreted in the urine as an N-acetyl-cysteine (NAC) conjugate. AITC possesses numerous biochemical and physiological activities. This study examined the induction of quinine reductase (QR) by AITC and synthetic AITC-NAC in Hepa1c1c7 murine hepatoma cells. AITC and AITC-NAC inhibited cell growth in a dose-dependent manner. The induction of QR activity and QR mRNA expression was dose-responsive over a range of 0.1-2.5 microM. AITC caused 2.0- and 3.1-fold inductions of QR with 1- and 2-microM treatments, respectively. By comparison, 1 and 2 microM AITC-NAC caused 2.9- and 3.7-fold inductions of QR, respectively. Considering the potential of ITC to prevent cancer, these results provide a basis for the use of NAC-ITC conjugates as chemopreventive agents.}, }
@article {pmid16609997, year = {2006}, author = {de Oliveira, CP and Simplicio, FI and de Lima, VM and Yuahasi, K and Lopasso, FP and Alves, VA and Abdalla, DS and Carrilho, FJ and Laurindo, FR and de Oliveira, MG}, title = {Oral administration of S-nitroso-N-acetylcysteine prevents the onset of non alcoholic fatty liver disease in rats.}, journal = {World journal of gastroenterology}, volume = {12}, number = {12}, pages = {1905-1911}, pmid = {16609997}, issn = {1007-9327}, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives/therapeutic use ; Administration, Oral ; Animals ; Disease Models, Animal ; Fatty Liver/physiopathology/*prevention &amp; control ; Lipid Peroxidation/drug effects ; Liver/drug effects/pathology ; Male ; Necrosis ; Nitrates/blood ; Rats ; Rats, Wistar ; Transaminases/blood ; }, abstract = {AIM: To evaluate the potential of S-nitroso-N-acetylcysteine (SNAC) in inhibition of lipid peroxidation and the effect of oral SNAC administration in the prevention of nonalcoholic fatty liver disease (NAFLD) in an animal model.<br><br>METHODS: NAFLD was induced in Wistar male rats by choline-deficient diet for 4 wk. SNAC-treated animals (n=6) (1.4 mg/kg per day of SNAC, orally) were compared to 2 control groups: one (n=6) received PBS solution and the other (n=6) received NAC solution (7 mg/kg per day). Histological variables were semiquantitated with respect to macro and microvacuolar fat changes, its zonal distribution, foci of necrosis, portal and perivenular fibrosis, and inflammatory infiltrate with zonal distribution. LOOHs from samples of liver homogenates were quantified by HPLC. Nitrate levels in plasma of portal vein were assessed by chemiluminescence. Aqueous low-density lipoprotein (LDL) suspensions (200 microg protein/mL) were incubated with CuCl(2) (300 micromol/L) in the absence and presence of SNAC (300 micromol/L) for 15 h at 37 degree Celsius. Extent of LDL oxidation was assessed by fluorimetry. Linoleic acid (LA) (18.8 micromol/L) oxidation was induced by soybean lipoxygenase (SLO) (0.056 micromol/L) at 37 degree Celsius in the presence and absence of N-acetylcysteine (NAC) and SNAC (56 and 560 micromol/L) and monitored at 234 nm.<br><br>RESULTS: Animals in the control group developed moderate macro and microvesicular fatty changes in periportal area. SNAC-treated animals displayed only discrete histological alterations with absence of fatty changes and did not develop liver steatosis. The absence of NAFLD in the SNAC-treated group was positively correlated with a decrease in the concentration of LOOH in liver homogenate, compared to the control group (0.7+/-0.2 nmol/mg vs 3.2+/-0.4 nmol/mg protein, respectively, P<0.05), while serum levels of aminotransferases were unaltered. The ability of SNAC in preventing lipid peroxidation was confirmed in in vitro experiments using LA and LDL as model substrates.<br><br>CONCLUSION: Oral administration of SNAC prevents the onset of NAFLD in Wistar rats fed with choline-deficient diet. This effect is correlated with the ability of SNAC to block the propagation of lipid peroxidation in vitro and in vitro.}, }
@article {pmid16609688, year = {2006}, author = {Agarwal, R}, title = {Proinflammatory effects of iron sucrose in chronic kidney disease.}, journal = {Kidney international}, volume = {69}, number = {7}, pages = {1259-1263}, doi = {10.1038/sj.ki.5000164}, pmid = {16609688}, issn = {0085-2538}, mesh = {Aged ; Chemokine CCL2/blood/urine ; Chronic Disease ; Ferric Compounds/*toxicity ; Ferric Oxide, Saccharated ; Glucaric Acid ; Humans ; Inflammation/*chemically induced ; Kidney Diseases/blood/*physiopathology/urine ; Kidney Failure, Chronic/blood/*physiopathology/urine ; Reproducibility of Results ; }, abstract = {Inflammation is a central component of progressive chronic kidney disease (CKD). Iron promotes oxidative stress and inflammatory response in animals and promotes progressive CKD. Parenteral iron provokes oxidative stress in patients with CKD; however, its potential to provoke an inflammatory response is unknown. In 20 veterans with CKD, 100 mg iron sucrose was administered intravenously over 5 min and urinary excretion rate and plasma concentration of monocyte chemoattractant protein-1 (MCP-1) were measured at timed intervals over 24 h. Patients were then randomized to placebo or N-acetyl cysteine (NAC) 600 mg b.i.d. and the experiment was repeated at 1 week. Iron sucrose markedly increased plasma concentration and urinary excretion rate of MCP-1 at baseline and at 1 week visits (P < 0.0001 for time effect). Urinary excretion peaked at 30 min and plasma concentration at 15 min. Plasma MCP-1 concentration fell from 164 +/- 17.7 to 135 +/- 17.7 pg/ml with NAC, whereas it remained unchanged from 133 +/- 12.5 to 132 +/- 17.7 pg/ml with placebo (P=0.001 for visit x antioxidant drug interaction). There was a reduction in MCP-1 urinary excretion rate from visit 1 to 2. At the baseline visit, the urinary excretion rate averaged 305 +/- 66 pg/min and at the second visit 245 +/- 67 pg/min (mean difference 60 +/- 28 pg/min, P = 0.030). There was no improvement in urinary MCP-1 excretion with NAC. In conclusion, iron sucrose causes rapid and transient generation and/or release of MCP-1 plasma concentration and increases urinary excretion rate, and systemic MCP-1 level but the urinary excretion rate is not abrogated with the antioxidant NAC. These results may have implications for the progression of CKD with parenteral iron.}, }
@article {pmid16607076, year = {2006}, author = {Niemi, TT and Munsterhjelm, E and Pöyhiä, R and Hynninen, MS and Salmenperä, MT}, title = {The effect of N-acetylcysteine on blood coagulation and platelet function in patients undergoing open repair of abdominal aortic aneurysm.}, journal = {Blood coagulation &amp; fibrinolysis : an international journal in haemostasis and thrombosis}, volume = {17}, number = {1}, pages = {29-34}, doi = {10.1097/01.mbc.0000195922.26950.89}, pmid = {16607076}, issn = {0957-5235}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Aged ; Aged, 80 and over ; Aortic Aneurysm, Abdominal/blood/*surgery ; Blood Coagulation/*drug effects ; Blood Platelets/*drug effects ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Humans ; Male ; Middle Aged ; Platelet Aggregation/*drug effects ; Prothrombin Time ; Thrombelastography ; Thromboxane B2/blood ; }, abstract = {N-acetylcysteine (NAC) may offer renal and hepatic protection during surgery, but in experimental studies it has been shown to impair coagulation. Since very little is known about the effects of NAC on blood coagulation in surgical patients, we studied its effects during abdominal aortic reconstruction. NAC (a bolus of 150 mg/kg followed by a continuous 24-h infusion of 150 mg/kg) or the same volume of placebo was given intravenously, in a randomized double-blinded fashion, to 20 patients undergoing abdominal aortic aneurysm repair. The haematocrit, platelet count, prothrombin time, thromboelastometry, and platelet aggregation were studied during and after surgery. Total blood loss was also measured. The median (25th-75th percentiles) decrease of the prothrombin time value was 33.0% (30-37%) after NAC treatment and 6.5% (4-8%) after placebo (P<0.001). Postoperative prothrombin time values remained lower in the patients receiving NAC. In thromboelastometry tracings the coagulation time was more prolonged after the bolus of NAC (P=0.02). Platelet aggregation induced with adenosine diphosphate decreased after NAC but not after placebo. Low prothrombin time values before and after bolus infusions were associated with increased blood loss (P=0.008 and P=0.015, respectively). NAC has anticoagulant and platelet-inhibiting properties in patients undergoing major vascular surgery. This abnormal haemostatic activity should be considered when NAC is administered to patients with increased bleeding risk.}, }
@article {pmid16603595, year = {2006}, author = {Carraro, S and Doherty, J and Zaman, K and Gainov, I and Turner, R and Vaughan, J and Hunt, JF and Márquez, J and Gaston, B}, title = {S-nitrosothiols regulate cell-surface pH buffering by airway epithelial cells during the human immune response to rhinovirus.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {290}, number = {5}, pages = {L827-32}, doi = {10.1152/ajplung.00406.2005}, pmid = {16603595}, issn = {1040-0605}, support = {2R01 HL 59337/HL/NHLBI NIH HHS/United States ; P01 AI 50989-04/AI/NIAID NIH HHS/United States ; }, mesh = {Cell Line ; Cell Membrane/drug effects/*physiology ; Cyclic GMP/analogs &amp; derivatives/pharmacology ; Cytokines/pharmacology ; Humans ; Hydrogen-Ion Concentration ; NG-Nitroarginine Methyl Ester/pharmacology ; Picornaviridae Infections/*immunology ; Respiratory Mucosa/drug effects/*physiopathology/virology ; Rhinovirus ; S-Nitrosothiols/*pharmacology ; Th1 Cells/immunology ; }, abstract = {Human rhinovirus infection is a common trigger for asthma exacerbations. Asthma exacerbations and rhinovirus infections are both associated with markedly decreased pH and ammonium levels in exhaled breath condensates. This observation is thought to be related, in part, to decreased activity of airway epithelial glutaminase. We studied whether direct rhinovirus infection and/or the host immune response to the infection decreased airway epithelial cell surface pH in vitro. Interferon-gamma and tumor necrosis factor-alpha, but not direct rhinovirus infection, decreased pH, an effect partly associated with decreased ammonium concentrations. This effect was 1) prevented by nitric oxide synthase inhibition; 2) independent of cyclic GMP; 3) associated with an increase in endogenous airway epithelial cell S-nitrosothiol concentration; 4) mimicked by the exogenous S-nitrosothiol, S-nitroso-N-acetyl cysteine; and 5) independent of glutaminase expression and activity. We then confirmed that decreased epithelial pH inhibits human rhinovirus replication in airway epithelial cells. These data suggest that a nitric oxide synthase-dependent host response to viral infection mediated by S-nitrosothiols, rather than direct infection itself, plays a role in decreased airway surface pH during human rhinovirus infection. This host immune response may serve to protect the lower airways from direct infection in the normal host. In patients with asthma, however, this fall in pH could be associated with the increased mucus production, augmented inflammatory cell degranulation, bronchoconstriction, and cough characteristic of an asthma exacerbation.}, }
@article {pmid16600541, year = {2006}, author = {Takatsuka, S and Morita, T and Koguchi, A and Horikiri, Y and Yamahara, H and Yoshino, H}, title = {Synergistic absorption enhancement of salmon calcitonin and reversible mucosal injury by applying a mucolytic agent and a non-ionic surfactant.}, journal = {International journal of pharmaceutics}, volume = {316}, number = {1-2}, pages = {124-130}, doi = {10.1016/j.ijpharm.2006.02.053}, pmid = {16600541}, issn = {0378-5173}, mesh = {Acetylcysteine/adverse effects/*pharmacology ; Animals ; Area Under Curve ; Calcitonin/administration &amp; dosage/blood/*pharmacokinetics ; Drug Delivery Systems ; Drug Synergism ; Expectorants/adverse effects/*pharmacology ; Injections, Intravenous ; Intestinal Absorption/*drug effects ; *Intestinal Mucosa/drug effects/metabolism/pathology ; Jejunum/drug effects/metabolism/pathology ; Male ; Octoxynol/adverse effects/*pharmacology ; Rats ; Rats, Wistar ; Surface-Active Agents/adverse effects/*pharmacology ; }, abstract = {The present study investigated the intestinal absorption enhancement of salmon calcitonin (SCT) and the intestinal mucosal damage when a mucolytic agent and a non-ionic surfactant were administered simultaneously to rats. N-acetylcysteine (NAC) and p-t-octyl phenol polyoxyethylene-9.5 (Triton X -100, TX-100) were chosen as the model mucolytic agent and the non-ionic surfactant, respectively. Dosing solutions containing these agents were administered directly into the rat jejunum, and the bioavailability of SCT up to 2 h was determined. NAC and TX-100, when they were used alone at a dose of 1 mg/head, did not show the apparent enhancement compared to the control. However, simultaneous use of NAC and TX-100 enhanced the intestinal absorption of SCT in a synergistic manner, and absolute bioavailability increased 12.5-fold compared to the control. The effect of NAC and TX-100 on SCT absorption was not dependent on their doses over the range of 0.2-2 mg/head, and the maximum effect was obtained at a dose of 1mg/head. Absorption enhancement of SCT by a combination of NAC and TX-100 was compared to those from the classical absorption enhancers. Absorption-enhancing ability of the combination of NAC and TX-100 was significantly higher than those of sodium deoxycholate, citrate, and the combination of citrate and taurocholate, and was comparable with that of the combination of citrate and taurodeoxycholate. Finally, the intestinal mucosal damage caused by the combination of NAC and TX-100 was assessed using a capsule device. Acute damage on intestinal mucosa was observed when they were exposed into rat intestine, but this morphological damage was found to be reversible. All these results suggest that simultaneous use of a mucolytic agent and a non-ionic surfactant would offer a potentiality for peroral delivery of peptide drugs like SCT.}, }
@article {pmid16579649, year = {2006}, author = {Guan, J and Stewart, J and Ware, JH and Zhou, Z and Donahue, JJ and Kennedy, AR}, title = {Effects of dietary supplements on the space radiation-induced reduction in total antioxidant status in CBA mice.}, journal = {Radiation research}, volume = {165}, number = {4}, pages = {373-378}, doi = {10.1667/rr3523.1}, pmid = {16579649}, issn = {0033-7587}, mesh = {Administration, Oral ; Animals ; Antioxidants/*metabolism ; *Cosmic Radiation ; *Dietary Supplements ; Dose-Response Relationship, Radiation ; Male ; Mice ; Mice, Inbred CBA ; Oxidative Stress/*drug effects/*radiation effects ; Radiation Dosage ; Radiation Tolerance/drug effects ; Radiation-Protective Agents/*administration &amp; dosage ; *Space Flight ; }, abstract = {In the present study, the total antioxidant status was used as a biomarker to evaluate oxidative stress induced by proton, HZE-particle and gamma radiation in CBA mice. The results demonstrated that the plasma level of TAS was significantly decreased (P < 0.05) in CBA mice after exposure to a 50-cGy dose of radiation from HZE particles or a 3-Gy dose of radiation from protons or gamma rays. Diet supplementation with Bowman-Birk Inhibitor Concentrate (BBIC), L-selenomethionine (L-SeM), or a combination of N-acetyl cysteine, sodium ascorbate, co-enzyme Q10 (CoQ10), alpha-lipoic acid, L-SeM and vitamin E succinate could partially or completely prevent the reduction in the plasma level of TAS in CBA mice exposed to proton or HZE-particle radiation. The selected antioxidant combination with or without CoQ10 has a comparable protective effect on the gamma-radiation-induced drop in TAS in CBA mice. These results indicate that BBIC, L-SeM and the selected antioxidant combinations may serve as countermeasures for space radiation-induced adverse biological effects.}, }
@article {pmid16574161, year = {2006}, author = {Kim, GH and Song, DK and Cho, CH and Yoo, SK and Kim, DK and Park, GY and Suh, SI and Jang, BC and Lim, JG}, title = {Muscular cell proliferative and protective effects of N-acetylcysteine by modulating activity of extracellular signal-regulated protein kinase.}, journal = {Life sciences}, volume = {79}, number = {7}, pages = {622-628}, doi = {10.1016/j.lfs.2006.02.008}, pmid = {16574161}, issn = {0024-3205}, mesh = {Acetylcysteine/*pharmacology ; Anesthetics, Local/pharmacology ; Antimetabolites ; Antioxidants/*pharmacology ; Blotting, Western ; Bromodeoxyuridine ; Bupivacaine/pharmacology ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Enzyme-Linked Immunosorbent Assay ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Muscle Cells/drug effects ; Muscle, Skeletal/*cytology ; Myoblasts/drug effects ; Regeneration/drug effects ; }, abstract = {N-acetylcysteine (NAC), an antioxidant and a precursor of glutathione, is currently in clinical use for various pathological conditions. No data is available as to the relationship between NAC and muscular cell proliferation or muscular degenerative disease. In this study, we assessed the effect of NAC on growth of L6 myoblasts, a rat skeletal muscle cell line, under normal or bupivacaine-treated condition. Of interest, under normal growth conditions, NAC treatment concentration-dependently increased viability, cell number, and DNA incorporation of L6 cells. Remarkably, NAC treatment for 12 to 24 h led to increased phosphorylation of ERKs, a family of mitogen-activated protein kinase known to involve in cell proliferation, in L6 cells, and specific inhibition of ERKs by PD98059, a selective inhibitor of ERKs, greatly abolished the ability of NAC to increase the number of L6 cells. More importantly, pretreatment with NAC effectively blocked decrease in the number and ERKs phosphorylation in L6 cells induced by the exposure of bupivacaine, a local anesthetic with myotoxicity. These results collectively suggest that NAC has muscular cell proliferative and protective effects and the effects by NAC appear to be, in part, mediated via increase in ERKs activation.}, }
@article {pmid16574159, year = {2006}, author = {Vanisree, AJ and Shyamaladevi, CS}, title = {The effect of N-acetylcysteine in combination with vitamin C on the activity of ornithine decarboxylase of lung carcinoma cells--In vitro.}, journal = {Life sciences}, volume = {79}, number = {7}, pages = {654-659}, doi = {10.1016/j.lfs.2006.02.009}, pmid = {16574159}, issn = {0024-3205}, mesh = {Acetylcysteine/*pharmacology ; Ascorbic Acid/*pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival/drug effects ; DNA, Neoplasm/biosynthesis ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Humans ; Lung Neoplasms/*drug therapy/*enzymology ; Ornithine Decarboxylase/metabolism ; *Ornithine Decarboxylase Inhibitors ; RNA, Neoplasm/biosynthesis ; Thymidine/metabolism ; }, abstract = {Ornithine decarboxylase (ODC) is a marker of lung cancer and is a key enzyme in the synthesis of polyamines, which are necessary for the promotion of the growth of malignant cells. This study assesses the dose-dependent effect of N-acetylcysteine (NAC), a chemopreventive agent, in combination with vitamin C (VC) on the activity of ODC in lung carcinoma cell line, NCI-H82. The cells were subjected to supplementation of NAC and VC both individually and in combination at different dosages for 24 h as well as 48 h. The cells were incubated with radiolabeled L-ornithine (14C) after the supplementation of NAC and VC individually as well as in combination. A microprocedure was carried out to estimate the activity of ODC in cells after 24 and 48 h of incubation. The activity which was found to be elevated in control cells was decreased significantly on drug supplementation in dose-dependent fashion. The content of nucleic acids also exhibited similar result and [3H]-thymidine incorporation was also affected by the supplementation.}, }
@article {pmid16573399, year = {2002}, author = {Atkinson, MC}, title = {The use of N-acetylcysteine in intensive care.}, journal = {Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine}, volume = {4}, number = {1}, pages = {21-27}, pmid = {16573399}, issn = {1441-2772}, abstract = {OBJECTIVE: To review the actions and clinical use of serum N-acetylcysteine in the critically ill patient.<br><br>DATA SOURCES: A review of articles published on the mechanisms of action and clinical use of N-acetylcysteine.<br><br>SUMMARY OF REVIEW: N-acetylcysteine (NAC) is an amino acid with a MW of 163.2. It acts as an antioxidant, both directly as a glutathione substitute and indirectly as a precursor for glutathione. It also causes vasodilation by increasing cyclic guanosine monophosphate levels, inhibits platelet aggregation, acts as a sulphydryl donor to regenerate endothelial-derived relaxing factor and reduces IL-8 and TNF-alpha production. While there is evidence for its effectiveness as an antidote to paracetamol poisoning, its use in other disorders has only experimental or anecdotal support. For example, in hepatic failure, there are few studies in man showing improved outcome following NAC therapy. There is also conflicting evidence for the use of NAC in sepsis or ARDS and while there is some evidence to suggest that NAC may be of benefit in acute myocardial infarction, the patient numbers are small. It may also be of use in ameliorating nitrate tolerance. It is also possible that NAC may confer benefit in reducing the risks of radiographic contrast nephropathy, although the study suggesting this was probably insufficiently powered to review all patient subsets (e.g. diabetics). N-acetylcysteine would also appear to enhance T cell function in HIV infected patients. However, the use of NAC for immunomodulation in HIV patients has not yet undergone prospective randomised controlled trials and therefore cannot be recommended as routine therapy in HIV infected, or other immune deficient, patients. There is currently insufficient evidence to propose NAC for the treatment of carbon monoxide poisoning. Whilst there is experimental evidence for a variety of novel roles for NAC, further clinical studies are required before it can be recommended for the routine management of any disorders other than that of paracetamol poisoning.<br><br>CONCLUSIONS: N-acetylcysteine has antioxidant properties that may be useful in many clinical conditions. Currently, however, it can only be recommended as therapy for paracetamol poisoning, in all other disorders it is still under evaluation.}, }
@article {pmid16572923, year = {2006}, author = {Kurcer, Z and Iraz, M and Kelesyilmaz, N and Kilic, N and Olmez, E}, title = {Beneficial effects of melatonin on diaphragmatic contractility and fatigability in Escherichia coli endotoxemic rats.}, journal = {Arzneimittel-Forschung}, volume = {56}, number = {2}, pages = {90-95}, doi = {10.1055/s-0031-1296707}, pmid = {16572923}, issn = {0004-4172}, mesh = {Animals ; Antioxidants/*pharmacology ; Diaphragm/drug effects ; Endotoxemia/metabolism/*physiopathology ; Female ; Lipid Peroxidation/drug effects ; Lipopolysaccharides ; Malondialdehyde/metabolism ; Melatonin/*pharmacology ; Muscle Contraction/drug effects ; Muscle Fatigue/*drug effects ; Muscle, Skeletal/*drug effects/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; }, abstract = {Sepsis impairs diaphragmatic contractility and endurance capacity and increases diaphragmatic fatigability. Several investigations have shown that administration of a number of free radical scavengers, such as N-acetylcysteine (NAC), protects the diaphragm from the development of endotoxin-mediated diaphragmatic dysfunction. The aim of this study was to evaluate the effects of melatonin (CAS 73-31-4), a naturally occurring potent antioxidant, on diaphragmatic contractility and lipid peroxidation as a marker of oxidative stress in endotoxemic rats. Rats were randomly divided into four groups: control group, endotoxemic group, melatonin group and endotoxemic plus melatonin group. Melatonin was administered by intraperitoneal injection 30 min before endotoxin inoculation to animals. Diaphragmatic function and malondialdehyde (MDA) level analysis as an indicator of lipid peroxidation were assessed 17 h after endotoxin or saline inoculation. Endotoxemia decreased the development of diaphragm fatigue and diaphragmatic MDA levels. The effects of endotoxemia on diaphragmatic contractions and fatigability were reversed and returned to control levels by melatonin administration. However, melatonin did not prevent the increase in muscle MDA content. In conclusion, the present study demonstrated that melatonin attenuated the endotoxin-induced impairment of diaphragm function. This effect of melatonin does not seem to be related to its antioxidant properties.}, }
@article {pmid16565438, year = {2006}, author = {Hwang, ES and Lee, HJ}, title = {Allyl isothiocyanate and its N-acetylcysteine conjugate suppress metastasis via inhibition of invasion, migration, and matrix metalloproteinase-2/-9 activities in SK-Hep 1 human hepatoma cells.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {231}, number = {4}, pages = {421-430}, doi = {10.1177/153537020623100408}, pmid = {16565438}, issn = {1535-3702}, mesh = {Acetylcysteine/*pharmacology ; Brassica/chemistry ; Carcinoma, Hepatocellular/genetics/metabolism/pathology ; Cell Adhesion/drug effects ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Isothiocyanates/*pharmacology ; Liver Neoplasms/genetics/metabolism/pathology ; Matrix Metalloproteinase 2/genetics/metabolism ; Matrix Metalloproteinase 9/genetics/metabolism ; Matrix Metalloproteinase Inhibitors ; Neoplasm Invasiveness ; *Neoplasm Metastasis ; RNA, Messenger/metabolism ; Tissue Inhibitor of Metalloproteinase-1/genetics/metabolism ; Tissue Inhibitor of Metalloproteinase-2/genetics/metabolism ; }, abstract = {Cruciferous vegetables contain a series of relatively unique secondary metabolites of amino acids, called glucosinolates. Sinigrin, the predominant aliphatic glucosinolate in cruciferous vegetables, is hydrolyzed to yield allyl isothiocyanate (AITC), which, after absorption and metabolism in humans, is excreted in the urine as an N-acetylcysteine (NAC) conjugate. We have determined the inhibitory effects of AITC and its NAC conjugate on cell proliferation, the expression of matrix metalloproteinases (MMPs), adhesion, invasion, and migration in SK-Hep 1 human hepatoma cells. Our results demonstrate that AITC and NAC-AITC suppress SK-Hep 1 cell proliferation in a dose-dependent manner; by 25% and 30% for 10 microM AITC and 10 microM NAC-AITC, respectively. We examined the influence of AITC and NAC-AITC on the gene expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). Gelatin zymography also revealed a significant downregulation of MMP-2/-9 expression in SK-Hep1 cells treated with 0.1-5 microM AITC and NAC-AITC compared with controls. Reverse transcriptase polymerase chain reaction revealed dose-dependent decreases in MMP-2/-9 messenger RNA levels in both AITC-treated and NAC-AITC-treated cells. TIMP-1/-2 activities were unaffected by treatment with AITC or NAC-AITC in our experiments. NAC-AITC inhibited cancer cell adhesion and invasion much more potently than its parent compound. NAC-AITC at 5 microM caused excellent inhibition of cell migration for 48 hrs. These results demonstrate the potential of AITC and NAC-AITC as chemopreventive agents.}, }
@article {pmid16563723, year = {2006}, author = {Hwang, ES and Lee, HJ}, title = {Phenylethyl isothiocyanate and its N-acetylcysteine conjugate suppress the metastasis of SK-Hep1 human hepatoma cells.}, journal = {The Journal of nutritional biochemistry}, volume = {17}, number = {12}, pages = {837-846}, doi = {10.1016/j.jnutbio.2006.02.004}, pmid = {16563723}, issn = {0955-2863}, mesh = {Acetylcysteine/chemistry/pharmacology ; Antineoplastic Agents/*pharmacology ; Carcinoma, Hepatocellular/*drug therapy/pathology ; Cell Adhesion/drug effects ; Cell Movement/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Isothiocyanates/chemistry/metabolism/*pharmacology ; Liver Neoplasms/*drug therapy/pathology ; Matrix Metalloproteinase 14/drug effects/genetics/metabolism ; Matrix Metalloproteinase 2/drug effects/metabolism ; Matrix Metalloproteinase 9/drug effects/metabolism ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Tissue Inhibitor of Metalloproteinase-1/drug effects/genetics/metabolism ; Tumor Cells, Cultured ; }, abstract = {Phenylethyl isothiocyanate (PEITC), a hydrolysis compound of gluconasturtiin, is metabolized to N-acetylcysteine (NAC)-PEITC in the body after the consumption of cruciferous vegetables. We observed an inhibitory effect of PEITC and its metabolite NAC-PEITC on cancer cell proliferation, adhesion, invasion, migration and metastasis in SK-Hep1 human hepatoma cells. PEITC and NAC-PEITC suppressed SK-Hep1 cell proliferation in a dose-dependent manner, and exposure to 10 microM PEITC or NAC-PEITC reduced cell proliferation by 25% and 30%, respectively. NAC-PEITC inhibited cancer cell adhesion, invasion and migration to a similar or to an even larger degree than PEITC. The expression of matrix metalloproteinase (MMP) 2, MMP-9 and membrane type 1 matrix metalloproteinase (MT1-MMP) is a known risk factor for metastatic disease. Gelatin zymography analysis revealed a significant downregulation of MMP-2/MMP-9 protein expression in SK-Hep1 cells treated with 0.1-5 microM PEITC or NAC-PEITC. PEITC and NAC-PEITC treatment caused dose-dependent decreases in MMP-2/MMP-9 and MT1-MMP mRNA levels, as determined by reverse transcription polymerase chain reaction. PEITC and NAC-PEITC also increased the mRNA levels of tissue inhibitors of matrix metalloproteinase (TIMPs) 1 and 2. Our data suggest that this inhibition is mediated by downregulation of MMP and upregulation of TIMPs.}, }
@article {pmid16563228, year = {2006}, author = {Kopp, J and Seyhan, H and Müller, B and Lanczak, J and Pausch, E and Gressner, AM and Dooley, S and Horch, RE}, title = {N-acetyl-L-cysteine abrogates fibrogenic properties of fibroblasts isolated from Dupuytren's disease by blunting TGF-beta signalling.}, journal = {Journal of cellular and molecular medicine}, volume = {10}, number = {1}, pages = {157-165}, pmid = {16563228}, issn = {1582-1838}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Biomarkers/analysis ; Case-Control Studies ; Down-Regulation ; Dupuytren Contracture/*metabolism/therapy ; Female ; Fibroblasts/*metabolism ; *Gene Expression Regulation ; Humans ; LIM Domain Proteins ; Male ; Middle Aged ; Muscle Proteins/genetics/metabolism ; Signal Transduction ; Smad7 Protein/metabolism ; Transforming Growth Factor beta/*metabolism ; }, abstract = {Dupuytren's disease, a benign fibroproliferative disorder of the palmar fascia, represents an ideal model to study tissue fibrosis. Transforming growth factor-beta1 (TGF-beta1) and its downstream Smad signalling system is well established as a key player during fibrogenesis. Thus, targeting this basic pathomechanism seems suitable to establish new treatment strategies. One such promising treatment involves the substance N-acetyl-L-cysteine (NAC), shown to have antifibrotic properties in hepatic stellate cells and rat fibroblasts. In order to investigate antifibrotic effects of N-acetyl-L-cysteine (NAC), fibroblasts were isolated from surgically resected fibrotic palmar tissues (Dupuytren fibroblasts, DF) and exposed to different concentrations of NAC and recombinant TGF-beta1. Fibroblasts isolated from tendon pulleys served as controls (control fibroblasts, CF). Smad signalling was investigated by a Smad binding element driven reporter gene analysis. Both cell types express TGF-beta1, indicating autocrine signalling in DF and CF. This was confirmed by comparing reporter gene activity from LacZ and Smad7 adenovirus infected cells. NAC treatment resulted in abrogation of Smad mediated signalling comparable to ectopically overexpressed Smad7, even when the cells were stimulated with recombinant TGF-beta1 or ectopically expressed a constitutively active TGF-beta receptor type I. Additionally, NAC dose-dependently decreased expression of three major indicators of impaired fibrotic matrix turnover, namely alpha-smooth muscle actin (alpha-SMA), alpha 1 type I procollagen (Col1A1), and plasminogen activator inhibitor-type I (PAI-1). Our results suggest that TGF-beta signalling and subsequent expression of fibrogenesis related proteins in Dupuytren's disease is abrogated by NAC thus providing a basis for a therapeutic strategy in Dupuytren's disease and other fibroproliferative disorders.}, }
@article {pmid16553950, year = {2006}, author = {Ravasi, S and Citro, S and Viviani, B and Capra, V and Rovati, GE}, title = {CysLT1 receptor-induced human airway smooth muscle cells proliferation requires ROS generation, EGF receptor transactivation and ERK1/2 phosphorylation.}, journal = {Respiratory research}, volume = {7}, number = {1}, pages = {42}, pmid = {16553950}, issn = {1465-993X}, mesh = {Acetylcysteine/pharmacology ; Androstadienes/pharmacology ; Bronchi/*cytology ; Cell Proliferation ; Cells, Cultured ; Chromones/pharmacology ; DNA/biosynthesis ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/*genetics ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Free Radical Scavengers/pharmacology ; Humans ; Leukotriene D4/pharmacology ; Membrane Proteins/*physiology ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Morpholines/pharmacology ; Myocytes, Smooth Muscle/*cytology/drug effects/metabolism ; Pertussis Toxin/pharmacology ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Reactive Oxygen Species/*metabolism ; Receptors, Leukotriene/*physiology ; Transcriptional Activation/*physiology ; Wortmannin ; ras Proteins/physiology ; }, abstract = {BACKGROUND: Cysteine-containing leukotrienes (cysteinyl-LTs) are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. In particular, cysteinyl-LTs exert a variety of effects with relevance to the aetiology of asthma such as smooth muscle contraction, eosinophil recruitment, increased microvascular permeability, enhanced mucus secretion and decreased mucus transport and, finally, airway smooth muscle cells (ASMC) proliferation. We used human ASMC (HASMC) to identify the signal transduction pathway(s) of the leukotriene D4 (LTD4)-induced DNA synthesis.<br><br>METHODS: Proliferation of primary HASMC was measured by [3H]thymidine incorporation. Phosphorylation of EGF receptor (EGF-R) and ERK1/2 was assessed with a polyclonal anti-EGF-R or anti-phosphoERKl/2 monoclonal antibody. A Ras pull-down assay kit was used to evaluate Ras activation. The production of reactive oxygen species (ROS) was estimated by measuring dichlorodihydrofluorescein (DCF) oxidation.<br><br>RESULTS: We demonstrate that in HASMC LTD4-stimulated thymidine incorporation and potentiation of EGF-induced mitogenic signaling mostly depends upon EGF-R transactivation through the stimulation of CysLT1-R. Accordingly, we found that LTD4 stimulation was able to trigger the increase of Ras-GTP and, in turn, to activate ERK1/2. We show here that EGF-R transactivation was sensitive to pertussis toxin (PTX) and phosphoinositide 3-kinase (PI3K) inhibitors and that it occurred independently from Src activity, despite the observation of a strong impairment of LTD4-induced DNA synthesis following Src inhibition. More interestingly, CysLT1-R stimulation increased the production of ROS and N-acetylcysteine (NAC) abolished LTD4-induced EGF-R phosphorylation and thymidine incorporation.<br><br>CONCLUSION: Collectively, our data demonstrate that in HASMC LTD4 stimulation of a Gi/o coupled CysLT1-R triggers the transactivation of the EGF-R through the intervention of PI3K and ROS. While PI3K and ROS involvement is an early event, the activation of Src occurs downstream of EGF-R activation and is followed by the classical Ras-ERK1/2 signaling pathway to control G1 progression and cell proliferation.}, }
@article {pmid16551877, year = {2006}, author = {Gabizon, AA and Tzemach, D and Horowitz, AT and Shmeeda, H and Yeh, J and Zalipsky, S}, title = {Reduced toxicity and superior therapeutic activity of a mitomycin C lipid-based prodrug incorporated in pegylated liposomes.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {12}, number = {6}, pages = {1913-1920}, doi = {10.1158/1078-0432.CCR-05-1547}, pmid = {16551877}, issn = {1078-0432}, mesh = {Animals ; Antineoplastic Agents/chemistry/pharmacology/therapeutic use ; Cell Line, Tumor ; Cell Survival/drug effects ; Female ; Inhibitory Concentration 50 ; Liposomes/*chemistry ; Mice ; Mice, Inbred BALB C ; Mitomycins/pharmacokinetics/*pharmacology/therapeutic use ; Molecular Structure ; Neoplasms, Experimental/*drug therapy/pathology ; Polyethylene Glycols/chemistry ; Prodrugs/pharmacokinetics/*pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Time Factors ; Treatment Outcome ; }, abstract = {PURPOSE: A lipid-based prodrug of mitomycin C [MMC; 2,3-(distearoyloxy)propane-1-dithio-4'-benzyloxycarbonyl-MMC] was designed for liposome formulation. The purpose of this study was to examine the in vitro cytotoxicity, pharmacokinetics, in vivo toxicity, and in vivo antitumor activity of this new lipid-based prodrug formulated in polyethylene glycol-coated (pegylated) liposomes.<br><br>EXPERIMENTAL DESIGN: MMC was released from the MMC lipid-based prodrug (MLP) by thiolytic-induced cleavage with a variety of thiol-containing reducing agents. MLP was incorporated with nearly 100% efficiency in cholesterol-free pegylated liposomes with hydrogenated phosphatidylcholine as the main component and a mean vesicle size of approximately 90 nm. This formulation was used for in vitro and in vivo tests in rodents.<br><br>RESULTS: In vitro, the cytotoxic activity of pegylated liposomal MLP (PL-MLP) was drastically reduced compared with free MMC. However, in the presence of reducing agents, such as cysteine or N-acetyl-cysteine, its activity increased to nearly comparable levels to those of free MMC. Intravenous administration of PL-MLP in rats resulted in a slow clearance indicating stable prodrug retention in liposomes and long circulation time kinetics, with a pharmacokinetic profile substantially different from that of free MMC. In vivo, PL-MLP was approximately 3-fold less toxic than free MMC. The therapeutic index and absolute antitumor efficacy of PL-MLP were superior to that of free MMC in the three tumor models tested. In addition, PL-MLP was significantly more active than a formulation of doxorubicin in pegylated liposomes (DOXIL) in the M109R tumor model, a mouse tumor cell line with a multidrug-resistant phenotype.<br><br>CONCLUSIONS: Delivery of MLP in pegylated liposomes is a potential approach for effective treatment of multidrug-resistant tumors while significantly buffering the toxicity of MMC.}, }
@article {pmid16551579, year = {2006}, author = {Floriano-Sánchez, E and Villanueva, C and Medina-Campos, ON and Rocha, D and Sánchez-González, DJ and Cárdenas-Rodríguez, N and Pedraza-Chaverrí, J}, title = {Nordihydroguaiaretic acid is a potent in vitro scavenger of peroxynitrite, singlet oxygen, hydroxyl radical, superoxide anion and hypochlorous acid and prevents in vivo ozone-induced tyrosine nitration in lungs.}, journal = {Free radical research}, volume = {40}, number = {5}, pages = {523-533}, doi = {10.1080/10715760500419365}, pmid = {16551579}, issn = {1071-5762}, mesh = {Animals ; Antioxidants/chemistry/pharmacology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/chemistry/*pharmacology ; Hydroxyl Radical/metabolism ; Hypochlorous Acid/metabolism ; Immunohistochemistry ; Lung/*drug effects/metabolism ; Male ; Masoprocol/chemistry/*pharmacology ; Ozone/*pharmacology ; Peroxynitrous Acid/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Singlet Oxygen/metabolism ; Superoxides/metabolism ; Tyrosine/metabolism ; }, abstract = {The antioxidant nordihydroguaiaretic acid (NDGA) has recently become well known as a putative anticancer drug. In this paper, it was evaluated the in vitro peroxynitrite (ONOO(-)), singlet oxygen ((1)O(2)), hydroxyl radical (OH(v)), hydrogen peroxide (H(2)O(2)), superoxide anion and hypochlorous acid (HOCl) scavenging capacity of NDGA. It was found that NDGA scavenges: (a) ONOO(-) (IC(50) = 4 +/- 0.94 microM) as efficiently as uric acid; (b) (1)O(2) (IC(50) = 151 +/- 20 microM) more efficiently than dimethyl thiourea, lipoic acid, N-acetyl-cysteine and glutathione; (c) OH(v) (IC(50) = 0.15 +/- 0.02 microM) more efficiently than dimethyl thiourea, uric acid, trolox, dimethyl sulfoxide and mannitol, (d) (IC(50) = 15 +/- 1 microM) more efficiently than N-acetyl-cysteine, glutathione, tempol and deferoxamine and (e) HOCl (IC(50) = 622 +/- 42 microM) as efficiently as lipoic acid and N-acetyl-cysteine. NDGA was unable to scavenge H(2)O(2). In an in vivo study in rats, NDGA was able to prevent ozone-induced tyrosine nitration in lungs. It is concluded that NDGA is a potent in vitro scavenger of ONOO(-), (1)O(2), OH(v), and HOCl and is able to prevent lung tyrosine nitration in vivo.}, }
@article {pmid16547393, year = {2006}, author = {Araya, H and Tomita, M and Hayashi, M}, title = {The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion III: the permeation mechanism of a poorly water soluble drug entrapped O/W microemulsion in rat isolated intestinal membrane by the Ussing chamber method.}, journal = {Drug metabolism and pharmacokinetics}, volume = {21}, number = {1}, pages = {45-53}, doi = {10.2133/dmpk.21.45}, pmid = {16547393}, issn = {1347-4367}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/pharmacokinetics ; Cell Membrane Permeability/drug effects ; Chemistry, Pharmaceutical ; Chromatography, High Pressure Liquid ; Diffusion Chambers, Culture ; Drug Compounding ; *Drug Delivery Systems ; Drug Design ; Emulsions ; Ibuprofen/administration &amp; dosage/pharmacokinetics ; In Vitro Techniques ; Intestinal Mucosa/*metabolism ; Male ; Mass Spectrometry ; Membranes/metabolism ; Micelles ; Mucins/metabolism ; Permeability ; Pharmaceutical Preparations/*chemistry ; Rats ; Rats, Sprague-Dawley ; Taurocholic Acid/pharmacology ; }, abstract = {We used ibuprofen as a poorly water soluble model drug, to examine the influence of bile salts and mucin layers on the permeability of that entrapped in an O/W microemulsion, in a rat isolated intestinal membrane by the Ussing chamber method. Under the presence of 3 kinds of the primary bile salts such a sodium taurocholate, etc., or a secondary bile salt such a sodium taurochenodeoxycholate at 0.01 mmol/L concentration, a significant difference was not demonstrated in the permeation clearance of the ibuprofen entrapped O/W microemulsion, as compared with the case without the bile salts. Thus, the bile salts did not have a remarkable influence on the permeability of the drug entrapped in the O/W microemulsion, and it was verified that this O/W microemulsion was hardly influenced by the flow of the bile secretion. On the other hand, when N-acetyl-L-cysteine (NAC) with the removal ability of a mucin layer was combined with the ibuprofen entrapped O/W microemulsion at the concentration of 3 and 10 mmol/L, it was shown that the permeation clearance of free ibuprofen did not decrease, but that of ibuprofen entrapped in the O/W microemulsion decreased with the increase of the NAC concentration. Therefore, it is confirmed that the mucin layer participates in the permeability of the drug entrapped in the O/W microemulsion. From these results, the mechanism in which the drug entrapped in the O/W microemulsion is released in a mucin layer, without passing through the route of the mixed micelle formation by bile, thereafter the drug permeates an intestinal membrane, is supposed.}, }
@article {pmid16546835, year = {2006}, author = {Mondo, CK and Zhang, Y and de Macedo Possamai, V and Miao, Y and Schyvens, CG and McKenzie, KU and Hu, L and Guo, Z and Whitworth, JA}, title = {N-acetylcysteine antagonizes the development but does not reverse ACTH-induced hypertension in the rat.}, journal = {Clinical and experimental hypertension (New York, N.Y. : 1993)}, volume = {28}, number = {2}, pages = {73-84}, doi = {10.1080/10641960500468219}, pmid = {16546835}, issn = {1064-1963}, mesh = {Acetylcysteine/*therapeutic use ; Adrenocorticotropic Hormone/toxicity ; Animals ; Blood Pressure/drug effects ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Hypertension/chemically induced/physiopathology/*prevention &amp; control ; Male ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome ; }, abstract = {We investigated the effect of antioxidant N-acetylcysteine (NAC) on adrenocorticotropic hormone (ACTH)-hypertension. Male Sprague-Dawley rats received NAC (10 mg/L) or water 4 days before ACTH/saline treatment for 13 days (prevention study). In a reversal study, NAC commenced on day 8 of ACTH/saline treatment and continued for 5 days. ACTH increased systolic blood pressure (SBP) in water drinking rats (111 +/- 1 to 131 +/- 3 mmHg, p < 0.001). In the prevention study, NAC + ACTH increased SBP (108 +/- 2 to 120 +/- 2 mmHg, p < 0.001) but less than ACTH alone (p' < 0.05). In the reversal study, NAC had no significant effect (132 +/- 4 to 124 +/- 3 mmHg, ns). Thus, NAC partially prevented but did not reverse ACTH-induced hypertension.}, }
@article {pmid16545586, year = {2006}, author = {Gamaley, I and Efremova, T and Kirpichnikova, K and Kever, L and Komissarchik, Y and Polozov, Y and Khaitlina, S}, title = {N-acetylcysteine-induced changes in susceptibility of transformed eukaryotic cells to bacterial invasion.}, journal = {Cell biology international}, volume = {30}, number = {4}, pages = {319-325}, doi = {10.1016/j.cellbi.2005.12.014}, pmid = {16545586}, issn = {1065-6995}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; *Cell Transformation, Neoplastic ; Cytoskeleton/drug effects/ultrastructure ; Escherichia coli/drug effects/*physiology/ultrastructure ; Eukaryotic Cells/*drug effects/*microbiology/pathology ; Fibroblasts/cytology/drug effects/ultrastructure ; Glutathione/metabolism ; Mice ; }, abstract = {The effect of N-acetylcysteine (NAC) on morphological and physiological properties of "normal" 3T3 and 3T3-SV40 fibroblasts was studied. Incubation of the cells with 10 and 20 mM NAC for 20 h resulted in a reversible increase in the intracellular level of reduced glutathione and disorganization of actin cytoskeleton. Surprisingly, upon removal of NAC, 3T3-SV40 fibroblasts demonstrated formation of well-adhered cells with structured 3T3-like stress-fibers. Neither changes in glutathione levels, nor cytoskeleton disorganization/assembly abolished resistance of 3T3 cells to invasion by the bacterium Escherichia coli A2. On the other hand, pretreatment with NAC converted bacteria-susceptible 3T3-SV40 cells into resistant ones. These results show that NAC can induce partial reversion of transformed phenotype. We suggest that this effect is due to NAC-induced modifications of cell surface proteins rather than to changes in the level of intracellular glutathione.}, }
@article {pmid16537378, year = {2006}, author = {Tirouvanziam, R and Conrad, CK and Bottiglieri, T and Herzenberg, LA and Moss, RB and Herzenberg, LA}, title = {High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {103}, number = {12}, pages = {4628-4633}, pmid = {16537378}, issn = {0027-8424}, support = {R01 CA 85949/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adolescent ; Antioxidants/metabolism ; Child ; Cystic Fibrosis/*drug therapy ; Female ; Glutathione/analysis/chemistry/*metabolism ; Humans ; Male ; Neutrophils/*drug effects ; Pancreatic Elastase/metabolism ; Pneumonia/*drug therapy ; Prodrugs/*administration &amp; dosage ; Treatment Outcome ; }, abstract = {Neutrophilic airway inflammation is a hallmark of cystic fibrosis (CF). As high oxidant producers, airway neutrophils contribute largely to the systemic redox imbalance seen in CF. In turn, this chronic and profound imbalance can impact circulating neutrophils before their migration into airways. Indeed, in 18 CF patients with stable disease, blood neutrophils were readily deficient in the pivotal antioxidant glutathione (P = 0.003, compared with 9 healthy controls). In a phase 1 study, this deficiency was improved (P = 0.025) by the glutathione prodrug N-acetylcysteine, given orally in high doses (0.6 to 1.0 g three times daily, for 4 weeks). This treatment was safe and markedly decreased sputum elastase activity (P = 0.006), the strongest predictor of CF pulmonary function. Consistently, neutrophil burden in CF airways was decreased upon treatment (P = 0.003), as was the number of airway neutrophils actively releasing elastase-rich granules (P = 0.005), as measured by flow cytometry. Pulmonary function measures were not improved, as expected with short-term treatment. After excluding data from subjects without baseline airway inflammation, positive treatment effects were more pronounced and included decreased sputum IL-8 levels (P = 0.032). Thus, high-dose oral N-acetylcysteine has the potential to counter the intertwined redox and inflammatory imbalances in CF.}, }
@article {pmid16530877, year = {2006}, author = {Ghaziani, T and Shan, Y and Lambrecht, RW and Donohue, SE and Pietschmann, T and Bartenschlager, R and Bonkovsky, HL}, title = {HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease expression of Bach1 in human hepatoma cells.}, journal = {Journal of hepatology}, volume = {45}, number = {1}, pages = {5-12}, doi = {10.1016/j.jhep.2005.12.020}, pmid = {16530877}, issn = {0168-8278}, support = {1N01 DK92326/DK/NIDDK NIH HHS/United States ; 1R01 DK38825/DK/NIDDK NIH HHS/United States ; 1U01 DK065193/DK/NIDDK NIH HHS/United States ; }, mesh = {Basic-Leucine Zipper Transcription Factors/*genetics ; Carcinoma, Hepatocellular/*enzymology/virology ; Cell Line, Tumor ; Fanconi Anemia Complementation Group Proteins/*genetics ; Gene Expression Regulation, Neoplastic ; Heme Oxygenase-1/*genetics ; Hepatitis C/complications/enzymology/*physiopathology ; Humans ; Liver Neoplasms/enzymology/virology ; Mitochondria, Liver/physiology ; Oxidative Stress ; RNA, Messenger/genetics ; Viral Proteins/*physiology ; }, abstract = {BACKGROUND/AIMS: Hepatitis C infection induces hepatic oxidative stress. Heme oxygenase (HO), the rate-controlling enzyme of heme catabolism, plays a key role as a protector against oxidative, and other stresses. Other recent work has implicated Bach1, a heme binding protein that represses gene expression, in the regulation of HO-1 gene expression.<br><br>METHODS: We investigated the effects of HCV polyprotein expression on expression of HO-1 and Bach1 genes in human hepatoma cells (Huh-7 cells).<br><br>RESULTS: HO-1 was up-regulated in the cell line expressing HCV proteins from core up to the aminoterminal domain of NS3. Addition of increasing concentrations of N-acetylcysteine (NAC) led to down-regulation of HO-1 in cells expressing HCV proteins. In contrast, Bach1 was significantly down-regulated in these cells. Sodium arsenite, a strong inducer of oxidative stress and HO-1, reduced Bach1 expression in wild type Huh-7 cells, and NAC partially abrogated this decrease.<br><br>CONCLUSIONS: Huh-7 cells expressing HCV proteins show significant up-regulation of the HO-1 gene, and reciprocal down-regulation of the Bach1 gene. Exogenous oxidative stressors and anti-oxidants can modulate expression of these genes. These and other results suggest a key role of down-regulation of Bach1 and up-regulation of HO-1 in diminishing cytotoxic effects of HCV proteins in human hepatocytes.}, }
@article {pmid16528968, year = {2006}, author = {Newman, RA and Yang, P and Hittelman, WN and Lu, T and Ho, DH and Ni, D and Chan, D and Vijjeswarapu, M and Cartwright, C and Dixon, S and Felix, E and Addington, C}, title = {Oleandrin-mediated oxidative stress in human melanoma cells.}, journal = {Journal of experimental therapeutics &amp; oncology}, volume = {5}, number = {3}, pages = {167-181}, pmid = {16528968}, issn = {1359-4117}, mesh = {Cardenolides/*pharmacology ; Cell Proliferation ; Cystine/analogs &amp; derivatives/pharmacology ; Humans ; Melanoma/drug therapy/*pathology ; Mitochondria/drug effects/physiology ; *Oxidative Stress ; Reactive Oxygen Species ; Skin Neoplasms/drug therapy/*pathology ; Tumor Cells, Cultured ; }, abstract = {While certain cardiac glycoside compounds such as oleandrin, bufalin and digitoxin are known to be associated with potent cytotoxicity to human tumor cells, the mechanisms by which this effect is produced are not clear. We now demonstrate that incubation of human malignant melanoma BRO cells with oleandrin results in a time-dependent formation of reactive oxygen species (ROS). Use of Mito-SOX and dihydroethidine dyes revealed the presence of oleandrin-mediated superoxide anions. Formation of superoxide anions correlated with a loss in cellular viability, proliferation and cellular defense mechanisms such as GSH content. Oleandrin also resulted in an unusual time-dependent mitochondrial condensation in BRO cells that could be blocked with use of N-acetyl cysteine (NAC). NAC was also shown to block ROS formation and partially prevent oleandrin-mediated loss of cellular GSH. Taken as a whole, the data suggest that exposure of human tumor cells such as BRO to oleandrin results in the formation of superoxide anion radicals that mediate mitochondrial injury and loss of cellular GSH pools. These mechanisms play a role in cardiac glycoside mediated tumor cell injury. Conversely, incubation of NAC, a precursor to GSH, largely prevents oleandrin-mediated inhibition of proliferation and mitochondria structural changes.}, }
@article {pmid16527898, year = {2006}, author = {Koptyra, M and Falinski, R and Nowicki, MO and Stoklosa, T and Majsterek, I and Nieborowska-Skorska, M and Blasiak, J and Skorski, T}, title = {BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance.}, journal = {Blood}, volume = {108}, number = {1}, pages = {319-327}, pmid = {16527898}, issn = {0006-4971}, support = {CA89052/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Benzamides ; Cell Line, Tumor ; DNA Damage ; Drug Resistance, Neoplasm/*genetics ; Fusion Proteins, bcr-abl ; Imatinib Mesylate ; Mice ; Mice, SCID ; *Mutagenesis ; Oxidation-Reduction ; Phenotype ; Piperazines/pharmacology ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/*genetics/*metabolism ; Pyrimidines/pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Mutations in the BCR/ABL kinase domain play a major role in resistance to imatinib mesylate (IM). We report here that BCR/ABL kinase stimulates reactive oxygen species (ROS), which causes oxidative DNA damage, resulting in mutations in the kinase domain. The majority of mutations involved A/T-->G/C and G/C-->A/T transitions, a phenotype detected previously in patients, which encoded clinically relevant amino acid substitutions, causing IM resistance. This effect was reduced in cells expressing BCR/ABL(Y177F) mutant, which does not elevate ROS. Inhibition of ROS in leukemia cells by the antioxidants pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine (NAC), and vitamin E (VE) decreased the mutagenesis rate and frequency of IM resistance. Simultaneous administration of IM and an antioxidant exerted better antimutagenic effect than an antioxidant alone. Therefore, inhibition of ROS should diminish mutagenesis and enhance the effectiveness of IM.}, }
@article {pmid16522657, year = {2006}, author = {Macedo, E and Abdulkader, R and Castro, I and Sobrinho, AC and Yu, L and Vieira, JM}, title = {Lack of protection of N-acetylcysteine (NAC) in acute renal failure related to elective aortic aneurysm repair-a randomized controlled trial.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {21}, number = {7}, pages = {1863-1869}, doi = {10.1093/ndt/gfl079}, pmid = {16522657}, issn = {0931-0509}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Acute Kidney Injury/*drug therapy ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aortic Aneurysm/*surgery/*therapy ; Double-Blind Method ; Female ; Free Radical Scavengers/*pharmacology ; Humans ; Ischemia/pathology ; Male ; Middle Aged ; Placebos ; Treatment Outcome ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) is an antioxidant drug largely tested in different clinical situations. Recently, NAC has been employed with variable success in the prevention of radiocontrast nephropathy. Since aortic aneurysm surgical repair is a condition that is frequently accompanied by acute renal failure (ARF), we sought to investigate whether NAC has any role in preventing ARF in this scenario.<br><br>METHODS: A randomized, placebo-controlled, double-blind trial with the following inclusion criteria: elective aortic aneurysm repair in patients with stable renal function. The groups were randomly matched for age, gender, presence of diabetes and pre-existent renal failure. NAC or placebo (control) was administered p.o. for 24 h before operation and maintained i.v. for 48 h after operation. The dose of NAC was 1200 mg b.i.d. the day before surgery and 600 mg b.i.d. after. The primary endpoint was the development of ARF up to the third post-operative day, defined as an increase in SCr > or = 25% from baseline. Secondary endpoints were: ICU mortality and ICU length of stay.<br><br>RESULTS: Forty-two patients (n = 18 for NAC group and n = 24 for control) were studied. The baseline SCr and calculated GFR did not differ between the groups (1.19 +/- 0.33 vs 1.37 +/- 0.49 mg/dl; and 64.6 +/- 26.22 vs 65.7 +/- 28.32 ml/min, NAC vs control, respectively, P = 0.17 and P = 0.90). Need for suprarenal aortic cross-clamping and its duration, occurrence of major bleeding, intra-operative hypotension and the post-operative peak of CPK did not differ between NAC and control groups. The overall incidence of ARF in the study was 36% (13/36), but it was not significantly different between groups (7/14, 50% in NAC vs 6/22, 27.3% in control, P = 0.16). The overall mortality was 23% (10/42) and was not different (P = 0.209) in NAC group (33.3%) when compared with control (16.7%), the same occurring with the length of ICU stay (2.93 +/- 1.53 vs 2.52 +/- 1.36 days, P = 0.40).<br><br>CONCLUSION: This study suggests that the putative beneficial effects of NAC on radiocontrast nephropathy might not be applicable to other situations, such as ARF associated with elective aortic aneurysm repair.}, }
@article {pmid16521697, year = {2005}, author = {Kogure, K and Manabe, S and Suzuki, I and Tokumura, A and Fukuzawa, K}, title = {Cytotoxicity of alpha-tocopheryl succinate, malonate and oxalate in normal and cancer cells in vitro and their anti-cancer effects on mouse melanoma in vivo.}, journal = {Journal of nutritional science and vitaminology}, volume = {51}, number = {6}, pages = {392-397}, doi = {10.3177/jnsv.51.392}, pmid = {16521697}, issn = {0301-4800}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Cell Death/*drug effects ; Cell Division/drug effects ; Male ; Melanoma, Experimental/*drug therapy/pathology ; Mice ; Mice, Nude ; Mitochondrial Membranes/drug effects ; Neoplasm Transplantation ; Superoxide Dismutase/pharmacology ; Tocopherols ; alpha-Tocopherol/*analogs &amp; derivatives/pharmacology ; }, abstract = {alpha-Tocopheryl succinate (TS), which is known to induce apoptosis selectively in cancer cells, has attracted attention as a chemotherapeutic agent. Recently, we found that alpha-tocopheryl malonate (TM) and alpha-tocopheryl oxalate (TO), among the alpha-tocopheryl esters tested, have high apoptogenic activity as well as TS. In this study, we investigated the characteristics of their cytotoxicity on normal cells and cancer cells in vitro, and their anti-cancer effects on mice inoculated with melanoma B16-F1 cells in vivo. The order of in vitro cytotoxicity was TO > or = TM >> TS in all cell lines examined. Addition of exogenous superoxide dismutase (SOD) and the antioxidant N-acetyl cysteine (NAC) inhibited TS- and TM- but not TO-induced cell deaths. A selective cytotoxic effect on cancer cells was observed with TS but not with TM or TO. c-Jun N-terminal kinase (JNK) inhibitor II prevented cell death induced by TS but did not prevent cell deaths induced either by TM or TO. Intravenous administration of vesiculated TS and TM to mice inoculated with melanoma B16-F1 cells prevented tumor growth and enhanced the mean survival time, but TO administration killed the mice due to its acute high toxicity. From these results, we discussed the characteristics of their selective cytotoxicity toward tumor cells in vitro and anti-cancer effects in vivo.}, }
@article {pmid16520658, year = {2006}, author = {Tang, L and Li, G and Song, L and Zhang, Y}, title = {The principal urinary metabolites of dietary isothiocyanates, N-acetylcysteine conjugates, elicit the same anti-proliferative response as their parent compounds in human bladder cancer cells.}, journal = {Anti-cancer drugs}, volume = {17}, number = {3}, pages = {297-305}, doi = {10.1097/00001813-200603000-00008}, pmid = {16520658}, issn = {0959-4973}, support = {R01 CA080962/CA/NCI NIH HHS/United States ; CA80962/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/chemistry/pharmacokinetics/*pharmacology ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Proliferation/drug effects ; Drug Screening Assays, Antitumor ; Humans ; Isothiocyanates/chemistry/pharmacokinetics/*pharmacology/urine ; Sulfoxides ; Thiocyanates/pharmacology ; Urinary Bladder Neoplasms/*drug therapy/metabolism/pathology/urine ; }, abstract = {Isothiocyanates (ITCs) are a class of well-known cancerpreventive phytochemicals, but are primarily disposed of and concentrated in the urine as N-acetylcysteine conjugates (NAC-ITCs) in vivo. Because human urinary bladder cancers occur almost exclusively in the bladder epithelium, which is directly exposed to the urine stored in the bladder, we undertook to examine the anti-cancer activity of NAC-ITCs in cultured human bladder cancer cells. In this paper, we report that the NAC conjugates of four naturally occurring ITCs, including allyl ITC, benzyl ITC (BITC), phenethyl ITC and sulforaphane, potently inhibited the growth of cells derived from both low-grade superficial and high-grade invasive human bladder cancers and drug-resistant bladder cancer cells. Moreover, the growth-inhibitory potencies were similar between the conjugates and their parent compounds. Further study of NAC-BITC and BITC as model compounds showed that both compounds accumulated in cells predominantly as the glutathione conjugate of BITC, but the accumulation of the former was slower. Moreover, both compounds also demonstrated the same anti-proliferative mechanisms: causing the cleavage of the same set of caspases (caspase-3, -8 and -9) in apoptosis induction, arresting cells in the same phases (S and G2/M) and targeting the same cell cycle regulator (Cdc25C), although a longer treatment time or slightly higher doses were needed for NAC-BITC to achieve the same effect as BITC, presumably due to slower cellular uptake of NAC-BITC. These data show that the NAC-ITCs are biologically similar to their parent compounds and are highly effective against human bladder cancer cells.}, }
@article {pmid16517958, year = {2006}, author = {Shoveller, AK and Brunton, JA and Brand, O and Pencharz, PB and Ball, RO}, title = {N-acetylcysteine is a highly available precursor for cysteine in the neonatal piglet receiving parenteral nutrition.}, journal = {JPEN. Journal of parenteral and enteral nutrition}, volume = {30}, number = {2}, pages = {133-142}, doi = {10.1177/0148607106030002133}, pmid = {16517958}, issn = {0148-6071}, mesh = {Acetylcysteine/administration &amp; dosage/*metabolism/pharmacokinetics ; Amino Acids/blood ; Animals ; Animals, Newborn/*metabolism ; Biological Availability ; Cysteine/administration &amp; dosage/*biosynthesis ; Methionine/administration &amp; dosage ; Nitrogen/metabolism/urine ; *Parenteral Nutrition ; Swine ; Weight Gain ; }, abstract = {BACKGROUND: Cysteine (CYS) is accepted as an indispensable amino acid for infants receiving parenteral nutrition (PN), and CYS is unstable in solution. Thus, developing a method to supply CYS in PN for neonates is needed. N-acetyl-L-cysteine (NAC) is stable in solution and safe for use in humans; therefore, NAC may be a means of supplying parenteral CYS.<br><br>METHODS: We determined the bioavailability of NAC in intravenously (IV)-fed piglets randomized to 1 of 4 diet treatments, each supplying 0.3 g/kg/d methionine and either 0.2 g/kg/d CYS (CON), 0 NAC (zeroNAC), 0.13 NAC (lowNAC), or 0.27 g/kg/d NAC (highNAC). Piglets (2 days old; 1.8 kg, n = 20) were surgically implanted with femoral and jugular catheters. On day 3 postsurgery, test diets were initiated and continued until day 8. Piglets were weighed daily. Blood was sampled 6 hours before test diet initiation and at 0, 6, 12, 18, 24, 36, 48, 60, 72, 84, 96, 108, and 120 hours. Urine was collected on ice in 24-hour sample periods.<br><br>RESULTS: Total mean weight gain was not different between groups; however, average daily gain in the zeroNAC and lowNAC groups declined significantly (p < .05) over the 5-day treatment period. Nitrogen retention was similar between the CON and highNAC groups, both were higher than the lowNAC group, and the zeroNAC treatment produced the lowest nitrogen retention. NAC percent retention was not different between lowNAC and highNAC and was 85.4% and 82.6%, respectively. Plasma NAC was higher in highNAC than lowNAC (p < .05).<br><br>CONCLUSIONS: These data demonstrate that NAC is available as a precursor for CYS to support growth and protein (nitrogen) accretion in piglets administered a parenteral solution.}, }
@article {pmid16516384, year = {2006}, author = {Pierce, DR and Cook, CC and Hinson, JA and Light, KE}, title = {Are oxidative mechanisms primary in ethanol induced Purkinje neuron death of the neonatal rat?.}, journal = {Neuroscience letters}, volume = {400}, number = {1-2}, pages = {130-134}, doi = {10.1016/j.neulet.2006.02.025}, pmid = {16516384}, issn = {0304-3940}, support = {P20 RR016460/RR/NCRR NIH HHS/United States ; P20 RR-16460/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Animals, Newborn ; Cell Count/methods ; Cell Death/drug effects ; Cerebellum/cytology ; Drug Interactions ; Enzyme-Linked Immunosorbent Assay/methods ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Male ; Peroxynitrous Acid/pharmacology ; Pregnancy ; Purkinje Cells/*drug effects ; Rats ; Rats, Sprague-Dawley ; Time Factors ; Tyrosine/*analogs &amp; derivatives/metabolism ; }, abstract = {Rat cerebellar Purkinje neurons are vulnerable to ethanol exposure during the brain growth spurt, especially during early postnatal exposure. A prominent hypothesis is that ethanol induces oxidative types of alterations that result in the neurodegeneration. The purpose of this study was to test this hypothesis in two ways. One was to determine if the reactive oxidative species, nitrotyrosine (NT), was produced in the cerebellum following ethanol exposure. Second, was to determine if co-administration of the clinically useful antioxidant N-acetylcysteine (NAC) afforded any protection from Purkinje neuron loss. Rat pups were treated on postnatal day 4 with a single ethanol (6.0 g/kg) or isocaloric intragastric intubation. The cerebelli were analyzed for NT with ELISA assays at 2, 4, 6, or 8 h following the single exposure. No evidence of NT was found at any of these time points. Another group of animals received ethanol exposure on PN4, or ethanol exposure plus NAC. Control groups included isocaloric intubated controls (IC), IC plus NAC, and mother reared controls. Twenty-four hours following the exposures, the pups were perfused and the cerebellum processed for cell counting. Ethanol exposure reduced the number of Purkinje neurons in the cerebellum. Concurrent treatment with antioxidant did not protect the Purkinje neurons from ethanol-related cell loss. These in vivo analyses do not support a robust oxidative mechanism involving the production of reactive nitrogen species as a significant means of Purkinje cell neurodegeneration.}, }
@article {pmid16516148, year = {2006}, author = {Dikshit, P and Goswami, A and Mishra, A and Nukina, N and Jana, NR}, title = {Curcumin enhances the polyglutamine-expanded truncated N-terminal huntingtin-induced cell death by promoting proteasomal malfunction.}, journal = {Biochemical and biophysical research communications}, volume = {342}, number = {4}, pages = {1323-1328}, doi = {10.1016/j.bbrc.2006.02.104}, pmid = {16516148}, issn = {0006-291X}, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Curcumin/*administration &amp; dosage ; Dose-Response Relationship, Drug ; Enzyme Inhibitors ; Humans ; Huntingtin Protein ; Nerve Tissue Proteins/*metabolism ; Nuclear Proteins/*metabolism ; Peptides/*metabolism ; Proteasome Endopeptidase Complex/drug effects/*metabolism ; }, abstract = {Formation of neuronal intranuclear inclusions of the disease proteins that are ubiquitinated and often associated with various proteasome components is the major hallmark of the polyglutamine diseases. Curcumin is a polyphenolic compound having anti-inflammatory, anti-tumor, and anti-oxidative properties. Recently, curcumin has been reported to suppress the amyloid-beta accumulation, oxidative damage, and inflammation in the transgenic mice model of Alzheimer's disease. Here, we found that the treatment of curcumin increases the polyglutamine-expanded truncated N-terminal huntingtin (mutant huntingtin) aggregation and mutant huntingtin-dependent cell death. Curcumin also causes rapid proteasomal malfunction in the mutant huntingtin expressing cells in comparison with normal glutamine repeat expressing cells. Finally, we show that N-acetyl cysteine (NAC), a potent antioxidant, reverted the curcumin-induced mutant huntingtin aggregation and proteasomal malfunction in the mutant huntingtin expressing cells. NAC also protects curcumin-induced cell death. Our result suggests that curcumin promotes mutant huntingtin-induced cell death by mimicking proteasomal dysfunction.}, }
@article {pmid16513190, year = {2006}, author = {Liu, Y and Zhang, Y and Liu, J and Huang, D}, title = {The role of reactive oxygen species in the herbicide acetochlor-induced DNA damage on Bufo raddei tadpole liver.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {78}, number = {1}, pages = {21-26}, doi = {10.1016/j.aquatox.2006.01.016}, pmid = {16513190}, issn = {0166-445X}, mesh = {Acetylcysteine/toxicity ; Animals ; Bufonidae/genetics/*physiology ; DNA/*drug effects ; *DNA Damage ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Herbicides/*toxicity ; Larva/drug effects/genetics ; Liver/cytology/drug effects ; Melatonin/toxicity ; Random Allocation ; Reactive Oxygen Species/analysis/*toxicity ; Statistics as Topic ; Toluidines/*toxicity ; Water Pollutants, Chemical/toxicity ; }, abstract = {After exposure of Bufo raddei tadpoles to acetochlor (ACETO) for 14 days, malondialdehyde (MDA) and DNA-single strand break (DNA-SSB) in livers were analyzed. An enhanced accumulation of MDA suggests that ACETO causes oxidative stress, and the significant increase in the level of DNA-SSB indicates that ACETO induces DNA damage in a dose-dependent manner as well. On the basis of the fact that oxidative stress is caused by excessive production of reactive oxygen species (ROS), and the present results, we speculate that ACETO-induced DNA damage may be a consequence of the generation of ROS. To evaluate this hypothesis, tadpoles were treated with ROS scavenger, N-acetyl-L-cysteine (NAC) or melatonin (MEL), prior to ACETO exposure. The decrease of DNA-SSB level and the increase of total antioxidant capability (TAC) show that ACETO-caused DNA damage can be attenuated by NAC and MEL. In addition, a negative correlation was observed between the extent of DNA damage and the level of TAC in tadpole liver. In conclusion, the results suggest that ACETO-induced DNA damage is mediated by ROS.}, }
@article {pmid16513172, year = {2006}, author = {Kaur, P and Aschner, M and Syversen, T}, title = {Glutathione modulation influences methyl mercury induced neurotoxicity in primary cell cultures of neurons and astrocytes.}, journal = {Neurotoxicology}, volume = {27}, number = {4}, pages = {492-500}, doi = {10.1016/j.neuro.2006.01.010}, pmid = {16513172}, issn = {0161-813X}, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Animals, Newborn ; Astrocytes/*drug effects ; Cell Count ; Cells, Cultured ; Cerebellum/cytology ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Ethylmaleimide/pharmacology ; Glutathione/*physiology ; *Mercury Poisoning, Nervous System/etiology/metabolism ; Methylmercury Compounds/metabolism/*toxicity ; Mice ; Mitochondria/drug effects ; Neurons/*drug effects ; Oxidoreductases/metabolism ; Reactive Oxygen Species/metabolism ; Tetrazolium Salts ; Thiazoles ; Time Factors ; }, abstract = {Methyl mercury (MeHg) is highly neurotoxic and may lead to numerous neurodegenerative disorders. In this study, we investigated the role of glutathione (GSH) and reactive oxygen species (ROS) in MeHg-induced neurotoxicity, using primary cell cultures of cerebellar neurons and astrocytes. To evaluate the effect of GSH on MeHg-induced cytotoxicity, ROS and GSH were measured using the fluorescent indicators chloro methyl derivative of di-chloro di-hydro fluorescein diacetate (CMH(2)DCFDA) and monochlorobimane (MCB). Cell-associated MeHg was measured with (14)C-radiolabeled MeHg. Mitochondrial dehydrogenase activity was detected by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. MTT timeline study was also performed to evaluate the effects of both the concentration and duration of MeHg exposure. The intracellular GSH content was modified by pretreatment with N-acetyl cysteine (NAC) or di-ethyl maleate (DEM) for 12 h. Treatment with 5 microM MeHg for 30 min led to significant (p<0.05) increase in ROS and reduction (p<0.001) in GSH content. Depletion of intracellular GSH by DEM further increased the generation of MeHg-induced ROS in both cell cultures. Conversely, NAC supplementation increased intracellular GSH and provided protection against MeHg-induced oxidative stress in both cell cultures. MTT studies also confirmed the efficacy of NAC supplementation in attenuating MeHg-induced cytotoxicity. The cell-associated MeHg was significantly (p<0.02) increased after DEM treatment. In summary, depletion of GSH increases MeHg accumulation and enhances MeHg-induced oxidative stress, and conversely, supplementation with GSH precursor protects against MeHg exposure in vitro.}, }
@article {pmid16507747, year = {2006}, author = {Tomko, RJ and Bansal, P and Lazo, JS}, title = {Airing out an antioxidant role for the tumor suppressor p53.}, journal = {Molecular interventions}, volume = {6}, number = {1}, pages = {23-5, 2}, doi = {10.1124/mi.6.1.5}, pmid = {16507747}, issn = {1534-0384}, mesh = {Animals ; Antioxidants/*metabolism ; Apoptosis ; Cell Survival ; Models, Biological ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {The tumor suppressor p53 exerts its activity by preventing DNA-damaged cells from dividing until either the chromosomal repair is effected or the cell undergoes apoptosis. Reactive oxygen species (ROS) are enhanced through the action of p53-mediated transcription of apoptosis-promoting genes; however, p53 also can promote the expression of many antioxidant genes that prevent apoptosis. New research indicates that in low cellular stress, low concentrations of p53 induce the expression of antioxidant genes, whereas in severe cellular stress, high concentrations of p53 promote the expression of genes that contribute to ROS formation and p53-mediated apoptosis. p53-depleted cells injected into athymic mice increased significantly in tumor volume, whereas injected p53(+/+) cells did not grow to the same degree. Interestingly, administration of the antioxidant compound N-acetylcysteine (NAC) inhibited the growth of tumor volume in p53-depleted injected cells, and NAC supplementation of p53(-/-) mice from birth greatly decreased the number of karyotype abnormalities and tumors formed in these mice by six months of age. Thus, under normal (or low stress) conditions, p53 appears to have an antioxidant role that protects cells from oxidative DNA damage and although this effect might depend on the concentration of p53, other cellular factors likely participate in a cell's final fate.}, }
@article {pmid16505371, year = {2006}, author = {Wang, X and Thomas, B and Sachdeva, R and Arterburn, L and Frye, L and Hatcher, PG and Cornwell, DG and Ma, J}, title = {Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {103}, number = {10}, pages = {3604-3609}, pmid = {16505371}, issn = {0027-8424}, mesh = {3T3 Cells ; Acetylcysteine/pharmacology ; Animals ; Benzoquinones/chemistry/metabolism/toxicity ; COS Cells ; Cell Line ; Chlorocebus aethiops ; Endoplasmic Reticulum/*drug effects/*metabolism ; Inactivation, Metabolic ; Mice ; Oxidative Stress/drug effects ; Quinones/chemistry/metabolism/*toxicity ; Signal Transduction ; Sulfhydryl Compounds/chemistry/metabolism ; }, abstract = {Quinones permeate our biotic environment, contributing to both homeostasis and cytotoxicity. All quinones generate reactive oxygen species through redox cycling, while partially substituted quinones also undergo arylation (Michael adduct formation) yielding covalent bonds with nucleophiles such as cysteinyl thiols. In contrast to reactive oxygen species, the role of arylation in quinone cytotoxicity is not well understood. We found that the arylating quinones, including unsubstituted 1,4-benzoquinone (1,4-BzQ) and partially substituted vitamin E congener gamma-tocopherol quinone (gamma-TQ), were cytotoxic, with gamma-TQ > 1,4-BzQ, whereas the fully substituted nonarylating vitamin E congener alpha-tocopherol quinone was not. In vitro, both arylating quinones formed Michael adducts with the thiol nucleophile N-acetylcysteine (NAC) at rates where 1,4-BzQ > gamma-TQ. In cultured cells, concurrent addition of NAC eliminated 1,4-BzQ caused toxicity, but preincubation was required for the same NAC detoxification effect on gamma-TQ. These data clearly established the role of arylation in quinone toxicity and revealed that arylating quinone structure affects cytotoxicity by governing detoxification through the rate of adduct formation. Furthermore, arylating quinones induced endoplasmic reticulum (ER) stress by activating the pancreatic ER kinase (PERK) signaling pathway including elF2alpha, ATF4, and C/EBP homologous protein (CHOP). Detoxification by NAC greatly attenuates CHOP induction in arylating quinone-treated cells, suggesting that ER stress is a cellular mechanism for arylating quinone cytotoxicity.}, }
@article {pmid16504020, year = {2006}, author = {Venketaraman, V and Rodgers, T and Linares, R and Reilly, N and Swaminathan, S and Hom, D and Millman, AC and Wallis, R and Connell, ND}, title = {Glutathione and growth inhibition of Mycobacterium tuberculosis in healthy and HIV infected subjects.}, journal = {AIDS research and therapy}, volume = {3}, number = {}, pages = {5}, pmid = {16504020}, issn = {1742-6405}, support = {R01 AI034436/AI/NIAID NIH HHS/United States ; R21 AI034436/AI/NIAID NIH HHS/United States ; R29 AI034436/AI/NIAID NIH HHS/United States ; }, abstract = {Intracellular levels of glutathione are depleted in patients with acquired immunodeficiency syndrome in whom the risk of tuberculosis, particularly disseminated disease is many times that of healthy individuals. In this study, we examined the role of glutathione in immunity against tuberculosis infection in samples derived from healthy and human immunodeficiency virus infected subjects. Our studies confirm that glutathione levels are reduced in peripheral blood mononuclear cells and in red blood cells isolated from human immunodeficiency virus-infected subjects (CD4>400/cumm). Furthermore, treatment of blood cultures from human immunodeficiency virus infected subjects with N-acetyl cysteine, a glutathione precursor, caused improved control of intracellular M. tuberculosis infection. N-acetyl cysteine treatment decreased the levels of IL-1, TNF-alpha, and IL-6, and increased the levels of IFN-gamma in blood cultures derived from human immunodeficiency virus-infected subjects, promoting the host immune responses to contain M. tuberculosis infection successfully.}, }
@article {pmid16500553, year = {2006}, author = {Leelarungrayub, N and Rattanapanone, V and Chanarat, N and Gebicki, JM}, title = {Quantitative evaluation of the antioxidant properties of garlic and shallot preparations.}, journal = {Nutrition (Burbank, Los Angeles County, Calif.)}, volume = {22}, number = {3}, pages = {266-274}, doi = {10.1016/j.nut.2005.05.010}, pmid = {16500553}, issn = {0899-9007}, mesh = {Antioxidants/analysis/chemistry/metabolism/*pharmacology ; Food Handling/*methods ; Free Radicals/*analysis/metabolism ; Garlic/*chemistry ; Humans ; In Vitro Techniques ; Lipid Peroxidation/drug effects ; Oxidation-Reduction/drug effects ; Phenols/analysis/metabolism ; Plant Extracts/analysis/chemistry/metabolism/*pharmacology ; Shallots/*chemistry ; }, abstract = {OBJECTIVE: Shallots and garlic are an important part of the diet of many populations and there is long-held belief in their health enhancing properties. This study tested whether fresh and commercial shallot and garlic preparations have antioxidant properties that might justify such claims.<br><br>METHODS: Samples produced by pressing and extraction of bulbs were tested for their ability to decrease free radicals of 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) and the results were compared with commercial preparations of aged garlic and with trolox, butylated hydroxytoluene, N-acetyl cysteine, and gallic acid. We also measured the phenolic content of the extracts and the amounts of diallyl sulfides present.<br><br>RESULTS: Antioxidant activities were directly related to the contents of phenolic compounds, with the fresh freeze-dried extracts significantly more potent than commercial preparations. Hexane-extracted shallot and garlic had the highest antioxidant activity, followed by water extracts, bulb pressings, and commercial products. Fresh shallot and garlic preparations inhibited lipid oxidation and accelerated their decomposition but had no effect on protein oxidation.<br><br>CONCLUSIONS: Organic solvent and aqueous extracts of garlic and shallot bulbs had significant antioxidant potential, as measured by decreases in free radicals and an ability to inhibit lipid oxidation.}, }
@article {pmid16496303, year = {2006}, author = {Zwingmann, C and Bilodeau, M}, title = {Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver.}, journal = {Hepatology (Baltimore, Md.)}, volume = {43}, number = {3}, pages = {454-463}, doi = {10.1002/hep.21075}, pmid = {16496303}, issn = {0270-9139}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Chemical and Drug Induced Liver Injury ; Citric Acid Cycle/drug effects/physiology ; *Cytoprotection/drug effects/physiology ; Disease Models, Animal ; Glutathione/biosynthesis ; Liver/*drug effects/*metabolism ; Liver Diseases/*metabolism ; Magnetic Resonance Spectroscopy ; Male ; Mice ; Mice, Inbred BALB C ; Mitochondria, Liver/metabolism ; Nitro Compounds ; Oxidative Stress ; Propionates ; Pyruvate Carboxylase/metabolism ; Pyruvate Dehydrogenase Complex/metabolism ; Taurine/analogs &amp; derivatives/biosynthesis ; tert-Butylhydroperoxide ; }, abstract = {The hepatoprotective mechanisms of N-acetylcysteine (NAC) in non-acetaminophen-induced liver injury have not been studied in detail. We investigated the possibility that NAC could affect key pathways of hepatocellular metabolism with or without changes in glutathione (GSH) synthesis. Hepatocellular metabolites and high-energy phosphates were quantified from mouse liver extracts by 1H- and 31P-NMR (nuclear magnetic resonance) spectroscopy. 13C-NMR-isotopomer analysis was used to measure [U-13C]glucose metabolism through pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC). NAC (150-1,200 mg/kg) increased liver concentrations of GSH from 8.60 +/- 0.48 to a maximum of 12.95 +/- 1.03 micromol/g ww, whereas hypotaurine (HTau) concentrations increased from 0.05 +/- 0.02 to 9.95 +/- 1.12 micromol/g ww. The limited capacity of NAC to increase GSH synthesis was attributed to impaired glucose metabolism through PC. However, 300 mg/kg NAC significantly increased the fractional 13C-enrichment in Glu (from 2.08% +/- 0.26% to 4.00% +/- 0.44%) synthesized through PDH, a key enzyme for mitochondrial energy metabolism. This effect could be uncoupled from GSH synthesis and was associated with the prevention of liver injury induced by tert-butylhydroperoxide and 3-nitropropionic acid. In conclusion, NAC (1) has a limited capacity to elevate GSH synthesis; (2) increases HTau formation linearly; and (3) improves mitochondrial tricarboxylic acid (TCA) cycle metabolism by stimulation of carbon flux through PDH. This latter effect is independent of the capacity of NAC to replete GSH stores. These metabolic actions, among other yet unknown effects, are critical for NAC's therapeutic value and should be taken into account when deciding on a wider use of NAC.}, }
@article {pmid16496214, year = {2006}, author = {Kamboj, A and Kiran, R and Sandhir, R}, title = {N-acetylcysteine ameliorates carbofuran-induced alterations in lipid composition and activity of membrane bound enzymes.}, journal = {Molecular and cellular biochemistry}, volume = {286}, number = {1-2}, pages = {107-114}, pmid = {16496214}, issn = {0300-8177}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Body Weight/drug effects ; Calcium-Transporting ATPases/*metabolism ; Carbofuran/*toxicity ; Cerebral Cortex/drug effects/enzymology/metabolism ; Cholesterol/metabolism ; Free Radical Scavengers/pharmacology ; Insecticides/toxicity ; Lipid Metabolism/*drug effects ; Lipid Peroxidation/drug effects ; Male ; Phospholipids/metabolism ; Rats ; Rats, Wistar ; Sodium-Potassium-Exchanging ATPase/*metabolism ; }, abstract = {The present work investigates the protective effects of N-acetylcysteine (NAC) on carbofuran-induced alterations in lipid composition and activity of membrane bound enzymes (Na+-K+-ATPase and Ca2+-ATPase) in the rat brain. Animals were exposed to carbofuran at a dose of 1 mg/kg body weight, orally, for a period of 28 days. A significant increase in lipid peroxidation in terms of TBARS was observed in brain after carbofuran exposure. NAC administration (200 mg/kg body weight) on the other hand lowered the carbofuran-induced lipid peroxidation to near normal. The increased lipid peroxidation following carbofuran exposure was accompanied by a significant decrease in the levels of total lipids, which is attributed to the reduction in phospholipid levels. Furthermore, NAC administration had a beneficial effect on carbofuran-induced alterations in lipid composition. The ratio of cholesterol to phospholipid, a major determinant of membrane fluidity, was increased in response to carbofuran exposure. This was associated with decreased activity of Na+-K+-ATPase and Ca2+-ATPase. NAC was observed to offer protection by restoring the cholesterol to phospholipid ratio along with the activity of Na+-K+-ATPase and Ca2+-ATPase. The results clearly suggest that carbofuran exerts its neurotoxic effects by increasing lipid peroxidation, altering lipid composition and activity of membrane bound enzymes. NAC administration ameliorated the effects of carbofuran suggesting its potential therapeutic effects in carbofuran neurotoxicity.}, }
@article {pmid16495022, year = {2006}, author = {Wang, YM and Peng, SQ and Zhou, Q and Wang, MW and Yan, CH and Yang, HY and Wang, GQ}, title = {Depletion of intracellular glutathione mediates butenolide-induced cytotoxicity in HepG2 cells.}, journal = {Toxicology letters}, volume = {164}, number = {3}, pages = {231-238}, doi = {10.1016/j.toxlet.2006.01.002}, pmid = {16495022}, issn = {0378-4274}, mesh = {Acetamides/*toxicity ; Cell Line, Tumor ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Furans/*toxicity ; Glutathione/*metabolism ; Humans ; Mycotoxins/*toxicity ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/pharmacology ; Time Factors ; }, abstract = {Butenolide, 4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone is one of the mycotoxins produced by Fusarium species which are often found on cereal grains and animal feeds throughout the world. It has been implicated as the etiology of some diseases both in animals and in humans. Though butenolide represents a potential threat to animal and human heath, there are few studies on its toxicity so far, especially on the toxic mechanisms. In this study, we investigated the cytotoxicity of butenolide on HepG2 cells and its possible mechanism from the viewpoint of oxidative stress. Butenolide reduced cell viability in a concentration- and time-dependent manner. A rapid depletion of intracellular glutathione (GSH) was observed after exposure cells to butenolide, concomitantly an increase in intracellular reactive oxygen species (ROS) production prior to cell death, indicating that oxidative stress was involved in butenolide cytotoxicity. To elucidate the role of GSH in the cytotoxicity of butenolide, intracellular GSH content was modulated before exposure to butenolide. l-buthionine-[S,R]-sulfoximine (BSO), a well-known inhibitor of GSH synthesis, aggravated butenolide-induced GSH depletion, ROS production and the loss in cell viability; in contrast, GSH depletion and ROS production was strongly inhibited, and the loss in cell viability was completely abrogated by thiol-containing compounds GSH, N-acetylcysteine (NAC) and dithiothreitol (DTT). Furthermore, a ROS scavenger catalase obviously abated ROS production and cytotoxicity induced by butenolide. Together, these results clearly demonstrate that oxidative stress plays an important role in butenolide cytotoxicity, and intracellular GSH depletion may be an original trigger of the onset of butenolide cytotoxicity.}, }
@article {pmid16493522, year = {2006}, author = {Kotake-Nara, E and Saida, K}, title = {Endothelin-2/vasoactive intestinal contractor: regulation of expression via reactive oxygen species induced by CoCl2, and Biological activities including neurite outgrowth in PC12 cells.}, journal = {TheScientificWorldJournal}, volume = {6}, number = {}, pages = {176-186}, doi = {10.1100/tsw.2006.37}, pmid = {16493522}, issn = {1537-744X}, mesh = {Animals ; Cobalt/*administration &amp; dosage ; Endothelin-2/*metabolism ; Gene Expression Regulation/drug effects/physiology ; Intercellular Signaling Peptides and Proteins ; Neurites/drug effects/*physiology ; Neurons/*diagnostic imaging/drug effects/*physiology ; PC12 Cells ; Peptides/*metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Ultrasonography ; }, abstract = {This paper reviews the local hormone endothelin-2 (ET-2), or vasoactive intestinal contractor (VIC), a member of the vasoconstrictor ET peptide family, where ET-2 is the human orthologous peptide of the murine VIC. While ET-2/VIC gene expression has been observed in some normal tissues, ET-2 recently has been reported to act as a tumor marker and as a hypoxia-induced autocrine survival factor in tumor cells. A recently published study reported that the hypoxic mimetic agent CoCl2 at 200 microM increased expression of the ET-2/VIC gene, decreased expression of the ET-1 gene, and induced intracellular reactive oxygen species (ROS) increase and neurite outgrowth in neuronal model PC12 cells. The ROS was generated by addition of CoCl2 to the culture medium, and the CoCl2-induced effects were completely inhibited by the antioxidant N-acetyl cysteine. Furthermore, interleukin-6 (IL-6) gene expression was up-regulated upon the differentiation induced by CoCl2. These results suggest that expression of ET-2/VIC and ET-1 mediated by CoCl2-induced ROS may be associated with neuronal differentiation through the regulation of IL-6 expression. CoCl2 acts as a pro-oxidant, as do Fe(II, III) and Cu(II). However, some biological activities have been reported for CoCl2 that have not been observed for other metal salts such as FeCl3, CuSO4, and NiCl2. The characteristic actions of CoCl2 may be associated with the differentiation of PC12 cells. Further elucidation of the mechanism of neurite outgrowth and regulation of ET-2/VIC expression by CoCl2 may lead to the development of treatments for neuronal disorders.}, }
@article {pmid16490347, year = {2006}, author = {Sleven, HJ and Gibbs, JE and Cock, HR}, title = {The antioxidant N-acetyl-L-cysteine does not prevent hippocampal glutathione loss or mitochondrial dysfunction associated with status epilepticus.}, journal = {Epilepsy research}, volume = {69}, number = {2}, pages = {165-169}, doi = {10.1016/j.eplepsyres.2006.01.006}, pmid = {16490347}, issn = {0920-1211}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Free Radical Scavengers/*therapeutic use ; Glutathione/*metabolism ; Hippocampus/*metabolism ; Male ; Mitochondria/*enzymology ; Rats ; Rats, Sprague-Dawley ; Status Epilepticus/*drug therapy/metabolism ; }, abstract = {Hippocampal reduced glutathione (GSH) levels diminish after status epilepticus (SE), which precedes damage to mitochondrial enzymes, which is associated with cell death. The rat perforant pathway stimulation model was used to assess whether intraperitoneal administration of the GSH precursor N-acetyl-L-cysteine (NAC) protected against these changes. NAC (300 mg/kg) treated animals exhibited the same GSH decrease post SE as vehicle treated. Furthermore, NAC treatment had no protective effects on mitochondrial dysfunction.}, }
@article {pmid16490171, year = {2006}, author = {Li, YQ and Zhang, ZX and Xu, YJ and Ni, W and Chen, SX and Yang, Z and Ma, D}, title = {N-Acetyl-L-cysteine and pyrrolidine dithiocarbamate inhibited nuclear factor-kappaB activation in alveolar macrophages by different mechanisms.}, journal = {Acta pharmacologica Sinica}, volume = {27}, number = {3}, pages = {339-346}, doi = {10.1111/j.1745-7254.2006.00264.x}, pmid = {16490171}, issn = {1671-4083}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Cells, Cultured ; Humans ; I-kappa B Kinase/*metabolism ; I-kappa B Proteins/metabolism ; Interleukin-1/pharmacology ; Macrophages, Alveolar/*metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B/*antagonists &amp; inhibitors ; Phosphorylation ; Pulmonary Disease, Chronic Obstructive/pathology ; Pyrrolidines/*pharmacology ; Thiocarbamates/*pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {AIM: To study the effects of N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) on the phosphorylation of IkappaB kinase (IKK) beta, IKK alpha, and IkB alpha in alveolar macrophages (AM), and to explore the pharmacological mechanisms of NAC and PDTC as inhibitors of NF-kappaB activation.<br><br>METHODS: AM were collected from bronchoalveolar lavage fluid from the patients with chronic obstructive pulmonary disease. The AM were incubated for 1.5 h with NAC and PDTC, and then stimulated for 90 min by either tumor necrosis factor (TNF)- alpha or interleukin (IL)-1. Western blotting was used to detect the protein phosphorylation levels of IKKbeta, IKK alpha, and IkappaB alpha. NF-kappaB activity was analyzed by using an electrophoretic mobility shift assay.<br><br>RESULTS: NAC inhibited the phosphorylation of IKKbeta, IKK alpha, and IkappaB alpha induced by TNF-a, but had no effect on the phosphorylation of IKKbeta, IKK alpha and IkappaB alpha induced by IL-1. PDTC did not inhibit the phosphorylation of IkappaB alpha induced by TNF- alpha or IL-1. Similarly, NAC inhibited the activation of NF-kB induced by TNF- alpha, but had no effect on the activation of NF-kappaB induced by IL-1. PDTC significantly inhibited the activation of NF-kappa B induced by TNF- alpha and IL-1. The electrophoretic mobility shift assay also showed that PDTC and NAC do not directly inhibit NF-kappa B DNA binding activity in vitro.<br><br>CONCLUSION: PDTC prevents the degradation of IkappaB alpha via the ubiquitylation-proteasome proteolytic pathway. NAC can inhibit the processes upstream of IKK activation induced by TNF- alpha, which results in the decline of NF-kappaB activity.}, }
@article {pmid16489261, year = {2005}, author = {Kurutas, EB and Cetinkaya, A and Bulbuloglu, E and Kantarceken, B}, title = {Effects of antioxidant therapy on leukocyte myeloperoxidase and Cu/Zn-superoxide dismutase and plasma malondialdehyde levels in experimental colitis.}, journal = {Mediators of inflammation}, volume = {2005}, number = {6}, pages = {390-394}, pmid = {16489261}, issn = {0962-9351}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/therapeutic use ; Carnitine/*therapeutic use ; *Colitis, Ulcerative/blood/drug therapy/enzymology ; Free Radical Scavengers/therapeutic use ; Leukocytes/*enzymology ; Male ; Malondialdehyde/*blood ; Peroxidase/*metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/*metabolism ; Vitamin B Complex/therapeutic use ; }, abstract = {The aim of the present study was to evaluate the effects of N-acetylcysteine (NAC) and L-carnitine (LCAR) supplementations on polymorphonuclear leukocytes myeloperoxidase (MPO) and Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and plasma malondialdehyde (MDA) in acetic acid (AA)-induced ulcerative colitis model. The mean polymorphonuclear leukocyte MPO and Cu/Zn-SOD activity was significantly higher in the colitis group than in the control group. Both NAC and LCAR pretreatment markedly decreased MPO and Cu/Zn-SOD activity compared to colitis group. AA administration significantly increased the levels of plasma MDA in comparison with controls. However, NAC and LCAR administration to the AA-treated rats significantly reduced the MDA levels compared to colitis group. In conclusion NAC and LCAR could be beneficial agents in restoring the circulating proinflammatory mediators.}, }
@article {pmid16487852, year = {2006}, author = {Marian, AJ and Senthil, V and Chen, SN and Lombardi, R}, title = {Antifibrotic effects of antioxidant N-acetylcysteine in a mouse model of human hypertrophic cardiomyopathy mutation.}, journal = {Journal of the American College of Cardiology}, volume = {47}, number = {4}, pages = {827-834}, pmid = {16487852}, issn = {1558-3597}, support = {P50 HL054313-080012/HL/NHLBI NIH HHS/United States ; P50 HL054313-060012/HL/NHLBI NIH HHS/United States ; P50 HL054313/HL/NHLBI NIH HHS/United States ; P50 HL054313-090012/HL/NHLBI NIH HHS/United States ; R01 HL068884-04/HL/NHLBI NIH HHS/United States ; R01 HL68884/HL/NHLBI NIH HHS/United States ; R01 HL068884-01/HL/NHLBI NIH HHS/United States ; R01 HL068884-03/HL/NHLBI NIH HHS/United States ; R01 HL068884-05/HL/NHLBI NIH HHS/United States ; R01 HL068884/HL/NHLBI NIH HHS/United States ; P50 HL054313-100012/HL/NHLBI NIH HHS/United States ; P50 HL054313-070012/HL/NHLBI NIH HHS/United States ; R01 HL068884-02/HL/NHLBI NIH HHS/United States ; P50 HL054313-08S10012/HL/NHLBI NIH HHS/United States ; P50-HL54313/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Cardiomyopathy, Hypertrophic/diagnostic imaging/*drug therapy/metabolism/pathology ; Collagen/analysis ; DNA/metabolism ; DNA, Mitochondrial/metabolism ; Echocardiography ; Fibrosis ; Gene Expression ; Heart/drug effects ; Lipid Peroxidation ; Malondialdehyde/analysis ; Matrix Metalloproteinase 1/metabolism ; Mice ; Mice, Transgenic ; Myocardium/metabolism/pathology ; Procollagen/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {OBJECTIVES: The objective was to determine the effects of antioxidant N-acetylcysteine (NAC) on reversal and attenuation of established interstitial fibrosis in the cardiac troponin T (cTnT) mouse model of human hypertrophic cardiomyopathy (HCM) mutation.<br><br>BACKGROUND: Interstitial fibrosis is a characteristic pathological feature of HCM and a risk factor for sudden cardiac death. The cTnT-Q92 transgenic mice, generated by cardiac-restricted expression of human HCM mutation, show a two- to four-fold increase in interstitial fibrosis.<br><br>METHODS: We randomized the cTnT-Q92 mice to treatment with a placebo or NAC (250, 500, or 1,000 mg/kg/day) and included non-transgenic mice as controls (N = 5 to 13 per group). We performed echocardiography before and 24 weeks after therapy, followed by histologic and molecular characterization.<br><br>RESULTS: There were no significant differences in the baseline characteristics of the groups. Treatment with NAC reduced myocardial concentrations of malondialdehyde and 4-hydroxy-2(E)-nonenal, markers of oxidative stress, by 40%. Collagen volume fractions comprised 1.94 +/- 0.76% of the myocardium in non-transgenic, 6.2 +/- 1.65% in the placebo, and 1.56 +/- 0.98% in the NAC (1,000 mg/kg/day) groups (p < 0.001). Expression levels of Col1a1 and Col1a2 were also reduced significantly, as were levels of phosphorylated but not total p44/42, p38, and c-Jun NH2-terminal kinase. Levels of oxidized mitochondrial and nuclear DNA were not significantly different.<br><br>CONCLUSIONS: Treatment with NAC reduced myocardial oxidative stress, stress-responsive signaling kinases, and fibrosis in a mouse model of HCM. The potential beneficial effects of NAC in reversal of cardiac phenotype in human HCM, the most common cause of sudden cardiac death in the young, merits investigation.}, }
@article {pmid16487264, year = {2006}, author = {Han, HJ and Heo, JS and Lee, YJ and Min, JJ and Park, KS}, title = {High glucose-induced inhibition of 2-deoxyglucose uptake is mediated by cAMP, protein kinase C, oxidative stress and mitogen-activated protein kinases in mouse embryonic stem cells.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {33}, number = {3}, pages = {211-220}, doi = {10.1111/j.1440-1681.2006.04348.x}, pmid = {16487264}, issn = {0305-1870}, mesh = {Alkaline Phosphatase/metabolism ; Animals ; Antimetabolites/antagonists &amp; inhibitors/*metabolism ; Blotting, Western ; Cell Membrane/metabolism ; Cells, Cultured ; Cyclic AMP/*physiology ; Cytosol/metabolism ; Deoxyglucose/antagonists &amp; inhibitors/*metabolism ; Fluorescent Antibody Technique ; Glucose/pharmacology ; Hydrogen Peroxide/pharmacology ; Lipid Peroxidation/drug effects ; Mice ; Mitogen-Activated Protein Kinases/*physiology ; Oxidative Stress/*physiology ; Protein Kinase C/*physiology ; RNA/biosynthesis/isolation &amp; purification ; Reactive Oxygen Species ; Stem Cells/enzymology/metabolism/*physiology ; }, abstract = {Abnormally high glucose levels may play an important role in early embryo development and function. In the present study, we investigated the effect of high glucose on 2-deoxyglucose (2-DG) uptake and its related signalling pathway in mouse embryonic stem (ES) cells. 2. 2-Deoxyglucose uptake was maximally inhibited by 25 mmol/L glucose after 24 h treatment. However, 25 mmol/L mannitol and dextran did not affect 2-DG uptake. Indeed, 25 mmol/L glucose decreased GLUT-1 mRNA and protein levels. The glucose (25 mmol/L)-induced inhibition of 2-DG uptake was blocked by pertussis toxin (a G(i)-protein inhibitor; 2 ng/mL), SQ 22,536 (an adenylate cyclase inhibitor; 10(-6) mol/L) and the protein kinase (PK) A inhibitor myristoylated PKI amide-(14-22) (10(-6) mol/L). Indeed, 25 mmol/L glucose increased intracellular cAMP content. 3. Furthermore, 25 mmol/L glucose-induced inhibition of 2-DG uptake was prevented by 10(-4) mol/L neomycin or 10(-6) mol/L U 73,122 (phospholipase C (PLC) inhibitors) and staurosporine or bisindolylmaleimide I (protein kinase (PK) C inhibitors). At 25 mmol/L, glucose increased translocation of PKC from the cytoplasmic fraction to the membrane fraction. The 25 mmol/L glucose-induced inhibition of 2-DG uptake and GLUT-1 protein levels was blocked by SQ 22,536, bisindolylmaleimide I or combined treatment. In addition, 25 mmol/L glucose increased cellular reactive oxygen species and the glucose-induced inhibition of 2-DG uptake were blocked by the anti-oxidants N-acetylcysteine (NAC; 10(-5) mol/L) or taurine (2 yen 10(-3) mol/L). 4. Glucose (25 mmol/L) activated p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK. Staurosporine (10(-6) mol/L), NAC (10(-5) mol/L) and PD 98059 (10(-7) mol/L) attenuated the phosphorylation of p44/42 MAPK. Both SB 203580 (a p38 MAPK inhibitor; 10(-7) mol/L) and PD 98059 (a p44/42 MAPK inhibitor; 10(-7) mol/L) blocked 25 mmol/L glucose-induced inhibition of 2-DG uptake. 5. In conclusion, high glucose inhibits 2-DG uptake through cAMP, PLC/PKC, oxidative stress or MAPK in mouse ES cells.}, }
@article {pmid16482631, year = {2006}, author = {Rana, SV and Attri, S and Vaiphei, K and Pal, R and Attri, A and Singh, K}, title = {Role of N-acetylcysteine in rifampicin-induced hepatic injury of young rats.}, journal = {World journal of gastroenterology}, volume = {12}, number = {2}, pages = {287-291}, pmid = {16482631}, issn = {1007-9327}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibiotics, Antitubercular/*toxicity ; Catalase/metabolism ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation/drug effects ; Liver/*drug effects/metabolism/pathology ; Male ; Rats ; Rats, Wistar ; Rifampin/*toxicity ; Superoxide Dismutase/metabolism ; }, abstract = {AIM: To study the role of N-acetylcysteine (NAC) as a protective agent in rifampicin (RMP)-induced oxidative hepatic injury of young rats.<br><br>METHODS: Hepatic injury was produced by giving 50 mg/kg body weight/day of RMP for 3 wk. A dose of NAC (100 mg/kg body weight/day) was given in combination with RMP intraperitoneally. Analysis of lipid peroxidation, thiol levels, cytochrome P450, superoxide dismutase (SOD), catalase, glutathione peroxidase, reductase and transferase were estimated in liver along with the body weight, liver weight and histological observations.<br><br>RESULTS: RMP exposure resulted in no change in body and liver weight while antioxidative enzymes were altered but the non protein thiol (GSH) status was well preserved. Cytochrome P450 system and peroxidation of lipids were induced by RMP exposure. Partial protection was observed with NAC against RMP-induced changes in liver, which was evidenced from the prevention of increase in lipid peroxidation and the reduction in SOD and catalase enzyme levels.<br><br>CONCLUSION: NAC protects young rats against RMP-induced oxidative hepatic injury.}, }
@article {pmid16482627, year = {2006}, author = {Eşrefoğlu, M and Gül, M and Ates, B and Batçioğlu, K and Selimoğlu, MA}, title = {Antioxidative effect of melatonin, ascorbic acid and N-acetylcysteine on caerulein-induced pancreatitis and associated liver injury in rats.}, journal = {World journal of gastroenterology}, volume = {12}, number = {2}, pages = {259-264}, pmid = {16482627}, issn = {1007-9327}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Ceruletide/*toxicity ; Female ; Lipid Peroxidation/drug effects ; Liver/drug effects/*pathology ; Melatonin/*pharmacology ; Pancreatitis/chemically induced/*drug therapy/metabolism/pathology ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; }, abstract = {AIM: To investigate the role of oxidative injury in pancreatitis-induced hepatic damage and the effect of antioxidant agents such as melatonin, ascorbic acid and N-acetyl cysteine on caerulein-induced pancreatitis and associated liver injury in rats.<br><br>METHODS: Thirty-eight female Wistar rats were used. Acute pancreatitis (AP) was induced by two i.p. injections of caerulein at 2-h intervals (at a total dose of 100 microg/kg b.wt). The other two groups received additional melatonin (20 mg/kg b.wt) or an antioxidant mixture containing L(+)-ascorbic acid (14.3 mg/kb.wt.) and N-acetyl cysteine (181 mg/kg b.wt.) i.p. shortly before each injection of caerulein. The rats were sacrificed by decapitation 12 h after the last injection of caerulein. Pancreatic and hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides measured as malondialdehyde (MDA) and changes in tissue antioxidant enzyme levels, catalase (CAT) and glutathione peroxidase (GPx). Histopathological examination was performed using scoring systems.<br><br>RESULTS: The degree of hepatic cell degeneration, intracellular vacuolization, vascular congestion, sinusoidal dilatation and inflammatory infiltration showed a significant difference between caerulein and caerulein + melatonin (P = 0.001), and careulein and caerulein + L(+)-ascorbic acid + N-acetyl cysteine groups (P = 0.002). The degree of aciner cell degeneration, pancreatic edema, intracellular vacuolization and inflammatory infiltration showed a significant difference between caerulein and caerulein + melatonin (P = 0.004), and careulein and caerulein + L(+)-ascorbic acid + N-acetyl cysteine groups (P = 0.002). Caerulein-induced pancreatic and liver damage was accompanied with a significant increase in tissue MDA levels (P = 0.01, P = 0.003, respectively) whereas a significant decrease in CAT (P = 0.002, P = 0.003, respectively) and GPx activities (P = 0.002, P = 0.03, respectively). Melatonin and L(+)-ascorbic acid+N-acetyl cysteine administration significantly decreased MDA levels in pancreas (P=0.03, P=0.002, respectively) and liver (P = 0.007, P = 0.01, respectively). Administration of these agents increased pancreatic and hepatic CAT and GPx activities. Melatonin significantly increased pancreatic and hepatic CAT (P = 0.002, P = 0.001, respectively) and GPx activities (P = 0.002, P = 0.001). Additionally, L(+)-ascorbic acid + N-acetyl cysteine significantly increased pancreatic GPx (P = 0.002) and hepatic CAT and GPx activities (P = 0.001, P = 0.007, respectively).<br><br>CONCLUSION: Oxidative injury plays an important role not only in the pathogenesis of AP but also in pancreatitis-induced hepatic damage. Antioxidant agents such as melatonin and ascorbic acid + N-acetyl cysteine, are capable of limiting pancreatic and hepatic damage produced during AP via restoring tissue antioxidant enzyme activities.}, }
@article {pmid16480687, year = {2006}, author = {Sato, H and Takahashi, M and Ise, H and Yamada, A and Hirose, S and Tagawa, Y and Morimoto, H and Izawa, A and Ikeda, U}, title = {Collagen synthesis is required for ascorbic acid-enhanced differentiation of mouse embryonic stem cells into cardiomyocytes.}, journal = {Biochemical and biophysical research communications}, volume = {342}, number = {1}, pages = {107-112}, doi = {10.1016/j.bbrc.2006.01.116}, pmid = {16480687}, issn = {0006-291X}, mesh = {Animals ; Antioxidants/pharmacology ; Ascorbic Acid/*analogs &amp; derivatives/pharmacology ; Biomarkers ; Cell Differentiation/*drug effects ; Cell Line ; Collagen/antagonists &amp; inhibitors/*biosynthesis ; Gene Expression Regulation/drug effects ; Heart/drug effects/embryology ; Mice ; Myocytes, Cardiac/*cytology/*drug effects/metabolism ; RNA, Messenger/drug effects ; Stem Cells/*cytology/*drug effects/metabolism ; }, abstract = {Ascorbic acid has been reported to promote the differentiation of embryonic stem (ES) cells into cardiomyocytes; however, the specific functions of ascorbic acid have not been defined. A stable form of ascorbic acid, namely, l-ascorbic acid 2-phosphate (A2-P), significantly enhanced cardiac differentiation; this was assessed by spontaneous beating of cardiomyocytes and expression of cardiac-specific markers obtained from mouse ES cells. This effect of ascorbic acid was observed only when A2-P was present during the early phase of differentiation. Treatment with two types of collagen synthesis inhibitors, l-2-azetidine carboxylic acid and cis-4-hydroxy-d-proline, significantly inhibited the A2-P-enhanced cardiac differentiation, whereas treatment with the antioxidant N-acetyl cysteine showed no effect. These findings demonstrated that ascorbic acid enhances differentiation of ES cells into cardiomyocytes through collagen synthesis and suggest its potential in the modification of cardiac differentiation of ES cells.}, }
@article {pmid16473382, year = {2006}, author = {Deshpande, VS and Kehrer, JP}, title = {Oxidative stress-driven mechanisms of nordihydroguaiaretic acid-induced apoptosis in FL5.12 cells.}, journal = {Toxicology and applied pharmacology}, volume = {214}, number = {3}, pages = {230-236}, doi = {10.1016/j.taap.2005.12.011}, pmid = {16473382}, issn = {0041-008X}, support = {CA83701/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; B-Lymphocytes/*drug effects/enzymology/metabolism ; Caspase 3 ; Caspases/metabolism ; Cell Line ; Cytochromes c/metabolism ; Dithiothreitol/pharmacology ; Electrophoresis, Polyacrylamide Gel ; Enzyme Inhibitors/pharmacology ; Lipoxygenase Inhibitors/*pharmacology ; Masoprocol/*pharmacology ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Oxidative Stress/*drug effects ; Phosphorylation ; }, abstract = {Nordihydroguaiaretic acid (NDGA), a general lipoxygenase (LOX) enzyme inhibitor, induces apoptosis independently of its activity as a LOX inhibitor in murine pro-B lymphocytes (FL.12 cells) by a mechanism that is still not fully understood. Glutathione depletion, oxidative processes and mitochondrial depolarization appear to contribute to the apoptosis induced by NDGA. The current data demonstrate that NDGA (20 microM)-induced apoptosis in FL5.12 cells is partially protected by N-acetylcysteine (NAC) (10 mM) and dithiothreitol (DTT) (500 microM) pretreatment, confirming a role for oxidative processes. In addition, the treatment of FL5.12 cells with NDGA led to an increase in phosphorylation and activation of the MAP kinases ERK, JNK and p38. Although pretreatment with ERK inhibitors (PD98059 or U0126) abolished ERK phosphorylation in response to NDGA, neither inhibitor had any effect on NDGA-induced apoptosis. SP600125, a JNK inhibitor, did not have any effect on NDGA-induced phosphorylation of JNK nor apoptosis. Pretreatment with the p38 inhibitor SB202190 attenuated NDGA-induced apoptosis by 30% and also abolished p38 phosphorylation, compared to NDGA treatment alone. NAC, but not DTT, also decreased the phosphorylation of p38 and JNK supporting a role for oxidative processes in activating these kinases. Neither NAC nor DTT blocked the phosphorylation of ERK suggesting that this activation is not related to oxidative stress. The release of cytochrome c and activation of caspase-3 induced by NDGA were inhibited by NAC. SB202190 slightly attenuated caspase-3 activation and had no effect on the release of cytochrome c. These data suggest that several independent mechanisms, including oxidative reactions, activation of p38 kinase and cytochrome c release contribute to NDGA-induced apoptosis.}, }
@article {pmid16469755, year = {2006}, author = {Last, K and Maharaj, L and Perry, J and Strauss, S and Fitzgibbon, J and Lister, TA and Joel, S}, title = {The activity of methylated and non-methylated selenium species in lymphoma cell lines and primary tumours.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {17}, number = {5}, pages = {773-779}, doi = {10.1093/annonc/mdl004}, pmid = {16469755}, issn = {0923-7534}, mesh = {Apoptosis/*drug effects ; Chronic Disease ; Flow Cytometry ; Glutathione/*analogs &amp; derivatives/pharmacology ; Humans ; Lymphoma, B-Cell/*pathology ; Lymphoma, Large B-Cell, Diffuse/*pathology ; *Methylation ; Organoselenium Compounds/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND: Diffuse large B-cell lymphoma patients with low serum selenium concentration at presentation have a lower response rate and overall survival than patients with higher serum selenium. The co-administration of selenium with conventional chemotherapy may be useful in these patients.<br><br>PATIENTS AND METHODS: We investigated the activity of two selenium species, methylseleninic acid (MSA) and selenodiglutathione (SDG) in a panel of human lymphoma cell lines and in a primary lymphoma culture system.<br><br>RESULTS: Both compounds demonstrated cytostatic and cytotoxic activity with EC(50) values in the range 1.0-10.2 microM. Cell death was associated with an increase in the sub-G1 (apoptotic) fraction by flow cytometry and was not preceded by any obvious cell cycle arrest. SDG, but not MSA, resulted in marked increases in intracellular ROS, particularly in CRL2261 and SUD4 cells in which the cytotoxic activity of SDG was partly, or completely, inhibited by n-acetyl cysteine, suggesting a dependence on ROS for activity in some cells. Both MSA and SDG showed a concentration dependent reduction in percentage viability after a 2-day exposure in primary lymphoma cultures, with EC(50) values in the range 39-300 microM and 9-28 microM, respectively.<br><br>CONCLUSION: The selenium compounds MSA and SDG induce cell death in lymphoma cell lines and primary lymphoma cultures, which with SDG may be partly attributable to the generation of ROS.}, }
@article {pmid16467130, year = {2006}, author = {Samikkannu, T and Thomas, JJ and Bhat, GJ and Wittman, V and Thekkumkara, TJ}, title = {Acute effect of high glucose on long-term cell growth: a role for transient glucose increase in proximal tubule cell injury.}, journal = {American journal of physiology. Renal physiology}, volume = {291}, number = {1}, pages = {F162-75}, doi = {10.1152/ajprenal.00189.2005}, pmid = {16467130}, issn = {1931-857X}, support = {HL-61356/HL/NHLBI NIH HHS/United States ; }, mesh = {Apoptosis/*physiology ; Cell Line ; *Cell Proliferation ; Diabetic Nephropathies/physiopathology ; Dose-Response Relationship, Drug ; Glucose/*physiology ; Humans ; Kidney Tubules, Proximal/chemistry/*cytology/drug effects ; Mitogen-Activated Protein Kinase 1/analysis/physiology ; Mitogen-Activated Protein Kinase 3/analysis/physiology ; NF-kappa B/analysis/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/physiology ; Time Factors ; }, abstract = {Although chronic exposure of renal cells to high glucose has been shown to cause cell injury, the effect of acute exposure has not been elucidated. In this study, we demonstrate that acute (10 min) exposure of human proximal tubule epithelial cells (hPTEC) to high glucose (25 mM) induces a time-dependent dual effect consisting of an early proliferation and a late apoptosis. Acute exposure of hPTEC to high glucose induced a twofold increase in DNA synthesis and cell number at 12 h. However, after 36 h, a significant decrease in cell growth is observed, followed by apoptosis. On glucose treatment, both p42/p44 mitogen-activated protein (MAP) kinases and the downstream signaling intermediate NF-kappaB were phosphorylated and translocated to the nucleus. Pretreatment of cells with MAP kinase and NF-kappaB-specific inhibitors abolished glucose-induced proliferation. However, these inhibitors were ineffective in preventing glucose-induced apoptosis. Interestingly, conditioned medium from cells exposed to high-glucose concentrations inhibited proliferation and concomitantly induced apoptosis in normal cells, suggesting that the inhibitory effect of glucose occurs through secretion of a secondary factor(s). In parallel to apoptosis, we observed an increased production of reactive oxygen species (ROS). Pretreatment of cells with the antioxidant N-acetyl cysteine reversed glucose-mediated ROS production and apoptosis, suggesting that ROS is involved in apoptosis. Our study demonstrates for the first time that a single high-glucose exposure for 10 min alone is sufficient to elicit proliferation and apoptosis in hPTEC and suggests that episodes of transient increase in glucose may contribute to cell damage leading to epithelial cell dysfunction.}, }
@article {pmid16465294, year = {1997}, author = {Franceschi, C and Franceschini, MG and Boschini, A and Trenti, T and Nuzzo, C and Castellani, G and Smacchia, C and De Rienzo, B and Roncaglia, R and Portolani, M and Pietrosemoli, P and Meacci, M and Pecorari, M and Sabbatini, A and Malorni, W and Cossarizza, A}, title = {Phenotypic characteristics and tendency to apoptosis of peripheral blood mononuclear cells from HIV+ long term non progressors.}, journal = {Cell death and differentiation}, volume = {4}, number = {8}, pages = {815-823}, doi = {10.1038/sj.cdd.4400305}, pmid = {16465294}, issn = {1350-9047}, abstract = {The aim of this study was to analyze (i) phenotype, (ii) in vitro spontaneous and induced apoptosis, (iii) glutathione (GSH) intracellular content and (iv) inhibitors of apoptosis of potential therapeutical use in peripheral blood mononuclear cells (PBMC) from HIV+ long term non progressors (LTNP), in comparison with progressors (HIV+P) and seronegative controls (HIV-). Three groups of subjects were studied: 15 HIV+P (patients losing >150 CD4+/year), 9 LTNP (subjects infected by HIV for at least 7 years without clinical and immunological signs of progression, with a mean of 898 CD4+/microL) and 18 HIV-. All subjects were living in a large community for former drug addicts, and were matched for age and sex. We used flow cytometry for analyzing PBMC phenotype and apoptosis; high performance liquid chromatography for measuring intracellular GSH content. PBMC phenotype of LTNP shared characteristics with those of both HIV- and HIV+P. Indeed, LTNP showed a normal number CD4+ cells (an inclusion criteria), but significantly increased numbers of CD8+ lymphocytes, activated T cells, CD19+, CD5+ B lymphocytes and CD57+ cells, as well as a decrease in CD19+, CD5- B lymphocytes and CD16+ cells. In LTNP, spontaneous apoptosis was similar to that of HIV- and significantly lower than that of HIV+P. Adding interleukin-2 (IL-2) or nicotinamide (NAM) significantly decreased spontaneous apoptosis in LTNP and HIV+P. Pokeweed mitogen-induced apoptosis was also similar in LTNP and HIV-, but significantly lower than that of HIV+P. In HIV+P, but also in LTNP, spontaneous apoptosis was inversely correlated to the absolute number and percentage of CD4+ cells and directly correlated to the number and percentage of activated T cells present in peripheral blood. GSH intracellular content was greatly decreased in PBMC from HIV+P and slightly, but significantly, reduced in LTNP. Adding 2-deoxy-D-ribose, an agent provoking apoptosis through GSH depletion, to quiescent PBMC resulted in similar levels of massive cell death in the three groups. This phenomenon was equally prevented in the three groups by N-acetyl-cysteine but not by IL-2. A complex immunological situation seems to occur in LTNP. Indeed, PBMC from LTNP are characterized by a normal in vitro tendency to undergo apoptosis despite the presence of a strong activation of their immune system, unexpectedly similar to that of HIV+P. Our data suggest that NAM and IL-2 are possible candidates for reducing spontaneous apoptosis in HIV infection.}, }
@article {pmid16464909, year = {2006}, author = {Khaldi, MZ and Elouil, H and Guiot, Y and Henquin, JC and Jonas, JC}, title = {Antioxidants N-acetyl-L-cysteine and manganese(III)tetrakis (4-benzoic acid)porphyrin do not prevent beta-cell dysfunction in rat islets cultured in high glucose for 1 wk.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {291}, number = {1}, pages = {E137-46}, doi = {10.1152/ajpendo.00145.2005}, pmid = {16464909}, issn = {0193-1849}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/metabolism ; Free Radical Scavengers/*pharmacology ; Glucose/*administration &amp; dosage/antagonists &amp; inhibitors/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Histocytochemistry ; Hydrogen Peroxide/antagonists &amp; inhibitors/metabolism ; Insulin/metabolism ; Insulin-Secreting Cells/*drug effects/metabolism ; Male ; Membrane Potentials/drug effects/physiology ; Metalloporphyrins/*pharmacology ; Microscopy, Phase-Contrast ; Proinsulin/genetics/metabolism ; Protein Precursors/genetics/metabolism ; RNA, Messenger/biosynthesis/genetics ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {We previously showed that the stimulation of heme oxygenase-1 expression by high glucose and hydrogen peroxide (H(2)O(2)) in cultured rat islets is prevented by antioxidants and suggested that this effect of high glucose results from an oxidative stress. However, the role of oxidative stress in high-glucose-induced beta-cell dysfunction is unclear. We therefore compared the preventative effects of N-acetyl-l-cysteine (NAC), a free radical scavenger, and manganese(III)tetrakis (4-benzoic acid)porphyrin (MnTBAP), a superoxide dismutase/catalase mimetic agent, on the alteration of stimulus-secretion coupling induced in rat islets by overnight exposure to hydrogen peroxide (H(2)O(2)-treated islets) or 1-wk culture in 30 vs. 10 mmol/l glucose (High-glucose vs. Control islets). The features of beta-cell dysfunction differed between the two groups: reduced glucose-induced insulin secretion without changes in glucose sensitivity in H(2)O(2)-treated islets; increased sensitivity to glucose with parallel reductions in insulin content and maximal rate of glucose-induced insulin secretion in High-glucose islets. The latter alterations were accompanied by a decrease in preproinsulin without changes in pancreatic and duodenal homeobox gene 1 mRNA levels. The functional alterations induced by H(2)O(2) were significantly prevented by addition of NAC or MnTBAP in the culture medium. In contrast, neither NAC nor MnTBAP affected the functional alterations induced by high glucose. These results suggest that beta-cell dysfunction induced by 1-wk culture in high glucose does not result from an increase in oxidative stress.}, }
@article {pmid16463896, year = {2005}, author = {Thomale, UW and Griebenow, M and Kroppenstedt, SN and Unterberg, AW and Stover, JF}, title = {The antioxidant effect of N-acethylcysteine on experimental contusion in rats.}, journal = {Acta neurochirurgica. Supplement}, volume = {95}, number = {}, pages = {429-431}, doi = {10.1007/3-211-32318-x_88}, pmid = {16463896}, issn = {0065-1419}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/administration &amp; dosage ; Brain Edema/etiology/*physiopathology/*prevention &amp; control ; Brain Injuries/complications/*drug therapy/*physiopathology ; *Disease Models, Animal ; Injections, Intraperitoneal ; Intracranial Pressure/*drug effects ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome ; }, abstract = {N-acethylcysteine (NAC) is known to have direct and indirect antioxidant abilities. We investigated the potential protective effect of NAC on ICP, brain edema and contusion volume after Controlled Cortical Impact (CCI) injury. A moderate CCI injury was induced on the left hemisphere in 48 Sprague Dawley rats. The animals were treated with intraperitoneal injection of NAC (163 mg/kg/KG) or physiological saline. Measurements of intracranial pressure (ICP) were performed and brains were removed at 24 hours. Gravimetric analysis of post-traumatic edema and morphometric measurements (TTC staining) of contusion volume were carried out in 24 animals, respectively. ICP measurements increased significantly over time with no significant differences between both groups. The relative difference in water content in NAC treated animals (1.45 +/- 0.1%) did not differ significantly versus placebo (1.47 +/- 0.2%). The contusion volume was diminished by 19% in the NAC group (53.52 +/- 5.3 mm3) versus placebo (66.28 +/- 4.7 mm3) without showing statistical significance. The antioxidant properties of NAC did not affect intracranial pressure or posttraumatic brain edema formation, although the moderate reduction of contusion volume might reveal beneficial effects on focal contusion.}, }
@article {pmid16458553, year = {2007}, author = {Sadowska, AM and Manuel-Y-Keenoy, B and De Backer, WA}, title = {Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {20}, number = {1}, pages = {9-22}, doi = {10.1016/j.pupt.2005.12.007}, pmid = {16458553}, issn = {1094-5539}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Dose-Response Relationship, Drug ; Humans ; Models, Biological ; Pulmonary Disease, Chronic Obstructive/*drug therapy/metabolism ; }, abstract = {In order to develop efficient therapeutic regimes for chronic obstructive pulmonary disease (COPD), N-acetylcysteine (NAC) has been tested as a medication which can suppress various pathogenic processes in this disease. Besides its well-known and efficient mucolytic action, NAC meets these needs by virtue of its antioxidant and anti-inflammatory modes of action. NAC is a thiol compound which by providing sulfhydryl groups, can act both as a precursor of reduced glutathione and as a direct ROS scavenger, hence regulating the redox status in the cells. In this way it can interfere with several signaling pathways that play a role in regulating apoptosis, angiogenesis, cell growth and arrest and inflammatory response. Overall, the antioxidant effects of NAC are well documented in in vivo and in vitro studies. It successfully inhibits oxidative stress at both high and low concentrations, under acute (in vitro) and chronic administration (in vivo). With regard to its anti-inflammatory action, in contrast, the effects of NAC differ in vivo and in vitro and are highly dose-dependent. In the in vitro settings anti-inflammatory effects are seen at high but not at low concentrations. On the other hand, some long-term effectiveness is reported in several in vivo studies even at low dosages. Increasing the dose seems to improve NAC bioavailability and may also consolidate some of its effects. In this way, the effects that are observed in the clinical and in vivo studies do not always reflect the success of the in vitro experiments. Furthermore, the results obtained with healthy volunteers do not always provide incontrovertible proof of its usefulness in COPD especially when number of exacerbations and changes in lung function are chosen as the primary outcomes. Despite these considerations and in view of the present lack of effective therapies to inhibit disease progression in COPD, NAC and its derivatives, because of their multiple molecular modes of action, remain promising medication once doses and route of administration are optimized.}, }
@article {pmid16456238, year = {2006}, author = {Das, S and Engelman, RM and Maulik, N and Das, DK}, title = {Angiotensin preconditioning of the heart: evidence for redox signaling.}, journal = {Cell biochemistry and biophysics}, volume = {44}, number = {1}, pages = {103-110}, doi = {10.1385/CBB:44:1:103}, pmid = {16456238}, issn = {1085-9195}, support = {HL 22559/HL/NHLBI NIH HHS/United States ; HL 33889/HL/NHLBI NIH HHS/United States ; HL 34360/HL/NHLBI NIH HHS/United States ; HL 56803/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Angiotensin II/*pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Gene Expression/drug effects ; Heart/drug effects ; Heart Rate/drug effects ; In Vitro Techniques ; *Ischemic Preconditioning, Myocardial ; Male ; Membrane Glycoproteins/genetics ; Membrane Transport Proteins/genetics ; Myocardial Infarction/etiology/metabolism/pathology ; Myocardial Reperfusion Injury/complications ; Myocardium/metabolism ; Myocytes, Cardiac/drug effects/metabolism ; NADPH Oxidase 2 ; NADPH Oxidases/genetics ; Oxidation-Reduction ; Perfusion ; Phosphoproteins/genetics ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*drug effects/physiology ; Ventricular Function, Left/drug effects ; Ventricular Remodeling/drug effects ; }, abstract = {Angiotensin II (Ang II) has been found to exert preconditioning-like effect on mammalian hearts. Diverse mechanisms are known to exist to explain the cardioprotective abilities of Ang II preconditioning. The present study hypothesized, based on the recent report that Ang II generates reactive oxygen species (ROS) through NADPH oxidase, that Ang II preconditioning occurs through redox cycling. To test this hypothesis, a group of rat hearts was treated with Ang II in the absence or presence of an NADPH oxidase inhibitor, apocynin; or a cell-permeable ROS scavenger, N-acetyl cysteine (NAC). Ang II pretreatment improved postischemic ventricular recovery; reduced myocardial infarction; and decreased the number of cardiomyocyte apoptosis, indicating its ability to precondition the heart against ischemic injury. Both apocynin and NAC almost abolished the preconditioning ability of Ang II. Ang II resulted in increase in ROS activity in the heart, which was reduced by either NAC or apocynin. Ang II also increased both the NADPH oxidase subunits gp91 phox and p22phox mRNA expression, which was abolished with apocynin and NAC. Our results thus demonstrate that the Ang II preconditioning was associated with enhanced ROS activities and increased NADPH oxidase subunits p22phox and gp91phox expression. Both NAC and apocynin reduced ROS activities simultaneously abolishing preconditioning ability of Ang II, suggesting that Ang II preconditioning occurs through redox cycling. That both NAC and apocynin reduced ROS activities and abolished Ang II-mediated increase in p22phox and gp91phox activity further suggest that such redox cycling occurs via both NADPH oxidase-dependent and -independent pathways.}, }
@article {pmid16455839, year = {2006}, author = {Bayram, H and Ito, K and Issa, R and Ito, M and Sukkar, M and Chung, KF}, title = {Regulation of human lung epithelial cell numbers by diesel exhaust particles.}, journal = {The European respiratory journal}, volume = {27}, number = {4}, pages = {705-713}, doi = {10.1183/09031936.06.00012805}, pmid = {16455839}, issn = {0903-1936}, mesh = {Apoptosis/*physiology ; Cell Count ; Cell Cycle/physiology ; Cell Division/*physiology ; Cyclin E/metabolism ; Cyclin-Dependent Kinase 2/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Epithelial Cells/*physiology ; Gene Expression ; Humans ; NF-kappa B/physiology ; Oxidative Stress/physiology ; Particle Size ; Pneumonia/*physiopathology ; RNA, Messenger/genetics ; Respiratory Mucosa/*physiology ; Vehicle Emissions/*toxicity ; }, abstract = {Particulate air pollution is associated with respiratory morbidity and has cytotoxic and pro-inflammatory effects. The effects of diesel exhaust particles (DEP) on proliferation and apoptosis of A549 lung epithelial cells were examined. When deprived of serum (serum starvation), epithelial cell numbers fell, but DEP (5-200 microg.mL-1) prevented this. Using flow cytometric analysis of propidium iodide (PI) staining, DEP (10 microg.mL-1) increased cells in the S phase of cell cycle from 12.85 to 18.75% after 48 h, reversing serum starvation-induced G0/1 arrest. DEP also reduced the increase in apoptotic cells, as defined by double expression of annexin V/PI, observed after serum starvation (from 28.35 to 15.46%). The antioxidants, N-acetylcysteine (NAC; 33 mM) and AEOL10113 (10-100 microM), the N-terminal c-jun kinase inhibitor, SP600125 (33 microM), and nuclear factor-kappaB inhibitor, SN50 (33 microM), inhibited DEP-induced cell number increase. NAC inhibited DEP-induced reduction of G0/1 and increase in cells in the S and G2/M phases. Expression of p21CIP1/WAF1 mRNA and protein seen with serum starvation was reduced by DEP. In conclusion, diesel exhaust particles prevented serum starvation-led decreases in A549 epithelial cells by inducing cell cycle progression and preventing apoptosis, processes involving oxidative stress, inhibition of p21CIP1/WAF1 expression and stimulation of N-terminal c-jun kinase and nuclear factor-kappaB. Therefore, low-dose diesel exhaust particle exposure may lead to lung epithelial cell hyperplasia.}, }
@article {pmid16452059, year = {2006}, author = {Yenicerioglu, Y and Yilmaz, O and Sarioglu, S and Ormen, M and Akan, P and Celik, A and Camsari, T}, title = {Effects of N-acetylcysteine on radiocontrast nephropathy in rats.}, journal = {Scandinavian journal of urology and nephrology}, volume = {40}, number = {1}, pages = {63-69}, doi = {10.1080/00365590500329445}, pmid = {16452059}, issn = {0036-5599}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Animals ; Contrast Media/adverse effects ; Disease Models, Animal ; Female ; Glomerular Filtration Rate ; Kidney Function Tests ; Kidney Tubules/*drug effects/pathology ; Probability ; Radiopharmaceuticals/*adverse effects ; Random Allocation ; Rats ; Rats, Wistar ; Reference Values ; Risk Factors ; Sensitivity and Specificity ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC) has yielded some promising results recently in the prevention of radiocontrast nephropathy (RCN). In this study, the structural and functional effects of NAC on RCN were analyzed.<br><br>MATERIAL AND METHODS: Twenty-eight Wistar rats were randomized into four groups, as follows: Group 1, controls; Group 2, contrast; Group 3, contrast+NAC; and Group 4, NAC. All rats were deprived of water for 24 h and then contrast medium (ioxoglate; 10 ml/kg) was administered to Groups 2 and 3. NAC (50 mg/kg) was introduced enterally to Groups 3 and 4 at a dose of 50 mg/kg in 0.5 ml of distilled water, in four sequential doses 12h apart, starting after 12?h of water deprivation. After 4 days, rats were sacrificed. Creatinine clearance was calculated. The malondialdehyde (MDA) level was quantified in tissue samples. Slides stained with hematoxylin-eosin and periodic acid-Schiff were examined by means of light microscopy. Each tubular cross-section from all images was scored as either mild (preserved brush border, no necrosis), moderate (loss of brush border, no necrosis) or severe (loss of brush border accompanied by necrosis) and the frequencies of these lesion severities were compared.<br><br>RESULTS: Mean baseline serum creatinine levels and creatinine clearances were similar in all groups. Mean serum creatinine level increased significantly only in Group 2 (0.6+/-0.1 vs 0.7+/-0.2 mg/dl; p<0.05). Tissue MDA levels were similar in all groups. Moderate (13.8%+/-1.5% vs 42%+/-1.4%; p<0.05) and severe (0% vs 40%+/-2.1%; p<0.05) lesions were significantly more frequent in Group 2 compared to Group 1. The frequency of severe lesions in Group 3 was found to be halved compared to that in Group 1 (40%+/-2.1% vs 20.2%+/-0.86%; p<0.05).<br><br>CONCLUSION: NAC protects the kidneys following exposure to contrast medium as it decreased the severity of tubular lesions in rats.}, }
@article {pmid16450384, year = {2006}, author = {Alexandre, J and Batteux, F and Nicco, C and Chéreau, C and Laurent, A and Guillevin, L and Weill, B and Goldwasser, F}, title = {Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo.}, journal = {International journal of cancer}, volume = {119}, number = {1}, pages = {41-48}, doi = {10.1002/ijc.21685}, pmid = {16450384}, issn = {0020-7136}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Free Radical Scavengers/*pharmacology ; Glutathione/pharmacology ; Humans ; Hydrogen Peroxide/*metabolism ; Lung Neoplasms/*drug therapy/*metabolism ; Paclitaxel/*pharmacology ; Reactive Oxygen Species/metabolism ; Spectrometry, Fluorescence ; }, abstract = {Intracellular events following paclitaxel binding to microtubules that lead to cell death remain poorly understood. Because reactive oxygen species (ROS) are involved in the cytotoxicity of anticancer agents acting through independent molecular targets, we explored the role of ROS in paclitaxel cytotoxicity. Within 15 min after in vitro exposure of A549 human lung cancer cells to paclitaxel, a concentration-dependent intracellular increase in O(o)(2)(-) and H(2)O(2) levels was detected by spectrofluorometry. Addition of N-acetylcysteine (NAC) or glutathione, two H(2)O(2) scavenger, induced a 4-fold increase in paclitaxel IC(50). Delaying NAC co-incubation by 4 hr, resulted in a 3-fold reduction in cell protection. The glutathione synthesis inhibitor, buthionine sulfoximine significantly increased paclitaxel cytotoxicity and H(2)O(2) accumulation, but did not modify O(o)(2)(-) levels. Co-incubation with diphenylene iodonium suggested that paclitaxel induced-O(o)(2)(-) production was in part associated with increased activity of cytoplasmic NADPH oxidase. Concomitant treatment with inhibitors of caspases 3 and 8 increased cell survival but did not prevent the early accumulation of H(2)O(2.) To evaluate the role of ROS in paclitaxel antitumoral activity, mice were injected with LLC1 lung cancer cells and treated with paclitaxel i.p. and/or NAC. The antitumoral activity of paclitaxel in mice was abolished by NAC. In conclusion, the accumulation of H(2)O(2) is an early and crucial step for paclitaxel-induced cancer cell death before the commitment of the cells into apoptosis. These results suggest that ROS participate in vitro and in vivo to paclitaxel cytotoxicity.}, }
@article {pmid16450075, year = {2006}, author = {Penna, C and Rastaldo, R and Mancardi, D and Raimondo, S and Cappello, S and Gattullo, D and Losano, G and Pagliaro, P}, title = {Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation.}, journal = {Basic research in cardiology}, volume = {101}, number = {2}, pages = {180-189}, doi = {10.1007/s00395-006-0584-5}, pmid = {16450075}, issn = {0300-8428}, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Enzyme Activation/drug effects/physiology ; Free Radical Scavengers/pharmacology ; Heart/drug effects/physiopathology ; Male ; Mitochondria/metabolism ; Myocardial Ischemia/*physiopathology ; Myocardial Reperfusion Injury/*prevention &amp; control ; Myocardium/pathology ; Organ Culture Techniques ; Oxidation-Reduction ; Potassium Channel Blockers/pharmacology ; Potassium Channels/*metabolism ; Protein Kinase C/*metabolism ; Protein Kinase Inhibitors/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/*physiology ; }, abstract = {Post-conditioning (Post-C) induced cardioprotection involves activation of guanylyl-cyclase. In the ischemic preconditioning scenario, the downstream targets of cGMP include mitochondrial ATP-sensitive K(+) (mK(ATP)) channels and protein kinase C (PKC), which involve reactive oxygen species (ROS) production. This study tests the hypothesis that mK(ATP), PKC and ROS are also involved in the Post-C protection. Isolated rat hearts underwent 30 min global ischemia (I) and 120 min reperfusion (R) with or without Post-C (i.e., 5 cycles of 10 s R/I immediately after the 30 min ischemia). In 6 groups (3 with and 3 without Post-C) either mK(ATP) channel blocker, 5- hydroxydecanoate (5-HD), or PKC inhibitor, chelerythrine (CHE) or ROS scavenger, N-acetyl-cysteine (NAC), were given during the entire reperfusion (120 min). In other 6 groups (3 with and 3 without Post-C), 5-HD, CHE or NAC were infused for 117 min only starting after 3 min of reperfusion not to interfere with the early effects of Post-C and/or reperfusion. In an additional group NAC was given during Post-C maneuvers (i.e., 3 min only). Myocardial damage was evaluated using nitro-blue tetrazolium staining and lactate dehydrogenase (LDH) release. Post-C attenuated myocardial infarct size (21 +/- 3% vs. 64 +/- 5% in control; p < 0.01). Such an effect was abolished by 5-HD or CHE given during either the 120 or 117 min of reperfusion as well as by NAC given during the 120 min or the initial 3 min of reperfusion. However, delayed NAC (i.e., 117 min infusion) did not alter the protective effect of Post- C (infarct size 32 +/- 5%; p < 0.01 vs. control, NS vs. Post-C). CHE, 5-HD or NAC given in the absence of Post-C did not alter the effects of I/R. Similar results were obtained in terms of LDH release. Our data show that Post-C induced protection involves an early redox-sensitive mechanism as well as a persistent activation of mK(ATP) and PKC, suggesting that the mK(ATP)/ROS/PKC pathway is involved in post-conditioning.}, }
@article {pmid16449798, year = {2006}, author = {Hsieh, CC and Papaconstantinou, J}, title = {Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {20}, number = {2}, pages = {259-268}, pmid = {16449798}, issn = {1530-6860}, support = {P01 AG021830/AG/NIA NIH HHS/United States ; P30 AG024832/AG/NIA NIH HHS/United States ; 1P01 AG 021830-01/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*metabolism ; Animals ; Catalytic Domain ; Cell Line ; Enzyme Activation ; Gene Expression Regulation, Enzymologic ; Heterozygote ; Liver/enzymology/*metabolism ; Longevity/physiology ; MAP Kinase Kinase Kinase 5/genetics/*metabolism ; *MAP Kinase Signaling System ; Mice ; Mice, Inbred Strains ; Phosphorylation ; Reactive Oxygen Species/*metabolism ; Rotenone ; Thioredoxins/genetics/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {We have proposed that the age-associated increase of reactive oxygen species (ROS) by electron transport chain (ETC) dysfunction may cause the elevated basal level of p38 MAPK stress response pathway activity. However, the mechanism by which ROS activates this pathway is not clear. Here we propose that activation of the p38 MAPK pathway by complex I (CI) generated ROS, in response to rotenone (ROT) treatment, is based on the ability of reduced Trx to bind to and inhibit ASK 1 and its release from the complex upon oxidation. This balance of free vs. bound ASK1 regulates the level of p38 MAPK pathway activity. To support this mechanism we demonstrate that the production of ROS by ROT treated AML12 hepatocyte cells dissociates the Trx-ASK1 complex, thereby increasing p38 MAPK pathway activity. This mechanism is supported by the ability of N-acetyl cysteine (NAC) to prevent dissociation of Trx-ASK1 and activation of the p38 MAPK pathway. We also demonstrated that the ratio of ASK1/Trx-ASK1 increases in aged mouse livers and that this correlates with the increased basal activity of the p38 MAPK pathway. The longevity of Snell dwarf mice has been attributed to their resistance to oxidative stress. A comparison of the levels of Trx-ASK1 in young and aged dwarfs showed a higher abundance of the complex than in their age-matched controls. These results, which are indicative of a decreased level of oxidative stress, suggest that increased ROS production in aged liver may alter the ratio of ASK1 and Trx-ASK1, thereby increasing the age-associated basal level of p38 MAPK pathway activity.}, }
@article {pmid16449100, year = {2006}, author = {LaRowe, SD and Mardikian, P and Malcolm, R and Myrick, H and Kalivas, P and McFarland, K and Saladin, M and McRae, A and Brady, K}, title = {Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals.}, journal = {The American journal on addictions}, volume = {15}, number = {1}, pages = {105-110}, pmid = {16449100}, issn = {1055-0496}, support = {T32 DA007288/DA/NIDA NIH HHS/United States ; RR01070/RR/NCRR NIH HHS/United States ; DA018501/DA/NIDA NIH HHS/United States ; P50 DA015369/DA/NIDA NIH HHS/United States ; F32 DA018501/DA/NIDA NIH HHS/United States ; M01 RR001070/RR/NCRR NIH HHS/United States ; DA015369/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*adverse effects/therapeutic use ; Adult ; Cocaine/*adverse effects ; Cocaine-Related Disorders/*rehabilitation ; Crack Cocaine/*adverse effects ; Cross-Over Studies ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neurologic Examination/drug effects ; Substance Abuse Treatment Centers ; Substance Withdrawal Syndrome/*drug therapy ; }, abstract = {A double-blind placebo-controlled crossover Phase I trial was conducted to assess the safety and tolerability of N-Acetylcysteine (NAC) in healthy, cocaine-dependent humans. Thirteen participants attended a three-day hospitalization in which they received placebo or NAC. Subjects were crossed over to receive the opposite medication condition during a second three-day hospitalization, which occurred the following week. Across placebo and NAC conditions, only mild side effects were noted, and the number of subjects reporting side effects did not differ. There were trends for a greater reduction in withdrawal symptoms and craving within the NAC condition. These preliminary results suggest that NAC is well tolerated in healthy, cocaine-dependent individuals and may reduce cocaine-related withdrawal symptoms and craving.}, }
@article {pmid16445699, year = {2006}, author = {Nitescu, N and Grimberg, E and Ricksten, SE and Guron, G}, title = {Effects of N-acetyl-L-cysteine on renal haemodynamics and function in early ischaemia-reperfusion injury in rats.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {33}, number = {1-2}, pages = {53-57}, doi = {10.1111/j.1440-1681.2006.04323.x}, pmid = {16445699}, issn = {0305-1870}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Gas Analysis ; Blood Pressure/drug effects ; Glomerular Filtration Rate/drug effects ; Heart Rate/drug effects ; Kidney/blood supply/*drug effects/physiopathology ; Male ; Rats ; Rats, Sprague-Dawley ; Renal Circulation/drug effects ; Reperfusion Injury/*physiopathology ; Time Factors ; }, abstract = {1. Renal ischaemia-reperfusion (IR) severely compromises kidney function and has been shown to cause persistent abnormalities in intrarenal blood flow. The aim of the present study was to examine whether N-acetyl-L-cysteine (NAC), a thiol-containing anti-oxidant, improves renal haemodynamics and function during early reperfusion in rats subjected to renal IR. 2. Male Sprague-Dawley rats were divided into groups receiving either isotonic saline (IR-Saline; n = 8) or NAC (IR-NAC; n = 8) prior to (200 mg/kg, i.p., 24 and 12 h before acute experimentation) and during acute renal clearance experiments (bolus 150 mg/kg followed by a continuous infusion of 43 mg/kg per h, i.v.). During acute experimentation, thiobutabarbital-anaesthetized rats were subjected to a right-sided nephrectomy, followed by left kidney IR (40 min renal artery occlusion). Left kidney function and blood flow and intrarenal cortical and outer medullary perfusion measured by laser-Doppler flowmetry was analysed at baseline, during ischaemia and for 80 min of reperfusion. 3. Renal IR produced an approximate 85% reduction in glomerular filtration rate (GFR) and a pronounced increase in fractional urinary sodium excretion, throughout reperfusion, with no statistically significant differences between groups. 4. During reperfusion, total renal blood flow and cortical and outer medullary perfusion rapidly returned to levels not significantly different from baseline in both groups. The relative increase in renal vascular resistance in response to IR was more pronounced in NAC-treated rats compared with saline-treated animals (P < 0.05). 5. In conclusion, treatment with NAC did not improve kidney function during the first 80 min after renal IR. In addition, the marked reduction in GFR following reperfusion was not associated with any detectable abnormalities in intrarenal perfusion.}, }
@article {pmid16445696, year = {2006}, author = {Kao, SJ and Wang, D and Lin, HI and Chen, HI}, title = {N-acetylcysteine abrogates acute lung injury induced by endotoxin.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {33}, number = {1-2}, pages = {33-40}, doi = {10.1111/j.1440-1681.2006.04320.x}, pmid = {16445696}, issn = {0305-1870}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Anesthesia ; Animals ; Blood Pressure/drug effects ; Body Weight/drug effects ; Bronchoalveolar Lavage Fluid/chemistry ; Endotoxins/administration &amp; dosage/*toxicity ; Exhalation/drug effects ; Heart Rate/drug effects ; Hematocrit ; Hypotension/chemically induced/physiopathology/prevention &amp; control ; Infusions, Intravenous ; Injections, Intravenous ; Interleukin-1/blood ; Leukocyte Count ; Leukopenia/blood/chemically induced/prevention &amp; control ; Lipopolysaccharides/administration &amp; dosage/toxicity ; Lung/drug effects/pathology/physiopathology ; Methylguanidine/blood ; Nitrates/blood ; Nitric Oxide/metabolism ; Nitriles/blood ; Organ Size/drug effects ; Proteins/metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome/chemically induced/mortality/*prevention &amp; control ; Survival Rate ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {1. Acute lung injury (ALI) or acute respiratory distress syndrome is a serious clinical problem with high mortality. N-Acetylcysteine (NAC) is an anti-oxidant and a free radical scavenger. It has been reported recently that NAC ameliorates organ damage induced by endotoxin (lipopolysaccharide; LPS) in conscious rats. The present study was designed to evaluate the effects of NAC on LPS-induced ALI and other changes in anaesthetized rats. 2. Sprague-Dawley rats were anaesthetized with pentobarbital (40 mg/kg, i.p.). Endotracheal intubation was performed to provide artificial ventilation. Arterial pressure and heart rate were monitored. The extent of ALI was evaluated with the lung weight (LW)/bodyweight ratio, LW gain, exhaled nitric oxide (NO) and protein concentration in bronchoalveolar lavage (PCBAL). Haematocrit, white blood cells, plasma nitrate/nitrite, methyl guanidine (MG), tumour necrosis factor (TNF)-alpha and interleukin (IL)-1b were measured. Pathological changes in the lung were examined and evaluated. 3. Endotoxaemia was produced by injection of 10 mg/kg, i.v., LPS (Escherichia coli). Animals were randomly divided into three groups. In the vehicle group, rats received an i.v. drip of physiological saline solution (PSS) at a rate of 0.3 mL/h. The LPS group received an i.v. drip of PSS for 1 h, followed by LPS (10 mg/kg by slow blous injection, i.v., over 1-2 min). Rats in the LPS + NAC group received NAC by i.v. drip at a rate of 150 mg/kg per h (0.3 mL/h) for 60 min starting 10 min before LPS administration (10 mg/kg by slow blous injection, i.v., over 1-2 min). Each group was observed for a period of 6 h. 4. N-Acetylcysteine treatment improved the LPS-induced hypotension and leukocytopenia. It also reduced the extent of ALI, as evidenced by reductions in LW changes, exhaled NO, PCBAL and lung pathology. In addition, NAC diminished the LPS-induced increases in nitrate/nitrite, MG, TNF-a and IL-1b. 5. In another series of experiments, LPS increased the mortality rate compared with the vehicle group (i.v. drip of PSS at a rate of 0.3 mL/h) during a 6 h observation period. N-Acetylcysteine, given 10 min prior to LPS, significantly increased the survival rate. 6. The results of the present study suggest that NAC exerts a protective effect on the LPS-induced ALI. The mechanisms of action may be mediated through the reduction of the production of NO, free radicals and pro-inflammatory cytokines.}, }
@article {pmid16443784, year = {2006}, author = {Nieuwdorp, M and van Haeften, TW and Gouverneur, MC and Mooij, HL and van Lieshout, MH and Levi, M and Meijers, JC and Holleman, F and Hoekstra, JB and Vink, H and Kastelein, JJ and Stroes, ES}, title = {Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo.}, journal = {Diabetes}, volume = {55}, number = {2}, pages = {480-486}, doi = {10.2337/diabetes.55.02.06.db05-1103}, pmid = {16443784}, issn = {0012-1797}, mesh = {Acetylcysteine/pharmacology ; Adult ; *Blood Coagulation ; Dextrans/metabolism ; Endothelial Cells/drug effects/*metabolism/*pathology ; Glucose/pharmacology ; Glucose Clamp Technique ; Glycocalyx/*metabolism ; Humans ; Hyperglycemia/chemically induced/*metabolism ; Male ; Mannitol/pharmacology ; Time Factors ; }, abstract = {Hyperglycemia is associated with increased susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the endothelium, is involved in the protective capacity of the vessel wall. We therefore evaluated whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability. The systemic glycocalyx volume was estimated by comparing the distribution volume of a glycocalyx permeable tracer (dextran 40) with that of a glycocalyx impermeable tracer (labeled erythrocytes) in 10 healthy male subjects. Measurements were performed in random order on five occasions: two control measurements, two measurements during normoinsulinemic hyperglycemia with or without N-acetylcysteine (NAC) infusion, and one during mannitol infusion. Glycocalyx measurements were reproducible (1.7 +/- 0.2 vs. 1.7 +/- 0.3 l). Hyperglycemia reduced glycocalyx volume (to 0.8 +/- 0.2 l; P < 0.05), and NAC was able to prevent the reduction (1.4 +/- 0.2 l). Mannitol infusion had no effect on glycocalyx volume (1.6 +/- 0.1 l). Hyperglycemia resulted in endothelial dysfunction, increased plasma hyaluronan levels (from 70 +/- 6 to 112 +/- 16 ng/ml; P < 0.05) and coagulation activation (prothrombin activation fragment 1 + 2: from 0.4 +/- 0.1 to 1.1 +/- 0.2 nmol/l; d-dimer: from 0.27 +/- 0.1 to 0.55 +/- 0.2 g/l; P < 0.05). Taken together, these data indicate a potential role for glycocalyx perturbation in mediating vascular dysfunction during hyperglycemia.}, }
@article {pmid16443689, year = {2006}, author = {Shima, H and Koike, E and Shinohara, R and Kobayashi, T}, title = {Oxidative ability and toxicity of n-hexane insoluble fraction of diesel exhaust particles.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {91}, number = {1}, pages = {218-226}, doi = {10.1093/toxsci/kfj119}, pmid = {16443689}, issn = {1096-6080}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Gas Chromatography-Mass Spectrometry ; Heme Oxygenase (Decyclizing)/metabolism ; Hexanes/*chemistry ; Magnetic Resonance Spectroscopy ; Male ; Mice ; Mice, Inbred BALB C ; *Oxidative Stress ; Rats ; Solubility ; Vehicle Emissions/*toxicity ; }, abstract = {Diesel exhaust particles (DEP) are known to induce adverse biological responses such as inflammation of the airway. However, the relationship between the chemical characteristics of organic compounds adsorbed on DEP and their biological effects is not yet fully understood. In this study, the dichloromethane-soluble fraction (DMSF) from DEP was fractionated into its n-hexane-soluble fraction (n-HSF) and n-hexane-insoluble fraction (n-HISF). Using these DEP fractions, we designed the present studies to elucidate (1) chemical characteristics, (2) biological characteristics, and (3) the relationship between the chemical and the biological characteristics of these DEP fractions. Dithiothreitol (DTT) assay, Fourier transform-infrared (FT-IR) spectroscopy, proton nuclear magnetic resonance (1H-NMR) spectroscopy, and gas chromatography-mass spectrometry (GC-MS) were used to characterize their chemical properties. Heme oxygenase-1 (HO-1) protein expression, viability of rat alveolar type II epithelial cell line (SV40T2), and inflammatory cell infiltration into the peritoneal cavity of BALB/c mice were evaluated as markers of oxidative stress, cytotoxicity, and inflammatory response, respectively. The oxidative ability of the DEP fractions was n-HISF > DMSF > n-HSF. IR, 1H-NMR, and GC-MS spectra showed that n-HISF was mainly composed of compounds having many functional groups related to oxygenation, such as hydroxyl and carbonyl groups. The relative strength of HO-1 protein expression, cytotoxicity, and inflammatory responses was also n-HISF > DMSF > n-HSF. All of the n-HISF-induced biological activities were decreased by reduction with N-acetyl-L-cysteine (NAC). These results suggest that n-HISF has high oxidative ability and many functional groups related to oxygenation and that this ability strongly contributes to the induction of oxidative stress, cytotoxicity, and inflammatory response.}, }
@article {pmid16441554, year = {2006}, author = {Winiarska, K and Fraczyk, T and Malinska, D and Drozak, J and Bryla, J}, title = {Melatonin attenuates diabetes-induced oxidative stress in rabbits.}, journal = {Journal of pineal research}, volume = {40}, number = {2}, pages = {168-176}, doi = {10.1111/j.1600-079X.2005.00295.x}, pmid = {16441554}, issn = {0742-3098}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Diabetes Mellitus, Experimental/*drug therapy/*metabolism ; Glutathione/blood/metabolism ; Hydroxyl Radical/blood/metabolism ; Kidney Cortex/enzymology/metabolism ; Liver/enzymology/metabolism ; Male ; Melatonin/*therapeutic use ; Oxidative Stress/*physiology ; Rabbits ; }, abstract = {Oxidative stress is considered to be the main cause of diabetic complications. As the role of antioxidants in diabetes therapy is still underestimated, the aim of the present investigation was to study the antioxidative action of melatonin in comparison with N-acetylcysteine (NAC) under diabetic conditions. Alloxan-diabetic rabbits were treated daily with either melatonin (1 mg/kg, i.p.), NAC (10 mg/kg, i.p.) or saline. Blood glutathione redox state and serum hydroxyl free radicals (HFR), creatinine and urea levels were monitored. After 3 wk of treatment animals were killed and HFR content, reduced glutathione/oxidized glutathione (GSH/GSSG) ratio as well as the activities of glutathione reductase, glutathione peroxidase and gamma-glutamylcysteine synthetase were estimated in both liver and kidney cortex. Diabetes evoked a several-fold increase in HFR levels accompanied by a significant decline in GSH/GSSG ratio in serum and the examined organs. In contrast to NAC, melatonin (at 1/10 the dose of NAC) attenuated diabetes-induced alterations in glutathione redox state and HFR levels, normalized creatinine concentration and diminished urea content in serum. Moreover, the indole resulted in an increase in glutathione reductase activity in both studied organs and in a rise in glutathione peroxidase and gamma-glutamylcysteine synthetase activities in the liver. In contrast to NAC, melatonin seems to be beneficial for diabetes therapy because of its potent antioxidative and nephroprotective action. The indole-induced increase in the activities of the enzymes of glutathione metabolism might be of importance for antioxidative action of melatonin under diabetic conditions.}, }
@article {pmid16440148, year = {2006}, author = {Orhan, G and Yapici, N and Yuksel, M and Sargin, M and Senay, S and Yalçin, AS and Aykaç, Z and Aka, SA}, title = {Effects of N-acetylcysteine on myocardial ischemia-reperfusion injury in bypass surgery.}, journal = {Heart and vessels}, volume = {21}, number = {1}, pages = {42-47}, pmid = {16440148}, issn = {0910-8327}, mesh = {Acetylcysteine/*therapeutic use ; Acridines ; Aged ; Biomarkers/blood ; Cardiopulmonary Bypass ; *Coronary Artery Bypass ; Coronary Artery Disease/surgery ; Creatine Kinase, MB Form/blood/drug effects ; Female ; Follow-Up Studies ; Free Radical Scavengers/*therapeutic use ; Humans ; Indicators and Reagents ; Inflammation Mediators/blood ; Luminescent Measurements ; Luminol ; Male ; Middle Aged ; Myocardial Reperfusion Injury/blood/*prevention &amp; control ; Oxidative Stress/drug effects ; Reactive Oxygen Species/blood ; Research Design ; Treatment Outcome ; Tumor Necrosis Factor-alpha/blood/drug effects ; }, abstract = {Myocardial ischemia-reperfusion injury may complicate coronary artery bypass grafting (CABG) operations. N-Acetylcysteine (NAC) had antioxidant and microcirculatory effects, and inhibits neutrophil aggregation. The aim of this study was to determine the effects of NAC in limiting myocardial ischemia-reperfusion injury in CABG operations. Twenty patients undergoing elective coronary bypass operation with cardiopulmonary bypass were enrolled and randomly assigned to two groups: a control group operated with a routine CABG protocol, and one where NAC was administered intravenously during the operation (NAC group). Blood samples from coronary sinus for tumor necrosis factor-alpha assay, myocardial biopsy specimens for chemiluminescent luminol, and lucigenin measurements of reactive oxygen species were taken. The luminol (specific for (*)OH, H(2)O(2), and HOCl(-) radicals) and lucigenin (specific for O(2) (*-)) levels and the difference ratios after reperfusion were significantly lower in the NAC group. Tumor necrosis factor-alpha levels increased in the control group but, in contrast, a significant decrease was detected in the NAC group (P < 0.01). Creatine kinase-MB levels at 6 and 12 hours were significantly lower in the NAC group (P = 0.02). N-Acetylcysteine has potential effects to limit ischemia reperfusion injury during CABG operations. We believe that its effects on clinical outcome may be more apparent in patients prone to ischemia-reperfusion injury.}, }
@article {pmid16440146, year = {2006}, author = {Yesilbursa, D and Serdar, A and Senturk, T and Serdar, Z and Sağ, S and Cordan, J}, title = {Effect of N-acetylcysteine on oxidative stress and ventricular function in patients with myocardial infarction.}, journal = {Heart and vessels}, volume = {21}, number = {1}, pages = {33-37}, pmid = {16440146}, issn = {0910-8327}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Biomarkers/blood ; Creatine Kinase, MB Form/blood/drug effects ; Drug Therapy, Combination ; Echocardiography, Doppler ; Female ; Fibrinolytic Agents/therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Malondialdehyde/blood ; Middle Aged ; Myocardial Infarction/blood/diagnostic imaging/*drug therapy/*physiopathology ; Nitroglycerin/therapeutic use ; Oxidative Stress/*drug effects ; Research Design ; Streptokinase/therapeutic use ; Stroke Volume/drug effects ; Treatment Outcome ; Vasodilator Agents/therapeutic use ; Ventricular Function, Left/*drug effects ; Ventricular Remodeling/drug effects ; }, abstract = {Recent evidence suggests that postischemic myocardial dysfunction ("stunning") may be mediated by oxygen free radicals. Various studies have reported the beneficial effects of antioxidants in ischemia-reperfusion injury. The aim of this study was to assess the effect of N-acetylcysteine (NAC) treatment on oxidative stress, infarct size, and left ventricular (LV) function, as adjunct therapy in myocardial infarction (MI). Patients with acute MI received either 15 g NAC infused over 24 h (n = 15) or no NAC (n = 15), combined with streptokinase. Peripheral venous blood was serially sampled to measure creatine kinase (CK)-MB levels. Plasma malondialdehyde (MDA) level was measured at admission and after 4 and 24 h. Echocardiography was performed within 3 days of MI and after 3 months. At admission, plasma MDA levels were not different between the groups. In the NAC-treated patients plasma MDA levels decreased, whereas in the nontreated NAC patients MDA levels increased at 4 and 24 h (P < 0.01 and P < 0.001, respectively). Left ventricular ejection fraction was higher (P < 0.05) and LV end-systolic and end-diastolic diameters were lower (P < 0.001 and P < 0.001) in patients receiving NAC on day 3. Left ventricular wall motion score index was significantly lower in patients treated with NAC on day 3 (P < 0.05). Left ventricular diastolic parameters were not different whether patients were treated with NAC or not. No difference in reduction of infarct size was detected between the groups according to CK-MB levels. It was thus demonstrated that administration of NAC in combination with streptokinase significantly diminished oxidative stress and improved LV function in patients with acute MI. These encouraging results would justify the performance of a larger controlled study.}, }
@article {pmid16439183, year = {2006}, author = {Wang, AL and Wang, JP and Wang, H and Chen, YH and Zhao, L and Wang, LS and Wei, W and Xu, DX}, title = {A dual effect of N-acetylcysteine on acute ethanol-induced liver damage in mice.}, journal = {Hepatology research : the official journal of the Japan Society of Hepatology}, volume = {34}, number = {3}, pages = {199-206}, doi = {10.1016/j.hepres.2005.12.005}, pmid = {16439183}, issn = {1386-6346}, abstract = {Reactive oxygen species (ROS) have been associated with acute ethanol-induced liver damage. N-acetylcysteine (NAC) is a glutathione (GSH) precursor and direct antioxidant. In this study, we investigated the effects of NAC on acute ethanol-induced liver damage. Female ICR mice were administered by gavage with a single dose of ethanol (6g/kg). NAC was administered in two different modes. In mode A, mice were injected with different doses of NAC at 30min before ethanol. In mode B, mice were injected with different doses of NAC at 4h after ethanol. Acute ethanol-induced liver damage was estimated by measuring serum alanine aminotransferase (ALT) activity and histopathological changes. Result showed that a single dose of ethanol (6g/kg) caused a significant increase in serum ALT activity, followed by microvesicular steatosis and necrosis in mouse liver. Pretreatment with NAC significantly protected against acute ethanol-induced liver damage in a dose-independent manner. Correspondingly, pretreatment with NAC significantly attenuated acute ethanol-induced lipid peroxidation and GSH depletion and inhibited hepatic TNF-alpha mRNA expression. By contrast, post-treatment with NAC aggravated ethanol-induced hepatic lipid peroxidation and worsened acute ethanol-induced liver damage in a dose-dependent manner. Taken together, NAC has a dual effect on acute ethanol-induced liver damage. Pretreatment with NAC prevent from acute ethanol-induced liver damage via counteracting ethanol-induced oxidative stress. When administered after ethanol, NAC might behave as a pro-oxidant and aggravate acute ethanol-induced liver damage.}, }
@article {pmid16436515, year = {2006}, author = {Moiseeva, O and Mallette, FA and Mukhopadhyay, UK and Moores, A and Ferbeyre, G}, title = {DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation.}, journal = {Molecular biology of the cell}, volume = {17}, number = {4}, pages = {1583-1592}, pmid = {16436515}, issn = {1059-1524}, mesh = {Acetylation ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle/*drug effects ; Cell Cycle Proteins/genetics/metabolism ; *Cellular Senescence ; Checkpoint Kinase 2 ; *DNA Damage ; DNA-Binding Proteins/genetics/metabolism ; Fibroblasts/drug effects/metabolism ; Histones/analysis/metabolism ; Humans ; Interferon-beta/*pharmacology ; Lysine/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics/metabolism ; RNA Interference ; Reactive Oxygen Species/metabolism ; Serine/metabolism ; Signal Transduction ; Transcription, Genetic ; Tumor Suppressor Protein p53/genetics/*metabolism ; Tumor Suppressor Proteins/genetics/metabolism ; }, abstract = {Interferons are cytokines with potent antiviral and antiproliferative activities. We report that although a transient exposure to beta-interferon induces a reversible cell cycle arrest, a sustained treatment triggers a p53-dependent senescence program. Beta-interferon switched on p53 in two steps. First, it induced the acetylation of p53 at lysine 320 and its dephosphorylation at serine 392 but not p53 activity. Later on, it triggered a DNA signaling pathway, the phosphorylation of p53 at serine 15 and its transcriptional activity. In agreement, beta-interferon-treated cells accumulated gamma-H2AX foci and phosphorylated forms of ATM and CHK2. The DNA damage signaling pathway was activated by an increase in reactive oxygen species (ROS) induced by interferon and was inhibited by the antioxidant N-acetyl cysteine. More important, RNA interference against ATM inhibited p53 phosphorylation at serine 15, p53 activity and senescence in response to beta-interferon. Beta-interferon-induced senescence was more efficient in cells expressing either, p53, or constitutive allele of ERK2 or RasV12. Hence, beta-interferon-induced senescence targets preferentially cells with premalignant changes.}, }
@article {pmid16434328, year = {2006}, author = {Spiller, HA and Winter, ML and Klein-Schwartz, W and Bangh, SA}, title = {Efficacy of activated charcoal administered more than four hours after acetaminophen overdose.}, journal = {The Journal of emergency medicine}, volume = {30}, number = {1}, pages = {1-5}, doi = {10.1016/j.jemermed.2005.02.019}, pmid = {16434328}, issn = {0736-4679}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage ; Adolescent ; Adult ; Aged ; Charcoal/*administration &amp; dosage ; Child ; Drug Overdose ; Female ; Humans ; Liver Function Tests ; Male ; Middle Aged ; Poison Control Centers ; Prospective Studies ; Treatment Outcome ; United States ; }, abstract = {To evaluate whether administration of activated charcoal, in addition to standard N-acetylcysteine (NAC) therapy, after acetaminophen overdose provides additional patient benefit over NAC therapy alone, a 1-year non-randomized prospective, multi-center, observational case series was performed at three poison centers and one poison center system. Entrance criteria were all acute acetaminophen overdoses with: 1) an acetaminophen blood concentration determined to be in the toxic range by the Rumack-Matthew nomogram; and 2) all therapies, including NAC and activated charcoal, initiated between 4 and 16 h post-ingestion. There were 145 patients meeting entrance criteria, of whom 58 patients (40%) received NAC only and 87 patients (60%) received NAC and activated charcoal. Overall, 23 patients had elevations of AST or ALT greater than 1000 IU/L, of which 21 patients received NAC only (38% of total NAC only group) and 2 patients received NAC and activated charcoal (2% of total NAC+AC group). Administration of activated charcoal in this series of patients with toxic acetaminophen concentrations treated with NAC was associated with reduced incidence of liver injury, as measured by elevated serum transaminases and prothrombin times.}, }
@article {pmid16433646, year = {2006}, author = {Sheets, DW and Okamoto, T and Dijkgraaf, LC and Milam, SB and Schmitz, JP and Zardeneta, G}, title = {Free radical damage in facsimile synovium: correlation with adhesion formation in osteoarthritic TMJs.}, journal = {Journal of prosthodontics : official journal of the American College of Prosthodontists}, volume = {15}, number = {1}, pages = {9-19}, doi = {10.1111/j.1532-849X.2006.00063.x}, pmid = {16433646}, issn = {1059-941X}, support = {DE12542/DE/NIDCR NIH HHS/United States ; }, mesh = {Animals ; Disease Models, Animal ; Female ; Free Radicals/*metabolism ; Hydrogen Peroxide/administration &amp; dosage ; Hydrophobic and Hydrophilic Interactions ; Injections, Subcutaneous ; Iron/administration &amp; dosage ; Osteoarthritis/*etiology/metabolism/pathology ; Oxidative Stress/*physiology ; Protein Carbonylation ; Rats ; Rats, Sprague-Dawley ; Synovial Membrane/*pathology ; Temporomandibular Joint Disorders/*etiology/metabolism/pathology ; Tissue Adhesions/etiology ; }, abstract = {PURPOSE: The purpose of this study was to use the rat air pouch model of facsimile synovium to evaluate oxidative stress as a primary mechanism in the pathogenesis of degenerative temporomandibular joint (TMJ) disease.<br><br>MATERIALS AND METHODS: Forty-nine Sprague-Dawley adult female rats were used to generate the standard rat air pouch model of facsimile synovium. This was accomplished by daily air injections (20 cc) subdermally through the dorsal skin. Hydrogen peroxide and ferrous iron (components of the Fenton reaction which generate free radicals) were introduced into the pouches of the 4-, 7-, and 14-day groups to generate oxidative stress. Control rats were injected with phosphate-buffered solution (PBS), pH 7.4. Either N-acetylcysteine (NAC), a powerful free radical scavenger, or ibuprofen were simultaneously injected with the Fenton reagents into the pouches of the 14-day treatment groups to modulate free radical-mediated protein damage to the synovium. Animals were euthanized at appropriate experimental intervals and biopsies obtained from specimens to analyze: (1) proteins' amino acid modification (carbonyl group formation), (2) protein hydrophobicity, (3) detection of low molecular weight protein degradation products, and (4) histological and gross anatomical observations.<br><br>RESULTS: Free radicals introduced into the rat air pouch interacted with synovial tissues causing oxidation and breakdown of proteins. Clinical evidence of adhesion formation consistent with features found in osteoarthritis of the TMJ developed. The groups subjected to oxidative stress experienced statistically significant (p < 0.05) increases in carbonyl formation, carbonyls/protein, and low molecular weight protein fragments. These groups also showed significant (p < 0.05) hydrophobicity changes consistent with free radical attack. Control synovial tissues were statistically undamaged. The 14-day NAC and ibuprofen treatment groups experienced statistically significant (p < 0.05) decreases in total carbonyl formation, carbonyls/protein, and hydrophobicity. Histological and gross observations in free radical damaged synovium exhibited features consistent with known arthoscopic and arthrocentesis findings in diseased TMJs.<br><br>CONCLUSIONS: This study suggests that the rat air pouch model of facsimile synovium develops clinical evidence of adhesions and biochemical signs of protein modification when subjected to free radical attack. NAC and ibuprofen prevented carbonyl formation as well as hydrophobicity changes indicative of oxidative stress damage in facsimile synovium. These findings are consistent with features of degenerative human TMJ disease. Future direction may be taken from this study to postulate new analysis techniques and treatment modalities for patients with degenerative TMJ disease.}, }
@article {pmid16430935, year = {2006}, author = {Ishihara, Y and Shiba, D and Shimamoto, N}, title = {Enhancement of DMNQ-induced hepatocyte toxicity by cytochrome P450 inhibition.}, journal = {Toxicology and applied pharmacology}, volume = {214}, number = {2}, pages = {109-117}, doi = {10.1016/j.taap.2005.12.003}, pmid = {16430935}, issn = {0041-008X}, mesh = {Animals ; Antioxidants/pharmacology ; Benzoquinones/chemistry/toxicity ; Catecholamines/pharmacology ; Cell Survival/drug effects ; *Cytochrome P-450 Enzyme Inhibitors ; Dose-Response Relationship, Drug ; Drug Synergism ; Enzyme Inhibitors/*pharmacology ; Glutathione Disulfide/metabolism ; Hepatocytes/cytology/*drug effects/metabolism ; Imidazolines/pharmacology ; Iron Chelating Agents/pharmacology ; Ketoconazole/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; Male ; Metyrapone/pharmacology ; Molecular Structure ; NADP/metabolism ; Naphthoquinones/chemistry/*toxicity ; Oxidative Stress/drug effects ; Proadifen/pharmacology ; Rats ; Rats, Wistar ; Superoxides/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Two mechanisms have been proposed to explain quinone cytotoxicity: oxidative stress via the redox cycle and the arylation of intracellular nucleophiles. As the redox cycle is catalyzed by NADPH cytochrome P450 reductase, cytochrome P450 systems are expected to be related to the cytotoxicity induced by redox-cycling quinones. Thus, we investigated the relationship between cytochrome P450 systems and quinone toxicity for rat primary hepatocytes using an arylator, 1,4-benzoquinone (BQ), and a redox cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). The hepatocyte toxicity of both BQ and DMNQ increased in a time- and dose-dependent manner. Pretreatment with cytochrome P450 inhibitors, such as SKF-525A (SKF), ketoconazole and 2-methy-1,2-di-3-pyridyl-1-propanone, enhanced the hepatocyte toxicity induced by DMNQ but did not affect BQ-induced hepatocyte toxicity. The production of superoxide anion and the levels of glutathione disulfide and thiobarbituric-acid-reactive substances were increased by treatment with DMNQ, and SKF pretreatment further enhanced their increases. In addition, NADPH oxidation in microsomes was increased by treatment with DMNQ and further augmented by pretreatment with SKF, and a NADPH cytochrome P450 reductase inhibitor, diphenyleneiodonium chloride completely suppressed NADPH oxidations increased by treatment with either DMNQ- or DMNQ + SKF. Pretreatment with antioxidants, such as alpha-tocopherol, reduced glutathione, N-acetyl cysteine or an iron ion chelator deferoxamine, totally suppressed DMNQ- and DMNQ + SKF-induced hepatocyte toxicity. These results indicate that the hepatocyte toxicity of redox-cycling quinones is enhanced under cytochrome P450 inhibition, and that this enhancement is caused by the potentiation of oxidative stress.}, }
@article {pmid16430375, year = {2006}, author = {Yi, JH and Hoover, R and McIntosh, TK and Hazell, AS}, title = {Early, transient increase in complexin I and complexin II in the cerebral cortex following traumatic brain injury is attenuated by N-acetylcysteine.}, journal = {Journal of neurotrauma}, volume = {23}, number = {1}, pages = {86-96}, doi = {10.1089/neu.2006.23.86}, pmid = {16430375}, issn = {0897-7151}, support = {NS-P50-08803/NS/NINDS NIH HHS/United States ; NS-R01-40978/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Adaptor Proteins, Vesicular Transport ; Animals ; Brain Injuries/*drug therapy/metabolism/physiopathology ; Cerebral Cortex/*drug effects/metabolism/physiopathology ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/therapeutic use ; Glutamic Acid/metabolism ; Hippocampus/drug effects/metabolism/physiopathology ; Male ; Nerve Degeneration/metabolism/physiopathology ; Nerve Tissue Proteins/*drug effects/metabolism ; Neurotoxins/metabolism ; Oxidative Stress/*drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; SNARE Proteins/drug effects/metabolism ; Synaptic Membranes/drug effects/metabolism ; Synaptic Transmission/drug effects/physiology ; Time Factors ; Up-Regulation/drug effects/physiology ; }, abstract = {Alteration of excitatory neurotransmission is a key feature of traumatic brain injury (TBI) in which extracellular glutamate levels rise. Although increased synaptic release of glutamate occurs at the injury site, the precise mechanism is unclear. Complexin I and complexin II constitute a family of cytosolic proteins involved in the regulation of neurotransmitter release, competing with the chaperone protein alpha-SNAP (soluble N-ethylmaleimide-sensitive factor-attachment protein) for binding to the synaptic vesicle protein synaptobrevin as well as the synaptic membrane proteins SNAP-25 and syntaxin, which together form the SNAP receptor (SNARE) complex. Complexin I is predominantly a marker of axosomatic (inhibitory) synapses, whereas complexin II mainly labels axodendritic and axospinous synapses, the majority of which are excitatory. In order to examine the role of these proteins in TBI, we have studied levels of both complexins in the injured hemisphere by immunoblotting over a time period ranging from 6 h to 7 days following lateral fluid-percussion brain injury in the rat. Transient increases in the levels of complexin I and complexin II proteins were detected in the injured cerebral cortex 6 h following TBI. This increase was followed by a decrease of complexin I in the injured cortex and hippocampus, and a decrease in both complexins in the injured thalamus region at day 3 and day 7 post-injury. The early, transient increase in the injured cortex was completely blocked by N-acetylcysteine (NAC) administered 5 min following trauma, suggesting an involvement of oxidative stress. Neuronal loss was also reduced in the injured hemisphere with post-TBI NAC treatment. Our findings suggest a dysregulation of both inhibitory and excitatory neurotransmission following traumatic injury that is responsive to antioxidant treatment. These alterations in complexin levels may also play an important role in neuronal cell loss following TBI, and thus contribute to the pathophysiology of cerebral damage following brain injury.}, }
@article {pmid16429300, year = {2006}, author = {Erdogan, H and Fadillioglu, E and Yagmurca, M and Uçar, M and Irmak, MK}, title = {Protein oxidation and lipid peroxidation after renal ischemia-reperfusion injury: protective effects of erdosteine and N-acetylcysteine.}, journal = {Urological research}, volume = {34}, number = {1}, pages = {41-46}, pmid = {16429300}, issn = {0300-5623}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/*pharmacology ; Kidney Diseases/*drug therapy/metabolism/pathology ; Kidney Tubules/metabolism/pathology ; Lipid Peroxidation/drug effects/physiology ; Male ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects/physiology ; Proteins/metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*drug therapy/metabolism/pathology ; Thioglycolates/*pharmacology ; Thiophenes/*pharmacology ; }, abstract = {Oxygen radicals have roles in the renal ischemia-reperfusion (IR) injury usually encountered in several conditions such as renal transplantation. The aim of this study was to investigate the effects of erdosteine and N-acetylcysteine (NAC) on the oxidant/antioxidant status and microscopy of renal tissues after IR injury. Male Sprague-Dawley rats were randomly assigned to four groups: control untreated rats, IR (30 min ischemia and 120 min reperfusion), IR + NAC (i.p.; 180 mg/kg) and IR + erdosteine (oral; 50 mg/kg/day for 2 days before experiments) groups. After unilateral renal IR, the right kidney was rapidly excised and sectioned vertically into two pieces for microscopic examination and biochemical analysis. Erdosteine and NAC treatment did not cause any significant change in the activity of superoxide dismutase (SOD) in comparison with the IR group, even if the SOD activity increased in IR groups than in the control group. Catalase (CAT) activity was decreased in the IR group in comparison with control and IR + erdosteine groups (P<0.05), whereas it was higher in the IR + erdosteine group than in the IR + NAC group (P<0.05). Xanthine oxidase (XO) activity was higher in all the IR-performed groups than in the control group (P<0.05). Thiobarbituric acid-reactive substances (TBARS) level and protein carbonyl (PC) content were increased after IR injury (P<0.05). Erdosteine or NAC treatments ameliorated these increased TBARS and PC contents in comparison with the IR group (P<0.05). Light microscopy of the IR group showed tubular dilatation, tubular necrosis and vacuole formation in epithelial cells. Erdosteine but not NAC apparently reduced the renal tissue damage. The pathological damage score after IR was significantly reduced after erdosteine treatment (P<0.05), but not after NAC treatment. In conclusion, renal IR resulted in oxidative damage as seen in biochemical lipid peroxidation and protein oxidation results with aggravated tubular necrosis. Erdosteine and NAC treatments improved the biochemical results of IR injury. However, on microscopic evaluations, animals receiving erdosteine showed a great reduction in renal damage when compared with the NAC group.}, }
@article {pmid16412983, year = {2006}, author = {Viola-Rhenals, M and Rieber, MS and Rieber, M}, title = {Suppression of survival in human SKBR3 breast carcinoma in response to metal-chelator complexes is preferential for copper-dithiocarbamate.}, journal = {Biochemical pharmacology}, volume = {71}, number = {6}, pages = {722-734}, doi = {10.1016/j.bcp.2005.11.028}, pmid = {16412983}, issn = {0006-2952}, mesh = {Antineoplastic Agents/chemistry/*pharmacology ; Breast Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Chelating Agents/chemistry/*pharmacology ; Copper/chemistry/*pharmacology ; Ditiocarb/*analogs &amp; derivatives/chemistry/pharmacology ; Fluoresceins/metabolism ; Humans ; Hydroxyquinolines/chemistry/pharmacology ; Organometallic Compounds/chemistry/*pharmacology ; Oxyquinoline ; Zinc/chemistry/pharmacology ; }, abstract = {Since diethyl dithiocarbamate (DEDTC) forms complexes with either zinc or copper, and 8-hydroxyquinoline (8-OHQ) also complexes with copper, we now compared the cytotoxic activity of Cu[DEDTC]2, Zn[DEDTC]2 and Cu[8-OHQ]2. This report shows that at nanomolar levels, only copper-[DEDTC]2, suppresses proliferation and clonogenicity of SKBR3 human breast carcinoma, concurrently with induction of apoptosis-associated PARP fragmentation. Susceptibility to these agents was paralleled by reactive oxygen generation (ROS) and greater expression of anti-oxidant enzymes like MnSOD and catalase, with no comparable effect on Cu/Zn superoxide dismutase. The lethal effects of Cu[DEDTC]2 manifested when adding the two separate aqueous components or the preformed synthetic complexes in DMSO, was prevented by N-acetyl cysteine or glutathione, with no comparable protection afforded by non-thiol anti-oxidants like mannitol or DMSO. Exogenously added catalase also protected cells from Cu[DEDTC]2, suggesting that this complex may kill after the levels of superoxide anion [O2*-] dismutated by MnSOD increase hydrogen peroxide-related stress. Cu[DEDTC]2 also induced p21WAF1, a cdk inhibitor usually not inducible in mutant p53 tumors like SKBR3 carcinoma, correlating with dephosphorylation of the Sp1 transcription factor. Concentrations of Cu[DEDTC]2 cytotoxic for SKBR3 carcinoma did not induce comparable damage versus normal diploid human WI-38 fibroblasts. In contrast to the cytotoxic effect of nM levels of Cu[DEDTC]2 against SKBRR3 cells, no response was seen in the same cells exposed to 20 microM cis-platin. Since neither DEDTC bound to zinc, nor copper bound to 8-OHQ showed comparable cytotoxicity, our results suggest that the greater activity of copper-DEDTC reflects a specific structure-activity relationship for the active complex. Since Cu[DEDTC]2 shows more effectiveness than other metal-chelator complexes, it may be worth further investigation as an alternative to cancer therapies.}, }
@article {pmid16412532, year = {2006}, author = {Guérin, PJ and Furtak, T and Eng, K and Gauthier, ER}, title = {Oxidative stress is not required for the induction of apoptosis upon glutamine starvation of Sp2/0-Ag14 hybridoma cells.}, journal = {European journal of cell biology}, volume = {85}, number = {5}, pages = {355-365}, doi = {10.1016/j.ejcb.2005.11.004}, pmid = {16412532}, issn = {0171-9335}, mesh = {Acetylcysteine/metabolism ; Acridine Orange/metabolism ; Animals ; Apoptosis/*physiology ; Caspases/metabolism ; Cell Line ; Enzyme Activation ; Ethidium/metabolism ; Fluorescent Dyes/metabolism ; Free Radical Scavengers/metabolism ; Glutamine/*deficiency ; Glutathione/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; *Oxidative Stress ; Protein Serine-Threonine Kinases/metabolism ; Reactive Oxygen Species/metabolism ; rho-Associated Kinases ; }, abstract = {L-glutamine (Gln) withdrawal rapidly triggers apoptosis in the murine hybridoma cell line Sp2/0-Ag14 (Sp2/0). In this report, we examined the possibility that Gln deprivation of Sp2/0 cells triggers an oxidative stress which would contribute to the activation of apoptotic pathways. Gln withdrawal triggered an oxidative stress in Sp2/0 cells, as indicated by an increased accumulation of reactive oxygen species (ROS) and an increase in the intracellular content in protein carbonyl groups. Gln starvation also caused a decrease in the intracellular levels of glutathione (GSH). However, a decrease in GSH was not sufficient to induce Sp2/0 cell death since reducing GSH levels with DL-buthionine-[S,R]-sulfoximine did not affect cell viability. The antioxidant N-acetyl-L-cysteine (NAC), while effective in inhibiting ROS accumulation and oxidative stress, did not prevent the loss in cell viability or the processing and activation of caspase-3 triggered by Gln starvation. On the other hand, NAC did reduce the formation of apoptotic bodies in dying cells. Altogether these results indicate that in Sp2/0 cells, Gln deprivation leads to the induction of an oxidative stress which, while involved in the formation of apoptotic bodies, is not essential to the activation of the cell death program.}, }
@article {pmid16412470, year = {2006}, author = {Cay, A and Alver, A and Küçük, M and Işik, O and Eminağaoğlu, MS and Karahan, SC and Değer, O}, title = {The effects of N-acetylcysteine on antioxidant enzyme activities in experimental testicular torsion.}, journal = {The Journal of surgical research}, volume = {131}, number = {2}, pages = {199-203}, doi = {10.1016/j.jss.2005.11.572}, pmid = {16412470}, issn = {0022-4804}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Catalase/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Male ; Malondialdehyde/analysis ; Oxidative Stress ; Rats ; Rats, Wistar ; Reperfusion Injury/etiology/*prevention &amp; control ; Superoxide Dismutase/metabolism ; Testicular Diseases/*complications ; Torsion Abnormality/complications ; }, abstract = {Testicular torsion is a serious problem in male children and, if not treated at the right time, can lead to subfertility and infertility. The main reason for testicular damage is ischemia-reperfusion injury. A number of chemical substances have been used to protect testes against ischemia-reperfusion injury in experimental animals. The possible protective effect of N-acetylcysteine on testicular tissue after testicular detorsion was examined in the current study. Twenty-four rats were divided into four groups: sham operation, torsion, detorsion, and NAC + detorsion groups (n = 6 for each group). Excluding sham operation group, the rats were subjected to unilateral torsion (720-degree rotation in clockwise direction). After torsion (5 h) and detorsion (2 h), unilateral orchidectomy was performed. Malondialdehyde levels and superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities were determined in testicular tissue. Administration of N-acetylcysteine caused a decrease in malondialdehyde levels and an increase in glutathione peroxidase levels compared to detorsion group. The results suggest that N-acetylcysteine may be a potential protective agent for preventing the negative biochemical changes related to oxidative stress in testicular injury caused by testis torsion.}, }
@article {pmid16403990, year = {2005}, author = {Furfaro, AL and Menini, S and Patriarca, S and Pesce, C and Odetti, P and Cottalasso, D and Marinari, UM and Pronzato, MA and Traverso, N}, title = {HNE-dependent molecular damage in diabetic nephropathy and its possible prevention by N-acetyl-cysteine and oxerutin.}, journal = {BioFactors (Oxford, England)}, volume = {24}, number = {1-4}, pages = {291-298}, doi = {10.1002/biof.5520240134}, pmid = {16403990}, issn = {0951-6433}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aldehydes/*pharmacology ; Animals ; Apoptosis/drug effects ; Cell Division/drug effects ; Diabetes Mellitus, Experimental/complications ; Diabetic Nephropathies/*pathology/*prevention &amp; control ; Glycation End Products, Advanced/metabolism ; Hydroxyethylrutoside/administration &amp; dosage/*analogs &amp; derivatives ; Immunohistochemistry ; Kidney Glomerulus/chemistry/metabolism/pathology ; Lipid Peroxidation ; Lysine/analogs &amp; derivatives/metabolism ; Male ; Rats ; Rats, Wistar ; Taurine/administration &amp; dosage ; }, abstract = {Accumulation of Advanced Lipoxidation End-products (ALE), such as MDA- and HNE-protein adducts, and Advanced Glycation End-products, such as carboxymethyl-lysine (CML), are probably involved in the development of diabetic nephropathy. In this study the effect of some antioxidant treatments (oxerutin, N-acetylcysteine, taurine and N-acetylcysteine+taurine) on kidney lipoxidative damage has been evaluated by immunohistochemistry in streptozotocined rats. Diabetic rats showed marked glomerular positivity for ALE, while the samples from Control rats were negative. All treatments except taurine were able to protect the glomeruli from ALE accumulation; the failure of taurine may be due to residual oxidative properties of its derivatives. These data are consistent with those of our previous study, which showed that all the antioxidants used except taurine protected the glomeruli from diabetes-induced enlargement, increased apoptotic rate, decreased cell density and CML accumulation. These data attest to a role of glycoxidative and lipoxidative damage in diabetes-dependent damage of the kidney, and indicate that specific antioxidants can prevent or attenuate diabetic nephropathy.}, }
@article {pmid16394696, year = {2006}, author = {Hoetzel, A and Leitz, D and Schmidt, R and Tritschler, E and Bauer, I and Loop, T and Humar, M and Geiger, KK and Pannen, BH}, title = {Mechanism of hepatic heme oxygenase-1 induction by isoflurane.}, journal = {Anesthesiology}, volume = {104}, number = {1}, pages = {101-109}, doi = {10.1097/00000542-200601000-00016}, pmid = {16394696}, issn = {0003-3022}, mesh = {Acetylcysteine/pharmacology ; Anesthetics, Inhalation/*pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Blotting, Northern ; Blotting, Western ; Dexamethasone/pharmacology ; Ditiocarb/pharmacology ; Enzyme Induction/drug effects ; Enzyme Inhibitors/pharmacology ; Gadolinium/pharmacology ; Heme Oxygenase-1/*biosynthesis ; Immunohistochemistry ; Isoflurane/*pharmacology ; Isothiuronium/analogs &amp; derivatives/pharmacology ; Liver/drug effects/*enzymology ; Male ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; RNA/analysis/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; }, abstract = {BACKGROUND: The heme oxygenase pathway represents a major cell and organ protective system in the liver. The authors recently showed that isoflurane and sevoflurane up-regulate the inducible isoform heme oxygenase 1 (HO-1). Because the activating cascade remained unclear, it was the aim of this study to identify the underlying mechanism of this effect.<br><br>METHODS: Rats were anesthetized with pentobarbital intravenously or with isoflurane per inhalation (2.3 vol%). Kupffer cell function was inhibited by dexamethasone or gadolinium chloride. Nitric oxide synthases were inhibited by either N(omega)-nitro-L-arginine methyl ester or S-methyl thiourea. N-acetyl-cysteine served as an antioxidant, and diethyldithiocarbamate served as an inhibitor of cytochrome P450 2E1. Protein kinase C and phospholipase A2 were inhibited by chelerythrine or quinacrine, respectively. HO-1 was analyzed in liver tissue by Northern blot, Western blot, immunostaining, and enzymatic activity assay.<br><br>RESULTS: In contrast to pentobarbital, isoflurane induced HO-1 after 4-6 h in hepatocytes in the pericentral region of the liver. The induction was prevented in the presence of dexamethasone (P < 0.05) and gadolinium chloride (P < 0.05). Inhibition of nitric oxide synthases or reactive oxygen intermediates did not affect isoflurane-mediated HO-1 up-regulation. In contrast, chelerythrine (P < 0.05) and quinacrine (P < 0.05) resulted in a blockade of HO-1 induction.<br><br>CONCLUSION: The up-regulation of HO-1 by isoflurane in the liver is restricted to parenchymal cells and depends on Kupffer cell function. The induction is independent of nitric oxide or reactive oxygen species but does involve protein kinase C and phospholipase A2.}, }
@article {pmid16394509, year = {2006}, author = {Nakano, H and Ikenaga, S and Aizu, T and Kaneko, T and Matsuzaki, Y and Tsuchida, S and Hanada, K and Arima, Y}, title = {Human metallothionein gene expression is upregulated by beta-thujaplicin: possible involvement of protein kinase C and reactive oxygen species.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {29}, number = {1}, pages = {55-59}, doi = {10.1248/bpb.29.55}, pmid = {16394509}, issn = {0918-6158}, mesh = {Acetylcysteine/pharmacology ; Alkaloids ; Benzophenanthridines ; Blotting, Western ; Enzyme Inhibitors/pharmacology ; Epidermal Cells ; Free Radical Scavengers/pharmacology ; Genes, Reporter/genetics ; Humans ; Keratinocytes/metabolism ; Metallothionein/*genetics ; Monoterpenes/*pharmacology ; Phenanthridines/pharmacology ; Plasmids/genetics ; Protein Kinase C/antagonists &amp; inhibitors/*metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tropolone/*analogs &amp; derivatives/pharmacology ; Up-Regulation/*drug effects ; }, abstract = {Recently, we discovered that beta-thujaplicin (BT) induces metallothionein (MT) expression in mouse keratinocytes, both in vivo and in vitro. However, the molecular mechanisms by which BT exerts its biological effects have not been elucidated. The purpose of this study is to explore the signal transduction pathway involved in the MT mRNA induction by BT. Using a HaCaT keratinocyte cell line, Northern blotting was performed for analyzing the human MT-IIA mRNA expression levels in combination with BT and a number of protein kinase (PK) inhibitors including H7, HA1004 and a PKC-specific inhibitor chelerythrin. CAT assays with the MT-IIA gene promorter-CAT construct were conducted for examining the transcriptional regulation by BT of MT. A free radical scavenger N-acetylcysteine (NAC) was used for analyzing a role of oxidative stress for the MT gene induction by BT. BT increased MT-IIA gene transcript levels and CAT activity in a dose-dependent fashion in HaCaT cells. The increase in MT-IIA mRNA levels and CAT activity were completely suppressed by H7 but not by HA1004. In addition, chelerythrin prevented BT-inducible MT-IIA promoter activation. Furthermore, NAC suppressed BT-inducible MT-IIA promoter activation. These results demonstrate that BT is a potent activator of the MT-IIA gene promoter and that PKC activation and reactive oxygen species are implicated in BT-inducible MT-IIA gene expression. BT may be a useful tool for dissecting the signal transduction pathway mediating MT-IIA promoter activation.}, }
@article {pmid16391241, year = {2006}, author = {Chen, CH and Cheng, TH and Lin, H and Shih, NL and Chen, YL and Chen, YS and Cheng, CF and Lian, WS and Meng, TC and Chiu, WT and Chen, JJ}, title = {Reactive oxygen species generation is involved in epidermal growth factor receptor transactivation through the transient oxidization of Src homology 2-containing tyrosine phosphatase in endothelin-1 signaling pathway in rat cardiac fibroblasts.}, journal = {Molecular pharmacology}, volume = {69}, number = {4}, pages = {1347-1355}, doi = {10.1124/mol.105.017558}, pmid = {16391241}, issn = {0026-895X}, mesh = {Animals ; Endothelin-1/*metabolism ; ErbB Receptors/*genetics ; Immunoprecipitation ; Oxidation-Reduction ; Protein Tyrosine Phosphatases/*metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; *Signal Transduction ; *Transcriptional Activation ; src Homology Domains ; }, abstract = {Endothelin-1 (ET-1) is implicated in fibroblast proliferation, which results in cardiac fibrosis. Both reactive oxygen species (ROS) generation and epidermal growth factor receptor (EGFR) transactivation play critical roles in ET-1 signal transduction. In this study, we used rat cardiac fibroblasts treated with ET-1 to investigate the connection between ROS generation and EGFR transactivation. ET-1 treatment was found to stimulate the phosphorylation of EGFR and ROS generation, which were abolished by ETA receptor antagonist N-(N-(N-((hexahydro-1H-azepin-1-yl)carbonyl)-L-leucyl)-D-tryptophyl)-D-tryptophan (BQ485). NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI), ROS scavenger N-acetyl cysteine (NAC), and p47phox small interfering RNA knockdown all inhibited the EGFR transactivation induced by ET-1. In contrast, EGFR inhibitor 4-(3'-chloroanilino)-6,7-dimethoxyquinazoline (AG-1478) cannot inhibit intracellular ROS generation induced by ET-1. Src homology 2-containing tyrosine phosphatase (SHP-2) was shown to be associated with EGFR during ET-1 treatment by EGFR coimmunoprecipitation. ROS have been reported to transiently oxidize the catalytic cysteine of phosphotyrosine phosphatases to inhibit their activity. We examined the effect of ROS on SHP-2 in cardiac fibroblasts using a modified malachite green phosphatase assay. SHP-2 was transiently oxidized during ET-1 treatment, and this transient oxidization could be repressed by DPI or NAC treatment. In SHP-2 knockdown cells, ET-1-induced phosphorylation of EGFR was dramatically elevated and is not influenced by NAC and DPI. However, this elevation was suppressed by GM6001 [a matrix metalloproteinase (MMP) inhibitor] and heparin binding (HB)-epidermal growth factor (EGF) neutralizing antibody. Our data suggest that ET-1-ETA-mediated ROS generation can transiently inhibit SHP-2 activity to facilitate the MMP-dependent and HB-EGF-stimulated EGFR transactivation and mitogenic signal transduction in rat cardiac fibroblasts.}, }
@article {pmid16390850, year = {2006}, author = {Nitescu, N and Ricksten, SE and Marcussen, N and Haraldsson, B and Nilsson, U and Basu, S and Guron, G}, title = {N-acetylcysteine attenuates kidney injury in rats subjected to renal ischaemia-reperfusion.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {21}, number = {5}, pages = {1240-1247}, doi = {10.1093/ndt/gfk032}, pmid = {16390850}, issn = {0931-0509}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/*drug therapy/pathology ; Analysis of Variance ; Animals ; Biopsy, Needle ; Creatinine/blood ; Disease Models, Animal ; Glomerular Filtration Rate/drug effects ; Glutathione/metabolism ; Immunohistochemistry ; Male ; Oxidative Stress/*drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Reference Values ; Renal Circulation/drug effects ; Reperfusion Injury/*drug therapy/pathology ; Statistics, Nonparametric ; }, abstract = {BACKGROUND: The aim of the present study is to examine the effects of N-acetylcysteine (NAC), a thiol-containing anti-oxidant, on renal function and morphology, and biomarkers of oxidative stress, in rats subjected to renal ischaemia-reperfusion (IR).<br><br>METHODS: Sprague-Dawley rats underwent unilateral nephrectomy and either contralateral renal IR (40 min of renal arterial clamping), or sham manipulation. Treatment groups were: (1) IR-Saline, (2) IR-NAC, (3) Sham-Saline and (4) Sham-NAC. The N-acetylcysteine was administered in a dose of 200 mg/kg intraperitoneally at 24, 12 and 2 h before, and 24, 48 and 72 h after, renal IR. Plasma creatinine was measured on days 1, 3 and 7 after IR, and kidney histology was assessed on day 7. In separate groups of animals we measured renal levels of the anti-oxidant glutathione, markers of systemic oxidative stress (plasma ascorbyl radical, urinary 8-iso-prostaglandin F2alpha), and glomerular filtration rate (GFR) by 51Cr-EDTA clearance, on day 1 after renal IR.<br><br>RESULTS: Treatment with NAC ameliorated the decline in GFR and reduced hyperkalaemia on day 1 (P<0.05), lowered plasma creatinine levels on days 1 and 3 (P<0.05), and decreased renal interstitial inflammation on day 7 (P<0.05), after renal IR. Kidney glutathione levels decreased significantly in group IR-Saline in response to IR (P<0.05), but were completely repleted in group IR-NAC. Groups with renal IR injury and acute renal failure showed increased plasma ascorbyl radical levels, and elevated urinary 8-iso-prostaglandin F2alpha excretion, compared with sham (P<0.05). N-acetylcysteine treatment reduced plasma ascorbyl concentrations 24 h after renal IR (P<0.05), but had no effect on the rate of urinary 8-iso-prostaglandin F2alpha excretion.<br><br>CONCLUSIONS: N-acetylcysteine improves kidney function, and reduces renal interstitial inflammation, in rats subjected to renal IR. These effects were associated with increased renal glutathione levels, and decreased plasma ascorbyl concentrations, suggesting that NAC attenuates renal and systemic oxidative stress in this model.}, }
@article {pmid16390827, year = {2006}, author = {Xia, Z and Nagareddy, PR and Guo, Z and Zhang, W and McNeill, JH}, title = {Antioxidant N-acetylcysteine restores systemic nitric oxide availability and corrects depressions in arterial blood pressure and heart rate in diabetic rats.}, journal = {Free radical research}, volume = {40}, number = {2}, pages = {175-184}, doi = {10.1080/10715760500484336}, pmid = {16390827}, issn = {1071-5762}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Arteries ; Blood Pressure/*drug effects ; Diabetes Mellitus, Experimental/*metabolism/prevention &amp; control ; Dinoprost/analogs &amp; derivatives/blood/metabolism ; Free Radicals/metabolism ; Heart Rate/*drug effects ; Lipid Peroxidation ; Male ; Nitrates/blood ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type III/metabolism ; Nitrites/blood ; Rats ; Rats, Wistar ; Streptozocin/toxicity ; Vasoconstrictor Agents/blood ; }, abstract = {Increased oxidative stress and reduced nitric oxide (NO) bioactivity are key features of diabetes mellitus that eventually result in cardiovascular abnormalities. We assessed whether N-acetylcysteine (NAC), an antioxidant and glutathione precursor, could prevent the hyperglycaemia induced increase in oxidative stress, restore NO availability and prevent depression of arterial blood pressure and heart rate in vivo in experimental diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were treated or not treated with NAC in drinking water for 8 weeks, initiated 1 week after induction of diabetes. At termination, plasma levels of free 15-F2t-isoprostane, a specific marker of oxygen free radical induced lipid peroxidation, was increased while the plasma total antioxidant concentration was decreased in untreated diabetic rats as compared to control rats (P<0.05). This was accompanied by a significant reduction of plasma levels of nitrate and nitrite, stable metabolites of NO, (P<0.05, D vs. C) and a reduced endothelial NO synthase protein expression in the heart and in aortic and mesenteric artery tissues. Systolic, diastolic and mean arterial blood pressures (SBP, DBP and MAP) and heart rate (HR) were reduced in diabetic rats (P<0.05 vs. C) and NAC normalised the changes that occurred in the diabetic rats. The protective effects may be attributable to restoration of NO bioavailability in the circulation.}, }
@article {pmid16390826, year = {2006}, author = {Niwa, K and Sakai, J and Karino, T and Aonuma, H and Watanabe, T and Ohyama, T and Inanami, O and Kuwabara, M}, title = {Reactive oxygen species mediate shear stress-induced fluid-phase endocytosis in vascular endothelial cells.}, journal = {Free radical research}, volume = {40}, number = {2}, pages = {167-174}, doi = {10.1080/10715760500474287}, pmid = {16390826}, issn = {1071-5762}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Aorta ; Cattle ; *Endocytosis ; Endothelium, Vascular/drug effects/*metabolism ; Enzyme Inhibitors/pharmacology ; Immunoprecipitation ; Indoles/pharmacology ; Isoquinolines ; Maleimides/pharmacology ; Membrane Fluidity ; NADPH Oxidases/antagonists &amp; inhibitors ; Naphthalenes/pharmacology ; Phase Transition ; Protein Kinase C/antagonists &amp; inhibitors ; Reactive Oxygen Species/*metabolism ; Shear Strength ; Solutions ; *Stress, Mechanical ; }, abstract = {To elucidate the role of shear stress in fluid-phase endocytosis of vascular endothelial cells (EC), we used a rotating-disk shearing apparatus to investigate the effects of shear stress on the uptake of lucifer yellow (LY) by cultured bovine aortic endothelial cells (BAEC). Exposure of EC to shear stress (area-mean value of 10 dynes/cm2) caused an increase in LY uptake that was abrogated by the antioxidant, N-acetyl-L-cysteine (NAC), the NADPH oxidase inhibitor, acetovanillone, and two inhibitors of protein kinase C (PKC), calphostin C and GF109203X. These results suggest that fluid-phase endocytosis is regulated by both reactive oxygen species (ROS) and PKC. Shear stress increased both ROS production and PKC activity in EC, and the increase in ROS was unaffected by calphostin C or GF109203X, whereas the activation of PKC was reduced by NAC and acetovanillone. We conclude that shear stress-induced increase in fluid-phase endocytosis is mediated via ROS generation followed by PKC activation in EC.}, }
@article {pmid16390346, year = {2006}, author = {Aitio, ML}, title = {N-acetylcysteine -- passe-partout or much ado about nothing?.}, journal = {British journal of clinical pharmacology}, volume = {61}, number = {1}, pages = {5-15}, pmid = {16390346}, issn = {0306-5251}, mesh = {Acetylcysteine/*therapeutic use ; Anti-HIV Agents/therapeutic use ; Antioxidants/therapeutic use ; Cardiovascular Diseases/drug therapy ; Drug Therapy, Combination ; Expectorants/*therapeutic use ; HIV Infections/drug therapy ; Humans ; Kidney Diseases/prevention &amp; control ; Liver Diseases/drug therapy ; Lung Diseases/drug therapy ; Neoplasms/drug therapy ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {In experimental studies, the old mucolytic agent N-acetylcysteine (NAC) has had beneficial effects in disorders supposedly linked to oxidative stress. Numerous, mainly small clinical trials with variable doses have yielded inconsistent results in a wide variety of diseases. NAC added to the conventional therapy of human immunodeficiency virus infection might be of benefit; in respect of chronic obstructive pulmonary disease, systematic reviews and meta-analyses suggested that prolonged treatment with NAC is efficacious, but a recent multicentre study has questioned this. In a large intervention trial on cancer recurrence, NAC was ineffective. NAC infusions have been widely used in acute hepatic failure but convincing evidence of its benefits is lacking. A preliminary study reported that NAC is effective in preventing radiocontrast-induced nephropathy but thereafter highly mixed results have been published, and even meta-analyses disagree on its efficacy. In intensive care NAC has mostly been a disappointment but recently it has 'given promises' in surgery with cardiopulmonary bypass. NAC therapy is routine only in paracetamol intoxication.}, }
@article {pmid16389042, year = {2006}, author = {Beloosesky, R and Gayle, DA and Amidi, F and Nunez, SE and Babu, J and Desai, M and Ross, MG}, title = {N-acetyl-cysteine suppresses amniotic fluid and placenta inflammatory cytokine responses to lipopolysaccharide in rats.}, journal = {American journal of obstetrics and gynecology}, volume = {194}, number = {1}, pages = {268-273}, doi = {10.1016/j.ajog.2005.06.082}, pmid = {16389042}, issn = {1097-6868}, support = {K01 DK 063994/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Amniotic Fluid/*metabolism ; Animals ; Antioxidants/*pharmacology ; Cytokines/*antagonists &amp; inhibitors ; Female ; Inflammation Mediators/*antagonists &amp; inhibitors ; Interleukin-10/blood ; Interleukin-6/blood/genetics/metabolism ; Lipopolysaccharides/*pharmacology ; Placenta/*metabolism ; Pregnancy ; RNA, Messenger/antagonists &amp; inhibitors/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: Maternal infections may induce placental, amniotic and, potentially, fetal inflammatory responses. As cytokine responses may be mediated by oxidative stress, we determined whether the antioxidant N-acetyl-cysteine (NAC), can attenuate maternally induced amniotic and placental cytokine responses to maternal infection (modeled by lipopolysaccharide [LPS]).<br><br>STUDY DESIGN: Gestation day 18 pregnant rats were (1) treated with LPS (100 microg/kg, body weight; intraperitoneally) alone; (2) pretreated with NAC (300 mg/kg body weight; intraperitoneally) 30 minutes before LPS; (3) posttreated with NAC 120 minutes after LPS; or (4) treated with NAC 30 minutes before and 120 minutes after LPS. Six hours after LPS administration, maternal serum and amniotic fluid interleukin-6 (IL-6) and IL-10 levels, and placental IL-6 messenger RNA levels were determined.<br><br>RESULTS: LPS increased maternal serum IL-6 (50 +/- 25 to 3444 +/- 584 pg/mL) and IL-10 (40 +/- 20 to 958 +/- 339 pg/mL) and amniotic fluid IL-6 (59 +/- 25 to 891 +/- 128 pg/mL). Pretreatment and/or posttreatment with NAC attenuated IL-6 in the maternal serum and amniotic fluid and IL-10 in the amniotic fluid. LPS also induced placental IL-6 messenger RNA that was inhibited by treatment with NAC before and after LPS.<br><br>CONCLUSION: NAC inhibition of inflammatory responses may protect the fetus from potential long-term sequelae.}, }
@article {pmid16388726, year = {2005}, author = {Salsano, F and Letizia, C and Proietti, M and Rossi, C and Proietti, AR and Rosato, E and Pisarri, S}, title = {Significant changes of peripheral perfusion and plasma adrenomedullin levels in N-acetylcysteine long term treatment of patients with sclerodermic Raynauds phenomenon.}, journal = {International journal of immunopathology and pharmacology}, volume = {18}, number = {4}, pages = {761-770}, doi = {10.1177/039463200501800420}, pmid = {16388726}, issn = {0394-6320}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Adrenomedullin ; Adult ; Aged ; Female ; Fingers/blood supply ; Free Radical Scavengers/adverse effects/*therapeutic use ; Humans ; Inflammation Mediators/metabolism ; Laser-Doppler Flowmetry ; Male ; Microcirculation/drug effects ; Middle Aged ; Peptides/*blood ; Raynaud Disease/*drug therapy/pathology/*physiopathology ; Regional Blood Flow/drug effects ; Scleroderma, Localized/*drug therapy/pathology/*physiopathology ; Skin/pathology ; Treatment Outcome ; }, abstract = {The unclear pathogenesis of scleroderma vascular lesions makes treatment of Raynaud's phenomenon (RP) in Systemic Sclerosis (SSc) patients very difficult and a new effective treatment is requested. Recently, a powerful antioxidant agent, the N-acetylcysteine (NAC) has been shown to decrease the frequency and severity of RP in SSc patients. Subsequently, using functional infrared imaging, we showed that a single 1-hour NAC infusion in these patients caused a significant increase of skin temperature. The aim of this study was to demonstrate the efficacy of long term therapy with NAC in an open clinical trial evaluating clinical, instrumental and laboratory parameters. Patients started the treatment receiving for two years, from October to May, intravenous NAC infusions of 15 mg/kg per hour each, for 5 consecutive hours, every two weeks. Before and after each infusion, patients underwent both Laser Doppler perfusion Imaging (LDPI) for the evaluation of the digital perfusion and a blood test to ascertain the plasma adrenomedullin (AM) levels. The NAC infusion increased global hands perfusion and induced a significant decreasing of plasma AM concentrations. Side effects were negligible, easy to control and reversible. Reduction of frequency and severity of RP attacks was recorded. In conclusion, NAC seems to act as an effective vasodilatator in the treatment of RP secondary to SSc and, in addition, it induced significant changes in plasma levels of AM, a potent vasodilator endothelial-derived peptide.}, }
@article {pmid16387404, year = {2006}, author = {Yang, SA and Paek, SH and Kozukue, N and Lee, KR and Kim, JA}, title = {Alpha-chaconine, a potato glycoalkaloid, induces apoptosis of HT-29 human colon cancer cells through caspase-3 activation and inhibition of ERK 1/2 phosphorylation.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {44}, number = {6}, pages = {839-846}, doi = {10.1016/j.fct.2005.11.007}, pmid = {16387404}, issn = {0278-6915}, mesh = {Apoptosis/*drug effects ; Caspase 3 ; Caspases/*metabolism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/*pharmacology ; HT29 Cells ; Humans ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/*metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/*metabolism ; Phosphorylation/drug effects ; Solanine/*analogs &amp; derivatives/pharmacology ; }, abstract = {Although alpha-chaconine, one of the two major potato trisaccharide glycoalkaloids, have shown cytotoxic effects on human cancer cells, the exact mechanism of this action of alpha-chaconine is not completely understood. In this study, we found that alpha-chaconine induced apoptosis of HT-29 cells in a time- and concentration-dependent manner by using flow cytometric analysis. We also found that caspase-3 activity and the active form of caspase-3 were increased 12 h after alpha-chaconine treatment. Caspase inhibitors, N-Ac-DEVD-CHO and Z-VAD-fmk, prevented alpha-chaconine-induced apoptosis, whereas alpha-chaconine-induced apoptosis was potentiated by PD98059, an extracellular signal-regulated kinase (ERK) inhibitor. However, pretreatment of the cells with LY294002 and SB203580, inhibitors of PI3K and p38, respectively, BAPTA-AM, an intracellular Ca(2+) chelator, and antioxidants such as N-acetylcysteine (NAC) and Trolox had no effect on the alpha-chaconine-induced cell death. In addition, phosphorylation of ERK was reduced by the treatment with alpha-chaconine. Moreover, alpha-chaconine-induced caspase-3 activity was further increased by the pretreatment with PD98059. Thus, the results indicate that alpha-chaconine induces apoptosis of HT-29 cells through inhibition of ERK and, in turn, activation of caspase-3.}, }
@article {pmid16387166, year = {2005}, author = {Chen, CF and Leu, FJ and Chen, HI and Wang, D}, title = {Oxygen radicals and matrix metalloproteinases mediate reperfusion liver injury.}, journal = {Transplantation proceedings}, volume = {37}, number = {10}, pages = {4547-4549}, doi = {10.1016/j.transproceed.2005.10.120}, pmid = {16387166}, issn = {0041-1345}, mesh = {Acetylcysteine/blood ; Animals ; Hepatic Artery ; Hydrogen Peroxide/*blood ; Ischemia/*blood ; *Liver Circulation ; Male ; Matrix Metalloproteinase 9/blood ; Matrix Metalloproteinases/*blood ; Portal Vein ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*prevention &amp; control ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Many pathological processes involve the breakdown and remodeling of the extracellular matrix, which is mediated by the family of important enzymes known as matrix metalloproteinases (MMPs). One such process is warm ischemia/reperfusion (I/R) injury, the most important cause of dysfunction of liver allografts. We monitored protein expression of MMP-9 by Western blotting in rat liver after I/R. We also monitored changes in total MMP activity in the serum before and after I/R. Ischemia was induced by clamping the common hepatic artery and portal vein for 40 minutes and reperfusing for 90 minutes. Blood samples collected before ischemia and after reperfusion were analyzed for AST, hydroxyl radical, and tumor necrosis factor (TNFalpha). This protocol resulted in a high level of MMP-9 expression in liver tissue. Total MMP activity in serum was also significantly increased. Levels of AST, hydroxyl radicals, and TNF alpha were concomitantly increased. Ilomastat, an MMP inhibitor, attenuated the I/R-induced liver injury. After administration of the oxygen radical scavenger N-acetylcysteine (NAC), total MMP activity was suppressed, and liver injury was again attenuated. These results indicated that reperfusion liver injury induced an increase in MMP-9 protein expression and in serum MMP activity. The protective effects of an MMP inhibitor and NAC indicate that oxygen radical production is involved in MMP expression and liver injury associated with I/R.}, }
@article {pmid16386719, year = {2006}, author = {Bartov, O and Sultana, R and Butterfield, DA and Atlas, D}, title = {Low molecular weight thiol amides attenuate MAPK activity and protect primary neurons from Abeta(1-42) toxicity.}, journal = {Brain research}, volume = {1069}, number = {1}, pages = {198-206}, doi = {10.1016/j.brainres.2005.10.079}, pmid = {16386719}, issn = {0006-8993}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Amides/*pharmacology ; Amyloid beta-Peptides/antagonists &amp; inhibitors/*toxicity ; Animals ; Animals, Newborn ; Blotting, Western/methods ; Cells, Cultured ; Cerebral Cortex/cytology ; Dipeptides/pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Free Radical Scavengers/*pharmacology ; Glutathione/analogs &amp; derivatives ; Lipid Peroxidation/drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; Molecular Weight ; Neurons/*drug effects/physiology ; Oligopeptides/pharmacology ; Oxidation-Reduction/drug effects ; Peptide Fragments/antagonists &amp; inhibitors/*toxicity ; Rats ; Rats, Sprague-Dawley ; Tetrazolium Salts ; Thiazoles ; Tyrosine/analogs &amp; derivatives/metabolism ; }, abstract = {Oxidative stress caused by various stimuli lead to oxidation of glutathione (GSH), the major redox power of the cell. Amyloid beta [Abeta(1-42)] is one of the key components of senile plaques and is involved in the progress initiation and triggers of Alzheimer's disease (AD). Lower GSH levels correlated with the activation of mitogen-activated proteins kinases (MAPK) have been demonstrated in AD, Parkinson's disease (PD) and other neurodegenerative disorders and have been proposed to play a central role in the deterioration of the aging and neurodegenerative brain. In this study, we evaluated the ability of low molecular weight thiol amides, N-acetyl cysteine amide (AD4) that replenishes GSH levels, N-acetyl glycine cysteine amide (AD7) and N-acetyl-Cys-Gly-Pro-Cys-amide (CB4) to protect primary neuronal culture against the oxidative and neurotoxic effects of Abeta(1-42) and to inhibit cisplatin- and hydrogen-peroxide-induced phosphorylation of two MAP kinases (MAPK), p38 and ERK1/2, in NIH3T3 cells. Cell death induced by Abeta(1-42) in primary neuronal cells was reversed by the thiol amides. Likewise, protein oxidation, loss of mitochondrial function and DNA fragmentation all returned to control levels by pretreatment with the three thiol amides. Elevated phosphorylation of ERK1/2 and p38 induced by cisplatin or H2O2 in NIH3T3 cells was lowered by AD4, AD7 and CB4 in a dose-dependent manner. Taken together, these results suggest that the thiol amides AD4, AD7 and CB4 protect neuronal cells against Abeta(1-42) toxicity by attenuating oxidative stress in correlation with inhibiting the MAPK phosphorylation cascade. These results are consistent with the notion that these small molecular thiol amides may play a viable protective role in the oxidative and neurotoxicity induced by Abeta(1-42) in AD brain.}, }
@article {pmid16384711, year = {2006}, author = {Sadowska, AM and Manuel-y-Keenoy, B and Vertongen, T and Schippers, G and Radomska-Lesniewska, D and Heytens, E and De Backer, WA}, title = {Effect of N-acetylcysteine on neutrophil activation markers in healthy volunteers: in vivo and in vitro study.}, journal = {Pharmacological research}, volume = {53}, number = {3}, pages = {216-225}, doi = {10.1016/j.phrs.2005.11.003}, pmid = {16384711}, issn = {1043-6618}, mesh = {Acetylcysteine/*pharmacology ; Adult ; *Chemotaxis, Leukocyte ; Dose-Response Relationship, Drug ; Female ; Humans ; In Vitro Techniques ; Interleukin-8/metabolism ; Male ; Middle Aged ; NF-kappa B/metabolism ; *Neutrophil Activation ; Neutrophils/*drug effects/enzymology ; Pancreatic Elastase/metabolism ; Respiratory Burst ; Time Factors ; }, abstract = {BACKGROUND AND AIMS: Neutrophil activation is implicated in the pathogenesis of inflammatory processes such as chronic obstructive pulmonary disease (COPD). We wished to evaluate both in vivo and in vitro whether N-acetylcysteine (NAC) has an effect on the response of activated neutrophils.<br><br>METHODS: Ten healthy volunteers took NAC (600 mg daily) for 14 days. The effects on basal and fMLP-induced respiratory burst and chemotaxis were assessed at baseline, 2 h and 14 days after NAC intake. Neutrophils from healthy volunteers (NAC na&#xef;ve) were pre-incubated with NAC for 30 min and the effects on the release of elastase and IL-8, the respiratory burst in response to fMLP and PMA, on TNFalpha-induced NFkappaB activation and on the migration across an endothelial-epithelial bilayer were investigated.<br><br>RESULTS: PMA and fMLP-induced neutrophil respiratory burst and chemotaxis were lower after 14 days of NAC intake but not after 2 h. In vitro incubation with NAC inhibited release of elastase (p < 0.05), IL-8 (p < 0.05), respiratory burst and NFkappaB activation at 10 mM but not at lower concentrations. This was accompanied by a decrease in cellular ATP content.<br><br>CONCLUSIONS: Our results suggest that acute in vitro addition of NAC can modulate neutrophil activity only when used at the high concentrations which directly affect cellular metabolism. On the other hand, the lower doses of NAC given in vivo might require longer times in order to achieve sustained effects on the cellular thiols which lead to changes in the redox status.}, }
@article {pmid16382175, year = {2005}, author = {Lattanzio, FA and Tiangco, D and Osgood, C and Beebe, S and Kerry, J and Hargrave, BY}, title = {Cocaine increases intracellular calcium and reactive oxygen species, depolarizes mitochondria, and activates genes associated with heart failure and remodeling.}, journal = {Cardiovascular toxicology}, volume = {5}, number = {4}, pages = {377-390}, doi = {10.1385/ct:5:4:377}, pmid = {16382175}, issn = {1530-7905}, mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium/*metabolism ; Calcium Channel Blockers/pharmacology ; Cocaine/*toxicity ; Dose-Response Relationship, Drug ; Female ; Gene Expression Regulation/*drug effects ; Glutathione/pharmacology ; Heart Failure/genetics ; Intracellular Membranes/drug effects/physiology ; Membrane Potentials/drug effects/physiology ; Microscopy, Confocal ; Mitochondria/*drug effects ; Myocytes, Cardiac/drug effects/metabolism ; Narcotics/*toxicity ; Oligonucleotide Array Sequence Analysis ; Rabbits ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Transcriptional Activation ; Ventricular Function, Left/drug effects/genetics ; Ventricular Remodeling/genetics ; }, abstract = {To determine the cardiovascular molecular events associated with acute exposure to cocaine, the present study utilized in vivo analysis of left-ventricular heart function in adult rabbits, fluorescence confocal microscopy of fluo-2, rhod-2, (5-(and-6) carboxy 2',7' dichlorodihydrofluores-cein diacetate (carboxy-H2DCFDA), and JC-1 in H9C2 cells and gene expression microarray technology for analysis of gene activation in both rabbit ventricular tissue and H9C2 cells. In the rabbit, acute cocaine exposure (2 mg/kg) caused left-ventricular dysfunction and 0.1-10 mM cocaine increased cytosolic and mitochondrial calcium activity and mitochondrial membrane depolarization in H9C2 cells. A 3-min pretreatment of H9C2 cells by 10 microM verapamil, nifedipine, or nadolol inhibited calcium increases, but only 1 mM N-acetylcysteine (NAC) or 1 mM glutathione blocked mitochondrial membrane depolarization. Cocaine induced activation of genes in the rabbit heart and H9C2 cells including angiotensinogen, ADRB1, and c-reactive protein (CRP). In H9C2 cells, NAC pretreatment blocked cocaine-mediated increases in CRP, FAS, FAS ligand, and cytokine receptor-like factor1 (CRLF1) expression. Collectively, these data suggest that acute cocaine administration initiates cellular and genetic changes that, if chronically manifested, could cause cardiac deficits similar to those seen in heart failure and ischemia, such as ventricular dysfunction, cardiac arrhythmias, and cardiac remodeling.}, }
@article {pmid16378625, year = {2006}, author = {Wu, CC and Hsu, MC and Hsieh, CW and Lin, JB and Lai, PH and Wung, BS}, title = {Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways.}, journal = {Life sciences}, volume = {78}, number = {25}, pages = {2889-2897}, doi = {10.1016/j.lfs.2005.11.013}, pmid = {16378625}, issn = {0024-3205}, mesh = {Animals ; Antioxidants/*pharmacology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cattle ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects/enzymology/metabolism ; Enzyme Inhibitors/pharmacology ; Extracellular Signal-Regulated MAP Kinases/antagonists &amp; inhibitors/*physiology ; Heme Oxygenase-1/*biosynthesis ; Oxidative Stress/drug effects ; Phosphatidylinositol 3-Kinases/*physiology ; Phosphoinositide-3 Kinase Inhibitors ; Signal Transduction/*drug effects ; Up-Regulation ; }, abstract = {Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated by various phytochemicals and we examined the ability of Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, to upregulate HO-1 expression in endothelial cells (ECs). We demonstrate that EGCG induces HO-1 expression in a concentration- and time-dependent manner. Furthermore, EGCG-mediated HO-1 induction was abrogated in the presence of actinomycin D and cycloheximide, indicating that this upregulation of HO-1 occurred at the transcriptional level. EGCG also upregulates Nrf2 levels in nuclear extracts and increases ARE-luciferase activity. Furthermore, EGCG is the most potent inducer of HO-1 expression of the different green tea constituents that we analyzed, but had no detectable cytotoxic effects over the 25-100 microM dosage range. The inhibition of intracellular ROS production by N-acetylcysteine (NAC), glutathione (GSH), superoxide dismutase (SOD), catalase and the mitochondrial complex I inhibitor, rotenone, results in a decrease in EGCG-dependent HO-1 expression. In addition, we determined that tyrosine kinase is involved in EGCG induction of HO-1 as this is abrogated by genistein. ECs treated with EGCG exhibit activation of Akt and ERK1/2. In addition, pharmacological inhibitors of phosphatidylinositol 3-kinase and MEK1/2, which are upstream of Akt and ERK1/2, respectively, attenuate EGCG-induced HO-1 expression. On the other hand, pretreatment of these cells with EGCG exerts significant cytoprotective effects against H2O2, suggesting that the induction of HO-1 is an important component in the protection against oxidative stress. Hence, EGCG is a novel phytochemical inducer of HO-1 expression and we further identify the principal underlying mechanisms involved in this process.}, }
@article {pmid16377126, year = {2006}, author = {Omata, Y and Lewis, JB and Lockwood, PE and Tseng, WY and Messer, RL and Bouillaguet, S and Wataha, JC}, title = {Gold-induced reactive oxygen species (ROS) do not mediate suppression of monocytic mitochondrial or secretory function.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {20}, number = {5}, pages = {625-633}, doi = {10.1016/j.tiv.2005.11.001}, pmid = {16377126}, issn = {0887-2333}, mesh = {Auranofin/toxicity ; Cells, Cultured ; Gold Compounds/*toxicity ; Gold Sodium Thiomalate/toxicity ; Humans ; Mitochondria/*drug effects/metabolism ; Monocytes/*drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {UNLABELLED: The toxicity of anti-rheumatic gold compounds has limited their use and development, yet both the toxicological and therapeutic actions of these compounds remain unclear. In the current study, we tested the hypothesis that intracellular reactive oxygen species (ROS) induced by Au(I) or Au(III) compounds mediate their ability to suppress mitochondrial activity.<br><br>METHODS: Human THP1 monocytes were exposed to HAuCl(4) x 3H(2)O (Au(III)), or the anti-rheumatic compounds auranofin (AF) or gold sodium thiomalate (GSTM) for 6-72 h, after which mitochondrial activity (succinate dehydrogenase) was measured. To assess the role of cellular redox status as a mediator of mitochondrial suppression, monocytes were pre-treated with a pro-oxidant (t-butyl hydroquinone, t-BHQ) or antioxidant (N-acetyl cysteine, NAC). ROS levels were measured 0-24h post-gold addition to determine their role as mediators of mitochondrial activity suppression.<br><br>RESULTS: AF was the most potent inhibitor of mitochondrial activity, followed by Au(III) and GSTM. Only Au(III) induced intracellular ROS; no ROS formation was observed in response to AF or GSTM exposure. Although anti- and pro-oxidants had some effects on mitochondrial suppression of Au compounds, collectively the data do not support redox effects or ROS formation as major mediators of Au-compound mitochondrial suppression.<br><br>CONCLUSIONS: Our results do not indicate that ROS and redox effects play major roles in mediating the cytotoxicity of AF, GSTM or Au(III).}, }
@article {pmid16377052, year = {2006}, author = {Demiralay, R and Gürsan, N and Erdem, H}, title = {The effects of erdosteine, N-acetylcysteine, and vitamin E on nicotine-induced apoptosis of pulmonary cells.}, journal = {Toxicology}, volume = {219}, number = {1-3}, pages = {197-207}, doi = {10.1016/j.tox.2005.11.020}, pmid = {16377052}, issn = {0300-483X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Bronchoalveolar Lavage Fluid/chemistry ; Epithelial Cells/drug effects ; Expectorants/*pharmacology ; Lung/*cytology/drug effects ; Nicotine/*toxicity ; Nicotinic Agonists/*toxicity ; *Nicotinic Antagonists ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Thioglycolates/*pharmacology ; Thiophenes/*pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Vitamin E/*pharmacology ; }, abstract = {This study was conducted to investigate the frequency of apoptosis in the pulmonary epithelial cells of rats after intratraperitoneal nicotine injection, in order to examine the role of inflammatory markers [myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-alpha)] in nicotine-induced lung damage, and to determine the protective effects of three known antioxidant agents [N-acetylcysteine (NAC), erdosteine, and vitamin E] on the lung toxicity of nicotine in the lungs. Female Wistar rats were divided into seven groups, each composed of nine rats: two negative control groups, two positive control groups, one erdosteine-treated group (500 mg/kg), one NAC-treated group (500 mg/kg), and one vitamin E-treated group (500 mg/kg). Nicotine was injected intraperitoneally at a dosage of 0.6 mg/kg for 21 days. Following nicotine injection, the antioxidants were administered orally, treatment was continued until the rats were killed. Lung tissue samples were stained with hematoxylin-eosin (H&amp;E) for histopathological assessments. The apoptosis level in the lung bronchiolar and alveolar epithelium was determined by using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) method. Cytoplasmic TNF-alpha in the bronchiolar and alveolar epithelial cells and the lung MPO activity were evaluated immunohistochemically. The protective effect of vitamin E on lung histology was stronger than that of erdosteine or NAC. Treatment with erdosteine, NAC, and vitamin E significantly reduced the rate of nicotine-induced pulmonary epithelial cell apoptosis, and there were no significant differences in apoptosis among the three antioxidants groups. Erdosteine, NAC, and vitamin E significantly reduced the increases in TNF-alpha staining and lung MPO activity. The effects of erdosteine on the increases in the local TNF-alpha level and lung MPO activity were weaker than that of NAC or vitamin E. This findings suggest that erdosteine and NAC can be as effective as vitamin E in protecting against nicotine-induced pulmonary cell apoptosis.}, }
@article {pmid16376982, year = {2006}, author = {Lee, DH and Lim, BS and Lee, YK and Ahn, SJ and Yang, HC}, title = {Involvement of oxidative stress in mutagenicity and apoptosis caused by dental resin monomers in cell cultures.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {22}, number = {12}, pages = {1086-1092}, doi = {10.1016/j.dental.2005.09.002}, pmid = {16376982}, issn = {0109-5641}, mesh = {Animals ; Apoptosis ; Cells, Cultured ; Composite Resins/chemistry/*toxicity ; Cricetinae ; Cricetulus ; DNA Damage ; Dental Pulp/cytology/*drug effects ; Epoxy Compounds/toxicity ; Fibroblasts/drug effects ; Lung/cytology/drug effects ; Methacrylates/*toxicity ; Mutagenicity Tests ; *Oxidative Stress ; Polyethylene Glycols/toxicity ; Polymethacrylic Acids/toxicity ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {OBJECTIVE: This investigation studied the possibility that apoptosis as well as mutagenicity induced by resin monomers are mediated by oxidative stress.<br><br>METHODS: A range of dilutions of three resin monomers (GMA, TEGDMA, and HEMA) was added to culture medium (DMEM/10% FBS), of V79-4 fibroblasts and RPC-C2A pulp cells for 24 h. Their cytotoxic effects were measured by a colorimetric functional assay (MTT). Chromosomal aberration induced by the resin monomers was investigated by counting micronuclei in V79-4 cells. The effects of the resin monomers on DNA fragmentation were viewed by agarose gel electrophoresis of DNA, isolated from RPC-C2A pulp cells that were treated by resin compounds. Resin monomer-induced apoptosis was further confirmed by flow cytometry (staining with both annexin V-FITC and PI).<br><br>RESULTS: All monomers exhibited a dose-dependent cytotoxic effect, and the ranking of the cytotoxicity based on TC50 was GMA > TEGDMA > HEMA. The resin monomer-induced cytotoxicity was significantly decreased by co-treatment with N-acetylcystein (NAC), an antioxidant. The authors also confirmed a dose-dependent genotoxicity of the resin monomers that had induced micronucleated cells in V79-4 fibroblasts. Similar to the effects on cytotoxicity, NAC reduced the numbers of micronuclei in comparison with those generated by the resin monomers. The preventive effects of NAC were also observed in monomer-induced apoptosis in RPC-C2A cells. A DNA ladder pattern, characteristic of apoptosis, was shown at cytotoxic concentrations, but NAC blocked the resin monomer-mediated DNA fragmentation. The preventive effects of NAC on apoptosis were confirmed by Annexin V staining. Cells exposed to 300 microM GMA, 7 mM TEGDMA, or 14 mM HEMA for 24 h showed a significant increase in apoptotic cells, while NAC co-treatment caused a reduction in apoptotic cells compared to controls.<br><br>SIGNIFICANCE: These findings suggest that glutathione depletion and oxidative stress are responsible for GMA, TEGDMA, and HEMA-induced mutagenicity and apoptosis.}, }
@article {pmid16374600, year = {2006}, author = {Lafleur, DL and Pittenger, C and Kelmendi, B and Gardner, T and Wasylink, S and Malison, RT and Sanacora, G and Krystal, JH and Coric, V}, title = {N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder.}, journal = {Psychopharmacology}, volume = {184}, number = {2}, pages = {254-256}, pmid = {16374600}, issn = {0033-3158}, support = {K05 AA 14906-01/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Drug Resistance ; Drug Synergism ; Female ; Fluvoxamine/*therapeutic use ; Humans ; Middle Aged ; Obsessive-Compulsive Disorder/*drug therapy/psychology ; Psychiatric Status Rating Scales ; Selective Serotonin Reuptake Inhibitors/*therapeutic use ; }, abstract = {RATIONALE: Dysfunction of glutamatergic neurotransmission has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and recent clinical reports suggest that some glutamate modulating agents are efficacious in the treatment of this disorder. N-acetylcysteine (NAC) is a readily available amino acid compound that is thought to attenuate glutamatergic neurotransmission. NAC may be useful in treating psychiatric disorders involving glutamatergic dysfunction such as OCD.<br><br>OBJECTIVES: To examine the efficacy of augmentation with NAC in a patient with serotonin reuptake inhibitor (SRI)-refractory OCD.<br><br>METHODS: A patient with SRI-refractory OCD was treated with an off-label use of NAC augmentation of fluvoxamine over several weeks.<br><br>RESULTS: NAC augmentation of fluvoxamine resulted in a marked decrease in Yale-Brown Obsessive Compulsive Scale (Y-BBOCS) score and a clinically significant improvement in OCD symptoms.<br><br>CONCLUSIONS: NAC augmentation was effective in treating SRI-refractory OCD in this single case. Further research is warranted to investigate the use of NAC and other glutamate modulating agents in the treatment of OCD.}, }
@article {pmid16371026, year = {2006}, author = {Amer, J and Ghoti, H and Rachmilewitz, E and Koren, A and Levin, C and Fibach, E}, title = {Red blood cells, platelets and polymorphonuclear neutrophils of patients with sickle cell disease exhibit oxidative stress that can be ameliorated by antioxidants.}, journal = {British journal of haematology}, volume = {132}, number = {1}, pages = {108-113}, doi = {10.1111/j.1365-2141.2005.05834.x}, pmid = {16371026}, issn = {0007-1048}, mesh = {Adolescent ; Adult ; Anemia, Sickle Cell/*blood/physiopathology ; Antioxidants/*pharmacology ; Blood Platelets/drug effects/physiology ; Cell Separation/methods ; Cells, Cultured ; Child ; Child, Preschool ; Erythrocytes/drug effects/physiology ; Female ; Flow Cytometry ; Glutathione/blood ; Humans ; Male ; Neutrophils/drug effects/physiology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/blood ; }, abstract = {Sickle cell disease (SCD) is basically a red blood cell (RBC) disorder characterised by sickling and haemolysis, but platelets and polymorphonuclear neutrophils (PMN) are also involved. Oxidative damage may play a role in the pathogenesis of SCD. Using flow cytometry, we measured oxidative-state markers simultaneously in RBC, platelets and PMN obtained from 25 normal donors, nine homozygous (SS) patients and six SS/beta-thalassaemia patients. Reactive oxygen species (ROS) and reduced glutathione (GSH) were measured following staining of blood samples with fluorescence probes and gating on specific subpopulations based on size and granularity. Ten- to 30-fold higher ROS production and 20-50% lower GSH content were found in RBC, platelets and PMN from SCD patients versus those of their normal counterparts. This could in part account for the clinical manifestations, such as haemolysis, a hypercoagulable state, recurrent bacterial infections and vaso-occlusive incidences, in SCD. We further showed that exposure of SCD samples to antioxidants, such as N-acetyl-cysteine, vitamin C and vitamin E, decreased their oxidative stress. These results suggest that antioxidant treatment of patients with SCD could reduce oxidative damage to RBC, PMN and platelets, thereby alleviating symptoms associated with their pathology. The flow cytometry techniques presented herein could assist in monitoring the efficacy of such treatment.}, }
@article {pmid16369183, year = {2006}, author = {Atis, S and Nayci, A and Ozge, A and Comelekoglu, U and Gunes, S and Bagdatoglu, O}, title = {N-acetylcysteine protects the rats against phrenic nerve dysfunction in sepsis.}, journal = {Shock (Augusta, Ga.)}, volume = {25}, number = {1}, pages = {30-35}, doi = {10.1097/01.shk.0000186927.49486.d6}, pmid = {16369183}, issn = {1073-2322}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Catalase/metabolism ; Electromyography/methods ; Malondialdehyde/metabolism ; Nitrates/metabolism ; Nitrites/metabolism ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Peroxidase/metabolism ; Phrenic Nerve/injuries/pathology/*physiopathology ; Rats ; Rats, Wistar ; Sepsis/*drug therapy/metabolism/pathology/physiopathology ; }, abstract = {This study investigates the association of oxidative stress with the function of the phrenic nerve and inquires whether N-acetylcysteine (NAC) may counteract the possible detrimental effects. Thirty rats were divided into three groups: sham, cecal ligation and puncture (CLP), and CLP plus NAC treatment. Sepsis was produced by the CLP procedure. NAC was administered at 70 mg/day for 7 days. Electrophysiology was evaluated by the needle electromyography of the diaphragm and phrenic nerve conduction study. Oxidative stress was evaluated by malondialdehyde (MDA), nitrite/nitrate (NN), and reduced-glutathione (ReGSH) levels and myeloperoxidase (MPO) and catalase (CAT) activities in the phrenic nerve. In the CLP group, ReGSH and CAT were decreased (P = 0.0001, P = 0.07, respectively); and MDA, MPO, and NN were increased (P = 0.02, P = 0.0001, P = 0.043, respectively), compared with the sham group. NAC administration increased the ReGSH (P = 0.036) and decreased the MDA, MPO, and NN (P = 0.008, P = 0.01, P = 0.032, respectively), compared with the CLP group. In the CLP group, electrophysiology revealed reductions in the number of motor unit action potentials (P = 0.0001) and prolongations in the latency of the compound nerve action potential (P = 0.0001), indicating phrenic nerve neuropathy. NAC administration significantly ameliorated these electrophysiological alterations (P = 0.011, P = 0.0001, respectively), compared with the CLP group. The present results showed that intraabdominal sepsis is closely associated with phrenic nerve neuropathy. In addition, NAC administration protects the rats against the detrimental events of sepsis.}, }
@article {pmid16368307, year = {2006}, author = {Zagler, A and Azadpour, M and Mercado, C and Hennekens, CH}, title = {N-acetylcysteine and contrast-induced nephropathy: a meta-analysis of 13 randomized trials.}, journal = {American heart journal}, volume = {151}, number = {1}, pages = {140-145}, doi = {10.1016/j.ahj.2005.01.055}, pmid = {16368307}, issn = {1097-6744}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Contrast Media/*adverse effects ; Coronary Angiography ; Female ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) following coronary angiography increases morbidity and mortality. Randomized trials of small sample size have evaluated whether N-acetylcysteine (NAC) prevents CIN in patients with renal dysfunction.<br><br>METHODS: To conduct a meta-analysis of the randomized trials the following databases were searched: MEDLINE (1966-2003), Cochrane Controlled Trials Register, ACP Journal Club online, published abstracts presented at the major cardiology and nephrology meetings, references from reviews. Two authors independently evaluated all relevant randomized trials. Eligibility criteria were (1) randomized placebo controlled trials of NAC, (2) patients with impaired renal function (creatinine >1.2 mg/dL) undergoing coronary angiography, (3) patients receiving intravenous fluids and low-osmolarity nonionic contrast media, (4) the primary outcome was CIN (increases in creatinine of either at least 0.5 mg/dL or 25% from baseline to 48 hours). Of 589 trials reviewed 3 disagreements were easily resolved by mutual discussion and 13 were selected. Data extraction included patient characteristics, intravenous fluid regimen, type and dose of contrast media, dosing regimen, creatinine at baseline and 48 hours and CIN requiring dialysis.<br><br>RESULTS: Four of the 13 trials reported statistically significant results. In meta-analysis of the 13 trials, which included 1892 patients, the RR was 0.68 (95%CI, 0.46-1.01). The addition of the trial of patients undergoing computerized tomography, which had formulated the hypothesis, yielded a statistically significant reduction (RR 0.64 [95%CI 0.42-0.96]) as did an earlier meta-analysis of 7 trials.<br><br>CONCLUSIONS: Our meta-analysis of the most currently available randomized data concerning NAC before coronary angiography to prevent CIN in patients with impaired renal function is neither conclusive nor provides proof beyond a reasonable doubt to influence clinical practice and public policy. The intervention has minimal toxicity but the width of the 95% CI remains compatible with a range from a large benefit to none at all. In addition, the trials used change in creatinine as the measure of outcome. Further randomized trials of large sample size and with clinical outcomes will add importantly relevant information to the totality of evidence and allow the most rational clinical decisions for individual patients as well as policy decisions for the health of the general public.}, }
@article {pmid16360994, year = {2005}, author = {Kotlyar, E and Keogh, AM and Thavapalachandran, S and Allada, CS and Sharp, J and Dias, L and Muller, D}, title = {Prehydration alone is sufficient to prevent contrast-induced nephropathy after day-only angiography procedures--a randomised controlled trial.}, journal = {Heart, lung &amp; circulation}, volume = {14}, number = {4}, pages = {245-251}, doi = {10.1016/j.hlc.2005.06.007}, pmid = {16360994}, issn = {1443-9506}, mesh = {Acetylcysteine/*administration &amp; dosage/economics ; Aged ; Aged, 80 and over ; Angiography/*adverse effects ; Cardiovascular Diseases/diagnostic imaging ; Contrast Media/*adverse effects ; Cost-Benefit Analysis ; Dose-Response Relationship, Drug ; Female ; *Fluid Therapy ; Free Radical Scavengers/*administration &amp; dosage/economics ; Humans ; Infusions, Intravenous ; Iohexol/adverse effects/*analogs &amp; derivatives ; Kidney Diseases/*chemically induced/diagnostic imaging/*prevention &amp; control ; Kidney Function Tests ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Contrast agents used in angiography procedures for patients with cardiovascular disease are known to cause contrast-induced nephropathy (CIN), which may be partially due to the production of nephrotoxic oxygen-free radicals. It is uncertain whether administration of intravenous (IV) anti-oxidant, N-acetylcysteine (NAC), can prevent reduction in renal function and whether this is a cost-effective approach.<br><br>METHODS: Sixty-five day-only patients with renal impairment (mean serum creatinine concentration 0.16+/-0.03 mmol/l) due to undergo coronary or peripheral angiography and/or stenting were randomly assigned to IV NAC 300 or 600 mg immediately before and after the procedure or IV fluid alone.<br><br>RESULTS: Of the 60 patients with complete data, none had acute CIN (increase in serum creatinine concentration > or = 0.044 mmol/l, 48 h after administration of contrast agent). Eight patients (13%) have demonstrated an increase in their serum creatinine concentration > or = 0.044 mmol/l 30 days after administration of contrast agent: 2/19 (11%) in the control group, 2/21 (10%) in the 600 mg NAC group and 4/20 (20%) the 300 mg NAC group (p = 0.66). The mean volumes of contrast agent used and prehydration given for each of the three groups did not differ significantly (p > 0.83). There was significant improvement in creatinine clearance within each group from baseline to 30 days (p < or = 0.03), but no significant difference between the groups at 48 h and 30 days (p > or = 0.43). Considering the cost of NAC and its administration, we estimate that this would translate to a saving of dollar 26,637 per annum.<br><br>CONCLUSION: For day-stay patients with mild-to-moderate chronic renal impairment undergoing angiography and/or intervention, prehydration alone is less complicated and more cost-effective than a combination of IV NAC (at doses used) and hydration.}, }
@article {pmid16359890, year = {2006}, author = {Boga, M and Discigil, B and Ozkisacik, EA and Gurcun, U and Badak, MI and Dikicioglu, E and Yenisey, C and Meteoglu, I}, title = {The combined effect of iloprost and N-acetylcysteine in preventing spinal cord ischemia in rabbits.}, journal = {European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery}, volume = {31}, number = {4}, pages = {366-372}, doi = {10.1016/j.ejvs.2005.10.027}, pmid = {16359890}, issn = {1078-5884}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Cytoprotection ; Iloprost/*pharmacology ; Ischemia/complications/*prevention &amp; control ; Male ; Models, Animal ; Nitric Oxide/blood ; Paraplegia/etiology/prevention &amp; control ; Phosphopyruvate Hydratase/blood ; Rabbits ; Random Allocation ; Spinal Cord/*blood supply/pathology ; Vasodilator Agents/*pharmacology ; }, abstract = {OBJECTIVES: This study investigated the cytoprotective effects of N-acetylcysteine (NAC) and iloprost on spinal cord ischemia in an experimental model.<br><br>MATERIALS AND METHODS: Thirty-five (male) New Zealand white rabbits were included in five study groups (n=7, each group). One group served as Sham. Rabbits in other groups had their abdominal aorta cross-clamped just above the iliac bifurcation for 40 min. During aortic cross clamping, iloprost, NAC, both iloprost and NAC or saline (control) were infused.<br><br>RESULTS: In NAC, iloprost, and iloprost+NAC groups, neurological status of rabbits (Tarlov score) 24 and 48 h after the operation was better than the control group (p<0.01), but worse than the Sham group (p<0.01). There was minimal neuronal damage in the iloprost treated groups compared to the NAC group (p<0.05). Mean viability index values in NAC, iloprost and iloprost+NAC groups were higher than the control group (p<0.01). Viability index in the NAC group was lower than the iloprost and iloprost+NAC groups.<br><br>CONCLUSIONS: The use of iloprost and NAC may provide better protection from spinal cord ischemia.}, }
@article {pmid16351032, year = {2005}, author = {Wilkes, JM and Clark, LE and Herrera, JL}, title = {Acetaminophen overdose in pregnancy.}, journal = {Southern medical journal}, volume = {98}, number = {11}, pages = {1118-1122}, doi = {10.1097/01.smj.0000184792.15407.51}, pmid = {16351032}, issn = {0038-4348}, mesh = {Acetaminophen/pharmacokinetics/*poisoning ; Acetylcysteine/therapeutic use ; Analgesics, Non-Narcotic/pharmacokinetics/*poisoning ; Chemical and Drug Induced Liver Injury/etiology ; Drug Overdose ; Female ; Fetus/drug effects ; Humans ; Liver/drug effects/metabolism ; Pregnancy ; Pregnancy Complications/*chemically induced ; }, abstract = {Acetaminophen (APAP) is the most common drug overdose in pregnancy. Available data regarding APAP overdose in pregnancy is limited to case reports and a small prospective case series. APAP has been demonstrated to cross the placenta and in toxic doses may harm the fetal and maternal hepatocytes. Fetal hepatocytes metabolize APAP into both active and toxic metabolites. These toxic metabolites may cause fetal hepatic necrosis. N-acetylcysteine (NAC) has also been demonstrated to cross the placenta and may bind toxic metabolites in both the mother and the fetus. Limited data suggest that the majority of morbidity and mortality from APAP overdose can be averted by initiation of NAC within the first 16 hours of ingestion and possibly even later. NAC may be safely administered during pregnancy and should be initiated early after APAP overdosage. The literature was reviewed through the use of OvidMEDLINE database, encompassing 1966 to the present. Searches were conducted using the key words acetaminophen, paracetamol, N-acetylcysteine, overdose, and hepatotoxicity. The search was further refined by selecting articles that contained these search words together with the key word pregnancy. Only English language papers were reviewed. Articles were selected on the basis of relevance to the topic. Pertinent citations found in the selected articles were also reviewed.}, }
@article {pmid16351030, year = {2005}, author = {Gurbuz, AK and Ozel, AM and Ozturk, R and Yildirim, S and Yazgan, Y and Demirturk, L}, title = {Effect of N-acetyl cysteine on Helicobacter pylori.}, journal = {Southern medical journal}, volume = {98}, number = {11}, pages = {1095-1097}, doi = {10.1097/01.smj.0000182486.39913.da}, pmid = {16351030}, issn = {0038-4348}, mesh = {2-Pyridinylmethylsulfinylbenzimidazoles ; Acetylcysteine/*administration &amp; dosage ; Anti-Bacterial Agents/administration &amp; dosage ; Clarithromycin/administration &amp; dosage ; Drug Therapy, Combination ; Expectorants/*administration &amp; dosage ; Female ; Helicobacter Infections/*drug therapy ; *Helicobacter pylori ; Humans ; Lansoprazole ; Male ; Middle Aged ; Omeprazole/administration &amp; dosage/analogs &amp; derivatives ; Proton Pump Inhibitors ; Stomach Diseases/*drug therapy/microbiology ; }, abstract = {BACKGROUND: Use of mucolytic agents that result in reduced mucous viscosity of the gastric mucous has been suggested to have an additive effect in curing Helicobacter pylori infection.<br><br>METHODS: Seventy Hpylori-positive patients were given either eradication treatment consisting of 500 mg clarithromycin bid and 30 mg lansoprazole bid for 10 days plus 10 mL (400 mg) N-acetyl cysteine (NAC) liquid tid (AC group) or eradication treatment only (control group). The results were compared 1 month after the completion of the treatment.<br><br>RESULTS: Fifty-eight patients were available for statistical analysis. Of the 28 patients in the AC group, 14 (50.0%) eradicated the infection after treatment, whereas only 7 of 30 (23.3%) patients in the control group had negative results. The difference between the AC group and the control group was statistically significant (P = 0.034). In both groups, there was no difference in the number of smokers and in the eradication rates between smokers and nonsmokers. Eradication treatment with or without NAC caused no significant side effects in either group.<br><br>CONCLUSIONS: Our findings suggest that NAC has an additive effect on the eradication rates of H pylori obtained with dual therapy with lansoprazole and clarithromycin. NAC does not have any known activity against H pylori, but it may improve the delivery of antibiotics at the site of infection due to its ability to reduce the thickness of the mucus.}, }
@article {pmid16344899, year = {2005}, author = {Huang, XL and Ling, YQ and Zhu, TN and Zhang, JL and Ling, YL}, title = {Multiple factors contributing to lipopolysaccharide-induced reactivity changes in rabbit pulmonary artery.}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {57}, number = {6}, pages = {737-741}, pmid = {16344899}, issn = {0371-0874}, mesh = {Acetylcysteine/metabolism ; Animals ; Carbon Monoxide/metabolism ; Hypertension, Pulmonary/etiology/*physiopathology ; Lipopolysaccharides/*toxicity ; Male ; Nitric Oxide/*metabolism ; Pulmonary Artery/drug effects/*physiopathology ; Rabbits ; Shock, Septic/*complications ; }, abstract = {To explore the underlying mechanism(s) of pulmonary arterial hypertension in endotoxic shock, the roles of N-acetylcysteine (NAC), nitric oxide (NO) and carbon monoxide (CO) were investigated. Pulmonary arterial rings (3-mm width) were prepared from 24 rabbits. Lipopolysaccharide (LPS), after 7-hour incubation, decreased the endothelium-dependent relaxation response of the arterial ring (pre-contracted with phenylephrine) to acetylcholine (1 mumol/L), but did not affect the endothelium-independent relaxation response to sodium nitroprusside. The LPS effects were reduced by a concomitant incubation with the free radical scavenger (NAC), NO donor (L-arginine), and CO donor (hemin), respectively. On the other hand, the LPS effects were enhanced by applying heme oxygenase-1 (HO-1) inhibitor (zinc protoporphyrin) to block CO production. The response to acetylcholine changed from relaxation to contraction, however, the contractile response to phenylephrine increased significantly after pre-incubation with nitric oxide synthase (NOS) inhibitor (L-NAME) to block NO production, confirming the importance of CO and NO. These results show that LPS impairs endothelium-dependent relaxation of the pulmonary artery, which can be greatly reduced by the antioxidant, or by supplying with NO and CO. Thus, multiple factors are involved in this model of endotoxin-induced pulmonary hypertension.}, }
@article {pmid16340385, year = {2005}, author = {Sadan, O and Bahat-Stromza, M and Gilgun-Sherki, Y and Atlas, D and Melamed, E and Offen, D}, title = {A novel brain-targeted antioxidant (AD4) attenuates haloperidol-induced abnormal movement in rats: implications for tardive dyskinesia.}, journal = {Clinical neuropharmacology}, volume = {28}, number = {6}, pages = {285-288}, doi = {10.1097/01.wnf.0000191331.54649.e3}, pmid = {16340385}, issn = {0362-5664}, mesh = {Acetylcysteine/*analogs &amp; derivatives/therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Behavior, Animal/drug effects ; Brain Chemistry/drug effects ; Disease Models, Animal ; Drug Interactions ; Dyskinesia, Drug-Induced/drug therapy/etiology ; Dyskinesias/*drug therapy/etiology ; Exploratory Behavior/drug effects ; Female ; Haloperidol ; Lipid Peroxidation/drug effects ; Oxidation-Reduction/drug effects ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {BACKGROUND: Tardive dyskinesia (TD), characterized by abnormal movements, is the major late-onset chronic side effect of antipsychotic treatment found in about 30% of those patients. The association of oxidative stress and the release of free radicals is one of the hallmarks of dopaminergic malfunctions and is one of the leading theories suggested for the pathophysiology of TD. To this day, no brain-targeted antioxidant has been tested as a potential treatment of TD. In light of this assumption, the authors chose a novel, low-molecular weight thiol antioxidant, N-acetyl cysteine amide (AD4), that crosses the blood-brain barrier as a possible treatment of TD.<br><br>OBJECTIVE: To examine the protective effects of the novel brain-penetrating antioxidant AD4 on TD experimental models.<br><br>METHODS: The typical vacuous chewing movement occurs in rats following chronic haloperidol injections (1.5 mg/kg/day intraperitoneally for 21 days). This purposeless mouth opening in the vertical plane is similar to TD symptoms in humans. The authors tested rats treated with haloperidol without or with AD4 in the drinking water (1 g/kg orally). Thiobarbituric acid reactive substances and anticarbonyl antibodies were used to measure oxidation of membranes and proteins.<br><br>RESULTS: Haloperidol increased the vacuous chewing movements to 66.5 +/- 7.6 movements/5 minutes compared with 16.4 +/- 2.4 movements/5 minutes in untreated rats (P < 0.01). Coadministration of haloperidol and AD4 decreased the vacuous chewing movements level to 42.1 +/- 6.7 movements/5 minutes (P < 0.05). Haloperidol also increased the level of lipid peroxidation and protein oxidation in the rat brain, whereas coadministration with AD4 preserved their normal levels.<br><br>CONCLUSION: Haloperidol causes behavioral abnormalities associated with oxidative stress in rats, similar to TD. AD4, the brain-targeted potent antioxidant, reduces the cellular oxidation markers and improves the typical clinical behavior. Hence, AD4 is a potential new treatment of antipsychotic-induced TD.}, }
@article {pmid16339532, year = {2005}, author = {Hadzic, T and Li, L and Cheng, N and Walsh, SA and Spitz, DR and Knudson, CM}, title = {The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {175}, number = {12}, pages = {7965-7972}, doi = {10.4049/jimmunol.175.12.7965}, pmid = {16339532}, issn = {0022-1767}, support = {P01CA066081/CA/NCI NIH HHS/United States ; R01CA100045/CA/NCI NIH HHS/United States ; R01CA88967/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Buthionine Sulfoximine/pharmacology ; *Cell Proliferation ; Cells, Cultured ; Glutathione/physiology ; Interleukin-2/*metabolism ; Interleukin-6/metabolism ; Lymphocyte Activation ; Mice ; Molecular Weight ; Signal Transduction ; Sulfhydryl Compounds/analysis/antagonists &amp; inhibitors/*physiology ; T-Lymphocytes/*cytology/*metabolism ; }, abstract = {Glutathione (GSH) is an abundant intracellular tripeptide that has been implicated as an important regulator of T cell proliferation. The effect of pharmacological regulators of GSH and other thiols on murine T cell signaling, proliferation, and intracellular thiol levels was examined. l-Buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH synthesis, markedly reduced GSH levels and blocked T cell proliferation without significant effect on cell viability. N-acetylcysteine markedly enhanced T cell proliferation without affecting GSH levels. Cotreatment of T cells with N-acetylcysteine and BSO failed to restore GSH levels, but completely restored the proliferative response. Both 2-ME and l-cysteine also reversed the BSO inhibition of T cell proliferation. Intracellular l-cysteine levels were reduced with BSO treatment and restored with cotreatment with NAC or l-cysteine. However, 2-ME completely reversed the BSO inhibition of proliferation without increasing intracellular cysteine levels. Therefore, neither GSH nor cysteine is singularly critical in limiting T cell proliferation. Reducing equivalents from free thiols were required because oxidation of the thiol moiety completely abolished the effect. Furthermore, BSO did not change the expression of surface activation markers, but effectively blocked IL-2 and IL-6 secretion. Importantly, exogenous IL-2 completely overcame BSO-induced block of T cell proliferation. These results demonstrate that T cell proliferation is regulated by thiol-sensitive pathway involving IL-2.}, }
@article {pmid16338951, year = {2006}, author = {Nishikawa-Ogawa, M and Wanibuchi, H and Morimura, K and Kinoshita, A and Nishikawa, T and Hayashi, S and Yano, Y and Fukushima, S}, title = {N-acetylcysteine and S-methylcysteine inhibit MeIQx rat hepatocarcinogenesis in the post-initiation stage.}, journal = {Carcinogenesis}, volume = {27}, number = {5}, pages = {982-988}, doi = {10.1093/carcin/bgi277}, pmid = {16338951}, issn = {0143-3334}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anticarcinogenic Agents/pharmacology ; *Carcinogens ; Cell Proliferation ; Cysteine/*analogs &amp; derivatives/pharmacology ; Down-Regulation ; Glutathione Transferase/metabolism ; Insulin-Like Growth Factor I/metabolism ; Liver Neoplasms/chemically induced/*metabolism ; Nitric Oxide Synthase Type II/metabolism ; Placenta/metabolism ; *Quinoxalines ; Rats ; Silver Staining ; Time Factors ; }, abstract = {N-acetylcysteine (NAC) and S-methylcysteine (SMC), water soluble organosulfur compounds contained in garlic, were evaluated for chemoprevention of hepatocarcinogenesis after 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) initiation in rats. Intergastric treatment with NAC or SMC five times a week resulted in decreased numbers and areas of preneoplastic, glutathione S-transferase placental form (GST-P) positive foci of the liver in a dose-dependent manner. Moreover, cell proliferation was reduced in GST-P positive foci by NAC and SMC. Insulin-like growth factor I (IGF-I) and inducible nitric oxide synthase (iNOS) mRNA expressions were found downregulated in the liver by NAC. The studies indicate that NAC can serve as a chemopreventive agent for rat hepatocarcinogenesis induced by MeIQx by reducing cell proliferation, which may involve IGF-I and iNOS downregulation.}, }
@article {pmid16327031, year = {2005}, author = {Davison, GW and Hughes, CM and Bell, RA}, title = {Exercise and mononuclear cell DNA damage: the effects of antioxidant supplementation.}, journal = {International journal of sport nutrition and exercise metabolism}, volume = {15}, number = {5}, pages = {480-492}, doi = {10.1123/ijsnem.15.5.480}, pmid = {16327031}, issn = {1526-484X}, mesh = {Adult ; Antioxidants/administration &amp; dosage/*pharmacology ; Comet Assay ; DNA Damage/*drug effects ; Dietary Supplements ; Double-Blind Method ; Exercise/*physiology ; Hematocrit ; Hemoglobins/analysis ; Humans ; L-Lactate Dehydrogenase/metabolism ; Leukocytes, Mononuclear/*drug effects/physiology ; Lipid Peroxidation/drug effects/physiology ; Male ; Oxidative Stress/*drug effects/physiology ; }, abstract = {The purpose of this investigation was to determine the effects of antioxidant supplementation on DNA damage following exercise. Fourteen subjects were randomly assigned to one of two groups and required to ingest either antioxidants (400 mg alpha-lipoic acid, 200 mg co-enzyme Q10, 12 mg manganese, 600 mg vitamin C, 800 mg N-acetyl cysteine, 400 microg selenium, and 400 IU alpha-tocopherol per day) or placebos for 7 d. Exercise increased DNA damage, PS, FRAP, and LDH (P < 0.05), but not selectively between groups. LDH and PS concentration decreased 1 h post-exercise (P < 0.05), while LH concentration decreased 1 h post-exercise in the antioxidant group only (P < 0.05). The antioxidant group had a higher concentration of LH (P < 0.05), perhaps due to a selective difference between groups post-exercise (P < 0.05). The main findings of this investigation demonstrate that exhaustive aerobic exercise induces DNA damage, while antioxidant supplementation does not protect against damage.}, }
@article {pmid16326815, year = {2006}, author = {Shebley, M and Jushchyshyn, MI and Hollenberg, PF}, title = {Selective pathways for the metabolism of phencyclidine by cytochrome p450 2b enzymes: identification of electrophilic metabolites, glutathione, and N-acetyl cysteine adducts.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {34}, number = {3}, pages = {375-383}, doi = {10.1124/dmd.105.007047}, pmid = {16326815}, issn = {0090-9556}, support = {CA-16954/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*metabolism ; Anesthetics/*metabolism ; Animals ; Aryl Hydrocarbon Hydroxylases/biosynthesis/*metabolism ; Biotransformation ; Cloning, Molecular ; Cytochrome P-450 CYP2B1/biosynthesis/*metabolism ; Cytochrome P-450 CYP2B6 ; Escherichia coli/genetics ; Glutathione/*metabolism ; Oxidoreductases, N-Demethylating/biosynthesis/*metabolism ; Phencyclidine/*metabolism ; Spectrometry, Mass, Electrospray Ionization ; }, abstract = {The metabolism of phencyclidine (PCP) has been studied previously in cytochrome P450 (P450)-containing microsomal systems. However, the reactive intermediate(s) that covalently binds to the P450 and leads to inactivation or leaves the active site to modify other proteins has not been identified. In this study two electrophilic intermediates of PCP were identified by mass spectrometry and by trapping with reduced glutathione (GSH) or N-acetyl cysteine (NAC). The tentative structures of these electrophilic intermediates were determined using mass spectrometry. P450s 2B1 and 2B4 formed a metabolite that exhibited an m/z of 240 corresponding to the mass of the 2,3-dihydropyridinium species of PCP or its conjugate base, the 1,2-dihydropyridine. Chemical reduction of the incubation mixture using NaBH4 resulted in the disappearance of the signal at m/z 240, consistent with reduction of a 2,3-dihydropyridinium species. Furthermore, the reactive metabolite trapped by GSH resulted in an adduct exhibiting an m/z of 547, consistent with the mass of the 2,3-dihydropyridinium species of PCP (m/z 240), that has reacted with a molecule of GSH (m/z 308). However, P450 2B6 formed a different reactive intermediate of PCP that was isolated as a GSH adduct exhibiting an m/z of 581 and an NAC adduct with an m/z of 437. Liquid chromatography-tandem mass spectrometry analysis of these adducts suggested that a di-oxygenated iminium metabolite of PCP could be the reactive intermediate formed by P450 2B6 but not by the other 2B isoforms. These data suggest that P450 2B6 favors oxidation pathways for PCP metabolism that are different from those of P450s 2B1 and 2B4.}, }
@article {pmid16321413, year = {2006}, author = {Pruett, SB and Fan, R and Zheng, Q}, title = {Involvement of three mechanisms in the alteration of cytokine responses by sodium methyldithiocarbamate.}, journal = {Toxicology and applied pharmacology}, volume = {213}, number = {2}, pages = {172-178}, doi = {10.1016/j.taap.2005.10.004}, pmid = {16321413}, issn = {0041-008X}, support = {R01 ES013708/ES/NIEHS NIH HHS/United States ; R01 ES09158/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Chelating Agents/*pharmacology ; Copper/metabolism ; Corticosterone/blood ; Crosses, Genetic ; Cytokines/*metabolism ; Female ; Free Radical Scavengers/*pharmacology ; Interleukin-10/metabolism ; Interleukin-12/metabolism ; Lipopolysaccharides/immunology ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Oxidation-Reduction/drug effects ; Pesticides/*pharmacology ; Statistics, Nonparametric ; Thiocarbamates/*pharmacology ; }, abstract = {Sodium methyldithiocarbamate (SMD) is the third most abundantly used conventional pesticide in the U.S. We recently reported that it alters the induction of cytokine production mediated though Toll-like receptor (TLR) 4 at relevant dosages in mice. Its chemical properties and evidence from the literature suggest the potential mechanisms of action for this compound. It could either act as a free radical scavenger (by means of its free S(-)group) or promote oxidation by breaking down to form methylisothiocyanate, which can deplete glutathione. It is a potent copper chelator and may affect the availability of copper to a number of copper-dependent enzymes (including some signaling molecules). SMD induces a classical neuroendocrine stress response characterized by elevated serum corticosterone concentrations, which could affect cytokine production. Although each of these mechanisms could potentially contribute to altered cytokine responses, direct evidence is lacking. The present study was conducted to obtain such evidence. The role of redox balance was investigated by pretreating mice with N-acetyl cysteine (NAC), which increases cellular glutathione concentrations, before administration of SMD. NAC exacerbated the SMD-induced suppression of IL-12 and the SMD-induced enhancement of IL-10 in the serum. The role of copper chelation was investigated by comparing the effects of SMD with an equimolar dose to SMD that was administered in the form of a copper chelation complex. Addition of copper significantly decreased the action of SMD on IL-12 production but not on IL-10 production. The role of the stress response was investigated by pretreating mice with antagonists of corticosterone and catecholamines. This treatment partially prevented the action of SMD on IL-10 and IL-12 in the peritoneal fluid. The results suggest that all of the proposed mechanisms have some role in the alteration of cytokine production by SMD.}, }
@article {pmid16319343, year = {2005}, author = {Pellegrino, R and Decramer, M and van Schayck, CP and Dekhuijzen, PN and Troosters, T and van Herwaarden, C and Olivieri, D and Del Donno, M and De Backer, W and Lankhorst, I and Ardia, A}, title = {Quality control of spirometry: a lesson from the BRONCUS trial.}, journal = {The European respiratory journal}, volume = {26}, number = {6}, pages = {1104-1109}, doi = {10.1183/09031936.05.00026705}, pmid = {16319343}, issn = {0903-1936}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Disease Progression ; Double-Blind Method ; Female ; Follow-Up Studies ; Forced Expiratory Volume ; Humans ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*diagnosis/*drug therapy ; Quality Control ; Reference Values ; Respiratory Function Tests ; Risk Assessment ; Sensitivity and Specificity ; Severity of Illness Index ; Spirometry/*methods ; }, abstract = {This report describes the quality control programme used within the Bronchitis Randomized on N-acetylcysteine (NAC) Cost-Utility Study, a trial designed to assess the decline in lung function, exacerbation rate, health status, and cost-effectiveness with NAC or a placebo in 523 patients with chronic obstructive pulmonary disease over a 3-yr period. Spirometry was scored from 0 (worst quality) to 6 (best quality). The mean score of 314 spirometries from 243 patients evaluated during the trial was 5.63+/-0.83. Linear regression analysis of the scores of 47 participating centres plotted against the time at which spirometries were performed yielded an intercept of 5.7+/-0.5 and a slope of -0.0001+/-0.001, which suggests that the initial high quality was maintained over time. Retrospective examination of a further 345 postbronchodilator spirometries from 208 patients with a forced expiratory volume at one second exceeding the mean individual value recorded over the study in excess of 20% revealed a slightly lower quality of the start-of-test manoeuvre compared with the 314 spirometries. In conclusion, these findings would suggest that the quality control programme is likely to have helped achieve and maintain long-term spirometry performance in the Bronchitis Randomized on N-acetylcysteine (NAC) Cost-Utility Study trial. Special care should be paid to the spirometries whose forced expiratory volume in one second values exceed the mean value.}, }
@article {pmid16319332, year = {2005}, author = {Barreiro, E and Sánchez, D and Gáldiz, JB and Hussain, SN and Gea, J and , }, title = {N-acetylcysteine increases manganese superoxide dismutase activity in septic rat diaphragms.}, journal = {The European respiratory journal}, volume = {26}, number = {6}, pages = {1032-1039}, doi = {10.1183/09031936.05.00003705}, pmid = {16319332}, issn = {0903-1936}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Biopsy, Needle ; Diaphragm/drug effects/pathology ; Disease Models, Animal ; Immunohistochemistry ; Male ; Probability ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reference Values ; Risk Factors ; Sensitivity and Specificity ; Sepsis/*drug therapy/*enzymology/pathology ; Superoxide Dismutase/drug effects/*metabolism ; }, abstract = {The antioxidant N-acetylcysteine (NAC) prevented sepsis-induced diaphragmatic dysfunction. As an indirect antioxidant NAC was shown to induce superoxide dismutase (SOD) activity in immune cells from endotoxaemic mice. The aim of this study was to assess whether NAC acts as an indirect antioxidant by inducing manganese (Mn)-SOD activity in the diaphragms of endotoxaemic rats, while preventing muscle dysfunction. A controlled study was conducted, in which protein carbonylation, Mn-SOD, catalase, and 3-nitrotyrosine immunoreactivity were detected using immunoblotting and immunohistochemistry in rat diaphragms. Six groups were studied for 24 h after a saline (control) or lipopolysaccharide (LPS; 20 mg.kg-1) i.p. injection in the absence and presence of NAC pre-treatment (either 1.5 or 3 mmol.kg(-1).24 h-1 for 7 days, oral administration). Diaphragm mitochondrial Mn-SOD activity and respiratory muscle function were also determined. Within 24 h, LPS induced maximal inspiratory pressure reduction, increasing diaphragmatic protein carbonylation and nitration. Pre-treatment with 3 mmol.kg-1 NAC clearly increased muscle Mn-SOD protein content and activity in both LPS- and saline-injected animals, while reducing protein carbonylation and nitration, and partially preventing the LPS-induced respiratory muscle dysfunction. Data produced from this study indicate that high doses of N-acetylcysteine induces manganese superoxide dismutase, as well as preserves its activity, possibly by preventing nitration of critical tyrosine residues of the enzyme.}, }
@article {pmid16316327, year = {2005}, author = {Lessio, C and de Assunção Silva, F and Glória, MA and Di Tommaso, AB and Gori Mouro, M and Di Marco, GS and Schor, N and Higa, EM}, title = {Cyclosporine A and NAC on the inducible nitric oxide synthase expression and nitric oxide synthesis in rat renal artery cultured cells.}, journal = {Kidney international}, volume = {68}, number = {6}, pages = {2508-2516}, doi = {10.1111/j.1523-1755.2005.00726.x}, pmid = {16316327}, issn = {0085-2538}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Cyclosporine/*pharmacology ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Enzymologic/drug effects ; Immunosuppressive Agents/*pharmacology ; Luminescence ; Male ; Muscle, Smooth, Vascular/cytology/drug effects/enzymology ; Nitric Oxide/biosynthesis/*metabolism ; Nitric Oxide Synthase Type II/*genetics ; RNA, Messenger/analysis ; Rats ; Rats, Wistar ; Renal Artery/cytology/*drug effects/enzymology ; }, abstract = {BACKGROUND: The immunosuppressor cyclosporine A (CsA) presents the nephrotoxicity as its major side effect that is mostly attributed to a renal vasoconstriction. This may be due to an excessive generation of vasoconstrictors like reactive oxygen species (ROS), or due to a reduction of vasodilators such as the nitric oxide, which in turn, can be caused by increased amounts of ROS. We evaluated the effect of CsA and the antioxidant N-acetylcysteine (NAC) on inducible nitric oxide synthase (iNOS) mRNA expression and nitric oxide synthesis, in rat renal artery vascular smooth muscle cells (rVSMCs) primary culture.<br><br>METHODS: In cells treated during 72 hours with CsA (10 microg/mL), its vehicle (control) (10 microL/mL), Escherichia coli lipopolysaccharide (LPS) (100 microg/mL), CsA + LPS, NAC (6.13 mmol/L), or CsA + NAC, we determined the nitric oxide synthesis (Griess and chemiluminescence methods), iNOS expression [reverse transcription-polymerase chain reaction (RT-PCR)] and cell viability (acridine orange method).<br><br>RESULTS: In rVSMCs, LPS increased nitric oxide and iNOS expression; CsA decreased basal and LPS-induced nitric oxide and iNOS expression; NAC increased nitric oxide and blunted the nitric oxide reduction caused by CsA, with no effect on iNOS. CsA reduced cell viability.<br><br>CONCLUSION: In this study, CsA reduced nitric oxide synthesis in rVSMCs, both through iNOS down-regulation and reduction of cell viability, which could be responsible for the vasoconstrictive effect of the CsA. In the effect of CsA on nitric oxide, probably a role is also played by free radical production, as this effect was blunted by NAC.}, }
@article {pmid16313723, year = {2005}, author = {Li, X and Meng, Y and Cai, SX and Yang, XS and Wu, PS}, title = {[Aldosterone stimulates alpha1-(1) procollagen mRNA expression in HSC via activation of ERK1/2 and AP-1].}, journal = {Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology}, volume = {13}, number = {11}, pages = {815-818}, pmid = {16313723}, issn = {1007-3418}, mesh = {Aldosterone/*pharmacology ; Cell Line ; Collagen Type I/*biosynthesis/genetics ; Collagen Type I, alpha 1 Chain ; Hepatocytes/cytology/*metabolism ; Humans ; Mitogen-Activated Protein Kinase 3/*metabolism ; RNA, Messenger/biosynthesis/genetics ; Transcription Factor AP-1/*metabolism ; }, abstract = {OBJECTIVE: It has been known that the intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in the fibrogenesis in livers. Aldosterone (Aldo), the principal effector molecule of the RAAS, exerts local effects on cell growth and fibrogenesis. However, the signal transduction mechanisms underlying the effects of Aldo on hepatic fibrogenesis remain to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying the effects of Aldo on the signal passageway of active protein-1 (AP-1).<br><br>METHODS: In vitro, HSCs-T6 cell line was treated with Aldo for 10 min, 30 min, 60 min, 120 min and 180 min, and protein expression of Phospho-P42/44 was detected by Western blot. In addition, HSCs-T6 cell line was preincubated for 60 min or not with U0126 (an inhibitor of the MAPK/ERK kinase), and also with antioxidant-N-acetylcysteine (NAC) prior to exposure to Aldo for the indicated times. Protein expression of Phospho-P42/44 was measured by Western blot. DNA biding activity of AP-1 was analyzed by electrophoretic gel mobility shift assay (EMSA). By means of RT-PCR, expression of alpha1(1) procollagen mRNA was detected.<br><br>RESULTS: Aldo stimulated HSC via extracellular signal-regulated kinase (ERK1/2) pathway. Time course experiments showed that Aldo induced Phospho-P42/44 expression, which was abrogated by U0126, reaching a maximum at 10 minutes, and then declined progressively. NAC inhibited the Phospho-P42/44 expression. EMSA showed that stimulation of HSC by Aldo markedly increased AP-1 DNA binding activity. U0126 markedly reduced AP-1 DNA binding activity induced by Aldo; NAC partly decreased AP-1 activity induced by Aldo. Aldo up-regulated expression of alpha1(1) procollagen mRNA, which was attenuated by U0126 and NAC.<br><br>CONCLUSION: Stimulation of HSC by Aldo results in activation of AP-1 via ERK1/2 pathway, leading to up-regulation of AP-1 target gene alpha1(1) procollagen mRNA expression.}, }
@article {pmid16311915, year = {2005}, author = {Liu, J and Zhang, Y and Huang, D and Song, G}, title = {Cadmium induced MTs synthesis via oxidative stress in yeast Saccharomyces cerevisiae.}, journal = {Molecular and cellular biochemistry}, volume = {280}, number = {1-2}, pages = {139-145}, pmid = {16311915}, issn = {0300-8177}, mesh = {Acetylcysteine/pharmacology ; Cadmium/*pharmacology ; Catalase/metabolism ; Cell Survival ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation ; Malondialdehyde/metabolism ; Metallothionein/*biosynthesis ; Oxidative Stress/*drug effects ; Saccharomyces cerevisiae/*drug effects/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {Yeast, Saccharomyces cerevisiae, exposed to CdCl2 for 17 h was analysed with reference to survival, MTs and oxidative stress biomarkers. An enhanced accumulation of MDA and the increased activities of SOD and GPx in the Cd-treated yeasts under aerobic condition indicated CdCl2-caused oxidative stress in S. cerevisiae. MTs were significantly induced by CdCl2 under aerobic condition and the induced MTs contents were positively correlated with the accumulation of MDA in this study. However, MTs induction can be prominently inhibited by coincubation with NAC or anaerobic culture via eliminating ROS. This oxidative stress reduction was reflected by the decreases in MDA level and SOD and GPx activities. The results suggest that MTs inductive activity of cadmium in yeast cells was mediated by oxidative stress. In addition, increase of MTs contents was observed in cells untreated with CdCl2 under anaerobic conditions or coincubation with NAC, suggesting MTs are also susceptive to reductive stress.}, }
@article {pmid16310922, year = {2006}, author = {Kozhukhar, AV and Yasinska, IM and Sumbayev, VV}, title = {Nitric oxide inhibits HIF-1alpha protein accumulation under hypoxic conditions: implication of 2-oxoglutarate and iron.}, journal = {Biochimie}, volume = {88}, number = {5}, pages = {411-418}, doi = {10.1016/j.biochi.2005.09.007}, pmid = {16310922}, issn = {0300-9084}, mesh = {Acetylcysteine/pharmacology ; Azoles/pharmacology ; Cell Hypoxia/*physiology ; Cell Line ; Glutathione/metabolism ; Humans ; Hypoxia-Inducible Factor 1/*metabolism/physiology ; Iron/metabolism ; Isoindoles ; Ketoglutaric Acids/metabolism ; Mitochondria/drug effects/metabolism ; Mitochondrial Proteins/metabolism ; Models, Biological ; Nitric Oxide/physiology ; Nitric Oxide Donors/*pharmacology ; Organoselenium Compounds/pharmacology ; S-Nitrosoglutathione/*pharmacology ; Signal Transduction/physiology ; Succinate Dehydrogenase/metabolism ; }, abstract = {Cells exposed to low oxygen conditions respond by initiating defense mechanisms, including the stabilization of hypoxia-inducible factor (HIF) 1alpha, a transcription factor that upregulates genes such as those involved in angiogenesis and glycolysis, which also plays a pivotal role in the regulation of cellular utilization of oxygen and is an essential regulator of angiogenesis in solid tumor and ischemic disorders. Nitric oxide and other inhibitors of mitochondrial respiration prevent the stabilization of HIF-1alpha during hypoxia. In the present study we found that nitric oxide inhibits HIF-1alpha accumulation under low oxygen (1%) conditions. The effect is supported by an increase in 3-nitrotyrosine and is more likely caused by the formation of peroxynitrite in the cells, which leads to the damage of mitochondria and their respiratory chain followed by the increase in 2-oxoglutarate (2-OG) and iron (the components needed to activate HIF-1alpha proline hydroxylases) concentrations in cell cytosol. The inhibiting effect of NO on HIF-1alpha accumulation was not observed in the cells lacking mitochondria. On the other hand the depletion of intracellular glutathione (GSH) was observed upon cell treatment with nitric oxide donors under hypoxic conditions. Treatment of those cells with N-acetyl cysteine (NAC) increased the amount of intracellular GSH and attenuated the NO effect and abolished the damage of mitochondria as well as 2-OG/iron release.}, }
@article {pmid16307977, year = {2005}, author = {Pinho, RA and Silveira, PC and Silva, LA and Luiz Streck, E and Dal-Pizzol, F and F Moreira, JC}, title = {N-acetylcysteine and deferoxamine reduce pulmonary oxidative stress and inflammation in rats after coal dust exposure.}, journal = {Environmental research}, volume = {99}, number = {3}, pages = {355-360}, doi = {10.1016/j.envres.2005.03.005}, pmid = {16307977}, issn = {0013-9351}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Coal ; Deferoxamine/*pharmacology ; Dust ; Free Radicals ; Inflammation/*prevention &amp; control ; Lipid Peroxidation ; Male ; *Oxidative Stress ; Rats ; Rats, Wistar ; Siderophores/*pharmacology ; Trachea ; }, abstract = {Coal dust inhalation induces oxidative damage and inflammatory infiltration on lung parenchyma. Thus, the aim of this study was to determine whether N-acetylcysteine (NAC) administered alone or in combination with deferoxamine (DFX), significantly reduced the inflammatory infiltration and oxidative damage in the lungs of rats exposed to coal dust. Forty-two male Wistar rats (200-250 g) were exposed to the coal dust (3mg/0.5 mL saline, 3 days/week, for 3 weeks) by intratracheal instillation. The animals were randomly divided into three groups: saline 0.9% (n=8), supplemented with NAC (20mg/kg of body weight/day, intraperitoneal injection (i.p.)) (n=8), and supplemented with NAC (20 mg/kg of body weight/day, i.p.) plus DFX (20 mg/kg of body weight/week) (n=8). Control animals received only saline solution (0.5 mL). Lactate dehydrogenase activity and total cell number were determined in the bronchoalveolar lavage fluid. We determined lipid peroxidation and oxidative protein damage parameters and catalase and superoxide dismutase activities in the lungs of animals. Intratracheal instillation of coal dust in the lungs of rats led to an inflammatory response and induced significant oxidative damage. The administration of NAC alone or in association with DFX reduced the inflammatory response and the oxidative stress parameters in rats exposed to coal dust.}, }
@article {pmid16307259, year = {2006}, author = {Kamboj, A and Kiran, R and Sandhir, R}, title = {Carbofuran-induced neurochemical and neurobehavioral alterations in rats: attenuation by N-acetylcysteine.}, journal = {Experimental brain research}, volume = {170}, number = {4}, pages = {567-575}, pmid = {16307259}, issn = {0014-4819}, mesh = {Acetylcholinesterase/metabolism ; Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Avoidance Learning/drug effects ; Behavior, Animal/*drug effects ; Brain/*drug effects/metabolism/pathology ; Brain Chemistry/*drug effects ; Carbofuran/*pharmacology ; Cholinesterase Inhibitors/*pharmacology ; Drug Interactions ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Male ; Rats ; Rats, Wistar ; Rotarod Performance Test/methods ; }, abstract = {Carbofuran, a widely used carbamate pesticide, has been reported to cause neurotoxicity. However, the underlying mechanisms involved in carbofuran neurotoxicity are not well understood. The present study was envisaged to investigate the possible role of oxidative stress in carbofuran neurotoxicity and to evaluate the protective effects of N-acetylcysteine (NAC). Acetylcholinesterase activity was significantly inhibited in all the regions of brain after carbofuran exposure (1 mg/kg body weight, orally, for 28 days). NAC, on the other hand, was found to partially restore the activity of acetylcholinesterase in carbofuran treated animals. Carbofuran exposure resulted in increased lipid peroxidation (LPO) in brain regions accompanied by decreased levels of glutathione. NAC administration to the carbofuran exposed animals lowered LPO along with partial repletion in glutathione levels. Concomitantly, the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase were significantly decreased after carbofuran exposure, while no significant change in the activity of glutathione-S-transferase was observed. NAC treatment to carbofuran treated rats resulted in protective effect on the activities of these enzymes. Marked impairment in the motor function was seen following carbofuran exposure, which is evident by significant decrease in the retention time of the rats on rotating rods. Cognitive deficits were also seen after carbofuran exposure as indicated by the significant decrease in active avoidance response. NAC treatment significantly improved the carbofuran-induced neurobehavioral deficits. The results clearly demonstrate that carbofuran exerts its neurotoxic effects by accentuating oxidative stress and suggest neuroprotective role of NAC in carbofuran neurotoxicity.}, }
@article {pmid16306132, year = {2006}, author = {Wu, D and Cederbaum, AI}, title = {Opposite action of S-adenosyl methionine and its metabolites on CYP2E1-mediated toxicity in pyrazole-induced rat hepatocytes and HepG2 E47 cells.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {290}, number = {4}, pages = {G674-84}, doi = {10.1152/ajpgi.00406.2005}, pmid = {16306132}, issn = {0193-1857}, support = {AA-06610/AA/NIAAA NIH HHS/United States ; AA-14132/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects/physiology ; Cell Survival/drug effects ; Cells, Cultured ; Cytochrome P-450 CYP2E1/*metabolism ; Dose-Response Relationship, Drug ; Hepatocytes/*drug effects/*metabolism ; Male ; Oxidative Stress/drug effects/physiology ; Pyrazoles/*toxicity ; Rats ; Rats, Sprague-Dawley ; S-Adenosylmethionine/*administration &amp; dosage/*metabolism ; }, abstract = {S-adenosyl-L-methionine (SAMe) is protective against a variety of hepatotoxins, including ethanol. The ability of SAMe to protect against cytochrome P-450 2E1 (CYP2E1)-dependent toxicity was studied in hepatocytes from pyrazole-treated rats and HepG2 E47 cells, both of which actively express CYP2E1. Toxicity was initiated by the addition of arachidonic acid (AA) or by depletion of glutathione after treatment with L-buthionine sulfoximine (BSO). In pyrazole hepatocytes, SAMe (0.25-1 mM) protected against AA but not BSO toxicity. SAMe elevated GSH levels, thus preventing the decline in GSH caused by AA, and SAMe prevented AA-induced lipid peroxidation. SAMe analogs such as methionine or S-adenosyl homocysteine, which elevate GSH, also protected against AA toxicity. 5'-Methylthioadenosine (MTA), which cannot produce GSH, did not protect. The toxicity of BSO was not prevented by SAMe and the analogs because GSH cannot be synthesized. In contrast, in E47 cells, SAMe and MTA but not methionine or S-adenosyl homocysteine potentiated AA and BSO toxicity. Antioxidants such as trolox or N-acetyl cysteine prevented this synergistic toxicity of SAMe plus AA or SAMe plus BSO, respectively. In pyrazole hepatocytes, SAMe prevented the decline in mitochondrial membrane potential produced by AA, whereas in E47 cells, SAMe potentiated the decline in mitochondrial membrane potential. In E47 cells, but not pyrazole hepatocytes, the combination of SAMe plus BSO lowered levels of the antioxidant transcription factor Nrf2. Because SAMe can be metabolized enzymatically or spontaneously to MTA, MTA may play a role in the potentiation of AA and BSO toxicity by SAMe, but the exact mechanisms require further investigation. In conclusion, contrasting effects of SAMe on CYP2E1 toxicity were observed in pyrazole hepatocytes and E47 cells. In hepatocytes, SAMe protects against CYP2E1 toxicity by a mechanism involving maintaining or elevating GSH levels.}, }
@article {pmid16305472, year = {2005}, author = {Blanusa, M and Varnai, VM and Piasek, M and Kostial, K}, title = {Chelators as antidotes of metal toxicity: therapeutic and experimental aspects.}, journal = {Current medicinal chemistry}, volume = {12}, number = {23}, pages = {2771-2794}, doi = {10.2174/092986705774462987}, pmid = {16305472}, issn = {0929-8673}, mesh = {Age Factors ; Animals ; Chelating Agents/*therapeutic use ; Environmental Exposure ; Humans ; Metals/*poisoning/toxicity ; }, abstract = {The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium, arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal poisoning are also different for each chelating drug. The chelating drugs with worldwide application are dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa(2)EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa(3)DTPA, ZnNa(3)DTPA), deferoxamine (DFO), deferiprone (L1), triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic homologues and experimental chelating agents have been designed and tested in vivo for their metal binding effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal poisoning. Within this context it has been shown in experiments using young and adult animals that metal toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of new therapeutic chelation protocols for metal toxicity.}, }
@article {pmid16301003, year = {2006}, author = {Escobales, N and Crespo, MJ}, title = {Angiotensin II-dependent vascular alterations in young cardiomyopathic hamsters: role for oxidative stress.}, journal = {Vascular pharmacology}, volume = {44}, number = {1}, pages = {22-28}, doi = {10.1016/j.vph.2005.09.008}, pmid = {16301003}, issn = {1537-1891}, support = {2SO6GM08224/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/antagonists &amp; inhibitors/*metabolism ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Animals ; Antioxidants/pharmacology ; Aorta/drug effects/*enzymology ; Blood Pressure/drug effects ; Cardiomyopathies/*metabolism/physiopathology ; Cricetinae ; Disease Models, Animal ; Losartan/pharmacology ; Male ; Mesocricetus ; NADPH Oxidases/metabolism ; *Oxidative Stress/drug effects ; Superoxides/metabolism ; }, abstract = {Recent studies indicate the presence of vascular alterations in 2-month-old Syrian cardiomyopathic hamsters (SCH). These alterations include enhanced angiotensin-converting enzyme (ACE) activity in the aorta, increased contractile response to angiotensin II and impaired vasorelaxation to acetylcholine in norepinephrine-precontracted aortic rings. The mechanisms leading to these vascular alterations are not known nor has their relationship to the cardiac abnormalities been established. We assessed the status of the cardiovascular system of 2-month-old hamsters first to establish if the observed vascular alterations are secondary to cardiac dysfunction, and second to examine the role of oxidative stress in the etiology of vascular dysfunction. Cardiac function parameters evaluated by echocardiography included stroke volume (SV), left ventricular end-diastolic volume (LVEDV), left ventricular fractional shortening (LVFS), ejection fraction (EF), cardiac output index (COI), heart rate (HR) and left ventricular posterior wall thickness (LVPWT). In addition, heart/body weight (heart/BW) ratios and systolic blood pressure were determined in normal hamsters and SCH. Our results indicated that systolic blood pressure increased 56% in SCH when compared to control animals (P<0.05). The increased blood pressure coexisted with normal COI, SV, LVEDV, LVPWT, LVFS, EF, HR and heart/BW ratios. NAD(P)H oxidase activity increased 77% in SCH compared to control animals (P<0.02). The increased oxidase activity was abolished by pre-treatment of animals with the angiotensin II type 1 receptor blocker losartan (25 mg/kg BW/day) for 10 days. Losartan also abolished the increased blood pressure observed at 2 months of age. The antioxidant N-acetylcysteine (NAC) abrogated the increased blood pressure when administered for 30 days to 1-month-old animals. Altogether, these findings suggest that the angiotensin II-dependent vascular abnormalities present in young cardiomyopathic hamsters are associated with oxidative stress and precede the echocardiographic abnormalities characteristic of heart failure.}, }
@article {pmid16300973, year = {2006}, author = {Bal-Price, A and Gartlon, J and Brown, GC}, title = {Nitric oxide stimulates PC12 cell proliferation via cGMP and inhibits at higher concentrations mainly via energy depletion.}, journal = {Nitric oxide : biology and chemistry}, volume = {14}, number = {3}, pages = {238-246}, doi = {10.1016/j.niox.2005.10.002}, pmid = {16300973}, issn = {1089-8603}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Cell Proliferation/drug effects ; Cell Respiration/drug effects ; Cyclic GMP/*metabolism ; *Glycolysis/drug effects ; Guanylate Cyclase/antagonists &amp; inhibitors/*metabolism ; Macrophage Activation ; Macrophages/drug effects/enzymology ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors ; Nitric Oxide/*physiology ; Nitric Oxide Donors/pharmacology ; Nitric Oxide Synthase Type II/antagonists &amp; inhibitors/metabolism ; Ornithine Decarboxylase Inhibitors ; PC12 Cells ; Poly(ADP-ribose) Polymerase Inhibitors ; Pyruvic Acid/pharmacology ; Rats ; Ribonucleotide Reductases/antagonists &amp; inhibitors ; Triazenes/pharmacology ; Uridine/pharmacology ; }, abstract = {We investigated the mechanisms by which nitric oxide (NO) from an NO donor (DETA/NO) regulates proliferation of pheochromocytoma PC12 cells. The NO donor stimulated proliferation at low concentrations, but reversibly and completely inhibited proliferation at higher concentrations. The stimulation (but not the inhibition) of proliferation was apparently due to NO stimulation of soluble guanylate cyclase to produce cGMP, as it was prevented by a specific cyclase inhibitor (ODQ), and replicated by a cell-permeable form of cGMP. The NO-induced cytostasis was not reversed by inhibitors of MEK kinase or poly(ADP-ribose)polymerase, or by treatments that bypass inhibition of ribonucleotide reductase or ornithine decarboxylase. Cytostatic concentrations of DETA/NO strongly inhibited respiration of PC12 cells, and specific respiratory inhibitors (rotenone, myxothiazol, or azide) caused complete cytostasis. Uridine and pyruvate reversed the cytostasis induced by the specific respiratory inhibitors, but not that induced by DETA/NO. However, the combination of uridine, pyruvate, and N-acetyl-cysteine did reverse DETA/NO-induced cytostasis. DETA/NO strongly and progressively inhibited glycolysis measured by glucose consumption, lactate production, and ATP level, and a specific glycolytic inhibitor (5 mM 2-deoxy-d-glucose) caused complete cytostasis. Our results indicate that NO at low concentrations increases cell proliferation via cGMP, while high concentrations of NO block proliferation via inhibition of both glycolysis and respiration, causing energy depletion.}, }
@article {pmid16298764, year = {2006}, author = {Gitika, B and Sai Ram, M and Sharma, SK and Ilavazhagan, G and Banerjee, PK}, title = {Quercetin protects C6 glial cells from oxidative stress induced by tertiary-butylhydroperoxide.}, journal = {Free radical research}, volume = {40}, number = {1}, pages = {95-102}, doi = {10.1080/10715760500335447}, pmid = {16298764}, issn = {1071-5762}, mesh = {Cell Survival/drug effects ; Cells, Cultured ; DNA Damage ; Drug Interactions ; Lipid Peroxidation/*drug effects ; Neuroglia/*drug effects/metabolism ; Oxidative Stress ; Quercetin/*pharmacology ; tert-Butylhydroperoxide/antagonists &amp; inhibitors/*pharmacology ; }, abstract = {The anti-oxidant and cyto-protective activity of quercetin against tertiary-butylhydroperoxide (t-BOOH) induced oxidative stress on C6 glial cells is reported. Exposure of the cells to t-BOOH resulted in a significant increase in cytotoxicity, reactive oxygen species (ROS) generation and lipid peroxidation. There was a significant increase in DNA strand breaks and fall in reduced GSH levels in cells exposed to t-BOOH. A significant increase in calcium ion influx was noticed in cells exposed to t-BOOH. Pre-treatment of cells with quercetin, vitamin C (vit C), Trolox, and deferoxamine (DFO) significantly inhibited t-BOOH induced cytotoxicity and ROS generation. Pretreatment of cells with quercetin, Trolox and DFO inhibited the DNA damage, maintained higher GSH levels and prevented calcium influx significantly. Although vit C protected the cells from cytotoxicity induced by t-BOOH, the intracellular Ca(2+) levels were significantly higher than the control cells. However, anti-oxidants like butylated hydroxy toluene (BHT), vitamin E (vit E), N-acetyl cysteine (NAC) did not have significant cytoprotection against t-BOOH induced oxidative injury in C6 glial cells.}, }
@article {pmid16298762, year = {2006}, author = {Mackenzie, GG and Zago, MP and Erlejman, AG and Aimo, L and Keen, CL and Oteiza, PI}, title = {alpha-Lipoic acid and N-acetyl cysteine prevent zinc deficiency-induced activation of NF-kappaB and AP-1 transcription factors in human neuroblastoma IMR-32 cells.}, journal = {Free radical research}, volume = {40}, number = {1}, pages = {75-84}, doi = {10.1080/10715760500312305}, pmid = {16298762}, issn = {1071-5762}, mesh = {Acetylcysteine/*pharmacology ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; NF-kappa B/*metabolism ; Neuroblastoma/metabolism ; Oxidants/metabolism ; Oxidative Stress/drug effects/physiology ; Phosphorylation/drug effects ; Thioctic Acid/*pharmacology ; Transcription Factor AP-1/antagonists &amp; inhibitors/*metabolism ; Zinc/*deficiency/pharmacology ; }, abstract = {This work investigated the capacity of alpha-lipoic acid (LA) and N-acetyl-L-cysteine (NAC) to reduce zinc deficiency-induced oxidative stress, and prevent the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), and the cross-talk between both activated cascades through beta-Transducin Repeat-containing Protein (beta-TrCP). IMR-32 cells were incubated in control media or media containing variable concentrations of zinc, without or with 0.5 mM LA or 1 mM NAC. Relative to control and zinc supplemented (15 microM Zn) groups, Hydrogen peroxide (H(2)O(2)) and total oxidant cell concentrations were higher, and total glutathione concentrations were lower in the zinc deficient groups (1.5 and 5 microM Zn). Both, LA and NAC, markedly reduced the increase in cell oxidants and the reduction in glutathione concentrations in the zinc deficient cells. Consistent with this, LA and NAC prevented zinc deficiency-induced activation of the early steps of NF- kappaB (IkappaBalpha phosphorylation) and AP-1 [c-Jun-N-terminal kinase (JNK) and p38 phophorylation] cascades, and the high NF-kappaB- and AP-1-DNA binding activities in total cell extracts. Thus, LA and NAC can reduce the oxidative stress associated with zinc deficiency and the subsequent triggering of NF-kappaB- and AP-1-activation in neuronal cells.}, }
@article {pmid16298736, year = {2005}, author = {Foschino Barbaro, MP and Serviddio, G and Resta, O and Rollo, T and Tamborra, R and Elisiana Carpagnano, G and Vendemiale, G and Altomare, E}, title = {Oxygen therapy at low flow causes oxidative stress in chronic obstructive pulmonary disease: Prevention by N-acetyl cysteine.}, journal = {Free radical research}, volume = {39}, number = {10}, pages = {1111-1118}, doi = {10.1080/10715760500250257}, pmid = {16298736}, issn = {1071-5762}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Blood Proteins/metabolism ; Erythrocytes/drug effects/metabolism ; Humans ; Male ; Middle Aged ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Oxygen/administration &amp; dosage/blood/pharmacology/therapeutic use ; Oxygen Inhalation Therapy/*adverse effects ; Pulmonary Disease, Chronic Obstructive/blood/*metabolism/*therapy ; }, abstract = {UNLABELLED: Exposure to high oxygen concentration produces toxicity by free radical release. We aimed to study: whether stable chronic obstructive pulmonary disease (COPD) patients present an unbalance in the blood redox status; the effect of oxygen administration on blood redox balance; the efficacy of N-acetyl-cysteine (NAC) treatment against the oxidative stress-induced by oxygen administration and whether it is dose-related. To this, 45 stable state III COPD patients were recruited and reduced glutathione (GSH) and oxidised glutathione (GSSG) in erythrocytes and thiol proteins (P-SH) and carbonyl proteins (PC) in both erythrocytes and plasma were evaluated. All COPD patients underwent 2 l/m oxygen for 18 h and NAC at 1200 or 1800 mg/day or placebo for 48 h starting with oxygen administration. Blood samples were collected at basal conditions, after 8 and 18 h of oxygen administration and 24 h after oxygen withdrawal.<br><br>RESULTS: COPD patients present an unstable redox equilibrium mainly due to plasma sulphydryl protein depletion. Oxygen administration oxidize erythrocyte GSH, decrease P-SH and increase PC levels in both plasma and erythrocytes. NAC administration counteract the oxidative stress and at the highest dose completely prevent protein oxidation. In conclusion, stable state III COPD patients present an unstable redox balance; long term low flow oxygen administration induces systemic oxidative stress, which is prevented by NAC treatment.}, }
@article {pmid16298685, year = {2005}, author = {Wu, S and Gao, J and Ohlemeyer, C and Roos, D and Niessen, H and Köttgen, E and Gessner, R}, title = {Activation of AP-1 through reactive oxygen species by angiotensin II in rat cardiomyocytes.}, journal = {Free radical biology &amp; medicine}, volume = {39}, number = {12}, pages = {1601-1610}, doi = {10.1016/j.freeradbiomed.2005.08.006}, pmid = {16298685}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/antagonists &amp; inhibitors/*pharmacology ; Angiotensin II Type 1 Receptor Blockers ; Animals ; Antioxidants/pharmacology ; Benzimidazoles/pharmacology ; Biphenyl Compounds ; Cells, Cultured ; Dose-Response Relationship, Drug ; HL-60 Cells ; Heart Ventricles/drug effects/metabolism ; Humans ; Myocytes, Cardiac/*drug effects/*metabolism ; NADPH Oxidases/biosynthesis/drug effects/metabolism ; Onium Compounds/pharmacology ; Oxidation-Reduction ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Receptor, Angiotensin, Type 1/drug effects/metabolism ; Tetrazoles/pharmacology ; Time Factors ; Transcription Factor AP-1/drug effects/*metabolism ; }, abstract = {Cardiovascular pathogenesis induced by angiotensin II (Ang-II) is a complex process often connected to oxidative stress. In the present study we show that, 4 h after addition, Ang-II induces a four- to fivefold increase in AP-1 activity in cultured neonatal rat cardiomyocytes and that the intracellular level of reactive oxygen species (ROS) correlates with the extent of AP-1 binding activity. Ang-II stimulated ROS generation in rat cardiomyocytes in a dose- and time-dependent manner. These effects of Ang-II were suppressed by the Ang-II receptor type I (AT1) inhibitor CV-11974 as well as by the antioxidants diphenylene iodonium (DPI) and N-acetyl-L-cysteine (NAC), but not by AT2 antagonist PD 122319. Furthermore, Ang-II induced a two- to threefold increase in protein synthesis and cell size during 12-24 h, which could be inhibited by CV-11974 as well as by DPI and NAC. Because the rat cardiomyocytes strongly expressed gp91(phox), this suggests that ROS generated in a gp91-containing NADPH oxidase are involved in signal transduction leading to AP-1 activation. Together, these findings indicate that Ang-II elicits the activation of the redox-sensitive AP-1 via ROS through AT1, resulting in effects on cardiomyocyte function such as hypertrophy.}, }
@article {pmid16295780, year = {2005}, author = {Hong, SY and Gil, HW and Yang, JO and Lee, EY and Kim, HK and Kim, SH and Chung, YH and Lee, EM and Hwang, SK}, title = {Effect of high-dose intravenous N-acetylcysteine on the concentration of plasma sulfur-containing amino acids.}, journal = {The Korean journal of internal medicine}, volume = {20}, number = {3}, pages = {217-223}, pmid = {16295780}, issn = {1226-3303}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacokinetics/pharmacology ; Amino Acids/*blood/chemistry ; Glutathione/blood ; Humans ; In Vitro Techniques ; Reactive Oxygen Species ; Sulfur/*blood ; }, abstract = {BACKGROUND: The purpose of this study was to determine the adequate loading and maintenance doses of N-acetylcyseteine (NAC) for patients suffering from acute ROS-induced injury.<br><br>METHODS: Concentrations of extra cellular NAC, cysteine (Cys), cystine (Cyst2), and methionine (Met) were measured in vitro, at which more than 50% of the intracellular ROS raised by paraquat were suppressed using Swiss 3T3 fibroblasts. An in vivo pharmacokinetic study followed on a healthy subject to determine the proper loading and maintenance doses of reduced NAC following intravenous administration of 25 mg/kg NAC.<br><br>RESULTS: In vivo, NAC suppressed ROS in a dose dependant manner. 10 mM of NAC suppressed about 50% of ROS, and was comparable to 10 microM of Cys and Met and 400 microM of Cys2. In vitro, the elimination of half life was achieved at 2.88+/-1.14 h for NAC and at 3.68+/-1.84 h for total NAC. The body clearances were 1.23+/-0.77 L h(-1) kg(-1) and 0.56+/-0.27 L h(-1) kg(-1) and the volumes of distribution were 3.07+/-0.10 L kg(-1) and 3.00+/-0.11 L kg(-1), respectively. The loading and maintenance NAC doses used to reach the target concentration of 10 mM, were 5010 mg. kg(-1) and 2250 mg min(-1) kg(-1), respectively<br><br>CONCLUSION: NAC provides an antioxidant effect on ROS produced by paraquat in vivo. However, in vitro, our results showed that the intravenous NAC dose could not be estimated from NAC plasma concentration or its metabolites.}, }
@article {pmid16291250, year = {2005}, author = {Srisook, K and Kim, C and Cha, YN}, title = {Cytotoxic and cytoprotective actions of O2- and NO (ONOO-) are determined both by cellular GSH level and HO activity in macrophages.}, journal = {Methods in enzymology}, volume = {396}, number = {}, pages = {414-424}, doi = {10.1016/S0076-6879(05)96035-7}, pmid = {16291250}, issn = {0076-6879}, mesh = {Animals ; Cell Line ; Glutathione/*metabolism ; Heme Oxygenase (Decyclizing)/*metabolism ; Macrophages/enzymology/*metabolism ; Mice ; Nitric Oxide/*metabolism ; Superoxides/*metabolism ; }, abstract = {Survival of macrophages, which serve as the first-line defense against invading pathogens by invoking the overproduction of highly toxic peroxynitrite (ONOO-), depends on their ability to maintain the intracellular GSH level and to induce the expression of heme oxygenase-1 (HO-1). The ONOO- is produced by macrophages stimulated by pathogens and is a powerful oxidant reacting directly with cellular GSH and proteins, killing both invading pathogens and macrophages themselves. However, macrophages can survive the toxicity of ONOO- by replenishing the depleted GSH level and by inducing HO-1 expression. In macrophages exposed to conditions overproducing O2-, NO, or ONOO-, the cellular level of GSH decreased rapidly, and when excessive, cells died. However, in cells surviving the toxicity caused by lower doses of O2-, NO, or ONOO-, the depleted intracellular GSH level was replenished, and HO-1 expression was increased, but not when they were coexposed to an inhibitor of HO-1 activity. Cells exposed to an inhibitor of GSH synthesis had greater induction of HO-1 expression and survived. However, cells exposed to an inhibitor of HO-1 activity died extensively and could not be revived by addition of N-acetylcysteine (NAC), a precursor of GSH synthesis. Thus, the dichotomous cytotoxic or cytoprotective effects of O2-, NO, or ONOO- in macrophages are determined both by cellular GSH level and by HO-1 activity.}, }
@article {pmid16289962, year = {2006}, author = {Hologne, M and Chen, Z and Reif, B}, title = {Characterization of dynamic processes using deuterium in uniformly 2H,13C,15N enriched peptides by MAS solid-state NMR.}, journal = {Journal of magnetic resonance (San Diego, Calif. : 1997)}, volume = {179}, number = {1}, pages = {20-28}, doi = {10.1016/j.jmr.2005.10.014}, pmid = {16289962}, issn = {1090-7807}, mesh = {Acetylcysteine/chemistry ; Carbon Isotopes ; Deuterium/*chemistry ; Leucine/chemistry ; Nitrogen Isotopes ; Nuclear Magnetic Resonance, Biomolecular/*methods ; Peptides/*chemistry ; Signal Processing, Computer-Assisted ; Valine/chemistry ; }, abstract = {We present in this paper 2H,13C MAS correlation experiments that are performed on a uniformly 2H,13C,15N labeled sample of Nac-Val, and on the uniformly 2H,15N labeled dipeptide Nac-Val-Leu-OH. The experiments involve the measurement of 2H T1 relaxation times at two different magnetic fields, as well as the measurement of the 2H tensor parameters by evolution of the 2H chemical shift. The data are interpreted quantitatively to differentiate between different side chain motional models.}, }
@article {pmid16289777, year = {2006}, author = {Takatsuka, S and Kitazawa, T and Morita, T and Horikiri, Y and Yoshino, H}, title = {Enhancement of intestinal absorption of poorly absorbed hydrophilic compounds by simultaneous use of mucolytic agent and non-ionic surfactant.}, journal = {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V}, volume = {62}, number = {1}, pages = {52-58}, doi = {10.1016/j.ejpb.2005.07.008}, pmid = {16289777}, issn = {0939-6411}, mesh = {Acetylcysteine ; Animals ; Biological Availability ; Decanoic Acids/pharmacology ; Dextrans/blood/pharmacokinetics ; Drug Combinations ; Drug Synergism ; Expectorants/administration &amp; dosage/*pharmacology ; Fluorescein-5-isothiocyanate/analogs &amp; derivatives/pharmacokinetics ; Fluorescent Dyes/pharmacokinetics ; Intestinal Absorption/*drug effects ; Intestinal Mucosa/drug effects/metabolism ; Jejunum/*drug effects/metabolism ; Male ; Octoxynol/pharmacology ; Rats ; Rats, Wistar ; Surface-Active Agents/administration &amp; dosage/*pharmacology ; Tartrates/pharmacology ; }, abstract = {The effect of co-administration of a mucolytic agent with a penetration enhancer was assessed on the intestinal absorption of poorly absorbed hydrophilic compounds. Fluorescein isothiocyanate-labeled dextran with average molecular weight of ca. 4.4 kDa (FD-4) was used as a model compound, and N-acetylcysteine (NAC) was used as a mucolytic agent. Sodium caprate (C10), tartaric acid (TA), sodium taurodeoxycholate (TDC), sodium dodecyl sulfate (SDS), p-t-octyl phenol polyoxyethylene-9.5 (Triton X-100, TX-100) were selected as penetration enhancers with different mechanisms of action. Various dosing solutions containing a penetration enhancer in the absence or in the presence of NAC were directly administered into the exposed rat jejunum, and the bioavailability of FD-4 up to 2 h was determined. The extent of improvement by co-administration was highly dependent on the penetration enhancer species applied. The observed enhancement was thought to result from the mucolytic activity of NAC, which can reduce the mucus viscosity and facilitate the penetration of FD-4 to mucosal membrane. Among the combinations tested, the simultaneous administration of NAC and TX-100 provided the highest enhancement (22.5-fold) of intestinal FD-4 absorption compared to the control. Although the detailed mechanism for the observed drastic improvement is unclear, one possible reason was thought to be due to the improved diffusivity of TX-100 micellar system in the mucus layer. All these results suggest that the combination of a mucolytic agent and a non-ionic surfactant may have potential as an enhancing system for peroral delivery of poorly absorbed hydrophilic compounds like protein and peptide drugs.}, }
@article {pmid16289659, year = {2006}, author = {Spagnuolo, G and D'Antò, V and Cosentino, C and Schmalz, G and Schweikl, H and Rengo, S}, title = {Effect of N-acetyl-L-cysteine on ROS production and cell death caused by HEMA in human primary gingival fibroblasts.}, journal = {Biomaterials}, volume = {27}, number = {9}, pages = {1803-1809}, doi = {10.1016/j.biomaterials.2005.10.022}, pmid = {16289659}, issn = {0142-9612}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cells, Cultured ; Fibroblasts/drug effects/metabolism ; Gingiva/cytology/*drug effects/metabolism ; Humans ; Methacrylates/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Previous investigations have shown that 2-hydroxyethyl methacrylate (HEMA) causes reactive oxygen species (ROS) production, which in turn affects cell survival and cell death. The purpose of this study was to evaluate the effects of the antioxidant N-acetyl-L-cysteine (NAC) on HEMA-induced toxicity in human primary gingival fibroblasts (HGF). HGF were treated with various concentrations of HEMA (0-12 mm) in the absence and presence of NAC (1, 5, and 10 mm). The 3-(4,5 dimethyiazol-2-1)-2-5-diphenyl tetrazolium bromide (MTT) assay was used to evaluate the mitochondrial dehydrogenase activity after HEMA exposure. Viability and cell death were determined by flow cytometry using Annexin V and PI staining. ROS production was detected by the increasing fluorescence of the oxidation-sensitive dye 2',7'-dichlorofluorescein diacetate (DCFH-DA) after HEMA treatment. After a 24h incubation period, HEMA concentrations higher then 10mm caused a decrease of cell viability, mitochondrial activity, and an increase of cell death. HEMA concentrations of 4-12 mm markedly increased ROS levels in a dose-dependent manner. High NAC concentrations (5 and 10 mm) significantly reduced cell death, and restored the mitochondrial activity after a 24 h co-treatment, but 1 mm NAC increased HEMA toxicity (p<0.05). All NAC concentrations significantly reduced ROS levels induced by HEMA after a 2 h exposure (p<0.05), but no such reduction was observed after a 4 h treatment. Furthermore, treatment with 10 mm HEMA and 1 mm NAC for 6h caused an increase in ROS levels compared to 10 mm HEMA alone (p<0.05). In conclusion, our results suggest that high NAC concentrations protect HGF against HEMA cytotoxicity by reducing the induced ROS levels.}, }
@article {pmid16289037, year = {2005}, author = {Borkham-Kamphorst, E and Meurer, SK and Gressner, AM and Weiskirchen, R}, title = {Disruption of intermolecular disulfide bonds in PDGF-BB dimers by N-acetyl-L-cysteine does not prevent PDGF signaling in cultured hepatic stellate cells.}, journal = {Biochemical and biophysical research communications}, volume = {338}, number = {4}, pages = {1711-1718}, doi = {10.1016/j.bbrc.2005.10.139}, pmid = {16289037}, issn = {0006-291X}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Becaplermin ; Disulfides/*chemistry ; Liver/cytology ; Male ; Platelet-Derived Growth Factor/chemistry/drug effects/*physiology ; Proto-Oncogene Proteins c-sis ; Rats ; Rats, Sprague-Dawley ; Receptors, Platelet-Derived Growth Factor/drug effects/physiology ; Recombinant Proteins/chemistry/drug effects ; Signal Transduction/drug effects/*physiology ; Transforming Growth Factor beta/physiology ; }, abstract = {Oxidative stress is important in the pathogenesis of liver fibrosis through its induction of hepatic stellate cell (HSC) proliferation and enhancement of collagen synthesis. Reactive oxygen species have been found to be essential second messengers in the signaling of both major fibrotic growth factors, platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), in cultured HSC and liver fibrosis. The non-toxic aminothiol N-acetyl-L-cysteine (NAC) inhibits cellular activation and attenuates experimental fibrosis in liver. Prior reports show that NAC is capable of reducing the effects of TGF-beta in biological systems, in cultured endothelial cells, and HSC through its direct reducing activity upon TGF-beta molecules. We here analyzed the effects of NAC on PDGF integrity, receptor binding, and downstream signaling in culture-activated HSC. We found that NAC dose-dependently induces disintegration of PDGF in vitro. However, even high doses (>20mM) were not sufficient to prevent the phosphorylation of the PDGF receptor type beta, extracellular signal-regulated kinase, or protein kinase B (PKB/Akt). Therefore, we conclude that the PDGF monomer is still active. The described antifibrotic effects are therefore mainly attributable to the structural impairment of TGF-beta signaling components reported previously.}, }
@article {pmid16286925, year = {2005}, author = {Sablina, AA and Budanov, AV and Ilyinskaya, GV and Agapova, LS and Kravchenko, JE and Chumakov, PM}, title = {The antioxidant function of the p53 tumor suppressor.}, journal = {Nature medicine}, volume = {11}, number = {12}, pages = {1306-1313}, pmid = {16286925}, issn = {1078-8956}, support = {R01 AG025278/AG/NIA NIH HHS/United States ; R01 AG025278-01A1/AG/NIA NIH HHS/United States ; R01 CA104903/CA/NCI NIH HHS/United States ; R01 CA104903-02/CA/NCI NIH HHS/United States ; R01 CA10490/CA/NCI NIH HHS/United States ; }, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/pharmacology ; Animals ; Apoptosis/*physiology ; Blotting, Northern ; Blotting, Western ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; *DNA Damage ; DNA Primers ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Gene Expression Regulation/*physiology ; Genetic Vectors ; Genomic Instability/drug effects ; Humans ; Karyotyping ; Lentivirus ; Mice ; *Models, Biological ; Mutagenesis ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Spleen/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; }, abstract = {It is widely accepted that the p53 tumor suppressor restricts abnormal cells by induction of growth arrest or by triggering apoptosis. Here we show that, in addition, p53 protects the genome from oxidation by reactive oxygen species (ROS), a major cause of DNA damage and genetic instability. In the absence of severe stresses, relatively low levels of p53 are sufficient for upregulation of several genes with antioxidant products, which is associated with a decrease in intracellular ROS. Downregulation of p53 results in excessive oxidation of DNA, increased mutation rate and karyotype instability, which are prevented by incubation with the antioxidant N-acetylcysteine (NAC). Dietary supplementation with NAC prevented frequent lymphomas characteristic of Trp53-knockout mice, and slowed the growth of lung cancer xenografts deficient in p53. Our results provide a new paradigm for a nonrestrictive tumor suppressor function of p53 and highlight the potential importance of antioxidants in the prophylaxis and treatment of cancer.}, }
@article {pmid16278210, year = {2006}, author = {Fernández, Y and Miller, TP and Denoyelle, C and Esteban, JA and Tang, WH and Bengston, AL and Soengas, MS}, title = {Chemical blockage of the proteasome inhibitory function of bortezomib: impact on tumor cell death.}, journal = {The Journal of biological chemistry}, volume = {281}, number = {2}, pages = {1107-1118}, doi = {10.1074/jbc.M511607200}, pmid = {16278210}, issn = {0021-9258}, support = {R01 CA107237/CA/NCI NIH HHS/United States ; }, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/chemistry/*pharmacology ; Antineoplastic Agents/pharmacology ; Antioxidants/chemistry ; Binding, Competitive ; Boronic Acids/*pharmacology ; Bortezomib ; Breast Neoplasms/metabolism ; Cell Death/*drug effects ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Drug Antagonism ; Fibroblasts/metabolism ; Free Radicals ; Humans ; Immunoblotting ; Kinetics ; Leupeptins/pharmacology ; Melanocytes/metabolism ; Melanoma/drug therapy ; Membrane Potentials ; Models, Biological ; Protease Inhibitors/pharmacology ; Proteasome Inhibitors ; Pyrazines/*pharmacology ; Reactive Oxygen Species ; Skin/pathology ; Time Factors ; }, abstract = {The proteasome inhibitor bortezomib is emerging as a potent anti-cancer agent. Still, recent clinical trials have revealed a significant secondary toxicity of bortezomib. Consequently, there is much interest in dissecting the mechanism of action of this compound to rationally improve its therapeutic index. The cytotoxic effect of bortezomib is frequently characterized by interfering with downstream events derived from the accumulation of proteasomal targets. Here we identify the first chemical agent able to act upstream of the proteasome to prevent cell killing by bortezomib. Specifically, we show that the polyhydroxyl compound Tiron can function as a competitive inhibitor of bortezomib. This effect of Tiron was surprising, since it is a classical radical spin trap and was expected to scavenge reactive oxygen species produced as a consequence of bortezomib action. The inhibitory effect of Tiron against bortezomib was selective, since it was not shared by other antioxidants, such as vitamin E, MnTBAP, L-N-acetyl-cysteine, and FK-506. Comparative analyses with nonboronated proteasome inhibitors (i.e. MG132) revealed a specificity of Tiron for bortezomib. We exploited this novel feature of Tiron to define the "point of no return" of proteasome inhibition in melanoma cells and to block cell death in a three-dimensional model of human skin. Cells from T-cell lymphoma, breast carcinoma, and non-small cell lung cancer were also responsive to Tiron, suggesting a broad impact of this agent as a bortezomib blocker. These results may have important implications for the analysis of bortezomib in vivo and for the design of drug mixtures containing proteasome inhibitors.}, }
@article {pmid16277400, year = {2005}, author = {Pan, MH and Sin, YH and Lai, CS and Wang, YJ and Lin, JK and Wang, M and Ho, CT}, title = {Induction of apoptosis by 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione through reactive oxygen species production, GADD153 expression, and caspases activation in human epidermoid carcinoma cells.}, journal = {Journal of agricultural and food chemistry}, volume = {53}, number = {23}, pages = {9039-9049}, doi = {10.1021/jf051476a}, pmid = {16277400}, issn = {0021-8561}, mesh = {Apoptosis/*drug effects ; Caspases/*metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; DNA Fragmentation ; Enzyme Activation/drug effects ; Gene Expression/drug effects ; Humans ; Ketones/*pharmacology ; Neoplasms/*enzymology ; Propane/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species/*metabolism ; Transcription Factor CHOP/*genetics ; }, abstract = {This study examined the growth inhibitory effects of the structurally related beta-diketones compounds in human cancer cells. Here, we report that 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB) induces growth inhibition of human cancer cells and induction of apoptosis in A431 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS). ROS generation occurs in the early stages of HMDB-induced apoptosis, preceding cytochrome c release, caspase activation, and DNA fragmentation. The changes occurred after single breaks in DNA were detected, suggesting that HMDB induced irreparable DNA damage, which in turn triggered the process of apoptosis. Up-regulation of Bad and p21; down-regulation of Bcl-2, Bcl-XL, Bid, p53, and fatty acid synthase; and cleavage of Bax were found in HMDB-treated A431 cells. Glutathione and N-acetylcysteine (NAC) suppress HMDB-induced apoptosis. HMDB markedly enhanced growth arrest DNA damage inducible gene 153 (GADD153) mRNA and protein in a time- and concentration-dependent manner. NAC prevented up-regulation of GADD153 mRNA expression caused by HMDB. These findings suggest that HMDB creates an oxidative cellular environment that induces DNA damage and GADD153 gene activation, which in turn helps trigger apoptosis in A431 cells.}, }
@article {pmid16274885, year = {2005}, author = {Elbekai, RH and El-Kadi, AO}, title = {The role of oxidative stress in the modulation of aryl hydrocarbon receptor-regulated genes by As3+, Cd2+, and Cr6+.}, journal = {Free radical biology &amp; medicine}, volume = {39}, number = {11}, pages = {1499-1511}, doi = {10.1016/j.freeradbiomed.2005.07.012}, pmid = {16274885}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; Arsenites/*pharmacology ; Buthionine Sulfoximine/pharmacology ; Cadmium Chloride/*pharmacology ; Cell Line, Tumor ; Chromium Compounds/*pharmacology ; Cytochrome P-450 CYP1A1/*biosynthesis/genetics ; Down-Regulation ; Drug Synergism ; Enzyme Induction ; Gene Expression Regulation, Enzymologic ; Glutathione Transferase/biosynthesis/genetics ; Heme Oxygenase-1/biosynthesis ; Membrane Proteins/biosynthesis ; Mice ; NAD(P)H Dehydrogenase (Quinone) ; NADPH Dehydrogenase/*biosynthesis/genetics ; Oxidative Stress/*drug effects ; Receptors, Aryl Hydrocarbon/*physiology ; Sodium Compounds/*pharmacology ; }, abstract = {Heavy metals alter the capacity of AhR ligands to induce the bioactivating phase I and the detoxifying phase II xenobiotic-metabolizing enzymes but the mechanism(s) remain unknown. In the present study, we evaluated the role of As(3+)-, Cd(2+)-, and Cr(6+)-induced oxidative stress on the expression of Cyp1a1, Nqo1, and Gst ya in Hepa 1c1c7 cells. Both Cd2+ and Cr6+, but not As3+, increased the production of ROS. However, all metals increased cellular GSH content and heme oxygenase-1 mRNA levels. Although all three metals inhibited the induction of Cyp1a1 activity by TCDD, Cyp1a1 mRNA levels were potentiated. When cellular GSH was depleted with buthionine-(S,R)-sulfoximine (BSO), Cyp1a1 mRNA expression was further potentiated whereas Cyp1a1 activity was further inhibited. In parallel, pretreatment with the antioxidant N-acetylcysteine (NAC) did not alter Cyp1a1 mRNA expression but completely abrogated the inhibition of Cyp1a1 activity induction by all three metals. On the other hand, all three metals, alone or in the presence of TCDD, enhanced Nqo1 and Gst ya mRNA levels and Nqo1 activity. These effects were potentiated in the presence of BSO and abrogated with NAC. Our data clearly show that As(3+)-, Cd(2+)-, and Cr(6+)-induced oxidative stress modulates Cyp1a1 at transcriptional and posttranscriptional levels but induces Nqo1 and Gst ya at the transcriptional level.}, }
@article {pmid16274829, year = {2006}, author = {Matsuyama, T and Morita, T and Horikiri, Y and Yamahara, H and Yoshino, H}, title = {Enhancement of nasal absorption of large molecular weight compounds by combination of mucolytic agent and nonionic surfactant.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {110}, number = {2}, pages = {347-352}, doi = {10.1016/j.jconrel.2005.09.047}, pmid = {16274829}, issn = {0168-3659}, mesh = {Acetylcysteine/pharmacology ; Animals ; Area Under Curve ; Biological Availability ; Calcitonin/administration &amp; dosage/pharmacokinetics ; Chemistry, Pharmaceutical ; Dextrans/pharmacokinetics ; Expectorants/*pharmacology ; Fluorescein-5-isothiocyanate/analogs &amp; derivatives/pharmacokinetics ; Fluorescent Dyes/pharmacokinetics ; Free Radical Scavengers/pharmacology ; Hemolysis/drug effects ; Male ; Molecular Weight ; Nasal Mucosa/drug effects/*metabolism ; Pharmaceutical Preparations/*metabolism ; Phospholipids/metabolism ; Polidocanol ; Polyethylene Glycols ; Rats ; Rats, Wistar ; Surface-Active Agents/*pharmacology ; }, abstract = {For improving the nasal absorption of poorly absorbable hydrophilic compounds, the suitability of a combination of a mucolytic agent, N-acetyl-L-cysteine (NAC), and a nonionic surfactant, polyoxyethylene (C25) lauryl ether (laureth-25), was examined. Rat studies with fluorescent isothiocyanate-labeled dextran (molecular weight ca. 4.4 kDa, FD-4) as a model hydrophilic compound revealed dramatic enhancement of nasal absorption when NAC and laureth-25 were simultaneously applied. The nasal bioavailability of FD-4 in saline solution was 8.2+/-0.6% but increased to 40.0+/-5.5% when 5% NAC and 5% laureth-25 were added. This synergistic enhancement could result from the mucolytic activity of NAC in reducing mucous viscosity by which the accessibilities of FD-4 and laureth-25 to the epithelial membrane were increased. Further rat studies proved that this formulation increased nasal absorption of salmon calcitonin. Absolute bioavailability from saline solution containing 5% NAC and 1% laureth-25 was 26.8+/-2.2%, 3.5 times that of the commercial calcitonin nasal spray Miacalcin (7.7+/-2.1%). The potential of the new formulation to cause tissue damage in terms of hemolytic activity and liberation of phospholipid from the nasal membranes was nil or slight. The combination of NAC and laureth-25 appears suitable for use in development of nasal products for poorly absorbable drugs, especially peptide and protein drugs.}, }
@article {pmid16273420, year = {2006}, author = {Kim, SJ and Kim, MS and Lee, JW and Lee, CH and Yoo, H and Shin, SH and Park, MJ and Lee, SH}, title = {Dihydroartemisinin enhances radiosensitivity of human glioma cells in vitro.}, journal = {Journal of cancer research and clinical oncology}, volume = {132}, number = {2}, pages = {129-135}, pmid = {16273420}, issn = {0171-5216}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Antimalarials/pharmacology ; Artemisinins/*pharmacology ; Blotting, Western ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Gamma Rays/*therapeutic use ; Glioma/*drug therapy/*radiotherapy ; Glutathione Transferase/*antagonists &amp; inhibitors ; Humans ; Radiation-Sensitizing Agents/*pharmacology ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; Transferrin/pharmacology ; Tumor Stem Cell Assay ; }, abstract = {PURPOSE: The antimalarial agent, artemisinin, also confers cancer-specific cytotoxic effects by reacting with ferrous iron atoms to form free radicals. Here, we investigated the radiosensitizing effects of dihydroartemisinin on glioma cells and assessed some possible mechanisms for these effects.<br><br>MATERIALS AND METHODS: U373MG glioma cells treated with various concentrations of dihydroartemisinin plus radiation, and efficiency of radiosensitization was assessed by clonogenic survival assay. Expression and activity of antioxidant enzymes, glutathione-S-transferase (GST) were quantified by western blot and enzymatic activity analyses, respectively.<br><br>RESULTS: Dihydroartemisinin showed higher cytotoxicity in the glioma cell lines than in the liver, breast or cervical cancer cell lines. In clonogenic survival assays, treatment with dihydroartemisinin alone dose-dependently reduced the number of U373MG colonies, while treatment with dihydroartemisinin plus gamma-irradiation showed far lower clonal survival than cultures treated with radiation or dihydroartemisinin alone. The radiosensitizing effect of dihydroartemisinin was blocked significantly by the free radical scavengers, NAC and TIRON, indicating association with dihydroartemisinin-induced ROS generation. In addition, the radiation-induced expression of endogenous GST was suppressed by treatment with dihydroartemisinin. The radiosensitizing effect of dihydroartemisinin was also markedly enhanced by the addition of holotransferrin<br><br>CONCLUSION: Taken together, our results strongly suggest that dihydroartemisinin triggers production of ROS and inhibits GST activity, leading to effective and therapeutically relevant radiosensitization of human glioma cells.}, }
@article {pmid16273231, year = {2005}, author = {Roomi, MW and Ivanov, V and Kalinovsky, T and Niedzwiecki, A and Rath, M}, title = {Anti-angiogenic effects of a nutrient mixture on human umbilical vein endothelial cells.}, journal = {Oncology reports}, volume = {14}, number = {6}, pages = {1399-1404}, pmid = {16273231}, issn = {1021-335X}, mesh = {Acetylcysteine/pharmacology ; Angiogenesis Inhibitors/*pharmacology ; Arginine/pharmacology ; Ascorbic Acid/pharmacology ; Capillaries/drug effects/growth &amp; development ; Cell Line ; Cell Movement/genetics ; Cell Proliferation/*drug effects ; Copper/pharmacology ; Culture Media/chemistry/*pharmacology ; Dose-Response Relationship, Drug ; Endothelial Cells/*drug effects/metabolism ; Humans ; Lysine/pharmacology ; Manganese/pharmacology ; Matrix Metalloproteinase 2/metabolism ; Plant Extracts/pharmacology ; Proline/pharmacology ; Selenium/pharmacology ; Tea/chemistry ; Umbilical Veins/cytology ; }, abstract = {Matrix metalloproteinases (MMPs) have been recognized as key players in the degradation of the extracellular matrix (ECM) by migration and proliferation of endothelial cells and their subsequent invasion of the underlying stroma. The prevention of ECM degradation through the inhibition of MMP activity has been shown to be a promising therapeutic approach to block the invasion that occurs during angiogenesis. In previous studies, we demonstrated the anti-tumor effect of a nutrient mixture (NM) containing ascorbic acid, lysine, proline, green tea extract, arginine, N-acetyl cysteine, selenium, copper and manganese on various tumor cell lines in vivo and in vitro. The aim of the present study was to determine whether this mixture has anti-angiogenic effects on human umbilical vein endothelial cells (HUVECs). At near confluence, the HUVEC cell cultures were tested with NM at 0, 10, 50, 100, 500, and 1000 microg/ml in triplicate at each dose for proliferation, migration, MMP expression, and invasion. Cell proliferation was evaluated by MTT assay, invasion potential by Matrigel invasion, MMP expression by gelatinase zymography, and cell migration by a 2 mm-wide scratch in plates. For tube formation, HUVECs were cultured in previously polymerized Matrigel. NM inhibited HUVEC migration, MMP expression and invasion through Matrigel in a dose-dependent manner. Zymography showed a dose-dependent inhibition of MMP-2 expression with virtual total inhibition at a 500 microg/ml concentration. Invasion through Matrigel was totally inhibited at 500 microg/ml NM. NM reduced cell migration by scratch test in a dose-dependent fashion with total inhibition at a 500 microg/ml concentration. NM also inhibited the tube formation of HUVECs, but did not significantly inhibit cell proliferation. These results together with our earlier findings suggest that NM is a relatively non-toxic formulation with anti-angiogenic effects, such as inhibiting vascular tube formation and endothelial cell invasion and migration.}, }
@article {pmid16269967, year = {2005}, author = {Lappas, G and Daou, GB and Anand-Srivastava, MB}, title = {Oxidative stress contributes to the enhanced expression of Gialpha proteins and adenylyl cyclase signaling in vascular smooth muscle cells from spontaneously hypertensive rats.}, journal = {Journal of hypertension}, volume = {23}, number = {12}, pages = {2251-2261}, doi = {10.1097/01.hjh.0000191905.26853.f1}, pmid = {16269967}, issn = {0263-6352}, mesh = {Acetylcysteine/pharmacology ; Adenylyl Cyclases/*metabolism ; Animals ; Antioxidants/pharmacology ; Cells, Cultured ; Colforsin/pharmacology ; Flavonoids/pharmacology ; GTP-Binding Protein alpha Subunits, Gi-Go/*metabolism ; GTP-Binding Protein alpha Subunits, Gs/metabolism ; Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology ; Hypertension/*metabolism ; Isoproterenol/pharmacology ; MAP Kinase Signaling System/drug effects ; Models, Biological ; Muscle, Smooth, Vascular/drug effects/*metabolism ; Onium Compounds/pharmacology ; Oxidative Stress ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Signal Transduction/drug effects ; Superoxides/metabolism ; }, abstract = {OBJECTIVE: We have previously shown an enhanced expression of Gialpha proteins in spontaneously hypertensive rats (SHR) that precedes the development of hypertension. Since oxidative stress has been shown to be increased in SHR, the present studies were undertaken to examine the role of oxidative stress in enhanced expression of Gialpha proteins in SHR.<br><br>METHODS: Aortic vascular smooth muscle cells (VSMC) from 12-week-old SHR and Wistar-Kyoto (WKY) rats were used for the present studies. The levels of inhibitory guanine nucleotide regulatory proteins (Gialpha-2 and Gialpha-3) and stimulatory proteins (Gsalpha) were determined by western blotting techniques. Adenylyl cyclase activity was determined by measuring [32P]cAMP formation from [alpha-32P]ATP.<br><br>RESULTS: VSMC from SHR exhibited enhanced expression of Gialpha-2 and Gialpha-3 proteins as compared with age-matched WKY rats; however, the levels of Gsalpha proteins were not different between the two groups. The levels of superoxide anion (O2-) were also increased in SHR as compared with WKY rats, and losartan, an AT1 receptor antagonist, restored the enhanced levels to control WKY rat levels. Treatment of VSMC with antioxidants such as N-acetyl-L-cysteine (NAC) or diphenyleneiodonium (DPI) for 24 h decreased the enhanced expression of Gialpha-2 and Gialpha-3 proteins in a concentration-dependent manner in VSMC from SHR. In addition, the inhibition of forskolin-stimulated enzyme activity by low concentrations of GTPgammaS (receptor-independent Gi functions) and C-ANP4-23-mediated inhibition of adenylyl cyclase (receptor-dependent Gi functions) that were significantly enhanced in SHR were restored to WKY rat levels by NAC and DPI treatments. Similarly, diminished stimulation of adenylyl cyclase by GTPgammaS, isoproterenol and sodium fluoride in SHR was also restored towards control WKY rat levels by NAC and DPI treatments. Furthermore, PD98059, a selective inhibitor of mitogen-activated protein kinase, was able to restore the enhanced expression of Gialpha proteins in VSMC from SHR towards WKY rat levels. In addition, the enhanced activity of extracellular signal-regulated kinase 1/2 in SHR as compared with WKY rats, as demonstrated by enhanced phosphorylation of extracellular signal-regulated kinase 1/2, was also restored to WKY rat levels by NAC or DPI.<br><br>CONCLUSIONS: These results suggest that enhanced levels of Gialpha proteins and associated functions in SHR may be attributed to the enhanced oxidative stress present in SHR, which exerts its effects through the mitogen-activated protein kinase signaling pathway.}, }
@article {pmid16268915, year = {2005}, author = {Dillioglugil, MO and Ilgazli, A and Maral, H and Sengul, C and Ozdemir, G and Ercin, C}, title = {Protective effects of N-acetylcysteine on the peroxidative changes of rat lungs exposed to inhalation of thinners.}, journal = {Respirology (Carlton, Vic.)}, volume = {10}, number = {5}, pages = {615-619}, doi = {10.1111/j.1440-1843.2005.00758.x}, pmid = {16268915}, issn = {1323-7799}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Glutathione/drug effects/metabolism ; Inhalation Exposure/*adverse effects ; Lipid Peroxidation/*drug effects ; Lung/*drug effects/pathology ; Male ; Malondialdehyde/metabolism ; Microscopy ; Organic Chemicals/*adverse effects/chemistry ; Rats ; Rats, Wistar ; Solvents/*adverse effects/chemistry ; Superoxide Dismutase/drug effects/metabolism ; }, abstract = {OBJECTIVE: Long-term inhalation of thinners may cause damage, both to the lungs and to other organ systems. It causes cellular damage via formation of reactive oxygen species. The lung is protected from oxidative stress by the glutathione (GSH) antioxidant system which can be augmented by the thiol drug, N-acetylcysteine (NAC). This study investigated the protective effect of NAC on peroxidative changes in rat lungs exposed to inhalation of thinners for 8 weeks.<br><br>METHODOLOGY: Seventy-two male Wistar albino rats were used and divided into two groups: one group inhaled only thinners (TI), while the other inhaled TI plus NAC. Rats in the TI and TI + NAC groups were divided into four subgroups (each consisting of eight rats) according to the duration of exposure to TI: 2, 4, 6 and 8 weeks. A control group (n = 7) of rats inhaled neither TI nor NAC. Malondialdehyde (MDA) and GSH levels, and superoxide dismutase (SOD) activities were determined in the lung tissues. Histopathological findings were evaluated as acute and chronic changes in the alveoli and interstitium in the TI and TI + NAC groups and compared with those in the control group.<br><br>RESULTS: While tissue MDA levels in the groups inhaling TI for 4, 6 and 8 weeks were significantly higher than those in the control groups (P < 0.01, P < 0.01, P < 0.0001, respectively), GSH levels were significantly lower (P < 0.05, P < 0.01, P < 0.01, respectively). Tissue SOD activities in the groups inhaling TI for 6 and 8 weeks were significantly lower than those in the control group (P < 0.05, P < 0.01, respectively). In the TI group, MDA levels were significantly increased (P < 0.01) with increasing duration of inhalation (from the second week through to the eighth week), while GSH levels and SOD activities were significantly decreased (P < 0.01, P < 0.01). Tissue MDA levels were significantly lower in the TI + NAC groups across all inhalation periods, when compared with the TI groups (P < 0.01, P < 0.0001, P < 0.0001, P < 0.0001, respectively). Tissue GSH levels in the TI + NAC groups were significantly higher than those of the TI groups (respective values: P < 0.05, P < 0.01, P < 0.01, P < 0.0001). Tissue SOD activities in the TI + NAC groups were significantly higher than those of the TI groups (respective values: P < 0.05, P < 0.0001, P < 0.05, P < 0.0001). Pathological examinations with light microscopy did not show any beneficial effect of NAC application in terms of deferring or alleviating the negative effects of TI.<br><br>CONCLUSIONS: Thinners are agents that cause imbalance between oxidants and antioxidants produced by aerobic cellular systems. This imbalance between oxidant and antioxidant systems is decreased by the effect of NAC. However, ultrastructural studies may be needed to substantiate this evidence morphologically, as light microscopy was inconclusive.}, }
@article {pmid16263306, year = {2005}, author = {Ramudo, L and Manso, MA and Vicente, S and De Dios, I}, title = {Pro- and anti-inflammatory response of acinar cells during acute pancreatitis. Effect of N-acetyl cysteine.}, journal = {Cytokine}, volume = {32}, number = {3-4}, pages = {125-131}, doi = {10.1016/j.cyto.2005.07.017}, pmid = {16263306}, issn = {1043-4666}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Animals ; Bile Ducts/surgery ; Cells, Cultured ; Flow Cytometry ; Hyperamylasemia/metabolism/pathology ; Inflammation Mediators/*metabolism ; Interleukin-10/biosynthesis ; Male ; Pancreas/*metabolism/*pathology/ultrastructure ; Pancreatic Ducts/surgery ; Pancreatitis/*metabolism/*pathology ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {We investigate the ability of acinar cells to produce tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) at different stages of acute pancreatitis (AP). Since oxidative stress is involved in the inflammatory response, the effect of N-acetyl cysteine (NAC) has also been evaluated. AP was induced in rats by bile-pancreatic duct obstruction (BPDO). NAC (50 mg/kg) was administered 1h before and 1h after BPDO. Acinar cells were incubated for 4 h at 37 degrees C in 5% CO2 atmosphere in absence and presence of 24-h BPDO-PAAF (20%, v/v) as stimulant agent. Acinar production of TNF-alpha and IL-10 was analysed by flow cytometry. Plasma amylase activity and histological studies of the pancreas indicated the severity of AP. PAAF significantly stimulated the acinar production of TNF-alpha and IL-10 in control rats. TNF-alpha production was also significantly stimulated in acinar cells of rats with AP, although a decrease in the pro-inflammatory response was found from 6 h after BPDO onwards. However, acinar cells failed to produce IL-10 from 3 h after BPDO. The protective effect of NAC treatment against oxidative cell damage reduced the pancreatic injury and maintained and enhanced the ability of acinar cells to produce IL-10 at early AP stages. As long as acinar cells were not severely damaged in the course of AP, greater ability to produce cytokines in response to PAAF was found in those with higher forward scatter (R2 cells). We suggest that the capability of acinar cells to maintain an appropriate balance between the production of pro- and anti-inflammatory mediators could contribute to determine the degree of severity of AP.}, }
@article {pmid16261333, year = {2006}, author = {Cheng-Hsien, C and Yung-Ho, H and Yuh-Mou, S and Chun-Cheng, H and Horng-Mo, L and Huei-Mei, H and Tso-Hsiao, C}, title = {Src homology 2-containing phosphotyrosine phosphatase regulates endothelin-1-induced epidermal growth factor receptor transactivation in rat renal tubular cell NRK-52E.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {452}, number = {1}, pages = {16-24}, pmid = {16261333}, issn = {0031-6768}, mesh = {Animals ; Cell Line ; Cysteine/metabolism ; Endothelin-1/*metabolism ; Epidermal Growth Factor/antagonists &amp; inhibitors/genetics/*metabolism ; Intracellular Signaling Peptides and Proteins/*metabolism ; Kidney Tubules/*metabolism ; Oxidation-Reduction ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; Protein Tyrosine Phosphatases/*metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; SH2 Domain-Containing Protein Tyrosine Phosphatases ; Signal Transduction/physiology ; Transcriptional Activation ; src Homology Domains/physiology ; }, abstract = {Epidermal growth factor (EGF) and endothelin-1 (ET-1) have been shown to be involved in proliferation and autoregeneration of renal tubular cells. This study aims to investigate the regulatory mechanism of ET-1-mediated EGF receptor (EGFR) transactivation in rat renal tubular cells (NRK-52E). Exposure of NRK-52E cells to ET-1 was found to stimulate the phosphorylation of EGFR and induce reactive oxygen species (ROS) generation. Both NAD(P)H oxidase inhibitor, diphenyliodonium (DPI) and ROS scavenger N-acetylcysteine (NAC), inhibited EGFR transactivation and extracellular signal-regulated kinase (ERK) phosphorylation caused by ET-1. In contrast, blockade of EGFR by AG1478 inhibited the phosphorylation of ERK but not ROS generation following ET-1 exposure. We found that the catalytic cysteine of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) was transiently oxidized by ET-1 treatment in a modified malachite green phosphatase assay. In EGFR co-immunoprecipitation, SHP-2 was also found to interact with EGFR following ET-1 treatment. In SHP-2 knockdown NRK-52E cells, ET-1-induced EGFR transactivation was dramatically elevated and not influenced by NAC. However, GM6001 (an MMP inhibitor) and heparin binding (HB)-EGF neutralizing antibody suppressed this elevation. Our data suggest that ROS-mediated oxidation of SHP-2 is essential for HB-EGF-mediated EGFR transactivation in ET-1 signaling pathway in NRK-52E cells.}, }
@article {pmid16253189, year = {2005}, author = {Li, X and Meng, Y and Cai, SX and Yang, XS and Zhang, YJ and Wu, PS}, title = {[Angiotensin II and aldosterone stimulate alpha1-(I) procollagen mRNA expression in hepatic stellate cells via activation of ERK1/2 and AP-1].}, journal = {Zhonghua yi xue za zhi}, volume = {85}, number = {26}, pages = {1831-1835}, pmid = {16253189}, issn = {0376-2491}, mesh = {Aldosterone/*pharmacology ; Angiotensin II/*pharmacology ; Cells, Cultured ; Hepatic Stellate Cells/drug effects/*metabolism ; Humans ; MAP Kinase Signaling System/*drug effects ; Procollagen/*metabolism ; RNA, Messenger/genetics ; Signal Transduction/drug effects ; Transcription Factor AP-1/*metabolism ; }, abstract = {OBJECTIVE: To investigate the signal transduction mechanism underlying the effects of angiotensin II (Ang II) and aldosterone (Aldo) on the signal passageway of active protein-1 (AP-1).<br><br>METHODS: In vitro, Hepatic stellate cells (HSCs) of the line HSC-T6 were cultured and treated with Ang II or Aldo, the principal effector molecules of the renin-angiotensin-aldosterone system (RAAS) for 10, 30, 60, 120, and 180 minutes respectively. The protein expression of phospho-P42/44 was detected by Western blotting. In addition, HSC-T6 cells were preincubated for 60 min with U0126, an inhibitor of MAPK/ERK kinase, irbesartan, an AT-1 receptor blocker, N-acetylcysteine (NAC), antioxidant, angiotensin converting enzyme inhibitor (ACEI), or tumor necrosis factor alpha (TNFalpha) prior to exposure to Ang II or Aldo. Then the protein expression of phospho-P42/44 was measured by Western blotting. The DNA biding activity of AP-1 was analyzed by electrophoretic gel mobility shift assay (EMSA). By means of RT-PCR, the mRNA expression of alpha1 (I) procollagen was detected.<br><br>RESULTS: The levels of phopho-ERK1/2 protein increased after the treatment of Ang II and Aldo at all time points and both peaked 10 minutes after (both P < 0.01). The levels of phopho-ERK1/2 protein of the irbesartan + Ang II and U0126 + Ang II groups were significantly lower than that of the Ang II group (both P < 0.01). The level of phopho-ERK1/2 protein of the Ang II group was lower than that of the TNFalpha group, however, was especially significantly lower than that of the Ang II + TNFalpha group (P < 0.01). The level of phopho-ERK1/2 protein of the U0126 + Aldo group was significantly lower than that of the Aldo group (P < 0.01). The phopho-ERK1/2 protein level of the NAC + Aldo group was not significantly different from that of the Aldo group (P > 0.05). The phopho-ERK1/2 protein level of the Aldo group was lower than that of the TNFalpha group, however, was especially significantly lower than that of the Aldo + TNFalpha group (P < 0.01). The AP-1 DNA binding protein increased after the treatment of Ang II and peaked 30 min after. U0126, irbesartan, and NAC, as well as ACEUI, significantly inhibited the increased AP-1 DNA binding activity induced by Ang II. The AP-1 DNA binding protein increased after the treatment of Aldo and peaked twice, 30 min and 240 min after. U0126 and NAC significantly and NAC partly inhibited the increased AP-1 DNA binding activity induced by Aldo.<br><br>CONCLUSION: Stimulation of HSC by Ang II and Aldo results in activation of AP-1 via ERK1/2 pathway leading to up-regulation of AP-1 target gene alpha1 (I) procollagen mRNA expression.}, }
@article {pmid16252256, year = {2006}, author = {McClintock, SD and Hoesel, LM and Das, SK and Till, GO and Neff, T and Kunkel, RG and Smith, MG and Ward, PA}, title = {Attenuation of half sulfur mustard gas-induced acute lung injury in rats.}, journal = {Journal of applied toxicology : JAT}, volume = {26}, number = {2}, pages = {126-131}, doi = {10.1002/jat.1115}, pmid = {16252256}, issn = {0260-437X}, mesh = {Acute Disease ; Animals ; Antioxidants/administration &amp; dosage/therapeutic use ; Catalase/administration &amp; dosage/therapeutic use ; Chemical Warfare Agents/*poisoning ; Complement System Proteins/physiology ; Drug Delivery Systems ; Enzyme Therapy ; Enzymes/administration &amp; dosage ; Liposomes ; Lung/pathology ; Lung Diseases/*chemically induced/pathology/*prevention &amp; control ; Male ; Mustard Gas/*analogs &amp; derivatives/poisoning ; Rats ; Rats, Long-Evans ; Reducing Agents/administration &amp; dosage/therapeutic use ; Superoxide Dismutase/administration &amp; dosage/therapeutic use ; }, abstract = {Airway instillation into rats of 2-chloroethyl ethyl sulfide (CEES), the half molecule of sulfur mustard compound, results in acute lung injury, as measured by the leak of plasma albumin into the lung. Morphologically, early changes in the lung include alveolar hemorrhage and fibrin deposition and the influx of neutrophils. Following lung contact with CEES, progressive accumulation of collagen occurred in the lung, followed by parenchymal collapse. The co-instillation with CEES of liposomes containing pegylated (PEG)-catalase (CAT), PEG-superoxide dismutase (SOD), or the combination, greatly attenuated the development of lung injury. Likewise, the co-instillation of liposomes containing the reducing agents, N-acetylcysteine (NAC), glutathione (GSH), or resveratrol (RES), significantly reduced acute lung injury. The combination of complement depletion and airway instillation of liposomes containing anti-oxidant compounds maximally attenuated CEES-induced lung injury by nearly 80%. Delayed airway instillation of anti-oxidant-containing liposomes (containing NAC or GSH, or the combination) significantly diminished lung injury even when instillation was delayed as long as 1 h after lung exposure to CEES. These data indicate that CEES-induced injury of rat lungs can be substantially diminished by the presence of reducing agents or anti-oxidant enzymes delivered via liposomes.}, }
@article {pmid16252075, year = {2006}, author = {Crack, PJ and Cimdins, K and Ali, U and Hertzog, PJ and Iannello, RC}, title = {Lack of glutathione peroxidase-1 exacerbates Abeta-mediated neurotoxicity in cortical neurons.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {113}, number = {5}, pages = {645-657}, pmid = {16252075}, issn = {0300-9564}, mesh = {Amyloid beta-Peptides/*toxicity ; Animals ; Animals, Newborn ; Blotting, Western/methods ; Caspase 3 ; Caspases/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Cerebral Cortex/*cytology ; Dose-Response Relationship, Drug ; Drug Interactions ; Glutathione Peroxidase/*deficiency ; Hydrogen Peroxide/pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/*drug effects/pathology ; Neurotoxicity Syndromes/*etiology/physiopathology ; Peptide Fragments/toxicity ; Tetrazolium Salts ; Thiazoles ; Glutathione Peroxidase GPX1 ; }, abstract = {The aetiologies of Alzheimer's disease (AD) are complex and multifactorial. Current therapies are largely ineffective, as the pathophysiological pathways are poorly understood. Observations in AD autopsies, as well as in vivo and in vitro observations in transgenic mice, have implicated oxidative stress as pathogenic in AD. This study used the Glutathione Peroxidase-1 knockout mouse (Gpx1--/--) model to investigate the role of antioxidant disparity in neuropathologies. Cultured neurons from control and Gpx1--/-- embryos were treated with AD-related peptides and the degree of cell loss compared. Results show that antioxidant disparity makes Gpx1--/-- cells more susceptible to Abeta toxicity. Surrogate replacement of Gpx1 with the reactive oxygen species scavenger N-acetyl cysteine and the Gpx1 mimetic ebselen, reverses the Gpx1--/-- increased susceptibility to Abeta toxicity. Such results support a role for oxidative stress in AD-related neuronal loss. This study is the first to report such findings using the Gpx1--/-- model, and supports a role for oxidative stress as one of the contributing factors, in development of AD-like pathologies.}, }
@article {pmid16251475, year = {2006}, author = {Moshal, KS and Sen, U and Tyagi, N and Henderson, B and Steed, M and Ovechkin, AV and Tyagi, SC}, title = {Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway.}, journal = {American journal of physiology. Cell physiology}, volume = {290}, number = {3}, pages = {C883-91}, doi = {10.1152/ajpcell.00359.2005}, pmid = {16251475}, issn = {0363-6143}, support = {HL-71010/HL/NHLBI NIH HHS/United States ; HL-74185/HL/NHLBI NIH HHS/United States ; }, mesh = {Calcium/metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects/metabolism ; Enzyme Activation ; Enzyme Induction/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Folic Acid/pharmacology ; Homocysteine/metabolism/*pharmacology ; Humans ; *MAP Kinase Signaling System ; Matrix Metalloproteinase 9/*metabolism ; Oxidative Stress ; Protein Kinase C/metabolism ; Protein-Tyrosine Kinases/metabolism ; Receptors, G-Protein-Coupled/metabolism ; }, abstract = {Homocysteine (Hcy) induces matrix metalloproteinase (MMP)-9 in microvascular endothelial cells (MVECs). We hypothesized that the ERK1/2 signaling pathway is involved in Hcy-mediated MMP-9 expression. In cultured MVECs, Hcy induced activation of ERK, which was blocked by PD-98059 and U0126 (MEK inhibitors). Pretreatment with BAPTA-AM, staurosporine (PKC inhibitor), or Gö6976 (specific inhibitor for Ca(2+)-dependent PKC) abrogated ERK phosphorylation, suggesting the role of Ca(2+) and Ca(2+)-dependent PKC in Hcy-induced ERK activation. ERK phosphorylation was suppressed by pertussis toxin (PTX), suggesting the involvement of G protein-coupled receptors (GPCRs) in initiating signal transduction by Hcy and leading to ERK activation. Pretreatment of MVECs with genistein, BAPTA-AM, or thapsigargin abrogated Hcy-induced ERK activation, suggesting the involvement of the PTK pathway in Hcy-induced ERK activation, which was mediated by intracellular Ca(2+) pool depletion. ERK activation was attenuated by preincubation with N-acetylcysteine (NAC) and SOD, suggesting the role of oxidation in Hcy-induced ERK activation. Pretreatment with an ERK1/2 blocker (PD-98059), staurosporine, folate, or NAC modulated Hcy-induced MMP-9 activation as measured using zymography. Our results provide evidence that Hcy triggers the PTX-sensitive ERK1/2 signaling pathway, which is involved in the regulation of MMP-9 in MVECs.}, }
@article {pmid16249925, year = {2006}, author = {Thomale, UW and Griebenow, M and Kroppenstedt, SN and Unterberg, AW and Stover, JF}, title = {The effect of N-acetylcysteine on posttraumatic changes after controlled cortical impact in rats.}, journal = {Intensive care medicine}, volume = {32}, number = {1}, pages = {149-155}, pmid = {16249925}, issn = {0342-4642}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain Edema/prevention &amp; control ; Brain Injuries/*drug therapy ; Cerebrovascular Circulation/drug effects ; Free Radical Scavengers/*pharmacology ; Male ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: The antioxidant potential N-Acetylcysteine (NAC) and its improvement of posttraumatic mitrochondrial dysfunction have been reported. This study investigated the effect of NAC on posttraumatic changes after controlled cortical Impact (CCI) injury.<br><br>DESIGN AND SETTING: Prospective randomized controlled animal study.<br><br>METHODS: A moderate left focal cortical contusion was induced using CCI. Either NAC (163 mg/kg bw) or physiological saline was administered intraperitoneally immediately and 2 and 4 h after trauma. Blood gases, temperature, mean arterial blood pressure (MABP), and intracranial pressure (ICP) were monitored. Twenty-four hours after trauma brains were removed and either posttraumatic edema was quantified gravimetrically (n=24], or contusion volume was determined morphometrically using slices staining and computerized image analysis (n=24]. Laser Doppler flowmetry was used to assess pericontusional cortical perfusion before trauma, 30 min and 4 and 24 h after trauma (n=14].<br><br>MEASUREMENTS AND RESULTS: Physiological parameters remained within normal limits. ICP measurements and water content in traumatized hemispheres did not differ between the groups. Relative contusion volume of the left hemisphere was slightly but nonsignificantly diminished in NAC-treated animals (4.7+/-0.4% vs. 5.9+/-0.5% in controls). In both groups pericontusional perfusion was significantly reduced at 4 h followed by a state of hyperperfusion at 24 h with no differences between the groups.<br><br>CONCLUSIONS: Despite previously reported neuroprotective abilities of NAC, no positive effect on posttraumatic perfusion, brain edema formation, or contusion volume after focal brain injury was observed in this study.}, }
@article {pmid16249273, year = {2006}, author = {Feliers, D and Gorin, Y and Ghosh-Choudhury, G and Abboud, HE and Kasinath, BS}, title = {Angiotensin II stimulation of VEGF mRNA translation requires production of reactive oxygen species.}, journal = {American journal of physiology. Renal physiology}, volume = {290}, number = {4}, pages = {F927-36}, doi = {10.1152/ajprenal.00331.2005}, pmid = {16249273}, issn = {1931-857X}, support = {DK-55875/DK/NIDDK NIH HHS/United States ; R01-DK-50790/DK/NIDDK NIH HHS/United States ; }, mesh = {Angiotensin II/*physiology ; Animals ; Cell Culture Techniques ; Enzyme Inhibitors/pharmacology ; Kidney Tubules, Proximal/cytology/*physiology ; Mice ; NADPH Oxidases/metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Oxidative Stress ; Phosphorylation ; Protein Biosynthesis ; RNA, Messenger/biosynthesis ; *Reactive Oxygen Species ; Vascular Endothelial Growth Factor A/*biosynthesis ; }, abstract = {ANG II, a mediator of renal injury in diabetic renal disease, promotes vascular endothelial growth factor (VEGF) mRNA translation in proximal tubular epithelial (MCT) cells (Feliers D, Duraisamy S, Barnes JL, Ghosh-Choudhury G, and Kasimath BS. Am J Physiol Renal Physiol 288: F521-F529, 2005). The mechanism by which ANG II elicits this effect is not known. ANG II is known to induce oxidative stress and the rapidity of the effect suggested a role for reactive oxygen species (ROS). The aim of this study is to test the hypothesis that ANG II regulates VEGF mRNA translation in MCT cells through ROS production. In MCT cells exposed to 1 nM ANG II, ROS production was increased in a time-dependent manner. Inhibition of ROS production by N-acetylcysteine (NAC), a precursor of glutathione, and diphenyleneiodonium (DPI), an inhibitor of flavoproteins that include NAD(P)H oxidase, prevented ANG II-stimulated VEGF protein expression. NAC and DPI also inhibited phosphorylation of 4E-BP1 on Thr46 and association of eIF4E with eIF4G, steps that are important in the initiation phase of mRNA translation. NAC and DPI also blocked Akt activation which is required for 4E-BP1 phosphorylation. LY-294002, a selective phosphatidylinositol (PI 3-kinase) inhibitor, did not prevent ROS accumulation in response to ANG II, whereas DPI blocked ANG II activation of PI 3-kinase, demonstrating that ROS production is upstream of the PI 3-kinase signaling pathway. Preincubation with catalase abolished ANG II stimulation of VEGF expression and mRNA translation, suggesting involvement of hydrogen peroxide (H(2)O(2)). H(2)O(2) reproduced the effects of ANG II on VEGF expression and aforementioned parameters of mRNA translation. Finally, neither preincubation of MCT cells with specific inhibitors of the mitochondrial respiratory chain nor inactivation of the mitochondrial respiratory chain in MCT cells prevented ANG II stimulation of VEGF expression. Inhibition of nitric oxide synthase by l-NAME had no effect on ANG II stimulation of VEGF expression. These data show that ROS, generated probably through activation of an NAD(P)H oxidase, mediate ANG II stimulation of VEGF mRNA translation.}, }
@article {pmid16248859, year = {2005}, author = {Ayonrinde, OT and Phelps, GJ and Hurley, JC and Ayonrinde, OA}, title = {Paracetamol overdose and hepatotoxicity at a regional Australian hospital: a 4-year experience.}, journal = {Internal medicine journal}, volume = {35}, number = {11}, pages = {655-660}, doi = {10.1111/j.1445-5994.2005.00947.x}, pmid = {16248859}, issn = {1444-0903}, mesh = {Acetaminophen/*poisoning ; Adolescent ; Adult ; Age Distribution ; Aged ; Aged, 80 and over ; Alcohol Drinking/*epidemiology ; Australia/epidemiology ; Chemical and Drug Induced Liver Injury/epidemiology/*etiology ; Child ; Child, Preschool ; Comorbidity ; Drug Overdose ; Female ; Hospitalization/*statistics &amp; numerical data ; Humans ; Infant ; Male ; Middle Aged ; Prevalence ; Retrospective Studies ; Risk Assessment/*methods ; Risk Factors ; Sex Distribution ; }, abstract = {BACKGROUND: Paracetamol is a component of a number of drugs taken in overdose (OD). The influence of alcohol use (acute or chronic) on the presentation and clinical course of paracetamol OD is contentious. This study explores the relationship between paracetamol OD, alcohol consumption and clinical outcomes at a regional Australian hospital.<br><br>AIMS: To determine the frequency, circumstances and outcomes of paracetamol OD presentations to a regional Australian general hospital over a 4-year period.<br><br>METHODS: Medical records of patients admitted to the Ballarat Health Services (BHS) as a result of paracetamol OD between January 2000 and December 2003 were reviewed. Patient demographics, amount of paracetamol ingested, other drug coingestions, alcohol history, previous medication OD, clinical course and outcomes were recorded.<br><br>RESULTS: Annual admissions resulting from paracetamol OD almost doubled during the 4 years studied. The risk of a repeat paracetamol OD was highest within 4 weeks of the initial OD. Alcohol, benzodiazepines and antidepressants were commonly coingested. The strongest predictor of severe hepatotoxicity was delayed or no N-acetyl cysteine treatment in patients consuming greater than 10 g of paracetamol or with toxic serum paracetamol levels. A history of alcohol consumption did not appear to worsen outcomes.}, }
@article {pmid16243047, year = {2005}, author = {Akca, T and Canbaz, H and Tataroglu, C and Caglikulekci, M and Tamer, L and Colak, T and Kanik, A and Bilgin, O and Aydin, S}, title = {The effect of N-acetylcysteine on pulmonary lipid peroxidation and tissue damage.}, journal = {The Journal of surgical research}, volume = {129}, number = {1}, pages = {38-45}, doi = {10.1016/j.jss.2005.05.026}, pmid = {16243047}, issn = {0022-4804}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/analysis ; Common Bile Duct/surgery ; Disease Models, Animal ; Injections, Intraperitoneal ; Jaundice, Obstructive/etiology/*metabolism/*pathology ; Ligation ; Lipid Peroxidation/*drug effects ; Lipopolysaccharides/administration &amp; dosage ; Lung/*metabolism/*pathology ; Male ; Malondialdehyde/analysis ; Peroxidase/analysis/blood ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: We aimed to investigate the effect of N-acetylcysteine (NAC) on pulmonary lipid peroxidation and tissue damage in experimental obstructive jaundice (OJ) stimulated by lipopolysaccharide (LPS) in this study.<br><br>MATERIALS AND METHODS: We randomized 40 rats into five groups. Group A: Sham (n = 8); group B: OJ (n = 8); group C: OJ + lipopolysaccharide (LPS; n = 8); group D: OJ + NAC + LPS (n = 8); group E: OJ + LPS + NAC (n = 8). OJ was performed by common bile duct ligation and division in all groups except the sham group. At the fifth day, the rats were jaundiced. At the fifth day of OJ, LPS was injected 10 mg/kg intraperitoneally to the rats and at the tenth day, the rats were sacrificed in group C. In group D; at the fifth day of OJ, NAC was started 100 mg/kg subcutaneously and the same dose NAC injection repeated every day for 5 days. At the tenth day of OJ, LPS was injected 10 mg/kg intraperitoneally to the rats and then after 6 h they were sacrificed. In group E; 10 mg/kg LPS was administered intraperitoneally at fifth day of OJ and after then NAC was started 100 mg/kg subcutaneously and the same dose NAC injection repeated every day for 5 days and at the tenth day, the rats were sacrificed. Tissue samples were harvested through a midline incision, and lungs were resected and examined histopathologically and immunohistochemically for tissue damage scoring. The blood was taken by cardiac puncture and malondialdehyde (MDA), myeloperoxidase (MPO), and levels of total antioxidant status were detected with biochemical methods to evaluate lung tissue damage.<br><br>RESULTS: Increase in lung and serum MDA and MPO levels, as well as decrease in total antioxidant status, were observed in groups B and C when compared with the sham group (P = 0.0001, for each comparison). Furthermore, the lung tissue damage was observed in the same groups by histopathological examination when compared with sham group. There was significant decrease at serum and lung MPO and MDA levels after the NAC application in groups D and E, when compared with group C (P = 0.0001, for each comparison). Antioxidant status in groups D and E were increased in the presence of NAC (P = 0.0001, for each comparison). Lung histology was prevented relatively in group D when compared with groups B and C.<br><br>CONCLUSION: Results of the study indicate that NAC has protective effect on pulmonary lipid peroxidation and tissue damage before and after LPS administration.}, }
@article {pmid16238546, year = {2006}, author = {Pechánová, O and Zicha, J and Kojsová, S and Dobesová, Z and Jendeková, L and Kunes, J}, title = {Effect of chronic N-acetylcysteine treatment on the development of spontaneous hypertension.}, journal = {Clinical science (London, England : 1979)}, volume = {110}, number = {2}, pages = {235-242}, doi = {10.1042/CS20050227}, pmid = {16238546}, issn = {0143-5221}, mesh = {Acetylcysteine/*therapeutic use ; Aging ; Animals ; Antioxidants/*therapeutic use ; Glutathione/metabolism ; Heart Ventricles/metabolism ; Hypertension/*drug therapy/metabolism ; Kidney/metabolism ; Male ; NF-kappa B/analysis ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II/analysis ; Nitric Oxide Synthase Type III/analysis ; Random Allocation ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Reactive Oxygen Species/metabolism ; }, abstract = {The imbalance between NO (nitric oxide) and ROS (reactive oxygen species) is an important factor in the development of hypertension. The aim of the present study was to determine the preventive and therapeutic effects of NAC (N-acetylcysteine) in SHRs (spontaneously hypertensive rats). Young and adult SHRs and WKY (Wistar-Kyoto) rats were treated with NAC (20 g/l in the drinking water). After 8 weeks of treatment, BP (blood pressure) and NOS (NO synthase) activity, conjugated dienes and GSH (reduced glutathione) in the kidney and left ventricle were determined. Protein expression of eNOS (endothelial NOS), inducible NOS and NF-kappaB (nuclear factor kappaB) were also determined in the left ventricle and kidney. Chronic NAC treatment partially attenuated the rise in BP in young SHRs (179+/-6 compared with 210+/-8 mmHg in untreated animals), but it had no significant effect on BP in adult SHRs. The antioxidant action of NAC, measured as a decrease of the concentration of conjugated dienes or inhibition of NF-kappaB expression, was greater in young than in adult SHRs. Similarly, eNOS protein expression was attenuated more in young than in adult SHRs, although NAC treatment increased NOS activity to a similar extent in both young and adult rats. In conclusion, both decreased ROS production and increased NOS activity appear to participate in the BP changes after NAC treatment in young SHRs. In adult SHRs with established hypertension, however, the secondary alterations (such as pronounced structural remodelling of resistance vessels) might attenuate the therapeutic effect of NAC.}, }
@article {pmid16235987, year = {2005}, author = {Banjerdpongchai, R and Wilairat, P}, title = {Effects of water-soluble antioxidants and MAPKK/MEK inhibitor on curcumin-induced apoptosis in HL-60 human leukemic cells.}, journal = {Asian Pacific journal of cancer prevention : APJCP}, volume = {6}, number = {3}, pages = {282-285}, pmid = {16235987}, issn = {1513-7368}, mesh = {Antineoplastic Agents/*pharmacology ; Antioxidants/chemistry/*pharmacology ; Apoptosis/*drug effects ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors ; Curcumin/*pharmacology ; Dose-Response Relationship, Drug ; Flavonoids/pharmacology ; HL-60 Cells ; Humans ; Membrane Potentials/drug effects ; Mitochondria ; Solubility ; }, abstract = {Curcumin is the main biologically active phytochemical compound in turmeric. It has been shown to have anticarcinogenic activity. The aims of the study were to identify the mechanism of apoptosis of HL-60 human promyelocytic leukemic cells induced by curcumin and to determine the effects of water-soluble antioxidants, ascorbic acid, Trolox (a water-soluble form of vitamin E), glutathione (GSH) and N-acetylcysteine (NAC) on this process. HL-60 cells were incubated with curcumin for 24 h and apoptotic cells were quantitated by flow cytometry following staining with annexin V-FITC and propidium iodide. Curcumin-treated HL-60 cells produced reactive oxygen species as detected by the dichlorofluorescein fluorescent assay. Apoptosis occurred via the mitochondria pathway as curcumin reduced mitochondrial membrane potential in a dose-dependent manner. In the presence of 10 microM curcumin, vitamin C (56 nM-5.6 microM) inhibited apoptosis of HL-60 cells; GSH at low concentration (1 microM) reduced apoptosis but had no effect at higher concentrations (10, 100 microM); and Trolox and NAC at 10 and 100 microM, respectively, enhanced apoptosis, but this effect was abolished at higher concentration (1 mM) of NAC. MAPKK/MEK inhibitor PD98059, enhanced curcumin-induced HL-60 apoptotic cell death.}, }
@article {pmid16231578, year = {2005}, author = {Adamy, C and Le Corvoisier, P and Candiani, G and Kirsch, M and Pavoine, C and Defer, N and Bourin, MC and Su, JB and Vermes, E and Hittinger, L and Pecker, E}, title = {Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.}, journal = {Archives des maladies du coeur et des vaisseaux}, volume = {98}, number = {9}, pages = {906-912}, pmid = {16231578}, issn = {0003-9683}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cardiotonic Agents/pharmacology ; Glutathione/deficiency/*metabolism ; Heart Failure/*metabolism ; Humans ; Myocardial Contraction ; Myocardial Ischemia/metabolism ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*metabolism ; }, abstract = {The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.}, }
@article {pmid16227407, year = {2005}, author = {Turbyville, TJ and Wijeratne, EM and Whitesell, L and Gunatilaka, AA}, title = {The anticancer activity of the fungal metabolite terrecyclic acid A is associated with modulation of multiple cellular stress response pathways.}, journal = {Molecular cancer therapeutics}, volume = {4}, number = {10}, pages = {1569-1576}, doi = {10.1158/1535-7163.MCT-05-0050}, pmid = {16227407}, issn = {1535-7163}, support = {1R01 CA09025-01/CA/NCI NIH HHS/United States ; }, mesh = {3T3 Cells ; Animals ; Antineoplastic Agents/*pharmacology ; Aspergillus/chemistry ; Cell Growth Processes/drug effects ; Flow Cytometry ; HeLa Cells ; Heat-Shock Response/drug effects/physiology ; Humans ; Mice ; NF-kappa B/antagonists &amp; inhibitors ; Oxidation-Reduction ; Reactive Oxygen Species/analysis/metabolism ; Sesquiterpenes/pharmacology ; Structure-Activity Relationship ; }, abstract = {Tumors are dependent on cellular stress responses, in particular the heat shock response, for survival in their hypoxic, acidotic, and nutrient-deprived microenvironments. Using cell-based reporter assays, we have identified terrecyclic acid A (TCA) from Aspergillus terreus, a fungus inhabiting the rhizosphere of Opuntia versicolor of the Sonoran desert, as a small-molecule inducer of the heat shock response that shows anticancer activity. Further characterization suggested that TCA also affects oxidative and inflammatory cellular stress response pathways. The presence of an alpha-methylene ketone moiety suggested that TCA may form adducts with sulfhydryl groups of proteins. Reaction with labile intracellular cysteines was supported by our finding that the glutathione precursor N-acetyl-cysteine protected tumor cells from the cytotoxic effects of TCA whereas the glutathione-depleting agent buthionine sulfoximine enhanced its activity. Related sesquiterpenes have been shown to increase levels of reactive oxygen species (ROS) and to inhibit nuclear factor kappaB (NF-kappaB) transcriptional activity. To assess whether TCA could have similar activities, we used a ROS-sensitive dye and flow cytometry to show that TCA does indeed increase ROS levels in 3LL cells. When tested in cells carrying NF-kappaB reporter constructs, TCA also exhibited concentration-dependent inhibition of cytokine-induced NF-kappaB transcriptional activity. These findings suggest that TCA modulates multiple stress pathways-the oxidative, heat shock, and inflammatory responses-in tumor cells that promote their survival. Small-molecule natural products such as TCA may serve as useful probes for understanding the relationships between these pathways, potentially providing leads for the design of novel and effective anticancer drugs.}, }
@article {pmid16222871, year = {2005}, author = {Tang, XL and Liu, XJ and Sun, WM and Zhao, J and Zheng, RL}, title = {Oxidative stress in Graves' disease patients and antioxidant protection against lymphocytes DNA damage in vitro.}, journal = {Die Pharmazie}, volume = {60}, number = {9}, pages = {696-700}, pmid = {16222871}, issn = {0031-7144}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Comet Assay ; DNA Damage/*drug effects ; Female ; Graves Disease/*metabolism ; Humans ; Indicators and Reagents ; Lymphocytes/*drug effects ; Male ; Malondialdehyde/blood ; Melatonin/pharmacology ; Oxidative Stress/*drug effects ; Quercetin/pharmacology ; Thyroid Gland/drug effects/physiology ; Thyrotropin/pharmacology ; Thyroxine/blood ; Triiodothyronine/blood ; }, abstract = {DNA damage to peripheral blood lymphocytes of patients with Graves' disease (GD) was studied in vitro before and after treatment with antioxidants, melatonin, quercetin, N-acetylcysteine (NAC) and vitamin C. DNA damage (comet %) was remarkably higher in patients (23.7 +/- 5.5%) than that in healthy persons (9.8 +/- 3.2%, p < 0.01). Plasma malondialdehyde (MDA) content (7.90 +/- 1.77 microM) of patients was significantly higher than that of healthy persons (4.71 +/- 1.19 microM, p < 0.01). Also, the plasma total antioxidant capacity (TAC) (7.53 +/- 1.35 U/ml) in GD patients was significantly lower than that in healthy persons (10.56 +/- 2.21 U/ml, p < 0.01). Negative correlations were observed between plasma TAC and DNA damage in lymphocytes (r = -0.599, p < 0.01), and between plasma TAC and MDA (r = -0.40, p < 0.05) in GD patients. After treatment with 100 microM melatonin, quercetin or NAC for 4 h in vitro, DNA damage in lymphocytes in GD patients declined significantly (from 23.8 +/- 4.4% to 14.4 +/- 4.0%, p < 0.001 for melatonin, from 23.4 +/- 4.7% to 18.1 +/- 4.3%, p < 0.01 for quercetin, from 23.7 +/- 4.0% to 18.7 +/- 5.7%, p < 0.05 for NAC), while there was little change with concentrations of 1-100 microM of vitamin C. However, 1000 microM vitamin C enhanced DNA damage significantly (from 23.8 +/- 2.3% to 30.3 +/- 3.9%, p < 0.05). Our results showed that oxidative stress existed in GD patients and the antioxidants melatonin, quercetin and NAC are beneficial for DNA damage in lymphocytes of GD patients in vitro.}, }
@article {pmid16222869, year = {2005}, author = {Zhao, J and Liu, XJ}, title = {Antioxidative and immunomodulatory role of melatonin, sodium selenite, N-acetyl-L-cysteine and quercetin on human umbilical blood.}, journal = {Die Pharmazie}, volume = {60}, number = {9}, pages = {683-688}, pmid = {16222869}, issn = {0031-7144}, mesh = {Acetylcysteine/*chemistry/*pharmacology ; Antioxidants/*chemistry/*pharmacology ; Cell Proliferation/drug effects ; Comet Assay ; DNA Damage/drug effects ; Fetal Blood/*chemistry/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Immunologic Factors/*chemistry/*pharmacology ; Indicators and Reagents ; K562 Cells ; Melatonin/*chemistry/*pharmacology ; Oxidative Stress/drug effects ; Quercetin/*chemistry/*pharmacology ; Sodium Selenite/*chemistry/*pharmacology ; }, abstract = {We have previously reported on the DNA oxidative damage and oxygen stress in healthy term neonates. The aim of the present study was to investigate the antioxidative and immunomodulatory role of melatonin, sodium selenite, N-acetyl-L-cysteine and quercetin on umbilical blood. The single cell gel electrophoresis (comet) assay was used for DNA oxidative damage. The lymphocytes proliferation and natural killer (NK) activity in umbilical blood were assayed by 3[H]-thymidine uptaken and MTT methods. Results using comet assay showed protection by melatonin, N-acetyl-L-cysteine (NAC) and quercetin, and a protective and damaging effect by selenite sodium. Melatonin, sodium selenite, NAC and quercetin greatly promoted the lymphocytes proliferation to IL-2. NK activity of the umbilical blood was significantly increased by melatonin and sodium selenite, but was not affected by NAC and quercetin. These data suggest that antioxidants are able to protect umbilical blood mononuclear cells against oxygen stress and affect oxygen stress mediated immune function inhibition of umbilical blood. These results will supply new experimental data for using umbilical blood to treat diseases.}, }
@article {pmid16221226, year = {2005}, author = {Briguori, C and Colombo, A and Airoldi, F and Morici, N and Sangiorgi, GM and Violante, A and Focaccio, A and Montorfano, M and Carlino, M and Condorelli, G and Ricciardelli, B}, title = {Nephrotoxicity of low-osmolality versus iso-osmolality contrast agents: impact of N-acetylcysteine.}, journal = {Kidney international}, volume = {68}, number = {5}, pages = {2250-2255}, doi = {10.1111/j.1523-1755.2005.00683.x}, pmid = {16221226}, issn = {0085-2538}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*chemically induced/prevention &amp; control ; Aged ; Contrast Media/*adverse effects ; Female ; Fluid Therapy ; Humans ; Iohexol/adverse effects/*analogs &amp; derivatives ; Kidney/drug effects ; Male ; Middle Aged ; Osmolar Concentration ; Renal Insufficiency, Chronic/*diagnosis ; Retrospective Studies ; Triiodobenzoic Acids/*adverse effects ; }, abstract = {BACKGROUND: Recent data support that iodixanol, an iso-osmolality contrast agent, is less nephrotoxic than low-osmolality contrast agents when hydration is the only prophylactic strategy used. We evaluated the nephrotoxicity of iso- and low-osmolality contrast agents with prophylactic administration of N-acetylcysteine (NAC) along with hydration.<br><br>METHODS: Two hundred and twenty-five patients with chronic renal insufficiency (serum creatinine >1.5 mg/dL or an estimated glomerular filtration rate <60 mL/min/1.73 m(2)), referred to our institution for coronary and/or peripheral procedures, were assigned to receive low-osmolality (iobitridol group; N = 115) or iso-osmolality (iodixanol group; N = 110) contrast dye. In all cases prophylactic administration of 0.45% saline intravenously and NAC (1200 mg orally twice daily) was used.<br><br>RESULTS: Baseline creatinine levels were similar in the 2 groups [iobitridol group = 1.70 (IQR: 1.54-1.98) mg/dL; iodixanol group = 1.73 (IQR: 1.56-2.00) mg/dL, P = 0.33]. The risk score for contrast nephrotoxicity was 5.0 +/- 1.6 in the iobitridol group versus 5.0 +/- 1.8 in the iodixanol group (P = 0.44). Increase of at least 0.5 mg/dL of the creatinine concentration 48 hours after the procedure occurred in 4/115 patients (3.5%) in the iobitridol group and 3/110 patients (2.7%) in the iodixanol group (P = 1.00; OR 0.78; 95% CI 0.17-3.56). Amount of contrast media administration was similar in the 2 groups (iobitridol group = 167 +/- 90 mL; iodixanol group = 164 +/- 82 mL; P = 0.61).<br><br>CONCLUSION: Nephrotoxicity of iso-osmolality and low-osmolality contrast agents was similar when a prophylactic strategy of hydration plus NAC was utilized.}, }
@article {pmid16221220, year = {2005}, author = {Shimizu, MH and Coimbra, TM and de Araujo, M and Menezes, LF and Seguro, AC}, title = {N-acetylcysteine attenuates the progression of chronic renal failure.}, journal = {Kidney international}, volume = {68}, number = {5}, pages = {2208-2217}, doi = {10.1111/j.1523-1755.2005.00677.x}, pmid = {16221220}, issn = {0085-2538}, mesh = {Acetylcysteine/*pharmacology ; Aldosterone/blood ; Animals ; Antioxidants/*pharmacology ; Drug Therapy, Combination ; Glomerular Filtration Rate/drug effects ; Kidney Failure, Chronic/*drug therapy/pathology/physiopathology ; Lipid Peroxidation/drug effects ; Male ; Mineralocorticoid Receptor Antagonists/pharmacology ; Nephrectomy ; Rats ; Rats, Wistar ; Spironolactone/pharmacology ; }, abstract = {BACKGROUND: Lipid peroxidation impairs renal function. Aldosterone contributes to renal injury in the remnant kidney model. This study aimed to determine the effects of the antioxidant N-acetylcysteine (NAC) on renal function and aldosterone levels in chronic renal failure.<br><br>METHODS: Adult male Wistar rats were submitted to 5/6 nephrectomy or laparotomy (sham-operated) and received NAC (600 mg/L in drinking water, initiated on postoperative day 7 or 60), spironolactone (1.5 g/kg of diet initiated on postoperative day 7), the NAC-spironolactone combination or no treatment. Clearance studies were performed on postoperative days 21, 60, and 120.<br><br>RESULTS: Mean daily NAC and spironolactone ingestion was comparable among the treated groups. Mean weight gain was higher in NAC-treated rats than in untreated rats. A significant decrease in urinary thiobarbituric acid reactive substances (TBARS) concentrations, a lipid peroxidation marker, was observed in NAC-treated rats. By day 120, glomerular filtration rate (GFR), which dropped dramatically in untreated rats, was stable (albeit below normal) in NAC-treated rats, which also presented lower proteinuria, glomerulosclerosis index, and blood pressure, together with attenuated cardiac and adrenal hypertrophy. These beneficial effects, observed even when NAC was initiated on postnephrectomy day 60, were accompanied by a significant reduction in plasma aldosterone and urinary potassium sodium [corrected] ratio. The NAC-spironolactone combination lowered blood pressure and improved GFR protection.<br><br>CONCLUSION: The NAC-spironolactone combination improves renal function more than does NAC alone. In the remnant kidney model, early or late NAC administration has a protective effect attributable to decreased plasma aldosterone and lower levels of lipid peroxidation.}, }
@article {pmid16220062, year = {2005}, author = {Ivanov, V and Roomi, MW and Kalinovsky, T and Niedzwiecki, A and Rath, M}, title = {Bioflavonoids effectively inhibit smooth muscle cell-mediated contraction of collagen matrix induced by angiotensin II.}, journal = {Journal of cardiovascular pharmacology}, volume = {46}, number = {5}, pages = {570-576}, doi = {10.1097/01.fjc.0000179432.73007.45}, pmid = {16220062}, issn = {0160-2446}, mesh = {Angiotensin II/*pharmacology ; Aorta ; Cell Culture Techniques ; Cells, Cultured ; Collagen Type I/*chemistry ; Dose-Response Relationship, Drug ; Flavonoids/chemistry/*pharmacology ; Humans ; Matrix Metalloproteinase 2/biosynthesis ; Molecular Structure ; Muscle, Smooth, Vascular/cytology/*drug effects ; Myocytes, Smooth Muscle/*drug effects ; Vasoconstriction/drug effects ; Vasoconstrictor Agents/*pharmacology ; }, abstract = {Plant-derived bioflavonoids have been recognized to support arterial wall structural integrity and interfere with a variety of proatherosclerotic stimuli. In this study we tested the effects of bioflavonoids on the contractile activity of cultured human aortic smooth muscle cells (SMC) embedded in a 3-dimensional type I collagen matrix. Collagen I solution mixed with human aortic SMC in 24-well plates were allowed to form gels. Tested compounds were added to the wells, and the gels were set afloat by gentle tapping. Digital photographs of the gels were taken after 24 hours of incubation at 37 degrees C. The area of contracted gel was measured and expressed as a percentage of the control gel area from 3 or more replicates. Expression of matrix metalloproteinase (MMP-2) in conditioned media was assessed by gel zymography. Different classes of bioflavanoids showed variable efficiency in inhibiting angiotensin II (ATII)-dependent collagen gel contraction by SMCs. An increase in the number of gallate groups per catechin molecule was associated with increased inhibition of angiotensin II-dependent collagen gel contraction by SMC. Antioxidants (N-acetyl cysteine and ascorbic acid) did not inhibit collagen gel contraction. Bioflavonoid inhibition of collagen gel contraction by SMC correlated with inhibition of matrix metalloproteinase-2 expression. Bioflavonoids participate in the regulation of SMC-mediated contraction and have a strong potential in counteracting pathophysiological effects of ATII. Bioflavonoid activity depends on structural characteristics and can be related to extracellular matrix integrity.}, }
@article {pmid16214382, year = {2006}, author = {Naik, AK and Tandan, SK and Dudhgaonkar, SP and Jadhav, SH and Kataria, M and Prakash, VR and Kumar, D}, title = {Role of oxidative stress in pathophysiology of peripheral neuropathy and modulation by N-acetyl-L-cysteine in rats.}, journal = {European journal of pain (London, England)}, volume = {10}, number = {7}, pages = {573-579}, doi = {10.1016/j.ejpain.2005.08.006}, pmid = {16214382}, issn = {1090-3801}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Behavior, Animal/drug effects/physiology ; Biomarkers/metabolism ; Disease Models, Animal ; Free Radical Scavengers/pharmacology/therapeutic use ; Glutathione/metabolism ; Ligation ; Male ; Malondialdehyde/metabolism ; Neuralgia/*drug therapy/metabolism/*physiopathology ; Oxidative Stress/drug effects/*physiology ; Pain Measurement/drug effects ; Peripheral Nervous System Diseases/*drug therapy/metabolism/*physiopathology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Sciatic Neuropathy/drug therapy/metabolism/physiopathology ; Superoxide Dismutase/metabolism ; Treatment Outcome ; }, abstract = {OBJECTIVES: The objectives of this study were to examine the role of reactive oxygen species and oxidative stress in peripheral neuropathy and behavioural pain responses in experimentally induced chronic constriction injury (CCI) of sciatic nerve of rat. Effect of N-acetyl-L-cysteine (NAC) administered intraperitoneally, was also investigated on CCI-induced neuropathic pain in rats.<br><br>METHODS: Neuropathy was induced by CCI of the right sciatic nerve in ketamine anaesthetized rats. Effect of intraperitoneally administered NAC in rats was also investigated using nociceptive behavioural tests. Malondialdehyde, an index of oxidative stress and antioxidant enzymes was also estimated in ligated sciatic nerve.<br><br>RESULTS: Behavioural tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after the CCI. The malondialdehyde levels of ligated sciatic nerves were significantly increased compared to non-ligated sciatic nerves (sham operated). The antioxidant enzyme reduced, glutathione was inhibited, while superoxide dismutase increased. However, catalase remained unaffected in the injured sciatic nerves. Intraperitoneal administration of NAC resulted in significant reduction of hyperalgesia in CCI-induced neuropathic rats.<br><br>CONCLUSIONS: This study identifies antioxidants superoxide dismutase and reduced glutathione, and oxidative stress as important determinants of neuropathological and behavioural consequences of CCI-induced neuropathy, and NAC may be a potential candidate for alleviation of neuropathic pain.}, }
@article {pmid16214328, year = {2006}, author = {Lim, Y and Levy, MA and Bray, TM}, title = {Dietary supplementation of N-acetylcysteine enhances early inflammatory responses during cutaneous wound healing in protein malnourished mice.}, journal = {The Journal of nutritional biochemistry}, volume = {17}, number = {5}, pages = {328-336}, doi = {10.1016/j.jnutbio.2005.08.004}, pmid = {16214328}, issn = {0955-2863}, support = {DK55847/DK/NIDDK NIH HHS/United States ; NS38315/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/*administration &amp; dosage ; Diet, Protein-Restricted ; Dietary Supplements ; Female ; I-kappa B Proteins/genetics ; Inflammation/*physiopathology ; Interleukin-1/genetics ; Mice ; Mice, Knockout ; NF-KappaB Inhibitor alpha ; Protein Deficiency/*complications ; RNA, Messenger/analysis ; Reactive Oxygen Species/metabolism ; Skin/*injuries ; Superoxide Dismutase/deficiency ; Tumor Necrosis Factor-alpha/genetics ; Wound Healing/*drug effects/physiology ; }, abstract = {Prolonged wound healing is a complication that contributes to the morbidity and mortality of protein malnutrition (PM). The molecular mechanisms that underlie impaired wound healing in PM may begin in the early inflammatory stage of the process. We hypothesized that the impaired wound healing observed in PM occurs as a consequence of excessive reactive oxygen species (ROS) production that impairs the wound healing process by depressing nuclear factor kappa B (NFkappaB) activation and the subsequent synthesis and release of proinflammatory cytokines that are critical mediators of the inflammatory response. In this study, we showed that the time to wound closure was significantly prolonged in PM mice. During the early wound healing in PM, inhibitory kappa B alpha (IkappaBalpha), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) expression and neutrophil infiltration were significantly decreased in PM mice. The role of excess ROS in PM was demonstrated by using transgenic mice with overexpression of copper zinc superoxide dismutase and with dietary supplementation of N-acetylcysteine (NAC). Both interventions improved the extent of wound closure in PM mice. Moreover, NAC supplementation in PM mice restored the expression of IkappaBalpha, IL-1beta and TNF-alpha and infiltration of neutrophils to levels observed in control animals. These findings support the notion that wound healing defects in PM may result from dysregulation of ROS-mediated and NFkappaB-regulated signaling pathways.}, }
@article {pmid16211988, year = {2004}, author = {Balderramo, DC and Verdu, MB and Ramacciotti, CF and Cremona, LS and Lemos, PA and Orías, M and Eduardo, M}, title = {Renoprotective effect of high periprocedural doses of oral N-acetylcysteine in patients scheduled to undergo a same-day angiography.}, journal = {Revista de la Facultad de Ciencias Medicas (Cordoba, Argentina)}, volume = {61}, number = {2}, pages = {13-19}, pmid = {16211988}, issn = {0014-6722}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Aged ; Angiography ; Antioxidants/administration &amp; dosage/*therapeutic use ; Contrast Media/*adverse effects ; Double-Blind Method ; Female ; Humans ; Kidney Failure, Chronic/chemically induced/*prevention &amp; control ; Male ; Prospective Studies ; }, abstract = {BACKGROUND: Few studies that have assessed the effect of abbreviated oral N-acetylcysteine (NAC) regimens in radiocontrast-induced nephropathy (RCIN) yield mixed results.<br><br>OBJECTIVE: To evaluate the renoprotective effect of high periprocedural oral doses (HPOD) of NAC in patients with chronic renal impairment undergoing a same-day angiography.<br><br>METHODS: Sixty one patients with renal impaired function scheduled to undergo a same-day angiography were randomly assigned to NAC 1200 mg orally 3 hours before and 3 after the procedure, or a placebo. All patients received 0.9% saline intravenous. RCIN was defined as an increase in SCC > 0.5 mg/dl 48 hours after the procedure.<br><br>RESULTS: The mean baseline SCC for all patients was 1.44 +/- 0.42 mg/dl. A significant difference in SCC change at 48 hours after the angiography was found (-0.07 mg/dl NAC, 0.09 mg/dl placebo, P = 0.04). RCIN occurred in 1 (3%) patient of NAC group and in 2 (7.1%) patients of placebo group (P = 0.59). Adverse effects were similar in both groups.<br><br>CONCLUSIONS: In patients with mild renal impairment patients undergoing angiographic procedures, HPOD of NAC were more effective than placebo in preventing SCC change 48 hours. A non significant benefit in RCIN incidence was found.}, }
@article {pmid16209984, year = {2005}, author = {Campbell, CL and Berger, PB and Nuttall, GA and Orford, JL and Santrach, PJ and Oliver, WC and Ereth, MH and Thompson, CM and Murphy, MK and McGlassen, DL and Schrader, LM and Steinhubl, SR}, title = {Can N-acetylcysteine reverse the antiplatelet effects of clopidogrel? An in vivo and vitro study.}, journal = {American heart journal}, volume = {150}, number = {4}, pages = {796-799}, doi = {10.1016/j.ahj.2005.01.015}, pmid = {16209984}, issn = {1097-6744}, mesh = {Acetylcysteine/*pharmacology ; Clopidogrel ; Drug Interactions ; Humans ; Platelet Aggregation/*drug effects ; Platelet Aggregation Inhibitors/*pharmacology ; Prospective Studies ; Ticlopidine/*analogs &amp; derivatives/antagonists &amp; inhibitors ; }, abstract = {BACKGROUND: The active metabolite of clopidogrel binds the P2Y12 ADP receptor on the platelet surface via a disulfide bond. N-Acetylcysteine (NAC) is able to reduce disulfide bonds. We postulated that NAC might reverse clopidogrel's effect on platelets.<br><br>METHODS: Two groups of patients were investigated. Group 1 included 11 patients with stable coronary disease who, after discontinuation of aspirin, received 14 days of clopidogrel, 75 mg/day. Bleeding time and whole-blood platelet aggregometry (with 5 micromol/L ADP) were compared before and after the 14 days. Patients were then treated with 6 g of NAC orally, followed by repeat measurement of bleeding time and aggregometry. In group 2, 14 patients were treated with clopidogrel (300 mg) and aspirin before a percutaneous coronary intervention. Blood was drawn 22 +/- 3 hours later and divided into 2 samples. One was sent immediately for platelet-rich plasma aggregometry (using 5 and 2 micromol/L ADP, collagen, and arachidonic acid as agonists), thromboelastography, and aggregometry using the Plateletworks assay (Helena Laboratories, Beaumont, Tex). The other sample was treated with NAC (500 mg/L), after which these same platelet function tests were performed.<br><br>RESULTS: In group 1, NAC therapy did not significantly change the bleeding time or results of aggregometry. In group 2, neither aggregometry nor the Plateletworks assay suggested reversal of inhibition by NAC.<br><br>CONCLUSIONS: These studies reveal that a large dose of NAC does not reduce inhibition of platelet aggregation by clopidogrel in vitro or in vivo.}, }
@article {pmid16204787, year = {2005}, author = {van Overveld, FJ and Demkow, U and Górecka, D and de Backer, WA and Zielinski, J}, title = {New developments in the treatment of COPD: comparing the effects of inhaled corticosteroids and N-acetylcysteine.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {56 Suppl 4}, number = {}, pages = {135-142}, pmid = {16204787}, issn = {1899-1505}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Adrenal Cortex Hormones/*administration &amp; dosage ; Adult ; Androstadienes/*administration &amp; dosage ; Anti-Inflammatory Agents/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Double-Blind Method ; Eosinophil Cationic Protein/blood/metabolism ; Expectorants/*administration &amp; dosage ; Female ; Fluticasone ; Forced Expiratory Volume/drug effects ; Glutathione Peroxidase/blood ; Humans ; Intercellular Adhesion Molecule-1/blood/metabolism ; Interleukin-8/blood/metabolism ; Male ; Oxidative Stress/drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy/metabolism/physiopathology ; Respiratory Function Tests ; Sputum/metabolism ; Treatment Outcome ; }, abstract = {Inhaled corticosteroids (ICS) are widely used for the treatment of COPD despite of controversial statements concerning their efficacy. The use of N-acetylcysteine (NAC), a mucolytic drug with antioxidant properties, is less clear, but it may counteract the oxidant-antioxidant imbalance in COPD. The aim of this study was to evaluate whether treatment of COPD patients with ICS or NAC is able to improve inflammatory indices and to enhance lung function. ICS treatment enhanced protective markers for oxidative stress such as glutathione peroxidase (GPx) (51.2 +/-5.8 vs. 62.2 +/-8.6 U/g Hb, P<0.02) and trolox-equivalent antioxidant capacity (TEAC) (1.44 +/-0.05 vs. 1.52 +/-0.06 mM, P<0.05). NAC decreased sputum eosinophil cationic protein (318 +/-73 vs. 163 +/-30 ng/ml, P<0.01) and sputum IL-8 (429 +/-80 vs. 347 +/-70 ng/ml, P<0.05). The increased antioxidant capacity prevented an up-regulation of adhesion molecules, since the levels of intracellular adhesion molecule 1 (ICAM-1) correlated negatively with GPx (P<0.0001) and TEAC (P<0.0001). On the other hand, expression of adhesion molecules was promoted by inflammation, reflected by a positive correlation between the levels of IL-8 and ICAM-1 (P<0.0001). The effects of treatment on lung function were only reflected in the FEV(1) values. The absolute value of FEV(1), both before and after salbutamol inhalation, increased from 1690 +/-98 to 1764 +/-110 ml, and 1818 +/-106 to 1906 +/-116 ml, respectively, after ICS (P<0.05) . Ten weeks after treatment, FEV(1) values dropped to 1716 +/-120 ml post-salbutamol (P<0.05). When followed by treatment with NAC, these values decreased even further to 1666 +/-84 ml. These results suggest that ICS improved lung function in COPD patients with moderate airflow obstruction, beside a minor improvement in the oxidant-antioxidant imbalance leading to a lesser expression of ICAM-1. Treatment with NAC decreased some inflammatory parameters and had indirectly an inhibitory effect on the expression of adhesion molecules.}, }
@article {pmid16204071, year = {2005}, author = {Ostenfeld, MS and Fehrenbacher, N and Høyer-Hansen, M and Thomsen, C and Farkas, T and Jäättelä, M}, title = {Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress.}, journal = {Cancer research}, volume = {65}, number = {19}, pages = {8975-8983}, doi = {10.1158/0008-5472.CAN-05-0269}, pmid = {16204071}, issn = {0008-5472}, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Breast Neoplasms/drug therapy/metabolism/pathology ; Caspases/metabolism ; Cathepsins/metabolism ; Cell Line, Transformed ; Cell Line, Tumor ; Cytochromes c/metabolism ; Female ; Fibrosarcoma/drug therapy/metabolism/pathology ; Humans ; Indoles/*pharmacology ; Ligands ; Lysosomes/*drug effects/metabolism ; Mice ; Mice, Inbred BALB C ; NIH 3T3 Cells ; Oxidative Stress/drug effects ; Receptors, sigma/*metabolism ; Spiro Compounds/*pharmacology ; Tumor Suppressor Protein p53/metabolism ; Xenograft Model Antitumor Assays ; }, abstract = {Acquired resistance to classic caspase-mediated apoptosis is a common problem for the treatment of human cancer. Here, we show that siramesine, a novel sigma-2 receptor ligand, effectively induces caspase-independent programmed cell death in immortalized and transformed cells of various origins. Siramesine-treated tumor cells displayed increased levels of reactive oxygen species, lysosomal membrane permeabilization, chromatin condensation, and shrinkage and detachment of cells. Lipid antioxidants (alpha-tocopherol and gamma-tocopherol), but not other tested antioxidants (butylated hydroxyanisol or N-acetyl cysteine), effectively inhibited siramesine-induced morphologic changes and cell death. Cathepsin B inhibitors (CA-074-Me and R-2525) conferred similar, but less pronounced protection, whereas ectopic expression of antiapoptotic protein Bcl-2, lack of wild-type p53 as well as pharmacologic inhibitors of caspases (zVAD-fmk, DEVD-CHO, and LEHD-CHO), calpains (PD150606), and serine proteases (N-tosyl-L-phenylalanine chloromethyl ketone and pefabloc) failed to protect cells against siramesine-induced death. Importantly, transformation of murine embryonic fibroblasts with activated c-src or v-Ha-ras oncogenes greatly sensitized them to siramesine-induced cytotoxicity. Furthermore, p.o. administration of well-tolerated doses of siramesine had a significant antitumorigenic effect in orthotopic breast cancer and s.c. fibrosarcoma models in mice. These results present siramesine as a promising new drug for the treatment of tumors resistant to traditional therapies.}, }
@article {pmid16201965, year = {2006}, author = {Sultan, I and Senkal, CE and Ponnusamy, S and Bielawski, J and Szulc, Z and Bielawska, A and Hannun, YA and Ogretmen, B}, title = {Regulation of the sphingosine-recycling pathway for ceramide generation by oxidative stress, and its role in controlling c-Myc/Max function.}, journal = {The Biochemical journal}, volume = {393}, number = {Pt 2}, pages = {513-521}, pmid = {16201965}, issn = {1470-8728}, support = {R01 CA088932/CA/NCI NIH HHS/United States ; CA-88932/CA/NCI NIH HHS/United States ; }, mesh = {Acylation ; Basic-Leucine Zipper Transcription Factors/genetics/*metabolism ; Cell Line, Tumor ; Ceramides/*biosynthesis/chemistry/metabolism ; Gene Expression Regulation ; Golgi Apparatus/metabolism ; Humans ; *Oxidative Stress ; Protein Binding ; Proto-Oncogene Proteins c-myc/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Sphingosine/*metabolism ; Substrate Specificity ; Thioredoxin Reductase 1 ; Thioredoxin-Disulfide Reductase/metabolism ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism/pharmacology ; }, abstract = {In the present study, the regulation of the sphingosine-recycling pathway in A549 human lung adenocarcinoma cells by oxidative stress was investigated. The generation of endogenous long-chain ceramide in response to exogenous C6-cer (C6-ceramide), which is FB1 (fumonisin B1)-sensitive, was employed to probe the sphingosine-recycling pathway. The data showed that ceramide formation via this pathway was significantly blocked by GSH and NAC (N-acetylcysteine) whereas it was enhanced by H2O2, as detected by both palmitate labelling and HPLC/MS. Similar data were also obtained using a novel approach that measures the incorporation of 17Sph (sphingosine containing 17 carbons) of 17C6-cer (C6-cer containing a 17Sph backbone) into long-chain 17C16-cer in cells by HPLC/MS, which was significantly decreased and increased in response to GSH and H2O2 respectively. TNF (tumour necrosis factor)-a, which decreases the levels of endogenous GSH, increased the generation of C16-cer in response to C6-cer, and this was blocked by exogenous GSH or NAC, or by the overexpression of TPx I (thioredoxin peroxidase I), an enzyme that reduces the generation of intracellular ROS (reactive oxygen species). Additional data showed that ROS regulated both the deacylation and reacylation steps of C6-cer. At a functional level, C6-cer inhibited the DNA-binding function of the c-Myc/Max oncogene. Inhibition of the generation of longchain ceramide in response to C6-cer by FB1 or NAC significantly blocked the modulation of the c-Myc/Max function. These data demonstrate that the sphingosine-recycling pathway for the generation of endogenous long-chain ceramide in response to exogenous C6-cer is regulated by ROS, and plays an important biological role in controlling c-Myc function.}, }
@article {pmid16201893, year = {2005}, author = {Kalaiselvi, P and Pragasam, V and Chinnikrishnan, S and Veena, CK and Sundarapandiyan, R and Varalakshmi, P}, title = {Counteracting adriamycin-induced oxidative stress by administration of N-acetyl cysteine and vitamin E.}, journal = {Clinical chemistry and laboratory medicine}, volume = {43}, number = {8}, pages = {834-840}, doi = {10.1515/CCLM.2005.140}, pmid = {16201893}, issn = {1434-6621}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antibiotics, Antineoplastic/administration &amp; dosage/*toxicity ; Antioxidants/*administration &amp; dosage ; Doxorubicin/administration &amp; dosage/*toxicity ; Drug Interactions ; Kidney/drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Vitamin E/*administration &amp; dosage ; }, abstract = {Adriamycin (ADR), a cytotoxic antineoplastic drug, is used in the treatment of various solid tumors. However, its efficacy continues to be challenged by significant toxicities including nephrotoxicity. In the present study, the effects of N-acetyl cysteine (NAC) and vitamin E, known antioxidants, were investigated on ADR-induced peroxidative damage in rat kidney. Adult male albino rats of Wistar strain were administered ADR as a single dose (10 mg/kg body weight, i.v.). Histopathological studies indicated that ADR-treated kidney sections show focal tubular necrosis and casts. ADR-injected rats showed a significant decline in the activities/levels of enzymic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) and non-enzymic antioxidants (thiols, vitamin C and vitamin E) with high malondialdehyde levels. The extent of nephrotoxicity was evident from the increased activities of urinary marker enzymes (alkaline phosphatase, lactate dehydrogenase and gamma-glutamyltransferase). Treatment with NAC and vitamin E (50 mg/kg b.w., i.p.) 1 day prior to ADR administration maintained near normal activities of the enzymes, significantly reduced lipid peroxidation and prevented the necrosis caused by ADR, thereby proving to be an effective thiol replenishing agent and antioxidant.}, }
@article {pmid16195391, year = {2006}, author = {Barreiro, E and Gáldiz, JB and Mariñán, M and Alvarez, FJ and Hussain, SN and Gea, J}, title = {Respiratory loading intensity and diaphragm oxidative stress: N-acetyl-cysteine effects.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {100}, number = {2}, pages = {555-563}, doi = {10.1152/japplphysiol.00780.2005}, pmid = {16195391}, issn = {8750-7587}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Diaphragm/*drug effects/metabolism ; Dogs ; Male ; Muscle Fatigue ; Oxidative Stress/*drug effects ; Protein Carbonylation ; Proteins/metabolism ; Respiration ; Tyrosine/analogs &amp; derivatives/metabolism ; Work of Breathing/*physiology ; }, abstract = {We hypothesized that resistive breathing of moderate to high intensity might increase diaphragm oxidative stress, which could be partially attenuated by antioxidants. Our objective was to assess the levels of oxidative stress in the dog diaphragm after respiratory muscle training of a wide range of intensities and whether N-acetyl-cysteine (NAC) might act as an antioxidant. Twelve Beagle dogs were anesthetized with 1% propophol, tracheostomized, and subjected to continuous inspiratory resistive breathing (IRB) (2 h/day for 2 wk). They were further divided into two groups (n = 6): NAC group (oral NAC administration/24 h for 14 days) and control group (placebo). Diaphragm biopsies were obtained before (baseline biopsy) and after (contralateral hemidiaphragm) IRB and NAC vs. placebo treatment. Oxidative stress was evaluated in all diaphragm biopsies through determination of 3-nitrotyrosine immunoreactivity, protein carbonylation, hydroxynoneal protein adducts, Mn-SOD, and catalase, using immunoblotting and immunohistochemistry. Both protein tyrosine nitration and protein carbonylation were directly related to the amount of the respiratory loads, and NAC treatment abrogated this proportional rise in these two indexes of oxidative stress in response to increasing inspiratory loads. A post hoc analysis revealed that only the diaphragms of dogs subjected to high-intensity loads showed a significant increase in both protein tyrosine nitration and carbonylation, which were also significantly reduced by NAC treatment. These results suggest that high-intensity respiratory loading-induced oxidative stress may be neutralized by NAC treatment during IRB in the canine diaphragm.}, }
@article {pmid16192891, year = {2005}, author = {Sawai, H and Funahashi, H and Okada, Y and Matsuo, Y and Sakamoto, M and Yamamoto, M and Takeyama, H and Manabe, T}, title = {Interleukin-1alpha enhances IL-8 secretion through p38 mitogen-activated protein kinase and reactive oxygen species signaling in human pancreatic cancer cells.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {11}, number = {10}, pages = {BR343-50}, pmid = {16192891}, issn = {1234-1010}, mesh = {Blotting, Western ; Culture Media, Conditioned ; Electrophoretic Mobility Shift Assay ; Enzyme-Linked Immunosorbent Assay ; Humans ; Interleukin-1/*physiology ; Interleukin-8/*metabolism ; NF-kappa B/metabolism ; Pancreatic Neoplasms/enzymology/*metabolism/pathology ; *Reactive Oxygen Species ; Signal Transduction/*physiology ; Transcription Factor AP-1/metabolism ; Tumor Cells, Cultured ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {BACKGROUND: Interleukin (IL)-1alpha plays an important role in modulating the expression of various growth factors and angiogenic factors in tumor cells. In here, we investigated effect of IL-1alpha on IL-8 secretion in human pancreatic cancer cells and underlying signal transduction pathways.<br><br>MATERIAL/METHODS: IL-8 expression and secretion by pancreatic cancer cells was measured by Western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Activation of extracellular signal regulated kinases-1/2 (ERK-1/2), p38 mitogen-activated protein kinase (MAPK), c-jun aminoterminal kinase, Akt, and nuclear factor-kappaB (NF-kappaB) was determined by Western blot. Involvement of reactive oxygen species (ROS) were examined by measuring the H2O2. Activity of activator factor-1 (AP-1) and NF-kappaB was examined by electrophoretic mobility sift assay (EMSA). Proliferation of human umbilical vein endothelial cells (HUVECs) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction method and cell count.<br><br>RESULTS: IL-1alpha modulated IL-8 secretion and induced activation of ERK-1/2 and p38 MAPK. Specific inhibitors for MEK-1 and p38 MAPK suppressed IL-8 secretion. IL-1alpha also induced production of ROS. Exogenous H2O2 enhanced IL-8 secretion and N-acetyl cysteine (NAC) prevented IL-1alpha-induced ROS production and IL-8 secretion. EMSA confirmed that IL-1alpha increased DNA-binding activity of AP-1 and NF-kappaB. Inhibitors and ROS scavenger studies revealed that upstream signalings for AP-1 and NF-kappaB were MAPK and ROS, respectively. Conditioned media from pancreatic cancer cells pretreated with IL-1alpha remarkably stimulated in vitro HUVECs growth.<br><br>CONCLUSIONS: These results suggest that MAPK/AP-1 and ROS/NF-kappaB signaling pathways are involved in IL-1alpha-induced IL-8 secretion and that these paracrine signaling pathways enhance endothelial cell proliferation.}, }
@article {pmid16189296, year = {2006}, author = {Rosato, RR and Maggio, SC and Almenara, JA and Payne, SG and Atadja, P and Spiegel, S and Dent, P and Grant, S}, title = {The histone deacetylase inhibitor LAQ824 induces human leukemia cell death through a process involving XIAP down-regulation, oxidative injury, and the acid sphingomyelinase-dependent generation of ceramide.}, journal = {Molecular pharmacology}, volume = {69}, number = {1}, pages = {216-225}, doi = {10.1124/mol.105.017145}, pmid = {16189296}, issn = {0026-895X}, support = {CA100866/CA/NCI NIH HHS/United States ; CA61774/CA/NCI NIH HHS/United States ; CA63753/CA/NCI NIH HHS/United States ; CA93738/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis/*drug effects ; Ceramides/*biosynthesis ; *Down-Regulation ; Enzyme Inhibitors/*pharmacology ; *Histone Deacetylase Inhibitors ; Humans ; Hydroxamic Acids/*pharmacology ; Jurkat Cells ; Leukemia/*pathology ; *Oxidative Stress ; Reverse Transcriptase Polymerase Chain Reaction ; Sphingomyelin Phosphodiesterase/*metabolism ; U937 Cells ; X-Linked Inhibitor of Apoptosis Protein/*physiology ; }, abstract = {Determinants of differentiation and apoptosis induction by the novel histone deacetylase inhibitor (HDACI) LAQ824 were examined in human leukemia cells (U937 and Jurkat). Exposure of U937 cells to a low concentration of LAQ824 (30 nM) resulted in a delayed (2 h) increase in reactive oxygen species (ROS), induction of p21(WAF1/CIP1), pRb dephosphorylation, growth arrest of cells in G(0)/G(1) phase, and differentiation. On the other hand, exposure of cells to a higher concentration of LAQ824 (75 nM) resulted in the early (30 min) generation of ROS, arrest of cells in G(2)/M phase, down-regulation of XIAP (at the transcriptional level) and Mcl-1 (through a caspase-mediated process), the acid sphingomyelinase-dependent generation of ceramide, and profound mitochondrial injury, caspase activation, and apoptosis. LAQ824-induced lethality in U937 cells did not involve the extrinsic apoptotic pathway, nor was it associated with death receptor up-regulation; instead, it was markedly inhibited by ectopic expression of Bcl-2, Bcl-x(L), XIAP, and Mcl-1. The free radical scavenger N-acetyl cysteine blocked LAQ824-mediated ROS generation, mitochondrial injury, Mcl-1 down-regulation, ceramide generation, and apoptosis, suggesting a primary role for oxidative injury in LAQ824 lethality. Together, these findings indicate that LAQ824-induced lethality represents a multifactorial process in which LAQ824-mediated ROS generation is necessary but not sufficient to induce apoptosis, and that the degree of XIAP and Mcl-1 down-regulation and ceramide generation determines whether this agent engages a maturation rather than an apoptotic program.}, }
@article {pmid16187297, year = {2006}, author = {Kato, N and Nakayama, Y and Nakajima, Y and Samoto, H and Saito, R and Yamanouchi, F and Masunaga, H and Shimizu, E and Ogata, Y}, title = {Regulation of bone sialoprotein (BSP) gene transcription by lipopolysaccharide.}, journal = {Journal of cellular biochemistry}, volume = {97}, number = {2}, pages = {368-379}, doi = {10.1002/jcb.20628}, pmid = {16187297}, issn = {0730-2312}, mesh = {Animals ; Antioxidants/pharmacology ; Base Sequence ; Cell Line ; Electrophoretic Mobility Shift Assay ; Integrin-Binding Sialoprotein ; Lipopolysaccharides/*pharmacology ; Molecular Sequence Data ; Osteogenesis/*drug effects ; Promoter Regions, Genetic ; RNA, Messenger/metabolism ; Rats ; Regulatory Elements, Transcriptional ; Sialoglycoproteins/*genetics/*metabolism ; Suppression, Genetic/drug effects ; *Transcription, Genetic ; Transfection ; }, abstract = {Lipopolysaccharide (LPS) is a major mediator of inflammatory responses in periodontal disease that inhibits bone formation and stimulates bone resorption. To determine the molecular mechanisms involved in the suppression of bone formation, we have analyzed the effects of LPS on BSP gene expression. Bone sialoprotein (BSP) is a mineralized tissue-specific protein that appears to function in the initial mineralization of bone. Treatment of osteoblast-like ROS 17/2.8 cells with LPS (1 microg/ml) for 12 h caused a marked reduction in BSP mRNA levels. The addition of antioxidant N-acetylcysteine (NAC; 20 mM) 30 min prior to stimulation with LPS attenuated the inhibition of BSP mRNA levels. Transient transfection analyses, using chimeric constructs of the rat BSP gene promoter linked to a luciferase reporter gene, revealed that LPS (1 microg/ml) suppressed expression of luciferase construct, encompassing BSP promoter nucleotides -108 to +60, transfected into ROS17/2.8 cells. The effects of LPS were inhibited by protein kinase A (PKA) inhibitor, H89 and the tyrosine kinase inhibitor, herbimycin A (HA). Introduction of 2 bp mutations in the inverted CCAAT box (ATTGG; nts -50 and -46), a cAMP response element (CRE; nts -75 to -68), a FGF response element (FRE; nts -92 to -85), and a pituitary specific transcription factor binding element (Pit-1; nts -111 to -105) showed that the LPS effects were mediated by the CRE and FRE. Whereas the FRE and 3'-FRE DNA-protein complexes were decreased by LPS, CRE DNA-protein complex did not change after LPS treatment. These studies, therefore, show that LPS suppresses BSP gene transcription through PKA and tyrosine kinase-dependent pathways and that the LPS effects are mediated through CRE and FRE elements in the proximal BSP gene promoter.}, }
@article {pmid16187210, year = {2005}, author = {Nicoletti, VG and Marino, VM and Cuppari, C and Licciardello, D and Patti, D and Purrello, VS and Stella, AM}, title = {Effect of antioxidant diets on mitochondrial gene expression in rat brain during aging.}, journal = {Neurochemical research}, volume = {30}, number = {6-7}, pages = {737-752}, pmid = {16187210}, issn = {0364-3190}, mesh = {Acetylcysteine/*pharmacology ; Aging/*metabolism ; Animals ; Antioxidants/*pharmacology ; Base Sequence ; Blotting, Western ; Brain/*drug effects/metabolism ; DNA Primers ; *Diet ; Electrophoresis, Polyacrylamide Gel ; Energy Intake ; *Gene Expression ; Male ; Mitochondria/*drug effects/genetics ; RNA, Messenger/genetics ; Rats ; Rats, Inbred WKY ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {Age-related increase of reactive oxygen species (ROS) is particularly detrimental in postmitotic tissues. Calorie restriction (CR) has been shown to exert beneficial effects, consistent with reduced ROS generation by mitochondria. Many antioxidant compounds also mimic such effects. N-acetyl cysteine (NAC) provides thiol groups to glutathione and to mitochondrial respiratory chain proteins; thus, it may counteract both ROS generation and effects. In the present study we investigated, in different rat brain areas during aging (6, 12, and 28 months), the effect of 1-year treatment with CR and dietary supplementation with NAC on the expression of subunit 39 kDa and ND-1 (mitochondrial respiratory complex I), subunit IV (complex IV), subunit alpha of F0F1-ATP synthase (complex V) and of adenine nucleotide translocator, isoform 1 (ANT-1). The observed age-related changes of expression were prevented by the dietary treatments. The present study provides further evidence for the critical role of mitochondria in the aging process.}, }
@article {pmid16181096, year = {2005}, author = {Okouchi, M and Okayama, N and Aw, TY}, title = {Differential susceptibility of naive and differentiated PC-12 cells to methylglyoxal-induced apoptosis: influence of cellular redox.}, journal = {Current neurovascular research}, volume = {2}, number = {1}, pages = {13-22}, doi = {10.2174/1567202052773535}, pmid = {16181096}, issn = {1567-2026}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-12/DK/NIDDK NIH HHS/United States ; DK44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis/physiology ; Caspase 3 ; Caspase 9 ; Caspases/metabolism ; *Cell Differentiation ; Enzyme Activation/physiology ; Glutathione/biosynthesis ; Ion Channels/physiology ; Kinetics ; Mitochondria/physiology ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Oxidation-Reduction/drug effects ; PC12 Cells/*cytology/drug effects/metabolism/*physiology ; Poly(ADP-ribose) Polymerases/chemistry ; Pyruvaldehyde/*pharmacology ; Rats ; }, abstract = {Neuropathologies have been associated with neuronal de-differentiation and oxidative susceptibility. To address whether cellular states determines their oxidative vulnerability, we have challenged naive (undifferentiated) and nerve growth factor-induced differentiated pheochromocytoma (PC12) with methylglyoxal (MG), a model of carbonyl stress. MG dose-dependently induced greater apoptosis (24 h) in naive (nPC12) than differentiated (dPC12) cells. This enhanced nPC12 susceptibility was correlated with a high basal oxidized cellular glutathione-to-glutathione disulfide (GSH/GSSG) redox and an MG-induced GSH-to-Disulfide (GSSG plus protein-bound SSG) imbalance. The loss of redox balance occurred at 30 min post-MG exposure, and was prevented by N-acetylcysteine (NAC) that was unrelated to de novo GSH synthesis. NAC was ineffective when added at 1h post-MG, consistent with an early window of redox signaling. This redox shift was kinetically linked to decreased BcL-2, increased Bax, and release of mitochondrial cytochrome c which preceded caspase-9 and -3 activation and poly ADP-ribose polymerase (PARP) cleavage (1-2 h), consistent with mitochondrial apoptotic signaling. The blockade of apoptosis by cyclosporine A supported an involvement of the mitochondrial permeability transition pore. The enhanced vulnerability of nPC12 cells to MG and its relationship to cellular redox shifts will have important implications for understanding differential oxidative vulnerability in various cell types and their transition states.}, }
@article {pmid16179752, year = {2005}, author = {Rudolf, E and Rudolf, K and Cervinka, M}, title = {Zinc induced apoptosis in HEP-2 cancer cells: the role of oxidative stress and mitochondria.}, journal = {BioFactors (Oxford, England)}, volume = {23}, number = {2}, pages = {107-120}, doi = {10.1002/biof.5520230206}, pmid = {16179752}, issn = {0951-6433}, mesh = {Apoptosis/*drug effects ; Apoptosis Inducing Factor ; Cell Line, Tumor ; Cytochromes c/metabolism ; Flavoproteins/metabolism ; Humans ; Intracellular Membranes/drug effects/physiology ; Laryngeal Neoplasms ; Membrane Potentials/drug effects ; Membrane Proteins/metabolism ; Mitochondria/drug effects/*physiology ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Permeability/drug effects ; Tumor Suppressor Protein p53/biosynthesis ; Zinc/metabolism ; Zinc Sulfate/*pharmacology ; }, abstract = {Induction of apoptosis by zinc sulfate was investigated during 96 h exposure on the cancer Hep-2 cell line. During 48 h of exposure, zinc translocated into mitochondria and stimulated production of reactive oxygen species (ROS), affected cellular GSH management and induced moderate activation of p53 and dissipation of mitochondrial membrane potential. In Zn-exposed cells, mitochondria released cytochrome c and AIF, whose translocation to the cytoplasm or the nucleus coincided with the activation of apoptosis. The use of various pharmacological inhibitors inhibiting particular apoptotic targets (antioxidants such as N-acetyl-cysteine and coenzyme Q, the caspase inhibitors z-DEVD-fmk and z-VAD-fmk, cyclosporin A and bonkgrekic acid) proved that Zn acts both directly and indirectly on mitochondria and observed apoptosis is executed by caspase-dependent and caspase-independent pathways.}, }
@article {pmid16178122, year = {2005}, author = {Kitamura, Y and Nishikawa, A and Nakamura, H and Furukawa, F and Imazawa, T and Umemura, T and Uchida, K and Hirose, M}, title = {Effects of N-acetylcysteine, quercetin, and phytic acid on spontaneous hepatic and renal lesions in LEC rats.}, journal = {Toxicologic pathology}, volume = {33}, number = {5}, pages = {584-592}, doi = {10.1080/01926230500246675}, pmid = {16178122}, issn = {0192-6233}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Kidney/*drug effects/pathology ; Liver/*drug effects/pathology ; Male ; Molecular Structure ; Oxidative Stress/drug effects ; Phytic Acid/chemistry/*pharmacology ; Quercetin/chemistry/*pharmacology ; Rats ; Rats, Inbred LEC ; Time Factors ; }, abstract = {The effects of anti-oxidants were examined in Long-Evans Cinnamon (LEC) rats, which develop acute hepatic injury, and subsequent hepatic and renal tumors due to accumulation of excess Cu. The rats, at the age of 15 weeks, were supplied a diet containing either 1% of N-acetylcysteine (NAC), quercetin (QC), or phytic acid (PA), or basal diet alone. At weeks 2 and 6 posttreatment, animals were sacrificed for collection of blood and tissue samples. In the NAC-treated group, the development of hepatic and renal lesions was dramatically reduced. In addition, accumulation of Cu and Fe in the liver was suppressed. Acrolein-modified protein, a new marker for lipid peroxidation, was not detected in the liver or kidney of NAC treated rats, even though deposition was evident in control. Neither QC nor PA affected the development of spontaneous hepatic lesions. These results indicate that oxidative stress was reduced by NAC in the liver and kidney, and suggest that Cu and Fe may be involved in the generation of oxidative stress in the liver. In addition, it was suggested that the different effects of the anti-oxidants on lesion development in LEC rats might be related to different mechanisms of action with regard to oxidative stress.}, }
@article {pmid16177005, year = {2005}, author = {de Araujo, M and Andrade, L and Coimbra, TM and Rodrigues, AC and Seguro, AC}, title = {Magnesium supplementation combined with N-acetylcysteine protects against postischemic acute renal failure.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {16}, number = {11}, pages = {3339-3349}, doi = {10.1681/ASN.2004100832}, pmid = {16177005}, issn = {1046-6673}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/*prevention &amp; control ; Animals ; Blood Flow Velocity/drug effects ; Cell Membrane/drug effects/metabolism ; *Dietary Supplements ; Disease Models, Animal ; Glomerular Filtration Rate/drug effects ; Ischemia/prevention &amp; control ; Kidney/blood supply/drug effects/pathology/physiology ; Magnesium Chloride/administration &amp; dosage/*therapeutic use ; Male ; Nitric Oxide Synthase Type III/metabolism ; Rats ; Rats, Wistar ; Renal Circulation/drug effects/*physiology ; }, abstract = {Magnesium is a potent vasodilator whose effects have not been evaluated in renal ischemia. The antioxidant properties of N-acetylcysteine (NAC) partially protect animals from ischemic/reperfusion injury. This study was designed to evaluate magnesium supplementation, alone or combined with NAC, on ischemic acute renal failure. Rats were maintained on normal diets, supplemented or not with MgCl(2).6H(2)O (1% in drinking water) for 23 d, and some rats received NAC (440 mg/kg body wt) on days 20 to 23. On day 21, ischemia was induced by clamping both renal arteries for 30 min. Five groups were studied: Normal, ischemia, ischemia+magnesium, ischemia+NAC, and ischemia+magnesium+NAC. GFR (inulin clearance), renal blood flow (RBF), FEH(2)O, and FENa were determined. Serum magnesium was decreased in ischemia-only rats. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. However, NAC completely restored the tubular damage induced by ischemia/reperfusion. Semiquantitative immunoblotting showed that NAC prevented the decreased expression of Na-K-2Cl co-transporter and aquaporin 2 after renal ischemia/reperfusion. Untreated rats with acute renal failure demonstrated markedly decreased endothelial nitric oxide synthase expression. Significantly, treatment with NAC, magnesium, or both completely inhibited downregulation of endothelial nitric oxide synthase. The tubular necrosis scores were lower in rats that were treated with NAC alone or with the magnesium-NAC combination. Magnesium prevented postischemia GFR and RBF decreases but did not protect against tubular damage. The NAC protected tubules from ischemia, decreased infiltrating macrophages/lymphocytes, and had a mild protective effect on GFR. In ischemic/reperfusion injury, renal function benefits more from the magnesium-NAC combination than from magnesium alone.}, }
@article {pmid16176268, year = {2005}, author = {Konarkowska, B and Aitken, JF and Kistler, J and Zhang, S and Cooper, GJ}, title = {Thiol reducing compounds prevent human amylin-evoked cytotoxicity.}, journal = {The FEBS journal}, volume = {272}, number = {19}, pages = {4949-4959}, doi = {10.1111/j.1742-4658.2005.04903.x}, pmid = {16176268}, issn = {1742-464X}, mesh = {Acetylcysteine/*pharmacology ; Amyloid/*antagonists &amp; inhibitors/*toxicity ; Antioxidants/metabolism/pharmacology ; Apoptosis/drug effects ; Cell Line ; Glutathione/metabolism/*pharmacology ; Humans ; Islet Amyloid Polypeptide ; Islets of Langerhans/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Reducing Agents/metabolism/*pharmacology ; Sulfhydryl Compounds/metabolism/*pharmacology ; }, abstract = {Human amylin (hA) is a small fibrillogenic protein that is the major constituent of pancreatic islet amyloid, which occurs in most subjects with type-2 diabetes mellitus (T2Dm). There is growing evidence that hA toxicity towards islet beta-cells is responsible for their gradual loss of function in T2Dm. Preventing hA-mediated cytotoxicity has been proposed as a route to halt the progression of this disease, although this has not yet been demonstrated in vivo. The aim of our studies, in which we show that a small number of hA-treated cells exhibit intracellular accumulation of reactive oxygen species (ROS), was to evaluate the role of oxidative stress in the mechanism of hA-mediated cytotoxicity. Here we report that catalase and n-propyl gallate, antioxidants that are thought to act mainly as free radical scavengers, afford RINm5F cells only limited protection against hA-mediated toxicity. By contrast, the thiol antioxidants, N-acetyl-L-cysteine (NAC), GSH and dithiothreitol, which not only react with ROS, but also modulate the cellular redox potential by increasing intracellular levels of GSH and/or by acting as thiol reducing agents, afford almost complete protection and inhibit the progression of hA-evoked apoptosis. We also show that hA treatment is not associated with changes in intracellular GSH levels and that inhibition of GSH biosynthesis has no effect on either hA-mediated cytotoxicity or NAC-mediated protection. These results indicate that, in addition to the induction of oxidative stress, hA appears to mediate cytotoxicity through signalling pathways that are sensitive to the actions of thiol antioxidants.}, }
@article {pmid16174550, year = {2006}, author = {Pan, J and Pei, DS and Yin, XH and Hui, L and Zhang, GY}, title = {Involvement of oxidative stress in the rapid Akt1 regulating a JNK scaffold during ischemia in rat hippocampus.}, journal = {Neuroscience letters}, volume = {392}, number = {1-2}, pages = {47-51}, doi = {10.1016/j.neulet.2005.08.057}, pmid = {16174550}, issn = {0304-3940}, mesh = {Adaptor Proteins, Signal Transducing/*metabolism ; Animals ; Blotting, Western/methods ; Hippocampus/*metabolism ; Immunoprecipitation/methods ; Ischemia/*metabolism/pathology ; MAP Kinase Kinase Kinases ; Male ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Oxidative Stress/*physiology ; Proto-Oncogene Proteins c-akt/*metabolism ; Rats ; Rats, Sprague-Dawley ; Time Factors ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; }, abstract = {It has been well documented that the activation of Akt1 and JNK pathways are involved in the neuronal cell death in cerebral ischemia. In this study, we describe a novel interaction between Akt1 and JNK interacting protein 1 (JIP-1). We first detected the interaction of Akt1 and JIP-1 in hippocampus at various time points of ischemia. In the basal state, JIP-1 bind to Akt1, MLK3 at maximum while JIP-1 binds to JNK3 at minimum. Ischemia stimulus decreased the Akt1-JIP-1 interaction and concomitantly increased association between JIP-1 and JNK3. While MLK3 binding to JIP-1 decreased, similar to Akt1-JIP-1 interaction during ischemia. These results indicated that Akt1 interaction with JIP-1 inhibited JIP-1-mediated potentiation of JNK activity by decreasing JIP-1 binding to specific JNK pathway kinases. Akt1 binding to JIP-1 acts as a regulatory gate preventing JNK activation, which is opened under conditions ischemia injury. Administration of antioxidant N-acetylcysteine (NAC) can obviously affected the level of MLK3, JNK3 and Akt1 binding to JIP-1 and JNK3 activation in the hippocampus at 15min ischemia. The findings suggest that Akt1 regulating JNK scaffold and then regulating JNK activation were closely associated with reactive oxygen species (ROS) during cerebral ischemia.}, }
@article {pmid16171780, year = {2005}, author = {Van Antwerpen, P and Boudjeltia, KZ and Babar, S and Legssyer, I and Moreau, P and Moguilevsky, N and Vanhaeverbeek, M and Ducobu, J and Nève, J}, title = {Thiol-containing molecules interact with the myeloperoxidase/H2O2/chloride system to inhibit LDL oxidation.}, journal = {Biochemical and biophysical research communications}, volume = {337}, number = {1}, pages = {82-88}, doi = {10.1016/j.bbrc.2005.09.013}, pmid = {16171780}, issn = {0006-291X}, mesh = {Acetylcysteine/analogs &amp; derivatives/chemistry ; Antioxidants/*chemistry ; Captopril/chemistry ; Chlorides/chemistry ; Flufenamic Acid/chemistry ; Glutathione/chemistry ; Hydrogen Peroxide/chemistry ; Lipoproteins, LDL/*chemistry ; Lysine/analogs &amp; derivatives/chemistry ; Oxidation-Reduction ; Peroxidase/*chemistry ; Sulfhydryl Compounds/*chemistry ; }, abstract = {Oxidized low-density lipoproteins (LDL) accumulate in the vascular wall and promote a local inflammatory process contributing to the progression of atheromatous plaque. The key role of myeloperoxidase (MPO) in this process has been documented and the enzyme has been involved in the oxidative modification of apolipoprotein B-100 in the intima and at the surface of endothelial cells. As the inhibition of this last phenomenon could be of relevance in pharmacological interventions, thiol-containing molecules such as glutathione, captopril, and N-acetylcysteine (NAC) and its lysinate salt (NAL) were tested in this system and their properties were compared with those of flufenamic acid (control). This last compound already demonstrated an inhibition of the production of HOCl by MPO and a more intense inhibition of MPO activity than glutathione, NAC, NAL, and captopril. However, NAC and NAL inhibited the oxidative modification of LDL more intensively than captopril and glutathione whereas flufenamic acid had no comparable inhibiting effect. This could be related to the presence of LDL close to the catalytic site of the enzyme. NAC and NAL therefore appeared as the most efficient inhibitors probably as a consequence of their relatively small size. The relevance of such effects has to be documented by in vivo studies.}, }
@article {pmid16170570, year = {2006}, author = {Shen, G and Xu, C and Chen, C and Hebbar, V and Kong, AN}, title = {p53-independent G1 cell cycle arrest of human colon carcinoma cells HT-29 by sulforaphane is associated with induction of p21CIP1 and inhibition of expression of cyclin D1.}, journal = {Cancer chemotherapy and pharmacology}, volume = {57}, number = {3}, pages = {317-327}, doi = {10.1007/s00280-005-0050-3}, pmid = {16170570}, issn = {0344-5704}, support = {R01 CA-073674-07/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anticarcinogenic Agents/pharmacology ; Blotting, Western ; Cell Proliferation/drug effects ; Cyclin D1/genetics/*metabolism ; Cyclin-Dependent Kinase Inhibitor p21/genetics/*metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; G1 Phase/*drug effects/genetics ; Gene Expression/drug effects ; Glutathione/pharmacology ; HT29 Cells ; Humans ; Isothiocyanates ; Mitogen-Activated Protein Kinases/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sulfoxides ; Tetrazolium Salts/chemistry/metabolism ; Thiocyanates/*pharmacology ; Time Factors ; Tumor Suppressor Protein p53/*metabolism ; Up-Regulation/drug effects ; }, abstract = {Isothiocyanate sulforaphane (SFN) is a potent cancer chemopreventive agent. We investigated the mechanisms underlying the anti-proliferative effects of SFN in the human colon carcinoma cell line, HT-29. We demonstrate that SFN inhibits the growth of HT-29 cells in a dose- and time-dependent manner. Treatment of serum-stimulated HT-29 cells with SFN suppressed the re-initiation of cell cycle by inducing a G(1) phase cell cycle arrest. At high doses (>25 microM), SFN dramatically induces the expression of p21(CIP1) while significantly inhibits the expression of the G(1) phase cell cycle regulatory genes such as cyclin D1, cyclin A, and c-myc. This regulation can be detected at both the mRNA and protein levels as early as 4 h post-treatment of SFN at 50 microM. Additionally, SFN activates MAPKs pathways, including ERK, JNK and p38. Exposure of HT-29 cells with both SFN and an antioxidant, either NAC or GSH, completely blocked the SFN-mediated activation of these MAPK signaling cascades, regulation of cyclin D1and p21(CIP1) gene expression, and G(1)phase cell cycle arrest. This finding suggests that SFN-induced oxidative stress plays a role in these observed effects. Furthermore, the activation of the ERK and p38 pathways by SFN is involved in the upregulation of p21(CIP1) and cyclin D1, whereas the activation of the JNK pathway plays a contradictory role and may be partially involved in the downregulation of cyclin D1. Because cyclin D1 and p21(CIP1) play opposing roles in G(1) phase cell cycle progression regulation, blocking the activation of each MAPK pathway with specific MAPK inhibitors, is unable to rescue the SFN-induced G(1) phase cell cycle arrest in HT-29 cells.}, }
@article {pmid16169029, year = {2006}, author = {Oh, SH and Lim, SC}, title = {A rapid and transient ROS generation by cadmium triggers apoptosis via caspase-dependent pathway in HepG2 cells and this is inhibited through N-acetylcysteine-mediated catalase upregulation.}, journal = {Toxicology and applied pharmacology}, volume = {212}, number = {3}, pages = {212-223}, doi = {10.1016/j.taap.2005.07.018}, pmid = {16169029}, issn = {0041-008X}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Cadmium/*toxicity ; Carcinoma, Hepatocellular/drug therapy/*enzymology/pathology ; Caspases/*metabolism ; Catalase/biosynthesis ; Cell Line ; Cell Survival/drug effects ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Drug Combinations ; Environmental Pollutants/*toxicity ; Humans ; In Situ Nick-End Labeling ; Membrane Potentials/drug effects ; Mitochondria, Liver/drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Up-Regulation/drug effects ; fas Receptor/metabolism ; }, abstract = {Although reactive oxygen species (ROS) have been implicated in cadmium (Cd)-induced hepatotoxicity, the role of ROS in this pathway remains unclear. Therefore, we attempted to determine the molecular mechanisms relevant to Cd-induced cell death in HepG2 cells. Cd was found to induce apoptosis in the HepG2 cells in a time- and dose-dependent fashion, as confirmed by DNA fragmentation analysis and TUNEL staining. In the early stages, both rapid and transient ROS generation triggered apoptosis via Fas activation and subsequent caspase-8-dependent Bid cleavage, as well as by calpain-mediated mitochondrial Bax cleavage. The timing of Bid activation was coincided with the timing at which the mitochondrial transmembrane potential (MMP) collapsed as well as the cytochrome c (Cyt c) released into the cytosol. Furthermore, mitochondrial permeability transition (MPT) pore inhibitors, such as cyclosporin A (CsA) and bongkrekic acid (BA), did not block Cd-induced ROS generation, MMP collapse and Cyt c release. N-acetylcysteine (NAC) pretreatment resulted in the complete inhibition of the Cd-induced apoptosis via catalase upregulation and subsequent Fas downregulation. NAC treatment also completely blocked the Cd-induced intracellular ROS generation, MMP collapse and Cyt c release, indicating that Cd-induced mitochondrial dysfunction may be regulated indirectly by ROS-mediated signaling pathway. Taken together, a rapid and transient ROS generation by Cd triggers apoptosis via caspase-dependent pathway and subsequent mitochondrial pathway. NAC inhibits Cd-induced apoptosis through the blocking of ROS generation as well as the catalase upregulation.}, }
@article {pmid16168547, year = {2006}, author = {Hsieh, TJ and Liu, TZ and Lu, FJ and Hsieh, PY and Chen, CH}, title = {Actinodaphnine induces apoptosis through increased nitric oxide, reactive oxygen species and down-regulation of NF-kappaB signaling in human hepatoma Mahlavu cells.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {44}, number = {3}, pages = {344-354}, doi = {10.1016/j.fct.2005.08.005}, pmid = {16168547}, issn = {0278-6915}, mesh = {Apoptosis/*drug effects ; Caspases/*metabolism ; DNA Damage ; Dioxolanes/*pharmacology ; Dose-Response Relationship, Drug ; Down-Regulation ; Drugs, Chinese Herbal/pharmacology ; Enzyme Activation ; Humans ; In Situ Nick-End Labeling ; Mitochondrial Membranes/drug effects/metabolism ; NF-kappa B/*drug effects/metabolism ; Nitric Oxide/*metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Actinodaphnine, extracted from Cinnamomum insularimontanum (Lauraceae), possesses cytotoxicity in some cancers, but the mechanism by which actinodaphnine induces apoptosis in human hepatoma cells remains poorly understood. In this study, we investigated the mechanisms of apoptosis induced by actinodaphnine in human hepatoma Mahlavu cells. Treatment with actinodaphnine dose-dependently induced apoptosis in Mahlavu cells that correlated with increased intracellular nitric oxide (NO) and reactive oxygen species (ROS), disruptive mitochondrial transmembrane potential (DeltaPsi(m)), and activation of caspase 3/7. Our data also demonstrated that actinodaphnine down-regulated activity of nuclear factor kappaB (NF-kappaB). The apoptotic response to actinodaphnine was markedly decreased in Mahlavu cells pretreated with dexsamethasone, a NO inhibitor, N-acetylcysteine (NAC), an antioxidant, and Boc-Asp(OMe)-fmk, a broad caspases inhibitor. These results suggested that actinodaphnine-induced apoptosis is initially mediated through the NO and/or ROS increase and caspases-dependent pathway. In conclusion, our results indicate that an increase of ROS and/or NO is the initial essential event that results in the decrease of DeltaPsi(m) and the activation of caspases that commits the cells to the apoptotic pathway in actinodaphnine-treated hepatoma Mahlavu cells.}, }
@article {pmid16168067, year = {2005}, author = {Wei, XM and Kim, HS and Kumar, RK and Heywood, GJ and Hunt, JE and McNeil, HP and Thomas, PS}, title = {Effects of cigarette smoke on degranulation and NO production by mast cells and epithelial cells.}, journal = {Respiratory research}, volume = {6}, number = {1}, pages = {108}, pmid = {16168067}, issn = {1465-993X}, mesh = {Animals ; Cell Degranulation/*drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Epithelial Cells/cytology/drug effects/*metabolism ; Mast Cells/drug effects/*metabolism ; Mice ; Mice, Inbred BALB C ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type II/*metabolism ; Nitric Oxide Synthase Type III ; Respiratory Mucosa/cytology/drug effects/*metabolism ; Tars/*pharmacology ; Trachea/cytology/drug effects/*metabolism ; }, abstract = {Exhaled nitric oxide (eNO) is decreased by cigarette smoking. The hypothesis that oxides of nitrogen (NOX) in cigarette smoke solution (CSS) may exert a negative feedback mechanism upon NO release from epithelial (AEC, A549, and NHTBE) and basophilic cells (RBL-2H3) was tested in vitro. CSS inhibited both NO production and degranulation (measured as release of beta-hexosaminidase) in a dose-dependent manner from RBL-2H3 cells. Inhibition of NO production by CSS in AEC, A549, and NHTBE cells was also dose-dependent. In addition, CSS decreased expression of NOS mRNA and protein expression. The addition of NO inhibitors and scavengers did not, however, reverse the effects of CSS, nor did a NO donor (SNP) or nicotine mimic CSS. N-acetyl-cysteine, partially reversed the inhibition of beta-hexosaminidase release suggesting CSS may act via oxidative free radicals. Thus, some of the inhibitory effects of CSS appear to be via oxidative free radicals rather than a NOX-related negative feedback.}, }
@article {pmid16167305, year = {2006}, author = {Wu, W and Goldstein, G and Adams, C and Matthews, RH and Ercal, N}, title = {Separation and quantification of N-acetyl-l-cysteine and N-acetyl-cysteine-amide by HPLC with fluorescence detection.}, journal = {Biomedical chromatography : BMC}, volume = {20}, number = {5}, pages = {415-422}, doi = {10.1002/bmc.583}, pmid = {16167305}, issn = {0269-3879}, support = {1R15ESO12167-01A1//PHS HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*isolation &amp; purification/pharmacokinetics ; Amides/chemistry/*isolation &amp; purification ; Animals ; Chromatography, High Pressure Liquid/*methods ; Cysteine/chemistry/isolation &amp; purification ; Fluorescence ; Glutathione/chemistry/isolation &amp; purification ; Molecular Structure ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Spectrometry, Fluorescence ; Sulfhydryl Compounds/chemistry/*isolation &amp; purification ; Tissue Distribution ; }, abstract = {N-acetyl-l-cysteine (NAC) is a well-known antioxidant that is capable of facilitating glutathione (GSH) biosynthesis and replenishing intracellular GSH under oxidatively challenging circumstances. N-acetyl-cysteine-amide (NACA), the amide form of NAC, is a newly designed and synthesized thiol-containing compound which is believed to be more lipophilic and permeable through cell membranes than NAC. The metabolic and antioxidant effects of these compounds in vitro and in vivo are under investigation. However, an analytical method that can separate and quantify both compounds simultaneously is not yet available, to the best of our knowledge. Because of their structural similarities, the two compounds are difficult to separate using earlier HPLC methods which were designed for NAC quantification. Therefore, the goal of this work was to develop an HPLC method with fluorescence detection for simultaneous quantification of NAC and NACA in biological blood and tissue samples. A gradient HPLC program with fluorescence detection (lambda(ex) = 330 nm, lambda(em) = 376 nm) using N-(1-pyrenyl)maleimide (NPM) as the derivatizing agent was developed. The calibration curves were linear over a concentration range of 25-5000 nm (r(2) > 0.997). The coefficients of variation for within-run precision and between-run precision ranged from 0.67 to 5.23% and for accuracy ranged from 0.98 to 10.54%; the percentage relative recovery ranged from 94.5 to 102.8%. This new method provides satisfactory separation of NAC and NACA, along with other biological thiols, in 20 min with a 5 nm limit of detection (LOD) per 5 microL injection volume.}, }
@article {pmid16166335, year = {2005}, author = {Yang, YM and Jhanwar-Uniyal, M and Schwartz, J and Conaway, CC and Halicka, HD and Traganos, F and Chung, FL}, title = {N-acetylcysteine conjugate of phenethyl isothiocyanate enhances apoptosis in growth-stimulated human lung cells.}, journal = {Cancer research}, volume = {65}, number = {18}, pages = {8538-8547}, doi = {10.1158/0008-5472.CAN-05-0236}, pmid = {16166335}, issn = {0008-5472}, support = {1R03CA110057-01/CA/NCI NIH HHS/United States ; CA46535/CA/NCI NIH HHS/United States ; }, mesh = {Adenocarcinoma/chemically induced/*drug therapy/pathology ; Animals ; Apoptosis/*drug effects/physiology ; Cell Line, Tumor ; Cysteine/*analogs &amp; derivatives/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation ; Humans ; JNK Mitogen-Activated Protein Kinases/biosynthesis/genetics/metabolism ; Lung/drug effects ; Lung Neoplasms/chemically induced/*drug therapy/pathology ; Mice ; Mice, Inbred A ; Tetradecanoylphorbol Acetate ; Thiocarbamates/*pharmacology ; Transcription Factor AP-1/physiology ; Transfection ; Tumor Suppressor Protein p53/biosynthesis/genetics ; }, abstract = {We previously showed that dietary treatment with the N-acetylcysteine conjugate of phenethyl isothiocyanate (PEITC-NAC) inhibited benzo(a)pyrene-induced lung tumorigenesis in A/J mice, and that tumor inhibition was associated with induction of activator protein-1 (AP-1) activity and stimulation of apoptosis in the lungs of mice. In the present study, we show that PEITC-NAC also induces apoptosis and AP-1 activity in human lung adenocarcinoma A549 cells, and that activation of AP-1 is important in PEITC-NAC induced apoptosis in these cells. PEITC-NAC induced AP-1 binding activity in A549 cells in a dose- and time-dependent manner; peak activity appeared at 10 micromol/L after 24 hours. At that time, flow cytometric analysis showed a sub-G1 peak, indicating that approximately 4.5% of the cells had undergone apoptosis. When wild-type c-jun cDNA was transfected into A549 cells, PEITC-NAC-mediated apoptosis was greatly increased in the c-jun-transfected cells compared with the control vector-transfected cells, based on cell morphology and analysis of DNA fragmentation. Furthermore, cells that were pretreated with 100 nmol/L 12-O-tetradecanoyl phorbol-13-acetate, and then treated with 25 micromol/L PEITC-NAC, underwent enhanced apoptosis compared with cells that were treated with PEITC-NAC alone; cells treated with 12-O-tetradecanoyl phorbol-13-acetate alone showed active cell growth without apoptosis. Bivariate flow cytometric analysis of DNA strand breaks versus DNA content showed that apoptosis induced by PEITC-NAC occurred predominantly in the G2-M phase. These findings suggest that growth-stimulated cells with an elevated basal AP-1 activity, i.e., A549 cells transfected with wild-type c-jun or treated with a tumor promoter, were more sensitive to PEITC-NAC-mediated apoptosis. The observation that PEITC-NAC induces apoptosis predominantly in growth-promoted cells, such as neoplastic cells, suggests a selective mechanism by which PEITC-NAC inhibits lung carcinogenesis.}, }
@article {pmid16162852, year = {2005}, author = {Xu, DX and Chen, YH and Wang, H and Zhao, L and Wang, JP and Wei, W}, title = {Effect of N-acetylcysteine on lipopolysaccharide-induced intra-uterine fetal death and intra-uterine growth retardation in mice.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {88}, number = {2}, pages = {525-533}, doi = {10.1093/toxsci/kfi300}, pmid = {16162852}, issn = {1096-6080}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Bone Development/drug effects ; Bone and Bones/drug effects/embryology ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Fetal Death/chemically induced/*prevention &amp; control ; Fetal Development/*drug effects ; Fetal Growth Retardation/chemically induced/*prevention &amp; control ; Lipopolysaccharides/administration &amp; dosage/*toxicity ; Male ; Maternal Exposure ; Mice ; Mice, Inbred ICR ; Pregnancy ; }, abstract = {Lipopolysaccharide (LPS) has been associated with adverse developmental outcome, including embryonic resorption, intra-uterine fetal death (IUFD), intra-uterine growth retardation (IUGR), and preterm delivery. Reactive oxygen species (ROS) have been associated with LPS-induced developmental toxicity. N-acetylcysteine (NAC) is a glutathione (GSH) precursor and direct antioxidant. The present study investigated the effects of NAC on LPS-induced IUFD and IUGR. All pregnant mice except controls were injected with LPS (75 microg/kg, ip) on gestational day (GD) 15-17. NAC was administered in two different modes. In mode A, the pregnant mice were pretreated with two doses of NAC (either 50 plus 25 mg/kg or 200 plus 100 mg/kg) before LPS, one (either 50 or 200 mg/kg) at 12 h before LPS and the other (either 25 or 100 mg/kg) at 15 min before LPS. In mode B, the pregnant mice were administered with two doses of NAC (either 50 plus 25 mg/kg or 200 plus 100 mg/kg) in 24 h, one (either 50 or 200 mg/kg) injected immediately after LPS and the other (either 25 or 100 mg/kg) injected 3 h after LPS. The number of live fetuses, dead fetuses and resorption sites was counted on GD 18. Live fetuses in each litter were weighed. Crown-rump and tail lengths were measured and skeletal development was evaluated. Results showed that pretreatment with NAC significantly alleviated LPS-induced fetal mortality and reversed LPS-induced growth and skeletal development retardation. Correspondingly, pretreatment with NAC significantly attenuated LPS-induced elevation in TNF-alpha concentration in maternal serum and amniotic fluid and lipid peroxidation in maternal and fetal livers. By contrast to pretreatment, posttreatment with NAC had no effect on LPS-induced TNF-alpha production and lipid peroxidation. When administered after LPS, NAC did not protect against LPS-induced IUFD and IUGR and in fact aggravated LPS-induced preterm labor. All these results indicate that NAC had a dual effect on LPS-induced IUFD and IUGR. Pretreatment with NAC improves fetal survival and reverses LPS-induced fetal growth and skeletal development retardation, whereas posttreatment with NAC aggravates LPS-induced preterm labor.}, }
@article {pmid16158970, year = {2005}, author = {Terasaka, H and Kadoma, Y and Sakagami, H and Fujisawa, S}, title = {Cytotoxicity and apoptosis-inducing activity of bisphenol A and hydroquinone in HL-60 cells.}, journal = {Anticancer research}, volume = {25}, number = {3B}, pages = {2241-2247}, pmid = {16158970}, issn = {0250-7005}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Antioxidants/administration &amp; dosage/pharmacology ; Apoptosis/*drug effects ; Benzhydryl Compounds ; Carcinoma, Squamous Cell/drug therapy/enzymology/pathology ; Caspase 3 ; Caspase 8 ; Caspase 9 ; Caspases/metabolism ; Cell Line ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; HL-60 Cells ; Humans ; Hydroquinones/administration &amp; dosage/*pharmacology ; Imidazoles/administration &amp; dosage/pharmacology ; Mouth Neoplasms/drug therapy/enzymology/pathology ; Nucleosomes/drug effects ; Phenols/administration &amp; dosage/*pharmacology ; Reactive Oxygen Species/metabolism ; Submandibular Gland/cytology/drug effects ; }, abstract = {BPA (bisphenol A or 2,2-bis(4-hydroxy-phenol)propane) and hydroquinone (HQ, 1,4-benzenediol) are present in dental resin materials, and small quantities of these substances may be eluted from the resins. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA and HQ. Thus, it is important to investigate the cytotoxicity and apoptosis-inducing activity of these compounds. BPA and HQ reduced the viable cell number of human promyelocytic leukemia (HL-60), human oral squamous cell carcinoma (HSC-2) and human submandibular gland (HSG) cell lines in a concentration-dependent manner. The cytotoxic activity of HQ, but not of BPA, was significantly reduced by the addition of N-acetyl-L-cysteine (NAC). In biomimetic studies of the prooxidant/antioxidant activity of thiols during oxidation of BPA or HQ, the radical-scavenging activities of mixtures of BPA or HQ and 2-mercapto-1-methylimidazole (MMI, a thiol) were investigated by the induction period method. BPA without MMI showed a higher induction period (antioxidant activity) than did HQ, but BPA with MMI did not cause oxygen uptake. In contrast, HQ with MMI caused oxygen uptake, suggesting formation of MMI thiyl radicals during oxidation of HQ followed by reaction with molecular oxygen. This indicates that HQ may produce intracellular reactive oxygen species (ROS) and provides an explanation for the decrease in the cytotoxicity of HQ by NAC. BPA induced internucleosomal DNA fragmentation, a biochemical marker of apoptosis, only in HL-60 cells. BPA activated caspase-9 and caspase-3, suggesting induction of apoptosis via caspase activation by the caspase recruitment domain. The cytotoxicity of BPA was 2-fold less than that of HQ, whereas the apoptosis-inducing activity of BPA was 10-fold less than that of HQ.}, }
@article {pmid16156512, year = {2005}, author = {Rauchová, H and Pechánová, O and Kunes, J and Vokurková, M and Dobesová, Z and Zicha, J}, title = {Chronic N-acetylcysteine administration prevents development of hypertension in N(omega)-nitro-L-arginine methyl ester-treated rats: the role of reactive oxygen species.}, journal = {Hypertension research : official journal of the Japanese Society of Hypertension}, volume = {28}, number = {5}, pages = {475-482}, doi = {10.1291/hypres.28.475}, pmid = {16156512}, issn = {0916-9636}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Aorta/drug effects/metabolism ; Cyclic N-Oxides/pharmacology ; Drug Interactions ; Enzyme Inhibitors/*pharmacology ; Hypertension/chemically induced/*metabolism/*prevention &amp; control ; Male ; NG-Nitroarginine Methyl Ester/*pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Spin Labels ; }, abstract = {The aim of this study was to evaluate the production of superoxide anions as well as their role in the induction and/or maintenance of high blood pressure in rats with N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. In the preventive study, we compared adult Wistar rats treated with L-NAME for 4 weeks with L-NAME-treated rats that were simultaneously given N-acetylcysteine (NAC) in their drinking water. Basal blood pressure, superoxide production, conjugated dienes concentration and NO synthase (NOS) activity were measured at the end of the experiment. Chronic NOS inhibition by L-NAME treatment increased blood pressure, enhanced superoxide production in the aorta and elevated the concentration of conjugated dienes in the heart and kidney. All these changes were prevented by simultaneous NAC administration, which augmented NOS activity in L-NAME-treated rats. In the therapeutic study, the effects of chronic NAC treatment were studied in rats with established hypertension which developed during 4 weeks of L-NAME administration. The blood pressure effects of chronic NAC treatment in established L-NAME hypertension were only moderate, although this treatment also restored NOS activity and lowered conjugated dienes in the heart and kidney. Since chronic NAC treatment had better preventive than therapeutic effects, it seems that reactive oxygen species play a more important role in the induction than in the maintenance of L-NAME hypertension.}, }
@article {pmid16154687, year = {2005}, author = {Pei, DS and Guan, QH and Sun, YF and Zhang, QX and Xu, TL and Zhang, GY}, title = {N-Acetylcysteine inhibit the translocation of mixed lineage kinase-3 from cytosol to plasma membrane during transient brain ischemia in rat hippocampus.}, journal = {Neuroscience letters}, volume = {391}, number = {1-2}, pages = {38-42}, doi = {10.1016/j.neulet.2005.08.029}, pmid = {16154687}, issn = {0304-3940}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Brain Ischemia/*metabolism ; Cell Membrane/drug effects/*metabolism ; Cytosol/drug effects/*metabolism ; Dose-Response Relationship, Drug ; Hippocampus/drug effects/*metabolism ; MAP Kinase Kinase Kinases/*metabolism ; Male ; Protein Transport/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; }, abstract = {Mixed lineage kinase-3 (MLK3) is a recently described member of the MLK subfamily of Ser/Thr protein kinases that interacts with mitogen-activated protein kinase (MAPK) pathways. In this study, we investigated the translocation of MLK3 during transient cerebral ischemia in rat hippocampus. Transient brain ischemia was induced by the four-vessel occlusion in Sprague-Dawley rats. Our data show that MLK3 can translocate from cytosolic fraction to the membrane fraction during ischemia and the increased MLK3 in the membrane fraction bind to postsynaptic density protein 95 (PSD-95). The antioxidant N-acetylcysteine (NAC) could inhibit the translocation of MLK3 from cytosolic fraction to the membrane fraction and decrease the interactions of MLK3 and PSD-95 in the membrane fraction. Consequently, these results indicate that reactive oxygen species (ROS) was closely associated with MLK3 translocation induced by transient global ischemia in rat hippocampus.}, }
@article {pmid16151648, year = {2005}, author = {Schiller, M and Blank, N and Heyder, P and Herrmann, M and Gaipl, US and Kalden, JR and Lorenz, HM}, title = {Induction of apoptosis by spermine-metabolites in primary human blood cells and various tumor cell lines.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {10}, number = {5}, pages = {1151-1162}, doi = {10.1007/s10495-005-1188-5}, pmid = {16151648}, issn = {1360-8185}, mesh = {Acetylcysteine/pharmacology ; Amine Oxidase (Copper-Containing)/blood ; Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins ; Caspase Inhibitors ; Cell Line, Tumor ; Cytochromes c/metabolism ; Dexamethasone/pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Leukocytes, Mononuclear/cytology/*drug effects ; Lymphoproliferative Disorders/blood ; Membrane Potentials/drug effects ; Mitochondria/drug effects ; Mitochondrial Proteins/metabolism ; Polyamines/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Putrescine/pharmacology ; Reactive Oxygen Species/metabolism ; Spermidine/pharmacology ; Spermine/pharmacology ; fas Receptor/genetics ; }, abstract = {Polyamines are involved in the regulation of cellular growth and survival by interacting with processes like translation, transcription or ion transport. The aim of our study was to analyze whether polyamines induce apoptosis in hematopoetic cells and to investigate the molecular mechanisms involved. We found an induction of apoptosis by spermine in primary human cells and malignant tumor cell lines. Spermine-treatment resulted in an intracellular increase of reactive oxygen species. Apoptosis was mediated by a collapse of mitochondrial membrane potential, a decrease in Bcl-2 expression and a release of apoptosis mediating molecules from mitochondrial intermembrane space (cytochrome C, Smac/DIABLO). Spermine-mediated apoptosis was caspase-dependent. To test whether spermine mediates apoptosis through metabolites we analyzed the effects of several molecules that interfere with its catabolism. Aminoguanidine, an inhibitor of serum amine oxidase, aldehyde-dehydrogenase, which degrades aldehydes to less reactive molecules or N-acetyl-cysteine, a glutathion precursor, significantly inhibited spermine-mediated apoptosis. From these data we conclude that spermine-derived aldehydes and intracellular accumulation of reactive oxygen species result in mitochondria mediated apoptosis.}, }
@article {pmid16148150, year = {2005}, author = {Look, DC and Stoll, LL and Romig, SA and Humlicek, A and Britigan, BE and Denning, GM}, title = {Pyocyanin and its precursor phenazine-1-carboxylic acid increase IL-8 and intercellular adhesion molecule-1 expression in human airway epithelial cells by oxidant-dependent mechanisms.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {175}, number = {6}, pages = {4017-4023}, doi = {10.4049/jimmunol.175.6.4017}, pmid = {16148150}, issn = {0022-1767}, mesh = {Antioxidants/pharmacology ; Cells, Cultured ; Epithelial Cells ; Free Radical Scavengers/pharmacology ; Humans ; Intercellular Adhesion Molecule-1/*biosynthesis ; Interleukin-8/*biosynthesis ; Oxidation-Reduction ; Phenazines/pharmacology ; Pseudomonas aeruginosa/pathogenicity ; Pyocyanine/*pharmacology ; Respiratory Mucosa/cytology/immunology/*metabolism ; Up-Regulation/drug effects ; Virulence Factors/pharmacology ; }, abstract = {Pseudomonas aeruginosa secretes numerous factors that alter host cell function and may contribute to disease pathogenesis. Among recognized virulence factors is the redox-active phenazine pyocyanin. We have recently demonstrated that the precursor for pyocyanin, phenazine-1-carboxylic acid (PCA), increases oxidant formation and alters gene expression in human airway epithelial cells. We report in this work that PCA and pyocyanin increase expression of ICAM-1 both in vivo and in vitro. Moreover, phenazines enhanced cytokine-dependent increases in IL-8 and ICAM-1. Antioxidant intervention studies indicated both similarities and differences between PCA and pyocyanin. The thiol antioxidant N-acetyl cysteine, extracellular catalase, and inducible NO synthase inhibitors inhibited ICAM-1 and IL-8 increases in response to both phenazines. However, pyocyanin was significantly more sensitive to N-acetylcysteine inhibition. Interestingly, hydroxyl radical scavengers inhibited the response to pyocyanin, but not to PCA. These studies suggest that P. aeruginosa phenazines coordinately up-regulate chemokines (IL-8) and adhesion molecules (ICAM-1) by mechanisms that are, at least in part, oxidant dependent. However, results indicate that the mechanisms by which PCA and pyocyanin exert their effects are not identical, and not all antioxidant interventions are equally effective in inhibiting phenazine-mediated proinflammatory effects.}, }
@article {pmid16144942, year = {2005}, author = {Hose, C and Kaur, G and Sausville, EA and Monks, A}, title = {Transcriptional profiling identifies altered intracellular labile iron homeostasis as a contributing factor to the toxicity of adaphostin: decreased vascular endothelial growth factor secretion is independent of hypoxia-inducible factor-1 regulation.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {11}, number = {17}, pages = {6370-6381}, doi = {10.1158/1078-0432.CCR-05-0291}, pmid = {16144942}, issn = {1078-0432}, support = {N01-C0-12400//PHS HHS/United States ; }, mesh = {Adamantane/*analogs &amp; derivatives/pharmacology ; Antioxidants/pharmacology ; Cell Hypoxia ; Culture Media, Conditioned/pharmacology ; Drug Combinations ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; HL-60 Cells ; Humans ; Hydroquinones/*pharmacology ; Hypoxia-Inducible Factor 1, alpha Subunit ; Iron/*metabolism ; Iron Chelating Agents/pharmacology ; Jurkat Cells ; K562 Cells ; Molecular Structure ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress ; RNA, Messenger/genetics/metabolism ; Receptors, Transferrin/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/*pharmacology ; Transcription, Genetic/*drug effects ; Vascular Endothelial Growth Factor A/*metabolism ; }, abstract = {PURPOSE: Adaphostin was developed as an inhibitor of the p210(bcr-abl) tyrosine kinase, but as its activity is not limited to tumor cell lines containing this translocation, transcriptional profiling was used as a tool to elucidate additional mechanisms responsible for adaphostin cytotoxicity.<br><br>EXPERIMENTAL DESIGN: Profiles of drug-induced transcriptional changes were measured in three hematopoietic cell lines following 1 and 10 micromol/L adaphostin for 2 to 6 hours and then confirmed with real-time reverse transcription-PCR (2-24 hours). These data indicated altered iron homeostasis, and this was confirmed experimentally. Alteration of vascular endothelial growth factor (VEGF) secretion through hypoxia-inducible factor-1 (HIF-1) regulation was also investigated.<br><br>RESULTS: Drug-induced genes included heat shock proteins and ubiquitins, but an intriguing response was the induction of ferritins. Measurement of the labile iron pool showed release of chelatable iron immediately after treatment with adaphostin and was quenched with the addition of an iron chelator. Pretreatment of cells with desferrioxamine and N-acetyl-cysteine reduced but did not ablate the sensitivity of the cells to adaphostin, and desferrioxamine was able to modulate adaphostin-induced activation of p38 and inactivation of AKT. VEGF secretion was shown to be reduced in cell lines after the addition of adaphostin but was not dependent on HIF-1.<br><br>CONCLUSIONS: Adaphostin-induced cytotoxicity is caused in part by a rapid release of free iron, leading to redox perturbations and cell death. Despite this, reduced VEGF secretion was found to be independent of regulation by the redox responsive transcription factor HIF-1. Thus, adaphostin remains an interesting agent with the ability to kill tumor cells directly and modulate angiogenesis.}, }
@article {pmid16144837, year = {2005}, author = {Sato, H and Shiiya, A and Kimata, M and Maebara, K and Tamba, M and Sakakura, Y and Makino, N and Sugiyama, F and Yagami, K and Moriguchi, T and Takahashi, S and Bannai, S}, title = {Redox imbalance in cystine/glutamate transporter-deficient mice.}, journal = {The Journal of biological chemistry}, volume = {280}, number = {45}, pages = {37423-37429}, doi = {10.1074/jbc.M506439200}, pmid = {16144837}, issn = {0021-9258}, mesh = {Amino Acid Transport System y+/*deficiency/genetics/*metabolism ; Amino Acids/blood ; Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; Cystine/blood ; Female ; Fibroblasts/metabolism ; Gene Deletion ; Glutathione/blood/metabolism ; Homozygote ; Male ; Mice ; Oxidation-Reduction ; }, abstract = {Cystine/glutamate transporter, designated as system x(-)(c), mediates cystine entry in exchange for intracellular glutamate in mammalian cells. This transporter consists of two protein components, xCT and 4F2 heavy chain, and the former is predicted to mediate the transport activity. This transporter plays a pivotal role for maintaining the intracellular GSH levels and extracellular cystine/cysteine redox balance in cultured cells. To clarify the physiological roles of this transporter in vivo, we generated and characterized mice lacking xCT. The xCT(-/-) mice were healthy in appearance and fertile. However, cystine concentration in plasma was significantly higher in these mice, compared with that in the littermate xCT(-/-) mice, while there was no significant difference in plasma cysteine concentration. Plasma GSH level in xCT(-/-) mice was lower than that in the xCT(-/-) mice. The embryonic fibroblasts derived from xCT(-/-) mice failed to survive in routine culture medium, and 2-mercaptoethanol was required for survival and growth. When 2-mercaptoethanol was removed from the culture medium, cysteine and GSH in these cells dramatically decreased, and cells started to die within 24 h. N-Acetyl cysteine also rescued xCT(-/-)-derived cells and permitted growth. These results demonstrate that system x(-)(c) contributes to maintaining the plasma redox balance in vivo but is dispensable in mammalian development, although it is vitally important to cells in vitro.}, }
@article {pmid16143259, year = {2005}, author = {Rega, FR and Wuyts, WA and Vanaudenaerde, BM and Jannis, NC and Neyrinck, AP and Verleden, GM and Lerut, TE and Van Raemdonck, DE}, title = {Nebulized N-acetyl cysteine protects the pulmonary graft inside the non-heart-beating donor.}, journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}, volume = {24}, number = {9}, pages = {1369-1377}, doi = {10.1016/j.healun.2004.10.013}, pmid = {16143259}, issn = {1557-3117}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aerosols ; Airway Resistance ; Animals ; Bronchoalveolar Lavage Fluid/chemistry ; Free Radical Scavengers/*administration &amp; dosage ; Glutathione/analysis ; Glutathione Disulfide/analysis ; Lung/blood supply/*drug effects ; Lung Transplantation/*methods ; Organ Preservation/*methods ; Reperfusion ; Sus scrofa ; Temperature ; Vascular Resistance ; }, abstract = {BACKGROUND: The use of lungs from non-heart-beating donors (NHBD) might significantly alleviate the organ shortage. The tolerable warm ischemic period after cardiac arrest, however, is limited to approximately 1 hour. If the lung could be safely protected inside the cadaver, this time period may be prolonged. This would help to obtain family consent and to organize organ retrieval.<br><br>METHODS: Pigs (30.8 +/- 0.6 kg) were killed, left untouched for 3 hours, and divided into 3 groups. Nebulized N-acetyl cysteine (NAC) (300 mg), a precursor of the antioxidant agent glutathione, was administered during 10 minutes before death in Group I (NAC-NHBD, n = 6) and 15 minutes after death in Group II (NHBD-NAC, n = 6). In the control group, no aerosol was administered (NHBD, n = 6). After a warm ischemic interval of 3 hours, both lungs in all groups were topically cooled for 1 hour. Thereafter, the left lung was prepared for evaluation in an isolated reperfusion circuit. Hemodynamic, aerodynamic, and oxygenation parameters were measured. Wet-to-dry weight ratio (W/D) was calculated after reperfusion. The right lung was used to measure reduced glutathione (GSH) and oxidized glutathione (GSSG) levels (micromol/g) in lung homogenates and total protein levels in bronchial lavage fluid.<br><br>RESULTS: Pulmonary vascular resistance, mean airway pressure, and W/D were significantly decreased in NAC-NHBD (1930 +/- 144 Dynes x sec x cm(-5), 14.2 +/- 0.5 cm H2O, and 7.4 +/- 0.4; p < 0.01, 0.01, and 0.05, respectively) and NHBD-NAC (1837 +/- 180 Dynes x sec x cm(-5), 13.3 +/- 1.2 cm H2O, and 7.3 +/- 0.3; p < 0.01, 0.05, and 0.05, respectively) when compared with the control group (5051 +/- 530 Dynes x sec x cm(-5), 17 +/- 0.4 cm H2O, 8.5 +/- 0.1, respectively). GSH/GSSG ratio was significantly higher and protein levels were significantly lower in NAC-NHBD (1.7 +/- 0.1 and 1315 +/- 60 microg/ml; p < 0.05 and 0.05, respectively) and NHBD-NAC (1.7 +/- 0.2 and 1475 +/- 159 microg/ml; p < 0.05 and 0.05, respectively) when compared with the control group (1.2 +/- 0.1 and 2150 +/- 200 microg/ml).<br><br>CONCLUSIONS: Nebulized NAC administered before or shortly after death attenuates early ischemia reperfusion injury via upregulation of glutathione. NAC might be a promising tool to protect the pulmonary graft from both controlled and uncontrolled NHBD.}, }
@article {pmid16140881, year = {2005}, author = {Ilan, E and Tirosh, O and Madar, Z}, title = {Triacylglycerol-mediated oxidative stress inhibits nitric oxide production in rat isolated hepatocytes.}, journal = {The Journal of nutrition}, volume = {135}, number = {9}, pages = {2090-2095}, doi = {10.1093/jn/135.9.2090}, pmid = {16140881}, issn = {0022-3166}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Nucleus/metabolism ; Cells, Cultured ; Emulsions ; Hepatocytes/*metabolism ; Lipid Metabolism ; Lipids/pharmacology ; Nitric Oxide/antagonists &amp; inhibitors/*biosynthesis ; Nitrites/metabolism ; Oxidative Stress/*physiology ; Rats ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/pharmacology ; Triglycerides/*pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {This study was designed to evaluate the effects of triacylglycerol (TG) on nitric oxide (NO) production, expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) and variables related to oxidative stress in rat isolated hepatocytes. Hepatocytes were isolated and exposed to TG in the form of a lipid emulsion (0.01-0.1% LE). Exposure to LE dose dependently decreased nitrite levels. Nitrite levels were inhibited 67% and intracellular reactive oxygen species (ROS) levels were increased 250% at 0.1% LE. The decline in nitrite levels was accompanied by 37 and 67% reductions in iNOS and eNOS expressions, respectively. To evaluate whether the increased oxidative stress inhibited NOS synthesis, cells were treated for 48 h with rotenone (a mitochondrial complex 1 inhibitor) or buthionine sulfoximine (a glutathione synthesis inhibitor). Both compounds elevated ROS production, which was followed by inhibition of nitrite production. To determine whether there is an association between LE-mediated ROS production and the inhibition of NO synthesis by the LE, hepatocytes were treated with antioxidants. N-Acetyl-l-cysteine (NAC), ascorbate, and resveratrol attenuated the reduction of nitrite levels due to LE alone. NAC inhibited the reductions in eNOS and iNOS transcription and protein levels. Nuclear factor-kappaB (NF-kappaB), one of the transcription factors involved in eNOS and iNOS transcriptional regulation, was decreased 15% in the nucleus by LE treatment. These results suggest that TG reduces nitrite production by elevating intracellular ROS levels (prolonged oxidative stress), and the downregulation of NOS enzymes may occur at least in part via the NFkappaB pathway.}, }
@article {pmid16140340, year = {2005}, author = {Smyrniotis, V and Arkadopoulos, N and Kostopanagiotou, G and Theodoropoulos, T and Theodoraki, K and Farantos, C and Kairi, E and Paphiti, A}, title = {Attenuation of ischemic injury by N-acetylcysteine preconditioning of the liver.}, journal = {The Journal of surgical research}, volume = {129}, number = {1}, pages = {31-37}, doi = {10.1016/j.jss.2005.07.028}, pmid = {16140340}, issn = {0022-4804}, mesh = {Acetylcysteine/*administration &amp; dosage ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Cyclic AMP/metabolism ; Glutathione Transferase/blood ; Ischemic Preconditioning/*methods ; Liver/*blood supply/metabolism/pathology ; Male ; Necrosis ; Platelet Aggregation/drug effects ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; Time Factors ; }, abstract = {BACKGROUND: Numerous previous studies have established the hepatoprotective properties of N-acetylcysteine (NAC). The present study was designed to investigate the effects of NAC on a warm hepatic ischemia-reperfusion rat model with a focus on the role of cAMP.<br><br>MATERIALS AND METHODS: Fifty-six male Wistar rats were allocated randomly into the control group (n = 28) or the study group (group NAC, n = 28). Group NAC animals received an intravenous bolus dose of 0.3 mg/g NAC, whereas control animals were given an equal volume of normal saline. Subsequently, 60-min partial liver ischemia was induced by occlusion of blood inflow to the left and middle liver lobes. Aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase levels, platelet aggregation, and ischemic tissue cyclic adenosine 5-monophosphate (cAMP) levels were examined at 30, 60, and 120 min after reperfusion. Parts of the ischemic liver were sampled at the same time-points. Measurements were obtained from seven animals at each time point.<br><br>RESULTS: The administration of NAC resulted in lower levels of aspartate aminotransferase, alanine aminotransferase, and alpha-glutathione S-transferase, decreased platelet aggregation, and increased levels of ischemic tissue cAMP at all time points after reperfusion. Histologically, fewer necrotic changes were observed in the NAC group at 60 and 120 min after reperfusion. All differences were statistically significant (P < 0.05).<br><br>CONCLUSIONS: In the present study, NAC seems to attenuate hepatic ischemia-reperfusion damage, as demonstrated by liver function tests and liver histology. The effects of NAC appear to be mediated by the decrease in platelet aggregation and increase in the levels of cAMP observed in ischemic liver tissue.}, }
@article {pmid16140212, year = {2005}, author = {Callapina, M and Zhou, J and Schmid, T and Köhl, R and Brüne, B}, title = {NO restores HIF-1alpha hydroxylation during hypoxia: role of reactive oxygen species.}, journal = {Free radical biology &amp; medicine}, volume = {39}, number = {7}, pages = {925-936}, doi = {10.1016/j.freeradbiomed.2005.05.009}, pmid = {16140212}, issn = {0891-5849}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Carcinoma, Hepatocellular ; Cell Line ; Humans ; Hydroxylation ; Hypoxia/*physiopathology ; Naphthoquinones/pharmacology ; Nitric Oxide/pharmacology/*physiology ; Nitric Oxide Donors/pharmacology ; Procollagen-Proline Dioxygenase/metabolism ; Reactive Oxygen Species/*metabolism ; Triazenes/antagonists &amp; inhibitors/pharmacology ; Tumor Cells, Cultured ; Von Hippel-Lindau Tumor Suppressor Protein/metabolism ; }, abstract = {The activity of hypoxia-inducible factor 1 (HIF-1) is primarily determined by stability regulation of its alpha subunit, which is stabilized under hypoxia but degraded during normoxia. Hydroxylation of HIF-1alpha by prolyl hydroxylases (PHDs) recruits the von Hippel-Lindau (pVHL) E3 ubiquitin ligase complex to initiate proteolytic destruction of the alpha subunit. Hypoxic stabilization of HIF-1alpha has been reported to be antagonized by nitric oxide (NO). By using a HIF-1alpha-pVHL binding assay, we show that NO released from DETA-NO restored prolyl hydroxylase activity under hypoxia. Destabilization of HIF-1alpha by DETA-NO was reversed by free radical scavengers such as NAC and Tiron, thus pointing to the involvement of reactive oxygen species (ROS). Therefore, we examined the effects of ROS on HIF-1alpha stabilization. Treatment of cells under hypoxia with low concentrations of the superoxide generator 2,3-dimethoxy-1,4-naphthoquinone lowered HIF-1alpha protein stabilization. In vitro HIF-1alpha-pVHL interaction assays demonstrated that low-level ROS formation increased prolyl hydroxylase activity, an effect antagonized by ROS scavengers. While determining intracellular ROS formation we noticed that reduced ROS production under hypoxia was restored by the addition of DETA-NO. We propose that an increase in ROS formation contributes to HIF-1alpha destabilization by NO donors under hypoxia via modulation of PHD activity.}, }
@article {pmid16137721, year = {2005}, author = {D'Agostini, F and Izzotti, A and Balansky, RM and Bennicelli, C and De Flora, S}, title = {Modulation of apoptosis by cancer chemopreventive agents.}, journal = {Mutation research}, volume = {591}, number = {1-2}, pages = {173-186}, doi = {10.1016/j.mrfmmm.2005.03.034}, pmid = {16137721}, issn = {0027-5107}, mesh = {Animals ; Anticarcinogenic Agents/*pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects/genetics/physiology ; Epithelium/drug effects/physiology ; Female ; Gene Expression Profiling ; Humans ; In Situ Nick-End Labeling ; Light ; Male ; Mice ; Mice, Nude ; Molecular Sequence Data ; Neoplasms/pathology/*prevention &amp; control ; Oligonucleotide Array Sequence Analysis ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Respiratory System/drug effects/metabolism/pathology ; Smoke ; Sulindac/pharmacology ; Nicotiana ; }, abstract = {A review of almost 2000 studies showed that the large majority of 39 putative cancer chemopreventive agents induced "spontaneous" apoptosis. Inhibition of the programmed cell death triggered by a variety of stimuli was consistently reported only with ascorbic acid, alpha-tocopherol, and N-acetylcysteine (NAC). We performed experimental studies in rodents exposed to cigarette smoke, either mainstream (MCS) or environmental (ECS), and UV-A/B-containing light. The nonsteroidal anti-inflammatory drug sulindac did not affect the apoptotic process in the skin of light-exposed mice and in the lungs of ECS-exposed mice. Likewise, 5,6-benzoflavone, indole-3-carbinol, 1,2-dithiole-3-thione and oltipraz failed to modulate apoptosis in the respiratory tract of ECS-exposed rats. Phenethyl isothiocyanate further enhanced the frequency of apoptosis in pulmonary alveolar macrophages and bronchial epithelial cells, and upregulated several genes in the lung of ECS-exposed rats. Both individually and in combination with oltipraz, NAC inhibited apoptosis in the respiratory tract of rats exposed either to MCS or ECS. Moreover, NAC attenuated the ECS-related overexpression of proapoptotic genes and normalized the levels of proapoptotic proteins in rat lung. The transplacental administration of NAC to mice considerably attenuated gene overexpression in the liver of fetuses exposed to ECS throughout pregnancy. Inhibition of apoptosis by chemopreventive agents reflects their ability to counteract certain upstream signals, such as genotoxic damage, redox imbalances, and other forms of cellular stress that trigger apoptosis. On the other hand, enhancement of apoptosis is a double-edged sword, since it represents a protective mechanism in carcinogenesis but may contribute to the pathogenesis of other degenerative diseases. We suggest that stimulation of apoptosis by so many chemopreventive agents, as reported in the literature, may often reflect the occurrence of toxic effects at high doses.}, }
@article {pmid16135398, year = {2006}, author = {Sandhya, T and Mishra, KP}, title = {Cytotoxic response of breast cancer cell lines, MCF 7 and T 47 D to triphala and its modification by antioxidants.}, journal = {Cancer letters}, volume = {238}, number = {2}, pages = {304-313}, doi = {10.1016/j.canlet.2005.07.013}, pmid = {16135398}, issn = {0304-3835}, mesh = {Antioxidants/*pharmacology ; Apoptosis/drug effects ; Breast Neoplasms/*drug therapy/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Humans ; *Medicine, Ayurvedic ; *Phyllanthus emblica ; *Phytotherapy ; Plant Extracts/*pharmacology ; Reactive Oxygen Species/metabolism ; *Terminalia ; }, abstract = {The cytotoxic effects of Triphala (TPL), an Indian Ayurvedic formulation with known anti-cancer properties, has been investigated on two human breast cancer cell lines differing in their p53 status. In vitro studies showed that MCF 7 with wild type p53 was more sensitive to TPL than T 47 D, which is p53 negative. TPL induced loss of cell viability was determined by MTT assay. After 72h incubation, the IC 50 values for MCF 7 was found to be approximately 8microg/ml and that for T 47 D was approximately 26microg/ml. Moreover, TPL inhibited the clonogenic growth of MCF 7 cells, which was significantly recovered by pifithrin-alpha, the p53 inhibitor. However, pifithrin-alpha, did not modify TPL induced cytotoxicity in T 47 D cells. Exogenous addition of antioxidants, glutathione (GSH) and N-Acetyl-Cysteine (NAC) inhibited the anti-proliferative ability of TPL in both MCF 7 and T47 D. Annexin-V and propidium iodide double staining of cells treated with TPL for 2h revealed that TPL induced significant apoptosis in both the cell lines in a dose dependant manner but magnitude of apoptosis was significantly higher in MCF 7 than in T 47-D cells. TPL was also found to induce dose and time dependent increase in intracellular reactive oxygen species in both the cell lines. Present results have demonstrated that MCF 7 and T 47 D cells exhibited differential sensitivity to TPL, which seems to be dependant on their p53 status. Inhibition of anti-proliferative ability of TPL by antioxidants suggests a role for TPL induced ROS in the induction of apoptosis. It is concluded that p53 status of cancer cells formed an important factor in predicting the response of cancer cells to prooxidant drugs.}, }
@article {pmid16134056, year = {2005}, author = {Herman, S and Zurgil, N and Deutsch, M}, title = {Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {54}, number = {7}, pages = {273-280}, doi = {10.1007/s00011-005-1355-8}, pmid = {16134056}, issn = {1023-3830}, mesh = {Acetylcysteine/pharmacology ; Annexin A5/pharmacology ; Anti-Inflammatory Agents/pharmacology ; Antimetabolites, Antineoplastic/administration &amp; dosage/*pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Arthritis, Rheumatoid ; Biological Assay ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Enzyme Inhibitors/pharmacology ; Fluorescein-5-isothiocyanate/pharmacology ; Fluorescent Dyes/pharmacology ; Humans ; Immunosuppressive Agents ; Jurkat Cells ; Leukocytes/metabolism ; Methotrexate/administration &amp; dosage/*pharmacology ; Monocytes/drug effects/*pathology ; Oxidative Stress ; Propidium/pharmacology ; Reactive Oxygen Species ; T-Lymphocytes/drug effects/*pathology ; Tetrazolium Salts/pharmacology ; Thiazoles/pharmacology ; Time Factors ; U937 Cells ; }, abstract = {BACKGROUND: The mechanism by which low dose methotrexate (MTX) exerts its anti-inflammatory and immunosuppressive effect in rheumatoid arthritis (RA) patients is still debated. Recently it has been related to the induction of apoptosis.<br><br>OBJECTIVE: We investigated the degree of apoptotic induction by MTX in lymphocytic (Jurkat T, EL4 T, and Raji B) and monocytic cell lines (U937 and THP1) and its relation to reactive oxygen species (ROS) generation, as a possible mechanism underlying the apoptotic events.<br><br>METHODS: All cell types were incubated with a range of MTX concentrations (0.001, 0.01, 0.1, 1, and 10 muM) for up to 24 h. Cytotoxicity was assessed by Trypan Blue exclusion and MTT test; cell size and granularity by forward and side scatters (FSC, SSC). Apoptosis was measured by Annexin V test and FDA polarization; and mitochondrial ROS generation by DHR123 probe and by NAC inhibition.<br><br>RESULTS: MTX significantly reduced cell viability and proliferation in all cell lines, being most effective in the Jurkat T lymphocytic line. The MTX cytotoxicity (at the optimal concentrations corresponding to low dose MTX therapy) was attributed to apoptosis, as suggested by morphological changes (shrinkage, increased granularity) and confirmed by Annexin V binding and FDA hyperpolarization. The apoptotic induction and the ROS generation (statistically correlated to apoptosis) were most pronounced in the Jurkat and EL4 T cell lines, and were partially inhibited by the antioxidant N-acetyl L-cysteine (NAC).<br><br>CONCLUSION: According to the present observations, MTX may most likely induce apoptosis through oxidative stress. The high susceptibility of T cell lines to MTX induced apoptosis may account for the beneficial effect of MTX treatment in rheumatoid arthritis, which is characterized by hyperproliferation of T cells.}, }
@article {pmid16129119, year = {2005}, author = {Sprague, CL and Elfarra, AA}, title = {Protection of rats against 3-butene-1,2-diol-induced hepatotoxicity and hypoglycemia by N-acetyl-l-cysteine.}, journal = {Toxicology and applied pharmacology}, volume = {207}, number = {3}, pages = {266-274}, doi = {10.1016/j.taap.2005.01.007}, pmid = {16129119}, issn = {0041-008X}, support = {ES06841/ES/NIEHS NIH HHS/United States ; GM08505-08/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetophenones/chemistry ; Acetylcysteine/*therapeutic use ; Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Chemical and Drug Induced Liver Injury/pathology/*prevention &amp; control ; Chromatography, High Pressure Liquid ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Glycols/*antagonists &amp; inhibitors/blood/*toxicity ; Hypoglycemia/chemically induced/pathology/*prevention &amp; control ; Insulin/blood ; Lactates/metabolism ; Male ; Mitochondria, Liver/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {3-Butene-1,2-diol (BDD), an allylic alcohol and major metabolite of 1,3-butadiene, has previously been shown to cause hepatotoxicity and hypoglycemia in male Sprague-Dawley rats, but the mechanisms of toxicity were unclear. In this study, rats were administered BDD (250 mg/kg) or saline, ip, and serum insulin levels, hepatic lactate levels, and hepatic cellular and mitochondrial GSH, GSSG, ATP, and ADP levels were measured 1 or 4 h after treatment. The results show that serum insulin levels were not causing the hypoglycemia and that the hypoglycemia was not caused by an enhancement of the metabolism of pyruvate to lactate because hepatic lactate levels were either similar (1 h) or lower (4 h) than controls. However, both hepatic cellular and mitochondrial GSH and GSSG levels were severely depleted 1 and 4 h after treatment and the mitochondrial ATP/ADP ratio was also lowered 4 h after treatment relative to controls. Because these results suggested a role for hepatic cellular and mitochondrial GSH in BDD toxicity, additional rats were administered N-acetyl-l-cysteine (NAC; 200 mg/kg) 15 min after BDD administration. NAC treatment partially prevented depletion of hepatic cellular and mitochondrial GSH and preserved the mitochondrial ATP/ADP ratio. NAC also prevented the severe depletion of serum glucose concentration and the elevation of serum alanine aminotransferase activity after BDD treatment without affecting the plasma concentration of BDD. Thus, depletion of hepatic cellular and mitochondrial GSH followed by the decrease in the mitochondrial ATP/ADP ratio was likely contributing to the mechanisms of hepatotoxicity and hypoglycemia in the rat.}, }
@article {pmid16127427, year = {2005}, author = {Jesnowski, R and Fürst, D and Ringel, J and Chen, Y and Schrödel, A and Kleeff, J and Kolb, A and Schareck, WD and Löhr, M}, title = {Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {85}, number = {10}, pages = {1276-1291}, doi = {10.1038/labinvest.3700329}, pmid = {16127427}, issn = {0023-6837}, mesh = {Acetylcysteine/*pharmacology ; Antigens, Polyomavirus Transforming/biosynthesis/genetics ; Biomarkers/metabolism ; Cell Cycle/drug effects ; *Cell Line ; Cell Proliferation/drug effects ; Collagen/*pharmacology ; Drug Combinations ; Fibrosis ; Gene Expression ; Humans ; Karyotyping ; Laminin/*pharmacology ; Pancreas/drug effects/*pathology ; Platelet-Derived Growth Factor/pharmacology ; Proteoglycans/*pharmacology ; Telomerase/biosynthesis/genetics ; Transforming Growth Factor beta/pharmacology ; Vitamin A/metabolism ; }, abstract = {Tissue fibrosis is one of the characteristics of chronic pancreatitis and pancreatic adenocarcinoma. Activated pancreatic stellate cells (PSC) play a central role in this process. However, analysis of the molecular mechanisms leading to PSC activation is hampered by the lack of an established human PSC line. To overcome this problem, we immortalized and characterized primary human PSC. The cells were isolated by the outgrowth method and were immortalized by transfection with SV40 large T antigen and human telomerase (hTERT). Primary human PSC served as controls. An immortalized line, RLT-PSC, was analyzed for the expression of stellate cell markers. Moreover, the effects of transforming growth factor beta 1(TGFbeta1) or platelet-derived growth factor stimulation and of cultivation on basement membrane components or N-acetylcysteine (NAC) treatment on gene and protein expression and proliferation were analyzed. Immortal RLT-PSC cells retained the phenotype of activated PSC proven by the expression of alpha-smooth muscle actin (alphaSMA), vimentin, desmin and glial fibrillary acidic protein (GFAP). TGFbeta1 treatment upregulated the expression of alphaSMA, collagen type I (Col I), fibronectin and TGFbeta1. Incubation of RLT-PSC cells and primary human activated PSC on Matrigel plus NAC treatment resulted in a deactivated phenotype as evidenced by a decrease of alphaSMA, connective tissue growth factor and Col I expression and by a decreased proliferation of the cells. Moreover, this treatment restored the ability of the cells to store vitamin A in cytoplasmic vesicles. In conclusion, we have established an immortal pancreatic stellate cell line, without changing the characteristic phenotype. Importantly, we were able to demonstrate that besides soluble factors, the matrix surrounding PSC plays a pivotal role in the maintenance of the activation process of PSC. Cultivation of activated PSC on a reconstituted basement membrane plus treatment with NAC was able to deactivate the cells, thus pointing to the possibility of an antifibrosis therapy in chronic pancreatitis.}, }
@article {pmid16127296, year = {2005}, author = {Edlundh-Rose, E and Kupershmidt, I and Gustafsson, AC and Parasassi, T and Serafino, A and Bracci-Laudiero, L and Greco, G and Krasnowska, EK and Romano, MC and Lundeberg, T and Nilsson, P and Lundeberg, J}, title = {Gene expression analysis of human epidermal keratinocytes after N-acetyl L-cysteine treatment demonstrates cell cycle arrest and increased differentiation.}, journal = {Pathobiology : journal of immunopathology, molecular and cellular biology}, volume = {72}, number = {4}, pages = {203-212}, doi = {10.1159/000086790}, pmid = {16127296}, issn = {1015-2008}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Antioxidants/administration &amp; dosage/pharmacology ; Cell Cycle/*drug effects ; Cell Differentiation/*drug effects ; Cell Proliferation ; Cell Survival ; Cells, Cultured ; DNA, Complementary ; *Gene Expression ; Humans ; Keratinocytes/*drug effects/metabolism/ultrastructure ; Microscopy, Electron, Scanning ; Oligonucleotide Array Sequence Analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Skin/cytology ; Thymidine/metabolism ; Time Factors ; }, abstract = {OBJECTIVES: Several cancer prevention programmes have previously been executed using treatment of antioxidant compounds. The antioxidant N-acetyl L-cysteine (NAC), a membrane-permeable aminothiol, is a sulfhydryl reductant reducing oxidised glutathione, as well as being a precursor of intracellular cysteine and glutathione. A previous report based on the cellular response to NAC treatment showed that NAC induced a 10-fold more rapid differentiation in normal primary keratinocytes as well as a reversion of a colon carcinoma cell line from neoplastic proliferation to apical-basolateral differentiation. In order to investigate molecular events underlying the changes in proliferation and differentiation induced by NAC treatment, we performed global gene expression analysis of normal human epidermal keratinocytes in a time series.<br><br>METHODS: Treated samples were compared to untreated samples through a reference design using a spotted cDNA array comprising approximately 30,000 features. B statistics was used to identify differentially expressed genes, and RT-PCR of a selected set of genes was performed to verify differential expression.<br><br>RESULTS: The number of differentially expressed genes increased over time, starting with 0 at 30 min, 73 at 3 h and increasing to 952 genes at 48 h. Results of the expression analysis showed arrest of the cell cycle and an upregulation of cytoskeletal reorganisation, implicating increased differentiation. A comparison to gene ontology groups indicated downregulation of a large number of genes involved in cell proliferation and regulation of the cell cycle.<br><br>CONCLUSIONS: A significant fraction of the differentially expressed genes could be classified according to their role in the differentiation process, demonstrating that NAC regulates the conversion from proliferation to differentiation at a transcriptional level.}, }
@article {pmid16124875, year = {2005}, author = {Farid, M and Reid, MB and Li, YP and Gerken, E and Durham, WJ}, title = {Effects of dietary curcumin or N-acetylcysteine on NF-kappaB activity and contractile performance in ambulatory and unloaded murine soleus.}, journal = {Nutrition &amp; metabolism}, volume = {2}, number = {}, pages = {20}, pmid = {16124875}, issn = {1743-7075}, support = {R01 AR049022/AR/NIAMS NIH HHS/United States ; R01 HL059878/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Unloading of skeletal muscle causes atrophy and loss of contractile function. In part, this response is believed to be mediated by the transcription factor nuclear factor-kappa B (NF-kappaB). Both curcumin, a component of the spice turmeric, and N-acetylcysteine (NAC), an antioxidant, inhibit activation of NF-kappaB by inflammatory stimuli, albeit by different mechanisms. In the present study, we tested the hypothesis that dietary curcumin or NAC supplementation would inhibit unloading-induced NF-kappaB activity in skeletal muscle and thereby protect muscles against loss of mass and function caused by prolonged unloading.<br><br>METHODS: We used hindlimb suspension to unload the hindlimb muscles of adult mice. Animals had free access to drinking water or drinking water supplemented with 1% NAC and to standard laboratory diet or diet supplemented with 1% curcumin. For 11 days, half the animals in each dietary group were suspended by the tail (unloaded) and half were allowed to ambulate freely.<br><br>RESULTS: Unloading caused a 51-53% loss of soleus muscle weight and cross-sectional area relative to freely-ambulating controls. Unloading also decreased total force and force per cross-sectional area developed by soleus. Curcumin supplementation decreased NF-kappaB activity measured in peripheral tissues of ambulatory mice by gel shift analysis. In unloaded animals, curcumin supplementation did not inhibit NF-kappaB activity or blunt the loss of muscle mass in soleus. In contrast, NAC prevented the increase in NF-kappaB activity induced by unloading but did not prevent losses of muscle mass or function.<br><br>CONCLUSION: In conclusion, neither dietary curcumin nor dietary NAC prevents unloading-induced skeletal muscle dysfunction and atrophy, although dietary NAC does prevent unloading induced NF-kappaB activation.}, }
@article {pmid16120436, year = {2005}, author = {Penugonda, S and Mare, S and Goldstein, G and Banks, WA and Ercal, N}, title = {Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12.}, journal = {Brain research}, volume = {1056}, number = {2}, pages = {132-138}, doi = {10.1016/j.brainres.2005.07.032}, pmid = {16120436}, issn = {0006-8993}, support = {1 R15 ES012167/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Drug Interactions ; Glutamic Acid/*toxicity ; L-Lactate Dehydrogenase/metabolism ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; PC12 Cells/*drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Tetrazolium Salts ; }, abstract = {Oxidative stress plays an important role in neuronal cell death associated with many different neurodegenerative conditions such as cerebral ischemia and Parkinson's disease. Elevated levels of glutamate are thought to be responsible for CNS disorders through various mechanisms causing oxidative stress induced by a nonreceptor-mediated oxidative pathway which blocks cystine uptake and results in depletion of intracellular glutathione (GSH). The newly designed amide form of N-acetylcysteine (NAC), N-acetylcysteine amide (NACA), was assessed for its ability to protect PC12 cells against oxidative toxicity induced by glutamate. NACA was shown to protect PC12 cells from glutamate (Glu) toxicity, as evaluated by LDH and MTS assays. NACA prevented glutamate-induced intracellular GSH loss. In addition, NACA restored GSH synthesis in a Glu (10 mM) plus buthionine-sulfoximine (BSO) (0.2 mM)-treated group, indicating that the intracellular GSH increase is independent of gamma-GSC (gamma-glutamylcysteinyl synthetase). The increase in levels of reactive oxygen species (ROS) induced by glutamate was significantly decreased by NACA. Measurement of malondialdehyde (MDA) showed that NACA reduced glutamate-induced elevations in levels of lipid peroxidation by-products. These results demonstrate that NACA can protect PC12 cells against glutamate cytotoxicity by inhibiting lipid peroxidation, and scavenging ROS, thus preserving intracellular GSH.}, }
@article {pmid16120311, year = {2002}, author = {Pandolfo, M}, title = {Frataxin deficiency and mitochondrial dysfunction.}, journal = {Mitochondrion}, volume = {2}, number = {1-2}, pages = {87-93}, doi = {10.1016/s1567-7249(02)00039-9}, pmid = {16120311}, issn = {1567-7249}, abstract = {Friedreich ataxia (FA) is an inherited recessive disorder characterized by progressive neurological disability and heart abnormalities. The Friedreich ataxia gene (FRDA) encodes a small mitochondrial protein, frataxin, which is produced in insufficient amounts in the disease as a consequence of a GAA triplet repeat expansion in the first intron of the gene. Frataxin deficiency leads to excessive free radical production, dysfunction of Fe-S center containing enzymes (in particular respiratory complexes I, II and III, and aconitase), and progressive iron accumulation in mitochondria. Frataxin may be a mitochondrial iron-binding protein that prevents this metal from participating in Fenton chemistry to generate toxic hydroxyl radicals. We investigated whether frataxin deficiency may in addition interfere with signaling pathways. First, we showed that exposure of FA fibroblasts to iron fails to produce the normally observed increase in expression of the stress defense protein manganese superoxide dismutase. This impaired induction involves a nuclear factor-kappaB-independent pathway that does not require free radical signaling intermediates. We also examined the role of frataxin in neuronal differentiation by using stably transfected clones of P19 embryonic carcinoma cells with antisense or sense frataxin constructs. We found that during retinoic acid-induced neurogenesis frataxin deficiency enhances apoptosis and reduces the number of terminally differentiated neuronal-like cells. The addition of the antioxidant N-acetyl-cysteine only rescues cells non-committed to the neuronal lineage, indicating that frataxin deficiency impairs differentiation mechanisms and survival responses through different mechanisms. Both studies suggest that some abnormalities in frataxin-deficient cells are related to free radical independent signaling pathways.}, }
@article {pmid16117612, year = {2005}, author = {Hwang, ES and Jeffery, EH}, title = {Induction of quinone reductase by sulforaphane and sulforaphane N-acetylcysteine conjugate in murine hepatoma cells.}, journal = {Journal of medicinal food}, volume = {8}, number = {2}, pages = {198-203}, doi = {10.1089/jmf.2005.8.198}, pmid = {16117612}, issn = {1096-620X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anticarcinogenic Agents/*pharmacology ; Brassica/*chemistry ; Carcinoma, Hepatocellular/prevention &amp; control ; Dose-Response Relationship, Drug ; Enzyme Induction/drug effects ; Glucosinolates/metabolism ; Isothiocyanates/metabolism ; Liver Neoplasms/prevention &amp; control ; NAD(P)H Dehydrogenase (Quinone)/biosynthesis/*drug effects ; *Phytotherapy ; Sulfoxides ; Thiocyanates/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {Broccoli belongs to a group of vegetables termed cruciferous vegetables and characterized by their glucosinolate content. These glucosinolates are secondary metabolites that, upon hydrolysis, release bioactive isothiocyanates (ITCs). Bioactive ITCs are considered to protect the body from cancer by inducing detoxification enzymes such as quinone reductase (QR). This has the potential to make dietary choice a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity from xenobiotic electrophiles and reactive forms of oxygen. The bioactive ITC sulforaphane (SF) is the hydrolysis product of glucoraphanin, the predominant aliphatic glucosinolate in broccoli. Because SF appears more potent than many other ITCs in induction of detoxification enzymes, it may have potential as a dietary cancer-preventative agent. One potential concern is that SF is highly reactive and has a very short half-life in the body, forming a glutathione conjugate that is further metabolized to the N-acetyl-L-cysteine conjugate (SF-NAC), the major excretory product found in the urine. However, the conjugate is a reversible complex, able to release free SF. The objective of this study was to compare QR-inducing activity by SF and its major metabolite SF-NAC, in murine hepatoma cells. Both SF and SF-NAC caused dose-related cell growth inhibition and QR induction. SF, 1 and 2 microM, resulted in a 3.0- and 3.5-fold induction of QR, respectively, and the same concentrations of SF-NAC caused a similar, although somewhat greater, induction of QR, 3.8- and 4.5-fold, respectively. These results strengthen the basis for considering that an effective therapeutic form of SF may be the ITC conjugate, formed in situ or given in place of purified ITC as prophylactic treatment to individuals at high risk for cancer.}, }
@article {pmid16114064, year = {2006}, author = {Tam, NN and Nyska, A and Maronpot, RR and Kissling, G and Lomnitski, L and Suttie, A and Bakshi, S and Bergman, M and Grossman, S and Ho, SM}, title = {Differential attenuation of oxidative/nitrosative injuries in early prostatic neoplastic lesions in TRAMP mice by dietary antioxidants.}, journal = {The Prostate}, volume = {66}, number = {1}, pages = {57-69}, doi = {10.1002/pros.20313}, pmid = {16114064}, issn = {0270-4137}, support = {CA15776/CA/NCI NIH HHS/United States ; CA62269/CA/NCI NIH HHS/United States ; DK61084/DK/NIDDK NIH HHS/United States ; }, mesh = {Adenocarcinoma/pathology/*prevention &amp; control ; Administration, Oral ; Animals ; Anticarcinogenic Agents/administration &amp; dosage/*therapeutic use ; Antioxidants/administration &amp; dosage/*therapeutic use ; Diet ; Male ; Mice ; Mice, Transgenic ; Oxygen Consumption ; Phytotherapy ; Plant Extracts/therapeutic use ; Prostatic Neoplasms/pathology/*prevention &amp; control ; Spinacia oleracea ; }, abstract = {BACKGROUND: Dietary antioxidants with yet unproven efficacies in averting prostate cancer (PCa) are widely used in the United States as preventives. Experimental evidence establishing a causal relationship between oxidative and nitrosative stress (OS/NS) and PCa development and showing its modulation by dietary antioxidants would help justify their usage.<br><br>METHODS: The TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) mouse model was used to demonstrate the OS/NS-associated damage, as evident by 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE)-protein-adducts and nitrotyrosine (Ntyr), in prostatic premalignant lesions, and to evaluate the antioxidant efficacy of various dietary supplements [natural antioxidant (NAO) from spinach extracts, (-) epigallocatechin-3-gallate (EGCG), or N-acetylcystein (NAC)] during the early PCa development.<br><br>RESULT: We show, for the first time, that oxidative/nitrosative damages of genomic DNA and cellular proteins were discretely localized in premalignant lesions, but not in adjacent morphologically normal epithelia, of TRAMP prostates; these injuries were absent in age-matched nontransgenic littermates. The extent of OS/NS-related injuries correlated well with the tempo of development and prevalence of premalignant lesions in various prostatic lobes and exhibited a clear trend of increase from 12 to 20 weeks of age. Treatment of TRAMP mice with various antioxidants as dietary supplements resulted in differential alleviation of OS/NS-related prostatic injuries. The antioxidant potencies of the dietary supplements did not fully correlate with their documented antiPCa actions, suggest that they may exert additional "nonantioxidant," antitumor effects in this model.<br><br>CONCLUSIONS: Our data indicate that in TRAMP mice, OS/NS injuries are likely involved in early prostatic tumorigenesis and can be modulated by various antioxidants.}, }
@article {pmid16111802, year = {2006}, author = {Pook, SH and Toh, CK and Mahendran, R}, title = {Combination of thiol antioxidant Silibinin with Brostallicin is associated with increase in the anti-apoptotic protein Bcl-2 and decrease in caspase 3 activity.}, journal = {Cancer letters}, volume = {238}, number = {1}, pages = {146-152}, doi = {10.1016/j.canlet.2005.07.002}, pmid = {16111802}, issn = {0304-3835}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Carcinoma, Hepatocellular/*drug therapy/metabolism ; Caspase 3 ; Caspases/*metabolism ; Cell Line, Tumor ; Down-Regulation/drug effects ; Drug Antagonism ; Drug Screening Assays, Antitumor ; Enzyme Activation/drug effects ; Guanidines/antagonists &amp; inhibitors/*pharmacology ; Humans ; Nasopharyngeal Neoplasms/*drug therapy/metabolism ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Pyrroles/antagonists &amp; inhibitors/*pharmacology ; Signal Transduction/*drug effects ; Silybin ; Silymarin/pharmacology ; Sulfhydryl Compounds/*pharmacology ; Up-Regulation/drug effects ; }, abstract = {The cytotoxic activity of Brostallicin was previously shown to be enhanced in the presence of high glutathione and glutathione transferase levels. We hypothesized that thiol antioxidants, N-acetylcysteine and Silibinin, could potentiate Brostallicin's cytotoxicity in a similar way. HepG2 and CNE-2 cells were treated with N-acetylcysteine, Silibinin and Brostallicin, either alone or in combination. Surprisingly, we found that NAC and Silibinin had adverse effects on Brostallicin's cytotoxicity. The mechanism underlying the interaction involved the apoptotic pathway as we demonstrated an increase in Bcl-2 protein levels and decrease in caspase 3 activity with the Silibinin-Brostallicin combination.}, }
@article {pmid16110502, year = {2005}, author = {Messer, RL and Lockwood, PE and Tseng, WY and Edwards, K and Shaw, M and Caughman, GB and Lewis, JB and Wataha, JC}, title = {Mercury (II) alters mitochondrial activity of monocytes at sublethal doses via oxidative stress mechanisms.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {75}, number = {2}, pages = {257-263}, doi = {10.1002/jbm.b.30263}, pmid = {16110502}, issn = {1552-4973}, mesh = {Biocompatible Materials ; Cell Line ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Humans ; Mercury/*pharmacology ; Mitochondria/*drug effects/physiology ; Monocytes/*drug effects/physiology ; Oxidative Stress/*drug effects/physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {The perennial controversy about the safety of mercury in dental amalgams has adversely affected the availability and the quality of dental care. Chronic Hg(II) blood concentrations above 300 nM are known to alter function of the nervous system and the kidney. However, the effects of blood concentrations of 10 to 75 nM, far more common in the general population, are not clear and mechanisms of any effects are not known. The monocyte is an important potential target of Hg(II) because of its critical role in directing inflammatory and immune responses. In the current study we tested the hypothesis that concentrations of Hg(II) of 10 to 300 nM alter monocyte activity via a redox-dependent mechanism. Mitochondrial activity was used to establish inhibitory concentrations of Hg(II) following 6 to 72 h of exposures to THP1 human monocytic cells. Then subinhibitory concentrations were applied, and total glutathione levels and reactive oxygen species (ROS) were measured. Antioxidants [N-acetyl cysteine, (NAC); Na2SeO3, (Se)] and a pro-oxidant (tert-butylhydroquinone, tBHQ) were used to support the hypothesis that Hg(II) effects were redox-mediated. After 72 h of exposure, 20 microM of Hg(II) inhibited monocytic mitochondrial activity by 50%. NAC mitigated Hg(II)-induced mitochondrial suppression only at concentrations of greater than 10 microM, but Se had few effects on Hg-induced mitochondrial responses. tBHQ significantly enhanced mitochondrial suppression at higher Hg(II) concentrations. Hg(II) concentrations of 75 and 300 nM (0.075 and 0.30 microM, respectively) significantly increased total glutathione levels, and NAC mitigated these increases. Se plus Hg(II) significantly elevated Hg-induced total cellular glutathione levels. Increased ROS levels were not detected in monocytes exposed to mercury. Hg(II) acts in monocytic cells, at least in part, through redox-mediated mechanisms at concentrations below those commonly associated with chronic mercury toxicity, but commonly occurring in the blood of some dental patients.}, }
@article {pmid16109412, year = {2005}, author = {Han, YH and Kim, HS and Kim, JM and Kim, SK and Yu, DY and Moon, EY}, title = {Inhibitory role of peroxiredoxin II (Prx II) on cellular senescence.}, journal = {FEBS letters}, volume = {579}, number = {21}, pages = {4897-4902}, doi = {10.1016/j.febslet.2005.07.049}, pmid = {16109412}, issn = {0014-5793}, mesh = {Acetylcysteine/metabolism ; Aging/physiology ; Animals ; Cell Cycle/physiology ; Cells, Cultured ; *Cellular Senescence ; Fibroblasts/cytology/metabolism ; Hydrogen Peroxide/metabolism ; Mice ; Mice, Knockout ; Oxidants/metabolism ; Peroxidases/genetics/*metabolism ; Peroxiredoxins ; Reactive Oxygen Species/metabolism ; }, abstract = {Reactive oxygen species (ROS) were generated in all oxygen-utilizing organisms. Peroxiredoxin II (Prx II) as one of antioxidant enzymes may play a protective role against the oxidative damage caused by ROS. In order to define the role of Prx II in organismal aging, we evaluated cellular senescence in Prx II(-/-) mouse embryonic fibroblast (MEF). As compared to wild type MEF, cellular senescence was accelerated in Prx II(-/-) MEF. Senescence-associated (SA)-beta-galactosidase (Gal)-positive cell formation was about 30% higher in Prx II(-/-) MEF. N-Acetyl-l-cysteine (NAC) treatment attenuated SA-beta-Gal-positive cell formation. Prx II(-/-) MEF exhibited the higher G2/M (41%) and lower S (1.6%) phase cells as compared to 24% and 7.3% [corrected] in wild type MEF, respectively. A high increase in the p16 and a slight increase in the p21 and p53 levels were detected in PrxII(-/-) MEF cells. The cellular senescence of Prx II(-/-) MEF was correlated with the organismal aging of Prx II(-/-) mouse skin. While extracellular signal-regulated kinase (ERK) and p38 activation was detected in Prx II(-/-) MEF, ERK and c-Jun N-terminal kinase (JNK) activation was detected in Prx II(-/-) skin. These results suggest that Prx II may function as an enzymatic antioxidant to prevent cellular senescence and skin aging.}, }
@article {pmid16109326, year = {2005}, author = {Schneider, MP and Delles, C and Schmidt, BM and Oehmer, S and Schwarz, TK and Schmieder, RE and John, S}, title = {Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension.}, journal = {American journal of hypertension}, volume = {18}, number = {8}, pages = {1111-1117}, doi = {10.1016/j.amjhyper.2005.02.006}, pmid = {16109326}, issn = {0895-7061}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Ascorbic Acid/administration &amp; dosage/*therapeutic use ; Blood Flow Velocity/drug effects ; Endothelium, Vascular/physiology ; Female ; Forearm/blood supply ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Hypertension/*drug therapy/physiopathology ; Infusions, Intra-Arterial ; Male ; Middle Aged ; Nitroprusside/pharmacology ; Superoxides/antagonists &amp; inhibitors ; Vasodilation/drug effects ; Vasodilator Agents/pharmacology ; }, abstract = {BACKGROUND: It is not known whether the beneficial effects of N-acetylcysteine (NAC) in conditions associated with increased oxidative stress are caused by direct superoxide scavenging. We therefore compared the acute superoxide scavenging efficacy of NAC against vitamin C (VITC) on impaired endothelium-dependent vasodilation in subjects with essential hypertension.<br><br>METHODS: In a cross-over randomized study, the effects of intra-arterial administration of either NAC (48 mg/min) or VITC (18 mg/min) were examined in 15 subjects with essential hypertension and in 15 normotensive control subjects. Both endothelium-dependent and endothelium-independent vasodilation were determined as forearm blood flow (FBF) response to the intra-arterial administration of acetylcholine (Ach) and sodium nitroprusside (NP) in doses of 12 and 48 mug/min and 3.2 and 12.8 mug/min, respectively.<br><br>RESULTS: Subjects with essential hypertension had impaired responses to both doses of Ach (Delta% FBF to higher dose of Ach: 325 +/- 146 in subjects with essential hypertension v 540 +/- 199 in control subjects; P = .02) and an impaired response to the higher dose of NP (330 +/- 108 v 500 +/- 199; P = .03). The intra-arterial administration of NAC had no effect on these responses (higher dose of Ach: 325 +/- 146 without v 338 +/- 112 with NAC, NS). In contrast, intra-arterial VITC improved both the response to Ach (320 +/- 132 without v 400 +/- 185 with VITC, P = .05) and to NP (383 +/- 162 v 447 +/- 170, P = .05).<br><br>CONCLUSIONS: We found that NAC showed no statistically significant effect on either endothelium-dependent or endothelium-independent vasodilation in hypertensive subjects, whereas VITC did. We conclude that NAC is therefore not an effective superoxide scavenger in vivo. Other, nonimmediate effects such as the generation of glutathione may explain the beneficial effects of NAC in conditions associated with oxidative stress.}, }
@article {pmid16109311, year = {2005}, author = {Jana, M and Pahan, K}, title = {Redox regulation of cytokine-mediated inhibition of myelin gene expression in human primary oligodendrocytes.}, journal = {Free radical biology &amp; medicine}, volume = {39}, number = {6}, pages = {823-831}, pmid = {16109311}, issn = {0891-5849}, support = {RG3422AI/1/RG/CSR NIH HHS/United States ; P20RR18759/RR/NCRR NIH HHS/United States ; R01 NS039940/NS/NINDS NIH HHS/United States ; NS39940/NS/NINDS NIH HHS/United States ; P20 RR018759/RR/NCRR NIH HHS/United States ; R01 NS039940-05A1/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Animals ; Antioxidants/chemistry ; Cells, Cultured ; Cytokines/*metabolism ; DNA Primers/chemistry ; Dose-Response Relationship, Drug ; Down-Regulation ; Encephalomyelitis, Autoimmune, Experimental/chemically induced ; Female ; *Gene Expression Regulation ; Humans ; Hydrogen Peroxide/pharmacology ; Inflammation ; Interleukin-1/metabolism ; Mice ; Multiple Sclerosis/*metabolism ; Myelin Basic Protein/metabolism ; Myelin Proteins ; Myelin Proteolipid Protein/chemistry ; Myelin Sheath/chemistry/*metabolism ; Myelin-Associated Glycoprotein/chemistry ; Myelin-Oligodendrocyte Glycoprotein ; Neuroglia/metabolism ; Oligodendroglia/*metabolism ; Oxidants/chemistry ; *Oxidation-Reduction ; Phosphoric Diester Hydrolases/chemistry ; Proline/analogs &amp; derivatives/chemistry ; Pyrrolidines/chemistry ; Reactive Oxygen Species ; Reverse Transcriptase Polymerase Chain Reaction ; Sulfhydryl Compounds ; Thiocarbamates/chemistry ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system (CNS) of unknown etiology. Several studies have shown that demyelination in MS is caused by proinflammatory mediators which are released by perivascular infiltrates and/or activated glial cells. To understand if proinflammatory mediators such as IL (interleukin)-1beta and TNF (tumor necrosis factor)-alpha are capable of modulating the expression of myelin-specific genes, we investigated the effect of these cytokines on the expression of myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) in human primary oligodendrocytes. Interestingly, both IL-1beta and TNF-alpha markedly inhibited the expression of MOG, CNPase, and PLP but not MBP, the effect that was blocked by antioxidants such as N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). Consistently, oxidants and prooxidants like H(2)O(2) and diamide also markedly inhibited the expression of MOG, CNPase, and PLP. Furthermore, both IL-1beta and TNF-alpha induced the production of H(2)O(2). Taken together, these studies suggest that proinflammatory cytokines inhibit the expression of myelin genes in human primary oligodendrocytes through the alteration of cellular redox.}, }
@article {pmid16102883, year = {2005}, author = {Ogita, A and Hirooka, K and Yamamoto, Y and Tsutsui, N and Fujita, K and Taniguchi, M and Tanaka, T}, title = {Synergistic fungicidal activity of Cu(2+) and allicin, an allyl sulfur compound from garlic, and its relation to the role of alkyl hydroperoxide reductase 1 as a cell surface defense in Saccharomyces cerevisiae.}, journal = {Toxicology}, volume = {215}, number = {3}, pages = {205-213}, doi = {10.1016/j.tox.2005.07.006}, pmid = {16102883}, issn = {0300-483X}, mesh = {Anti-Infective Agents/*pharmacology ; Antifungal Agents/*pharmacology ; Cell Survival/drug effects ; Cell Wall/*drug effects/enzymology ; Copper/*pharmacology ; Detergents/pharmacology ; Disulfides ; Dose-Response Relationship, Drug ; Drug Synergism ; Peroxidases/*metabolism ; Peroxiredoxins ; Reactive Oxygen Species ; Saccharomyces cerevisiae/*drug effects ; Sarcosine/analogs &amp; derivatives/pharmacology ; Sulfinic Acids/*pharmacology ; }, abstract = {Cu(2+) showed a dose-dependent fungicidal activity against Saccharomyces cerevisiae cells, and its lethal effect was extremely enhanced in the presence of allicin, an allyl sulfur compound from garlic. The fungicidal activity of Cu(2+) was unaffected or rather attenuated by other sulfur-containing compounds such as N-acetyl-cysteine, l-cysteine or dithiothreitol. Ca(2+) could absolutely protect against the lethal effect of Cu(2+) itself, but showed no protection against the fungicidal activity of Cu(2+) newly generated in combination with allicin. Cu(2+) accelerated an endogenous generation of reactive oxygen species (ROS) in S. cerevisiae cells at a lethal concentration, but such intracellular oxidative stress induction was not observed during cell death progression upon treatment with Cu(2+) and allicin. A surfactant, sodium N-lauroyl sarcosinate (SLS), enhanced the solubilization of a few proteins including alkyl hydroperoxide reductase 1 (AHP1) in intact cells, accounting for the absence of this protein in the extract from allicin-treated cells. Allicin-treated cells were rendered extremely sensitive to the subsequent Cu(2+) treatment as in the case of SLS-treated cells. Allicin-treated cells and SLS-treated cells similarly showed an increased sensitivity to exogenously added tert-butyl hydroperoxide (t-BOOH), an organic peroxide that is detoxified by the action of AHP1. Our study suggests that allicin influences the mode of cell surface localization or the related function of AHP1 as a defense against phospholipid peroxidation by the external action of Cu(2+).}, }
@article {pmid16101137, year = {2005}, author = {Okada, N and Hirata, A and Murakami, Y and Shoji, M and Sakagami, H and Fujisawa, S}, title = {Induction of cytotoxicity and apoptosis and inhibition of cyclooxygenase-2 gene expression by eugenol-related compounds.}, journal = {Anticancer research}, volume = {25}, number = {5}, pages = {3263-3269}, pmid = {16101137}, issn = {0250-7005}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/*pharmacology ; DNA Fragmentation ; Enzyme Induction/drug effects ; Eugenol/*analogs &amp; derivatives/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; HL-60 Cells ; Humans ; Macrophages/cytology/drug effects/enzymology ; Membrane Proteins ; Mice ; Nucleosomes/drug effects ; Prostaglandin-Endoperoxide Synthases/*biosynthesis/genetics ; RNA, Messenger/biosynthesis/genetics ; Superoxide Dismutase/biosynthesis/genetics ; }, abstract = {Induction of cytotoxicity and internucleosomal DNA fragmentation by 4-allyl-2-methoxyphenol (eugenol, EUG), 2-methoxy-4-methylphenol (MMP), 3,3'-dimethoxy-5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol (bis-EUG) and 3,3'-di-methoxy-5,5'-dimethyl-1,1'-biphenyl-2,2'-diol (bis-MMP) were investigated in HL-60 leukemia cells. The 50% cytotoxic concentrations (CC50) for EUG, MMP, bis-EUG and bis-MMP were 0.38 mM, 0.38 mM, 0.18 mM and 0.20 mM, respectively. DNA fragmentation was induced most strongly by bis-EUG, followed by EUG, MMP and bis-MMP. The expression of MnSOD and, less strongly, Cu/ZnSOD activity, as assessed by acrylamide gel electrophoresis, was inhibited by EUG, suggesting mitochondrial dysfunction. The expression of the mRNAs for MnSOD and Cu/ZnSOD in HL-60 cells, as assessed by RT-PCR, was significantly inhibited by treatment with 1 mM EUG for 1 hour. Furthermore, inhibition of SOD mRNAs expression by EUG was strongly potentiated by the addition of 5 mM N-acetyl cysteine (NAC) or glutathione (GSH), whereas NAC or GSH alone did not affect the expression of SOD mRNAs. The cytotoxicity of EUG was significantly enhanced by high concentrations of NAC or GSH, which may be attributed to the inhibition of SOD mRNAs expression by the synergistic action of EUG and GSH or NAC. The regulatory effects of eugenol-related compounds on lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2) gene expression in RAW 264.7 cells were investigated by Northern blot analysis. Bis-EUG, MMP and bis-MMP inhibited COX-2 gene expression at concentrations of 300 microM, 500 microM and 500 microM, respectively. In contrast, no inhibitory effect of EUG was found over the wide concentration range of 10-500 microM, possibly as a result of the extensive mitochondrial dysfunction induced by this compound, which possesses potent pro-oxidative activity. Eugenol-related compounds, particularly bis-EUG, may act as nonsteroidal anti-inflammatory drug (NSAID)-like compounds.}, }
@article {pmid16099896, year = {2005}, author = {Morrison, JP and Coleman, MC and Aunan, ES and Walsh, SA and Spitz, DR and Kregel, KC}, title = {Thiol supplementation in aged animals alters antioxidant enzyme activity after heat stress.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {99}, number = {6}, pages = {2271-2277}, doi = {10.1152/japplphysiol.00412.2005}, pmid = {16099896}, issn = {8750-7587}, support = {01-CA-100045/CA/NCI NIH HHS/United States ; P01-CA66081/CA/NCI NIH HHS/United States ; R01-AG-12350/AG/NIA NIH HHS/United States ; R01-HL51469/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Aging/drug effects/*metabolism ; Animals ; Antioxidants/*metabolism ; Enzyme Activation/drug effects ; Heat Stress Disorders/*enzymology/*prevention &amp; control ; Heat-Shock Response/*drug effects ; Injections, Intraperitoneal ; Male ; Oxidoreductases/*metabolism ; Rats ; Rats, Inbred F344 ; Sulfhydryl Compounds/administration &amp; dosage ; }, abstract = {Declines in oxidative and thermal stress tolerance are well documented in aging systems. It is thought that these alterations are due in part to reductions in antioxidant defenses. Although intracellular thiols are major redox buffers, their role in maintaining redox homeostasis is not completely understood, particularly during aging, where the reliance on antioxidant enzymes and proteins may be altered. To determine whether thiol supplementation improved the antioxidant enzyme profile of aged animals after heat stress, young and old Fischer 344 rats were treated with N-acetylcysteine (NAC; 4 mmol/kg ip) 2 h before heat stress. Liver tissue was collected before and 0, 30, and 60 min after heat stress. Aging was associated with a significant decline in tissue cysteine and glutathione (GSH) levels. There was also an age-related decrease in copper-zinc superoxide dismutase activity. Heat stress did not alter liver GSH, glutathione disulfide, or antioxidant enzyme activity. With NAC treatment, old animals took up more cysteine than young animals as reflected in an increase in liver GSH and a corresponding decrease in glutamate cysteine ligase activity. Catalase activity increased after NAC treatment in both age groups. Copper-zinc superoxide dismutase activity did not change with heat stress or drug treatment, whereas manganese superoxide dismutase activity was increased in old animals only. These data indicate that GSH synthesis is substrate limited in old animals. Furthermore, aged animals were characterized by large fluctuations in antioxidant enzyme balance after NAC treatment, suggesting a lack of fine control over these enzymes that may leave aged animals susceptible to subsequent stress.}, }
@article {pmid16098720, year = {2005}, author = {Kim, KA and Lim, YS and Kim, KM and Yoon, JH and Lee, HS}, title = {15d-Deoxy-Delta12,14-prostaglandin J2 modulates collagen type I synthesis in human hepatic stellate cells by inducing oxidative stress.}, journal = {Prostaglandins, leukotrienes, and essential fatty acids}, volume = {73}, number = {5}, pages = {361-367}, doi = {10.1016/j.plefa.2005.06.003}, pmid = {16098720}, issn = {0952-3278}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Collagen Type I/*biosynthesis ; Dose-Response Relationship, Drug ; Humans ; Liver/*cytology/drug effects/metabolism ; Oxidative Stress/drug effects/*physiology ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology ; }, abstract = {15 deoxy-Delta(12,14)-prostaglandin(2) (15d-PGJ(2)) is known to inhibit the proliferation of hepatic stellate cells (HSCs), major cellular components that cause hepatic fibrosis, in vitro. It also induces oxidative stress, which results in hepatic myofibroblast death. On the other hand, oxidative stress generally induces HSC proliferation and collagen synthesis in vitro, and liver fibrogenesis in vivo. In this study, we evaluated the effects of 15d-PGJ(2) at various concentrations on the viability and collagen synthesis of HSCs. 15d-PGJ(2) increased intracellular reactive oxygen species (ROS), and reduced the viability of human HSCs at concentrations 5 microM by inducing apoptotic cell death. In addition, the antioxidants alpha-tocopherol and N-acetylcysteine (NAC) blocked 15d-PGJ(2)-induced HSC death. Collagen I synthesis was increased 1.5-fold by 0.5 microM 15d-PGJ(2) treatment, but was reduced to 30% of the control level by 10 microM 15d-PGJ(2), and NAC pretreatment prevented these changes in collagen production by 15d-PGJ(2). We conclude that 15d-PGJ(2) may either induce or prevent hepatic fibrogenesis depending on its concentration.}, }
@article {pmid16092976, year = {2005}, author = {Li, X and Meng, Y and Yang, XS and Wu, PS and Zhang, ZS}, title = {[Aldosterone stimulating PDGF-B expression in HSC via activation of EGR-1].}, journal = {Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology}, volume = {13}, number = {8}, pages = {567-570}, pmid = {16092976}, issn = {1007-3418}, mesh = {Aldosterone/*pharmacology ; Cell Line ; Early Growth Response Protein 1/*biosynthesis/genetics ; Hepatocytes/cytology/*metabolism ; Humans ; Mitogen-Activated Protein Kinase 3/biosynthesis/genetics ; Proto-Oncogene Proteins c-sis/*biosynthesis/genetics ; *Signal Transduction ; }, abstract = {OBJECTIVE: It is known that intrahepatic renin-angiotensin-aldosterone system (RAAS) plays a key role in liver fibrogenesis. Aldosterone (Aldo), the principal effector molecule of the RAAS, exerts local effects on cell growth and fibrogenesis. However, the signal transduction mechanisms underlying the effects of Aldo on hepatic fibrogenesis remain to be fully elucidated. The present study aims to investigate the signal transduction mechanism underlying the effects of Aldo on extracellular signal-regulated kinase 1/2 (ERK1/2), early growth response-1 (EGR-1) and on the platelet-derived growth factor-B (PDGF-B).<br><br>METHODS: In vitro, hepatic stellate cell (HSC)-T6 cell line was treated with Aldo for 10 min, 0.5 h, 1 h, 2 h and 3 h. Protein expression of phospho-p42/44 was detected by Western blot. In addition, HSC-T6 were preincubated for 1 h or not at all with U0126 (an inhibitor of the MAPK/ERK kinase), and antioxidant-N-acetylcysteine (NAC) prior to exposure to Aldo for the indicated times. Protein expressions of phospho-p42/44 and PDGF-B were measured by Western blot. DNA biding activity of EGR-1 was analyzed by electrophoretic gel mobility shift assay (EMSA). By means of immunohistochemistry, expression of PDGF-B was detected.<br><br>RESULTS: Aldo induced phospho-p42/44 expression could be abrogated by U0126; NAC did not inhibit phospho-p42/44 expression. Gel shift study showed that stimulation of HSC by Aldo markedly increased the EGR-1 DNA binding activity, which was abrogated by U0126, reaching a maximum at 60 minutes, and then declined progressively. NAC did not reduce the EGR-1 activity. Aldo increased the PDGF-B protein level in HSC, which was not attenuated by NAC and U0126.<br><br>CONCLUSIONS: Stimulation of HSC by Aldo results in activation of EGR-1 via ERK1/2 pathway, leading to up-regulation of PDGF-B expression.}, }
@article {pmid16088932, year = {2005}, author = {Kim, KS and Hwang, HA and Chae, SK and Ha, H and Kwon, KS}, title = {Upregulation of Daxx mediates apoptosis in response to oxidative stress.}, journal = {Journal of cellular biochemistry}, volume = {96}, number = {2}, pages = {330-338}, doi = {10.1002/jcb.20545}, pmid = {16088932}, issn = {0730-2312}, mesh = {Adaptor Proteins, Signal Transducing ; *Apoptosis/drug effects ; Carrier Proteins/genetics/*metabolism ; Cell Line ; Co-Repressor Proteins ; Humans ; Hydrogen Peroxide/pharmacology ; Intracellular Signaling Peptides and Proteins/genetics/*metabolism ; Molecular Chaperones ; Nuclear Proteins/genetics/*metabolism ; Oxidation-Reduction/drug effects ; *Oxidative Stress ; RNA, Messenger/genetics ; Reactive Oxygen Species/metabolism ; *Up-Regulation/drug effects ; }, abstract = {Oxidative stress induces apoptosis in a variety of cell types by as yet unclear signaling mechanisms. The Daxx protein is reportedly involved in apoptosis through its interactions with Fas, transforming growth factor-beta receptor, and promyelocytic leukemia protein (PML). Here, we explored the possible roles of Daxx in oxidative stress-induced apoptosis. We found that both the mRNA and protein levels of Daxx markedly increased when cells underwent apoptosis after H2O2 treatment. Pretreatment with the cell-permeable antioxidant, N-acetyl cysteine, prevented cells from H2O2-induced Daxx upregulation and subsequent apoptosis, indicating that the endogenous oxidant regulated Daxx expression. Furthermore, suppression of endogenous Daxx expression by antisense oligonucleotide technology inhibited oxidative stress-induced apoptosis in HeLa cells. Taken together, these results suggest that Daxx acts as an intermediary messenger of pro-apoptotic signals triggered by oxidative stress.}, }
@article {pmid16088183, year = {2005}, author = {Mumcu, S and Alhan, E and Türkyilmaz, S and Kural, BV and Erçin, C and Kalyoncu, NI}, title = {Effects of N-acetylcysteine on acute necrotizing pancreatitis in rats.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {37}, number = {3}, pages = {173-178}, doi = {10.1159/000085965}, pmid = {16088183}, issn = {0014-312X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bronchoalveolar Lavage Fluid/chemistry ; Detergents ; Glycodeoxycholic Acid ; Lung/metabolism ; Male ; Necrosis ; Pancreas/drug effects/metabolism/pathology ; Pancreatitis, Acute Necrotizing/chemically induced/*metabolism/mortality/*pathology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The aim of this study was to investigate the influence of N-acetylcysteine (NAC) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. The induction of ANP resulted in significant increase in mortality rate, pancreatic necrosis and serum activity of amylase, alanine aspartate transferase (ALT), interleukin-6 (IL-6), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, serum concentration of urea, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in the pancreas and lung, and significant decrease of concentrations of calcium, blood pressure, urine output and pO(2). The use of NAC inhibited the changes in urine output, pO(2), tissue activity of MPO and MDA in pancreas and lungs, and the serum activity of IL-6, ALT, and serum concentrations of urea and calcium. NAC reduced the mortality and pancreatic damage. The use of NAC has a beneficial effect on the course of ANP in rats. It may be used in the treatment of acute pancreatitis.}, }
@article {pmid16086031, year = {2005}, author = {Park, SJ and Kim, IS}, title = {The role of p38 MAPK activation in auranofin-induced apoptosis of human promyelocytic leukaemia HL-60 cells.}, journal = {British journal of pharmacology}, volume = {146}, number = {4}, pages = {506-513}, pmid = {16086031}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Antirheumatic Agents/*pharmacology ; Apoptosis/*drug effects ; Auranofin/*pharmacology ; Caspases/metabolism ; Cell Survival/drug effects ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; HL-60 Cells/drug effects/enzymology ; Humans ; Imidazoles/pharmacology ; MAP Kinase Signaling System/*drug effects ; Mitochondria/drug effects/enzymology ; Phosphorylation/drug effects ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Time Factors ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; }, abstract = {In a previous study, we reported an antileukaemic activity of auranofin (AF), demonstrating its dual effects: on the induction of apoptotic cell death and its synergistic action with retinoic acid on cell differentiation. In this study, we investigated the downstream signalling events of AF-induced apoptosis to determine the molecular mechanisms of AF activity. Treatment of HL-60 cells with AF induced apoptosis in a concentration- and time-dependent manner. Western blot analysis showed that AF-induced apoptosis was accompanied by the activation of caspase-8, caspase-9, and caspase-3, and the release of cytochrome c from the mitochondria. The phosphorylation and kinase activities of p38 mitogen-activated protein kinase (p38 MAPK) increased gradually until 12 h after AF (2 microM) treatment, and p38 MAPK was also activated concentration-dependently. Pretreatment with SB203580, a specific inhibitor of p38 MAPK, significantly blocked DNA fragmentation and the cleavage of procaspase-8, procaspase-3, and poly-ADP-ribose polymerase (PARP), whereas SB203580 alone had no effect. Reactive oxygen species (ROS) were also detected within 1 h after AF treatment, and the antioxidant N-acetyl-L-cysteine (NAC) effectively protected the cells from apoptosis by inhibiting the phosphorylation of p38 MAPK and the activation of caspases. These results suggest that ROS generation and the subsequent activation of p38 MAPK are essential for the proapoptotic effects of AF in human promyelocytic leukaemia HL-60 cells.}, }
@article {pmid16085180, year = {2005}, author = {Ronis, MJ and Butura, A and Sampey, BP and Shankar, K and Prior, RL and Korourian, S and Albano, E and Ingelman-Sundberg, M and Petersen, DR and Badger, TM}, title = {Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition.}, journal = {Free radical biology &amp; medicine}, volume = {39}, number = {5}, pages = {619-630}, pmid = {16085180}, issn = {0891-5849}, support = {R01 AA009300/AA/NIAAA NIH HHS/United States ; R21 AA012031-02/AA/NIAAA NIH HHS/United States ; R01 AA09300/AA/NIAAA NIH HHS/United States ; R01 AA009300-10/AA/NIAAA NIH HHS/United States ; R01 AA008645-11/AA/NIAAA NIH HHS/United States ; R01 AA008645/AA/NIAAA NIH HHS/United States ; R21 AA12931/AA/NIAAA NIH HHS/United States ; R01 AA08645/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aldehydes/metabolism ; Animals ; Antioxidants/metabolism ; Cattle ; Central Nervous System Depressants/pharmacology ; Cytochrome P-450 CYP2E1/metabolism ; Cytokines/metabolism ; Cytosol/metabolism ; Enteral Nutrition ; Ethanol/metabolism/*pharmacology/urine ; Glutathione/metabolism ; Immune System ; Immunohistochemistry ; Inflammation ; Kupffer Cells/metabolism ; Lipid Peroxidation ; Lipopolysaccharide Receptors/biosynthesis ; Lipopolysaccharides/metabolism ; Liver/*drug effects/metabolism/pathology ; Lymphotoxin-alpha/metabolism ; Male ; Malondialdehyde/metabolism ; Necrosis ; Oxidants/metabolism ; Oxidative Stress ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {The effects of the dietary antioxidant N-acetylcysteine (NAC) on alcoholic liver damage were examined in a total enteral nutrition (TEN) model of ethanol toxicity in which liver pathology occurs in the absence of endotoxemia. Ethanol treatment resulted in steatosis, inflammatory infiltrates, occasional foci of necrosis, and elevated ALT in the absence of increased expression of the endotoxin receptor CD 14, a marker of Kupffer cell activation by LPS. In addition, ethanol treatment induced CYP 2 E1 and increased TNFalpha and TGFbeta mRNA expression accompanied by suppressed hepatic IL-4 mRNA expression. Ethanol treatment also resulted in the hepatic accumulation of malondialdehyde (MDA) and hydroxynonenal (HNE) protein adducts, decreased antioxidant capacity, and increased antibody titers toward serum hydroxyethyl radical (HER), MDA, and HNE adducts. NAC treatment increased cytosolic antioxidant capacity, abolished ethanol-induced lipid peroxidation, and inhibited the formation of antibodies toward HNE and HER adducts without interfering with CYP 2 E1 induction. NAC also decreased ethanol-induced ALT release and inflammation and prevented significant loss of hepatic GSH content. However, the improvement in necrosis score and reduction of TNFalpha mRNA elevation did not reach statistical significance. Although a direct correlation was observed among hepatic MDA and HNE adduct content and TNFalpha mRNA expression, inflammation, and necrosis scores, no correlation was observed between oxidative stress markers or TNFalpha and steatosis score. These data suggest that ethanol-induced oxidative stress can contribute to inflammation and liver injury even in the absence of Kupffer cell activation by endotoxemia.}, }
@article {pmid16084531, year = {2005}, author = {Pfeffer, U and Ferrari, N and Dell'Eva, R and Indraccolo, S and Morini, M and Noonan, DM and Albini, A}, title = {Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses.}, journal = {Mutation research}, volume = {591}, number = {1-2}, pages = {198-211}, doi = {10.1016/j.mrfmmm.2005.04.014}, pmid = {16084531}, issn = {0027-5107}, mesh = {Acetylcysteine/*pharmacology ; Angiogenesis Inhibitors/pharmacology ; Anticarcinogenic Agents/*pharmacology ; Apoptosis/physiology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Movement/drug effects ; Cells, Cultured ; Endothelial Cells/cytology/*drug effects/*physiology ; Free Radical Scavengers/*pharmacology ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; NF-kappa B/metabolism ; Oligonucleotide Array Sequence Analysis ; RNA, Messenger/metabolism ; Reproducibility of Results ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {The anti-oxidants N-acetyl-l-cysteine (NAC) and (-)-epigallocatechin-3-gallate (EGCG) inhibit tumor vascularization by reducing endothelial cell migration and invasion in a similar, non additive and non synergistic manner but do not alter the growth of human umbilical vein endothelial cells. Here we address the effects of the two chemopreventive drugs on endothelial cell signaling by means of expression profiling and real-time PCR validation. We identify a series of angiogenesis related genes that are similarly regulated by the two drugs. Anti-oxidant treated endothelial cells show gene expression profiles compatible with a less activated, less apoptosis prone and less migratory phenotype. The anti-oxidants affect expression of several components of the TNFalpha response pathway including downstream genes that are regulated in the opposite direction in the absence of the inflammatory cytokine. The interference with the TNFalpha pathway is reflected by reduced NFkappaB activation in anti-oxidants treated cells but the compounds are not able to contrast TNFalpha mediated activation of NFkappaB. The chemopreventive action of these compounds thus relies on a reduction of basal levels of endothelial cell activation. Down-regulation of the TNFalpha responsive pro-metastatic, pro-inflammatory genes, urokinase plasminogen activator and selectin E, further implies anti-metastatic effects for these drugs.}, }
@article {pmid16083920, year = {2005}, author = {Izzotti, A and Bagnasco, M and Cartiglia, C and Longobardi, M and Camoirano, A and Tampa, E and Lubet, RA and De Flora, S}, title = {Modulation of multigene expression and proteome profiles by chemopreventive agents.}, journal = {Mutation research}, volume = {591}, number = {1-2}, pages = {212-223}, doi = {10.1016/j.mrfmmm.2005.03.032}, pmid = {16083920}, issn = {0027-5107}, support = {N01-CN-752008/CN/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Anticarcinogenic Agents/*pharmacology ; Antineoplastic Agents/pharmacology ; Cluster Analysis ; Free Radical Scavengers/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation/*drug effects ; Male ; Mice ; Oligonucleotide Array Sequence Analysis ; *Proteome/analysis ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Smoke ; Sulindac/pharmacology ; Nicotiana ; }, abstract = {Analysis of transcriptome and proteome profiles by microarray technologies provides a formidable, new tool in cancer chemoprevention research. An ideal chemopreventive agent should not excessively alter per se the basal make-up of multigene expression and protein synthesis and should at the same time be able to attenuate alterations induced by risk factors. In order to validate this working hypothesis, we previously performed a series of studies in animal models using the thiol N-acetyl-l-cysteine (NAC) and the nonsteroidal antiinflammatory drug sulindac. We report herein the results of new studies evaluating modulation of DNA adduct levels and expression of 4858 genes in lung and liver of Sprague-Dawley rats, either unexposed or exposed to environmental cigarette smoke (ECS). The tested chemopreventive agents included NAC, oltipraz (OPZ), 5,6-benzoflavone (5,6-BF), phenethyl isothiocyanate (PEITC), and indole 3-carbinol (I3C). Combinations of OPZ with NAC and of PEITC with I3C were also assayed. Excepting OPZ, all treatments inhibited by at least 50% the formation of bulky DNA adducts in the lung of ECS-exposed rats. Hierarchical cluster analysis and principal component analysis allowed us to classify the agents according to their influence on basal gene expression and their ability to attenuate ECS-induced transcriptome alterations. PEITC and I3C were the most effective but the least safe agents. 5,6-BF displayed intermediate patterns. OPZ was poorly effective in lung and considerably altered the basal gene expression in liver. NAC had a medium efficacy and was the safest agent, as also supported by the analysis of 518 proteins in rat lung.}, }
@article {pmid16083753, year = {2005}, author = {Okay, E and Karadenizli, A and Müezzinoglu, B and Zeybek, U and Arzu Ergen, H and Isbir, T}, title = {N-acetylcysteine attenuates bacterial translocation after partial hepatectomy in rats.}, journal = {The Journal of surgical research}, volume = {127}, number = {2}, pages = {164-170}, doi = {10.1016/j.jss.2005.02.012}, pmid = {16083753}, issn = {0022-4804}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Bacterial Translocation/*drug effects ; Colony Count, Microbial ; Drug Administration Schedule ; Hepatectomy/*methods ; Ileum/drug effects/immunology/pathology ; Intestinal Mucosa/drug effects/immunology/pathology ; Lung/microbiology/pathology ; Lymph Nodes/microbiology ; Male ; Mesentery ; Neutrophil Infiltration ; Postoperative Period ; Preoperative Care ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Translocating enteric bacteria have been suggested as playing a major role in the development of infections after partial hepatectomy. We investigated the effect of N-acetylcysteine (NAC) on bacterial translocation (BT) and intestinal mucosa as the first line of defense against BT.<br><br>MATERIALS AND METHODS: We compared four groups of eight Sprague-Dawley male rats each: sham, control (partially hepatectomized), partial hepatectomy plus preoperative single-dose NAC, and a fourth that received partial hepatectomy with a preoperative single-dose NAC plus treatment with NAC for 2 days. Microorganism counts of tissues, lung injury score, lung tissue glutathione, and malondialdehyde levels and microscopy of intestinal mucosa were studied at the end of 48 h.<br><br>RESULTS: Microorganism count in the lung and mesenteric lymph node cultures and lung injury score were significantly higher in the control group when compared with the sham, third, and fourth groups (lung: 9919.6 versus 0.0, 2912.9, 1550.0 cfu/g tissue; mesenteric lymph nodes: 8458.3 versus 0.0, 89.0, 88.9 cfu/g tissue; lung injury score: 3.25 versus 0.5, 1.13, 1.75). In the control group, the villous height of the distal ileal mucosa was significantly shorter than the sham group (65.25 versus 75.25 microm) and the difference from groups 3 and 4 was not statistically significant. Neutrophil infiltration in the distal ileal mucosa of the control group was significantly higher than the sham, third and fourth groups (3.13 versus 0.25, 0.38 and 1.0).<br><br>CONCLUSIONS: The parenteral use of NAC attenuates bacterial translocation after partial hepatectomy in rats. Attenuation of the lung injury after partial hepatectomy in NAC-treated groups might be attributable to both anti-inflammatory effect and the effect on BT.}, }
@article {pmid16083524, year = {2005}, author = {Fischer, UM and Tossios, P and Mehlhorn, U}, title = {Renal protection by radical scavenging in cardiac surgery patients.}, journal = {Current medical research and opinion}, volume = {21}, number = {8}, pages = {1161-1164}, doi = {10.1185/030079905X53289}, pmid = {16083524}, issn = {0300-7995}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Disease ; Acute Kidney Injury/etiology/*prevention &amp; control ; Aged ; Cardiopulmonary Bypass ; Cardiovascular Surgical Procedures/*adverse effects ; Coronary Vessels/*surgery ; Creatinine/blood ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Male ; Randomized Controlled Trials as Topic ; Retrospective Studies ; }, abstract = {OBJECTIVE: Renal function impairment is a common complication in cardiac surgery patients. Because cardiopulmonary bypass and cardioplegic arrest are associated with formation of free radicals, which have been shown to impair various organs including the kidneys, radical scavenging may protect renal function. Therefore, the purpose of our study was to evaluate the impact of the radical scavenger N-acetylcysteine (NAC) versus placebo on peri-operative renal function in cardiac surgery patients.<br><br>RESEARCH DESIGN AND METHODS: We reanalyzed the data of our previous study in which 40 coronary artery surgery patients (66 +/- 9 [SD] years, 9 women and 31 men) with normal pre-operative renal function had been randomized in a double-blind fashion to receive either NAC (100 mg/kg into the cardiopulmonary bypass prime followed by infusion at 20 mg/kg/h; n = 20) or placebo (n = 20). We determined serum creatinine levels as an indicator for renal function pre- and at 1 day post-surgery as well as peri-operative urinary output and diuretic medication. Creatinine clearance was calculated according to Cockcroft and Gault.<br><br>RESULTS: Biometric and intra-operative patient data were similar between both groups. In the placebo group, serum creatinine increased from 93.1 +/- 35.4 micromol/L pre-operatively to 115.9 +/- 47.2 micromol/L on post-op day 1 (p < 0.001). In contrast, serum creatinine in the NAC group remained unchanged (92.3 +/- 31.3 micromol/L pre-op; 99.3 +/- 25.4 micromol/L on post-op day 1; p = 0.084). Accordingly, creatinine clearance decreased by 16.9 +/- 14.3 mL/min in the placebo group as compared to 7.5 +/- 17.7 mL/min in the NAC group (p = 0.039). Urinary output and diuretic medication were similar between NAC and placebo.<br><br>CONCLUSIONS: Our data suggest that free radical-scavenging using NAC protects renal function in patients subjected to cardiac surgery on cardiopulmonary bypass.}, }
@article {pmid16083313, year = {2006}, author = {Balkan, A and Balkan, M and Yasar, M and Korkmaz, A and Erdem, O and Kiliç, S and Kutsal, O and Bilgic, H}, title = {Pulmonary protective effects of hyberbaric oxygen and N-acetylcysteine treatment in necrotizing pancreatitis.}, journal = {Physiological research}, volume = {55}, number = {1}, pages = {25-31}, doi = {10.33549/physiolres.930765}, pmid = {16083313}, issn = {0862-8408}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Ceruletide ; Glutathione Peroxidase/metabolism ; *Hyperbaric Oxygenation ; Lung/drug effects/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Oxidative Stress ; Pancreatitis, Acute Necrotizing/etiology/pathology/*therapy ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome/etiology/pathology/*prevention &amp; control ; Superoxide Dismutase/metabolism ; }, abstract = {The purpose of this study is to analyze the protective effect of combining N-acetylcysteine (NAC) and hyberbaric oxygen (HBO) treatment in the lung tissue during acute pancreatitis. Sixty Sprague-Dawley male rats were randomly divided into five groups; Group I; Control group (n=12), Group II; pancreatitis group (n=12), Group III; pancreatitis + NAC treatment group (n=12), Group IV; pancreatitis + HBO treatment group (n=12), Group V; pancreatitis + HBO + NAC treatment group (n=12). HBO was applied postoperatively for 5 days, twice a day at 2.5 fold absolute atmospheric pressure for 90 min. Lung tissue was obtained for measuring malondialdehyde (MDA), superoxide dismutase (Cu/Zn-SOD) and glutathione peroxidase (GSH-Px) levels along with histopathological tissue examinations. This study showed that all three treated groups (HBO alone, NAC alone and combined HBO+NAC treatment) had pulmonary protective effects during acute necrotizing pancreatitis.}, }
@article {pmid16082188, year = {2005}, author = {Carlsson, H and Yhr, M and Petersson, S and Collins, N and Polyak, K and Enerbäck, C}, title = {Psoriasin (S100A7) and calgranulin-B (S100A9) induction is dependent on reactive oxygen species and is downregulated by Bcl-2 and antioxidants.}, journal = {Cancer biology &amp; therapy}, volume = {4}, number = {9}, pages = {998-1005}, doi = {10.4161/cbt.4.9.1969}, pmid = {16082188}, issn = {1538-4047}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Calcium-Binding Proteins/*biosynthesis/genetics ; Calgranulin B/*biosynthesis/genetics ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Down-Regulation ; Epithelial Cells/drug effects ; Humans ; Keratinocytes/drug effects ; Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism ; Reactive Oxygen Species/*metabolism ; S100 Calcium Binding Protein A7 ; S100 Proteins ; Tumor Cells, Cultured ; }, abstract = {S-100 proteins are calcium-binding proteins with important growth regulatory functions. Of these proteins, psoriasin and calgranulin-B have been shown to be highly upregulated in ductal carcinoma in situ (DCIS) of the breast and in psoriasis. The purpose of this study was to further elucidate the functional relevance of the overexpression of these two S-100 proteins in psoriasis and DCIS. We report the induction of both proteins by reactive oxygen species, phorbol ester TPA, and the induction of psoriasin in response to the PI3K inhibitor wortmannin. We also demonstrate that Bcl-2 overexpression represses the induction of psoriasin and calgranulin-B under these different conditions. The same effect was obtained with the antioxidant NAC, which indicates that the suppression of psoriasin and calgranulin-B induction is mediated by the antioxidant function of Bcl-2. Furthermore, we demonstrate that overexpression of a dominant negative IKKbeta also inhibits the induction of psoriasin suggesting that the NFkappaB pathway is involved in the induction of this protein. Also, we found NFkappaB responsive DNA elements in the upstream promoter region of psoriasin. MCF10A cells with a stable retroviral overexpression of psoriasin were significantly more resistant to H2O2-induced cell death than control cells further supporting the hypothesis that these S-100 proteins may play a role in oxidative stress response.}, }
@article {pmid16081117, year = {2006}, author = {Dambach, DM and Durham, SK and Laskin, JD and Laskin, DL}, title = {Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity.}, journal = {Toxicology and applied pharmacology}, volume = {211}, number = {2}, pages = {157-165}, doi = {10.1016/j.taap.2005.06.024}, pmid = {16081117}, issn = {0041-008X}, support = {CA100994/CA/NCI NIH HHS/United States ; ES004738/ES/NIEHS NIH HHS/United States ; ES005022/ES/NIEHS NIH HHS/United States ; GM034310/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/administration &amp; dosage/toxicity ; Animals ; Blotting, Western ; Chemical and Drug Induced Liver Injury/*etiology/metabolism/pathology ; Chemokine CCL2/biosynthesis/genetics ; Chemokines/genetics/metabolism ; Gene Expression/drug effects ; Glutathione/metabolism ; Humans ; Inflammation Mediators/*metabolism ; Injections, Intraperitoneal ; Interleukin-1/biosynthesis/genetics ; Interleukin-10/biosynthesis/genetics ; Interleukin-4/genetics/metabolism ; Liver/chemistry/drug effects/metabolism ; Macrophage Inflammatory Proteins/genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Mice, Knockout ; NF-kappa B p50 Subunit/genetics/*physiology ; Necrosis/chemically induced/pathology ; Oxidative Stress ; RNA, Messenger/drug effects/genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Superoxide Dismutase/metabolism ; Time Factors ; Transcription Factors/genetics/metabolism ; Transforming Growth Factor beta/genetics/metabolism ; Tumor Necrosis Factor-alpha/genetics/metabolism ; }, abstract = {Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. In addition to inducing direct cellular damage, oxidants can activate transcription factors including NF-kappaB, which regulate the production of inflammatory mediators implicated in hepatotoxicity. Here, we investigated the role of APAP-induced oxidative stress and NF-kappaB in inflammatory mediator production. Treatment of mice with APAP (300 mg/kg, i.p.) resulted in centrilobular hepatic necrosis and increased serum aminotransferase levels. This was correlated with depletion of hepatic glutathione and CuZn superoxide dismutase (SOD). APAP administration also increased expression of the proinflammatory mediators, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha), macrophage chemotactic protein-1 (MCP-1), and KC/gro, and the anti-inflammatory cytokine, interleukin-10 (IL-10). Pretreatment of mice with the antioxidant, N-acetylcysteine (NAC) prevented APAP-induced depletion of glutathione and CuZnSOD, as well as hepatotoxicity. NAC also abrogated APAP-induced increases in TNFalpha, KC/gro, and IL-10, but augmented expression of the anti-inflammatory cytokines interleukin-4 (IL-4) and transforming growth factor-beta (TGFbeta). No effects were observed on IL-1beta or MCP-1 expression. To determine if NF-kappaB plays a role in regulating mediator production, we used transgenic mice with a targeted disruption of the gene for NF-kappaB p50. As observed with NAC pretreatment, the loss of NF-kappaB p50 was associated with decreased ability of APAP to upregulate TNFalpha, KC/gro, and IL-10 expression and increased expression of IL-4 and TGFbeta. However, in contrast to NAC pretreatment, the loss of p50 had no effect on APAP-induced hepatotoxicity. These data demonstrate that APAP-induced cytokine expression in the liver is influenced by oxidative stress and that this is dependent, in part, on NF-kappaB. However, NF-kappaB p50-dependent responses do not appear to play a major role in the pathogenesis of toxicity in this model.}, }
@article {pmid16080696, year = {2005}, author = {Oh, HK and So, MK and Yang, J and Yoon, HC and Ahn, JS and Lee, JM and Kim, JT and Yoo, JU and Byun, TH}, title = {Effect of N-Acetylcystein on butyrate-treated Chinese hamster ovary cells to improve the production of recombinant human interferon-beta-1a.}, journal = {Biotechnology progress}, volume = {21}, number = {4}, pages = {1154-1164}, doi = {10.1021/bp050057v}, pmid = {16080696}, issn = {8756-7938}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Bioreactors ; Butyrates/*pharmacology ; CHO Cells/drug effects ; Caspase 3 ; Caspases/drug effects/metabolism ; *Cell Culture Techniques/instrumentation ; Cells, Cultured ; Cricetinae ; Cricetulus ; Cytochromes c/drug effects/metabolism ; DNA Fragmentation ; Encephalomyocarditis virus/drug effects ; Glutathione/metabolism ; Glycosylation ; Humans ; Interferon Type I/drug effects/genetics/metabolism/pharmacology ; Interferon beta-1a ; Interferon-beta/drug effects/*genetics/metabolism/pharmacology ; N-Acetylneuraminic Acid/metabolism ; Recombinant Proteins ; }, abstract = {Sodium butyrate (NaBu) is used as a productivity enhancer for the production of therapeutic recombinant proteins in Chinese hamster ovary (CHO) cells. However, NaBu is well-known for having a cytotoxic effect, thereby inducing apoptosis. As an endeavor to reduce this defect, we studied 11 antioxidants known for inhibiting apoptosis, according to a Plackett-Burman statistical design on CHO cells producing recombinant interferon-beta-1a (IFN-beta). None of the antioxidants that we tested were as effective as N-acetylcystein (NAC) from the point of view of maintaining long-term survival of CHO cells and increasing the production of IFN-beta. In 7.5-L perfusion bioreactor cultures, the addition of NaBu and NAC elongated the culture period to almost 200 h throughout production phase and increased the production yield by 2-fold compared to control cultures containing only NaBu. Glycosylation patterns of produced IFN-beta at each run were also compared in IEF analysis. IEF profiles of where NaBu and NAC were added showed to be more isoforms with a lower pI than those of the control run. The sialic acid content was also increased by 17.7% according to HPLC analysis. Taken together, the data obtained demonstrate that the addition of NAC has positive effects on the elongation of the culture period, improving the production and increasing the sialylation of IFN-beta in NaBu-treated CHO cells.}, }
@article {pmid16076765, year = {2005}, author = {Lee, CC and Cheng, YW and Kang, JJ}, title = {Motorcycle exhaust particles induce IL-8 production through NF-kappaB activation in human airway epithelial cells.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {68}, number = {17-18}, pages = {1537-1555}, doi = {10.1080/15287390590967496}, pmid = {16076765}, issn = {1528-7394}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Cell Line, Tumor ; Cell Survival ; Epithelial Cells/*drug effects/immunology/metabolism ; Flavonoids/pharmacology ; Gene Expression Regulation ; Humans ; Interleukin-8/*biosynthesis/genetics ; *Motorcycles ; NF-kappa B/*biosynthesis ; Proline/analogs &amp; derivatives/pharmacology ; RNA, Messenger/biosynthesis ; Thiocarbamates/pharmacology ; Vehicle Emissions/*toxicity ; }, abstract = {Motorcycle exhaust particles (MEP) are among the major air pollutants, especially in urban area of Taiwan. In our previous study, data showed that MEP induce proinflammatory and proallergic response profiles in BALB/c mice. Effects of MEP on interleukin (IL)-8 production in A549 human airway epithelial cells were further investigated in this study. It was found that MEP enhanced IL-8 protein and mRNA expression in human epithelial cells. Pretreatment with an NF-kappaB inhibitor (1 mM PDTC), extracellular signal-regulated kinase (ERK) inhibitor (50 microM PD98059), JNK inhibitor (25 microM SP600125), p38 inhibitor (2 microM SB203580), and three antioxidants (500 U/ml superoxide dismutase [SOD], 50 microM vitamin E, 10 mMN-acetylcysteine [NAC]) attenuated the MEP-induced increase in IL-8 production. Through further, direct detection of nuclear factor (NF)-kappaB activation in epithelial cells using immunoblotting of nuclear p65 and NF-kappaB reporter assay, data showed that MEP induced nuclear translocation of p65 and enhancement of NF-kappaB luciferase gene expression. MEP also induced activation of ERK, JNK, and p38 signaling pathways and produced an increase of oxidative stress in A549 cells. By using mitogen-activated protein kinase (MAPK) inhibitors and antioxidant, it was demonstrated that ERK inhibitor, JNK inhibitor, and antioxidants but not p38 inhibitor attenuated the MEP-induced increase in NF-kappaB reporter activity. In conclusion, evidence shows that filter-trapped particles emitted from unleaded gasoline-fueled, two-stroke motorcycle engines induce an increase in IL-8 production by activation of NF-kappaB in human airway epithelial cells.}, }
@article {pmid16061357, year = {2006}, author = {Wan, FJ and Tung, CS and Shiah, IS and Lin, HC}, title = {Effects of alpha-phenyl-N-tert-butyl nitrone and N-acetylcysteine on hydroxyl radical formation and dopamine depletion in the rat striatum produced by d-amphetamine.}, journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology}, volume = {16}, number = {2}, pages = {147-153}, doi = {10.1016/j.euroneuro.2005.07.002}, pmid = {16061357}, issn = {0924-977X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Body Temperature/drug effects ; Cyclic N-Oxides ; Dextroamphetamine/*pharmacology ; Dopamine/*physiology ; Dopamine Uptake Inhibitors/*pharmacology ; Free Radical Scavengers/*pharmacology ; Hydroxybenzoates/metabolism ; Hydroxyl Radical/*metabolism ; Lipid Peroxidation/drug effects ; Male ; Microdialysis ; Neostriatum/drug effects/*metabolism ; Neuroprotective Agents/*pharmacology ; Neurotoxicity Syndromes/metabolism/pathology/psychology ; Nitrogen Oxides/*pharmacology ; Pilot Projects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Previous studies have shown that treatment with free radical scavengers attenuated the D-amphetamine (AMPH) neurotoxicity. But several of these agents also prevent AMPH-induced elevation of body temperature in the rat. Thus, further studies are needed to determine if blockade of the production of free radical or hypothermia are related to the neuroprotective mechanism of the free radical scavengers for AMPH neurotoxicity. In the present study, we examined the effects of the free radical scavengers alpha-phenyl-N-tert-butyl nitrone (PBN) and N-acetylcysteine (NAC) on long-term depletion of striatal dopamine (DA) and lipid peroxidation formation and on hyperthermia induced by AMPH. We also determined their effects on acute hydroxyl radical formation after direct intrastriatal infusion of AMPH. The results showed that both significantly attenuated long-term DA depletion and lipid peroxidation formation in the rat striatum at the dose range that did not block hyperthermia induced by AMPH. These agents also completely inhibited the production of hydroxyl radical after AMPH infusion into the striatum. Our results suggest that free radical scavengers such as PBN and NAC could protect against AMPH-induced oxidative stress and DAergic terminal toxicity via their free radical removing property independent of lowering the core body temperature of rats, and imply that supplement with antioxidants is a potential strategy in the treatment of AMPH neurotoxicity.}, }
@article {pmid16060123, year = {2005}, author = {Mour, G and Feinfeld, DA and Caraccio, T and McGuigan, M}, title = {Acute renal dysfunction in acetaminophen poisoning.}, journal = {Renal failure}, volume = {27}, number = {4}, pages = {381-383}, pmid = {16060123}, issn = {0886-022X}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/*chemically induced/drug therapy/epidemiology ; Adult ; Age Distribution ; Aged ; Drug Overdose/epidemiology/radiotherapy/therapy ; Emergency Treatment/methods ; Female ; Follow-Up Studies ; Humans ; Incidence ; Kidney Function Tests ; Male ; Middle Aged ; New York City/epidemiology ; Risk Assessment ; Severity of Illness Index ; Sex Distribution ; Treatment Outcome ; }, abstract = {Although acetaminophen (APAP)-associated liver injury is well recognized, there are few reports describing APAP nephrotoxicity, and most of them are single cases. It has also been suggested that N-acetylcysteine (NAC), used to treat the hepatotoxicity, may be harmful to the kidneys. To examine this contention and to determine whether renal involvement in APAP poisoning is at all common, we analyzed the incidence and outcome of acute renal dysfunction in patients hospitalized for APAP overdose reported to our regional poison center over a year. Eleven APAP-poisoned patients had elevated liver function tests; nine of them had azotemia. Those with higher AST levels tended to be younger and to have lower APAP levels on admission. Two patients with acute renal injury died after admission. The other seven patients with renal dysfunction recovered in 2 to 7 days. Six of these received NAC; their mean serum creatinine fell from 3.2 +/- 2.0 versus 1.7 +/- 0.9 mg/dL (p < 0.05). We conclude that acute renal failure is not uncommon in APAP poisoning and appears to be unrelated to the degree of liver injury. NAC therapy did not seem to worsen nephrotoxicity.}, }
@article {pmid16060087, year = {2005}, author = {Zaniew, M and Zachwieja, J and Warzywoda, A and Stefaniak, E and Runowski, D and Lewandowska-Stachowiak, M}, title = {[Influence of vitamin E and N-acetylcysteine on intracellular oxidative stress in T lymphocytes in children treated with dialysis].}, journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)}, volume = {58 Suppl 1}, number = {}, pages = {58-65}, pmid = {16060087}, issn = {0043-5147}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adolescent ; Adult ; Antigens, CD/drug effects ; Antioxidants/administration &amp; dosage/*pharmacology ; Case-Control Studies ; Child ; Child, Preschool ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Humans ; Kidney Failure, Chronic/physiopathology/*therapy ; Male ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Poland ; Renal Dialysis/*adverse effects ; Statistics, Nonparametric ; T-Lymphocytes/*drug effects ; Time Factors ; Treatment Outcome ; Vitamin E/administration &amp; dosage/*pharmacology ; }, abstract = {UNLABELLED: End-stage renal disease (ESRD) patients are subjected to enhanced oxidative stress. Excess of reactive oxygen species (ROS) may lead to the functional disabilities of lymphocytes. The aim of the study was to investigate the effect of vitamin E and N-acetylcysteine (NAC) on antioxidant status and intracellular oxidative stress in T-cells in children treated with dialysis.<br><br>MATERIAL AND METHODS: 18 children treated with dialysis (hemodialysis n = 5 and peritoneal dialysis n = 13) were enrolled into the study. The age range was 2-20 ys. with a mean of 10.94 +/-5.86 ys. Vitamin E and NAC were given for six months orally. Throughout the study total antioxidant status (TAS), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity, and intracellular oxidative stress in T lymphocytes was measured.<br><br>RESULTS: In children treated with dialysis, TAS was significantly reduced compared to the controls (p = 0.012). We found no differences in GPx and SOD activities between patient and control groups. Mean fluorescence intensity (MFI), which reflected intracellular oxidative stress, was significantly increased in: CD3+, CD3+CD4- and CD8+CD28-. After six months of antioxidant treatment, a significant reduction in MFI was noted in most T-cell subsets (p < 0.001). MFI in T-helper cells remained unchanged. Although there was a trend toward rise in TAS and GPx activity, only significant differences in SOD activity were found (p = 0.022).<br><br>CONCLUSIONS: In children with ESRD treated with dialysis reduced TAS coexists with enhanced intracellular oxidative stress in T lymphocytes. The combined treatment with vitamin E and NAC lead to the reduction in oxidative stress within T-cells that might be of therapeutic value in dialyzed patients.}, }
@article {pmid16054126, year = {2005}, author = {Wu, SJ and Ng, LT and Lin, CC}, title = {Effects of antioxidants and caspase-3 inhibitor on the phenylethyl isothiocyanate-induced apoptotic signaling pathways in human PLC/PRF/5 cells.}, journal = {European journal of pharmacology}, volume = {518}, number = {2-3}, pages = {96-106}, doi = {10.1016/j.ejphar.2005.06.021}, pmid = {16054126}, issn = {0014-2999}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Regulatory Proteins ; Apoptotic Protease-Activating Factor 1 ; BH3 Interacting Domain Death Agonist Protein ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism/pathology/physiopathology ; Carrier Proteins/metabolism ; Caspase 3 ; Caspase 8 ; Caspase 9 ; *Caspase Inhibitors ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cysteine Proteinase Inhibitors/pharmacology ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Enzyme Activation/drug effects ; Flow Cytometry ; Humans ; Intracellular Membranes/drug effects/physiology ; Intracellular Signaling Peptides and Proteins ; Isothiocyanates/*pharmacology ; Liver Neoplasms/metabolism/pathology/physiopathology ; Membrane Potentials/drug effects ; Mitochondria/drug effects/metabolism/physiology ; Mitochondrial Proteins/metabolism ; Oligopeptides/pharmacology ; Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Signal Transduction/*drug effects ; Time Factors ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation/drug effects ; Vitamin E/pharmacology ; X-Linked Inhibitor of Apoptosis Protein ; bcl-2-Associated X Protein ; fas Receptor/metabolism ; }, abstract = {Phenylethyl isothiocyanate (PEITC) is a well recognized potential chemopreventive compound against human cancers. In this study, the molecular mechanism of PEITC-induced apoptosis was examined with two antioxidants (N-acetyl-cysteine and vitamin E) and a caspase-3 inhibitor (z-DEVD-fmk). Results demonstrated that PEITC significantly induced human hepatoma PLC/PRF/5 (CD95-negative) cells undergoing apoptosis. Treatment with 0 approximately 10 microM PEITC-triggered cell apoptosis as revealed by the externalization of annexin V-targeted phosphatidylserine and the subsequent appearance of sub-G1 population. Results also displayed that PEITC-induced apoptosis involves the up-regulation of p53 and Bax protein, down-regulation of the XIAP, Bcl-2, Bcl-(XL) and Mcl-1 proteins, cleavage of Bid, and the release of cytochrome c and Smac/Diablo, which were accompanied by the activation of caspases -9, -3 and -8. PEITC-induced the generation of reactive oxygen species and the decrease of mitochondrial membrane potential (Deltapsim) in a time-dependent pattern. N-acetyl-cysteine and vitamin E at 100 microM, and z-DEVD-fmk at 50 microM markedly blocked PEITC-induced apoptosis, which was demonstrated by a decline in the reactive oxygen species generation and the release of the cytochrome c and Smac/Diablo from mitochondria to the cytosol. N-acetyl-cysteine, vitamin E and z-DEVD-fmk also prevented the PEITC in inducing the loss of Deltapsim. They also affected the activity of XIAP and Bax proteins. Taken together, these studies suggest that PEITC is an apoptotic inducer that acts on the mitochondria and the feedback amplification loop of caspase-8/Bid pathways in PLC/PRF/5 cells.}, }
@article {pmid16042792, year = {2005}, author = {Akan, I and Akan, S and Akca, H and Savas, B and Ozben, T}, title = {Multidrug resistance-associated protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine sulfoximine.}, journal = {Cancer cell international}, volume = {5}, number = {1}, pages = {22}, pmid = {16042792}, issn = {1475-2867}, abstract = {BACKGROUND: Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation. The exact mechanism of MRP1 involved multidrug resistance has not been clarified yet, though glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-Buthionine (S,R)-sulfoximine (BSO) is an inhibitor of GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated vincristine resistance in Human Embryonic Kidney (HEK293) and its MRP1 transfected 293MRP cells. Human Embryonic Kidney (HEK293) cells were transfected with a plasmid encoding whole MRP1 gene. Both cells were incubated with vincristine in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. GSH, Glutathione S-Transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs.<br><br>RESULTS: N-acetylcysteine increased the resistance of both cells against vincristine and BSO decreased NAC-enhanced MRP1-mediated vincristine resistance, indicating that induction of MRP1-mediated vincristine resistance depends on GSH. Vincristine decreased cellular GSH concentration and increased GPx activity. Glutathione S-Transferase activity was decreased by NAC.<br><br>CONCLUSION: Our results demonstrate that NAC and BSO have opposite effects in MRP1 mediated vincristine resistance and BSO seems a promising chemotherapy improving agent in MRP1 overexpressing tumor cells.}, }
@article {pmid16040014, year = {2005}, author = {Zhang, CG and Welin, D and Novikov, L and Kellerth, JO and Wiberg, M and Hart, AM}, title = {Motorneuron protection by N-acetyl-cysteine after ventral root avulsion and ventral rhizotomy.}, journal = {British journal of plastic surgery}, volume = {58}, number = {6}, pages = {765-773}, doi = {10.1016/j.bjps.2005.04.012}, pmid = {16040014}, issn = {0007-1226}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Death/physiology ; Female ; Motor Neurons/*drug effects/physiology ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Rhizotomy/*methods ; Sciatic Nerve/*injuries/surgery ; Spinal Nerve Roots/*injuries/surgery ; }, abstract = {Motor recovery after proximal nerve injury remains extremely poor, despite advances in surgical care. Several neurobiological hurdles are implicated, the most fundamental being extensive cell death within the motorneuron pool. N-acetyl-cysteine almost completely protects sensory neurons after peripheral axotomy, hence its efficacy in protecting motorneurons after ventral root avulsion/rhizotomy was investigated. In adult rats, the motorneurons supplying medial gastrocnemius were unilaterally pre-labelled with retrograde tracer (true-blue/fluoro-gold), prior to L5 and 6 ventral root avulsion, or rhizotomy. Groups received either intraperitoneal N-acetyl-cysteine (ip, 150 or 750 mg/kg/day), immediate or delayed intrathecal N-acetyl-cysteine treatment (it, 2.4 mg/day), or saline; untreated animals served as controls. Either 4 (avulsion model) or 8 (rhizotomy model) weeks later, the pre-labelled motorneurons' mean soma area and survival were quantified. Untreated controls possessed markedly fewer motorneurons than normal due to cell death (avulsion 53% death; rhizotomy 26% death, P<0.01 vs. normal). Motorneurons were significantly protected by N-acetyl-cysteine after avulsion (ip 150 mg/kg/day 40% death; it 30% death, P<0.01 vs. no treatment), but particularly after rhizotomy (ip 150 mg/kg/day 17% death; ip 750 mg/kg/day 7% death; it 5% death, P<0.05 vs. no treatment). Delaying intrathecal treatment for 1 week after avulsion did not impair neuroprotection, but a 2-week delay was deleterious (42% death, P<0.05 vs. 1-week delay, 32% death). Treatment prevented the decrease in soma area usually found after both types of injury. N-acetyl-cysteine has considerable clinical potential for adjuvant treatment of major proximal nerve injuries, including brachial plexus injury, in order that motorneurons may survive until surgical repair facilitates regeneration.}, }
@article {pmid16039951, year = {2005}, author = {Kapitza, S and Jakupec, MA and Uhl, M and Keppler, BK and Marian, B}, title = {The heterocyclic ruthenium(III) complex KP1019 (FFC14A) causes DNA damage and oxidative stress in colorectal tumor cells.}, journal = {Cancer letters}, volume = {226}, number = {2}, pages = {115-121}, doi = {10.1016/j.canlet.2005.01.002}, pmid = {16039951}, issn = {0304-3835}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Collagen Type XI/drug effects/metabolism ; Colorectal Neoplasms/*metabolism ; DNA Damage/*drug effects ; Dose-Response Relationship, Drug ; Humans ; Indazoles/*pharmacology ; Mitochondria/drug effects ; Organometallic Compounds ; Oxidative Stress/*drug effects ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; Ruthenium Compounds/*pharmacology ; }, abstract = {The Ru(III) complex salt KP1019 induced formation of H2O2 in colorectal tumor cells in a dose-dependent way. It also caused DNA-strand breaks if only weakly doubling tail length to 55.87+/-3.97 microm. Both effects were prevented by 5mM N-acetylcysteine (NAC) which also reduced cytotoxicity (IC(50) 55 vs 30 microM without NAC). Induction of apoptosis was shown by loss of mitochondrial membrane potential in 63.4+/-2.1% of the population and by caspase-dependent cleavage of poly-(ADP-ribose)-polymerase (PARP). Both effects were inhibited by NAC which reduced the population with depolarized mitochondrial membranes to 24.1+/-1.2% and prevented PARP-cleavage indicating a central role oxidative stress in KP1019-induced apoptosis.}, }
@article {pmid16037314, year = {2005}, author = {Billaud, C and Maraschin, C and Peyrat-Maillard, MN and Nicolas, J}, title = {Maillard reaction products derived from thiol compounds as inhibitors of enzymatic browning of fruits and vegetables: the structure-activity relationship.}, journal = {Annals of the New York Academy of Sciences}, volume = {1043}, number = {}, pages = {876-885}, doi = {10.1196/annals.1333.099}, pmid = {16037314}, issn = {0077-8923}, mesh = {Cysteine ; Enzyme Inhibitors/*pharmacology ; Fructose ; *Fruit ; Glucose ; *Maillard Reaction ; Structure-Activity Relationship ; Sulfhydryl Compounds/*pharmacology ; *Vegetables ; }, abstract = {Some thiol-derived Maillard reaction products (MRPs) may exert antioxidant activity, depending on the reaction conditions as well as on the sugar and the sulphydryl compound. Recently, we reported that MRPs derived from glucose or fructose with cysteine (CSH) or glutathione (GSH) mixtures greatly inhibited polyphenoloxidases (PPOs), oxidoreductases responsible for discoloration of fresh or minimally processed fruits and vegetables. Glucose and GSH were shown to be the most active in producing inhibitory MRPs. Therefore, we examined the way in which the nature of the reactants affected their synthesis, in order to establish a structure-activity relationship for the inhibitory products. Various aqueous (0.083 M, 0.125 M, or 0.25 M) mixtures of a sugar (hexose, pentose, or diholoside) with either a CSH-related compound (CSH, GSH, N-acetyl-cysteine, cysteamine, cysteic acid, methyl-cysteine, cysteine methyl ester), an amino acid (gamma-glutamic acid, glycine, methionine), or other sulfur compound (thiourea, 1,4-dithiothreitol, 2-mercaptoethanol) were heated at 103 degrees C for 14 h. Soluble MRPs were compared for their ability to inhibit apple PPO activity. In the presence of CSH, the rated sugars (same molar concentration) ranked as to inhibitory effect were pentoses > sucrose > hexoses > or = maltose. In the presence of glucose, the simultaneous presence of an amino group, a carboxyl group, and a free thiol group on the same molecule seemed essential for the production of highly inhibitory compounds.}, }
@article {pmid16037291, year = {2005}, author = {Horiuchi, S and Unno, Y and Usui, H and Shikata, K and Takaki, K and Koito, W and Sakamoto, Y and Nagai, R and Makino, K and Sasao, A and Wada, J and Makino, H}, title = {Pathological roles of advanced glycation end product receptors SR-A and CD36.}, journal = {Annals of the New York Academy of Sciences}, volume = {1043}, number = {}, pages = {671-675}, doi = {10.1196/annals.1333.076}, pmid = {16037291}, issn = {0077-8923}, mesh = {3T3 Cells ; Adipocytes/physiology ; Animals ; CD36 Antigens/*physiology ; Diabetic Nephropathies/prevention &amp; control ; Glycation End Products, Advanced/*metabolism ; Leptin/antagonists &amp; inhibitors/genetics ; Mice ; Mice, Knockout ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic/*physiology ; Receptors, Leukotriene/deficiency/genetics/*physiology ; }, abstract = {The pathological significance of advanced glycation end product (AGE)-modified proteins deposited in several lesions is generally accounted for by their cellular interaction via the AGE receptors and subsequent acceleration of the inflammatory process. In this study, we focused on two AGE receptors-specifically, the role of SR-A in pathogenesis of diabetic nephropathy and the role of CD36 in AGE-induced downregulation of leptin by adipocytes. In terms of SR-A, diabetic wild-type mice exhibited increased urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion, whereas SR-A-knockout mice showed reduced glomerular size and mesangial matrix area. In these diabetic SR-A-knockout mice, the number of macrophages that infiltrated into glomeruli was remarkably reduced (P < 0.05), suggesting that SR-A-dependent glomerular migration of macrophages plays an important role in the pathogenesis of diabetic nephropathy. In terms of CD36, incubation of glycolaldehyde-modified bovine serum albumin (GA-BSA) with 3T3-L1 adipocytes reduced leptin secretion by these cells. The binding of GA-BSA to these cells and subsequent endocytic degradation were effectively inhibited by a neutralizing anti-CD36 antibody. AGE-induced downregulation of leptin was protected by N-acetyl-cysteine, an antioxidant. These results indicate that the interaction of AGE ligands with 3T3-L1 adipocytes via CD36 induces oxidative stress and leads to inhibition of leptin expression by these cells, suggesting a potential link of this phenomenon to exacerbation of the insulin sensitivity in metabolic syndrome.}, }
@article {pmid16026929, year = {2005}, author = {Kim, YM and Kim, MN and Lee, JJ and Lee, MK}, title = {Inhibition of dopamine biosynthesis by tetrahydropapaveroline.}, journal = {Neuroscience letters}, volume = {386}, number = {1}, pages = {1-4}, doi = {10.1016/j.neulet.2005.04.105}, pmid = {16026929}, issn = {0304-3940}, mesh = {Adrenal Medulla/drug effects/enzymology ; Animals ; Antioxidants/pharmacology ; Cattle ; Dopamine/*biosynthesis ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/metabolism/toxicity ; Levodopa/pharmacology ; Nerve Degeneration/metabolism/physiopathology ; Neurons/drug effects/*enzymology ; Oxidative Stress/drug effects/*physiology ; PC12 Cells ; Parkinson Disease/metabolism/physiopathology ; Rats ; Tetrahydropapaveroline/*metabolism/toxicity ; Tyrosine 3-Monooxygenase/antagonists &amp; inhibitors/metabolism ; Up-Regulation/drug effects/physiology ; }, abstract = {Tetrahydropapaveroline (THP) at 5-15 microM has been found to induce L-DOPA-induced oxidative apoptosis in PC12 cells. In this study, the inhibitory effects of THP on dopamine biosynthesis in PC12 cells and tyrosine hydroxylase (TH) activity in bovine adrenal were investigated. Treatment of PC12 cells with THP at 2.5-10 microM significantly decreased the intracellular dopamine content in a concentration-dependent manner (21.3% inhibition at THP 10 microM). The activity of TH was also inhibited by the treatment with THP at 2.5-10 microM (23.4% inhibition at 10 microM). In addition, THP had an inhibitory effect on bovine adrenal TH (IC50 value, 153.9 microM). THP exhibited uncompetitive inhibition on bovine adrenal TH with a substrate l-tyrosine with the Ki value with L-tyrosine of 0.30 mM. Treatment with L-DOPA at 20-50 microM increased the intracellular dopamine content in PC12 cells and the increase in dopamine content by L-DOPA was in part inhibited when L-DOPA (20 and 50 microM) was associated with THP at non-cytotoxic (5-10 microM) or cytotoxic (15 microM) concentration ranges. However, the reduction of dopamine content by THP (15 microM) or THP (15 microM) associated with L-DOPA (20 and 50 microM) in PC12 cells was inversed by the antioxidant N-acetyl-cysteine (0.1mM). These results indicate that THP at 5-10 microM decreases the basal dopamine content and reduces the increased dopamine content induced by L-DOPA in part by the inhibition of TH activity, and that THP at 15 microM does by oxidative stress in PC12 cells.}, }
@article {pmid16026512, year = {2005}, author = {Bi, WF and Yang, HY and Liu, JC and Cheng, TH and Chen, CH and Shih, CM and Lin, H and Wang, TC and Lian, WS and Chen, JJ and Chiu, HC and Chang, NC}, title = {Inhibition of cyclic strain-induced endothelin-1 secretion by tetramethylpyrazine.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {32}, number = {7}, pages = {536-540}, doi = {10.1111/j.1440-1681.2005.04227.x}, pmid = {16026512}, issn = {0305-1870}, mesh = {Cells, Cultured ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal/chemistry/pharmacology ; Endothelin-1/*metabolism ; Endothelium, Vascular/cytology/drug effects/metabolism ; Humans ; Ligusticum ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Pyrazines/chemistry/*pharmacology ; Reactive Oxygen Species/metabolism ; Transcription Factor AP-1/metabolism ; }, abstract = {1. Chuanxiong is a Chinese herb that has been used widely in China to treat vascular disorders. 2,3,5,6-Tetramethylpyrazine (TMP) is one of the major components purified from chuanxiong. Many studies have demonstrated that TMP is effective in the treatment of cardiovascular diseases. However, the mechanism of action by which TMP exerts relaxation in vascular vessels remains unclear. 2. Endothelin (ET)-1 is a potent vasopressor synthesised by endothelial cells both in culture and in vivo. The aims of the present study were to test the hypothesis that TMP may alter strain-induced ET-1 secretion and to identify the putative underlying signalling pathways in endothelial cells. 3. We showed that TMP inhibits strain-induced ET-1 secretion. 2,3,5,6-Tetramethylpyrazine also inhibits the strain-induced formation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. Furthermore, pretreating cells with TMP or the anti-oxidant N-acetyl-cysteine decreased strain-induced increases in ET-1 secretion and ERK1/2 phosphorylation. Using a reporter gene assay, TMP and N-acetyl-cysteine were demonstrated to also attenuate the strain-induced activity of the activator protein-1 reporter. 4. In summary, we have demonstrated, for the first time, that TMP inhibits strain-induced ET-1 gene expression, in part by interfering with the ERK1/2 pathway via attenuation of ROS formation. Thus, the present study provides important new insights into the molecular pathways that may contribute to the proposed beneficial effects of TMP in the vascular system.}, }
@article {pmid16025744, year = {2005}, author = {Yoshimoto, T and Gochou, N and Fukai, N and Sugiyama, T and Shichiri, M and Hirata, Y}, title = {Adrenomedullin inhibits angiotensin II-induced oxidative stress and gene expression in rat endothelial cells.}, journal = {Hypertension research : official journal of the Japanese Society of Hypertension}, volume = {28}, number = {2}, pages = {165-172}, doi = {10.1291/hypres.28.165}, pmid = {16025744}, issn = {0916-9636}, mesh = {Acetylcysteine/pharmacology ; Adrenomedullin ; Angiotensin II/*physiology ; Animals ; Antioxidants/pharmacology ; Cyclic AMP-Dependent Protein Kinases/antagonists &amp; inhibitors ; Dose-Response Relationship, Drug ; Endothelial Cells/*metabolism ; Enzyme Inhibitors/pharmacology ; Male ; NADH, NADPH Oxidoreductases/antagonists &amp; inhibitors ; NADPH Oxidases ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Peptides/*physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Up-Regulation/drug effects ; Vasodilator Agents/metabolism ; }, abstract = {Adrenomedullin (AM), a potent vasodilator peptide, has recently been suggested to function as an endogenous antioxidant. However, its potential site of action at the cellular level has not been clarified. The present study was undertaken to investigate whether AM directly inhibits intracellular reactive oxygen species (ROS) generation and redox-sensitive gene expression stimulated by angiotensin (Ang) II in rat aortic endothelial cells (ECs). Ang II (10(-7) mol/l) significantly increased intracellular ROS levels in ECs as measured by dichlorofluorescein (DCF) fluorescence. AM inhibited Ang II-stimulated ROS generation in a dose-dependent manner and this effect was abolished by a superoxide radical scavenger, NAD(P)H oxidase inhibitor, and a protein kinase A (PKA) inhibitor, and mimicked by a cell-permeable cAMP analog. A real-time reverse transcription-polymerase chain reaction (RT-PCR) study showed that Ang II significantly upregulated a set of redox-sensitive genes (ICAM-1, VCAM-1, PAI-1, tissue factor, MCP-1, osteopontin), and these effects were blocked by an antioxidant, N-acetyl cysteine (NAC). AM similarly and dose-dependently inhibited the Ang II-induced upregulation of the entire set of these genes via a receptor-mediated and PKA-dependent pathway, and the degrees of inhibition were similar to those by NAC. In conclusion, the present study demonstrated that AM potently blocked the Ang II-stimulated intracellular ROS generation from NAD(P)H oxidase and the subsequent redox-sensitive gene expression via a cAMP-dependent mechanism in ECs, suggesting that AM has vasculoprotective effects against pro-oxidant stimuli.}, }
@article {pmid16025522, year = {2005}, author = {Matuszczak, Y and Farid, M and Jones, J and Lansdowne, S and Smith, MA and Taylor, AA and Reid, MB}, title = {Effects of N-acetylcysteine on glutathione oxidation and fatigue during handgrip exercise.}, journal = {Muscle &amp; nerve}, volume = {32}, number = {5}, pages = {633-638}, doi = {10.1002/mus.20385}, pmid = {16025522}, issn = {0148-639X}, support = {HL45721/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Exercise ; Female ; Glutathione/*drug effects/*metabolism ; *Hand Strength ; Humans ; Male ; Muscle Fatigue/*drug effects ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Risk Factors ; Treatment Outcome ; }, abstract = {Fatigue of hand and forearm muscle groups can limit task performance by astronauts wearing space suits. Countermeasures to delay fatigue would therefore be useful to the space program. N-acetylcysteine (NAC) has been shown to inhibit fatigue during other tasks so we tested its effects during handgrip exercise. Volunteers practiced isometric handgrip maneuvers until performance was reproducible over three successive sessions (baseline). Performance then was retested after ingesting NAC (150 mg.kg(-1)) or saline. Drug administration increased NAC and cysteine blood levels (P < 0.001). Performance of sustained maximal efforts was unaffected. During repetitive submaximal efforts, NAC delayed fatigue (130% baseline) and inhibited glutathione oxidation. Saline did not alter glutathione status or performance of sustained maneuvers; repetitive task performance was increased by 15% (P < 0.05), a placebo effect. These data indicate that NAC supports glutathione homeostasis in exercising humans and may delay muscle fatigue during repetitive handgrip exercise. Our findings support oxidative stress as a causal factor in human muscle fatigue and argue for larger translational studies to define NAC effects on human performance.}, }
@article {pmid16024664, year = {2005}, author = {Lu, HR and Zhu, H and Huang, M and Chen, Y and Cai, YJ and Miao, ZH and Zhang, JS and Ding, J}, title = {Reactive oxygen species elicit apoptosis by concurrently disrupting topoisomerase II and DNA-dependent protein kinase.}, journal = {Molecular pharmacology}, volume = {68}, number = {4}, pages = {983-994}, doi = {10.1124/mol.105.011544}, pmid = {16024664}, issn = {0026-895X}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Blotting, Western ; Breast Neoplasms/enzymology/pathology ; Cell Line, Tumor ; DNA/drug effects ; DNA Damage ; DNA-Activated Protein Kinase ; DNA-Binding Proteins/*antagonists &amp; inhibitors ; Enzyme Inhibitors/pharmacology ; Humans ; Naphthoquinones/pharmacology ; Nuclear Proteins ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors ; Reactive Oxygen Species/*metabolism ; *Topoisomerase II Inhibitors ; }, abstract = {Reactive oxygen species (ROS) are produced by all aerobic cells and have been implicated in the regulation of diverse cellular functions, including intracellular signaling, transcription activation, proliferation, and apoptosis. Salvicine, a novel diterpenoid quinone compound, demonstrates a broad spectrum of antitumor activities. Although salvicine is known to trap the DNA-topoisomerase II (Topo II) complex and induce DNA double-strand breaks (DSBs), its precise antitumor mechanisms remain to be clarified. In this study, we investigated whether salvicine altered the levels of ROS in breast cancer MCF-7 cells and whether these ROS contributed to the observed antitumoral activity. Our data revealed that salvicine stimulated intracellular ROS production and subsequently elicited notable DSBs. The addition of N-acetyl cysteine (NAC), an antioxidant, effectively attenuated the salvicine-induced ROS enhancement and subsequent DNA DSBs. Heat treatment reversed the accumulation of DNA DSBs, and the addition of NAC attenuated the Topo II-DNA cleavable complexes formation and the growth inhibition of salvicine-treated JN394top2-4 yeast cells, collectively indicating that Topo II is a target of the salvicine-induced ROS. On the other hand, when examining the impact of salvicine on DNA repair pathways, we unexpectedly observed that salvicine selectively down-regulated the catalytic subunit of DNA-dependent protein kinase (DNA-PK(CS)) protein levels and repressed DNA-PK kinase activity; both of these effects were attenuated by NAC pretreatment of MCF-7 cells. Finally and most importantly, NAC attenuated salvicine-induced apoptosis and cytotoxicity in MCF-7 cells. These results indicate that apart from its direct actions, salvicine generates ROS that modulate DNA damage and repair, contributing to the comprehensive biological consequences of salvicine treatment, such as DNA DSBs, apoptosis, and cytotoxicity in tumor cells. The finding of salvicine-induced ROS provides new evidence for the molecular mechanisms of this compound. Moreover, the effects of salvicine-induced ROS on Topo II and DNA-PK give new insights into the diverse biological activities of ROS.}, }
@article {pmid16024053, year = {2005}, author = {Wu, XJ and Kassie, F and Mersch-Sundermann, V}, title = {The role of reactive oxygen species (ROS) production on diallyl disulfide (DADS) induced apoptosis and cell cycle arrest in human A549 lung carcinoma cells.}, journal = {Mutation research}, volume = {579}, number = {1-2}, pages = {115-124}, doi = {10.1016/j.mrfmmm.2005.02.026}, pmid = {16024053}, issn = {0027-5107}, mesh = {Acetylcysteine/pharmacology ; Allyl Compounds/*pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Carcinoma/drug therapy/metabolism/*pathology ; Cell Cycle/*drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Disulfides/*pharmacology ; Dose-Response Relationship, Drug ; Humans ; Lung Neoplasms/drug therapy/metabolism/*pathology ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Diallyl disulfide (DADS), an oil soluble constituent of garlic (Allium sativum), has been reported to cause antimutagentic and anticarcinogenic effects in vitro and in vivo by modulating phases I and II enzyme activities. In recent years, several studies suggested that the chemopreventive effects of DADS can also be attributed to induction of cell cycle arrest and apoptosis in cancer cells. In the present study, we reported that DADS-induced cell cycle arrest at G2/M and apoptosis in human A549 lung cancer cells in a time- and dose-dependent manner. Additionally, a significant increase of intracellular reactive oxygen species (ROS) was induced in A549 cells less than 0.5h after DADS treatment, indicating that ROS may be an early event in DADS-modulated apoptosis. Treatment of A549 cells with N-acetyl cysteine (NAC) completely abrogated DADS-induced cell cycle arrest and apoptosis. The result indicated that oxidative stress modulates cell proliferation and cell death induced by DADS.}, }
@article {pmid16020401, year = {2005}, author = {Cankayali, I and Demirag, K and Eris, O and Ersoz, B and Moral, AR}, title = {The effects of N-acetylcysteine on oxidative stress in organophosphate poisoning model.}, journal = {Advances in therapy}, volume = {22}, number = {2}, pages = {107-116}, doi = {10.1007/BF02849882}, pmid = {16020401}, issn = {0741-238X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Hemodynamics ; Lipid Peroxidation/*drug effects ; Male ; *Organophosphate Poisoning ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; }, abstract = {Organophosphate compounds act by irreversible inhibition of cholinesterase. In addition to their muscarinic, nicotinic, and central nervous system effects, some organophosphate insecticides cause oxidative stress by increasing lipid peroxidation in erythrocytes and by increasing levels of the enzymes superoxide dismutase and catalase. In this study, the effects of an antioxidant, N-acetylcysteine (NAC), in organophosphate poisoning were investigated. After obtaining Animal Ethics Committee approval, 16 male Wistar rats were divided into 2 groups. Following anesthesia, rats were tracheostomized and mechanically ventilated. Invasive hemodynamic monitoring was begun and all rats were injected with 70 mg/kg of dichlorvos (DDVP) intraperitoneally. The rats in group 1 received placebo intravenous 0.9% NaCl and the rats in group 2 received 150 mg/kg intravenous NAC. Blood samples were obtained before injection of DDVP and 60 minutes after injection to determine levels of malondialdehyde, superoxide dismutase, and catalase. Hemodynamic data and biochemistry test results were compared by analysis of variance and Wilcoxon test. P<.05 was regarded as statistically significant. Superoxide dismutase and malondialdehyde levels were significantly increased in group 1 while no difference was observed in group 2. It was concluded that organophosphate compounds might cause oxidative stress by interfering with antioxidant defense mechanisms in erythrocytes and that NAC might prevent increased lipid peroxidation. In addition to classic treatments, drugs with antioxidant effects might therefore be promising in the treatment of organophosphate poisoning.}, }
@article {pmid16010245, year = {2005}, author = {Khan, AW and Fuller, BJ and Shah, SR and Davidson, BR and Rolles, K}, title = {A prospective randomized trial of N-acetyl cysteine administration during cold preservation of the donor liver for transplantation.}, journal = {Annals of hepatology}, volume = {4}, number = {2}, pages = {121-126}, pmid = {16010245}, issn = {1665-2681}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Cold Temperature ; Female ; Humans ; Liver Transplantation ; Male ; Middle Aged ; Organ Preservation/*methods ; Pilot Projects ; Prospective Studies ; Reperfusion Injury/etiology/*prevention &amp; control ; Tissue and Organ Harvesting/*adverse effects ; }, abstract = {AIMS: N-acetyl cysteine (NAC), an anti oxidant and a glutathione precursor, is effective in ameliorating liver injury of Tylenol overdose. There is experimental evidence that it also reduces ischemia reperfusion (I/R) injury. This clinical study was undertaken to study the effect of NAC administered in the donor operation.<br><br>METHODS: 22 patients were randomized to receive NAC (IV &amp; Portal flush) or no NAC (Control Group) during donor operation. Peak AST levels and 1-hour post-reperfusion biopsies were used to assess I/R injury. Episodes of acute rejection were recorded together with immunosuppressive drug levels.<br><br>RESULTS: There were 4 exclusions (re-exploration for post-operative hemorrhage x3, OLT for acute liver failure x1). The two groups (n = 9 each) were matched for recipient and donor ages and sex. Viral hepatitis accounted for cirrhosis in 3 patients in NAC Group and 6 patients in Control Group. Statistically, Cold and warm ischemia times were not significantly different as was the use of blood and blood products in both groups. Serum peak AST levels were similar and post- reperfusion biopsy showed moderate to severe reperfusion injury in 3 recipients in the NAC Group and 4 in the Control Group. Excluding ones associated with low Tacrolimus levels (n = 4), there were 6 episodes of acute rejection (2- mild, 4- moderate) in the NAC Group and 5 in the Control Group (3- mild,1- moderate, 1- severe).<br><br>CONCLUSION: In this pilot study, NAC administered during donor operation did not show a protective effect on I/R injury or on acute cellular rejection.}, }
@article {pmid16005153, year = {2005}, author = {Rhoden, CR and Wellenius, GA and Ghelfi, E and Lawrence, J and González-Flecha, B}, title = {PM-induced cardiac oxidative stress and dysfunction are mediated by autonomic stimulation.}, journal = {Biochimica et biophysica acta}, volume = {1725}, number = {3}, pages = {305-313}, doi = {10.1016/j.bbagen.2005.05.025}, pmid = {16005153}, issn = {0006-3002}, support = {HL07118/HL/NHLBI NIH HHS/United States ; P50 ES00002/ES/NIEHS NIH HHS/United States ; R01 HL/ES68073/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/pharmacology ; Air Pollutants/*toxicity ; Animals ; Autonomic Agents/antagonists &amp; inhibitors ; Autonomic Nervous System/drug effects/*physiology ; Glycopyrrolate/pharmacology ; Heart Diseases/*chemically induced/*physiopathology ; Heart Rate/drug effects ; Inhalation Exposure ; Isoproterenol/pharmacology ; Male ; Muscarine/pharmacology ; *Oxidative Stress ; Particle Size ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; }, abstract = {Epidemiological studies show that increases in particulate air pollution (PM) are associated with increases in cardiopulmonary morbidity and mortality. However, the mechanism(s) underlying the cardiac effects of PM remain unknown. We used pharmacological strategies to determine whether oxidants are implicated in PM-dependent cardiac dysfunction and whether PM-induced increase in autonomic stimulation on the heart mediates cardiac oxidative stress and toxicity. Adult Sprague-Dawley rats were exposed to either intratracheal instillation of urban air particles (UAP 750 microg) or to inhalation of concentrated ambient particles (CAPs mass concentration 700+/-180 microg/m3) for 5 h. Oxidative stress and cardiac function were evaluated 30 min after UAP instillation or immediately after exposure to CAPs. Instillation of UAP led to significant increases in heart oxidants measured as organ chemiluminescence (UAP: 38+/-5 cps/cm2, sham: 10+/-1 cps/cm2) or thiobarbituric acid reactive substances (TBARS, UAP: 76+/-10, Sham 30+/-6 pmol/mg protein). Heart rate increased immediately after exposure (UAP: 390+/-20 bpm, sham: 350+/-10 bpm) and returned to basal levels over the next 30 min. Heart rate variability (SDNN) was unchanged immediately after exposure, but significantly increased during the recovery phase (UAP: 3.4+/-0.2, Sham: 2.4+/-0.3). To determine the role of ROS in the development of cardiac malfunction, rats were treated with 50 mg/kg N-acetylcysteine (NAC) 1 h prior to UAP instillation or CAPs inhalation. NAC prevented changes in heart rate and SDNN in UAP-exposed rats (340+/-8 and 2.9+/-0.3, respectively). To investigate the role of the autonomic nervous system in PM-induced oxidative stress, rats were given 5 mg/kg atenolol (beta-1 receptor antagonist), 0.30 mg/kg glycopyrrolate (muscarinic receptor antagonist) or saline immediately before exposure to CAPs aerosols. Both atenolol and glycopyrrolate effectively prevented CAPs-induced cardiac oxidative stress (CL(ATEN): 11+/-1 cps/cm2, CL(GLYCO): 10+/-1 cps/cm2, TBARS(ATEN): 40+/-6 pmol/mg protein, TBARS(GLYCO): 38+/-6 pmol/mg protein). These data indicate that PM exposure increases cardiac oxidants via autonomic signals and the resulting oxidative stress is associated with significant functional alterations in the heart.}, }
@article {pmid16002186, year = {2005}, author = {Smith, A and Letters, S and Lange, A and Perrett, D and McHugh, S and Bagg, J}, title = {Residual protein levels on reprocessed dental instruments.}, journal = {The Journal of hospital infection}, volume = {61}, number = {3}, pages = {237-241}, doi = {10.1016/j.jhin.2005.01.021}, pmid = {16002186}, issn = {0195-6701}, mesh = {Acetylcysteine/chemistry ; Cross Infection/prevention &amp; control ; Decontamination/methods ; *Dental Instruments ; *Equipment Contamination ; Fluorescence ; Humans ; Microscopy ; Proteins/*analysis ; Staining and Labeling ; United Kingdom ; o-Phthalaldehyde/chemistry ; }, abstract = {Reduction of the initial bioburden on instruments, prior to sterilization, is believed to reduce transmission risks of iatrogenic Creutzfeldt-Jakob disease. Endodontic files are used in the preparation of root canals and are likely to have close contact and become contaminated with neural material from branches of the maxillary and mandibular cranial nerves. This study examined methods used by 22 dental practices to clean endodontic files, and scored visible debris and residual protein levels adhering to 220 dental endodontic files that had been used, cleaned, autoclaved and were deemed ready for re-use. Visible debris was scored after examination under a dissecting light microscope. Residual protein was quantified using a fluorescent assay based on reaction of proteins with o-phthaldialdehyde/N-acetyl cysteine. There was wide variation in the methods used by practices to clean endodontic files. The cleaning process varied from a wipe with an alcohol-impregnated cloth to hand scrubbing and/or use of an ultrasonic bath. Surface debris was visually detected on 98% of files. Residual protein was detected on all the files examined (median amount: 5.4 microg; range: 0.5-63.2 microg). These results demonstrate that the cleaning of some instruments reprocessed routinely in primary care is incomplete, and such instruments cannot be excluded as a potential source of cross-infection.}, }
@article {pmid16001974, year = {2005}, author = {Gustafsson, AC and Kupershmidt, I and Edlundh-Rose, E and Greco, G and Serafino, A and Krasnowska, EK and Lundeberg, T and Bracci-Laudiero, L and Romano, MC and Parasassi, T and Lundeberg, J}, title = {Global gene expression analysis in time series following N-acetyl L-cysteine induced epithelial differentiation of human normal and cancer cells in vitro.}, journal = {BMC cancer}, volume = {5}, number = {}, pages = {75}, pmid = {16001974}, issn = {1471-2407}, mesh = {Acetylcysteine/*chemistry ; Antioxidants/chemistry ; Cadherins/metabolism ; Cell Differentiation/*drug effects ; Cell Line ; Cell Line, Tumor ; Cell Lineage ; Cell Proliferation ; Cytoskeleton/metabolism ; Down-Regulation ; Epithelium/metabolism/*pathology ; *Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Genome, Human ; Humans ; Keratinocytes/cytology ; Kinetics ; Oligonucleotide Array Sequence Analysis ; Polymerase Chain Reaction ; Skin Neoplasms/metabolism/*pathology ; Time Factors ; Transcription, Genetic ; Up-Regulation ; }, abstract = {BACKGROUND: Cancer prevention trials using different types of antioxidant supplements have been carried out at several occasions and one of the investigated compounds has been the antioxidant N-acetyl-L-cysteine (NAC). Studies at the cellular level have previously demonstrated that a single supplementation of NAC induces a ten-fold more rapid differentiation in normal primary human keratinocytes as well as a reversion of a colon carcinoma cell line from neoplastic proliferation to apical-basolateral differentiation. The investigated cells showed an early change in the organization of the cytoskeleton, several newly established adherens junctions with E-cadherin/beta-catenin complexes and increased focal adhesions, all features characterizing the differentiation process.<br><br>METHODS: In order to investigate the molecular mechanisms underlying the proliferation arrest and accelerated differentiation induced by NAC treatment of NHEK and Caco-2 cells in vitro, we performed global gene expression analysis of NAC treated cells in a time series (1, 12 and 24 hours post NAC treatment) using the Affymetrix GeneChip Human Genome U95Av2 chip, which contains approximately 12,000 previously characterized sequences. The treated samples were compared to the corresponding untreated culture at the same time point.<br><br>RESULTS: Microarray data analysis revealed an increasing number of differentially expressed transcripts over time upon NAC treatment. The early response (1 hour) was transient, while a constitutive trend was commonly found among genes differentially regulated at later time points (12 and 24 hours). Connections to the induction of differentiation and inhibition of growth were identified for a majority of up- and down-regulated genes. All of the observed transcriptional changes, except for seven genes, were unique to either cell line. Only one gene, ID-1, was mutually regulated at 1 hour post treatment and might represent a common mediator of early NAC action. The detection of several genes that previously have been identified as stimulated or repressed during the differentiation of NHEK and Caco-2 provided validation of results. In addition, real-time kinetic PCR analysis of selected genes also verified the differential regulation as identified by the microarray platform.<br><br>CONCLUSION: NAC induces a limited and transient early response followed by a more consistent and extensively different expression at later time points in both the normal and cancer cell lines investigated. The responses are largely related to inhibition of proliferation and stimulation of differentiation in both cell types but are almost completely lineage specific. ID-1 is indicated as an early mediator of NAC action.}, }
@article {pmid15998281, year = {2005}, author = {Kishida, KT and Pao, M and Holland, SM and Klann, E}, title = {NADPH oxidase is required for NMDA receptor-dependent activation of ERK in hippocampal area CA1.}, journal = {Journal of neurochemistry}, volume = {94}, number = {2}, pages = {299-306}, pmid = {15998281}, issn = {0022-3042}, support = {F31 NS047852/NS/NINDS NIH HHS/United States ; N5034007//PHS HHS/United States ; N5047852//PHS HHS/United States ; }, mesh = {6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology ; Acetylcysteine/analogs &amp; derivatives/pharmacology ; Animals ; Azoles/pharmacology ; Blotting, Western/methods ; Catalase/pharmacology ; Catecholamines/pharmacology ; Dopamine Agonists ; Drug Interactions ; Enzyme Activation/drug effects/physiology ; Enzyme Inhibitors/pharmacology ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Excitatory Postsynaptic Potentials/drug effects/physiology/radiation effects ; Extracellular Signal-Regulated MAP Kinases/classification/*metabolism ; Free Radical Scavengers/pharmacology ; Hippocampus/*cytology/enzymology ; Imidazolines/pharmacology ; In Vitro Techniques ; Isoindoles ; Lysine/analogs &amp; derivatives/pharmacology ; Metalloporphyrins/pharmacology ; Mice ; Mice, Inbred C57BL ; N-Methylaspartate/pharmacology ; NADPH Oxidases/*metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Neurons/drug effects/*physiology ; Organoselenium Compounds/pharmacology ; Patch-Clamp Techniques/methods ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; Receptors, N-Methyl-D-Aspartate/*physiology ; Superoxide Dismutase/pharmacology ; }, abstract = {Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor activation results in production of reactive oxygen species (ROS) and activation of extracellular signal-regulated kinase (ERK) in hippocampal area CA1. In addition, application of ROS to hippocampal slices has been shown to result in activation of ERK in area CA1. To determine whether these events were linked causally, we investigated whether ROS are required for NMDA receptor-dependent activation of ERK. In agreement with previous studies, we found that treatment of hippocampal slices with NMDA resulted in activation of ERK in area CA1. The NMDA receptor-dependent activation of ERK was either blocked or attenuated by a number of antioxidants, including the general antioxidant N-acetyl-L-cysteine (L-NAC), the superoxide-scavenging enzyme superoxide dismutase (SOD), the membrane-permeable SOD mimetic Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), the hydrogen peroxide-scavenging enzyme catalase, and the catalase mimetic ebselen. The NMDA receptor-dependent activation of ERK also was blocked by the NADPH oxidase inhibitor diphenylene iodonium (DPI) and was absent in mice that lacked p47(phox), one of the required protein components of NADPH oxidase. Taken together, our results suggest that ROS production, especially superoxide production via NADPH oxidase, is required for NMDA receptor-dependent activation of ERK in hippocampal area CA1.}, }
@article {pmid15997091, year = {2005}, author = {Chularojmontri, L and Wattanapitayakul, SK and Herunsalee, A and Charuchongkolwongse, S and Niumsakul, S and Srichairat, S}, title = {Antioxidative and cardioprotective effects of Phyllanthus urinaria L. on doxorubicin-induced cardiotoxicity.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {28}, number = {7}, pages = {1165-1171}, doi = {10.1248/bpb.28.1165}, pmid = {15997091}, issn = {0918-6158}, mesh = {Animals ; Antioxidants/*pharmacology ; Cardiotonic Agents/*pharmacology ; Caspase 3 ; Caspases/metabolism ; Cell Line ; Doxorubicin/*toxicity ; Heart/*drug effects ; Lipid Peroxidation/drug effects ; NF-kappa B/metabolism ; Phyllanthus/*drug effects ; Rats ; }, abstract = {Cardiac toxicity is a major adverse effect caused by doxorubicin (DOX) therapy. Many recent studies have shown that DOX toxicity involves generation of reactive oxygen species (ROS). Although protection or alleviation of DOX toxicity can be achieved by administration of antioxidant vitamins such as ascorbic acid and vitamin E, their cardioprotective effect remains controversial. Thus alternative naturally occurring antioxidants may potentially be candidates for antioxidant therapy. In this study, we investigated the antioxidative and cytoprotective effects of Phyllanthus urinaria (PU) against DOX toxicity using H9c2 cardiac myoblasts. The total antioxidant capacity of PU (1 mg/ml) was 5306.75+/-461.62 FRAP value (microM). DOX IC50 values were used to evaluate the cytoprotective effects of PU ethanolic extract (1 or 10 microg/ml) in comparison with those of ascorbic acid (VIT C, 100 microM) and N-acetylcysteine (NAC, 100 microM). PU treatments (1 or 10 microg/ml) dose dependently caused rightward DOX IC50 shifts of 2.8- and 8.5-fold, respectively while treatments with VIT C and NAC increased DOX IC50 by 3.3- and 4.2-fold, respectively. Additionally, lipid peroxidation and caspase-3 activity were parameters used to evaluate cytoprotective effect. All antioxidants completely inhibited cellular lipid peroxidation and caspase-3 activation induced by DOX (1 microM). Endogenous antioxidant defense such as total glutathione (tGSH), catalase and superoxide dismutase (SOD) activity was also modulated by the antioxidants. PU treatment alone dose dependently increased tGSH, and this effect was retained in the presence of DOX. Similar effect was observed in the assessment of catalase and SOD enzyme activity. The nuclear factor kappaB (NFkappaB) transcription factor assay demonstrated that all antioxidants significantly inhibited DOX-induced NFkappaB activation. Our results suggest that PU protection against DOX cardiotoxicity was mediated through multiple pathways and this plant may serve as an alternative source of antioxidants for prevention of DOX cardiotoxicity.}, }
@article {pmid15990827, year = {2005}, author = {Katsinelos, P and Kountouras, J and Paroutoglou, G and Beltsis, A and Mimidis, K and Zavos, C}, title = {Intravenous N-acetylcysteine does not prevent post-ERCP pancreatitis.}, journal = {Gastrointestinal endoscopy}, volume = {62}, number = {1}, pages = {105-111}, doi = {10.1016/s0016-5107(05)01574-9}, pmid = {15990827}, issn = {0016-5107}, mesh = {Adult ; Aged ; Aged, 80 and over ; Amylases/blood ; Antioxidants/*administration &amp; dosage ; Cholangiopancreatography, Endoscopic Retrograde/*adverse effects ; Cystine/administration &amp; dosage/*analogs &amp; derivatives ; Double-Blind Method ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Pancreatitis, Acute Necrotizing/enzymology/*etiology/*prevention &amp; control ; Prospective Studies ; Severity of Illness Index ; Treatment Outcome ; }, abstract = {BACKGROUND: Acute pancreatitis remains the most common complication of ERCP. Prophylactic administration of N-acetylcysteine (NAC) probably decreases the incidence and the severity of experimental pancreatitis. The aim of the present study was to assess the efficacy of intravenous NAC for prevention of post-ERCP pancreatitis in humans, who represent an appropriate model to study the potential role of NAC in this setting.<br><br>METHODS: A prospective, double-blind, placebo-controlled trial was conducted in 256 patients who underwent ERCP. Patients were randomized to receive intravenous NAC at a loading dose of 70 mg/kg 2 hours before and 35 mg/kg at 4-hour intervals for a total of 24 hours after the procedure, or to receive normal saline solution as placebo. Patients were clinically evaluated, and serum amylase levels were measured before and 6 hours and 24 hours after the procedure. Standardized criteria were used to diagnose and to grade the severity of post-ERCP pancreatitis.<br><br>RESULTS: A total of 249 patients were included in the analysis. The two groups were matched for age, gender, underlying disease and indication for treatment, ERCP findings, and type of treatment. The overall incidence of post-ERCP acute pancreatitis was 10.8%, with 12.1% in the NAC group and 9.6% in the placebo group. There were no statistical differences in the incidence or severity grades between the groups. The mean duration of hospitalization for pancreatitis also was similar in the NAC group and the placebo group (3.6 +/- 0.9 and 3 +/- 1.5 days, respectively).<br><br>CONCLUSIONS: The results of this trial show the absence of any beneficial effect of NAC on the incidence and the severity of ERCP-induced pancreatitis.}, }
@article {pmid15982852, year = {2006}, author = {Iiyama, M and Kakihana, K and Kurosu, T and Miura, O}, title = {Reactive oxygen species generated by hematopoietic cytokines play roles in activation of receptor-mediated signaling and in cell cycle progression.}, journal = {Cellular signalling}, volume = {18}, number = {2}, pages = {174-182}, doi = {10.1016/j.cellsig.2005.04.002}, pmid = {15982852}, issn = {0898-6568}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Cycle/drug effects ; Cell Cycle Proteins/metabolism ; Cell Line ; Erythropoietin/antagonists &amp; inhibitors/*pharmacology ; Hematopoietic Stem Cells/drug effects/*metabolism ; Interleukin-3/antagonists &amp; inhibitors/*pharmacology ; Mice ; Proto-Oncogene Proteins c-myc/metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, Erythropoietin/*metabolism ; Receptors, Interleukin-3/*metabolism ; Signal Transduction ; }, abstract = {Hematopoietic cytokines, including interleukin (IL)-3 and erythropoietin (Epo), regulate hematopoiesis by stimulating their receptors coupled with the Jak2 tyrosine kinase to induce receptor tyrosine phosphorylation and activate mainly the STAT5, PI3K/Akt, and Ras/MEK/ERK signaling pathways. Here we demonstrate that IL-3 or Epo induces a rapid and transient (peaking at 30 min) as well as late progressive increase in reactive oxygen species (ROS) in a hematopoietic progenitor model cell line, 32Dcl3, and its subclone expressing the Epo receptor (EpoR), 32D/EpoR-Wt. The cytokine-induced ROS generation was not affected in 32Dcl3 cells depleted of mitochondrial DNA. The antioxidant N-acetyl-L-cysteine (NAC) inhibited IL-3-induced tyrosine phosphorylation of Jak2, IL-3 receptor betac subunit (IL-3Rbetac), and STAT5 as well as activation-specific phosphorylation of Akt, MEK, and ERK, while treatment of cells with H2O2 activated these signaling events. NAC also inhibited the EpoR-induced transphosphorylation of IL-3Rbetac. Moreover, NAC treatment reduced the expression levels of c-Myc, Cyclin D2, and Cyclin E, and induced expression of p27, thus inhibiting the G1 to S phase transition of cells cultured with IL-3. Further studies have shown that the degradation of c-Myc was facilitated or inhibited by treatment of cells with NAC or H2O2, respectively. These data indicate that the rapid generation of ROS by cytokine stimulation, which is at least partly independent of mitochondria, may play a role in activation of Jak2 and the STAT5, PI3K/Akt, and Ras/MEK/ERK signaling pathways as well as in transactivation of cytokine receptors. The cytokine-induced ROS generation was also implicated in G1 to S progression, possibly through stabilization of c-Myc and induction of G1 phase Cyclin expression leading to suppression of p27.}, }
@article {pmid15982189, year = {2005}, author = {Fusai, G and Glantzounis, GK and Hafez, T and Yang, W and Quaglia, A and Sheth, H and Kanoria, S and Parkes, H and Seifalian, A and Davidson, BR}, title = {N-Acetylcysteine ameliorates the late phase of liver ischaemia/reperfusion injury in the rabbit with hepatic steatosis.}, journal = {Clinical science (London, England : 1979)}, volume = {109}, number = {5}, pages = {465-473}, doi = {10.1042/CS20050081}, pmid = {15982189}, issn = {0143-5221}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/metabolism ; Animals ; Bile/metabolism ; Cholesterol, Dietary/administration &amp; dosage ; Fatty Liver/*complications/etiology/pathology ; Hemodynamics/drug effects ; Liver/physiopathology ; Liver Circulation/drug effects ; Magnetic Resonance Spectroscopy ; Microcirculation/drug effects ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Rabbits ; Reperfusion Injury/etiology/*prevention &amp; control ; }, abstract = {Steatotic livers are highly susceptible to I/R (ischaemia/reperfusion) injury and, therefore, the aim of the present study was to evaluate the in vivo effect of NAC (N-acetylcysteine) on hepatic function in the early and initial late phase of warm liver I/R injury in steatotic rabbits. Twelve New Zealand White rabbits were fed a high-cholesterol (2%) diet. The control group (n=6) underwent lobar liver ischaemia for 1 h, followed by 6 h of reperfusion. In the treated group receiving NAC (n=6), an intravenous infusion of NAC was administered prior to and during the 6 h reperfusion period. Systemic and hepatic haemodynamics were monitored continuously. ALT (alanine aminotransferase) activity and bile production were measured. NMR spectroscopy was used to analyse bile composition. Oxidation of DHR (dihydrorhodamine) to RH (rhodamine) was used as a marker of production of reactive oxygen and nitrogen species. Moderate centrilobular hepatic steatosis was demonstrated by histology. The results showed that NAC administration significantly improved portal flow, hepatic microcirculation, bile composition and bile flow after 5 h of reperfusion. NAC administration was also associated with less hepatocellular injury, as indicated by ALT serum activity, and decreased the oxidation of DHR to RH. In conclusion, NAC administration decreased the extent of I/R injury in the steatotic liver, particularly during the late phase of reperfusion.}, }
@article {pmid15981033, year = {2005}, author = {Aykin-Burns, N and Franklin, EA and Ercal, N}, title = {Effects of N-acetylcysteine on lead-exposed PC-12 cells.}, journal = {Archives of environmental contamination and toxicology}, volume = {49}, number = {1}, pages = {119-123}, doi = {10.1007/s00244-004-0025-0}, pmid = {15981033}, issn = {0090-4341}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Combinations ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Lead/*toxicity ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Oxidative Stress/*drug effects ; PC12 Cells/*drug effects/metabolism/pathology ; Rats ; Trypan Blue/metabolism ; }, abstract = {The neurotoxicity of lead has been well established through numerous studies. However, the cellular processes of lead neurotoxicity, as well as techniques to prevent or reverse cellular damage after lead exposure, remain unknown. If oxidative stress plays a primary role in lead-induced neurotoxicity, antioxidants should assist in reviving lead-exposed cells. The present study explores N-acetylcysteine (NAC) as an antioxidant agent in PC-12 cells after lead exposure. Selective oxidative stress parameters, including glutathione (GSH), glutathione disulfide (GSSG), and malondialdehyde (MDA), were measured in PC-12 cells exposed to various concentrations of lead acetate. Administering NAC after lead exposure improved cell survival as measured by Trypan Blue exclusion. NAC treatment also increased the GSH/GSSG ratio compared to the lead-only group, and reduced MDA to near control levels. These results imply that NAC protects cells from lead-induced oxidative damage by boosting the PC-12 cells' antioxidant defense mechanisms.}, }
@article {pmid15979588, year = {2005}, author = {Viggiano, A and Monda, M and Viggiano, A and Viggiano, D and Viggiano, E and Chiefari, M and Aurilio, C and De Luca, B}, title = {Trigeminal pain transmission requires reactive oxygen species production.}, journal = {Brain research}, volume = {1050}, number = {1-2}, pages = {72-78}, doi = {10.1016/j.brainres.2005.05.021}, pmid = {15979588}, issn = {0006-8993}, mesh = {2-Methoxyestradiol ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Enzyme Inhibitors/pharmacology ; Estradiol/analogs &amp; derivatives/pharmacology ; Facial Pain/*metabolism/physiopathology ; Hydrogen Peroxide/metabolism ; Male ; Microdialysis ; Nociceptors/*physiology ; Pain Measurement ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/antagonists &amp; inhibitors ; Trigeminal Nerve/*metabolism/physiopathology ; }, abstract = {Three experiments were conducted in order to investigate the possible involvement of the reactive oxygen species in the nociception within the subnucleus caudalis of the spinal trigeminal nucleus (Vc). In the first experiment the extracellular level of hydrogen peroxide was evaluated by microdialysis in the Vc of two groups of six rats before and after a formalin (group 1) or saline solution (group 2) injection into the upper lip. In the second experiment the formalin test was conducted in three groups of 6 rats after a microinjection of 2-methoxyestradiol (2-ME, a superoxide-dismutase inhibitor; group 1) or N-acetylcysteine (NAC, an oxygen intermediate scavenger; group 2) or saline solution (group 3) into the Vc. In the third experiment an histochemical assay for superoxide dismutase activity was performed on two groups of 4 rats each 2 h after a formalin (group 1) or saline solution (group 2) injection into the upper lip. The results showed that (1) the level of hydrogen peroxide increases into the Vc during facial pain (134% of baseline); (2) the inhibition of superoxide dismutase or the removal of oxygen intermediate within the Vc decreases the sensibility to facial pain stimuli; and (3) persistent facial pain stimuli decrease the superoxide activity into the Vc (90% of counter-lateral). These data indicate that reactive oxygen species are produced in the Vc during persistent facial pain and are necessary for the transmission of pain.}, }
@article {pmid15979014, year = {2005}, author = {Jallali, N and Ridha, H and Thrasivoulou, C and Underwood, C and Butler, PE and Cowen, T}, title = {Vulnerability to ROS-induced cell death in ageing articular cartilage: the role of antioxidant enzyme activity.}, journal = {Osteoarthritis and cartilage}, volume = {13}, number = {7}, pages = {614-622}, doi = {10.1016/j.joca.2005.02.011}, pmid = {15979014}, issn = {1063-4584}, mesh = {Animals ; Cartilage, Articular/*drug effects/metabolism ; Catalase/metabolism ; Cell Death/*drug effects ; Chondrocytes/*drug effects/metabolism ; Glutathione Peroxidase/metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVES: To test the hypothesis that age-related loss of chondrocytes in cartilage is associated with impaired reactive oxygen species (ROS) homeostasis resulting from reduced antioxidant defence.<br><br>METHODS: Cell numbers: The total number of chondrocytes in the articular cartilage of the femoral head of young, mature and old rats was estimated using an unbiased stereological method. ROS quantification: Fluorescence intensity in chondrocytes was quantified using the oxygen free radical sensing probe dihydrorhodamine 123 (DHR 123), confocal laser scanning microscopy and densitometric image analysis. In order to delineate the reactive species, explants were pre-treated with N-acetylcysteine (NAC) or N(G)-nitro-l-arginine methyl ester (l-NAME) prior to ROS quantification. Induction of intracellular ROS: Explants were incubated in the redox-cycling drug menadione after which they underwent ROS quantification and cell-viability assay. Antioxidant enzyme activity: The activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPX) was measured.<br><br>RESULTS: Chondrocyte numbers: A significant and progressive loss of chondrocytes was observed with ageing. Cellular ROS levels: A significant age-related increase in cellular ROS-induced fluorescence was demonstrated. NAC significantly reduced ROS levels in old chondrocytes only. Induction of intracellular ROS: Menadione increased cellular ROS levels dose-dependently in young and old chondrocytes, with a greater effect in the latter. Old chondrocytes were more vulnerable to menadione-induced cytotoxicity. Antioxidant enzymes: Catalase activity declined significantly in aged cartilage whilst SOD and GPX activities were unaltered.<br><br>CONCLUSIONS: Substantial loss of chondrocytes occurs in rat articular cartilage which may result from increased vulnerability to elevated intracellular ROS levels, consequent upon a decline in antioxidant defence.}, }
@article {pmid15978632, year = {2005}, author = {Kim, YH and Park, EJ and Han, ST and Park, JW and Kwon, TK}, title = {Arsenic trioxide induces Hsp70 expression via reactive oxygen species and JNK pathway in MDA231 cells.}, journal = {Life sciences}, volume = {77}, number = {22}, pages = {2783-2793}, doi = {10.1016/j.lfs.2005.04.024}, pmid = {15978632}, issn = {0024-3205}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Blotting, Western ; Cells, Cultured ; DNA Primers ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation/*drug effects ; HSP70 Heat-Shock Proteins/*metabolism ; Heat Shock Transcription Factors ; Humans ; Luciferases ; MAP Kinase Kinase 4/antagonists &amp; inhibitors/*metabolism ; Oxides/*pharmacology ; Reactive Oxygen Species/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/*physiology ; Transcription Factors/metabolism ; }, abstract = {In the present study, we determined the molecular pathways that induce the heat shock proteins (Hsps) after treatment of cells with arsenic trioxide. Administration of arsenic trioxide to MDA231 cells leads to induce Hsp70, which is accompanied by generation of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK). We showed that arsenic trioxide-induced Hsp70 expression was caused by activation of ROS and prevented by the antioxidant N-Acetyl-Cysteine (NAC). SP600125 and dominant-negative SEK suppressed Hsp70 promoter-driven reporter gene expression, suggesting that JNK would be preferentially associated with the protective heat shock response against arsenic trioxide stress. In addition, SP600125, a specific JNK inhibitor, significantly reduced the amount of phosphorylated HSF1 upon administration of arsenic trioxide. It is likely that Hsp70 expression against arsenic trioxide exposure protects cells from oxidative injury and apoptotic cell death by means of JNK activity.}, }
@article {pmid15978279, year = {2005}, author = {Lockwood, DB and Wataha, JC and Lewis, JB and Tseng, WY and Messer, RL and Hsu, SD}, title = {Blue light generates reactive oxygen species (ROS) differentially in tumor vs. normal epithelial cells.}, journal = {Dental materials : official publication of the Academy of Dental Materials}, volume = {21}, number = {7}, pages = {683-688}, doi = {10.1016/j.dental.2004.07.022}, pmid = {15978279}, issn = {0109-5641}, mesh = {Antioxidants/pharmacology ; Carcinoma, Squamous Cell ; Color ; Dose-Response Relationship, Radiation ; Epithelial Cells/drug effects/metabolism/*radiation effects ; Fluoresceins ; Fluorescent Dyes ; *Light ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured/drug effects/metabolism/*radiation effects ; }, abstract = {OBJECTIVES: Blue light of high intensity is commonly used in dentistry to activate polymerization of resin restorative materials. Other than its effects on the retina, the biological effects of blue light (380-500nm wavelengths) are poorly studied. Limited evidence suggests that blue light acts by forming intracellular reactive oxygen species (ROS) that then affect critical cell functions. If the biological effects of blue light are redox-mediated, antioxidants might be used to mitigate unwanted side effects of blue light during clinical use, or blue light might be used therapeutically to modulate redox-sensitive cell signaling responses.<br><br>METHODS: Intracellular ROS were estimated using HFLUOR-DA (dihydrofluorescein diacetate), a vital fluorescein-based, redox-sensitive dye. ROS were measured in normal (NHEK) and oral squamous carcinoma (OSC2) epithelial cells, shown previously to respond differentially to blue light irradiation. Two-hour cumulative levels of ROS and approximate ROS lifetimes were measured after irradiation doses of 5-30 J/cm(2). The blue light-induced generation of ROS was further tested by the ability of the antioxidants N-acetylcysteine (NAC) and vitamin E to mitigate intracellular ROS levels.<br><br>RESULTS: Dose-dependent ROS levels were generated in both NHEK and OSC2 cells, but cumulative levels were higher and persisted longer in the OSC2 cells. Both vitamin E and NAC significantly reduced blue-light-induced levels of ROS, but were more effective in the OSC2 cells.<br><br>SIGNIFICANCE: The induction of intracellular ROS by blue light implies that redox effects may mediate cellular responses to blue light. This result suggests the opportunity to mitigate any effects of direct or coincident exposure during dental treatment via antioxidants, and the opportunity to exploit differences in redox processing among cells for possible treatment of epithelial cancer or wound healing.}, }
@article {pmid15976188, year = {2005}, author = {Xu, DX and Chen, YH and Wang, JP and Sun, MF and Wang, H and Wei, LZ and Wei, W}, title = {Perinatal lipopolysaccharide exposure downregulates pregnane X receptor and Cyp3a11 expression in fetal mouse liver.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {87}, number = {1}, pages = {38-45}, doi = {10.1093/toxsci/kfi239}, pmid = {15976188}, issn = {1096-6080}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aryl Hydrocarbon Hydroxylases/*genetics/metabolism ; Cytochrome P-450 CYP3A ; Down-Regulation ; Female ; Fetus/*drug effects/metabolism ; Gene Expression Regulation/*drug effects ; Lipid Peroxidation/drug effects ; Lipopolysaccharides/*toxicity ; Liver/*metabolism ; Male ; Membrane Proteins ; Mice ; Mice, Inbred ICR ; Oxidoreductases, N-Demethylating/*genetics/metabolism ; Pregnane X Receptor ; RNA, Messenger/analysis ; Receptors, Cytoplasmic and Nuclear/*genetics ; Receptors, Steroid/*genetics ; }, abstract = {The pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates cytochrome P450 3A (CYP3A) gene transcription in a ligand-dependent manner. Lipopolysaccharide (LPS)-induced downregulation on PXR and cyp3a11 in adult mouse liver has been well characterized. In this study, we investigated the effects of maternal LPS exposure on PXR and cyp3a11 expression in fetal mouse liver. Pregnant ICR mice were injected intraperitoneally with different doses of LPS (0.1 approximately 0.5 mg/kg) on gestational day (GD) 17. PXR and cyp3a11 mRNA levels were determined using RT-PCR. Erythromycin N-demethylase (ERND) activity was used as an indicator of CYP3A expression in this study. Results showed that LPS significantly downregulated PXR and cyp3a11 mRNA levels and ERND activity in fetal liver in a dose-dependent manner. LPS-induced downregulation of PXR and cyp3a11 mRNA expression and ERND activity was attenuated after pregnant mice were pretreated with alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Additional experiment revealed that LPS significantly increased lipid peroxidation in fetal liver, which was also attenuated by PBN pretreatment. Furthermore, LPS-induced downregulation of PXR and cyp3a11 mRNA expression and ERND activity was prevented by maternal pretreatment with N-acetylcysteine (NAC). Maternal pretreatment with NAC also inhibited LPS-initiated lipid peroxidation and GSH depletion in fetal liver. However, maternal LPS treatment did not affect nitrite plus nitrate concentration in fetal liver. Correspondingly, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase (iNOS), has no effect on LPS-induced downregulation of PXR and cyp3a11 expression and ERND activity in fetal liver. These results indicated that maternal LPS exposure downregulates PXR and cyp3a11 in fetal mouse liver. Reactive oxygen species (ROS) may be involved in LPS-induced downregulation of PXR and cyp3a11 in fetal mouse liver.}, }
@article {pmid15975667, year = {2005}, author = {Mayo, JC and Sainz, RM and Tan, DX and Hardeland, R and Leon, J and Rodriguez, C and Reiter, RJ}, title = {Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages.}, journal = {Journal of neuroimmunology}, volume = {165}, number = {1-2}, pages = {139-149}, doi = {10.1016/j.jneuroim.2005.05.002}, pmid = {15975667}, issn = {0165-5728}, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/immunology ; Cell Line ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/pharmacology ; Dinoprostone/antagonists &amp; inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Indoles/pharmacology ; Kynuramine/*analogs &amp; derivatives/metabolism/pharmacology ; Lipopolysaccharides/pharmacology ; Macrophage Activation/drug effects/immunology ; Macrophages/cytology/*drug effects/enzymology/metabolism ; Melatonin/metabolism/*physiology ; Mice ; Nitric Oxide Synthase/antagonists &amp; inhibitors/biosynthesis ; Nitric Oxide Synthase Type II ; Nitrites/antagonists &amp; inhibitors/metabolism ; Prostaglandin Antagonists/pharmacology ; Prostaglandin-Endoperoxide Synthases/biosynthesis/metabolism ; Superoxides/metabolism ; }, abstract = {Inflammation is a complex phenomenon involving multiple cellular and molecular interactions which must be tightly regulated. Cyclooxygenase-2 (COX) is the key enzyme that catalyzes the two sequential steps in the biosynthesis of PGs from arachidonic acid. The inducible isoform of COX, namely COX-2, plays a critical role in the inflammatory response and its over-expression has been associated with several pathologies including neurodegenerative diseases and cancer. Melatonin is the main product of the pineal gland with well documented antioxidant and immuno-modulatory effects. Since the action of the indole on COX-2 has not been previously described, the goal of the present report was to test the effect of melatonin on the activities of COX-2 and inducible nitric oxide synthase (iNOS), using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as a model. Melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), prevented COX-2 activation induced by LPS, without affecting COX-1 protein levels. The structurally related compound 6-methoxy-melatonin only partially prevented the increase in COX-2 protein levels induced by the toxin. Likewise melatonin prevented iNOS activation and reduced the concentration of products from both enzymes, PGE(2) and nitric oxide. Another endogenous antioxidant like N-acetyl-cysteine (NAC) did not reduced COX-2 significantly. The current finding corroborates a role of melatonin as an anti-inflammatory agent and, for the first time, COX-2 and iNOS as molecular targets for either melatonin or its metabolites AFMK and AMK. These anti-inflammatory actions seem not to be exclusively mediated by the free radical scavenging properties of melatonin. As a consequence, the present work suggests these substances as a new class of potential anti-inflammatory agents without the classical side effects due to COX-1 inhibition.}, }
@article {pmid15974925, year = {2005}, author = {Tucker, S and Ahl, M and Bush, A and Westaway, D and Huang, X and Rogers, JT}, title = {Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer's APP 5' untranslated region.}, journal = {Current Alzheimer research}, volume = {2}, number = {2}, pages = {249-254}, doi = {10.2174/1567205053585855}, pmid = {15974925}, issn = {1567-2050}, support = {5K01MH002001/MH/NIMH NIH HHS/United States ; AG18884/AG/NIA NIH HHS/United States ; AG21081/AG/NIA NIH HHS/United States ; }, mesh = {5' Untranslated Regions/antagonists &amp; inhibitors/genetics/*metabolism ; Acetylcysteine/chemistry/pharmacology/therapeutic use ; Alzheimer Disease/*drug therapy/genetics/metabolism ; Amyloid beta-Protein Precursor/antagonists &amp; inhibitors/genetics/*metabolism ; Animals ; *Drug Approval ; Drugs, Investigational/chemistry/pharmacology/*therapeutic use ; Erythromycin/chemistry/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; Paroxetine/chemistry/pharmacology/therapeutic use ; Pilot Projects ; }, abstract = {A pilot study was conducted employing a well known mouse model for Alzheimer's disease to evaluate the anti-amyloid efficacy of three FDA pre-approved drugs. Paroxetine (SSRI and APP 5'UTR directed lead compound), N-acetyl cysteine (antioxidant), and erythromycin (macrolide antibiotic) were provided to the drinking water of TgCRND8 mice for three months. This report provides data that measured the steady-state levels of amyloid Abeta-40 and Abeta-42 Abeta as pmol Abeta per gram of mouse brain cortex in drug treated and placebo animals. The relative levels of Abeta peptide levels were reduced after exposure of mice to paroxetine (N=5), NAC (N=7), and erythromycin (N=7) relative to matched placebo counterparts. These results demonstrated proof-of concept for a strategy to further screen the APP 5'UTR target to identify novel drugs that exhibit anti-amyloid efficacy in vivo. These data also demonstrated a statistically significant anti-amyloid trend for paroxetine, NAC and erythromycin. The potential for conducting further studies with these compounds using larger cohorts of TgCRND8 mice is discussed.}, }
@article {pmid15970627, year = {2004}, author = {Tchantchou, F and Graves, M and Ortiz, D and Rogers, E and Shea, TB}, title = {Dietary supplementation with 3-deaza adenosine, N-acetyl cysteine, and S-adenosyl methionine provide neuroprotection against multiple consequences of vitamin deficiency and oxidative challenge: relevance to age-related neurodegeneration.}, journal = {Neuromolecular medicine}, volume = {6}, number = {2-3}, pages = {93-103}, pmid = {15970627}, issn = {1535-1084}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Apolipoproteins E/deficiency ; Cell Line, Tumor ; *Dietary Supplements ; Disease Models, Animal ; Folic Acid Deficiency/*prevention &amp; control ; Glutathione/metabolism ; Glutathione Synthase/metabolism ; Maze Learning/drug effects ; Mice ; Mice, Knockout ; Neuroblastoma ; Neuroprotective Agents/administration &amp; dosage/*pharmacology ; Oxidative Stress/drug effects/*physiology ; S-Adenosylmethionine/administration &amp; dosage/*pharmacology ; Thiobarbituric Acid Reactive Substances/metabolism ; Tubercidin/administration &amp; dosage/*pharmacology ; Vitamin E Deficiency/*prevention &amp; control ; }, abstract = {Folate deprivation induces neurotoxicity that is potentiated by additional nutritional and genetic deficiencies including vitamin E and apolipoprotein E deficiency. These deficiencies collectively induce oxidative damage, cognitive impairment, and compensatory alteration in glutathione generation. Treatment with agents that regulate distinct portions of the methionine cycle, including the S-adenosyl homocysteine hydrolase inhibitor, 3-deaza adenosine, the methyl donor S-adenosyl methionine, and the antioxidant N-acetyl cysteine, provide neuroprotection against various aspects of neurotoxicity in normal and apolipoprotein E-deficient mice and in cultured neuronal cells deprived of dietary folate and vitamin E and subjected to iron overload. Here it is demonstrated that simultaneous treatment with these agents provide superior neuroprotection by alleviating individual and overlapping neurotoxic consequences. These findings support combinatorial treatments with agents that compensate for differential insults in age-related neurodegenerative disorders.}, }
@article {pmid15967733, year = {2005}, author = {Jansson, AH and Eriksson, C and Wang, X}, title = {Effects of budesonide and N-acetylcysteine on acute lung hyperinflation, inflammation and injury in rats.}, journal = {Vascular pharmacology}, volume = {43}, number = {2}, pages = {101-111}, doi = {10.1016/j.vph.2005.03.006}, pmid = {15967733}, issn = {1537-1891}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; Bronchoalveolar Lavage Fluid/chemistry ; Budesonide/*pharmacology/therapeutic use ; Chemokine CCL2/analysis ; Chemokine CXCL1 ; Chemokine CXCL2 ; Chemokines, CXC/analysis ; Dose-Response Relationship, Drug ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Instillation, Drug ; Interleukin-1/analysis ; Interleukin-6/analysis ; Lipopolysaccharides/administration &amp; dosage/toxicity ; Lung/drug effects/pathology/physiopathology ; Organ Size/drug effects ; Pneumonia/*drug therapy/metabolism/pathology ; Rats ; Rats, Wistar ; Respiratory Distress Syndrome/chemically induced/*drug therapy ; Total Lung Capacity/drug effects ; Tumor Necrosis Factor-alpha/analysis ; }, abstract = {Leukocyte activation and production of inflammatory mediators and reactive oxygen species are important in the pathogenesis of lipopolysaccharide (LPS)-induced acute lung injury. The present study investigated acute lung hyperinflation, edema, and lung inflammation 4 h after an intratracheal instillation of LPS (0.5, 2.5, 5, 10, 50, 100, 500, 1000, and 5000 microg/ml/kg). Effects of budesonide, an inhaled anti-inflammatory corticosteroids, and N-acetylcysteine (NAC), an antioxidant, were evaluated in Wistar rats receiving either low (2.5 microg/ml/kg) or high (50 microg/ml/kg) concentrations of LPS. This study demonstrates that LPS in a concentration-dependent pattern induces acute lung hyperinflation measured by excised lung gas volume (25-45% above control), lung injury indicated by increased lung weight (10-60%), and lung inflammation characterized by the infiltration of leukocytes (40-14000%) and neutrophils (80-17000%) and the production of cytokines (up to 2700%) and chemokines (up to 350%) in bronchoalveolar lavage fluid (BALF). Pretreatment with NAC partially prevented tumor necrosis factor alpha (TNFalpha) production induced by the low concentration of LPS, while pretreatment with budesonide totally prevented the increased production of TNFalpha, interleukin (IL)-1beta, IL-6, and monocyte chemoattractive protein (MCP)-1 after LPS challenge at both low and high concentrations. Budesonide failed to prevent BALF levels of macrophage inflammatory protein (MIP)-2 and cytokine-induced neutrophil chemoattractant 1 (GRO/CINC-1) as well as lung hyperinflation induced by both low and high concentrations of LPS. Pretreatment with budesonide totally prevented the formation of lung edema at the low concentration of LPS and had partial effects on acute lung injury and leukocyte influx at the high concentrations. Thus, our data indicate that therapeutic effects of budesonide and NAC are dependent upon the severity of the disease.}, }
@article {pmid15966690, year = {2005}, author = {Kopke, R and Bielefeld, E and Liu, J and Zheng, J and Jackson, R and Henderson, D and Coleman, JK}, title = {Prevention of impulse noise-induced hearing loss with antioxidants.}, journal = {Acta oto-laryngologica}, volume = {125}, number = {3}, pages = {235-243}, doi = {10.1080/00016480410023038}, pmid = {15966690}, issn = {0001-6489}, mesh = {Acetylcarnitine/*pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Chinchilla ; Disease Models, Animal ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Female ; Hair Cells, Auditory/drug effects/pathology ; Hearing Loss, Noise-Induced/*prevention &amp; control ; Recovery of Function/drug effects ; }, abstract = {CONCLUSION: These findings indicate a strong protective effect of ALCAR and NAC on impulse noise-induced cochlear damage, and suggest the feasibility of using clinically available antioxidant compounds to protect the ear from acute acoustic injury.<br><br>OBJECTIVE: Reactive oxygen species have been shown to play a significant role in noise-induced hearing loss. In the current study, the protective effects of two antioxidants, acetyl-L-carnitine (ALCAR) and N-L-acetylcysteine (NAC), were investigated in a chinchilla model of hearing loss resulting from impulse noise. It was hypothesized that pre- and post-treatment with these antioxidants would ameliorate the effects of impulse noise compared to saline-treated controls.<br><br>MATERIAL AND METHODS: Eighteen animals were randomly assigned to 1 of 3 groups and exposed to impulse noise at a level of 155 dB peak SPL for 150 repetitions. ALCAR or NAC were administered twice daily (b.i.d.) for 2 days and 1 h prior to and 1 h following noise exposure, and then b.i.d. for the following 2 days. For the control group, saline was injected at the same time points. Auditory brainstem responses (ABRs) were recorded. Cochlear surface preparations were made to obtain cytocochleograms.<br><br>RESULTS: Three weeks after exposure, permanent threshold shifts for the experimental groups were significantly reduced to approximately = 10-30 dB less than that for the control group (p < 0.01). Less hair cell loss was also observed in the ALCAR and NAC groups than in the control group.}, }
@article {pmid15965078, year = {2005}, author = {Yang, LY and Ko, WC and Lin, CM and Lin, JW and Wu, JC and Lin, CJ and Cheng, HH and Shih, CM}, title = {Antioxidant N-acetylcysteine blocks nerve growth factor-induced H2O2/ERK signaling in PC12 cells.}, journal = {Annals of the New York Academy of Sciences}, volume = {1042}, number = {}, pages = {325-337}, doi = {10.1196/annals.1338.056}, pmid = {15965078}, issn = {0077-8923}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Hydrogen Peroxide/*metabolism ; MAP Kinase Signaling System/*drug effects ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; Nerve Growth Factor/*pharmacology ; PC12 Cells ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Rats ; Superoxides/metabolism ; }, abstract = {We investigated whether H2O2, superoxide, and ERK participate in nerve growth factor (NGF)-induced signaling cascades and whether antioxidant N-acetylcysteine (NAC) regulates these NGF-induced responses. PC12 cells were cultured in medium containing NGF or vehicle with or without NAC pretreatment, and the intracellular H2O2 and superoxide levels and the amount of phosphorylated ERK were evaluated by flow cytometry and Western blotting, respectively. We found that NGF increased intracellular H2O2 concentration and activated ERK but failed to affect intracellular superoxide level. Moreover, NAC counteracted these NGF-induced responses. These findings demonstrate that NAC blocks the NGF-induced H2O2/ERK signaling in PC12 cells.}, }
@article {pmid15958570, year = {2005}, author = {Xia, S and Rosen, EM and Laterra, J}, title = {Sensitization of glioma cells to Fas-dependent apoptosis by chemotherapy-induced oxidative stress.}, journal = {Cancer research}, volume = {65}, number = {12}, pages = {5248-5255}, doi = {10.1158/0008-5472.CAN-04-4332}, pmid = {15958570}, issn = {0008-5472}, support = {NS 95704/NS/NINDS NIH HHS/United States ; }, mesh = {Antibodies/*pharmacology ; Apoptosis/*drug effects ; Camptothecin/*pharmacology ; Cell Line, Tumor ; Drug Synergism ; Glioblastoma/*drug therapy/immunology/metabolism/*pathology ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Oxidative Stress/drug effects/physiology ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; fas Receptor/*physiology ; }, abstract = {A prominent feature of glioblastoma is its resistance to death from Fas pathway activation. In this study, we explored the modulation of Fas-induced glioblastoma death with chemotherapeutic agents. Camptothecin significantly increased the glioblastoma cell death response to Fas receptor activation regardless of p53 status. Sublethal concentrations of camptothecin reduced the IC50 of agonistic anti-Fas antibody (CH-11) 10-fold, from 500 to 50 ng/mL, in human U87 glioblastoma cells (p53 wild-type). Cell viability in response to camptothecin, CH-11 alone, and the combination of camptothecin + CH-11 was found to be 84%, 85%, and 47% (P < 0.001), respectively. A similar pattern of relative cytotoxicity was found in U373 cells (p53 mutant). We further examined the pathways and mechanisms involved in this apparent synergistic cytotoxic response. Cell death was found to be predominantly apoptotic involving both extrinsic and intrinsic pathways as evidenced by annexin V staining, cleavage of caspases (3, 8, and 9), increased caspase activities, Smac release, and cytoprotection by caspase inhibitors. Expression of Fas-associated death domain, and not Fas, Fas ligand, or caspase proteins, increased following cell treatment with camptothecin + CH-11. Camptothecin treatment enhanced c-jun-NH2-kinase activation in response to CH-11, but inhibition of c-jun-NH2-kinase did not prevent cell death induced by the combination treatment. Reactive oxygen species, especially H2O2, were elevated following camptothecin treatment; and H2O2 enhanced cell death induced by CH-11. The antioxidants glutathione and N-acetyl-cysteine prevented cell death induced by camptothecin + CH-11. These findings show that camptothecin synergizes with Fas activation to induce glioblastoma apoptosis via a mechanism involving reactive oxygen species and oxidative stress pathways.}, }
@article {pmid15956778, year = {2005}, author = {Yang, S and Chintapalli, J and Sodagum, L and Baskin, S and Malhotra, A and Reiss, K and Meggs, LG}, title = {Activated IGF-1R inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination.}, journal = {American journal of physiology. Renal physiology}, volume = {289}, number = {5}, pages = {F1144-52}, doi = {10.1152/ajprenal.00094.2005}, pmid = {15956778}, issn = {1931-857X}, support = {1R01-CA/NS-95518/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Cell Culture Techniques ; Cell Survival ; Comet Assay ; *DNA Damage ; DNA Repair ; Glomerular Mesangium/cytology ; Hyperglycemia/*complications ; Ligands ; Mice ; Oxidative Stress ; Reactive Oxygen Species ; Receptor, IGF Type 1/*physiology ; *Recombination, Genetic ; }, abstract = {The IGF-1R is a genetic determinant of oxidative stress and longevity. Hyperglycemia induces an exponential increase in the production of a key danger signal, reactive oxygen intermediates, which target genomic DNA. Here, we report for the first time that ligand activation of the IGF-1R prevents hyperglycemia-induced genotoxic stress and enhances DNA repair, maintaining genomic integrity and cell viability. We performed single gel electrophoresis (comet assay) to evaluate DNA damage in serum-starved SV40 murine mesangial cells (MMC) and normal human mesangial cells (NHMC), maintained at high ambient glucose concentration. Hyperglycemia inflicted an impressive array of DNA damage in the form of single-strand breaks (SSBs) and double-strand breaks (DSBs). The inclusion of IGF-1 to culture media of MMC and NHMC prevented hyperglycemia-induced DNA damage. To determine whether DNA damage was mediated by reactive oxygen species (ROS), ROS generation was evaluated, in the presence of IGF-1, or the free radical scavenger n-acetyl-cysteine (NAC). IGF-1 and NAC inhibited hyperglycemic-induced ROS production and hyperglycemia-induced DNA damage. We next asked whether IGF-1 promotes the repair of DSB under hyperglycemic conditions, by homologous recombination (HRR) or nonhomologous end joining (NHEJ). Repair of DSB by NHEJ and HRR was operative in MMC maintained under hyperglycemic conditions. IGF-1 increased HRR by nearly twofold, whereas IGF-1 did not affect DNA repair by NHEJ. IGF-1R enhancement of HRR correlated with the translocation of Rad51 to foci of DNA damage. Inhibition of Rad51 expression by short interfering RNA experiments markedly decreased percentage of MMC positive for Rad51 nuclear foci and increased hyperglycemic DNA damage. We conclude that the activated IGF-1R rescues mesangial cells from hyperglycemia-induced danger signals that target genomic DNA by suppressing ROS and enhancing DNA repair by HRR.}, }
@article {pmid15956119, year = {2005}, author = {Rikitake, Y and Liao, JK}, title = {Rho-kinase mediates hyperglycemia-induced plasminogen activator inhibitor-1 expression in vascular endothelial cells.}, journal = {Circulation}, volume = {111}, number = {24}, pages = {3261-3268}, pmid = {15956119}, issn = {1524-4539}, support = {P01 NS010828/NS/NINDS NIH HHS/United States ; R01 DK062729-01A1/DK/NIDDK NIH HHS/United States ; R01 HL070274-02/HL/NHLBI NIH HHS/United States ; P01 NS010828-330036/NS/NINDS NIH HHS/United States ; R01 DK062729-02/DK/NIDDK NIH HHS/United States ; R01 HL052233-05/HL/NHLBI NIH HHS/United States ; R01 HL070274-01/HL/NHLBI NIH HHS/United States ; HL52233/HL/NHLBI NIH HHS/United States ; R01 HL052233-07/HL/NHLBI NIH HHS/United States ; P50 NS010828/NS/NINDS NIH HHS/United States ; R01 HL052233-06/HL/NHLBI NIH HHS/United States ; R01 HL052233/HL/NHLBI NIH HHS/United States ; R01 DK062729/DK/NIDDK NIH HHS/United States ; R01 HL070274/HL/NHLBI NIH HHS/United States ; R01 HL070274-03/HL/NHLBI NIH HHS/United States ; P50 NS010828-290036/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology ; Cells, Cultured ; Endothelium, Vascular/cytology/*metabolism ; Gene Expression Regulation ; Humans ; Hyperglycemia/enzymology/*metabolism ; Intracellular Signaling Peptides and Proteins ; Mice ; Mice, Knockout ; Oxidative Stress ; Plasminogen Activator Inhibitor 1/analysis/*genetics ; Protein Kinase C/metabolism ; Protein Serine-Threonine Kinases/deficiency/*metabolism ; RNA Stability ; RNA, Messenger/analysis ; rho-Associated Kinases ; }, abstract = {BACKGROUND: Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are associated with myocardial infarction and stroke, especially in patients with diabetes. The induction of PAI-1 expression by hyperglycemia involves oxidative stress and protein kinase C (PKC). However, the mechanism by which hyperglycemia increases PAI-1 expression is unknown.<br><br>METHODS AND RESULTS: Compared with normoglycemia, exposure of human endothelial cells to hyperglycemia, but not mannitol, increased Rho-kinase activity in a time- and concentration-dependent manner. This increase was inhibited by a PKC inhibitor, GF109203X, and antioxidants N-acetylcysteine (NAC) and reduced form of glutathione (GSH). This correlated with inhibition of hyperglycemia-induced PAI-1 expression by GF109203X, NAC, and GSH. Hyperglycemia-increased PAI-1 mRNA and protein levels were inhibited by Rho-kinase inhibitors hydroxyfasudil and Y27632 and by a dominant-negative mutant of Rho-kinase. The mechanism for this inhibition occurs at the level of gene transcription because Rho-kinase inhibitors repress hyperglycemia-stimulated PAI-1 promoter activity without affecting mRNA stability. Hyperglycemia failed to stimulate Rho-kinase activity and PAI-1 expression in heterozygous ROCK I-knockout murine endothelial cells.<br><br>CONCLUSIONS: Hyperglycemia stimulates Rho-kinase activity via PKC- and oxidative stress-dependent pathways, leading to increased PAI-1 gene transcription. These results suggest that inhibition of ROCK I may be a novel therapeutic target for preventing thromboembolic complications of diabetes and cardiovascular disease.}, }
@article {pmid15954987, year = {2005}, author = {Mishima, T and Yamada, T and Matsunaga, S and Wada, M}, title = {N-acetylcysteine fails to modulate the in vitro function of sarcoplasmic reticulum of diaphragm in the final phase of fatigue.}, journal = {Acta physiologica Scandinavica}, volume = {184}, number = {3}, pages = {195-202}, doi = {10.1111/j.1365-201X.2005.01443.x}, pmid = {15954987}, issn = {0001-6772}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Calcium/metabolism ; Calcium-Transporting ATPases/metabolism ; Diaphragm/*drug effects/metabolism/physiology ; Male ; Muscle Fatigue/*physiology ; Rats ; Rats, Wistar ; Sarcoplasmic Reticulum/*drug effects/physiology ; }, abstract = {AIM: In the present study, we tested the hypothesis whether N-acetylcysteine (NAC), a non-specific antioxidant, might influence fatigue by modulating Ca2+-handling capacity by the sarcoplasmic reticulum (SR).<br><br>METHODS: In the presence (10 mm) or absence of NAC, bundles of rat diaphragm were stimulated with tetanic trains (350 ms, 30-40 Hz) at 1 train every 2 s for 300 s. SR functions, as assessed by SR Ca2+-uptake and release rates and SR Ca2+-ATPase activity, were measured in vitro on muscle homogenates.<br><br>RESULTS: Following the 300-s stimulation, the force developed by NAC-treated muscles is approximately 1.8-fold higher (P < 0.05) than that of muscles without NAC treatment. Stimulation elicited an 18-30% depression in SR function (P < 0.05). Despite the differing degrees of fatigue between NAC-treated and non-treated muscles, SR functions in these muscles were reduced to similar extents.<br><br>CONCLUSIONS: These results suggest that modulation of SR function measured in vitro may not be a major contributor to inhibition of diaphragmic fatigue with antioxidant, at least, in the final phase of fatigue where force output is remarkably reduced.}, }
@article {pmid15954970, year = {2005}, author = {Saricaoglu, F and Dal, D and Salman, AE and Atay, OA and Doral, MN and Salman, MA and Kilinç, K and Aypar, U}, title = {Effect of low-dose N-acetyl-cysteine infusion on tourniquet-induced ischaemia-reperfusion injury in arthroscopic knee surgery.}, journal = {Acta anaesthesiologica Scandinavica}, volume = {49}, number = {6}, pages = {847-851}, doi = {10.1111/j.1399-6576.2005.00722.x}, pmid = {15954970}, issn = {0001-5172}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Anesthesia, General ; *Arthroscopy ; Double-Blind Method ; Female ; Humans ; Lipid Peroxides/blood ; Male ; Malondialdehyde/blood ; Middle Aged ; Prospective Studies ; Reperfusion Injury/blood/*prevention &amp; control ; Tourniquets/*adverse effects ; }, abstract = {BACKGROUND: Temporary occlusion of blood flow is used during arthroscopic knee surgery in order to provide a bloodless surgical field. The resulting ischaemia-reperfusion causes lipid peroxidation, which contributes to tissue injury. The aim of the study was to investigate the effect of low-dose n-acetyl cysteine (NAC) infusion on oxidative stress by determining malondialdehyde (MDA) levels during arthroscopic knee surgery.<br><br>METHODS: Thirty patients, ASA I - II, undergoing arthroscopic knee debridement under a tourniquet were divided into NAC and control groups. Anaesthesia was induced with propofol, fentanyl and vecuronium bromide and maintained with desflurane in an equal parts O(2)-N(2)O mixture. In the NAC group, an infusion of NAC, 5 mg kg(-1).h(-1), was started after intubation, and continued until extubation. An equal volume of saline was infused to the control group. Duration of ischaemia, anaesthesia time, total dose of NAC infused were also recorded. Venous blood and synovial membrane tissue samples were obtained 10 min after the onset of NAC infusion but before tourniquet inflation (t1), after 30 min of ischaemia (t2), and after 5 min of reperfusion following tourniquet release (t3).<br><br>RESULTS: Plasma MDA levels were significantly lower in the NAC group on reperfusion. There were no differences between the groups in tissue MDA levels at ischaemia and reperfusion times.<br><br>CONCLUSION: Low-dose n-acetyl cysteine infusion attenuates lipid peroxidation and ischaemia-reperfusion injury in arthroscopic knee surgery requiring tourniquet application.}, }
@article {pmid15953715, year = {2005}, author = {Izzotti, A and Bagnasco, M and Cartiglia, C and Longobardi, M and Balansky, RM and Merello, A and Lubet, RA and De Flora, S}, title = {Chemoprevention of genome, transcriptome, and proteome alterations induced by cigarette smoke in rat lung.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {41}, number = {13}, pages = {1864-1874}, doi = {10.1016/j.ejca.2005.04.011}, pmid = {15953715}, issn = {0959-8049}, mesh = {Animals ; Blotting, Western ; DNA Adducts/drug effects ; Gene Expression ; Genome/*drug effects ; Lung Neoplasms/*etiology/prevention &amp; control ; Male ; Microarray Analysis ; Proteome/*drug effects ; Pulmonary Surfactants/analysis/pharmacology ; Rats ; Rats, Sprague-Dawley ; Smoking/*adverse effects ; Survival Analysis ; Tobacco Smoke Pollution/*adverse effects ; }, abstract = {Post-genomic methodologies have provided novel tools for evaluating safety and efficacy of cancer chemopreventive agents. We exposed rats to environmental cigarette smoke (ECS) for 28 days, with or without oral administration of N-acetylcysteine (NAC). As assessed by 32P-postlabelling, ECS caused a 10-fold increase of DNA adduct levels, which were significantly reduced by NAC. Of 518 proteins tested by antibody microarray, ECS stimulated 56 activities involved in stress response, protein removal, cell replication, apoptosis, phagocytosis, and immune response. NAC alone did not change the amounts of any protein, whereas it significantly decreased the amounts of 6 ECS-induced proteins. The intensity of expression of 278 related genes, assessed by cDNA microarray, was significantly correlated with protein amounts. These observed molecular alterations, which can be attenuated by NAC, represent in part adaptive responses and in part reflect mechanisms contributing to the pathogenesis of smoke-related diseases, including lung cancer, asthma, chronic bronchitis, and emphysema.}, }
@article {pmid15951398, year = {2005}, author = {Dickey, DT and Wu, YJ and Muldoon, LL and Neuwelt, EA}, title = {Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {314}, number = {3}, pages = {1052-1058}, doi = {10.1124/jpet.105.087601}, pmid = {15951398}, issn = {0022-3565}, support = {NS 33618/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Agents/*toxicity ; Apoptosis/drug effects ; Blotting, Western ; Cell Survival/drug effects ; Cisplatin/*toxicity ; Female ; Hearing/drug effects ; Kidney/drug effects ; Rats ; Rats, Long-Evans ; Signal Transduction/drug effects ; Thiosulfates/*pharmacology ; }, abstract = {Cisplatin (CDDP) is a common, highly toxic chemotherapeutic agent. This study investigates chemoprotective effects of N-acetylcysteine (NAC) and sodium thiosulfate (STS) on in vitro and in vivo CDDP toxicities. For ototoxicity studies, CDDP (6 mg/kg) was administered to rats via a retrograde carotid artery infusion. Auditory brainstem response thresholds at 4 to 20 kHz were tested before and 7 days post-treatment. STS (8 g/m(2) i.v.) was administered at 4, 8, or 12 h after CDDP. For nephrotoxicity studies, rats were treated with CDDP intraperitoneally (10 mg/kg) before or after NAC (400 mg/kg) or STS (8 g/m(2)), and blood urea nitrogen (BUN) and creatinine concentrations were measured after 3 days. In vitro cytotoxicity and chemoprotection in human tumor cell lines were assessed by cell viability and immunoblotting assays. Rats treated with STS 4 h after CDDP exhibited no hearing change. The STS 8-h group had less otoprotection, whereas 12-h rats had ototoxicity. CDDP induced high BUN and creatinine, corresponding to renal tubule toxicities. All NAC-treated animals showed normal BUN and reduced creatinine levels compared with CDDP alone and no histopathological evidence of nephrotoxicity. Delayed STS treatment was not consistently protective against nephrotoxicity. STS administration fully protected against the in vitro cytotoxic and apoptotic effects of CDDP if added within 2 h of CDDP, but chemoprotection decreased if STS administration was 4 h, and was minimal by 6 h, after CDDP. Thus, the chemoprotection route and timing of administration can be manipulated to maintain CDDP antitumor efficacy while protecting against toxicities.}, }
@article {pmid15948191, year = {2005}, author = {Kotake-Nara, E and Takizawa, S and Quan, J and Wang, H and Saida, K}, title = {Cobalt chloride induces neurite outgrowth in rat pheochromocytoma PC-12 cells through regulation of endothelin-2/vasoactive intestinal contractor.}, journal = {Journal of neuroscience research}, volume = {81}, number = {4}, pages = {563-571}, doi = {10.1002/jnr.20568}, pmid = {15948191}, issn = {0360-4012}, mesh = {Animals ; Antimutagenic Agents/*pharmacology ; Antioxidants/pharmacology ; Cell Differentiation/drug effects/physiology ; Cell Division/drug effects/physiology ; Cobalt/*pharmacology ; Endothelin-1/genetics/metabolism ; Endothelin-2/*genetics/metabolism ; Gene Expression/drug effects/physiology ; Intercellular Signaling Peptides and Proteins ; Interleukin-6/genetics ; Neurites/*drug effects/physiology ; PC12 Cells ; Peptides/*genetics/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {We investigated whether endothelin-2/vasoactive intestinal contractor (ET-2/VIC) gene expression, upregulated by hypoxia in cancer cells, was associated with differentiation in neuronal cells. RT-PCR analysis, morphological observations, and immunostaining revealed that CoCl2, a hypoxic mimetic agent, at 200 microM increased expression of the ET-2/VIC gene, decreased expression of the ET-1 gene, and induced neurite outgrowth in PC-12 rat pheochromocytoma cells. These effects induced by 200 microM CoCl2 were completely inhibited by the antioxidant N-acetyl cysteine at 20 mM. In addition, CoCl2 increased the level of intracellular reactive oxygen species (ROS) at an early stage. Furthermore, interleukin (IL)-6 gene expression was upregulated upon the differentiation induced by CoCl2. These results suggest that expression of ET-2/VIC and ET-1 mediated by ROS may be associated with neuronal differentiation through the regulation of IL-6. When the cells were treated with 500 microM CoCl2 for 24 hr, however, ET-2/VIC gene expression disappeared, IL-6 gene expression was downregulated, and necrosis was subsequently induced in the PC-12 cells.}, }
@article {pmid15945272, year = {2005}, author = {Ito, K and Kajikawa, S and Nii, A and Doi, K}, title = {Nitrofurazone-induced gene expressions in rat hepatocytes and their modification by N-acetylcysteine.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {56}, number = {6}, pages = {333-339}, doi = {10.1016/j.etp.2004.11.002}, pmid = {15945272}, issn = {0940-2993}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Infective Agents, Local/*toxicity ; Biomarkers/metabolism ; Cell Proliferation/drug effects ; DNA Primers/chemistry ; Drug Interactions ; Free Radicals/antagonists &amp; inhibitors/metabolism ; Gene Expression/*drug effects ; Growth Substances/*genetics/metabolism ; Hepatocytes/*drug effects/metabolism/pathology ; Male ; Nitrofurazone/*toxicity ; Oncogene Proteins/*genetics/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Inbred F344 ; Reverse Transcriptase Polymerase Chain Reaction ; Specific Pathogen-Free Organisms ; Tumor Necrosis Factor-alpha/genetics/metabolism ; }, abstract = {The antibiotic nitrofurazone (NF) at a subtoxic dose has been shown to increase hepatocyte DNA synthesis with no preceding cell damage or necrosis. This was suppressed by concomitant administration of the antioxidant N-acetylcysteine (NAC), which suggests that free radical production is involved in the process. In this study, male F344 rats were given a single oral subtoxic dose of NF to investigate the changes in genes implicated in hepatocyte proliferation between 1 and 20h postdose by real-time PCR. Some rats were also given NAC to examine the involvement of free radicals. There were transient and sequential increases in mRNA levels of c-myc and c-jun shortly after the administration, followed by tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-alpha (TGF-alpha), c-Ha-ras, and cyclin E. The increases were blocked by concomitant administration of NAC. In contrast, there were no NF-specific increases in c-fos, hepatocyte growth factor, epidermal growth factor or cyclin D1 mRNAs. These results indicate that the induction of hepatocyte proliferation by NF is triggered by free radicals, with a pathway involving increases in c-jun, c-myc, TNF-alpha, TGF-alpha, c-Ha-ras, and cyclin E. The results also indicate that NF-induced proliferation resembles that of other mitogens.}, }
@article {pmid15944340, year = {2005}, author = {Ullian, ME and Gelasco, AK and Fitzgibbon, WR and Beck, CN and Morinelli, TA}, title = {N-acetylcysteine decreases angiotensin II receptor binding in vascular smooth muscle cells.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {16}, number = {8}, pages = {2346-2353}, doi = {10.1681/ASN.2004060458}, pmid = {15944340}, issn = {1046-6673}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/chemistry/pharmacology ; Cell Membrane/metabolism ; Disulfides ; Dose-Response Relationship, Drug ; Green Fluorescent Proteins/metabolism ; Immunoblotting ; Inositol Phosphates/chemistry ; Kinetics ; Male ; Muscle, Smooth, Vascular/*cytology ; Myocytes, Smooth Muscle/*metabolism ; Oxygen/chemistry ; Phosphates/chemistry ; Protein Binding ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Receptor, Angiotensin, Type 1/metabolism ; Receptors, Angiotensin/*metabolism ; Signal Transduction ; Temperature ; Thioctic Acid/analogs &amp; derivatives/chemistry ; Time Factors ; Vitamin E/chemistry ; }, abstract = {Antioxidants seem to inhibit angiotensin II (Ang II) actions by consuming stimulated reactive oxygen species. An alternative hypothesis was investigated: Antioxidants that are also strong reducers of disulfide bonds inhibit the binding of Ang II to its surface receptors with consequent attenuation of signal transduction and cell action. Incubation of cultured vascular smooth muscle cells, which possess Ang II type 1a receptors, with the reducing agent n-acetylcysteine (NAC) for 1 h at 37 degrees C resulted in decreased Ang II radioligand binding in a concentration-dependent pattern. NAC removal restored Ang II binding within 30 min. Incubation with n-acetylserine, a nonreducing analogue of NAC, did not lower Ang II binding, and oxidized NAC was less effective than reduced NAC in lowering Ang II binding. NAC did not decrease Ang II type 1a receptor protein content. Other antioxidants regulated Ang II receptors differently: alpha-Lipoic acid lowered Ang II binding after 24 h, and vitamin E did not lower Ang II binding at all. NAC inhibited Ang II binding in cell membranes at 21 or 37 but not 4 degrees C. Dihydrolipoic acid (the reduced form of alpha-lipoic acid), which contains free sulfhydryl groups as NAC does, decreased Ang II receptor binding in cell membranes, whereas alpha-lipoic acid, which does not contain free sulfhydryl groups, did not. Ang II-stimulated inositol phosphate formation was decreased by preincubation with NAC (1 h) or alpha-lipoic acid (24 h) but not vitamin E. In conclusion, certain antioxidants that are reducing agents lower Ang II receptor binding, and Ang II-stimulated signal transduction is decreased in proportion to decreased receptor binding.}, }
@article {pmid15939536, year = {2005}, author = {Patil, S and Chan, C}, title = {Palmitic and stearic fatty acids induce Alzheimer-like hyperphosphorylation of tau in primary rat cortical neurons.}, journal = {Neuroscience letters}, volume = {384}, number = {3}, pages = {288-293}, doi = {10.1016/j.neulet.2005.05.003}, pmid = {15939536}, issn = {0304-3940}, mesh = {Alzheimer Disease/*metabolism/pathology ; Amyloid/metabolism ; Animals ; Animals, Newborn ; Astrocytes/*metabolism/pathology ; Cerebral Cortex/metabolism/pathology ; Fatty Acids, Nonesterified/*metabolism ; Neurons/*metabolism/pathology ; Palmitic Acid/*metabolism ; Phosphorylation/drug effects ; Rats ; Rats, Sprague-Dawley ; Stearic Acids/*metabolism ; tau Proteins/*metabolism/ultrastructure ; }, abstract = {Epidemiological studies suggest that high fat diets significantly increase the risk of Alzheimer's disease (AD). In addition, the AD brain is characterized by high fatty acid content compared to that of healthy subjects. Nevertheless, the basic mechanism relating elevated fatty acids and the pathogenesis of AD remains unclear. The present study examines the role of fatty acids in causing hyperphosphorylation of the tau protein, one of the characteristic signatures of AD pathology. Hyperphosphorylation of tau disrupts the cell cytoskeleton and leads to neuronal degeneration. Here, primary rat cortical neurons and astrocytes were treated with saturated free fatty acids (FFAs), palmitic and stearic acids. There was no change in the levels of phosphorylated tau in rat cortical neurons treated directly with these FFAs. The conditioned media from FFA-treated astrocytes, however, caused hyperphosphorylation of tau in the cortical neurons at AD-specific phospho-epitopes. Co-treatment of neurons with N-acetyl cysteine, an antioxidant, reduced FFA-induced hyperphosphorylation of tau. The present results establish a central role of FFAs in causing hyperphosphorylation of tau through astroglia-mediated oxidative stress.}, }
@article {pmid15939316, year = {2005}, author = {Yildirim, Z and Kotuk, M and Iraz, M and Kuku, I and Ulu, R and Armutcu, F and Ozen, S}, title = {Attenuation of bleomycin-induced lung fibrosis by oral sulfhydryl containing antioxidants in rats: erdosteine and N-acetylcysteine.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {18}, number = {5}, pages = {367-373}, doi = {10.1016/j.pupt.2005.02.001}, pmid = {15939316}, issn = {1094-5539}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Animals ; Antioxidants/administration &amp; dosage/*therapeutic use ; Bleomycin/*toxicity ; Disease Models, Animal ; Drug Interactions ; Male ; Pulmonary Fibrosis/chemically induced/pathology/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/administration &amp; dosage/*therapeutic use ; Thioglycolates/administration &amp; dosage/therapeutic use ; Thiophenes/administration &amp; dosage/therapeutic use ; }, abstract = {Antioxidant therapy may be useful in diseases with impaired oxidant antioxidant balance such as lung fibrosis. The effects of sulfhydryl-containing antioxidant agents N-acetylcysteine (NAC) and erdosteine on the bleomycin-induced lung fibrosis were compared in rats. The animals were divided into four groups: Vehicle + vehicle, vehicle + bleomycin (2.5 U/kg), bleomycin + (10 mg/kg), and bleomycin + NAC (3 mmol/kg). Bleomycin administration resulted in prominent lung fibrosis as measured by lung hydroxyproline content and lung histology which is almost completely prevented by erdosteine and NAC. Hydroxyproline content was 18.7 +/- 3.5 and 11.2 +/- 0.6 mg/g dried tissue in bleomycin and saline treated rats, respectively (P < 0.001), and this level was 11.3 +/- 1.2 and 13.8 +/- 1.2 mg/g dried tissue in erdosteine and NAC pretreated, respectively. Erdosteine and NAC significantly reduced depletion of glutathione peroxidase, and prevented increases in myeloperoxidase activities, nitric oxide, and malondialdehyde levels in lung tissue produced by bleomycin. Data presented here indicate that erdosteine and NAC similarly prevented bleomycin-induced lung fibrosis and their antioxidant effects were also similar in this experiment.}, }
@article {pmid15935209, year = {2005}, author = {Gabryel, B and Toborek, T and Małecki, A}, title = {Immunosuppressive immunophilin ligands attenuate damage in cultured rat astrocytes depleted of glutathione and exposed to simulated ischemia in vitro. Comparison with N-acetylcysteine.}, journal = {Neurotoxicology}, volume = {26}, number = {3}, pages = {373-384}, doi = {10.1016/j.neuro.2005.03.004}, pmid = {15935209}, issn = {0161-813X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Astrocytes/*drug effects ; Benzimidazoles ; Brain Ischemia/*pathology ; Cell Separation ; Cells, Cultured ; Cyclosporine/pharmacology ; Fluorescent Dyes ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism/*physiology ; Immunophilins/*pharmacology ; Immunosuppressive Agents/*pharmacology ; Ligands ; Mitochondria/drug effects ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Tacrolimus/pharmacology ; Tetrazolium Salts ; Thiazoles ; }, abstract = {The aim of the present study was to test the hypothesis that exposure of astrocytes depleted of glutathione (GSH) to simulated ischemia conditions in vitro and treated with immunosuppressant immunophilin ligands (cyclosporin A (CsA) and FK506) can increase intracellular GSH levels and that such mechanism may be responsible, at least in part, for their protective effects. In addition, we also compared the antioxidant properties of these immunosuppressants with N-acetylcysteine (NAC), a precursor of GSH synthesis. GSH depletion was induced by 24 h pretreatment with L-buthionine sulfoximine (BSO). Cultures of rat astrocytes were exposed to CsA (1-50 microM) and FK506 (1-1000 nM) and NAC (100 or 200 microM). We examined the effects of these compounds on apoptosis, cell viability, reactive oxygen species production and GSH content. Our study demonstrated that toxicity of simulated ischemia conditions were enhanced when intracellular GSH was depleted, and immunosuppressants (especially 100 nM FK506 and 10 microM CsA) effectively prevented ischemia toxicity in GSH depleted astrocytes. In addition, we have shown that interfering with the generation of GSH and attenuation, the rise of oxidative stress level by NAC may be a powerful tool for prevention of ischemia-induced glial cell damage.}, }
@article {pmid15934011, year = {2005}, author = {Huang, FM and Chou, LS and Chou, MY and Chang, YC}, title = {Protective effect of NAC on formaldehyde-containing-ZOE-based root-canal-sealers-induced cyclooxygenase-2 expression and cytotoxicity in human osteoblastic cells.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {74}, number = {2}, pages = {768-773}, doi = {10.1002/jbm.b.30283}, pmid = {15934011}, issn = {1552-4973}, mesh = {*Acetylcysteine/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Cyclooxygenase 2/*biosynthesis/toxicity ; Cyclooxygenase Inhibitors/*pharmacology ; *Formaldehyde/antagonists &amp; inhibitors/toxicity ; Humans ; Osteoblasts/*drug effects/*enzymology ; RNA, Messenger/biosynthesis ; Root Canal Filling Materials/*toxicity ; Zinc Oxide-Eugenol Cement/*pharmacology ; }, abstract = {Cyclooxygenase-2 (COX-2) is an inducible enzyme believed to be responsible for prostaglandin synthesis at site of inflammation. Recently, the activation of COX-2 expression may be one of the important pathogenesis of root-canal-sealers-induced periapical inflammation. However, little is known about whether chemical interaction can modulate the COX-2 expression and cytotoxicity induced by formaldehyde-containing-ZOE-based root canal sealers. The aim of this study was to investigate the effects of antioxidants such as catalase, superoxide dismutase (SOD), and N-acetyl-L-cysteine (NAC) on N2- and endomethasone-induced COX-2 mRNA gene and cytotoxicity in human osteoblastic cell line U2OS cells. Our data demonstrated that both formaldehyde-containing-ZOE-based root canal sealers were found to induce COX-2 mRNA gene expression in U2OS cells. The addition of glutathione (GSH) precursor NAC led to decrease the induction of COX-2 mRNA gene expression and cytotoxicity by both N2 and Endomethasone (p < 0.05). However, catalase and SOD lacked the ability to prevent cytotoxicity and COX-2 mRNA gene expression induced by N2 and Endomethasone (p > 0.05). The data presented here demonstrated that the activation of COX-2 mRNA gene expression may be one of the pathogenesis of formaldehyde-containing-ZOE-based root-canal-sealers-induced periapical inflammation. In addition, GSH depletion, but not the attack of oxygen free radicals, could be the mechanism for cytotoxicity and COX-2 mRNA gene expression induced by formaldehyde-containing-ZOE-based root canal sealers. NAC appears as a useful agent in protecting cell damage mediated by formaldehyde-containing-ZOE-based root canal sealers.}, }
@article {pmid15930723, year = {2005}, author = {Satoh, E and Okada, M and Takadera, T and Ohyashiki, T}, title = {Glutathione depletion promotes aluminum-mediated cell death of PC12 cells.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {28}, number = {6}, pages = {941-946}, doi = {10.1248/bpb.28.941}, pmid = {15930723}, issn = {0918-6158}, mesh = {Animals ; Cell Death/drug effects/physiology ; Cell Survival/drug effects/physiology ; Dose-Response Relationship, Drug ; Glutathione/*deficiency ; Intracellular Fluid/drug effects/metabolism ; Organometallic Compounds/*toxicity ; PC12 Cells ; Pyrones/*toxicity ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Exposure of rat phenochromocytoma cells (PC12 cells) to aluminum maltolate complex, Al(maltol)3, induced a decrease in intracellular glutathione (GSH) concentration, resulting in a facilitated release of lactate dehydrogenase (LDH) from the cell and an increase in trypan blue-stained cells. Similar phenomena were observed as the cells were treated with L-buthione-[S,R]-sulfoximine (BSO) in the presence of Al(maltol)3. On the other hand, treatment of PC 12 cells with BSO alone in the absence of Al(maltol)3 did not affect the cell viability. Pre-treatment of PC12 cells with N-acetylcysteine (NAC) for 30 min before a 48 h-exposure to Al(maltol)3 effectively protected the cells from Al(maltol)3 toxicity by increasing intracellular GSH concentration. NAC also effectively inhibited reactive oxygen species (ROS) generation induced by treatment of the cells with Al(maltol)3. However, several lipophilic radical scavengers such as alpha-tocopherol and 3(2)-tert-butyl-4-hydroxyanisole, and an iron chelator, desferrioxamine, did not prevent Al(maltol)3-mediated ROS production or the decrease of cell viability. Based on these results, we discussed the role of intracellular GSH against the onset of aluminum toxicity in the context of ROS production.}, }
@article {pmid15921899, year = {2005}, author = {Patriarca, S and Furfaro, AL and Domenicotti, C and Odetti, P and Cottalasso, D and Marinari, UM and Pronzato, MA and Traverso, N}, title = {Supplementation with N-acetylcysteine and taurine failed to restore glutathione content in liver of streptozotocin-induced diabetics rats but protected from oxidative stress.}, journal = {Biochimica et biophysica acta}, volume = {1741}, number = {1-2}, pages = {48-54}, doi = {10.1016/j.bbadis.2005.04.003}, pmid = {15921899}, issn = {0006-3002}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Diabetes Mellitus, Experimental/*metabolism ; Dioxygenases/metabolism ; Glutathione/*metabolism ; Liver/*metabolism ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Taurine/*pharmacology ; }, abstract = {Rats were rendered diabetic with streptozotocin and supplemented or not with N-acetylcysteine (NAC) and taurine (TAU). The liver was examined for the quantity of glutathione (GSH), both total and oxidised (GSSG), by HPLC assay. Moreover, the liver expression of gamma-glutamyl-cysteine synthetase, cysteine dioxygenase and heme oxygenase 1 was evaluated. Streptozotocin-diabetic rats showed decreased levels of liver glutathione (GSH); dietary supplementation with the antioxidants NAC and TAU failed to restore liver GSH to the level of control rats. Gamma-glutamyl-cysteine synthetase expression was not reduced in the diabetic rats, so the low hepatic GSH level in the supplemented diabetic rats cannot be ascribed to decreased expression of the biosynthetic key enzyme. Moreover, the diabetic rats showed no evidence of increased expression of cysteine dioxygenase, which could have indicated that NAC-derived cysteine was consumed in metabolic pathways different from GSH synthesis. However, NAC+TAU treatment provided partial protection from glutathione oxidation in the liver of diabetic rats; moreover, the antioxidant treatment reduced the hepatic overexpression of heme oxygenase 1 (HO-1) mRNA which was detected in the diabetic rats. In conclusion, although NAC was not able to restore liver GSH levels, the antioxidant treatment restrained GSH oxidation and HO-1 overexpression, which are markers of cellular oxidative stress: diabetic rats probably exploit NAC as an antioxidant itself rather than as a GSH precursor.}, }
@article {pmid15920536, year = {2005}, author = {Parasassi, T and Brunelli, R and Bracci-Laudiero, L and Greco, G and Gustafsson, AC and Krasnowska, EK and Lundeberg, J and Lundeberg, T and Pittaluga, E and Romano, MC and Serafino, A}, title = {Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms.}, journal = {Cell death and differentiation}, volume = {12}, number = {10}, pages = {1285-1296}, doi = {10.1038/sj.cdd.4401663}, pmid = {15920536}, issn = {1350-9047}, mesh = {Acetylcysteine/pharmacology ; CSK Tyrosine-Protein Kinase ; Cadherins/metabolism ; Cell Adhesion/drug effects/physiology ; Cell Adhesion Molecules/metabolism ; Cell Differentiation/drug effects/*physiology ; Cell Line, Tumor ; Colonic Neoplasms/metabolism/*pathology ; Cytoskeletal Proteins/metabolism ; Female ; Humans ; Keratinocytes/cytology/drug effects/metabolism ; Ovarian Neoplasms/metabolism/*pathology ; Phosphotransferases/antagonists &amp; inhibitors/metabolism ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins/antagonists &amp; inhibitors/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sulfhydryl Compounds/*metabolism ; Thymidine/metabolism ; Trans-Activators ; beta Catenin ; src-Family Kinases ; }, abstract = {We examined the morphological, biochemical and molecular outcome of a nonspecific sulfhydryl reduction in cells, obtained by supplementation of N-acetyl-L-cysteine (NAC) in a 0.1-10 mM concentration range. In human normal primary keratinocytes and in colon and ovary carcinoma cells we obtained evidences for: (i) a dose-dependent inhibition of proliferation without toxicity or apoptosis; (ii) a transition from a proliferative mesenchymal morphology to cell-specific differentiated structures; (iii) a noticeable increase in cell-cell and cell-substratum junctions; (iv) a relocation of the oncogenic beta-catenin at the cell-cell junctions; (v) inhibition of microtubules aggregation; (vi) upregulation of differentiation-related genes including p53, heat shock protein 27 gene, N-myc downstream-regulated gene 1, E-cadherin, and downregulation of cyclooxygenase-2; (vii) inhibition of c-Src tyrosine kinase. In conclusion, a thiol reduction devoid of toxicity as that operated by NAC apparently leads to terminal differentiation of normal and cancer cells through a pleiade of converging mechanisms, many of which are targets of the recently developed differentiation therapy.}, }
@article {pmid15919110, year = {2005}, author = {Pagoria, D and Geurtsen, W}, title = {The effect of N-acetyl-l-cysteine and ascorbic acid on visible-light-irradiated camphorquinone/N,N-dimethyl-p-toluidine-induced oxidative stress in two immortalized cell lines.}, journal = {Biomaterials}, volume = {26}, number = {31}, pages = {6136-6142}, doi = {10.1016/j.biomaterials.2005.04.001}, pmid = {15919110}, issn = {0142-9612}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; Ascorbic Acid/*pharmacology ; Cell Line ; Composite Resins/pharmacology ; Dental Cementum/drug effects/*metabolism/radiation effects ; Dental Materials/pharmacology ; Drug Interactions ; Light ; Mice ; Oxidative Stress/*drug effects/*radiation effects ; Reactive Oxygen Species/*metabolism ; Terpenes/*pharmacology ; }, abstract = {Recent studies have revealed that visible-light (VL)-irradiated camphorquinone (CQ), in the presence of a tertiary amine (e.g., N,N-dimethyl-p-toluidine, DMT), generates initiating radicals that may indiscriminately react with molecular oxygen forming reactive oxygen species (ROS). In this study, the ability of the antioxidants N-acetyl-l-cysteine (NAC) and ascorbic acid (AA) to reduce intracellular oxidative stress induced by VL-irradiated CQ/DMT or VL-irradiated hydrogen peroxide (H(2)O(2)) was assessed in an immortalized Murine cementoblast cell line (OCCM.30) and an immortalized Murine fibroblast cell line, 3T3-Swiss albino (3T3). Intracellular oxidative stress was measured with the membrane permeable dye, 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCF-DA). VL-irradiated CQ/DMT and VL-irradiated H(2)O(2) each produced significantly (p<0.001) elevated intracellular oxidative levels in both cell types compared to intracellular ROS levels in VL-irradiated untreated cells. OCCM.30 cementoblasts were found to be almost twice as sensitive to VL-irradiated CQ/DMT and VL-irradiated H(2)O(2) treatment compared to 3T3 fibroblasts. Furthermore, 10mm NAC and 10mm AA each eliminated oxidative stress induced by VL-irradiated CQ/DMT and VL-irradiated H(2)O(2) in both cell types. Our results suggest that NAC and AA may effectively reduce or eliminate oxidative stress in cells exposed to VL-irradiated CQ/DMT following polymerization.}, }
@article {pmid15919066, year = {2005}, author = {Jayalakshmi, K and Sairam, M and Singh, SB and Sharma, SK and Ilavazhagan, G and Banerjee, PK}, title = {Neuroprotective effect of N-acetyl cysteine on hypoxia-induced oxidative stress in primary hippocampal culture.}, journal = {Brain research}, volume = {1046}, number = {1-2}, pages = {97-104}, doi = {10.1016/j.brainres.2005.03.054}, pmid = {15919066}, issn = {0006-8993}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Cell Death/physiology ; Cells, Cultured ; DNA Fragmentation/physiology ; Free Radicals/metabolism ; Hippocampus/cytology/*metabolism ; Hypoxia/drug therapy/*metabolism ; Male ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {Hippocampus has received a considerable attention in the recent past due to its role in a number of important functions such as learning and memory. The effect of hypoxia on neuronal cell injury especially on hippocampal cells is not well known. The aim of the present study was to characterize the biochemical changes in primary cultured hippocampal neurons during hypoxic exposure and the protective effect of N-acetyl cysteine on hypoxia-induced cytotoxicity. The hippocampal culture grown in 24-well plates was exposed to hypoxia for 3 h in a dessicator in 95% N(2), 5% CO(2) atmosphere at 37 degrees C. Later, the cells were allowed to recover for 1 h under normoxia. It was observed that there is an appreciable increase in cytotoxicity in cells exposed to hypoxia. Further, there was a significant decrease in mitochondrial membrane potential and appreciable increase in reactive oxygen species and single-strand DNA breaks in cells exposed to hypoxia compared to control. There is a significant fall in glutathione peroxidase, glutathione reductase, reduced glutathione levels, and nitric oxide in the cells exposed to hypoxia. Significant elevation in the intracellular calcium level in the cells on exposure to hypoxia was observed. Supplementation with NAC (50 microM) resulted in a significant cytoprotection, fall in ROS generation, and higher antioxidant levels similar to that of control cells. NAC also inhibited DNA strand breaks induced by hypoxia. The study indicates that NAC has significant neuroprotective activity during hypoxia in primary hippocampal culture.}, }
@article {pmid15910882, year = {2005}, author = {Partridge, CR and Williams, ES and Barhoumi, R and Tadesse, MG and Johnson, CD and Lu, KP and Meininger, GA and Wilson, E and Ramos, KS}, title = {Novel genomic targets in oxidant-induced vascular injury.}, journal = {Journal of molecular and cellular cardiology}, volume = {38}, number = {6}, pages = {983-996}, doi = {10.1016/j.yjmcc.2005.03.006}, pmid = {15910882}, issn = {0022-2828}, support = {CA90301/CA/NCI NIH HHS/United States ; HL 62539/HL/NHLBI NIH HHS/United States ; HL62863/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Acrolein/metabolism/pharmacology ; Allylamine/metabolism/pharmacology ; Animals ; Aorta/metabolism ; Blotting, Western ; Cluster Analysis ; Cytoskeleton/metabolism ; Dinoprost/analogs &amp; derivatives/biosynthesis ; Dose-Response Relationship, Drug ; Gene Expression Regulation ; Genome ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/metabolism/pharmacology ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Integrin alpha1/metabolism ; Integrins/metabolism ; Male ; Microscopy, Fluorescence ; NF-kappa B/metabolism ; Oligonucleotide Array Sequence Analysis ; Osteopontin ; Oxidants/metabolism/*pharmacology ; Oxidative Stress ; Oxygen/metabolism ; RNA/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Reverse Transcriptase Polymerase Chain Reaction ; Sialoglycoproteins/metabolism ; Tropomyosin/chemistry/metabolism ; }, abstract = {To study the complex interaction between oxidative injury and the pathogenesis of vascular disease, vascular gene expression was examined in male Sprague-Dawley rats given 35 or 70 mg/kg allylamine, a synthetic amine converted to acrolein and hydrogen peroxide within the vascular wall. Vascular lesions and extensive vascular remodeling, coupled to increased production of 8-epi-PGF2alpha, nuclear localization of NFkappaB, and alterations in glutathione homeostasis, were observed in animals treated with allylamine for up to 20 days. Transcriptional profiling, immunohistochemistry, and in situ hybridization showed that genes involved in adhesion and extracellular matrix (ECM) (alpha(1) integrin, collagen), cytoskeletal rearrangements (alpha-smooth muscle actin, alpha-tropomyosin), and signal transduction (NFkappaB, osteopontin, and LINE) were altered by oxidant treatment. To evaluate mechanisms of gene dysregulation, cultured aortic smooth muscle cells were challenged with allylamine or its metabolites and processed for molecular analysis. These agents increased formation of reactive oxygen species and elicited changes in gene expression similar to those observed in vivo. Oxidative stress and changes in gene expression were inhibited by N-acetyl cysteine, a precursor of glutathione. These results indicate that genes along the ECM-integrin-cytoskeletal axis, in addition to LINE, are molecular targets in oxidant-induced vascular injury.}, }
@article {pmid15909775, year = {2005}, author = {Anwar, M and Ledger, S}, title = {Review of contrast-induced nephropathy and current use of N-acetylcysteine (NAC).}, journal = {CANNT journal = Journal ACITN}, volume = {15}, number = {1}, pages = {33-8,quiz 38-9}, pmid = {15909775}, issn = {1498-5136}, mesh = {Acetylcysteine/*therapeutic use ; Contrast Media/*adverse effects ; Humans ; Kidney Diseases/*chemically induced/prevention &amp; control ; }, }
@article {pmid15908511, year = {2005}, author = {Zalups, RK and Ahmad, S}, title = {Transport of N-acetylcysteine s-conjugates of methylmercury in Madin-Darby canine kidney cells stably transfected with human isoform of organic anion transporter 1.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {314}, number = {3}, pages = {1158-1168}, doi = {10.1124/jpet.105.086645}, pmid = {15908511}, issn = {0022-3565}, support = {ES05157/ES/NIEHS NIH HHS/United States ; ES05980/ES/NIEHS NIH HHS/United States ; ES11288/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacokinetics ; Amino Acids/pharmacology ; Animals ; Biological Transport ; Cell Line ; Cell Survival/drug effects ; Dogs ; Dose-Response Relationship, Drug ; Humans ; Kidney/*metabolism ; Methylmercury Compounds/*pharmacokinetics/toxicity ; Organic Anion Transport Protein 1/genetics/*physiology ; Probenecid/pharmacology ; Temperature ; Transfection ; p-Aminohippuric Acid/pharmacokinetics/pharmacology ; }, abstract = {Recent studies have implicated the activity of the organic anion transporter 1 (OAT1) protein in the basolateral uptake of inorganic mercuric species in renal proximal tubular epithelial cells. However, very little is known about the potential role of OAT1 (and other OATs) in the renal epithelial transport of organic forms of mercury such as methylmercury (CH(3)Hg(+)). The present investigation was designed to study the transport of N-acetyl cysteine (NAC) S-conjugates of both methylmercury (CH(3)Hg-NAC) and inorganic mercury (NAC-Hg-NAC) in renal epithelial cells [Madin-Darby canine kidney (MDCK) cells] stably transfected with the human isoform of OAT1 (hOAT1). These mercuric species were studied because numerous mercapturates have been shown to be substrates of OATs. Data on saturation kinetics, time dependence, substrate specificity, and temperature dependence for the transport of CH(3)Hg-NAC and NAC-Hg-NAC indicate that both of these two mercuric species are indeed transportable substrates of hOAT1. Substrate specificity data also show that CH(3)Hg-NAC is a substrate of a transporter in MDCK cells that is not hOAT1. These data indicate that an amino acid carrier system is a likely candidate responsible for this transport. Furthermore, the rates of survival of the hOAT1-transfected MDCK cells were significantly lower than those of corresponding control MDCK cells when they were exposed to cytotoxic concentrations of CH(3)Hg-NAC or NAC-Hg-NAC. Collectively, the present data support the hypothesis that CH(3)Hg-NAC and NAC-Hg-NAC are transportable substrates of OAT1 and thus potentially transportable mercuric species taken up in vivo at the basolateral membrane of proximal tubular epithelial cells.}, }
@article {pmid15908180, year = {2005}, author = {Kim, WH and Lee, JW and Gao, B and Jung, MH}, title = {Synergistic activation of JNK/SAPK induced by TNF-alpha and IFN-gamma: apoptosis of pancreatic beta-cells via the p53 and ROS pathway.}, journal = {Cellular signalling}, volume = {17}, number = {12}, pages = {1516-1532}, doi = {10.1016/j.cellsig.2005.03.020}, pmid = {15908180}, issn = {0898-6568}, mesh = {Animals ; Anthracenes/pharmacology ; Apoptosis ; Caspase 3 ; Caspases/metabolism ; Cell Culture Techniques ; Cell Line, Tumor ; Insulin-Secreting Cells/*metabolism ; Interferon-gamma/*physiology ; JNK Mitogen-Activated Protein Kinases/*metabolism ; *MAP Kinase Signaling System ; Membrane Potentials ; Mice ; Mice, Inbred ICR ; Mice, Inbred NOD ; Mitochondria/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species/*metabolism ; Transfection ; Tumor Necrosis Factor-alpha/*physiology ; Tumor Suppressor Protein p53/genetics/metabolism ; bcl-X Protein/metabolism ; }, abstract = {IFN-gamma and TNF-alpha are major proinflammatory cytokines implicated in islet beta-cell destruction, which results in type-1 diabetes; however, the underlying mechanism is not clear. Using pancreatic beta-cell line MIN6N8 cells, co-treatment with TNF-alpha and IFN-gamma, but neither cytokine alone, synergistically induced apoptosis, correlated with the activation of the JNK/SAPK, which resulted in the production of reactive oxidative species (ROS) and loss of mitochondrial transmembrane potential (delta psi m). Additionally, cells transfected with wild-type JNK1 became more susceptible to apoptosis induced by TNF-alpha/IFN-gamma through ROS production and loss of delta psi m, while cascading apoptotic events were prevented in dominant-negative JNK1-transfected or JNK inhibitor SP600125-treated cells. As the antioxidant, N-acetyl-cysteine, failed to completely suppress apoptosis induced by TNF-alpha/IFN-gamma, an additional pathway was considered to be involved. The level of p53 was significantly increased through synergistic activation of JNK by TNF-alpha/IFN-gamma. Furthermore, the synergistic effect of TNF-alpha/IFN-gamma on apoptosis and ROS production was further potentiated by the overexpression of wild-type p53, but not with mutant p53. This synergistic activation of JNK/SAPK by TNF-alpha/IFN-gamma was also induced in insulin-expressing pancreatic islet cells, and increased ROS production and p53 level, which was significantly inhibited by SP600125. Collectively, these data demonstrate that TNF-alpha/IFN-gamma synergistically activates JNK/SAPK, playing an important role in promoting apoptosis of pancreatic beta-cell via activation of p53 pathway together with ROS.}, }
@article {pmid15907767, year = {2005}, author = {Dousset, E and Carrega, L and Steinberg, JG and Clot-Faybesse, O and Jouirou, B and Sauze, N and Devaux, C and Autier, Y and Jammes, Y and Martin-Eauclaire, MF and Guieu, R}, title = {Evidence that free radical generation occurs during scorpion envenomation.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {140}, number = {2}, pages = {221-226}, doi = {10.1016/j.cca.2005.02.003}, pmid = {15907767}, issn = {1532-0456}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/therapeutic use ; Epinephrine/therapeutic use ; Female ; Free Radical Scavengers/therapeutic use ; Free Radicals/*metabolism ; Lethal Dose 50 ; Lipid Peroxidation/drug effects ; Mice ; Mice, Inbred C57BL ; Neurotoxins/*toxicity ; Nitric Oxide/metabolism ; Rats ; Rats, Wistar ; Scorpion Stings/drug therapy/*physiopathology ; Scorpion Venoms/*toxicity ; Scorpions ; }, abstract = {Although it is well established that symptomatology, morbidity and death following scorpion envenomation are due to increases in neurotransmitter release secondary to toxins binding to voltage-sensitive sodium channels, the mechanism by which venom action is involved in damaging heart, liver, lungs and kidneys remains unclear. We hypothesized that scorpion toxins could induce the generation of high levels of free radicals responsible for membrane damage in organs targeted by venom action. We have investigated lipid peroxidation in different organs, through the evaluation of thiobarbituric acid reactive substances (TBARS), after experimental envenomation of rats by toxic fractions of Androctonus australis Hector venom. We have shown that scorpion toxins cause considerable lipid peroxidation in most vital organs. We also evaluated the protective effects of antioxidants in mice injected with lethal doses of toxins. Among the drugs tested, N-acetylcysteine (NAC) was effective in protecting the mice when injected prior to toxin application. However, the free radical scavenging properties of NAC seem less implicated in these protective effects than its ability to increase the fluidity of bronchial secretions. We therefore conclude that free radical generation only plays a minor role in the toxicity of scorpion venom.}, }
@article {pmid15907373, year = {2006}, author = {O'Loghlen, A and Pérez-Morgado, MI and Salinas, M and Martín, ME}, title = {N-acetyl-cysteine abolishes hydrogen peroxide-induced modification of eukaryotic initiation factor 4F activity via distinct signalling pathways.}, journal = {Cellular signalling}, volume = {18}, number = {1}, pages = {21-31}, doi = {10.1016/j.cellsig.2005.03.013}, pmid = {15907373}, issn = {0898-6568}, mesh = {Acetylcysteine/antagonists &amp; inhibitors/*pharmacology ; Animals ; Carrier Proteins/drug effects/*metabolism ; Eukaryotic Initiation Factor-4F/drug effects/*metabolism ; Eukaryotic Initiation Factor-4G/drug effects/metabolism ; Hydrogen Peroxide/*antagonists &amp; inhibitors/pharmacology ; Imidazoles/pharmacology ; Intracellular Signaling Peptides and Proteins ; Okadaic Acid/pharmacology ; PC12 Cells ; Phosphoproteins/drug effects/*metabolism ; Pyridines/pharmacology ; Rats ; Signal Transduction/drug effects/*physiology ; Sirolimus/pharmacology ; }, abstract = {During the oxidative stress generated by hydrogen peroxide (H2O2) in nerve growth factor (NGF)-differentiated PC12 cells, eIF4E binding protein (4E-BP1) and initiation factor 4E (eIF4E) phosphorylated levels decrease significantly, and an enhancement of the association of 4E-BP1 to eIF4E, which in turn decreases eIF4F formation is observed. The treatment with N-acetyl-cysteine (NAC) completely abolishes the H2O2-induced decrease in eIF4E phosphorylated levels, whereas the decrease in 4E-BP1 phosphorylated levels and eIF4F activity inhibition are significantly but not fully reversed. Rapamycin, the mammalian target of rapamycin (FRAP/mTOR) inhibitor, prevents the effect of NAC on H2O2-induced eIF4F complex formation inhibition. Besides the inhibitor induces a similar decrease in 4E-BP1 phosphorylated levels to that promote by H2O2. However, rapamycin has no effect on the NAC-induced recovery in phosphorylated eIF4E levels. Neither the MAP kinase inhibitors, PD98056 and SB203580, or the protein phosphatase 2A inhibitor, okadaic acid, mimic NAC effect on the H2O2-induced eIF4E dephosphorylation. Altogether our findings suggest that the effects caused by oxidative stress on eIF4s factors depends on two MAP kinase-independent signal transduction pathways, being at least one of them rapamycin-dependent.}, }
@article {pmid15904944, year = {2005}, author = {Molina-Jiménez, MF and Sánchez-Reus, MI and Cascales, M and Andrés, D and Benedí, J}, title = {Effect of fraxetin on antioxidant defense and stress proteins in human neuroblastoma cell model of rotenone neurotoxicity. Comparative study with myricetin and N-acetylcysteine.}, journal = {Toxicology and applied pharmacology}, volume = {209}, number = {3}, pages = {214-225}, doi = {10.1016/j.taap.2005.04.009}, pmid = {15904944}, issn = {0041-008X}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antioxidants/*metabolism ; Blotting, Northern ; Blotting, Western ; Catalase/antagonists &amp; inhibitors/metabolism ; Coumarins/metabolism/*pharmacology ; Cytosol/drug effects/enzymology ; Dose-Response Relationship, Drug ; Flavonoids/metabolism/*pharmacology ; Flow Cytometry ; Fluorescence ; Glutathione Peroxidase/genetics/metabolism ; Glutathione Reductase/genetics/metabolism ; HSP70 Heat-Shock Proteins/genetics/*metabolism ; Humans ; Immunoblotting ; Luminescent Measurements ; Mitochondria/drug effects/enzymology ; Neuroblastoma/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Rotenone/*pharmacology ; Superoxide Dismutase/metabolism ; Tumor Cells, Cultured ; }, abstract = {Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. Recently, it has been shown that fraxetin (coumarin) and myricetin (flavonoid) have significant neuroprotective effects against apoptosis induced by rotenone, increase the total glutathione levels in vitro, and inhibit lipid peroxidation. Thus, these considerations prompted us to investigate the way in which fraxetin and myricetin affect the endogenous antioxidant defense system, such as Mn and CuZn superoxide dismutase (MnSOD, CuZnSOD), catalase, glutathione reductase (GR), and glutathione peroxidase (GPx) on rotenone neurotoxicity in neuroblastoma cells. N-acetylcysteine (NAC), a potent antioxidant, was employed as a comparative agent. Also, the expression and protein levels of HSP70 by Northern and Western blot analysis were assayed in SH-SY5Y cells. After incubation for 16 h, rotenone significantly increased the expression and activity of MnSOD, GPx, and catalase. When cells were preincubated with fraxetin, there was a decrease in the protein levels and activity of both MnSOD and catalase, in comparison with the rotenone treatment. The myricetin effect was less pronounced. Activity and expression of GPx were increased by rotenone and pre-treatment with fraxetin did not modify significantly these levels. The significant enhancement in HSP70 expression at mRNA and protein levels induced by fraxetin was observed by pre-treatment of cells 0.5 h before rotenone insult. These data suggest that major features of rotenone-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that fraxetin partially protects against rotenone toxicity affecting the main protection system of the cells against oxidative injury.}, }
@article {pmid15900378, year = {2005}, author = {Akinci, SB and Erden, IA and Kanbak, M and Aypar, U}, title = {Lack of effect of N-acetylcysteine treatment to ameliorate the progression of multiple organ failure.}, journal = {Saudi medical journal}, volume = {26}, number = {4}, pages = {651-655}, pmid = {15900378}, issn = {1658-3175}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Multiple Organ Failure/*prevention &amp; control ; Prospective Studies ; }, abstract = {OBJECTIVE: To investigate whether prolonged infusion of the oxygen free radical scavenger N-acetylcysteine (NAC) that is commenced immediately after admission to intensive care unit (ICU) could ameliorate the development or progression of multiple organ failure (MOF).<br><br>METHODS: After receiving ethical committee approval, a prospective randomized, double-blind, placebo controlled study was performed in the Anesthesiology and Reanimation Intensive Care Unit, Hacettepe University Hospital, Ankara, Turkey between December 2002 and May 2003. Twenty-six patients were randomized to receive either NAC in 5% dextrose 40 mg/kg/day or the same volume of 5% dextrose both in 4 divided doses. Two patients were withdrawn due to ICU stay <24 hours. Treatment effect on organ function was assessed by the sequential organ failure assessment (SOFA) scores according to physiological parameters of respiratory, hematological, hepatic, cardiovascular, central nervous system (CNS) and renal system scores that were obtained on admission, then daily. Chi-square, Mann Whitney U tests were used for statistical analysis.<br><br>RESULTS: There was no significant difference between the 2 groups in any of the 5 organ dysfunction parameters, total maximum SOFA, delta SOFA length of intensive care stay, days of mechanical ventilation and mortality. In the NAC treatment group, the maximum SOFA coagulation score was higher than the control group (p<0.05).<br><br>CONCLUSION: N-acetylcysteine (40 mg/kg/day) that was commenced immediately after admission to ICU did not ameliorate the progression of MOF in this small cohort of patients. We believe routine prophylactic use of low-dose NAC in all critically ill patients does not provide positive protection.}, }
@article {pmid15897776, year = {2005}, author = {Weinbroum, AA}, title = {N-acetyl-L-cysteine mitigates aortic tone injury following liver ischemia-reperfusion.}, journal = {Journal of cardiovascular pharmacology}, volume = {45}, number = {6}, pages = {509-515}, doi = {10.1097/01.fjc.0000159640.36900.5d}, pmid = {15897776}, issn = {0160-2446}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta/*drug effects/physiology ; Dose-Response Relationship, Drug ; In Vitro Techniques ; Liver/*blood supply/*drug effects ; Male ; Rats ; Rats, Wistar ; Reperfusion Injury/*physiopathology ; }, abstract = {Liver ischemia and subsequent reperfusion (IR) are associated with secondary, remote organ reperfusion injury attributable to oxidative stress mediators. Because N-acetyl-L-cysteine (NAC) was effective in attenuating lung reperfusion injury, its properties on aortic dysfunction were tested. Rat isolated perfused aortic rings (n = 8/group) were evaluated during and after exposure to liver postischemia perfusate. Aortic response to phenylephrine under these conditions was also assessed in the presence or absence of increasing concentrations of NAC. Aortic rings incubated with postischemia perfusates exhibited abnormally protracted contraction. Their response to phenylephrine was reduced to 18 +/- 7% and 65 +/- 11% of controls during and after the exposure, respectively, and their subsequent relaxation was irregular. NAC 0.25 mM best attenuated the IR-induced aortic tone impairments, 0.12 mM affected it slightly, and IR-NAC 0.5 mM and IR-NAC 0.74 mM solutions dilated the rings proportionately, abolishing reactions to both IR solutions and phenylephrine. Xanthine oxidase activity and reduced glutathione (GSH) level in all IR ring tissues were inversely proportionate, but not directly so. Thus, liver IR impaired aortic tone and its response to phenylephrine, even after removal of toxic elements. NAC concentrations directly and inversely correlated with xanthine oxidase activity but not with GSH level. It preserved aortic functions dose-specifically, mainly by oxidant quenching.}, }
@article {pmid15896341, year = {2005}, author = {Bello, RI and Gómez-Díaz, C and López-Lluch, G and Forthoffer, N and Córdoba-Pedregosa, MC and Navas, P and Villalba, JM}, title = {Dicoumarol relieves serum withdrawal-induced G0/1 blockade in HL-60 cells through a superoxide-dependent mechanism.}, journal = {Biochemical pharmacology}, volume = {69}, number = {11}, pages = {1613-1625}, doi = {10.1016/j.bcp.2005.03.012}, pmid = {15896341}, issn = {0006-2952}, mesh = {Cell Survival/drug effects/physiology ; Culture Media, Serum-Free/*pharmacology ; Dicumarol/*pharmacology ; G1 Phase/*drug effects/physiology ; HL-60 Cells ; Humans ; Resting Phase, Cell Cycle/*drug effects/physiology ; Superoxides/*pharmacology ; }, abstract = {This work was set to study how dicoumarol affects the cell cycle in human myeloid leukemia HL-60 cells. Cells were accumulated in G0/1 after serum deprivation. However, when cells were treated with 5 microM dicoumarol in serum-free medium, a significant increment in the number of cells in S-phase was observed. Inhibition of G0/1 blockade was confirmed by the increase of thymidine incorporation, the phosphorylation of retinoblastoma protein, and the promotion of cell growth in long-term treatments in the absence of serum. Dicoumarol treatment increased superoxide levels, but did not affect peroxide. Increase of cellular superoxide was essential for inhibition of G0/1 blockade, since scavenging this reactive species with a cell-permeable form of SOD and the SOD mimetics 2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine (ambroxol, 100 microM) and copper[II]diisopropyl salicylate (CuDIPS, 10 microM) completely abolished the effect of dicoumarol. However, N-acetyl-cysteine, overexpression of Bcl-2 or a cell-permeable form of catalase were not effective. 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenol)methyl]-indole-4,7-dione (ES936), a mechanism-based irreversible inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), did not promote S phase entry, and dicoumarol still inhibited G0/1 blockade in the presence of ES936. We demonstrate that dicoumarol inhibits the normal blockade in G0/1 in HL-60 cells through a mechanism involving superoxide, but this effect is not dependent solely on the inhibition of the NQO1 catalytic activity. Our results send a precautionary message about use of dicoumarol to elucidate cellular processes involving oxidoreductases.}, }
@article {pmid15895825, year = {2005}, author = {Di Biase, A and Di Benedetto, R and Salvati, S and Attorri, L and Leonardi, F and Pietraforte, D}, title = {Effects of L-mono methyl-arginine, N-acetyl-cysteine and diphenyleniodonium on free radical release in C6 glial cells enriched in hexacosenoic acid.}, journal = {Neurochemical research}, volume = {30}, number = {2}, pages = {215-223}, pmid = {15895825}, issn = {0364-3190}, mesh = {Acetylcysteine/*toxicity ; Animals ; Blotting, Western ; Cell Line ; Enzyme Inhibitors/*toxicity ; Fatty Acids/metabolism ; Fatty Acids, Monounsaturated/*pharmacology ; Free Radical Scavengers/*pharmacology ; Free Radicals/*metabolism ; Glutathione/metabolism ; Lipopolysaccharides/pharmacology ; Mitogen-Activated Protein Kinases/metabolism ; Nerve Tissue Proteins/antagonists &amp; inhibitors ; Neuroglia/drug effects/*metabolism ; Nitric Oxide Synthase/antagonists &amp; inhibitors/biosynthesis ; Nitric Oxide Synthase Type I ; Nitric Oxide Synthase Type II ; Onium Compounds/*pharmacology ; Oxidation-Reduction ; Phosphorylation ; Rats ; Superoxides/metabolism ; omega-N-Methylarginine/*toxicity ; }, abstract = {Previously, we have shown that C6 glial cells enriched in hexacosenoic acid (HA) incubated with oxidative stressors released higher amounts of nitric oxide (NO) products and superoxide (O2(-)), compared to native C6 cells. In the present study, we examined the effects of pretreatment with some of free radical release inhibitors. The aim was to determine the origin of the enhanced generation of NO and superoxide, and to test the possibility of preventing it. Pre-treatment with L-mono-methyl-arginine and N-acetyl-cysteine in oxidized low-density lipoprotein (ox-LDL) exposed HA cells, inhibited not only nitrite but also superoxide production suggesting that O2(-) anion could partially derive from inducible NO synthase. We also observed that ox-LDL treatment of HA cells reduced the intracellular glutathione levels and activated extracellular signal-related kinases. Since this signalling is related to neurotoxic effect, our data substantiate the role of the free radicals in X-linked adrenoleukodystrophy pathogenesis, as HA cells have been used as an in vitro model for this disease.}, }
@article {pmid15892579, year = {2005}, author = {Baer, BR and Rettie, AE and Henne, KR}, title = {Bioactivation of 4-ipomeanol by CYP4B1: adduct characterization and evidence for an enedial intermediate.}, journal = {Chemical research in toxicology}, volume = {18}, number = {5}, pages = {855-864}, doi = {10.1021/tx0496993}, pmid = {15892579}, issn = {0893-228X}, support = {GM07750/GM/NIGMS NIH HHS/United States ; GM49054/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Aldehydes/chemistry/*metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Aryl Hydrocarbon Hydroxylases/*metabolism ; Biotransformation ; Cytochrome P-450 Enzyme System/classification/metabolism ; Glutathione/chemistry/metabolism ; Humans ; Liver/metabolism ; Lung/metabolism ; Lysine/chemistry ; NADP/chemistry ; Pyrroles/chemistry/metabolism ; Rabbits ; Spectrometry, Mass, Electrospray Ionization ; Terpenes/*metabolism/toxicity ; }, abstract = {4-Ipomeanol (IPO) is a pneumotoxin that is bioactivated to a reactive intermediate that binds to DNA and other cellular macromolecules. Despite over 30 years of research in this area, detailed structural information on the nature of the IPO reactive intermediate is still lacking. In the present study, we reacted IPO with rabbit CYP4B1 in the presence of exogenous nucleophiles and analyzed the products by liquid chromatography/electrospray ionization-mass spectrometry. Coincubation of IPO and rabbit CYP4B1 with glutathione gave rise to multiple products due likely to the presence of both sulfur and nitrogen nucleophiles in the same trapping molecule. Reaction mixtures containing equimolar N-acetyl cysteine (NAC) and N-acetyl lysine (NAL) provided a major NADPH- and CYP4B1-dependent product. A combination of high-resolution mass spectrometry and two-dimensional NMR analysis following large-scale isolation of the biologically derived material provided evidence for an N-substituted cysteinyl pyrrole derivative of IPO, analogous to that characterized previously in model chemical studies conducted with cis-2-butene-1,4-dial. Purified native rabbit lung CYP4B1 and purified recombinant rabbit CYP4B1 produced the trapped NAC/NAL-IPO pyrrole adduct at rates of 600-700 nmol/nmol P450/30 min. A panel of 14 commercially available recombinant human CYPs was also studied, and substantial rates of IPO bioactivation (>100 nmol/nmol/30 min) were observed with CYP1A2, CYP2C19, CYP2D6, and CYP3A4. These studies provide evidence for the formation of an enedial reactive intermediate during CYP-mediated IPO bioactivation, identify multiple human liver P450s capable of IPO bioactivation, and demonstrate that the same reactive intermediate is formed by both rabbit CYP4B1 and human P450s.}, }
@article {pmid15890017, year = {2005}, author = {Menon, SG and Coleman, MC and Walsh, SA and Spitz, DR and Goswami, PC}, title = {Differential susceptibility of nonmalignant human breast epithelial cells and breast cancer cells to thiol antioxidant-induced G(1)-delay.}, journal = {Antioxidants &amp; redox signaling}, volume = {7}, number = {5-6}, pages = {711-718}, doi = {10.1089/ars.2005.7.711}, pmid = {15890017}, issn = {1523-0864}, support = {CA66081/CA/NCI NIH HHS/United States ; HL51469/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Breast/*cytology/pathology ; Breast Neoplasms/metabolism/*pathology ; Cell Cycle Proteins/metabolism ; Cell Line ; Epithelial Cells/*cytology/*drug effects/metabolism/pathology ; G1 Phase/*drug effects ; Humans ; Oxidation-Reduction/drug effects ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {Reactive oxygen species (ROS) and ROS signaling have been implicated in a variety of human pathophysiological conditions that involve aberrant cellular proliferation, particularly cancer. We hypothesize that intracellular redox state differentially affects cell-cycle progression in nonmalignant versus malignant cells. The thiol antioxidant, N-acetyl-L-cysteine (NAC), was used to alter intracellular redox state in nonmalignant human breast epithelial (MCF-10A) and breast cancer cells (MCF-7 and MDA-MB-231). Treatment of cells with NAC resulted in significant augmentation of intracellular small-molecular-weight thiols, glutathione and cysteine. In addition, NAC treatment decreased oxidation of a prooxidant-sensitive dye in MCF-10A cells, but not in MDA-MB-231 and MCF-7 cells. NAC-induced shifts in intracellular redox state toward a more reducing environment caused G(1) delays in MCF-10A cells without causing any significant changes in MCF-7 and MDA-MB-231 cell-cycle progression. NAC treatment of MCF-10A (but not MCF-7 and MDA-MB-231) was accompanied by a decrease in cyclin D1 and an increase in p27 protein levels, which correlated with increased retinoblastoma protein hypophosphorylation. These results show differential redox control of progression from G(1) to S in nonmalignant versus malignant cells and support the hypothesis that loss of a redox control of the cell cycle could contribute to aberrant proliferation seen in cancer cells.}, }
@article {pmid15888667, year = {2005}, author = {Ledirac, N and Antherieu, S and d'Uby, AD and Caron, JC and Rahmani, R}, title = {Effects of organochlorine insecticides on MAP kinase pathways in human HaCaT keratinocytes: key role of reactive oxygen species.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {86}, number = {2}, pages = {444-452}, doi = {10.1093/toxsci/kfi192}, pmid = {15888667}, issn = {1096-6080}, mesh = {Cell Line ; Cell Survival/drug effects ; Fluoresceins/metabolism ; Humans ; Hydrocarbons, Chlorinated/*toxicity ; Insecticides/*toxicity ; Phosphorylation ; Protein Serine-Threonine Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Organochlorine pesticides (OCs) are reported as potential carcinogens in humans. The aim of this study was to investigate the effects of four OCs (dieldrin, endosulfan, heptachlor, and lindane) on mitogen-activated protein kinase (MAPK) cascades and more specifically to identify the mechanism underlying OC-induced ERK1/2 activation. Organochlorine pesticides increased phosphorylated Raf, MEK1/2, ERK1/2, and c-Jun in human HaCaT cells, but they had no effect on p38 MAPK activation. Moreover, blockade of Raf, MEK1/2, or PKC activation with geldanamycin, U0126, or calphostin C inhibited ERK1/2 phosphorylation, demonstrating a PKC-Raf-MEK1/2 pathway. We also showed that these insecticides induced the production of reactive oxygen species (ROS). Pre-treatment with the antioxidant molecule N-acetyl cysteine sharply decreased the level of phospho-ERK1/2 and had no effect on Raf and MEK1/2 activation, suggesting a Raf-independent mechanism. This study indicates that OCs strongly activate the ERK1/2 pathway, and it identifies a critical role of ROS in OC-induced ERK activation, probably by stabilizing its phosphorylation.}, }
@article {pmid16465270, year = {1997}, author = {Gardner, A and Xu, FH and Fady, C and Sarafian, T and Tu, Y and Lichtenstein, A}, title = {Evidence against the hypothesis that BCL-2 inhibits apoptosis through an anti-oxidant effect.}, journal = {Cell death and differentiation}, volume = {4}, number = {6}, pages = {487-496}, doi = {10.1038/sj.cdd.4400264}, pmid = {16465270}, issn = {1350-9047}, abstract = {We contrasted possible protection against apoptosis afforded by either BCL-2 expression or anti-oxidant inhibitors in the same tumor target challenged by two distinct triggers of apoptosis. Exposure of L929 fibroblasts to tumor necrosis factor (TNF) or etoposide (VP-16) induced apoptotic death with similar kinetics. Enforced expression of BCL-2 significantly protected against apoptosis induced by VP-16 but had no effect against TNF-induced apoptosis. In contrast, the anti-oxidants desferrioxamine, butylated hydroxyanisol and N-acetyl cysteine all inhibited TNF-induced apoptosis in a concentration-dependent fashion. Although exposure to VP-16 resulted in a significant generation of intracellular oxyradicals, the above three anti-oxidant inhibitors had no effect on VP-16-induced apoptotic death. Interestingly, enforced expression of BCL-2 also inhibited the ability of VP-16 to generate oxy-radicals and to depress intracellular glutathione levels. These results indicate that BCL-2 can exert anti-oxidant effects but argue against the hypothesis that these effects are critical to its protection against apoptosis.}, }
@article {pmid17180085, year = {1996}, author = {Gilbert, MS and Rupnow, BA and Ramirez, DA and Trisler, KD and Knox, SJ}, title = {Over-expression of Bcl-2 protects against apoptosis induced by the bioreductive cytotoxic drug SR4233 (Tirapazamine).}, journal = {Cell death and differentiation}, volume = {3}, number = {2}, pages = {215-222}, pmid = {17180085}, issn = {1350-9047}, abstract = {The human B-cell lymphoma cell line PW undergoes radiation-induced programmed cell death (PCD). Bcl-2 transfected PW cells, that overexpressed Bcl-2, were significantly more radioresistant than parental or neomycin control transfected PW cells. The viability of Bcl-2 transfected cells was significantly greater than that of parental PW cells treated with the bioreductive cytotoxin SR4233 under aerobic conditions. Bcl-2 transfectants were also significantly more resistant to hypoxia-induced PCD. However, there was no significant difference in the viability of parental and Bcl-2 transfected cells exposed to SR4233 under hypoxic conditions (pO(2)<100 ppm). Incubation of parental PW cells with N-acetyl cysteine decreased the cytotoxicity of SR4233 under aerobic but not anaerobic conditions. Depletion of cellular glutathione with buthionine sulphoxamine killed nearly 100% of control PW cells, but none of the Bcl-2 transfectants under the same conditions. The TBARS assay for lipid peroxidation showed that Bcl-2 transfectants had a significantly lower level of lipid peroxidation than parental PW cells following a 24 hour constant exposure to SR4233 under aerobic conditions. These results suggest that Bcl-2 overexpression inhibits PCD induced by the bioreductive cytotoxin SR4233 under aerobic conditions as well as PCD induced by hypoxia, and that there are other pathways leading to PCD that are unaffected by Bcl-2 overexpression.}, }
@article {pmid15886359, year = {2005}, author = {Quadrilatero, J and Hoffman-Goetz, L}, title = {N-acetyl-l-cysteine protects intestinal lymphocytes from apoptotic death after acute exercise in adrenalectomized mice.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {288}, number = {6}, pages = {R1664-72}, doi = {10.1152/ajpregu.00843.2004}, pmid = {15886359}, issn = {0363-6119}, mesh = {Acetylcysteine/*pharmacology ; *Adrenalectomy ; Animals ; Antigens, Surface/metabolism ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3 ; Caspases/metabolism ; Corticosterone/metabolism ; Cytochromes c/metabolism ; Female ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; Glucocorticoids/pharmacology ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Intestines/*cytology ; Lymphocytes/*drug effects ; Membranes/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidative Stress/drug effects ; Phosphatidylserines/metabolism ; Physical Exertion/*physiology ; Propidium/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; }, abstract = {Lymphocyte apoptosis has been observed after strenuous exercise. Both glucocorticoids (GC) and reactive oxygen species (ROS) have been suggested to contribute to exercise-induced lymphocyte apoptosis. The aims of this study were to 1) examine the direct contribution of GC during exercise-induced intestinal lymphocyte (IL) apoptosis and 2) determine the contribution of oxidative stress, in the absence of GC, to exercise-induced IL apoptosis. Mice were bilaterally adrenalectomized (ADX) and randomly assigned to receive saline (SAL) or N-acetyl-l-cysteine (NAC) 30 min before treadmill exercise (EX). EX consisted of 90 min of continuous running at a 2 degrees slope (30 min at 22 m/min, 30 min at 25 m/min; and 30 min at 28 m/min), and then killed immediately (Imm) or 24 h (24 h) postexercise. Control mice were exposed to a nonexercised (NonEX) condition consisting of treadmill noise and vibration without running. ILs were isolated and measured for apoptotic (phosphatidylserine externalization, mitochondrial membrane depolarization, Bcl-2, caspase 3, and cytosolic cytochrome c) and oxidative stress (H(2)O(2) and glutathione) markers. Plasma was analyzed for corticosterone (CORT) by radioimmunoassay. ADX eliminated the exercise-induced elevation in CORT but did not prevent IL apoptosis and cell loss relative to NonEX mice. In contrast, administration of NAC to ADX mice protected ILs from apoptotic cell death and inhibited post-exercise cell loss. These findings suggest that GC are not responsible for exercise-induced apoptosis and cell loss of ILs. The protective effect provided by the antioxidant NAC strongly suggest that oxidative stress is the primary pathway for IL apoptosis and cell loss after strenuous exercise.}, }
@article {pmid15884711, year = {2005}, author = {Abla, LE and Gomes, HC and Percario, S and Ferreira, LM}, title = {Acetylcysteine in random skin flap in rats.}, journal = {Acta cirurgica brasileira}, volume = {20}, number = {2}, pages = {121-123}, doi = {10.1590/s0102-86502005000200004}, pmid = {15884711}, issn = {0102-8650}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Dermatologic Surgical Procedures ; Male ; Necrosis/prevention &amp; control ; Postoperative Complications/*prevention &amp; control ; Random Allocation ; Rats ; Rats, Wistar ; Skin/*drug effects/*pathology ; Surgical Flaps/*adverse effects/*pathology ; }, abstract = {PURPOSE: Analyze the ability of Acetylcysteine to reduce distal necrosis in a random skin flap, in the rat.<br><br>METHODS: The present study utilized 28 adult male Wistar-EPM rats distributed, at random, in two groups of 14 animals. Control group rats (CG) received distilled water and Acetylcysteine group animals (NACG) received NAC (300 mg/kg) by oral infusion, 15 minutes before flap elevation. On the seventh postoperative day, percentage of distal necrosis was determined and skin samples collected in order to allow determination of MDA levels.<br><br>RESULTS: The mean necrotic area in CG group (control) was 66% and in NACG group (Acetylcysteine) 52%, a statistically significant difference according to the Mann-Whitney test (U calc = 25; U crit = 45). MDA levels were lower in the CG flap skin samples than in the NACG samples (U calc = 24; U crit = 45), the oposite being true in the normal skin samples (U calc = 10; U crit = 45).<br><br>CONCLUSION: Acetylcysteine was effective, according to the model used, reducing the percentage of distal necrosis in NACG rats.}, }
@article {pmid15882270, year = {2005}, author = {Ivanovski, O and Szumilak, D and Nguyen-Khoa, T and Ruellan, N and Phan, O and Lacour, B and Descamps-Latscha, B and Drüeke, TB and Massy, ZA}, title = {The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice.}, journal = {Kidney international}, volume = {67}, number = {6}, pages = {2288-2294}, doi = {10.1111/j.1523-1755.2005.00332.x}, pmid = {15882270}, issn = {0085-2538}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Aorta/pathology ; Apolipoproteins E/genetics/*physiology ; Arteriosclerosis/metabolism/pathology/*prevention &amp; control ; Body Weight/drug effects ; Collagen/analysis ; Female ; Mice ; Mice, Knockout ; Tyrosine/*analogs &amp; derivatives/analysis ; Uremia/*complications ; }, abstract = {BACKGROUND: Cardiovascular disease is the most frequent cause of mortality in chronic renal failure (CRF). Therefore, it is important to identify appropriate treatment measures. The antioxidant N-acetylcysteine (NAC) has been shown to reduce cardiovascular events in hemodialysis patients. Here we examine a possible direct effect of NAC supplementation on uremia-enhanced atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice.<br><br>METHODS: Uremia was induced surgically in 8-week-old female apoE(-/-) mice. Two weeks after creation of CRF mice were randomized to receive either NAC (daily oral gavage with 200 mg/kg for 8 weeks) or placebo. They were compared to a control group of sham-operated apoE(-/-) mice receiving placebo. After 8 weeks of treatment, the mice were sacrificed, and the cross-section surface area of atherosclerotic plaques was measured in aortic root and descending aorta.<br><br>RESULTS: At 10 weeks following surgery, atherosclerotic lesions were significantly larger in uremic apoE(-/-) mice than in nonuremic controls. This accelerated atherosclerosis was associated with an increase in aortic nitrotyrosine expression and collagen plaque content. NAC treatment inhibited the progression of atherosclerotic lesions and plaque collagen content compared with placebo treatment. In addition, plaques from NAC-treated uremic animals showed a significant decrease in nitrotyrosine expression whereas the degree of macrophage infiltration was comparable in both uremic groups. There was no difference in mean arterial blood pressure between the three groups.<br><br>CONCLUSION: We show for the first time that the antioxidant NAC is capable of reducing atheroma progression, in an animal model of uremia-enhanced atherosclerosis, probably via a decrease in oxidative stress.}, }
@article {pmid15878387, year = {2005}, author = {Tsai, CL and Chang, WT and Weng, TI and Fang, CC and Walson, PD}, title = {A patient-tailored N-acetylcysteine protocol for acute acetaminophen intoxication.}, journal = {Clinical therapeutics}, volume = {27}, number = {3}, pages = {336-341}, doi = {10.1016/j.clinthera.2005.03.002}, pmid = {15878387}, issn = {0149-2918}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adolescent ; Adult ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Child ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; }, abstract = {BACKGROUND: Hepatotoxicity as a result of acetaminophen(APAP) intoxication has become an important problem, but early intervention with N-acetylcysteine (NAC) is effective in preventing hepatic injury. Two NAC regimens are currently approved for acute APAP intoxication: NAC administered orally every 4 hours for 72 hours, and NAC administered intravenously for 20 hours within 8 to 10 hours after ingestion of a potentially hepatotoxic amount of APAP. However, clinical observations suggest that a variable treatment duration may be more appropriate than use of these predetermined, fixed-duration protocols.<br><br>OBJECTIVES: This study investigated the tolerability and efficacy of a patient-tailored NAC protocol for acute APAP intoxication by comparing the incidence of hepatotoxicity in patients receiving this protocol and in historical controls receiving 1 of 2 fixed-duration protocols: oral NAC for 72 hours and intravenous NAC for 20 hours within 8 to 10 hours after ingestion of a potentially hepatotoxic amount of APAP.<br><br>METHODS: This was a retrospective case series study that included all patients admitted through the emergency department (ED) of the National Taiwan University Hospital with a diagnosis of APAP intoxication between October 1997 and October 2002. According to the patient-tailored protocol, which had been used in the ED since 1997, patients with a serum APAP concentration above the limit for possible risk based on a modified Rumack-Matthew nomogram received oral treatment with NAC 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours. NAC treatment was discontinued when the APAP concentration was <10 mg/L and serum aspartate aminotransferase (AST) was <40 IU/L. For the purposes of assessing clinical outcomes, patients were divided into 3 groups based on duration of treatment: the short-course group (</=36 hours), the intermediate-course group (37-72 hours), and the long-course group (>/=73 hours). The primary outcome measure was development of hepatotoxicity, defined as a serum AST or alanine aminotransferase concentration >1000 IU/L.<br><br>RESULTS: Twenty-seven patients were included in the study, 17 in the short-course group, 4 in the intermediate-course group, and 6 in the long-course group. The mean (SD) durations of NAC treatment in the respective groups were 22.1 (5.5) hours, 45.0 (8.2) hours, and 97.3 (33.2) hours. All 6 patients (22%) in the long-course group had hepatotoxicity (peak AST range, 1083-9770 IU/L); their treatment duration ranged from 80 to 164 hours. No patients in the short- or intermediate-course group had evidence of hepatotoxicity. One woman in the long-course group in whom initiation of NAC treatment was delayed by 28 hours died of fulminant hepatic failure. The overall incidence of hepatotoxicity was similar to that in the historical controls.<br><br>CONCLUSIONS: In this retrospective case series inpatients who received patient-tailored NAC therapy for acute APAP intoxication, the incidence of hepatotoxicity was low and comparable to that in historical controls who received treatment with 1 of 2 fixed-duration regimens. Use of this protocol may have the potential to shorten hospital stays without increasing the risk to patients. However, the sample size was small, and the findings require confirmation in prospective clinical trials.}, }
@article {pmid15878161, year = {2005}, author = {Chao, HH and Juan, SH and Liu, JC and Yang, HY and Yang, E and Cheng, TH and Shyu, KG}, title = {Resveratrol inhibits angiotensin II-induced endothelin-1 gene expression and subsequent proliferation in rat aortic smooth muscle cells.}, journal = {European journal of pharmacology}, volume = {515}, number = {1-3}, pages = {1-9}, doi = {10.1016/j.ejphar.2005.03.035}, pmid = {15878161}, issn = {0014-2999}, mesh = {Angiotensin II/*pharmacology ; Animals ; Aorta/cytology ; Binding Sites/genetics ; Blotting, Northern ; Blotting, Western ; Cell Proliferation/*drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelin-1/*genetics ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Gene Expression/*drug effects ; Hydrogen Peroxide/pharmacology ; Luciferases/genetics/metabolism ; Male ; Muscle, Smooth, Vascular/cytology/*drug effects/metabolism ; Phosphorylation/drug effects ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/*pharmacology ; Transcription Factor AP-1/metabolism ; Transfection ; }, abstract = {Resveratrol is a phytoestrogen naturally found in grapes and is the major constituent of wine thought to have a cardioprotective effect. The aims of this study were to examine whether resveratrol alters angiotenisn II-induced cell proliferation and endothelin-1 gene expression and to identify the putative underlying signaling pathways in rat aortic smooth muscle cells. Cultured rat aortic smooth muscle cells were preincubated with resveratrol then stimulated with angiotensin II, after which [3H]thymidine incorporation and endothelin-1 gene expression were examined. The intracellular mechanism of resveratrol in cellular proliferation and endothelin-1 gene expression was elucidated by examining the phosphorylation level of angiotensin II-induced extracellular signal-regulated kinase (ERK). The inhibitory effects of resveratrol (1-100 microM) on angiotensin II-induced DNA synthesis and endothelin-1 gene expression were demonstrated with Northern blot and promoter activity assays. Measurements of 2'7'-dichlorofluorescin diacetate, a redox-senstive fluorescent dye, showed a resveratrol-mediated inhibition of intracellular reactive oxygen species generated by the effects of angiotensin II. The inductive properties of angiotensin II and H2O2 on ERK phosphorylation and activator protein-1-mediated reporter activity were found reversed with resveratrol and antioxidants such as N-acetyl-cysteine. In summary, we speculate that resveratrol inhibits angiotensin II-induced cell proliferation and endothelin-1 gene expression, and does so in a manner which involves the disruption of the ERK pathway via attenuation of reactive oxygen species generation. Thus, this study provides important insight into the molecular pathways that may contribute to the proposed beneficial effects of resveratrol on the cardiovascular system.}, }
@article {pmid15877083, year = {2005}, author = {Marsman, WA and Buskens, CJ and Wesseling, JG and Van Lanschot, JJ and Bosma, PJ}, title = {Gene therapy for barrett's esophagus: adenoviral gene transfer in different intestinal models.}, journal = {Cancer gene therapy}, volume = {12}, number = {9}, pages = {778-786}, doi = {10.1038/sj.cgt.7700841}, pmid = {15877083}, issn = {0929-1903}, mesh = {Acetylcysteine/pharmacology ; Adenoviridae/*genetics ; Animals ; Barrett Esophagus/*therapy ; Caco-2 Cells ; DEAE-Dextran/pharmacology ; Disease Models, Animal ; *Genetic Therapy ; Green Fluorescent Proteins/analysis/genetics ; Humans ; Intestinal Mucosa/metabolism ; Rats ; Transduction, Genetic/*methods ; }, abstract = {Adenoviral gene therapy could potentially be used for treatment of patients with a Barrett's esophagus. In order to study the feasibility of this approach it is important to study adenoviral intestinal transduction both in vitro and in vivo. In the present study, we used differentiating Caco-2 cells, closed intestinal loops and a Barrett's esophagus rat model to test transduction of adenoviruses expressing green fluorescent protein. We observed a decreased adenoviral transduction from 18.6 to 2.3% in undifferentiated and differentiated Caco-2 cells, respectively. This could be improved by the use of the mucolytic agent N-acetylcysteine (NAC) and the polycation diethylaminoethyl-dextran (DEAE-dextran), which improved transduction in differentiated cells five- and ten-fold, respectively. Also an RGD-retargeted adenovirus showed an improved transduction in differentiated cells. In closed intestinal loops adenoviral transduction was limited and the use of NAC and DEAE-dextran or RGD targeting had little effect. The Barrett's esophagus rat model consisted of an esophagojejunostomy, which results in a Barrett's esophagus and esophageal tumors within 6 months. Adenoviral transduction in this model was limited and mainly localized in the basal layer of normal esophagus and stromal tissue of a Barrett's segment. We conclude that although the adenovirus shows promising results in vitro, the current adenoviral vectors are probably not suitable for patients with Barrett's esophagus.}, }
@article {pmid15870362, year = {2005}, author = {Olofsson, AC and Hermansson, M and Elwing, H}, title = {Use of a quartz crystal microbalance to investigate the antiadhesive potential of N-acetyl-L-cysteine.}, journal = {Applied and environmental microbiology}, volume = {71}, number = {5}, pages = {2705-2712}, pmid = {15870362}, issn = {0099-2240}, mesh = {Acetylcysteine/*pharmacology ; Bacillus cereus/drug effects/growth &amp; development ; Bacterial Adhesion/*drug effects ; Elasticity ; Quartz ; Spores, Bacterial/drug effects ; Stainless Steel ; Viscosity ; }, abstract = {The reduction of bacterial biofilm formation on stainless steel surfaces by N-acetyl-L-cysteine (NAC) is attributed to effects on bacterial growth and polysaccharide production, as well as an increase in the wettability of steel surfaces. In this report, we show that NAC-coated stainless steel and polystyrene surfaces affect both the initial adhesion of Bacillus cereus and Bacillus subtilis and the viscoelastic properties of the interaction between the adhered bacteria and the surface. A quartz crystal microbalance with dissipation was shown to be a powerful and sensitive technique for investigating changes in the applied NAC coating for initial cell surface interactions of bacteria. The kinetics of frequency and dissipation shifts were dependent on the bacteria, the life cycle stage of the bacteria, and the surface. We found that exponentially grown cells gave rise to a positive frequency shift as long as their cell surface hydrophobicity was zero. Furthermore, when the characteristics of binding between the cell and the surface for different growth phases were compared, the rigidity increased from exponentially grown cells to starved cells. There was a trend in which an increase in the viscoelastic properties of the interaction, caused by the NAC coating on stainless steel, resulted in a reduction in irreversibly adhered cells. Interestingly, for B. cereus that adhered to polystyrene, the viscoelastic properties decreased, while there was a reduction in adhered cells, regardless of the life cycle stage. Altogether, NAC coating on surfaces was often effective and could both decrease the initial adhesion and increase the detachment of adhered cells and spores. The most effective reduction was found for B. cereus spores, for which the decrease was caused by a combination of these two parameters.}, }
@article {pmid15869837, year = {2005}, author = {Chen, YH and Wang, JP and Wang, H and Sun, MF and Wei, LZ and Wei, W and Xu, DX}, title = {Lipopolysaccharide treatment downregulates the expression of the pregnane X receptor, cyp3a11 and mdr1a genes in mouse placenta.}, journal = {Toxicology}, volume = {211}, number = {3}, pages = {242-252}, doi = {10.1016/j.tox.2005.03.011}, pmid = {15869837}, issn = {0300-483X}, mesh = {ATP Binding Cassette Transporter, Subfamily B/*biosynthesis/genetics ; ATP-Binding Cassette Transporters/*biosynthesis/genetics ; Acetylcysteine/pharmacology ; Animals ; Aryl Hydrocarbon Hydroxylases/*biosynthesis/genetics ; Cyclic N-Oxides ; Cytochrome P-450 CYP3A ; Down-Regulation/drug effects ; Female ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Lipopolysaccharides/*pharmacology ; Male ; Membrane Proteins ; Mice ; Mice, Inbred ICR ; Nitrogen Oxides/pharmacology ; Oxidoreductases, N-Demethylating/*biosynthesis/genetics ; Placenta/*drug effects/enzymology/metabolism/physiology ; Pregnancy ; Pregnane X Receptor ; RNA, Messenger/biosynthesis/genetics ; Reactive Oxygen Species/metabolism ; Receptors, Cytoplasmic and Nuclear/*biosynthesis/genetics ; Receptors, Steroid/*biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The cytochrome P450 3A (CYP3A) is a member of the cytochrome P450 monooxygenase superfamily. The multidrug resistance 1 (MDR1) gene belongs to the ATP-binding cassette (ABC) family. Pregnane X receptor (PXR) is a nuclear receptor that regulates its target gene transcription in a ligand-dependent manner. Lipopolysaccharide (LPS)-induced downregulation of PXR, CYP3A and MDR1 in liver has been demonstrated in a series of studies. However, it is not clear whether LPS represses the expression of PXR, CYP3A and MDR1 in placenta. In the present study, we investigated the effects of LPS on the expression of PXR, cyp3a11 and mdr1a in mouse placenta. Pregnant ICR mice were injected intraperitoneally with different doses of LPS (0.1-0.5 mg/kg) on gestational day (gd) 17. Placental PXR, cyp3a11 and mdr1a mRNA levels were determined at 12 h after LPS treatment using RT-PCR. Results showed that LPS significantly downregulated PXR, cyp3a11 and mdr1a mRNA levels in a dose-dependent manner. LPS-induced downregulation of PXR, cyp3a11 and mdr1a mRNA in placenta was significantly attenuated after pregnant mice were pre- and post-treated with alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Additional experiments revealed that LPS increased lipid peroxidation and proinflammatory cytokine expressions in mouse placenta, all of which were also attenuated by PBN. Furthermore, LPS-induced downregulation of PXR, cyp3a11 and mdr1a mRNA in mouse placenta was prevented by N-acetylcysteine (NAC). NAC also inhibited LPS-initiated lipid peroxidation, GSH depletion and proinflammatory cytokine expressions in mouse placenta. These results indicated that LPS downregulates placental PXR, cyp3a11 and mdr1a mRNA expressions. Reactive oxygen species (ROS) may be involved in LPS-induced downregulation of PXR, cyp3a11 and mdr1a in mouse placenta.}, }
@article {pmid15866309, year = {2005}, author = {Decramer, M and Rutten-van Mölken, M and Dekhuijzen, PN and Troosters, T and van Herwaarden, C and Pellegrino, R and van Schayck, CP and Olivieri, D and Del Donno, M and De Backer, W and Lankhorst, I and Ardia, A}, title = {Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial.}, journal = {Lancet (London, England)}, volume = {365}, number = {9470}, pages = {1552-1560}, doi = {10.1016/S0140-6736(05)66456-2}, pmid = {15866309}, issn = {1474-547X}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Administration, Inhalation ; Antioxidants/*therapeutic use ; Disease Progression ; Double-Blind Method ; Female ; Forced Expiratory Volume ; Glucocorticoids/administration &amp; dosage ; Humans ; Male ; Middle Aged ; Oxidative Stress ; Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology ; Vital Capacity ; }, abstract = {BACKGROUND: Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes.<br><br>METHODS: In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat.<br><br>FINDINGS: The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI -25 to 10). The number of exacerbations per year did not differ between groups (1.25 [SD 1.35] vs 1.29 [SD 1.46]; hazard ratio 0.99 [95% CI 0.89-1.10, p=0.85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation.<br><br>INTERPRETATION: N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.}, }
@article {pmid15864552, year = {2005}, author = {Lee, KY and Shibutani, M and Kuroiwa, K and Takagi, H and Inoue, K and Nishikawa, H and Miki, T and Hirose, M}, title = {Chemoprevention of acrylamide toxicity by antioxidative agents in rats--effective suppression of testicular toxicity by phenylethyl isothiocyanate.}, journal = {Archives of toxicology}, volume = {79}, number = {9}, pages = {531-541}, doi = {10.1007/s00204-005-0656-6}, pmid = {15864552}, issn = {0340-5761}, mesh = {Acrylamide/*antagonists &amp; inhibitors/*toxicity ; Animals ; Antioxidants/*pharmacology ; Axons/drug effects/pathology ; Body Weight/drug effects ; Cerebellar Cortex/metabolism ; Drinking/drug effects ; Gait/drug effects ; Immunohistochemistry ; Isothiocyanates/*pharmacology ; Male ; Nerve Degeneration/chemically induced/pathology ; Nervous System Diseases/chemically induced/prevention &amp; control ; Organ Size/drug effects ; Rats ; Sciatic Nerve/pathology ; Spinal Cord/pathology ; Synaptophysin/metabolism ; Testicular Diseases/*chemically induced/*prevention &amp; control ; Trigeminal Ganglion/pathology ; }, abstract = {The efficacies of N-acetylcysteine (NAC), phenylethyl isothiocyanate (PEITC), and 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) at preventing the neurotoxicity and testicular toxicity of acrylamide (ACR) were investigated in rats. To this end, Sprague-Dawley males were given 0.02% ACR in drinking water, with or without 1% NAC, 0.5% PEITC or 0.1% HTHQ in the diet for four weeks. A group of untreated controls was also included in the study. All ACR-treated animals exhibited progressive neurotoxicity as judged by gait scores, and among the chemicals co-administered, only HTHQ caused any suppression by the end of the experiment, and this was slight. The severity of the neurotoxicity, as judged by axonal degeneration in the spinal gracile fasciculus and sciatic nerve (distal portion) and aberrant dot-like synaptophysin immunoreactivity, reflecting nerve terminal degeneration in the cerebellar molecular layer, was not clearly reduced by co-administration of HTHQ, NAC or PEITC either. ACR-induced sciatic nerve axon atrophy was marginally and non-significantly reduced by HTHQ. In contrast, in terms of ACR-induced testicular toxicity, exfoliation of spermatids into seminiferous lumen was clearly reduced by co-administered PEITC and was marginally reduced by co-administered HTHQ. These antioxidative agents may therefore reduce/prevent ACR-induced toxicity, at least in the testes.}, }
@article {pmid15862948, year = {2005}, author = {Galfi, P and Jakus, J and Molnar, T and Neogrady, S and Csordas, A}, title = {Divergent effects of resveratrol, a polyphenolic phytostilbene, on free radical levels and type of cell death induced by the histone deacetylase inhibitors butyrate and trichostatin A.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {94}, number = {1-3}, pages = {39-47}, doi = {10.1016/j.jsbmb.2004.12.019}, pmid = {15862948}, issn = {0960-0760}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Butyrates/*pharmacology ; Cell Death/*drug effects ; Cell Line, Tumor ; Enzyme Inhibitors/*pharmacology ; Female ; Free Radicals/metabolism ; *Histone Deacetylase Inhibitors ; Humans ; Hydroxamic Acids/*pharmacology ; Intestinal Mucosa/cytology/drug effects ; Kinetics ; Mammary Neoplasms, Animal ; Mice ; Necrosis ; Resveratrol ; Stilbenes/*pharmacology ; }, abstract = {We investigated the effects of the polyphenolic phytostilbene resveratrol on the steady-state free radical (FR) concentration and mode of cell death induced by the histone deacetylase inhibitors butyrate and trichostatin A. (i) There was no correlation between cell death induction by butyrate or trichostatin A (TSA) and FR levels. (ii) Treatment with resveratrol or N-acetyl-l-cystein (NAC) of cells, in which the FR concentration was high, resulted in an almost complete reduction of FR levels. (iii) When, however, the cellular FR concentration was marginal, resveratrol caused a minor, and NAC a marked increase of FRs as well as of the extent of cell death. Thus, resveratrol and NAC acted as antioxidants only when the cellular FR levels were high, and acted as pro-oxidants when facing a low FR concentration. (iv) Since resveratrol and the antioxidant NAC exhibited analogous effects, it is concluded that the observed actions of resveratrol are due to polyphenolic redox reactions and not related to the stilbene moiety of the molecule. (v) The results indicate that the redox status of a given cell type plays an important role in determining whether resveratrol and other antioxidants promote cell death or protect cells from it.}, }
@article {pmid15862602, year = {2005}, author = {Lachmanová, V and Hnilicková, O and Povýsilová, V and Hampl, V and Herget, J}, title = {N-acetylcysteine inhibits hypoxic pulmonary hypertension most effectively in the initial phase of chronic hypoxia.}, journal = {Life sciences}, volume = {77}, number = {2}, pages = {175-182}, doi = {10.1016/j.lfs.2004.11.027}, pmid = {15862602}, issn = {0024-3205}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*pharmacology ; Chronic Disease ; Hypertension, Pulmonary/etiology/*prevention &amp; control ; Hypoxia/*complications ; Male ; Rats ; Rats, Wistar ; }, abstract = {Exposure to chronic hypoxia results in hypoxic pulmonary hypertension (HPH). In rats HPH develops during the first two weeks of exposure to hypoxia, then it stabilizes and does not increase in severity. We hypothesize that free radical injury to pulmonary vascular wall is an important mechanism in the early days of the hypoxic exposure. Thus antioxidant treatment just before and at the beginning of hypoxia should be more effective in reducing HPH than antioxidant therapy of developed pulmonary hypertension. We studied adult male rats exposed for 4 weeks to isobaric hypoxia (F(iO2) = 0.1) and treated with the antioxidant, N-acetylcysteine (NAC, 20 g/l in drinking water). NAC was given "early" (7 days before and the first 7 days of hypoxia) or "late" (last two weeks of hypoxic exposure). These experimental groups were compared with normoxic controls and untreated hypoxic rats (3-4 weeks hypoxia). All animals kept in hypoxia had significantly higher mean pulmonary arterial blood pressure (PAP) than normoxic animals. PAP was significantly lower in hypoxic animals with early (27.1 +/- 0.9 mmHg) than late NAC treatment (30.5 +/- 1.0 mmHg, P < 0.05; hypoxic without NAC 32.6 +/- 1.2 mmHg, normoxic controls 14.9 +/- 0.7 mmHg). Early but not late NAC treatment inhibited hypoxia-induced increase in right ventricle weight and muscularization of distal pulmonary arteries assessed by quantitative histology. We conclude that release of free oxygen radicals in early phases of exposure to hypoxia induces injury to pulmonary vessels that contributes to their structural remodeling and development of HPH.}, }
@article {pmid15854525, year = {2005}, author = {Li, X and Meng, Y and Jiang, B and Yang, XS and Wang, WW and Guo, D and Lai, ZS and Zhang, ZS}, title = {[Effects of angiotensin II and aldosterone on NF-kappaB binding activity in hepatic stellate cells].}, journal = {Zhonghua yi xue za zhi}, volume = {85}, number = {6}, pages = {374-380}, pmid = {15854525}, issn = {0376-2491}, mesh = {Aldosterone/*pharmacology ; Angiotensin II/*pharmacology ; Animals ; DNA-Binding Proteins/metabolism ; I-kappa B Proteins/biosynthesis ; Liver/pathology ; Liver Cirrhosis/*metabolism ; Male ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Rats ; Rats, Wistar ; Signal Transduction ; }, abstract = {OBJECTIVE: To investigate the signal transduction mechanism underlying the effects of angiotensin II (AngII) and aldosterone (Aldo) on nuclear factor-kappaB (NF-kappaB) DNA binding activity.<br><br>METHODS: Sixty male Wistar rats were randomly divided into 4 groups: model group (Mo group), injected with CCl(4) subcutaneously twice a week to establish a model of hepatic fibrosis; perindopril group (Pe group), injected with CCl(4) subcutaneously twice a week and perfused with perindopril once a day; losartan group (Lo group), injected with CCl(4) subcutaneously twice a week and perfused with losartan once a day; and control group (Nc group), injected with olive oil subcutaneously. The rats were killed in batches respectively 4 and 6 weeks after and their livers were collected to undergo Masson staining and be observed by light microscope. Electrophoretic gel mobility shift assay (EMSA) was used to detect the NF-kappaB DNA binding activity in the liver tissues. Western blotting was used to detect the expression of IkappaBalpha in the plasma protein. Hepatic stellate cells (HSCs)-T6 were cultured and preincubated for 1 h or not with U0126 (an inhibitor of MAPK/ERK kinase MEK), irbesartan (an AT-1 receptor blocker), and N-acetylcysteine (NAC, an antioxidant), angiotensin-converting enzyme inhibitor (ACEI), or tumor necrosis factor alpha (TNFalpha) prior to exposure to AngII or Aldo for 0.5 h, 1 h, 2 h, and 4 h respectively. The binding activities of NF-kappaB DNA were observed by EMSA. The expression of IkappaBalpha protein was detected with Western blotting. Histochemistry was used to detect the expression of NF-kappaB p65. RT-PCR was used to detect the expression of TNFalpha mRNA in HSC-T6 cells.<br><br>RESULTS: The binding activity to NF-kappaB of the liver tissues was the strongest in the Mo group, followed by the Pe and Lo groups and Nc group. The IkappaBalpha expressions in liver tissues 4 and 6 weeks after the beginning of experiment in the Pe and Lo groups were significantly stronger than that in the Mo group (both P < 0.05). 0.5 hour after the intervention of AngII the DNA binding activity of the HSCs began to increase and peaked 1 hour later and then gradually decreased. The increase of NF-kappaB activity induced by AngII could be inhibited by irbesartan, ACEI and NAC pretreatment and could not be inhibited by U0126 pretreatment. Combined action of AngII and TNFalpha significantly increased the NF-kappaB DNA binding activity. The IkappaBalpha expression began to decrease 0.5 hour after the intervention of AngII and reached the lowest value 2 hours after. The expression of IkappaBalpha protein was increased by ACEI (P < 0.05), irbesartan and NAC (both P < 0.01). EMSA showed that 0.5 hour after the intervention of Aldo the DNA binding activity began to be increased and peaked by 1 hour and then began to be decreased. NAC, but not U0126 partly inhibited the increased of NF-kappaB activity induced by Aldo. Combined action of Aldo and TNFalpha significantly increased the NF-kappaB activity. Aldo increased the expression of IkappaBalpha protein in the HSCs at different time points (all P < 0.05). 0.5 hour after the AngII intervention the IkappaBalpha protein expression began to decrease and reach the lowest value 1 hour later and then began to increase 2 hours later. the IkappaBalpha protein expression was significantly decreased in the NAC and NAC+ Aldo intervention groups (both P < 0.05). There was no significant difference in IkappaBalpha protein expression between the Aldo intervention group and U0126 + Aldo, TNFalpha, and Aldo + TNFalpha treatment groups (all P > 0.05). Before stimulation, NF-kappaB was expressed in the plasma of HSCs, however, after the stimulation of AngII or Aldo for 1 hour it was expressed in the nuclei, and then transferred from the nuclei to the plasma 4 hours after the stimulation. However, little nuclear transfer was observed after pretreatment of NAC followed by AngII or Aldo intervention. The TNFalpha mRNA expression was significantly increased in the AngII and Aldo treatment groups in comparison with the control group (both P < 0.05). The TNFalpha mRNA expression was significantly weaker in the irbesartan + AngII, NAC + AngII, and ACEI groups in comparison with the AngII group (all P < 0.05).<br><br>CONCLUSION: Stimulation of NF-kappaB activity mediates hepatic fibrosis induced by intrahepatic renin-angiotensin-aldosterone system (RAAS).}, }
@article {pmid15853972, year = {2005}, author = {Chang, YC and Lai, CC and Lin, LF and Ni, WF and Tsai, CH}, title = {The up-regulation of heme oxygenase-1 expression in human gingival fibroblasts stimulated with nicotine.}, journal = {Journal of periodontal research}, volume = {40}, number = {3}, pages = {252-257}, doi = {10.1111/j.1600-0765.2005.00804.x}, pmid = {15853972}, issn = {0022-3484}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase/pharmacology ; Cattle ; Fibroblasts/*drug effects/metabolism ; Ganglionic Stimulants/*adverse effects ; Gingiva/*drug effects/metabolism ; Heme Oxygenase (Decyclizing)/antagonists &amp; inhibitors/*metabolism ; Heme Oxygenase-1 ; Humans ; Male ; Membrane Proteins ; Nicotine/*adverse effects ; Smoking/adverse effects ; Superoxide Dismutase/pharmacology ; Up-Regulation ; }, abstract = {BACKGROUND: Cigarette smoking is a major risk factor in the development and further progression of periodontal diseases. Heme oxygenase-1 (HO-1) is known as a stress-inducible protein and functions as an antioxidant enzyme. There is limited information on the expression of HO-1 in smoking-associated periodontal disease.<br><br>OBJECTIVES: The aim of the present study was to investigate the effects of nicotine on the expression of HO-1 protein in cultured human gingival fibroblasts in vitro and further to compare HO-1 expression in gingival tissues obtained from cigarette smokers and non-smokers in vivo.<br><br>METHODS: Western blot assay was used to investigate the effects on human gingival fibroblasts exposed to nicotine. In addition, antioxidants catalase, superoxide dismutase (SOD), and N-acetyl-l-cysteine (NAC) were added to test how they modulated the effects on nicotine-induced HO-1 expression. Gingival biopsies taken from the flap surgery of 20 male patients with periodontal disease (10 cigarette smokers and 10 non-smokers) were examined by immunohistochemistry.<br><br>RESULTS: The exposure of quiescent human gingival fibroblasts to 10 mm nicotine resulted in the induction of HO-1 protein expression in a time-dependent manner (p < 0.05). The addition of glutathione (GSH) precursor NAC inhibited the nicotine-induced HO-1 protein expression (p < 0.05). However, SOD and catalase did not decrease the nicotine-induced HO-1 protein expression (p > 0.05). The results from immunohistochemistry demonstrated that HO-1 expression was significantly higher in cigarette smokers (p < 0.05). HO-1 was noted in the basal layers of epithelium, inflammatory cells, and fibroblasts in specimens from cigarette smoking.<br><br>CONCLUSIONS: Taken together, these results suggest that HO-1 expression is significantly up-regulated in gingival tissues from cigarette smokers, and nicotine may, among other constituents, be responsible for the enhanced HO-1 expression in vivo. The regulation of HO-1 expression induced by nicotine is critically dependent on the intracellular GSH concentration.}, }
@article {pmid15851851, year = {2005}, author = {Tchantchou, F and Graves, M and Rogers, E and Ortiz, D and Shea, TB}, title = {N-acteyl cysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {7}, number = {2}, pages = {135-8; discussion 173-80}, doi = {10.3233/jad-2005-7206}, pmid = {15851851}, issn = {1387-2877}, mesh = {Acetylcysteine/*metabolism ; Alzheimer Disease/*metabolism/pathology ; Animals ; Animals, Genetically Modified ; Apolipoproteins E/*genetics ; Brain/*metabolism ; Folic Acid/metabolism ; Mice ; Oxidative Stress/*physiology ; Vitamin E Deficiency/metabolism ; }, abstract = {Oxidative stress is an early neurodegenerative insult in Alzheimer's disease (AD). Antioxidant mechanisms, including elements of the glutathione (GSH) pathway, undergo at least a transient compensatory increase that is apparently insufficient due to continued oxidative damage during disease progression. Mice deficient in apolipoprotein E, which provide a model for some aspects of AD, undergo increased oxidative damage to brain tissue and cognitive decline when maintained on a folate-free diet, despite a compensatory increase in glutathione synthase transcription and activity as well as increased levels of GSH. Dietary supplementation with N-acetyl cysteine (1 g/kg diet), a cell-permeant antioxidant and GSH precursor, alleviated oxidative damage and cognitive decline, and restored glutathione synthase and GSH levels in ApoE-deficient mice deprived of folate to those of normal mice maintained in the presence of folate. These data support the administration of antioxidant precursors to buffer oxidative damage in neurodegenerative disorders.}, }
@article {pmid15845704, year = {2005}, author = {Nandate, K and Ogata, M and Tamura, H and Kawasaki, T and Sata, T and Shigematsu, A}, title = {N-acetyl-cysteine attenuates endotoxin-induced adhesion molecule expression in human whole blood.}, journal = {Anesthesia and analgesia}, volume = {100}, number = {5}, pages = {1453-1457}, doi = {10.1213/01.ANE.0000148616.24996.E7}, pmid = {15845704}, issn = {0003-2999}, mesh = {Acetylcysteine/*pharmacology ; CD11b Antigen/*biosynthesis ; Cell Adhesion Molecules/*biosynthesis ; Dose-Response Relationship, Drug ; Endotoxins/*pharmacology ; Humans ; Interleukin-8/pharmacology ; L-Selectin/biosynthesis ; Leukocytes/metabolism ; }, abstract = {Leukocyte adhesion to endothelial cells plays a pivotal role in the early stage of endotoxin shock. The attenuation of the leukocyte response to endotoxin may contribute to the prevention of further organ dysfunction. Recent evidence implies that N-acetyl-cysteine (NAC) attenuates endotoxin-induced pathophysiological changes. We investigated the effect of NAC on the expression of CD11b and CD62L in endotoxin-stimulated human whole blood. NAC (>10 mM) significantly inhibited the lipopolysaccharide (LPS)-induced upregulation of CD11b in a concentration-dependent manner. However, NAC did not affect the LPS-induced downregulation of CD62L. We also analyzed the effect of NAC on interleukin-8 (IL-8)-induced expression of CD11b in human whole blood. IL-8 (10 ng/mL) significantly upregulated the expression of CD11b, and the IL-8-induced upregulation was significantly attenuated by NAC (>10 mM) in a dose-dependent manner. We conclude that NAC attenuates the increased expression of CD11b in either LPS or IL-8-stimulated human whole blood.}, }
@article {pmid15843042, year = {2005}, author = {Chen, YC and Shen, SC and Tsai, SH}, title = {Prostaglandin D(2) and J(2) induce apoptosis in human leukemia cells via activation of the caspase 3 cascade and production of reactive oxygen species.}, journal = {Biochimica et biophysica acta}, volume = {1743}, number = {3}, pages = {291-304}, doi = {10.1016/j.bbamcr.2004.10.016}, pmid = {15843042}, issn = {0006-3002}, mesh = {Amino Acid Chloromethyl Ketones/pharmacology ; *Apoptosis ; Arachidonic Acid ; Caspase 3 ; Caspases/*metabolism ; Cell Survival/drug effects ; Cyclooxygenase 2 ; Enzyme Activation ; Guanine Nucleotide Dissociation Inhibitors/metabolism ; HL-60 Cells ; Humans ; Jurkat Cells ; Membrane Proteins ; PPAR gamma/agonists ; Poly(ADP-ribose) Polymerases/metabolism ; *Prostaglandin D2/*analogs &amp; derivatives/antagonists &amp; inhibitors ; Prostaglandin-Endoperoxide Synthases/biosynthesis ; Reactive Oxygen Species/*metabolism ; Tetradecanoylphorbol Acetate ; rho Guanine Nucleotide Dissociation Inhibitor beta ; rho-Specific Guanine Nucleotide Dissociation Inhibitors ; }, abstract = {The presence of prostaglandins (PGs) has been demonstrated in the processes of carcinogenesis and inflammation. In the present study, we found that 12-o-tetradecanoylphorbol 13-acetate (TPA) induced cyclooxygenase 2 (COX-2), but not COX-1, protein expression in HL-60 cells, and the addition of arachidonic acid (AA) in the presence or absence of TPA significantly reduced the viability of HL-60 cells, an effect that was blocked by adding the COX inhibitors, NS398 and aspirin. The AA metabolites, PGD(2) and PGJ(2), but not PGE(2) or PGF(2alpha), reduced the viability of the human HL60 and Jurkat leukemia cells according to the MTT assay and LDH release assay. Apoptotic characteristics including DNA fragmentation, apoptotic bodies, and hypodiploid cells were observed in PGD(2)- and PGJ(2)-treated leukemia cells. A dose- and time-dependent induction of caspase 3 protein procession, and PARP and D4-GDI protein cleavage with activation of caspase 3, but not caspase 1, enzyme activity was detected in HL-60 cells treated with PGD(2) or PGJ(2). Additionally, DNA ladders induced by PGD(2) and PGJ(2) were significantly inhibited by the caspase 3 peptidyl inhibitor, Ac-DEVD-FMK, but not by the caspase 1 peptidyl inhibitor, Ac-YVAD-FMK, in accordance with the blocking of caspase 3, PARP, and D4-GDI protein procession. An increase in intracellular peroxide levels by PGD(2) and PGJ(2) was identified by the DCHF-DA assay, and anti-oxidant N-acetyl cysteine (NAC), mannitol (MAN), and tiron significantly inhibited cell death induced by PGD(2) and PGJ(2) by reducing reactive oxygen species (ROS) production. The PGJ(2) metabolites, 15-deoxy-Delta(12,14)-PGJ(2) and Delta(12)-PGJ(2), exhibited effective apoptosis-inducing activity in HL-60 cells through ROS production via activation of the caspase 3 cascade. The proliferator-activated receptor-gamma (PPAR-gamma) agonists, rosiglitazone (RO), troglitazone (TR), and ciglitazone (CI), induced apoptosis in cells which was blocked by the addition of the PPAR-gamma antagonists, GW9662 and BADGE, via blocking of caspase 3 and PARP cleavage. However, neither GW9662 nor BADGE showed any protective effect on PGD(2)- and PGJ(2)-induced apoptosis. A differential apoptotic effect of PGs through ROS production, followed by activation of the caspase 3 cascade, was demonstrated.}, }
@article {pmid15843034, year = {2005}, author = {Song, Z and Uriarte, S and Sahoo, R and Chen, T and Barve, S and Hill, D and McClain, C}, title = {S-adenosylmethionine (SAMe) modulates interleukin-10 and interleukin-6, but not TNF, production via the adenosine (A2) receptor.}, journal = {Biochimica et biophysica acta}, volume = {1743}, number = {3}, pages = {205-213}, doi = {10.1016/j.bbamcr.2004.12.001}, pmid = {15843034}, issn = {0006-3002}, support = {AA000297/AA/NIAAA NIH HHS/United States ; AA010496/AA/NIAAA NIH HHS/United States ; AA010762/AA/NIAAA NIH HHS/United States ; AA013170/AA/NIAAA NIH HHS/United States ; AA01485/AA/NIAAA NIH HHS/United States ; }, mesh = {Adenosine A2 Receptor Antagonists ; Animals ; Cell Line ; Cyclic AMP/metabolism ; Dependovirus ; Glutathione/metabolism ; Interleukin-10/biosynthesis/metabolism ; Interleukin-6/biosynthesis/metabolism ; Lipopolysaccharides ; Mice ; Receptors, Adenosine A2/*drug effects/metabolism ; S-Adenosylmethionine/*pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {S-adenosylmethionine (SAMe) is the first product in methionine metabolism and serves as a precursor for glutathione (GSH) as well as a methyl donor in most transmethylation reactions. The administration of exogenous SAMe has beneficial effects in many types of liver diseases. One mechanism for the hepatoprotective action is its ability to regulate the immune system by modulating cytokine production from LPS stimulated monocytes. In the present study, we investigated possible mechanism(s) by which exogenous SAMe supplementation modulated production of TNF, IL-10 and IL-6 in LPS stimulated RAW 264.7 cells, a murine monocyte cell line. Our results demonstrated that exogenous SAMe supplementation inhibited TNF production but enhanced both IL-10 and IL-6 production. SAMe increased intracellular GSH level, however, N-acetylcysteine (NAC), the GSH pro-drug, decreased the production of all three cytokines. Importantly, SAMe increased intracellular adenosine levels, and exogenous adenosine supplementation had effects similar to SAMe on TNF, IL-10 and IL-6 production. 3-Deaza-adenosine (DZA), a specific inhibitor of S-adenosylhomocysteine (SAH) hydrolase, blocked the elevation of IL-10 and IL-6 production induced by SAMe, which was rescued by the addition of exogenous adenosine. Furthermore, the enhancement of LPS-stimulated IL-10 and IL-6 production by both SAMe and adenosine was inhibited by ZM241385, a specific antagonist of the adenosine (A(2)) receptor. Our results suggest that increased adenosine levels with subsequent binding to the A(2) receptor account, at least in part, for SAMe modulation of IL-10 and IL-6, but not TNF production, from LPS stimulated monocytes.}, }
@article {pmid15842963, year = {2005}, author = {Yuta, A and Baraniuk, JN}, title = {Therapeutic approaches to mucus hypersecretion.}, journal = {Current allergy and asthma reports}, volume = {5}, number = {3}, pages = {243-251}, pmid = {15842963}, issn = {1529-7322}, mesh = {Animals ; Cholinergic Antagonists/therapeutic use ; Deoxyribonucleases/therapeutic use ; Expectorants/therapeutic use ; Glucocorticoids/therapeutic use ; Humans ; Macrolides/therapeutic use ; Mucus/*metabolism ; Peptide Hydrolases/therapeutic use ; Purinergic Agonists ; Respiratory Tract Diseases/*drug therapy ; Sulfhydryl Compounds/therapeutic use ; Water ; }, abstract = {Mucolytic and related agents have been in use since prehistoric times. Although widely prescribed and used extensively in over-the-counter preparations, their efficacy and mechanisms of action remain in doubt. These agents belong to several distinct chemical classes. Mucolytic agents such as N-acetyl-cysteine are thiols with a free-sulfhydryl group. They are assumed to break disulfide bonds between gel-forming mucins and thus reduce mucus viscosity. Mucokinetic agents are thiols with a blocked sulfhydryl group. Expectorants such as guaifenesin increase mucus secretion. They may act as irritants to gastric vagal receptors, and recruit efferent parasympathetic reflexes that cause glandular exocytosis of a less viscous mucus mixture. Cough may be provoked. This combination may flush tenacious, congealed mucopurulent material from obstructed small airways and lead to a temporary improvement in dyspnea or the work of breathing. The roles of anticholinergic agents, DNase, and other drugs are also discussed with regard to their roles in reducing mucus production in rhinitis and other airway diseases.}, }
@article {pmid15841722, year = {2005}, author = {Shi, C and Zhao, X and Wang, X and Andersson, R}, title = {Role of nuclear factor-kappaB, reactive oxygen species and cellular signaling in the early phase of acute pancreatitis.}, journal = {Scandinavian journal of gastroenterology}, volume = {40}, number = {1}, pages = {103-108}, doi = {10.1080/00365520410009555}, pmid = {15841722}, issn = {0036-5521}, mesh = {Acute Disease ; Animals ; Biomarkers/*blood ; Disease Models, Animal ; Interleukin-10/metabolism ; Interleukin-6/metabolism ; Male ; NF-kappa B/*metabolism ; Pancreatitis/*blood/physiopathology ; Peroxidase/analysis/*metabolism ; Probability ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/analysis/*metabolism ; Signal Transduction ; Statistics, Nonparametric ; Transcription Factor RelA ; }, abstract = {OBJECTIVE: Increased knowledge of regulation of signaling proteins in acute pancreatitis (AP) could potentially contribute to the development of novel agents targeted at regulation of cellular signaling.<br><br>MATERIAL AND METHODS: Severe AP was induced by administration of 5% sodium taurodeoxycholate in rats. Thirty minutes prior to induction of AP, the animals had an intraperitoneal injection of the antioxidant, N-acetylcysteine (NAC; 10 mg/kg), the NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100 mg/kg), the ERK inhibitor, PD-98059 (1 mg/kg), or the tyrosine kinase inhibitor, Genistein (1 mg/kg). Plasma levels of IL-6 and IL-10 were determined by ELISA and myeloperoxidase (MPO) levels were measured in the pancreas and lungs 3 and 6 h after sham operation or induction of AP.<br><br>RESULTS: AP results in significant increases in plasma levels of IL-6 at 6 h and IL-10 at 3 and 6 h. Plasma levels of IL-6 were significantly decreased after administration of NAC. NAC pretreatment also increased the ratio of IL-10/IL-6. MPO levels in the pancreas (at 3 and 6 h) and lungs (3 h) were significantly increased in animals with pancreatitis. Pretreatment with NAC, PDTC, PD98059 or Genistein significantly decreased MPO levels in the pancreas at 3 and 6 h and following the administration of PD-98059 or NAC at 6 h. Pretreatment with NAC significantly decreased MPO levels in the lungs at 3 h.<br><br>CONCLUSIONS: Pretreatment with NAC could regulate the pro-and anti-inflammatory cytokine balance, probably through NF-kappaB and ROS signaling pathways. The regulation of signaling pathways during the sequestration of neutrophils in acute pancreatitis seems to vary between organs.}, }
@article {pmid15840558, year = {2005}, author = {Gong, Y and Agani, FH}, title = {Oligomycin inhibits HIF-1alpha expression in hypoxic tumor cells.}, journal = {American journal of physiology. Cell physiology}, volume = {288}, number = {5}, pages = {C1023-9}, doi = {10.1152/ajpcell.00443.2004}, pmid = {15840558}, issn = {0363-6143}, support = {NS-41309/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amino Acids, Dicarboxylic/toxicity ; Cell Hypoxia/physiology ; Chromans/pharmacology ; DNA-Binding Proteins/*metabolism ; Deferoxamine/toxicity ; Electron Transport/drug effects/physiology ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects/*physiology ; Humans ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit ; Mitochondria/drug effects/*metabolism ; Nuclear Proteins/*metabolism ; Oligomycins/*pharmacology ; Proton-Translocating ATPases/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/*metabolism ; Transcription Factors/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Hypoxia-inducible factor-1 (HIF-1) is a key regulator of cellular responses to reduced oxygen availability. The contribution of mitochondria in regulation of HIF-1alpha in hypoxic cells has received recent attention. We demonstrate that inhibition of electron transport complexes I, III, and IV diminished hypoxic HIF-1alpha accumulation in different tumor cell lines. Hypoxia-induced HIF-1alpha accumulation was not prevented by the antioxidants Trolox and N-acetyl-cysteine. Oligomycin, inhibitor of F(0)F(1)-ATPase, prevented hypoxia-induced HIF-1alpha protein accumulation and had no effect on HIF-1alpha induction by hypoxia-mimicking agents desferrioxamine or dimethyloxalylglycine. The inhibitory effect of mitochondrial respiratory chain inhibitors and oligomycin on hypoxic HIF-1alpha content was pronounced in cells exposed to hypoxia (1.5% O(2)) but decreased markedly when cells were exposed to severe oxygen deprivation (anoxia). Taken together, these results do not support the role for mitochondrial reactive oxygen species in HIF-1alpha regulation, but rather suggest that inhibition of electron transport chain and impaired oxygen consumption affect HIF-1alpha accumulation in hypoxic cells indirectly via effects on prolyl hydroxylase function.}, }
@article {pmid15840023, year = {2005}, author = {Lee, EA and Seo, JY and Jiang, Z and Yu, MR and Kwon, MK and Ha, H and Lee, HB}, title = {Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 up-regulation in mesangial cells and in diabetic kidney.}, journal = {Kidney international}, volume = {67}, number = {5}, pages = {1762-1771}, doi = {10.1111/j.1523-1755.2005.00274.x}, pmid = {15840023}, issn = {0085-2538}, mesh = {Animals ; Antioxidants/pharmacology ; Base Sequence ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; DNA, Complementary/genetics ; Diabetes Mellitus, Experimental/genetics/metabolism ; Diabetic Nephropathies/*genetics/*metabolism ; Fibrinolysin/metabolism ; Glomerular Mesangium/drug effects/*metabolism ; Glucose/*metabolism/pharmacology ; Glutathione/metabolism ; Male ; Oxidative Stress ; Plasminogen Activator Inhibitor 1/*genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Taurine/pharmacology ; Transforming Growth Factor beta/antagonists &amp; inhibitors/metabolism ; Transforming Growth Factor beta1 ; Up-Regulation/drug effects ; }, abstract = {BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in remodeling of extracellular matrix (ECM) in the glomeruli. PAI-1 is up-regulated by high glucose and is overexpressed in diabetic kidney. Since reactive oxygen species (ROS) mediate ECM accumulation in diabetic glomeruli and was recently found to mediate transforming growth factor-beta1 (TGF-beta1)-induced PAI-1 up-regulation in glomerular mesangial cells, we examined the role of ROS in high glucose-induced PAI-1 expression in cultured glomerular mesangial cells and in streptozotocin-induced diabetic rat glomeruli.<br><br>METHODS: Growth arrested and synchronized primary rat mesangial cells were treated with different concentrations of glucose in the presence or absence of N-acetylcysteine (NAC) or trolox, or after cellular reduced form of glutathione (GSH) depleted with DL-buthionine-(S,R)-sulfoximine (BSO). Taurine was administered to diabetic rats from 2 days to 4 weeks after streptozotocin injection. Urinary protein excretion, glomerular volume, and fractional mesangial area were measured as markers of renal injury and lipid peroxide (LPO) as an oxidative stress marker. PAI-1 mRNA expression was measured by Northern blot analysis in mesangial cells and reverse transcription-polymerase chain reaction (RT-PCR) in glomeruli, PAI-1 protein by Western blot analysis and enzyme-linked immunosorbent assay (ELISA), and plasmin activity by fluorometry.<br><br>RESULTS: High glucose significantly increased PAI-1 mRNA and protein expression and decreased plasmin activity in mesangial cells. Equimolar concentrations of l-glucose or mannitol did not affect PAI-1 expression. BSO pretreatment significantly increased basal PAI-1 expression and amplified the response to high glucose. NAC effectively inhibited high glucose-induced, but not basal, PAI-1 expression. Reduced plasmin activity in mesangial cells by high glucose was rescued by antioxidants. Anti-TGF-beta antibody inhibited both high glucose- and H(2)O(2)-induced PAI-1 up-regulation. Taurine significantly reduced plasma LPO, glomerular PAI-1 expression, glomerular volume, fractional mesangial area, and proteinuria in streptozotocin-induced diabetic rats.<br><br>CONCLUSION: These results demonstrate that ROS mediate high glucose-induced up-regulation of PAI-1 expression in cultured mesangial cells and in diabetic glomeruli. Since both high glucose and TGF-beta1 induce cellular ROS and ROS mediate both high glucose- and TGF-beta1-induced PAI-1, ROS appear to amplify TGF-beta1 signaling in high glucose-induced PAI-1 up-regulation. Antioxidants can prevent accumulation of ECM protein in diabetic glomeruli partly by abrogating up-regulation of PAI-1 and suppression of plasmin activity.}, }
@article {pmid15837587, year = {2005}, author = {Onyango, IG and Bennett, JP and Tuttle, JB}, title = {Endogenous oxidative stress in sporadic Alzheimer's disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids.}, journal = {Neurobiology of disease}, volume = {19}, number = {1-2}, pages = {312-322}, doi = {10.1016/j.nbd.2005.01.026}, pmid = {15837587}, issn = {0969-9961}, support = {AG14373/AG/NIA NIH HHS/United States ; NS39005/NS/NINDS NIH HHS/United States ; NS39788/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Alzheimer Disease/genetics/*metabolism/*pathology ; Apoptosis/*physiology ; Cell Death/physiology ; Cell Line, Tumor ; Cell Survival/physiology ; Cerebral Amyloid Angiopathy/genetics/metabolism/pathology ; Humans ; Neurons/*metabolism ; Oxidants/*pharmacology ; Oxidative Stress/*physiology ; Signal Transduction/physiology ; }, abstract = {Although oxidative stress and mitochondrial dysfunction have been linked to neurodegenerative diseases such as Alzheimer's disease (AD), it is not fully understood how mitochondrial oxidative stress may induce neuronal death. We used mitochondrial transgenic neuronal cell cybrid models of sporadic AD (SAD) to investigate the effects of endogenously generated reactive oxygen species (ROS) on viability and cell death mechanisms. Compared to control (CTL) cybrids, SAD cybrids have increased accumulation of oxidative stress markers and increased apoptosis that is blocked by N-acetylcysteine (NAC) and zVAD.fmk. SAD cybrids also have increased basal activation of the MAPKs, Akt, and NF-kappa B. NF-kappa B activation and cybrid viability are enhanced by NAC. Inhibiting the activity of the PI3K pathway or NF-kappa B aggravates neuronal death. Exposure of CTL cybrids to H2O2 decreased viability and activated in a NAC-sensitive manner, the same intracellular signaling pathways active under basal conditions in SAD cybrids.}, }
@article {pmid15836997, year = {2005}, author = {Fisher, MT and Nagarkatti, M and Nagarkatti, PS}, title = {Aryl hydrocarbon receptor-dependent induction of loss of mitochondrial membrane potential in epididydimal spermatozoa by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).}, journal = {Toxicology letters}, volume = {157}, number = {2}, pages = {99-107}, doi = {10.1016/j.toxlet.2005.01.008}, pmid = {15836997}, issn = {0378-4274}, mesh = {Animals ; Apoptosis/drug effects ; Dose-Response Relationship, Drug ; Environmental Pollutants/*toxicity ; Epididymis/drug effects ; Injections, Intraperitoneal ; Male ; Membrane Potentials/drug effects ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/*drug effects/metabolism/physiology ; Polychlorinated Dibenzodioxins/*toxicity ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/genetics/*metabolism ; Spermatozoa/*drug effects/metabolism/physiology ; Time Factors ; }, abstract = {2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental contaminant known to exhibit toxic effects on the male reproductive system, including the epididymus and spermatozoa. However, the mechanism(s) that mediate dioxin toxicity in spermatozoa remain unclear. The aim of the present study was to investigate whether exposure to TCDD would cause a loss in mitochondrial membrane potential (Deltapsi(m)) in spermatozoa and whether such an effect is mediated by the Ah receptor (AhR). Exposure of C57BL/6 male mice to TCDD at concentrations of 0.1-50 microg/kg for 24 h caused a dose-dependent loss of Deltapsi(m) in epididymal spermatozoa compared to spermatozoa from vehicle-treated mice. However, this effect was not apparent in spermatozoa from AhR knockout (KO) mice. Exposure of spermatozoa from C57BL/6 mice to 1 nM or 5 nM TCDD in vitro also induced loss of Deltapsi(m). TCDD-exposed C57BL/6 mice failed to exhibit changes in the morphology of testes and epididymus, and did not show any increase in number of apoptotic germ cells. In addition, comparison of reactive oxygen species (ROS) production in spermatozoa from vehicle- and TCDD-treated mice indicated that exposure to TCDD resulted in elevated ROS levels in the spermatozoa from TCDD-treated mice. Moreover, blockade of ROS production by pretreatment with ROS scavenger N-acetylcysteine (NAC) mitigated the loss of Deltapsi(m) following TCDD exposure. Taken together, these data suggest that direct exposure of spermatozoa to TCDD triggers loss of Deltapsi(m) that is mediated by AhR-dependent production of ROS.}, }
@article {pmid15832819, year = {2005}, author = {Yoo, JM and Lee, YS and Choi, HK and Lee, YM and Hong, JT and Yun, YP and Oh, S and Yoo, HS}, title = {Protection of LLC-PK1 cells against hydrogen peroxide-induced cell death by modulation of ceramide level.}, journal = {Archives of pharmacal research}, volume = {28}, number = {3}, pages = {311-318}, doi = {10.1007/BF02977798}, pmid = {15832819}, issn = {0253-6269}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Death/drug effects ; Ceramides/*metabolism ; Desipramine/pharmacology ; Glutathione/metabolism ; Glutathione S-Transferase pi ; Glutathione Transferase/biosynthesis ; Hydrogen Peroxide/*metabolism ; Isoenzymes/biosynthesis ; LLC-PK1 Cells ; Oxidative Stress ; Sphingolipids/biosynthesis ; Sphingomyelin Phosphodiesterase/antagonists &amp; inhibitors ; Swine ; }, abstract = {Oxidative stress has been reported to elevate ceramide level during cell death. The purpose of the present study was to modulate cell death in relation to cellular glutathione (GSH) level and GST (glutathione S-transferase) expression by regulating the sphingolipid metabolism. LLC-PK1 cells were treated with H2O2 in the absence of serum to induce cell death. Subsequent to exposure to H2O2, LLC-PK1 cells were treated with desipramine, sphingomyelinase inhibitor, and N-acetylcysteine (NAC), GSH substrate. Based on comparative visual observation with H2O2-treated control cells, it was observed that 0.5 microM of desipramine and 25 mM of NAC exhibited about 90 and 95% of cytoprotection, respectively, against H2O2-induced cell death. Desipramine and NAC lowered the release of LDH activity by 36 and 3%, respectively, when compared to 71% in H2O2-exposed cells. Cellular glutathione level in 500 microM H2O2-treated cells was reduced to 890 pmol as compared to control level of 1198 pmol per mg protein. GST P1-1 expression was decreased in H2O2-treated cells compared to healthy normal cells. In conclusion, it has been inferred that H2O2-induced cell death is closely related to cellular GSH level and GST P1-1 expression in LLC-PK1 cells and occurs via ceramide elevation by sphingomyelinase activation.}, }
@article {pmid15829913, year = {2005}, author = {Pu, H and Tian, J and Andras, IE and Hayashi, K and Flora, G and Hennig, B and Toborek, M}, title = {HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK 1/2 activation.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {25}, number = {10}, pages = {1325-1335}, doi = {10.1038/sj.jcbfm.9600125}, pmid = {15829913}, issn = {0271-678X}, support = {P42 ES007380/ES/NIEHS NIH HHS/United States ; AA013843/AA/NIAAA NIH HHS/United States ; MH63022/MH/NIMH NIH HHS/United States ; NS39254/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Blood-Brain Barrier/drug effects ; Gene Expression Regulation/*drug effects ; Gene Products, tat/administration &amp; dosage/*pharmacology ; Hippocampus ; Inflammation ; Membrane Proteins/*genetics ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase 3/*metabolism/physiology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Phosphoproteins/*genetics ; RNA, Messenger/analysis ; Signal Transduction ; Zonula Occludens-1 Protein ; }, abstract = {HIV-1 Tat protein plays an important role in inducing monocyte infiltration into the brain and may alter the structure and functions of the blood-brain barrier (BBB). The BBB serves as a frontline defense system, protecting the central nervous system from infected monocytes entering the brain. Therefore, the aim of the present study was to examine the mechanisms of Tat effect on the integrity of the BBB in the mouse brain. Tat was injected into the right hippocampi of C57BL/6 mice and expression of tight junction protein zonula occludens-1 (ZO-1) was determined in control and treated mice. Tat administration resulted in decreased mRNA levels of ZO-1 and marked disruption of ZO-1 continuity. These changes were associated with accumulation of inflammatory cells in brain tissue of Tat-treated mice. Further experiments indicated that Tat-mediated alterations of redox-related signaling may be responsible for decreased ZO-1 expression. Specifically, injections with Tat resulted in activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and pretreatment with U 0126, a specific inhibitor of ERK kinase, effectively ameliorated the Tat-induced diminished ZO-1 levels. In addition, administration of N-acetylcysteine (NAC), a precursor of glutathione and a potent antioxidant, attenuated both Tat-induced ERK 1/2 activation and alterations in ZO-1 expression. These results indicate that Tat-induced oxidative stress can play an important role in affecting the integrity of the BBB through the ERK 1/2 pathway.}, }
@article {pmid15829704, year = {2005}, author = {Reich, H and Tritchler, D and Herzenberg, AM and Kassiri, Z and Zhou, X and Gao, W and Scholey, JW}, title = {Albumin activates ERK via EGF receptor in human renal epithelial cells.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {16}, number = {5}, pages = {1266-1278}, doi = {10.1681/ASN.2004030222}, pmid = {15829704}, issn = {1046-6673}, mesh = {Albumins/*pharmacology ; Cells, Cultured ; Epithelial Cells/cytology/metabolism ; ErbB Receptors/genetics/*metabolism ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Humans ; Interleukin-8/genetics ; Kidney/*cytology/metabolism ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3/*metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Emerging clinical and experimental evidence strongly implicates proteinuria in the progression of kidney disease. One pathway involves the activation of NFkappaB by albumin, and it has been demonstrated that the activation of NFkappaB induced by albumin is dependent on mitogen-activated protein kinase ERK1/ERK2. To study the effect of albumin on gene expression, primary human renal tubular cells were exposed in vitro to albumin (1%) for 6 h, and gene expression profiling was performed with the human oligonucleotide microarray, U133A Affymetrix Gene Chip. In all, 223 genes were differentially regulated by albumin, including marked upregulation of the EGF receptor (EGFR) and IL-8. Accordingly, the authors sought to delineate the signaling pathway linking albumin to the EGFR and activation of ERK1/ERK2. It was found that albumin led to a dose- and time-dependent activation of ERK1/ERK2. Treatment with albumin led to EGFR phosphorylation, but the activation of ERK1/ERK2 was prevented by pretreatment of the cells with AG-1478, the EGFR kinase inhibitor, at a dose that inhibited EGF-induced ERK1/ERK2 activation. Exogenously administered reactive oxygen species (ROS) were found to activate ERK1/ERK2 via the EGFR and src tyrosine kinase activity and pretreatment of cells with the antioxidant N-acetylcysteine (NAC) and the NADPH oxidase inhibitor DPI abrogated albumin-induced activation of ERK1/ERK2. The src tyrosine kinase inhibitor, PP2, also inhibited the albumin-induced activation of ERK1/ERK2. Finally, pretreatment with AG-1478, the MEK inhibitor UO126, and NAC prevented the albumin-induced increase in IL-8 expression. The authors conclude that the EGF receptor plays a central role in the signaling pathway that links albumin to the activation of ERK1/ERK2 and increased expression of IL-8. Gene profiling studies suggest that there may be a positive feedback loop through the EGFR that amplifies the response of the proximal tubule cell to albumin. Taken together, these results suggest that the EGFR may be an important treatment target for kidney disease associated with proteinuria.}, }
@article {pmid15823396, year = {2005}, author = {Buijtels, PC and Petit, PL}, title = {Comparison of NaOH-N-acetyl cysteine and sulfuric acid decontamination methods for recovery of mycobacteria from clinical specimens.}, journal = {Journal of microbiological methods}, volume = {62}, number = {1}, pages = {83-88}, doi = {10.1016/j.mimet.2005.01.010}, pmid = {15823396}, issn = {0167-7012}, mesh = {*Acetylcysteine ; Decontamination/*methods ; Humans ; Mycobacterium/*isolation &amp; purification ; Mycobacterium Infections/*microbiology ; Rural Population ; *Sodium Hydroxide ; Sputum/*microbiology ; *Sulfuric Acids ; }, abstract = {We compared the NaOH-N-acetyl cysteine (NaOH-NALC) and the sulfuric acid decontamination procedure in the detection of mycobacteria using the Mycobacteria Growth Indicator Tube (MGIT). In total 219 sputum specimens were collected from 142 Zambian patients and subjected to mycobacterial culture. One half of the specimen was decontaminated with NaOH-NALC and the other half was decontaminated with sulfuric acid. From the 438 samples a total of 261 (60%) cultures yielded growth of mycobacteria, consisting of 22 different species. The sulfuric acid method was more successful than the NaOH-NALC method in recovering mycobacteria in MGITs (146 versus 115 respectively, p = 0.001). Of the 146 positive mycobacterial cultures recovered after sulfuric acid decontamination 28 were Mycobacterium tuberculosis, 84 nontuberculous mycobacteria (NTM) and 34 acid fast bacterial isolates which could not be identified to the species level. The 115 mycobacteria recovered by the NaOH-NALC method consisted of 34 M. tuberculosis strains, 55 NTM and 26 acid fast bacteria that could not be identified. The most frequently isolated NTM were Mycobacterium lentiflavum and Mycobacterium intracellulare. Comparing the two decontamination methods the recovery of NTM in the sulfuric acid group was significant higher than in the NaOH-NALC group (p = 0.001). In contrast, no significant difference was found for the recovery of M. tuberculosis. These results show that the decontamination method used affects the recovery of nontuberculous mycobacteria in particular.}, }
@article {pmid15823179, year = {2005}, author = {Nie, X and Li, Q and Cai, G and Dai, Y and Zhang, J}, title = {The effect of N-acetylcysteine on Clara cells and Clara cell 16 kDa protein in a murine model of allergen-induced airway inflammation.}, journal = {Respirology (Carlton, Vic.)}, volume = {10}, number = {2}, pages = {157-163}, doi = {10.1111/j.1440-1843.2005.00698.x}, pmid = {15823179}, issn = {1323-7799}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Blotting, Western ; Bronchi/drug effects/metabolism/pathology ; Bronchial Hyperreactivity/immunology/metabolism/*prevention &amp; control ; Bronchoalveolar Lavage Fluid/chemistry ; Cell Count ; Disease Models, Animal ; Female ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred BALB C ; Ovalbumin/immunology ; Uteroglobin/*metabolism ; }, abstract = {OBJECTIVE: The aim of this study was to investigate the number of Clara cells and the production and secretion of Clara cell 16 kDa protein (CC16) in a murine model of allergen-induced airway inflammation, as well as the effects of N-acetylcysteine (NAC) on CC16 and Clara cell numbers, in order to determine the mechanism of the anti-inflammatory effect of NAC.<br><br>METHODOLOGY: BALB/c mice were divided into control, ovalbumin (OVA) and NAC groups. An allergen-induced airway inflammation model (OVA group) was established by sensitizing and challenging mice with OVA. NAC was administered as an oral treatment. The number of Clara cells and the production of CC16 were determined by immunohistochemistry. The CC16 levels in bronchoalveolar lavage fluid (BALF) were determined by Western blotting.<br><br>RESULTS: The proportion of Clara cells in terminal and respiratory bronchioles significantly decreased in the OVA group compared to the control group (P < 0.01). NAC treatment did not change the proportion of Clara cells in the OVA group (P > 0.05). CC16 production by Clara cells in the OVA groups was significantly lower than that of the control group (P < 0.01), but was elevated following NAC treatment (P < 0.05). The CC16 level in BALF of the OVA group was lower than that of the control group (P < 0.01), but was elevated by NAC treatment (P < 0.05). NAC reduced the total number of white cells and the percentage of eosinophils in BALF. Moreover, it inhibited airway inflammation.<br><br>CONCLUSIONS: The number of Clara cells and the production and secretion of CC16 were reduced in a murine model of allergen-induced airway inflammation. Antioxidants can enhance the expression of CC16, which might be a mechanism by which they suppress airway inflammation.}, }
@article {pmid15821276, year = {2005}, author = {Lee, TY and Chen, CM and Lee, CN and Chiang, YC and Chen, HY}, title = {Compatibility and osmolality of inhaled N-acetylcysteine nebulizing solution with fenoterol and ipratropium.}, journal = {American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists}, volume = {62}, number = {8}, pages = {828-833}, doi = {10.1093/ajhp/62.8.828}, pmid = {15821276}, issn = {1079-2082}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Adrenergic beta-Agonists/*administration &amp; dosage ; Bronchodilator Agents/*administration &amp; dosage ; Fenoterol/*administration &amp; dosage ; Hydrogen-Ion Concentration ; Ipratropium/*administration &amp; dosage ; Mass Spectrometry ; Nebulizers and Vaporizers ; Osmolar Concentration ; Oxidation-Reduction ; Solutions/*standards ; }, abstract = {PURPOSE: The compatibility, pH, and osmolality of N-acetylcysteine (NAC) nebulizing solution in the presence of ipratropium bromide or fenoterol hydrobromide were studied.<br><br>METHODS: Portions (400 microL) of each mixture were sampled immediately upon mixing and one, two, three, four, five, six, and seven hours after mixing and assayed by high-performance liquid chromatography. Osmolality was measured by sampling 100 microL from the filling cup at a five-minute interval during nebulization and by the freezing-point-depression method.<br><br>RESULTS: Adding NAC solution to fenoterol solution raised the pH from 3.20 to 7.90 and the osmolality to a mean +/- S.D. of 1400.67 +/- 4.51 mOsm/kg. Fenoterol concentrations decreased to 93.71% and NAC concentrations to 92.54% of initial concentrations after seven hours. Mixing ipratropium with NAC solution raised the pH from 3.74 to 7.95 and the osmolality to a mean +/- S.D. of 1413 +/- 11.79 mOsm/kg. The initial ipratropium concentration declined 7.39% and 10.91% one and two hours after mixing with NAC solution, respectively.<br><br>CONCLUSION: NAC and ipratropium were stable in nebulizing solution within one hour of mixing. NAC and fenoterol were compatible for at least seven hours.}, }
@article {pmid15821223, year = {2005}, author = {Spapen, HD and Diltoer, MW and Nguyen, DN and Hendrickx, I and Huyghens, LP}, title = {Effects of N-acetylcysteine on microalbuminuria and organ failure in acute severe sepsis: results of a pilot study.}, journal = {Chest}, volume = {127}, number = {4}, pages = {1413-1419}, doi = {10.1378/chest.127.4.1413}, pmid = {15821223}, issn = {0012-3692}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Adult ; Aged ; Aged, 80 and over ; Albuminuria/*drug therapy/etiology ; Female ; Humans ; Male ; Middle Aged ; Multiple Organ Failure/*drug therapy/etiology ; Pilot Projects ; Sepsis/*complications ; Severity of Illness Index ; }, abstract = {STUDY OBJECTIVE: The level of microalbuminuria is thought to reflect the severity of inflammation-induced systemic vascular permeability and may have prognostic value with regard to organ dysfunction and survival. N-acetylcysteine (NAC) has been shown to decrease capillary leakage in experimental sepsis. The present study investigated the effect of early treatment with NAC on microalbuminuria and organ dysfunction in severe clinical sepsis.<br><br>DESIGN: Prospective, randomized, placebo-controlled study.<br><br>SETTING: A 24-bed multidisciplinary ICU in a university teaching hospital.<br><br>PATIENTS: Thirty-five patients included within 4 h of fulfilling consensus criteria of severe sepsis.<br><br>INTERVENTIONS: Patients were randomly assigned to receive either NAC (continuous infusion starting with 50 mg/kg/4 h followed by 100 mg/kg/24 h for 44 h; n = 18) or placebo (n = 17) in addition to standard therapy.<br><br>MEASUREMENTS AND RESULTS: Urine samples for measurement of microalbuminuria/creatinine ratio (MACR) were collected on inclusion and after 4 h, 24 h, and 48 h. Severity of illness and degree of organ failure were determined by using, respectively, the APACHE (acute physiology and chronic health evaluation) II score and the sequential organ failure assessment (SOFA) score. The MACR did not differ over time between the placebo- and the NAC-treated groups. SOFA scores were comparable between both treatment groups at baseline (6.2 +/- 3.9 vs 6.5 +/- 2.7, NAC vs placebo; p = 0.6) and increased during treatment in the NAC-treated patients but not in the placebo group (7.9 +/- 3.7 vs 5.9 +/- 2.5, p = 0.09 and 7.7 +/- 3.8 vs 5.1 +/- 2.1, p < 0.05; NAC vs placebo, respectively, at 24 h and at 48 h). The cardiovascular SOFA score progressively increased during NAC treatment, reaching higher values as compared to time-matched scores in the placebo group.<br><br>CONCLUSIONS: Early NAC administration does not influence the course of MACR in severe clinical sepsis, suggesting that NAC might not attenuate endothelial damage in this condition. NAC treatment even aggravated sepsis-induced organ failure, in particular cardiovascular failure.}, }
@article {pmid15819723, year = {2005}, author = {Zhang, Q and Tsukahara, F and Maru, Y}, title = {N-acetyl-cysteine enhances growth in BCR-ABL-transformed cells.}, journal = {Cancer science}, volume = {96}, number = {4}, pages = {240-244}, doi = {10.1111/j.1349-7006.2005.00038.x}, pmid = {15819723}, issn = {1347-9032}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blotting, Western ; Cell Line, Transformed ; Cell Transformation, Neoplastic/drug effects/metabolism ; Focal Adhesion Kinase 1 ; Focal Adhesion Protein-Tyrosine Kinases ; *Genes, abl ; Genes, ras ; HSP90 Heat-Shock Proteins/antagonists &amp; inhibitors ; Male ; Mice ; Neoplasm Transplantation ; Neoplasms, Experimental/*pathology ; Oncogene Proteins v-abl ; Protein-Tyrosine Kinases/deficiency ; Rats ; }, abstract = {N-acetyl-cysteine (NAC) has been reported to have anticancer properties such as counteractions against mutagens and prevention of tumor progression by scavenging reactive oxygen species (ROS). However, here we report that NAC can enhance the anchorage-independent growth of cells transformed by activated ABL tyrosine kinases or Ras. This effect was not dependent on loss of focal adhesion kinase activation. NAC rescued cell growth that was suppressed by heat shock protein (Hsp) 90 inhibitors possibly by chemical modification of their quinone moiety. NAC rendered Rat1/BCR-ABL cells resistance to a Ras inhibitor manumycin in soft agar colony formation. In the absence of Hsp90 inhibitors, NAC stimulated the activation of MAP kinase in BCR-ABL-transformed but not in the parental Rat1 cells. We propose that NAC should be used carefully in cancer treatment.}, }
@article {pmid15818509, year = {2005}, author = {Kang, J and Chen, J and Shi, Y and Jia, J and Wang, Z}, title = {Histone hypoacetylation is involved in 1,10-phenanthroline-Cu2+-induced human hepatoma cell apoptosis.}, journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry}, volume = {10}, number = {2}, pages = {190-198}, pmid = {15818509}, issn = {0949-8257}, mesh = {Acetylation ; Apoptosis/drug effects/*physiology ; Carcinoma, Hepatocellular/metabolism ; Cell Line, Tumor ; Histones/*metabolism ; Humans ; Phenanthrolines/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {The 1,10-orthophenanthroline (OP)-Cu(2+) combination, one generally used reactive oxygen species (ROS) generation system, is known to induce cell apoptosis, but the mechanism of ROS generation in this process remains unclear. Here we found that in the presence of 5 microM Cu(2+), OP inhibited histone acetyltransferase (HAT) activity, resulting in decreased acetylation in both histone H3 and H4. This inhibition of histone acetylation and HAT activity was significantly attenuated by preventing or scavenging ROS generation with the Cu(2+) chelator of bathocuproine disulfonate, or the antioxidants of N-acetyl-cysteine and mannitol, respectively, indicating the involvement of ROS generation in OP-Cu(2+) -induced histone hypoacetylation. At the same time, this ROS generation is found to be involved in OP-Cu(2+) -induced apoptosis in human hepatoma Hep3B cells. The important role of histone hypoacetylation in the induction of apoptosis was also proven by the marked diminution of apoptosis by 100 nM trichostatin A, a specific inhibitor of histone deacetylase, or the overexpression of p300, an HAT protein. Collectively, these observations suggest that histone hypoacetylation represents one unrevealed mechanism involved in the in vivo function of OP-Cu(2+) -generated ROS, at least in their induction of cell apoptosis.}, }
@article {pmid15817678, year = {2005}, author = {Lee, NK and Choi, YG and Baik, JY and Han, SY and Jeong, DW and Bae, YS and Kim, N and Lee, SY}, title = {A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation.}, journal = {Blood}, volume = {106}, number = {3}, pages = {852-859}, doi = {10.1182/blood-2004-09-3662}, pmid = {15817678}, issn = {0006-4971}, mesh = {Animals ; Bone Marrow Cells ; Carrier Proteins/*pharmacology ; Cell Differentiation/*drug effects ; Cell Lineage ; MAP Kinase Signaling System ; Macrophages/cytology ; Membrane Glycoproteins/*pharmacology ; Mice ; Mice, Inbred C57BL ; Monocytes/cytology ; NADH, NADPH Oxidoreductases/metabolism ; NADPH Oxidase 1 ; Neuropeptides/metabolism ; Osteoclasts/*cytology ; RANK Ligand ; Reactive Oxygen Species/*metabolism ; Receptor Activator of Nuclear Factor-kappa B ; TNF Receptor-Associated Factor 6/metabolism ; rac GTP-Binding Proteins/metabolism ; rac1 GTP-Binding Protein ; }, abstract = {Signaling by receptor activator of NF-kappaB (nuclear factor-kappaB) ligand (RANKL) is essential for differentiation of bone marrow monocyte-macrophage lineage (BMM) cells into osteoclasts. Here, we show RANKL stimulation of BMM cells transiently increased the intracellular level of reactive oxygen species (ROS) through a signaling cascade involving TNF (tumor necrosis factor) receptor-associated factor (TRAF) 6, Rac1, and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (Nox) 1. A deficiency in TRAF6 or expression of a dominant-interfering mutant of TRAF6 blocks RANKL-mediated ROS production. Application of N-acetylcysteine (NAC) or blocking the activity of Nox, a protein leading to the formation of ROS, with diphenylene iodonium (DPI) inhibits the responses of BMM cells to RANKL, including ROS production, activation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein (MAP) kinase, and extracellular signal-regulated kinase (ERK), and osteoclast differentiation. Moreover, both RANKL-mediated ROS production and osteoclast differentiation were completely blocked in precursors depleted of Nox1 activity by RNA interference or by expressing a dominant-negative mutant of Rac1. Together, these results indicate that ROSs act as an intracellular signal mediator for osteoclast differentiation.}, }
@article {pmid15817458, year = {2005}, author = {Staniszewska, MM and Nagaraj, RH}, title = {3-hydroxykynurenine-mediated modification of human lens proteins: structure determination of a major modification using a monoclonal antibody.}, journal = {The Journal of biological chemistry}, volume = {280}, number = {23}, pages = {22154-22164}, doi = {10.1074/jbc.M501419200}, pmid = {15817458}, issn = {0021-9258}, support = {P30 EY 11373/EY/NEI NIH HHS/United States ; R01 EY 09912/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Antibodies, Monoclonal/*chemistry ; Antigens/chemistry ; Arginine/*analogs &amp; derivatives/chemistry ; Binding, Competitive ; Blotting, Western ; Cell Membrane/metabolism ; Chromatography, High Pressure Liquid ; Cross-Linking Reagents/pharmacology ; Dose-Response Relationship, Drug ; Electrophoresis, Polyacrylamide Gel ; Enzyme-Linked Immunosorbent Assay ; Histidine/*analogs &amp; derivatives/chemistry ; Humans ; Immunohistochemistry ; Kynurenine/*analogs &amp; derivatives/chemistry/*pharmacology ; Lens, Crystalline/*drug effects/metabolism ; Lysine/*analogs &amp; derivatives/chemistry ; Magnetic Resonance Spectroscopy ; Models, Chemical ; Ninhydrin/chemistry ; Oxygen/metabolism ; Protein Conformation ; Spectrophotometry ; Time Factors ; Tryptophan/chemistry ; Water/chemistry ; }, abstract = {Tryptophan can be oxidized in the eye lens by both enzymatic and non-enzymatic mechanisms. Oxidation products, such as kynurenines, react with proteins to form yellow-brown pigments and cause covalent cross-linking. We generated a monoclonal antibody against 3-hydroxykynurenine (3OHKYN)-modified keyhole limpet hemocyanin and characterized it using 3OHKYN-modified amino acids and proteins. This monoclonal antibody reacted with 3OHKYN-modified N(alpha)-acetyl lysine, N(alpha)-acetyl histidine, N(alpha)-acetyl arginine, and N(alpha)-acetyl cysteine. Among the several tryptophan oxidation products tested, 3OHKYN produced the highest concentration of antigen when reacted with human lens proteins. A major antigen from the reaction of 3OHKYN and N(alpha)-acetyl lysine was purified by reversed phase high pressure liquid chromatography, which was characterized by spectroscopy and identified as 2-amino-3-hydroxyl-alpha-((5S)-5-acetamino-5-carboxypentyl amino)-gamma-oxo-benzene butanoic acid. Enzyme-digested cataractous lens proteins displayed 3OHKYN-derived modifications. Immunohistochemistry revealed 3OHKYN modifications in proteins associated with the lens fiber cell plasma membrane. The low molecular products (<10,000 Da) isolated from normal lenses after reaction with glucosidase followed by incubation with proteins generated 3OHKYN-derived products. Human lens epithelial cells incubated with 3OHKYN showed intense immunoreactivity. We also investigated the effect of glycation on tryptophan oxidation and kynurenine-mediated modification of lens proteins. The results showed that glycation products failed to oxidize tryptophan or generate kynurenine modifications in proteins. Our studies indicate that 3OHKYN modifies lens proteins independent of glycation to form products that may contribute to protein aggregation and browning during cataract formation.}, }
@article {pmid15816549, year = {2005}, author = {Kinoshita, N and Hashimoto, K and Yamamura, T and Teranuma, H and Koizumi, T and Satoh, K and Katayama, T and Sakagami, H}, title = {Protection by antioxidants of copper-induced decline of proliferation and SOD activity.}, journal = {Anticancer research}, volume = {25}, number = {1A}, pages = {283-289}, pmid = {15816549}, issn = {0250-7005}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Biphenyl Compounds/metabolism ; Cell Proliferation/drug effects ; Copper/*pharmacology ; Culture Media ; Electron Spin Resonance Spectroscopy ; Free Radical Scavengers/pharmacology ; HL-60 Cells ; Humans ; Hydrazines/metabolism ; Hydroxyl Radical/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages/cytology/drug effects/metabolism ; Nitric Oxide/biosynthesis ; Picrates ; Superoxide Dismutase/*antagonists &amp; inhibitors/metabolism ; }, abstract = {The effect of Cu plate on the cellular function was investigated by two different methods: an extraction method (Method I) and a direct contact method (Method II). In Method I, the supernatant of the culture medium, which had been pre-incubated with Cu plate, was added to mouse macrophage-like Raw 264.7 cells. This supernatant dose-dependently inhibited the proliferation and nitric oxide (NO) production by lipopolysaccharide-stimulated Raw 264.7 cells. In Method II, human promyelocytic leukemic HL-60 cells in suspension were incubated with culture medium which contained Cu plate. The direct contact with Cu plate rapidly suppressed the proliferation and MnSOD and Cu/ZnSOD activities. The suppressed proliferation and SOD activity reverted to or exceeded the control level by sodium ascorbate, whereas N-acetyl-L-cysteine (NAC) only reactivated the proliferation, but not the SOD activity. ESR spectroscopy showed that contact with Cu plate slightly diminished the hydroxyl radical (generated by Fenton reaction), without affecting the intensity of NO (produced from NOC-7) and DPPH radical. The present study suggests that two representative antioxidants, such as sodium ascorbate and NAC, protect the cells from Cu-induced cytotoxicity via different mechanisms.}, }
@article {pmid15816534, year = {2005}, author = {Terasaka, H and Morshed, SR and Hashimoto, K and Sakagami, H and Fujisawa, S}, title = {Hydroquinone-induced apoptosis in HL-60 cells.}, journal = {Anticancer research}, volume = {25}, number = {1A}, pages = {161-170}, pmid = {15816534}, issn = {0250-7005}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; DNA Fragmentation/drug effects ; Drug Interactions ; Electrophoresis, Agar Gel ; HL-60 Cells ; Humans ; Hydroquinones/*pharmacology ; Isoenzymes ; Nucleosomes/drug effects/genetics ; RNA, Messenger/biosynthesis/genetics ; Superoxide Dismutase/biosynthesis/genetics/metabolism ; }, abstract = {To clarify the mechanisms by which hydroquinone (HQ; 1,4-benzenediol) produces apoptosis, HQ-induced cytotoxicity, intemucleosomal DNA fragmentation, activation of superoxide dismutase (SOD), expression of Mn and Cu/ZnSOD mRNA and activation of caspase-3, -8 and -9 were investigated in the human promyelocytic leukemic cell line HL-60. Electrophoresis and activity staining of the SOD-enriched fraction showed that HQ reduced MnSOD activation more than Cu/ZnSOD activation, suggesting that it induces mitochondrial dysfunction at an early stage of apoptosis. Furthermore, the expression of MnSOD mRNA was suppressed to a greater extent than that of Cu/ZnSOD mRNA, implying that HQ causes apoptosis by inhibiting MnSOD induction. Release of cytochrome c and activation of procaspase-3 and -9, but not of procaspase-8, occurred more rapidly (as early as 6 h) in HQ-treated cells, suggesting that HQ activates the intrinsic pathway of apoptosis. Addition of the antioxidant N-acetyl-L-cysteine (NAC) significantly reduced the cytotoxicity of HQ. At a concentration that was cytotoxic to 50% of the cells (approximately 0.05 mM), HQ activated caspase-3; this effect was reduced in the presence of NAC. Interestingly, higher concentrations of HQ (0.1-0.2 mM) caused direct cell death; however, when combined with 5 mM NAC, the activation of caspase-3 was strongly enhanced, suggesting the promotion of apoptosis. The activation of caspase-3 by HQ/NAC combinations suggests that NAC, a precursor of intracellular glutathione synthesis, acts as a co-catalyst during HQ-induced apoptosis.}, }
@article {pmid15809833, year = {2005}, author = {Zachwieja, J and Zaniew, M and Bobkowski, W and Stefaniak, E and Warzywoda, A and Ostalska-Nowicka, D and Dobrowolska-Zachwieja, A and Lewandowska-Stachowiak, M and Siwińska, A}, title = {Beneficial in vitro effect of N-acetyl-cysteine on oxidative stress and apoptosis.}, journal = {Pediatric nephrology (Berlin, Germany)}, volume = {20}, number = {6}, pages = {725-731}, pmid = {15809833}, issn = {0931-041X}, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Annexin A5/metabolism ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; CD3 Complex/metabolism ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Case-Control Studies ; Cells, Cultured ; Child ; Child, Preschool ; Female ; Humans ; Intracellular Membranes/metabolism ; Kidney Failure, Chronic/*metabolism/physiopathology ; Male ; Oxidative Stress/*drug effects ; T-Lymphocytes/metabolism ; }, abstract = {Chronic renal failure (CRF) is usually accompanied by abnormalities of both humoral and cellular immune response. The aim of the study was to investigate the influence of N-acetyl-cysteine (NAC) on intracellular oxidative stress and apoptosis rate of T lymphocytes in children with CRF. Twenty-two children (aged 4-16, mean 7.4) with CRF treated with dialysis were enrolled in the study. Intracellular reactive oxygen species (ROS) production was quantified by mean rhodamine 123 (RHO) fluorescence intensity with flow cytometry. Annexin V FITC was used for identifying apoptotic cells. Mean fluorescence intensity (MFI), which reflected intracellular oxidative stress in T lymphocytes, was increased in patients with CRF compared with the controls (CD3+: 31.58+/-11.58 vs 22.55+/-4.97, p = 0.043; CD3+CD4+: 32.50+/-8.59 vs 27.75+/-12.76, NS; CD3+CD8+: 32.10+/-11.85 vs 20.77+/- 4.89, p =0.012). Apoptotic T lymphocytes occurred more frequently in patients with CRF treated with hemodialysis (HD) (11.36+/-6.96%) than in the controls (6.14%+/-3.36%; p = 0.025). After 24 h incubation with NAC MFI and apoptosis rate decreased significantly in all subpopulations of lymphocytes. NAC, as a strong antioxidant, has a favorable effect on intracellular oxidative stress and apoptosis rate of T lymphocytes in patients with CRF. A decreased apoptosis rate may have positive effect on functional abnormalities of T cells already found in patients with CRF.}, }
@article {pmid15808665, year = {2005}, author = {Montero, EF and Quireze, C and d'Oliveira, DM}, title = {Bile duct exclusion from selective vascular inflow occlusion in rat liver: role of ischemic preconditioning and N-acetylcysteine on hepatic reperfusion injury.}, journal = {Transplantation proceedings}, volume = {37}, number = {1}, pages = {425-427}, doi = {10.1016/j.transproceed.2004.12.194}, pmid = {15808665}, issn = {0041-1345}, mesh = {Acetylcysteine/*pharmacology ; Alanine Transaminase/metabolism ; Alkaline Phosphatase/metabolism ; Animals ; Aspartate Aminotransferases/metabolism ; Bile Ducts/*physiology ; Bilirubin/metabolism ; *Ischemic Preconditioning ; Liver Circulation/drug effects/*physiology ; Male ; Portal System ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; gamma-Glutamyltransferase/metabolism ; }, abstract = {AIM: To study the effects of N-acetylcysteine and ischemic preconditioning on the portal triad clamping compared to arterial and portal clamping alone.<br><br>METHODS: Eighty EPM 1-Wistar rats were randomized into two groups, depending on inclusion (Group 1) or not (Group 2) of the bile duct in the hepatic vascular pedicle occlusion. Each group was divided into four subgroups as follows. IR 1: 20 minutes after celiotomy, the pedicle containing vascular elements and bile duct to the left lateral and median liver lobes was occluded for 40 minutes, followed by 30 minutes of reperfusion. IPC 1: after 10 minutes of ischemia and 10 minutes of reperfusion, the ischemic preconditioning period, the rats were submitted to the same procedure described for IR 1 Group. NAC 1: the rats received N-acetylcysteine (150 mg/kg) 15 minutes before 40 minutes of ischemia and 5 minutes before 30 minutes of reperfusion. SHAM 1: The hepatic pedicle for the lateral and median liver lobes was dissected after 20 minutes, the bile duct alone was clamped for 40 minutes, and released for an additional 30 minutes. In the IR 2, IPC 2, and NAC 2 groups, ischemia was achieved with an exclusive vascular occlusion. SHAM 2: dissection and observation for 90 minutes. The blood was sampled for liver enzyme levels. Statistical analysis was done (P </= .05).<br><br>RESULTS: Hepatic IR injury was less severe for animals from the classic portal triad clamping (group 1), with regard to AST (IR 1 Group 766 vs IR 2 Group 1380 U/L) and ALT (IR 1 Group 840 vs IR 2 Group 1576 U/L); IPC, but not NAC administration, was able to protect the liver from IR injury for animals from the classic portal triad clamping group, with regard to AST (IPC 1 Group 421 vs NAC 1 Group 1131 U/L) and ALT (IPC 1 Group 315 vs NAC 1 Group 1085 U/L).<br><br>CONCLUSIONS: IPC protects the liver from IR injury; classic portal triad clamping results in a less severe hepatic IR injury when compared to bile duct exclusion.}, }
@article {pmid15808420, year = {2005}, author = {Aronis, A and Madar, Z and Tirosh, O}, title = {Mechanism underlying oxidative stress-mediated lipotoxicity: exposure of J774.2 macrophages to triacylglycerols facilitates mitochondrial reactive oxygen species production and cellular necrosis.}, journal = {Free radical biology &amp; medicine}, volume = {38}, number = {9}, pages = {1221-1230}, doi = {10.1016/j.freeradbiomed.2005.01.015}, pmid = {15808420}, issn = {0891-5849}, mesh = {Animals ; Cell Line ; Glutathione/metabolism ; Macrophages/*drug effects/metabolism ; Mice ; Mitochondria/*drug effects/metabolism ; Necrosis ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Triglycerides/*pharmacology ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {The aim of this study was to elucidate death pathways in macrophages resulting from exposure to triacylglycerols (TG), mechanisms which may be relevant to the development of atherosclerosis. A commercial TG emulsion (lipid emulsion, LE; 0.1-1.5 mg lipids/ml) was added to J774.2 cells in culture. Within the first 24 h after TG treatment, cellular reactive oxygen species (ROS) levels were strongly elevated and basal caspase-3 activity was attenuated. In contrast, after 48 h, ROS production was arrested. TG-mediated ROS production was demonstrated to be via mitochondrial complex 1 of the electron-transfer chain since the inhibitor of complex 1 rotenone significantly attenuated the cellular ROS levels in TG-treated cells. The TG effect culminated in cell death, with no caspase-3 activation. We therefore evaluated the effect of TG on apoptotic cells showing high caspase activity. TG induced elevated ROS levels and suppressed caspase-3 in apoptotic cells pretreated for 24 h with cycloheximide. Dual staining with propidium iodide and Annexin V followed by flow cytometric analysis showed that TG facilitated cell death with clear necrotic characteristics. To elucidate whether the necrotic cell death process is indeed oxidant dependent, antioxidant protection was studied. Treatment with N-acetylcysteine (NAC) (0.5 mM), ascorbic acid (0.5 mM), and resveratrol (0.2 mM) protected against the TG lipotoxic effect, while, surprisingly, lipophilic antioxidants did not. The combination of NAC, ascorbic acid, and resveratrol, each at much lower concentrations, had a synergistic protective effect. In conclusion, we show here for the first time that exposure to TG can directly regulate lipotoxicity in macrophages by inducing mitochondria-mediated prolonged oxidative stress; this, in turn, can inactivate the apoptotic caspase system, resulting in necrotic cell death which can be prevented by specific antioxidants.}, }
@article {pmid15802865, year = {2005}, author = {Hamasu, T and Inanami, O and Asanuma, T and Kuwabara, M}, title = {Enhanced induction of apoptosis by combined treatment of human carcinoma cells with X rays and death receptor agonists.}, journal = {Journal of radiation research}, volume = {46}, number = {1}, pages = {103-110}, doi = {10.1269/jrr.46.103}, pmid = {15802865}, issn = {0449-3060}, mesh = {Acetylcysteine/administration &amp; dosage ; Apoptosis/*drug effects/*radiation effects ; Apoptosis Regulatory Proteins ; Carcinoma/*metabolism/*pathology ; Cell Line, Tumor/metabolism/pathology/radiation effects ; Dose-Response Relationship, Drug ; Humans ; Membrane Glycoproteins/administration &amp; dosage ; Radiation Dosage ; Radiation Tolerance/drug effects ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; Receptors, Tumor Necrosis Factor/*antagonists &amp; inhibitors ; TNF-Related Apoptosis-Inducing Ligand ; Tumor Necrosis Factor-alpha/administration &amp; dosage ; Tumor Suppressor Protein p53/*metabolism ; X-Rays ; fas Receptor/*drug effects ; }, abstract = {The death receptors Fas and DR5 are known to be expressed not only in immune cells but also in various tumor cells. The aim of the present study was to determine whether X irradiation enhanced induction of apoptosis in Tp53 wild type and Tp53-mutated tumor cell lines treated with agonists against these death receptors. We showed that 5 Gy of X irradiation significantly up-regulated the expression of death receptors Fas and DR5 on the plasma membrane in gastric cancer cell lines MKN45 and MKN28, lung cancer cell line A549, and prostate cancer cell line DU145, and that subsequent treatments with agonistic molecules for these death receptors, Fas antibody CH11 and TRAIL, increased the formation of active fragment p20 of caspase 3 followed by the induction of apoptosis. This death-receptor-mediated apoptosis was independent of Tp53 status since MKN28 and DU145 were Tp53-mutated. The post-irradiation treatment of the cells with N-acetyl-L-cysteine (NAC) abolished the up-regulation of the expression of Fas and DR5 on the plasma membrane. NAC also attenuated the increase in the formation of p20 and the induction of apoptosis by agonistic molecules. These results suggested that the increase in the induction of apoptosis by combined treatment with X irradiation and CH11 or TRAIL occurred through a change of the intracellular redox state independent of Tp53 status in human carcinoma cell lines.}, }
@article {pmid15800030, year = {2005}, author = {Yang, MY and Lau, SS and Monks, TJ}, title = {2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane potential.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {86}, number = {1}, pages = {92-100}, doi = {10.1093/toxsci/kfi165}, pmid = {15800030}, issn = {1096-6080}, support = {ES06694/ES/NIEHS NIH HHS/United States ; ES09224/ES/NIEHS NIH HHS/United States ; }, mesh = {Apoptosis/*drug effects ; Caspase 9 ; Caspases/metabolism ; Cytochromes c/*metabolism ; Glutathione/*analogs &amp; derivatives/toxicity ; HL-60 Cells ; Humans ; Hydroquinones/*toxicity ; Leukemia, Promyelocytic, Acute/*pathology ; *Membrane Potentials ; Mitochondria/*enzymology/physiology ; Reactive Oxygen Species ; Subcellular Fractions/enzymology/metabolism ; Tumor Cells, Cultured ; }, abstract = {2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ), a metabolite of benzene, induces apoptosis in human promyelocytic leukemia (HL-60) cells. However, the mechanisms by which TGHQ induces apoptosis are unclear, and they were the focus of the present investigation. TGHQ stimulated the rapid formation (30 min) of reactive oxygen species (ROS) in HL-60 cells, and co-treatment with catalase or the antioxidant N-acetylcysteine (NAC) completely blocked TGHQ-induced apoptosis, implicating a causative role for ROS in HL-60 cell death. Western blot analysis revealed the complete disappearance of pro-caspase 9 between 1 and 2 hours after exposure of HL-60 cells to TGHQ, concomitant with the appearance of cleaved caspase 9 and increases in caspase 9 activity. The appearance of two cleaved forms of caspase 3 occurred subsequent to increases in caspase 9 activity. Levels of the anti-apoptotic Bcl-2 protein remained constant during TGHQ-induced apoptosis of HL-60 cells, but Bcl-2 S70 phosphorylation decreased. In contrast, changes in the subcellular localization of the pro-apoptotic molecule Bax were observed, with a rapid (15-60 min) increase in the ratio of cytosolic to mitochondrial Bax. Cytochrome c release from mitochondria to the cytosol occurred after Bax translocation and the dephosphorylation of pS70 Bcl-2. However the mitochondrial inner transmembrane potential (deltapsi(m)) was maintained, even after cytochrome c was released from the mitochondria. Cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition pore (PTP), did not completely rescue HL-60 cells from apoptosis. Taken together, we conclude that TGHQ facilitates ROS production, alters the post-translational modification of Bcl-2 and subcellular localization of Bax, culminating in the release of cytochrome c and caspase activation.}, }
@article {pmid15798812, year = {2004}, author = {Treitinger, A and Spada, C and Masokawa, IY and Verdi, JC and Van Der Sander Silveira, M and Luis, MC and Reis, M and Ferreira, SI and Abdalla, DS}, title = {Effect of N-acetyl-L-cysteine on lymphocyte apoptosis, lymphocyte viability, TNF-alpha and IL-8 in HIV-infected patients undergoing anti-retroviral treatment.}, journal = {The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases}, volume = {8}, number = {5}, pages = {363-371}, doi = {10.1590/s1413-86702004000500005}, pmid = {15798812}, issn = {1413-8670}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Adult ; Anti-HIV Agents/*therapeutic use ; Apoptosis/*drug effects ; CD4 Lymphocyte Count ; Cysteine/blood ; Double-Blind Method ; Glutathione/blood ; HIV Infections/blood/*drug therapy ; Humans ; Interleukin-8/*blood ; Lymphocytes/*drug effects ; Middle Aged ; Time Factors ; Tumor Necrosis Factor-alpha/*analysis ; Viral Load ; }, abstract = {N-acetyl-L-cysteine (NAC) has been proposed as an additional therapeutic agent for AIDS patients because it reduces human immunodeficiency virus type 1 (HIV-1) replication in stimulated CD4+ lymphocytes, and it ameliorates immunological reactivity. In a randomized, 180-day, double-blind, placebo-controlled trial performed with HIV-infected patients classified as A2 and A3 according to the criteria of the Center for Disease Control and Prevention, we investigated the effects of oral administration of NAC on HIV-infected patients undergoing their first anti-retroviral therapy; viral load, CD4+ lymphocyte, lymphocyte viability and apoptosis, and TNF-alpha and IL-8 levels were determined. Sixteen patients who received anti-retroviral therapy plus a placebo formed the control group and the study group consisted of 14 patients who received anti-retroviral therapy and NAC supplementation. A significant decrease was seen in viral load, TNF-alpha and IL-8 levels, and lymphocyte apoptosis, and a significant increase was found in levels of CD4+ lymphocytes and lymphocyte viability in both groups after anti-retroviral treatment, but no measurable benefits of anti-retroviral therapy plus NAC oral supplementation (600 mg/day) were found in relation to anti-retroviral therapy alone, and the baseline levels of cysteine and glutathione in plasma were not recovered by this treatment. In conclusion, the daily doses of NAC necessary for the total recuperation of plasma cysteine and glutathione levels in HIV-infected patients and the additional benefits following the supplementation of NAC in patients submitted to anti-retroviral therapy, need to be studied further.}, }
@article {pmid15797566, year = {2005}, author = {Omodeo Salè, F and Vanzulli, E and Montorfano, G and Monti, D}, title = {Major artifacts encountered in studying biological samples containing ferric protoporphyrin IX.}, journal = {Analytical biochemistry}, volume = {339}, number = {2}, pages = {257-261}, doi = {10.1016/j.ab.2005.01.028}, pmid = {15797566}, issn = {0003-2697}, mesh = {Acetylcysteine/chemistry ; Arachidonic Acid/chemistry ; *Artifacts ; Cell Membrane/drug effects/metabolism ; Erythrocyte Membrane/drug effects ; Freezing ; Heme/*analysis/chemistry/pharmacology ; Lipid Peroxidation/drug effects ; Membrane Lipids/chemistry ; Micelles ; Proteins/analysis ; Solubility ; }, abstract = {Heme (ferric protoporphyrin IX, FP) dissolves very rapidly into the lipid phase of membranes, and a large number of studies have focused attention on its possible toxic effect in whole cells or isolated membranes. However, because of its molecular structure and reactivity, different problems can be encountered during the course of studying biological samples containing FP. In this article, we discuss important interferences by FP and artifacts that can affect the experimental values. First, FP interferes with the Lowry's protein determination; therefore, membranes containing FP are overestimated in their protein content determined by this procedure. Second, freezing membranes at -20 degrees C artifactually increases the local concentration of FP, thereby enhancing FP-induced lipid peroxidation. Third, in the presence of thiol compounds such as N-acetyl cysteine, FP is degraded to products that interfere with the thiobarbituric acid assay, one of the most widely used methods to measure the extent of lipoperoxidation.}, }
@article {pmid15790131, year = {2005}, author = {Akgun, E and Caliskan, C and Celik, HA and Ozutemiz, AO and Tuncyurek, M and Aydin, HH}, title = {Effects of N-acetylcysteine treatment on oxidative stress in acetic acid-induced experimental colitis in rats.}, journal = {The Journal of international medical research}, volume = {33}, number = {2}, pages = {196-206}, doi = {10.1177/147323000503300207}, pmid = {15790131}, issn = {0300-0605}, mesh = {Acetic Acid/*pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Colitis/*chemically induced ; Colon/enzymology/pathology ; Disease Models, Animal ; Female ; Free Radicals ; Glutathione/metabolism ; Inflammation ; Inflammatory Bowel Diseases/drug therapy ; Male ; Nitric Oxide/metabolism ; *Oxidative Stress ; Peroxidase/metabolism ; Rats ; Sodium Chloride/pharmacology ; Time Factors ; }, abstract = {We assessed the possible protective effects of N-acetylcysteine (NAC) against toxic damage in the rat colon. Two doses of NAC (20 mg/kg and 100 mg/kg) given for 2 days and 7 days after acetic acid administration (to induce colitis) were tested. NAC was dissolved in saline and administered locally (intracolonic), systemically (intraperitoneal) or in a combination (intracolonic and intraperitoneal). Several parameters, including macroscopic and histopathological scores and myeloperoxidase, glutathione and nitric oxide concentrations were measured using standard assay procedures. Treatment with 100 mg/kg NAC for 7 days significantly decreased tissue myeloperoxidase, glutathione and nitric oxide concentrations. The 20 mg/kg dose had no protective effects. The data indicate that NAC substantially reduced the degree of colonic injury, probably by regulating free radical production and inhibiting inflammation. It may, therefore, have a role in the treatment of inflammatory bowel disease.}, }
@article {pmid15789388, year = {2005}, author = {Duong, MH and MacKenzie, TA and Malenka, DJ}, title = {N-acetylcysteine prophylaxis significantly reduces the risk of radiocontrast-induced nephropathy: comprehensive meta-analysis.}, journal = {Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography &amp; Interventions}, volume = {64}, number = {4}, pages = {471-479}, doi = {10.1002/ccd.20342}, pmid = {15789388}, issn = {1522-1946}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Contrast Media/administration &amp; dosage/adverse effects ; Coronary Angiography/*adverse effects/methods ; Female ; Follow-Up Studies ; Humans ; Kidney Function Tests ; Male ; Primary Prevention/methods ; Radiopharmaceuticals/*adverse effects ; Randomized Controlled Trials as Topic ; Risk Assessment ; Severity of Illness Index ; Tomography, X-Ray Computed/*adverse effects/methods ; }, abstract = {The objectives of this study was to assess the overall effect of N-acetylcysteine (NAC) in preventing radiocontrast-induced nephropathy (RCIN) using all available data in the literature. RCIN is associated with increased morbidity and mortality. Existing randomized trials of NAC are small and show inconsistent results. Prior meta-analyses do not include data from the most current studies. We used standard search protocols to identify all published articles and abstracts of prospective trials using NAC with fluid hydration compared to hydration alone in patients with chronic renal insufficiency undergoing contrast procedures. A rise in serum creatinine by 0.5 mg/dl or 25% above baseline at 48-72 hr after contrast exposure was used as the primary outcome. We identified 14 trials of NAC with 1,584 patients published as full-text articles. Using a random-effects model, the use of oral NAC resulted in a significant reduction in the risk for developing RCIN (RR = 0.57; 95% CI = 0.37-0.84; P = 0.01). This finding did not significantly change in a fixed-effect model (RR = 0.55; 95% CI = 0.42-0.73) or when the data were reanalyzed using only randomized trials in all forms (i.e., articles and abstracts; RR = 0.67; 95% CI = 0.47-0.95). We identified only one important difference between the positive and the negative studies: the cumulative exposure to contrast media (174 vs. 152 ml). Metaregression did not show a significant relationship between contrast volume and the RR of developing RCIN (P > 0.10). In the trials showing benefit for NAC, the treated patients' postprocedure creatinine unexpectedly decreased by 0.21 mg/dl (95% CI = 0.33-0.08). Prophylaxis with NAC significantly reduces the risk for RCIN. The reasons for improvement in serum creatinine in patients treated with NAC are unclear, but may include improved renal blood flow due to NAC and/or vigorous hydration.}, }
@article {pmid15773218, year = {2005}, author = {Rochat, T and Leuenberger, P}, title = {[Pneumology. Treatment of idiopathic pulmonary fibrosis: hopes and disappointment].}, journal = {Revue medicale suisse}, volume = {1}, number = {2}, pages = {153-4, 156-8}, pmid = {15773218}, issn = {1660-9379}, mesh = {Humans ; Interferon-gamma/therapeutic use ; Pulmonary Fibrosis/*therapy ; Randomized Controlled Trials as Topic ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) is now recognized as a separate nosological entity. Despite the progresses in understanding the basic mechanisms of the disease, its prognosis remains poor. The classical treatment combines prednisone with a cytotoxic agent. Interferon gamma has the in vitro capacity of inhibiting fibroblasts proliferation. A pilot study showed positive results, but a more recent randomized double blind trial was unable to demonstrate a clear benefit to the patients. On the other hand there are many evidences for an oxydant-antioxydant imbalance in the pathogenesis of IPF. In a human controlled study N-acetylcysteine (NAC) at high doses (1800 mg per day orally) improved the pulmonary function tests when given on top of a combined therapy with prednisone and azathioprine.}, }
@article {pmid15772575, year = {2005}, author = {Guerin, JC and Leophonte, P and Lebas, FX and Liard, F and Terrioux, P and Boulanger, P}, title = {[Oxidative stress in bronchopulmonary disease: contribution of N-acetylcysteine (NAC)].}, journal = {Revue de pneumologie clinique}, volume = {61}, number = {1 Pt 1}, pages = {16-21}, doi = {10.1016/s0761-8417(05)84777-7}, pmid = {15772575}, issn = {0761-8417}, mesh = {Acetylcysteine/*pharmacology ; Glutathione/biosynthesis ; Humans ; Inflammation ; Lung Diseases/*genetics/immunology ; *Oxidative Stress ; }, abstract = {Oxidative stress is a frequent mechanism involved in the pathogenesis of bronchopulmonary disease. The cause can be exogenous, in particular related to to atmospheric pollution and tobacco smoke, or endogenous, related to mobilization of inflammatory cells (macrophages and polymorphonuclear neutrophils). In this general review, we present work demonstrating this oxidative stress and activation of inflammatory cells. We discuss the effect of oxidative stress on the bronchial tree and the need to maintain an adequate balance between oxidants and anti-oxidants. This reviews focuses on experimental studies proving the anti-oxidant effect of NAC on glutathione synthesis and on different pharmacological models. We then discuss human trials, initially experimental then in different bronchopulmonary pathologies related to oxidative stress. Acetaminophen intoxication and pulmonary fibrosis are models for use of NAC. Recent work on COPD appears to show a decrease in exacerbations, improvement in symptoms and quality-of-life, and perhaps a reduction in the alteration of ventilatory function.}, }
@article {pmid15771228, year = {2005}, author = {Keely, S and Rullay, A and Wilson, C and Carmichael, A and Carrington, S and Corfield, A and Haddleton, DM and Brayden, DJ}, title = {In vitro and ex vivo intestinal tissue models to measure mucoadhesion of poly (methacrylate) and N-trimethylated chitosan polymers.}, journal = {Pharmaceutical research}, volume = {22}, number = {1}, pages = {38-49}, pmid = {15771228}, issn = {0724-8741}, mesh = {Animals ; Chitosan/analysis/chemistry/*metabolism ; HT29 Cells ; Humans ; Intestinal Mucosa/*metabolism ; Intestines/chemistry/cytology ; Models, Biological ; Polymers/analysis/chemistry/metabolism ; Polymethacrylic Acids/analysis/chemistry/*metabolism ; Rats ; Tissue Adhesives/analysis/chemistry/*metabolism ; }, abstract = {PURPOSE: The adhesion of a range of polymers based on poly(2-(dimethylamino-ethyl) methacrylate (pDMAEMA) was assessed using human mucus-secreting and non mucus-secreting intestinal cell monolayers, HT29-MTX-E12 (E12) and HT29 monolayers, as well as excised non-everted intestinal sacs from rats. Differentiation of mucoadhesion from bioadhesion was achieved by pre-treatment with the mucolytic agent, N-acetyl cysteine (NAC). Adherence of pDMAEMA polymers was compared to that obtained with the mucoadhesive, N-trimethylated chitosan (TMC).<br><br>METHODS: The quantity of adherent coumarin 343-conjugated polymers to HT29, E12, and intestinal sacs was measured by fluorescence. Confocal laser scanning microscopy (CLSM), light microscopy, and fluorescent microscopy were used to provide direct evidence. Measurements of transepithelial electrical resistance (TEER), permeability to FITC-dextran 4000 (FD-4), and the release of lactate dehydrogenase (LDH) were used to assess potential cytotoxicity of polymers.<br><br>RESULTS: Adherence of unquaternized and of 10%, 24%, and 32% methyl iodide-quaternized pDMAEMA polymers was measured in E12, HT29, and sacs. All pDMAEMA polymers showed significantly higher levels of adhesion to mucus (mucoadhesion) than to epithelium (bioadhesion). Colocalization of pDMAEMA with mucus was confirmed in E12 by microscopy. TMC showed equally high levels of mucoadhesion as unquaternized and 24% quaternized pDMAEMA, but displayed higher levels of bioadhesion. pDMAEMA-based polymers demonstrated lower levels of adherence to E12 and rat sacs in the presence of NAC, whereas adherence of TMC was unchanged. pDMAEMA significantly decreased the permeability of FD-4 across E12 monolayers and sacs and was less cytotoxic in E12 than in HT29. In contrast, TMC increased the permeability of FD-4 across E12 and sacs and was less cytotoxic in E12 than in HT29.<br><br>CONCLUSIONS: Human mucus-producing E12 monolayers can be used to assess polymer mucoadhesion and give similar data to isolated rat intestinal sacs. pDMAEMA displayed similar levels of mucoadhesion and lower levels of bioadhesion than a chitosan derivative and it was not cytotoxic. pDMAEMA decreased FD-4 flux in the presence of mucus, whereas TMC increased it. The combination of mucus and methacrylate polymers appears to increase barrier function of the apical membrane.}, }
@article {pmid15770640, year = {2005}, author = {Kobrinsky, NL and Sjolander, DE and Goldenberg, JA and Ortmeier, TC}, title = {Successful treatment of doxorubicin and cisplatin resistant hepatoblastoma in a child with Beckwith-Wiedemann syndrome with high dose acetaminophen and N-acetylcysteine rescue.}, journal = {Pediatric blood &amp; cancer}, volume = {45}, number = {2}, pages = {222-225}, doi = {10.1002/pbc.20330}, pmid = {15770640}, issn = {1545-5009}, mesh = {Acetaminophen/*administration &amp; dosage ; Acetylcysteine/*therapeutic use ; Antineoplastic Agents/*administration &amp; dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use ; Beckwith-Wiedemann Syndrome/complications ; Cisplatin/administration &amp; dosage/pharmacology ; Doxorubicin/pharmacology ; *Drug Resistance, Neoplasm ; Drug Therapy, Combination ; Female ; Hepatoblastoma/complications/*drug therapy/pathology ; Humans ; Infant ; Liver Neoplasms/complications/*drug therapy/pathology ; }, abstract = {High dose acetaminophen (HDAC) with N-acetylcysteine (NAC) has been effective in adults with advanced malignancies. We report HDAC with NAC in a child with progressive hepatoblastoma, confirmed at biopsy of an unresectable hepatic mass. Alpha-fetoprotein (AFP) increased despite four courses of doxorubicin and one course of cisplatin, 5-flurouracil, and vincristine. Following HDAC with NAC, AFP markedly decreased. A continued response without toxicity was observed during four subsequent courses of HDAC with NAC and cisplatin. The residual necrotic tumor was resected. The child is now over 8 years disease free. HDAC and NAC are effective and well tolerated for progressive hepatoblastoma.}, }
@article {pmid15770292, year = {2005}, author = {Alhamdan, AA}, title = {The effect of dietary supplementation of N-acetyl-L-cysteine on glutathione concentration and lipid peroxidation in cigarette smoke-exposed rats fed a low-protein diet.}, journal = {Saudi medical journal}, volume = {26}, number = {2}, pages = {208-214}, pmid = {15770292}, issn = {0379-5284}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Diet ; Dietary Proteins/*administration &amp; dosage ; *Dietary Supplements ; Glutathione/*blood ; Lipid Peroxidation/*drug effects ; Male ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances ; *Tobacco Smoke Pollution ; }, abstract = {OBJECTIVE: The aim of the study is to investigate the modulatory effects of dietary supplementation of N-acetyl-L-cysteine (NAC) on glutathione (GSH) concentration in liver and lung, and lipid peroxidation in cigarette smoke-exposed rats fed a low-protein diet.<br><br>METHODS: Rats were divided randomly into 4 dietary groups; 8 per group. The control group (Group 1) was fed a normal-protein diet and received room air as a sham-smoke exposure. Group 2 was fed a normal-protein diet, Group 3 was fed with a low-protein diet and Group 4 was fed with a low-protein diet supplemented with NAC, and exposed to the smoke of 10 cigarettes/hour/day until the end of the experiment (4 weeks) period. Glutathione in liver and lung and serum albumin level were measured. Also, thiobarbituric acid reactive substances (TBARS) were measured, as an indication of oxidative stress. The study was conducted in the College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia, in the year 2003.<br><br>RESULTS: Smoke-exposed rats fed with the low-protein diet had significantly lower hepatic GSH concentration compared to other dietary groups. Moreover, NAC supplementation to the low-protein diet, in the smoke-exposed rats, significantly increased hepatic GSH concentration compared to the corresponding animals fed the same amount of protein, but without NAC supplementation. No reduction in lung GSH concentration occurred in cigarette-smoke rats fed a low-protein diet supplemented with NAC. Cigarette smoking significantly increased the level of TBARS in serum in all dietary groups compared to the control. However, the elevation in the TBARS level was higher in the low protein dietary group.<br><br>CONCLUSION: The results show no significant reduction in the lung and hepatic GSH concentration in cigarette smoke-exposed rats fed a normal-protein diet compared with the corresponding control rats fed a same level of protein. The study indicates the efficiency of NAC supplementation in scavenging free-radicals and enhancing GSH concentration in smoke-exposed rats fed a low-protein diet.}, }
@article {pmid15769933, year = {2005}, author = {Zhou, X and Ferraris, JD and Cai, Q and Agarwal, A and Burg, MB}, title = {Increased reactive oxygen species contribute to high NaCl-induced activation of the osmoregulatory transcription factor TonEBP/OREBP.}, journal = {American journal of physiology. Renal physiology}, volume = {289}, number = {2}, pages = {F377-85}, doi = {10.1152/ajprenal.00463.2004}, pmid = {15769933}, issn = {1931-857X}, mesh = {Carrier Proteins/biosynthesis/genetics ; Catalase/metabolism ; Cell Line ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; GABA Plasma Membrane Transport Proteins ; Humans ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Ouabain/pharmacology ; Oxidants/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Sodium Chloride/antagonists &amp; inhibitors/*pharmacology ; Superoxides/metabolism ; Transcription Factors/*genetics/*physiology ; Transcriptional Activation/drug effects/genetics ; Water-Electrolyte Balance/drug effects/*genetics ; }, abstract = {The signaling pathways leading to high NaCl-induced activation of the transcription factor tonicity-responsive enhancer binding protein/osmotic response element binding protein (TonEBP/OREBP) remain incompletely understood. High NaCl has been reported to produce oxidative stress. Reactive oxygen species (ROS), which are a component of oxidative stress, contribute to regulation of transcription factors. The present study was undertaken to test whether the high NaCl-induced increase in ROS contributes to tonicity-dependent activation of TonEBP/OREBP. Human embryonic kidney 293 cells were used as a model. We find that raising NaCl increases ROS, including superoxide. N-acetylcysteine (NAC), an antioxidant, and MnTBAP, an inhibitor of superoxide, reduce high NaCl-induced superoxide activity and suppress both high NaCl-induced increase in TonEBP/OREBP transcriptional activity and high NaCl-induced increase in expression of BGT1mRNA, a transcriptional target of TonEBP/OREBP. Catalase, which decomposes hydrogen peroxide, does not have these effects, whether applied exogenously or overexpressed within the cells. Furthermore, NAC and MnTBAP, but not catalase, blunt high NaCl-induced increase in TonEBP/OREBP transactivation. N(G)-monomethyl-l-arginine, a general inhibitor of nitric oxide synthase, has no significant effect on either high NaCl-induced increase in superoxide or TonEBP/OREBP transcriptional activity, suggesting that the effects of ROS do not involve nitric oxide. Ouabain, an inhibitor of Na-K-ATPase, attenuates high NaCl-induced superoxide activity and inhibits TonEBP/OREBP transcriptional activity. We conclude that the high NaCl-induced increase in ROS, including superoxide, contributes to activation of TonEBP/OREBP by increasing its transactivation.}, }
@article {pmid15764673, year = {2005}, author = {Bailey, SR and Mitra, S and Flavahan, S and Flavahan, NA}, title = {Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {289}, number = {1}, pages = {H243-50}, doi = {10.1152/ajpheart.01305.2004}, pmid = {15764673}, issn = {0363-6135}, support = {AR-46126/AR/NIAMS NIH HHS/United States ; HL-080119/HL/NHLBI NIH HHS/United States ; HL-67331/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Arteries/physiology ; Biological Transport ; Cell Line ; Cells, Cultured ; *Cold Temperature ; Electron Transport Complex I/antagonists &amp; inhibitors ; Humans ; In Vitro Techniques ; Mice ; Mitochondria, Muscle/*metabolism ; Muscle, Smooth/*metabolism ; Myocytes, Smooth Muscle/metabolism ; Protein Isoforms/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Receptors, Adrenergic, alpha-2/metabolism ; Rotenone/pharmacology ; Skin/*blood supply ; Vasoconstriction/drug effects/*physiology ; rhoA GTP-Binding Protein/physiology ; }, abstract = {Cold constricts cutaneous blood vessels by selectively increasing the activity of smooth muscle alpha2-adrenoceptors (alpha2-ARs). In mouse tail arteries, alpha2-AR constriction is mediated by alpha2A-ARs at 37 degrees C, whereas the cold-induced augmentation in alpha2-AR activity is mediated entirely by alpha2C-ARs. Cold causes translocation of alpha2C-ARs from the trans-Golgi to the plasma membrane, mediated by cold-induced activation of RhoA and Rho kinase. The present experiments analyzed the mechanisms underlying these responses. Mouse tail arteries were studied in a pressure myograph. Cooling the arteries (28 degrees C) caused a rapid increase in reactive oxygen species (ROS) in smooth muscle cells, determined by confocal microscopy of arteries loaded with the ROS-sensitive probes, dichlorodihydrofluorescein or reduced Mitotracker Red. The inhibitor of mitochondrial complex I rotenone (10 micromol/l), the antioxidant N-acetylcysteine (NAC; 20 mmol/l), or the cell-permeable mimic of superoxide dismutase MnTMPyP (50 micromol/l) did not affect vasoconstriction to alpha2-AR stimulation (UK-14304) at 37 degrees C but dramatically inhibited the response at 28 degrees C. Indeed, these ROS inhibitors abolished the cold-induced increase in alpha2-AR constrictor activity. NAC (20 mmol/l) or MnTMPyP (50 micromol/l) also abolished the cold-induced activation of RhoA in human cultured vascular smooth muscle cells and the cold-induced mobilization of alpha2C-ARs to the cell surface in human embryonic kidney 293 cells transfected with the receptor. The combined results suggest that cold-induced constriction is mediated by redox signaling in smooth muscle cells, initiated by mitochondrial generation of ROS, which stimulate RhoA/Rho kinase signaling and the subsequent mobilization of alpha2C-ARs to the cell surface. Altered activity of ROS may contribute to cold-induced vasospasm occurring in Raynaud's phenomenon.}, }
@article {pmid15761843, year = {2005}, author = {Ramudo, L and Manso, MA and Sevillano, S and de Dios, I}, title = {Kinetic study of TNF-alpha production and its regulatory mechanisms in acinar cells during acute pancreatitis induced by bile-pancreatic duct obstruction.}, journal = {The Journal of pathology}, volume = {206}, number = {1}, pages = {9-16}, doi = {10.1002/path.1747}, pmid = {15761843}, issn = {0022-3417}, mesh = {Acute Disease ; Animals ; Blotting, Western/methods ; Cell Culture Techniques ; Cholestasis/complications/metabolism ; Flow Cytometry ; Male ; Models, Animal ; NF-kappa B/metabolism ; Pancreas/*metabolism ; Pancreatic Ducts/metabolism ; Pancreatitis/*metabolism/pathology ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Cytokines play a critical role in acute pancreatitis (AP) but the contribution of different cell sources to cytokine production is unclear. Unfortunately, there are no data concerning the molecular mechanisms involved in the inflammatory response in humans during AP. For this reason, the aim of this study was to analyse the ability of acinar cells, in comparison with leukocytes, to produce TNF-alpha at different stages of AP induced in rats by bile-pancreatic duct obstruction (BPDO) and to investigate the time course of oxidant-sensitive mechanisms involved in cytokine production. The role of oxygen free radicals as messengers of the mechanisms underlying acinar cell TNF-alpha production was assessed in BPDO rats treated with N-acetylcysteine (NAC). While monocytes were not able to produce TNF-alpha until 12 h after inducing AP, acinar cells triggered TNF-alpha production from 6 h after BPDO, at which time the pancreas develops maximal oxidative stress. Phosphorylated p38-MAPK and activated NF-kappaB were detected in acinar cells from 6 h after BPDO. NAC treatment reduced pancreatic glutathione depletion during the early stages of AP and attenuated the activation of p38-MAPK and NF-kappaB for 48 h following BPDO. As a result, acinar cells in NAC-treated rats failed to produce TNF-alpha during AP. In addition, NAC delayed monocyte TNF-alpha production, thereby maintaining low TNF-alpha levels in plasma during BPDO. In conclusion, acinar cells contribute directly to the inflammatory response during BPDO-induced AP by producing TNF-alpha even before inflammatory cells in the peripheral blood. The blockade of oxidant-mediated signal transduction pathways induced by NAC treatment prevented acinar cell TNF-alpha production.}, }
@article {pmid15761783, year = {2005}, author = {Lukas, R and Schärling, B and Schultze-Werninghaus, G and Gillissen, A}, title = {[Antioxidant treatment with N-acetylcysteine and vitamin C in patients with chronic bronchitis].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {130}, number = {11}, pages = {563-567}, doi = {10.1055/s-2005-865062}, pmid = {15761783}, issn = {0012-0472}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/*therapeutic use ; Ascorbic Acid/*therapeutic use ; Blood Sedimentation ; Bronchitis, Chronic/*drug therapy/metabolism ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*therapeutic use ; Glutathione/blood ; Humans ; Leukocyte Count ; Leukocytes, Mononuclear/drug effects/metabolism ; Luminescent Measurements ; Male ; Middle Aged ; Neutrophils/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; Spirometry ; Surveys and Questionnaires ; Treatment Failure ; }, abstract = {BACKGROUND AND OBJECTIVE: N-acetylcysteine (NAC) is known to have direct antioxidant properties due to its thiol-group on the one hand as well as indirect antioxidant capacity as cysteine-donor to cellular glutathione-synthesis on the other hand. Therefore NAC appears to be attractive in antioxidant therapy of inflammatory disorders of the lung. This study aimed to investigate the use of antioxidant therapy with NAC in chronic bronchitis.<br><br>PATIENTS AND METHODS: In this randomized, double-blinded and placebo-controlled trial 100 patients divided into four groups were observed over a period of 3 months. The treatment consisted of either 600 mg NAC bid, 500 mg Vitamin C bid, a combination of those two substances using the same dosage or a placebo-preparation. The release of reactive oxygen species from isolated neutrophilic granulocytes and mononuclear cells was quantified before treatment and after three months using chemiluminescence (primary outcome parameter). Furthermore cellular glutathione content of these inflammatory cells was quantified spectrometrically. In addition, leukocyte-count and erythrocyte sedimentation rate as well as spirometry and a standardized symptom-based questionnaire were used to monitor the clinical efficacy.<br><br>RESULTS: None of the above substances were able to significantly reduce the release of reactive oxygen species from the examined population of inflammatory cells. They also failed to increase intracellular glutathione-levels. Concordantly, no changes in spirometry and the results of the symptom-based questionnaire were found.<br><br>CONCLUSION: In summary NAC, Vitamin C and the NAC/ Vitamin C-combination did neither enhance antioxidant protection in the blood nor is it of any clinical benefit in chronic bronchitis. Possible reasons may be a lack of antioxidant deficiency in these patients and negative feedback mechanisms of the glutathione-system.}, }
@article {pmid15759051, year = {2005}, author = {Wu, L}, title = {The pro-oxidant role of methylglyoxal in mesenteric artery smooth muscle cells.}, journal = {Canadian journal of physiology and pharmacology}, volume = {83}, number = {1}, pages = {63-68}, doi = {10.1139/y04-112}, pmid = {15759051}, issn = {0008-4212}, mesh = {Animals ; Cells, Cultured ; Glycation End Products, Advanced/*metabolism ; Heme Oxygenase (Decyclizing)/biosynthesis ; Heme Oxygenase-1 ; Immunohistochemistry ; Mesenteric Arteries/cytology/*drug effects/metabolism ; Muscle, Smooth, Vascular/cytology/*drug effects/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/*drug effects ; Pyruvaldehyde/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Methylglyoxal (MG), a highly reactive metabolite of glucose, causes non-enzymatic glycation of proteins to form irreversible advanced glycation endproducts (AGEs). The present study investigated whether methylglyoxal induced oxidative stress and activated nuclear factor kappa B (NF-kappaB) in freshly isolated and cultured smooth muscle cells (SMCs) from rat mesenteric artery. The treatment of cells with MG (50 or 100 micromol/L) induced a significant increase in AGE formation and oxidation of DCF. MG-enhanced generation of AGEs and the oxidation of DCF was markedly inhibited by antioxidant n-acetylcysteine (NAC, 600 micromol/L). MG at a concentration of 100 micromol/L increased the heme-oxygenase-1 expression in these cells. Moreover, MG activated NF-kappaB p65, indicated by an increased immuno cytochemistry stain for NF-kappaB p65 located in the nucleus after the treatment of mesenteric artery SMCs with MG. MG-induced activation of NF-kappaB p65 was inhibited by NAC. In summary, MG significantly increases oxidative stress and activates NF-kappaB p65 in mesenteric artery SMCs. The pro-oxidant role of methylglyoxal may contribute to various pathological changes of SMCs from resistance arteries.}, }
@article {pmid15754030, year = {2005}, author = {Taniguchi, T and Takahashi, M and Shinohara, F and Sato, T and Echigo, S and Rikiishi, H}, title = {Involvement of NF-kappaB and mitochondrial pathways in docetaxel-induced apoptosis of human oral squamous cell carcinoma.}, journal = {International journal of molecular medicine}, volume = {15}, number = {4}, pages = {667-673}, pmid = {15754030}, issn = {1107-3756}, mesh = {Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/*drug effects/physiology ; Carcinoma, Squamous Cell/*drug therapy/metabolism ; Caspase 8 ; Caspases/metabolism ; Cytochromes c/metabolism ; Docetaxel ; Humans ; Membrane Potentials/drug effects ; Mitochondria/drug effects/*metabolism ; Mouth Neoplasms/*drug therapy/metabolism ; NF-kappa B/*metabolism ; Reactive Oxygen Species/metabolism ; Taxoids/pharmacology ; Tumor Cells, Cultured ; }, abstract = {Apoptosis induced by docetaxel that interferes with microtubule polymerization dynamics and is used clinically to treat advanced cancers, has not been fully defined in squamous cell carcinoma. In this study, apoptotic events involved in docetaxel treatment were investigated. When the human oral squamous cell carcinoma cell line HSC-3 was exposed to docetaxel for 72 h, a dose-dependent effect was observed in apoptosis using the TUNEL method. We observed activation of caspase cascade including activities like caspase-3, -8, and -9. And the pan-caspase inhibitor z-VAD-fmk prevented apoptosis induced by docetaxel (0.1 microM), showing participation of caspases in this process. Since an antagonistic CD95-antibody (ZB4) exerted no effect on docetaxel-induced apoptosis, CD95/CD95L interaction was not involved in this pathway. The caspase-8-like activity was inhibited not only by IETD-fmk (caspase-8) but also by DEVD-fmk (caspase-3). The results indicate that the caspase-8-like activation occurred downstream of DEVDase. Docetaxel promoted the formation of reactive oxygen species (ROS) in mitochondria, and preincubation of cells with anti-oxidants such as N-acetyl cysteine and pyrrolidine dithiocarbamate, protected against apoptosis mediated by docetaxel. Furthermore, treatment with docetaxel elicited reduction of mitochondrial membrane potential, and release of cytochrome c to cytosol, after 48 h of treatment. We observed binding activity to NF-kappaB consensus site and interference with the mitochondrial function via NF-kappaB after docetaxel treatment. Preventing pro-apoptotic property of NF-kappaB inhibited docetaxel-induced apoptosis. Thus, these results suggest that, following the activation of NF-kappaB by docetaxel, apoptosis is elicited through a mitochondria-dependent pathway.}, }
@article {pmid15748703, year = {2005}, author = {Ko, CH and Shen, SC and Hsu, CS and Chen, YC}, title = {Mitochondrial-dependent, reactive oxygen species-independent apoptosis by myricetin: roles of protein kinase C, cytochrome c, and caspase cascade.}, journal = {Biochemical pharmacology}, volume = {69}, number = {6}, pages = {913-927}, doi = {10.1016/j.bcp.2004.12.005}, pmid = {15748703}, issn = {0006-2952}, mesh = {Animals ; Apoptosis/*drug effects/physiology ; Caspases/*metabolism ; Cells, Cultured ; Cytochromes c/*metabolism ; Flavonoids/chemistry/*pharmacology ; HL-60 Cells ; Humans ; Jurkat Cells ; Male ; Mice ; Mitochondria/*drug effects/metabolism ; Protein Kinase C/*metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {Abrogation of mitochondrial permeability and induction of reactive oxygen species (ROS) production have been observed in chemical-induced apoptosis; however, the relationship between the mitochondria and intracellular ROS levels in apoptosis is still unclear. In the present study, myricetin (ME) but not its respective glycoside, myricitrin (MI; myricetin-3-O-rhamnose) reduced the viability of human leukemia HL-60 cells via apoptosis, characterized by the occurrence of DNA ladders and hypodiploid cells. Results of Western blotting and caspase activity assays showed that activation of caspases 3 and 9 but not caspases 1, 6 or 8 with cleavage of PARP and D4-GDI proteins is involved in ME-induced apoptosis. A reduction in mitochondrial functions characterized by a decrease in the Bcl-2/Bax protein ratio and translocation of cytochrome c (cyt c) from the mitochondria to the cytosol in accordance with a decrease in mitochondrial membrane potential were observed in ME-treated HL-60 cells. No significant induction of intracellular ROS levels by ME was observed by the DCHF-DA assay, DPPH assay or plasmid digestion assay, and antioxidants including N-acetyl-cysteine (NAC), catalase (CAT), superoxide dismutase (SOD), and tiron (TIR) showed no protective effects on ME-induced apoptosis. A PKC activator, 12-O-tetradecaoylphorbol-13-acetate (TPA) significantly attenuated ME-induced apoptosis via preventing cytochrome c release to the cytosol and maintaining the mitochondrial membrane potential by inhibiting the decrease in the Bcl-2/Bax protein ratio; these effects were blocked by protein kinase C (PKC) inhibitors including GF-109203X, H7, and staurosporin. Removing mitochondria by ethidium bromide (EtBr) treatment reduced the apoptotic effect of ME. Results of SAR studies showed that the presence of OH at C3', C4', and C5' is important for the apoptosis-inducing activities of ME, and that ME induces apoptosis in another leukemia cell line, Jurkat cells, but not in primary human polymorphonuclear (PMN) cells or in murine peritoneal macrophages (PMs). The results of the present study suggest that apoptosis induced by ME occurs through a novel mitochondrion-dependent, ROS-independent pathway; TPA protects cells from ME-induced apoptosis via PKC activation which prevents the occurrence of mitochondrial destruction during apoptosis.}, }
@article {pmid15744519, year = {2005}, author = {Liang, SC and Wang, H and Zhang, ZM and Zhang, HS}, title = {Determination of thiol by high-performance liquid chromatography and fluorescence detection with 5-methyl-(2-(m-iodoacetylaminophenyl)benzoxazole.}, journal = {Analytical and bioanalytical chemistry}, volume = {381}, number = {5}, pages = {1095-1100}, doi = {10.1007/s00216-004-3006-2}, pmid = {15744519}, issn = {1618-2642}, mesh = {Benzoxazoles/*chemistry ; Chromatography, High Pressure Liquid/*methods ; Fluorescent Dyes/*chemistry ; Humans ; Sulfhydryl Compounds/*analysis/urine ; }, abstract = {A new high-performance liquid chromatographic (HPLC) method for measuring low molecular weight (LMW) thiol-containing compounds, including cysteine (CysH), glutathione (GSH), N-acetylcysteine (Nac), penicillamine (PA), and 2-mercaptoethanol (2-ME), has been developed by using 5-methyl-(2-(m-iodoacetylaminophenyl)benzoxazole (MIPBO) as fluorescence-labeling reagent. The derivatization and separation conditions have been investigated in detail. Detection limits ranging from 3.5 to 15.0 fmol were achieved for the thiols investigated in a 16 min separation with detection wavelengths 310 and 375 nm for the excitation and emission, respectively. The utility of the proposed method has been validated by measuring CysH in human urine samples.}, }
@article {pmid15744360, year = {2004}, author = {Lazárová, M and Stejskal, D and Lacnák, B and Václavík, J and Adamovská, S and Ochmanová, R and Hanák, V and Skácelová, M}, title = {The antioxidant acetylcysteine reduces oxidative stress by decreasing level of AOPPs.}, journal = {Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia}, volume = {148}, number = {2}, pages = {131-133}, pmid = {15744360}, issn = {1213-8118}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Arteriosclerosis/blood ; Biomarkers/blood ; Blood Proteins ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Risk Factors ; }, abstract = {Oxidative stress and especially its connection with many diseases has been discussed much recently. Among markers of oxidative stress there appear new and quite specific ones called advanced oxidation protein products (AOPPs). We tried to influence the level of AOPPs by an antioxidant therapy with N-acetylcysteine. Fourteen individuals with many cardiovascular risk factors were examined. All these patients were administered acetylcysteine (NAC) 600 mg/day orally during 20 days. Before starting the therapy we determined AOPP, albumin cobalt binding (ACB), glucose, creatinine, urea, ALT, AST, cholesterol, LDL, HDL and triglycerides values in peripheral venous blood in all individuals. After finishing our intervention we determined AOPP, ACB and glucose level again. Our results show a statistically significant decrease in AOPP levels after 20-day N-acetylcysteine therapy (medians, initially 82.2, at study end 74.3 umol/l, p = 0.039). We demonstrate a significant decrease in AOPP levels after 20-day N-acetylcysteine therapy in dose 600 mg/day.}, }
@article {pmid15738581, year = {2005}, author = {Dong, F and Zhang, X and Li, SY and Zhang, Z and Ren, Q and Culver, B and Ren, J}, title = {Possible involvement of NADPH oxidase and JNK in homocysteine-induced oxidative stress and apoptosis in human umbilical vein endothelial cells.}, journal = {Cardiovascular toxicology}, volume = {5}, number = {1}, pages = {9-20}, doi = {10.1385/ct:5:1:009}, pmid = {15738581}, issn = {1530-7905}, support = {NIH R03 AG21324-01/AG/NIA NIH HHS/United States ; P20 RR15640/RR/NCRR NIH HHS/United States ; RR-16474/RR/NCRR NIH HHS/United States ; }, mesh = {Apoptosis/drug effects/*physiology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelium, Vascular/drug effects/*enzymology ; Homocysteine/*toxicity ; Humans ; NADPH Oxidases/*physiology ; Oxidative Stress/drug effects/*physiology ; Umbilical Veins/drug effects/enzymology ; }, abstract = {Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases, although the mechanism leading to vascular dysfunction is not clear. The aim of this study was to examine the effect of homocysteine (Hcy) on oxi-dative stress and apoptosis in human umbilical vein endothelial cells (HUVECs). HUVECs were challenged for 24 h with Hcy (10 microM-3 mM) in the presence of various stress signaling inhibitors, including the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (100 microM), the p38 mito-gen-activated protein kinase inhibitor SB203580 (2.5 microM), the extracellular signal-regulated kinase inhibitor U0126 (2.5 microM), the stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) inhibitor JNK inhibitor II (10 microM), and antioxidants alpha-tocopherol (5 microg/mL) and N-acetyl cysteine (NAC, 2 mM). Reactive oxygen species (ROS) were detected using 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate. Apoptosis was evaluated by 4',6'-diamidino-2'-phenylindoladihydrochloride staining, annexin-V phosphatidyl- serine/propidium iodide, and caspase-3 assay. NADPH oxidase and SAPK/JNK signal were evaluated with immunoblotting. Hcy significantly enhanced ROS generation and apoptosis after 24-h incubation. Apocynin prevented Hcy-induced ROS generation but only partially restored Hcy-induced apoptosis. JNK inhibitor II, alpha-tocopherol, and NAC partially reduced Hcy-induced apoptosis, although SB203580 and U0126 had no effect. Immunoblotting analysis confirmed upregulation of NADPH oxidase and SAPK/JNK signaling. Collectively, our results suggested that Hcy may induce oxidative stress and apopto-sis through an NADPH oxidase and/or JNK-dependent mechanism(s).}, }
@article {pmid15737736, year = {2005}, author = {Onyango, IG and Tuttle, JB and Bennett, JP}, title = {Activation of p38 and N-acetylcysteine-sensitive c-Jun NH2-terminal kinase signaling cascades is required for induction of apoptosis in Parkinson's disease cybrids.}, journal = {Molecular and cellular neurosciences}, volume = {28}, number = {3}, pages = {452-461}, doi = {10.1016/j.mcn.2004.10.006}, pmid = {15737736}, issn = {1044-7431}, support = {AG14373/AG/NIA NIH HHS/United States ; NS39005/NS/NINDS NIH HHS/United States ; NS39788/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aged ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Collagen Type XI/metabolism ; DNA, Mitochondrial/physiology ; Enzyme Activation/drug effects/physiology ; Enzyme Inhibitors/pharmacology ; Female ; Gene Amplification/physiology ; Humans ; Hybrid Cells/drug effects/*metabolism ; JNK Mitogen-Activated Protein Kinases/drug effects/*metabolism ; Male ; Middle Aged ; NF-kappa B/metabolism ; Oxidative Stress/drug effects/physiology ; Parkinson Disease/*metabolism/physiopathology ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; Signal Transduction/drug effects/*physiology ; Up-Regulation/physiology ; p38 Mitogen-Activated Protein Kinases/drug effects/*metabolism ; }, abstract = {Cytoplasmic hybrid cells (cybrids) are created by selective amplification of mitochondrial genes against constant nuclear genetic and environmental backgrounds. Cybrids from patients with sporadic Parkinson's disease (PD) recapitulate disease features such as decreased complex I activity, increased oxidative stress, elevated activation of NF-kappaB, and production of Lewy body inclusions. We examined the activation of signaling pathways and NF-kappaB in PD cybrids after exposure to MAPK inhibitors and/or the antioxidant N-acetylcysteine (NAC). Under basal replicating conditions, PD cybrids have decreased viability that is associated with increased DNA condensation and poly-ADP ribose polymerase (PARP) cleavage as well as elevated p38 and JNK activity. Pharmacological inhibition of oxidative stress diminished the elevated p38, JNK activity and PARP cleavage, and enhanced PD cybrid viability. PD mitochondrial genes expressed in cybrids stimulate pro-apoptotic cell signaling and biochemistry through oxidative stress. These results support development of antioxidative therapeutics for PD.}, }
@article {pmid15736113, year = {2005}, author = {Doshi, S and McDowell, I and Goodfellow, J and Stabler, S and Boger, R and Allen, R and Newcombe, R and Lewis, M and Moat, S}, title = {Relationship between S-adenosylmethionine, S-adenosylhomocysteine, asymmetric dimethylarginine, and endothelial function in healthy human subjects during experimental hyper- and hypohomocysteinemia.}, journal = {Metabolism: clinical and experimental}, volume = {54}, number = {3}, pages = {351-360}, doi = {10.1016/j.metabol.2004.09.015}, pmid = {15736113}, issn = {0026-0495}, mesh = {Acetylcysteine/administration &amp; dosage ; Adult ; Arginine/*analogs &amp; derivatives/*blood ; Blood Flow Velocity ; Brachial Artery ; Cross-Over Studies ; Cystathionine/blood ; Cysteine/blood ; Dipeptides/blood ; Double-Blind Method ; Endothelium, Vascular/*physiopathology ; Female ; Homocysteine/administration &amp; dosage/*blood ; Humans ; Hyperhomocysteinemia/*blood ; Kinetics ; Male ; Methionine/administration &amp; dosage/blood ; Placebos ; S-Adenosylhomocysteine/*blood ; S-Adenosylmethionine/*blood ; Vasodilation ; }, abstract = {Experimental hyperhomocysteinemia after an oral methionine or homocysteine load is associated with impaired nitric oxide-dependent vasodilatation in healthy human beings. However, it remains unproven that this effect is mediated by elevations in plasma homocysteine. There is evidence that an increase in plasma homocysteine may increase the formation of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase. The methyl groups within ADMA are derived from the conversion of S -adenosylmethionine to S -adenosylhomocysteine intermediates in the methionine/homocysteine pathway. No previous study has assessed the role of methylation status, its impact on ADMA formation, and their association with endothelial function in healthy human beings. In a randomized, placebo-controlled, crossover study, 10 healthy subjects (mean age, 29.1 +/- 3.9 years) were administered an oral dose of methionine (0.1 g/kg), l -homocysteine (0.01 g/kg), N-acetylcysteine (NAC) (0.1 g/kg), or placebo. Endothelial function as assessed by flow-mediated dilatation (FMD) of the brachial artery was impaired after both the methionine and homocysteine load compared with placebo at 4 hours (36 +/- 15, 67 +/- 23 vs 219 +/- 26 microm, respectively, P < .001). N-Acetylcysteine had no effect on flow-mediated dilatation. Plasma total homocysteine was significantly elevated at 4 hours after methionine (23.1 +/- 6.2) and homocysteine (41.5 +/- 8.9) loading, but significantly reduced after NAC 2.4 +/- 0.6 vs 7.1 +/- 2.1 micromol/L in the placebo (P < .001). Plasma S-adenosylmethionine/S-adenosylhomocysteine ratio was significantly (P < .001) increased at 4 hours after methionine (10.9 +/- 0.7) compared with homocysteine (5.4 +/- 0.4), NAC (5.0 +/- 0.3), and placebo (6.0 +/- 0.5). Plasma ADMA concentrations were not altered by any intervention. Our results suggest that endothelial dysfunction due to methionine or homocysteine loading is not associated with an increase in plasma ADMA or a disruption in methylation status.}, }
@article {pmid15733769, year = {2005}, author = {Gundersen, Y and Vaagenes, P and Thrane, I and Sterri, SH and Opstad, PK}, title = {N-Acetylcysteine administered as part of the immediate post-traumatic resuscitation regimen does not significantly influence initiation of inflammatory responses or subsequent endotoxin hyporesponsiveness.}, journal = {Resuscitation}, volume = {64}, number = {3}, pages = {377-382}, doi = {10.1016/j.resuscitation.2004.09.005}, pmid = {15733769}, issn = {0300-9572}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Endotoxins/blood ; Inflammation/blood/etiology ; Interleukin-1/blood ; Leukocytes ; Neutrophils ; Norway ; Reactive Oxygen Species/blood ; *Resuscitation ; Swine ; Tumor Necrosis Factor-alpha/analysis ; Wounds and Injuries/blood/immunology/*therapy ; }, abstract = {Polytrauma and resuscitative efforts induce extensive alterations in the host's internal environment and cellular responses that may be a serious threat to these patients. Administration of exogenous thiols has been recommended to modulate the post-traumatic inflammatory responses. In this study, we have investigated the effect of N-acetylcysteine (NAC) on the early markers of leukocyte activation and subsequent endotoxin hyporesponsiveness. Twenty-eight pigs were exposed to a standardized gunshot injury. First aid treatment and initial life saving surgery was started without delay. One group (n = 14) was randomised to receive NAC 200 mg kg(-1) over 20 min, the remaining group was given the same volume of vehicle. Blood samples drawn at time points 0 and 75 min were also studied in vitro and stimulated with LPS or LPS plus NAC. Selected physiologic variables and degree of organ injury were equal in both groups. TNF-alpha, IL-1beta, and reactive oxygen species (ROS) tended to be lower in the NAC-group (NS). In vitro, NAC significantly reduced the release of the same cytokines after the LPS challenge in blood drawn before injury. NAC did not influence post-traumatic endotoxin tolerance. Adding NAC to the immediate resuscitation fluid did not influence the early post-traumatic organ injury, and initiation of inflammatory responses significantly, or endotoxin tolerance. In vitro, NAC significantly reduced proinflammatory cytokine release, but only in normal blood. The clinical value of this treatment regimen is probably restricted, both due to the unfavourable post-traumatic internal environment and imposed dosing limitations.}, }
@article {pmid15730776, year = {2004}, author = {Hu, ZY and Ni, LD and Jin, AJ and Dong, HX and Zhong, M and Li, JN and Weng, XH}, title = {[Study on the method for rapid detection of Mycobacterium tuberculosis by phage amplified biologically assay].}, journal = {Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases}, volume = {27}, number = {12}, pages = {801-805}, pmid = {15730776}, issn = {1001-0939}, mesh = {Animals ; Antitubercular Agents/pharmacology ; Colony Count, Microbial ; Culture Media ; Drug Resistance, Bacterial ; Humans ; Microbial Sensitivity Tests/*methods ; *Mycobacteriophages ; Mycobacterium Infections/diagnosis/microbiology ; Mycobacterium tuberculosis/drug effects/growth &amp; development/*isolation &amp; purification ; Predictive Value of Tests ; Sensitivity and Specificity ; Sputum/microbiology ; }, abstract = {OBJECTIVE: To set up a method for rapid detection of Mycobacterium tuberculosis (MTB) by phage amplified biologically (PhaB) assay and to investigate the optimal test condition.<br><br>METHODS: Various test conditions were compared in order to observe the influence on detective results after MTB was infected by Mycobacteriophage. The test condition established was used for detection of sputum samples, and the results were compared with BIOTEC Lab test.<br><br>RESULTS: The bacterial concentration of MTB in 200 - 500/ml was detected by PhaB assay at 1 x 10(9) plaque forming unite (PFU)/ml of Mycobacteriophage, 37 degrees C for 60 min. The optimal concentration of virucidal for inactivation of Mycobacteriophage was 100 mmol/ml for 5 min at room temperature. The bacteriolytic plaque was clear at the concentration of 1 x 10(8)/ml indicator cells. Bacterium inactivated by heat can not be infected by Mycobacteriophage. Positive result was observed for control strains of H(37)Rv, H(37)Ra and M. bovis while negative result was obtained for 7 strains of non-Mycobacterium and 16 control strains of non-Tuberculosis Mycobacteria (NTM). The 4 strains of NTM (M. fortuitum, M. intrcellulare, M. aurum, M. phlei) showed positive reaction at higher concentrations (> 1 x 10(5)/ml). The repetition test showed that the differentiation coefficient in batch and inner was all under 15%. There was a significantly difference (P < 0.01) in positive rate between two digestion-decontamination procedure with N-acetyl-cysteine-NaOH liquefacient (94%) and NaOH liquefacient (62%). The positive rate of the samples cultured one day (65%) was significantly higher than that of the samples without preculture (40%). The results for detection of clinical samples by two reagents, ours and BIOTEC Lab, were nearly the same.<br><br>CONCLUSION: Because its rapidity, simplicity, and sensitivity, PhaB assay can be used for rapid detection of MTB, but the condition of test is very important.}, }
@article {pmid15724855, year = {2005}, author = {Bobb, AJ and Arfsten, DP and Jederberg, WW}, title = {N-acetyl-L-Cysteine as prophylaxis against sulfur mustard.}, journal = {Military medicine}, volume = {170}, number = {1}, pages = {52-56}, doi = {10.7205/milmed.170.1.52}, pmid = {15724855}, issn = {0026-4075}, mesh = {Acetylcysteine/administration &amp; dosage/chemistry/*therapeutic use ; Animals ; Chemical Warfare Agents/*toxicity ; Chemoprevention ; Humans ; Mustard Gas/*toxicity ; Protective Agents/administration &amp; dosage/chemistry/*therapeutic use ; Safety ; }, abstract = {Sulfur mustard (HD) is a blister agent targeting the eyes, respiratory system, skin, and possibly other organs. Extensive exposure can destroy the immune system by destruction of bone marrow cells. There is no antidote for HD or effective treatment other than rapid decontamination. Clinical trials have demonstrated activity for N-acetyl-L-cysteine (NAC) against a number of significant human pathologies involving free radicals, and animal and tissue studies have suggested efficacy for NAC as a chemoprotectant against many toxic chemicals. Among these are studies demonstrating that NAC significantly reduces the effects of HD and HD simulants, both in cultured cells and animals. Given the historical effectiveness of HD, the lack of any effective treatment, the demonstrated chemoprotective properties of NAC, its low toxicity, the lack of regulatory controls, and the data supporting efficacy against HD effects, we suggest daily oral administration of the maximum safe dose of NAC to personnel entering combat zones.}, }
@article {pmid15721990, year = {2005}, author = {Cocco, T and Sgobbo, P and Clemente, M and Lopriore, B and Grattagliano, I and Di Paola, M and Villani, G}, title = {Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine.}, journal = {Free radical biology &amp; medicine}, volume = {38}, number = {6}, pages = {796-805}, doi = {10.1016/j.freeradbiomed.2004.11.034}, pmid = {15721990}, issn = {0891-5849}, mesh = {Acetylcysteine/*chemistry ; *Aging ; Animal Feed ; Animal Nutritional Physiological Phenomena ; Animals ; Antioxidants/metabolism ; Brain/metabolism/pathology ; Carbon/chemistry ; Cerebral Cortex/metabolism ; Citrate (si)-Synthase/metabolism ; Cytochromes/metabolism ; Cytosol/metabolism ; *Diet ; Glutathione/metabolism ; Male ; Mitochondria/*metabolism ; Mitochondria, Heart/metabolism ; Myocardium/metabolism ; Oxidative Phosphorylation ; Oxidative Stress ; Oxygen/metabolism ; Oxygen Consumption ; Phosphorylation ; Rats ; Rats, Wistar ; Spectrophotometry ; Time Factors ; }, abstract = {The understanding of the involvement of mitochondrial oxidative phosphorylation (OXPHOS) in the aging process has often been biased by the different methodological approaches as well as the choice of the biological material utilized by the various groups. In the present paper, we have carried out a detailed analysis of several bioenergetic parameters and oxidative markers in brain and heart mitochondria from young (2 months) and old (28 months) rats. This analysis has revealed an age-related decrease in respiratory fluxes in brain but not in heart mitochondria. The age-related decrease in respiratory rate (-43%) by NAD-dependent substrates was associated with a consistent decline (-40%) of complex I activity in brain mitochondria. On the other hand, heart mitochondria showed an age-related decline of complex II activity. Both tissues showed, however, an age-associated accumulation of oxidative damage. We have then performed the same analysis on old (28 months) rats subjected to a long-term (16 months) diet containing the antioxidant N-acetylcysteine (NAC). The treated old rats showed a slight brain-specific improvement of mitochondrial energy production efficiency, mostly with NAD-dependent substrates, together with a decrease in carbonyl protein content and an increase in the amount of protein thiols of brain cytosolic fraction. A full recovery of complex II activity was detected in heart mitochondria from NAC-treated old rats. The present work documents the marked tissue specificity of the decline of bioenergetic functions in isolated mitochondria from aged rats and provides the first data on the effects of a long-term treatment with N-acetylcysteine.}, }
@article {pmid15721278, year = {2005}, author = {Zheng, X and Zhang, Y and Chen, YQ and Castranova, V and Shi, X and Chen, F}, title = {Inhibition of NF-kappaB stabilizes gadd45alpha mRNA.}, journal = {Biochemical and biophysical research communications}, volume = {329}, number = {1}, pages = {95-99}, doi = {10.1016/j.bbrc.2005.01.105}, pmid = {15721278}, issn = {0006-291X}, mesh = {Animals ; DNA Damage ; Dactinomycin/pharmacology ; Fibroblasts/metabolism ; Genes, Reporter ; Hydrogen Peroxide/pharmacology ; I-kappa B Kinase ; Immunoblotting ; Immunoprecipitation ; Intracellular Signaling Peptides and Proteins ; Luciferases/metabolism ; Mice ; Mice, Knockout ; NF-kappa B/*antagonists &amp; inhibitors/metabolism ; Phosphoproteins/biosynthesis/metabolism ; Phosphorylation ; Protein Binding ; Protein Serine-Threonine Kinases/genetics ; Protein Synthesis Inhibitors/pharmacology ; Proteins/*chemistry/metabolism ; RNA Processing, Post-Transcriptional ; RNA, Messenger/*metabolism ; RNA-Binding Proteins/biosynthesis/metabolism ; Reactive Oxygen Species ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Time Factors ; Transgenes ; Up-Regulation ; GADD45 Proteins ; Nucleolin ; }, abstract = {Growth arrest- and DNA damage-inducible protein alpha (gadd45alpha) is an important regulator for cell cycle, genomic stability, and cell apoptosis. In the present report, we demonstrated that NF-kappaB inhibition due to Ikkbeta deficiency enhanced the stability of gadd45alpha mNRA. Using embryo fibroblast cells derived from wild type (wt) or Ikkbeta gene knockout (Ikkbeta(-/-)) mice, reverse transcription-polymerase chain reaction revealed a three- to fourfold increase of gadd45alpha mRNA in Ikkbeta(-/-) cells compared with wt cells. The deficiency in Ikkbeta substantially decreased basal NF-kappaB activity and increased accumulation of reactive oxygen species (ROS). However, such deficiency had no effect on the basal expression or activity of Akt, FoxO3a, p53, and c-myc that regulate the transcription of gadd45alpha gene positively or negatively. Analysis of gadd45alpha mRNA stability showed a ROS-dependent increase in the half-life of gadd45alpha mRNA in Ikkbeta(-/-) cells. Immunoprecipitation experiments indicated an increased binding of a RNA stabilizing protein, nucleolin, to gadd45alpha mRNA in Ikkbeta(-/-) cells. The binding of nucleolin to gadd45alpha mRNA could be prevented by the antioxidant, N-acetyl-cysteine. Thus, these data are the first to suggest that inhibition of Ikkbeta-NF-kappaB signaling up-regulates the expression of gadd45alpha mNRA through a post-transcriptional, rather than a transcriptional, mechanism.}, }
@article {pmid15718492, year = {2005}, author = {Chiu, JJ and Chen, LJ and Chang, SF and Lee, PL and Lee, CI and Tsai, MC and Lee, DY and Hsieh, HP and Usami, S and Chien, S}, title = {Shear stress inhibits smooth muscle cell-induced inflammatory gene expression in endothelial cells: role of NF-kappaB.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {25}, number = {5}, pages = {963-969}, doi = {10.1161/01.ATV.0000159703.43374.19}, pmid = {15718492}, issn = {1524-4636}, support = {HL19454/HL/NHLBI NIH HHS/United States ; }, mesh = {Cell Adhesion/immunology ; Cell Communication/physiology ; Cells, Cultured ; Chemokine CCL2/genetics ; Chromatin/physiology ; Coculture Techniques ; Endothelium, Vascular/cytology/*physiology ; Gene Expression Regulation/immunology ; Humans ; Immunoprecipitation ; Intercellular Adhesion Molecule-1/genetics ; Monocytes/cytology ; Muscle, Smooth, Vascular/cytology/*physiology ; NF-kappa B p50 Subunit/genetics/*metabolism ; Oligonucleotide Array Sequence Analysis ; Promoter Regions, Genetic/physiology ; RNA, Messenger/analysis ; Stress, Mechanical ; Transcription Factor RelA/genetics/*metabolism ; Vasculitis/genetics/immunology/*physiopathology ; }, abstract = {OBJECTIVES: Vascular endothelial cells (ECs) are influenced by shear stress and neighboring smooth muscle cells (SMCs). We investigated the inflammation-relevant gene expression in EC/SMC cocultures under static condition and in response to shear stress.<br><br>MATERIALS AND METHODS: Under static condition, DNA microarrays and reverse-transcription polymerase chain reaction identified 23 inflammation-relevant genes in ECs whose expression was significantly affected by coculture with SMCs, with 18 upregulated and 5 downregulated. Application of shear stress (12 dynes/cm2) to the EC side of the coculture for 6 hours inhibited most of the proinflammatory gene expressions in ECs induced by coculture with SMCs. Inhibition of nuclear factor-kappaB (NF-kappaB) activation by the p65-antisense, lactacystin, and N-acetyl-cysteine blocked the coculture-induced EC expression of proinflammatory genes, indicating that the NF-kappaB binding sites in the promoters of these genes play a significant role in their expression as a result of coculture with SMCs. Chromatin immunoprecipitation assays demonstrated the in vivo regulation of NF-kappaB recruitment to selected target promoters. Shear stress inhibited the SMC coculture-induced NF-kappaB activation in ECs and monocytic THP-1 cell adhesion to ECs.<br><br>CONCLUSIONS: Our findings suggest that shear stress plays an inhibitory role in the proinflammatory gene expression in ECs located in close proximity to SMCs.}, }
@article {pmid15715193, year = {2005}, author = {Sadowska, AM and van Overveld, FJ and Górecka, D and Zdral, A and Filewska, M and Demkow, UA and Luyten, C and Saenen, E and Zielinski, J and De Backer, WA}, title = {The interrelationship between markers of inflammation and oxidative stress in chronic obstructive pulmonary disease: modulation by inhaled steroids and antioxidant.}, journal = {Respiratory medicine}, volume = {99}, number = {2}, pages = {241-249}, doi = {10.1016/j.rmed.2004.07.005}, pmid = {15715193}, issn = {0954-6111}, mesh = {Administration, Inhalation ; Aged ; Androstadienes/*administration &amp; dosage ; Anti-Inflammatory Agents/*administration &amp; dosage ; Antioxidants/*administration &amp; dosage ; Biomarkers/analysis ; Bronchitis/diagnosis ; Cross-Over Studies ; Female ; Fluticasone ; Forced Expiratory Volume/physiology ; Humans ; Interleukin-8/analysis ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Pulmonary Disease, Chronic Obstructive/*drug therapy ; Spirometry ; Sputum/chemistry ; Vital Capacity/physiology ; }, abstract = {BACKGROUND: Chronic obstructive pulmonary disease (COPD) is accompanied by both airway and systemic inflammation and by oxidative stress. This study aimed to characterise the relationship between oxidative stress and inflammatory components in induced sputum and blood.<br><br>MATERIAL &amp; METHODS: We studied blood and sputum samples from stable COPD patients (mean FEV1 60.5+/-7.5% predicted) at baseline (no treatment) and after 10 weeks treatment with either inhaled steroid, fluticasone propionate (FP) (1000 microg/d) or 10 weeks treatment with N-acetylcysteine (600mg/d) (NAC). We assessed the inflammatory markers (IL-8, ECP, sICAM-1, NE) in sputum and serum and we compared them with blood markers of oxidative stress (SOD, GPx, TEAC, albumin, vitamin E and A).<br><br>RESULTS: At baseline blood sICAM-1 correlated with IL-8 levels (P<0.01, r = 0.62) and negatively with GPx (P<0.01, r = -0.63) and with TEAC (P<0.05, r = -0.53). TEAC correlated positively with GPx (P<0.01, r = 0.70). Correlation between sICAM and IL-8 disappeared after NAC treatment. The correlation between sICAM and GPx disappeared after FP treatment. The correlation between TEAC and GPx was maintained after both NAC and FP.<br><br>CONCLUSIONS: The relationship between markers of inflammation, adhesion and antioxidant capacity is significantly modulated by treatment with N-acetylcysteine or inhaled corticosteroids.}, }
@article {pmid15710544, year = {2005}, author = {Arrais-Silva, WW and Collhone, MC and Ayres, DC and de Souza Souto, PC and Giorgio, S}, title = {Effects of hyperbaric oxygen on Leishmania amazonensis promastigotes and amastigotes.}, journal = {Parasitology international}, volume = {54}, number = {1}, pages = {1-7}, doi = {10.1016/j.parint.2004.07.002}, pmid = {15710544}, issn = {1383-5769}, mesh = {Animals ; Cells, Cultured ; Humans ; Hyperbaric Oxygenation ; Leishmania/*growth &amp; development/ultrastructure ; Leishmaniasis/parasitology ; Life Cycle Stages ; Macrophages, Peritoneal/parasitology ; Mice ; Mice, Inbred BALB C ; Oxygen/*pharmacology ; }, abstract = {In the present study, we evaluated the effects of hyperbaric oxygen (HBO) exposure in both Leishmania amazonensis life stages (promastigotes and amastigotes) and on macrophage cultures infected with the parasite. HBO treatment protocols, which can be tolerated by humans and animals, induced irreversible metabolic damage and affected parasite morphology, growth and ability to transform. The observation that the antioxidant N-acetylcysteine (NAC) prevents some of these deleterious effects indicated an involvement of oxidative stress during parasite HBO exposure. In addition, HBO exposed L. amazonensis-infected macrophage cultures showed reduction of the percentage of infected cells and of the number of intracellular parasites per cell. Thus, the demonstration that HBO, a therapy used in the management of different diseases, is toxic for both L. amazonensis life stages and can alter macrophage susceptibility to the infection encourages further studies of this therapy in animal models of Leishmania infection.}, }
@article {pmid15705376, year = {2005}, author = {Rizk, AY and Bedaiwy, MA and Al-Inany, HG}, title = {N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate-resistant patients with polycystic ovary syndrome.}, journal = {Fertility and sterility}, volume = {83}, number = {2}, pages = {367-370}, doi = {10.1016/j.fertnstert.2004.07.960}, pmid = {15705376}, issn = {0015-0282}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Clomiphene/*administration &amp; dosage ; Drug Resistance ; Drug Therapy, Combination ; Female ; Fertility Agents, Female/*administration &amp; dosage ; Humans ; Polycystic Ovary Syndrome/*drug therapy ; Pregnancy ; *Pregnancy Outcome ; }, abstract = {OBJECTIVE: To evaluate the effect of N-acetyl-cysteine (NAC), a mucolytic drug with insulin sensitizing properties, as an adjuvant therapy in subjects with polycystic ovary syndrome (PCOS) resistant to clomiphene citrate (CC).<br><br>DESIGN: Placebo-controlled, double-blind randomized trial.<br><br>SETTING: University-based hospital and private infertility practice.<br><br>PATIENT(S): One hundred fifty women diagnosed with CC-resistant PCOS, aged 18-39 years undergoing therapy for infertility were included.<br><br>INTERVENTION(S): The patients were assigned randomly to receive either NAC 1.2 g/d (group I) or placebo (group II) with CC 100 mg/d for 5 days starting at day 3 of the cycle.<br><br>MAIN OUTCOME MEASURE(S): Ovulation rate and pregnancy rate (PR).<br><br>RESULT(S): Combination of CC and NAC significantly increased both ovulation rate and PR in women with CC-resistant PCOS (49.3% vs. 1.3% and 21.3% vs. 0%, respectively). No cases of ovarian hyperstimulation syndrome (OHSS) were reported in the NAC group; two cases of miscarriage (12.5%) were reported.<br><br>CONCLUSION(S): The NAC as an adjuvant to CC was more effective than placebo for CC-resistant patients with PCOS. It is safe and well tolerated.}, }
@article {pmid15700780, year = {2005}, author = {Chen, J and Wanming, D and Zhang, D and Liu, Q and Kang, J}, title = {Water-soluble antioxidants improve the antioxidant and anticancer activity of low concentrations of curcumin in human leukemia cells.}, journal = {Die Pharmazie}, volume = {60}, number = {1}, pages = {57-61}, pmid = {15700780}, issn = {0031-7144}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/chemistry/*pharmacology ; Ascorbic Acid/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Curcumin/*pharmacology ; Glutathione/pharmacology ; HL-60 Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Indicators and Reagents ; Leukemia/*drug therapy/*metabolism ; Lipid Peroxidation/drug effects ; Malondialdehyde/metabolism ; Oxidants/pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {Curcumin (Cur) is a promising antioxidant and anticancer drug, but several recent studies indicate that Cur exerts its anticancer activity through promoting reactive oxygen species (ROS) generation. In the present study, concentration-dependent regulation of Cur on cell proliferation, viability and ROS generation, and effect of water-soluble antioxidants ascorbic acid (ASA), N-acetyl-cysteine (NAC) and reduced glutathione (GSH) on the antioxidant and anticancer activity of Cur were investigated in human myeloid leukemia cells (HL-60 cells). We found that although Cur concentration- and time-dependently decreased the proliferation and viability of cells, its effect on ROS generation (as indicated by the level of malondialdehyde, MDA) varied with its concentrations. I.e., low concentrations of Cur diminished the ROS generation, while high Cur promoted it. Combined with the opposite effect of 50 microM H2O2 on low or high Cur-induced MDA alteration, cell proliferation arrest and cell death, these results proved that low Cur exerted its anticancer activity through diminishing ROS generation in HL-60 cells, while high Cur through promoting ROS generation. Further studies showed that all water-soluble antioxidants ASA, NAC and GSH significantly enhanced both the antioxidant and the anticancer activity of low Cur. Considering that the extra accumulation of ROS is harmful to normal cells, the data presented here indicate that instead of using high doses, combining low doses of Cur with water-soluble antioxidants is a better strategy for us to improve the anticancer activity of Cur.}, }
@article {pmid15699178, year = {2005}, author = {Ohtani, T and Nakagawa, S and Kurosawa, M and Mizuashi, M and Ozawa, M and Aiba, S}, title = {Cellular basis of the role of diesel exhaust particles in inducing Th2-dominant response.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {174}, number = {4}, pages = {2412-2419}, doi = {10.4049/jimmunol.174.4.2412}, pmid = {15699178}, issn = {0022-1767}, mesh = {Acetylcysteine/pharmacology ; Adult ; Air Pollutants/antagonists &amp; inhibitors/*toxicity ; Antioxidants/pharmacology ; Catechin/*analogs &amp; derivatives/pharmacology ; Cells, Cultured ; Cytokines/biosynthesis/genetics ; Dendritic Cells/drug effects/immunology/metabolism ; Female ; Humans ; Immunosuppressive Agents/antagonists &amp; inhibitors/*toxicity ; Inflammation Mediators/antagonists &amp; inhibitors/toxicity ; Interferon-gamma/antagonists &amp; inhibitors/biosynthesis/genetics ; Interleukin-10/antagonists &amp; inhibitors/biosynthesis/genetics ; Lymphocyte Activation/*drug effects/immunology ; Male ; Monocytes/drug effects/immunology/metabolism ; Oxidative Stress/drug effects/immunology ; RNA, Messenger/biosynthesis ; Th2 Cells/*drug effects/*immunology/metabolism ; Vehicle Emissions/*toxicity ; }, abstract = {There is growing evidence that diesel exhaust particles (DEP) can induce allergic diseases with increased IgE production and preferential activation of Th2 cells. To clarify the cellular basis of the role of DEP in the induction of Th2-dominant responses, we examined the effects of DEP on the cytokine production by T cells stimulated with anti-CD3/CD28 Ab and on that by monocyte-derived dendritic cells (MoDCs) stimulated with CD40L and/or IFN-gamma. We examined IFN-gamma, IL-4, IL-5, IL-8, and IL-10 produced by T cells and TNF-alpha, IL-1beta, IL-10, and IL-12 produced by MoDCs using real-time PCR analysis or by ELISA. To highlight the effects of DEP, we compared the effects of DEP with those of dexamethasone (DEX) and cyclosporin A (CyA). DEP significantly suppressed IFN-gamma mRNA expression and protein production, while it did not affect IL-4 or IL-5 mRNA expression or protein production. The suppressive effect on IFN-gamma mRNA expression was more potent than that of DEX and comparable at 30 mug/ml with 10(-7) M CyA. The suppressive effect on IFN-gamma production was also more potent than that of either DEX or CyA. DEP suppressed IL-12p40 and IL-12p35 mRNA expression and IL-12p40 and IL-12p70 production by MoDCs, while it augmented IL-1beta mRNA expression. Finally, by using a thiol antioxidant, N-acetyl cysteine, we found that the suppression of IFN-gamma production by DEP-treated T cells was mediated by oxidative stress. These data revealed a unique characteristic of DEP, namely that they induce a Th2 cytokine milieu in both T cells and dendritic cells.}, }
@article {pmid15698947, year = {2004}, author = {Clifton, IJ and Morton, AM and Ambrose, NS and Peckham, DG and Conway, SP}, title = {Treatment of resistant distal intestinal obstruction syndrome with a modified antegrade continence enema procedure.}, journal = {Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society}, volume = {3}, number = {4}, pages = {273-275}, doi = {10.1016/j.jcf.2004.06.008}, pmid = {15698947}, issn = {1569-1993}, mesh = {Adolescent ; Cecum ; Chronic Disease ; Colon, Ascending ; Cystic Fibrosis/complications ; Enema/*methods ; Female ; Humans ; Ileum ; Intestinal Obstruction/complications/*therapy ; Syndrome ; Treatment Outcome ; }, abstract = {We report a case of a patient with CF who had a long history of recurrent distal intestinal obstruction syndrome. She had been treated with conventional treatment including gastrografin, n-acetyl cysteine, Klean prep and Picolax. She underwent a modified antegrade continence enema procedure. She currently irrigates her conduit every 2-3 days. She has had no further symptoms of distal intestinal obstruction syndrome.}, }
@article {pmid15698432, year = {2005}, author = {Pat, B and Yang, T and Kong, C and Watters, D and Johnson, DW and Gobe, G}, title = {Activation of ERK in renal fibrosis after unilateral ureteral obstruction: modulation by antioxidants.}, journal = {Kidney international}, volume = {67}, number = {3}, pages = {931-943}, doi = {10.1111/j.1523-1755.2005.00157.x}, pmid = {15698432}, issn = {0085-2538}, mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis ; Cell Differentiation ; Cell Proliferation ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/*physiology ; Fibrosis ; Kidney/*pathology/physiopathology ; Male ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Ureteral Obstruction/enzymology/*pathology ; }, abstract = {BACKGROUND: A recent in vitro model of oxidative stress-induced renal fibrosis demonstrated that activated or phosphorylated extracellular signal-regulated protein kinase (pERK) played a role in apoptosis of renal fibroblasts, but not tubular epithelium where it promoted cell growth and survival. The present study utilized an in vivo model of renal fibrosis after unilateral ureteral obstruction (UUO) to examine the relationship between pERK, apoptosis, proliferation, and differentiation in renal fibroblast and tubular epithelial cells, in comparison with the in vitro results.<br><br>METHODS: UUO was induced in rats for 0 (controls, untreated), 6, and 24 hours, 2, 4, and 7 days (N= 4), and tissue analyzed for fibrotic characteristics using microscopy and special stains, Western immunoblots and reverse transcription-polymerase chain reaction (RT-PCR). Controls and UUO animals were also treated with vitamin E, N-acetylcysteine (NAC), or fluvastatin to assess any antioxidant effect on attenuation of fibrosis and pERK expression.<br><br>RESULTS: Azan stain and alpha-smooth muscle actin (alpha-SMA), collagen III, and fibronectin expression confirmed development of UUO-induced fibrosis. Oxidative stress markers heme oxygenase-1 (HO-1) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) confirmed oxidative stress at all UUO time points. Tubular epithelial and interstitial mitosis and apoptosis were significantly increased over controls at 2 to 7 days after UUO (P < 0.01). The pERK/ERK ratio increased significantly at 1 to 7 days of UUO in comparison with controls (three- to fivefold, P < 0.05). There was a significant spatiotemporal correlation between pERK and tubular epithelial proliferation (P < 0.001). pERK occasionally colocalized with apoptotic cells (dual labeling) in the interstitium but not in the tubular epithelium. Fluvastatin was the only treatment that attenuated fibrosis (decreased alpha-SMA, fibronectin, tubular epithelial apoptosis) and it also significantly decreased expression of 8-OHdG at 2 and 7 days (P < 0.05). It was associated with decreased pERK at 7 days, compared with UUO alone (P < 0.05).<br><br>CONCLUSION: Promotion of tubular epithelial proliferation and survival, and interstitial cell apoptosis, may minimize renal fibrosis after UUO. In the present study, both were linked spatially and temporally with increased pERK expression. Fluvastatin treatment attenuated UUO-induced fibrosis via an antioxidant and pERK-related mechanism.}, }
@article {pmid15683734, year = {2005}, author = {Akiyama, N and Shimma, N and Takashiro, Y and Hatori, Y and Hirabayashi, T and Horie, S and Saito, T and Murayama, T}, title = {Decrease in cytosolic phospholipase A2alpha mRNA levels by reactive oxygen species via MAP kinase pathways in PC12 cells: effects of dopaminergic neurotoxins.}, journal = {Cellular signalling}, volume = {17}, number = {5}, pages = {597-604}, doi = {10.1016/j.cellsig.2004.10.005}, pmid = {15683734}, issn = {0898-6568}, mesh = {1-Methyl-4-phenylpyridinium/*pharmacology ; Animals ; Down-Regulation ; Gene Expression Regulation ; Group IV Phospholipases A2 ; Hydrogen Peroxide/pharmacology ; *MAP Kinase Signaling System/drug effects ; PC12 Cells ; Phospholipases A/genetics/*metabolism ; Phospholipases A2 ; Protein Kinase Inhibitors/pharmacology ; RNA, Messenger/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Tetrahydroisoquinolines/*pharmacology ; }, abstract = {Excess production of reactive oxygen species (ROS), including H2O2, leads to neuronal death in pathological conditions. Although ROS stimulates alpha-type cytosolic phospholipase A2 (cPLA2alpha) activity, their role in cPLA2alpha expression has not been elucidated. We investigated the effect of ROS on cPLA2alpha mRNA levels and signaling pathways in rat pheochromocytoma PC12 cells. Treatment with H2O2 and xanthine-xanthine oxidase (X/XO) for 4 h decreased cPLA2alpha mRNA levels without changing the mRNA levels of other tested proteins. H2O2 and X/XO caused cell toxicity not after 4 h but 24 h after their addition. The H2O2-induced decrease in cPLA2alpha mRNA levels was inhibited in cells treated with N-acetyl-cysteine and selective inhibitors of mitogen-activated protein kinase (MAPK) pathways (extracellular signal-regulated kinase and p38 MAPK). Treatment with dopaminergic neurotoxins, including 1,2,3,4-tetrahydroisoquinoline (TIQ)-inducing ROS formation, decreased cPLA2alpha mRNA levels. These findings suggest that ROS decreases cPLA2alpha mRNA levels via MAPK pathways in PC12 cells.}, }
@article {pmid15680482, year = {2005}, author = {Saito, T and Itoh, H and Yamashita, J and Doi, K and Chun, TH and Tanaka, T and Inoue, M and Masatsugu, K and Fukunaga, Y and Sawada, N and Sakaguchi, S and Arai, H and Tojo, K and Tajima, N and Hosoya, T and Nakao, K}, title = {Angiotensin II suppresses growth arrest specific homeobox (Gax) expression via redox-sensitive mitogen-activated protein kinase (MAPK).}, journal = {Regulatory peptides}, volume = {127}, number = {1-3}, pages = {159-167}, doi = {10.1016/j.regpep.2004.11.006}, pmid = {15680482}, issn = {0167-0115}, mesh = {Angiotensin II/*metabolism ; Animals ; Cells, Cultured ; Enzyme Activation ; *Gene Expression Regulation ; Homeodomain Proteins/genetics/*metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Muscle Proteins/genetics/*metabolism ; Muscle, Smooth, Vascular/cytology ; Myocytes, Smooth Muscle/cytology/metabolism ; Oxidants/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Phosphorylation ; RNA, Messenger/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {Oxidative stress is known to be involved in growth control of vascular smooth muscle cells (VSMCs). We and others have demonstrated that angiotensin II (Ang II) has an important role in vascular remodeling. Several reports suggested that VSMC growth induced by Ang II was elicited by oxidative stress. Gax, growth arrest-specific homeobox is a homeobox gene expressed in the cardiovascular system. Over expression of Gax is demonstrated to inhibit VSMC growth. We previously reported that Ang II down-regulated Gax expression. To address the regulatory mechanism of Gax, we investigated the significance of oxidative stress in Ang II-induced suppression of Gax expression. We further examined the involvement of mitogen-activated protein kinases (MAPKs), which is crucial for cell growth and has shown to be activated by oxidative stress, on the regulation of Gax expression by Ang II. Ang II markedly augmented intracellular H2O2 production which was decreased by pretreatment with N-acetylcystein (NAC), an anti-oxidant. Ang II and H2O2 decreased Gax expression dose-dependently and these effects were blocked by administration of both NAC and pyrrolidine dithiocarbamate (PDTC), another anti-oxidant. Ang II and H2O2 induced marked activation of extracellular signal-responsive kinase1/2 (ERK1/2), which was blocked by NAC. Ang II and H2O2 also activated p38MAPK, and they were blocked by pre-treatment with NAC. However, the level of activated p38MAPK was quite low in comparison with ERK1/2. Ang II- or H2O2 -induced Gax down-regulation was significantly inhibited by PD98059, an ERK1/2 inhibitor but not SB203580, a p38MAPK inhibitor. The present results demonstrated the significance of regulation of Gax expression by redox-sensitive ERK1/2 activation.}, }
@article {pmid15680334, year = {2005}, author = {Yi, JH and Hazell, AS}, title = {N-acetylcysteine attenuates early induction of heme oxygenase-1 following traumatic brain injury.}, journal = {Brain research}, volume = {1033}, number = {1}, pages = {13-19}, doi = {10.1016/j.brainres.2004.10.055}, pmid = {15680334}, issn = {0006-8993}, mesh = {Acetylcysteine/*administration &amp; dosage/therapeutic use ; Animals ; Blotting, Western/methods ; Brain Injuries/*drug therapy/*enzymology ; Disease Models, Animal ; Enzyme Induction/drug effects ; Heat-Shock Proteins/*metabolism ; Heme Oxygenase (Decyclizing) ; Immunohistochemistry/methods ; Male ; Oxygenases/*metabolism ; Percussion/adverse effects ; Rats ; Rats, Sprague-Dawley ; Statistics, Nonparametric ; Tetrazolium Salts ; Time Factors ; }, abstract = {Traumatic brain injury (TBI) results in a cascade of events that includes the production of reactive oxygen species. Heme oxygenase-1 (HO-1) is induced in glial cells following head trauma, suggestive of oxidative stress. We have studied the temporal and spatial effects of the antioxidant N-acetylcysteine (NAC) on HO-1 levels following lateral fluid-percussion injury by immunoblotting and immunohistochemistry. In the injured cerebral cortex, maximal HO-1 induction was seen 6 h post-TBI and was maintained for up to 24 h following the insult, while the ipsilateral hippocampus and thalamus showed marked induction at 24 h postinjury. In all three brain regions, little or no HO-1 immunoreactivity was observed on the contralateral side. Astrocytes exhibited positive immunoreactivity for HO-1 in the injured cerebral cortex, hippocampus, and thalamus, while some neurons and microglia were also immunoreactive in the injured cortex. The administration of NAC 5 min following TBI resulted in a marked reduction in this widespread induction of HO-1, concomitant with a decrease in the volume of injury in all three brain regions. Together, these findings indicate that HO-1 induction is related to both oxidative and injury characteristics of the affected tissue, suggesting that protein expression of this gene is a credible marker of oxidative damage in this model of TBI.}, }
@article {pmid15680252, year = {2005}, author = {Lee, YJ and Shukla, SD}, title = {Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes.}, journal = {European journal of pharmacology}, volume = {508}, number = {1-3}, pages = {31-45}, doi = {10.1016/j.ejphar.2004.12.006}, pmid = {15680252}, issn = {0014-2999}, support = {AA11962/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetaldehyde/*pharmacology ; Acetylcysteine/pharmacology ; Animals ; Anthracenes/pharmacology ; Apoptosis/*drug effects/physiology ; Blotting, Western ; Butadienes/pharmacology ; Buthionine Sulfoximine/pharmacology ; Caspase 3 ; Caspases/metabolism ; Cell Nucleus/drug effects/metabolism ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Ethanol/*pharmacology ; Genistein/pharmacology ; Hepatocytes/cytology/*drug effects/metabolism ; Hydrogen Peroxide/pharmacology ; Indoles/pharmacology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Male ; Maleates/pharmacology ; Maleimides/pharmacology ; Microscopy, Fluorescence ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase 3/antagonists &amp; inhibitors/metabolism ; Nitriles/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Time Factors ; }, abstract = {We have examined the significance of the activation of c-Jun N-terminal kinase (JNK) and p42/44 mitogen-activated protein kinase (MAPK) by ethanol and acetaldehyde in rat hepatocyte apoptosis. Acetaldehyde induced rapid and transient (15 min) activation of p42/44 MAPK followed by activation of JNK, which remained above control up to 1 h. Ethanol activated JNK for up to 4 h. Both ethanol and acetaldehyde caused apoptosis as determined by DNA fragmentation, caspase-3 activation and 2'[4-ethoxyphenyl]-5-[4-methyl-piperazinyl]-2,5'-bi-1H-benzimidazole (Hoechst 33342) staining. Ethanol-induced apoptosis was blocked by JNK inhibitor 1,9-pyrazoloanthrone (SP600125), indicating that JNK activation is pro-apoptotic. In contrast, acetaldehyde-induced apoptosis was not suppressed by this inhibitor. In fact, SP600125 potentiated acetaldehyde-induced apoptosis, suggesting that JNK activation is anti-apoptotic. Inhibition of p42/44 MAPK by MAPK kinase (MKK1) inhibitor, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), potentiated apoptosis by acetaldehyde or ethanol, suggesting anti-apoptotic role of p42/44 MAPK. The activation of JNK by ethanol or acetaldehyde was insensitive to the genistein (tyrosine kinase inhibitor), GF109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide, protein kinase C [PKC] inhibitor) and N-acetylcysteine (N-AC) (antioxidant), whereas p42/44 MAPK activation by acetaldehyde was inhibited by genistein and GF109203X. Furthermore, p42/44 MAPK activation is not necessary for the JNK activation. In summary, transient activation of JNK by acetaldehyde is anti-apoptotic, whereas sustained activation of JNK by ethanol is pro-apoptotic. The activation of p42/44 MAPK appears to be anti-apoptotic for both ethanol and acetaldehyde. Thus, JNK activation by ethanol and acetaldehyde can be both pro- and anti-apoptotic in hepatocytes.}, }
@article {pmid15673194, year = {2004}, author = {Chae, HJ and Park, JM and Lee, GY and Park, HR and Chae, SW and Jeong, GS and Kim, HM and Kim, SB and Yoo, SK and Kim, HR}, title = {Yuk-Hap-Tang induces apoptosis by intervening mn-SOD in human cervical carcinoma HeLa cells.}, journal = {The American journal of Chinese medicine}, volume = {32}, number = {6}, pages = {883-895}, doi = {10.1142/S0192415X04002491}, pmid = {15673194}, issn = {0192-415X}, mesh = {Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Survival/drug effects ; Free Radical Scavengers/metabolism ; HeLa Cells ; Humans ; Kinetics ; Korea ; *Medicine, East Asian Traditional ; Phytotherapy ; Plant Extracts/*pharmacology ; Superoxide Dismutase/drug effects/*genetics ; }, abstract = {Yuk-Hap-Tang (YHT) induces cell death in human cervical carcinoma HeLa cells. Caspase-3, -6 and -9 were markedly activated in HeLa cells treated with YHT. The preferred substrate for caspase-3 cysteine protease, PARP, was cleaved to its 85-kDa cleavage product. YHT increased the amount of the anti-apoptotic protein, Bcl-2, and the pro-apoptotic protein, Bax. Although p53 has been reported to accumulate in cancer cells in response to anticancer agents, the p53 expression level was not changed in HeLa cells treated with YHT. Manganese (Mn)-TBAP, a mitochondria-specific SOD mimetic agent and NAC/GSH (N-acetyl cysteine/ reduced glutathione) reduced the YHT-induced cytotoxicity and decreased the number of the YHT-induced apoptotic cells. Furthermore, YHT reduced the expression of Mn-SOD protein and its activity in HeLa cells. The data demonstrate that YHT induces the apoptosis of human cervical carcinoma HeLa cells by intervening Mn-SOD.}, }
@article {pmid15670485, year = {2005}, author = {Shi, XF and Guo, SH and Wu, G and Mao, Q and Yu, YS and Wang, JK and Zhang, L and Wang, ZY and Zhang, XQ and Zhang, QH and Zhao, YR and Zeng, WQ}, title = {[A multi-center clinical study of N-acetylcysteine on chronic hepatitis B].}, journal = {Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology}, volume = {13}, number = {1}, pages = {20-23}, pmid = {15670485}, issn = {1007-3418}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Antiviral Agents/*therapeutic use ; Double-Blind Method ; Female ; Hepatitis B, Chronic/*drug therapy ; Humans ; Male ; Middle Aged ; }, abstract = {OBJECTIVES: To evaluate the effectiveness and safety of N-acetylcysteine (NAC) in treating chronic hepatitis B patients.<br><br>METHODS: 144 patients with chronic hepatitis B (total bilirubin, TBil>170 mmol/L) from several centers were chosen for a randomized and double blind clinical trial. The patients were divided into a NAC group and a placebo group and all of them were treated with an injection containing the same standardized therapeutic drugs. A daily dose of 8 microgram NAC was added to the injection of the NAC group. The trial lasted 45 days. Hepatic function and other biochemistry parameters were checked at the experimental day 0 and days 15, 30, 45.<br><br>RESULTS: Each group consisted of 72 patients of similar demology and disease characteristics. During the trial, 28 cases of the 144 patients dropped out. In the NAC group, at day 0 and day 30, the TBil were 401.7 vs. 149.2 and 160.1+/-160.6. In the placebo group, the TBil on the corresponding days were 384.1+/-134.0 and 216.3+/-199.9. Its decrease in the NAC group was 62% and 42% in the placebo group. At day 0 and day 45 of treatment, the effective PTa increase rate was 72% in the NAC group and 54% in the placebo group. The total effective rate (TBil + PTa) was 90% in the NAC group and 69% in the placebo group. The parameters of the two groups showed a remarkable difference. The rate of side effects was 14% in the NAC and 5% in the placebo groups.<br><br>CONCLUSION: NAC can decrease the level of serum TBil, increase the PTa and reduce the time of hospitalization. NAC showed no serious adverse effects during the period of our treatment. We find that NCA is effective and secure in treating chronic hepatitis B patients.}, }
@article {pmid15669759, year = {2004}, author = {Lin, CC and Yin, MC and Hsu, CC and Lin, MP}, title = {Effect of five cysteine-containing compounds on three lipogenic enzymes in Balb/cA mice consuming a high saturated fat diet.}, journal = {Lipids}, volume = {39}, number = {9}, pages = {843-848}, pmid = {15669759}, issn = {0024-4201}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blood Glucose/metabolism ; Cysteine/*analogs &amp; derivatives/*pharmacology ; Diet ; Dietary Fats/pharmacology ; Fatty Acid Synthases/*drug effects/metabolism ; Fatty Acids/pharmacology ; Glucosephosphate Dehydrogenase/*drug effects/metabolism ; Glutathione Peroxidase/drug effects/metabolism ; Hyperlipidemias/drug therapy/metabolism ; Insulin/blood ; Kidney/drug effects/enzymology ; Liver/drug effects/metabolism ; Malate Dehydrogenase/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Myocardium/enzymology ; Uric Acid/blood ; }, abstract = {The in vivo effects of N-acetyl cysteine (NAC), S-allyl cysteine, S-ethyl cysteine (SEC), S-methyl cysteine (SMC), and S-propyl cysteine (SPC) against hyperlipidemia development and oxidation stress in Balb/cA mice consuming a high saturated fat diet were examined. The influence of these agents on plasma levels of glucose, insulin, uric acid, TG, cholesterol, and the activity of three lipogenic enzymes--glucose-6-phosphate dehydrogenase, malic enzyme, and FA synthase--was determined. All mice consumed the coconut oil-basd, high saturated fat diet, water, and cysteine or one of the five cysteine-containing compounds for 4 wk. The diet with 18% saturated fat significantly elevated the activity of three lipogenic enzymes and significantly increased TG and cholesterol biosynthesis in plasma and liver (P < 0.05). When compared with the water and cysteine groups, the treatments from five cysteine-containing agents significantly reduced high saturated fat diet-increased malic enzyme and FA synthase activities, and significantly lowered TG levels in plasma and liver (P< 0.05); however, only NAC, SAC, and SMC treatments significantly reduced cholesterol levels in plasma and liver (P < 0.05). The five cysteine-containing agents significantly restored high saturated fat diet-decreased glutathione peroxidase (GPX) activity in liver (P< 0.05); however, only SMC and SPC significantly restored GPX activity in heart and kidney (P< 0.05). These agents also significantly improved high saturated fat diet-related hyperglycemia, hyperuricemia, and oxidation stress (P < 0.05). These data support the hypothesis that these compounds are potential multiply-protective agents for hyperlipidemia prevention or therapy.}, }
@article {pmid15664999, year = {2005}, author = {Harmon, JS and Stein, R and Robertson, RP}, title = {Oxidative stress-mediated, post-translational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells.}, journal = {The Journal of biological chemistry}, volume = {280}, number = {12}, pages = {11107-11113}, doi = {10.1074/jbc.M410345200}, pmid = {15664999}, issn = {0021-9258}, support = {R01 DK 38325/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line, Tumor ; Glucose/*toxicity ; Homeodomain Proteins/physiology ; Islets of Langerhans/*metabolism ; Maf Transcription Factors, Large ; Mice ; *Oxidative Stress ; Promoter Regions, Genetic ; RNA, Messenger/analysis ; Trans-Activators/analysis/genetics/*metabolism/physiology ; }, abstract = {Glucose toxicity in pancreatic islet beta cells causes loss of insulin gene expression, content, and secretion due to loss of binding of transcription factors, most notably PDX-1 and RIPE-3b1 activator, to the promoter region of the insulin gene. Recently, RIPE-3b1 activator was cloned and identified as the mammalian homologue of avian MafA/Maf-L (MafA). This enabled us to carry out more extensive studies of the role of MafA in glucotoxicity than were hitherto possible. Northern analysis of glucotoxic HIT-T15 cells revealed normal amounts of MafA mRNA, but Western analysis demonstrated a 97 +/- 1% reduction in MafA protein (p < 0.0001). The proteasome is a likely site for MafA degradation as lactacystin, an irreversible proteasome inhibitor, caused an accumulation of MafA protein. Antioxidants have previously been shown to prevent the adverse effects of glucose toxicity on beta cell function both in vivo and in vitro. In the current study, chronic culturing of HIT-T15 cells with the antioxidant N-acetylcysteine (NAC) prevented loss of MafA protein (late passage = 18.9 +/- 10.4% of early passage, p < 0.001; late passage with NAC = 68.7 +/- 19.7% of early passage, p = not significant) and loss of DNA binding (late passage = 63.7 +/- 9% of early passage, p < 0.02; late passage with NAC = 116 +/- 10% of early passage, p = not significant). Additionally, transient transfection of PDX-1 or MafA cDNA into glucotoxic cells increased PDX-1 and MafA protein levels and individually increased insulin promoter activity (untreated = 34%, PDX-1 = 70%, MafA = 78%; percentage of activity of early passage cells), whereas the combined transfection of MafA and PDX-1 completely restored insulin promoter activity. This recovery of promoter activity following transient transfection had no effect on endogenous insulin mRNA. However, adenoviral infection of MafA and PDX-1 significantly increased endogenous insulin mRNA levels by 93% (121 +/- 9 versus 233 +/- 18 density light units; n = 5, p < 0.001). We conclude that the absence of MafA protein from beta cells via chronic oxidative stress contributes importantly to the loss of endogenous insulin gene expression as glucose toxicity develops.}, }
@article {pmid15659115, year = {2005}, author = {Chen, XC and Zhou, YC and Chen, Y and Zhu, YG and Fang, F and Chen, LM}, title = {Ginsenoside Rg1 reduces MPTP-induced substantia nigra neuron loss by suppressing oxidative stress.}, journal = {Acta pharmacologica Sinica}, volume = {26}, number = {1}, pages = {56-62}, doi = {10.1111/j.1745-7254.2005.00019.x}, pmid = {15659115}, issn = {1671-4083}, mesh = {Animals ; *Apoptosis ; Ginsenosides/isolation &amp; purification/*pharmacology ; Glutathione/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; *MPTP Poisoning/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/pathology ; Neuroprotective Agents/pharmacology ; Oxidative Stress/*drug effects ; Panax/chemistry ; Plants, Medicinal/chemistry ; *Substantia Nigra/pathology ; Superoxide Dismutase/metabolism ; }, abstract = {AIM: To investigate the effect of ginsenoside Rg1, an effective ingredient from ginsenoside, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced substantia nigra neuron lesion.<br><br>METHODS: C57-BL mice were given MPTP to prepare Parkinson disease mice model. Different doses of Rg1 (5, 10, and 20 mg.kg(-1).d(-1)) or N-acetylcystein (NAC) (300 mg.kg(-1).d(-1)) were given 3 d prior to MPTP in the pretreatment groups. Glutathione (GSH) level and total superoxide dismutase (T-SOD) activity in substantia nigra were determined by spectrophotometry. Nissl staining, tyrosine hydroxylase immunostaining, and TUNEL labeling were used to observe the damage and apoptosis of nigral neurons. Western blot analysis was used to detect the phospho-JNK and phospho-c-Jun levels in midbrain homogenates.<br><br>RESULTS: Pretreatments of C57-BL mice with different doses of Rg1 or NAC were found to protect against MPTP-induced substantia nigra neurons loss. Rg1 or NAC prevented GSH reduction and T-SOD activation in substantia nigra, and attenuated the phosphorylations of JNK and c-Jun following MPTP treatment.<br><br>CONCLUSION: The antioxidant property of Rg1 along with the blocking of JNK signaling cascade might contribute to the neuroprotective effect of ginsenoside Rg1 against MPTP.}, }
@article {pmid15657783, year = {2005}, author = {Soldini, D and Zwahlen, H and Gabutti, L and Marzo, A and Marone, C}, title = {Pharmacokinetics of N-acetylcysteine following repeated intravenous infusion in haemodialysed patients.}, journal = {European journal of clinical pharmacology}, volume = {60}, number = {12}, pages = {859-864}, pmid = {15657783}, issn = {0031-6970}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacokinetics ; Aged ; Antioxidants/administration &amp; dosage/*pharmacokinetics ; Area Under Curve ; Blood Urea Nitrogen ; Cysteine/blood ; Drug Administration Schedule ; Expectorants/administration &amp; dosage/*pharmacokinetics ; Female ; Glutathione/blood ; Humans ; Infusions, Intravenous ; Kidney Failure, Chronic/metabolism/*therapy ; Male ; Metabolic Clearance Rate ; Middle Aged ; Pilot Projects ; Renal Dialysis ; }, abstract = {OBJECTIVE: N-acetylcysteine (NAC) is a mucolytic agent with anti-oxidant properties. It might have potential positive effects in renal patients and, therefore, its pharmacokinetics and safety in haemodialysis was investigated.<br><br>METHODS: Twelve dialysis patients received 2 g NAC (10 ml NAC 20% solution i.v.) mixed with 500 ml saline during the first 3 h of the session for six dialysis sessions. A bolus of heparin was injected intravenously as LWH-heparin. In six patients, one session was repeated with NAC mixed with heparin and infused through the heparin pump.<br><br>RESULTS: Baseline NAC was on average 454 ng ml(-1); its concentration increased to 9,253 ng ml(-1) at the second infusion and attained a steady state between 14,000 ng ml(-1) and 17,000 ng ml(-1) at the fourth dose. We observed a C (max) of 53,458 ng ml(-1) with a t (max) of 3.0 h. Plasma clearance was 1.25 l h(-1) and dialytic clearance 5.52 l h(-1). No side effects were observed.<br><br>CONCLUSION: In the case of repeated doses, the NAC pre-dose concentration after repeated infusion of 2 g of the drug during the first 3 h of a dialysis session reached the steady state at the fourth infusion, without further accumulation. The dialytic clearance is effective, the total body clearance being reduced to 1.25 l h(-1). In dialysis patients, 2 g NAC given intravenously over 3 h is a safe dosage, with no short-term side effects.}, }
@article {pmid15654955, year = {2005}, author = {Chen, Z and Seo, JY and Kim, YK and Lee, SR and Kim, KH and Cho, KH and Eun, HC and Chung, JH}, title = {Heat modulation of tropoelastin, fibrillin-1, and matrix metalloproteinase-12 in human skin in vivo.}, journal = {The Journal of investigative dermatology}, volume = {124}, number = {1}, pages = {70-78}, doi = {10.1111/j.0022-202X.2004.23550.x}, pmid = {15654955}, issn = {0022-202X}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antibodies ; Antioxidants/pharmacology ; Dermis/*physiology ; Enzyme Inhibitors/pharmacology ; Epidermis/*physiology ; Fibrillin-1 ; Fibrillins ; Gene Expression/drug effects/physiology ; Genistein/pharmacology ; *Hot Temperature ; Humans ; Male ; Matrix Metalloproteinase 12 ; Metalloendopeptidases/*genetics/metabolism ; Microfilament Proteins/*genetics/immunology/metabolism ; RNA, Messenger/analysis ; Tropoelastin/*genetics/immunology/metabolism ; }, abstract = {Photoaged skin contains elastotic materials in the upper reticular dermis. This phenomenon is commonly known as solar elastosis. In this study, we investigated the effects of heat on the expression of tropoelastin and fibrillin-1, two main components of elastic fibers, and on matrix metalloproteinase (MMP)-12, the most active MMP against elastin, in human skin in vivo. Heat was found to increase tropoelastin mRNA and protein expression in the epidermis and in the dermis. Fibrillin-1 mRNA and protein expression were increased by heat in the epidermis, but were decreased in the dermis. We found that pre-treatment of skin with N-acetyl cysteine or genistein for 24 h prior to heat treatment inhibited the heat-induced expression of tropoelastin, but not of fibrillin-1. These data indicate that reactive oxygen species may play a role in tropoelastin expression by heat, but not in fibrillin-1 expression. We also found that heat treatment increases MMP-12 mRNA and protein expression in human skin. Our results suggest that the abnormal production of tropoelastin and fibrillin by heat in human skin and that their degradation by various MMP, such as MMP-12, may contribute to the accumulation of elastotic material in photoaged skin.}, }
@article {pmid15652379, year = {2005}, author = {Guayerbas, N and Puerto, M and Hernanz, A and Miquel, J and De la Fuente, M}, title = {Thiolic antioxidant supplementation of the diet reverses age-related behavioural dysfunction in prematurely ageing mice.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {80}, number = {1}, pages = {45-51}, doi = {10.1016/j.pbb.2004.10.015}, pmid = {15652379}, issn = {0091-3057}, mesh = {Aging/*drug effects/physiology/psychology ; Aging, Premature/*drug therapy/physiopathology/psychology ; Animals ; Antioxidants/*administration &amp; dosage ; *Dietary Supplements ; Female ; Male ; Maze Learning/drug effects/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred ICR ; Sulfhydryl Compounds/*administration &amp; dosage ; }, abstract = {We have studied in a model of premature ageing in mice based on their impaired behavioural response in a simple T-maze test the effect of the ingestion of thioproline (TP) plus N-acetylcysteine (NAC) (0.1% w/w of each antioxidant) by female and male mice of Swiss and BALB/c strains on performance in two behaviour tests. The antioxidant treatment (4 weeks in two different periods of life, i.e., adult and old age) protected all animals against early-age-associated behavioural impairment, but this improvement was more evident in the prematurely ageing mice (PAM) in comparison to the control group or non-prematurely ageing mice (NPAM). An improvement of the exploratory activity and neuromuscular coordination after the thiolic antioxidant treatment was found in the PAM, bringing the behavioural parameters to the NPAM levels. These effects could be due to the glutathione precursor role of NAC and TP that replenish the intracellular reduced glutathione (GSH) levels despite advancing age. In conclusion, diet supplementation with thiolic compounds appears to be an effective therapy for protection against early behavioural decline in prematurely ageing mice.}, }
@article {pmid15652270, year = {2005}, author = {Huang, HL and Chen, CC and Yeh, CY and Huang, RL}, title = {Reactive oxygen species mediation of baizhu-induced apoptosis in human leukemia cells.}, journal = {Journal of ethnopharmacology}, volume = {97}, number = {1}, pages = {21-29}, doi = {10.1016/j.jep.2004.09.058}, pmid = {15652270}, issn = {0378-8741}, mesh = {Antineoplastic Agents/isolation &amp; purification/*pharmacology ; Apoptosis/*drug effects/physiology ; *Atractylodes ; Drugs, Chinese Herbal/isolation &amp; purification/pharmacology ; HL-60 Cells ; Humans ; Jurkat Cells ; Reactive Oxygen Species/*metabolism ; U937 Cells ; }, abstract = {Baizhu (Atractylodes macrocephala Koidz) has traditionally been used as an important ingredient of several Chinese herbal medicines, which have been used for abdominal pain and gastroenterology diseases for thousands of years. Despite its popularity in herbal therapies, little is known about the anticancer effect of Baizhu. In this study, the anticancer potential of Baizhu on human hepatoma and leukemia cell lines was evaluated. Baizhu methanol extract induced apoptosis in human lymphoma Jurkat T cells, leukemia U937, and HL-60 cells. This was confirmed by several methods, including hypodiploid cells detection using flow cytometry, the examination of apoptotic bodies containing cells using confocal laser scanning microscopy, and hypodiploid cell population inhibition using the broad spectrum caspase inhibitor z-VAD. Finally, the intracellular reactive oxygen species (ROS), especially hydrogen peroxide (H(2)O(2)) and superoxide anion (O(2)(-)), were found to be elevated after treatment of these cells with Baizhu extracts. Antioxidant N-acetyl cysteine (NAC) pretreatment almost completely inhibited Baizhu-induced apoptosis, suggesting that ROS are the key mediators for Baizhu-induced apoptosis. All these data indicate that Baizhu is a possible anti-tumor agent that induces apoptosis of human leukemia cells through ROS generation.}, }
@article {pmid15649637, year = {2005}, author = {Babich, H and Krupka, ME and Nissim, HA and Zuckerbraun, HL}, title = {Differential in vitro cytotoxicity of (-)-epicatechin gallate (ECG) to cancer and normal cells from the human oral cavity.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {19}, number = {2}, pages = {231-242}, doi = {10.1016/j.tiv.2004.09.001}, pmid = {15649637}, issn = {0887-2333}, mesh = {Antioxidants/chemistry/classification/*pharmacology ; Apoptosis/drug effects ; Carcinoma, Squamous Cell/*drug therapy/pathology ; Catechin/*analogs &amp; derivatives/chemistry/classification/*pharmacology ; Cell Survival/drug effects ; DNA/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Fibroblasts/*drug effects/pathology ; Gingiva/*cytology ; Humans ; Mouth Neoplasms/*drug therapy/pathology ; Structure-Activity Relationship ; Tumor Cells, Cultured/drug effects ; }, abstract = {This study evaluated the biologic activity of epicatechin gallate (ECG), a polyphenol in tea, to carcinoma HSC-2 cells and normal HGF-2 fibroblasts cells from the human oral cavity. The relative cytotoxicity of ECG, as compared to five other polyphenols in tea, was evaluated. For the HSC-2 carcinoma cells, ECG, catechin gallate (CG), and epigallocatechin gallate (EGCG) grouped as highly toxic, epigallocatechin (EGC) as moderately toxic, and catechin (C) and epicatechin (EC) as least toxic. For the HGF-2 fibroblasts, ECG and CG grouped as highly toxic, EGCG as moderately toxic, and EGC, C, and EC as least toxic. The cytotoxic effects of the polyphenols were more pronounced to the carcinoma, than to the normal, cells. The addition of ECG to cell culture medium led to the generation of hydrogen peroxide (H2O2). However, ECG, as compared to EGCG, was a poor generator of H2O2 and, hence, the cytotoxicity of ECG was unaffected by the presence of the antioxidants, N-acetyl cysteine and glutathione, and catalase. The cytotoxicity of ECG was unaffected by a metabolic activating system, i.e., a hepatic microsomal S-9 mix. DNA fragmentation, caspase-3 activity, and nuclear staining, both with acridine orange and the TUNEL procedure, were used to assess ECG-induced apoptosis. ECG induced apoptosis in the carcinoma HSC-2 cells, but not in the normal HGF-2 fibroblasts. This research supports those studies suggesting that tea green is an effective chemopreventive agent of oral carcinoma.}, }
@article {pmid15649630, year = {2005}, author = {Kang, J and Zhang, D and Chen, J and Liu, Q and Lin, C}, title = {Antioxidants and trichostatin A synergistically protect against in vitro cytotoxicity of Ni2+ in human hepatoma cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {19}, number = {2}, pages = {173-182}, doi = {10.1016/j.tiv.2004.07.002}, pmid = {15649630}, issn = {0887-2333}, mesh = {Acetylation ; Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Ascorbic Acid/pharmacology ; Carcinoma, Hepatocellular ; Cell Line, Tumor ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Enzyme Inhibitors/*pharmacology ; Glutathione/pharmacology ; Hepatocytes/*drug effects/pathology ; *Histone Deacetylase Inhibitors ; Histones/drug effects/metabolism ; Humans ; Hydroxamic Acids/*pharmacology ; Liver Neoplasms ; Nickel/*toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {The objective of this study was to investigate the separate and combined effects of antioxidants, trichostatin A (TSA) and their combination on the in vitro cytotoxicity of Ni2+ in human hepatoma cells. Cell viability, lactate dehydrogenase (LDH) release, and DNA fragmentation were measured as indicators of cell damage. Reactive oxygen species (ROS) generation and histone acetylation were also measured. The cytotoxicity of Ni2+ increased in a time- and dose-dependent manner. In the presence of 2 mM Ni2+, ROS generation increased 365% (p<0.05), while histone acetylation decreased 37% (p<0.05). Although antioxidants, ascorbic acid (AA, 0.5 or 1 mM), reduced glutathione (GSH, 100 or 200 microM) and N-acetyl-cysteine (NAC, 0.5 or 1 mM) strongly inhibited ROS generation, their effect on Ni2+-caused histone hypoacetylation was not so obvious. On the contrary, TSA (100 nM) showed no inhibition on ROS generation but significantly increased histone acetylation in both control and Ni2+-exposed cells. As expected, the combination of antioxidants and TSA possessed the activity of both diminishing ROS generation and increasing histone hypoacetylation caused by Ni2+. Further studies found that both antioxidants and TSA could diminish the cytotoxicity of Ni2+, and their combined effects obviously improved each of their protection roles, indicating that both ROS generation and histone hypoacetylation are involved in the cytotoxicity of Ni2+, and the combination of antioxidants and TSA may act as a useful strategy to protect against this cytotoxicity.}, }
@article {pmid15647642, year = {2005}, author = {Lucena, MI and López-Torres, E and Verge, C and Andrade, RJ and Puche, MJ and Seoane, J and de la Cuesta, FS}, title = {The administration of N-acetylcysteine causes a decrease in prothrombin time in patients with paracetamol overdose but without evidence of liver impairment.}, journal = {European journal of gastroenterology &amp; hepatology}, volume = {17}, number = {1}, pages = {59-63}, doi = {10.1097/00042737-200501000-00012}, pmid = {15647642}, issn = {0954-691X}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*pharmacology/therapeutic use ; Adult ; Analgesics, Non-Narcotic/poisoning ; Antidotes/*pharmacology/therapeutic use ; Blood Coagulation/*drug effects ; Drug Overdose/blood/drug therapy/physiopathology ; False Positive Reactions ; Female ; Humans ; Liver/physiopathology ; Male ; Prognosis ; *Prothrombin Time ; Retrospective Studies ; }, abstract = {OBJECTIVE: To explore the effect of intravenous N-acetylcysteine (NAC) on the prothrombin time (PT) in patients with paracetamol overdose and persistent normal liver profile.<br><br>MATERIALS AND METHODS: This retrospective case series study examined all admissions with a diagnosis of paracetamol poisoning in a tertiary hospital between 1989 and 2002. Patients were included if they had ever received NAC infusion, had no biochemical evidence of liver damage, and had more than two measurements of PT. Patients who had also ingested other drugs were excluded.<br><br>RESULTS: Of 65 admissions wtih paracetamol poisoning, 18 patients (10 men) met the inclusion criteria. The median age was 29 years, and the median quantity of paracetamol ingested was 186 mg/kg. The mean number of PT measurements per patient was 4.8. The baseline PT (as a percentage) 8.6 h after paracetamol ingestion was 89.6%. During NAC infusion the PT fell in all patients (range, 4.8-53.4% relative to baseline; P < 0.0001) at 14 h. The PT was less than 60% in 28% of the patients. Eight hours after the initiation of NAC there was a 16% fall in PT (range, 4.3-34%; P < 0.0001). At the end of NAC infusion all PTs returned to values close to baseline. Nine patients were hospitalized.<br><br>CONCLUSIONS: In patients with paracetamol overdose without evidence of liver damage a marked decrease in PT often occurs, which seems to be due to the overload of NAC infused at the beginning of treatment. This particular feature should be noted in clinical practice guidelines as a potentially misleading indicator of the development of severe liver dysfunction.}, }
@article {pmid15646799, year = {2004}, author = {Lee, YS}, title = {Role of intracellular Ca2+ signal in the ascorbate-induced apoptosis in a human hepatoma cell line.}, journal = {Archives of pharmacal research}, volume = {27}, number = {12}, pages = {1245-1252}, doi = {10.1007/BF02975889}, pmid = {15646799}, issn = {0253-6269}, mesh = {Apoptosis/drug effects/*physiology ; Ascorbic Acid/*toxicity ; Calcium Signaling/drug effects/*physiology ; Carcinoma, Hepatocellular/*metabolism ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Humans ; Intracellular Fluid/drug effects/physiology ; Liver Neoplasms/*metabolism ; }, abstract = {Although ascorbate (vitamin C) has been shown to have anti-cancer actions, its effect on human hepatoma cells has not yet been investigated, and thus, the exact mechanism of this action is not fully understood. In this study, the mechanism by which ascorbate induces apoptosis using HepG2 human hepatoblastoma cells is investigated. Ascorbate induced apoptotic cell death in a dose-dependent manner in the cells, was assessed through flow cytometric analysis. Contrary to expectation, ascorbate did not alter the cellular redox status, and treatment with antioxidants (N-acetyl cysteine and N,N-diphenyl-p-phenylenediamine) had no influence on the ascorbate-induced apoptosis. However, ascorbate induced a rapid and sustained increase in intracellular Ca2+ concentration. EGTA, an extracellular Ca2+ chelator did not significantly alter the ascorbate-induced intracellular Ca2+ increase and apoptosis, whereas dantrolene, an intracellular Ca2+ release blocker, completely blocked these actions of ascorbate. In addition, phospholipase C (PLC) inhibitors (U-73122 and manoalide) significantly suppressed the intracellular Ca2+ release and apoptosis induced by ascorbate. Collectively, these results suggest that ascorbate induced apoptosis without changes in the cellular redox status in HepG2 cells, and that the PLC-coupled intracellular Ca2+ release mechanism may mediate ascorbate-induced apoptosis.}, }
@article {pmid15644661, year = {2005}, author = {Ramudo, L and Manso, MA and De Dios, I}, title = {Biliary pancreatitis-associated ascitic fluid activates the production of tumor necrosis factor-alpha in acinar cells.}, journal = {Critical care medicine}, volume = {33}, number = {1}, pages = {143-8; discussion 248}, doi = {10.1097/01.ccm.0000150654.13653.5b}, pmid = {15644661}, issn = {0090-3493}, mesh = {Acute Disease ; Animals ; Ascitic Fluid/*immunology ; Cholestasis, Extrahepatic/*immunology ; Cytokines/metabolism ; Disease Models, Animal ; Endothelial Cells/immunology ; Flow Cytometry ; Lymphocytes/immunology ; Male ; Monocytes/immunology ; NF-kappa B/metabolism ; Pancreas, Exocrine/*immunology ; Rats ; Rats, Wistar ; Systemic Inflammatory Response Syndrome/immunology ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {OBJECTIVE: Acute pancreatitis is associated with increased cytokine release from different cell sources. We have investigated the ability of acinar cells, in comparison with inflammatory peripheral blood cells, to produce tumor necrosis factor (TNF)-alpha in response to pancreatitis-associated ascitic fluid (PAAF).<br><br>DESIGN: Controlled, randomized animal study.<br><br>SETTING: University research laboratory.<br><br>SUBJECTS: Male Wistar rats.<br><br>INTERVENTIONS: Flow cytometry using phycoerythrin-labeled monoclonal anti-TNF-alpha antiserum.<br><br>MEASUREMENTS AND MAIN RESULTS: PAAF (20%, v:v) obtained from rats with acute pancreatitis induced by bile-pancreatic duct obstruction significantly increased TNF-alpha production in acinar cells, as measured by flow cytometry using phycoerythrin-labeled monoclonal anti-TNF-alpha antiserum. Neither heating of PAAF nor the addition of soybean trypsin inhibitor or neutralizing amounts of anti-TNF-alpha monoclonal antiserum reduced the acinar cell TNF-alpha production. Monocytes and lymphocytes did not produce TNF-alpha in response to PAAF. Likewise, the typical monocyte and lymphocyte stimulating factors-lipopolysaccharide (10 microg/microL) and phorbol 12-myristate 13-acetate (250 ng/mL) plus ionomycin (1 microg/mL), respectively-were not able to produce TNF-alpha in acinar cells. By comparison of the two acinar cell populations differentiated by flow cytometry, R2 cells (with higher forward scatter values) showed a greater ability to produce TNF-alpha in response to PAAF than R1 cells. Acinar cell nuclear factor-kappaB was activated, but TNF-alpha production was not totally inhibited in presence of N-acetyl cysteine (30, 100 mM).<br><br>CONCLUSIONS: The production of TNF-alpha from different cell sources is selectively activated. PAAF may be involved in the pathophysiology of acute pancreatitis by TNF-alpha production in acinar cells through mechanisms partially mediated by nuclear factor-kappaB activation. PAAF components, such as TNF-alpha or trypsin, are not responsible for acinar cell activation. TNF-alpha was induced by heat-resistant PAAF factors, displaying acinar cells with higher forward scatter (R2) a greater ability to increase the TNF-alpha production than R1 cells.}, }
@article {pmid15643543, year = {2004}, author = {Lee, CJ and Seok, JH and Hur, GM and Lee, JH and Park, JS and Seol, IC and Kim, YH}, title = {Effects of ursolic acid, betulin and sulfur-containing compounds on mucin release from airway goblet cells.}, journal = {Planta medica}, volume = {70}, number = {12}, pages = {1119-1122}, doi = {10.1055/s-2004-835837}, pmid = {15643543}, issn = {0032-0943}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/*pharmacology/therapeutic use ; *Betula ; *Cornus ; Cricetinae ; Dose-Response Relationship, Drug ; Goblet Cells/drug effects/metabolism ; Male ; Mesna/administration &amp; dosage/pharmacology/therapeutic use ; Mesocricetus ; Mucins/*biosynthesis ; *Phytotherapy ; Trachea/cytology/drug effects ; Triterpenes/administration &amp; dosage/pharmacology/therapeutic use ; Ursolic Acid ; }, abstract = {In this study, we investigated whether ursolic acid, betulin and 2 kinds of sulfur-containing compounds--NAC and MESNA--affect mucin release from airway goblet cells and compared the possible activities of these agents with the inhibitory action on mucin release by PLL and the stimulatory action by ATP. Confluent primary hamster tracheal surface epithelial (HTSE) cells were metabolically radiolabeled using 3H-glucosamine for 24 h and chased for 30 min in the presence of varying concentrations of each agent to assess the effects on 3H-mucin release. The results were as follows: ursolic acid, betulin, MESNA and NAC increased mucin release (40-50 % above control) at the highest concentrations (10(-5) M-10(-3) M). We conclude that ursolic acid and betulin can stimulate mucin release by directly acting on airway mucin-secreting cells and suggest that these agents be further investigated for the possible use as mucoregulators in the treatment of chronic airway diseases.}, }
@article {pmid15637469, year = {2005}, author = {Feldman, L and Efrati, S and Dishy, V and Katchko, L and Berman, S and Averbukh, M and Aladjem, M and Averbukh, Z and Weissgarten, J}, title = {N-acetylcysteine ameliorates amphotericin-induced nephropathy in rats.}, journal = {Nephron. Physiology}, volume = {99}, number = {1}, pages = {p23-7}, doi = {10.1159/000081799}, pmid = {15637469}, issn = {1660-2137}, mesh = {*Amphotericin B ; Animals ; *Disease Models, Animal ; Glomerular Filtration Rate/*drug effects ; Kidney Diseases/chemically induced/diagnosis/*drug therapy/*physiopathology ; Male ; Rats ; Rats, Sprague-Dawley ; Treatment Outcome ; }, abstract = {BACKGROUND: Amphotericin B may cause acute reduction in renal function. N-acetylcysteine (NAC) has a renoprotective activity in several nephrotoxic renal insults, but its effect on amphotericin-induced renal failure has not been investigated yet.<br><br>METHODS: Acute renal failure was induced in 30 Sprague-Dawley rats by a single intraperitoneal injection of amphotericin B (50 mg/kg). NAC (10 mg/kg) in isotonic saline or isotonic saline alone were administered daily for 4 days, starting 1 day before the amphotericin B injection. Glomerular filtration rate (GFR) was assessed using 99m-technetium diethylene triaminepentaacetic acid. Before and following amphotericin B administration, a 24-hour urine collection was performed for sodium, potassium and magnesium determination. The kidneys were preserved for pathologic examination.<br><br>RESULTS: Amphotericin B induced a significant decrease of GFR in both groups. Four days after amphotericin injection the GFR in the NAC-treated group was significantly higher than in the control group (0.62 +/- 0.20 vs. 0.46 +/- 0.14 ml/min, p = 0.042). Histologic signs of acute tubular necrosis were attenuated in the NAC-treated group. There were no significant differences between the groups in sodium, potassium and magnesium urine excretion after amphotericin injection.<br><br>CONCLUSIONS: NAC treatment exerted a renoprotective effect on deterioration of GFR in a rat model of amphotericin-induced renal failure. No functional protection on tubular function, as obviated by similar polyuria and urine losses of potassium and magnesium in both groups, was observed.}, }
@article {pmid15634548, year = {2004}, author = {Xu, JF and Qu, JM and He, LX and Zhang, J and Li, ZZ and Chen, XH and Pan, J and Li, HP}, title = {[The effect of antioxidant treatment in pneumonia of granulocytopenic rats].}, journal = {Zhonghua nei ke za zhi}, volume = {43}, number = {11}, pages = {853-856}, pmid = {15634548}, issn = {0578-1426}, mesh = {Acetylcysteine/pharmacology ; Agranulocytosis/*complications ; Animals ; Antioxidants/*pharmacology ; Disease Models, Animal ; Male ; Pneumonia, Bacterial/complications/*drug therapy ; Pseudomonas Infections/complications/*drug therapy ; *Pseudomonas aeruginosa ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: To evaluate the therapeutic role of antioxidant intervention in granulocytopenia rats with pseudomonas aeruginosa pneumonia.<br><br>METHODS: 90 male Sprague-Dawley rats were randomly divided into two groups. Group A: the control granulocytopenia group, in which the granulocytopenia was induced by using cyclophosphamide and cortisone acetate. Group B: the antioxidant intervention group, in which the granulocytopenia model was the same as group A, while peritoneal injection of NAC 150 mg.kg(-1).d(-1) half an hour after the immunocompromised model was reproduced, and the injection was continued for a consecutive 7 days, and NAC was injected once more half an hour before bacterial tracheal inoculation. The model of pulmonary infection was established by using standard a strain of pseudomonas aeruginosa. The time-course of the following was observed 0 h before bacterial inoculation, and 6 h, 9 h, 24 h, 48 h and 72 h after infection: the peripheral white blood cells, mortality, oxidant/antioxidant indexes, bacterial burden of lung tissue homogenate, pulmonary vascular permeability and lung wet/dry weight ratio, and the pulmonary histopathological changes.<br><br>RESULTS: The peripheral white blood cells of both groups were less than 4 x 10(9)/L. The concentration of superoxide dismutase in both serum and lung tissue in group B were higher than that in group A, while concentration of malondialdehyde in group B was lower than that in group A. Pulmonary vascular permeability and lung wet/dry ratio of group B were much lower than that of group A. There was no difference in bacterial burden of lung tissue between the two groups. Group B showed a lower mortality than group A (16.3% vs 23.4%). Lung histopathological observation showed that lung injury, pulmonary congestion and hemorrhage were more serious or obvious in group A as compared with group B. Apoptotic bodies were found in the lung epithelial cells of Group A.<br><br>CONCLUSIONS: Antioxidant intervention can alleviate lung injury in the granulocytopenia rats with pseudomonas aeruginosa pneumonia. It may become an important subsidiary approach to pneumonia in granulocytopenia patients.}, }
@article {pmid15632668, year = {2005}, author = {Quadrilatero, J and Hoffman-Goetz, L}, title = {N-acetyl-L-cysteine inhibits exercise-induced lymphocyte apoptotic protein alterations.}, journal = {Medicine and science in sports and exercise}, volume = {37}, number = {1}, pages = {53-56}, doi = {10.1249/01.mss.0000149809.95484.3d}, pmid = {15632668}, issn = {0195-9131}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Blotting, Western ; Caspase 3 ; Caspases/metabolism ; Cytochromes c/metabolism ; Exercise Test ; Female ; Lymphocytes/*drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Random Allocation ; }, abstract = {PURPOSE: To investigate the effect of strenuous exercise and antioxidant administration on pro- and antiapoptotic protein expression in intestinal lymphocytes.<br><br>METHODS: Female C57BL/6 mice (N = 52) were randomly assigned to receive N-acetyl-L-cysteine (NAC; 1 g.kg(-1)) or saline (SAL) 30 min before treadmill exercise (EX) for 90 min and 2 degrees slope (30 min at 22 m.min(-1), 30 min at 25 m.min(-1), and 30 min at 28 m.min(-1)) and sacrificed immediately (Imm) or 24 h (24 h) after exercise. Control mice were exposed to treadmill noise and vibration without running (nonexercised). Intestinal lymphocytes (IL) were isolated and pro- and antiapoptotic protein expression was evaluated by Western blot analysis.<br><br>RESULTS: IL protein levels of proapoptotic (caspase 3 and cytosolic cytochrome c) and antiapoptotic (Bcl-2) were significantly different among groups. Relative to nonexercised mice, protein levels of caspase 3 (P < 0.001) and cytosolic cytochrome c (P < 0.005) were significantly elevated, whereas Bcl-2 (P < 0.05) was significantly lower immediately after exercise in mice receiving saline (EX + SAL + Imm) but not in animals receiving NAC (EX + NAC + Imm) or both 24 h postgroups (EX + SAL + 24 h and EX + NAC + 24 h).<br><br>CONCLUSION: These results suggest that oxidative stress acting through a mitochondrial pathway may play a role in intestinal lymphocyte apoptosis after strenuous exercise.}, }
@article {pmid15630340, year = {2004}, author = {Raskatovas, D}, title = {[Chemoprevention possibilities of lung cancer].}, journal = {Medicina (Kaunas, Lithuania)}, volume = {40}, number = {12}, pages = {1151-1157}, pmid = {15630340}, issn = {1648-9144}, mesh = {Antioxidants/administration &amp; dosage/*therapeutic use ; Disease Progression ; Double-Blind Method ; Female ; Humans ; Isotretinoin/administration &amp; dosage/*therapeutic use ; Lung Neoplasms/etiology/mortality/*prevention &amp; control ; Male ; Middle Aged ; Primary Prevention ; Randomized Controlled Trials as Topic ; Risk Factors ; Selenium/administration &amp; dosage/*therapeutic use ; Smoking/adverse effects ; Smoking Cessation ; Time Factors ; Vitamin E/administration &amp; dosage/*therapeutic use ; }, abstract = {Objective of the paper was to review the latest scientific reference data on chemoprevention possibilities of lung cancer. Lung cancer is the leading cause of cancer death in Lithuania. The current lung cancer therapy includes surgery, radiation and chemotherapy. These interventions have not produced declines in mortality rates. This overview argues strongly for new approach for controlling this disease. Chemoprevention is the use of specific natural or synthetic substances with the objective of reversing, suppressing or preventing carcinogenic progression to invasive cancer. Whether primary, secondary or tertiary prevention has the potential to improve the dismal statistics associated with this cancer? Several randomized clinical or translational chemoprevention trials have been conducted. All have so far produced either neutral (using retinal, retinyl palmitate, N-acetyl cysteine or isotretinoin) or harmful (using beta-carotene) primary endpoint results showing that lung cancer was not prevented in smokers. Secondary results supporting treatment with isotretinoin in "never" and former smokers and data from prevention trials involving selenium and vitamin E, however, are encouraging and offer a promising direction for future clinical study.}, }
@article {pmid15630201, year = {2004}, author = {Ray, SD and Lam, TS and Rotollo, JA and Phadke, S and Patel, C and Dontabhaktuni, A and Mohammad, S and Lee, H and Strika, S and Dobrogowska, A and Bruculeri, C and Chou, A and Patel, S and Patel, R and Manolas, T and Stohs, S}, title = {Oxidative stress is the master operator of drug and chemically-induced programmed and unprogrammed cell death: Implications of natural antioxidants in vivo.}, journal = {BioFactors (Oxford, England)}, volume = {21}, number = {1-4}, pages = {223-232}, doi = {10.1002/biof.552210144}, pmid = {15630201}, issn = {0951-6433}, mesh = {Acetaminophen/administration &amp; dosage/toxicity ; Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Cell Death/*drug effects/physiology ; Furosemide/administration &amp; dosage/toxicity ; Liver/drug effects/*pathology ; Male ; Mice ; Mice, Inbred ICR ; Oxidative Stress/*physiology ; Phytotherapy ; Plant Extracts/administration &amp; dosage/*pharmacology ; Reactive Oxygen Species/metabolism ; }, abstract = {ROS, RNS, BRIs and ROS-RNS hybrids are produced during drug or chemical metabolism in vivo. These reactive species are instrumental to the culmination of cellular oxidative stress (OS). OS, once turned on, does not spare any vital intracellular macromolecule, such as glutathione, DNA, RNA, proteins, enzymes, lipids and ATP. Since concentration gradients of such components are very delicately balanced for normal cellular functioning, a gross perturbation leads to cell injury and cell death. Abundant evidence now suggests that intracellular antioxidants keep OS in check and maintain homeostasis. Our laboratory has focused on the role of OS in orchestrating various forms of cell death during drug and chemically-induced target organ toxicity and their counteraction by various natural or synthetic antioxidants in in vivo models. Despite complexity of the in vivo models, results show that metabolism of xenobiotics are invariably associated with different degrees of OS and natural antioxidants such as grape seed extract, bitter melon extract (Momordica charantia) and N-acetylcysteine (NAC) which were very effective in counteracting organ toxicities by minimizing events linked to OS (lipid peroxidation and total glutathione), and CAD-mediated DNA fragmentation. Phytoextract exposure rescued cells from toxic assaults, protected genomic integrity, and minimized apoptotic, necrotic and apocrotic (oncotic necrosis) cell deaths. Pre-exposure mode was more effective than post-exposure route. Overall scenario suggests that OS may have been the prime modulator of death and/or survival programs, whereas, antioxidants may have imparted a dual role in either erasing death signals or reviving survival signals, and a combination of antioxidants may be more beneficial than a single entity to influence a number of intracellular events operating simultaneously to neutralize chaotic toxicological consequences.}, }
@article {pmid15629104, year = {2005}, author = {Kamata, H and Oka, S and Shibukawa, Y and Kakuta, J and Hirata, H}, title = {Redox regulation of nerve growth factor-induced neuronal differentiation of PC12 cells through modulation of the nerve growth factor receptor, TrkA.}, journal = {Archives of biochemistry and biophysics}, volume = {434}, number = {1}, pages = {16-25}, doi = {10.1016/j.abb.2004.07.036}, pmid = {15629104}, issn = {0003-9861}, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cell Differentiation/drug effects ; Glutathione/metabolism ; Nerve Growth Factor/metabolism/*pharmacology ; Neurons/*cytology/*drug effects/metabolism ; Oxidation-Reduction ; Oxidative Stress ; PC12 Cells ; Phosphorylation ; Protein Tyrosine Phosphatases/metabolism ; Rats ; Receptor, trkA/*metabolism ; Signal Transduction ; Transcription Factor AP-1/metabolism ; }, abstract = {We investigated the effects of the cellular redox state on nerve growth factor (NGF)-induced neuronal differentiation and its signaling pathways. Treatment of PC12 cells with buthionine sulfoximine (BSO) reduced the levels of GSH, a major cellular reductant, and enhanced NGF-induced neuronal differentiation, activation of AP-1 and the NGF receptor tyrosine kinase, TrkA. Conversely, incubation of the cells with a reductant, N-acetyl-L-cysteine (NAC), inhibited NGF-induced neuronal differentiation and AP-1 activation. Consistent with the suppression, NAC inhibited NGF-induced activation of TrkA, formation of receptor complexes comprising TrkA, Shc, Grb2, and Sos, and activation of phospholipase Cgamma and phosphatidylinositol 3-kinase. Biochemical analysis suggested that the cellular redox state regulates TrkA activity through modulation of protein tyrosine phosphatases (PTPs). Thus, cellular redox state regulates signaling pathway of NGF through PTPs, and then modulates neuronal differentiation.}, }
@article {pmid15628716, year = {2004}, author = {Huynh, HQ and Couper, RT and Tran, CD and Moore, L and Kelso, R and Butler, RN}, title = {N-acetylcysteine, a novel treatment for Helicobacter pylori infection.}, journal = {Digestive diseases and sciences}, volume = {49}, number = {11-12}, pages = {1853-1861}, pmid = {15628716}, issn = {0163-2116}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Drug Resistance, Bacterial ; Expectorants/*therapeutic use ; Female ; Gastric Mucosa/drug effects/microbiology ; Gastritis/drug therapy/microbiology ; Helicobacter Infections/*drug therapy ; Helicobacter felis/drug effects ; Helicobacter pylori/*drug effects ; Hydrophobic and Hydrophilic Interactions ; Mice ; Mice, Inbred C57BL ; Time Factors ; }, abstract = {N-Acetylcysteine (NAC), being both a mucolytic agent and a thiol-containing antioxidant, may affect the establishment and maintenance of H. pylori infection within the gastric mucus layer and mucosa. Agar and broth dilution susceptibility tests determined the MIC of H. pylori strain SSI to NAC. H. pylori load in SSI strain-infected C57BL mice was determined as colony forming units per gram of gastric tissue. Gastritis assessment was scored and gastric surface hydrophobicity was determined by contact angle measurement. MICs of NAC were 5 to 10 and 10 to 15 mg/ml using the agar dilution and broth dilution methods, respectively. NAC (120 mg per day for 14 days) reduced the H. pylori load in mice by almost 1 log compared with sham treatment. Pretreatment with NAC (40 mg/day) also significantly reduced the H. pylori load but did not prevent H. pylori colonization. Both H. pylori infection and NAC reduced the surface hydrophobicity of murine gastric mucosa. No significant differences were observed in the gastritis scores of H. felis- or H. pylori-infected mice receiving either NAC or sham treatments. This study demonstrates that NAC inhibits the growth of H. pylori in both agar and broth susceptibility tests and in H. pylori-infected mice. NAC did not alter the severity of H. pylori- or H. felis-induced gastritis.}, }
@article {pmid15624308, year = {2004}, author = {Murley, JS and Kataoka, Y and Cao, D and Li, JJ and Oberley, LW and Grdina, DJ}, title = {Delayed radioprotection by NFkappaB-mediated induction of Sod2 (MnSOD) in SA-NH tumor cells after exposure to clinically used thiol-containing drugs.}, journal = {Radiation research}, volume = {162}, number = {5}, pages = {536-546}, doi = {10.1667/rr3256}, pmid = {15624308}, issn = {0033-7587}, support = {CA99005/CA/NCI NIH HHS/United States ; P01 CA66081/CA/NCI NIH HHS/United States ; R01 CA37435/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amifostine/pharmacology ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; Blotting, Western ; Captopril/pharmacology ; Cell Line, Tumor ; Cell Survival ; DNA Damage ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; I-kappa B Proteins/metabolism ; Mercaptoethylamines/pharmacology ; Mesna/pharmacology ; Mice ; Mutation ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Phosphorylation ; Plasmids/metabolism ; Protective Agents/pharmacology ; Radiation-Protective Agents/pharmacology ; Serine/chemistry ; Sulfhydryl Compounds/metabolism ; Superoxide Dismutase/*metabolism ; Time Factors ; Transfection ; }, abstract = {The ability of thiol-containing reducing agents to activate transcription factors leading to changes in gene expression and enzyme activities provides an additional mechanism to potentially protect against radiation-induced cell killing. Manganese superoxide dismutase (Sod2) is one such gene whose expression levels have been shown to be elevated after exposure to the thiol compounds WR-1065 and N-acetyl-L-cysteine (NAC), resulting in an increase in radiation resistance. To further characterize this effect, SA-NH sarcoma cells, both wild-type and a clone stably transfected with a plasmid containing an IkappaBalpha gene mutated at serines 32 and 36, which prevents the inducible phosphorylation of these residues and the subsequent activation of NFkappaB (SA-NH+mIkappaBalpha1), were grown to confluence and then exposed to amifostine's free thiol WR-1065 at a concentration of 4 mM for 30 min. Effects of thiol exposure on NFKB activation in SA-NH+mIkappaBalpha1 cells were determined by a gel shift assay, and changes in Sod2 protein levels in these cells 24 h after exposure to 40 microM or 4 mM WR-1065 were measured by Western blot analysis and compared with wild-type cells exposed to the NFkappaB inhibitor BAY 11-7082. Changes in radiation response, measured immediately after thiol exposure or 24 h later, were determined using a colony-forming assay and were correlated with NFKB activation and Sod2 protein levels. The effects of captopril, mesna and NAC, each at a dose of 4 mM, on radiation response were also determined and contrasted with those of WR-1065. Only WR-1065 and captopril protected SA-NH cells when present during irradiation, i.e. 1.57 and 1.31 times increase in survival at 2 Gy, respectively. All four thiols were protective if irradiation with 2 Gy occurred 24 h later; i.e. increases in survival of 1.40, 1.22, 1.35, and 1.25 times were found for WR-1065, captopril, mesna and NAC, respectively. This delayed radioprotective effect correlated with elevated Sod2 protein levels in wild-type SA-NH tumor cells but was not observed in SA-NH+mIkappaBalpha1 cells, indicating that interference with thiol-induced NFKB activation abrogates this delayed radioprotective effect. Because the delayed radioprotective effect is readily demonstrable at a radiation dose of 2 Gy 24 h after exposure to clinically approved thiol-containing drugs such as amifostine, captopril, mesna and NAC, it suggests a new potential concern regarding the issue of tumor protection and the use of these agents in cancer therapy.}, }
@article {pmid15623347, year = {2004}, author = {He, YY and Chignell, CF and Miller, DS and Andley, UP and Roberts, JE}, title = {Phototoxicity in human lens epithelial cells promoted by St. John's Wort.}, journal = {Photochemistry and photobiology}, volume = {80}, number = {3}, pages = {583-586}, doi = {10.1562/0031-8655(2004)080&lt;0583:PIHLEC&gt;2.0.CO;2}, pmid = {15623347}, issn = {0031-8655}, mesh = {Anthracenes ; Cell Death/drug effects/radiation effects ; Cell Line ; Epithelial Cells/cytology/*drug effects/*radiation effects ; Humans ; Hypericum/*toxicity ; Lens, Crystalline/cytology/*drug effects/*radiation effects ; Perylene/analogs &amp; derivatives/pharmacology ; Photosensitizing Agents/*toxicity ; }, abstract = {St. John's Wort (SJW), an over-the-counter antidepressant, contains hypericin, which absorbs light in the UV and visible ranges and is phototoxic to skin. To determine if it also could be phototoxic to the eye, we exposed human lens epithelial cells to 0.1-10 microM hypericin and irradiated them with 4 J/cm2 UV-A or 0.9 J/cm2 visible light. Neither hypericin exposure alone nor light exposure alone reduced cell viability. In contrast, cells exposed to hypericin in combination with UV-A or visible light underwent necrosis and apoptosis. The ocular antioxidants lutein and N-acetyl cysteine did not prevent damage. Thus, ingested SJW is potentially phototoxic to the eye and could contribute to early cataractogenesis. Precautions should be taken to protect the eye from intense sunlight while taking SJW.}, }
@article {pmid15622367, year = {2004}, author = {Rashid, ST and Salman, M and Myint, F and Baker, DM and Agarwal, S and Sweny, P and Hamilton, G}, title = {Prevention of contrast-induced nephropathy in vascular patients undergoing angiography: a randomized controlled trial of intravenous N-acetylcysteine.}, journal = {Journal of vascular surgery}, volume = {40}, number = {6}, pages = {1136-1141}, doi = {10.1016/j.jvs.2004.09.026}, pmid = {15622367}, issn = {0741-5214}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/chemically induced/diagnosis/*prevention &amp; control ; Adult ; Aged ; Aged, 80 and over ; Angiography/*adverse effects/methods ; Antioxidants/*administration &amp; dosage ; Contrast Media/*adverse effects ; Creatinine/blood ; Double-Blind Method ; Female ; Humans ; Infusions, Intravenous ; Iohexol/adverse effects ; Male ; Middle Aged ; Peripheral Vascular Diseases/diagnostic imaging/therapy ; Prospective Studies ; Treatment Outcome ; }, abstract = {OBJECTIVE(S): Apart from proper hydration, only oral N-acetylcysteine (NAC) has shown efficacy in reducing radiographic contrast media (RCM)-induced acute renal failure, though its benefit has been challenged. We investigated the effect of intravenous (i.v.) NAC on renal function in patients with vascular disease receiving RCM for angiography.<br><br>METHODS: Single-center, randomized, double-blind, placebo-controlled trial. Based on a previous study, a trial with 44 patients each in placebo and treatment arms would give at least 80% power to show a statistically significant difference at the 5% level. Vascular patients undergoing angiography were consented and segregated into those whose serum creatinine (SC) level was normal or raised (men >1.32 mg/dl; women >1.07 mg/dL). All patients received 500 mL i.v. normal saline 6 to 12 hours prior to and then after angiography. Groups with normal SC and raised SC were randomly assigned to either 1 g of NAC with normal saline before and after angiography or nothing (placebo). Main outcome measures were change in SC and creatinine clearance (CrCl) as measured 1, 2, and 7 days postangiography (with comparison between active and placebo groups using unpaired t test) and incidence of acute renal decline (>25% or 0.5 mg/dL rise in SC) at 48 hours (with comparison between active and placebo using the Fisher exact test).<br><br>RESULTS: Forty-six patients received NAC (29 normal SC, 17 raised SC), and 48 received placebo (27 normal SC, 21 raised SC). There was no significant difference in postangiography SC or CrCl at any of the time points measured between NAC and placebo in patients with either normal or raised SC. In the raised SC group, 3 patients from both the NAC and placebo groups suffered acute renal declines. Importantly, at 48 hours, the impaired SC group had a significant reduction in CrCl (-14% +/- 41% vs +18% +/- 58%: P = .0142) and a significant rise in SC (+7.0 +/- 25% vs -1.6% +/- 10%; P = .0246) when compared with the normal SC group.<br><br>CONCLUSIONS: NAC (i.v. at 1 g) precontrast and postcontrast does not confer any benefit in preventing RCM-induced nephropathy in vascular patients. Patients with pre-existing raised SC have an increased risk of renal impairment as defined by a fall in CrCl and a rise in SC post-RCM when compared with patients with normal SC who appear to benefit from hydration.}, }
@article {pmid15621418, year = {2005}, author = {Kumar, KS and Dayananda, S and Subramanyam, C}, title = {Copper alone, but not oxidative stress, induces copper-metallothionein gene in Neurospora crassa.}, journal = {FEMS microbiology letters}, volume = {242}, number = {1}, pages = {45-50}, doi = {10.1016/j.femsle.2004.10.040}, pmid = {15621418}, issn = {0378-1097}, mesh = {Ascorbic Acid/metabolism ; Copper/*metabolism ; Culture Media/chemistry ; Electrophoretic Mobility Shift Assay ; *Gene Expression Regulation, Fungal ; Hydrogen Peroxide/metabolism ; Metallothionein/*genetics ; Neurospora crassa/*genetics/metabolism ; *Oxidative Stress ; Transcriptional Activation ; Vitamin K 3/metabolism ; }, abstract = {Two metal response elements, flanking an antioxidant response element, were identified in regions upstream (-3730 bp) to copper metallothionein (CuMT) gene of Neurospora crassa. Presence of copper in culture media, but not of pro-oxidants like H2O2 or menadione, induced CuMT gene expression that could not be completely abolished by antioxidants such as N-acetyl cysteine and ascorbic acid. Gel shift assays revealed the ability of nuclear extracts from copper induced cultures to bind PCR-amplified metal response or antioxidant response elements. Similar observations could not be made with cultures exposed either to pro-oxidants or antioxidants. These results differentiate between CuMT gene induction by copper from antioxidant functions associated with the identified upstream elements.}, }
@article {pmid15619135, year = {2004}, author = {Brown, M and Bjorksten, A and Medved, I and McKenna, M}, title = {Pharmacokinetics of intravenous N-acetylcysteine in men at rest and during exercise.}, journal = {European journal of clinical pharmacology}, volume = {60}, number = {10}, pages = {717-723}, pmid = {15619135}, issn = {0031-6970}, mesh = {Acetylcysteine/adverse effects/blood/*pharmacokinetics ; Adult ; Drug Stability ; *Exercise ; Humans ; Infusions, Intravenous ; Male ; Metabolic Clearance Rate ; *Rest ; Solutions ; }, abstract = {OBJECTIVE: We aimed to determine the pharmacokinetics (PK) of N-acetylcysteine (NAC) at rest and during exercise when given by continuous intravenous infusion intended to maintain relatively constant plasma concentrations.<br><br>METHODS: Plasma concentrations of NAC were measured in 24 healthy male subjects during and after a two-stage intravenous infusion designed to provide constant NAC concentrations during cycling exercise, including intense exercise to fatigue.<br><br>RESULTS: A three-compartment, open PK model was the best fit using population PK analysis with NONMEM. Whole-body clearance (CL) was 0.58 l kg(-1) h(-1) (95% CI 0.44-0.72) for reduced NAC (NACR) and 0.16 (0.13-0.20) l kg(-1) h(-1) for total NAC (NACT). The central volume of distribution (V1) was 0.064 (0.008-0.12) l kg(-1) for NACR and 0.037 (0.02-0.06) l kg(-1) for NACT. Exercise was a significant covariate in the model, resulting in a 25 and 23% reduction in CL of NACR and NACT, respectively. V1 in our subjects was smaller than expected, resulting in higher-than-anticipated initial concentrations of NAC. Despite these findings, the incidence of adverse effects attributable to NAC was minimal without using prophylactic or concomitant drug therapy.<br><br>CONCLUSIONS: NAC can be given to healthy exercising men by intravenous infusion and to the plasma concentrations seen in this study with minimal adverse effects due to the drug. The PK parameters of NAC at rest in volunteers are consistent with previously reported values and are significantly altered by vigorous cycling exercise.}, }
@article {pmid15618233, year = {2005}, author = {D'Agostini, F and Balansky, RM and Camoirano, A and De Flora, S}, title = {Modulation of light-induced skin tumors by N-acetylcysteine and/or ascorbic acid in hairless mice.}, journal = {Carcinogenesis}, volume = {26}, number = {3}, pages = {657-664}, doi = {10.1093/carcin/bgi008}, pmid = {15618233}, issn = {0143-3334}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ascorbic Acid/*pharmacology ; Female ; Mice ; Mice, Hairless ; Skin Neoplasms/*etiology/pathology/*prevention &amp; control ; Ultraviolet Rays/*adverse effects ; }, abstract = {The light emitted by halogen quartz bulbs contains a broad spectrum of UV wavelengths, is strongly genotoxic and is a potent inducer of skin tumors in hairless mice. By using a UVC filter, this light mimics solar radiation and induces a variety of genomic and transcriptional alterations in mouse skin. UV-related carcinogenesis involves depletion of antioxidants and glutathione in skin cells. On this basis, we evaluated modulation of carcinogenicity of UVC-filtered halogen lamps in SKH-1 hairless mice by the antioxidants N-acetyl-l-cysteine (NAC) and ascorbic acid (AsA). Both agents were given in the drinking water, either individually or in combination. The earliest skin lesions were detected after 300 days' exposure to light and became confluent in a number of mice after 480 days. NAC administration prolonged the latency time by 90 days. Moreover, NAC considerably and significantly decreased both incidence and multiplicity of light-induced skin tumors, prevented the occurrence of malignant lesions (squamocellular carcinomas) and reduced the tumor size. In contrast, AsA, which may behave as a prooxidant rather than an antioxidant, increased the multiplicity of total skin tumors, carcinomas in situ and squamocellular carcinomas. Co-administration of NAC with AsA significantly attenuated the negative effect of AsA, presumably due to the ability of this thiol to maintain a reduced environment. Therefore, in agreement with our previous in vitro findings, oral NAC is able to attenuate the detrimental effects of AsA.}, }
@article {pmid15614283, year = {2005}, author = {Powers, KA and Zurawska, J and Szaszi, K and Khadaroo, RG and Kapus, A and Rotstein, OD}, title = {Hypertonic resuscitation of hemorrhagic shock prevents alveolar macrophage activation by preventing systemic oxidative stress due to gut ischemia/reperfusion.}, journal = {Surgery}, volume = {137}, number = {1}, pages = {66-74}, doi = {10.1016/j.surg.2004.05.051}, pmid = {15614283}, issn = {0039-6060}, mesh = {Animals ; Intestinal Mucosa/metabolism ; Intestines/immunology ; Macrophages/*immunology ; Male ; NF-kappa B/metabolism ; Neutrophils/immunology ; Oxidants/metabolism ; Oxidative Stress ; Pulmonary Alveoli/cytology/immunology/metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*immunology/metabolism/*therapy ; Resuscitation/*methods ; Saline Solution, Hypertonic/pharmacology ; Shock, Hemorrhagic/*immunology/metabolism/*therapy ; }, abstract = {BACKGROUND: The gut is a target organ of shock/resuscitation (S/R); however, it also contributes to distant inflammation through the generation of oxidants. S/R with antioxidants such as N-acetylcysteine (NAC) prevents lipopolysaccharide (LPS)-induced cytokine production and NF-kappaB activation in rat alveolar macrophages. Therefore, we hypothesized that hypertonic saline (HTS) might exerts its protective effect by preventing gut ischemia/reperfusion injury, thus decreasing oxidative stress and distant priming in alveolar macrophages.<br><br>METHODS: A two-hit rat model of shock resuscitation was used. Plasma levels of 8-iso-prostaglandin, a marker of lipid peroxidation, was quantified by eicosanoid immunoassay with acetylcholinesterase kit. Gut histology with hematoxylin and eosin staining was performed 1 to 6 hours after resuscitation. Alternatively, alveolar macrophages from bronchoalveolar lavage (BAL) at end resuscitation were incubated in vitro with LPS (0.01 mug/mL), and NF-kappaB translocation was observed by immunofluorescent staining with anti-p65 antibody.<br><br>RESULTS: HTS resuscitation prevented leukosequestration in the alveolar space, and it abrogated the progressive rise in blood 8-iso-prostaglandin production observed with Ringer's lactate (RL) resuscitation. Inhibition of oxidant stress with NAC corresponded with the ability of HTS to prevent S/R-induced edema, villus flattening, and mucosal sloughing in the mid-ileum. LPS-induced NF-kappaB translocation in alveolar macrophages after RL was 42% compared to 20% after HTS. Similar attenuation was observed with NAC resuscitation (16%).<br><br>CONCLUSIONS: HTS resuscitation prevents systemic oxidative stress by reducing gut ischemia/reperfusion injury and consequently attenuates distant alveolar macrophage priming, thereby reducing LPS-induced NF-kappaB nuclear translocation in alveolar macrophages and organ injury. This represents a novel mechanism whereby HTS exerts its immunomodulatory effects.}, }
@article {pmid15612810, year = {2004}, author = {Demirkol, O and Adams, C and Ercal, N}, title = {Biologically important thiols in various vegetables and fruits.}, journal = {Journal of agricultural and food chemistry}, volume = {52}, number = {26}, pages = {8151-8154}, doi = {10.1021/jf040266f}, pmid = {15612810}, issn = {0021-8561}, mesh = {Acetylcysteine/analysis ; Captopril/analysis ; Chromatography, High Pressure Liquid ; Cysteine/analysis ; Fruit/*chemistry ; Homocysteine/analysis ; Sulfhydryl Compounds/*analysis ; Vegetables/*chemistry ; }, abstract = {Biological thiols are important antioxidants, and recent studies showed that their contents vary depending on the groups of foodstuffs. Therefore, we investigated the levels of some biological thiols in various vegetables and fruits by using a sensitive high-performance liquid chromatography (HPLC) technique. Biological thiols measured in some vegetables and fruits include glutathione (L-glutamyl-L-cysteinly glycine, GSH), N-acetylcysteine (NAC), captopril [CAP (C9H15NO3S)], homocysteine (HCYS), cysteine (CYS), and gamma-glutamyl cysteine (GGC). Our results show that biological thiol contents are between 3-349 nM/g wet weight in vegetables and 4-136 nM/g wet weight in fruits. CAP is only found in asparagus (28 nM/g wet weight). Furthermore, none of the biological thiols analyzed were found in cabbages, red grapes, blackberries, apples, and peaches. Therefore, various vegetables and fruits differ significantly in their thiol contents. Oxidation of these important thiols may occur and result in the production of toxic byproducts, if they are exposed to radiation and ozone treatment for sterilization purposes. Further studies should be performed to monitor the levels of these biological thiols.}, }
@article {pmid15607898, year = {2005}, author = {Schaser, KD and Bail, HJ and Schewior, L and Stover, JF and Melcher, I and Haas, NP and Mittlmeier, T}, title = {Acute effects of N-acetylcysteine on skeletal muscle microcirculation following closed soft tissue trauma in rats.}, journal = {Journal of orthopaedic research : official publication of the Orthopaedic Research Society}, volume = {23}, number = {1}, pages = {231-241}, doi = {10.1016/j.orthres.2004.05.009}, pmid = {15607898}, issn = {0736-0266}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Communication ; Endothelial Cells/physiology ; Immunohistochemistry ; Laser-Doppler Flowmetry ; Leukocytes/physiology ; Male ; Microcirculation/drug effects ; Muscle, Skeletal/*blood supply ; Nitric Oxide/physiology ; Rats ; Rats, Sprague-Dawley ; Soft Tissue Injuries/*physiopathology ; }, abstract = {Trauma-induced microcirculatory dysfunction, formation of free radicals and decreased endothelial release of nitric oxide (NO) contribute to evolving tissue damage following skeletal muscle injury. Administration of N-acetylcysteine (NAC) known to scavenge free radicals and generate NO is considered a valuable therapeutic approach. Thus, the objective of this study was to quantitatively analyze the acute effects of NAC on skeletal muscle microcirculation and leukocyte-endothelial cell interaction following severe standardized closed soft tissue injury (CSTI). Severe CSTI was induced in the hindlimbs of 14 male anesthetized Sprague-Dawley rats using the controlled impact injury technique. Rats were randomly assigned (n = 7) to high-dose intravenous infusion of NAC (400 mg/kg body weight) or isovolemic normal saline (NS). Non-injured, sham-operated animals (n = 7) were subjected to the same surgical procedures but did not receive any additional fluid. Creatin kinase (CK) activity was assessed at baseline, 1 h before and 2 h following posttraumatic NAC or NS infusion. Microcirculation of the extensor digitorum longus (EDL) muscle was analyzed using intravital microscopy and Laser-Doppler flowmetry (LDF). Edema index (EI) was calculated by measuring the EDL wet-to-dry weight ratio (EI=injured/contralateral limb). EDL-muscles were analyzed for desmin immunoreactivity and granulocyte infiltration. Microvascular deteriorations observed following NS-infusion were effectively reversed by NAC: Functional capillary density was restored to levels found in sham-operated animals and leukocyte adherence was significantly (p < 0.05) reduced compared to the NS group. NAC significantly (p < 0.05) increased erythrocyte flux determined by Laser-Doppler flowmetry. Posttraumatic serum CK levels and EI were significantly (p < 0.05) decreased by NAC. During the posttraumatic acute phase, single infusion of NAC markedly reduced posttraumatic microvascular dysfunction, attenuated both leukocyte adherence and tissue infiltration. NAC also decreased CSTI-induced edema formation and myonecrosis as reflected by attenuated serum CK levels and attenuated loss of desmin immunoreactivity. NAC may serve as an effective therapeutic strategy by supporting microvascular blood supply and tissue viability in the early posttraumatic period. Additional studies aimed at long-term analysis and investigation of injury severity--or dosage dependency are needed.}, }
@article {pmid15607333, year = {2005}, author = {Kowluru, RA}, title = {Effect of advanced glycation end products on accelerated apoptosis of retinal capillary cells under in vitro conditions.}, journal = {Life sciences}, volume = {76}, number = {9}, pages = {1051-1060}, doi = {10.1016/j.lfs.2004.10.017}, pmid = {15607333}, issn = {0024-3205}, mesh = {Animals ; Apoptosis/*drug effects ; Capillaries/drug effects ; Cattle ; Diabetic Retinopathy/*etiology ; Glycation End Products, Advanced/*toxicity ; NF-kappa B/metabolism ; Oxidative Stress ; Retina/*drug effects/metabolism/pathology ; Serum Albumin, Bovine/*toxicity ; }, abstract = {Advanced glycation end-products (AGEs) are considered to play an important role in the development of retinopathy in diabetes, and are shown to induce retinal vascular changes resembling that of diabetic retinopathy. We have shown that apoptosis of retinal capillary cells is accelerated in diabetes. The aim of this study is to investigate the role of AGEs in accelerated retinal capillary cell death in in vitro conditions, and to identify the possible mechanism involved. Bovine retinal endothelial cells and pericytes were incubated in the presence of 5 microM AGE-bovine serum albumin (AGE-BSA) or untreated control BSA (BSA) for up to five days. The cell death was determined by performing ELISA for cytoplasmic histone-associated DNA fragments and by measuring the activity of caspase-3. Incubation of endothelial cells or pericytes with AGE-BSA increased oxidative stress and NO by 60%, and in the same cells nuclear transcriptional factor (NF-kB) was also activated by over 60%. AGE-BSA induced their apoptosis by 55%, and activated caspase-3 by about 50% compared to the cells incubated with unmodified BSA. Co-addition of AGE-BSA and antioxidants (N-acetyl cysteine or alpha-lipoic acid) inhibited oxidative stress, nitrotyrosine formation, NF-kB activation and capillary cell apoptosis. These data strongly suggest that increased AGE in diabetes could play an important role in retinal capillary apoptosis and that oxidative stress is involved in this process. Inhibition of AGEs in the retinal capillary cells could prevent their apoptosis, and ultimately, the development of retinopathy in diabetes.}, }
@article {pmid15607126, year = {2005}, author = {De Benedetto, F and Aceto, A and Dragani, B and Spacone, A and Formisano, S and Pela, R and Donner, CF and Sanguinetti, CM}, title = {Long-term oral n-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {18}, number = {1}, pages = {41-47}, doi = {10.1016/j.pupt.2004.09.030}, pmid = {15607126}, issn = {1094-5539}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; *Administration, Oral ; Aged ; Breath Tests/instrumentation/methods ; Drug Administration Schedule ; Exhalation/*drug effects/physiology ; Female ; Humans ; Hydrogen Peroxide/chemistry/*metabolism ; Male ; Pulmonary Disease, Chronic Obstructive/*drug therapy/etiology/physiopathology ; Spirometry/instrumentation/methods ; Time Factors ; }, abstract = {Oxidative stress caused by airway inflammation is increased in chronic obstructive pulmonary disease (COPD) and may account for the progressive deterioration of structure and function of the respiratory tract observed in this disease. Antioxidant defences of the respiratory tract may be overwhelmed by the oxidant burden in COPD and possibly restored with antioxidant therapy. The level of hydrogen peroxide (H(2)O(2)) concentration in exhaled air condensate (EAC) is a valuable tool for assessing and monitoring oxidative stress. This study aimed to verify the effect of 2-month oral N-acetylcysteine (NAC) treatment compared to placebo on the H(2)O(2) content in EAC of 55 clinically stable COPD patients (48 males), mean age 65.93+/-9.3 years. After clinical examination, pulmonary function tests, and collection of EAC for the basal (T0) assay of H(2)O(2), patients were randomly allocated to group A (usual therapy plus oral NAC 600 mg b.i.d. for 2 months) or group B (usual therapy plus placebo b.i.d. for 2 months). H(2)O(2) assay in EAC was repeated at 15 (T15), 30 (T30), and 60 (T60) days after the start of therapy in each group. All patients were non-smokers or ex smokers for at least 5 years and the two groups were comparable in terms of demographic, respiratory function, and EAC data at baseline. The H(2)O(2) level in EAC of group A was significantly decreased at T15 (1.00+/-0.38 SD microM; p=0.003), T30 (0.91+/-0.44 microM; p=0.007), and T60 (0.83+/-0.41 microM; p=0.000) compared to T0 (1.28+/-0.61 microM). No significant decrease in H(2)O(2) of group B was found at any time point. We conclude that oral NAC 600 mg b.i.d. for 2 months rapidly reduces the oxidant burden in airways of stable COPD patients.}, }
@article {pmid15607048, year = {2004}, author = {Guayerbas, N and Puerto, M and Alvarez, P and de la Fuente, M}, title = {Improvement of the macrophage functions in prematurely ageing mice by a diet supplemented with thiolic antioxidants.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {50 Online Pub}, number = {}, pages = {OL677-81}, pmid = {15607048}, issn = {0145-5680}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aging, Premature/genetics/*prevention &amp; control ; Animals ; Antioxidants/*therapeutic use ; Chemotaxis/physiology ; Diet ; Female ; Macrophages, Peritoneal/*drug effects/metabolism ; Maze Learning/drug effects ; Mice ; Mice, Inbred ICR ; Phagocytosis/physiology ; Sulfhydryl Compounds/therapeutic use ; Superoxides/analysis/metabolism ; Thiazoles/administration &amp; dosage/*therapeutic use ; Thiazolidines ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {In a model of prematurely ageing mice, based on the different behavioral response in a simple T-maze test, we have studied in the present work the effect of a short-term (five-weeks) ingestion of thioproline (TP) plus n-acetylcysteine (NAC) (0.1% w/w of each antioxidant) on several functions of peritoneal macrophages from female Swiss mice. The antioxidant treatment increased the chemotaxis, phagocytosis and IL-1beta release and decreased the superoxide levels and TNFalpha production. These effects were more striking in macrophages from prematurely-ageing mice (PAM), than in those from the control group or non-prematurely-ageing mice (NPAM), bringing the above functions of the PAM to the NPAM levels. Diet supplementation with these thiolic compounds, namely TP and NAC, seems an effective therapy for protection against early immune decline in prematurely ageing mice.}, }
@article {pmid15604726, year = {2004}, author = {Baek, D and Nam, J and Koo, YD and Kim, DH and Lee, J and Jeong, JC and Kwak, SS and Chung, WS and Lim, CO and Bahk, JD and Hong, JC and Lee, SY and Kawai-Yamada, M and Uchimiya, H and Yun, DJ}, title = {Bax-induced cell death of Arabidopsis is meditated through reactive oxygen-dependent and -independent processes.}, journal = {Plant molecular biology}, volume = {56}, number = {1}, pages = {15-27}, pmid = {15604726}, issn = {0167-4412}, mesh = {Animals ; *Apoptosis ; Arabidopsis/genetics/*physiology ; Arabidopsis Proteins/genetics/physiology ; Cell Size ; DNA Fragmentation ; Dexamethasone/pharmacology ; Gene Expression ; Green Fluorescent Proteins/genetics/metabolism ; Luminescent Proteins/genetics/metabolism ; Membrane Proteins/genetics/physiology ; Mice ; Microscopy, Fluorescence ; Mitochondria/metabolism ; Models, Biological ; Plants, Genetically Modified ; Proto-Oncogene Proteins c-bcl-2/genetics/*physiology ; Protoplasts/cytology/drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Signal Transduction ; Time Factors ; Transformation, Genetic ; Vacuoles/metabolism ; bcl-2-Associated X Protein ; Red Fluorescent Protein ; }, abstract = {An Arabidopsis protoplast system was developed for dissecting plant cell death in individual cells. Bax, a mammalian pro-apoptotic member of the Bcl-2 family, induces apoptotic-like cell death in Arabidopsis. Bax accumulation in Arabidopsis mesophyll protoplasts expressing murine Bax cDNA from a glucocorticoid-inducible promoter results in cytological characteristics of apoptosis, namely DNA fragmentation, increased vacuolation, and loss of plasma membrane integrity. In vivo targeting analysis monitored using jellyfish green fluorescent protein (GFP) reporter indicated full-length Bax was localized to the mitochondria, as it does in animal cells. Deletion of the carboxyl-terminal transmembrane domain of Bax completely abolished targeting to mitochondria. Bax expression was followed by reactive oxygen species (ROS) accumulation. Treatment of protoplasts with the antioxidant N -acetyl- -cysteine (NAC) during induction of Bax expression strongly suppressed Bax-mediated ROS production and the cell death phenotype. However, some population of the ROS depleted cells still induced cell death, indicating that there is a process that Bax-mediated plant cell death is independent of ROS accumulation. Accordingly, suppression of Bax-mediated plant cell death also takes place in two different processes. Over-expression of a key redox-regulator, Arabidopsis nucleoside diphosphate kinase 2 (AtNDPK2) down-regulated ROS accumulation and suppressed Bax-mediated cell death and transient expression of Arabidopsis Bax inhibitor-1 (AtBI-1) substantially suppressed Bax-induced cell death without altering cellular ROS level. Taken together, our results collectively suggest that the Bax-mediated cell death and its suppression in plants is mediated by ROS-dependent and -independent processes.}, }
@article {pmid15598336, year = {2004}, author = {Nanda, K}, title = {Non-alcoholic steatohepatitis in children.}, journal = {Pediatric transplantation}, volume = {8}, number = {6}, pages = {613-618}, doi = {10.1111/j.1399-3046.2004.00241.x}, pmid = {15598336}, issn = {1397-3142}, mesh = {Animals ; Biopsy ; Child ; Comorbidity ; Disease Progression ; *Fatty Liver/diagnosis/epidemiology/pathology/therapy ; *Hepatitis/diagnosis/epidemiology/pathology/therapy ; Humans ; Liver/pathology ; Liver Transplantation ; Obesity/epidemiology ; Prevalence ; Risk Factors ; }, abstract = {Obesity has emerged as a significant new health problem in the pediatric population. Non-alcoholic steatohepatitis (NASH) is an entity in the spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from fat in the liver -- simple steatosis, NASH/ steatohepatitis -- fat with inflammation and/or fibrosis to advanced fibrosis and cirrhosis when fat may no longer be present. NASH is associated with obesity, diabetes, insulin resistance (IR), and hypertriglyceridemia. While majority of individuals with risk factors like obesity and IR have steatosis only a minority develop steatohepatitis, possible mechanisms have been discussed. Clinical experience with pediatric NASH is limited. Children generally present in the prepubertal age group, have a male predominance with a higher incidence in children of Hispanic origin. Body mass index (BMI) of 25-29.9 is considered to be overweight and that > or =30 obese. Acanthosis nigricans as a marker of IR should be looked for. As NASH is a diagnosis of exclusion, other causes of chronic liver disease must be excluded. Increased echogenicity in the liver is noted on ultrasound. Liver biopsy is considered the gold standard in establishing the diagnosis. Histopathological lesions thought to be necessary for diagnosis of NASH include steatosis (macrovesicular > microvesicular), mixed mild lobular inflammation and hepatocyte ballooning. A system of grading depending on degree of steatosis and/or inflammation and staging depending on the extent of fibrosis has also been proposed. Although there is no consensus for the treatment for NASH, effort needs to be made to prevent development of fibrosis, which results in cirrhosis and portal hypertension. Slow, consistent weight loss has been shown to be effective in childhood NAFLD, based on improvement of serum aminotransferases or liver sonogram. A low glycemic index diet has been shown to be more effective than a low fat diet in lowering BMI. Family based behavioral intervention may also enhance success with diet. Several pharmacological agents have been used including ursodeoxycholic acid, vitamin E, betaine, n-acetyl cysteine, and insulin sensitizing agents like metformin, rosiglitazone, and pioglitazone. Transplantation for overt NASH is rare, accounting for < 1% of liver transplantations in the USA. The disease can recur after liver transplantation. A strong association exists between the presence of steatosis in a donor liver and poor graft function. As a result, cadaveric donor livers with macrovesicular steatosis >40% are not used routinely. Prognosis in NASH is dependent not only on severity and number of risk factors but also on the degree of histological damage. Clinical trials are needed to identify an effective treatment that halts the progression of NAFLD to NASH in both pretransplantation and post-transplantation patients.}, }
@article {pmid15598086, year = {2004}, author = {Alicigüzel, Y and Aslan, M}, title = {N-acetyl cysteine, L-cysteine, and beta-mercaptoethanol augment selenium-glutathione peroxidase activity in glucose-6-phosphate dehydrogenase-deficient human erythrocytes.}, journal = {Clinical and experimental medicine}, volume = {4}, number = {1}, pages = {50-55}, doi = {10.1007/s10238-004-0038-z}, pmid = {15598086}, issn = {1591-8890}, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Case-Control Studies ; Child ; Child, Preschool ; Cysteine/*pharmacology ; Erythrocytes/*drug effects/*enzymology ; Glucosephosphate Dehydrogenase Deficiency/*blood ; Glutathione Peroxidase/*metabolism ; Humans ; Male ; Mercaptoethanol/*pharmacology ; }, abstract = {In glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes, failure to maintain normal levels of reduced glutathione (GSH) due to decreased NADPH regeneration in the hexose monophosphate pathway results in acute hemolytic anemia following exposure to oxidative insults, such as ingestion of Vicia fava beans or use of certain drugs. GSH is a source of protection against oxidative attack, used by the selenium-dependent glutathione peroxidase (Se-GSH-Px)/reductase (GR) system to detoxify hydrogen peroxide and organic peroxides, provided that sufficient GSH is made available. In this study, Se-GSH-Px activity was analyzed in G6PD-deficient patients in the presence of reducing agents such as N-Acetyl cysteine, L-cysteine, and beta-mercaptoethanol. Se-GSH-Px activity was decreased in G6PD-deficient red blood cells (RBCs). N-Acetyl cysteine, L-cysteine, and beta-mercaptoethanol increased Se-GSH-Px activity in G6PD-deficient human erythrocytes, indicating that other reducing agents can be utilized to complement Se-GSH-Px activity in G6PD deficiency. Based on the increased susceptibility of G6PD-deficient patients to oxidative stress, the reported increase in Se-GSH-Px activity can facilitate the detoxification of reactive oxygen species.}, }
@article {pmid15589408, year = {2005}, author = {Chevelkov, V and Chen, Z and Bermel, W and Reif, B}, title = {Resolution enhancement in MAS solid-state NMR by application of 13C homonuclear scalar decoupling during acquisition.}, journal = {Journal of magnetic resonance (San Diego, Calif. : 1997)}, volume = {172}, number = {1}, pages = {56-62}, doi = {10.1016/j.jmr.2004.09.017}, pmid = {15589408}, issn = {1090-7807}, mesh = {Acetylcysteine/chemistry ; Amino Acids/*chemistry ; Carbon Isotopes ; Leucine/chemistry ; Nitrogen Isotopes ; Nuclear Magnetic Resonance, Biomolecular/*methods ; Peptides/*chemistry ; Signal Processing, Computer-Assisted ; Valine/chemistry ; }, abstract = {Spectral resolution imposes a major problem on the evaluation of MAS solid-state NMR experiments as larger biomolecular systems are concerned. We show in this communication that decoupling of the (13)C-(13)C homonuclear scalar couplings during stroboscopic detection can be successfully applied to increase the spectral resolution up to a factor of 2-2.5 and sensitivity up to a factor of 1.2. We expect that this approach will be useful for the study of large biomolecular systems like membrane proteins and amyloidogenic peptides and proteins where spectral overlap is critical. The experiments are demonstrated on a uniformly (13)C,(15)N-labelled sample of Nac-Val-Leu-OH and applied to a uniformly (13)C,(15)N-enriched sample of a hexameric amyloidogenic peptide.}, }
@article {pmid15589382, year = {2005}, author = {Grinberg, L and Fibach, E and Amer, J and Atlas, D}, title = {N-acetylcysteine amide, a novel cell-permeating thiol, restores cellular glutathione and protects human red blood cells from oxidative stress.}, journal = {Free radical biology &amp; medicine}, volume = {38}, number = {1}, pages = {136-145}, doi = {10.1016/j.freeradbiomed.2004.09.025}, pmid = {15589382}, issn = {0891-5849}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacology ; Cell Membrane/*metabolism ; Cell Membrane Permeability/*drug effects ; Erythrocytes/*drug effects/metabolism ; Glutathione/*metabolism ; Hemoglobins/metabolism ; Humans ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {Oxidative stress plays an important role in the progression of neurodegenerative and age-related diseases, causing damage to proteins, DNA, and lipids. A novel thiol N-acetylcysteine amide (AD4), the amide form of N-acetylcysteine (NAC) and a Cu(2+) chelator, was assessed for its antioxidant and protective effects using human red blood cells (RBCs) as a model. AD4 was shown by flow cytometry to inhibit tert.-butylhydroxyperoxide (BuOOH)-induced intracellular oxidation in RBCs stained with the oxidant-sensitive probe 2',7'-dichlorofluorescein diacetate. In addition, AD4 retarded BuOOH-induced thiol depletion and hemoglobin oxidation. Restoration of the thiol-depleted RBCs by externally applied AD4 was significantly greater compared with NAC and, unlike NAC, was accompanied by hemoglobin protection from oxidation. In a cell-free system we have demonstrated that AD4 reacted with oxidized glutathione (GSSG) to generate reduced glutathione (GSH). The formation of GSH was determined enzymatically using GSH peroxidase and by HPLC. Based on these results a thiol-disulfide exchange between AD4 and GSSG is proposed as the mechanism underlying the antioxidant effects of AD4 on BuOOH-treated RBCs. Together, these studies demonstrate that AD4 readily crosses cell membranes, replenishes intracellular GSH, and, by incorporating into the redox machinery, defends the cell from oxidation. These results provide further evidence for the efficient membrane permeation of AD4 over NAC, and support the possibility that it could be explored for treatment of neurodegeneration and other oxidation-mediated disorders.}, }
@article {pmid15588682, year = {2005}, author = {Prasad, RC and Herzog, B and Boone, B and Sims, L and Waltner-Law, M}, title = {An extract of Syzygium aromaticum represses genes encoding hepatic gluconeogenic enzymes.}, journal = {Journal of ethnopharmacology}, volume = {96}, number = {1-2}, pages = {295-301}, doi = {10.1016/j.jep.2004.09.024}, pmid = {15588682}, issn = {0378-8741}, support = {DK02887/DK/NIDDK NIH HHS/United States ; DK26657/DK/NIDDK NIH HHS/United States ; P30 CA68485/CA/NCI NIH HHS/United States ; P30 DK58404/DK/NIDDK NIH HHS/United States ; P60 DK20593/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; Chromones/pharmacology ; Enzyme Activation ; Gluconeogenesis/*genetics ; Glucose-6-Phosphatase/*biosynthesis/genetics ; Hypoglycemic Agents/chemistry/*pharmacology ; Liver/*drug effects/enzymology ; Morpholines/pharmacology ; Phosphoenolpyruvate Carboxykinase (GTP)/*biosynthesis/genetics ; Plant Extracts/chemistry/pharmacology ; Plant Leaves/chemistry ; Polymerase Chain Reaction ; Seeds/chemistry ; *Syzygium ; }, abstract = {Insulin action is impaired in diabetic patients, which leads to increased hepatic glucose production. Plants and herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Since dietary management is a starting point for the treatment of diabetes, it is important to recognize the effect of plant-based compounds on tissues that regulate glucose metabolism, such as the liver. In a recent study, several herbs and spices were found to increase glucose uptake into adipocytes, an insulin-like effect. Our data reveal that Syzygium aromaticum (L.) Merrill and Perry (Myrtaceae) (commonly referred to as clove) extract acts like insulin in hepatocytes and hepatoma cells by reducing phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) gene expression. Much like insulin, clove-mediated repression is reversed by PI3K inhibitors and N-acetylcysteine (NAC). A more global analysis of gene expression by DNA microarray analysis reveals that clove and insulin regulate the expression of many of the same genes in a similar manner. These results demonstrate that consumption of certain plant-based diets may have beneficial effects for the treatment of diabetes and indicate a potential role for compounds derived from clove as insulin-mimetic agents.}, }
@article {pmid15587587, year = {2004}, author = {Chen, J and Kang, J and Da, W and Ou, Y}, title = {Combination with water-soluble antioxidants increases the anticancer activity of quercetin in human leukemia cells.}, journal = {Die Pharmazie}, volume = {59}, number = {11}, pages = {859-863}, pmid = {15587587}, issn = {0031-7144}, mesh = {Acetylcysteine/chemistry/pharmacology ; Antineoplastic Agents/*chemistry/*pharmacology ; Antioxidants/*chemistry/*pharmacology ; Ascorbic Acid/chemistry/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Glutathione/chemistry/pharmacology ; HL-60 Cells ; Humans ; Hydrogen Peroxide/chemistry ; Indicators and Reagents ; Leukemia/*drug therapy ; Lipid Peroxidation/drug effects ; Malondialdehyde/chemistry ; Quercetin/*chemistry/*pharmacology ; Reactive Oxygen Species ; Solubility ; }, abstract = {While accumulation of reactive oxygen species (ROS) is believed to be harmful to organisms, recent studies show that quercetin (QU), a promising antioxidant and anticancer drug, exerts its anticancer role through either diminishing or promoting ROS generation under different conditions. In the present study, it was investigated whether the water-soluble antioxidants ascorbic acid (ASA), N-acetyl-cysteine (NAC) and reduced glutathione (GSH) can enhance both the antioxidant and anticancer activity of quercetin in human myeloid leukemia cells (HL-60 cells). Proliferation, viability and ROS accumulation (indicated by the level of malondialdehyde, MDA) was significantly decreased by QU in HL-60 cells. 50 microM H2O2 markedly attenuated the antioxidant and anticancer activity of QU, proving that diminution of ROS accumulation considerably contributes to the QU-induced decrease of HL-60 cells proliferation and viability. When the effects of water-soluble antioxidants were tested, ASA at 1 mM, NAC at 500 microM, or GSH at 250 microM significantly enhanced QU-mediated proliferation arrest, cell death and ROS diminution. These results indicate that certain amounts of ROS are critical for the proliferation and viability of HL-60 cells, while water-soluble antioxidants enhance the anticancer activity of QU through scavenging ROS. Combing QU with water-soluble antioxidants could be a useful strategy to improve the anticancer activity of QU by increasing its antioxidant activity.}, }
@article {pmid15582350, year = {2005}, author = {Kling, DE and Aidlen, JT and Fisher, JC and Kinane, TB and Donahoe, PK and Schnitzer, JJ}, title = {Nitrofen induces a redox-dependent apoptosis associated with increased p38 activity in P19 teratocarcinoma cells.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {19}, number = {1}, pages = {1-10}, doi = {10.1016/j.tiv.2004.04.010}, pmid = {15582350}, issn = {0887-2333}, support = {HL062615/HL/NHLBI NIH HHS/United States ; HL069684/HL/NHLBI NIH HHS/United States ; P01HD039942/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*drug effects ; Cell Line, Tumor/drug effects/enzymology/pathology ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Herbicides/*toxicity ; In Situ Nick-End Labeling ; Mice ; Oxidation-Reduction ; Phenyl Ethers/*toxicity ; Teratocarcinoma/drug therapy/enzymology/*pathology ; p38 Mitogen-Activated Protein Kinases/*metabolism ; }, abstract = {Nitrofen is a diphenyl ether herbicide that produces a spectrum of fetal abnormalities in rodents. To characterize the molecular mechanisms of nitrofen-mediated birth defects at the cellular level, we explored its effects on undifferentiated P19 teratocarcinoma cells. Nitrofen induces a time-dependent cell death of P19 cells that is associated with increases in TUNEL-positivity and caspase-3 cleavage suggesting that nitrofen induces P19 cell apoptosis. In addition, the increase in TUNEL-positive cells was inhibited with zVAD-fmk, suggesting that nitrofen induces a caspase-dependent apoptosis. Nitrofen treatment was associated with increased p38 MAP kinase activity, though pretreatment of cells with multiple p38 inhibitors did not affect nitrofen-mediated caspase-3 cleavage, suggesting caspase-3 cleavage is p38-independent. Nitrofen induced a dose-dependent increase in reactive oxygen species (ROS), which was accompanied by a decrease in the ratio of reduced/oxidized glutathione, indicating that nitrofen alters the cellular redox state of these cells. Furthermore, pretreatment of cells with N-acetyl cysteine gave a dose- and time-dependent reduction of caspase-3 cleavage, supporting the observations that caspase-3 cleavage is cell-redox-dependent. Therefore, nitrofen induces P19 cell apoptosis that is cell-redox-dependent and is associated with increases in p38 activity and ROS and may play a role in nitrofen-mediated birth defects.}, }
@article {pmid15581425, year = {2004}, author = {Black, PN and Morgan-Day, A and McMillan, TE and Poole, PJ and Young, RP}, title = {Randomised, controlled trial of N-acetylcysteine for treatment of acute exacerbations of chronic obstructive pulmonary disease [ISRCTN21676344].}, journal = {BMC pulmonary medicine}, volume = {4}, number = {}, pages = {13}, pmid = {15581425}, issn = {1471-2466}, abstract = {BACKGROUND: Prophylactic treatment with N-acetylcysteine (NAC) for 3 months or more is associated with a reduction in the frequency of exacerbations of chronic obstructive pulmonary disease (COPD). This raises the question of whether treatment with NAC during an acute exacerbation will hasten recovery from the exacerbation.<br><br>METHODS: We have examined this in a randomised, double-blind, placebo controlled trial. Subjects, admitted to hospital with an acute exacerbation of COPD, were randomised within 24 h of admission to treatment with NAC 600 mg b.d. (n = 25) or matching placebo (n = 25). Treatment continued for 7 days or until discharge (whichever occurred first). To be eligible subjects had to be > or = 50 years, have an FEV1 < or = 60% predicted, FEV1/VC < or = 70% and > or = 10 pack year smoking history. Subjects with asthma, heart failure, pneumonia and other respiratory diseases were excluded. All subjects received concurrent treatment with prednisone 40 mg/day, nebulised salbutamol 5 mg q.i.d and where appropriate antibiotics. FEV1, VC, SaO2 and breathlessness were measured 2 hours after a dose of nebulised salbutamol, at the same time each day. Breathlessness was measured on a seven point Likert scale.<br><br>RESULTS: At baseline FEV1 (% predicted) was 22% in the NAC group and 24% in the control group. There was no difference between the groups in the rate of change of FEV1, VC, SaO2 or breathlessness. Nor did the groups differ in the median length of stay in hospital (6 days for both groups).<br><br>CONCLUSIONS: Addition of NAC to treatment with corticosteroids and bronchodilators does not modify the outcome in acute exacerbations of COPD.}, }
@article {pmid15570020, year = {2004}, author = {Hsu, CC and Yen, HF and Yin, MC and Tsai, CM and Hsieh, CH}, title = {Five cysteine-containing compounds delay diabetic deterioration in Balb/cA mice.}, journal = {The Journal of nutrition}, volume = {134}, number = {12}, pages = {3245-3249}, doi = {10.1093/jn/134.12.3245}, pmid = {15570020}, issn = {0022-3166}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Glucose/drug effects/*metabolism ; Body Weight/drug effects ; Catalase/metabolism ; Cysteine/*analogs &amp; derivatives/*therapeutic use ; Diabetes Mellitus/*prevention &amp; control ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Kidney/drug effects/metabolism ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; }, abstract = {The effects of n-acetyl cysteine (NAC), s-allyl cysteine (SAC), s-ethyl cysteine, s-methyl cysteine and s-propyl cysteine (SPC) activity on Balb/cA mice against diabetic complications were examined. These complications included hyperglycemia, hyperlipidemia, oxidation stress, blood coagulation, and cytokine imbalance. To induce diabetes, mice were treated with streptozotocin i.p. for 5 consecutive days. Five cysteine-containing compounds at 1 g/L were added to the drinking water. After intake of the 5 cysteine-containing agents for 4 wk, body weight loss, plasma concentrations of glucose and insulin, and fibronectin levels were improved (P < 0.05) in diabetic mice. The administration of these agents restored the glutathione level (P < 0.05), reduced the loss of catalase and glutathione peroxidase activities in kidney and liver (P < 0.05), and decreased glucose-induced lipid oxidation, as assessed by malondialdehyde formation (P < 0.05). In all diabetic mice, the intake of these agents reduced triglyceride levels in plasma and liver (P < 0.05); however, only NAC, SAC and SPC treatments reduced cholesterol level in liver (P < 0.05). These cysteine-containing agents elevated the activity of 2 fibrinolytic factors, protein C and antithrombin III (P < 0.05). The overexpression of interleukin-6 and tumor necrosis factor-alpha in diabetic mice was suppressed by the intake of the 5 cysteine-containing agents (P < 0.05). Via their antioxidant activities, the 5 compounds effectively improved glycemic control, delayed oxidation damage, downregulated inflammatory cytokines, and enhanced anticoagulant activity in diabetic mice. These data support the multiple roles of these agents as potential protective agents for delaying diabetic deterioration.}, }
@article {pmid15569303, year = {2004}, author = {Fukami, K and Ueda, S and Yamagishi, S and Kato, S and Inagaki, Y and Takeuchi, M and Motomiya, Y and Bucala, R and Iida, S and Tamaki, K and Imaizumi, T and Cooper, ME and Okuda, S}, title = {AGEs activate mesangial TGF-beta-Smad signaling via an angiotensin II type I receptor interaction.}, journal = {Kidney international}, volume = {66}, number = {6}, pages = {2137-2147}, doi = {10.1111/j.1523-1755.2004.66004.x}, pmid = {15569303}, issn = {0085-2538}, mesh = {Angiotensin II/metabolism ; Animals ; Cells, Cultured ; DNA/biosynthesis ; DNA-Binding Proteins/*metabolism ; Fibronectins/metabolism ; Glomerular Mesangium/cytology ; Glycation End Products, Advanced/*pharmacology ; Humans ; Male ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptor for Advanced Glycation End Products ; Receptor, Angiotensin, Type 1/*metabolism ; Receptors, Immunologic/metabolism ; Signal Transduction/*drug effects ; Smad Proteins ; Trans-Activators/*metabolism ; Transforming Growth Factor beta/*metabolism ; }, abstract = {BACKGROUND: The renin-angiotensin system (RAS) and the accumulation of advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetic nephropathy. Whether there is a functional interaction between the RAS and AGEs in diabetic nephropathy is not known. In this study, we investigated whether AGEs could activate autocrine angiotensin II (Ang II) signaling and subsequently induce transforming growth factor-beta (TGF-beta)-Smad signaling in cultured rat mesangial cells.<br><br>METHODS: The intracellular formation of reactive oxygen species (ROS) was detected using the fluorescent probe CM-H2DCFDA. Ang II was measured by radioimmunoassay. TGF-beta released into media was quantitatively analyzed in an enzyme-linked immunosorbent assay (ELISA). Smad2, p27(Kip1) (p27), fibronectin, and receptor for AGEs (RAGE) protein expression were determined by Western blot analysis. TGF-beta-inducible promoter activity was analyzed by a luciferase assay. DNA synthesis was evaluated by 5-bomo-2'-deoxyuridine (BrdU) incorporation and de novo protein synthesis was determined by [3H]leucine incorporation.<br><br>RESULTS: AGEs increased intracellular ROS generation in mesangial cells, and this effect was significantly inhibited by an antiserum against RAGE. AGEs also were found to stimulate Ang II production in a time- and dose-dependent manner, which was completely prevented by an antioxidant, N-acetylcysteine (NAC). AGE-induced TGF-beta overproduction was completely blocked by candesartan, an Ang II type 1 receptor (AT1R) antagonist. Both candesartan and neutralizing antibody against TGF-beta completely prevented AGEs-induced Smad2 phosphorylation and TGF-beta-inducible promoter activity. Furthermore, AGEs were found to inhibit DNA synthesis and to stimulate de novo protein synthesis and fibronectin production in association with up-regulation of p27. All of these phenomena were completely prevented by candesartan or a polyclonal antibody against TGF-beta.<br><br>CONCLUSION: The present study suggests that AGE-RAGE-mediated ROS generation activates TGF-beta-Smad signaling and subsequently induces mesangial cell hypertrophy and fibronectin synthesis by autocrine production of Ang II. This pathway may provide an important link between metabolic and haemodynamic factors in promoting the development and progression of diabetic nephropathy.}, }
@article {pmid15564655, year = {2004}, author = {Nehru, B and Kanwar, SS}, title = {N-acetylcysteine exposure on lead-induced lipid peroxidative damage and oxidative defense system in brain regions of rats.}, journal = {Biological trace element research}, volume = {101}, number = {3}, pages = {257-264}, doi = {10.1385/BTER:101:3:257}, pmid = {15564655}, issn = {0163-4984}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism ; Brain Chemistry/*drug effects/*physiology ; Catalase/metabolism ; Female ; Free Radical Scavengers/*pharmacology ; Lead/*pharmacology ; Lipid Peroxidation/*drug effects ; Proteins/metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {Lead (Pb) is known to disrupt the pro-oxidant/antioxidant balance of tissues, which leads to biochemical and physiological dysfunction. Oxidative stress is considered a possible molecular mechanism involved in Pb neurotoxicity. Considering the vulnerability of the brain to oxidative stress under Pb neurotoxicity, this study investigated the effects of exposure of the thiol antioxidant N-acetylcysteine (NAC) on lead-induced oxidative damage and lipid peroxidation in brain regions of the rat. Wister strain rats were exposed to lead in the form of lead acetate (20 mg/kg body wt/d) for a period of 2 wk and the effects of NAC on lead-induced neurotoxicity in rat brain regions were assessed by postadministration of NAC (160 mg/kg body wt/d) for a period of 3 wk. The lipid peroxidation byproduct, malondialdehyde (MDA) increased following lead exposure in both of the regions, and the antioxidant capacities of the cell in terms of the activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) was diminished. Following NAC treatment, lead-induced lipid peroxidation decreased and antioxidant enzyme activities improved, with CAT showing enhancement in the cerebral region only and SOD showing enhancements in the cerebellar region. Our result suggests that thiol-antioxidant supplementation following Pb exposure might enhance the reductive status of brain regions by arresting the lipid peroxidative damage in brain regions.}, }
@article {pmid15562964, year = {2004}, author = {Guranda, DT and Shapovalova, IV and Shviadas, VK}, title = {[A new N-acyl derivative of (S)-cysteine for quantitative determination of enantiomers of amino compounds by HPLC method with a precolumn modification with o-phthalaldehyde].}, journal = {Bioorganicheskaia khimiia}, volume = {30}, number = {5}, pages = {451-457}, doi = {10.1023/b:rubi.0000043781.72807.f5}, pmid = {15562964}, issn = {0132-3423}, mesh = {Acetylcysteine/chemistry ; Alcaligenes faecalis/enzymology ; Amines/*analysis/chemistry ; Amino Alcohols/analysis/chemistry ; Chromatography, High Pressure Liquid/instrumentation/*methods ; Cysteine/*analogs &amp; derivatives/*chemistry/metabolism ; Indoles/analysis/chemistry ; Penicillin Amidase/chemistry/metabolism ; Stereoisomerism ; Sulfhydryl Compounds/*chemistry ; o-Phthalaldehyde/*chemistry ; }, abstract = {N-Phenylacetyl-(R)-phenylglycyl-(S)-cysteine (NPPC) was used for the determination of enantiomers of primary amines by rpHPLC with a precolumn modification with o-phthalaldehyde. NPPC was compared with the classic SH reagent N-acetyl-(S)-cysteine (NAC) in the analysis of stereomers of nonfunctionalized amines and amino alcohols. After the NAC modification, the resulting diastereomeric isoindoles were difficult to separate by HPLC, and satisfactory resolution was achieved only for some aliphatic amino alcohols. The use of NPPC improved the chromatographic analysis of stereomeric amino alcohols and, in addition, allowed the enantiomeric analysis of the nonfunctionalized amines. Similarity between the side radicals of the amino component and the thiol reagent favored the diastereomer separation. This method was used for determination of the absolute concentration of individual enantiomers of amines in the course of stereoselective enzymatic reactions. The optically active NPPC was prepared with a high yield by a chemoenzymatic synthesis based on a regioselective acylation of the (S)-cysteine amino group in aqueous medium by the action of penicillin acylase. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 5; see also http: // www.maik.ru.}, }
@article {pmid15555789, year = {2004}, author = {Ocal, K and Avlan, D and Cinel, I and Unlu, A and Ozturk, C and Yaylak, F and Dirlik, M and Camdeviren, H and Aydin, S}, title = {The effect of N-acetylcysteine on oxidative stress in intestine and bacterial translocation after thermal injury.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {30}, number = {8}, pages = {778-784}, doi = {10.1016/j.burns.2004.05.006}, pmid = {15555789}, issn = {0305-4179}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents/*pharmacology ; Antioxidants/*pharmacology ; Bacterial Translocation/*drug effects ; Burns/microbiology/*physiopathology ; Colony Count, Microbial ; Glutathione/analysis ; Ileum/drug effects/*metabolism ; Liver/microbiology ; Lymph Nodes/microbiology ; Malondialdehyde/analysis ; Mesentery/microbiology ; Oxidative Stress/*drug effects ; Peroxidase/analysis ; Rats ; Rats, Wistar ; Spleen/microbiology ; }, abstract = {Ischemia due to transient splanchnic vasoconstriction following major burns causes oxidative and/or nitrosative damage in intestinal tissue followed by reperfusion injury. Thus, burn injury leads to breakdown in the intestinal mucosal barrier which can induce bacterial translocation (BT). As an antioxidant and anti-inflammatory agent the protective effects of N-acetylcysteine (NAC) are documented in several studies. This study was designed to determine the effect of NAC treatment on the oxidative stress in the intestine and BT after burn injury. To evaluate this, 32 Wistar rats were randomly divided into four groups as sham (n = 8), burn (n = 8), pre-burn, NAC injection (150 mgkg(-1), intraperitoneally) 15 min before thermal injury (n = 8), post-burn, NAC injection (150 mgkg(-1), intraperitoneally) 2h after thermal injury. Under anesthesia, the shaved dorsal skin of rats was exposed to boiling water for 12s to induce burn injury in a standardized manner. Twenty-four hours later, tissue samples from mesenteric lymph nodes (MLN), spleen, and liver were obtained under sterile conditions for microbiological analysis and ileum samples were harvested for biochemical analysis. In the burn group, the incidence of isolating bacteria in MLN, spleen, and liver specimens was significantly higher than other groups. NAC treatment prevented burn-induced BT in both pre- and post-burn groups. Thermal injury caused a significant decrease in glutathione (GSH) level, significant increases in malondialdehyde (MDA) and myeloperoxidase (MPO) activity at post-burn 24th hour. Treatment of rats with NAC significantly elevated the reduced GSH levels while decreasing MDA levels and MPO activity. These data suggested that NAC has a crucial cytoprotective role in intestinal mucosal barrier and preventive effects against burn injury-induced BT.}, }
@article {pmid15555443, year = {2004}, author = {Zhang, J and Li, SQ and Li, HZ and Qi, HW and Wu, CG}, title = {[NF-kappaB expression in lung tissue of acute lung injury rat model and the influence by antioxidant N-acetylcysteine].}, journal = {Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology}, volume = {20}, number = {6}, pages = {712-715}, pmid = {15555443}, issn = {1007-8738}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Epithelial Cells/metabolism ; Lipopolysaccharides ; Lung/*metabolism/pathology ; Lung Diseases/chemically induced/*metabolism/pathology ; Male ; NF-kappa B/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIM: To observe the NF-kappaB expression in the lung tissue of LPS-induced acute lung injury(ALI) rat model and the influence of N-acetylcysteine (NAC) on NF-kappaB expression.<br><br>METHODS: The expression of NF-kappaB in lung tissue in ALI rat model and the influence of NAC on NF-kappaB expression were detected by immunohistochemical (ABC) staining and Western blot.<br><br>RESULTS: There were a small amount of sporadic NF-kappaB cells in airway epithelium and interstitium in normal control group. In contrast, nuclear NF-kappaB expression-positive cells increased obviously in airway mucosa, lung interestium, alveolar cavity and vascular wall of ALI rats. NF-kappaB(+) cells were mainly airway mucosa epithelial cells, infiltrating inflammatory cells, alveolar epithelial cells, and vascular endothelial cells. The NF-kappaB expression-positive cells in NAC therapy group notably decreased compared with ALI group and control group(P<0.01). Western blot analysis showed that the expression of NF-kappaB was different at various time points, reaching the peak at 3 h and then decreased (P<0.01) after LPS induced lung injury.<br><br>CONCLUSION: In LPS induced acute lung injury rat model, the NF-kappaB nuclear expression increased obviously in airway mucosa, lung interestium and alveolar cavity. Most cells in lung tissue participated in the activation of NF-kappaB. NAC could alleviate inflammation by inhibiting activation of NF-kappaB.}, }
@article {pmid15555419, year = {2004}, author = {Flora, SJ and Pande, M and Kannan, GM and Mehta, A}, title = {Lead induced oxidative stress and its recovery following co-administration of melatonin or N-acetylcysteine during chelation with succimer in male rats.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {50 Online Pub}, number = {}, pages = {OL543-51}, pmid = {15555419}, issn = {0145-5680}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Brain/drug effects ; Brain Chemistry ; Chelating Agents/*therapeutic use ; Kidney/chemistry/drug effects ; Lead/analysis ; Lead Poisoning/enzymology/metabolism/*prevention &amp; control ; Liver/chemistry/drug effects ; Male ; Melatonin/administration &amp; dosage/*therapeutic use ; Oxidative Stress/*drug effects ; Rats ; Succimer/*therapeutic use ; }, abstract = {Lead is a ubiquitous element in the environment causing oxidative burst in the exposed individuals leading to tissue damage. Antioxidants have long been known to reduce the free radical-mediated oxidative stress while, thiol chelators have been used to treat arsenic toxicity. The therapeutic efficacy of melatonin or N-acetylcysteine (NAC) was studied in the present study, both individually and in combination with a potent thiol-chelating agent, meso 2,3-dimercaptosuccinic acid (DMSA), in reducing lead concentration in blood and other soft tissues. Their ability to restore altered haematopoietic, hepatic and other biochemical variables indicative of tissue oxidative stress in male rats was also investigated. Administration of melatonin and NAC individually, provided significant protection to lead induced disturbed antioxidant defense that may significantly compromise normal cellular function. Administration of melatonin and NAC also provided a significant protection to thiobarbituric acid reactive substances (TBARS) levels, reduced glutathione (GSH) and oxidized glutathione (GSSG) contents in tissues, suggesting their ability to act as a free radical scavenger and in protecting cells against toxic insult. NAC, a thiol containing antioxidant, has been used under several clinical conditions with few adverse side effects. It has a high toxicity threshold and its wide therapeutic window enhances its utility. The antioxidant action of NAC is due to its ability to interact with reactive oxygen species (ROS) or its ability to stimulate endogenous glutathione (GSH) synthesis. DMSA, on the other hand when given alone, provided significant recovery in restoring the altered lead sensitive biochemical indices like blood delta-aminolevulinic acid dehydratase (ALAD), urinary delta-aminolevulinic acid (ALA), beside increasing urinary lead excretion and decreasing lead concentration in blood and soft tissues. Interestingly, combined treatment of DMSA and NAC provided more pronounced efficacy in restoring altered biochemical variables and in reducing body lead burden than monotherapy with DMSA. The results thus, suggest the involvement of ROS in lead toxicity and a pronounced beneficial role of NAC in therapeutic implications of lead poisoning when co-administered with a thiol chelator (DMSA) supporting the hypothesis that cellular redox status may be significantly reversed by utilizing a thiol containing antioxidant compound. It can be concluded that, combined therapy with an antioxidant moiety and a thiol-chelating agent may be a better choice for treating plumbism.}, }
@article {pmid15546888, year = {2005}, author = {Efrati, S and Averbukh, M and Berman, S and Feldman, L and Dishy, V and Kachko, L and Weissgarten, J and Golik, A and Averbukh, Z}, title = {N-Acetylcysteine ameliorates lithium-induced renal failure in rats.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {20}, number = {1}, pages = {65-70}, doi = {10.1093/ndt/gfh573}, pmid = {15546888}, issn = {0931-0509}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biopsy, Needle ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Glomerular Filtration Rate ; Immunohistochemistry ; Injections, Intraperitoneal ; Kidney Function Tests ; Lithium ; Male ; Probability ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reference Values ; Renal Insufficiency/*pathology/*prevention &amp; control ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: Prolonged lithium treatment may induce progressive deterioration of renal function in humans and experimental animals. N-Acetylcysteine (NAC) has been shown to be effective in the prevention of hypoperfusion and toxin-induced renal failure, but its effect on lithium nephrotoxicity has not been evaluated yet. The purpose of this study was to examine a possible renoprotective effect of NAC against lithium-induced renal failure in a rat model.<br><br>METHODS: Moderate renal failure was induced in 40 Sprague-Dawley rats using a 5 week protocol including 3 weeks of lithium chloride administration in the drinking water. The animals were divided randomly into two equal groups receiving either 10 mg/kg NAC or saline by two daily intraperitoneal injections. In week 6, the glomerular filtration rate (GFR) was assessed by 99mTechnetium diethylene triaminepentaacetic acid, and serum creatinine, blood urea nitrogen (BUN) and 24 h urinary protein and osmolarity were measured. Kidneys were excised for pathological evaluation.<br><br>RESULTS: At the end of the lithium protocol, the GFR was significantly higher in the NAC-treated group compared with the control group, 0.92+/-0.35 vs 0.56+/-0.25 ml/min/100 g, respectively, P = 0.002. Serum creatinine and BUN were also significantly lower in the NAC-treated group 1.009+/-0.107 vs 1.143+/-0.118 mg/dl, P = 0.001, and 83.9+/-6.8 vs 88.95+/-7.1 mg/dl, P = 0.28, respectively. The percentages of tubular necrosis and tubular lumen obstruction, evaluated by light microscopy, were significantly lower in the NAC-treated group, P = 0.002 and P = 0.007, respectively.<br><br>CONCLUSIONS: NAC treatment has a renoprotective effect against lithium-induced renal failure in a rat model.}, }
@article {pmid15545171, year = {2004}, author = {Miyazono, Y and Gao, F and Horie, T}, title = {Oxidative stress contributes to methotrexate-induced small intestinal toxicity in rats.}, journal = {Scandinavian journal of gastroenterology}, volume = {39}, number = {11}, pages = {1119-1127}, doi = {10.1080/00365520410003605}, pmid = {15545171}, issn = {0036-5521}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase/analysis ; Intestinal Mucosa/metabolism/pathology ; Intestine, Small/*drug effects/metabolism/pathology ; Luminescent Measurements ; Male ; Methotrexate/*toxicity ; Neutrophil Infiltration ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/analysis ; Thiobarbituric Acid Reactive Substances/analysis ; Tungsten Compounds/pharmacology ; Xanthine Dehydrogenase/antagonists &amp; inhibitors/metabolism ; }, abstract = {BACKGROUND: Gastrointestinal toxicity is one of the most serious side effects in the methotrexate (MTX) treatment. However, the mechanism of the toxicity has not been completely clarified, which may be the reason why symptomatic therapy is carried out. On the other hand, the oxidative stress is known to play an important role in various diseases and drug-induced side effects. In this study the focus was on the oxidative stress in order to clarify the mechanism of MTX-induced small intestinal damage, especially neutrophil infiltration.<br><br>METHODS: MTX (20 mg/kg body wt) was administered to rats intravenously. Mucosal homogenates were prepared from the small intestine and used for assay of biochemical parameters, by which induction of oxidative stress and neutrophil infiltration were evaluated. N-acetylcysteine (NAC; 80 mg/kg body wt), an antioxidant or sodium tungstate (tungsten; 0.7 g/kg body wt), an inhibitor of xanthine dehydrogenase (XD)/xanthine oxidase (XO) known as an important source of reactive oxygen species (ROS) was given to rats with MTX to investigate the contribution of ROS to neutrophil infiltration.<br><br>RESULTS: The MTX treatment of rats induced the oxidative stress in the small intestine. The ROS production was seen preceding an increase of myeloperoxidase activity, which suggested neutrophil infiltration. Both treatments of NAC and tungsten prevented the MTX-induced ROS production and neutrophil infiltration.<br><br>CONCLUSIONS: These results suggest that oxidative stress plays an important role in the MTX-induced small intestinal damage, especially neutrophil infiltration. Thus, the modulation of oxidative stress would be useful in reducing intestinal damage in MTX treatment.}, }
@article {pmid15542721, year = {2004}, author = {Hashimoto, K and Tsukada, H and Nishiyama, S and Fukumoto, D and Kakiuchi, T and Shimizu, E and Iyo, M}, title = {Effects of N-acetyl-L-cysteine on the reduction of brain dopamine transporters in monkey treated with methamphetamine.}, journal = {Annals of the New York Academy of Sciences}, volume = {1025}, number = {}, pages = {231-235}, doi = {10.1196/annals.1316.028}, pmid = {15542721}, issn = {0077-8923}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Dopamine Plasma Membrane Transport Proteins ; Macaca mulatta ; Male ; Membrane Glycoproteins/antagonists &amp; inhibitors/*metabolism ; Membrane Transport Modulators ; Membrane Transport Proteins/antagonists &amp; inhibitors/*metabolism ; Methamphetamine/*pharmacology ; Nerve Tissue Proteins/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). The present study undertakes to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography (PET) studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [11C]b-CFT (for DAT). In contrast, the binding of [11C]DASB to 5-hydroxytryptamine transporter (5-HTT) in the monkey brain was slightly decreased after the administration of MAP, although the difference was not statistically significant. The binding of [11C]SCH 23390 to dopamine D1 receptors in the striatum was also not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before administration of MAP and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity on dopaminergic nerve terminals related to chronic use of MAP in humans.}, }
@article {pmid15542064, year = {2004}, author = {Gong, P and Hu, B and Cederbaum, AI}, title = {Diallyl sulfide induces heme oxygenase-1 through MAPK pathway.}, journal = {Archives of biochemistry and biophysics}, volume = {432}, number = {2}, pages = {252-260}, doi = {10.1016/j.abb.2004.09.024}, pmid = {15542064}, issn = {0003-9861}, support = {AA 03312/AA/NIAAA NIH HHS/United States ; }, mesh = {Allyl Compounds/*pharmacology ; Antineoplastic Agents/pharmacology ; Basic-Leucine Zipper Transcription Factors ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Neoplastic/drug effects ; Heme Oxygenase (Decyclizing)/*metabolism ; Heme Oxygenase-1 ; Hepatoblastoma/*enzymology ; Humans ; Membrane Proteins ; Mitogen-Activated Protein Kinases/*metabolism ; Multienzyme Complexes/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/*metabolism ; Sulfides/*pharmacology ; Transcription Factors/*metabolism ; Transcriptional Activation ; }, abstract = {Diallyl sulfide (DAS), is protective against chemically induced heptotoxicity, mutagenesis, and carcinogenesis. The mechanism of its protective effects is not fully understood. In this study, we found that DAS can induce the expression of heme oxygenase-1 (HO-1), which plays a critical role in the cell defense system against oxidative stress. DAS causes a dose- and time-dependent increase of HO-1 protein and mRNA level without toxicity in HepG2 cells. DAS-induced HO-1 protein expression is dependent on newly synthesized mRNA and newly synthesized protein. DAS increases Nrf2 protein expression, nuclear translocation, and DNA-binding activity. The MAP kinase ERK is activated by DAS. Both ERK and p38 pathways play an important role in DAS-induced Nrf2 nuclear translocation and ho-1 gene activation. DAS stimulates a transient increase of reactive oxygen species (ROS). N-Acetyl-cysteine blocked this increase of ROS production as well as DAS-induced ERK activation, Nrf2 protein expression and nuclear translocation, and ho-1 gene activation. The increase in HO-1 produced by DAS protected the HepG2 cells against toxicity by hydrogen peroxide or arachidonic acid. These results suggest that DAS induces ho-1 through production of ROS, and Nrf2 and MAPK (ERK and p38) mediate this induction. Induction of ho-1 may play a role in the protective effects of DAS.}, }
@article {pmid15537745, year = {2005}, author = {Wei, M and Arnold, L and Cano, M and Cohen, SM}, title = {Effects of co-administration of antioxidants and arsenicals on the rat urinary bladder epithelium.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {83}, number = {2}, pages = {237-245}, doi = {10.1093/toxsci/kfi033}, pmid = {15537745}, issn = {1096-6080}, support = {1 P20 RR16469/RR/NCRR NIH HHS/United States ; }, mesh = {Administration, Oral ; Animals ; Antioxidants/*pharmacology ; Cacodylic Acid/administration &amp; dosage/*toxicity ; Carcinogens/administration &amp; dosage/*toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Interactions ; Female ; Oxidative Stress/drug effects ; Rats ; Rats, Inbred F344 ; Tissue Array Analysis ; Urinary Bladder/*drug effects/metabolism/pathology ; Urothelium/*drug effects/metabolism/pathology ; }, abstract = {Oxidative stress has been increasingly recognized as a possible mechanism in the toxicity and carcinogenicity of various chemicals, including arsenic. Therefore, treatment with antioxidants may afford a protective effect against arsenic-induced cytotoxicity and carcinogenesis. Dimethylarsinic acid (DMAV) has been shown to be a bladder carcinogen in rats when administered at high doses (100 ppm) in the diet or in the drinking water. The main purpose of the present study was to evaluate the effects of co-administration of antioxidants with arsenicals on the rat urinary bladder epithelium in vitro and in vivo. In a previous experiment, treatment with 1000 ppm melatonin for two weeks did not inhibit cell proliferation induced in the rat urothelium by 100 ppm DMAV. In the current study, we examined the effects of five antioxidants that act via different mechanisms, on the in vitro cytotoxicity of various arsenicals, for the purpose of determining which antioxidants might have protective effects against arsenic-induced cytotoxicity. The antioxidants that inhibited cytotoxicity in vitro were then studied also in vivo. Melatonin showed slight inhibition of the cytotoxicity of arsenite, but had no effect on the other arsenicals. N-acetylcysteine (NAC) inhibited the cytotoxicity of monomethylarsonous acid (MMAIII), DMAV, dimethylarsinous acid (DMAIII), and trimethylarsine oxide (TMAO). Vitamin C inhibited cytotoxicity induced by arsenate, arsenite, MMAIII) and DMAIII. Tiron and Trolox had no effect on the cytotoxicity of any arsenical. The in vitro inhibitory effects of NAC and vitamin C on DMAV and on DMAIII, suggested that these antioxidants might afford preventive effects on DMAV-induced bladder cytotoxicity and carcinogenesis in rats. To test this hypothesis, a 10-week rat bioassay was conducted. Melatonin was also included to clarify the results of the previous two-week experiment. The sodium salt of vitamin C (Na-Asc), but not melatonin or NAC, inhibited the proliferative effects of DMAV on the bladder epithelium in rats. These results suggest that oxidative stress is at least in part involved in DMAV-induced rat bladder toxicity and proliferation, and therefore, vitamin C may afford inhibitory effects in DMAV-induced bladder carcinogenesis in rats. Microarray analysis of DMAV-responsive genes revealed that DMAV did not have a consistent modifying effect on gene expression in the rat bladder epithelium, suggesting that proteins and/or lipids may be the targets of damage by DMAV-induced oxidative stress.}, }
@article {pmid15536073, year = {2005}, author = {Lin, Y and Berg, AH and Iyengar, P and Lam, TK and Giacca, A and Combs, TP and Rajala, MW and Du, X and Rollman, B and Li, W and Hawkins, M and Barzilai, N and Rhodes, CJ and Fantus, IG and Brownlee, M and Scherer, PE}, title = {The hyperglycemia-induced inflammatory response in adipocytes: the role of reactive oxygen species.}, journal = {The Journal of biological chemistry}, volume = {280}, number = {6}, pages = {4617-4626}, doi = {10.1074/jbc.M411863200}, pmid = {15536073}, issn = {0021-9258}, support = {R01-HL-073163-01/HL/NHLBI NIH HHS/United States ; DK61228/DK/NIDDK NIH HHS/United States ; P01-AG021654/AG/NIA NIH HHS/United States ; 1R01-DK55758/DK/NIDDK NIH HHS/United States ; R01 DK050610/DK/NIDDK NIH HHS/United States ; T32-GM07288/GM/NIGMS NIH HHS/United States ; }, mesh = {3T3-L1 Cells ; 8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/chemistry ; Adenoviridae/genetics ; Adipocytes/metabolism/*pathology ; Animals ; Blotting, Northern ; Cell Differentiation ; Deoxyguanosine/*analogs &amp; derivatives/chemistry ; Diabetes Mellitus, Experimental ; Dicarboxylic Acid Transporters/metabolism ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation ; Glucose/metabolism ; Hyperglycemia/*metabolism ; Immunoblotting ; Inflammation ; Insulin/metabolism ; Interleukin-6/metabolism ; Membrane Potentials ; Mice ; Mitochondria/metabolism ; Oxidative Stress ; Oxygen/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species ; Reverse Transcriptase Polymerase Chain Reaction ; Streptozocin/pharmacology ; Time Factors ; Transcription, Genetic ; Up-Regulation ; }, abstract = {Hyperglycemia is a major independent risk factor for diabetic macrovascular disease. The consequences of exposure of endothelial cells to hyperglycemia are well established. However, little is known about how adipocytes respond to both acute as well as chronic exposure to physiological levels of hyperglycemia. Here, we analyze adipocytes exposed to hyperglycemia both in vitro as well as in vivo. Comparing cells differentiated at 4 mm to cells differentiated at 25 mm glucose (the standard differentiation protocol) reveals severe insulin resistance in cells exposed to 25 mm glucose. A global assessment of transcriptional changes shows an up-regulation of a number of mitochondrial proteins. Exposure to hyperglycemia is associated with a significant induction of reactive oxygen species (ROS), both in vitro as well as in vivo in adipocytes isolated from streptozotocin-treated hyperglycemic mice. Furthermore, hyperglycemia for a few hours in a clamped setting will trigger the induction of a pro-inflammatory response in adipose tissue from rats that can effectively be reduced by co-infusion of N-acetylcysteine (NAC). ROS levels in 3T3-L1 adipocytes can be reduced significantly with pharmacological agents that lower the mitochondrial membrane potential, or by overexpression of uncoupling protein 1 or superoxide dismutase. In parallel with ROS, interleukin-6 secretion from adipocytes is significantly reduced. On the other hand, treatments that lead to a hyperpolarization of the mitochondrial membrane, such as overexpression of the mitochondrial dicarboxylate carrier result in increased ROS formation and decreased insulin sensitivity, even under normoglycemic conditions. Combined, these results highlight the importance ROS production in adipocytes and the associated insulin resistance and inflammatory response.}, }
@article {pmid15534662, year = {2004}, author = {Rygnestad, T and Fagerhaug, &#xd8;}, title = {[Acute deliberate self-poisonings in the area of Trondheim, 1978-2002].}, journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke}, volume = {124}, number = {21}, pages = {2736-2739}, pmid = {15534662}, issn = {0807-7096}, mesh = {Adult ; Female ; Humans ; Incidence ; Length of Stay/statistics &amp; numerical data ; Male ; Norway/epidemiology ; Poisoning/complications/*epidemiology/mortality ; Prospective Studies ; Self-Injurious Behavior/complications/*epidemiology/mortality ; Suicide/*statistics &amp; numerical data ; Suicide, Attempted/*statistics &amp; numerical data ; }, abstract = {BACKGROUND: Deliberate self-poisoning is a big health problem. We wanted to study if there had been changes in drug use, morbidity and mortality in this group over the last 25 years in our hospital's catchment area.<br><br>MATERIAL AND METHODS: In this study, 924 patients admitted to our hospital after deliberate self-poisoning in 1978, 1987 and 2002 were studied prospectively.<br><br>RESULTS: From 1978 to 1987, there was a significant increase in the incidence of self-poisoning followed by a decline from 1987 to 2002 among both men and women. The age distribution remained the same. Benzodiazepines were the most commonly used drugs during the whole period (20% of patients in 1978, 39% in 1987, and 30% in 2002). There has been a significant reduction in the use of acetylsalicylic acid, tricyclic antidepressants and a significant increase in paracetamol and selective serotonin reuptake inhibitor poisonings. The use of gastric lavage and activated charcoal declined. The main antidote in 1978 was physostigmine, in 1987 and 2002 n-acetyl cysteine. During the whole period, complications (usually minor) were recorded in approximately 10% of cases. In 1978, mortality was 1.3%, in 1987 0.9%; no patient died in 2002.<br><br>INTERPRETATION: The incidence of deliberate self-poisoning has fallen over the last 25 years. Selective serotonin reuptake inhibitors have to a large extent replaced tricyclic antidepressants and paracetamol has replaced acetylsalicylic acid.}, }
@article {pmid15528999, year = {2004}, author = {You, S and Kong, BW and Jeon, SY and Foster, DN and Kim, H}, title = {Deregulation of catalase, not MnSOD, is associated with necrotic death of p53-defective DF-1 cells under antimycin A-induced oxidative stress.}, journal = {Molecules and cells}, volume = {18}, number = {2}, pages = {220-229}, pmid = {15528999}, issn = {1016-8478}, mesh = {Animals ; Antimycin A/pharmacology ; Catalase/genetics/*physiology ; Cell Line ; Chick Embryo ; Fibroblasts/metabolism/*pathology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects/*physiology ; Humans ; Necrosis ; *Oxidative Stress ; Superoxide Dismutase/genetics/*physiology ; Transfection ; Tumor Suppressor Protein p53/*deficiency ; }, abstract = {One of distinct genetic alterations in spontaneously immortalized DF-1 cells was found to be dysfunction of p53 and E2F-1 as well as altered antioxidant gene expression (upregulation of MnSOD and downregulation of catalase). We have characterized the cellular responses of primary and immortal DF-1 cells to oxidative stress and found that DF-1 cells were more sensitive to oxidative stress than their primary counterparts when treated with antimycin A. The increased DF-1 cell death by oxidative stress was accompanied by an increase in the levels of intracellular superoxide anions and hydrogen peroxide. The cell death in DF-1 cells by antimycin A showed none of the hallmarks of apoptosis, but displayed a significantly increased necrotic cell population. Anti-apoptotic Bcl-2 failed to inhibit oxidative-induced necrotic cell death in the DF-1 cells. However, this necrotic cell death was significantly decreased by treatment with hydrogen peroxide scavengers such as sodium pyruvate and N-acetyl-cysteine. Interestingly, overexpression of human catalase in DF-1 cells endowed cells resistant to the oxidative stress by antimycin A treatment, although the downregulation of MnSOD by an antisense strategy showed no evident change in the cytotoxic effect caused by antimycin A. Taken together, the present study might provide new therapeutic approach for tumor cells having the loss of p53 function and the altered antioxidant functions.}, }
@article {pmid15527868, year = {2005}, author = {James, SJ and Slikker, W and Melnyk, S and New, E and Pogribna, M and Jernigan, S}, title = {Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors.}, journal = {Neurotoxicology}, volume = {26}, number = {1}, pages = {1-8}, doi = {10.1016/j.neuro.2004.07.012}, pmid = {15527868}, issn = {0161-813X}, mesh = {Acetylcysteine/pharmacology ; Anti-Infective Agents, Local/antagonists &amp; inhibitors/*toxicity ; Astrocytes/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Culture Media ; Cystine/pharmacology ; Dose-Response Relationship, Drug ; Electrochemistry ; Glutathione/*analogs &amp; derivatives/*metabolism/*pharmacology ; Humans ; Neurons/drug effects ; Thimerosal/antagonists &amp; inhibitors/*toxicity ; }, abstract = {Thimerosol is an antiseptic containing 49.5% ethyl mercury that has been used for years as a preservative in many infant vaccines and in flu vaccines. Environmental methyl mercury has been shown to be highly neurotoxic, especially to the developing brain. Because mercury has a high affinity for thiol (sulfhydryl (-SH)) groups, the thiol-containing antioxidant, glutathione (GSH), provides the major intracellular defense against mercury-induced neurotoxicity. Cultured neuroblastoma cells were found to have lower levels of GSH and increased sensitivity to thimerosol toxicity compared to glioblastoma cells that have higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity was associated with depletion of intracellular GSH in both cell lines. Pretreatment with 100 microM glutathione ethyl ester or N-acetylcysteine (NAC), but not methionine, resulted in a significant increase in intracellular GSH in both cell types. Further, pretreatment of the cells with glutathione ethyl ester or NAC prevented cytotoxicity with exposure to 15 microM Thimerosal. Although Thimerosal has been recently removed from most children's vaccines, it is still present in flu vaccines given to pregnant women, the elderly, and to children in developing countries. The potential protective effect of GSH or NAC against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccinations.}, }
@article {pmid15524403, year = {2004}, author = {Koksel, O and Ozdulger, A and Ercil, M and Tamer, L and Ercan, B and Atik, U and Cinel, L and Cinel, I and Kanik, A}, title = {Effects of N-acetylcysteine on oxidant-antioxidant balance in oleic acid-induced lung injury.}, journal = {Experimental lung research}, volume = {30}, number = {6}, pages = {431-446}, doi = {10.1080/01902140490476319}, pmid = {15524403}, issn = {0190-2148}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism ; Disease Models, Animal ; Drug Administration Schedule ; Female ; Injections, Intravenous ; Lung/drug effects/metabolism ; Malondialdehyde/analysis ; Oleic Acid/toxicity ; Oxidative Stress/*drug effects ; Peroxidase/blood ; Rats ; Rats, Wistar ; Respiratory Distress Syndrome/chemically induced/pathology/*prevention &amp; control ; Sodium-Potassium-Exchanging ATPase/metabolism ; Time Factors ; }, abstract = {The antioxidant and anti-inflammatory properties of N-acetylcysteine has been documented in many experimental lung injury models. Because intravenous injection of oleic acid induces histopathologic changes similar to those seen in human acute lung injury or acute respiratory distress syndrome, the authors evaluated the effects of N-acetylcysteine (NAC) on oxidative stress and lung damage in an oleic acid (OA)-induced lung injury model. Thirty-five rats were divided into 5 groups as sham, NAC, OA, pre-OA-NAC, and post-OA-NAC. Lung damage was induced by intravenous administration of oleic acid. Pre-OA-NACgroup received intravenous (IV) N-acetylcysteine 15 minutes before oleic acid infusion and post-OA-NAC group received IV N-acetylcysteine 2 hours after oleic acid infusion. In both of the N-acetylcysteine treatment groups, blood and tissue samples were collected 4 hours after oleic acid infusion, independent from the time of N-acetylcysteine infusion. In other groups, blood and tissue samples were collected 4 hours after ethanol, NAC, or OA infusions. Serum myeloperoxidase activity, total antioxidant capacity, malondialdehyde levels, and lung tissue Na+ - K+ ATPase activity were measured and light microscopic analyses of lung specimens were performed. The administration of N-acetylcysteine significantly restored Na+ - K+ ATPase activity and total antioxidant capacity levels and ameliorated lung architecture. N-acetylcysteine has been shown to have some attenuating effects in experimental animal studies. However, further investigations are necessary to suggest N-acetylcysteine as a treatment agent in critically ill patients with lung injury.}, }
@article {pmid15522899, year = {2005}, author = {Leehey, DJ and Palubiak, DJ and Chebrolu, S and Agarwal, R}, title = {Sodium ferric gluconate causes oxidative stress but not acute renal injury in patients with chronic kidney disease: a pilot study.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {20}, number = {1}, pages = {135-140}, doi = {10.1093/ndt/gfh565}, pmid = {15522899}, issn = {0931-0509}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acute Kidney Injury/chemically induced/epidemiology ; Aged ; Aged, 80 and over ; Analysis of Variance ; Anemia/*drug therapy/etiology ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Ferric Compounds/*adverse effects/therapeutic use ; Humans ; Infusions, Intravenous ; Kidney Failure, Chronic/complications/diagnosis ; Kidney Function Tests ; Male ; Malondialdehyde/metabolism ; Oxidative Stress/*physiology ; Pilot Projects ; Probability ; Prognosis ; Prospective Studies ; Risk Assessment ; Severity of Illness Index ; Single-Blind Method ; }, abstract = {BACKGROUND: Intravenous (i.v) iron is widely used to treat anaemia in patients with chronic kidney disease (CKD). Although beneficial and usually well tolerated, concerns have been raised about its ability to cause oxidative stress and renal injury.<br><br>METHODS: To determine if i.v. iron causes oxidative stress [as assessed by plasma and urine malondialdehye (MDA)] and/or renal injury (as assessed by urinary albumin, total protein and enzymuria), we conducted a prospective, four-way randomized crossover, blinded end-point trial in eight patients with CKD. Two widely used doses of sodium ferric gluconate (125 mg infused over 1 h and 250 mg infused over 2 h) were given with or without the antioxidant N-acetylcysteine (NAC), resulting in four treatment dose-antioxidant/placebo combinations in each patient. Transferrin saturation was measured with urea polyacrylamide gel electrophoresis, MDA by high performance liquid chromatography, and albuminuria and proteinuria by standard clinical methods. Enzymuria was assessed by measurement of N-acetyl-beta-D-glucosaminidase (NAG) excretion by colorimetric assay.<br><br>RESULTS: I.v. ferric gluconate infusion at both doses resulted in a marked increase in transferrin saturation and a significant increase in plasma MDA levels. Urinary MDA levels also increased at the higher dose of iron. There was no evidence of acute renal injury, as assessed by albuminuria, proteinuria or enzymuria. Pre-treatment with NAC had no effect on oxidative stress or the above urinary parameters.<br><br>CONCLUSIONS: I.v. ferric gluconate caused oxidative stress (as reflected by increased MDA), but this was not associated with biochemical manifestations of acute renal injury.}, }
@article {pmid15522273, year = {2004}, author = {Fiordaliso, F and Bianchi, R and Staszewsky, L and Cuccovillo, I and Doni, M and Laragione, T and Salio, M and Savino, C and Melucci, S and Santangelo, F and Scanziani, E and Masson, S and Ghezzi, P and Latini, R}, title = {Antioxidant treatment attenuates hyperglycemia-induced cardiomyocyte death in rats.}, journal = {Journal of molecular and cellular cardiology}, volume = {37}, number = {5}, pages = {959-968}, doi = {10.1016/j.yjmcc.2004.07.008}, pmid = {15522273}, issn = {0022-2828}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Apoptosis/*drug effects ; Cardiomegaly/prevention &amp; control ; Cell Nucleus/chemistry/metabolism ; Diabetes Mellitus, Experimental/*drug therapy/metabolism ; Glucose/metabolism/*pharmacology ; Glutathione/analysis/metabolism ; Heart Ventricles/cytology ; Myocardium/chemistry/metabolism ; Myocytes, Cardiac/chemistry/*drug effects/metabolism ; Oxidative Stress/drug effects ; Rats ; Reactive Oxygen Species/analysis/metabolism ; }, abstract = {Diabetes and oxidative stress concur to cardiac myocyte death in various experimental settings. We assessed whether N-acetyl-L-cysteine (NAC), an antioxidant and glutathione precursor, has a protective role in a rat model of streptozotocin (STZ)-induced diabetes and in isolated myocytes exposed to high glucose (HG). Diabetic rats were treated with NAC (0.5 g/kg per day) or vehicle for 3 months. At sacrifice left ventricle (LV) myocyte number and size, collagen deposition and reactive oxygen species (ROS) were measured by quantitative histological methods. Diabetes reduced LV myocyte number by 29% and increased myocyte volume by 20% compared to non-diabetic controls. NAC protected from myocyte loss (+25% vs. untreated diabetics, P < 0.05) and reduced reactive hypertrophy (-16% vs. untreated diabetics, P < 0.05). Perivascular fibrosis was high in diabetic rats (+88% vs. control, P < 0.001) but prevented by NAC. ROS production and fraction of ROS-positive cardiomyocyte nuclei were drastically raised in diabetic rats (2.4- and 5.1-fold vs. control, P < 0.001) and normalized by NAC. In separate experiments, isolated adult rat ventricular myocytes were incubated in a medium containing high concentrations of glucose (HG, 25 mM) +/- 0.01 mM NAC; myocyte survival (Trypan blue exclusion and apoptosis by TUNEL) and glutathione content were evaluated. The number of dead and apoptotic myocytes increased five and 6.7-fold in HG and glutathione decreased by 48% (P < 0.05). NAC normalized cell death and apoptosis and prevented glutathione loss. NAC effectively protects from hyperglycemia-induced myocyte cell death and compensatory hypertrophy through direct scavenging of ROS and replenishment of the intracellular glutathione content.}, }
@article {pmid15522207, year = {2004}, author = {Kim, JM and Kim, H and Kwon, SB and Lee, SY and Chung, SC and Jeong, DW and Min, BM}, title = {Intracellular glutathione status regulates mouse bone marrow monocyte-derived macrophage differentiation and phagocytic activity.}, journal = {Biochemical and biophysical research communications}, volume = {325}, number = {1}, pages = {101-108}, doi = {10.1016/j.bbrc.2004.09.220}, pmid = {15522207}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Bone Marrow Cells/cytology/drug effects/*physiology ; Cell Differentiation/*physiology ; Cells, Cultured ; Female ; Glutathione/*metabolism ; Macrophage Colony-Stimulating Factor/metabolism ; Macrophages/cytology/drug effects/*physiology ; Methionine Sulfoximine/*analogs &amp; derivatives/pharmacology ; Mice ; Mice, Inbred C57BL ; Monocytes/cytology/*physiology ; Oxidation-Reduction ; Phagocytosis/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Although a redox shift can regulate the development of cells, including proliferation, differentiation, and survival, the role of the glutathione (GSH) redox status in macrophage differentiation remains unclear. In order to elucidate the role of a redox shift, macrophage-like cells were differentiated from the bone marrow-derived monocytes that were treated with a macrophage colony stimulating factor (M-CSF or CSF-1) for 3 days. The macrophagic cells were characterized by a time-dependent increase in three major symptoms: the number of phagocytic cells, the number of adherent cells, and the mRNA expression of c-fms, a M-CSF receptor that is one of the macrophage-specific markers and mediates development signals. Upon M-CSF-driven macrophage differentiation, the GSH/GSSG ratio was significantly lower on day 1 than that observed on day 0 but was constant on days 1-3. To assess the effect of the GSH-depleted and -repleted status on the differentiation and phagocytosis of the macrophages, GSH depletion by BSO, a specific inhibitor of the de novo GSH synthesis, inhibited the formation of the adherent macrophagic cells by the down-regulation of c-fms, but did not affect the phagocytic activity of the macrophages. To the contrary, GSH repletion by the addition of NAC, which is a GSH precursor, or reduced GSH in media had no effect on macrophage differentiation, and led to a decrease in the phagocytic activity. Furthermore, we observed that there is checkpoint that is capable of releasing from the inhibition of the formation of the adherent macrophagic cells according to GSH depletion by BSO. Summarizing, these results indicate that the intracellular GSH status plays an important role in the differentiation and phagocytosis of macrophages.}, }
@article {pmid15521608, year = {2004}, author = {Hydzik, P and Drozdz, M and Sułowicz, W and Groszek, B}, title = {[Liver albumin dialysis--application in acetaminophen poisoning].}, journal = {Przeglad lekarski}, volume = {61}, number = {4}, pages = {377-382}, pmid = {15521608}, issn = {0033-2240}, mesh = {Acetaminophen/blood/*poisoning ; Adult ; Analgesics, Non-Narcotic/blood/poisoning ; Drug Overdose ; Female ; Hepatic Encephalopathy/chemically induced/*therapy ; Humans ; Liver Failure, Acute/chemically induced/*therapy ; Male ; Middle Aged ; *Renal Dialysis/methods ; Serum Albumin/*metabolism ; Treatment Outcome ; }, abstract = {UNLABELLED: Acetaminophen is found to be potentially hepatotoxic drug. Both, acute acetaminophen intoxication (dose >10 g) and therapeutic dose administration in the case of glutathion depletion (chronic alcohol abuse) hepatotoxic effect may occur. Late N-acetylcysteine (NAC) administration does not prevent liver injury. Molecular Adsorbents Recirculating System (MARS) is useful liver support device based on albumin dialysis for saving time for spontaneous liver regeneration or bridging technique to liver transplantation.<br><br>CASE SERIES: Two cases admitted to the Department in 19 and 20 hour post-ingestion of hepatotoxic paracetamol doses as confirmed by toxiocological examination (serum paracetamol concentration). Despite of NAC administration the signs of the liver injury (progressive encephalopathy and jaundice, decreased prothrombin activity) developed. On day four post exposure according to King's College of Medicine London criteria both cases were qualified to MARS therapy. Albumin dialysis of 8 hour duration was performed in both cases and a full recovery with normalization of the liver function was noted. Patient three: patient with the liver and the kidney insufficiency due to alcohol-paracetamol syndrome admitted to the Department of Clinical Toxicology for MARS therapy. Five performed dialysis resulted in the liver function improvement. The patient was disqualified from the liver transplant because of heart failure, pneumonia, hyperthyroidism and alcoholism. Patient died because of heart failure.}, }
@article {pmid15519005, year = {2004}, author = {Maeder, M and Klein, M and Fehr, T and Rickli, H}, title = {Contrast nephropathy: review focusing on prevention.}, journal = {Journal of the American College of Cardiology}, volume = {44}, number = {9}, pages = {1763-1771}, doi = {10.1016/j.jacc.2004.06.075}, pmid = {15519005}, issn = {0735-1097}, mesh = {Acute Kidney Injury/*chemically induced/epidemiology/prevention &amp; control ; Contrast Media/*adverse effects ; Humans ; Primary Prevention ; Review Literature as Topic ; Risk Factors ; }, abstract = {Contrast nephropathy (CN) accounts for significant morbidity and mortality. Patients with pre-existing renal insufficiency, especially those with diabetic nephropathy, are at particular risk. Medullary hypoxia due to decreased renal blood flow and direct cytotoxicity contribute to the pathogenesis. Contrast nephropathy is usually defined as an increase in serum creatinine concentration >0.5 mg/dl or 25% above the baseline level within 48 h. Intravenous hydration (saline 0.45%, if tolerated 0.9% at a rate of 1 ml/kg/h) 12 h before and after contrast exposure and the use of low or iso-osmolality contrast agents are advisable. The benefit of low-dose dopamine as well as the selective dopamine-1 receptor agonist fenoldopam is unproven. Studies on the effectiveness of the adenosine antagonist theophylline have led to conflicting results. Because theophylline has a narrow therapeutic range and may be associated with adverse effects, it is not a prophylactic agent of first choice. The administration of N-acetylcysteine (NAC) has been evaluated in several trials with inconsistent results. Newer data suggest a benefit of high-dose NAC (1,200 mg twice daily) for patients receiving high doses (>140 ml) of contrast agent, or those with advanced renal insufficiency (creatinine >2.5 mg/dl). Whereas prophylactic hemodialysis does not prevent CN, a recent study demonstrated a marked benefit of prophylactic hemofiltration.}, }
@article {pmid15514602, year = {2004}, author = {Denlinger, CE and Rundall, BK and Jones, DR}, title = {Proteasome inhibition sensitizes non-small cell lung cancer to histone deacetylase inhibitor-induced apoptosis through the generation of reactive oxygen species.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {128}, number = {5}, pages = {740-748}, doi = {10.1016/j.jtcvs.2004.07.010}, pmid = {15514602}, issn = {0022-5223}, support = {CA 83920/CA/NCI NIH HHS/United States ; F32 CA 10149 7/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis/*drug effects ; Boronic Acids/pharmacology ; Bortezomib ; Carcinoma, Non-Small-Cell Lung/*drug therapy/physiopathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Synergism ; Enzyme Inhibitors/*pharmacology ; Histone Deacetylase Inhibitors ; Humans ; Hydroxamic Acids/pharmacology ; Lung Neoplasms/*drug therapy/physiopathology ; Mitochondria/drug effects ; NF-kappa B/genetics/metabolism ; Proteasome Inhibitors ; Pyrazines/pharmacology ; Reactive Oxygen Species/*metabolism ; Transcription, Genetic/drug effects ; Vorinostat ; }, abstract = {OBJECTIVES: The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis in some malignancies through mitochondrial injury and generation of reactive oxygen species. Histone deacetylase inhibitors also activate the antiapoptotic transcription factor nuclear factor kappaB. We hypothesize that proteasome inhibition with bortezomib (Velcade; Millennium Pharmaceuticals, Inc, Cambridge, Mass)will inhibit nuclear factor kappaB activation, enhance suberoylanilide hydroxamic acid-induced mitochondrial injury, and sensitize non-small cell lung cancer cells to apoptosis.<br><br>METHODS: Four tumorigenic non-small cell lung cancer cell lines were treated with nothing, suberoylanilide hydroxamic acid, bortezomib, or both drugs. Nuclear factor kappaB-dependent transcription was determined by reporter gene assays and endogenous interleukin 8 transcription. Reactive oxygen species were quantified by using the fluorophore H 2 DCFDA. Cell viability was determined on the basis of clonogenic survival, and apoptosis was measured by quantifying caspase-3 activity and DNA fragmentation. Apoptosis and cell-survival assays were repeated in similarly treated cells incubated in the presence or absence of N-acetyl cysteine. Statistical significance was determined by means of analysis of variance.<br><br>RESULTS: Suberoylanilide hydroxamic acid significantly enhanced interleukin 8 and nuclear factor kappaB-dependent reporter gene transcription, and these effects were inhibited by bortezomib (P < or = .01). Combined treatment with suberoylanilide hydroxamic acid and bortezomib induced greater reactive oxygen species generation, more apoptosis (P < or = .02), and more cell death (P < or = .001) than either drug alone. N-acetyl cysteine diminished the induction of apoptosis and enhanced cell survival (P < or = .04).<br><br>CONCLUSIONS: Suberoylanilide hydroxamic acid and bortezomib synergistically induce reactive oxygen species generation in non-small cell lung cancer, and this plays a critical role in the induction of apoptosis after treatment. Combined treatment with suberoylanilide hydroxamic acid and bortezomib might be an effective treatment strategy for non-small cell lung cancer.}, }
@article {pmid15513815, year = {2004}, author = {Steerenberg, PA and Withagen, CE and van Dalen, WJ and Dormans, JA and van Loveren, H}, title = {Adjuvant activity of ambient particulate matter in macrophage activity-suppressed, N-acetylcysteine-treated, iNOS- and IL-4-deficient mice.}, journal = {Inhalation toxicology}, volume = {16}, number = {13}, pages = {835-843}, doi = {10.1080/08958370490506600}, pmid = {15513815}, issn = {0895-8378}, mesh = {Acetylcysteine/immunology/metabolism/*pharmacology ; Adjuvants, Immunologic/administration &amp; dosage/*pharmacokinetics ; Administration, Intranasal ; Air Pollutants/analysis/immunology ; Animals ; Cation Transport Proteins/immunology/metabolism ; Dust/analysis/immunology ; Interleukin-4/*deficiency/genetics/immunology ; Macrophage Activation/drug effects ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Knockout/*genetics ; Netherlands ; Nitric Oxide Synthase/*deficiency/genetics/immunology ; Nitric Oxide Synthase Type II ; Ovalbumin/immunology/pharmacology ; *Particle Size ; Polycyclic Aromatic Hydrocarbons/analysis/immunology ; Time Factors ; }, abstract = {In previous studies, we have shown strong adjuvant activity for Ottawa dust (EHC-93) after coexposure of the BALB/c mouse to EHC-93 and ovalbumin. Mice were intranasally sensitized at days 0 and 14 with 200 microg ovalbumin and 150 microg EHC-93, and challenged with ovalbumin at days 35, 38, and 41 with 200 microg ovalbumin. Mice were autopsied at day 42. This adjuvant activity was shown for the antibody response to ovalbumin (immunoglobulins E, G1, and G2a), histopathological lesions in the lung, cytokines, and the numbers of eosinophils in lung lavages. To study the mechanisms of this adjuvant activity, mice (BALB/cC.D2-Vil6) with natural-resistance-associated macrophage protein (Nramp1s), BALB/c mice pretreated with the antioxidant N-acetylcysteine (NAC), mice (B6.129P2-Nos2tmLau) deficient in inducible nitric oxide synthase (iNOS), and mice with interleukin-4 (IL-4) deficiency (BALB/cIl4< tm2Nnt) were coexposed to ovalbumin and EHC-93. Our studies have shown that the adjuvant activity induced after such coexposure does not change if the macrophage activation of the mice is disturbed or if the mice have been pretreated with N-acetylcysteine. In addition, the adjuvant activity does not develop through the pathway in which inducible nitric oxide synthase is involved. Because the histopathological lesions are statistically significant less in the IL-4 knockout strain in comparison with the wild type, we conclude that interleukin-4 might play an important role in the adjuvant activity caused by EHC-93.}, }
@article {pmid15502923, year = {2004}, author = {Irie, J and Shimada, A and Oikawa, Y and Shigihara, T and Saruta, T}, title = {N-acetyl-cysteine accelerates transfer of diabetes into non-obese diabetic scid mice.}, journal = {Diabetologia}, volume = {47}, number = {10}, pages = {1803-1809}, pmid = {15502923}, issn = {0012-186X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cytokines/blood/genetics ; Diabetes Mellitus, Type 1/*physiopathology ; Disease Models, Animal ; Female ; Islets of Langerhans/drug effects/metabolism ; *Lymphocyte Transfusion ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Polymerase Chain Reaction ; Spleen ; Time Factors ; }, abstract = {AIMS/HYPOTHESIS: Type 1 diabetes mellitus is caused by autoimmune pancreatic beta cell destruction, and the destructive process involves several molecular mechanisms including oxygen-reactive species. A cysteine derivative, N-acetyl-cysteine, is widely used as an antioxidant, but the role of N-acetyl-cysteine in the protection of pancreatic beta cells in type 1 diabetes remains unclear. The aim of this study was to clarify the effect of N-acetyl-cysteine on beta cells using an adoptive transfer system in a murine model of type 1 diabetes.<br><br>METHODS: Splenocytes from diabetic female non-obese diabetic mice were transferred into female non-obese diabetic scid/ scid recipients to induce diabetes. Just after transfer, N-acetyl-cysteine was administered to non-obese diabetic scid recipients. Two weeks after transfer, the pancreas of the recipients was examined histologically, and cytokine mRNA expression in the pancreas was analysed. In vitro, CD4-positive splenocytes from diabetic donor mice were stimulated with anti-CD3 and anti-CD28 antibodies with or without N-acetyl-cysteine.<br><br>RESULTS: Treatment with N-acetyl-cysteine significantly accelerated the transfer of diabetes into non-obese diabetic scid recipients. Treatment with N-acetyl-cysteine accelerated the infiltration of mononuclear cells accompanied by CD8-positive cells into the intra-islet region of the recipient's pancreas, and enhanced interferon-gamma mRNA expression in the pancreas. In vitro, treatment with N-acetyl-cysteine enhanced interferon-gamma and interleukin-2 production by CD4-positive splenocytes of the diabetic donor mice.<br><br>CONCLUSIONS/INTERPRETATION: N-acetyl-cysteine accelerates the transfer of diabetes into non-obese diabetic scid mice and this effect is accompanied by the promotion of local infiltration and T-helper cell type 1 responses.}, }
@article {pmid15499198, year = {2004}, author = {Harada, D and Anraku, M and Fukuda, H and Naito, S and Harada, K and Suenaga, A and Otagiri, M}, title = {Kinetic studies of covalent binding between N-acetyl-L-cysteine and human serum albumin through a mixed-disulfide using an N-methylpyridinium polymer-based column.}, journal = {Drug metabolism and pharmacokinetics}, volume = {19}, number = {4}, pages = {297-302}, doi = {10.2133/dmpk.19.297}, pmid = {15499198}, issn = {1347-4367}, mesh = {Acetylcysteine/analysis/*pharmacokinetics ; Aged ; Disulfides/analysis/*pharmacokinetics ; Female ; Humans ; Male ; Polymers/*pharmacokinetics ; Protein Binding/physiology ; Pyridinium Compounds/*pharmacokinetics ; Serum Albumin/analysis/*pharmacokinetics ; }, abstract = {The binding properties of the disulfide covalent bond between N-acetyl-L-cysteine (NAC) and human serum albumin (HSA) were investigated. HSA, purified from either healthy subjects or renal failure patients, was incubated with NAC in buffer and analyzed by 4VP-EG-Me column chromatography, which can distinguish between the redox states of the only free thiol of HSA. Although intact HSA was found to consist of mainly three sub-types, marcaptoalbumin (HMA), cysteine-bound nonmercaptoalbumin (HNA(Cys)) and a further oxidized form (HNA(oxy)), the formation of a new type of nonmercaptoalbumin (HNA(NAC)) was confirmed after incubation with NAC. Interestingly, NAC rapidly dissociated Cys from HNA(Cys) and NAC itself bound very slowly to HSA. These findings suggest that the interaction between NAC and HSA proceeds in a 2-step processes. The first-order binding and dissociation rate constants of NAC to healthy HSA (k(on,NAC)) and Cys from healthy HNA(Cys) (k(off,Cys)) were approximately 0.0032 and 1.3 (h(-1)), respectively. On the other hand, HSA from renal failure patients showed decreased HMA and increased HNA(Cys). The k(on,NAC) and k(off,Cys) were 0.0094 and 0.45 (h(-1)), respectively, suggesting that the pathological state may affect the binding properties of HSA and NAC.}, }
@article {pmid15496615, year = {2005}, author = {Wu, YJ and Muldoon, LL and Neuwelt, EA}, title = {The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {312}, number = {2}, pages = {424-431}, doi = {10.1124/jpet.104.075119}, pmid = {15496615}, issn = {0022-3565}, support = {NS33618/NS/NINDS NIH HHS/United States ; NS34608/NS/NINDS NIH HHS/United States ; NS44687/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/*antagonists &amp; inhibitors/*toxicity ; Apoptosis/*drug effects ; Blotting, Western ; Caspases/*physiology ; Cell Line, Tumor ; Cisplatin/*antagonists &amp; inhibitors/*toxicity ; Dose-Response Relationship, Drug ; Extracellular Signal-Regulated MAP Kinases/physiology ; Genes, p53/drug effects ; Humans ; Immunohistochemistry ; Kinetics ; Proto-Oncogene Proteins c-bcl-2/biosynthesis/genetics ; Signal Transduction/*drug effects ; bcl-2-Associated X Protein ; p38 Mitogen-Activated Protein Kinases/physiology ; }, abstract = {Thiols such as N-acetylcysteine (NAC) are increasingly used in clinical trials of platinum chemotherapy as chemoprotectants. NAC can prevent cisdiamminedichloroplatinum (cisplatin)-induced ototoxicity, nephrotoxicity, and gastrointestinal toxicity; however, the molecular mechanisms of NAC on apoptosis and cisplatin cytotoxicity remain unknown. We investigated cisplatin cytotoxicity and NAC chemoprotection in human tumor cell lines, as assessed by immunoblotting and immunocytochemistry. Cisplatin cytotoxicity was associated with nuclear translocation of apoptosis induction factor, expression of the pro-apoptotic Bax protein, cleavage of caspases 3 and 9, and cleavage of PARP. NAC administration reversed the cytotoxic and apoptotic effects if added concurrent with cisplatin or up to 2 h after cisplatin, but chemoprotection was reduced if NAC administration was delayed more than 2 h and was minimal by 8 h after cisplatin. Expression of tumor suppressor p53 and the cell cycle regulatory protein p21 was stimulated within 5 to 10 min by cisplatin in p53-positive LX-1 small cell lung carcinoma cells, and this effect was blocked by NAC. In p53-negative SKOV3 cells, cisplatin toxicity and NAC chemoprotection remained effective, suggesting that chemoprotection may be mediated through both p53-dependent and -independent pathways. Specific kinase inhibitors demonstrated that cisplatin induced apoptosis through the p38 mitogen-activated protein kinase (MAPK) pathway, not the extracellular signal-regulated kinase MAPK pathway. These results show that NAC blocks both the death receptor and the mitochondrial apoptotic pathways induced by cisplatin. The time course for NAC chemoprotection after cisplatin matches our previous in vivo results and provides an opportunity to manipulate route and timing to maintain cisplatin antitumor efficacy while protecting against chemotherapy side effects.}, }
@article {pmid15489055, year = {2004}, author = {Grattagliano, I and Portincasa, P and Cocco, T and Moschetta, A and Di Paola, M and Palmieri, VO and Palasciano, G}, title = {Effect of dietary restriction and N-acetylcysteine supplementation on intestinal mucosa and liver mitochondrial redox status and function in aged rats.}, journal = {Experimental gerontology}, volume = {39}, number = {9}, pages = {1323-1332}, doi = {10.1016/j.exger.2004.06.001}, pmid = {15489055}, issn = {0531-5565}, mesh = {Acetylcysteine/*pharmacology ; Aging/metabolism ; Animals ; *Caloric Restriction ; Colon/metabolism ; *Dietary Supplements ; Glutathione/metabolism ; Ileum/metabolism ; Intestinal Mucosa/*drug effects/metabolism ; Male ; Mitochondria, Liver/*drug effects/metabolism/physiology ; Oxidation-Reduction/drug effects ; Rats ; Rats, Wistar ; }, abstract = {The age-related changes of glutathione (GSH) levels and the effect of hypocaloric regimen and N-acetylcysteine (NAC) supplementation were investigated in intestinal mucosa and liver mitochondria of 28 months rats. Old rats exhibited lower proteins, GSH and protein sulphydrils (PSH) concentrations, higher GSH-peroxidase (GSH-Px) activity and protein carbonyl deposit, partial inhibition of succinate stimulated mitochondrial state III respiration and decreased mitochondrial nitrosothiols (RSNO) concentration. Lower electric potential and current intensity were found in the colonic mucosa. Old rats undergone hypocaloric regimen showed higher intestinal concentrations of GSH, lower oxidized protein accumulation and GSH-Px activity and higher mitochondrial RSNO levels. Mitochondrial state III respiration and intestinal transport were improved. NAC supplementation enhanced GSH and PSH levels in the ileal but not in the colonic mucosa, GSH and RSNO in liver mitochondria, while GSH-Px and protein carbonyls were decreased everywhere. Mitochondrial respiration ameliorated. In conclusion, ageing is characterized by a spread decrease of GSH concentrations, increased protein oxidation and decreased mitochondrial NO content. Hypocaloric diet ameliorated intestinal transport and, as well as NAC, was effective in enhancing GSH levels but at different extent according to the investigated districts. Both interventions reduced the age-associated increase of GSH-Px and protein carbonyls and improved mitochondrial respiration.}, }
@article {pmid15486247, year = {2004}, author = {Bettmann, MA}, title = {Frequently asked questions: iodinated contrast agents.}, journal = {Radiographics : a review publication of the Radiological Society of North America, Inc}, volume = {24 Suppl 1}, number = {}, pages = {S3-10}, doi = {10.1148/rg.24si045519}, pmid = {15486247}, issn = {1527-1323}, mesh = {*Contrast Media/administration &amp; dosage/adverse effects ; Humans ; *Iodine Compounds/administration &amp; dosage/adverse effects ; Kidney Diseases/chemically induced/prevention &amp; control ; Risk Factors ; }, abstract = {Although iodinated contrast agents are safe and widely used, adverse events occur and questions remain about their use, safety, and interactions. Some questions are easily answered and others still require extensive investigation. For one frequent question--is informed consent necessary before all contrast media injections--the simple answer is no. Another question concerns use of contrast media in patients with prior reactions or allergies. Contrast agents can be safely used in such patients, but special care must be taken to be aware of what the previous reaction was and to be ready to treat any reaction. The protective role of pre-treatment with steroids is well established for minor reactions, but they may not prevent major reactions. It is important to realize that even life-threatening, anaphylactoid reactions are not the result of a true allergy to contrast media. Many questions arise about contrast agent-induced nephropathy. Baseline serum creatinine values should be obtained in patients who are at risk, not all patients. The incidence and natural history of contrast agent-induced nephropathy remain unclear. It occurs only in patients with compromised renal function before contrast agent injection, but even patients with normal serum creatinine levels can have renal dysfunction. Calculated creatinine clearance is a better way to determine risk and to follow this complication. The outcome in almost all patients is benign, with progression to end-stage renal disease being rare. The major risk factors, in addition to renal dysfunction, are long-standing diabetes mellitus, dehydration, and use of other nephrotoxic medications. Recent work in preventing and ameliorating contrast agent-induced nephropathy with N-acetyl cysteine, substitution of an isosmolal nonionic contrast agent, and various hydration regimens has been promising. Another common concern is use of iodinated contrast agents in pregnant or breast-feeding women. In both cases, there is no evidence of harm to the fetus or infant, but it is prudent to weigh the theoretical risks and benefits and avoid contrast agent administration unless it is truly necessary.}, }
@article {pmid15486074, year = {2005}, author = {Xu, S and Zhu, B and Teffera, Y and Pan, DE and Caldwell, CG and Doss, G and Stearns, RA and Evans, DC and Beconi, MG}, title = {Metabolic activation of fluoropyrrolidine dipeptidyl peptidase-IV inhibitors by rat liver microsomes.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {33}, number = {1}, pages = {121-130}, doi = {10.1124/dmd.104.001842}, pmid = {15486074}, issn = {0090-9556}, mesh = {Animals ; Biotransformation ; Dipeptidyl Peptidase 4/*metabolism ; Fluorine/chemistry/metabolism/pharmacology ; Male ; Microsomes, Liver/*enzymology ; Protease Inhibitors/chemistry/*metabolism/*pharmacology ; Protein Binding/drug effects/physiology ; Pyrrolidines/chemistry/*metabolism/pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The current study evaluated the potential for two dipeptidyl peptidase-IV (DPP-IV) inhibitor analogs (1S)-1-(trans-4-([(4-trifluoromethoxyphenyl)sulfonyl]amino)cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride and (1S)-1-(trans-4-([(2,4-difluorophenyl)sulfonyl]amino)cyclohexyl)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-oxoethanaminium chloride (MRL-A and MRL-B), containing a fluoropyrrolidine moiety in the structure, to undergo metabolic activation. The irreversible binding of these tritium-labeled compounds to rat liver microsomal protein was time- and NADPH-dependent and was attenuated by the addition of reduced glutathione (GSH) or N-acetylcysteine (NAC) to the incubation, indicating that chemically reactive intermediates were formed and trapped by these nucleophiles. Mass spectrometric analyses and further trapping experiments with semicarbazide indicated that the fluoropyrrolidine ring had undergone sequential oxidation and defluorination events resulting in the formation of GSH or NAC conjugates of the pyrrolidine moiety. The bioactivation of MRL-A was catalyzed primarily by rat recombinant CYP3A1 and CYP3A2. Pretreatment of rats with prototypic CYP3A1 and 3A2 inducers (pregnenolone-16alpha-carbonitrile and dexamethasone) enhanced the extent of bioactivation which, in turn, led to a higher degree of in vitro irreversible binding to microsomal proteins (5- and 9-fold increase, respectively). Herein, we describe studies that demonstrate that the fluoropyrrolidine ring is prone to metabolic activation and that GSH or NAC can trap the reactive intermediates to form adducts that provide insight into the mechanisms of bioactivation.}, }
@article {pmid15479130, year = {2004}, author = {Kucharská, J and Ulicná, O and Gvozdjáková, A and Sumbalová, Z and Vancová, O and Bozek, P and Nakano, M and Greksák, M}, title = {Regeneration of coenzyme Q9 redox state and inhibition of oxidative stress by Rooibos tea (Aspalathus linearis) administration in carbon tetrachloride liver damage.}, journal = {Physiological research}, volume = {53}, number = {5}, pages = {515-521}, pmid = {15479130}, issn = {0862-8408}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antioxidants/*therapeutic use ; Aspalathus/*metabolism ; *Beverages ; Carbon Tetrachloride ; Liver Failure, Acute/*drug therapy/*metabolism ; Liver Regeneration/*drug effects ; Male ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Phytotherapy/methods ; Plant Extracts/administration &amp; dosage ; Rats ; Rats, Wistar ; Treatment Outcome ; Ubiquinone/*metabolism ; }, abstract = {The effect of rooibos tea (Aspalathus linearis) on liver antioxidant status and oxidative stress was investigated in rat model of carbon tetrachloride-induced liver damage. Synthetic antioxidant N-acetyl-L-cysteine (NAC) was used for comparison. Administration of carbon tetrachloride (CCl4) for 10 weeks decreased liver concentrations of reduced and oxidized forms of coenzyme Q9 (CoQ9H2 and CoQ9), reduced -tocopherol content and simultaneously increased the formation of malondialdehyde (MDA) as indicator of lipid peroxidation. Rooibos tea and NAC administered to CCl4-damaged rats restored liver concentrations of CoQ9H2 and alpha-tocopherol and inhibited the formation of MDA, all to the values comparable with healthy animals. Rooibos tea did not counteract the decrease in CoQ9, whereas NAC was able to do it. Improved regeneration of coenzyme Q9 redox state and inhibition of oxidative stress in CCl4-damaged livers may explain the beneficial effect of antioxidant therapy. Therefore, the consumption of rooibos tea as a rich source of natural antioxidants could be recommended as a market available, safe and effective hepatoprotector in patients with liver diseases.}, }
@article {pmid15477121, year = {2004}, author = {Koksel, O and Cinel, I and Tamer, L and Cinel, L and Ozdulger, A and Kanik, A and Ercan, B and Oral, U}, title = {N-acetylcysteine inhibits peroxynitrite-mediated damage in oleic acid-induced lung injury.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {17}, number = {5}, pages = {263-270}, doi = {10.1016/j.pupt.2004.05.002}, pmid = {15477121}, issn = {1094-5539}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Female ; Lung/drug effects/*metabolism/*pathology ; Malondialdehyde/metabolism ; Microscopy ; Oleic Acid/*adverse effects ; Peroxidase/metabolism ; Peroxynitrous Acid/metabolism ; Rats ; Rats, Wistar ; Tyrosine/*analogs &amp; derivatives/metabolism ; }, abstract = {Since oleic acid (OA) induces morphologic and cellular changes similar to those observed in human acute lung injury (ALI) and acute respiratory distress syndrome, it has become a widely used model to investigate the effects of several agents on pathogenesis of lung injury. The antioxidant and anti-inflammatory properties of N-acetylcysteine (NAC) has been documented in many lung injury models. In this study, we evaluated the role of NAC in an OA-induced lung injury model by measuring myeloperoxidase (MPO) activity, malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) levels in lung tissue. Five groups labelled Sham, NAC, OA, Pre-OA-NAC and Post-OA-NAC were determined. ALI was induced by intravenous administration of OA. The pre-OA-NAC group received iv NAC 15 min before OA infusion and the post-OA-NAC group received iv NAC 2 h after OA infusion. In both of the NAC treatment groups' blood and tissue samples were collected 4 h after OA infusion, independent from the time of NAC infusion. The MPO activity, MDA and 3-NT levels in lung homogenates were found to be increased in OA group and the administration of NAC significantly reduced tissue MPO, MDA and 3-NT levels (p = 0.0001) Lung histopathology was also affected by NAC in this OA-induced experimental lung injury model.}, }
@article {pmid15477016, year = {2004}, author = {Samuni, AM and DeGraff, W and Cook, JA and Krishna, MC and Russo, A and Mitchell, JB}, title = {The effects of antioxidants on radiation-induced apoptosis pathways in TK6 cells.}, journal = {Free radical biology &amp; medicine}, volume = {37}, number = {10}, pages = {1648-1655}, doi = {10.1016/j.freeradbiomed.2004.08.006}, pmid = {15477016}, issn = {0891-5849}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects/*physiology/radiation effects ; Caspase 3 ; Caspases/metabolism ; Cell Survival/drug effects/*physiology/radiation effects ; Collagen Type XI/metabolism ; Cyclic N-Oxides/*pharmacology ; Humans ; MAP Kinase Signaling System/physiology ; Phosphorylation/drug effects/radiation effects ; Radiation ; Spin Labels ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/metabolism ; }, abstract = {This study was designed to determine if radiation-mediated activation of the apoptotic pathways would be influenced by antioxidants and if a correlation would be found between radioprotection and changes in transduction pathways. Human lymphoblastoid TK6 cells, known to undergo apoptosis as a result of radiation, were irradiated (6 Gy) with and without antioxidants, and then whole-cell lysates were collected. Parallel studies were conducted to assess the survival (clonogenic assay) and apoptotic index. The impacts of two nitroxide antioxidants, tempol and CAT-1, differing in cell permeability, as well as the sulfhydryl antioxidant N-acetyl-L-cysteine (L-NAC), were estimated. Changes in apoptotic pathway proteins and p53 were assessed by Western blotting. Fraction of apoptotic cells was determined by flow cytometry. Tempol (10 mM), which readily enters cells, partially radioprotected TK6 cells against clonogenic killing, but had no effect on radiation-induced apoptotic parameters such as cleaved caspase 3 or cleaved PARP. Tempol alone did not induce cytotoxicity, yet did increase cleaved PARP levels. The radiation-induced increase in p53 protein was partly inhibited by tempol, but was unaffected by CAT-1 and L-NAC. Both CAT-1 (10 mM), which does not enter cells, and L-NAC (10 mM) had no radioprotective effect on cell survival. Although L-NAC did not protect against radiation-induced cytotoxicity, it completely inhibited radiation-induced increase in cleaved caspase 3 and cleaved PARP. Collectively, the results question the validity of using selected apoptosis pathway members as sole indicators of cytotoxicity.}, }
@article {pmid15474518, year = {2004}, author = {Demeule, M and Brossard, M and Turcotte, S and Regina, A and Jodoin, J and Béliveau, R}, title = {Diallyl disulfide, a chemopreventive agent in garlic, induces multidrug resistance-associated protein 2 expression.}, journal = {Biochemical and biophysical research communications}, volume = {324}, number = {2}, pages = {937-945}, doi = {10.1016/j.bbrc.2004.09.141}, pmid = {15474518}, issn = {0006-291X}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Acetylcysteine/metabolism ; Allyl Compounds/metabolism/*pharmacology ; Animals ; Anticarcinogenic Agents/*pharmacology ; Blotting, Western ; Cell Membrane/metabolism ; Cisplatin/pharmacology ; Cysteine/*analogs &amp; derivatives/metabolism ; Disulfides/metabolism/*pharmacology ; Garlic/*metabolism ; Glutathione/metabolism ; Glutathione Transferase/metabolism ; Kidney/metabolism ; Kidney Cortex/metabolism ; Liver/metabolism ; Male ; Microvilli/metabolism ; Mitochondrial Proteins/*biosynthesis/genetics ; Plant Extracts/*pharmacology ; Protein Isoforms ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reverse Transcriptase Polymerase Chain Reaction ; Ribosomal Proteins/*biosynthesis/genetics ; Saccharomyces cerevisiae Proteins/*biosynthesis/genetics ; }, abstract = {The organosulfur compounds (OSCs), present in garlic, are studied for their protective effect against human cancers. P-glycoprotein (P-gp) and multidrug resistance protein 2 (Mrp2) are two transporters involved in the defense of cells and in the development of multidrug resistance. Whereas OSCs increase glutathione S-transferase activity (GST), Mrp2 plays a role in the transport of glutathione (GSH)-conjugates. In this study, we have investigated the effect of two OSCs, diallyl disulfide (DADS) and S-allyl cysteine (SAC), on P-gp and Mrp2 expression in renal brush-border membranes. By Western blot analysis, our results show that DADS induces Mrp2 expression (by 7-fold), which correlates with the rise of GST activity and GSH levels. Surprisingly, a co-administration of OSC with cisplatin, an anticancer drug, significantly increased Mrp2 gene and protein expression (by 30-fold), suggesting that DADS could potentiate the effects of cisplatin. Interestingly, SAC and cisplatin in co-treatment decreased P-gp protein expression and mdr1b isoform mRNA levels. In addition, modulation of the mdr1b isoform and Mrp2 by cisplatin was completely abolished by a glutathione precursor, N-acetyl cysteine. These results indicate that OSCs present in a garlic-rich diet might alter chemotherapeutic treatments using P-gp or Mrp2 substrates.}, }
@article {pmid15474247, year = {2004}, author = {Pata, O and Yazici, G and Apa, DD and Tok, E and Oz, U and Kaplanoğlu, M and Aban, M and Dilek, S}, title = {The effect of inducible nitric oxide synthase on postoperative adhesion formation in rats.}, journal = {European journal of obstetrics, gynecology, and reproductive biology}, volume = {117}, number = {1}, pages = {64-69}, doi = {10.1016/j.ejogrb.2003.10.034}, pmid = {15474247}, issn = {0301-2115}, mesh = {Acetylcysteine/pharmacology ; Animals ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Female ; Fibrosis/prevention &amp; control ; Inflammation/prevention &amp; control ; Nitric Oxide Synthase/antagonists &amp; inhibitors/*physiology ; Nitric Oxide Synthase Type II ; Peritoneal Diseases/enzymology/pathology/*prevention &amp; control ; Peritoneum/surgery ; Postoperative Complications/enzymology/pathology/*prevention &amp; control ; Rats ; Rats, Wistar ; Tissue Adhesions/enzymology/pathology/prevention &amp; control ; }, abstract = {OBJECTIVE: To evaluate the effect of iNOS on adhesion formation and to assess whether inhibition of iNOS expression affected adhesion formation according to adhesion maturation days.<br><br>STUDY DESIGN: Forty Wistar Albino rats were subjected to standardized lesion by cecal abrasion and parietal peritoneal defect and were randomly divided into four groups. Group I (control) received no treatment; groups II-IV received N-acetyl-cystein (NAC) 15 mg/100 g per day intramuscularly on days 4-14, 0-14 and 0-3, respectively, after surgery. On the postoperative 14th day adhesion score, tissue iNOS expression, inflammatory cell reaction (ICR) and tissue fibrosis score were determined.<br><br>RESULTS: Inflammation score of groups I and II was lower than that of groups III and IV (P < 0.05). Adhesion scores and tissue fibrosis of group II were significantly lower than that of the other groups (P < 0.001).<br><br>CONCLUSION: iNOS inhibition during the first 3 days postoperatively caused a delay in the resolution of inflammatory cell reaction. On the other hand, when inhibited after the first 3 days, adhesion formation and fibrosis were reduced both clinically and histopathologically.}, }
@article {pmid15473893, year = {2004}, author = {Akan, I and Akan, S and Akca, H and Savas, B and Ozben, T}, title = {N-acetylcysteine enhances multidrug resistance-associated protein 1 mediated doxorubicin resistance.}, journal = {European journal of clinical investigation}, volume = {34}, number = {10}, pages = {683-689}, doi = {10.1111/j.1365-2362.2004.01411.x}, pmid = {15473893}, issn = {0014-2972}, mesh = {Acetylcysteine/*pharmacology ; Antibiotics, Antineoplastic/*therapeutic use ; Cell Line, Tumor ; Cell Survival ; Doxorubicin/*therapeutic use ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Transferase/metabolism ; Humans ; Multidrug Resistance-Associated Proteins/*pharmacology ; Transfection ; }, abstract = {BACKGROUND: Resistance of cancer cells against anticancer agents is caused partly by multidrug resistance-associated protein 1 (MRP1). The exact mechanism of MRP1-involved multidrug resistance has not yet been clarified, although glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-buthionine (S,R)-sulfoximine (BSO) inhibits GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated doxorubicin resistance in human embryonic kidney (HEK293) and its MRP1-transfected 293MRP cells.<br><br>MATERIALS AND METHODS: Human embryonic kidney cells were transfected with a plasmid encoding the whole MRP1 gene. Both cells were incubated with doxorubicin in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. Glutathione, glutathione S-transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs.<br><br>RESULTS: N-acetylcysteine increased the resistance of both cells against doxorubicin. DL-buthionine (S,R)-sulfoximine decreased NAC-enhanced MRP1-mediated doxorubicin resistance, indicating that induction of MRP1-mediated doxorubicin resistance depends on GSH synthesis. Doxorubicin decreased the cellular GSH concentration and increased GPx activity. Glutathione S-transferase activity was decreased by NAC.<br><br>CONCLUSION: Our results demonstrate that NAC enhances MRP1-mediated doxorubicin resistance and this effect depends on GSH synthesis. DL-buthionine (S,R)-sulfoximine seems a promising chemotherapy improving agent in MRP1 overexpressing tumour cells.}, }
@article {pmid15473663, year = {2004}, author = {Piao, HZ and Jin, SA and Chun, HS and Lee, JC and Kim, WK}, title = {Neuroprotective effect of wogonin: potential roles of inflammatory cytokines.}, journal = {Archives of pharmacal research}, volume = {27}, number = {9}, pages = {930-936}, doi = {10.1007/BF02975846}, pmid = {15473663}, issn = {0253-6269}, mesh = {Animals ; Brain Ischemia/drug therapy/metabolism ; Cells, Cultured ; Cytokines/*antagonists &amp; inhibitors/*physiology ; Dose-Response Relationship, Drug ; Flavanones/*pharmacology/therapeutic use ; Inflammation Mediators/*antagonists &amp; inhibitors/physiology ; Male ; Neuroprotective Agents/*pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Wogonin (5,7-dihydroxy-8-methoxyflavone), an active component originated from the root of Scutellaria baicalensis Georgi, has been reported to possess antioxidant and anti-inflammatory properties. In this study, we investigated the neuroprotective effect of wogonin in a focal cerebral ischemia rat model. Wogonin markedly reduced the infarct volume after 2 h middle cerebral artery occlusion followed by 22 h reperfusion. Wogonin decreased the production of nitric oxide and inflammatory cytokines such as TNF-alpha and IL-6 in lipopolisaccharide-stimulated microglial cells. While wogonin reduced the activity of NF-kappaB, it did not change the activity of mitogen-activated protein kinases family members, p38, ERK and JNK. The lipopolisaccharide-stimulated production of NO and cytokines was significantly blocked by various kinds of NF-kappaB inhibitors such as N-acetyl cysteine, pyrrolidinedithiocarbamate and MG-132. The data may indicate that wogonin has neuroprotective effect by preventing the overactivation of microglial cells, possibly by inactivating NF-kappaB signaling pathway.}, }
@article {pmid15472963, year = {2004}, author = {Lin, CC and Liu, CY}, title = {Proline-coated column for the capillary electrochromatographic separation of amino acids by in-column derivatization.}, journal = {Electrophoresis}, volume = {25}, number = {18-19}, pages = {3216-3223}, doi = {10.1002/elps.200406037}, pmid = {15472963}, issn = {0173-0835}, mesh = {Amino Acids/*isolation &amp; purification ; Chromatography, Micellar Electrokinetic Capillary/*instrumentation/methods ; Hydrogen-Ion Concentration ; Indicators and Reagents ; Proline/*chemistry ; }, abstract = {With 3-trimethoxysilylpropyl chloride as the spacer, a proline-coated capillary column was prepared for the capillary electrochromatographic (CEC) separation of amino acids by in-column derivatization. Nine standard mixtures, including aspartic acid, glutamic acid, valine, phenylalanine, alanine, isoleucine, leucine, tyrosine, and tryptophan, were injected. o-Phthalaldehyde (OPA), OPA/2-mercaptoethanol (2-ME) and OPA/N-acetylcysteine (NAC) in borate buffer were tested as the derivatizing agent. Among them, OPA (50 mM) in borate buffer (pH 9.5, 50 mM) gave the best performance. The formation of isoindole could be detected by UV detection. The sandwich-type injection was carried out in hydrostatic mode (10 cm) with the program R(10 s)S(10 s) R(10 s)W(10 min) with R, S, and W being the reagent, sample, and waiting times. Mesityl oxide, benzyl alcohol, and acetone showed some interaction with the column. A current monitoring method was used instead of the determination of the electroosmotic flow (EOF). The direction of EOF was from anode to cathode even under acidic condition lower than the pI value (6.31) of the bonded group due to some unreacted silanol groups. Some parameters including pH, nature, and concentration of the mobile phase and the effect of organic modifier with regard to the CEC separation were investigated. With the proline-coated column (75 (50) cm x 75 microm ID) the best separation was performed in phosphate buffer (pH 4.00, 100 mM) with an applied voltage of -15 kV. The established method was also compared with those precolumn derivatized prior to the separation with proline-coated column as well as with in-capillary derivatization and separation with a bare fused-silica column.}, }
@article {pmid15466245, year = {2005}, author = {Reid, AB and Kurten, RC and McCullough, SS and Brock, RW and Hinson, JA}, title = {Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {312}, number = {2}, pages = {509-516}, doi = {10.1124/jpet.104.075945}, pmid = {15466245}, issn = {0022-3565}, support = {1P20 RR-16460/RR/NCRR NIH HHS/United States ; 1R24 CA-82899/CA/NCI NIH HHS/United States ; R01 GM-58887/GM/NIGMS NIH HHS/United States ; T32 ES-10952/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/antagonists &amp; inhibitors/*toxicity ; Alanine Transaminase/metabolism ; Analgesics, Non-Narcotic/antagonists &amp; inhibitors/*toxicity ; Animals ; Cell Separation ; Chemical and Drug Induced Liver Injury/*pathology ; Fluorescent Dyes ; Hepatocytes/*drug effects ; In Vitro Techniques ; Male ; Mice ; Microscopy, Confocal ; Mitochondria, Liver/*drug effects ; Oxidative Stress/drug effects/*physiology ; Permeability/drug effects ; Spectrometry, Fluorescence ; }, abstract = {Freshly isolated mouse hepatocytes were used to determine the role of mitochondrial permeability transition (MPT) in acetaminophen (APAP) toxicity. Incubation of APAP (1 mM) with hepatocytes resulted in cell death as indicated by increased alanine aminotransferase in the media and propidium iodide fluorescence. To separate metabolic events from later events in toxicity, hepatocytes were preincubated with APAP for 2 h followed by centrifugation of the cells and resuspension of the pellet to remove the drug and reincubating the cells in media alone. At 2 h, toxicity was not significantly different between control and APAP-incubated cells; however, preincubation with APAP followed by reincubation with media alone resulted in a marked increase in toxicity at 3 to 5 h that was not different from incubation with APAP for the entire time. Inclusion of cyclosporine A, trifluoperazine, dithiothreitol (DTT), or N-acetylcysteine (NAC) in the reincubation phase prevented hepatocyte toxicity. Dichlorofluorescein fluorescence increased during the reincubation phase, indicating increased oxidative stress. Tetramethylrhodamine methyl ester perchlorate fluorescence decreased during the reincubation phase indicating a loss of mitochondrial membrane potential. Inclusion of cyclosporine A, DTT, or NAC decreased oxidative stress and loss of mitochondrial membrane potential. Confocal microscopy studies with the dye calcein acetoxymethyl ester indicated that MPT had also occurred. These data are consistent with a hypothesis where APAP-induced cell death occurs by two phases, a metabolic phase and an oxidative phase. The metabolic phase occurs with GSH depletion and APAP-protein binding. The oxidative phase occurs with increased oxidative stress, loss of mitochondrial membrane potential, MPT, and toxicity.}, }
@article {pmid15464296, year = {2004}, author = {Previati, M and Lanzoni, I and Corbacella, E and Magosso, S and Giuffrè, S and Francioso, F and Arcelli, D and Volinia, S and Barbieri, A and Hatzopoulos, S and Capitani, S and Martini, A}, title = {RNA expression induced by cisplatin in an organ of Corti-derived immortalized cell line.}, journal = {Hearing research}, volume = {196}, number = {1-2}, pages = {8-18}, doi = {10.1016/j.heares.2004.04.009}, pmid = {15464296}, issn = {0378-5955}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Butylated Hydroxytoluene/pharmacology ; Cell Line, Transformed ; Cell Survival/drug effects ; Cisplatin/*pharmacology ; Cytoprotection ; Dithiothreitol/pharmacology ; Gene Expression/drug effects ; Malondialdehyde/metabolism ; Mice ; Mice, Transgenic ; Oligonucleotide Array Sequence Analysis ; Organ of Corti/cytology/*drug effects/*metabolism/physiology ; RNA/*metabolism ; Time Factors ; }, abstract = {Cisplatin [cis-diamminedichloroplatinum(II)] (CDDP) is an organic compound that is widely used for the treatment of a large number of tumors. Its clinical use is limited by the presence of some undesired side effects, like as oto- and nephro toxicity, whose mechanisms of action are not understood. One of the possible CDDP toxicity mechanism seems to involve the generation of reactive oxygen species (ROS), that can impair morphology and function of hair cells (HC) in the organ of Corti. To test this hypothesis we evaluated the effect of CDDP treatment on RNA steady-state levels of 15,000 genes by microarray analysis, using, as a experimental model, the OC-k3 cell line, obtained from the organ of Corti of transgenic mice and constitutively expressing the large SV40 T antigen. We have found overexpression of several genes related to arachidonate mobilization including phospholipase A2, group IV and V, phospholipase A2 activating protein and lysophospholipase I and III, as well as lipoxygenation like arachidonate 12-lipoxygenase and arachidonate 5-lipoxygenase activating protein. In addition, we found significant transcription of genes regulating cell respiration, including cyt c oxidase, as well as genes involved in xenobiotic detoxification and lipid peroxidation such as cyt P450, and other oxidases including spermine oxidase and monoamine oxidase. As a whole, overexpression of the group of different genes seems to indicate that an oxidative burst could take place during cisplatin administration. We therefore searched for evidences of superoxide anion and hydrogen peroxide by means of electron paramagnetic resonance (EPR) spectroscopy and flow cytometry, but failed to detect them. On the other hand, we found an increase of malondialdehyde (MDA) synthesis and protein carbonylation products, indicating the occurence of lipid peroxidative degradation. When we tested the effectiveness of butylated hydroxytoluene (BHT), dithiothreitol (DTT) and N-acetylcysteine (N-Ac) as cytoprotectants, all of them reduced protein carbonylation to control levels and significantly protected OC-k3 from CDDP-induced cell death, with an higher protection when using the lipophylic antioxidant BHT. The same antioxidants prevented also the onset of protein carbonylation, which extent was decreased to basal levels. These data indicate that CDDP is able to stimulate gene expression up to 12 h after the beginning of the treatment. This increase in gene transcription involves a large number of genes potentially able to increase the level of cell ROS. Consistently, cells survival is improved by cotreatment with antioxidants, in particular lipophilics.}, }
@article {pmid15461841, year = {2004}, author = {Liu, S and Yu, SY}, title = {[Protective effect of N-acetylcysteine on acute lung injury caused by exposure to rocket liquid propellant].}, journal = {Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue}, volume = {16}, number = {10}, pages = {611-614}, pmid = {15461841}, issn = {1003-0603}, mesh = {Acetylcysteine/*therapeutic use ; Acute Lung Injury/chemically induced/*drug therapy/metabolism/pathology ; Animals ; Bronchoalveolar Lavage Fluid/chemistry ; Dimethylhydrazines/*toxicity ; Disease Models, Animal ; Glutathione Peroxidase/metabolism ; Lipid Peroxidation/*drug effects ; Lung/drug effects/metabolism/pathology ; Male ; Malondialdehyde/metabolism ; Nitrogen Oxides/*toxicity ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: To investigate the protective effect and its mechanisms of N-acetylcysteine (NAC) on acute lung injury (ALI) caused by exposure to high concentration rocket liquid propellants asymmetrical dimethylhydrazine (UDMH) and dinitrogen tetroxide (N(2)O(4)).<br><br>METHODS: Forty-two rats were randomly divided into three groups: the control group, the exposure group and the exposure plus the treatment group (NAC group). The rats of the latter two groups were exposed to UDMH 0.98 mg/L for 10 minutes and then N(2)O(4) 0.19 mg/L for another 10 minutes. After the exposure, the NAC group rats received immediately 150 mg/kg of NAC intravenously, and rein forced by intraperitoneal injection of NAC with a dose of 50 mg/kg 3 hours after the intravenous injection. The rats of other group were treated with saline in equal volume. All rats were killed after 6 hours. The lung wet to dry ratio (W/D), the contents of lactate dehydrogenase (LDH) and total protein in bronchoalveolar lavage fluid (BALF), the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissue, and the malondialdehyde (MDA) of plasma were measured. Pathological examination was performed.<br><br>RESULTS: The lung W/D ratio, the LDH and total protein in BALF, and the MDA of plasma were increased in the exposure group, while the activities of SOD and GSH-Px in lung tissue were decreased. The histopathology of the rats of exposure groups showed that there was exudation within alveolar spaces and prominent interstitial thickening of septa. In the NAC group, the values of the above findings were lowered, and the degree of lung injury was alleviated in histopathology. The lung W/D were negatively correlated with the activities of SOD and GSH-Px in lung tissue, and the correlation coefficient were-0662 (P<0.01) and -0707(P<0.01) respectively.<br><br>CONCLUSION: The administration of NAC appears to attenuate the injury to the lung after an exposure to UDMH and N(2)O(4) in high concentration, and the antioxidant activity of NAC may be responsible for the protective effect.}, }
@article {pmid15460446, year = {2004}, author = {Kim, S and Moon, A}, title = {Capsaicin-induced apoptosis of H-ras-transformed human breast epithelial cells is Rac-dependent via ROS generation.}, journal = {Archives of pharmacal research}, volume = {27}, number = {8}, pages = {845-849}, doi = {10.1007/BF02980177}, pmid = {15460446}, issn = {0253-6269}, mesh = {Apoptosis/drug effects/*physiology ; Breast/cytology/drug effects/metabolism ; Capsaicin/*pharmacology ; Cell Line ; Cell Line, Transformed ; Dose-Response Relationship, Drug ; Epithelial Cells/cytology/drug effects/*metabolism ; Genes, ras/drug effects/*physiology ; Growth Inhibitors/*pharmacology ; Humans ; Reactive Oxygen Species/*metabolism ; rac GTP-Binding Proteins/*metabolism ; }, abstract = {Many studies have focused on the anticarcinogenic, antimutagenic or chemopreventive activities of capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) which is a major pungent ingredient in red pepper. We have previously shown that capsaicin selectively induces apoptosis in H-ras-transformed MCF10A human breast epithelial cells but not in their normal cell counterparts (Int. J. Cancer, 103, 475-482, 2003). In this study, we investigated the possible roles of reactive oxygen species (ROS) and Rac1 in capsaicin-induced apoptosis of H-ras MCF10A cells. Selective induction of ROS generation by capsaicin treatment was observed only in H-ras MCF10A cells. Pretreatment of H-ras MCF10A cells with an antioxidant N-acetylcysteine (NAC) significantly reversed capsaicin-induced growth inhibition, suggesting that ROS may mediate the apoptosis of H-ras-transformed cells induced by capsaicin. Rac1 was prominently activated by H-ras in MCF10A cells. Based on the studies using a wild type Rac1 and a dominant negative Rac1 constructs, we propose that Rac1 activity is critical for inhibitory effect of capsaicin on growth of H-ras-transformed MCF10A cells possibly through ROS generation.}, }
@article {pmid15459602, year = {2004}, author = {Miner, SE and Dzavik, V and Nguyen-Ho, P and Richardson, R and Mitchell, J and Atchison, D and Seidelin, P and Daly, P and Ross, J and McLaughlin, PR and Ing, D and Lewycky, P and Barolet, A and Schwartz, L}, title = {N-acetylcysteine reduces contrast-associated nephropathy but not clinical events during long-term follow-up.}, journal = {American heart journal}, volume = {148}, number = {4}, pages = {690-695}, doi = {10.1016/j.ahj.2004.05.015}, pmid = {15459602}, issn = {1097-6744}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Angioplasty, Balloon, Coronary/*adverse effects ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Coronary Disease/complications/diagnostic imaging/mortality/therapy ; Creatinine/blood ; Diabetes Complications ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Kidney Diseases/blood/chemically induced/*prevention &amp; control ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Contrast-associated nephropathy (CAN) is associated with increased morbidity and mortality following percutaneous coronary intervention (PCI). N-acetylcysteine (NAC) has been shown to reduce the risk of nephropathy; however, the impact of NAC on long-term clinical outcomes has not been assessed.<br><br>METHODS: This randomized, double-blind, placebo-controlled trial enrolled 180 patients with moderate renal dysfunction undergoing PCI or coronary angiography with a high likelihood of ad hoc PCI; 171 patients completed the clinical follow-up. Patients received oral NAC (2000 mg/dose, n = 95) or placebo (n = 85) twice a day for 3 doses if randomized the night prior to the procedure, and 2 doses if randomized the day of the procedure. The primary end point was the incidence of a > or =25% increase in serum creatinine level 48 to 72 hours after PCI. Secondary end points were the inhospital incidence of death, nonfatal myocardial infarction, or urgent dialysis, and the 9-month incidence of death, nonfatal myocardial infarction, need for dialysis, or repeat hospitalization for cardiac reasons.<br><br>RESULTS: CAN occurred in 9.6% of patients assigned to NAC and 22.2% of patients assigned to placebo (P =.04); 1 patient receiving NAC required urgent dialysis. The inhospital composite end point occurred in 7 (7.4%) NAC-treated and 3 (3.5%) placebo-treated patients, P = NS. At 9 months, the composite end point occurred in 23 (24.2%) NAC-treated patients and 18 (21.2%) placebo-treated, P = NS.<br><br>CONCLUSION: Although high-dose NAC prevented periprocedural CAN, this benefit did not translate into a decrease in adverse outcomes over 9 months. Further studies to determine the clinical utility of this drug are required.}, }
@article {pmid15458774, year = {2004}, author = {Erbas, H and Aydogdu, N and Kaymak, K}, title = {Effects of N-acetylcysteine on arginase, ornithine and nitric oxide in renal ischemia-reperfusion injury.}, journal = {Pharmacological research}, volume = {50}, number = {5}, pages = {523-527}, doi = {10.1016/j.phrs.2004.04.005}, pmid = {15458774}, issn = {1043-6618}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Arginase/*metabolism ; Enzyme Activation/drug effects ; Female ; Ischemia/drug therapy/enzymology/metabolism ; Kidney/*blood supply/enzymology/*metabolism ; Nitric Oxide/*metabolism ; Ornithine/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/drug therapy/enzymology/*metabolism ; }, abstract = {BACKGROUND: Renal ischemia-reperfusion (I/R) is a complex syndrome involving several mechanisms such as renal vasoconstrictions, extensive tubular damage and glomerular injury. N-Acetylcysteine (NAC), a potent antioxidant by itself, may serve as a precursor for glutathione synthesis. The aim of this study was to investigate the possible effects of NAC on liver and kidney tissue arginase activity, ornithine and plasma nitric oxide levels during the I/R injury of kidney.<br><br>METHODS: Twenty-four female Sprague-Dawley rats divided into three groups: group 1; was given saline intraperitoneally (i.p.). Saline to group 2 and NAC (300 mg kg(-1)) to group 3 were injected i.p. 30 min before induction of ischemia. Groups 2 and 3; subjected to bilateral renal ischemia (60 min) followed by reperfusion (24 h). After the reperfusion period, the rats were sacrificed and liver and kidney tissue arginase activities, ornithine and plasma nitric oxide (NO) levels were determined.<br><br>RESULTS: NAC had an increasing effect on both of liver and kidney tissue arginase activities and ornithine levels while decreasing plasma NO concentration.<br><br>CONCLUSION: The stimulatory effect of NAC on arginase activity may result in an inhibition of the plasma NO level. Moreover, it could be possible that one of the protective mechanisms of NAC might be through the stimulation on the both liver and kidney tissue ornithine levels.}, }
@article {pmid15453636, year = {2004}, author = {Macone, A and Matarese, RM and Gentili, V and Antonucci, A and Duprè, S and Nardini, M}, title = {Effect of aminoethylcysteine ketimine decarboxylated dimer, a natural sulfur compound present in human plasma, on tert-butyl hydroperoxide-induced oxidative stress in human monocytic U937 cells.}, journal = {Free radical research}, volume = {38}, number = {7}, pages = {705-714}, doi = {10.1080/10715760410001705159}, pmid = {15453636}, issn = {1071-5762}, mesh = {Antioxidants/pharmacology ; Catalase/metabolism ; Cell Survival/drug effects ; Gas Chromatography-Mass Spectrometry ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Humans ; Morpholines/*blood/chemistry/*pharmacology ; Oxidants/metabolism ; Oxidative Stress/*drug effects ; Sulfur Compounds/chemistry/metabolism/pharmacology ; Thiobarbituric Acid Reactive Substances/metabolism ; U937 Cells ; tert-Butylhydroperoxide/*pharmacology ; }, abstract = {Aminoethylcysteine ketimine decarboxylated dimer (AECK-DD) is a natural sulphur compound present in human plasma and urine and in mammalian brain. Recently, it has been detected in many common dietary vegetables. The aim of the present study was to evaluate the ability of AECK-DD to affect cellular response of U937 human monocytic cells to tert-butyl hydroperoxide-induced oxidative stress. AECK-DD was incorporated into cells, as confirmed by GC-MS analyses, without any cytotoxic effect. A 24 h treatment with 50 and 250 microM AECK-DD resulted in the incorporation of 0.10 +/- 0.01 and 0.47 +/- 0.08ng AECK-DD x 10(6) cells, respectively. U937 cells pretreated with AECK-DD (in the range 4-100 microM) showed an increased resistance to tert-butyl hydroperoxide-induced necrotic death, as revealed by a higher percent of survival measured at all incubation times with respect to control cells. Moreover, the protective effect exhibited by AECK-DD is significantly stronger with respect to that obtained with other common antioxidants (N-acetyl cysteine and trolox) and comparable, although somewhat higher, to that of vitamin E. This effect seems to be due to the ability of AECK-DD to reduce glutathione depletion and to inhibit lipid peroxidation during tert-butyl hydroperoxide treatment. It can be concluded that AECK-DD protects cultured human monocytic cells against tert-butyl hydroperoxide-induced oxidative stress and subsequent cell death, likely through an antioxidant action inside the cell. Due to its presence in both human plasma and urine, AECK-DD may play a role in the modulation of oxidative processes in vivo.}, }
@article {pmid15451797, year = {2004}, author = {Bourraindeloup, M and Adamy, C and Candiani, G and Cailleret, M and Bourin, MC and Badoual, T and Su, JB and Adubeiro, S and Roudot-Thoraval, F and Dubois-Rande, JL and Hittinger, L and Pecker, F}, title = {N-acetylcysteine treatment normalizes serum tumor necrosis factor-alpha level and hinders the progression of cardiac injury in hypertensive rats.}, journal = {Circulation}, volume = {110}, number = {14}, pages = {2003-2009}, doi = {10.1161/01.CIR.0000143630.14515.7C}, pmid = {15451797}, issn = {1524-4539}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Collagen/analysis ; Disease Progression ; Drug Evaluation, Preclinical ; Glutathione/deficiency/*physiology ; Heart Ventricles/chemistry ; Hypertension/blood/chemically induced/complications/*drug therapy ; Male ; Matrix Metalloproteinase 2/analysis ; Matrix Metalloproteinase 9/analysis ; Myocardial Contraction ; Myocardium/metabolism ; NG-Nitroarginine Methyl Ester/toxicity ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; Sodium Chloride, Dietary/toxicity ; Sphingomyelin Phosphodiesterase/metabolism ; Tumor Necrosis Factor-alpha/*analysis ; Ultrasonography ; Ventricular Dysfunction, Left/blood/diagnostic imaging/etiology/*prevention &amp; control ; Ventricular Remodeling/*drug effects ; }, abstract = {BACKGROUND: Studies in isolated cardiomyocytes showed that replenishment in cellular glutathione, achieved with the glutathione precursor N-acetylcysteine (NAC), abrogated deleterious effects of tumor necrosis factor-alpha (TNF-alpha).<br><br>METHODS AND RESULTS: We examined the ability of NAC to limit the progression of cardiac injury in the rat model of hypertension, induced by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) (50 mg/kg per day SC) and high-salt diet (HS) (8% NaCl). Four-week HS/L-NAME administration induced hypertension (193+/-8 versus 122+/-4 mm Hg for low-salt diet [LS] group) and left ventricular (LV) dysfunction, revealed by echocardiography and characterized by decreased LV shortening fraction (38+/-2% versus 49+/-4% for LS group; P<0.05) and decreased LV posterior wall thickening (49+/-3% versus 70+/-4% for LS group; P<0.05). LV dysfunction worsened further after 6-week HS/L-NAME administration. Importantly, increase in serum TNF-alpha level was strongly correlated with shortening fraction decrease and cardiac glutathione depletion. NAC (75 mg/d) was given as a therapeutic treatment in a subgroup of HS/L-NAME animals during weeks 5 and 6 of HS/L-NAME administration. NAC treatment, which replenished cardiac glutathione, had no effect on hypertension but reduced LV remodeling and dysfunction, normalized serum TNF-alpha level, and limited activation of matrix metalloproteinases -2 and -9 and collagen deposition in LV tissues.<br><br>CONCLUSIONS: These findings suggest that glutathione status determines the adverse effects of TNF-alpha in cardiac failure and that TNF-alpha antagonism may be achieved by glutathione supplementation.}, }
@article {pmid15451550, year = {2004}, author = {Raghuvar Gopal, DV and Narkar, AA and Badrinath, Y and Mishra, KP and Joshi, DS}, title = {Protection of Ewing's sarcoma family tumor (ESFT) cell line SK-N-MC from betulinic acid induced apoptosis by alpha-DL-tocopherol.}, journal = {Toxicology letters}, volume = {153}, number = {2}, pages = {201-212}, doi = {10.1016/j.toxlet.2004.03.027}, pmid = {15451550}, issn = {0378-4274}, mesh = {Acetylcysteine/pharmacology ; Annexin A5/analysis ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Ascorbic Acid/pharmacology ; Cell Line ; Cell Line, Tumor ; Cell Survival/drug effects ; Humans ; Membrane Potentials/drug effects ; Mitochondria/drug effects/physiology ; Pentacyclic Triterpenes ; Reactive Oxygen Species ; Sarcoma, Ewing/drug therapy/*pathology ; Triterpenes/*pharmacology ; alpha-Tocopherol/*pharmacology ; Betulinic Acid ; }, abstract = {Betulinic acid (BA) is known to induce apoptosis in melanoma neuroectodermal and malignant brain cancer cell lines. Present report describes the role of antioxidants on the BA-induced toxicity to human cell line SK-N-MC. Hydrophilic antioxidants viz., L-ascorbic acid (VitC) and N-acetyl-L-cysteine (l-NAC) had no protective effect on BA-induced apoptosis at the maximal concentrations tested. The lipophilic antioxidant, alpha-DL-tocopherol (VitE) showed a concentration and a time dependent effect on the protection of SK-N-MC cells from BA-induced apoptosis. The apoptotic parameters were analyzed using FACS analysis of propidium iodide (PI) stained nuclei, PS externalization using Annexin-V assay and changes in mitochondrial membrane potential. Generation of superoxide radical was monitored by the fluorescent dye hydroethidium (HE). Cells showed Annexin-V positivity and an increase in the propidium iodide (PI) uptake in the early hours of treatment with BA, which was concomitant with the loss of mitochondrial membrane potential. Addition of alpha-DL-tocopherol to the cell cultures 1-h prior to the treatment with BA abolished all the effects of BA-induced apoptosis. These observations suggest that BA initiates events at membrane level leading to induction of apoptosis. The observed ineffectiveness of hydrophilic antioxidants and substantial protection by lipophilic antioxidants indicate involvement of membrane-associated damages that form the basis of BA-induced cytotoxicity.}, }
@article {pmid15450950, year = {2004}, author = {Oh, SH and Lee, BH and Lim, SC}, title = {Cadmium induces apoptotic cell death in WI 38 cells via caspase-dependent Bid cleavage and calpain-mediated mitochondrial Bax cleavage by Bcl-2-independent pathway.}, journal = {Biochemical pharmacology}, volume = {68}, number = {9}, pages = {1845-1855}, doi = {10.1016/j.bcp.2004.06.021}, pmid = {15450950}, issn = {0006-2952}, mesh = {*Apoptosis ; BH3 Interacting Domain Death Agonist Protein ; Cadmium/*pharmacology ; Calpain/metabolism ; Carrier Proteins/*metabolism ; Caspase 8 ; Caspase 9 ; Caspases/metabolism ; Cell Line ; Cytochrome c Group/*metabolism ; Enzyme Activation/drug effects ; Humans ; Mitochondria/drug effects/physiology ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/*metabolism ; Reactive Oxygen Species/metabolism ; Tumor Suppressor Protein p53/metabolism ; bcl-2-Associated X Protein ; }, abstract = {Previous reports have demonstrated that cadmium (Cd) may induce cell death via apoptosis, but the mechanism responsible for cellular death is not clear. In this study, we investigated the signaling pathways implicated in Cd-induced apoptosis in lung epithelial fibroblast (WI 38) cells. Apoptotic features were observed using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, propidium iodide staining and DNA laddering. A treatment of cadmium caused the caspase-8-dependent Bid cleavage, the release of cytochrome c (Cyt c), activation of caspase-9 and -3, and PARP cleavage. A caspase-8 specific inhibitor prevented the Bid cleavage, caspase-3 activation and cell death. Alternatively, we observed that full-length Bax was cleaved into 18-kDa fragment (p18/Bax); this was initiated after 12 h and by 36 h the full-length Bax protein was totally cleaved to the p18/Bax, which caused a drastic release of Cyt c from mitochondria. The p18/Bax was detected exclusively in the mitochondrial fraction, and it originated from mitochondrial full-length Bax, but not from the cytosol full-length Bax. Cd also induced the activation of the mitochondrial 30-kDa small subunit of calpain that was preceded by Bax cleavage. Cd induced the upregulation of Bcl-2 and the degradation of p53 protein. N-acetyl cysteine effectively inhibited the Cd-induced DeltaPsim reduction, indicating ROS acts upstream of mitochondrial membrane depolarization. Taken together, our results suggest that Cd-induced apoptosis was thought to be mediated at least two pathways; caspase-dependent Bid cleavage, and the other is calpain-mediated mitochondrial Bax cleavage. Moreover, we found that the function of Bid and Bax was not dependent of Bcl-2, and that ROS can also contribute in the Cd-induced cell death.}, }
@article {pmid15450387, year = {2004}, author = {Lappas, M and Permezel, M and Ho, PW and Moseley, JM and Wlodek, ME and Rice, GE}, title = {Effect of nuclear factor-kappa B inhibitors and peroxisome proliferator-activated receptor-gamma ligands on PTHrP release from human fetal membranes.}, journal = {Placenta}, volume = {25}, number = {8-9}, pages = {699-704}, doi = {10.1016/j.placenta.2004.02.003}, pmid = {15450387}, issn = {0143-4004}, mesh = {Acetylcysteine/pharmacology ; Adult ; Amnion/*drug effects/metabolism ; Cells, Cultured ; Chorion/*drug effects/metabolism ; Chromans/pharmacology ; Dose-Response Relationship, Drug ; Female ; Humans ; Immunologic Factors/pharmacology ; Ligands ; NF-kappa B/*antagonists &amp; inhibitors ; PPAR gamma/*pharmacology ; Parathyroid Hormone-Related Protein/*metabolism ; Pregnancy ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology ; Sulfasalazine/pharmacology ; Thiazolidinediones/pharmacology ; Troglitazone ; }, abstract = {Parathyroid hormone-related protein (PTHrP) has been implicated in many processes during normal and pathological pregnancies. In the human fetal membranes, PTHrP exhibits cytokine-like actions. We have recently shown that inhibitors of the nuclear factor-kappa B (NF-kappaB) and activators of the peroxisome proliferator-activated receptor (PPAR)-gamma signalling pathways down-regulate cytokine release from human gestational tissues. Therefore, the aim of this study was to determine whether NF-kappaB and PPAR-gamma also regulate PTHrP release from human fetal membranes. Human amnion and choriodecidua explants were incubated in the absence (control) or presence of two known NF-kappaB inhibitors (1, 5 and 10 mM sulphasalazine (SASP) or 5, 10 and 15 mM N-acetyl-cysteine (NAC)), and two PPAR-gamma ligands (15 and 30 microM 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) or 15 and 30 microM troglitazone), under basal conditions. After 18 h incubation, the tissues were collected and NF-kappaB p65 DNA binding activity in nuclear extracts was assessed by ELISA, and the incubation medium was collected and the release of PTHrP was quantified by RIA. Treatment of amnion and choriodecidual tissues with SASP concentrations greater than 5 mM, 15 mM NAC, 30 microM 15d-PGJ(2) and 30 microM troglitazone significantly reduced the release of PTHrP (p < 0.05). This study demonstrates that PTHrP release from human fetal membranes is regulated by inhibitors of NF-kappaB, and ligands of PPAR-gamma.}, }
@article {pmid15389835, year = {2004}, author = {Paintlia, MK and Paintlia, AS and Barbosa, E and Singh, I and Singh, AK}, title = {N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain.}, journal = {Journal of neuroscience research}, volume = {78}, number = {3}, pages = {347-361}, doi = {10.1002/jnr.20261}, pmid = {15389835}, issn = {0360-4012}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; NS-40144/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; }, mesh = {2',3'-Cyclic-Nucleotide Phosphodiesterases/genetics/metabolism ; Acetylcysteine/*therapeutic use ; Age Factors ; Analysis of Variance ; Animals ; Animals, Newborn ; Antigens/genetics/metabolism ; CD11b Antigen/metabolism ; Cell Count/methods ; Cell Death/drug effects ; Cytokines/genetics/metabolism ; Demyelinating Diseases/etiology/prevention &amp; control ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Interactions ; Embryo, Mammalian ; Female ; Humans ; Immunohistochemistry/methods ; In Situ Nick-End Labeling/methods ; Infant, Newborn ; Leukomalacia, Periventricular/chemically induced/complications/*prevention &amp; control ; Lipopolysaccharides/toxicity ; Male ; Myelin Basic Protein/metabolism ; Nerve Degeneration/*prevention &amp; control ; Neuroprotective Agents/*therapeutic use ; O Antigens/metabolism ; Oligodendroglia/*drug effects ; Pregnancy ; Proteoglycans/genetics/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Stem Cells/*drug effects ; Survival Rate ; Time Factors ; Transcription Factors/genetics/metabolism ; }, abstract = {Periventricular leukomalacia (PVL), the dominant form of brain injury in premature infants, is characterized by diffuse white matter injury and is associated with cerebral palsy (CP). Maternal and placental infections are major causes of prematurity and identifiable etiology of PVL and CP. Here we have evaluated the therapeutic efficacy of N-acetylcysteine (NAC), a potent antioxidant and precursor of glutathione, to attenuate lipopolysaccharide (LPS)-induced white matter injury and hypomyelination in the developing rat brain, an animal model of PVL. Intraperitoneal pretreatment of pregnant female rats with NAC (50 mg/kg), 2 hr prior to administration of LPS at embryonic day 18 (E18), attenuated the LPS-induced expression of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta, and inducible nitric oxide synthase in fetal rat brains. There were significantly reduced numbers of TUNEL(+) nuclei coimmunostained for platelet-derived growth factor-alphaR(+) [a surface marker for oligodendrocyte progenitor cells (OPCs)] at E20 in the subventricular zone of fetal rat brain in the NAC + LPS group compared with the untreated LPS group. Interestingly, immunostaining for O4 and O1 as markers for late OPCs and immature oligodendrocytes demonstrated fewer O4(+) and O1(+) cells in the LPS group compared with the NAC + LPS and control groups. Consistent with O4(+)/O1(+) cell counts, the expression of myelin proteins such as myelin basic protein, proteolipid protein, and 2'3'-cyclic nucleotide phosphodiesterase, including transcription factors such as MyT1 and Gtx, was less in the LPS group at late postnatal days, indicating severe hypomyelination in the developing rat brain when compared with NAC + LPS and control groups. Collectively, these data support the hypothesis that NAC may provide neuroprotection and attenuate the degeneration of OPCs against LPS evoked inflammatory response and white matter injury in developing rat brain. Moreover, these data suggest the possible use of NAC as a treatment for pregnant women with maternal or placental infection as a means of minimizing the risk of PVL and CP.}, }
@article {pmid15389563, year = {2005}, author = {Bowes, TJ and Gupta, RS}, title = {Induction of mitochondrial fusion by cysteine-alkylators ethacrynic acid and N-ethylmaleimide.}, journal = {Journal of cellular physiology}, volume = {202}, number = {3}, pages = {796-804}, doi = {10.1002/jcp.20178}, pmid = {15389563}, issn = {0021-9541}, mesh = {Animals ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Cell Line ; Cell Survival ; Cricetinae ; Cysteine/*metabolism ; Ethacrynic Acid/chemistry/*pharmacology ; Ethylmaleimide/*pharmacology ; Glutathione/metabolism ; *Membrane Fusion ; Mitochondria/*drug effects/*metabolism/ultrastructure ; Molecular Structure ; Sulfhydryl Reagents/*pharmacology ; Vitamin E/pharmacology ; }, abstract = {Mitochondrial fusion and fission are important aspects of eukaryotic cell function that permit the adoption of varied mitochondrial morphologies depending upon cellular physiology. We previously observed that ethacrynic acid (EA) induced mitochondrial fusion in cultured BSC-1 and CHO/wt cells. However, the mechanism responsible for it was not clear since EA has a number of known cellular effects including glutathione (GSH) depletion and alkylation of cysteine residues. To gain insight, we have tested the effects of a variety of compounds on EA induced cellular toxicity and mitochondrial fusion. N-acetyl cysteine (NAC), a GSH precursor, was found to abrogate both the toxic and fusion-inductive effects, whereas diethylmaleate (dEM), a GSH depletor, potentiated both these effects in a dose-dependent manner. However, treatment with dEM alone, which depleted GSH to the same degree as EA, did not induce mitochondrial fusion. These results indicate that although detoxification of EA via formation of GSH conjugates is dependant upon GSH levels, the depletion of GSH by EA is not responsible for its effect on mitochondrial fusion. Dihydro-EA (DH-EA), a saturated EA analogue, lacked EA's toxicity and effect on fusion, indicating that the alpha,beta-unsaturated ketone is central to its observed effects. N-ethylmaleimide (NEM), another well-known cysteine-alkylator, also induced mitochondrial fusion at near toxic concentrations. These data suggests that cysteine-alkylation is the causative factor for fusion and toxicity. In live BSC-1 cells, EA induced fusion of mitochondria occurred very rapidly (<20 min), which suggests that it is inducing fusion by modifying certain critical cysteine residue(s) in proteins involved in the process.}, }
@article {pmid15389228, year = {2004}, author = {Webb, JG and Pate, GE and Humphries, KH and Buller, CE and Shalansky, S and Al Shamari, A and Sutander, A and Williams, T and Fox, RS and Levin, A}, title = {A randomized controlled trial of intravenous N-acetylcysteine for the prevention of contrast-induced nephropathy after cardiac catheterization: lack of effect.}, journal = {American heart journal}, volume = {148}, number = {3}, pages = {422-429}, doi = {10.1016/j.ahj.2004.03.041}, pmid = {15389228}, issn = {1097-6744}, mesh = {Acetylcysteine/*therapeutic use ; *Cardiac Catheterization ; Contrast Media/*adverse effects ; Coronary Angiography ; Coronary Disease/complications/diagnostic imaging ; Creatinine/metabolism ; Double-Blind Method ; Female ; Humans ; Infusions, Intravenous ; Kidney Diseases/chemically induced/metabolism/*prevention &amp; control ; Male ; Middle Aged ; Treatment Failure ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) after cardiac catheterization is common in patients with preexisting renal dysfunction. Studies of oral acetylcysteine to prevent CIN have produced conflicting results. Intravenous N-acetylcysteine (NAC) has logistic advantages in this setting. The objective of this study was to evaluate, in a blinded, randomized, placebo-controlled fashion, whether intravenous NAC reduced CIN in the setting of cardiac catheterization in patients with preexisting renal insufficiency.<br><br>METHODS: Patients with renal dysfunction undergoing cardiac catheterization were randomly assigned to intravenous NAC 500 mg immediately before the procedure or placebo. All patients received isotonic saline (200 mL) beforehand, followed by 1.5 mL/kg per hour for 6 hours, unless contraindicated. Exclusion criteria included acute renal failure, creatinine >400 micromol/L, concurrent dialysis, unstable clinical status, and prior NAC use. Baseline creatinine was obtained immediately before the procedure and repeated 2 to 8 days later. The primary end point was the occurrence of CIN defined as a reduction in creatinine clearance from baseline of >5 mL/min (Cockcroft-Gault formula).<br><br>RESULTS: The study was terminated early because of a determination of futility by the Data Safety Monitoring Committee after enrollment of 487 patients. The median baseline creatinine clearance was 44 mL/min (interquartile range, 33, 55). Median contrast received was 120 mL (interquartile range, 80, 175). Baseline characteristics were similar in the two groups. Altogether, 98 (22.0%) subjects had the primary end point: 23.3% in the NAC group and 20.7% in the placebo arm (P =.57).<br><br>CONCLUSIONS: In this large, randomized trial, enrolling a high-risk group of patients with impaired renal function, intravenous NAC was ineffective in preventing CIN.}, }
@article {pmid15388243, year = {2004}, author = {Gatti, R and Belletti, S and Uggeri, J and Vettori, MV and Mutti, A and Scandroglio, R and Orlandini, G}, title = {Methylmercury cytotoxicity in PC12 cells is mediated by primary glutathione depletion independent of excess reactive oxygen species generation.}, journal = {Toxicology}, volume = {204}, number = {2-3}, pages = {175-185}, doi = {10.1016/j.tox.2004.06.023}, pmid = {15388243}, issn = {0300-483X}, mesh = {Animals ; Cell Survival/drug effects/physiology ; Glutathione/*metabolism ; Intracellular Fluid/drug effects/metabolism ; Methylmercury Compounds/*toxicity ; PC12 Cells ; Rats ; Reactive Oxygen Species/*metabolism ; }, abstract = {Low doses, chronic exposure to mercurial organic compounds is a worldwide health concern and could be pathogenetically relevant as co-factor in several neurodegenerative diseases. In this in vitro study we wanted to further improve our knowledge on the mechanisms of toxicity of methylmercury hydroxide (MeHgOH) in the unprimed PC12 cell line. Cell viability, mitochondrial function, redox state, and cell morphology were recorded at different time points to sequence the events leading to cell death. The lowest cytotoxic concentration and EC50 were 0.3 and 1.3 microM, respectively. 5 microM MeHgOH was fatal for 80% of the cell population after 24 h; within 1 h it caused glutathione (GSH) depletion and a partial dissipation of Deltapsim. At this concentration, reactive oxygen species (ROS) generation was only slight and delayed. After 6h more than 50% of ATP was available and caspase 3 was active. Time-lapse confocal microscopy showed that only a fraction of the cells completed apoptosis while others turned toward necrosis (necrapoptosis). Pre-incubation with N-acetylcysteine (NAC) and GSH but not Cyclosporin A rescued over 80% of the cells. These results provide experimental evidence that, in this cell model, MeHgOH triggers cell death via a primary depletion of GSH but in the absence of ROS overproduction.}, }
@article {pmid15385622, year = {2004}, author = {Staleva, L and Hall, A and Orlow, SJ}, title = {Oxidative stress activates FUS1 and RLM1 transcription in the yeast Saccharomyces cerevisiae in an oxidant-dependent Manner.}, journal = {Molecular biology of the cell}, volume = {15}, number = {12}, pages = {5574-5582}, pmid = {15385622}, issn = {1059-1524}, support = {R01 EY010223/EY/NEI NIH HHS/United States ; EY10223/EY/NEI NIH HHS/United States ; }, mesh = {Cell Membrane Permeability ; Gene Expression Regulation, Fungal/*drug effects ; Hydrogen Peroxide/metabolism/pharmacology ; Levodopa/pharmacology ; MADS Domain Proteins ; MAP Kinase Signaling System/drug effects ; Membrane Proteins/genetics/metabolism ; Mitogen-Activated Protein Kinases/genetics/metabolism ; Mutation/genetics ; Oxidants/*pharmacology ; Oxidative Stress/*drug effects ; Pheromones/pharmacology ; Phosphorylation/drug effects ; Saccharomyces cerevisiae/drug effects/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/*genetics/metabolism ; Transcription Factors/*genetics/metabolism ; Transcription, Genetic/*drug effects ; }, abstract = {Mating in haploid Saccharomyces cerevisiae occurs after activation of the pheromone response pathway. Biochemical components of this pathway are involved in other yeast signal transduction networks. To understand more about the coordination between signaling pathways, we used a "chemical genetic" approach, searching for compounds that would activate the pheromone-responsive gene FUS1 and RLM1, a reporter for the cell integrity pathway. We found that catecholamines (l-3,4-hydroxyphenylalanine [l-dopa], dopamine, adrenaline, and noradrenaline) elevate FUS1 and RLM1 transcription. N-Acetyl-cysteine, a powerful antioxidant in yeast, completely reversed this effect, suggesting that FUS1 and RLM1 activation in response to catecholamines is a result of oxidative stress. The oxidant hydrogen peroxide also was found to activate transcription of an RLM1 reporter. Further genetic analysis combined with immunoblotting revealed that Kss1, one of the mating mitogen-activated protein kinases (MAPKs), and Mpk1, an MAPK of the cell integrity pathway, participated in l-dopa-induced stimulation of FUS1 and RLM1 transcription. We also report that Mpk1 and Hog1, the high osmolarity MAPK, were phosphorylated upon induction by hydrogen peroxide. Together, our results demonstrate that cells respond to oxidative stress via different signal transduction machinery dependent upon the nature of the oxidant.}, }
@article {pmid15382121, year = {2004}, author = {Fang, Y and Han, SI and Mitchell, C and Gupta, S and Studer, E and Grant, S and Hylemon, PB and Dent, P}, title = {Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes.}, journal = {Hepatology (Baltimore, Md.)}, volume = {40}, number = {4}, pages = {961-971}, doi = {10.1002/hep.20385}, pmid = {15382121}, issn = {0270-9139}, support = {P01-CA72955/CA/NCI NIH HHS/United States ; P01-DK38030/DK/NIDDK NIH HHS/United States ; R01-AI57189/AI/NIAID NIH HHS/United States ; R01-CA63753/CA/NCI NIH HHS/United States ; R01-CA77141/CA/NCI NIH HHS/United States ; R01-CA88906/CA/NCI NIH HHS/United States ; R01-DK52825/DK/NIDDK NIH HHS/United States ; R01-DK57543/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Deoxycholic Acid/*pharmacology ; ErbB Receptors/*metabolism ; Hepatocytes/cytology/drug effects/*metabolism ; MAP Kinase Signaling System/*drug effects/physiology ; Male ; Mitochondria/drug effects/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Taurodeoxycholic Acid/*pharmacology ; }, abstract = {Previous studies have demonstrated in hepatocytes that deoxycholic acid (DCA) promotes inactivation of protein tyrosine phosphatases (PTPases) and activation of ERBB1 and the extracellular-regulated kinase (ERK) 1/2 pathway. The present studies have determined the biochemical mechanism(s) through which these events occur. DCA and taurodeoxycholic acid (TDCA) (100 micromol/L) caused activation of ERBB1, insulin receptor, and the ERK1/2 and AKT pathways in primary rodent hepatocytes. DCA- and TDCA-induced receptor and signaling pathway activations were blocked by the reactive oxygen species (ROS) scavengers N-acetyl cysteine (NAC) and Trolox (TX), as well as by cyclosporin A (CsA) and bongkrekic acid (BKA). DCA activated the ERK1/2 pathway in HuH7 human hepatoma cells that was blocked by the incubation of cells with an ERBB1 inhibitor, NAC, TX, CsA, or BKA. DCA did not activate the ERK1/2 pathway in mitochondria-defective HuH7 Rho 0 cells. In HuH7 cells and primary hepatocytes, DCA enhanced the production of ROS, an effect that was abolished in Rho 0 cells and by prior incubation of cells with CsA or BKA. In hepatocytes and HuH7 cells, DCA inhibited PTPase activity. Incubation of hepatocytes with either CsA or BKA prevented DCA-induced inhibition of PTPase activity. Loss of mitochondrial function in Rho 0 cells also abolished the inhibitory effects of DCA on PTPase activity. In conclusion, DCA and TDCA cause ROS generation in hepatocytes that is dependent on metabolically active mitochondria. The generation of ROS is essential for PTPase inactivation, receptor tyrosine kinase activation, and enhanced signaling down the ERK1/2 and AKT pathways.}, }
@article {pmid15378764, year = {2004}, author = {Chung, YW and Oh, HY and Kim, JY and Kim, JH and Kim, IY}, title = {Allergen-induced proteolytic cleavage of annexin-1 and activation of cytosolic phospholipase A2 in the lungs of a mouse model of asthma.}, journal = {Proteomics}, volume = {4}, number = {11}, pages = {3328-3334}, doi = {10.1002/pmic.200400895}, pmid = {15378764}, issn = {1615-9853}, mesh = {Animals ; Annexin A1/*metabolism ; Asthma/immunology/*metabolism ; Disease Models, Animal ; Eosinophils/immunology/metabolism ; Leukotrienes/biosynthesis ; Lung/*metabolism ; Mice ; Ovalbumin/immunology/*metabolism ; Phospholipases A/*metabolism ; Phospholipases A2 ; }, abstract = {To identify proteins that might play an important role in allergen-induced asthma, we analyzed lung extracts prepared from allergen (ovalbumin)-challenged animals in a mouse model of this condition. The combination of two-dimensional gel electrophoresis and mass spectrometry revealed that annexin-1, a 37 kDa anti-inflammatory protein that inhibits the activity of cytosolic phospholipase A(2) (cPLA(2)), was down-regulated by allergen challenge in the lungs of ovalbumin-sensitized mice. Immunoblot analysis showed that this effect of ovalbumin challenge was attributable to proteolytic cleavage of annexin-1. The ovalbumin-induced degradation of annexin-1 was blocked by pretreatment of mice with the antioxidant N-acetylcysteine (NAC) or with sodium selenite, both of which have previously been shown to exert anti-inflammatory effects in this asthma model. Ovalbumin challenge also both increased the expression of cPLA(2) in lung tissue and reduced the extent of the interaction between cPLA(2) and annexin-1, and these effects were inhibited by NAC or selenite. Moreover, the concentrations of cysteinyl leukotrienes in bronchoalveolar lavage fluid and of leukotriene B(4) in lung tissue were increased by ovalbumin challenge in a NAC- or selenite-sensitive manner. Together, these results suggest that allergen-induced oxidative stress results in proteolysis of annexin-1 and consequent up-regulation of cPLA(2) activity and leukotriene production in this mouse model of asthma, and that the anti-inflammatory effects of selenite may provide a basis for the development of new antiasthmatic drugs.}, }
@article {pmid15378659, year = {2004}, author = {Ji, KA and Yang, MS and Jou, I and Shong, MH and Joe, EH}, title = {Thrombin induces expression of cytokine-induced SH2 protein (CIS) in rat brain astrocytes: involvement of phospholipase A2, cyclooxygenase, and lipoxygenase.}, journal = {Glia}, volume = {48}, number = {2}, pages = {102-111}, doi = {10.1002/glia.20059}, pmid = {15378659}, issn = {0894-1491}, mesh = {Animals ; Animals, Newborn ; Astrocytes/drug effects/enzymology/*metabolism ; Cells, Cultured ; DNA-Binding Proteins/drug effects/metabolism ; Dinoprostone/metabolism/pharmacology ; Encephalitis/chemically induced/*metabolism ; Enzyme Inhibitors/pharmacology ; Feedback, Physiological/drug effects/genetics ; Free Radical Scavengers/pharmacology ; Immediate-Early Proteins/drug effects/genetics/*metabolism ; Inflammation Mediators/*metabolism ; Interferon-gamma/metabolism/pharmacology ; Leukotriene B4/metabolism/pharmacology ; Lipoxygenase/drug effects/metabolism ; Phospholipases A/drug effects/metabolism ; Phospholipases A2 ; Prostaglandin-Endoperoxide Synthases/drug effects/metabolism ; RNA, Messenger/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; STAT1 Transcription Factor ; Suppressor of Cytokine Signaling Proteins ; Thrombin/*pharmacology ; Trans-Activators/drug effects/metabolism ; Up-Regulation/drug effects/genetics ; }, abstract = {Previously we have reported that thrombin induces inflammatory mediators in brain glial cells (Ryu et al. 2000. J Biol Chem 275:29955). In the present study, we found that thrombin induced a negative regulator of a cytokine signaling molecule, cytokine-induced SH2 protein (CIS), in rat brain astrocytes. In response to thrombin, CIS expression was increased at both the mRNA and protein levels. Although STAT5 is known to regulate CIS expression, thrombin did not activate STAT5, and inhibitors of JAK2 (AG490) and JAK3 (WHI-P97 and WHI-P154) had little effect on thrombin-induced CIS expression. In contrast, cytosolic phospholipase A(2) (cPLA(2)), cyclooxygenase (COX), and lipoxygenase (LO) play a role in CIS expression, since inhibitors of cPLA(2), cyclooxygenase (COX), and LO significantly reduced CIS expression. Reactive oxygen species (ROS) scavengers (N-acetyl-cysteine [NAC] and trolox) reduced thrombin-induced CIS expression, and inhibitors of COX and LO reduced ROS produced by thrombin. Furthermore, prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)), products of COX and LO, respectively, potentiated thrombin-induced CIS expression, indicating that ROS, and PGE(2) and LTB(4) generated by COX and LO, mediate CIS expression. Since interferon-gamma (IFN-gamma)-induced GAS-luciferase activity and tyrosine phosphorylation of STAT1 and STAT3 were lower in CIS-transfected cells compared to control vector-transfected cells, CIS could have anti-inflammatory activity. These data suggest that thrombin-stimulation of ROS and prostaglandin and leukotriene production via the cPLA(2), COX and LO pathways results in CIS expression. More importantly, CIS expression may be a negative feedback mechanism that prevents prolonged inflammatory responses.}, }
@article {pmid15376207, year = {2004}, author = {Glantzounis, GK and Yang, W and Koti, RS and Mikhailidis, DP and Seifalian, AM and Davidson, BR}, title = {Continuous infusion of N-acetylcysteine reduces liver warm ischaemia-reperfusion injury.}, journal = {The British journal of surgery}, volume = {91}, number = {10}, pages = {1330-1339}, doi = {10.1002/bjs.4694}, pmid = {15376207}, issn = {0007-1323}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Free Radical Scavengers/*administration &amp; dosage ; Indocyanine Green/pharmacokinetics ; Ischemic Preconditioning/methods ; Liver/*blood supply ; Liver Circulation ; Liver Function Tests ; Microcirculation ; Rabbits ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) may modulate the initial phase (less than 2 h) of liver warm ischaemia-reperfusion (IR) injury but its effect on the late phase remains unclear. The present study investigated the role of NAC during the early and late phases in a rabbit lobar IR model.<br><br>METHODS: Liver ischaemia was induced by inflow occlusion to the median and left liver lobes for 60 min, followed by 7 h of reperfusion. In the NAC group (n = 6), NAC was administered intravenously at 150 mg per kg over the 15 min before reperfusion and maintained at 10 mg per kg per h during reperfusion. In the IR group (n = 6), 20 ml 5 per cent dextrose was infused over the 15 min before reperfusion and continued at a rate of 10 ml/h. Animals in a sham operation group (n = 6) underwent laparotomy but no liver ischaemia. All animals were killed at the end of the experiment.<br><br>RESULTS: Intracellular tissue oxygenation was improved after the second hour of reperfusion in animals treated with NAC compared with that in the IR group (P = 0.023). Hepatic microcirculation improved after 5 h of reperfusion (P = 0.036) and liver injury was reduced after 5 h, as indicated by alanine aminotransferase activity (P = 0.007) and indocyanine green clearance (uptake, P = 0.001; excretion, P = 0.032).<br><br>CONCLUSION: The main protective effect of NAC becomes apparent 5 h after hepatic ischaemic injury.}, }
@article {pmid15375156, year = {2004}, author = {Qanungo, S and Wang, M and Nieminen, AL}, title = {N-Acetyl-L-cysteine enhances apoptosis through inhibition of nuclear factor-kappaB in hypoxic murine embryonic fibroblasts.}, journal = {The Journal of biological chemistry}, volume = {279}, number = {48}, pages = {50455-50464}, doi = {10.1074/jbc.M406749200}, pmid = {15375156}, issn = {0021-9258}, support = {P30 CA43703/CA/NCI NIH HHS/United States ; R01 NS39469/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; Apoptosis/*physiology ; Cell Survival/physiology ; Cytochromes c/metabolism ; Fibroblasts/*metabolism ; Glutathione/metabolism ; Hypoxia/*metabolism ; I-kappa B Proteins/metabolism ; Mice ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Proteins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; X-Linked Inhibitor of Apoptosis Protein ; }, abstract = {In this study, we investigated the role of reduced glutathione (GSH) and nuclear factor-kappaB (NFkappaB) in hypoxia-induced apoptosis. Hypoxia caused p53-dependent apoptosis in murine embryonic fibroblasts transfected with Ras and E1A. N-Acetyl-l-cysteine (NAC) but not other antioxidants, such as the vitamin E analog trolox and epigallocatechin-3-gallate, enhanced hypoxia-induced caspase-3 activation and apoptosis. NAC also enhanced hypoxia-induced apoptosis in two human cancer cell lines, MIA PaCa-2 pancreatic cancer cells and A549 lung carcinoma cells. In murine embryonic fibroblasts, all three antioxidants blocked hypoxia-induced reactive oxygen species formation. NAC did not enhance hypoxia-induced cytochrome c release but did enhance poly-(ADP ribose) polymerase cleavage, indicating that NAC acted at a post-mitochondrial level. NAC-mediated enhancement of apoptosis was mimicked by incubating cells with GSH monoester, which increased intracellular GSH similarly to NAC. Hypoxia promoted degradation of an inhibitor of kappaB(IkappaBalpha), NFkappaB-p65 translocation into the nucleus, NFkappaB binding to DNA, and subsequent transactivation of NFkappaB, which increased X chromosome-linked inhibitor of apoptosis protein levels. NAC failed to block degradation by IkappaBalpha and sequestration of the p65 subunit of NFkappaB to the nucleus. However, NAC did abrogate hypoxia-induced NFkappaB binding to DNA, NFkappaB-dependent gene expression, and induction of X chromosome-linked inhibitor of apoptosis protein. In conclusion, NAC enhanced hypoxic apoptosis by a mechanism apparently involving GSH-dependent suppression of NFkappaB transactivation.}, }
@article {pmid15371664, year = {2004}, author = {Lin, A and Sekhon, C and Sekhon, B and Smith, A and Chavin, K and Orak, J and Singh, I and Singh, A}, title = {Attenuation of ischemia-reperfusion injury in a canine model of autologous renal transplantation.}, journal = {Transplantation}, volume = {78}, number = {5}, pages = {654-659}, doi = {10.1097/01.tp.0000131664.18670.17}, pmid = {15371664}, issn = {0041-1337}, support = {NS 22576/NS/NINDS NIH HHS/United States ; NS 34741/NS/NINDS NIH HHS/United States ; NS 37766/NS/NINDS NIH HHS/United States ; NS 40810/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Adenosine ; Allopurinol ; Aminoimidazole Carboxamide/*analogs &amp; derivatives/therapeutic use ; Animals ; Apoptosis ; Creatinine/blood ; Disease Models, Animal ; Dogs ; Glutathione ; Graft Survival/immunology/physiology ; Immunohistochemistry ; Insulin ; Kidney/cytology/pathology ; Kidney Transplantation/methods/*pathology/physiology ; Male ; Nephrectomy ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II ; Organ Preservation/methods ; Organ Preservation Solutions ; Raffinose ; Reperfusion Injury/*prevention &amp; control ; Ribonucleotides/therapeutic use ; Transplantation, Autologous ; Tumor Necrosis Factor-alpha/analysis/genetics ; }, abstract = {BACKGROUND: This study examined the potential therapeutic effects of a combination therapy consisting of 5-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) and N-acetyl cysteine (NAC) to attenuate ischemia-reperfusion (I/R) injury in a canine model of autologous renal transplantation.<br><br>METHODS: Male mongrel dogs (15-20 kg) underwent left nephrectomy followed by flushing and static preservation of the kidney in University of Wisconsin (UW) solution for 48 hr. The treatment group received AICAR (50 mg/kg) plus NAC (100 mg/kg) intravenously before the left nephrectomy. The compounds were added to the UW solution as well. All dogs underwent right nephrectomy 48 hr later followed by autotransplantation of the preserved left kidney. Treated dogs received a second dose of AICAR and NAC before implantation of the renal autograft.<br><br>RESULTS: The treated dogs had excellent urine output posttransplant, with peak serum creatinine of 7.26 mg/dL on postoperative day (POD) 3 that normalized after 14 days. The control group were anuric and developed clinical symptoms of uremia on POD 1. Morphologic evaluation supported the protective effects of combination therapy. Immunohistochemical analysis revealed decrease of tumor necrosis factor-alpha, interferon-gamma, and inducible nitric oxide synthase; and TUNEL assay showed decreased apoptosis in the treated group.<br><br>CONCLUSIONS: Combination therapy with AICAR and NAC attenuates renal I/R injury and improves the outcome of the transplanted kidney after prolonged cold preservation.}, }
@article {pmid15371635, year = {2004}, author = {Baliga, RS and Liu, C and Hoyt, DG and Chaves, AA and Bauer, JA}, title = {Vascular endothelial toxicity induced by HIV protease inhibitor: evidence of oxidant-related dysfunction and apoptosis.}, journal = {Cardiovascular toxicology}, volume = {4}, number = {2}, pages = {199-206}, doi = {10.1385/ct:4:2:199}, pmid = {15371635}, issn = {1530-7905}, mesh = {Animals ; Aorta, Thoracic/drug effects/physiology ; *Apoptosis ; Cell Line ; Cell Survival/drug effects ; Endothelial Cells/cytology/*drug effects ; Endothelium, Vascular/cytology/*drug effects/physiology ; HIV Protease Inhibitors/*toxicity ; Humans ; In Vitro Techniques ; Male ; Necrosis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Saquinavir/*toxicity ; Umbilical Veins ; Vasodilation/drug effects ; }, abstract = {HIV-protease inhibitor (HIV-PI) drugs are critical for highly active antiretroviral therapy (HAART) efficacy, but several recent reports have suggested that metabolic and/or cardiovascular toxicities are associated with these drugs. Given the importance of the HIV-PI drug class and the widespread and chronic use of these agents in an expanding patient population, further understanding of this potential drug toxicity is imperative. Here, we investigated a role for direct endothelial toxicity induced by saquinavir (SAQ), the first HIV-PI drug marketed in the United States and still an important component of HAART therapies. In initial studies using isolated vascular tissues, we observed selective impairment of endothelium-dependent vasodilation with no effect on contractile responses. Subsequent studies using human endothelial cells in culture at clinically relevant concentrations (5 and 10 microM, 2-48 h) demonstrated concentration-dependent increases in cell death, mainly via apoptosis rather than necrosis (determined via Annexin-V positive membrane labeling). Live cell imaging also demonstrated increased intracellular oxidant production (as measured by DCF fluorescence), which could be abrogated by incubation with the antioxidant N-acetylcysteine (NAC). NAC also prevented SAQ- induced apoptotic cell death. These data demonstrate that SAQ has direct toxicological effects on endothelial cells, and that the toxicity apparently involves apoptotic pathway activation via reactive oxygen and/or nitrogen species.}, }
@article {pmid15371168, year = {2004}, author = {Arfsten, D and Johnson, E and Thitoff, A and Jung, A and Wilfong, E and Lohrke, S and Bausman, T and Eggers, J and Bobb, A}, title = {Impact of 30-day oral dosing with N-acetyl-L-cysteine on Sprague-Dawley rat physiology.}, journal = {International journal of toxicology}, volume = {23}, number = {4}, pages = {239-247}, doi = {10.1080/10915810490502041}, pmid = {15371168}, issn = {1091-5818}, mesh = {Acetylcysteine/administration &amp; dosage/*toxicity ; Alanine Transaminase/blood ; Animals ; Antidotes/administration &amp; dosage/*toxicity ; Dose-Response Relationship, Drug ; Female ; Glutathione/metabolism ; Glutathione Transferase/metabolism ; Kidney/drug effects/enzymology ; Male ; Rats ; Rats, Sprague-Dawley ; Skin/drug effects/enzymology ; Toxicity Tests ; }, abstract = {A number of studies have demonstrated a protective effect associated with N-acetyl-l-cysteine (NAC) against toxic chemical exposure. However, the impact of long-term oral dosing on tissue pathology has not been determined. In this study, the authors assessed the impact of long-term oral NAC administration on organ histopathology and tissue glutathione (GSH) and total glutathione-S-transferase (GST) activity levels in Sprague-Dawley (SD) rats. Groups of 20 SD rats (10 males, 10 females), 8 weeks of age, were dosed daily by oral gavage with deionized H2O (negative controls) or NAC solution at a rate of 600 or 1200 mg/kg/day for 30 days. Animals were euthanized 6 h after treatment on study day 30. There were no significant differences in final body weights or weekly average weight gain between treatment groups. Serum alanine aminotransferase (ALT) activities were significantly elevated (p =.05) in NAC-treated animals compared to controls when measured on study day 30. Histopathologic evaluation of the stomach, small intestine, liver, kidneys, spleen, thymus, and lungs revealed no lesions associated with NAC administration. When measured on study day 30, total GST activity for kidney and skin from NAC-treated animals were increased 39% to 131% as compared to controls. Tissue GSH concentrations from NAC-treated animals were increased 24% to 81% as compared with negative controls. Further studies are needed to determine if the observed increase in tissue GSH concentration and GST activity provide a degree of chemoprotection against dermal and systemic chemical toxicants.}, }
@article {pmid15367896, year = {2004}, author = {Linning, KD and Tai, MH and Madhukar, BV and Chang, CC and Reed, DN and Ferber, S and Trosko, JE and Olson, LK}, title = {Redox-mediated enrichment of self-renewing adult human pancreatic cells that possess endocrine differentiation potential.}, journal = {Pancreas}, volume = {29}, number = {3}, pages = {e64-76}, doi = {10.1097/00006676-200410000-00015}, pmid = {15367896}, issn = {1536-4828}, support = {R21 DK57173-01/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenoviridae/genetics ; Adult ; Albumins/biosynthesis/genetics ; C-Peptide/biosynthesis/genetics ; Cell Aggregation ; Cell Differentiation/drug effects ; Cell Separation ; Cells, Cultured/cytology ; Chromones/pharmacology ; Culture Media/pharmacology ; Culture Media, Serum-Free ; Exenatide ; Gene Expression Regulation/drug effects ; Genetic Vectors/genetics/pharmacology ; Glucagon/biosynthesis/genetics ; Homeodomain Proteins/biosynthesis/genetics ; Humans ; Insulin/biosynthesis/genetics ; Intermediate Filament Proteins/biosynthesis/genetics ; Intracellular Fluid/metabolism ; Islets of Langerhans/*cytology ; Morpholines/pharmacology ; Nerve Tissue Proteins/biosynthesis/genetics ; Nestin ; Niacinamide/pharmacology ; Oxidation-Reduction ; Peptides/pharmacology ; RNA, Messenger/biosynthesis/genetics ; Recombinant Fusion Proteins/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Somatostatin/biosynthesis/genetics ; Stem Cells/*cytology/drug effects/metabolism ; Trans-Activators/biosynthesis/genetics ; Transcription Factors/biosynthesis/genetics ; Venoms/pharmacology ; Vimentin/biosynthesis/genetics ; alpha-Amylases/biosynthesis/genetics ; }, abstract = {OBJECTIVES: The limited availability of transplantable human islets has stimulated the development of methods needed to isolate adult pancreatic stem/progenitor cells capable of self-renewal and endocrine differentiation. The objective of this study was to determine whether modulation of intracellular redox state with N-acetyl-L-cysteine (NAC) would allow for the propagation of pancreatic stem/progenitor cells from adult human pancreatic tissue.<br><br>METHODS: Cells were propagated from human pancreatic tissue using a serum-free, low-calcium medium supplemented with NAC and tested for their ability to differentiate when cultured under different growth conditions.<br><br>RESULTS: Human pancreatic cell (HPC) cultures coexpressed alpha-amylase, albumin, vimentin, and nestin. The HPC cultures, however, did not express other genes associated with differentiated pancreatic exocrine, duct, or endocrine cells. A number of transcription factors involved in endocrine cell development including Beta 2, Islet-1, Nkx6.1, Pax4, and Pax6 were expressed at variable levels in HPC cultures. In contrast, pancreatic duodenal homeobox factor 1 (Pdx-1) expression was extremely low and at times undetectable. Overexpression of Pdx-1 in HPC cultures stimulated somatostatin, glucagon, and carbonic anhydrase expression but had no effect on insulin gene expression. HPC cultures could form 3-dimensional islet-like cell aggregates, and this was associated with expression of somatostatin and glucagon but not insulin. Cultivation of HPCs in a differentiation medium supplemented with nicotinamide, exendin-4, and/or LY294002, an inhibitor of phosphatidylinositol-3 kinase, stimulated expression of insulin mRNA and protein.<br><br>CONCLUSION: These data support the use of intracellular redox modulation for the enrichment of pancreatic stem/progenitor cells capable of self-renewal and endocrine differentiation.}, }
@article {pmid15363497, year = {2004}, author = {Lochmann, D and Stadlhofer, S and Weyermann, J and Zimmer, A}, title = {New protamine quantification method in microtiter plates using o-phthaldialdehyde/N-acetyl-L-cysteine reagent.}, journal = {International journal of pharmaceutics}, volume = {283}, number = {1-2}, pages = {11-17}, doi = {10.1016/j.ijpharm.2004.05.032}, pmid = {15363497}, issn = {0378-5173}, mesh = {Acetylcysteine ; Heparin Antagonists/*chemistry ; Indicators and Reagents ; Protamines/*chemistry ; *Technology, Pharmaceutical ; o-Phthalaldehyde ; }, abstract = {Protamine is a well-known excipient in pharmaceutics. It represents a peptide consisting of exclusive aliphatic amino acids, hence it cannot be quantified by UV-spectroscopy (lambdamax 280 nm). A new and sensitive quantification method based on the derivatisation of protamine with ortho-phthaldialdehyde (OPA) in the presents of 2-mercaptoethanol (ME) or N-acetyl-L-cysteine (NAC) in basic aqueous solution using 96-well microtiter plates are introduced in this report. The resulting isoindol derivatives reveal a fluorescence excitation (maximum lambdaex 345 nm) and emission (maximum lambdaem 450 nm) spectra. Derivatives of OPA/NAC reagent were found to be useful for protamine quantification in pharmaceutical nanoparticle preparation containing DNA. A sufficient stability of the isoindol derivatives was shown. It was possible to determine protamine free base, protamine sulphate and protamine chloride with limits of detection less than 1.1 microg/ml.}, }
@article {pmid15362604, year = {2004}, author = {Andrew, E and Berg, KJ}, title = {Nephrotoxic effects of X-ray contrast media.}, journal = {Journal of toxicology. Clinical toxicology}, volume = {42}, number = {3}, pages = {325-332}, doi = {10.1081/clt-120037430}, pmid = {15362604}, issn = {0731-3810}, mesh = {Acute Kidney Injury/*chemically induced/diagnosis/physiopathology/prevention &amp; control ; Chemical Phenomena ; Chemistry, Physical ; Contrast Media/*adverse effects/chemistry/pharmacokinetics ; Humans ; Risk Factors ; }, abstract = {The annual sale of x-ray contrast media (CM) now represents 60 million doses, and contrast nephropathy (CN) has been the third-leading cause of hospital-acquired acute renal failure. In this review article, physicochemical, pharmacokinetic, and pharmacodynamic properties of CM are surveyed. The definition of CN is presented, as well as the mechanisms involved in the pathogenesis. Low osmolar monomeric CM (LOCM) are less nephrotoxic than the older ionic high osmolar CM (HOCM), but in risk patients the incidence of CN is still high after intravascular administration of LOCM. Non-ionic dimeric CM are iso-osmolar to plasma (IOCM), and they have reduced the nephrotoxicity even more than LOCM. The most important risk factors for CN are diabetes mellitus and impaired renal function. Selection of patients, hydration, and type of CM are essential for prevention and prophylaxis of CN. We do not recommend routine prophylaxis with N-acetylcysteine (NAC) during CM investigations, but its use in high-risk patients should be considered.}, }
@article {pmid15361285, year = {2004}, author = {Yang, SX and Yan, J and Deshpande, SS and Irani, K and Lowenstein, CJ}, title = {Rac1 regulates the release of Weibel-Palade Bodies in human aortic endothelial cells.}, journal = {Chinese medical journal}, volume = {117}, number = {8}, pages = {1143-1150}, pmid = {15361285}, issn = {0366-6999}, mesh = {Aorta/*ultrastructure ; Endothelial Cells/*ultrastructure ; Humans ; Reactive Oxygen Species ; Signal Transduction ; Thrombin/pharmacology ; Weibel-Palade Bodies/*physiology ; rac1 GTP-Binding Protein/*physiology ; }, abstract = {BACKGROUND: The release of Weibel-Palade Bodies (WPB) is a form of endothelial cell activation. But the signal transduction pathway leading to WPB release is not yet defined. We hypothesized that small G-protein rac1 and reactive oxygen species (ROS) mediate the ligand induced release of Weibel-Palade Bodies.<br><br>METHODS: We tested this hypothesis by using wild-type and mutant adenoviral rac1 expression vectors, and by manipulating the production and destruction of superoxide and hydrogen peroxide in human aortic endothelial cells (HAEC).<br><br>RESULTS: Thrombin (1.0 Unit, 30 min) induced the increase of WPB release by 3.7-fold in HAEC, and that H2O2 (0.1 mmol/L, 30 min) induced by 4.5-fold. These results correlated with thrombin-stimulated activation of rac-GTP binding activity by 3.5-fold, and increase of ROS production by 3.4-fold. The dominant negative adenoviral rac-N17 gene transfer dramatically inhibited the release of WPB by 64.2% (control) and 77.3% (thrombin-stimulation), and decreased ROS production by 65.5% (control) and 83.6% (thrombin-stimulation) compared with non-infected cells, respectively. Anti-oxidants, catalase and N-acetyl-cysteine significantly decreased the release of WPB by 34% and 79% in control cells, and further decreased by 63.6% and 46.7% in rac-N17 transferred cells compared with non-infected cells. We also confirmed that rac1 was located upstream of ROS in the WPB release pathway.<br><br>CONCLUSIONS: Small G-protein rac1 medicates ligand-induced release of Weibel-Palade Bodies in human aortic endothelial cells, and the signal pathway of WPB release is a rac1-dependent ROS regulating mechanism.}, }
@article {pmid15356963, year = {2004}, author = {Guru, V and Fremes, SE}, title = {The role of N-acetylcysteine in preventing radiographic contrast-induced nephropathy.}, journal = {Clinical nephrology}, volume = {62}, number = {2}, pages = {77-83}, doi = {10.5414/cnp62077}, pmid = {15356963}, issn = {0301-0430}, mesh = {Acetylcysteine/*therapeutic use ; Contrast Media/*adverse effects ; Humans ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: There have been many small randomized controlled trials evaluating the effectiveness of N-acetylcysteine (NAC) in preventing radiographic contrast-induced nephropathy. Most studies have suggested a beneficial NAC effect. This meta-analysis describes the effect of NAC in the prevention of radiographic contrast-induced nephropathy in the aggregated trial data.<br><br>METHODS: A search using MEDLINE from 1966 to December 2003 identified all randomized control trials that evaluated NAC in those patients at risk of acute renal failure (ARF) following either angiographic or CT scan contrast exposure. All studies included in the review employed the use of either low-osmolar (n = 9 trials) or iso-osmolar (n = 2 trials) contrast agents. The outcome of interest was ARF as defined by a rise in serum creatinine (Cr > or = 0.5 mg/dl rise or > 25% increase from baseline) after exposure to contrast. The data were aggregated by the methods of Mantel and Haenszel.<br><br>RESULTS: The overall summary odds ratio estimate of 0.46 (95% confidence interval 0.32 - 0.66) suggests a strong protective effect of NAC in preventing radiographic-induced nephropathy.<br><br>CONCLUSION: In summary, there is good aggregate trial evidence to suggest that patients who have an elevated serum creatinine level at baseline benefit from receiving periprocedure NAC in the prevention of contrast-induced ARF.}, }
@article {pmid15356956, year = {2004}, author = {Varma, PS and Aruna, K and Rukkumani, R and Menon, VP}, title = {Alcohol and thermally oxidized pufa induced oxidative stress: role of N-acetyl cysteine.}, journal = {The Italian journal of biochemistry}, volume = {53}, number = {1}, pages = {10-15}, pmid = {15356956}, issn = {0021-2938}, mesh = {Acetylcysteine/*pharmacology ; Alkaline Phosphatase/blood/metabolism ; Animals ; Antioxidants/*pharmacology ; Diet ; Ethanol/*toxicity ; Fatty Acids, Unsaturated/*toxicity ; Glutathione/metabolism ; Kidney/chemistry ; Liver/chemistry/*drug effects/enzymology ; Male ; Myocardium/chemistry ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Plant Oils/*toxicity ; Rats ; Rats, Wistar ; Sunflower Oil ; Thiobarbituric Acid Reactive Substances/metabolism ; Triglycerides/blood/metabolism ; gamma-Glutamyltransferase/blood/metabolism ; }, abstract = {Alcohol related disabilities are one of the world's major public health concerns. The effects of alcohol intake include alteration of redox state, acetaldehyde and free radical production, which lead to membrane damage. The damage caused by alcohol is enhanced by polyunsaturated fatty acid ingestion. When alcohol is taken along with thermally oxidized sunflower oil, the toxicity is still more pronounced due to toxic metabolites produced during heating. In our study, we have analysed the effects of a thiol supplier N-acetyl cysteine on alcohol, thermally oxidized sunflower oil and alcohol + thermally oxidized sunflower oil induced toxic effects in male Wistar rats. The activities of liver marker enzymes (alkaline phosphatase and gamma-glutamyl transferase), triglycerides in plasma and lipid peroxidative indices (thiobarbituric acid reactive substances and hydroperoxides) were increased in these groups when compared to normal, which were brought down in N-acetyl cysteine treated groups. The antioxidant status (Superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase) was decreased in tissues of these groups, which were found to be improved in N-acetyl cysteine treated groups. Thus our results show that N-acetyl cysteine regresses the oxidative damage induced by Alcohol, thermally oxidized sunflower oil and alcohol + thermally oxidized sunflower oil.}, }
@article {pmid15355665, year = {2004}, author = {Xu, L and Cai, BQ and Zhu, YJ and Guo, ZJ and Zhang, H and Gu, L and Xu, XX}, title = {[Influence of N-acetylcysteine on the cytokines and matrix metalloproteinases in chronic obstructive pulmonary disease rat models].}, journal = {Zhonghua nei ke za zhi}, volume = {43}, number = {8}, pages = {595-599}, pmid = {15355665}, issn = {0578-1426}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Interferon-gamma/metabolism ; Interleukin-4/metabolism ; Male ; Matrix Metalloproteinase 12 ; Matrix Metalloproteinase 9/metabolism ; Metalloendopeptidases/metabolism ; Pulmonary Disease, Chronic Obstructive/*metabolism/physiopathology ; Rats ; Rats, Wistar ; Tissue Inhibitor of Metalloproteinase-1/metabolism ; Tobacco Smoke Pollution ; }, abstract = {OBJECTIVE: To investigate the changes of interferon-gamma (IFNgamma), interleukin (IL)-4, matrix metalloproteinase (MMP)-9, MMP-12 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 in smoke-induced chronic obstructive pulmonary disease (COPD) rat models and the therapeutic effect of N-acetylcysteine (NAC).<br><br>METHODS: Male Wistar rats were exposed to cigarette smoke for 3.5 months. NAC was given in the last month. Lung function was measured at the end of the study. The levels of IL-4 and IFNgamma in broncho-alveolar lavage fluid (BALF) and lung tissues were determined by ELISA. The expression of MMP-9, MMP-12 and TIMP-1 mRNA in lung tissues were determined by RT-PCR.<br><br>RESULTS: (1) In comparison with the control group, smoke exposed group presented a significant decrease in forced expiratory volume in 0.3 second (FEV(0.3))/forced vital capacity (FVC), dynamic lung compliance (Cdyn), mean alveolar numbers (MAN) and a significant increase in expiratory resistance (Re), pulmonary mean linear intercept (Lm) (P < 0.05). After treatment with NAC, FEV(0.3)/FVC, Re and Cdyn were improved significantly (P < 0.05). No significant changes were found in Lm and MAN (P > 0.05). (2) In the lung tissues of smoke exposed group, IL-4 level was 10.00 pg/ml, IFNgamma level was 19.37 pg/ml, and the IL-4/IFNgamma ratio was 0.49. In the lung tissues of the control group, they were 4.38 pg/ml, 54.94 pg/ml and 0.10, respectively. There were significant differences in these indexes between the smoke exposed group and the control group (P < 0.05). IL-4 level in the NAC group was 7.99 pg/ml which was similar to that in the smoke exposed group (P > 0.05). IFNgamma and IL-4/IFNgamma ratio were 43.40 pg/ml and 0.15, the former being significantly higher and the latter being significantly lower than those in the smoke exposed group (P < 0.05). (3) The expression of MMP-12 mRNA and MMP-12/TIMP-1 ratio in the smoke exposed group (0.36, 1.21) were significantly higher than those in the control group (0.24, 0.88) (P < 0.05). There was no difference in TIMP-1 (P > 0.05). The expression of MMP-12, TIMP-1 mRNA and the MMP-12/TIMP-1 ratio in NAC group were similar to those in the smoke exposed group (P > 0.05).<br><br>CONCLUSIONS: (1) Cigarette smoke exposure increased IL-4 and decreased IFNgamma. This may contribute to smoke-induced changes in lung function. NAC had no effect on IL-4, but increased IFNgamma, and the IL-4/IFNgamma ratio returned to normal. This might be one of the mechanisms of NAC in improving lung function. (2) Cigarette smoke promoted MMP-12 gene expression and increased the MMP-12/TIMP-1 ratio. This may play a role in smoke-induced emphysema. NAC did not alter MMP-12/TIMP-1 ratio when given in the late phase of smoke exposure. This result could explain the emphysematous changes in the NAC group.}, }
@article {pmid15352173, year = {2004}, author = {Tsuboi, H and Hossain, K and Akhand, AA and Takeda, K and Du, J and Rifa'i, M and Dai, Y and Hayakawa, A and Suzuki, H and Nakashima, I}, title = {Paeoniflorin induces apoptosis of lymphocytes through a redox-linked mechanism.}, journal = {Journal of cellular biochemistry}, volume = {93}, number = {1}, pages = {162-172}, doi = {10.1002/jcb.20134}, pmid = {15352173}, issn = {0730-2312}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Benzoates/*pharmacology ; Bridged-Ring Compounds/*pharmacology ; Caspases/metabolism ; Curcumin/pharmacology ; Dithiothreitol/pharmacology ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Glucosides/*pharmacology ; Humans ; Jurkat Cells/drug effects/metabolism ; Lymphocytes/*drug effects ; Membrane Potentials/drug effects ; Mice ; Mitochondria/drug effects/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Monoterpenes ; Oxidation-Reduction ; Paeonia/chemistry ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Paeoniflorin (PF), isolated from paeony root, has been used as a herbal medicine for more than 1,200 years in China, Korea, and Japan for its anti-allergic, anti-inflammatory, and immunoregulatory effects. In this study, we found that PF induces apoptosis in both murine T-lineage cells and human T-cell leukemia Jurkat cells. This apoptosis was mediated through the reduction of mitochondrial membrane potential, activation of caspase, and fragmentation of DNA. Interestingly, PF induced generation of reactive oxygen species (ROS) and a reducing agent, dithiothreitol (DTT), and a ROS scavenger, N-acetyl cysteine (NAC), successfully attenuated the PF-induced apoptosis. Additionally, PF induced the phosphorylation of three mitogen-activated protein (MAP) family kinases, extracellular signal-regulated kinase, c-Jun amino-terminal kinase (JNK), and p38 MAP kinase. Curcumin, an anti-oxidant and JNK inhibitor, inhibited PF-induced apoptosis, suggesting the possible involvement of curcumin-sensitive JNK or other redox-sensitive elements in PF-induced apoptosis. These results partially explain the action mechanism of PF-containing paeony root as a herbal medicine.}, }
@article {pmid15344883, year = {2004}, author = {Efremova, TN and Kirpichnikova, KM and Khaĭtlina, SIu and Gamaleĭ, IA}, title = {[Antioxidants-induced rearrangements of actin cytoskeleton in 3T3 and 3T3-SV40 fibroblasts].}, journal = {Tsitologiia}, volume = {46}, number = {5}, pages = {395-403}, pmid = {15344883}, issn = {0041-3771}, mesh = {3T3 Cells ; Acetylcysteine/pharmacology ; Actin Cytoskeleton/drug effects/*metabolism ; Actins/metabolism ; Animals ; Antioxidants/*pharmacology ; Cell Line, Transformed ; Glutathione/pharmacology ; Mice ; Pyrrolidonecarboxylic Acid ; Reactive Oxygen Species/metabolism ; Simian virus 40 ; Stress Fibers/metabolism ; Thiazoles/pharmacology ; Thiazolidines ; Time Factors ; }, abstract = {Effect of antioxidants on actin cytoskeleton in 3T3 fibroblasts and 3T3 fibroblasts transformed with SV40 virus (3T3-SV40 cells) was studied. Antioxidants used were as follows: N-acetyl-L-cysteine (NAC), (-)-2-oxo-4-thiazolidine-carboxylic acid (OTZ), and glutathione in the reduced form (GSH). Both NAC and OTZ are precursors of GSH in the cell, but, in contrast to NAC, OTZ reduces inside the cell forming L-cysteine. The presence of NAC (5-20 mM) in the culture medium of both cell types resulted in loosening of monolayer, fragmentation of stress fibers, and the appearance of amorphous actin structures. As 3T3-SV40 cells contain less actin stress fibers than 3T3 cells, the NAC-induced rearrangements of actin cytoskeleton were stronger in these cells than in 3T3 cells. In contrast to NAC, OTZ (10-20 mM) did not destroy monolayer and did not induce any visible disappearance of stress fibers either in 3T3 or 3T3-SV40 cells. However, in the presence of OTZ, amorphous actin-containing structures were observed in 3T3-SV40 cells. The effect of glutathione on both cell types was similar to that of NAC. The time required for GSH-induced alterations of actin cytoskeleton (about 5 h) was consistent with the increase in the intracellular level of reactive oxygen species (4 h after addition of GSH to the culture medium). Upon removal of the antioxidants from the medium, actin filament structures were reconstructed. However, within 24 h after withdrawal of NAC or GSH, only a partial reconstruction of stress fibers was observed in 3T3 cells. On the contrary, 3T3-SV40 cells demonstrated formation of well-structured actin fibers similar to normal fibroblasts. These results suggest that GSH can act as a pro-oxidant in the absence of oxidative stress.}, }
@article {pmid15336443, year = {2004}, author = {Li, L and Julien, B and Grenard, P and Teixeira-Clerc, F and Mallat, A and Lotersztajn, S}, title = {Molecular mechanisms regulating the antifibrogenic protein heme-oxygenase-1 in human hepatic myofibroblasts.}, journal = {Journal of hepatology}, volume = {41}, number = {3}, pages = {407-413}, doi = {10.1016/j.jhep.2004.05.016}, pmid = {15336443}, issn = {0168-8278}, mesh = {Cell Proliferation/drug effects ; Cells, Cultured ; Collagen Type I/genetics ; Enzyme Induction/drug effects ; Gene Expression/drug effects ; Heme Oxygenase (Decyclizing)/*genetics/*metabolism ; Heme Oxygenase-1 ; Humans ; Liver/*cytology/drug effects/*enzymology ; Liver Cirrhosis/enzymology/genetics ; MAP Kinase Signaling System ; Membrane Proteins ; Oxidation-Reduction ; Oxidative Stress ; Prostaglandin D2/*analogs &amp; derivatives/pharmacology ; RNA Stability ; RNA, Messenger/genetics/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {BACKGROUND/AIMS: Hepatic myofibroblasts are central in liver fibrogenesis associated with chronic liver diseases. We previously showed that heme-oxygenase-1 (HO-1) displays antifibrogenic properties in human hepatic myofibroblasts. Here, we further investigated the mechanisms regulating HO-1 expression.<br><br>METHODS: Expression of HO-1 was assayed in cultured human hepatic myofibroblasts by Northern and Western blot. Functional studies were also performed in cultured human hepatic myofibroblasts.<br><br>RESULTS: 15-Deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) elicited inhibition of proliferation and of alpha1(I) collagen mRNA expression. These effects were reproduced by the glutathione depletor diethyl maleate and blunted by the glutathione precursor N-acetyl cysteine, indicating the involvement of oxidative stress. Two consecutive events mediated inhibition of proliferation and of alpha1(I) collagen mRNA expression by 15-d-PGJ2: (i) mild oxidative stress characterized by a transient GSH decrease and (ii) activation of p38 MAPK, resulting in increased HO-1 mRNA stability.<br><br>CONCLUSIONS: Our results provide new insights into the regulatory mechanisms governing HO-1 expression in human hepatic myofibroblasts and identify mild oxidative stress and p38 MAPK as two consecutive early signals promoting HO-1 induction that are crucial for its antifibrogenic properties, namely inhibition of growth and extracellular matrix gene expression.}, }
@article {pmid15332826, year = {2004}, author = {Afshar, RK and Patra, AK and Olmstead, MM and Mascharak, PK}, title = {Syntheses, structures, and reactivities of (Fe-NO)6 nitrosyls derived from polypyridine-carboxamide ligands: photoactive NO-donors and reagents for S-nitrosylation of alkyl thiols.}, journal = {Inorganic chemistry}, volume = {43}, number = {18}, pages = {5736-5743}, doi = {10.1021/ic040057c}, pmid = {15332826}, issn = {0020-1669}, support = {GM 61636/GM/NIGMS NIH HHS/United States ; }, mesh = {Amides/*chemistry ; Crystallography, X-Ray ; Indicators and Reagents ; *Iron/chemistry ; Ligands ; Models, Chemical ; Molecular Structure ; Nitric Oxide/*chemistry ; *Nitrogen Oxides/chemical synthesis/chemistry ; *Organometallic Compounds/chemical synthesis/chemistry ; Photochemistry ; Polymers/chemistry ; Pyridines/*chemistry ; Sulfhydryl Compounds/*chemistry ; }, abstract = {Two new iron nitrosyls derived from two designed pentadentate ligands N,N-bis(2-pyridylmethyl)-amine-N'-(2-pyridylmethyl)acetamide and N,N-bis(2-pyridylmethyl)-amine-N'-[1-(2-pyridinyl)ethyl]acetamide (PcPy(3)H and MePcPy(3)H, respectively, where H is the dissociable amide proton) have been structurally characterized. These complexes are similar to a previously reported (Fe-NO)6 complex, [(PaPy(3))Fe(NO)](ClO(4))(2) (1) that releases NO under mild conditions. The present nitrosyls, namely [(PcPy(3))Fe(NO)](ClO(4))(2) (2) and [(MePcPy(3))Fe(NO)](ClO(4))(2) (3), belong to the same (Fe-NO)6 family and exhibit (a) clean (1)H NMR spectra in CD(3)CN indicating S = 0 ground state, (b) almost linear Fe-N-O angles (177.3(5) degrees and 177.6(4) degrees for 2 and 3, respectively), and (c) N-O stretching frequencies (nu(NO)) in the range 1900-1925 cm(-)(1). The binding of NO at the non-heme iron centers of 1-3 is completely reversible and all three nitrosyls rapidly release NO when exposed to light (50 W tungsten bulb). In addition to acting as photoactive NO-donors, these complexes also nitrosylate thiols such as N-acetylpenicillamine, 3-mercaptopropionic acid, and N-acetyl-cysteine-methyl-ester in yields that range from 30 to 90% in the absence of light. The addition of alkyl or aryl thiolate (RS(-)) to the (Fe-NO)6 complexes in the absence of dioxygen results in the reduction of the iron metal center to afford the corresponding (Fe-NO)7 species.}, }
@article {pmid15328380, year = {2005}, author = {Song, HJ and Lee, TS and Jeong, JH and Min, YS and Shin, CY and Sohn, UD}, title = {Hydrogen peroxide-induced extracellular signal-regulated kinase activation in cultured feline ileal smooth muscle cells.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {312}, number = {1}, pages = {391-398}, doi = {10.1124/jpet.104.074401}, pmid = {15328380}, issn = {0022-3565}, mesh = {Animals ; Calcium/metabolism ; Calmodulin/metabolism ; Cats ; Cells, Cultured ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/drug effects/*metabolism ; Hydrogen Peroxide/*pharmacology ; Ileum/*cytology ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System/*drug effects ; Mitogen-Activated Protein Kinases/metabolism ; Muscle, Smooth/*drug effects/enzymology ; Protein Kinase C/metabolism ; Receptors, Growth Factor/metabolism ; Signal Transduction ; ras Proteins/metabolism ; }, abstract = {H(2)O(2) has been shown to act as a signaling molecule involved in many cellular functions such as apoptosis and proliferation. In the present study, we characterized the effects of H(2)O(2) on the activation of mitogen-activated protein (MAP) kinases and examined the factors involved in the process of extracellular signal-regulated kinase (ERK) activation by H(2)O(2) in ileal smooth muscle cells (ISMC). ISMC were cultured and exposed to H(2)O(2). Western blot analysis was performed with phosphospecific MAP kinase antibodies. Potent activation of ERK and moderate activation of stress-activated protein kinase/c-Jun NH(2)-terminal kinase occurred within 30 min of 1 mM H(2)O(2) treatment. However, p38 MAP kinase was not activated by H(2)O(2). The activation of ERK by H(2)O(2) was reduced by the mitogen-activated/ERK-activating kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one], Ras inhibitor S-farnesylthiosalicylic acid, removal of extracellular Ca(2+), depletion of the intracellular Ca(2+) pool by thapsigargin, or pretreatment of ISMC with the calmodulin antagonist W-7. Also, H(2)O(2)-induced ERK activation was attenuated by a receptor tyrosine kinase inhibitor, tyrphostin 51, but not by down-regulation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate or by a PKC inhibitor, GF109203X [3-[1-(dimethylaminopropyl)indol-3-yl]-4-(indol-3-yl)maleimide hydrochloride]. Growth factor receptor antagonist suramin pretreatment inhibited H(2)O(2)-induced ERK activation, highlighting a role for growth factor receptors in this activation. Furthermore, the ERK activation by H(2)O(2) was blocked by pretreatment with either N-acetyl-cysteine, o-phenanthroline, or mannitol indicating that metal-catalyzed free radical formation may mediate the initiation of signal transduction by H(2)O(2). These data suggest that short-term stimulation with H(2)O(2) activates the signaling pathways of cell mitogenic effects which are thought to be a protective response against intestinal oxidative stress.}, }
@article {pmid15315779, year = {2004}, author = {Wu, W and Ercal, N}, title = {Determination of thiocyl in biological samples by liquid chromatography with ThioGlo 3 derivatization.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {809}, number = {2}, pages = {295-299}, doi = {10.1016/j.jchromb.2004.06.037}, pmid = {15315779}, issn = {1570-0232}, mesh = {Benzoates/*analysis ; Calibration ; Chromatography, High Pressure Liquid/*methods ; Kinetics ; Pyrans/*chemistry ; Pyrroles/*chemistry ; Reproducibility of Results ; Sensitivity and Specificity ; Sulfhydryl Compounds ; Thimerosal ; }, abstract = {Thiocyl (sodium thiosalicylate) belongs to a salicylate group of drugs, thus it has analgesic, antipyretic and anti-inflammatory effects. It possesses metal chelating function because it also belongs to a thiol-containing group of compounds which are well-known chelators. The studies of our research group showed that thiocyl is a promising chelator of lead poisoning due to its antioxidant and metal-chelating abilities. To the best of our knowledge, no methods were currently available for measuring thiocyl in biological samples. Therefore, we developed a reversed-phase HPLC method using fluorescence detection (lambdaex = 365 nm, lambdaem = 445 nm) with a one-step derivatizing reaction between thiocyl and a derivatizing agent-ThioGlo 3 (9-acetoxy-2-(4-(2, 5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)pyenyl)-3-oxo-3H-naphtho[2,1-b]pyran). Most biological thiols (such as N-acetylcysteine (NAC), cysteine (CYS), glutathione (GSH) and homocysteine (HCYS)) do not interfere with the detection of thiocyl by using this technique. The linear range of its calibration curve was determined to be 25-2500 nM, and the detection limit of thiocyl was found to be 3 nM with 20 microL injection volume. The coefficients of variation (CV) for within-run precision and between-run precision ranged from 0.93 to 7.21%. This assay proved to be a rapid, sensitive and simple method for determining thiocyl in biological samples.}, }
@article {pmid15314550, year = {2004}, author = {Kalamasz, D and Long, SA and Taniguchi, R and Buckner, JH and Berenson, RJ and Bonyhadi, M}, title = {Optimization of human T-cell expansion ex vivo using magnetic beads conjugated with anti-CD3 and Anti-CD28 antibodies.}, journal = {Journal of immunotherapy (Hagerstown, Md. : 1997)}, volume = {27}, number = {5}, pages = {405-418}, doi = {10.1097/00002371-200409000-00010}, pmid = {15314550}, issn = {1524-9557}, mesh = {Acetylcysteine/pharmacology ; CD28 Antigens/*immunology ; CD3 Complex/*immunology ; Cell Culture Techniques/*methods ; Flow Cytometry ; Humans ; Lymphocyte Activation/drug effects/*immunology ; Magnetics ; T-Lymphocytes/*cytology/drug effects/immunology ; }, abstract = {T-cell receptor engagement and accompanying costimulatory signals control the level of activation and functional potential of individual T cells. The authors previously developed a novel technology in which human T cells are activated and expanded in culture ex vivo using anti-CD3 and anti-CD28 monoclonal antibodies covalently linked to superparamagnetic beads (Xcyte Dynabeads). In this study the addition of N-acetyl L-cysteine (NAC) to the cultures markedly increased the expansion of T cells from human peripheral blood mononuclear cells without diminishing cell function. NAC increased the rate of T-cell division, reduced apoptosis, and increased the percentage of antigen-specific memory T cells in the cultures. The effect of varying the ratio of beads to T cells (1:10-10:1) at culture initiation was also evaluated. Polyclonal T cells were expanded at all bead-to-T cell ratios tested (range 1:10-10:1). While high bead-to-T cell ratios (5:1 and 10:1) deleted, low ratios (1:10 and 1:5) preserved memory T cells directed against cytomegalovirus, Epstein-Barr virus, and influenza virus antigens. Adding more anti-CD3/anti-CD28 beads during the culture led to further expansion of T cells. Experiments also revealed that reducing the amount of anti-CD3 antibodies relative to the amount of anti-CD28 antibodies on the beads favored the proliferation of antigen-specific T cells. In summary, these data indicate that T cell-stimulating effects of anti-CD3/anti-CD28 beads can be further manipulated to control the expansion of antigen-specific memory T cells and can be used to rapidly expand antigen-specific T cells ex vivo for potential clinical applications.}, }
@article {pmid15313229, year = {2004}, author = {Dean, B and Chang, S and Doss, GA and King, C and Thomas, PE}, title = {Glucuronidation, oxidative metabolism, and bioactivation of enterolactone in rhesus monkeys.}, journal = {Archives of biochemistry and biophysics}, volume = {429}, number = {2}, pages = {244-251}, doi = {10.1016/j.abb.2004.06.023}, pmid = {15313229}, issn = {0003-9861}, mesh = {4-Butyrolactone/*analogs &amp; derivatives/*pharmacokinetics ; Acetylcysteine/administration &amp; dosage ; Animals ; Chromatography, High Pressure Liquid ; Female ; Lignans/*pharmacokinetics ; Liver/metabolism ; Macaca mulatta ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Oxidation-Reduction ; }, abstract = {Enterolactone (ENL) and enterodiol (END) are mammalian lignans derived from the plant lignans matairesionol (MAT), secoisolariciresinol (SECO), and other dietary precursors. ENL was found to undergo extensive glucuronidation with rhesus liver microsomes to form O-glucuronides at both phenolic hydroxy groups. In addition to glucuronidation, ENL was found to be a good substrate for oxidative metabolism. The major products had a m/z of 313 or 295 by LC-MS analysis in negative ion mode and were determined to be products of monohydroxylation of ENL. The m/z 295 products were the result of a dehydration of the m/z 313 in the MS source. Addition of N-acetylcysteine (NAC) to the NADPH incubations resulted in a decrease of at least 2 major monohydroxylated products and the formation of a major and several minor new products with a m/z of 474. The major adduct was isolated, purified for NMR, and confirmed to be the NAC adduct of the ENL catechol. Incubations of ENL with liver microsomes containing UDPGA, NADPH, and NAC resulted in the formation of ENL-glucuronides; no NAC adducts were detected by LC-MS. Incubations of ENL with human and rhesus hepatocytes resulted in several metabolites. The major metabolites in hepatocytes were the glucuronic acid conjugates; minor amounts of the sulfate conjugate(s) and monohydroxylated products were also detected by LC-MS. Glutathione or other thiol adducts were not detected in hepatocytes. Conclusion. The high efficiency and specificity for the glucuronidation of ENL decrease its potential toxicity via CYP450 bioactivation.}, }
@article {pmid15312855, year = {2004}, author = {Briguori, C and Colombo, A and Airoldi, F and Violante, A and Castelli, A and Balestrieri, P and Paolo Elia, P and Golia, B and Lepore, S and Riviezzo, G and Scarpato, P and Librera, M and Focaccio, A and Ricciardelli, B}, title = {N-Acetylcysteine versus fenoldopam mesylate to prevent contrast agent-associated nephrotoxicity.}, journal = {Journal of the American College of Cardiology}, volume = {44}, number = {4}, pages = {762-765}, doi = {10.1016/j.jacc.2004.04.052}, pmid = {15312855}, issn = {0735-1097}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Contrast Media/*adverse effects ; Coronary Angiography/adverse effects ; Coronary Artery Disease/diagnostic imaging ; Creatinine/blood ; Dopamine Agonists/*administration &amp; dosage ; Drug Administration Schedule ; Female ; Fenoldopam/*administration &amp; dosage ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Infusions, Intravenous ; Kidney Diseases/blood/chemically induced/*prevention &amp; control ; Male ; }, abstract = {OBJECTIVES: We performed a study to assess the efficacy of fenoldopam mesylate (a specific agonist of the dopamine-1 receptor) as compared with N-acetylcysteine (NAC) in preventing contrast agent-associated nephrotoxicity (CAN).<br><br>BACKGROUND: Prophylactic administration of NAC, along with hydration, prevents CAN in patients with chronic renal insufficiency who are undergoing contrast media administration. Preliminary data support the hypothesis that fenoldopam might be as effective as NAC.<br><br>METHODS: One hundred ninety-two consecutive patients with chronic renal insufficiency, referred to our institution for coronary and/or peripheral procedures, were assigned randomly to receive 0.45% saline intravenously and NAC (1,200 mg orally twice daily; NAC group; n = 97) or fenoldopam (0.10 microg/kg/min; fenoldopam group; n = 95) before and after a nonionic, iso-osmolality contrast dye administration.<br><br>RESULTS: Baseline creatinine levels were similar in the two groups: NAC group = 1.72 mg/dl (interquartile range, 1.55 to 1.90 mg/dl) and fenoldopam group = 1.75 mg/dl (interquartile range, 1.62 to 2.01 mg/dl) (p = 0.17). An increase of at least 0.5 mg/dl of the creatinine concentration 48 h after the procedure occurred in 4 of 97 patients (4.1%) in the NAC group and in 13 of 95 patients (13.7%) in the fenoldopam group (p = 0.019; odds ratio 0.27; 95% confidence interval 0.08 to 0.85). The amount of contrast media administration was similar in the two groups (NAC group = 160 +/- 82 ml; fenoldopam group = 168 +/- 104 ml; p = 0.54).<br><br>CONCLUSIONS: N-acetylcysteine seems to be more effective than fenoldopam in preventing CAN.}, }
@article {pmid15312215, year = {2004}, author = {Emet, S and Memis, D and Pamukçu, Z}, title = {The influence of N-acetyl-L-cystein infusion on cytokine levels and gastric intramucosal pH during severe sepsis.}, journal = {Critical care (London, England)}, volume = {8}, number = {4}, pages = {R172-9}, pmid = {15312215}, issn = {1466-609X}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Cytokines/*blood/drug effects ; Double-Blind Method ; Female ; Gastric Mucosa/*drug effects ; Hemodynamics/drug effects ; Humans ; Infusions, Intravenous ; Intensive Care Units ; Male ; Middle Aged ; Monitoring, Physiologic ; Oxidative Stress ; Oxygen Consumption/drug effects ; Sepsis/*drug therapy/mortality/physiopathology ; Severity of Illness Index ; Statistics, Nonparametric ; }, abstract = {INTRODUCTION: The purpose of the present study was to evaluate the effects of continuously infused N-acetyl-L-cystein (NAC) on serum cytokine levels and gastric intramucosal pH in humans suffering from severe sepsis.<br><br>METHODS: Fifty-three patients were included in the study. In the NAC group (n = 27), after an initial intravenous bolus of NAC (150 mg/kg over 5 min), a continuous intravenous infusion of 12.5 mg/kg per hour was given for 6 hours. Patients in the control group (n = 26) were administered dextrose (5% solution) at the same dosage. We recorded the following: haemodynamic parameters, nasopharyngeal temperature, arterial blood gas changes, plasma cytokine levels, biochemical parameters, intramucosal pH, length of stay in the intensive care unit, duration of of mechanical ventilation and mortality. All measurements were taken at baseline (15 min before the start of the study) and were repeated immediately after the bolus infusion, and at 24 and 48 hours after initiation of the continuous NAC infusion.<br><br>RESULTS: No differences were found between groups in levels of the major cytokines, duration of ventilation and intensive care unit stay, gastric intramucosal pH and arterial oxygen tension/inspired fractional oxygen ratio (P > 0.05).<br><br>CONCLUSION: We found that NAC infusion at the doses given did not affect cytokine levels, outcomes, or gastric intramucosal pH in patients with severe sepsis. Because of the limited number of patients included in the study and the short period of observation, our findings need confirmation in larger clinical trials of NAC infused in a dose-titrated manner. However, our results do not support the use of NAC in patients with severe sepsis.}, }
@article {pmid15297790, year = {2004}, author = {Sandberg, K and Fellman, V and Stigson, L and Thiringer, K and Hjalmarson, O}, title = {N-acetylcysteine administration during the first week of life does not improve lung function in extremely low birth weight infants.}, journal = {Biology of the neonate}, volume = {86}, number = {4}, pages = {275-279}, doi = {10.1159/000080089}, pmid = {15297790}, issn = {0006-3126}, mesh = {Acetylcysteine/*administration &amp; dosage ; Bronchopulmonary Dysplasia/prevention &amp; control ; Glutathione/physiology ; Humans ; Infant, Newborn ; *Infant, Premature ; *Infant, Very Low Birth Weight ; Intensive Care, Neonatal ; Lung/*drug effects/*physiopathology ; Lung Compliance ; Placebos ; Respiratory Function Tests ; }, abstract = {Oxygen toxicity is thought to be an important factor involved in development of bronchopulmonary dysplasia (BPD) in the very preterm infant. Glutathione (GSH) plays a major role in the antioxidant defense system in the preterm lung and there are theoretical implications that N-acetylcysteine (NAC) treatment could improve its function. The purpose of this study was to investigate whether NAC treatment during the first week of life to preterm infants improved neonatal lung function as a measure of lung injury. The study was part of a multi-center Nordic controlled trial with prophylactic intravenous NAC treatment (16-32 mg/kg/day) for 6 days in newborn infants with birth weights 500-999 g. Lung mechanics, with calculations of compliance and resistance of the respiratory system, together with measurements of functional residual capacity and indices of gas mixing efficiency in the lung, were performed in 33 preterm infants (18 received NAC and 15 placebo) before discharge from the NICU. Median (range) gestational age was 25 (24-28) weeks in the NAC-treated infants and 25 (24-29) in the placebo group. Corresponding mean (SD) birth weights were 0.774 (0.11) and 0.761 (0.12) kg respectively. Lung function measurements did not show any significant differences between NAC-treated infants compared to placebo when examined before discharge from the NICU. We conclude that prophylactic NAC treatment to extremely low birth weight infants during the first week of life does not improve lung function at term.}, }
@article {pmid15297771, year = {2004}, author = {Kyaw, M and Yoshizumi, M and Tsuchiya, K and Izawa, Y and Kanematsu, Y and Fujita, Y and Ali, N and Ishizawa, K and Yamauchi, A and Tamaki, T}, title = {Antioxidant effects of stereoisomers of N-acetylcysteine (NAC), L-NAC and D-NAC, on angiotensin II-stimulated MAP kinase activation and vascular smooth muscle cell proliferation.}, journal = {Journal of pharmacological sciences}, volume = {95}, number = {4}, pages = {483-486}, doi = {10.1254/jphs.sc0040061}, pmid = {15297771}, issn = {1347-8613}, mesh = {Acetylcysteine/chemistry/*pharmacology ; Angiotensin II/*pharmacology ; Animals ; Antioxidants/chemistry/*pharmacology ; Aorta, Thoracic/cytology ; Cell Proliferation ; Enzyme Activation ; Glutathione/metabolism ; In Vitro Techniques ; JNK Mitogen-Activated Protein Kinases/metabolism ; Male ; Mitogen-Activated Protein Kinases/*metabolism ; Muscle, Smooth, Vascular/cytology/*metabolism ; Myocytes, Smooth Muscle/cytology/*metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Stereoisomerism ; Thymidine/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism ; }, abstract = {We examined the effects of the stereoisomers of N-acetylcysteine (NAC), L-NAC and D-NAC, on cellular glutathione (GSH) concentration and whether NAC-regulated cellular GSH levels are directly associated with angiotensin II (Ang II)-induced intracellular signaling events in vascular smooth muscle cells (VSMC). Both L-NAC and D-NAC similarly increased intracellular GSH concentration. We found that L-NAC and D-NAC both inhibited Ang II-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and [(3)H]-thymidine incorporation in VSMC. Our present study indicates the comparable effects of NAC stereoisomers in regulating intracellular GSH and the redox-dependent intracellular signaling mechanisms in VSMC.}, }
@article {pmid15295387, year = {2004}, author = {Bisseling, TM and Maria Roes, E and Raijmakers, MT and Steegers, EA and Peters, WH and Smits, P}, title = {N-acetylcysteine restores nitric oxide-mediated effects in the fetoplacental circulation of preeclamptic patients.}, journal = {American journal of obstetrics and gynecology}, volume = {191}, number = {1}, pages = {328-333}, doi = {10.1016/j.ajog.2003.12.033}, pmid = {15295387}, issn = {0002-9378}, mesh = {Acetylcysteine/*pharmacology ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*drug effects ; Female ; Humans ; In Vitro Techniques ; Nitric Oxide/*physiology ; Placenta/*drug effects/physiology ; Placental Circulation/*drug effects/physiology ; Pre-Eclampsia/*physiopathology ; Pregnancy ; }, abstract = {OBJECTIVE: Preeclampsia is associated with an imbalance between oxidants and antioxidants, resulting in reduced effects of the endothelium-derived, relaxing-factor nitric oxide (NO). Antioxidants, like N-acetylcysteine (NAC), remove reactive oxygen species, resulting in an improvement of endothelial function. We aimed to investigate the effect of NAC on the NO-pathway in the human fetoplacental circulation in preeclampsia and control pregnancies.<br><br>STUDY DESIGN: The NO-pathway was investigated by use of the NO-synthase inhibitor L-NAME in an ex vivo cotyledon perfusion model.<br><br>RESULTS: At baseline, fetoplacental arterial pressure was comparable in preeclamptic pregnancies (n=8) and control pregnancies (n=8), and increased dose-dependently after L-NAME. The maximal L-NAME-induced rise in fetoplacental arterial pressure was attenuated in preeclamptic versus control pregnancies (20.8 +/- 2.0 mm Hg vs 36.7 +/- 3.5 mm Hg, P<.05). Addition of NAC increased the L-NAME-induced rise in fetoplacental arterial pressure to 36.4 +/- 3.4 mm Hg in preeclampsia pregnancies (P<.05) and to 49.2 +/- 2.6 mm Hg in control pregnancies (P<.05).<br><br>CONCLUSION: Preeclampsia is associated with a dysfunction of the NO-pathway. N-acetylcysteine increases NO-mediated effects in the fetoplacental circulation in preeclamptic placentas as well as in healthy control placentas.}, }
@article {pmid15292218, year = {2004}, author = {Masuda, Y and Shima, G and Aiuchi, T and Horie, M and Hori, K and Nakajo, S and Kajimoto, S and Shibayama-Imazu, T and Nakaya, K}, title = {Involvement of tumor necrosis factor receptor-associated protein 1 (TRAP1) in apoptosis induced by beta-hydroxyisovalerylshikonin.}, journal = {The Journal of biological chemistry}, volume = {279}, number = {41}, pages = {42503-42515}, doi = {10.1074/jbc.M404256200}, pmid = {15292218}, issn = {0021-9258}, mesh = {Acetylcysteine/chemistry/pharmacology ; Antineoplastic Agents, Phytogenic/pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Blotting, Northern ; Blotting, Western ; Cell Death ; Cell Line ; Cell Line, Tumor ; Coloring Agents/pharmacology ; Cytochromes c/metabolism ; Cytosol/metabolism ; DNA, Complementary/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Etoposide/pharmacology ; Gene Expression Regulation ; Genetic Vectors ; HL-60 Cells ; HSP90 Heat-Shock Proteins/*physiology ; Humans ; K562 Cells ; Mitochondria/metabolism/pathology ; Naphthoquinones/*pharmacology ; Oligonucleotide Array Sequence Analysis ; Plasmids/metabolism ; RNA, Small Interfering/metabolism ; Reactive Oxygen Species ; Subcellular Fractions/metabolism ; Time Factors ; Transfection ; }, abstract = {beta-Hydroxyisovalerylshikonin (beta-HIVS), a compound isolated from the traditional oriental medicinal herb Lithospermum radix, is an ATP non-competitive inhibitor of protein-tyrosine kinases, such as v-Src and EGFR, and it induces apoptosis in various lines of human tumor cells. However, the way in which beta-HIVS induces apoptosis remains to be clarified. In this study, we performed cDNA array analysis and found that beta-HIVS suppressed the expression of the gene for tumor necrosis factor receptor-associated protein 1 (TRAP1), which is a member of the heat-shock family of proteins. When human leukemia HL60 cells and human lung cancer DMS114 cells were treated with beta-HIVS, the amount of TRAP1 in mitochondria decreased in a time-dependent manner during apoptosis. A similar reduction in the level of TRAP1 was also observed upon exposure of cells to VP16. Treatment of DMS114 cells with TRAP1-specific siRNA sensitized the cells to beta-HIVS-induced apoptosis. Moreover, the reduction in the level of expression of TRAP1 by TRAP1-specific siRNA enhanced the release of cytochrome c from mitochondria when DMS114 cells were treated with either beta-HIVS or VP16. The suppression of the level of TRAP1 by either beta-HIVS or VP16 was blocked by N-acetyl-cysteine, indicating the involvement of reactive oxygen species (ROS) in the regulation of the expression of TRAP1. These results suggest that suppression of the expression of TRAP1 in mitochondria might play an important role in the induction of apoptosis caused via formation of ROS.}, }
@article {pmid15289318, year = {2004}, author = {Reliene, R and Fischer, E and Schiestl, RH}, title = {Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice.}, journal = {Cancer research}, volume = {64}, number = {15}, pages = {5148-5153}, doi = {10.1158/0008-5472.CAN-04-0442}, pmid = {15289318}, issn = {0008-5472}, support = {K02 ES 00299/ES/NIEHS NIH HHS/United States ; R01 ES 09519/ES/NIEHS NIH HHS/United States ; }, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*pharmacology ; Animals ; Ataxia Telangiectasia/*metabolism ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins ; DNA Damage/*drug effects ; DNA-Binding Proteins ; Deoxyguanosine/*analogs &amp; derivatives/metabolism ; Dietary Supplements ; Female ; Free Radical Scavengers/*pharmacology ; Genomic Instability ; Male ; Mice ; Mice, Knockout ; Optic Nerve/metabolism/pathology ; *Oxidative Stress ; Pigment Epithelium of Eye/metabolism/pathology ; Protein Serine-Threonine Kinases/genetics/*physiology ; Sequence Deletion ; Sulfhydryl Compounds ; Tumor Suppressor Proteins ; }, abstract = {Ataxia telangiectasia (AT) is a hereditary human disorder resulting in a wide variety of clinical manifestations, including progressive neurodegeneration, immunodeficiency, and high incidence of lymphoid tumors. Cells from patients with AT show genetic instability, hypersensitivity to radiation, and a continuous state of oxidative stress. Oxidative stress and genetic instability, including DNA deletions, are involved in carcinogenesis. We examined the effect of dietary supplementation with the thiol-containing antioxidant N-acetyl-l-cysteine (NAC) on levels of oxidative DNA damage and the frequency of DNA deletions in Atm-deficient (AT-mutated) mice. We confirmed that Atm-deficient mice display an increased frequency of DNA deletions (Bishop et al., Cancer Res 2000;60:395). Furthermore, we found that Atm-deficient mice have significantly increased levels of 8-OH deoxyguanosine, an indication of oxidative DNA damage. Dietary supplementation with NAC significantly reduced 8-OH deoxyguanosine level and the frequency of DNA deletions in Atm-deficient mice. These levels were similar to the levels in wild-type mice. Our findings demonstrate that NAC counteracts genetic instability and suggest that genetic instability may be a consequence of oxidative stress in Atm-deficient mice.}, }
@article {pmid15288682, year = {2004}, author = {Claes, P and Wintzen, M and Allard, S and Simons, P and De Coninck, A and Lacor, P}, title = {Nevirapine-induced toxic epidermal necrolysis and toxic hepatitis treated successfully with a combination of intravenous immunoglobulins and N-acetylcysteine.}, journal = {European journal of internal medicine}, volume = {15}, number = {4}, pages = {255-258}, doi = {10.1016/j.ejim.2004.04.007}, pmid = {15288682}, issn = {1879-0828}, abstract = {We describe a case of an HIV-seropositive patient presenting with a severe stomatitis that initially improved with anti-infective agents. Only 13 days after the onset of the stomatitis, the patient developed rapidly progressive constitutional symptoms and a cutaneous eruption. He was diagnosed with a Stevens-Johnson syndrome (SJS) caused by the antiretroviral drug nevirapine (NVP). Despite meticulous supportive care and withdrawal of all drugs, his situation worsened and developed into a toxic epidermal necrolysis (TEN), or Lyell's syndrome, complicated by a toxic hepatitis. Treatment with a novel combination of intravenous immunoglobulins (IVIG) and N-acetylcysteine (NAC) resulted in an exceptionally fast recovery. A literature research revealed no other cases of patients treated with both NAC and IVIG for the combination of TEN and toxic hepatitis. Because of the rapid clinical recovery, this approach merits further investigation. This case report also illustrates the importance of early suspicion of SJS when an HIV-infected patient treated with nevirapine presents with stomatitis.}, }
@article {pmid15288573, year = {2004}, author = {Shih, CM and Lin, H and Liang, YC and Lee, WS and Bi, WF and Juan, SH}, title = {Concentration-dependent differential effects of quercetin on rat aortic smooth muscle cells.}, journal = {European journal of pharmacology}, volume = {496}, number = {1-3}, pages = {41-48}, doi = {10.1016/j.ejphar.2004.06.016}, pmid = {15288573}, issn = {0014-2999}, mesh = {Animals ; Aorta, Thoracic/cytology/*drug effects/physiology ; Dose-Response Relationship, Drug ; Male ; Muscle, Smooth, Vascular/cytology/*drug effects/physiology ; Quercetin/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Quercetin is one of the most ubiquitous bioflavonoids in foods of plant origin. Although quercetin is generally considered to provide protection against oxidative injury and inflammation, recent studies have demonstrated that its cytoprotective effects occur within a narrow concentration range. We attempted to examine the concentration-dependent effect on proliferation and inflammation in the primary culture of rat aortic smooth muscle cells. We demonstrate that quercetin inhibited [3H]thymidine incorporation into rat aortic smooth muscle cells only at concentrations < or =50 microM in a concentration-dependent manner. Nevertheless, quercetin, at concentrations > or =100 microM, reduced cell viability; this was further characterized as being due to apoptosis, which occurred through the proteolytic activation of pro-caspase-3. Additionally, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) substantially increased in rat aortic smooth muscle cells exposed to 100 microM quercetin, results which differ from observations by others and ourselves of cells exposed to < or =50 microM quercetin. Unlike P-JNK and P-p38, the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/ERK2) was not significantly affected by the concentration-dependent effects of quercetin. Surprisingly, the adverse effects of higher concentrations of quercetin could be ameliorated by adding the antioxidants, catalase, and N-acetylcysteine (NAC). Furthermore, the electrophoretic mobility shift assay (EMSA) showed that rat aortic smooth muscle cells exposed to quercetin at concentrations of < or =50 microM caused concentration-dependent inhibition of nuclear factor kappa B (NF-kappaB) activity, whereas concentrations of > or =100 microM resulted in increased NF-kappaB binding activity. We demonstrate for the first time that quercetin at low concentrations has antiproliferative and antiinflammatory effects, but at concentrations of > or =100 microM, is likely to induce the opposite effects on rat aortic smooth muscle cells.}, }
@article {pmid15287004, year = {2004}, author = {Selloum, L and Djelili, H and Sebihi, L and Arnhold, J}, title = {Scavenger effect of flavonols on HOCl-induced luminol chemiluminescence.}, journal = {Luminescence : the journal of biological and chemical luminescence}, volume = {19}, number = {4}, pages = {199-204}, doi = {10.1002/bio.772}, pmid = {15287004}, issn = {1522-7235}, mesh = {Acetylcysteine/chemistry ; Flavonols/*chemistry ; Hypochlorous Acid/*chemistry ; *Luminescence ; Luminol/*chemistry ; Rutin/chemistry ; }, abstract = {Hypochlorous acid (HOCl), the main product of the myeloperoxidase system, is a strong oxidant and a potent chlorinating agent, which can damage host tissues. In the present work, the scavenger effect of three aglycone flavonols (myricetin, quercetin and kaempferol) and of the natural glycoside flavonol, rutin, was studied towards HOCl using luminol-dependent chemiluminescence (CL). At 1 micro mol/L fi nal concentration, rutin was the most powerful scavenger of HOCl with an inhibitory luminol oxidation of 91.4% +/- 3.2%. Quercetin, kaempferol and myricetin inhibited the luminol-dependent CL at the same concentration only by 75.9% +/- 3.4%, 57.7% +/- 5.3% and 43.3% +/- 3.5%, respectively. With increasing concentration of these flavonols, a dose-dependent inhibition of luminol CL was observed. In order to prove to what extent flavonols scavenge HOCl, their concentrations that gave 50% inhibition of luminescence (IC50) were compared to IC50 values of the sulphur-containing compounds N-acetyl cysteine (NAC) and taurine. The scavenging activities of compounds tested decrease in the order: rutin > NAC > quercetin > kaempferol > taurine. The present study revealed that rutin was the most effective scavenger agent.}, }
@article {pmid15284390, year = {2004}, author = {Tang, L and Zhang, Y}, title = {Dietary isothiocyanates inhibit the growth of human bladder carcinoma cells.}, journal = {The Journal of nutrition}, volume = {134}, number = {8}, pages = {2004-2010}, doi = {10.1093/jn/134.8.2004}, pmid = {15284390}, issn = {0022-3166}, support = {R01 CA080962/CA/NCI NIH HHS/United States ; CA80892/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis/drug effects ; Cell Cycle/drug effects ; *Diet ; Humans ; Isothiocyanates/administration &amp; dosage/*therapeutic use ; Tumor Cells, Cultured ; Urinary Bladder Neoplasms/*prevention &amp; control ; }, abstract = {Many isothiocyanates (ITCs), some of which are abundant in cruciferous vegetables, have been repeatedly shown to inhibit carcinogenesis in a variety of rodent organs. However, several naturally occurring ITCs also promoted bladder tumorigenesis in rodents, raising the question of whether ITCs behave differently in bladder cells. Alternatively, the observed carcinogenic effects of ITCs may result from prolonged exposure of the bladder epithelium, where the tumors originate, to high concentrations of electrophilic ITCs in the urine. Ingested ITCs are almost exclusively excreted and highly concentrated in the urine as N-acetylcysteine conjugates (NAC-ITC). While several NAC-ITCs also are known anticarcinogens, they are unstable and readily dissociate into parent ITCs. In this study, ITCs, including those that have carcinogenic potential in the rodent bladders, induced apoptosis and/or arrested cell-cycle progression in 2 human bladder carcinoma lines (UM-UC-3 and T24) at 7.5-30 micromol/L. Multiple caspases, including caspase-9, -8, and -3, as well as poly(ADP-ribose)polymerase, were cleaved upon ITC exposure. The ITCs blocked cell-cycle progression at the G(2)/M and/or S phases in these cells and downregulated several cell-cycle regulators. However, further increases in ITC concentrations abolished their activities, described above. These findings show that urinary ITC concentrations may need to be maintained at low micromolar concentrations for bladder cancer prevention.}, }
@article {pmid15282185, year = {2004}, author = {Izyumov, DS and Avetisyan, AV and Pletjushkina, OY and Sakharov, DV and Wirtz, KW and Chernyak, BV and Skulachev, VP}, title = {"Wages of fear": transient threefold decrease in intracellular ATP level imposes apoptosis.}, journal = {Biochimica et biophysica acta}, volume = {1658}, number = {1-2}, pages = {141-147}, doi = {10.1016/j.bbabio.2004.05.007}, pmid = {15282185}, issn = {0006-3002}, mesh = {Adenosine Triphosphate/analysis/deficiency/*metabolism ; Apoptosis/*physiology ; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology ; Caspases/metabolism ; Cytochromes c/metabolism ; Cytosol/metabolism ; Deoxyglucose/pharmacology ; Enzyme Inhibitors/pharmacology ; HeLa Cells ; Humans ; Intracellular Space/*metabolism ; Methacrylates ; Mitochondria/metabolism ; Oligomycins/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Thiazoles/pharmacology ; bcl-2-Associated X Protein ; }, abstract = {In HeLa cells, complete inhibition of oxidative phosphorylation by oligomycin, myxothiazol or FCCP combined with partial inhibition of glycolysis by DOG resulted in a steady threefold decrease in the intracellular ATP level. The ATP level recovers when the DOG-containing medium was replaced by that with high glucose. In 48 h after a transient (3 h) [ATP] lowering followed by recovery of the ATP level, the majority of the cells commits suicide by means of apoptosis. The cell death does not occur if DOG or an oxidative phosphorylation inhibitor was added separately, treatments resulting in 10-35% lowering of [ATP]. Apoptosis is accompanied by Bax translocation to mitochondria, cytochrome c release into cytosol, caspase activation, reactive oxygen species (ROS) generation, and reorganization and decomposition of chromatin. Apoptosis appears to be sensitive to oncoprotein Bcl-2 and a pancaspase inhibitor zVADfmk. In the latter case, necrosis is shown to develop instead of apoptosis. The cell suicide is resistant to cyclosporine A, a phospholipase inhibitor trifluoroperazine, the JNK and p38 kinase inhibitors, oligomycin, N-acetyl cysteine and mitoQ, differing in these respects from the tumor necrosis factor (TNF)- and H(2)O(2)-induced apoptoses. It is suggested that the ATP concentration in the cell is monitored by intracellular "ATP-meter(s)" generating a cell suicide signal when ATP decreases, even temporarily, below some critical level (around 1 mM).}, }
@article {pmid15281093, year = {2004}, author = {Rochat, T and Lacroix, JS and Jornot, L}, title = {N-acetylcysteine inhibits Na+ absorption across human nasal epithelial cells.}, journal = {Journal of cellular physiology}, volume = {201}, number = {1}, pages = {106-116}, doi = {10.1002/jcp.20066}, pmid = {15281093}, issn = {0021-9541}, mesh = {Acetylcysteine/*pharmacology ; Amiloride/pharmacology ; Cell Polarity/physiology ; Cells, Cultured ; Chlorides/metabolism ; Cystic Fibrosis/drug therapy/metabolism ; Diffusion Chambers, Culture ; Diuretics/pharmacology ; Epithelial Sodium Channels ; Expectorants/*pharmacology ; Glutathione/metabolism ; Humans ; Membrane Potentials/physiology ; Nasal Mucosa/cytology/*drug effects/*metabolism ; Potassium/metabolism ; RNA, Messenger/metabolism ; Sodium/*metabolism ; Sodium Channels/genetics/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; }, abstract = {N-acetylcysteine (NAC) is a widely used mucolytic drug in patients with a variety of respiratory disorders. The mechanism of action is based on rupture of the disulfide bridges of the high molecular glycoproteins present in the mucus, resulting in smaller subunits of the glycoproteins and reduced viscosity of the mucus. Because Na(+) absorption regulates airway surface liquid volume and thus the efficiency of mucociliary clearance, we asked whether NAC affects the bioelectric properties of human nasal epithelial cells. A 24-h basolateral treatment with 10 mM of NAC decreased the transepithelial potential difference and short-circuit current (I(SC)) by 40%, and reduced the amiloride-sensitive current by 50%, without affecting the transepithelial resistance. After permeabilization of the basolateral membranes of cells with amphotericin B in the presence of a mucosal-to-serosal Na(+) gradient (135:25 mM), NAC inhibited 45% of the amiloride-sensitive current. The Na(+)-K(+)-ATPase pump activity and the basolateral K(+) conductance were not affected by NAC treatment. NAC did not alter total cell mRNA and protein levels of alpha-epithelial Na(+) channel (EnaC) subunit, but reduced abundance of alpha-ENaC subunits in the apical cell membrane as quantified by biotinylation. This effect can be ascribed to the sulphydryl (SH) group of NAC, since N-acetylserine and S-carboxymethyl-l-cysteine were ineffective. Given the importance of epithelial Na(+) channels in controlling the thin layer of fluid that covers the surface of the airways, the increase in the fluidity of the airway mucus following NAC treatment in vivo might be in part related to downregulation of Na(+) absorption and consequently water transport.}, }
@article {pmid15276330, year = {2004}, author = {Risso-de Faverney, C and Orsini, N and de Sousa, G and Rahmani, R}, title = {Cadmium-induced apoptosis through the mitochondrial pathway in rainbow trout hepatocytes: involvement of oxidative stress.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {69}, number = {3}, pages = {247-258}, doi = {10.1016/j.aquatox.2004.05.011}, pmid = {15276330}, issn = {0166-445X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cadmium/*toxicity ; Caspases/metabolism ; Cyclic N-Oxides/pharmacology ; Cytochromes c/metabolism ; Dose-Response Relationship, Drug ; Hepatocytes/*metabolism ; Mitochondria/*metabolism ; Oncorhynchus mykiss/*metabolism ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins/metabolism ; *Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species/metabolism ; Statistics, Nonparametric ; Time Factors ; bcl-2-Associated X Protein ; }, abstract = {Cadmium (Cd) induces oxidative stress and apoptosis in trout hepatocytes. We therefore investigated the involvement of the mitochondrial pathway in the initiation of apoptosis and the possible role of oxidative stress in that process. This study demonstrates that hepatocyte exposure to Cd (2, 5 and 10 microM) triggers significant caspase-3, but also caspase-8 and -9 activation in a dose-dependent manner. Western-blot analysis of hepatocyte mitochondrial and cytosolic fractions revealed that cytochrome c (Cyt c) was released in the cytosol in a dose-dependent manner, whereas the pro-apoptotic protein Bax was redistributed to mitochondria after 24 and 48 h exposure. We also found that the expression of anti-apoptotic protein Bcl-xL, known to be regulated under mild oxidative stress to protect cells from apoptosis, did not change after 3 and 6 h exposure to Cd, then increased after 24 and 48 h exposure to 10 microM Cd. In the second part of this work, two antioxidant agents, 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) (100 microM) and N-acetylcysteine (NAC, 100 microM) were used to determine the involvement of reactive oxygen species (ROS) in Cd-induced apoptosis. Simultaneously exposing trout hepatocytes to Cd and TEMPO or NAC significantly reduced caspase-3 activation after 48 h and had a suppressive effect on caspase-8 and -9 also, mostly after 24 h. Lastly, the presence of either one of these antioxidants in the treatment medium also attenuated Cd-induced Cyt c release in cytosol and the level of Bax in the mitochondria after 24 and 48 h, while high Bcl-xL expression was observed. Taken together, these data clearly evidenced the key role of mitochondria in the cascade of events leading to trout hepatocyte apoptosis in response to Cd and the relationship that exists between oxidative stress and cell death.}, }
@article {pmid15273823, year = {2004}, author = {Rodrigues, AJ and Evora, PR and Schaff, HV}, title = {Protective effect of N-acetylcysteine against oxygen radical-mediated coronary artery injury.}, journal = {Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas}, volume = {37}, number = {8}, pages = {1215-1224}, doi = {10.1590/s0100-879x2004000800012}, pmid = {15273823}, issn = {0100-879X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Coronary Vessels/*drug effects/physiopathology ; Dogs ; Endothelium, Vascular/*drug effects/physiopathology ; Female ; Male ; Myocardial Reperfusion Injury/physiopathology ; *Oxidative Stress ; Reactive Oxygen Species ; Vasoconstriction/drug effects ; Vasodilation/drug effects ; }, abstract = {The present study investigated the protective effect of N-acetylcysteine (NAC) against oxygen radical-mediated coronary artery injury. Vascular contraction and relaxation were determined in canine coronary arteries immersed in Kreb's solution (95% O2-5% CO2), incubated or not with NAC (10 mM), and exposed to free radicals (FR) generated by xanthine oxidase (100 mU/ml) plus xanthine (0.1 mM). Rings not exposed to FR or NAC were used as controls. The arteries were contracted with 2.5 microM prostaglandin F2alpha. Subsequently, concentration-response curves for acetylcholine, calcium ionophore and sodium fluoride were obtained in the presence of 20 microM indomethacin. Concentration-response curves for bradykinin, calcium ionophore, sodium nitroprusside, and pinacidil were obtained in the presence of indomethacin plus Nomega-nitro-L-arginine (0.2 mM). The oxidative stress reduced the vascular contraction of arteries not exposed to NAC (3.93 +/- 3.42 g), compared to control (8.56 +/- 3.16 g) and to NAC group (9.07 +/- 4.0 g). Additionally, in arteries not exposed to NAC the endothelium-dependent nitric oxide (NO)-dependent relaxation promoted by acetylcholine (1 nM to 10 microM) was also reduced (maximal relaxation of 52.1 +/- 43.2%), compared to control (100%) and NAC group (97.0 +/- 4.3%), as well as the NO/cyclooxygenase-independent receptor-dependent relaxation provoked by bradykinin (1 nM to 10 microM; maximal relaxation of 20.0 +/- 21.2%), compared to control (100%) and NAC group (70.8 +/- 20.0%). The endothelium-independent relaxation elicited by sodium nitroprusside (1 nM to 1 microM) and pinacidil (1 nM to 10 microM) was not affected. In conclusion, the vascular dysfunction caused by the oxidative stress, expressed as reduction of the endothelium-dependent relaxation and of the vascular smooth muscle contraction, was prevented by NAC.}, }
@article {pmid15271854, year = {2004}, author = {Scott, DW and Loo, G}, title = {Curcumin-induced GADD153 gene up-regulation in human colon cancer cells.}, journal = {Carcinogenesis}, volume = {25}, number = {11}, pages = {2155-2164}, doi = {10.1093/carcin/bgh239}, pmid = {15271854}, issn = {0143-3334}, mesh = {Antineoplastic Agents ; Apoptosis/drug effects ; Cell Line, Tumor ; Colonic Neoplasms/*genetics/pathology ; Curcumin/*pharmacology ; DNA Damage ; DNA Primers ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Kinetics ; Polymerase Chain Reaction ; RNA, Messenger/genetics ; Transcription Factor CHOP/*genetics ; }, abstract = {Ingestion of plant products containing the phenolic phytochemical, curcumin, has been linked to lower incidences of colon cancer, suggesting that curcumin has cancer chemopreventive effects. Supporting this suggestion at the cellular level, apoptosis occurs in human colon cancer cells exposed to curcumin. However, the mechanism is unclear, prompting this investigation to further clarify the molecular effects of curcumin. HCT-116 colonocytes were incubated with 0-20 microM curcumin for 0-48 h. In concentration-dependent and time-dependent manners, curcumin induced DNA damage, resulting later in the appearance of cellular features characteristic of apoptosis. To identify a potential pro-apoptotic gene that could be responsive to the DNA damage in curcumin-treated cells, growth arrest and DNA damage-inducible gene 153 (GADD153) was considered. Curcumin increased GADD153 mRNA (and also protein) expression, which was prevented by actinomycin D and also by a broad protein kinase C inhibitor, but not by selective MAPK inhibitors. These findings suggest that curcumin-induced up-regulation of GADD153 mRNA expression was at the level of transcription, but apparently without depending on upstream MAPK. In determining the involvement of reactive oxygen species in mediating the effect of curcumin on GADD153, the antioxidants pyrrolidine dithiocarbamate and N-acetylcysteine (NAC), but neither alpha-tocopherol nor catalase, also blunted or prevented up-regulation of GADD153 mRNA expression caused by curcumin. Most noteworthy, when NAC was tested, it inhibited the DNA damage and apoptosis caused by curcumin. Because expression of GADD153 protein was detected before the appearance of apoptotic features, this observation raises the possibility that GADD153 protein might be important for curcumin-induced apoptosis.}, }
@article {pmid15271736, year = {2004}, author = {Kerbaul, F and Van der Linden, P and Pierre, S and Rondelet, B and Melot, C and Brimioulle, S and Naeije, R}, title = {Prevention of hemodilution-induced inhibition of hypoxic pulmonary vasoconstriction by N-acetylcysteine in dogs.}, journal = {Anesthesia and analgesia}, volume = {99}, number = {2}, pages = {547-51, table of contents}, doi = {10.1213/01.ANE.0000125111.56859.7D}, pmid = {15271736}, issn = {0003-2999}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Gas Analysis ; Blood Pressure/drug effects ; Blood Viscosity/drug effects ; Cardiac Output/drug effects ; Dogs ; Hemodilution/*adverse effects ; Hypoxia/physiopathology ; Lung Compliance/drug effects ; Pulmonary Circulation/*drug effects/*physiology ; Vascular Resistance/drug effects ; Vasoconstriction/*drug effects/*physiology ; }, abstract = {We investigated the possible contributions of reactive oxygen species and of viscosity changes to hemodilution-induced inhibition of hypoxic pulmonary vasoconstriction (HPV) in dogs. Fourteen isoflurane-anesthetized dogs were randomly assigned to receive N-acetylcysteine (NAC) 200 mg/kg IV (n = 7) or placebo (n = 7). Mean pulmonary artery pressure (Ppa) was measured with cardiac output maintained constant by a manipulation of venous return in hyperoxia (fraction of inspired oxygen, 0.4) and in hypoxia (fraction of inspired oxygen, 0.1) at baseline and after stepwise reductions in hematocrit from 40% to 20%. Measured Ppa was compared with predicted Ppa by using a viscoelastic model. HPV was expressed as hypoxic Ppa minus hyperoxic Ppa. Hemodilution was associated with a decrease in HPV from 7 +/- 1 mm Hg to 3 +/- 1 mm Hg (P < 0.01), and this was completely prevented by NAC (HPV was unchanged, from 8 +/- 1 to 8 +/- 1 mm Hg; not significant). Hemodilution in the model decreased HPV from 8 +/- 1 mm Hg to 6 +/- 1 mm Hg (P < 0.05). We conclude that hemodilution-induced inhibition of HPV is in part explained by viscosity changes and can be prevented by the administration of NAC, which is possibly explained by the scavenging of reactive oxygen species.}, }
@article {pmid15270590, year = {2004}, author = {Bondza-Kibangou, P and Millot, C and Dufer, J and Millot, JM}, title = {Modifications of cellular autofluorescence emission spectra under oxidative stress induced by 1 alpha,25dihydroxyvitamin D(3) and its analog EB1089.}, journal = {Technology in cancer research &amp; treatment}, volume = {3}, number = {4}, pages = {383-391}, doi = {10.1177/153303460400300409}, pmid = {15270590}, issn = {1533-0346}, mesh = {Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; Calcitriol/*analogs &amp; derivatives/*pharmacology ; Cell Differentiation ; Cytoplasm/metabolism ; Dose-Response Relationship, Drug ; Fluorescent Dyes/pharmacology ; HL-60 Cells ; Humans ; Lasers ; Microscopy, Confocal ; *Oxidative Stress ; Reactive Oxygen Species ; Spectrometry, Fluorescence/*methods ; Spectrophotometry ; Time Factors ; Ultraviolet Rays ; }, abstract = {We attempted to characterize the cellular autofluorescence phenomenon of living HL-60 cells and to appraise its modifications under oxidative stress conditions induced by 1 alpha,25(OH)(2)D(3) (VD(3)) and its analog EB1089. Autofluorescence emission spectra of human promyelocytic HL-60 leukemic cells were monitored using laser scanning confocal microspectrofluorometry under UV excitation. Evaluation of reactive oxygen species (ROS) release was performed using the 2',7'-dichlorodihydrofluorescein diacetate (H(2)-DCFDA) staining and fluorescence emission measurement. VD(3) (1, 10, 100 nM) or EB1089 (0.1, 1 and 10 nM) induces a decrease in autofluorescence emission intensity that can be attributed to the oxidation of the coenzyme nicotinamide adenine dinucleotide (phosphate) NAD(P)H into NAD(P)(+). A dose-dependent increase (p<0.05) in ROS release is observed in VD(3)- and EB1089-treated cells. As compared with VD(3)- or EB1089-treated cells, doxorubicin-VD(3) or doxorubicin-EB1089 treatments strongly decrease the autofluorescence intensity and induce a higher release of ROS (p<0.05). The association of antioxidants (N-acetyl cysteine, superoxide dismutase, catalase) with VD(3) or EB1089 induce a more limited autofluorescence decrease and a weaker ROS generation, as compared with VD(3) and EB1089 treated cells. In conclusion, the free radicals release, generated by VD(3) and EB1089, was associated with the decrease in autofluorescence emission and can be modulated by doxorubicin and antioxidants.}, }
@article {pmid15262176, year = {2004}, author = {Venugopal, SK and Devaraj, S and Jialal, I}, title = {RRR-alpha-tocopherol decreases the expression of the major scavenger receptor, CD36, in human macrophages via inhibition of tyrosine kinase (Tyk2).}, journal = {Atherosclerosis}, volume = {175}, number = {2}, pages = {213-220}, doi = {10.1016/j.atherosclerosis.2004.03.012}, pmid = {15262176}, issn = {0021-9150}, support = {K24 AT 00596/AT/NCCIH NIH HHS/United States ; }, mesh = {Antioxidants/*pharmacology ; CD36 Antigens/*metabolism ; Cell Culture Techniques ; Humans ; Lipoproteins, LDL/metabolism ; Macrophages/*drug effects/*metabolism ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/metabolism ; Reference Values ; TYK2 Kinase ; alpha-Tocopherol/*pharmacology ; }, abstract = {The class B scavenger receptor, CD36, binds to oxidized LDL (OxLDL), is present in atherosclerotic lesions, and is upregulated by OxLDL or AcLDL. Previously we have shown that RRR-alpha-tocopherol (AT) enrichment of human monocyte-derived macrophages inhibited OxLDL or AcLDL induced CD36 expression. The mechanism by which AT inhibited CD36 expression is not known. In the present study, we explored the mechanism by which AT decreases CD36 expression in human macrophages. Macrophages were enriched with AT (100 microM) or N-acetyl cysteine (NAC, 6 mM) overnight and then incubated with oxLDL or AcLDL for 48 h. The effect of protein kinase C inhibitors, and tyrosine kinase inhibitors on OxLDL or AcLDL-induced CD36 expression was quantitated by flow cytometry. Protein kinase C inhibitors or NAC had no effect while there was a significant inhibition with tyrosine kinase inhibitors (P < 0.01). OxLDL or AcLDL significantly increased tyrosine kinase activity which was significantly inhibited by pre-incubation with AT or with tyrosine kinase inhibitors. Western blotting revealed an increase in Tyk2 as well as phosphotyk2 with OxLDL or AcLDL. Immunoprecipitation of CD36 followed by Western blotting with Tyk2 antibodies revealed that Tyk2 was associated with CD36. In conclusion, this study demonstrates an additional direct cellular effect of AT, i.e. inhibition of CD36 expression via inhibition of tyrosine kinase (Tyk2).}, }
@article {pmid15256811, year = {2004}, author = {Hoffmann, U and Banas, B and Fischereder, M and Krämer, BK}, title = {N-acetylcysteine in the prevention of radiocontrast-induced nephropathy: clinical trials and end points.}, journal = {Kidney &amp; blood pressure research}, volume = {27}, number = {3}, pages = {161-166}, doi = {10.1159/000079804}, pmid = {15256811}, issn = {1420-4096}, mesh = {Acetylcysteine/*therapeutic use ; Clinical Trials as Topic ; Contrast Media/*adverse effects ; Humans ; Kidney Diseases/*prevention &amp; control ; Radiopharmaceuticals/*adverse effects ; }, abstract = {N-acetylcysteine (NAC) has been suggested to prevent radiocontrast-induced nephropathy (RCIN) in patients with a reduced renal function. However, clinical studies have not been demonstrating this effect consistently. Also, reviews and meta-analyses dealing with the question of prevention of RCIN by NAC have been controversial. Nearly all investigators used serum creatinine as surrogate end point of their trials, and changes in serum creatinine concentrations are thought to reflect the extent of renal injury as primary outcome. In a recent study, an effect of NAC on creatinine values and estimated glomerular filtration rate without any effect on cystatin C levels has been shown in volunteers with a normal renal function. Therefore, before renal protective effects of NAC in RCIN are proposed, any direct effects of NAC on creatinine, urea, and estimated glomerular filtration rate should be addressed. In future trials, the glomerular filtration rate should preferentially be measured directly, or at least additional markers of the renal function (e.g., serum cystatin C) have to be assessed. Furthermore, additional 'hard' end points, i.e., hospital morbidity, mortality, or dialysis dependency, should be considered in the design of future studies of RCIN.}, }
@article {pmid15256225, year = {2004}, author = {Lee, JY and Je, JH and Jung, KJ and Yu, BP and Chung, HY}, title = {Induction of endothelial iNOS by 4-hydroxyhexenal through NF-kappaB activation.}, journal = {Free radical biology &amp; medicine}, volume = {37}, number = {4}, pages = {539-548}, doi = {10.1016/j.freeradbiomed.2004.05.011}, pmid = {15256225}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Aging ; Aldehydes/*chemistry ; Animals ; Apoptosis ; Blotting, Western ; Cell Nucleus/metabolism ; Cell Survival ; Coloring Agents/pharmacology ; Culture Media, Serum-Free/pharmacology ; Cytosol/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation ; Free Radicals ; Gene Expression Regulation ; Lipid Peroxidation ; Luciferases/metabolism ; Male ; NF-kappa B/*metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/*metabolism ; Nitric Oxide Synthase Type II ; Nitriles/pharmacology ; Oxidation-Reduction ; Oxidative Stress ; Prostate/pathology ; Rats ; Sulfones/pharmacology ; Tetrazolium Salts/pharmacology ; Thiazoles/pharmacology ; Time Factors ; Transcription, Genetic ; Transfection ; Up-Regulation ; }, abstract = {Lipid peroxidation and its end-product, 4-hydroxyhexenal (HHE), are known to affect redox balance during aging, which causes various degenerative processes including vascular alterations from endothelial cell deterioration. To better understand the molecular action of HHE in the development of vascular abnormalities during the aging process, we investigated whether the upregulation of inducible endothelial nitric oxide synthase (iNOS) by HHE is mediated through nuclear factor kappaB (NF-kappaB) activation. Results indicate that HHE stimulates iNOS by the transcriptional regulation of NF-kappaB activation through cytosolic kappaB degradation inhibitors (IkappaB). Pretreatment with NF-kappaB inhibitors Bay 11-7082 and N-acetyl cysteine (NAC) suppressed the upregulation of iNOS by blunting IkappaB degradation and NF-kappaB binding activity. Because inflammatory stimuli induce iNOS to generate large amounts of nitric oxide (NO), intracellular NO levels in the presence of Bay 11-7082, NAC, and caffeic acid methyl ester were estimated. These inhibitors significantly suppressed the HHE-induced NO levels to a basal level. These findings strongly suggest that in endothelial cells, HHE induces iNOS gene expression through NF-kappaB activation, which can lead to vascular dysfunction by the activation of various proinflammatory genes.}, }
@article {pmid15256221, year = {2004}, author = {Andreadou, I and Iliodromitis, EK and Mikros, E and Bofilis, E and Zoga, A and Constantinou, M and Tsantili-Kakoulidou, A and Kremastinos, DT}, title = {Melatonin does not prevent the protection of ischemic preconditioning in vivo despite its antioxidant effect against oxidative stress.}, journal = {Free radical biology &amp; medicine}, volume = {37}, number = {4}, pages = {500-510}, doi = {10.1016/j.freeradbiomed.2004.05.005}, pmid = {15256221}, issn = {0891-5849}, mesh = {Acetylcysteine/chemistry/pharmacology ; Aldehydes/pharmacology ; Animals ; Antioxidants/metabolism/*pharmacology ; Free Radicals ; *Ischemic Preconditioning ; Lipid Peroxidation ; Magnetic Resonance Spectroscopy ; Male ; Malondialdehyde/pharmacology ; Melatonin/*metabolism ; Models, Statistical ; *Oxidative Stress ; Rabbits ; Reperfusion Injury ; Superoxide Dismutase/metabolism ; Time Factors ; }, abstract = {Free radicals are involved in the protective mechanism of preconditioning (PC), whereas antioxidant compounds abolish this benefit. Melatonin is a hormone with antioxidant properties. The aim of our study was to evaluate the effect of melatonin on infarct size in ischemic preconditioning in vivo. We randomly divided 33 male rabbits into four groups and subjected them to 30 min of myocardial ischemia and 3 h of reperfusion with the following prior interventions: (i) no intervention, (ii) iv melatonin at a total dose of 50 mg/kg, (iii) PC with two cycles of 5 min ischemia and 10 min reperfusion, and (iv) combined melatonin and PC. In a second series of experiments, another antioxidant agent N-acetylcysteine (NAC) was used in a control and in a PC group. Myocardial infarct size was determined and blood samples were drawn at different time points for the determination of lipid peroxidation products, total superoxide dismutase (SOD) activity, and (1)H-NMR spectra to evaluate the changes in the metabolic profile. Melatonin showed no effect on myocardial infarct size in the group of sustained ischemia (42.9 +/- 3.6% vs 47.4 +/- 4.9%) and it did not attenuate the reduction of myocardial infarct size in the PC group (13.6 +/- 2.4% vs 14.0 +/- 1.7%). A similar effect was found in NAC-treated groups (44.8 +/- 3.4% vs 14.3 +/- 1.3%). Lipid peroxidation product levels were significantly elevated in the control and PC groups, whereas melatonin decreased them in both groups. The SOD activity was enhanced in the PC group compared to controls; melatonin kept SOD activity unchanged during ischemia/reperfusion and enhanced its activity when it was combined with PC. Melatonin did not change the metabolic profile of the control and PC groups. Melatonin does not prevent the beneficial effect of ischemic PC on infarct size despite its antioxidant properties.}, }
@article {pmid15255940, year = {2004}, author = {Chalimoniuk, M and King-Pospisil, K and Pedersen, WA and Malecki, A and Wylegala, E and Mattson, MP and Hennig, B and Toborek, M}, title = {Arachidonic acid increases choline acetyltransferase activity in spinal cord neurons through a protein kinase C-mediated mechanism.}, journal = {Journal of neurochemistry}, volume = {90}, number = {3}, pages = {629-636}, doi = {10.1111/j.1471-4159.2004.02535.x}, pmid = {15255940}, issn = {0022-3042}, support = {P42 ES007380/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology ; Arachidonic Acid/*pharmacology ; Cells, Cultured ; Chelating Agents/pharmacology ; Choline O-Acetyltransferase/drug effects/genetics/*metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Activators/pharmacology ; Enzyme Inhibitors/pharmacology ; Mice ; Neurons/drug effects/*enzymology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Nitric Oxide Synthase Type I ; Oxidative Stress/drug effects ; Phosphoric Monoester Hydrolases/antagonists &amp; inhibitors ; Protein Kinase C/drug effects/*metabolism ; Protein Synthesis Inhibitors/pharmacology ; RNA, Messenger/biosynthesis ; Spinal Cord/*cytology/embryology ; }, abstract = {Arachidonic acid (AA) plays an important role as a signaling factor in the CNS. Therefore, exposure to AA may affect cholinergic neurons in the spinal cord. To test this hypothesis, mRNA expression and activity of choline acetyltransferase (ChAT) was measured in cultured spinal cord neurons treated with increasing concentrations (0.1-10 microm) of AA. Exposure to AA increased mRNA levels and activity of ChAT in dose- and time-dependent manners. The most marked effect of AA on ChAT expression was observed in spinal cord neurons treated with 10 microm AA for 1 h. To study the mechanisms associated with these effects, ChAT mRNA levels and activity were measured in cultured spinal cord neurons exposed to AA and inhibitors of protein kinase C (PKC), such as 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dichloride (H-7) and chelerythrine. Inhibition of PKC completely prevented an AA-induced increase in ChAT expression. In addition, exposure of spinal cord neurons to phorbol-12-myristate-13-acetate (PMA), an activator of PKC, mimicked AA-induced stimulation of ChAT activity. The AA-mediated increase in ChAT mRNA levels and activity was also prevented by treatments with EGTA, indicating the role of calcium metabolism in induction of this enzyme. In contrast, treatments with 7-nitroindazole (7-NI, a specific inhibitor of neuronal nitric oxide synthase), sodium vanadate (NaV, a non-specific inhibitor of phosphatases), and N-acetyl-cysteine (NAC, an antioxidant) had no effect on AA-induced changes in ChAT activity. The protein synthesis inhibitor cycloheximide completely blocked AA-mediated increase in ChAT activity. These results indicate that the AA-evoked increase in ChAT activity in spinal cord neurons is mediated by PKC, presumably at the transcriptional level.}, }
@article {pmid15254344, year = {2004}, author = {Martin, KR and Jokinen, MP and Honeycutt, HP and Quinn, A and Kari, FW and Barrett, JC and French, JE}, title = {Tumor profile of novel p53 heterozygous Tg.AC (v-Ha-ras) bitransgenic mice treated with benzo(a)pyrene and fed dietary N-acetyl-L-cysteine (NAC).}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {81}, number = {2}, pages = {293-301}, doi = {10.1093/toxsci/kfh226}, pmid = {15254344}, issn = {1096-6080}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Anticarcinogenic Agents ; Antioxidants/*pharmacology ; Benzo(a)pyrene/*toxicity ; Carcinogens/*toxicity ; Diet ; Female ; Gastric Mucosa/pathology ; Genes, p53/*genetics ; Genes, ras/*genetics ; Hematologic Neoplasms/chemically induced/pathology ; Male ; Mice ; Mice, Inbred Strains ; Mice, Transgenic ; Neoplasms/*chemically induced/*pathology ; Papilloma/chemically induced/epidemiology/pathology ; Pseudolymphoma/chemically induced/epidemiology/pathology ; Sex Characteristics ; Survival Analysis ; Urinary Bladder Neoplasms/chemically induced/epidemiology/pathology ; }, abstract = {We designed a novel short-term bitransgenic model to better characterize the effects of benzo(a)pyrene (BP) exposure on multi-organ carcinogenesis and to evaluate the effects of a well-recognized antioxidant, N-acetyl-L-cysteine (NAC), on neoplasia. We selected the p53 heterozygous Tg.AC (v-Ha-ras) mouse model for our studies because these mice possess a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele. Both mutations occur frequently in human cancers. In a 2 x 2 experimental design, both female and male mice were fed basal diet alone or containing 3% NAC and administered by gavage corn oil vehicle alone or containing 20 mg BP/kg body weight given twice weekly for 10 weeks. Mice (n = 15 for each grouping and sex) were subsequently observed an additional 18 weeks followed by tissue collection for evaluation of multi-organ pathology. Benzo(a)pyrene increased neoplasia in the thymus, spleen, stomach, and hematopoietic system after 28 weeks. We observed modest NAC-associated decreases in BP-induced pathology of the liver, papilloma formation and hyperplasia in the forestomach, and the occurrence of malignant lymphoma. Benzo(a)pyrene exposure reduced survival to approximately 40% in male mice, suggesting toxicity; however, survival in control groups was approximately 60%. Survival decreased to approximately 30% for females in all groups. We noted a clear, but nonsignificant, 15% decline in body weights of male, but not female, mice fed NAC, although food intake did not differ. Collectively, the data suggested carcinogen and antioxidant-associated effects on neoplasia that appeared sex-dependent. Thus, this novel short-term bitransgenic model may potentially be useful for testing dietary modulation of carcinogenesis.}, }
@article {pmid15252871, year = {2004}, author = {Chatterjee, D and Mukherjee, S and Smith, MG and Das, SK}, title = {Evidence of hair loss after subacute exposure to 2-chloroethyl ethyl sulfide, a mustard analog, and beneficial effects of N-acetyl cysteine.}, journal = {Journal of biochemical and molecular toxicology}, volume = {18}, number = {3}, pages = {150-153}, doi = {10.1002/jbt.20020}, pmid = {15252871}, issn = {1095-6670}, mesh = {Acetylcysteine/*pharmacology ; Alopecia/*chemically induced ; Animals ; Biomarkers ; Guinea Pigs ; Hair/*drug effects/pathology ; Mustard Gas/*analogs &amp; derivatives/*toxicity ; *Toxicity Tests, Acute ; }, abstract = {Mustard gas has been used as a vesicant chemical warfare agent. However, a suitable biomarker for monitoring mustard gas exposure is not known. We observed that the hairs of the guinea pigs exposed intratracheally to subacute doses of 2-chloroethyl ethyl sulfide (CEES), a mustard analog, came out very easily though there was no sign of skin lesions or skin damage. Also the hairs looked rough and dry and lost the shiny glaze. There was no recovery from this hair loss, though the animals never became hairless, following CEES exposure. Hairs were observed in this study both visually and with light microscopy. Treatment with N-acetylcysteine (NAC) prior to CEES exposure could prevent the hair loss completely. Hence, sudden hair loss might be a good biomarker for subacute exposure of mustard gas to subjects at risks when the victims might have no other visible symptom of toxicity.}, }
@article {pmid15252869, year = {2004}, author = {Hsiao, CJ and Stapleton, SR}, title = {Characterization of Cd-induced molecular events prior to cellular damage in primary rat hepatocytes in culture: activation of the stress activated signal protein JNK and transcription factor AP-1.}, journal = {Journal of biochemical and molecular toxicology}, volume = {18}, number = {3}, pages = {133-142}, doi = {10.1002/jbt.20018}, pmid = {15252869}, issn = {1095-6670}, mesh = {Animals ; Blotting, Western ; Cadmium/*toxicity ; Cells, Cultured ; Electrophoretic Mobility Shift Assay ; Enzyme Activation/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Hepatocytes/*drug effects ; JNK Mitogen-Activated Protein Kinases/genetics/metabolism ; Kinetics ; Male ; Proto-Oncogene Proteins c-jun/metabolism ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Second Messenger Systems ; Signal Transduction/drug effects ; Transcription Factor AP-1/metabolism ; }, abstract = {The effect of Cadmium (Cd) on the expression of c-Jun N-terminal kinase (JNK), c-jun, and activator protein-1 (AP-1) has been investigated. We previously reported that Cd causes cell damage as indicated by increases in the cytotoxic parameters, lactate dehydrogenase and lipid peroxidation, and this damage was mediated by decreases in cellular concentration of glutathione. In the present study, we investigate the molecular events involved prior to the Cd-induced cellular toxicity and damage in primary rat hepatocytes. We propose that Cd, through the generation of reactive oxygen species (ROS) and prior to significant cellular damage, activates the stress activated signal protein JNK, regulates c-jun expression, and promotes the binding of a redox sensitive transcription factor AP-1. We show JNK activity and c-jun mRNA level significantly increased at 1 h and AP-1 DNA binding activity significantly enhanced at 3 h in the presence of 4 microM cadmium chloride. Blocking the Cd induction of JNK activity, c-jun mRNA level, and AP-1 binding activity using the antioxidants N-acetyl cysteine (10 mM) or carnosol (0.5 microg/mL) suggests a role for ROS. Blocking JNK activity and c-jun mRNA by SP600125 (20 microM), a JNK inhibitor, supports the role of JNK in transmission of signals induced by Cd.}, }
@article {pmid15249511, year = {2004}, author = {Cai, W and He, JC and Zhu, L and Peppa, M and Lu, C and Uribarri, J and Vlassara, H}, title = {High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase stimulant in diabetic patients.}, journal = {Circulation}, volume = {110}, number = {3}, pages = {285-291}, doi = {10.1161/01.CIR.0000135587.92455.0D}, pmid = {15249511}, issn = {1524-4539}, support = {AG-09453/AG/NIA NIH HHS/United States ; M01-RR-00071/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Administration, Oral ; Antioxidants/pharmacology ; Cardiovascular Diseases/prevention &amp; control ; Diabetes Complications/prevention &amp; control ; Diabetes Mellitus/blood/diet therapy/*enzymology ; Endothelium, Vascular/drug effects/enzymology/metabolism ; Enzyme Activation ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Female ; Glycation End Products, Advanced/administration &amp; dosage/*pharmacology ; Humans ; Lipoproteins, LDL/blood/chemistry/*toxicity ; Male ; Middle Aged ; NADPH Oxidases/antagonists &amp; inhibitors ; NF-kappa B/metabolism ; Oxidation-Reduction ; Transcriptional Activation ; Vascular Cell Adhesion Molecule-1/biosynthesis ; }, abstract = {BACKGROUND: LDL modification by endogenous advanced glycation end products (AGEs) is thought to contribute to cardiovascular disease of diabetes. It remains unclear, however, whether exogenous (diet-derived) AGEs influence glycoxidation and endothelial cell toxicity of diabetic LDL.<br><br>METHODS AND RESULTS: Twenty-four diabetic subjects were randomized to either a standard diet (here called high-AGE, HAGE) or a diet 5-fold lower in AGE (LAGE diet) for 6 weeks. LDL pooled from patients on HAGE diet (Db-HAGE-LDL) was more glycated than LDL from the LAGE diet group (Db-LAGE-LDL) (192 versus 92 AGE U/mg apolipoprotein B) and more oxidized (5.7 versus 1.5 nmol malondialdehyde/mg lipoprotein). When added to human endothelial cells (ECV 304 or human umbilical vein endothelial cells), Db-HAGE-LDL promoted marked ERK1/2 phosphorylation (pERK1/2) (5.5- to 10-fold of control) in a time- and dose-dependent manner compared with Db-LAGE-LDL or native LDL. In addition, Db-HAGE-LDL stimulated NF-kappaB activity significantly in ECV 304 and human umbilical vein endothelial cells (2.3-fold above baseline) in a manner inhibitable by a MEK inhibitor PD98059 (10 micromol/L), the antioxidant N-acetyl-l-cysteine, NAC (30 mmol/L), and the NADPH oxidase inhibitor DPI (20 micromol/L). In contrast to Db-LAGE-LD and native LDL, Db-HAGE-LDL induced significant soluble vascular cell adhesion molecule-1 production (2.3-fold), which was blocked by PD98059, NAC, and DPI.<br><br>CONCLUSIONS: Exposure to daily dietary glycoxidants enhances LDL-induced vascular toxicity via redox-sensitive mitogen-activated protein kinase activation. This can be prevented by dietary AGE restriction.}, }
@article {pmid15248029, year = {2004}, author = {Kang, J and Chen, J and Zhang, D and Da, W and Ou, Y}, title = {Synergistic killing of human leukemia cells by antioxidants and trichostatin A.}, journal = {Cancer chemotherapy and pharmacology}, volume = {54}, number = {6}, pages = {537-545}, doi = {10.1007/s00280-004-0845-7}, pmid = {15248029}, issn = {0344-5704}, mesh = {Acetylation ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antioxidants/administration &amp; dosage/pharmacology ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; HL-60 Cells ; Histones/metabolism ; Humans ; Hydroxamic Acids/administration &amp; dosage/*pharmacology ; L-Lactate Dehydrogenase/analysis ; Leukemia/*drug therapy ; Reactive Oxygen Species/analysis ; }, abstract = {PURPOSE: Antioxidants and trichostatin A (TSA) are promising anticancer drugs, and are capable of enhancing the neoplastic toxicity of other chemicals that exert anticancer activity via different mechanisms. Since antioxidants and TSA (the specific inhibitor of histone deacetylase) are believed to combat cancer via different mechanisms, we sought to determine whether combining them would improve their anticancer activity in human leukemia cells (HL-60).<br><br>MATERIALS AND METHODS: HL-60 cells were treated with antioxidants (ascorbic acid, AA and N-acetyl-cysteine, NAC), TSA or their combination, and cell proliferation arrest, lactate dehydrogenase (LDH) release and cell viability were measured as indicators of cell damage. Accumulation of reactive oxygen species (ROS) and the acetylation of histones were also measured.<br><br>RESULTS: The cytotoxicity of AA, NAC and TSA increased in a time- and dose-dependent manner. AA (1, 2 and 4 mM) and NAC (0.2, 0.5 and 1 mM) were able to diminish ROS generation but showed no influence on histone acetylation in HL-60 cells. In contrast, TSA (20, 50, 100 and 200 nM) did not inhibit ROS generation but significantly increased histone acetylation, indicating a possible role for both scavenging ROS and increasing histone acetylation in the induction of cell death in HL-60 cells. This conclusion was further confirmed by the finding that the combination of antioxidant and TSA not only diminished ROS generation, but also increased histone acetylation, and hence showed greater cytotoxicity in HL-60 cells than either component alone.<br><br>CONCLUSIONS: Our findings show that combining antioxidants and TSA can enhance their neoplastic toxicity at least in human leukemia HL-60 cells, providing a new approach to the design of chemotherapy strategies and the development of anticancer drugs.}, }
@article {pmid15247300, year = {2004}, author = {da-Silva, WS and Gómez-Puyou, A and de Gómez-Puyou, MT and Moreno-Sanchez, R and De Felice, FG and de Meis, L and Oliveira, MF and Galina, A}, title = {Mitochondrial bound hexokinase activity as a preventive antioxidant defense: steady-state ADP formation as a regulatory mechanism of membrane potential and reactive oxygen species generation in mitochondria.}, journal = {The Journal of biological chemistry}, volume = {279}, number = {38}, pages = {39846-39855}, doi = {10.1074/jbc.M403835200}, pmid = {15247300}, issn = {0021-9258}, mesh = {Animals ; Antioxidants/*metabolism ; Cells, Cultured ; Cerebral Cortex/cytology ; Glucose/analogs &amp; derivatives ; Glucose-6-Phosphate/metabolism ; Hexokinase/*metabolism ; Hydrogen Peroxide/metabolism ; Hyperglycemia/metabolism ; Male ; Mitochondria/*enzymology ; Neurons/cytology/*enzymology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {Brain hexokinase is associated with the outer membrane of mitochondria, and its activity has been implicated in the regulation of ATP synthesis and apoptosis. Reactive oxygen species (ROS) are by-products of the electron transport chain in mitochondria. Here we show that the ADP produced by hexokinase activity in rat brain mitochondria (mt-hexokinase) controls both membrane potential (Deltapsi(m)) and ROS generation. Exposing control mitochondria to glucose increased the rate of oxygen consumption and reduced the rate of hydrogen peroxide generation. Mitochondrial associated hexokinase activity also regulated Deltapsi(m), because glucose stabilized low Deltapsi(m) values in state 3. Interestingly, the addition of glucose 6-phosphate significantly reduced the time of state 3 persistence, leading to an increase in the Deltapsi(m) and in H(2)O(2) generation. The glucose analogue 2-deoxyglucose completely impaired H(2)O(2) formation in state 3-state 4 transition. In sharp contrast, the mt-hexokinase-depleted mitochondria were, in all the above mentioned experiments, insensitive to glucose addition, indicating that the mt-hexokinase activity is pivotal in the homeostasis of the physiological functions of mitochondria. When mt-hexokinase-depleted mitochondria were incubated with exogenous yeast hexokinase, which is not able to bind to mitochondria, the rate of H(2)O(2) generation reached levels similar to those exhibited by control mitochondria only when an excess of 10-fold more enzyme activity was supplemented. Hyperglycemia induced in embryonic rat brain cortical neurons increased ROS production due to a rise in the intracellular glucose 6-phosphate levels, which were decreased by the inclusion of 2-deoxyglucose, N-acetyl cysteine, or carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Taken together, the results presented here indicate for the first time that mt-hexokinase activity performed a key role as a preventive antioxidant against oxidative stress, reducing mitochondrial ROS generation through an ADP-recycling mechanism.}, }
@article {pmid15246875, year = {2004}, author = {Hou, DX and Uto, T and Tong, X and Takeshita, T and Tanigawa, S and Imamura, I and Ose, T and Fujii, M}, title = {Involvement of reactive oxygen species-independent mitochondrial pathway in gossypol-induced apoptosis.}, journal = {Archives of biochemistry and biophysics}, volume = {428}, number = {2}, pages = {179-187}, doi = {10.1016/j.abb.2004.06.007}, pmid = {15246875}, issn = {0003-9861}, mesh = {Acetylcysteine/metabolism ; *Apoptosis ; BH3 Interacting Domain Death Agonist Protein ; Blotting, Western ; Carrier Proteins/metabolism ; Caspase 3 ; Caspase 8 ; Caspase 9 ; Caspases/metabolism ; Catalase/metabolism ; Cell Survival ; Contraceptive Agents, Male/pharmacology ; Cytochromes c/metabolism ; Cytosol/metabolism ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Electrophoresis, Agar Gel ; Flow Cytometry ; Gossypol/*pharmacology ; HL-60 Cells ; Humans ; Membrane Potentials ; Mitochondria/metabolism/*pathology ; Poly(ADP-ribose) Polymerases/metabolism ; *Reactive Oxygen Species ; Subcellular Fractions ; Time Factors ; }, abstract = {Gossypol is a component present in cottonseeds and has been demonstrated to be an effective contraceptive drug in preventing spermatogenesis in mammalian species. In the present, we reported that gossypol could induce apoptosis in human promyelocytic leukemia cells (HL-60), as characterized by DNA fragmentation, poly(ADP) ribose polymerase (PARP) cleavage. The efficacious induction of apoptosis was observed at 50 microM for 6 h. Further molecular analysis showed that gossypol induced the truncation of Bid protein, the loss of mitochondrial membrane potential (DeltaPsi m), cytochrome c release from mitochondria into cytosol, and activation of caspase-3, -8, and -9. However, gossypol did not increase the level of reactive oxygen species (ROS), and antioxidants including N-acetyl cysteine (NAC) and catalase could not block gossypol-induced apoptosis in the HL-60 cells. These data suggest that gossypol induces apoptosis in HL-60 cells through ROS-independent mitochondrial dysfunction pathway.}, }
@article {pmid15246558, year = {2004}, author = {Tong, X and Lin, S and Fujii, M and Hou, DX}, title = {Echinocystic acid induces apoptosis in HL-60 cells through mitochondria-mediated death pathway.}, journal = {Cancer letters}, volume = {212}, number = {1}, pages = {21-32}, doi = {10.1016/j.canlet.2004.03.035}, pmid = {15246558}, issn = {0304-3835}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Cytochromes c/metabolism ; *DNA Damage ; HL-60 Cells ; Humans ; Mitochondria/*pathology ; Oleanolic Acid/*analogs &amp; derivatives/*pharmacology ; Poly(ADP-ribose) Polymerases/pharmacology ; }, abstract = {Echinocystic acid (EA) is a natural triterpone enriched in various herbs and used for medicinal purpose in many Asian countries. In the present study, we reported that EA can induce apoptosis in human promyelocytic leukemia cells (HL-60), as characterized by DNA fragmentation, poly (ADP) ribose polymerase cleavage. The efficacious induction of apoptosis was observed at 100 microM for 6 h. Further molecular analysis showed that EA induced the cleavage of Bid protein, the loss of mitochondrial membrane potential (DeltaPsim) cytochrome c release from mitochondria into cytosol, and activation of caspase-3, -8 and -9. However, EA did not generate reactive oxygen species (ROS), and antioxidants including N-acetyl cysteine and catalase could not block EA-induced apoptosis in the HL-60 cells. These data suggest that EA induces apoptosis in HL-60 cells through ROS-independent mitochondrial dysfunction pathway.}, }
@article {pmid15246351, year = {2004}, author = {Salter, L and Clifford, T and Morley, N and Gould, D and Campbell, S and Curnow, A}, title = {The use of comet assay data with a simple reaction mechanism to evaluate the relative effectiveness of free radical scavenging by quercetin, epigallocatechin gallate and N-acetylcysteine in UV-irradiated MRC5 lung fibroblasts.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {75}, number = {1-2}, pages = {57-61}, doi = {10.1016/j.jphotobiol.2004.05.007}, pmid = {15246351}, issn = {1011-1344}, mesh = {Acetylcysteine/*pharmacology ; Catechin/*analogs &amp; derivatives/*pharmacology ; Cells, Cultured ; Comet Assay ; DNA/*radiation effects ; DNA Damage/*drug effects ; Fibroblasts ; Free Radical Scavengers/*pharmacology ; Humans ; Quercetin/*pharmacology ; Ultraviolet Rays ; }, abstract = {Comet assay data (tail DNA %) have been gathered for the concentration dependent role of three antioxidants (AOs); quercetin (Q), epigallocatechin gallate (EGCG) and N-acetylcysteine (NAC) in reducing UV-induced damage to DNA in normal fetal lung fibroblasts (MRC5). All three compounds demonstrate a concentration dependent reduction maximum with a pro-oxidant effect at higher (though not cytotoxic) concentrations. Manipulation of a simple 4-step reaction mechanism for free radical (FR) scavenging by AOs produced rate constant ratios which allowed the relative effectiveness (Q > EGCG > NAC) of the AOs to be evaluated.}, }
@article {pmid15239099, year = {2004}, author = {Carreras, MC and Converso, DP and Lorenti, AS and Barbich, M and Levisman, DM and Jaitovich, A and Antico Arciuch, VG and Galli, S and Poderoso, JJ}, title = {Mitochondrial nitric oxide synthase drives redox signals for proliferation and quiescence in rat liver development.}, journal = {Hepatology (Baltimore, Md.)}, volume = {40}, number = {1}, pages = {157-166}, doi = {10.1002/hep.20255}, pmid = {15239099}, issn = {0270-9139}, mesh = {Aging/metabolism ; Animals ; Animals, Newborn ; Cell Division/physiology ; Cytosol/metabolism ; Embryo, Mammalian ; Embryonic and Fetal Development ; Hepatocytes/*cytology ; Homeostasis ; Hydrogen Peroxide/metabolism ; Liver/*embryology/*growth &amp; development ; Mitochondria, Liver/*enzymology/physiology ; Nitric Oxide Synthase/*metabolism ; Osmolar Concentration ; Oxidation-Reduction ; Rats ; Rats, Wistar ; Signal Transduction/*physiology ; }, abstract = {Mitochondrial nitric oxide synthase (mtNOS) is a fine regulator of oxygen uptake and reactive oxygen species that eventually modulates the activity of regulatory proteins and cell cycle progression. From this perspective, we examined liver mtNOS modulation and mitochondrial redox changes in developing rats from embryonic days 17-19 and postnatal day 2 (proliferating hepatocyte phenotype) through postnatal days 15-90 (quiescent phenotype). mtNOS expression and activity were almost undetectable in fetal liver, and progressively increased after birth by tenfold up to adult stage. NO-dependent mitochondrial hydrogen peroxide (H(2)O(2)) production and Mn-superoxide dismutase followed the developmental modulation of mtNOS and contributed to parallel variations of cytosolic H(2)O(2) concentration ([H(2)O(2)](ss)) and cell fluorescence. mtNOS-dependent [H(2)O(2)](ss) was a good predictor of extracellular signal-regulated kinase (ERK)/p38 activity ratio, cyclin D1, and tissue proliferation. At low 10(-11)-10(-12) M [H(2)O(2)](ss), proliferating phenotypes had high cyclin D1 and phospho-ERK1/2 and low phospho-p38 mitogen-activated protein kinase, while at 10(-9) M [H(2)O(2)](ss), quiescent phenotypes had the opposite pattern. Accordingly, leading postnatal day 2-isolated hepatocytes to embryo or adult redox conditions with H(2)O(2) or NO-H(2)O(2) scavengers, or with ERK inhibitor U0126, p38 inhibitor SB202190 or p38 activator anisomycin resulted in correlative changes of ERK/p38 activity ratio, cyclin D1 expression, and [(3)H] thymidine incorporation in the cells. Accordingly, p38 inhibitor SB202190 or N-acetyl-cysteine prevented H(2)O(2) inhibitory effects on proliferation. In conclusion, the results suggest that a synchronized increase of mtNOS and derived H(2)O(2) operate on hepatocyte signaling pathways to support the liver developmental transition from proliferation to quiescence.}, }
@article {pmid15234256, year = {2004}, author = {Fukami, G and Hashimoto, K and Koike, K and Okamura, N and Shimizu, E and Iyo, M}, title = {Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine.}, journal = {Brain research}, volume = {1016}, number = {1}, pages = {90-95}, doi = {10.1016/j.brainres.2004.04.072}, pmid = {15234256}, issn = {0006-8993}, mesh = {Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Behavior, Animal/drug effects ; Central Nervous System Stimulants ; Chromatography, High Pressure Liquid/methods ; Dopamine/metabolism ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Interactions ; Free Radical Scavengers/*therapeutic use ; Male ; *Methamphetamine ; Neurotoxicity Syndromes/etiology/*prevention &amp; control ; Rats ; Time Factors ; }, abstract = {Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-L-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kg x 4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.}, }
@article {pmid15229859, year = {2004}, author = {Amer, J and Goldfarb, A and Fibach, E}, title = {Flow cytometric analysis of the oxidative status of normal and thalassemic red blood cells.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {60}, number = {1}, pages = {73-80}, doi = {10.1002/cyto.a.20017}, pmid = {15229859}, issn = {1552-4922}, mesh = {Erythrocytes/*physiology ; *Flow Cytometry ; Glutathione/*blood ; Humans ; Lipid Peroxidation ; Reactive Oxygen Species/*blood ; Thalassemia/*blood/pathology ; }, abstract = {BACKGROUND: The oxidative status of cells has been shown to modulate various cell functions and be involved in physiological and pathological conditions, including hereditary chronic anemias, such as thalassemia. It is maintained by the balance between oxidants, such as reactive oxygen species (ROS), and antioxidants, such as reduced glutathione (GSH).<br><br>METHODS: We studied peripheral RBC derived from normal and thalassemic donors. Flow cytometric methods were used to measure (1) generation of ROS; (2) the content of reduced GSH; and (3) peroxidation of membrane lipids as an indication of membrane damage.<br><br>RESULTS: ROS and lipid peroxidation were found to be higher, and GSH lower, in thalassemic RBC compared with normal RBC, both at baseline as well as following oxidative stress, such as exposure to hydrogen peroxide. To simulate a state of iron overload, normal RBC were exposed to extracellular ferric ammonium citrate or hemin, or their Hb was denatured by phenylhydrazine. All these treatments increased ROS and lipid peroxidation and decreased GSH. These effects were reversed by N-acetyl cysteine, a known ROS scavenger.<br><br>CONCLUSIONS: Flow cytometry can be useful for measuring oxidative stress and its effects on RBC in various diseases and for studying various chemical agents as antioxidants.}, }
@article {pmid15229242, year = {2004}, author = {Pannu, R and Won, JS and Khan, M and Singh, AK and Singh, I}, title = {A novel role of lactosylceramide in the regulation of lipopolysaccharide/interferon-gamma-mediated inducible nitric oxide synthase gene expression: implications for neuroinflammatory diseases.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {24}, number = {26}, pages = {5942-5954}, pmid = {15229242}, issn = {1529-2401}, support = {R01 NS037766/NS/NINDS NIH HHS/United States ; R01 NS022576/NS/NINDS NIH HHS/United States ; R01 NS040144/NS/NINDS NIH HHS/United States ; R01 NS034741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-40144/NS/NINDS NIH HHS/United States ; R01 NS040810/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; R37 NS022576/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antigens, CD/pharmacology/*physiology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Astrocytes/drug effects/enzymology ; Cells, Cultured/drug effects/enzymology ; Demyelinating Diseases/drug therapy ; Drug Evaluation, Preclinical ; Enzyme Induction/drug effects ; Enzyme Inhibitors/pharmacology ; Fatty Acids/metabolism ; Female ; Gait Disorders, Neurologic/etiology/prevention &amp; control ; Galactosyltransferases/genetics/metabolism ; I-kappa B Proteins/metabolism ; Inflammation ; Interferon-gamma/*pharmacology ; Lactosylceramides/pharmacology/*physiology ; Lipopolysaccharides/*pharmacology ; Morpholines/pharmacology ; NF-kappa B/metabolism ; Nerve Tissue Proteins/*biosynthesis/genetics ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/*biosynthesis/genetics ; Nitric Oxide Synthase Type II ; Oxidation-Reduction ; Phosphorylation/drug effects ; Proline/*analogs &amp; derivatives/pharmacology ; Protein Processing, Post-Translational/drug effects ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins ; Signal Transduction ; Spinal Cord Injuries/complications/drug therapy/*enzymology ; Thiocarbamates/pharmacology ; Transfection ; }, abstract = {In the present study a possible role of glycosphingolipids (GSLs) in inducible nitric oxide synthase (iNOS) gene expression and nitric oxide (NO) production after spinal cord injury (SCI) in rats has been established. In primary rat astrocytes lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) treatment increased the intracellular levels of lactosylceramide (LacCer) and induced iNOS gene expression. d-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol.HCI (PDMP), a glucosylceramide synthase and LacCer synthase (galactosyltransferase, GalT-2) inhibitor, inhibited LPS/IFN-gamma induced iNOS expression, which was reversed by exogenously supplied LacCer, but not by other glycosphingolipids. LPS/IFN-gamma caused a rapid increase in the activity of GalT-2 and synthesis of LacCer. Silencing of GalT-2 gene with the use of antisense oligonucleotides resulted in decreased LPS/IFN-gamma-induced iNOS, TNF-alpha, and IL-1beta gene expression. The PDMP-mediated reduction in LacCer production and inhibition of iNOS expression correlated with decreased Ras and ERK1/2 activation along with decreased IkappaB phosphorylation, NF-kappaB DNA binding activity, and NF-kappaB-luciferase reporter activity. LacCer-mediated Ras activation was redox-mediated and was attenuated by antioxidants N-acetyl cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC). In vivo administration of PDMP after SCI resulted in improved functional outcome (Basso, Beattie, Bresnahan score); inhibition of iNOS, TNF-alpha, and IL-1beta expression; decreased neuronal apoptosis; and decreased tissue necrosis and demyelination. The in vivo studies supported the conclusions drawn from cell culture studies and provided evidence for the possible role of GalT-2 and LacCer in SCI-induced inflammation and pathology. To our knowledge this is the first report of a role of LacCer in iNOS expression and the advantage of GSL depletion in attenuating post-SCI inflammation to improve the outcome of SCI.}, }
@article {pmid15226698, year = {2004}, author = {Genest, M and Pochmalicki, G}, title = {[Diagnostic and therapeutic progress. Venous thromboembolism, cardiac insufficiency and radio contrast agents].}, journal = {Presse medicale (Paris, France : 1983)}, volume = {33}, number = {9 Pt 1}, pages = {623-630}, doi = {10.1016/s0755-4982(04)98690-3}, pmid = {15226698}, issn = {0755-4982}, mesh = {Acetylcysteine/therapeutic use ; Acute Disease ; Adrenergic beta-Antagonists/therapeutic use ; Anticoagulants/therapeutic use ; Counterpulsation/methods/trends ; Diastole ; Diuretics/therapeutic use ; Echocardiography/methods/trends ; Electric Countershock/methods/trends ; Fibrin Fibrinogen Degradation Products/metabolism ; Fluid Therapy/methods/trends ; Heart Failure/complications/*diagnosis/mortality/*therapy ; Hemofiltration/methods/trends ; Heparin/therapeutic use ; Humans ; Kidney Failure, Chronic/etiology/prevention &amp; control ; Natriuretic Peptide, Brain/metabolism ; Oxygen Inhalation Therapy ; Pulmonary Edema/etiology ; Thromboembolism/complications/*diagnosis/mortality/*therapy ; Tissue Plasminogen Activator/therapeutic use ; Treatment Outcome ; Vasodilator Agents/therapeutic use ; Venous Thrombosis/complications/*diagnosis/mortality/*therapy ; }, abstract = {MODALITIES FOR THE DIAGNOSIS OF VENOUS THROMBOEMBOLISM: Currently rely on the confrontation of the initial clinical data and the results of D-dimer measurements, a venous Doppler, although reliable, is not a first-line exploration. REGARDING TREATMENT: Indications for thrombolysis are currently limited to massive pulmonary oedema with shock. Alteplase added to heparin improves the progression of severe embolism; it spares the patients from heavy interventions of resuscitation but the mortality remains the same. Concerning anticoagulant treatments, prolonged antivitamin K at classical doses is more effective than low doses and for limited duration if phlebitis is an idiopathic one. FOR HEART FAILURE WITH PRESERVED EJECTION FRACTION: Treatment of these heart failures, formerly know as 'diastolic' is similar to that of the acute phase of systolic heart failure. However, care should be taken with vasodilatators. CONCERNING HEART FAILURE IN GENERAL: The brain natriuretic peptide (BNP) represents a remarkable progress for the aetiological diagnosis of dyspnoea (inferior to 80 pg/ml in the case of pulmonary origin, superior to 300 pg/ml in the case of cardiac origin or severe pulmonary embolism). Regarding treatment, for acute heart failure, it is still the association of nitrates and diuretics, with oxygen therapy and eventually inotropics. Beta-blockers, which have revolutionized the treatment of chronic heart failure, must be maintained whenever possible in the case of the onset of acute pulmonary oedema. Multisite pacing is increasingly used in refractory chronic heart failure. Implantable defibrillation has become common practice. Non-invasive ventilation (Bi or C-PAP) is interesting in acute cardiogenic pulmonary oedema. THE PREVENTIVE ROLE OF N ACETYL-CYSTEINE: N acetyl cysteine reduces the incidence of nephropathies induced by the radio contrast products in patients with chronic kidney failure. Combined with hydratation, it must be proposed the day before and on the day of the procedure in any patient with diabetes or kidney failure.}, }
@article {pmid15219317, year = {2004}, author = {Thomas Dickey, D and Muldoon, LL and Kraemer, DF and Neuwelt, EA}, title = {Protection against cisplatin-induced ototoxicity by N-acetylcysteine in a rat model.}, journal = {Hearing research}, volume = {193}, number = {1-2}, pages = {25-30}, doi = {10.1016/j.heares.2004.02.007}, pmid = {15219317}, issn = {0378-5955}, support = {N 33618//PHS HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antineoplastic Agents/*poisoning ; Body Weight/drug effects ; Cisplatin/*poisoning ; Drug Administration Schedule ; Ear Diseases/*chemically induced/*prevention &amp; control ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Hearing Loss/chemically induced/prevention &amp; control ; Rats ; Rats, Long-Evans ; }, abstract = {Cisplatin (CDDP) is a widely used chemotherapeutic agent that is highly ototoxic. Animal studies and clinical trials have shown that thiosulfates can protect against platinum-induced ototoxicity. This study investigated a new model for CDDP ototoxicity in the rat, and tested the potential chemoprotective effect of administering N-acetylcysteine (NAC) before giving CDDP. Long Evans rats were treated with CDDP 6 mg/kg delivered to the aorta via a retrograde right external carotid artery infusion, 15 min after intravenous (IV) infusion of saline (n=8) or NAC 400 mg/kg (n=8), such that the vertebral arteries were perfused. Subsequent groups were similarly treated with NAC 30 min before (n=7) and 4 h after (n=7) CDDP. Auditory brainstem response (ABR) thresholds were tested at 4-20 kHz, 7 days after treatment and compared to baseline ABR values. The NAC-treated rats exhibited no significant change from baseline values at all time intervals, while the saline-treated rats showed marked ototoxicity, especially at higher frequencies. Furthermore, the rats treated with NAC 15 min before CDDP exhibited less overall toxicity to CDDP, as evidenced in weight loss 7 days post-treatment (mean for saline=-39.63 g; mean for NAC=-21.13 g; p=0.0084). These data show that treatment with NAC can prevent CDDP-induced ototoxicity in rats.}, }
@article {pmid15213978, year = {2004}, author = {Oguri, S and Hibino, M and Mizunuma, M}, title = {Performance of throughout in-capillary derivatization capillary electrophoresis employing an on-line sample and run buffer loading device.}, journal = {Electrophoresis}, volume = {25}, number = {12}, pages = {1810-1816}, doi = {10.1002/elps.200305945}, pmid = {15213978}, issn = {0173-0835}, mesh = {Aspartic Acid/*chemistry ; Buffers ; *Electrophoresis, Capillary ; Nitrophenols/*chemistry ; o-Phthalaldehyde/*chemistry ; }, abstract = {We report on the effect on performance of varying the length of the capillary during throughout in-capillary derivatization (TICD) capillary electrophoresis (CE). Performance was evaluated by on-line coupling with a sample and CE runbuffer loading device that was newly introduced for this study. The device was assembled with a low cost using two 5 mm inner diameter (ID) disposable polyethylene syringes. First, a sequence was manually formed consisting of a 200 microL run buffer solution plug, a 100 microL sample plug and another 200 microL run buffer solution plug. Each plug was separated from its neighbor by a 100 microL air plug. When each plug reached the injection point where both a platinum-wire anode and the end of the separation capillary tube were located, 340 V/cm separation voltage (electrophoresis voltage) and 34 V/cm injection voltage were applied to the capillary for 3 s. Then the analytes were derivatized during migration in 50 microm ID capillaries filled with 2 mM o-phthalaldehyde (OPA)/N-acetylcysteine (NAC) in a 20 mM phosphate-borate buffer (pH 10), followed by separating and detecting of OPA derivatives by absorbance of 340 nm. Derivatization, separation, and detection were performed systematically using capillaries which varied in length from 5 to 80 cm. In the case of TICD-CE of a mixture containing 1 mM aspartic acid (Asp) and 20 mM m-nitorophenol (MNP) as a test solution, it was determined that peak area and peak width ratios of Asp to MNP did not depend on capillary length. Enantiomeric separations of DL-alanine (Ala) and Asp were examined using a run buffer consisting of a 45 microM beta-cyclodextrin (CD)-2 mM OPA/NAC-20 mM phosphate-borate buffer (pH 10). Even though the resolution of these enantiomeric pairs decreased with decreasing capillary length, as expected, the peaks corresponding to both enantiomeric amino acids were identified even when a 5 cm capillary was used. An 8-component amino acid mixture was also tested with 5 cm and 10 cm capillaries.}, }
@article {pmid15212815, year = {2004}, author = {Carvalho, M and Remião, F and Milhazes, N and Borges, F and Fernandes, E and Carvalho, F and Bastos, ML}, title = {The toxicity of N-methyl-alpha-methyldopamine to freshly isolated rat hepatocytes is prevented by ascorbic acid and N-acetylcysteine.}, journal = {Toxicology}, volume = {200}, number = {2-3}, pages = {193-203}, doi = {10.1016/j.tox.2004.03.016}, pmid = {15212815}, issn = {0300-483X}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cell Separation ; Cell Survival/drug effects ; Chromatography, High Pressure Liquid ; Deoxyepinephrine/*analogs &amp; derivatives/*antagonists &amp; inhibitors/*toxicity ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Glutathione Transferase/metabolism ; Hallucinogens/antagonists &amp; inhibitors/toxicity ; Hepatocytes/*drug effects/enzymology ; In Vitro Techniques ; Male ; N-Methyl-3,4-methylenedioxyamphetamine/antagonists &amp; inhibitors/toxicity ; Rats ; Spectrophotometry, Ultraviolet ; }, abstract = {In the past decade, clinical evidence has increasingly shown that the liver is a target organ for 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") toxicity. The aims of the present in vitro study were: (1) to evaluate and compare the hepatotoxic effects of MDMA and one of its main metabolites, N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and (2) to investigate the ability of antioxidants, namely ascorbic acid and N-acetyl-L-cysteine (NAC), to prevent N-Me-alpha-MeDA-induced toxic injury, using freshly isolated rat hepatocytes. Cell suspensions were incubated with MDMA or N-Me-alpha-MeDA in the final concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 mM for 3 h. To evaluate the potential protective effects of antioxidants, cells were preincubated with ascorbic acid in the final concentrations of 0.1 and 0.5 mM, or NAC in the final concentrations of 0.1 and 1 mM for 15 min before treatment with 1.6 mM N-Me-alpha-MeDA for 3 h (throughout this incubation period the cells were exposed to both compounds). The toxic effects were evaluated by measuring the cell viability, glutathione (GSH) and glutathione disulfide (GSSG), ATP, and the cellular activities of GSH peroxidase (GPX), GSSG reductase (GR), and GSH S-transferase (GST). MDMA induced a concentration- and time-dependent GSH depletion, but had a negligible effect on cell viability, ATP levels, or on the activities of GR, GPX, and GST. In contrast, N-Me-alpha-MeDA was shown to induce not only a concentration- and time-dependent depletion of GSH, but also a depletion of ATP levels accompanied by a loss in cell viability, and decreases in the antioxidant enzyme activities. For both compounds, GSH depletion was not accompanied by increases in GSSG levels, which seems to indicate GSH depletion by adduct formation. Importantly, the presence of ascorbic acid (0.5 mM) or NAC (1 mM) prevented cell death and GSH depletion induced by N-Me-alpha-MeDA. The results provide evidence that MDMA and its metabolite N-Me-alpha-MeDA induce toxicity to freshly isolated rat hepatocytes. Oxidative stress may play a major role in N-Me-alpha-MeDA-induced hepatic toxicity since antioxidant defense systems are impaired and administration of antioxidants prevented N-Me-alpha-MeDA toxicity.}, }
@article {pmid15210298, year = {2004}, author = {Wang, YC and Chaung, RH and Tung, LC}, title = {Comparison of the cytotoxicity induced by different exposure to sodium arsenite in two fish cell lines.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {69}, number = {1}, pages = {67-79}, doi = {10.1016/j.aquatox.2004.04.007}, pmid = {15210298}, issn = {0166-445X}, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Arsenites/*toxicity ; Cell Cycle/*drug effects ; Cell Line ; Cell Size/drug effects ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; Dithiothreitol/pharmacology ; Epithelial Cells/*cytology/drug effects ; Fibroblasts/*cytology/drug effects ; Flow Cytometry ; Fluorescent Antibody Technique ; Microtubules/*drug effects ; Sodium Compounds/*toxicity ; *Tilapia ; }, abstract = {Arsenic, a common environmental pollutant, is toxic to many mammalian cells. However, the arsenic-induced toxicity to aquatic animal species is unclear. This study attempted to compare the arsenic-induced cytotoxicity in various fish cells. Two fish cell lines, JF (fin cells of Therapon jarbua) and TO-2 cells (ovary cells of Tilapia), were treated with sodium arsenite in two ways to mimic acute and subacute exposure. The distinguishable alterations of cell morphology and microtubule network were observed in the cells treated by two arsenite exposure protocols. By the colony-forming assay, we demonstrated that the survival of both cell lines, treated with the high concentrations of arsenite (20-160 microM) for 2 h or with the low concentrations (0.125-10 microM) for 24 h, was decreased in a dose-dependent manner. The difference between the susceptibility of JF and TO-2 cells to arsenite was revealed by the factorial ANOVA to compare the survival rates of the arsenite-treated cells; JF cells were more sensitive than TO-2 cells (P = 0.008 and 0.013 for the high-concentration and the low-concentration treatment, respectively). The possible mechanisms to provoke the cytotoxicity of arsenite in two cell lines were also addressed. Antioxidants, N-acetyl-cysteine and dithiothreitol, significantly prevented JF cells, but not TO-2 cells, from the arsenite-induced inhibition of survival. Additionally, apparent apoptosis of JF cells and a mitotic arrest of TO-2 cells in response to the treatment of arsenite were also demonstrated by the DNA-fragmentation analysis and the flow cytometric analysis of cell-cycle progression. The results indicate that sodium arsenite induces apoptosis in JF cells probably by causing oxidative stress and disturbs the cell cycle of TO-2 cells. These two fish cell lines can serve as the potential tools to in detail study the toxicity and the hazards of arsenic compounds to aquatic animals at molecular level in the future.}, }
@article {pmid15209578, year = {2004}, author = {Ochoa, A and Pellizzon, G and Addala, S and Grines, C and Isayenko, Y and Boura, J and Rempinski, D and O'Neill, W and Kahn, J}, title = {Abbreviated dosing of N-acetylcysteine prevents contrast-induced nephropathy after elective and urgent coronary angiography and intervention.}, journal = {Journal of interventional cardiology}, volume = {17}, number = {3}, pages = {159-165}, doi = {10.1111/j.1540-8183.2004.09880.x}, pmid = {15209578}, issn = {0896-4327}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Contrast Media/*adverse effects ; *Coronary Angiography ; Dose-Response Relationship, Drug ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Kidney Diseases/chemically induced/*prevention &amp; control ; Male ; Prospective Studies ; }, abstract = {BACKGROUND AND HYPOTHESIS: Several studies have utilized low-dose regimens of N-acetylcysteine (NAC) for 48 hours to prevent contrast-induced nephropathy (CIN) after cardiac catheterization (cath) and percutaneous coronary intervention (PCI). A lengthy pretreatment period with NAC may not be feasible in urgent situations. The purpose of this study was to assess the efficacy of an abbreviated, higher dose regimen of NAC for the prevention of CIN after elective and urgent coronary angiography (cath) and/or percutaneous coronary intervention (PCI).<br><br>METHODS: We prospectively evaluated 80 patients referred for elective or urgent cath and/or PCI with stable chronic renal insufficiency (creatinine clearance <50 cc/min). Patients were randomized to: NAC 1000 mg PO 1 hour before cath/PCI and 4 hours later, or placebo. All patients received hydration (0.9% saline) before and after cath/PCI (minimum total volume > or = 1500 mL). CIN was defined as an increase of Cr > or = 0.5 mg/dL or > or = 25% 48 hours after cath/PCI.<br><br>RESULTS: CIN occurred in 3 of 36 (8%) patients of the NAC group vs. 11 of 44 (25%) in the placebo group (P = 0.051; OR 3.7, 95% CI 0.94-14.4). Serum creatinine (mean +/- SD) remained stable in the NAC group after cath/PCI (2.02 +/- 0.56 vs. 2.10 +/- 0.81 mg/dL; P = 0.34), but increased after cath/PCI in the placebo group (1.93 +/- 0.53 vs. 2.10 +/- 0.74 mg/dL; P < 0.01).<br><br>CONCLUSIONS: An abbreviated, higher dose regimen of NAC prevents the rise of serum creatinine 48 hours after cath/PCI, and may prevent CIN after cath/PCI.}, }
@article {pmid15209356, year = {2004}, author = {Chae, HJ and Chae, SW and Kim, HR}, title = {N-acetyl cysteine regulates TNF-alpha-inhibited differentiation in ROS 17/2.8 osteoblasts.}, journal = {Immunopharmacology and immunotoxicology}, volume = {26}, number = {2}, pages = {203-213}, doi = {10.1081/iph-120037716}, pmid = {15209356}, issn = {0892-3973}, mesh = {Acetylcysteine/*pharmacology ; Alkaline Phosphatase/antagonists &amp; inhibitors/metabolism ; Animals ; Cell Differentiation/drug effects ; Cell Line ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; I-kappa B Proteins/genetics/metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B/metabolism ; Osteoblasts/cytology/*drug effects/metabolism ; Rats ; Signal Transduction/drug effects ; Transfection ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Osteoblasts play a pivotal role in bone remodeling. The alkaline phosphatase (ALPase) activity was decreased in ROS 17/2.8 osteoblast treated with TNF-alpha (2, 5 or 10 ng/ml). The treatment of TNF-alpha inhibited osteoblast differentiation such as ALPase activity in ROS 17/2.8 osteoblast. TNF-gamma (10 ng/ml) increased NF-kappaB DNA binding activity in nuclear extracts of osteoblasts. The addition of NAC (N-acetyl cysteine), free radical scavenger, completely prevented TNF-alpha-induced activation of NF-kappaB. In addition, IkappaB alpha and IkappaB beta were rapidly degraded, allowing the activated NF-kappaB to enter the nucleus and promote gene transcription. To determine whether IkappaB alpha signal transduction pathway is important in the differentiation, we generated IkappaB (KD)-stably transfected ROS 17/2.8 cells. These IkappaB (KD) transfectants did not show any regulation of ALPase in osteoblasts. Here, we suggest that the degradations of IkappaB alpha and IkappaB beta and the following activation of NF-kappaB are the targets of NAC and that NF-kappaB transcription factor is a pivotal clue to regulation of differentiation in TNFalpha-exposed osteoblasts.}, }
@article {pmid15208668, year = {2004}, author = {Hwang, YS and Jeong, M and Park, JS and Kim, MH and Lee, DB and Shin, BA and Mukaida, N and Ellis, LM and Kim, HR and Ahn, BW and Jung, YD}, title = {Interleukin-1beta stimulates IL-8 expression through MAP kinase and ROS signaling in human gastric carcinoma cells.}, journal = {Oncogene}, volume = {23}, number = {39}, pages = {6603-6611}, doi = {10.1038/sj.onc.1207867}, pmid = {15208668}, issn = {0950-9232}, mesh = {Cell Line, Tumor ; Culture Media, Conditioned ; Gene Expression Regulation, Neoplastic/*physiology ; Humans ; Interleukin-1/*physiology ; Interleukin-8/*genetics ; Mitogen-Activated Protein Kinases/*metabolism ; RNA, Messenger/genetics ; *Reactive Oxygen Species ; Signal Transduction/*physiology ; Stomach Neoplasms/enzymology/*metabolism/pathology ; }, abstract = {Recent studies have suggested that the expression of interleukin-8 (IL-8) directly correlates with the vascularity of human gastric carcinomas. In this study, the effect of IL-1beta on IL-8 expression in human gastric cancer TMK-1 cells and the underlying signal transduction pathways were investigated. IL-1beta induced the IL-8 expression in a time- and concentration-dependent manner. IL-1beta induced the activation of extracellular signal-regulated kinases-1/2 and P38 mitogen-activated protein kinase (MAPK), but not the activation of c-jun amino-terminal kinse and Akt. Specific inhibitors of MEK-1 (PD980590) and P38 MAPK (SB203580) were found to suppress the IL-8 expression and the IL-8 promoter activity. Expression of vectors encoding a mutated-type MEK-1 and P38 MAPK resulted in decrease in the IL-8 promoter activity. IL-1beta also induced the production of reactive oxygen species (ROS). N-acetyl cysteine (NAC) prevented the IL-1beta-induced ROS production and IL-8 expression. In addition, exogenous H2O2 could induce the IL-8 expression. Deletional and site-directed mutagenesis studies on the IL-8 promoter revealed that activator protein-1 (AP-1) and nuclear factor (NF)-kappaB sites were required for the IL-1beta-induced IL-8 transcription. Electrophoretic mobility shift assay confirmed that IL-1beta increased the DNA-binding activity of AP-1 and NF-kappaB. Inhibitor (PD980590, SB203580) and ROS scavenger (NAC) studies revealed that the upstream signalings for the transcription factors AP-1 and NF-kappaB were MAPK and ROS, respectively. Conditioned media from the TMK-1 cells pretreated with IL-1beta could remarkably stimulate the in vitro growth of HUVEC and this effect was partially abrogated by IL-8-neutralizing antibodies. The above results suggest that MAPK-AP-1 and ROS-NF-kappaB signaling pathways are involved in the IL-1beta-induced IL-8 expression and that these paracrine signaling pathways induce endothelial cell proliferation.}, }
@article {pmid15204747, year = {2004}, author = {Sciuto, AM and Hurt, HH}, title = {Therapeutic treatments of phosgene-induced lung injury.}, journal = {Inhalation toxicology}, volume = {16}, number = {8}, pages = {565-580}, doi = {10.1080/08958370490442584}, pmid = {15204747}, issn = {0895-8378}, mesh = {Administration, Inhalation ; Animals ; Chemical Warfare Agents/*toxicity ; Disease Models, Animal ; Inhalation Exposure ; Lung Diseases/*drug therapy/etiology/pathology ; Mice ; *Pharmaceutical Preparations/classification ; Phosgene/administration &amp; dosage/*toxicity ; Rabbits ; }, abstract = {A series of studies was performed to address treatment against the former chemical warfare edemagenic gas phosgene. Both in situ and in vivo models were used to assess the efficacy of postexposure treatment of phosgene-induced lung injury using clinically existing drugs. The degree of efficacy was judged by examining treatment effects on pulmonary edema formation (PEF) as measured by wet/dry weight (WW/DW) ratios, real-time (in situ) lung weight gain (LWG), survival rates (SR), odds ratios, and glutathione (GSH) redox states. Drugs included N-acetylcysteine (NAC), ibuprofen (IBU), aminophylline (AMIN), and isoproterenol (ISO). Using the in situ isolated perfused rabbit lung model (IPRLM), intratracheal (IT) NAC (40 mg/kg bolus) delivered 45-60 min after phosgene exposure (650 mg/m(3)) for10 min lowered pulmonary artery pressure, LWG, leukotrienes (LT) C(4)/D(4)/E(4), lipid peroxidation, and oxidized GSH. We concluded that NAC protected against phosgene-induced lung injury by acting as an antioxidant by maintaining protective levels of GSH, reducing both lipid peroxidation and production of arachidonic acid metabolites. Also in IPRLM, administration of AMIN (30 mg/kg) 80-90 min after phosgene exposure significantly reduced lipid peroxidation and perfusate LTC(4)/D(4)/E(4), reduced LWG, and prevented phosgene-induced decreases in lung tissue cAMP. These data suggest that protective mechanisms observed with AMIN involve decreased LTC(4)/D(4)/E(4) mediated pulmonary capillary permeability and attenuated lipid peroxidation. Direct antipermeability effects of AMIN-induced upregulation of cAMP on cellular contraction may also be important in protection against phosgene-induced lung injury. Posttreatment with ISO in the IPRLM by either combined intravascular (iv; infused into pulmonary artery at 24 microg/min infused) + IT (24 microg bolus) or IT route alone 50-60 min after phosgene exposure significantly lowered pulmonary artery pressure, tracheal pressure, and LWG. ISO treatment significantly enhanced GSH products or maintained protective levels when compared with results from phosgene-exposed only rabbits. These data suggest that protective mechanisms for ISO involve reduction in vascular pressure, decreased LTC(4)/D(4)/E(4)-mediated pulmonary capillary permeability, and favorably maintained lung tissue GSH redox states. For in vivo male mouse (CD-1, 25-30 g) studies IBU was administered ip within 20 min after a lethal dose of phosgene (32 mg/m(3) for 20 min) at 0 (saline), 3, 9, or 15 mg/mouse. Five hours later, a second IBU injection was given but at half the original doses (0, 1.5, 4.5, and 7.5 mg/mouse); therefore, these treatment groups are now referred to as the 0/0, 3/1.5, 9/4.5, and 15/7.5 mg IBU/mouse groups. SRs and odds ratios were calculated for each dose at 12 and 24 h. The 12-h survival was 63% for 9/4.5 mg IBU and 82% for the 15/7.5 mg IBU groups, compared with 25% for saline-treated phosgene-exposed mice. At 24 h, those survival rates were reduced to 19%, 19%, and 6%, respectively. In the 15/7.5 mg IBU group, lung WW/DW ratios were significantly lower than in saline-treated mice at 12 h. Lipid peroxidation was lower only for the 9/4.5 mg IBU dose; however, nonprotein sulfhydryls (a measure of GSH) were greater across all IBU doses. The odds ratio was 5 for the 9/4.5 IBU group at 12 h and 13 for the 15/7.5 mg IBU group, compared with 3.5 for both groups at 24 h. IBU posttreatment increased the survival of mice at 12 h by reducing PEF, lipid peroxidation, and GSH depletion. In conclusion, effective treatment of phosgene-induced lung injury involves early postexposure intervention that could reduce free radical species responsible for lipid peroxidation, correct the imbalance in the GSH redox state, and prevent the release of biological mediators such as leukotrienes, which are accountable for increased permeability.}, }
@article {pmid15204746, year = {2004}, author = {van Helden, HP and van de Meent, D and Oostdijk, JP and Joosen, MJ and van Esch, JH and Hammer, AH and Diemel, RV}, title = {Protection of rats against perfluoroisobutene (PFIB)-induced pulmonary edema by curosurf and N-acetylcysteine.}, journal = {Inhalation toxicology}, volume = {16}, number = {8}, pages = {549-564}, doi = {10.1080/08958370490442575}, pmid = {15204746}, issn = {0895-8378}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Inhalation ; Animals ; Animals, Outbred Strains ; Biological Products/*therapeutic use ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Drug Therapy, Combination ; Expectorants/*therapeutic use ; Fluorocarbons/administration &amp; dosage/*toxicity ; Inhalation Exposure ; Lung/drug effects/pathology/physiopathology ; Male ; Organ Size/drug effects ; Phospholipids/analysis/*therapeutic use ; Proteins/analysis ; Pulmonary Edema/etiology/physiopathology/*prevention &amp; control ; Rats ; Rats, Wistar ; Respiratory Function Tests ; Specific Pathogen-Free Organisms ; Surface Tension/drug effects ; }, abstract = {Airborne exposure to lung-toxic agents may damage the lung surfactant system and epithelial and endothelial cells, resulting in a life-threatening pulmonary edema that is known to be refractory to treatment. The aim of this study was to investigate in rats (1) the respiratory injury caused by nose-only exposure to perfluoroisobutene (PFIB), and (2) the therapeutic efficacy of a treatment at 4 and/or 8 h after exposure consisting of the natural surfactant Curosurf and/or the anti-inflammatory drug N-acetylcysteine (NAC). For that purpose, the following parameters were examined: respiratory frequency (RF), lung compliance (Cdyn), airway resistance (Raw), lung wet weight (LWW), airway histopathology; and in brochoalveolar lavage (BAL) fluid, total protein, total phospholipid, cell count and differentiation, and changes in the surface tension of the BAL fluid. The mean (+/- SEM) surface tension of BAL fluid derived from PFIB-exposed (C . t = 1100-1200 mg min(-1) m(-3), approximately 1LCt50; t = 20 min) animals at 24 h following exposure (11 +/- 3 mN/m) was higher than that of unexposed rats (0.8 +/- 0.4 mN/m), reflecting damage to the surfactant system and justifying treatment with exogenous surfactant. Curosurf treatment (62.5 mg/kg i.t.) decreased pulmonary edema caused by PFIB, reflected by a decreased LWW, and decreased the amount of protein in BAL fluid. NAC treatment (1000 mmol/kg ip) inhibited the interstitial pneumonia reflected by a decreased percentage of neutrophils in the alveolar space. It was concluded that a combined treatment of Curosurf + NAC improved respiration, that is, RF and Cdyn, whereby Curosurf predominantly decreased pulmonary edema and NAC predominantly reduced the inflammatory process. A combined treatment may therefore be considered a promising therapeutic approach in early-stage acute respiratory distress caused by PFIB, although the treatment regimes need further investigation.}, }
@article {pmid15203191, year = {2004}, author = {Li, WQ and Qureshi, HY and Liacini, A and Dehnade, F and Zafarullah, M}, title = {Transforming growth factor Beta1 induction of tissue inhibitor of metalloproteinases 3 in articular chondrocytes is mediated by reactive oxygen species.}, journal = {Free radical biology &amp; medicine}, volume = {37}, number = {2}, pages = {196-207}, doi = {10.1016/j.freeradbiomed.2004.04.028}, pmid = {15203191}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/pharmacology ; Azoles/pharmacology ; Blotting, Northern ; Blotting, Western ; Cartilage, Articular/*metabolism ; Cattle ; Cells, Cultured ; Chondrocytes/*metabolism ; Culture Media, Serum-Free/pharmacology ; Cycloheximide/pharmacology ; DNA-Binding Proteins/metabolism ; Down-Regulation ; Free Radicals ; Growth Substances/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Isoindoles ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Kinase 4 ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Oligonucleotides, Antisense/pharmacology ; Organoselenium Compounds/pharmacology ; Oxidation-Reduction ; Phosphorylation ; RNA/chemistry/metabolism ; RNA, Messenger/metabolism ; *Reactive Oxygen Species ; Signal Transduction ; Smad2 Protein ; Species Specificity ; Time Factors ; Tissue Inhibitor of Metalloproteinase-3/*metabolism ; Trans-Activators/metabolism ; Transfection ; Transforming Growth Factor beta/*metabolism ; Transforming Growth Factor beta1 ; }, abstract = {Transforming growth factor beta1 (TGF-beta1) stimulates cartilage extracellular matrix synthesis but, in excess, evokes synovial inflammation, hyperplasia, and osteophyte formation in arthritic joints. TGF-beta1 induces tissue inhibitor of metalloproteinases 3 (TIMP-3), an inhibitor of cartilage-damaging matrix metalloproteianases and aggrecanases. We investigated the role of reactive oxygen species (ROS) in TIMP-3 induction by TGF-beta1. In primary human and bovine chondrocytes, ROS scavenger and antioxidant N-acetylcysteine (NAC) inhibited TGF-beta1-induced TIMP-3 mRNA and protein increases. Ebselen and ascorbate also reduced this induction. TGF-beta1 time-dependently induced ROS production that was suppressed by NAC. Hydrogen peroxide, a ROS, induced TIMP-3 RNA. The TIMP-3 increase induced by TGF-beta1 was partly Smad2-dependent. TGF-beta1-stimulated Smad2 phosphorylation was inhibited by NAC. Reduced glutathione and L-cysteine also blocked Smad2 and TIMP-3 induction by TGF-beta1, whereas a nonthiol, N-acetylalanine, did not. Smad2 was not activated by H2O2. Smad2 phosphorylation was independent, and TIMP-3 expression was dependent, on new protein synthesis. TGF-beta-stimulated ERK and JNK phosphorylation was also inhibited by NAC. However, inhibitory actions of NAC were not mediated by ERK activation. Thus, ROS mediate TGF-beta1-induced TIMP-3 gene expression. Blocking TGF-beta1-induced gene expression by modulating cellular redox status with thiols can be potentially beneficial for treating arthritic and other disorders caused by excessive TGF-beta1.}, }
@article {pmid15202509, year = {2004}, author = {Jing, YW and Yi, J and Chen, YY and Hu, QS and Shi, GY and Li, H and Tang, XM}, title = {Dicoumarol alters cellular redox state and inhibits nuclear factor kappa B to enhance arsenic trioxide-induced apoptosis.}, journal = {Acta biochimica et biophysica Sinica}, volume = {36}, number = {3}, pages = {235-242}, doi = {10.1093/abbs/36.3.235}, pmid = {15202509}, issn = {1672-9145}, mesh = {Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Dicumarol/*pharmacology ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Synergism ; Emodin/*pharmacology ; Enzyme Inhibitors/pharmacology ; HeLa Cells ; Humans ; NF-kappa B/*metabolism ; Oxidation-Reduction/drug effects ; Oxides/*pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {The effects of a number of cytotoxic drugs are influenced by cellular reduction/oxidation (redox) state. In the present study, we attempt to explore if dicoumarol, an inhibitor of NADPH: quinone oxidoreductase (NQO1), alters the cellular redox state and how this alteration affects the redox-related apoptosis. Flow cytometry was used to assess the reactive oxygen species (ROS) level and apoptotic rates of HeLa cells treated with arsenic trioxide (As2O3) alone or in combination with natural anthraquinone emodin and dicoumarol or plus N-acetyl-cysteine. Western blot, immunofluorescence, electrophoretic mobility shift assay and luciferase assay were used to detect Nuclear Factor kappa B (NF-kappaB) activation. The results showed that dicoumarol synergized with emodin to sensitize HeLa cells to As2O3-induced apoptosis through raising the ROS level. More notably, this enhanced susceptibility was associated with a ROS-mediated inhibition of NF-kappaB activation in which the combinative treatment with dicoumarol prevented NF-kappaB from binding to target DNA. It was suggested that dicoumarol in combination with anthraquinones might be a novel strategy to expand the chemotherapeutic spectrum of As2O3 by means of interfering the cellular redox state.}, }
@article {pmid15199373, year = {2004}, author = {Hashimoto, K and Tsukada, H and Nishiyama, S and Fukumoto, D and Kakiuchi, T and Shimizu, E and Iyo, M}, title = {Protective effects of N-acetyl-L-cysteine on the reduction of dopamine transporters in the striatum of monkeys treated with methamphetamine.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {29}, number = {11}, pages = {2018-2023}, doi = {10.1038/sj.npp.1300512}, pmid = {15199373}, issn = {0893-133X}, mesh = {Acetylcysteine/*metabolism/pharmacology ; Animals ; Corpus Striatum/drug effects/*metabolism ; Dopamine Plasma Membrane Transport Proteins ; Macaca mulatta ; Male ; Membrane Glycoproteins/*metabolism ; Membrane Transport Proteins/*metabolism ; Methamphetamine/*metabolism/pharmacology ; Nerve Tissue Proteins/*metabolism ; Neuroprotective Agents/*metabolism/pharmacology ; Positron-Emission Tomography/methods ; }, abstract = {Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). We undertook the present study to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [11C]beta-CFT. In contrast, the binding of [11C]SCH 23390 to dopamine D1 receptors in the monkey striatum was not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before MAP administration and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.}, }
@article {pmid15199099, year = {2004}, author = {Nikinmaa, M and Pursiheimo, S and Soitamo, AJ}, title = {Redox state regulates HIF-1alpha and its DNA binding and phosphorylation in salmonid cells.}, journal = {Journal of cell science}, volume = {117}, number = {Pt 15}, pages = {3201-3206}, doi = {10.1242/jcs.01192}, pmid = {15199099}, issn = {0021-9533}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimetabolites/pharmacology ; Antioxidants/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Cysteine/chemistry ; DNA/*chemistry/*metabolism ; Dimerization ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Hydroxylation ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit ; Immunoblotting ; Immunoprecipitation ; Oncorhynchus mykiss ; *Oxidation-Reduction ; Oxidative Stress ; Oxygen/metabolism ; Phosphorylation ; Proline/metabolism ; Propyl Gallate/pharmacology ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA/chemistry ; Time Factors ; Transcription Factors/*metabolism ; Transcriptional Activation ; }, abstract = {Rainbow trout (Oncorhynchus mykiss) hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor structurally similar to mammalian HIF-1. It consists of HIF-1alpha and HIF-1beta subunits, of which the HIF-1alpha subunit confers the hypoxia sensitivity. HIF-1alpha is rapidly degraded by a proteasome under normal oxygen (21% O2) conditions, mainly as a result of prolyl hydroxylation needed for protein destabilization. Although prolyl hydroxylation at conserved proline residues is a major factor controlling HIF-1alpha stability, the redox state of the cells may, in addition, influence the function of HIF-1alpha like proteins by influencing their stability, DNA binding and phosphorylation. Sensitivity of the protein to oxidation/reduction may be due to cysteine residues at critical positions. The predicted amino acid sequence of rainbow trout HIF-1alpha contains several unique cysteine residues, notably in the DNA-binding area at position 28 and in the transactivation domain of the molecule in the vicinity of the conserved proline residue at position 564 of mammalian HIF-1alpha. In the present studies we have investigated if the redox state influences HIF-1alpha stability, DNA binding and phosphorylation in two established salmonid cell lines RTG-2 and CHSE-214. The results indicate that reducing conditions, achieved using N-propylgallate (nPG) or N-acetylcysteine (NAC), stabilize HIF-1alpha, facilitate its DNA binding, and increase its phosphorylation even under normal oxygen conditions. On the other hand, oxidizing conditions, achieved using L-buthionine sulfoximine (BSO) dampen the hypoxia response. Furthermore, the hypoxia-like effect of cobalt is increased in the presence of the reducing agent. On the basis of these results, we suggest that redox state influences the accessibility of the conserved prolyl residues to oxygen-dependent hydroxylation and the accessibility of the residues involved in the phosphorylation of HIF-1alpha.}, }
@article {pmid15198077, year = {2004}, author = {Pal, S and Chatterjee, AK}, title = {Protective effect of N-acetylcysteine against arsenic-induced depletion in vivo of carbohydrate.}, journal = {Drug and chemical toxicology}, volume = {27}, number = {2}, pages = {179-189}, doi = {10.1081/dct-120037501}, pmid = {15198077}, issn = {0148-0545}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Arsenites/*antagonists &amp; inhibitors/toxicity ; Blood Glucose/drug effects ; Chemical and Drug Induced Liver Injury/enzymology/metabolism/*prevention &amp; control ; Enzyme Inhibitors/*toxicity ; Glucose-6-Phosphatase/metabolism ; Hypoglycemia/chemically induced/prevention &amp; control ; Kidney/drug effects/enzymology ; Male ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Sodium Compounds/*antagonists &amp; inhibitors/toxicity ; }, abstract = {N-acetylcysteine (NAC), a synthetic aminothiol, possesses antioxidative and cytoprotective properties. The present study evaluates the effect of NAC supplementation on arsenic-induced depletion in vivo of carbohydrates. Arsenic (as sodium arsenite) treatment (i.p.) of male Wistar rats (120-140 g b.w.) at a dose of 5.55 mg/kg body weight (35% of LD50) per day for a period of 30 days produced a significant decrease in blood glucose level (hypoglycemia) and a fall in liver glycogen and pyruvic acid contents. The free amino acid nitrogen content of liver increased while that of kidney decreased after arsenic treatment. Arsenic also enhanced the liver lactate dehydrogenase activity whereas glucose 6-phosphatase activity in both liver and kidney decreased significantly following arsenic treatment. Transaminase activities in liver and kidney were not significantly altered except the glutamate-pyruvate transaminase activity that was reduced in kidney after arsenic treatment. Oral administration of NAC (163.2 mg/kg/day) for last 7 days of treatment prevented the arsenic-induced hypoglycemia and glycogenolytic effects to an appreciable extent. There was also recovery of liver pyruvic acid as well as liver and kidney free amino acid nitrogen content after NAC supplementation. Arsenic-induced alteration of glucose 6-phosphatase activity in both liver and kidney was also counteracted by NAC. It is suggested that carbohydrate depletion in vivo due to exposure to arsenic can be counteracted by NAC supplementation.}, }
@article {pmid15197348, year = {2004}, author = {Yacoub, A and Mitchell, C and Hong, Y and Gopalkrishnan, RV and Su, ZZ and Gupta, P and Sauane, M and Lebedeva, IV and Curiel, DT and Mahasreshti, PJ and Rosenfeld, MR and Broaddus, WC and James, CD and Grant, S and Fisher, PB and Dent, P}, title = {MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells.}, journal = {Cancer biology &amp; therapy}, volume = {3}, number = {8}, pages = {739-751}, doi = {10.4161/cbt.3.8.968}, pmid = {15197348}, issn = {1538-4047}, support = {P01-CA72955/CA/NCI NIH HHS/United States ; P01-NS31492/NS/NINDS NIH HHS/United States ; P50-CA83591/CA/NCI NIH HHS/United States ; R01-CA63753/CA/NCI NIH HHS/United States ; R01-CA77141/CA/NCI NIH HHS/United States ; R01-CA88906/CA/NCI NIH HHS/United States ; R01-CA97318/CA/NCI NIH HHS/United States ; R01-CA98712/CA/NCI NIH HHS/United States ; R01-DK52825/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenoviridae/genetics ; Adjuvants, Immunologic/pharmacology ; Apoptosis/drug effects/*radiation effects ; Astrocytes/drug effects/radiation effects ; Brain Neoplasms/metabolism/*therapy ; Caspase 8 ; Caspase 9 ; Caspase Inhibitors ; Caspases/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects/*radiation effects ; Colony-Forming Units Assay ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/metabolism ; Genes, Tumor Suppressor ; Genes, erbB-1/physiology ; Glioblastoma/metabolism/*therapy ; Humans ; Interleukins/metabolism/*pharmacology ; JNK Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; MAP Kinase Kinase 4 ; Mitogen-Activated Protein Kinase Kinases/antagonists &amp; inhibitors/metabolism ; PTEN Phosphohydrolase ; Phosphoric Monoester Hydrolases/metabolism ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Radiation Tolerance ; Radiation-Sensitizing Agents/*pharmacology ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/metabolism ; bcl-2-Associated X Protein ; bcl-X Protein ; }, abstract = {We examined the impact of purified bacterially synthesized GST-MDA-7 (IL-24) and ionizing radiation on the proliferation and survival of nonestablished human glioblastoma multiforme (GBM) cells. Glioma cell types expressing mutated PTEN and p53 molecules, activated ERBB1VIII, overexpressing wild type ERBB1 or without receptor overexpression were selected. In MTT assays, GST-MDA-7 caused a dose-dependent reduction in the proliferation of nonestablished glioma cells; however only at higher concentrations did GST-MDA-7 reduce cell viability. The anti-proliferative and cytotoxic effects of GST-MDA-7 were enhanced by radiation in a greater than additive fashion that correlated with JNK1/2/3 activation. The reduction in cell growth and enhancement in cell killing by the combination of GST-MDA-7 and radiation were blocked by an ROS scavenger, N-acetyl cysteine (NAC), a JNK1/2/3 inhibitor SP600125, a pan-caspase inhibitor (zVAD) and by an inhibitor of caspase 9 (LEHD), but not by an inhibitor of caspase 8 (IETD). Low concentrations of either GST-MDA-7 or radiation reduced clonogenic survival, however colony formation ability was significantly further decreased when the two treatments were combined, which was also blocked by inhibition of caspase 9 function. In general agreement with activation of the intrinsic caspase pathway, cell death correlated with reduced BCL-XL expression and with increased levels of the pro-apoptotic proteins BAD and BAX. Inhibition of caspase 9 after combination treatment blunted neither JNK1/2/3 activation nor the enhanced expression of BAD and BAX, but did block caspase 3 cleavage, reduced expression of BCL-XL and inhibition of ERK1/2 activity. In contrast, incubation with NAC blocked JNK1/2/3 activation and cell killing, but not the increases in BAD and BAX expression. These findings argue that after combination treatment JNK1/2/3 activation is a primary pro-apoptotic event and loss of BCL-XL expression and ERK1/2 activity are secondary caspase-dependent processes. This data also argues that GST- MDA-7 induces two parallel pro-apoptotic pathways via ROS-dependent and -independent mechanisms. Infection of primary human astrocytes with a recombinant adenovirus to express MDA-7, Ad.mda-7, but not infection with either Ad.cmv or Ad.mda-7SP- lacking MDA-7 secretion, resulted in the suppression of GBM cell colony formation in soft agar overlay assays, an effect that was enhanced in a greater than additive fashion by radiation. Collectively, our findings demonstrate that MDA-7 reduces proliferation and enhances the radiosensitivity of nonestablished human GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs independently of basal EGFR/ERK1/2/AKT activity or the functions of PTEN and p53.}, }
@article {pmid15194675, year = {2004}, author = {Medved, I and Brown, MJ and Bjorksten, AR and Murphy, KT and Petersen, AC and Sostaric, S and Gong, X and McKenna, MJ}, title = {N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {97}, number = {4}, pages = {1477-1485}, doi = {10.1152/japplphysiol.00371.2004}, pmid = {15194675}, issn = {8750-7587}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Biological Availability ; Cross-Over Studies ; Cysteine/*pharmacokinetics ; Double-Blind Method ; Exercise Test ; Glutathione/*pharmacokinetics ; Humans ; Infusions, Intravenous ; Male ; Muscle Fatigue/drug effects/*physiology ; Muscle, Skeletal/*drug effects/*physiology ; Physical Endurance/drug effects/*physiology ; Physical Exertion/drug effects/*physiology ; Physical Fitness/physiology ; }, abstract = {The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated the effects of the antioxidant compound N-acetylcysteine (NAC) on muscle cysteine, cystine, and glutathione and on time to fatigue during prolonged, submaximal exercise in endurance athletes. Eight men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling for 45 min at 71% peak oxygen consumption (VO2 peak) and then to fatigue at 92% VO2 peak. NAC was intravenously infused at 125 mg.kg(-1).h(-1) for 15 min and then at 25 mg.kg(-1).h(-1) for 20 min before and throughout exercise. Arterialized venous blood was analyzed for NAC, glutathione status, and cysteine concentration. A vastus lateralis biopsy was taken preinfusion, at 45 min of exercise, and at fatigue and was analyzed for NAC, total glutathione (TGSH), reduced glutathione (GSH), cysteine, and cystine. Time to fatigue at 92% VO2 peak was reproducible in preliminary trials (coefficient of variation 5.6 +/- 0.6%) and with NAC was enhanced by 26.3 +/- 9.1% (NAC 6.4 +/- 0.6 min vs. Con 5.3 +/- 0.7 min; P <0.05). NAC increased muscle total and reduced NAC at both 45 min and fatigue (P <0.005). Muscle cysteine and cystine were unchanged during Con, but were elevated above preinfusion levels with NAC (P <0.001). Muscle TGSH (P <0.05) declined and muscle GSH tended to decline (P=0.06) during exercise. Both were greater with NAC (P <0.05). Neither exercise nor NAC affected whole blood TGSH. Whereas blood GSH was decreased and calculated oxidized glutathione increased with exercise (P <0.05), both were unaffected by NAC. In conclusion, NAC improved performance in well-trained individuals, with enhanced muscle cysteine and GSH availability a likely mechanism.}, }
@article {pmid15194290, year = {2004}, author = {Portella, AO and Montero, EF and Poli de Figueiredo, LF and Bueno, AS and Thurow, AA and Rodrigues, FG}, title = {Effects of N-acetylcysteine in hepatic ischemia-reperfusion injury during hemorrhagic shock.}, journal = {Transplantation proceedings}, volume = {36}, number = {4}, pages = {846-848}, doi = {10.1016/j.transproceed.2004.03.047}, pmid = {15194290}, issn = {0041-1345}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Disease Models, Animal ; L-Lactate Dehydrogenase/blood ; Liver/*blood supply/pathology ; Liver Function Tests ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; Shock, Hemorrhagic/*prevention &amp; control ; }, abstract = {This article seeks to standardize an experimental model of liver ischemia-reperfusion in rats following hemorrhagic shock modulated by N-acetylcysteine (NAC). Twenty-seven adult Wistar rats were randomized into three groups: the HS-IR-Garm underwent hemorrhagic shock with selective hepatic ischemia followed by reperfusion; the HSIR + NAC-G, the same procedure plus NAC; and the control group, only venous catheterization. Blood was withdrawn for 10 minutes until MABP reached 35 mm Hg, which was maintained for 1 hour. The blood was then reinjected as required to maintain MABP at that level. Ringer's lactate solution was infused in a volume equivalent to three times the shed blood, over a period of 15 minutes. Half of the shed blood was reinfused over 5 minutes. HSIR + NAC-G received 150 mg/kg of NAC, during treatment of the shock, and again 10 minutes before reperfusion and continued for 30 minutes. Finally, both groups were subjected to 40 minutes of warm selective hepatic ischemia and reperfusion for 1 hour. Data were analyzed by nonparametric tests (P < or =.05). Liver enzyme levels were higher in HS-IR-G (DHL = 6094 +/- 1688, AST = 746 +/- 175, and ALT = 457 +/- 90) than in HSIR + NAC-G group (DHL = 2920 +/- 284, AST = 419 +/- 113, and ALT = 253 +/- 26). The values in the control group were lower than both experimental groups (DHL = 965 +/- 173, AST = 163 +/- 42, and ALT = 82 +/- 28). Our data showed that liver ischemia-reperfusion injury following hemorrhagic shock produces important hepatic damage and that NAC reduces injury in this rat model.}, }
@article {pmid15193998, year = {2004}, author = {Jang, BC and Paik, JH and Jeong, HY and Oh, HJ and Park, JW and Kwon, TK and Song, DK and Park, JG and Kim, SP and Bae, JH and Mun, KC and Suh, MH and Yoshida, M and Suh, SI}, title = {Leptomycin B-induced apoptosis is mediated through caspase activation and down-regulation of Mcl-1 and XIAP expression, but not through the generation of ROS in U937 leukemia cells.}, journal = {Biochemical pharmacology}, volume = {68}, number = {2}, pages = {263-274}, doi = {10.1016/j.bcp.2004.03.007}, pmid = {15193998}, issn = {0006-2952}, mesh = {Antibiotics, Antineoplastic/pharmacology ; *Apoptosis ; Caspases/*metabolism/physiology ; Cell Survival ; Down-Regulation ; Enzyme Activation ; Fatty Acids, Unsaturated/chemistry/*pharmacology ; Gene Expression ; Humans ; Leukemia/pathology ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins/*metabolism ; Proteins/*metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; U937 Cells ; X-Linked Inhibitor of Apoptosis Protein ; }, abstract = {Leptomycin B (LMB), which is originally isolated from Streptomyces, possesses anti-tumor properties in vivo and in vitro. Though it was previously reported that LMB induces cell cycle arrest and p53-mediated apoptosis in certain cancer cells, however, the mechanism by which LMB induces apoptosis remains poorly understood. Here, we investigated the mechanisms of apoptosis induced by LMB in U937 cells. Treatment with LMB concentration-dependently induced cytotoxicity and apoptosis in U937 cells that correlated temporally with activation of caspases and down-regulation of Mcl-1 and XIAP. LMB did not change the expressions of Bcl-2 or Bax. A broad spectrum caspase inhibitor, z-VAD-fmk, blocked caspase-3 activation and elevated the survival in LMB-treated U937 cells, suggesting that caspase-3 activation is critical for LMB-induced apoptosis. Interestingly, Bcl-2 overexpression that blocked cytochrome c release by LMB effectively attenuated the apoptotic response to LMB, suggesting that LMB-induced apoptosis is mediated through the mitochondrial pathway. Antioxidants or antioxidant enzymes had no effects on LMB-induced apoptosis. Data of flow cytometry analysis using 2',7'-dichlorofluorescein-diacetate further revealed no reactive oxygen species (ROS) generation by LMB, indicating that apoptosis induced by LMB is ROS-independent. However, the apoptotic response to LMB was not shown in U937 cells pretreated with the sulfhydryl group-containing antioxidant N-acetylcysteine (NAC). Further analysis suggested that NAC directly binds LMB and abolishes the apoptotic effects of LMB. Collectively, these findings suggest that LMB potently induces apoptosis in U937 cells, and LMB-induced apoptosis in U937 cells is related with cytochrome c release, activation of caspases, and selective down-regulation of Mcl-1 and XIAP.}, }
@article {pmid15193838, year = {2004}, author = {Miyamoto, M and Kishimoto, C and Nimata, M and Nakamura, H and Yodoi, J}, title = {Thioredoxin, a redox-regulating protein, is expressed in spontaneous myocarditis in inbred strains of mice.}, journal = {International journal of cardiology}, volume = {95}, number = {2-3}, pages = {315-319}, doi = {10.1016/j.ijcard.2003.10.009}, pmid = {15193838}, issn = {0167-5273}, mesh = {Acetylcysteine/therapeutic use ; Aging/*metabolism ; Animals ; Biomarkers ; Free Radical Scavengers/therapeutic use ; Immunohistochemistry ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Myocarditis/*metabolism/pathology/prevention &amp; control ; Myocardium/pathology ; *Oxidative Stress ; Thioredoxins/*metabolism ; }, abstract = {Redox-regulating mechanisms may be involved in the pathogenesis of aging. Thioredoxin (TRX) is a small multifunctional protein which contains a redox active sequence. Spontaneous myocarditis is often observed in aged mice. In this study, we examined the histopathology and characteristics of TRX expression in spontaneous myocarditis in inbred strains of mice. No spontaneous myocarditis was found in adult 4-week-old inbred strains of mice. High incidence of spontaneous myocarditis was found in aged 8-week-old DBA/2 mice, and low incidence was in 8-week-old BALB/c or C57BL/6 mice. The lesions, limited to the right ventricle, were most severe in DBA/2 mice. TRX was upregulated, and the expression was correlated with the severity of the disease in these strains. Also, 8-hydroxy-2'-deoxyguanosine (8-OHdG), which was an established marker for oxidative stress, was concomitantly positive in necrotic lesions among them. In addition, the long-term anti-oxidant treatment with N-acetylcysteine (NAC) suppressed the development of spontaneous myocarditis. Thus, TRX may be induced by the spontaneously developed myocarditis, and the redox-regulating system may play an important role in the development of aging-related myocarditis.}, }
@article {pmid15193829, year = {2004}, author = {Jeremias, A and Dusa, C and Forudi, F and Jacobsen, DW and Vince, DG and Nissen, SE and Tuzcu, EM}, title = {N-acetyl-cysteine in the prevention of vascular restenosis after percutaneous balloon angioplasty.}, journal = {International journal of cardiology}, volume = {95}, number = {2-3}, pages = {255-260}, doi = {10.1016/j.ijcard.2003.05.024}, pmid = {15193829}, issn = {0167-5273}, mesh = {Acetylcysteine/*pharmacology ; *Angioplasty, Balloon ; Animals ; Cysteine/blood ; Free Radical Scavengers/*pharmacology ; Glutathione/blood ; Iliac Artery/pathology ; Immunohistochemistry ; Prospective Studies ; Rabbits ; Vascular Patency/*drug effects ; }, abstract = {BACKGROUND: Vascular inflammation generating oxidized metabolites at the site of balloon angioplasty is believed to play a major role in the process of vessel restenosis. Glutathione, the most potent endogenous antioxidant, may have protective effects after angioplasty by suppressing local inflammatory response. The aim of the study was to test the hypothesis that oral administration of N-acetyl-cysteine (NAC, a precursor of glutathione) reduces restenosis in an animal model of vascular injury.<br><br>METHODS: In New Zealand white rabbits, an atherosclerotic lesion was introduced to both iliac arteries by air denudation of the endothelium while feeding the animals a high-cholesterol diet. After 4 weeks, all animals underwent balloon angioplasty of the endothelial injury site and half of the group was started on 150 mg/kg NAC per day. Quantitative angiography was performed prior to the angioplasty and at the final procedure 3 weeks later. Glutathione levels were determined in all animals at the beginning and the end of the study.<br><br>RESULTS: Although not statistically significant, plasma glutathione level increased in the NAC group from 32.4+/-4.4 to 39.7+/-11.6 micromol/l, while it decreased from 30.6+/-13.4 to 28.3+/-11.5 micromol/l in the control group. During the study period, 6 vessels occluded leaving 14 vessels for analysis. Quantitative angiographic analyses prior to angioplasty and at follow-up showed no significant difference with respect to stenosis progression between the groups. Measurement of neointima formation by histology showed also no significant difference between the groups (0.175+/-0.040 mm(2) vs. 0.123+/-0.075 mm(2)), neither did intimal macrophage count as a marker for local inflammatory response.<br><br>CONCLUSIONS: Despite an increase in plasma glutathione level in the NAC-treated group, there was no reduction in lesion progression after balloon angioplasty. Therefore, NAC does not seem to prevent restenosis after vascular intervention in this animal model.}, }
@article {pmid15184067, year = {2004}, author = {Quadrilatero, J and Hoffman-Goetz, L}, title = {N-Acetyl-L-cysteine prevents exercise-induced intestinal lymphocyte apoptosis by maintaining intracellular glutathione levels and reducing mitochondrial membrane depolarization.}, journal = {Biochemical and biophysical research communications}, volume = {319}, number = {3}, pages = {894-901}, doi = {10.1016/j.bbrc.2004.05.068}, pmid = {15184067}, issn = {0006-291X}, mesh = {Acetylcysteine/*metabolism ; Animals ; Antioxidants/metabolism ; Apoptosis/*physiology ; CD3 Complex/metabolism ; Cell Survival ; Female ; Glutathione/*metabolism ; Hydrogen Peroxide/metabolism ; Intestinal Mucosa/metabolism ; Intestines/*cytology ; Lymphocytes/*metabolism ; Membrane Potentials ; Mice ; Mice, Inbred C57BL ; Mitochondria/*physiology ; Oxidants/metabolism ; *Physical Conditioning, Animal ; Random Allocation ; Running ; }, abstract = {Intense exercise leads to post-exercise lymphocytopenia and immunosuppression, possibly by triggering lymphocyte apoptosis. To test the role of oxidative stress on exercise-induced lymphocyte apoptosis, we administered the antioxidant N-acetyl--cysteine (NAC) and measured apoptosis in intestinal lymphocytes (IL) from exhaustively exercised animals. Eighty-seven female C57BL/6 mice were randomly assigned to receive NAC (1 g/kg) or saline 30 min prior to treadmill exercise for 90 min at 2degrees slope (30 min at 22 m min(-1), 30 min at 25 m min(-1), and 30 min at 28 m min(-1)) and sacrificed immediately (Imm) or 24 hours (24 h) after cessation of exercise. Control mice (nonexercised) were exposed to treadmill noise and vibration without running. Exercise increased IL phosphatidylserine externalization (p<0.001), mitochondrial membrane depolarization (p<0.05), and decreased intracellular glutathione concentrations (p<0.05) immediately following exercise in saline relative to nonexercised mice. At 24 h post-exercise, saline injected mice had fewer total (p<0.001) and CD3+ (p<0.005) IL compared to nonexercised animals. NAC injection in mice maintained intracellular glutathione levels, prevented phosphatidylserine externalization, mitochondrial membrane depolarization, and loss of IL immediately and 24 h after exercise. These data suggest that lymphocyte apoptosis precedes post-exercise lymphocytopenia and may be due to oxidative stress.}, }
@article {pmid15183235, year = {2004}, author = {Honda, H and Kondo, T and Zhao, QL and Feril, LB and Kitagawa, H}, title = {Role of intracellular calcium ions and reactive oxygen species in apoptosis induced by ultrasound.}, journal = {Ultrasound in medicine &amp; biology}, volume = {30}, number = {5}, pages = {683-692}, doi = {10.1016/j.ultrasmedbio.2004.02.008}, pmid = {15183235}, issn = {0301-5629}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Calcium/analysis/*physiology ; Calcium Channel Blockers/pharmacology ; Caspase 3 ; Caspases/metabolism ; Chelating Agents/pharmacology ; Contrast Media/pharmacology ; DNA, Neoplasm/physiology ; Egtazic Acid/*analogs &amp; derivatives/pharmacology ; Flow Cytometry/methods ; Glutathione/analysis ; Humans ; Membrane Potentials/physiology ; Microscopy, Electron ; Mitochondria/physiology ; Polysaccharides/pharmacology ; Reactive Oxygen Species/*metabolism ; U937 Cells ; Ultrasonics/*adverse effects ; Verapamil/pharmacology ; }, abstract = {Recently, we have reported that ultrasound (US)-induced apoptosis is due to inertial cavitation and that extracellular reactive oxygen species (ROS) generated by inertial cavitation are not directly correlated with the apoptosis (Honda et al. 2002). The molecular mechanism of apoptosis induced by US is not yet sufficiently clear. Here, we examine the role of intracellular calcium ions and the intracellular ROS on apoptosis induced by US. Human myelomonocytic lymphoma U937 cells were exposed to continuous 1-MHz US at an intensity of 4.9 W/cm(2) (I(SPTA)) in the presence of air, and changes of intracellular calcium ion concentration ([Ca(2+)]i) in individual cells by digital imaging, various flow cytometric analyses of endpoints of apoptosis (early apoptosis, secondary necrosis, loss of mitochondria membrane potential, superoxide formation, caspase-3 activation) and DNA fragmentation were explored. Furthermore, the effects of an intracellular calcium ion chelator (BAPTA-AM), an antioxidant (N-acetyl-L-cysteine, NAC), a calcium channel blocker (verapamil), Ca(2+)-free buffer and Levovist were also investigated. These results indicate that: 1. the mitochondria-caspase pathway and the Ca(2+)-dependent pathway play cardinal roles in apoptosis induced by US because BAPTA-AM partially inhibited DNA fragmentation, loss of mitochondria membrane potential and caspase-3 activation; 2. intracellular ROS generated from mitochondria, rather than extracellular ROS (which were directly produced by inertial cavitation in the medium), are involved in the regulation of apoptosis induced by US because addition of NAC after sonication showed effective suppression of the apoptosis; and 3. increase of [Ca(2+)]i appears to be due to nonspecific influx from outside the cells because verapamil is not effective and no increase of [Ca(2+)]i due to sonication could be observed in the Ca(2+)-free buffer.}, }
@article {pmid15183009, year = {2004}, author = {Stredrick, DL and Stokes, AH and Worst, TJ and Freeman, WM and Johnson, EA and Lash, LH and Aschner, M and Vrana, KE}, title = {Manganese-induced cytotoxicity in dopamine-producing cells.}, journal = {Neurotoxicology}, volume = {25}, number = {4}, pages = {543-553}, doi = {10.1016/j.neuro.2003.08.006}, pmid = {15183009}, issn = {0161-813X}, support = {ES 0 10563/ES/NIEHS NIH HHS/United States ; R01 GM 38931/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; Cell Line, Tumor ; Cell Survival/drug effects/physiology ; Dopamine/*biosynthesis ; Dose-Response Relationship, Drug ; Glutathione/metabolism/pharmacology ; Growth Inhibitors/metabolism/*toxicity ; Humans ; Manganese/*adverse effects ; Mice ; Neuroblastoma/metabolism/pathology ; Reactive Oxygen Species/metabolism/toxicity ; }, abstract = {Manganese (Mn) is an essential metal that, at excessive levels in the brain, produces extrapyramidal symptoms similar to those in patients with Parkinson's disease (PD). In the present study, Mn toxicity was characterized in a human neuroblastoma (SK-N-SH) cell line and in a mouse catecholaminergic (CATH.a) cell line. Mn was demonstrated to be more toxic in the catecholamine-producing CATH.a cells (EC50 = 60 microM) than in non-catecholaminergic SK-N-SH cells (EC50 = 200 microM). To test the hypothesis that the sensitivity of CATH.a cells to Mn is associated with their dopamine (DA) content, DA concentrations were suppressed in these cells by pretreatment with alpha-methyl-para-tyrosine (AMPT). Treatment for 24 h with 100 microM AMPT decreased intracellular DA, but offered no significant protection from Mn exposure (EC50 = 60 microM). Additional studies were carried out to assess if Mn toxicity was dependent on glutathione (GSH) levels. CATH.a cells were significantly protected by the addition of 5mM GSH (Mn EC50 = 200 microM) and 10mM N-acetyl cysteine (NAC) (Mn EC50 = 300 microM), therefore, indirectly identifying intracellular ROS formation as a mechanism for Mn neurotoxicity. Finally, apoptotic markers of Mn-induced cell death were investigated. DNA fragmentation, caspase-3 activation, and apoptosis-related gene expression were studied in CATH.a cells. No internucleosomal fragmentation or caspase activation was evident, even in the presence of "supraphysiological" Mn concentrations. cDNA hydridization array analysis with two differing Mn concentrations and time points, identified no noteworthy mRNA inductions of genes associated with programmed cell death. In conclusion, DA content was not responsible for the enhanced sensitivity of CATH.a cells to Mn toxicity, but oxidative stress was implicated as a probable mechanism of cytotoxicity.}, }
@article {pmid15182952, year = {2004}, author = {Park, SW and Kim, SH and Park, KH and Kim, SD and Kim, JY and Baek, SY and Chung, BS and Kang, CD}, title = {Preventive effect of antioxidants in MPTP-induced mouse model of Parkinson's disease.}, journal = {Neuroscience letters}, volume = {363}, number = {3}, pages = {243-246}, doi = {10.1016/j.neulet.2004.03.072}, pmid = {15182952}, issn = {0304-3940}, mesh = {Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Antioxidants/*therapeutic use ; Blotting, Western/methods ; Brain/drug effects/metabolism/pathology ; Cell Count ; Cell Death/drug effects ; Disease Models, Animal ; Dopamine/metabolism ; Dopamine Agents/toxicity ; Dose-Response Relationship, Drug ; Drug Interactions ; Immunohistochemistry/methods ; JNK Mitogen-Activated Protein Kinases ; MPTP Poisoning/*prevention &amp; control ; Male ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinases/metabolism ; PC12 Cells ; Pyrrolidonecarboxylic Acid ; Rats ; Thiazoles/*therapeutic use ; Thiazolidines ; Time Factors ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Oxidative stress to dopaminergic neurons is believed to be one of the causes of neurodegeneration in Parkinson's disease (PD). It was investigated whether N-acetylcysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) have a preventive effect in an oxidative stress-induced model of PD. We found that NAC and OTC prevent degradation of PARP during auto-oxidized dopamine- or auto-oxidized L-DOPA-induced apoptosis in PC12 cells. In an animal model study, NAC and OTC showed a preventive effect against MPTP-induced loss of tyrosine hydroxylase-positive neurons, and suppressed the nuclear translocation of c-jun N-terminal kinase (JNK), suggesting that NAC and OTC can prevent MPTP-induced apoptosis by suppressing JNK activation. Therefore, these results suggest that NAC and OTC can be used as potential agents to prevent the progression of PD.}, }
@article {pmid15180920, year = {2004}, author = {Donnelly, LE and Newton, R and Kennedy, GE and Fenwick, PS and Leung, RH and Ito, K and Russell, RE and Barnes, PJ}, title = {Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {287}, number = {4}, pages = {L774-83}, doi = {10.1152/ajplung.00110.2004}, pmid = {15180920}, issn = {1040-0605}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Cell Culture Techniques/methods ; Cell Line ; Dexamethasone/pharmacology ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Inflammation/prevention &amp; control ; Kinetics ; Lung ; Quercetin/pharmacology ; Respiratory Mucosa/drug effects/*physiology ; Resveratrol ; Stilbenes/*pharmacology ; Transfection ; }, abstract = {Resveratrol (3,4',5-trihydroxystilbene) is a polyphenolic stilbene found in the skins of red fruits, including grapes, that may be responsible for some of the health benefits ascribed to consumption of red wine. Resveratrol has been shown to have antioxidant properties and can act as an estrogen agonist. This study examined the anti-inflammatory effects of resveratrol on human airway epithelial cells. Resveratrol and the related molecule quercetin, but not deoxyrhapontin, inhibited IL-8 and granulocyte-macrophage colony-stimulating factor release from A549 cells. Neither the estrogen receptor antagonist tamoxifen nor the glucocorticoid antagonist mifepristone altered the inhibitory effect of resveratrol. The mechanism of resveratrol action was investigated further using luciferase reporter genes stably transfected into A549 cells. Resveratrol and quercetin inhibited NF-kappaB-, activator protein-1-, and cAMP response element binding protein-dependent transcription to a greater extent than the glucocorticosteroid dexamethasone. These compounds also had no significant effect on acetylation or deacetylation of core histones. Resveratrol, but not estradiol or N-acetyl cysteine, inhibited cytokine-stimulated inducible nitric oxide synthase expression and nitrite production (IC50 = 3.6 +/- 2.9 microM) in human primary airway epithelial cells. Resveratrol also inhibited granulocyte-macrophage colony-stimulating factor release (IC50 = 0.44 +/- 0.17 microM), IL-8 release (IC50 = 4.7 +/- 3.3 microM), and cyclooxygenase-2 expression in these cells. This study demonstrates that resveratrol and quercetin have novel nonsteroidal anti-inflammatory activity that may have applications for the treatment of inflammatory diseases.}, }
@article {pmid15180331, year = {2004}, author = {Visser, CC and Voorwinden, LH and Crommelin, DJ and Danhof, M and de Boer, AG}, title = {Characterization and modulation of the transferrin receptor on brain capillary endothelial cells.}, journal = {Pharmaceutical research}, volume = {21}, number = {5}, pages = {761-769}, pmid = {15180331}, issn = {0724-8741}, mesh = {Acetylcysteine/pharmacology ; Animals ; Astrocytes/metabolism/physiology ; Capillaries/metabolism ; Cattle ; Cells, Cultured ; Cerebrovascular Circulation/*physiology ; Deferoxamine/pharmacology ; Down-Regulation ; Endocytosis/drug effects/physiology ; Endothelial Cells/*metabolism ; Extracellular Space/metabolism ; Free Radical Scavengers/pharmacology ; Inflammation/metabolism ; Iron/pharmacology ; Lipopolysaccharides/pharmacology ; Receptors, Transferrin/*metabolism ; Transferrin/metabolism ; Tyrphostins/pharmacology ; }, abstract = {PURPOSE: The expression level of the transferrin receptor (TfR) on brain capillary endothelial cells (BCECs) and the endocytosis of 125I-transferrin (125I-Tf) by this receptor was investigated. Furthermore, the influence of iron, the iron scavenger deferoxamine mesylate (DFO), astrocytic factors, a GTP-ase inhibitor (tyrphostin-A8, T8), lipopolysaccharide (LPS), and the radical scavenger N-acetyl-L-cysteine (NAC) on the TfR expression was studied to gain insight in the use and optimization of the TfR for drug targeting to the brain.<br><br>METHODS: Experiments were performed with primary cultured bovine BCECs that were incubated with 125I-Tf at 4 degrees C (to determine binding) or at 37 degrees C (to determine endocytosis) in the absence or presence of the modulators. For full saturation curves in the absence or presence of iron or DFO, analysis was performed with a population approach using NONMEM, allowing us to estimate a single value for affinity (Kd, concentration of 50% receptor occupancy) and separate values for maximum receptor occupancy (B(max).<br><br>RESULTS: On BCECs, the TfR is expressed extracellularly (B(max) of 0.13 fmol/microg cell protein), but also has a large intracellular pool (total B(max) of 1.37 fmol/microg cell protein), and is actively endocytosing Tf via clathrin-coated vesicles. At 4 degrees C, a Kd of 2.38 microg/ml was found, whereas the Kd at 37 degrees C was 5.03 microg/ml. Furthermore, DFO is able to increase both the extracellular as well as the total binding capacity to 0.63 and 3.67 fmol/microg cell protein, respectively, whereas it had no influence on Kd. B(max) at 37 degrees C after DFO preincubation was also increased from 0.90 to 2.31 fmol/microg cell protein. Other modulators had no significant influence on the TfR expression levels, though LPS increased cellular protein concentrations after 2-h preincubation.<br><br>CONCLUSIONS: The TfR is expressed on BCECs and actively endocytoses Tf, making it a suitable target for drug delivery to the bloodbrain barrier and the CNS. DFO up-regulates the TfR expression level, which may influence targeting efficiency.}, }
@article {pmid15175554, year = {2004}, author = {Shi, J and Wang, X and Qiu, J and Si, Q and Sun, R and Guo, H and Wu, Q}, title = {Roles of NF-kappaB and SP-1 in oxidative stress-mediated induction of platelet-derived growth factor-B by TNFalpha in human endothelial cells.}, journal = {Journal of cardiovascular pharmacology}, volume = {44}, number = {1}, pages = {26-34}, doi = {10.1097/00005344-200407000-00004}, pmid = {15175554}, issn = {0160-2446}, mesh = {Antineoplastic Agents/pharmacology ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Humans ; Muscle, Smooth, Vascular/*drug effects ; NF-kappa B/*pharmacology ; Oxidative Stress/*drug effects ; Podophyllin/*analogs &amp; derivatives/pharmacology ; Podophyllotoxin/analogs &amp; derivatives ; Proto-Oncogene Proteins c-sis/*metabolism ; Tumor Necrosis Factor-alpha/*pharmacology ; Umbilical Veins ; }, abstract = {Platelet-derived growth factor-B (PDGF-B) is upregulated by proinflamatory stimuli in the early stages of atherosclerosis. However, its mechanisms are not fully elucidated. In the present study, by using the antioxidant N-acetylcysteine (NAC), we investigated in human umbilical vein endothelial cells (HUVECs) the roles of oxidative stress in PDGF-B expression induced by tumor necrosis factor alpha (TNFalpha) and its underlying mechanisms. Exposure of HUVECs to TNFalpha (200 U/ml) for 24 hours caused significant increases of both the PDGF-B expression and its promoter/enhancer activity, which were abolished by NAC (20 mmol/L). Accordingly, a prolonged oxidative stress was induced by TNFalpha and that was prevented by pretreatment with NAC. Electrophoresis mobility shift assay (EMSA) and Western blot analysis showed that both the nuclear factor-kappaB (NF-kappaB) and the specificity protein-1 (SP-1) were activated by TNFalpha. However, NAC only partially inhibited the TNFalpha-induced activation of NF-kappaB, but abolished the activation of SP-1. Mutation of the NF-kappaB binding site resulted in a moderate reduction in the TNFalpha-induced activity of PDGF-B promoter/enhancer, whereas mutation of SP-1 binding site resulted in an absence of induction by TNFalpha. These results suggest that oxidative stress mediates the TNFalpha-induced expression of PDGF-B in HUVECs through redox-sensitive transcription factors, predominantly the SP-1 and possibly, to some extent of NF-kappaB.}, }
@article {pmid15169975, year = {2004}, author = {Kannan, M and Wang, L and Kang, YJ}, title = {Myocardial oxidative stress and toxicity induced by acute ethanol exposure in mice.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {229}, number = {6}, pages = {553-559}, doi = {10.1177/153537020422900614}, pmid = {15169975}, issn = {1535-3702}, support = {HL59225/HL/NHLBI NIH HHS/United States ; HL63760/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cardiomyopathy, Alcoholic/*metabolism ; Creatine Kinase/blood ; Cytosol/metabolism ; Ethanol/blood/*toxicity ; Female ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Lipid Peroxidation/drug effects/physiology ; Mice ; Mice, Inbred Strains ; Mitochondria/metabolism/pathology ; Myocardium/cytology/*metabolism/pathology ; Myocytes, Cardiac/drug effects/pathology/ultrastructure ; Oxidative Stress/*physiology ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Alcoholic cardiomyopathy has been known for a long time, but there is little mechanistic insight into this important clinical problem. The present study was undertaken using a mouse model to test the hypothesis that alcohol exposure induces cardiac injury through induction of oxidative stress. Adult female Friend Virius B-type (FVB) mice were treated with ethanol by gavage at a dose of 5 g/kg. Six hours after the treatment, ethanol-induced myocardial injury was observed, as indicated by a significant increase in serum creatine phosphokinase activity, a common biomarker of myocardial injury, and myocardial ultrastructural alterations, predominantly mitochondrial swelling and cristae disarray and reduction in numbers. The myocardial injury was associated with a significant increase in the myocardial lipid peroxidation, determined by measuring thiobarbituric acid reactive substances (TBARS), and a significant increase in protein oxidation as measured by a protein carbonyl content assay. Acute alcohol exposure decreased glutathione (GSH) content in the heart, more so in the mitochondria than in the cytosol. These alcohol-induced myocardial injuries and oxidative stresses were all significantly inhibited by supplementation with N-acetyl-L-cysteine (NAC) prior to alcohol exposure. However, NAC did not affect the rise in blood alcohol concentrations following alcohol exposure. This study thus demonstrates that acute alcohol administration causes myocardial injury through, at least in part, the induction of oxidative stress. A rapid decrease in mitochondrial GSH content may be partially responsible for the observed mitochondrial damage.}, }
@article {pmid15162071, year = {2004}, author = {Strijdom, H and Genade, S and Lochner, A}, title = {Nitric Oxide synthase (NOS) does not contribute to simulated ischaemic preconditioning in an isolated rat cardiomyocyte model.}, journal = {Cardiovascular drugs and therapy}, volume = {18}, number = {2}, pages = {99-112}, doi = {10.1023/B:CARD.0000029027.50796.84}, pmid = {15162071}, issn = {0920-3206}, mesh = {Animals ; Cyclic GMP/metabolism ; Enzyme Inhibitors/*pharmacology ; Ischemic Preconditioning/*methods ; Male ; Myocytes, Cardiac/*drug effects/metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide/biosynthesis/*physiology ; Nitric Oxide Synthase/antagonists &amp; inhibitors/*physiology ; Rats ; Rats, Wistar ; }, abstract = {UNLABELLED: It is widely accepted that nitric oxide (NO) is a trigger and mediator of late ischaemic preconditioning (IP), however its role in classic (protection observed within 2-4 hours after the IP stimulus) IP is less certain. In addition, the contribution of cardiomyocyte nitric oxide synthase (NOS) activation to NO production in ischaemia is unknown. The aim of this study was therefore to investigate the role of NOS, NO, reactive oxygen species (ROS) and cGMP in IP in an isolated cardiomyocyte model.<br><br>METHODS: Adult rat cardiomyocytes were isolated by collagenase perfusion. Hypoxia was induced by covering pelleted cardiomyocytes with mineral oil. The IP protocol was one 10 min hypoxia/20 min reoxygenation cycle, followed by 2 hr sustained hypoxia. Non-IP cells were subjected to 2 hr sustained hypoxia only. The contribution of NO was investigated by NOS inhibition (L-NAME 50 microM) or by pre-treatment of cells with a NO donor (SNP 100 microM), and that of ROS by inclusion of ROS scavengers (MPG and N-acetyl-cysteine) or pre-treatment with H(2)O(2). End-points were cellular cGMP content and cell viability as assessed by trypan blue exclusion (TBE) and cell morphology.<br><br>RESULTS: IP significantly improved myocyte viability (54% increase in TBE) at the end of sustained hypoxia. Treatment of cells with L-NAME and ROS scavengers during either the IP protocol or during sustained hypoxia had no effect on cell viability after 2 hr hypoxia, whereas viability of non-IP cells treated with L-NAME during sustained hypoxia improved significantly. cGMP levels were reduced in IP cells. Pre-treatment with SNP and H(2)O(2) did not mimic IP.<br><br>CONCLUSIONS: IP conferred cardioprotection in isolated cardiomyocytes. Protection in this model was not due to activation of cardiomyocyte NOS or ROS production. However, NOS activation induced by sustained hypoxia, appeared to be harmful to non-IP cells.}, }
@article {pmid15158790, year = {2004}, author = {Bickley, JF and Ciucci, A and Evans, P and Roberts, SM and Ross, N and Santoro, MG}, title = {Reactions of some cyclopentenones with selected cysteine derivatives and biological activities of the product thioethers.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {12}, number = {12}, pages = {3221-3227}, doi = {10.1016/j.bmc.2004.03.061}, pmid = {15158790}, issn = {0968-0896}, mesh = {Cyclopentanes/*chemistry ; Cysteine/*chemistry ; Gene Expression Regulation/drug effects ; Glutathione/chemistry ; HeLa Cells ; Humans ; Inhibitory Concentration 50 ; Lethal Dose 50 ; Methyl Ethers/chemistry ; Molecular Structure ; Sulfides/*chemistry/*pharmacology/toxicity ; }, abstract = {The conjugate addition reaction between glutathione, N-Boc-cysteine methyl ester, N-acetyl cysteine methyl ester and N-acetyl cysteine and several substituted cyclopentenones is described. The reversibility of this process was demonstrated by thio-adduct metathesis on treatment of the adduct with a different cysteinyl derivative. The levels at which these compounds inhibit the function of nuclear factor kappa B (NF-kappaB) and potentiate heat shock factor (HSF) are reported and the possible relevance of these studies concerning the antiviral and anti-inflammatory activities of the cyclopentenone prostanoids is discussed.}, }
@article {pmid15158123, year = {2004}, author = {Takeda, K and Lin, J and Okubo, S and Akazawa-Kudoh, S and Kajinami, K and Kanemitsu, S and Tsugawa, H and Kanda, T and Matsui, S and Takekoshi, N}, title = {Transient glucose deprivation causes upregulation of heme oxygenase-1 and cyclooxygenase-2 expression in cardiac fibroblasts.}, journal = {Journal of molecular and cellular cardiology}, volume = {36}, number = {6}, pages = {821-830}, doi = {10.1016/j.yjmcc.2004.03.008}, pmid = {15158123}, issn = {0022-2828}, mesh = {Alkaloids ; Animals ; Antioxidants/pharmacology ; Benzophenanthridines ; Cells, Cultured ; Cyclooxygenase 2 ; Enzyme Activation ; Fibroblasts/drug effects/enzymology/metabolism ; Glucose/*deficiency ; Heat-Shock Proteins/*genetics ; Heme Oxygenase (Decyclizing) ; Imidazoles/pharmacology ; Isoenzymes/*genetics ; Myocardium/*cytology/enzymology/*metabolism ; Oxygenases/*genetics ; Phenanthridines/pharmacology ; Prostaglandin-Endoperoxide Synthases/*genetics ; Protein Kinase C/antagonists &amp; inhibitors/metabolism ; Protein Transport/drug effects ; Pyridines/pharmacology ; RNA, Messenger/genetics/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; *Up-Regulation ; p38 Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Transient glucose deprivation (TGD) has been shown to induce a resistance to a subsequent ischemia and reperfusion injury in the heart. Induction of cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) is known to mediate the powerful defensive adaptation of the heart against oxidative stress. In this study, we found that a 30-min incubation in the absence of glucose resulted in a rapid increased expression of COX-2 and HO-1 in cardiac fibroblasts as examined by real-time quantitative polymerase chain reaction (PCR) and western blot analysis. Interestingly, TGD increased the generation of reactive oxygen species (ROS) and caused the transient phosphorylation of p38 mitogen-activated protein kinase (MAPK) as well as the translocation of protein kinase C (PKC)- from the cytosolic to the membrane fraction. However, no significant change in the distribution of PKC-delta isoform was observed compared with the control. Pretreatment of the cells with an antioxidant, N-acetylcysteine (NAC), resulted in the inhibition of p38 MAPK phosphorylation and PKC- translocation during TGD. In addition, the induction of COX-2 and HO-1 expression by TGD was prevented by pretreatment with NAC or SB203580, a p38 MAPK inhibitor. Surprisingly, pretreatment with chelerythrine, an inhibitor of PKC, strongly augmented the HO-1 mRNA expression but blocked the COX-2 mRNA induction by TGD. These results demonstrate that briefly removing glucose from cultured cardiac fibroblasts induces COX-2 and HO-1 expression via generation of ROS and p38 MAPK phosphorylation, while the translocation of PKC- to the membrane fraction may participate in the induction of COX-2 but not in the HO-1 expression.}, }
@article {pmid15157958, year = {2004}, author = {Duan, M and Qiu, J and Laurell, G and Olofsson, A and Counter, SA and Borg, E}, title = {Dose and time-dependent protection of the antioxidant N-L-acetylcysteine against impulse noise trauma.}, journal = {Hearing research}, volume = {192}, number = {1-2}, pages = {1-9}, doi = {10.1016/j.heares.2004.02.005}, pmid = {15157958}, issn = {0378-5955}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/*administration &amp; dosage ; Auditory Threshold/drug effects ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Hair Cells, Auditory, Inner/drug effects/pathology ; Hair Cells, Auditory, Outer/drug effects/pathology ; Hearing Loss, Noise-Induced/pathology/physiopathology/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Noise-induced hearing loss is one of the most common causes of hearing disability, and at present there is no effective biological protection or cure. Firearms and some industrial equipment can generate very high levels of impulse noise, which is known to cause sensorineural hearing loss. It has been shown that antioxidants such as N-L-acetylcysteine (NAC) can protect the inner ear from oxidative damage. The present study investigates whether NAC (i.p.) can protect the cochlea from impulse noise trauma. Rats were exposed to 50 noise pulses at 160 dB SPL peak value. Electrophysiological hearing thresholds were assessed with auditory brainstem response (ABR) up to 4 weeks after noise exposure. Animals exposed to impulse noise, without treatment of NAC, had larger threshold shifts in the frequency range 4-40 kHz than animals injected with NAC. Hair cell loss was significantly reduced using a schedule of three NAC injections in the rats. These results suggest that NAC can partially protect the cochlea against impulse noise trauma.}, }
@article {pmid15157676, year = {2004}, author = {Kitatani, K and Akiba, S and Sato, T}, title = {Ceramide-induced enhancement of secretory phospholipase A2 expression via generation of reactive oxygen species in tumor necrosis factor-alpha-stimulated mesangial cells.}, journal = {Cellular signalling}, volume = {16}, number = {8}, pages = {967-974}, doi = {10.1016/j.cellsig.2004.02.003}, pmid = {15157676}, issn = {0898-6568}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Ceramides/*pharmacology ; Cyclooxygenase 2 ; Glomerular Mesangium/drug effects/*enzymology ; NF-kappa B/metabolism ; Phospholipases A/*biosynthesis ; Phospholipases A2 ; Prostaglandin-Endoperoxide Synthases/*biosynthesis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sphingomyelin Phosphodiesterase/metabolism ; Sphingomyelins/metabolism ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Since prostanoids such as prostaglandin E2 play a pivotal role in modulating renal function, we investigated the involvement of ceramide in expression of secretory phospholipase A2 (sPLA2) and cyclooxygenase-2 (COX-2) in tumor necrosis factor-alpha (TNF-alpha)-stimulated mesangial cells. TNF-alpha stimulation increased ceramide generation in parallel with a decrease in sphingomyelin. Pretreatment with exogenous sphingomyelinase (SMase) dose-dependently enhanced TNF-alpha-stimulated increases in COX-2 protein and sPLA) activity. SMase also augmented TNF-alpha-mediated nuclear factor kappaB (NF-kappaB) activation. N-acetylcysteine (NAC), an antioxidant, completely inhibited the SMase-induced increase in sPLA2 activity, whereas NAC inhibited partially the activity stimulated with TNF-alpha alone. Under the conditions, NAC completely inhibited reactive oxygen species (ROS) production induced by SMase followed by TNF-alpha. These results suggest that ceramide elicits up-regulation of NF-kappaB through ROS production, which, in turn, leads to stimulation of COX-2 and sPLA2 expression. Therefore, ceramide may be implicated in the pathogenesis of renal abnormalities.}, }
@article {pmid15153235, year = {2004}, author = {Asfar, P and De Backer, D and Meier-Hellmann, A and Radermacher, P and Sakka, SG}, title = {Clinical review: influence of vasoactive and other therapies on intestinal and hepatic circulations in patients with septic shock.}, journal = {Critical care (London, England)}, volume = {8}, number = {3}, pages = {170-179}, pmid = {15153235}, issn = {1466-609X}, mesh = {Acetylcysteine/therapeutic use ; Fluid Therapy ; Hemodynamics/*physiology ; Humans ; Intestinal Mucosa/*blood supply ; Liver/*blood supply ; Multiple Organ Failure/physiopathology/prevention &amp; control ; Oxygen/blood ; Respiration, Artificial ; Shock, Septic/drug therapy/*physiopathology/*therapy ; Splanchnic Circulation/drug effects/*physiology ; Vasoconstrictor Agents/therapeutic use ; }, abstract = {The organs of the hepatosplanchnic system are considered to play a key role in the development of multiorgan failure during septic shock. Impaired oxygenation of the intestinal mucosa can lead to disruption of the intestinal barrier, which may promote a vicious cycle of inflammatory response, increased oxygen demand and inadequate oxygen supply. Standard septic shock therapy includes supportive treatment such as fluid resuscitation, administration of vasopressors (adrenergic and nonadrenergic drugs), and respiratory and renal support. These therapies may have beneficial or detrimental effects not only on systemic haemodynamics but also on splanchnic haemodynamics, at both the macrocirculatory and microcirculatory levels. This clinical review focuses on the splanchnic haemodynamic and metabolic effects of standard therapies used in patients with septic shock, as well as on the recently described nonconventional therapies such as vasopressin, prostacyclin and N-acetyl cysteine.}, }
@article {pmid15151648, year = {2004}, author = {Cakir, O and Oruc, A and Kaya, S and Eren, N and Yildiz, F and Erdinc, L}, title = {N-acetylcysteine reduces lung reperfusion injury after deep hypothermia and total circulatory arrest.}, journal = {Journal of cardiac surgery}, volume = {19}, number = {3}, pages = {221-225}, doi = {10.1111/j.0886-0440.2004.04059.x}, pmid = {15151648}, issn = {0886-0440}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Pressure/drug effects ; Cardiac Output/drug effects ; Cardiopulmonary Bypass ; Disease Models, Animal ; Dogs ; Female ; Free Radical Scavengers/*pharmacology ; *Heart Arrest, Induced ; Heart Rate/drug effects ; *Hypothermia, Induced ; Lung/metabolism/physiopathology ; Lung Compliance/drug effects ; *Lung Injury ; Male ; Malondialdehyde/metabolism ; Models, Cardiovascular ; Neutrophils/drug effects/metabolism ; Oxygen/metabolism ; Pulmonary Circulation/drug effects ; Reperfusion Injury/*therapy ; Vascular Resistance/drug effects ; }, abstract = {OBJECTIVE: We hypothesized that the use of N-acetylcysteine would ameliorate the lung reperfusion injury observed after deep hypothermia and total circulatory arrest (DHTSA).<br><br>METHODS: Experiments were carried out on 12 adult mongrel dogs of either sex weighing 25 to 30 kg. The animals were randomly divided into two groups of six animals each. All animals were cooled to an esophageal temperature of 15 degrees C during 30 minutes and underwent 60 minutes of DHTSA, followed by the reinstitution of cardiopulmonary bypass (CPB) and rewarming. Before rewarming, while 100 mL physiologic saline solution was added into the pump in group I, 50 mg/kg N-acetylcysteine(NAC) was given in group II. Heart rate, mean arterial pressure, pulmonary arterial pressure, left atrial pressure, central venous pressure, and cardiac output were recorded. To measure lung tissue malondialdehyde (MDA), water content and polymorphonuclear leukocytes (PMNs) count, lung tissue samples were taken before CPB and after weaning CPB. In addition, alveolar-arterial oxygen difference (AaDO(2))()for tissue oxygenation was calculated by obtaining arterial blood gas samples. Dynamic lung compliance (DLC) was measured before CPB and after CPB.<br><br>RESULTS: MDA levels before CPB of 44.2 +/- 3.9 nmol/g tissue rose to 76.6 +/- 5.6 nmol/g tissue after weaning CPB in group I (p = 0.004). In group II also, the MDA levels increased from 43.5 +/- 4.2 to 57.4 +/- 5.6 nmol MDA/g tissue after weaning CPB (p = 0.006). The MDA increase in group II after CPB was found to be significantly lower than in group I (p = 0.006). The wet-to-dry lung weight ratio in the NAC group was 5.1 +/- 0.2, significantly less than in the control group (5.9 +/- 0.3), (p = 0.004). AaDO(2) significantly increased in the group I and II (p = 0.002 and p = 0.002, respectively); this elevation in group I was significant than in group II (p = 0.044). In histopathological examination, it was observed that neutrophil counts in the lung parenchyma rose significantly after CPB in both groups (p < 0.001). The increase in group I was significantly larger than group II (p < 0.001).<br><br>CONCLUSIONS: Results represented in our study indicate that addition of NAC into the pump after DHTSA can reduce lung reperfusion injury.}, }
@article {pmid15150444, year = {2004}, author = {Kim, YS and Jhon, DY and Lee, KY}, title = {Involvement of ROS and JNK1 in selenite-induced apoptosis in Chang liver cells.}, journal = {Experimental &amp; molecular medicine}, volume = {36}, number = {2}, pages = {157-164}, doi = {10.1038/emm.2004.22}, pmid = {15150444}, issn = {1226-3613}, mesh = {Acetylcysteine/pharmacology ; Anthracenes/pharmacology ; Apoptosis/*drug effects ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line ; DNA Fragmentation/*drug effects ; Free Radical Scavengers/pharmacology ; Humans ; Liver/cytology/*metabolism ; Mitogen-Activated Protein Kinase 8/antagonists &amp; inhibitors/*metabolism ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Selenium/*pharmacology ; Signal Transduction/drug effects ; }, abstract = {Selenium is a dietary essential trace nutrient with important biological roles. Selenocompounds were reported to induce apoptosis in many types of tumor cells. In this study, we investigated the signaling pathway involved in the selenite-induced apoptosis using Chang liver cells as a non-malignant cell model. The Chang liver cell apoptosis induced by selenite (10 microM) was confirmed by DNA fragmentation and typical apoptotic nuclear changes. Treatment of selenite increased intracellular reactive oxygen species (ROS) level and c-Jun N-terminal kinase1 (JNK1) phosphorylation. The selenite-induced cell death was attenuated by SP600125, a specific inhibitor of JNK, and by dominant negative JNK1 (DN-JNK1). Antioxidants such as glutathione (GSH), N-acetyl cysteine (NAC), curcumin, epigallocatechin gallate (EGCG) and epicatechin (EC) inhibited selenite-induced intracellular ROS elevation and JNK1 phosphorylation. Our results suggest that selenite-induced apoptosis in Chang liver cells was preceded by the ROS generation and JNK1 activation.}, }
@article {pmid15149824, year = {2004}, author = {Abreo, K and Sella, M and Alvarez-Hernandez, X and Jain, S}, title = {Antioxidants prevent aluminum-induced toxicity in cultured hepatocytes.}, journal = {Journal of inorganic biochemistry}, volume = {98}, number = {6}, pages = {1129-1134}, doi = {10.1016/j.jinorgbio.2004.03.012}, pmid = {15149824}, issn = {0162-0134}, mesh = {Aluminum/*toxicity ; Animals ; Antioxidants/metabolism/*pharmacology ; Cell Proliferation/drug effects ; Hepatocytes/*metabolism/pathology ; Iron/metabolism ; Lipid Peroxidation/drug effects ; Mice ; Oxidative Stress/*drug effects ; }, abstract = {Cellular Al accumulation has been shown to alter iron metabolism and induce peroxidative injury. Therefore antioxidants could potentially reduce or prevent peroxidative injury in Al-loaded cells. To test this hypothesis we assessed the effect of the antioxidants N-acetyl cysteine (NAC), catalase, superoxide dismutase (SOD), and tetramethylpiperidine 1-oxyl (TEMPO) in abrogating Al-associated cell toxicity and melonyldialdehyde (MDA) accumulation in mouse hepatocytes. Mouse hepatocytes (MH) were grown in media containing the minimum toxic concentration of Al (100 microg/L as Al-transferrin). All antioxidants protected MH from injury as assessed by cell growth and enzyme leakage into media. The antioxidants did not affect Al uptake by MH, protect MH from lipid peroxidation or decrease the reactive iron content of MH. Although antioxidants protected Al loaded MH from injury the mechanisms of this effect are unknown.}, }
@article {pmid15149341, year = {2004}, author = {Agarwal, R and Vasavada, N and Sachs, NG and Chase, S}, title = {Oxidative stress and renal injury with intravenous iron in patients with chronic kidney disease.}, journal = {Kidney international}, volume = {65}, number = {6}, pages = {2279-2289}, doi = {10.1111/j.1523-1755.2004.00648.x}, pmid = {15149341}, issn = {0085-2538}, mesh = {Acetylcysteine/pharmacology ; Aged ; Aged, 80 and over ; Free Radical Scavengers/pharmacology ; Humans ; Infusions, Intravenous ; Iron/administration &amp; dosage/*adverse effects ; Kidney/*drug effects/*injuries ; Kidney Failure, Chronic/*drug therapy/metabolism ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Models, Biological ; Oxidative Stress/*drug effects ; Transferrin/metabolism ; }, abstract = {BACKGROUND: Intravenous iron is widely prescribed in patients with chronic kidney disease (CKD) and can cause oxidative stress. The relationship of oxidative stress and renal injury in patients with CKD is unknown. Whether renal injury can occur at a time point when transferrin is incompletely saturated is also unclear.<br><br>METHODS: We conducted a randomized, open-label, parallel group trial to compare the oxidative stress induced by intravenous administration of 100 mg iron sucrose over 5 minutes and its protection with N-acetylcysteine (NAC) in 20 subjects with stage 3 or 4 CKD. Transferrin saturation was measured with urea polyacrylamide gel electrophoresis, oxidative stress by malondialdehyde (MDA) measurement by high-performance liquid chromatography, and renal injury by enzymuria and proteinuria. Reduced and oxidized glutathione and free radical scavengers as well as urinary monocyte chemoattractant protein-1 were also measured.<br><br>RESULTS: Parenteral iron increased plasma concentration and urinary excretion rate of MDA, a biomarker of lipid peroxidation, within 15 to 30 minutes of iron sucrose administration. This was accompanied by enzymuria and increase in proteinuria. In contrast, saturation of transferrin was not maximally seen until 3 hours after the end of infusion. Oxidative stress, enzymuria and proteinuria were transient and were completely resolved in 24 hours. NAC reduced acute generation of systemic oxidative stress but failed to abrogate proteinuria or enzymuria.<br><br>CONCLUSION: Intravenous iron produces oxidative stress that is associated with transient proteinuria and tubular damage. The rapid production of oxidative stress even when transferrin is not completely saturation suggests free iron independent mechanism(s) to be operative in producing oxidative stress and transient renal injury. Long-term implications of these findings need further study.}, }
@article {pmid15145276, year = {2004}, author = {Kilic-Okman, T and Kucuk, M}, title = {N-acetyl-cysteine treatment for polycystic ovary syndrome.}, journal = {International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics}, volume = {85}, number = {3}, pages = {296-297}, doi = {10.1016/j.ijgo.2004.03.002}, pmid = {15145276}, issn = {0020-7292}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Humans ; Insulin Resistance ; Polycystic Ovary Syndrome/*drug therapy ; Prospective Studies ; }, }
@article {pmid15139008, year = {2004}, author = {Park, J and Choi, K and Jeong, E and Kwon, D and Benveniste, EN and Choi, C}, title = {Reactive oxygen species mediate chloroquine-induced expression of chemokines by human astroglial cells.}, journal = {Glia}, volume = {47}, number = {1}, pages = {9-20}, doi = {10.1002/glia.20017}, pmid = {15139008}, issn = {0894-1491}, support = {CA97247/CA/NCI NIH HHS/United States ; MH63650/MH/NIMH NIH HHS/United States ; NS29719/NS/NINDS NIH HHS/United States ; NS36765/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Astrocytes/*drug effects/metabolism ; Biphenyl Compounds/pharmacology ; Cells, Cultured ; Chemokines/genetics/*metabolism ; Chloroquine/*adverse effects ; Dose-Response Relationship, Drug ; Encephalitis/chemically induced/metabolism ; Humans ; Inflammation Mediators/*pharmacology ; Leupeptins/pharmacology ; NF-kappa B/drug effects/metabolism ; Onium Compounds/pharmacology ; RNA, Messenger/drug effects/metabolism ; Reaction Time/drug effects/physiology ; Reactive Oxygen Species/*metabolism ; Tosylphenylalanyl Chloromethyl Ketone/pharmacology ; }, abstract = {We have previously demonstrated that chloroquine may evoke inflammatory responses in the central nervous system by inducing expression of pro-inflammatory cytokines by astroglial cells. In this study, we further examined the molecular mechanism responsible for chloroquine-induced activation of NF-kappaB and subsequent expression of chemokines by astroglial cells. We observed that (1) chloroquine induced expression of chemokines such as CCL2 and CXCL8 in a dose- and time-dependent manner in human astroglial cells; (2) other lysosomotropic agents such as ammonium chloride and bafilomycin A1 had minimal effects on chemokine expression; (3) inhibition of NF-kappaB by MG-132 and TPCK suppressed chloroquine-induced mRNA expression of chemokines; (4) chloroquine increased the intracellular level of reactive oxygen species (ROS) in a dose- and time-dependent manner by human astroglial cells, but not by monocytic/microglial cells; (5) chloroquine-induced increase of intracellular ROS level was suppressed by pre-incubation with diphenyl iodonium (DPI) and N-acetyl cysteine (NAC); and (6) inhibition of chloroquine-induced ROS production by DPI or NAC suppressed chloroquine-mediated activation of NF-kappaB and subsequent mRNA expression of chemokines in astroglial cells. These results collectively suggest that chloroquine generates ROS, which is responsible for NF-kappaB activation and subsequent expression of pro-inflammatory chemokines in human astroglial cells.}, }
@article {pmid15133752, year = {2004}, author = {Takatori, A and Ishii, Y and Itagaki, S and Kyuwa, S and Yoshikawa, Y}, title = {Amelioration of the beta-cell dysfunction in diabetic APA hamsters by antioxidants and AGE inhibitor treatments.}, journal = {Diabetes/metabolism research and reviews}, volume = {20}, number = {3}, pages = {211-218}, doi = {10.1002/dmrr.428}, pmid = {15133752}, issn = {1520-7552}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antioxidants/*administration &amp; dosage ; Biomarkers/analysis ; Blood Glucose/analysis ; Cell Division ; Cricetinae ; Diabetes Mellitus, Experimental/*physiopathology ; Glucose Tolerance Test ; Glycation End Products, Advanced/*antagonists &amp; inhibitors ; Guanidines/administration &amp; dosage ; Immunohistochemistry ; Islets of Langerhans/*drug effects/pathology/*physiopathology ; Male ; Oxidative Stress ; Pancreatitis-Associated Proteins ; Pyridoxamine/administration &amp; dosage ; Serum Albumin/analysis ; Glycated Serum Albumin ; }, abstract = {BACKGROUND: In our recent report, probucol treatment ameliorated glucose intolerance and increased the insulin-positive area in the pancreas of streptozotocin (SZ)-induced diabetic APA hamsters. The data suggested that the beneficial effects of probucol treatment on beta-cell function might result from its additive effect as an antioxidant. Here, we examined the antioxidant effects on the beta-cell function in SZ-induced diabetic APA hamsters treated with three different agents, N-acetyl-L-cysteine (NAC), aminoguanidine (AG) and pyridoxamine (PM).<br><br>METHODS: The control (CB group) and diabetic (SZ group) hamsters were treated with NAC, AG or PM for four weeks from several days after SZ injection.<br><br>RESULTS: Non-fasting plasma glucose and glycoalbumin levels were significantly reduced in SZ animals by NAC or PM treatment. Glucose tolerance test revealed that fasting plasma glucose levels of SZNAC and SZPM animals were low, similar to the corresponding control animals. Thirty minutes after glucose injection, amelioration in the plasma glucose levels of SZNAC and SZPM animals was observed. Immunohistochemistry revealed that the pancreata of SZNAC, SZAG and SZPM animals showed significantly higher percentages of insulin-positive area than those of non-treated SZ animals. The plasma 8OHdG and malondialdehyde plus 4-hydroxy-2-nonenal (4HNE) levels were significantly decreased especially in SZNAC and SZPM animals. 4HNE-positive cells stained by anti-4HNE antibody were reduced in the islets of each agent-treated animal. SZNAC and SZPM animals showed significantly increased beta-cell proliferation determined by insulin and BrdU double staining. All SZ groups treated with NAC, AG or PM had the high expression levels of Reg and INGAP, which are known to be expressed in regenerating islets.<br><br>CONCLUSIONS: These data suggest that NAC and PM treatment of SZ-injected diabetic hamsters reduces oxidative stress and restores beta-cell function, but that AG treatment has little beneficial effect on the diabetic conditions of SZ-injected hamsters.}, }
@article {pmid15131064, year = {2004}, author = {Stanziale, SF and Petrowsky, H and Adusumilli, PS and Ben-Porat, L and Gonen, M and Fong, Y}, title = {Infection with oncolytic herpes simplex virus-1 induces apoptosis in neighboring human cancer cells: a potential target to increase anticancer activity.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {10}, number = {9}, pages = {3225-3232}, doi = {10.1158/1078-0432.ccr-1083-3}, pmid = {15131064}, issn = {1078-0432}, support = {R01 CA61524/CA/NCI NIH HHS/United States ; R01 CA72632/CA/NCI NIH HHS/United States ; R01 CA75416/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Cell Line, Tumor ; Flow Cytometry ; Gastrointestinal Neoplasms/pathology/prevention &amp; control/virology ; Gene Expression/drug effects ; Green Fluorescent Proteins ; Herpesvirus 1, Human/genetics/*growth &amp; development ; Humans ; In Situ Nick-End Labeling ; Luminescent Proteins/genetics/metabolism ; }, abstract = {PURPOSE: The antitumor efficacy of a herpes simplex virus (HSV)-1 oncolytic virus depends on the cytotoxic effect of the virus, but also on viral replication and spread within the tumor. Apoptosis is considered a defense mechanism of infected cells that minimizes the spread of viral progeny by limiting cellular production of virus. We sought to determine whether oncolytic HSV-1 infection induces apoptosis in neighboring, uninfected cells and whether manipulation of apoptosis can increase viral replication and cytotoxicity.<br><br>EXPERIMENTAL DESIGN: NV1066 is an oncolytic HSV-1 mutant that contains the marker gene for enhanced green fluorescent protein. OCUM human gastric cancer cells were infected with NV1066 in vitro and inspected for apoptosis by Hoechst and terminal deoxynucleotidyltransferase-mediated nick end labeling staining and for infection by expression of green fluorescence.<br><br>RESULTS: A significant increase in apoptosis was seen in cells infected by NV1066. More interestingly, a significant percentage (10%) of uninfected cells also proceeded to apoptosis. After NV1066 infection, cells were also treated with N-acetylcysteine (NAC), an inhibitor of apoptosis. By day 4 after infection, 2.7x more NV1066 was produced in cells exposed to NAC than in those not exposed to NV1066 (P = 0.04). NAC also increased tumor kill when administered with virus.<br><br>CONCLUSIONS: These data suggest that NV1066 induces apoptosis in uninfected cocultured cells, potentially hindering propagation of viral progeny and concomitant tumor kill. Inhibition of apoptosis may improve the efficacy of oncolytic HSV-1 therapy.}, }
@article {pmid15128912, year = {2004}, author = {Ahola, T and Fellman, V and Kjellmer, I and Raivio, KO and Lapatto, R}, title = {Plasma 8-isoprostane is increased in preterm infants who develop bronchopulmonary dysplasia or periventricular leukomalacia.}, journal = {Pediatric research}, volume = {56}, number = {1}, pages = {88-93}, doi = {10.1203/01.PDR.0000130478.05324.9D}, pmid = {15128912}, issn = {0031-3998}, mesh = {Biomarkers ; Bronchopulmonary Dysplasia/diagnosis/*metabolism ; Dehydroascorbic Acid/*analogs &amp; derivatives/blood ; Dinoprost/*analogs &amp; derivatives/*blood ; Female ; Humans ; Infant, Newborn ; Infant, Premature/*metabolism ; Leukomalacia, Periventricular/diagnosis/*metabolism ; Male ; Oxidative Stress ; }, abstract = {Our aim was to assess the plasma free 8-epi-prostaglandin F(2alpha) (8-isoprostane) and ascorbyl radical as risk indicators for oxidative damage in extremely low birth weight infants (ELBWIs) and the effect of N-acetylcysteine (NAC) on these markers. Plasma samples were collected on days 3 and 7 of life from infants who were enrolled in a randomized, controlled trial in which i.v. NAC or placebo was administered to ELBWIs during the first week of life, with the aim of preventing bronchopulmonary dysplasia (BPD). Plasma 8-isoprostane was analyzed in 83 infants using an enzyme immunoassay kit. Ascorbyl radical concentration was measured in 61 infants with electron spin resonance spectroscopy. The 8-isoprostane concentrations were similar in the NAC and placebo groups. In infants who later developed BPD or died (n = 29), the median (range) 8-isoprostane concentration was significantly higher (p = 0.001) on day 3 and day 7 [50.0 pg/mL (19-360) and 57.0 pg/mL (14-460), respectively] than in survivors without BPD [n = 54; 34.5 pg/mL (5-240) and 39.5 pg/mL (7-400), respectively]. The 8-isoprostane levels increased significantly more (p < 0.05) in infants who later developed periventricular leukomalacia. NAC treatment or the later development of BPD was not related to the ascorbyl radical levels. The ascorbyl radical level decreased significantly in all groups from day 3 to day 7, but the difference between the groups was not significant. The mean (SD) ascorbyl radical level on day 3 was significantly higher (p < 0.01) in infants who later developed periventricular leukomalacia [287 (124) versus 194 (90)]. These data suggest that plasma 8-isoprostane could serve as a marker in assessing the risk for BPD development in ELBWIs.}, }
@article {pmid15128133, year = {2004}, author = {Zhang, C and Sheng, ZY and Hu, S and Gao, JC and Li, JY and Liu, Y}, title = {The role of oxygen-free radical in the apoptosis of enterocytes in scalded rats after delayed resuscitation.}, journal = {The Journal of trauma}, volume = {56}, number = {3}, pages = {611-617}, doi = {10.1097/01.ta.0000085128.59895.a2}, pmid = {15128133}, issn = {0022-5282}, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Animals ; Apoptosis/*physiology ; Burns/*physiopathology ; DNA Fragmentation ; Enterocytes/*physiology ; Glutathione/metabolism ; Ilium/blood supply ; In Situ Nick-End Labeling ; Intestinal Mucosa/blood supply ; Male ; Oxidative Stress/physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Reperfusion Injury/physiopathology ; *Resuscitation ; Shock/physiopathology ; Xanthine Oxidase/metabolism ; }, abstract = {BACKGROUND: This study aimed to evaluate the relation between apoptosis of enterocytes and oxygen-free radical injury in scalded rats with delayed resuscitation as well as the role of antioxidants in the prevention of enterocyte apoptosis.<br><br>METHODS: For this study, 150 male Wistar rats were divided randomly into four groups representing early resuscitation (ER), delayed resuscitation (DR), N-acetylcysteine (NAC) treatment, and allopurinol (Allo) treatment. The animals were subjected to a 30% total body surface area, full-thickness scald. Fluid therapy was started 6 hours after the injury in the DR and treatment groups. Apoptosis of enterocytes was identified by DNA fragmentation (ap%), DNA agarose gel electrophoresis, and terminal deoxynucleotidyl transferace (TdT)-mediated dUPT-biotin nick end labeling (TUNEL). The contents of malondialdehyde (MDA), total sulfhydryl (TSH), and nonprotein sulfhydryl (NPSH) and the activity of xanthine oxidase in intestinal mucosa were determined after the burn in the four groups.<br><br>RESULTS: Apoptosis of enterocytes increased significantly in all the groups. The animals in the DR group showed an earlier and greater increase in ap% than the animals in the ER group. Similar results were seen for electrophoresis, TUNEL assay, and levels of MDA, xanthine oxidase (XO), TSH, and NPSH. Treatment with NAC was associated with a decrease in ap% and MDA, but not XO, as compared with the levels in the DR group, whereas treatment with Allo was associated with a decrease in MDA and XO, but not ap%. Delayed resuscitation was associated with significant decreases in TSH and NPSH, as compared with the levels in the ER group, whereas both the NAC and Allo groups had significantly higher levels of TSH and NPSH than the DR group.<br><br>CONCLUSIONS: Significant apoptosis of enterocytes was induced by oxidative stress in the intestinal mucosa after a burn in rats. The findings show that NAC blunted intestinal apoptosis induced by oxygen-free radical, which was generated in the process of ischemia-reperfusion injury after a burn because of delayed resuscitation.}, }
@article {pmid15124904, year = {2004}, author = {Kim, YM and Kim, HJ and Song, EJ and Lee, KJ}, title = {Glucuronic acid is a novel inducer of heat shock response.}, journal = {Molecular and cellular biochemistry}, volume = {259}, number = {1-2}, pages = {23-33}, pmid = {15124904}, issn = {0300-8177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Annexin A3/metabolism ; Apoptosis/drug effects/*physiology ; Calreticulin/metabolism ; Cell Line ; Enzyme Activation/drug effects/physiology ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Glucuronic Acid/*pharmacology ; HSP70 Heat-Shock Proteins/*biosynthesis ; HSP90 Heat-Shock Proteins/metabolism ; Heat-Shock Response/*drug effects ; Hydrogen Peroxide/pharmacology ; Mice ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Onium Compounds/pharmacology ; Oxidative Stress/drug effects/*physiology ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Thioredoxins/metabolism ; Tubulin/metabolism ; Vimentin/metabolism ; rac1 GTP-Binding Protein/metabolism ; }, abstract = {The elevated expression of 70 kDa heat shock protein (Hsp70) induces resistance to stress-induced apoptosis. We have screened a variety of natural products for their ability to enhance Hsp70 expression as anti-apoptotic agent. We found that glucuronic acid (GA) induced the synthesis of Hsp70 and that cells pretreated with GA were significantly tolerant to stress including heat shock and hydrogen peroxide. We also found that GA induces the production of reactive oxygen species (ROS), a process inhibited by NADPH oxidase inhibitor, diphenyleneiodonium chloride (DPI) and antioxidant N-acetylcysteine (NAC). GA-induced ROS production was also inhibited in RacN17 cell line overexpressing a dominant negative mutant of Rac1. Furthermore, GA treatment induces MAPKs activation (SAPK/JNK and p38) and Hsp70 expression in ROS dependent manner, suggesting that GA turns on the signaling pathway by generation of ROS through Rac1. We analyzed the profiles of newly synthesized proteins by GA with 2-dimensional gel electrophoresis and MALDI-TOF MS and found that two families of proteins were expressed by GA. One was similar to the protein family synthesized by heat shock (Hsp70, Hsp73, Hsp65, Hsp90, vimentin, tubulin, Ras homolog); and the other was a family of protein specific to GA (calreticulin, annexin III, thioredoxin peroxidase). These results suggest that GA-induced stress responses are mediated by ROS generation and are similar, in part, to heat shock-induced responses and GA can be possibly adopted for the protecting agent from cell death.}, }
@article {pmid15123225, year = {2004}, author = {Szkudlarek, U and Zdziechowski, A and Witkowski, K and Kasielski, M and Luczyńska, M and Luczyński, R and Sarniak, A and Nowak, D}, title = {Effect of inhaled N-acetylcysteine on hydrogen peroxide exhalation in healthy subjects.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {17}, number = {3}, pages = {155-162}, doi = {10.1016/j.pupt.2004.01.007}, pmid = {15123225}, issn = {1094-5539}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Inhalation ; Adult ; Antioxidants/administration &amp; dosage/*pharmacology ; Breath Tests ; Exhalation ; Female ; Humans ; Hydrogen Peroxide/*metabolism ; Male ; }, abstract = {N-acetylcysteine (NAC) has antioxidant properties and its oral administration decreased H(2)O(2) exhalation in patients with chronic obstructive pulmonary disease. In this study we tested whether inhaled NAC could suppress H(2)O(2) levels in exhaled breath condensate (EBC) of eight healthy subjects that have never smoked (never-smokers). Original NAC solution (ACC vial, 300 mg NAC in 3 ml solvent), NAC-placebo (vehicle), sterile 0.9% NaCl or distilled water were nebulized via the pneumatic De Vilbiss nebulizer once daily every 7 days and H(2)O(2) and thiols exhalation was measured just before, 30 min and 3 h after the end of drug administration. Additional in vitro experiments were performed to evaluate NAC stability during nebulization, reactivity with H(2)O(2) and possible H(2)O(2) generation in aqueous NAC solutions. NAC almost completely abolished H(2)O(2) exhalation 30 min after inhalation (0.02+/-0.04 vs. 0.21+/-0.09 microM, p<0.001). However, 3 h later the H(2)O(2) levels raised 1.8-fold from baseline (p<0.01). Other inhaled solutions did not affect H(2)O(2) levels. Mean thiol concentration in EBC rose (p<0.05) after treatment with NAC and reached 1.03+/-0.48 microM at 3 h. Although, 25 and 50 mM NAC completely inhibited H(2)O(2)-peroxidase-luminol-dependent chemiluminescence, detectable amounts of H(2)O(2) were generated in NAC solutions. It was accompanied by moderate loss of -SH groups. Catalase and ascorbic acid prevented H(2)O(2) formation in NAC solutions. In conclusion inhaled NAC revealed biphasic effect on H(2)O(2) exhalation in healthy subjects, which depends on direct H(2)O(2) scavenging and H(2)O(2) generation related to drug oxidation. The net result of these processes may determine anti- or pro-oxidant action of inhaled NAC.}, }
@article {pmid15122756, year = {2004}, author = {Laurent, A and Nicco, C and Tran Van Nhieu, J and Borderie, D and Chéreau, C and Conti, F and Jaffray, P and Soubrane, O and Calmus, Y and Weill, B and Batteux, F}, title = {Pivotal role of superoxide anion and beneficial effect of antioxidant molecules in murine steatohepatitis.}, journal = {Hepatology (Baltimore, Md.)}, volume = {39}, number = {5}, pages = {1277-1285}, doi = {10.1002/hep.20177}, pmid = {15122756}, issn = {0270-9139}, mesh = {Animals ; Antioxidants/metabolism/*pharmacology ; Biomarkers ; Body Weight/drug effects ; Caspase 3 ; Caspases/metabolism ; Cytochromes c/metabolism ; Fatty Liver/*drug therapy/*metabolism/pathology ; Lipid Peroxidation/drug effects/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Mitochondria, Liver/metabolism ; Nitric Oxide/metabolism ; Superoxide Dismutase/metabolism ; Superoxides/*metabolism ; }, abstract = {Nonalcoholic fatty liver disease, frequently associated with obesity, can lead to nonalcoholic steatohepatitis (NASH) and cirrhosis. The pathophysiology of NASH is poorly understood, and no effective treatment is available. In view of a potential deleterious role for reactive oxygen species (ROS), we investigated the origin of ROS overproduction in NASH. Mitochondrial production of ROS and its alterations in the presence of antioxidant molecules were studied in livers from ob/ob mice that bear a mutation of the leptin gene and develop experimental NASH. N-acetyl-cysteine and the superoxide dismutase (SOD) mimics ambroxol, manganese [III] tetrakis (5,10,15,20 benzoic acid) (MnTBAP), and copper [II] diisopropyl salicylate (CuDIPS) were used to target different checkpoints of the oxidative cascade to determine the pathways involved in ROS production. Liver mitochondria from ob/ob mice generated more O(2)*- than those of lean littermates (P <.01). Ex vivo, all three SOD mimics decreased O(2)*- generation (P <.001) and totally inhibited lipid peroxidation (P <.001) versus untreated ob/ob mice. Those modifications were associated with in vivo improvements: MnTBAP and CuDIPS reduced weight (P <.02) and limited the extension of histological liver steatosis by 30% and 52%, respectively, versus untreated ob/ob mice. In conclusion, these data demonstrate deleterious effects of superoxide anions in NASH and point at the potential interest of nonpeptidyl mimics of SOD in the treatment of NASH in humans.}, }
@article {pmid15122653, year = {2004}, author = {Bellei, E and Rota, C and Bergamini, S and Manfredini, P and Albertazzi, A and Tomasi, A and Iannone, A}, title = {Effect of alpha-tocopherol and N-acetylcysteine on benzoyl peroxide toxicity in human keratinocytes.}, journal = {Journal of biochemical and molecular toxicology}, volume = {18}, number = {2}, pages = {107-114}, doi = {10.1002/jbt.20008}, pmid = {15122653}, issn = {1095-6670}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Benzoyl Peroxide/*toxicity ; Cell Line ; Cell Membrane/metabolism ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Humans ; Keratinocytes/*drug effects/metabolism ; Mice ; alpha-Tocopherol/metabolism/*pharmacology ; }, abstract = {Benzoyl peroxide is a free-radical generating compound widely used in the polymer industry and also in pharmaceuticals as antimicrobial agent to treat acne. However, benzoyl peroxide causes irritation and contact dermatitis in about 1% of patients. Concern over the use of this compound is motivated by the demonstration that it can also act as skin tumor promoter in mice. In addition, benzoyl peroxide induces DNA strand breaks in many cells, including keratinocytes. Benzoyl peroxide toxicity is presumably mediated by the formation of reactive free radicals and by the consumption of intracellular antioxidants. In this work we investigated the effect of both the lipophilic antioxidant alpha-tocopherol and the hydrophilic thiol donor N-acetylcysteine (NAC) in human keratinocyte line HaCaT exposed to benzoyl peroxide. A protective effect against benzoyl peroxide cytotoxicity was achieved when cells were grown on a alpha-tocopherol layer. On the contrary, the addition of alpha-tocopherol dissolved in ethanol had a pro-oxidant effect, leading to an enhancement of benzoyl peroxide toxicity. Cytotoxicity was also reduced adding NAC to the culture medium; the presence of both NAC and alpha-tocopherol exerts a synergistic cytoprotection.}, }
@article {pmid15120578, year = {2004}, author = {Molina-Jiménez, MF and Sánchez-Reus, MI and Andres, D and Cascales, M and Benedi, J}, title = {Neuroprotective effect of fraxetin and myricetin against rotenone-induced apoptosis in neuroblastoma cells.}, journal = {Brain research}, volume = {1009}, number = {1-2}, pages = {9-16}, doi = {10.1016/j.brainres.2004.02.065}, pmid = {15120578}, issn = {0006-8993}, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; *Apoptosis ; Blotting, Southern/methods ; Cell Line, Tumor ; Cell Survival/drug effects ; Coumarins/*pharmacology ; DNA/metabolism ; Dose-Response Relationship, Drug ; Ethidium/*analogs &amp; derivatives/metabolism ; Flavonoids/*pharmacology ; Fluoresceins/metabolism ; Glutathione/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Microscopy, Confocal/methods ; Neuroblastoma/pathology ; Neuroprotective Agents/*pharmacology ; Reactive Oxygen Species/metabolism ; Rotenone/*analogs &amp; derivatives/*antagonists &amp; inhibitors ; Time Factors ; }, abstract = {Rotenone-induced apoptosis is considered to contribute to the etiology of Parkinson's disease (PD). We try to prevent the apoptosis induced by rotenone toxicity with 50 microM myricetin, 100 microM fraxetin and 100 microM N-acetylcysteine (NAC) that protect against reactive oxygen species (ROS), on SH-SY5Y human neuroblastoma cell line. Morphological changes induced by rotenone and intracellular ROS were assessed in live SH-SY5Y dopaminergic cells by confocal microscopy using the fluorescent dyes, dihydroethidium and 2',7'-dichlorofluorescein diacetate (DCFH-DA). DNA fragmentation was assayed as index of apoptosis. We also investigated oxidative stress parameters such as the glutathione redox status and lipid peroxidation. The exposure of the SH-SY5Y cells to rotenone 5 microM for 16 h produced severe morphological changes, DNA fragmentation and significative increases in the levels of hydrogen peroxide and superoxide anion. These increases were reduced by a 30-min pretreatment with fraxetin 100 microM or NAC 100 microM. DNA laddering produced by rotenone treatment was also inhibited by fraxetin and NAC. Treatment with 5 microM rotenone induced loss of reduced glutathione (GSH) and increased cellular levels of oxidized glutathione (GSSG). Fraxetin and NAC treatments restored glutathione redox ratio diminished after rotenone challenge and decreased the levels of lipid peroxidation. These results suggest that the natural antioxidants, such as fraxetin, may prevent the apoptotic death of dopaminergic cells induced by rotenone and mediated by oxidative stress.}, }
@article {pmid15118249, year = {2004}, author = {Sugino, N and Karube-Harada, A and Taketani, T and Sakata, A and Nakamura, Y}, title = {Withdrawal of ovarian steroids stimulates prostaglandin F2alpha production through nuclear factor-kappaB activation via oxygen radicals in human endometrial stromal cells: potential relevance to menstruation.}, journal = {The Journal of reproduction and development}, volume = {50}, number = {2}, pages = {215-225}, doi = {10.1262/jrd.50.215}, pmid = {15118249}, issn = {0916-8818}, mesh = {Acetylcysteine/metabolism/pharmacology ; Adult ; Antioxidants/pharmacology ; Cells, Cultured ; Cyclooxygenase 2 ; Cysteine Endopeptidases ; Dinoprost/*metabolism ; Endometrium/pathology ; Enzyme Activation ; Estradiol/metabolism ; Female ; Free Radicals ; Humans ; Isoenzymes/metabolism ; Leupeptins/pharmacology ; Medroxyprogesterone Acetate/metabolism ; Membrane Proteins ; Menstruation ; Multienzyme Complexes/antagonists &amp; inhibitors ; NF-kappa B/*metabolism ; Ovary/cytology/*metabolism ; Oxygen/*metabolism ; Progesterone/metabolism ; Prostaglandin-Endoperoxide Synthases/metabolism ; Proteasome Endopeptidase Complex ; RNA/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species ; Reverse Transcriptase Polymerase Chain Reaction ; Steroids/*physiology ; Stromal Cells/*cytology ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; Time Factors ; }, abstract = {The present study was undertaken to investigate whether withdrawal of estrogen and progesterone (EP-withdrawal) stimulates prostaglandin F2alpha (PGF2alpha) production through oxygen radical (ROS)-induced NF-kappaB activation in human endometrial stromal cells (ESC). To study the EP-withdrawal, ESC that had been treated with estradiol (E, 10(-8) M) and medroxyprogesterone acetate (MPA, 10(-6) M) for 12 days were then incubated with or without E+MPA for a further 11 days. PGF2alpha concentrations in the medium and cyclooxygenase-2 (COX-2) mRNA levels were significantly increased after EP-withdrawal, while they were unchanged by the continuous treatment with E+MPA. When ESC were incubated with N-acetyl-L-cysteine (Nac, 50 mM), an antioxidant, during EP-withdrawal, Nac blocked the increases in PGF2alpha production and COX-2 mRNA expression caused by EP-withdrawal. Next, we examined whether ROS generated in response to EP-withdrawal acted through NF-kappaB activation. Electrophoretic mobility shift assay revealed that EP-withdrawal caused marked increases in NF-kappaB DNA binding activity, which was completely suppressed by Nac. Furthermore, when ESC were incubated with MG132 (3 microM), which inhibits NF-kappaB activation, during EP-withdrawal, MG132 blocked the increases in PGF2alpha production and COX-2 mRNA expression caused by EP-withdrawal. In conclusion, EP-withdrawal stimulates COX-2 expression and PGF2alpha production through ROS-induced NF-kappaB activation, suggesting a possible mechanism for menstruation.}, }
@article {pmid15115886, year = {2004}, author = {Bajt, ML and Knight, TR and Lemasters, JJ and Jaeschke, H}, title = {Acetaminophen-induced oxidant stress and cell injury in cultured mouse hepatocytes: protection by N-acetyl cysteine.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {80}, number = {2}, pages = {343-349}, doi = {10.1093/toxsci/kfh151}, pmid = {15115886}, issn = {1096-6080}, support = {P01DK059349/DK/NIDDK NIH HHS/United States ; R01AA009156/AA/NIAAA NIH HHS/United States ; R01AA12916/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetaminophen/*antagonists &amp; inhibitors/*toxicity ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Cell Separation ; Cell Survival/drug effects ; Cells, Cultured ; Fluoresceins ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Hepatocytes/*drug effects/metabolism ; L-Lactate Dehydrogenase/metabolism ; Male ; Mice ; Mice, Inbred C3H ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Tetrazolium Salts ; Trypan Blue ; }, abstract = {The increase in cellular and mitochondrial glutathione disulfide (GSSG) levels and the GSSG:GSH ratio after acetaminophen (AAP) overdose suggest the involvement of an oxidant stress in the pathophysiology. However, the initial severe depletion of hepatocellular glutathione makes quantitative assessment of the oxidant stress difficult. Therefore, we tested the hypothesis that oxidant stress precedes the onset of cell injury in a cell culture model using 2',7'-dichlorofluorescein (DCF) fluorescence as a marker for intracellular oxidant stress. Cultured primary murine hepatocytes were exposed to 5 mM AAP. DCF fluorescence, XTT reduction, lactate dehydrogenase (LDH) release, and trypan blue uptake were determined from 0 to 12 h. After glutathione depletion at 3 h, DCF fluorescence increased by 16-fold and was maintained at that level up to 12 h. At 1.5 h after AAP, a significant decrease of the cellular XTT reduction capacity was observed, which continued to decline until 9 h. Cell necrosis (LDH release, trypan blue uptake) was detectable in 20% of cells at 6 h, with a significant further increase at later time points. Pretreatment with 20 mM N-acetylcysteine (NAC) 1 h before AAP enhanced cellular glutathione content, prevented or attenuated the AAP-induced decrease of GSH levels and XTT reduction capacity, respectively, and reduced the loss of cell viability. Additionally, treatment with NAC 2 h after AAP exposure prevented further deterioration of XTT reduction at 3 h and later, and attenuated cell necrosis. Thus, AAP-induced oxidant stress precedes cell necrosis and, in cultured hepatocytes, the oxidant stress is involved in the propagation of cell injury.}, }
@article {pmid15114624, year = {2004}, author = {Khan, M and Sekhon, B and Jatana, M and Giri, S and Gilg, AG and Sekhon, C and Singh, I and Singh, AK}, title = {Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke.}, journal = {Journal of neuroscience research}, volume = {76}, number = {4}, pages = {519-527}, doi = {10.1002/jnr.20087}, pmid = {15114624}, issn = {0360-4012}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; NS-40144/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Brain Ischemia/*prevention &amp; control ; Cerebrovascular Circulation/drug effects ; Cytokines/metabolism ; DNA Fragmentation/drug effects/physiology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Ectodysplasins ; Free Radical Scavengers/*therapeutic use ; Glial Fibrillary Acidic Protein/metabolism ; Glutathione/metabolism ; Immunohistochemistry/methods ; In Situ Nick-End Labeling/methods ; Infarction, Middle Cerebral Artery/complications/drug therapy ; Inflammation/prevention &amp; control ; Ischemic Attack, Transient/*drug therapy/pathology ; Male ; Membrane Proteins/metabolism ; Neurologic Examination/methods ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Regional Blood Flow/drug effects ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Tetrazolium Salts ; Time Factors ; }, abstract = {Free radicals and inflammatory mediators are involved in transient focal cerebral ischemia (FCI). Preadministration of N-acetylcysteine (NAC) has been found to attenuate the cerebral ischemia-reperfusion injury in a rat model of experimental stroke. This study was undertaken to investigate the neuroprotective potential of NAC administered after ischemic events in experimental stroke. FCI was induced for 30 min by occluding the middle cerebral artery (MCA). NAC (150 mg/kg) was administered intraperitoneally at the time of reperfusion followed by another dose 6 hr later. Animals were sacrificed after 24 hr of reperfusion. The cerebral infarct consistently involved the cortex and striatum. Infarction was assessed by staining the brain sections with 2,3,5-triphenyltetrazolium chloride. Animals treated with NAC showed a significant reduction in infarct area and infarct volume and an improvement in neurologic scores and glutathione level. Reduction in infarction was significant even when a single dose of NAC was administered at 6 hr of reperfusion. Immunohistochemical and quantitative real-time PCR studies demonstrated a reduction in the expression of proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta) and inducible nitric oxide synthase (iNOS) in NAC compared to that in vehicle-treated animals. The expression of activated macrophage/microglia (ED1) and apoptotic cell death in ischemic brain was also reduced by NAC treatment. These results indicate that in a rat model of experimental stroke, administration of NAC even after ischemia onset protected the brain from free radical injury, apoptosis, and inflammation, with a wide treatment window.}, }
@article {pmid15112170, year = {2004}, author = {Fung, JW and Szeto, CC and Chan, WW and Kum, LC and Chan, AK and Wong, JT and Wu, EB and Yip, GW and Chan, JY and Yu, CM and Woo, KS and Sanderson, JE}, title = {Effect of N-acetylcysteine for prevention of contrast nephropathy in patients with moderate to severe renal insufficiency: a randomized trial.}, journal = {American journal of kidney diseases : the official journal of the National Kidney Foundation}, volume = {43}, number = {5}, pages = {801-808}, doi = {10.1053/j.ajkd.2004.01.010}, pmid = {15112170}, issn = {1523-6838}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*chemically induced/*prevention &amp; control ; Aged ; Cardiovascular Diseases/complications ; Comorbidity ; Contrast Media/*adverse effects ; Coronary Angiography ; Creatinine/blood ; Female ; Glomerular Filtration Rate ; Humans ; Male ; Middle Aged ; Renal Insufficiency/complications ; Urea/blood ; }, abstract = {BACKGROUND: The effect of N-acetylcysteine (NAC) to prevent contrast nephropathy (CN) in patients with moderate to severe renal insufficiency undergoing coronary angiography or interventions is not clear.<br><br>METHODS: This is a prospective, open-label, randomized, controlled trial. Ninety-one consecutive patients with a serum creatinine level of 1.69 to 4.52 mg/dL (149 to 400 micromol/L) undergoing coronary procedures were recruited and randomly assigned to administration of either oral NAC, 400 mg, thrice daily the day before and day of the contrast procedure (the NAC group) or no drug (the control group). Serum creatinine was measured before and 48 hours after contrast exposure. The primary end point of this study was the development of CN, defined as an increase in serum creatinine concentration of 0.5 mg/dL or greater (> or =44 micromol/L) or a reduction in estimated glomerular filtration rate (GFR) of 25% or greater of the baseline value 48 hours after the procedure.<br><br>RESULTS: There were no significant differences between the 2 groups (46 patients, NAC group; 45 patients, control group) in baseline characteristics or mean volume of contrast agent administered. Six patients (13.3%) in the control group and 8 patients (17.4%) in the NAC group developed CN (P = 0.8). Serum creatinine levels increased from 2.27 +/- 0.54 to 2.45 +/- 0.65 mg/dL (201 +/- 48 to 217 +/- 57 micromol/L; P = 0.003) in the NAC group and 2.37 +/- 0.61 to 2.40 +/- 0.70 mg/dL (210 +/- 54 to 212 +/- 62 micromol/L; P = 0.6) in the control group. The increase in serum creatinine levels between the 2 groups had no difference (P = 0.7). Estimated GFR decreased from 30.3 +/- 8.4 to 28.1 +/- 8.4 mL/min (P = 0.01) in the NAC group and 28.4 +/- 8.6 to 27.5 +/- 8.8 mL/min (P = 0.3) in the control group. The decline in estimated GFR between the 2 groups had no difference (P = 0.7).<br><br>CONCLUSION: In the current study, oral NAC had no effect on the prevention of CN in patents with moderate to severe renal insufficiency undergoing coronary angiography or interventions. However, the sample size of our present study is small. Our findings highlight the need for a large-scale, randomized, controlled trial to determine the exact beneficial effect of NAC.}, }
@article {pmid15111315, year = {2004}, author = {Agarwal, A and Muñoz-Nájar, U and Klueh, U and Shih, SC and Claffey, KP}, title = {N-acetyl-cysteine promotes angiostatin production and vascular collapse in an orthotopic model of breast cancer.}, journal = {The American journal of pathology}, volume = {164}, number = {5}, pages = {1683-1696}, pmid = {15111315}, issn = {0002-9440}, support = {P01-HL70694-01/HL/NHLBI NIH HHS/United States ; P01 HL070694/HL/NHLBI NIH HHS/United States ; R01 CA064436/CA/NCI NIH HHS/United States ; CA064436/CA/NCI NIH HHS/United States ; R29 CA064436/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Angiostatins/*biosynthesis/metabolism ; Animals ; Antioxidants/metabolism/pharmacology ; Apoptosis ; Breast Neoplasms/*drug therapy/*metabolism ; Cell Division ; Cell Line, Tumor ; Cell Survival ; Chickens ; DNA, Complementary/metabolism ; *Disease Models, Animal ; Endothelial Cells/pathology ; Free Radical Scavengers/*pharmacology ; Green Fluorescent Proteins ; Humans ; In Situ Nick-End Labeling ; Luminescent Proteins/metabolism ; Lymphatic Metastasis ; Mammary Neoplasms, Animal/drug therapy ; Mice ; Mice, Nude ; Microcirculation ; Microscopy, Fluorescence ; Models, Biological ; Necrosis ; Neoplasm Metastasis ; Neoplasm Transplantation ; RNA/chemistry ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Endothelial Growth Factor A/metabolism ; }, abstract = {The antioxidant N-acetyl-cysteine (NAC) has been shown to be chemopreventive in clinical studies, and in recent studies, has shown promise in preventing tumor progression. Although the effects of NAC on tumorigenesis have been associated with decreased angiogenesis, the mechanism of the anti-angiogenic activity has not been determined. In the following study, we describe a novel mechanism whereby NAC therapy blocks MDA-MB-435 breast carcinoma cell proliferation and metastasis in an in vivo tumorigenic model. Athymic nude mice bearing MDA-MB-435 xenografts were treated with systemic NAC daily for 8 weeks. NAC treatment resulted in endothelial cell apoptosis and reduction of microvascular density within the core of the tumor leading to significant tumor cell apoptosis/necrosis. Angiostatin accumulated in tumors from NAC-treated but not control animals. Additional studies using a vascular endothelial growth factor-dependent chicken chorioallantoic membrane angiogenic assay recapitulated NAC-induced endothelial apoptosis and coordinate production of angiostatin, a potent endothelial apoptotic factor. In vitro studies showed angiostatin was formed in endothelial cultures in a vascular endothelial growth factor- and NAC-dependent manner, a process that requires endothelial cell surface plasminogen activation. These results suggest that systemic NAC therapy promotes anti-angiogenesis through angiostatin production, resulting in endothelial apoptosis and vascular collapse in the tumor.}, }
@article {pmid15106733, year = {2004}, author = {Chae, HJ and Chae, SW and Reed, JC and Kim, HR}, title = {Salicylate regulates COX-2 expression through ERK and subsequent NF-kappaB activation in osteoblasts.}, journal = {Immunopharmacology and immunotoxicology}, volume = {26}, number = {1}, pages = {75-91}, doi = {10.1081/iph-120029946}, pmid = {15106733}, issn = {0892-3973}, mesh = {Animals ; Antioxidants/pharmacology ; Blotting, Western ; Cell Line ; Cyclooxygenase 2 ; Dinoprostone/metabolism ; Electrophoretic Mobility Shift Assay ; Extracellular Signal-Regulated MAP Kinases/metabolism/*physiology ; Flavonoids/pharmacology ; Gene Expression Regulation/*drug effects/physiology ; I-kappa B Proteins/metabolism/physiology ; Interferon-gamma/pharmacology ; Isoenzymes/*metabolism ; MAP Kinase Kinase 1/antagonists &amp; inhibitors/physiology ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; NF-kappa B/metabolism/*physiology ; Osteoblasts/drug effects/metabolism/*physiology ; Phosphorylation/drug effects ; Prostaglandin-Endoperoxide Synthases/*metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Signal Transduction/drug effects/physiology ; Sodium Salicylate/*pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation and can be inhibited with sodium salicylate. TNF-alpha plus IFN-gamma can induce extracellular signal-regulated kinase (ERK), IKK, IkappaB degradation and NF-kappaB activation. The inhibition of the ERK pathway with selective inhibitor, PD098059, blocked cytokine-induced COX-2 expression and PGE2 release. Salicylate treatment inhibited COX-2 expression induced by TNF-alpha/IFN-gamma and regulated the activation of ERK, IKK and IkappaB degradation and subsequent NF-kappaB activation in MC3T3E1 osteoblasts. As well, antioxidant-catalase, N-acetyl-cysteine or reduced glutathione-attenuated COX-2 expression in combined cytokines-treated cells. These antioxidants also inhibited the activation of ERK, IKK and NF-kappaB in MC3T3E1 osteoblasts. In addition, TNF-alpha/IFN-gamma stimulated ROS release in the osteoblasts. However salicylate had no obvious effect on ROS release in DCFDA assay. The results showed that salicylate inhibited the activation of ERK and IKK, IkappaB degradation and NF-kappaB activation independent of ROS release and suggested that salicylate exerts its anti-inflammatory action in part through inhibition of the ERK, IKK, IkappaB, NF-kappaB and resultant COX-2 expression pathway.}, }
@article {pmid15106729, year = {2004}, author = {Lee, J and Kim, MS and Park, C and Jung, EB and Choi, DH and Kim, TY and Moon, SK and Park, R}, title = {Morphine prevents glutamate-induced death of primary rat neonatal astrocytes through modulation of intracellular redox.}, journal = {Immunopharmacology and immunotoxicology}, volume = {26}, number = {1}, pages = {17-28}, doi = {10.1081/iph-120029941}, pmid = {15106729}, issn = {0892-3973}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Apoptosis/*drug effects ; Astrocytes/*drug effects/metabolism/pathology ; Benzeneacetamides/pharmacology ; Benzimidazoles/chemistry ; Bisbenzimidazole/chemistry ; Carbocyanines/chemistry ; Cell Line, Tumor ; Cell Nucleus/drug effects/pathology ; Cell Survival/drug effects ; Cells, Cultured ; Dizocilpine Maleate/pharmacology ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology ; Enkephalin, D-Penicillamine (2,5)-/pharmacology ; Glutamic Acid/*pharmacology ; Glutathione/metabolism/pharmacology ; Hydrogen Peroxide/metabolism ; Ion Channels/drug effects ; Microscopy, Fluorescence ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Permeability Transition Pore ; Morphine/*pharmacology ; Naloxone/pharmacology ; Narcotic Antagonists ; Neuroglia/drug effects/metabolism/pathology ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Pyrrolidines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors ; Rhodamine 123/chemistry ; }, abstract = {This study is designed to investigate the effect of morphine on glutamate-induced toxicity of primary rat neonatal astrocytes. Glutamate decreases the intracellular GSH level, and thereby induces cytolysis of astrocytes and C6 glial cells accompanied by apoptotic features. Glutamate-induced cytotoxicity is protected by morphine and antioxidants such as GSH and NAC, whereas MK-801, an antagonist of glutamate receptor NMDA does not protect astrocytes against glutamate toxicity. Also, morphine antagonist, naloxone, as well as selective ligands for opioid receptor subtypes, including DAMGO, DPDPE, and U69593, do not inhibit the protective effect of morphine on glutamate-induced cytotoxicity. Morphine significantly prevents the depletion of GSH by glutamate and thereby inhibits the generation of H2O2 in a dose-dependent manner. Furthermore, morphine prevents the change of mitochondrial permeability transition by glutamate. Taken together, we suggest that morphine protects the primary rat neonatal astrocytes from glutamate toxicity via modulation of intracellular redox status.}, }
@article {pmid15086476, year = {2004}, author = {Pannu, N and Manns, B and Lee, H and Tonelli, M}, title = {Systematic review of the impact of N-acetylcysteine on contrast nephropathy.}, journal = {Kidney international}, volume = {65}, number = {4}, pages = {1366-1374}, doi = {10.1111/j.1523-1755.2004.00516.x}, pmid = {15086476}, issn = {0085-2538}, mesh = {Acetylcysteine/*therapeutic use ; Contrast Media/administration &amp; dosage/*adverse effects ; Humans ; Injections, Intravenous ; Kidney Diseases/*chemically induced/*prevention &amp; control ; Randomized Controlled Trials as Topic ; Sample Size ; }, abstract = {BACKGROUND: The efficacy of N-acetylcysteine (NAC) for preventing contrast nephropathy is uncertain. We performed a systematic review and meta-analysis to assess the efficacy of NAC for preventing contrast nephropathy after administration of intravenous contrast media.<br><br>METHODS: Data were obtained from searching MEDLINE (1969-2003) and EMBASE (1988-2003), Cochrane Controlled Clinical Trial Registry (2002, Volume 3), and conference proceedings. We considered all randomized studies that compared changes in renal function between groups that received and did not receive NAC. Studies in which the control group also received active therapy were excluded, although co-intervention directed at both groups was permitted. Two reviewers independently extracted quantitative and qualitative data. Disagreements were resolved by consensus with the aid of a third party.<br><br>RESULTS: Fifteen studies with a total of 1776 patients satisfied inclusion and exclusion criteria. Contrast nephropathy was typically defined by an increase in serum creatinine of 0.5 mg/dL within 24 to 48 hours of contrast administration. The pooled random effect relative risk was 0.65 (0.43-1.00, P= 0.049), indicating that NAC significantly reduced the incidence of contrast nephropathy. However, the effect of NAC was not statistically significant in several prespecified subgroup analyses, and the results were not robust to the addition of hypothetical new or unidentified randomized trials. There was evidence of significant heterogeneity in NAC effect across studies (Q = 26.3, P= 0.02). Random effects meta-regression did not implicate identified differences in participant or study characteristics as responsible for the observed heterogeneity.<br><br>CONCLUSION: NAC may reduce the incidence of acutely increased serum creatinine after administration of intravenous contrast, but this finding was of borderline statistical significance, and there was significant heterogeneity between trials. Before NAC becomes the standard of care for all patients receiving intravenous contrast, new randomized trials evaluating its effect on clinically relevant outcomes are required.}, }
@article {pmid15083943, year = {2004}, author = {Eisen, JS and Koren, G and Juurlink, DN and Ng, VL}, title = {N-acetylcysteine for the treatment of clove oil-induced fulminant hepatic failure.}, journal = {Journal of toxicology. Clinical toxicology}, volume = {42}, number = {1}, pages = {89-92}, doi = {10.1081/clt-120028751}, pmid = {15083943}, issn = {0731-3810}, mesh = {Acetylcysteine/*therapeutic use ; Antidotes/*therapeutic use ; Clove Oil/*poisoning ; Decontamination ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Infant ; Liver Failure/*etiology/pathology/*therapy ; Treatment Outcome ; }, abstract = {We present a 3-month-old female who developed fulminant hepatic failure after ingesting less than 8 mL of clove oil. Initial treatment involved gastrointestinal decontamination, supportive measures, and admission to hospital. She subsequently developed fulminant hepatic failure and was treated with intravenous N-acetylcysteine (N-AC) according to a protocol used for acetaminophen poisoning. Over the next 72 h her liver synthetic function and clinical status improved, and she made a complete recovery. Previous reported cases of clove oil toxicity and the potential role of N-AC therapy are reviewed.}, }
@article {pmid15078764, year = {2004}, author = {Rubio, ML and Martin-Mosquero, MC and Ortega, M and Peces-Barba, G and González-Mangado, N}, title = {Oral N-acetylcysteine attenuates elastase-induced pulmonary emphysema in rats.}, journal = {Chest}, volume = {125}, number = {4}, pages = {1500-1506}, doi = {10.1378/chest.125.4.1500}, pmid = {15078764}, issn = {0012-3692}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Animals ; Collagen/analysis ; Forced Expiratory Volume ; Free Radical Scavengers/*administration &amp; dosage ; Lung/chemistry/pathology/physiopathology ; Lung Compliance/physiology ; Male ; *Pancreatic Elastase ; Pulmonary Emphysema/*chemically induced/pathology ; Rats ; Rats, Wistar ; }, abstract = {STUDY OBJECTIVE: To study the effect of the antioxidant N-acetylcysteine (NAC) in the development of elastase-induced emphysema in rats.<br><br>MATERIALS AND METHODS: Wistar rats (n = 72) were orotracheally instilled with 75 IU elastase or saline solution. Eighteen rats from each group received the antioxidant NAC from 2 days before induction of the lesion until they were killed 2, 8, and 28 days after instillation. The effects of treatment were assessed by measuring collagen content for the left lung, a histopathology evaluation (ie, mean alveolar internal surface area (AIA) and mean linear intercept measurement), and lung function.<br><br>RESULTS: Twenty-eight days after elastase instillation, rats treated with NAC showed significant attenuation of the lesion in comparison with rats treated only with elastase, including the following: normalization of mean (+/- SEM) collagen content (1.23 +/- 0.09 vs 1.51 +/- 0.10 mg per left lung, respectively; p < 0.05); partial inhibition of mean AIA (14,860 +/- 1,135 vs 19,622 +/- 1,294 micro m(2), respectively; p < 0.05) and mean linear intercept (108.8 +/- 3.7 vs 123.0 +/- 4.2 micro m, respectively; p < 0.05); and increases and improvement in expiratory flows (27.8 +/- 1.2 vs 23.4 +/- 1.3 mL/s, respectively; p < 0.05). NAC was not able to avoid the compliance increase in the elastase-plus-NAC group.<br><br>CONCLUSION: Consistent with the results of anatomic, pathologic, and functional studies, NAC is able to attenuate the lesions induced by elastase in rats, which is in accordance with previous data supporting the idea that oxidant injury could contribute to the development of elastase-induced emphysema.}, }
@article {pmid15078196, year = {2004}, author = {Tang, L and Zhang, Y}, title = {Isothiocyanates in the chemoprevention of bladder cancer.}, journal = {Current drug metabolism}, volume = {5}, number = {2}, pages = {193-201}, doi = {10.2174/1389200043489027}, pmid = {15078196}, issn = {1389-2002}, support = {R01 CA080962/CA/NCI NIH HHS/United States ; R01 CA 80962/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Anticarcinogenic Agents/*therapeutic use ; Disease Models, Animal ; Humans ; Isothiocyanates/*therapeutic use ; Prognosis ; Rodentia ; Urinary Bladder Neoplasms/diagnosis/enzymology/*prevention &amp; control ; Urothelium/metabolism ; }, abstract = {Development of effective preventive strategies for bladder cancer is of critical importance. Bladder cancer is among the most common human malignancies and typically recurs after treatment. Many plant-derived isothiocyanates (ITCs) have shown cancer-preventive activity in a variety of rodent organs. They are known to inhibit carcinogen-activating enzymes, and to induce carcinogen-detoxifying enzymes, apoptosis, cell cycle arrest, and differentiation of cancer cells. More importantly, orally ingested ITCs are efficiently absorbed, rapidly and almost exclusively excreted and concentrated in the urine as N-acetylcysteine conjugates (NAC-ITC). NAC-ITCs also possess anticarcinogenic activity, perhaps due largely to their facile dissociation to free ITCs. Storage of urine in the bladder makes the bladder epithelium, which lines the inner surface of the bladder and gives rise to the majority of bladder cancers, the most exposed tissue to ITCs/NAC-ITCs upon their ingestion. Storage of urine in the bladder also will increase the release of ITCs from NAC-ITCs. Consequently, the amount of ITCs needed orally to achieve cancer prevention in the bladder may be much lower than that required for other organs. As a result, potential systemic adverse effects of ITCs may be minimized when using ITCs for chemoprevention of bladder carcinogenesis. Taken together, ITCs may be especially useful for the prevention of bladder cancer.}, }
@article {pmid15065005, year = {2004}, author = {Yagci, G and Gul, H and Simsek, A and Buyukdogan, V and Onguru, O and Zeybek, N and Aydin, A and Balkan, M and Yildiz, O and Sen, D}, title = {Beneficial effects of N-acetylcysteine on sodium taurocholate-induced pancreatitis in rats.}, journal = {Journal of gastroenterology}, volume = {39}, number = {3}, pages = {268-276}, doi = {10.1007/s00535-003-1287-4}, pmid = {15065005}, issn = {0944-1174}, mesh = {Acetylcysteine/administration &amp; dosage/*metabolism/*pharmacology ; Acute Disease ; Amylases/blood ; Animals ; Antioxidants/administration &amp; dosage/*metabolism/*pharmacology ; Cholagogues and Choleretics ; Glutathione Peroxidase/metabolism ; Lipase/blood ; Male ; Malondialdehyde/blood ; Nitrates/blood ; Nitrites/blood ; Pancreatitis/chemically induced/drug therapy/*metabolism ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Taurocholic Acid ; Time Factors ; }, abstract = {BACKGROUND: Acute pancreatitis (AP) is a complex disease associated with significant complications and a high rate of mortality. Although several mechanisms are put forward, oxidative stress seems the most important early event in the pathophysiology of AP. Therefore, we evaluated the beneficial effects of N-acetylcysteine (NAC), a strong antioxidant, in experimental AP.<br><br>METHODS: Forty-nine Sprague-Dawley rats were used. Acute pancreatitis (AP) was induced by the intraductal infusion of sodium taurocholate. Rats were divided into seven groups (each containing seven rats): control, sham-operated (saline-treated, 3.5 and 12 h), non-treated AP (3.5 and 12 h) and NAC-treated AP (3.5 and 12 h). Treated rats received intraperitoneal (i.p.) NAC 1000 mg/kg 24 h before and just before the induction of pancreatitis.<br><br>RESULTS: Rats with AP had extensive parenchymal and fat necrosis and NAC treatment at 12 h reduced tissue necrosis significantly (P < 0.05). NAC treatment at 12 h reduced leukocytic infiltration significantly (P < 0.05). Edema and hemorrhage were significantly increased in the AP groups when compared to controls (P < 0.001). NAC treatment reduced edema and hemorrhage at both 3.5 and 12 h slightly but not significantly. The total pathological mean score was significantly increased in the AP groups (P < 0.05) and it was reduced by NAC treatment (P < 0.05). NAC treatment decreased plasma amylase and lipase levels significantly (P < 0.05). While glutathione peroxidase (GPx) activity of pancreatic tissue was similar in the NAC-treated and AP groups, hepatic tissue GPx activity was lower in the AP groups, and NAC treatment restored it (P < 0.05). NAC had no effect on pancreatic superoxide dismutase level. In the NAC-treated rats, the serum NO(2)/NO(3) (nitrite/nitrate) level was significantly increased in the 3.5-h group when compared to the respective AP group (P < 0.05). NAC treatment also significantly reduced the serum concentration of the lipid peroxidation product, malondialdehyde, at 12 h (P < 0.05).<br><br>CONCLUSIONS: NAC treatment had beneficial effects in sodium taurocholate-induced AP in rats. It reduced pancreatic tissue necrosis and lipid peroxidation. In our study, the mechanism underlying the beneficial effects of NAC seemed to be its antioxidant activity, either by increasing hepatic GPx activity, or by a direct scavenging effect on free radicals, thus enhancing the production of and/or inhibiting the degradation of nitric oxide.}, }
@article {pmid15059930, year = {2004}, author = {Weber, DS and Taniyama, Y and Rocic, P and Seshiah, PN and Dechert, MA and Gerthoffer, WT and Griendling, KK}, title = {Phosphoinositide-dependent kinase 1 and p21-activated protein kinase mediate reactive oxygen species-dependent regulation of platelet-derived growth factor-induced smooth muscle cell migration.}, journal = {Circulation research}, volume = {94}, number = {9}, pages = {1219-1226}, doi = {10.1161/01.RES.0000126848.54740.4A}, pmid = {15059930}, issn = {1524-4571}, support = {HL58000/HL/NHLBI NIH HHS/United States ; HL58863/HL/NHLBI NIH HHS/United States ; }, mesh = {3-Phosphoinositide-Dependent Protein Kinases ; Acetylcysteine/pharmacology ; Animals ; Aorta, Thoracic/cytology ; Azoles/pharmacology ; Becaplermin ; Cell Movement/drug effects/physiology ; Cells, Cultured/drug effects/enzymology ; Enzyme Activation/drug effects ; Humans ; Isoindoles ; Mitogen-Activated Protein Kinase 1/physiology ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/physiology ; Muscle, Smooth, Vascular/*cytology ; Myocytes, Smooth Muscle/drug effects/*enzymology ; Organoselenium Compounds/pharmacology ; Phosphorylation/drug effects ; Platelet-Derived Growth Factor/*pharmacology ; Protein Processing, Post-Translational/drug effects ; Protein Serine-Threonine Kinases/genetics/*physiology ; Proto-Oncogene Proteins c-sis ; Rats ; Reactive Oxygen Species/*pharmacology ; Receptors, Platelet-Derived Growth Factor/drug effects/physiology ; Recombinant Fusion Proteins/pharmacology/physiology ; Signal Transduction/drug effects ; p21-Activated Kinases ; rac GTP-Binding Proteins/physiology ; src-Family Kinases/antagonists &amp; inhibitors/*physiology ; }, abstract = {Smooth muscle cell migration in response to platelet-derived growth factor (PDGF) is a key event in several vascular pathologies, including atherosclerosis and restenosis. PDGF increases intracellular levels of reactive oxygen species (ROS) in vascular smooth muscle cells (VSMCs), but the ROS sensitivity of migration and of the signaling pathways leading to migration are largely unknown. In VSMCs, PDGF dose-dependently increased migration compared with nonstimulated cells, with a maximum increase at 10 ng/mL. Pretreatment with the antioxidant N-acetyl-cysteine, the flavin-containing enzyme inhibitor diphenylene iodonium, or the glutathione peroxidase mimetic ebselen significantly attenuated migration (PDGF alone, 5.0+/-1.1-fold; NAC, 1.8+/-0.2-fold; diphenylene iodonium, 1.4+/-0.3-fold migration; and ebselen, 2.0+/-0.5-fold migration), as did overexpression of catalase. Pretreatment of VSMCs with the Src inhibitor PP1 or dominant-negative Rac adenovirus significantly inhibited migration, but only Src activation was attenuated by ROS inhibitors. Phosphorylation of the Src- and Rac-effector p21-activated protein kinase (PAK) 1 on Thr423 (the phosphoinositide-dependent kinase-1 [PDK1] site) was attenuated by ROS inhibition, and infection of VSMCs with dominant-negative PAK1 adenovirus attenuated migration. Moreover, kinase-inactive K111N-PDK1 inhibited PAK1 phosphorylation on Thr423, and both K111N-PDK1 and Y9F-PDK1 significantly inhibited VSMC migration. PDK1 tyrosine phosphorylation was also ROS dependent. These data indicate that PDGF-induced VSMC migration is ROS dependent and identify the Src/PDK1/PAK1 signaling pathway as an important ROS-sensitive mediator of migration. Such information is critical to understanding the role of ROS in vascular diseases in which migration of VSMCs is an important component.}, }
@article {pmid14726501, year = {2004}, author = {Rosati, E and Sabatini, R and Ayroldi, E and Tabilio, A and Bartoli, A and Bruscoli, S and Simoncelli, C and Rossi, R and Marconi, P}, title = {Apoptosis of human primary B lymphocytes is inhibited by N-acetyl-L-cysteine.}, journal = {Journal of leukocyte biology}, volume = {76}, number = {1}, pages = {152-161}, doi = {10.1189/jlb.0403148}, pmid = {14726501}, issn = {0741-5400}, mesh = {Acetylcysteine/*pharmacology ; Antiviral Agents/*pharmacology ; Apoptosis/*drug effects/physiology ; B-Lymphocytes/*drug effects/immunology ; Blotting, Western ; Caspase 3 ; Caspase 7 ; Caspases/drug effects/metabolism ; Cells, Cultured ; Cytochromes c/drug effects/metabolism ; Humans ; Palatine Tonsil/cytology/immunology ; Time Factors ; }, abstract = {Thiols are important molecules to control apoptosis. This study examined the effect of N-acetyl-L-cysteine (NAC) on in vitro spontaneous apoptosis of human tonsillar B lymphocytes (TBL). Results show that NAC inhibits TBL apoptosis and maintains their survival in vitro. The antiapoptotic action of NAC is progressively reduced when its addition to culture is delayed, is reversible, and is not blocked by cycloheximide. The antiapoptotic activity of NAC is associated with its ability to inhibit caspase-3 and -7 proteolytic processing, DNA-fragmentation factor 45 cleavage, and DNA fragmentation. Furthermore, NAC inhibits BID cleavage and cytochrome c release from mitochondria and increases the expression of Bcl-2 and Bcl(XL) survival proteins. However, it has no effect on caspase-9 cleavage and increases that of caspase-8 and poly(adenosine 5'-diphosphate-ribose)polymerase. We conclude that NAC-induced inhibition of TBL apoptosis is associated with inhibition of caspase-3 and -7 processing and is accompanied by changes in several regulatory components of the apoptotic process. These results pose the question of whether microenvironment thiols may in part contribute to in vivo B cell survival.}, }
@article {pmid15056806, year = {2004}, author = {Rhoden, CR and Lawrence, J and Godleski, JJ and González-Flecha, B}, title = {N-acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambient particles.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {79}, number = {2}, pages = {296-303}, doi = {10.1093/toxsci/kfh122}, pmid = {15056806}, issn = {1096-6080}, support = {P01 ES008129/ES/NIEHS NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; P01 ES08129/ES/NIEHS NIH HHS/United States ; R01 HL/ES68073/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Air Pollutants/analysis/*toxicity ; Animals ; Antioxidants/*pharmacology ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; *Inhalation Exposure ; Male ; Metals/analysis ; Neutrophils/immunology ; Oxidative Stress/immunology ; Particle Size ; Pneumonia/etiology/*prevention &amp; control ; Protective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Thiobarbituric Acid Reactive Substances/analysis ; Time Factors ; }, abstract = {Lung inflammation is a key response to increased levels of particulate air pollution (PM); however, the cellular mechanisms leading to this response are poorly understood. To determine whether oxidants are implicated in PM-dependent lung inflammation, we tested the ability of N-acetylcysteine (NAC) to prevent lung inflammation in a rat model of short-term exposure to concentrated ambient particles (CAPs). Adult Sprague-Dawley rats were exposed to either CAPs aerosols (CAPs mass concentration 1060 +/- 300 microg/m(3)) or filtered air (Sham controls) for 5 h. NAC-treated rats received 50 mg/kg (ip) NAC 1 h prior to exposure to CAPs. Oxidative stress and recruitment of inflammatory cells into bronchoalveolar lavage were evaluated 24 h after removal of the animals from the exposure chamber. Rats breathing CAPs aerosols showed significant oxidative stress, determined by the accumulation of thiobarbituric reactive substances (TBARS, 90 +/- 15 pmol/mg protein; sham control: 50 +/- 5 pmol/mg protein, p < 0.02) and oxidized proteins (1.6 +/- 0.4 nmol/mg protein, sham: 0.70 +/- 0.02 nmol/mg protein, p < 0.01) in their lungs. CAPs-induced oxidative stress was associated with increased numbers of polymorphonuclear leukocytes in bronchoalveolar lavage (BAL) (9 +/- 2%; sham: 1.6 +/- 0.5%, p < 0.001) and slight lung edema (wet/dry ratio: 4.77 +/- 0.03, sham: 4.69 +/- 0.02). No significant change was found in BAL protein concentration, total cell count, or lactate dehydrogenase (LDH) activity. NAC pretreatment effectively prevented CAPs-induced TBARS accumulation (30 +/- 10 pmol/mg protein, p < 0.006), lung edema (4.64 +/- 0.08, p < 0.05), and polymorphonuclear neutrophil (PMN) influx into the lungs (2.1 +/- 0.5%, p < 0.001), but did not alter the protein carbonyl content. Histological evaluation of tissue samples confirmed the BAL findings. CAPs-exposed animals showed slight bronchiolar inflammation and thickened vessels at the bronchiole, whereas NAC treated animals showed no histological alterations. Regression analyses showed strong associations between increased TBARS accumulation and the CAPs content of Al, Si, and Fe, and trends of association between carbonyl content and Cr and Na concentrations, and between BAL PMN count and Cr, Zn, and Na. These data demonstrate that oxidants are critical mediators of the inflammatory response elicited by PM inhalation.}, }
@article {pmid15053755, year = {2004}, author = {Filkowski, J and Yeoman, A and Kovalchuk, O and Kovalchuk, I}, title = {Systemic plant signal triggers genome instability.}, journal = {The Plant journal : for cell and molecular biology}, volume = {38}, number = {1}, pages = {1-11}, doi = {10.1111/j.1365-313X.2004.02025.x}, pmid = {15053755}, issn = {0960-7412}, mesh = {Acetylcysteine/pharmacology ; DNA Damage ; Free Radical Scavengers/pharmacology ; Free Radicals/metabolism ; *Genome, Plant ; Genomic Instability ; Mutagens/toxicity ; Plants, Genetically Modified ; Recombination, Genetic ; Rose Bengal/pharmacology ; Signal Transduction ; Nicotiana/drug effects/*genetics/metabolism/radiation effects ; Ultraviolet Rays ; }, abstract = {Previously, we have shown that infection of tobacco plants with a viral pathogen triggers local and systemic induction of homologous recombination (HR). Here, we have tested the hypothesis of whether free radicals are potentially involved in the induction of the systemic effect. We report a significant induction of HR in tobacco plants treated with radical-generating agents, UVC or rose Bengal (RB). Importantly, the recombination increase was observed in local (treated) as well as systemic (non-treated) tissue. The systemic increase in recombination implies the existence of a signal that is transmitted to non-treated tissue. Several sets of grafting experiments proved the generation of said signal by both RB and UVC exposure. A statistically significant increase in HR was observed in tissue that received a systemic signal via a grafted leaf. Similar data were obtained from transgenic plants naphthalene degrading salicylate 1-hydroxylase (NahG) unable to accumulate salicylic acid (SA). Interestingly, pre-treatment of plants with the radical-scavenging compound N-acetyl-l-cysteine (NAC) led to a significantly lower recombination increase upon grafting after treatment with UVC and RB. Moreover, leaves taken for grafting from NAC-pre-treated plants exhibited a lower level of oxidized organic compounds. Our data suggest the involvement of free radical production in either generation or maintenance of the recombination signal. We discuss potential mechanisms for generation of the signal and possible adaptive advantages of enhanced genomic flexibility following exposure to DNA-damaging agents.}, }
@article {pmid15051739, year = {2004}, author = {Cox, CD and Tsikouris, JP}, title = {Preventing contrast nephropathy: what is the best strategy? A review of the literature.}, journal = {Journal of clinical pharmacology}, volume = {44}, number = {4}, pages = {327-337}, doi = {10.1177/0091270004263466}, pmid = {15051739}, issn = {0091-2700}, mesh = {Acetylcysteine/therapeutic use ; Contrast Media/*adverse effects ; Fluid Therapy ; Free Radical Scavengers/therapeutic use ; Humans ; Renal Insufficiency/chemically induced/drug therapy/*prevention &amp; control ; Risk Factors ; }, abstract = {Patients receiving radiocontrast for diagnostic and interventional procedures are at risk for developing contrast nephropathy (CN). In fact, radiocontrast nephropathy is currently the third leading cause of hospital-acquired renal failure. Understanding that CN has been associated with increased length of hospitalization and mortality, determining the best prevention strategy is of utmost importance. Patients at the greatest risk for developing acute renal failure are patients with diabetes and underlying renal insufficiency. Several therapies have been investigated for the prevention of CN; unfortunately, very few have shown a consistent benefit. Therapies that have been studied include saline hydration, N-acetylcysteine (NAC), theophylline, calcium channel blockers, diuretics, dopamine, endothelin receptor antagonists, atrial natriuretic peptide, angiotensin-converting enzyme inhibitors, and prostaglandin E-1. Using adequate hydration, using low-osmolar dyes, and minimizing the dose of contrast have all been shown to be effective in reducing CN and are considered the standard of care. While trials with many pharmacologic agents have produced conflicting results, intervention with NAC has also been promising. This article reviews the pathophysiology, risk factors, and therapies that are currently available for the prevention of CN.}, }
@article {pmid15051519, year = {2004}, author = {Di Loreto, S and Caracciolo, V and Colafarina, S and Sebastiani, P and Gasbarri, A and Amicarelli, F}, title = {Methylglyoxal induces oxidative stress-dependent cell injury and up-regulation of interleukin-1beta and nerve growth factor in cultured hippocampal neuronal cells.}, journal = {Brain research}, volume = {1006}, number = {2}, pages = {157-167}, doi = {10.1016/j.brainres.2004.01.066}, pmid = {15051519}, issn = {0006-8993}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blotting, Western/methods ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Interactions ; Embryo, Mammalian ; Enzyme-Linked Immunosorbent Assay/methods ; Fluoresceins ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Hippocampus/*cytology ; Interleukin-1/*metabolism ; Nerve Growth Factor/*metabolism ; Neurons/*drug effects ; Oxidative Stress/*drug effects/physiology ; Pyruvaldehyde/*toxicity ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Superoxide Dismutase/metabolism ; Time Factors ; Up-Regulation ; }, abstract = {Methylglyoxal (MG) is one of the most powerful glycating agents of proteins and other important cellular components and has been shown to be toxic to cultured cells. Under hyperglycaemic conditions, an increase in the concentration of MG has been observed in human body fluids and tissues that seems to be responsible for diabetic complications. Recent data suggest that diabetes may cause impairment of cognitive processes, according to a mechanism involving both oxidative stress and advanced glycation end product (AGE) formation. In this work, we explored the molecular mechanism underlying MG toxicity in neural cells, by investigating the effect of MG on both the interleukin-1beta (IL-1beta), as the major inducer of the acute phase response, and the nervous growth factor (NGF) expression. Experiments were performed on cultured neural cells from rat hippocampus, being this brain region mostly involved in cognitive processes and, therefore, possible target of diabetes-mediated impairment of cognitive abilities. Results show that MG treatment causes in hippocampal neural cells extensive, oxidative stress-mediated cell death, in consequence of a strong catalase enzymatic activity and protein inhibition. MG also causes a very significant increase in both transcript and protein expression of the NGF as well as of the pro-inflammatory cytokine IL-1beta. MG co-treatment with the antioxidant N-acetylcysteine (NAC) completely abrogates the observed effects. Taken together, these data demonstrate that hippocampal neurons are strongly susceptible to MG-mediated oxidative stress.}, }
@article {pmid15051148, year = {2004}, author = {Hart, AM and Terenghi, G and Kellerth, JO and Wiberg, M}, title = {Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury.}, journal = {Neuroscience}, volume = {125}, number = {1}, pages = {91-101}, doi = {10.1016/j.neuroscience.2003.12.040}, pmid = {15051148}, issn = {0306-4522}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Axotomy ; Dose-Response Relationship, Drug ; Ganglia, Spinal/drug effects/pathology ; In Situ Nick-End Labeling ; Lumbosacral Region ; Male ; Microscopy, Electron ; Mitochondria/*drug effects/ultrastructure ; Nerve Degeneration/*drug therapy ; Neurons, Afferent/drug effects/*pathology ; Neuroprotective Agents/*therapeutic use ; Rats ; Sciatic Nerve/pathology/surgery ; }, abstract = {Neuronal death is a major factor in many neuropathologies, particularly traumatic, and yet no neuroprotective therapies are currently available clinically, although antioxidants and mitochondrial protection appear to be fruitful avenues of research. The simplest system involving neuronal death is that of the dorsal root ganglion after peripheral nerve trauma, where the loss of approximately 40% of primary sensory neurons is a major factor in the overwhelmingly poor clinical outcome of the several million nerve injuries that occur each year worldwide. N-acetyl-cysteine (NAC) is a glutathione substrate which is neuroprotective in a variety of in vitro models of neuronal death, and which may enhance mitochondrial protection. Using TdT uptake nick-end labelling (TUNEL), optical disection, and morphological studies, the effect of systemic NAC treatment upon L4 and 5 primary sensory neuronal death after sciatic nerve transection was investigated. NAC (150 mg/kg/day) almost totally eliminated the extensive neuronal loss found in controls both 2 weeks (no treatment 21% loss, NAC 3%, P=0.03) and 2 months after axotomy (no treatment 35% loss, NAC 3%, P=0.002). Glial cell death was reduced (mean number TUNEL positive cells 2 months after axotomy: no treatment 51/ganglion pair, NAC 16/ganglion pair), and mitochondrial architecture was preserved. The effects were less profound when a lower dose was examined (30 mg/kg/day), although significant neuroprotection still occurred. This provides evidence of the importance of mitochondrial dysregulation in axotomy-induced neuronal death in the peripheral nervous system, and suggests that NAC merits investigation in CNS trauma. NAC is already in widespread clinical use for applications outside the nervous system; it therefore has immediate clinical potential in the prevention of primary sensory neuronal death, and has therapeutic potential in other neuropathological systems.}, }
@article {pmid15050407, year = {2004}, author = {Kim, SH and Sharma, RP}, title = {Mercury-induced apoptosis and necrosis in murine macrophages: role of calcium-induced reactive oxygen species and p38 mitogen-activated protein kinase signaling.}, journal = {Toxicology and applied pharmacology}, volume = {196}, number = {1}, pages = {47-57}, doi = {10.1016/j.taap.2003.11.020}, pmid = {15050407}, issn = {0041-008X}, mesh = {Animals ; Apoptosis/*drug effects ; Calcium/*metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Enzyme Activation ; Macrophages/*drug effects/metabolism/pathology ; Mercuric Chloride/*toxicity ; Mice ; Mice, Inbred BALB C ; Mitogen-Activated Protein Kinases/*metabolism ; Necrosis ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {The current study characterizes the mechanism by which mercury, a toxic metal, induces death in murine macrophages. The cytotoxic EC(50) of mercury ranged from 62.7 to 81.1 microM by various assays in J774A.1 cultures; accordingly, we employed 70 microM of mercuric chloride in most experiments. Mercury-induced intracellular calcium modulated reactive oxygen species (ROS) production, which resulted in both cell apoptosis and necrosis indicated by annexin V binding and caspase-3 activity, and propidium-iodide binding. Calcium antagonists abolished ROS production. Mercury stimulated p38 mitogen-activated protein kinase (MAPK) and additively stimulated lipopolysaccharide-activated p38. Mercury-activated p38 was decreased by pretreatment of cells with antioxidants, N-acetylcysteine (NAC) and silymarin, indicating that mercury-induced ROS were involved in p38 activation. Mercury increased the expression of tumor necrosis factor alpha (TNFalpha); antioxidants and a specific p38 inhibitor decreased this effect. Pretreatment with antioxidants, p38 inhibitor, and anti-TNFalpha antibody decreased mercury-induced necrosis; however, anti-TNFalpha antibody did not decrease mercury-induced apoptosis. Results suggest that mercury-induced macrophage death is a mix of apoptosis and necrosis employing different pathways. P38-mediated caspase activation regulates mercury-induced apoptosis and p38-mediated TNFalpha regulates necrosis in these cells. Calcium regulates ROS production and mercury-induced ROS modulate downstream p38 that regulates both apoptosis and necrosis.}, }
@article {pmid15044633, year = {2004}, author = {Marchand, A and Barouki, R and Garlatti, M}, title = {Regulation of NAD(P)H:quinone oxidoreductase 1 gene expression by CYP1A1 activity.}, journal = {Molecular pharmacology}, volume = {65}, number = {4}, pages = {1029-1037}, doi = {10.1124/mol.65.4.1029}, pmid = {15044633}, issn = {0026-895X}, mesh = {Adenoviridae/physiology ; Cytochrome P-450 CYP1A1/antagonists &amp; inhibitors/genetics/metabolism/*physiology ; Enzyme Induction ; *Gene Expression Regulation, Enzymologic ; Glucuronosyltransferase/genetics/metabolism ; Humans ; NAD(P)H Dehydrogenase (Quinone)/genetics/*metabolism ; Oxidative Stress/physiology ; Polychlorinated Dibenzodioxins/*pharmacology ; RNA, Small Interfering/pharmacology ; Reactive Oxygen Species/metabolism ; Teratogens/pharmacology ; Tumor Cells, Cultured ; }, abstract = {The dioxin 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) induces phase I and II xenobiotic metabolizing enzymes (XME) which act sequentially to eliminate different classes of xenobiotics. The transcriptional effects of TCDD are generally mediated by the arylhydrocarbon receptor (AhR). We hypothesized that TCDD could also act indirectly, by increasing the activity of cytochrome P450 1A1 (CYP1A1), a phase I gene, which could then mediate the induction of other XME genes, such as the NAD(P)H:quinone oxidoreductase 1 (NQO1). To test this hypothesis, NQO1 gene expression was monitored after either overexpression of CYP1A1 or siRNA-mediated knock-down of CYP1A1 activity in the hepatoma cell line HepG2. Overexpression of CYP1A1 in the absence of TCDD was carried out using either adenoviral infection or the "Tet-off" system. Recombinant adenoviruses were produced encoding no protein, CYP1A1 (Ad1A1), or a mutated inactive CYP1A1 (Ad1A1mut). In the HepG2 Tet-off cell line, CYP1A1 expression was induced by the removal of doxycycline (dox) from the cell medium. Ad1A1 infection or dox removal induced CYP1A1 activity and H(2)O(2) production similarly to TCDD treatment. Moreover, in both systems, the amount of NQO1 mRNA increased to the same level as after TCDD treatment (approximately 2-fold). The UDP-glucuronosyl transferase 1A6 (UGT1A6) gene is also similarly regulated. NQO1 gene expression was not induced when mutant, inactive CYP1A1 was overexpressed or when the antioxidant N-acetyl cysteine (NAC) was added to Ad1A1. Finally, either NAC or siRNA directed against CYP1A1 mRNA decreased the induction of NQO1 gene expression by TCDD. We conclude that, after exposure to TCDD, the NQO1 gene expression can be controlled by CYP1A1 activity through an oxidative stress mediated pathway.}, }
@article {pmid15040427, year = {2004}, author = {Goodman, SR}, title = {The irreversibly sickled cell: a perspective.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {50}, number = {1}, pages = {53-58}, pmid = {15040427}, issn = {0145-5680}, support = {HL070588/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Anemia, Sickle Cell/drug therapy/metabolism/*pathology ; Cytoskeleton/metabolism/pathology ; Dehydration/pathology ; Humans ; Models, Biological ; Symporters/metabolism ; K Cl- Cotransporters ; }, abstract = {The irreversibly sickled cell (ISC) is poorly deformable, dehydrated, of short life span, correlated to hemolysis, and a contributor to the pathophysiology of vaso-occlusive (VOC) episodes. The altered redox status and increased oxygen radical levels within high density sickle cells leads to oxidative damage and glutathiolation of cysteine residues. The formation of a disulfide bridge between Cys 284 and Cys 373 in ISC beta-actin leads to actin filaments which depolymerize poorly at 37 degrees C. Glutathiolation of cysteines within spectrin results in this key membrane skeletal protein losing it's E2/E3 ubiquitin-ligating/conjugating activity and therefore ability to self ubiquitinate. The resulting loss of ubiquitination in ISC alpha-spectrin repeats 20/21 causes a higher affinity ISC spectrin-4.1-actin ternary complex. Therefore, reversible oxidative damage to beta-actin and loss of ubiquitination of alpha-spectrin leads to an ISC membrane skeleton that disassembles poorly at 37 degrees C. The result is a membrane skeleton which is "locked" because it cannot disassemble or reassemble. N-acetylcysteine (NAC) is an antioxidant which raises intracellular reduced glutathione levels, and blocks the formation of ISCs in vitro. NAC, in a phase II human trial, caused a downward trend in ISCs, significantly decreased dense cells, and substantially decreased the rate of VOC episodes.}, }
@article {pmid15039469, year = {2004}, author = {Bhat, RS and Bhaskaran, M and Mongia, A and Hitosugi, N and Singhal, PC}, title = {Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation.}, journal = {Journal of leukocyte biology}, volume = {75}, number = {6}, pages = {1131-1138}, doi = {10.1189/jlb.1203639}, pmid = {15039469}, issn = {0741-5400}, support = {R01 DA 12111/DA/NIDA NIH HHS/United States ; }, mesh = {Animals ; Anti-Anxiety Agents/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Calcium/metabolism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Epoetin Alfa ; Erythropoietin/metabolism ; Heme Oxygenase (Decyclizing)/metabolism ; Macrophages, Peritoneal/metabolism/*pathology ; Mice ; Morphine/*pharmacology ; NADPH Oxidases/antagonists &amp; inhibitors ; Narcotics/*pharmacology ; Nitric Oxide/metabolism ; Onium Compounds/toxicity ; Oxidative Stress/*drug effects ; Phospholipase D/antagonists &amp; inhibitors ; Propranolol/pharmacology ; Recombinant Proteins ; Superoxides/*metabolism ; Thapsigargin/pharmacology ; Transforming Growth Factor beta/antagonists &amp; inhibitors/immunology ; }, abstract = {Occurrence of macrophage apoptosis has been implicated for the altered immune function found in an opiate milieu. In the present study, we evaluated the role of oxidative stress in morphine-induced macrophage apoptosis. Morphine promoted the apoptosis of macrophages. This effect of morphine was associated with the production of superoxide and nitric oxide (NO). Antioxidants provided protection against morphine-induced macrophage injury. In addition, diphenyleneiodonium chloride, an inhibitor of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, attenuated the proapoptotic effect of morphine. Antitransforming growth factor-beta (anti-TGF-beta) antibody and propranolol (an inhibitor of the phospholipase D pathway) inhibited morphine-induced superoxide generation as well as apoptosis. N'-Tetraacetic acid tetra (acetoxymethyl) ester, a calcium-chelating agent, inhibited morphine-induced apoptosis, whereas thapsigargin (a calcium agonist) stimulated macrophage apoptosis under basal as well as morphine-stimulated states. These studies suggest that morphine-induced macrophage apoptosis is mediated through downstream signaling involving TGF-beta and NO production. Moreover, there is NADPH oxidation activation involving phospholipase D and Ca(2+), leading to the generation of superoxide. In in vivo studies, administration of N-acetyl cysteine and preinduction of heme oxygenase activity and epoetin alpha prevented morphine-induced peritoneal macrophage apoptosis, thus further confirming the role of oxidative stress in morphine-induced macrophage apoptosis.}, }
@article {pmid15038770, year = {2004}, author = {Zhao, W and Goswami, PC and Robbins, ME}, title = {Radiation-induced up-regulation of Mmp2 involves increased mRNA stability, redox modulation, and MAPK activation.}, journal = {Radiation research}, volume = {161}, number = {4}, pages = {418-429}, doi = {10.1667/3155}, pmid = {15038770}, issn = {0033-7587}, support = {DK51612/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology ; Blotting, Northern ; Blotting, Western ; Butadienes/pharmacology ; Cell Line ; Cells, Cultured ; DNA, Complementary/metabolism ; Dactinomycin/pharmacology ; Dose-Response Relationship, Radiation ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/metabolism ; Flavonoids/pharmacology ; Genes, Dominant ; Kidney Tubules/cytology ; Kinetics ; *MAP Kinase Signaling System ; Matrix Metalloproteinase 2/*biosynthesis ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Mutation ; Nitriles/pharmacology ; Oxidation-Reduction ; Oxidative Stress ; Phosphorylation ; Puromycin/pharmacology ; RNA/chemistry ; RNA, Messenger/*radiation effects ; Rats ; Signal Transduction ; Time Factors ; Transfection ; *Up-Regulation ; }, abstract = {We have previously observed time- and dose-dependent increases in matrix metalloproteinase 2 (Mmp2) protein levels in rat tubule epithelial cells (NRK52E) after irradiation. However, the mechanism(s) involved remains unclear. In the present study, irradiating NRK52E cells with 0-20 Gy gamma rays was associated with time- and dose-dependent increases in Mmp2 mRNA. Studies using the transcription inhibitor actinomycin D (ActD) added 24 h after irradiation revealed the t(1/2) of Mmp2 mRNA to be approximately 8 h in control cells. In contrast, the increase in Mmp2 mRNA levels in irradiated cells was essentially unchanged after incubation with ActD for up to 12 h. Incubating cells with the antioxidants N-acetylcysteine or ebselen or the MEK pathway inhibitors PD98059 and U0126 prior to irradiation abolished the radiation-induced up-regulation of Mmp2. Irradiating NRK52E cells led to reactive oxygen species-mediated Erk1/2 activation; preincubation with NAC prevented the radiation-induced increase in phosphorylated Erk1/2. Transfecting cells with a dominant-negative ERK mutant completely inhibited radiation-induced Erk phosphorylation and abolished the radiation-induced up-regulation of Mmp2 protein. Thus the radiation-induced up-regulation of Mmp2 mRNA is due in part to increased mRNA stability and is mediated by redox; the ERK MAPK signaling pathway may be involved.}, }
@article {pmid15036418, year = {2004}, author = {Zhang, J and Dai, J and Lu, Y and Yao, Z and O'Brien, CA and Murtha, JM and Qi, W and Hall, DE and Manolagas, SC and Ershler, WB and Keller, ET}, title = {In vivo visualization of aging-associated gene transcription: evidence for free radical theory of aging.}, journal = {Experimental gerontology}, volume = {39}, number = {2}, pages = {239-247}, doi = {10.1016/j.exger.2003.10.024}, pmid = {15036418}, issn = {0531-5565}, support = {AG-15884/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aging/*genetics/physiology ; Animals ; Free Radical Scavengers/pharmacology ; Gene Expression ; Interleukin-6/biosynthesis/blood/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitosis ; Muscle, Skeletal/metabolism ; NF-kappa B/metabolism ; RNA, Messenger/genetics ; Reactive Oxygen Species/*pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription, Genetic/drug effects/*physiology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The expression of a variety of proteins is elevated with aging through unknown mechanisms. The free radical theory of aging promulgates that reactive oxygen species (ROS) promote the aging process. However, the mechanisms as to how ROS contribute to the aging process are not clear. We present data here that demonstrate that aging induced ROS promote aging-associated interleukin-6 (IL-6) gene transcription in mice that are transgenic for the murine IL-6 promoter driving a luciferase reporter cDNA. N-acetylcysteine (NAC), an antioxidant, completely reverses the increased endogenous IL-6 promoter activity in the old mice determined by real-time bioluminescence imaging (BLI). We conclude that ability of ROS to act as secondary messengers and induce gene expression may contribute to the aging process.}, }
@article {pmid15034207, year = {2004}, author = {Dugas, TR and Kanz, MF and Hebert, VY and Hennard, KL and Liu, H and Santa Cruz, V and Conklin, D and Boor, PJ}, title = {Vascular medial hyperplasia following chronic, intermittent exposure to 4,4'-methylenedianiline.}, journal = {Cardiovascular toxicology}, volume = {4}, number = {1}, pages = {85-96}, doi = {10.1385/ct:4:1:85}, pmid = {15034207}, issn = {1530-7905}, support = {1F32 ES05892/ES/NIEHS NIH HHS/United States ; ES06348/ES/NIEHS NIH HHS/United States ; K22 ES11025/ES/NIEHS NIH HHS/United States ; T32 ES07254/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aniline Compounds/pharmacokinetics/*toxicity ; Animals ; Bile Ducts/pathology ; Biotransformation ; Blood Vessels/*drug effects/*pathology ; Carcinogens/pharmacokinetics/*toxicity ; Cell Division/drug effects ; Cells, Cultured ; Epithelial Cells/pathology ; Female ; Fibrosis/pathology ; Free Radical Scavengers/pharmacology ; Glutathione Transferase/metabolism ; Hepatic Artery/pathology ; Hyperplasia ; Liver Cirrhosis, Biliary/chemically induced/pathology ; Male ; Muscle, Smooth, Vascular/*drug effects/*pathology ; Oxidation-Reduction ; Portal Vein/pathology ; Rats ; Rats, Sprague-Dawley ; Sex Characteristics ; }, abstract = {4,4'-Methylenedianiline (DAPM) is an aromatic amine used in the synthesis of polyurethanes and epoxy resins. Acute exposure to DAPM produces hepatobiliary toxicity in humans as well as animal models. However, the toxic effects of intermittent DAPM exposure have not been explored. We treated male and female rats with 25 mg DAPM/kg or vehicle once per week for 17-22 wk. Though concentric fibrosis around bile ducts of the liver was noted, vascular medial hyperplasia was also prominent. Morphometric analysis of histologic sections revealed that in male rats, vessel wall area increased relative to lumen area in hepatic arteries by 22 wk. However, in female rats, wall areas of both hepatic and pulmonary arteries increased relative to lumen area by 17 wk. In both male and female rats, increased wall thickness was localized to the medial layer; no intimal changes were noted. In vitro treatment of vascular smooth muscle cells (VSMC) with 25-100 microM DAPM resulted in increased DNA synthesis and VSMC proliferation. To test whether the observed alterations in cell cycle control involved VSMC-mediated metabolism of DAPM to electrophilic intermediates, cells were treated with DAPM or DAPM plus 50 microM N-acetylcysteine (NAC). Coincubation with NAC afforded dramatic protection against DAPM-induced VSMC proliferation. Though DAPM had no appreciable effect on levels of reduced glutathione, oxidized glutathione, or oxidant production, DAPM increased glutathione-S-transferase activity in VSMC. These data indicate that DAPM can initiate VSMC proliferation, possibly via VSMC-mediated metabolism of DAPM to reactive intermediates.}, }
@article {pmid15033544, year = {2004}, author = {Souza, V and Escobar Md, Mdel C and Gómez-Quiroz, L and Bucio, L and Hernández, E and Cossio, EC and Gutiérrez-Ruiz, MC}, title = {Acute cadmium exposure enhances AP-1 DNA binding and induces cytokines expression and heat shock protein 70 in HepG2 cells.}, journal = {Toxicology}, volume = {197}, number = {3}, pages = {213-228}, doi = {10.1016/j.tox.2004.01.006}, pmid = {15033544}, issn = {0300-483X}, mesh = {Cadmium Chloride/*toxicity ; Carcinoma, Hepatocellular/pathology ; Cell Survival/drug effects ; Cytokines/*biosynthesis/genetics ; DNA/*metabolism ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; HSP70 Heat-Shock Proteins/*biosynthesis ; Humans ; Lipid Peroxides/metabolism ; Liver Neoplasms/pathology ; Protein Binding ; RNA, Messenger/biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; Transcription Factor AP-1/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Cadmium (Cd) has been regarded as one of the inflammation-related xenobiotics. Cd has been extensively studied in many cellular systems, but a lot of parameters have been evaluated in different experimental conditions. This study was undertaken to examine the effects of low cadmium concentrations in HepG2 cells in the oxidative stress produced, the IL-1beta, tumor necrosis factor (TNF-alpha), IL-6, and IL-8 expression, production of heat shock protein 70 (Hsp70) and the activation of nuclear factors activation protein-1 (AP-1) and NF-kappaB under the same experimental conditions. Also, the participation of TNF-alpha and oxidative stress in AP-1 activation was evaluated. Lipid peroxidation damage increased 1.5 times after the first hour of Cd treatment and increased 1.9 times after 2h. Similar values were maintained until 6h. Reduced glutathione (GSH) diminished 65% after 6h CdCl(2) treatment. N-acetylcysteine (NAC) pre-treatment increased 332% GSH in Cd-treated cells. RNA was isolated from HepG2 cells after 0.5, 1, 3, or 6h incubation with 1, 5, or 10 microM CdCl(2). TNF-alpha and IL-1beta presented a maximum response after 1h treatment, while IL-6 and IL-8 maximum response was after 3h treatment. The Hsp70, determined by Western blot, was constitutively produced, and it increased after 3h Cd treatment. NF-kappaB activation, determined by EMSA, was not increased as a result of Cd treatment. DNA binding of AP-1 was detected and increased, with time up to 4h with an increment of 24 times control value with 5 microM CdCl(2). The HepG2 cells were pretreated with anti-TNF-alpha antibody or 1mM N-acetylcysteine 1h before Cd treatment. Anti-TNF-alpha treatment reduced 67% AP-1 activation, while NAC 47.5%. These data indicate that, Cd-induced TNF-alpha and IL-1beta, that probably, activate AP-1 transcription factor and IL-6 and IL-8 were induced. Anti-TNF-alpha and NAC partially inhibited AP-1 activation. All imply that, a number of factors participate in AP-1 cadmium-induced activation. The Hsp70 is produced by the HepG2 cells after cadmium treatment, and probably has a role in the non-participation of NF-kappaB in the cellular response.}, }
@article {pmid15030979, year = {2004}, author = {Majano, PL and Medina, J and Zubía, I and Sunyer, L and Lara-Pezzi, E and Maldonado-Rodríguez, A and López-Cabrera, M and Moreno-Otero, R}, title = {N-Acetyl-cysteine modulates inducible nitric oxide synthase gene expression in human hepatocytes.}, journal = {Journal of hepatology}, volume = {40}, number = {4}, pages = {632-637}, doi = {10.1016/j.jhep.2003.12.009}, pmid = {15030979}, issn = {0168-8278}, mesh = {Acetylcysteine/*pharmacology ; Cell Line ; Cytokines/pharmacology ; Enzyme Induction/drug effects ; Gene Expression/drug effects ; Hepatocytes/*drug effects/*enzymology/metabolism ; Humans ; Inflammation Mediators/metabolism ; NF-kappa B/metabolism ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase/biosynthesis/*genetics ; Nitric Oxide Synthase Type II ; Promoter Regions, Genetic/drug effects ; RNA, Messenger/genetics/metabolism ; }, abstract = {BACKGROUND/AIMS: A major role has been described for inducible nitric oxide (NO) synthase in several chronic inflammatory liver diseases. N-Acetyl-cysteine (NAC) is a sulfhydryl donor molecule with antioxidant and antiinflammatory effects. It attenuates NO generation following lipopolysaccharide injection in rats. Our goal was to study the effect of NAC on NO synthase induction in hepatocytes in response to proinflammatory cytokines.<br><br>METHODS: The effect of NAC on NO synthase induction was studied in the human hepatocyte cell lines HepG2 and 2.2.15 treated with a mixture of proinflammatory cytokines. Interactions between NAC and cytokines on nuclear factor-kappaB (NF-kappaB) activation and NO synthase promoter transactivation were investigated.<br><br>RESULTS: NAC dose-dependently modulated the induction of NO synthase mRNA expression, the release of nitrites and the formation of NF-kappaB binding complexes in cytokine-treated hepatocytes. NAC also reduced the transactivation of the NO synthase promoter.<br><br>CONCLUSIONS: Our data show that exposure of hepatocytes to NAC modulated NO synthase expression and NF-kappaB activity, the key responses of the hepatocyte to inflammatory mediators. These data constitute preliminary evidence that NAC might have hepatoprotective actions of potential relevance in chronic inflammatory liver diseases, mediated partially through the modulation of NO production.}, }
@article {pmid15030484, year = {2004}, author = {Lee, JY and Je, JH and Kim, DH and Chung, SW and Zou, Y and Kim, ND and Ae Yoo, M and Suck Baik, H and Yu, BP and Chung, HY}, title = {Induction of endothelial apoptosis by 4-hydroxyhexenal.}, journal = {European journal of biochemistry}, volume = {271}, number = {7}, pages = {1339-1347}, doi = {10.1111/j.1432-1033.2004.04042.x}, pmid = {15030484}, issn = {0014-2956}, mesh = {Aldehydes/*pharmacology ; Animals ; *Apoptosis ; Blotting, Western ; Cell Division ; Cell Nucleus/metabolism ; Cell Survival ; Dose-Response Relationship, Drug ; Endothelium/*drug effects/metabolism/*pathology ; Lipid Peroxidation ; Male ; Microscopy, Confocal ; Nitric Oxide/pharmacology ; Oxidants/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Penicillamine/pharmacology ; Peroxynitrous Acid/pharmacology ; Prostate/metabolism ; Rats ; Reactive Oxygen Species ; }, abstract = {Lipid peroxidation and its products such as 4-hydroxy-2-nonenal (HNE) and 4-hydroxyhexenal (HHE) are known to affect redox balance during aging and various degenerative processes, including vascular dysfunction. Deterioration of the endothelial cells that line the vascular wall is known to be an underlying cause of vascular dysfunction. At present, little is known about the mechanism by which HHE induces endothelial cell death (i.e. apoptosis), although HNE-induced apoptotic cell death has been reported. The aim of this study was to determine whether apoptosis induced by HHE in endothelial cells involves peroxynitrite (ONOO(-)). Our results show that in endothelial cells HHE triggers apoptotic cell death by inducing apoptotic Bax coupled with a decrease in anti-apoptotic Bcl-2. Results show that HHE induces reactive oxygen species (ROS), nitric oxide, and ONOO(-) generation, leading to redox imbalance. Furthermore, the antioxidant N-acetyl cysteine, ROS scavenger, and penicillamine, an ONOO(-) scavenger, were found to block HHE-mediated apoptosis. We used confocal laser microscopy to estimate the ability of these inhibitors to attenuate HHE-induced intracellular ONOO(-) levels thus confirming the oxidative mediation of apoptosis in endothelial cells. These findings strongly suggest that accumulated HHE triggers reactive species-mediated endothelial apoptosis, leading to vascular dysfunction as well as vascular aging. During aging, increased lipid peroxidation and its associated production of HHE may exacerbate the weakened redox balance, leading to various chronic degenerative processes including vascular dysfunction.}, }
@article {pmid15026306, year = {2004}, author = {Toyoda, T and Hayashi, T and Miyamoto, L and Yonemitsu, S and Nakano, M and Tanaka, S and Ebihara, K and Masuzaki, H and Hosoda, K and Inoue, G and Otaka, A and Sato, K and Fushiki, T and Nakao, K}, title = {Possible involvement of the alpha1 isoform of 5'AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {287}, number = {1}, pages = {E166-73}, doi = {10.1152/ajpendo.00487.2003}, pmid = {15026306}, issn = {0193-1849}, mesh = {AMP-Activated Protein Kinases ; Acetylcysteine/*pharmacology ; Animals ; Dose-Response Relationship, Drug ; Glucose/*metabolism ; Hydrogen Peroxide/*pharmacology ; In Vitro Techniques ; Isoenzymes/antagonists &amp; inhibitors/metabolism ; Leucine/*analogs &amp; derivatives/pharmacology ; Male ; Multienzyme Complexes/*metabolism ; Muscle, Skeletal/drug effects/*metabolism ; Oxidative Stress/drug effects/*physiology ; Protein Serine-Threonine Kinases/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Recent studies have suggested that 5'AMP-activated protein kinase (AMPK) is activated in response to metabolic stresses, such as contraction, hypoxia, and the inhibition of oxidative phosphorylation, which leads to insulin-independent glucose transport in skeletal muscle. In the present study, we hypothesized that acute oxidative stress increases the rate of glucose transport via an AMPK-mediated mechanism. When rat epitrochlearis muscles were isolated and incubated in vitro in Krebs buffer containing the oxidative agent H(2)O(2), AMPKalpha1 activity increased in a time- and dose-dependent manner, whereas AMPKalpha2 activity remained unchanged. The activation of AMPKalpha1 was associated with phosphorylation of AMPK Thr(172), suggesting that an upstream kinase is involved in the activation process. H(2)O(2)-induced AMPKalpha1 activation was blocked in the presence of the antioxidant N-acetyl-l-cysteine (NAC), and H(2)O(2) significantly increased the ratio of oxidized glutathione to glutathione (GSSG/GSH) concentrations, a sensitive marker of oxidative stress. H(2)O(2) did not cause an increase in the conventional parameters of AMPK activation, such as AMP and AMP/ATP. H(2)O(2) increased 3-O-methyl-d-glucose transport, and this increase was partially, but significantly, blocked in the presence of NAC. Results were similar when the muscles were incubated in a superoxide-generating system using hypoxanthine and xanthine oxidase. Taken together, our data suggest that acute oxidative stress activates AMPKalpha1 in skeletal muscle via an AMP-independent mechanism and leads to an increase in the rate of glucose transport, at least in part, via an AMPKalpha1-mediated mechanism.}, }
@article {pmid15025780, year = {2004}, author = {Hein, OV and Ohring, R and Schilling, A and Oellerich, M and Armstrong, VW and Kox, WJ and Spies, C}, title = {N-acetylcysteine decreases lactate signal intensities in liver tissue and improves liver function in septic shock patients, as shown by magnetic resonance spectroscopy: extended case report.}, journal = {Critical care (London, England)}, volume = {8}, number = {2}, pages = {R66-71}, pmid = {15025780}, issn = {1466-609X}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Aged ; Antioxidants/pharmacology/*therapeutic use ; Female ; Hemodynamics/drug effects ; Humans ; Lactates/analysis ; Lidocaine/administration &amp; dosage/analogs &amp; derivatives ; Liver/*blood supply/drug effects ; Liver Circulation/*drug effects ; Liver Function Tests ; Magnetic Resonance Spectroscopy ; Male ; Middle Aged ; Oxygen Consumption/drug effects ; Prospective Studies ; Shock, Septic/*drug therapy/mortality/physiopathology ; Signal Transduction ; Survival Analysis ; Vasoconstriction/drug effects ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) has been shown to improve splanchnic blood flow in experimental studies. This report evaluates the effects of NAC on liver perfusion and lactate signal intensities in the liver tissue of septic shock patients using proton magnetic resonance imaging and spectroscopy. Furthermore, the monoethylglycinexylidide (MEGX) test was used to investigate hepatic function.<br><br>METHODS: Five septic shock patients received 150 mg/kg body weight NAC as an intravenous bolus injection over 15 min. Lidocaine was injected both prior to and following NAC administration in order to determine MEGX formation. Measurements (hemodynamics, oxygen transport-related variables, blood samples for lactate, liver-related markers) were performed 1 hour before and 1 hour after NAC injection. In addition to the proton magnetic resonance imaging patients received two proton magnetic resonance spectra, one prior to and one 30 min subsequent to the onset of the NAC infusion at a 1.5 Tesla clinical scanner, for measurement of liver perfusion and liver lactate signal intensity.<br><br>MAIN FINDINGS: Following NAC infusion, the lactate signal intensity in the liver tissue showed a median decrease of 89% (11-99%), there was a median increase in liver perfusion of 41% (-14 to 559%), and the MEGX serum concentration increased three times (1.52-5.91).<br><br>CONCLUSIONS: A decrease in the lactate signal intensity in the liver tissue and an increase in the MEGX serum concentration and in liver perfusion might indicate improved liver function as a result of NAC administration. Patients with compromised hepatosplanchnic function, such as patients with septic shock due to peritonitis, may therefore benefit from NAC therapy.}, }
@article {pmid15022809, year = {2004}, author = {Timlin, M and Condron, C and Toomey, D and Power, C and Thornes, B and Kearns, S and Street, J and Murray, P and Bouchier-Hayes, D}, title = {N-acetylcysteine attenuates lung injury in a rodent model of fracture.}, journal = {Acta orthopaedica Scandinavica}, volume = {75}, number = {1}, pages = {61-65}, doi = {10.1080/00016470410001708120}, pmid = {15022809}, issn = {0001-6470}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bronchoalveolar Lavage Fluid/chemistry ; Disease Models, Animal ; Femoral Fractures/*complications/metabolism/surgery ; Fracture Fixation, Intramedullary/*adverse effects ; Free Radical Scavengers/*therapeutic use ; Lung/enzymology/pathology ; Male ; Organ Size ; Peroxidase/metabolism ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome/*etiology/metabolism/*prevention &amp; control ; }, abstract = {BACKGROUND: Neutrophil-mediated lung injury is a cause of significant morbidity and mortality in patients with multiple injuries. We have shown previously that fracture hematoma can activate neutrophils and is thus a putative mediator of the systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF) in those patients with severe skeletal trauma. Our aim was to establish a rodent model of fracture which caused lung injury and subsequently to administer a drug following fracture to attenuate the lung injury. The drug we chose was N-acetylcysteine, a potent antioxidant.<br><br>ANIMALS AND METHODS: Adult Sprague-Dawley rats were assigned to 4 groups: (1) general anesthetic only, (2) general anesthetic with bilateral femur fractures and nailing, (3) general anesthetic and N-acetylcysteine, (4) general anesthetic with bilateral femur fractures and nailing and N-acetylcysteine after the injury (n = 6 in each group). The dose of N-acetylcysteine was 0.5 mg/kg which was given intraperitoneally after injury to the treated groups. The rats were killed 24 hours after injury and some parameters of lung injury were evaluated--i.e., bronchoalveolar lavage (BAL), lung tissue myeloperoxidase levels (MPO) and wet/dry ratios of lung tissue. The results were analyzed, using one-way analysis of variance.<br><br>RESULTS: Bilateral femur fracture produced a significant lung injury, measured by increases in MPO (25-43 microg/g tissue) and BAL protein (460-605 microg/mL). This effect was attenuated by treatment with N-acetylcysteine (MPO 43-9 microg/mL, BAL protein 605-198 microg/mL).<br><br>INTERPRETATION: N-acetyl cysteine, if given after skeletal trauma, is of potential therapeutic benefit, in preventing SIRS, ARDS and MOF.}, }
@article {pmid15020296, year = {2004}, author = {O'Malley, YQ and Reszka, KJ and Spitz, DR and Denning, GM and Britigan, BE}, title = {Pseudomonas aeruginosa pyocyanin directly oxidizes glutathione and decreases its levels in airway epithelial cells.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {287}, number = {1}, pages = {L94-103}, doi = {10.1152/ajplung.00025.2004}, pmid = {15020296}, issn = {1040-0605}, support = {P01-CA-66081/CA/NCI NIH HHS/United States ; }, mesh = {Cells, Cultured ; Epithelial Cells/metabolism ; Glutathione/*antagonists &amp; inhibitors/*metabolism ; Glutathione Disulfide/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Oxidation-Reduction ; Pseudomonas aeruginosa/*metabolism ; Pulmonary Alveoli/cytology/*metabolism ; Pyocyanine/metabolism/*pharmacology ; Sulfhydryl Compounds/metabolism ; }, abstract = {Production of pyocyanin enhances Pseudomonas aeruginosa virulence. Many of pyocyanin's in vitro and in vivo cytotoxic effects on human cells appear to result from its ability to redox cycle. Pyocyanin directly accepts electrons from NADH or NADPH with subsequent electron transfer to oxygen, generating reactive oxygen species. Reduced glutathione (GSH) is an important cellular antioxidant, and it contributes to the regulation of redox-sensitive signaling systems. Using the human bronchial epithelial (HBE) and the A549 human type II alveolar epithelial cell lines, we tested the hypothesis that pyocyanin can deplete airway epithelial cells of GSH. Incubation of both cell types with pyocyanin led to a concentration-dependent loss of cellular GSH (up to 50%) and an increase in oxidized GSH (GSSG) in the HBE, but not A549 cells, at 24 h. An increase in total GSH, mostly as GSSG, was detected in the culture media, suggesting export of GSH or GSSG from the pyocyanin-exposed cells. Loss of GSH could be due to pyocyanin-induced H(2)O(2) formation. However, overexpression of catalase only partially prevented the pyocyanin-mediated decline in cellular GSH. Cell-free electron paramagnetic resonance studies revealed that pyocyanin directly oxidizes GSH, forming pyocyanin free radical and O(2)(-). Pyocyanin oxidized other thiol-containing compounds, cysteine and N-acetyl-cysteine, but not methionine. Thus GSH may enhance pyocyanin-induced cytotoxicity by functioning as an alternative source of reducing equivalents for pyocyanin redox cycling. Pyocyanin-mediated alterations in cellular GSH may alter epithelial cell functions by modulating redox sensitive signaling events.}, }
@article {pmid15019974, year = {2004}, author = {Ko, CH and Shen, SC and Chen, YC}, title = {Hydroxylation at C4' or C6 is essential for apoptosis-inducing activity of flavanone through activation of the caspase-3 cascade and production of reactive oxygen species.}, journal = {Free radical biology &amp; medicine}, volume = {36}, number = {7}, pages = {897-910}, doi = {10.1016/j.freeradbiomed.2003.12.020}, pmid = {15019974}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Carrier Proteins/metabolism ; Caspase 3 ; Caspases/*metabolism ; Catalase/pharmacology ; Cytochromes c/metabolism ; DNA Fragmentation ; Flavanones/*chemistry/*toxicity ; Flow Cytometry ; Genes, bcl-2/physiology ; Guanine Nucleotide Dissociation Inhibitors/metabolism ; HL-60 Cells ; Humans ; Hydroxylation ; Male ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/pharmacology ; bcl-2-Associated X Protein ; bcl-Associated Death Protein ; bcl-X Protein ; rho Guanine Nucleotide Dissociation Inhibitor beta ; rho-Specific Guanine Nucleotide Dissociation Inhibitors ; }, abstract = {Previous studies demonstrated that hydroxyl groups play important roles in the antioxidative activities of flavonoids; however, the importance of structurally related hydroxylation in their apoptosis-inducing activities is still undefined. In the present study, flavanone with hydroxylation at C4' and C6 had a significant cytotoxic effect in human leukemia HL-60 cells accompanied by the occurrence of DNA ladders, apoptotic bodies, and hypodiploid cells, characteristics of apoptosis. The replacement of a hydroxyl group (OH) by a methoxyl (OCH3) group at C4' or C6 attenuated the apoptotic effect in cells, and there was no significant cytotocity of flavanone or flavanone with OH or OCH3 in C7-treated HL-60 cells. Induction of enzyme activity of caspase-3 and -9, but not caspase-1 and -8, accompanied by release of cytocrome C from mitochondria to cytosol and the appearance of cleaved of PARP (85 kDa), D4-GDI (23 kDa), and caspase-3 (p17/p15) fragments, was identified in 4'-OH- or 6-OH- flavanone-treated HL-60 cells. Caspase-3 and -9 inhibitors Ac-DEVD-FMK and Ac-LEHD-FMK, but not caspase-1 and -8 inhibitors Ac-YVAD-FMK and Ac-LETD-FMK, attenuated 4'-OH- or 6-OH-flavanone-induced cell death. And, inhibition of capsase-9 activity by Ac-LEHD-FMK suppresses caspase-3 protein procession induced by 4'-OH- and 6-OH-flavanone, indicative of caspase-9 activation locating upstream of caspase-3. A decrease in the antiapoptotic protein Mcl-1 and increases in the pro-apoptotic proteins Bax and Bad were found in 4'-OH- or 6-OH-flavanone-treated HL-60 cells. Induction of endogenous ROS production was detected in 4'-OH- or 6-OH-flavanone-treated HL-60 cells by the DCHF-DA assay. Antioxidants such as N-acetylcysteine (NAC), catalase (CAT), superoxide dismutase (SOD), and allopurinol (ALL), but not pyrrolidine dithiocarbamate (PDTC) or diphenylene iodonium (DPI), significantly inhibited 4'-OH- or 6-OH-flavanone-induced ROS production, with blocking of the apoptosis induced by 4'-OH- or 6-OH-flavanone. The apoptosis-inducing activity of 4'-OH- or 6-OH-flavanone was also observed in another leukemia cell line (Jurkat), but was not found in mature monocytic cells (THP-1) and normal human polymorphonuclear neutrophils (PMNs). This suggests that hydroxylation at C4' or C6 is important to the apoptosis-inducing activities of flavanone through ROS production, and that activation of the caspase-3 cascade, downstream of caspase-9 activation, is involved.}, }
@article {pmid15018304, year = {2003}, author = {Yamagishi, S and Inagaki, Y and Abe, R and Kikuchi, S and Sasaki, N and Takeuchi, M}, title = {Nifedipine inhibits apoptotic cell death of cultured endothelial cells induced by tumor necrosis factor-alpha.}, journal = {Drugs under experimental and clinical research}, volume = {29}, number = {4}, pages = {141-145}, pmid = {15018304}, issn = {0378-6501}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Calcium Channel Blockers/*pharmacology ; Cell Count ; Cell Survival/drug effects ; Cells, Cultured ; Endothelial Cells/*drug effects ; Free Radical Scavengers/pharmacology ; Humans ; Nifedipine/*pharmacology ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/*pharmacology ; }, abstract = {Impaired endothelial cell (EC) growth and function have been suggested to be an initial event that leads to the development of atherosclerosis. We have very recently found that nifedipine, one of the most popularly used dihydropyridine-based calcium antagonists, prevented EC monocyte chemoattractant protein-1 production elicited by tumor necrosis factor-alpha (TNF-alpha through its antioxidative properties. However, the effects of nifedipine on EC growth and apoptosis are not fully understood. In this study, we investigated whether nifedipine could inhibit tumor necrosis factor (TNF)-alpha-induced growth retardation and apoptotic cell death in human umbilical vein ECs (HUVECs). TNF-alpha inhibited EC proliferation, which was significantly blocked by nifedipine or antioxidant N-acetylcysteine (NAC). Nifedipine or NAC was also found to significantly inhibit apoptotic cell death of TNF-alpha-exposed HUVECs. Our present study suggests that nifedipine may play a protective role against the development and progression of atherosclerosis by promoting EC repair through its antioxidative properties.}, }
@article {pmid15016658, year = {2004}, author = {Chiao, JW and Wu, H and Ramaswamy, G and Conaway, CC and Chung, FL and Wang, L and Liu, D}, title = {Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest.}, journal = {Carcinogenesis}, volume = {25}, number = {8}, pages = {1403-1408}, doi = {10.1093/carcin/bgh136}, pmid = {15016658}, issn = {0143-3334}, mesh = {Acetylcysteine/chemistry ; Animals ; Anticarcinogenic Agents/therapeutic use ; Apoptosis ; Blotting, Western ; Bromodeoxyuridine/pharmacology ; Cell Cycle ; Cell Cycle Proteins/metabolism ; Cell Division ; Cell Line, Tumor ; Cell Separation ; Coloring Agents/pharmacology ; Cyclin D ; Cyclin E/metabolism ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-Dependent Kinase Inhibitor p27 ; Cyclins/metabolism ; Flow Cytometry ; G1 Phase ; Humans ; Isothiocyanates/chemistry/*metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitosis ; Neoplasm Transplantation ; Neoplasms/metabolism ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Prostatic Neoplasms/drug therapy ; S Phase ; Time Factors ; Tumor Suppressor Proteins/metabolism ; Up-Regulation ; Vegetables/*metabolism ; }, abstract = {Epidemiological surveys indicate that intake of cruciferous vegetables is inversely related to prostate cancer incidence, although the responsible dietary factors have not been identified. Our studies demonstrated that exposure of human prostate cancer cells in culture to the N-acetylcysteine (NAC) conjugate of phenethyl isothiocyanate (PEITC-NAC), the major metabolite of PEITC that is abundant in watercress, inhibited proliferation and tumorigenesis. The PEITC-NAC is known to mediate cytoprotection at initiation of carcinogenesis. The relevance of PEITC-NAC in diets on the growth of prostate tumor cells has been evaluated in immunodeficient mice with xenografted tumors of human prostate cancer PC-3 cells. The daily PEITC-NAC (8 micromol/g) supplemented diet group showed a significant reduction in tumor size in 100% of the mice during the 9-week treatment period. Tumor weight at autopsy was reduced by 50% compared with mice on the diet without PEITC-NAC (P = 0.05). Mitosis and in vivo 5-bromo-2'-deoxyuridine labeled proliferating cells were reduced in these tumors. The PEITC-NAC diet up-regulated the inhibitors of cyclin-dependent kinases p21WAF-1/Cip-1 and p27Kip1, and reduced the expression of cyclins D and E, indicating they were potential molecular targets. As a result, phosphorylated Rb was significantly decreased and the G1- to S-phase transition retarded. The treated tumors also showed a significant increase in apoptosis as determined by in situ end-labeling, and by poly ADP-ribose polymerase cleavage. This study demonstrates the first in vivo evidence of dietary PEITC-NAC inhibiting tumorigenesis of prostate cancer cells. PEITC-NAC may prevent initiation of carcinogenesis and modulate the post-initiation phase by targeting cell cycle regulators and apoptosis induction.}, }
@article {pmid15016472, year = {2004}, author = {Monti, B and Virgili, M and Contestabile, A}, title = {Alterations of markers related to synaptic function in aging rat brain, in normal conditions or under conditions of long-term dietary manipulation.}, journal = {Neurochemistry international}, volume = {44}, number = {8}, pages = {579-584}, doi = {10.1016/j.neuint.2003.10.007}, pmid = {15016472}, issn = {0197-0186}, mesh = {Acetylcysteine/pharmacology ; Aging/*physiology ; Animals ; Biomarkers ; Blotting, Western ; Body Weight/physiology ; Brain/*physiology ; Brain Chemistry/*physiology ; Choline O-Acetyltransferase/metabolism ; Densitometry ; *Diet ; Free Radical Scavengers/pharmacology ; Male ; Ornithine Decarboxylase/metabolism ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/drug effects/metabolism ; Spinal Cord/drug effects/metabolism ; Synapses/*physiology ; }, abstract = {Neurochemical alterations of markers related to synaptic function are potential candidates for age-related impairment of brain function and cognition. The process of aging, including brain aging, can be counteracted to some degree by maintaining animals in long-term conditions of caloric restriction, or supplementing their diet with antioxidant substances. We report here that the age-related decline of the cholinergic and GABAergic systems, that takes place in some CNS regions of aged rats, is not affected by maintaining them under conditions of dietary restriction and, therefore, of reduced calorie intake, from the 12th to the 30th month of age. We also notice the same lack of effect by adding, during the same period, the aging rat diet with the potential antioxidant substance, N-acetylcysteine (NAC). The same dietary manipulations are also unable to counteract the derangement of the first step of the main biosynthetic pathway for polyamines, putative neuromodulators in the CNS, that occurs in the aged spinal cord. Some age-related alterations in the expression of different subunits of the NMDA-type glutamate receptors in some CNS regions of aged rats were instead, at least in some cases, counteracted by long-term dietary manipulation.}, }
@article {pmid15007512, year = {2004}, author = {Hildebrandt, W and Hamann, A and Krakowski-Roosen, H and Kinscherf, R and Dugi, K and Sauer, R and Lacher, S and Nöbel, N and Bodens, A and Bellou, V and Edler, L and Nawroth, P and Dröge, W}, title = {Effect of thiol antioxidant on body fat and insulin reactivity.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {82}, number = {5}, pages = {336-344}, pmid = {15007512}, issn = {0946-2716}, mesh = {Acetylcysteine/*therapeutic use ; Adipose Tissue/*drug effects/metabolism ; Adult ; Antioxidants/pharmacology/*therapeutic use ; Body Weight/drug effects ; Cell Line ; Creatine/therapeutic use ; Cysteine/pharmacology ; Cystine/blood ; Female ; Glucose Tolerance Test ; Humans ; Hyperlipidemias/drug therapy ; Insulin/*blood/metabolism ; Male ; Middle Aged ; Obesity/*drug therapy/metabolism/pathology ; Receptor, Insulin/antagonists &amp; inhibitors/*metabolism ; Sulfhydryl Compounds/blood/pharmacology/therapeutic use ; }, abstract = {Insulin signaling is enhanced by moderate concentrations of reactive oxygen species (ROS) and suppressed by persistent exposure to ROS. Diabetic patients show abnormally high ROS levels and a decrease in insulin reactivity which is ameliorated by antioxidants, such as N-acetylcysteine (NAC). A similar effect of NAC has not been reported for non-diabetic subjects. We now show that the insulin receptor (IR) kinase is inhibited in cell culture by physiologic concentrations of cysteine. In two double-blind trials involving a total of 140 non-diabetic subjects we found furthermore that NAC increased the HOMA-R index (derived from the fasting insulin and glucose concentrations) in smokers and obese patients, but not in nonobese non-smokers. In obese patients NAC also caused a decrease in glucose tolerance and body fat mass. Simultaneous treatment with creatine, a metabolite utilized by skeletal muscle and brain for the interconversion of ADP and ATP, reversed the NAC-mediated increase in HOMA-R index and the decrease in glucose tolerance without preventing the decrease in body fat. As the obese and hyperlipidemic patients had lower plasma thiol concentrations than the normolipidemic subjects, our results suggest that low thiol levels facilitate the development of obesity. Supplementation of thiols plus creatine may reduce body fat without compromising glucose tolerance.}, }
@article {pmid15007422, year = {2004}, author = {Shim, YH and Arimondo, PB and Laigle, A and Garbesi, A and Lavielle, S}, title = {Relative DNA binding affinity of helix 3 homeodomain analogues, major groove binders, can be rapidly screened by displacement of prebound ethidium bromide. A comparative study.}, journal = {Organic &amp; biomolecular chemistry}, volume = {2}, number = {6}, pages = {915-921}, doi = {10.1039/b314758d}, pmid = {15007422}, issn = {1477-0520}, mesh = {Amino Acid Sequence ; Antennapedia Homeodomain Protein ; Base Sequence ; Binding Sites ; Cysteine/chemistry ; DNA/*chemistry/metabolism ; DNA-Binding Proteins/*chemistry/metabolism ; Ethidium/*chemistry ; Homeodomain Proteins/*chemistry/metabolism ; Molecular Sequence Data ; Nuclear Proteins/*chemistry/metabolism ; Peptides/chemistry/metabolism ; Protein Structure, Secondary ; Transcription Factors/*chemistry/metabolism ; }, abstract = {The binding affinity for a 12-bp dsDNA of Antennapedia helix 3 analogues, major groove binders, has been measured by displacement of prebound ethidium bromide, a fluorescent displacement assay proposed for minor groove binders by Boger et al.(J. Am. Chem. Soc., 2000, 122, 6382-6394). Relative binding affinities determined by this method were compared to those obtained by gel mobility shift and footprinting assays for the 12-bp dsDNA and a 178-bp DNA fragment. The present work demonstrates that the fluorescence displacement assay is suitable for rapid screening of major groove binders, even though about 60 to 70% of the prebound ethidium bromide is displaced by these peptides. Total (100%) displacement of ethidium bromide was serendipitously achieved by addition in the peptide sequence, at the N-terminus, of a S-3-nitro-2-pyridinesulfenyl-N-acetyl-cysteine residue. S-3-nitro-2-pyridinesulfenylcysteine was shown to (i) bind to dsDNA with a micromolar affinity and (ii) direct within DNA grooves a peptide with no affinity for dsDNA.}, }
@article {pmid15006539, year = {2004}, author = {Montiel-Duarte, C and Ansorena, E and López-Zabalza, MJ and Cenarruzabeitia, E and Iraburu, MJ}, title = {Role of reactive oxygen species, glutathione and NF-kappaB in apoptosis induced by 3,4-methylenedioxymethamphetamine ("Ecstasy") on hepatic stellate cells.}, journal = {Biochemical pharmacology}, volume = {67}, number = {6}, pages = {1025-1033}, doi = {10.1016/j.bcp.2003.10.020}, pmid = {15006539}, issn = {0006-2952}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*physiology ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Drug Interactions ; Glutathione/*physiology ; Hepatocytes/*drug effects ; N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology ; NF-kappa B/*metabolism/physiology ; Oxidative Stress/*physiology ; Quinine/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Stellate Ganglion/cytology ; Vitamin K 3/pharmacology ; }, abstract = {"Ecstasy" (3,4-methylenedioxymethamphetamine, MDMA), is a derivative of amphetamine with hepatotoxic effects that has been shown to induce apoptosis of cultured liver cells. In the present work, we studied the role played by oxidative stress in the apoptotic response caused by MDMA on a cell line of hepatic stellate cells (HSC). MDMA-treatment provoked oxidative stress determined as reactive oxygen species (ROS) accumulation and decrease of intracellular reduced glutathione levels. Pre-treatment with the antioxidant pyrrolidine dithiocarbamate blocked ROS production but did not prevent MDMA-induced apoptosis of HSC. The pro-oxidant menadione induced in HSC ROS production and apoptosis that were prevented by pyrrolidine dithiocarbamate, showing HSC to be susceptible to oxidative stress-induced apoptosis. Addition of exogenous GSH or its precursor NAC potentiated the apoptotic action of MDMA but blocked apoptosis induced by menadione. Pre-treatment of HSC with the cytochrome P450 inhibitor quinine diminished the extent of apoptosis caused by MDMA, suggesting the involvement of a metabolic derivative of MDMA on its apoptotic effect. Nuclear factor NF-kappaB was activated by MDMA in a oxidative stress independent fashion and played a protective role in the apoptotic response, since inhibition of NF-kappaB by treatment with parthenolide or by viral infection with a dominant-negative form of NIK (Ad5dnNIK) resulted in an increase of MDMA-induced cell death. In summary, MDMA-induced apoptosis of HSC is accompanied, but not caused by oxidative stress; a metabolic derivative of the drug is responsible for the apoptotic effect of MDMA, which is partially blocked by NF-kappaB activation.}, }
@article {pmid15005626, year = {2004}, author = {Quélo, I and Akhouayri, O and Prud'homme, J and St-Arnaud, R}, title = {GSK3 beta-dependent phosphorylation of the alpha NAC coactivator regulates its nuclear translocation and proteasome-mediated degradation.}, journal = {Biochemistry}, volume = {43}, number = {10}, pages = {2906-2914}, doi = {10.1021/bi036256+}, pmid = {15005626}, issn = {0006-2960}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Active Transport, Cell Nucleus/drug effects ; Adenosine Triphosphate/analogs &amp; derivatives/metabolism ; Animals ; COS Cells ; Cell Nucleus/*metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; Drug Synergism ; Glycogen Synthase Kinase 3/antagonists &amp; inhibitors/*physiology ; Glycogen Synthase Kinase 3 beta ; Isoenzymes/antagonists &amp; inhibitors/physiology ; Molecular Chaperones ; Mutagenesis, Site-Directed ; Peptide Hydrolases/metabolism/*physiology ; Phosphorus Radioisotopes/metabolism ; Phosphorylation ; *Proteasome Endopeptidase Complex ; Signal Transduction/physiology ; Substrate Specificity/genetics ; Trans-Activators/antagonists &amp; inhibitors/genetics/*metabolism ; Transfection ; }, abstract = {c-Jun is an immediate-early gene whose degradation by the proteasome pathway is required for an efficient transactivation. In this report, we demonstrated that the c-Jun coactivator, nascent polypeptide associated complex and coactivator alpha (alphaNAC) was also a target for degradation by the 26S proteasome. The proteasome inhibitor lactacystin increased the metabolic stability of alphaNAC in vivo, and lactacystin, MG-132, or epoxomicin treatment of cells induced nuclear translocation of alphaNAC. We have shown that the ubiquitous kinase glycogen synthase kinase 3beta (GSK3beta) directly phosphorylated alphaNAC in vitro and in vivo. Inhibition of the endogenous GSKappa3beta activity resulted in the stabilization of this coactivator in vivo. We identified the phosphoacceptor site in the C-terminal end of the coactivator, on position threonine 159. We demonstrated that the inhibition of GSK3beta activity by treatment of cells with the inhibitor 5-iodo-indirubin-3'-monoxime, as well as with a dominant-negative GSK3beta mutant, induced the accumulation of alphaNAC in the nuclei of cells. Mutation of the GSK3beta phosphoacceptor site on alphaNAC induced a significant increase of its coactivation potency. We conclude that GSK3beta-dependent phosphorylation of alphaNAC was the signal that directed the protein to the proteasome. The accumulation of alphaNAC caused by the inhibition of the proteasome pathway or the activity of GSK3beta contributes to its nuclear translocation and impacts on its coactivating function.}, }
@article {pmid15003703, year = {2004}, author = {Pine, M and Schroeder, M and Greer, K and Hokanson, R and Busbee, D}, title = {Generation and partial characterization of a transformed cetacean cell line.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {67}, number = {2}, pages = {195-202}, doi = {10.1016/j.aquatox.2004.01.003}, pmid = {15003703}, issn = {0166-445X}, support = {P3009106//PHS HHS/United States ; U50 07541//PHS HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Animals ; Antigens, Viral, Tumor/genetics/metabolism ; Cell Division/drug effects ; Cell Line, Transformed ; *Dolphins ; Fluorescent Antibody Technique ; Gentamicins ; Glutamine/pharmacology ; Glutathione/pharmacology ; Keratins/metabolism ; Plasmids/*genetics ; Simian virus 40/genetics/*immunology ; }, abstract = {A primary epithelial cell line, DK1, established from renal tissue of a spontaneously aborted female Atlantic bottlenose dolphin was transfected with linearized pSV3.neo, an SV40 virus-derived plasmid encoding large tumor antigen (Tag). Transfected cells were grown in cetacean culture medium supplemented with 400 microg/ml geneticin (G418), and individual clones were selected using cloning rings. DKN1 was the first clone to be evaluated for future research use, and has been continuously cultured for 8 years. Intracellular cytokeratin and the expression of Tag were determined in DKN1, and cell growth was evaluated under different concentrations of l-glutamine, glutathione, and N-acetylcysteine. DKN1 cells did not require high levels of l-glutamine as previously reported for cetacean cells, and addition of antioxidants at the concentrations used in this study (2.0mM) decreased the rate of cell division. These data suggest strongly that these immortalized bottlenose dolphin epithelial cells have different levels of, and requirements for, glutathione than would be considered normal for terrestrial mammalian cells, do not require high levels of l-glutamine as previously suggested for dolphin cells, and exhibit decreased levels of cell growth and viability in high levels of the antioxidant GSH and its precursor, NAC.}, }
@article {pmid15001526, year = {2004}, author = {Li, L and Sawamura, T and Renier, G}, title = {Glucose enhances human macrophage LOX-1 expression: role for LOX-1 in glucose-induced macrophage foam cell formation.}, journal = {Circulation research}, volume = {94}, number = {7}, pages = {892-901}, doi = {10.1161/01.RES.0000124920.09738.26}, pmid = {15001526}, issn = {1524-4571}, mesh = {Acetylcysteine/pharmacology ; Adult ; Aged ; Anti-Infective Agents/pharmacology ; Antioxidants/pharmacology ; Arteriosclerosis/etiology/metabolism ; Cells, Cultured/drug effects/metabolism ; Curcumin/pharmacology ; Diabetes Mellitus, Type 2/complications ; Enzyme Inhibitors/pharmacology ; Female ; Flavonoids/pharmacology ; Foam Cells/metabolism/*pathology ; Gene Expression Regulation/drug effects ; Glucose/*pharmacology ; Glycation End Products, Advanced/analysis ; Humans ; Hyperglycemia/genetics/*metabolism ; MAP Kinase Signaling System/drug effects ; Macrophages/*drug effects/metabolism/pathology ; Male ; Mesylates/pharmacology ; Middle Aged ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/antagonists &amp; inhibitors/physiology ; Nitriles ; Phosphorylation/drug effects ; Protein Kinase C/antagonists &amp; inhibitors/metabolism ; Protein Kinase C beta ; Protein Processing, Post-Translational/drug effects ; Pyrroles/pharmacology ; RNA, Messenger/biosynthesis ; Receptors, LDL/biosynthesis/genetics/*physiology ; Signal Transduction/drug effects ; Sulfones ; Transcription Factor AP-1/antagonists &amp; inhibitors/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Lectin-like oxidized LDL receptor-1 (LOX-1) is a newly identified receptor for oxidized LDL that is expressed by vascular cells. LOX-1 is upregulated in aortas of diabetic rats and thus may contribute to the pathogenesis of human diabetic atherosclerosis. In this study, we examined the regulation of human monocyte-derived macrophage (MDM) LOX-1 expression by high glucose and the role of LOX-1 in glucose-induced foam cell formation. Incubation of human MDMs with glucose (5.6 to 30 mmol/L) enhanced, in a dose- and time-dependent manner, LOX-1 gene and protein expression. Induction of LOX-1 gene expression by high glucose was abolished by antioxidants, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), and activated protein-1 (AP-1) inhibitors. In human MDMs cultured with high glucose, increased expression of PKCbeta2 and enhanced phosphorylation of extracellular signal-regulated protein kinase 1/2 was observed. Activation of these kinases was inhibited by the antioxidant N-acetyl-L-cysteine (NAC) and by the PKCbeta inhibitor LY379196. High glucose also enhanced the binding of nuclear proteins extracted from human MDMs to the NF-kappaB and AP-1 regulatory elements of the LOX-1 gene promoter. This effect was abrogated by NAC and PKC/MAPK inhibitors. Finally, high glucose induced human macrophage-derived foam cell formation through a LOX-1-dependent pathway. Overall, these results demonstrate that high glucose concentrations enhance LOX-1 expression in human MDMs and that this effect is associated with foam cell formation. Pilot data showing that MDMs of patients with type 2 diabetes overexpress LOX-1 support the relevance of this work to human diabetic atherosclerosis.}, }
@article {pmid15001462, year = {2004}, author = {Koechlin, C and Couillard, A and Simar, D and Cristol, JP and Bellet, H and Hayot, M and Prefaut, C}, title = {Does oxidative stress alter quadriceps endurance in chronic obstructive pulmonary disease?.}, journal = {American journal of respiratory and critical care medicine}, volume = {169}, number = {9}, pages = {1022-1027}, doi = {10.1164/rccm.200310-1465OC}, pmid = {15001462}, issn = {1073-449X}, mesh = {Acetylcysteine/blood/pharmacokinetics/pharmacology/therapeutic use ; Administration, Oral ; Aged ; Antioxidants/metabolism/pharmacokinetics/pharmacology/therapeutic use ; Biological Availability ; Cross-Over Studies ; Double-Blind Method ; Drug Monitoring ; Forced Expiratory Volume ; Humans ; Lipid Peroxidation/drug effects ; Male ; Middle Aged ; Muscle, Skeletal/drug effects/metabolism/*physiopathology ; *Oxidative Stress/drug effects ; *Physical Endurance/drug effects ; *Pulmonary Disease, Chronic Obstructive/complications/metabolism/physiopathology ; Thigh ; Thiobarbituric Acid Reactive Substances/metabolism ; Time Factors ; Treatment Outcome ; Vital Capacity ; }, abstract = {The role of exercise-induced oxidative stress in the reduced quadriceps endurance of chronic obstructive pulmonary disease (COPD) patients has never been shown. We conducted a randomized, double-blind, and crossover study in which nine severe patients performed localized dynamic quadriceps endurance tests at 40% of maximal strength after oral treatment with the antioxidant, N-acetylcysteine (NAC), and placebo. Venous blood was sampled before, immediately after exercise, and 6 hours later. Endurance time improved by 25% after NAC treatment compared with placebo (p < 0.05). Superoxide anion (oxidant) release by stimulated phagocytes decreased after treatment (p < 0.05). No change in the antioxidant system was observed. Lipid peroxidation, an index of oxidative stress, was significantly increased 6 hours after exercise in the placebo condition (p < 0.05) but not after treatment. Advanced oxidized protein products, another index of oxidative stress, were also increased 6 hours after exercise by 139 +/- 27% in the placebo condition but only by 54 +/- 19% after treatment (p < 0.05). This study shows that NAC treatment in COPD reduced basal disturbance in the prooxidant system, improved endurance time, and prevented exercise-induced oxidative stress. Oxidative stress thus seems to be implicated in the reduced quadriceps endurance of patients with COPD.}, }
@article {pmid15000873, year = {2004}, author = {Ghezzi, P and Ungheri, D}, title = {Synergistic combination of N-acetylcysteine and ribavirin to protect from lethal influenza viral infection in a mouse model.}, journal = {International journal of immunopathology and pharmacology}, volume = {17}, number = {1}, pages = {99-102}, doi = {10.1177/039463200401700114}, pmid = {15000873}, issn = {0394-6320}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Disease Models, Animal ; Drug Synergism ; Influenza A virus/drug effects/immunology ; Male ; Mice ; Orthomyxoviridae Infections/drug therapy/*mortality/*prevention &amp; control ; Ribavirin/*therapeutic use ; Survival Rate ; }, abstract = {Oxidative stress is implicated in the pathogenesis of pulmonary damage during viral infections. In a previous study we observed a significant improvement of survival of influenza-infected mice with NAC, 1g/kg divided in two daily administrations, for 8 days including a pretreatment on day 1 before infection. In order to test NAC in a more realistic model, we studied the effect of combined treatment with NAC and the antiviral drug, ribavirin. Since in the present work we wanted to test a possible synergistic effect by combination of NAC and ribavirin, we used a different NAC's treatment regimen (1 g/kg, once a day for 4 days) that, alone, did not significantly protect mice from death. Mice (12 per group) infected intranasally with a lethal dose of influenza A virus APR/8. NAC was given as a single daily dose of 1000 mg/kg starting from 4 h after infection and until day 4 after infection, in association with ribavirin (100 mg/kg, i.p.). End-point evaluation was 14-day survival. With this schedule survival in infected mice was 17%, it was not significantly changed by NAC (25%). Survival increased to 58% with ribavirin and to 92% (n=12) with a combined treatment with ribavirin and NAC. This suggest that antioxidant therapy can increase survival by either improving the defenses against virus or by protecting from the pathogenesis of lung inflammation.}, }
@article {pmid14998531, year = {2004}, author = {Rubino, FM and Verduci, C and Giampiccolo, R and Pulvirenti, S and Brambilla, G and Colombi, A}, title = {Molecular characterization of homo- and heterodimeric mercury(II)-bis-thiolates of some biologically relevant thiols by electrospray ionization and triple quadrupole tandem mass spectrometry.}, journal = {Journal of the American Society for Mass Spectrometry}, volume = {15}, number = {3}, pages = {288-300}, pmid = {14998531}, issn = {1044-0305}, mesh = {Environmental Exposure ; Environmental Pollutants/analysis ; Ions ; Mercury Compounds/*analysis/chemistry ; Molecular Structure ; Spectrometry, Mass, Electrospray Ionization/*methods ; Sulfhydryl Compounds/*analysis/chemistry ; }, abstract = {A series of 24 compounds of general formula R(1)S-Hg-SR(2), R(1) and R(2) being biologically relevant thiol-containing amino acids and peptides (cysteine, homo-cysteine, penicillamine, N-acetyl-cysteine, N-acetyl-penicillamine, cysteinyl-glycine, gamma-glutamyl-cysteine and glutathione) were prepared by direct reaction of mercury(II) ions and thiols in water at millimolar concentration. The obtained products were characterized by electrospray ionization and triple quadrupole tandem mass spectrometry. The source spectra of equimolar mixtures of two different thiols reacting with a stoichiometric amount of mercury(II) show the peak clusters of the three theoretically expected bis-thiolato-mercury(II) complexes with relative intensities close to the theoretically expected 1:2:1 ratio, thus pointing at lack of substantial discrimination between the different thiols, the only observed exception being homo-cysteine, which is less reactive than cysteine and penicillamine. The fragment spectra are structure-specific for the different ligands bound to the metal ion and allow a stand-alone discrimination of some constitutional isomer pairs. Among the peculiar fragmentation processes observed, loss of neutral ammonia from protonated symmetrical and unsymmetrical mercury(II)-bis-thiolates with free, protonizable amino groups leads to the formation of thiirane-carboxylic bound species; this process is suppressed when the protonated amino group is in the gamma-position with respect to the sulfur atom, as in the case of compounds with homo-cysteine. This unusual behavior may hint at unforeseen mechanisms for the interaction of mercury(II) with biological structures, ultimately leading to cellular and organ toxicity. Compounds with N-acetylated amino acids show distinctive fragment ions to which the connectivity of a protonated 2-methyl-oxazoline-5-carboxylic acid may be proposed on the basis of the loss of water and of the elements of formic acid. Finally, the adducts of mercury(II) with glutathione and gamma-glutamyl-cysteine feature a distinctive decomposition channel by loss of a pyroglutamic unit, much the same as protonated glutathione, glutathione disulfide, the S-glutathionyl adducts of biologically occurring electrophiles and other (pseudo)-peptides with gamma-glutamyl bonds.}, }
@article {pmid14994441, year = {2004}, author = {Zhao, ZC and Zheng, SS and Cheng, WL and Wang, X and Qi, Y}, title = {Suppressing progress of pancreatitis through selective inhibition of NF-KappaB activation by using NAC.}, journal = {Journal of Zhejiang University. Science}, volume = {5}, number = {4}, pages = {477-482}, doi = {10.1631/jzus.2004.0477}, pmid = {14994441}, issn = {1009-3095}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; In Situ Hybridization ; NF-kappa B/*metabolism ; Pancreas/metabolism/pathology ; Pancreatitis/*drug therapy/etiology/metabolism/pathology ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/genetics/metabolism ; }, abstract = {OBJECTIVE: To explore the characteristics of NF-KappaB activation in the progress of pancreatitis, the relationship with expression of TNF-alpha in the inflammatory reaction, and prevent the exacerbation of pancreatitis by using NAC.<br><br>METHOD: Forty-eight rats were divided into three groups: therapy (group C), pancreatitis (group B) and control (group A). NAC served as the inhibitor of NF-KappaB activation. In the time intervals of 1.5, 3.0, 6.0, 12.0 hour, NF-KappaB activation was detected with flow cytometry (FCM) and the expression of TNF-alpha mRNA and protein with in situ hybridization (ISH) and enzyme-linked immuno-sorbent assay (ELISA) respectively. Meanwhile, the level of lipase and amylase in the serum was assayed and the pathological change was evaluated.<br><br>RESULT: NF-KappaB activation in the pancreatitis group was higher than that in the control group (P<0.01), peaked at 3 hours, and was depressed by the inhibitor of NF-KappaB, NAC. The expression of TNF-alpha as well as the level of lipase and amylase in the serum also rose synchronously with activation of NF-KappaB. In contrast to group A, it was significantly different (P<0.01) in group B. After using NAC in group C, all of these values were decreased and the inflammatory reaction in the pancreas abated evidently. The pathology changes of the pancreas were shown to be alleviated in group C.<br><br>CONCLUSION: First, NF-KappaB activity is intensively initiated in the course of pancreatitis and shown to have closely relationship with the release of cytokines. Second, use of NAC markedly depressed NF-KappaB activation. TNF-alpha expression is down regulated by cytokines. It is suggested that NAC probably acts as a useful agent for treatment of pancreatitis by indirectly inhibiting activation of NF-KappaB.}, }
@article {pmid14988435, year = {2004}, author = {Wu, G and Fang, YZ and Yang, S and Lupton, JR and Turner, ND}, title = {Glutathione metabolism and its implications for health.}, journal = {The Journal of nutrition}, volume = {134}, number = {3}, pages = {489-492}, doi = {10.1093/jn/134.3.489}, pmid = {14988435}, issn = {0022-3166}, support = {P30-ES09106/ES/NIEHS NIH HHS/United States ; R01CA61750/CA/NCI NIH HHS/United States ; }, mesh = {Cysteine/metabolism ; Glutamic Acid/metabolism ; Glutathione/biosynthesis/*metabolism ; Glycine/metabolism ; *Health ; Humans ; }, abstract = {Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.}, }
@article {pmid14982601, year = {2004}, author = {Jafari, B and Ouyang, B and Li, LF and Hales, CA and Quinn, DA}, title = {Intracellular glutathione in stretch-induced cytokine release from alveolar type-2 like cells.}, journal = {Respirology (Carlton, Vic.)}, volume = {9}, number = {1}, pages = {43-53}, doi = {10.1111/j.1440-1843.2003.00527.x}, pmid = {14982601}, issn = {1323-7799}, support = {HL 03920/HL/NHLBI NIH HHS/United States ; HL 39150/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Blotting, Northern ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Cytokines/*metabolism ; Epithelial Cells/metabolism ; Glutathione/*analogs &amp; derivatives/*metabolism/pharmacology ; Humans ; Interleukin-1/metabolism ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Isoprostanes/metabolism ; Lipid Peroxidation ; NF-kappa B/metabolism ; *Oxidative Stress/drug effects/physiology ; Pulmonary Alveoli/cytology/drug effects/*metabolism ; Respiratory Distress Syndrome/metabolism ; Stress, Mechanical ; Transcription Factor AP-1/metabolism ; }, abstract = {OBJECTIVE: Ventilator-induced lung injury (VILI) is characterized by release of inflammatory cytokines, but the mechanisms are not well understood. We hypothesized that stretch-induced cytokine production is dependent on oxidant release and is regulated by intracellular glutathione (GSH) inhibition of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding.<br><br>METHODOLOGY: Type 2-like alveolar epithelial cells (A549) were exposed to cyclic stretch at 15% strain for 4 h at 20 cycles/min with or without N-acetylcysteine (NAC) or glutathione monoethylester (GSH-e) to increase intracellular GSH, or buthionine sulfoximine (BSO), to deplete intracellular GSH.<br><br>RESULTS: Cyclic stretch initially caused a decline in intracellular GSH and a rise in the levels of isoprostane, a marker of oxidant injury. This was followed by a significant increase in intracellular GSH and a decrease in isoprostane. Stretch-induced IL-8 and IL-6 production were significantly inhibited when intracellular GSH was further increased by NAC or GSH-e (P < 0.0001). Stretch-induced IL-8 and IL-6 production were augmented when intracellular GSH was depleted by BSO (P < 0.0001). NAC blocked stretch-induced NF-kappa B and AP-1 binding and inhibited IL-8 mRNA expression.<br><br>CONCLUSIONS: We conclude that oxidant release may play a role in lung cell stretch-induced cytokine release, and antioxidants, which increase intracellular GSH, may protect lung cells against stretch-induced injury.}, }
@article {pmid14978478, year = {2004}, author = {Rao, PV and Maddala, R and John, F and Zigler, JS}, title = {Expression of nonphagocytic NADPH oxidase system in the ocular lens.}, journal = {Molecular vision}, volume = {10}, number = {}, pages = {112-121}, pmid = {14978478}, issn = {1090-0535}, support = {EY 12201/EY/NEI NIH HHS/United States ; EY 13573/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Blotting, Western ; Cattle ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/drug effects/enzymology ; Growth Substances/pharmacology ; Humans ; Lens, Crystalline/drug effects/*enzymology ; Macaca ; NADPH Oxidases/antagonists &amp; inhibitors/*genetics/*metabolism ; Phosphoproteins/metabolism ; Rats ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; }, abstract = {PURPOSE: The primary goal of this study was to characterize the Rac GTPase associated, NADPH oxidase-mediated Reactive Oxygen Species (ROS)-generating system in the lens tissue.<br><br>METHODS: NADPH oxidase activity in lens tissue was determined by quantifying superoxide-induced lucigenin photoemission. Immunological and PCR/RT-PCR techniques were utilized to determine expression of different components of the NADPH oxidase system in lens tissue. Growth factor stimulated ROS production was determined quantitatively in human lens epithelial cells using dichlorofluorescein diacetate.<br><br>RESULTS: Lens homogenates from different species showed generation of superoxide in a lucigenin-enhanced chemiluminescence assay in the presence of NADPH. This activity was found to be lens protein concentration dependent, heat sensitive, and inhibitable by superoxide dismutase and the flavoprotein inhibitor, diphenyleneiodonium (DPI). The distribution of superoxide generating activity in lens was confined predominantly to the lens epithelium, with very low levels in cortex and none in the nucleus. Immunological assays have demonstrated the presence of p67phox and p47phox in lens tissue, while PCR and RT-PCR reactions amplified DNA products corresponding to the p67phox, p40phox, p22phox, gp91phox, and Rac1 components of the NADPH oxidase complex from human and mouse lens cDNA libraries. Serum starved human lens epithelial cells stimulated with different growth factors including EGF, b-FGF, PDGF, TGF-beta, and LPA demonstrated increased production of ROS, a response which was blocked by inhibitors of NADPH oxidase, such as DPI and the antioxidant-N-acetyl cysteine (NAC). RT-PCR analysis of human lens RNA confirmed readily detectable levels of expression of low molecular weight protein tyrosine phosphatase (LMW-PTP), which is a well-characterized target of redox signaling pathway(s).<br><br>CONCLUSIONS: These data demonstrate the presence of a functional nonphagocytic NADPH oxidase system in lens that is predominantly localized to the lens epithelium. Several growth factors appear to stimulate the activity of lens NADPH oxidase, resulting in increased production of ROS in lens epithelial cells, indicating that redox signaling may have an important role in growth factor effects on lens growth and development.}, }
@article {pmid14977773, year = {2004}, author = {Berry, M and Ellingham, RB and Corfield, AP}, title = {Human preocular mucins reflect changes in surface physiology.}, journal = {The British journal of ophthalmology}, volume = {88}, number = {3}, pages = {377-383}, pmid = {14977773}, issn = {0007-1161}, mesh = {Biomarkers/analysis ; Conjunctiva/*physiology ; Humans ; Mucin 5AC ; Mucin-2 ; Mucins/analysis/*chemistry/physiology ; Tears/*physiology ; }, abstract = {BACKGROUND/AIMS: Mucin function is associated with both peptide core and glycosylation characteristics. The authors assessed whether structural alterations occurring during mucin residence in the tear film reflect changes in ocular surface physiology.<br><br>METHODS: Ocular surface mucus was collected from normal volunteers as N-acetyl cysteine (NAcCys) washes or directly from the speculum after cataract surgery. To assess the influence of surface health on mucins, NAcCys washings were also obtained from patients with symptoms, but no clinical signs of dry eye (symptomatics). Mucins were extracted in guanidine hydrochloride (GuHCl) with protease inhibitors. Buoyant density of mucin species, a correlate of glycosylation density, was followed by reactivity with anti-peptide core antibodies. Mucin hydrodynamic volume was assessed by gel filtration on Sepharose CL2B.<br><br>RESULTS: Surface fluid and mucus contained soluble forms of MUC1, MUC2, MUC4, and MUC5AC and also the same species requiring DTT solubilisation. Reactivity with antibodies to MUC2 and MUC5AC peaked at 1.3-1.5 g/ml in normals, while dominated by underglycosylated forms in symptomatics. Surface mucins were predominantly smaller than intracellular species. MUC2 size distributions were different in symptomatics and normals, while those of MUC5AC were similar in these two groups.<br><br>CONCLUSIONS: A reduction in surface mucin size indicates post-secretory cleavage. Dissimilarities in surface mucin glycosylation and individual MUC size distributions in symptomatics suggest changes in preocular mucin that might precede dry eye signs.}, }
@article {pmid14977522, year = {2004}, author = {Song, J and Lee, SC and Kim, SS and Koh, HJ and Kwon, OW and Kang, JJ and Kim, EK and Shin, SH and Lee, JH}, title = {Zn2+-induced cell death is mediated by the induction of intracellular ROS in ARPE-19 cells.}, journal = {Current eye research}, volume = {28}, number = {3}, pages = {195-201}, doi = {10.1076/ceyr.28.3.195.26251}, pmid = {14977522}, issn = {0271-3683}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cell Line ; Cell Survival ; Chlorides/*pharmacology ; Fluorescein-5-isothiocyanate ; Humans ; In Situ Nick-End Labeling ; *JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Necrosis ; Pigment Epithelium of Eye/metabolism/*pathology ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Zinc Compounds/*pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {PURPOSE: Recent studies have shown that Zn2+ induced cell death in retinal pigment epithelial cells. Here we sought to investigate the mode of Zn2+-induced cell death and the role of reactive oxygen species (ROS) in human retinal pigment epithelial cell line, ARPE-19 cells.<br><br>METHODS: Cell viability was measured by MTT assay. Cell death of ARPE-19 cells was measured by annexin V-fluorescein isothiocyanate (FITC) binding assay, TUNEL assay. The formation of intracellular ROS was measured using 2',7'-dichlorofluorescein diacetate (DCFH-DA). The activation of mitogen-activated protein kinase (MAPK) was examined by Western blot analysis.<br><br>RESULTS: This study demonstrated that Zn2+ treatment induced both necrosis and apoptosis in ARPE-19 cells. Exposure of ARPE-19 cells to Zn2+ led to the activation of ERK1/2, JNK1/2/3, and p38 MAPKs. The activation of these MAPKs was blocked by treatment with the antioxidant, N-acetylcystein (NAC). More importantly, inhibition of ROS production by NAC completely prevented Zn2+-induced cell death in RPE cells.<br><br>CONCLUSIONS: This study suggests that Zn2+ induces both apoptosis and necrosis in ARPE-19 cells and that its cytotoxicity may depend on the induction of intracellular ROS.}, }
@article {pmid14975505, year = {2004}, author = {Ginsburg, I}, title = {Bactericidal cationic peptides can also function as bacteriolysis-inducing agents mimicking beta-lactam antibiotics?; it is enigmatic why this concept is consistently disregarded.}, journal = {Medical hypotheses}, volume = {62}, number = {3}, pages = {367-374}, doi = {10.1016/j.mehy.2003.11.017}, pmid = {14975505}, issn = {0306-9877}, mesh = {Anti-Bacterial Agents/*pharmacology ; Antimicrobial Cationic Peptides/*pharmacology ; Bacteria/drug effects ; Bacterial Infections/*drug therapy ; beta-Lactams/*pharmacology ; }, abstract = {Although there is a general consensus that highly cationic peptides kill bacteria primarily by injuring their membranes, an additional hypothesis is proposed suggesting that a large variety of cationic peptides might also render bacteria non viable by activating their autolytic wall enzymes - muramidases (a "Trojan Horse" phenomenon), resulting in bacteriolysis. This group of cationic peptides includes: lysozyme, lactoferrin, neutrophil-derived permeability increasing peptides, defensins, elastase, cathepsin G, and secretory phopholipase A2. In this respect, cationic peptides mimic the bactericidal/bacteriolytic effects exerted by of beta-lactam antibiotics. Bacteriolysis results in a massive release of the pro-inflammatory cell-wall components, endotoxin (LPS), lipoteichoic acid (LTA) and peptidoglycan (PPG), which if not effectively controlled, can trigger the coagulation and complement cascades, the release from phagocytes of inflammatory cytokines, reactive oxygen and nitrogen species, and proteinases. Synergism (a "cross-talk") among such agonists released following bacteriolysis, is probably the main cause for septic shock and multiple organ failure. It is proposed that a use of bacteriolysis-inducing antibiotics should be avoided in bacteremic patients and particularly in those patients already suspected of developing shock symptoms as these might further enhance bacteriolysis and the release of LPS, LTA and PPG. Furthermore, in additonal to the supportive regimen exercised in intensive care settings, a use of non bacteriolysis-inducing antibiotics when combined with highly sulfated compounds (e.g. heparin, and other clinically certified polysufates) should be considered instead, as these might prevent the activation of the microbial own autolytic systems induced either by highly cationic peptides released by activated phagocytes or by the highly bacteriolytic beta-lactams. Polysulfates might also depress the deleterious effects of the complement cascade and the use of combinations among anti-oxidants (N-acetyl cysteine), proteinase inhibitors and phospholipids might prove effective to depress the synergistic cytotoxic effects induced by inflammatory agonists. Also, a use of gamma globulin enriched either in anti-LPS or in anti-LTA activities might serve to prevent the binding of these toxins to receptors upon macrophage which upon activation generate inflammatory cytokines. Thus, a use of "cocktails" of anti-inflammatory agents might replace the unsuccessful use of single antagonists proven in scores of clinical trials of sepsis to by ineffective in prolonging the lives of patients. It is enigmatic why the concept, and the publications which support a role for cationic peptides also as potent inducers of bacteriolysis, an arch evil and a deleterious phenomenon which undoubtedly plays a pivotal role in the pathophysiology of post-infectious sequelae, has been consistently disregarded.}, }
@article {pmid14975183, year = {2003}, author = {Lee, JJ and Huang, WT and Shao, DZ and Liao, JF and Lin, MT}, title = {Blocking NF-kappaB activation may be an effective strategy in the fever therapy.}, journal = {The Japanese journal of physiology}, volume = {53}, number = {5}, pages = {367-375}, doi = {10.2170/jjphysiol.53.367}, pmid = {14975183}, issn = {0021-521X}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Analgesics, Non-Narcotic/*pharmacology ; Animals ; Antibodies, Monoclonal/pharmacology ; Curcumin/administration &amp; dosage/pharmacology ; Cytokines/biosynthesis ; Fever/chemically induced/drug therapy/*metabolism ; Humans ; Injections, Intravenous ; Interleukin-1/blood/immunology ; Interleukin-6/blood/immunology ; Leukocytes, Mononuclear/drug effects/metabolism ; Lipopolysaccharides/pharmacology ; Male ; NF-kappa B/*antagonists &amp; inhibitors/immunology/*metabolism ; Pyridines/administration &amp; dosage/pharmacology ; Pyrrolidines/administration &amp; dosage/pharmacology ; Rabbits ; Thiocarbamates/administration &amp; dosage/pharmacology ; Thiones ; Time Factors ; Tumor Necrosis Factor-alpha/immunology/metabolism ; }, abstract = {Lipopolysaccharide (LPS) stimulates peripheral mononuclear cells (PBMC) to synthesize or release pyrogenic cytokines, including interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha). Nuclear factor-kappa B (NF-kappaB) influences inflammatory responses through the regulation of genes encoding cytokines. In the present study, experiments were carried out to determine whether an inhibition of NF-kappaB mechanisms causes an inhibition of pyrogenic cytokine synthesis or release from PBMC and results in antipyresis. Intravenous administration of the supernatant fluids obtained from the human PBMC incubated with LPS caused feverlike hyperthermia in rabbits. The febrile responses were in parallel with the levels of IL-1beta, IL-6, and TNF-alpha in supernatant fluids. Both the fever and the increased levels of these cytokines in supernatant fluids were decreased by incubating LPS-PBMC with NF-kappaB inhibitors, including pyrrolidine dithiocarbamate, sodium pyrithione, N-acetyl-cysteine, and curcumin. Moreover, an intravenous administration of LPS (0.5-2 microg/kg) produced dose-dependent fever in the rabbits. The fevers were in parallel with the levels of IL-1beta, IL-6, and TNF-alpha in rabbit serum. A pretreatment of rabbits with an intravenous injection of pyrrolidine dithiocarbamate, sodium pryithione, N-acetyl-cysteine, or curcumin 1 h before the intravenous administration of LPS significantly attenuated the LPS-induced fever and/or increased levels of these cytokines in the serum of rabbits. Furthermore, pretreatment with an intravenous dose of anti-IL-1beta, anti-IL-6, or anti-TNF-alpha monoclonal antibody significantly attenuated the fever induced by the intravenous injection of LPS in rabbits. The antipyretic effects exerted by anti-L-1beta monoclonal antibody were greater than those exerted by anti-L-6 or anti-NF-alpha monoclonal antibody. The data indicate that NF-kappaB activation correlates with an LPS-induced synthesis or a release of cytokines (in particular, IL-1beta) from PBMC and triggers fever. Blocking NF-kappaB mechanisms in the PBMC with NF-kappaB inhibitors may be an effective strategy in the fever therapy.}, }
@article {pmid14972420, year = {2004}, author = {Briguori, C and Colombo, A and Violante, A and Balestrieri, P and Manganelli, F and Paolo Elia, P and Golia, B and Lepore, S and Riviezzo, G and Scarpato, P and Focaccio, A and Librera, M and Bonizzoni, E and Ricciardelli, B}, title = {Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity.}, journal = {European heart journal}, volume = {25}, number = {3}, pages = {206-211}, doi = {10.1016/j.ehj.2003.11.016}, pmid = {14972420}, issn = {0195-668X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Contrast Media/*adverse effects ; Drug Administration Schedule ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Iohexol/*adverse effects/*analogs &amp; derivatives ; Kidney Diseases/*chemically induced/prevention &amp; control ; Male ; Prospective Studies ; }, abstract = {AIMS: Prophylactic administration of N-acetylcysteine (NAC) (600mg orally twice daily), along with hydration, prevents contrast agent-associated nephrotoxicity (CAN) induced by a low dose of non-ionic, low-osmolality contrast dye. We tested whether a double dose of NAC is more effective to prevent CAN.<br><br>METHODS AND RESULTS: Two-hundred-twenty-four consecutive patients with chronic renal insufficiency (creatinine level > or =1.5mg/dl and/or creatinine clearance <60ml/min), referred to our institution for coronary and/or peripheral procedures, were randomly assigned to receive 0.45% saline intravenously and NAC at the standard dose (600mg orally twice daily; SD Group; n=110) or at a double dose (1200mg orally twice daily; DD Group; n=114) before and after a non-ionic, low-osmolality contrast dye administration. Increase of at least 0.5mg/dl of the creatinine concentration 48h after the procedure occurred in 12/109 patients (11%) in the SD Group and 4/114 patients (3.5%) in the DD Group (P=0.038; OR=0.29; 95% CI=0.09-0.94). In the subgroup with low (<140ml, or contrast ratio <=1) contrast dose, no significant difference in renal function deterioration occurred between the 2 groups. In the subgroup with high (> or =140ml, or contrast ratio >1) contrast dose, the event was significantly more frequent in the SD Group. Conclusions Double dose of NAC seems to be more effective than the standard dose in preventing CAN, especially with high volumes of non-ionic, low-osmolality contrast agent.}, }
@article {pmid14972012, year = {2004}, author = {Das, DK and Maulik, N}, title = {Conversion of death signal into survival signal by redox signaling.}, journal = {Biochemistry. Biokhimiia}, volume = {69}, number = {1}, pages = {10-17}, doi = {10.1023/b:biry.0000016345.19027.54}, pmid = {14972012}, issn = {0006-2979}, support = {HL 22559/HL/NHLBI NIH HHS/United States ; HL 33889/HL/NHLBI NIH HHS/United States ; HL 5642/HL/NHLBI NIH HHS/United States ; HL 56803/HL/NHLBI NIH HHS/United States ; HL 63317/HL/NHLBI NIH HHS/United States ; P30 ES06639/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Cell Death ; Cell Survival ; Myocardial Ischemia/*metabolism/*pathology ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; }, abstract = {Reperfusion of ischemic myocardium produces reactive oxygen species (ROS) and results in apoptotic cell death and DNA fragmentation. Several redox-sensitive anti- and pro- apoptotic transcription factors including nuclear factor kappaB (NF-kappaB) and heterodimeric transcription factor AP-1 progressively and steadily increase in the heart as a function of the duration of ischemia and reperfusion. When the heart is adapted to ischemic stress by repeated short-term ischemia and reperfusion, NF-kappaB remains high, while AP-1 is lowered to almost baseline value. The anti-apoptotic gene Bcl-2 is downregulated in the ischemic/reperfused heart, while it is upregulated in the adapted myocardium. Cardioprotective abilities of the adapted myocardium are abolished when heart is pre-perfused with N-acetyl cysteine to scavenge ROS, suggesting a role of redox signaling. Mammalian heart is protected by several defense systems, which include, among others, the redox-regulated protein thioredoxin. Reperfusion of ischemic myocardium results in the downregulation of thioredoxin 1 (Trx 1) expression, which was upregulated in the adapted myocardium. The increased expression of Trx 1 is completely blocked with an inhibitor of Trx 1, cis-diammine-dichloroplatinum, which also abolished cardioprotection afforded by ischemic adaptation. The cardioprotective role of Trx 1 is further confirmed with transgenic mouse hearts overexpressing Trx 1. The Trx 1 mouse hearts displayed significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size and apoptosis compared to the corresponding wild-type mouse hearts. The results of this study implicate a crucial role of redox signaling in transmitting anti-death signal.}, }
@article {pmid14967593, year = {2004}, author = {Levanon, D and Manov, I and Iancu, TC}, title = {Qualitative and quantitative analysis of the effects of acetaminophen and N-acetylcysteine on the surface morphology of Hep3B hepatoma cells in vitro.}, journal = {Ultrastructural pathology}, volume = {28}, number = {1}, pages = {3-14}, pmid = {14967593}, issn = {0191-3123}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/*toxicity ; Antidotes/*pharmacology ; Carcinoma, Hepatocellular/*drug therapy/ultrastructure ; Cell Line, Tumor ; Cell Surface Extensions/*drug effects/ultrastructure ; Humans ; Microscopy, Electron, Scanning ; }, abstract = {Acetaminophen (AAP) is harmful to the liver if consumed in excessive doses. Its toxicity can be counteracted by N-acetylcysteine (NAC). The authors studied cultures of Hep3B cells exposed to AAP or NAC or both, at 24 and 48 h, using the scanning electron microscope. Using morphometric software, they found that cultures exposed for 24 h to AAP or AAP + NAC suffered reduction in cell confluence. Exposure increased the incidence of rounding cells and of apoptotic and autoschizic appearances. Differences between control cultures cultivated without serum versus those exposed to xenobiotics were merely quantitative, not essential.}, }
@article {pmid14967008, year = {2004}, author = {Tsou, TC and Yeh, SC and Tsai, FY and Chang, LW}, title = {The protective role of intracellular GSH status in the arsenite-induced vascular endothelial dysfunction.}, journal = {Chemical research in toxicology}, volume = {17}, number = {2}, pages = {208-217}, doi = {10.1021/tx034202v}, pmid = {14967008}, issn = {0893-228X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis ; Arsenites/*toxicity ; Cells, Cultured ; Endothelium, Vascular/cytology/*drug effects/physiology ; Flow Cytometry ; Glutathione/*metabolism ; *JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Signal Transduction ; Swine ; Transcription Factor AP-1/metabolism ; Up-Regulation ; }, abstract = {In this study, we used porcine aortic endothelial cells (PAECs) as an in vitro system to investigate the role of intracellular GSH status in arsenite-induced vascular endothelial damage. Exposure of PAECs to l-buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS), markedly enhanced the arsenite-induced cytotoxicity. The data implied that intracellular GSH might play an important role in protection of PAECs from arsenite-induced cytotoxicity. Low concentrations of arsenite exposure increased intracellular GSH concentrations, whereas high concentrations of arsenite exposure decreased intracellular GSH concentrations. We further modulated intracellular GSH concentration by using GSH modulators. N-Acetyl cysteine (NAC) and l-cystine (oxidized l-cysteine), by up-regulating intracellular GSH concentrations, were shown to protect PAECs from arsenite-induced cytotoxicity. On the other hand, BSO and monosodium glutamate (MSG), which down-regulated the intracellular GSH concentrations, further potentiated arsenite-induced cytotoxicity. Moreover, exposure of PAECs to NAC alleviated the arsenite-induced JNK/AP-1 activation and apoptosis, whereas exposure of PAECs to BSO enhanced the arsenite-induced JNK/AP-1 activation and apoptosis. These results indicated that an increase in GSH content represented one of the detoxification mechanisms responding to arsenite exposure and probably played critical roles in the regulation of stress-response signaling molecules as well as in protection of PAECs from arsenite attack.}, }
@article {pmid14967005, year = {2004}, author = {Hutzler, JM and Steenwyk, RC and Smith, EB and Walker, GS and Wienkers, LC}, title = {Mechanism-based inactivation of cytochrome P450 2D6 by 1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]- 4-[4-(trifluoromethyl)-2-pyridinyl]piperazine: kinetic characterization and evidence for apoprotein adduction.}, journal = {Chemical research in toxicology}, volume = {17}, number = {2}, pages = {174-184}, doi = {10.1021/tx034199f}, pmid = {14967005}, issn = {0893-228X}, mesh = {*Cytochrome P-450 CYP2D6 Inhibitors ; Enzyme Inhibitors/*pharmacology ; Imidazoles/*pharmacology ; Magnetic Resonance Spectroscopy ; Pyridines/*pharmacology ; Recombinant Proteins/antagonists &amp; inhibitors ; Spectrophotometry, Ultraviolet ; }, abstract = {The kinetics for inactivation of cytochrome P450 2D6 by (1-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-[4-(trifluoromethyl)-2-pyridinyl]piperazine (EMTPP) were characterized, and the mechanism was determined in an effort to understand the observed time-based inactivation. Loss of dextromethorphan O-demethylase activity following coincubation with EMTPP followed pseudo-first-order kinetics and was both NADPH- and EMTPP-dependent. Inactivation was characterized by an apparent Ki of 5.5 microM with a maximal rate constant for inactivation (kinact) of 0.09 min(-1), a t1/2 of 7.7 min, and a partition ratio of approximately 99. P450 2D6 inactivation was unaffected by coincubation with exogenous nucleophiles or reactive oxygen scavengers and was protected by the competing inhibitors N-4-(trifluoromethyl)benzyl quinidinium bromide and quinidine. After a 30 min incubation with 100 microM EMTPP, dextromethorphan O-demethylase activity was decreased approximately 76%, with a disproportionate loss (approximately 35%) in carbon monoxide binding. Additional mechanistic studies showed no evidence of either metabolite inhibitory complex formation or heme adduction. However, a P450 2D6 apoprotein adduct was characterized that had a mass shift relative to unadducted P450 2D6 apoprotein consistent with the molecular mass of EMTPP (353 Da). In vitro metabolism studies revealed that EMTPP is susceptible to P450 2D6-mediated hydroxylation and dehydrogenation, postulated to both form via initial hydrogen atom abstraction from the alpha-carbon of the imidazole ethyl substituent. Additional studies demonstrated that while a dehydrogenated EMTPP metabolite was apparently stable and observable, we propose that a thermodynamic partitioning may exist, which results in formation of a second dehydrogenated imidazo-methide-like metabolite that may serve as the reactive species causing mechanism-based inactivation of P450 2D6. Last, trapping studies with EMTPP yielded an N-acetyl cysteine conjugate, which upon tandem MS and NMR analysis revealed adduction to the alpha-carbon of the imidazole ethyl substituent. Overall, evidence suggests that nucleophilic attack of an imidazo-methide-like intermediate by a P450 2D6 active site residue leads to apoprotein adduction and consequent inactivation.}, }
@article {pmid14966349, year = {2004}, author = {Kim, J and Son, JW and Lee, JA and Oh, YS and Shinn, SH}, title = {Methylglyoxal induces apoptosis mediated by reactive oxygen species in bovine retinal pericytes.}, journal = {Journal of Korean medical science}, volume = {19}, number = {1}, pages = {95-100}, pmid = {14966349}, issn = {1011-8934}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Caspase 3 ; Caspases/metabolism ; Cattle ; Cell Death ; Cell Survival ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Glucose/metabolism ; NF-kappa B/metabolism ; Nucleosomes/metabolism ; Oxidative Stress ; Pericytes/*drug effects ; Pyruvaldehyde/*pharmacology ; *Reactive Oxygen Species ; Retina/cytology/*drug effects ; }, abstract = {One of the histopathologic hallmarks of early diabetic retinopathy is the loss of pericytes. Evidences suggest that the pericyte loss in vivo is mediated by apoptosis. However, the underlying cause of pericyte apoptosis is not fully understood. This study investigated the influence of methylglyoxal (MGO), a reactive alpha-dicarbonyl compound of glucose metabolism, on apoptotic cell death in bovine retinal pericytes. Analysis of internucleosomal DNA fragmentation by ELISA showed that MGO (200 to 800 microM) induced apoptosis in a concentration-dependent manner. Intracellular reactive oxygen species were generated earlier and the antioxidant, N-acetyl cysteine, inhibited the MGO-induced apoptosis. NF-kappaB activation and increased caspase-3 activity were detected. Apoptosis was also inhibited by the caspase-3 inhibitor, Z-DEVD-fmk, or the NF-kappaB inhibitor, pyrrolidine dithiocarbamate. These data suggest that elevated MGO levels observed in diabetes may cause apoptosis in bovine retinal pericytes through an oxidative stress mechanism and suggests that the nuclear activation of NF-kappaB are involved in the apoptotic process.}, }
@article {pmid14962364, year = {2003}, author = {Ginsburg, H and Golenser, J}, title = {Glutathione is involved in the antimalarial action of chloroquine and its modulation affects drug sensitivity of human and murine species of Plasmodium.}, journal = {Redox report : communications in free radical research}, volume = {8}, number = {5}, pages = {276-279}, doi = {10.1179/135100003225002907}, pmid = {14962364}, issn = {1351-0002}, mesh = {Acetylcysteine/pharmacology ; Amodiaquine/pharmacology ; Animals ; Antimalarials/*pharmacology ; Chloroquine/*pharmacology ; Drug Resistance ; Glutathione/*metabolism ; Hemin/metabolism ; Humans ; Malaria/drug therapy ; Mice ; Plasmodium/*drug effects ; }, abstract = {Ferriprotoporphyrin IX (FP) is released inside the food vacuole of the malaria parasite during the digestion of host cell hemoglobin. FP is detoxified by its biomineralization to hemozoin. This process is effectively inhibited by chloroquine (CQ) and amodiaquine (AQ). Undegraded FP accumulates in the membrane fraction and inhibits enzymes of infected cells in parallel with parasite killing. FP is demonstrably degraded by reduced glutathione (GSH) in a radical-mediated mechanism. This degradation is inhibited by CQ and AQ in a competitive manner, thus explaining the ability of increased GSH levels in Plasmodium falciparum-infected cells to increase resistance to CQ and vice versa, and to render Plasmodium berghei that were selected for CQ resistance in vivo sensitive to the CQ when glutathione synthesis is inhibited. Some over-the-counter drugs that are known to reduce GSH in body tissues when used in excess were found to enhance the antimalarial action of CQ and AQ in mice infected either with P. berghei or Plasmodium vinckei. In contrast, N-acetyl-cysteine which is expected to increase the cellular levels of GSH, antagonized the action of CQ. These results suggest that some over-the-counter drugs can be used in combination with some antimalarials to which the parasite has become resistant.}, }
@article {pmid14961186, year = {2004}, author = {Nygren, H and Malmberg, P and Sahlin, H}, title = {Development of a wound dressing targeting neutrophil function.}, journal = {World journal of surgery}, volume = {28}, number = {3}, pages = {337-342}, pmid = {14961186}, issn = {0364-2313}, mesh = {Acetylcysteine/*pharmacology ; Bandages ; Blood Bactericidal Activity ; Cells, Cultured ; Down-Regulation ; Glutathione/*pharmacology ; Humans ; Luminescent Measurements ; Neutrophils/*physiology ; Nitric Oxide/metabolism ; Reactive Oxygen Species/*metabolism ; Sensitivity and Specificity ; Staphylococcus aureus/*metabolism ; Tissue Engineering ; Wound Healing/drug effects/*physiology ; Wounds and Injuries/therapy ; }, abstract = {Earlier studies show that neutrophils are virtually unable to kill Staphylococcus aureus in vitro. However, upon addition of 10 mM N-acetylcysteine (NAC) or reduced glutathione (GSH) the neutrophil bacterial killing ability becomes excellent. We want to exploit this phenomenon to develop a wound dressing material that will improve neutrophil function. To study the mechanisms behind the downregulation of neutrophil elimination of bacteria, we used different markers for neutrophil function on surface-adhering neutrophils in contact with S. aureus with or without addition of the antioxidants NAC or GSH. Analysis by scanning electron microscopy showed cell shrinkage and numerous cytoplasmic processes on surface-adhering neutrophils exposed to S. aureus. In cells exposed to S. aureus and GSH, the cells were of normal size and the cytoplasm was spread as in normal attachment. Staining for intracellular GSH, a hallmark of oxidative stress, showed little difference between the experimental groups, indicating that the cells were not damaged by traditional oxidative stress. The H(2)O(2) production of neutrophils, measured by Amplex red, was correlated to bacterial exposure and was not affected by the addition of scavengers. The intracellular and extracellular production of ROS was measured by luminol-amplified chemiluminescence. The apparent ROS-production was mostly intracellular and decreased in the presence of scavengers. However, extracellular production of ROS was not affected by the addition of NAC. The production of nitric oxide (NO) was measured spectrophotometrically as the production of nitrate apparently decreased in the presence of scavengers, probably as a result of interference with the reagents in the test system. In conclusion, differences between leukocytes that were able to eliminate S. aureus and those that were not were mainly seen in the morphology of the cells and in cell viability. The morphological findings point to a difference in NO signaling in the absence and presence of ROS scavengers.}, }
@article {pmid14769780, year = {2004}, author = {Han, S and Espinoza, LA and Liao, H and Boulares, AH and Smulson, ME}, title = {Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2-chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes.}, journal = {British journal of pharmacology}, volume = {141}, number = {5}, pages = {795-802}, pmid = {14769780}, issn = {0007-1188}, mesh = {Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Humans ; Jurkat Cells ; Lymphocytes/*drug effects/metabolism ; Mustard Gas/*analogs &amp; derivatives/*toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {1. The mechanism of toxicity of sulphur mustard was investigated by examining the biochemical effects of the analog 2-chloroethylethyl sulphide (CEES) in both human Jurkat cells as well as normal human lymphocytes. 2. Exposure of both types of cells to CEES resulted in a marked decrease in the intracellular concentration of the reduced form of glutathione (GSH), and CEES-induced cell death was potentiated by l-buthionine sulphoximine, an inhibitor of GSH synthesis. 3. CEES increased the endogenous production of reactive oxygen species (ROS) in Jurkat cells, and CEES-induced cell death was potentiated by hydrogen peroxide. 4. CEES induced various hallmarks of apoptosis, including collapse of the mitochondrial membrane potential, proteolytic processing and activation of procaspase-3, and cleavage of poly (ADP-ribose) polymerase. 5. The effects of CEES on the accumulation of ROS, the intracellular concentration of GSH, the mitochondrial membrane potential, and caspase-3 activity were all inhibited by pretreatment of cells with the GSH precursor N-acetyl cysteine or with GSH-ethyl ester. Furthermore, CEES-induced cell death was also prevented by these antioxidants. 6. CEES toxicity appears to be mediated, at least in part, by the generation of ROS and consequent depletion of GSH. Given that sulphur mustard is still a potential biohazard, the protective effects of antioxidants against CEES toxicity demonstrated in Jurkat cells and normal human lymphocytes may provide the basis for the development of a therapeutic strategy to counteract exposure to this chemical weapon.}, }
@article {pmid14767336, year = {2004}, author = {Fuller, TF and Serkova, N and Niemann, CU and Freise, CE}, title = {Influence of donor pretreatment with N-acetylcysteine on ischemia/reperfusion injury in rat kidney grafts.}, journal = {The Journal of urology}, volume = {171}, number = {3}, pages = {1296-1300}, doi = {10.1097/01.ju.0000103928.64939.6a}, pmid = {14767336}, issn = {0022-5347}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Free Radical Scavengers/*therapeutic use ; Kidney/*blood supply/metabolism ; *Kidney Transplantation ; Male ; Preoperative Care ; Rats ; Rats, Inbred Lew ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {PURPOSE: N-acetylcysteine (NAC) has been shown to ameliorate ischemic acute renal failure. We determined the effect of donor pretreatment with NAC on ischemia reperfusion (I/R) injury in rat kidney grafts.<br><br>MATERIALS AND METHODS: Lewis rats were divided into 3 groups (8 per group) and treated with saline, mannitol (1 gm/kg) or NAC (1 gm/kg intravenously) prior to donor nephrectomy. Cold stored kidneys (24 hours in UW solution) were transplanted into bilaterally nephrectomized recipients. Blood and graft tissue samples were taken 24 hours after transplantation for assessment of metabolic changes, histological damage and renal function. Metabolites associated with renal I/R injury were quantified in blood and renal tissue by magnetic resonance spectroscopy.<br><br>RESULTS: The degree of histological damage was similar between the treatment groups. Of the counted tubules 60%were mildly damaged, whereas 40% showed moderate damage. Measurement of the metabolites allantoin and trimethylamine-N-oxide (TMAO) indicated a beneficial effect of NAC treatment. In graft tissue and recipient blood allantoin, a uric acid metabolite, was significantly lower in the NAC group vs the mannitol and saline groups (p <0.05). In recipient blood TMAO, an established marker of renal medullary injury, was significantly decreased in the NAC group vs mannitol and saline (p <0.05). Serum creatinine levels were not different between treatment groups.<br><br>CONCLUSIONS: Donor pretreatment with NAC preserves renal metabolism and may improve outcomes of I/R injured kidney transplants. Allantoin and TMAO are sensitive metabolic markers of renal I/R injury that can be detected before the onset of functional and morphological changes.}, }
@article {pmid14756449, year = {2003}, author = {Griffin, RJ and Monzen, H and Williams, BW and Park, H and Lee, SH and Song, CW}, title = {Arsenic trioxide induces selective tumour vascular damage via oxidative stress and increases thermosensitivity of tumours.}, journal = {International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group}, volume = {19}, number = {6}, pages = {575-589}, doi = {10.1080/0265673031000124316}, pmid = {14756449}, issn = {0265-6736}, support = {CA13353/CA/NCI NIH HHS/United States ; CA44114/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Cell Line, Tumor/drug effects/metabolism ; Endothelium, Vascular/cytology ; Female ; Humans ; *Hyperthermia, Induced ; Intercellular Adhesion Molecule-1/metabolism ; *Mammary Neoplasms, Animal ; Mice ; Mice, Inbred C3H ; Oxidative Stress/*drug effects ; Oxides/*pharmacology ; Rubidium Radioisotopes ; Umbilical Veins/cytology ; }, abstract = {It has previously been found that the anti-leukaemia agent Arsenic Trioxide (ATO) causes vascular shutdown in solid tumours and markedly sensitizes tumours to hyperthermia. The present study was designed to evaluate the mechanism of action and dose-dependence of ATO-induced thermosensitization in FSaII and SCK murine tumours. The role of oxidative stress was studied by observing ATO-induced vascular shutdown in vivo and ATO-induced endothelial cell adhesion molecule expression in vitro in the presence or absence of an anti-oxidant. It was found that a dose as low as 2 mg/kg ATO impaired vascular function, as estimated by 86Rb uptake, in the tumour. The degree of tumour growth delay induced by 1 h of hyperthermia at 42.5 degrees C, applied 2 h after ATO injection, was proportional to the dose of ATO administered. In addition, it was found that ATO can directly thermosensitize tumour cells in vitro. The development of massive tissue necrosis in the tumour was observed in the days after treatment, especially with the combination of ATO and heating. ATO-induced adhesion molecule expression in vitro was abolished when the anti-oxidant n-acetyl-cysteine (NAC) was introduced prior to exposure, while the addition of NAC in vivo partially blocked ATO-induced vascular shutdown. These results suggest that the expression of adhesion molecules by the vasculature due to oxidative stress contribute to the ATO-induced selective tumour vascular effects observed and that the clinical use of ATO to increase tumour thermosensitivity via direct cellular and vascular effects appears feasible.}, }
@article {pmid14750028, year = {2003}, author = {Chen, CH and Chern, CL and Lin, CC and Lu, FJ and Shih, MK and Hsieh, PY and Liu, TZ}, title = {Involvement of reactive oxygen species, but not mitochondrial permeability transition in the apoptotic induction of human SK-Hep-1 hepatoma cells by shikonin.}, journal = {Planta medica}, volume = {69}, number = {12}, pages = {1119-1124}, doi = {10.1055/s-2003-45193}, pmid = {14750028}, issn = {0032-0943}, mesh = {Antineoplastic Agents/administration &amp; dosage/*pharmacology/therapeutic use ; Apoptosis/*drug effects ; Cell Line, Tumor/drug effects ; DNA Fragmentation/drug effects ; Flow Cytometry ; Humans ; In Situ Nick-End Labeling ; *Lithospermum ; Mitochondria/drug effects/metabolism ; Naphthoquinones/administration &amp; dosage/*pharmacology/therapeutic use ; *Phytotherapy ; Plant Roots ; Reactive Oxygen Species/chemistry ; }, abstract = {Shikonin has been demonstrated to exhibit anti-cancer activity, but the underlying mechanisms are poorly understood. In this report, we showed that the administration of shikonin could result in the induction of apoptotic cell death of human hepatoma cell line, SK-Hep-1. As evident by the flow-cytometric studies, shikonin has the capability of generating increased amounts of intracellular reactive oxygen species (ROS) during the early stage of this apoptotic process (ca. one-hour), and subsequently accompanied by the dissipation of mitochondrial transmembrane potential (deltapsi (m)) at 3 hours. Further studies indicated that this apoptotic process could effectively be protected by the pretreatment of shikonin-treated cells with glutathione (GSH) and N-acetylcysteine (NAC), a precursor of GSH, but not by cyclosporin A (CyA), an inhibitor of mitochondrial permeability transition (MPT) pore. These data further proved that ROS-mediated oxidative stress was the pivotal element involved in the induction of apoptosis of SK-Hep-1 cells. Taken together, we suggest that shikonin-induced apoptosis of SK-Hep-1 cells proceeds by an oxidative stress-mediated pathway.}, }
@article {pmid14747387, year = {2004}, author = {Hoffmann, U and Fischereder, M and Krüger, B and Drobnik, W and Krämer, BK}, title = {The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {15}, number = {2}, pages = {407-410}, doi = {10.1097/01.asn.0000106780.14856.55}, pmid = {14747387}, issn = {1046-6673}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; *Chemical and Drug Induced Liver Injury ; Contrast Media/*adverse effects ; Female ; Humans ; Liver Diseases/*prevention &amp; control ; Male ; Prospective Studies ; Radiopharmaceuticals/*adverse effects ; }, abstract = {Prevention of contrast agent-induced nephropathy is of crucial importance for a number of diagnostic studies. N-Acetylcysteine (NAC) was recently reported to decrease serum creatinine levels in this setting, and its administration before radiocontrast medium administration has been widely recommended. The objective of this prospective study was to investigate whether there are effects of NAC on serum creatinine levels that are independent of alterations in GFR. Volunteers with normal renal function who did not receive radiocontrast medium were studied. Fifty healthy volunteers completed the study protocol. NAC was administered orally at a dose of 600 mg every 12 h, for a total of four doses. Surrogate markers of renal function, such as serum creatinine, urea, albumin, and cystatin C levels, were measured and estimated GFR (eGFR) was assessed immediately before the administration of NAC and 4 and 48 h after the last dose. There was a significant decrease in the mean serum creatinine concentration (P < 0.05) and a significant increase in the eGFR (P < 0.02) 4 h after the last dose of NAC. The cystatin C concentrations did not change significantly. In several studies, a protective effect of NAC on renal function after radiocontrast medium administration has been postulated. This is the first study to demonstrate an effect of NAC on creatinine levels and eGFR, surrogate markers of renal injury, without any effect on cystatin C levels. Before renoprotective effects of NAC against contrast agent-induced nephropathy are considered, the direct effects of NAC on creatinine levels, urea levels, and eGFR should be assessed.}, }
@article {pmid14744743, year = {2004}, author = {Rouzaud, G and Young, SA and Duncan, AJ}, title = {Hydrolysis of glucosinolates to isothiocyanates after ingestion of raw or microwaved cabbage by human volunteers.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {13}, number = {1}, pages = {125-131}, doi = {10.1158/1055-9965.epi-085-3}, pmid = {14744743}, issn = {1055-9965}, mesh = {Brassica/*metabolism ; Cooking ; Female ; Glucosinolates/*metabolism ; Glycoside Hydrolases/metabolism ; Humans ; Hydrolysis ; Isothiocyanates/administration &amp; dosage/*metabolism/urine ; Male ; *Mustard Plant ; }, abstract = {Cabbage contains the glucosinolate sinigrin, which is hydrolyzed by myrosinase to allyl isothiocyanate. Isothiocyanates are thought to inhibit the development of cancer cells by a number of mechanisms. The effect of cooking cabbage on isothiocyanate production from glucosinolates during and after their ingestion was examined in human subjects. Each of 12 healthy human volunteers consumed three meals, at 48-h intervals, containing either raw cabbage, cooked cabbage, or mustard according to a cross-over design. At each meal, watercress juice, which is rich in phenethyl isothiocyanate, was also consumed to allow individual and temporal variation in postabsorptive isothiocyanate recovery to be measured. Volunteers recorded the time and volume of each urination for 24 h after each meal. Samples of each urination were analyzed for N-acetyl cysteine conjugates of isothiocyanates as a measure of entry of isothiocyanates into the peripheral circulation. Excretion of isothiocyanates was rapid and substantial after ingestion of mustard, a source of preformed allyl isothiocyanate. After raw cabbage consumption, allyl isothiocyanate was again rapidly excreted, although to a lesser extent than when mustard was consumed. On the cooked cabbage treatment, excretion of allyl isothiocyanate was considerably less than for raw cabbage, and the excretion was delayed. The results indicate that isothiocyanate production is more extensive after consumption of raw vegetables but that isothiocyanates still arise, albeit to a lesser degree, when cooked vegetables are consumed. The lag in excretion on the cooked cabbage treatment suggests that the colon microflora catalyze glucosinolate hydrolysis in this case.}, }
@article {pmid14743397, year = {2004}, author = {Shih, CM and Ko, WC and Wu, JS and Wei, YH and Wang, LF and Chang, EE and Lo, TY and Cheng, HH and Chen, CT}, title = {Mediating of caspase-independent apoptosis by cadmium through the mitochondria-ROS pathway in MRC-5 fibroblasts.}, journal = {Journal of cellular biochemistry}, volume = {91}, number = {2}, pages = {384-397}, doi = {10.1002/jcb.10761}, pmid = {14743397}, issn = {0730-2312}, mesh = {Amino Acid Chloromethyl Ketones/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor ; Cadmium/*pharmacology ; Caspases/*physiology ; Cell Survival ; Cells, Cultured ; Electron Transport ; Fibroblasts/*cytology ; Flavoproteins/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Lung/cytology ; Membrane Proteins/metabolism ; Mitochondria/*metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Cadmium (Cd) is an environmental pollutant of global concern with a 10-30-year biological half-life in humans. Accumulating evidence suggests that the lung is one of the major target organs of inhaled Cd compounds. Our previous report demonstrated that 100 microM Cd induces MRC-5 cells, normal human lung fibroblasts, to undergo caspase-independent apoptosis mediated by mitochondrial membrane depolarization and translocation of apoptosis-inducing factor (AIF) from mitochondria into the nucleus. Here, using benzyloxycarbonyl-Val-Ala-Asp-(ome) fluoromethyl ketone (Z-VAD.fmk) as a tool, we further demonstrated that Cd could induce caspase-independent apoptosis at concentrations varied from 25 to 150 microM, which was modulated by reactive oxygen species (ROS) scavengers, such as N-acetylcysteine (NAC), mannitol, and tiron, indicating that ROS play a crucial role in the apoptogenic activity of Cd. Consistent with this notion, the intracellular hydrogen peroxide (H2O2) was 2.9-fold elevated after 3 h of Cd treatment and diminished rapidly within 1 h as detected by flow cytometry with 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Using inhibitors of the mitochondrial electron transport chain (ETC) (oligomycin A and rotenone for complex I and V, respectively) and mitochondrial permeability transition pore (MPTP) (cyclosporin A and aristolochic acid), we coincidently found the ROS production, mitochondrial membrane depolarization, and apoptotic content were almost completely or partially abolished. As revealed by confocal microscopy staining with chloromethyl-X-rosamine (CMXRos) and an anti-AIF antibody, the collapse of mitochondrial membrane potential induced by Cd (3 h-treatment) was a prelude to the translocation of caspase-independent pro-apoptotic factor, AIF, into the nucleus (after 4 h of Cd treatment). In summary, this study demonstrated that, in MRC-5 fibroblasts, Cd induced caspase-independent apoptosis through a mitochondria-ROS pathway. More importantly, we provide several lines of evidence supporting a role of mitochondrial ETC and MPTP in the regulation of caspase-independent cell death triggered by Cd.}, }
@article {pmid14734830, year = {2003}, author = {Shao, ZH and Vanden Hoek, TL and Xie, J and Wojcik, K and Chan, KC and Li, CQ and Hamann, K and Qin, Y and Schumacker, PT and Becker, LB and Yuan, CS}, title = {Grape seed proanthocyanidins induce pro-oxidant toxicity in cardiomyocytes.}, journal = {Cardiovascular toxicology}, volume = {3}, number = {4}, pages = {331-339}, doi = {10.1385/ct:3:4:331}, pmid = {14734830}, issn = {1530-7905}, support = {AT00381/AT/NCCIH NIH HHS/United States ; AT01575/AT/NCCIH NIH HHS/United States ; HL65558/HL/NHLBI NIH HHS/United States ; HL68951/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Caspase 3 ; Caspases/metabolism ; Cell Membrane/drug effects/pathology ; Cell Size/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Chick Embryo ; Enzyme Activation ; Fluoresceins/metabolism ; Heart Ventricles/cytology ; L-Lactate Dehydrogenase/biosynthesis ; Microscopy, Fluorescence ; Myocytes, Cardiac/*metabolism ; Oxidants/administration &amp; dosage/*adverse effects/pharmacology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Plant Extracts/administration &amp; dosage/adverse effects ; Proanthocyanidins/administration &amp; dosage/*adverse effects ; Reactive Oxygen Species/metabolism ; Seeds ; *Vitis ; }, abstract = {Grape seed proanthocyanidin extract (GSPE), a polyphenolic compound with antioxidant properties, may protect against cardiac ischemia and reperfusion injury. However, its potential toxicity at higher doses is unknown. The authors tested the effects of GSPE on reactive oxygen species (ROS) generation, cell survival, lactate dehydrogenase (LDH) release, and caspase- 3 activity using chick cardiomyocytes incubated with GSPE at 5, 10, 50, 100, or 500 micrograms/mL in medium for 8 h. Exposure to increasing concentrations of GSPE (100 or 500 micrograms/mL) resulted in an increase in ROS generation and cell death as measured by propidium iodide uptake and LDH release. Caspase-3 activity was significantly increased fourfold in cells exposed to GSPE 500 micrograms/ mL compared to controls; this was abolished by the selective caspase-3 inhibitor Ac-Asp-Gln-Thr-Asp-H (50 microM), which also significantly reduced the cell death resulting from GSPE (500 micrograms/mL). The antioxidant N-acetylcysteine (NAC, 100 microM) reduced cell death induced by GSPE (500 micrograms/mL) but failed to attenuate caspase-3 activation. Collectively, the authors conclude that higher doses of GSPE could cause apoptotic cell injury via effector caspase-3 activation and subsequent induction of ROS generation. Consumers may take higher doses of dietary supplements in the belief that natural herbs have no major side effects. This study demonstrates that dosages of GSPE should be optimized to avoid potential harmful pro-oxidant effects.}, }
@article {pmid14734137, year = {2004}, author = {Wuyts, WA and Vanaudenaerde, BM and Dupont, LJ and Van Raemdonck, DE and Demedts, MG and Verleden, GM}, title = {N-acetylcysteine inhibits interleukin-17-induced interleukin-8 production from human airway smooth muscle cells: a possible role for anti-oxidative treatment in chronic lung rejection?.}, journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}, volume = {23}, number = {1}, pages = {122-127}, doi = {10.1016/s1053-2498(03)00099-8}, pmid = {14734137}, issn = {1053-2498}, mesh = {Acetylcysteine/*pharmacology ; Bronchi/drug effects/immunology ; Cells, Cultured ; Free Radical Scavengers/*pharmacology ; Graft Rejection/immunology/prevention &amp; control ; Humans ; Interleukin-17/*antagonists &amp; inhibitors ; Interleukin-8/antagonists &amp; inhibitors/*biosynthesis ; Isoprostanes/antagonists &amp; inhibitors/biosynthesis ; Lung Transplantation/*immunology ; Myocytes, Smooth Muscle/*drug effects/immunology ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND: Long-term survival of lung transplantation is threatened by obliterative bronchiolitis, or its clinical equivalent, bronchiolitis obliterans syndrome. With a prevalence of >50% at 5 years after transplantation, it has emerged as the most significant long-term complication. Neutrophilic inflammation and increased interleukin (IL)-8 production seem to be part of the basic pathophysiologic mechanism of chronic rejection. Recently, it has been suggested that reactive oxygen species may also play an important role in the pathogenesis because they are known to induce smooth muscle proliferation.<br><br>METHODS: Human airway smooth muscle cells in vitro were stimulated with IL-17 (0.1 to 10 ng/ml) or with IL-17 (10 ng/ml) and the anti-oxidative agent N-acetylcysteine (1 micromol/liter to 10 mmol/liter). Production of 8-isoprostane was measured with a commercially available enzyme immunoassay kit and production of IL-8 was measured using a standard enzyme-linked immunoassay technique.<br><br>RESULTS: IL-17 produced a concentration-dependent increase in 8-isoprostane with a maximum of 136.5 +/- 15.5 pg/ml with IL-17 (10 ng/ml, p < 0.001, n = 12, vs unstimulated cells). N-acetylcysteine (NAC) was able to decrease IL-17-induced 8-isoprostane production, with a maximum decrease of 59.3 +/- 9% (p < 0.001, n = 12) with 10 mmol/liter of N-acetylcysteine, which also decreased IL-17-induced IL-8 production in a concentration-dependent manner (with maximum inhibition of 86.3% when combined with NAC 10 mmol/liter as compared with IL-17 alone).<br><br>CONCLUSIONS: We demonstrated that human airway smooth muscle cells, when stimulated with IL-17, are able to produce 8-isoprostane, which could be inhibited by adding N-acetylcysteline, and which was also able to decrease IL-17-induced IL-8 production. The clinical significance of these in vitro findings for prevention or treatment of chronic rejection after lung transplantation remains to be investigated.}, }
@article {pmid14732751, year = {2004}, author = {Cailleret, M and Amadou, A and Andrieu-Abadie, N and Nawrocki, A and Adamy, C and Ait-Mamar, B and Rocaries, F and Best-Belpomme, M and Levade, T and Pavoine, C and Pecker, F}, title = {N-acetylcysteine prevents the deleterious effect of tumor necrosis factor-(alpha) on calcium transients and contraction in adult rat cardiomyocytes.}, journal = {Circulation}, volume = {109}, number = {3}, pages = {406-411}, doi = {10.1161/01.CIR.0000109499.00587.FF}, pmid = {14732751}, issn = {1524-4539}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium/*metabolism ; Calcium-Binding Proteins/metabolism ; Cells, Cultured ; Glutathione/*analogs &amp; derivatives/metabolism/pharmacology ; Male ; Myocardial Contraction ; Myocytes, Cardiac/drug effects/metabolism/*physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Sphingomyelin Phosphodiesterase/metabolism ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/toxicity ; }, abstract = {BACKGROUND: The negative effect of tumor necrosis factor-alpha (TNF-alpha) on heart contraction, which is mediated by sphingosine, is a major component in heart failure. Because the cellular level of glutathione may limit sphingosine production via the inhibition of the Mg-dependent neutral sphingomyelinase (N-SMase), we hypothesized that cardiac glutathione status might determine the negative contractile response to TNF-alpha.<br><br>METHODS AND RESULTS: We examined the effects of TNF-alpha in isolated cardiomyocytes obtained from control rats or rats that were given the glutathione precursor N-acetylcysteine (NAC, 100 mg IP per animal). In cardiomyocytes obtained from control rats, 25 ng/mL TNF-alpha increased reactive oxygen species generation and N-SMase activity (500% and 34% over basal, respectively) and decreased the amplitude of [Ca(2+)](i) in response to electrical stimulation (22% below basal). NAC treatment increased cardiac glutathione content by 42%. In cardiomyocytes obtained from NAC-treated rats, 25 ng/mL TNF-alpha had no effect on reactive oxygen species production or N-SMase activity but increased the amplitude of [Ca(2+)](i) transients and contraction in response to electrical stimulation by 40% to 50% over basal after 20 minutes. This was associated with a hastened relaxation (20% reduction in t(1/2) compared with basal) and an increased phosphorylation of both Ser(16)- and Thr(17)-phospholamban residues (260% and 115% of maximal isoproterenol effect, respectively).<br><br>CONCLUSIONS: It is concluded that cardiac glutathione status, by controlling N-SMase activation, determines the severity of the adverse effects of TNF-alpha on heart contraction. Glutathione supplementation may therefore provide therapeutic benefits for vulnerable hearts.}, }
@article {pmid14730207, year = {2004}, author = {Hong, HJ and Liu, JC and Chan, P and Juan, SH and Loh, SH and Lin, JG and Cheng, TH}, title = {17beta-estradiol downregulates angiotensin-II-induced endothelin-1 gene expression in rat aortic smooth muscle cells.}, journal = {Journal of biomedical science}, volume = {11}, number = {1}, pages = {27-36}, doi = {10.1007/BF02256546}, pmid = {14730207}, issn = {1021-7770}, mesh = {Angiotensin II/*metabolism ; Animals ; Antioxidants/metabolism ; Aorta ; Cell Division/physiology ; Cells, Cultured ; *Down-Regulation ; Endothelin-1/genetics/*metabolism ; Estradiol/*physiology ; Female ; Genes, Reporter ; Humans ; Male ; Mitogen-Activated Protein Kinases/metabolism ; Muscle, Smooth, Vascular/*cytology/physiology ; Myocytes, Smooth Muscle/cytology/*physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; }, abstract = {It is well documented that 17beta-estradiol (E(2)) exerts a cardiovascular protective effect. A possible role of E(2) in the regulation of endothelin-1 (ET-1) production has been reported. However, the complex mechanisms by which E(2) inhibits ET-1 expression are not completely understood. The aims of this study were to examine whether E(2) may alter angiotensin II (Ang II)-induced cell proliferation and ET-1 gene expression and to identify the putative underlying signaling pathways in rat aortic smooth muscle cells. Cultured rat aortic smooth muscle cells were preincubated with E(2), then stimulated with Ang II, and [(3)H]thymidine incorporation and ET-1 gene expression were examined. The effect of E(2) on Ang-II-induced extracellular signal-regulated kinase (ERK) phosphorylation was tested to elucidate the intracellular mechanism of E(2) in proliferation and ET-1 gene expression. Ang II increased DNA synthesis which was inhibited with E(2) (1- 100 nM). E(2), but not 17alpha-estradiol, inhibited the Ang-II-induced ET-1 gene expression as revealed by Northern blotting and promoter activity assay. This effect was prevented by coincubation with the estrogen receptor antagonist ICI 182,780 (1 microM). E(2) also inhibited Ang-II-increased intracellular reactive oxygen species (ROS) as measured by a redox-sensitive fluorescent dye, 2',7'-dichlorofluorescin diacetate, and ERK phosphorylation. Furthermore, E(2) and antioxidants, such as N-acetyl cysteine and diphenylene iodonium, decreased Ang-II-induced cell proliferation, ET-1 promoter activity, ET-1 mRNA, ERK phosphorylation, and activator protein-1-mediated reporter activity. In summary, our results suggest that E(2) inhibits Ang-II-induced cell proliferation and ET-1 gene expression, partially by interfering with the ERK pathway via attenuation of ROS generation. Thus, this study provides important new insight regarding the molecular pathways that may contribute to the proposed beneficial effects of estrogen on the cardiovascular system.}, }
@article {pmid14730205, year = {2004}, author = {Liu, JC and Chan, P and Chen, JJ and Lee, HM and Lee, WS and Shih, NL and Chen, YL and Hong, HJ and Cheng, TH}, title = {The inhibitory effect of trilinolein on norepinephrine-induced beta-myosin heavy chain promoter activity, reactive oxygen species generation, and extracellular signal-regulated kinase phosphorylation in neonatal rat cardiomyocytes.}, journal = {Journal of biomedical science}, volume = {11}, number = {1}, pages = {11-18}, doi = {10.1007/BF02256544}, pmid = {14730205}, issn = {1021-7770}, mesh = {Acetylcysteine/metabolism ; Animals ; Animals, Newborn ; Cells, Cultured ; Fluorescent Dyes/metabolism ; Free Radical Scavengers/metabolism ; Gene Expression Regulation/drug effects ; Hydrogen Peroxide/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Molecular Structure ; Myocytes, Cardiac/cytology/*drug effects/metabolism ; Myosin Heavy Chains/*genetics/metabolism ; Norepinephrine/*pharmacology ; Oxidants/metabolism ; Oxidation-Reduction ; Phosphorylation ; Promoter Regions, Genetic/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Triglycerides/chemistry/*pharmacology ; Ventricular Myosins/*genetics/metabolism ; }, abstract = {The myocardial protective effects of trilinolein, isolated from the traditional Chinese herb Sanchi (Panax notoginseng), are thought to be related to its antioxidant activity. However, the intracellular mechanism underlying the protective effect of trilinolein in the heart remains unclear. In the present study, we investigated the effect of trilinolein on norepinephrine (NE)-induced protein synthesis in cardiomyocytes. Cultured neonatal rat cardiomyocytes were stimulated with NE, then protein content, [(3)H]-leucine incorporation, and beta-myosin heavy chain (beta-MyHC) promoter activity were examined. The effect of trilinolein on NE-induced intracellular reactive oxygen species (ROS) generation was measured with a redox- sensitive fluorescent dye (2',7'-dichlorofluorescin diacetate) and extracellular signal-regulated kinase (ERK) phosphorylation by Western blotting. Trilinolein inhibited NE-increased protein synthesis, beta-MyHC promoter activity, and intracellular ROS. Both trilinolein and the antioxidant, N-acetyl-cysteine, decreased NE- and H(2)O(2)-induced protein synthesis, beta-MyHC promoter activity, and ERK phosphorylation. These data indicate that trilinolein inhibits NE-induced protein synthesis via attenuation of ROS generation in cardiomyocytes.}, }
@article {pmid14726217, year = {2004}, author = {Cağlikülekci, M and Pata, C and Apa, DD and Dirlik, M and Tamer, L and Yaylak, F and Kanik, A and Aydin, S}, title = {The effect of N-acetylcysteine (NAC) on liver and renal tissue inducible nitric oxide synthase (iNOS) and tissue lipid peroxidation in obstructive jaundice stimulated by lipopolysaccharide (LPS).}, journal = {Pharmacological research}, volume = {49}, number = {3}, pages = {227-238}, doi = {10.1016/j.phrs.2003.09.013}, pmid = {14726217}, issn = {1043-6618}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Gene Expression Regulation, Enzymologic/drug effects/physiology ; Jaundice, Obstructive/*enzymology/etiology/pathology/prevention &amp; control ; Kidney/drug effects/*enzymology/pathology ; Lipid Peroxidation/*drug effects/physiology ; Lipopolysaccharides/*toxicity ; Liver/drug effects/*enzymology/pathology ; Male ; Nitric Oxide Synthase/antagonists &amp; inhibitors/*biosynthesis ; Nitric Oxide Synthase Type II ; Rats ; Rats, Wistar ; }, abstract = {Morbidity and mortality rates are very high in obstructive jaundice when it is associated with sepsis and multiple organ failure. Nitric oxide (NO) formation and increased expression of inducible nitric oxide synthase (iNOS) also take place in obstructive jaundice (OJ). N-Acetylcysteine (NAC) has a beneficial effect by demonstrating anti-inflammatory activity such as inhibits cytokine expression/release, inhibiting the adhesion molecule expression and inhibiting nuclear factor kappa B (NFkappaB). The aim of this study was to investigate the effects of NAC on liver and renal tissue iNOS, and liver tissue lipid peroxidation in lipopolysaccharide (LPS) induced obstructive jaundice. We randomized 48 rats into six groups. Group A: Sham group; group B: OJ group; group C: OJ+NAC; group D: OJ+LPS (Escherichia coli LPS serotype L-2630, 100mg, Sigma) group E: OJ+NAC+LPS; group F: OJ+LPS+NAC. NAC was started subcutaneously 100mg/kg. LPS was injected intraperitoneally and then at the tenth day we sacrificed the rats. Liver malondialdehyde (MDA) increased and liver ATPase decreased in groups B-D when compared to group A. After the administration of NAC (groups C-E), liver MDA levels decreased, tissue ATPase levels increased as compared to other groups. The liver and renal tissue iNOS expression was increased in groups B, D, and F. After the administration of NAC (groups C-E) the liver and renal tissue iNOS expression were decreased. Our results indicated that NAC prevented the deleterious effects of LPS in OJ by reducing iNOS expression via lipid peroxidation in liver and renal tissue; if it was administrated before LPS. But NAC failed to prevent the iNOS expression and lipid peroxidation if there was established endotoxemia in OJ.}, }
@article {pmid14722249, year = {2004}, author = {Bauer, D and Wolfram, N and Kahl, GF and Hirsch-Ernst, KI}, title = {Transcriptional regulation of CYP2B1 induction in primary rat hepatocyte cultures: repression by epidermal growth factor is mediated via a distal enhancer region.}, journal = {Molecular pharmacology}, volume = {65}, number = {1}, pages = {172-180}, doi = {10.1124/mol.65.1.172}, pmid = {14722249}, issn = {0026-895X}, mesh = {Animals ; Cytochrome P-450 CYP2B1/genetics/*metabolism ; Enzyme Inhibitors/pharmacology ; Epidermal Growth Factor/*pharmacology ; Gene Expression Regulation/drug effects ; Gene Expression Regulation, Enzymologic/*drug effects ; Growth Hormone/pharmacology ; Hepatocytes/*drug effects/enzymology ; Mice ; Permethrin/pharmacology ; Phenobarbital/pharmacology ; Promoter Regions, Genetic/drug effects ; Protein Binding ; Rats ; Rats, Wistar ; Transcription, Genetic/*drug effects ; Transcriptional Activation ; }, abstract = {Phenobarbital (PB) alters expression of numerous hepatic genes, including genes involved in xenobiotic metabolism. Phenobarbital-dependent induction of cytochrome P-450 2B1 (CYP2B1) is subject to regulation by cytokines [e.g., by epidermal growth factor (EGF)], hormones [e.g., by growth hormone (GH)], or the cellular redox status. To investigate mechanisms involved in regulation of CYP2B1 transcription, we performed promoter activation studies using primary rat hepatocyte cultures transiently transfected with individual CYP2B1 promoter-luciferase reporter gene constructs. The 2679-bp native 5'-flanking region of the CYP2B1 gene conferred reporter gene activation by PB and the potent PB-like inducer permethrin (PM). Furthermore, this region mediated EGF- and GH-dependent repression of gene activation by PB-like inducers. A wide promoter mapping strategy with constructs bearing internal CYP2B1 promoter deletions led to identification of a distal responsive CYP2B1 enhancer region at -2230 to -2170, encompassing the section equivalent to the 51-bp PB-responsive enhancer module situated in the distal mouse Cyp2b10-5'-flanking region. The distal CYP2B1 enhancer region conferred gene activation by PM, repression of PM-dependent activation by EGF, and enhancement of activation by the antioxidant N-acetylcysteine (NAC). Mutational analyses of the region at -2230 to -2170 suggested that the mechanisms of PB-dependent induction of CYP2B1 and the modulating effects by EGF or NAC are closely related.}, }
@article {pmid14720322, year = {2004}, author = {Futakuchi, M and Ogawa, K and Tamano, S and Takahashi, S and Shirai, T}, title = {Suppression of metastasis by nuclear factor kappaB inhibitors in an in vivo lung metastasis model of chemically induced hepatocellular carcinoma.}, journal = {Cancer science}, volume = {95}, number = {1}, pages = {18-24}, doi = {10.1111/j.1349-7006.2004.tb03165.x}, pmid = {14720322}, issn = {1347-9032}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aspirin/pharmacology ; Blotting, Western ; Carcinogens/toxicity ; Diethylnitrosamine/toxicity ; E-Selectin/biosynthesis/drug effects ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Intercellular Adhesion Molecule-1/biosynthesis/drug effects ; Liver Neoplasms, Experimental/chemically induced/drug therapy/pathology/*secondary ; Lung Neoplasms/*drug therapy/*secondary ; Male ; NF-kappa B/antagonists &amp; inhibitors/*drug effects ; Neoplasm Metastasis/*drug therapy ; Nitrosamines/toxicity ; Pentoxifylline/pharmacology ; RNA, Messenger/analysis ; Rats ; Reverse Transcriptase Polymerase Chain Reaction ; Vascular Cell Adhesion Molecule-1/biosynthesis/drug effects ; }, abstract = {To evaluate the suppressive effects of nuclear factor kappa B (NF-kappaB) inhibitors on metastasis, three agents, pentoxifylline (PTX, 0.5% in diet), N-acetyl-L-cysteine (NAC, 0.5% in diet), and aspirin (ASP, 0.5% in diet) were applied in an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration of NF-kappaB inhibitors for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. The incidence of HCC was 100% at week 23, regardless of treatment with NF-kappaB inhibitors. PTX, NAC, and ASP did not exert any significant effect on the development or differentiation of HCCs, although PTX tended to decrease the multiplicity of HCC. Although no lung metastasis was observed in the rats killed at the end of the period of carcinogen exposure, lung metastasis was found in 100% of animals in all the groups at the end of the experiment. Multiplicity of lung metastasis was significantly decreased by PTX and NAC, whereas ASP was without significant influence. The size of metastatic nodules was also significantly reduced in the PTX treatment group. Furthermore, the inhibitory kappa-B (IkappaB) protein level, considered to be a marker for the degree of NF-kappaB transcription, was significantly suppressed by PTX. mRNA expression in HCC for vascular cell adhesion molecule-1 (VCAM-1), which is considered to play a key role in attachment of cancer cells to the endothelium, was significantly suppressed by PTX. Among the splicing variants of VEGF, VEGF-A120, VEGF-A144, VEGF-A164, and VEGF-A188, suppressed mRNA expression of VEGF-A188 appeared to be correlated with suppression of lung metastasis formation. In conclusion, the present study demonstrated that NF-kappaB inhibitors have the potential to inhibit lung metastasis from rat HCCs in vivo, and PTX is especially promising. Its mechanism of action may involve suppression of VCAM-1 and VEGF-A188 production.}, }
@article {pmid14718647, year = {2004}, author = {Argentin, G and Cicchetti, R}, title = {Genotoxic and antiapoptotic effect of nicotine on human gingival fibroblasts.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {79}, number = {1}, pages = {75-81}, doi = {10.1093/toxsci/kfh061}, pmid = {14718647}, issn = {1096-6080}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Benzimidazoles ; Catalase/pharmacology ; Cell Culture Techniques ; Cell Division/drug effects/physiology ; Cell Survival/drug effects ; DNA Fragmentation/drug effects/genetics ; Dose-Response Relationship, Drug ; Fibroblasts/cytology/*drug effects ; Fluoresceins ; Fluorescence ; Fluorescent Dyes ; Gingiva/cytology/drug effects ; Humans ; Micronuclei, Chromosome-Defective/drug effects ; Micronucleus Tests/methods ; Nicotine/*adverse effects/antagonists &amp; inhibitors/metabolism ; Reactive Oxygen Species/adverse effects/metabolism ; Staurosporine/adverse effects/antagonists &amp; inhibitors/pharmacokinetics ; }, abstract = {Growing evidence suggests that nicotine, the addictive component of cigarettes, can have a direct role in tumor development by enhancing cell proliferation and impairing apoptotic process in certain types of human cancer cell lines. Since the correlation between apoptosis and DNA damage is already well documented, we investigated the response of human gingival fibroblasts (HGFs) to nicotine exposure by examining its effect on DNA damage induction and apoptotic process in parallel. To assess the genotoxicity of this drug, the cytokinesis-block micronucleus (CBMN) test was performed. Treatment of HGFs with nicotine, at a concentration of 1 microM, caused a statistically significant increase of micronucleus (MN) frequency at the tested time intervals, while no change was detected in cell growth under the same conditions. Furthermore, we found that preincubation of HGFs with 1 microM nicotine strongly attenuated staurosporine (STP)-induced apoptosis. Finally, we found that cultures exposed to nicotine showed an increase of reactive oxygen species, as determined by increased levels of 2,7-dichlorofluorescein (DCF). When cells were prelabeled with N-acetyl-cysteine (NAC), a substrate for glutathione synthesis, and catalase (CAT), the oxygen free radical scavenger, a significant reduction in cytogenetic damage was observed. Thus, for the first time, we report a concomitant genotoxic and antiapoptotic effect of nicotine in HGFs.}, }
@article {pmid14718582, year = {2004}, author = {Carraway, RE and Hassan, S and Cochrane, DE}, title = {Polyphenolic antioxidants mimic the effects of 1,4-dihydropyridines on neurotensin receptor function in PC3 cells.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {309}, number = {1}, pages = {92-101}, doi = {10.1124/jpet.103.060442}, pmid = {14718582}, issn = {0022-3565}, support = {DK 32520/DK/NIDDK NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology ; Calcium/metabolism ; Calcium Channel Agonists/pharmacology ; Calcium Channel Blockers/*pharmacology ; Calcium Channels/*metabolism ; Dihydropyridines/chemistry/*pharmacology ; Electron-Transferring Flavoproteins/metabolism ; Flavonoids/*pharmacology ; Humans ; Male ; Oxidation-Reduction/drug effects ; Oxidoreductases/metabolism ; Phenols/*pharmacology ; Polyphenols ; Potassium/metabolism ; Receptors, Neurotensin/drug effects/*metabolism ; Sodium/metabolism ; Sulfhydryl Compounds/metabolism ; Tumor Cells, Cultured ; }, abstract = {This study aimed to determine the mechanism(s) by which 1,4-dihydropyridine Ca2+ channel blockers (DHPs) enhance the binding of neurotensin (NT) to prostate cancer PC3 cells and inhibit NT-induced inositol phosphate formation. Earlier work indicated that these effects, which involved the G protein-coupled NT receptor NTR1, were indirect and required cellular metabolism or architecture. At the micromolar concentrations used, DHPs can block voltage-sensitive and store-operated Ca2+ channels, K+ channels, and Na+ channels, and can inhibit lipid peroxidation. By varying [Ca2+] and testing the effects of stimulators and inhibitors of Ca2+ influx and internal Ca2+ release, we determined that although DHPs may have inhibited inositol phosphate formation partly by blocking Ca2+ influx, the effect on NT binding was Ca2+-independent. By varying [K+] and [Na+], we showed that these ions did not contribute to either effect. For a series of DHPs, the activity order for effects on NTR1 function followed that for antioxidant ability. Antioxidant polyphenols (luteolin and resveratrol) mimicked the effects of DHPs and showed structural similarity to DHPs. Antioxidants with equal redox ability, but without structural similarity to DHPs (such as alpha-tocopherol, riboflavin, and N-acetyl-cysteine) were without effect. A flavoprotein oxidase inhibitor (diphenylene iodonium) and a hydroxy radical scavenger (butylated hydroxy anisole) also displayed the effects of DHPs. In conclusion, DHPs indirectly alter NTR1 function in live cells by a mechanism that depends on the drug's ability to donate hydrogen but does not simply involve sulfhydryl reduction.}, }
@article {pmid14715469, year = {2001}, author = {Marangolo, M and McGee, MM and Tipton, KF and Williams, DC and Zisterer, DM}, title = {Oxidative stress induces apoptosis in C6 glioma cells: involvement of mitogen-activated protein kinases and nuclear factor kappa B.}, journal = {Neurotoxicity research}, volume = {3}, number = {4}, pages = {397-409}, pmid = {14715469}, issn = {1029-8428}, abstract = {Excessive oxidative stress has been implicated in the induction of cell death in a variety of neurodegenerative diseases. In the present study, hydrogen peroxide (H2O2)-induced cell death in rat C6 glioma cells was used as a model system for studying the molecular events associated with oxidative stress-induced cell death in glial cells. We demonstrate that exposure of C6 glioma cells to H2O2 results in apoptotic cell death in a concentration-dependent manner, and caused activation of a member of the caspase-3-like family of proteases resulting in cleavage of the DNA repair enzyme poly(ADP-ribose)polymerase, PARP. Furthermore, H2O2 induced a transient activation of the transcription factor, nuclear factor kappa B (NF(Kappa)B). Pre-treatment of cells with the antioxidant N-acetylcysteine, (NAC), prevented both the activation of NF(Kappa)B and the induction of apoptosis by H2O2, suggesting a possible role for this transcription factor in oxidant-induced apoptosis in glial cells. Exposure of the cells to H2O2 led to transient activation of both c-Jun N-terminal kinase (JNK) and p38 kinase but has no effect on extracellular regulated kinase (ERK) activity. Inhibition of p38 by SB203580 did not protect the cells against H2O2-induced apoptosis suggesting that activation of p38 is not essential for H2O2-mediated cell death in C6 glioma cells.}, }
@article {pmid14714769, year = {2003}, author = {Eren, N and Cakir, O and Oruc, A and Kaya, Z and Erdinc, L}, title = {Effects of N-acetylcysteine on pulmonary function in patients undergoing coronary artery bypass surgery with cardiopulmonary bypass.}, journal = {Perfusion}, volume = {18}, number = {6}, pages = {345-350}, doi = {10.1191/0267659103pf696oa}, pmid = {14714769}, issn = {0267-6591}, mesh = {Acetylcysteine/*therapeutic use ; *Cardiopulmonary Bypass ; *Coronary Artery Bypass ; Double-Blind Method ; Female ; Humans ; Lipid Peroxidation ; Male ; Middle Aged ; Placebos ; Prospective Studies ; Pulmonary Gas Exchange/*drug effects ; Respiratory Function Tests ; }, abstract = {Cardiopulmonary bypass (CPB) has been implicated in causing poor pulmonary gas exchange postoperatively in patients undergoing coronary artery bypass grafting (CABG) procedures. In this prospective, randomized, double-blind, placebo-controlled study, we examined the pulmonary effects of N-acetylcysteine (NAC) in patients undergoing CABG. Twenty patients undergoing elective CABG and early tracheal extubation were randomized into two groups. Group I (ten patients) received a physiologic salt solution as a placebo in a continuous intravenous infusion for one hour before CPB and 24 hours after CPB; Group II (ten patients) received 100 mg/ kg NAC intravenously for one hour before CPB and 40 mg/kg/day at 24 hours after CPB. Perioperative hemodynamic and pulmonary data were recorded. Postoperative tracheal extubation was accomplished at the earliest appropriate time. The postoperative clinical course was similar in the two groups. Both groups exhibited significant postoperative increases in A-a oxygen gradient (p < 0.01), but patients in Group II exhibited significantly lower increases in postoperative A-a oxygen gradient (p < 0.006). Other hemodynamic and pulmonary data (pulmonary capillary wedge pressure, pulmonary vascular resistance (PVR), cardiac index (CI), shunt flow, dynamic lung compliance and static lung compliance) exhibited no differences between the groups. There was no significant difference in terms of intubation time. The malondialdehyde (MDA) increase in Group II following CPB was found to be significantly lower than in Group I (p = 0.043). This clinical study reveals that administration of NAC to patients undergoing elective CABG with CPB improves systemic oxygenation. There was no effect in other pulmonary parameters and in terms of intubation time.}, }
@article {pmid14712421, year = {2004}, author = {Alonso, A and Lau, J and Jaber, BL and Weintraub, A and Sarnak, MJ}, title = {Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials.}, journal = {American journal of kidney diseases : the official journal of the National Kidney Foundation}, volume = {43}, number = {1}, pages = {1-9}, doi = {10.1053/j.ajkd.2003.09.009}, pmid = {14712421}, issn = {1523-6838}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/chemically induced/*prevention &amp; control ; Cardiac Catheterization/adverse effects ; Contrast Media/*adverse effects ; Cystine/*analogs &amp; derivatives/therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Kidney Failure, Chronic/complications ; Randomized Controlled Trials as Topic ; Tomography, X-Ray Computed/adverse effects ; }, abstract = {BACKGROUND: Radiocontrast nephropathy (RCN) is a common cause of hospital-acquired acute renal failure. Results of several studies using N-acetylcysteine (NAC) for the prevention of RCN have yielded conflicting results. We performed a meta-analysis of group data extracted from previously published studies to assess the effect of NAC on the prevention of RCN in patients with pre-existing chronic kidney disease (CKD).<br><br>METHODS: Ovid's multidatabase search for MEDLINE, Cochrane Central Registry of Controlled Trials, Cochrane Database of Systematic Reviews, and HealthSTAR were used to identify candidate articles. Abstracts from proceedings of scientific meetings also were screened. We selected blinded and unblinded randomized controlled trials (RCTs) performed in humans 18 years and older with pre-existing CKD, defined by a mean baseline serum creatinine level of 1.2 mg/dL or greater (> or =106.1 micromol/L) or creatinine clearance less than 70 mL/min (<1.17 mL/s). The overall risk ratio (RR) for the development of RCN was computed using a random-effects model.<br><br>RESULTS: Eight RCTs (n = 885 patients) published in full-text articles were included in the primary analysis. In the control group, the overall rate of RCN was 18.5% (95% confidence interval [CI], 15 to 22). In the primary analysis, overall RR for RCN associated with the use of NAC was 0.41 (95% CI, 0.22 to 0.79; P = 0.007). In a sensitivity analysis that included 4 additional RCTs published in abstract form, RR remained significant at 0.55 (95% CI, 0.34 to 0.91; P = 0.020).<br><br>CONCLUSION: NAC reduces the risk for RCN in patients with CKD.}, }
@article {pmid14709335, year = {2004}, author = {Sylvester, J and Liacini, A and Li, WQ and Zafarullah, M}, title = {Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes.}, journal = {Cellular signalling}, volume = {16}, number = {4}, pages = {469-476}, doi = {10.1016/j.cellsig.2003.09.008}, pmid = {14709335}, issn = {0898-6568}, mesh = {ADAM Proteins ; ADAMTS4 Protein ; Acetylcysteine/pharmacology ; Animals ; Cartilage, Articular/drug effects/metabolism ; Cattle ; Cells, Cultured ; Chondrocytes/drug effects/*metabolism ; Collagenases/*metabolism ; Curcumin/pharmacology ; Enzyme Inhibitors/pharmacology ; Humans ; Interleukin-17/*pharmacology ; JNK Mitogen-Activated Protein Kinases ; Masoprocol/pharmacology ; Matrix Metalloproteinase 13 ; Matrix Metalloproteinase 3/*metabolism ; Metalloendopeptidases/*metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Phosphorylation ; Procollagen N-Endopeptidase ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/metabolism ; Signal Transduction ; Transcription Factor AP-1/metabolism ; p38 Mitogen-Activated Protein Kinases ; NF-kappaB-Inducing Kinase ; }, abstract = {Interleukin (IL)-17 promotes cartilage breakdown by inducing matrix metalloproteinases (MMPs) and aggrecanases (a disintegrin and metalloproteinase with thrombospondin motif, ADAMTS) in arthritic joints. We investigated IL-17 signaling pathways inducing MMP-3, MMP-13 and ADAM-TS4 genes in bovine articular chondrocytes. IL-17 stimulated phosphorylation of extracellular signal-regulated kinase (ERK), protein 38 (p38) and c-Jun N-terminal kinase (JNK). ERK pathway inhibitors, PD98059 and U0126, down-regulated IL-17-induced MMP and ADAM-TS4 gene expression. Protein 38 and JNK pathway inhibitors, SB203580 and SP600125, also reduced induction of these genes. Antioxidants and activating protein-1 transcription factor inhibitors, nordihydroguaiaretic acid and N-acetyl-L-cysteine (NAC) suppressed MMP and ADAM-TS4 genes. Similarly, nuclear factor kappa B (NF-kappaB) pathways inhibitors curcumin and Bay-11-7085 also blocked their induction. Thus MMP-3, MMP-13 and ADAM-TS4 genes are coordinately up-regulated by IL-17 via MAP kinases, activating protein-1 (AP-1) and NF-kappaB mediators, which could be targeted for reducing IL-17-triggered cartilage damage.}, }
@article {pmid14706870, year = {2004}, author = {Krasowska, A and Konat, GW}, title = {Vulnerability of brain tissue to inflammatory oxidant, hypochlorous acid.}, journal = {Brain research}, volume = {997}, number = {2}, pages = {176-184}, doi = {10.1016/j.brainres.2003.09.080}, pmid = {14706870}, issn = {0006-8993}, mesh = {Animals ; Antioxidants/pharmacology/therapeutic use ; Brain/*drug effects/metabolism ; Dose-Response Relationship, Drug ; Female ; Hypochlorous Acid/*toxicity ; Inflammation/*chemically induced/metabolism/prevention &amp; control ; Oxidants/*toxicity ; Protein Biosynthesis ; Rats ; Rats, Sprague-Dawley ; }, abstract = {CNS inflammation is a sequela of a variety of neuropathological conditions resulting in extensive tissue loss. Inflammation is mediated primarily by phagocytic cells, but the mechanisms of CNS tissue destruction are not fully understood. Hypochlorous acid (HOCl) is by far the most abundant agent generated by phagocytic cells and may be the major mediator of inflammatory tissue damage. However, the effects of HOCl on nervous tissue have not been examined. In this study we used an in vitro model system of rat brain slices to determine neurotoxicity of HOCl. The slices were exposed to HOCl at pathologically relevant doses, and the incorporation of [3H]leucine into proteins and lipids was analyzed in total homogenate, and in particulate fractions obtained by density gradient centrifugation. The results demonstrated that a brief HOCl exposure profoundly suppressed protein biosynthesis in the slices. Also, lipid synthesis was suppressed in nonmyelin particulate fraction. However, lipid synthesis in myelin was significantly stimulated in HOCl-exposed slices indicating that oligodendrocyte response to the oxidant differs from that of other CNS cells. The effects of HOCl could be blocked by coadministration of antioxidants, i.e., N-acetylcystein (NAC), uric acid (UA) and ascorbic acid (AA). The protective potency of the antioxidants was NAC>UA>AA. In conclusion, our study demonstrated that HOCl generated by phagocytic cells during inflammatory episodes has a potential to damage surrounding CNS tissue, and that tissue damage can be prevented by HOCl scavenging with clinically applicable antioxidants.}, }
@article {pmid14706622, year = {2004}, author = {Lagunas, L and Bradbury, CM and Laszlo, A and Hunt, CR and Gius, D}, title = {Indomethacin and ibuprofen induce Hsc70 nuclear localization and activation of the heat shock response in HeLa cells.}, journal = {Biochemical and biophysical research communications}, volume = {313}, number = {4}, pages = {863-870}, doi = {10.1016/j.bbrc.2003.12.018}, pmid = {14706622}, issn = {0006-291X}, mesh = {Active Transport, Cell Nucleus/drug effects ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; DNA/metabolism ; DNA-Binding Proteins/metabolism ; HSC70 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins/*metabolism ; HeLa Cells ; Heat Shock Transcription Factors ; Heat-Shock Response/*drug effects ; Humans ; Ibuprofen/*pharmacology ; Indomethacin/*pharmacology ; MAP Kinase Signaling System ; Mice ; Models, Biological ; NIH 3T3 Cells ; Oxidative Stress ; Transcription Factors ; }, abstract = {It has been established that non-steroidal anti-inflammatory drugs (NSAIDs), such as sodium salicylate, sulindac, ibuprofen, and indomethacin, induce anti-inflammatory and anti-proliferative effects independent of cyclooxygenase. These cyclooxygenase-independent pharmacodynamic effects appear to regulate several signaling pathways involving proliferation, apoptosis, and heat shock response. However, the mechanisms of these actions remain an area of ongoing investigation. Hsc70 is a cytoplasmic chaperone protein involved in folding and trafficking of client proteins to different subcellular compartments, plays roles in signal transduction and apoptosis processes, and translocates to the nucleus following exposure to heat shock. Since NSAIDs induce some aspects of the heat shock response, we hypothesized that they may also induce Hsc70 nuclear translocation. Western immunoblotting and indirect cellular immunofluorescence showed that indomethacin and ibuprofen induce Hsc70 nuclear translocation at concentrations previously shown to induce HSF DNA-binding activity. Chemical inhibition of both p38(MAPK) and Erk42/44 had no effect on localization patterns. In addition, while indomethacin has been shown to behave as an oxidative stressor, the radical scavenging agent, N-acetyl cysteine, did not inhibit nuclear translocation. These results indicate that induction of the heat shock response by NSAIDs occurs at concentrations fivefold greater than those required to inhibit cyclooxygenase activity, suggesting a cyclooxygenase-independent mechanism, and in the presence or absence of kinase inhibitors and a free radical scavenger, suggesting independence of Erk42/44 or p38(MAPK) activities and intracellular oxidoreductive state.}, }
@article {pmid14704308, year = {2004}, author = {Hsu, CC and Huang, CN and Hung, YC and Yin, MC}, title = {Five cysteine-containing compounds have antioxidative activity in Balb/cA mice.}, journal = {The Journal of nutrition}, volume = {134}, number = {1}, pages = {149-152}, doi = {10.1093/jn/134.1.149}, pmid = {14704308}, issn = {0022-3166}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Catalase/blood/metabolism ; Cholesterol/blood ; Cysteine/*analogs &amp; derivatives/*pharmacology ; Fibronectins/blood ; Garlic/chemistry ; Glutathione/analysis/blood ; Glutathione Peroxidase/blood/metabolism ; Kidney/enzymology ; Lipid Peroxidation/drug effects ; Liver/enzymology ; Male ; Mice ; Mice, Inbred BALB C ; Triglycerides/blood ; }, abstract = {Balb/cA mice were used to study the in vivo effect of N-acetyl cysteine, S-allyl cysteine, S-ethyl cysteine, S-methyl cysteine and S-propyl cysteine, all derived from garlic, on glutathione (GSH) concentration and catalase and glutathione peroxidase (GPX) activities in plasma, kidney and liver. Cysteine was used for comparison. The effects of these compounds on the levels of fibronectin, triglyceride (TG), cholesterol and alpha-tocopherol were also evaluated. Cysteine or cysteine-containing compounds were added to drinking water at 1 g/L. After 4 wk of treatment, GSH levels in kidney and liver were greater (P<0.05) than in controls. Cysteine decreased catalase and GPX activities in liver, and enhanced both Fe2+- and glucose-induced lipid oxidation in plasma, kidney and liver compared with the control group (P<0.05). However, the administration of the five cysteine-containing compounds enhanced catalase and GPX activities in kidney and liver, and reduced Fe2+- and glucose-induced lipid oxidation in plasma, kidney and liver compared with the control and cysteine-treated groups (P<0.05). Intake of the five cysteine-containing compounds reduced fibronectin, TG and cholesterol concentrations in plasma and liver, and increased the alpha-tocopherol concentration in plasma, kidney and liver compared with the control and cysteine-treated groups (P<0.05). The five cysteine-containing compounds derived from garlic had marked effects on antioxidant enzymes and spared alpha-tocopherol in mice. Furthermore, these compounds reduced fibronectin, TG and cholesterol concentrations in plasma. These data indicate that these compounds have a range of protective effects for cardiovascular disease prevention or therapy.}, }
@article {pmid14704304, year = {2004}, author = {Mariotti, F and Simbelie, KL and Makarios-Lahham, L and Huneau, JF and Laplaize, B and Tomé, D and Even, PC}, title = {Acute ingestion of dietary proteins improves post-exercise liver glutathione in rats in a dose-dependent relationship with their cysteine content.}, journal = {The Journal of nutrition}, volume = {134}, number = {1}, pages = {128-131}, doi = {10.1093/jn/134.1.128}, pmid = {14704304}, issn = {0022-3166}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Cysteine/administration &amp; dosage/*analysis ; Dietary Proteins/*administration &amp; dosage ; Glucose/administration &amp; dosage ; Glutathione/*analysis/blood ; Kinetics ; Lactalbumin/administration &amp; dosage ; Liver/*chemistry ; Male ; Milk Proteins/administration &amp; dosage ; Myocardium/chemistry ; Oxidation-Reduction ; *Physical Exertion ; Rats ; Rats, Wistar ; }, abstract = {Dietary sulfur amino acids affect glutathione synthesis, but their acute effect under conditions of oxidative stress is unknown. We assessed the effect of the selective ingestion of alpha-lactalbumin, a cysteine-rich protein, on glutathione homeostasis before a single bout of exhaustive exercise. One hour before a 2-h run on a treadmill, untrained rats ingested a meal enriched with either milk protein (TMP), alpha-lactalbumin-enriched milk protein (alpha-LAC), glucose (GLUC) or milk protein plus 150 mg N-acetyl-L-cysteine, a pharmacologic cysteine donor (NAC). Glutathione status was monitored in the blood and measured postexercise in the liver and heart. A group of fed sedentary rats was used as a control (CON). Blood total glutathione levels declined over time in all test groups. Although postexercise heart glutathione did not differ among groups, postexercise liver glutathione was curvilinearly related to prior cysteine intake (R2=0.999, P<0.05). In alpha-LAC rats, liver glutathione was 60-80% higher than in GLUC or CON rats (P<0.05) and did not differ from that of NAC rats. Cysteine from dietary proteins exhibits a considerable, dose-dependent and acute stimulatory effect on liver glutathione during exercise but does not immediately benefit whole-body glutathione homeostasis, presumably because of an overlap between the postprandial and exercise-related states.}, }
@article {pmid14703729, year = {2003}, author = {Kowluru, RA and Koppolu, P and Chakrabarti, S and Chen, S}, title = {Diabetes-induced activation of nuclear transcriptional factor in the retina, and its inhibition by antioxidants.}, journal = {Free radical research}, volume = {37}, number = {11}, pages = {1169-1180}, doi = {10.1080/10715760310001604189}, pmid = {14703729}, issn = {1071-5762}, mesh = {Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Ascorbic Acid/administration &amp; dosage ; Chromans/administration &amp; dosage ; Cysteine/administration &amp; dosage ; Diabetes Mellitus, Experimental/*metabolism ; Diabetic Retinopathy/*metabolism ; Glucose/pharmacology ; Lipid Peroxides/metabolism ; Male ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II ; Rats ; Rats, Sprague-Dawley ; Retina/*enzymology ; Selenium/administration &amp; dosage ; Tyrosine/*analogs &amp; derivatives/metabolism ; alpha-Tocopherol/administration &amp; dosage ; beta Carotene/administration &amp; dosage ; }, abstract = {Oxidative stress is increased in the retina in diabetes, and long-term administration of antioxidants inhibits the development of retinopathy in diabetic rats. The purpose of this study is to determine how diabetes affects the activation of a redox-sensitive nuclear transcriptional factor in the retina, NF-kappaB, and its inhibition by antioxidants. Alloxan diabetic rats were assigned to receive standard diet or the diet supplemented with multiple antioxidants, including ascorbic acid, Trolox, dl alpha-tocopherol acetate, N-acetyl cysteine, beta-carotene, and selenium for up to 14 months. NF-kappaB activation, oxidative stress and nitric oxides were measured in the retina at 2, 8 and 14 months of diabetes. Retinal NF-kappaB was activated by about 60% at two months after induction of diabetes, remained activated for up to 14 months of diabetes, and the duration of diabetes had no effect on the intensity of NF-kappaB activation. Similarly, oxidative stress and nitric oxides were elevated by over 50% in the retina of rats diabetic for 14 months, and nitrotyrosine levels were elevated by over two folds. Administration of the antioxidants to the rats for the entire duration of diabetes inhibited activation of NF-kappaB and elevations in oxidative stress, nitric oxides and nitrotyrosine formation without ameliorating the severity of hyperglycemia. These in vivo results were confirmed by in vitro studies showing that high glucose activates NF-kappaB and elevates NO and lipid peroxides in both retinal endothelial cells and pericytes that can be inhibited by antioxidants. Thus, the results suggest that the activation of retinal NF-KB in diabetes is an early event in the development of retinopathy, and it remains active when the retinal capillary cell death is accelerating, and histopathology is developing. Beneficial effects of antioxidants on the development of diabetic retinopathy might involve inhibition of NF-kappaB activation and its downstream pathways in the retina.}, }
@article {pmid14703013, year = {2003}, author = {Berg, C and Trofast, C and Bengtsson, T}, title = {Platelets induce reactive oxygen species-dependent growth of human skin fibroblasts.}, journal = {European journal of cell biology}, volume = {82}, number = {11}, pages = {565-571}, doi = {10.1078/0171-9335-00344}, pmid = {14703013}, issn = {0171-9335}, mesh = {Acetophenones/pharmacology ; Acetylcysteine/pharmacology ; Becaplermin ; Blood Platelets/cytology/*metabolism ; Cell Division/drug effects/*physiology ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Fibroblasts/cytology/*metabolism ; Fluoresceins/chemistry ; Humans ; Lysophospholipids/antagonists &amp; inhibitors/pharmacology ; NADPH Oxidases/antagonists &amp; inhibitors ; Onium Compounds/pharmacology ; Platelet-Derived Growth Factor/pharmacology ; Proto-Oncogene Proteins c-sis ; Reactive Oxygen Species/*metabolism ; Skin/cytology/*metabolism ; Sphingosine/analogs &amp; derivatives/antagonists &amp; inhibitors/pharmacology ; Thiocarbamates/pharmacology ; Transforming Growth Factor beta/pharmacology ; Transforming Growth Factor beta1 ; }, abstract = {A growing amount of evidence suggests that reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, regulate intracellular signalling and have a role in cell proliferation. In the present study, we show that platelets increase the mitogenic rate in human fibroblasts and that this effect was inhibited by the intracellular antioxidant N-acetyl-L-cysteine (NAC) and the NADPH-oxidase inhibitor diphenyleneiodonium chloride (DPI). The mitogenic effects of platelets were mimicked by the platelet factors platelet-derived growth factor BB-isoform (PDGF-BB), transforming growth factor beta1 (TGF-beta1) and sphingosine-1-phosphate (S1P). The sphingosine kinase inhibitor DL-threo-dihydrosphingosine (DL-dihydro) abrogated the platelet-induced growth, while antibodies directed against PDGF or TGF-beta had modest effects. Exposure of fibroblasts to platelets, PDGF-BB, TGF-beta1 or S1P caused an extensive intracellular ROS production, measured as changes in dichlorofluorescein fluorescence. This ROS production was totally inhibited by NAC, pyrrolidinethiocarbamate (PDTC), DPI and apocynin. In conclusion, the results presented are indicative of a crucial role of ROS in the platelet-mediated regulation of fibroblast proliferation.}, }
@article {pmid14701705, year = {2004}, author = {Blanchet, S and Ramgolam, K and Baulig, A and Marano, F and Baeza-Squiban, A}, title = {Fine particulate matter induces amphiregulin secretion by bronchial epithelial cells.}, journal = {American journal of respiratory cell and molecular biology}, volume = {30}, number = {4}, pages = {421-427}, doi = {10.1165/rcmb.2003-0281RC}, pmid = {14701705}, issn = {1044-1549}, mesh = {Air Pollutants/chemistry/*pharmacology ; Amphiregulin ; Bronchi/*cytology/drug effects/metabolism ; Cells, Cultured ; EGF Family of Proteins ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/*drug effects/metabolism ; ErbB Receptors/antagonists &amp; inhibitors/drug effects/metabolism ; Flavonoids/pharmacology ; Gene Expression Regulation/drug effects ; Glycoproteins/*drug effects/genetics/*metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Humans ; Imidazoles/pharmacology ; Intercellular Signaling Peptides and Proteins/genetics/*metabolism ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/drug effects/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/drug effects/metabolism ; Particle Size ; Pyridines/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Vehicle Emissions/adverse effects ; }, abstract = {Particulate matter (PM) is thought to be responsible for respiratory health problems. Epithelial cells exposed to particles release pro-inflammatory cytokines leading to inflammation of airways. However, the signaling cascades triggered by particles are poorly understood. We demonstrate that PM with an aerodynamic diameter < 2.5 microm (PM2.5) or diesel exhaust particles upregulate the expression of amphiregulin (AR), a ligand of the epidermal growth factor receptor (EGFR), in human bronchial epithelial cells. AR secretion was blocked by an inhibitor of the EGFR tyrosine kinase (AG1478), or a selective mitogen-activated protein (MAP) kinase/extracellular regulated kinase (Erk) inhibitor (PD98059), but not by the p38 MAP kinase inhibitor (SB203580). Thus, AR secretion is mediated through the activation of the EGFR and Erk MAP kinase pathway. In addition, AR secretion was inhibited by the antioxidant N-acetyl cysteine, but not by a neutralizing anti-EGFR, suggesting an EGFR transactivation via oxidative stress. AR may be involved in cytokine secretion, as AR can induce granulocyte macrophage-colony-stimulating factor (GM-CSF) release and a neutralizing anti-EGFR reduces the particle-induced GM-CSF release. This study indicates that PM2.5 induces the expression and secretion of AR, an EGFR ligand contributing to GM-CSF release, which may reflect an important mechanism for sustaining the proinflammatory response.}, }
@article {pmid14695932, year = {2003}, author = {Cooper, JM and Schapira, AH}, title = {Friedreich's Ataxia: disease mechanisms, antioxidant and Coenzyme Q10 therapy.}, journal = {BioFactors (Oxford, England)}, volume = {18}, number = {1-4}, pages = {163-171}, doi = {10.1002/biof.5520180219}, pmid = {14695932}, issn = {0951-6433}, mesh = {Antioxidants/*therapeutic use ; Coenzymes ; Electron Transport ; Friedreich Ataxia/*drug therapy/genetics/physiopathology ; Humans ; Iron/metabolism ; Iron Chelating Agents ; Iron-Binding Proteins/physiology ; Mitochondria/metabolism ; Oxidative Stress ; Ubiquinone/*analogs &amp; derivatives/*therapeutic use ; Frataxin ; }, abstract = {Mitochondria clearly play a central role in the pathogenesis of Friedreich's Ataxia. The most common genetic abnormality results in the deficiency of the protein frataxin, which is targeted to the mitochondrion. Research since this discovery has indicated that mitochondrial respiratory chain dysfunction, mitochondrial iron accumulation and oxidative damage are important components of the disease mechanism. While the role of frataxin is not known, evidence is currently pointing to a role in either mitochondrial iron handling or iron sulphur centre synthesis. These advances in our understanding of the disease mechanisms are enabling therapeutic avenues to be explored, in particular the use of established drugs such as antioxidants and enhancers of respiratory chain function. Vitamin E therapy has been shown to be beneficial in patients with ataxia with vitamin E deficiency, and CoQ10 therapy was effective in some patients with ataxia associated with CoQ10 deficiency. A combined therapy involving long term treatment with high doses of vitamin E and coenzyme Q10 has jointly targeted two of the major features of Friedreich's Ataxia; decreased mitochondrial respiratory chain function and increased oxidative stress. This therapy clearly showed a rapid and sustained increase in the energy generated by the FRDA heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation parallel those of the heart but to a lower level. While this therapy appeared to slow the predicted progression of some clinical symptoms a larger placebo controlled study is required to confirm these observations. Other antioxidant strategies have involved the use of Idebenone, selenium and N acetyl cysteine but only the use of Idebenone has involved structured trials with relatively large patient numbers. Idebenone clearly had an impact upon the cardiac hypertrophy in the majority of patients, although there have not been any other significant benefits reported to date.}, }
@article {pmid14693707, year = {2004}, author = {Wang, X and Li, H and De Leo, D and Guo, W and Koshkin, V and Fantus, IG and Giacca, A and Chan, CB and Der, S and Wheeler, MB}, title = {Gene and protein kinase expression profiling of reactive oxygen species-associated lipotoxicity in the pancreatic beta-cell line MIN6.}, journal = {Diabetes}, volume = {53}, number = {1}, pages = {129-140}, doi = {10.2337/diabetes.53.1.129}, pmid = {14693707}, issn = {0012-1797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Enzymes/drug effects/genetics ; *Gene Expression Profiling ; Islets of Langerhans/drug effects/*physiology ; Okadaic Acid/pharmacology ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress/drug effects/*physiology ; Protein Kinases/*genetics ; RNA Processing, Post-Transcriptional/drug effects ; Reactive Oxygen Species/*pharmacology ; }, abstract = {Oligonucleotide microarrays were used to define oleic acid (OA)-regulated gene expression and proteomic technology to screen protein kinases in MIN6 insulinoma cells. The effects of oxidative stress caused by OA and potential protective effects of N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species (ROS), on global gene expression and beta-cell function were investigated. Long-term exposure of MIN6 cells to OA led to a threefold increase in basal insulin secretion, a 50% decrease in insulin content, an inhibition of glucose-stimulated insulin secretion (GSIS), and a twofold increase in the level of ROS. The addition of NAC normalized both the OA-induced insulin content and ROS elevation, but it failed to restore GSIS. Microarray studies and subsequent quantitative PCR analysis showed that OA consistently regulated the expression of 45 genes involved in metabolism, cell growth, signal transduction, transcription, and protein processing. The addition of NAC largely normalized the expression of the OA-regulated genes involved in cell growth and differentiation but not other functions. A protein kinase screen showed that OA regulated the expression and/or phosphorylation levels of kinases involved in stress-response mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and cell cycle control pathways. Importantly, these findings indicate that chronic OA exposure can impair beta-cell function through ROS-dependent and -independent mechanisms.}, }
@article {pmid14693051, year = {2003}, author = {Chen, YB and Hou, J and Fu, WJ and Ding, SQ and Wang, DX and Yuan, ZG and Kong, XT}, title = {[Mechanism of arsenic trioxide-induced cytotoxicity on multiple myeloma cells].}, journal = {Ai zheng = Aizheng = Chinese journal of cancer}, volume = {22}, number = {12}, pages = {1276-1279}, pmid = {14693051}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Cell Division/drug effects ; Cell Survival/drug effects ; Drug Interactions ; Glutathione/pharmacology ; Humans ; Multiple Myeloma/*pathology ; Oxides/*pharmacology ; Tumor Cells, Cultured ; Vitamin K 3/pharmacology ; }, abstract = {BACKGROUND &amp; OBJECTIVE: Multiple myeloma (MM), a plasma cell tumor, is difficult to cure by now. Previous study showed that As2O3 could inhibit the proliferation and induce the apoptosis of myeloma cell in vitro. The aim of this study was to explore the possible mechanism of arsenic trioxide (As2O3) on multiple myeloma cells.<br><br>METHODS: The cytotoxic effects of As2O3 on five myeloma cell lines U266, SKO-007, LP-1, HS-Sultan, and KM3 were examined using MTT bioassay, and the concentration of 50% growth inhibition (IC(50)) was calculated. The synergistic or antagonistic effects of menadione (VK(3)), N-acetyl-cysteine (NAC), and reduced glutathione (GSH) combined with As2O3 were also examined. The cellular GSH levels in five MM cell lines and its changes in U266 cells after treated with As2O3, VK(3), NAC, and exogenous GSH were determined by colorimetric assay, and the relationship between IC(50) and cellular GSH levels was analyzed.<br><br>RESULTS: As2O3 inhibited the proliferation of all five myeloma cells, but with different sensitivity. GSH contents in five MM cells were correlated with its IC(50) significantly (r=0.87,P< 0.05). Oxidant VK(3) had significant synergistic effect with As2O3, and antioxidants NAC and GSH partly blocked the growth inhibition of As2O3. Both As2O3 and VK(3) decreased the GSH contents, NAC and GSH increased them contrarily.<br><br>CONCLUSION: One of the mechanisms of effect of As2O3 on myeloma cells may be through decreasing the cellular GSH levels and inducing myeloma cell apoptosis.}, }
@article {pmid14690799, year = {2003}, author = {Lomnitski, L and Bergman, M and Nyska, A and Ben-Shaul, V and Grossman, S}, title = {Composition, efficacy, and safety of spinach extracts.}, journal = {Nutrition and cancer}, volume = {46}, number = {2}, pages = {222-231}, doi = {10.1207/S15327914NC4602_16}, pmid = {14690799}, issn = {0163-5581}, mesh = {Animals ; Anti-Inflammatory Agents ; Antimutagenic Agents ; Antineoplastic Agents ; Antioxidants ; Estrogens ; Food Hypersensitivity/etiology ; Health Promotion ; Humans ; Plant Extracts/adverse effects/*chemistry/*therapeutic use ; Spinacia oleracea/*chemistry ; }, abstract = {Spinach leaves, containing several active components, including flavonoids, exhibit antioxidative, antiproliferative, and antiinflammatory properties in biological systems. Spinach extracts have been demonstrated to exert numerous beneficial effects, such as chemo- and central nervous system protection and anticancer and antiaging functions. In this review article, we present a compilation of data generated in our laboratories and those of other investigators describing the chemical composition of spinach, its beneficial effects, relative safety information, and its recommended inclusion in the human diet. A powerful, water-soluble, natural antioxidant mixture (NAO), which specifically inhibits the lipoxygenase enzyme, was isolated from spinach leaves. The antioxidative activity of NAO has been compared to that of other known antioxidants and found to be superior in vitro and in vivo to that of green tea, N-acetylcysteine (NAC), butylated hydroxytoluene (BHT), and vitamin E. NAO has been tested for safety and is well tolerated in several species, such as mouse, rat, and rabbit. NAO has been found to be nonmutagenic and has shown promising anticarcinogenic effects in a few experimental models, such as skin and prostate cancer; it has not shown any target-organ toxicity or side effects. The current review provides epidemiological and preclinical data supporting the efficacy of extracts of spinach and the safety of its consumption.}, }
@article {pmid14688023, year = {2004}, author = {Miyoshi, N and Takabayashi, S and Osawa, T and Nakamura, Y}, title = {Benzyl isothiocyanate inhibits excessive superoxide generation in inflammatory leukocytes: implication for prevention against inflammation-related carcinogenesis.}, journal = {Carcinogenesis}, volume = {25}, number = {4}, pages = {567-575}, doi = {10.1093/carcin/bgh051}, pmid = {14688023}, issn = {0143-3334}, mesh = {Anticarcinogenic Agents/*pharmacology ; Cell Differentiation/drug effects ; Glutathione/metabolism ; HL-60 Cells ; Humans ; Inflammation/*complications ; Isothiocyanates/*pharmacology ; Kinetics ; Leukocytes/drug effects/*physiology ; NADPH Oxidases/antagonists &amp; inhibitors ; Neoplasms/physiopathology/*prevention &amp; control ; Protein Kinase C/metabolism ; Protein Transport ; Superoxides/*metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; }, abstract = {Inhibitors of excessive superoxide (O2-) generation have been indicated to be more effective antioxidants than radical scavengers because O2- anion is one of the precursors of several types of reactive oxygen species (ROS). We demonstrated here that benzyl isothiocyanate (BITC) is a potent inhibitor of leukocytic NADPH oxidase generating a great amount of O2- in oxidative burst. The exposure of BITC to the differentiated HL-60 cells resulted in the inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced O2- generation, while the methylthiocarbamate analog of BITC, hardly reactive with thiols including glutathione and protein sulfhydryl, did not show any effect. Pre-treatment of the cells with diethyl maleate significantly potentiated the BITC-induced inhibition, while pre-treatment with N-acetyl-cysteine counteracted it. These results led us to assume that a plausible intracellular target molecule(s) having a reactive sulfhydryl moiety might be regulated by the covalent attachment with BITC. In spite of no ability to affect the translocation of protein kinase C beta to the membrane, BITC probably modifies the electron transport system of cytochrome b558, consistent with the observation that BITC inhibited the substrate utilization. Pre-treatments of mouse skin with BITC significantly attenuated the TPA-enhanced hydrogen peroxide level, suggesting that BITC indeed acts as an inhibitor of O2- generation in mouse skin. A histological study also demonstrated that BITC inhibited TPA-induced leukocyte infiltration in the dermis. Because we have found several O2- generation inhibitors to be effective chemopreventors against mouse skin carcinogenesis, the modifying effect of the topical application of BITC on TPA-induced mouse skin tumor promotion was investigated. We demonstrated for the first time that the pre-treatment with BITC 40 min prior to each TPA treatment significantly inhibited the number of papillomas per mouse. In conclusion, the results from this study provided biological evidence that BITC has a potential to prevent inflammation-related carcinogenesis including skin cancer.}, }
@article {pmid14684966, year = {2003}, author = {Harada, M and Kishimoto, K and Hagiwara, R and Nakashima, Y and Kurisu, K and Kawaguchi, Y}, title = {Infertility observed in female rats treated with N-acetyl-L-cysteine: Histopathological examination of ovarian follicles and recovery of fertility.}, journal = {Congenital anomalies}, volume = {43}, number = {3}, pages = {168-176}, doi = {10.1111/j.1741-4520.2003.tb01040.x}, pmid = {14684966}, issn = {0914-3505}, mesh = {Acetylcysteine/administration &amp; dosage/*toxicity ; Animals ; Estrous Cycle/drug effects ; Female ; Fertility/*drug effects ; Free Radical Scavengers/administration &amp; dosage/*toxicity ; Granulosa Cells/drug effects ; Infertility, Female/*chemically induced/physiopathology ; Male ; Oocytes/*pathology/ultrastructure ; Ovarian Follicle/*pathology/ultrastructure ; Rats ; Rats, Sprague-Dawley ; Recovery of Function ; Zona Pellucida/*drug effects/pathology ; }, abstract = {We previously reported infertility in female rats that received N-acetyl-L-cysteine (NAC) intravenously at a dosage of 1000 mg/kg/day. Unfertilized oocytes and gestation day 1 and 2 embryos were assessed morphologically, and the results suggested that absence or thinning of the zona pellucida (ZP) is related to infertility. However, the morphological characteristics of oocytes before ovulation and recovery from the effects of NAC were not clarified. In the present study, the ovarian follicles were histopathologically examined and the recovery of reproductive function was evaluated to investigate the effects of NAC. Female Sprague-Dawley rats at 10 weeks of age received NAC intravenously at 1000 mg/kg/day for more than 1 week. Thinning of the ZP was observed in the ovarian follicles in all stages of growth by light microscopy. Outflow of the components of the ZP between the corona radiata and disarrangement of the corona radiata were more pronounced in growing follicles than in large secondary follicles. Similar findings were observed by electron microscopy, and the effects of NAC were limited to the ZP. Infertility and thinning of the ZP were observed in the no-recovery NAC group, but not in the recovery NAC group, in which animals recovered within four estrous cycles after NAC administration. It has been reported that the ZP is expressed by oocytes or by both oocytes and granulosa cells, but no changes were noted in these cells. The present findings suggest that NAC affects the ZP directly and that reproductive function may recover from the effects of NAC.}, }
@article {pmid14684458, year = {2003}, author = {Baker, DA and McFarland, K and Lake, RW and Shen, H and Toda, S and Kalivas, PW}, title = {N-acetyl cysteine-induced blockade of cocaine-induced reinstatement.}, journal = {Annals of the New York Academy of Sciences}, volume = {1003}, number = {}, pages = {349-351}, doi = {10.1196/annals.1300.023}, pmid = {14684458}, issn = {0077-8923}, support = {DA03906/DA/NIDA NIH HHS/United States ; DA06074/DA/NIDA NIH HHS/United States ; DA07288/DA/NIDA NIH HHS/United States ; DA12513/DA/NIDA NIH HHS/United States ; MH40817/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Carrier Proteins/metabolism ; Cocaine/*antagonists &amp; inhibitors/*pharmacology ; Cocaine-Related Disorders/*drug therapy/psychology ; Conditioning, Operant/drug effects ; Microdialysis ; Rats ; Secondary Prevention ; }, }
@article {pmid14680076, year = {2003}, author = {Mata, M and Ruíz, A and Cerdá, M and Martinez-Losa, M and Cortijo, J and Santangelo, F and Serrano-Mollar, A and Llombart-Bosch, A and Morcillo, EJ}, title = {Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats.}, journal = {The European respiratory journal}, volume = {22}, number = {6}, pages = {900-905}, doi = {10.1183/09031936.03.00018003}, pmid = {14680076}, issn = {0903-1936}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Administration, Oral ; Animals ; Antibiotics, Antineoplastic/administration &amp; dosage/*adverse effects ; Bleomycin/administration &amp; dosage/*adverse effects ; Free Radical Scavengers/*administration &amp; dosage ; Gene Expression ; Hyperplasia ; Lung/*pathology ; Male ; Models, Animal ; Mucin 5AC ; Mucins/genetics/immunology ; Oxidative Stress/genetics/immunology ; Pulmonary Fibrosis/chemically induced/genetics/*immunology/pathology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Oxidative stress is involved in the pathogenesis of pulmonary fibrosis, therefore antioxidants may be of therapeutic value. Clinical work indicates that N-acetylcysteine (NAC) may be beneficial in this disease. The activity of this antioxidant was examined on bleomycin-induced lung damage, mucus secretory cells hyperplasia and mucin Muc5ac gene expression in rats. NAC (3 mmol x kg(-1) x day(-1)) or saline was given orally to Sprague-Dawley rats for 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) and for 14 days postinstillation. NAC decreased collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,257+/-323 and 3,200+/-192 microg x lung(-1) in vehicle- and NAC-treated rats, respectively) and lessened the fibrotic area assessed by morphometric analysis. The bleomycin-induced increases in lung tumour necrosis factor-alpha and myeloperoxidase activity were reduced by NAC treatment. The numbers of mucus secretory cells in airway epithelium, and the Muc5ac messenger ribonucleic acid and protein expression, were markedly augmented in rats exposed to bleomycin. These changes were significantly reduced in NAC-treated rats. These results indicate that bleomycin increases the number of airway secretory cells and their mucin production, and that oral N-acetylcysteine improved pulmonary lesions and reduced the mucus hypersecretion in the bleomycin rat model.}, }
@article {pmid14669999, year = {2003}, author = {Victor, VM and Rocha, M and De la Fuente, M}, title = {N-acetylcysteine protects mice from lethal endotoxemia by regulating the redox state of immune cells.}, journal = {Free radical research}, volume = {37}, number = {9}, pages = {919-929}, doi = {10.1080/1071576031000148727}, pmid = {14669999}, issn = {1071-5762}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blotting, Western ; Catalase/drug effects/metabolism ; Electrophoretic Mobility Shift Assay ; Endotoxemia/*drug therapy ; Female ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; Glutathione/biosynthesis/drug effects ; Lipopolysaccharides/toxicity ; Lymphocytes/*metabolism ; Macrophages/*metabolism ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred BALB C ; NF-kappa B/drug effects/metabolism ; Nitric Oxide Synthase/biosynthesis/drug effects ; Nitric Oxide Synthase Type II ; Oxidation-Reduction/drug effects ; Protein Transport/drug effects ; Superoxide Dismutase/drug effects/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis/drug effects ; }, abstract = {The excessive production of reactive oxygen species (ROS) associated with inflammation leads to oxidative stress, which is involved with the high mortality from several diseases such as endotoxic shock and can be controlled to a certain degree by antioxidants. The immune cells use ROS in order to support their functions and, therefore, need adequate levels of antioxidant defenses in order to avoid the harmful effect of an excessive ROS production. In the present work, the effect of the administration of the antioxidant N-acetylcysteine (NAC) on the redox state of peritoneal macrophages and lymphocytes from mice with lethal endotoxic shock (100 mg/kg i.p. of lipopolysaccharide, LPS), was studied. In both types of immune cells at 0, 2, 4, 12 and 24 h after LPS injection, an increase of ROS, of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha), the lipid peroxidation (malonaldehyde levels, MDA), inducible nitric oxide synthase (iNOS) expression and the oxidized/reduced glutathione (GSSG/GSH) ratio, as well as a decrease of enzymatic antioxidant defenses, such as superoxide dismutase (SOD) and catalase (CAT) activity, was observed. The injection of NAC (150 mg/kg i.p. at 30 min after LPS injection) decreased the ROS, the TNFalpha the MDA levels, iNOS expression and the GSSG/GSH ratio, and increased the antioxidant defenses in both macrophages and lymphocytes. Moreover, the NAC treatment prevented the activation of nuclear translocation of the nuclear factor kappaB (NF-kappaB), which regulates ROS, inflammatory cytokines and antioxidant levels. Our present results provide evidence that both cell types have a relevant role in the pathogenesis of endotoxic shock, and that NAC, by improving the redox state of these immune cells, could increase mouse survival. Thus, antioxidants could offer an alternative treatment of human endotoxic shock.}, }
@article {pmid14669316, year = {2003}, author = {Gunduz, H and Karabay, O and Tamer, A and Ozaras, R and Mert, A and Tabak, OF}, title = {N-acetyl cysteine therapy in acute viral hepatitis.}, journal = {World journal of gastroenterology}, volume = {9}, number = {12}, pages = {2698-2700}, pmid = {14669316}, issn = {1007-9327}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Adolescent ; Adult ; Alanine Transaminase/blood ; Antiviral Agents/*therapeutic use ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Female ; Hepatitis A/*drug therapy ; Hepatitis B/*drug therapy ; Humans ; Liver Function Tests ; Male ; Middle Aged ; Reference Values ; }, abstract = {AIM: To investigate the effect of N-acetyl cysteine (NAC) on acute viral hepatitis (AVH).<br><br>METHODS: We administered 200 mg oral NAC three times daily (600 mg/day) to the study group and placebo capsules to the control group. All patients were hospitalized and diagnosed as AVH. Blood total and direct bilirubin, ALT, AST, alkaline phosphatase, albumin and globulin levels of each patient were measured twice weekly until total bilirubin level dropped under 2 mg/dl, ALT level under 100 U/L, follow up was continued and then the patients were discharged.<br><br>RESULTS: A total of 41(13 female and 28 male) AVH patients were included in our study. The period for normalization of ALT and total bilirubin in the study group was 19.7+/-6.9 days and 13.7 +/- 8.5 days respectively. In the control group it was 20.4 +/- 6.5 days and 16.9 +/- 7.8 days respectively (P>0.05).<br><br>CONCLUSION: NAC administration effected neither the time necessary for normalization of ALT and total bilirubin values nor duration of hospitalization, so we could not suggest NAC for the treatment of icteric AVH cases. However, our results have shown that this drug is not harmful to patients with AVH.}, }
@article {pmid14668186, year = {2003}, author = {Vento, AE and Nemlander, A and Aittomäki, J and Salo, J and Karhunen, J and Rämö, OJ}, title = {N-acetylcysteine as an additive to crystalloid cardioplegia increased oxidative stress capacity in CABG patients.}, journal = {Scandinavian cardiovascular journal : SCJ}, volume = {37}, number = {6}, pages = {349-355}, doi = {10.1080/14017430310015406}, pmid = {14668186}, issn = {1401-7431}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Blood Chemical Analysis ; *Cardioplegic Solutions ; Coronary Artery Bypass/*methods ; Coronary Artery Disease/surgery ; Energy Metabolism/drug effects ; Free Radical Scavengers/*administration &amp; dosage/adverse effects ; Hemodynamics/drug effects ; Humans ; Lipid Peroxidation/drug effects ; Male ; Middle Aged ; Oxidative Stress/*drug effects ; Peroxidase/blood ; Prospective Studies ; Treatment Outcome ; Ventricular Function/*drug effects ; }, abstract = {OBJECTIVE: This prospective, randomized study was designed to assess the effects of N-acetylcysteine (NAC) in coronary artery bypass graft (CABG) patients.<br><br>DESIGN: Thirty-five consenting CABG patients with normal myocardial function were randomly divided into control (C) patients (N = 20) who received crystalloid (Plegisol) cardioplegia, and NAC patients receiving NAC in a 0.04 mol/l solution (N = 15) in Plegisol. Simultaneous coronary sinus and aortic blood samples, and myocardial biopsies were taken 1, 5 and 10 min after declamping. Hemodynamics was measured invasively for 24 h.<br><br>RESULTS: There were no adverse effects observed. The myocardial glutathione content was significantly better preserved (p = 0.0001) and myeloperoxidase activity was over two times lower in the NAC group than in the C group (p = 0.03). The trap capacity gradient between the aorta and the coronary sinus increased significantly during the first minute of reperfusion in the treatment group (p = 0.001) when compared with the C group. In the first minute after reperfusion there were more leukocytes sequestered in the coronary circulation (p = 0.04) in the C group. The invasive hemodynamic data did not differ significantly between the groups. The incidence of arrhythmias was equal.<br><br>CONCLUSION: NAC increased tissue capacity against oxidative stress and decreased inflammatory response in CABG patients with normal ejection fraction.}, }
@article {pmid14666672, year = {2003}, author = {Ryoyama, K and Mori, N and Nara, M and Kidachi, Y and Yamaguchi, H and Umetsu, H and Fuke, Y}, title = {Augmented gene expression of quinone reductase by 6-(methylsulfinyl)hexyl isothiocyanate through avoiding its cytotoxicity.}, journal = {Anticancer research}, volume = {23}, number = {5A}, pages = {3741-3748}, pmid = {14666672}, issn = {0250-7005}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Induction/drug effects ; Gene Expression Regulation, Enzymologic/*drug effects ; Isothiocyanates/antagonists &amp; inhibitors/*pharmacology ; Mice ; NAD(P)H Dehydrogenase (Quinone)/*biosynthesis/genetics ; }, abstract = {We examined both the induction of quinone reductase (QR) by 6-(methylsulfinyl)hexyl isothiocyanate and its cytotoxicity in Hepa1c1c7 cells, and compared the sensitivity of these two responses to NAC. QR activity was increased by 6-(methylsulfinyl)hexyl isothiocyanate in a dose-dependent manner. At 80 microM, the compound was significantly toxic to cells, but the resulting QR inhibition was dose-dependently overcome by NAC. Augmentation of QR activity by 6-(methylsulfinyl)hexyl isothiocyanate seemed to be due to augmented expression of QR mRNA, which was significantly increased by the compound. Inhibition of QR gene expression was seen at 80 microM and could be overcome by NAC. Optimal induction of QR gene expression by the compound (at 40 microM) was slightly but significantly inhibited by 10 mM NAC but not by 1 mM. The present study suggests that induction of Phase 2 detoxification enzymes by isothiocyanate compounds may be further enhanced by suppression of their inherent cytotoxic activity.}, }
@article {pmid14663554, year = {2004}, author = {Cheng, TH and Liu, JC and Lin, H and Shih, NL and Chen, YL and Huang, MT and Chan, P and Cheng, CF and Chen, JJ}, title = {Inhibitory effect of resveratrol on angiotensin II-induced cardiomyocyte hypertrophy.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {369}, number = {2}, pages = {239-244}, pmid = {14663554}, issn = {0028-1298}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/*metabolism/pharmacology ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Cells, Cultured ; Hypertrophy/prevention &amp; control ; Leucine/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Muscle, Smooth, Vascular/drug effects/metabolism/pathology ; Myocytes, Cardiac/*drug effects/metabolism/pathology ; Myosin Heavy Chains/genetics ; Phosphorylation ; Promoter Regions, Genetic ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/*pharmacology ; Transfection ; Ventricular Myosins/genetics ; }, abstract = {Resveratrol is proposed to account in part for the protective effect of red wine on the cardiovascular system. Angiotensin II (Ang II) is a potent hypertrophic stimulus in cardiomyocytes. In this study, we determined the effect of resveratrol on Ang II-induced cardiomyocyte hypertrophy. Cultured neonatal rat cardiomyocytes were stimulated with Ang II, and [3H]leucine incorporation and beta-myosin heavy chain (beta-MyHC) promoter activity were examined. Intracellular reactive oxygen species (ROS) were measured by a redox-sensitive fluorescent dye, 2' 7'-dichlorofluorescin diacetate, and the extracellular signal-regulated kinase (ERK) phosphorylation was examined by Western blotting. Resveratrol inhibited Ang II-increased intracellular ROS levels. Furthermore, resveratrol, as well as the antioxidant N-acetyl-cysteine, decreased Ang II- or H2O2-increased protein synthesis, beta-MyHC promoter activity, and ERK phosphorylation. In summary, we demonstrate for the first time that resveratrol inhibits Ang II-induced cardiomyocyte hypertrophy via attenuation of ROS generation.}, }
@article {pmid14661012, year = {2003}, author = {Oldemeyer, JB and Biddle, WP and Wurdeman, RL and Mooss, AN and Cichowski, E and Hilleman, DE}, title = {Acetylcysteine in the prevention of contrast-induced nephropathy after coronary angiography.}, journal = {American heart journal}, volume = {146}, number = {6}, pages = {E23}, doi = {10.1016/S0002-8703(03)00511-8}, pmid = {14661012}, issn = {1097-6744}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Biomarkers/blood ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Creatinine/blood ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Kidney Diseases/chemically induced/*prevention &amp; control ; Male ; Prospective Studies ; Statistics as Topic ; }, abstract = {BACKGROUND: Contrast-induced nephropathy (CIN) after coronary angiography is associated with increased morbidity and mortality rates. Preliminary studies with N-acetylcysteine (NAC) have found conflicting results in the prevention of CIN in patients undergoing coronary angiography. This study was designed to evaluate the efficacy and safety of NAC in the prevention of CIN in patients undergoing coronary angiography.<br><br>METHODS: This study was prospective, randomized, double-blind, and placebo-controlled. Patients referred for elective coronary angiography with a baseline creatinine clearance level <50 mL/min and serum creatinine >1.2 mg/dL were randomly assigned to 1500 mg NAC or placebo, starting the evening before angiography and given every 12 hours for 4 doses. The primary study end point was the development of CIN, which was defined as an increase of >0.5 mg/dL or an increase of > or =25% in serum creatinine over baseline within 48 hours of angiography. Secondary end points included changes in serum creatinine and blood urea nitrogen, requirement of dialysis, side effects of study medication, hospital length of stay, and hospital charges.<br><br>RESULTS: CIN occurred in 8.2% (4/49) of patients taking NAC and 6.4% (3/47) of patients taking placebo. Changes in BUN and serum creatinine from baseline were not significantly different in the two treatment groups. Baseline BUN and volume of contrast were the only independent predictors of CIN. More patients with diabetes had development of CIN (5/43; 12%) compared with nondiabetic patients (2/52; 4%), but the difference was not significant (P =.15). The incidence of CIN in diabetic patients was not different in the two treatment groups. No patient with development of CIN required dialysis. Side effects (mostly gastrointestinal) occurred in 16% of patients taking NAC and in none of the patients taking placebo. Length of stay and hospital charges were not different between the treatment groups.<br><br>CONCLUSIONS: In patients with reduced renal function undergoing elective coronary angiography, NAC does not reduce the risk of CIN.}, }
@article {pmid14660655, year = {2004}, author = {Han, DC and Lee, MY and Shin, KD and Jeon, SB and Kim, JM and Son, KH and Kim, HC and Kim, HM and Kwon, BM}, title = {2'-benzoyloxycinnamaldehyde induces apoptosis in human carcinoma via reactive oxygen species.}, journal = {The Journal of biological chemistry}, volume = {279}, number = {8}, pages = {6911-6920}, doi = {10.1074/jbc.M309708200}, pmid = {14660655}, issn = {0021-9258}, mesh = {Acetylcysteine/chemistry ; Acrolein/analogs &amp; derivatives/chemistry/*pharmacology ; Aldehydes/*pharmacology ; Alkyl and Aryl Transferases/metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Benzoates/chemistry/*pharmacology ; Blotting, Western ; Carcinoma/drug therapy/*pathology ; Caspase 3 ; Caspases/metabolism ; Cell Cycle ; Cell Line, Tumor ; DNA/chemistry ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Down-Regulation ; Enzyme Activation ; ErbB Receptors/metabolism ; Farnesyltranstransferase ; Flow Cytometry ; Genes, p53/*genetics ; Humans ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Oxidative Stress ; Phosphorylation ; Poly(ADP-ribose) Polymerases/metabolism ; Precipitin Tests ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; *Reactive Oxygen Species ; Time Factors ; }, abstract = {2'-hydroxycinnamaldehyde (HCA) has been shown to have inhibitory effects on farnesyl protein transferase in vitro, angiogenesis, and tumor cell growth. However, mechanism for these inhibitions remains unknown. As a derivative of HCA, BCA (2'-benzoyl-oxycinnamaldehyde) was synthesized by replacing hydroxyl group with benzoyl-oxyl group. When p53-mutated cancer cell lines (MDA-MB-231 breast cancer cell and SW620 colon cancer cell) were treated with 10 microM HCA or BCA, it induced growth arrest and apoptosis of tumor cells. Markers of apoptosis such as degradations of chromosomal DNA and poly(ADP-ribose) polymerase and activation of caspase-3 were detected after HCA or BCA treatment. BCA-induced apoptosis was blocked by pretreatment of cells with anti-oxidants, glutathione, or N-acetyl-cysteine. In addition, BCA-induced activation of caspase-3 and degradation of poly(ADP-ribose) polymerase were abolished by pretreatment of cells with the anti-oxidants. These results suggest that reactive oxygen species are major regulator of BCA-induced apoptosis. HCA or BCA-induced accumulation of reactive oxygen species was detected by using DCF-DA, an intracellular probe of oxidative stress. Furthermore, when BCA (100 mg/kg) was administrated intraperitoneally or orally into a nude mouse, it inhibited >88 or 41% of tumor growth, respectively, without any detectable weight change. These results suggest that BCA is a good drug candidate for cancer therapy.}, }
@article {pmid14657813, year = {2003}, author = {Ahola, T and Lapatto, R and Raivio, KO and Selander, B and Stigson, L and Jonsson, B and Jonsbo, F and Esberg, G and Stövring, S and Kjartansson, S and Stiris, T and Lossius, K and Virkola, K and Fellman, V}, title = {N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial.}, journal = {The Journal of pediatrics}, volume = {143}, number = {6}, pages = {713-719}, doi = {10.1067/S0022-3476(03)00419-0}, pmid = {14657813}, issn = {0022-3476}, mesh = {Antioxidants/*administration &amp; dosage ; Bronchopulmonary Dysplasia/*prevention &amp; control ; Cystine/*administration &amp; dosage/*analogs &amp; derivatives ; Double-Blind Method ; Female ; Humans ; Infant, Newborn ; Infant, Premature ; Infant, Very Low Birth Weight ; Infusions, Intravenous ; Male ; }, abstract = {OBJECTIVE: To evaluate whether N-acetylcysteine (NAC) infusion during the first week of life reduces the risk of death or bronchopulmonary dysplasia (BPD) in infants with extremely low birth weight. Study design In a Nordic multicenter, double-blind trial, infants (n=391) weighing 500 to 999 g and on ventilator or nasal continuous positive airway pressure were randomized before the age of 36 hours to receive NAC 16 to 32 mg/kg/d (n=194) or placebo (n=197) intravenously for 6 days. Primary end points were death or BPD, defined as supplementary oxygen requirement at 36 weeks' gestational age.<br><br>RESULTS: There was no difference in the combined incidence of the primary end points death or BPD, 51% vs. 49%, between the NAC group and control group. Also similar was the incidence of BPD in survivors at 36 weeks' gestational age, 40% vs. 40%, and the mean oxygen requirement at the age of 28 days, 31.2% vs. 30.7%, respectively. The severity of BPD was similar in both groups.<br><br>CONCLUSIONS: A 6-day course of intravenous N-acetylcysteine at the dosage used does not prevent BPD or death in infants with extremely low birth weight.}, }
@article {pmid14657342, year = {2003}, author = {Laragione, T and Bonetto, V and Casoni, F and Massignan, T and Bianchi, G and Gianazza, E and Ghezzi, P}, title = {Redox regulation of surface protein thiols: identification of integrin alpha-4 as a molecular target by using redox proteomics.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {100}, number = {25}, pages = {14737-14741}, pmid = {14657342}, issn = {0027-8424}, support = {TCP01010/TI_/Telethon/Italy ; }, mesh = {Acetylcysteine/chemistry ; Actins/metabolism ; Cell Adhesion ; Cell Line ; Cell Membrane/metabolism ; Cytosol/metabolism ; Dose-Response Relationship, Drug ; Electrophoresis ; Electrophoresis, Gel, Two-Dimensional ; Free Radicals ; Glutathione/metabolism ; Humans ; Integrin alpha4/metabolism/*physiology ; Jurkat Cells ; Leukocytes, Mononuclear/metabolism ; Mass Spectrometry ; Myosin Heavy Chains/chemistry ; Myosin Light Chains/chemistry ; Oxidation-Reduction ; Proteome ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Sulfhydryl Compounds ; Time Factors ; }, abstract = {Thiols affect a variety of cell functions, an effect known as redox regulation. We show here that treatment (1-2 h) of cells with 0.1-5 mM N-acetyl-L-cysteine (NAC) increases surface protein thiol expression in human peripheral blood mononuclear cells. This effect is not associated with changes in cellular glutathione (GSH) and is also observed with a non-GSH precursor thiol N-acetyl-D-cysteine or with GSH itself, which is not cell-permeable, suggesting a direct reducing action. NAC did not augment protein SH in the cytosol, indicating that they are already maximally reduced under normal, nonstressed, conditions. By using labeling with a non permeable, biotinylated SH reagent followed by two-dimensional gel electrophoresis and analysis by MS, we identified some of the proteins associated with the membrane that are reduced by NAC. These proteins include the following: integrin alpha-4, myosin heavy chain (nonmuscle type A), myosin light-chain alkali (nonmuscle isoform), and beta-actin. NAC pretreatment augmented integrin alpha-4-dependent fibronectin adhesion and aggregation of Jurkat cells without changing its expression by fluorescence-activated cell sorter, suggesting that reduction of surface disulfides can affect proteins function. We postulate that some of the activities of NAC or other thiol antioxidants may not only be due to free radical scavenging or increase of intracellular GSH and subsequent effects on transcription factors, but could modify the redox state of functional membrane proteins with exofacial SH critical for their activity.}, }
@article {pmid14656924, year = {2004}, author = {Bleeke, T and Zhang, H and Madamanchi, N and Patterson, C and Faber, JE}, title = {Catecholamine-induced vascular wall growth is dependent on generation of reactive oxygen species.}, journal = {Circulation research}, volume = {94}, number = {1}, pages = {37-45}, doi = {10.1161/01.RES.0000109412.80157.7D}, pmid = {14656924}, issn = {1524-4571}, support = {HL62584/HL/NHLBI NIH HHS/United States ; }, mesh = {Adrenergic alpha-1 Receptor Agonists ; Adrenergic alpha-Agonists/pharmacology ; Angioplasty, Balloon ; Animals ; Antioxidants/pharmacology ; Aorta/cytology ; Arterial Occlusive Diseases/etiology/metabolism ; Catalase/pharmacology ; Cell Division/drug effects ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Muscle, Smooth, Vascular/cytology/drug effects/*metabolism ; NADPH Oxidases/antagonists &amp; inhibitors ; Norepinephrine/antagonists &amp; inhibitors/*pharmacology ; Organ Culture Techniques ; Phenylephrine/antagonists &amp; inhibitors/pharmacology ; Phosphoproteins/physiology ; Prazosin/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Tunica Media/cytology/metabolism ; }, abstract = {Alpha1-adrenoceptor-dependent proliferation of vascular smooth muscle cells (VSMCs) is strongly augmented by vascular injury, and may contribute to intimal growth and lumen loss. Because reactive oxygen species (ROS) are increased by injury and have been implicated as second messengers in proliferation of VSMCs, we investigated the role of ROS in catecholamine-induced VSMC growth. Rat aortae were isolated 4 days after balloon injury, maintained in organ culture under circumferential wall tension, and exposed to agents for 48 hours. The antioxidants N-acetylcysteine (NAC, 10 mmol/L) and Tiron (5 mmol/L) and the flavin-inhibitor diphenylene iodonium (DPI, 20 micromol/L) abolished norepinephrine-induced increases in protein synthesis and DNA content in media. In aortic sections, norepinephrine augmented ROS production (dihydroethidium confocal microscopy), which was dose-dependently inhibited by NAC, Tiron, and DPI. In cultured VSMCs, phenylephrine caused time- and dose-dependent ROS generation (aconitase activity), had similar efficacy to thrombin (1 U/mL), and was eliminated by the superoxide dismutase (SOD) mimetic Mn-(III)-tetrakis-(4-benzoic-acid)-porphyrin-chloride (200 micromol/L) and Tiron. Phenylephrine-induced ROS production and increases in DNA and protein content were blocked by prazosin (0.3 micromol/L) and abolished in p47phox-/- cells. PEG-SOD (25 U/mL) had little effect, whereas PEG-catalase (50 U/mL) eliminated phenylephrine-induced proliferation in VSMCs. DPI (10 micromol/L) and apocynin (30 micromol/L) abolished phenylephrine-stimulated mitogenesis, whereas inhibitors of other intracellular ROS sources had not effect. Furthermore, PE increased p47phox expression (RT-PCR). These data demonstrate that the trophic effect of catecholamines on vascular wall cells is dependent on a ROS-sensitive step that we hypothesize consists of activation of the NAD(P)H-dependent vascular oxidase.}, }
@article {pmid14654070, year = {2003}, author = {Das, DK and Maulik, N}, title = {Preconditioning potentiates redox signaling and converts death signal into survival signal.}, journal = {Archives of biochemistry and biophysics}, volume = {420}, number = {2}, pages = {305-311}, doi = {10.1016/j.abb.2003.09.023}, pmid = {14654070}, issn = {0003-9861}, support = {HL 22559/HL/NHLBI NIH HHS/United States ; HL 33889/HL/NHLBI NIH HHS/United States ; HL 5642/HL/NHLBI NIH HHS/United States ; HL 56803/HL/NHLBI NIH HHS/United States ; HL 63317/HL/NHLBI NIH HHS/United States ; }, mesh = {Adaptation, Physiological/physiology ; Animals ; Apoptosis/*physiology ; Cell Survival/*physiology ; Gene Expression Regulation ; Humans ; *Ischemic Preconditioning, Myocardial ; Myocardial Ischemia/genetics/metabolism ; Myocardial Reperfusion Injury/genetics/metabolism ; Myocytes, Cardiac/cytology/*physiology ; Oxidation-Reduction ; Proto-Oncogene Proteins/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Transcription Factors/genetics/metabolism ; }, abstract = {Reactive oxygen species (ROS) play a crucial role in the pathophysiology of ischemic heart disease by causing cardiac dysfunction and cell death. Several redox-sensitive anti- and pro-apoptotic transcription factors including NFkappaB and AP-1 progressively and steadily increase in the heart as a function of the duration of ischemia and reperfusion. When the heart is preconditioned to ischemic stress by repeated short-term ischemia and reperfusion, NFkappaB remains high while AP-1 is lowered to almost baseline value. The anti-apoptotic gene Bcl-2 is downregulated in the ischemic/reperfused heart, while it is upregulated in the adapted myocardium. Cardioprotective abilities of the preconditioning are abolished when heart is pre-perfused with N-acetyl cysteine, a scavenger for ROS, suggesting the role of ROS in redox signaling. Mammalian heart is protected by several defense systems which include among others, redox-regulated protein, thioredoxin. Reperfusion of ischemic myocardium results in the downregulation of thioredoxin 1 (Trx 1) expression, which was upregulated in the preconditioned myocardium. The increased expression of Trx 1 is completely blocked with an inhibitor of Trx 1, CDDP, which also abolished cardioprotection afforded by ischemic adaptation. The cardioprotective role of Trx 1 is confirmed further with transgenic mouse hearts overexpressing Trx 1. The Trx 1 mouse hearts displayed significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size and apoptosis as compared to the corresponding wild-type mouse hearts. Taken together, preconditioning appears to potentiate redox signaling, which converts the "death signal" into "survival signal."}, }
@article {pmid14644566, year = {2003}, author = {Morley, N and Curnow, A and Salter, L and Campbell, S and Gould, D}, title = {N-acetyl-L-cysteine prevents DNA damage induced by UVA, UVB and visible radiation in human fibroblasts.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {72}, number = {1-3}, pages = {55-60}, doi = {10.1016/j.jphotobiol.2003.06.004}, pmid = {14644566}, issn = {1011-1344}, mesh = {Acetylcysteine/*pharmacology ; Cells, Cultured ; DNA Damage/*drug effects/physiology/*radiation effects ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Fetus ; Fibroblasts/*drug effects/physiology/*radiation effects ; Free Radical Scavengers/*pharmacology ; Humans ; Light/adverse effects ; Ultraviolet Rays/adverse effects ; }, abstract = {The thiol N-acetyl-L-cysteine (NAC) is a source of cysteine for the synthesis of the endogenous antioxidant glutathione (GSH) which is depleted by ultraviolet radiation. It is also associated with the scavenging of reactive oxygen species (ROS). In this study the effects of NAC were examined in cultured human fibroblasts during prolonged exposure to ultraviolet B (UVB), ultraviolet A (UVA) and visible irradiation (280-700 nm), delivered by a 150 W xenon-arc lamp. The alkaline comet assay was used to assess the DNA damage in individual cells. It was found that incubating skin and lung fibroblasts at 37 degrees C for 1 h with an optimal 6 mM NAC supplement prior to light exposure, significantly reduced the level of DNA damage in both cell types, however, the skin fibroblasts were less sensitive to xenon-arc lamp irradiation than lung fibroblasts. NAC incubation resulted in an initial delay in DNA damage when the cells were irradiated. There was also a significant reduction in the overall levels of DNA damage observed with continued irradiation. NAC significantly reduced the DNA damage produced in lung fibroblasts depleted of normal GSH protection by the glutamylcysteinyl synthetase inhibitor, L-buthionine-[S,R]-sulfoximine. Although the specific mechanism of NAC protection has not yet been elucidated, these results support the hypothesis that NAC may protect the cells directly, by scavenging ROS induced by UVA and visible radiation, and indirectly by donating cysteine for GSH synthesis.}, }
@article {pmid14644347, year = {2003}, author = {Izzotti, A and Balansky, RM and Camoirano, A and Cartiglia, C and Longobardi, M and Tampa, E and De Flora, S}, title = {Birth-related genomic and transcriptional changes in mouse lung. Modulation by transplacental N-acetylcysteine.}, journal = {Mutation research}, volume = {544}, number = {2-3}, pages = {441-449}, doi = {10.1016/j.mrrev.2003.05.004}, pmid = {14644347}, issn = {0027-5107}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Animals, Newborn ; Disease Models, Animal ; Female ; Free Radical Scavengers/administration &amp; dosage/pharmacology ; Gene Expression Regulation, Developmental/*drug effects ; Genomics ; Lung/*physiology/radiation effects ; Maternal-Fetal Exchange ; Mice ; Pregnancy ; Transcription, Genetic/*drug effects ; }, abstract = {Birth is characterized by a sudden transition from the maternal-mediated respiration to the autonomous pulmonary respiration. Notwithstanding the importance of the involved functional and metabolic changes, little is known about possible DNA alterations occurring in the lung during the perinatal period. We comparatively evaluated genomic and transcriptional changes in the lung of fetuses and newborn Swiss albino mice, whose dams had either been untreated or treated with oral N-acetyl-L-cysteine (NAC) throughout the pregnancy period. In the less than 24h period elapsing between the end of fetal life and the start of post-natal life, nucleotide alterations occurred in mouse lung, as shown by a significant increase of both bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine levels, detected by 32P post-labeling procedures. The frequency of micronuclei in peripheral blood erythrocytes was not significantly increased after birth. Multigene expression analysis of 746 selected genes, by cDNA arrays, showed that 33 of them (4.4%) were upregulated in the lung of newborn mice, as compared with fetuses. The overexpressed genes were mainly involved in protective mechanism as a response to oxidative changes, alterations of glutathione metabolism, cellular stress, and damage to DNA and proteins. The transplacental treatment with NAC totally prevented birth-related genomic alterations in lung DNA. NAC did not change the basal gene expression in mouse fetal lung, but attenuated the upregulation of most genes involved in oxidative stress, stress response, and DNA repair in the lung of newborn mice. In fact, only 13 genes (1.7%) were overexpressed in newborns from NAC-treated dams. It therefore appears that administration of NAC during pregnancy is beneficial not only to counteract the adverse effects of toxic agents, as supported by previous studies, but also to attenuate birth-related DNA alterations.}, }
@article {pmid14647418, year = {2004}, author = {Yu, C and Rahmani, M and Almenara, J and Sausville, EA and Dent, P and Grant, S}, title = {Induction of apoptosis in human leukemia cells by the tyrosine kinase inhibitor adaphostin proceeds through a RAF-1/MEK/ERK- and AKT-dependent process.}, journal = {Oncogene}, volume = {23}, number = {7}, pages = {1364-1376}, doi = {10.1038/sj.onc.1207248}, pmid = {14647418}, issn = {0950-9232}, support = {CA 93738/CA/NCI NIH HHS/United States ; CA63753/CA/NCI NIH HHS/United States ; }, mesh = {Adamantane/*analogs &amp; derivatives/*pharmacology ; Apoptosis/*drug effects ; Apoptosis Inducing Factor ; Cytochromes c/drug effects ; Flavoproteins/drug effects ; Humans ; Hydroquinones/*pharmacology ; Jurkat Cells ; Leukemia/*drug therapy ; MAP Kinase Kinase Kinases/metabolism ; Membrane Proteins/drug effects ; Mitogen-Activated Protein Kinases/metabolism ; *Protein Serine-Threonine Kinases ; Protein-Tyrosine Kinases/*antagonists &amp; inhibitors ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins c-raf ; }, abstract = {Effects of the tyrphostin tyrosine kinase inhibitor adaphostin (NSC 680410) have been examined in human leukemia cells (Jurkat, U937) in relation to mitochondrial events, apoptosis, and perturbations in signaling and cell cycle regulatory events. Exposure of cells to adaphostin concentrations > or =0.75 microM for intervals > or =6 h resulted in a pronounced release of cytochrome c and AIF, activation of caspase-9, -8, and -3, and apoptosis. These events were accompanied by the caspase-independent downregulation of Raf-1, inactivation of MEK1/2, ERK, Akt, p70S6K, dephosphorylation of GSK-3, and activation of c-Jun-N-terminal kinase (JNK) and p38 MAPK. Adaphostin also induced cleavage and dephosphorylation of pRb on CDK2- and CDK4-specific sites, as well as the caspase-dependent downregulation of cyclin D1. Inducible expression of a constitutively active MEK1 construct markedly diminished adaphostin-induced cytochrome c and AIF release, JNK activation, and apoptosis in Jurkat cells. Ectopic expression of Raf-1 or constitutively activated (myristolated) Akt also significantly attenuated adaphostin-induced apoptosis, but protection was less than that conferred by enforced activation of MEK. Lastly, antioxidants (e.g., L-N-acetylcysteine; L-NAC) opposed adaphostin-mediated mitochondrial dysfunction, Raf-1/MEK/ERK downregulation, JNK activation, and apoptosis. However, in contrast to L-NAC, enforced activation of MEK failed to block adaphostin-mediated ROS generation. Together, these findings demonstrate that the tyrphostin adaphostin induces multiple perturbations in signal transduction pathways in human leukemia cells, particularly inactivation of the cytoprotective Raf-1/MEK/ERK and Akt cascades, that culminate in mitochondrial injury, caspase activation, and apoptosis. They also suggest that adaphostin-related oxidative stress acts upstream of perturbations in these signaling pathways to trigger the cell death process.}, }
@article {pmid14637194, year = {2003}, author = {Alencar, JL and Chalupsky, K and Sarr, M and Schini-Kerth, V and Vanin, AF and Stoclet, JC and Muller, B}, title = {Inhibition of arterial contraction by dinitrosyl-iron complexes: critical role of the thiol ligand in determining rate of nitric oxide (NO) release and formation of releasable NO stores by S-nitrosation.}, journal = {Biochemical pharmacology}, volume = {66}, number = {12}, pages = {2365-2374}, doi = {10.1016/j.bcp.2003.07.017}, pmid = {14637194}, issn = {0006-2952}, mesh = {Acetylcysteine/pharmacology ; Animals ; Arteries/drug effects/physiology ; Cyclic GMP/metabolism ; Glutathione/chemistry/pharmacology ; Iron/*pharmacology ; Male ; Mercuric Chloride/pharmacology ; Molecular Weight ; Nitric Oxide/*metabolism ; Nitrogen Oxides/*pharmacology ; Nitrosation ; Rats ; Rats, Wistar ; S-Nitrosothiols/metabolism ; Sulfhydryl Compounds/metabolism ; Vasoconstriction/*drug effects ; Vasodilation/drug effects ; }, abstract = {The inhibition of arterial tone produced by two nitric oxide (NO) derivatives of biological relevance, dinitrosyl-iron complexes with cysteine (DNIC-CYS) or with glutathione (DNIC-GSH), was compared. Both compounds induced vasorelaxation within the same concentration range (3-300 nM) in endothelium-denuded rat aortic rings. Consistent with a faster rate of NO release from DNIC-CYS than from DNIC-GSH, the relaxant effect of DNIC-CYS was rapid in onset and tended to recover with time, whereas the one of DNIC-GSH developed slowly and was sustained. In addition, DNIC-GSH (0.3 and 1 microM) but not DNIC-CYS (1 microM) induced, even after washout of the drug, a persistent hyporesponsiveness to vasoconstrictors and a relaxant effect of low molecular weight thiols like N-acetylcysteine (NAC, which can displace NO from preformed NO stores). Both effects of DNIC-GSH were associated with elevation of cyclic GMP content and were attenuated by NO scavengers or a cyclic GMP-dependent protein kinases inhibitor. In rings previously exposed to DNIC-GSH, addition of mercuric chloride (which can cleave the cysteine-NO bond of S-nitrosothiols) elicited relaxation, completely blunted the one of NAC and also abolished the persistent elevation of NO content. In conclusion, this study shows that whereas both DNIC-CYS and DNIC-GSH elicited a NO release-associated relaxant effect in isolated arteries, only DNIC-GSH induced an inhibition of contraction which persisted after drug removal. The persistent effect of DNIC-GSH was attributed to the formation of releasable NO stores in arterial tissue, most probably as S-nitrosothiols. Thus, the nature of the thiol ligand plays a critical role in determining the mechanisms and duration of the effect of LMW-DNIC in arteries.}, }
@article {pmid14636949, year = {2003}, author = {Sevillano, S and de la Mano, AM and Manso, MA and Orfao, A and De Dios, I}, title = {N-acetylcysteine prevents intra-acinar oxygen free radical production in pancreatic duct obstruction-induced acute pancreatitis.}, journal = {Biochimica et biophysica acta}, volume = {1639}, number = {3}, pages = {177-184}, doi = {10.1016/j.bbadis.2003.09.003}, pmid = {14636949}, issn = {0006-3002}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Amylases/blood ; Animals ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Free Radicals/metabolism ; Male ; Pancreas/drug effects/pathology/ultrastructure ; Pancreatic Ducts/*drug effects ; Pancreatitis/*drug therapy ; Rats ; Rats, Wistar ; }, abstract = {Although oxygen free radicals (OFR) are considered to be one of the pathophysiological mechanisms involved in acute pancreatitis (AP), the contribution of acinar cells to their production is not well established. The aim of the present study was to determine the effect of N-acetylcysteine (NAC) in the course of AP induced by pancreatic duct obstruction (PDO) in rats, directly analysing by flow cytometry the quantity of OFR generated in acinar cells. NAC (50 mg/kg) was administered 1 h before and 1 h after PDO. Measurements by flow cytometry of OFR generated in acinar cells were taken at different PDO times over 24 h, using dihydrorhodamine-123 as fluorescent dye. Histological studies of pancreas and measurements of neutrophil infiltration in the pancreas, pancreatic glutathione (GSH), malondialdehyde (MDA) levels, plasma amylase activity and hemoconcentration were carried out in order to assess the severity of AP at different stages. NAC effectively blunted GSH depletion at early AP stages and prevented OFR generation found in acinar cells as a consequence of AP induced by PDO. This attenuation of the redox state impairment reduced cellular oxidative damage, as reflected by less severe pancreatic lesions, normal pancreatic MDA levels, as well as diminished neutrophil infiltration in pancreas. Hyperamylasemia and hemoconcentration following AP induction were ameliorated by NAC administration at early stages, when oxidative stress seems to be critical in the development of pancreatitis. In conclusion, NAC reinforces the antioxidant defences in acinar cells, preventing OFR generation therefore attenuating oxidative damage and subsequently reducing the severity of PDO-induced AP at early stages of the disease.}, }
@article {pmid14636833, year = {2003}, author = {Gong, J and Chen, SS}, title = {Polyphenolic antioxidants inhibit peptide presentation by antigen-presenting cells.}, journal = {International immunopharmacology}, volume = {3}, number = {13-14}, pages = {1841-1852}, doi = {10.1016/j.intimp.2003.08.010}, pmid = {14636833}, issn = {1567-5769}, support = {U19 AI-42244/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antigen Presentation/*drug effects/immunology ; Antigen-Presenting Cells/*drug effects/immunology/metabolism ; Antigens, CD/drug effects/immunology ; Antioxidants/*pharmacology ; B-Lymphocytes/drug effects/immunology/metabolism ; B7-2 Antigen ; Bone Marrow Cells/drug effects ; CD40 Antigens/drug effects/immunology ; Chlorogenic Acid/chemistry/isolation &amp; purification/pharmacology ; Cysteine Endopeptidases ; Down-Regulation ; Fibroblasts/cytology ; Flavonoids/*pharmacology ; Histocompatibility Antigens Class II/immunology ; Hybridomas ; Interleukin-2/antagonists &amp; inhibitors/biosynthesis ; Intracellular Signaling Peptides and Proteins ; Lymphocyte Activation/immunology ; Mast Cells/drug effects/metabolism ; Membrane Glycoproteins/drug effects/immunology ; Mice ; Mice, Inbred BALB C ; Nuclear Proteins ; Phenols/*pharmacology ; Plant Extracts/chemistry ; Plant Leaves/chemistry ; Polyphenols ; Protein Biosynthesis ; Proteins/antagonists &amp; inhibitors ; Quercetin/chemistry/isolation &amp; purification/pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors ; Rutin/chemistry/isolation &amp; purification/pharmacology ; Signal Transduction ; Spleen/cytology/drug effects ; T-Lymphocytes/cytology/immunology ; Tobacco, Smokeless/chemistry/pharmacology ; Transfection/methods ; Tumor Cells, Cultured ; Tumor Necrosis Factor alpha-Induced Protein 3 ; }, abstract = {Antigen-presenting cells (APC) provide two essential signals, e.g., antigenic peptides as well as costimulatory molecules for T-cell activation. Small molecules of smoke tobacco extracts (SM-STE) inhibited antigen presentation of A20 to OVAp-specific T-cell hybridomas. Pretreatment of A20 but not T hybridomas abrogates the APC function. Viability of APC and levels of MHCII, CD40 and B7 of APC were not affected by this treatment. The active principle, inhibiting APC was reproduced with pure tobacco polyphenols, quercetin and its glycoside, rutin. Antioxidant activity of rutin is relevant since rutin downregulated levels of reactive oxygen species (ROS) in phorbol ester-stimulated A20; moreover, another antioxidant, N-acetyl cysteine (NAC) also inhibited antigen presentation, albeit at a higher concentration. Other types of APC, such as bone marrow-derived mast cells (BMMC), MHCII-transfected fibroblast, and splenocytes are affected by tobacco polyphenols. We propose that polyphenols may affect redox-sensitive signal transduction pathway since APC function of PD 98059, MEK inhibitor-pretreated A20 were similarly abrogated. Taken together, we propose that maintaining appropriate intracellular redox of APC is crucial for its antigen-presenting function.}, }
@article {pmid14633709, year = {2003}, author = {Burdick, AD and Davis, JW and Liu, KJ and Hudson, LG and Shi, H and Monske, ML and Burchiel, SW}, title = {Benzo(a)pyrene quinones increase cell proliferation, generate reactive oxygen species, and transactivate the epidermal growth factor receptor in breast epithelial cells.}, journal = {Cancer research}, volume = {63}, number = {22}, pages = {7825-7833}, pmid = {14633709}, issn = {0008-5472}, support = {R01 ES 07259/ES/NIEHS NIH HHS/United States ; }, mesh = {Benzopyrenes/*toxicity ; Breast/cytology/*drug effects/*metabolism ; Breast Neoplasms/chemically induced/metabolism ; Cell Count ; Cell Division/drug effects ; Electron Spin Resonance Spectroscopy ; Enzyme Activation/drug effects ; Epidermal Growth Factor/deficiency ; ErbB Receptors/*metabolism ; Flow Cytometry ; Humans ; Hydrogen Peroxide/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Oxidative Stress ; Phosphorylation/drug effects ; *Protein Serine-Threonine Kinases ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Reactive Oxygen Species/*metabolism ; Signal Transduction/physiology ; Transcriptional Activation ; }, abstract = {Polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP), are known mammary carcinogens in rodents and may be involved in human breast cancer. We have reported previously that BaP can mimic growth factor signaling and increase cell proliferation in primary human mammary epithelial cells and the human mammary epithelial cell line MCF-10A. BaP-quinones (BPQs) are important metabolites of BaP that have been associated with the production of reactive oxygen species. Using a model of epidermal growth factor (EGF) withdrawal in MCF-10A, we hypothesized that production of reactive oxygen species by BPQs could lead to the activation of the EGF receptor (EGFR). Here, we demonstrate through electron paramagnetic resonance spectroscopy and flow cytometry that 1,6-BPQ and 3,6-BPQ produce superoxide anion and hydrogen peroxide in MCF-10A cells. Furthermore, we show that BPQs increase EGFR, Akt, and extracellular signal-regulated kinase activity, leading to increased cell number in the absence of EGF. The BPQ-induced EGFR activity and associated cell proliferation were attenuated by the EGFR inhibitor AG1478, as well as by the antioxidant N-acetyl cysteine. Overexpression of catalase, but not Cu/Zn superoxide dismutase, reduced the extent of BPQ-dependent increased cell number and EGFR pathway activation. Moreover, the direct treatment of MCF-10A cells with hydrogen peroxide enhanced EGFR, Akt, and extracellular-regulated kinase phosphorylation that could be similarly inhibited by AG1478, N-acetyl cysteine, and catalase. Taken together, these data indicate that BPQs, through the generation of hydrogen peroxide, activate the EGFR in MCF-10A cells, leading to increased cell number under EGF-deficient conditions.}, }
@article {pmid14633141, year = {2003}, author = {Efrati, S and Dishy, V and Averbukh, M and Blatt, A and Krakover, R and Weisgarten, J and Morrow, JD and Stein, MC and Golik, A}, title = {The effect of N-acetylcysteine on renal function, nitric oxide, and oxidative stress after angiography.}, journal = {Kidney international}, volume = {64}, number = {6}, pages = {2182-2187}, doi = {10.1046/j.1523-1755.2003.00322.x}, pmid = {14633141}, issn = {0085-2538}, support = {CA 77839/CA/NCI NIH HHS/United States ; DK 26657/DK/NIDDK NIH HHS/United States ; DK 48831/DK/NIDDK NIH HHS/United States ; GM 15431/GM/NIGMS NIH HHS/United States ; GM 5M01-RR0095/GM/NIGMS NIH HHS/United States ; HL 04012/HL/NHLBI NIH HHS/United States ; HL 56251/HL/NHLBI NIH HHS/United States ; HL 65082/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aged ; Angiography/*adverse effects ; Antioxidants/pharmacology ; Creatinine/urine ; Double-Blind Method ; Female ; Humans ; Kidney/*diagnostic imaging/drug effects/physiology ; Kidney Failure, Chronic/*diagnostic imaging ; Male ; Middle Aged ; Nitric Oxide/*urine ; Oxidative Stress/*drug effects ; }, abstract = {BACKGROUND: Renal failure induced by radiographic contrast agents is a known complication of coronary angiography, especially among patients with chronic renal failure. Recently, treatment with N-acetylcysteine (NAC) has been shown to have a protective effect but the mechanisms are unknown. We examined the hypothesis that NAC protected against contrast-induced renal impairment through effects on nitric oxide metabolism and oxidative stress.<br><br>METHODS: Patients with a serum creatinine concentration above 10(6) micromol/L undergoing coronary angiography were randomly assigned to receive either NAC 1 g (N= 24) or placebo (N= 29) twice daily 24 hours before and after angiography with 0.45% saline hydration in a double-blind study. Creatinine clearance was calculated and urinary nitric oxide and F2-isoprostane excretion were measured at baseline, 24 and 96 hours after angiography.<br><br>RESULTS: Treatment with NAC significantly improved the effect of contrast media on creatinine clearance, and maximal beneficial effect was observed 24 hours after angiography. Creatinine clearance (mL/min) was 59.5 +/- 4.4, 64.7 +/- 5.8, and 58.7 + 3.9 at baseline, 24, and 96 hours after angiography in the NAC group, respectively, and 65.2 +/- 3.2, 51.5 +/- 3.7, and 53.6 +/- 3.9 in the placebo group, respectively (P < 0.0001). NAC treatment prevented the reduction in urinary nitric oxide after angiography. The urinary nitric oxide/creatinine ratio (micromol/mg) was 0.0058 +/- 0.0004, 0.0057 +/- 0.0004, and 0.0052 +/- 0.0004 at baseline, 24, and 96 hours after angiography in NAC group, respectively, and 0.0057 +/- 0.0007, 0.0031 +/- 0.0005, and 0.0039 +/- 0.0005 in the placebo group, respectively (P= 0.013). NAC had no significant effect on urinary F2-isoprostanes.<br><br>CONCLUSION: NAC treatment has renoprotective effect in patients with mild chronic renal failure undergoing coronary angiography that may be mediated in part by an increase in nitric oxide production.}, }
@article {pmid14630064, year = {2004}, author = {Zhang, S and Fu, J and Zhou, Z}, title = {In vitro effect of manganese chloride exposure on reactive oxygen species generation and respiratory chain complexes activities of mitochondria isolated from rat brain.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {18}, number = {1}, pages = {71-77}, doi = {10.1016/j.tiv.2003.09.002}, pmid = {14630064}, issn = {0887-2333}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/pharmacology ; Brain/*ultrastructure ; Chlorides/*adverse effects/antagonists &amp; inhibitors ; Cytochromes c/drug effects/metabolism ; Dose-Response Relationship, Drug ; Drug Combinations ; Electron Transport/*drug effects/physiology ; Glutathione/pharmacology ; Manganese Compounds/*adverse effects/antagonists &amp; inhibitors ; Membrane Potentials/drug effects/physiology ; Mitochondria/chemistry/*drug effects/pathology ; NADH, NADPH Oxidoreductases/drug effects/metabolism ; Oxygen Consumption/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Rhodamine 123 ; Succinate Dehydrogenase/drug effects/metabolism ; Ubiquinone/analogs &amp; derivatives/drug effects ; }, abstract = {Manganese (Mn) is known to induce mitochondrial dysfunction in excessive dose; however the mechanisms underlying its action are not elucidated clearly. To determine if Mn2+ can act directly on mitochondria or indirectly by producing reactive oxygen species (ROS), isolated mitochondria were exposed to different concentration of Mn2+ (5, 50, 500, 1000 microM). ROS generation, respiratory control ratio (RCR), mitochondrial membrane potential (MMP) and respiratory chain complexes activities were investigated. Dose-dependent inhibition of respiratory chain complexes and induction of ROS were observed; these changes were paralleled by decreasing of respiratory control ratio (RCR) both with succinate or glutamate + malate. Further investigation indicated that the membrane potential determined by Rhodamine123 release decreased after MnCl2 exposure at 1000 microM. In addition, effects of the antioxidants NAC (500 microM), GSH (500 microM) and Vitamin C (500 microM) were studied at 500 microM Mn2+. The results indicate that the effect of Mn2+ exposure on respiratory chain is not site-specific, and antioxidants can protect the mitochondria function by reducing the formation of free radicals.}, }
@article {pmid14627497, year = {2003}, author = {Shen, WH and Zhang, CY and Zhang, GY}, title = {Antioxidants attenuate reperfusion injury after global brain ischemia through inhibiting nuclear factor-kappa B activity in rats.}, journal = {Acta pharmacologica Sinica}, volume = {24}, number = {11}, pages = {1125-1130}, pmid = {14627497}, issn = {1671-4083}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Brain Ischemia/complications ; Hippocampus/pathology ; I-kappa B Proteins/metabolism ; Male ; NF-KappaB Inhibitor alpha ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; NF-kappa B p50 Subunit ; Neurons/pathology ; Phosphorylation ; Pyrrolidines/antagonists &amp; inhibitors/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/etiology/*metabolism ; Thiocarbamates/antagonists &amp; inhibitors/*pharmacology ; Transcription Factor RelA ; }, abstract = {AIM: To investigate the effects of two antioxidants on the alterations of nuclear factor kappaB (NF-kappaB) activity and p65, p50 protein expression and phosphorylation of IkappaBalpha in rat hippocampus following global brain ischemia.<br><br>METHODS: Using a 4-vessel occlusion (4-VO) as brain ischemia model, NF-kappaB protein (p65 or p50 subunit) expression was examined by Western blot analysis, and NF-kappaB activity was assayed by electrophoretic mobility shift assay (EMSA), and neuronal loss was observed by histology.<br><br>RESULTS: NF-kappaB activity displayed a time-dependent manner, and p65, p50 proteins showed their peak levels after ischemia/reperfusion 6 h. NF-kappaB inductions (p65: 4.79+/-0.78, p50: 5.50+/-0.33, sham control=1) and activity (4.93+/-0.95) after 6 h of reperfusion were markedly reduced by pretreatment with antioxidants pyrrolidine dithiocarbamate (PDTC, 200 mg/kg) (p65: 1.11+/-0.74, p50: 1.38+/-0.98, activity: 2.20+/-0.86, respectively) or N-acetylcysteine (NAC, 300 mg/kg) (p65: 0.64+/-0.39, p50: 1.89+/-0.87, activity: 0.61+/-0.65), and histological observations of the pyramidal layer of CA1 also showed a reduction of neuronal loss in rat hippocampus (70 %+/-5 % or 92 %+/-4 % cells are survival, respectively). Furthermore, PDTC and NAC prevented the decrease (from 0.50+/-0.10 to 0.80+/-0.20 or 1.20+/-0.24, respectively) and phosphorylation (from 2.00+/-0.15 to 0.46+/-0.10 or 0.41+/-0.10, respectively) of IkappaBalpha protein in the cytoplasm.<br><br>CONCLUSION: The protective effects of antioxidants against ischemia/reperfusion-induced injury may be mediated by down-regulation of NF-kappaB activity. NF-kappaB activation and deactivation are controlled mainly through phosphorylation and degradation of IkappaBalpha following brain ischemia.}, }
@article {pmid14623829, year = {2003}, author = {Liu, JC and Chen, JJ and Chan, P and Cheng, CF and Cheng, TH}, title = {Inhibition of cyclic strain-induced endothelin-1 gene expression by resveratrol.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {42}, number = {6}, pages = {1198-1205}, doi = {10.1161/01.HYP.0000103162.76220.51}, pmid = {14623829}, issn = {1524-4563}, mesh = {Antioxidants/*pharmacology ; Cells, Cultured ; Endothelin-1/*biosynthesis/genetics ; Endothelium, Vascular/*drug effects/metabolism ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; NADPH Oxidases/metabolism ; Periodicity ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/metabolism ; Resveratrol ; Stilbenes/*pharmacology ; Stress, Mechanical ; Transcription Factor AP-1/metabolism ; Transcription, Genetic/drug effects ; }, abstract = {Resveratrol is a phytoestrogen naturally found in grapes and is among the major constituents of wine thought to have a cardioprotective effect. Endothelin-1 (ET-1) is a potent vasopressor synthesized by endothelial cells both in culture and in vivo. The aims of this study were to test the hypothesis that resveratrol may alter strain-induced ET-1 gene expression and to identify the putative underlying signaling pathways in endothelial cells. We show that resveratrol indeed potently inhibits strain-induced ET-1 secretion, ET-1 mRNA level, and ET-1 promoter activity. Resveratrol also inhibits strain-increased NADPH oxidase activity, reactive oxygen species formation, and extracellular signal-regulated kinases1/2 (ERK1/2) phosphorylation. Furthermore, pretreating cells with resveratrol or antioxidant N-acetyl-cysteine decreases strain-increased or hydrogen peroxide-increased ET-1 secretion, ET-1 promoter activity, and ET-1 mRNA and ERK1/2 phosphorylation. Using both the electrophoretic mobility shift assay and a reporter gene assay, resveratrol and N-acetyl-cysteine also attenuated the strain-stimulated activator protein-1 binding activity and activator protein-1 reporter activity. In summary, we demonstrate for the first time that resveratrol inhibits strain-induced ET-1 gene expression, partially by interfering with the ERK1/2 pathway through attenuation of reactive oxygen species formation. Thus, this study provides important new insights in the molecular pathways that may contribute to the proposed beneficial effects of resveratrol in the cardiovascular system.}, }
@article {pmid14618631, year = {2004}, author = {Balansky, RM and De Flora, S}, title = {Interactions between N-acetylcysteine and sodium selenite in modulating the clastogenicity of urethane and 2-acetylaminofluorene in mice.}, journal = {International journal of cancer}, volume = {108}, number = {1}, pages = {158-161}, doi = {10.1002/ijc.11512}, pmid = {14618631}, issn = {0020-7136}, mesh = {2-Acetylaminofluorene/administration &amp; dosage/*pharmacology ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antimutagenic Agents/administration &amp; dosage/*pharmacology ; Drug Interactions ; Hematopoietic Stem Cells ; Male ; Mice ; Mice, Inbred BALB C ; Micronucleus Tests ; Sodium Selenite/administration &amp; dosage/*pharmacology ; Urethane/administration &amp; dosage/*pharmacology ; }, abstract = {Combined treatment with different agents represents a promising approach in cancer chemoprevention. Therefore, it is useful to assess in preclinical models the efficacy of combinations that are selected by taking into account mechanistic considerations. We designed 2 studies evaluating the interaction between N-acetylcysteine (NAC) and sodium selenite (Se), both given with the drinking water to Balb/c mice, in modulating clastogenic effects in bone marrow polychromatic erythrocytes. In a first study, a single i.p. injection of urethane considerably enhanced the frequency of micronucleated cells. While NAC produced a significant inhibition, Se further enhanced urethane clastogenicity. When given in combination at the same doses, NAC prevented the adverse effect of Se. In a second study, a single i.p. injection of 2-acetylaminofluorene enhanced the frequency of micronucleated cells. Se did not reduce this effect to a significant extent, while NAC produced a dose-dependent inhibition. When tested at the lower dose in combination with Se, the protective effect of NAC was unchanged. Especially in association with Se, NAC also prevented the toxicity of 2-acetylaminofluorene by normalizing the ratio of polychromatic to normochromatic erythrocytes. In conclusion, NAC attenuated the clastogenicity of both urethane and 2-acetylaminofluorene and the toxicity of this aromatic amine. In addition, NAC prevented the clastogenic and toxic effects resulting from the interaction of Se with urethane. Together with the findings of previous studies, it appears that, besides its intrinsic protective properties in carcinogenesis, NAC is capable of attenuating the adverse effects of several cytotoxic drugs and chemopreventive agents.}, }
@article {pmid14613752, year = {2003}, author = {Wessner, B and Strasser, EM and Spittler, A and Roth, E}, title = {Effect of single and combined supply of glutamine, glycine, N-acetylcysteine, and R,S-alpha-lipoic acid on glutathione content of myelomonocytic cells.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {22}, number = {6}, pages = {515-522}, doi = {10.1016/s0261-5614(03)00053-0}, pmid = {14613752}, issn = {0261-5614}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Antioxidants/pharmacology ; Chromatography, High Pressure Liquid ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Glutamine/*pharmacology ; Glutathione/*metabolism ; Glycine/*pharmacology ; Humans ; In Vitro Techniques ; Models, Biological ; Monocytes/*drug effects/metabolism ; Oxidative Stress/drug effects ; Thioctic Acid/*pharmacology ; U937 Cells ; }, abstract = {BACKGROUND &amp; AIMS: Several diseases are characterised by decreased glutathione (GSH) levels due to an enhanced formation of oxygen radicals. To increase GSH levels, the additional supply of GSH precursors was suggested. In this study we evaluated the potency of a single and combined administration of the GSH modulating substances glutamine (GLN), N-acetylcysteine (NAC), and glycine (GLY) as well as R,S-alpha-lipoic acid (LA) to enhance intracellular GSH content in a well-defined model system.<br><br>RESULTS: Exposure of myelomonocytic U937 cells for 24 h to GLN revealed a 1.5-fold enhancement of GSH levels with a concomitant decrease in the formation of reactive oxygen species and lipid peroxidation. Addition of NAC stimulated GSH formation only at subphysiological GLN levels. GLY enhanced GSH levels under GLN starvation, but caused a diminution of GSH content under optimal GLN supply. LA in combination with 2 mmol/l GLN evoked a 3.6-fold enhancement of GSH content compared to GLN starved cells.<br><br>CONCLUSION: These results demonstrate that the GSH content of U937 cells is dependent on the supply of GLN, NAC, LA, and GLY. Combinations of the single substances can enhance but also decrease the intracellular GSH content, which is of clinical importance when supplying GSH-modulating substances to patients.}, }
@article {pmid14612554, year = {2003}, author = {Kim, BR and Hu, R and Keum, YS and Hebbar, V and Shen, G and Nair, SS and Kong, AN}, title = {Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane.}, journal = {Cancer research}, volume = {63}, number = {21}, pages = {7520-7525}, pmid = {14612554}, issn = {0008-5472}, support = {R01 CA 073647/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Antioxidants/*metabolism ; Apoptosis/*drug effects/physiology ; Buthionine Sulfoximine/pharmacology ; Caspase 3 ; Caspases/metabolism ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Glutathione/metabolism/pharmacology/*physiology ; Humans ; Isothiocyanates ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases/metabolism ; Response Elements/*drug effects ; Sulfoxides ; Thiocyanates/chemistry/*pharmacology ; }, abstract = {Sulforaphane (SFN) and its N-acetyl-L-cysteine (NAC) conjugate are effective inhibitors of tumorigenesis in animal models. These compounds induce the expression of the antioxidant response element (ARE)-related genes and cause apoptosis. We studied the role of reduced glutathione (GSH) in the activations of ARE-mediated gene expression, apoptosis, and the activation of c-Jun NH(2)-terminal kinase (JNK) in HepG2-C8 cells. The cellular level of GSH decreased transiently when cells were exposed to SFN and then increased from 4 h, reaching 2.2-fold over control at 24 h. In contrast, SFN-NAC did not change the GSH level substantially during the time of incubation. ARE expression was increased in a dose-dependent manner up to 35 micro M SFN and 75 micro M SFN-NAC, respectively. The induction of ARE by SFN was 8.6-fold higher than that by SFN-NAC. Pretreatment with L-buthionine sulfoximine increased SFN-induced ARE expression significantly. The decrease in ARE expression at higher concentrations of SFN and SFN-NAC was correlated with accelerated apoptotic cell death, with a dose-dependent activation of caspase 3 activity by SFN. On addition of extracellular GSH within 6 h of treatment with SFN, the effect on ARE expression was blocked almost completely. SFN was able to activate JNK1/2, and that activation was blocked by treatment with exogenous GSH. Taken together, these results suggest that the biological effects of SFN and SFN-NAC on the induction of ARE-related gene expression and apoptosis could be different from each other; however, the different effects on ARE-related gene expression and apoptosis elicited by SFN can be blocked by the addition of GSH.}, }
@article {pmid14610365, year = {2003}, author = {Park, ES and Kim, SD and Lee, MH and Lee, HS and Lee, IS and Sung, JK and Yoon, YS}, title = {Protective effects of N-acetylcysteine and selenium against doxorubicin toxicity in rats.}, journal = {Journal of veterinary science}, volume = {4}, number = {2}, pages = {129-136}, pmid = {14610365}, issn = {1229-845X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Astrocytes/*cytology/drug effects/pathology ; Cell Survival/drug effects ; Cells, Cultured ; Doxorubicin/antagonists &amp; inhibitors/*toxicity ; Liver/cytology/*drug effects/pathology ; Male ; Rats ; Rats, Sprague-Dawley ; Spermatocytes/cytology/drug effects/pathology ; }, abstract = {To investigate the neutralizing effect of N-acetylcysteine (NAC) and selenium (Se) against doxorubicin (DOX) toxicity in rats, NAC (140 mg/kg, p.o.) and Se (0.5 mg/kg, p.o.) were administered for 2 days before DOX injection and then 3 times a week. Cell viability and the level of lipid peroxidation were examined in cultured-rat astrocytes. Severe morphologic changes in the kidney of DOX group; thickening of Bowmans capsule, presence of multifocal tubular casts were observed, but not in the other treated groups. Vacuoles in some hepatic cells and focal aggregation of stellate macrophages were also detected in DOX group, but not in the other treated groups. However, the severe inhibition of spermatogenesis was found in all treated groups. The cell viability of DOX (10 mg/ml) treated group and NAC (5 mM) or Se (0.001 mg/ml) combined-treated group was 52.5-/+2.0 %, 85.3-/+4.5 % and 75.5-/+1.6 %, respectively. In MDA (malondialdehyde) assay, the level of lipid peroxidation on DOX (10 mg/ml), NAC (5 mM) and Se (0.001 mg/ml) was 0.77-/+0.06, 0.35-/+0.06 and 0.54-/+0.11 nmol/mg protein, respectively. Thus, it is known that NAC and Se have protective effects in kidney and liver but not in the testes. Morphological change was not detected in brain and heart in all groups for experiment period. From this in vitro study, it is known that NAC and Se protect well the astrocytes against DOX induced-cell damage.}, }
@article {pmid14607909, year = {2003}, author = {Monick, MM and Samavati, L and Butler, NS and Mohning, M and Powers, LS and Yarovinsky, T and Spitz, DR and Hunninghake, GW}, title = {Intracellular thiols contribute to Th2 function via a positive role in IL-4 production.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {171}, number = {10}, pages = {5107-5115}, doi = {10.4049/jimmunol.171.10.5107}, pmid = {14607909}, issn = {0022-1767}, support = {CA66081/CA/NCI NIH HHS/United States ; ES09607/ES/NIEHS NIH HHS/United States ; HL51469/HL/NHLBI NIH HHS/United States ; HL60316/HL/NHLBI NIH HHS/United States ; RR00059/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Active Transport, Cell Nucleus/drug effects/immunology ; Adjuvants, Immunologic/*physiology ; Animals ; Antigen-Presenting Cells/immunology ; CD3 Complex/metabolism/pharmacology ; Cell Nucleus/immunology/metabolism ; Cells, Cultured ; Cytokines/biosynthesis ; DNA-Binding Proteins/metabolism ; Down-Regulation/drug effects/immunology ; Drug Combinations ; Female ; Interferon-gamma/antagonists &amp; inhibitors/biosynthesis ; Interleukin-12/antagonists &amp; inhibitors/pharmacology ; Interleukin-4/*biosynthesis/metabolism ; Interphase/immunology ; Intracellular Fluid/*physiology ; Lymphocyte Activation/drug effects/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; NFATC Transcription Factors ; *Nuclear Proteins ; STAT6 Transcription Factor ; Solubility ; Spleen/cytology/immunology ; Sulfhydryl Compounds/*physiology ; Th1 Cells/immunology/metabolism ; Th2 Cells/*immunology/*metabolism/physiology ; Trans-Activators/antagonists &amp; inhibitors/metabolism ; Transcription Factor AP-1/metabolism ; Transcription Factors/metabolism ; Up-Regulation/drug effects/immunology ; }, abstract = {A number of lung diseases, including many interstitial lung diseases and HIV infection, are associated with decreases in intracellular thiols. Altered Th1/Th2 T cell balance has also been associated with disease progression in many of the same diseases. IFN-gamma and IL-4 are critical effector cytokines of Th1 and Th2 cells, respectively. To determine the effect of thiols on the production of IFN-gamma and IL-4 by splenocytes, cells were incubated in the presence and the absence of N-acetylcysteine (NAC) and stimulated with alphaCD3 or alphaCD3 and IL-12. Augmenting intracellular soluble thiol pools (approximately 2-fold) with 15 mM NAC blocked induction of IFN-gamma and increased production of IL-4 without causing significant changes in intracellular glutathione levels. The effect of NAC on IL-4 production was not linked to an increase in STAT6 phosphorylation, as STAT6 levels were decreased, nor did the increase in IL-4 occur with purified CD4 cells. We found that NAC increased splenocyte IL-4 production via an effect on APCs. We also found that NAC increased two IL-4 relevant transcription factors (AP-1) and NFATc. These studies suggest that increasing intracellular reduced thiol pools decreases IL-12 signaling and IFN-gamma production, while increasing IL-4 production. The sum of these effects may contribute to alterations in the balance between Th1 and Th2 responses in lung diseases associated alterations in intracellular thiol pools.}, }
@article {pmid14607527, year = {2003}, author = {Kinscherf, R and Cafaltzis, K and Röder, F and Hildebrandt, W and Edler, L and Deigner, HP and Breitkreutz, R and Feussner, G and Kreuzer, J and Werle, E and Michel, G and Metz, J and Dröge, W}, title = {Cholesterol levels linked to abnormal plasma thiol concentrations and thiol/disulfide redox status in hyperlipidemic subjects.}, journal = {Free radical biology &amp; medicine}, volume = {35}, number = {10}, pages = {1286-1292}, doi = {10.1016/j.freeradbiomed.2003.07.001}, pmid = {14607527}, issn = {0891-5849}, mesh = {Amino Acids/blood ; Cholesterol/blood ; Cholesterol, HDL/*blood ; Cholesterol, LDL/blood ; Coronary Disease/*blood ; Cysteine/blood ; Disulfides/*blood ; Glutathione/metabolism ; Humans ; Hyperlipidemias/*blood ; *Oxidation-Reduction ; Sulfhydryl Compounds/*blood ; Taurine/blood ; Triglycerides/blood ; }, abstract = {Treatment of hyperlipidemic patients with the thiol compound N-acetylcysteine (NAC) was previously shown to cause a significant dose-related increase in the high-density lipoprotein (HDL)-cholesterol serum level, suggesting the possibility that its disease-related decrease may result from a diminished thiol concentration and/or thiol/disulfide redox status (REDST) in the plasma. We therefore investigated plasma thiol levels and REDST in normo-/hyperlipidemic subjects with and without coronary heart disease (CHD). The thiol level, REDST, and amino acid concentrations in the plasma and intracellular REDST of peripheral blood mononuclear cells (PBMC) have been determined in 62 normo- and hyperlipidemic subjects. Thirty-three of these subjects underwent coronary angiography, because of clinical symptoms of CHD. All groups of hyperlipidemic patients under test and those normolipidemic individuals with documented coronary stenoses showed a marked decrease in plasma thiol concentrations, plasma and intracellular REDST of PBMCs, and a marked increase in plasma taurine levels. Individual plasma thiol concentrations and plasma REDST were strongly negatively correlated with the serum LDL-cholesterol and positively correlated with the serum HDL-cholesterol level. Together with the earlier report about the effect of NAC on the HDL-cholesterol serum level, our findings suggest strongly that lower HDL-cholesterol serum levels may result from a decrease in plasma thiol level and/or REDST possibly through an excessive cysteine catabolism into taurine.}, }
@article {pmid14603257, year = {2003}, author = {Huang, HL and Fang, LW and Lu, SP and Chou, CK and Luh, TY and Lai, MZ}, title = {DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation.}, journal = {Oncogene}, volume = {22}, number = {50}, pages = {8168-8177}, doi = {10.1038/sj.onc.1206979}, pmid = {14603257}, issn = {0950-9232}, mesh = {*Adaptor Proteins, Signal Transducing ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects/*radiation effects ; Carrier Proteins/metabolism ; Caspase 8 ; Caspase 9 ; Caspases/metabolism ; Cisplatin/pharmacology ; DNA Damage/*radiation effects ; Fas Ligand Protein ; Fas-Associated Death Domain Protein ; Gamma Rays ; Humans ; Jurkat Cells ; Membrane Glycoproteins/metabolism ; Reactive Oxygen Species/*metabolism ; fas Receptor/*radiation effects ; }, abstract = {DNA-damaging reagents may kill tumor cells through the generation of reactive oxygen species (ROS). Cytotoxic reagents may also induce apoptosis of cancer cells in Fas-FADD-dependent manners. In this study, we explored the possible link between these two apparently distinct pathways in T leukemia cell Jurkat. Our results demonstrated that gamma-irradiation, similar to cisplatin, induced apoptosis by triggering Fas aggregation and activating FADD-caspase-8 apoptotic cascade. The absence of caspase-8 or Fas greatly reduced the sensitivity to apoptosis mediated by DNA-damaging agents. In addition, apoptosis induced by cisplatin and gamma-irradiation, but not by Fas, was inhibited by ROS scavengers, including N-acetyl cysteine, MnTBAP, and C60. Importantly, these ROS scavengers effectively prevented the clustering of Fas receptor induced by cisplatin and gamma-irradiation. Our results suggest that cisplatin and gamma-irradiation promote ROS production, which in turn contributes to Fas receptor aggregation and cell death. The novel coupling between ROS and Fas clustering likely plays a significant role in apoptosis triggered by DNA-damaging reagents in Fas-expressing leukemia cells.}, }
@article {pmid14597979, year = {2003}, author = {Lalé, A and Herbert, JM and Savi, P}, title = {The antiaggregating activity of clopidogrel is not affected by N-acetyl L-cysteine.}, journal = {Thrombosis and haemostasis}, volume = {90}, number = {5}, pages = {839-843}, doi = {10.1160/TH03-01-0001}, pmid = {14597979}, issn = {0340-6245}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Diphosphate ; Animals ; Blood Platelets/drug effects ; Cells, Cultured ; Clopidogrel ; Drug Interactions ; Female ; Humans ; Male ; Membrane Proteins/metabolism ; Platelet Aggregation/drug effects ; Platelet Aggregation Inhibitors/*pharmacology ; Rats ; Receptors, Purinergic P2/metabolism ; Receptors, Purinergic P2Y12 ; Ticlopidine/*analogs &amp; derivatives/metabolism/*pharmacology ; }, abstract = {N-acetyl L-cysteine (NAC) is widely used to treat obstructive bronchopulmonary diseases. It has thiol reactive properties, accounting for its mucolytic activity. Clopidogrel is a potent antithrombotic compound, metabolised by the liver which generates an active metabolite containing a thiol reactive group, responsible for an irreversible interaction with the platelet P2Y(12) ADP receptor. The aim of this study was to determine if NAC interferes with the antiaggregating activity of clopidogrel. For this purpose, NAC (100 micro M) was incubated with platelets from rats treated or not with clopidogrel (5 mg/kg, PO, -2 h). Clopidogrel treatment strongly inhibited aggregation but this effect was not modified by NAC. In another experiment, a low concentration of the active metabolite of clopidogrel (0.3 micro g/ml) was incubated with platelets from men or rats, in the absence or presence of NAC (100 micro M). When stimulated by ADP (2.5 micro M), platelet aggregation was inhibited by the active metabolite when incubated alone. In the presence of NAC, the inhibition by the active metabolite was not modified, therefore clearly indicating that NAC cannot reduce the thiol reactive part of the active metabolite of clopidogrel and does not interfere with its anti-aggregating activity. Moreover, in rats treated for 5 days with NAC (150 mg/kg), the activity of clopidogrel (5 or 10 mg/kg) against ADP-induced platelet aggregation was neither inhibited nor increased. This demonstrates that the generation of the active metabolite of clopidogrel is not affected by NAC. In conclusion, we have found that NAC does not restore the "normal" properties of P2Y(12) on platelets from clopidogrel-treated animals, it does not interfere with the antiaggregating activity of the active metabolite of clopidogrel, and does not interfere with the generation of the active metabolite.}, }
@article {pmid14588145, year = {2003}, author = {Usatyuk, PV and Vepa, S and Watkins, T and He, D and Parinandi, NL and Natarajan, V}, title = {Redox regulation of reactive oxygen species-induced p38 MAP kinase activation and barrier dysfunction in lung microvascular endothelial cells.}, journal = {Antioxidants &amp; redox signaling}, volume = {5}, number = {6}, pages = {723-730}, doi = {10.1089/152308603770380025}, pmid = {14588145}, issn = {1523-0864}, support = {HL 57260/HL/NHLBI NIH HHS/United States ; HL 69909/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Blotting, Western ; Cattle ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*cytology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Glutathione/metabolism ; Hydrogen Peroxide/pharmacology ; Imidazoles/pharmacology ; Lung/*blood supply ; MAP Kinase Signaling System ; *Microcirculation ; Mitogen-Activated Protein Kinases/*metabolism ; *Oxidation-Reduction ; Permeability ; Pyridines/pharmacology ; *Reactive Oxygen Species ; Time Factors ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Reactive oxygen species (ROS)-mediated compromise of endothelial barrier integrity has been implicated in a number of pulmonary disorders, including adult respiratory distress syndrome, pulmonary edema, and vasculitis. The mechanisms by which ROS increase endothelial permeability are unclear. We hypothesized that ROS-induced changes in cellular redox status (thiols) may contribute to endothelial barrier dysfunction. To test this hypothesis, we used N-acetylcysteine (NAC) and diamide to modulate intracellular levels of cellular glutathione (GSH) and investigated hydrogen peroxide (H(2)O(2))-mediated mitogen-activated protein kinase (MAPK) activation and transendothelial electrical resistance (TER). Exposure of bovine lung microvascular endothelial cells (BLMVECs) to H(2)O(2), in a dose- and time-dependent fashion, increased endothelial permeability. Pretreatment of BLMVECs with NAC (5 mM) for 1 h resulted in partial attenuation of H(2)O(2)-induced TER (a measure of increase in permeability) and GSH. Furthermore, treatment of BLMVECs with diamide, which is known to reduce the intracellular GSH, resulted in significant reduction in TER, which was prevented by NAC. To understand further the role of MAPKs in ROS-induced barrier dysfunction, we examined the role of extracellular signal-regulated kinase (ERK) and p38 MAPK on H(2)O(2)- and diamide-mediated permeability changes. Both H(2)O(2) and diamide, in a dose-dependent manner, activated ERK and p38 MAPK in BLMVECs. However, SB203580, an inhibitor of p38 MAPK, but not PD98059, blocked H(2)O(2)- and diamide-induced TER. Also, NAC prevented H(2)O(2)- and diamide-induced p38 MAPK, but not ERK activation. These results suggest a role for redox regulation of p38 MAPK in ROS-dependent endothelial barrier dysfunction.}, }
@article {pmid14580892, year = {2003}, author = {Tandon, SK and Singh, S and Prasad, S and Khandekar, K and Dwivedi, VK and Chatterjee, M and Mathur, N}, title = {Reversal of cadmium induced oxidative stress by chelating agent, antioxidant or their combination in rat.}, journal = {Toxicology letters}, volume = {145}, number = {3}, pages = {211-217}, doi = {10.1016/s0378-4274(03)00265-0}, pmid = {14580892}, issn = {0378-4274}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Administration, Oral ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Brain/enzymology/metabolism ; Cadmium Chloride/*toxicity ; *Cadmium Poisoning/drug therapy/enzymology/metabolism ; Catalase/blood/metabolism ; Chelating Agents/*pharmacology/therapeutic use ; Drug Synergism ; Drug Therapy, Combination ; Glutathione/blood/metabolism ; Liver/enzymology/metabolism ; Male ; Malondialdehyde/blood/metabolism ; Mannitol/pharmacology/therapeutic use ; Oxidative Stress/*drug effects ; Rats ; Succimer/*analogs &amp; derivatives/pharmacology/therapeutic use ; Superoxide Dismutase/blood/metabolism ; }, abstract = {The influence of an antioxidant agent such as N-acetyl cysteine (NAC) or mannitol on the cadmium chelating ability of monoisoamyl 2,3-dimercaptosuccinate (MiADMS) was investigated in cadmium pre-exposed rats. This ester of 2,3-dimercaptosuccinic acid (DMSA), an accepted drug for lead poisoning, being lipophilic in nature was expected to be an efficient cadmium chelator. The treatment of cadmium intoxicated animals with MiADMS reversed cadmium induced increase in blood catalase, superoxide dismutase (SOD) and malondialdehyde (MDA), liver MDA and brain SOD and MDA levels but not the decrease in blood, liver brain reduced glutathione (GSH) and increase in oxidized glutathione (GSSG) levels, consistent with the lowering of tissue cadmium burden. The administration of NAC or mannitol reversed the cadmium induced alterations in blood and liver GSH, GSSG, blood catalase, SOD, MDA, liver SOD, MDA and brain MDA levels without lowering blood and tissue cadmium contents. However, treatments with the combination of MiADMS and NAC or MiADMS and mannitol reversed these alterations as well as reduced blood and tissue cadmium concentrations. The combined treatment with MiADMS and mannitol was better than that with MiADMS and NAC, and was significantly more effective in normalizing blood, liver GSH, GSSG, brain GSSG, and their GSH/GSSG ratios than that by either of them alone. The combined treatments also improved liver and brain endogenous zinc levels, which were decreased due to cadmium toxicity. The results suggest that the administration of an antioxidant during chelation of cadmium may provide beneficial effects by reducing oxidative stress without its cadmium removing ability.}, }
@article {pmid14578855, year = {2003}, author = {Biswas, KK and Sarker, KP and Abeyama, K and Kawahara, K and Iino, S and Otsubo, Y and Saigo, K and Izumi, H and Hashiguchi, T and Yamakuchi, M and Yamaji, K and Endo, R and Suzuki, K and Imaizumi, H and Maruyama, I}, title = {Membrane cholesterol but not putative receptors mediates anandamide-induced hepatocyte apoptosis.}, journal = {Hepatology (Baltimore, Md.)}, volume = {38}, number = {5}, pages = {1167-1177}, doi = {10.1053/jhep.2003.50459}, pmid = {14578855}, issn = {0270-9139}, mesh = {Animals ; Apoptosis/*physiology ; Arachidonic Acids/blood/*physiology ; Cannabinoid Receptor Modulators/blood/*physiology ; Cell Membrane/metabolism ; Cells, Cultured ; Cholesterol/*physiology ; Endocannabinoids ; Female ; Hepatitis/blood ; Hepatocytes/*physiology ; Humans ; Oxidative Stress/physiology ; Polyunsaturated Alkamides ; Rats ; Rats, Wistar ; }, abstract = {The endogenous cannabinoid anandamide, a lipid mediator, induces various physiologic events such as vascular relaxation, inhibition of gap-junctions formation, tumor proliferation, neurologic analgesia, and apoptosis. Although increased concentration of anandamide in plasma has been implicated in pathophysiologic states including endotoxin-induced hypotension, the effects of anandamide on hepatocytes still remain unclear. In this study, we present evidence that plasma anandamide concentration is highly increased in severe hepatitis and cirrhosis patients. In addition, concentrations of anandamide within the pathophysiologic range potently induced apoptosis of hepatoma cell line (Hep G2) and primary hepatocytes, suggesting a possible link between increased anandamide level and hepatocyte damage. Anandamide-induced cell death was preceded by G0/G1 cell-cycle arrest, activation of proapoptotic signaling (i.e., p38 MAPK and JNK), and inhibition of antiapoptotic signaling (i.e., PKB/Akt) pathways. Moreover, anandamide increased susceptibility to oxidative stress-induced hepatocyte damage. In this context, methyl-beta-cyclodextrin (MCD), a membrane cholesterol depletor, or mevastatin, an HMG-CoA reductase inhibitor, or N-acetyl cysteine, an antioxidant, potently inhibited the anandamide-induced proapoptotic events and cell death, whereas putative cannabinoid receptor antagonists did not exhibit an inhibitory effect on anandamide-induced cell death. Furthermore, binding assay using polymyxin beads revealed that anandamide could interact with cholesterol. In conclusion, our data suggest that cholesterol present in the cell membrane determines the fate of hepatocytes exposed to anandamide, possibly functioning as an anandamide receptor.}, }
@article {pmid14577570, year = {2003}, author = {Lee, JR}, title = {Reactive oxygen species play roles on B cell surface receptor CD40-mediated proximal and distal signaling events: effects of an antioxidant, N-acetyl-L-cysteine treatment.}, journal = {Molecular and cellular biochemistry}, volume = {252}, number = {1-2}, pages = {1-7}, pmid = {14577570}, issn = {0300-8177}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; CD40 Antigens/chemistry/*metabolism ; Cell Line, Tumor ; Mass Spectrometry ; Mice ; Phosphorylation ; *Reactive Oxygen Species ; Receptors, Antigen, B-Cell/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Serine/metabolism ; *Signal Transduction ; Spectrometry, Fluorescence ; }, abstract = {Reactive oxygen species (ROS) have been indicated as important signal mediators for many cell surface receptors. We previously demonstrated that ROS are generated by cross-linking surface receptor CD40 and consequently induce c-Jun N-terminal kinase activation and interleukin-6 secretion in murine B cells. In this study, we investigated further the involvement of ROS in CD40-mediated signaling events in B cells. CD40-mediated proximal events, which include protein serine phosphorylation, protein translocation between membranes and cytosol, as well as receptor complex formation, were inhibited after the pre-incubation of cells with an antioxidant N-acetyl-L-cysteine (NAC). Additionally, B cell responses after long-term ligation of CD40, such as protein expression, nuclear transcription factor kappaB (NFkappaB) activation, and cell proliferation, were also affected when cells were treated with NAC. These data suggest that CD40-induced ROS play critical roles in CD40-mediated B cell regulation.}, }
@article {pmid14575811, year = {2003}, author = {Zhang, Q and Tian, H and Fu, X and Zhang, G}, title = {Delayed activation and regulation of MKK7 in hippocampal CA1 region following global cerebral ischemia in rats.}, journal = {Life sciences}, volume = {74}, number = {1}, pages = {37-45}, doi = {10.1016/j.lfs.2003.06.025}, pmid = {14575811}, issn = {0024-3205}, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain Ischemia/*enzymology ; Enzyme Activation ; Hippocampus/*enzymology ; MAP Kinase Kinase 7 ; Male ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; }, abstract = {c-Jun N-terminal protein kinase (JNK) activation and subsequent c-Jun phosphorylation which stimulates its transcriptional activity have been well studied in cerebral ischemia. To determine whether mitogen-activated protein kinase kinase 7 (MKK7) play a role in JNK activation in response to the stress of global cerebral ischemia, we tested the activation of such a kinase by using phospho-Ser and phospho-Thr antibodies. Immunoprecipitation and Western blot analysis revealed that MKK7 was expressed at similar levels in all conditions, whereas phospho-MKK7 was highly augmented from 1 to 5 days and reached its peak at 3 days after 15 min of ischemia. Consistent with the active phase, the interaction of MLK3, ASK1 and phospho-JNK with MKK7 was increased compared with sham control, as shown by coimmunoprecipitation experiments. Moreover, MKK7 activation was markedly reduced by pretreatment of the free radical scavenging thiol antioxidant N-acetylcysteine (NAC). Together with previous studies, the late activation of MKK7 in hippocampal CA1 region may contribute to delayed cell death, and the protective effects of antioxidant against ischemia-induced injury may be partially mediated by the down-regulation of JNK signal pathway.}, }
@article {pmid14574078, year = {2003}, author = {Calvillo, L and Masson, S and Salio, M and Pollicino, L and De Angelis, N and Fiordaliso, F and Bai, A and Ghezzi, P and Santangelo, F and Latini, R}, title = {In vivo cardioprotection by N-acetylcysteine and isosorbide 5-mononitrate in a rat model of ischemia-reperfusion.}, journal = {Cardiovascular drugs and therapy}, volume = {17}, number = {3}, pages = {199-208}, doi = {10.1023/a:1026182404805}, pmid = {14574078}, issn = {0920-3206}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Blood Pressure/drug effects ; Drug Therapy, Combination ; Free Radical Scavengers/*therapeutic use ; Isosorbide Dinitrate/*analogs &amp; derivatives/*therapeutic use ; Male ; Monocytes/pathology ; Myocardial Infarction/drug therapy/mortality/pathology ; Myocardial Reperfusion Injury/mortality/pathology/*prevention &amp; control ; Neutrophils/pathology ; Nitric Oxide Donors/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; }, abstract = {AIMS: We evaluated the effect of N-acetylcysteine (NAC, infused i.v.), isosorbide 5-mononitrate (IS5MN, by gavage), or their combination on cardiac injury in an in vivo rat model of 30-min ischemia followed by 24 hours or 7 days of reperfusion.<br><br>RESULTS: When administered immediately prior to reperfusion with continuous infusion for 24 h, the combination of NAC + IS5MN reduced infarct size (29 +/- 6 vs. 59 +/- 4% area-at-risk, p < 0.01) and the infiltration of polymorphonuclear leukocytes (226 +/- 15 vs. 315 +/- 18 cells mm(-2) of area-at-risk, p = 0.002) and monocytes/macrophages (118 +/- 8 vs. 194 +/- 22 cells mm(-2), p = 0.012), compared to vehicle. NAC or IS5MN alone did not reduce infarct size at 24 hours of reperfusion. The same dose regimen of NAC and IS5MN did not reduce infarct size with permanent ischemia for 24 hours not followed by reperfusion. After 7 days of reperfusion (3 days of treatment with NAC + IS5MN or vehicle and 4 days of wash-out), infarct size was similar in the vehicle and NAC + IS5MN groups, but LV end-diastolic pressure and diastolic LV chamber wall stress were significantly lower in the animals treated with NAC + IS5MN (5 +/- 1 mmHg and 62 +/- 7 dyne mm(-2), respectively) compared to vehicle (9 +/- 1 mmHg and 123 +/- 18 dyne mm(-2), p < 0.05).<br><br>CONCLUSIONS: We demonstrate in a rat model of cardiac ischemia-reperfusion treated with NAC and IS5MN, according to a regimen that mimicked a clinical situation (drugs started at time of reperfusion), that the short-term benefit seen after 24 h of reperfusion (51% reduction of infarct size) is maintained after one week, possibly through modulation of the inflammatory response to cardiac injury.}, }
@article {pmid14573751, year = {2003}, author = {Lin, MT and Yen, ML and Lin, CY and Kuo, ML}, title = {Inhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation.}, journal = {Molecular pharmacology}, volume = {64}, number = {5}, pages = {1029-1036}, doi = {10.1124/mol.64.5.1029}, pmid = {14573751}, issn = {0026-895X}, mesh = {Antigens, CD ; Antioxidants/*pharmacology ; CSK Tyrosine-Protein Kinase ; Cadherins/*metabolism ; Cell Division/drug effects ; Cell Movement/drug effects ; Cells, Cultured ; Drug Interactions ; Endothelium, Vascular/drug effects/physiology ; Humans ; Neovascularization, Physiologic/*drug effects ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/metabolism ; Resveratrol ; Stilbenes/*pharmacology ; Tyrosine/metabolism ; Vascular Endothelial Growth Factor A/*pharmacology ; src-Family Kinases/metabolism ; }, abstract = {Resveratrol, a polyphenolic compound found in grapes and other fruits, has been reported to inhibit angiogenesis with an as yet elusive mechanism. Here, we investigate the detailed mechanism by which resveratrol inhibits vascular endothelial growth factor (VEGF)-induced angiogenic effects in human umbilical endothelial cells (HUVECs). Exposure of HUVECs to 1 to 2.5 muM resveratrol significantly blocked VEGF-mediated migration and tube formation but not cell proliferation. Under the same concentrations, resveratrol failed to affect VEGF-stimulated activation of VEGF receptor, extracellular signal-regulated protein kinase 1/2, p38 mitogen-activated protein kinase, and Akt. Of interest, resveratrol, at the dose of 1 or 2.5 muM, effectively abrogated VEGF-mediated tyrosine phosphorylation of vascular endothelial (VE)-cadherin and its complex partner, beta-catenin. This inhibitory effect of resveratrol reflected on the retention of VE-cadherin at cell-cell contacts as demonstrated by immunofluorescence. Src kinase assay showed that VEGF-induced endogenous Src kinase activation was strongly inhibited by 1 and 2.5 muM resveratrol. Supportively, inhibition of Src activity by overexpression of Csk resulted in attenuation of the tyrosine phosphorylation of VE-cadherin and endothelial cell (EC) tube formation. Again, transfection with v-Src, an active form of Src, could reverse resveratrol inhibition of VE-cadherin tyrosine phosphorylation and EC tube formation. Reactive oxygen species (ROS) has been shown to be involved in VE-cadherin phosphorylation and its related functions. Flow cytometric analysis showed that VEGF stimulated an evident increase of peroxide, which was strongly attenuated by resveratrol. In addition, antioxidant N-acetyl-cysteine was demonstrated to strongly inhibit VEGF-mediated Src activation, VE-cadherin tyrosine phosphorylation, and HUVEC tube formation. Together, our data suggest that resveratrol inhibition of VEGF-induced angiogenesis was mediated by disruption of ROS-dependent Src kinase activation and the subsequent VE-cadherin tyrosine phosphorylation.}, }
@article {pmid14570764, year = {2003}, author = {Grillo, MP and Knutson, CG and Sanders, PE and Waldon, DJ and Hua, F and Ware, JA}, title = {Studies on the chemical reactivity of diclofenac acyl glucuronide with glutathione: identification of diclofenac-S-acyl-glutathione in rat bile.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {31}, number = {11}, pages = {1327-1336}, doi = {10.1124/dmd.31.11.1327}, pmid = {14570764}, issn = {0090-9556}, mesh = {Animals ; Bile/*metabolism ; Chromatography, High Pressure Liquid/methods ; Diclofenac/analysis/chemistry/*metabolism ; Glucuronides/analysis/chemistry/*metabolism ; Glutathione/analysis/chemistry/*metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Diclofenac, a nonsteroidal anti-inflammatory drug, is metabolized to a reactive acyl glucuronide that has been proposed to mediate toxic adverse drug reactions associated with its use. In the present study, we examined the ability of diclofenac acyl glucuronide (D-1-O-G) to transacylate glutathione (GSH) in vitro in buffer and in vivo in rats. Thus, in vitro reactions of D-1-O-G (100 microM) with GSH (10 mM) at pH 7.4 and 37 degrees C showed a linear time-dependent formation of diclofenac-S-acyl-glutathione (D-SG, 3 microM/h) through 60 min of incubation, reaching a maximum of 3.7 microM after 2 h of incubation. The major reaction that occurred was acyl migration of D-1-O-G (t1/2, 54 min) to less reactive isomers. The D-SG thioester product was shown to be unstable by degrading primarily to 1-(2,6-dichlorophenyl)indolin-2-one and by hydrolysis to diclofenac. After administration of diclofenac to rats (200 mg/kg), bile was collected and analyzed for D-SG by liquid chromatography-tandem mass spectrometry. Results indicated the presence of D-SG, which was confirmed by coelution with synthetic standard and by its tandem mass spectrum. When the reactivity of D-SG (100 microM) was compared with D-1-O-G (100 microM) in vitro in reactions with N-acetylcysteine (NAC, 10 mM), results showed the quantitative reaction of D-SG with NAC after 30 min of incubation, whereas only approximately 1% of D-1-O-G reacted to form diclofenac-S-acyl-NAC at the same time point. Results from these studies indicate that GSH reacts with D-1-O-G in vitro, and presumably in vivo, to form D-SG, and that the product D-SG thioester is chemically more reactive in transacylation-type reactions than the D-1-O-G metabolite.}, }
@article {pmid14569887, year = {2003}, author = {Kołaciński, Z and Rusiński, P}, title = {[Paracetamol: therapeutic action, pathogenesis and treatment of acute poisonings complicated by severe liver damage].}, journal = {Przeglad lekarski}, volume = {60}, number = {4}, pages = {218-222}, pmid = {14569887}, issn = {0033-2240}, mesh = {Acetaminophen/*adverse effects ; Anti-Inflammatory Agents, Non-Steroidal/*adverse effects ; Benzoquinones/metabolism ; Cyclooxygenase 1 ; Electron Transport Complex IV/metabolism ; Humans ; Imines/metabolism ; Isoenzymes/metabolism ; Liver Failure, Acute/*chemically induced ; Membrane Proteins/metabolism ; Prostaglandin-Endoperoxide Synthases/metabolism ; Saccharomyces cerevisiae Proteins ; }, abstract = {The biosynthesis of prostaglandins proceeds in the presence of fatty acid cycloxygenases (COX-1, COX-2). COX-1 is responsible for the synthesis of prostaglandins indispensable for normal homeostasis, while COX-2 regulates local expression of pro-inflammatory prostaglandins. Paracetamol is a selective inhibitor of COX-2 thus having an analgesic and antipyretic potential. The drug is metabolised primarily in the liver. About 5% of the dose transforms into N-acetylo-p-benzoquinoneimine (NAPQI), a highly active compound. Ingestion of a single paracetamol dose higher than 8 g leads to a depletion of hepatic glutathione reserves and a loss of the detoxifying property of the liver. As a result, hepatic necrosis develops. The specific antidote is N-acetylcysteine (NAC). If applied within 10-15 h since the poisoning it enables complete survival. The efficacy of specific treatment decreases after 24 h but blood paracetamol is an indication for NAC therapy. The surviving patients with advanced paracetamol poisoning require long-lasting conservative treatment with ornithine and phospholipids as well as a light diet.}, }
@article {pmid14568351, year = {2003}, author = {Peña-Llopis, S and Ferrando, MD and Peña, JB}, title = {Fish tolerance to organophosphate-induced oxidative stress is dependent on the glutathione metabolism and enhanced by N-acetylcysteine.}, journal = {Aquatic toxicology (Amsterdam, Netherlands)}, volume = {65}, number = {4}, pages = {337-360}, doi = {10.1016/s0166-445x(03)00148-6}, pmid = {14568351}, issn = {0166-445X}, mesh = {Acetylcysteine/*metabolism/pharmacology ; Analysis of Variance ; Animals ; Apoptosis/drug effects ; Dichlorvos/*toxicity ; Dose-Response Relationship, Drug ; Eels/*metabolism ; Glutathione/chemistry/*metabolism/pharmacology ; Insecticides/toxicity ; Liver/enzymology ; Muscles/enzymology ; Neurotoxicity Syndromes/*veterinary ; Oxidative Stress/*drug effects ; Proportional Hazards Models ; Toxicity Tests, Acute/*statistics &amp; numerical data ; }, abstract = {Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP) is an organophosphorus (OP) insecticide and acaricide extensively used to treat external parasitic infections of farmed fish. In previous studies we have demonstrated the importance of the glutathione (GSH) metabolism in the resistance of the European eel (Anguilla anguilla L.) to thiocarbamate herbicides. The present work studied the effects of the antioxidant and glutathione pro-drug N-acetyl-L-cysteine (NAC) on the survival of a natural population of A. anguilla exposed to a lethal concentration of dichlorvos, focusing on the glutathione metabolism and the enzyme activities of acetylcholinesterase (AChE) and caspase-3 as biomarkers of neurotoxicity and induction of apoptosis, respectively. Fish pre-treated with NAC (1 mmol kg(-1), i.p.) and exposed to 1.5 mg l(-1) (the 96-h LC85) of dichlorvos for 96 h in a static-renewal system achieved an increase of the GSH content, GSH/GSSG ratio, hepatic glutathione reductase (GR), glutathione S-transferase (GST), glutamate:cysteine ligase (GCL), and gamma-glutamyl transferase (gammaGT) activities, which ameliorated the glutathione loss and oxidation, and enzyme inactivation, caused by the OP pesticide. Although NAC-treated fish presented a higher survival and were two-fold less likely to die within the study period of 96 h, Cox proportional hazard models showed that hepatic GSH/GSSG ratio was the best explanatory variable related to survival. Hence, tolerance to a lethal concentration of dichlorvos can be explained by the individual capacity to maintain and improve the hepatic glutathione redox status. Impairment of the GSH/GSSG ratio can lead to excessive oxidative stress and inhibition of caspase-3-like activity, inducing cell death by necrosis, and, ultimately, resulting in the death of the organism. We therefore propose a reconsideration of the individual effective dose or individual tolerance concept postulated by Gaddum 50 years ago for the log-normal dose-response relationship. In addition, as NAC increased the tolerance to dichlorvos, it could be a potential antidote for OP poisoning, complementary to current treatments.}, }
@article {pmid14568024, year = {2003}, author = {Lin, HH and Chen, CH and Hsieh, WK and Chiu, TH and Lai, CC}, title = {Hydrogen peroxide increases the activity of rat sympathetic preganglionic neurons in vivo and in vitro.}, journal = {Neuroscience}, volume = {121}, number = {3}, pages = {641-647}, doi = {10.1016/s0306-4522(03)00517-7}, pmid = {14568024}, issn = {0306-4522}, mesh = {6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology ; Anesthetics, Local/pharmacology ; Animals ; Autonomic Fibers, Preganglionic/*drug effects/physiology ; Blood Pressure/drug effects ; Catalase/pharmacology ; Cysteine/pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Electroencephalography ; Excitatory Amino Acid Agonists/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Excitatory Postsynaptic Potentials/drug effects/physiology ; Heart Rate/drug effects ; Hydrogen Peroxide/*pharmacology ; In Vitro Techniques ; Injections, Spinal ; Neural Inhibition/drug effects ; Neurons/*drug effects/physiology ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Tetrodotoxin/pharmacology ; Time Factors ; Valine/*analogs &amp; derivatives/pharmacology ; }, abstract = {Reactive oxygen species (ROS) have been shown to modulate neuronal synaptic transmission and have also been implicated in cardiovascular diseases such as hypertension. The hypothesis that H(2)O(2) acting on sympathetic preganglionic neurons (SPNs) affects spinal sympathetic outflow was tested in the present study. H(2)O(2) was applied intrathecally via an implanted cannula to the T7-T9 segments of urethane-anesthetized rats. Blood pressure and heart rate were used as indices to evaluate the spinal sympathetic effects of H(2)O(2) in vivo. Intrathecal H(2)O(2) (100-1000 nmol) dose-dependently increased both the mean arterial pressure and heart rate. Reproducible pressor effects of H(2)O(2) (1000 nmol) applied consecutively at intervals of 30 min were observed. The pressor effects of intrathecal H(2)O(2) (1000 nmol) were attenuated by pretreatment with intrathecal administration of catalase (500 units), or N-acetyl-cysteine (1000 nmol). The pressor effects of intrathecal H(2)O(2) (1000 nmol) were also antagonized dose-dependently by prior intrathecal injection of AP-5 (DL-2-amino-5- phosphonovaleric acid, 10 and 30 nmol), or 6-cyano-7- nitroquinoxaline-2,3-dione, 10 and 30 nmol. In vitro electrophysiological study in spinal cord slices showed that superfusion of 1 mM H(2)O(2) for 3 min, which had no effect on membrane potential, caused an increase in amplitude of excitatory postsynaptic potentials in SPNs, but had little effect on that of inhibitory postsynaptic potentials. Taken together, these results demonstrated that oxidative stress in spinal cord may cause an increase in spinal sympathetic tone by acting on SPNs, which may contribute to ROS-induced cardiovascular dysfunction.}, }
@article {pmid14567291, year = {2003}, author = {Mantovani, G and Madeddu, C and Gramignano, G and Lusso, MR and Mocci, M and Massa, E and Ferreli, L and Astara, G and Macciò, A and Serpe, R}, title = {Subcutaneous interleukin-2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: phase II study evaluating clinical, quality of life, and laboratory parameters.}, journal = {Journal of experimental therapeutics &amp; oncology}, volume = {3}, number = {4}, pages = {205-219}, doi = {10.1046/j.1359-4117.2003.01096.x}, pmid = {14567291}, issn = {1359-4117}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Antioxidants/metabolism/*therapeutic use ; C-Reactive Protein/analysis ; Cytokines/blood ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/therapeutic use ; Humans ; Interleukin-2/administration &amp; dosage ; Leptin/blood ; Lymphocyte Count ; Male ; Medroxyprogesterone Acetate/administration &amp; dosage ; Middle Aged ; Neoplasm Staging ; Neoplasms/blood/*drug therapy/pathology ; *Quality of Life ; Survival Rate ; Thioctic Acid/therapeutic use ; Treatment Outcome ; }, abstract = {We carried out an open, non-randomized phase II study including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response (complete response, CR, or partial response, PR) or stable disease (SD). The treatment consisted of administration of recombinant interleukin-2 (rIL-2) at a dose of 1.8 MIU subcutaneously three times/week (every other day) for the first 2 weeks of every month plus medroxyprogesterone acetate (MPA) 500 mg/day every other day plus antioxidant agents alpha-lipoic acid 300 mg/day and N-acetyl cysteine 1800 mg/day or carbocysteine lysine salt oral solution 2.7 g/day. The treatment was administered for 1 year except when progression of disease occurred. The primary study endpoints were to define clinical outcome, i.e. duration of response, survival (overall survival, OS and progression-free survival, PFS), the toxicity profile, and the evaluation of quality of life (QL). As secondary endpoints, we measured the changes of lymphocyte count, serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin, blood levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione peroxidase, GPx and superoxide dismertase, SOD). From July 1998 to June 2003, 42 patients were enrolled in the study (M/F ratio, 39/3; mean age, 62.5 years). Twenty (47.6%) patients were elderly (> 65 years). The majority of patients had either head and neck cancer or lung cancer, 88% had locally advanced or metastatic disease at diagnosis, and 76% had ECOG 0. Forty patients were previously treated with chemotherapy (27 also with radiotherapy), two with IL-2 and interfiron (IFN), one with endocrine therapy and one with only surgery. We obtained an objective response to maintenance treatment of 50%. Median duration of response was 19 months and median PFS was 33 months. Median duration of maintenance treatment was 12 months, median follow-up duration from diagnosis to June 2003 was 40 months, and median follow-up duration from study entry to June 2003 was 17 months. The median overall survival has not been reached. Toxicity was negligible. As for QL, a significant improvement of cognitive functions was observed, whereas all other functioning and symptom scales did not change significantly. As for laboratory parameters, absolute lymphocyte count increased significantly, IL-6, IL-1 beta, tumor necrosis factor-alpha, CRP, and fibrinogen decreased significantly whereas IL-2 and leptin increased significantly after treatment. ROS decreased significantly, whereas GPx increased significantly after treatment. Patients alive at study end showed a significant increase in absolute lymphocyte count, IL-2, leptin, and GPx and a significant decrease of proinflammatory cytokines, CRP, fibrinogen, and ROS, whereas patients who died before study end exhibited only a significant increase in absolute lymphocyte count, IL-2, and GPx and a significant decrease of ROS. Long-term combined maintenance therapy with rIL-2 + MPA + antioxidant agents is feasible, has a very low toxicity, and results in the improvement of clinical outcome, QL, and laboratory parameters.}, }
@article {pmid14563407, year = {2003}, author = {Hwang, ES and Jeffery, EH}, title = {Evaluation of urinary N-acetyl cysteinyl allyl isothiocyanate as a biomarker for intake and bioactivity of Brussels sprouts.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {41}, number = {12}, pages = {1817-1825}, doi = {10.1016/s0278-6915(03)00235-7}, pmid = {14563407}, issn = {0278-6915}, mesh = {Acetylcysteine/metabolism ; Animals ; Anticarcinogenic Agents/*urine ; Biomarkers ; Brassica/*metabolism ; Cooking ; Diet ; Dose-Response Relationship, Drug ; Eating ; Glucosinolates/metabolism ; Humans ; Isothiocyanates/*urine ; Male ; NAD(P)H Dehydrogenase (Quinone)/metabolism ; Proteins/metabolism ; Rats ; Rats, Inbred F344 ; }, abstract = {Isothiocyanates (ITC), glucosinolate hydrolysis products from Brussels sprouts (BS) and other cruciferous vegetables, are considered to protect the body from cancer by induction of detoxification enzymes such as quinone reductase (QR). Urinary N-acetyl-cysteine (NAC) conjugates of ITC have been proposed as biomarkers of crucifer intake. Here we asked if dietary intake and induction of detoxification enzymes are dose-related to urinary NAC conjugate appearance. Male F344 rats (4/group) received an AIN 76B-40 diet containing 0, 10 or 20% freeze-dried BS for 6 days. A human subject ingested 500 g BS. Urinary AITC-NAC was identified in human and rat urine. Ten and 20% BS diets caused a 1.4- and 2.3-fold induction of QR in the pancreas, a 1.5- and 2.5-fold induction in liver and a 3.1- and 3.6-fold induction in colonic epithelium, respectively. Liver and pancreatic QR induction was dose-related, whereas induction of QR in colon was less different between the two doses. Excretion of the conjugate was dose-related only on day 1, and unrelated to dose after day 2. These results suggest that urinary NAC-AITC is a qualitative biomarker for ingestion and bioactivity of BS, but that it may not be dose-related when rats are fed continuously for 2 or more days.}, }
@article {pmid14558014, year = {2003}, author = {Montero, EF and Abrahão, MS and Koike, MK and Manna, MC and Ramalho, CE}, title = {Intestinal ischemia and reperfusion injury in growing rats: hypothermia and N-acetylcysteine modulation.}, journal = {Microsurgery}, volume = {23}, number = {5}, pages = {517-521}, doi = {10.1002/micr.10163}, pmid = {14558014}, issn = {0738-1085}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cytoprotection/drug effects ; Free Radical Scavengers/*administration &amp; dosage ; Hypothermia, Induced/*methods ; Intestine, Small/blood supply/drug effects/*physiopathology ; Male ; Models, Animal ; Rats ; Rats, Wistar ; Reperfusion Injury/pathology/*prevention &amp; control ; }, abstract = {Our objective was to evaluate intestinal ischemia-reperfusion injury in growing rats, modulated by hypothermia (I/RH) and N-acetylcysteine (NAC). We used 30 EPM-1 Wistar male rats, aged around 35 days, weighing 90 g. Rats were randomized into 5 groups with 6 animals in each: I/RH group, intestinal ischemia under hypothermia for 40 min and reperfusion for 30 min; I/RH-NAC group, same procedure but adding NAC (150 mg x kg(-1)), previously with ischemia; S-H group, topic hypothermia for 40 min, and observation for 30 min; I/R H-Ve group; and S-NAC group, NAC administration and observation for 70 min. All animals were heparinized and anesthetized with ketamine (60 mg kg(-1)) and xylazine (10 mg kg(-1)) intramuscularly. Surgical procedures were done under microsurgical technique (augmentation, 10x). After laparotomy, the superior mesenteric artery was dissected and clamped to promote ischemia. Topic hypothermia was obtained by using plastic bags at 4 degrees C, changed every 10 min. Rats were sacrificed by exsanguination, and blood samples were utilized to measure D(-)lactate. Intestinal fragments were removed for morphological study. Statistical analysis was done with nonparametric tests (P <or= 0.05). Concerning to D(-)lactate, the data showed biochemical tissue injury, with hypothermia only (S-H = 27 mg/dl), and this became more important when intestinal ischemia and reperfusion were associated to hypothermia (I/RH = 36 mg/dl). NAC decreased ischemia-reperfusion injury (I/RH-NAC = 19 mg/dl). Morphologic tissue injuries, evaluated by hematoxylin-eosin staining, showed grades 4 and 5 for the I/RH and I/RH-Ve groups, respectively, in contrast with other groups (I/RH-NAC = 2, S-H = 1, and S-NAC = 1). Based on our data, we conclude that intestinal ischemia reperfusion injury occurred morphologically as well as functionally, even under hypothermia. However, NAC showed a protective effect on the small bowel from ischemia-reperfusion injury.}, }
@article {pmid14556849, year = {2003}, author = {Wang, YZ and Ingram, JL and Walters, DM and Rice, AB and Santos, JH and Van Houten, B and Bonner, JC}, title = {Vanadium-induced STAT-1 activation in lung myofibroblasts requires H2O2 and P38 MAP kinase.}, journal = {Free radical biology &amp; medicine}, volume = {35}, number = {8}, pages = {845-855}, doi = {10.1016/s0891-5849(03)00399-x}, pmid = {14556849}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carbon/adverse effects ; Catalase/pharmacology ; DNA-Binding Proteins/*metabolism ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/metabolism ; Fibroblasts/drug effects/metabolism ; Hydrogen Peroxide/*metabolism ; Lung/cytology/*drug effects/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Phosphorylation/drug effects ; Rats ; STAT1 Transcription Factor ; Trans-Activators/*metabolism ; Vanadium Compounds/*pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Vanadium compounds present in air pollution particulate matter activate signal transduction pathways in pulmonary cell types leading to pathological outcomes including aberrant cell proliferation, apoptosis, and cytokine expression. Vanadium has been proposed to activate transcription factors via the generation of hydrogen peroxide (H2O2). We investigated the mechanisms through which vanadium pentoxide (V2O5), the major form of vanadium released from the industrial burning of fuel oil, activated the signal transducer and activator of transcription (STAT)-1. V2O5-induced STAT-1 activation was blocked by catalase and N-acetyl-L-cysteine (NAC), suggesting vanadium-induced generation of H2O2. Surprisingly, however, V2O5 did not increase H2O2 levels released by rat lung myofibroblasts into cell culture supernatants. Instead, these quiescent myofibroblasts spontaneously released micromolar concentrations of H2O2, and the addition of V2O5 reduced H2O2 levels in cell culture supernatants within minutes. V2O5 suppressed H2O2 for as long as 24 h. Differences in the temporal activation of STAT-1 and p38 MAPK were observed following V2O5 or H2O2 treatment, and STAT-1 activation by V2O5 or H2O2 was attenuated by an inhibitor of the EGF receptor tyrosine kinase (AG1478) or p38 MAPK (SB203580). The phosphorylation of p38 MAPK by V2O5 was inhibited by NAC and catalase, yet the EGF receptor inhibitor AG1478 had no effect on V2O5-induced p38 MAPK activation. Collectively, our findings support the novel hypothesis that H2O2 spontaneously generated by myofibroblasts fuels vanadium-induced activation of STAT-1. Moreover, p38 MAPK and EGF receptor activation are required for V2O5-induced STAT-1 activation.}, }
@article {pmid14556662, year = {2003}, author = {Aizawa, S and Ookawa, K and Kudo, T and Asano, J and Hayakari, M and Tsuchida, S}, title = {Characterization of cell death induced by ethacrynic acid in a human colon cancer cell line DLD-1 and suppression by N-acetyl-L-cysteine.}, journal = {Cancer science}, volume = {94}, number = {10}, pages = {886-893}, doi = {10.1111/j.1349-7006.2003.tb01371.x}, pmid = {14556662}, issn = {1347-9032}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/metabolism/pharmacology ; Cell Death/drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Colonic Neoplasms/metabolism/*pathology ; Enzyme Inhibitors/pharmacology ; Ethacrynic Acid/*antagonists &amp; inhibitors/*pharmacology ; Fluorescence ; Glutathione/metabolism ; Glutathione S-Transferase pi ; Glutathione Transferase/metabolism ; Humans ; Isoenzymes/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; }, abstract = {Since ethacrynic acid (EA), an SH modifier as well as glutathione S-transferase (GST) inhibitor, has been suggested to induce apoptosis in some cell lines, its effects on a human colon cancer cell line DLD-1 were examined. EA enhanced cell proliferation at 20-40 microM, while it caused cell death at 60-100 microM. Caspase inhibitors did not block cell death and DNA ladder formation was not detected. Poly(ADP-ribose) polymerase, however, was cleaved into an 82-kDa fragment, different from an 85-kDa fragment that is specific for apoptosisis. The 82-kDa fragment was not recognized by antibody against PARP fragment cleaved by caspase 3. N-Acetyl-L-cysteine (NAC) completely inhibited EA-induced cell death, but 3(2)-t-butyl-4-hydroxyanisole or pyrrolidinedithiocarbamate ammonium salt did not. Glutathione (GSH) levels were dose-dependently increased in cells treated with EA and this increase was hardly affected by NAC addition. Mitogen-activated protein kinase (MAPK) kinase (MEK) 1, extracellular signal-regulated kinase (ERK) 1 and GST P1-1 were increased in cells treated with 25-75 microM EA, while c-Jun N-terminal kinase (JNK) 1 and p38 MAPK were markedly decreased by 100 microM EA. NAC repressed EA-induced alterations in these MAPKs and GST P1-1. p38 MAPK inhibitors, SB203580 and FR167653, dose-dependently enhanced EA-induced cell death. An MEK inhibitor, U0126, did not affect EA-induced cell death. These studies revealed that EA induced cell death concomitantly with a novel PARP fragmentation, but without DNA fragmentation. p38 MAPK was suggested to play an inhibitory role in EA-induced cell death.}, }
@article {pmid14551521, year = {2003}, author = {Tepel, M}, title = {Acetylcysteine for the prevention of radiocontrast -induced nephropathy.}, journal = {Minerva cardioangiologica}, volume = {51}, number = {5}, pages = {525-530}, pmid = {14551521}, issn = {0026-4725}, mesh = {Acetylcysteine/*therapeutic use ; Chemical and Drug Induced Liver Injury/*etiology/*prevention &amp; control ; Contrast Media/*adverse effects ; Free Radical Scavengers/*therapeutic use ; Humans ; }, abstract = {Radiocontrast-induced nephropathy is the 3rd most common cause of in-hospital acute renal failure after hypotension and surgery. Radio-graphic contrast media are used at a progressive rate for several diagnostic and therapeutic applications. Prevention of radiocontrast-induced nephropathy will become more important, including risk of patient impairment and costs. Radiocontrast-induced ne-phropathy is due to vasoconstriction-mediated renal medullary ischemia and direct toxic damage to renal tubular epithelial cells. These effects may in part be mediated by generation of reactive oxygen species. Several prospective, randomized, placebo-controlled studies in patients with moderate renal insufficiency showed that the prophylactic oral administration of acetylcysteine at a dose of 600 mg twice daily along with hydration prevents the reduction in renal function after radiocontrast administration. Recently, intravenous administration of acetyl-cysteine has also been shown to be effective. Use of acetylcysteine together with hydration is the treatment of choice to prevent radiocontrast-induced nephropathy.}, }
@article {pmid14551238, year = {2003}, author = {Byrne, JA and Grieve, DJ and Bendall, JK and Li, JM and Gove, C and Lambeth, JD and Cave, AC and Shah, AM}, title = {Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy.}, journal = {Circulation research}, volume = {93}, number = {9}, pages = {802-805}, doi = {10.1161/01.RES.0000099504.30207.F5}, pmid = {14551238}, issn = {1524-4571}, mesh = {Angiotensin II/*pharmacology ; Animals ; Aorta/physiopathology ; *Bacterial Proteins ; Blood Pressure ; Cardiomegaly/chemically induced/*enzymology/*etiology ; Constriction, Pathologic ; Disease Models, Animal ; Disease Progression ; Hypertension/*complications ; Isoenzymes/genetics/metabolism ; Male ; Membrane Glycoproteins/deficiency/genetics/metabolism ; Mice ; Mice, Knockout ; Myocardium/enzymology ; NADH, NADPH Oxidoreductases/genetics/metabolism ; NADPH Oxidase 2 ; NADPH Oxidase 4 ; NADPH Oxidases/deficiency/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Increased production of reactive oxygen species (ROS) is implicated in the development of left ventricular hypertrophy (LVH). Phagocyte-type NADPH oxidases are major cardiovascular sources of ROS, and recent data indicate a pivotal role of a gp91phox-containing NADPH oxidase in angiotensin II (Ang II)-induced LVH. We investigated the role of this oxidase in pressure-overload LVH. gp91phox-/- mice and matched controls underwent chronic Ang II infusion or aortic constriction. Ang II-induced increases in NADPH oxidase activity, atrial natriuretic factor (ANF) expression, and cardiac mass were inhibited in gp91phox-/- mice, whereas aortic constriction-induced increases in cardiac mass and ANF expression were not inhibited. However, aortic constriction increased cardiac NADPH oxidase activity in both gp91phox-/- and wild-type mice. Myocardial expression of an alternative gp91phox isoform, Nox4, was upregulated after aortic constriction in gp91phox-/- mice. The antioxidant, N-acetyl-cysteine, inhibited pressure-overload-induced LVH in both gp91phox-/- and wild-type mice. These data suggest a differential response of the cardiac Nox isoforms, gp91phox and Nox4, to Ang II versus pressure overload.}, }
@article {pmid14550752, year = {2003}, author = {Dorval, J and Hontela, A}, title = {Role of glutathione redox cycle and catalase in defense against oxidative stress induced by endosulfan in adrenocortical cells of rainbow trout (Oncorhynchus mykiss).}, journal = {Toxicology and applied pharmacology}, volume = {192}, number = {2}, pages = {191-200}, doi = {10.1016/s0041-008x(03)00281-3}, pmid = {14550752}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; *Adrenal Cortex/drug effects/enzymology/metabolism ; Amitrole/pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Catalase/antagonists &amp; inhibitors/*metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Interactions ; Endosulfan/*toxicity ; Glutathione/antagonists &amp; inhibitors/*metabolism ; Insecticides/*toxicity ; Kidney/drug effects/enzymology/metabolism ; Lipid Peroxidation/drug effects ; Lipid Peroxides/analysis ; Oncorhynchus mykiss/*metabolism ; Oxidation-Reduction ; Oxidative Stress/drug effects ; }, abstract = {The role of antioxidants in maintaining the functional integrity of adrenocortical cells during in vitro exposure to endosulfan, an organochlorine pesticide, was investigated in rainbow trout (Oncorhynchus mykiss). Aminotriazole (ATA), an inhibitor of catalase (CAT), L-buthionine sulfoximine (L-BSO), an inhibitor of glutathione (GSH) synthesis, and N-acetyl cysteine (NAC), a glutathione precursor, were used to investigate the role of CAT and GSH redox cycle in protection against the adrenal toxicity of endosulfan, a pesticide that impairs cell viability (LC50 366 microM) and cortisol secretion (EC50 19 microM) in a concentration-related manner. Pretreatment with ATA and L-BSO enhanced the toxicity of endosulfan (LC50 and EC50, respectively, 302 and 2.6 microM with ATA, 346 and 3.1 microM with L-BSO), while pretreatment with NAC had no significant effect on cell viability and increased the EC50 of endosulfan to 51 microM. CAT activity was significantly reduced following exposure to endosulfan when cells were pretreated with ATA. Pretreatment with L-BSO significantly decreased glutathione peroxidase (GPx) activity and reduced glutathione (GSH) levels in a concentration-related manner following exposure to endosulfan, while GSH levels were significantly higher in NAC pretreated cells compared to untreated cells. Finally, pretreatment with ATA and L-BSO increased, while pretreatment with NAC decreased, lipid hydroperoxides (LOOH) levels. CAT, GPx, and GSH were identified as important antioxidants in maintaining the function and integrity of rainbow trout adrenocortical cells and ATA, L-BSO, and NAC were identified as effective modulators of CAT and GSH redox cycle. Moreover, this study suggests that the glutathione redox cycle may be more efficient than catalase in protecting adrenocortical cells against endosulfan-induced oxidative stress.}, }
@article {pmid14532864, year = {2003}, author = {Shiraishi, K and Yoshida, K and Fujimiya, T and Naito, K}, title = {Angiotensin II dependent testicular fibrosis and effects on spermatogenesis after vasectomy in the rat.}, journal = {The Journal of urology}, volume = {170}, number = {5}, pages = {2104-2108}, doi = {10.1097/01.ju.0000080299.29929.f9}, pmid = {14532864}, issn = {0022-5347}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/metabolism ; Angiotensin II/antagonists &amp; inhibitors/*physiology ; Angiotensin II Type 1 Receptor Blockers ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; Antioxidants/pharmacology ; Enalapril/pharmacology ; Fibrosis/pathology ; HSP47 Heat-Shock Proteins ; Heat-Shock Proteins/metabolism ; Leydig Cells/drug effects/pathology ; Losartan/pharmacology ; Male ; Rats ; Rats, Wistar ; Spermatogenesis/drug effects/*physiology ; Testis/drug effects/*pathology ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta1 ; *Vasectomy ; }, abstract = {PURPOSE: Vasectomy induces testicular interstitial fibrosis in time dependent fashion and inhibits spermatogenesis. We investigated the contribution of angiotensin II (Ang II) to the development of interstitial fibrosis after vasectomy.<br><br>MATERIALS AND METHODS: Bilateral vasectomy was performed in 8-week-old Wistar rats and the testes were harvested 1 to 24 weeks after vasectomy. Interstitial fibrosis was evaluated by Masson's trichrome staining. Western blotting and immunohistochemistry were done to examine the expressions of heat shock protein 47 (HSP47), HNE (4-hydroxy-2,3-nonenal) and transforming growth factor-beta1 (TGF-beta1). The antioxidative agent N-acetylcysteine (NAC), the Ang II type 1 receptor antagonist losartan or the Ang converting enzyme inhibitor enalapril was given orally for 24 weeks to vasectomized rats. Spermatogenesis was evaluated by testicular weight and the percent of haploid cells was analyzed by flow cytometry.<br><br>RESULTS: Vasectomy significantly increased interstitial fibrosis (more than 8 weeks) and induced the expression of HSP47, HNE modified protein and TGF-beta1. TGF-beta1 and HSP47 immunoreactivity was localized to Leydig cells and fibroblasts. NAC or losartan but not enalapril inhibited the expression of these molecules induced by vasectomy. Increased interstitial fibrosis and impaired spermatogenesis were partially abrogated by NAC or losartan administration.<br><br>CONCLUSIONS: There is Ang II type 1 receptor dependent fibrosis after vasectomy. Oxidative condition is considered to trigger and promote these fibrogenic processes. Ang II contributes to the regulation of intratesticular autocrine or paracrine functions after vasectomy.}, }
@article {pmid14529474, year = {2003}, author = {Santangelo, F}, title = {Intracellular thiol concentration modulating inflammatory response: influence on the regulation of cell functions through cysteine prodrug approach.}, journal = {Current medicinal chemistry}, volume = {10}, number = {23}, pages = {2599-2610}, doi = {10.2174/0929867033456567}, pmid = {14529474}, issn = {0929-8673}, mesh = {Acetylcysteine/pharmacology ; Acute-Phase Proteins/metabolism ; Animals ; Cell Cycle/drug effects/physiology ; Cysteine/*analogs &amp; derivatives/metabolism/*pharmacology ; Cytokines/metabolism ; Glutathione/metabolism ; Humans ; Inflammation/immunology/*metabolism ; Prodrugs/chemistry/*pharmacology ; Sulfhydryl Compounds/*metabolism/pharmacology ; Thiazoles/chemistry/pharmacology ; }, abstract = {Oxidative stress is defined as the consequence of overpowering of the immune system's reaction, which causes increased production of the reactive oxidative species (ROS) greater than the antioxidant protection. Tissue injury and oxidation of the circulating molecules may be the consequences. Moreover, the sulphur-containing amino acids (SAA) fate is perturbed during stress. The altered biochemical rules during inflammation weaken the anti-oxidant mechanism, and the extra-supply of SAA under inflammatory conditions can help to restore homeostasis. In brief, the main biochemical steps during inflammation are: The production of Cytokines, Acute Phase Protein, and Glutathione (GSH) pool are strongly modified during inflammation. The GSH participates in many important physiological processes controlling the homeostasis of the cells. A higher demand of Cysteine (Cys) supply causes difficulties in maintaining a constant GSH level. The role of GSH as a key regulator of thiol redox intracellular balance is established. This reveals that GSH is essential in regulating the cell's life cycle and that the reduction of intracellular GSH contributes to chronic inflammation. The fact that Cys availability is generally a limiting factor for the GSH synthesis stimulated the development of a pharmacologically useful Cys pro-drug. The simplest derivative is N-acetylcysteine (NAC), which appears to be the prototype of all Cys suppliers. Different approaches are presented here.}, }
@article {pmid14527779, year = {2003}, author = {Marchese, A and Bozzolasco, M and Gualco, L and Debbia, EA and Schito, GC and Schito, AM}, title = {Effect of fosfomycin alone and in combination with N-acetylcysteine on E. coli biofilms.}, journal = {International journal of antimicrobial agents}, volume = {22 Suppl 2}, number = {}, pages = {95-100}, doi = {10.1016/s0924-8579(03)00232-2}, pmid = {14527779}, issn = {0924-8579}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Biofilms/*drug effects ; Dose-Response Relationship, Drug ; Drug Synergism ; Escherichia coli/*drug effects ; Fosfomycin/*pharmacology ; Microbial Sensitivity Tests ; }, abstract = {Four slime-producing uropathogenic Escherichia coli strains were used to investigate the activity of fosfomycin and N-acetylcysteine (NAC) against biofilms developed on 96-well polystyrene tissue culture plates. Biofilms aged, respectively, 5 (initial) and 48 h (mature) and two fosfomycin concentrations (128 and 2000 mg/l) were used. The effect of various levels (0.007-8 mg/ml) of NAC alone and in combination with fosfomycin on the formation or disruption of biofilms was assessed. Following exposure to the drugs, the percentage of residual slime relative to the control, ranged from 62.5-100 to 26.2-64.1% in the presence of 0.007 and 8 mg/ml of NAC. After treatment of pre-formed biofilms with NAC at the highest concentrations used, the remaining exopolysaccharide matrix was reduced to 25-68% of the amount found with the untreated control. Exposure to fosfomycin at 2000 mg/l reduced biofilms 40-57 and 41-49% for the initial and mature forms, respectively. Fosfomycin was more active at 2000 mg/l combined with NAC 2 mg/ml. Under these conditions initial and mature biofilms were reduced 66-80 and 60-73%, respectively. NAC, when used in combination, enhanced fosfomycin bactericidal activity producing a 99-99.9% reduction in viable cells. Fosfomycin and NAC at concentrations achievable in urine displayed a synergistic effect promoting both the formation of biofilms and reduction of sessile cell viability.}, }
@article {pmid14525940, year = {2003}, author = {Bernhard, D and Pfister, G and Huck, CW and Kind, M and Salvenmoser, W and Bonn, GK and Wick, G}, title = {Disruption of vascular endothelial homeostasis by tobacco smoke: impact on atherosclerosis.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {17}, number = {15}, pages = {2302-2304}, doi = {10.1096/fj.03-0312fje}, pmid = {14525940}, issn = {1530-6860}, mesh = {Acetylcysteine/pharmacology ; Arteriosclerosis/etiology ; Endothelium, Vascular/*cytology/drug effects/pathology ; Homeostasis ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Models, Biological ; Necrosis ; *Smoking ; }, abstract = {The World Health Organization (WHO) predicts that by 2020 tobacco will become the largest single health problem worldwide and will cause an estimated 8.4 million deaths annually (http://www5.who.int/tobacco/). Although the impact of smoking on human health is well defined from the medical point of view, surprisingly little is known about the mechanisms by which tobacco smoke mediates its disastrous effects. Here, we demonstrate that tobacco smoke dramatically changes vascular endothelial cell and tissue morphology, leading to a loss of endothelial barrier function within minutes. Long-term exposure of endothelial cells to tobacco smoke extracts induces necrosis that may trigger a pro-inflammatory status of the vessel wall. Pre-incubation of the extracts without cells for 6 h at 37 degrees C led to a complete loss of activity. Further, the endothelium could be rescued by changing to fresh medium even at times when the extracts had lost their activity. Finally, we show that N-acetyl cysteine and statins inhibit the adverse tobacco smoke effects.}, }
@article {pmid14522998, year = {2003}, author = {Xiao, GG and Wang, M and Li, N and Loo, JA and Nel, AE}, title = {Use of proteomics to demonstrate a hierarchical oxidative stress response to diesel exhaust particle chemicals in a macrophage cell line.}, journal = {The Journal of biological chemistry}, volume = {278}, number = {50}, pages = {50781-50790}, doi = {10.1074/jbc.M306423200}, pmid = {14522998}, issn = {0021-9258}, support = {P0-1 AI50495/AI/NIAID NIH HHS/United States ; R0-1 ES10553/ES/NIEHS NIH HHS/United States ; R0-1 ES12053/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; *Air Pollutants ; Animals ; Antioxidants/chemistry ; Blotting, Western ; Cell Line ; Cell Survival ; Dose-Response Relationship, Drug ; Electrophoresis, Gel, Two-Dimensional ; Glutathione/chemistry/metabolism ; Hydrogen-Ion Concentration ; Immunoblotting ; Kinetics ; Macrophages ; Methanol/chemistry ; Mice ; Models, Biological ; Oxidants/chemistry ; Oxidation-Reduction ; Oxidative Stress ; Oxygen/metabolism ; Propidium/pharmacology ; *Proteome ; Signal Transduction ; Spectrometry, Mass, Electrospray Ionization ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Time Factors ; *Vehicle Emissions ; }, abstract = {Epidemiological studies demonstrate an association between short term exposure to ambient particulate matter (PM) and cardiorespiratory morbidity and mortality. Although the biological mechanisms of these adverse effects are unknown, emerging data suggest a key role for oxidative stress. Ambient PM and diesel exhaust particles (DEP) contain redox cycling organic chemicals that induce pro-oxidative and pro-inflammatory effects in the lung. These responses are suppressed by N-acetylcysteine (NAC), which directly complexes to electrophilic DEP chemicals and exert additional antioxidant effects at the cellular level. A proteomics approach was used to study DEP-induced responses in the macrophage cell line, RAW 264.7. We demonstrate that in the dose range 10-100 microg/ml, organic DEP extracts induce a progressive decline in the cellular GSH/GSSG ratio, in parallel with a linear increase in newly expressed proteins on the two-dimensional gel. Using matrix-assisted laser desorption ionization time-of-flight mass spectrometry and electrospray ionization-liquid chromatography/mass spectrometry/mass spectrometry analysis, 32 newly induced/NAC-suppressed proteins were identified. These include antioxidant enzymes (e.g. heme oxygenase-1 and catalase), pro-inflammatory components (e.g. p38MAPK and Rel A), and products of intermediary metabolism that are regulated by oxidative stress. Heme oxygenase-1 was induced at low extract dose and with minimal decline in the GSH/GSSG ratio, whereas MAP kinase activation required a higher chemical dose and incremental levels of oxidative stress. Moreover, at extract doses >50 microg/ml, there is a steep decline in cellular viability. These data suggest that DEP induce a hierarchical oxidative stress response in which some of these proteins may serve as markers for oxidative stress during PM exposures.}, }
@article {pmid14522581, year = {2003}, author = {Lin, S and Fujii, M and Hou, DX}, title = {Rhein induces apoptosis in HL-60 cells via reactive oxygen species-independent mitochondrial death pathway.}, journal = {Archives of biochemistry and biophysics}, volume = {418}, number = {2}, pages = {99-107}, doi = {10.1016/j.abb.2003.08.004}, pmid = {14522581}, issn = {0003-9861}, mesh = {Anthraquinones/*pharmacology ; Apoptosis/*drug effects ; BH3 Interacting Domain Death Agonist Protein ; Carrier Proteins/metabolism ; Caspase 3 ; Caspases/biosynthesis/drug effects ; Cytochromes c/metabolism ; DNA Fragmentation/drug effects/physiology ; Dose-Response Relationship, Drug ; Enzyme Activation ; HL-60 Cells/drug effects/enzymology/physiology ; Humans ; *JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; Membrane Potentials/drug effects ; Mitochondria/*drug effects/enzymology/*metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; }, abstract = {Rhein is an anthraquinone compound enriched in the rhizome of rhubarb, a traditional Chinese medicine herb showing anti-tumor promotion function. In this study, we first reported that rhein could induce apoptosis in human promyelocytic leukemia cells (HL-60), characterized by caspase activation, poly(ADP)ribose polymerase (PARP) cleavage, and DNA fragmentation. The efficacious induction of apoptosis was observed at 100 microM for 6h. Mechanistic analysis demonstrated that rhein induced the loss of mitochondrial membrane potential (DeltaPsi(m)), cytochrome c release from mitochondrion to cytosol, and cleavage of Bid protein. Rhein also induced generation of reactive oxygen species (ROS) and the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 kinase. However, these actions seem not to be associated with the apoptosis induction because antioxidants including N-acetyl cysteine (NAC), Tiron, and catalase did not block rhein-induced apoptosis, although they could block the generation of ROS and the phosphorylation of JNK and p38 kinase. Our data demonstrate that rhein induces apoptosis in HL-60 cells via a ROS-independent mitochondrial death pathway.}, }
@article {pmid14521521, year = {2003}, author = {Sevillano, S and de Dios, I and de la Mano, AM and Manso, MA}, title = {N-acetylcysteine induces beneficial changes in the acinar cell cycle progression in the course of acute pancreatitis.}, journal = {Cell proliferation}, volume = {36}, number = {5}, pages = {279-289}, pmid = {14521521}, issn = {0960-7722}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Amylases/blood ; Animals ; Cell Cycle/*drug effects ; Flow Cytometry ; Free Radicals/*metabolism ; Male ; Oxidative Stress/drug effects ; Pancreatitis/metabolism/*pathology ; Rats ; Rats, Wistar ; }, abstract = {Oxygen free radicals (OFR) are produced in the course of acute pancreatitis (AP). In addition to injurious oxidative effects, they are also involved in the regulation of cell growth. The aim of the present study was to examine the relationship between the effectiveness of N-acetyl-l-cysteine (NAC) to prevent the generation of OFR and the changes in the cell-cycle pattern of acinar cells in the course of AP induced in rats by pancreatic duct obstruction (PDO). NAC (50 mg/kg) was administered 1 h before and 1 h after PDO. Flow-cytometric measurement of OFR generation in acinar cells was carried out using dihydrorhodamine as fluorescent dye. Plasma amylase activity, pancreatic glutathione (GSH) content and TNF-alpha plasma levels were also measured. The distribution of acinar cells throughout the different cell-cycle phases was analysed at different AP stages by flow cytometry using propidium iodide staining. NAC administration reduced the depletion of pancreatic GSH content and prevented OFR generation in acinar cells of rats with PDO-induced acute pancreatitis. As a result, AP became less severe as reflected by the significant improvement of hyper-amylasaemia and maintenance of plasma TNF-alpha levels at values not significantly different from controls were found. NAC administration inhibited progression of cell-cycle phases, maintaining acinar cells in quiescent state at early PDO times. The protection from oxidative damage by NAC treatment during early AP, allows the pancreatic cell to enter S-phase actively at later stages, thereby allowing acinar cells to proliferate and preventing the pancreatic atrophy provoked by PDO-induced AP. The results provide evidence that OFR play a critical role in the progression of acinar cell-cycle phases. Prevention of OFR generation of acinar cells in rats with PDO-induced AP through NAC treatment, not only protects pancreas from oxidative damage but also promotes beneficial changes in the cell cycle progression which reduce the risk of pancreatic atrophy.}, }
@article {pmid14521055, year = {2003}, author = {Gonchar, IV and Burova, EB and Dorosh, VN and Gamaleĭ, IA and Nikol'skiĭ, NN}, title = {[Dependence of EGF receptor and STAT factor activation on redox of A431 cells].}, journal = {Tsitologiia}, volume = {45}, number = {5}, pages = {478-487}, pmid = {14521055}, issn = {0041-3771}, mesh = {Acetylcysteine ; Antioxidants ; Cell Line, Tumor ; DNA-Binding Proteins/*metabolism ; Epidermal Growth Factor/*pharmacology ; ErbB Receptors/drug effects/*metabolism ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors ; Onium Compounds/pharmacology ; Oxidation-Reduction ; Phosphorylation ; STAT1 Transcription Factor ; STAT3 Transcription Factor ; Time Factors ; Trans-Activators/*metabolism ; }, abstract = {Reactive oxygen species (ROS) were established to play an important role in cellular signaling as second messengers by integrating different pathways. Recently, we showed that EGF initiated a rapid tyrosine phosphorylation of both EGF-receptor and STAT factors with simultaneous increase in the intracellular ROS level. Now, we have investigated the effect of intracellular red-ox state on EGF- and H2O2-induced activation of EGF receptor, STAT1 and STAT3. We demonstrated that the pretreatment of A431 cells with antioxidant N-acetyl-L-cysteine (NAC) partly reduced the level of EGF-induced phosphorylation of proteins under investigation. Besides, H2O2-induced activation of EGF receptor, and STAT factors was fully prevented by NAC pretreatment. The inhibition of ROS generation by DPI declined EGF-dependent activation of EGF receptor and STAT factors to basal level. Our results demonstrate the essential role of cellular red-ox status in the modulation of EGF-mediated activation of receptor and STAT factors. We have postulated that EGF-induced ROS generation is a very important initial event promoting physiological activation of EGF receptor and subsequent STAT factor activation.}, }
@article {pmid14520656, year = {2003}, author = {Klein, M and Koedel, U and Pfister, HW and Kastenbauer, S}, title = {Meningitis-associated hearing loss: protection by adjunctive antioxidant therapy.}, journal = {Annals of neurology}, volume = {54}, number = {4}, pages = {451-458}, doi = {10.1002/ana.10684}, pmid = {14520656}, issn = {0364-5134}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Anti-Bacterial Agents/therapeutic use ; Antioxidants/*therapeutic use ; Audiometry ; Ceftriaxone/therapeutic use ; Cell Count/methods ; Cochlea/drug effects/pathology ; Disease Models, Animal ; Drug Interactions ; Evans Blue/metabolism ; Evoked Potentials, Auditory, Brain Stem/physiology ; Hearing Loss/etiology/*prevention &amp; control ; Labyrinthitis/microbiology/pathology ; Male ; Meningitis, Pneumococcal/*complications/microbiology ; Metalloporphyrins/therapeutic use ; Peroxynitrous Acid/*therapeutic use ; Rats ; Rats, Wistar ; Spiral Ganglion/drug effects/pathology ; Time Factors ; }, abstract = {Hearing loss is the most frequent long-term complication of pneumococcal meningitis, affecting up to 40% of survivors. Unfortunately, adjuvant therapy with dexamethasone has failed to satisfactorily reduce its incidence. Therefore, we evaluated the use of antioxidants for the adjunctive therapy of meningitis-associated deafness. Eighteen hours after intracisternal injection of 7.5 x 10(5) colony-forming units of Streptococcus pneumoniae, rats were treated systemically either with ceftriaxone and the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-benzoic acid)-porphyrin (MnTBAP) or N-acetyl-L-cysteine (NAC) or placebo (1 ml phosphate-buffered saline) for 4 days. Hearing was assessed by auditory brainstem response audiometry. Adjunctive antioxidant therapy significantly reduced the long-term hearing loss (14 days after infection) for square wave impulses (mean hearing loss +/- SD: ceftriaxone and placebo, 45+/-26 dB; ceftriaxone and MnTBAP, 9+/-23 dB; ceftriaxone and NAC, 19+/-30 dB) as well as 1 kHz (ceftriaxone and placebo, 28+/-19 dB; ceftriaxone and MnTBAP, 10+/-16 dB; ceftriaxone and NAC, 10+/-17 dB), and 10 kHz tone bursts (ceftriaxone and placebo, 62+/-27 dB; ceftriaxone and MnTBAP, 16+/-13 dB; ceftriaxone and NAC, 25+/-26 dB). Furthermore, both antioxidants attenuated the morphological correlates of meningogenic hearing loss, namely, long-term blood-labyrinth barrier disruption, spiral ganglion neuronal loss, and fibrous obliteration of the perilymphatic spaces. Adjuvant antioxidant therapy is highly otoprotective in meningitis and therefore is a promising future treatment option.}, }
@article {pmid14515149, year = {2003}, author = {Józkowicz, A and Huk, I and Nigisch, A and Cisowski, J and Weigel, G and Dulak, J}, title = {Prostaglandin-J(2) upregulates expression of matrix metalloproteinase-1 independently of activation of peroxisome proliferator-activated receptor-gamma.}, journal = {Acta biochimica Polonica}, volume = {50}, number = {3}, pages = {677-689}, pmid = {14515149}, issn = {0001-527X}, mesh = {Acetylcysteine/pharmacology ; Cells, Cultured ; Endothelial Cells/*metabolism ; Humans ; Matrix Metalloproteinase 1/*metabolism ; Neovascularization, Physiologic/drug effects ; Oxidative Stress/drug effects ; Prostaglandin D2/*analogs &amp; derivatives/*pharmacology ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Thiazolidinediones/pharmacology ; Transcription Factors/*metabolism ; Up-Regulation/*drug effects ; }, abstract = {Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-inducible nuclear receptor that functions as a transcription factor involved in lipid metabolism, inflammatory response and angiogenesis. The most potent endogenous PPARgamma activator is 15-deoxy-Delta(12,14)prostaglandin-J(2) (15d-PGJ(2)), whereas synthetic ligands include the oral antidiabetic drugs thiazolidinediones (TZDs). Activation of PPARgamma was reported to decrease the synthesis of matrix metalloproteinases (MMPs) in vascular smooth muscle cells and macrophages. We aimed to investigate the effect of PPARgamma ligands on expression of MMP-1 and urokinase plasminogen activator (uPA) in human microvascular endothelial cells (HMEC-1). We found that treatment of HMEC-1 with 15d-PGJ(2) increased the synthesis of MMP-1 protein up to 168% comparing to untreated cells. TZDs (ciglitazone and troglitazone), more potent activators of PPARgamma in HMEC-1, did not influence MMP-1 production, arguing against the involvement of PPARgamma in this process. Importantly, the stimulatory effect of 15d-PGJ(2) was reversed by the antioxidant N-acetyl-cysteine (NAC), suggesting a contribution of oxidative stress. We demonstrated also that 15d-PGJ(2) did not change the activity of MMP-1 promoter, but increased the stability of MMP-1 mRNA. In contrast, 15d-PGJ(2) very potently inhibited the synthesis of uPA. This effect was in part mimicked by ciglitazone and troglitazone implying an involvement of PPARgamma. Accordingly, NAC did not modify the inhibitory effect of 15d-PGJ(2) on uPA expression. In conclusion, we postulate that 15d-PGJ(2) may differently regulate the synthesis of proteases involved in angiogenesis: it upregulates MMP-1 expression in HMEC-1 through induction of oxidative stress, and inhibits uPA synthesis partly by activation of PPARgamma.}, }
@article {pmid14511644, year = {2003}, author = {Wang, JH and Yun, C and Kim, S and Lee, JH and Yoon, G and Lee, MO and Cho, H}, title = {Reactive oxygen species modulates the intracellular level of HBx viral oncoprotein.}, journal = {Biochemical and biophysical research communications}, volume = {310}, number = {1}, pages = {32-39}, doi = {10.1016/j.bbrc.2003.08.113}, pmid = {14511644}, issn = {0006-291X}, mesh = {Adaptor Proteins, Signal Transducing ; Antioxidants/pharmacology ; Carrier Proteins/*metabolism ; Cell Line, Tumor ; Doxorubicin/antagonists &amp; inhibitors/pharmacology ; Humans ; *Reactive Oxygen Species ; Viral Nonstructural Proteins/*metabolism ; }, abstract = {HBx (hepatitis B virus X) viral oncoprotein is a multifunctional protein of which the cellular level may be one of the important factors in determining HBV-mediated pathological progression of liver diseases, chronic hepatitis, and hepatocellular carcinoma. Our previous work revealed that adriamycin, a chemotherapeutic agent, caused a marked increase in the intracellular level of HBx by retarding its rapid degradation. In the present study, modulation of HBx expression was found to be confined to adriamycin but not to other chemotherapeutic agents, cisplatin and 5-fluorouracil. Interestingly, adriamycin caused a rapid increase of reactive oxygen species (ROS) and its accumulation continued until 24h. In contrast, two other agents had little effect on ROS generation, suggesting the possible involvement of ROS in the HBx regulation. In fact, direct addition of H(2)O(2) to the cells significantly increased the level of HBx protein in HBx-expressing ChangX-34 cells as well as in hepatitis B virus-related hepatoma cells, PLC/PRF/5 and HepG2.2.15 cells. Furthermore, antioxidants, N-acetyl-cysteine and pyrrolidinedithiocarbamate (PDTC), completely abolished the increase of HBx protein induced by adriamycin, indicating that adriamycin modulates the intracellular HBx level via ROS generation. Together, these findings provide a novel aspect of HBx regulation by cellular ROS level. Therefore, intracellular microenvironments generating ROS such as severe inflammation may aggravate the pathogenesis of liver disease by accumulating the HBx level.}, }
@article {pmid14511233, year = {2003}, author = {Iijima, N and Yanagawa, Y and Iwabuchi, K and Onoé, K}, title = {Selective regulation of CD40 expression in murine dendritic cells by thiol antioxidants.}, journal = {Immunology}, volume = {110}, number = {2}, pages = {197-205}, pmid = {14511233}, issn = {0019-2805}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antigens, CD/metabolism ; Antioxidants/*pharmacology ; B7-1 Antigen/metabolism ; B7-2 Antigen ; CD40 Antigens/genetics/*metabolism ; CD40 Ligand/metabolism ; Dendritic Cells/*drug effects/*immunology ; Female ; Gene Expression Regulation/drug effects ; Glutathione/pharmacology ; Interleukin-12/biosynthesis ; Major Histocompatibility Complex/drug effects/immunology ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Inbred BALB C ; RNA, Messenger/genetics ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Interaction of CD40 on dendritic cells (DC) with CD40 ligand induces interleukin-12 (IL-12) production by these DC during the antigen presentation. Thus, the level of CD40 expression appears to influence the capability of DC to induce a T helper 1 (Th1) response. However, it is not fully understood how CD40 expression on DC is regulated. In the present study, we examined the effects of the reducing agents, N-acetyl-l-cysteine (NAC) and reduced glutathione (GSH), on tumour necrosis factor-alpha (TNF-alpha)-induced phenotypic changes in murine DC. TNF-alpha markedly increased the expression on DC of major histocompatibility complex (MHC) and the costimulatory molecules, CD40, CD80 and CD86. Both NAC and GSH completely abolished the TNF-alpha-induced enhancement of CD40 expression, but had no considerable effect on the expression of CD80, CD86 and MHC. The marked decrease of CD40 protein with NAC was also detected by Western blotting, but was not associated with the expression level of CD40 mRNA in DC. Thus, NAC appears to reduce CD40 expression on DC by regulating a post-transcriptional pathway. The inhibitory effect of NAC or GSH on TNF-alpha-induced CD40 expression was released by simply removing these agents from the culture. In contrast, culture of TNF-alpha-treated DC with NAC or GSH markedly decreased the expression of CD40 within 12 hr. These results demonstrate that reducing agents selectively, rapidly and reversibly regulate CD40 expression on DC, which may eventually affect the capability of DC for Th1/Th2 polarization.}, }
@article {pmid14506319, year = {2003}, author = {Sokołowska, M and Włodek, L}, title = {Influence of N-acetylcysteine on bioactivation of nitroglycerin to nitric oxide and S-nitrosothiols in the liver and brain of mice.}, journal = {Polish journal of pharmacology}, volume = {55}, number = {3}, pages = {401-408}, pmid = {14506319}, issn = {1230-6002}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/*drug effects/enzymology/metabolism ; Drug Synergism ; Female ; Glutathione Transferase/metabolism ; Lipid Peroxidation/drug effects ; Liver/*drug effects/enzymology/metabolism ; Mice ; Nitric Oxide/*biosynthesis ; Nitric Oxide Donors/*pharmacology ; Nitrites/analysis ; Nitroglycerin/*pharmacology ; S-Nitrosothiols/*metabolism ; gamma-Glutamyltransferase/metabolism ; }, abstract = {Three-day nitroglycerin (NTG) administration at progressively increasing doses caused a drop in the liver S-nitrosothiol (SNT) and malonyldialdehyde (MDA) concentrations below the control levels. It suggests that NTG administered in this way, exhibits antioxidant activity due to releasing the biologically active SNT and nitric oxide (NO). On the other hand, in the brain, NTG did not influence SNT concentrations, but slightly elevated NO formation. N-acetylcysteine (NAC) given jointly with NTG substantially stimulated NTG bioactivation to the biologically active NO and SNT as well in the liver as in the brain. It was accompanied by a rise in non-protein sulfhydryl thiol (NPSH) level and additional suppression of lipid peroxidation in hepatocytes. Therefore, is seems that the combined administration of NTG and thiols or other antioxidants is very much justified not only because of their influence on the vascular endothelial cells but also on such organs as the liver and brain.}, }
@article {pmid14500654, year = {2003}, author = {Kurita-Ochiai, T and Amano, S and Fukushima, K and Ochiai, K}, title = {Cellular events involved in butyric acid-induced T cell apoptosis.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {171}, number = {7}, pages = {3576-3584}, doi = {10.4049/jimmunol.171.7.3576}, pmid = {14500654}, issn = {0022-1767}, mesh = {Apoptosis/*drug effects/immunology ; Butyric Acid/*pharmacology ; Ceramides/biosynthesis ; Humans ; Immunity, Cellular/drug effects ; JNK Mitogen-Activated Protein Kinases ; Jurkat Cells ; Mitochondria/drug effects/enzymology/immunology/metabolism ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/physiology ; Oligonucleotide Array Sequence Analysis ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/immunology ; T-Lymphocytes/*cytology/*drug effects/enzymology/metabolism ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {We have previously demonstrated that butyric acid induces cytotoxicity and apoptosis of murine thymocytes, splenic T cells, and human Jurkat T cells. Therefore, to determine the apoptotic signaling pathway induced by butyric acid, we investigated the contribution of reactive oxygen species (ROS), mitochondria, ceramide, and mitogen-activated protein kinases in butyric acid-induced human Jurkat cell apoptosis. After exposure of cells to butyric acid, a pronounced accumulation of ROS was seen. Pretreatment of cells with the antioxidant N-acetyl-cysteine or 3-aminobenzamide attenuated butyric acid-induced apoptosis through a reduction of ROS generation. Cytochrome c, apoptosis-inducing factor, and second mitochondria-derived activator of caspases protein release from mitochondria into the cytosol were detected shortly after butyric acid treatment. Exposure of cells to butyric acid resulted in an increase in cellular ceramide in a time-dependent fashion. In addition, butyric acid-induced apoptosis was inhibited by DL-threo-dihidrosphingosine, a potent inhibitor of sphingosine kinase. Using anti-extracellular signal-regulated kinase (ERK), anti-c-Jun N-terminal kinase (JNK), and anti-p38 phosphospecific Abs, we showed a decrease in ERK, but not in JNK and p38 phosphorylation after treatment of cells with butyric acid. Pretreatment of cells with the JNK inhibitor SP600125 attenuated the effect of butyric acid on apoptosis, whereas no effect was seen with the p38 inhibitor SB202190 or the ERK inhibitor PD98059. Taken together, our results indicate that butyric acid-induced T cell apoptosis is mediated by ceramide production, ROS synthesis in mitochondria, and JNK activation in the mitogen-activated protein kinase cascade. Finally, these results were further substantiated by the expression profile of butyric acid-treated Jurkat cells obtained by means of cDNA array.}, }
@article {pmid13679210, year = {2003}, author = {Stewart, J and Siavash, H and Hebert, C and Norris, K and Nikitakis, NG and Sauk, JJ}, title = {Phenotypic switching of VEGF and collagen XVIII during hypoxia in head and neck squamous carcinoma cells.}, journal = {Oral oncology}, volume = {39}, number = {8}, pages = {862-869}, doi = {10.1016/s1368-8375(03)00110-6}, pmid = {13679210}, issn = {1368-8375}, support = {DE-R01-3118/DE/NIDCR NIH HHS/United States ; DE12606-04/DE/NIDCR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Androstadienes/pharmacology ; Antimutagenic Agents/pharmacology ; Biomarkers/analysis ; Cell Hypoxia/*physiology ; Cell Line, Tumor ; Cobalt/pharmacology ; Collagen Type XVIII/*metabolism ; Enzyme Inhibitors/pharmacology ; HSP47 Heat-Shock Proteins ; Head and Neck Neoplasms/blood supply/*metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Imidazoles/pharmacology ; MAP Kinase Signaling System ; *Neovascularization, Pathologic ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphodiesterase Inhibitors/pharmacology ; Phosphoinositide-3 Kinase Inhibitors ; *Protein Serine-Threonine Kinases ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt ; Pyridines/pharmacology ; Vascular Endothelial Growth Factor A/*metabolism ; Wortmannin ; }, abstract = {The present study sought to determine the potential role of stress activated MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating phenotypic switching between angiogenic and angiostatic elements among squamous cell carcinoma (SCC) cell lines. In particular, we investigated the effects of hypoxia and those of cobalt chloride (CoCl(2)), which mimics the hypoxic response including the production of reactive oxygen species, on such phenotypic shifts. The expression and production of collagen XVIII, and CBP2/Hsp47 provided a measure of an angiostatic phenotype, while vascular endothelial growth factor (VEGF) expression was used to assess potential angiogenic states. These studies revealed that hypoxia produced a slight up-regulation of collagen XVIII and CBP2/Hsp47 that was inhibited by the stress kinase inhibitor SB203580 but was unaffected by N-acetylcysteine (NAC). In addition, VEGF expression was increased following hypoxia and this effect was reversed with inhibition of by SB203580. Conversely, CoCl(2) significantly diminished the expression of both collagen XVIII and CBP2/Hsp47 and enhanced VEGF expression. These changes were reversed by the PI3K inhibitor wortmannin and by treating cells with NAC. These studies show that phenotypic switching between collagen XVIII and VEGF is controlled by stress activated kinases under hypoxia, and PI3K signaling pathways as well as reactive oxygen species (ROS) following CoCl(2) treatment. Furthermore, modulation of the angiogenic switch is most profound during Akt activation than during activation of stress activated kinases.}, }
@article {pmid13677510, year = {2003}, author = {Peña-Llopis, S and Ferrando, MD and Peña, JB}, title = {Increased recovery of brain acetylcholinesterase activity in dichlorvos-intoxicated European eels Anguilla anguilla by bath treatment with N-acetylcysteine.}, journal = {Diseases of aquatic organisms}, volume = {55}, number = {3}, pages = {237-245}, doi = {10.3354/dao055237}, pmid = {13677510}, issn = {0177-5103}, mesh = {Acetylcholinesterase/*drug effects ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Analysis of Variance ; Anguilla/*metabolism ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Baths ; Brain/drug effects/*enzymology ; Cholinesterase Inhibitors/pharmacokinetics/toxicity ; Dichlorvos/*pharmacokinetics/toxicity ; Dose-Response Relationship, Drug ; Environmental Monitoring/methods ; Glutathione/metabolism ; Glutathione Reductase/drug effects ; Inactivation, Metabolic ; Insecticides/*pharmacokinetics/toxicity ; Prodrugs/administration &amp; dosage/metabolism ; Toxicity Tests, Acute ; Water Pollutants, Chemical/pharmacokinetics/toxicity ; }, abstract = {Organophosphate (OP) pesticides are widely used as antiparasitic chemicals in finfish aquaculture. However, current antidotes cannot be applied to treat intoxicated fish. We showed in previous studies the importance of glutathione (GSH) metabolism in pesticide resistance of the European eel Anguilla anguilla L. The present work studied the effects of the antioxidant and glutathione pro-drug N-acetyl-L-cysteine (NAC) on the recovery of European eels exposed for 96 h to a sublethal concentration (0.17 mg l(-1); 20% of its 96 h LC50) of the OP pesticide dichlorvos (2,2-dichlorovinyl dimethyl phosphate; DDVP). This insecticide and acaricide decreased muscular GSH content and increased oxidised glutathione (GSSG), lowering the GSH:GSSG ratio, which is indicative of a condition of oxidative stress. Acetylcholinesterase (AChE) and glutathione reductase (GR) activities in the brain, which were biomarkers of neurotoxicity and oxidative stress, respectively, were also highly inhibited. Recovery in a 0.5 mM (81.6 mg l(-1)) NAC concentration ameliorated muscular GSH depletion, GSH:GSSG ratio, and the inhibition of brain AChE and GR activities. Hence, this is the first evidence of improved recovery of organophosphate-poisoned fish by bath treatments.}, }
@article {pmid13677383, year = {2003}, author = {Ollivier, FJ and Brooks, DE and Kallberg, ME and Komaromy, AM and Lassaline, ME and Andrew, SE and Gelatt, KN and Stevens, GR and Blalock, TD and van Setten, GB and Schultz, GS}, title = {Evaluation of various compounds to inhibit activity of matrix metalloproteinases in the tear film of horses with ulcerative keratitis.}, journal = {American journal of veterinary research}, volume = {64}, number = {9}, pages = {1081-1087}, doi = {10.2460/ajvr.2003.64.1081}, pmid = {13677383}, issn = {0002-9645}, support = {EY05587/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Corneal Ulcer/enzymology/*veterinary ; Doxycycline/pharmacology ; Edetic Acid/pharmacology ; Electrophoresis/veterinary ; Horse Diseases/*enzymology ; Horses ; Hydroxamic Acids/pharmacology ; Image Processing, Computer-Assisted ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; *Matrix Metalloproteinase Inhibitors ; Protease Inhibitors/*pharmacology ; Tears/*enzymology ; alpha 1-Antitrypsin/pharmacology ; }, abstract = {OBJECTIVE: To examine in vitro effects of various antiproteolytic compounds on activity of matrix metalloproteinase (MMP)-2 and -9 in the tear film of horses with active corneal ulcers.<br><br>SAMPLE POPULATION: Samples of tear film obtained from the eyes of 34 horses with active ulcerative keratitis.<br><br>PROCEDURE: Horses were sedated, and tear samples were collected from the lower fornix of 34 ulcerated eyes by use of capillary tubes. The protease inhibitors 0.2% EDTA, 0.1% doxycycline, 10% N-acetylcysteine (NAC), 0.1% solution of a modified dipeptide that contains hydroxamic acid (ie, ilomostat), 0.1% alpha1-proteinase inhibitor (PI), 0.5% alpha1-PI, and 100% fresh equine serum (ES) were used to treat pooled samples. Amount of latent and active MMP-2 and -9 was measured by optical density scanning of gelatin zymograms of treated and untreated tear samples.<br><br>RESULTS: Pooled tear samples obtained from ulcerated eyes contained the latent and active forms of MMP-2 and -9. Compared with MMP activity in untreated samples, total MMP activity (sum of all bands detected) observed on the gelatin zymogram gels was reduced by 99.4% by EDTA, 96.3% by doxycycline, 98.8% by NAC, 98.9% by ilomostat, 52.4% by 0.1% alpha1-PI, 93.6% by 0.5% alpha1-PI, and 90.0% by ES.<br><br>We documented that EDTA, doxycycline, NAC, ilomostat, alpha1PI, and ES inhibited MMP activity in vitro. Because these compounds use different mechanisms to inhibit various families of proteases in the tear film of horses, a combination of these protease inhibitors may be beneficial for treatment of corneal ulcers in horses.}, }
@article {pmid12975476, year = {2003}, author = {Lean, JM and Davies, JT and Fuller, K and Jagger, CJ and Kirstein, B and Partington, GA and Urry, ZL and Chambers, TJ}, title = {A crucial role for thiol antioxidants in estrogen-deficiency bone loss.}, journal = {The Journal of clinical investigation}, volume = {112}, number = {6}, pages = {915-923}, pmid = {12975476}, issn = {0021-9738}, support = {/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Antimetabolites/metabolism ; Antioxidants/*metabolism ; Bone Marrow Cells/cytology/metabolism ; Bone Resorption/*metabolism ; Buthionine Sulfoximine/metabolism ; Cells, Cultured ; Estradiol/administration &amp; dosage/metabolism ; Estrogens/*deficiency ; Female ; Femur/cytology/physiology ; Glutathione/metabolism ; Glutathione Reductase/metabolism ; Mice ; Osteoblasts/cytology/metabolism ; Ovariectomy ; Rats ; Rats, Wistar ; Sulfhydryl Compounds/*metabolism ; Thioredoxins/metabolism ; }, abstract = {The mechanisms through which estrogen prevents bone loss are uncertain. Elsewhere, estrogen exerts beneficial actions by suppression of reactive oxygen species (ROS). ROS stimulate osteoclasts, the cells that resorb bone. Thus, estrogen might prevent bone loss by enhancing oxidant defenses in bone. We found that glutathione and thioredoxin, the major thiol antioxidants, and glutathione and thioredoxin reductases, the enzymes responsible for maintaining them in a reduced state, fell substantially in rodent bone marrow after ovariectomy and were rapidly normalized by exogenous 17-beta estradiol. Moreover, administration of N-acetyl cysteine (NAC) or ascorbate, antioxidants that increase tissue glutathione levels, abolished ovariectomy-induced bone loss, while l-buthionine-(S,R)-sulphoximine (BSO), a specific inhibitor of glutathione synthesis, caused substantial bone loss. The 17-beta estradiol increased glutathione and glutathione and thioredoxin reductases in osteoclast-like cells in vitro. Furthermore, in vitro NAC prevented osteoclast formation and NF-kappaB activation. BSO and hydrogen peroxide did the opposite. Expression of TNF-alpha, a target for NF-kappaB and a cytokine strongly implicated in estrogen-deficiency bone loss, was suppressed in osteoclasts by 17-beta estradiol and NAC. These observations strongly suggest that estrogen deficiency causes bone loss by lowering thiol antioxidants in osteoclasts. This directly sensitizes osteoclasts to osteoclastogenic signals and entrains ROS-enhanced expression of cytokines that promote osteoclastic bone resorption.}, }
@article {pmid12971512, year = {2003}, author = {Treeprasertsuk, S and Krudsood, S and Tosukhowong, T and Maek-A-Nantawat, W and Vannaphan, S and Saengnetswang, T and Looareesuwan, S and Kuhn, WF and Brittenham, G and Carroll, J}, title = {N-acetylcysteine in severe falciparum malaria in Thailand.}, journal = {The Southeast Asian journal of tropical medicine and public health}, volume = {34}, number = {1}, pages = {37-42}, pmid = {12971512}, issn = {0125-1562}, support = {R01 AI051310/AI/NIAID NIH HHS/United States ; R01 AI051310-01/AI/NIAID NIH HHS/United States ; R01 A151310//PHS HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Adolescent ; Adult ; Aged ; Antimalarials/administration &amp; dosage/*therapeutic use ; Artemisinins/administration &amp; dosage/therapeutic use ; Artesunate ; Female ; Humans ; Injections, Intravenous ; Malaria, Falciparum/*drug therapy ; Male ; Middle Aged ; Sesquiterpenes/administration &amp; dosage/therapeutic use ; Survival Rate ; Thailand ; Treatment Outcome ; }, abstract = {One hundred and eight patients with severe falciparum malaria underwent a placebo controlled trial with the antioxidant, N-acetylcysteine (NAC), as an adjunctive therapy along with standard intravenous artesunate therapy. Three NAC dosage regimens were used: an intravenous loading dose of 140 mg/kg followed by 70 mg/kg every four hours intravenously for up to 18 doses (Group 1); a single intravenous loading dose followed by oral NAC in the same amount as for Group 1 (Group 2); a regimen identical to Group 1 except that oral NAC was administered after the first 24 hours (Group 3). Fifty-four patients received placebo plus artesunate. Two critically ill patients died in Group 1. No patient sustained an adverse reaction to the NAC other than vomiting, and the deaths were attributed to severe disease with multiple organ involvement. The excellent results with NAC, the lack of adverse effects, and the rationale for NAC benefit supports the need for a large, double blind trial of NAC as an adjunctive therapy for severe malaria.}, }
@article {pmid12969110, year = {2003}, author = {Koivusalo, AM and Yildirim, Y and Vakkuri, A and Lindgren, L and Höckerstedt, K and Isoniemi, H}, title = {Experience with albumin dialysis in five patients with severe overdoses of paracetamol.}, journal = {Acta anaesthesiologica Scandinavica}, volume = {47}, number = {9}, pages = {1145-1150}, doi = {10.1034/j.1399-6576.2003.00190.x}, pmid = {12969110}, issn = {0001-5172}, mesh = {Acetaminophen/blood/*poisoning ; Adult ; Drug Overdose/therapy ; Female ; Hemodiafiltration/adverse effects/*methods ; Humans ; Male ; Middle Aged ; Serum Albumin/*metabolism ; }, abstract = {Five patients in whom the serum paracetamol levels or the amount of ingested paracetamol was high enough to cause severe liver injury were treated with N-acetyl-cysteine (NAC) and a molecular absorbant recirculating system (MARS). MARS treatment was started as early as possible in order to prevent or retard the development of hepatocyte necrosis. Four of our five patients survived without liver transplantation, and one died due to brain oedema. The early commencement with NAC and MARS treatments in paracetamol intoxication might give enough time for the liver to regenerate and thus avoid liver transplantation.}, }
@article {pmid12965223, year = {2003}, author = {Napolitano, M and Rainaldi, G and Bravo, E and Rivabene, R}, title = {Influence of thiol balance on micellar cholesterol handling by polarized Caco-2 intestinal cells.}, journal = {FEBS letters}, volume = {551}, number = {1-3}, pages = {165-170}, doi = {10.1016/s0014-5793(03)00842-1}, pmid = {12965223}, issn = {0014-5793}, mesh = {Biological Transport ; Caco-2 Cells ; Cell Membrane Permeability ; Cell Polarity ; Cholesterol/*metabolism ; Cholesterol Esters/metabolism ; Glutathione/*metabolism ; Humans ; Intestinal Mucosa/*metabolism/ultrastructure ; Micelles ; Oxidation-Reduction ; Sulfhydryl Compounds/metabolism ; }, abstract = {The in vitro thiol redox modulation of cholesterol homeostasis was investigated in polarized Caco-2 intestinal cells. Cells were pre-incubated with the pro-oxidant compound CuSO4 or with the antioxidant N-acetylcysteine (NAC), to induce a mild shift of the intracellular redox potential toward, respectively, a more oxidizing or a more reducing equilibrium, via a manipulation of intracellular soluble thiols (glutathione). Then, monolayers were exposed to micellar cholesterol and both the cholesterol uptake and export, as well as the cholesteryl ester cycle, were analyzed. We found that pro-oxidizing conditions induced a significant cholesterol retention within the cells, particularly in the unesterified form (FC), as a result of an augmented sterol incorporation coupled with a reduced rate of FC esterification. A reduction in FC export was also evident. Furthermore, the combination of FC retention and the oxidative imbalance leads to significant alterations of the monolayer integrity, evidenced by both the enhanced tight junction permeability and the lactate dehydrogenase release into the basolateral medium. In contrast, a more reducing environment generated by NAC pre-treatment favors the limitation of the resident time of FC into the cells, via a reduced cholesterol uptake and a concomitant increased cholesterol esterification. In addition, a significant higher FC extrusion into the basolateral medium was also appreciable. Our results indicate that the thiol balance of intestinal cells may be critical for the regulation of cholesterol homeostasis at the intestinal level, influencing the lipid transport throughout the intestinal barrier.}, }
@article {pmid12963645, year = {2003}, author = {Wong, RK and Pettit, AI and Quinn, PA and Jennings, SC and Davies, JE and Ng, LL}, title = {Advanced glycation end products stimulate an enhanced neutrophil respiratory burst mediated through the activation of cytosolic phospholipase A2 and generation of arachidonic Acid.}, journal = {Circulation}, volume = {108}, number = {15}, pages = {1858-1864}, doi = {10.1161/01.CIR.0000089372.64585.3B}, pmid = {12963645}, issn = {1524-4539}, mesh = {Acetylcysteine/pharmacology ; Adult ; Arachidonic Acid/*biosynthesis/physiology ; Arachidonic Acids/pharmacology ; Cells, Cultured/drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Glycation End Products, Advanced/*pharmacology ; Group IV Phospholipases A2 ; Humans ; Indomethacin/pharmacology ; N-Formylmethionine Leucyl-Phenylalanine/pharmacology ; Neutrophils/drug effects/*physiology ; Organophosphonates/pharmacology ; Oxidation-Reduction ; Phospholipases A/antagonists &amp; inhibitors/*physiology ; Phospholipases A2 ; Quinacrine/pharmacology ; Reactive Oxygen Species/metabolism ; Respiratory Burst/drug effects/*physiology ; Vascular Diseases/etiology/physiopathology ; }, abstract = {BACKGROUND: Advanced glycation end products (AGEs) enhance NADPH oxidase, and hence respiratory burst activity, of stimulated neutrophils. They are thus potentially vasculopathic, especially in diabetes, uremia, and aging, in which AGEs classically accumulate. We investigated the underlying mechanisms.<br><br>METHODS AND RESULTS: Neutrophils prelabeled with [3H]arachidonic acid display increased [3H]arachidonate release on exposure to AGE-albumin over exposure to albumin alone (by 151+/-16%, P<0.01). Arachidonic acid (AA) itself seems to mediate the AGE-augmented neutrophil respiratory burst (ascertained by chemiluminescence). Inhibitors of the cyclooxygenase pathway (indomethacin) and lipoxygenase pathway (MK-886) do not impair this AGE effect, excluding a contribution from AA metabolites. Cytosolic phospholipase A2 (cPLA2) controls AA generation. Its inhibition by methyl arachidonyl fluorophosphonate abrogates the AGE-enhanced activated neutrophil respiratory burst, and it is demonstrably stimulated in AGE-exposed neutrophils, as evidenced by isoform gel-shift and an increasingly membrane-translocated state in Western blots of neutrophil subfractions. Inhibition of other PLA2 isoforms, secretory PLA2 and calcium-independent PLA2, by manoalide and haloenol-lactone suicide substrate, respectively, does not affect this effect of AGEs relative to inhibitor-treated controls. The thiol antioxidant NAC reduces activation of cPLA2 (assessed by isoform gel-shift and membrane translocation), production of AA in AGE-albumin-exposed neutrophils (H3 release reduced to 104+/-17%, P=0.94 compared with albumin-exposed neutrophils), and the AGE-augmented neutrophil respiratory burst.<br><br>CONCLUSIONS: AGE augmentation of the activated neutrophil respiratory burst requires AA generation, through which neutrophil NADPH oxidase may be upregulated, enhancing reactive oxygen species output. AA is generated by cPLA2, which may be stimulated through an AGE-activated redox-sensitive pathway.}, }
@article {pmid12960112, year = {2003}, author = {Yacoub, A and Mitchell, C and Lister, A and Lebedeva, IV and Sarkar, D and Su, ZZ and Sigmon, C and McKinstry, R and Ramakrishnan, V and Qiao, L and Broaddus, WC and Gopalkrishnan, RV and Grant, S and Fisher, PB and Dent, P}, title = {Melanoma differentiation-associated 7 (interleukin 24) inhibits growth and enhances radiosensitivity of glioma cells in vitro and in vivo.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {9}, number = {9}, pages = {3272-3281}, pmid = {12960112}, issn = {1078-0432}, support = {CA72955/CA/NCI NIH HHS/United States ; CA97318/CA/NCI NIH HHS/United States ; DK52875/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Adenoviridae/genetics ; Animals ; Astrocytes/drug effects/radiation effects ; Blotting, Western ; Brain Neoplasms/metabolism/radiotherapy/*therapy ; Cell Division/drug effects/radiation effects ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Cells, Cultured ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Down-Regulation ; Gene Transfer Techniques ; Genes, Tumor Suppressor ; Glioblastoma/metabolism/radiotherapy/*therapy ; Glioma/*drug therapy/metabolism/radiotherapy ; Glutathione Transferase/metabolism ; Humans ; Interleukins/*genetics/metabolism ; Necrosis ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Radiation-Sensitizing Agents/*therapeutic use ; Rats ; Rats, Inbred F344 ; Tetrazolium Salts/pharmacology ; Thiazoles/pharmacology ; Time Factors ; bcl-2-Associated X Protein ; bcl-X Protein ; }, abstract = {PURPOSE: Despite therapeutic interventions including surgery, chemotherapy, and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required.<br><br>EXPERIMENTAL DESIGN: Melanoma differentiation-associated 7 (mda-7) (interleukin 24), when expressed via a recombinant replication-defective adenovirus, adenovirus (Ad).mda-7, has profound antiproliferative and cytotoxic effects in a variety of tumor cells but not in nontransformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cell lines.<br><br>RESULTS: Ad.mda-7 caused a dose-dependent reduction in the proliferation of glioma cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The antiproliferative effects of Ad.mda-7 were enhanced by radiation in a greater than additive fashion. These effects were not observed in cultures of nontransformed primary astrocytes. Purified MDA-7 protein caused a similar dose-dependent reduction in GBM cell growth that was enhanced after radiation exposure. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. These modifications in cell phenotype correlated with reduced expression of Bcl-(XL) and enhanced expression of BAX. Overexpression of Bcl-(XL) protected cells from the antiproliferative and cytotoxic effects of Ad.mda-7 + radiation. Incubation of cells with N-acetyl cysteine abolished the enhancing effects of radiation. In vitro, Ad.mda-7 and radiation reduced colony formation ability, which was significantly increased when the two treatments were combined. In vivo, Ad.mda-7 enhanced the survival of Fischer 344 rats implanted intracranially with glioma cells. Radiation did not alter survival in control infected animals, whereas it prolonged survival in those infected with Ad.mda-7.<br><br>CONCLUSIONS: These findings demonstrate that mda-7 reduces the proliferation and enhances the radiosensitivity of GBM cells in vitro and in vivo.}, }
@article {pmid12959960, year = {2004}, author = {Medved, I and Brown, MJ and Bjorksten, AR and McKenna, MJ}, title = {Effects of intravenous N-acetylcysteine infusion on time to fatigue and potassium regulation during prolonged cycling exercise.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {96}, number = {1}, pages = {211-217}, doi = {10.1152/japplphysiol.00458.2003}, pmid = {12959960}, issn = {8750-7587}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Adult ; Bicycling/physiology ; Cross-Over Studies ; Double-Blind Method ; Free Radical Scavengers/*administration &amp; dosage/adverse effects ; Humans ; Infusions, Intravenous ; Male ; Muscle Fatigue/*drug effects/physiology ; Muscle, Skeletal/metabolism/physiology ; Oxygen Consumption/drug effects/physiology ; Physical Exertion/*drug effects/physiology ; Potassium/*blood ; Reactive Oxygen Species/metabolism ; }, abstract = {The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated whether the antioxidant compound N-acetylcysteine (NAC) augments time to fatigue during prolonged, submaximal cycling exercise. Seven men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling exercise, comprising 45 min at 70% of peak oxygen consumption (Vo2 peak) and then to fatigue at 90% Vo2 peak. NAC was intravenously infused at 125 mg.kg-1.h-1 for 15 min and then 25 mg.kg-1.h-1 for 20 min before and throughout exercise, which was continued until fatigue. Arterialized venous blood was analyzed for NAC concentration, hematology, and plasma electrolytes. NAC induced no serious adverse reactions and did not affect hematology, acid-base status, or plasma electrolytes. Time to fatigue was reproducible in preliminary trials (coefficient of variation 7.4 +/- 1.2%) and was not augmented by NAC (NAC 14.6 +/- 4.5 min; control 12.8 +/- 5.4 min). However, time to fatigue during NAC trials was correlated with Vo2 peak (r = 0.78; P < 0.05), suggesting that NAC effects on performance may be dependent on training status. The rise in plasma K+ concentration at fatigue was attenuated by NAC (P < 0.05). The ratio of rise in K+ concentration to work and the percentage change in time to fatigue tended to be inversely related (r = -0.71; P < 0.07). Further research is required to clarify a possible training status-dependent effect of NAC on muscle performance and K+ regulation.}, }
@article {pmid12959930, year = {2004}, author = {Liu, RM and Liu, Y and Forman, HJ and Olman, M and Tarpey, MM}, title = {Glutathione regulates transforming growth factor-beta-stimulated collagen production in fibroblasts.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {286}, number = {1}, pages = {L121-8}, doi = {10.1152/ajplung.00231.2003}, pmid = {12959930}, issn = {1040-0605}, support = {ES-011831/ES/NIEHS NIH HHS/United States ; HL-58655/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Collagen Type I/*genetics ; Collagen Type III/*genetics ; Fibroblasts/drug effects/*physiology ; Gene Expression/drug effects/physiology ; Glutathione/*metabolism ; Mice ; NIH 3T3 Cells ; RNA, Messenger/analysis ; Reactive Oxygen Species/metabolism ; Signal Transduction/physiology ; Transforming Growth Factor beta/*pharmacology ; Tritium ; }, abstract = {Transforming growth factor-beta (TGF-beta) is a potent fibrogenic cytokine. The molecular mechanism underlying TGF-beta fibrogenesis, however, has not been completely elucidated. In this study, we showed that TGF beta decreased the intracellular GSH content in murine embryo fibroblasts (NIH 3T3), which was followed by an increase in collagen I mRNA content and collagen protein production. Prevention of GSH depletion with N-acetylcysteine (NAC), GSH, or GSH ester abrogated TGF-beta-stimulated collagen production, whereas a decrease in intracellular GSH content with L-buthionine-S,R-sulfoximine, an inhibitor of de novo GSH synthesis, enhanced TGF-beta-stimulated collagen production. These results suggest that GSH depletion induced by TGF-beta may mediate TGF-beta-stimulated collagen production. In addition, we showed that TGF-beta stimulated superoxide production and increased release of H2O2 from the cells, whereas GSH ester decreased basal and TGF-beta + glucose oxidase-stimulated H2O2 release. H2O2, exogenously added or continuously generated by glucose oxidase, enhanced TGF-beta-stimulated collagen production, whereas suppression of superoxide production by diphenyliodonium, an NAD(P)H oxidase inhibitor, blocked TGF-beta-stimulated collagen production. These data further suggest that reactive oxygen species are involved in TGF-beta-stimulated collagen production and that the effect of GSH depletion on TGF-beta-stimulated collagen production may be mediated by facilitating reactive oxygen species signaling.}, }
@article {pmid12958548, year = {2003}, author = {Cakir, O and Erdem, K and Oruc, A and Kilinc, N and Eren, N}, title = {Neuroprotective effect of N-acetylcysteine and hypothermia on the spinal cord ischemia-reperfusion injury.}, journal = {Cardiovascular surgery (London, England)}, volume = {11}, number = {5}, pages = {375-379}, doi = {10.1016/S0967-2109(03)00077-2}, pmid = {12958548}, issn = {0967-2109}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; *Hypothermia, Induced ; Motor Neurons/metabolism ; Neuroprotective Agents/*therapeutic use ; Paraplegia/pathology/prevention &amp; control ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Rabbits ; Reperfusion Injury/metabolism/pathology/*prevention &amp; control ; Spinal Cord Ischemia/metabolism/pathology/*prevention &amp; control ; }, abstract = {The purpose of this study was to investigate the effect of N-acetylcysteine (NAC) on spinal cord ischemia-reperfusion (I-R) in rabbits. Thirty rabbits were divided into five equal groups, group I (sham-operated, no I-R), group II (control, only I-R), group III (I-R+NAC), group IV (I-R+hypothermia), group V (I-R+NAC+hypothermia). Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the aortic bifurcation. Forty-eight hours postoperatively, the motor function of the lower limbs was evaluated in each animal according to Tarlov Score. Spinal cord samples were taken to evaluate the histopathological changes. The sham-operated rabbits (group I) showed no neurologic deficit (Score=4). Paraplegia (Score=0) developed in all rabbits in the control group (group II). Administration of 50 mg/kg of NAC (group III) resulted in significant reduction of motor dysfunction (Score=3.1+/-1.3, p=0.002). Application of hypothermia alone (group IV) showed significant recovery of motor functions (Score=3.0+/-1.1, p=0.002), and combination of hypothermia and 50 mg/kg of NAC (group V) showed complete recovery of lower limb motor function (Score=4, p=0.001). Histologic examination of the spinal cord in rabbits with paraplegia revealed several injured neurons. The cords of animals with no motor function deficits showed only minimal cellular infiltrates in the gray matter, and there was good preservation of nerve cells. NAC showed protective effects of the spinal cord. Moderate hypothermia alone also showed protective effects. Combined use of NAC and hypothermia resulted in highly significant recovery of spinal cord function.}, }
@article {pmid12957654, year = {2003}, author = {Coulon, L and Calzada, C and Moulin, P and Véricel, E and Lagarde, M}, title = {Activation of p38 mitogen-activated protein kinase/cytosolic phospholipase A2 cascade in hydroperoxide-stressed platelets.}, journal = {Free radical biology &amp; medicine}, volume = {35}, number = {6}, pages = {616-625}, doi = {10.1016/s0891-5849(03)00386-1}, pmid = {12957654}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Arachidonic Acid/metabolism ; Blood Platelets/*drug effects/enzymology ; Cytosol/drug effects/*enzymology ; Diabetes Mellitus, Type 2/blood ; Enzyme Activation/drug effects ; Glutathione Peroxidase/metabolism ; Humans ; Hydrogen Peroxide/*pharmacology ; Leukotrienes/pharmacology ; Mitogen-Activated Protein Kinases/genetics/*metabolism ; Oxidative Stress/*drug effects ; Oxygen/metabolism ; Phospholipases A/*metabolism ; Phospholipases A2 ; Phospholipids/metabolism ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {12-Hydroperoxy-eicosatetraenoic acid (12-HpETE), the main hydroperoxide formed in platelets from arachidonic acid (AA) by 12-lipoxygenase, has been shown to increase the sensitivity of platelets to agonists resulting in increased aggregation. The aim of the present study was to determine the direct effect of low concentrations of 12-HpETE on the signaling pathways leading to AA release from membrane phospholipids and thromboxane A2 (TxA2) formation. Exogenous 12-HpETE activated platelet p38 mitogen-activated protein kinase (p38 MAPK), as assessed by its phosphorylation, at a concentration as low as 100 nM and was much more potent than hydrogen peroxide. Moreover, the incubation of platelets with 100 nM 12-HpETE for 2 min led to the phosphorylation of cytosolic phospholipase A2 (cPLA2). It was associated with a significant decrease in the concentration of AA esterified in phospholipids and an increased concentration of thromboxane B2, the stable catabolite of TxA2. Additionally, decreasing glutathione peroxidase activity pharmacologically favored endogenous 12-HpETE formation and led to an increase in phosphorylated p38 MAPK, while a thiol-reducing agent such as N-acetyl-cysteine fully prevented it. Finally, significant activation of p38 MAPK was also observed in platelets from type 2 diabetic patients with mild hyperglycemia. In conclusion, our data provide a new insight into the mechanism of 12-HpETE-induced platelet priming, suggesting that hydroperoxide-induced p38 MAPK activation could play a relevant role in the exacerbated platelet activation associated with oxidative stress as found in diabetes.}, }
@article {pmid12957649, year = {2003}, author = {Behar, TN and Colton, CA}, title = {Redox regulation of neuronal migration in a Down Syndrome model.}, journal = {Free radical biology &amp; medicine}, volume = {35}, number = {6}, pages = {566-575}, doi = {10.1016/s0891-5849(03)00329-0}, pmid = {12957649}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Chemotaxis/drug effects ; *Disease Models, Animal ; Dithiothreitol/pharmacology ; Down Syndrome/genetics/*metabolism/*pathology ; Fetus ; Glutamic Acid/pharmacology ; Mice ; N-Methylaspartate/pharmacology ; Neurons/drug effects/metabolism/*pathology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; Trisomy/genetics ; }, abstract = {Down Syndrome (DS), one of the major genetic causes of mental retardation, is characterized by disrupted corticogenesis produced, in part, by an abnormal layering of neurons in cortical laminas II and III. Because defects in the normal migration of neurons during corticogenesis can result in delayed cortical radial expansion and abnormalities in cortical layering, we have examined neuronal migration in murine trisomy 16 (Ts16), a mouse model for DS. Using an in vitro assay for chemotaxis, our data demonstrate that the number of acutely dissociated Ts16 cortical neurons migrating in response to glutamate or N-methyl-D-aspartate (NMDA), known chemotactic factors, was decreased compared to normal littermates, suggesting a defect in NMDA receptor- (NMDAR-) mediated events. Ts16 neurons did not lack NMDAR since expression of mRNA and protein for NMDAR subunits was observed in Ts16 cells. However, the number of cells that generated an observable current in response to NMDA was decreased compared to normal littermates. Similar to DS, Ts16 CNS demonstrated an inherent oxidative stress likely caused by the triplication of genes such as SOD1. To determine if the abnormal redox state was a factor in the failure of NMDAR-mediated migration in Ts16, we treated Ts16 neurons with either n-acetyl cysteine (NAC) or dithiothrietol (DTT), known antioxidants. The reduction in NMDAR-mediated migration observed in Ts16 neurons was returned to normal littermate values by NAC or DTT. Our data indicate that oxidative stress may play a key role in the abnormal glutamate-mediated responses during cortical development in the Ts16 mouse and may have an impact on neuronal migration at critical stages.}, }
@article {pmid12951070, year = {2003}, author = {Kim, YH and Shin, HC and Song, DW and Lee, SH and Furumai, T and Park, JW and Kwon, TK}, title = {Arisostatins A induces apoptosis through the activation of caspase-3 and reactive oxygen species generation in AMC-HN-4 cells.}, journal = {Biochemical and biophysical research communications}, volume = {309}, number = {2}, pages = {449-456}, doi = {10.1016/j.bbrc.2003.07.009}, pmid = {12951070}, issn = {0006-291X}, mesh = {*Aminoglycosides ; Anti-Bacterial Agents/*pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Caspase 3 ; Caspases/drug effects/*metabolism ; Cell Division/drug effects ; Cell Survival/drug effects ; Cyclin D1/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Head and Neck Neoplasms/*metabolism ; *Macrolides ; Membrane Potentials/drug effects ; Mitochondria/drug effects ; Reactive Oxygen Species/agonists/*metabolism ; Signal Transduction/drug effects ; Tumor Cells, Cultured/drug effects/metabolism ; }, abstract = {A microbial secondary metabolite, arisostatins A (As-A), was originally discovered as a substance carrying the antibiotic activity against Gram-positive bacteria and shown to possess potent anti-tumor properties. The mechanism by which arisostatins A initiates apoptosis remains poorly understood. In the present report we investigated the effect of arisostatins A on activation of the apoptotic pathway in HN-4 cells. Arisostatins A was shown to be responsible for the inhibition of HN-4 cell growth by inducing apoptosis. Treatment with 4 microM arisostatins A for 24h produced morphological features of apoptosis and DNA fragmentation in HN-4 cells. Arisostatins A caused dose-dependent apoptosis and DNA fragmentation of HN-4 cells used as a model. Treatment with caspase inhibitor significantly reduced the arisostatins A-induced caspase 3 activation. In addition, arisostatins A-induced apoptosis was associated with the generation of reactive oxygen species (ROS), which was prevented by an antioxidant NAC (N-acetyl-cysteine). These data indicate that cytotoxic effect of arisostatins A on HN-4 cells is attributable to the induced apoptosis and that arisostatins A-induced apoptosis is mediated by caspase-3 activation pathway, loss of mitochondrial transmembrane potential (DeltaPsi(m)), and release of cytochrome c into cytosol.}, }
@article {pmid12949729, year = {2003}, author = {Reinehr, R and Graf, D and Häussinger, D}, title = {Bile salt-induced hepatocyte apoptosis involves epidermal growth factor receptor-dependent CD95 tyrosine phosphorylation.}, journal = {Gastroenterology}, volume = {125}, number = {3}, pages = {839-853}, doi = {10.1016/s0016-5085(03)01055-2}, pmid = {12949729}, issn = {0016-5085}, mesh = {Animals ; Apoptosis/*drug effects ; Bile Acids and Salts/*toxicity ; Cell Membrane/metabolism ; ErbB Receptors/*physiology ; Hepatocytes/*drug effects/physiology ; JNK Mitogen-Activated Protein Kinases ; Male ; Mitogen-Activated Protein Kinases/metabolism ; Oxidative Stress ; Phosphorylation ; Protein Transport/drug effects ; Rats ; Rats, Wistar ; Tyrosine/metabolism ; fas Receptor/*metabolism ; }, abstract = {BACKGROUND &amp; AIMS: Hydrophobic bile acids induce CD95-dependent hepatocyte apoptosis.<br><br>METHODS: The mechanisms of bile acid-induced CD95 activation were studied in 24-hour cultured rat hepatocytes, in situ-perfused rat livers, and livers from bile duct-ligated rats.<br><br>RESULTS: Within 1 minute, the proapoptotic bile salts taurolithocholate-3-sulfate and glycochenodeoxycholate induced oxidative stress and EGF receptor (EGF-R) tyrosine phosphorylation followed by rapid c-Jun-N-terminal kinase (JNK) activation. Thereafter, EGF-R associated with CD95 with subsequent CD95 tyrosine phosphorylation, CD95 membrane targeting, and death-inducing signal complex (DISC) formation. All of these responses were also triggered by taurochenodeoxycholate except that DISC formation only occurred in the presence of phosphatidylinositol 3-kinase inhibitors. No activation of EGF-R or CD95 was observed with tauroursodeoxycholate or taurocholate. Taurolithocholate-3-sulfate-induced EGF-R phosphorylation was sensitive to N-acetylcysteine (NAC) and genistein, whereas CD95/EGF-R association was inhibited by NAC, JNK, or protein kinase C inhibition but not by AG1478. However, the latter compound as well as NAC, genistein, inhibition of JNK, or protein kinase C inhibited CD95 tyrosine phosphorylation, membrane trafficking, and DISC formation.<br><br>CONCLUSIONS: Induction of apoptosis by hydrophobic bile salts involves EGF-R activation and EGF-R-dependent CD95 tyrosine phosphorylation, which triggers CD95 membrane targeting and Fas-associated death domain/caspase-8 recruitment. The latter step is apparently also controlled by phosphatidylinositol 3-kinase.}, }
@article {pmid12949437, year = {2003}, author = {Sevillano, S and De la Mano, AM and De Dios, I and Ramudo, L and Manso, MA}, title = {Major pathological mechanisms of acute pancreatitis are prevented by N-acetylcysteine.}, journal = {Digestion}, volume = {68}, number = {1}, pages = {34-40}, doi = {10.1159/000073223}, pmid = {12949437}, issn = {0012-2823}, mesh = {Acetylcysteine/*pharmacology ; Acute Disease ; Animals ; Free Radical Scavengers/*pharmacology ; Male ; Microscopy, Electron ; Oxidative Stress ; Pancreas/metabolism/*pathology ; Pancreatitis/*pathology/prevention &amp; control ; Rats ; Rats, Wistar ; }, abstract = {AIM: To analyze the capability of N-acetylcysteine (NAC) to prevent major intra-acinar pathogenic mechanisms involved in the development of acute pancreatitis (AP).<br><br>METHODS: AP was induced by pancreatic duct obstruction (PDO) in rats. Some animals received NAC (50 mg/kg) 1 h before and 1 h after PDO. During a 24-hour period of PDO, plasma amylase activity and pancreatic glutathione and malondialdehyde levels were measured. Cytosolic Ca(2+) levels and enzyme (amylase and trypsinogen) load in acinar cells were also analyzed by flow cytometry, and histological analysis of the pancreas was performed by electron microscopy.<br><br>RESULTS: NAC avoided glutathione depletion at early AP stages, thereby preventing pancreatic oxidative damage, as reflected by normal malondialdehyde levels. By limiting oxidative stress, NAC treatment effectively prevented the impairment of Ca(2+) homeostasis found in acinar cells from early AP onwards, thus protecting the pancreas from damage. In addition, lower quantities of digestive enzymes were accumulated within acinar cells. This finding, together with the significantly lower hyperamylasemia observed in these animals, suggests that NAC treatment palliates the exocytosis blockade induced by PDO.<br><br>CONCLUSION: By preventing oxidative stress at early AP stages, NAC administration prevents other pathological mechanisms of AP from being developed inside acinar cells, thus palliating the severity of disease.}, }
@article {pmid12948862, year = {2003}, author = {Deharo, E and Barkan, D and Krugliak, M and Golenser, J and Ginsburg, H}, title = {Potentiation of the antimalarial action of chloroquine in rodent malaria by drugs known to reduce cellular glutathione levels.}, journal = {Biochemical pharmacology}, volume = {66}, number = {5}, pages = {809-817}, doi = {10.1016/s0006-2952(03)00396-4}, pmid = {12948862}, issn = {0006-2952}, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/pharmacology ; Aminoquinolines/pharmacology ; Animals ; Antimalarials/*therapeutic use ; Chloroquine/*therapeutic use ; Disulfiram/pharmacology ; Drug Synergism ; Glutathione/*metabolism ; Indomethacin/pharmacology ; Malaria/*drug therapy ; Mice ; Plasmodium berghei ; Plasmodium falciparum ; }, abstract = {Ferriprotoporphyrin IX (FP) is released inside the food vacuole of the malaria parasite during the digestion of host cell hemoglobin. FP is detoxified by its biomineralization to hemozoin. This process is effectively inhibited by 4-aminoquinolines. As a result FP accumulates in the membrane fraction and associates with enzymes of infected cells in parallel with parasite killing. Free FP is degraded by reduced glutathione (GSH). This degradation is inhibited by chloroquine (CQ) and amodiaquine (AQ) but not by quinine (Q) or mefloquine (MQ). Increased GSH levels in Plasmodium falciparum-infected cells confer resistance to CQ and vice versa, and sensitize CQ-resistant Plasmodium berghei by inhibiting the synthesis of glutathione. Some drugs are known to reduce GSH in body tissues when used in excess, either due to their pro-oxidant activity or their ability to form conjugates with GSH. We show that acetaminophen, indomethacin and disulfiram were able to potentiate the antimalarial action of sub-curative doses of CQ and AQ in P. berghei- or Plasmodium vinckei petteri-infected mice, but not that of Q and MQ. In contrast, N-acetyl-cysteine which is expected to increase the cellular levels of GSH, antagonized the action of CQ. Although these results imply that alteration in GSH are involved, measurement of total glutathione either in uninfected or P. berghei-infected mice, treated with these drugs did not reveal major changes. In conclusion, experimental evidences provided in this study suggest that some off the counter drugs can be used in combination with some antimalarials to which the parasite has become resistant.}, }
@article {pmid12948086, year = {2003}, author = {Pajoumand, A and Jalali, N and Abdollahi, M and Shadnia, S}, title = {Successful treatment of acetaminophen overdose associated with hepatic failure.}, journal = {Human &amp; experimental toxicology}, volume = {22}, number = {8}, pages = {453-458}, doi = {10.1191/0960327103ht325cr}, pmid = {12948086}, issn = {0960-3271}, mesh = {Acetaminophen/metabolism/pharmacokinetics/*pharmacology ; Acetylcysteine/therapeutic use ; Adult ; Analgesics, Non-Narcotic/metabolism/pharmacokinetics/*pharmacology ; Antidotes/therapeutic use ; Drug Overdose ; Female ; Humans ; Liver/metabolism ; Liver Failure, Acute/chemically induced/*drug therapy ; }, abstract = {Acetaminophen is the most widely used antipyretic and analgesic drug in the world. Acetaminophen poisoning and the following hepatic failure are not rare and are the most common indications of liver transplantation in the USA and Europe. In this case report, the patient was a 25-year old woman with hepatic failure who was brought to Loghman-Hakim Poison Centre 24 hours after attempted suicide with 100 tablets of acetaminophen, 325 mg. She was treated with N-acetylcysteine (NAC) and discharged from the hospital 12 days after admission and followed up for 1 month. In conclusion, acetaminophen poisoning should be considered in the differential diagnoses of hepatic failure. In acetaminophen-induced hepatic damage the administration of NAC must always be considered even after 24 hours of overdose.}, }
@article {pmid12943989, year = {2003}, author = {An, JJ and Cho, SR and Jeong, DW and Park, KW and Ahn, YS and Baik, JH}, title = {Anti-proliferative effects and cell death mediated by two isoforms of dopamine D2 receptors in pituitary tumor cells.}, journal = {Molecular and cellular endocrinology}, volume = {206}, number = {1-2}, pages = {49-62}, doi = {10.1016/s0303-7207(03)00236-3}, pmid = {12943989}, issn = {0303-7207}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Dopamine/pharmacology ; Dopamine Agonists/pharmacology ; Dopamine Antagonists/pharmacology ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Pituitary Neoplasms/*pathology ; Protein Isoforms/physiology ; Rats ; Receptors, Dopamine D2/metabolism/*physiology ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Stable rat pituitary tumor cell lines expressing two isoforms of the dopamine D2 receptor, D2L (long) and D2S (short) (the GH3D2L and GH3D2S cell lines, respectively), were established, and the signaling pathway underlying the anti-proliferative and cell death effects of dopaminergic agonists was examined in these cells. After either dopamine or quinpirole treatment, the cell viability decreased significantly only in GH3D2L cells and GH3D2S cells, but not in GH3 cells where D2 receptors are absent. Treatment with haloperidol, a specific D2 receptor antagonist, rescued the dopamine-mediated decreased cell viability in both the GH3D2L and GH3D2S cells. Treatment of these cells with dopamine decreased the DNA synthesis rate, as demonstrated by the incorporation of 5-bromo-2'-deoxyuridine (BrdU). Dopamine-induced cell death was observed in the GH3D2L and GH3D2S cells, and was accompanied by DNA laddering and caspase-3 activation, which were blunted by haloperidol, indicating that dopamine-induced cell death in these cells is mediated by the dopamine D2 receptors. D2 receptor-mediated cell death in these cells correlated with the sustained and enhanced activation of p38 mitogen-activated protein kinase (MAPK) and the extracellular-signal regulated kinase (ERK)1/2 pathways. Treatment with SB203580, which is a specific p38 MAPK inhibitor and PD98059, which is an inhibitor of MEK1/ERK signaling, selectively abrogates dopamine-induced cell death. It was further shown that p38 MAPK and ERK activation was inhibited by the antioxidant, N-acetylcysteine (NAC), and that a treatment with haloperidol completely blocked the p38 and ERK activation induced by dopamine. These results suggest that dopamine induces an anti-proliferative effect and cell death via the dopamine D2 receptors, by means of the p38 MAPK and ERK pathways involving oxidative stress, in the pituitary tumor cells.}, }
@article {pmid12942544, year = {2003}, author = {Chen, JX and Berry, LC and Christman, BW and Meyrick, B}, title = {Glutathione mediates LPS-stimulated COX-2 expression via early transient p42/44 MAPK activation.}, journal = {Journal of cellular physiology}, volume = {197}, number = {1}, pages = {86-93}, doi = {10.1002/jcp.10353}, pmid = {12942544}, issn = {0021-9541}, support = {HL 49530/HL/NHLBI NIH HHS/United States ; HL 55649/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Blotting, Western ; Cattle ; Cells, Cultured ; Cyclooxygenase 1 ; Cyclooxygenase 2 ; Endothelium, Vascular/cytology/drug effects/*enzymology ; Enzyme Activation/drug effects/physiology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Glutathione/*analogs &amp; derivatives/*metabolism/pharmacology ; Isoenzymes/*biosynthesis/drug effects/genetics ; Lipopolysaccharides/pharmacology ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/drug effects/*metabolism ; Prostaglandin-Endoperoxide Synthases/*biosynthesis/drug effects/genetics ; Prostaglandins/metabolism ; Pulmonary Artery/cytology ; Radiation-Protective Agents/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {This study examines whether endotoxin (LPS)-stimulated COX-2 is modulated by an interaction between mitogen activated protein kinases (MAPK) and intracellular glutathione. Bovine pulmonary artery endothelial cells (BPAEC) were pretreated for 30 min with the following prior to addition of 0.1 microg/ml endotoxin in 2% FBS in medium 199: 5 mM N-acetylcysteine (NAC) or 5 mM glutathione ethyl ester (GSE) (modulators of intracellular glutathione); 10 microM SB203580 or 25 microM PD98059 (inhibitors of p38 and p42/44 MAPKs, respectively). End-points included assessment of COX-1 and COX-2 gene expression by reverse transcription polymerase chain reaction (RT-PCR); COX-1, COX-2, p38, and p42/44 protein by Western analysis; and measurement of PGE2 and 6-keto-PGF1alpha releases by GC/MS. Both GSE and NAC resulted in significant exacerbation of the LPS-stimulated increase in COX-2 gene and protein expression and prostaglandin release, and suppressed the LPS-induced decrease in COX-1. LPS caused a biphasic activation of p42/44 MAPKs, an early increase peaking at 30 min and a second sustained phase, lasting up to 24 h; LPS also caused an early and sustained increase p38 MAPK activity. Pretreatment of cells with either GSE or NAC increased the early LPS-stimulated activation of p42/44 but had little effect on the sustained phase. Inhibition of either p38 or p42/44 MAPKs suppressed LPS-stimulated COX-2 gene and protein expression, and prostaglandin release (P<0.05) but had little effect on COX-1. We conclude that intracellular glutathione modulates LPS-stimulated COX-2 gene expression and prostaglandin synthesis in BPAEC via early activation of p42/44 MAPKs.}, }
@article {pmid12941446, year = {2003}, author = {Tian, H and Zhang, Q and Li, H and Zhang, G}, title = {Antioxidant N-acetylcysteine and AMPA/KA receptor antagonist DNQX inhibited mixed lineage kinase-3 activation following cerebral ischemia in rat hippocampus.}, journal = {Neuroscience research}, volume = {47}, number = {1}, pages = {47-53}, doi = {10.1016/s0168-0102(03)00186-x}, pmid = {12941446}, issn = {0168-0102}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Brain Ischemia/*enzymology ; Enzyme Activation/drug effects/physiology ; Excitatory Amino Acid Antagonists/pharmacology ; Hippocampus/drug effects/enzymology ; MAP Kinase Kinase Kinases/*antagonists &amp; inhibitors/metabolism ; Male ; Quinoxalines/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/*antagonists &amp; inhibitors/metabolism ; Receptors, Kainic Acid/*antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinase Kinase Kinase 11 ; }, abstract = {We measured the MLK3 expression, activity and backphosphorylation following cerebral ischemia. Our data showed that MLK3 protein levels were unalterable during ischemia and reperfusion. However, during ischemia MLK3 activity gradually increased and reached its peak at 30 min of ischemia. While its backphosphorylation reduced from 5 min of ischemia to 30 min of ischemia. In addition, we also detected MLK3 alteration at various time points of reperfusion after 15 min of ischemia, which showed that MLK3 activity increased twice, whereas MLK3 backphosphorylation was similarly consistent with its activity during reperfusion. To further analyze the reason of MLK3 activation, antioxidant N-acetylcysteine (NAC) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)/kainate (KA) receptor antagonist 6,7-dinitroquinoxaline-2,3(1H, 4H)-dione (DNQX) were given to the rats 20 min prior to ischemia. The results illustrated that NAC preferably inhibited the MLK3 activation during the ischemia and the early reperfusion, whereas DNQX effectively attenuated the MLK3 activation of the late reperfusion. We think that MLK3 activation is certainly associated with reactive oxygen species (ROS) and AMPA/KA receptor in response to ischemic insult.}, }
@article {pmid12941301, year = {2003}, author = {O'Loghlen, A and Pérez-Morgado, MI and Salinas, M and Martín, ME}, title = {Reversible inhibition of the protein phosphatase 1 by hydrogen peroxide. Potential regulation of eIF2 alpha phosphorylation in differentiated PC12 cells.}, journal = {Archives of biochemistry and biophysics}, volume = {417}, number = {2}, pages = {194-202}, doi = {10.1016/s0003-9861(03)00368-0}, pmid = {12941301}, issn = {0003-9861}, mesh = {Animals ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Eukaryotic Initiation Factor-2B/*metabolism ; Homeostasis ; Hydrogen Peroxide/*pharmacology ; PC12 Cells/*drug effects/*metabolism ; Phosphoprotein Phosphatases/*antagonists &amp; inhibitors/*metabolism ; Phosphorylation/drug effects ; Protein Phosphatase 1 ; Rats ; }, abstract = {Oxidative inactivation of protein tyrosine phosphatases and calcineurin is a well established mechanism; however, little information with regard to the effect of oxidants on PP1 and PP2A activity is available. Herein, we show that PP1 activity is inhibited by H(2)O(2) treatment in differentiated PC12 cells both in vitro and in vivo experiments. Thiol-antioxidant N-acetyl-cysteine (NAC) and reduced glutathione (GSH), when added in vitro to lysates from H(2)O(2)-treated cells, reversed PP1 inhibition. H(2)O(2) treatment increased eIF2 alpha phosphorylated levels (eIF2 alpha P) in a time- and dose-dependent fashion and promoted protein synthesis inhibition. Interestingly, NAC pretreatment protected cells from H(2)O(2)-induced PP1 inactivation and, consequently, it abolished increased H(2)O(2)-induced eIF2 alpha phosphorylation and protein synthesis inhibition. In addition, PP1 inhibitor tautomycin prevented both NAC-induced PP1 reactivation and eIF2 alpha P dephosphorylation in H(2)O(2)-treated cells. Taken together, our findings support a role for PP1 in eIF2 alpha phosphorylation and oxidative stress-triggered translation down regulation.}, }
@article {pmid12934647, year = {2003}, author = {Kwon, KS and Chae, HJ}, title = {Sodium salicylate inhibits expression of COX-2 through suppression of ERK and subsequent NF-kappaB activation in rat ventricular cardiomyocytes.}, journal = {Archives of pharmacal research}, volume = {26}, number = {7}, pages = {545-553}, doi = {10.1007/BF02976879}, pmid = {12934647}, issn = {0253-6269}, mesh = {Animals ; Cyclooxygenase 2 ; Cyclooxygenase 2 Inhibitors ; Cyclooxygenase Inhibitors/pharmacology ; Heart Ventricles/drug effects/metabolism ; Isoenzymes/*antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; Myocytes, Cardiac/*drug effects/metabolism ; NF-kappa B/*metabolism ; Prostaglandin-Endoperoxide Synthases/metabolism ; Rats ; Rats, Wistar ; Sodium Salicylate/*pharmacology ; }, abstract = {The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation, which can be inhibited with sodium salicylate. IL-1beta and TNF-alpha can induce extracellular signal-regulated kinase (ERK), IKK, IkappaB degradation and NF-kappaB activation. Salicylate inhibited the IL-1beta and TNF-alpha-induced COX-2 expressions, regulated the activation of ERK, IKK and IkappaB degradation, and the subsequent activation of NF-kappaB, in neonatal rat ventricular cardiomyocytes. The inhibition of the ERK pathway, with a selective inhibitor, PD098059, blocked the expressions of IL-1beta and TNF-alpha-induced COX-2 and PGE2 release. The antioxidant, N-acetyl-cysteine, also reduced the glutathione or catalase- attenuated COX-2 expressions in IL-1beta and TNF-alpha-treated cells. This antioxidant also inhibited the activation of ERK and NF-kappaB in neonatal rat cardiomyocytes. In addition, IL-1beta and TNF-alpha stimulated the release of reactive oxygen species (ROS) in the cardiomyocytes. However, salicylate had no inhibitory effect on the release of ROS in the DCFDA assay. The results showed that salicylate inhibited the activation of ERK and IKK, IkappaB degradation and NF-kappaB activation, independently of the release of ROS, which suggested that salicylate exerts its anti-inflammatory action through the inhibition of ERK, IKK, IkappaB and NF-kappaB, and the resultant COX-2 expression pathway in neonatal rat ventricular cardiomyocytes.}, }
@article {pmid12930301, year = {2003}, author = {Ashida, M and Bito, T and Budiyanto, A and Ichihashi, M and Ueda, M}, title = {Involvement of EGF receptor activation in the induction of cyclooxygenase-2 in HaCaT keratinocytes after UVB.}, journal = {Experimental dermatology}, volume = {12}, number = {4}, pages = {445-452}, doi = {10.1034/j.1600-0625.2003.00101.x}, pmid = {12930301}, issn = {0906-6705}, mesh = {Base Sequence ; Cell Line ; Cyclooxygenase 2 ; Dinoprostone/biosynthesis ; Enzyme Induction/radiation effects ; ErbB Receptors/antagonists &amp; inhibitors/*metabolism ; Humans ; Isoenzymes/*biosynthesis/genetics ; Keratinocytes/*metabolism/*radiation effects ; MAP Kinase Signaling System/radiation effects ; Membrane Proteins ; Mitogen-Activated Protein Kinases/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Prostaglandin-Endoperoxide Synthases/*biosynthesis/genetics ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/radiation effects ; Ultraviolet Rays/adverse effects ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Because selective inhibition of cyclooxygenase-2 (COX-2) suppressed the induction of skin tumors in mice by UV and as UV has been shown to induce expression of COX-2 in skin and cells, COX-2 may be crucial for photocarcinogenesis of the skin. We studied the mechanism of UVB-induced expression of COX-2 focusing on the signal transduction pathway involved. Hydrogen peroxide (H2O2) treatment of HaCaT cells induced expression of COX-2 and pretreatment with the antioxidant N-acetylcysteine (NAC) partly inhibited the UVB-induced expression of COX-2 protein in HaCaT cells, suggesting that oxidative stress contributes to COX-2 induction. To examine the signaling pathways involved in the UVB-induced expression of COX-2 in HaCaT cells, we analysed the expression of COX-2 protein after treatment with various inhibitors of signaling molecules. Inhibition of EGFR by a specific inhibitor and by a neutralizing antibody suppressed the induction of COX-2 expression by UV. Although a neutralizing antibody to transforming growth factor-alpha (TGF-alpha) suppressed COX-2 expression induced by TGF-alpha, it did not suppress COX-2 expression by UV, indicating that a direct activation of EGFR is involved. Treatment of cells at low temperature (4 degrees C) inhibited UVB-induced JNK activation, but it did not inhibit COX-2 expression by UV. Inhibitors of MEK, p38 MAP kinase and PI3-kinase, suppressed the induction of COX-2 expression by UV. In contrast, an erbB-2 inhibitor augmented the UVB-induced increase of COX-2 protein. These data indicate that oxidative stress in association with activation of EGFR, ERK, p38 MAP kinase, and PI3-kinase plays crucial roles in the UVB induction of expression of COX-2.}, }
@article {pmid12929751, year = {2003}, author = {Pupe, A and Degreef, H and Garmyn, M}, title = {Induction of tumor necrosis factor-alpha by UVB: a role for reactive oxygen intermediates and eicosanoids.}, journal = {Photochemistry and photobiology}, volume = {78}, number = {1}, pages = {68-74}, doi = {10.1562/0031-8655(2003)078&lt;0068:iotnfb&gt;2.0.co;2}, pmid = {12929751}, issn = {0031-8655}, mesh = {Antioxidants/pharmacology ; Cyclooxygenase Inhibitors/metabolism ; Eicosanoids/*physiology ; Ferrous Compounds/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Keratinocytes/enzymology ; Lipoxygenase/metabolism ; NF-kappa B/physiology ; Oxidative Stress ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/genetics/*metabolism ; *Ultraviolet Rays ; }, abstract = {UVB irradiation induces nuclear factor-kappaB (NF-kappaB) activation, tumor necrosis factor-alpha (TNF-alpha) expression and reactive oxygen intermediates (ROI) in keratinocytes. We investigated whether ROI play a role in UVB-induced TNF-alpha mRNA expression. The antioxidants N-acetyl cysteine, NAC, epigallocathin gallate, EGCG, butylated hydroxyanisole (BHA) and vitamin C could reduce UVB-induced TNF-alpha mRNA levels to various degrees; vitamin E (alpha-tocopherol) had no effect. BHA was the most potent inhibitor. The oxidant tertiary butylated hydroperoxide could effectively induce TNF-alpha mRNA expression. Nordihydroguaiaretic acid (NDGA) and MK-886, inhibitors of lipoxygenase (LOX), and indometacin and quinacrine, inhibitors of cyclooxygenase (COX) and phospholipase A2, respectively, could also reduce UVB-induced TNF-alpha mRNA expression. Inhibition by NDGA was in concordance with the results for BHA. NDGA, indometacin, quinacrine and BHA could also effectively inhibit the inhibitor of NF-kappaB degradation, thereby maintaining NF-kappaB inactivity. In conclusion, we show that ROI are implicated in the induction of TNF-alpha mRNA by UVB and that not all antioxidants are equally effective inhibitors. COX products and more importantly LOX products, which themselves are products of an oxidative metabolism, are the main ROI implicated in this induction of TNF-alpha expression by UVB probably via activation of NF-kappaB.}, }
@article {pmid12928788, year = {2003}, author = {Mantovani, G and Macciò, A and Madeddu, C and Mura, L and Gramignano, G and Lusso, MR and Massa, E and Mocci, M and Serpe, R}, title = {Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {81}, number = {10}, pages = {664-673}, pmid = {12928788}, issn = {0946-2716}, mesh = {Adult ; Aged ; Aged, 80 and over ; Antioxidants/*pharmacology ; Body Mass Index ; *Cachexia ; Case-Control Studies ; *Cell Cycle ; Cytokines/blood ; Disease Progression ; Female ; Humans ; Leukocytes, Mononuclear ; Lymphocytes/*metabolism ; Male ; Middle Aged ; Neoplasms/immunology/*metabolism/pathology ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; }, abstract = {This study assessed in a wide population of advanced cancer patients the biological parameters relevant to cancer cachexia, such as serum levels of proinflammatory cytokines (IL-1beta, IL-6, TNFalpha), IL-2, acute-phase proteins (C-reactive protein and fibrinogen), leptin, and relevant to oxidative stress (OS), such as ROS, body antioxidant enzymes GPx and SOD. We also studied the ability of effective antioxidant agents alpha-lipoic acid (ALA), N-acetyl cysteine (NAC), and amifostine (AMI) added into culture to induce lymphocyte progression through the cell cycle, namely to enter into S phase. Additionally, we assessed the most significant clinical indexes of nutritional status such as body mass index and disease progression such as stage and ECOG-PS in the same cancer patient population. Cell cycle analysis of cultured unstimulated or PHA-stimulated PBMCs isolated from 120 cancer patients and 60 controls, with or without ALA, NAC, or AMI, was studied. The biological parameters relevant to cancer cachexia and OS were also studied. The addition of antioxidants ALA, NAC and AMI, enhanced significantly the progression through the cell cycle, namely from G0/G1 to S phase, of PBMCs isolated from cancer patients (+132%, +150% and +141%, respectively). The percentage of PHA-stimulated PBMCs of cancer patients entering S phase, which was significantly lower than that of controls, increased significantly to more than physiological level after coculture with antioxidants. ROS levels were significantly higher and GPx and SOD activities significantly lower in cancer patients than controls. Serum levels of IL-1 beta, IL-6, and TNFalpha were significantly higher and serum levels of IL-2 and leptin significantly lower in cancer patients than controls. Serum levels of C-reactive protein and fibrinogen were significantly higher in cancer patients than controls. A significant correlation was found in laboratory parameters only between serum levels of leptin and body mass index. Patients with advanced cancer thus exhibit both a high-grade OS and a chronic inflammatory condition. Antioxidant agents ALA, NAC, and AMI enhanced significantly the PBMCs progression through the cell cycle, thus providing evidence of their potential role in the functional restoration of the immune system in advanced cancer patients. Our data warrant further investigation with adequate clinical trials.}, }
@article {pmid12928590, year = {2003}, author = {Dhaunsi, GS and Kaur, J and Turner, RB}, title = {Role of NADPH oxidase in cytomegalovirus-induced proliferation of human coronary artery smooth muscle cells.}, journal = {Journal of biomedical science}, volume = {10}, number = {5}, pages = {505-509}, doi = {10.1007/BF02256111}, pmid = {12928590}, issn = {1021-7770}, mesh = {Cell Division/*physiology ; Cells, Cultured ; Coronary Disease/physiopathology ; Coronary Vessels/*cytology/immunology/virology ; Cytomegalovirus/*physiology ; DNA Replication ; Humans ; Inflammation ; Interleukin-8/analysis ; Muscle, Smooth, Vascular/*cytology/immunology/virology ; NADPH Oxidases/*metabolism ; }, abstract = {A number of infectious agents have been implicated in the development of vascular diseases such as atherosclerosis and posttransplantation arterial restenosis. Cytomegalovirus (CMV) has been reported to cause obliteration of coronary arteries by a progressive vasculopathy that involves proliferation of medial smooth muscle cells (SMC). In this study, we report that CMV enhances the serum-induced proliferation of human coronary SMC through activation of a superoxide-generating NADPH oxidase. Exposure of SMC to CMV for 2 h was associated with an 80% increase in NADPH oxidase. This increase in oxidase activity was associated with a two-fold increase in serum-induced DNA synthesis (5-bromo-2'-deoxyuridine incorporation) and significant interleukin-8 (IL-8) production by SMC. Diphenylene iodonium, an inhibitor of NADPH oxidase, significantly inhibited CMV-induced IL-8 production and promotion of serum-induced DNA synthesis. Similar effects were seen following pretreatment of SMC with N-acetyl cysteine, a potent antioxidant, suggesting that oxidative stress following CMV exposure might be responsible for triggering the proliferation of SMC. From this study, we conclude that CMV-mediated promotion of SMC growth is redox sensitive and may be mediated by NADPH oxidase.}, }
@article {pmid12925816, year = {2003}, author = {Zou, J and Bretlau, P and Pyykkö, I and Toppila, E and Olovius, NP and Stephanson, N and Beck, O and Miller, JM}, title = {Comparison of the protective efficacy of neurotrophins and antioxidants for vibration-induced trauma.}, journal = {ORL; journal for oto-rhino-laryngology and its related specialties}, volume = {65}, number = {3}, pages = {155-161}, doi = {10.1159/000072253}, pmid = {12925816}, issn = {0301-1569}, mesh = {Animals ; Antioxidants/*pharmacology ; Audiometry, Evoked Response ; Auditory Threshold/drug effects ; Endolymph/metabolism ; Guinea Pigs ; Hair Cells, Auditory/drug effects ; Hearing Loss, Sensorineural/etiology/*physiopathology/*prevention &amp; control ; Nerve Growth Factors/metabolism/*pharmacology ; Neuroprotective Agents/*pharmacology ; Vibration ; }, abstract = {BACKGROUND: Patients undergoing temporal bone surgery or subjects working with vibrating tools may develop vibration-induced hearing loss (VHL). The aim of this study was to characterize the effects of pretreatment with N-acetylcysteine (NAC) or the neurotrophic factors, brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), on VHL in an animal model.<br><br>METHODS: Trauma to the cochlea was created with a vibrating probe placed on the bone of the external ear canal. BDNF and CNTF(Ax1) were delivered into the cochlea with mini-osmotic pumps. NAC was delivered into the cochlea by round window membrane (RWM) injection, by RWM permeation, or by oral administration. Hearing was evaluated with electrocochleography (ECoG).<br><br>RESULTS: For control animals, vibration resulted in an average immediate threshold shift of 42 +/- 26 dB. NAC provided no protective benefit in animals subjected to VHL, regardless of the delivery method, with average threshold shifts varying from 38 to 56 dB across groups. NAC injection through the round window membrane was toxic, causing a ECoG threshold shift of >25 dB. In BDNF+CNTF(Ax1)-treated animals, immediate hearing loss was similar to that in control animals. There was a trend of threshold recovery by 1 day after vibration; however, the improvement was not statistically significant, nor was there a significant difference in 1-day thresholds across groups.<br><br>CONCLUSIONS: Local infusion of BDNF and CNTF(Ax1) may enhance the rate of recovery from VHL, compared to control animals. In contrast, NAC had no effect on VHL, and when delivered by RWM injection, was actually toxic to the inner ear.}, }
@article {pmid12920036, year = {2003}, author = {Chandra, J and Hackbarth, J and Le, S and Loegering, D and Bone, N and Bruzek, LM and Narayanan, VL and Adjei, AA and Kay, NE and Tefferi, A and Karp, JE and Sausville, EA and Kaufmann, SH}, title = {Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells.}, journal = {Blood}, volume = {102}, number = {13}, pages = {4512-4519}, doi = {10.1182/blood-2003-02-0562}, pmid = {12920036}, issn = {0006-4971}, support = {R01 CA085972/CA/NCI NIH HHS/United States ; F32 CA93055/CA/NCI NIH HHS/United States ; R01 CA 85972/CA/NCI NIH HHS/United States ; R01 CA91542/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adamantane/*analogs &amp; derivatives/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; *DNA Damage ; DNA, Neoplasm/drug effects ; Enzyme Inhibitors/*pharmacology ; Fusion Proteins, bcr-abl/antagonists &amp; inhibitors ; Glutathione/analysis ; Humans ; Hydroquinones/*pharmacology ; K562 Cells/drug effects/metabolism ; Leukemia/*pathology ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Leukemia, Myeloid/pathology ; Neoplasm Proteins/antagonists &amp; inhibitors ; Neoplastic Stem Cells/*drug effects ; Quinones/*pharmacology ; Reactive Oxygen Species/*metabolism ; Tumor Stem Cell Assay ; Tyrphostins/pharmacology ; }, abstract = {Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned.}, }
@article {pmid12918029, year = {2003}, author = {Stanislawski, L and Lefeuvre, M and Bourd, K and Soheili-Majd, E and Goldberg, M and Périanin, A}, title = {TEGDMA-induced toxicity in human fibroblasts is associated with early and drastic glutathione depletion with subsequent production of oxygen reactive species.}, journal = {Journal of biomedical materials research. Part A}, volume = {66}, number = {3}, pages = {476-482}, doi = {10.1002/jbm.a.10600}, pmid = {12918029}, issn = {1549-3296}, mesh = {Adult ; Antioxidants/*pharmacology ; Fibroblasts/cytology/*drug effects/metabolism ; Glutathione/*metabolism ; Humans ; Polyethylene Glycols/*toxicity ; Polymethacrylic Acids/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {Triethylene glycol dimethacrylate (TEGDMA) is a dentin-bonding agent and a major component of various dental restorative biomaterials. TEGDMA monomers are released from dental resins and induce dental pulp inflammation and necrosis. In this study, we have investigated the mechanism of TEGDMA-induced cytotoxicity of fibroblasts. Treatment of cultured human gingival and pulpal fibroblasts with 0.1-3 mM of TEGDMA for 24 h induced a concentration-dependent and variable cytotoxic effect. Fifty percent of toxicity (TC(50)) was obtained with 1.2 +/- 0.9 and 2.6 +/- 1.1 mM of TEGDMA for gingival and pulpal fibroblasts, respectively. Moreover, TEGDMA-induced cytotoxicity was associated with an early and drastic depletion of cellular glutathione (GSH), which started at 15-30 min and was almost complete at 4-6 h. Antioxidants, such as Trolox (0.01 mM), ascorbate (0.2 mM), and N-acetylcysteine (NAC) (5 mM) prevented the TEGDMA-induced cytotoxicity while GSH depletion was partially inhibited. Finally, a late production of reactive oxygen species (ROS) occurred in fibroblasts treated with TEGDMA for 3-4 h, as determined by 2',7'-dichlorofluorescein fluorescence, and was completely inhibited by Trolox (5 microM). The data show that TEGDMA induced a drastic GSH depletion followed by production of ROS, which may contribute to the toxicity of gingival and pulpal fibroblasts. Antioxidants, such as NAC, ascorbate, and particularly Trolox, appear useful in preventing cell damage mediated by resin-containing dental restorative materials.}, }
@article {pmid12913252, year = {2003}, author = {Kurozumi, R and Tokuzumi, S and Kojima, S}, title = {Does peroxynitrite involve in the elevation of cellular glutathione induced by sodium nitroprusside (SNP) in RAW 264.7 cells?.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {26}, number = {8}, pages = {1070-1075}, doi = {10.1248/bpb.26.1070}, pmid = {12913252}, issn = {0918-6158}, mesh = {Animals ; Cell Line ; Enzyme Induction/genetics ; Glutamate-Cysteine Ligase/biosynthesis/genetics ; Glutathione/biosynthesis/*metabolism ; Intracellular Fluid/drug effects/metabolism ; Mice ; Nitroprusside/*pharmacology ; Peroxynitrous Acid/*metabolism ; RNA, Messenger/metabolism ; Up-Regulation/drug effects ; }, abstract = {The mechanism underlying the elevation of intracellular glutathione (GSH) in RAW 264.7 cells exposed to low-level sodium nitroprusside (SNP) was investigated by measuring the expression of mRNA for gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme of de novo GSH synthesis, and the GSH content. A significant elevation of expression of mRNA for gamma-GCS was observed at 3 h after exposure of the cells to SNP at a concentration of 0.25 mM. 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), N-acetylcysteine (NAC), or ebselen (Ebs) significantly suppressed the elevations induced by SNP, suggesting that hydrogen peroxide or peroxynitrite (ONOO(-)) is involved in this event as a triggering molecule. Hydrogen peroxide itself, however, did not induce the elevation of gamma-GCS mRNA and glutathione. Chemiluminescenses induced by SIN-1, a chemical ONOO(-) donor, and ONOO(-) itself were completely blocked by Ebs. SIN-1 also significantly elevated the cellular glutathione level, and the elevation was absolutely blocked by Ebs. These results suggest that the elevation of intracellular GSH in RAW 264.7 cells exposed to low-level SNP occurs via the de novo GSH pathway through transcriptional up-regulation of the gamma-GCS gene induced by peroxynitrite molecule.}, }
@article {pmid12910481, year = {2003}, author = {Yilmaz, O and Celik, S}, title = {A combination of alpha-tocopherol, vitamin C and N-acetyl cysteine increases unsaturated fatty acid levels in hydrogen peroxide-induced Candida tropicalis (ATCC 13803).}, journal = {Cell biochemistry and function}, volume = {21}, number = {3}, pages = {269-274}, doi = {10.1002/cbf.1022}, pmid = {12910481}, issn = {0263-6484}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Ascorbic Acid/*pharmacology ; Candida tropicalis/chemistry/*drug effects ; Cell Division/drug effects ; Data Interpretation, Statistical ; Fatty Acids/analysis ; Fatty Acids, Monounsaturated/analysis ; Fatty Acids, Unsaturated/*analysis ; Hydrogen Peroxide/*toxicity ; Lipids/analysis/chemistry ; alpha-Tocopherol/*pharmacology ; }, abstract = {This research was aimed at evaluating the antioxidant effects of combinations of alpha lipoic acid (LA), vitamin C (VC), N-acetyl cysteine (NAC) and alpha-tocopherol (TOC) on lipid level and fatty acid composition of C. tropicalis (ATCC 13803) against hydrogen peroxide toxicity. According to the experimental results, the cell density of C. tropicalis increased significantly in NAC+LA+H2O2, NAC+TOC+ H2O2 and NAC+VC+H2O2 groups (p<0.001) at the end of 48 and 72 h incubation times. The total lipid level in H2O2 and H2O2 + antioxidant-supplemented groups was lower than that of the control group. In the fatty acid composition of C. tropicalis, the palmitic acid level was raised in the NAC group (p<0.05), whereas its level was reduced in the other supplemented groups. While the oleic acid level increased in NAC+TOC+H2O2 and NAC+VC+H2O2 (p<0.001) groups, its level slightly decreased in the H2O2 group. The linolenic acid level was low in all the supplemented groups, but linoleic acid and total mono-unsaturated fatty acid (MUFA) levels were high in these groups compared with the control group. Total polyunsaturated fatty acid level (PUFA) decreased in NAC and H2O2 groups (p<0.01), but its level increased in NAC+LA+H2O2 and NAC+TOC+H2O2 groups (respectively, p<0.01, p<0.001). Total saturated fatty acid level decreased significantly in NAC+TOC+H2O2, NAC+H2O2 and NAC+VC+H2O2 (p<0.001) groups (p<0.01), whereas total unsaturated fatty acid level increased in NAC, NAC+H2O2, NAC+LA+H2O2, NAC+TOC+H2O2 and NAC+VC+H2O2 groups. In conclusion, our data showed that the levels of total unsaturated fatty acid, MUFA and PUFA were raised with the combinations of NAC and TOC, LA and VC in C. tropicalis cells subjected to hydrogen peroxide toxicity.}, }
@article {pmid12907675, year = {2003}, author = {Alves-Guerra, MC and Rousset, S and Pecqueur, C and Mallat, Z and Blanc, J and Tedgui, A and Bouillaud, F and Cassard-Doulcier, AM and Ricquier, D and Miroux, B}, title = {Bone marrow transplantation reveals the in vivo expression of the mitochondrial uncoupling protein 2 in immune and nonimmune cells during inflammation.}, journal = {The Journal of biological chemistry}, volume = {278}, number = {43}, pages = {42307-42312}, doi = {10.1074/jbc.M306951200}, pmid = {12907675}, issn = {0021-9258}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Bone Marrow Transplantation ; Carrier Proteins/biosynthesis/metabolism ; Dexamethasone/pharmacology ; Free Radicals/metabolism ; *Gene Expression Regulation/drug effects ; Immune System/*cytology ; Intestines ; Ion Channels ; Lipopolysaccharides/pharmacology ; Lung ; Membrane Transport Proteins/biosynthesis/metabolism ; Mice ; Mice, Knockout ; Mitochondrial Proteins/biosynthesis/*metabolism ; Organ Specificity ; Spleen ; Tissue Distribution ; Uncoupling Protein 2 ; }, abstract = {The mitochondrial uncoupling protein 2 (UCP2) is expressed in spleen, lung, intestine, white adipose tissue, and immune cells. Bone marrow transplantation in mice was used to assess the contribution of immune cells to the expression of UCP2 in basal condition and during inflammation. Immune cells accounted for the total amount of UCP2 expression in the spleen, one-third of its expression in the lung, and did not participate in its expression in the intestine. LPS injection stimulated UCP2 expression in lung, spleen, and intestine in both immune and non-immune cells. Successive injections of LPS and dexamethasone or N-acetyl-cysteine prevented the induction of UCP2 in all three tissues, suggesting that oxygen free radical generation plays a role in UCP2 regulation. Finally, both previous studies and our data show that there is down-regulation of UCP2 in immune cells during their activation in the early stages of the LPS response followed by an up-regulation in UCP2 during the later stages to protect all cells against oxidative stress.}, }
@article {pmid12902805, year = {2003}, author = {McComsey, G and Southwell, H and Gripshover, B and Salata, R and Valdez, H}, title = {Effect of antioxidants on glucose metabolism and plasma lipids in HIV-infected subjects with lipoatrophy.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {33}, number = {5}, pages = {605-607}, doi = {10.1097/00126334-200308150-00009}, pmid = {12902805}, issn = {1525-4135}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Ascorbic Acid/therapeutic use ; Body Composition ; Cholesterol/blood ; Female ; Glucose/analysis/*metabolism ; HIV-Associated Lipodystrophy Syndrome/chemically induced/*drug therapy/metabolism ; Hospitals, University ; Humans ; Lipids/blood ; Male ; Middle Aged ; Ohio ; Pilot Projects ; Reverse Transcriptase Inhibitors/adverse effects/therapeutic use ; Vitamin E/therapeutic use ; }, abstract = {Ten HIV-infected nucleoside reverse transcriptase inhibitor-treated subjects with lipoatrophy or sustained hyperlactatemia were given antioxidants: vitamins C, E, and N-acetyl cysteine. After 24 weeks, anthropometrics did not change significantly, except for a modest decrease in the waist-to-hip ratio. Fasting low-density lipoprotein cholesterol trended toward lower values. Fasting glucose significantly increased along with a significant increase in homeostatic model assessment values, reflecting an increase in insulin resistance. Controlled trials are required to evaluate directly the effects of these agents on lipid and glucose metabolism.}, }
@article {pmid12902275, year = {2003}, author = {Olofsson, AC and Hermansson, M and Elwing, H}, title = {N-acetyl-L-cysteine affects growth, extracellular polysaccharide production, and bacterial biofilm formation on solid surfaces.}, journal = {Applied and environmental microbiology}, volume = {69}, number = {8}, pages = {4814-4822}, pmid = {12902275}, issn = {0099-2240}, mesh = {Acetylcysteine/*pharmacology ; Bacteria/*drug effects/growth &amp; development/metabolism ; Bacterial Adhesion/drug effects ; Biofilms/*drug effects ; Polysaccharides, Bacterial/*biosynthesis ; }, abstract = {N-Acetyl-L-cysteine (NAC) is used in medical treatment of patients with chronic bronchitis. The positive effects of NAC treatment have primarily been attributed to the mucus-dissolving properties of NAC, as well as its ability to decrease biofilm formation, which reduces bacterial infections. Our results suggest that NAC also may be an interesting candidate for use as an agent to reduce and prevent biofilm formation on stainless steel surfaces in environments typical of paper mill plants. Using 10 different bacterial strains isolated from a paper mill, we found that the mode of action of NAC is chemical, as well as biological, in the case of bacterial adhesion to stainless steel surfaces. The initial adhesion of bacteria is dependent on the wettability of the substratum. NAC was shown to bind to stainless steel, increasing the wettability of the surface. Moreover, NAC decreased bacterial adhesion and even detached bacteria that were adhering to stainless steel surfaces. Growth of various bacteria, as monocultures or in a multispecies community, was inhibited at different concentrations of NAC. We also found that there was no detectable degradation of extracellular polysaccharides (EPS) by NAC, indicating that NAC reduced the production of EPS, in most bacteria tested, even at concentrations at which growth was not affected. Altogether, the presence of NAC changes the texture of the biofilm formed and makes NAC an interesting candidate for use as a general inhibitor of formation of bacterial biofilms on stainless steel surfaces.}, }
@article {pmid12901850, year = {2003}, author = {Turpaev, K and Litvinov, D and Justesen, J}, title = {Redox modulation of NO-dependent induction of interleukin 8 gene in monocytic U937 cells.}, journal = {Cytokine}, volume = {23}, number = {1-2}, pages = {15-22}, doi = {10.1016/s1043-4666(03)00114-5}, pmid = {12901850}, issn = {1043-4666}, mesh = {Gene Expression Regulation/*physiology ; Humans ; Interleukin-8/biosynthesis/*genetics ; Monocytes/*metabolism ; Nitric Oxide/*metabolism ; Oxidation-Reduction ; Signal Transduction/physiology ; Transcriptional Activation ; U937 Cells ; }, abstract = {We have examined the effects of various antioxidants and inhibitors of redox-sensitive signal transduction pathways on induction of interleukin 8 (IL-8) gene by NO in monocytic U937 cells. We have observed that nitrosoglutathione or another NO-generating compound spermine NONOate caused significant accumulation of IL-8 mRNA. Pretreatment of cells with pyrrolidine dithiocarbamate or with antioxidants, which scavenge hydroxyl radical, dimethyl sulfoxide (DMSO), or dimetylthiourea (DMTU) completely abrogated NO-dependent induction of IL-8 gene expression. The transcriptional activation of IL-8 gene was not affected by sodium formate or sodium salicylate, suggesting that suppression of the IL-8 gene induction is specific to the class of hydroxyl radical scavenger used. Furthermore, we have shown that IL-8 induction was not inhibited by catalase and the iron chelator deferoxamine, indicating that the inhibitory actions of DMSO and DMTU are not related to scavenging of reactive oxygen species produced from hydrogen peroxide in the iron-catalyzed reactions. Finally, we have not observed any significant inhibition of NO-dependent IL-8 gene induction by superoxide scavengers such as N-acetyl cysteine, uric acid, and superoxide dismutase. Therefore, it seems likely that in U937 cells, hydroxyl radicals or species with reactivity similar to hydroxyl radicals contribute to NO-mediated IL-8 gene induction.}, }
@article {pmid12900770, year = {2003}, author = {Sjöö, F and Aschan, J and Barkholt, L and Hassan, Z and Ringdén, O and Hassan, M}, title = {N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of busulfan during conditioning prior to allogeneic stem cell transplantation.}, journal = {Bone marrow transplantation}, volume = {32}, number = {4}, pages = {349-354}, doi = {10.1038/sj.bmt.1704143}, pmid = {12900770}, issn = {0268-3369}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Area Under Curve ; Bilirubin/pharmacology ; Busulfan/blood/*pharmacology ; Child ; Cyclophosphamide/*analogs &amp; derivatives/metabolism/pharmacology ; Female ; Glutathione/metabolism ; Humans ; Immunosuppressive Agents/pharmacology ; Infant ; Liver/drug effects/enzymology ; Male ; Middle Aged ; Stem Cell Transplantation/*methods ; Transplantation Conditioning ; Transplantation, Homologous/*methods ; Treatment Outcome ; }, abstract = {Busulfan is currently used as a main component in the conditioning regimen prior to allogeneic stem cell transplantation (SCT). Several studies have shown a correlation between exposure to busulfan and transplantation-related liver toxicity, such as venoocclusive disease (VOD) in patients undergoing SCT. Busulfan is metabolized mainly through glutathione (GSH). During high-dose therapy, busulfan may deplete hepatocellular levels of GSH. As part of the conditioning therapy, busulfan is usually followed by high doses of cyclophosphamide. The activation of cyclophosphamide yields a cytotoxic metabolite, 4-hydroxy cyclophosphamide, which is highly reactive and detoxified through GSH. According to recent studies using cell lines and animal models N-acetyl-L-cysteine (NAC), a GSH precursor, does not hamper the myeloablative effect of busulfan during conditioning. In the present study, we administered NAC during conditioning to 10 patients at risk of VOD due to pretransplant liver disorders or elevated liver enzymes. No side effects related to the NAC infusions were observed and busulfan concentrations were not affected. All patients became pancytopenic and engrafted with 100% donor cells. None of the patients developed VOD or liver failure. Increased liver enzymes during conditioning decreased or normalized in all patients. We suggest that NAC therapy is safe and does not impair the myeloablative effect of busulfan during conditioning prior to SCT.}, }
@article {pmid12898340, year = {2003}, author = {Chen, XC and Fang, F and Zhu, YG and Chen, LM and Zhou, YC and Chen, Y}, title = {Protective effect of ginsenoside Rg1 on MPP+-induced apoptosis in SHSY5Y cells.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {110}, number = {8}, pages = {835-845}, doi = {10.1007/s00702-003-0005-y}, pmid = {12898340}, issn = {0300-9564}, mesh = {1-Methyl-4-phenylpyridinium/*antagonists &amp; inhibitors/toxicity ; Apoptosis/*drug effects/physiology ; Caspase 3 ; Caspases/metabolism ; Cell Line, Tumor ; Down-Regulation/drug effects/physiology ; Ginsenosides/*pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases/metabolism ; Neuroblastoma/drug therapy/metabolism ; Neurons/*drug effects/enzymology ; Neuroprotective Agents/*pharmacology ; Oxidative Stress/drug effects/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/physiology ; }, abstract = {The neuroprotective mechanism of Rg1 was studied in this paper by means of its obvious anti-apoptotic effect on human SHSY5Y cells. SHSY5Y cells were treated with MPP+ (1-methyl-4-phenyl-pyridinium) for 72 hours to induce apoptosis. During the apoptosis, production of reactive oxygen species (ROS), activation of c-Jun N-terminal kinase (JNK) and activation of caspase-3 were observed. The results showed that the signal transduction pathway of MPP+-induced apoptosis might be ROS to JNK, then to caspase-3. MPP+-induced apoptosis in SHSY5Y cells was obviously inhibited in both NAC (N-acetylcysteine) pretreated groups and Rg1 pretreated groups. Meanwhile, compared to that of the controls, our results showed decreased level of ROS, less JNK activity and lower expression of cleaved caspase-3 in pretreated NAC groups and in Rg1 pretreated groups. The protection by Rg1 might be mediated by removing of ROS. The removal of ROS might inhibit the activity of JNK and the expression of cleaved caspase-3. These results suggest that ginsenoside Rg1 may take effect through its anti-apoptotic activity in neurodegenerative diseases.}, }
@article {pmid12897406, year = {2003}, author = {Chen, GJ and Xu, J and Lahousse, SA and Caggiano, NL and de la Monte, SM}, title = {Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {5}, number = {3}, pages = {209-228}, doi = {10.3233/jad-2003-5305}, pmid = {12897406}, issn = {1387-2877}, support = {AA-02169/AA/NIAAA NIH HHS/United States ; AA-02666/AA/NIAAA NIH HHS/United States ; AA-11431/AA/NIAAA NIH HHS/United States ; P20RR15578/RR/NCRR NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy/etiology/pathology ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Antibodies, Monoclonal/immunology ; Cerebral Cortex/embryology/*pathology ; Cyclin-Dependent Kinases/*metabolism ; Hypoxia/*complications ; Mitogen-Activated Protein Kinases/*metabolism ; Neurons/*metabolism/*pathology ; Neuroprotective Agents/*therapeutic use ; Oxidative Stress/physiology ; Phosphotransferases/immunology/metabolism ; Radioimmunoprecipitation Assay ; Rats ; Time Factors ; }, abstract = {Familial Alzheimer's Disease (AD) has been linked to amyloid beta protein precursor (AbetaPP) and presenilin gene mutations. In sporadic AD, which accounts for the vast majority of cases, the pathogenesis of neurodegeneration is unknown; however, recent evidence suggests a role for oxidative stress. The present study demonstrates that transient hypoxic injury to cortical neurons causes several of the molecular and biochemical abnormalities that occur in AD including, mitochondrial dysfunction, impaired membrane integrity, increased levels of DNA damage, reactive oxygen species, phospho-tau, phospho-MAP-1B, and ubiquitin immunoreactivity, and AbetaPP cleavage with accumulation of Abeta-immunoreactive products. These abnormalities were associated with activation of kinases that phosphorylate tau, including glycogen synthase kinase 3beta (GSK-3beta), mitogen-activated protein kinase (MAPK), and cyclin-dependent kinase 5 (Cdk-5). Further studies showed that significant neuro-protection with sparing of mitochondrial function and membrane integrity could be achieved by pre-treating the cortical neurons with N-acetyl cysteine, glutathione, or inhibitors of GSK-3beta, MAP kinase, or AbetaPP gamma-secretase. Therefore, in the absence of underlying gene mutations, oxidative stress can cause AD-type abnormalities, including aberrant post-translational processing of neuronal cytoskeletal proteins and APP. Our results also suggest that pre-treatment with agents that block specific components of the AD neurodegeneration cascade may provide neuroprotection against oxidative stress-induced impairments in membrane integrity, mitochondrial function, and viability.}, }
@article {pmid12897100, year = {2003}, author = {Galli, F and Ghibelli, L and Buoncristiani, U and Bordoni, V and D'Intini, V and Benedetti, S and Canestrari, F and Ronco, C and Floridi, A}, title = {Mononuclear leukocyte apoptosis in haemodialysis patients: the role of cell thiols and vitamin E.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {18}, number = {8}, pages = {1592-1600}, doi = {10.1093/ndt/gfg210}, pmid = {12897100}, issn = {0931-0509}, mesh = {Aged ; Apoptosis/physiology ; Ascorbic Acid/*physiology ; Female ; Humans ; Kidney Failure, Chronic/*physiopathology/therapy ; Leukocytes, Mononuclear/*physiology ; Male ; Middle Aged ; Oxidative Stress/physiology ; Peritoneal Dialysis ; Renal Dialysis ; Sulfhydryl Compounds/*physiology ; Ultrafiltration ; }, abstract = {BACKGROUND: An increased apoptotic rate of peripheral blood mononuclear leukocytes (PBMLs) in haemodialysis (HD) patients has been reported in several studies, but its underlying mechanisms remain poorly understood. Oxidant stress is a well known cause of cell damage, and several lines of evidence suggest that it might influence the induction and signalling steps of mononuclear cell apoptosis through different mechanisms so as to provoke disturbances of the intracellular pool of thiols (SHi). In this study, we investigated the in vitro apoptotic rate and SHi of PBMLs in end-stage renal disease (ESRD) patients on HD or peritoneal dialysis (PD).<br><br>METHODS: Apoptosis and SHi were evaluated in vitro in PBMLs obtained from 40 ESRD patients (HD, n = 30 and PD, n = 10) and 10 healthy controls. A subgroup of HD patients was also studied before and after 1 month of treatment with a vitamin E-coated dialyser (CL-E). Cell thiols and viability were also assessed in the monocyte-like cell line U937 and PBMLs after incubation in the presence of uraemic plasma with or without supplementation of the antioxidants vitamin E (70 micro M) or N-acetyl-cysteine (NAC) (0.5 mM).<br><br>RESULTS: After 24 h in culture, the PBMLs of HD patients, but not those of CAPD patients, showed an apoptotic rate twice that of healthy controls and a 40% decrease of SHi levels (P < 0.01 in both). A negative correlation between the apoptotic rate and SHi was observed in both patients and controls (r = 0.648, P < 0.001). Plasma and ultrafiltrate samples from HD patients contained solutes (mainly in the low-middle molecular weight range) able to trigger apoptosis and oxidative stress in U937 cells. The treatment of HD patients with CL-E, as well as the in vitro supplementation of U937 cells with vitamin E or NAC during the exposure to uraemic plasma, decreased the rate of apoptosis and partially restored SHi.<br><br>CONCLUSIONS: This study showed an association between an increased apoptotic rate and decreased SHi in PBML of HD patients, but not of CAPD patients. These changes are partially due to different pro-apoptogens that accumulate in the plasma and are at least partially prevented by exogenous antioxidants able to restore SHi, such as vitamin E or thiol suppliers.}, }
@article {pmid12893416, year = {2003}, author = {Kim, SJ and Kim, TS and Hong, S and Rhim, H and Kim, IY and Kang, S}, title = {Oxidative stimuli affect polyglutamine aggregation and cell death in human mutant ataxin-1-expressing cells.}, journal = {Neuroscience letters}, volume = {348}, number = {1}, pages = {21-24}, doi = {10.1016/s0304-3940(03)00657-8}, pmid = {12893416}, issn = {0304-3940}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ataxin-1 ; Ataxins ; Buthionine Sulfoximine/pharmacology ; Cell Aggregation/*physiology ; Cell Death/*physiology ; Fluorescent Antibody Technique/methods ; Free Radical Scavengers/pharmacology ; Green Fluorescent Proteins ; HeLa Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Immunoblotting/methods ; Luminescent Proteins/metabolism ; Mutation ; Nerve Tissue Proteins/biosynthesis/genetics/*physiology ; Nuclear Proteins/biosynthesis/genetics/*physiology ; Oxidants/pharmacology ; Oxidative Stress/drug effects/*physiology ; Peptides/immunology/*metabolism ; Radiation-Protective Agents/pharmacology ; Rats ; Time Factors ; Transfection ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {Spinocerebellar ataxia 1 (SCA1), one of the inherited polyglutamine neurodegenerative diseases, is associated with intracellular aggregates. However, the process of aggregate formation and the factors that influence aggregation remain unclear. Here, we show that oxidative stimuli and alteration of the cellular redox state significantly affect aggregation and cell death in cells expressing mutant ataxin-1, the SCA gene product. Treatment of cells with buthionine sulfoximine, hydrogen peroxide or t-butylhydroperoxide increased the formation of mutant ataxin-1 aggregates, but treatment with the anti-oxidant, N-acetylcysteine (NAC), decreased aggregate formation. Oxidative damage of mutant ataxin-1 protein increased its recruitment in nuclear aggregates and increased cell death. However, NAC treatments reduced cell death and the number of cells with abnormal morphology. Our results might give insight into the mechanism whereby polyglutamine proteins aggregate and suggest that treatment of appropriate antioxidant reagents might prevent progression of SCA1 and other polyglutamine diseases.}, }
@article {pmid12888907, year = {2003}, author = {Hou, DX and Ose, T and Lin, S and Harazoro, K and Imamura, I and Kubo, M and Uto, T and Terahara, N and Yoshimoto, M and Fujii, M}, title = {Anthocyanidins induce apoptosis in human promyelocytic leukemia cells: structure-activity relationship and mechanisms involved.}, journal = {International journal of oncology}, volume = {23}, number = {3}, pages = {705-712}, pmid = {12888907}, issn = {1019-6439}, mesh = {Acetylcysteine/pharmacology ; Anthocyanins/chemistry/*pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Blotting, Western ; Caspase 3 ; Caspases/metabolism ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Electrophoresis, Polyacrylamide Gel ; Enzyme Activation ; HL-60 Cells ; Humans ; Hydrogen Peroxide/metabolism ; Leukemia, Promyelocytic, Acute/*pathology ; Models, Chemical ; Oxidative Stress ; Phosphorylation ; Proto-Oncogene Proteins c-jun/metabolism ; RNA/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Structure-Activity Relationship ; Time Factors ; }, abstract = {Anthocyanidins are the aglycon nucleuses of anthocyanins, which are reddish pigments widely spread in colored fruits and vegetables. To investigate their anti-cancer effect, induction of apoptosis was tested in human promyelocytic leukemia cells (HL-60), which is a valid model for testing antileukemic or general antitumoral compounds. Of six anthocyanidins representing the aglycons of most of anthocyanins, only those with an ortho-dihydroxyphenyl structure on the B-ring induce apoptosis, suggesting that the ortho-dihydroxyphenyl structure of anthocyanidins may contribute to the induction of apoptosis. Delphinidin, the most potent inducer, causes apoptosis in a time- and dose-dependent manner. The efficacious induction of apoptosis was observed at 100 micro M for 6 h. Concomitant with the apoptosis, delphinidin stimulates JNK pathway activation including JNK phosphorylation and c-jun gene expression, and activates caspase-3. Antioxidants including N-acetyl-L-cysteine (NAC) and catalase effectively block delphinidin-induced JNK phosphorylation, caspase-3 activation, and DNA fragmentation. Moreover, anthocyanidins directly cause HL-60 cells to generate intracellular hydrogen peroxide. Thus, anthocyanidins may trigger an apoptotic death program through an oxidative stress-involved JNK signaling pathway. The induction of apoptosis by anthocyanins may be the pivotal mechanism by which its chemopreventive action against cancer is based.}, }
@article {pmid12888577, year = {2003}, author = {Saito, Y and Yoshida, Y and Akazawa, T and Takahashi, K and Niki, E}, title = {Cell death caused by selenium deficiency and protective effect of antioxidants.}, journal = {The Journal of biological chemistry}, volume = {278}, number = {41}, pages = {39428-39434}, doi = {10.1074/jbc.M305542200}, pmid = {12888577}, issn = {0021-9258}, mesh = {Antioxidants/*pharmacology ; Cell Death/*drug effects ; Cell Survival/drug effects ; Glutathione Peroxidase/metabolism ; Humans ; Jurkat Cells ; Lipid Peroxides/metabolism ; Proteins/metabolism ; Reactive Oxygen Species/metabolism ; Selenium/*deficiency/metabolism/pharmacology ; Selenoproteins ; Thioredoxin-Disulfide Reductase/metabolism ; Vitamin E/pharmacology ; }, abstract = {Selenium is an essential trace element and it is well known that selenium is necessary for cell culture. However, the mechanism underlying the role of selenium in cellular proliferation and survival is still unknown. The present study using Jurkat cells showed that selenium deficiency in a serum-free medium decreased the selenium-dependent enzyme activity (glutathione peroxidases and thioredoxin reductase) within cells and cell viability. To understand the mechanism of this effect of selenium, we examined the effect of other antioxidants, which act by different mechanisms. Vitamin E, a lipid-soluble radical-scavenging antioxidant, completely blocked selenium deficiency-induced cell death, although alpha-tocopherol (biologically the most active form of vitamin E) could not preserve selenium-dependent enzyme activity. Other antioxidants, such as different isoforms and derivatives of vitamin E, BO-653 and deferoxamine mesylate, also exerted an inhibitory effect. However, the water-soluble antioxidants, such as ascorbic acid, N-acetyl cysteine, and glutathione, displayed no such effect. Dichlorodihydrofluorescein (DCF) assay revealed that cellular reactive oxygen species (ROS) increased before cell death, and sodium selenite and alpha-tocopherol inhibited ROS increase in a dose-dependent manner. The generation of lipid hydroperoxides was observed by fluorescence probe diphenyl-1-pyrenylphosphine (DPPP) and HPLC chemiluminescence only in selenium-deficient cells. These results suggest that the ROS, especially lipid hydroperoxides, are involved in the cell death caused by selenium deficiency and that selenium and vitamin E cooperate in the defense against oxidative stress upon cells by detoxifying and inhibiting the formation of lipid hydroperoxides.}, }
@article {pmid12883092, year = {2003}, author = {James, LP and McCullough, SS and Lamps, LW and Hinson, JA}, title = {Effect of N-acetylcysteine on acetaminophen toxicity in mice: relationship to reactive nitrogen and cytokine formation.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {75}, number = {2}, pages = {458-467}, doi = {10.1093/toxsci/kfg181}, pmid = {12883092}, issn = {1096-6080}, support = {DK02971/DK/NIDDK NIH HHS/United States ; GM 58884/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/administration &amp; dosage/*toxicity ; Animals ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury ; Chemokines/*metabolism ; Drug Interactions ; Immunoenzyme Techniques ; Injections, Intraperitoneal ; Liver/drug effects/metabolism/pathology ; Liver Diseases/metabolism/*prevention &amp; control ; Male ; Mice ; Mice, Inbred Strains ; Necrosis ; Nitric Oxide/metabolism ; *Reactive Nitrogen Species ; Up-Regulation/drug effects ; }, abstract = {The relationship between acetaminophen (APAP) reactive metabolite formation, nitrotyrosine (NT) production, and cytokine elevation in APAP toxicity was investigated. Mice were dosed with 300 mg/kg of APAP and sacrificed at 1, 2, 4, 8, and 12 h. Serum aspartate aminotransferase (AST) was elevated by 4 h. The relative amount of NT correlated with toxicity and was localized in the necrotic cells. IL-1b was increased at 1 h, whereas IL-6, MIP-2, and MCP-1 were increased by 4-8 h. To determine the importance of reversible versus toxic events, N-acetylcysteine (NAC) was administered to mice either before APAP or 1, 2, or 4 h after APAP. The animals were sacrificed at 12 h. NAC treatment before APAP resulted in serum AST, serum nitrate plus nitrite as a measure of nitric oxide (NO) production, and hepatic cytokine levels that were similar to the controls. No APAP protein adducts or NT was present in these animals. In mice treated with NAC at 1 h, cytokines and serum AST were normal at 12 h, but APAP protein adducts were present in the hepatic centrilobular areas. No NT was present in these animals. In mice treated with NAC at 2 h and sacrificed at 12 h, serum AST was reduced by 80%. APAP adducts and NT were present in the centrilobular areas. Mice receiving NAC at 4 h had no protection from toxicity and serum nitrate plus nitrite. The NT and cytokine levels were similar to those of mice receiving APAP alone. The data suggest a relationship between metabolic events in APAP toxicity and the upregulation of NO, and IL-1b. IL-6, MIP-2, and MCP-1 appear to follow the toxicity. While it is a pre-requisite event, covalent binding per se does not appear to be a toxic event in the development of toxicity.}, }
@article {pmid12883035, year = {2003}, author = {Yacoub, A and Mitchell, C and Brannon, J and Rosenberg, E and Qiao, L and McKinstry, R and Linehan, WM and Su, ZS and Sarkar, D and Lebedeva, IV and Valerie, K and Gopalkrishnan, RV and Grant, S and Fisher, PB and Dent, P}, title = {MDA-7 (interleukin-24) inhibits the proliferation of renal carcinoma cells and interacts with free radicals to promote cell death and loss of reproductive capacity.}, journal = {Molecular cancer therapeutics}, volume = {2}, number = {7}, pages = {623-632}, pmid = {12883035}, issn = {1535-7163}, support = {CA97318/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenoviridae/genetics ; Adjuvants, Immunologic/*pharmacology ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/pharmacology ; Brain Neoplasms/drug therapy/metabolism/pathology ; Carcinoma, Renal Cell/*drug therapy/metabolism/pathology ; Caspases/metabolism ; Cell Division/drug effects ; Free Radical Scavengers/pharmacology ; Free Radicals/*metabolism ; Genes, Tumor Suppressor ; Glioma/drug therapy/metabolism/pathology ; Glutathione Transferase/metabolism ; Humans ; Interleukins/*pharmacology ; Kidney/drug effects/metabolism ; Kidney Neoplasms/*drug therapy/metabolism/pathology ; Oxides/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Receptors, Virus/metabolism ; Recombinant Fusion Proteins/metabolism ; Tumor Cells, Cultured ; bcl-X Protein ; }, abstract = {The median survival of metastatic renal cell carcinoma (RCC) is 12 months, and the majority of treatment options are palliative. MDA-7 (interleukin-24), when expressed via a recombinant replication defective adenovirus, Ad.mda-7, has profound antiproliferative and cytotoxic effects in a wide variety of tumor cells but not in nontransformed cells. The studies in this study examined the impact of MDA-7 on RCC proliferation and survival. RCC lines (A498 and UOK121N), but not primary renal epithelial cells, were resistant to adenoviral infection that correlated with a lack of coxsackievirus and adenovirus receptor expression. Additional studies were performed using purified preparations of bacterially synthesized glutathione S-transferase (GST)-MDA-7 protein. GST-MDA-7, but not GST, caused a dose-dependent inhibition of RCC proliferation but not of primary renal epithelial cells. Clinically achievable concentrations of the novel therapeutic agent arsenic trioxide (0.5-1 micro M) were found to have little effect on RCC growth. However, the combination of GST-MDA-7 and arsenic trioxide resulted in a greater than additive reduction in cell growth that correlated with a large increase in tumor cell death. The free radical scavenger N-acetyl cysteine abolished the potentiating effect of arsenic trioxide. Although pro-caspase 3, poly(ADP-ribose) polymerase, and Bcl-(XL) levels, as well as nucleosomal DNA integrity, were reduced by combined treatment, cell killing was predominantly nonapoptotic. Combined treatment of RCC lines with GST-MDA-7 and arsenic trioxide also resulted in a substantial reduction in clonogenic survival compared with either treatment individually. Collectively, these findings demonstrate that MDA-7 protein, in combination with agents that generate free radicals, may have potential in the treatment of RCC.}, }
@article {pmid12882931, year = {2003}, author = {Maingrette, F and Renier, G}, title = {Leptin increases lipoprotein lipase secretion by macrophages: involvement of oxidative stress and protein kinase C.}, journal = {Diabetes}, volume = {52}, number = {8}, pages = {2121-2128}, doi = {10.2337/diabetes.52.8.2121}, pmid = {12882931}, issn = {0012-1797}, mesh = {Animals ; Arteriosclerosis/immunology/metabolism ; Diabetes Mellitus, Type 2/immunology/metabolism ; Diabetic Angiopathies/immunology/metabolism ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Leptin/*pharmacology ; Lipoprotein Lipase/genetics/*metabolism ; Macrophages/cytology/*enzymology/metabolism ; Mice ; Monocytes/cytology ; Nuclear Proteins/metabolism ; Oxidative Stress/*physiology ; Promoter Regions, Genetic/physiology ; Protein Kinase C/*metabolism ; RNA, Messenger/analysis ; Receptors, Cell Surface/metabolism ; Receptors, Leptin ; Transcription Factor AP-1/metabolism ; Tumor Cells, Cultured ; }, abstract = {Recent data suggest that plasma leptin may represent a cardiovascular risk factor in diabetic patients. To gain further insight into the role of leptin in atherogenesis associated with diabetes, we investigated in the present study the role of this hormone in the regulation of macrophage lipoprotein lipase (LPL), a proatherogenic cytokine overexpressed in patients with type 2 diabetes. Treatment of human macrophages with leptin (1-10 nmol/l) increased LPL expression, at both the mRNA and protein levels. Pretreatment of these cells with anti-leptin receptor (Ob-R) antibody, protein kinase C (PKC) inhibitors, calphostin C, and GF109203X, or the antioxidant N-acetylcysteine (NAC) blocked the effects of leptin. Similar results were observed in leptin-treated J774 macrophages. In these cells, leptin increased the membrane expression of conventional PKC isoforms and downregulation of endogenous PKC expression abolished the effects of leptin on macrophage LPL expression. In leptin-treated J774 cells, enhanced LPL synthetic rate and increased binding of nuclear proteins to the activated protein-1 (AP-1) consensus sequence of the LPL gene promoter were also observed. This latter effect was abrogated by GF109203X. Overall, these data demonstrate that binding of leptin at the macrophage cell surface increases, through oxidative stress- and PKC-dependent pathways, LPL expression. This effect appears to be exerted at the transcriptional level and to involve AP-1 activation.}, }
@article {pmid12882449, year = {2003}, author = {Wuyts, WA and Vanaudenaerde, BM and Dupont, LJ and Demedts, MG and Verleden, GM}, title = {N-acetylcysteine reduces chemokine release via inhibition of p38 MAPK in human airway smooth muscle cells.}, journal = {The European respiratory journal}, volume = {22}, number = {1}, pages = {43-49}, doi = {10.1183/09031936.03.00064803}, pmid = {12882449}, issn = {0903-1936}, mesh = {Acetylcysteine/*pharmacology ; Asthma/enzymology/*immunology ; Blotting, Northern ; Cells, Cultured ; Chemokine CCL11 ; Chemokine CCL2/metabolism ; Chemokines/*metabolism ; Chemokines, CC/antagonists &amp; inhibitors/metabolism ; *Dinoprost/*analogs &amp; derivatives ; Enzyme Activation ; Enzyme-Linked Immunosorbent Assay ; F2-Isoprostanes/metabolism ; Humans ; Interleukin-1/*pharmacology ; *JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase Kinases ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Muscle, Smooth/*drug effects/enzymology/immunology ; Signal Transduction ; Statistics, Nonparametric ; Stimulation, Chemical ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Reactive oxygen species are involved in the activation of several mitogen-activated protein kinases (MAPKs), key-players in the production of several cytokines. Therefore the current study investigated whether N-acetylcysteine (NAC), an antioxidative agent, inhibits the interleukin (IL)-1beta-induced expression and production of eotaxin and monocyte chemotactic protein (MCP)-1 in human airway smooth muscle cells (HASMC). NAC (10 mM) decreased the expression of eotaxin and MCP-1, by 46 +/- 11% (n=7) and 87 +/- 4% (n=6), respectively; the eotaxin release was inhibited by 75 +/- 5% (n=7), whereas the MCP-1 release was decreased by 69 +/- 41% (n=10). NAC (1 mM) also decreased the IL-1beta-induced activation of p38 MAPK. Compared with unstimulated cells, a four-fold increase in 8-isoprostane production in IL-1beta-stimulated HASMC was observed, which could be inhibited by NAC in a concentration-dependent way, with a maximum inhibition of 39 +/- 12%, with 1 mM NAC. The present study demonstrated that N-acetylcysteine inhibits the interleukin-1beta-induced eotaxin and monocyte chemotactic protein 1 expression and production due to a decreased activation of p38 mitogen-activated protein kinase. This study has also shown that N-acetylcysteine decreases the interleukin-1beta-induced production of reactive oxygen species, as suggested by a reduction in the 8-isoprostane production.}, }
@article {pmid12881702, year = {2003}, author = {Kurosu, T and Fukuda, T and Miki, T and Miura, O}, title = {BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells.}, journal = {Oncogene}, volume = {22}, number = {29}, pages = {4459-4468}, doi = {10.1038/sj.onc.1206755}, pmid = {12881702}, issn = {0950-9232}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects/physiology ; Cysteine Endopeptidases/drug effects/metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; DNA-Binding Proteins/drug effects/*genetics/metabolism ; Doxycycline/pharmacology ; Etoposide/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Leupeptins/pharmacology ; Lymphoma, B-Cell/*drug therapy/genetics/*pathology ; Membrane Potentials/drug effects ; Mitochondria/drug effects ; Multienzyme Complexes/antagonists &amp; inhibitors/drug effects/metabolism ; Mutation ; Proteasome Endopeptidase Complex ; Proto-Oncogene Proteins/drug effects/*genetics/metabolism ; Proto-Oncogene Proteins c-bcl-6 ; Reactive Oxygen Species/*metabolism ; Transcription Factors/drug effects/*genetics/metabolism ; Tumor Cells, Cultured ; }, abstract = {Chromosomal translocations and somatic mutations occurring in the 5' noncoding region of the BCL6 gene, encoding a transcriptional repressor, are most frequent genetic abnormalities associated with non-Hodgkin B-cell lymphoma and result in deregulated expression of BCL6. However, the significance of deregulated expression of BCL6 in lymphomagenesis and its effect on clinical outcomes of lymphoma patients have remained elusive. In the present study, we established Daudi and Raji B-cell lymphoma cell lines that overexpress BCL6 or its mutant, BCL6-Ala333/343, in which serine residues required for degradation through the proteasome pathway in B-cell receptor-stimulated cells are mutated. BCL6 overexpression did not have any significant effect on cell proliferation, but significantly inhibited apoptosis caused by etoposide, which induced a proteasome-dependent degradation of BCL6. BCL6-Ala333/343 was not degraded after etoposide treatment and strongly inhibited apoptosis. In these lymphoma cell lines, etoposide increased the generation of reactive oxygen species (ROS) and reduced mitochondria membrane potential, both of which were inhibited by the antioxidant N-acetyl-L-cysteine (NAC). NAC also inhibited apoptosis. Furthermore, BCL6 overexpression was found to inhibit the increase in ROS levels and apoptosis in response to etoposide and other chemotherapeutic reagents. These results raise the possibility that deregulated expression of BCL6 may endow lymphoma cells with resistance to chemotherapeutic reagents, most likely by enhancing the antioxidant defense systems.}, }
@article {pmid12877907, year = {2003}, author = {Anfossi, G and Russo, I and Massucco, P and Mattiello, L and Trovati, M}, title = {Platelet resistance to the antiaggregating effect of N-acetyl-L-cysteine in obese, insulin-resistant subjects.}, journal = {Thrombosis research}, volume = {110}, number = {1}, pages = {39-46}, doi = {10.1016/s0049-3848(03)00284-6}, pmid = {12877907}, issn = {0049-3848}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Diphosphate/pharmacology ; Adult ; Amifostine/pharmacology ; Antioxidants/pharmacology ; Collagen/pharmacology ; Cyclic GMP/biosynthesis/blood ; Drug Resistance ; Female ; Free Radical Scavengers/pharmacology ; Humans ; *Insulin Resistance ; Male ; Nitric Oxide/blood ; Nitric Oxide Donors/pharmacology ; Nitroglycerin/pharmacology ; Nitroprusside/pharmacology ; Obesity/*blood ; Platelet Aggregation/*drug effects ; Platelet Aggregation Inhibitors/*pharmacology ; Superoxide Dismutase/pharmacology ; }, abstract = {INTRODUCTION: We investigated whether the platelets from obese subjects are sensitive as those from controls to the antiaggregating effects of N-acetyl-L-cysteine (NAC)-an antioxidant thiol that increases availability of endogenous nitric oxide (NO)-and of superoxide dismutase (SOD) and amifostine which act as scavengers of superoxide anion.<br><br>MATERIALS AND METHODS: In platelets from obese subjects (n=20, body mass index [BMI]=34.2+/-1.9 kg/m(2), homeostasis model assessment [HOMA] index=5.5+/-1.1) and controls (n=20, BMI=21.4+/-0.6 kg/m(2), HOMA index=1.4+/-0.2), we investigated the effects of NAC on aggregation and on 3',5'-cyclic guanosine monophosphate (cGMP) synthesis and the interplay between NAC and the organic nitrates glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). Similar experiments were carried out with SOD and amifostine.<br><br>RESULTS: We found that a 3-min platelet exposure to NAC decreased aggregation and increased cGMP in controls, but not in obese subjects. Only more prolonged incubations exerted a small effect also in obese subjects. GTN and SNP increased platelet cGMP in both groups, but their effect was much lower in obese subjects. NAC (3 mmol/l), SOD (150 U/ml), and amifostine (50 micromol/l) enhanced the increase of cGMP elicited by NO donors, but again, the effect was much lower in obese subjects.<br><br>CONCLUSIONS: Since antioxidants do not restore the effects of NO in platelets from obese subjects, we hypothesize that oxidative stress is not the unique cause of platelet resistance to NO in obesity and suggest that a resistance to the NO action at the guanylate cyclase level could play a role in this phenomenon, potentially involved in the increased atherothrombotic risk linked to obesity.}, }
@article {pmid12877656, year = {2003}, author = {Phillips, DC and Griffiths, HR}, title = {Ceramide induces a loss in cytosolic peroxide levels in mononuclear cells.}, journal = {The Biochemical journal}, volume = {375}, number = {Pt 3}, pages = {567-579}, pmid = {12877656}, issn = {1470-8728}, mesh = {Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Line, Tumor ; Ceramides/metabolism/*pharmacology ; Cytosol/drug effects/metabolism ; DNA Fragmentation/drug effects ; Dose-Response Relationship, Drug ; Fas Ligand Protein ; Glutathione/metabolism ; Humans ; Immunophenotyping ; Jurkat Cells ; Leukocytes, Mononuclear/*drug effects/immunology/metabolism ; Membrane Glycoproteins/pharmacology ; Peroxides/*metabolism ; U937 Cells ; }, abstract = {Ceramide (a sphingolipid) and reactive oxygen species are each partly responsible for intracellular signal transduction in response to a variety of agents. It has been reported that ceramide and reactive oxygen species are intimately linked and show reciprocal regulation [Liu, Andreieu-Abadie, Levade, Zhang, Obeid and Hannun (1998) J. Biol. Chem. 273, 11313-11320]. Utilizing synthetic, short-chain ceramide to mimic the cellular responses to fluctuations in natural endogenous ceramide formation or using stimulation of CD95 to induce ceramide formation, we found that the principal redox-altering property of ceramide is to lower the [peroxide](cyt) (cytosolic peroxide concentration). Apoptosis of Jurkat T-cells, primary resting and phytohaemagglutinin-activated human peripheral blood T-lymphocytes was preceded by a loss in [peroxide](cyt), as measured by the peroxide-sensitive probe 2',7'-dichlorofluorescein diacetate (also reflected in a lower rate of superoxide dismutase-inhibitable cytochrome c reduction), and this was not associated with a loss of membrane integrity. Where growth arrest of U937 monocytes was observed without a loss of membrane integrity, the decrease in [peroxide](cyt) was of a lower magnitude when compared with that preceding the onset of apoptosis in T-cells. Furthermore, decreasing the cytosolic peroxide level in U937 monocytes before the application of synthetic ceramide by pretreatment with either of the antioxidants N -acetyl cysteine or glutathione conferred apoptosis. However, N -acetyl cysteine or glutathione did not affect the kinetics or magnitude of ceramide-induced apoptosis of Jurkat T-cells. Therefore the primary redox effect of cellular ceramide accumulation is to lower the [peroxide](cyt) of both primary and immortalized cells, the magnitude of which dictates the cellular response.}, }
@article {pmid12874837, year = {2003}, author = {Shen, SC and Chen, YC and Hsu, FL and Lee, WR}, title = {Differential apoptosis-inducing effect of quercetin and its glycosides in human promyeloleukemic HL-60 cells by alternative activation of the caspase 3 cascade.}, journal = {Journal of cellular biochemistry}, volume = {89}, number = {5}, pages = {1044-1055}, doi = {10.1002/jcb.10559}, pmid = {12874837}, issn = {0730-2312}, mesh = {Apoptosis/*drug effects ; Caspase 1/metabolism ; Caspase 3 ; Caspase Inhibitors ; Caspases/*metabolism ; Cell Survival/drug effects ; Chromosomes/drug effects/ultrastructure ; DNA/analysis/drug effects ; Diploidy ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Glycosides/chemistry/*pharmacology ; HL-60 Cells ; Humans ; Leukemia, Myeloid/*metabolism ; Monocytes/cytology/drug effects ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins/analysis ; Peroxides/analysis ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/analysis ; Quercetin/*analogs &amp; derivatives/*pharmacology ; }, abstract = {Flavonoids were demonstrated to possess several biological effects including antitumor, antioxidant, and anti-inflammatory activities in our previous studies. However, the effect of glycosylation on their biological functions is still undefined. In the present study, the apoptosis-inducing activities of three structure-related flavonoids including aglycone quercetin (QUE), and glycone rutin (RUT; QUE-3-O-rutinoside), and glycone quercitrin (QUI; QUE-3-O-rhamnoside) were studied. Both RUT and QUI are QUE glycosides, and possess rutinose and rhamnose at the C3 position of QUE, respectively. Results of the MTT assay showed that QUE, but not RUT and QUI, exhibits significant cytotoxic effect on HL-60 cells, accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including an increase in DNA ladder intensity, morphological changes, apoptotic bodies, and an increase in hypodiploid cells by flow cytometry analysis. QUE, but not RUT or QUI, caused rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity, according to cleavage of caspase 3 substrates poly(ADP-ribose) polymerase (PARP) and D4-GDI proteins, and the appearance of cleaved caspase 3 fragments being detected in QUE- but not RUT- or QUI-treated HL-60 cells. A decrease in the anti-apoptotic protein, Mcl-1, was detected in QUE-treated HL-60 cells, whereas other Bcl-2 family proteins including Bax, Bcl-2, Bcl-XL, and Bag remained unchanged. The caspase 3 inhibitor, Ac-DEVD-FMK, but not the caspase 1 inhibitor, Ac-YVAD-FMK, attenuated QUE-induced cell death. Results of DCHF-DA assay indicate that no significant increase in intracellular peroxide level was found in QUE-treated cells, and QUE inhibited the H(2)O(2)-induced intracellular peroxide level. Free radical scavengers N-acetyl-cysteine (NAC) and catalase showed no prevention of QUE-induced apoptosis. In addition, QUE did not induce apoptosis in an mature monocytic cell line THP-1, as characterized by a lack of DNA ladders, caspase 3 activation, PARP cleavage, and an Mcl-1 decrease, compared with those in HL-60 cells. Our experiments provide evidence to indicate that the addition of rutinose or rhamnose attenuates the apoptosis-inducing activity of QUE, and that the caspase 3 cascade but not free radical production is involved.}, }
@article {pmid12874275, year = {2003}, author = {Abdelmohsen, K and Gerber, PA and von Montfort, C and Sies, H and Klotz, LO}, title = {Epidermal growth factor receptor is a common mediator of quinone-induced signaling leading to phosphorylation of connexin-43: role of glutathione and tyrosine phosphatases.}, journal = {The Journal of biological chemistry}, volume = {278}, number = {40}, pages = {38360-38367}, doi = {10.1074/jbc.M306785200}, pmid = {12874275}, issn = {0021-9258}, mesh = {Animals ; Benzoquinones/*pharmacology ; Blotting, Western ; Cell Line ; Connexin 43/*metabolism ; Dose-Response Relationship, Drug ; Epithelial Cells/cytology ; ErbB Receptors/*physiology ; Gap Junctions ; Glutathione/metabolism ; HeLa Cells ; Humans ; Immunohistochemistry ; Indicators and Reagents/pharmacology ; Liver/cytology ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Models, Biological ; Naphthoquinones/pharmacology ; Oxidation-Reduction ; *Phosphorylation ; Precipitin Tests ; Rats ; *Signal Transduction ; Time Factors ; Ultraviolet Rays ; Vitamin K 3/pharmacology ; }, abstract = {Rat liver epithelial cells were exposed to three quinones with different properties: menadione (2-methyl-1,4-naphthoquinone, vitamin K3), an alkylating as well as redox-cycling quinone, the strongly alkylating p-benzoquinone (BQ), and the non-arylating redox-cycler, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). All three quinones induced the activation of extracellular signal-regulated kinase (ERK) 1 and ERK 2 via the activation of epidermal growth factor receptor (EGFR) and MAPK/ERK kinases (MEK) 1/2. ERK activation resulted in phosphorylation at Ser-279 and Ser-282 of the gap junctional protein, connexin-43, known to result in the loss of gap junctional intercellular communication. Another EGFR-dependent pathway was stimulated, leading to the activation of the antiapoptotic kinase Akt via phosphoinositide 3-kinase. The activation of EGFR-dependent signaling by these quinones was by different mechanisms: (i) menadione, but not BQ or DMNQ, inhibited a protein-tyrosine phosphatase regulating the EGFR, as concluded from an EGFR dephosphorylation assay; (ii) although menadione-induced activation of ERK was unimpaired by pretreatment of cells with N-acetyl cysteine, activation by BQ and DMNQ was prevented; (iii) cellular glutathione (GSH) levels were strongly depleted by BQ. The mere depletion of GSH by application of diethyl maleate EGFR-dependently activated ERK and Akt, thus mimicking BQ effects. GSH levels were only moderately decreased by menadione and not affected by DMNQ. In summary, EGFR-dependent signaling was mediated by protein-tyrosine phosphatase inactivation (menadione), GSH depletion (BQ), and redox-cycling (DMNQ), funneling into the same signaling pathway.}, }
@article {pmid12870650, year = {2003}, author = {Kang, JL and Lee, HS and Pack, IS and Hur, KC and Castranova, V}, title = {Phosphoinositide 3-kinase activity leads to silica-induced NF-kappaB activation through interacting with tyrosine-phosphorylated I(kappa)B-alpha and contributing to tyrosine phosphorylation of p65 NF-kappaB.}, journal = {Molecular and cellular biochemistry}, volume = {248}, number = {1-2}, pages = {17-24}, pmid = {12870650}, issn = {0300-8177}, mesh = {Acetylcysteine/chemistry ; Androstadienes/pharmacology ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Cell Line ; Cell Nucleus/metabolism ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation, Enzymologic ; I-kappa B Proteins/*metabolism ; Lipopolysaccharides/pharmacology ; Mice ; Models, Biological ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation ; Precipitin Tests ; Protein Binding ; Pyrrolidines/pharmacology ; Reactive Oxygen Species ; Silicon Dioxide/*pharmacology ; Superoxide Dismutase/metabolism ; Thiocarbamates/pharmacology ; Time Factors ; Tyrosine/metabolism ; Wortmannin ; eIF-2 Kinase/*metabolism ; }, abstract = {The role of the subunits of phosphoinositide (PI) 3-kinase in NF-kappaB activation in silica-stimulated RAW 264.7 cells was investigated. Results indicate that PI3-kinase activity was increased in response to silica. The p85alpha subunit of PI3-kinase interacted with tyrosine-phosphorylated I(kappa)B-alpha in silica-stimulated cells. PI3-kinase specific inhibitors, such as wortmannin and LY294003, substantially blocked both silica-induced PI3-kinase and NF-kappaB activation. The inhibition of NF-KB activation by PI3-kinase inhibitors was also observed in pervanadate-stimulated but not in LPS-stimulated cells. Furthermore, tyrosine phosphorylation of NF-kappaB p65 was enhanced in cells stimulated with silica, pervanadate or LPS, and wortmannin substantially inhibited the phosphorylation event induced by the first two stimulants but not LPS. Antioxidants, such as superoxide dismutase (SOD), N-acetylcysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), blocked silica-induced PI3-kinase activation, suggesting that reactive oxygen species may be important regulatory molecules in NF-kappaB activation by mediating PI3-kinase activation. Our data suggest that p85 and p110 subunits of PI3-kinase play a role in NF-kappaB activation through interaction with tyrosine-phosphorylated I(kappa)B-alpha and contributing to tyrosine phosphorylation of p65 NF-kappaB.}, }
@article {pmid12860993, year = {2003}, author = {Rocic, P and Seshiah, P and Griendling, KK}, title = {Reactive oxygen species sensitivity of angiotensin II-dependent translation initiation in vascular smooth muscle cells.}, journal = {The Journal of biological chemistry}, volume = {278}, number = {38}, pages = {36973-36979}, doi = {10.1074/jbc.M302099200}, pmid = {12860993}, issn = {0021-9258}, support = {HL38206/HL/NHLBI NIH HHS/United States ; HL58000/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/*metabolism ; Animals ; Aorta/cytology ; Azoles/pharmacology ; Blotting, Western ; Carrier Proteins/metabolism ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Eukaryotic Initiation Factor-4E/*metabolism ; Genes, Dominant ; Imidazoles/pharmacology ; Intracellular Signaling Peptides and Proteins ; Isoindoles ; Muscle, Smooth, Vascular/*cytology ; Okadaic Acid/pharmacology ; Onium Compounds/pharmacology ; Organoselenium Compounds/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoprotein Phosphatases/metabolism ; Phosphoproteins/metabolism ; Phosphorylation ; *Protein Biosynthesis ; Protein Phosphatase 2 ; Pyridines/pharmacology ; Rats ; *Reactive Oxygen Species ; Serine/chemistry ; Threonine/chemistry ; Time Factors ; }, abstract = {Translation initiation, the rate-limiting step in protein synthesis, is a key event in vascular smooth muscle cell growth, a major component of vascular disease. Translation initiation is regulated by interaction between PHAS-I and the eukaryotic initiation factor 4E (eIF4E). Although angiotensin II (Ang II)-induced vascular smooth muscle cell hypertrophy requires the generation of reactive oxygen species (ROS), the ROS sensitivity of these events and their upstream activators remain unclear. Here, we investigated the role of ROS in the regulation of PHAS-I phosphorylation on Thr-70 and Ser-65, an event required for the release of eIF4E from PHAS-I. Ang II-induced Ser-65 phosphorylation was ROS-dependent as assessed by pretreatment with ebselen (3.6 +/- 0.2 versus 1.1 +/- 0.2), diphenylene iodonium (3.6 +/- 0.2 versus 1.0 +/- 0.1), and N-acetyl cysteine (3.6 +/- 0.2 versus 1.2 +/- 0.1), but Ang II-stimulated phosphorylation of Thr-70 was ROS-insensitive. Although phosphatidylinositol 3-kinase pathway inhibition by LY294004 blocked both Ser-65 and Thr-70 phosphorylation (3.8 +/- 0.1 versus 0.8 +/- 0.1 and 3.2 +/- 0.2 versus 1.0 +/- 0.01, respectively), protein phosphatase 2A inhibition by okadaic acid selectively increased (3.3 +/- 0.1 versus 5.2 +/- 0.1) and p38 mitogen-activated protein kinase inhibition by SB203580 selectively decreased (3.8 +/- 0.1 versus 1.4 +/- 0.3) Ser-65 phosphorylation. Dominant negative Akt adenovirus also inhibited only Ser-65 phosphorylation (3.7 +/- 0.1 versus 1.0 +/- 0.03). These results demonstrate a unique differential ROS sensitivity of two separate residues on PHAS-I, which seems to be explained by the selective involvement of distinct signaling pathways in the regulation of these phosphorylation events.}, }
@article {pmid12850468, year = {2003}, author = {Koksal, C and Bozkurt, AK and Cangel, U and Ustundag, N and Konukoglu, D and Musellim, B and Sayin, AG}, title = {Attenuation of ischemia/reperfusion injury by N-acetylcysteine in a rat hind limb model.}, journal = {The Journal of surgical research}, volume = {111}, number = {2}, pages = {236-239}, doi = {10.1016/s0022-4804(03)00094-5}, pmid = {12850468}, issn = {0022-4804}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bicarbonates/blood ; Constriction ; Creatine Kinase/blood ; Dimethyl Sulfoxide/therapeutic use ; Disease Models, Animal ; Free Radical Scavengers/*therapeutic use ; Hindlimb/blood supply ; L-Lactate Dehydrogenase/blood ; Male ; Muscle, Skeletal/chemistry ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*drug therapy ; Thiobarbituric Acid Reactive Substances/analysis ; }, abstract = {BACKGROUND: Ischemia/reperfusion is a complex set of events with severe pathologic consequences. Reperfusion initiates both the local and systemic damage in part through rapid oxygen generation. N-acetylcysteine (NAC) is a scavenger of free radical species, inhibits neutrophil accumulation, acts as a vasodilator and also improves microcirculation. In present study, we examined the protective effect of NAC in a rat hind limb ischemia/ reperfusion model. Dimethyl-sulfoxide (DMSO), a well-known antioxidant was also tested for comparison.<br><br>MATERIALS AND METHODS: Ischemia was induced for 4 h by vascular clamping and followed by 1 h of reperfusion. Muscle injury was evaluated in 3 groups as a saline group (control), DMSO group, and NAC group. Plasma levels of creatine kinase, lactate dehydrogenase, thiobarbituric acid reactive substances (TBARS), and blood HCO(3), as well as muscle tissue TBARS, were measured at the end of reperfusion. Muscle tissue samples were taken for histological evaluation.<br><br>RESULTS: DMSO and NAC group showed significant amelioration of plasma CPK (P < 0.05, P < 0.05), plasma TBARS (P < 0.05, P < 0.05), and muscle tissue TBARS (P < 0.05, P < 0.05) compared with the control group. Similarly, neutrophil infiltration in DMSO and NAC groups were significantly less prominent than the control group (P < 0.01, P < 0.01).<br><br>CONCLUSIONS: These results show that NAC improved effectively ischemia reperfusion injury in a rat hind limb model.}, }
@article {pmid12850392, year = {2003}, author = {Girouard, H and Chulak, C and Wu, L and Lejossec, M and de Champlain, J}, title = {N-acetylcysteine improves nitric oxide and alpha-adrenergic pathways in mesenteric beds of spontaneously hypertensive rats.}, journal = {American journal of hypertension}, volume = {16}, number = {7}, pages = {577-584}, doi = {10.1016/s0895-7061(03)00863-x}, pmid = {12850392}, issn = {0895-7061}, mesh = {Acetylcysteine/*pharmacology ; Adrenergic Fibers/*drug effects/physiology ; Animals ; Hemodynamics/drug effects/physiology ; Hypertension/physiopathology ; Mesenteric Arteries/*drug effects/physiology ; Nitric Oxide/*physiology ; Rats ; Splanchnic Circulation/*drug effects/physiology ; }, abstract = {BACKGROUND: The aim of this study was to assess the effects of N-acetylcysteine (NAC) on nitric oxide and adrenergic pathways in mesenteric artery from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY).<br><br>METHODS: Rats were treated with 4 g x kg(-1) x day(-1) of NAC during 4 weeks or mesenteric beds were treated with 10 mmol/L of NAC during 20 min.<br><br>RESULTS: In conscious rats, the NAC treatment produced a significant reduction of mean arterial pressure (MAP) and heart rate in SHR (P <.001). N(omega)-nitro-L-arginine methyl ester (L-NAME) caused a MAP increase in NAC-treated SHR of magnitude similar to that in WKY, which was significantly higher than that observed in control untreated SHR (P <.05). Chronic treatments with NAC improved the maximal relaxation of mesenteric arteries to A23187 in SHR (P <.001). Acute NAC treatment in vitro induced a vasodilation in Phe preconstricted arteries (P <.001) that was stronger in SHR than in WKY (P <.05) and was not abolished by L-NAME. The vasoconstrictory response and increases in inositol phosphate production induced by superoxide anion were attenuated by NAC treatment through its superoxide scavenging properties. In contrast, chronic and acute NAC treatments did not alter the vasodilatory response to beta-adrenergic receptor stimulation.<br><br>CONCLUSIONS: The increase in NO-mediated vasodilator tone and the possible decrease in adrenergic vasoconstriction induced by NAC treatment in SHR could explain the hypotensive effect of NAC in this model of hypertension.}, }
@article {pmid12850239, year = {2003}, author = {Kim, MS and Lee, J and Lee, KM and Yang, SH and Choi, S and Chung, SY and Kim, TY and Jeong, WH and Park, R}, title = {Involvement of hydrogen peroxide in mistletoe lectin-II-induced apoptosis of myeloleukemic U937 cells.}, journal = {Life sciences}, volume = {73}, number = {10}, pages = {1231-1243}, doi = {10.1016/s0024-3205(03)00418-1}, pmid = {12850239}, issn = {0024-3205}, mesh = {Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspases/metabolism ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; Drug Antagonism ; Enzyme Inhibitors/pharmacology ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors/*metabolism ; JNK Mitogen-Activated Protein Kinases ; Mistletoe/*chemistry ; Mitogen-Activated Protein Kinases/metabolism ; Plant Lectins/antagonists &amp; inhibitors/*pharmacology ; Plant Preparations/antagonists &amp; inhibitors/*pharmacology ; *Plant Proteins ; *Plants, Medicinal ; Ribosome Inactivating Proteins, Type 2 ; Toxins, Biological/*pharmacology ; U937 Cells ; }, abstract = {Mistletoe lectin-II, a major component of Korean mistletoe (Viscum album var. coloratum) induces apoptotic death in cancer cells. In this study, we demonstrated that lectin-II induced the generation of pro-oxidants and thus resulted in the apoptotic death of human myeloleukemic U937 cells. We observed that lectin-II-induced apoptotic death was inhibited by antioxidants including reduced glutathione (GSH), N-acetylcysteine (NAC), ebselen, mnTBP, catalase and pyrrolidine dithiocarbamate (PDTC). GSH and NAC also abolished the apoptotic DNA ladder pattern fragmentation of U937 cells after lectin-II stimulation. Obviously, lectin-II treatment of cells resulted in a remarkable generation of intracellular hydrogen peroxide (H2O2) as an early event, which was monitored fluorimetrically using scopoletin-horse radish peroxidase (HRP) assay and peroxide-sensitive fluorescent probe, DCF-DA. In addition, antioxidants inhibited the activation of c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) as well as cytosolic release of cytochrome c by mistletoe lectin-II. Moreover, lectin-II-induced activation of caspase-9 and 3-like protease and cleavage of poly(ADP-ribose) polymerase (PARP) were inhibited by pretreatment of cells with thiol antioxidants, GSH and NAC. Taken together, these results suggest that Korean mistletoe lectin-II is a strong inducer of pro-oxidant generation such as H2O2, which mediates the JNK/SAPK activation, cytochrome c release, activation of caspase-9 and caspase 3-like protease, and PARP cleavage in human myeloleukemic U937 cells.}, }
@article {pmid12849721, year = {2003}, author = {Kim, SH and Sharma, RP}, title = {Cytotoxicity of inorganic mercury in murine T and B lymphoma cell lines: involvement of reactive oxygen species, Ca(2+) homeostasis, and cytokine gene expression.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {17}, number = {4}, pages = {385-395}, doi = {10.1016/s0887-2333(03)00040-7}, pmid = {12849721}, issn = {0887-2333}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis ; Calcium/*metabolism ; Calcium Channel Blockers/pharmacology ; Cell Line, Tumor ; Cytokines/*biosynthesis/*genetics ; DNA Replication ; DNA, Neoplasm/biosynthesis ; Gene Expression Regulation, Neoplastic/*drug effects ; Homeostasis/physiology ; Lymphoma, B-Cell/*drug therapy/metabolism/pathology ; Lymphoma, T-Cell/*drug therapy/metabolism/pathology ; Mercury/*toxicity ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Necrosis ; Protein Synthesis Inhibitors/pharmacology ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/metabolism ; }, abstract = {Mercury is a highly toxic heavy metal; exposure to mercury in humans and animals causes damage in several organs or systems including the immune system. To characterize the toxicity of mercury in the immune cells, the cytotoxic effects of inorganic mercury were studied in two distinct lymphoma lines, the murine T lymphoma (EL4) and B lymphoma (A20) cells. Mercury concentration-dependently decreased cell viability, membrane integrity, and proliferation in both EL4 and A20 cells. Mercury increased the reactive oxygen species (ROS) production in both EL4 and A20 cells, and pretreatment with antioxidants reversed mercury-induced ROS generation. Pretreatment of cells with antioxidants N-acetylcysteine (NAC) and silymarin decreased mercury-induced lactate dehydrogenase (LDH) release in both types of cells; however, Ca(2+) channel blocker lanthanum (La(2+)) decreased it only in A20 cells. The mode of cytotoxicity was a mixture of both apoptosis and necrosis. Mercury-induced apoptosis and necrosis in the two cell lines were indicated by staining with Hoechst 33258, propidium iodide, and co-staining with annexin V and propidium iodide. Both mercury-induced apoptosis and necrosis were attenuated by antioxidants. Mercury increased gene expression of IL-4 and TNFalpha in EL4 cells; these cytokines were not expressed in A20 cells. Data suggested different pathways of mercury-induced cytotoxicity in T and B lymphoma cells and involvement of ROS, Ca(2+) homeostasis, and inflammatory cytokine gene expression.}, }
@article {pmid12847563, year = {2003}, author = {Pettersson, K and Bergstrand, H}, title = {The antiatherogenic effect of DiNAC: experimental findings supporting immunomodulation as a new treatment for atherosclerosis related diseases.}, journal = {Cardiovascular drug reviews}, volume = {21}, number = {2}, pages = {119-132}, doi = {10.1111/j.1527-3466.2003.tb00110.x}, pmid = {12847563}, issn = {0897-5957}, mesh = {Adjuvants, Immunologic/chemistry/*pharmacology/*therapeutic use ; Animals ; Antioxidants/chemistry/pharmacology/therapeutic use ; Arteriosclerosis/*drug therapy/immunology/prevention &amp; control ; Clinical Trials as Topic ; Cystine/*analogs &amp; derivatives/chemistry/*pharmacology/*therapeutic use ; Drug Evaluation, Preclinical ; Endothelium, Vascular/physiopathology ; Humans ; Hypersensitivity, Delayed/immunology ; Quantitative Structure-Activity Relationship ; Vasodilation/drug effects ; }, abstract = {Inflammatory processes in the arterial wall are important in atherogenesis. The present review discusses the development of DiNAC as a potential new treatment modality for atherosclerosis related diseases. DiNAC, N,N'-diacetyl-L-cystine, is the disulphide dimer of N-acetyl cysteine, NAC. It was selected as an immunomodulating drug candidate due to its ability to modify contact sensitivity/delayed type hypersensitivity (CS/DTH) reactions in vivo. Initial structure-activity relationship (SAR) studies indicated that an intact disulfide bridge was essential for this effect. Antioxidants, like probucol and some close analogs with two sulphurs in close proximity (but not disulphides), were also found to have similar effects on CS/DTH reactions. These antioxidants have antiatherosclerotic effects, while structurally related compounds without sulphurs do not. Therefore, it was hypothesized that DiNAC might also possess antiatherosclerotic effects. This was investigated in WHHL rabbits and mice. In both species, DiNAC had antiatherosclerotic activity similar to that of probucol. The effect of DiNAC was not due to an alteration of lipid metabolism. Impaired endothelium mediated relaxation is known to be associated with atherosclerosis. DiNAC was shown to reverse this process in WHHL rabbits with advanced atherosclerosis, probably due to an action on the vessel wall itself that is not related to the extent of atherosclerosis or to plasma lipid levels. Preliminary data from a clinical investigation in hypercholesterolemic subjects suggest that DiNAC is likely to have similar effects also in patients. Taken together, these findings suggest immunomodulation to be a potential new therapy for atherosclerosis related diseases. DiNAC may represent a new treatment modality for such diseases.}, }
@article {pmid12843619, year = {2003}, author = {Kanno, S and Matsukawa, E and Miura, A and Shouji, A and Asou, K and Ishikawa, M}, title = {Diethyldithiocarbamate-induced cytotoxicity and apoptosis in leukemia cell lines.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {26}, number = {7}, pages = {964-968}, doi = {10.1248/bpb.26.964}, pmid = {12843619}, issn = {0918-6158}, mesh = {Apoptosis/*drug effects/physiology ; Cell Line, Tumor/drug effects/metabolism ; Cell Survival/drug effects/physiology ; Ditiocarb/*toxicity ; HL-60 Cells ; Humans ; Jurkat Cells ; Leukemia/*metabolism ; U937 Cells ; }, abstract = {Diethyldithiocarbamate (DDTC) has been shown to induce cytotoxicity in several different systems. We examined whether the DDTC-induced cytotoxicity was via apoptosis, or in relation to intracellular glutathione (GSH) in various murine and human leukemia cell lines. The cells most sensitive to DDTC-induced cytotoxicity were P388 lymphoid neoplasma cells and NALM-6, a B cell line of acute lymphocytic leukemia (ALL). The next level of susceptible cells included J774.1, having a macrophage function, HL-60 premyelocytic leukemia cells, MOLT-4, an acute lymphoblastic leukemia cell, and Jurkat, a T-cell leukemia. U937 (expressing many monocyte-like characteristics), K562 erythroleukemia and K562/DXR (a multidrug-resistant clone derived from K562) were almost unaffected by DDTC. P388 was also highly susceptible to H(2)O(2), a most useful exogenous reactive oxygen species generator, and was lower in intracellular total GSH content than other leukemia cells. DDTC-induced cytotoxicity was closely related to intracellular GSH, but the level of cellular GSH did not always correlate with H(2)O(2)-induced cytotoxicity in this experiment. K562 had a higher intracellular total GSH content and showed lower susceptibility to DDTC and H(2)O(2), but with the combination of DDTC and DL-buthionine-(S,R)-sulfoximine (BSO), cytotoxicity increased significantly. The ratio of GSH/GSSG in P388 was reduced by DDTC or H(2)O(2). H(2)O(2)-induced cytotoxicity was completely blocked by catalase (CAT), while it was enhanced by superoxide dismutase (SOD). CAT or SOD did not affect DDTC-induced cytotoxicity. N-Acetylcysteine (NAC: 1 mM), a vanguard substance of GSH, and aurintricarboxylic acid (ATA: 100 microM), an endonuclease inhibitor, ameliorated DDTC-induced cytotoxicity and apoptosis. In conclusion, we suggest that DDTC-induced cytotoxicity was via an oxidative shift in the intracellular redox state, and accompanied the activation of endonuclease through apoptosis in leukemia cell lines.}, }
@article {pmid12842456, year = {2003}, author = {Chan, EL and Murphy, JT}, title = {Reactive oxygen species mediate endotoxin-induced human dermal endothelial NF-kappaB activation.}, journal = {The Journal of surgical research}, volume = {111}, number = {1}, pages = {120-126}, doi = {10.1016/s0022-4804(03)00050-7}, pmid = {12842456}, issn = {0022-4804}, support = {3 P50 GM2 1681-36S2/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Cell Line, Transformed ; Cell Nucleus/metabolism ; Electrophoretic Mobility Shift Assay ; Endothelium, Vascular/*metabolism/ultrastructure ; Ferrous Compounds/pharmacology ; Fluoresceins ; Fluorescent Dyes ; Humans ; Hydrogen Peroxide/pharmacology ; Lipopolysaccharides/*pharmacology ; Microscopy, Confocal ; NF-kappa B/*metabolism ; Reactive Oxygen Species/*metabolism ; Skin/*blood supply ; Xanthine/pharmacology ; Xanthine Oxidase/pharmacology ; }, abstract = {BACKGROUND: Microvascular endothelial cell "activation" by endotoxin is an early and critical phenomenon underlying organ dysfunction related to sepsis. Dermal endothelial cells contribute to many of the manifestations of septic shock, such as cutaneous interstitial edema and loss of peripheral vasomotor regulation. Human dermal endothelial cell activation by endotoxin (lipopolysaccharide [LPS]) is characterized by the generation of reactive oxygen species (ROS) that enhance nuclear translocation of the transcription factor kappa-B (NF-kappaB).<br><br>METHODS: We tested our hypothesis by stimulating human dermal microvascular endothelial cells (HMEC.1) with endotoxin and assaying for endothelial generation of ROS and nuclear translocation of NF-kappaB subunits. HMEC.1 cultures were treated individually with LPS, hydrogen peroxide, or xanthine, xanthine oxidase, and ferrous sulfate (xanthine/XO/Fe(2+)). Nuclear proteins were isolated and consensus sequence binding was assessed by electrophoretic mobility shift assay (EMSA). 2',7'-Dichlorofluorescin diacetate and confocal microscopy were used to examine ROS production in LPS-stimulated HMEC.1.<br><br>RESULTS: Nuclear translocation of the p65/p50 NF-kappaB heterodimer was detectable 30 min after stimulation with LPS alone or the xanthine/XO/Fe(2+) combination, but not with hydrogen peroxide. Antioxidant N-acetylcysteine (NAC) inhibited LPS-stimulated ROS production in HMEC.1. Antioxidant prior to or simultaneously with LPS exposure, but not following LPS, also prevented NF-kappaB activation. NAC was ineffective at inhibiting NF-kappaB translocation at increased LPS concentrations.<br><br>CONCLUSIONS: Dermal endothelial cells, a microvascular cell type that may contribute to the systemic response to blood-borne endotoxemia, generate ROS in the absence of other inflammatory cells. These LPS-activated endothelial cells, in turn, rapidly translocate transcription factor NF-kappaB to cell nuclei, a process regulated in part by intracellular ROS.}, }
@article {pmid12839997, year = {2003}, author = {Hayakawa, M and Miyashita, H and Sakamoto, I and Kitagawa, M and Tanaka, H and Yasuda, H and Karin, M and Kikugawa, K}, title = {Evidence that reactive oxygen species do not mediate NF-kappaB activation.}, journal = {The EMBO journal}, volume = {22}, number = {13}, pages = {3356-3366}, pmid = {12839997}, issn = {0261-4189}, mesh = {Acetylcysteine/pharmacology ; Base Sequence ; Cell Line ; DNA Primers ; Humans ; NF-kappa B/*metabolism ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/*metabolism ; Receptors, Tumor Necrosis Factor/metabolism ; Signal Transduction/*physiology ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/metabolism/physiology ; }, abstract = {It has been postulated that reactive oxygen species (ROS) may act as second messengers leading to nuclear factor (NF)-kappaB activation. This hypothesis is mainly based on the findings that N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), compounds recognized as potential antioxidants, can inhibit NF-kappaB activation in a wide variety of cell types. Here we reveal that both NAC and PDTC inhibit NF-kappaB activation independently of antioxidative function. NAC selectively blocks tumor necrosis factor (TNF)-induced signaling by lowering the affinity of receptor to TNF. PDTC inhibits the IkappaB-ubiquitin ligase activity in the cell-free system where extracellular stimuli-regulated ROS production does not occur. Furthermore, we present evidence that endogenous ROS produced through Rac/NADPH oxidase do not mediate NF-kappaB signaling, but instead lower the magnitude of its activation.}, }
@article {pmid12839837, year = {2003}, author = {Liu, X and Spolarics, Z}, title = {Methemoglobin is a potent activator of endothelial cells by stimulating IL-6 and IL-8 production and E-selectin membrane expression.}, journal = {American journal of physiology. Cell physiology}, volume = {285}, number = {5}, pages = {C1036-46}, doi = {10.1152/ajpcell.00164.2003}, pmid = {12839837}, issn = {0363-6143}, support = {GM 55005/GM/NIGMS NIH HHS/United States ; }, mesh = {Cell Membrane/drug effects/metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; E-Selectin/*biosynthesis ; Endothelium, Vascular/*metabolism/*physiology ; Gene Expression Regulation/physiology ; Humans ; Interleukin-6/*biosynthesis/metabolism ; Interleukin-8/*biosynthesis/metabolism ; Methemoglobin/*physiology ; RNA, Messenger/biosynthesis ; }, abstract = {Infection and injury are frequently accompanied by hemolysis. Endothelial cells are direct targets of free Hb or its oxidative derivatives, including methemoglobin (MHb) and hemin. This study tested whether Hb or its derivatives alter chemokine (IL-8) and cytokine (IL-6) production and the membrane expression of cell adhesion molecule (E-selectin) in human umbilical vein endothelial cells (passages 2-4, HUVECs). E-selectin membrane content and IL-6 and IL-8 release were quantified by ELISA; cellular mRNA levels were determined by RT-PCR. MHb in vitro resulted in a dose (1-50 microM)- and time (2-16 h)-dependent increase in E-selectin membrane content and IL-6 and IL-8 release in HUVECs. The stimulatory effect of MHb (12 microM) on E-selectin membrane expression and IL-6 and IL-8 release was similar to that produced after treatment with TNF-alpha (5 ng/ml) and IL-1beta (0.25 ng/ml). In contrast, Hb or hemin had no effects. As expected, MHb, Hb, and hemin markedly induced heme oxygenase-1 expression in HUVECs. Haptoglobin, cytochalasin D, and actinomycin inhibited the MHb-induced responses, whereas zinc protoporphyrin IX (a heme oxygenase inhibitor) or desferroxamine (an iron chelator) did not inhibit MHb-induced responses. MHb also increased cellular mRNA levels of E-selectin, IL-6, and IL-8. MHb treatment activated cellular NF-kappaB and NF-kappaB inhibitors; N-acetyl cysteine, SN50, and caffeic acid phenylethyl ester inhibited the MHb-induced responses. These data indicate that MHb is a potent activator of endothelial cells through NF-kappaB-mediated upregulation of cell adhesion molecule expression and chemokine and cytokine production. MHb-induced endothelial cell activation may have clinical significance after infections, hemolysis, or methemoglobinemia.}, }
@article {pmid12835357, year = {2003}, author = {Alsalim, W and Fadel, M}, title = {Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Oral methionine compared with intravenous n-acetyl cysteine for paracetamol overdose.}, journal = {Emergency medicine journal : EMJ}, volume = {20}, number = {4}, pages = {366-367}, doi = {10.1136/emj.20.4.366}, pmid = {12835357}, issn = {1472-0213}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Drug Overdose/drug therapy ; Evidence-Based Medicine ; Humans ; Methionine/*therapeutic use ; }, abstract = {A short cut review was carried out to establish whether methionine was better than n-acetyl cysteine at reducing the severity of liver damage after paracetamol overdose. Thirty nine papers were found using the reported search, of which two presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.}, }
@article {pmid12835115, year = {2003}, author = {Jara-Prado, A and Ortega-Vazquez, A and Martinez-Ruano, L and Rios, C and Santamaria, A}, title = {Homocysteine-induced brain lipid peroxidation: effects of NMDA receptor blockade, antioxidant treatment, and nitric oxide synthase inhibition.}, journal = {Neurotoxicity research}, volume = {5}, number = {4}, pages = {237-243}, pmid = {12835115}, issn = {1029-8428}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain/*metabolism ; Dizocilpine Maleate/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Free Radical Scavengers/pharmacology ; Homocysteine/metabolism/*toxicity ; Indazoles/pharmacology ; Lipid Peroxidation/drug effects/physiology ; Male ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase/*antagonists &amp; inhibitors/metabolism ; Nitroarginine/pharmacology ; Rats ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate/*antagonists &amp; inhibitors/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The effect of homocysteine (HCY) on lipid peroxidation (LP), a current mechanism of oxidative neurotoxicity, was investigated in rat brain synaptosomes. LP was assessed by measuring the amount of thiobarbituric acid-reactive substances (TBARS) formed from synaptosomal fractions following HCY treatment. Increasing HCY concentrations (5-1000 micro M) enhanced the TBARS formation in brain synaptosomes in a concentration-dependent manner. When compared at equimolar concentrations (100 micro M), the oxidative potency of HCY was lower than that of the oxidant ferrous sulfate, similar to that produced by glutamate (Glu) and the mitochondrial toxin 3-nitropropionic acid, and higher than that of the Glu agonists, kainate and quinolinate. The N-methyl-D-aspartate receptor (NMDAr) antagonist dizocilpine (MK-801) completely blocked the HCY-induced LP at concentrations between 5 to 1000 micro M, whereas the well-known antioxidant N-acetylcysteine (NAC) was less effective, but still protective against the HCY oxidative toxicity at higher concentrations (400 and 1000 micro M). Three nitric oxide synthase (NOS) inhibitors, 7-nitroindazole (7-NI), Nomega-nitro-L-arginine (L-NARG) and Nomega-nitro-L-arginine methyl ester (L-NAME), were also tested on HCY-induced LP at increasing concentrations. Both nonspecific NOS inhibitors (L-NARG and L-NAME) decreased more effectively the HCY-induced LP than did the selective neuronal NOS inhibitor, 7-NI. These results show that submillimolar concentrations of HCY can induce oxidative injury to nerve terminals, and this effect involves NMDAr stimulation, NOS activation, and associated free radicals formation.}, }
@article {pmid12834176, year = {2003}, author = {Trimarchi, H and Mongitore, MR and Baglioni, P and Forrester, M and Freixas, EA and Schropp, M and Pereyra, H and Alonso, M}, title = {N-acetylcysteine reduces malondialdehyde levels in chronic hemodialysis patients--a pilot study.}, journal = {Clinical nephrology}, volume = {59}, number = {6}, pages = {441-446}, doi = {10.5414/cnp59441}, pmid = {12834176}, issn = {0301-0430}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Male ; Malondialdehyde/*blood ; Middle Aged ; Oxidative Stress ; Pilot Projects ; *Renal Dialysis ; }, abstract = {BACKGROUND: Oxidative stress has been implicated in the development of endothelial damage in hemodialysis (HD). We have assessed the effects of N-acetylcysteine (NAC), a compound with antioxidant effects, on malondialdehyde (MDA), a marker of oxidative stress on lipid peroxidation.<br><br>METHODS: A clinical trial was conducted in which 24 chronic HD patients were divided into 2 groups according to gender, age, time on HD and cause of renal failure. The NAC group (n = 12) received 600 mg of NAC twice a day for 30 days. The remaining patients constituted the control group (n = 12). MDA levels were measured pre- and post-dialysis at the beginning of the study (baseline) and on day 30 (30 days).<br><br>RESULTS: Baseline pre- and post-dialysis MDA levels were not different between both groups and were above normal values. A significant decrease was found in the NAC group when either pre- or post-dialysis MDA levels were compared to the corresponding control group levels on day 30 (pre-dialysis NAC vs control group 3.01 +/- 0.6 vs 4.5 +/- 0.73 micromol/l, p < 0.0001, post-dialysis NAC vs control group 2.76 +/- 0.5 vs 4.39 +/- 0.7 micromol/l, p < 0.0001). Only in the NAC group were pre-dialysis MDA 30-day levels different from pre-dialysis baseline levels (3.01 +/- 0.6 vs 5.07 +/- 1.6 micromol/l, p < 0.002). Post-dialysis MDA 30-day concentrations were significantly lower than post-dialysis MDA baseline levels (2.76 +/- 0.5 vs 4.32 +/- 0.7 micromol/l, p < 0.002) and pre-dialysis MDA 30-day measurements (2.76 +/- 0.5 vs 3.01 +/- 0.6 micromol/l, p < 0.011).<br><br>CONCLUSIONS: MDA levels are elevated in chronic HD patients and are not significantly reduced by HD. NAC significantly reduces malondialdehyde levels in chronic HD patients.}, }
@article {pmid12832326, year = {2003}, author = {Jain, SK and Kannan, K and Lim, G and Matthews-Greer, J and McVie, R and Bocchini, JA}, title = {Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes.}, journal = {Diabetes care}, volume = {26}, number = {7}, pages = {2139-2143}, doi = {10.2337/diacare.26.7.2139}, pmid = {12832326}, issn = {0149-5992}, mesh = {Acetoacetates/*pharmacology ; Adolescent ; Age of Onset ; Cells, Cultured ; Child ; Diabetes Mellitus, Type 1/*blood/immunology ; Diabetic Ketoacidosis/*blood/immunology ; Glycated Hemoglobin/metabolism ; Humans ; Interleukin-6/*blood ; Ketone Bodies/blood ; Reactive Oxygen Species/metabolism ; Reference Values ; Siblings ; U937 Cells/drug effects/metabolism ; }, abstract = {OBJECTIVE: Diabetic patients have elevated blood levels of interleukin-6 (IL-6), which is known to increase inflammation and the development of vascular disease and atherosclerosis. This study examined the hypothesis that ketosis increases the circulating levels of IL-6 in type 1 diabetic patients as well as the secretion of IL-6 in vitro in a cell culture model using U937 monocytes.<br><br>RESEARCH DESIGN AND METHODS: Fasting blood was obtained from type 1 diabetic patients and healthy siblings. To examine the effect of ketosis, U937 monocytes were cultured with ketone bodies (acetoacetate [AA], beta-hydroxybutyrate [BHB]) in the presence or absence of high glucose levels in the medium at 37 degrees C for 24 h. IL-6 was determined by the sandwich enzyme-linked immunosorbent assay method, and intracellular reactive oxygen species (ROS) generation was detected using dihydroethidium dye.<br><br>RESULTS: The blood level of IL-6 was higher in hyperketonemic (HK) diabetic patients than in normoketonemic (NK) diabetic patients (P < 0.05) and normal control subjects (P < 0.05). There was a significant correlation between ketosis and IL-6 levels (r = 0.36, P < 0.04, n = 34) in the blood of diabetic patients. Cell culture studies found that exogenous addition of the ketone body AA, but not BHB, increases IL-6 secretion and ROS generation in U937 cells. N-acetylcysteine (NAC) prevented the IL-6 secretion in acetoacetate-treated U937 monocytes.<br><br>CONCLUSIONS: This study demonstrates that hyperketonemia increases IL-6 levels in the blood of type 1 diabetic patients and that NAC can inhibit IL-6 secretion by U937 monocytic cells cultured in a ketotic medium.}, }
@article {pmid12831779, year = {2003}, author = {Poliandri, AH and Cabilla, JP and Velardez, MO and Bodo, CC and Duvilanski, BH}, title = {Cadmium induces apoptosis in anterior pituitary cells that can be reversed by treatment with antioxidants.}, journal = {Toxicology and applied pharmacology}, volume = {190}, number = {1}, pages = {17-24}, doi = {10.1016/s0041-008x(03)00191-1}, pmid = {12831779}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Ascorbic Acid/pharmacology ; Cadmium/antagonists &amp; inhibitors/*toxicity ; Caspases/metabolism ; Cell Survival/drug effects ; Chromans/pharmacology ; DNA Fragmentation/drug effects ; Free Radical Scavengers/pharmacology ; Hormones/metabolism ; Immunohistochemistry ; Male ; Oxidative Stress/drug effects/physiology ; Pituitary Gland, Anterior/*cytology/drug effects ; Prolactin/metabolism ; Rats ; Rats, Wistar ; Tetrazolium Salts ; Thiazoles ; Vitamin E/pharmacology ; }, abstract = {Cadmium (Cd(2+)) is an ubiquitous toxic metal that is involved in a variety of pathological conditions. Several reports indicate that Cd(2+) alters normal pituitary hormone secretion; however, little is known about the mechanisms that induce this misregulation. This paper reports the effect of Cd(2+) on anterior pituitary cell viability and its relation to prolactin secretion. Cd(2+) concentrations above 10 microM were found to be cytotoxic for pituitary cells. Morphological studies as well as DNA ladder fragmentation and caspase activation showed that Cd(2+)-treated cells undergo apoptosis. Even though several hours were needed to detect Cd(2+)-induced cytotoxicity, the effect of the metal became irreversible very quickly, requiring only 3 h of treatment. Prolactin release (measured at 48 h) was inhibited when the cells were exposed to Cd(2+) for 1 h, before any change in cell viability was observed. The antioxidants N-acetyl-cysteine and Trolox (a hydrosoluble derivative of vitamin E), but not ascorbic acid, reversed both Cd(2+)-mediated cytotoxicity and the inhibition of prolactin release, supporting the involvement of oxidative stress in the mechanism of Cd(2+) action. In summary, the present work demonstrates that Cd(2+) is cytotoxic for anterior pituitary cells, that this effect is due to an induction of apoptosis, and that it can be reversed by antioxidants.}, }
@article {pmid12826269, year = {2003}, author = {Choi, YJ and Kim, TG and Kim, YH and Lee, SH and Kwon, YK and Suh, SI and Park, JW and Kwon, TK}, title = {Immunosuppressant PG490 (triptolide) induces apoptosis through the activation of caspase-3 and down-regulation of XIAP in U937 cells.}, journal = {Biochemical pharmacology}, volume = {66}, number = {2}, pages = {273-280}, doi = {10.1016/s0006-2952(03)00282-x}, pmid = {12826269}, issn = {0006-2952}, mesh = {*Apoptosis ; Caspase 3 ; Caspases/*metabolism ; Diterpenes/*pharmacology ; Down-Regulation ; Enzyme Activation ; Epoxy Compounds ; Humans ; Immunosuppressive Agents/*pharmacology ; Neoplasm Proteins/metabolism ; *Phenanthrenes ; Proteins/*metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; U937 Cells ; X-Linked Inhibitor of Apoptosis Protein ; }, abstract = {PG490 (triptolide) is a natural, biologically active compound extracted from Chinese herb Tripterygium wilfordii. It possesses potent anti-inflammatory and immunosuppressive properties. The mechanism by which triptolide initiates apoptosis remains poorly understood. In the present report, we investigated the effect of triptolide on the apoptotic pathway in U937 human promonocytic cells. We show that triptolide inhibits U937 cells growth by inducing apoptosis. Following treatment of U937 cells with 25 nM triptoride for 24 hr, morphological features of apoptosis and DNA fragmentation were observed. Caspase inhibitors significantly reduced triptolide-induced caspase-3 activation. In addition, apoptosis triggered by triptolide was not associated with the generation of reactive oxygen species, which was not affected by the antioxidant N-acetylcysteine (NAC). The data collectively indicate that the cytotoxic effect of triptolide in U937 cells is attributable to apoptosis mediated by the caspase-3 activation pathway that may be associated with XIAP down-regulation.}, }
@article {pmid12826064, year = {2003}, author = {Severina, IS and Bussygina, OG and Pyatakova, NV and Malenkova, IV and Vanin, AF}, title = {Activation of soluble guanylate cyclase by NO donors--S-nitrosothiols, and dinitrosyl-iron complexes with thiol-containing ligands.}, journal = {Nitric oxide : biology and chemistry}, volume = {8}, number = {3}, pages = {155-163}, doi = {10.1016/s1089-8603(03)00002-8}, pmid = {12826064}, issn = {1089-8603}, mesh = {Acetylcysteine/metabolism ; Blood Platelets/enzymology/metabolism ; Copper ; Enzyme Activation ; Glutathione/metabolism ; Guanylate Cyclase/*metabolism ; Humans ; Iron/metabolism ; Ligands ; Nitric Oxide Donors/*metabolism ; Nitrogen Oxides/metabolism ; S-Nitrosothiols/metabolism ; Solubility ; Sulfhydryl Compounds ; }, abstract = {We studied the capability of dimeric forms of dinitrosyl-iron complexes and S-nitrosothiols to activate soluble guanylate cyclase (sGC) from human platelet cytosol. The dinitrosyl-iron complexes had the ligands glutathione (DNIC-GS) or N-acetylcysteine (DNIC-NAC). The S-nitrosothiols were S-nitrosoglutathione (GS-NO) or S-nitrosoacetylcysteine (SNAC). For both glutathione and N-acetylcysteine, the DNIC and S-nitrosothiol forms are equally effective activators of sGC. The activation mechanism is strongly affected by the presence of intrinsic metal ions. Pretreatment with the potent iron chelator, disodium salt of bathophenanthroline disulfonic acid (BPDS), suppressed sGC activation by GS-NO: the concentration of GS-NO producing maximal sGC activation was increased by two orders of magnitude. In contrast, activation by DNIC-GS is strongly enhanced by BPDS. When BPDS was added 10 min after supplementation of DNIC-GS or GS-NO at 4 degrees C, it exerted a similar effect on sGC activation by either NO donor: BPDS only enhanced the sGC stimulation at low concentrations of the NO donors. Our experiments demonstrated that both Fe(2+) and Cu(2+) ions contribute to the decomposition of GS-NO in the presence of ascorbate. The decomposition of GS-NO induced by Fe(2+) ions was accompanied by formation of DNIC. BPDS protected GS-NO against the destructive action of Fe(2+) but not Cu(2+) ions. Additionally, BPDS is a sufficiently strong chelator to remove the iron from DNIC-GS complexes. Based on our data, we propose that S-nitrosothiols activate sGC via a two-step iron-mediated process: In the first step, intrinsic Fe(2+) ions catalyze the formation of DNICs from S-nitrosothiols. In the secondary step, these newly formed DNICs act as the real NO donors responsible for sGC activation.}, }
@article {pmid12825870, year = {2003}, author = {Olanders, K and Börjesson, A and Sun, ZW and Andersson, R}, title = {Protective effects of N-acetyl-L-cysteine and platelet activating factor inhibition are not linked to intercellular adhesion molecule-1 expression after intestinal ischemia and reperfusion injury in rats.}, journal = {Scandinavian journal of gastroenterology}, volume = {38}, number = {6}, pages = {618-625}, doi = {10.1080/00365520310002201}, pmid = {12825870}, issn = {0036-5521}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cytoprotection/immunology ; Free Radical Scavengers/*pharmacology ; Imidazoles/*pharmacology ; Intercellular Adhesion Molecule-1/*biosynthesis/immunology ; Interleukin-1/biosynthesis ; Intestinal Mucosa/drug effects/metabolism ; Intestines/*blood supply/drug effects ; Ischemia/*metabolism ; Leucine/*analogs &amp; derivatives/*pharmacology ; Male ; Neutrophil Infiltration/drug effects ; Permeability/drug effects ; *Platelet Activating Factor/antagonists &amp; inhibitors ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/drug therapy/immunology/*metabolism ; }, abstract = {BACKGROUND: Intestinal ischemia and reperfusion (I/R) injury may result in development of the systemic inflammatory response syndrome (SIRS). The interactions between activated leukocytes and endothelial cells, mediated by adhesion molecules, seem to be pivotal in these conditions, leading as they do to extravasation of circulating leukocytes within the inflamed tissue. The intercellular adhesion molecule-1 (ICAM-1) mediating firm adhesion of activated leukocytes is upregulated in many organs after I/R injury, but the regulatory mechanisms are complex and have not been fully investigated.<br><br>METHODS: We evaluated whether ICAM-1 expression was linked with a potential protective effect of N-acetyl-L-cysteine (NAC) and the platelet activating factor (PAF) inhibitor (Lexipafant), administered 15 min after the start of reperfusion, in a model of intestinal ischemia (40 min) and reperfusion (12 h) in the rat.<br><br>RESULTS: ICAM-1 expression increased significantly in the ileum, colon, lungs and pancreas after intestinal I/R. Treatments with NAC and the PAF inhibitor did not affect this response. An increased endothelial albumin-leakage was observed in the same organs after I/R. Treatment with NAC reduced the endothelial leakage of albumin in the ileum, colon and lungs, whereas administration of the PAF inhibitor alone demonstrated a protective effect only in the ileum. Furthermore, neutrophil sequestration in the lungs and IL-1beta levels in plasma increased significantly after I/R, and these changes were markedly reduced by both treatment regimes.<br><br>CONCLUSION: The protective effect of NAC and the PAF inhibitor Lexipafant in intestinal I/R injury is not due to a decreased expression of ICAM-1.}, }
@article {pmid12824244, year = {2003}, author = {Aoun, P and Simpkins, JW and Agarwal, N}, title = {Role of PPAR-gamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {44}, number = {7}, pages = {2999-3004}, doi = {10.1167/iovs.02-1060}, pmid = {12824244}, issn = {0146-0404}, support = {AG10485/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*pharmacology ; Buthionine Sulfoximine/toxicity ; Cell Line, Transformed ; Cell Survival ; Chromans/*pharmacology ; Cytoprotection ; Glutamic Acid/*toxicity ; Ligands ; Neuroprotective Agents/*pharmacology ; Prostaglandin D2/analogs &amp; derivatives/*pharmacology ; Rats ; Receptors, Cytoplasmic and Nuclear/agonists/metabolism/*physiology ; Retinal Ganglion Cells/cytology/*drug effects ; Thiazoles/*pharmacology ; *Thiazolidinediones ; Transcription Factors/agonists/metabolism/*physiology ; Troglitazone ; }, abstract = {PURPOSE: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is the target of the insulin sensitizing thiazolidinediones (TZDs), a class of drugs used in the treatment of type 2 diabetes mellitus. Glaucoma and other retinal disorders are some of the major complications in diabetes. In the present study, the role that PPAR-gamma ligands play in protecting retinal ganglion cells (RGC-5) against glutamate insult was explored.<br><br>METHODS: Transformed rat RGC (RGC-5 cells) and two PPAR-gamma agonists, 15-deoxy-D(12,14)-prostaglandin J2 (15d-PGJ2) and troglitazone were used. RGC-5 cells were incubated with either of the PPAR-gamma ligands and were exposed to either L-glutamic acid or buthionine sulfoximine (BSO). Cell viability was determined with the neutral red dye uptake assay. Levels of PPAR-gamma receptor proteins were monitored by immunoblot analysis.<br><br>RESULTS: Glutamate treatment resulted in RGC-5 cell death, and both 15d-PGJ2 and troglitazone protected the RGC-5 cells from glutamate cytotoxicity. The neuroprotective concentrations of both compounds ranged from approximately 1 to 5 micro M. Troglitazone further protected against BSO toxicity, whereas 15d-PGJ2 did not. Glutamate treatment appears to exert its cytotoxicity through oxidative damage, because pretreatment of RGC-5 cells with the antioxidants N-acetyl cysteine (NAC) and thiourea resulted in the reversal of glutamate cytotoxicity. Furthermore, the glutamate effect was not reversed by pretreatment with MK801 or DL-threo-betabenzyloxyaspartate (DL-TBOA), suggesting that glutamate cytotoxicity is not mediated through the NMDA receptor and/or glutamate transporter, respectively. Levels of PPAR-gamma receptor protein did not show any appreciable change in response to glutamate exposure, with or without 15d-PGJ2 or troglitazone.<br><br>CONCLUSIONS: Two PPAR-gamma ligands, 15d-PGJ2 and troglitazone, protect RGC-5, an established transformed rat retinal ganglion cell line, against glutamate cytotoxicity. The neuroprotective effects of the two compounds appear to be mediated through an antioxidant rather than a PPAR-gamma-dependent pathway. These results suggest that PPAR-gamma agonists, in addition to improving insulin sensitivity, may also provide a valuable antioxidant benefit that could prove valuable in targeting ocular complications including glaucoma.}, }
@article {pmid12824000, year = {2003}, author = {Dugas, B and Dugas, N and Conti, M and Calenda, A and Pino, P and Thomas, Y and Mazier, D and Vouldoukis, I}, title = {Wheat gliadin promotes the interleukin-4-induced IgE production by normal human peripheral mononuclear cells through a redox-dependent mechanism.}, journal = {Cytokine}, volume = {21}, number = {6}, pages = {270-280}, doi = {10.1016/s1043-4666(03)00100-5}, pmid = {12824000}, issn = {1043-4666}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cells, Cultured ; Free Radicals/metabolism ; Gliadin/*pharmacology ; Humans ; Immunoglobulin A/drug effects/metabolism ; Immunoglobulin E/drug effects/*metabolism ; Immunoglobulin G/drug effects/metabolism ; Immunoglobulin M/drug effects/metabolism ; Interleukin-4/*pharmacology ; Leukocytes, Mononuclear/*drug effects/immunology/metabolism ; Lymphocytes/drug effects/metabolism ; Oxidation-Reduction ; Receptors, IgE/drug effects/metabolism ; Sulfhydryl Compounds/pharmacology ; Superoxide Dismutase/pharmacology ; Superoxide Dismutase-1 ; Triticum/chemistry ; Zein/pharmacology ; }, abstract = {Increased levels of serum IgE have been described in gliadin-intolerant patients; however, biological mechanisms implicated in this immunoglobulin production remained unknown. In this study, we demonstrated that in vitro crude gliadins and gliadin lysates (Glilys) promoted the IL-4-induced IgE production by human peripheral blood mononuclear cells (PBMC), indicating that the biological process related to gliadin intolerance and/or allergy may lead to IgE production in vivo. It was found that crude gliadin and Glilys potentiated, after 13 days of culture in a dose-dependent manner, IL-4-induced IgE production and, to a lesser extent, the IgG production, while they did not affect IgA or IgM productions. This promoting effect of gliadin and Glilys on the IL-4-induced activation of normal human PBMC was also observed on the early release (2 days) of the soluble fraction of CD23, suggesting its possible involvement in IgE potentiation. The promoting effect of crude gliadin and Glilys appeared to be indirect because they did not modify purified B-lymphocytes IgE production after IL-4 and anti-CD40 monoclonal antibody stimulation. In addition, as revealed by luminol-dependent chemiluminescence, we demonstrated that crude gliadin and Glilys promoted a substantial production of free radicals by normal human PBMC, treated or not with IL-4. This redox imbalance associated with an increased IgE production led us to evaluate the effect of pharmacological antioxidants (N-acetyl-cysteine (NAC) and Cu/Zn-superoxide dismutase (SOD1)) on IgE production by human PBMC. The NAC and the intracellularly delivered SOD1 were found to suppress the IL-4+/-crude gliadin or Glilys-induced IgE production by normal human PBMC. Taken together, these data indicated that gliadin specifically enhanced IL-4-induced IgE production by normal human PBMC, probably by the regulation of redox pathways, and that this 'pro-allergenic' effect could be counteracted by natural antioxidants: thiols and/or vectorized SOD1.}, }
@article {pmid12823615, year = {2003}, author = {Sener, G and Sehirli, AO and Ayanoğlu-Dülger, G}, title = {Protective effects of melatonin, vitamin E and N-acetylcysteine against acetaminophen toxicity in mice: a comparative study.}, journal = {Journal of pineal research}, volume = {35}, number = {1}, pages = {61-68}, doi = {10.1034/j.1600-079x.2003.00050.x}, pmid = {12823615}, issn = {0742-3098}, mesh = {Acetaminophen/*antagonists &amp; inhibitors/*toxicity ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/*antagonists &amp; inhibitors/*toxicity ; Animals ; Blood Urea Nitrogen ; Creatinine/blood ; Kidney/metabolism ; Liver/metabolism ; Melatonin/*pharmacology ; Mice ; Vitamin E/*pharmacology ; }, abstract = {Acetaminophen (AA) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis and nephrotoxic effects in both humans and experimental animals. It has been reported that the toxic effects of AA are the result of oxidative reactions that take place during its metabolism. In this study we investigated if melatonin, vitamin E or N-acetylcysteine (NAC) are protective against AA toxicity in mice. The doses of the antioxidants used were as follows: melatonin (10 mg/kg), vitamin E (30 mg/kg) and NAC (150 mg/kg). Blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels in blood, and glutathione (GSH), malondialdehyde (MDA), oxidized protein levels and myeloperoxidase (MPO) activity in liver and kidney tissues were measured. BUN and serum creatinine, ALT and AST levels which were increased significantly following AA treatment decreased significantly after pretreatment with either vitamin E, melatonin or NAC; however, they were not reduced to control levels. ALT and AST levels were significantly higher at 4 hr compared with the 24 hr levels after AA administration. However, BUN and creatinine levels were significantly elevated only at 24 hr. GSH levels were reduced while MDA, MPO and oxidized protein levels were increased significantly following AA administration. These changes were reversed by pretreatment with either melatonin, vitamin E or NAC. Liver toxicity was higher at 4 hr, whereas nephrotoxicity appeared to be more severe 24 hr after treatment with AA. Vitamin E was the least efficient agent in reversing AA toxicity while melatonin, considering it was given as at lower dose than either vitamin E or NAC, was the most effective. This may be the result of the higher efficacy of melatonin in scavenging various free radicals and also because of its ability in stimulating the antioxidant enzymes.}, }
@article {pmid12821233, year = {2003}, author = {Baker, CS and Wragg, A and Kumar, S and De Palma, R and Baker, LR and Knight, CJ}, title = {A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study.}, journal = {Journal of the American College of Cardiology}, volume = {41}, number = {12}, pages = {2114-2118}, doi = {10.1016/s0735-1097(03)00487-x}, pmid = {12821233}, issn = {0735-1097}, mesh = {Acetylcysteine/*administration &amp; dosage/*therapeutic use ; Aged ; Cardiac Catheterization/*adverse effects ; Clinical Protocols ; Contrast Media/*administration &amp; dosage/*adverse effects ; Creatinine/blood ; Drug Administration Schedule ; Drug Therapy, Combination ; Female ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Prospective Studies ; Rehydration Solutions/*administration &amp; dosage/*therapeutic use ; Renal Insufficiency/blood/*chemically induced/*prevention &amp; control ; Sodium Chloride/*administration &amp; dosage/*therapeutic use ; Time Factors ; Triiodobenzoic Acids/*administration &amp; dosage/*adverse effects ; }, abstract = {OBJECTIVES: This study was designed to test a rapid protocol of intravenous acetylcysteine for prevention of radiocontrast-induced nephropathy (RCIN).<br><br>BACKGROUND: Oral acetylcysteine (NAC) may provide better prophylaxis against RCIN than intravenous (i.v.) hydration alone. Current protocols preclude prophylaxis of same-day or emergency patients owing to the need for prolonged pretreatment.<br><br>METHODS: We prospectively randomized 80 patients with stable renal dysfunction undergoing cardiac catheterization/intervention to a rapid protocol of i.v. NAC (150 mg/kg in 500 ml N/saline over 30 min immediately before contrast followed by 50 mg/kg in 500 ml N/saline over 4 h, n = 41, 67 +/- 10 years, 90% men) or i.v. hydration (1 ml/kg/h N/saline for 12 h pre- and post-contrast, n = 39, 71 +/- 8.8 years, 85% men).<br><br>RESULTS: Radiocontrast-induced nephropathy occurred in 2 of the 41 patients in the NAC group (5%) and in 8 of the 39 patients in the hydration group (21%; p = 0.045; relative risk: 0.28; 95% confidence interval 0.08 to 0.98). In the NAC group, mean serum creatinine fell from 1.85 +/- 0.59 to 1.77 +/- 0.73 and 1.79 +/- 0.73 mg/dl 48 h and four days post-contrast (p = 0.02 and 0.023 vs. baseline, respectively). In the hydration group, serum creatinine increased from 1.75 +/- 0.41 to 1.81 +/- 0.6 48 h and 1.80 +/- 0.50 mg/dl four days post-contrast (p = 0.99 and 0.23, respectively). NAC infusion was ceased after the bolus in three patients (7%) due to flushing, itching, or a transient rash.<br><br>CONCLUSIONS: Administration of i.v. NAC should be considered in all patients at risk of RCIN before contrast exposure when time constraints preclude adequate oral prophylaxis, provided the patient is able to tolerate this degree of volume loading.}, }
@article {pmid12818576, year = {2003}, author = {Nakagami, H and Takemoto, M and Liao, JK}, title = {NADPH oxidase-derived superoxide anion mediates angiotensin II-induced cardiac hypertrophy.}, journal = {Journal of molecular and cellular cardiology}, volume = {35}, number = {7}, pages = {851-859}, doi = {10.1016/s0022-2828(03)00145-7}, pmid = {12818576}, issn = {0022-2828}, support = {R01 DK062729-01A1/DK/NIDDK NIH HHS/United States ; R01 HL070274-02/HL/NHLBI NIH HHS/United States ; P01 NS010828-330036/NS/NINDS NIH HHS/United States ; R01 HL052233-05/HL/NHLBI NIH HHS/United States ; R01 HL070274-01/HL/NHLBI NIH HHS/United States ; HL48743/HL/NHLBI NIH HHS/United States ; HL52233/HL/NHLBI NIH HHS/United States ; R01 HL052233-07/HL/NHLBI NIH HHS/United States ; R01 HL052233-06/HL/NHLBI NIH HHS/United States ; P50 NS010828-290036/NS/NINDS NIH HHS/United States ; P01 HL048743-120008/HL/NHLBI NIH HHS/United States ; }, mesh = {Angiotensin II/pharmacology ; Animals ; Antioxidants/pharmacology ; Atrial Natriuretic Factor/biosynthesis/genetics ; Cardiomegaly/drug therapy/*metabolism ; Myocytes, Cardiac/drug effects ; NADPH Oxidases/*metabolism ; Promoter Regions, Genetic ; Rats ; Reactive Oxygen Species/metabolism ; Superoxides/*metabolism ; Vasoconstrictor Agents/pharmacology ; rac1 GTP-Binding Protein/genetics/metabolism ; }, abstract = {Cardiac hypertrophy is an adaptive response to increases in blood pressure. Recent studies indicate that the hypertrophic process is associated with increases in intracellular oxidative stress in cardiomyocytes. We hypothesize that superoxide anion mediates the hypertrophic response and that antioxidant therapy may be effective in attenuating cardiac hypertrophy. Neonatal rat cardiac myocytes were stimulated with angiotensin II (AngII, 1 microM) with and without various antioxidants. N-acetylcysteine (NAC, 10 mM) and probucol (50 microM), and to a lesser extent, vitamin C (500 microM) and reduced glutathione (1 mM), inhibited AngII-induced [(3)H]-leucine uptake and atrial natriuretic factor (ANF) promoter activity. The hypertrophic response is mediated by superoxide anion (O(2)(-).) since cell-permeable polyethylene glycol (PEG)-conjugated superoxide dismutase (50 U/ml), but not PEG-catalase (500 U/ml), attenuated AngII-induced [(3)H]-leucine uptake and ANF promoter activity. Furthermore, NAC blocked AngII-induced increase in myocardial oxidative stress, decreased the expression of ANF and myosin light chain-2v, and inhibited the re-organization of cytoskeletal proteins, desmin and alpha-actinin. These effects of AngII were abolished by angiotensin type 1 receptor blocker, losartan, but not type 2 receptor blocker, PD123319. Indeed, co-administration of losartan (10 mg/kg/d, 14 d) or NAC (200 mg/kg/d, 14 d) inhibited AngII-induced O(2)(-). production and cardiac hypertrophy in rats without affecting blood pressure. These findings indicate that the generation of O(2)(-). contributes to oxidant-induced hypertrophic response and suggest that antioxidant therapy may have beneficial effects in cardiac hypertrophy.}, }
@article {pmid12816750, year = {2003}, author = {Gu, W and Weihrauch, D and Tanaka, K and Tessmer, JP and Pagel, PS and Kersten, JR and Chilian, WM and Warltier, DC}, title = {Reactive oxygen species are critical mediators of coronary collateral development in a canine model.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {285}, number = {4}, pages = {H1582-9}, doi = {10.1152/ajpheart.00318.2003}, pmid = {12816750}, issn = {0363-6135}, support = {HL-54820/HL/NHLBI NIH HHS/United States ; HL-63705/HL/NHLBI NIH HHS/United States ; HL-65203/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cell Division ; *Collateral Circulation ; *Coronary Circulation ; Coronary Disease/metabolism/pathology/*physiopathology ; Coronary Vessels/metabolism/pathology ; Dogs ; Endothelial Growth Factors/metabolism ; Endothelium, Vascular/pathology ; Extracellular Space/metabolism ; Intercellular Signaling Peptides and Proteins/metabolism ; Lymphokines/metabolism ; Muscle, Smooth, Vascular/pathology ; Myocardium/metabolism ; Neovascularization, Pathologic ; Reactive Oxygen Species/*metabolism ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {Recent evidence suggests that reactive oxygen species (ROS) promote proliferation and migration of vascular smooth muscle (VSMC) and endothelial cells (EC). We tested the hypothesis that ROS serve as crucial messengers during coronary collateral development. Dogs were subjected to brief (2 min), repetitive coronary artery occlusions (1/h, 8/day, 21 day duration) in the absence (occlusion, n = 8) or presence of N-acetylcysteine (NAC) (occlusion + NAC, n = 8). A sham group (n = 8) was instrumented identically but received no occlusions. In separate experiments, ROS generation after a single 2-min coronary artery occlusion was assessed with dihydroethidium fluorescence. Coronary collateral blood flow (expressed as a percentage of normal zone flow) was significantly increased (71 +/- 7%) in occlusion dogs after 21 days but remained unchanged (13 +/- 3%) in sham dogs. Treatment with NAC attenuated increases in collateral blood flow (28 +/- 8%). Brief coronary artery occlusion and reperfusion caused ROS production (256 +/- 33% of baseline values), which was abolished with NAC (104 +/- 12%). Myocardial interstitial fluid produced tube formation and proliferation of VSMC and EC in occlusion but not in NAC-treated or sham dogs. The results indicate that ROS are critical for the development of the coronary collateral circulation.}, }
@article {pmid12815614, year = {2003}, author = {Das, SK and Mukherjee, S and Smith, MG and Chatterjee, D}, title = {Prophylactic protection by N-acetylcysteine against the pulmonary injury induced by 2-chloroethyl ethyl sulfide, a mustard analogue.}, journal = {Journal of biochemical and molecular toxicology}, volume = {17}, number = {3}, pages = {177-184}, doi = {10.1002/jbt.10076}, pmid = {12815614}, issn = {1095-6670}, support = {2S06-GM 08037/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Caspases/metabolism ; Ceramides/metabolism ; Electrophoretic Mobility Shift Assay ; Free Radical Scavengers/*pharmacology ; Free Radicals/metabolism ; Guinea Pigs ; Lung/pathology ; Lung Diseases/*chemically induced/pathology/*prevention &amp; control ; Male ; Mustard Gas/*toxicity ; NF-kappa B/metabolism ; Sphingomyelin Phosphodiesterase/metabolism ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Mustard gas exposure causes adult respiratory distress syndrome associated with lung injury. The purpose of this study was to investigate whether an antioxidant, such as N-acetylcysteine (NAC), has any protective effect. Guinea pigs were given single exposure (0.5-6 mg/kg body weight) of 2-chloroethyl ethyl sulfide (CEES) as a mustard analogue intratracheally and maintained for various lengths of time (1 h to 21 days). Within 1 h of CEES infusion at 4 mg/kg, high levels of tumor necrosis factor alpha (TNF-alpha), ceramides, and nuclear factor kappaB accumulated in lung and alveolar macrophages. Both acid and neutral sphingomyelinases were activated within 4 h. These signal transduction events were associated with alteration in the oxygen defense system. Within 1 h of exposure to CEES (6 mg/kg body weight), there was 10-fold increase in the (125)I-BSA leakage into lung tissue, indicating severe lung injury. Although low level of CEES exposure (0.5 mg/kg body weight) produced symptoms of chemical burn in lung as early as 1 h after exposure, the severity of edema, congestion, hemorrhage, and inflammation increased progressively with time (1 h to 21 days). Feeding of single dose of NAC (0.5 g) by gavage just before the CEES infusion was ineffective to counteract these effects. However, consumption of the antioxidant in drinking water for 3 or 30 days prior to CEES exposure significantly inhibited the induction of TNF-alpha, activation of neutral and acid sphingomyelinases, production of ceramides, activation of caspases, leakage of (125)I-bovine serum albumin ((125)I-BSA) into lung tissue, and histological alterations in lung. Pretreatment with NAC for 3 and 30 days protected against 69-76% of the acute lung injury. Therefore, NAC may be an antidote for CEES-induced lung injury.}, }
@article {pmid12811453, year = {2003}, author = {Sevillano Cabeza, A and Moliner Martinez, Y and Molins Legua, C and Campíns Falcó, P}, title = {Rapid fluorimetric assay for primary amine groups in water samples.}, journal = {Analytical and bioanalytical chemistry}, volume = {376}, number = {6}, pages = {918-922}, doi = {10.1007/s00216-003-2004-0}, pmid = {12811453}, issn = {1618-2642}, abstract = {Bond Elut C(18) solid-phase extraction cartridges were used for pre-concentration followed by derivatization with o-phthaldialdehyde-N-acetylcysteine (OPA-NAC) of primary amines in water. Optimal conditions were: conditioning the cartridges with borate buffer pH 10.4, retention of the primary amines, addition of the OPA-NAC(3.7 mmol L(-1)) 1:1 molar ratio and borate buffer pH 8, elution of the isoindol with MeOH-borate buffer (9:1) pH 10.2 and fluorescence measurement. The equations of the calibration graphs for methylamine, ethylamine, propylamine, butylamine, pentylamine, and beta-phenylethylamine at lambda(excitation)=330 nm and lambda(emission)=440 nm, in the optimal conditions are presented. The solid-phase extraction procedure improved ten times the detection limits of the solution derivatization. Those values are in the 0.01-0.06 mg L(-1) interval in function of the amine. Also, it is possible to estimate the total primary aliphatic amine concentration in water, expressed as molar concentration of -NH(2) group or -NH(2)-N mg L(-1). On the basis of these studies, the method was applied for the determination of primary amino groups in tap, ground, factory and source water samples.}, }
@article {pmid12810678, year = {2003}, author = {Lin, X and Zhang, F and Bradbury, CM and Kaushal, A and Li, L and Spitz, DR and Aft, RL and Gius, D}, title = {2-Deoxy-D-glucose-induced cytotoxicity and radiosensitization in tumor cells is mediated via disruptions in thiol metabolism.}, journal = {Cancer research}, volume = {63}, number = {12}, pages = {3413-3417}, pmid = {12810678}, issn = {0008-5472}, support = {1 K08 CA72602-01/CA/NCI NIH HHS/United States ; P01 CA66081/CA/NCI NIH HHS/United States ; P01 CA75556/CA/NCI NIH HHS/United States ; P20 CA91709/CA/NCI NIH HHS/United States ; R01 HL51469/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Line, Transformed/drug effects/radiation effects ; Cell Transformation, Viral ; Cysteine/metabolism ; Deoxyglucose/pharmacology/*toxicity ; Dose-Response Relationship, Drug ; Fibroblasts/drug effects/metabolism/radiation effects ; Free Radicals ; Genes, fos ; Glucose/antagonists &amp; inhibitors/metabolism ; Glutathione/metabolism ; HeLa Cells/drug effects/metabolism/radiation effects ; Humans ; Oncogene Proteins v-fos/physiology ; Oxidation-Reduction ; Oxidative Stress ; Radiation-Protective Agents/pharmacology ; Radiation-Sensitizing Agents/pharmacology/*toxicity ; Rats ; Sulfhydryl Compounds/*metabolism ; Tumor Stem Cell Assay ; }, abstract = {Exposure to ionizing radiation is believed to cause cell injury via the production of free radicals that are thought to induce oxidative damage. It has been proposed that exposure to agents that enhance oxidative stress-induced injury by disrupting thiol metabolism may sensitize cells to the cytotoxic effects of ionizing radiation. Recently, it has been shown that glucose deprivation selectively induces cell injury in transformed human cells via metabolic oxidative stress (J. Biol. Chem., 273: 5294-5299; Ann. N.Y. Acad. Sci., 899: 349-362), resulting in profound disruptions in thiol metabolism. Because 2-deoxy-D-glucose (2DG) is a potent inhibitor of glucose metabolism thought to mimic glucose deprivation in vivo, the hypothesis that exposure to 2DG might be capable of inducing radiosensitization in transformed cells via perturbations in thiol metabolism was tested. When HeLa cells were exposed to 2DG (4-10 mM) for 4-72 h, cell survival decreased (20-90%) in a dose- and time-dependent fashion. When HeLa cells were treated with 6 mM 2DG for 16 h before ionizing radiation exposure, radiosensitization was observed with a sensitizer enhancement ratio of 1.4 at 10% isosurvival. Treatment with 2DG was also found to cause decreases in intracellular total glutathione content (50%). Simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC; 30 mM) protected HeLa cells against the cytotoxicity and radiosensitizing effects of 2DG, without altering radiosensitivity in the absence of 2DG. Furthermore, treatment with NAC partially reversed the 2DG-induced decreases in total glutathione content, as well as augmented intracellular cysteine content. Finally, the cytotoxicity and radiosensitizing effects of 2DG were more pronounced in v-Fos-transformed versus nontransformed immortalized rat cells, and this radiosensitization was also inhibited by treatment with NAC. These results support the hypothesis that exposure to 2DG causes cytotoxicity and radiosensitization via a mechanism involving perturbations in thiol metabolism and allows for the speculation that these effects may be more pronounced in transformed versus normal cells.}, }
@article {pmid12810389, year = {2003}, author = {Yan, QC and Xiong, AH and Xiao, X and Luo, YT}, title = {[Significance of plasma 8-iso-prostaglandin F2alpha level in acute myocardial ischemia and intervention effect of N-acetylcysteine: a study in rats].}, journal = {Di 1 jun yi da xue xue bao = Academic journal of the first medical college of PLA}, volume = {23}, number = {6}, pages = {605-607}, pmid = {12810389}, issn = {1000-2588}, mesh = {Acetylcysteine/*pharmacology ; Animals ; *Dinoprost/*analogs &amp; derivatives ; Electrocardiography ; F2-Isoprostanes/analysis/*blood ; Male ; Myocardial Infarction/*blood/physiopathology ; Myocardium/chemistry ; Rats ; Rats, Wistar ; }, abstract = {OBJECTIVE: To examine the correlation between 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) levels in the plasma and myocardial tissue of rats with myocardial ischemia and observe the intervention effect of N-acetylcysteine (NAC), for the purpose of assessing the value of 8-iso-PGF2alpha in estimating the extent of free radical damage and implementing possible interventions.<br><br>METHODS: Forty-five Wistar rats were divided into ischemia, ischemia+NAC and control groups, and in the former 2 groups, acute myocardial ischemia models were produced by pituitrin. Elevated ST segment in ECG served as the indicator for myocardial ischemia. Rats in ischemia+NAC group were pre-treated with NAC (0.1 g/kg x d) for three weeks before the ischemia 8-iso-PGF2alpha levels in the plasma and myocardial tissue were determined by enzyme-linked immunosorbent assay (ELISA).<br><br>RESULTS: In ischemia group, the 8-iso-PGF2alpha levels in the plasma and myocardial tissue were 187.4+/-45.8 pg/ml and 259.3+/-47.5 pg/g, respectively, higher than those in the control group (60.4+/-13.7 pg/ml and 88.6+/-16.9 pg/g, respectively, P<0.01) and those in ischemia+NAC group (88.2+/-16.4 pg/ml and 109.4+/-24.7 pg/g, respectively, P<0.01). A positive correlation was noted between the 8-iso-PGF2alpha levels in the plasma and myocardial tissue (r=0.865, P<0.01). In comparison with the control group, elevation of the ST segment of ECG in rats with myocardial ischemia was obvious, and the peak elevation occurred 45 min after ischemia (0.34+/-0.05 mV, P<0.01). Pre-treatment with NAC proved to help alleviate the subsequent ischemia, with ST segment elevation of only 0.18+/-0.05 mV.<br><br>CONCLUSION: In condition of acute myocardial ischemia in rats, 8-iso-PGF2alpha levels tend to increase, which can be indicative of the degree of myocardial ischemia. NAC pre-treatment can alleviate the ischemic condition by offsetting the damage caused by the free radicals.}, }
@article {pmid12808161, year = {2003}, author = {Locatelli, F and Canaud, B and Eckardt, KU and Stenvinkel, P and Wanner, C and Zoccali, C}, title = {Oxidative stress in end-stage renal disease: an emerging threat to patient outcome.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {18}, number = {7}, pages = {1272-1280}, doi = {10.1093/ndt/gfg074}, pmid = {12808161}, issn = {0931-0509}, mesh = {Cardiovascular Diseases/etiology/*mortality/*physiopathology ; *Consensus ; Humans ; Kidney Failure, Chronic/complications/*mortality/*physiopathology ; Oxidative Stress/*physiology ; Risk Factors ; Survival Rate ; }, abstract = {INTRODUCTION: Patients affected by end-stage renal disease (ESRD) experience an excess of morbidity and mortality due to cardiovascular disease (CVD), which cannot be fully explained by the classical CVD risk factors. Among emerging CVD risk factors, oxidative stress is currently being given emphasis.<br><br>METHODS: We achieved a consensus on key points relating to oxidative stress in ESRD patients.<br><br>RESULTS: ESRD patients are subjected to enhanced oxidative stress, as a result of reduced anti-oxidant systems (vitamin C and selenium deficiency, reduced intracellular levels of vitamin E, reduced activity of the glutathione system) and increased pro-oxidant activity (advanced age, high frequency of diabetes, chronic inflammatory state, uraemic syndrome, bio-incompatibility of dialysis membranes and solutions). Oxidative stress and inflammation are deeply inter-related, as different oxidant free radicals are generated by phagocytic cells in response to inflammatory stimuli: both are related to endothelial dysfunction, as the endothelium is a source and a target of oxidants and participates in the inflammatory response. There is growing evidence, from experimental and clinical studies, that oxidative stress may be implicated in the pathogenesis of atherosclerosis and other complications of ESRD, namely dialysis-related amyloidosis, malnutrition and anaemia. Given that free radicals have very short half-lives (seconds), the clinical assessment of oxidative stress is based on the measurement of different stable oxidized compounds (such as lipid peroxidation products, advanced glycation and oxidation lipid and protein products, nucleic acid oxidation derivatives) or antibodies directed against oxidized epitopes (such as anti-oxidized low-density lipoprotein antibodies). At the same time, both enzymatic anti-oxidants (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic anti-oxidants (glutathione, vitamin C, vitamin E, negative inflammatory proteins) can be evaluated. However, many laboratory methods assessing various oxidative stress components still have to be standardized. Moreover, it is still uncertain whether it is better measuring plasma and/or intracellular concentrations or activities of these components. The possibility of improving patient outcome by therapeutic interventions aimed at reducing oxidative stress, e.g. by vitamin C or vitamin E supplementation, currently is to the fore, but results so far have remained inconclusive.<br><br>CONCLUSIONS: It is important to consider oxidative stress as a potentially important source of patient morbidity and mortality, although this knowledge is not yet immediately applicable in the clinical arena. Further well-designed, randomized controlled clinical trials with anti-oxidants (e.g. vitamin E, vitamin C, N-acetyl cysteine, L-arginine) are required to establish evidence-based recommendations for clinical practice.}, }
@article {pmid12807727, year = {2003}, author = {Woo, JH and Kim, YH and Choi, YJ and Kim, DG and Lee, KS and Bae, JH and Min, DS and Chang, JS and Jeong, YJ and Lee, YH and Park, JW and Kwon, TK}, title = {Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt.}, journal = {Carcinogenesis}, volume = {24}, number = {7}, pages = {1199-1208}, doi = {10.1093/carcin/bgg082}, pmid = {12807727}, issn = {0143-3334}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Carcinoma, Renal Cell/metabolism/pathology ; Caspases/*metabolism ; Curcumin/*pharmacology ; Cytochrome c Group/*metabolism ; Down-Regulation ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Neoplastic ; Humans ; Inhibitor of Apoptosis Proteins ; Kidney Neoplasms/metabolism/pathology ; Mitochondria/drug effects ; Poly(ADP-ribose) Polymerases/metabolism ; *Protein Serine-Threonine Kinases ; Proteins/antagonists &amp; inhibitors/metabolism ; Proto-Oncogene Proteins/*antagonists &amp; inhibitors/genetics/metabolism ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins c-bcl-2/antagonists &amp; inhibitors/*metabolism ; RNA, Messenger/metabolism ; *Reactive Oxygen Species ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured ; bcl-2-Associated X Protein ; bcl-X Protein ; }, abstract = {Curcumin, a natural, biologically active compound extracted from rhizomes of Curcuma species, has been shown to possess potent anti-inflammatory, anti-tumor and anti-oxidative properties. The mechanism by which curcumin initiates apoptosis remains poorly understood. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human renal Caki cells. Treatment of Caki cells with 50 microM curcumin resulted in the activation of caspase 3, cleavage of phospholipase C-gamma1 and DNA fragmentation. Curcumin-induced apoptosis is mediated through the activation of caspase, which is specifically inhibited by the caspase inhibitor, benzyloxycarbony-Val-Ala-Asp-fluoromethyl ketone. Curcumin causes dose-dependent apoptosis and DNA fragmentation of Caki cells, which is preceded by the sequential dephosphorylation of Akt, down-regulation of the anti-apoptotic Bcl-2, Bcl-XL and IAP proteins, release of cytochrome c and activation of caspase 3. Cyclosporin A, as well as caspase inhibitor, specifically inhibit curcumin-induced apoptosis in Caki cells. Pre-treatment with N-acetyl-cysteine, markedly prevented dephosphorylation of Akt, and cytochrome c release, and cell death, suggesting a role for reactive oxygen species in this process. The data indicate that curcumin can cause cell damage by inactivating the Akt-related cell survival pathway and release of cytochrome c, providing a new mechanism for curcumin-induced cytotoxicity.}, }
@article {pmid12802283, year = {2003}, author = {Alonso, MM and Asumendi, A and Villar, J and Gil, MJ and Martínez-Merino, V and Encío, IJ and Migliaccio, M}, title = {New benzo(b)thiophenesulphonamide 1,1-dioxide derivatives induce a reactive oxygen species-mediated process of apoptosis in tumour cells.}, journal = {Oncogene}, volume = {22}, number = {24}, pages = {3759-3769}, doi = {10.1038/sj.onc.1206435}, pmid = {12802283}, issn = {0950-9232}, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase 3 ; Caspase 8 ; Caspase 9 ; Caspases/metabolism ; Humans ; Membrane Proteins/analysis ; Mitochondria/drug effects/physiology ; Oligopeptides/pharmacology ; Proto-Oncogene Proteins/analysis ; Proto-Oncogene Proteins c-bcl-2/analysis ; Reactive Oxygen Species/*metabolism ; Sulfonamides/*pharmacology ; Thiophenes/pharmacology ; Tumor Cells, Cultured ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein ; bcl-X Protein ; }, abstract = {In this work, we describe the process of cell death induced by a series of new benzo(b)thiophenesulphonamide 1,1-dioxide derivatives (BTS) that have been selected as candidate antineoplastic drugs. Human leukaemic CCRF-CEM cells incubated with BTS undergo a typical apoptotic process that includes cell shrinkage, phosphatidylserine translocation to the cell surface, mitochondrial dysfunction, caspase activation, chromatin condensation and internucleosomal DNA degradation. Mitochondrial alterations included dissipation of the mitochondrial membrane potential, oxidation of the phospholipid cardiolipin, release of cytochrome c and uncoupling of the mitochondrial respiratory chain, leading to a decrease of the intracellular ATP pool. Activation of caspase-8, -9 and -3 takes place during BTS-induced apoptosis. Either the addition of the specific caspase-8 inhibitor Z-IETD-fmk, or the overexpression of the antiapoptotic protein Bcl-2 significantly prevented BTS-induced apoptosis, suggesting the involvement of both caspase-8-regulated and mitochondria-dependent signalling pathways in this process. BTS induce a significant increase in the production and accumulation of intracellular reactive oxygen species (ROS) that can be observed within minutes after drug addition. Moreover, cytochrome c release, caspase-3 activation and cell death can be completely abrogated by a previous incubation with the antioxidant N-acetyl-cysteine. These results suggest that ROS are essential mediators in BTS-induced apoptosis.}, }
@article {pmid12801522, year = {2003}, author = {Sumbayev, VV}, title = {S-nitrosylation of thioredoxin mediates activation of apoptosis signal-regulating kinase 1.}, journal = {Archives of biochemistry and biophysics}, volume = {415}, number = {1}, pages = {133-136}, doi = {10.1016/s0003-9861(03)00199-1}, pmid = {12801522}, issn = {0003-9861}, mesh = {Antioxidants/pharmacology ; Blotting, Western ; Cell Line ; Colorimetry ; Dose-Response Relationship, Drug ; Enzyme Activation ; Humans ; Kidney/drug effects/enzymology ; MAP Kinase Kinase Kinase 5 ; MAP Kinase Kinase Kinases/*biosynthesis/*chemistry ; Nitrosation ; S-Nitrosoglutathione/*chemistry/pharmacology ; Sulfur/chemistry/metabolism ; Thioredoxins/*chemistry/*metabolism ; }, abstract = {Apoptosis signal-regulating kinase 1 (ASK1) was recently discovered as a typical member of the mitogen-activated protein (MAP) kinase kinase kinase family, which induces apoptosis by activation of c-Jun-N-terminal kinase/p38 MAP kinase pathways. In normal cells ASK1 is directly inhibited by thioredoxin (Trx), a 12-kDa protein ubiquitously expressed in all living cells, which has a variety of biological functions related to cell proliferation and apoptosis. Here we found that purified Trx is sensitive to S-nitrosylation. Stimulation of HEK-293 cells with S-nitrosoglutathione (GSNO) for 2, 4, 8, and 16h also caused Trx S-nitrosylation, which showed straight correlation with ASK1 activation based on Western blot detection of the enzyme, immunoprecipitation assay, and measurement of its catalytic activity. These results suggest that S-nitrosylation of Trx induces ASK1 activation. Treatment of cells with N-acetyl-cysteine for 2h after 8h of pretreatment with GSNO caused an increase in glutathione and nullified ASK1 activation.}, }
@article {pmid12799770, year = {2003}, author = {Hirano, S and Cui, X and Li, S and Kanno, S and Kobayashi, Y and Hayakawa, T and Shraim, A}, title = {Difference in uptake and toxicity of trivalent and pentavalent inorganic arsenic in rat heart microvessel endothelial cells.}, journal = {Archives of toxicology}, volume = {77}, number = {6}, pages = {305-312}, doi = {10.1007/s00204-003-0447-x}, pmid = {12799770}, issn = {0340-5761}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants ; Arsenates/metabolism/pharmacokinetics/*toxicity ; Arsenites/metabolism/pharmacokinetics/*toxicity ; Biological Transport/*drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Death/drug effects ; Cell Division/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Drug-Related Side Effects and Adverse Reactions ; Endothelium, Vascular/cytology/*drug effects/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Enzymologic/drug effects ; Heme Oxygenase (Decyclizing)/biosynthesis/genetics ; Heme Oxygenase-1 ; Humans ; Membrane Proteins ; NADP/biosynthesis/genetics ; Oligonucleotide Array Sequence Analysis ; Oxidative Stress ; Rats ; Thioredoxins/biosynthesis/genetics ; }, abstract = {Intake of inorganic arsenic is known to cause vascular diseases as well as skin lesions and cancer in humans. We investigated the differences in cytotoxicity, uptake rate of arsenic, and gene expression of antioxidative enzymes between arsenite (As(3+))- and arsenate (As(5+))-exposed rat heart microvessel endothelial cells. As(3+) was more cytotoxic than As(5+), and LC(50) values were calculated to be 36 and 220 micro M, respectively. As(3+) (1-25 micro M) increased mRNA levels of antioxidant enzymes such as heme oxygenase-1 (HO-1), thioredoxin peroxidase 2, NADPH dehydrogenase, and glutathione S-transferase P subunit. HO-1 mRNA levels showed the most remarkable increase in response to As(3+). cDNA microarray analysis indicated that there was no prominent difference in arsenic-induced transcriptional changes between As(3+)- and As(5+)-exposed cells, when the cells were exposed to one-fourth the LC(50) concentration of arsenic (9 and 55 micro M for As(3+) and As(5+), respectively). N-acetyl- l-cysteine (NAC) reduced both the cytotoxicity of inorganic arsenic and the HO-1 mRNA level, and buthionine sulfoximine enhanced cytotoxicity of inorganic arsenic. As(3+) was taken up by the endothelial cells 6-7 times faster than As(5+), and the presence of NAC in the culture medium did not change the uptake rate of As(3+). These results suggest that the effects of NAC on arsenic-induced cytotoxicity and oxidative stress were due to the antioxidative role of non-protein thiols and not to chelation of arsenic in the culture medium. The difference in cellular uptake of arsenic between As(3+) and As(5+) appeared not to be due to the ionic charge on arsenic (at physiological pH, trivalent arsenic is neutral whereas pentavalent arsenic is negatively charged). These results suggest that the higher toxicity of As(3+) compared with that of As(5+) is probably due to the faster uptake of As(3+) by endothelial cells, and inorganic arsenic exerts its toxicity at least in part via intracellular oxidative stress.}, }
@article {pmid12799318, year = {2003}, author = {Haber, CA and Lam, TK and Yu, Z and Gupta, N and Goh, T and Bogdanovic, E and Giacca, A and Fantus, IG}, title = {N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress.}, journal = {American journal of physiology. Endocrinology and metabolism}, volume = {285}, number = {4}, pages = {E744-53}, doi = {10.1152/ajpendo.00355.2002}, pmid = {12799318}, issn = {0193-1849}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Glucose/analysis/metabolism ; Glucose/*administration &amp; dosage ; Insulin/blood/*metabolism ; Insulin Resistance/*physiology ; Male ; Muscle, Skeletal/*metabolism ; Oxidative Stress/drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; Taurine/*pharmacology ; }, abstract = {Exposure to high concentrations of glucose and insulin results in insulin resistance of metabolic target tissues, a characteristic feature of type 2 diabetes. High glucose has also been associated with oxidative stress, and increased levels of reactive oxygen species have been proposed to cause insulin resistance. To determine whether oxidative stress contributes to insulin resistance induced by hyperglycemia in vivo, nondiabetic rats were infused with glucose for 6 h to maintain a circulating glucose concentration of 15 mM with and without coinfusion of the antioxidant N-acetylcysteine (NAC), followed by a 2-h hyperinsulinemic-euglycemic clamp. High glucose (HG) induced a significant decrease in insulin-stimulated glucose uptake [tracer-determined disappearance rate (Rd), control 41.2 +/- 1.7 vs. HG 32.4 +/- 1.9 mg. kg-1. min-1, P < 0.05], which was prevented by NAC (HG + NAC 45.9 +/- 3.5 mg. kg-1. min-1). Similar results were obtained with the antioxidant taurine. Neither NAC nor taurine alone altered Rd. HG caused a significant (5-fold) increase in soleus muscle protein carbonyl content, a marker of oxidative stress that was blocked by NAC, as well as elevated levels of malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation, which were reduced by taurine. In contrast to findings after long-term hyperglycemia, there was no membrane translocation of novel isoforms of protein kinase C in skeletal muscle after 6 h. These data support the concept that oxidative stress contributes to the pathogenesis of hyperglycemia-induced insulin resistance.}, }
@article {pmid12794160, year = {2003}, author = {Woo, CH and Yoo, MH and You, HJ and Cho, SH and Mun, YC and Seong, CM and Kim, JH}, title = {Transepithelial migration of neutrophils in response to leukotriene B4 is mediated by a reactive oxygen species-extracellular signal-regulated kinase-linked cascade.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {170}, number = {12}, pages = {6273-6279}, doi = {10.4049/jimmunol.170.12.6273}, pmid = {12794160}, issn = {0022-1767}, mesh = {Animals ; Cell Differentiation/drug effects ; Diffusion Chambers, Culture ; Enzyme Activation/drug effects/physiology ; Epithelial Cells/*cytology/drug effects/metabolism/*physiology ; Female ; HL-60 Cells ; Humans ; Intubation, Intratracheal ; Leukotriene B4/administration &amp; dosage/*pharmacology ; MAP Kinase Signaling System/*physiology ; Mice ; Mice, Inbred BALB C ; Mitogen-Activated Protein Kinases/*physiology ; Neutrophil Infiltration/drug effects/*physiology ; Neutrophils/cytology/drug effects/enzymology/*physiology ; Reactive Oxygen Species/*metabolism ; Respiratory Mucosa/drug effects/enzymology/metabolism/physiology ; }, abstract = {The epithelial cells that form a barrier lining the lung airway are key regulators of neutrophil trafficking into the airway lumen in a variety of lung inflammatory diseases. Although the lipid mediator leukotriene B(4) (LTB(4)) is known to be a principal chemoattractant for recruiting neutrophils to inflamed sites across the airway epithelium, the precise signaling mechanism involved remains largely unknown. In the present study, therefore, we investigated the signaling pathway through which LTB(4) induces transepithelial migration of neutrophils. We found that LTB(4) induces concentration-dependent transmigration of DMSO-differentiated HL-60 neutrophils and human polymorphonuclear neutrophils across A549 human lung epithelium. This effect was mediated via specific LTB(4) receptors and was inhibited by pretreating the cells with N-acetylcysteine (NAC), an oxygen free radical scavenger, with diphenylene iodonium (DPI), an inhibitor of NADPH oxidase-like flavoproteins, or with PD98059, an extracellular signal-regulated kinase (ERK) inhibitor. Consistent with those findings, LTB(4)-induced ERK phosphorylation was completely blocked by pretreating cells with NAC or DPI. Taken together, our observations suggest LTB(4) signaling to transepithelial migration is mediated via generation of reactive oxygen species, which leads to downstream activation of ERK. The physiological relevance of this signaling pathway was demonstrated in BALB/c mice, in which intratracheal instillation of LTB(4) led to acute recruitment of neutrophils into the airway across the lung epithelium. Notably, the response to LTB(4) was blocked by NAC, DPI, PD98059, or CP105696, a specific LTB(4) receptor antagonist.}, }
@article {pmid12787403, year = {2003}, author = {Zager, RA and Johnson, AC and Hanson, SY}, title = {Radiographic contrast media-induced tubular injury: evaluation of oxidant stress and plasma membrane integrity.}, journal = {Kidney international}, volume = {64}, number = {1}, pages = {128-139}, doi = {10.1046/j.1523-1755.2003.00059.x}, pmid = {12787403}, issn = {0085-2538}, support = {R01 DK 38432/DK/NIDDK NIH HHS/United States ; R0154200//PHS HHS/United States ; }, mesh = {Adenosine Triphosphate/metabolism ; Animals ; Caveolin 1 ; Caveolins/metabolism ; Cell Line ; Cell Membrane ; *Contrast Media/pharmacology ; Cytochromes c/metabolism ; Humans ; In Vitro Techniques ; Kidney Diseases/*chemically induced/metabolism ; Kidney Tubules, Proximal/*drug effects/*metabolism ; Lipid Peroxidation/drug effects ; Male ; Mice ; Mice, Inbred Strains ; Mitochondria/drug effects ; Ouabain/pharmacology ; Oxidative Stress ; Phospholipases A/pharmacology ; Phospholipases A2 ; Sodium-Potassium-Exchanging ATPase/metabolism ; *Triiodobenzoic Acids/pharmacology ; }, abstract = {BACKGROUND: Experimental and clinical investigations suggest that oxidant stress is a critical determinant of radiocontrast nephropathy (RCN), and that N acetyl cysteine (NAC) can prevent this damage. This study addresses these issues directly at the tubular cell level. Potential alternative mechanisms for RCN have also been sought.<br><br>METHODS: Isolated mouse proximal tubule segments (PTS), or cultured proximal tubule (HK-2) cells, were subjected to radiocontrast media (RCM) (Ioversol, Optiray 320) exposure, followed by assessments of cellular viability [% lactate dehydrogenase (LDH) release, tetrazolium dye (MTT), uptake] and lipid peroxidation. These experiments were conducted in the absence or presence of a variety of antioxidants [NAC, glutathione (GSH), superoxide dismutase, catalase] or pro-oxidant (GSH depletion, heme oxygenase inhibition) strategies. RCM effects on mitochondrial and plasma membrane integrity were also assessed.<br><br>RESULTS: RCM exposure did not induce PTS lipid peroxidation. Neither antioxidant nor pro-oxidant interventions mitigated or exacerbated RCM-induced tubular cell injury, respectively. RCM impaired mitochondrial integrity, as assessed by ouabain-resistant ATP reductions, and by cytochrome c release (before cell death). RCM also induced plasma membrane damage, as indicated by loss of key resident proteins (NaK-ATPase, caveolin) and by increased susceptibility to phospholipase A2 (PLA2) attack (increase of >/=2 times in free fatty acid and NaK-ATPase release). Hyperosmolality could not account for RCM's toxic effects.<br><br>CONCLUSION: RCM toxicity can be dissociated from tubular cell oxidant stress. Alternative mechanisms may include mitochondrial injury/cytochrome c release and plasma membrane damage. The latter results in critical protein loss, as well as a marked increase in plasma membrane susceptibility to exogenous/endogenous PLA2 attack.}, }
@article {pmid12787398, year = {2003}, author = {Witko-Sarsat, V and Gausson, V and Nguyen, AT and Touam, M and Drüeke, T and Santangelo, F and Descamps-Latscha, B}, title = {AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: a potential target for N-acetylcysteine treatment in dialysis patients.}, journal = {Kidney international}, volume = {64}, number = {1}, pages = {82-91}, doi = {10.1046/j.1523-1755.2003.00044.x}, pmid = {12787398}, issn = {0085-2538}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Blood Proteins/administration &amp; dosage/*metabolism/pharmacology ; Dose-Response Relationship, Drug ; Humans ; Monocytes/*metabolism ; NADP/metabolism ; Neutrophils/drug effects/*metabolism ; Oxidation-Reduction/drug effects ; Oxygen/metabolism ; Peroxidase/metabolism ; Platelet Activating Factor/pharmacology ; Serum Albumin/pharmacology ; Uremia/metabolism/pathology ; }, abstract = {UNLABELLED: AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: A potential target forN-acetylcysteine treatment in dialysis patients.<br><br>BACKGROUND: Oxidative stress largely contributes to hemodialysis-associated lethal complications, thus explaining the urgent need of antioxidant-based therapeutic strategies in hemodialysis patients. We previously identified advanced oxidation protein products (AOPP) in the uremic plasma as exquisite markers of oxidative stress and potent mediators of monocyte activation. The present study was aimed at searching whether (1) AOPP can also trigger activation of polymorphonuclear neutrophils (PMN), and (2) whether AOPP-induced activation could be inhibited by N-acetylcysteine (NAC), a widely used compound which has been shown to prevent oxidative injury to kidney.<br><br>METHODS: Both human serum albumin (HAS) AOPP (i.e., HOCl-modified HSA in vitro preparations and AOPP extracted from plasma of hemodialysis patients) were tested for their capacity to trigger phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase (MPO)-dependent activities as measured by lucigenin- and luminol-amplified chemiluminescence (CL), respectively, as compared to receptor-dependent [opsonized zymosan or receptor-independent phorbol myristate acetate (PMA)]. The effect of PMN priming by platelet-activating factor (PAF), and the effect of NAC on normal monocyte and on normal or hemodialysis patient's (N = 16) PMN oxidative responses were compared.<br><br>RESULTS: HSA-AOPP triggered in a HOCl dose-dependent manner both NADPH-oxidase- and MPO-dependent CL of PMN. This latter was further enhanced by PAF priming. Plasma-derived AOPP obtained from hemodialysis patients also triggered PMN respiratory burst. NAC significantly reduced HSA-AOPP-mediated responses of normal monocyte and of normal and uremic PMN but had no significant effect on opsonized zymosan- or PMA-induced CL responses.<br><br>CONCLUSION: This dual potential of NAC to inhibit phagocyte oxidative responses induced by HSA-AOPP without affecting those mediated by compounds mimicking pathogens supports the proposal of a therapeutic trial with NAC aimed at reducing oxidative stress-related inflammation in hemodialysis patients.}, }
@article {pmid12785062, year = {2003}, author = {Zhang, M and An, L and Feng, H and Chen, T and Chen, K and Liu, Y and Tang, H and Chang, J and Wang, X}, title = {The cascade mechanisms of nitric oxide as a second messenger of ultraviolet B in inhibiting mesocotyl elongations.}, journal = {Photochemistry and photobiology}, volume = {77}, number = {2}, pages = {219-225}, doi = {10.1562/0031-8655(2003)077&lt;0219:tcmono&gt;2.0.co;2}, pmid = {12785062}, issn = {0031-8655}, mesh = {Nitric Oxide/*physiology ; Second Messenger Systems/*physiology ; *Ultraviolet Rays ; Zea mays/*growth &amp; development ; }, abstract = {In this report, a number of physiological aspects was examined during developmental growth of maize seedling's mesocotyl. It was found that ultraviolet B (UVB) radiation was able to significantly induce nitric oxide synthase (NOS) activities and speedup the release of apparent nitric oxide (NO) of mesocotyl and that exogenous NO donor's rhizospheric treatments may mimic the responses of the mesocotyl to UVB radiation, such as the inhibition of mesocotyl elongation, the decrease in exo- and endoglucanase activities and the increase in protein content of cell wall of mesocotyl. When the seedlings were treated with N-nitro-L-arginine, an inhibitor of NOS, the mesocotyl elongation was promoted, the exo- and endoglucanase activities were raised and the protein content was reduced. However, under UVB radiation, the effects of exogenous NO on several physiological aspects of mesocotyl were similar to those of exogenous reactive oxygen species (ROS) eliminator, N-acetyl-cysteine. All the physiological changes were associated with either the exogenous NO supply or the activities of NOS in plant. Accordingly, it is assumed that reduction in mesocotyl length caused by UVB radiation was possibly achieved through modification of the chemical properties of the cell wall polysaccharides, which was induced by NO and ROS synergically mediated changes in exo- and endo-beta-D-glucanases activities in cell walls, and NO was one of the main signaling molecule of UVB radiation in inhibiting mesocotyl elongations. So NO might function as both a second messenger and an antioxidant of UVB radiation during developmental growth of the mesocotyl.}, }
@article {pmid12784861, year = {2003}, author = {Ou, CC and Tsao, SM and Lin, MC and Yin, MC}, title = {Protective action on human LDL against oxidation and glycation by four organosulfur compounds derived from garlic.}, journal = {Lipids}, volume = {38}, number = {3}, pages = {219-224}, pmid = {12784861}, issn = {0024-4201}, mesh = {Acetylcysteine/pharmacology ; Allyl Compounds/pharmacology ; Amphotericin B/pharmacology ; Antioxidants/*pharmacology ; Chelating Agents/pharmacology ; Copper/pharmacology ; Cysteine/*analogs &amp; derivatives/pharmacology ; Disulfides/pharmacology ; Edetic Acid/pharmacology ; *Garlic ; Glucose/pharmacology ; Humans ; Lipoproteins, LDL/drug effects/*metabolism ; Oxidation-Reduction ; Sulfides/pharmacology ; Sulfur Compounds/*pharmacology ; Superoxides/metabolism ; Xanthine Oxidase/drug effects/metabolism ; }, abstract = {Human LDL were used to study the protective action of four organosulfur compounds (diallyl sulfide, DAS; diallyl disulfide, DADS; S-ethylcysteine, SEC; N-acetylcysteine, NAC) derived from garlic against oxidation and glycation. The four organosulfur compounds significantly inhibited superoxide production by xanthine-xanthine oxidase (P < 0.05) and showed marked copper-chelating capability. DAS and DADS exhibited greater antioxidant activities against copper- and amphotericin B-induced LDL oxidation (P < 0.05) than SEC and NAC. However, SEC and NAC were more effective in sparing LDL alpha-tocopherol (P < 0.05). When oxidation was minimized, SEC was the most powerful agent against LDL glycation (P < 0.05); however, DADS was superior to other agents in suppressing both oxidation and glycation when LDL oxidation occurred simultaneously with glycation. These results suggest that the four organosulfur compounds derived from garlic are potent agents for protecting LDL against oxidation and glycation, and that they may benefit patients with diabetes mellitus or cardiovascular diseases by preventing complications.}, }
@article {pmid12781632, year = {2003}, author = {Tonkin, EG and Valentine, HL and Zimmerman, LJ and Valentine, WM}, title = {Parenteral N,N-diethyldithiocarbamate produces segmental demyelination in the rat that is not dependent on cysteine carbamylation.}, journal = {Toxicology and applied pharmacology}, volume = {189}, number = {2}, pages = {139-150}, doi = {10.1016/s0041-008x(03)00093-0}, pmid = {12781632}, issn = {0041-008X}, support = {ES06387/ES/NIEHS NIH HHS/United States ; ES07028/ES/NIEHS NIH HHS/United States ; F32 AA05569/AA/NIAAA NIH HHS/United States ; P30 ES00267/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Body Weight/drug effects ; Chelating Agents/*toxicity ; Chromatography, High Pressure Liquid ; Cysteine/*chemistry ; Demyelinating Diseases/blood/*chemically induced/pathology ; Ditiocarb/*analogs &amp; derivatives/chemistry/*toxicity ; Globins/analysis ; Infusion Pumps, Implantable ; Infusions, Parenteral ; Male ; Neurofilament Proteins/analysis ; Peripheral Nerves/*drug effects/ultrastructure ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Disulfiram, a dithiocarbamate drug used in alcohol aversion therapy, produces a peripheral neuropathy characterized in rats as segmental demyelination accompanied by generation of S-(diethylaminocarbonyl)cysteine (DETC-Cys) adducts. N,N-Diethyldithiocarbamate (DEDC) is a major metabolite of disulfiram that can undergo methylation and oxidation to S-methyl-N,N-diethylthiocarbamate (MeDETC) sulfoxide and sulfone, thought to be responsible for carbamylation of sulfhydryl functions by disulfiram. To assess the role of cysteine carbamylation in disulfiram toxicity, DEDC and MeDETC were administered parenterally to male Sprague-Dawley rats for 4 and 8 weeks. The roles of the disulfide linkage in disulfiram and of carbamylated glutathione metabolites were assessed by administering S-(diethylaminodithiocarbonyl)N-acetylcysteine (DS-NAC) and S-(diethylaminocarbonyl)-N-acetylcysteine (DETC-NAC), respectively, parenterally for 12 weeks. Following exposure, spinal cord-derived neurofilament preparations and hemoglobin were isolated and analyzed by RP-HPLC and LC/MS/MS for the presence of DETC-Cys adducts. Peripheral nerve sections were also obtained and examined by light and electron microscopy for morphological lesions. RP-HPLC analysis of globin preparations from DEDC-, MeDETC-, and DS-NAC-exposed animals demonstrated a late-eluting peak, identical to that reported for disulfiram-generated DETC-Cys adducts on the beta(3)-globin chain. DETC-NAC exposure did not result in detectable globin modification by RP-HPLC. The quantity of DETC-Cys adducts produced on globin and neurofilament preparations determined by LC/MS/MS was twofold greater for MeDETC than DEDC following equimolar doses of each compound. Primary myelin lesions consisting of demyelinated axons and myelin splitting were observed in peripheral nerves following exposure to DEDC for 8 weeks. No lesions were detected following exposure to MeDETC, DS-NAC, or DETC-NAC at any time point or dose level. These results are consistent with DEDC, but not the other metabolites, being a demyelinating agent and thus a potential proximate toxic species for disulfiram-mediated demyelination. The production of significantly greater levels of DETC-Cys adducts by MeDETC relative to DEDC in the absence of neurotoxicity for MeDETC is consistent with cysteine carbamylation not contributing to the demyelination produced by disulfiram and DEDC.}, }
@article {pmid12777158, year = {2003}, author = {Patrick, L}, title = {Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity.}, journal = {Alternative medicine review : a journal of clinical therapeutic}, volume = {8}, number = {2}, pages = {106-128}, pmid = {12777158}, issn = {1089-5159}, mesh = {Antioxidants/*therapeutic use ; Arsenic/metabolism ; Arsenic Poisoning/complications/*drug therapy ; Cadmium/metabolism ; Cadmium Poisoning/complications/*drug therapy ; Chelating Agents/*therapeutic use ; Heavy Metal Poisoning ; Humans ; Metals, Heavy/metabolism ; Methylation ; Risk Factors ; }, abstract = {Exposure to toxic metals has become an increasingly recognized source of illness worldwide. Both cadmium and arsenic are ubiquitous in the environment, and exposure through food and water as well as occupational sources can contribute to a well-defined spectrum of disease. The symptom picture of arsenic toxicity is characterized by dermal lesions, anemia, and an increased risk for cardiovascular disease, diabetes, and liver damage. Cadmium has a significant effect on renal function, and as a result alters bone metabolism, leading to osteoporosis and osteomalacia. Cadmium-induced genotoxicity also increases risk for several cancers. The mechanisms of arsenic- and cadmium-induced damage include the production of free radicals that alter mitochondrial activity and genetic information. The metabolism and excretion of these heavy metals depend on the presence of antioxidants and thiols that aid arsenic methylation and both arsenic and cadmium metallothionein-binding. S-adenosylmethionine, lipoic acid, glutathione, selenium, zinc, N-acetylcysteine (NAC), methionine, cysteine, alpha-tocopherol, and ascorbic acid have specific roles in the mitigation of heavy metal toxicity. Several antioxidants including NAC, zinc, methionine, and cysteine, when used in conjunction with standard chelating agents, can improve the mobilization and excretion of arsenic and cadmium.}, }
@article {pmid12776794, year = {2003}, author = {Bond, GR and Wiegand, CB and Hite, LK}, title = {The difficulty of risk assessment for hepatic injury associated with supra-therapeutic acetaminophen use.}, journal = {Veterinary and human toxicology}, volume = {45}, number = {3}, pages = {150-153}, pmid = {12776794}, issn = {0145-6296}, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Adolescent ; Adult ; Aged ; Alcohol Drinking ; Analgesics, Non-Narcotic/administration &amp; dosage/*toxicity ; Chemical and Drug Induced Liver Injury/*epidemiology/etiology/*pathology ; Child ; Cohort Studies ; Female ; Humans ; Liver Function Tests ; Male ; Medical Records ; Middle Aged ; Nonprescription Drugs/administration &amp; dosage/toxicity ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Self Medication ; Severity of Illness Index ; Virginia/epidemiology ; }, abstract = {We examined historical and laboratory features to identify patients who do not experience hepatic injury when presenting with a history of repeated supra-therapeutic acetaminophen use by performing a retrospective, double cohort comparison over almost 5 y. One cohort included patients suffering severe hepatic injury after supra-therapeutic acetaminophen ingestion; the control cohort included all patients in a geographically limited population with repeated supra-therapeutic acetaminophen ingestion who did not experience severe hepatic injury. Demographics, baseline health, medications, ethanol consumption, acetaminophen dosage, reason for excessive acetaminophen dosing, acetaminophen concentration at presentation, presentation and peak hepatic enzymes, N-acetylcysteine (NAC) treatment, highest measured AST and outcome were abstracted from 1114 possible patient contacts. Twenty two of these met all inclusion criteria. Ten suffered severe hepatic injury, 12 did not. The actual acetaminophen dose consumed over a period of time was difficult to establish, but the historic quantity ingested exceeded 20 g in the majority of patients in both groups. High ethanol use was common in both groups. All patients who ultimately suffered severe liver injury presented with some injury. No patient who presented without some injury suffered severe injury. None of these patients were treated with NAC. Two patients who presented with minor injury (1 of whom received NAC), did not progress to severe injury. Future investigations of the cause of liver injury in patients exposed to supra-therapeutic doses of acetaminophen will require larger patient numbers. The lack of injury in similarly exposed patients underscores the peril of attempting to assess the role of risk factors without an appropriate control group. Our experience suggests history is unlikely to be clinically useful in predicting risk of injury. Future risk assessment studies should focus on objective presentation features like presence or absence of injury or serum acetaminophen levels.}, }
@article {pmid12773760, year = {2003}, author = {Kang, J and Zhang, Y and Chen, J and Chen, H and Lin, C and Wang, Q and Ou, Y}, title = {Nickel-induced histone hypoacetylation: the role of reactive oxygen species.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {74}, number = {2}, pages = {279-286}, doi = {10.1093/toxsci/kfg137}, pmid = {12773760}, issn = {1096-6080}, mesh = {Acetylation ; Acetyltransferases/*antagonists &amp; inhibitors ; Antioxidants/pharmacology ; Carcinogens/*toxicity ; Carcinoma, Hepatocellular/enzymology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Combinations ; Enzyme Inhibitors/pharmacology ; Hepatocytes/drug effects/enzymology ; Histone Acetyltransferases ; Histone Deacetylase Inhibitors ; Histones/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Hydroxamic Acids/pharmacology ; Nickel/*toxicity ; Reactive Oxygen Species/*metabolism ; }, abstract = {The carcinogenicity of specific insoluble nickel compounds is mainly due to their intracellular generation of Ni2+ ion and its suppression on gene transcription, while the inhibition of Ni2+ on histone acetylation plays an important role in the suppression or silencing of genes. Recent studies on Ni2+ and histone H4 acetylation suggest that Ni2+ inhibits the acetylation of histone H4 through binding with its N-terminal histidine-18. It is well known that bound Ni2+ readily produces reactive oxygen species (ROS) in vivo, a critical factor inversely related with the occurrence of resistance of mammalian cells to Ni2+. Thus, we tried to find the possible role of ROS in the induction of Ni2+ on histone acetylation in the present study. We found that a high concentration of Ni2+ (no less than 600 microM) caused a significant decrease of histone acetylation in human hepatoma cells. This inhibition was shown to result mainly from the influence of Ni2+ on the overall histone acetyltransferase (HAT) activity indicated by the histone acetylation assay with the presence of a specific histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). The in vitro HAT and HDAC assays further confirmed this result. At the same time, we found that the exposure of hepatoma cells to Ni2+ generated ROS. Coadministration of hydrogen peroxide with Ni2+ generated more ROS and more histone acetylation inhibition. Addition of the antioxidants 2-mercaptoethanol (2-ME) at 2 mM or N-acetyl-cysteine (NAC) at 1 mM, with Ni2+ together, completely suppressed ROS generation and significantly diminished the induced histone hypoacetylation. The data presented here prove that the ROS generation plays a role in the inhibition of histone acetylation, and, hence, the gene suppression and carcinogenesis caused by Ni2+ exposure, providing a new door for us to continuously understand the mechanism of ROS in the carcinogenicity of Ni2+ and the resistance of mammalian cells to Ni2+.}, }
@article {pmid12767482, year = {2003}, author = {Tian, H and Zhang, G and Li, H and Zhang, Q}, title = {Antioxidant NAC and AMPA/KA receptor antagonist DNQX inhibited JNK3 activation following global ischemia in rat hippocampus.}, journal = {Neuroscience research}, volume = {46}, number = {2}, pages = {191-197}, doi = {10.1016/s0168-0102(03)00057-9}, pmid = {12767482}, issn = {0168-0102}, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain Ischemia/*enzymology ; Calcium Channel Blockers/pharmacology ; Excitatory Amino Acid Antagonists/*pharmacology ; Free Radical Scavengers/*pharmacology ; Immunoblotting ; Ketamine/pharmacology ; Male ; Mitogen-Activated Protein Kinase 10 ; Mitogen-Activated Protein Kinases/*drug effects/*metabolism ; Nifedipine/pharmacology ; Protein Transport ; Protein-Tyrosine Kinases/*drug effects/*metabolism ; Quinoxalines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/antagonists &amp; inhibitors ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors ; Time Factors ; }, abstract = {c-Jun N-terminal kinase-3 (JNK3), the only neural-specific isoform, may play an important role in excitotoxicity and neuronal injury. To analyze the variation of JNK3 activation, levels of phospho-JNK3 were measured at various time points of ischemia and selected time points of reperfusion, respectively. Our study illustrated that JNK3 was rapidly activated and translocated from cytosol to nucleus during ischemia. During reperfusion, two peaks of JNK3 activation occurred at 30 min and 3 days, respectively. To further define the mechanism of JNK3 activation, antioxidant N-acetylcysteine (NAC), alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist 6,7-dinitro-quinoxaline-2,3(1H,4H)-dione (DNQX), N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and L-type voltage-gated Ca(2+) channel (L-VGCC) antagonist nifedipine were given to the rats 20 min prior to ischemia. The results showed that NAC obviously inhibited JNK3 activation during the early reperfusion, whereas DNQX preferably attenuated JNK3 activation during the latter reperfusion. Ketamine and nifedipine had no significant effects on JNK3 activation during reperfusion. Consequently, reactive oxygen species (ROS) and AMPA/KA receptor were closely associated with JNK3 activation following global ischemia.}, }
@article {pmid12765672, year = {2003}, author = {Puertollano, MA and de Pablo, MA and Alvarez de Cienfuegos, G}, title = {Anti-oxidant properties of N-acetyl-L-cysteine do not improve the immune resistance of mice fed dietary lipids to Listeria monocytogenes infection.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {22}, number = {3}, pages = {313-319}, doi = {10.1016/s0261-5614(03)00031-1}, pmid = {12765672}, issn = {0261-5614}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/pharmacology ; Bacterial Adhesion/drug effects ; Dietary Fats/*administration &amp; dosage ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Lipid Peroxidation/drug effects ; Listeria monocytogenes/growth &amp; development/immunology/*physiology ; Listeriosis/epidemiology/*immunology ; Male ; Mice ; Mice, Inbred BALB C ; Random Allocation ; Reactive Oxygen Species/metabolism ; Spleen/cytology/microbiology ; }, abstract = {BACKGROUND &amp; AIMS: Current knowledge of the potential effects that several dietary lipids exert on immune functions indicates that these substances participate actively in the modulation of immune system by which they contribute to the improvement of the conditions of patients suffering from inflammatory disorders. However, long-chain n-3 polyunsaturated fatty acids induce an immunosuppressive status that leads to a reduction of the host natural resistance to infectious agents as well as to an enhancement of oxidative damage. Hence, the present study has been designed to evaluate the effects on the immune system of the antioxidant N-acetyl-L-cysteine (NAC) in mice fed dietary lipids and infected with Listeria monocytogenes.<br><br>METHODS: Balb/c mice were fed for 4 weeks with diets containing either olive oil (OO, 20% by weight), fish oil (FO, 20% by weight) or hydrogenated coconut oil (HCO, 20% by weight). After dietary lipid administration mice were experimentally infected with L. monocytogenes or treated with NAC (25mg/ml intraperitoneally).<br><br>RESULTS: NAC at a concentration of 1mM promoted a loss of cell viability, although no differences were observed among the four groups. After injection of NAC in combination with L. monocytogenes, 25% of mice fed a low-fat (LF) diet survived. However, in the groups fed dietary lipids no effect on survival of mice was found. NAC participated in the reduction of superoxide anion generation measured with nitroblue tetrazolium (NBT) in the group fed a FO diet. Finally, NAC reduced the recovery of L. monocytogenes from spleen of mice fed diets containing LF or HCO.<br><br>CONCLUSIONS: On the basis of these results, we can confirm that the administration of NAC improves survival in mice fed LF diet, whereas a reduction in the generation of superoxide radicals was measured in mice fed a FO diet and infected with L. monocytogenes. Similarly, bacterial recovery was diminished in mice fed diets containing LF or HCO. Hence, these data reveal a beneficial effect of NAC in mice fed LF or HCO and a detrimental action of this antioxidant in mice fed diets containing FO or OO.}, }
@article {pmid12765247, year = {2003}, author = {Coleman, CA and Hull, BE and McDougal, JN and Rogers, JV}, title = {The effect of m-xylene on cytotoxicity and cellular antioxidant status in rat dermal equivalents.}, journal = {Toxicology letters}, volume = {142}, number = {1-2}, pages = {133-142}, doi = {10.1016/s0378-4274(03)00020-1}, pmid = {12765247}, issn = {0378-4274}, support = {R01 OH354-03/OH/NIOSH CDC HHS/United States ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/*metabolism/pharmacology ; Catalase/metabolism/pharmacology ; Cell Survival/drug effects ; Dermis/*drug effects/metabolism ; Dose-Response Relationship, Drug ; Fibroblasts/drug effects/metabolism ; Formazans/metabolism ; In Vitro Techniques ; Male ; Oxidative Stress/physiology ; Rats ; Rats, Inbred F344 ; Tetrazolium Salts/metabolism ; Toxicity Tests/methods ; Xylenes/*toxicity ; }, abstract = {Exposure of the skin to volatile organic chemicals (VOCs) can lead to irritation, inflammation and cytotoxicity. Since VOCs are used in industrial, commercial and military applications, concern is mounting with respect to VOC safe exposure limits. Although traditional toxicological assessment of VOCs has utilized animal models, the use of alternative in vitro models is becoming more widespread. We have previously developed a sealed exposure system that prevents chemical loss through evaporation and enables calculation of target cell chemical dose. The present study utilized this in vitro exposure method to assess m-xylene-induced cytotoxicity and antioxidant status in dermal equivalents (dermal fibroblasts in a collagen matrix). At the end of a 1- or 4-h exposure, cytotoxicity was measured using the MTT assay and the EC50 values determined were 1481 +/- 88 and 930 +/- 33, respectively. Decreases in cellular thiols and catalase activity were observed, which occurred in a time and dose-dependent manner. Treatment of dermal equivalents with the antioxidants N-acetylcysteine (NAC) and catalase provided some protection against m-xylene-induced cytotoxicity. When compared to m-xylene exposures, treatment with either 1.0 or 5.0 mM NAC led to increases in the EC50 values at 1 and 4 h. Increases in these EC50 values ranged from 1.22- to 1.32-fold at 1 h and 1.27- to 1.54-fold at 4 h. Although treatment with catalase (1000 U/ml) led to a 1.35-fold increase in cell viability at 1 h, no significant differences were observed at either 1 or 4 h when compared to dermal equivalents exposed to m-xylene alone. These results suggest that exposure to m-xylene leads to a time- and dose-dependent decrease in cellular antioxidants and that cellular thiols may provide protection against the cytotoxic properties of m-xylene.}, }
@article {pmid12756201, year = {2003}, author = {Townsend, DM and Marto, JA and Deng, M and Macdonald, TJ and Hanigan, MH}, title = {High pressure liquid chromatography and mass spectrometry characterization of the nephrotoxic biotransformation products of Cisplatin.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {31}, number = {6}, pages = {705-713}, pmid = {12756201}, issn = {0090-9556}, support = {R01 CA057530/CA/NCI NIH HHS/United States ; R01CA57530/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*adverse effects/pharmacokinetics ; Biotransformation ; Chromatography, High Pressure Liquid ; Cisplatin/*adverse effects/analogs &amp; derivatives/pharmacokinetics ; Cysteine/metabolism ; Glutathione/metabolism ; Kidney Tubules, Proximal/*drug effects/enzymology/pathology ; LLC-PK1 Cells ; Mass Spectrometry ; Platinum/adverse effects/pharmacokinetics ; Spectrophotometry, Atomic ; Swine ; gamma-Glutamyltransferase/metabolism ; }, abstract = {Previous studies have shown that cisplatin requires metabolic activation to become nephrotoxic. The activation is proposed to be via the metabolism of a glutathione-platinum conjugate to a cysteinyl-glycine-platinum conjugate, which is further processed to a cysteine conjugate. Preincubating cisplatin with glutathione (GSH), cysteinyl-glycine, or N-acetylcysteine (NAC) results in a transient increase in the toxicity of cisplatin toward renal proximal tubular cells. In this study, the preincubation solutions were analyzed by high pressure liquid chromatography (HPLC), atomic absorption spectrometry, and mass spectrometry (MS) to characterize the formation and structure of the platinum conjugates. HPLC analysis of the cisplatin-GSH, cisplatin-cysteinyl-glycine, and cisplatin-NAC preincubation solutions revealed two new platinum-containing peaks in each of the solutions. MS-MS analysis of the peaks revealed a diplatinum- and a monoplatinum conjugate in each of the solutions. Analysis of the composition and toxicity of the solutions with time showed that the transient increase in toxicity correlated with the formation of the monoplatinum conjugate whereas prolonged preincubation decreased toxicity and correlated with the formation of the diplatinum conjugate. The monoplatinum-monoglutathione conjugate is a substrate for gamma-glutamyl transpeptidase, an enzyme that is essential for the nephrotoxicity of cisplatin. The monoplatinum-mono-NAC conjugate can be deacetylated to a cysteine conjugate, which is a substrate for pyroxidol phosphate (PLP)-dependent cysteine S-conjugate beta-lyase. This PLP-dependent enzyme is proposed to catalyze the final step in the metabolic activation of cisplatin. Identification of the structure and toxicity of these conjugates further elucidates the metabolism of cisplatin to a nephrotoxin.}, }
@article {pmid12755497, year = {2003}, author = {Li, J and Zuo, L and Shen, T and Xu, CM and Zhang, ZN}, title = {Induction of apoptosis by sodium selenite in human acute promyelocytic leukemia NB4 cells: involvement of oxidative stress and mitochondria.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {17}, number = {1}, pages = {19-26}, doi = {10.1016/S0946-672X(03)80041-X}, pmid = {12755497}, issn = {0946-672X}, mesh = {Acetylcysteine/pharmacology ; Acridines/pharmacology ; *Apoptosis ; Cell Division ; Cell Survival ; DNA Fragmentation ; Electrophoresis, Agar Gel ; Flow Cytometry ; G1 Phase ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Humans ; Leukemia, Promyelocytic, Acute/*drug therapy/*pathology ; Luminescent Measurements ; Membrane Potentials ; Mitochondria/*physiology ; *Oxidative Stress ; Reactive Oxygen Species ; Sodium Selenite/*pharmacology ; Superoxide Dismutase/metabolism ; Time Factors ; Tumor Cells, Cultured ; }, abstract = {The mechanisms involved in the anti-carcinogenic activity of selenium remained to be elucidated. In the present study, we examined sodium selenite induced apoptosis and oxidative stress in human acute promyelocytic leukemia cell lines (NB4). Cell growth and viability were assessed by trypan blue exclusion and cell counting; apoptosis by DNA electrophoresis and analysis of intracellular DNA contents; reactive oxygen species and reduced glutathione in the cell were measured by lucigenin dependent chemoluminescent (CL) test and spectrophotometer; mitochondrial transmembrane potential was measured by flow cytometry. Sodium selenite could inhibit the growth and induce apoptosis of NB4 cells. Sodium selenite could increase the production of reactive oxygen species (ROS) in NB4 cells and decrease the level of intracellular reduced glutathione, but caused no change in the activity of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx). Sodium selenite enhanced the collapse of mitochondrial transmembrane potential (MTP), in parallel with the production of ROS. Finally antioxidant N-acetylcysteine (NAC) could inhibit the ROS production, MTP collapse and apoptosis in NB4 cells. Our results suggested that sodium selenite could induce apoptosis of NB4 cells through mitochondrial change mediated by production of reactive oxygen species within the cells.}, }
@article {pmid12754411, year = {2003}, author = {Kang, SH and Song, JH and Kang, HK and Kang, JH and Kim, SJ and Kang, HW and Lee, YK and Park, DB}, title = {Arsenic trioxide-induced apoptosis is independent of stress-responsive signaling pathways but sensitive to inhibition of inducible nitric oxide synthase in HepG2 cells.}, journal = {Experimental &amp; molecular medicine}, volume = {35}, number = {2}, pages = {83-90}, doi = {10.1038/emm.2003.12}, pmid = {12754411}, issn = {1226-3613}, mesh = {Antioxidants/administration &amp; dosage/pharmacology ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/administration &amp; dosage/*pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/*pharmacology ; Humans ; Nitric Oxide Synthase/*antagonists &amp; inhibitors/metabolism ; Nitric Oxide Synthase Type II ; *Oxidative Stress/drug effects ; Oxides/administration &amp; dosage/*pharmacology ; *Signal Transduction/drug effects ; }, abstract = {Arsenic trioxide (As(2)O(3)) has been found to be remarkably effective in the treatment of patients with acute promyelocytic leukemia (APL). Although evidences for the proapoptotic activity of As(2)O(3) have been suggested in leukemic and other solid cancer cells, the nature of intracellular mechanisms is far from clear. In the present study, we investigated As(2)O(3) affect on the stress-responsive signaling pathways and pretreatment with antioxidants using HepG2 cells. When treated with micromolar concentrations of As(2)O(3), HepG2 cells became highly apoptotic paralleled with activation of caspase-3 and members of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and c-jun NH(2)-terminal kinase (JNK) but not p38 MAP kinase. However, inhibition of each kinase activity failed to inhibit apoptosis by As(2)O(3). Addition of n-acetyl cysteine (NAC) or diphenyleneiodonium (DPI) effectively protected cells from apoptosis and significantly lowered As(2)O(3)-induced activation of caspase-3. However, neither NAC nor DPI was able to effect ERK or JNK activation induced by As(2)O(3). Guanidinoethyldisulfide dihydrochloride (GED) and 2-ethyl-2-thiopseudourea (ETU), known inhibitors of the inducible nitric oxide synthase (iNOS), also suppressed the apoptotic activity of As(2)O(3). These results suggest that As2O3 induces caspase-mediated apoptosis involving a mechanism generating oxidative stress. However, activation of some stress-responsive signaling pathways by As(2)O(3) may not be the major determinant in the course of apoptotic processes.}, }
@article {pmid12754095, year = {2003}, author = {Rieber, M and Rieber, MS}, title = {N-Acetylcysteine enhances UV-mediated caspase-3 activation, fragmentation of E2F-4, and apoptosis in human C8161 melanoma: inhibition by ectopic Bcl-2 expression.}, journal = {Biochemical pharmacology}, volume = {65}, number = {10}, pages = {1593-1601}, doi = {10.1016/s0006-2952(03)00147-3}, pmid = {12754095}, issn = {0006-2952}, mesh = {Acetylcysteine/*pharmacology ; *Apoptosis ; Caspase 3 ; Caspases/*metabolism ; DNA/drug effects/metabolism ; DNA-Binding Proteins/*metabolism ; E2F4 Transcription Factor ; Enzyme Activation/radiation effects ; Humans ; JNK Mitogen-Activated Protein Kinases ; Melanoma/pathology ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation ; Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2/*pharmacology ; Transcription Factors/*metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/metabolism ; *Ultraviolet Rays ; }, abstract = {Redox imbalance due to oxidative stress or excessive antioxidant levels can alter apoptotic responses. Recently, antioxidants like N-acetylcysteine (NAC) were reported to inhibit H(2)O(2)-mediated necrotic cell death, although they were inactive against apoptosis induced by other agents like etoposide. NAC was also found to kill preferentially tumor cells compared to normal fibroblasts at 20-50mM, but these concentrations are lethal to normal splenocytes. We now demonstrate that 10mM NAC, a non-toxic concentration, can enhance the UV radiation-mediated apoptosis of human C8161 melanoma cells. Compared to treatment with UV radiation alone, combination treatment with NAC doubled the ratio of activated caspase-3 to pro-caspase-3 and produced greater fragmentation of the retinoblastoma protein and the E2F-4 transcription factor without affecting the E2F-1 protein. These effects of joint NAC-UV radiation treatment were counteracted by the overexpression of the bcl-2 gene. To our knowledge, this report is the first to: (i) demonstrate a synergy between DNA-damaging agents, like UV radiation, and antioxidants, like NAC, and (ii) show that a Bcl-2-inhibitable E2F-4 fragmentation occurs concurrently with caspase-3 activation and apoptosis.}, }
@article {pmid12750841, year = {2003}, author = {Hu, XM and Hirano, T and Oka, K}, title = {Arsenic trioxide induces apoptosis in cells of MOLT-4 and its daunorubicin-resistant cell line via depletion of intracellular glutathione, disruption of mitochondrial membrane potential and activation of caspase-3.}, journal = {Cancer chemotherapy and pharmacology}, volume = {52}, number = {1}, pages = {47-58}, doi = {10.1007/s00280-003-0629-5}, pmid = {12750841}, issn = {0344-5704}, mesh = {Antibiotics, Antineoplastic/*pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Caspase 3 ; Caspases/*metabolism ; Cell Survival/drug effects ; Daunorubicin/*pharmacology ; Drug Resistance ; Enzyme Activation ; Glutathione/deficiency ; Humans ; Membrane Potentials/*drug effects ; Mitochondria/*drug effects ; Oxides/*pharmacology ; Tumor Cells, Cultured/*drug effects ; }, abstract = {PURPOSE: To demonstrate that arsenic trioxide (As(2)O(3)) induces apoptosis via a mitochondrial pathway in both parent T lymphoblastoid leukemia MOLT-4 cells and cells of its daunorubicin-resistant subline, MOLT-4/DNR, expressing functional P-gp.<br><br>METHODS: Cell growth was measured using an MTT assay. Cell viability was determined using a dye exclusion test. Intracellular glutathione (GSH) was measured using a glutathione assay kit. Mitochondrial membrane potential (MMP) was assessed by rhodamine 123 (Rh123) staining intensity on flow cytometry. Caspase-3 activity was evaluated using a commercially available assay kit on flow cytometry. The percentage of cells undergoing apoptosis was estimated in terms of caspase(+)/PI(-) cells on flow cytometry after assessment for activation of caspase-3 by adding PI.<br><br>RESULTS: MOLT-4 cells and MOLT-4/DNR cells were similarly sensitive to the apoptosis-inducing effect of As(2)O(3). Buthionine sulfoxide (BSO) and ascorbic acid (AA) rendered these cells more sensitive to As(2)O(3), whereas N-acetylcysteine (NAC) reduced this sensitivity. BSO and AA decreased, but NAC increased, the intracellular GSH contents of both MOLT-4 and MOLT-4/DNR cells. Decreasing GSH with BSO potentiated As(2)O(3)-mediated growth inhibition, disruption of MMP, activation of caspase-3 and apoptosis of cells. Clinically relevant doses of AA enhanced the anticancer effects of As(2)O(3) via the disruption of MMP, activation of caspase-3, and induction of apoptosis. In contrast, increase GSH levels with NAC attenuated all of these As(2)O(3)-mediated actions.<br><br>CONCLUSIONS: The sensitivity of MOLT-4 and MOLT-4/DNR cells to As(2)O(3) was associated with the intracellular GSH content. As(2)O(3) induced apoptosis in parent MOLT-4 cells and MOLT-4/DNR cells expressing functional P-gp via depletion of intracellular GSH, and subsequent disruption of MMP and activation of caspase-3.}, }
@article {pmid12743010, year = {2003}, author = {Kanellis, J and Watanabe, S and Li, JH and Kang, DH and Li, P and Nakagawa, T and Wamsley, A and Sheikh-Hamad, D and Lan, HY and Feng, L and Johnson, RJ}, title = {Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {41}, number = {6}, pages = {1287-1293}, doi = {10.1161/01.HYP.0000072820.07472.3B}, pmid = {12743010}, issn = {1524-4563}, support = {1P50DK-064233-01/DK/NIDDK NIH HHS/United States ; HL 68607/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Chemokine CCL2/*biosynthesis/genetics ; Cyclooxygenase 2 ; Gene Expression Regulation ; Isoenzymes/genetics/*physiology ; Mitogen-Activated Protein Kinase 1/physiology ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/*physiology ; Muscle, Smooth, Vascular/drug effects/enzymology/*metabolism ; NF-kappa B/metabolism ; Oxidation-Reduction ; Prostaglandin-Endoperoxide Synthases/genetics/*physiology ; RNA, Messenger/biosynthesis ; Rats ; Transcription Factor AP-1/metabolism ; Up-Regulation ; Uric Acid/*pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Previous studies have reported that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation in vitro. We hypothesized that uric acid may also have direct proinflammatory effects on VSMCs. Crystal- and endotoxin-free uric acid was found to increase VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a time- and dose-dependent manner, peaking at 24 hours. Increased mRNA and protein expression occurred as early as 3 hours after uric acid incubation and was partially dependent on posttranscriptional modification of MCP-1 mRNA. In addition, uric acid activated the transcription factors nuclear factor-kappaB and activator protein-1, as well as the MAPK signaling molecules ERK p44/42 and p38, and increased cyclooxygenase-2 (COX-2) mRNA expression. Inhibition of p38 (with SB 203580), ERK 44/42 (with UO126 or PD 98059), or COX-2 (with NS398) each significantly suppressed uric acid-induced MCP-1 expression at 24 hours, implicating these pathways in the response to uric acid. The ability of both n-acetyl-cysteine and diphenyleneionium (antioxidants) to inhibit uric acid-induced MCP-1 production suggested involvement of intracellular redox pathways. Uric acid regulates critical proinflammatory pathways in VSMCs, suggesting it may have a role in the vascular changes associated with hypertension and vascular disease.}, }
@article {pmid12727827, year = {2003}, author = {Menon, SG and Sarsour, EH and Spitz, DR and Higashikubo, R and Sturm, M and Zhang, H and Goswami, PC}, title = {Redox regulation of the G1 to S phase transition in the mouse embryo fibroblast cell cycle.}, journal = {Cancer research}, volume = {63}, number = {9}, pages = {2109-2117}, pmid = {12727827}, issn = {0008-5472}, support = {CA66081/CA/NCI NIH HHS/United States ; CA69593/CA/NCI NIH HHS/United States ; HL51469/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Cycle Proteins/antagonists &amp; inhibitors/metabolism ; Embryo, Mammalian ; Fibroblasts/*cytology/metabolism ; Flow Cytometry ; G1 Phase/drug effects/*physiology ; Mice ; Oxidation-Reduction ; S Phase/drug effects/*physiology ; Signal Transduction/drug effects/physiology ; Tumor Suppressor Protein p53/physiology ; }, abstract = {The hypothesis that intracellular oxidation/reduction (redox) reactions regulate the G(0)-G(1) to S-phase transition in the mouse embryonic fibroblast cell cycle was investigated. Intracellular redox state was modulated with a thiol-antioxidant, N-acetyl-L-cysteine (NAC), and cell cycle progression was measured using BrdUrd pulse-chase and flow cytometric analysis. Treatment with NAC for 12 h resulted in an approximately 6-fold increase in intracellular low-molecular-weight thiols and a decrease in the MFI of an oxidation-sensitive probe, dihydrofluorescein diacetate, indicating a shift in the intracellular redox state toward a more reducing environment. NAC-induced alterations in redox state caused selective delays in progression from G(0)-G(1) to S phase in serum-starved cells that were serum stimulated to reenter the cell cycle as well as to inhibit progression from G(1) to S phase in asynchronous cultures with no significant alterations in S phase, and G(2)+M transits. NAC treatment also showed a 70% decrease in cyclin D1 protein levels and a 3-4-fold increase in p27 protein levels, which correlated with decreased retinoblastoma protein phosphorylation. Cells released from the NAC treatment showed a transient increase in dihydrofluorescein fluorescence and oxidized glutathione content between 0 and 8 h after release, indicating a shift in intracellular redox state to a more oxidizing environment. These changes in redox state were followed by an increase in cyclin D1, a decrease in p27, retinoblastoma protein hyperphosphorylation and subsequent entry into S phase by 8-12 h after the removal of NAC. These results support the hypothesis that a redox cycle within the mammalian cell cycle might provide a mechanistic link between the metabolic processes early in G(1) and the activation of G(1)-regulatory proteins in preparation for the entry of cells into S phase.}, }
@article {pmid12727294, year = {2003}, author = {Raza, M and Ahmad, M and Gado, A and Al-Shabanah, OA}, title = {A comparison of hepatoprotective activities of aminoguanidine and N-acetylcysteine in rat against the toxic damage induced by azathioprine.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {134}, number = {4}, pages = {451-456}, doi = {10.1016/s1532-0456(03)00022-x}, pmid = {12727294}, issn = {1532-0456}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Azathioprine/*toxicity ; Chemical and Drug Induced Liver Injury ; Drug Therapy, Combination ; Guanidines/*pharmacology/therapeutic use ; Liver/*drug effects/metabolism ; Liver Diseases/drug therapy/metabolism ; Male ; Rats ; Rats, Wistar ; }, abstract = {Azathioprine (AZA) is an important drug used in the therapy of autoimmune system disorders. It induces hepatotoxicity that restricts its use. The rationale behind this study was the proven efficacy of N-acetylcysteine (NAC; a replenisher of sulfhydryls) and reports on the antioxidant potential of aminoguanidine (AG; an iNOS inhibitor), that might be useful to protect against the toxic implications of AZA. AG (100 mg/kg; i.p.) or NAC (100 mg/kg; i.p.) were administered to the Wistar male rats for 7 days and after that AZA (15 mg/kg, i.p.) was given as a single dose. This caused an increase in the activity of hepatic aminotransferases (AST and ALT) in the serum 24 h after AZA treatment. AZA (7.5 or 15 mg/kg, i.p.) also caused an increase in rat liver lipid peroxides and a lowering of reduced glutathione (GSH) contents. In the other part of experiment, protective effects of AG and NAC were observed on AZA induced hepatotoxicity. NAC significantly protected against the toxic effects produced by AZA. Pretreatment with NAC prevented any change in the activities of both the aminotransferases after AZA. This pretreatment also resulted in a significant decline in the contents of lipid peroxides and a significant elevation in GSH level was evident after AZA treatment. In the group with AG pretreatment the activities of AST and ALT did not increase significantly after AZA when compared to control. However, the lipid peroxides and GSH levels did not have any significant difference when compared to AZA group. These observations also indicate that the improvement in the GSH levels by NAC is the most significant protective mechanism rather than any other mechanistic profile. The protective effect of AG against the enzyme leakage seems to be through the liver cell membrane permeability restoration and is independent of any effects on liver GSH contents.}, }
@article {pmid12717738, year = {2003}, author = {Xu, J and Maki, D and Stapleton, SR}, title = {Mediation of cadmium-induced oxidative damage and glucose-6-phosphate dehydrogenase expression through glutathione depletion.}, journal = {Journal of biochemical and molecular toxicology}, volume = {17}, number = {2}, pages = {67-75}, doi = {10.1002/jbt.10062}, pmid = {12717738}, issn = {1095-6670}, mesh = {Acetylcysteine/pharmacology ; Animals ; Blotting, Northern ; Buthionine Sulfoximine/pharmacology ; Cadmium/*toxicity ; Enzyme Inhibitors/pharmacology ; Glucosephosphate Dehydrogenase/*biosynthesis ; Glutathione/deficiency/*physiology ; Hepatocytes/drug effects/enzymology ; L-Lactate Dehydrogenase/metabolism ; Male ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Oxidative Stress/*drug effects ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The effect of cadmium (Cd), a significant environmental contaminant, on the expression of glucose-6-phosphate dehydrogenase (G6PDH), has been investigated. G6PDH is the key rate-limiting enzyme in the pentose pathway and the expression of its gene has been shown to be redox-sensitive. We show that incubation of primary rat hepatocytes with Cd induces oxidative stress in a time- and concentration-dependent manner as measured by increases in the cytotoxic parameters, lactate dehydrogenase (LDH) and lipid peroxidation (LPO). Significant increases in LDH leakage and LPO can be measured after 12 and 24 h, respectively, in the presence of 4 microM cadmium chloride. However, prior to significant increases in cytotoxic parameters, and within only 6 h of Cd treatment, significant decreases in reduced glutathione and increases in the expression of G6PDH as measured by mRNA levels and enzyme activity are observed. The signal protein MAP kinase (MAPK) is also induced by Cd within 6 h. Blocking the Cd induction of MAPK using the antioxidant N-acetyl cysteine (10 mM) or Trolox (0.5 mM) or the MEK specific inhibitor PD098059 (20 microM) also blocks the Cd induction of G6PDH suggesting that MAPK is a signal protein involved in the redox regulation of this gene.}, }
@article {pmid12716756, year = {2003}, author = {Wentzel, P and Ejdesjö, A and Eriksson, UJ}, title = {Maternal diabetes in vivo and high glucose in vitro diminish GAPDH activity in rat embryos.}, journal = {Diabetes}, volume = {52}, number = {5}, pages = {1222-1228}, doi = {10.2337/diabetes.52.5.1222}, pmid = {12716756}, issn = {0012-1797}, mesh = {Animals ; Cattle ; Congenital Abnormalities/embryology/epidemiology ; Diabetes Mellitus, Experimental/*blood ; Embryo, Mammalian/enzymology ; Female ; Glyceraldehyde-3-Phosphate Dehydrogenases/genetics/*metabolism ; Hyperglycemia/*blood ; Organ Culture Techniques ; Pregnancy ; Pregnancy in Diabetics/*blood ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {The aim of the present study was to investigate whether diabetic embryopathy may be associated with the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) resulting from an excess of reactive oxygen species (ROS) in the embryo. Recent demonstrations of enhanced ROS production in mitochondria of bovine aortic endothelial cells exposed to high glucose have supported the idea that the pathogenesis of diabetic complications may involve ROS-induced GAPDH inhibition. We investigated whether a teratogenic diabetic environment also inhibits embryonic GAPDH activity and alters GAPDH gene expression and whether antioxidants diminish such GAPDH inhibition. In addition, we determined whether the inhibition of GAPDH with iodoacetate induces dysmorphogenesis, analogous to that caused by high glucose concentration, and whether antioxidants modulated the putative teratogenic effect of such direct GAPDH inhibition. We found that embryos from diabetic rats and embryos cultured in high glucose concentrations showed decreased activity of GAPDH (by 40-60%) and severe dysmorphogenesis on gestational days 10.5 and 11.5. GAPDH mRNA was decreased in embryos of diabetic rats compared to control embryos. Supplementing the high-glucose culture with the antioxidant N-acetylcysteine (NAC) increased GAPDH activity and diminished embryonic dysmorphogenesis. Embryos cultured with iodoacetate showed both decreased GAPDH activity and dysmorphogenesis; supplementing the culture with NAC increased both parameters toward normal values. In conclusion, dysmorphogenesis caused by maternal diabetes is correlated with ROS-induced inhibition of GAPDH in embryos, which could indicate that inhibition of GAPDH plays a causal role in diabetic embryopathy.}, }
@article {pmid12713590, year = {2003}, author = {Kang, S and Chung, JH and Lee, JH and Fisher, GJ and Wan, YS and Duell, EA and Voorhees, JJ}, title = {Topical N-acetyl cysteine and genistein prevent ultraviolet-light-induced signaling that leads to photoaging in human skin in vivo.}, journal = {The Journal of investigative dermatology}, volume = {120}, number = {5}, pages = {835-841}, doi = {10.1046/j.1523-1747.2003.12122.x}, pmid = {12713590}, issn = {0022-202X}, mesh = {Acetylcysteine/*pharmacology ; Aging ; Antioxidants/pharmacology ; Collagenases/metabolism ; Enzyme Activation ; Erythema ; Free Radical Scavengers/pharmacology ; Genistein/*pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; JNK Mitogen-Activated Protein Kinases ; Light ; Mitogen-Activated Protein Kinases/metabolism ; Models, Biological ; Reverse Transcriptase Polymerase Chain Reaction ; *Signal Transduction ; Skin/drug effects/metabolism ; *Ultraviolet Rays ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Human skin is exposed to solar ultraviolet radiation. Ultraviolet radiation damages human skin and results in an old and wrinkled appearance, called photoaging. We have previously reported that molecular mechanisms by which ultraviolet light causes photoaging involve activation of growth factor and cytokine receptors in keratinocytes and dermal cells. They lead to downstream signal transduction through activation of mitogen-activated protein kinase (extracellular signal-regulated kinase, c-jun N-terminal protein kinase, and p38) pathways. These signaling pathways converge in the nucleus of cells to form an activated complex of transcription factor activator protein 1 (cFos/cJun), which induces matrix metalloproteinases that degrade skin connective tissue. In addition to cell surface receptor activation, generation of reactive oxygen species by ultraviolet radiation is believed to be critical in triggering mitogen-activated protein kinase pathways. We investigated the ability of (i) ultraviolet irradiation to generate reactive oxygen species in human skin in vivo; and (ii) genistein, which possesses both tyrosine kinase inhibitory and antioxidant activities, and n-acetyl cysteine, which can be converted into the endogenous antioxidant glutathione, to impair responses to ultraviolet light that eventuate in photoaging in human skin in vivo. Ultraviolet irradiation caused a rapid and significant increase in hydrogen peroxide levels in human skin in vivo. Pretreatment of human skin with genistein inhibited ultraviolet-induced epidermal growth factor receptor tyrosine kinase activity, whereas n-acetyl cysteine did not. Genistein inhibited ultraviolet induction of both extracellular signal-regulated kinase and cJun N-terminal protein kinase activities. n-Acetyl cysteine inhibited extracellular signal-regulated kinase but not cJun N-terminal protein kinase activation. Both genistein and n-acetyl cysteine prevented ultraviolet induction of cJun protein. Consistent with this, genistein and n-acetyl cysteine blocked ultraviolet induction of cJun-driven enzyme, collagenase. Neither genistein nor n-acetyl cysteine acted as sunscreens as they had no effect on ultraviolet-induced erythema. These data indicate that compounds similar to genistein and n-acetyl cysteine, which possess tyrosine kinase inhibitory and/or antioxidant activities, may prevent photoaging.}, }
@article {pmid12711838, year = {2003}, author = {Ventura, P and Panini, R and Abbati, G and Marchetti, G and Salvioli, G}, title = {Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy.}, journal = {Pharmacology}, volume = {68}, number = {2}, pages = {105-114}, doi = {10.1159/000069535}, pmid = {12711838}, issn = {0031-7012}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Adult ; Chromatography, High Pressure Liquid ; *Cysteine/blood/urine ; Dose-Response Relationship, Drug ; Expectorants/administration &amp; dosage/*pharmacology ; Female ; *Homocysteine/blood/urine ; Humans ; Male ; Middle Aged ; }, abstract = {Acute administration of N-acetylcysteine (NAC) may induce alterations in plasma and urinary levels of homocysteine (Hcy) and cysteine (Cys). We studied the effects of continuous oral NAC therapy on different Hcy and Cys plasma and urinary forms in 40 healthy subjects assigned to three groups (groups A: n = 13, no therapy; group B: n = 14, NAC 600 mg/day, and group C: n = 14, NAC 1,800 mg/day) for 1 month (T(1)). After a 1-month washout period without therapy (T(2)), all subjects were treated with oral NAC (1,800 mg/day) for 2 months and (T(3) and T(4)) reassessed monthly for plasma and urinary thiols. The treated subjects showed a significant decrease in plasma total Hcy and a slight increase in total Cys levels; the alterations of different forms of plasma thiols suggested an NAC-induced increase in disulfide forms and an increase in urinary Hcy and Cys excretion as disulfide forms. The effects appeared to be dose dependent, being more marked in subjects treated with higher dosages. This approach may be important, as an association or alternative therapy in hyperhomocysteinemic conditions of poor responses to vitamins.}, }
@article {pmid12709406, year = {2003}, author = {Izzotti, A and Balansky, RM and Cartiglia, C and Camoirano, A and Longobardi, M and De Flora, S}, title = {Genomic and transcriptional alterations in mouse fetus liver after transplacental exposure to cigarette smoke.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {17}, number = {9}, pages = {1127-1129}, doi = {10.1096/fj.02-0967fje}, pmid = {12709406}, issn = {1530-6860}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anticarcinogenic Agents/pharmacology ; Apoptosis ; Cell Cycle/drug effects ; Cell Division/drug effects ; Cell Hypoxia ; DNA Adducts/metabolism ; DNA Repair ; Female ; Fetus/anatomy &amp; histology/*drug effects ; Gene Expression Regulation/*drug effects ; Genome ; Hematopoietic Stem Cells/cytology/drug effects ; Liver/*drug effects/embryology/metabolism ; *Maternal Exposure ; Mice ; Oxidation-Reduction ; Oxidative Stress ; Parity/drug effects ; Placenta/anatomy &amp; histology/drug effects ; Pregnancy ; *Smoking/adverse effects ; Transcription, Genetic ; }, abstract = {The transplacental exposure of fetuses to maternal cigarette smoke may increase the risk of developmental impairments, congenital diseases, and childhood cancer. The whole-body exposure of Swiss mice to environmental cigarette smoke (ECS) during pregnancy decreased the number of fetuses per dam, placenta weight, and fetus weight. ECS increased DNA adducts, oxidative nucleotide alterations, and cytogenetic damage in fetus liver. Evaluation by cDNA array of 746 genes showed that 61 of them were expressed in fetus liver under basal conditions. The oral administration of N-acetylcysteine (NAC) during pregnancy enhanced the expression of three genes only, including two glutathione S-transferases and alpha1-antitrypsin precursor, whose deficiency plays a pathogenetic role in congenital emphysema. Transplacental ECS upregulated the expression of 116 genes involved in metabolism, response to oxidative stress, DNA and protein repair, and signal transduction. NAC inhibited the ECS-related genetic damage and upregulation of most genes. ECS stimulated pro-apoptotic genes and genes downregulating the cell cycle, which may justify growth impairments in the developing fetus. Thus, both genetic and epigenetic mechanisms were modulated by ECS. Moreover, hypoxia-related genes and several oncogenes and receptors involved in proliferation and differentiation of leukocytes were induced in the fetal liver, which also bears hematopoietic functions.}, }
@article {pmid12708964, year = {2003}, author = {Raijmakers, MT and Schilders, GW and Roes, EM and van Tits, LJ and Hak-Lemmers, HL and Steegers, EA and Peters, WH}, title = {N-Acetylcysteine improves the disturbed thiol redox balance after methionine loading.}, journal = {Clinical science (London, England : 1979)}, volume = {105}, number = {2}, pages = {173-180}, doi = {10.1042/CS20030052}, pmid = {12708964}, issn = {0143-5221}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/metabolism ; Cross-Over Studies ; Cysteine/blood ; Female ; Homocysteine/blood ; Humans ; Lipid Peroxidation/drug effects ; Male ; Methionine/antagonists &amp; inhibitors/*pharmacology ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/*blood ; }, abstract = {Methionine loading seems to be accompanied by increased oxidative stress and damage. However, it is not known how this oxidative stress is generated. We performed the present crossover study to further elucidate the effects of methionine loading on oxidative stress in the blood of healthy volunteers, and to examine possible preventative effects of N -acetylcysteine (NAC) administration. A total of 18 healthy subjects were given two oral methionine loads of 100 mg/kg body weight, 4 weeks apart, one without NAC (Met group), and one in combination with supplementation with 2x900 mg doses of NAC (Met+NAC group). Blood samples were collected before and 2, 4, 8 and 24 h after methionine loading for measurements of thiol levels, protein carbonyls, lipid peroxidation, cellular fibronectin and ferric reducing ability of plasma (FRAP; i.e. antioxidant capacity). After methionine loading, whole-blood levels of free and oxidized cysteine and homocysteine were increased in both groups. Furthermore, the total plasma levels of homocysteine were higher, whereas those of cysteine were lower, after methionine loading in both groups. Lower levels of oxidized homocysteine and a higher free/oxidized ratio were found in the Met+NAC group compared with the Met group. Although the antioxidant capacity decreased after methionine loading, no major changes over time were found for protein carbonyls or cellular fibronectin in either group. Our results suggest that methionine loading may initiate the generation of reactive oxygen species by the (auto)-oxidation of homocysteine. In addition, supplementation with NAC seems to be able to partially prevent excessive increases in the levels of homocysteine in plasma and of oxidized homocysteine in whole blood, and might thereby contribute to the prevention of oxidative stress.}, }
@article {pmid12706764, year = {2003}, author = {Mérat, S and Perez, JP and Rüttimann, M and Bordier, E and Lienhard, A and Lenoir, B and Pats, B}, title = {[Acute poisoning by chemical warfare agent: sulfur mustard].}, journal = {Annales francaises d'anesthesie et de reanimation}, volume = {22}, number = {2}, pages = {108-118}, doi = {10.1016/s0750-7658(02)00860-2}, pmid = {12706764}, issn = {0750-7658}, mesh = {Alkylating Agents/history/pharmacology ; Chemical Warfare/*history ; Chemical Warfare Agents/history/pharmacology/*poisoning ; History, 19th Century ; History, 20th Century ; Humans ; Mustard Gas/history/pharmacology/*poisoning ; Poisoning/diagnosis/history/prevention &amp; control ; Terrorism ; }, abstract = {OBJECTIVE: To review story, mechanism of action, clinical and therapeutic bases of a sulfur mustard poisoning, by accidental, terrorism or war exposure.<br><br>DATA SOURCES: References were obtained from computerised bibliographic research (Medline), from personnel data (academic memoir, documents under approbation of the National Defense Office) and from the Library of Military Medical Service.<br><br>DATA SYNTHESIS: Sulfur mustard is a chemical warfare agent with peace time results: leak, accidental handling, acts of terrorism. Sulfur mustard is a vesicant agent, an organochlorine agent, who alkylate DNA. Under liquid or gas form its main target are skin and lungs. Clinical effects are like burns with loss of immunity, with respiratory failure, ophthalmic, gastrointestinal and haematological signs. The last studies have improved knowledge about the mechanism of action, detection, protection and treatment. Methods for determination of sulfur mustard are based on gas chromatographic method and mass spectrometry. During sulfur mustard contamination the first priorities of treatment are to remove victims from the contaminated place and to initiate decontamination. Emergency workers and materials must take protection to avoid secondary contamination of emergency unit. With treatment of vital functions and respiratory failure, the new ways of treatment are about N-acetyl cysteine for lung injury, poly (ADP-ribose) polymerase inhibitors, calmodulin antagonists and Ca(++) chelators. Interactions between sulfur mustard and anaesthetic agents are not well known and are based on clinical observations.<br><br>CONCLUSION: Emergency care unit can be confronted with sulfur mustard during accidental contamination or acts of terrorism. First and most efficacy priorities of treatment are to remove and to decontaminate victims. New means of detection and treatment are studied since several years but are not still appropriate to human victims or mass treatment.}, }
@article {pmid12704789, year = {2003}, author = {Albright, CD and Salganik, RI and Craciunescu, CN and Mar, MH and Zeisel, SH}, title = {Mitochondrial and microsomal derived reactive oxygen species mediate apoptosis induced by transforming growth factor-beta1 in immortalized rat hepatocytes.}, journal = {Journal of cellular biochemistry}, volume = {89}, number = {2}, pages = {254-261}, doi = {10.1002/jcb.10498}, pmid = {12704789}, issn = {0730-2312}, support = {AG09525/AG/NIA NIH HHS/United States ; DK55865/DK/NIDDK NIH HHS/United States ; DK56350/DK/NIDDK NIH HHS/United States ; ES10126/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Cell Division/physiology ; Cell Line, Transformed ; Cytochrome P-450 Enzyme System/metabolism ; Hepatocytes/cytology/enzymology/*metabolism ; Microsomes, Liver/enzymology/*metabolism ; Mitochondria, Liver/enzymology/*metabolism ; Rats ; *Reactive Oxygen Species ; Signal Transduction ; Transforming Growth Factor beta/*physiology ; Transforming Growth Factor beta1 ; }, abstract = {Transforming growth factor-beta1 (TGFbeta1) is a multifunctional cytokine that is over expressed during liver hepatocytes injury and regeneration. SV40-transformed CWSV-1 rat hepatocytes that are p53-defective undergo apoptosis in response to choline deficiency (CD) or TGFbeta1, which mediates CD-apoptosis. Reactive oxygen species (ROS) are essential mediators of apoptosis. We have shown that apoptosis induced by TGFbeta1 is accompanied by ROS generation and the ROS-trapping agent N-acetylcysteine (NAC) inhibits TGFbeta1-induced apoptosis. While persistent induction of ROS contributes to this form of apoptosis, the source of ROS generated downstream of TGFbeta1 is not clear. The mitochondria and the endoplasmic reticulum both harbor potent electron transfer chains that might be the source of ROS essential for completion of TGFbeta1-apoptosis. Here we show that CWSV-1 cells treated with cyclosporine A, which prevents opening of mitochondrial membrane pores required for ROS generation, inhibits TGFbeta1-induced apoptosis. A similar effect was obtained by treating these cells with rotenone, an inhibitor of complex 1 of the mitochondrial electron transfer chain. However, we demonstrate that TGFbeta1 induces cytochrome P450 1A1 and that metyrapone, a potent inhibitor of cytochrome P450 1A1, inhibits TGFbeta1-induced apoptosis. Therefore, our studies indicate that concurrent with promoting generation of ROS from mitochondria, TGFbeta1 also promotes generation of ROS from the cytochrome P450 electron transfer chain. Since inhibition of either of these two sources of ROS interferes with apoptosis, it is reasonable to conclude that the combined involvement of both pathways is essential for completion of TGFbeta1-induced apoptosis.}, }
@article {pmid12704649, year = {2003}, author = {Costanzo, A and Moretti, F and Burgio, VL and Bravi, C and Guido, F and Levrero, M and Puri, PL}, title = {Endothelial activation by angiotensin II through NFkappaB and p38 pathways: Involvement of NFkappaB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin.}, journal = {Journal of cellular physiology}, volume = {195}, number = {3}, pages = {402-410}, doi = {10.1002/jcp.10191}, pmid = {12704649}, issn = {0021-9541}, support = {TCP00081/TI_/Telethon/Italy ; }, mesh = {Angiotensin II/antagonists &amp; inhibitors/*pharmacology ; Aspirin/pharmacology ; Cells, Cultured ; Endothelium, Vascular/drug effects/enzymology/*metabolism ; Humans ; Intercellular Adhesion Molecule-1/biosynthesis ; Mitogen-Activated Protein Kinases/*metabolism ; NF-kappa B/*metabolism ; Protein Serine-Threonine Kinases/physiology ; Proteins/physiology ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; TNF Receptor-Associated Factor 2 ; Transcriptional Activation ; Tumor Necrosis Factor-alpha/pharmacology ; Vascular Cell Adhesion Molecule-1/biosynthesis ; p38 Mitogen-Activated Protein Kinases ; NF-kappaB-Inducing Kinase ; }, abstract = {Angiotensin-II (AII), the dominant effector of the renin-angiotensin system, is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis. Upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin in endothelial cells by inflammatory cytokines through nuclear factor kappa B (NFkappaB) activation is implicated in formation and progression of atherosclerotic plaque. Here we show that AII induces NFkappaB-dependent transcription in primary endothelial cell lines, leading to the upregulation of ICAM-1 and VCAM-1 expression. NFkappaB activation by AII is mediated by the NFkappaB-inducing kinase (NIK), a common mediator of NFkappaB activation by inflammatory cytokines, such as TNF-alpha. However, NFkappaB stimulation by AII differs from that of TNF-alpha since a TNF-receptor associated factor 2 (TRAF-2) dominant negative mutant does not prevent AII-mediated NFkappaB activation. In analogy with TNF-alpha-dependent activation of NFkappaB, treatment with either the anti-oxidant N-acetyl cysteine (NAC) or the cyclooxygenase (COX) inhibitor acetyl salicylic acid (aspirin), but not indometacin, prevents the induction of NFkappaB-dependent transcription by AII. Thus, production of reactive oxygen species, aspirin (asp)-sensitive enzymes of the arachidonate metabolism, and NIK are common transducers of AII- and TNF-dependent pathways to NFkappaB. AII also activates the inflammatory p38 kinase in endothelial cells, an effect inhibited by exposure to either NAC or asp. Pharmacological interference of the p38 pathway, with the inhibitor SB 202190, prevented AII-mediated activation of the NFkappaB target V-CAM, without affecting degradation of IkappaBalpha. These results support a pro-inflammatory effect of the vasoactive peptide AII in endothelial cells, through at least two pathways-NFkappaB and p38-both of which are sensitive to asp and antioxidants.}, }
@article {pmid12682719, year = {2003}, author = {Molnar, Z and Szakmany, T and Koszegi, T}, title = {Prophylactic N-acetylcysteine decreases serum CRP but not PCT levels and microalbuminuria following major abdominal surgery. A prospective, randomised, double-blinded, placebo-controlled clinical trial.}, journal = {Intensive care medicine}, volume = {29}, number = {5}, pages = {749-755}, pmid = {12682719}, issn = {0342-4642}, mesh = {Abdomen/surgery ; Acetylcysteine/*therapeutic use ; Aged ; Albuminuria/metabolism/*prevention &amp; control ; C-Reactive Protein/*metabolism ; Calcitonin/*blood ; Calcitonin Gene-Related Peptide ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Intensive Care Units ; Male ; Middle Aged ; Multiple Organ Failure/prevention &amp; control ; Postoperative Period ; Protein Precursors/*blood ; Systemic Inflammatory Response Syndrome/*prevention &amp; control ; }, abstract = {OBJECTIVE: Our objective was to investigate whether short-term infusion of the oxygen free radical scavenger N-acetylcysteine (NAC) administered before and during extensive abdominal surgery could ameliorate the progression of early systemic inflammatory response.<br><br>DESIGN: Prospective, randomised, double-blinded, placebo-controlled clinical trial.<br><br>SETTING: Twenty-bed intensive care unit in a university hospital.<br><br>PATIENTS: Following written informed consent, 100 patients were randomised into NAC and placebo groups. Three patients from the NAC group and four from the placebo group withdrew before the final analysis.<br><br>INTERVENTION: The treatment group (n=47) received NAC (150 mg/kg(-1) bolus followed by a continuous infusion of 12 mg/kg(-1)/h(-1)) and the placebo group (n=46) received the same volume of 5% dextrose during surgery.<br><br>MEASUREMENTS AND RESULTS: Serum procalcitonin (PCT), C-reactive protein (CRP) and microalbuminuria was monitored preoperatively, on admission to ICU, then daily during the first 3 postoperative days. For statistical analysis Mann Whitney and Chi-squared tests were used. Patients' clinical course was similar in each group as monitored by the Multiple Organ Dysfunction Scores. There was no significant difference between the two groups regarding PCT and microalbuminuria at any assessment point. Significantly lower CRP levels were found in the NAC group on days 1 and 2 (t(24): median: 84.5 interquartile range: [62-120] vs. 118 [86-137] mg/l; p=0.020; t(48): 136 [103-232] vs. 195 [154-252] mg/l; p=0.013, NAC vs. placebo respectively).<br><br>CONCLUSION: In this study, short-term NAC treatment decreased CRP levels, but failed to attenuate any other inflammatory response, as monitored by serum PCT and microalbuminuria. Overall, our results do not support the routine prophylactic use of NAC as a free radical scavenger in abdominal surgery.}, }
@article {pmid12701116, year = {2003}, author = {Pace, BS and Shartava, A and Pack-Mabien, A and Mulekar, M and Ardia, A and Goodman, SR}, title = {Effects of N-acetylcysteine on dense cell formation in sickle cell disease.}, journal = {American journal of hematology}, volume = {73}, number = {1}, pages = {26-32}, doi = {10.1002/ajh.10321}, pmid = {12701116}, issn = {0361-8609}, support = {HL 35680/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/blood/*therapeutic use ; Adolescent ; Adult ; Anemia, Sickle Cell/*blood/complications/*drug therapy ; Double-Blind Method ; Erythrocytes, Abnormal/chemistry/*pathology ; Female ; Glutathione/blood ; Humans ; Male ; Placebos ; Vascular Diseases/etiology/prevention &amp; control ; }, abstract = {The extent to which dense and irreversible sickle cells (ISCs) contribute to vaso-occlusive episodes in sickle cell disease remains unclear. N-Acetylcysteine (NAC) inhibits dense cell and ISC formation in sickle erythrocytes in vitro and restores glutathione levels toward normal. A phase II double-blind randomized clinical trial was completed to determine the efficacy of NAC in decreasing dense cell and ISC formation, and vaso-occlusive episodes in sickle cell disease. Twenty-one subjects with a history of at least two vaso-occlusive episodes per year and 6% dense cells were enrolled. Four treatment groups were analyzed; NAC at a dose of 2,400 mg per day decreased the percent dense cells from 20.1 +/- 2.9 to 12.6 +/- 2.1 (P < 0.05) and increased red cell glutathione levels from 292.8 +/- 74.5 to 576.7 +/- 155.1 (P < 0.05). In addition, we observed a decrease in vaso-occlusive episodes from 0.03 to 0.006 episodes per person-days and a decreased in relative risk to R = 0.39. Although NAC did not significantly decrease the number of ISCs, there was a downward trend at all doses tested. In summary, NAC inhibited dense cell formation, restored glutathione levels toward normal, and decreased vaso-occlusive episodes at a well-tolerated dose of 2,400 mg per day. To determine the long-term efficacy and safety of NAC, a multicenter phase III clinical trial is required.}, }
@article {pmid12699905, year = {2003}, author = {Hirano, S and Furuyama, A and Koike, E and Kobayashi, T}, title = {Oxidative-stress potency of organic extracts of diesel exhaust and urban fine particles in rat heart microvessel endothelial cells.}, journal = {Toxicology}, volume = {187}, number = {2-3}, pages = {161-170}, doi = {10.1016/s0300-483x(03)00053-2}, pmid = {12699905}, issn = {0300-483X}, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/chemistry/*toxicity ; Animals ; Antioxidants/pharmacology ; Cell Line ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Endothelium, Vascular/cytology/drug effects/*metabolism ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione Transferase/drug effects/genetics ; HSP72 Heat-Shock Proteins ; Heat-Shock Proteins/drug effects/genetics ; Heme Oxygenase (Decyclizing)/drug effects/genetics ; Myocardium/cytology ; NADPH Dehydrogenase/drug effects/genetics ; *Neoplasm Proteins ; *Oxidative Stress ; Particle Size ; Peroxidases/drug effects/genetics ; Peroxiredoxins ; Rats ; Vehicle Emissions/*toxicity ; }, abstract = {Exposure to fine particulate materials is associated with an increase in mortality rate of cardiovascular diseases. Particles deposited in the lung may affect the vascular system both directly (leaching of soluble components from particles) and indirectly (via cytokines and mediators). The present study addressed cytotoxicity and oxidative stress potency of organic extracts of diesel exhaust particles (OE-DEP) and urban fine particles (OE-UFP) in rat heart microvessel endothelial (RHMVE) cells. The LC(50) values of OE-DEP and OE-UFP were calculated to be 17 and 34 microg/ml, respectively, suggesting that OE-DEP was more cytotoxic than OE-UFP. The viability of OE-DEP- and OE-UFP-exposed cells was ameliorated by N-acetyl-L-cysteine (NAC). The cell monolayer was exposed to 0 (control), 1, 3, and 10 microg/ml OE-DEP for 6 h and mRNA levels of antioxidant enzymes such as heme oxygenase-1 (HO-1), thioredoxin peroxidase 2 (TRPO), glutathione S-transferase P subunit (GST-P), and NADPH dehydrogenase (NADPHD) were quantitated by northern analysis. All those mRNA levels increased dose-dependently with OE-DEP and HO-1 mRNA showed the most marked response to OE-DEP. mRNA levels of those antioxidant enzymes and heat shock protein 72 (HSP72) in OE-DEP-exposed cells were higher than those of OE-UFP-exposed cells as compared at the same concentration. The transcription levels of HO-1 and HSP72 in OE-DEP- and OE-UFP-exposed cells were also reduced by NAC. Those results suggest that the organic fraction of particulate materials in the urban air has a potency to cause oxidative stress to endothelial cells and may be implicated in cardiovascular diseases through functional changes of endothelial cells.}, }
@article {pmid12695417, year = {2003}, author = {Vetter, M and Chen, ZJ and Chang, GD and Che, D and Liu, S and Chang, CH}, title = {Cyclosporin A disrupts bradykinin signaling through superoxide.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {41}, number = {5}, pages = {1136-1142}, doi = {10.1161/01.HYP.0000068201.48340.3B}, pmid = {12695417}, issn = {1524-4563}, support = {P01 HL-41618/HL/NHLBI NIH HHS/United States ; R01 HL-56791/HL/NHLBI NIH HHS/United States ; }, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Bradykinin/*pharmacology ; Cyclic GMP/metabolism ; Cyclosporine/*pharmacology ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; GTP-Binding Proteins/metabolism ; Guanylate Cyclase/metabolism ; LLC-PK1 Cells/drug effects/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors/metabolism ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type III ; Onium Compounds/pharmacology ; Phospholipases/metabolism ; Quercetin/pharmacology ; Receptor, Bradykinin B2 ; Receptors, Bradykinin/metabolism ; Signal Transduction ; Solubility ; Superoxides/antagonists &amp; inhibitors/*metabolism ; Swine ; Tyrosine/*analogs &amp; derivatives/metabolism ; Vitamin K 3/pharmacology ; }, abstract = {Cyclosporin A (CsA) is used to reduce transplant rejection rates. Chronic use, however, has a destructive toxic effect on the kidney, resulting in hypertension. In this study, we investigated the effects of CsA treatment on the bradykinin/soluble guanylate cyclase signaling cascade and the involvement of superoxide in LLC-PK1 porcine kidney proximal tubule cells. Treatment with 1 micromol/L CsA for 24 hours increased basal cGMP levels by 41%, whereas CsA inhibited bradykinin-stimulated cGMP production by 26%. Western blotting showed increased expression of eNOS, but no other protein in the bradykinin/soluble guanylate cyclase (sGC) pathway was affected. Using lucigenin-dependent chemiluminescence, we found that CsA treatment significantly increased superoxide production. Production of O2- was not significantly reduced by 10 micromol/L oxypurinol or 30 micromol/L ketoconazole. However, it was inhibited by the NADPH oxidase inhibitor diphenyleneiodonium chloride (10 micromol/L) as well as the O2- scavenger superoxide dismutase (SOD) (100 U). On treatment with 50 micromol/L quercetin, 10 mmol/L N-acetyl-cysteine, both antioxidants, as well as the O2- scavenger Tiron (10 mmol/L), concomitant with 1 micromol/L CsA for 24 hours the activation of cGMP production, was restored in combination with a reduction in O2-. Incubation with 100 micromol/L menadione, a reactive oxygen generator, and 10 nmol/L bradykinin showed similar effects on the level of cGMP as with CsA. CsA treatment was found to increase nitrotyrosine levels. These findings suggest that CsA activates a NADPH oxidase that releases O2- and disrupts the bradykinin/soluble guanylate cyclase pathway, probably by binding with NO to form peroxynitrite (ONOO-).}, }
@article {pmid12691831, year = {2003}, author = {Sekhon, B and Sekhon, C and Khan, M and Patel, SJ and Singh, I and Singh, AK}, title = {N-Acetyl cysteine protects against injury in a rat model of focal cerebral ischemia.}, journal = {Brain research}, volume = {971}, number = {1}, pages = {1-8}, doi = {10.1016/s0006-8993(03)02244-3}, pmid = {12691831}, issn = {0006-8993}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; NS-40144/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/metabolism/*pathology ; Free Radical Scavengers/*pharmacology ; Immunohistochemistry ; Infarction, Middle Cerebral Artery/*drug therapy ; Male ; Models, Theoretical ; Nitric Oxide Synthase/biosynthesis/drug effects ; Nitric Oxide Synthase Type II ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*prevention &amp; control ; Tumor Necrosis Factor-alpha/biosynthesis/drug effects ; }, abstract = {Ischemic cerebrovascular disease (stroke) is one of the leading causes of death and long-time disability. Ischemia/reperfusion to any organ triggers a complex series of biochemical events, which affect the structure and function of every organelle and subcellular system of the affected cells. The purpose of this study was to investigate the therapeutic efficacy of N-acetyl cysteine (NAC), a precursor of glutathione and a potent antioxidant, to attenuate ischemia/reperfusion injury to brain tissue caused by a focal cerebral ischemia model in rats. A total of 27 male Sprague-Dawley rats weighing 250-300 g were used in this study. Focal cerebral ischemia (45 min) was induced in anesthetized rats by occluding the middle cerebral artery (MCA) with an intra-luminal suture through the internal carotid artery. The rats were scored post-reperfusion for neurological deficits. They were then sacrificed after 24 h of reperfusion and infarct volume in the brain was assessed by 2,3,5-triphenyl tetrazolium chloride (TTC). Brain sections were immunostained for tumor necrosis factor (TNF-alpha) and inducible nitric oxide synthase (iNOS). Animals treated with NAC showed a 49.7% (S.E.M.=1.25) reduction in brain infarct volume and 50% (S.E.M.=0.48) reduction in the neurological evaluation score as compared to the untreated animals. NAC treatment also blocked the ischemia/reperfusion-induced expression of tumor necrosis factor and inducible nitric oxide synthase. The data suggest that pre-administration of NAC attenuates cerebral ischemia and reperfusion injury in this brain ischemia model. This protective effect may be as a result of suppression of TNF-alpha and iNOS.}, }
@article {pmid12690631, year = {2003}, author = {Nakamura, M and Ando, Y}, title = {[Amyloidosis and oxidative stress].}, journal = {Rinsho byori. The Japanese journal of clinical pathology}, volume = {51}, number = {2}, pages = {140-145}, pmid = {12690631}, issn = {0047-1860}, mesh = {Amyloidosis/drug therapy/*etiology/metabolism ; Free Radical Scavengers/therapeutic use ; Glycation End Products, Advanced/metabolism ; Humans ; Lipid Peroxidation ; Mutation ; *Oxidative Stress/physiology ; Superoxide Dismutase/genetics ; }, abstract = {Recent studies on oxidative stress have revealed that free radical injury appears to be involved in either the amyloid formation process or in post-fibrillar modification in several types of amyloidosis. Here, we report the role of oxidative stress in the pathogenesis of dialysis-related amyloidosis(DRA) and familial amyloidotic polyneuropathy(FAP), and propose radical scavenger treatment for such amyloidosis. For patients under maintenance hemodialysis, EC-SOD Arg213Gly was a risk factor for the progression of DRA, atherosclerosis, and renal failure causing hemodialysis. In FAP patients who had EC-SOD Arg213Gly, massive amyloid deposition which may be related to increased oxidative stress in loco was found especially prominently around blood vessels in the interstitial tissues. Histological and biochemical examinations revealed that oxidative stress is deeply connected with amyloid formation mechanisms in FAP. We started radical scavenger therapy, such as N-acetyl cysteine, vitamin E and vitamin C in 20 Swedish FAP patients for 6 months. Although no improvement was found in the amount of amyloid deposition in biopsy specimens, modified body mass index(mBMI), an index of nutritional status, tended to be increased, suggesting the therapeutic possibility of radical scavenger treatment for amyloidosis.}, }
@article {pmid12690112, year = {2003}, author = {Taillé, C and Almolki, A and Benhamed, M and Zedda, C and Mégret, J and Berger, P and Lesèche, G and Fadel, E and Yamaguchi, T and Marthan, R and Aubier, M and Boczkowski, J}, title = {Heme oxygenase inhibits human airway smooth muscle proliferation via a bilirubin-dependent modulation of ERK1/2 phosphorylation.}, journal = {The Journal of biological chemistry}, volume = {278}, number = {29}, pages = {27160-27168}, doi = {10.1074/jbc.M300364200}, pmid = {12690112}, issn = {0021-9258}, mesh = {Animals ; Asthma/enzymology/etiology/pathology ; Base Sequence ; Bilirubin/*metabolism ; Cell Division/drug effects ; Cells, Cultured ; Guinea Pigs ; Heme Oxygenase (Decyclizing)/antagonists &amp; inhibitors/genetics/*metabolism ; Heme Oxygenase-1 ; Humans ; Immunization ; Membrane Proteins ; Mitogen-Activated Protein Kinase 1/*metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/*metabolism ; Oligodeoxyribonucleotides, Antisense/genetics/pharmacology ; Ovalbumin/immunology ; Oxidation-Reduction ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Respiratory Muscles/*cytology/drug effects/immunology/*metabolism ; }, abstract = {The aim of this study was to investigate whether the heme oxygenase (HO) pathway could modulate proliferation of airway smooth muscle (ASM) and the mechanism(s) involved in this phenomenon. In cultured human ASM cells, 10% fetal calf serum or 50 ng/ml platelet-derived growth factor AB induced cell proliferation, extracellular and intracellular reactive oxygen species (ROS) production and ERK1/2 phosphorylation. Pharmacological HO-1 induction (by 10 microm hemin or by 20 microm cobalt-protoporphyrin) and HO inhibition (by 25 microm tin-protoporphyrin or by an antisense oligonucleotide), respectively, reduced and enhanced significantly both cell proliferation and ROS production. Neither the carbon monoxide scavenger myoglobin (5-20 microm) nor the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one could reverse ASM proliferation induced by tin-protoporphyrin, making a role of the CO-cGMP pathway in HO-modulated proliferation unlikely. By contrast, bilirubin (1 microm) and the antioxidant N-acetyl-cysteine (1 mm) significantly reduced mitogen-induced cell proliferation, ROS production, and ERK1/2 phosphorylation. Furthermore, both bilirubin and N-acetyl-cysteine and the ERK1/2 inhibitor PD98059 significantly reversed the effects of HO inhibition on ASM proliferation. These results could be relevant to ASM alterations observed in asthma because activation of the HO pathway prevented the increase in bronchial smooth muscle area induced by repeated ovalbumin challenge in immunized guinea pigs, whereas inhibition of HO had the opposite effect. In conclusion, this study provides evidence for an antiproliferative effect of the HO pathway in ASM in vitro and in vivo through a bilirubin-mediated redox modulation of phosphorylation of ERK1/2.}, }
@article {pmid12688549, year = {2003}, author = {Ozdulger, A and Cinel, I and Koksel, O and Cinel, L and Avlan, D and Unlu, A and Okcu, H and Dikmengil, M and Oral, U}, title = {The protective effect of N-acetylcysteine on apoptotic lung injury in cecal ligation and puncture-induced sepsis model.}, journal = {Shock (Augusta, Ga.)}, volume = {19}, number = {4}, pages = {366-372}, doi = {10.1097/00024382-200304000-00012}, pmid = {12688549}, issn = {1073-2322}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Apoptosis/*drug effects ; Cecum/injuries ; Disease Models, Animal ; Intestinal Perforation/*complications ; Ligation ; Lipid Peroxidation ; Lung/chemistry ; Lung Diseases/etiology/*prevention &amp; control ; Male ; Malondialdehyde/analysis ; Nitrates/analysis ; Nitrites/analysis ; Oxidative Stress ; Peroxidase/analysis ; Rats ; Rats, Wistar ; Resuscitation ; Systemic Inflammatory Response Syndrome/*complications ; }, abstract = {Apoptotic loss of parenchymal cells may lead to organ dysfunctions in critically ill patients with septic states. As an antioxidant, the protective effects of N-acetylcysteine (NAC) are documented in many experimental and clinical studies. In this experimental study, we investigated the role of chronically used NAC in septic lung injury on a cecal ligation and puncture (CLP) model. To evaluate this, 30 male Wistar rats were randomly divided into four groups as sham (n = 7), CLP (n = 8), sham + NAC (n = 7) and CLP + NAC (n = 8) groups. NAC was administered 150 mg kg(-1) day through intramuscular route beginning 6 h after the operations and lasting for a period of 1 week. One week later, histopathology and epithelial apoptosis were assessed by hematoxylin-eosin and immunohistochemically by M30 and caspase 3 staining to demonstrate septic lung injury. Additionally, lung tissue myeloperoxidase (MPO) activity, malondialdehyde (MDA), and nitrite/nitrate levels were measured. The MPO activity and MDA levels in lung homogenates were found to be increased in CLP group and the administration of NAC prevented their increase significantly (P < 0.05). However, there were no significant differences among the groups regarding nitrite/nitrate levels. The number of apoptotic cells was significantly lower in CLP+NAC group than CLP group, and this finding was supported by M30 and caspase 3 expression in lung (P < 0.05). Lung histopathology was also protected by NAC in CLP-induced sepsis. In conclusion, the chronic use of NAC inhibited MPO activity and lipid peroxidation, which resulted in reduction of apoptosis in lung in this CLP model. Because lung tissue nitrite/nitrate levels did not change significantly, organs other than the lungs may be responsible for producing the increased nitric oxide during sepsis. The chronic use of NAC needs further investigation for its possible antiapoptotic potential in septic states besides its documented antioxidant and antiinflammatory effects.}, }
@article {pmid12682431, year = {2003}, author = {Zhang, Q and Huang, X}, title = {Induction of interleukin-6 by coal containing bioavailable iron is through both hydroxyl radical and ferryl species.}, journal = {Journal of biosciences}, volume = {28}, number = {1}, pages = {95-100}, pmid = {12682431}, issn = {0250-5991}, support = {ES00260/ES/NIEHS NIH HHS/United States ; OH 03561/OH/NIOSH CDC HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Biological Availability ; Catalase/pharmacology ; Cell Line ; Coal/*analysis ; Coal Mining ; Epithelial Cells/*drug effects/metabolism ; Humans ; Hydroxyl Radical/*toxicity ; Interleukin-6/*biosynthesis ; Iron/analysis/*toxicity ; Lung/cytology ; Oxidants/*toxicity ; Particle Size ; Pneumoconiosis/etiology ; RNA, Messenger/analysis/metabolism ; Reactive Oxygen Species ; Superoxide Dismutase/pharmacology ; }, abstract = {Coal mining causes health problems, such as pneumoconiosis. We have previously shown that prevalence of pneumoconiosis in workers from various coalmine regions positively correlates with levels of bioavailable iron (BAI) in the coals from that region. In the present study, the nature of reactive oxygen species formed by BAI in the coals and its mechanisms of the induction of biological responses were investigated. Human lung epithelial cell line, A549 cells, were used to examine the induction of interleukin-6 (IL-6), a pro-inflammatory cytokine, which is known to play a crucial role in the development of pneumoconiosis. We found that levels of IL-6 protein as well as its mRNA were significantly increased in the cells treated for 24 h with 20 microg/cm2 of the BAI-containing Pennsylvania (PA) coal; for example we observed 6.7-fold increase in IL-6 protein. Levels of IL-6 protein in cells treated with the Utah (UT) coal containing low-BAI were only 1.9-fold of the control levels. The enhancing effect on the IL-6 by the PA coal was similar to that caused by hydrogen peroxide. Superoxide dismutase (SOD), catalase (CAT), and N-acetyl-L-cysteine (NAC) all had inhibitory effects on the PA coal-induced IL-6 formation. However, CAT had the least protective effect as compared to SOD and NAC. Our results indicate that BAI in the PA coal may induce IL-6 through both ferryl species (via iron autoxidation) and hydroxyl radicals (via the Fenton/Haber Weiss reactions).}, }
@article {pmid12681446, year = {2003}, author = {Lai, MT and Huang, KL and Chang, WM and Lai, YK}, title = {Geldanamycin induction of grp78 requires activation of reactive oxygen species via ER stress responsive elements in 9L rat brain tumour cells.}, journal = {Cellular signalling}, volume = {15}, number = {6}, pages = {585-595}, doi = {10.1016/s0898-6568(03)00004-4}, pmid = {12681446}, issn = {0898-6568}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/antagonists &amp; inhibitors/*pharmacology ; Antioxidants/pharmacology ; Base Sequence ; Benzoquinones ; Brain Neoplasms/genetics/*metabolism ; Carrier Proteins/biosynthesis/*genetics ; Endoplasmic Reticulum/drug effects/metabolism ; *Heat-Shock Proteins ; Kinetics ; Lactams, Macrocyclic ; Molecular Chaperones/biosynthesis/*genetics ; Molecular Sequence Data ; Oxidative Stress ; Promoter Regions, Genetic ; Pyrrolidines/pharmacology ; Quinones/antagonists &amp; inhibitors/*pharmacology ; RNA, Messenger/biosynthesis ; Rats ; Reactive Oxygen Species/*metabolism ; *Response Elements ; Thiocarbamates/pharmacology ; Transcriptional Activation ; Tumor Cells, Cultured ; }, abstract = {The molecular mechanism whereby anticancer agent geldanamycin (GA) impacts endoplasmic reticulum (ER) stress pathway is largely unknown. Here, we investigate the effect of GA on the expression of grp78 coding for ER stress protein and the mechanistic relationship of GA signalling to ER stress. GA induces the expression of mRNA and protein of grp78 by Northern blot analysis and metabolic labelling experiment in cultured rat brain tumour 9L cells. The induced grp78 expression is sensitive to antioxidant N-acetylcysteine (NAC) addition, indicating the involvement of reactive oxygen species (ROS) in GA-induced ER stress. Results from direct determination of oxidation status using dichlorodihydrofluorescein diacetate (H(2)DCFDA) showed that accumulation of ROS elicited GA was quenched by addition of NAC. Reporter genes harbouring deletions of transcription elements from grp78 promoter demonstrated that controlling elements of ERSE1, ERSE2 and CRE are required in GA treatment. The critical ROS-dependent elements in grp78 promoter can be confined within ER stress responsive element (ERSE) region, since reporter constructs loss of ERSE elements that lost the susceptibility to be modulated by NAC after GA treatment. Hence, ER stress elements correlate well with ROS-mediated elements in grp78 promoter. Reporter construct loss of ERSE element retains the susceptibility by NAC after GA treatment, indicating that CRE element might represent a ROS-independent, GA-inductive element. Conclusively, we show that ROS is required for GA to launch the transactivation of grp78, and a firm link was established between the ROS signalling pathway to specific promoter elements-ERSE1 and ERSE2 elements in ER stress marker gene grp78 promoter.}, }
@article {pmid12686517, year = {2003}, author = {Zhou, X and Yin, W and Doi, SQ and Robinson, SW and Takeyasu, K and Fan, X}, title = {Stimulation of Na,K-ATPase by low potassium requires reactive oxygen species.}, journal = {American journal of physiology. Cell physiology}, volume = {285}, number = {2}, pages = {C319-26}, doi = {10.1152/ajpcell.00536.2002}, pmid = {12686517}, issn = {0363-6143}, support = {NS-23241/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Binding Sites/drug effects/physiology ; Catalase/metabolism/pharmacology ; Cell Line ; Cell Membrane/drug effects/*enzymology ; Dogs ; Dose-Response Relationship, Drug ; Eukaryotic Cells/drug effects/*enzymology ; Gene Expression Regulation, Enzymologic/drug effects/genetics ; Genes, Reporter/drug effects/genetics ; Potassium Deficiency/*metabolism ; Promoter Regions, Genetic/drug effects/genetics ; Protein Subunits/drug effects/metabolism ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects/genetics ; Sodium-Potassium-Exchanging ATPase/*genetics/*metabolism ; }, abstract = {The signaling pathway that transduces the stimulatory effect of low K+ on the biosynthesis of Na,K-ATPase remains largely unknown. The present study was undertaken to examine whether reactive oxygen species (ROS) mediated the effect of low K+ in Madin-Darby canine kidney (MDCK) cells. Low K+ increased ROS activity in a time- and dose-dependent manner, and this effect was abrogated by catalase and N-acetylcysteine (NAC). To determine the role of ROS in low-K+-induced gene expression, the cells were first stably transfected with expression constructs in which the reporter gene chloramphenicol acetyl transferase (CAT) was under the control of the avian Na,K-ATPase alpha-subunit 1.9 kb and 900-bp 5'-flanking regions that have a negative regulatory element. Low K+ increased the CAT expression in both constructs. Catalase or NAC inhibited the effect of low K+. To determine whether the increased CAT activity was mediated through releasing the repressive effect or a direct stimulation of the promoter, the cells were transfected with a CAT expression construct directed by a 96-bp promoter fragment that has no negative regulatory element. Low K+ also augmented the CAT activity expressed by this construct. More importantly, both catalase and NAC abolished the effect of low K+. Moreover, catalase and NAC also inhibited low-K+-induced increases in the Na,K-ATPase alpha1- and beta1-subunit protein abundance and ouabain binding sites. The antioxidants had no significant effect on the basal levels of CAT activity, protein abundance, or ouabain binding sites. In conclusion, low K+ enhances the Na,K-ATPase gene expression by a direct stimulation of the promoter activity, and ROS mediate this stimulation and also low-K+-induced increases in the Na,K-ATPase protein contents and cell surface molecules.}, }
@article {pmid12686498, year = {2003}, author = {Shen, DX and Shi, X and Fu, JL and Zhang, YM and Zhou, ZC}, title = {The role of thiol reduction in hydroquinone-induced apoptosis in HEK293 cells.}, journal = {Chemico-biological interactions}, volume = {145}, number = {2}, pages = {225-233}, doi = {10.1016/s0009-2797(03)00003-6}, pmid = {12686498}, issn = {0009-2797}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; Humans ; Hydroquinones/*pharmacology ; Kidney/cytology/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Hydroquinone (HQ) is a chemical used as a reducing agent, antioxidant, polymerization inhibitor, and chemical intermediate. It has a minor use as a bleaching agent in dermatologic preparations. HQ also occurs as a main metabolite of benzene. In the present study, HQ-induced apoptosis was evaluated by cell morphology changes, determination of phosphatidylserine (PS) externalization and analysis of sub-G1 cells. The effect of HQ on intracellular thiol concentration, including glutathione and protein thiol, and the effect of N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) pretreatment on HQ-induced apoptosis were investigated. The results showed that HQ was able to induce typical apoptosis in HEK293 cells (human embryonic kidney cells) in a dose-dependent manner. Intracellular thiol, including glutathione and protein thiol, was decreased following treatment with HQ. NAC, a precursor of intracellular GSH synthesis, significantly inhibited HQ-induced apoptosis. However, BSO, a specific inhibitor of intracellular GSH synthesis, enhanced HQ-induced apoptosis significantly. Taken together, the present study demonstrates that HQ is able to induce apoptosis in HEK293 cells, most probably through depletion of intracellular thiol. The results also suggest that, at least in HEK293 cells, the control of intracellular redox homeostasis has a central role in the regulation of cell death induced by HQ.}, }
@article {pmid12683710, year = {2003}, author = {Sharma, R and Guleria, R and Pande, JN}, title = {Idiopathic pulmonary fibrosis: newer concepts and management strategies.}, journal = {The Indian journal of chest diseases &amp; allied sciences}, volume = {45}, number = {1}, pages = {31-49}, pmid = {12683710}, issn = {0377-9343}, mesh = {Humans ; *Pulmonary Fibrosis/therapy ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histologic appearance of usual interstitial pneumonia (UIP) on lung biopsy. It is characterized by progresive dyspnea, worsening of pulmonary function and radiographically, by patchy subpleural interstitial infiltrates with minimal ground glass appearance predominantly affecting the lung bases. The etiology is unknown and no therapy has been clearly shown to prolong survival. The diagnosis, which earlier was difficult to establish, is now based on guidelines of American Thoracic Society. Newer insight into its etiopathogenesis, particularly the mechanisms involved including T helper 1 (Th1) and T helper 2 (Th2) types of responses occurring after the initial and repetitive lung insults and the ineffectiveness of conventional modes of therapy has prompted clinicians worldwide to look for alternative modes of therapy. Conventional therapy for this disorder has been steroids and immunosuppressives. Immunomodulators (Interferon gamma 1b) and antioxidants (Glutathione and its precursor N-acetyl cysteine) are promising results in this, otherwise, uniformly fatal condition.}, }
@article {pmid12683233, year = {2003}, author = {Gamaleĭ, IA and Aksenov, ND and Efremova, TN and Kirpichnikova, KM}, title = {[Effect of agents changing the intracellular level of reactive oxygen species on the cell cycle phase distribution in 3T3 and 3T3SV40 cell lines].}, journal = {Tsitologiia}, volume = {45}, number = {1}, pages = {26-33}, pmid = {12683233}, issn = {0041-3771}, mesh = {3T3 Cells ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Cycle/*drug effects ; Cell Line, Transformed ; Dose-Response Relationship, Drug ; Glutathione/biosynthesis ; Mice ; Pyrrolidonecarboxylic Acid ; Reactive Oxygen Species/*metabolism ; Thiazoles/pharmacology ; Thiazolidines ; }, abstract = {A comparison of cell cycle phase distribution of 3T3 cells and their transformants 3T3SV40 treated with different substances changing the intracellular level of reactive oxygen species (ROS) has been made. In this study the following glutathione synthesis modulating agents were tested: two precursors of intracellular glutathione, antioxidant N-acetyl-L-cysteine (NAC) (-)-2-oxo-4-thiazolidine-carboxylic acid (OTZ), and inhibitor of glutathione synthesis, DL-buthionine-S, R-sulfoximine (BSO). It has been shown that both NAC (10-20 mM) and OTZ (20 mM) decreased the intracellular level of ROS in both cell lines. OTZ was more potent than NAC. However, only NAC caused changes in cell cycle progression of both cell types in dose-dependent manner. These changes differed in 3T3 and 3T3SV40 cells. Flow cytometric analysis of cell cycle phase distribution indicated that NAC (20 mM) blocked cell cycle in the G1 phase. The G1--arrest was completely reversible after removal of NAC from the medium. NAC (10-20 mM) caused a decrease in S and G2/M phases of transformants 3T3SV40. Moreover, a part of the population died apoptoticaly. Different mechanisms of NAC effect on normal and transformed cells are discussed. It is suggested that there is no strong correlation between cell cycle progression and intracellular level of ROS.}, }
@article {pmid12679464, year = {2003}, author = {Lappas, M and Permezel, M and Rice, GE}, title = {N-Acetyl-cysteine inhibits phospholipid metabolism, proinflammatory cytokine release, protease activity, and nuclear factor-kappaB deoxyribonucleic acid-binding activity in human fetal membranes in vitro.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {88}, number = {4}, pages = {1723-1729}, doi = {10.1210/jc.2002-021677}, pmid = {12679464}, issn = {0021-972X}, mesh = {Acetylcysteine/*pharmacology ; Amnion/drug effects/metabolism ; Chorion/drug effects/metabolism ; Culture Techniques ; Cytokines/*metabolism ; DNA/metabolism ; Decidua/drug effects/metabolism ; Dinoprost/metabolism ; Endopeptidases/*metabolism ; Extraembryonic Membranes/*drug effects/metabolism ; F2-Isoprostanes/metabolism ; Female ; Humans ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; L-Lactate Dehydrogenase/metabolism ; Matrix Metalloproteinase 9/metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Oxidative Stress ; Phospholipases A/antagonists &amp; inhibitors/metabolism ; Phospholipids/*metabolism ; Pregnancy ; Urokinase-Type Plasminogen Activator/metabolism ; }, abstract = {The production of reactive oxygen species (ROS), prostaglandins (PGs), proinflammatory cytokines, and proteases has been implicated in the pathogenesis of term and preterm labor. The nuclear factor-kappaB (NF-kappaB) transcription pathway is activated by ROS and is a key regulator of PGs, proinflammatory cytokine release, and protease activity. N-Acetyl-cysteine (NAC) is an antioxidant that through its ability to scavenger ROS suppresses NF-kappaB DNA-binding activity and resultant gene expression. The aim of this study was to elucidate the effect of NAC on NF-kappaB DNA-binding activity, phospholipid metabolism, cytokine release, and protease activity from human fetal membranes. Human amnion and choriodecidua (n = 9 separate placentas) were treated with 0 (control), 5, 10, or 15 mM NAC in the presence of 10 micro g/ml lipopolysaccharide. After 6-h incubation, the tissues were collected, NF-kappaB DNA binding activity was assessed by gel shift binding assays, and matrix metalloproteinase-9 and urokinase-type plasminogen activator activity were determined by zymography. The incubation medium was collected and assayed for type II phospholipase A(2) tissue content, IL-6, IL-8, TNFalpha, and 8-isoprostane release by ELISA. The release of PGF(2alpha) was measured by RIA. Treatment of fetal membranes with NAC significantly suppressed lipopolysaccharide-stimulated type II phospholipase A(2) release and content; PGF(2alpha), IL-6, IL-8, TNFalpha, and 8-isoprostane release; and matrix metalloproteinase-9 and urokinase-type plasminogen activator enzyme activity and suppressed NF-kappaB DNA-binding activity (by ANOVA, P < 0.05). The data presented in this study demonstrate that NAC inhibits an NF-kappaB-activated pathway and subsequent phospholipid metabolism, proinflammatory cytokine release, and protease activity in human fetal membranes.}, }
@article {pmid12679188, year = {2003}, author = {Sener, G and Tosun, O and Sehirli, AO and Kaçmaz, A and Arbak, S and Ersoy, Y and Ayanoğlu-Dülger, G}, title = {Melatonin and N-acetylcysteine have beneficial effects during hepatic ischemia and reperfusion.}, journal = {Life sciences}, volume = {72}, number = {24}, pages = {2707-2718}, doi = {10.1016/s0024-3205(03)00187-5}, pmid = {12679188}, issn = {0024-3205}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Biomarkers ; Female ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Ischemia/*drug therapy/pathology ; Lipid Peroxidation/drug effects ; Liver/pathology ; Liver Circulation/drug effects/*physiology ; Liver Function Tests ; Male ; Malondialdehyde/metabolism ; Melatonin/*therapeutic use ; Neutrophil Infiltration/drug effects ; Oxidation-Reduction ; Peroxidase/metabolism ; Proteins/metabolism ; Rats ; Rats, Wistar ; Reperfusion Injury/*drug therapy/pathology ; }, abstract = {This study was designed to study the effects of Melatonin (Mel) and N-Acetylcystein (NAC) on hepatic ischemia/reperfusion (I/R) injury in rats. For this purpose Wistar albino rats were subjected to 45 minutes of hepatic ischemia followed by 60 minutes of reperfusion period. Melatonin (10 mg/kg) or NAC (150 mg/kg) were administered alone or in combination, intraperitoneally, 15 minutes prior to ischemia and just before reperfusion. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined to assess liver functions. Liver tissues were taken for determination of malondialdehyde (MDA) levels, an end product of lipid peroxidation; glutathione (GSH) levels, a key antioxidant; protein carbonyl concentration (protein oxidation) (PO), a specific marker of oxidative damage of proteins; and myeloperoxidase (MPO) activity, as an indirect index of neutrophil infiltration. Plasma ALT and AST activities were higher in ischemia/reperfusion group than in control. They were decreased in the groups given Mel, NAC or the combination. Hepatic GSH levels, significantly depressed by I/R, were elevated to control levels in the combination group, whereas treatment with Mel or NAC alone provided only a limited protection. Hepatic MDA and PO levels, and MPO activity were significantly increased by I/R. The increase in these parameters were partially decreased by Mel or NAC alone, whereas treatment with the combination reduced these values back to control levels. In conclusion, considering the dosages used, Mel appeared to be significantly more potent than NAC in reversing the oxidative damage induced by I/R. Our findings show that Mel and NAC have beneficial effects against the I/R injury and due to their synergistic effects, when administered in combination, may have a more pronounced protective effects on the liver.}, }
@article {pmid12676445, year = {2003}, author = {Descotes, J}, title = {From clinical to human toxicology: linking animal research and risk assessment in man.}, journal = {Toxicology letters}, volume = {140-141}, number = {}, pages = {3-10}, doi = {10.1016/s0378-4274(02)00490-3}, pmid = {12676445}, issn = {0378-4274}, mesh = {Animals ; Dose-Response Relationship, Drug ; Humans ; Poison Control Centers/organization &amp; administration ; Poisoning/*therapy ; *Research ; Risk Assessment ; *Toxicology/classification/trends ; }, abstract = {Since the 1960s, clinical toxicologists have primarily focused on acute poisonings. This proved very successful as the prognosis markedly improved with the use of resuscitation methods, evidence-based management and new antidotes. This latter area was the first major instance linking animal research and clinical toxicology, as illustrated with N-acetyl-cysteine or specific antibodies. Simultaneously the evolution of poison centers was a critical turning point as '2nd generation' centers are increasingly involved in risk assessment and toxicovigilance. Human toxicology is a broader area in that it is also involved in the toxicity evaluation of xenobiotics with the resulting need to link animal research and risk assessment to match the results of preclinical studies with clinical observations. However, this is not an easy task as experimental and clinical toxicologists seldom share ideas and expertise. Immunotoxicology is an example of this situation. Most of the available data on immunosuppression was obtained in animals and not in man, whereas allergic reactions have been extensively investigated in man, but overlooked in animals until recently. One of the major challenges facing toxicology is to bridge the gap between animal research and risk assessment in man. Human toxicology is expected to play a role in taking up this challenge.}, }
@article {pmid12674508, year = {2003}, author = {Kim, CH and Kim, JH and Lee, J and Hsu, CY and Ahn, YS}, title = {Thiol antioxidant reversal of pyrrolidine dithiocarbamate-induced reciprocal regulation of AP-1 and NF-kappaB.}, journal = {Biological chemistry}, volume = {384}, number = {1}, pages = {143-150}, doi = {10.1515/BC.2003.015}, pmid = {12674508}, issn = {1431-6730}, mesh = {Animals ; Antioxidants/*pharmacology ; Cattle ; Electrophoretic Mobility Shift Assay ; Endothelium, Vascular/cytology/drug effects ; Glutathione/metabolism ; NF-kappa B/drug effects/*metabolism ; Oxidation-Reduction ; Pyrrolidines/*antagonists &amp; inhibitors/pharmacology ; Sulfhydryl Compounds/*pharmacology ; Thiocarbamates/*antagonists &amp; inhibitors/pharmacology ; Transcription Factor AP-1/drug effects/*metabolism ; Zinc/chemistry/pharmacology ; }, abstract = {Pyrrolidine dithiocarbamate (PDTC) has been shown to have unique reciprocal activities in activating AP-1 and inhibiting NF-kappaB, two oxidative stress-sensitive transcription factors. The opposing effects of PDTC on these two transcription factors have been attributed to its thiol antioxidant properties. In the present study, PDTC activation of AP-1, like its inhibition of NF-kappaB, in bovine cerebral endothelial cells (BCECs) was zinc-dependent, consistent with the contention that PDTC acts as a zinc ionophore and the apparent reciprocal actions of PDTC are mediated by zinc. Unlike PDTC, other thiols and non-thiol antioxidants did not activate AP-1 on their own. Thiol, but not non-thiol, antioxidants reversed PDTC actions on AP-1 and NF-kappaB. PDTC reduced the intracellular glutathione content, and depletion of the cellular glutathione store by buthionine sulfoximine (BSO) further augmented PDTC actions on AP-1 and NF-kappaB. N-acetylcysteine (NAC), a thiol antioxidant, reversed PDTC actions even after irreversible depletion of the cellular glutathione store by BSO. These findings together suggest that thiol antioxidant reversal of PDTC actions on AP-1 and NF-kappaB is independent of their established roles in scavenging oxygen free radicals or repleting the cellular glutathione content. The results in the present and earlier studies suggest that thiol antioxidants are likely to act as metal chelators that buffer zinc mediation of the reciprocal actions of PDTC on AP-1 and NF-kappaB.}, }
@article {pmid12670672, year = {2003}, author = {Perez, MRSG and Zuurmond, AWW and Bezemer, DP and Kuik, JD and van Loenen, CA and de Lange, JJ and Zuidhof, JA}, title = {The treatment of complex regional pain syndrome type I with free radical scavengers: a randomized controlled study.}, journal = {Pain}, volume = {102}, number = {3}, pages = {297-307}, doi = {10.1016/S0304-3959(02)00414-1}, pmid = {12670672}, issn = {0304-3959}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Analysis of Variance ; Chi-Square Distribution ; Dimethyl Sulfoxide/*therapeutic use ; Double-Blind Method ; Female ; Follow-Up Studies ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Middle Aged ; Reflex Sympathetic Dystrophy/*drug therapy/physiopathology ; Regression Analysis ; Statistics, Nonparametric ; }, abstract = {To compare the effects of two free radical scavengers, dimethylsulfoxide 50% (DMSO) and N-acetylcysteine (NAC), for treatment of complex regional pain syndrome I (CRPS I), a randomized, double-dummy controlled, double-blind trial was conducted. Two outpatient clinics of two university hospitals in The Netherlands participated in the study and 146 patients, were included over a period of 24 months. Patients were randomized into two treatment groups, one was instructed to apply DMSO 50% five times daily to the affected extremity, the second was treated with NAC 600mg effervescent tablets three times daily, both combined with placebo. Interventions were accompanied by pain medication, occupational therapy for upper extremity CRPS I and physical therapy for lower extremity CRPS I in specific circumstances. Treatment was given for 17 weeks, with a possibility to continue or switch medication after this period, up to 1 year following the onset of treatment. An impairment level sum score was the primary outcome measure. Upper and lower extremity skills and functions, and general health status were also evaluated. Overall, no significant differences were found between NAC and DMSO after 17 and 52 weeks on impairment level and general health status. Significant differences were found for subscores of lower extremity function, in favor of DMSO-treatment. Subgroup analysis showed more favorable results for DMSO for warm CRPS I and significantly better performance of NAC for patients with a cold CRPS I. Results tended to be negatively influenced if the duration of the complaint was longer. Treatment with DMSO and NAC are generally equally effective in treatment of CRPS I. Strong indications exist for differences in effects for subgroups of patients with warm or cold CRPS I: for warm CRPS I, DMSO-treatment appears more favorable, while for cold CRPS I, NAC-treatment appears to be more effective.}, }
@article {pmid12657201, year = {2000}, author = {Ungheri, D and Pisani, C and Sanson, G and Bertani, A and Schioppacassi, G and Delgado, R and Sironi, M and Ghezzi, P}, title = {Protective effect of n-acetylcysteine in a model of influenza infection in mice.}, journal = {International journal of immunopathology and pharmacology}, volume = {13}, number = {3}, pages = {123-128}, pmid = {12657201}, issn = {2058-7384}, abstract = {Reactive oxygen intermediates (ROI) and cytokines, particularly tumor necrosis factor (TNF) have been implicated in the pathogenesis of influenza. Using a murine model of influenza, we have studied the levels of TNF, interleukin 6 (IL-6) and of superoxide-generating xanthine oxidase (XO). Mice infected intranasally with influenza virus APR/8 had high levels of XO, TNF and IL-6 in the broncoalveolar lavage, as early as 3 d after infection. XO was elevated also in serum and lung tissue. Administration of the antioxidant N-acetylcysteine (NAC,1 g/kg per day, orally) significantly decreased the mortality in infected mice, indicating a role for RO1 in the lethality associated with influenza infection.}, }
@article {pmid12653105, year = {2003}, author = {Sehirli, AO and Sener, G and Satiroglu, H and Ayanoğlu-Dülger, G}, title = {Protective effect of N-acetylcysteine on renal ischemia/reperfusion injury in the rat.}, journal = {Journal of nephrology}, volume = {16}, number = {1}, pages = {75-80}, pmid = {12653105}, issn = {1121-8428}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Free Radical Scavengers ; Glutathione/analysis ; Injections, Intraperitoneal ; Ischemia/pathology/*therapy ; Ischemic Preconditioning ; Kidney Diseases/pathology/*therapy ; Kidney Function Tests ; Kidney Tubules, Collecting/drug effects ; Male ; Malondialdehyde/analysis ; Nephrectomy ; Peroxidase/analysis ; Probability ; Rats ; Rats, Wistar ; Reperfusion Injury/*drug therapy/*prevention &amp; control ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: Oxygen free radicals are important components involved in the pathophysiological tissue alterations observed during ischemia/reperfusion (I/R).<br><br>METHODS: The protective effect of N-acetylcysteine (NAC) against the damage inflicted by reactive oxygen species during renal I/R was investigated in Wistar Albino rats using biochemical parameters. Animals were unilaterally nephrectomized, and subjected to 45 min of renal pedicle occlusion followed by lh of reperfusion. N-acetylcysteine (150 mg/kg, i.p.) or vehicle was administered twice, 15 min prior to ischemia and immediately before the reperfusion period. At the end of the reperfusion period, rats were killed by decapitation. For biochemical analysis, the lipid peroxidation product malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and protein oxidation (PO) were tested. Serum creatinine and BUN concentrations were measured for the evaluation of renal function.<br><br>RESULTS: I/R induced nephrotoxicity, as evidenced by increases in BUN and creatinine, was reversed by NAC. The decrease in GSH and increases in MDA, MPO and PO induced by I/R indicated that renal injury involves free radical formation.<br><br>CONCLUSIONS: Since NAC reversed these oxidant responses, and protected rat renal proximal tubules from in vitro simulated reperfusion injury, it seems that NAC protects kidney tissue against oxidative damage.}, }
@article {pmid12649560, year = {2003}, author = {Haraldsen, P and Sun, ZW and Börjesson, A and Olanders, K and Lasson, A and Andersson, R}, title = {Multimodal management - of value in fulminant acute pancreatitis?.}, journal = {Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]}, volume = {3}, number = {1}, pages = {14-25}, doi = {10.1159/000069148}, pmid = {12649560}, issn = {1424-3903}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Animals ; Antibodies, Monoclonal/*therapeutic use ; Capillary Permeability/drug effects ; Drug Therapy, Combination ; Free Radical Scavengers/*therapeutic use ; Imidazoles/*therapeutic use ; Leucine/*analogs &amp; derivatives/*therapeutic use ; Male ; Pancreatitis/*drug therapy/physiopathology ; Platelet Activating Factor/antagonists &amp; inhibitors ; Platelet Endothelial Cell Adhesion Molecule-1/*immunology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: The multiple organ dysfunction syndrome (MODS) is the major cause of morbidity and mortality associated with acute pancreatitis. Presently, therapy is merely organ supportive as no effective therapy against underlying causative pathophysiological mechanisms exists.<br><br>AIMS: To evaluate the effect of treatment with a platelet-activating factor inhibitor (PAFI), a monoclonal antibody against platelet endothelial cell adhesion molecule 1 (PECAM-1-MAb) and an oxygen free radical scavenger (N-acetylcystein; NAC), alone or in combination, on systemic organ dysfunction in experimental acute pancreatitis.<br><br>METHODS: Severe acute pancreatitis was induced in rats by the intraductal administration of taurodeoxycholate. Treatment was given after 1 or 3 h, and evaluations were performed 6 h after induction. Organ dysfunction was evaluated by means of endothelial integrity impairment expressed as endothelial barrier leakage index.<br><br>RESULTS: Severe acute pancreatitis caused a significant impairment in endothelial integrity in all organs studied and decreased levels of protease inhibitors compared to controls. The endothelial barrier impairment was significantly ameliorated by all treatment modalities, either given early or later. Combinations of NAC and the PECAM-1-MAb or the PECAM-1-MAb and the PAFI were the only schedules to restore endothelial barrier integrity to normal levels in most of the organs studied.<br><br>CONCLUSION: Combination therapy with NAC and PECAM-1-MAb and/or PAFI may offer effective, causative-directed supplements to organ-supportive therapy of MODS in severe acute pancreatitis.}, }
@article {pmid12649537, year = {2003}, author = {Sekhon, CS and Sekhon, BK and Singh, I and Orak, JK and Singh, AK}, title = {Attenuation of renal ischemia/reperfusion injury by a triple drug combination therapy.}, journal = {Journal of nephrology}, volume = {16}, number = {1}, pages = {63-74}, pmid = {12649537}, issn = {1121-8428}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis ; Biopsy, Needle ; Disease Models, Animal ; Dogs ; Drug Therapy, Combination ; Glycopeptides/*pharmacology ; Immunohistochemistry ; In Situ Nick-End Labeling ; Ischemia/pathology/*therapy ; Kidney/drug effects/pathology ; Kidney Diseases/pathology/*therapy ; Male ; Nitroprusside/*pharmacology ; Probability ; Random Allocation ; Reperfusion Injury/*drug therapy/*prevention &amp; control ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: Renal ischemia is of great clinical interest because of its role in renal failure and renal graft rejection. The purpose of this study was to investigate the therapeutic effects of a combination therapy of: n-acetyl cysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor and phosphormidon (P), an endothelin-1 converting enzyme inhibitor, on tissue protection against renal ischemia/reperfusion injury in the canine model.<br><br>METHODS: In this study, 15-20 kg male dogs were subjected to 90 minutes of warm unilateral renal ischemia after removal of one kidney and then divided into control, ischemia alone and treatment groups. Blood samples were collected from these dogs for measurement of kidney function tests and the kidneys were harvested at different time intervals for morphological evaluation, immunostaining and Tunnel Assay.<br><br>RESULTS: Kidney function tests (serum creatinine and blood urea nitrogen [BUN]) showed a significant difference between untreated and treated groups. ** P <0.01, * P< 0.0001 for treated versus untreated. The protective effect of the combination therapy is also supported by light microscopic studies, immunostaining of renal tissue sections for pro-inflammatory cytokines (TNF-alpha and IFN-gamma), iNOS, and apoptosis by TUNEL assay.<br><br>CONCLUSIONS: Our results suggest that pre-administration of a combination of NAC, SNP, and P attenuates renal ischemia/reperfusion injury. This has potential application in preservation of donor kidney for transplantation by protecting cells against free radical damage.}, }
@article {pmid12648168, year = {2003}, author = {Landis, BN and Beghetti, M and Morel, DR and Giger, R and Rimensberger, PC and Lacroix, JS}, title = {Somato-sympathetic vasoconstriction to intranasal fluid administration with consecutive decrease in nasal nitric oxide.}, journal = {Acta physiologica Scandinavica}, volume = {177}, number = {4}, pages = {507-515}, doi = {10.1046/j.1365-201X.2003.01099.x}, pmid = {12648168}, issn = {0001-6772}, mesh = {Acetylcysteine/administration &amp; dosage ; Administration, Intranasal ; Adult ; Anesthetics, Local/administration &amp; dosage ; Chronic Disease ; Expectorants/administration &amp; dosage ; Female ; Histamine/administration &amp; dosage ; Humans ; Laser-Doppler Flowmetry/methods ; Lidocaine/administration &amp; dosage ; Male ; Middle Aged ; Nasal Mucosa/metabolism/*physiopathology ; Nebulizers and Vaporizers ; Nitric Oxide/*analysis ; Reflex ; Sinusitis/drug therapy/*physiopathology ; Sodium Chloride/administration &amp; dosage ; Sympathetic Nervous System/*drug effects/physiopathology ; Vasoconstriction/*drug effects ; }, abstract = {AIM: Patients suffering from non-allergic chronic rhinosinusitis (NACRS) increasingly use intranasal saline sprays. They report better nasal comfort.<br><br>METHODS: In order to better understand this phenomenon, we studied intranasal laser Doppler flowmetry (LDF) and nasal nitric oxide (NO) variations evoked by local administration of saline, histamine, N-acetylcysteine (NAC) and lidocaine at room temperature (22 degrees C).<br><br>RESULTS: There was a significant (P < 0.05) 14 +/- 3.8% decrease in LDF signal after 30 s, which lasted for 60-90 s, for all the substances applied at 22 degrees C. This pharmaco-independent vasoconstriction was further studied in patients under general anaesthesia (GA), with saline at 37 degrees C and after intranasal adrenaline treatment. While GA did not influence the vasoconstriction, saline at 37 degrees C and adrenaline pre-treatment abolished it. Nasal NO is influenced by vasoconstriction. Therefore we investigated, whether the observed vasoconstriction also changes nasal NO. A significant (P < 0.001) 8.03 +/- 0.59% decrease in nasal NO was recorded 60 s after administration of all the substances, and under GA after 22 degrees C saline application. This NO decrease was absent after intranasal adrenaline pre-treatment. An additional experiment tested the effect of nose blowing on nasal NO concentration. We registered an NO decrease with a similar pattern than observed with the other substances.<br><br>CONCLUSIONS: Intranasal fluid nebulization at 22 degrees C induces a sympathetic mediated, transient vasoconstrictor reflex response. This somato-sympathetic vasoconstriction induces a decrease in nasal NO. Both could be related to the subjective comfort experienced by NACRS patients using intranasal saline sprays.}, }
@article {pmid12647014, year = {2003}, author = {Kolb, RJ and Ghazi, AM and Barfuss, DW}, title = {Inhibition of basolateral transport and cellular accumulation of cDDP and N-acetyl- L-cysteine-cDDP by TEA and PAH in the renal proximal tubule.}, journal = {Cancer chemotherapy and pharmacology}, volume = {51}, number = {2}, pages = {132-138}, doi = {10.1007/s00280-002-0537-0}, pmid = {12647014}, issn = {0344-5704}, mesh = {Acetylcysteine/*metabolism/toxicity ; Animals ; Biological Transport ; Cisplatin/*metabolism/toxicity ; Kidney Tubules, Proximal ; Platinum/analysis/metabolism ; Rabbits ; Tetraethylammonium/*pharmacology ; p-Aminohippuric Acid/*pharmacology ; }, abstract = {PURPOSE: The objective of this study was to determine the effect of para-aminohippurate (PAH) and tetraethylammonium (TEA) on basolateral cellular accumulation (C(Pt)) and bath-to-lumen transepithelial transport rates (J(B)(-->)(L)) of platinum from cisplatin (cDDP) and a conjugate of cDDP, N-acetyl- L-cysteine-cDDP (NAC-cDDP), in S(1), S(2), and S(3) segments of the rabbit proximal tubule.<br><br>METHODS: Cellular accumulations and transport rates were determined using the isolated perfused tubule technique and samples were analyzed by ICP-MS.<br><br>RESULTS: First, to establish the control data, each tubular segment was bathed in free cDDP (2 m M) which resulted in no observable toxicity. Next, TEA (4 m M) was added to the bathing solution containing cDDP. This resulted in a reduction in platinum J(B)(-->)(L) by approximately 75% in the S(1) segment and 50% in the S(2) and S(3) segments. C(Pt) was reduced by 80-90% in relation to control values with no observable changes in toxicity. In the next experiment, exposure of the basolateral membrane to NAC-cDDP (2 m M) elicited pronounced toxicity after 20-30 min of perfusion. The J(B)(-->)(L) for NAC-cDDP was similar for each of the three nephron segments. There were no significant differences in the ability of these three segments to accumulate NAC-cDDP, but the conjugate increased uptake of platinum by 200-300% in the S(1) and S(2) segments, with no significant change in the S(3) segments, compared cDDP control values. The presence of PAH (4 m M) in the bathing solution significantly reduced J(B)(-->)(L) (by approximately 90%) for NAC-cDDP in all segments and the C(Pt) by approximately 80%. This also abrogated the NAC-cDDP-induced toxicity.<br><br>CONCLUSIONS: There was axial heterogeneity among the basolateral membranes of the S(1), S(2), and S(3) segments of the proximal tubule in accumulating free cDDP and transport of NAC-cDDP. Generally, the NAC-cDDP molecule was transported more avidly than free cDDP across the basolateral membrane, except in the S(3) segment, where accumulation was similar to that of free cDDP. It is concluded that a PAH-sensitive organic anion transporter is involved in the accumulation of NAC-cDDP at the basolateral membrane and a TEA-sensitive organic cation transport system is involved in the accumulation of free cDDP.}, }
@article {pmid12644946, year = {2003}, author = {Reber, F and Geffarth, R and Kasper, M and Reichenbach, A and Schleicher, ED and Siegner, A and Funk, RH}, title = {Graded sensitiveness of the various retinal neuron populations on the glyoxal-mediated formation of advanced glycation end products and ways of protection.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {241}, number = {3}, pages = {213-225}, doi = {10.1007/s00417-002-0528-1}, pmid = {12644946}, issn = {0721-832X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects ; Caspase 3 ; Caspases/metabolism ; Dose-Response Relationship, Drug ; Female ; Glycation End Products, Advanced/*metabolism ; Glyoxal/*toxicity ; Guanidines/pharmacology ; Immunoenzyme Techniques ; In Situ Nick-End Labeling ; Lysine/*analogs &amp; derivatives/metabolism ; Male ; Neurons/*drug effects/metabolism/pathology ; Niacinamide/pharmacology ; Organ Culture Techniques ; Proto-Oncogene Proteins ; *Proto-Oncogene Proteins c-bcl-2 ; Rats ; Rats, Sprague-Dawley ; Retina/*drug effects/metabolism/pathology ; Thioctic Acid/pharmacology ; Vanadates/pharmacology ; bcl-2-Associated X Protein ; }, abstract = {BACKGROUND: The accumulation of advanced glycation end products (AGEs) in retinal cells is known to be associated with the risk of diabetic retinopathy. To develop a model of AGE-related metabolic stress in retinal organ cultures, we investigated the accumulation of a typical glycoxidation product (N(epsilon)-[carboxymethyl] lysine [CML]) and its possible pro-apoptotic effects on different retinal cell populations.<br><br>METHODS: Retinal organ cultures (rat) were kept for 9 h in the Ames medium containing 0 (control), 5, 25, 50, 150, 300 and 800 micro M glyoxal. The expression of bax, active caspase-3, and the accumulation of CML were studied by using immunohistochemistry after the paraffin embedding of retinal explants. Apoptosis was studied using the terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling (TUNEL) test and electron microscopy. Alpha lipoic acid (alpha-LA), sodium metavanadate (NaVO(3)), N-acetylcysteine (NAC), aminoguanidine (AG), and nicotinamide (NA) were used to influence glyoxal effects in organ cultures.<br><br>RESULTS: In cultured normal non-diabetic retinae, small amounts of CML and the apoptosis-promoting factors bax and active caspase-3 were present. CML, bax and active caspase-3 increased after incubation with glyoxal. Incubation with glyoxal (<300 micro M, 9 h) increased apoptotic events in all layers. At low glyoxal concentrations, we found a graded sensitiveness of the different layers: at 25 micro M 39.4% in GCL, 28.2% in INL, 11.9% in ONL. After 800 micro M glyoxal, approximately 50% of the cells in all layers of the retina were apoptotic. In the ONL, this ratio was reduced by NaVO(3) (17%), by AG (27%), by NA (24.8%), by NAC (25.2%), and by alpha-LA (33.5%). In the INL, AG (25.9%) produced the best result. In the GCL, NAC, NaVO(3) and AG reduced apoptosis. A-LA had no significant protective effect.<br><br>CONCLUSION: The glyoxal-induced rapid formation of CML shows the ability of our retina model to simulate AGE-related effects in vitro. The dose-dependent expression of apoptosis-promotor molecules indicates that the apoptosis-inducing machinery starts in most retinal cells within 9 h. The neurotoxicity of glyoxal-induced AGE formation was shown by the significantly increased rate of cell death in the retina. The significant decrease of apoptotic events (P<0.01) indicates that antioxidants and AGE formation blocker can exert a differentiated cytoprotection for each of the retinal cell layers.}, }
@article {pmid12643600, year = {2003}, author = {Chu, SH and Kim, H and Seo, JY and Lim, JW and Mukaida, N and Kim, KH}, title = {Role of NF-kappaB and AP-1 on Helicobater pylori-induced IL-8 expression in AGS cells.}, journal = {Digestive diseases and sciences}, volume = {48}, number = {2}, pages = {257-265}, pmid = {12643600}, issn = {0163-2116}, mesh = {Analysis of Variance ; Base Sequence ; Blotting, Northern ; Blotting, Western ; Cells, Cultured ; Epithelial Cells ; Gastric Mucosa/cytology/microbiology ; Helicobacter Infections/pathology ; *Helicobacter pylori ; Humans ; Interleukin-8/analysis/*metabolism ; Molecular Sequence Data ; NF-kappa B/analysis/*metabolism ; Polymerase Chain Reaction ; Probability ; RNA, Messenger/*analysis ; Reactive Oxygen Species ; Sensitivity and Specificity ; Stomach Ulcer/microbiology/pathology ; Transcription Factor AP-1/analysis/*metabolism ; }, abstract = {Oxygen radicals are important regulators in Helicobacter pylori-induced gastric ulceration and carcinogenesis. IL-8 may be regulated by oxidant-sensitive transcription factors, NF-kappaB, and AP-1. The present study aims to investigate whether H. pylori-induced IL-8 expression is regulated by NF-kappaB and AP-1 in gastric epithelial AGS cells and whether this transcriptional regulation of IL-8 is inhibited by N-acetylcysteine (NAC). As a result, H. pylori induced the expression of mRNA and protein for IL-8 via activation of NF-kappaB and AP-1. NF-kappaB activation accompanied by a decrease in I-kappaBalpha and activated AP-1 complex was a c-jun/c-fos heterodimer in H. pylori-infected AGS cells. NAC inhibited H. pylori-induced activation of transcription factors and IL-8 expression in AGS cells. In conclusion, oxygen radicals induce the activation of NF-kappaB and AP-1 and IL-8 expression. Antioxidants such as NAC might be useful anti-inflammatory agents by inhibiting activation of transcription factors and decreasing IL-8 production in H. pylori-induced gastric inflammation.}, }
@article {pmid12641975, year = {2002}, author = {Pan, D and Li, Z}, title = {[Effect of neuroprotectant agent combined with cocktail on expression of anti-apoptotic protein bcl-2 in rats after focal cerebral ischemia].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {36}, number = {6}, pages = {390-393}, pmid = {12641975}, issn = {0253-9624}, mesh = {Acetylcysteine/administration &amp; dosage ; Actins/analysis ; Animals ; Brain Ischemia/*drug therapy/metabolism ; Dizocilpine Maleate/administration &amp; dosage ; Drug Therapy, Combination ; Fructosediphosphates/administration &amp; dosage ; Male ; Molecular Weight ; Neuroprotective Agents/*administration &amp; dosage ; Proto-Oncogene Proteins c-bcl-2/*analysis ; Rats ; Rats, Wistar ; }, abstract = {OBJECTIVE: To investigate whether the protective effect of therapy with different combined neuroprotectant agents was better than that of single agent on focal cerebral ischemia.<br><br>METHODS: The right middle cerebral artery in the rats was occluded with suture occlusion technique. The rats were divided into five groups treated with FDP (50 mg/kg, n = 10), MK-801 (1 mg/kg, n = 10) and NAC (150 mg/kg, n = 10) singly, or in combination, respectively, by intraperitoneal infusion 30 minutes after vessel occlusion. The rats were weighed and assessed neurologically, based on a 5-point scale, six and 24 hours after focal cerebral ischemia. The expression of anti-apoptotic protein bcl-2 was observed with SDS-PAGE protein electrophoresis and Western blot technique.<br><br>RESULT: The optical density of bcl-2 increased more distinctly in the rats treated with combined neuroprotective agents than that with any single agent six and 24 hours after cerebral ischemia, with a statistically significant difference (P < 0.05).<br><br>CONCLUSIONS: Treatment with combined neuroprotectant agents could un-regulate the anti-apoptotic protein bcl-2 more distinctly than that with any single agents. Combined use of neuroprotectants might be more effective than that of single agent in protecting rats' brain from ischemia.}, }
@article {pmid12640750, year = {2001}, author = {Goldberg, M and Six, N and Decup, F and Buch, D and Soheili Majd, E and Lasfargues, JJ and Salih, E and Stanislawski, L}, title = {Application of bioactive molecules in pulp-capping situations.}, journal = {Advances in dental research}, volume = {15}, number = {}, pages = {91-95}, doi = {10.1177/08959374010150012401}, pmid = {12640750}, issn = {0895-9374}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/therapeutic use ; Biocompatible Materials/*therapeutic use ; Bone Morphogenetic Protein 7 ; Bone Morphogenetic Proteins/therapeutic use ; Calcium Hydroxide/therapeutic use ; Dental Pulp/drug effects/pathology ; *Dental Pulp Capping ; Dental Pulp Cavity/drug effects/pathology ; Dental Pulp Exposure/therapy ; Dental Restoration, Permanent ; Dentin/drug effects/pathology/physiology ; Dentin, Secondary/drug effects/pathology ; Dentinogenesis/drug effects ; Free Radical Scavengers/therapeutic use ; Glass Ionomer Cements ; Integrin-Binding Sialoprotein ; Male ; Pharmaceutical Vehicles ; Rats ; Rats, Sprague-Dawley ; Sialoglycoproteins/therapeutic use ; Time Factors ; Transforming Growth Factor beta/therapeutic use ; Wound Healing/drug effects ; }, abstract = {To evaluate the effects of bioactive molecules in pulpal wound healing, we carried out experiments using the rat upper molars as an in vivo model. Cavities were prepared on the mesial aspect, and pulp perforation was accomplished by the application of pressure with the tip of a steel probe. After the pulp-capping procedure, the cavities were filled with a glass-ionomer cement. Comparison was made between and among: (1) sham-operated controls with dentin and predentin fragments implanted in the pulp during perforation after 8, 14, and 28 days; (2) carrier without bioactive substance; (3) calcium hydroxide; (4) Bone Sialoprotein (BSP); (5) different concentrations of Bone Morphogenetic Protein-7 (BMP-7), also termed Osteogenic Protein-1 (OP-1); and (6) N-Acetyl Cysteine (NAC), an anti-oxidant agent preventing glutathione depletion. Histologic and morphometric comparison, carried out among the first 4 groups on demineralized tissue sections, indicated that, at 28 days after implantation, BSP was the most efficient bioactive molecule, inducing homogeneous and well-mineralized reparative dentin. BMP-7 gave reparative dentin of the osteodentin type in the coronal part of the pulp, and generated the formation of a homogeneous mineralized structure in the root canal. These findings indicate that the crown and radicular parts of the pulp bear their own specificity. Both BSP and BMP-7 were superior to calcium hydroxide in their mineralization-inducing properties, and displayed larger areas of mineralization containing fewer pulp tissue inclusions. The overall mineralization process to these molecules appeared to proceed by mechanisms that involved the recruitment of cells which differentiate into osteoblast-like cells, producing a mineralizing extracellular matrix. We also provide preliminary evidence that NAC induces reparative dentin formation in the rat molar model. Pulp-capping with bioactive molecules provides new prospects for dental therapy.}, }
@article {pmid12636934, year = {2003}, author = {Hultberg, B}, title = {Modulation of extracellular homocysteine concentration in human cell lines.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {330}, number = {1-2}, pages = {151-159}, doi = {10.1016/s0009-8981(03)00052-4}, pmid = {12636934}, issn = {0009-8981}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Transport Systems/antagonists &amp; inhibitors ; Carcinoma, Hepatocellular/metabolism ; Copper/chemistry/pharmacology ; Cysteine/analysis ; Dithiothreitol/pharmacology ; Extracellular Fluid/*chemistry ; HeLa Cells ; Homocysteine/*analysis/metabolism ; Humans ; Oxidation-Reduction ; Sulfhydryl Compounds/metabolism/pharmacology ; Sulfonic Acids/chemistry/pharmacology ; Tumor Cells, Cultured ; }, abstract = {BACKGROUND: Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Information about the metabolism of homocysteine is, therefore, essential for an understanding of its role in atherogenesis, thereby enabling a modulation of that risk.<br><br>METHODS: In the present study, we have examined the modulation of extracellular homocysteine in HeLa and hepatoma cell cultures in relation to a changed extracellular thiol redox status and in the presence of specific inhibitors of amino acid transporters.<br><br>RESULTS: The findings in the present study show that a changed thiol redox status by copper ions, copper chelator or the monothiol, N-acetylcysteine (NAC), affects extracellular homocysteine in the same way in hepatoma cell cultures, but not to the same extent as observed in HeLa cell cultures. However, the dithiols, dithiothreitol (DTT) and alpha-lipoic acid (LA), which lowered extracellular homocysteine concentration in HeLa cell cultures, increased the extracellular total homocysteine concentration in hepatoma cell cultures, probably mainly as a result of increased release of homocysteine extracellularly. Studies with specific inhibitors of amino acid transporters in HeLa cell cultures showed that homocysteine uptake occurred mainly by system A and glutamate transporters. Hepatoma cells seemed to have a much smaller uptake capacity of homocysteine compared to HeLa cells.<br><br>CONCLUSION: The lack of uptake capacity of homocysteine in hepatoma cells indicates that hepatocytes only play a small role in the elimination of homocysteine from circulation. Intracellular metabolism, cellular export and the complex pattern of homocysteine uptake in different cells are important to examine further in order to possibly be able to lower plasma homocysteine levels.}, }
@article {pmid12633746, year = {2003}, author = {Neal, R and Matthews, RH and Lutz, P and Ercal, N}, title = {Antioxidant role of N-acetyl cysteine isomers following high dose irradiation.}, journal = {Free radical biology &amp; medicine}, volume = {34}, number = {6}, pages = {689-695}, doi = {10.1016/s0891-5849(02)01372-2}, pmid = {12633746}, issn = {0891-5849}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*metabolism ; Animals ; Antioxidants/*metabolism ; Catalase/metabolism ; Deoxyguanosine/*analogs &amp; derivatives/pharmacology ; Erythrocytes/metabolism/radiation effects ; Glutaredoxins ; Glutathione/metabolism ; Glutathione Reductase/metabolism ; Isomerism ; Lung/drug effects/*metabolism/*radiation effects ; Male ; Malondialdehyde/pharmacology ; Mice ; Mice, Inbred C57BL ; Oxidants/pharmacology ; Oxidation-Reduction ; Oxidoreductases/metabolism ; *Protein Disulfide Reductase (Glutathione) ; Radiation Injuries, Experimental/*prevention &amp; control ; Radiation-Protective Agents/pharmacology ; Whole-Body Irradiation ; }, abstract = {High dose, acute radiation exposure, as in radiation accidents, induces three clinical syndromes that reflect consequences of oxidative protein, lipid, and DNA damage to tissues such as intestine, lung, and liver. In the present study, we irradiated C57BL/6 mice with 18 Gy whole-body radiation (XRT) and evaluated N-acetyl cysteine (NAC) isomers LNAC and DNAC as potential radioprotectors under conditions that would model the gastrointestinal syndrome. We focused on tissues thought not immediately involved in the gastrointestinal syndrome. Both LNAC and DNAC protected the lung and red blood cells (RBC) from glutathione (GSH) depletion following radiation exposure. However, only LNAC also supplemented the spleen GSH levels following XRT. Protection from increased malondialdehyde (MDA) levels (lung) and increased 8-hydroxy-deoxyguanosine (8-oxo-dG) presence (liver) following XRT was observed with treatment by either isomer of NAC. These results imply that either NAC isomer can act as a radioprotectant against many aspects of oxidative damage; chirality is only important for certain aspects. This pattern would be consistent with direct action of NAC in many radioprotection and repair processes, with a delimited role for NAC in GSH synthesis in some aspects of the problem.}, }
@article {pmid12631578, year = {2003}, author = {Kumar, A and Boriek, AM}, title = {Mechanical stress activates the nuclear factor-kappaB pathway in skeletal muscle fibers: a possible role in Duchenne muscular dystrophy.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {17}, number = {3}, pages = {386-396}, doi = {10.1096/fj.02-0542com}, pmid = {12631578}, issn = {1530-6860}, support = {63134//PHS HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium Signaling ; Culture Techniques ; Diaphragm ; Free Radical Scavengers/pharmacology ; I-kappa B Kinase ; I-kappa B Proteins/metabolism ; Interleukin-1/biosynthesis/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscle Fibers, Skeletal/*metabolism ; Muscle, Skeletal/*metabolism ; Muscular Dystrophy, Duchenne/etiology/*metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism/physiology ; Protein Serine-Threonine Kinases/metabolism ; RNA, Messenger/biosynthesis ; *Signal Transduction ; Stress, Mechanical ; Tumor Necrosis Factor-alpha/biosynthesis/genetics ; }, abstract = {The ex vivo effects of passive mechanical stretch on the activation of nuclear factor-kappaB (NF-kappaB) pathways in skeletal muscles from normal and mdx mouse, a model of Duchenne muscular dystrophy (DMD), were investigated. The NF-kappaB/DNA binding activity of the diaphragm muscle was increased by the application of axial mechanical stretch in a time-dependent manner. The increased activation of NF-kappaB was associated with a concomitant increase in I-kappaB (IkappaB) kinase activity and the degradation of IkappaBalpha protein. Pretreatment of the muscles with nifedipine (a Ca2+ channel blocker) and gadolinium(III) chloride (a stretch-activated channel blocker) did not alter the level of activation of NF-kappaB, ruling out involvement of Ca2+ influx through these channels. Furthermore, N-acetyl cysteine, a free radical inhibitor, blocked the mechanical stretch-induced NF-kappaB activation, suggesting the involvement of free radicals. Compared with normal diaphragm, the basal level of NF-kappaB activity was higher in muscles from mdx mice, and it was further enhanced in mechanically stretched muscles. Furthermore, activation of NF-kappaB and increased expression of inflammatory cytokines IL-1beta and tumor necrosis factor alpha in the mdx mouse precede the onset of muscular dystrophy. Our results show that mechanical stretch activates the classical NF-kappaB pathway and this pathway could be predominately active in DMD.}, }
@article {pmid12631128, year = {2003}, author = {Heyman, SN and Goldfarb, M and Shina, A and Karmeli, F and Rosen, S}, title = {N-acetylcysteine ameliorates renal microcirculation: studies in rats.}, journal = {Kidney international}, volume = {63}, number = {2}, pages = {634-641}, doi = {10.1046/j.1523-1755.2003.00783.x}, pmid = {12631128}, issn = {0085-2538}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/complications/pathology/physiopathology ; Animals ; Dinoprostone/metabolism ; Enzyme Inhibitors/pharmacology ; Hypoxia/complications/pathology/physiopathology ; Kidney Cortex/drug effects/metabolism ; Kidney Diseases/pathology/physiopathology ; Kidney Medulla/pathology/physiopathology ; Male ; Microcirculation/drug effects ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide/metabolism ; Rats ; Rats, Sprague-Dawley ; Renal Circulation/*drug effects ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) administration has been shown to ameliorate experimental acute renal failure induced by ischemia-reflow, and was found to prevent radiocontrast nephropathy in high-risk patients. While the protective effect of NAC has been primarily attributed to scavenging oxygen free radicals, improving renal microcirculation also may play a role in the prevention of acute renal failure.<br><br>METHODS: This study was designed to explore the effect of NAC on renal microcirculation. Blood pressure, total renal blood flow and selective regional cortical and outer medullary blood flow were continuously monitored in anesthetized Sprague Dawley rats with ultrasonic and laser-Doppler probes during the infusion of NAC (60 mg/kg).<br><br>RESULTS: In control intact rats blood pressure and renal microcirculation were unaffected by NAC. By contrast, following renal vasoconstriction induced by the radiocontrast agent iothalamate meglumine, NAC decreased total, cortical and medullary vascular resistance by 7 to 10% (P < 0.05). NAC also reduced renal vascular resistance by 16% when given during angiotensin II infusion (P < 0.05). Altered renal microcirculation, induced by the cyclooxygenase inhibitor indomethacin, by the nitric oxide synthase-inhibitor, Nomeganitro-l-arginine (L-NAME), or with their combination was partially restored by NAC. Nevertheless, NAC administration failed to attenuate renal function and morphology in a rat model of acute renal failure with selective outer medullary hypoxic injury, induced by indomethacin, L-NAME and iothalamate.<br><br>CONCLUSIONS: NAC ameliorates renal vasoconstriction, an effect that seems to be mediated by mechanisms other than prostaglandins and nitric oxide. The potential renoprotective outcome of NAC and the role of its vasodilating effect on the pre-constricted renal vasculature should be evaluated further.}, }
@article {pmid12628482, year = {2003}, author = {Vicente, AM and Guillén, MI and Alcaraz, MJ}, title = {Heme oxygenase-1 induction and regulation in unstimulated mouse peritoneal macrophages.}, journal = {Biochemical pharmacology}, volume = {65}, number = {5}, pages = {905-909}, doi = {10.1016/s0006-2952(02)01657-x}, pmid = {12628482}, issn = {0006-2952}, mesh = {Animals ; Blotting, Western ; Cells, Cultured ; Enzyme Induction ; Heme Oxygenase (Decyclizing)/*biosynthesis ; Heme Oxygenase-1 ; Immunohistochemistry ; Macrophages, Peritoneal/*enzymology/metabolism ; Membrane Proteins ; Mice ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism ; Oxidation-Reduction ; }, abstract = {Heme oxygenase-1 (HO-1) is a stress protein induced by a variety of stimuli in inflammatory cells. This study was set up to investigate the induction of this protein in unstimulated macrophages. Resident mouse peritoneal macrophages purified by adhesion and cultured in basal conditions strongly induced HO-1 in a time-dependent manner, with a peak at 20 hr. At the same time, low levels of nitrite accumulated in the culture medium and expression of nitric oxide synthase-2 (NOS-2) and NOS-3 protein was detected. Inhibition of NO production and/or NOS expression by incubating macrophages with different drugs inhibiting NOS activity or modulating the redox state of the cell, such as N-acetylcysteine (NAC) resulted in inhibition of HO-1 expression, suggesting that NO is an endogenous mediator of this stress response. In conclusion, mouse peritoneal macrophages cultured in basal conditions develop an adaptive response with up-regulation of HO-1 as a very sensitive marker of oxidative stress.}, }
@article {pmid12628296, year = {2002}, author = {Park, JE and Yang, JH and Yoon, SJ and Lee, JH and Yang, ES and Park, JW}, title = {Lipid peroxidation-mediated cytotoxicity and DNA damage in U937 cells.}, journal = {Biochimie}, volume = {84}, number = {12}, pages = {1199-1205}, doi = {10.1016/s0300-9084(02)00039-1}, pmid = {12628296}, issn = {0300-9084}, mesh = {Acetylcysteine/pharmacology ; Amidines/pharmacology ; Catalase/antagonists &amp; inhibitors/metabolism ; Cell Survival/drug effects/genetics ; Cyclic N-Oxides ; *DNA Damage ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/*pharmacology ; Glucosephosphate Dehydrogenase/antagonists &amp; inhibitors/metabolism ; Glutathione/metabolism ; Glutathione Peroxidase/antagonists &amp; inhibitors/metabolism ; Humans ; Lipid Peroxidation/*drug effects ; Microscopy, Confocal/methods ; NADP/metabolism ; Nitrogen Oxides/pharmacology ; Oxidants/pharmacology ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/antagonists &amp; inhibitors/metabolism ; Time Factors ; U937 Cells ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {Membrane lipid peroxidation processes yield products that may react with DNA and proteins to cause oxidative modifications. In the present study, we evaluated lipid peroxidation-mediated cytotoxicity and oxidative DNA damage in U937 cells. Upon exposure of U937 cells to tert-butylhydroperoxide (t-BOOH) and 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH), which induce lipid peroxidation in membranes, the cells exhibited a reduction in viability and an increase in the endogenous production of reactive oxygen species (ROS), as measured by the oxidation of 2',7'-dichlorodihydrofluorescein. In addition, a significant decrease in the intracellular GSH level and the activities of major antioxidant enzymes were observed. We also observed lipid peroxidation-mediated oxidative DNA damage, reflected by an increase in 8-OH-dG level and loss of the ability of DNA to renature. When the cells were pretreated with the antioxidant N-acetylcysteine (NAC) or the spin trap alpha-phenyl-N-t-butylnitrone (PBN), lipid peroxidation-mediated cytotoxicity in U937 cells was protected. This effect seems to be due to the ability of NAC and PBN to reduce ROS generation induced by lipid peroxidation. These results suggest that lipid peroxidation resulted in a pro-oxidant condition of U937 cells by the depletion of GSH and inactivation of antioxidant enzymes, which consequently leads to a decrease in survival and oxidative damage to DNA. The results indicate that the peroxidation of lipid is probably one of the important intermediary events in oxidative stress-induced cellular damage.}, }
@article {pmid12622248, year = {2003}, author = {Kolar, M and Dobcnik, D}, title = {Chemically prepared silver electrode for determination of N-acetyl-L-cysteine by flow-injection potentiometry.}, journal = {Die Pharmazie}, volume = {58}, number = {1}, pages = {25-28}, pmid = {12622248}, issn = {0031-7144}, mesh = {Acetylcysteine/*analysis ; Electrochemistry ; Electrodes ; Flow Injection Analysis ; Indicators and Reagents ; Potentiometry ; Silver ; }, abstract = {This paper describes the use of the silver electrode by means of chemical pretreatment of the electrode surface with mercuric(II) chloride solution and potassium iodide solution in flow injection analysis (FIA). The electrode is used as a potentiometric sensor for the indirect determination of NAC in a carrier stream containing iodine. A one-channel flow system that consists of a peristaltic pump, injection valve, a silver wire electrode and a saturated calomel reference electrode (SCE) was used. Some typical FIA parameters such as flow rate, tube length and composition of the carrier stream were varied. The electrode is further characterised by a constant linear response within the concentration range for NAC between 4.0 x 10(-6) and 1.0 x 10(-3) M at the slope of 60.6 +/- 1.0 mV/p(NAC). Some pharmaceutical products containing NAC were also tested. These results can be compared to the results obtained by the direct potentiometric titrations with silver nitrate and are also in good agreement with values declared by pharmaceutical manufacturers.}, }
@article {pmid12622181, year = {2002}, author = {Sridharan, S and Shyamaladevi, CS}, title = {Protective effect of N-acetylcysteine against gamma ray induced damages in rats--biochemical evaluations.}, journal = {Indian journal of experimental biology}, volume = {40}, number = {2}, pages = {181-186}, pmid = {12622181}, issn = {0019-5189}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ascorbic Acid/blood ; Catalase/blood ; Cell Membrane/metabolism ; Creatine Kinase/blood ; Cytosol/metabolism ; Free Radicals ; *Gamma Rays ; Glutathione/metabolism ; Glutathione Peroxidase/blood ; Hydrogen Peroxide/pharmacology ; Intestines/drug effects/radiation effects ; L-Lactate Dehydrogenase/blood ; Lipid Peroxidation ; Liver/drug effects/radiation effects ; Rats ; Sulfhydryl Reagents/metabolism ; Superoxide Dismutase/blood ; Time Factors ; Transaminases/blood ; Vitamin A/blood ; Vitamin E/blood ; }, abstract = {The effect of N-acetylcysteine (NAC) (Ig/kg body weight in saline for 7 days) against the damages induced by gamma ray was studied. Whole body exposure of rats to gamma-rays (3.5 Gy) caused increases in lipid peroxides (P < 0.01). Reduced glutathione (GSH) (P < 0.01) and total sulphydryl groups (TSH) (P < 0.05), were found to be increased probably to counteract the damages produced by the lipid peroxides. The plasma antioxidant vitamins E, C and A were reduced. The activities of antioxidant enzymes, superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were enhanced, which might be to eliminate the superoxide radical and H2O2 and accompanied by a fall in glutathione-s-transferase (GST) and glutathione reductase (GR) activity. The excessive production of free radicals and lipid peroxides might have caused the leakage of cytosolic enzymes such as aminotransferases (AST and ALT), lactate dehydrogenase (LDH), creatine kinase (CK) and phosphatases. Membrane damage is quite evident from histological studies undertaken in the intestinal tissue, which is susceptible to radiation damage. Intragastric pretreatment of NAC (1g/kg body weight in saline for 7 days) prevented the radiation induced damage to an appreciable extent. From the results it may be concluded that NAC is effective in protecting from the damages caused by gamma-ray radiations and its prospects as an adjuvant to radiotherapy should be considered.}, }
@article {pmid12620935, year = {2003}, author = {Harada, M and Kishimoto, K and Furuhashi, T and Naito, K and Nakashima, Y and Kawaguchi, Y and Hiraoka, I}, title = {Infertility observed in reproductive toxicity study of N-acetyl-L-cysteine in rats.}, journal = {Biology of reproduction}, volume = {69}, number = {1}, pages = {242-247}, doi = {10.1095/biolreprod.102.013862}, pmid = {12620935}, issn = {0006-3363}, mesh = {Acetylcysteine/administration &amp; dosage/*toxicity ; Animals ; Embryonic and Fetal Development/drug effects ; Female ; Infertility, Female/*chemically induced ; Male ; Oocytes/drug effects/pathology ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Reproduction/*drug effects ; Zona Pellucida/drug effects/pathology ; }, abstract = {The toxic effects of i.v. administration of N-acetyl-l-cysteine (NAC), a component of parenteral nutrition solutions, on fertility and embryonic development were investigated in SD male and female rats at doses of 100, 300, and 1000 mg kg-1 day-1. Infertility was observed in females in the 1000-mg/kg group throughout the period from before mating to embryogenesis. No effect of NAC on the reproductive ability of the male rats was seen. The oocytes and embryos were assessed morphologically to clarify the cause of the effects of NAC. The unfertilized oocytes (UO) recovered from the ampullae of the uterine tubes and Gestational Day (GD) 1 and 2 embryos recovered from the oviducts or uterus of the rats that received NAC i.v. at a dosage of 1000 mg kg-1 day-1 for more than 1 wk before mating were assessed morphologically by stereomicroscopy. In addition, the thickness of the zona pellucida (ZP) was calculated by morphometric evaluation of the UO. Fewer UO were collected in the NAC group than in the control (nontreatment) group. Interestingly, ZP-lacking or partially ZP-lacking oocytes were observed in the NAC group, and the morphometric evaluation of the UO showed thinning of the ZP. The number of embryos in each animal was markedly decreased on GD1, and no embryos were recovered on GD2 in the NAC group. The oocytes that had ZP affected by NAC treatment were abnormal or nonviable. The findings of the present study suggest that changes in the ZP are related to the infertility associated with NAC.}, }
@article {pmid12619881, year = {2003}, author = {Tian, J and Liu, J and Garlid, KD and Shapiro, JI and Xie, Z}, title = {Involvement of mitogen-activated protein kinases and reactive oxygen species in the inotropic action of ouabain on cardiac myocytes. A potential role for mitochondrial K(ATP) channels.}, journal = {Molecular and cellular biochemistry}, volume = {242}, number = {1-2}, pages = {181-187}, pmid = {12619881}, issn = {0300-8177}, support = {GM-55324/GM/NIGMS NIH HHS/United States ; HL-36573/HL/NHLBI NIH HHS/United States ; HL-63238/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/administration &amp; dosage/*pharmacology ; Fluorescence ; In Vitro Techniques ; Mitochondria/*drug effects/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Muscle Contraction/drug effects ; Myocytes, Cardiac/cytology/*drug effects/enzymology/metabolism ; Ouabain/administration &amp; dosage/*pharmacology ; Proto-Oncogene Proteins pp60(c-src)/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Sodium-Potassium-Exchanging ATPase/*metabolism ; ras Proteins/metabolism ; }, abstract = {Binding of ouabain to Na+/K+-ATPase activated multiple signal transduction pathways including stimulation of Src, Ras, p42/44 MAPKs and production of reactive oxygen species (ROS) in rat cardiac myocytes. Inhibition of either Src or Ras ablated ouabain-induced increase in both [Ca2+]i and contractility. While PD98059 abolished the effects of ouabain on [Ca2+]i it only caused a partial inhibition of ouabain-induced increases in contractility. On the other hand, pre-incubation of myocytes with N-acetyl cysteine (NAC) reduced the effects of ouabain on contractility, but not [Ca2+]i. Furthermore, 5-hydroxydecanoate (5-HD) blocked ouabain-induced ROS production and partially inhibited ouabain-induced increases in contractility in cardiac myocytes. Pre-incubation of myocytes with both 5-HD and PD98059 completely blocked ouabain's effect on contractility. Finally, we found that opening of mitochondrial K(ATP) channel by diazoxide increased intracellular ROS and significantly raised contractility in cardiac myocytes. These new findings indicate that ouabain regulates cardiac contractility via both [Ca2+]i and ROS. While activation of MAPKs leads to increases in [Ca2+]i, opening of mitochondrial K(ATP) channel relays the ouabain signal to increased ROS production in cardiac myocytes.}, }
@article {pmid12618349, year = {2003}, author = {Ohinata, Y and Miller, JM and Schacht, J}, title = {Protection from noise-induced lipid peroxidation and hair cell loss in the cochlea.}, journal = {Brain research}, volume = {966}, number = {2}, pages = {265-273}, doi = {10.1016/s0006-8993(02)04205-1}, pmid = {12618349}, issn = {0006-8993}, support = {DC-04058/DC/NIDCD NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Acoustic Stimulation/*adverse effects ; Animals ; Auditory Threshold/drug effects/physiology ; Cell Count/methods ; Cochlea/drug effects/*metabolism ; *Dinoprost/*analogs &amp; derivatives ; Disease Models, Animal ; Dizocilpine Maleate/analogs &amp; derivatives/pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Evoked Potentials, Auditory, Brain Stem/physiology ; F2-Isoprostanes/analysis/metabolism ; Free Radical Scavengers/pharmacology ; Guinea Pigs ; Hair Cells, Auditory/*drug effects/physiopathology ; Hearing Loss, Noise-Induced/*metabolism/prevention &amp; control ; Lipid Peroxidation/drug effects/*physiology ; Male ; NG-Nitroarginine Methyl Ester/pharmacology ; Noise/adverse effects ; Piperidines/pharmacology ; Reactive Oxygen Species/metabolism ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors ; }, abstract = {In order to delineate mechanisms of noise-induced hearing loss, we assessed noise trauma and its pharmacological modulation in the guinea pig. Auditory threshold shifts (measured by auditory brainstem responses), hair cell loss and lipid peroxidation (8-isoprostane formation) were determined in the absence or presence of agents known to influence the formation or action of reactive oxygen species (ROS): the non-specific N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801, its inactive isomer (-)-MK-801, the selective NR1/2B NMDA receptor antagonist PD 174494, the nitric oxide synthase (NOS) inhibitor L-N(omega)-Nitroarginine methyl ester (L-NAME) and the anti-oxidant N-acetylcysteine (NAC). (+)-MK-801 and NAC attenuated threshold shifts and hair cell loss effectively while PD 174494 did so partially. L-NAME attenuated threshold shifts at 2 kHz but increased them at 20 kHz, and (-)-MK-801 was ineffective. Noise-induced elevation in 8-isoprostane in the cochlea was significantly attenuated by (+)-MK-801 and PD 174494 in the organ of Corti and modiolar core, by L-NAME in the lateral wall and modiolar core, and by NAC in all three regions. (-)-MK-801 did not influence noise-induced 8-isoprostane formation. There was a significant correlation between threshold shifts at 4 kHz, hair cell loss and the level of 8-isoprostane formed in the organ of Corti, but not in the lateral wall tissues. This finding suggests a causal relationship between ROS formation and functional and morphological damage. NMDA receptors and, to some extent, NOS may be involved in noise-induced ROS formation. The data also indicate that lipid peroxidation in the lateral wall tissues does not influence permanent threshold shifts.}, }
@article {pmid12616822, year = {2002}, author = {Szakmány, T and Tóth, I and Márton, S and Molnár, Z}, title = {[Effect of prophylactic N-acetylcysteine on postoperative organ dysfunction and inflammatory markers after major abdominal surgery for cancer. Prospective, randomized, double-blind, placebo-controlled clinical trial].}, journal = {Magyar sebeszet}, volume = {55}, number = {6}, pages = {369-374}, pmid = {12616822}, issn = {0025-0295}, mesh = {Abdominal Neoplasms/blood/mortality/*surgery ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aged ; Albuminuria/prevention &amp; control ; Biomarkers/blood ; C-Reactive Protein/*metabolism ; Calcitonin/*blood ; Calcitonin Gene-Related Peptide ; Critical Care ; Double-Blind Method ; Female ; Humans ; Inflammation/blood ; Infusions, Intravenous ; Length of Stay ; Male ; Middle Aged ; Multiple Organ Failure/etiology/mortality/*prevention &amp; control ; Prospective Studies ; Protein Precursors/*blood ; Respiration, Artificial ; Treatment Outcome ; }, abstract = {OBJECTIVES: To investigate whether short-term N-acetylcysteine (NAC) infusion administered before and during extensive abdominal surgery could modify the progression of early postoperative organ dysfunction and systemic inflammatory response.<br><br>METHODS: After randomisation the treatment group (n = 47) received NAC (150 mg kg-1 bolus followed by a continuous infusion of 12 mg kg-1 h-1) and the placebo group (n = 46) received the same volume of 5% dextrose during surgery. Clinical progress was monitored by the Multiple organ dysfunction score, systemic inflammatory response by serum procalcitonin (PCT), C-reactive protein (CRP) and microalbuminuria during the first 3 postoperative days. Mann-Whitney and chi 2 tests were used for statistical analysis.<br><br>RESULTS: There was no significant difference between the two groups regarding the MODS, organ dysfunction, length of intensive care stay, days of mechanical ventilation and mortality. PCT and microalbuminuria did not differ significantly. Significantly lower CRP levels were found in the NAC group on day one and two [t24: median: 84.5 interquartile range: (62.48-120.25) vs. 118 (86-137) mg/l; p = 0.020; t48: 136 (103-232) vs. 195 (154.5-252) mg/l p = 0.013, NAC vs. placebo].<br><br>CONCLUSION: The results of this study do not support the routine use of NAC as a prophylactic drug during surgery, and reinforce previous evidence which challenge the indication of NAC in the critically ill patient.}, }
@article {pmid12615076, year = {2003}, author = {Nakamura, Y and Miyamoto, M and Murakami, A and Ohigashi, H and Osawa, T and Uchida, K}, title = {A phase II detoxification enzyme inducer from lemongrass: identification of citral and involvement of electrophilic reaction in the enzyme induction.}, journal = {Biochemical and biophysical research communications}, volume = {302}, number = {3}, pages = {593-600}, doi = {10.1016/s0006-291x(03)00219-5}, pmid = {12615076}, issn = {0006-291X}, mesh = {Animals ; Antioxidants/pharmacology ; Biochemistry/*methods ; Blotting, Western ; Carbon/metabolism ; Cell Line ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Cymbopogon/*metabolism ; Dose-Response Relationship, Drug ; Epithelial Cells/metabolism ; Female ; Glutathione/metabolism ; Glutathione Transferase/metabolism ; Hydrocarbons ; Mice ; Mice, Inbred ICR ; Models, Chemical ; Oxidative Stress ; Plant Extracts/pharmacology ; Rats ; Structure-Activity Relationship ; Time Factors ; }, abstract = {We have developed a simple system for the sensitive detection and measurement of glutathione S-transferase (GST) activity that detoxifies polycyclic aromatic hydrocarbons using the cultured rat normal liver epithelial cell line, RL34 cells. Citral (3,7-dimethyl-2,6-octadienal) was isolated from the methanol extract of lemongrass (Cymbopogon citratus) and identified as a novel inducer of GST. Citral, a mixture of the two stereoisomers geranial and neral, dose- and time-dependently induced the total and pi-class-specific activities of GST. The structure-activity relationship study revealed that geranial, an E-isomer, was mainly responsible for the inducing activity of citral mixture and the aldehyde group conjugated with a trans-double bond is an essential structural factor. The data were consistent with the in vitro observation that both glutathione (GSH) and protein thiol quickly and specifically reacted with the active isomer geranial, but not neral. Pretreatment of the cells with diethyl maleate significantly enhanced not only the basal activity but also the citral-stimulated activity of GST, while pretreatment with N-acetyl-cysteine inhibited it. Moreover, the treatment of RL 34 cells with geranial for 30 min significantly attenuated the intracellular GSH level, while application for 18 h enhanced it. These results strongly suggested that the electrophilic property characterized by the reactivity with intracellular nucleophiles including protein thiol or glutathione (GSH) plays an important role in the induction of GST. The present study also implied the antioxidant role of GST induction by citral in mouse skin, providing a new insight into skin cancer prevention.}, }
@article {pmid12614387, year = {2003}, author = {Gopaul, S and Farrell, K and Abbott, F}, title = {Effects of age and polytherapy, risk factors of valproic acid (VPA) hepatotoxicity, on the excretion of thiol conjugates of (E)-2,4-diene VPA in people with epilepsy taking VPA.}, journal = {Epilepsia}, volume = {44}, number = {3}, pages = {322-328}, doi = {10.1046/j.1528-1157.2003.07202.x}, pmid = {12614387}, issn = {0013-9580}, mesh = {Acetylcysteine/metabolism/*urine ; Adolescent ; Adult ; Age Factors ; Anticonvulsants/*adverse effects/*metabolism/therapeutic use ; *Chemical and Drug Induced Liver Injury ; Child ; Child, Preschool ; Drug Therapy, Combination ; Enzyme Induction/physiology ; Epilepsy/*drug therapy/metabolism/*urine ; Female ; Humans ; Liver Diseases/*metabolism/urine ; Male ; Risk Factors ; Valproic Acid/*adverse effects/*metabolism/therapeutic use ; }, abstract = {PURPOSE: Valproic acid (VPA) is an antiepileptic drug (AED) used for generalized and absence seizures. It has a rare but potentially fatal hepatotoxicity side effect, and many researchers believe that reactive metabolites of VPA could be involved. We demonstrated here that the thiol conjugates of (E)-2,4-diene VPA were significantly elevated in a high-risk group of patients.<br><br>METHODS: Thirty-four patients with seizures were divided into three groups. Group A (n = 14) were being treated with VPA; group B (n = 12) received VPA as well as other AEDs that do not induce P450-VPA metabolism; and group C (n = 8) received VPA and AEDs that induce P450-VPA metabolism. The NAC conjugates of (E)-2,4-diene VPA (NAC I and NAC II) were identified in the urine of patients by gas chromatography/mass spectrography NICI analysis.<br><br>RESULTS: VPA monotherapy (group A) or VPA polytherapy with non-P450-enzyme-inducing drugs (group B), showed that patients younger than 7.5 years excreted significantly higher concentrations of the two conjugates compared with older patients (older than 7.5 years) in the same groups (p < 0.05). Patients receiving VPA polytherapy with P450-enzyme-inducing drugs were all older than 7. 5 years (group C). They excreted significantly higher concentrations of NAC I and NAC II compared with patients in groups A and B who were older than 7.5 years (p < 0.05).<br><br>CONCLUSIONS: There were no significant differences in the excretion of NAC I and NAC II between patients in group C and those who were 7.5 years or younger in groups A and B. High doses of VPA also were a significant factor associated with elevated NAC I and NAC II among young patients and in polytherapy patients.}, }
@article {pmid12613655, year = {2003}, author = {Zafarullah, M and Li, WQ and Sylvester, J and Ahmad, M}, title = {Molecular mechanisms of N-acetylcysteine actions.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {60}, number = {1}, pages = {6-20}, doi = {10.1007/s000180300001}, pmid = {12613655}, issn = {1420-682X}, support = {R0-1 HL66508-01/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis ; Cell Survival ; Free Radical Scavengers/*pharmacology ; Humans ; JNK Mitogen-Activated Protein Kinases ; Liver/drug effects/metabolism ; Mitogen-Activated Protein Kinases/drug effects/metabolism ; Muscle, Smooth, Vascular/drug effects/metabolism ; NF-kappa B/drug effects/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Signal Transduction ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Oxidative stress generated by an imbalance between reactive oxygen species (ROS) and antioxidants contributes to the pathogenesis of arthritis, cancer, cardiovascular, liver and respiratory diseases. Proinflammatory cytokines and growth factors stimulate ROS production as signaling mediators. Antioxidants such as N-acetylcysteine (NAC) have been used as tools for investigating the role of ROS in numerous biological and pathological processes. NAC inhibits activation of c-Jun N-terminal kinase, p38 MAP kinase and redox-sensitive activating protein-1 and nuclear factor kappa B transcription factor activities regulating expression of numerous genes. NAC can also prevent apoptosis and promote cell survival by activating extracellular signal-regulated kinase pathway, a concept useful for treating certain degenerative diseases. NAC directly modifies the activity of several proteins by its reducing activity. Despite its nonspecificity, ability to modify DNA and multiple molecular modes of action, NAC has therapeutic value for reducing endothelial dysfunction, inflammation, fibrosis, invasion, cartilage erosion, acetaminophen detoxification and transplant prolongation.}, }
@article {pmid12609744, year = {2003}, author = {Masatsugu, K and Itoh, H and Chun, TH and Saito, T and Yamashita, J and Doi, K and Inoue, M and Sawada, N and Fukunaga, Y and Sakaguchi, S and Sone, M and Yamahara, K and Yurugi, T and Nakao, K}, title = {Shear stress attenuates endothelin and endothelin-converting enzyme expression through oxidative stress.}, journal = {Regulatory peptides}, volume = {111}, number = {1-3}, pages = {13-19}, doi = {10.1016/s0167-0115(02)00219-7}, pmid = {12609744}, issn = {0167-0115}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Aspartic Acid Endopeptidases/*biosynthesis/genetics ; Carotid Arteries/cytology ; Cattle ; Cells, Cultured ; DNA Primers/genetics ; DNA Probes/genetics ; Down-Regulation ; Endothelin-1/*biosynthesis/genetics ; Endothelin-Converting Enzymes ; Endothelium, Vascular/cytology/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Metalloendopeptidases ; Oxidative Stress/*physiology ; RNA, Messenger/analysis/biosynthesis ; Stress, Mechanical ; Time Factors ; Umbilical Veins/cytology ; }, abstract = {Shear stress is known to dilate blood vessels and exert an antiproliferative effect on vascular walls. These effects have partly been ascribed to shear stress-induced regulation of the secretion of endothelium-derived vasoactive substances. In this study, to elucidate the role of shear stress in endothelin production by endothelial cells, we examined the effect of physiological shear stress on the mRNA expression of endothelin-converting enzyme-1 (ECE-1) as well as endothelin-1 (ET-1) in cultured bovine carotid artery endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs), using a parallel plate-type flow chamber. ECE-1 mRNA expression was significantly down-regulated by shear stress in an intensity- and time-dependent manner within the physiological range (1.5 to 15 dyn/cm(2)). ET-1 mRNA expression decreased together with ECE-1 mRNA expression. Shear stress at 15 dyn/cm(2) for 30 min induced a significant increase in the intracellular peroxide concentration, and the down-regulation of ECE-1 and ET-1 mRNA expression by shear stress was attenuated almost completely on treatment with N-acetyl cysteine (NAC), an antioxidant (20 mM). Furthermore, when H(2)O(2) (0.5 to 2 mM) was added to BAECs in static culture, the ECE-1 as well as ET-1 mRNA expression was attenuated in proportion to the concentration of H(2)O(2). It is suggested that endothelial cells sense shear stress as oxidative stress and transduce signal for the regulation of the gene expression of ECE as well as ET to attenuate vascular tone and inhibit the proliferation of vascular smooth muscle cells.}, }
@article {pmid12606766, year = {2003}, author = {Aslamkhan, AG and Han, YH and Yang, XP and Zalups, RK and Pritchard, JB}, title = {Human renal organic anion transporter 1-dependent uptake and toxicity of mercuric-thiol conjugates in Madin-Darby canine kidney cells.}, journal = {Molecular pharmacology}, volume = {63}, number = {3}, pages = {590-596}, doi = {10.1124/mol.63.3.590}, pmid = {12606766}, issn = {0026-895X}, support = {ES05157/ES/NIEHS NIH HHS/United States ; ES05980/ES/NIEHS NIH HHS/United States ; ES11288/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Biological Transport ; Cell Survival/drug effects ; Cells, Cultured ; Dogs ; Humans ; Kidney/cytology ; Mercury/*toxicity ; Mercury Isotopes/metabolism ; Organic Anion Transport Protein 1/*metabolism ; }, abstract = {Mercuric ions are highly reactive and form a variety of organic complexes or conjugates in vivo. The renal proximal tubule is a primary target for mercury uptake and toxicity, and circumstantial evidence implicates organic anion transporters in these processes. To test this hypothesis directly, the transport and toxicity of mercuric-thiol conjugates were characterized in a Madin-Darby canine kidney cell line stably transfected with the human organic anion transporter 1 (hOAT1). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-terazolium bromide assays (for mitochondrial dehydrogenase) confirmed that mercuric conjugates of the thiols N-acetylcysteine (NAC), cysteine, or glutathione were more toxic in hOAT1-transfected cells than in the nontransfected cells. The NAC-Hg(2+) conjugate was most cytotoxic, inducing greater than 50% cellular death over 18 h at a concentration of 100 microM. The cytotoxic effects were fully reversed by probenecid (an OAT1 inhibitor) and partially reversed by p-aminohippurate (an OAT1 substrate). Toxicity of this conjugate was reduced by the OAT1-exchangeable dicarboxylates alpha-ketoglutarate, glutarate, and adipate, but not by succinate, a nonexchangeable dicarboxylate. (203)Hg-uptake studies showed probenecid-sensitive uptake of mercury-thiol conjugates in the hOAT1-transfected cells. The apparent K(m) for the NAC-Hg(2+) conjugate was 44 +/- 9 microM. Uptake of the NAC-Hg(2+) conjugate was cis-inhibited by glutarate, but not by methylsuccinate, paralleling their effects on toxicity. Probenecid-sensitive transport of the NAC-Hg(2+) conjugate was also shown to occur in Xenopus laevis oocytes expressing the hOAT1 or the rOAT3 transporters, suggesting that OAT3 may also transport thiol-Hg(2+) conjugates. Thus, renal accumulation and toxicity of thiol-Hg(2+) conjugates may depend in part on the activity of the organic transport system.}, }
@article {pmid12604262, year = {2003}, author = {Sofou, S and Thomas, JL}, title = {Stable adhesion of phospholipid vesicles to modified gold surfaces.}, journal = {Biosensors &amp; bioelectronics}, volume = {18}, number = {4}, pages = {445-455}, doi = {10.1016/s0956-5663(02)00153-7}, pmid = {12604262}, issn = {0956-5663}, mesh = {Adsorption ; Biosensing Techniques/instrumentation/*methods ; Coated Materials, Biocompatible/*chemical synthesis/chemistry ; *Electrodes ; Feasibility Studies ; Fluoresceins/analysis ; Gold/*chemistry ; Liposomes/chemical synthesis/*chemistry ; Membrane Fusion ; Phospholipids/*chemistry ; Reproducibility of Results ; Sensitivity and Specificity ; Spectrometry, Fluorescence/instrumentation/*methods ; }, abstract = {Phospholipid vesicles are well-studied biomembrane mimics that are of increasing interest in drug delivery, immunoassays, and sensor chips. In a number of biosensor applications it is desirable to be able to adhere vesicles to a surface in a manner which does not result in their rupture or fusion. Such behavior should, in principle, be achievable by controlling the vesicle-surface and vesicle-vesicle interactions. We have varied vesicle composition and charge (phosphatidylcholine, phosphatidylcholine-phosphatidic acid 18 mol%) and solution ionic strength, to study the adhesion of fluorescent vesicles to glass, gold, and gold modified with chemisorbed acetyl-cysteine. The extent of chemisorption was characterized with angle-resolved X-ray photoelectron spectroscopy (ARXPS), and vesicle integrity and behavior was studied using entrapped and lipophilic fluorescent markers, together and in separate measurements. Vesicle fusion (by energy transfer), adhesion of intact vesicles (with entrapped calcein) and diffusion coefficients (by photobleaching recovery) were monitored using confocal fluorescence microscopy. Acetyl-cysteine modified gold surfaces were shown to be appropriate substrates for adhesion of intact vesicles. Finally, as a 'proof of principle' for fluorescence amplification, release of a self-quenching entrapped reporter dye (calcein) by the detergent Triton X-100 was followed in real time.}, }
@article {pmid12603840, year = {2003}, author = {Farr, SA and Poon, HF and Dogrukol-Ak, D and Drake, J and Banks, WA and Eyerman, E and Butterfield, DA and Morley, JE}, title = {The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice.}, journal = {Journal of neurochemistry}, volume = {84}, number = {5}, pages = {1173-1183}, doi = {10.1046/j.1471-4159.2003.01580.x}, pmid = {12603840}, issn = {0022-3042}, support = {R01 AA 12743/AA/NIAAA NIH HHS/United States ; R01 NS 41863/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Age Factors ; Amyloid beta-Peptides/biosynthesis ; Animals ; Antioxidants/*therapeutic use ; Appetitive Behavior/drug effects ; Behavior, Animal/drug effects ; Blood-Brain Barrier/drug effects ; Brain/*drug effects/physiopathology ; Cognition/drug effects ; Disease Models, Animal ; Male ; Maze Learning/drug effects ; Memory Disorders/*drug therapy/physiopathology ; Mice ; Mice, Inbred Strains ; Mice, Neurologic Mutants ; Oxidative Stress/drug effects ; Specific Pathogen-Free Organisms ; Thioctic Acid/*therapeutic use ; Treatment Outcome ; }, abstract = {Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.}, }
@article {pmid12603607, year = {2003}, author = {Rocha-Vieira, E and Ferreira, E and Vianna, P and De Faria, DR and Gaze, ST and Dutra, WO and Gollob, KJ}, title = {Histopathological outcome of Leishmania major-infected BALB/c mice is improved by oral treatment with N-acetyl-l-cysteine.}, journal = {Immunology}, volume = {108}, number = {3}, pages = {401-408}, pmid = {12603607}, issn = {0019-2805}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antiprotozoal Agents/*therapeutic use ; Cytokines/metabolism ; Female ; *Leishmania major/isolation &amp; purification ; Leishmaniasis, Cutaneous/*drug therapy/immunology/parasitology/pathology ; Lymph Nodes/immunology ; Macrophages/immunology ; Mice ; Mice, Inbred BALB C ; }, abstract = {Leishmania major infected BALB/c mice were treated with N-acetyl-l-cysteine (NAC), a glutathione precursor, to evaluate the role of in vivo glutathione on lesion pathology and cytokine profiles following infection. Mice were maintained on NAC-containing water 2 days before infection for a total of 14 weeks. The BALB/c response to L. major infection was improved by oral administration of NAC, at the level of histopathological outcome, lesion progression and cytokine profile. A significantly improved histopathological outcome of the footpad lesion, characterized by a mixed inflammatory infiltrate organized in a focal pattern with little tissue destruction and a reduced parasite load, was observed in NAC-treated BALB/c mice. Histopathological modulation was accompanied by a modified cytokine pattern from popliteal lymph node cells, demonstrated by a sustained higher frequency of interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha)-producing cells. This work points to an important role for glutathione in the modulation of effector responses in BALB/c mice.}, }
@article {pmid12600242, year = {2003}, author = {Chiu, SJ and Lee, MY and Chou, WG and Lin, LY}, title = {Germanium oxide enhances the radiosensitivity of cells.}, journal = {Radiation research}, volume = {159}, number = {3}, pages = {391-400}, doi = {10.1667/0033-7587(2003)159[0391:goetro]2.0.co;2}, pmid = {12600242}, issn = {0033-7587}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimutagenic Agents/pharmacology ; CHO Cells ; Catalase/metabolism ; Cell Survival/*radiation effects ; Cricetinae ; DNA Damage/*radiation effects ; DNA Repair ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Free Radical Scavengers/pharmacology ; Germanium/*pharmacology ; Glutathione Transferase/metabolism ; Radiation Tolerance/*drug effects ; Reactive Oxygen Species ; Sulfhydryl Compounds/metabolism/pharmacology ; Time Factors ; X-Rays ; }, abstract = {We investigated here the combined effect of GeO(2) and radiation on cell viability. Cells were treated with 0 to 22 mM GeO(2) for 12 h followed by 1 Gy X irradiation. A synergistic cytotoxic effect was observed for the combined treatment with a dose-dependent reduction of cell viability. Complete survival curves showed a 2.3- and 2.75-fold increase in radiosensitivity for 50% cell death in the presence of 5 and 15 mM GeO(2), respectively. The increased radiosensitivity also occurred when GeO(2) was given either 4 h prior to irradiation or immediately after radiation exposure. GeO(2) did not affect the total soluble thiol content or the activities of catalase and glutathione S-transferase. Analysis of the production of reactive oxygen species (ROS) revealed that the combined treatment dramatically increased the synthesis of ROS. Addition of N-acetyl cysteine (NAC, 20 mM) decreased the production of ROS in cells. NAC, however, increased cell viability only slightly after treatment with GeO(2) and radiation. Thus increased production of ROS makes little or no contribution to the observed death. The combination of GeO(2) and X radiation, however, significantly increased the frequency of DNA double-strand breaks (DSBs). Notably, the presence of GeO(2) also reduced the efficiency of DNA repair. We conclude that treatment with GeO(2) followed by X irradiation increases DNA DSBs and cell death.}, }
@article {pmid12598971, year = {2002}, author = {Koivusalo, A and Kauppinen, H and Anttila, A and Rautelin, H and Jusufovic, J and Lindahl, H and Rintala, R}, title = {Intraluminal casein model of necrotizing enterocolitis for assessment of mucosal destruction, bacterial translocation, and the effects of allopurinol and N-acetylcysteine.}, journal = {Pediatric surgery international}, volume = {18}, number = {8}, pages = {712-717}, doi = {10.1007/s00383-002-0871-7}, pmid = {12598971}, issn = {0179-0358}, mesh = {Acetylcysteine/*pharmacology ; Allopurinol/*pharmacology ; Analysis of Variance ; Animals ; Animals, Newborn ; *Bacterial Translocation/drug effects ; Caseins ; Disease Models, Animal ; Enterocolitis, Necrotizing/microbiology/*pathology ; Ileum/drug effects/microbiology/*pathology ; Intestinal Mucosa/drug effects/microbiology/*pathology ; Lymphatic System/microbiology ; Male ; Swine ; }, abstract = {An intraluminal casein model (ICM) of necrotizing enterocolitis (NEC) is able to produce small-bowel changes reminiscent of human NEC in neonatal animals. We studied bacterial translocation (BT) in NEC induced by using the ICM in neonatal piglets. We also studied whether allopurinol (AL) and N-acetylcysteine (NAC) have an effect on BT and mucosal changes in the ICM of NEC. Twenty-eight neonatal piglets were randomized into four groups. NEC was induced in 21 by injecting casein-d-gluconate into a loop of terminal ileum: group Cas (n = 7) had no premedication, in group Cas/AL (n = 7) intravenous (i.v.) Al (100 mg/kg), and in group Cas/NAC (n = 7) i.v. NAC (200 mg/kg) was given. Group Sham (n = 7) had the ileum injected with 0.9% saline with no premedication. Immediately after the injection a mesenteric lymph node (MLN) adjacent to the loop was harvested for quantitative aerobic bacterial culture; 4 h after the injection another MLN and samples of spleen, liver, kidney, and lung were harvested and cultured. Comparison of the incidence of samples with positive bacterial cultures and the number of colony-forming units (CFU) in samples was made between groups. The severity of NEC in the ileum was graded from 0 to 3 according to macroscopic and histologic findings. NEC changes in the bowel were most severe in Cas piglets, less severe in Cas/NAC piglets (P < 0.5), and sham piglets had the least severe changes (P < 0.05). piglets with NEC changes in the ileum had a higher incidence of BT into the MLN than piglets without NEC changes (P < 0.05), but the difference in CFU was not significant (P > 0.05). In Cas and Cas/NAC piglets a high incidence of BT into the MLN was noted as early at -5 min after casein injection. The incidence of BT into the MLN was significantly higher in Cas and Cas/NAC piglets than in Sham piglets (P < 0.05), the difference in CFU being not significant (P > 0.05). BT in Cas/Al piglets was not significantly different from that of Cas piglets (P > 0.05), but less than in Cas/NAC piglets (P < 0.05). Four hours after casein injection into the ileum there was significant BT into the MLN. Premedication with NAC was associated with less severe NEC changes, but neither NAC nor AL significantly affected BT.}, }
@article {pmid12597448, year = {2003}, author = {Nyska, A and Suttie, A and Bakshi, S and Lomnitski, L and Grossman, S and Bergman, M and Ben-Shaul, V and Crocket, P and Haseman, JK and Moser, G and Goldsworthy, TL and Maronpot, RR}, title = {Slowing tumorigenic progression in TRAMP mice and prostatic carcinoma cell lines using natural anti-oxidant from spinach, NAO--a comparative study of three anti-oxidants.}, journal = {Toxicologic pathology}, volume = {31}, number = {1}, pages = {39-51}, doi = {10.1080/01926230390173833}, pmid = {12597448}, issn = {0192-6233}, mesh = {Acetylcysteine/isolation &amp; purification/therapeutic use ; Administration, Oral ; Animals ; Antioxidants/isolation &amp; purification/*therapeutic use ; Carcinoma/*drug therapy/metabolism/pathology ; Catechin/*analogs &amp; derivatives/isolation &amp; purification/therapeutic use ; Cell Division/drug effects ; Disease Progression ; Drug Screening Assays, Antitumor ; G1 Phase/drug effects ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Prostatic Hyperplasia/metabolism/*pathology ; Prostatic Neoplasms/*drug therapy/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Spinacia oleracea/*chemistry ; Tumor Cells, Cultured ; }, abstract = {The TRAMP model and human prostatic cancer (PCA) cell lines DU145 and PC3 are useful forchemopreventive studies. We compared the efficacy of 3 anti-oxidants [a water-soluble natural anti-oxidant. NAO (200 mg/kg). found in spinach leaves; epigallocatechin-3 gallate, EGCG (200 mg/kg), a major green tea polyphenol; and N-acetylcysteine, NAC (125 mg/kg)] plus vehicle in slowing spontaneous tumorigenic progression in TRAMP and wild-type male mice. Sacrifices occurred on weeks 5, 9, and 13. Prostatic histopathology and oxidative-stress blood markers were evaluated. Hyperplasias were ranked by a combination of severity grade and distribution (focal, multifocal, and diffuse). The effectivity of each tested compound in reducing the severity/focalness of hyperplasia varied from lobe to lobe. NAO exerted a significant effect on the dorsal and lateral lobes; NAC, on the anterior and ventral lobes, and EGCG, on the ventral lobe. When the most severe hyperplasia in all 4 lobes of TRAMPs was evaluated, only NAO reduced hyperplasia at weeks 9 and 13. Plasma peroxide levels in TRAMPs were reduced following oral administration of NAO or NAC for 13 weeks; EGCG only slightly reduced these levels. In NAO-treated DU 145 and PC3 PCA cells, inhibition of cellular proliferation occurred in a dose-dependent manner, increasing numbers of G1 cells and reducing ROS levels. The anti-oxidative and antiproliferative properties of NAO may explain its efficacy in slowing the spontaneous prostatic carcinogenic process in the TRAMP and its effects in the cell lines.}, }
@article {pmid12594272, year = {2003}, author = {Tonomura, N and McLaughlin, K and Grimm, L and Goldsby, RA and Osborne, BA}, title = {Glucocorticoid-induced apoptosis of thymocytes: requirement of proteasome-dependent mitochondrial activity.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {170}, number = {5}, pages = {2469-2478}, doi = {10.4049/jimmunol.170.5.2469}, pmid = {12594272}, issn = {0022-1767}, support = {R01 AG47922/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Apoptosis/*drug effects/immunology ; Cell Death/immunology ; Cells, Cultured ; Cysteine Endopeptidases/metabolism/*physiology ; Dexamethasone/*administration &amp; dosage ; Female ; Hydrogen Peroxide/metabolism ; Injections, Intraperitoneal ; Mice ; Mice, Inbred BALB C ; Mitochondria/drug effects/*enzymology/immunology/metabolism ; Multienzyme Complexes/metabolism/*physiology ; Oxygen/physiology ; Proteasome Endopeptidase Complex ; Reactive Oxygen Species/pharmacology ; Thymus Gland/*cytology/*drug effects/enzymology/immunology ; }, abstract = {Thymocytes undergo negative and positive selection during development in the thymus. During this selection process, the majority of thymocytes are eliminated by apoptosis through signaling via TCR or die by neglect, possibly mediated through glucocorticoids. In this study, we report that thymocytes require molecular oxygen to undergo apoptosis induced by dexamethasone (DEX), a synthetic glucocorticoid, and treatment with N-acetyl-L-cysteine (NAC), a thiol antioxidant, inhibits thymocyte apoptosis in vivo as well as ex vivo. We detected elevated intracellular levels of hydrogen peroxide (H(2)O(2)) during DEX-induced apoptosis, which is reduced by NAC treatment, indicating that the elevated levels of intracellular H(2)O(2) are proapoptotic. We also show that loss of mitochondrial membrane potential, cytochrome c release, as well as caspase-3 activation induced by DEX are attenuated by NAC treatment. We identified the production site for H(2)O(2) as the ubiquinone cycle at complex III of mitochondria by using various inhibitors of the mitochondrial electron transport chain, and we show that the cell death events mediated by mitochondria are also significantly reduced when the inhibitors were used. Through inhibition of the proteasome, we also show that the production of H(2)O(2) and the cell death events mediated by mitochondria are regulated by proteosomal activities in DEX-induced thymocyte apoptosis. We conclude that in DEX-treated thymocytes, the increased production of H(2)O(2) originates from mitochondria and is proapoptotic for cell death mediated by mitochondria. We also conclude that all the apoptotic events mediated by mitochondria are regulated by proteasomes.}, }
@article {pmid12593787, year = {2002}, author = {Merla, A and Romani, GL and Di Luzio, S and Di Donato, L and Farina, G and Proietti, M and Pisarri, S and Salsano, S}, title = {Raynaud's phenomenon: Infrared functional imaging applied to diagnosis and drug effects.}, journal = {International journal of immunopathology and pharmacology}, volume = {15}, number = {1}, pages = {41-52}, doi = {10.1177/039463200201500106}, pmid = {12593787}, issn = {2058-7384}, abstract = {A non-invasive, innovative approach to the study of Raynaud's Phenomenon is proposed. A group of patients, with respect of a control group, underwent a simultaneous assessment of thermal properties of all ten fingers using infrared functional imaging (IRFI). The assessment highlighted a quite different behaviour between patients with Primary- (PRP) and those with scleroderma - Raynaud's Phenomenon (SSc) and, compared with other existing techniques, seems to be an objective and effective tool to discriminate between PRP and RP secondary to SSc. 18 healthy volunteers (Norm), 20 Primary Raynaud's Phenomenon (PRP) and 20 Secondary Scleroderma (SSc) patients were studied subsequently to clinical evaluation and nail fold capillaroscopy. High-resolution infrared imaging of finger re-warming processes, immediately after a 2 min cold stress, allowed to identify objective parameters. Temperature integral Q (the temperature evaluation of the area under the time-temperature curve along the re-warming period) provided particularly effective figures in describing thermal properties of the fingers. Grand average Q values were (383.4 ∓ 12.5) °C×min, (502.9 ± 88.1) °C×min and (1022.0 ± 110.2) °C×min for the PRP, SSc and Normal groups, respectively. Separate evaluation of the temperature integral for each finger leads to very similar results for the fingers of all the PRP patients; a different thermoregulatory response was observed in SSc patients. The sensitivity of the method in order to distinguish healthy from ill fingers was 100%. The specificity in distinguishing SSc from PRP was 95%. In addition, IRFI parameters provided a better understanding of the impaired control of the finger's temperature in PRP and SSc with respect to the Normal group. This pilot study also applied IRFI for the measurement of drug effects in patients with Raynaud's Phenomenon. Sixteen out of twenty SSc patients were tested in a single 1-hour session of N-acetylcysteine infusion. IRFI clearly documented a significant increase of face and hands temperature during the drug administration. The grand average value of the finger's temperature after the 1 hour NAC administration was (29.6 ± 3.7) °C, while its value before was (27.9 ± 3.7) °C (p<0.001). N-acetylcysteine seems to act as a vasodilator in patients with Raynaud's phenomenon secondary to systemic sclerosis (scleroderma).}, }
@article {pmid12592670, year = {2002}, author = {Medina, S and Martínez, M and Hernanz, A}, title = {Antioxidants inhibit the human cortical neuron apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42.}, journal = {Free radical research}, volume = {36}, number = {11}, pages = {1179-1184}, doi = {10.1080/107157602100006445}, pmid = {12592670}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Amyloid beta-Peptides/*toxicity ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Ascorbic Acid/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Cerebral Cortex/*pathology ; Dopamine/*toxicity ; Free Radical Scavengers/pharmacology ; Glutathione/pharmacology ; Humans ; Hydrogen Peroxide/*toxicity ; Membrane Potentials/drug effects ; Mitochondria/physiology ; Neurons/*pathology ; Peptide Fragments/*toxicity ; Tumor Necrosis Factor-alpha/*toxicity ; }, abstract = {Several substances related to the neurodegenerative diseases of Alzheimer and Parkinson, such as hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42, have been shown to induce apoptosis in tumoral cell lines and rat neurons but not in human neurons. Moreover, the role of mitochondria (membrane potential) during neuronal apoptosis is still a matter of debate. We present here, for the first time, in cultured human cortical neurons that the DNA fragmentation induced by these substances was preceded by a decrease of the mitochondrial membrane potential. We have also examined the antiapoptotic effect of the antioxidants glutathione, N-acetyl-cysteine and ascorbic acid. All these antioxidants inhibited the apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42, since they were able to inhibit completely the mitochondrial membrane potential depolarization and the DNA fragmentation.}, }
@article {pmid12586627, year = {2003}, author = {Shatrov, VA and Sumbayev, VV and Zhou, J and Brüne, B}, title = {Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation via redox-dependent mechanisms.}, journal = {Blood}, volume = {101}, number = {12}, pages = {4847-4849}, doi = {10.1182/blood-2002-09-2711}, pmid = {12586627}, issn = {0006-4971}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cell Line ; Enzyme Inhibitors/pharmacology ; Gene Expression/drug effects ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; Lipoproteins, LDL/*pharmacology ; Macrophages/metabolism ; NADPH Oxidases/antagonists &amp; inhibitors ; Nitric Oxide Donors/pharmacology ; Onium Compounds/pharmacology ; Oxidation-Reduction ; RNA, Messenger/analysis ; Reactive Oxygen Species/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; S-Nitrosoglutathione/pharmacology ; Transcription Factors/*biosynthesis/genetics ; Transfection ; }, abstract = {Oxidized low-density lipoprotein (oxLDL) and macrophages play a central role in atherosclerosis. Here, we obtained evidence that oxLDL induced hypoxia-inducible factor-1alpha (HIF-1alpha) protein accumulation in human macrophages (Mono-Mac-6) under normoxia. HIF-1alpha accumulation was attenuated by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC), the nitric oxide (NO) donor S-nitrosoglutathione (GSNO), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors such as diphenyleniodonium (DPI) or 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), thus implicating the contribution of oxLDL-generated reactive oxygen species (ROS). Whereas oxLDL did not modulate HIF-1alpha mRNA levels, experiments with cycloheximide pointed to a translational mechanism in oxLDL action. HIF-1-dependent luciferase reporter gene analysis underscored HIF-1 transactivation. Our results indicate that oxLDL induced HIF-1alpha accumulation and HIF-1-dependent reporter gene activation in human macrophages via a redox-mediated pathway. This finding may suggest a role of HIF-1 in atherosclerosis and oxLDL-induced pathogenesis.}, }
@article {pmid12581860, year = {2003}, author = {Ibuki, Y and Mizuno, S and Goto, R}, title = {gamma-Irradiation-induced DNA damage enhances NO production via NF-kappaB activation in RAW264.7 cells.}, journal = {Biochimica et biophysica acta}, volume = {1593}, number = {2-3}, pages = {159-167}, doi = {10.1016/s0167-4889(02)00385-3}, pmid = {12581860}, issn = {0006-3002}, mesh = {Animals ; Cell Line ; *DNA Damage ; Enzyme Activation ; Gamma Rays ; Immunoblotting ; Interferon-gamma ; Lipopolysaccharides ; Mice ; NF-kappa B/antagonists &amp; inhibitors/biosynthesis ; Nitric Oxide/antagonists &amp; inhibitors/*biosynthesis ; Nitric Oxide Synthase/biosynthesis ; Nitric Oxide Synthase Type II ; Poly(ADP-ribose) Polymerases/metabolism ; Signal Transduction ; Time Factors ; }, abstract = {We investigated the mechanism of augmentation of nitric oxide (NO) production in the murine macrophage cell line RAW264.7 after gamma-irradiation. The cells treated with interferon-gamma (IFN-gamma) or lipopolysaccharide (LPS) showed enhanced NO production by gamma-irradiation in a dose-dependent manner, accompanying the induction of inducible nitric oxide synthase (iNOS) expression. Nuclear factor kappa B (NF-kappaB) activation was induced 1 h after gamma-irradiation dose-dependently, which was detected by the degradation of I-kappaB. Inhibitors of I-kappaB degradation, MG132 and N(alpha)-p-tosyl-L-lysine chloromethyl ketone (TLCK), suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production, showing that gamma-irradiation induced NO production via NF-kappaB activation. Although NF-kappaB is known to be a redox-sensitive transcription factor, the antioxidant agents N-acetyl-cysteine (NAC) and 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylic acid (trolox) showed no suppression and treatment with H(2)O(2) showed only slight enhancement of IFN-gamma-induced NO production. The DNA damaging agents camptothecin and etoposide enhanced IFN-gamma-induced NO production and showed I-kappaB degradation, indicating that the increase in NO production was due to direct DNA damage. Furthermore, 3-aminobenzamide (3AB) and benzamide, inhibitors of poly (ADP-ribose) polymerase (PARP) that are activated upon recognition of DNA strand breaks, suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production and the I-kappaB degradation by gamma-irradiation. We concluded that (1) the increase in NO production was due to direct DNA damage by gamma-irradiation, and that (2) PARP activation through DNA damage induced NF-kappaB activation, leading to iNOS expression and NO production.}, }
@article {pmid12576300, year = {2003}, author = {Takizawa, H and Abe, S and Okazaki, H and Kohyama, T and Sugawara, I and Saito, Y and Ohtoshi, T and Kawasaki, S and Desaki, M and Nakahara, K and Yamamoto, K and Matsushima, K and Tanaka, M and Sagai, M and Kudoh, S}, title = {Diesel exhaust particles upregulate eotaxin gene expression in human bronchial epithelial cells via nuclear factor-kappa B-dependent pathway.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {284}, number = {6}, pages = {L1055-62}, doi = {10.1152/ajplung.00358.2002}, pmid = {12576300}, issn = {1040-0605}, mesh = {Acetylcysteine/pharmacology ; Antibodies ; Antioxidants/pharmacology ; Bronchi/cytology/metabolism ; Cells, Cultured ; Chemokine CCL11 ; Chemokines, CC/*genetics/immunology ; Electrophoretic Mobility Shift Assay ; Epithelial Cells/*drug effects/metabolism ; Expectorants/pharmacology ; Gene Expression/drug effects ; Humans ; In Vitro Techniques ; Interleukin-13/metabolism ; NF-kappa B/*metabolism ; Proline/*analogs &amp; derivatives/pharmacology ; RNA, Messenger/analysis ; Respiratory Mucosa/cytology/*metabolism ; STAT6 Transcription Factor ; Signal Transduction/drug effects ; Thiocarbamates/pharmacology ; Trans-Activators/metabolism ; Up-Regulation/drug effects ; Vehicle Emissions/*adverse effects ; }, abstract = {Fine particles derived from diesel engines, diesel exhaust particles (DEP), have been shown to augment gene expression of several inflammatory cytokines in human airway epithelial cells in vitro. However, it remains unclear whether or not DEP have any effect on the expression and production of eotaxin, an important chemokine involved in eosinophil recruitment into the airways. We studied the effects of DEP by using a conventional suspended DEP and by a recently established in vitro cell exposure system to diesel exhaust (Abe S, Takizawa H, Sugawara I, and Kudoh S, Am J Respir Cell Mol Biol 22: 296-303, 2000). DEP showed a dose-dependent stimulatory effect on eotaxin production by normal human peripheral airway epithelial cells as well as by bronchial epithelial cell line BET-1A as assessed by specific ELISA. mRNA levels increased by DEP were shown by RT-PCR. DEP showed an additive effect on IL-13-stimulated eotaxin expression. DEP induced NF-kappaB activation by EMSA as previously reported but did not induce signal transducer and activator of transcription (STAT) 6 activation according to Western blot analysis. Finally, antioxidant agents (N-acetyl cysteine and pyrrolidine dithiocarbamate), which inhibited NF-kappaB activation but failed to affect STAT6 activation, almost completely attenuated DEP-induced eotaxin production, whereas these agents failed to attenuate IL-13-induced eotaxin production. These findings suggested that DEP stimulated eotaxin gene expression via NF-kappaB-dependent, but STAT6-independent, pathways.}, }
@article {pmid12572667, year = {2003}, author = {Núñez, MT and Núñez-Millacura, C and Tapia, V and Muñoz, P and Mazariegos, D and Arredondo, M and Muñoz, P and Mura, C and Maccioni, RB}, title = {Iron-activated iron uptake: a positive feedback loop mediated by iron regulatory protein 1.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {16}, number = {1}, pages = {83-90}, doi = {10.1023/a:1020743405347}, pmid = {12572667}, issn = {0966-0844}, mesh = {Analysis of Variance ; Animals ; Cell Line ; Electron Transport ; Homeostasis ; Humans ; Iron/*metabolism ; Iron Regulatory Protein 1/*metabolism ; K562 Cells ; Kinetics ; Mice ; Tumor Cells, Cultured ; }, abstract = {The love-hate relationship between iron and living matter has generated mechanisms to maintain iron concentration in a narrow range, above and below which deleterious effects occur. At the cellular level, iron homeostasis is accomplished by the activity of the IRP proteins, which, under conditions of iron depletion, up-regulate the expression of the iron acquisition proteins TfR and DMT1. It has been shown that hydrogen peroxide activates IRP1 and that this activation mediates a potentially harmful increase in cell iron uptake. Here we show that IRP1 activity is also induced by iron-mediated oxidative stress. When cells were incubated with up to 20 microM of iron, a typical decrease in IRP1 and IRP2 activity was observed. Interestingly, when iron was further increased to 40 or 80 microM. IRP1 was reactivated in three of the four different cell lines tested, i.e., Caco-2 cells, N2A cells and HepG2 cells. In the fourth cell line (K562) IRP1 activity did not increase, but neither did it decrease. This response to iron was largely abrogated when the antioxidant N-acetyl cysteine was added along with iron to the culture medium. Thus, the effect of iron was mediated by oxidative stress. Increases in IRP1 activity were accompanied by increases in cell iron uptake, an indication that the activated IRP1 was functional in the activation of iron uptake. Hence, this iron-induced iron uptake feedback loop results in the increase of intracellular iron and increased oxidative stress.}, }
@article {pmid12569075, year = {2003}, author = {Phillips, DC and Woollard, KJ and Griffiths, HR}, title = {The anti-inflammatory actions of methotrexate are critically dependent upon the production of reactive oxygen species.}, journal = {British journal of pharmacology}, volume = {138}, number = {3}, pages = {501-511}, pmid = {12569075}, issn = {0007-1188}, mesh = {Anti-Inflammatory Agents/administration &amp; dosage/*pharmacology ; Antigens, Surface/metabolism ; Apoptosis ; Cell Adhesion/drug effects ; Cell Cycle/drug effects ; Dose-Response Relationship, Drug ; Endothelium, Vascular/cytology/physiology ; Flow Cytometry ; Glutathione/metabolism ; Humans ; Jurkat Cells ; Methotrexate/administration &amp; dosage/*pharmacology ; Monocytes/drug effects/physiology ; Peroxides/metabolism ; Reactive Oxygen Species/*metabolism ; T-Lymphocytes/drug effects/metabolism ; Time Factors ; U937 Cells ; Umbilical Veins/cytology ; }, abstract = {1 The mechanism of action by which methotrexate (MTX) exerts its anti-inflammatory and immunosuppressive effects remains unclear. The aim of this study is to investigate the hypothesis that MTX exerts these effects via the production of reactive oxygen species (ROS). 2 Addition of MTX (100 nM-10 micro M) to U937 monocytes induced a time and dose dependent increase in cytosolic peroxide [peroxide](cyt) from 6-16 h. MTX also caused corresponding monocyte growth arrest, which was inhibited (P<0.05) by pre-treatment with N-acetylcysteine (NAC; 10 mM) or glutathione (GSH; 10 mM). In contrast, MTX induction of [peroxide](cyt) in Jurkat T cells was more rapid (4 h; P<0.05), but was associated with significant apoptosis at 16 h at all doses tested (P<0.05) and was significantly inhibited by NAC or GSH (P<0.05). 3 MTX treatment of monocytes (10 nM-10 micro M) for 16 h significantly reduced total GSH levels (P<0.05) independently of dose (P>0.05). However, in T-cells, GSH levels were significantly elevated following 30 nM MTX treatment (P<0.05) but reduced by doses exceeding 1 micro M compared to controls (P<0.05). 4 MTX treatment significantly reduced monocyte adhesion to 5 h and 24 h LPS (1 micro g ml(-1)) activated human umbilical vein endothelial cells (HUVEC; P<0.05) but not to resting HUVEC. Pre-treatment with GSH prevented MTX-induced reduction in adhesion. 5 In conclusion, ROS generation by MTX is important for cytostasis in monocytes and cytotoxicity T-cells. Furthermore, MTX caused a reduction in monocyte adhesion to endothelial cells, where the mechanism of MTX action requires the production of ROS. Therefore its clinical efficacy can be attributed to multiple targets.}, }
@article {pmid12565201, year = {2003}, author = {Malaplate-Armand, C and Ferrari, L and Masson, C and Siest, G and Batt, AM}, title = {Astroglial CYP1B1 up-regulation in inflammatory/oxidative toxic conditions: IL-1beta effect and protection by N-acetylcysteine.}, journal = {Toxicology letters}, volume = {138}, number = {3}, pages = {243-251}, doi = {10.1016/s0378-4274(02)00417-4}, pmid = {12565201}, issn = {0378-4274}, mesh = {Acetylcysteine/*pharmacology ; Aryl Hydrocarbon Hydroxylases/genetics/immunology/*metabolism ; Astrocytes/drug effects/*enzymology/immunology ; Astrocytoma ; Cytochrome P-450 CYP1B1 ; Cytochrome P-450 CYP2D6/genetics/immunology/metabolism ; Drug Interactions ; Gene Expression Regulation, Enzymologic/drug effects/immunology ; Humans ; Interleukin-1/antagonists &amp; inhibitors/*toxicity ; Isoenzymes/genetics/immunology/metabolism ; Microsomes/metabolism ; Oxidative Stress/drug effects/*immunology ; RNA, Messenger/biosynthesis/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured ; Up-Regulation/immunology ; }, abstract = {The present work aims to determine the relevance of an astrocytoma cell line U373 MG, for assessing the role of some astroglial cytochrome P450 in neurotoxicity and neuroprotection. CYP1B1, CYP2C8, CYP2C9, CYP2D6, CYP2J2, CYP2E1 and CYP4A11 mRNA were detected by reverse transcriptase-polymerase chain reaction in control U373 MG cell cultures. Among them we focused on CYP1B1 expression. After 48 h treatment with a range of concentrations of interleukin-1beta (1, 5, 10 ng/ml) used to simulate stress conditions, CYP1B1 mRNA expression was enhanced in a dose-dependent way. This increased expression was followed 24 h later by an increase in protein level, determined by Western-blot. N-acetylcysteine (NAC) partially inhibited this effect both on the mRNA and protein levels. As CYP1B1 activates procarcinogenic compounds to reactive metabolites, an increase in this P450 isoform will participate to toxic consequences of an inflammatory/oxidative stress. NAC will prevent this deleterious effect.}, }
@article {pmid12563020, year = {2003}, author = {Botham, KM and Zheng, X and Napolitano, M and Avella, M and Cavallari, C and Rivabene, R and Bravo, E}, title = {The effects of dietary n-3 polyunsaturated fatty acids delivered in chylomicron remnants on the transcription of genes regulating synthesis and secretion of very-low-density lipoprotein by the liver: modulation by cellular oxidative state.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {228}, number = {2}, pages = {143-151}, doi = {10.1177/153537020322800203}, pmid = {12563020}, issn = {1535-3702}, mesh = {Acetylcysteine/pharmacology ; Acyltransferases/genetics/metabolism ; Animals ; Apolipoproteins B/genetics/metabolism ; Carrier Proteins/genetics/metabolism ; Cells, Cultured ; Chylomicrons/*administration &amp; dosage/chemistry/metabolism ; Copper Sulfate/pharmacology ; Corn Oil/administration &amp; dosage/chemistry ; Diacylglycerol O-Acyltransferase ; Dietary Fats ; Fatty Acids, Omega-3/*administration &amp; dosage/*metabolism ; Fish Oils/administration &amp; dosage/chemistry ; Free Radical Scavengers/pharmacology ; Hepatocytes/chemistry/cytology/drug effects/*metabolism ; Lipoproteins, VLDL/genetics/*metabolism ; Male ; Oxidation-Reduction ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Wistar ; Sterol O-Acyltransferase/genetics/metabolism ; *Transcription, Genetic ; Sterol O-Acyltransferase 2 ; }, abstract = {The influence of chylomicron remnants enriched in n-3 or n-6 polyunsaturated fatty acids (PUFA) (derived from fish or corn oil, respectively) on the expression of mRNA for four genes involved in the regulation of the synthesis, assembly, and secretion of very-low-density lipoprotein (VLDL) in the liver was investigated in normal rat hepatocytes and after manipulation of the cellular oxidative state by incubation with N-acetyl cysteine (NAC) or CuSO(4). The four genes investigated were those encoding apolipoprotein B (apoB), the microsomal triacylglycerol transfer protein (MTP), and the enzymes acyl coenzyme A:diacylglycerol acyltransferase (DGAT) and acyl coenzyme A:cholesterol acyltransferase 2 (ACAT2), which play a role in the regulation of triacylglycerol and cholesteryl ester synthesis, respectively. mRNA levels for apoB, MTP, and DGAT were unaffected by either fish or corn oil chylomicron remnants, but the amount of ACAT2 mRNA was significantly reduced after incubation of the hepatocytes with fish oil remnants as compared with corn oil remnants or without remnants. These findings indicate that the delivery of dietary n-3 PUFA to hepatocytes in chylomicron remnants downregulates the expression of mRNA for ACAT2, and this may play a role in their inhibition of VLDL secretion. However, when the cells were shifted into a pro-oxidizing or pro-reducing state by pretreatment with CuSO(4) (1 mM) or NAC (5 mM) for 24 hr, levels of mRNA for MTP were increased by about 2- or 4-fold, respectively, by fish oil remnants, whereas corn oil remnants had no significant effect. Fish oil remnants also caused a smaller increase in apoB mRNA in comparison with corn oil remnants in NAC-treated cells (+38%). These changes would be expected to lead to increased VLDL secretion rather than the decrease associated with dietary n-3 PUFA in normal conditions. These findings suggest that relatively minor changes in cellular redox levels can have a major influence on important liver functions such as VLDL synthesis and secretion.}, }
@article {pmid12561536, year = {2002}, author = {Pu, Y and Yin, L and Yuan, H and Liang, G}, title = {[Oxidative stress of cooking oil fume on rat type II lung cells].}, journal = {Wei sheng yan jiu = Journal of hygiene research}, volume = {31}, number = {2}, pages = {85-87}, pmid = {12561536}, issn = {1000-8020}, mesh = {Animals ; Cooking ; *DNA Damage ; Hot Temperature ; Lung/*cytology ; *Oxidative Stress ; *Plant Oils ; Rats ; Smoke/*adverse effects ; }, abstract = {The relationship between the oxidative stress and damages in rat type II lung cells exposed to cooking oil fume (COF) was studied. The cytotoxicity, DNA cross-links and DNA single strand breaks could be observed in the cells exposed to COF. The contents of MDA were increased and GSH were decreased significantly with exposure doses of COF and with time dependence. Pretreatment with antioxidant N-acetylcysteine (NAC) could reduce the toxicity of COF to the cells. The results suggested that cytotoxicity and DNA damages of rat type II lung cells induced by cooking oil fume might be related to the oxidative stress and the possible pathways might be the formation of lipid peroxides and interfering the GSH anti-oxidative systems of the cells.}, }
@article {pmid12560087, year = {2003}, author = {Sumbayev, VV and Budde, A and Zhou, J and Brüne, B}, title = {HIF-1 alpha protein as a target for S-nitrosation.}, journal = {FEBS letters}, volume = {535}, number = {1-3}, pages = {106-112}, doi = {10.1016/s0014-5793(02)03887-5}, pmid = {12560087}, issn = {0014-5793}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; Kidney/cytology/drug effects/metabolism ; Nitric Oxide/chemistry/*metabolism ; Nitric Oxide Donors/chemistry/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors/metabolism ; Nitric Oxide Synthase Type II ; Nitrosation/drug effects ; Oxidation-Reduction/drug effects ; Protein Synthesis Inhibitors/pharmacology ; S-Nitroso-N-Acetylpenicillamine/chemistry/pharmacology ; S-Nitrosoglutathione/chemistry/pharmacology ; Sulfhydryl Compounds/*chemistry/*metabolism ; Transcription Factors/*chemistry/drug effects/*metabolism ; }, abstract = {Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a master regulator to sense decreased oxygen partial pressure. HIF-1 alpha stability regulation initiates a complex biological response that allows cells to act appropriately to meet patho-physiological situations of decreased oxygen availability. Recently, nitric oxide emerged as a messenger with the ability to stabilize HIF-1 alpha and to transactivate HIF-1 under normoxia. Considering that reactive nitrogen species are recognized for post-translation protein modifications, among others S-nitrosation, we asked whether HIF-1 alpha is a target for S-nitrosation. In vitro NO+ donating NO donors such as GSNO and SNAP provoked massive S-nitrosation of purified HIF-1 alpha. All 15 free thiol groups found in human HIF-1 alpha are subjected to S-nitrosation. Thiol modification is not shared by spermine-NONOate, a NO radical donating compound. However, spermine-NONOate in the presence of O(2)(-), generated by xanthine/xanthine oxidase, regained S-nitrosation, most likely via formation of a N(2)O(3)-like species. In vitro, S-nitrosation of HIF-1 alpha was attenuated by the addition of GSH or ascorbate. In RCC4 and HEK293 cells GSNO or SNAP reproduced S-nitrosation of HIF-1 alpha, however with a significantly reduced potency that amounted to modification of three to four thiols, only. Importantly, endogenous formation of NO in RCC4 cells via inducible NO synthase elicited S-nitrosation of HIF-1 alpha that was sensitive to inhibition of inducible NO synthase activity with N-monomethyl-L-arginine. NO-stabilized HIF-1 alpha was susceptible to the addition of N-acetyl-cysteine that destabilized HIF-1 alpha in close correlation to the disappearance of S-nitrosated HIF-1 alpha. In conclusion, HIF-1 alpha is a target for S-nitrosation by exogenously and endogenously produced NO.}, }
@article {pmid12556733, year = {2003}, author = {Lepor, NE}, title = {A review of contemporary prevention strategies for radiocontrast nephropathy: a focus on fenoldopam and N-acetylcysteine.}, journal = {Reviews in cardiovascular medicine}, volume = {4 Suppl 1}, number = {}, pages = {S15-20}, pmid = {12556733}, issn = {1530-6550}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Contrast Media/*adverse effects ; Diabetes Complications ; Dogs ; Dopamine Agonists/*therapeutic use ; Evaluation Studies as Topic ; Fenoldopam/*therapeutic use ; Fluid Therapy/methods ; Free Radical Scavengers/*therapeutic use ; Humans ; *Ischemia ; Kidney Diseases/*chemically induced/complications/*prevention &amp; control ; Kidney Tubules/*blood supply ; Models, Animal ; }, abstract = {The mechanism most likely responsible for the development of radiocontrast nephropathy (RCN) is contrast-induced renal tubular ischemia. At this time, intravenous hydration remains the mainstay for preventing RCN. The antihypertensive agent fenoldopam has been shown in a canine model, as well as in small, retrospective, prospective, and randomized human evaluations, to be effective for preventing RCN. In addition, studies have reported the ability of the free radical scavenger N-acetylcysteine (NAC) to prevent RCN. The clinical trial data for NAC, however, are not consistent regarding this effect, which, if present, appears to be modest and perhaps restricted to lower-risk clinical scenarios.}, }
@article {pmid12552508, year = {2003}, author = {Friedman, AN and Bostom, AG and Laliberty, P and Selhub, J and Shemin, D}, title = {The effect of N-acetylcysteine on plasma total homocysteine levels in hemodialysis: a randomized, controlled study.}, journal = {American journal of kidney diseases : the official journal of the National Kidney Foundation}, volume = {41}, number = {2}, pages = {442-446}, doi = {10.1053/ajkd.2003.50054}, pmid = {12552508}, issn = {1523-6838}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Aged ; Dietary Supplements ; Female ; Homocysteine/*blood ; Humans ; Male ; Middle Aged ; Renal Dialysis/*methods ; Vitamins/administration &amp; dosage ; }, abstract = {BACKGROUND: The chronic hemodialysis population has an accelerated rate of cardiovascular morbidity and death. Furthermore, elevated levels of the putative atherothrombotic risk factor homocysteine are almost ubiquitous in this population. Attempts to normalize elevated plasma total homocysteine (tHcy) levels in dialysis patients using pharmacological-dose vitamin therapy or other strategies generally have been unsuccessful. Preliminary uncontrolled evidence suggests that N-acetylcysteine (NAC) may be an effective tHcy-lowering agent. We designed a randomized placebo-controlled study to determine the effect of prolonged oral NAC therapy on lowering tHcy levels in vitamin-replete chronic hemodialysis patients.<br><br>METHODS: Thirty-eight subjects were treated before intervention with a standard dialysis vitamin supplement to ensure a uniform vitamin-replete state. They were then block randomized to treatment with NAC, 1.2 g twice a day, for 4 weeks or matched placebo.<br><br>RESULTS: There were no significant baseline differences between the two groups, although differences in pyridoxal 5'-phosphate (active form of vitamin B(6)) levels approached significance (P = 0.06). In a paired analysis, there was no statistically significant difference between the NAC and placebo groups. NAC was very well tolerated in hemodialysis patients.<br><br>CONCLUSION: This randomized placebo-controlled trial found that chronic oral NAC therapy did not significantly reduce tHcy levels in hemodialysis patients. Although a larger sample size theoretically could have increased the statistical significance between groups, implications of the potentially very modest reduction in tHcy levels are not yet known. Finally, based on this limited study, NAC appears to be a safe and well-tolerated therapy in the hemodialysis population.}, }
@article {pmid12548218, year = {2003}, author = {Buhimschi, IA and Buhimschi, CS and Weiner, CP}, title = {Protective effect of N-acetylcysteine against fetal death and preterm labor induced by maternal inflammation.}, journal = {American journal of obstetrics and gynecology}, volume = {188}, number = {1}, pages = {203-208}, doi = {10.1067/mob.2003.112}, pmid = {12548218}, issn = {0002-9378}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Female ; Fetal Death/etiology/*prevention &amp; control ; Gestational Age ; Glutathione/analysis ; Inflammation/chemically induced/*complications ; Kinetics ; Lipopolysaccharides/administration &amp; dosage ; Liver/chemistry/drug effects ; Mice ; Mice, Inbred C57BL ; Obstetric Labor, Premature/etiology/*prevention &amp; control ; Oxidation-Reduction ; Pregnancy ; *Pregnancy Complications ; }, abstract = {OBJECTIVE: Intrauterine and maternal systemic infections are proposed causes of preterm labor. The resulting prematurity is associated with 75% of infant mortality and 50% of long-term neurologic handicaps. We hypothesize that free radicals generated in large quantities during an inflammatory response shift the fetomaternal redox balance to an oxidative state, compromising the fetus. Thus, if our working hypothesis is correct, selective inactivation of free radicals with N-acetylcysteine (NAC), an antioxidant and glutathione (GSH) precursor, would improve the outcome of preterm deliveries associated with inflammation. We tested aspects of this hypothesis in an animal model of preterm labor and fetal damage (death).<br><br>STUDY DESIGN: NAC (1 g/kg) was administered orally to C57Bl/6 mice injected intraperitoneally with either 10 microg lipopolysaccharide (LPS) or saline solution (CRL) on day 16 of gestation. The latency period (time from injection to delivery of the first pup) and fetal viability were recorded. To discriminate between an effect of prematurity from an effect of inflammation, and to document any improvement in survival, mice were killed at 3, 6, and 16 hours after injection. Maternal and fetal redox states were approximated by measuring hepatic GSH.<br><br>RESULTS: Each C57Bl/6 LPS-treated mouse delivered prematurely after a significantly shorter latency period (LPS: 16.8 hours [95% CI 15.9-17.6] vs CRL: 54.7 hours [95% CI 43.8-65.5]). NAC doubled the latency interval of LPS-treated animals to 35.2 hours (95% CI 21.0-49.2). LPS alone resulted in a 100% rate of stillbirth. Fifty-eight percent of fetuses were already dead 16 hours after LPS. In contrast, only 33% of fetuses were dead 16 hours after LPS (P =.001) when NAC was given. LPS was followed by a reduction in maternal (LPS: 26.3 nmol/mg [95% CI 19.9-32.8] vs CRL: 41.3 nmol/mg [95% CI 34.7-47.9, P <.01]) and fetal GSH (LPS: 19.7 nmol/mg [95% CI 11.7-27.8] vs CRL: 34.5 nmol/mg [95% CI 32.0-37.0, P <.001]). This decline was reversed by NAC (NAC/LPS maternal GSH: 37.0 nmol/mg [95% CI 22.5-51.5] and fetal GSH: 28.4 nmol/mg [95% CI 22.8-33.9]). Importantly, maternal liver GSH impacted on fetal survival. NAC/LPS mothers with living pups 16 hours after LPS had significantly higher liver GSH compared with NAC/LPS mothers whose pups died in utero. In fact, all NAC-treated mice whose hepatic GSH exceeded 20 nmol/mg had living fetuses at 16 hours.<br><br>CONCLUSION: Maternal inflammation in C57Bl/6 mice results in oxidative stress associated with maternal and fetal GSH depletion. Oxidative stress damages the fetus independent of prematurity. Restoration of maternal and fetal oxidative balance by NAC protects the fetus and reduces the rate of preterm birth.}, }
@article {pmid12544450, year = {2003}, author = {Girouard, H and Chulak, C and LeJossec, M and Lamontagne, D and de Champlain, J}, title = {Chronic antioxidant treatment improves sympathetic functions and beta-adrenergic pathway in the spontaneously hypertensive rats.}, journal = {Journal of hypertension}, volume = {21}, number = {1}, pages = {179-188}, doi = {10.1097/00004872-200301000-00028}, pmid = {12544450}, issn = {0263-6352}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adenylyl Cyclases/metabolism ; Adrenergic beta-Agonists/pharmacology ; Animals ; Antioxidants/*administration &amp; dosage ; Aorta/drug effects ; Binding Sites/drug effects ; Binding, Competitive ; Blood Pressure/drug effects ; Catecholamines/blood ; Drug Administration Schedule ; Heart Rate/drug effects ; Hypertension/*physiopathology ; In Vitro Techniques ; Isoproterenol/pharmacology ; Male ; Melatonin/*administration &amp; dosage ; Mesenteric Arteries/drug effects ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Receptors, Adrenergic, beta/drug effects/*metabolism ; Sympathetic Nervous System/drug effects/*physiopathology ; }, abstract = {BACKGROUND: Correlations have been found between oxidative stress and hypertension.<br><br>OBJECTIVE: To determine whether antioxidants can normalize sympathetic dysfunction at pre- or postsynaptic levels in spontaneously hypertensive rats (SHRs).<br><br>METHODS AND RESULTS: Untreated SHRs and Wistar-Kyoto (WKY) rats were compared with rats treated with melatonin (30 mg/kg per day) or N-acetylcysteine (NAC) (4 g/kg per day) given in drinking water for 4 weeks. At the presynaptic level, SHRs had greater plasma noradrenaline concentrations (P <0.01) and an enhanced release of [3H]noradrenaline from isolated atria (P <0.001). At the postsynaptic level, they exhibited an increased proportion of beta2-adrenoceptors in the heart (P <0.001)and a decrease in the chronotropic and mean arterial pressure (MAP) responses to isoproterenol (P <0.001). Melatonin and NAC decreased MAP (P <0.001) and heart rate (P <0.05), and restored the plasma noradrenaline concentrations (P<0.01 and P <0.001, respectively), the chronotropic response to isoproterenol (P <0.05) and the proportions of beta(1)/beta(2)-adrenoceptors in the heart (P <0.05) in SHRs to the levels found in WKY rats. The same treatments decreased the release of [3H]noradrenaline from isolated atria (P <0.05), and melatonin slightly improved the relaxation in the aorta in SHRs only (P <0.05). Plasma concentrations of adrenaline, the isoproterenol-induced relaxation in mesenteric arteries, the total density and affinity of beta-adrenoceptors in the heart, and the adenylate cyclase reactivity of cardiac membranes to isoproterenol, forskolin, sodium fluoride and guanylylimidophosphate were not altered by the treatments.<br><br>CONCLUSION: These results suggest that NAC and melatonin decreased the MAP and heart rate and improved the chronotropic response to isoproterenol in SHRs, in association with an inhibition of sympathetic activity and the restoration of cardiac beta-adrenoceptor function.}, }
@article {pmid12540627, year = {2003}, author = {Odetti, P and Pesce, C and Traverso, N and Menini, S and Maineri, EP and Cosso, L and Valentini, S and Patriarca, S and Cottalasso, D and Marinari, UM and Pronzato, MA}, title = {Comparative trial of N-acetyl-cysteine, taurine, and oxerutin on skin and kidney damage in long-term experimental diabetes.}, journal = {Diabetes}, volume = {52}, number = {2}, pages = {499-505}, doi = {10.2337/diabetes.52.2.499}, pmid = {12540627}, issn = {0012-1797}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anticoagulants/pharmacology ; Blood Glucose/metabolism ; Collagen/metabolism ; Diabetes Mellitus, Experimental/blood/*pathology ; Diabetic Angiopathies/pathology ; Hydroxyethylrutoside/*analogs &amp; derivatives/*pharmacology ; Kidney/drug effects/*pathology ; Male ; Rats ; Rats, Wistar ; Skin/drug effects/*pathology ; Taurine/*pharmacology ; Time Factors ; }, abstract = {This study analyzes the effect of chronic treatment with different antioxidants (N-acetyl-cysteine [NAC], taurine, a combination of NAC and taurine, and oxerutin) on long-term experimental diabetes induced by streptozotocin in rats. Glycoxidative damage was evaluated in the skin; glomerular structural changes were studied with morphometry and immunohistochemistry. Oxerutin treatment and the combined NAC plus taurine treatment resulted in reduced accumulation of collagen-linked fluorescence in skin in comparison with untreated diabetic rats. All treatments except taurine reduced glomerular accumulation of N(epsilon)-(carboxymethyl)lysine and protected against the increase in glomerular volume typical of diabetes; furthermore, the apoptosis rate was significantly decreased and the glomerular cell density was better preserved. Glycoxidative markers in the skin turned out to be good indicators of the glomerular condition. The findings that emerged from our study support the hypothesis that glomerular damage in diabetes can be prevented or at least attenuated by supplementation with specific antioxidants. Treatment with oxerutin and combined treatment with NAC plus taurine gave the most encouraging results, whereas the results of taurine-only treatment were either negligible or negative and therefore suggest caution in the use of this molecule in single-drug treatment courses.}, }
@article {pmid12538039, year = {2003}, author = {Víctor, VM and Rocha, M and De la Fuente, M}, title = {Regulation of macrophage function by the antioxidant N-acetylcysteine in mouse-oxidative stress by endotoxin.}, journal = {International immunopharmacology}, volume = {3}, number = {1}, pages = {97-106}, doi = {10.1016/s1567-5769(02)00232-1}, pmid = {12538039}, issn = {1567-5769}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Chemotaxis/drug effects ; Female ; Glutathione/metabolism ; Lipopolysaccharides/*pharmacology ; Macrophages, Peritoneal/*drug effects/immunology/*metabolism ; Mice ; Oxidative Stress/*drug effects ; Phagocytosis/drug effects ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Changes in several functions of peritoneal macrophages from mice with oxidative stress caused by intraperitoneal injection of endotoxin (Escherichia coli lipopolysaccharide, LPS) (100 mg/kg), and associated with a high production of reactive oxygen species (ROS), have been observed in our previous studies. Antioxidants such as N-acetylcysteine (NAC) are free radical scavengers that improve and modulate the immune response, especially in oxidative stress situations. Therefore, in the present work, we have studied the effects of the administration of NAC (150 mg/kg i.p.) on different functions of peritoneal macrophages from Swiss mice suffering that oxidative stress, caused by LPS (100 mg/kg). NAC was injected 30 min after LPS injection, and the peritoneal macrophages were obtained at 2, 4, 12, and 24 h after endotoxin injection. The following functions, key stages of the phagocytic process, were studied: adherence to substrate, chemotaxis, ingestion of particles, and production of ROS (reactive oxygen species), as well as tumor necrosis factor (TNFalpha) release. The decrease in chemotaxis and the increase in adherence, ingestion, superoxide anion production, and TNFalpha release shown by macrophages from animals with oxidative stress were counteracted by NAC injection. These data suggest that NAC administration may be useful for the treatment of oxidative stress-linked endotoxic shock, modulating the function of macrophages, specifically in decreasing the production of ROS and of inflammatory cytokines such as TNFalpha.}, }
@article {pmid12537522, year = {2003}, author = {Kuin, A and Kruse, JJ and Stewart, FA}, title = {Proteinuria and vascular changes after renal irradiation: the role of reactive oxygen species (ROS) and vascular endothelial growth factor (Vegf).}, journal = {Radiation research}, volume = {159}, number = {2}, pages = {174-181}, doi = {10.1667/0033-7587(2003)159[0174:pavcar]2.0.co;2}, pmid = {12537522}, issn = {0033-7587}, mesh = {Angiogenesis Inducing Agents/genetics/*metabolism ; Animals ; Catalase/administration &amp; dosage/metabolism ; Female ; Kidney/*blood supply/metabolism/pathology/*radiation effects ; Mice ; Mice, Inbred C3H ; Oxidation-Reduction ; Protein Isoforms/genetics/metabolism ; Proteinuria/*blood/drug therapy/genetics/urine ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/administration &amp; dosage/metabolism ; Time Factors ; *Vascular Endothelial Growth Factor A ; }, abstract = {Proteinuria occurs in all degrees of radiation nephropathy and can be present without other symptoms. In this study, radiation-induced proteinuria in C3H mice demonstrated a clear dose-response relationship and was apparent before the onset of significant structural vascular changes and decreases in renal function. This suggests that proteinuria is not a secondary event due to loss of the vascular structure. In an attempt to ameliorate radiation-induced proteinuria and progressive renal failure, two factors were studied. The influence of reactive oxygen species (ROS), which are generated by infiltrating neutrophils and mediate proteinuria in models of acute glomerular injury, was the first to be investigated. Short-term administration of the reactive oxygen scavengers superoxide dismutase (SOD) and catalase did not reverse an established radiation-induced proteinuria. Continuous administration of the antioxidant N-acetylcysteine (NAC) also failed to inhibit this proteinuria. However, since no direct assessment of the impact of these interventions on renal redox status was made, the putative role of ROS in radiation-induced proteinuria and nephropathy remains undefined. The second factor studied was vascular endothelial growth factor (Vegf), which is suggested to be involved in glomerular vessel permeability and the development of proteinuria in some models of renal disease. Northern blot analysis of mRNA from whole kidneys did not demonstrate any increased expression of Vegf after irradiation. There was also no change in the ratio of the different Vegf isoforms (PCR analysis), either in the whole kidney or in isolated glomeruli. No significant role for Vegf was identified for radiation-induced vascular changes or proteinuria, although post-transcriptional changes cannot be excluded.}, }
@article {pmid12535868, year = {2003}, author = {Gaillard, PJ and de Boer, AB and Breimer, DD}, title = {Pharmacological investigations on lipopolysaccharide-induced permeability changes in the blood-brain barrier in vitro.}, journal = {Microvascular research}, volume = {65}, number = {1}, pages = {24-31}, doi = {10.1016/s0026-2862(02)00009-2}, pmid = {12535868}, issn = {0026-2862}, mesh = {Animals ; Astrocytes/drug effects/physiology ; Blood-Brain Barrier/*drug effects/physiology ; Brain/blood supply ; Capillary Permeability/drug effects/physiology ; Cattle ; Cycloheximide/pharmacology ; Dexamethasone/pharmacology ; Endothelium, Vascular/cytology/drug effects/physiology ; Free Radicals/metabolism ; In Vitro Techniques ; Lipopolysaccharides/*toxicity ; Protein Synthesis Inhibitors/pharmacology ; Tight Junctions/drug effects/physiology ; Transcription, Genetic/drug effects ; }, abstract = {Lipopolysaccharide-induced changes in blood-brain barrier (BBB) permeability were investigated with a pharmacological approach in vitro. Lipopolysaccharide induced a concentration- and time-dependent (non)reversible opening of the BBB, and brain astrocytes make brain capillary endothelial cells (BCEC) resistant to this BBB disruption. De novo protein synthesis was essential for the recovery, because cycloheximide prevented the recovery process. Dexamethasone pretreated BCEC were more resistant to lipopolysaccharide, while no protective response was induced by heat shock nor by inhibition of P-glycoprotein. BBB opening was tempered by free radical inhibitors (i.e., pretreatment with N-acetyl-cysteine or uric acid combined with deferroxamine mesylate). No effects of modulators of prostanoid-, leukotriene-, or platelet-activating factor pathways were observed. Therefore, lipopolysaccharide-induced BBB opening seems to be primarily mediated by excessive free radical production.}, }
@article {pmid12527565, year = {2003}, author = {Dragnev, KH and Stover, D and Dmitrovsky, E and , }, title = {Lung cancer prevention: the guidelines.}, journal = {Chest}, volume = {123}, number = {1 Suppl}, pages = {60S-71S}, doi = {10.1378/chest.123.1_suppl.60s}, pmid = {12527565}, issn = {0012-3692}, support = {R01 CA 62275/CA/NCI NIH HHS/United States ; R01 CA 87546/CA/NCI NIH HHS/United States ; }, mesh = {*Anticarcinogenic Agents/administration &amp; dosage ; Cell Transformation, Neoplastic/pathology ; Chemoprevention/*methods ; Humans ; Lung Neoplasms/etiology/*prevention &amp; control ; Smoking/adverse effects ; Smoking Cessation ; }, abstract = {Lung carcinogenesis is a chronic and multi-step process resulting in malignant lung tumors. This progression from normal to neoplastic pulmonary cells or tissues could be arrested or reversed through pharmacologic treatments, which are known as cancer chemoprevention. These therapeutic interventions should reduce or avoid the clinical consequences of lung cancer by treating early neoplastic lesions before the development of clinically evident signs or symptoms of malignancy. Preclinical, clinical, and epidemiologic findings relating to different classes of candidate chemopreventive agents provide strong support for lung cancer prevention as an attractive therapeutic strategy. Smoking prevention and smoking cessation represent an essential approach to reduce the societal impact of tobacco carcinogenesis. However, even if all the goals of the national antismoking efforts were met, there still would be a large population of former smokers who would be at increased risk for lung cancers. Lung cancer also can occur in those persons who never have smoked. This article focuses on what is now known about pharmacologic strategies for lung cancer prevention. Randomized clinical trials using beta-carotene, retinol, isotretinoin or N-acetyl-cysteine did not show benefit for primary and tertiary lung cancer prevention. There is also evidence that the use of beta-carotene and isotretinoin for lung cancer chemoprevention in high-risk individuals may increase the risk for lung cancer, especially in individuals who continue to smoke. There is a need for relevant in vitro models to identify pathways that activate chemopreventive effects in the lung. An improved understanding of cancer prevention mechanisms should aid in the design of clinical trials and in the validation of candidate chemopreventive targets as well as the discovery of new targets. Until such studies are completed, no agent or combination of agents should be used for lung cancer prevention outside of a clinical trial.}, }
@article {pmid12524169, year = {2003}, author = {Zhang, Q and Zhang, G and Meng, F and Tian, H}, title = {Biphasic activation of apoptosis signal-regulating kinase 1-stress-activated protein kinase 1-c-Jun N-terminal protein kinase pathway is selectively mediated by Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors involving oxidative stress following brain ischemia in rat hippocampus.}, journal = {Neuroscience letters}, volume = {337}, number = {1}, pages = {51-55}, doi = {10.1016/s0304-3940(02)01295-8}, pmid = {12524169}, issn = {0304-3940}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Brain Ischemia/enzymology/*metabolism ; Calcium/*metabolism ; Calcium Channel Blockers/pharmacology ; Calcium Channels, L-Type/drug effects/metabolism ; Enzyme Activation ; Hippocampus/*metabolism ; Ion Channel Gating ; JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase Kinase 5 ; MAP Kinase Kinase Kinases/*metabolism ; Male ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinases/*metabolism ; Nifedipine/pharmacology ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/antagonists &amp; inhibitors/*metabolism ; Spermine/*analogs &amp; derivatives/pharmacology ; }, abstract = {Stress-activated protein kinase/extracellular signal-regulated kinase-1 (SEK1/MKK4) was examined in a rat model of global brain ischemia. Western blot assay showed that SEK1 activation was biphasic in CA1 but not CA3/dentate gyrus. The second activation peak (3 days after ischemia) was prevented by pretreatment with l-naphthyl acetyl spermine (Naspm), a channel blocker of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, or N-acetylcysteine (NAC), a free radical scavenger. Concomitantly, the late activation of apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal protein kinase (JNK) was also prevented by Naspm or NAC. Moreover, phospho-SEK1 and phospho-JNK co-immunoprecipitated with ASK1 and the bindings peaked at 3 days of reperfusion. Together with previous results, these findings indicate that Ca(2+)-permeable AMPA receptors are important routes to mediate the late activation of ASK1-SEK1-JNK pathway involving oxidative stress in hippocampal CA1 region after ischemia.}, }
@article {pmid12521669, year = {2003}, author = {Labib, R and Abdel-Rahman, MS and Turkall, R}, title = {N-acetylcysteine pretreatment decreases cocaine and endotoxin-induced hepatotoxicity.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {66}, number = {3}, pages = {223-239}, doi = {10.1080/15287390306370}, pmid = {12521669}, issn = {1528-7394}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cocaine/*metabolism/pharmacokinetics/*toxicity ; Endotoxins/*toxicity ; Lipopolysaccharides/*toxicity ; Liver/metabolism/*pathology ; Liver Function Tests ; Male ; Mice ; Oxidation-Reduction ; }, abstract = {Cocaine produces hepatotoxicity by a mechanism that remains undefined but has been linked to its oxidative metabolism. Endotoxin (lipopolysaccharide, LPS) is also a well-known cause of hepatic damage, and exposure to noninjurious doses of LPS increases the toxicity of certain hepatotoxins. Previously it was demonstrated that exposure to noninjurious doses of LPS dramatically increases cocaine-mediated hepatotoxicity (CMH). This study was conducted to investigate whether pretreatment with N-acetylcysteine (NAC), a glutathione (GSH) precursor and an antioxidant agent, inhibits LPS potentiation of CMH. For 5 consecutive days, male CF-1 mice were administered daily oral NAC (200 mg/kg) or sterile saline followed an hour later by cocaine (20 mg/kg) or sterile saline. Four hours following the last cocaine or saline treatment, the mice were administered 12 x 10(6) EU LPS/kg or sterile saline. For the cocaine alone and cocaine and LPS groups, NAC pretreatment significantly decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities with absence of necrotic hepatic lesions, indicating a reduction of liver injury. In addition, in all groups pretreated with NAC, hepatic GSH concentration was significantly increased, as were hepatic and blood glutathione peroxidase (GPx) and catalase (CAT) activities. In conclusion, the results demonstrate that NAC pretreatment exerted a protective effect against LPS potentia-tion of CMH.}, }
@article {pmid12519694, year = {2003}, author = {Venhorst, J and Rooseboom, M and Vermeulen, NP and Commandeur, JN}, title = {Studies on the inhibition of human cytochromes P450 by selenocysteine Se-conjugates.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {33}, number = {1}, pages = {57-72}, doi = {10.1080/0049825021000022357}, pmid = {12519694}, issn = {0049-8254}, mesh = {Acetylation ; Binding, Competitive ; Cytochrome P-450 CYP1A1/antagonists &amp; inhibitors/metabolism ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/*metabolism ; Fluorescent Dyes ; Humans ; Isoenzymes/antagonists &amp; inhibitors/metabolism ; Kinetics ; Selenium/*metabolism ; Selenocysteine/chemical synthesis/*metabolism/pharmacology ; }, abstract = {1. To investigate whether cytochrome P450 (P450) inhibition can contribute to the chemopreventive activity of selenocysteine Se-conjugates (SeCys conjugates), 21 SeCys conjugates were screened for their inhibitory potency towards seven of the most important human P450s. 2. The majority of the SeCys conjugates produced near complete inhibition of CYP1A1 at a concentration of 250 microm. The most potent inhibitor, Se-benzyl-L-selenocysteine, displayed an IC50 of 12.8 +/- 1.2 microm. CYP2C9, -2C19 and -2D6 were moderately (50-60%) inhibited by the SeCys conjugates. CYP1A2, -2E1 and -3A4 were least inhibited. 3. Studies on the susceptibility of CYP1A1 to SeCys conjugates implicated a thiol-reactive intermediate, as evidenced by reduced inhibition levels in the presence of glutathione and N-acetyl cysteine. Uncoupling of the P450-catalytic cycle was of no importance as ROS scavengers did not influence inhibition levels. 4. P450 inhibition by two physiologically relevant metabolite classes of SeCys conjugates was also studied. N-acetylation of SeCys conjugates consistently increased the inhibitory potency towards CYP1A2, -2C19, -2E1 and -3A4. Beta-lyase catalysed bioactivation of alkyl-substituted SeCys conjugates or Se-benzyl-L-selenocysteine produced little or no additional inhibition of P450 activity. For Se-phenyl-L-selenocysteine, however, significant increases in P450 inhibition were obtained by beta-lyase pre-incubation. 5. It is concluded that the potent and relatively selective CYP1A1 inhibition exerted by SeCys conjugates may contribute to their chemopreventive activity.}, }
@article {pmid12518892, year = {2002}, author = {Love, RM and Branton, RL and Karlsson, J and Brundin, P and Clarke, DJ}, title = {Effects of antioxidant pretreatment on the survival of embryonic dopaminergic neurons in vitro and following grafting in an animal model of Parkinson's disease.}, journal = {Cell transplantation}, volume = {11}, number = {7}, pages = {653-662}, doi = {10.3727/000000002783985431}, pmid = {12518892}, issn = {0963-6897}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Cells, Cultured ; Chromans/pharmacology ; Disease Models, Animal ; Dopamine/metabolism ; Drug Combinations ; Female ; Fetus ; Glutathione/pharmacology ; Graft Survival/*drug effects/physiology ; Male ; Neurons/cytology/*drug effects/metabolism ; Oxidopamine/pharmacology ; Parkinsonian Disorders/*therapy ; Piperazines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Stem Cell Transplantation/*methods/trends ; Stem Cells/cytology/*drug effects/metabolism ; Substantia Nigra/cytology/*drug effects/transplantation ; }, abstract = {The effect of pretreating cell suspensions of embryonic rat ventral mesencephala (VM) with antioxidant combinations on the survival of dopaminergic (DA) neurons was studied in vitro and following transplantation into the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease. The in vitro experiments examined the effects of two thiol antioxidants, N-acetyl-L-cysteine (NAC) and reduced glutathione (GSH), and a member of the lazaroid family of 21-aminosteroids, U-83836E, singly and in combination, on survival of DA neurons derived from dissociated E14 rat VM tissue. For in vivo studies, cell suspensions were pretreated with combinations of NAC, GSH, and U-83836E prior to transplanting into 6-OHDA-lesioned rats to investigate whether DA neuron survival could be further improved. NAC, GSH, and U-83836E individually increased DA neuron survival in vitro and a combination of all three resulted in the greatest survival. In vivo, pretreatment with U-83836E alone resulted in a significantly greater reduction in amphetamine-induced rotation 6 weeks postgrafting compared with a control group receiving nontreated graft tissue. This functional effect correlated with a significant improvement in DA neuron survival 6 weeks postgrafting. The thiol combination pretreatment of NAC and GSH, and the triple combination of NAC, GSH, and U-83836E, however, failed to improve both functional recovery and DA neuron survival when compared with the nontreated control grafts.}, }
@article {pmid12517395, year = {2003}, author = {Ali, AA and Bilodeau, JF and Sirard, MA}, title = {Antioxidant requirements for bovine oocytes varies during in vitro maturation, fertilization and development.}, journal = {Theriogenology}, volume = {59}, number = {3-4}, pages = {939-949}, doi = {10.1016/s0093-691x(02)01125-1}, pmid = {12517395}, issn = {0093-691X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Blastocyst/drug effects/physiology ; Catalase/pharmacology ; Cattle/*embryology ; Cells, Cultured ; Culture Media/chemistry ; Cysteine/pharmacology ; Embryonic and Fetal Development/*drug effects ; Fertilization in Vitro/veterinary ; Free Radical Scavengers/metabolism ; Morula/drug effects/physiology ; Oocytes/*drug effects/physiology ; Reactive Oxygen Species ; Superoxide Dismutase/pharmacology ; }, abstract = {Antioxidants may be beneficial additives to synthetic culture media because these well defined media lack serum or other macromolecules that serve as reactive oxygen species scavengers. In this study, three separate experiments were performed to determine the effects of antioxidants on the development of oocytes to the morula and blastocyst stage when added during in vitro maturation (IVM) of bovine oocytes, during in vitro fertilization (IVF), and during embryo culture for the first 72 h of the development period. Bovine oocytes were matured, fertilized (under 20% O(2)), and embryos were cultured (under 7% O(2)) in defined conditioned medium in vitro with or without supplementation with the antioxidant cysteine, N-acetyl-L-cysteine (NAC), catalase and superoxide dismutase (SOD). Significant improvements in the proportion of oocytes undergoing morula and blastocyst development (33.3% versus 20.3%, P<0.05) were achieved when cysteine (0.6 mM) was added to the maturation medium as compared to control medium without antioxidant supplementation. However, the addition of NAC (0.6mM), catalase (5 or 127 U/ml) or SOD (10 or 1000 U/ml) to the maturation medium did not improve the proportion of oocytes undergoing morula and blastocyst development. During the IVF period, addition of antioxidants (cysteine or NAC 0.6mM, catalase 127U/ml, SOD 100U/ml) significantly reduced the subsequent rate of bovine embryo development to the morula and blastocyst stage (P<0.05). In a defined medium for embryo culture (7% O(2)), the addition of cysteine improved the development of bovine embryos while NAC, catalase and SOD had no positive effect on embryonic development. Our study showed that medium supplementation with cysteine during IVM and in vitro culture (IVC) improved the rate of bovine embryo development, in contrast to extracellular antioxidants like catalase and SOD that caused no improvement.}, }
@article {pmid12512991, year = {2002}, author = {Aydin, S and Ozaras, R and Uzun, H and Belce, A and Uslu, E and Tahan, V and Altug, T and Dumen, E and Senturk, H}, title = {N-acetylcysteine reduced the effect of ethanol on antioxidant system in rat plasma and brain tissue.}, journal = {The Tohoku journal of experimental medicine}, volume = {198}, number = {2}, pages = {71-77}, doi = {10.1620/tjem.198.71}, pmid = {12512991}, issn = {0040-8727}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism ; Brain/*metabolism ; Catalase/metabolism ; Erythrocytes/metabolism ; Ethanol/*antagonists &amp; inhibitors/*pharmacology ; Free Radical Scavengers/*pharmacology ; Glutathione Peroxidase/metabolism ; Male ; Malondialdehyde/metabolism ; Nitric Oxide/metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {Chronic ethanol administration is able to induce an oxidative stress in the central nervous system. N-Acetylcysteine (NAC) has antioxidant properties; as a sulphydryl donor, it contributes to the regeneration of glutathione and it acts through a direct reaction with hydroxyl radicals. In this study we investigated a possible beneficial effect of NAC on some of the free radical related parameters. Twenty four male Wistar rats were divided in to three groups and were given ethanol (Group 1), ethanol and NAC (Group 2) and isocaloric dextrose (Group 3). Ethanol and NAC were given intragastrically at doses of 6 g/kg/day and 1 g/kg/day, respectively. Our results show that chronic ethanol intake elicits statistically significant increase in MDA and NO levels and decrease in SOD and GSH levels in both plasma and brain (p < 0.001). GPx levels decreased in erythrocytes (p < 0.001). CAT activity showed significant decrease only in brain samples (p < 0.001). NAC administration effectively restores the above results to nearly normal levels. Therefore we suggest that reactive free radicals are, at least partly, involved in the ethanol-induced injury of brain cells and NAC mitigate the toxic effects of ethanol on the oxidant-antioxidant system of rat plasma and brain.}, }
@article {pmid12506132, year = {2003}, author = {Townsend, DM and Deng, M and Zhang, L and Lapus, MG and Hanigan, MH}, title = {Metabolism of Cisplatin to a nephrotoxin in proximal tubule cells.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {14}, number = {1}, pages = {1-10}, pmid = {12506132}, issn = {1046-6673}, support = {R01 CA057530/CA/NCI NIH HHS/United States ; R01CA57530/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/administration &amp; dosage/*adverse effects/*metabolism ; Carbon-Sulfur Lyases/antagonists &amp; inhibitors ; Cisplatin/administration &amp; dosage/*adverse effects/analogs &amp; derivatives/*metabolism ; Drug Administration Schedule ; Drug Synergism ; Kidney Tubules, Proximal/cytology/*drug effects/*metabolism ; LLC-PK1 Cells ; Swine ; gamma-Glutamyltransferase/antagonists &amp; inhibitors/metabolism ; }, abstract = {Cisplatin, a commonly used chemotherapeutic agent, is nephrotoxic. The mechanism by which cisplatin selectively kills the proximal tubule cells was heretofore unknown. Recent studies in mice and rats have shown that the nephrotoxicity of cisplatin can be blocked by acivicin or (aminooxy)acetic acid, the same enzyme inhibitors that block the metabolic activation of a series of nephrotoxic halogenated alkenes. In this study, it was hypothesized that cisplatin is activated in the kidney to a toxic metabolite through the same pathway that has been shown to activate the halogenated alkenes. This activation begins with the formation of a glutathione-conjugate that is metabolized to a cysteinyl-glycine-conjugate, to a cysteine-conjugate, and finally to a reactive thiol. In this study, a protocol was developed in which confluent monolayers of LLC-PK(1) cells were exposed to clinically relevant concentrations of cisplatin or cisplatin-conjugate for 3 h. Cell viability was assayed at 72 h. The role of gamma-glutamyl transpeptidase (GGT) and cysteine-S-conjugate beta-lyase in the metabolism of each of the cisplatin-conjugates was investigated. Pre-incubation of cisplatin with glutathione, cysteinyl-glycine, or N-acetyl-cysteine to allow for the spontaneous formation of cisplatin-conjugates increased the toxicity of cisplatin toward LLC-PK(1) cells. Inhibition of GGT activity showed that GGT was necessary only for the toxicity of the cisplatin-glutathione-conjugate. Inhibition of cysteine-S-conjugate beta-lyase reduced the toxicity of each of the cisplatin-conjugates. These data demonstrate that metabolism of cisplatin in proximal tubule cells is required for its nephrotoxicity. The elucidation of this pathway provides new targets for the inhibition of cisplatin nephrotoxicity.}, }
@article {pmid12504894, year = {2003}, author = {Fan, X and Subramaniam, R and Weiss, MF and Monnier, VM}, title = {Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation.}, journal = {Archives of biochemistry and biophysics}, volume = {409}, number = {2}, pages = {274-286}, doi = {10.1016/s0003-9861(02)00599-4}, pmid = {12504894}, issn = {0003-9861}, support = {DK 9900020/DK/NIDDK NIH HHS/United States ; DK45619/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Cattle ; Dose-Response Relationship, Drug ; Enzyme Activation ; MAP Kinase Kinase Kinase 3 ; MAP Kinase Kinase Kinases/metabolism ; Macrophages/*metabolism ; Mice ; Mitogen-Activated Protein Kinases/drug effects/*metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Protein Kinase C/drug effects/metabolism ; Pyruvaldehyde/*pharmacology ; Reactive Oxygen Species/antagonists &amp; inhibitors/*metabolism ; Serum Albumin, Bovine/*pharmacology ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*metabolism ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Accumulating evidence suggests that the pathophysiology of diabetes is analogous to chronic inflammatory states. Circulating levels of inflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNFalpha) are increased in both type 1 and type 2 diabetes. TNFalpha plays an important role in the pathogenesis of insulin resistance in type 2 diabetes. However, the reason for this increase remains unclear. Levels of the dicarbonyl methylglyoxal (MGO) are elevated in diabetic plasma and MGO-modified bovine serum albumin (MGO-BSA) can trigger cellular uptake of TNF. Therefore we tested the hypothesis that MGO-modified proteins may cause TNFalpha secretion in macrophage-like RAW 264.7 cells. Treatment of cells with MGO-BSA induced TNFalpha release in a dose-dependent manner. MGO-modified ribonuclease A and chicken egg ovalbumin had similar effects. Cotreatment of cells with antioxidant reagent N-acetylcysteine (NAC) inhibited MGO-BSA-induced TNFalpha secretion. MGO-BSA stimulated the simultaneous activation of p44/42 and p38 mitogen-activated protein kinase. PD98059, a selective MEK inhibitor, inhibited MGO-BSA-induced TNFalpha release as well as ERK phosphorylation. Pretreatment of cells with NAC also resulted in inhibition of MGO-BSA-induced ERK phosphorylation. MGO-BSA induced dose-dependent NFkappaB activation as shown by electrophoresis mobility shift assay. The MGO-BSA-induced NFkappaB activation was prevented in the presence of PD98059, NAC, and parthenolide, a selective inhibitor of NFkappaB. Furthermore, the NFkappaB inhibitor parthenolide suppressed MGO-BSA-induced TNFalpha secretion. Confocal microscopy using dichlorofluorescein to demonstrate intracellular reactive oxygen species (ROS) showed that MGO-BSA produced more ROS compared with native BSA. MGO-BSA could also stimulate protein kinase C (PKC) translocation to the cell membrane, considered a key signaling pathway in diabetes. However, there was no evidence that PKC was involved in TNFalpha release based on inhibition by calphostin C and staurosporine. Our findings suggest that the presence of chronically elevated levels of MGO-modified bovine serum albumin may contribute to elevated levels of TNFalpha in diabetes.}, }
@article {pmid12504821, year = {2003}, author = {Nitobe, J and Yamaguchi, S and Okuyama, M and Nozaki, N and Sata, M and Miyamoto, T and Takeishi, Y and Kubota, I and Tomoike, H}, title = {Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes.}, journal = {Cardiovascular research}, volume = {57}, number = {1}, pages = {119-128}, doi = {10.1016/s0008-6363(02)00646-6}, pmid = {12504821}, issn = {0008-6363}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/*pharmacology ; Apoptosis ; Caspase 8 ; Caspase 9 ; Caspases/*metabolism ; Catalase/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Doxorubicin/*pharmacology ; Fas Ligand Protein ; Membrane Glycoproteins/metabolism ; Myocytes, Cardiac/cytology/drug effects/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*pharmacology ; Superoxide Dismutase/pharmacology ; Thiobarbituric Acid Reactive Substances/metabolism ; Time Factors ; }, abstract = {OBJECTIVE: Fas ligand (FasL) is a key cytokine which initiates apoptosis when FasL binds to its receptor, Fas. Cardiac myocytes are generally resistant to Fas-induced apoptosis. However, sublethal dose of doxorubicin (Dox) can sensitize cardiac myocytes to Fas-induced apoptosis. We investigated the molecular mechanism by which Dox sensitizes cardiac myocytes to Fas-induced apoptosis. FLICE inhibitory protein (FLIP) is a key molecule for blocking Fas-induced apoptosis by functioning as a caspase-8 dominant negative.<br><br>METHODS AND RESULTS: FLIP was constitutively expressed in cultured neonatal rat cardiac myocytes. FLIP protein levels were markedly down-regulated by Dox in a time-dependent and dose-dependent manner. Next, we examined the relation of reactive oxygen species (ROS) by Dox to the expression of FLIP. Both of N-acetylcysteine (NAC) and the combination of superoxide dismutase and catalase restored the decreased FLIP in Dox-treated cardiac myocytes to the basal level. NAC also restored the increased formation of thiobarbituric acid-reactive substance after Dox-treatment. Concurrently, the susceptibility to Fas-mediated apoptosis disappeared with the treatments of the antioxidant agents. Hydrogen peroxide down-regulated FLIP in a dose-dependent fashion and also sensitized cardiac myocytes to Fas-induced apoptosis.<br><br>CONCLUSIONS: FLIP, an inhibitor of apoptosis induced by cytokines of TNF family, contributes at least partly to Dox-induced sensitization to Fas-mediated apoptosis in cardiac myocytes. The expression of FLIP in cardiac myocytes is regulated by ROS.}, }
@article {pmid12502184, year = {2002}, author = {Cisowski, J and Zarebski, A and Koj, A}, title = {IL-1-mediated inhibition of IL-6-induced STAT3 activation is modulated by IL-4, MAP kinase inhibitors and redox state of HepG2 cells.}, journal = {Folia histochemica et cytobiologica}, volume = {40}, number = {4}, pages = {341-345}, pmid = {12502184}, issn = {0239-8508}, mesh = {Anti-Inflammatory Agents/pharmacology ; Antioxidants/classification/metabolism/pharmacology ; Cells, Cultured ; DNA-Binding Proteins/agonists/biosynthesis/*metabolism ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Humans ; Imidazoles/pharmacology ; Interleukin-1/antagonists &amp; inhibitors/metabolism/*pharmacology ; Interleukin-4/metabolism/*pharmacology ; Interleukin-6/*antagonists &amp; inhibitors/metabolism/pharmacology ; Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors ; Oxidation-Reduction ; Pyridines/pharmacology ; Receptor Cross-Talk ; STAT3 Transcription Factor ; Signal Transduction ; Trans-Activators/agonists/biosynthesis/*metabolism ; }, abstract = {It is known that during acute phase reaction IL-6 activates STAT3 in hepatoma cells and IL-1 downregulates this response. We found that the inhibitory properties of IL-1 on STAT signalling cascade in human hepatoma HepG2 cells are considerably decreased not only in the presence of MAP kinase inhibitors SB203580 and PD98059 but also by some antioxidants (N-acetyl cysteine and pyrrolidine dithiocarbamate) and by anti-inflammatory cytokine IL-4. It appears that cytokine crosstalk between IL-6 and IL-1 includes a direct pathway sensitive to antioxidants and MAP kinase inhibitors, whereas the indirect prolonged response depends probably on synthesis of suppressors of cytokine signalling (SOCS).}, }
@article {pmid12496140, year = {2003}, author = {Medved, I and Brown, MJ and Bjorksten, AR and Leppik, JA and Sostaric, S and McKenna, MJ}, title = {N-acetylcysteine infusion alters blood redox status but not time to fatigue during intense exercise in humans.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {94}, number = {4}, pages = {1572-1582}, doi = {10.1152/japplphysiol.00884.2002}, pmid = {12496140}, issn = {8750-7587}, mesh = {Acetylcysteine/*administration &amp; dosage/blood ; Acid-Base Equilibrium ; Adult ; Cross-Over Studies ; Cysteine/blood ; Cystine/blood ; Double-Blind Method ; Electrolytes/blood ; Exercise/*physiology ; Fatigue/etiology ; Free Radical Scavengers/*administration &amp; dosage/blood ; Glutathione/*blood ; Glutathione Disulfide/*blood ; Humans ; Infusions, Intravenous ; Male ; Osmolar Concentration ; *Physical Endurance ; Potassium/blood ; Time Factors ; }, abstract = {Infusion of the antioxidant N-acetylcysteine (NAC) reduces fatigability in electrically evoked human muscle contraction, but due to reported adverse reactions, no studies have investigated NAC infusion effects during voluntary exercise in humans. We investigated whether a modified NAC-infusion protocol (125 mg. kg(-1). h(-1) for 15 min, then 25 mg. kg(-1). h(-1)) altered blood redox status and enhanced performance during intense, intermittent exercise. Eight untrained men participated in a counterbalanced, double-blind, crossover study in which they received NAC or saline (control) before and during cycling exercise, which comprised three 45-s bouts and a fourth bout that continued to fatigue, at 130% peak oxygen consumption. Arterialized venous blood was analyzed for glutathione status, hematology, and plasma electrolytes. NAC infusion induced no severe adverse reactions. Exercise decreased the reduced glutathione (P < 0.005) and increased oxidized glutathione concentrations (P < 0.005); NAC attenuated both effects (P < 0.05). NAC increased the rise in plasma K(+) concentration-to-work ratio (P < 0.05), indicating impaired K(+) regulation, although time to fatigue was unchanged (NAC 102 +/- 45 s; saline 107 +/- 53 s). Thus NAC infusion altered blood redox status during intense, intermittent exercise but did not attenuate fatigue.}, }
@article {pmid12494466, year = {2003}, author = {Winnett, G and van Hagen, D and Schrey, M}, title = {Prostaglandin J2 metabolites inhibit aromatase activity by redox-sensitive mechanisms: potential implications for breast cancer therapy.}, journal = {International journal of cancer}, volume = {103}, number = {5}, pages = {600-605}, doi = {10.1002/ijc.10878}, pmid = {12494466}, issn = {0020-7136}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Aromatase/metabolism ; *Aromatase Inhibitors ; Breast/metabolism ; Breast Neoplasms/*enzymology/prevention &amp; control ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/*pharmacology ; Female ; Fibroblasts/enzymology ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Oxidation-Reduction ; Prostaglandin D2/analogs &amp; derivatives/*pharmacology ; Receptors, Cytoplasmic and Nuclear/*agonists ; Sulfhydryl Reagents/pharmacology ; Transcription Factors/*agonists ; Tumor Cells, Cultured/drug effects ; }, abstract = {The mechanisms by which prostaglandin (PG)J(2) metabolites inhibit tumorigenicity are poorly understood but may involve thiol reactivity or peroxisome proliferator-activated receptor (PPAR)-dependent pathways. Because aromatase is an important therapeutic target in breast cancer treatment, we have investigated the effect of PGJ(2) metabolites on aromatase activity and evaluated a potential role for redox status during PGJ(2) metabolite action. 15-deoxy-Delta(12,14)PGJ(2) (15d-PGJ(2)) and 9-deoxy-Delta(9,12)13,14-dihydroPGD(2) (Delta(12)PGJ(2)) caused dose-dependent inhibition of both pre-induced aromatase activity in human breast fibroblasts and MDA MB 231 breast cancer cells and of constitutive aromatase activity in JEG-3 choriocarcinoma cells. Structure-activity studies showed that this inhibition was mimicked by 4-cyclopentene-1,3-dione but not by the PPARgamma agonist troglitazone nor the eicosanoids PGE(2) or arachidonic acid. The thiol oxidants diamide and H(2)O(2) simulated the inhibitory action of 15d-PGJ(2) on aromatase activity, whereas the glutathione (GSH) repletor and antioxidant N-acetyl-cysteine (NAC) reversed these actions of 15d-PGJ(2) and H(2)O(2) on aromatase. 15d-PGJ(2) also caused a direct dose-dependent inhibition of aromatase activity in JEG-3 cell sonicates, which was also reversed in the presence of GSH. Kinetic analysis of this 15d-PGJ(2)-induced inhibition of cell-free aromatase indicated the involvement of a non-competitive mechanism possibly resulting from direct thiol-targeted alkylation of the enzyme. These redox-sensitive, PPARgamma-independent actions of 15d-PGJ(2) on aromatase activity demonstrate a novel therapeutic potential for such cyclopentenone PGs in breast cancer treatment.}, }
@article {pmid12490582, year = {2003}, author = {Martin, EJ and Racz, WJ and Forkert, PG}, title = {Mitochondrial dysfunction is an early manifestation of 1,1-dichloroethylene-induced hepatotoxicity in mice.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {304}, number = {1}, pages = {121-129}, doi = {10.1124/jpet.102.041392}, pmid = {12490582}, issn = {0022-3565}, mesh = {Acetylcysteine/pharmacology ; Adenosine Diphosphate/metabolism ; Alanine Transaminase/metabolism ; Animals ; Chemical and Drug Induced Liver Injury/*pathology ; Dichloroethylenes/*toxicity ; Dose-Response Relationship, Drug ; Female ; Glutathione/metabolism ; In Vitro Techniques ; Indicators and Reagents ; Mice ; Mitochondria, Liver/drug effects/*pathology ; Oxygen Consumption/drug effects ; Polarography ; Time Factors ; }, abstract = {Hepatotoxicity induced by 1,1-dichloroethylene (DCE) is mediated by cytochrome P450-dependent metabolism to reactive intermediates, including the epoxide. We have tested the hypothesis that mitochondria are a primary target of toxicity by investigating dose- and time-dependent effects of DCE on mitochondrial respiration. Hepatotoxicity, as assessed by serum alanine aminotransferase (ALT) activity, was evaluated. We have also determined the effectiveness of N-acetyl-L-cysteine (NAC) in protecting against respiratory perturbations and hepatotoxicity. Liver mitochondria were isolated 2 h after DCE (50, 75, 100, 125, and 150 mg/kg) treatment. Glutamate (complex I)- and succinate (complex II)-supported mitochondrial respiration was assessed by measurement of state 3 (ADP-stimulated) and state 4 (resting) rates of oxygen consumption. The corresponding respiratory control ratios (RCRs, state 3/state 4) and ADP:O ratios were then calculated. A DCE dose of 125 mg/kg significantly inhibited glutamate- and succinate-supported state 3 respiration, leading to a significant reduction in corresponding RCRs and ADP:O ratios. In time-dependent studies, state 3 respiration rates and RCRs for glutamate-supported respiration were significantly decreased as early as 20 min after DCE (125 mg/kg) treatment, whereas those for succinate-supported respiration were significantly decreased at 90 min. Additionally, ADP:O ratios for glutamate-supported respiration were significantly decreased starting at 60 min, and those for succinate-supported respiration at 90 min. Alterations in mitochondrial function preceded significant increases in ALT activity, which was first manifested at 2 h. Pretreatment with NAC (1200 mg/kg) abrogated DCE-induced GSH depletion and inhibited disturbances in mitochondrial respiration. Moreover, NAC protected against increased ALT activity, suggesting that the protective effect of NAC is due to increased GSH for conjugation reactions and/or its antioxidant property. These results showed that DCE-mediated mitochondrial dysfunction is an early event that preceded the onset of hepatotoxicity.}, }
@article {pmid12488139, year = {2002}, author = {Fitsanakis, VA and Amarnath, V and Moore, JT and Montine, KS and Zhang, J and Montine, TJ}, title = {Catalysis of catechol oxidation by metal-dithiocarbamate complexes in pesticides.}, journal = {Free radical biology &amp; medicine}, volume = {33}, number = {12}, pages = {1714-1723}, doi = {10.1016/s0891-5849(02)01169-3}, pmid = {12488139}, issn = {0891-5849}, support = {ES00267/ES/NIEHS NIH HHS/United States ; ES07028/ES/NIEHS NIH HHS/United States ; ES10196/ES/NIEHS NIH HHS/United States ; }, mesh = {Carbamates/*chemistry ; Catalysis ; Catechols/*chemistry ; Oxidants/chemistry ; Oxidation-Reduction ; Oxidative Stress ; Oxygen/chemistry ; Pesticides/*chemistry ; Reactive Oxygen Species/analysis/chemistry ; Spectrophotometry, Ultraviolet ; Structure-Activity Relationship ; X-Ray Diffraction ; }, abstract = {Dithiocarbamate (DTC)-based pesticides have been implicated in Parkinson's disease (PD) through epidemiological links to increased risk of PD, clinical reports of parkinsonism following occupational exposure to the DTC-based pesticide maneb, and experimental studies showing dopaminergic neurodegeneration with combined exposure of rats to maneb and paraquat. We hypothesize that the manganese-ethylene-bis-dithiocarbamate (MnEBDC) complex in maneb may produce oxidative stress by catalyzing catechol oxidation. We tested this hypothesis by performing a structure-function analysis of metal-EBDC and metal-diethyldithiocarbamate (DEDC) complexes of Mn2+, Zn2+, and Cu2+ to catalyze oxidation of N-acetyldopamine (NA-DA) and 3,4-dihydroxyphenylacetic acid (DP) in the presence and absence of N-acetylcysteine (NAC), a model of glutathione. Both Mn-DTCs retained the capacity of the parent ion to catalyze one-electron oxidation of NA-DA, but lost the ability to catalyze DP oxidation. Strikingly, while Zn2+ did not catalyze catechol oxidation, both Zn-DTCs catalyzed one-electron oxidation of NA-DA but not DP. While Cu2+ catalyzed oxidation of both catechols, Cu-DTCs were inert. Similar results were obtained with MnEBDC and dopamine or norepinephrine; however, zinc-ethylene-bis-dithiocarbamate was less efficient at catalyzing oxidation of these catechols. Our results point to the potential for manganese- and zinc-containing EBDC pesticides to promote oxidative stress in catecholaminergic regions of the brain.}, }
@article {pmid12488130, year = {2002}, author = {Jain, AK and Lim, G and Langford, M and Jain, SK}, title = {Effect of high-glucose levels on protein oxidation in cultured lens cells, and in crystalline and albumin solution and its inhibition by vitamin B6 and N-acetylcysteine: its possible relevance to cataract formation in diabetes.}, journal = {Free radical biology &amp; medicine}, volume = {33}, number = {12}, pages = {1615-1621}, doi = {10.1016/s0891-5849(02)01109-7}, pmid = {12488130}, issn = {0891-5849}, mesh = {Acetylcysteine/*pharmacology ; Albumins/metabolism ; Animals ; Cataract/chemically induced/*complications/metabolism/pathology ; Cells, Cultured ; *Diabetes Complications ; Diabetes Mellitus/metabolism ; Dose-Response Relationship, Drug ; Glucose/antagonists &amp; inhibitors/*pharmacology ; Lens, Crystalline/cytology/*drug effects/metabolism ; Nephelometry and Turbidimetry ; Oxidants/antagonists &amp; inhibitors/*pharmacology ; Oxidation-Reduction/drug effects ; Proteins/*metabolism ; Rabbits ; Vitamin B 6/*pharmacology ; }, abstract = {Diabetic patients have elevated levels of glucose in their blood and other body fluids. This project studied the effect of high-glucose concentrations (HG) on the protein oxidation in cultured lens cells and in crystalline protein solution. In addition, we also examined the effect of HG on the oxidation and turbidity (aggregation) of albumin protein solution. This study also examined whether vitamin B6 [pyridoxine (P), pyridoxamine (PM)] or n-acetylcysteine (NAC) is capable of preventing protein oxidation similar to that seen in cataracts. For cell culture studies, rabbit lens cells were cultured in control or HG medium at 37 degrees C for 2 d. For studies with protein solution, a buffered solution of serum albumin or crystalline protein was incubated with normal glucose (5 mM) or HG (50-100 mM) in a water bath at 37 degrees C for 4 d. All treatments were carried out with and without the addition of P, PM, or NAC. We found significantly higher levels of carbonyl protein (an index of protein oxidation) in HG-treated compared with normal glucose-treated lens cells and in crystalline protein solution. P, PM, and NAC significantly decreased the protein oxidation in lens cells and crystalline protein solution. We also found significantly higher levels of protein oxidation and turbidity (an index of protein aggregation) and its inhibition by P, PM, and NAC in HG-treated compared with normal glucose-treated albumin solution. This suggests that HG can cause the oxidation and modification of proteins in the lens, and that vitamin B6 and NAC supplementation may be helpful in slowing the oxidation of lens proteins. This study explains the cause of early cataract development and the potential benefit of supplementation with vitamin B6 and NAC in the prevention of the development of cataract among the diabetic population.}, }
@article {pmid12487368, year = {2002}, author = {Mehta, A and Sekhon, CP and Giri, S and Orak, JK and Singh, AK}, title = {Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine, sodium nitroprusside and phosphoramidon.}, journal = {Molecular and cellular biochemistry}, volume = {240}, number = {1-2}, pages = {19-29}, pmid = {12487368}, issn = {0300-8177}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Glycopeptides/*pharmacology ; Immunohistochemistry ; Ischemia/enzymology/metabolism/prevention &amp; control ; Ischemic Preconditioning ; JNK Mitogen-Activated Protein Kinases ; Male ; Mitogen-Activated Protein Kinases/*metabolism ; Nitroprusside/*pharmacology ; Phosphorylation ; Proto-Oncogene Proteins c-fos/analysis ; Proto-Oncogene Proteins c-jun/analysis ; Rats ; Rats, Sprague-Dawley ; Reperfusion/adverse effects ; Reperfusion Injury/*enzymology/metabolism/*prevention &amp; control ; Survival Rate ; Time Factors ; Transcription Factor AP-1/analysis ; }, abstract = {Ischemia followed by reperfusion has a number of clinically significant consequences. A number of pathophysiological processes appear to be involved in ischemia/reperfusion (I/R) injury. The mitogen activated protein kinases (MAPK) are integral components of the parallel MAP kinase cascades activated in response to a variety of cellular stress inducing ischemia/ATP depletion and inflammatory cytokines. Many studies suggest that members of the MAP kinase family in particular Jun N-terminal kinase (JNK) are activated in kidney following ischemia/reperfusion of this tissue. The present study underlines the therapeutic potential of the combination of N-acetyl cysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor and phosphoramidon (P), an endothelin-1 converting enzyme inhibitor in ameliorating the MAPK induced damage during renal ischemia/reperfusion injury. Our previous results showed that 90 min of ischemia followed by reperfusion caused very severe injury and that the untreated animals had 100% mortality after the 3rd day whereas there was improved renal function and 100% survival of animals in the three drug combination treatment group. The present study, mainly on tissue sections, further supports the protection provided by the triple drug therapy. A higher degree of expression of all the three classes of MAPK, i.e. JNK, P38 MAP kinases and P-extracellular signal regulated kinases (ERKs) can be seen in kidneys subjected to ischemia/reperfusion insult. Pretreatment with a combination of N-acetyl cysteine, sodium nitroprusside, and phosphoramidon completely inhibits all three classes of MAPK and ameliorates AP-1 whereas individual or a combination of any two drugs is not as effective.}, }
@article {pmid12487367, year = {2002}, author = {Dobashi, K and Singh, I and Orak, JK and Asayama, K and Singh, AK}, title = {Combination therapy of N-acetylcysteine, sodium nitroprusside and phosphoramidon attenuates ischemia-reperfusion injury in rat kidney.}, journal = {Molecular and cellular biochemistry}, volume = {240}, number = {1-2}, pages = {9-17}, pmid = {12487367}, issn = {0300-8177}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; NS-40810/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants ; Catalase/metabolism ; Disease Models, Animal ; Drug Therapy, Combination ; Glutathione Peroxidase/metabolism ; Glycopeptides/*pharmacology ; Ischemic Preconditioning ; Kidney/*drug effects/enzymology/*pathology ; Male ; Nitroprusside/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/pathology/*prevention &amp; control ; Superoxide Dismutase/metabolism ; Time Factors ; }, abstract = {Renal ischemia is of clinical interest because of its role in renal failure and also renal graft rejection. To evaluate the effect of the combination of N-acetylcysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor, and phosphoramidon (P), an endothelin converting enzyme inhibitor, on tissue protection against ischemia-reperfusion injury, we studied the biochemical and morphological changes due to 90 min of renal ischemia-reperfusion in the rat model. Ninety min of ischemia caused very severe injury and the animals could not survive after 4 days without any treatment. Whereas, animals in the treated groups survived i.e. the NAC group (25%), NAC + SNP group (43%) and in the NAC + SNP + P group (100%), 2 weeks after 90 min of ischemia. A significant increase in the serum levels of creatinine and urea nitrogen was shown in the untreated group and to a much lesser extent in the treated group, especially in the NAC + SNP + P group. The protective effect was also supported by light microscopic studies on renal tissue sections. We also measured the activities of antioxidant enzymes in tissue homogenates. With the exception of Mn-superoxide dismutase, the activities of antioxidant enzymes (catalase, glutathione peroxidase, CuZn-superoxide dismutase) were decreased in the untreated kidney. The administration of NAC alone and NAC + SNP protected against the loss of activities. Treatment with a combination of NAC, SNP and P showed a synergistic effect as evidenced by the best protection. These results suggest that pre-administration of a combination of antioxidant (NAC) with endothelin derived vasodilators (sodium nitroprusside and Phosphoramidon) attenuates renal ischemia-reperfusion injury, e.g. in donor kidney for transplantation, by protecting cells against free radical damage.}, }
@article {pmid12486618, year = {2002}, author = {Reichenberger, F and Tamm, M}, title = {[N-acetylcystein in the therapy of chronic bronchitis].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {56}, number = {12}, pages = {793-797}, doi = {10.1055/s-2002-36122}, pmid = {12486618}, issn = {0934-8387}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Anti-Bacterial Agents/therapeutic use ; Antioxidants/therapeutic use ; Bacterial Infections/complications/*drug therapy ; Bronchitis/*drug therapy ; Chronic Disease ; Clinical Trials as Topic ; Expectorants/*therapeutic use ; Female ; Humans ; Male ; Pilot Projects ; Treatment Outcome ; }, abstract = {Chronic bronchitis (CB) shows an increasing global morbidity and mortality with major impact on socioeconomics. N-Acetylcysteine (NAC), previously used as a mucolytic compound in CB, has also antioxidative effects. Furthermore it influences intrabronchial bacterial colonisation. In a randomised pilot study of 24 patients (16-male, 8 female, mean age 66 +/- 10 years) with acute exacerbation of CB and positive bacterial culture in the sputum, the addition of twice daily 600 mg NAC to standard antibiotic therapy lead to a significantly higher bacterial eradication rate (70 % versus 36 %, p < 0.03). Clinical studies suggest that treatment with NAC has different effects in CB including a reduction of the number and duration of acute exacerbation episodes and possibly influences lung function. The improvement of symptoms and quality of life also has an impact on socio-economic costs. The use of NAC in CB as an antioxidative rather than a mucolytic compound should be considered. However, further placebo controlled studies are undergoing to definitively establish the role of NAC for the treatment of CB and COPD.}, }
@article {pmid12485928, year = {2002}, author = {Kelly, RG and Nally, K and Shanahan, F and O'Connell, J}, title = {Type I insulin-like growth factor receptor expression on colorectal adenocarcinoma cell lines is decreased in response to the chemopreventive agent N-acetyl-l-cysteine.}, journal = {Annals of the New York Academy of Sciences}, volume = {973}, number = {}, pages = {555-558}, doi = {10.1111/j.1749-6632.2002.tb04700.x}, pmid = {12485928}, issn = {0077-8923}, mesh = {Acetylcysteine/*pharmacology ; Adenocarcinoma ; Anticarcinogenic Agents/*pharmacology ; Cell Division/drug effects ; Colorectal Neoplasms ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Receptor, IGF Type 1/*genetics ; Tumor Cells, Cultured ; }, abstract = {Increased expression of the type I insulin-like growth factor receptor (IGF-1R) is associated with colon cancer, while the antioxidant N-acetyl-l-cysteine (NAC) is known to suppress colonic proliferation. We demonstrate that NAC down-regulates the expression of IGF-1R on three colorectal adenocarcinoma cell lines (HT29, SW480, and LoVo). NAC also abrogates the proliferative effect of IGF-I on HT29 cells. This indicates a novel mechanism for the therapeutic effects of NAC.}, }
@article {pmid12483020, year = {2002}, author = {Castillo, M and Bellot, JL and García-Cabanes, C and Miquel, J and Orts, A and Palmero, M}, title = {Effects of hypoxia on retinal pigmented epithelium cells: protection by antioxidants.}, journal = {Ophthalmic research}, volume = {34}, number = {6}, pages = {338-342}, doi = {10.1159/000067050}, pmid = {12483020}, issn = {0030-3747}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Cattle ; Cell Death/drug effects ; Cell Hypoxia/drug effects/physiology ; Cell Survival/drug effects ; Cells, Cultured ; DNA Fragmentation/drug effects/physiology ; Free Radical Scavengers/pharmacology ; Oxygen/*metabolism ; Pigment Epithelium of Eye/*drug effects/injuries/pathology ; }, abstract = {Age-related macular degeneration and other eye diseases, such as diabetic retinopathy, are probably linked to the effects of oxygen radicals derived from light or metabolic reactions. We have investigated the effects of hypoxia on bovine retinal pigmented epithelial cells (RPE) and the response of these cells to two antioxidants that have previously shown a beneficial action against free radical-linked senescent involution. The main results of the study were as follows: (i) Hypoxia induced apoptotic damage on RPE cells, with LDH leakage and ATP reduction; (ii) both vitamin C (VC) and N-acetyl-cysteine (NAC) treatment protected against hypoxia-induced apoptosis, with less DNA fragmentation. In our opinion, these findings justify further experimental and clinical work to investigate the role of hypoxia in the mechanisms of age-related RPE injury and death as well as the potential of antioxidant administration to prevent or delay retinal degenerative processes caused by oxygen-dependent pathophysiological conditions.}, }
@article {pmid12482032, year = {2002}, author = {Vasdev, S and Gill, V and Parai, S and Longerich, L and Gadag, V}, title = {Dietary vitamin E and C supplementation prevents fructose induced hypertension in rats.}, journal = {Molecular and cellular biochemistry}, volume = {241}, number = {1-2}, pages = {107-114}, pmid = {12482032}, issn = {0300-8177}, mesh = {Animals ; Ascorbic Acid/*administration &amp; dosage ; Blood Platelets/drug effects/metabolism ; Body Weight ; Calcium/metabolism ; Drinking Behavior ; Feeding Behavior ; Fructose/*administration &amp; dosage ; Hypertension/*chemically induced/prevention &amp; control ; Organ Size/drug effects ; Rats ; Rats, Inbred WKY ; Vitamin E/*administration &amp; dosage ; }, abstract = {In fructose-induced hypertension in Wistar-Kyoto (WKY) rats, excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound N-acetyl cysteine prevents fructose-induced hypertension by binding excess endogenous aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of the present study was to investigate whether dietary supplementation of vitamin E and vitamin C which are known to increase tissue glutathione, a storage form of cysteine, prevents this hypertension and its associated biochemical and histopathological changes. Starting at 7 weeks of age, animals were divided into four groups of six animals each and treated as follows: control group, normal diet and normal drinking water; fructose group, normal diet and 4% fructose in drinking water; fructose + vitamin E group, diet supplemented with vitamin E (34 mg/ kg feed) and 4% fructose in drinking water; fructose + vitamin C group, diet supplemented with vitamin C (1,000 mg/kg feed) and 4% fructose in drinking water. At 14 weeks, systolic blood pressure, platelet [Ca2+]i and kidney and aortic aldehyde conjugates were significantly higher in the fructose group. These animals also displayed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin E and C supplementation in fructose-treated WKY rats prevented the increase in systolic blood pressure by normalizing cytosolic [Ca2+]i and kidney and aortic aldehyde conjugates and preventing adverse renal vascular changes.}, }
@article {pmid12480817, year = {2002}, author = {Ushio-Fukai, M and Tang, Y and Fukai, T and Dikalov, SI and Ma, Y and Fujimoto, M and Quinn, MT and Pagano, PJ and Johnson, C and Alexander, RW}, title = {Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis.}, journal = {Circulation research}, volume = {91}, number = {12}, pages = {1160-1167}, doi = {10.1161/01.res.0000046227.65158.f8}, pmid = {12480817}, issn = {1524-4571}, support = {HL55425/HL/NHLBI NIH HHS/United States ; HL60728/HL/NHLBI NIH HHS/United States ; HL66575/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cell Division/drug effects/physiology ; Cell Movement/drug effects/physiology ; Cells, Cultured ; Endothelial Growth Factors/pharmacology/*physiology ; Endothelium, Vascular/cytology/drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Genes, Dominant ; Genes, Reporter ; Humans ; Intercellular Signaling Peptides and Proteins/pharmacology/*physiology ; Lymphokines/pharmacology/*physiology ; Membrane Glycoproteins/antagonists &amp; inhibitors/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NADPH Oxidase 2 ; NADPH Oxidases/*metabolism ; Neovascularization, Physiologic/drug effects/*physiology ; Oligonucleotides, Antisense/pharmacology ; Phosphorylation/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects/*physiology ; Subcellular Fractions/metabolism ; Superoxides/metabolism ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; Vascular Endothelial Growth Factors ; rac1 GTP-Binding Protein/biosynthesis/genetics ; }, abstract = {Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell proliferation and migration, primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). Reactive oxygen species (ROS) derived from NAD(P)H oxidase are critically important in many aspects of vascular cell regulation, and both the small GTPase Rac1 and gp91(phox) are critical components of the endothelial NAD(P)H oxidase complex. A role of NAD(P)H oxidase in VEGF-induced angiogenesis, however, has not been defined. In the present study, electron spin resonance spectroscopy is utilized to demonstrate that VEGF stimulates O2*- production, which is inhibited by the NAD(P)H oxidase inhibitor, diphenylene iodonium, as well as by overexpression of dominant-negative Rac1 (N17Rac1) and transfection of gp91(phox) antisense oligonucleotides in human umbilical vein endothelial cells (ECs). Antioxidants, including N-acetylcysteine (NAC), various NAD(P)H oxidase inhibitors, and N17Rac1 significantly attenuate not only VEGF-induced KDR tyrosine phosphorylation but also proliferation and migration of ECs. Importantly, these effects of VEGF are dramatically inhibited in cells transfected with gp91(phox) antisense oligonucleotides. By contrast, ROS are not involved in mediating these effects of sphingosine 1-phosphate (S1P) on ECs. Sponge implant assays demonstrate that VEGF-, but not S1P-, induced angiogenesis is significantly reduced in wild-type mice treated with NAC and in gp91(phox-/-) mice, suggesting that ROS derived from gp91(phox)-containing NAD(P)H oxidase play an important role in angiogenesis in vivo. These studies indicate that VEGF-induced endothelial cell signaling and angiogenesis is tightly controlled by the reduction/oxidation environment at the level of VEGF receptor and provide novel insights into the NAD(P)H oxidase as a potential therapeutic target for angiogenesis-dependent diseases.}, }
@article {pmid12479865, year = {2003}, author = {Koeck, T and Kremser, K}, title = {L-Carnitine alters nitric oxide synthase activity in fibroblasts depending on the peroxisomal status.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {35}, number = {2}, pages = {149-156}, doi = {10.1016/s1357-2725(02)00183-8}, pmid = {12479865}, issn = {1357-2725}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism/pharmacology ; Carnitine/deficiency/*pharmacology ; Cattle ; Cells, Cultured ; Fatty Acids/analysis/blood ; Fibroblasts/drug effects/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Nitric Oxide Synthase/drug effects/*metabolism ; Nitric Oxide Synthase Type III ; Oxidative Stress ; Peroxisomes/drug effects/*metabolism ; Proteins/drug effects/metabolism ; Reference Values ; Toxicity Tests ; Zellweger Syndrome/pathology ; }, abstract = {Fibroblast cellular models are widely used for research on fatty acid metabolism. Due to the importance of L-carnitine in intermediary metabolism we studied the effects of L-carnitine on healthy human skin fibroblasts and fibroblasts without functional peroxisomes (Zellweger Syndrome) cultivated under carnitine deficiency, which is caused by standard media compositions. The application of physiological (0.1mM) or super-physiological (1mM) doses of L-carnitine causes a significant decrease of the specific activity of nitric oxide synthase (NOS, 2.25+/-0.10 to 1.36 pmol/(minmg)+/-0.09 pmol/(minmg) at 0.1mM), proliferation and a tendentious decrease of the antioxidant defence potential against hydrogen peroxide only in control cells. Simultaneous application of L-carnitine and 100 micro M N-acetylcysteine (NAC) prevents the alterations in control cells. Thus, L-carnitine alters the cellular regulation of the NOS probably by reactive oxygen species (ROS), which suggests that carnitine deficient media neither reflect physiological conditions for cellular models for fatty acid metabolism nor for the regulation of NOS.}, }
@article {pmid12476359, year = {2003}, author = {Dick, CA and Brown, DM and Donaldson, K and Stone, V}, title = {The role of free radicals in the toxic and inflammatory effects of four different ultrafine particle types.}, journal = {Inhalation toxicology}, volume = {15}, number = {1}, pages = {39-52}, doi = {10.1080/08958370304454}, pmid = {12476359}, issn = {0895-8378}, mesh = {Air Pollutants/*toxicity ; Animals ; Antioxidants/pharmacology ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Carbon/*toxicity ; Cell Count ; Chemokine CXCL2 ; Cobalt/*toxicity ; Free Radicals/metabolism ; In Vitro Techniques ; Inflammation/chemically induced/*metabolism ; Inhalation Exposure ; Lung/drug effects/metabolism ; Macrophages, Alveolar/metabolism ; Male ; Monokines/analysis ; Nickel/*toxicity ; Particle Size ; Rats ; Rats, Wistar ; Titanium/*toxicity ; Tumor Necrosis Factor-alpha/metabolism ; gamma-Glutamyltransferase/analysis ; }, abstract = {PM10 contains an ultrafine component, which is generally derived from combustion processes. This ultrafine fraction may be a factor in the increases in exacerbations of respiratory disease and deaths from cardiorespiratory causes associated with transient increases in levels of PM10. By using four different ultrafine particles (carbon black, cobalt, nickel, and titanium dioxide), we set out to determine the attributes of the ultrafine particle (surface area, chemical composition, particle number, or surface reactivity) that contribute most to its toxicity and proinflammatory effects both in vivo and in vitro. Instillation of 125 micro g ultrafine carbon black (UFCB) and ultrafine cobalt (UFCo) particles induced a significant influx of neutrophils at both 4 and 18 h postinstillation. Accompanying the influx of neutrophils was an increase in macrophage inflammatory protein-2 (MIP-2) (at 4 h) and an increase in gamma-glutamyl transpeptidase (at 18 h) in bronchoalveolar lavage fluid (BAL). Ultrafine nickel (UFNi) did not induce a significant increase in neutrophil influx until 18 h postinstillation. The increase in neutrophils induced by UFNi at this timepoint was comparable to that induced by UFCo and UFCB. UFTi did not induce a significant increase in neutrophils following instillation into the rat lung. The levels of MIP-2 observed at 4 h and neutrophil influx at 18 h induced by the particle samples were consistent with the pattern of surface free radical generation (as measured by the plasmid scission assay) whereby UFCo, UFCB, and UFNi all cause significant increases in inflammatory markers, as well as inducing a significant depletion of supercoiled plasmid DNA, indicative of hydroxyl radical generation. A role for free radicals and reactive oxygen species (ROS) in mediating ultrafine inflammation is further strengthened by the ability of the antioxidants N-acetylcysteine (NAC) and glutathione monoethyl ester (GSHme) to block the particle induced release of tumour necrosis factor-alpha (TNF-alpha) from alveolar macrophages in vitro. The ultrafine particles in PM10 may cause adverse effects via oxidative stress, and this could have implications for susceptible individuals. Susceptible individuals, such as those with COPD or asthma, already exhibit preexisting oxidative stress and hence are in a primed state for further oxidative stress induced by occupational or environmental particles.}, }
@article {pmid12472195, year = {2002}, author = {Fernández-Fúnez, A and Polo, FJ and Broseta, L and Valer, J and Zafrilla, L}, title = {Effects of N-acetylcysteine on myoglobinuric-acute renal failure in rats.}, journal = {Renal failure}, volume = {24}, number = {6}, pages = {725-733}, doi = {10.1081/jdi-120015676}, pmid = {12472195}, issn = {0886-022X}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/chemically induced/pathology/*prevention &amp; control ; Animals ; Cryoprotective Agents/adverse effects ; Disease Models, Animal ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Glycerol/adverse effects ; Hypertonic Solutions/adverse effects ; Injections, Intraperitoneal ; Kidney/drug effects/pathology/physiopathology ; Myoglobinuria/chemically induced/pathology/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Severity of Illness Index ; Time Factors ; }, abstract = {Oxygen metabolites play an important role in renal injury during myoglobinuric acute renal failure (ARF). This study was designed to determine the protective influence of N-acetylcysteine (NAC), a hydroxyl radical scavenger, and treatment in an experimental model of myoglobinuric-ARF induced by intramuscular injection of hypertonic glycerol in rats. The rats were randomly distributed into five groups: Group 0 (n = 10), was assigned to receive 2mL saline (0,9%) intraperitoneally (ip); Group 1 (n = 10), NAC ip in a dose of 0 mg/100 g of body weight 30 min before the intramuscular (im) injection of 50% glycerol (10 mg/kg); Group 2 (n = 10), received saline 0,9% ip in a equivalent volume of NAC in Group I before the im injection of glycerol; Group 3 (n = 10), received NAC ip in a dose of 10 mg/100 g after im injection of glycerol; Group 4 (n = 10), saline 0,9% ip in a equivalent volume of NAC of the Group 3 after im administration of glycerol. After 24 h rats were sacrificed and kidney morphology and renal function were determined. A severe renal failure was produced by glycerol injection in the Groups 1, 2, 3, and 4, with significant tubular proximal necrosis and cast formation, and creatinine and urea concentrations were elevated in these groups without significant differences among groups, but Group 0 where the values were significantly lower. The results of this study suggests that ip administration of NAC in rats before or after glycerol injection do not confer protection against impairment of renal function under these conditions in this model of myoglobinuric-ARF.}, }
@article {pmid12471614, year = {2003}, author = {Gordon, J and Wu, CH and Rastegar, M and Safa, AR}, title = {Beta2-microglobulin induces caspase-dependent apoptosis in the CCRF-HSB-2 human leukemia cell line independently of the caspase-3, -8 and -9 pathways but through increased reactive oxygen species.}, journal = {International journal of cancer}, volume = {103}, number = {3}, pages = {316-327}, doi = {10.1002/ijc.10828}, pmid = {12471614}, issn = {0020-7136}, support = {CA 80734/CA/NCI NIH HHS/United States ; }, mesh = {Annexin A5/metabolism ; Apoptosis/*drug effects ; Apoptosis Inducing Factor ; Blotting, Western ; Caspases/*metabolism ; Cytochrome c Group/metabolism ; Enzyme Inhibitors/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Flavoproteins/metabolism ; Flow Cytometry ; HLA Antigens/metabolism ; Humans ; Leukemia-Lymphoma, Adult T-Cell/metabolism/*pathology ; Membrane Potentials/drug effects ; Membrane Proteins/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured/drug effects/metabolism ; beta 2-Microglobulin/*pharmacology ; }, abstract = {Exogenous beta(2)-microglobulin (beta(2)m) induces significant apoptosis in the CCRF-HSB-2 human lymphoblastic leukemia cell line as detected by DNA fragmentation, DAPI staining and annexin V binding assay. beta(2)m treatment induced the release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria, but no change in mitochondrial membrane potential (DeltaPsim) was observed during apoptosis, suggesting that cytochrome c may be released through a mechanism independent of mitochondrial permeability transition (MPT) pore formation. Moreover, the beta(2)m-induced release of cytochrome c and AIF from the mitochondria in CCRF-HSB-2 cells was caspase-independent, since Z-VAD-fmk, a general inhibitor of caspases, did not block the release of these factors. However, Z-VAD-fmk treatment significantly blocked beta(2)m-induced apoptosis, while Western blot analysis revealed that caspases-1, -2, -3, -6, -7, -8 and -9 are not activated during beta(2)m-induced apoptosis in these cells. These results collectively indicate that a post-mitochondrial caspase-dependent mechanism is involved in beta(2)m-induced apoptosis. Moreover, beta(2)m significantly enhanced the production of reactive oxygen species (ROS) during 12-48 hr treatment, and beta(2)m-induced apoptosis was almost totally inhibited in cells pre-treated with the antioxidant N-acetylcysteine (NAC), providing evidence that beta(2)m-induced apoptosis in CCRF-HSB-2 cells is ROS-dependent. Therefore, these results reveal that beta(2)m-induced apoptosis in CCRF-HSB-2 cells may occur through an unknown caspase-dependent and ROS-dependent mechanism(s) that is associated with cytochrome c and AIF release from mitochondria, but is independent of the caspase -3, -8 and -9 pathways.}, }
@article {pmid12470707, year = {2003}, author = {Tseng, WP and Lin-Shiau, SY}, title = {Activation of NMDA receptor partly involved in beta-bungarotoxin-induced neurotoxicity in cultured primary neurons.}, journal = {Neurochemistry international}, volume = {42}, number = {4}, pages = {333-344}, doi = {10.1016/s0197-0186(02)00118-3}, pmid = {12470707}, issn = {0197-0186}, mesh = {Animals ; Antioxidants/pharmacology ; Bungarotoxins/*toxicity ; Caspases/physiology ; Cell Nucleus/drug effects/metabolism ; Cell Survival ; Cells, Cultured ; Cerebellum/cytology ; Dizocilpine Maleate/metabolism ; Excitatory Amino Acid Antagonists/metabolism/pharmacology ; Kinetics ; Male ; Neurites/drug effects/metabolism ; Neurons/*drug effects/ultrastructure ; Neurotoxins/*toxicity ; Rats ; Reactive Oxygen Species/metabolism ; Receptors, N-Methyl-D-Aspartate/*agonists/antagonists &amp; inhibitors ; Signal Transduction/drug effects ; Tetrazolium Salts ; Thiazoles ; }, abstract = {In this study, we demonstrated that a snake presynaptic toxin, beta-bungarotoxin (beta-BuTX), was capable of binding to NMDA receptors of the cultured primary neurons (cerebellar granule neurons, CGNs). We labeled beta-BuTX with fluorescent FITC (FITC-beta-BuTX) and showed that the binding of FITC-beta-BuTX was inhibited by unlabeled beta-BuTX and MK801 (an NMDA receptor antagonist). Meanwhile, the binding of [3H]-MK801 was also reduced by unlabeled MK801 and beta-BuTX. In addition, beta-BuTX produced a very potent neurotoxic effect on mature CGNs with the EC(50) of 3ng/ml (equivalent to 144pM), but was less effective in immature CGNs. We explored the signaling pathway of neuronal death and found that it was apparently due to the excessive production of reactive oxygen species (ROS) induced by beta-BuTX. MK801 and antioxidants (Vitamin C, N-acetylcysteine (NAC), melatonin, epigallocatechin gallate (EGCG), superoxide dismutase (SOD) and catalase) attenuated not only ROS production but also beta-BuTX-neurotoxicity. The downstream signaling of ROS was identified as the activation of caspase-3. Caspase inhibitor (z-DEVD-fmk) and antioxidants depressed both caspase-3 activation and neurotoxicity. Based on these findings and our previous reports, we conclude that the binding and activation of NMDA receptors by beta-BuTX was crucial step to produce the potent neurotoxic effect. The binding of NMDA receptors resulted in excessive Ca(2+) influx, followed by ROS production and activation of caspase-3. This snake toxin is considered not only to be a useful tool for exploring the death-signaling pathway of neurotoxicity, but also provides a model for searching neuroprotective agents.}, }
@article {pmid12468440, year = {2003}, author = {Pardo, A and Ruiz, V and Arreola, JL and Ramírez, R and Cisneros-Lira, J and Gaxiola, M and Barrios, R and Kala, SV and Lieberman, MW and Selman, M}, title = {Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl transpeptidase-deficient mice.}, journal = {American journal of respiratory and critical care medicine}, volume = {167}, number = {6}, pages = {925-932}, doi = {10.1164/rccm.200209-1007OC}, pmid = {12468440}, issn = {1073-449X}, support = {ES 07827/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Bleomycin/*adverse effects ; Bronchoalveolar Lavage Fluid/cytology/immunology ; Collagen/analysis ; Cysteine/analysis ; *Disease Models, Animal ; Glutathione/analysis ; Inflammation ; Leukocyte Count ; Matrix Metalloproteinase 9/immunology ; Mice ; Mice, Inbred Strains ; Neutrophils/immunology ; Pulmonary Fibrosis/*chemically induced/drug therapy/*immunology/pathology ; Severity of Illness Index ; Time Factors ; gamma-Glutamyltransferase/*deficiency ; }, abstract = {To investigate repair mechanisms in bleomycin-induced pulmonary fibrosis, we used mice deficient in gamma-glutamyl transpeptidase (GGT-/-), a key enzyme in glutathione (GSH) and cysteine metabolism. Seventy-two hours after bleomycin (0.03 U/g), GGT-/- mice displayed a different inflammatory response to wild-type mice as judged by a near absence of neutrophils in lung tissue and bronchoalveolar lavage and a less pronounced rise in matrix metalloproteinase-9. Inflammation in GGT-/- mice consisted mainly of lymphocytes and macrophages. At 1 month, lungs from bleomycin-treated GGT-/- mice exhibited minimal areas of fibrosis compared with wild-type mice(light microscopy fibrosis index: 510 +/- 756 versus 1975 +/- 817, p < 0.01). Lung collagen content revealed a significant increase in bleomycin-treated wild-type (15.1 +/- 3.8 versus 8.5 +/- 0.7 microg hydroxy(OH)-proline/mg dry weight, p < 0.01) but not in GGT-/- (10.4 +/- 1.7 versus 8.8 +/- 0.8). Control lungs from GGT-/- showed a significant reduction of cysteine (0.03 +/- 0.005 versus 0.055 +/- 0.001, p < 0.02) and GSH levels (1.24 +/- 0.055 versus 1.79 +/- 0.065, p < 0.002). These values decreased after 72 hours of bleomycin in both GGT-/- and wild-type but reached their respective control values after 1 month. Supplementation with N-acetyl cysteine partially ameliorated the effects of GGT deficiency. These findings suggest that increased neutrophils and matrix metalloproteinase-9 during the early inflammatory response and adequate thiol reserves are key elements in the fibrotic response after bleomycin-induced pulmonary injury.}, }
@article {pmid12467525, year = {2002}, author = {Hoffer, E and Baum, Y and Nahir, AM}, title = {N-Acetylcysteine enhances the action of anti-inflammatory drugs as suppressors of prostaglandin production in monocytes.}, journal = {Mediators of inflammation}, volume = {11}, number = {5}, pages = {321-323}, pmid = {12467525}, issn = {0962-9351}, mesh = {Acetylcysteine/*pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Diclofenac/*pharmacology ; Dinoprostone/*biosynthesis ; Drug Synergism ; Expectorants/*pharmacology ; Humans ; In Vitro Techniques ; Lactones/pharmacology ; Lipopolysaccharides/pharmacology ; Monocytes/*drug effects/metabolism ; Sulfones ; }, abstract = {The anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with inhibition of cyclooxygenase (COX), the rate-limiting enzyme responsible for the synthesis of prostaglandins. Since oxygen free radicals can act as second cellular messengers, especially to modulate the metabolism of arachidonic acid and the prostaglandin tract, it seems plausible that antioxidants might affect the production of prostaglandin by activated cells. This research is focused on the effect of the antioxidant N-acetylcysteine (NAC) on the inhibition of prostaglandin E(2) formation in activated monocytes by specific and non-specific COX inhibitors. We found that lipopolysaccharide-induced prostaglandin E(2) formation was significantly reduced by rofecoxib and by diclofenac, two NSAIDs. Addition of NAC to each of these drugs enhanced the effect of the NSAIDs. These results suggest that one might expect either a potentiation of the anti-inflammatory effect of COX inhibitors by their simultaneous administration with NAC, or obtaining the same anti-inflammatory at lower drug levels.}, }
@article {pmid12467214, year = {2002}, author = {Cen, D and Gonzalez, RI and Buckmeier, JA and Kahlon, RS and Tohidian, NB and Meyskens, FL}, title = {Disulfiram induces apoptosis in human melanoma cells: a redox-related process.}, journal = {Molecular cancer therapeutics}, volume = {1}, number = {3}, pages = {197-204}, pmid = {12467214}, issn = {1535-7163}, support = {P30CA62203/CA/NCI NIH HHS/United States ; }, mesh = {Antimetabolites, Antineoplastic/pharmacology ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Division/drug effects ; Disulfiram/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Glutathione/analysis ; Melanocytes/chemistry/drug effects ; Melanoma/drug therapy/*pathology ; Membrane Potentials/drug effects ; Mitochondria/drug effects/physiology/ultrastructure ; Neoplasm Metastasis ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured/drug effects ; }, abstract = {Melanoma is highly resistant to conventional chemotherapy. We have demonstrated that redox regulation in melanoma cells is aberrant, and redox-modulating agents can induce cell apoptosis. We have currently explored the effect of disulfiram (DSF), a member of the dithiocarbamate family, on apoptosis of melanoma cells in vitro. Human metastatic melanoma cells c81-46A, c81-61, and c83-2C were treated with DSF and apoptosis measured. DSF, at a dose of 25-50 ng/ml, consistently caused a 4-6-fold increase in apoptosis. The same dose of DSF did not significantly affect apoptosis in melanocytes. Coincubation of N-acetyl-cysteine reversed the DSF-induced apoptosis. Buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl-cysteine synthetase, as a single agent caused a approximately 2-fold increase in apoptosis when incubated with melanoma cells for 4 days. BSO slightly enhanced the level of apoptosis induced by DSF (4-10% higher than DSF alone). Intracellular glutathione was remarkably depleted with BSO treatment. DSF did not cause glutathione depletion; however, the ratio of reduced and oxidized glutathione was significantly decreased (14% of control), and N-acetyl-cysteine partially restored the ratio to 30% of control. There was a transient (2-fold) elevation of intracellular superoxide level after 24 h of DSF treatment (before the overt apoptosis). The intracellular H2O2 level progressively decreased with time. DSF decreased the mitochondrial membrane polarization in a time-dependent manner, and there was a significant inverse correlation between apoptosis and mitochondrial membrane polarization. We propose that DSF-induced apoptosis is redox related but involves a different mechanism from BSO-induced apoptosis in tumor cells. Our findings have provided new data for additional understanding of drug-induced apoptosis in melanoma cells and suggests an alternative therapeutic approach to melanoma.}, }
@article {pmid12467136, year = {2002}, author = {Martin, KR and Saulnier, MJ and Kari, FW and Barrett, JC and French, JE}, title = {Timing of supplementation with the antioxidant N-acetyl-L-cysteine reduces tumor multiplicity in novel, cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) transgenic mice but has no impact on malignant progression.}, journal = {Nutrition and cancer}, volume = {43}, number = {1}, pages = {59-66}, doi = {10.1207/S15327914NC431_7}, pmid = {12467136}, issn = {0163-5581}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Antioxidants/*administration &amp; dosage ; Carcinoma, Squamous Cell/chemically induced/mortality/*prevention &amp; control ; Cell Transformation, Neoplastic/*drug effects ; Cross-Over Studies ; *Dietary Supplements ; Disease Models, Animal ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Genes, ras/*genetics ; Linear Models ; Male ; Mice ; Mice, Transgenic ; Sarcoma/chemically induced/mortality/*prevention &amp; control ; Skin Neoplasms/chemically induced/mortality/*prevention &amp; control ; Survival Rate ; Time Factors ; }, abstract = {Epidemiological studies support the protective role of dietary antioxidants in preventing cancer. However, emerging evidence suggests that antioxidant supplements may actually exacerbate carcinogenesis. We explored this paradox in a model containing two common genotypic characteristics of human cancers. We selected p53 haploinsufficient Tg.AC (v-Ha-ras) mice as a model, because it contains an activated, carcinogen-inducible ras oncogene and an inactivated p53 tumor suppressor gene. These mice develop chemically induced benign and malignant skin tumors rapidly. Mice were fed basal diet with or without 3% N-acetyl-L-cysteine (NAC) before and after topical application of the carcinogen benzo[a]pyrene (64 micrograms twice per week for 7 wk) until 50% of mice within a group displayed at least one lesion. Half each of mice fed the basal and the NAC-supplemented diet were then switched to the alternate diet. Mice fed the NAC-supplemented diet or switched from the NAC-supplemented to the basal diet displayed 38% and 26% reductions, respectively, in tumor multiplicity and a 15% reduction if switched from the basal to the NAC-supplemented diet. Although latency was unaffected, NAC induced a lag in tumor incidence, which exceeded 90% at 10 wk for all groups. The timing of NAC supplementation did not affect malignant progression. Thus dietary NAC was chemoprotective by slowing tumorigenesis but did not affect malignant conversion.}, }
@article {pmid12466149, year = {2003}, author = {Allen, DL and Teitelbaum, DH and Kurachi, K}, title = {Growth factor stimulation of matrix metalloproteinase expression and myoblast migration and invasion in vitro.}, journal = {American journal of physiology. Cell physiology}, volume = {284}, number = {4}, pages = {C805-15}, doi = {10.1152/ajpcell.00215.2002}, pmid = {12466149}, issn = {0363-6143}, support = {5P60-AR-20557/AR/NIAMS NIH HHS/United States ; HL-53713/HL/NHLBI NIH HHS/United States ; M01-RR-00042/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Cell Movement/drug effects/physiology ; Cells, Cultured ; Fibroblast Growth Factor 2/pharmacology ; Fibronectins/pharmacology ; Growth Substances/*pharmacology ; Matrix Metalloproteinase 1/metabolism ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Matrix Metalloproteinases/*metabolism ; Mice ; Mice, SCID ; Myoblasts/*drug effects/*physiology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {We investigated the role of growth factors and fibronectin on matrix metalloproteinase (MMP) expression and on migration and invasion of mouse skeletal myoblasts in vitro. None of the growth factors tested significantly affected MMP-1 or MMP-2 activity as revealed by gelatin zymography, but both basic FGF (bFGF) and tumor necrosis factor (TNF)-alpha significantly increased MMP-9 activity (10- and 30-fold, respectively). The increase in secreted MMP-9 activity with TNF-alpha stimulation was due at least in part to an increase in MMP-9 gene transcription, because an MMP-9 promoter construct was approximately fivefold more active in TNF-alpha-treated myoblasts than in control myoblasts, as well as an increase in MMP-9 proteolytic activation. However, whereas fibronectin, bFGF, hepatocyte growth factor, and TGF-beta1 significantly augmented migration of mouse myoblasts, TNF-alpha did not, nor did PDGF-BB or IGF-I. Fibronectin and bFGF also significantly augmented invasion of myoblasts across a Matrigel barrier, and plasmin cotreatment potentiated whereas N-acetyl cysteine suppressed the effects of bFGF and fibronectin on myoblast migration and invasion. Finally, transient transfection with an MMP-9 overexpression construct had only minimal effects on myoblast migration/invasion, whereas overexpression of either MMP-2 or MMP-1 significantly augmented myoblast migration and invasion. These observations support the hypothesis that MMP activity is a necessary component of growth factor-mediated myoblast migration but suggest that other consequences of growth factor signaling are also necessary for migration to occur.}, }
@article {pmid12460740, year = {2002}, author = {Tsukagoshi, H and Kawata, T and Shimizu, Y and Ishizuka, T and Dobashi, K and Mori, M}, title = {4-Hydroxy-2-nonenal enhances fibronectin production by IMR-90 human lung fibroblasts partly via activation of epidermal growth factor receptor-linked extracellular signal-regulated kinase p44/42 pathway.}, journal = {Toxicology and applied pharmacology}, volume = {184}, number = {3}, pages = {127-135}, doi = {10.1006/taap.2002.9514}, pmid = {12460740}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/*pharmacology ; Cell Line ; Culture Media, Conditioned/chemistry ; ErbB Receptors/*metabolism ; Fibroblasts/cytology/drug effects/metabolism ; Fibronectins/analysis/*metabolism ; Humans ; Imidazoles/pharmacology ; Lipid Peroxidation/physiology ; Lung/cytology/drug effects/*metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/*metabolism ; Pyridines/pharmacology ; Quinazolines ; Signal Transduction ; Tyrphostins/pharmacology ; }, abstract = {To elucidate the underlying mechanisms in oxidative stress-related airway remodeling observed in chronic inflammatory pulmonary diseases such as asthma, we studied the effects of a thiol antioxidant, N-acetylcysteine (NAC), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG-1478, and tyrphostin-1 as a negative control for AG-1478 on an aldehydic product of lipid peroxidation 4-hydroxy-2-nonenal (HNE)-induced secretion of fibronectin by IMR-90 human lung fibroblasts. We also studied signal transduction pathways involved in the secretion of fibronectin evident after exposure of IMR-90 cells to HNE. Twenty-five-micromole HNE treatments of IMR-90 cells activated extracellular signal-regulated kinase p44/42 (Erk1/2) with little activation of p38 mitogen-activated protein kinase (p38MAPK) and no activation of c-Jun NH(2)-terminal kinase. HNE-induced secretion of fibronectin was inhibited by U-0126, an inhibitor of the Erk1/2 pathway, while no significant inhibition by SB-203580, an inhibitor of p38MAPK pathway, was observed. NAC and AG-1478, but not tyrphostin-1, inhibited HNE-induced fibronectin secretion accompanied by a pallarel inhibition of Erk1/2 activation. These data suggest that pulmonary oxidative stress-related lipid peroxidation may play an important role in developing airway remodeling through activating lung fibroblasts to further produce extracellular matrices, such as fibronectin, partly via activation of an EGFR-linked Erk1/2 signal transduction pathway, and that the antioxidant NAC and the EGFR tyrosine kinase inhibitor AG-1478 can be potentially useful in pulmonary diseases involving airway remodeling.}, }
@article {pmid12460510, year = {2002}, author = {Fu, Z and Yang, Z and Liu, L and Liu, Z and He, B and Liu, Z and Wu, J}, title = {[The influence of N-acetyl-L-cysteine on pulmonary injury and oxygen stress after smoke inhalation injury].}, journal = {Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns}, volume = {18}, number = {3}, pages = {152-154}, pmid = {12460510}, issn = {1009-2587}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bronchoalveolar Lavage Fluid ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Leukocytes/*drug effects ; Oxidative Stress/*drug effects ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Smoke Inhalation Injury/enzymology/*metabolism/pathology ; }, abstract = {OBJECTIVE: To investigate the influence of N-acetyl-L-cysteine (NAC) on pulmonary injury and oxygen stress caused by smoke inhalation injury.<br><br>METHODS: Rats inflicted with smoke inhalation injury were employed as the model. WBC in BALF (bronchoalveolar lavage fluid), MPO (myeloperoxidase) activity, hydrogen peroxide (H(2)O(2)) content, GSH (glutathione) content and total antioxidant (TAO) capacity in pulmonary tissue were determined.<br><br>RESULTS: Postinjury WBC in BALF, MPO activity in pulmonary tissue and H(2)O(2) content decreased obviously after NAC treatment. But the pulmonary tissue contents of GSH and ATO increased evidently after the treatment with NAC.<br><br>CONCLUSION: NAC treatment could ameliorate pulmonary oxygen stress after smoke inhalation injury. AS a result, the pulmonary antioxidant capacity was improved.}, }
@article {pmid12459675, year = {2002}, author = {Tanaka, K and Weihrauch, D and Kehl, F and Ludwig, LM and LaDisa, JF and Kersten, JR and Pagel, PS and Warltier, DC}, title = {Mechanism of preconditioning by isoflurane in rabbits: a direct role for reactive oxygen species.}, journal = {Anesthesiology}, volume = {97}, number = {6}, pages = {1485-1490}, doi = {10.1097/00000542-200212000-00021}, pmid = {12459675}, issn = {0003-3022}, support = {GM 08377/GM/NIGMS NIH HHS/United States ; HL 03690/HL/NHLBI NIH HHS/United States ; HL 54820/HL/NHLBI NIH HHS/United States ; HL 63705/HL/NHLBI NIH HHS/United States ; }, mesh = {Analysis of Variance ; Anesthetics, Inhalation/*therapeutic use ; Animals ; Hemodynamics/*drug effects ; Isoflurane/*therapeutic use ; Male ; Myocardial Infarction/*prevention &amp; control ; Rabbits ; Reactive Oxygen Species/metabolism/*therapeutic use ; }, abstract = {BACKGROUND: Reactive oxygen species (ROS) contribute to myocardial protection during ischemic preconditioning, but the role of the ROS in protection against ischemic injury produced by volatile anesthetics has only recently been explored. We tested the hypothesis that ROS mediate isoflurane-induced preconditioning in vivo.<br><br>METHODS: Pentobarbital-anesthetized rabbits were instrumented for measurement of hemodynamics and were subjected to a 30 min coronary artery occlusion followed by 3 h reperfusion. Rabbits were randomly assigned to receive vehicle (0.9% saline), or the ROS scavengers N-acetylcysteine (NAC; 150 mg/kg) or N-2-mercaptopropionyl glycine (2-MPG; 1 mg. kg(-1).min(-1)), in the presence or absence of 1.0 minimum alveolar concentration (MAC) isoflurane. Isoflurane was administered for 30 min and then discontinued 15 min before coronary artery occlusion. A fluorescent probe for superoxide anion production (dihydroethidium, 2 mg) was administered in the absence of the volatile anesthetic or 5 min before exposure to isoflurane in 2 additional groups (n = 8). Myocardial infarct size and superoxide anion production were assessed using triphenyltetrazolium staining and confocal fluorescence microscopy, respectively.<br><br>RESULTS: Isoflurane (P < 0.05) decreased infarct size to 24 +/- 4% (mean +/- SEM; n = 10) of the left ventricular area at risk compared with control experiments (43 +/- 3%; n = 8). NAC (43 +/- 3%; n = 7) and 2-MPG (42 +/- 5%; n = 8) abolished this beneficial effect, but had no effect on myocardial infarct size (47 +/- 3%; n = 8 and 46 +/- 3; n = 7, respectively) when administered alone. Isoflurane increased superoxide anion production as compared with control experiments (28 +/- 12 -6 +/- 9 fluorescence units; P < 0.05).<br><br>CONCLUSIONS: The results indicate that ROS produced following administration of isoflurane contribute to protection against myocardial infarction in vivo.}, }
@article {pmid12459467, year = {2002}, author = {Zhu, BZ and Carr, AC and Frei, B}, title = {Pyrrolidine dithiocarbamate is a potent antioxidant against hypochlorous acid-induced protein damage.}, journal = {FEBS letters}, volume = {532}, number = {1-2}, pages = {80-84}, doi = {10.1016/s0014-5793(02)03637-2}, pmid = {12459467}, issn = {0014-5793}, support = {AT00066/AT/NCCIH NIH HHS/United States ; ES00210/ES/NIEHS NIH HHS/United States ; ES11497/ES/NIEHS NIH HHS/United States ; HL60886/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aldehydes/metabolism ; Antioxidants/chemistry/*pharmacology ; Chlorine/metabolism ; Cyclohexanones/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Ferrocyanides/metabolism ; Glutathione/pharmacology ; Hypochlorous Acid/*antagonists &amp; inhibitors ; Lipoproteins, LDL/metabolism ; Oxidants/*antagonists &amp; inhibitors ; Oxidation-Reduction ; Oxidative Stress ; Pyrrolidines/chemistry/*pharmacology ; Serum Albumin/metabolism ; Thiocarbamates/chemistry/*pharmacology ; alpha 1-Antitrypsin/metabolism ; }, abstract = {The antioxidant potential of the dithiol compound pyrrolidine dithiocarbamate (PDTC) against protein damage induced by hypochlorous acid (HOCl) was investigated. The effects of PDTC were compared to those of reduced glutathione (GSH) and N-acetylcysteine (NAC). PDTC markedly and in a concentration-dependent manner inhibited HOCl-induced inactivation of alpha(1)-antiproteinase, protein carbonyl formation on serum albumin and oxidation of human low-density lipoprotein. The direct scavenging of HOCl by PDTC was demonstrated by two quantitative methods, oxidation of ferrocyanide and chlorination of monochlorodimedon. In all assay systems, PDTC was two to three times more potent than GSH and NAC, while diethyldithiocarbamate was about as effective as PDTC. These data demonstrate that PDTC is a potent antioxidant against HOCl-induced protein oxidative damage, suggesting that PDTC might be useful in the prevention and treatment of inflammatory conditions.}, }
@article {pmid12458670, year = {2002}, author = {Harada, D and Naito, S and Otagiri, M}, title = {Kinetic analysis of covalent binding between N-acetyl-L-cysteine and albumin through the formation of mixed disulfides in human and rat serum in vitro.}, journal = {Pharmaceutical research}, volume = {19}, number = {11}, pages = {1648-1654}, pmid = {12458670}, issn = {0724-8741}, mesh = {Acetylcysteine/blood/*metabolism ; Animals ; Disulfides/blood/*metabolism ; Humans ; Male ; Pharmacokinetics ; Protein Binding/drug effects/physiology ; Rats ; Rats, Sprague-Dawley ; Serum Albumin/*metabolism ; }, abstract = {PURPOSE: Covalent binding between N-acetyl-L-cysteine (NAC) and albumin was evaluated kinetically by conducting in vitro experiments.<br><br>METHOD: After 14C-NAC was incubated with human or rat serum, the solution was analyzed by anion-exchange HPLC. The albumin-bound 14C-NAC was quantified by measuring the radioactivity in the albumin fraction.<br><br>RESULTS: Ultraviolet chromatograms and/or radiochromatograms indicated the presence of a stable covalent bond between 14C-NAC and either human or rat albumin. By analyzing the time dependence of this protein binding in serum, the first-order binding and dissociation rate constants (k(on) and k(off) were obtained. The serum was treated in a CO2 incubator to avoid oxidative interference, and the initial rates were determined separately. The k(on) values obtained were 0.33 (h(-1)) and 0.48 (h(-1)) for human and rat serum, respectively. L-Cysteine was required to initiate the dissociation of 14C-NAC bound to albumin. Following the addition of appropriate amounts of L-cysteine, the k(off) values were determined to be 0.30-1.0 h(-1) and 0.54-1.4 h(-1) for human and rat serum, respectively.<br><br>CONCLUSIONS: The k(on) and k(off) values obtained for rat serum were in good agreement with the in vivo plasma protein binding kinetics of NAC in rats, indicating the reliability of this in vitro method for evaluating protein binding. No species differences in protein binding kinetics were found between human and rat serum.}, }
@article {pmid12448825, year = {2002}, author = {Kowluru, RA and Koppolu, P}, title = {Diabetes-induced activation of caspase-3 in retina: effect of antioxidant therapy.}, journal = {Free radical research}, volume = {36}, number = {9}, pages = {993-999}, doi = {10.1080/1071576021000006572}, pmid = {12448825}, issn = {1071-5762}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Antioxidants/*therapeutic use ; Apoptosis ; Ascorbic Acid/administration &amp; dosage ; Caspase 3 ; Caspases/*metabolism ; Diabetes Mellitus, Experimental/*enzymology ; Diabetic Retinopathy/enzymology/pathology/*prevention &amp; control ; Endothelium, Vascular/enzymology/pathology ; Enzyme Activation ; Glucose/metabolism ; In Vitro Techniques ; Male ; Oxidative Stress ; Pericytes/enzymology/pathology ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; Rats, Sprague-Dawley ; Retina/*enzymology ; Selenium/administration &amp; dosage ; Thiobarbituric Acid Reactive Substances/metabolism ; alpha-Tocopherol/administration &amp; dosage ; beta Carotene/administration &amp; dosage ; }, abstract = {Apoptosis of retinal endothelial cells and pericytes is postulated to contribute to the development of retinopathy in diabetes. The goal of this study is to investigate diabetes-induced activation of retinal caspase-3, an apoptosis executer enzyme, in retina, and examine the effects of antioxidants on the activation. Caspase-3 activation was determined in the retina of alloxan diabetic rats (2-14 months duration) and in the isolated retinal capillary cells (endothelial cells and pericytes) by measuring cleavage of caspase-3 specific fluorescent substrate, and cleavage of caspase-3 holoenzyme and poly (ADP ribosyl) polymerase. Effect of antioxidants on the activation of caspase-3 was determined by feeding a group of diabetic rats diet supplemented with a comprehensive mixture of antioxidants, including Trolox, alpha-tocopherol, N-acetyl cysteine, ascorbic acid, beta-carotene and selenium for 2-14 months, and also under in vitro conditions by incubating isolated retinal capillary cells with antioxidants with wide range of actions. Caspase-3 was activated in the rat retina at 14 months of diabetes (P < 0.05 vs. normal), but not at 2 months of diabetes, and administration of antioxidants for the entire duration inhibited this activation. In the isolated retinal capillary cells incubated in 25 mM glucose medium, caspase-3 activity was increased by 50% compared to the cells incubated in 5 mM glucose (P < 0.02), and antioxidants or caspase-3 inhibitor inhibited this increase. Our results suggest that increased oxidative stress in diabetes is involved in the activation of retinal caspase-3 and apoptosis of endothelial cells and pericytes. Antioxidants might be inhibiting the development of diabetic retinopathy by inhibiting microvascular apoptosis.}, }
@article {pmid12446176, year = {2002}, author = {Failli, P and Palmieri, L and D'Alfonso, C and Giovannelli, L and Generini, S and Rosso, AD and Pignone, A and Stanflin, N and Orsi, S and Zilletti, L and Matucci-Cerinic, M}, title = {Effect of N-acetyl-L-cysteine on peroxynitrite and superoxide anion production of lung alveolar macrophages in systemic sclerosis.}, journal = {Nitric oxide : biology and chemistry}, volume = {7}, number = {4}, pages = {277-282}, doi = {10.1016/s1089-8603(02)00120-9}, pmid = {12446176}, issn = {1089-8603}, mesh = {Acetylcysteine/*pharmacology ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Female ; Humans ; Immunohistochemistry/methods ; Lung/metabolism/pathology ; Macrophages, Alveolar/drug effects/*metabolism ; Male ; Middle Aged ; Nitric Oxide Synthase/biosynthesis ; Nitric Oxide Synthase Type II ; Peroxynitrous Acid/analysis/*biosynthesis ; Scleroderma, Systemic/*metabolism/pathology ; Superoxides/analysis/*metabolism ; }, abstract = {Lung macrophages may play a relevant role in oxidative processes producing both superoxide anion (O(2)(-)) and NO. In this view, an antioxidant therapy can be useful in the treatment of systemic sclerosis (SSc) patients. N-Acetylcysteine (NAC) is able to expand natural antioxidant defenses by increasing intracellular gluthatione concentration and it has been proposed as an antioxidant therapy in respiratory distress syndromes. The aim of our study was to determine whether lung macrophages obtained from SSc patient bronchoalveolar lavage (BAL) express the inducible form of nitric oxide synthase (iNOS) and whether NAC can reduce the peroxynitrite (ONOO(-)) and O(2)(-) production of these cells. Alveolar macrophages were isolated from BAL of 32 patients and used for the immunocytochemical determination of iNOS, and the production of ONOO(-) and O(2)(-) was measured by fluorimetric or spectrophotometric methods, respectively. Lung macrophages obtained from SSc patients expressed a higher level of iNOS compared to healthy subject cells. NAC preincubation (5 x 10(-5)M, 24h) significantly reduced (-21%) the ONOO(-) production in formyl Met-Leu-Phe (fMLP)-activated cells and slightly reduced it under resting conditions, whereas NAC preincubation was unable to modify the release of O(2)(-) both in basal condition and in fMLP-stimulated cells. We conclude that since SSc lung macrophages express high levels of iNOS and produce a significant quantity of ONOO(-), NAC administration reduces ONOO(-) production and can be an useful treatment to alleviate SSc symptoms.}, }
@article {pmid12439841, year = {2002}, author = {Vallero, A and Cesano, G and Pozzato, M and Garbo, R and Minelli, M and Quarello, F and Formica, M}, title = {[Contrast nephropathy in cardiac procedures: no advantages with prophylactic use of N-acetylcysteine (NAC)].}, journal = {Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia}, volume = {19}, number = {5}, pages = {529-533}, pmid = {12439841}, issn = {0393-5590}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Kidney Injury/chemically induced/*prevention &amp; control ; *Angioplasty, Balloon ; Contrast Media/*adverse effects ; *Coronary Angiography ; Creatinine/blood ; Drug Administration Schedule ; Ferric Compounds/*adverse effects ; Fluid Therapy ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Hypotonic Solutions/therapeutic use ; Iron/*adverse effects ; Kidney Function Tests ; Oxides/*adverse effects ; *Premedication ; Prospective Studies ; Risk Factors ; Sodium Chloride/therapeutic use ; Treatment Failure ; Triiodobenzoic Acids/*adverse effects ; }, abstract = {BACKGROUND: Acute renal failure induced by contrast agents represents the third cause of acute nephropathy in hospitalized patients. Some mediators are potentially involved in this process: recent data underscored the role of oxidising agents and prophylactic administration of NAC showed a lower incidence of acute renal damage after using contrast agents.<br><br>METHODS: We analyzed 100 patients consecutively undergoing coronary angiography and/or transluminal angioplasty: the study group was given NAC orally at a dose of 600 mg twice daily, on the day before and on the day of administration of the contrast agent, together with hydration, while the control group was given only the hydration protocol with hypotonic saline.<br><br>RESULTS: Twenty patients had baseline serum creatinine concentrations > 1.2 mg/dL (mild renal insufficiency group). The mean dose of contrast agent (Iodixanol; Visipaque 320, Nycomed) was 203 mL/procedure, with no statistical difference between groups. Among the patients with normal renal function, 5.7% in the NAC group and 8.8% in the control group had baseline serum creatinine concentrations above 0.3 mg/dL after 48 hours (p=NS). In patients with mild renal failure, 16.6% in the NAC group and 0% in the control group had serum creatinine concentrations > 0.5 mg/dL at 48 h (p=NS). We found no significant differences in serum creatinine values at 48 hours vs. baseline in anyone (NAC group with normal renal function or mild renal insufficiency, control group with normal renal function or mild renal insufficiency). Similarly, serum creatinine values at either baseline or after 48 hours were not significantly different in patients with normal renal function (NAC vs. control group) and with mild renal failure.<br><br>CONCLUSIONS: Our study showed no potential advantage in the prevention of acute nephropathy, induced by high volumes of contrast agent, through the administration of NAC in patients with normal renal function and mild renal failure. However, the NAC dose used in our study might not be sufficient in balancing the contrast agent volume employed in these procedures.}, }
@article {pmid12439169, year = {2002}, author = {Blakley, BW and Cohen, JI and Doolittle, ND and Muldoon, LL and Campbell, KC and Dickey, DT and Neuwelt, EA}, title = {Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001.}, journal = {The Laryngoscope}, volume = {112}, number = {11}, pages = {1997-2001}, doi = {10.1097/00005537-200211000-00016}, pmid = {12439169}, issn = {0023-852X}, support = {CA31770/CA/NCI NIH HHS/United States ; NS33618/NS/NINDS NIH HHS/United States ; NS34608/NS/NINDS NIH HHS/United States ; R13 CA86959/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*adverse effects ; Antioxidants/*pharmacology ; Blood-Brain Barrier ; Carboplatin/*adverse effects ; Cisplatin/*adverse effects ; Head and Neck Neoplasms/*drug therapy ; Hearing Loss/*chemically induced/*prevention &amp; control ; Humans ; Methionine/pharmacology ; Platinum Compounds/*adverse effects ; Thiosulfates/pharmacology ; }, abstract = {OBJECTIVES: To summarize the findings relevant to otolaryngology from the annual meeting of the Blood-Brain Barrier Disruption Consortium in Gleneden Beach, Oregon, March 10, 2001.<br><br>STUDY DESIGN: Summaries are provided by the speakers, as well as related data from the published literature. Findings in otology and oncology regarding ototoxicity that were discussed at the meeting are included.<br><br>RESULTS: Data considered included physiological research, animal studies, and clinical trials that relate to platinum-based chemotherapy and prevention of toxicity.<br><br>CONCLUSIONS: The dose-limiting side effects of platinum-based chemotherapy are preventable, but questions about the effect of the protective agents on oncological efficacy remain. Strategies for prevention of chemotherapy-induced toxicity include temporal or anatomical separation of cisplatin or carboplatin from sodium thiosulfate, D-methionine, or N-acetyl-cysteine. Clinical application of these methods has begun. The mechanisms presumably involve free radicals or drug conjugation, or both. Understanding the role of free radicals in medicine is likely to become important in the future.}, }
@article {pmid12431779, year = {2002}, author = {Kim, E and Kim, JH and Kim, HS and Ryu, SH and Suh, PG}, title = {Thimerosal stimulates focal adhesion kinase and cytoskeletal changes by redox modulation.}, journal = {Biochimica et biophysica acta}, volume = {1593}, number = {1}, pages = {9-15}, doi = {10.1016/s0167-4889(02)00275-6}, pmid = {12431779}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Actins/drug effects ; Calcium/metabolism ; Cytoskeleton/*drug effects ; Enzyme Inhibitors/pharmacology ; Focal Adhesion Kinase 1 ; Focal Adhesion Protein-Tyrosine Kinases ; Free Radical Scavengers/pharmacology ; HeLa Cells ; Humans ; Oxidation-Reduction ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/*drug effects ; Reactive Oxygen Species/metabolism ; Stress Fibers/drug effects ; Thimerosal/*pharmacology ; Tyrphostins/pharmacology ; }, abstract = {Thimerosal is one of the most widely used preservatives and has been reported to cause chemically mediated side effects. However, the mechanism of the side effects is not clearly understood yet. In the present study, we showed that HeLa S cells treated by thimerosal generated reactive oxygen species (ROS). Thimerosal-generated ROS stimulated the tyrosine phosphorylation of focal adhesion kinase (FAK) and also induced cytoskeletal changes. Pretreatment with intracellular calcium chelator, BAPTA did not block the thimerosal-mediated FAK tyrosine phosphorylation. On the other hand, either FAK inhibitor, tyrphostin or ROS scavenger, N-acetyl-L-cysteine (NAC) suppressed the tyrosine phosphorylation and cytoskeletal changes. These results suggest that thimerosal seems to induce FAK tyrosine phosphorylation and cytoskeletal changes by ROS generation but not by intracellular calcium mobilization. We think the present finding can be an important clue to understanding the mechanism of thimerosal-mediated side effects, such as contact dermatitis, and allergy.}, }
@article {pmid12427904, year = {2002}, author = {Edwards, MJ and Hargreaves, IP and Heales, SJ and Jones, SJ and Ramachandran, V and Bhatia, KP and Sisodiya, S}, title = {N-acetylcysteine and Unverricht-Lundborg disease: variable response and possible side effects.}, journal = {Neurology}, volume = {59}, number = {9}, pages = {1447-1449}, doi = {10.1212/wnl.59.9.1447}, pmid = {12427904}, issn = {0028-3878}, mesh = {Acetylcysteine/*administration &amp; dosage/*adverse effects ; Adult ; Antioxidants/*administration &amp; dosage/*adverse effects ; Female ; Glutathione/blood ; Humans ; Male ; Middle Aged ; Unverricht-Lundborg Syndrome/blood/*drug therapy ; }, abstract = {Serum glutathione levels were assessed in a patient with genetically proven Unverricht-Lundborg disease (ULD) before and during treatment with the antioxidant N-acetylcysteine (NAC). Glutathione levels were low before treatment, and increased during treatment. This increase was mirrored by an improvement in seizures, but not in myoclonus or ataxia. Three other patients with clinically determined ULD showed a variable response and some notable side effects during treatment with NAC.}, }
@article {pmid12427146, year = {2002}, author = {Durham, JD and Caputo, C and Dokko, J and Zaharakis, T and Pahlavan, M and Keltz, J and Dutka, P and Marzo, K and Maesaka, JK and Fishbane, S}, title = {A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography.}, journal = {Kidney international}, volume = {62}, number = {6}, pages = {2202-2207}, doi = {10.1046/j.1523-1755.2002.00673.x}, pmid = {12427146}, issn = {0085-2538}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/chemically induced/epidemiology/*prevention &amp; control ; Aged ; Aged, 80 and over ; Contrast Media/*adverse effects ; Coronary Angiography/*adverse effects ; Coronary Disease/*diagnostic imaging ; Female ; Follow-Up Studies ; Free Radical Scavengers/*pharmacology ; Humans ; Incidence ; Male ; Middle Aged ; Prospective Studies ; }, abstract = {BACKGROUND: Contrast nephropathy (CN) is a common cause of renal dysfunction after cardiac angiography. Recently, N-acetylcysteine (NAC) has been found to reduce the risk of CN after CT imaging with contrast enhancement. The purpose of the current study was to evaluate the efficacy of NAC for the prevention of CN in the setting of cardiac angiography.<br><br>METHODS: Eligible patients were those undergoing cardiac angiography with serum creatinine>1.7 mg/dL. Patients were randomized to one of two groups: Group 1, IV hydration and NAC, 1200 mg one hour before angiography, and a second dose 3 hours after; Group 2, IV hydration and placebo. CN was defined as an increase of 0.5 mg/dL in serum creatinine.<br><br>RESULTS: Seventy-nine patients completed the study. There were no significant differences between the groups in baseline characteristics, duration of angiography, mean volume of dye infused or mean IV hydration. Contrast nephropathy developed in 24.0% of subjects, 26.3% NAC, and 22.0% placebo (P = NS). Among subjects with diabetes mellitus, there was no significant difference in the rate of CN between the groups (42.1% NAC, 27.8% placebo; P = 0.09). The independent predictors of CN risk were diabetes mellitus and preexisting chronic renal insufficiency.<br><br>CONCLUSIONS: NAC was not effective for the prevention of CN after cardiac angiography.}, }
@article {pmid12424738, year = {2002}, author = {Belletti, S and Orlandini, G and Vettori, MV and Mutti, A and Uggeri, J and Scandroglio, R and Alinovi, R and Gatti, R}, title = {Time course assessment of methylmercury effects on C6 glioma cells: submicromolar concentrations induce oxidative DNA damage and apoptosis.}, journal = {Journal of neuroscience research}, volume = {70}, number = {5}, pages = {703-711}, doi = {10.1002/jnr.10419}, pmid = {12424738}, issn = {0360-4012}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Adenosine Triphosphate/metabolism ; Animals ; Apoptosis/*drug effects ; Cell Division/drug effects ; Cell Survival/drug effects ; *DNA Damage ; Deoxyguanosine/*analogs &amp; derivatives ; Fluoresceins ; *Glioma ; In Situ Nick-End Labeling ; Membrane Potentials/physiology ; Methylmercury Compounds/*toxicity ; Microscopy, Confocal ; Mitochondria/metabolism ; Oxidative Stress/*drug effects ; Rats ; Time Factors ; Tumor Cells, Cultured/cytology/drug effects/metabolism ; }, abstract = {Organic mercury is a well-known neurotoxicant although its mechanism of action has not been fully clarified. In addition to a direct effect on neurons, much experimental evidence supports an involvement of the glial component. We assessed methylmercury hydroxide (MeHgOH) toxicity in a glial model, C6 glioma cells, exposed in the 10(-5)-10(-8) M range. The time course of the effects was studied by time-lapse confocal microscopy and supplemented with biochemical data. We have monitored cell viability and proliferation rate, reactive oxygen species (ROS), mitochondrial transmembrane potential, DNA oxidation, energetic metabolism and modalities of cell death. The earliest effect was a measurable ROS generation followed by oxidative DNA damage paralleled by a partial mitochondrial depolarization. The effect on cell viability was dose dependent. TUNEL, caspase activity and real-time morphological observation of calcein-loaded cells showed that apoptosis was the only detectable mode of cell death within this concentration range. N-acetyl-cysteine (NAC) or reduced glutathione (GSH) completely prevent the apoptotic effect of MeHgOH. The lowest effective MeHgOH concentration was 10(-7) M for ROS and DNA OH-adducts generation. The effect of submicromolar concentrations of MeHgOH on C6 cells could be relevant in the developmental neurotoxicity caused by low dose, long-term exposures, such as those of food origin. In addition, we have shown that the same concentrations are effective in the induction of DNA oxidative damage, with further potential pathogenetic implications.}, }
@article {pmid12421841, year = {2002}, author = {Li, J and Quan, N and Bray, TM}, title = {Supplementation of N-acetylcysteine normalizes lipopolysaccharide-induced nuclear factor kappaB activation and proinflammatory cytokine production during early rehabilitation of protein malnourished mice.}, journal = {The Journal of nutrition}, volume = {132}, number = {11}, pages = {3286-3292}, doi = {10.1093/jn/132.11.3286}, pmid = {12421841}, issn = {0022-3166}, support = {R01 NS 38315/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Biological Transport ; Cell Nucleus/metabolism ; Chromatography, High Pressure Liquid ; Cytokines/*biosynthesis ; Dietary Supplements ; Glutathione/metabolism ; I-kappa B Proteins/genetics ; In Situ Hybridization ; Interleukin-1/genetics ; Lipopolysaccharides/*pharmacology ; Male ; Mice ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Oxidation-Reduction ; Protein Deficiency/*drug therapy ; RNA, Messenger/biosynthesis ; Tumor Necrosis Factor-alpha/genetics ; }, abstract = {Increased sensitivity to septic shock has been reported in protein malnourished patients. In this study, we used an animal septic shock model to investigate effects of glutathione (GSH) levels on nuclear factor kappaB (NFkappaB) activation and proinflammatory cytokine production in protein malnutrition. We further investigated molecular mechanisms by which protein malnutrition influenced inflammatory responses. CD-1 mice were fed for 3 wk a normal protein (150 g/kg) diet or a protein-deficient (5 g/kg) diet, or for 2 wk a protein-deficient diet followed by 1 wk of N-acetylcysteine (NAC) supplementation. Lipopolysaccharide (LPS) was injected intravenously, and liver was collected at 0, 15 min, 1, 4, 24 and 48 h after LPS administration. Protein malnutrition significantly increased the activation of NFkappaB and transcription levels of its downstream genes interleukin-1beta and tumor necrosis factor-alpha. Peak NFkappaB activation was inversely associated with GSH levels (r = -0.939, P < 0.0001) but positively correlated with the GSH disulfide/2GSH reduction potential (r = 0.944 P < 0.0001). We noted unusual NFkappaB p50/p50 homodimer translocation that was significantly elevated in tissue from protein malnourished mice, along with decreased peak levels of normal p65/p50 heterodimer translocation. Interestingly, mRNA levels of IkappaB-alpha were not affected by protein malnutrition. However, early supplementation of NAC to protein malnourished mice without replenishing with dietary protein restored GSH levels and reduction potential, and normalized NFkappaB activation and proinflammatory cytokine production. Taken together, these findings provide evidence supporting the role of GSH in NFkappaB activation and inflammatory response in protein malnutrition, and the use of NAC in early rehabilitation of protein malnutrition without a high protein diet.}, }
@article {pmid12420741, year = {2002}, author = {Schaaf, GJ and Maas, RF and de Groene, EM and Fink-Gremmels, J}, title = {Management of oxidative stress by heme oxygenase-1 in cisplatin-induced toxicity in renal tubular cells.}, journal = {Free radical research}, volume = {36}, number = {8}, pages = {835-843}, doi = {10.1080/1071576021000005267}, pmid = {12420741}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Cell Line ; Cell Survival ; Cisplatin/pharmacology/*toxicity ; Coloring Agents/pharmacology ; Dose-Response Relationship, Drug ; Heme Oxygenase (Decyclizing)/*pharmacology ; Heme Oxygenase-1 ; Hemin/pharmacology ; Kidney Tubules/*cytology ; Oxidation-Reduction ; *Oxidative Stress ; Oxygen/metabolism ; Reactive Oxygen Species ; Swine ; Tetrazolium Salts/pharmacology ; Thiazoles/pharmacology ; Time Factors ; alpha-Tocopherol/pharmacology ; }, abstract = {Induction of heme oxygenase-1 (HO-1) may serve as an immediate protective response during treatment with the cytostatic drug cisplatin (CDDP). Oxidative pathways participate in the characteristic nephrotoxicity of CDDP. In the present study, cultured tubular cells (LLC-PK1) were used to investigate whether induction of HO provided protection against CDDP by maintaining the cellular redox balance. The antioxidants, alpha-tocopherol (TOCO) and N-acetylcysteine (NAC), were used to demonstrate that elevation of ROS levels contribute to the development of CDDP-induced cytotoxicity. Chemical modulators of HO activity were used to investigate the role of HO herein. Hemin was used to specifically induce HO-1, while exposure of the cells to tin-protoporphyrin (SnPP) was shown to inhibit HO activity. Hemin treatment prior to CDDP-exposure significantly decreased the generation of ROS to control levels, while inhibition of HO increased the ROS levels beyond the levels measured in cells treated with CDDP alone. Furthermore, HO induction protected significantly against the cytotoxicity of CDDP, although this protection was limited. Similar results were obtained when the cells were preincubated with TOCO, suggesting that mechanisms other than impairment of the redox ratio are important in CDDP-induced loss of cell viability in vitro. In addition, SnPP treatment exacerbated the oxidative response and cytotoxicity of CDDP, especially at low CDDP concentrations. We therefore conclude that HO is able to directly limit the CDDP-induced oxidative stress response and thus serves as safeguard of the cellular redox balance.}, }
@article {pmid12417265, year = {2002}, author = {Kyaw, M and Yoshizumi, M and Tsuchiya, K and Kirima, K and Suzaki, Y and Abe, S and Hasegawa, T and Tamaki, T}, title = {Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and activator protein-1 (AP-1).}, journal = {Biochemical pharmacology}, volume = {64}, number = {10}, pages = {1521-1531}, doi = {10.1016/s0006-2952(02)01349-7}, pmid = {12417265}, issn = {0006-2952}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Cell Division/drug effects ; Cyclic N-Oxides/pharmacology ; DNA/drug effects/metabolism ; Dose-Response Relationship, Drug ; Endothelin-1/pharmacology ; Endothelins/*pharmacology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Humans ; Imidazoles/pharmacology ; JNK Mitogen-Activated Protein Kinases ; Male ; Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/metabolism ; Muscle, Smooth, Vascular/cytology/*drug effects ; Onium Compounds/pharmacology ; Peptide Fragments/*pharmacology ; Pyridines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Time Factors ; Transcription Factor AP-1/*antagonists &amp; inhibitors/metabolism ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {We previously found that human chymase cleaves big endothelins (ETs) at the Tyr(31)-Gly(32) bond and produces 31-amino acid ETs (1-31), without any further degradation products. In the present study, we investigated the effects of various antioxidants on the ET-1 (1-31)-induced change in intracellular signaling and proliferation of cultured rat aortic smooth muscle cells (RASMC). ET-1 (1-31) stimulated rapid and significant activation of the mitogen-activated protein (MAP) kinase family, i.e. extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK, in RASMC to an extent similar to that of ET-1. All of the antioxidants examined, i.e. N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), and L-(+)-ascorbic acid (ascorbic acid), inhibited both ET-1 (1-31)- and ET-1-induced JNK and p38 MAPK activation but not ERK1/2 activation. Electron paramagnetic resonance (EPR) spectroscopy measurements revealed that NAC, DPI, and ascorbic acid inhibited xanthine oxidase-induced superoxide (O(2)(.-)) generation in a cell-free system. ET-1 (1-31) in addition to ET-1 increased the generation of cellular reactive oxygen species (ROS) in RASMC. ET-1 (1-31)- and ET-1-induced cellular ROS generation was inhibited similarly by NAC, DPI, and ascorbic acid in RASMC. Gel-mobility shift analysis showed that ET-1 (1-31) and ET-1 caused an increase in activator protein-1 (AP-1)-DNA binding activity in RASMC that was inhibited by the above three antioxidants. ET-1 (1-31) increased [3H]thymidine incorporation into cells to an extent similar to that of ET-1. This ET-1 (1-31)-induced increase in [3H]thymidine incorporation was also inhibited by NAC and DPI, but not by ascorbic acid. These results suggest that antioxidants inhibit ET-1 (1-31)-induced RASMC proliferation by inhibiting ROS generation within the cells. The underlying mechanisms of the inhibition of cellular proliferation by antioxidants may be explained, in part, by the inhibition of JNK activation and the resultant inhibition of AP-1-DNA binding.}, }
@article {pmid12414524, year = {2002}, author = {Sun, Y and Zhang, J and Lu, L and Chen, SS and Quinn, MT and Weber, KT}, title = {Aldosterone-induced inflammation in the rat heart : role of oxidative stress.}, journal = {The American journal of pathology}, volume = {161}, number = {5}, pages = {1773-1781}, pmid = {12414524}, issn = {0002-9440}, support = {R01 HL067888/HL/NHLBI NIH HHS/United States ; R01-HL66575/HL/NHLBI NIH HHS/United States ; R01 HL066575/HL/NHLBI NIH HHS/United States ; R01-HL67888/HL/NHLBI NIH HHS/United States ; R01-HL6229/HL/NHLBI NIH HHS/United States ; }, mesh = {Aldosterone/*pharmacology ; Animals ; Antioxidants/pharmacology ; Cardiomyopathies/chemically induced/*immunology/metabolism ; Cell Division ; Cell Movement ; Fibrosis ; Heart/drug effects ; Immunologic Factors/biosynthesis/genetics ; Inflammation/chemically induced/immunology/metabolism ; Lymphocytes/immunology ; Macrophages/immunology ; Male ; Mineralocorticoid Receptor Antagonists/pharmacology ; Monocytes/immunology ; Myocardium/immunology/metabolism/pathology ; NADPH Oxidases/metabolism ; NF-kappa B/metabolism ; *Oxidative Stress ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Spironolactone/pharmacology ; Tyrosine/*analogs &amp; derivatives/analysis ; }, abstract = {Heart failure and hypertension have each been linked to an induction of oxidative stress transduced by neurohormones, such as angiotensin II and catecholamines. Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury found in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment. Uninephrectomized rats received ALDO (0.75 micro g/hour) together with 1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o. daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg s.c. daily) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and untreated age- and gender-matched rats served as controls. We monitored spatial and temporal responses in molecular and cellular events using serial, coronal sections of right and left ventricles. Our studies included: assessment of systolic blood pressure; immunohistochemical detection of NADPH oxidase expression and activity; analysis of redox-sensitive nuclear factor-kappaB activation; in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha mRNA expression; monitoring cell growth and infiltration of macrophages and T cells; and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart. However, at weeks 4 and 5 of treatment, increased gp91(phox) and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in time and space with these events was increased mRNA expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. Macrophages, lymphocytes, and proliferating endothelial and vascular smooth muscle cells and fibroblast-like cells were seen at each of these sites, together with an accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant increase in ventricular collagen volume fraction. Co-treatment with spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as well as the appearance of fibrosis at vascular and nonvascular sites of injury. Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt treatment is accompanied by a time-dependent sustained activation of NADPH oxidase with 3-nitrotyrosine generation and nuclear factor-kappaB activation expressed by endothelial cells and inflammatory cells. This leads to a proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of injury found, respectively, in both normotensive and hypertensive right and left ventricles. Spionolactone, PDTC, and NAC each attenuated these responses suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for the appearance of this proinflammatory phenotype.}, }
@article {pmid12411394, year = {2002}, author = {Lopes, NH and Vasudevan, SS and Gregg, D and Selvakumar, B and Pagano, PJ and Kovacic, H and Goldschmidt-Clermont, PJ}, title = {Rac-dependent monocyte chemoattractant protein-1 production is induced by nutrient deprivation.}, journal = {Circulation research}, volume = {91}, number = {9}, pages = {798-805}, doi = {10.1161/01.res.0000040421.54108.81}, pmid = {12411394}, issn = {1524-4571}, support = {R01 HL-71536/HL/NHLBI NIH HHS/United States ; }, mesh = {Active Transport, Cell Nucleus/drug effects/physiology ; Antioxidants/pharmacology ; Cell Culture Techniques/methods ; Cell Line ; Chemokine CCL2/*biosynthesis/genetics ; Culture Media/pharmacology ; Endothelium, Vascular/cytology/drug effects/*metabolism ; Enzyme Inhibitors/pharmacology ; Genes, Reporter ; Humans ; NADPH Oxidases/antagonists &amp; inhibitors ; NF-kappa B/antagonists &amp; inhibitors/genetics/metabolism ; Peptides/pharmacology ; Reactive Oxygen Species/metabolism ; Recombinant Fusion Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Superoxides/metabolism ; Time Factors ; Transfection ; rac1 GTP-Binding Protein/genetics/*metabolism ; }, abstract = {Under ischemic conditions, the vessel wall recruits inflammatory cells. Human aortic endothelial cells (HAECs) exposed to hypoxia followed by reoxygenation produce monocyte chemoattractant protein-1 (MCP-1); however, most experiments have been performed in the presence of nutrient deprivation (ND). We hypothesized that ND rather than hypoxia mediates endothelial MCP-1 production during ischemia, and that the small GTP-binding protein Rac1 and reactive oxygen species (ROS) are involved in this process. ND was generated by shifting HAECs from 10% to 1% FBS. Superoxide production by HAECs was increased 6 to 24 hours after ND, peaking at 18 hours. MCP-1 production was increased over a similar time frame, but peaked later at 24 hours. These effects were blocked by treatment with antioxidants such as superoxide dismutase mimetic and N-acetylcysteine (NAC), or NADPH oxidase inhibitors, DPI and gp91ds-tat. Superoxide and MCP-1 production were enhanced by RacV12 (constitutively active) in the absence of ND, and were inhibited by RacN17 (dominant-negative) adenoviral transduction under ND, suggesting that the small G-protein Rac1 is required. In conclusion, ND, an important component of ischemia, is sufficient to induce MCP-1 production by HAECs, and such production requires a functional Rac1, redox-dependent pathway.}, }
@article {pmid12410497, year = {2002}, author = {Allaqaband, S and Tumuluri, R and Malik, AM and Gupta, A and Volkert, P and Shalev, Y and Bajwa, TK}, title = {Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy.}, journal = {Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography &amp; Interventions}, volume = {57}, number = {3}, pages = {279-283}, doi = {10.1002/ccd.10323}, pmid = {12410497}, issn = {1522-1946}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Aged, 80 and over ; Angioplasty, Balloon, Coronary ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Antihypertensive Agents/*therapeutic use ; Cardiovascular Diseases/complications/diagnosis/therapy ; Contrast Media/administration &amp; dosage/*adverse effects ; Coronary Angiography ; Creatinine/blood ; Female ; Fenoldopam/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Kidney Diseases/*chemically induced/epidemiology/*prevention &amp; control ; Male ; Middle Aged ; Prospective Studies ; Radiopharmaceuticals/administration &amp; dosage/*adverse effects ; Risk Factors ; Sodium Chloride/*therapeutic use ; Stroke Volume/physiology ; Treatment Outcome ; }, abstract = {The objective of this study was to compare the efficacy of N-acetylcysteine (NAC), fenoldopam, and saline in preventing radiocontrast-induced nephropathy (RCIN) in high-risk patients undergoing cardiovascular procedures. We prospectively enrolled 123 patients who were scheduled for cardiovascular procedures and had a baseline creatinine > 1.6 mg/dl or creatinine clearance of < 60 ml/min. Patients were randomly assigned to receive either saline (0.45% normal saline at 1 cc/kg) for 12 hr before and 12 hr after the procedure, or fenoldopam (0.1 microg/kg/min) plus saline for 4 hr prior and 4 hr after the procedure, or NAC orally (600 mg) plus saline every 12 hr for 24 hr prior and 24 hr after the procedure. All the patients received low-osmolality nonionic contrast. RCIN was defined as an increase in creatinine level > 0.5 mg/dl after 48 hr. The incidence of RCIN was 17.7% in the NAC group, 15.3% in the saline group, and 15.7% in the fenoldopam group (P = 0.919). Of the 20 patients who developed RCIN, 2 required dialysis. Serum creatinine decreased after 48 hr (vs. baseline) in 38% patients in the NAC group, 18% in the fenoldopam group, and 15% in the saline group. In patients with chronic renal insufficiency, NAC or fenoldopam offered no additional benefit over hydration with saline in preventing RCIN.}, }
@article {pmid12408474, year = {2002}, author = {De Deene, Y and Hurley, C and Venning, A and Vergote, K and Mather, M and Healy, BJ and Baldock, C}, title = {A basic study of some normoxic polymer gel dosimeters.}, journal = {Physics in medicine and biology}, volume = {47}, number = {19}, pages = {3441-3463}, doi = {10.1088/0031-9155/47/19/301}, pmid = {12408474}, issn = {0031-9155}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Dose-Response Relationship, Drug ; Dose-Response Relationship, Radiation ; Models, Chemical ; Organophosphorus Compounds/*pharmacology ; Oxygen/metabolism ; Phantoms, Imaging ; Phosphates/pharmacology ; Polymers/chemistry ; Radiometry/*methods ; Radiotherapy, Conformal/*methods ; Sensitivity and Specificity ; Time Factors ; }, abstract = {Polymer gel dosimeters offer a wide range of potential applications in the three-dimensional verification of complex dose distribution such as in intensity-modulated radiotherapy (IMRT). Until now, however, polymer gel dosimeters have not been widely used in the clinic. One of the reasons is that they are difficult to manufacture. As the polymerization in polymer gels is inhibited by oxygen, all free oxygen has to be removed from the gels. For several years this was achieved by bubbling nitrogen through the gel solutions and by filling the phantoms in a glove box that is perfused with nitrogen. Recently another gel formulation was proposed in which oxygen is bound in a metallo-organic complex thus removing the problem of oxygen inhibition. The proposed gel consists of methacrylic acid, gelatin, ascorbic acid, hydroquinone and copper(II)sulphate and is given the acronym MAGIC gel dosimeter. These gels are fabricated under normal atmospheric conditions and are therefore called 'normoxic' gel dosimeters. In this study, a chemical analysis on the MAGIC gel was performed. The composition of the gel was varied and its radiation response was evaluated. The role of different chemicals and the reaction kinetics are discussed. It was found that ascorbic acid alone was able to bind the oxygen and can thus be used as an anti-oxidant in a polymer gel dosimeter. It was also found that the anti-oxidants N-acetyl-cysteine and tetrakis(hydroxymethyl)phosphonium were effective in scavenging the oxygen. However, the rate of oxygen scavenging is dependent on the anti-oxidant and its concentration with tetrakis(hydroxymethyl)phosphonium being the most reactive anti-oxidants. Potentiometric oxygen measurements in solution provide an easy way to get a first impression on the rate of oxygen scavenging. It is shown that cupper(II)sulphate operates as a catalyst in the oxidation of ascorbic acid. We, therefore, propose some new normoxic gel formulations that have a less complicated chemical formulation than the MAGIC gel.}, }
@article {pmid12406911, year = {2003}, author = {Mas, VM and Hernandez, H and Plo, I and Bezombes, C and Maestre, N and Quillet-Mary, A and Filomenko, R and Demur, C and Jaffrézou, JP and Laurent, G}, title = {Protein kinase Czeta mediated Raf-1/extracellular-regulated kinase activation by daunorubicin.}, journal = {Blood}, volume = {101}, number = {4}, pages = {1543-1550}, doi = {10.1182/blood-2002-05-1585}, pmid = {12406911}, issn = {0006-4971}, mesh = {8-Bromo Cyclic Adenosine Monophosphate/pharmacology ; Acetylcysteine/pharmacology ; Androstadienes/pharmacology ; Antibiotics, Antineoplastic/pharmacology ; Antioxidants/pharmacology ; Bridged-Ring Compounds/pharmacology ; Cell Death/drug effects ; Daunorubicin/*pharmacology ; Diglycerides/biosynthesis ; Enzyme Activation/drug effects ; Flavonoids/pharmacology ; Humans ; Leukemia ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/*metabolism ; Norbornanes ; Phosphatidylcholines/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Protein Kinase C/genetics/*metabolism ; Proto-Oncogene Proteins c-raf/antagonists &amp; inhibitors/*metabolism ; Reactive Oxygen Species/pharmacology ; Thiocarbamates ; Thiones/pharmacology ; Transfection ; Tumor Cells, Cultured ; Wortmannin ; }, abstract = {In light of the emerging concept of a protective function of the mitogen-activated protein kinase (MAPK) pathway under stress conditions, we investigated the influence of the anthracycline daunorubicin (DNR) on MAPK signaling and its possible contribution to DNR-induced cytotoxicity. We show that DNR increased phosphorylation of extracellular-regulated kinases (ERKs) and stimulated activities of both Raf-1 and extracellular-regulated kinase 1 (ERK1) within 10 to 30 minutes in U937 cells. ERK1 stimulation was completely blocked by either the mitogen-induced extracellular kinase (MEK) inhibitor PD98059 or the Raf-1 inhibitor 8-bromo-cAMP (cyclic adenosine monophosphate). However, only partial inhibition of Raf-1 and ERK1 stimulation was observed with the antioxidant N-acetylcysteine (N-Ac). Moreover, the xanthogenate compound D609 that inhibits DNR-induced phosphatidylcholine (PC) hydrolysis and subsequent diacylglycerol (DAG) production, as well as wortmannin that blocks phosphoinositide-3 kinase (PI3K) stimulation, only partially inhibited Raf-1 and ERK1 stimulation. We also observed that DNR stimulated protein kinase C zeta (PKCzeta), an atypical PKC isoform, and that both D609 and wortmannin significantly inhibited DNR-triggered PKCzeta activation. Finally, we found that the expression of PKCzeta kinase-defective mutant resulted in the abrogation of DNR-induced ERK phosphorylation. Altogether, these results demonstrate that DNR activates the classical Raf-1/MEK/ERK pathway and that Raf-1 activation is mediated through complex signaling pathways that involve at least 2 contributors: PC-derived DAG and PI3K products that converge toward PKCzeta. Moreover, we show that both Raf-1 and MEK inhibitors, as well as PKCzeta inhibition, sensitized cells to DNR-induced cytotoxicity.}, }
@article {pmid12404881, year = {2002}, author = {Allegra, L and Dal Sasso, M and Bovio, C and Massoni, C and Fonti, E and Braga, PC}, title = {Human neutrophil oxidative bursts and their in vitro modulation by different N-acetylcysteine concentrations.}, journal = {Arzneimittel-Forschung}, volume = {52}, number = {9}, pages = {669-676}, doi = {10.1055/s-0031-1299949}, pmid = {12404881}, issn = {0004-4172}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Candida albicans/immunology ; Cell-Free System ; Dose-Response Relationship, Drug ; Escherichia coli/immunology ; Free Radical Scavengers/*pharmacology ; Humans ; Hydrogen Peroxide ; Hypochlorous Acid ; Immunity, Cellular/drug effects ; Luminescent Measurements ; Luminol ; N-Formylmethionine Leucyl-Phenylalanine/pharmacology ; Neutrophils/*drug effects ; Oxidants ; Phagocytosis/drug effects ; Respiratory Burst/*drug effects ; Staphylococcus aureus/immunology ; Xanthine Oxidase/metabolism ; }, abstract = {Reactive oxygen species released by activated polymorphonuclear leukocytes as an expression of their defensive function are considered to be a major source of the cytotoxic oxidant stress, that triggers a self-sustaining phlogogenic loop in the respiratory system. N-Acetylcysteine (CAS 616-91-1, NAC), a known mucolytic drug, possesses also antioxidant properties, but it undergoes a rapid and extensive first-pass metabolism resulting in low tissue availability. Thus to further improve the NAC bioavailability a single oral administration of 1200 mg NAC has been recently proposed. This study has been performed to investigate in vitro by means of luminol amplified chemiluminescence the ability of the concentration of 35 mumol/l NAC available after single oral administration of 1200 NAC to interfere with human neutrophil oxidative burst evoked by both corpuscolate and soluble stimulants, in comparison with 16 mumol/l NAC, the serum concentration obtainable after single oral administration of 600 mg NAC. At concentrations of 16 and 35 mumol/l, NAC significantly reduced in a concentration-dependent manner the activation of polymorphonuclear neutrophils (PMNs) oxidative bursts induced by all of the stimulants (C. albicans, formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate (PMA)). This effect was also present in cell-free systems, thus confirming the scavenger activity of these two concentrations of NAC. The fact that no effects were seen on PMN phagocytosis and bacterial killing indicates that NAC has no negative influence on other PMN functions such as antimicrobial activity.}, }
@article {pmid12404184, year = {2002}, author = {Recchioni, R and Marcheselli, F and Moroni, F and Pieri, C}, title = {Apoptosis in human aortic endothelial cells induced by hyperglycemic condition involves mitochondrial depolarization and is prevented by N-acetyl-L-cysteine.}, journal = {Metabolism: clinical and experimental}, volume = {51}, number = {11}, pages = {1384-1388}, doi = {10.1053/meta.2002.35579}, pmid = {12404184}, issn = {0026-0495}, mesh = {Acetylcysteine/*pharmacology ; Aorta ; *Apoptosis/drug effects ; Cells, Cultured ; Endothelium, Vascular/cytology/*ultrastructure ; Flow Cytometry ; Fluorescence ; Free Radical Scavengers/*pharmacology ; Humans ; Hyperglycemia/*pathology/*physiopathology ; Intracellular Membranes/drug effects ; Membrane Potentials/drug effects ; Mitochondria/*drug effects ; Time Factors ; }, abstract = {We investigated whether the dissipation of mitochondrial transmembrane potential (Delta(Psi)(m)) was involved in apoptosis of cultured human aortic endothelial cells (HAECs) exposed to hyperglycemic conditions (30 mmol/L glucose). In parallel experiments, N-acetyl-L-cysteine (NAC) was added to the culture medium to verify whether this antioxidant may prevent apoptosis in these cells. The binding of annexin V and DNA fragmentation were measured, in addition to the production of reactive oxygen species (ROS), the number of cells with depolarized mitochondria, and the intracellular glutathione (GSH) content. As compared to the control (5 mmol/L glucose), high-glucose treatment increases both ROS generation and the number of cells binding annexin V. Moreover, a simultaneous decrease of intracellular GSH content was observed, which was accompanied by an increased number of cells showing both depolarized mitochondria and fragmented DNA. Incubation of HAECs with high glucose in the presence of 10 mmol/L NAC prevented the drop of intracellular GSH content, and decreased both ROS generation and the number of cells committed to apoptosis. These results suggest that high glucose triggers the same cascade of molecular events as do other apoptosis inducers in other cells. Among these events, the disruption of mitochondrial membrane barrier function might be decisive because it causes the release of soluble proteins from intermembrane space, which then induce nuclear apoptotic changes.}, }
@article {pmid12401520, year = {2003}, author = {Chang, WM and Chen, KD and Chen, LY and Lai, MT and Lai, YK}, title = {Mitochondrial calcium-mediated reactive oxygen species are essential for the rapid induction of the grp78 gene in 9L rat brain tumour cells.}, journal = {Cellular signalling}, volume = {15}, number = {1}, pages = {57-64}, doi = {10.1016/s0898-6568(02)00055-4}, pmid = {12401520}, issn = {0898-6568}, mesh = {Activating Transcription Factor 2 ; Animals ; Antioxidants/pharmacology ; Brain Neoplasms ; Calcium/*physiology ; Calcium Channels ; Calcium-Binding Proteins/antagonists &amp; inhibitors ; Carrier Proteins/biosynthesis/*genetics ; Chelating Agents/pharmacology ; Cyclic AMP Response Element-Binding Protein/metabolism ; Egtazic Acid/*analogs &amp; derivatives/pharmacology ; Endoplasmic Reticulum Chaperone BiP ; *Heat-Shock Proteins ; Heat-Shock Response ; Hydrogen Peroxide/metabolism ; Kinetics ; Mitochondria/*metabolism ; Molecular Chaperones/biosynthesis/*genetics ; Okadaic Acid/pharmacology ; Promoter Regions, Genetic ; RNA, Messenger/biosynthesis ; Rats ; Reactive Oxygen Species/*metabolism ; Ruthenium Red/pharmacology ; Signal Transduction ; Transcription Factors/metabolism ; *Transcriptional Activation ; Tumor Cells, Cultured ; }, abstract = {The glucose-regulated protein grp78 gene is rapidly transactivated in 9L rat brain tumour (RBT) cells treated with okadaic acid (OA) followed by heat shock (HS) (termed OA-->HS treatment). By Northern blotting analyses and transient transfection assays, we herein show that transactivation of grp78 by OA-->HS is abolished by an intracellular calcium chelator, bis(aminophenoxy)ethane N,N'-tetraacetic acid (BAPTA), and an inhibitor of mitochondrial Ca(2+) uniporter, ruthenium red (RR), while unaffected by cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MTP). The inhibitory effects of BAPTA and RR also present in OA-->HS induction of transient elevation of intracellular hydrogen peroxide. The requirement of reactive oxygen intermediates (ROIs) is confirmed by substitutional addition of antioxidants, N-acetyl cysteine (NAC) and pyrrolidinedithiocarbamate (PDTC) during OA-->HS treatment, mimicking these inhibitory effects of BAPTA and RR. Western blotting analyses show that phosphorylation of transcription factor CREB is diminished only by BAPTA but not by RR, while phosphorylation of ATF-2 is unaffected by either agent. Conclusively, we present that both the disturbances of mitochondrial calcium homeostasis and reactive oxygen intermediates are essential for rapid transactivation of grp78, and this pathway is separate from protein kinase A (PKA)-dependent CREB activation or p38 mitogen-activated protein kinase (p38(MAPK))-dependent ATF-2 activation and signalling.}, }
@article {pmid12397613, year = {2002}, author = {Samoto, H and Shimizu, E and Matsuda-Honjo, Y and Saito, R and Yamazaki, M and Kasai, K and Furuyama, S and Sugiya, H and Sodek, J and Ogata, Y}, title = {TNF-alpha suppresses bone sialoprotein (BSP) expression in ROS17/2.8 cells.}, journal = {Journal of cellular biochemistry}, volume = {87}, number = {3}, pages = {313-323}, doi = {10.1002/jcb.10301}, pmid = {12397613}, issn = {0730-2312}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Benzoquinones ; Cell Line ; Cyclic AMP/genetics/metabolism ; DNA/metabolism ; Dose-Response Relationship, Drug ; Down-Regulation/*drug effects ; Electrophoretic Mobility Shift Assay/methods ; Enzyme Inhibitors/pharmacology ; Integrin-Binding Sialoprotein ; Lactams, Macrocyclic ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic/genetics ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/metabolism ; Quinones/pharmacology ; RNA, Messenger/biosynthesis ; Rats ; Response Elements/genetics ; Rifabutin/analogs &amp; derivatives ; Sialoglycoproteins/antagonists &amp; inhibitors/*biosynthesis/genetics ; Transcription, Genetic/drug effects/physiology ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*pharmacology ; }, abstract = {Tumor necrosis factor-alpha (TNF-alpha) is a major mediator of inflammatory responses in many diseases that inhibits bone formation and stimulates bone resorption. To determine molecular mechanisms involved in the suppression of bone formation we have analyzed the effects of TNF-alpha on BSP gene expression. Bone sialoprotein (BSP) is a mineralized tissue-specific protein that appears to function in the initial mineralization of bone. Previous studies have demonstrated that BSP mRNA expression is essentially restricted to fully-differentiated cells of mineralized connective tissues and that the expression of BSP is developmentally regulated. Treatment of rat osteosarcoma ROS 17/2.8 cells with TNF-alpha (10 ng/ml) for 24 h caused a marked reduction in BSP mRNA levels. The addition of antioxidant N-acetylcysteine (NAC; 20 mM) 30 min prior to stimulation with TNF-alpha attenuated the inhibition of BSP mRNA levels. Transient transfection analyses, using chimeric constructs of the rat BSP gene promoter linked to a luciferase reporter gene, revealed that TNF-alpha (10 ng/ml) suppressed expression in all constructs, including a short construct (pLUC3; nts -116 to +60), transfected into ROS17/2.8 cells. Further deletion analysis of the BSP promoter showed that a region within nts -84 to -60 was targeted by TNF-alpha, the effects which were inhibited by NAC and the tyrosine kinase inhibitor, herbimycin A (HA). Introduction of 2bp mutations in the inverted CCAAT box (ATTGG; nts -50 and -46), a putative cAMP response element (CRE; nts -75 to -68), and a FGF response element (FRE; nts -92 to -85) showed that the TNF-alpha effects were mediated by the CRE. These results were supported by gel mobility shift assays, using a radiolabeled double-stranded CRE oligonucleotide, which revealed decreased binding of a nuclear protein from TNF-alpha-stimulated ROS 17/2.8 cells. Further, the inhibitory effect of TNF-alpha on CRE DNA-protein complex was completely abolished by NAC or HA treatment. These studies, therefore, show that TNF-alpha suppresses BSP gene transcription through a tyrosine kinase-dependent pathway that generates reactive oxygen species and that the TNF-alpha effects are mediated by a CRE element in the proximal BSP gene promoter.}, }
@article {pmid12393931, year = {2002}, author = {Cai, W and Gao, QD and Zhu, L and Peppa, M and He, C and Vlassara, H}, title = {Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {8}, number = {7}, pages = {337-346}, pmid = {12393931}, issn = {1076-1551}, support = {AG09453/AG/NIA NIH HHS/United States ; DK54788/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cattle ; Cells, Cultured ; Cross-Linking Reagents/chemistry ; Dose-Response Relationship, Drug ; Endothelium, Vascular/cytology/*drug effects/*metabolism ; Food/*adverse effects ; Glutathione/analysis ; Glutathione Peroxidase/analysis ; Glycation End Products, Advanced/chemical synthesis/*pharmacology ; Guanidines/pharmacology ; Humans ; Lipoproteins, LDL/analysis ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Umbilical Veins/cytology ; }, abstract = {BACKGROUND: The general increase in reactive oxygen species generated from glucose-derived advanced glycation endproducts (AGEs) is among the key mechanisms implicated in tissue injury due to diabetes. AGE-rich foods could exacerbate diabetic injury, at least by raising the endogenous AGE.<br><br>MATERIALS AND METHODS: Herein, we tested whether, prior to ingestion, diet-derived AGEs contain species with cell activating (TNFalpha), chemical (cross-linking) or cell oxidative properties, similar to native AGEs. Glutathione (GSH) and GSH peroxidase (GPx) were assessed after exposure of human umbilical vein endothelial cell (HUVECs) to affinity-purified food-AGE extracts, each exposed to 250 degrees C, for 10 min, along with synthetic AGEs.<br><br>RESULTS: Animal product-derived AGE, like synthetic methylglyoxal-bovine serum albumin (MG-BSA), AGE-BSA, and AGE-low density lipoprotein (AGE-LDL), induced a dose- and time-dependent depletion of GSH (()60-75%, p, 0.01) and an increase in GPx activity (()500-600%, p < 0.01), consistent with marked TNFalpha and cross-link formation (p < 0.05); this contrasted with the low bioreactivity of starch/vegetable AGE-extracts, which was similar to that of control BSA and CML- BSA and BSA (p:NS). Anti-AGE-R1,2,3 and -RAGE IgG each inhibited cell-associated (125) I-dAGE by approximately 30-55%; GSH/GPx were effectively blocked by N-acetyl-cysteine (NAC, 800 uM, p < 0.01) and aminoguanidine-HCl (AG, 100 uM, p < 0.01).<br><br>CONCLUSION: Thus, food-derived AGE, prior to absorption, contain potent carbonyl species, that can induce oxidative stress and promote inflammatory signals.}, }
@article {pmid12392891, year = {2002}, author = {Mallet, RT and Squires, JE and Bhatia, S and Sun, J}, title = {Pyruvate restores contractile function and antioxidant defenses of hydrogen peroxide-challenged myocardium.}, journal = {Journal of molecular and cellular cardiology}, volume = {34}, number = {9}, pages = {1173-1184}, doi = {10.1006/jmcc.2002.2050}, pmid = {12392891}, issn = {0022-2828}, support = {HL-50441/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*metabolism ; Energy Metabolism ; Glutathione/metabolism ; Glycolysis ; Guinea Pigs ; Hemodynamics/drug effects ; Hydrogen Peroxide/*pharmacology ; Male ; Myocardial Contraction/*drug effects ; Myocardium/*metabolism ; Oxidants/*pharmacology ; Phosphocreatine/metabolism ; Phosphorylation ; Pyruvic Acid/*pharmacology ; }, abstract = {PURPOSE: Pyruvate, a natural energy-yielding fuel in myocardium, neutralizes peroxides by a direct decarboxylation reaction, and indirectly augments the glutathione (GSH) antioxidant system by generating NADPH reducing power via citrate formation. The possibility that pyruvate's antioxidant actions could mediate its enhancement of contractile performance in prooxidant-challenged myocardium was investigated in isolated working guinea-pig hearts reversibly injured by hydrogen peroxide.<br><br>METHODS: Hearts were challenged by 10 min perfusion with 100 microM H(2)O(2), followed by 90 min H(2)O(2)-free perfusion. Metabolic and antioxidant treatments (each 5m M) were administered at 30-90 min post-H(2)O(2). Phosphocreatine phosphorylation state, GSH/glutathione disulfide redox potential (GSH/GSSG) and key enzyme activities were measured in snap-frozen myocardium.<br><br>RESULTS: H(2)O(2) exposure depleted myocardial energy and antioxidant reserves and produced marked contractile impairment that persisted throughout the H(2)O(2) washout period. Relative to untreated post-H(2)O(2) myocardium, pyruvate restored contractile performance, increased GSH/GSSG 52% and maintained phosphocreatine phosphorylation state; in contrast, lactate lowered cardiac performance and phosphorylation state. Neither the pharmacological antioxidant N -acetylcysteine (NAC) nor the pyruvate analog alpha-ketobutyrate increased cardiac function; both treatments increased GSH/GSSG but lowered phosphocreatine potential. H(2)O(2) partially inactivated aconitase, creatine kinase and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), but all three enzymes spontaneously recovered during H(2)O(2) washout. Pyruvate did not further activate these enzymes and unexpectedly inhibited GAPDH by 60-70%.<br><br>CONCLUSION: Pyruvate promoted robust contractile recovery of H(2)O(2)-challenged myocardium by the combination of citrate-mediated antioxidant mechanisms and maintenance of myocardial energy reserves.}, }
@article {pmid12391710, year = {2002}, author = {Jaber, R}, title = {Respiratory and allergic diseases: from upper respiratory tract infections to asthma.}, journal = {Primary care}, volume = {29}, number = {2}, pages = {231-261}, doi = {10.1016/s0095-4543(01)00008-2}, pmid = {12391710}, issn = {0095-4543}, mesh = {Asthma/*therapy ; Clinical Competence ; *Complementary Therapies ; *Diet Therapy ; Humans ; Patient Education as Topic ; Physician-Patient Relations ; Pulmonary Disease, Chronic Obstructive/*therapy ; Respiratory Tract Infections/*therapy ; United States ; }, abstract = {Patients with asthma and allergic rhinitis may benefit from hydration and a diet low in sodium, omega-6 fatty acids, and transfatty acids, but high in omega-3 fatty acids (i.e., fish, almonds, walnuts, pumpkin, and flax seeds), onions, and fruits and vegetables (at least five servings a day). Physicians may need to be more cautious when prescribing antibiotics to children in their first year of life when they are born to families with a history of atopy. More research is needed to establish whether supplementation with probiotics (lactobacillus and bifidobacterium) during the first year of life or after antibiotic use decreases the risk of developing asthma and allergic rhinitis. Despite a theoretic basis for the use of vitamin C supplements in asthmatic patients, the evidence is still equivocal, and long-term studies are needed. The evidence is stronger for exercise-induced asthma, in which the use of vitamin C supplementation at a dosage of 1 to 2 g per day may be helpful. It is also possible that fish oil supplements, administered in a dosage of 1 to 1.2 g of EPA and DHA per day, also may be helpful to some patients with asthma. Long-term studies of fish oil and vitamin C are needed for more definite answers. For the patient interested in incorporating nutritional approaches, vitamin C and fish oils have a safe profile. However, aspirin-sensitive individuals should avoid fish oils, and red blood cell magnesium levels may help in making the decision whether to use additional magnesium supplements. Combination herbal formulas should be used in the treatment of asthma with medical supervision and in collaboration with an experienced herbalist or practitioner of TCM. Safe herbs, such as Boswellia and gingko, may be used singly as adjuncts to a comprehensive plan of care if the patient and practitioner have an interest in trying them while staying alert for drug-herb interactions. No data on the long-term use of these single herbs in asthma exist. For the motivated patient, mind-body interventions such as yoga, hypnosis, and biofeedback-assisted relaxation and breathing exercises are beneficial for stress reduction in general and may be helpful in further controlling asthma. Encouraging parents to learn how to massage their asthmatic children may appeal to some parents and provide benefits for parents and children alike. Acupuncture and chiropractic treatment cannot be recommended at this time, although some patients may derive benefit because of the placebo effect. For patients with allergic rhinitis, there are no good clinical research data on the use of quercetin and vitamin C. Similarly, freeze-dried stinging nettle leaves may be tried, but the applicable research evidence also is poor. Further studies are needed to assess the efficacy of these supplements and herbs. Homeopathic remedies based on extreme dilutions of the allergen may be beneficial in allergic rhinitis but require collaboration with an experienced homeopath. There are no research data on constitutional homeopathic approaches to asthma and allergic rhinitis. Patients with COPD are helped by exercise, pulmonary rehabilitation, and increased caloric protein and fat intake. Vitamin C and n-3 supplements are safe and reasonable; however, studies are needed to establish their efficacy in COPD. On the other hand, there are convincing data in favor of N-acetyl-cysteine supplementation for the patient with COPD at doses ranging between 400 and 1200 mg daily. Red blood cell magnesium levels may guide the use of magnesium replacement. The use of L-carnitine and coenzyme Q10 in patients with COPD needs further study. The addition of essential oils to the dietary regimen of patients with chronic bronchitis is worth exploring. Patients with upper respiratory tract infections can expect a shorter duration of symptoms by taking high doses of vitamin C (2 g) with zinc supplements, preferably the nasal zinc gel, at the onset of their symptoms. Adding an herb such as echinacea or Andrographis shortens the duration of the common cold. The one study on Elderberry's use for the flu was encouraging, and the data on the homeopathic remedy Oscillococcinum interesting, but more studies should be performed. Saline washes may be helpful to patients with allergic rhinitis and chronic sinusitis. Patients also may try the German combination (available in the United States) of elderberry, vervain, gentian, primrose, and sorrel that has been tested in randomized clinical trials. Bromelain is safe to try; the trials of bromelain supplementation were promising but were never repeated. The preceding suggestions need to be grounded in a program based on optimal medical management. Patients need to be well educated in the proper medical management of their disease and skilled at monitoring disease stability and progress. Asthmatic patients need to monitor their bronchodilator usage and peak flow meter measurements to step up their medical treatment in a timely manner, if needed. Patients welcome physician guidance when exploring the breadth of treatments available today. A true patient-physician partnership is always empowering to patients who are serious about regaining their function and health.}, }
@article {pmid12388243, year = {2003}, author = {Lee, YW and Hennig, B and Toborek, M}, title = {Redox-regulated mechanisms of IL-4-induced MCP-1 expression in human vascular endothelial cells.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {284}, number = {1}, pages = {H185-92}, doi = {10.1152/ajpheart.00524.2002}, pmid = {12388243}, issn = {0363-6135}, support = {P42 ES007380/ES/NIEHS NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology ; Cells, Cultured ; Chemokine CCL2/genetics/*metabolism ; DNA/antagonists &amp; inhibitors/metabolism ; DNA-Binding Proteins/metabolism/physiology ; Endothelium, Vascular/*metabolism ; Gene Expression/drug effects ; Humans ; Interleukin-4/*pharmacology ; Oxidation-Reduction ; Proline/*analogs &amp; derivatives/pharmacology ; STAT1 Transcription Factor ; Thiocarbamates/pharmacology ; Trans-Activators/metabolism/physiology ; Transcription Factors/physiology ; }, abstract = {The present study focused on the molecular signaling pathways of monocyte chemoattractant protein-1 (MCP-1) induction by interleukin-4 (IL-4) in human umbilical vein endothelial cells (HUVEC). RT-PCR showed that MCP-1 mRNA accumulation was markedly increased in IL-4-treated HUVEC in a time- and dose-dependent manner. Antioxidants, such as pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), significantly inhibited IL-4-induced MCP-1 mRNA expression. These effects correlated well with the PDTC-mediated inhibition of MCP-1 promoter transcriptional activity observed in IL-4-treated HUVEC. IL-4-induced MCP-1 gene expression was paralleled by a concomitant production of MCP-1 protein. In agreement with MCP-1 gene expression, PDTC attenuated IL-4-mediated induction of MCP-1 protein expression. In addition, IL-4 dramatically increased the transcription factor signal transducers and activators of transcription 1 (STAT1) DNA binding activity, an effect that was attenuated by PDTC. The role of STAT1 in the regulation of the IL-4-induced MCP-1 gene expression was further confirmed in HUVEC transfected with a reporter construct of the MCP-1 promoter with a mutated STAT1 binding site. These results demonstrate that IL-4-dependent MCP-1 induction in HUVEC is mediated by redox-regulated STAT1 activation.}, }
@article {pmid12384173, year = {2002}, author = {Rodríguez-Martín, E and Casarejos, MJ and Canals, S and de Bernardo, S and Mena, MA}, title = {Thiolic antioxidants protect from nitric oxide-induced toxicity in fetal midbrain cultures.}, journal = {Neuropharmacology}, volume = {43}, number = {5}, pages = {877-888}, doi = {10.1016/s0028-3908(02)00150-8}, pmid = {12384173}, issn = {0028-3908}, mesh = {Animals ; Antioxidants/*pharmacology ; Arachidonic Acid/toxicity ; Cell Death/drug effects ; Cell Survival/drug effects ; Dopamine/physiology ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Immunohistochemistry ; Mesencephalon/drug effects/*pathology ; Neurons/drug effects/*pathology ; *Neuroprotective Agents ; Nitric Oxide/*antagonists &amp; inhibitors/*toxicity ; Nitrites/metabolism ; Organ Culture Techniques ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {Nitric oxide (NO) may act as a neuroprotector or neurotoxic agent in dopamine neurons, depending on cell redox status. We have investigated the effect of several thiolic antioxidants, glutathione (GSH), its cell permeable analog GSH ethyl ester (GSHEE), and the GSH synthesis precursor L-N-acetyl cysteine (L-NAC), as well as non-thiolic antioxidants like ascorbic acid (AA) and uric acid, on NO-induced toxicity in fetal midbrain cultures. The cultures were treated for 8-24 h with neurotoxic doses of the NO donor diethylamine/nitric oxide complex sodium DEA/NO (200-400 micro M) and/or antioxidants. Thiolic antioxidants, at equimolar concentrations, added at the same time or previous to DEA/NO, protected from cell death, from tyrosine hydroxylase (TH) positive cell number decrease and from intracellular GSH depletion, induced by DEA/NO, without increasing intracellular GSH content. In these conditions, S-nitrosothiol compound formation was detected in the culture media. Protection disappeared when antioxidants were supplied 30 min after NO treatment. Nevertheless, non-thiolic antioxidants, AA and uric acid, with similar peroxynitrite scavenging activity to thiolic antioxidants, and free radical-scavenging enzymes as catalase and Cu/Zn-superoxide dismutase, which prevent extracellular peroxynitrite ion formation, and 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron), which prevents intracellular peroxynitrite ion formation, did not rescue cell cultures from neurotoxicity induced by NO. In addition, AA exacerbated DEA/NO-induced toxicity in a dose-dependent manner from 200 micro M AA. The present results suggest that only antioxidants with thiol group exert neuroprotection from NO-induced toxicity in fetal midbrain cultures, probably by direct interaction of NO and thiol groups, resulting in NO blocking. On the other hand, some classical antioxidants, like AA, exacerbate neurotoxicity due to NO.}, }
@article {pmid12377745, year = {2002}, author = {Vásquez-Vivar, J and Duquaine, D and Whitsett, J and Kalyanaraman, B and Rajagopalan, S}, title = {Altered tetrahydrobiopterin metabolism in atherosclerosis: implications for use of oxidized tetrahydrobiopterin analogues and thiol antioxidants.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {22}, number = {10}, pages = {1655-1661}, doi = {10.1161/01.atv.0000029122.79665.d9}, pmid = {12377745}, issn = {1524-4636}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/*metabolism ; Aorta, Thoracic/chemistry/drug effects/enzymology/pathology ; Arteriosclerosis/enzymology/*metabolism/pathology ; Biopterins/*analogs &amp; derivatives/*metabolism ; Calcimycin/pharmacology ; Cholesterol/blood ; Diet ; Endothelium, Vascular/drug effects/enzymology ; Free Radical Scavengers/pharmacology ; Hyperlipidemias/enzymology/metabolism/pathology ; Ionophores/pharmacology ; Male ; Muscle, Smooth, Vascular/drug effects/enzymology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism/physiology ; Nitric Oxide Synthase Type III ; Oxidation-Reduction ; Oxygen/metabolism ; Pteridines/pharmacology ; *Pterins ; Rabbits ; Sulfhydryl Compounds/*metabolism ; Vasodilator Agents/pharmacology ; }, abstract = {OBJECTIVE: Tetrahydrobiopterin (BH4) is of fundamental importance for the normal function of endothelial NO synthase. The purpose of this study was to investigate the effects of hyperlipidemia on vascular BH4 levels and the effect of supplementation with sepiapterin in the presence and absence of N-acetylcysteine (NAC).<br><br>METHODS AND RESULTS: New Zealand White rabbits were fed normal chow (normocholesterolemic [NC] group) or hyperlipidemic chow (hyperlipidemic [HL] group) for 8 to 10 weeks. Mean cholesterol levels were 1465+/-333 and 53+/-17 mg/dL in the HL and NC group, respectively. Markedly diminished BH4 levels were found in the HL group compared with the NC group, but these levels could be restored after 6 hours of incubation with sepiapterin. Peak relaxations to acetylcholine and A23187 were impaired in the HL group. Supplementation with sepiapterin resulted in a further diminution of relaxation in the HL but not NC group. Incubation with NAC for 6 hours failed to raise BH4 levels, whereas NAC in conjunction with sepiapterin raised BH4 levels approximately 221-fold. However, this increase did not improve relaxations to A23187 and acetylcholine.<br><br>CONCLUSIONS: Prolonged exposure to sepiapterin impairs vasorelaxation in hyperlipidemia despite repletion of endogenous BH4. Antioxidant thiols do not correct this impairment. These studies have implications for the use of sepiapterin in the correction of vasomotor tone in atherosclerosis.}, }
@article {pmid12372563, year = {2002}, author = {Cammer, W}, title = {Protection of cultured oligodendrocytes against tumor necrosis factor-alpha by the antioxidants coenzyme Q(10) and N-acetyl cysteine.}, journal = {Brain research bulletin}, volume = {58}, number = {6}, pages = {587-592}, doi = {10.1016/s0361-9230(02)00830-4}, pmid = {12372563}, issn = {0361-9230}, support = {RG2971/RG/CSR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; Cells, Cultured ; Coenzymes ; Oligodendroglia/cytology/*drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Telencephalon/cytology/drug effects/metabolism ; Tumor Necrosis Factor-alpha/*pharmacology ; Ubiquinone/*analogs &amp; derivatives/*pharmacology ; }, abstract = {Tumor necrosis factor-alpha (TNF-alpha) retards the rate of terminal maturation of oligodendrocytes in vitro. The following respective compounds were used along with TNF-alpha in order to try and restore the normal rate of maturation: (1). the antioxidant, coenzyme Q(10) (CoQ(10)); (2). the antioxidant, N-acetyl cysteine (NAC); (3). creatine, which helps to preserve cellular energy; and (4) S-adenosyl methionine (SAM), which contributes to the biosynthesis of lipids and proteins. Of these compounds, only CoQ(10) or NAC was able to restore the numbers of mature myelin basic protein-positive cells and the ability of the oligodendrocytes to form membrane sheets. If TNF-alpha treatment causes oxidative damage by compromising oxidative metabolism in oligodendrocytes, increasing products of lipid peroxidation and/or generating radical oxygen species that can interfere with maturation signals, CoQ(10) and NAC may protect oligodendrocytes by reversing one or more of those destructive processes during terminal maturation.}, }
@article {pmid12371608, year = {2002}, author = {Simkeviciene, V and Straukas, J and Uleckiene, S}, title = {N-acetil-l-cysteine and 2-amino-2-thiiazoline N-acetyl-l-cysteinate as a possible cancer chemopreventive agents in murine models.}, journal = {Acta biologica Hungarica}, volume = {53}, number = {3}, pages = {293-298}, doi = {10.1556/ABiol.53.2002.3.5}, pmid = {12371608}, issn = {0236-5383}, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemistry/*pharmacology ; Adenoma/*prevention &amp; control ; Animals ; Anticarcinogenic Agents/*pharmacology ; Dose-Response Relationship, Drug ; Female ; Lung Neoplasms/*prevention &amp; control ; Mice ; Mice, Inbred BALB C ; *Models, Animal ; Thiazoles/*chemistry ; }, abstract = {The aim of this study was to investigate N-acetyl-cysteine (NAC) and its 2-amino-2-thiazoline salt (NACAT) as potential chemopreventive agents on experimentally induced lung tumours by urethane (U) in mice. Female BALB/c mice were used. U was given by intraperitoneal injections during 2 weeks (single dose - 10 mg/mouse, total - 50 mg/mouse). Mice were treated daily per os with NAC 1/10 LD50, NACAT 1/10 or 1/100 LD50 starting 2 weeks prior U administration, then during U treatment and thereafter for 2 months. The duration of experiment was 4 months. The results showed that NAC (1000 mg/kg) reduced the lung tumour incidence to 30% that of controls, P < or = 0.05. Most effective of NACAT was 100 mg/kg dose; it reduced an average of lung adenomas per mouse by 26%, P < or = 0.05, but lower dose (10 mg/kg) was less effective. In order to achieve similar chemopreventive effect (approximately 30%) on mice, it is necessary to use 0.38 mM/kg of NACAT or 6.13 mM/kg of NAC. It means that 16 times less of NACAT is required, if calculated by molar concentration. In general, NAC and NACAT have a moderate chemopreventive effect on lung tumorigenesis induced by urethane in mice.}, }
@article {pmid12368900, year = {2002}, author = {Yan, Y and Harper, S and Speicher, DW and Marmorstein, R}, title = {The catalytic mechanism of the ESA1 histone acetyltransferase involves a self-acetylated intermediate.}, journal = {Nature structural biology}, volume = {9}, number = {11}, pages = {862-869}, doi = {10.1038/nsb849}, pmid = {12368900}, issn = {1072-8368}, support = {R01 GM060293/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylation ; Acetyltransferases/*metabolism ; Catalysis ; Crystallography, X-Ray ; Cysteine/metabolism ; Escherichia coli ; Glutamic Acid/metabolism ; Histone Acetyltransferases ; Histones/metabolism ; Mass Spectrometry ; Recombinant Proteins/chemistry ; Saccharomyces cerevisiae Proteins/*metabolism ; }, abstract = {Yeast ESA1 is a member of the MYST subfamily of histone acetyltransferases (HATs), which use acetyl-coenzyme A (CoA) to acetylate specific Lys residues within histones to regulate gene expression. The structure of an ESA1-CoA complex reveals structural similarity to the catalytic core of the GCN5/PCAF subfamily of HAT proteins. Here we report additional structural and functional studies on ESA1 that demonstrate that histone acetylation proceeds through an acetyl-cysteine enzyme intermediate. This Cys residue is strictly conserved within the MYST members, suggesting a common mode of catalysis by this HAT subfamily. However, this mode of catalysis differs dramatically from the GCN5/PCAF subfamily, which mediate direct nucleophilic attack of the acetyl-CoA cofactor by the enzyme-deprotonated substrate lysine of the histone. These results demonstrate that different HAT subfamilies can use distinct catalytic mechanisms, which have implications for their distinct biological roles and for the development of HAT-specific inhibitors.}, }
@article {pmid12368228, year = {2002}, author = {Schubert, SY and Neeman, I and Resnick, N}, title = {A novel mechanism for the inhibition of NF-kappaB activation in vascular endothelial cells by natural antioxidants.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {16}, number = {14}, pages = {1931-1933}, doi = {10.1096/fj.02-0147fje}, pmid = {12368228}, issn = {1530-6860}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cattle ; Cells, Cultured ; Endothelium, Vascular/drug effects/*metabolism ; I-kappa B Proteins/metabolism ; Lythraceae/chemistry ; Models, Biological ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism ; Phosphorylation/drug effects ; Serine/metabolism ; Transcription Factor RelA ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/pharmacology ; *Wine ; }, abstract = {The activation of Nuclear Factor kappa B (NF-kappaB) in vascular endothelial cells, in response to biochemical or biomechanical stimuli, is associated with vascular pathologies such as atherosclerosis. The present manuscript studies the ability of the natural antioxidant-pomegranate wine (PW), to inhibit tumor necrosis factor alpha (TNF-alpha) or shear stress-mediated-NF-kappaB activation in vascular endothelial cells and compares it to that of red wine (RW) and N-acetyl cysteine (NAC). PW and RW act as potent antioxidants in vascular endothelial cells, inhibiting the oxidation of 2',7'-dichloroflurescin diacetate in TNF-alpha treated cells. PW (as well as RW and NAC) acted as potent inhibitors of NF-kappaB activation (migration into the nucleus and DNA binding activity) in vascular endothelial cells. Nevertheless, PW and NAC failed to inhibit TNF-a induced serine 32/36 phosphorylation and IkappaBalpha degradation. Surprisingly, these antioxidants alone induced enhanced IkappaB serine phosphorylation, which was not accompanied by IkappaBalpha degradation, or NF-kappaB nuclear translocation. This phosphorylation did not involve serine 32/36. Furthermore, we show for the first time that NAC inhibited TNF-alpha mediated phosphorylation of p65 (ser536), whereas PW had no effect on this phosphorylation. Thus, natural antioxidants may serve as potent NF-kappaB inhibitors in vascular endothelial cells, yet act through unique and divergent pathways.}, }
@article {pmid12367554, year = {2002}, author = {Choi, SE and Noh, HL and Kim, HM and Yoon, JW and Kang, Y}, title = {Streptozotocin upregulates GAD67 expression in MIN6N8a mouse beta cells.}, journal = {Journal of autoimmunity}, volume = {19}, number = {1-2}, pages = {1-8}, doi = {10.1006/jaut.2002.0602}, pmid = {12367554}, issn = {0896-8411}, mesh = {Animals ; Anti-Bacterial Agents/*pharmacology ; Antioxidants/metabolism ; Autoantigens/metabolism ; Diabetes Mellitus, Experimental/enzymology/etiology ; Glutamate Decarboxylase/*metabolism ; Islets of Langerhans/*enzymology ; Isoenzymes/*metabolism ; Mice ; NAD/metabolism ; NF-kappa B/metabolism ; Streptozocin/*pharmacology ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation/drug effects ; }, abstract = {Glutamic acid decarboxylase (GAD) is one major autoantigen involved in the pathogenesis of autoimmune insulin dependent diabetes mellitus (IDDM). Molecular mechanisms regulating GAD expression in pancreatic beta cell are still ill-defined. Here we investigated the effect of streptozotocin (STZ), a beta cell-specific toxin, on the expression of GAD67 in MIN6N8a mouse beta cell. A 5-6-fold increase in the expression GAD67 mRNA was found in cells treated with 1.25mM STZ for 12h. Addition of NAD+ to the incubation medium slightly reduced the STZ-induced upregulation of GAD67. STZ increased p53 levels that in turn up-modulated GAD67 expression. This effect was abolished upon addition of the antioxidant N-acetyl cysteine (NAC). STZ also activated NF-kappaB and blockade of NF-kappaB activation inhibited the STZ-mediated upregulation of GAD67 expression. As a whole these data show that low dose of STZ up-regulates GAD67 expression in mouse bate cell and that NF-kappaB activation through oxidative stress plays a key role in this phenomenon. They also suggest that various stimuli promoting NF-kappaB activation may up-regulate expression of GAD autoantigen in mouse beta cells.}, }
@article {pmid12366393, year = {2002}, author = {Guayerbas, N and Puerto, M and Ferrández, MD and De La Fuente, M}, title = {A diet supplemented with thiolic anti-oxidants improves leucocyte function in two strains of prematurely ageing mice.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {29}, number = {11}, pages = {1009-1014}, doi = {10.1046/j.1440-1681.2002.03758.x}, pmid = {12366393}, issn = {0305-1870}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Aging, Premature/*drug therapy/immunology ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Dietary Supplements ; *Disease Models, Animal ; Female ; Leukocytes/*drug effects/immunology ; Mice ; Mice, Inbred BALB C ; Species Specificity ; Sulfhydryl Compounds/pharmacology/*therapeutic use ; Thiazoles/pharmacology/therapeutic use ; Thiazolidines ; }, abstract = {1. According to previous studies, Swiss mice of the same age showed striking interindividual differences in behaviour when exposed to a T-maze test, with a slow performance being linked to an impaired immune function, hyperemotional response to stress and a shorter life span compared with mice that quickly explore the maze. These facts led us to propose the slow mice as a model of prematurely ageing mice (PAM). 2. In the present study, we investigated whether this prematurely ageing model could be found in other strains of mice, such as BALB/c mice, by analysing several lymphocytes functions, such as adherence, chemotaxis, proliferative response to the mitogen concanavalin A (Con A), interleukin (IL)-2 release and natural killer (NK) activity. In addition, we tested the probable beneficial effects on these functions of dietary supplementation with thioproline (TP) plus N-acetylcysteine (NAC; 0.1% w/w of each anti-oxidant) in female Swiss and BALB/c mice. 3. Our model of premature ageing, previously reported in Swiss mice, has also been reproduced in the inbred BALB/c mouse strain, in which PAM showing an immunosenescence in several lymphocyte functions, such as lower chemotaxis, proliferative response to Con A, IL-2 release and NK activity, as well as higher adherence, were observed. A short-term (5 week) ingestion of TP + NAC by female Swiss and BALB/c mice improved leucocyte function, increasing chemotaxis, the proliferative response to Con A, IL-2 release and NK activity and decreasing the adherence of lymphocytes. These effects are greatest in cells from PAM of both strains. 4. In conclusion, our model of premature ageing has been reproduced in an inbred strain. In addition, the ingestion of a diet supplemented with two thiolic anti-oxidants, such as NAC and TP, has been shown to be beneficial to the immune response in PAM.}, }
@article {pmid12366370, year = {2001}, author = {Tragoulias, ST and Anderton, PJ}, title = {The effect of N-acetylcysteine on the microscopic fluid dynamics of rat tears.}, journal = {Clinical &amp; experimental optometry}, volume = {84}, number = {5}, pages = {282-286}, doi = {10.1111/j.1444-0938.2001.tb05039.x}, pmid = {12366370}, issn = {1444-0938}, abstract = {BACKGROUND: The classical view of the tear film is of a 10-micron film of aqueous tears, sandwiched between thin layers of lipid and mucus. This has been challenged recently by the revelation that the tear film may be considerably thicker than 10 microns and that dissolved mucus and protein may play a much more important role than simply promoting tear adherence. In particular, the primary role of mucus may be to form a structured aqueous gel that adheres closely to the corneal surface and evens out its irregularities, thus providing a high-quality optical surface. METHODS: We have used the robust tear film of the rat eye as an animal model to investigate the contribution of mucus and low-molecular-weight (LMW) proteins to tear film structure. The ocular surface was first exposed to saline, which washed away the tear film. Single drops of a tear/saline mixture, treated with various concentrations of the thiol-reducing agent N-acetylcysteine (NAC), were placed on the ocular surface and the resulting fluid behaviour was recorded with video-microscopy. RESULTS: At five per cent concentration, NAC appeared to degrade the gap-filling and anti-evaporative qualities of the tears, features that give the rat tear film its robust characteristics. Lower concentrations had no significant effect. DISCUSSION: In a previous publication, we showed that five per cent NAC alters the profile of LMW proteins in rat tears. The present observations suggest that the robust wetting properties of rat tears depend critically on their mucus and/or LMW protein content and possibly are related to the formation of an aqueous/mucous gel.}, }
@article {pmid12361192, year = {2002}, author = {Barrios, V and Calderón, A and Navarro-Cid, J and Lahera, V and Ruilope, LM}, title = {N-acetylcysteine potentiates the antihypertensive effect of ACE inhibitors in hypertensive patients.}, journal = {Blood pressure}, volume = {11}, number = {4}, pages = {235-239}, doi = {10.1080/08037050213760}, pmid = {12361192}, issn = {0803-7051}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Angiotensin-Converting Enzyme Inhibitors/*administration &amp; dosage ; Antihypertensive Agents/*administration &amp; dosage ; Blood Pressure/drug effects ; Blood Pressure Monitoring, Ambulatory ; Circadian Rhythm ; Cross-Over Studies ; Drug Synergism ; Drug Therapy, Combination ; Female ; Humans ; Hypertension/*drug therapy ; Male ; Middle Aged ; Smoking ; }, abstract = {Sulfhydryl group donors, such as N-acetylcysteine (NAC), may enhance the antihypertensive effect of some drugs through a nitric oxide (NO) mechanism. It has been observed that the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEIs) is, at least partially, mediated by NO. We performed a within patient crossover study with the aim to investigate the potential effect of NAC on the ACEI antihypertensive action, via an NO-dependent mechanism. We studied 18 smoker (> 10 years of habit and > 10 cigarettes daily) hypertensive patients (15 males and three females, aged 69 +/- 5 years) on ACEI therapy (11 captopril and seven enalapril). Patients were randomly allocated to two treatment arms. In one arm, the patients (n = 10) initially received the addition of NAC (600 mg t.i.d.) to the ACEI regimen. In the other group (n = 8), the patients remained only on ACEI. After 21 days, the therapeutic patterns were crossed. The first group received only ACEI, and the second group received ACEI and NAC and completed other 21-day treatment period. We evaluate the effect of NAC on each patient by ambulatory blood pressure monitoring (ABPM), performed at the end of each therapeutic regimen. A significant decrease in systolic and diastolic 24-h blood pressure (24 hBP) and daytime BP (dtBP) was achieved with the combination of ACEI and NAC (ACEI + NAC) when compared to the period with only ACEI: 24 hBP = 146.1 +/- 4.2 vs 137 +/- 3.1 (p < 0.05) and 89.2 +/- 2.8 vs 83.5 +/- 3.7mmHg (p = 0.01). DtBP: 149.7 +/- 5.6 vs 141 +/- 3.7 and 92.1 +/- 4 vs 86 +/- 3.2 (both, p < 0.05). No significant difference was observed in night-time BP (ntBP). The NAC effect was not statistically different for the two ACEIs. In conclusion, the addition of NAC to an ACEI potentiates its antihypertensive effect during 24hBP and dtBP in smoker hypertensives. This effect may be mediated by an NO-dependent mechanism, probably through the protective effect of NAC on NO oxidation.}, }
@article {pmid12359631, year = {2002}, author = {Ahn, SM and Yoon, HY and Lee, BG and Park, KC and Chung, JH and Moon, CH and Lee, SH}, title = {Fructose-1,6-diphosphate attenuates prostaglandin E2 production and cyclo-oxygenase-2 expression in UVB-irradiated HaCaT keratinocytes.}, journal = {British journal of pharmacology}, volume = {137}, number = {4}, pages = {497-503}, pmid = {12359631}, issn = {0007-1188}, mesh = {Cell Line ; Cyclooxygenase 2 ; Dinoprostone/*biosynthesis/radiation effects ; Fructosediphosphates/*pharmacology ; Gene Expression Regulation/drug effects/radiation effects ; Humans ; Isoenzymes/*biosynthesis/radiation effects ; Keratinocytes/*drug effects/radiation effects ; Male ; Membrane Proteins ; Prostaglandin-Endoperoxide Synthases/*biosynthesis/radiation effects ; *Ultraviolet Rays ; }, abstract = {1. Fructose-1,6-diphosphate (FDP), a glycolytic metabolite, is reported to ameliorate inflammation and inhibit the nitric oxide production in murine macrophages stimulated with endotoxin. It is also reported that FDP has cytoprotective effects against hypoxia or ischaemia/reperfusion injury in brain and heart. However, underlying mechanisms of its various biological activities are not completely understood. 2. In this study, we examined the effects of FDP on UVB-induced prostaglandin production in HaCaT keratinocytes. 3. Ultraviolet B (UVB, 280-320 nm) irradiation (30 mJ cm(-2)) increased prostaglandin E(2)(PGE(2)) production, which was significantly decreased by FDP in a concentration dependent manner. NS-398, a cyclo-oxygenase-2 (COX-2) selective inhibitor completely inhibited UVB-induced PGE(2) production showing that COX-2 activity is responsible for the increase in PGE(2) production under our experimental conditions. 4. UVB irradiation increased total COX activity and COX-2 mRNA in HaCaT keratinocytes, which were significantly blocked by FDP in a concentration dependent manner. 5. N-acetylcysteine (NAC) significantly attenuated UVB-induced PGE(2) production, COX activity and COX-2 mRNA expression indicating oxidative components might contribute to these events. 6. FDP reduced UVB-induced increase in cellular reactive oxygen species (ROS) level although it did not show direct radical scavenging effect in the experiment using 1,1-diphenyl-2picrylhydrazil (DPPH). FDP preserved the cellular antioxidant capacity including catalase activity and GSH content after irradiation. 7. Our data obtained hitherto suggest that FDP may have a protective role in UVB-injured keratinocyte by attenuating PGE(2) production and COX-2 expression, which are possibly through blocking intracellular ROS accumulation.}, }
@article {pmid12359191, year = {2002}, author = {Tandon, SK and Singh, S and Prasad, S and Srivastava, S and Siddiqui, MK}, title = {Reversal of lead-induced oxidative stress by chelating agent, antioxidant, or their combination in the rat.}, journal = {Environmental research}, volume = {90}, number = {1}, pages = {61-66}, doi = {10.1006/enrs.2002.4386}, pmid = {12359191}, issn = {0013-9351}, mesh = {Acetylcysteine/*pharmacology ; Aminolevulinic Acid/blood ; Animals ; Antioxidants/*pharmacology ; Brain/metabolism ; Catalase/blood ; Chelating Agents/*pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/blood ; Kidney/metabolism ; Lead/blood/metabolism/*toxicity ; Lead Poisoning/drug therapy ; Male ; Malondialdehyde/blood ; Oxidative Stress/drug effects ; Rats ; Succimer/*analogs &amp; derivatives/*pharmacology ; }, abstract = {The influence of N-acetyl cysteine (NAC), an antioxidant, on the therapeutic efficacy of meso-2,3-dimercaptosuccinic acid (DMSA), a hydrophilic, and its ester, monoisoamyl 2,3-dimercaptosuccinate (MiADMS), a lipophilic, both soft tissue lead mobilizers, was investigated in lead-preexposed rats. The subsequent treatment of lead-exposed animals with DMSA, MiADMS, or NAC reversed the lead-induced alterations in blood delta-aminolevulinic acid dehydratase, catalase, malondialdehyde (MDA), reduced glutathione, oxidized glutathione, and brain MDA levels. The combined treatment with DMSA and NAC was more effective than that with MiADMS and NAC in enhancing the restoration of all these parameters indicative of lead-induced oxidative stress. These reversals were consistent with the lead-removing ability of DMSA and MiADMS but not that of NAC. As the reversal of these parameters by NAC was independent of its lead-mobilizing capability, this ought to be mainly due to its strong antioxidant property. The increase in blood and brain zinc levels upon lead exposure appears to be the result of the redistribution of endogenous zinc due to lead. Subsequent treatment with DMSA, MiADMS, NAC, or their combination decreased the brain zinc as its excretable complexes with a transient increase in blood zinc level. The ideal treatment of lead poisoning seems to be a combination of a lead chelator and an antioxidant.}, }
@article {pmid12358931, year = {2002}, author = {Klingler, W and Kreja, L and Nothdurft, W and Selig, C}, title = {Influence of different radioprotective compounds on radiotolerance and cell cycle distribution of human progenitor cells of granulocytopoiesis in vitro.}, journal = {British journal of haematology}, volume = {119}, number = {1}, pages = {244-254}, doi = {10.1046/j.1365-2141.2002.03795.x}, pmid = {12358931}, issn = {0007-1048}, mesh = {Antigens, CD34/metabolism ; Cell Cycle/*radiation effects ; Cell Survival ; Dose-Response Relationship, Radiation ; Flow Cytometry/methods ; Granulocytes/*radiation effects ; Hematopoiesis/*radiation effects ; Hematopoietic Stem Cells/*radiation effects ; Humans ; Radiation Tolerance ; Radiation-Protective Agents/*pharmacology ; }, abstract = {Ficoll-separated mononuclear cells (MNC) of cryopreserved human bone marrow were incubated with isotoxic doses of diltiazem, N-acetylcysteine (NAC), glycopolysaccharide extract of spirulina platensis (SPE), tempol, thiopental, WR2721 and WR1065. After irradiation with a single dose of 0.73 Gy, survival of granulocyte/macrophage colony-forming cells (GM-CFC) was determined at d 10-14, using an agar culture system. Diltiazem, NAC, tempol and WR1065 significantly improved radiotolerance with protection factors (PF) between 1.21 and 1.36 (n = 5, P < 0.05) at 0.73 Gy (PF-0.73 Gy). The survival curves of diltiazem (D0 = 0.88 Gy, n = 1.00), NAC (D0 = 0.92 Gy, n = 1.10), tempol (D0 = 0.99 Gy, n = 1.10), WR1065 (D0 = 0.89 Gy, n = 1.16) and control (D0 = 0.78 Gy, n = 1.00) over 0.36-2.91 Gy showed a significant radioprotective effect for D0 only for tempol (P = 0.018) and for the extrapolation number 'n' only in the case of NAC (P = 0.023). Cell cycle analysis of the CD34+ cell subpopulation (control-0 h: G1 = 82.7%, S = 13.7%, G2/M = 3.6%) revealed that all compounds with a significant PF-0.73 Gy also caused a significant increase in CD34+ cells in S phase up to 48 h. Within the first 24 h, only NAC (26.7 +/- 4.1%), tempol (14.3 +/- 1.0%) and possibly WR1065 (15.5 +/- 1.6%) had higher fractions of CD34+ S-phase cells compared with controls. This observation and the improvement of GM-CFC cloning efficiency indicated that only NAC was able to recruit progenitor cells in the cell cycle, whereas tempol and WR1065 possibly inhibited cell cycle progression by S and G2/M arrest. Of the radioprotectors tested, NAC, tempol and WR1065 may be suitable to support, alone or combined with cytokine therapy, accelerated haematopoietic recovery after irradiation.}, }
@article {pmid12358493, year = {2002}, author = {Yin, MC and Hwang, SW and Chan, KC}, title = {Nonenzymatic antioxidant activity of four organosulfur compounds derived from garlic.}, journal = {Journal of agricultural and food chemistry}, volume = {50}, number = {21}, pages = {6143-6147}, doi = {10.1021/jf0204203}, pmid = {12358493}, issn = {0021-8561}, mesh = {Acetylcysteine/analysis/pharmacology ; Allyl Compounds/analysis/pharmacology ; Antioxidants/*analysis/*pharmacology ; Cysteine/*analogs &amp; derivatives/analysis/pharmacology ; Disulfides/analysis/pharmacology ; Garlic/*chemistry ; Hydrogen-Ion Concentration ; Lipid Peroxidation/drug effects ; Sulfides/analysis/pharmacology ; Sulfur Compounds/*analysis/*pharmacology ; alpha-Tocopherol/pharmacology ; }, abstract = {The nonenzymatic antioxidant activity of diallyl sulfide (DAS), diallyl disulfide (DADS), S-ethyl cysteine (SEC), and N-acetyl cysteine (NAC) in the liposome system was examined. The antioxidant protection from these organosulfur agents was concentration dependent (p < 0.05). SEC and NAC showed significantly lower lipophilicity and greater reducing power than DAS and DADS (p < 0.05). Greater antioxidant protection was presented in the combinations of alpha-tocopherol with four organosulfur agents than alpha-tocopherol treatment alone (p < 0.05), and SEC and NAC showed greater sparing effects on alpha-tocopherol (p < 0.05). Four organosulfur agents lost antioxidant activity when the temperature was 65 degrees C (p < 0.05). At pH 2.5 and 10, DAS and DADS still showed antioxidant activity (p < 0.05). On the basis of the observed nonenzymatic antioxidant protection, these organosulfur compounds are potent agents for enhancing lipid stability.}, }
@article {pmid12349898, year = {2002}, author = {Vasdev, S and Gill, V and Parai, S and Longerich, L and Gadag, V}, title = {Dietary vitamin E supplementation lowers blood pressure in spontaneously hypertensive rats.}, journal = {Molecular and cellular biochemistry}, volume = {238}, number = {1-2}, pages = {111-117}, pmid = {12349898}, issn = {0300-8177}, mesh = {Administration, Oral ; Aldehydes/analysis ; Animals ; Antihypertensive Agents/pharmacology/therapeutic use ; Blood Platelets/drug effects/metabolism ; Blood Pressure/*drug effects ; Body Weight/drug effects ; Calcium/blood ; Dietary Supplements ; Drinking Behavior/drug effects ; Eating/drug effects ; Hypertension/drug therapy ; Organ Size/drug effects ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Time Factors ; Vitamin E/administration &amp; dosage/*pharmacology/therapeutic use ; }, abstract = {In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. Vitamin E increases tissue glutathione levels--a storage form of cysteine. The aim of the present study was to investigate whether a dietary supplementation of vitamin E lowers blood pressure and prevents renal vascular changes by normalizing tissue aldehyde conjugates and cytosolic [Ca2+] in SHRs. Starting at 12 weeks of age, animals were divided into three groups of six animals each. Animals in the WKY-control group and SHR-control group were given a normal diet and the SHR-vitamin E group a diet supplemented with vitamin E (34 mg/ kg feed) for the next 9 weeks. After 9 weeks, systolic blood pressure, platelet [Ca2+]i, and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared to WKY controls and the SHR-vitamin E group. SHR-controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidney. Dietary vitamin E supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+], tissue aldehyde conjugates and attenuated adverse renal vascular changes.}, }
@article {pmid12297694, year = {2002}, author = {Park, HK and Lee, KW and Choi, JS and Joo, CK}, title = {Mitomycin C-induced cell death in mouse lens epithelial cells.}, journal = {Ophthalmic research}, volume = {34}, number = {4}, pages = {213-219}, doi = {10.1159/000063880}, pmid = {12297694}, issn = {0030-3747}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/*pharmacology ; Cell Death/drug effects ; Cell Division/drug effects ; Cell Line ; Dicumarol/pharmacology ; Epithelial Cells/physiology ; Free Radical Scavengers/pharmacology ; Lens, Crystalline/cytology/*physiology ; Mice ; Mitomycin/*pharmacology ; }, abstract = {The mode of action of mitomycin C (MMC)-induced cell death in lens epithelia was investigated using cell culture system. The cytotoxicity of MMC on alpha-TN4 mouse lens epithelial cells (LECs) was measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT)-based assay. To determine the type of cell death induced by MMC, we stained LECs with acridine orange and ethidium bromide, and performed TUNEL assay and electron microscopic examination. The activation of MMC was also investigated with N-acetly-L-cystein (NAC), a free radical scavenger, and dicumarol, an inhibitor of DT-diaphorase, to analyze one- and two-electron reduction pathways involved in the activation of MMC. MTT assay showed that 400 microg/ml of MMC decreased the cell viability of the control cells to 45%, and the cytotoxicity of MMC on alpha-TN4 cells was increased in a dose-dependent manner. Based on the results obtained from acridine orange and ethidium bromide staining, the TUNEL assay, and transmission electron microscopic examination, we confirmed that MMC-induced cell death, at 400 microg/ml of MMC, occurs with necrosis as well as apoptotis. The treatment of cells with 2 mM NAC for 1 h or 20 microM dicumarol for 30 min, prior to 5 min of MMC (400 microg/ml) treatment, restored the growth suppression to 76 and 80% of the control level, respectively. In addition, the cotreatment of cells with NAC and dicumarol restored cell viability to 90% of the control level. The cellular death in MMC-treated LECs showed the involvement of oxidative stress in this apoptosis accounting for 22% of the observed cell death at 400 microg/ml of MMC.}, }
@article {pmid12269697, year = {2002}, author = {Doğru-Abbasoğlu, S and Balkan, J and Kanbağli, O and Cevikbaş, U and Aykaç-Toker, G and Uysal, M}, title = {Aminoguanidine, an inducible nitric oxide synthase inhibitor, plus N-acetylcysteine treatment reduce the lipopolysaccharide-augmented hepatotoxicity in rats with cirrhosis.}, journal = {Human &amp; experimental toxicology}, volume = {21}, number = {7}, pages = {359-364}, doi = {10.1191/0960327102ht256oa}, pmid = {12269697}, issn = {0960-3271}, mesh = {Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Free Radical Scavengers/therapeutic use ; Guanidines/*therapeutic use ; Lipopolysaccharides/antagonists &amp; inhibitors/*toxicity ; Liver Cirrhosis, Experimental/*drug therapy/enzymology/pathology ; Male ; Nitric Oxide Synthase/*antagonists &amp; inhibitors ; Oxidative Stress/drug effects ; Rats ; Rats, Wistar ; }, abstract = {Hepatic cirrhosis is produced in rats by administration of thioacetamide (TAA) (0.3 g/L tap water for a period of three months). This treatment caused an increase in oxidative stress in the liver. Lipopolysaccharide (LPS) administration (5 mg/kg) to rats with cirrhosis was observed to increase hepatotoxicity as well as oxidative stress according to biochemical and histopathological findings. However, aminoguanidine (AG), an inducible nitric oxide synthase (iNOS) inhibitor, plus N-acetylcysteine (NAC) treatment reduced the LPS-augmented hepatotoxicity in rats with cirrhosis without making any changes in oxidative stress in the liver.}, }
@article {pmid12243773, year = {2002}, author = {Shimizu, E and Hashimoto, K and Komatsu, N and Iyo, M}, title = {Roles of endogenous glutathione levels on 6-hydroxydopamine-induced apoptotic neuronal cell death in human neuroblastoma SK-N-SH cells.}, journal = {Neuropharmacology}, volume = {43}, number = {3}, pages = {434-443}, doi = {10.1016/s0028-3908(02)00108-9}, pmid = {12243773}, issn = {0028-3908}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Benzimidazoles ; Brain Neoplasms/*pathology ; Buthionine Sulfoximine/pharmacology ; Cystine/pharmacology ; DNA Fragmentation/drug effects ; Fluorescent Dyes ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism/pharmacology/*physiology ; Humans ; Neuroblastoma/*pathology ; Neurons/*drug effects ; Oxidopamine/*antagonists &amp; inhibitors/*toxicity ; Sympatholytics/*antagonists &amp; inhibitors/*toxicity ; Tumor Cells, Cultured ; }, abstract = {We investigated the roles of endogenous glutathione on 6-hydroxydopamine (6-OHDA)-induced apoptosis in human neuroblastoma SK-N-SH cells using DNA fragmentation enzyme-immunoassay and the DNA dye Hoechst 33258 staining. We observed that exogenous reduced glutathione (GSH), but not oxidized glutathione (GSSG), protected 6-OHDA (25 micro M)-induced apoptosis in a dose-dependent manner. Preincubation (18 h) with the glutathione synthesis inhibitor DL-buthionine-(S,R)-sulfoximine (BSO) significantly potentiated the toxic effects of 6-OHDA (12.5 or 25 micro M). In contrast to BSO, N-acetylcysteine (NAC) blocked, and L-(-)-cystine, the glutathione precursor, significantly attenuated 6-OHDA (25 micro M)-induced apoptosis, respectively. No alterations in endogenous glutathione concentrations were detected at 5, 15, 30, 60 min, 1 hour, 3 hours, or 6 hours after 6-OHDA (25 micro M) treatment. However, we found a 3.5-fold increase of intracellular glutathione levels 24 hours later. On the contrary, higher concentration (100 micro M) of 6-OHDA treatment, which caused more severe cell death, showed no changes of glutathione levels. These results suggest that delayed induction of endogenous glutathione might play an important role in the neuroprotective mechanism against dopamine cell death. In addition, we found that NAC might work as a beneficial catecholaminergic neuron-survival factor more efficiently than exogenous glutathione or L-cystine.}, }
@article {pmid12237339, year = {2002}, author = {Koh, AS and Simmons-Willis, TA and Pritchard, JB and Grassl, SM and Ballatori, N}, title = {Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: transport by the renal organic anion transporter-1.}, journal = {Molecular pharmacology}, volume = {62}, number = {4}, pages = {921-926}, doi = {10.1124/mol.62.4.921}, pmid = {12237339}, issn = {0026-895X}, support = {DK48823/DK/NIDDK NIH HHS/United States ; ES01247/ES/NIEHS NIH HHS/United States ; ES06484/ES/NIEHS NIH HHS/United States ; ES07026/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antidotes/*pharmacology ; Biological Transport/drug effects ; Kidney/*drug effects/metabolism ; Kinetics ; Metals/urine ; Methylmercury Compounds/*antagonists &amp; inhibitors/toxicity ; Oocytes ; Organic Anion Transport Protein 1/*metabolism ; Organic Anion Transporters, Sodium-Independent/metabolism ; Substrate Specificity ; Unithiol/*pharmacology ; Xenopus laevis ; }, abstract = {N-Acetylcysteine (NAC) and dimercaptopropanesulfonate (DMPS) are sulfhydryl-containing compounds that produce a dramatic acceleration of urinary methylmercury (MeHg) excretion in poisoned animals, but the molecular mechanism for this effect is unknown. NAC and DMPS are themselves excreted in urine in high concentrations. The present study tested the hypothesis that the complexes formed between MeHg and these anionic chelating agents are transported from blood into proximal tubule cells by the basolateral membrane organic anion transporters (Oat) 1 and Oat3. Xenopus laevis oocytes expressing rat Oat1 showed increased uptake of [(14)C]MeHg when complexed with either NAC or DMPS but not when complexed with L-cysteine, glutathione, dimercaptosuccinate, penicillamine, or gamma-glutamylcysteine. In contrast, none of these MeHg complexes were transported by Oat3-expressing oocytes. The apparent K(m) values for Oat1-mediated transport were 31 +/- 2 microM for MeHg-NAC and 9 +/- 2 microM for MeHg-DMPS, indicating that these are relatively high-affinity substrates. Oat1-mediated uptake of [(14)C]MeHg-NAC and [(14)C]MeHg-DMPS was inhibited by prototypical substrates for Oat1, including p-aminohippurate (PAH), and was trans-stimulated when oocytes were preloaded with 2 mM glutarate but not glutamate. Conversely, efflux of [(3)H]PAH from Oat1-expressing oocytes was trans-stimulated by glutarate, PAH, NAC, DMPS, MeHg-NAC, MeHg-DMPS, and a mercapturic acid, indicating that these are transported solutes. [(3)H]PAH uptake was competitively inhibited by NAC (K(i) of 2.0 +/- 0.3 mM) and DMPS (K(i) of 0.10 +/- 0.02 mM), providing further evidence that these chelating agents are substrates for Oat1. These results indicate that the MeHg antidotes NAC and DMPS and their mercaptide complexes are transported by Oat1 but are comparatively poor substrates for Oat3. This is the first molecular identification of a transport mechanism by which these antidotes may enhance urinary excretion of toxic metals.}, }
@article {pmid12234769, year = {2002}, author = {Cargnoni, A and Ceconi, C and Gaia, G and Agnoletti, L and Ferrari, R}, title = {Cellular thiols redox status: a switch for NF-kappaB activation during myocardial post-ischaemic reperfusion.}, journal = {Journal of molecular and cellular cardiology}, volume = {34}, number = {8}, pages = {997-1005}, doi = {10.1006/jmcc.2002.2046}, pmid = {12234769}, issn = {0022-2828}, mesh = {Animals ; Myocardial Ischemia/metabolism ; *Myocardial Reperfusion ; Myocardium/*metabolism ; NF-kappa B/*metabolism ; *Oxidation-Reduction ; Rats ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Myocardial ischaemia/reperfusion induces NF-kappaB activation, but little is known about the stimuli through which it occurs. Aims of the study were to investigate whether: (a) oxidative stress induced by ischaemia/reperfusion is linked with NF-kappaB activation; (b) counteraction of oxidative stress by N-acetyl cysteine (NAC) reduces NF-kappaB activation. At this purpose, in isolated rat hearts, we induced mild (15 min) and severe (30 min) ischaemia; a group of the hearts submitted to severe ischaemia were treated with NAC. Our data indicate that reperfusion after severe ischaemia activates NF-kappaB: the presence of p65 in the nuclear extracts was 274.5+/-18.6% vs aerobia; (P<0.05) and an induced DNA-binding activity was detected. NF-kappaB translocation occurs in parallel with myocardial decrease in reduced glutathione and protein -SH (from 9.2+/-0.4 to 5.4+/-0.3 nmol/mg prot, P<0.01, and from 350.3+/-16.6 to 296.0+/-9.1 nmol/mg prot, P<0.05) and accumulation of oxidised glutathione-GSSG-(from 0.075+/-0.005 to 0.118+/-0.007 nmol/mg prot, P<0.01). When ischaemia/reperfusion does not result in any oxidative stress (in mild ischaemia or severe ischaemia plus NAC), NF-kappaB does not translocate. A significant correlation was found between the activation of NF-kappaB and the accumulation of GSSG in the myocardium. Our data indicate that an oxidative shift of cellular thiolic pools can modulate the genic transcription of the heart through NF-kappaB activation.}, }
@article {pmid12220944, year = {2002}, author = {Stolarek, R and Białasiewicz, P and Nowak, D}, title = {N-acetylcysteine effect on the luminol-dependent chemiluminescence pattern of reactive oxygen species generation by human polymorphonuclear leukocytes.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {15}, number = {4}, pages = {385-392}, doi = {10.1006/pupt.2002.0369}, pmid = {12220944}, issn = {1094-5539}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Female ; Free Radical Scavengers/pharmacology ; Humans ; In Vitro Techniques ; Indicators and Reagents/pharmacology ; Luminescent Measurements ; Luminol/pharmacology ; Male ; Neutrophil Activation/drug effects/physiology ; Neutrophils/*drug effects/physiology ; Reactive Oxygen Species/*metabolism ; Respiratory Burst/*drug effects/physiology ; }, abstract = {The evidence of the effect of N-acetylcysteine on reactive oxygen species produced by human polymorphonuclear leukocytes (PMNs) is often contradictory, as thiol compounds may react with not only reactive oxygen and nitrogen species but also they may influence intracellular glutathione levels. The effect of 20, 100 and 200 microM N-aceylcysteine (NAC) on luminol dependent chemiluminescence (LDCL) of human PMNs (10(6) cells/ml phospate buffered saline (PBS)) and whole blood to N-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol-12-myristate-13-acetate (PMA) was studied. Further, the ability of NAC to increase PMNs intracellular thiols and affect subsequent PMNs, stimulation was assessed. NAC 100 and 200 microM, but not 20 microM, was found to attenuate the kinetic parameters of initial phase of fMLP-stimulated PMNs oxidative burst. NAC at the concentration of 100 and 200 microM decreased the rate, maximum and integrated value of PMNs response to fMLP. The integrated value of PMA-induced PMNs and fMLP-induced whole blood LDCL response was also decreased by 100 and 200 microM NAC. Furthermore, all tested NAC concentrations decreased LDCL of resting PMNs suspension. The chemiluminescence pattern of reactive oxygen species (ROS) generation by PMNs stimulated with fMLP or PMA did not differ significantly from those preincubated with either 20, 100, or 200 microM NAC. Similarly, NAC did not increase the concentration of intracellular thiols in resting PMNs. However, addition of 200 microM NAC to PMA-stimulated PMNs prevented the decline in intracellular thiols pool. Both PMA- and fMLP-activated PMNs oxidized extracellular NAC. These results indicate that NAC decreases the intensity of PMNs oxidative burst by direct scavenger activity.}, }
@article {pmid12215212, year = {2002}, author = {Nakamura, H and Masutani, H and Yodoi, J}, title = {Redox imbalance and its control in HIV infection.}, journal = {Antioxidants &amp; redox signaling}, volume = {4}, number = {3}, pages = {455-464}, doi = {10.1089/15230860260196245}, pmid = {12215212}, issn = {1523-0864}, mesh = {Antioxidants/metabolism/therapeutic use ; Glutathione/deficiency/metabolism ; HIV Infections/drug therapy/*metabolism ; HIV-1/*metabolism ; Humans ; Models, Biological ; Oxidation-Reduction ; *Oxidative Stress ; Prodrugs/metabolism ; Prognosis ; Reactive Oxygen Species/metabolism ; Response Elements ; Thioredoxins/blood ; }, abstract = {Human immunodeficiency virus (HIV)-infected individuals are suffering from systemic oxidative stress. Reactive oxygen species act as second messengers for the activation of nuclear factor-kappaB (NF-kappaB), which augments the replication of HIV. Intracellular levels of glutathione (GSH), a major cytosolic antioxidant, in T cells decrease during the disease progression. Another redox-regulating molecule, thioredoxin (TRX), is also transiently down-regulated in the cells by acute HIV infection. In contrast, plasma levels of TRX are elevated in the late stage of HIV infection. Intracellular GSH and plasma TRX can be biomarkers to predict the prognosis of the disease. N-Acetylcysteine (NAC), a prodrug of cysteine that is necessary for GSH synthesis, has been used for HIV infection to prevent the activation of NF-kappaB and the replication of HIV. NAC shows some beneficial effects for HIV-infected individuals, although the intracellular GSH levels in lymphocytes are not significantly restored. The control of imbalanced redox status by antioxidants may be beneficial for the quality of life in HIV infection even in the era after the effective therapy with protease inhibitors has been applied. Redox control will be an important therapeutic strategy for oxidative stress-associated disorders including HIV infection.}, }
@article {pmid12214018, year = {2001}, author = {Dhitavat, S and Rivera, ER and Rogers, E and Shea, TB}, title = {Differential efficacy of lipophilic and cytosolic antioxidants on generation of reactive oxygen species by amyloid-beta.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {3}, number = {6}, pages = {525-529}, pmid = {12214018}, issn = {1875-8908}, abstract = {Exposure of neurons to amyloid-beta (Abeta) is accompanied by a cascade of oxidative damage that initiates with lipid peroxidation followed by subsequent generation of cytosolic free radicals and reactive oxygen species (ROS). The antioxidant vitamin E has been utilized to counteract Abeta-induced oxidative stress. We considered herein whether or not the lipid-solubility of vitamin E limits its neuroprotection to membrane-related oxidative damage, and renders it relatively ineffective where prior lipid peroxidation has already generated cytosolic free radicals and ROS. To test this possibility, we treated differentiated SH-SY-5Y human neuroblastoma with vitamin E or a cell-permeant antioxidant, N-acetyl cysteine (NAC), simultaneously with or 15 min after the application of Abeta. Both vitamin E and NAC prevented Abeta-induced ROS generation when applied simultaneously with Abeta, but only NAC prevented Abeta-induced ROS generation when added to cultures that had previously been exposed to Abeta. These results support the hypothesis that vitamin E can quench Abeta-induced lipid peroxidation, but cannot effectively quench ROS generated by prior lipid peroxidation. These findings in cell culture may provide limited insight into why vitamin E is not fully effective against neurodegeneration in AD in clinical settings, since some neuronal populations are likely to already have been compromised by prior Abeta exposure before vitamin E treatment was initiated.}, }
@article {pmid12213524, year = {2002}, author = {Puerto, M and Guayerbas, N and Víctor, V and De la Fuente, M}, title = {Effects of N-acetylcysteine on macrophage and lymphocyte functions in a mouse model of premature ageing.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {73}, number = {4}, pages = {797-804}, doi = {10.1016/s0091-3057(02)00902-4}, pmid = {12213524}, issn = {0091-3057}, mesh = {Acetylcysteine/*pharmacology ; Aging, Premature/*drug therapy/immunology/prevention &amp; control ; Animals ; *Disease Models, Animal ; Female ; Lymphocytes/*drug effects/immunology ; Macrophages/*drug effects/immunology ; Mice ; Reactive Oxygen Species/immunology ; }, abstract = {In previous studies, we have observed that mice of the same strain and age show striking interindividual differences in behavior when exposed to a T-maze test. The animals that take longer to explore a T-shaped maze ("slow" animals) show high levels of emotionality/anxiety in other standard behavioral tests, prematurely aged immune functions, and a shorter life span, in comparison to "fast" mice. In these slow mice, which are a model of premature immunosenescence, the immune functions were improved after the ingestion of the thiolic antioxidant thioproline in the diet. In the present work, we studied the effects in vivo (0.1% w/w, for 4 weeks) and in vitro (0.001, 0.01, 0.1, 1, and 2.5 mM) of the thiolic antioxidant N-acetylcysteine (NAC) on different functions of peritoneal macrophages and lymphocytes from slow and fast adult Swiss mice. The results showed an improvement of all the functions studied, namely adherence to substrate, directed migration or chemotaxis, phagocytosis, and reactive oxygen species (ROS) production, after in vivo and in vitro treatment with NAC. The effect of this antioxidant was stronger in the cells from the slow than in those from the fast mice.}, }
@article {pmid12212833, year = {2002}, author = {Nisar, S and Feinfeld, DA}, title = {N-acetylcysteine as salvage therapy in cisplatin nephrotoxicity.}, journal = {Renal failure}, volume = {24}, number = {4}, pages = {529-533}, doi = {10.1081/jdi-120006780}, pmid = {12212833}, issn = {0886-022X}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*chemically induced ; Antineoplastic Agents/*adverse effects ; Carcinoma, Squamous Cell/drug therapy ; Cisplatin/*adverse effects ; Esophageal Neoplasms/drug therapy ; Female ; Humans ; Middle Aged ; *Salvage Therapy ; }, abstract = {N-acetylcysteine (NAC) repletes intracellular stores of reduced glutathione and may be a scavenger of oxygen free radicals. We report a 52-year-old female who developed acute renal insufficiency after administration of one dose of 150 mg of cisplatin for treatment of squamous cell cancer of the esophagus. Her blood urea nitrogen and creatinine rose from 12 and 0.7 mg/dL, respectively, to 24 and 1.8 mg/dL on day 5 after cisplatin. On that day the patient was begun on NAC, starting with a loading dose of 140-mg/kg-body weight followed by 70mg/kg every 4h for 4 days. Two days after starting NAC her renal function began to improve, and although she failed to complete a full course of the drug, by day 10 her serum creatinine had fallen to 0.8 mg/dL. A previous report showed that N-acetylcysteine might reverse cisplatin-induced renal toxicity. Our case supports this hypothesis.}, }
@article {pmid12209267, year = {2002}, author = {Buwalda, M and Ince, C}, title = {Opening the microcirculation: can vasodilators be useful in sepsis?.}, journal = {Intensive care medicine}, volume = {28}, number = {9}, pages = {1208-1217}, doi = {10.1007/s00134-002-1407-2}, pmid = {12209267}, issn = {0342-4642}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Animals ; Epoprostenol/pharmacology/therapeutic use ; Hemodynamics ; Humans ; Microcirculation/*drug effects ; Netherlands ; Nitric Oxide Donors/pharmacology/therapeutic use ; Oxygen/metabolism ; Pentoxifylline/pharmacology/therapeutic use ; Sepsis/*drug therapy/metabolism/physiopathology ; Treatment Outcome ; Vasodilator Agents/pharmacology/*therapeutic use ; }, abstract = {OBJECTIVE: A prominent feature of sepsis is dysfunction of the microcirculation, with impaired perfusion and regional tissue oxygenation causing a deficit in oxygen extraction. If shunting of oxygen transport past closed hypoxic microcirculatory beds is responsible for this, vasodilator therapy, which raises the driving pressure of the microcirculation and thereby promotes flow, could recruit such shunted microcirculatory units and improve tissue oxygenation.<br><br>DESIGN: A literature search was conducted in Medline for evidence of this expected benefit of vasodilators in sepsis.<br><br>METHODS: Studies were searched using the keyword for vasodilating drugs in combination with "sepsis," "septic," "multiple organ failure," or "critically ill patients." The search included animal and clinical investigations but only where the effects of vasodilator therapy were demonstrated by regional measures of oxygen transport variables (e.g., oxygen extraction variables, regional ischemia, microcirculatory flow or tissue oxygenation measurements). The vasodilating drugs investigated included prostacyclin, pentoxifylline, N-acetyl-cysteine, and nitric oxide donors used in animal and human sepsis.<br><br>RESULTS: Prostacyclin and nitric oxide donors are the best studied vasodilating agents in experimental sepsis and have shown improved tissue perfusion and oxygen extraction. In several clinical studies prostacyclin has also been shown to have such beneficial effects. Recent studies using orthogonal polarization spectral imaging have shown microcirculatory recruitment by nitric oxide donors in hemodynamically resuscitated septic patients. Whether such therapeutic modalities aimed at recruitment of the microcirculation improve outcome, however, still has to be determined.}, }
@article {pmid12208514, year = {2002}, author = {Kitazawa, M and Nakano, T and Chuujou, H and Shiojiri, E and Iwasaki, K and Sakamoto, K}, title = {Intracellular redox regulation by a cystine derivative suppresses UV-induced NF-kappa B activation.}, journal = {FEBS letters}, volume = {526}, number = {1-3}, pages = {106-110}, doi = {10.1016/s0014-5793(02)03152-6}, pmid = {12208514}, issn = {0014-5793}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Cell Line ; Cell Nucleus/metabolism/radiation effects ; Cystine/*analogs &amp; derivatives/*pharmacology ; Cytosol/metabolism/radiation effects ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Humans ; Kinetics ; NF-kappa B/metabolism/*radiation effects ; Oxidation-Reduction ; *Ultraviolet Rays ; }, abstract = {Nuclear factor (NF)-kappa B pathways are influenced by the intracellular reduction-oxidation (redox) balance. While NF-kappa B is activated through inhibitor (I)-kappa B degradation by oxidative stress, its DNA binding is accelerated in the reduced state. We found that N,N'-diacetyl-L-cystine dimethylester (DACDM) suppressed the UVB-induced NF-kappa B binding activity at a much lower concentration (50-100 microM) than N-acetyl-L-cysteine (NAC, 10-30 mM). While NAC suppressed the I-kappa B degradation but not the DNA binding, DACDM prevented the activated NF-kappa B from binding DNA, without influencing the I-kappa B degradation. These properties of DACDM make it possible to effectively regulate the intracellular redox balance.}, }
@article {pmid12202152, year = {2002}, author = {Nambiar, MP and Fisher, CU and Enyedy, EJ and Warke, VG and Kumar, A and Tsokos, GC}, title = {Oxidative stress is involved in the heat stress-induced downregulation of TCR zeta chain expression and TCR/CD3-mediated [Ca(2+)](i) response in human T-lymphocytes.}, journal = {Cellular immunology}, volume = {215}, number = {2}, pages = {151-161}, doi = {10.1016/s0008-8749(02)00006-0}, pmid = {12202152}, issn = {0008-8749}, support = {AI42269/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Calcium/metabolism ; Calcium Signaling/*physiology ; Cell Fractionation ; DNA-Binding Proteins/genetics/metabolism ; *Down-Regulation ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Hot Temperature ; Humans ; Immunosuppressive Agents/pharmacology ; Interleukin-2/metabolism ; Lymphocyte Activation ; Membrane Proteins/genetics/*metabolism ; Muromonab-CD3/pharmacology ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Receptor-CD3 Complex, Antigen, T-Cell/*metabolism ; Receptors, Antigen, T-Cell/genetics/*metabolism ; T-Lymphocytes/drug effects/immunology/*metabolism ; Transcription Factors/genetics/metabolism ; }, abstract = {Exposure of human T-lymphocytes to heat downregulates TCR zeta chain expression and inhibits (TCR)/CD3-mediated production of inositol triphosphate and [Ca(2+)](i) signaling. Here we investigated whether oxidative stress is involved in the heat-induced downregulation of TCR/CD3-mediated signaling. To this end, we have studied the effect of a thiol antioxidant, N-acetyl-L-cysteine (NAC), and a non-thiol antioxidant, allopurinol, on heat-induced downregulation of TCR/CD3-mediated signaling. We found that preincubation of cells with 10mM NAC significantly reversed the downregulation of TCR/CD3-mediated [Ca(2+)](i) response and restored the suppression of TCR zeta chain protein expression as well as prevented its increased membrane distribution in heat-treated cells. NAC also reversed the downregulation of TCR zeta chain mRNA expression and the active 94kDa TCR zeta chain transcription factor, Elf-1, in heat-treated cells. Consistent with the increase in the TCR zeta chain, preincubation with NAC increased the levels of antigen receptor-induced tyrosine phosphorylation of several cytosolic proteins. Finally, treatment with NAC was able to reverse the suppression of IL-2 production in heat-treated cells. Inactive analog, N-acetylserine, failed to reverse the heat-induced downregulation of TCR/CD3-mediated signaling. Allopurinol, another potent non-thiol antioxidant, also restored the TCR/CD3-mediated [Ca(2+)](i) response in heat-treated cells. These results demonstrate that antioxidants restore the expression of TCR zeta chain and reverse the TCR/CD3-mediated signaling abnormalities associated with heat stress and suggest that heat shock-induced oxidative stress is a mediator of the heat-induced biochemical damage that leads to downregulation of signaling in human T-lymphocytes.}, }
@article {pmid12198013, year = {2002}, author = {Badaloo, A and Reid, M and Forrester, T and Heird, WC and Jahoor, F}, title = {Cysteine supplementation improves the erythrocyte glutathione synthesis rate in children with severe edematous malnutrition.}, journal = {The American journal of clinical nutrition}, volume = {76}, number = {3}, pages = {646-652}, doi = {10.1093/ajcn/76.3.646}, pmid = {12198013}, issn = {0002-9165}, support = {1R01 DK56689/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Deuterium ; Dietary Supplements ; Erythrocytes/*metabolism ; Female ; Glutathione/*blood ; Glycine ; Humans ; Infant ; Kwashiorkor/blood/*drug therapy ; Male ; Protein-Energy Malnutrition/blood/*drug therapy ; }, abstract = {BACKGROUND: Children with severe edematous malnutrition have higher than normal oxidant damage and lower concentrations of the antioxidant reduced glutathione (GSH), which are associated with slower synthesis of GSH and with low extra- and intracellular concentrations of the precursor amino acid cysteine.<br><br>OBJECTIVE: We tested whether early dietary supplementation with cysteine could restore a normal GSH concentration and synthesis rate in these children.<br><br>DESIGN: Erythrocyte cysteine and GSH concentrations and the fractional and absolute synthesis rates of GSH were measured in 2 groups of 16 edematous malnourished children, 10 boys and 6 girls aged 6-18 mo, at 3 times after hospital admission: at approximately 2 d (period 1), when they were malnourished and infected; at approximately 11 d (period 2), when they were malnourished but cleared of infection; and at approximately 50 d (period 3), when they had recovered. Supplementation with either 0.5 mmol. kg(-1). d(-1) N-acetylcysteine (NAC group) or alanine (control group) started immediately after period 1 and continued until recovery.<br><br>RESULTS: From period 1 to period 2 the concentration and the absolute synthesis rate of GSH increased significantly (P < 0.05) in the NAC group but not in the control group. The increases in the GSH concentration and synthesis rate were approximately 150% and 510% greater, respectively, in the NAC group than in the control group. The increases in the NAC group were associated with a significant effect of supplement (P < 0.03) on erythrocyte cysteine concentration.<br><br>CONCLUSION: These results suggest that the GSH synthesis rate and concentration can be restored during the early phase of treatment if patients are supplemented with cysteine.}, }
@article {pmid12197140, year = {2002}, author = {Irvine, RJ and Dallas, JF}, title = {Efficient polymerase chain reaction detection of the second internal transcribed spacer of mucosa-derived larvae is dependent on the larval extraction method.}, journal = {The Journal of parasitology}, volume = {88}, number = {4}, pages = {807-809}, doi = {10.1645/0022-3395(2002)088[0807:EPCRDO]2.0.CO;2}, pmid = {12197140}, issn = {0022-3395}, mesh = {Acetylcysteine ; Animals ; DNA, Helminth/analysis ; DNA, Ribosomal Spacer/*analysis ; Deer/*parasitology ; Hydrochloric Acid ; Larva ; Nematoda/genetics/*isolation &amp; purification ; Pepsin A ; Polymerase Chain Reaction/*methods ; Sheep/*parasitology ; Time Factors ; }, abstract = {Methods for estimating abundance of arrested gastrointestinal larvae in large mammal hosts by digestion of the gastrointestinal mucosa are well established. The effects of digestion on the success of species identification using the polymerase chain reaction (PCR) are, however, unknown. In this study, the relationship between numerical recovery of arrested larvae and the success of PCR-typing for the second internal transcribed spacer of ribosomal genes was characterized. Fresh and prefrozen mucosa of 4 sheep yielded very similar rates of recovery and PCR detection. When sheep mucosa were digested with neutral N-acetyl cysteine, recovery increased, whereas PCR detection remained constant (60-80%) with digest duration (1-16 hr). In contrast, when sheep and Svalbard reindeer mucosa were digested with acid-pepsin, recovery increased, whereas PCR detection declined to 0 with digest duration. Thus, to optimize recovery and PCR analysis of arrested gastrointestinal nematode larvae, acid-pepsin digestion of 1-2 hr for PCR detection and 16 hr for recovery, or neutral N-acetyl cysteine digestion of 8-16 hr for both assays, should be used.}, }
@article {pmid12196069, year = {2002}, author = {Brophy, DF}, title = {Role of N-acetylcysteine in the prevention of radiocontrast-induced nephropathy.}, journal = {The Annals of pharmacotherapy}, volume = {36}, number = {9}, pages = {1466-1470}, doi = {10.1345/aph.1A482}, pmid = {12196069}, issn = {1060-0280}, mesh = {Acetylcysteine/*therapeutic use ; Acute Kidney Injury/*chemically induced/physiopathology/*prevention &amp; control ; Clinical Trials as Topic ; Contrast Media/*adverse effects ; Humans ; }, abstract = {OBJECTIVE: To examine the role of N-acetylcysteine (NAC) in the prevention of radiocontrast-induced nephropathy (RIN).<br><br>DATA SOURCES: A literature search of MEDLINE (1966-December 2001) was performed using the following search terms: N-acetylcysteine, nephropathy, acute renal failure, and radiocontrast.<br><br>STUDY SELECTION: Pertinent English-language animal and human studies were reviewed.<br><br>DATA SYNTHESIS: Few small animal trials have demonstrated that NAC significantly prevents the development or reduces the severity of acute renal failure. Two human studies demonstrated NAC significantly reduces the occurrence of RIN.<br><br>CONCLUSIONS: NAC may reduce the occurrence of RIN in high-risk patients. Further large-scale studies are needed to corroborate findings from earlier trials.}, }
@article {pmid12193733, year = {2002}, author = {Von Knethen, A and Brüne, B}, title = {Activation of peroxisome proliferator-activated receptor gamma by nitric oxide in monocytes/macrophages down-regulates p47phox and attenuates the respiratory burst.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {169}, number = {5}, pages = {2619-2626}, doi = {10.4049/jimmunol.169.5.2619}, pmid = {12193733}, issn = {0022-1767}, mesh = {Animals ; Cell Line ; *Down-Regulation/drug effects ; Enzyme Induction/drug effects ; Free Radicals/antagonists &amp; inhibitors/metabolism ; Humans ; Macrophages/drug effects/enzymology/*metabolism ; Mice ; Monocytes/drug effects/enzymology/*metabolism ; NADPH Oxidases ; Nitric Oxide/metabolism/*physiology ; Nitric Oxide Donors/pharmacology ; Nitric Oxide Synthase/biosynthesis ; Nitric Oxide Synthase Type II ; Peroxisomes/*metabolism ; Phosphoproteins/*antagonists &amp; inhibitors/biosynthesis ; Receptors, Cytoplasmic and Nuclear/*metabolism/physiology ; Respiratory Burst/drug effects/*physiology ; S-Nitrosoglutathione/pharmacology ; Superoxides/antagonists &amp; inhibitors/metabolism ; Transcription Factors/*metabolism/physiology ; U937 Cells ; }, abstract = {NO appears as an important determinant in auto and paracrine macrophage function. We hypothesized that NO switches monocyte/macrophage function from a pro- to an anti-inflammatory phenotype by activating anti-inflammatory properties of the peroxisome proliferator-activated receptor (PPAR)gamma. NO-releasing compounds (100 micro M S-nitrosoglutathione or 50 micro M spermine-NONOate) as well as inducible NO synthase induction provoked activation of PPARgamma. This was proven by EMSAs, with the notion that supershift analysis pointed to the involvement of PPARgamma. PCR analysis ruled out induction of PPARgamma mRNA as a result of NO supplementation. Reporter assays, with a construct containing a triple PPAR response element in front of a thymidine kinase minimal promoter driving the luciferase gene, were positive in response to NO delivery. DNA binding capacity as well as the transactivating capability of PPARgamma were attenuated by addition of the antioxidant N-acetyl-cysteine or in the presence of the NO scavenger 2-phenyl-4,4,5,6-tetramethyl-imidazoline-1-oxyl 3-oxide. Having established that NO but not lipophilic cyclic GMP analogs activated PPARgamma, we verified potential anti-inflammatory consequences. The oxidative burst of macrophages, evoked by phorbol ester, was attenuated in association with NO-elicited PPARgamma activation. A cause-effect relationship was demonstrated when PPAR response element decoy oligonucleotides, supplied in front of NO delivery, allowed to regain an oxidative response. PPARgamma-mediated down-regulation of p47 phagocyte oxidase, a component of the NAD(P)H oxidase system, was identified as one molecular mechanism causing inhibition of superoxide radical formation. We conclude that NO participates in controlling the pro- vs anti-inflammatory phenotype of macrophages by modulating PPARgamma.}, }
@article {pmid12189187, year = {2002}, author = {Hecht, SS and Upadhyaya, P and Wang, M and Bliss, RL and McIntee, EJ and Kenney, PM}, title = {Inhibition of lung tumorigenesis in A/J mice by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine and myo-inositol, individually and in combination.}, journal = {Carcinogenesis}, volume = {23}, number = {9}, pages = {1455-1461}, doi = {10.1093/carcin/23.9.1455}, pmid = {12189187}, issn = {0143-3334}, support = {CA-46535/CA/NCI NIH HHS/United States ; CA-77598/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*therapeutic use ; Carcinogenicity Tests ; Cell Transformation, Neoplastic ; Cysteine/analogs &amp; derivatives/*therapeutic use ; Disease Models, Animal ; Female ; Inositol/*therapeutic use ; Isothiocyanates/chemistry ; Lung Neoplasms/chemically induced/*prevention &amp; control ; Mice ; Thiocarbamates/*therapeutic use ; }, abstract = {Isothiocyanates, their N-acetylcysteine conjugates, and myo-inositol (MI) are inhibitors of lung tumorigenesis in A/J mice. However, chemoprevention by combinations of these compounds in different temporal sequences has not been examined. This is important for developing practical approaches to lung cancer chemoprevention in smokers and ex-smokers. We used a tumor model in which A/J mice are treated with 8 weekly doses of benzo[a]pyrene (B[a]P) plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and killed 19 weeks after the final treatment. In Experiment 1, isothiocyanates or their N-acetylcysteine conjugates were added to the diet (1 or 3 micro mol/g) from 1 week before until 1 week after carcinogen treatment. The compounds were 2-phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), N-acetyl-S-(N-benzyl-thiocarbamoyl)-L-cysteine (BITC-NAC), N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine (PEITC-NAC), and N-acetyl-S-(N-3-phenylpropylthiocarbamoyl)-L-cysteine (PPITC-NAC). Significant reductions in lung tumor multiplicity were observed in mice treated with PEITC, PEITC-NAC, PPITC and PPITC-NAC. PEITC-NAC was chosen for combination studies with MI (Experiment 2). Mice were treated with B[a]P plus NNK without or with PEITC-NAC (3 micro mol/g diet), MI (55.5 micro mol/g diet), or PEITC-NAC plus MI (3 micro mol plus 55.5 micro mol/g diet). Different temporal sequences of dietary additions were investigated: carcinogen treatment phase; post-carcinogen treatment phase; entire experiment; 50% of carcinogen treatment phase until termination; and 75% of carcinogen treatment phase until termination. All treatments reduced lung tumor multiplicity except PEITC-NAC post-carcinogen or from 75% of the carcinogen treatment phase. Reduction of lung tumor multiplicity by PEITC-NAC plus MI was greater than that in the mice treated with the agents alone in all temporal sequences. When all results were combined, PEITC-NAC plus MI was significantly more effective than the agents alone. There was a significant trend for reduction in lung tumor multiplicity with increased duration of treatment by the chemopreventive agents. These results provide a basis for further development of mixtures of PEITC-NAC and MI for chemoprevention of lung cancer.}, }
@article {pmid12187333, year = {2002}, author = {Chen, SY and Lu, FJ and Gau, RJ and Yang, ML and Huang, TS}, title = {15-Deoxy-delta12,14-prostaglandin J2 induces apoptosis of a thyroid papillary cancer cell line (CG3 cells) through increasing intracellular iron and oxidative stress.}, journal = {Anti-cancer drugs}, volume = {13}, number = {7}, pages = {759-765}, doi = {10.1097/00001813-200208000-00011}, pmid = {12187333}, issn = {0959-4973}, mesh = {Apoptosis/*drug effects ; Carcinoma, Papillary/metabolism/*pathology ; Caspases/metabolism ; Cell Count ; Cell Survival/drug effects ; Enzyme Activation/drug effects ; Humans ; Immunologic Factors/*pharmacology ; Indicators and Reagents ; Iron/*metabolism ; Iron Chelating Agents ; Lipid Peroxidation/drug effects ; Oxidative Stress/*drug effects ; Prostaglandin D2/analogs &amp; derivatives/*pharmacology ; Reactive Oxygen Species/metabolism ; Stimulation, Chemical ; Thyroid Neoplasms/metabolism/*pathology ; Tumor Cells, Cultured ; }, abstract = {Treatment of carcinoma cell lines with 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma, has been reported to induce apoptosis and/or inhibit proliferation. In this study, we investigated the cytotoxic effect and the action mechanisms of 15d-PGJ2 in a thyroid papillary cancer cell line, CG3. The results indicate that 15d-PGJ2 caused cytotoxicity and increased the amount of intracellular reactive oxygen species (ROS) in these cells. Mitochondrial oxidative phosphorylation inhibitors (carbonyl cyanide m-chloro-phenylhydrazone, oligomycin, cyclosporin A and rotenone), NADPH oxidase inhibitor (diphenyleneiodonium), xanthine oxidase inhibitor (allopurinol) and NO synthase inhibitor (N-monomethyl-L-arginine acetate) did not reduce the generation of ROS. However, catalase, N-acetyl-cysteine and the iron chelator desferri-oxamine decreased the intracellular ROS of 15d-PGJ2-treated CG3 cells. Furthermore, 15d-PGJ2 enhanced the accumulation of iron in the CG3 cells. These data suggest that 15d-PGJ2 induces the generation of ROS by enhancing the accumulation of intracellular iron and that the increased oxidative stress may cause apoptosis of CG3 cells.}, }
@article {pmid12183103, year = {2002}, author = {Zalups, RK and Barfuss, DW}, title = {Renal organic anion transport system: a mechanism for the basolateral uptake of mercury-thiol conjugates along the pars recta of the proximal tubule.}, journal = {Toxicology and applied pharmacology}, volume = {182}, number = {3}, pages = {234-243}, doi = {10.1006/taap.2002.9448}, pmid = {12183103}, issn = {0041-008X}, support = {ES05157/ES/NIEHS NIH HHS/United States ; ES05980/ES/NIEHS NIH HHS/United States ; ES11288/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacokinetics ; Animals ; Cysteine/pharmacokinetics ; Female ; Glutathione/pharmacokinetics ; In Vitro Techniques ; Ion Transport ; Kidney Tubules, Proximal/*metabolism ; Mercury/*pharmacokinetics/toxicity ; Organic Anion Transporters/*metabolism ; Rabbits ; Specific Pathogen-Free Organisms ; p-Aminohippuric Acid/pharmacokinetics ; }, abstract = {The basolateral handling of 20 microM inorganic mercury (Hg(2+)), in the form of mercuric conjugates of cysteine (Cys), N-acetylcysteine (NAC), or glutathione (GSH), was studied in isolated perfused S2 segments of the rabbit proximal tubule. One of the primary aims of the present study was to determine in a direct manner whether basolateral uptake of Hg(++) occurs in the pars recta of the proximal tubule and, more importantly, whether the p-aminohippurate-sensitive (PAH) organic anion transport system is involved in this process. Basolateral uptake and accumulation of Hg(++) occurred when the basolateral membrane of the tubular segments was exposed to mercuric conjugates of Cys, NAC, or GSH. Net basolateral uptake of Hg(++) was more than twice as great in the tubules exposed to mercuric conjugates of Cys or NAC than in the tubules exposed to mercuric conjugates of GSH, indicating that mercuric conjugates of Cys or NAC are transported more efficiently than mercuric conjugates of GSH. When PAH (1 mM) was added to the basolateral compartment (bath) surrounding a perfused S2 segment, the net uptake of Hg(++) (in the form of the mercuric conjugates) was reduced by 60-70%. In addition, when glutarate (4 mM), a transportable substrate for both the sodium-dependent dicarboxylate transporter and the dicarboxylate/organic anion exchanger (OAT1), was added to the basolateral compartment, there was a significant reduction in the uptake and accumulation of Hg(++) in the form of mercuric conjugates of Cys. Overall, these data indicate that Hg(++), in the form of biologically relevant mercuric conjugates of Cys, NAC, or GSH, is taken up significantly at the basolateral membrane of pars recta segments of the proximal tubule, and this uptake is mediated mainly by the actions of the PAH-sensitive organic anion transport system.}, }
@article {pmid12181751, year = {2002}, author = {Pias, EK and Aw, TY}, title = {Early redox imbalance mediates hydroperoxide-induced apoptosis in mitotic competent undifferentiated PC-12 cells.}, journal = {Cell death and differentiation}, volume = {9}, number = {9}, pages = {1007-1016}, doi = {10.1038/sj.cdd.4401064}, pmid = {12181751}, issn = {1350-9047}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-09/DK/NIDDK NIH HHS/United States ; DK44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*physiology ; Caspase 3 ; Caspases/drug effects/metabolism ; Cytochrome c Group/drug effects/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Eukaryotic Cells/cytology/drug effects/*metabolism ; Glutathione/drug effects/*metabolism/pharmacology ; Kinetics ; Mitochondria/drug effects/*metabolism ; Mitosis/drug effects/physiology ; Oxidative Stress/drug effects/*physiology ; PC12 Cells ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; Proteins/drug effects/metabolism ; Proto-Oncogene Proteins/drug effects/metabolism ; Proto-Oncogene Proteins c-bcl-2/drug effects/metabolism ; Rats ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; bcl-2-Associated X Protein ; tert-Butylhydroperoxide/*pharmacology ; }, abstract = {Our recent study has demonstrated that cellular redox imbalance can directly initiate apoptosis in a mitotic competent PC-12 cell line without the involvement of reactive oxygen species (ROS). However, whether cell apoptosis induced by ROS is, in fact, mediated by a loss of redox balance caused by the oxidant is unresolved. The linkage between oxidant-mediated apoptosis and the induction of cellular redox was examined in PC-12 cells using the oxidant, tert-butylhydroperoxide (TBH). TBH caused cell apoptosis in 24 h that was preceded by an early increase (30 min) in oxidized glutathione (GSSG). Pretreatment with N-acetyl cysteine prevented TBH-induced GSSG increases and cell apoptosis. Altered Bax/BcL-2 expression and release of mitochondrial cytochrome c occurred post-redox imbalance and was kinetically linked to caspase-3 activation and poly ADP-ribose polymerase cleavage. Moreover, cell apoptosis was attenuated by inhibition of caspase-9, but not caspase-8, and blockade of mitochondrial ROS generation and permeability transition pore attenuated caspase 3 activation and cell apoptosis. Collectively, these results show that TBH-induced GSSG elevation is associated with the disruption of mitochondrial integrity, activation of caspase-3 and cell apoptosis. This redox induction of the apoptotic cascade was dissociated from cellular GSH efflux.}, }
@article {pmid12180262, year = {2002}, author = {Gutiérrez-Correa, J and Stoppani, AO}, title = {Myeloperoxidase-generated phenothiazine cation radicals inactivate Trypanosoma cruzi dihydrolipoamide dehydrogenase.}, journal = {Revista Argentina de microbiologia}, volume = {34}, number = {2}, pages = {83-94}, pmid = {12180262}, issn = {0325-7541}, mesh = {Amino Acids, Aromatic/pharmacology ; Animals ; Ascorbic Acid/pharmacology ; Cations/*pharmacology ; Dihydrolipoamide Dehydrogenase/*antagonists &amp; inhibitors ; Enzyme Inhibitors/*pharmacology ; Free Radical Scavengers/pharmacology ; Free Radicals ; Humans ; Hydrogen Peroxide/metabolism ; Peroxidase/metabolism/*pharmacology ; Phenothiazines/*chemistry ; Protozoan Proteins/*antagonists &amp; inhibitors ; Recombinant Fusion Proteins/antagonists &amp; inhibitors ; Structure-Activity Relationship ; Sulfhydryl Compounds/pharmacology ; Trypanocidal Agents/*chemistry ; Trypanosoma cruzi/drug effects/*enzymology ; }, abstract = {Peroxidase/H2O2/phenothiazine systems irreversibly inhibit Trypanosoma cruzi dihydrolipoamide dehydrogenase (LADH). Inactivation of the parasite enzyme depended on (a) phenothiazine structure; (b) peroxidase nature; (c) incubation time and (d) the presence of a cation radical scavenger. With the myeloperoxidase/H2O2/system, promazine, trimeprazine, thioridazine, promethiazine, prochlorperazine, chlorpromazine and perphenazine were the most effective derivatives out of twelve phenothiazines studied. An electronegative substituent at position 2 of the phenothiazine ring such as Cl, or trifluoromethyl, propionyl and nitrile groups decreased or nullified phenothiazine activity. Myeloperoxidase/H2O2/, horseradish peroxidase/H2O2/, and myoglobin/H2O2/systems activated phenothiazines producing the corresponding cation radicals, myeloperoxidase being the most selective one with respect to phenothiazine structure. The myoglobin/H2O2/system activated phenothiazines that were scarcely active or inactivate with the MPO/H2O2/system, such as the trifluoromethyl derivatives. Production of phenothiazine cation radicals was demonstrated by optical spectroscopy. Phenothiazine cation radical stability depended on their structure as illustrated by promazine and thioridazine. Thiol compounds (GSH, N-acetyl-cysteine and penicillamine), aromatic aminoacids (L-tyrosine, L-tryptophan, and the corresponding peptides) and ascorbate scavenged phenothiazine cation radicals, thus preventing LADH inactivation. Comparison of the summarized phenothiazine effects with those of phenothiazines on T. cruzi suggest the role of cation radicals in phenothiazines chemotherapeutic actions.}, }
@article {pmid12180121, year = {2002}, author = {Fernandez, V and Videla, LA and Tapia, G and Israel, Y}, title = {Increases in tumor necrosis factor-alpha in response to thyroid hormone-induced liver oxidative stress in the rat.}, journal = {Free radical research}, volume = {36}, number = {7}, pages = {719-725}, doi = {10.1080/10715760290032566}, pmid = {12180121}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Animals ; Body Temperature ; Enzyme-Linked Immunosorbent Assay ; Female ; Free Radical Scavengers/pharmacology ; Gadolinium/pharmacology ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Liver/*drug effects/metabolism ; Oligonucleotides, Antisense/pharmacology ; Organothiophosphorus Compounds/pharmacology ; Oxidative Stress/*drug effects ; Oxygen Consumption ; Phosphorothioate Oligonucleotides ; Rats ; Rats, Sprague-Dawley ; Time Factors ; Tocopherols/pharmacology ; Triiodothyronine/*pharmacology ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Thyroid hormone-induced calorigenesis contributes to liver oxidative stress and promotes an increased respiratory burst activity in Kupffer cells, which could conceivably increase the expression of redox-sensitive genes, including those coding for cytokines. Our aim was to test the hypothesis that L-3,3',5-triiodothyronine (T3)-induced liver oxidative stress would markedly increase the production of TNF-alpha by Kupffer cells and its release into the circulation. Sprague-Dawley rats receive a single dose of 0.1 mg T3/kg or vehicle (controls) and determinations of liver O2 consumption, serum TNF-alpha, rectal temperature, and serum T3 levels, were carried out at different times after treatment. Hepatic content of total reduced glutathione (GSH) and biliary glutathione disulfide (GSSG) efflux were measured as indices of oxidative stress. In some studies, prior to T3 injection animals were administered either (i) the Kupffer cell inactivator gadolinium chloride (GdCl3), (ii) the antioxidants alpha-tocopherol and N-acetyl-L-cysteine (NAC), or (iii) an antisense oligonucleotide against TNF-alpha (ASO TJU-2755). T3 elicited an 80-fold increase in the serum levels of TNF-alpha at 22h after treatment, which coincided with the onset of thyroid calorigenesis. Pretreatment with GdCl3, alpha-tocopherol, NAC, and ASO TJU-2755 virtually abolished this effect and markedly reduced T3-induced liver GSH depletion and the increases in biliary GSSG efflux. It is concluded that the hyperthyroid state in the rat increases the circulating levels of TNF-alpha by actions exerted at the Kupffer cell level and these are related to the oxidative stress status established in the liver by thyroid calorigenesis.}, }
@article {pmid12176728, year = {2002}, author = {Langen, RC and Schols, AM and Kelders, MC and Van Der Velden, JL and Wouters, EF and Janssen-Heininger, YM}, title = {Tumor necrosis factor-alpha inhibits myogenesis through redox-dependent and -independent pathways.}, journal = {American journal of physiology. Cell physiology}, volume = {283}, number = {3}, pages = {C714-21}, doi = {10.1152/ajpcell.00418.2001}, pmid = {12176728}, issn = {0363-6143}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Differentiation/*drug effects ; Cell Line ; Creatine Kinase/metabolism ; Enzyme Activation/drug effects ; Glutathione/metabolism ; Mice ; Muscle Development/*drug effects ; Muscle, Skeletal/cytology/*drug effects/metabolism ; NF-kappa B/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/drug effects/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects/physiology ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Muscle wasting accompanies diseases that are associated with chronic elevated levels of circulating inflammatory cytokines and oxidative stress. We previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) inhibits myogenic differentiation via the activation of nuclear factor-kappaB (NF-kappaB). The goal of the present study was to determine whether this process depends on the induction of oxidative stress. We demonstrate here that TNF-alpha causes a decrease in reduced glutathione (GSH) during myogenic differentiation of C(2)C(12) cells, which coincides with an elevated generation of reactive oxygen species. Supplementation of cellular GSH with N-acetyl-l-cysteine (NAC) did not reverse the inhibitory effects of TNF-alpha on troponin I promoter activation and only partially restored creatine kinase activity in TNF-alpha-treated cells. In contrast, the administration of NAC before treatment with TNF-alpha almost completely restored the formation of multinucleated myotubes. NAC decreased TNF-alpha-induced activation of NF-kappaB only marginally, indicating that the redox-sensitive component of the inhibition of myogenic differentiation by TNF-alpha occurred independently, or downstream of NF-kappaB. Our observations suggest that the inhibitory effects of TNF-alpha on myogenesis can be uncoupled in a redox-sensitive component affecting myotube formation and a redox independent component affecting myogenic protein expression.}, }
@article {pmid12175980, year = {2002}, author = {Fisher, JC and Kling, DE and Kinane, TB and Schnitzer, JJ}, title = {Oxidation-reduction (redox) controls fetal hypoplastic lung growth.}, journal = {The Journal of surgical research}, volume = {106}, number = {2}, pages = {287-291}, doi = {10.1006/jsre.2002.6461}, pmid = {12175980}, issn = {0022-4804}, support = {HL03132/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Congenital Abnormalities/*embryology ; Embryonic and Fetal Development/drug effects/physiology ; Fetus/drug effects/physiology ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Lung/drug effects/*embryology ; Organ Culture Techniques ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; }, abstract = {INTRODUCTION: The persistent morbidity and mortality of congenital diaphragmatic hernia are largely due to associated pulmonary hypoplasia. We have shown previously that three antioxidants (vitamin C, glutathione, and vitamin E) could accelerate the growth of fetal hypoplastic lungs grown in culture. We hypothesize that this occurs via a reductant mechanism.<br><br>METHODS: Timed-pregnant rats were gavage-fed nitrofen (100 mg) on day 9.5 of gestation (term = day 22). Fetal lungs were harvested on day 13.5 and placed in organ culture containing serum-free BGJb medium with antibiotics. After randomization, the lung organ cultures were divided into a control group (n = 31) and an experimental group that received the antioxidant N-acetylcysteine (NAC, 100 microM, n = 31). The fetal lung organ cultures were grown for 4 days at 37 degrees C with 5% CO(2). Computer-assisted digital tracings of the airways were performed daily on live, unstained specimens, and lung bud count, perimeter, and area were measured. After 4 days, lungs were pooled, homogenized, and assayed for reduced and oxidized glutathione, normalized to protein, as an estimate of the tissue redox potential. Data were expressed as means +/- SEM, and statistical comparisons were performed using Student's unpaired t test, with P < 0.05 considered significant.<br><br>RESULTS: Area, perimeter, lung bud count, and complexity (as measured by the perimeter/square root of area) were all significantly increased with NAC treatment from day 2 onward. Reduced glutathione levels were significantly increased following NAC administration (67.1 +/- 5.8 versus 37.5 +/- 4.2 micromol/mg, P = 0.0004). The ratio of reduced to oxidized glutathione was 2.23.<br><br>CONCLUSIONS: N-Acetylcysteine stimulates nitrofen-induced hypoplastic fetal lung growth in organ culture and increases the ratio of reduced to oxidized glutathione. These data support the concept that oxidation-reduction (redox) may be an important control mechanism for fetal lung growth.}, }
@article {pmid12175821, year = {2002}, author = {Ricardo, KF and Shishido, SM and de Oliveira, MG and Krieger, MH}, title = {Characterization of the hypotensive effect of S-nitroso-N-acetylcysteine in normotensive and hypertensive conscious rats.}, journal = {Nitric oxide : biology and chemistry}, volume = {7}, number = {1}, pages = {57-66}, doi = {10.1016/s1089-8603(02)00009-5}, pmid = {12175821}, issn = {1089-8603}, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives/*pharmacology ; Animals ; Blood Pressure/*drug effects ; Cyclic GMP/metabolism ; Dose-Response Relationship, Drug ; Drug Stability ; Drug Synergism ; Drug Therapy, Combination ; Hypertension/*drug therapy ; Male ; Rats ; Rats, Wistar ; Sulfhydryl Compounds/metabolism ; Vasodilation/drug effects ; }, abstract = {S-Nitrosothiols (RSNOs) are potent vasodilators found naturally in vivo. A variety of synthetic RSNOs have been considered as potential nitric oxide (NO) donors for biomedical applications. We have characterized the hypotensive effect of the RSNO S-nitroso-N-acetylcysteine (SNAC) in normotensive and hypertensive conscious rats. SNAC reduced the medium arterial pressure in a dose-response manner in both normotensive and hypertensive animals. At the same doses (EC(50) of SNAC), SNAC showed a vasodilator effect in normotensive rats more potent and more prolonged than that of sodium nitroprusside (SNP). The hypotensive effect of SNAC was also more potent in methylene blue-treated rats, where the cGMP-dependent pathway had been blockaded. These data indicate that SNAC acts by both cGMP-dependent and cGMP-independent pathways. It was also shown that the thiol N-acetylcysteine (NAC) potentiates the action of SNP in hypertensive rats, pointing to the mediation of thiols in the vasodilator action of SNP in this condition. Such mediation may involve the formation of a more potent thiol complex with the nitroprusside anion or the transfer of NO to NAC, generating SNAC as a primary vasoactive species. The kinetic monitoring of the decomposition reactions of SNAC and SNP showed that both compounds are quite stable under the infusion conditions used. Therefore, their vasodilator action cannot be assigned to their breakdown with release of free NO in solution. As the two compounds are unlikely to cross the plasmalemma of smooth muscle cells, their actions are probably associated with the mediation of endogenous thiols in transnitrosation reactions.}, }
@article {pmid12173553, year = {2000}, author = {James, JS}, title = {NAC and glutathione: recent publications.}, journal = {AIDS treatment news}, volume = {}, number = {352}, pages = {6-8}, pmid = {12173553}, issn = {1052-4207}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Glutathione/*blood ; HIV Infections/*blood ; Humans ; }, }
@article {pmid12173552, year = {2000}, author = {James, JS}, title = {NAC: Stanford San Francisco study report shows blood glutathione improvement, possible survival benefit.}, journal = {AIDS treatment news}, volume = {}, number = {352}, pages = {2-5}, pmid = {12173552}, issn = {1052-4207}, mesh = {Acetylcysteine/*therapeutic use ; Glutathione/*blood ; HIV Infections/*blood ; Humans ; Placebos ; San Francisco ; }, }
@article {pmid12171932, year = {2002}, author = {Yellaturu, CR and Bhanoori, M and Neeli, I and Rao, GN}, title = {N-Ethylmaleimide inhibits platelet-derived growth factor BB-stimulated Akt phosphorylation via activation of protein phosphatase 2A.}, journal = {The Journal of biological chemistry}, volume = {277}, number = {42}, pages = {40148-40155}, doi = {10.1074/jbc.M206376200}, pmid = {12171932}, issn = {0021-9258}, support = {R01-HL64165/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Aorta/cytology ; Apoptosis ; Becaplermin ; Blotting, Western ; Cell Death ; Cell Division ; Cell Survival ; Endothelium, Vascular/cytology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Ethylmaleimide/*pharmacology ; Male ; Muscle, Smooth/*cytology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoprotein Phosphatases/*metabolism ; Phosphorylation ; Platelet-Derived Growth Factor/*chemistry/metabolism ; Protein Binding ; Protein Phosphatase 2 ; *Protein Serine-Threonine Kinases ; Proto-Oncogene Proteins/*metabolism ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins c-sis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Ribosomal Protein S6/metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {The redox state plays an important role in gene regulation. Thiols maintain the intracellular redox homeostasis. To understand the role of thiols in redox signaling, we have studied the effect of thiol alkylation on platelet-derived growth factor-BB (PDGF-BB)-induced cell survival events in vascular smooth muscle cells. PDGF-BB stimulated Akt phosphorylation predominantly at Ser-473. N-Ethylmaleimide (NEM), a thiol alkylating agent, blocked PDGF-BB-induced Akt phosphorylation without affecting its upstream phosphatidylinositol 3-kinase (PI3K). On the other hand, LY294002 and wortmannin, specific inhibitors of PI3K, prevented PDGF-BB-induced phosphorylation of Akt and its downstream effector molecules, p70S6K, ribosomal protein S6, 4E-BP1, and eIF4E. NEM also abrogated the phosphorylation of p70S6K, ribosomal protein S6, 4E-BP1, and eIF4E induced by PDGF-BB, suggesting that thiol alkylation interferes with the PI3K/Akt pathway at the level of Akt. In addition, NEM blocked PDGF-BB-induced phosphorylation of BAD and forkhead transcription factor FKHR-L1, and these events correlated with increased apoptosis. NEM alone and in concert with PDGF-BB increased reactive oxygen species (ROS) production and protein phosphatase 2A (PP2A) activity in VSMC. The inhibition of PDGF-BB-induced Akt phosphorylation by NEM was completely reversed by PP2A inhibitors fostriecin and okadaic acid, ceramide synthase inhibitor fumonisin B1, and ROS scavenger N-acetylcysteine (NAC). NAC also attenuated the apoptosis induced by NEM, alone or in combination with PDGF-BB. Together, these findings demonstrate for the first time that PP2A mediates thiol alkylation-dependent redox regulation of Akt and cell survival.}, }
@article {pmid12169748, year = {2002}, author = {Markos, F and Campion, DP and Carey, M and O'Connor, JJ}, title = {An investigation into the mechanism of action of almitrine on isolated rat diaphragm muscle fatigue.}, journal = {Respiration; international review of thoracic diseases}, volume = {69}, number = {4}, pages = {339-343}, doi = {10.1159/000063267}, pmid = {12169748}, issn = {0025-7931}, mesh = {Almitrine/*pharmacology ; Animals ; Diaphragm ; In Vitro Techniques ; Male ; Muscle Fatigue/*drug effects ; Rats ; Rats, Sprague-Dawley ; Respiratory Muscles/*drug effects/physiology ; Respiratory System Agents/*pharmacology ; }, abstract = {BACKGROUND: Previous studies have shown that almitrine bismesylate, a respiratory stimulant which acts on the mitochondrial electron transport chain, enhances recovery of rat diaphragm muscle from fatigue.<br><br>OBJECTIVES: Our aim is to investigate if the enhanced recovery is due to an anti-oxidant property of almitrine, since the electron transport chain is a major site of intracellular free radical production.<br><br>METHODS: A low-frequency fatigue protocol was used (30 Hz; 250 ms; delivered once every 2 s for 5 min), and the effects of almitrine before and after fatigue onset were compared to those of the anti-oxidant compound N-acetylcysteine (NAC).<br><br>RESULTS: Almitrine (6 and 10 microg/ml) given before fatigue gave better recovery rates than postfatigue application. In contrast, NAC (100 microM) application before fatigue onset was not as effective as NAC given immediately after the cessation of the fatigue protocol. However, almitrine (6 microg/ml) completely reversed the reduction in baseline twitch tension brought about by a free-radical-producing mixture of FeCl(3) + ADP (1 mM + 2.5 mM, respectively).<br><br>CONCLUSION: The results of this study confirm that almitrine enhances recovery from fatigue and, in contrast to NAC prefatigue application, is more effective. Also, almitrine was shown to have an anti-oxidant effect, but it does not act like a typical anti-oxidant.}, }
@article {pmid12168106, year = {2002}, author = {Choi, YJ and Park, JW and Suh, SI and Mun, KC and Bae, JH and Song, DK and Kim, SP and Kwon, TK}, title = {Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt.}, journal = {International journal of oncology}, volume = {21}, number = {3}, pages = {603-610}, pmid = {12168106}, issn = {1019-6439}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects/physiology ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Caspase 3 ; Caspase Inhibitors ; Caspases/metabolism ; Cytochrome c Group/metabolism ; Enzyme Activation/drug effects ; Humans ; Oxides/*pharmacology ; Phosphorylation/drug effects ; *Protein Serine-Threonine Kinases ; Proto-Oncogene Proteins/*antagonists &amp; inhibitors ; Proto-Oncogene Proteins c-akt ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Reactive Oxygen Species/*metabolism ; U937 Cells ; }, abstract = {Arsenic trioxide has recently been shown to inhibit growth and induce apoptosis in acute promyelocytic leukemia (APL), but little is known about the molecular mechanisms mediating these effects. In the present study, we determined the molecular pathways that lead to apoptosis after treatment of cells with arsenic trioxide. Arsenic trioxide treatment of U937 cells leads to apoptosis, which is accompanied by activation of caspase 3 (as measured by decreased levels of the 32 kDa inactive form and increased proteolytic cleavage of PLC-gamma1). The broad-range caspase inhibitor z-VAD-fmk inhibits this induction of apoptosis, supporting a direct link between caspase activation and arsenic trioxide induction of apoptosis. This activation of apoptosis is accompanied by release of cytochrome c, down-regulation of cIAP1, and inactivation of Akt. Bcl-2 overexpression attenuates arsenic trioxide-induced apoptosis in U937 cells by inhibition of caspase 3 activity, but not inhibition of Akt. In addition, arsenic trioxide-induced apoptosis was caused by the generation of reactive oxygen species, which was prevented by antioxidant NAC (N-acetyl-cysteine). Co-treatment with NAC markedly prevented dephosphorylation of Akt, activation of caspase 3, and down-regulation of cIAP1. These data indicate that arsenic trioxide can cause cell damage by inactivating the Akt-related cell survival pathway and generating the reactive oxygen species, providing a new mechanism for arsenic trioxide-induced apoptosis.}, }
@article {pmid12165081, year = {2002}, author = {Giordani, L and Quaranta, MG and Malorni, W and Boccanera, M and Giacomini, E and Viora, M}, title = {N-acetylcysteine inhibits the induction of an antigen-specific antibody response down-regulating CD40 and CD27 co-stimulatory molecules.}, journal = {Clinical and experimental immunology}, volume = {129}, number = {2}, pages = {254-264}, pmid = {12165081}, issn = {0009-9104}, mesh = {Acetylcysteine/*pharmacology ; Antibody Formation/*drug effects ; Antibody-Producing Cells/drug effects/immunology ; Antigens ; Antioxidants/pharmacology ; B-Lymphocytes/cytology/drug effects/immunology ; CD40 Antigens/*metabolism ; Cell Survival/drug effects ; Cytokines/biosynthesis ; Down-Regulation/drug effects ; Humans ; In Vitro Techniques ; Interferon-gamma/biosynthesis ; Interleukin-4/biosynthesis ; Lymphocyte Activation/drug effects ; Th1 Cells/drug effects/immunology ; Tumor Necrosis Factor Receptor Superfamily, Member 7/*metabolism ; Up-Regulation/drug effects ; }, abstract = {We investigated the effect of N-acetylcysteine (NAC) on normal human B cell functions. We found that NAC significantly inhibited both the induction of the specific antibody response to the T-dependent antigen Candida albicans and T-dependent pokeweed mitogen (PWM)-induced polyclonal Ig production. NAC did not induce either cell death due to a non-specific toxicity or apoptosis. The NAC-induced inhibitory effect might be a functional consequence of: (i) a down-regulation of the expression on the B cell surface of CD40 and CD27 co-stimulatory molecules and (ii) a down-regulation of interleukin (IL-4) production. In contrast, NAC up-regulated interferon-gamma (IFN-gamma) production. NAC did not induce any effect on the T cell-independent B cell polyclonal activation system. These results indicate that NAC down-regulates T dependent B cell activation and leads to T helper cell type 1 (Th1) polarization.}, }
@article {pmid12163654, year = {2002}, author = {Huang, RF and Huang, SM and Lin, BS and Hung, CY and Lu, HT}, title = {N-Acetylcysteine, vitamin C and vitamin E diminish homocysteine thiolactone-induced apoptosis in human promyeloid HL-60 cells.}, journal = {The Journal of nutrition}, volume = {132}, number = {8}, pages = {2151-2156}, doi = {10.1093/jn/132.8.2151}, pmid = {12163654}, issn = {0022-3166}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects/*physiology ; Ascorbic Acid/*pharmacology ; Folic Acid/pharmacology ; HL-60 Cells ; Homocysteine/*analogs &amp; derivatives/antagonists &amp; inhibitors/*pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Leukemia, Myeloid ; Vitamin E/*pharmacology ; }, abstract = {We showed previously that homocysteine thiolactone (HcyT) is a potent inducer of apoptosis in HL-60 cells. In the present study, the role of some radical scavengers (N-acetylcysteine, vitamin C, vitamin E and folate) on the reduction of HcyT-induced apoptosis was investigated. Preincubation of HcyT-treated HL-60 cells with vitamin C (Vit C; 100 micro mol/L) or vitamin E (Vit E; 100 micro mol/L) for 2 h significantly reduced the proportion of apoptotic cells with hypodiploid DNA contents or with membrane phosphatidylserine exposure, and attenuated the apoptotic DNA fragmentation. Preincubation of cells with N-acetylcysteine (NAC; 5 mmol/L) for 2 h significantly reduced HcyT-promoted apoptosis measured by membrane phosphatidylserine exposure only. The reduction of HcyT-induced apoptosis by NAC, Vit C or Vit E occurred simultaneously with a significant decrease in intracellular H(2)O(2) levels and reduced caspase-3 enzymatic activity. In contrast, folate had no H(2)O(2) scavenging capacity and did not suppress caspase-3 activity 6 h after HcyT treatment, although folate exhibited antioxidant behavior toward superoxide anions, hydroxyl radicals and peroxynitrite. Preincubation of cells with folate (10 micro mol/L) for 3 d did not affect the extent of HcyT-promoted apoptotic damage. Taken together, our findings suggest that antioxidant pretreatment with NAC, Vit C or Vit E exerts more beneficial effects than folate on reducing apoptotic cell damage induced by homocysteine thiolactone.}, }
@article {pmid12163056, year = {2002}, author = {Hashizume, K and Hatanaka, Y and Fukuda, I and Sano, T and Yamaguchi, Y and Tani, Y and Danno, G and Suzuki, K and Ashida, H}, title = {N-acetyl-L-cysteine suppresses constitutive expression of CD11a/LFA-1alpha protein in myeloid lineage.}, journal = {Leukemia research}, volume = {26}, number = {10}, pages = {939-944}, doi = {10.1016/s0145-2126(02)00037-1}, pmid = {12163056}, issn = {0145-2126}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Cell Lineage ; DNA Probes/metabolism ; Down-Regulation/drug effects ; HL-60 Cells ; Humans ; Lymphocyte Function-Associated Antigen-1/drug effects/*metabolism ; Monocytes/drug effects/metabolism ; Myeloid Cells/*drug effects/metabolism ; NF-kappa B/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Protein Binding/drug effects ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/pharmacology ; Thiocarbamates/pharmacology ; U937 Cells ; }, abstract = {We investigated the possible involvement of redox regulation in constitutive expression of CD11a/LFA-1alpha, a leukocyte integrin alpha subunit, in myeloid cells using antioxidants. In unstimulated HL-60 cells, CD11a/LFA-1alpha was highly expressed, however, no expression of CD11b and CD11c proteins was detected. N-acetyl-L-cysteine (NAC) markedly down-regulated CD11a/LFA-1alpha expression in a dose-dependent manner. The down-regulated CD11a/LFA-1alpha expression was gradually recovered when NAC was deprived 24h after treatment. Pyrrolidine dithiocarbamate (PDTC) also suppressed the level of expression CD11a/LFA-1alpha protein, although the effect of PDTC was less potent than NAC. Both NAC and PDTC suppressed NF-kappaB binding activity to consensus DNA probe, and this result was correlated with a suppressive effect to CD11a/LFA-1alpha expression. Furthermore, NAC also down-regulated CD11a/LFA-1alpha expression in both U937 cells and peripheral blood monocytes. These results indicated that the constitutive CD11a/LFA-1alpha expression in the myeloid lineage is implicated in oxidative stress occurring spontaneously, suggesting that alteration of the intracellular redox state using antioxidants may be effective in the modulation of cell adhesion associated with extravasation in leukocytes, at least, in myeloid cells.}, }
@article {pmid12162429, year = {2002}, author = {Li, J and Huang, B and Shi, X and Castranova, V and Vallyathan, V and Huang, C}, title = {Involvement of hydrogen peroxide in asbestos-induced NFAT activation.}, journal = {Molecular and cellular biochemistry}, volume = {234-235}, number = {1-2}, pages = {161-168}, pmid = {12162429}, issn = {0300-8177}, support = {CA13687/CA/NCI NIH HHS/United States ; ES00260/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Asbestos/*pharmacology ; Cell Line ; Cyclosporine/metabolism ; DNA-Binding Proteins/*metabolism ; Dose-Response Relationship, Drug ; Hydrogen Peroxide/*metabolism ; Mice ; NFATC Transcription Factors ; *Nuclear Proteins ; Superoxide Dismutase/metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Time Factors ; Transcription Factors/*metabolism ; Transcriptional Activation/*drug effects ; }, abstract = {The present study investigated the role of reactive oxygen species (ROS) in activation of nuclear factor of activated T cells (NFAT), a pivotal transcription factor responsible for regulation of cytokines, by asbestos in mouse embryo fibroblast PW cells. Exposure of cells to asbestos led to the transactivation of NFAT in a time- and dose-dependent manner. Scavenging of asbestos-induced H2O2 with N-acety-L-cyteine (NAC, a general antioxidant) or catalase (a specific H2O2 inhibitor) resulted in inhibition of NFAT activation. In contrast, an increase in H2O2 generation by the addition of superoxide dismutase (SOD) slightly enhanced asbestos-induced NFAT activation. In addition, pretreatment of cells with sodium formate did not exhibit any inhibition of NFAT activity induced by asbestos. These results demonstrated that H2O2 appeared to play an important role in asbestos-induced NFAT transactivation. Furthermore, it was observed that incubation of cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) not only resulted in NFAT activation by itself, but also enhanced asbestos-induced NFAT induction. Pretreatment of cells with cyclosporin A (CSA), a pharmacological inhibitor of the phosphatase calcineurin, blocked both asbestos- and TPA plus asbestos-induced NFAT activation. These data suggest that asbestos is able to induce NFAT activation through H2O2-dependent and CSA-sensitive pathways, which may be involved in asbestos-induced carcinogenesis.}, }
@article {pmid12153530, year = {2002}, author = {Kuperstein, F and Yavin, E}, title = {ERK activation and nuclear translocation in amyloid-beta peptide- and iron-stressed neuronal cell cultures.}, journal = {The European journal of neuroscience}, volume = {16}, number = {1}, pages = {44-54}, doi = {10.1046/j.1460-9568.2002.02056.x}, pmid = {12153530}, issn = {0953-816X}, mesh = {Active Transport, Cell Nucleus ; Amyloid beta-Peptides/*adverse effects/metabolism ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Butadienes/pharmacology ; Caspase 3 ; Caspases/metabolism ; Cell Culture Techniques ; Cell Nucleus/enzymology/*metabolism ; Cerebral Cortex/enzymology/*metabolism ; Deferoxamine/pharmacology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Iron/*adverse effects/metabolism ; Iron Chelating Agents/pharmacology ; Lipid Peroxidation ; Mitochondria/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Neurons/enzymology/*metabolism ; Nitriles/pharmacology ; Oxidative Stress/*drug effects ; Peptide Fragments/*adverse effects/metabolism ; Protein Transport ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Time Factors ; }, abstract = {Oxidative stress in the human brain has been strongly implicated as the cause of neuronal cell losses in Alzheimer's disease patients, but the exact mechanism still remains unknown. In this report several oxidative stress parameters and an associated signalling transduction cascade predating neuronal cell death in cultures treated with the oxidative stressors Fe(2+) (5 microm) and the amyloid beta (A beta(1-40)) peptide (5 microm) were studied. Production of reactive oxygen species as detected by dichlorofluorescein staining was apparent within 5 min in the presence of both agents. Lipid peroxide content increased by approximately 10-fold after 2 h, while mitochondrial activity was impaired by 40% after 6 h. Caspase-3 activity was elevated 5-6 fold, all indicative of oxidative cell stress. The combined presence of A beta(1-40) and Fe(2+) resulted in a rapid (5 min) ERK activation followed by a decline by 30 min and a second activation that continued up to 24 h when nuclear translocation was noticed. Neither treatment with Fe(2+) nor that with A beta(1-40) alone caused similar changes. Addition of either deferroxamine (DFe, 25 microm), catalase (0.4 mg/mL) or N-acetyl cysteine (0.5 mm) - the last two known as suppressants of oxidative stress - attenuated ERK activation and nuclear translocation. The mitogen-activated protein/ERK kinase (MEK) inhibitor U0126 blocked ERK and caspase 3 activation, suppressed ERK translocation and reduced the number of apoptotic cells, suggesting a central role for the ERK signalling cascade in A beta(1-40) plus Fe(2+) (A beta(1-40)/Fe(2+)) -induced apoptotic death. The full peptide A beta(1-42) was very effective at 0.5 microm while the inverse peptide A beta(40-1) at 5 microm was ineffective. The acetyl-amyloid-beta protein amide fragment 15-20 (V-pep) known to be an A beta aggregation inhibitor, prevented A beta(1-40)/Fe(2+)-induced toxicity. These findings indicate that metal ions chelators and antioxidants suppress the A beta(1-40)/Fe(2+)-induced oxidative stress cascade and may be beneficial in reducing the severity of Alzheimer's disease.}, }
@article {pmid12151316, year = {2002}, author = {Wu, HM and Wen, HC and Lin, WW}, title = {Proteasome inhibitors stimulate interleukin-8 expression via Ras and apoptosis signal-regulating kinase-dependent extracellular signal-related kinase and c-Jun N-terminal kinase activation.}, journal = {American journal of respiratory cell and molecular biology}, volume = {27}, number = {2}, pages = {234-243}, doi = {10.1165/ajrcmb.27.2.4792}, pmid = {12151316}, issn = {1044-1549}, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Cell Line ; Chemotaxis ; Cysteine Endopeptidases ; Cysteine Proteinase Inhibitors/*pharmacology ; Enzyme Activation ; Epithelial Cells/*drug effects ; Genes, Reporter ; Humans ; Interleukin-8/*biosynthesis/genetics ; JNK Mitogen-Activated Protein Kinases ; Leupeptins/pharmacology ; MAP Kinase Kinase Kinases/*metabolism ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/*metabolism ; Multienzyme Complexes/*antagonists &amp; inhibitors ; NF-kappa B/metabolism ; Neutrophils/metabolism ; Proteasome Endopeptidase Complex ; Reactive Oxygen Species/metabolism ; Transcription Factor AP-1/metabolism ; Transcription Factors/metabolism ; Tumor Cells, Cultured ; ras Proteins/*metabolism ; }, abstract = {In this study, we investigated the effects of proteasome inhibibors (MG132 and lactacystin) on interleukin (IL)-8 induction. In human epithelial A549 cells, MG132 and lactacystin induced IL-8 release within the range of 0.1-30 microM. The effect of MG132 resulted from IL-8 gene transcription and was blocked by PD 98059, but was unaffected by GF109203X, Ro 31-8220, or SB 203580. Mutational analysis of the 5' flanking region of the IL-8 gene revealed that activator protein (AP)-1-binding element, but not that element responsive to nuclear factor (NF)-IL-6 or NF-kappaB, was necessary for MG132 stimulation. Consistent with this, MG132 and lactacystin increased the DNA-binding and reporter activities of AP-1, but reduced cytokine-elicited kappaB activation. Moreover, AP-1 stimulation was associated with increased extracellular signal-related kinase (ERK), mitogen-activated protein/ERK kinase (MEK), and c-Jun N-terminal kinase (JNK) phosphorylation, whereas IL-8 activity was sensitive to the dominant-negative mutants of JNK1, JNK2, SEK, ASK, ERK2, and Ras, but not those of MEKK1, TAK, and p38 mitogen-activated protein kinase. In addition, activations of the IL-8 gene and AP-1 by MG132 and lactacystin were inhibited by GSH and NAC. Herein we present a novel action of proteasome inhibitors, possibly through ROS production, of targeting the upstream signaling molecules, ERK and JNK, which leads to AP-1 activation and IL-8 gene expression.}, }
@article {pmid12151057, year = {2002}, author = {Orzechowski, A and Łokociejewska, M and Muras, P and Hocquette, JF}, title = {Preconditioning with millimolar concentrations of vitamin C or N-acetylcysteine protects L6 muscle cells insulin-stimulated viability and DNA synthesis under oxidative stress.}, journal = {Life sciences}, volume = {71}, number = {15}, pages = {1793-1808}, doi = {10.1016/s0024-3205(02)01942-2}, pmid = {12151057}, issn = {0024-3205}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Culture Media ; DNA/*biosynthesis ; DNA Fragmentation/drug effects ; Free Radical Scavengers/*pharmacology ; Free Radicals/metabolism ; Histocytochemistry ; Insulin/*pharmacology ; Mitochondria, Muscle/drug effects/metabolism ; Mitogens/pharmacology ; Muscle, Skeletal/*drug effects ; Nucleosomes/chemistry ; Oxidative Stress/*drug effects ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {The effect of reactive oxygen/nitrogen species (ROS/RNS)(hydrogen peroxide -- H(2)O(2), superoxide anion radical O(2)*- and hydroxyl radical *OH -- the reaction products of hypoxanthine/xanthine oxidase system), nitric oxide (NO* from sodium nitroprusside -- SNP), and peroxynitrite (ONOO(-) from 3-morpholinosydnonimine -- SIN-1) on insulin mitogenic effect was studied in L6 muscle cells after one day pretreatment with/or without antioxidants. ROS/RNS inhibited insulin-induced mitogenicity (DNA synthesis). Insulin (0.1 microM), however, markedly improved mitogenicity in the muscle cells treated with increased concentrations (0.1, 0.5, 1 mM) of donors of H(2)O(2), O(2)*-, *OH, ONOO(-) and NO*. Cell viability assessed by morphological criteria was also monitored. Massive apoptosis was induced by 1 mM of donors of H(2)O(2) and ONOO(-), while NO* additionally induced necrotic cell death. Taken together, these results have shown that ROS/RNS provide a good explanation for the developing resistance to the growth promoting activity of insulin in myoblasts under conditions of oxidative or nitrosative stress. Cell viability showed that neither donor induced cell death when given below 0.5 mM. In order to confirm the deleterious effects of ROS/RNS prior to the subsequent treatment with ROS/RNS plus insulin one day pretreatment with selected antioxidants (sodium ascorbate - ASC (0.01, 0.1, 1 mM), or N-acetylcysteine - NAC (0.1, 1, 10 mM) was carried out. Surprisingly, at a low dose (micromolar) antioxidants did not abrogate and even worsened the concentration-dependent effects of ROS/RNS. In contrast, pretreatment with millimolar dose of ASC or NAC maintained an elevated mitogenicity in response to insulin irrespective of the ROS/RNS donor type used.}, }
@article {pmid12140766, year = {2002}, author = {Wu, CH and Gordon, J and Rastegar, M and Ogretmen, B and Safa, AR}, title = {Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant.}, journal = {Oncogene}, volume = {21}, number = {33}, pages = {5160-5174}, doi = {10.1038/sj.onc.1205639}, pmid = {12140766}, issn = {0950-9232}, support = {CA 56078/CA/NCI NIH HHS/United States ; CA 80734/CA/NCI NIH HHS/United States ; CA 90878/CA/NCI NIH HHS/United States ; }, mesh = {Apoptosis/*drug effects ; Caspase Inhibitors ; Caspases/metabolism ; DNA Fragmentation ; *Down-Regulation ; Doxorubicin/*pharmacology ; *Drug Resistance, Neoplasm ; Flow Cytometry ; Gene Expression Regulation, Neoplastic ; HL-60 Cells ; Humans ; In Situ Nick-End Labeling ; Inhibitory Concentration 50 ; Intracellular Membranes/metabolism ; Membrane Potentials ; Mitochondria/metabolism ; Myeloblastin ; Oligonucleotides, Antisense/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Serine Endopeptidases/biosynthesis/genetics/*metabolism ; }, abstract = {We report here that expression of proteinase 3 (PR3), a serine protease, is down-regulated in the HL60/ADR multidrug resistant variant of the human myelogenous leukemia cell line HL-60, and that down-regulation of PR3 is associated with doxorubicin (DOX) resistance in these cells. To determine whether PR3 is involved in DOX-induced apoptosis in HL-60 cells, and whether its loss causes resistance to DOX, we inhibited PR3 expression by an anti-sense PR3 oligodeoxynucleotide and showed that inhibition of PR3 expression results in a significant reduction in DOX-induced DNA fragmentation and increased resistance to DOX-induced apoptosis. Our results revealed that PR3-mediated DOX-induced apoptosis in HL-60 cells is independent of the loss of mitochondrial membrane potential (deltapsi(m)) and activation of the caspase-8 and -9 pathways. Moreover, while PR3 is involved in the cleavage of caspase-3, PR3-mediated DOX-induced DNA fragmentation and apoptosis were not prevented by a specific inhibitor of caspase-3. These data suggest that activation of caspase-3 alone is not sufficient to trigger PR3-mediated DOX-induced apoptosis. Treatment with an anti-PR3 oligomer significantly decreased reactive oxygen species (ROS) generation in cells treated with low concentrations of DOX, revealing a role for PR3 in enhancing production of DOX-induced ROS. Moreover, DOX-induced apoptosis at 0.001-0.01 microM was only inhibited in HL-60 cells pre-treated with the antioxidant N-acetyl-cysteine in the absence of anti-PR3, revealing that DOX-induced apoptosis in these cells is PR3- and ROS-dependent. Our results show that PR3 is involved in DOX-induced ROS-dependent apoptosis and that its loss is associated with resistance to DOX in HL-60 cells.}, }
@article {pmid12138358, year = {2002}, author = {Hizoh, I and Haller, C}, title = {Radiocontrast-induced renal tubular cell apoptosis: hypertonic versus oxidative stress.}, journal = {Investigative radiology}, volume = {37}, number = {8}, pages = {428-434}, doi = {10.1097/00004424-200208000-00003}, pmid = {12138358}, issn = {0020-9996}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Cell Line ; *Contrast Media ; DNA Fragmentation ; Diatrizoate/pharmacology ; Dogs ; Flow Cytometry ; In Vitro Techniques ; Kidney Tubules/*drug effects/pathology ; Osmolar Concentration ; Oxidative Stress ; Sodium Chloride/pharmacology ; Taurine/pharmacology ; }, abstract = {RATIONALE AND OBJECTIVES: Radiocontrast-induced nephropathy (RCIN) is a major complication of intravascular radiocontrast administration. Renal tubular cell apoptosis is a feature of RCIN, which is related to hypertonicity of contrast agents. Because a hyperosmolal extracellular environment induces oxidative stress via reactive oxygen species, we tested the hypothesis that antioxidants decrease hypertonicity-induced apoptosis of renal epithelial cells. We analyzed the effects of the antioxidants N-acetylcysteine (NAC) and taurine on hypertonicity-induced apoptosis of renal epithelial cells in vitro.<br><br>METHODS: Madin Darby Canine Kidney (MDCK) cells were incubated with the highly hyperosmolal, ionic radiocontrast agent diatrizoate (20% vol/vol, 6 hours) or with equally hyperosmolal (640 mOsm/kg) NaCl solutions. DNA fragmentation, which is a hallmark feature of apoptosis, was assessed quantitatively using flow cytometry after propidium iodide staining and qualitatively using agarose gel electrophoresis.<br><br>RESULTS: Both diatrizoate and NaCl induced DNA fragmentation in MDCK cells. Taurine (10 mmol/L) reduced DNA degradation in both diatrizoate- [79.5 +/- 2.3% versus 72.2 +/- 3.0%; P = 0.0088] and NaCl- [49.5 +/- 4.0% versus 39.4 +/- 1.0%; P = 0.0271] treated cells. In contrast, NAC (10 mmol/L) failed to reduce the DNA breakdown in this model of hypertonicity-induced renal tubular cell apoptosis.<br><br>CONCLUSIONS: The radiocontrast/hypertonicity-induced DNA fragmentation of MDCK cells is attenuated by taurine but not by NAC. Because both agents are antioxidants, the antioxidant property is not sufficient for the observed cytoprotective effect. Hence, the antiapoptotic effect of taurine has to be attributed to other, yet to be defined mechanisms. Our results suggest that pharmacological doses of taurine may be particularly protective against RCIN.}, }
@article {pmid12132446, year = {2001}, author = {}, title = {Nutrition. Two German studies find NAC supplements helpful.}, journal = {TreatmentUpdate}, volume = {12}, number = {9}, pages = {3-5}, pmid = {12132446}, issn = {1181-7186}, mesh = {Acetylcysteine/*therapeutic use ; Anti-HIV Agents/therapeutic use ; CD4 Lymphocyte Count ; Female ; HIV Infections/*drug therapy/immunology ; Humans ; Male ; Placebos ; Viral Load ; }, }
@article {pmid12127835, year = {2002}, author = {Mathy-Hartert, M and Deby-Dupont, GP and Reginster, JY and Ayache, N and Pujol, JP and Henrotin, YE}, title = {Regulation by reactive oxygen species of interleukin-1beta, nitric oxide and prostaglandin E(2) production by human chondrocytes.}, journal = {Osteoarthritis and cartilage}, volume = {10}, number = {7}, pages = {547-555}, doi = {10.1053/joca.2002.0789}, pmid = {12127835}, issn = {1063-4584}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Antioxidants/pharmacology ; Cartilage, Articular/drug effects/metabolism/pathology ; Cell Culture Techniques ; Chondrocytes/drug effects/*metabolism ; Cyclooxygenase 2 ; Dinoprostone/*biosynthesis ; Female ; Gene Expression Regulation/drug effects ; Humans ; Interleukin-1/biosynthesis/genetics ; Isoenzymes/biosynthesis/genetics ; Male ; Membrane Proteins ; Middle Aged ; Nitric Oxide/biosynthesis/*physiology ; Nitric Oxide Synthase/biosynthesis/genetics ; Nitric Oxide Synthase Type II ; Osteoarthritis, Knee/*metabolism ; Prostaglandin-Endoperoxide Synthases/biosynthesis/genetics ; RNA, Messenger/genetics ; Reactive Oxygen Species/*metabolism ; }, abstract = {OBJECTIVES: To determine the effects of two drugs, N-monomethyl-L-arginine (L-NMMA) and N-acetylcysteine (NAC), on interleukin-1beta (IL-1beta), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production by human chondrocytes. The effect of aceclofenac (ACECLO), a non-steroidal antiinflammatory drug (NSAID), was also examined.<br><br>METHODS: Human chondrocytes were enzymatically isolated from osteoarthritic knee cartilage and then maintained in culture in suspension for 48h in the absence or in the presence of lipopolysaccharide (LPS) (10 microg/ml), L-NMMA (0.5mM), NAC (1mM) or ACECLO (6.10(-6)M). IL-1beta and PGE(2) productions were quantified by specific immunoassays. Nitrite was measured in the culture supernatants by a spectrophotometric method based upon the Griess reaction. Cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS) and IL-1beta gene expressions were quantified by transcription of mRNA followed by real time and quantitative polymerase chain reaction. COX-2 protein expression was analysed by Western blot.<br><br>RESULTS: LPS markedly increased the expression of IL-1beta, iNOS and COX-2 genes. In parallel, NO(2) and PGE(2) amounts found in the culture supernatants were significantly enhanced whereas IL-1beta was immunologically undetectable. The addition of L-NMMA (0.5mM) fully blocked LPS-induced NO production but greatly increased PGE(2) production, suggesting a negative effect of NO on PGE(2) synthesis. Inversely, NO production was stimulated by NAC while PGE(2) production was not affected. Interestingly, NAC increased the IL-1beta and iNOS mRNA levels but did not significantly modify COX-2 mRNA expression. L-NMMA did not significantly affect the expression of IL-1beta, iNOS and COX-2. The amount of COX-2 protein did not change in the presence of the antioxidants. Finally, ACECLO fully blocked the production of PGE(2) by chondrocytes without affecting the levels of COX-2 mRNA.<br><br>CONCLUSIONS: The stimulation of IL-1beta, NO and PGE(2) production by LPS is differentially controlled by reactive oxygen species (ROS). In fact, L-NMMA and NAC have different mechanisms of action on the regulation of NO and PGE(2) productions. L-NMMA fully inhibits NO but increases PGE(2) production whereas NAC up-regulates NO but does not modify PGE(2) synthesis. The stimulating effect of L-NMMA on PGE(2) production is not controlled at the transcriptional level. These findings suggest that antioxidant therapy could have different effects according to the oxygen radical species targeted.}, }
@article {pmid12114203, year = {2002}, author = {Kim, HJ and Liu, X and Wang, H and Kohyama, T and Kobayashi, T and Wen, FQ and Romberger, DJ and Abe, S and MacNee, W and Rahman, I and Rennard, SI}, title = {Glutathione prevents inhibition of fibroblast-mediated collagen gel contraction by cigarette smoke.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {283}, number = {2}, pages = {L409-17}, doi = {10.1152/ajplung.00059.2002}, pmid = {12114203}, issn = {1040-0605}, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Collagen/*physiology ; Fibroblasts/*physiology ; Fibronectins/antagonists &amp; inhibitors/genetics/metabolism ; Gels ; Glutathione/metabolism/*physiology ; Humans ; Intracellular Membranes/metabolism ; RNA, Messenger/metabolism ; *Smoke ; *Nicotiana ; }, abstract = {Cigarette smoke, the major risk factor for the development of emphysema, contains over 4,700 chemical compounds, including free radicals and other oxidants (10(14)/puff). An imbalance between oxidants and antioxidants has been proposed in the pathogenesis of chronic obstructive pulmonary disease. Inhibition of repair processes has been suggested to be one pathway contributing to the development of emphysema. We hypothesized that cigarette smoke inhibition of repair might result from a shift of the oxidant/antioxidant balance in favor of oxidants. To evaluate this hypothesis, N-acetyl-L-cysteine (NAC), which serves as a substrate for glutathione (GSH) production, and buthionine sulfoximine (BSO), which inhibits GSH production, were incubated in the presence and absence of cigarette smoke extract (CSE) with fibroblasts in three-dimensional collagen gels. Neither agent alone altered gel contraction. CSE inhibition of gel contraction, however, was mitigated by NAC and potentiated by BSO. Parallel effects were observed on cigarette smoke inhibition of fibronectin production and mRNA expression as well as by changes in intracellular GSH content. Pretreatment of fibroblasts with NAC or BSO resulted in similar effects, suggesting that neither agent was acting directly on smoke but, rather, was altering cellular response to smoke. In conclusion, smoke inhibition of fibroblast repair, as reflected by collagen gel contraction and fibronectin production, may be modulated by intracellular GSH levels.}, }
@article {pmid12113286, year = {2002}, author = {Spada, C and Treitinger, A and Reis, M and Masokawa, IY and Verdi, JC and Luiz, MC and Silveira, MV and Michelon, CM and Avila-Junior, S and Gil, lD and Ostrowskyl, S}, title = {The effect of N-acetylcysteine supplementation upon viral load, CD4, CD8, total lymphocyte count and hematocrit in individuals undergoing antiretroviral treatment.}, journal = {Clinical chemistry and laboratory medicine}, volume = {40}, number = {5}, pages = {452-455}, doi = {10.1515/CCLM.2002.077}, pmid = {12113286}, issn = {1434-6621}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Anti-HIV Agents/*administration &amp; dosage/pharmacology ; CD4-Positive T-Lymphocytes/cytology/*drug effects ; CD8-Positive T-Lymphocytes/cytology/*drug effects ; Double-Blind Method ; Drug Therapy, Combination ; Female ; HIV Infections/blood/*drug therapy/immunology ; Hematocrit ; Humans ; Lymphocyte Count ; Male ; *Viral Load ; }, abstract = {Individuals infected with the human immunodeficiency virus (HIV-1) present with decreased CD4, a progressive increase in viral load, compromised cell immune defense, and hematologic alterations. The aim of this study was to assess the serum viral load, CD4, CD8, lymphocyte count and hematocrit at the beginning of antiretroviral therapy in individuals who were supplemented with N-acetylcysteine (NAC). Twenty volunteers participated in this double-blind, placebo-controlled 180-day study. Ten participants received 600 mg of NAC per day (NAC group) and the other ten serving as a control group received placebo. The above mentioned parameters were determined before treatment, and after 60, 120 and 180 days. In NAC-treated patients hematocrit remained stable and an increase in CD4 cell count took place earlier than that in the control group.}, }
@article {pmid12102537, year = {2002}, author = {Kozer, E and McGuigan, M}, title = {Treatment strategies for early presenting acetaminophen overdose: a survey of medical directors of poison centers in North America and Europe.}, journal = {Human &amp; experimental toxicology}, volume = {21}, number = {3}, pages = {123-127}, doi = {10.1191/0960327102ht235oa}, pmid = {12102537}, issn = {0960-3271}, mesh = {Acetaminophen/analysis/*poisoning ; Acetylcysteine/pharmacology ; Charcoal/pharmacology ; Data Collection ; Drug Overdose ; Europe ; Humans ; North America ; Physician Executives/*statistics &amp; numerical data ; Poison Control Centers/*statistics &amp; numerical data ; Poisoning/drug therapy ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Acetaminophen is frequently used in self-poisoning in Western countries. Although treatment with N-acetylcysteine (NAC) reduces liver injury, no consensus exists on the preferred management of acetaminophen toxicity.<br><br>OBJECTIVES: To describe the approach taken by toxicologists in North America and Europe toward the management of acetaminophen toxicity.<br><br>METHODS: Medical directors of poison centers in the US, Canada, and Europe were surveyed by means of a questionnaire presenting two clinical scenarios of acetaminophen overdose: a healthy adolescent with no risk factors who had an acute ingestion of acetaminophen, and an adult with both acute ingestion and possible risk factors. For each case, several questions about the management of these patients were asked.<br><br>RESULTS: Questionnaires were sent to medical directors of 76 poison centers in North America and 48 in Europe, with response rates of 62% and 44%, respectively. Forty percent of responders suggested using charcoal 4 hours after ingestion of a potential toxic dose of acetaminophen, and 90% recommended treatment with NAC when levels were above 150 microg/mL but below 200 microg/mL 4 hours after ingestion. Duration of treatment with oral NAC ranged from 24 to 96 hours; 38 responders suggested a duration of 72 hours. Of 49 centers recommending oral NAC, 18 (36.7%) said they might consider treatment for less than 72 hours. Eleven of 29 (37.9%) responders suggested treatment with intravenous NAC for more than 20 hours as their usual protocol or a protocol for specific circumstances.<br><br>CONCLUSIONS: Our study showed large variability in the management of acetaminophen overdose. Variations in treatment protocols should be addressed in clinical trials to optimize the treatment for this common problem.}, }
@article {pmid12101081, year = {2002}, author = {Chong, IW and Lin, SR and Hwang, JJ and Huang, MS and Wang, TH and Hung, JY and Paulauskis, JD}, title = {Expression and regulation of the macrophage inflammatory protein-1 alpha gene by nicotine in rat alveolar macrophages.}, journal = {European cytokine network}, volume = {13}, number = {2}, pages = {242-249}, pmid = {12101081}, issn = {1148-5493}, mesh = {Animals ; Cell Line ; Chemokine CCL4 ; Gene Expression Regulation/drug effects ; Half-Life ; Kinetics ; Macrophage Inflammatory Proteins/*genetics ; Macrophages, Alveolar/drug effects/*immunology ; Molecular Weight ; Nicotine/*pharmacology ; RNA, Messenger/genetics ; Rats ; Transcription, Genetic/*drug effects ; Transcriptional Activation/drug effects ; }, abstract = {Cigarette smoking causes inflammation mainly confined to the airway and lung. Nicotine is one of the primary constituents in cigarette smoke. Alveolar macrophages apparently play a pivotal role in mediating pulmonary inflammation via the production of chemokines. Macrophage inflammatory protein-1 alpha (MIP-1 alpha), a member of CC chemokines, has been shown to contribute to monocyte/macrophage and neutrophil chemotaxis and activation. Our previous work demonstrated that MIP-1 alpha mRNA expression in macrophages is induced by a variety of stimuli. In the present study, we further investigate whether nicotine can regulate the gene expression of MIP-1 alpha in macrophages and determine the mechanism leading to increased expression. A rat alveolar macrophage (RAM) cell line, NR8383, was treated with nicotine at a dose of 3.1, 31, 310 microM, or 3.1 mM. Northern blot analysis showed that the induction of MIP-1 alpha mRNA expression was dose-dependent. To define the time course of the inflammatory response, RAM cells were exposed to 31 microM nicotine, MIP-1 alpha mRNA was induced as early as 1 h after treatment, was maximally expressed at 4 and 6 hours, and reduced by 8 hours. Western blot analysis demonstrated a single band with an estimated molecular weight of 10 kD for MIP-1 alpha which was induced after nicotine treatment, suggesting that expression of MIP-1 alpha mRNA could reflect in protein synthesis. In addition. the increase in MIP-1 alpha mRNA expression induced by nicotine was attenuated by co-treatment with the antioxidant N-acetylcysteine (NAC), at doses of 10 and 20 mM, suggesting that the induction of MIP-1 alpha mRNA is mediated via the generation of reactive oxygen species (ROS). To further investigate transcriptional regulation of the MIP-1 alpha gene expression, RAM cells were exposed to nicotine. MIP-1 alpha mRNA levels were significantly increased in nuclear RNA preparations, indicating that transcriptional activation is involved in increased expression of MIP-1 alpha mRNA. Moreover, we performed RNA decay assay by measuring the half-life of MIP-1 alpha mRNA. Treatment of RAM cells with the transcriptional inhibitor actinomycin D following exposure to nicotine revealed that the half-life of MIP-1 alpha mRNA was markedly increased by nicotine treatment, supporting a role of post-transcriptional stabilization in MIP-1 alpha gene expression. These observations indicate that nicotine can induce MIP-1 alpha mRNA expression and protein synthesis in RAM cells, mediating, at least in part, via the generation of ROS. In addition, the increase in MIP-1 alpha mRNA level involves, both transcriptional activation and post-transcriptional stabilization.}, }
@article {pmid12097231, year = {2002}, author = {Li, C and Wright, MM and Jackson, RM}, title = {Reactive species mediated injury of human lung epithelial cells after hypoxia-reoxygenation.}, journal = {Experimental lung research}, volume = {28}, number = {5}, pages = {373-389}, doi = {10.1080/01902140290092001}, pmid = {12097231}, issn = {0190-2148}, support = {DK-97-010/DK/NIDDK NIH HHS/United States ; HL 57801/HL/NHLBI NIH HHS/United States ; }, mesh = {Adenocarcinoma, Papillary ; Adenosine Triphosphate/metabolism ; Annexin A5/analysis ; Apoptosis/physiology ; Carbon Dioxide/pharmacology ; Cell Hypoxia/*physiology ; Dimerization ; Epithelial Cells/chemistry/*metabolism ; Ethidium ; Fluoresceins ; Fluorescent Dyes ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; L-Lactate Dehydrogenase/metabolism ; Lung Neoplasms ; Mitochondria/metabolism ; Necrosis ; Oxidative Stress/physiology ; Oxygen/*pharmacology ; Oxygen Consumption/physiology ; Respiratory Mucosa/*cytology/*metabolism ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; Tumor Cells, Cultured ; Uncoupling Agents/pharmacology ; }, abstract = {This study tested the hypothesis that hypoxia exposure predisposed lung epithelial cells to reactive oxygen species-(ROS) mediated cellular injury. Human lung carcinoma cells (ATCC line H441) having epithelial characteristics (including lamellar bodies, surfactant protein [SP]-A, and SP-B) were cultured in air (air/5% CO(2)) or hypoxia (< 1% O(2)/5% CO(2)) for 0 to 24 hours before imposition of oxidant stress. Cellular manganese superoxide dismutase (MnSOD) activity (units/mg protein) decreased significantly after 24 hours of hypoxia. In normoxic culture after hypoxia, the cells produced increased ROS, detected as dichlorofluorescein (DCF) fluorescence and H(2)O(2) accumulation in medium. Antioxidants N-acetylcysteine (N-Ac) and ebselen inhibited increased DCF fluorescence after hypoxia. To test their ability to tolerate oxidant stress, some cells were incubated with antimycin A (100 microM) and trifluorocarbonylcyanide phenylhydrazone (10 microM) (anti A + FCCP), a mitochondrial complex III inhibitor and respiratory chain uncoupler, which together increase mitochondrial superoxide (O(2)(-)) and H(2)O(2) production. Lung epithelial cells preexposed to hypoxia released more lactate dehydrogenase (LDH) than normoxic controls in response to increased O(2)(-) production. Increased LDH release from hypoxia-preexposed cells treated with anti A + FCCP was inhibited by 1 mM N-Ac. Rotenone and myxothiazole increased DCF oxidation more in hypoxic than in normoxic cells, suggesting that mitochondrial electron transport complex I may have been altered by hypoxia preexposure.}, }
@article {pmid12095135, year = {2002}, author = {Bulger, EM and Garcia, I and Maier, RV}, title = {Intracellular antioxidant activity is necessary to modulate the macrophage response to endotoxin.}, journal = {Shock (Augusta, Ga.)}, volume = {18}, number = {1}, pages = {58-63}, doi = {10.1097/00024382-200207000-00011}, pmid = {12095135}, issn = {1073-2322}, support = {R01 GM45873-09/GM/NIGMS NIH HHS/United States ; T32-GM07037/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/pharmacology ; Animals ; Antioxidants/*metabolism/pharmacology ; Ascorbic Acid/pharmacology ; Blood Coagulation Factors/metabolism ; Butylated Hydroxyanisole/metabolism/pharmacology ; Cells, Cultured ; Chromans/pharmacology ; Endotoxins ; F2-Isoprostanes/metabolism ; Inflammation/metabolism/physiopathology ; Macrophages, Alveolar/drug effects/*metabolism ; Male ; Rabbits ; Reactive Oxygen Species/metabolism ; Respiratory Distress Syndrome/*physiopathology ; Signal Transduction ; Superoxide Dismutase/pharmacology ; Tumor Necrosis Factor-alpha/drug effects/genetics/metabolism ; }, abstract = {The tissue-fixed macrophage (Mphi) is a key cell in the coordination of the excessive systemic immunoinflammatory response underlying the adult respiratory distress syndrome (ARDS). Macrophage-generated reactive oxygen intermediates (ROIs) are involved in both tissue destruction via lipid peroxidation and in the activation of these inflammatory cells. It is unclear whether oxidant-induced activation involves an extracellular effect and membrane destabilization or occurs through intracellular alteration of the redox state and direct involvement as second messengers. In this study, we compare the differential effects of known intracellular vs. extracellular antioxidants on the Mphi response to endotoxin. Rabbit alveolar Mphi were obtained by bronchoalveolar lavage and exposed to either the extracellular antioxidants [vitamin C (VC) (10-1000 microM), Trolox (100-1000 microM, superoxide dismutase (SOD) (10-500 microM))] or the intracellular antioxidants [N-acetylcysteine (NAC) (0.1-10 mM) or butylated hydroxyanisole (BHA) (10-200 microM)] for 1 h. Cells were subsequently stimulated with lipopolysaccharide at 10 ng/mL. After 18 h, supernatants were analyzed for tumor necrosis factor (TNF) and F2 isoprostane (F2ISP) production and cellular monolayers for procoagulant activity (PCA). A dose response inhibition of both TNF and PCA production was demonstrated after both NAC and BHA pretreatment but not with VC, Trolox, or SOD. In addition, northern blots revealed inhibition of TNF mRNA production by both NAC and BHA. F2ISP, a marker of membrane lipid peroxidation, was inhibited by BHA and Trolox but not NAC, VC, or SOD. In conclusion, antioxidants that are incorporated intracellularly are expected to be beneficial in the treatment of excessive inflammatory responses through the interruption of redox dependent signal transduction pathways and subsequent modulation of the Mphi proinflammatory response.}, }
@article {pmid12094258, year = {2002}, author = {Almenara, J and Rosato, R and Grant, S}, title = {Synergistic induction of mitochondrial damage and apoptosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA).}, journal = {Leukemia}, volume = {16}, number = {7}, pages = {1331-1343}, doi = {10.1038/sj.leu.2402535}, pmid = {12094258}, issn = {0887-6924}, support = {CA 63753/CA/NCI NIH HHS/United States ; CA 83705/CA/NCI NIH HHS/United States ; }, mesh = {Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Caspase 8 ; Caspase 9 ; Caspases/metabolism ; Cyclin-Dependent Kinases/antagonists &amp; inhibitors ; Drug Synergism ; Enzyme Inhibitors/*pharmacology ; Flavonoids/*pharmacology ; HL-60 Cells ; Histone Deacetylase Inhibitors ; Humans ; Hydroxamic Acids/*pharmacology ; Leukemia/*drug therapy/metabolism/pathology ; Mitochondria/*drug effects/pathology ; Piperidines/*pharmacology ; U937 Cells ; Vorinostat ; }, abstract = {Interactions between the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) and the cyclin-dependent kinase (CDK) inhibitor flavopiridol (FP) were examined in human leukemia cells. Simultaneous exposure (24 h) of myelomonocytic leukemia cells (U937) to SAHA (1 microM) and FP (100 nM), which were minimally toxic alone (1.5 +/- 0.5% and 16.3 +/- 0.5% apoptosis respectively), produced a dramatic increase in cell death (ie 63.2 +/- 1.9% apoptotic), reflected by morphology, procaspase-3 and -8 cleavage, Bid activation, diminished DeltaPsi(m), and enhanced cytochrome c release. FP blocked SAHA-mediated up-regulation of p21(CIP1) and CD11b expression, while inducing caspase-dependent Bcl-2 and pRb cleavage. Similar interactions were observed in HL-60 and Jurkat leukemic cells. Enhanced apoptosis in SAHA/FP-treated cells was accompanied by a marked reduction in clonogenic surivival. Ectopic expression of either dominant-negative caspase-8 (C8-DN) or CrmA partially attenuated SAHA/FP-mediated apoptosis (eg 45 +/- 1.5% and 38.2 +/- 2.0% apoptotic vs 78 +/- 1.5% in controls) and Bid cleavage. SAHA/FP induced-apoptosis was unaffected by the free radical scavenger L-N-acetyl cysteine or the PKC inhibitor GFX. Finally, ectopic Bcl-2 expression marginally attenuated SAHA/FP-related apoptosis/cytochrome c release, and failed to restore clonogenicity in cells exposed to these agents. Together, these findings indicate that SAHA and FP interact synergistically to induce mitochondrial damage and apoptosis in human leukemia cells, and suggest that this process may also involve engagement of the caspase-8-dependent apoptotic cascade.}, }
@article {pmid12091442, year = {2002}, author = {Tanito, M and Nishiyama, A and Tanaka, T and Masutani, H and Nakamura, H and Yodoi, J and Ohira, A}, title = {Change of redox status and modulation by thiol replenishment in retinal photooxidative damage.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {43}, number = {7}, pages = {2392-2400}, pmid = {12091442}, issn = {0146-0404}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*pharmacology ; Animals ; Blotting, Western ; Cross-Linking Reagents/pharmacology ; Deoxyguanosine/*analogs &amp; derivatives/metabolism ; Electroretinography ; Glutaredoxins ; Glutathione/metabolism ; Light ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Oxidation-Reduction ; Oxidative Stress/*radiation effects ; Oxidoreductases/*metabolism ; Proteins/metabolism ; Radiation Injuries, Experimental/metabolism/pathology/*prevention &amp; control ; Retina/*drug effects/metabolism/pathology/*radiation effects ; Retinal Degeneration/metabolism/pathology/*prevention &amp; control ; Thioredoxins/metabolism ; }, abstract = {PURPOSE: Cellular or tissue reduction-oxidation (redox) is crucial in various diseases. The present study was conducted to analyze how tissue redox status is affected by photooxidative stress and whether the exogenous thiol antioxidant N-acetylcysteine (NAC) affects photooxidative stress-induced retinal damage.<br><br>METHODS: Mice were intraperitoneally injected with either NAC (250 mg/kg) or phosphate-buffered saline (PBS) and exposed to white fluorescent light (8000 lux) for 2 hours. Levels of thioredoxin (TRX), glutaredoxin (GRX), and glutathione (GSH), endogenous regulators of redox; 4-hydroxy-2-nonenal (HNE)-modified protein, a marker of lipid peroxidation; and nuclear factor (NF)-kappaB, a redox-sensitive transcription factor in retinal samples, was measured by immunohistochemistry and Western blot or enzymatic recycling assay. Light-induced retinal damage estimated by electroretinography and quantitative immunohistochemistry for 8-hydroxy-2-deoxyguanosine (8OHdG index), a marker of oxidative stress-induced DNA damage, was compared in NAC- and PBS-treated mice.<br><br>RESULTS: Upregulation of TRX and HNE-modified protein, decrease of GSH, and nuclear translocation of NF-kappaB were noted after light exposure in PBS-treated mice. These changes were suppressed in NAC-treated mice compared with PBS-treated mice. GRX was not upregulated after light exposure in any mice. The a- and b-wave amplitudes were significantly higher, and the 8OHdG index was significantly lower after light exposure in NAC-treated mice than in PBS-treated mice.<br><br>CONCLUSIONS: Retinal redox status is altered by intense light and is normalized partially by the effect of NAC on TRX and GSH tissue levels. Manipulation of the tissue redox state by exogenous thiol replenishment may be a useful strategy to prevent retinal photooxidative damage.}, }
@article {pmid12088194, year = {2002}, author = {Schrier, BP and Lichtendonk, WJ and Witjes, JA}, title = {The effect of N-acetyl-L-cysteine on the viscosity of ileal neobladder mucus.}, journal = {World journal of urology}, volume = {20}, number = {1}, pages = {64-67}, doi = {10.1007/s00345-001-0234-3}, pmid = {12088194}, issn = {0724-4983}, mesh = {Acetylcysteine/*therapeutic use ; Expectorants/*therapeutic use ; Humans ; Ileum/*metabolism/*surgery ; Mucus/chemistry/*drug effects/*metabolism ; *Surgically-Created Structures ; Urinary Bladder/*surgery ; Urine/chemistry ; Viscosity ; }, abstract = {N-acetyl-L-cysteine (NAC) proved to be an effective mucolytic in pulmonary secretions. Our goal was to investigate the in vitro effect of NAC on viscosity of ileal neobladder mucus. The urine of a patient with an ileal neobladder was collected during the first 7 days postoperatively and stored in a refrigerator. After precipitation, the urine was decanted. The residue was stirred to a homogeneous suspension. To samples of 4.5 ml mucus, 0.5 ml NAC 10% was added. To the control sample, 0.5 ml water was added. The samples were incubated in a water bath at 37 degrees C for 5, 30 and 60 min. Viscosity was measured in the Bohlin VOR Rheometer. The viscosity of the ileal neobladder mucus decreased quickly after incubating with NAC 10%. Viscosity increased slightly after I h of incubation. The viscosity in the control sample was higher than in the other incubated samples. NAC was found to decrease the viscosity of ileal neobladder mucus, supporting the in vivo experience that NAC can be useful in patients with an ileal neobladder to facilitate the evacuation of mucus by decreasing viscosity.}, }
@article {pmid12086962, year = {2002}, author = {Jain, SK and Kannan, K and Lim, G and McVie, R and Bocchini, JA}, title = {Hyperketonemia increases tumor necrosis factor-alpha secretion in cultured U937 monocytes and Type 1 diabetic patients and is apparently mediated by oxidative stress and cAMP deficiency.}, journal = {Diabetes}, volume = {51}, number = {7}, pages = {2287-2293}, doi = {10.2337/diabetes.51.7.2287}, pmid = {12086962}, issn = {0012-1797}, mesh = {3-Hydroxybutyric Acid/*pharmacology ; Acetoacetates/*pharmacology ; Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cyclic AMP/blood/*physiology ; Diabetes Mellitus, Type 1/blood/*physiopathology ; Humans ; Ketone Bodies/*blood ; Mitogen-Activated Protein Kinases/metabolism ; Monocytes/drug effects/*physiology ; Oxidative Stress/*physiology ; Protein Kinase C/blood ; Reference Values ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Necrosis Factor-alpha/*metabolism ; U937 Cells ; }, abstract = {An elevated blood level of tumor necrosis factor (TNF)-alpha is a validated marker of vascular inflammation, which can result in the development of vascular disease and atherosclerosis. This study examined the hypothesis that ketosis increases the TNF-alpha secretion, both in a cell culture model using U937 monocytes and in type 1 diabetic patients in vivo. U937 cells were cultured with ketone bodies (acetoacetate [AA] and beta-hydroxybutyrate [BHB]) in the presence or absence of high levels of glucose in medium at 37 degrees C for 24 h. This study demonstrates the following points. First, hyperketonemic diabetic patients have significantly higher levels of TNF-alpha than normoketonemic diabetic patients (P < 0.01) and normal control subjects (P < 0.01). There was a significant correlation (r = 0.36, P < 0.05; n = 34) between ketosis and oxidative stress as well as between oxidative stress and TNF-alpha levels (r = 0.47, P < 0.02; n = 34) in the blood of diabetic patients. Second, ketone body AA treatment increases TNF-alpha secretion, increases oxygen radicals production, and lowers cAMP levels in U937 cells. However, BHB did not have any effect on TNF-alpha secretion or oxygen radicals production in U937 cells. Third, exogenous addition of dibutyryl cAMP, endogenous stimulation of cAMP production by forskolin, and antioxidant N-acetylcysteine (NAC) prevented stimulation of TNF-alpha secretion caused by AA alone or with high glucose. Similarly, NAC prevented the elevation of TNF-alpha secretion and lowering of cAMP levels in H(2)O(2)-treated U937 cells. Fourth, the effect of AA on TNF-alpha secretion was inhibited by specific inhibitors of protein kinase A (H89), p38-mitogen-activated protein kinase (SB203580), and nuclear transcription factor (NF)kappaB (NFkappaB-SN50). This study demonstrates that hyperketonemia increases TNF-alpha secretion in cultured U937 monocytic cells and TNF-alpha levels in the blood of type 1 diabetic patients and is apparently mediated by AA-induced cellular oxidative stress and cAMP deficiency.}, }
@article {pmid12086398, year = {2002}, author = {Kim, H and Lim, JW and Seo, JY and Kim, KH}, title = {Oxidant-sensitive transcription factor and cyclooxygenase-2 by Helicobacter pylori stimulation in human gastric cancer cells.}, journal = {Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer}, volume = {21}, number = {2}, pages = {121-129}, pmid = {12086398}, issn = {0731-8898}, mesh = {Adenocarcinoma/*pathology ; Antioxidants/pharmacology ; Blotting, Northern ; Blotting, Western ; Cyclooxygenase 2 ; Helicobacter Infections/*pathology ; Humans ; Isoenzymes/*biosynthesis ; Membrane Proteins ; NF-kappa B/*pharmacology ; Prostaglandin-Endoperoxide Synthases/*biosynthesis ; RNA, Messenger/biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; Stomach Neoplasms/*pathology ; Tumor Cells, Cultured ; }, abstract = {Helicobacter pylori (H. pylori) infection might activate nuclear factor-kappaB (NF-kappaB), an oxidant-sensitive transcription regulator of inducible expression of inflammatory genes such as cyclooxygenase-2 (COX-2). We studied the role of NF-kappaB on expression of COX-2 in H. pylori-stimulated gastric cancer cell lines by using antioxidants, glutathione (GSH), and N-acetylcysteine (NAC) as well as an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC). Gastric adenocarcinoma cell lines derived from Caucasian (AGS) cells and Korean (SNU-484) cells were used to study the role of NF-kappaB on COX-2 expression by H. pylori. They were treated with GSH, NAC, or PDTC in the presence of H. pylori. mRNA expression and protein level for COX-2 were determined by Northern blot and RT-PCR analysis as well as Western blot analysis. NF-kappaB activation was examined by electrophoretic mobility shift assay. As a result, H. pylori induced a time-dependent expression of mRNA and protein for COX-2 via activation of NF-kappaB, which was inhibited by GSH, NAC, and PDTC in the cells. In conclusion, oxidant-sensitive transcription factor NF-kappaB may play a novel role in expression of COX-2 by H. pylori stimulation in gastric cancer cells.}, }
@article {pmid12086016, year = {2002}, author = {Davidson, SD and Milanesa, DM and Mallouh, C and Choudhury, MS and Tazaki, H and Konno, S}, title = {A possible regulatory role of glyoxalase I in cell viability of human prostate cancer.}, journal = {Urological research}, volume = {30}, number = {2}, pages = {116-121}, doi = {10.1007/s00240-002-0244-7}, pmid = {12086016}, issn = {0300-5623}, mesh = {Acetylcysteine/pharmacology ; Cell Survival/drug effects ; Enzyme Inhibitors/pharmacology ; Glyceraldehyde-3-Phosphate Dehydrogenases/antagonists &amp; inhibitors ; Glycolysis/drug effects ; Humans ; In Vitro Techniques ; Lactoylglutathione Lyase/antagonists &amp; inhibitors/*metabolism ; Male ; Prostatic Neoplasms/*physiopathology ; Pyruvaldehyde/pharmacology ; Tumor Cells, Cultured ; }, abstract = {A role of glyoxalase I (Gly-I), a detoxifying enzyme, in cell viability of prostate cancer was investigated. Cell extracts obtained from 66 prostate tissue specimens and prostatic cancer PC-3 cells were assayed for Gly-I activity using the spectrophotometric method. Gly-I activity was consistently more than eightfold higher in prostate cancer (CAP) specimens (n = 37) than in non-cancerous (NCP) specimens (n = 29). To understand the importance of such a high Gly-I activity in CAP specimens, the effects of methylglyoxal (MG) on PC-3 cells were examined in vitro. MG, a putative toxic glycolytic metabolite, was capable of inducing severe (> 99%) cell death in 24 h, along with a significant reduction in activities of Gly-I as well as glyceraldehyde 3-phosphate dehydrogenase (G3PDH), a key glycolytic enzyme. However, such severe cell death was effectively (approximately 85%) prevented with N-acetylcysteine (NAC), a precursor of reduced glutathione (GSH) that is an essential cofactor for Gly-I, accompanied by the intact Gly-I and G3PDH activities. Therefore, Gly-I may play a critical detoxifying role in glycolysis to maintain cellular activity and viability of prostatic cancer cells.}, }
@article {pmid12082021, year = {2002}, author = {Seril, DN and Liao, J and Ho, KL and Yang, CS and Yang, GY}, title = {Inhibition of chronic ulcerative colitis-associated colorectal adenocarcinoma development in a murine model by N-acetylcysteine.}, journal = {Carcinogenesis}, volume = {23}, number = {6}, pages = {993-1001}, doi = {10.1093/carcin/23.6.993}, pmid = {12082021}, issn = {0143-3334}, support = {ES0052/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adenocarcinoma/pathology/*prevention &amp; control ; Animals ; Anticarcinogenic Agents/*pharmacology ; Antioxidants/*pharmacology ; Cell Division/drug effects ; Colitis, Ulcerative/complications/*prevention &amp; control ; Colorectal Neoplasms/pathology/*prevention &amp; control ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred C57BL ; }, abstract = {Long-term ulcerative colitis (UC) patients are at increased risk for developing colorectal cancer. In order to develop strategies for preventing UC-associated carcinogenesis, we studied the effect of the antioxidant N-acetylcysteine (NAC) on UC-associated cancer development in a mouse model. Female C57BL/6J mice were subjected to long-term administration of dextran sulfate sodium (DSS) in the drinking fluid and 2-fold iron-enriched AIN76A diet, with or without NAC. In the DSS-plus-2-fold iron positive control group, gross tumor incidence was 88.5% (23/26 mice) after 12 DSS cycles (1 DSS cycle = 7 day DSS treatment period followed by 10 day recovery period). The tumor multiplicity was 2.1 +/- 0.2 tumors/tumor-bearing mouse, and the tumor volume was 0.054 +/- 0.019 cm3. With 0.2% NAC administration, tumor incidence was significantly reduced (68%, 17/25 mice; P < 0.05), as was the tumor multiplicity (1.5 +/- 0.1 tumors/tumor-bearing mouse; P < 0.05). The tumor volume was lower (0.014 +/- 0.004 cm3), but not significantly decreased. The proliferation index was significantly decreased in non-cancerous epithelia (48.5 +/- 6.0% vs 32.0 +/- 3.7%; P < 0.05), but not in tumor cells. NAC significantly induced apoptosis in both non-cancerous epithelia and colorectal adenocarcinoma. The number of cells immunostained-positive for nitrotyrosine was markedly decreased in the non-cancerous mucosa of NAC-treated mice (102.4 +/-16.6 positive cells/mm2 mucosa vs 53.6 +/- 14.9 cells/mm2; P < 0.05). In addition, the number of inducible nitric oxide synthase (iNOS)-positive inflammatory cells in the non-cancerous mucosa of the distal colon was markedly decreased by NAC. This study indicates that the antioxidant NAC has the potential to serve as a preventive agent for UC-associated colorectal cancer, possibly via inhibition of cellular proliferation and nitrosative stress-caused cellular damage.}, }
@article {pmid12079405, year = {2002}, author = {Ribardo, DA and Kuhl, KR and Boldogh, I and Peterson, JW and Houston, CW and Chopra, AK}, title = {Early cell signaling by the cytotoxic enterotoxin of Aeromonas hydrophila in macrophages.}, journal = {Microbial pathogenesis}, volume = {32}, number = {4}, pages = {149-163}, doi = {10.1006/mpat.2001.0490}, pmid = {12079405}, issn = {0882-4010}, support = {P30 ES006676/ES/NIEHS NIH HHS/United States ; AI41611/AI/NIAID NIH HHS/United States ; }, mesh = {*Aeromonas hydrophila ; *Bacterial Proteins ; Blotting, Western ; Calcium/metabolism ; Calcium Signaling/drug effects ; Carbon-Oxygen Lyases/metabolism ; Cell Line ; Cytotoxins/*pharmacology ; *DNA-(Apurinic or Apyrimidinic Site) Lyase ; Dinoprostone/metabolism ; Enterotoxins/*pharmacology ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Macrophages/*drug effects/metabolism ; NF-kappa B/metabolism ; Oxidative Stress/drug effects ; Protein Kinases/metabolism ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {A cytotoxic enterotoxin (Act) of Aeromonas hydrophila is an important virulence factor with hemolytic, cytotoxic and enterotoxic activities. In this report, we demonstrated Act rapidly mobilized calcium from intracellular stores and evoked influx of calcium from the extracellular milieu in macrophages. A direct role of calcium in Act-induced prostaglandin (e.g. PGE(2)) and tumor necrosis factor alpha (TNF alpha) production was demonstrated in macrophages using a cell-permeable calcium chelator BAPTA-AM, which also down-regulated activation of transcription factor NF-kappa B. We showed that Act's capacity to increase PGE(2) and TNF alpha production could be blocked by inhibitors of tyrosine kinases and protein kinase A. In addition, Act caused up-regulation of the DNA repair enzyme redox factor-1 (Ref-1), which potentially could promote DNA binding of the transcription factors allowing modulation of various genes involved in the inflammatory response. Taken together, a link between Act-induced calcium release, regulation of downstream kinase cascades and Ref-1, and activation of NF-kappa B leading to PGE(2) and TNF alpha production was established. Since Act also caused extensive tissue damage, we showed that Act increased reactive oxygen species, and the antioxidant N-acetyl cysteine, blocked Act-induced PGE(2) and TNF alpha production, as well as NF-kappa B nuclear translocation in macrophages. We have demonstrated for the first time early cell signaling initiated in eukaryotic cells by Act, which leads to various biological effects associated with this toxin.}, }
@article {pmid12079021, year = {2002}, author = {Mulhall, KJ and Curtin, WA and Given, HF}, title = {Inhibition of polymethylmethacrylate particle-induced monocyte activation and IL-1beta and TNF-alpha expression by the antioxidant agent N-acetylcysteine.}, journal = {Acta orthopaedica Scandinavica}, volume = {73}, number = {2}, pages = {206-212}, doi = {10.1080/000164702753671821}, pmid = {12079021}, issn = {0001-6470}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/*antagonists &amp; inhibitors ; Bone Cements/*pharmacology ; Free Radical Scavengers/*pharmacology ; Humans ; In Vitro Techniques ; Interleukin-1/*antagonists &amp; inhibitors ; Interleukin-1beta ; Lymphokines/*antagonists &amp; inhibitors/*drug effects/ultrastructure ; Macrophage Activation/*drug effects ; Macrophages/drug effects/ultrastructure ; Microscopy, Electron, Scanning ; Monocytes/*drug effects ; Particle Size ; Peptide Fragments/*antagonists &amp; inhibitors/*drug effects ; Polymethyl Methacrylate/*pharmacology ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/*drug effects ; }, abstract = {We investigated the effectiveness of an antioxidant agent, N-acetylcysteine (NAC), in suppressing macrophage activation and mediator release in response to particulate debris. Polymethylmethacrylate (PMMA) particle-stimulated monocyte-macrophages were cultured alone and with varying concentrations of NAC. Tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) expression in the resultant cultures were measured using enzyme-linked immunosorbant assays. The ultrastructural effect of treatment was also assessed by electron microscopy. Cell viability in the various cultures was measured to rule out an effect of cytotoxicity. NAC treatment reduced TNFalpha and IL-1beta expression by the monocyte-macrophages. Culturing with NAC was also associated with less ultrastructural activation of the monocytes. Furthermore, NAC was not associated with any adverse effect on cell viability in the concentrations used. Our findings demonstrate the effectiveness of the antioxidant N-acetylcysteine in suppressing the cell activation and TNFalpha release seen on exposure to wear debris. This represents a novel potential therapeutic method in the prevention or treatment of periprosthetic osteolysis.}, }
@article {pmid12076523, year = {2002}, author = {Custódio, JB and Cardoso, CM and Almeida, LM}, title = {Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis.}, journal = {Chemico-biological interactions}, volume = {140}, number = {2}, pages = {169-184}, doi = {10.1016/s0009-2797(02)00020-0}, pmid = {12076523}, issn = {0009-2797}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/drug effects/*physiology ; Etoposide/*pharmacology ; Intracellular Membranes/drug effects/*physiology ; Kinetics ; Membrane Potentials/drug effects/physiology ; Mitochondria, Liver/drug effects/*physiology ; Mitochondrial Swelling/drug effects/*physiology ; Permeability ; Rats ; Rats, Wistar ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {Etoposide (VP-16) is known to promote cell apoptosis either in cancer or in normal cells as a side effect. This fact is preceded by the induction of several mitochondrial events, including increase in Bax/Bcl-2 ratio followed by cytochrome c release and consequent activation of caspase-9 and -3, reduction of ATP levels, depolarization of membrane potential (DeltaPsi) and rupture of the outer membrane. These events are apoptotic factors essentially associated with the induction of the mitochondrial permeability transition (MPT). VP-16 has been shown to stimulate the Ca2+-dependent MPT induction similarly to prooxidants and to promote apoptosis by oxidative stress mechanisms, which is prevented by glutathione (GSH) and N-acetylcysteine (NAC). Therefore, the aim of this work was to study the effects of antioxidants and thiol protecting agents on MPT promoted by VP-16, attempting to identify the underlying mechanisms on VP-16-induced apoptosis. The increased sensitivity of isolated mitochondria to Ca2+-induced swelling, Ca2+ release, depolarization of DeltaPsi and uncoupling of respiration promoted by VP-16, which are prevented by cyclosporine A proving that VP-16 induces the MPT, are also efficiently prevented by ascorbate, the primary reductant of the phenoxyl radicals produced by VP-16. The thiol reagents GSH, dithiothreitol and N-ethylmaleimide, which have been reported to prevent the MPT induction, also protect this event promoted by VP-16. The inhibition of the VP-16-induced MPT by antioxidants agrees with the prevention of etoposide-induced apoptosis by GSH and NAC and suggests the generation of oxidant species as a potential mechanism underlying the MPT that may trigger the release of mitochondrial apoptogenic factors responsible for apoptotic cascade activation.}, }
@article {pmid12071352, year = {2002}, author = {Sagristá, ML and García, AE and Africa De Madariaga, M and Mora, M}, title = {Antioxidant and pro-oxidant effect of the thiolic compounds N-acetyl-L-cysteine and glutathione against free radical-induced lipid peroxidation.}, journal = {Free radical research}, volume = {36}, number = {3}, pages = {329-340}, doi = {10.1080/10715760290019354}, pmid = {12071352}, issn = {1071-5762}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Brain/*metabolism ; Cattle ; Diphenylhexatriene/*analogs &amp; derivatives/chemistry ; Electron Spin Resonance Spectroscopy ; Free Radical Scavengers/*pharmacology ; Free Radicals/chemistry ; Glutathione/*pharmacology ; *Lipid Peroxidation ; Liposomes/*chemistry/metabolism ; Reactive Oxygen Species/*pharmacology ; Sulfhydryl Compounds/*chemistry ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The antioxidant ability of thiol compounds has been the subject of much of the current research about oxidative stress. The direct scavenging of hydroxyl radicals by thiols has been suggested as their protection mechanisms. Nevertheless, the interaction of thiols with reactive radicals can generate thiyl radicals, which, in turn, may impart a pro-oxidant function. The purpose of this study has been to establish the effect of the thiol compounds N-acetyl-L-cysteine (NAC) and glutathione (GSH) against the peroxidative processes involving membrane lipids. The results obtained support the ability of NAC and GSH to suppress the 2,2'-azobis-(2-amidinopropane) dihydrochloride (AAPH)-dependent or to enhance the Fe2+/H2O2-dependent oxidative actions. The evaluation of thiobarbituric acid reactive substances (TBARS) production, the study of the influence of oxidants on membrane fluidity and the measurements of the changes in the fluorescence of bilayer probes, such as 3-(p-(6-phenyl)-1,3,5-hexatrienyl)phenylpropionic acid (DPH-PA), have shown the antioxidant and pro-oxidant effects of both NAC and GSH. Also their dependence on the nature of the radicals generated by the oxidative systems used has been shown. The use of ESR spectroscopy has allowed us to establish the ability of these compounds to scavenge the AAPH-derived radicals, to determine the formation of thiyl radicals in the iron-mediated oxidation and to evaluate the enhanced production of hydroxyl radicals by NAC and GSH.}, }
@article {pmid12069163, year = {2002}, author = {Harada, D and Naito, S and Hiraoka, I and Otagiri, M}, title = {In vivo kinetic analysis of covalent binding between N-acetyl-L-cysteine and plasma protein through the formation of mixed disulfide in rats.}, journal = {Pharmaceutical research}, volume = {19}, number = {5}, pages = {615-620}, pmid = {12069163}, issn = {0724-8741}, mesh = {Acetylcysteine/administration &amp; dosage/blood/*pharmacokinetics ; Animals ; Blood Proteins/*metabolism ; Chromatography, High Pressure Liquid ; Infusions, Intravenous ; Injections, Intravenous ; Kinetics ; Male ; Models, Biological ; Protein Binding ; Rats ; Rats, Sprague-Dawley ; }, abstract = {PURPOSE: This investigation was undertaken to study the relationship between plasma drug clearance and covalent protein-binding kinetics of N-acetyl-L-cysteine (NAC).<br><br>METHODS: NAC was intravenously administered to rats via a bolus injection or continuous infusion. Plasma concentrations of protein-unbound and total NAC were analyzed using a compartment model, taking into consideration of the protein binding process, and the apparent first-order binding and dissociation rate constants (kon and koff) were obtained.<br><br>RESULTS: Plasma total NAC after a bolus injection showed biphasic elimination with an inflection point at 1 hr. After 1 hr, NAC was largely present in the covalent protein-bound form. During the steady state of the infusion, approximately 30%-40% of plasma NAC bound with protein covalently. The kon, koff, and the elimination rate constant of protein-unbound drug (ke) were 0.23, 0.57, and 4.3 hr(-1). The dissociation half-life of NAC from protein estimated from koff was in agreement with the elimination half-life of plasma total NAC. This suggests that the dissociation of NAC from protein rate-limited the drug elimination in plasma (koff < ke).<br><br>CONCLUSION: We demonstrated that plasma total drug clearance is kinetically limited by covalent protein binding. The compartmental model described here is useful for analyzing its kinetics in vivo.}, }
@article {pmid12066227, year = {2002}, author = {Mantovani, G and Macciò, A and Madeddu, C and Mulas, C and Massa, E and Astara, G and Ferreli, L and Mudu, MC and Gramignano, G and Murgia, V and Lusso, MR and Mocci, M and Cardia, A and Mura, L}, title = {Phase II study of subcutaneously administered interleukin-2 in combination with medroxyprogesterone acetate and antioxidant agents as maintenance treatment in advanced cancer responders to previous chemotherapy.}, journal = {Oncology reports}, volume = {9}, number = {4}, pages = {887-896}, pmid = {12066227}, issn = {1021-335X}, mesh = {Acetylcysteine/administration &amp; dosage ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; C-Reactive Protein/analysis ; Cytokines/blood ; Female ; Humans ; Injections, Subcutaneous ; Interleukin-2/administration &amp; dosage ; Leptin/blood ; Lymphocyte Count ; Male ; Medroxyprogesterone Acetate/administration &amp; dosage ; Middle Aged ; Neoplasm Staging ; Neoplasms/blood/*drug therapy/pathology ; Survival Rate ; Thioctic Acid/administration &amp; dosage ; Treatment Outcome ; }, abstract = {An open, non-randomized phase II study was carried out including patients with advanced solid tumors who achieved an objective response or disease stabilization as a result of previous chemotherapy, to receive a maintenance treatment with recombinant interleukin-2 (rIL-2) plus medroxyprogesterone acetate (MPA) plus antioxidant agents alpha-lipoic acid (ALA) and N-acetyl cysteine (NAC). The first study endpoints were to define clinical outcome and toxicity as well as the evaluation of quality of life. As secondary endpoints we measured the changes of lymphocyte absolute count, the serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin after treatment. rIL-2 was administered at a dose of 1.8 MIU subcutaneously 3 times/week on alternate days for the first two weeks of every month and MPA was given orally at a dose of 500 mg/day at alternate days without interruption. ALA 300 mg/day orally and NAC 1800 mg/day orally were also administered continuously. Twenty-eight patients were enrolled in the study. The median duration of maintenance treatment was 10 months (6-30+). The response to maintenance treatment at September 15, 2001 was: CR 11 patients (39.3%); SD 2 patients (7.1%); PD 15 patients (53.6%). The median duration of response was 11 months (6-34+). The median follow-up duration was 11 months (6-34+). The median OS was not reached. The median PFS was 21.5 months (1-40+). The 1-year survival rate was 72.2%. At September 15, 2001, 16 patients were still surviving. No grade 3/4 toxicity and one grade 2 skin toxicity were observed. We found a significant increase of the absolute lymphocyte count and serum levels of IL-2 and a significant decrease of TNF alpha after treatment. The evaluation of patient subgroups showed the following: the patients alive at the end of study had a significant increase of lymphocyte count, IL-2 and leptin, and a significant decrease of IL-1 beta, IL-6 and TNF alpha, whereas the patients who had died had only a significant increase of lymphocyte count and IL-2. Among the patients alive, those in objective clinical response (CR + PR) + those in SD had a significant increase of lymphocyte count, IL-2 and leptin and a significant decrease of IL-1 beta, IL-6 and TNFalpha, whereas those with PD had no significant changes in any of the above values. We conclude that the combination of s.c. rIL-2 with oral MPA and anti-oxidant agents ALA and NAC in an intermittent schedule, repeated for a long-term period, is feasible, has a very low toxicity and results in the improvement of biological markers which are predictive for patient outcome.}, }
@article {pmid12065697, year = {2002}, author = {Masamune, A and Kikuta, K and Satoh, M and Satoh, A and Shimosegawa, T}, title = {Alcohol activates activator protein-1 and mitogen-activated protein kinases in rat pancreatic stellate cells.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {302}, number = {1}, pages = {36-42}, doi = {10.1124/jpet.302.1.36}, pmid = {12065697}, issn = {0022-3565}, mesh = {Acetaldehyde/pharmacology ; Animals ; Antioxidants/pharmacology ; Biotransformation/drug effects ; Blotting, Northern ; Blotting, Western ; Cell Nucleus/chemistry ; Cells, Cultured ; Central Nervous System Depressants/*pharmacology ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Ethanol/*pharmacology ; Imidazoles/pharmacology ; Luciferases ; Male ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; NF-kappa B/metabolism ; Pancreas/cytology/drug effects/*metabolism ; Pyridines/pharmacology ; Rats ; Rats, Wistar ; Transcription Factor AP-1/*metabolism ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Alcohol is a major cause of both acute and chronic pancreatitis. Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic inflammation and fibrosis. Herein, we examined the effect of ethanol and acetaldehyde on the activation of transcription factors and mitogen-activated protein (MAP) kinases in PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype. PSCs were treated with ethanol and acetaldehyde at clinically relevant concentrations (50 mM and 200 microM, respectively). Ethanol and acetaldehyde activated activator protein-1 but not nuclear factor-kappaB. In addition, they activated three classes of MAP kinases: extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 MAP kinase. Ethanol- and acetaldehyde-induced activation of activator protein-1 and MAP kinases was blocked by the antioxidant N-acetyl-cysteine, suggesting a role of oxidative stress in the signal transduction. Ethanol and acetaldehyde induced alpha1(I) procollagen gene expression but did not induce intercellular adhesion molecule-1 and monocyte chemoattractant protein-1. The acetaldehyde-induced increase of alpha1(I) procollagen gene expression was inhibited by the p38 MAP kinase inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580) but not by the MAP kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059). Specific activation of these signal transduction pathways may play a role in the pathogenesis of alcohol-induced pancreatic injury.}, }
@article {pmid12065696, year = {2002}, author = {Kitazawa, M and Wagner, JR and Kirby, ML and Anantharam, V and Kanthasamy, AG}, title = {Oxidative stress and mitochondrial-mediated apoptosis in dopaminergic cells exposed to methylcyclopentadienyl manganese tricarbonyl.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {302}, number = {1}, pages = {26-35}, doi = {10.1124/jpet.302.1.26}, pmid = {12065696}, issn = {0022-3565}, support = {R01 ES010586/ES/NIEHS NIH HHS/United States ; R0S ES 10586/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Blotting, Western ; Caspase 3 ; Caspases/metabolism ; Cell Survival/drug effects ; DNA Fragmentation/drug effects ; Dopamine/metabolism/*physiology ; Enzyme Activation/physiology ; Gasoline/*toxicity ; In Situ Hybridization ; L-Lactate Dehydrogenase/metabolism ; Membrane Potentials/drug effects ; Mitochondria/drug effects/*physiology ; Neurotransmitter Agents/metabolism ; Organometallic Compounds/*toxicity ; Oxidative Stress/drug effects/*physiology ; PC12 Cells ; Proto-Oncogene Proteins c-bcl-2/physiology ; Rats ; Reactive Oxygen Species/metabolism ; }, abstract = {Methylcyclopentadienyl manganese tricarbonyl (MMT), an organic manganese-containing gasoline additive, was investigated to determine whether MMT potentially causes dopaminergic neurotoxic effects. MMT is acutely cytotoxic and dopamine-producing cells (PC-12) seemed to be more susceptible to cytotoxic effects than nondopaminergic cells (striatal gamma-aminobutyric acidergic and cerebellar granule cells). MMT also potently depleted dopamine apparently by cytoplasmic vesicular release to the cytosol, a neurochemical change resembling other dopaminergic neurotoxicants. Generation of reactive oxygen species (ROS), an early effect in toxicant-induced apoptosis, occurred within 15 min of MMT exposure. MMT caused a loss of mitochondrial transmembrane potential (DeltaPsim), a likely source of ROS generation. The ROS signal further activated caspase-3, an important effector caspase, which could be inhibited by antioxidants (Trolox or N-acetyl cysteine). Predepletion of dopamine by using alpha-methyl-p-tyrosine (tyrosine hydroxylase inhibitor) treatment partially prevented caspase-3 activation, denoting a significant dopamine and/or dopamine by-product contribution to initiation of apoptosis. Genomic DNA fragmentation, a terminal hallmark of apoptosis, was induced concentration dependently by MMT but completely prevented by pretreatment with Trolox, deprenyl (monoamine oxidase-B inhibitor), and alpha-methyl-p-tyrosine. A final set of critical experiments was performed to verify the pharmacological studies using a stable Bcl-2-overexpressing PC-12 cell line. Bcl-2-overexpressing cells were significantly refractory to MMT-induced ROS generation, caspase-3 activation, and loss of DeltaPsim and were completely resistant to MMT-induced DNA fragmentation. Taken together, the results presented herein demonstrate that oxidative stress plays an important role in mitochondrial-mediated apoptotic cell death in cultured dopamine-producing cells after exposure to MMT.}, }
@article {pmid12061835, year = {2002}, author = {Mazzeo, D and Sacco, S and Di Lucia, P and Penna, G and Adorini, L and Panina-Bordignon, P and Ghezzi, P}, title = {Thiol antioxidants inhibit the formation of the interleukin-12 heterodimer: a novel mechanism for the inhibition of IL-12 production.}, journal = {Cytokine}, volume = {17}, number = {6}, pages = {285-293}, doi = {10.1006/cyto.2002.1014}, pmid = {12061835}, issn = {1043-4666}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cell Line ; Dimerization ; Disulfides ; Glutathione/pharmacology ; Humans ; Interferon-gamma/pharmacology ; Interleukin-12/biosynthesis/*chemistry/genetics ; Protein Subunits ; RNA, Messenger/drug effects/genetics ; Sulfhydryl Compounds/*pharmacology ; Transcription, Genetic/drug effects ; }, abstract = {IL-12 is a 75 kDa heterodimeric cytokine composed of two disulfide-linked subunits, p35 and p40, which plays an important role in the regulation of the immune response. We tested the hypothesis that thiol antioxidants might interfere with dimerization of the two IL-12 subunits. We thus studied the effect of reduced glutathione (GSH) and N-acetyl-cysteine (NAC) on IL-12 p75 production by human THP-1 cell stimulated with IFN-gamma and Staphylococcus aureus Cowan strain I (SAC), using ELISAs specific for IL-12 p75 or the p40 subunit. NAC and GSH, but not cystine, at concentrations of 5-10 mM inhibited production of IL-12 p75 but not of the p40 subunit. NAC did not inhibit p40 or p35 mRNA expression in dendritic cells or THP-1 cells, or NF-kappa B activation in THP-1 cells. The effect of NAC was specific for IL-12 p75, as NAC did not affect induction of MHC class II expression by IFN-gamma-stimulated THP-1 cells. IL-12 dimer formation appears to be reduced by NAC also in vivo, because pretreatment with NAC (1 g/kg, orally), before LPS injection in mice, inhibited peak IL-12 p75 serum levels without affecting those of p40. We conclude that thiol levels regulate IL-12 p75 production and that assembly of the heterodimer is a step that might represent a target for pharmacological intervention.}, }
@article {pmid12057717, year = {2002}, author = {Fulghesu, AM and Ciampelli, M and Muzj, G and Belosi, C and Selvaggi, L and Ayala, GF and Lanzone, A}, title = {N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome.}, journal = {Fertility and sterility}, volume = {77}, number = {6}, pages = {1128-1135}, doi = {10.1016/s0015-0282(02)03133-3}, pmid = {12057717}, issn = {0015-0282}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Androgens/blood ; Drug Administration Schedule ; Female ; Glucose Tolerance Test ; Humans ; Hyperinsulinism/blood ; Insulin/blood/metabolism ; Insulin Resistance/*physiology ; Liver/metabolism ; Polycystic Ovary Syndrome/*drug therapy/*physiopathology ; Prospective Studies ; Testosterone/blood ; }, abstract = {OBJECTIVE: To evaluate the effect of N-acetyl-cysteine (NAC) on insulin secretion and peripheral insulin resistance in subjects with polycystic ovary syndrome (PCOS).<br><br>DESIGN: Prospective data analysis.<br><br>SETTING: Volunteer women in an academic research environment.<br><br>PATIENT(S): Six lean and 31 obese subjects, aged 19-33 years.<br><br>INTERVENTION(S): Patients were treated for 5-6 weeks with NAC at a dose of 1.8 g/day orally. A dose of 3 g/day was arbitrarily chosen for massively obese subjects. Six of 31 obese patients with PCOS were treated with placebo and served as controls.<br><br>MAIN OUTCOME MEASURE(S): Before and after the treatment period, the hormonal and lipid blood profile and insulin sensitivity, assessed by an hyperinsulinemic euglycemic clamp, were evaluated and an oral glucose tolerance test (OGTT) was performed.<br><br>RESULT(S): Fasting glucose, fasting insulin, and glucose area under curve (AUC) were unchanged after treatment. Insulin AUC after OGTT was significantly reduced, and the peripheral insulin sensitivity increased after NAC administration, whereas the hepatic insulin extraction was unaffected. The NAC treatment induced a significant fall in T levels and in free androgen index values (P<.05). In analyzing patients according to their insulinemic response to OGTT, normoinsulinemic subjects and placebo-treated patients did not show any modification of the above parameters, whereas a significant improvement was observed in hyperinsulinemic subjects.<br><br>CONCLUSION(S): NAC may be a new treatment for the improvement of insulin circulating levels and insulin sensitivity in hyperinsulinemic patients with polycystic ovary syndrome.}, }
@article {pmid12052825, year = {2002}, author = {Lennon, AM and Ramaugé, M and Dessouroux, A and Pierre, M}, title = {MAP kinase cascades are activated in astrocytes and preadipocytes by 15-deoxy-Delta(12-14)-prostaglandin J(2) and the thiazolidinedione ciglitazone through peroxisome proliferator activator receptor gamma-independent mechanisms involving reactive oxygenated species.}, journal = {The Journal of biological chemistry}, volume = {277}, number = {33}, pages = {29681-29685}, doi = {10.1074/jbc.M201517200}, pmid = {12052825}, issn = {0021-9258}, mesh = {Adipocytes/*drug effects/enzymology ; Animals ; Astrocytes/*drug effects/enzymology ; Cells, Cultured ; Enzyme Activation ; MAP Kinase Signaling System/*drug effects ; Prostaglandin D2/*analogs &amp; derivatives/*pharmacology ; Rats ; *Reactive Oxygen Species ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Thiazoles/*pharmacology ; *Thiazolidinediones ; Transcription Factors/*metabolism ; }, abstract = {15-Deoxy-Delta(12-14)-prostaglandin J(2) (dPGJ2) and thiazolidinediones are known as ligands for the peroxisome proliferator activator receptor gamma (PPAR gamma) a member of the nuclear receptor superfamily. Herein, we show that dPGJ2 activates, in cultured primary astrocytes, Erk, Jnk, p38 MAP kinase, and ASK1, a MAP kinase kinase kinase, which can be involved in the activation of Jnk and p38 MAP kinase. The activation kinetic is similar for the three MAP kinase. The activation of the MAP kinases is detectable around 0.5 h. The activation increases with dPGJ2 in a dose dependent manner (0-15 microm). A scavenger of reactive oxygenated species (ROS), N-acetylcysteine (NAC) at 20 mm, completely suppresses the activation of MAP kinases and ASK1, suggesting a role for oxidative stress in the activation mechanism. Other prostaglandin cyclopentenones than dPGJ2, A(2), and to a lesser degree, A(1) also stimulate the MAP kinases, although they do not bind to PPAR gamma. Ciglitazone (20 microm), a thiazolidinedione that mimics several effects of dPGJ2 in different cell types, also activates the three MAP kinase families and ASK1 in cultured astrocytes. However the activation is more rapid (it is detectable at 0.25 h) and more sustained (it is still strong after 4 h). NAC prevents the activation of the three MAP kinase families by ciglitazone. Another thiazolidinedione that binds to PPAR gamma, rosiglitazone, does not activate MAP kinases, indicating that the effect of ciglitazone on MAP kinases is independent of PPAR gamma. Ciglitazone and less strongly dPGJ2 activate Erk in undifferentiated cells of the adipocyte cell line 1B8. Ciglitazone also activates Jnk and p38 MAP kinase in these preadipocytes. Our findings suggest that a part of the biological effects of dPGJ2 and ciglitazone involve the activation of the three MAP kinase families probably through PPAR gamma-independent mechanisms involving ROS.}, }
@article {pmid12049840, year = {2002}, author = {Hultberg, B and Andersson, A and Isaksson, A}, title = {Lipoic acid increases glutathione production and enhances the effect of mercury in human cell lines.}, journal = {Toxicology}, volume = {175}, number = {1-3}, pages = {103-110}, doi = {10.1016/s0300-483x(02)00060-4}, pmid = {12049840}, issn = {0300-483X}, mesh = {Acetylcysteine/metabolism ; Antioxidants/*metabolism ; Dithiothreitol/metabolism ; Drug Synergism ; Glutathione/*biosynthesis ; HeLa Cells/drug effects/metabolism ; Hepatocytes/drug effects/metabolism ; Homocysteine/metabolism ; Humans ; Mercury/metabolism/*toxicity ; Thioctic Acid/metabolism/*toxicity ; }, abstract = {Thiols are known to influence the metabolism of glutathione. In a previous study (Toxicology 156 (2001) 93) dithiothreitol (DTT) did not show any effect on intra- or extracellular glutathione concentrations in HeLa cell cultures but increased the effects of mercury ions on glutathione concentrations, whereas monothiols such as N-acetylcysteine (NAC) or glutathione did not. In the present study, we have investigated the effects of thiols as well as the interaction between thiols and mercury ions in cultures of both HeLa and hepatoma cells. Furthermore, we have added alpha-lipoic acid (LA) to the previously used test panel of thiols, since it is metabolised intracellularly to a dithiol (dihydrolipoate). The present study shows that LA increased intra- and extracellular concentrations of glutathione in both HeLa and hepatoma cell cultures. In contrast to results for HeLa cells, the presence of DTT increased the intracellular glutathione concentration in hepatoma cells. No increase of glutathione concentrations was observed in hepatoma cell cultures in the presence of the monothiols (NAC, homocysteine or glutathione) tested, in agreement with previous findings in HeLa cell cultures. The presence of dithiols, either DTT or dihydrolipoate (the metabolite of LA), increased the effects of mercury ions on glutathione concentrations in hepatoma cells, whereas monothiols such as NAC or glutathione did not, in agreement with previous findings in HeLa cells. Thus, metabolic effects of mercury ions were observed in hepatoma cells as well as in HeLa cells at a lower concentration than the supposed toxicity threshold for mercury in blood.}, }
@article {pmid12047048, year = {2002}, author = {Watanabe, T and Pakala, R and Katagiri, T and Benedict, CR}, title = {Antioxidant N-acetylcysteine inhibits vasoactive agents-potentiated mitogenic effect of mildly oxidized LDL on vascular smooth muscle cells.}, journal = {Hypertension research : official journal of the Japanese Society of Hypertension}, volume = {25}, number = {2}, pages = {311-315}, doi = {10.1291/hypres.25.311}, pmid = {12047048}, issn = {0916-9636}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cardiovascular Agents/*pharmacology ; Cells, Cultured ; DNA/biosynthesis ; Humans ; Lipoproteins, LDL/antagonists &amp; inhibitors/*pharmacology ; Male ; Mitogens/antagonists &amp; inhibitors/*pharmacology ; Muscle, Smooth, Vascular/cytology/*drug effects/metabolism ; Rabbits ; }, abstract = {Mildly oxidized LDL (mox-LDL) has been shown to induce monocyte-endothelial interactions and vascular smooth muscle cell (VSMC) proliferation, key events in the formation of the atherosclerotic lesion. Growth factors and vasoactive peptides are also thought to play a major role in atherogenesis. We examined the interaction between mox-LDL and well-known vasoactive agents such as serotonin (5-HT), angiotensin II (Ang-II), endothelin-1 (ET-1), or urotensin II (U-II) in inducing DNA synthesis in VSMCs. Growth-arrested VSMCs were incubated with different concentrations of native LDL, mox-LDL, or highly oxidized LDL (ox-LDL) with 5-HT, Ang-II, ET-1, or U-II in the absence or presence of N-acetylcysteine (NAC), an intracellular free radical scavenger. DNA synthesis in VSMCs was examined by [3H]thymidine incorporation into cellular DNA. Mox-LDL and ox-LDL stimulated [3H]thymidine incorporation with a maximal effect at 5 microg/ml (211%, 154%), which values were significantly greater than that for native LDL (128%). 5-HT, Ang-II, ET-1, or U-II also stimulated [3H]thymidine incorporation in a dose-dependent manner. 5-HT had a maximal stimulatory effect at a concentration of 50 micromol/l (205%), Ang-II at 1.75 micromol/l (202%), ET-1 at 0.1 micromol/l (205%), and U-II at 0.05 micromol/l (161%). When added together, mox-LDL (100 ng/ml)-induced [3H]thymidine incorporation was potentiated by low concentrations of 5-HT (1 micromol/l), Ang-II (0.5 micromol/l), ET-1 (1 nmol/l), or U-II (10 nmol/l) (114% to 330%, 325%, 338%, or 345%, respectively). Synergistic interactions of mox-LDL with 5-HT, Ang-II, ET-1, or U-II were significantly inhibited by NAC (400 micromol/l). Our results suggest that mild oxidation of LDL may enhance its atherogenic potential and exert a synergistic interaction with vasoactive agents in inducing DNA synthesis via the generation of reactive oxygen species in VSMCs.}, }
@article {pmid12040046, year = {2002}, author = {Park, SU and Ferrer, JV and Javitch, JA and Kuhn, DM}, title = {Peroxynitrite inactivates the human dopamine transporter by modification of cysteine 342: potential mechanism of neurotoxicity in dopamine neurons.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {22}, number = {11}, pages = {4399-4405}, pmid = {12040046}, issn = {1529-2401}, support = {DA06067/DA/NIDA NIH HHS/United States ; DA14942/DA/NIDA NIH HHS/United States ; K02 MH057324/MH/NIMH NIH HHS/United States ; R01 DA011495/DA/NIDA NIH HHS/United States ; F31 DA006067/DA/NIDA NIH HHS/United States ; MH57324/MH/NIMH NIH HHS/United States ; DA11495/DA/NIDA NIH HHS/United States ; DA10756/DA/NIDA NIH HHS/United States ; R01 DA010756/DA/NIDA NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology ; Biological Transport/drug effects ; Biotin/*analogs &amp; derivatives/pharmacology ; Cell Line ; Cysteine/*drug effects/metabolism ; Dopamine/*metabolism/pharmacokinetics ; Dopamine Plasma Membrane Transport Proteins ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Humans ; Kidney/cytology/drug effects/metabolism ; *Membrane Glycoproteins ; *Membrane Transport Modulators ; Membrane Transport Proteins/*antagonists &amp; inhibitors/genetics/metabolism ; Mutagenesis, Site-Directed ; *Nerve Tissue Proteins ; Neurons/*drug effects ; Neurotoxicity Syndromes/etiology ; Peroxynitrous Acid/metabolism/*pharmacology ; Structure-Activity Relationship ; Substrate Specificity ; Sulfhydryl Reagents/pharmacology ; Transfection ; }, abstract = {Peroxynitrite (ONOO(-)) has been implicated as a causative factor in dopamine neuronal damage resulting from exposure to methamphetamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and it may be involved in the etiology of Parkinson's Disease. ONOO(-) causes a concentration-dependent and irreversible reduction in dopamine uptake by EM4 cells stably expressing the human dopamine transporter (hDAT). The effect of ONOO(-) is manifested as a reduction in V(max). Cysteine, dithiothreitol, glutathione, and N-acetyl-cysteine, reagents that interact directly with ONOO(-), prevent this inhibition, whereas a scavenger of hydroxyl radical (dimethylsulfoxide), hydrogen peroxide (catalase), and superoxide (superoxide dismutase) did not. Dopamine in the extracellular medium protects the hDAT from ONOO(-), whereas intracellular dopamine does not. Parachloromercuribenzoic acid and 2-aminoethyl methanethiosulfonate (MTSEA), which share with ONOO(-) the ability to modify cysteine sulfhydryls, also inhibit hDAT function. ONOO(-) treatment lowers cysteine-specific labeling of the hDAT by MTSEA-biotin, suggesting that ONOO(-) reacts with one or more cysteines in hDAT. A mutant of hDAT (X7C) in which all intracellular and extracellular loop cysteines were mutated was resistant to inhibition by ONOO(-). Sensitivity to ONOO(-) was restored in mutants of hDAT in which reduced cysteines were present only in the first (C135) and third (C342) intracellular loops (CD-DAT), or in which C342 alone had been reintroduced into X7C (X7C-M342C). These results indicate that the hDAT is inhibited by ONOO(-) through oxidation of cysteine 342. Our studies also substantiate the possibility that drugs known to decrease DAT function in vivo (e.g., methamphetamine and MPTP) may exert their effects through ONOO(-)-mediated oxidative stress.}, }
@article {pmid12039859, year = {2002}, author = {Pias, EK and Aw, TY}, title = {Apoptosis in mitotic competent undifferentiated cells is induced by cellular redox imbalance independent of reactive oxygen species production.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {16}, number = {8}, pages = {781-790}, doi = {10.1096/fj.01-0784com}, pmid = {12039859}, issn = {1530-6860}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-09/DK/NIDDK NIH HHS/United States ; DK 44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*physiology ; Caspase 3 ; Caspases/drug effects/metabolism ; Cell Differentiation ; Cytochrome c Group/drug effects/metabolism ; Dehydroepiandrosterone/pharmacology ; Diamide/pharmacology ; Drug Synergism ; Enzyme Activation/drug effects ; Free Radical Scavengers/pharmacology ; Glucose/pharmacology ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Kinetics ; Mitosis/*physiology ; NADP/metabolism ; Oxidation-Reduction ; PC12 Cells ; Proto-Oncogene Proteins/drug effects/metabolism ; Proto-Oncogene Proteins c-bcl-2/drug effects/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; bcl-2-Associated X Protein ; }, abstract = {Oxidants are known to induce cell apoptosis. Because oxidants also elicit redox imbalance, it is difficult to distinguish the direct effects of cellular redox from that of oxidants. This study tests the hypothesis that induction of redox imbalance independent of reactive oxygen species (ROS), can induce cell apoptosis in a mitotic competent, undifferentiated cell line, PC-12. Cells grown in standard DMEM containing 25 mM glucose were treated with diamide, a thiol oxidant, at a concentration that did not generate ROS. Diamide caused a rapid increase in oxidized glutathione (GSSG) and a loss of mitochondrial cytochrome c in 15-30 min, caspase-3 activation in 2 h, and apoptosis in 24 h. N-Acetyl cysteine attenuated GSSG elevation and diamide-induced apoptosis. Incubation of cells in 5 mM glucose or inhibition of the pentose phosphate pathway maintained GSSG elevation and accelerated cell apoptosis. Collectively, these results show that loss of redox balance is an upstream event that kinetically preceded mitochondrial apoptotic signaling. A sustained redox change was not critical or necessary for apoptotic progression, but its prolongation exacerbated apoptotic death. The potentiation of apoptosis by sustained redox imbalance was correlated with decreases in NADPH supply for GSSG reduction.}, }
@article {pmid12031897, year = {2002}, author = {Zheng, X and Rivabene, R and Cavallari, C and Napolitano, M and Avella, M and Bravo, E and Botham, KM}, title = {The effects of chylomicron remnants enriched in n-3 or n-6 polyunsaturated fatty acids on the transcription of genes regulating their uptake and metabolism by the liver: influence of cellular oxidative state.}, journal = {Free radical biology &amp; medicine}, volume = {32}, number = {11}, pages = {1123-1131}, doi = {10.1016/s0891-5849(02)00830-4}, pmid = {12031897}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Chylomicrons/*pharmacology ; Copper Sulfate/pharmacology ; DNA Primers/chemistry ; Fatty Acids, Omega-3/*pharmacology ; Fatty Acids, Omega-6 ; Fatty Acids, Unsaturated/*pharmacology ; *Gene Expression Regulation ; Glutathione/metabolism ; Hepatocytes/drug effects ; Liver/*drug effects/metabolism ; Low Density Lipoprotein Receptor-Related Protein-1/*genetics/metabolism ; Male ; Oxidation-Reduction ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Receptors, Cytoplasmic and Nuclear/*genetics/metabolism ; Receptors, LDL/*genetics/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/*genetics/metabolism ; }, abstract = {The influence of chylomicron remnants enriched in n-6 or n-3 polyunsaturated fatty acids (PUFA) on the expression of mRNA for the low density lipoprotein receptor (LDLr), LDLr-related protein (LRP), and peroxisome proliferator activated receptor alpha (PPAR(alpha)) was investigated in normal hepatocytes and after manipulation of the cellular oxidative state by incubation with N-acetyl cysteine (NAC) or CuSO(4). In normal cells, mRNA levels for the LDLr were unaffected by incubation with chylomicron remnants, but those for the LRP and PPAR(alpha) were downregulated by remnants enriched in n-3 as compared to n-6 PUFA, suggesting that the transcription of these genes are influenced directly by the type of fatty acid delivered to the liver from the diet. Treatment with NAC or CuSO(4) was found to shift the hepatocytes into a pro-reducing or pro-oxidizing state, respectively. The abundance of mRNA for the LDLr, LRP, and PPAR(alpha) was increased after incubation with remnants enriched in n-3, but not n-6, PUFA in pro-reducing as compared to pro-oxidizing cells, and PPAR(alpha) mRNA levels were also decreased by remnants high in n-6 PUFA in the more reduced cells. These results indicate that the effects of fatty acids from the diet delivered to the liver in chylomicron remnants on the expression of hepatic genes regulating their uptake and metabolism are modulated by the redox state of the cells, and that the type of fatty acid carried by the particles also plays a part in determining the response observed.}, }
@article {pmid12031258, year = {2001}, author = {Woo Lee, Y and Joo Park, H and Hennig, B and Toborek, M}, title = {Linoleic acid induces MCP-1 gene expression in human microvascular endothelial cells through an oxidative mechanism.}, journal = {The Journal of nutritional biochemistry}, volume = {12}, number = {11}, pages = {648-654}, doi = {10.1016/s0955-2863(01)00186-3}, pmid = {12031258}, issn = {1873-4847}, support = {P42 ES007380/ES/NIEHS NIH HHS/United States ; }, abstract = {Linoleic acid is a dietary fatty acid that appears to play an important role in activation of the vascular endothelium under a variety of pathological conditions, including development of atherosclerosis or cancer metastasis. Evidence indicates that inflammatory responses may be an underlying cause of endothelial cell pathology induced by linoleic acid. However, the profile of inflammatory mediators and the potential mechanisms involved in inflammatory reactions stimulated by the exposure to linoleic acid are not fully understood. The present study focused on the mechanisms of linoleic acid-induced expression of monocyte chemoattractant protein-1 (MCP-1) gene in human microvascular endothelial cells (HMEC-1). Treatment of HMEC-1 with increasing doses of linoleic acid markedly activated an oxidative stress-responsive transcription factor, nuclear factor-kappaB (NF-kappaB). In addition, exposure to linoleic acid induced a time- and concentration-dependent overexpression of the MCP-1 gene. Increased MCP-1 mRNA levels were observed in HMEC-1 treated with linoleic acid at doses as low as 10 &amp;mgr;M. Linoleic acid-induced overexpression of the MCP-1 gene was associated with a significant elevation of MCP-1 protein levels. Most importantly, preexposure of HMEC-1 to antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), attenuated linoleic acid-induced MCP-1 mRNA expression. The obtained results indicate that linoleic acid triggers MCP-1 gene expression in human microvascular endothelial cells through oxidative stress/redox-related mechanisms.}, }
@article {pmid12030732, year = {2002}, author = {Behr, J and Degenkolb, B and Krombach, F and Vogelmeier, C}, title = {Intracellular glutathione and bronchoalveolar cells in fibrosing alveolitis: effects of N-acetylcysteine.}, journal = {The European respiratory journal}, volume = {19}, number = {5}, pages = {906-911}, doi = {10.1183/09031936.02.00204902}, pmid = {12030732}, issn = {0903-1936}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Adult ; Bronchoalveolar Lavage Fluid/*chemistry/cytology ; Female ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glutathione/*analysis/biosynthesis ; Humans ; Interleukin-8/analysis ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Peroxidase/analysis ; Prospective Studies ; Pulmonary Fibrosis/*physiopathology/*therapy ; }, abstract = {Extracellular glutathione deficiency and exaggerated oxidative stress may contribute to the pathogenesis of fibrosing alveolitis (FA). High-dose N-acetylcysteine (NAC) supplementation partially reverses extracellular glutathione depletion and oxidative damage, but effects on intracellular glutathione are unknown. Intracellular total glutathione (GSHt) and activation of bronchoalveolar lavage cells (BAC) obtained from 18 FA patients (9 males, aged 52+/-2 yrs), before and after 12 weeks of oral NAC (600 mg t.i.d.), were assessed. Eight healthy nonsmokers (2 males, aged 36+/-6 yrs) served as a control group. Intracellular GSHt was decreased in FA (1.57+/-0.20 nmol 1x10(6) BAC(-1) versus 2.78+/-0.43 nmol x 10(6) BAC(-1)). After NAC treatment, the intracellular GSHt content increased (1.57+/-0.20 versus 1.87+/-0.19 nmol x 1 x 10(6) BAC(-1)). The spontaneous oxidative activity of BAC decreased after NAC treatment (2.7+/-0.8 versus 1.0+/-0.2 nmol x 1 x 10(6) BAC(-1) x h(-1)). Interleukin-8 concentration (82.1+/-31.5 versus 80.0+/-22.6 pg x mL bronchoalveolar fluid (BALF), nonsignificant (NS)) and myeloperoxidase activity (1.93+/-0.64 versus 1.55+/-0.47 mU x mL(-1) BALF, NS) did not change significantly, but were found to be inversely correlated to intracellular GSHt. In conclusion, high-dose N-acetylcysteine supplementation increases intracellular glutathione levels slightly. This increase is associated with a mild reduction of oxidative activity but not with a reduction of bronchoalveolar cell activation in these patients.}, }
@article {pmid12028665, year = {2002}, author = {Scarfe, GB and Nicholson, JK and Lindon, JC and Wilson, ID and Taylor, S and Clayton, E and Wright, B}, title = {Identification of the urinary metabolites of 4-bromoaniline and 4-bromo-[carbonyl-13C]-acetanilide in rat.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {32}, number = {4}, pages = {325-337}, doi = {10.1080/00498250110079806}, pmid = {12028665}, issn = {0049-8254}, mesh = {Acetanilides/metabolism/*urine ; Aniline Compounds/metabolism/*urine ; Animals ; Carbon Isotopes/metabolism/*urine ; Chromatography, High Pressure Liquid ; Glucuronidase/metabolism ; Male ; Mass Spectrometry ; Nuclear Magnetic Resonance, Biomolecular ; Rats ; Rats, Sprague-Dawley ; }, abstract = {1. The urinary excretion of 4-bromoaniline and its [carbonyl-(13)C]-labelled N-acetanilide, together with their corresponding metabolites, have been investigated in the rat following i.p. administration at 50 mg kg(-1). 2. Metabolite profiling was performed by reversed-phase HPLC with UV detection, whilst identification was performed using a combination of enzymic hydrolysis and directly coupled HPLC-NMR-MS analysis. The urinary metabolite profile was quantitatively and qualitatively similar for both compounds with little of either excreted unchanged. 3. The major metabolite present in urine was 2-amino-5-bromophenylsulphate, but, in addition, a number of metabolites with modification of the N-acetyl moiety were identified (from both the [(13)C]-acetanilide or produced following acetylation of the free bromoaniline). 4. For 4-bromoacetanilide, N-deacetylation was a major route of metabolism, but despite the detection of the acetanilide following the administration of the free aniline, there was no evidence of reacetylation (futile deacetylation). 5. Metabolites resulting from the oxidation of the acetyl group included a novel glucuronide of an N-glycolanilide, an unusual N-oxanilic acid and a novel N-acetyl cysteine conjugate.}, }
@article {pmid12027535, year = {2002}, author = {Ayache, N and Boumediene, K and Mathy-Hartert, M and Reginster, JY and Henrotin, Y and Pujol, JP}, title = {Expression of TGF-betas and their receptors is differentially modulated by reactive oxygen species and nitric oxide in human articular chondrocytes.}, journal = {Osteoarthritis and cartilage}, volume = {10}, number = {5}, pages = {344-352}, doi = {10.1053/joca.2001.0499}, pmid = {12027535}, issn = {1063-4584}, mesh = {Acetylcysteine/pharmacology ; Cartilage, Articular/metabolism ; Cells, Cultured ; Chondrocytes/*metabolism ; Female ; Humans ; Lipopolysaccharides/pharmacology ; Male ; Middle Aged ; Nitric Oxide/biosynthesis/*physiology ; Osteoarthritis, Knee/*metabolism/pathology ; RNA, Messenger/genetics ; Reactive Oxygen Species/*metabolism ; Receptors, Transforming Growth Factor beta/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transforming Growth Factor beta/genetics/*metabolism ; Up-Regulation/drug effects/physiology ; omega-N-Methylarginine/pharmacology ; }, abstract = {OBJECTIVES: To study the effects exerted by two antioxidants, N-monomethyl-L-arginine (L-NMMA), as an inhibitor of nitric oxide (NO) synthesis, and N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, on the expression of the major growth factor involved in cartilage repair, TGF-beta, under the three isoforms beta1, beta2 and beta3, and the receptors I and II of this factor, using lipopolysaccharide (LPS)-treated human chondrocytes in culture.<br><br>METHODS: Suspension cultures of human chondrocytes derived from the knee of osteoarthritic patients were treated for 48 h with lipopolysaccharide (LPS) (10 microg/ml), L-NMMA (0.5 mM) or NAC (1 mM). Nitrite levels were assayed on the culture media using the Griess spectrophotometric method. After total RNA extraction, the expression of inducible NO synthase (iNOS), TGF-beta1, TGF-beta2, TGF-beta3, TGF-beta receptors I and II, was determined by semi-quantitative polymerase chain-reaction (RT-PCR).<br><br>RESULTS: LPS induced a dramatic increase of both NO production and iNOS mRNA level. The addition of L-NMMA (0.5 mM) abolished NO production without affecting iNOS mRNA levels. In contrast NAC (1 mM) strongly synergized with LPS to stimulate NO synthesis. LPS treatment did not significantly alter TGF-beta1 expression whereas L-NMMA inhibited its production. TGF-beta2 mRNA level was decreased by LPS and was not changed in the presence of L-NMMA. On the other hand, NAC was capable of counteracting the LPS-induced inhibition of TGF-beta2 expression. TGFbeta3 mRNA level was markedly reduced by LPS alone, or with both L-NMMA and NAC. Finally, the expression of TGF-betaRI was slightly increased in the presence of combined LPS and L-NMMA or NAC whereas that of TGFbeta-RII was reduced in the same conditions.<br><br>CONCLUSIONS: The modulation of TGF-beta system was found to be differentially controlled by NO and ROS productions. Indeed, the control exerted on TGF-beta expression varied according to the isoform: TGF-beta1 mRNA level depends on NO whereas that of TGF-beta2 is regulated by ROS and TGF-beta3 seems to be unaffected by both of them. The expression of TGF-beta receptors appeared to be modulated by NO and ROS levels. The relevance of the present findings to osteoarthritis (OA) physiopathology and the potential use of antioxidant therapy to treat this disease are discussed.}, }
@article {pmid12023963, year = {2002}, author = {Xu, YC and Wu, RF and Gu, Y and Yang, YS and Yang, MC and Nwariaku, FE and Terada, LS}, title = {Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase.}, journal = {The Journal of biological chemistry}, volume = {277}, number = {31}, pages = {28051-28057}, doi = {10.1074/jbc.M202665200}, pmid = {12023963}, issn = {0021-9258}, support = {R01 HL061897/HL/NHLBI NIH HHS/United States ; R01-HL61897/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Binding Sites ; Cloning, Molecular ; DNA, Complementary ; Endothelium, Vascular/*physiology ; Enzyme Activation ; Gene Library ; Humans ; JNK Mitogen-Activated Protein Kinases ; Lung ; Mitogen-Activated Protein Kinases/*metabolism ; NADPH Oxidases/metabolism ; Oxidation-Reduction ; Phosphoproteins/metabolism ; Proteins/*metabolism ; Receptors, Tumor Necrosis Factor/physiology ; Recombinant Fusion Proteins/metabolism ; Recombinant Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; TNF Receptor-Associated Factor 4 ; Transfection ; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ; beta-Galactosidase/genetics ; }, abstract = {We previously found that the angiogenic factors TNFalpha and HIV-1 Tat activate an NAD(P)H oxidase in endothelial cells, which operates upstream of c-Jun N-terminal kinase (JNK), a MAPK involved in the determination of cell fate. To further understand oxidant-related signaling pathways, we screened lung and endothelial cell libraries for interaction partners of p47(phox) and recovered the orphan adapter TNF receptor-associated factor 4 (TRAF4). Domain analysis suggested a tail-to-tail interaction between the C terminus of p47(phox) and the conserved TRAF domain of TRAF4. In addition, TRAF4, like p47(phox), was recovered largely in the cytoskeleton/membrane fraction. Coexpression of p47(phox) and TRAF4 increased oxidant production and JNK activation, whereas each alone had minimal effect. In addition, a fusion between p47(phox) and the TRAF4 C terminus constitutively activated JNK, and this activation was decreased by the antioxidant N-acetyl cysteine. In contrast, overexpression of the p47(phox) binding domain of TRAF4 blocked endothelial cell JNK activation by TNFalpha and HIV-1 Tat, suggesting an uncoupling of p47(phox) from upstream signaling events. A secondary screen of endothelial cell proteins for TRAF4-interacting partners yielded a number of proteins known to control cell fate. We conclude that endothelial cell agonists such as TNFalpha and HIV-1 Tat initiate signals that enter basic signaling cassettes at the level of TRAF4 and an NAD(P)H oxidase. We speculate that endothelial cells may target endogenous oxidant production to specific sites critical to cytokine signaling as a mechanism for increasing signal specificity and decreasing toxicity of these reactive species.}, }
@article {pmid12019068, year = {2002}, author = {Lupetti, A and Paulusma-Annema, A and Senesi, S and Campa, M and Van Dissel, JT and Nibbering, PH}, title = {Internal thiols and reactive oxygen species in candidacidal activity exerted by an N-terminal peptide of human lactoferrin.}, journal = {Antimicrobial agents and chemotherapy}, volume = {46}, number = {6}, pages = {1634-1639}, pmid = {12019068}, issn = {0066-4804}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism/pharmacology ; Candida albicans/*drug effects/*metabolism ; Colony Count, Microbial ; Diamide/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Lactoferrin/*pharmacology ; Luminescent Measurements ; Microbial Sensitivity Tests ; Mitochondria/drug effects/metabolism ; Peptide Fragments/*pharmacology ; Peptides/pharmacology ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/*metabolism ; Sulfhydryl Reagents/pharmacology ; }, abstract = {We previously showed that the energized mitochondrion and extracellular ATP are essential for the candidacidal activity of the N-terminal peptide of human lactoferrin, subsequently referred to as hLF(1-11). The present study focuses on the involvement of internal thiols and reactive oxygen species (ROS) in the candidacidal activity exerted by hLF(1-11). Our results reveal that hLF(1-11) reduced the internal thiol level of Candida albicans by 20%. In agreement, N-acetyl-L-cysteine (NAC), which is a precursor of glutathione and an ROS scavenger, inhibited the candidacidal activity of hLF(1-11). In addition, azodicarboxylic acid bis(N,N-dimethylamide) (diamide), which oxidizes internal thiols, was candidacidal. Furthermore, hLF(1-11) increased the level of ROS production by C. albicans in a dose-dependent manner, and a correlation between ROS production and candidacidal activity was found. 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox), which is an ROS scavenger, partially inhibited the hLF(1-11)-induced, but not the diamide-triggered, candidacidal activity. It is of interest that hLF(1-11) and diamide acted synergistically in killing C. albicans and in ROS production. In agreement, oxidized ATP, an irreversible inhibitor of extracellular ATP receptors, partially blocked the hLF(1-11)-induced, but not the diamide-triggered, candidacidal activity. Finally, the hLF(1-11)-induced activation of mitochondria was inhibited by NAC, indicating that internal thiols and ROS affect mitochondrial activity. Therefore, the candidacidal activity of hLF(1-11) involves both generation of ROS and reduction of internal thiols.}, }
@article {pmid12017280, year = {2002}, author = {Hitosugi, N and Ohno, R and Hatsukari, I and Nakamura, S and Mizukami, S and Nagasaka, H and Matsumoto, I and Satoh, K and Negoro, T and Hashimoto, K and Sakagami, H}, title = {Induction of cell death by pro-oxidant action of Moxa smoke.}, journal = {Anticancer research}, volume = {22}, number = {1A}, pages = {159-163}, pmid = {12017280}, issn = {0250-7005}, mesh = {Acetylcysteine/pharmacology ; Carcinoma, Squamous Cell/metabolism/therapy ; Cell Death/drug effects ; Cell Survival/drug effects ; Free Radicals/metabolism ; HL-60 Cells/drug effects/metabolism ; Humans ; Mammary Neoplasms, Animal/metabolism/therapy ; Mitochondria/drug effects ; *Moxibustion ; Reactive Oxygen Species/*pharmacology ; Salivary Gland Neoplasms/metabolism/therapy ; Smoke ; Superoxide Dismutase/metabolism ; Tumor Cells, Cultured ; }, abstract = {Moxa smoke induced internucleosomal DNA fragmentation in human promyelocytic leukemic HL-60 cells, but not in other cell lines. The cytotoxic activity of Moxa smoke was significantly reduced by a popular antioxidant, N-acetyl-L-cysteine (NAC). Moxa smoke showed oxidation potential (measured by NO monitor) and produced carbon radical (measured by ESR spectroscopy). The addition of NAC significantly reduced both the oxidation potential and carbon radical intensity of Moxa smoke. Activity staining of polyacryamide gel electrophoresis of MnSOD revealed the possible modification of the conformation and/or activity of this enzyme at an early stage of HL-60 cell death. These data suggest that Moxa smoke induces cytotoxicity by its pro-oxidant action.}, }
@article {pmid12017214, year = {2002}, author = {Küçükardali, Y and Cinan, U and Acar, HV and Ozkan, S and Top, C and Nalbant, S and Cermik, H and Cankir, Z and Danaci, M}, title = {Comparison of the therapeutic efficacy of 4-methylpyrazole and N-acetylcysteine on acetaminophen (paracetamol) hepatotoxicity in rats.}, journal = {Current medical research and opinion}, volume = {18}, number = {2}, pages = {78-81}, doi = {10.1185/030079902125000336}, pmid = {12017214}, issn = {0300-7995}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Alcohol Dehydrogenase/*antagonists &amp; inhibitors ; Analgesics, Non-Narcotic/*toxicity ; Animals ; Antidotes/administration &amp; dosage/*therapeutic use ; Drug Therapy, Combination ; Fomepizole ; Liver/*drug effects/pathology ; Male ; Necrosis ; Pyrazoles/administration &amp; dosage/*therapeutic use ; Rats ; Rats, Wistar ; Transaminases/blood ; }, abstract = {Obtaining effective analgesia with a minimal erosive effect on gastric mucosal tissue has increased the consumption of acetaminophen (paracetamol), especially among the elderly. However, the hepatotoxic effects of acetaminophen have also increased. We aimed to compare the effects of 4-methylpyrazole (4-MP), N-acetylcysteine (NAC) and their combined use on the hepatotoxicity of acetaminophen in a rat model. Male Wistar Albino rats were divided into six groups. Groups 1-5 received 2,000 mg/kg acetaminophen by gavage while the control group was group 6. Group 2 animals were given NAC (loading dose 140 mg/kg followed by seven doses at 4 h intervals); group 3 received 50 mg/kg 4-MP; group 4 received 200mg/kg 4-MP; and group 5 received NAC as in group 2 plus 200 mg/kg 4-MP. Blood samples were taken for measurements of serum AST and ALT levels. The livers of the rats were removed for microscopic examination and grading of hepatic necrosis. AST and ALT levels in groups 2-5 were lower than that of group 1 (p < 0.001), although no significant difference was noted between groups 2-5 (p > 0.05). Higher levels of ALT were found in group 5 than in group 2 (p < 0.05), and higher levels of AST were found in group 5 than in group 3 (p < 0.01). Median necrosis scores were 3.36 for rats receiving acetaminophen alone (p < 0.001, compared with groups 2-6), 1.45-1.81 for groups 2-5 (p > 0.05, compared with each other), and 0.18 for control rats (p < 0.001, compared with groups 1-5). In conclusion, the administration of 4-MP and/or NAC after 4 h of administering toxic dose of acetaminophen, inhibits hepatotoxicity in rats. There was no difference between the 4-MP and NAC-treated groups as reflected by comparable levels of serum transaminases and the degree of hepatic necrosis. Combining of 4-MP and NAC offers no benefit.}, }
@article {pmid12020599, year = {2002}, author = {Hammond, AH and Garle, MJ and Sooriakumaran, P and Fry, JR}, title = {Modulation of hepatocyte thiol content by medium composition: implications for toxicity studies.}, journal = {Toxicology in vitro : an international journal published in association with BIBRA}, volume = {16}, number = {3}, pages = {259-265}, doi = {10.1016/s0887-2333(02)00008-5}, pmid = {12020599}, issn = {0887-2333}, mesh = {Acetone/*analogs &amp; derivatives/toxicity ; Amino Acids, Sulfur/analysis/pharmacology ; Animals ; Cell Culture Techniques/*methods ; Cell Survival/drug effects ; Culture Media/chemistry ; Dose-Response Relationship, Drug ; Drug Combinations ; Glutathione/*metabolism ; Hepatocytes/drug effects/*metabolism/pathology ; Male ; Maleates/toxicity ; Propanols/toxicity ; Rats ; Rats, Wistar ; Toxicity Tests/*methods ; alpha-Chlorohydrin/*analogs &amp; derivatives/toxicity ; }, abstract = {Toxicity of compounds requiring glutathione for detoxification, thiol content and synthesis were determined in 24-h rat hepatocytes cultured in medium containing different concentrations of the sulphur amino acids. Glutathione synthesis was determined following prior depletion of glutathione with diethylmaleate. L-15 medium, which has high levels of cysteine and methionine (1 mM of each), provided some protection against dichloroacetone, dibromopropanol and dichloropropanol toxicity, and had a small effect on increasing glutathione content and synthesis, relative to Williams' medium E (WE) which has low levels (less than 0.5 mM) of both amino acids. However, WE containing N-acetylcysteine (NAC) (1 mM final cysteine concentration), with or without methionine (final concentration 1 mM), was a better cytoprotectant medium than L-15, markedly reducing toxicity of all three compounds, and rapidly (within 1.5 h) increasing cellular glutathione content. WE supplemented with methionine alone stimulated glutathione synthesis after an initial lag phase, and protected cultures against dichloropropanol, but not dibromopropanol or dichloroacetone, both of which are highly reactive in these cultures. There was a clear association between glutathione content at early time points in culture and toxicity observed at later time points, and overall these results indicate that differences in culture medium composition can alter intracellular glutathione content and xenobiotic toxicity.}, }
@article {pmid12006386, year = {2002}, author = {Yamakawa, T and Tanaka, S and Yamakawa, Y and Kamei, J and Numaguchi, K and Motley, ED and Inagami, T and Eguchi, S}, title = {Lysophosphatidylcholine activates extracellular signal-regulated kinases 1/2 through reactive oxygen species in rat vascular smooth muscle cells.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {22}, number = {5}, pages = {752-758}, doi = {10.1161/01.atv.0000015903.02749.71}, pmid = {12006386}, issn = {1524-4636}, support = {DK20593/DK/NIDDK NIH HHS/United States ; HL03320/HL/NHLBI NIH HHS/United States ; HL58205/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Cell Line ; Cells, Cultured ; Enzyme Activation/drug effects ; Hydrogen Peroxide/pharmacology ; Lysophosphatidylcholines/antagonists &amp; inhibitors/*metabolism ; MAP Kinase Signaling System/physiology ; Mitogen-Activated Protein Kinases/*metabolism ; Muscle, Smooth, Vascular/cytology/*enzymology ; NADPH Oxidases/antagonists &amp; inhibitors/physiology ; Onium Compounds/pharmacology ; Phosphorylation/drug effects ; Protein Kinase C/metabolism ; Proto-Oncogene Proteins c-fos/biosynthesis ; Proto-Oncogene Proteins c-raf/metabolism ; Proto-Oncogene Proteins p21(ras)/metabolism ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Transcription Factor AP-1/metabolism ; }, abstract = {Lysophosphatidylcholine (lysoPC) acts on vascular smooth muscle cells (VSMCs) to produce a mitogenic response through the activation of extracellular signal-regulated kinases 1/2 (ERK1/2). In the present study, we examined the importance of reactive oxygen species (ROS) in lysoPC-stimulated ERK1/2 activation in cultured rat VSMCs. Treatment with lysoPC for 3 minutes caused a 2-fold increase in intracellular ROS that was blocked by the NADH/NADPH oxidase inhibitor, diphenylene iodonium (DPI). Antioxidants, N-acetyl-L-cysteine, glutathione monoester, or alpha -tocopherol, inhibited ERK1/2 activation by lysoPC. Almost identical results were obtained in the VSMC line A10. Pretreatment of VSMCs with DPI but not allopurinol or potassium cyanide (KCN) abrogated the activation of ERK1/2. The Flag-tagged p47phox expressed in A10 cells was translocated from the cytosol to the membrane after 2 minutes of stimulation with lysoPC. The overexpression of dominant-negative p47phox in A10 cells suppressed lysoPC-induced ERK activation. The ROS-dependent ERK activation by lysoPC seems to involve protein kinase C- and Ras-dependent raf-1 activation. Induction of c-fos expression and enhanced AP-1 binding activity by lysoPC were also inhibited by DPI and NAC. Taken together, these data suggest that ROS generated by NADH/NADPH oxidase contribute to lysoPC-induced activation of ERK1/2 and subsequent growth promotion in VSMCs.}, }
@article {pmid12003792, year = {2002}, author = {Day, RM and Suzuki, YJ and Lum, JM and White, AC and Fanburg, BL}, title = {Bleomycin upregulates expression of gamma-glutamylcysteine synthetase in pulmonary artery endothelial cells.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {282}, number = {6}, pages = {L1349-57}, doi = {10.1152/ajplung.00338.2001}, pmid = {12003792}, issn = {1040-0605}, support = {HL-42376/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antimetabolites, Antineoplastic/pharmacology ; Bleomycin/*pharmacology ; Cattle ; Cells, Cultured ; DNA/metabolism ; DNA-Binding Proteins/metabolism ; Electrophoretic Mobility Shift Assay ; Endothelium, Vascular/cytology/*drug effects/*enzymology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; GA-Binding Protein Transcription Factor ; Glutamate-Cysteine Ligase/genetics/*metabolism ; Glutathione/metabolism ; NF-E2-Related Factor 1 ; NF-kappa B/metabolism ; Nuclear Respiratory Factors ; Proto-Oncogene Proteins c-fos/metabolism ; Proto-Oncogene Proteins c-jun/metabolism ; Pulmonary Artery/cytology/*drug effects/*enzymology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/antagonists &amp; inhibitors/metabolism ; Trans-Activators/metabolism ; Transcription Factors/metabolism ; Up-Regulation/drug effects ; }, abstract = {The chemotherapeutic agent bleomycin induces pulmonary fibrosis through the generation of reactive oxygen species (ROS), which are thought to contribute to cellular damage and pulmonary injury. We hypothesized that bleomycin activates oxidative stress response pathways and regulates cellular glutathione (GSH). Bovine pulmonary artery endothelial cells exposed to bleomycin exhibit growth arrest and increased cellular GSH content. gamma-Glutamylcysteine synthetase (gamma-GCS) controls the key regulatory step in GSH synthesis, and Northern blots indicate that the gamma-GCS catalytic subunit [gamma-GCS heavy chain (gamma-GCS(h))] is upregulated by bleomycin within 3 h. The promoter for human gamma-GCS(h) contains consensus sites for nuclear factor-kappaB (NF-kappaB) and the antioxidant response element (ARE), both of which are activated in response to oxidative stress. Electrophoretic mobility shift assays show that bleomycin activates the transcription factor NF-kappaB as well as the ARE-binding factors Nrf-1 and -2. Nrf-1 and -2 activation by bleomycin is inhibited by the ROS quenching agent N-acetylcysteine (NAC), but not by U-0126, a MEK1/2 inhibitor that blocks bleomycin-induced MAPK activation. In contrast, NF-kappaB activation by bleomycin is inhibited by U-0126, but not by NAC. NAC and U-0126 both inhibit bleomycin-induced upregulation of gamma-GCS expression. These data suggest that bleomycin can activate oxidative stress response pathways and upregulate cellular GSH.}, }
@article {pmid12003789, year = {2002}, author = {Kulisz, A and Chen, N and Chandel, NS and Shao, Z and Schumacker, PT}, title = {Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {282}, number = {6}, pages = {L1324-9}, doi = {10.1152/ajplung.00326.2001}, pmid = {12003789}, issn = {1040-0605}, support = {HL-32646/HL/NHLBI NIH HHS/United States ; HL-35440/HL/NHLBI NIH HHS/United States ; HL-66315/HL/NHLBI NIH HHS/United States ; }, mesh = {4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology ; Animals ; Antifungal Agents/pharmacology ; Antioxidants/pharmacology ; Azides/pharmacology ; Cell Hypoxia/drug effects/*physiology ; Cell Respiration/drug effects/physiology ; Cell Separation ; Cells, Cultured ; Chelating Agents/pharmacology ; Chick Embryo ; Diffusion Chambers, Culture ; Enzyme Inhibitors/pharmacology ; Mitochondria, Heart/drug effects/*metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Myocardium/cytology/*metabolism ; Oxidants/pharmacology ; Phosphorylation/drug effects ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Uncoupling Agents/pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {The p38 mitogen-activated protein kinase (MAPK) is phosphorylated in response to oxidative stress. Mitochondria in cardiomyocytes increase their generation of reactive oxygen species (ROS) during hypoxia (1-5% O(2)). These ROS participate in signal transduction pathways involved in adaptive responses, including ischemic preconditioning and gene transcription. The present study therefore tested the hypothesis that hypoxia induces p38 MAPK phosphorylation by augmenting mitochondrial ROS generation. In cardiomyocytes, phosphorylation of p38 was observed in a PO(2)-dependent manner during hypoxia. This response was inhibited by rotenone, thenoyltrifluoroacetone, and myxothiazol, inhibitors of mitochondrial complexes I, II, and III, respectively. A similar inhibition was observed in the cells pretreated with anion channel inhibitor DIDS, which may block ROS release from mitochondria. During normoxia, increases in mitochondrial ROS elicited by azide (1-2 mM) or by the mitochondrial inhibitor antimycin A caused increased phosphorylation of p38. Brief treatment with exogenous H(2)O(2) during normoxia also induced phosphorylation of p38 as hypoxia, but this effect was not abolished by myxothiazol or DIDS. The antioxidant N-acetyl-cysteine abolished the p38 response to hypoxia, presumably by scavenging H(2)O(2), but the mitogen extracellular receptor kinase inhibitor PD-98059 did not inhibit p38 phosphorylation during hypoxia. Thus physiological hypoxia leads to p38 phosphorylation through a mechanism that requires electron flux in the proximal region of the mitochondrial electron transport chain, which suggests that either H(2)O(2) or superoxide participates in activating that process.}, }
@article {pmid11999763, year = {2002}, author = {Mengerink, Y and Kutlán, D and Tóth, F and Csámpai, A and Molnár-Perl, I}, title = {Advances in the evaluation of the stability and characteristics of the amino acid and amine derivatives obtained with the o-phthaldialdehyde/3-mercaptopropionic acid and o-phthaldialdehyde/N-acetyl-L-cysteine reagents. High-performance liquid chromatography-mass spectrometry study.}, journal = {Journal of chromatography. A}, volume = {949}, number = {1-2}, pages = {99-124}, doi = {10.1016/s0021-9673(01)01282-1}, pmid = {11999763}, issn = {0021-9673}, mesh = {3-Mercaptopropionic Acid/*chemistry ; Acetylcysteine/*chemistry ; Chromatography, High Pressure Liquid/*methods ; Indicators and Reagents/*chemistry ; Spectrometry, Mass, Electrospray Ionization/*methods ; Spectrophotometry, Ultraviolet ; o-Phthalaldehyde/*chemistry ; }, abstract = {The composition of the amino acid and amine derivatives obtained with the o-phthaldialdehyde (OPA)/3-mercaptopropionic acid (MPA) and with the OPA/N-acetyl-L-cysteine (NAC) reagents was investigated by on-line HPLC-electrospray ionization MS. The initially formed derivatives proved to be, as expected, the corresponding isoindoles while their transformed species contained one additional OPA molecule. Based on the MS spectra of all transformed OPA derivatives a reaction pathway is suggested. This reaction mechanism was supported both by the molecular ions of the endproducts and by the presence of several selective fragment ions that served as an explanation to the structure of the believed to be less stable OPA derivatives. It has been shown that more than one OPA derivative forms in all those cases when the compound to be derivatized does contain the NH2-CH2-R moiety. Thus, amino acids like e.g. glycine, histidine, beta-alanine, gamma-aminobutyric acid, epsilon-aminocaproic acid, ornithine, and also several aliphatic mono- and diamines provide more than one OPA derivative. Analytical consequences of this experience were utilized by altering the reagent's composition. Reagents containing mole ratios of [OPA]/[MPA] or [OPA]/[NAC]=1/50 resulted in two benefits, simultaneously: (i) in a decrease of the transformation rate of the initially formed derivative, and, (ii) in an increase of the overall stability of the total of derivatives.}, }
@article {pmid11999740, year = {2002}, author = {Kutlán, D and Presits, P and Molnár-Perl, I}, title = {Behavior and characteristics of amine derivatives obtained with o-phthaldialdehyde/3-mercaptopropionic acid and with o-phthaldialdehyde/N-acetyl-L-cysteine reagents.}, journal = {Journal of chromatography. A}, volume = {949}, number = {1-2}, pages = {235-248}, doi = {10.1016/s0021-9673(01)01610-7}, pmid = {11999740}, issn = {0021-9673}, mesh = {3-Mercaptopropionic Acid/*chemistry ; Acetylcysteine/*chemistry ; Amines/*chemistry ; Chromatography, High Pressure Liquid/methods ; Indicators and Reagents/*chemistry ; Mass Spectrometry ; o-Phthalaldehyde/*chemistry ; }, abstract = {A comprehensive evaluation of papers dealing with the HPLC quantitation of amines as o-phthaldialdehyde (OPA) derivatives has been given and discussed in details. The stability and characteristics of selected representatives of mono [methyl-, ethyl-, n-/isopropyl, n-/isobutyl-, tert.-butyl-, sec.-butyl-, isoamyl amines and ethanolamine), di- and polyamines (ethylenediamine, 1,2-propylenediamine, 1,3-propylenediamine, agmatine, tyramine, putrescine, cadaverine, histamine, spermine, spermidine, and bis(hexamethylene)triamine] have been investigated as their OPA/3-mercaptopropionic acid (MPA) and OPA/N-acetyl-L-cysteine (NAC) derivatives, from an analytical point of view, performing photodiode array and fluorescence detection, simultaneously. All amines having in their original structure the NH2-CH2-R moiety, in accord with the amino acids of the same structure, furnished more than one OPA derivative: their initially formed species transformed to further ones. On the basis of on-line HPLC-MS the transformed derivatives were proved to be the corresponding isoindoles that contain an additional OPA molecule. In order to achieve optimum analytical conditions derivatization reagents have been applied in different composition, in parallel. The OPA and the SH-group additive contents of the reagents have been varied in the mole ratios of OPA/MPA(NAC)=1:3 and OPA/MPA(NAC)=1:50. Data obtained proved that performing derivatizations by means of the OPA/MPA(NAC)=1:50 reagents resulted in two benefits: both the stability of derivatives could have been increased and the number of the transformed derivatives decreased. In case of aliphatic amines and in ethanolamine, the transformation of the initially formed derivative can be either quantitatively avoided as in the case of ethanolamine, or considerably decreased, below 1%, as in the cases of the other aliphatic monoamines investigated. As to the behavior of di- and polyamines the stability of derivatives has been considerably improved, the number of species have been decreased from four to two with the exception of spermidine. Stability values characterized both by the UV and fluorescence responses, as a function of the reaction time (from 90 s up to 6 h) have been given in details.}, }
@article {pmid11999701, year = {2002}, author = {Victor, VM and De la Fuente, M}, title = {N-acetylcysteine improves in vitro the function of macrophages from mice with endotoxin-induced oxidative stress.}, journal = {Free radical research}, volume = {36}, number = {1}, pages = {33-45}, doi = {10.1080/10715760210160}, pmid = {11999701}, issn = {1071-5762}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anions ; Antioxidants/pharmacology ; Blotting, Western ; Cell Adhesion ; Dose-Response Relationship, Drug ; Endotoxins/*pharmacology ; Escherichia coli/metabolism ; Female ; Free Radical Scavengers/pharmacology ; Free Radicals ; Lipopolysaccharides/metabolism ; Macrophages/*drug effects/metabolism ; Mice ; Mice, Inbred BALB C ; Oxidative Stress ; Phagocytosis ; Reactive Oxygen Species ; Superoxides ; Time Factors ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Reactive oxygen species (ROS) and proinflammatory cytokines produced by immune cells cause the oxidative stress involved in septic shock induced by endotoxin. This oxidative stress can be controlled to a certain degree by antioxidants, which is specially important for a type of immune cell, i.e. the phagocyte, that uses ROS to kill microorganisms and needs antioxidants in order to support its functions. In a previous study we have observed changes in several functions of peritoneal macrophages from BALB/c mice with lethal endotoxic shock caused by intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS) (100 mg/kg), which were associated with a high production of superoxide anion. N-acetylcysteine (NAC) is a thiolic antioxidant that improves the immune response, and we have observed that when administered intraperitoneally (150 mg/kg) at 30 min after LPS injection it counteracts the effects of LPS on macrophages and lymphocytes. In the present work, we have studied the in vitro effect of several concentrations of NAC (0.001, 0.01, 0.1, 1 and 2.5 mM) on the following functions: adherence to substrate, chemotaxis, ingestion of particles, ROS production and the release of tumor necrosis factor (TNFalpha) of peritoneal macrophages from BALB/c mice at 2, 4,12 and 24 h after LPS injection. The results show that the administration of NAC (especially at 0.1 mM) decreases raised adherence, ingestion, ROS production and TNFalpha levels in macrophages from animals injected with LPS, bringing these functions to values near those of control animals. These effects which seem to be linked to a modulation of NF-kappaB, suggest that the improvement of immune functions observed in previous work after injection of NAC to animals with endotoxic shock could be due to a direct action of this thiol antioxidant on immune cells.}, }
@article {pmid11999379, year = {2002}, author = {De La Fuente, M and Miquel, J and Catalán, MP and Víctor, VM and Guayerbas, N}, title = {The amount of thiolic antioxidant ingestion needed to improve several immune functions is higher in aged than in adult mice.}, journal = {Free radical research}, volume = {36}, number = {2}, pages = {119-126}, doi = {10.1080/10715760290006439}, pmid = {11999379}, issn = {1071-5762}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Aging/*immunology ; Animals ; Antioxidants/*administration &amp; dosage/*pharmacology ; Cell Adhesion/drug effects ; Chemotaxis, Leukocyte/drug effects ; Diet ; Dose-Response Relationship, Drug ; Female ; Leukocytes/drug effects/immunology ; Lymphocytes/drug effects/immunology ; Mice ; Phagocytosis/drug effects ; Sulfhydryl Compounds/*administration &amp; dosage/*pharmacology ; Superoxides/metabolism ; Thiazoles/administration &amp; dosage/pharmacology ; Thiazolidines ; }, abstract = {With aging there is an increase of oxidative stress due to an imbalance between the oxidant production and the antioxidant levels in favor of the former. Since immune cell functions are specially linked to reactive oxygen species (ROS) generation, the oxidant/antioxidant balance is essential for these cells. Although low levels of antioxidants cause a decrease in immune function, very high levels of antioxidant compounds could show prooxidant effects. In the present work, we have studied the effect of diet supplementation, for 4 weeks, with two different doses of two thiolic antioxidants, namely thioproline (TP) and N-acetylcysteine (NAC), at 0.1% (w/w) and 0.3% (w/w, of each antioxidant) on the main immune system cells, i.e.: macrophages, lymphocytes and natural killer (NK) cells of adult (33+/-1 week old) and aged (75+/-1 week old) female Swiss mice. Two groups of animals, adult and aged mice, fed standard diet were used as controls. The results show that the ingestion of 0.1% doses of thiols improves, in the adult mice, several immune functions such as the chemotaxis capacity of both macrophages and lymphocytes, the phagocytosis of macrophages, the lymphoproliferative response to the mitogen Con A and the NK activity. Moreover, no change was observed in adherence capacity of immune cells, and superoxide production was decreased. By contrast, in aged mice the ingestion of these amounts of antioxidants did not change the immune functions studied with the exception of NK activity, which was stimulated. The ingestion of 0.3% of antioxidants by adult mice only increased some immune functions such as adherence and superoxide production, which are markers of oxidative stress. Other functions such as chemotaxis or lymphoproliferative response decreased. However, the ingestion of these very high amounts of thiols by aged animals increased the phagocytosis, the NK activity and specially the lymphoproliferative response to the mitogen, a function that is very depressed with aging.}, }
@article {pmid11995811, year = {2002}, author = {Kuruganti, PA and Wurster, RD and Lucchesi, PA}, title = {Mitogen activated protein kinase activation and oxidant signaling in astrocytoma cells.}, journal = {Journal of neuro-oncology}, volume = {56}, number = {2}, pages = {109-117}, pmid = {11995811}, issn = {0167-594X}, support = {HL03282/HL/NHLBI NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology ; Astrocytoma/*metabolism ; Central Nervous System Neoplasms/*metabolism ; Cystine/*analogs &amp; derivatives/pharmacology ; DNA/biosynthesis ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacokinetics ; Humans ; Hydrogen Peroxide/*pharmacology ; Mitogen-Activated Protein Kinase 1/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Oxidants/antagonists &amp; inhibitors/*pharmacology ; *Signal Transduction ; Tumor Cells, Cultured ; }, abstract = {Presence of increased reactive oxygen species (ROS) has been observed in most high risk factors for brain tumor development. Our past study demonstrated that ROS could induce increased brain tumor cell proliferation. Growth effects of ROS may involve modifications of cellular proteins such as mitogen-activated protein kinases (MAPKs), which regulate cell proliferation. Here, we report effects of a ROS (hydrogen peroxide, H2O2) and an antioxidant (N-acetylcysteine, NAC) on MAPK activation in astrocytoma (U373-MG) cells. MAPKs are activated by phosphorylation that can be detected by Western blot analysis. The unphosphorylated/inactivated form of MAPK exhibits slower mobility on SDS-PAGE compared to the phosphorylated/activated form. Densitometric analysis was used to measure MAPK activation. Results indicate that H2O2 caused a dose and time-dependent increase in MAPK activation in astrocytoma cells. Furthermore, ROS-induced activation was almost completely suppressed by NAC. NAC also inhibited serum-induced MAPK activation indicating there may be an oxidant-sensitive component to serum-induced growth signaling. Modifications of MAPKs by H2O2 demonstrate that ROS-induced proliferation is via biochemical pathways similar to other known growth stimuli. Understanding of processes that link a proliferation signal (ROS) to cell proliferation can aid in the selection of therapy used to suppress brain tumor growth.}, }
@article {pmid11985902, year = {2002}, author = {Sochman, J}, title = {N-acetylcysteine in acute cardiology: 10 years later: what do we know and what would we like to know?!.}, journal = {Journal of the American College of Cardiology}, volume = {39}, number = {9}, pages = {1422-1428}, doi = {10.1016/s0735-1097(02)01797-7}, pmid = {11985902}, issn = {0735-1097}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Cardiology/trends ; Clinical Trials as Topic ; Free Radical Scavengers/*pharmacology/therapeutic use ; Humans ; Myocardial Infarction/drug therapy/physiopathology ; Myocardial Reperfusion Injury/*physiopathology/prevention &amp; control ; Oxidative Stress/*physiology ; Reactive Oxygen Species/metabolism ; Ventricular Function, Left/drug effects ; }, abstract = {N-acetylcysteine (NAC) is known in a variety of branches of medicine. This paper addresses in detail the action of NAC as it is emerging from research and clinical trials over the past decade in cardiology, giving rise to new concepts. The result is a process resembling creation of a mosaic from individual pieces. Also, the role of NAC in acute cardiology, during acute reperfusion in particular, is defined.}, }
@article {pmid11980127, year = {2002}, author = {Chikina, SIu and Iagmurov, BKh and Kopylev, ID and Soodaeva, SK and Chuchalin, AG}, title = {[N-Acetylcysteine: low and high doses in the treatment of chronic obstructive lung diseases in Chernobyl accident liquidators].}, journal = {Terapevticheskii arkhiv}, volume = {74}, number = {3}, pages = {62-65}, pmid = {11980127}, issn = {0040-3660}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Chronic Disease ; Dose-Response Relationship, Drug ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Lung Diseases, Obstructive/*drug therapy ; Male ; Middle Aged ; Power Plants ; *Radioactive Hazard Release ; Ukraine ; }, abstract = {AIM: To study clinical effectiveness and antioxidant activity of N-acetylcisteine (NAC) in daily doses 600, 1200, 1800 and 2400 mg in Chernobyl wreckers suffering from chronic obstructive pulmonary diseases (COPD).<br><br>MATERIAL AND METHODS: Cough intensity and expectoration, malonic dialdehyde (MD), plasma calcium ions concentrations were studied in patients taking NAC.<br><br>RESULTS: Cough intensity diminished insignificantly. Expectoration improved significantly only after intake of 1200 mg/day NAC. In higher doses expectoration difficulties appeared again. Five patients received a maintenance dose 200 mg/day as a result of which their expectoration improved. MDA in the above patients was 3.3 times higher than normal level, free calcium ion concentration was 1.7 times higher. Only 1200 mg/day dose of NAC brought MDA level to normal, higher doses made it subnormal. Calcium ions concentration decreased but insignificantly. Maintenance dose 200 mg/day returned MDA and calcium to initial level.<br><br>CONCLUSION: For patients with radiation-induced affection of the respiratory tracts NAC dose 1200 mg/day is optimal both clinically and in terms of antioxidant activity.}, }
@article {pmid11978899, year = {2002}, author = {Watt, G and Jongsakul, K and Ruangvirayuth, R}, title = {A pilot study of N-acetylcysteine as adjunctive therapy for severe malaria.}, journal = {QJM : monthly journal of the Association of Physicians}, volume = {95}, number = {5}, pages = {285-290}, doi = {10.1093/qjmed/95.5.285}, pmid = {11978899}, issn = {1460-2725}, mesh = {Acetylcysteine/*therapeutic use ; Adjuvants, Pharmaceutic/therapeutic use ; Adult ; Antimalarials/*therapeutic use ; Double-Blind Method ; Humans ; Interferon-gamma/blood ; Interleukin-10/blood ; Interleukin-6/blood ; Lactic Acid/blood ; Malaria/blood/*drug therapy ; Male ; Pilot Projects ; Prospective Studies ; Quinine/*therapeutic use ; Statistics, Nonparametric ; Time Factors ; Tumor Necrosis Factor-alpha/analysis ; }, abstract = {BACKGROUND: The case fatality rate of severe malaria remains unacceptably high. N-acetylcysteine (NAC) is a safe compound that inhibits tumour necrosis factor (TNF) and impedes cytoadherence, both of which have been implicated in the pathogenesis of malaria complications.<br><br>AIM: To evaluate NAC as adjunctive therapy in severe malaria.<br><br>DESIGN: A placebo-controlled, double-blind prospective study, with serum lactate level as the principal objective measure of response.<br><br>METHODS: Thirty adult males with severe, quinine-treated malaria received either 300 mg/kg of NAC or placebo, over 20 h.<br><br>RESULTS: Serum lactate levels normalized twice as quickly after NAC (median 21 h, 95%CI 12-36 h) as after placebo (median 42 h, 95%CI 30-84 h; p=0.002, Mann-Whitney U test). Twenty-four hours after admission, 10/15 (67%) NAC-group patients but only 3/15 (20%) placebo-group patients had normal lactate concentrations (p=0.01, Fisher exact test). NAC-treated patients could be switched from intravenous to oral therapy earlier than individuals who received placebo (42 h vs. 51 h after admission) but the difference was not significant (p=0.28, Mann-Whitney U test).<br><br>DISCUSSION: NAC's mechanism of action in malaria is unclear, since it did not markedly alter plasma cytokine profiles. Trials of NAC adjunctive therapy for complicated malaria, with mortality as an endpoint, appear to be warranted.}, }
@article {pmid11976899, year = {2001}, author = {Barrios, R and Shi, ZZ and Kala, SV and Wiseman, AL and Welty, SE and Kala, G and Bahler, AA and Ou, CN and Lieberman, MW}, title = {Oxygen-induced pulmonary injury in gamma-glutamyl transpeptidase-deficient mice.}, journal = {Lung}, volume = {179}, number = {5}, pages = {319-330}, doi = {10.1007/s004080000071}, pmid = {11976899}, issn = {0341-2040}, support = {ES 07827/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cysteine/metabolism ; Glutamate-Cysteine Ligase/metabolism ; Glutathione/*physiology ; Hyperoxia/etiology/*metabolism ; Lung/metabolism ; *Lung Injury ; Mice ; RNA/genetics ; gamma-Glutamyltransferase/*deficiency ; }, abstract = {We used mice with a targeted disruption in g-glutamyl transpeptidase (GGT-deficient mice) to study the role of glutathione (GSH) in protection against oxygen-induced lung injury. These mice had reduced levels of lung GSH and restricted ability to synthesize GSH because of low levels of cysteine. When GGT-deficient mice were exposed to 80% oxygen, they developed diffuse pulmonary injury and died within eight days. Ten of 12 wild-type mice were alive after 18 days. Administration of N-acetylcysteine (NAC) to GGT-deficient mice corrected GSH values and prevented the development of severe pulmonary injury and death. Oxygen exposure induced an increase in lung GSH levels in both wild-type and GGT-deficient mice, but induced levels in the mutant mice were <50% of those in wild-type mice. Cysteine levels were approximately 50-fold lower than GSH levels the lungs of both wild-type and GGT-deficient mice. Levels of lung RNA coding for the heavy subunit of g-glutamyl cysteine synthetase rose three- to fourfold after oxygen exposure in both wild-type and GGT-deficient mice. In contrast, oxygen exposure failed to provoke increases in glutathione synthetase, glutathione peroxidase, glutaredoxin, or thioredoxin.}, }
@article {pmid11974970, year = {2001}, author = {Béani, JC}, title = {[Enhancement of endogenous antioxidant defenses: a promising strategy for prevention of skin cancers].}, journal = {Bulletin de l'Academie nationale de medecine}, volume = {185}, number = {8}, pages = {1507-25; discussion 1526-7}, pmid = {11974970}, issn = {0001-4079}, mesh = {Antioxidants/*pharmacology/therapeutic use ; Cell Culture Techniques ; Cell Line ; DNA Damage ; Fibroblasts/*physiology ; Glutathione/*pharmacology/therapeutic use ; Glutathione Peroxidase/metabolism ; Humans ; *Oxidative Stress ; Selenium/*pharmacology/therapeutic use ; Skin Neoplasms/*prevention &amp; control ; Sunscreening Agents ; Ultraviolet Rays/adverse effects ; Zinc/*pharmacology/therapeutic use ; }, abstract = {There is considerable evidence that ultraviolet radiation (UV) from sunlight is implicated in skin carcinogenesis. So the risks of cutaneous cancer have increased during the last decade due to increase of sun exposure. For a long time, ultraviolet B radiation (UVB: 290-320 nm) have been considered to be the more efficient wavelength in eliciting carcinogenesis in human skin. It is today clear that UVA (320-400 nm), especially UVA1 (340-400 nm) also participate to photo carcinogenesis. One of molecular mechanisms in the biological effects of UV is the induction of reactive oxygen species (ROS) directly or through endogenous photosensitization reactions. UVA radiation mainly acts via this production of ROS and the subsequent oxidative stress seems to play a crucial role in the deleterious effects of UVA. Fortunately, the skin possesses a wide range of interlinked antioxidant defence mechanism to protect itself from damage by UV-induced ROS. However, the capacity of these systems is not unlimited; they can be overwhelmed by excessive exposure to UV and then ROS can reach damaging levels. An interesting strategy to provide photoprotection would be to support or enhance one or more of these endogenous systems. In our experiments, we have evaluated the protective effect of glutathion, selenium and zinc, three compounds playing a pivotal role in the cellular defence against oxidative damage. We have irradiated both by UVA1 and UVB culture of human normal skin fibroblasts or of spontaneously immortalised human keratinocyte cell line Hacat. Before irradiation, treated cells were submitted to zinc deprivation by a diffusible zinc chelator, NNN' N'-tetrakis (2-pyridylmethyl) ethylene diamine (TPEN) or supplied with zinc chloride, thiols (N-acetyl-cysteine; N-acetyl-homocysteine-thiolactone, L2oxothiozolidine-4 carboxylate) selenium as sodium selenite. The cell viability was measured using the adhesion-proliferation method or a tetrazolium colorimetric assay. The damages induced to cellular membrane were appreciated by determination of thiobarbituric reactants (Tbars) by a fluorometric micromethod. Cellular DNA damage was examined by strand break determination carried out using the method described by Birnboim and Jevcak and by the Comet assay. Our results show that: UVA1 have a main part in cytotoxic effect of UVA and this effect is linked to ROS; thiols and selenium protect cells against UVA radiation with a synergic interaction and this protection acts though an increase in glutathion peroxidase activity; zinc protects against cytotoxicity of UVA and UVB and against UVB induced DNA damages; above all, DNA damages induced by UVA or UVB are significantly prevented by thiol molecules, selenium and zinc. As DNA damages have a main place in photocarcinogenesis, our results point out the potential interest of a photoprotection based on the support of endogenous antioxidant system. The research of new ways for photoprotection is indeed a necessity because sunscreens did not give convincing evidences of efficacy in preventing skin cancers.}, }
@article {pmid11972027, year = {2002}, author = {Malins, DC and Hellstrom, KE and Anderson, KM and Johnson, PM and Vinson, MA}, title = {Antioxidant-induced changes in oxidized DNA.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {99}, number = {9}, pages = {5937-5941}, pmid = {11972027}, issn = {0027-8424}, support = {R01 CA079479/CA/NCI NIH HHS/United States ; CA 79479/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; DNA/biosynthesis/drug effects/*metabolism ; *DNA Damage ; Female ; Free Radical Scavengers/pharmacology ; Gas Chromatography-Mass Spectrometry ; Guanine/*analogs &amp; derivatives/pharmacology ; Mice ; Mice, Inbred BALB C ; Nucleic Acid Conformation ; Oxygen/*metabolism ; Spectroscopy, Fourier Transform Infrared ; }, abstract = {N-acetylcysteine (NAC), a strong antioxidant, has antigenotoxic and anticarcinogenic properties currently being investigated in clinical trials. NAC detoxifies free radicals (e.g., the hydroxyl radical,.OH) that cause DNA changes implicated in disease (e.g., cancer). The.OH reacts with purines to form mutagenic 8-hydroxypurine (8-OH) and putatively nonmutagenic formamidopyrimidine (Fapy) lesions. Fapy lesions inhibit DNA synthesis likely modulating the mutagenic potential of the 8-OH lesions, which would suggest that the ratio of these oxidized bases is biologically important. However, little is known about how NAC modifies oxidized DNA structure or how such modifications may affect cellular processes, such as replication and transcription. By using gas chromatography-mass spectrometry and Fourier transform-infrared spectroscopy, we found that dietary NAC (5% in the diet for 14 days) affected.OH-induced structural changes in DNA of the hind leg of the BALB/c mouse. For example, mutagenic 8-hydroxyguanine (8-OH-Gua) was reduced approximately 50% (P = 0.02) in mice fed NAC compared with controls. NAC reduced the log(10) (8-OH-Gua/FapyGua) ratio from 0.58 +/- 0.15 to essentially zero, a virtually neutral redox status. DNA from control mice had a remarkably high variance compared with mice fed NAC. Moreover, the DNA from treated and control mice was distinct with respect to base structure and vertical base-stacking interactions. The findings showing that NAC lowered the concentration of 8-OH-Gua, the log ratio, and the variance (previously associated with neoplastic changes) suggest that NAC reduces the mutagenic potential of oxidized DNA. These benefits could be offset by the other structural changes found after NAC exposure, which may affect the fidelity of DNA synthesis.}, }
@article {pmid11970911, year = {2002}, author = {Kosmidou, I and Vassilakopoulos, T and Xagorari, A and Zakynthinos, S and Papapetropoulos, A and Roussos, C}, title = {Production of interleukin-6 by skeletal myotubes: role of reactive oxygen species.}, journal = {American journal of respiratory cell and molecular biology}, volume = {26}, number = {5}, pages = {587-593}, doi = {10.1165/ajrcmb.26.5.4598}, pmid = {11970911}, issn = {1044-1549}, mesh = {Animals ; Cell Line ; Ditiocarb/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Hydrogen Peroxide/pharmacology ; Interleukin-6/genetics/*metabolism ; Mice ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Muscle, Skeletal/cytology/drug effects/*metabolism ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Oxidants/pharmacology ; Oxidation-Reduction/drug effects ; Pyrogallol/pharmacology ; RNA, Messenger/metabolism ; Reactive Oxygen Species/*metabolism/pharmacology ; Xanthine/pharmacology ; Xanthine Oxidase/pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {In the present study we have tested the ability of reactive oxygen species (ROS) to stimulate the production of interleukin (IL)- 6 from skeletal myocytes. Differentiated C2C12 murine skeletal muscle cells (myotubes) exposed to pyrogallol (PYR), xanthine/ xanthine-oxidase (X/XO), or H(2)O(2) for 24 h exhibited a concentration-dependent increase in IL-6 production. Unlike myotubes, incubation of myoblasts and endothelial cells with X/XO or PYR did not result in increased IL-6 release. In myotubes, superoxide dismutase and catalase blocked the ROS-induced IL-6 release. Exposure of myotubes to H(2)O(2) increased steady-state IL-6 mRNA levels, and pretreatment of myotubes with actinomycin D or cycloheximide abolished the ROS-induced IL-6 production. In addition, pretreatment of cells with N-acetyl-cysteine blocked tumor necrosis factor (TNF)-alpha-induced IL-6 release, suggesting that endogenously produced ROS participate in IL-6 production. Myotubes stimulated with H(2)O(2) exhibited increased I kappa B-alpha phosphorylation and degradation, and treatment of C2C12 with ROS-generating agents increased activator protein (AP)-1 and nuclear factor (NF)-kappa B-dependent promoter activity. Finally, preincubation of myotubes with the pharmacologic inhibitor of NF-kappa B, diethyldithiocarbamate, or transient transfection with an I kappa B-alpha mutant, inhibited the ROS-stimulated IL-6 release. In conclusion, ROS stimulate IL-6 production from skeletal myotubes in a manner that involves transcriptional activation of the IL-6 gene through an NF-kappa B-dependent pathway.}, }
@article {pmid11970856, year = {2002}, author = {Rota, C and Bergamini, S and Daneri, F and Tomasi, A and Virgili, F and Iannone, A}, title = {N-Acetylcysteine negatively modulates nitric oxide production in endotoxin-treated rats through inhibition of NF-kappaB activation.}, journal = {Antioxidants &amp; redox signaling}, volume = {4}, number = {1}, pages = {221-226}, doi = {10.1089/152308602753625988}, pmid = {11970856}, issn = {1523-0864}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Citrulline/metabolism ; DNA/metabolism ; Endotoxins/*pharmacology ; Enzyme Activation ; Free Radical Scavengers/pharmacology ; Lipopolysaccharides/metabolism ; Male ; NF-kappa B/*metabolism ; Nitrates/metabolism ; Nitric Oxide/*metabolism ; Nitrites/metabolism ; Protein Binding ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {N-Acetylcysteine (NAC) has a wide spectrum of biological activities, either related to the ability to increase intracellular thiols or directly acting as an antioxidant. We used an in vivo animal model to study NAC modulation of nitric oxide (NO) production in response to lipopolysaccharide treatment. A comparison was made between NAC and the N-[3-(aminomethyl)benzyl] acetamidine (1400W), an inhibitor of the inducible NO synthase (iNOS). Both inhibit NO production, although NAC lacks any effect if given when iNOS is already induced; this indicates that the decrease of NO generation is not due to an effect on iNOS activity. We found that the DNA binding activity of nuclear transcription factor-kappaB in peripheral blood cells was inhibited by NAC given before lipopolysaccharide, whereas tumor necrosis factor-alpha secretion was not affected.}, }
@article {pmid11969376, year = {2002}, author = {Boulares, AH and Contreras, FJ and Espinoza, LA and Smulson, ME}, title = {Roles of oxidative stress and glutathione depletion in JP-8 jet fuel-induced apoptosis in rat lung epithelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {180}, number = {2}, pages = {92-99}, doi = {10.1006/taap.2002.9350}, pmid = {11969376}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Benzamides/pharmacology ; Buthionine Sulfoximine/pharmacology ; Caspase 3 ; Caspases/analysis/biosynthesis ; Epithelial Cells ; Free Radical Scavengers/pharmacology ; Glutathione/deficiency/*metabolism ; Hydrocarbons/metabolism/pharmacology/*toxicity ; Hydrogen Peroxide/pharmacology ; Membrane Potentials/drug effects ; Mitochondria/drug effects/metabolism ; Oxidative Stress/drug effects ; Poly(ADP-ribose) Polymerase Inhibitors ; Rats ; Teratogens/metabolism/pharmacology/*toxicity ; }, abstract = {The toxic jet fuel JP-8 induces morphological and biochemical changes characteristic of apoptosis in rat lung epithelial (RLE-6TN) cells. The mechanism of JP-8 toxicity in these cells was further investigated in an attempt to identify potential therapeutic interventions. Given that oxidative stress and changes in the concentrations of endogenous antioxidants, such as glutathione (GSH), have been associated with the cellular damage elicited by numerous toxicants, the possibility that JP-8 induces cellular oxidative stress was investigated. Experimentally induced depletion of intracellular GSH or exposure of cells to a low concentration of H(2)O(2) markedly enhanced JP-8-induced cell death. A significant reduction in intracellular concentrations of GSH was noted in RLE-6TN cells shortly after exposure to JP-8. Furthermore, JP-8 induced the generation of reactive oxygen species (ROS) in RLE-6TN cells. Consistent with the notion that JP-8 toxicity is mediated by generation of ROS and depletion of intracellular GSH, JP-8-induced cell death was inhibited by exogenous GSH or the thiol-containing antioxidant N-acetyl-cysteine. This protective effect was associated with marked inhibition of both the activation of caspase-3 and the loss of the mitochondrial membrane potential induced by JP-8. Inhibition of the JP-8-induced activation of poly(ADP-ribose) polymerase by 3-aminobenzamide did not protect cells against JP-8 toxicity. Together, these results indicate that thiol antioxidants are highly effective in rescuing cells from JP-8-induced cell death and that they may provide a basis for new therapeutic approaches to counteract JP-8 toxicity.}, }
@article {pmid11969373, year = {2002}, author = {Rojas, M and Rugeles, MT and Gil, DP and Patiño, P}, title = {Differential modulation of apoptosis and necrosis by antioxidants in immunosuppressed human lymphocytes.}, journal = {Toxicology and applied pharmacology}, volume = {180}, number = {2}, pages = {67-73}, doi = {10.1006/taap.2001.9359}, pmid = {11969373}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antigens, CD/biosynthesis ; Antigens, Differentiation, T-Lymphocyte/biosynthesis ; Antioxidants/*pharmacology ; Apoptosis/drug effects/*immunology ; Ascorbic Acid/pharmacology ; Cyclosporine/adverse effects/immunology ; Dexamethasone/adverse effects/immunology ; Glucocorticoids/adverse effects/immunology ; Humans ; Immunosuppressive Agents/adverse effects/antagonists &amp; inhibitors/*immunology ; In Situ Nick-End Labeling ; L-Lactate Dehydrogenase/metabolism ; Lectins, C-Type ; Lymphocyte Activation/drug effects/immunology ; Lymphocytes/cytology/drug effects/*immunology/metabolism ; Male ; Necrosis ; Phytohemagglutinins/pharmacology ; Superoxides/metabolism ; }, abstract = {In the present study, we explored whether mitogenic stimulation of dexamethasone (DXM)- and cyclosporine A (CsA)-immunosuppressed peripheral blood lymphocytes (PBML) induced apoptosis or necrosis and their relation with the production of reactive oxygen intermediates. Our results indicate that both phenomena can occur in these cells and that antioxidants such as N-acetyl cysteine (NAC) and ascorbic acid (AA) can modulate them. However, DXM-induced apoptosis was only partially inhibited by NAC and AA, suggesting that DXM-treated PBMC had an additional apoptotic pathway independent of ROIs. Furthermore, we observed that the inhibition of apoptosis by antioxidants correlated with an increased cell proliferation, suggesting that the immunomodulation of both DXM and CsA may be related to induction of apoptosis. The ability to differentially modulate apoptosis and necrosis by antioxidants opens new possibilities in the management of immunosuppressive therapy, since the inhibition of necrosis may avoid inflammation and the tissue damage associated with immunosuppressors.}, }
@article {pmid11959652, year = {2002}, author = {Kumaran, C and Shivakumar, K}, title = {Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {282}, number = {5}, pages = {H1855-62}, doi = {10.1152/ajpheart.00747.2001}, pmid = {11959652}, issn = {0363-6135}, mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium/*metabolism ; Cell Division/*drug effects ; Chelating Agents/pharmacology ; Collagen/biosynthesis ; Egtazic Acid/pharmacology ; Fibroblasts/*cytology ; Homeostasis ; Mitogens/pharmacology ; Myocardium/*cytology ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; Receptors, Neurokinin-1/drug effects/physiology ; Substance P/administration &amp; dosage/*pharmacology ; Superoxide Dismutase/pharmacology ; Superoxides/*metabolism ; }, abstract = {Substance P is released from nerve endings in the heart under pathological conditions like ischemia, but its action on cardiac cells has not been investigated. This study tested the hypothesis that substance P is mitogenic to adult cardiac fibroblasts and delineated the underlying mechanism(s). Substance P, acting via neurokinin-1 (NK-1) receptors, stimulated cellular hyperplasia over a range of 1-10 micromol/l. It elicited no change in net collagen production, total protein synthesis, or cell protein content but increased (45)Ca uptake and superoxide generation. EGTA, N-acetyl-cysteine, and superoxide dismutase attenuated the hyperplastic response to substance P. A combination of substance P and EGTA enhanced superoxide generation without an increase in DNA synthesis, showing that an increase in superoxide production does not result in hyperplasia when extracellular Ca(2+) is chelated. Together, the data suggest that substance P may activate, via NK-1 receptors, a hyperplastic but not hypertrophic response in adult cardiac fibroblasts and that alterations in redox state and Ca(2+) homeostasis may act in concert to mediate its mitogenic action.}, }
@article {pmid11959459, year = {2002}, author = {Gibson, GE and Zhang, H and Xu, H and Park, LC and Jeitner, TM}, title = {Oxidative stress increases internal calcium stores and reduces a key mitochondrial enzyme.}, journal = {Biochimica et biophysica acta}, volume = {1586}, number = {2}, pages = {177-189}, doi = {10.1016/s0925-4439(01)00091-6}, pmid = {11959459}, issn = {0006-3002}, support = {PP (AG14930)/AG/NIA NIH HHS/United States ; R0-1 (AG11921)/AG/NIA NIH HHS/United States ; R0-1 (AG19589)/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Bombesin ; Calcium/analysis/*metabolism ; Cell Line ; Chromans/pharmacology ; Dimethyl Sulfoxide/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation ; Fibroblasts/drug effects/*metabolism ; Humans ; Hydrogen Peroxide ; Ketoglutarate Dehydrogenase Complex/analysis/*metabolism ; Mitochondrial Proteins/analysis/*metabolism ; Oxidative Stress/*physiology ; Reactive Oxygen Species/analysis/metabolism ; Time Factors ; }, abstract = {Fibroblasts from patients with genetic and non-genetic forms of Alzheimer's disease (AD) show many abnormalities including increased bombesin-releasable calcium stores (BRCS), diminished activities of the mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC), and an altered ability to handle oxidative stress. The link between genetic mutations (and the unknown primary event in non-genetic forms) and these other cellular abnormalities is unknown. To determine whether oxidative stress could be a convergence point that produces the other AD-related changes, these experiments tested in fibroblasts the effects of H(2)O(2), in the presence or absence of select antioxidants, on BRCS and KGDHC. H(2)O(2) concentrations that elevated carboxy-dichlorofluorescein (c-H(2)DCF)-detectable ROS increased BRCS and decreased KGDHC activity. These changes are in the same direction as those in fibroblasts from AD patients. Acute treatments with the antioxidants Trolox, or DMSO decreased c-H(2)DCF-detectable ROS by about 90%, but exaggerated the H(2)O(2)-induced increases in BRCS by about 4-fold and did not alter the reduction in KGDHC. Chronic pretreatments with Trolox more than doubled the BRCS, tripled KGDHC activities, and reduced the effects of H(2)O(2). Pretreatment with DMSO or N-acetyl cysteine diminished the BRCS and either had no effect, or exaggerated the H(2)O(2)-induced changes in these variables. The results demonstrate that BRCS and KGDHC are more sensitive to H(2)O(2) derived species than c-H(2)DCF, and that oxidized derivatives of the antioxidants exaggerate the actions of H(2)O(2). The findings support the hypothesis that select abnormalities in oxidative processes are a critical part of a cascade that leads to the cellular abnormalities in cells from AD patients.}, }
@article {pmid11958954, year = {2002}, author = {Pajonk, F and Riess, K and Sommer, A and McBride, WH}, title = {N-acetyl-L-cysteine inhibits 26S proteasome function: implications for effects on NF-kappaB activation.}, journal = {Free radical biology &amp; medicine}, volume = {32}, number = {6}, pages = {536-543}, doi = {10.1016/s0891-5849(02)00743-8}, pmid = {11958954}, issn = {0891-5849}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/pharmacology ; Humans ; I-kappa B Kinase ; Macrophages/drug effects/metabolism ; Mice ; NF-kappa B/*metabolism ; Peptide Hydrolases/drug effects/*metabolism ; *Proteasome Endopeptidase Complex ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/radiation effects ; Radiation, Ionizing ; Tumor Cells, Cultured ; }, abstract = {Ionizing radiation shares with cytokines, such as TNF-alpha, an ability to generate free radicals in cells and activate downstream proinflammatory responses through NF-kappaB-dependent signal transduction pathways. Support for the role of free radicals in triggering such responses comes from the use of free radical scavengers like N-acetyl-L-cysteine (NAC). The nature of the link between free radical generation and NF-kappaB activation is, however, unclear. In this study, we explore the possibility that scavenging of free radicals by NAC might not be the mechanism by which it inhibits NF-kappaB activation, but rather that NAC acts through inhibition of proteasome function. The effect of NAC on the chymotryptic function of the 26s and 20s proteasome complex was measured in extracts from EVC 304 bladder carcinoma cells by assessing degradation of fluorogenic substrates. NAC inhibited 26s but not 20s proteasome activity, suggesting that it interferes with 19s regulatory subunit function. NAC blocked radiation-induced NF-kappaB activity in ECV 304 cells and RAW 264.7 macrophages, as measured by a gel shift assay, at doses that inhibited proteasome activity. This provides a possible mechanism whereby NAC could block NF-kappaB activation and affect the expression of other molecules that are dependent on the ubiquitin/proteasome system for their degradation, other than by scavenging free radicals.}, }
@article {pmid11958950, year = {2002}, author = {Antonicelli, F and Parmentier, M and Drost, EM and Hirani, N and Rahman, I and Donaldson, K and MacNee, W}, title = {Nacystelyn inhibits oxidant-mediated interleukin-8 expression and NF-kappaB nuclear binding in alveolar epithelial cells.}, journal = {Free radical biology &amp; medicine}, volume = {32}, number = {6}, pages = {492-502}, doi = {10.1016/s0891-5849(01)00820-6}, pmid = {11958950}, issn = {0891-5849}, mesh = {Acetylcysteine/analogs &amp; derivatives/*pharmacology ; Binding Sites ; Cell Line ; Chemotaxis/drug effects/physiology ; Epithelial Cells/*drug effects/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Interleukin-8/*biosynthesis/genetics/metabolism ; Lysine/analogs &amp; derivatives/*pharmacology ; NF-kappa B/*metabolism ; Oxidants/*metabolism ; Oxidation-Reduction ; Pulmonary Alveoli/drug effects ; RNA, Messenger/biosynthesis ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Nacystelyn (NAL), a recently developed lysine salt of N-acetyl-L-cytokine (NAC) has mucolytic and antioxidant properties. In this study, we investigated the effect of NAL upon oxidant-mediated interleukin (IL)-8 release and the activation of the redox-sensitive transcription factors AP-1, NF-kappaB, and C/EBP in a human alveolar epithelial cell line (A549). NAL (5 mM) enhanced intracellular glutathione (GSH) after 4 h and abolished H(2)O(2)-induced IL-8 release from A549 cells. This was associated with inhibition of NF-kappaB and C/EBP DNA-binding, measured by the Electrophoretic Mobility Shift Assay (EMSA). NAL also abolished the transcriptional activation of IL-8 in an IL-8-chloramphenicol acetyl transferase (CAT) reporter system, transfected into A549 cells. Supernatants obtained from H(2)O(2)-treated A549 cells induced chemotaxis of polymorphonuclear neutrophils, which could be inhibited by co-incubation with NAL. These data indicate that NAL may be used to modulate pro-inflammatory process by inhibiting cytokine release in the lungs and thus has therapeutic potential in inflammatory lung diseases.}, }
@article {pmid11956647, year = {2002}, author = {Mantovani, G and Macciò, A and Mulas, C and Massa, E and Madeddu, C and Mura, L and Contu, P and Versace, R}, title = {Dose-intense phase II study of weekly cisplatin and epidoxorubicin plus medroxyprogesterone acetate and recombinant interleukin 2 in stage IIIB-IV non-small cell lung cancer.}, journal = {Oncology reports}, volume = {9}, number = {3}, pages = {661-670}, pmid = {11956647}, issn = {1021-335X}, mesh = {Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Carcinoma, Non-Small-Cell Lung/*drug therapy ; Cisplatin/administration &amp; dosage ; Disease-Free Survival ; Epirubicin/administration &amp; dosage ; Female ; Humans ; Interleukin-1/blood ; Interleukin-2/administration &amp; dosage/blood ; Interleukin-6/blood ; Lung Neoplasms/*drug therapy ; Male ; Medroxyprogesterone Acetate/administration &amp; dosage ; Middle Aged ; Quality of Life ; Recombinant Proteins/administration &amp; dosage ; Time Factors ; Treatment Outcome ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {The purpose of the study was to evaluate the effectiveness in terms of response rates, toxicity and survival of the combination chemotherapy regimen cisplatin and epidoxorubicin (epirubicin) including medroxyprogesterone acetate (MPA), recombinant IL-2 (rIL-2) and antioxidants in patients with advanced (stage IIIB-IV) non-small cell lung cancer (NSCLC). Thirty-three chemotherapy-naive patients with NSCLC were enrolled in the study and 30 of them were evaluable. The mean age of the patients was 61 years. Twenty (66.7%) out of 30 patients were >or=60 years, and 5 (16.7%) patients were >or=70 years. The ECOG performance status was 0 to 1 in 30 patients and 2 in 3 patients. Twenty-six patients (78.8%) had stage IIIB disease and 7 (21.2%) had stage IV; histology was mainly squamous cell carcinoma (72.7%). The treatment consisted of cisplatin 40 mg/m2/week and epirubicin 40 mg/m2/week both intravenously on day 1, rIL-2 1.8 MIU/day subcutaneously, MPA 1 g/day orally, alpha-lipoic acid 300 mg/day orally and N-acetyl cysteine 1.8 g/day orally. The treatment was administered for 6 weeks. Patients with a complete response (CR), partial response (PR) or stable disease (SD) continued the treatment, according to response re-evaluation, until 15 weeks. The present study reports the results of 6, 9, 12 and 15-week treatment. After 6 weeks, 30 patients were assessable for response: no CR was observed, a PR was achieved in 15 patients (50%; ORR 50%). After 15 weeks, 1 CR and 8 PR were observed (ORR 30.0%). The median follow-up period was 13 months. The median duration of response was 9 months. The median overall survival (OS) was 15 months. The one-year survival rate was 55.8%. The median progression-free survival (PFS) was 10 months. The toxicity was, as expected, mainly hematologic: neutropenia was the most significant symptom. The non-hematologic toxicity was quite low. Therefore, the treatment's toxicity was quite acceptable. There was no toxic death. The 30.0% ORR, the 15 month OS and the 10 month PFS obtained in this study are comparable with those observed with cisplatin plus epirubicin (ORR 39-54%) in phase II studies and in a previous phase III study (ORR 33%, OS 10.5 months). Moreover, the toxicity was acceptable and it was mainly hematologic. Serum levels of proinflammatory cytokines significantly decreased after treatment.}, }
@article {pmid11942326, year = {2002}, author = {Tozawa, K and Okamoto, T and Hayashi, Y and Sasaki, S and Kawai, N and Kohri, K}, title = {N-acetyl-L-cysteine enhances chemotherapeutic effect on prostate cancer cells.}, journal = {Urological research}, volume = {30}, number = {1}, pages = {53-58}, doi = {10.1007/s00240-001-0226-1}, pmid = {11942326}, issn = {0300-5623}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Antineoplastic Agents/pharmacology ; Cisplatin/pharmacology ; Etoposide/pharmacology ; Humans ; Interleukin-6/metabolism ; Male ; NF-kappa B/*drug effects/physiology ; Prostatic Neoplasms/*drug therapy ; Tumor Cells, Cultured ; }, abstract = {Transcription factor nuclear factor kappaB (NF-kappaB) controls gene expression of a number of genes, including cytokines such as interleukin-6 (IL-6), granulocyte-macrophage (GM)-CSF, and interleukin-8 (IL-8). IL-6 is known to play important roles in the growth of prostate cancer cells, activation of androgen receptor, and prostate-specific protein expression. NF-kappaB is activated by extracellular signals such as proinflammatory cytokines, chemotherapeutic reagents, and radiation. Here we demonstrate that cisplatin (CDDP) and etoposide (VP-16) induce nuclear translocation of NF-kappaB in prostate cancer cell lines, followed by secretion of IL-6. We also demonstrated that the growth of hormone-independent prostate cancer cell lines can be inhibited by the anti-NF-kappaB reagent N-acetyl-L-cysteine (NAC). These observations indicate that NF-kappaB can be a target of new adjuvant therapy against hormone refractory prostate cancer.}, }
@article {pmid11940570, year = {2002}, author = {Hsu, HY and Wen, MH}, title = {Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression.}, journal = {The Journal of biological chemistry}, volume = {277}, number = {25}, pages = {22131-22139}, doi = {10.1074/jbc.M111883200}, pmid = {11940570}, issn = {0021-9258}, mesh = {Animals ; Carrier Proteins/pharmacology ; Cell Line ; Chromones/pharmacology ; Curcumin/pharmacology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Flavonoids/pharmacology ; *Gene Expression Regulation ; Genes, Dominant/genetics ; Imidazoles/pharmacology ; Interleukin-1/*biosynthesis/metabolism ; *Intracellular Signaling Peptides and Proteins ; *JNK Mitogen-Activated Protein Kinases ; Lipopolysaccharides/*metabolism ; MAP Kinase Kinase 4 ; Macrophages/enzymology/metabolism ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Models, Biological ; Morpholines/pharmacology ; Naphthalenes/pharmacology ; Oxygen/metabolism ; Protein Binding ; Pyridines/pharmacology ; *Reactive Oxygen Species ; *Signal Transduction ; Time Factors ; Transfection ; p38 Mitogen-Activated Protein Kinases ; rac1 GTP-Binding Protein/metabolism ; }, abstract = {Lipopolysaccharide (LPS) stimulates macrophages to release inflammatory cytokines, interleukin-1 beta (IL-1), and tumor necrosis factor (TNF). LPS-induced TNF suppresses scavenger receptor functions in macrophages (van Lenten, B. J., and Fogelman, A. M. (1992) J. Immunol. 148, 112-116), which is regulated by TNF-mediated protein kinases (Hsu, H. Y., and Twu, Y. C. (2000) J. Biol. Chem. 275, 41035-41048). To examine the molecular mechanism for LPS induction of IL-1 in macrophages, we demonstrated that LPS quickly stimulated reactive oxygen species (ROS), and 3 h later induced prointerleukin-1 beta (pro-IL-1, precursor of IL-1) production and IL-1 secretion. LPS stimulated pro-IL-1 message/protein between 3 and 10 h; however, there was a 40% reduction of pro-IL-1 in preincubation of the antioxidant, N-acetylcysteine (NAC). Moreover, NAC moderated LPS-induced IL-1 secretion partially via interleukin 1-converting enzyme. The maximal activity of LPS-induced ERK, JNK, and p38 was 12- (30 min), 5- (30 min), and 16-fold (15 min), respectively. In contrast, NAC reduced ERK activity to 60% and decreased p38 activity to the basal level, but JNK activity was induced 2-fold. Furthermore, the pharmacological antagonists LY294002, SB203580, curcumin, calphostin C, and PD98059 revealed the diverse roles of LPS-mediated protein kinases in pro-IL-1. On the other hand, NAC and diphenyleneiodonium chloride partially inhibited LPS-induced Rac activity and protein-tyrosine kinase (PTK), indicating that LPS-mediated ROS and NADPH oxidase correspond to Rac activation and IL-1 expression. Our findings establish for the first time that LPS-mediated PTK/phosphatidylinositol 3-kinase/Rac/p38 pathways play a more important role than pathways of PTK/PKC/MEK/ERK and of PTK/phosphatidylinositol 3-kinase/Rac/JNK in the regulation of pro-IL-1/IL-1. The findings also further elucidate the critical role of LPS-mediated ROS in signal transduction pathways. Our results suggest that understanding LPS-transduced signals in IL-1 induction upon the antibacterial action of macrophages should provide a therapeutic strategy for aberrant inflammatory responses leading to severe cellular injury or concurrent multiorgan septic damage.}, }
@article {pmid11939711, year = {2002}, author = {Rankin, GO and Hong, SK and Anestis, DK and Henderson, TT and Ball, JG and Valentovic, MA and Brown, PI}, title = {Effect of three n-acetylamino acids on N-(3,5-dichlorophenyl)succinimide (NDPS) and ndps metabolite nephrotoxicity in Fischer 344 rats.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {65}, number = {7}, pages = {539-556}, doi = {10.1080/15287390252807993}, pmid = {11939711}, issn = {1528-7394}, support = {DK31210/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Alanine/*analogs &amp; derivatives/pharmacology ; Amino Acids/*pharmacology ; Animals ; Fungicides, Industrial/*toxicity ; Injections, Intraperitoneal ; Kidney/drug effects ; Kidney Diseases/*chemically induced ; Kidney Function Tests ; Liver/drug effects ; Male ; Rats ; Rats, Inbred F344 ; Serine/*analogs &amp; derivatives/pharmacology ; Serotonin/*analogs &amp; derivatives/*toxicity ; Succinates/toxicity ; Succinimides/toxicity ; }, abstract = {The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) induces nephrotoxicity in mammals characterized as polyuric renal failure and proximal tubular necrosis. Recent studies have suggested that NDPS-induced nephrotoxicity may be mediated by metabolites arising from the nephrotoxic NDPS metabolites N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS) and/or N-(3,5-dichlorophenyl)-2-succinamic acid (2-NDHSA). The purpose of this study was to examine the effects of N-acetylcysteine (NAC), a nucleophilic agent, and two nonnucleophilic N-acetylamino acids, N-acetylserine (NAS) and N-acetylalanine (NAA), on NDPS and NDPS metabolite-induced nephrotoxicity. Male Fischer 344 rats (4-8/group) were administered intraperitoneally (ip) an N-acetylamino acid (1 mmol/kg) 2 h before an ip injection of NDPS (0.4 mmol/kg), NDHS (0.1 mmol/kg), 2-NDHSA (0.1 mmol/kg), or vehicle. Renal function was then monitored at 24 and 48 h. NAC pretreatment markedly attenuated NDPS-, NDHS-, and 2-NDHSA-mediated nephrotoxicity. The nonnucleophilic N-acetylamino acids (NAS, NAA) only partly reduced NDPS and NDHS nephrotoxicity, and they had little effect on 2-NDHSA nephrotoxicity. These results suggest that reactive NDPS metabolites may be formed from NDHS and 2-NDHSA and that nucleophilic substrates (e.g., NAC) may offer protection from NDPS-induced nephrotoxicity. However, mechanisms other than chemical neutralization of reactive NDPS metabolites may also be contributing to the attenuation of NDPS nephrotoxicity, since nonnucleophilic N-acetylamino acids (e.g., NAA) also provided some protection against NDPS and NDHS nephrotoxicity.}, }
@article {pmid11937079, year = {2002}, author = {Popat, A and Shear, NH and Malkiewicz, I and Thomson, S and Neuman, MG}, title = {Mechanism of Impila (Callilepis laureola)-induced cytotoxicity in Hep G2 cells.}, journal = {Clinical biochemistry}, volume = {35}, number = {1}, pages = {57-64}, doi = {10.1016/s0009-9120(02)00271-0}, pmid = {11937079}, issn = {0009-9120}, mesh = {Acetylcysteine/pharmacology ; Cell Division/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Formazans ; Glutathione/*metabolism ; Hepatoblastoma/*drug therapy/metabolism ; Humans ; Liver Neoplasms/*drug therapy/metabolism ; Medicine, African Traditional ; Plant Extracts/*toxicity ; Plants, Medicinal/*toxicity ; Tetrazolium Salts ; Time Factors ; Tumor Cells, Cultured/drug effects/metabolism ; }, abstract = {OBJECTIVES: To determine the mechanism(s) of Impila (Callilepis laureola)-induced toxicity in human hepatoblastoma Hep G2 cells in vitro and the possible prevention of this toxicity by N-acetylcysteine (NAC).<br><br>DESIGN AND METHODS: Cells were treated with an aqueous extract of Impila (10 mg/mL) for up to 24 h. NAC (5 mM) was administered either concomitantly with Impila or one hour post Impila treatment. Cytotoxicity was quantitated spectrophotometrically by the metabolism of the tetrazolium dye MTT. Total glutathione (GSH) was measured using the Tietze assay.<br><br>RESULTS: Impila produced cytotoxicity and depleted GSH in a concentration- and time-dependent manner. A significant depletion in GSH was observed after 15 min (p < 0.0001 vs. control), whereas significant cytotoxicity was only observed after at least 3 h (p < 0.0001 vs. control). Both concomitant and posttreatment with NAC prevented Impila-induced GSH depletion and resulted in a significant decrease in Impila-induced cytotoxicity (p < 0.001 vs. NAC-untreated cells).<br><br>CONCLUSION: Our results suggest the mechanism of Impila-induced cytotoxicity in Hep G2 cells in vitro involves depletion of cellular GSH. Preventing GSH depletion by supplementing cells with NAC reduces cytotoxicity.}, }
@article {pmid11933167, year = {2002}, author = {Lee, CK and Piedrahita, JA}, title = {Inhibition of apoptosis in serum starved porcine embryonic fibroblasts.}, journal = {Molecular reproduction and development}, volume = {62}, number = {1}, pages = {106-112}, doi = {10.1002/mrd.10058}, pmid = {11933167}, issn = {1040-452X}, support = {HL 51587/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; *Apoptosis ; Cells, Cultured ; Culture Media, Serum-Free ; Female ; Fibroblasts/cytology/*drug effects ; Free Radical Scavengers/pharmacology ; Protease Inhibitors/pharmacology ; Swine ; alpha-Macroglobulins/pharmacology ; }, abstract = {In nuclear transplantation, serum starvation is a general method to synchronize donor cells at the quiescent stage (G(0)) of the cell cycle. However, serum starvation during culture of mammalian cells may induce cell death, especially through apoptosis, thus contributing to the low efficiency of nuclear transplantation. This study was performed to characterize apoptosis during serum starvation and to determine the effects of apoptosis inhibitors such as a protease inhibitor [alpha(2)-macroglobulin (MAC)] and antioxidants [N-acetylcysteine (NAC), glutathione (GSH)] on serum starved porcine embryonic fibroblasts (PEF). PEF, collected from day 25-30 porcine fetuses, were cultured for 5 days in media containing 0.5% FBS to induce quiescence. Serum starved PEF showed typical morphology of apoptotic cells and stained for DNA fragmentation by TUNEL assay (26.7%). All apoptosis inhibitors tested in this study significantly (P < 0.05) reduced apoptosis of serum starved PEF, with antioxidants having better results (MAC: 7.4% vs. NAC: 1.0%, and GSH: 0.8%). Equally and importantly, the treatment with apoptosis inhibitors did not change the proportion of G(0)/G(1) stage cells. Therefore, the addition of MAC and antioxidants during serum starvation of PEF reduces apoptosis of quiescent fibroblasts and may contribute to increasing the efficiency of nuclear transplantation by improving the quality of donor nuclei.}, }
@article {pmid11926292, year = {2002}, author = {Manov, I and Hirsh, M and Iancu, TC}, title = {Acetaminophen hepatotoxicity and mechanisms of its protection by N-acetylcysteine: a study of Hep3B cells.}, journal = {Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie}, volume = {53}, number = {6}, pages = {489-500}, doi = {10.1078/0940-2993-00215}, pmid = {11926292}, issn = {0940-2993}, mesh = {Acetaminophen/antagonists &amp; inhibitors/*toxicity ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/antagonists &amp; inhibitors/*toxicity ; Apoptosis/drug effects ; Carcinoma, Hepatocellular ; Cell Nucleus/drug effects/ultrastructure ; Cell Survival/drug effects ; Cytoplasm/drug effects/ultrastructure ; Dose-Response Relationship, Drug ; Drug Antagonism ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Hepatocytes/*drug effects/metabolism/pathology ; Humans ; Liver Neoplasms ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured/drug effects/metabolism/pathology ; }, abstract = {Acetaminophen (AAP) hepatotoxicity, resulting in centrilobular necrosis, is frequently encountered following suicidal attempts, especially by adolescents, but also after its excessive use in infants. The subcellular and molecular sequences leading to hepatocellular cell death are not yet clear. We therefore investigated AAP hepatotoxicity by using cultured hepatoma-derived cells (Hep3B) exposed to AAP and N-acetylcysteine (NAC), used as a protective agent. Specifically, we studied the role of apoptosis and oxidative damage as putative mechanisms of AAP-associated cytotoxicity. Hep3B cells were exposed to AAP (5-25 mM) and NAC (5 mM) for different time periods. Cell viability was assessed by the Alamar Blue Reduction Test and LDH. Oxidative damage was evaluated by measuring reactive oxygen species (ROS) and glutathione. AAP-induced apoptosis was investigated by flow cytometry and transmission electron microscopy. We found that: 1. In Hep3B cells, AAP causes a time- and concentration-dependent cytotoxic effect, leading to oxidative stress, mitochondrial dysfunction, alterations of membrane permeability and apoptosis; 2. In the course of AAP cytotoxicity, the generation of ROS appears as an early event which precedes decrease of viability, LDH leakage, glutathione depletion and apoptosis; 3. NAC protects Hep3B cells from AAP-induced oxidative injury, but does not prevent apoptosis.}, }
@article {pmid11922866, year = {2002}, author = {Carpenter, LR and Moy, JN and Roebuck, KA}, title = {Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1.}, journal = {BMC infectious diseases}, volume = {2}, number = {}, pages = {5}, pmid = {11922866}, issn = {1471-2334}, support = {AR45835/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antiviral Agents/pharmacology ; Chemokines/biosynthesis/*genetics ; Dexamethasone/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects/*physiology ; Glucocorticoids/pharmacology ; Humans ; Lung Neoplasms/genetics/metabolism ; NF-kappa B/antagonists &amp; inhibitors/metabolism/*physiology ; Oxidation-Reduction ; Respiratory Syncytial Viruses/drug effects/isolation &amp; purification/*metabolism ; Signal Transduction/drug effects/physiology ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/metabolism/*physiology ; }, abstract = {BACKGROUND: Respiratory syncytial virus (RSV) infection of airway epithelial cells stimulates the expression and secretion of a variety of cytokines including the chemotactic cytokines interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and RANTES (regulated upon activation, normal T cell expressed and secreted). Chemokines are important chemoattractants for the recruitment of distinct sets of leukocytes to airway sites of inflammation.<br><br>RESULTS: We have shown previously that chemokine expression is regulated in airway epithelial cells (A549) in a stimulus-specific manner in part through the redox-responsive transcription factors AP-1 and NF-kappaB. In this study, we examined the NF-kappaB-mediated effects of RSV and the proinflammatory cytokine TNFalpha on the induction of IL-8, MCP-1 and RANTES chemokine gene expression in A549 epithelial cells. The results demonstrate that RSV induces chemokine expression with distinct kinetics that is associated with a specific pattern of NF-kappaB binding activity. This distinction was further demonstrated by the differential effects of the NF-kappaB inhibitors dexamethasone (DEX) and N-acetyl-L-cysteine (NAC). NAC preferentially inhibited RSV induced chemokine expression, whereas DEX preferentially inhibited TNFalpha induced chemokine expression. DNA binding studies using NF-kappaB subunit specific binding ELISA demonstrated that RSV and TNFalpha induced different NF-kappaB binding complexes containing Rel A (p65) and NF-kappaB1 (p50). Both TNFalpha and RSV strongly induced Rel A the activation subunit of NF-kappaB, whereas only TNFalpha was able to substantially induce the p50 subunit. Consistent with the expression studies, RSV but not TNFalpha induction of Rel A and p50 were markedly inhibited by NAC, providing a mechanism by which TNFalpha and RSV can differentially activate chemokine gene expression via NF-kappaB.<br><br>CONCLUSIONS: These data suggest that RSV induction of chemokine gene expression, in contrast to TNFalpha, involves redox-sensitive NF-kappaB complexes containing predominantly Rel A.}, }
@article {pmid11920607, year = {2002}, author = {Balansky, RM and Ganchev, G and D'Agostini, F and De Flora, S}, title = {Effects of N-acetylcysteine in an esophageal carcinogenesis model in rats treated with diethylnitrosamine and diethyldithiocarbamate.}, journal = {International journal of cancer}, volume = {98}, number = {4}, pages = {493-497}, doi = {10.1002/ijc.10215}, pmid = {11920607}, issn = {0020-7136}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Diethylnitrosamine/*administration &amp; dosage ; Ditiocarb/*administration &amp; dosage ; Drug Synergism ; Esophageal Neoplasms/chemically induced/mortality/*prevention &amp; control ; Esophagus/drug effects/pathology ; Free Radical Scavengers/*pharmacology ; Hyperplasia ; Keratosis ; Liver Neoplasms/chemically induced/prevention &amp; control ; Rats ; Rats, Inbred Strains ; Survival Rate ; }, abstract = {Due to the increasing role of esophageal tumors in human cancer pathology, there is need for animal models evaluating the mechanisms of esophageal carcinogenesis and investigating protective factors toward this disease. Several N-nitrosamines have been shown to induce esophageal tumors in rats. We designed a study in BD(6) rats treated with N-diethylnitrosamine (DEN) according to a simple protocol involving weekly i.p. injections of this carcinogen for 8 consecutive weeks. This treatment resulted in a high incidence and multiplicity of liver tumors and in occurrence of preneoplastic lesions and papillomas in the esophagus. Intraperitoneal injections of diethyldithiocarbamate (DEDTC), 4 hr after each DEN injection, i.e., during the period of DEN metabolization, improved survival of rats and did not affect the liver tumor yield but doubled the incidence of esophageal tumors and enhanced 4.9x their multiplicity. Moreover, 15% of rats developed esophageal squamocellular carcinomas. The oral administration of the thiol N-acetyl-L-cysteine (NAC), a precursor and analogue of reduced glutathione, to rats treated with the DEN/DEDTC combination did not change the liver tumor yield but attenuated esophageal carcinogenesis by producing a significant shift of preneoplastic lesions to milder forms as well as a significant decrease of tumor multiplicity. Therefore, the DEN/DEDTC protocol appears to provide an interesting 2-organ model of N-nitrosamine-induced carcinogenesis in rats, in which NAC is moderately effective as an inhibitor. The mechanisms underlying enhancement of DEN-induced esophageal carcinogenesis by DEDTC and the protective effects of NAC are discussed.}, }
@article {pmid11916964, year = {2002}, author = {Cemerski, S and Cantagrel, A and Van Meerwijk, JP and Romagnoli, P}, title = {Reactive oxygen species differentially affect T cell receptor-signaling pathways.}, journal = {The Journal of biological chemistry}, volume = {277}, number = {22}, pages = {19585-19593}, doi = {10.1074/jbc.M111451200}, pmid = {11916964}, issn = {0021-9258}, mesh = {Antibodies, Monoclonal/metabolism ; CD3 Complex/biosynthesis ; Cell Division ; Coculture Techniques ; Dose-Response Relationship, Drug ; Flow Cytometry ; Humans ; Immunoblotting ; Membrane Proteins/*chemistry/metabolism ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Neutrophils/metabolism ; Oxidative Stress ; Phosphorylation ; *Reactive Oxygen Species ; Receptors, Antigen, T-Cell/*chemistry/*metabolism ; *Signal Transduction ; Time Factors ; }, abstract = {Oxidative stress plays an important role in the induction of T lymphocyte hyporesponsiveness observed in several human pathologies including cancer, rheumatoid arthritis, leprosy, and AIDS. To investigate the molecular basis of oxidative stress-induced T cell hyporesponsiveness, we have developed an in vitro system in which T lymphocytes are rendered hyporesponsive by co-culture with oxygen radical-producing activated neutrophils. We have observed a direct correlation between the level of T cell hyporesponsiveness induced and the concentration of reactive oxygen species produced. Moreover, induction of T cell hyporesponsiveness is blocked by addition of N-acetyl cysteine, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, and catalase, confirming the critical role of oxidative stress in this system. The pattern of tyrosine-phosphorylated proteins was profoundly altered in hyporesponsive as compared with normal T cells. In hyporesponsive T cells, T cell receptor (TCR) ligation no longer induced phospholipase C-gamma1 activation and caused reduced Ca(2+) flux. In contrast, despite increased levels of ERK1/2 phosphorylation, TCR-dependent activation of mitogen-activated protein kinase ERK1/2 was unaltered in hyporesponsive T lymphocytes. A late TCR-signaling event such as caspase 3 activation was as well unaffected in hyporesponsive T lymphocytes. Our data indicate that TCR-signaling pathways are differentially affected by physiological levels of oxidative stress and would suggest that although "hyporesponsive" T cells have lost certain effector functions, they may have maintained or gained others.}, }
@article {pmid11915034, year = {2002}, author = {Schmidt, LE and Dalhoff, K and Poulsen, HE}, title = {Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity.}, journal = {Hepatology (Baltimore, Md.)}, volume = {35}, number = {4}, pages = {876-882}, doi = {10.1053/jhep.2002.32148}, pmid = {11915034}, issn = {0270-9139}, mesh = {Acetaminophen/administration &amp; dosage/*adverse effects ; Adult ; Aging/physiology ; Alcohol Drinking/*adverse effects ; Analgesics, Non-Narcotic/*administration &amp; dosage ; *Chemical and Drug Induced Liver Injury ; Dose-Response Relationship, Drug ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Prognosis ; Time Factors ; }, abstract = {The aim of this study was to determine by multivariate analysis how alcohol and other factors affect the clinical course and outcome in patients with acetaminophen (paracetamol) poisoning. A total of 645 consecutive patients admitted from 1994 to 2000 with single-dose acetaminophen poisoning were studied, giving special attention to alcohol history, time between overdose and intravenous N-acetylcysteine (NAC) treatment ("time to NAC"), and other data available at the time of admittance. Up until 72 hours after ingestion, time to NAC was the single most important independent risk factor. With a time to NAC less than 12 hours, the mortality rate was 0.42% (95% CI, 0.05-2.7). When time to NAC exceeded 12, 24, and 48 hours, the mortality rate increased to 6.1%, 13%, and 19%, respectively. Chronic alcohol abuse was an independent risk factor of mortality (odds ratio [OR], 3.52; 95% CI, 1.78-6.97). Acute alcohol ingestion was an independent protective factor regarding mortality in alcoholic patients (OR, 0.08; 95% CI, 0.01-0.66) but not in nonalcoholic patients (OR, 0.21; 95% CI, 0.03-1.67). Patient age and quantity of acetaminophen were independent risk factors. In conclusion, time to NAC was confirmed as the major risk factor in acetaminophen-induced hepatotoxicity and mortality. Chronic alcohol abuse was an independent risk factor that could be counteracted by concomitant acute alcohol ingestion. We suggest that patients with chronic alcoholism and suspected acetaminophen poisoning due to an increased risk of developing hepatotoxicity should be treated with NAC regardless of risk estimation.}, }
@article {pmid11909699, year = {2002}, author = {Sekhar, KR and Spitz, DR and Harris, S and Nguyen, TT and Meredith, MJ and Holt, JT and Gius, D and Marnett, LJ and Summar, ML and Freeman, ML}, title = {Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase.}, journal = {Free radical biology &amp; medicine}, volume = {32}, number = {7}, pages = {650-662}, doi = {10.1016/s0891-5849(02)00755-4}, pmid = {11909699}, issn = {0891-5849}, support = {R01HL551469/HL/NHLBI NIH HHS/United States ; R01 CA038079/CA/NCI NIH HHS/United States ; CA47479/CA/NCI NIH HHS/United States ; CA38079/CA/NCI NIH HHS/United States ; P30ES00267/ES/NIEHS NIH HHS/United States ; }, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Blotting, Northern ; Carcinoma, Hepatocellular/*drug therapy/enzymology ; Carrier Proteins/*metabolism ; Chloramphenicol O-Acetyltransferase/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Fluorescent Antibody Technique, Indirect ; Glutamate-Cysteine Ligase/genetics/*metabolism ; Glutathione/metabolism ; Humans ; Ibuprofen/pharmacology ; Indomethacin/*pharmacology ; Leucine Zippers ; Liver Neoplasms/*drug therapy/enzymology ; MAP Kinase Kinase 1 ; Mitogen-Activated Protein Kinase Kinases/metabolism ; NF-E2-Related Factor 2 ; Oxidation-Reduction ; Promoter Regions, Genetic ; Protein Serine-Threonine Kinases/metabolism ; RNA, Messenger/metabolism ; Trans-Activators/genetics/*metabolism ; Transfection ; Tumor Cells, Cultured/drug effects/enzymology/metabolism ; }, abstract = {Exposure of HepG2 cells to nonsteroidal anti-inflammatory drugs (i.e., indomethacin and ibuprofen; NSAIDs) as well as resveratrol, caused increased expression of the mRNAs coding for the catalytic (Gclc) and modifier (Gclm) subunits of the glutathione synthetic enzyme, gamma-glutamylcysteine synthetase. In addition, indomethacin exposure increased intracellular glutathione content as well as inhibited glutathione depletion and cytotoxicity caused by diethyl maleate. Indomethacin-induced increases in the expression of gamma-glutamylcysteine synthetase mRNA were preceded by increases in steady state levels of intracellular pro-oxidants and glutathione disulfide accumulation. Simultaneous incubation with the thiol antioxidant N-acetylcysteine (NAC) inhibited indomethacin-mediated increases in GCLC mRNA, suggesting that increases in GCLC message were triggered by changes in intracellular oxidation/reduction (redox) reactions. Indirect immunofluorescence using intact cells demonstrated that indomethacin induced the nuclear translocation of Nrf2, a transcription factor believed to regulate GCLC expression. Immunoprecipitation studies showed that indomethacin treatment also inhibited Nrf2 tethering to KIAA0132 (the human homolog of Keap1 accession #D50922), which is believed to be a negative regulator of Nrf2. Consistent with this idea, over-expression of Nrf2 increased GCLC reporter gene expression and over-expression of KIAA0132 inhibited GCLC reporter gene activity as well as inhibited indomethacin-induced increases in the expression of GCLC. Finally, simultaneous treatment with NAC inhibited both indomethacin-induced release of Nrf2 from KIAA0132 and indomethacin-induced nuclear translocation of Nrf2. These results demonstrate that NSAIDs and resveratrol cause increases in the expression of gamma-glutamylcysteine synthetase mRNA and identify these agents as being capable of stimulating glutathione metabolism. These results also support the hypothesis that indomethacin-induced transcriptional activation of GCLC involves the redox-dependent release of KIAA0132 from Nrf2 followed by the nuclear translocation of Nrf2.}, }
@article {pmid11899429, year = {2001}, author = {Viora, M and Quaranta, MG and Straface, E and Vari, R and Masella, R and Malorni, W}, title = {Redox imbalance and immune functions: opposite effects of oxidized low-density lipoproteins and N-acetylcysteine.}, journal = {Immunology}, volume = {104}, number = {4}, pages = {431-438}, pmid = {11899429}, issn = {0019-2805}, mesh = {Acetylcysteine/*pharmacology ; Cell Division/drug effects ; Cells, Cultured ; Cytokines/biosynthesis ; Cytotoxicity, Immunologic/drug effects ; Down-Regulation/drug effects ; Free Radical Scavengers/*pharmacology ; Humans ; Killer Cells, Natural/drug effects/immunology ; Leukocytes, Mononuclear/*drug effects/immunology ; Lipoproteins, LDL/*pharmacology ; Lymphocyte Activation/drug effects ; Mitogens/immunology ; Oxidation-Reduction ; Oxidative Stress/*immunology ; Up-Regulation/drug effects ; }, abstract = {This study investigates the in vitro effects of oxidized low-density lipoproteins (ox-LDL), 'physiological' pro-oxidants, N-acetylcysteine (NAC), a free radical scavenger and glutathione precursor, and their combination on human peripheral blood mononuclear cell functions. We found that treatment with ox-LDL induced a significant down-regulation of proliferative response to mitogens, antigens and interleukin-2. Lipid extracts from ox-LDL were able to reproduce the same effect as the lipoprotein. On the other hand, NAC exposure induced a significant up-regulation of proliferative responses to all the stimuli used. Moreover, we showed that natural killer (NK) cell-mediated cytotoxic activity was significantly down-regulated by ox-LDL while treatment with NAC induced a significant up-regulation of NK-cell activity. Finally, we found that ox-LDL and NAC exerted opposite effects on the cytokine network, interfering both at the protein secretion level and the messenger RNA synthesis level. More importantly, when NAC was used in combination with ox-LDL the proliferative responses, NK-cell-mediated cytotoxic activity and cytokine production were restored to values comparable to controls. These data indicate that ox-LDL and NAC modulate immune functions, exerting opposite effects reflecting their pro-oxidant and antioxidant behaviours. Our results add new insights to the key role played by redox imbalance as a modulator of immune system homeostasis and suggest that an antioxidant drug such as NAC could be useful against pathologies associated with an increase in lipid peroxidation.}, }
@article {pmid11897511, year = {2002}, author = {He, YY and Häder, DP}, title = {UV-B-induced formation of reactive oxygen species and oxidative damage of the cyanobacterium Anabaena sp.: protective effects of ascorbic acid and N-acetyl-L-cysteine.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {66}, number = {2}, pages = {115-124}, doi = {10.1016/s1011-1344(02)00231-2}, pmid = {11897511}, issn = {1011-1344}, mesh = {Acetylcysteine/*pharmacology ; Anabaena/*drug effects/genetics/metabolism/radiation effects ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Chlorophyll/radiation effects ; DNA Damage ; DNA, Bacterial/drug effects/radiation effects ; Free Radical Scavengers/*pharmacology ; Lipid Peroxidation/drug effects/radiation effects ; Oxidative Stress/*drug effects ; Photosynthesis/radiation effects ; Reactive Oxygen Species/*metabolism ; Ultraviolet Rays ; }, abstract = {Reactive oxygen species (ROS) are involved in the oxidative damage of the cyanobacterium Anabaena sp. caused by UV-B (280-315 nm) radiation. UV-B-induced overproduction of ROS as well as the oxidative stress was detected in vivo by using the ROS-sensitive probe 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). Thiobarbituric acid reactive substances (TBARS) and fluorometric analysis of DNA unwinding (FADU) methods were adapted to measure lipid peroxidation and DNA strand breaks in Anabaena sp. Moderate UV-B radiation causes an increase of ROS production, enhanced lipid peroxidation and DNA strand breaks, yielding a significantly decreased survival. In contrast, the supplementation of UV-A in our work only showed a significant increase in total ROS levels and DNA strand breaks while no significant effect on lipid peroxidation, chlorophyll bleaching or survival was observed. The presence of ascorbic acid and N-acetyl-L-cysteine (NAC) reversed the oxidative stress and protected the organisms from chlorophyll bleaching and the damage of photosynthetic apparatus induced by UV-B significantly, resulting in a considerably higher survival rate. Ascorbic acid also exhibited a significant protective effect on lipid peroxidation and DNA strand breaks while NAC did not show a substantial effect. These results suggest that ascorbic acid exhibited significantly higher protective efficiency with respect to DNA strand breaks and survival than NAC while NAC appears to be especially effective in defending the photosynthetic apparatus from oxidative damage.}, }
@article {pmid11896744, year = {2002}, author = {Parcell, S}, title = {Sulfur in human nutrition and applications in medicine.}, journal = {Alternative medicine review : a journal of clinical therapeutic}, volume = {7}, number = {1}, pages = {22-44}, pmid = {11896744}, issn = {1089-5159}, mesh = {Amino Acids, Essential/*therapeutic use ; Antioxidants/therapeutic use ; Arteriosclerosis/therapy ; Chondroitin Sulfates/therapeutic use ; Diet ; Dimethyl Sulfoxide/therapeutic use ; Glucosamine/therapeutic use ; Glutathione Transferase/therapeutic use ; HIV Infections/therapy ; Humans ; Muscle Fatigue ; Sulfur/physiology/*therapeutic use ; Thioctic Acid/therapeutic use ; }, abstract = {Because the role of elemental sulfur in human nutrition has not been studied extensively, it is the purpose of this article to emphasize the importance of this element in humans and discuss the therapeutic applications of sulfur compounds in medicine. Sulfur is the sixth most abundant macromineral in breast milk and the third most abundant mineral based on percentage of total body weight. The sulfur-containing amino acids (SAAs) are methionine, cysteine, cystine, homocysteine, homocystine, and taurine. Dietary SAA analysis and protein supplementation may be indicated for vegan athletes, children, or patients with HIV, because of an increased risk for SAA deficiency in these groups. Methylsulfonylmethane (MSM), a volatile component in the sulfur cycle, is another source of sulfur found in the human diet. Increases in serum sulfate may explain some of the therapeutic effects of MSM, DMSO, and glucosamine sulfate. Organic sulfur, as SAAs, can be used to increase synthesis of S-adenosylmethionine (SAMe), glutathione (GSH), taurine, and N-acetylcysteine (NAC). MSM may be effective for the treatment of allergy, pain syndromes, athletic injuries, and bladder disorders. Other sulfur compounds such as SAMe, dimethylsulfoxide (DMSO), taurine, glucosamine or chondroitin sulfate, and reduced glutathione may also have clinical applications in the treatment of a number of conditions such as depression, fibromyalgia, arthritis, interstitial cystitis, athletic injuries, congestive heart failure, diabetes, cancer, and AIDS. Dosages, mechanisms of action, and rationales for use are discussed. The low toxicological profiles of these sulfur compounds, combined with promising therapeutic effects, warrant continued human clinical trails.}, }
@article {pmid11888918, year = {2002}, author = {Havre, PA and O'Reilly, S and McCormick, JJ and Brash, DE}, title = {Transformed and tumor-derived human cells exhibit preferential sensitivity to the thiol antioxidants, N-acetyl cysteine and penicillamine.}, journal = {Cancer research}, volume = {62}, number = {5}, pages = {1443-1449}, pmid = {11888918}, issn = {0008-5472}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Line ; Cell Transformation, Neoplastic/*drug effects ; Fibroblasts/drug effects ; Genes, myc ; Humans ; Neoplasms/*drug therapy/pathology ; Penicillamine/*pharmacology ; Tumor Suppressor Protein p53/biosynthesis/physiology ; }, abstract = {Thiol antioxidants, typified by N-acetyl cysteine, are known to induce p53-dependent apoptosis in transformed mouse embryo fibroblasts but not in normal mouse embryo fibroblasts. We now report that this is also the case for human cells. First, we used an isogenic fibroblast cell lineage exhibiting progressive stages of transformation, from primary derived cells to v-MYC immortalized to tumorigenic. At the immortalization stage, cells became 12- and 480-fold more sensitive to the thiol antioxidants N-acetyl cysteine (NAC) and penicillamine (PEN), respectively. Although immortalization of these cells was associated with v-MYC expression, overexpression of MYC was not sufficient for sensitizing these cells to antioxidants. To test whether sensitivity to antioxidants is a general property of immortalized human cells, including fully transformed cells, 12 tumor-derived cell lines were treated with PEN, the more potent of the two antioxidants. Ten of 11 caspase-proficient tumor cell lines underwent apoptosis after treatment, whereas primary fibroblasts and keratinocytes were resistant. The difference between normal and transformed cells was apparent whether the assay used measured caspase 3 activation, Annexin V binding, or cell viability. Tumor cell lines containing wild-type p53 were more sensitive than p53-null cell lines. The requirement for p53 was tested using the p53 inhibitor, pifithrin-alpha, or using stable transfectants of a v-MYC-immortalized, telomerase-positive cell line that expresses HPV16 E6 to bind and degrade p53. In the latter case, > or = 80% of the PEN-induced apoptosis was dependent on the presence of wild-type p53. These studies suggest that treatment with thiol-containing antioxidants, such as PEN, may offer a useful approach for preferential induction of apoptosis in preneoplastic and neoplastic cells.}, }
@article {pmid11887346, year = {2002}, author = {Ortolani, O and Conti, A and De Gaudio, AR and Moraldi, E and Novelli, GP}, title = {[Glutathione and N-acetylcysteine in the prevention of free-radical damage in the initial phase of septic shock].}, journal = {Recenti progressi in medicina}, volume = {93}, number = {2}, pages = {125-129}, pmid = {11887346}, issn = {0034-1193}, mesh = {Acetylcysteine/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Free Radicals/*antagonists &amp; inhibitors ; Glutathione/*therapeutic use ; Humans ; Shock, Septic/*complications ; }, abstract = {The hyperproduction of oxygen free radicals (OFR) and the weakening of natural scavenging mechanisms are implicated in endothelial damage and in multiple organ failure during septic shock. Many authors have proposed the use of antioxidants to decrease OFR damage. Glutathione (GSH) is one of the most important endogenous antioxidants. It plays the role of a sulphydryl group provider for scavenging reactions. N-Acetylcysteine (NAC) is an artificial precursor of GSH which both increases GSH levels and acts as OFR scavenger. The authors carried out a clinical trial to confirm the capacity of high doses of GSH and NAC to cooperate in reducing lipoperoxidative damage in patients with early septic shock. Patients were divided into three groups who received shock therapy only or shock therapy plus GSH or shock therapy plus GSH plus NAC. OFR damage was evaluated by measuring expired ethane, plasma malondialdehyde, complement activation and clinical scores. The study demonstrated that the group who received GSH and NAC showed a significant decrease in peroxidative indexes and an improvement of the clinical scores if compared with the other two groups. In conclusion the administration of high doses of NAC added to GSH significantly decreases the peroxidative stress of patients with early septic shock.}, }
@article {pmid11886795, year = {2002}, author = {Hakimelahi, GH and Gassanov, GSh and Hsu, MH and Hwu, JR and Hakimelahi, S}, title = {A novel approach towards studying non-genotoxic enediynes as potential anticancer therapeutics.}, journal = {Bioorganic &amp; medicinal chemistry}, volume = {10}, number = {5}, pages = {1321-1328}, doi = {10.1016/s0968-0896(01)00393-5}, pmid = {11886795}, issn = {0968-0896}, mesh = {Alkenes/*chemical synthesis/pharmacology ; Alkynes/*chemical synthesis/pharmacology ; Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology ; Cell Division/drug effects ; Cell Size/drug effects ; Doxorubicin/pharmacology ; Drug Synergism ; Glutathione/drug effects/metabolism ; Humans ; Mutagenicity Tests ; Tumor Cells, Cultured/drug effects ; Uracil/*analogs &amp; derivatives/chemistry/pharmacology ; }, abstract = {A novel uracil-containing enediyne was synthesized by the fusion at N(1) and N(3) of uracil with an 11-membered cyclic enediyne. Compound was found to be stable against cycloaromatization at 80 degreesC. Thus, it did not cause DNA-damage. Unlike other alkylated uracil derivatives 2--6, highly strained uracil-containing enediyne was reacted with methyl thioglycolate at 25 degreesC to produce uracil () and linear enediyne. This reactivity toward a sulfhydryl group may play a significant role in the mechanism by which compound directed its cytotoxicity toward tumor cell lines. Tumor cells were found to be more susceptible to enediyne than normal human embryonic lung cells. A combination of with adriamycin or 1-(beta-D-arabinofuranosyl)cytosine resulted in synergistic anticancer activity against murine L1210 and P388 leukemias, Sarcoma 180, and human CCRF--CEM lymphoblastic leukemia. After treatment of Molt-4 cells with uracil-containing enediyne, light microscope examination demonstrated the presence of cell shrinkage and nuclear segmentation. Treatment of cultured Molt-4 human leukemia cells with enediyne resulted in a time-dependent depletion of glutathione (GSH) whereas the exposure of the cells to the GSH precursor N-acetylcysteine (NAC) resulted in a substantial suppression of this effect. As such, involvement of GSH depletion in the process of apoptosis may explain the mechanism of action of non-genotoxic enediyne against malignant tumor cell lines.}, }
@article {pmid11886167, year = {2002}, author = {Kim, HH and Lee, SE and Chung, WJ and Choi, Y and Kwack, K and Kim, SW and Kim, MS and Park, H and Lee, ZH}, title = {Stabilization of hypoxia-inducible factor-1alpha is involved in the hypoxic stimuli-induced expression of vascular endothelial growth factor in osteoblastic cells.}, journal = {Cytokine}, volume = {17}, number = {1}, pages = {14-27}, doi = {10.1006/cyto.2001.0985}, pmid = {11886167}, issn = {1043-4666}, mesh = {Acetylcysteine/chemistry ; Blotting, Western ; Calcitriol/pharmacology ; Cell Line ; Cobalt/pharmacology ; Dexamethasone/pharmacology ; Dinoprostone/pharmacology ; Dose-Response Relationship, Drug ; Endothelial Growth Factors/*biosynthesis/chemistry ; Free Radical Scavengers/pharmacology ; Gene Expression ; Glucocorticoids/pharmacology ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit ; Luciferases/metabolism ; Lymphokines/*biosynthesis/chemistry ; *MAP Kinase Kinase Kinase 1 ; Mitogen-Activated Protein Kinases/metabolism ; Osteoblasts/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Serine-Threonine Kinases/metabolism ; RNA, Messenger/metabolism ; Reactive Oxygen Species ; Response Elements ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; Transcription Factors/*chemistry/*metabolism ; Transfection ; Transforming Growth Factor beta/pharmacology ; Transforming Growth Factor beta1 ; Up-Regulation ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {It has been suggested that blood vessel formation is an important event coupled to bone formation. The expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been shown to be greatly stimulated in osteoblasts by hypoxic stimuli such as deprivation of oxygen and treatment with cobalt. In other cell types, hypoxia-inducible factor-1 (HIF-1) that binds hypoxia-response element (HRE) has been shown to mediate gene expression induced by hypoxic stimuli. In this study, we investigated the effects of hypoxic stimuli on HIF-1, HRE, and VEGF in osteoblastic cell lines. Exposure of these cells to hypoxia or cobalt resulted in a great increase in the protein level of HIF-1alpha and the gene expression of VEGF. Transforming growth factor-beta1, prostaglandin E2, dexamethasone, and 1,25-dihydroxyvitamin D3 that have been shown to regulate VEGF gene expression in osteoblasts had no effect on HIF-1alpha induction. Blocking the enzymatic activity of phosphatidylinositol 3-kinase, p38, MEK-1 did not have any effect on the cobalt-stimulated increase of HIF-1alpha in these cells. In contrast, N-acetylcysteine (NAC), a scavenger of reactive oxygen species, abolished the cobalt induction of HIF-1alpha and that of the VEGF and a HRE-driven reporter genes. However, the hypoxia responses were not affected by NAC. These findings suggest that hypoxia and cobalt can induce VEGF gene expression in osteoblasts by increasing the level of HIF-1alpha protein through different mechanisms.}, }
@article {pmid11881979, year = {2001}, author = {Márquez, R and Santángelo, G and Sastre, J and Goldschmidt, P and Luyckx, J and Pallardó, FV and Viña, J}, title = {Cyanoside chloride and chromocarbe diethylamine are more effective than vitamin C against exercise-induced oxidative stress.}, journal = {Pharmacology &amp; toxicology}, volume = {89}, number = {5}, pages = {255-258}, doi = {10.1034/j.1600-0773.2001.d01-156.x}, pmid = {11881979}, issn = {0901-9928}, mesh = {Alanine Transaminase/blood/drug effects ; Animals ; *Anthocyanins ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Biomarkers ; Chromones/chemistry/*pharmacology ; Creatine Kinase/blood/drug effects ; Diethylamines/chemistry/*pharmacology ; Drug Combinations ; Flavonoids/chemistry/*pharmacology ; Glutathione/blood/drug effects ; L-Lactate Dehydrogenase/blood/drug effects ; Lactic Acid/blood ; Male ; Malondialdehyde/blood ; Muscle, Skeletal/enzymology ; Oxidative Stress/*drug effects ; Physical Conditioning, Animal/adverse effects ; Rats ; Rats, Wistar ; }, abstract = {Exercise generates free radicals only when it is exhaustive. Free radicals are involved in tissue damage caused by exercise. Antioxidant vitamins (vitamin C and E) and other antioxidants such as coenzyme Q, and N-acetyl cysteine prevent muscle damage and decrease muscle fatigue. The main aim of this paper was to test the possible protective effect of two new antioxidants, cyanoside chloride and chromocarbe diethylamine, on the oxidative stress generated by exhaustive exercise. The antioxidants were given to rats daily (50 mg/kg) in drinking water for 30 days. Blood oxidized glutathione/ reduced glutathione ratio, and plasma malondialdehyde levels were determined as indexes of oxidative stress. Plasma creatine kinase, alanine-aminotransferase and lactate dehydrogenase activities were used as markers of muscle damage. Both cyanoside chloride and chromocarbe diethylamine were more effective than vitamin C in the prevention of glutathione oxidation in blood. Furthermore, cyanoside chloride and chromocarbe diethylamine partially prevented muscle damage. Chromocarbe diethylamine was the most effective compound in the prevention of exercise-induced lipid peroxidation (malondialdehyde) in plasma.}, }
@article {pmid11880902, year = {2002}, author = {Ryu, R and Shin, Y and Choi, JW and Min, W and Ryu, H and Choi, CR and Ko, H}, title = {Depletion of intracellular glutathione mediates zinc-induced cell death in rat primary astrocytes.}, journal = {Experimental brain research}, volume = {143}, number = {2}, pages = {257-263}, doi = {10.1007/s00221-001-0991-7}, pmid = {11880902}, issn = {0014-4819}, mesh = {Animals ; Astrocytes/*drug effects/*metabolism ; Cell Death/drug effects ; Cells, Cultured ; Glioma/metabolism/pathology ; Glutathione/*metabolism ; Membrane Potentials/drug effects ; Mitochondria/drug effects/metabolism ; Prefrontal Cortex/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Tumor Cells, Cultured ; Zinc/*pharmacology ; }, abstract = {In the present study, we investigated the possible mechanisms of cellular injury induced by zinc in rat primary astrocytes and C6 glioma cells. Reactive oxygen species (ROS) production, cellular glutathione (GSH) level and mitochondrial transmembrane potential were examined. Exposure to 200-300 microM Zn2+ for 24 h resulted in significant lactate dehydrogenase (LDH) release in rat primary astrocytes and C6 glioma cells. An exposure of 200 microM Zn2+ resulted in profound morphological changes, for example, shrunken and fragmented nuclei. Pretreatment of a protein synthesis inhibitor, cycloheximide, did not attenuate cellular toxicity induced by Zn2+. Zn2+ exposure increased intracellular ROS levels by about 250%, and depleted cellular GSH within 2 h, which preceded observable LDH release from the cell. Addition of GSH, N-acetylcysteine (NAC) and ascorbic acid substantially attenuated cellular death induced by Zn+ in a concentration dependent manner. ROS production and morphological changes induced by zinc were also inhibited by co-treatment of GSH or NAC with Zn2+. Zn2+ significantly depolarized mitochondrial transmembrane potential, which was reversed by co-treatment of GSH or NAC with zinc. In summary, ROS generation, GSH depletion and mitochondrial dysfunction may be key factors in Zn2+-induced glial toxicity.}, }
@article {pmid11876893, year = {2000}, author = {Xiao, C and Yi, J and Mao, Y}, title = {[Clinical application of irradiated drug-containing porcine-cornea to patients with ocular burns].}, journal = {Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns}, volume = {16}, number = {6}, pages = {331-333}, pmid = {11876893}, issn = {1009-2587}, mesh = {Acetylcysteine/pharmacology ; Adolescent ; Adult ; Animals ; Child ; Child, Preschool ; Cornea/radiation effects ; *Corneal Transplantation ; Eye Burns/*surgery ; Female ; Glutathione/pharmacology ; Humans ; Infant ; Male ; Middle Aged ; Ofloxacin/pharmacology ; Swine ; }, abstract = {OBJECTIVE: To explore a new method for the management of patients with ocular burns.<br><br>METHODS: Fifty-five cases of patients with ocular burns (in 88 eyes) were randomly divided into treatment and control groups. Thirty cases in treatment group with 49 eyes were transplanted with irradiated drug-containing (ofloxacin, acetyl cysteine and reduced glutathione) porcine-cornea. 25 cases in control group with 39 eyes were treated with routine program.<br><br>RESULTS: Thirty-two eyes were rescued in treatment group with the cure rate of 65.3%. But only 17 eyes were saved in control group with the cure rate of 43.59%, indicating significant difference of the cure rate between the two groups (P < 0.05).<br><br>CONCLUSION: Irradiated drug-containing porcine-cornea might well be an ideal therapeutic material for the management of patients with ocular burns.}, }
@article {pmid11876867, year = {2000}, author = {Fu, Z and Yang, Z and Li, A}, title = {[The effects of NAC on the expression and activity of SPA in rats inflicted by smoke inhalation injury].}, journal = {Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns}, volume = {16}, number = {3}, pages = {173-176}, pmid = {11876867}, issn = {1009-2587}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bronchoalveolar Lavage Fluid ; Lung Compliance ; Proteolipids/*genetics/physiology ; Pulmonary Surfactant-Associated Proteins ; Pulmonary Surfactants/*genetics/physiology ; RNA, Messenger/analysis ; Rats ; Rats, Wistar ; Smoke Inhalation Injury/*drug therapy/physiopathology ; Surface Tension ; }, abstract = {OBJECTIVE: To investigate the effects of NAC (N-acetyl-L-cysteine) on the expression and activity of SPA (surfactant-associated protein A) in rats inflicted by smoke inhalation injury.<br><br>METHODS: Wistar rats inflicted with smoke inhalation injury were employed as the model. The expression of SPA mRNA, the static pulmonary compliance, the surface tension of the alveolar lavage and the morphology of lamellae bodies (LB) of type II alveolar cells were examined.<br><br>RESULTS: After the application of NAC, there exhibited an increase in SPA mRNA expression and static pulmonary compliance, and the restoration of the BAL surface tension to normal.<br><br>CONCLUSION: The application of NAC could promote the expression of SPA mRNA after smoke inhalation injury and improve the SPA-related function.}, }
@article {pmid11870230, year = {2002}, author = {Otala, M and Erkkilä, K and Tuuri, T and Sjöberg, J and Suomalainen, L and Suikkari, AM and Pentikäinen, V and Dunkel, L}, title = {Cell death and its suppression in human ovarian tissue culture.}, journal = {Molecular human reproduction}, volume = {8}, number = {3}, pages = {228-236}, doi = {10.1093/molehr/8.3.228}, pmid = {11870230}, issn = {1360-9947}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/*pharmacology ; *Apoptosis ; Caspase 3 ; Caspases/metabolism ; Culture Techniques ; Enzyme Activation ; Female ; Humans ; In Situ Nick-End Labeling ; Microscopy, Electron ; Ovary/drug effects/metabolism/*pathology ; *Oxidative Stress ; }, abstract = {In women with premature ovarian failure, fertility may be preserved by ovarian tissue culture in vitro. However, techniques for tissue culture and follicle maturation have remained suboptimal. Our aim was to characterize ovarian tissue degeneration in cultures and to establish a model for cell death research in cultured ovarian tissue. Precise knowledge on the process resulting in cell death in cultured ovarian tissue will ultimately facilitate work aimed at improving long-term culture conditions. Ovarian tissue apoptosis was studied in a serum-free culture model in which nuclear DNA fragmentation was shown to occur within 24 h of the start of the culture. Activation of caspase-3 was detected in some stromal cells and a few oocytes. Since not all of the tissue exhibited signs of apoptosis and since DNA fragmentation increased over time, the tissue probably gradually dies by apoptosis. The antioxidant N-acetyl-L-cysteine (NAC; 25, 50 and 100 mmol/l) was found to inhibit this apoptosis. Thus, apoptosis appears to play a critical role in the degeneration of human ovarian cortical tissue cultures, and this cell death can be suppressed by NAC. The present tissue culture model can be used for identifying components capable of inhibiting cell death in vitro.}, }
@article {pmid11867563, year = {2002}, author = {Wu, Z and Turner, DR and Oliveira, DB}, title = {Antioxidants inhibit mercuric chloride-induced early vasculitis.}, journal = {International immunology}, volume = {14}, number = {3}, pages = {267-273}, doi = {10.1093/intimm/14.3.267}, pmid = {11867563}, issn = {0953-8178}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Line ; Chymases ; Deferoxamine/chemistry/metabolism ; Immunoenzyme Techniques ; Immunoglobulin E/biosynthesis/immunology ; Interleukin-4/biosynthesis/immunology ; Male ; Mast Cells/immunology/metabolism ; Mercuric Chloride/antagonists &amp; inhibitors ; Pyruvic Acid/chemistry/metabolism ; Rats ; Rats, Inbred BN ; Serine Endopeptidases/metabolism ; Vasculitis/chemically induced/immunology/*prevention &amp; control ; }, abstract = {In the Brown Norway (BN) rat, mercuric chloride (HgCl(2)) induces a T(h)2-dominated autoimmune syndrome which includes an early phase of mast cell-dependent vasculitis. We have shown in vitro that oxidative stress up-regulates IL-4 in mast cells and predisposes to degranulation. The aim of this study was to determine whether administration of antioxidants inhibits HgCl(2)-induced early vasculitis in vivo, and, if so, to examine whether modulation of the oxidative/antioxidative balance influences IgE and IL-4 expression by mast cells in situ. Groups of rats were given HgCl(2) + saline, HgCl(2) + N-acetyl-L-cysteine (NAC), saline + saline or saline + NAC respectively and blood was taken and animals killed 48 h later. NAC significantly reduced both HgCl2-induced early vasculitis and HgCl(2)-enhanced IgE expression on mast cells with a trend to a decrease in HgCl(2)-enhanced IL-4 expression in these cells. In addition, there was an increased rat mast cell protease (RMCP) II concentration in the serum after HgCl(2) injection and the elevated levels of RMCP II stimulated by HgCl(2) were totally abolished by the administration NAC in the HgCl(2) + NAC group. However, there was no significant change in serum total IgE concentrations between the HgCl(2) + saline group and the HgCl(2) + NAC group. The non-sulphydryl-containing antioxidants desferrioxamine and pyruvate demonstrated a similar effect in inhibiting HgCl(2)-induced early vasculitis. Our data show that administration of an antioxidant to BN rats reduces HgCl(2)-induced early vasculitis, suggesting that oxidative stress plays a role in the pathogenesis of HgCl(2)-induced early vasculitis. This finding may have implications for the understanding of the initiation in this experimental model of T(h)2 cell-driven autoimmunity and possibly of analogous human diseases.}, }
@article {pmid11867504, year = {2002}, author = {Van Schooten, FJ and Besaratinia, A and De Flora, S and D'Agostini, F and Izzotti, A and Camoirano, A and Balm, AJ and Dallinga, JW and Bast, A and Haenen, GR and Van't Veer, L and Baas, P and Sakai, H and Van Zandwijk, N}, title = {Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {11}, number = {2}, pages = {167-175}, pmid = {11867504}, issn = {1055-9965}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Adult ; Anticarcinogenic Agents/administration &amp; dosage/*therapeutic use ; Antioxidants/administration &amp; dosage/*therapeutic use ; Biomarkers/analysis ; Cotinine/metabolism ; DNA Adducts ; DNA Damage ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Male ; Mutagenicity Tests ; Neoplasms/etiology/*prevention &amp; control ; Smoking/adverse effects/*metabolism ; }, abstract = {N-Acetyl-L-cysteine (NAC) has been shown to exert cancer-protective mechanisms and effects in experimental models. We report here the results of a randomized, double-blind, placebo-controlled, Phase II chemoprevention trial with NAC in healthy smoking volunteers. The subjects were supplemented daily with 2 x 600 mg of oral tablets of NAC (n = 20) or placebo (n = 21) for a period of 6 months, and internal dose markers [plasma and bronchoalveolar lavage (BAL) fluid cotinine, urine mutagenicity], biologically effective dose markers [smoking-related DNA adducts and hemoglobin (Hb) adducts], and biological response markers (micronuclei frequency and antioxidants scavenging capacity) were assessed at both pre- and postsupplementation times (T(0) and T(1), respectively). Overall, the internal dose markers remained unchanged at T(1) as compared with T(0) in both NAC and placebo groups. When quantifying the biologically effective dose markers, we observed an inhibitory effect of NAC toward the formation of lipophilic-DNA adducts (5.18 +/- 0.73 versus 4.08 +/- 1.03/10(8) nucleotides; mean +/- SE; P = 0.05) as well as of 7,8-dihydro-8-oxo-2'-deoxyguanosine adducts in BAL cells (3.9 +/- 0.6 versus 2.3 +/- 0.2/10(5) nucleotides; P = 0.003). There was no effect of NAC on the formation of lipophilic-DNA adducts in peripheral blood lymphocytes or polycyclic aromatic hydrocarbon-DNA adducts in mouth floor/buccal mucosa cells or 4-aminobiphenyl-Hb adducts. Likewise, quantification of the biological response markers showed an inhibitory effect of NAC on the frequency of micronuclei in mouth floor and in soft palate cells (1.3 +/- 0.2 versus 0.9 +/- 0.2; P = 0.001) and a stimulating effect of NAC on plasma antioxidant scavenging capacity (393 +/- 14 versus 473 +/- 19 microM Trolox; P = 0.1) but not on BAL fluid antioxidant scavenging capacity. We conclude that NAC has the potential to impact upon tobacco smoke carcinogenicity in humans because it can modulate certain cancer-associated biomarkers in specific organs.}, }
@article {pmid11867340, year = {2002}, author = {Ouadrhiri, Y and Pilette, C and Monteiro, RC and Vaerman, JP and Sibille, Y}, title = {Effect of IgA on respiratory burst and cytokine release by human alveolar macrophages: role of ERK1/2 mitogen-activated protein kinases and NF-kappaB.}, journal = {American journal of respiratory cell and molecular biology}, volume = {26}, number = {3}, pages = {315-332}, doi = {10.1165/ajrcmb.26.3.4590}, pmid = {11867340}, issn = {1044-1549}, mesh = {Antigens, CD/immunology/metabolism ; Carcinogens/pharmacology ; Humans ; Immunoglobulin A/*immunology/pharmacology ; In Vitro Techniques ; Lipopolysaccharides/pharmacology ; Macrophage Activation/drug effects/immunology ; Macrophages, Alveolar/immunology/*metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Receptors, Fc/immunology/metabolism ; Respiratory Burst/*immunology ; Signal Transduction/drug effects/immunology ; Tetradecanoylphorbol Acetate/pharmacology ; Up-Regulation/drug effects ; }, abstract = {Human alveolar macrophages (HAM) express FcalphaR receptors for immunoglobulin (Ig)A which could link humoral and cellular branches of lung immunity. Here, we investigate the effects of polymeric (p-IgA) and secretory (S-IgA) IgA interaction with Fc(alpha)R on lipopolysaccharide (LPS)- and phorbol myristate acetate (PMA)-activated respiratory burst and TNF-alpha release by HAM. Activation of HAM with LPS and PMA increases the respiratory burst and TNF-alpha release through activation of the extracellular signal-related protein kinases 1 and 2 (ERK1/2) pathway, because these effects are inhibited by treatment of HAM with PD98059, a selective inhibitor of mitogen-activated protein (MAP)/ERK kinases (MEK) pathway. S-IgA and p-IgA downregulate the LPS-increased respiratory burst in HAM through an inhibition of ERK1/2 activity. In contrast, p- and S-IgA induce an increase in the respiratory burst of PMA-treated HAM. This effect is associated with an upregulation by IgA of the PMA-induced phosphorylation of ERK1/2 and is also inhibited by PD98059. Moreover, p-IgA and S-IgA enhance TNF-alpha release by HAM through an alternative pathway distinct from ERK1/2. Because LPS is known to activate nuclear factor-kappaB (NF-kappaB) in HAM, we evaluate the effect of IgA on NF-kappaB. Treatment of HAM with LPS, p- and S-IgA, but not PMA, induces NF-kappaB activation through IkappaBalpha phosphorylation and subsequent proteolysis. Antioxidants, namely N-acetylcysteine (NAC) and glutathione (GSH), have no effects on IgA-mediated NF-kappaB nuclear translocation and only a minor and late effect on that of LPS, suggesting that reactive oxygen intermediates (ROI) play a minor role in HAM activation through NF-kappaB. TNF-alpha release by LPS-activated HAM is sensitive to NF-kappaB inhibition and only partly to oxidant scavenging. In contrast, TNF-alpha release by IgA-treated HAM is not dependent on oxidants and only partly dependent on NF-kappaB. Our results show a differential HAM regulation by IgA through both dependent and independent modulation of ERK pathway. In addition, IgA activates NF-kappaB and this effect was independent on oxidants. These data may help to understand the role of IgA in both lung protection and inflammation.}, }
@article {pmid11862160, year = {2002}, author = {Liu, JJ and Wang, JY and Zhang, C and Nilsson, A and Duan, RD}, title = {Hepatic cirrhosis increases sensitivity of kidney to endotoxin in rats.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {8}, number = {2}, pages = {BR56-60}, pmid = {11862160}, issn = {1234-1010}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Endotoxins/*toxicity ; Kidney/*drug effects/physiopathology ; Liver Cirrhosis/*physiopathology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Renal failure in cirrhotic patients is a severe complication and endotoxemia might be involved. We investigated the effect of endotoxin on renal function of cirrhotic rats and the potential protective role of N-acetylcysteine (NAC).<br><br>MATERIAL/METHODS: Hepatic cirrhosis was generated in a rat model by carbon tetrachloride. Both cirrhotic and normal rats were insulted by endotoxin intravenously, while another cirrhotic group was pre-treated with NAC. Blood urea nitrogen (BUN) and creatinine were assayed eight hours later. The changes in serum tumor necrosis factor-a (TNF-a) were assayed by ELISA. The histological changes in the kidney were observed after hematoxylin and eosin staining.<br><br>RESULTS: Endotoxin increased the BUN and creatinine levels in both normal and cirrhotic rats, with a much higher elevation in the latter group. TNF-a concentration was also increased by endotoxin; the changes are positively correlated with BUN and creatinine. NAC pretreatment significantly attenuates the effects of endotoxin on BUN, creatinine and TNF-a levels in cirrhotic rats with no improvement in systemic toxicity symptoms. There were no obvious histological changes in the kidney of these animals.<br><br>CONCLUSIONS: Hepatic cirrhosis increased the sensitivity of renal function to endotoxemia, which may be protected by NAC.}, }
@article {pmid11862087, year = {2002}, author = {Yalçin, E and Altin, F and Cinhüseyinoglue, F and Arslan, MO}, title = {N-acetylcysteine in chronic blepharitis.}, journal = {Cornea}, volume = {21}, number = {2}, pages = {164-168}, doi = {10.1097/00003226-200203000-00007}, pmid = {11862087}, issn = {0277-3740}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Administration, Topical ; Adult ; Anti-Bacterial Agents/administration &amp; dosage ; Blepharitis/*drug therapy/metabolism ; Chronic Disease ; Female ; Fluorophotometry ; Glucocorticoids/administration &amp; dosage ; Humans ; Male ; Mucins/chemistry ; Prednisolone/administration &amp; dosage/*analogs &amp; derivatives ; Prospective Studies ; Tears/chemistry/metabolism ; Tobramycin/administration &amp; dosage ; }, abstract = {PURPOSE: To investigate the effects of N-acetylcysteine (NAC) in chronic posterior blepharitis.<br><br>METHODS: This was a prospective randomized, controlled study that included 79 eyes of 40 patients with chronic posterior blepharitis. Routine ophthalmologic examination, Schirmer-1 test, fluorescein break-up time (FBUT), and mucous fern tests were carried out during the first visit of all patients. A topical steroid, topical antibiotic, and artificial tears were started in 36 eyes of 18 patients. The therapy group (43 eyes of 22 patients) was administered three daily doses of 100 mg oral NAC. All patients were examined weekly for 1 to 4 months (average, 24 +/- 0.7). A Schirmer-1 test and FBUT were administered at every visit, but mucous fern tests were administered every two weeks. The results of the first and last Schirmer-1 tests, FBUT, and mucous fern test were compared between the therapy and control groups. Student's t and Mann-Whitney U tests were used for statistical analysis.<br><br>RESULTS: FBUT was significantly increased (p < 0.0001), and the mucous fern pattern was also significantly improved (p = 0.0096) in the therapy group.<br><br>CONCLUSION: NAC is thought to increase FBUT and improve mucous fern pattern by blocking lipid peroxidation in chronic blepharitis.}, }
@article {pmid11861267, year = {2002}, author = {Hildebrandt, W and Alexander, S and Bärtsch, P and Dröge, W}, title = {Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: linkage between plasma thiol redox state and O(2) chemosensitivity.}, journal = {Blood}, volume = {99}, number = {5}, pages = {1552-1555}, doi = {10.1182/blood.v99.5.1552}, pmid = {11861267}, issn = {0006-4971}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Erythropoietin/*biosynthesis/blood ; Humans ; Hypoxia/*physiopathology ; Male ; Oxidation-Reduction ; Oxygen/blood/physiology ; Pulmonary Ventilation/drug effects ; Respiration/*drug effects ; Sulfhydryl Compounds/blood/physiology ; Time Factors ; }, abstract = {Oxygen-sensing chemoreceptors contribute significantly to the regulation of the respiratory drive and arterial PO(2) levels. The hypoxic ventilatory response (HVR) decreases strongly with age and is modulated by prolonged hypoxia and physical exercise. Several earlier studies indicated that the regulation of the ventilatory response and erythropoietin (EPO) production by the respective oxygen sensors involves redox-sensitive signaling pathways, which are triggered by the O(2)-dependent production of reactive oxygen species. The hypothesis that HVR and EPO production are modulated by thiol compounds or changes in the plasma thiol-disulfide redox state (REDST) was investigated. It was demonstrated that both responses are enhanced by oral treatment with N-acetyl-cysteine (NAC) and that HVR is correlated with plasma thiol level and REDST. Results suggest the possibility that age-related changes in plasma REDST may account for the age-related changes in HVR.}, }
@article {pmid11860910, year = {2000}, author = {Li, H and Fu, S}, title = {[Toxicity to neural cell development of lead and its relation to glutathione].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {34}, number = {2}, pages = {98-100}, pmid = {11860910}, issn = {0253-9624}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Differentiation/drug effects ; Cell Division/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Embryo, Mammalian ; Female ; Glutathione/*metabolism ; Lead/*toxicity ; Mesencephalon/*cytology/growth &amp; development/metabolism ; Neurons/drug effects ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; }, abstract = {OBJECTIVE: To investigate the toxicity of lead to embryonic neural cell development and its relation to glutathione level.<br><br>METHODS: Rat midbrain micromass culture method was used to observe effects of lead on viability, differentiation and glutathione (GSH) content of embryonic neural cells.<br><br>RESULTS: Lead concentrations at 3.69 micromol/L and 1.03 micromol/L could inhibit neural cell variability and differentiation by 50%, respectively, both in a significant dose-response pattern. Lead also could cause increase level of glutathione. N-acetylcysteine (NAC), an antioxidant, could not only reduce adverse effect of lead on GSH, but also antagonize its toxicity to cell survival and differentiation.<br><br>CONCLUSION: Lead can specifically inhibit neural cell differentiation and its neurotoxic effects on brain cell development correlated to imbalance in redox status which is mainly mediated by decrease of GSH content.}, }
@article {pmid11859152, year = {2002}, author = {Whitekus, MJ and Li, N and Zhang, M and Wang, M and Horwitz, MA and Nelson, SK and Horwitz, LD and Brechun, N and Diaz-Sanchez, D and Nel, AE}, title = {Thiol antioxidants inhibit the adjuvant effects of aerosolized diesel exhaust particles in a murine model for ovalbumin sensitization.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {168}, number = {5}, pages = {2560-2567}, doi = {10.4049/jimmunol.168.5.2560}, pmid = {11859152}, issn = {0022-1767}, support = {AI 07126/AI/NIAID NIH HHS/United States ; P01 AI 50495/AI/NIAID NIH HHS/United States ; P01 ES 09481/ES/NIEHS NIH HHS/United States ; R01 ES 10553/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adjuvants, Immunologic/*antagonists &amp; inhibitors ; Administration, Inhalation ; Aerosols ; Animals ; Antioxidants/*pharmacology ; Cell Line ; Cysteine/analogs &amp; derivatives/*pharmacology ; Hypersensitivity, Immediate/*immunology/metabolism/therapy ; Immunoglobulin E/biosynthesis ; Immunoglobulin G/biosynthesis ; Lipid Peroxidation/drug effects ; Lung/drug effects/metabolism ; Mice ; Ovalbumin/administration &amp; dosage/immunology ; Oxidative Stress/drug effects ; Sulfhydryl Compounds/pharmacology ; *Vehicle Emissions ; }, abstract = {Although several epidemiological studies indicate a correlation between exposure to ambient particulate matter and adverse health effects in humans, there is still a fundamental lack of understanding of the mechanisms involved. We set out to test the hypothesis that reactive oxygen species are involved in the adjuvant effects of diesel exhaust particles (DEP) in a murine OVA sensitization model. First, we tested six different antioxidants, N-acetylcysteine (NAC), bucillamine (BUC), silibinin, luteolin, trolox (vitamin E), and ascorbic acid, for their ability to interfere in DEP-mediated oxidative stress in vitro. Of the six agents tested, only the thiol antioxidants, BUC and NAC, were effective at preventing a decrease in intracellular reduced glutathione:glutathione disulfide ratios, protecting cells from protein and lipid oxidation, and preventing heme oxygenase 1 expression. Therefore, we selected the thiol antioxidants for testing in the murine OVA inhalation sensitization model. Our data demonstrate that NAC and BUC effectively inhibited the adjuvant effects of DEP in the induction of OVA-specific IgE and IgG1 production. Furthermore, NAC and BUC prevented the generation of lipid peroxidation and protein oxidation in the lungs of OVA- plus DEP-exposed animals. These findings indicate that NAC and BUC are capable of preventing the adjuvant effects of inhaled DEP and suggest that oxidative stress is a key mechanistic component in the adjuvant effect of DEP. Antioxidant treatment strategies may therefore serve to alleviate allergic inflammation and may provide a rational basis for treating the contribution of particulate matter to asthmatic disease.}, }
@article {pmid11857775, year = {2002}, author = {Bomser, JA}, title = {Selective induction of mitogen-activated protein kinases in human lens epithelial cells by ultraviolet radiation.}, journal = {Journal of biochemical and molecular toxicology}, volume = {16}, number = {1}, pages = {33-40}, doi = {10.1002/jbt.10016}, pmid = {11857775}, issn = {1095-6670}, mesh = {Blotting, Western ; Cell Line ; Dose-Response Relationship, Radiation ; Enzyme Induction/radiation effects ; Epithelial Cells/*enzymology/*radiation effects ; Hot Temperature ; Humans ; Indoles/pharmacology ; *JNK Mitogen-Activated Protein Kinases ; Lens, Crystalline/cytology/*enzymology/*radiation effects ; MAP Kinase Kinase 4 ; MAP Kinase Signaling System/radiation effects ; Maleimides/pharmacology ; Mitogen-Activated Protein Kinase Kinases/biosynthesis ; Mitogen-Activated Protein Kinases/*biosynthesis ; Signal Transduction/drug effects ; Time Factors ; *Ultraviolet Rays ; }, abstract = {The present study investigates the effects of ultraviolet radiation (UVR) on mitogen-activated protein kinase (MAPK) activity in human lens epithelial (HLE) cells. Irradiation of HLE cells with ultraviolet B and ultraviolet C radiation activates the stress-response MAPK proteins, p38 and c-Jun NH(2)-terminal kinase (JNK), in a dose- and time-dependent manner, while the extracellular-regulated signal kinase (ERK 44/42) cascade was not altered by UVR exposure. Ultraviolet A radiation failed to elicit a MAPK response. UVR-induced MAPK activation does not require protein kinase C or phosphatidylinositol 3-kinase activity, suggesting that this is not a receptor-mediated event. Inhibition of ribosomal translation completely abolished UVR-induced MAPK activation, while treatment with the antioxidant, N-acetyl cysteine, and mild heat shock had no effect on this activation. These data demonstrate for the first time the selective activation of MAPK cascades in a lens epithelial cell line.}, }
@article {pmid11855796, year = {2001}, author = {Kowluru, RA}, title = {Diabetes-induced elevations in retinal oxidative stress, protein kinase C and nitric oxide are interrelated.}, journal = {Acta diabetologica}, volume = {38}, number = {4}, pages = {179-185}, doi = {10.1007/s592-001-8076-6}, pmid = {11855796}, issn = {0940-5429}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Diabetic Retinopathy/etiology/*metabolism ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Glucose/*metabolism ; Indoles/pharmacology ; Male ; Maleimides/pharmacology ; NG-Nitroarginine Methyl Ester ; Nitric Oxide/antagonists &amp; inhibitors/*metabolism ; Oxidative Stress/*physiology ; Protein Kinase C/antagonists &amp; inhibitors/*metabolism ; Rats ; Rats, Sprague-Dawley ; Retina/*metabolism/pathology ; Thiobarbituric Acid Reactive Substances/analysis ; }, abstract = {Hyperglycemia results in various retinal metabolic abnormalities that can contribute to the development of retinopathy, but it has been difficult to recognize which abnormalities are critical. In this study, the possible interrelationship between hyperglycemia-stimulated oxidative stress, protein kinase C (PKC), and nitric oxide (NO) was investigated by examining the effects of inhibitors of oxidative stress, PKC and NO on glucose-induced retinal oxidative stress, PKC activity and NO levels concentrations, both under in vitro conditions in retinal endothelial cells and isolated retina, and in vivo in the retina from diabetic rats. Bovine retinal endothelial cells were incubated in 5 or 30 mM glucose for 3 days in the presence or absence of inhibitors of oxidative stress (N-acetyl cysteine), PKC (LY333531), or NO (L-NAME). Incubation of retinal endothelial cells in 30 mM glucose resulted in an approximately 2-fold elevation in retinal TBARS, PKC and NO. Addition of N-acetyl cysteine, LY333531, or L-NAME significantly inhibited glucose-induced elevation in oxidative stress, NO and PKC. Similar results were obtained when intact retinas from normal rats were incubated with 30 mM glucose for 6 hours. In diabetic rats, elevations in retinal TBARS, PKC and NO were observed at 2 months of diabetes, and administration of N-acetyl cysteine, LY333531 or aminoguanidine prevented diabetes-induced elevation in retinal TBARS and NO levels, and PKC activity. Thus, these results suggest that diabetes-induced metabolic abnormalities, originally considered to be independent abnormalities, are apparently interrelated in retina; inhibiting a single retinal abnormality may have multiple beneficial effects to correct retinal dysmetabolism and to inhibit the development of retinopathy.}, }
@article {pmid11851362, year = {2002}, author = {Higuchi, Y and Otsu, K and Nishida, K and Hirotani, S and Nakayama, H and Yamaguchi, O and Matsumura, Y and Ueno, H and Tada, M and Hori, M}, title = {Involvement of reactive oxygen species-mediated NF-kappa B activation in TNF-alpha-induced cardiomyocyte hypertrophy.}, journal = {Journal of molecular and cellular cardiology}, volume = {34}, number = {2}, pages = {233-240}, doi = {10.1006/jmcc.2001.1505}, pmid = {11851362}, issn = {0022-2828}, mesh = {Animals ; Cardiomegaly/etiology/metabolism ; Cell Size/physiology ; Myocardium/*metabolism ; NF-kappa B/*physiology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Signal Transduction/physiology ; Tumor Necrosis Factor-alpha/*physiology ; }, abstract = {We examined the intracellular signaling mechanism for tumor necrosis factor-alpha (TNF-alpha)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes. TNF-alpha enhanced the expression of a kappa B-dependent reporter gene construct in a dose-dependent manner, which was transiently transfected in cardiomyocytes. Electrophoretic mobility shift assay demonstrated that TNF-alpha induced nuclear factor- kappa B (NF-kappa B)-specific DNA binding. Cultured cardiomyocytes were infected with a recombinant adenoviral vector expressing a degradation-resistant mutant of I kappa B alpha (AdI kappa B alpha 32/36A). The I kappa B alpha mutant suppressed NF-kappa B activation induced by TNF- alpha. In cardiomyocytes infected with AdI kappa B alpha 32/36A, TNF-alpha-induced hypertrophic responses, including increases in cell size, protein synthesis and atrial natriuretic factor production and enhancement of sarcomeric organization, were remarkably attenuated compared to the cells infected with an adenovirus expressing bacterial beta-galactosidase. Using a reactive oxygen species (ROS)-sensitive fluorescent dye, 2', 7'-dichlorofluorescin, we observed an increase in fluorescent signal in cardiomyocytes over time, upon addition of TNF-alpha. Preincubation of n-acetyl cysteine (NAC), an antioxidant, prior to TNF-alpha treatment, abolished TNF-alpha -induced ROS generation. NAC abolished TNF-alpha-induced NF-kappa B activation and hypertrophic responses. These findings indicated that TNF-alpha-induced cardiomyocyte hypertrophy is mediated through NF-kappa B activation via the generation of ROS.}, }
@article {pmid11848284, year = {2002}, author = {Yamauchi, A and Ueda, N and Hanafusa, S and Yamashita, E and Kihara, M and Naito, S}, title = {Tissue distribution of and species differences in deacetylation of N-acetyl-L-cysteine and immunohistochemical localization of acylase I in the primate kidney.}, journal = {The Journal of pharmacy and pharmacology}, volume = {54}, number = {2}, pages = {205-212}, doi = {10.1211/0022357021778394}, pmid = {11848284}, issn = {0022-3573}, mesh = {Acetylation ; Acetylcysteine/*pharmacokinetics ; Amidohydrolases/*metabolism ; Animals ; Biotransformation ; Blotting, Western ; Chromatography, High Pressure Liquid ; Dogs ; Electrophoresis, Polyacrylamide Gel ; Humans ; Immunohistochemistry ; Kidney/*enzymology ; Liver/enzymology ; Macaca fascicularis ; Organ Specificity ; Parenteral Nutrition ; Rabbits ; Rats ; Rats, Wistar ; Species Specificity ; Tissue Distribution ; }, abstract = {Species differences in the biotransformation of N-acetyl-L-cysteine (NAC) have been investigated to evaluate the usefulness of NAC as a constituent in parenteral nutrition solutions in place of cysteine. The activity of NAC-deacetylating enzyme (acylase) was measured in various tissues of different species (rat, rabbit, dog, monkey, and man). Acylase activity was highest in the kidney in all species studied. Enzyme activity in the liver was 10 %-22 % of that in the kidney in the rat, rabbit, monkey, and man, but almost no hepatic activity was seen in the dog. NAC-deacetylating activity was very low in other organs. The tissue distribution of acylase I was determined by Western blotting and an immunohistochemical method employing specific antibody against porcine acylase I (EC 3.5.1.14). The immunoblotting study showed a 46-kDa protein band corresponding to porcine acylase I in the kidney of all species. In liver cytosol, 46 kDa and/or 29 kDa bands were observed in the rat, rabbit, monkey, and man, but not in the dog. In the immunohistochemical study, positive staining with anti-acylase I antibody was observed clearly in the renal proximal tubules in the monkey and man. These results suggested that the kidney and liver were the main organs responsible for the biotransformation of NAC to cysteine in mammals other than the dog.}, }
@article {pmid11841837, year = {2002}, author = {Ghezzi, P and Romines, B and Fratelli, M and Eberini, I and Gianazza, E and Casagrande, S and Laragione, T and Mengozzi, M and Herzenberg, LA and Herzenberg, LA}, title = {Protein glutathionylation: coupling and uncoupling of glutathione to protein thiol groups in lymphocytes under oxidative stress and HIV infection.}, journal = {Molecular immunology}, volume = {38}, number = {10}, pages = {773-780}, doi = {10.1016/s0161-5890(01)00114-6}, pmid = {11841837}, issn = {0161-5890}, mesh = {Acetylcysteine ; Diamide/chemistry/metabolism ; Glutathione/chemistry/*metabolism ; HIV Infections/*blood ; Humans ; *Oxidative Stress ; Proteins/chemistry/*metabolism ; Sulfhydryl Compounds ; T-Lymphocytes/chemistry/*metabolism ; }, abstract = {We show here that exposure to oxidative stress induces glutathione (GSH) modification of protein cysteinyl residues (glutathionylation) in T cell blasts. Treating the cells with the oxidant diamide induces thiolation of a series of proteins that can be detected by 2D electrophoresis when 35S-cysteine is used to label the intracellular GSH pool. This thiolation is reversible, proteins are rapidly dethiolated and GSH is released from proteins once the oxidants are washed and the cells are allowed to recover. Dethiolation is dependent on the availability of GSH and thiols, since it is inhibited by GSH-depleting agents and improved by N-acetyl-L-cysteine (NAC). The capacity of these agents to reverse glutathionylation is diminished in T cell blasts infected in vitro with HIV, which is known to cause oxidative stress. Consistent with these findings, the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an enzyme known to be inhibited by glutathionylation, is inhibited in diamide-treated cells and recovers rapidly when cells are allowed to dethiolate. Further, GAPDH activity is diminished by GSH-depleting agents and augmented by NAC. Thus, reversible glutathionylation of proteins can rapidly shift the activity of a key metabolic enzyme and thereby result in dramatic, reversible changes in cellular metabolism.}, }
@article {pmid11841806, year = {2002}, author = {Haddad, JJ}, title = {The involvement of L-gamma-glutamyl-L-cysteinyl-glycine (glutathione/GSH) in the mechanism of redox signaling mediating MAPK(p38)-dependent regulation of pro-inflammatory cytokine production.}, journal = {Biochemical pharmacology}, volume = {63}, number = {2}, pages = {305-320}, doi = {10.1016/s0006-2952(01)00870-x}, pmid = {11841806}, issn = {0006-2952}, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Cytokines/*metabolism ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/biosynthesis ; Glutathione Disulfide/*metabolism ; HSP27 Heat-Shock Proteins ; *Heat-Shock Proteins ; Interleukin-6/metabolism ; Intracellular Signaling Peptides and Proteins ; Lipopolysaccharides/*pharmacology ; Mitogen-Activated Protein Kinases/*metabolism ; Neoplasm Proteins/metabolism ; Oxidation-Reduction ; Phosphorylation ; Protein Serine-Threonine Kinases/metabolism ; Rats ; Signal Transduction/*drug effects ; Tumor Necrosis Factor-alpha/metabolism ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Redox regulation of mitogen-activated protein kinase (MAPK(p38))-mediated pro-inflammatory cytokine production is not well characterized in the alveolar epithelium. It was hypothesized that the involvement of the MAPK(p38) pathway in regulating lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha and interleukin-6 secretion is redox-sensitive and affected by NAC, an antioxidant and a precursor of glutathione, and L-buthionine-(S,R)-sulfoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis. Exposure of fetal alveolar type II epithelial cells to Escherichia coli-derived LPS induced, in a time-dependent manner, the phosphorylation/activation of MAPK(p38) (peak at 15min). In addition, LPS up-regulated the phosphorylation of MAPK(p38) in a dose-dependent manner. The effect of LPS on the MAPK(p38) pathway was associated with the activation of MAPK-activated protein kinase, which phosphorylated the small 27kDa heat-shock protein (Hsp27). LPS induced the phosphorylation of Hsp27 in a time- and dose-dependent manner. Selective blockage of the MAPK(p38) pathway by a pyridinyl-imidazole (SB-203580) abrogated LPS-induced release of TNF-alpha and IL-6. Pre-treatment with NAC reduced LPS-mediated secretion of TNF-alpha and IL-6. Incubation of cells with NAC induced intracellular accumulation of GSH, but reduced the concentration of GSSG. On the other hand, pre-treatment with BSO augmented LPS-mediated secretion of TNF-alpha and IL-6. In addition, BSO induced intracellular accumulation of GSSG, but reduced the concentration of GSH. Whereas NAC blocked the phosphorylation/activation of MAPK(p38), BSO amplified the LPS-mediated effect on MAPK(p38). These results indicated that intracellular redox signaling plays an important role in regulating LPS-induced activation of the MAPK(p38) pathway and MAPK(p38)-mediated regulation of LPS-dependent inflammatory cytokine production in the alveolar epithelium.}, }
@article {pmid11841797, year = {2002}, author = {Lee, WR and Shen, SC and Lin, HY and Hou, WC and Yang, LL and Chen, YC}, title = {Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease.}, journal = {Biochemical pharmacology}, volume = {63}, number = {2}, pages = {225-236}, doi = {10.1016/s0006-2952(01)00876-0}, pmid = {11841797}, issn = {0006-2952}, mesh = {Acetylcysteine/metabolism ; *Apoptosis ; Calcium/metabolism ; Caspase 1/metabolism ; Caspase 3 ; Caspases/*metabolism ; Catalase/metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; Endonucleases/*metabolism ; Enzyme Activation/drug effects ; *Flavanones ; Flavonoids/*pharmacology ; Flavonols ; Free Radical Scavengers/pharmacology ; HL-60 Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Leukemia, Promyelocytic, Acute ; Oligopeptides/pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Seven structurally related flavonoids including luteolin, nobiletin, wogonin, baicalein, apigenin, myricetin and fisetin were used to study their biological activities on the human leukemia cell line, HL-60. On MTT assay, wogonin, baicalein, apigenin, myricetin and fisetin showed obvious cytotoxic effects on HL-60 cells, with wogonin and fisetin being the most-potent apoptotic inducers among them. The cytotoxic effects of wogonin and fisetin were accompanied by the dose- and time-dependent appearance of characteristics of apoptosis including DNA fragmentation, apoptotic bodies and the sub-G1 ratio. Treatment with an apoptosis-inducing concentration of wogonin or fisetin causes rapid and transient induction of caspase 3/CPP32 activity, but not caspase 1 activity. Further, cleavage of poly(ADP-ribose) polymerase (PARP) and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated HL-60 cells. An increase in the pro-apoptotic protein, bax, and a decrease in the anti-apoptotic protein, Mcl-1, were detected in fisetin- and wogonin-treated HL-60 cells. However, Bcl-2, Bcl-XL, and Bad all remained unchanged in wogonin- and fisetin-treated HL-60 cells. In vitro chromatin digestion revealed that endonuclease activity was profoundly enhanced in wogonin- and fisetin-treated HL-60 cells, and the addition of ethylenediaminetetraacetic acid (EDTA) or ethyleneglycoltetraacetic acid (EGTA) into the reaction blocked endonuclease activation and at an optimum pH of 7.5. The caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor, Ac-YVAD-CHO, attenuated wogonin- and fisetin-induced DNA ladders, PARP cleavage, and endonuclease activation. Pretreatment of HL-60 cells with N-acetyl-cysteine or catalase efficiently inhibited H(2)O(2) (200 microM)-induced apoptosis, but showed no inhibitory effect on wogonin- and fisetin-induced DNA ladders, caspase 3 activation, or bax protein induction. Decrease in endogenous ROS production was detected in wogonin- and fisetin-treated HL-60 cells by DCHF-DA assay. In conclusion, our experiments indicate that a decrease in intracellular peroxide level was involved in wogonin- and fisetin-induced apoptosis; activation of caspase 3 and endonuclease, induction of bax protein and suppression of Mcl-1 protein were detected in the process.}, }
@article {pmid11841790, year = {2002}, author = {Lennon, AM and Ramauge, M and Pierre, M}, title = {Role of redox status on the activation of mitogen-activated protein kinase cascades by NSAIDs.}, journal = {Biochemical pharmacology}, volume = {63}, number = {2}, pages = {163-170}, doi = {10.1016/s0006-2952(01)00826-7}, pmid = {11841790}, issn = {0006-2952}, mesh = {Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Apoptosis ; Astrocytes ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; HT29 Cells ; Humans ; Hydrogen Peroxide/metabolism ; MAP Kinase Kinase Kinase 5 ; MAP Kinase Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; NAD(P)H Dehydrogenase (Quinone)/antagonists &amp; inhibitors/metabolism ; Oxidation-Reduction/drug effects ; Oxidative Stress/*drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Vitamin K 3/pharmacology ; }, abstract = {High concentrations of non steroidal antiinflammatory drugs (NSAIDs) exert preventive effects against carcinogenesis. Their molecular mechanism of action remains to be elucidated. Based on previous reports with salicylate, we have made the hypothesis that various NSAIDs can activate the mitogen-activated protein kinases (MAPK). Moreover, we tested the idea that NSAIDs act by increasing the effects of oxidative stress. We report that in human colorectal carcinoma cells NSAIDs stimulated the three families of MAPK, extracellular regulated kinases, c-Jun N-terminal kinases, p38 MAPK and that this stimulation is prevented by N-acetyl cysteine. In cultured astrocytes, a biological system less sensitive to oxidative stress, we show that a short treatment by NSAIDs strongly activated the three MAP kinases in the presence of H(2)O(2). A 25 microM H(2)O(2), unable to stimulate by itself the MAP kinases, promote an almost complete activation of MAP kinases in the presence of NSAIDs. The activation of MAP kinases by H(2)O(2) and NSAIDs was suppressed by quinone reductase inhibitors, suggesting that "redox cycling" was involved in the activation mechanisms of MAP kinases by H(2)O(2) and NSAIDs. The mobility on SDS-PAGE of the apoptosis signal-regulating kinase, which activates C-Jun N-terminal kinases and p38 MAPK cascades, was reduced by H(2)O(2) and NSAIDs, suggesting, that H(2)O(2) and NSAIDs activated apoptosis signal-regulating kinase by increasing its state of phosphorylation. In conclusion, we demonstrate that various NSAIDs can activate the three families of MAP kinases and that this activation depends on the presence of reactive oxygenated species. These results give a new insight into the mechanism of the action of NSAIDs.}, }
@article {pmid11795900, year = {2002}, author = {Will, Y and Kaetzel, RS and Brown, MK and Fraley, TS and Reed, DJ}, title = {In vivo reversal of glutathione deficiency and susceptibility to in vivo dexamethasone-induced apoptosis by N-acetylcysteine and L-2-oxothiazolidine-4-carboxylic acid, but not ascorbic acid, in thymocytes from gamma-glutamyltranspeptidase-deficient knockout mice.}, journal = {Archives of biochemistry and biophysics}, volume = {397}, number = {2}, pages = {399-406}, doi = {10.1006/abbi.2001.2662}, pmid = {11795900}, issn = {0003-9861}, support = {ES-00210/ES/NIEHS NIH HHS/United States ; ES-01978/ES/NIEHS NIH HHS/United States ; ES-09001/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*physiology ; Ascorbic Acid/pharmacology ; Dexamethasone/pharmacology ; Glutathione/deficiency/*metabolism ; Mice ; Mice, Knockout ; Pyrrolidonecarboxylic Acid ; Thiazoles/pharmacology ; Thiazolidines ; Thymus Gland/cytology/*metabolism ; gamma-Glutamyltransferase/*deficiency ; }, abstract = {Cellular glutathione is released during apoptosis and may play a role in the regulation of the mitochondrial permeability transition pore. The question of whether only cytosolic glutathione is important in apoptosis, or whether mitochondrial glutathione also plays a role, was investigated using gamma-glutamyltranspeptidase-deficient knockout mice. Thymocytes from these mice were found to have both glutathione pools diminished and they were more susceptible to dexamethasone (DEX)-induced apoptosis. Supplementation with N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid replenished both glutathione pools and provided protection from apoptosis. Ascorbate supplementation was beneficial to the mitochondrial glutathione pool, but apoptosis was not prevented. NAC supplementation caused an increase in reactive oxygen species formation and cardiolipin oxidation, but had no adverse affect on the amount of apoptotic cells. Our results suggest that the glutathione status is an important factor in apoptosis and indirect evidence indicates that the cytosolic pool of glutathione may be important in DEX-induced apoptosis, with mitochondrial events being secondary, and may reflect the execution phase.}, }
@article {pmid11795881, year = {2002}, author = {Sentürker, S and Tschirret-Guth, R and Morrow, J and Levine, R and Shacter, E}, title = {Induction of apoptosis by chemotherapeutic drugs without generation of reactive oxygen species.}, journal = {Archives of biochemistry and biophysics}, volume = {397}, number = {2}, pages = {262-272}, doi = {10.1006/abbi.2001.2681}, pmid = {11795881}, issn = {0003-9861}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*physiology ; Burkitt Lymphoma/*drug therapy ; Cisplatin/*pharmacology ; Cyclic N-Oxides/pharmacology ; Etoposide/*pharmacology ; F2-Isoprostanes/analysis ; Humans ; Hydrogen Peroxide/pharmacology ; Metalloporphyrins/pharmacology ; Methionine/*analogs &amp; derivatives/analysis ; Oxidants/analysis ; Reactive Oxygen Species/*metabolism ; Spin Labels ; }, abstract = {Studies in a variety of cell types have suggested that cancer chemotherapy drugs induce tumor cell apoptosis in part by inducing formation of reactive oxygen species (ROS). Using human B lymphoma cells as the targets, we have found that apoptosis can be induced in the absence of any detectable oxidative stress. Apoptosis was induced with the chemotherapy drugs VP-16 and cisplatin. To determine whether oxidants are formed as part of the drug-induced apoptotic process, intracellular markers of oxidative stress were examined. These included measurement of (1) protein carbonyl groups by Western blot immunoassay, (2) protein methionine sulfoxide residues by amino acid analysis, (3) protein sulfhydryl oxidation by Western blot immunoassay, (4) F2-isoprostanes by GC/MS, and (5) intracellular ROS production using the oxidant-sensitive dyes DCFDA and dihydrorhodamine 123. Apoptosis was quantified using fluorescence microscopy to assess nuclear morphology. The results show that VP-16 and cisplatin induce extensive apoptosis in the absence of any detectable protein or lipid oxidation, measured in both the cytosolic and mitochondrial compartments of the cell. In contrast, H2O2, which kills the cells by nonapoptotic pathways, caused increases in both protein and lipid oxidation. Three different antioxidant compounds (N-acetyl cysteine, Tempol, and MnTBAP) failed to inhibit VP-16-induced apoptosis, while inhibiting H2O2-induced cell death. Only N-acetyl cysteine inhibited cisplatin-induced cell death and this is attributed to its known ability to react directly with and inactivate cisplatin before it enters the cell. The results demonstrate that, at least in B lymphoma cells, chemotherapy-induced apoptosis occurs using a mechanism that does not involve oxidants.}, }
@article {pmid11836580, year = {2002}, author = {Chiao, JW and Chung, FL and Kancherla, R and Ahmed, T and Mittelman, A and Conaway, CC}, title = {Sulforaphane and its metabolite mediate growth arrest and apoptosis in human prostate cancer cells.}, journal = {International journal of oncology}, volume = {20}, number = {3}, pages = {631-636}, doi = {10.3892/ijo.20.3.631}, pmid = {11836580}, issn = {1019-6439}, support = {P01 CA046535/CA/NCI NIH HHS/United States ; CA46535/CA/NCI NIH HHS/United States ; }, mesh = {Anticarcinogenic Agents/*pharmacology ; *Apoptosis ; Cell Cycle ; Cell Division ; Cyclin D1/biosynthesis ; Dose-Response Relationship, Drug ; Humans ; Isothiocyanates ; Male ; Prostate-Specific Antigen/biosynthesis ; Prostatic Neoplasms/*drug therapy/*pathology ; Sulfoxides ; Thiocyanates/*metabolism/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {The relation between the consumption of cruciferous vegetables and reduced prostate cancer occurrence has been documented, although the responsible phytochemicals are unknown. The effects of sulforaphane (SFN) which occurs as the precursor glucosinolate in broccoli and other cruciferous vegetables, and its metabolite N-acetylcysteine conjugate (SFN-NAC) on prostate cancer cells were investigated. SFN and SFN-NAC were analyzed with the androgen-dependent human prostate cancer LNCaP cell line model. Cell growth and apoptosis were determined with the expression of androgen receptor and prostate specific antigen, DNA synthesis, cell cycle progression, DNA strand breaks and caspase activation to ascertain the effects and mechanism. SFN and SFN-NAC were demonstrated for the first time to mediate a dose-dependent apoptosis and growth arrest in the prostate cancer cells. Caspases were activated and DNA strand breaks were detected in apoptotic cells. The expression of phosphorylated and dephosphorylated androgen receptors, and the production of prostate specific antigen were attenuated. The expression of cyclin D1 and DNA synthesis were inhibited along with G1 cell cycle block, causing decreased cell density and growth. SFN and its metabolite SFN-NAC have similar activities to induce growth arrest and apoptosis, indicating that the effects of SFN are maintained through the metabolic processes. SFN as a dietary component of cruciferous vegetables active in the prevention of prostate cancer is discussed.}, }
@article {pmid11828388, year = {2002}, author = {Jornot, L and Morris, MA and Petersen, H and Moix, I and Rochat, T}, title = {N-acetylcysteine augments adenovirus-mediated gene expression in human endothelial cells by enhancing transgene transcription and virus entry.}, journal = {The journal of gene medicine}, volume = {4}, number = {1}, pages = {54-65}, doi = {10.1002/jgm.232}, pmid = {11828388}, issn = {1099-498X}, mesh = {*Acetylcysteine ; Adenoviridae/*physiology ; Cells, Cultured ; Coxsackie and Adenovirus Receptor-Like Membrane Protein ; Endothelium, Vascular/*physiology ; Gene Expression ; *Gene Transfer Techniques ; *Genetic Vectors ; Humans ; Lac Operon ; Receptors, Virus/physiology ; Thioctic Acid/physiology ; Transcription, Genetic ; Transgenes ; Umbilical Veins ; Up-Regulation ; beta-Galactosidase ; }, abstract = {BACKGROUND: It has previously been shown that oxidants reduce the efficiency of adenoviral transduction in human umbilical vein endothelial cells (HUVECs). In this study, the effect of the antioxidant N-acetylcysteine (NAC) in adenovirus-mediated gene transfer has been investigated.<br><br>METHODS: HUVECs were pretreated or not with NAC, and infected with E1E3-deleted adenovirus (Ad) containing the LacZ gene expressed from the RSV-LTR promoter/enhancer in the presence and absence of NAC. Transgene expression was assessed at the protein level (histochemical staining, measurement of beta-Gal activity, and western blot), mRNA level (real-time RT-PCR) and gene level (nuclear run on) 24 h and 48 h after infection. Adenoviral DNA was quantitated by real-time PCR, and cell surface expression of Coxsackie/adenovirus receptors (CAR) was determined by FACS analysis.<br><br>RESULTS: Pretreatment of cells with NAC prior to Ad infection enhanced beta-Gal activity by two-fold due to an increase in viral DNA, which was related to increased CAR expression. When NAC was present only during the post-infection period, a five-fold increase in beta-Gal activity and LacZ gene transcriptional activity was observed. When NAC was present during both the pretreatment and the post-infection period, beta-Gal activity was further enhanced, by 15-fold. Augmentation of beta-Gal activity was paralleled by an increase in beta-Gal protein and mRNA levels. NAC did not affect the half-life of LacZ mRNA.<br><br>CONCLUSION: Pretreatment with NAC prior to Ad infection enhances virus entry, while treatment with NAC post-infection increases transgene transcription. This strategy permits the use of lower adenoviral loads and thus might be helpful for gene therapy of vascular diseases.}, }
@article {pmid11828026, year = {2002}, author = {Costet, L and Dorey, S and Fritig, B and Kauffmann, S}, title = {A pharmacological approach to test the diffusible signal activity of reactive oxygen intermediates in elicitor-treated tobacco leaves.}, journal = {Plant &amp; cell physiology}, volume = {43}, number = {1}, pages = {91-98}, doi = {10.1093/pcp/pcf012}, pmid = {11828026}, issn = {0032-0781}, mesh = {Acetylcysteine/pharmacology ; Free Radical Scavengers/pharmacology ; Fungal Proteins/*pharmacology ; Gene Expression Regulation, Plant/drug effects ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent/metabolism ; Membrane Glycoproteins/*pharmacology ; Oxygen Consumption/drug effects ; Plant Leaves/cytology/*drug effects/enzymology ; Plant Proteins/genetics/metabolism ; Reactive Oxygen Species/*metabolism ; Rose Bengal/pharmacology ; Salicylic Acid/metabolism ; *Signal Transduction ; Nicotiana/cytology/*drug effects/enzymology ; }, abstract = {The capacity of H(2)O(2), the most stable of the reactive oxygen species (ROI), to diffuse freely across biological membranes and to signal gene expression suggests that H(2)O(2) could function as a short-lived second messenger diffusing from cell to cell. We tested this hypothesis in tobacco plants treated with a glycoprotein elicitor. Applied at 50 nM, it induces H(2)O(2) accumulation and the hypersensitive response restricted to the infiltrated zone 1 tissue. Stimulation of a set of defense responses also occurs in the surrounding zone 2 tissue without diffusion of the elicitor. ROI levels in zone 1 were modulated using N-acetyl-L-cysteine (NAC) as a ROI scavenger and Rose Bengal (RB) as a ROI generator. We found that ROI appeared to act as signalling intermediates in pathways leading to salicylic acid accumulation, to PR1, PR5 and 3-hydroxy-3-methylglutarylCoA reductase expression in glycoprotein-treated zone 1 tissues. Compared to the treatment with the elicitor alone, co-infiltration of the glycoprotein and NAC increased the surface of zone 2 showing PR1 and O-methyltransferase expression. Application of RB had the opposite effect. The data suggest that, in our system, ROI did not act as a cell-to-cell diffusible signal to activate PR protein and O-methyltransferase expression in zone 2.}, }
@article {pmid11823008, year = {2002}, author = {Moffatt, J and Kennedy, DO and Kojima, A and Hasuma, T and Yano, Y and Otani, S and Murakami, A and Koshimizu, K and Ohigashi, H and Matsui-Yuasa, I}, title = {Involvement of protein tyrosine phosphorylation and reduction of cellular sulfhydryl groups in cell death induced by 1' -acetoxychavicol acetate in Ehrlich ascites tumor cells.}, journal = {Chemico-biological interactions}, volume = {139}, number = {2}, pages = {215-230}, doi = {10.1016/s0009-2797(01)00301-5}, pmid = {11823008}, issn = {0009-2797}, mesh = {Animals ; Anticarcinogenic Agents/*pharmacology ; Benzoquinones ; Benzyl Alcohols ; Blotting, Western ; Carcinoma, Ehrlich Tumor/*drug therapy/metabolism/pathology ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Inhibitors/pharmacology ; Glutathione/metabolism ; Lactams, Macrocyclic ; Oxidation-Reduction ; Phosphorylation ; Quinones/pharmacology ; Rifabutin/analogs &amp; derivatives ; Sulfhydryl Compounds/metabolism ; Terpenes/*pharmacology ; Time Factors ; Tumor Cells, Cultured/drug effects ; Tyrosine/*metabolism ; }, abstract = {Elucidation of the mechanisms underlying potential anticancer drugs continues and unraveling these mechanisms would not only provide a conceptual framework for drug design but also promote use of natural products for chemotherapy. To further evaluate the efficacy of the anticancer activity of 1'-acetoxychavicol acetate (ACA), this study investigates the underlying mechanisms by which ACA induces death of Ehrlich ascites tumor cells. ACA treatment induced loss of cell viability, and Western blotting analysis revealed that the compound stimulated tyrosine phosphorylation of several proteins with 27 and 70 kDa proteins being regulated in both dose- and time-dependent manner prior to loss of viability. Protein tyrosine kinase inhibitor herbimycin A moderately protected cells from ACA-induced toxicity. In addition, cellular glutathione and protein sulfydryl groups were also significantly reduced both dose- and time-dependently during evidence of cell death. Replenishing thiol levels by antioxidant, N-acetylcysteine (NAC), an excellent supplier of glutathione and precursor of glutathione, substantially recovered the viability loss, but the recovery being time-dependent, as late addition of NAC (at least 30 min after ACA addition to cultures) was, however, ineffective. Addition of NAC to ACA treated cultures also abolished tyrosine phosphorylation of the 27 kDa protein. These results, at least partly, identify cellular sulfhydryl groups and protein tyrosine phosphorylation as targets of ACA cytotoxicity in tumor cells.}, }
@article {pmid11820937, year = {2002}, author = {Takagi, M and Satofuka, H and Amano, S and Mizuno, H and Eguchi, Y and Hirata, K and Miyamoto, K and Fukui, K and Imanaka, T}, title = {Cellular toxicity of cadmium ions and their detoxification by heavy metal-specific plant peptides, phytochelatins, expressed in Mammalian cells.}, journal = {Journal of biochemistry}, volume = {131}, number = {2}, pages = {233-239}, doi = {10.1093/oxfordjournals.jbchem.a003093}, pmid = {11820937}, issn = {0021-924X}, mesh = {Acetylcysteine/metabolism ; Aminoacyltransferases/genetics/metabolism/pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Cadmium/*toxicity ; Cell Nucleus/metabolism ; Cells, Cultured/drug effects/metabolism ; Chelating Agents/metabolism/*pharmacology ; DNA Primers/chemistry ; Drug Resistance ; Free Radical Scavengers/metabolism ; Glutathione/metabolism ; Humans ; Inactivation, Metabolic ; JNK Mitogen-Activated Protein Kinases ; Jurkat Cells/*drug effects ; MAP Kinase Kinase 4 ; Metalloproteins/metabolism/*pharmacology ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Oxidative Stress ; Phytochelatins ; Plants/chemistry ; Plasmids ; Polymerase Chain Reaction ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Time Factors ; Transfection ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {The apoptotic cell death of Jurkat cells due to Cd(2+) toxicity was studied by fluorescence microscopic observation and DNA fragmentation assaying. It was suggested that the apoptotic response to Cd(2+) was less clear than that to a typical apoptosis inducer, ultraviolet light (254 nm). Examination of MAP kinase phosphorylation (p38, JNKs, and c-Jun) due to Cd(2+) toxicity indicated that the phosphorylation was very slowly activated (4 h after stimulation), while UV light could activate the phosphorylation immediately. Therefore, it was suggested that Cd(2+) may not be a typical apoptosis inducer. Antioxidants [glutathione (GSH) and N-acetylcysteine (NAC)] could detoxify Cd(2+), indicating that the toxicity is a kind of oxidative stress. The detoxification effect of antioxidants showed cooperation with Bcl-2, suggesting that Cd(2+)-treatment causes diversified toxic signals including oxidative stress. On the addition of a plant-specific peptide, phytochelatin [PC(7), (gammaGlu-Cys)(7)-Gly], to the medium, the detoxification of Cd(2+) and cooperation with Bcl-2 were more intense than in the cases of GSH and NAC. Using an appropriate vector, a PC synthase gene was transferred from Arabidopsis thaliana to the Jurkat cell. The transfectant exhibited resistance to Cd(2+) and production of plant-specific PC (PC(2-6)).}, }
@article {pmid11820854, year = {2002}, author = {Ozcan, C and Polat, G and Görür, K and Talas, DU and Bağdatoğlu, O and Cinel, I}, title = {The effect of local administration of N-acetylcysteine in perforated rat tympanic membrane: an experimental study in myringosclerosis.}, journal = {Pharmacological research}, volume = {45}, number = {1}, pages = {5-9}, doi = {10.1006/phrs.2001.0906}, pmid = {11820854}, issn = {1043-6618}, mesh = {Acetylcysteine/*pharmacology ; Administration, Topical ; Animals ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Microscopy/methods ; Nitric Oxide/metabolism ; Otitis Media/etiology/metabolism ; Otosclerosis/etiology/*metabolism ; Oxygen/metabolism ; Rats ; Rats, Sprague-Dawley ; Tympanic Membrane/*drug effects/metabolism/pathology ; Tympanic Membrane Perforation/*complications ; }, abstract = {Myringosclerosis (MyS) is a common sequela of acute and chronic otitis media and ventilation tube treatment of serous otitis media. We aimed to study the effect of topical administration of N -acetylcysteine (NAC) on MyS by assessment of otomicroscopic evaluation, lipid peroxidation and nitric oxide (NO) (nitrite/nitrate) levels in experimental myringotomized rat tympanic membrane. Thirty adult rats were used and the upper posterior quadrant of the tympanic membranes of rats was myringotomized. Thereafter, they were divided into four groups. Group I received no treatment, group II was treated with saline, groups III and IV were treated with topical NAC (0.1 ml of 6 and 12 mg ml(-1), respectively). The levels of nitrite/nitrate and malondialdehyde (MDA) were measured in serum samples. In the otomicroscopic evaluation, non-treated and saline treated ears (controls) showed extensive occurrence of myringosclerotic plaques. Groups III and IV showed fewer occurrences of sclerotic plaques. There was no significant difference between groups III and IV regarding the development of MyS. The development of myringosclerotic lesion was found to be significantly different between NAC treated groups (III and IV) and the control groups (I and II). The levels of nitrite/nitrate of both groups III and IV were significantly lower than the control groups. The levels of MDA of these groups were also significantly lower than the control group. The relationship between groups III and IV was not statistically significant for the levels of nitrite/nitrate and MDA. We conclude that the topical treatment of NAC reduces the levels of MDA and NO products in rats. These results suggest that topical NAC application may be useful for the prevention of MyS.}, }
@article {pmid11820781, year = {2002}, author = {Tatebe, S and Sinicrope, FA and Kuo, MT}, title = {Induction of multidrug resistance proteins MRP1 and MRP3 and gamma-glutamylcysteine synthetase gene expression by nonsteroidal anti-inflammatory drugs in human colon cancer cells.}, journal = {Biochemical and biophysical research communications}, volume = {290}, number = {5}, pages = {1427-1433}, doi = {10.1006/bbrc.2002.6367}, pmid = {11820781}, issn = {0006-291X}, support = {CA 72404/CA/NCI NIH HHS/United States ; CA16672/CA/NCI NIH HHS/United States ; CA79085/CA/NCI NIH HHS/United States ; }, mesh = {ATP Binding Cassette Transporter, Subfamily B/biosynthesis/*genetics ; ATP-Binding Cassette Transporters/biosynthesis/*genetics ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Colonic Neoplasms/*enzymology/*genetics/metabolism ; Cyclooxygenase 2 ; Enzyme Induction/drug effects/genetics ; Gene Expression Regulation, Enzymologic/*drug effects ; Gene Expression Regulation, Neoplastic/*drug effects ; Glutamate-Cysteine Ligase/biosynthesis/*genetics ; HT29 Cells/drug effects/enzymology/metabolism ; Humans ; Isoenzymes/biosynthesis/genetics ; Membrane Proteins ; Multidrug Resistance-Associated Proteins/biosynthesis/*genetics ; Multigene Family/drug effects ; Prostaglandin-Endoperoxide Synthases/biosynthesis/genetics ; Reactive Oxygen Species/metabolism ; Transfection ; Tumor Cells, Cultured ; }, abstract = {Nonsteroidal anti-inflammatory drugs (NSAIDs) have been demonstrated to suppress colorectal tumorigenesis. NSAIDs have also been used to treat inflammatory illnesses. However, the underlying mechanisms of action by NSAIDs have not been completely elucidated. In this study, we reported that among the six members of the multidrug resistance protein gene (MRP1 to MRP6) family which encode membrane transporters for a diverse group of antitumor agents, expression of MRP1 and MRP3 but not the others in human colorectal cancer cell lines was induced by sulindac. This induction profile is consistent with the results using prooxidants which produce reactive oxygen species (ROS) and generate oxidative stress as previously reported. Moreover, treatment of colorectal cancer cells with sulindac induced ROS. Suppression of ROS formation by antioxidant N-acetylcysteine (NAC) downregulated the induction of MRP1 and MRP3 expression. Expression of another oxidative stress-sensitive gene, gamma-glutamylcysteine synthetase heavy subunit gene (gamma-GCSh), which encodes the rate-limiting enzyme in glutathione biosynthesis, was also induced by sulindac. However, the suppression of sulindac-induced gamma-GCSh expression by NAC was less sensitive compared with that of MRP1 and MRP3. We also demonstrated that induction of MRP3 and gamma-GCSh was independent of intracellular COX-2 levels. These results, collectively, suggest a ROS-related, COX-2-independent mechanism for the induction of drug resistance gene expression that bears important implications to the roles of NSAIDs in colorectal carcinogenesis and inflammatory response.}, }
@article {pmid11819251, year = {1998}, author = {Zhao, C and Sheryl, D and Zhou, YX}, title = {Effects of combined use of diallyl disulfide and Nacetyl-cysteine on acetaminophen hepatotoxicity in beta-naphthoflavone pretreated mice.}, journal = {World journal of gastroenterology}, volume = {4}, number = {2}, pages = {112-116}, pmid = {11819251}, issn = {2219-2840}, abstract = {AIM:To assess the protective effect of diallyl disulfide (DADS) and its combined use with N-acetyl-cysteine (NAC) on acetaminophen (APAP) hepatotoxicity in C57BL/6N (B6) mice pretreated with beta-naphthoflavone (BNF).METHODS:B6 mice were divided into six groups and all compounds used were injected intraperitoneally. Except for control and APAP group (receiving APAP only), the other groups received an injection of APAP (350mg/kg) 48 hours after BNF (200mg/kg) and either of DADS (200mg/kg), or NAC (500mg/kg) or both DADS and NAC.DADS was given 2 hours before APAP and NAC was injected with APAP.The mean survival time was recorded and livers were examined histologically.Hepatic glutathione (GSH) levels and plasma ALT were also determined at different time points.To evaluate the effect of DADS or NAC on hepatic P450 induction by BNF,liver microsomes were prepared and 7-ethoxyresorufin O-dealkylase (ERD) activity was determined using spectrofluorometrical methods. In vitro effect of DADS or NAC on ERD activity was assayed by directly incubating microsomal suspension with DADS or NAC of different concentrations.RESULTS:APAP was not toxic to mice without BNF pretreatment, but caused severe liver necrosis and death of all BNF-treated mice in 4 hours. A sharp depletion of GSH (approximately 62% of its initial content at 2 hours and 67% at 4 hours) and a linear elevation of ALT levels (536.8 plus minus 29.5 Sigma units at 2 hours and 1302.5 plus minus74.9 at 4 hours) were observed.DADS and NAC given individually produced mild protection,resulting in prolonged survival,a slower decline of GSH level and a less steeper elevation of ALT level.All mice died eventually. Co-administration of DADS and NAC completely protected mice.GSH level in this group lowered by about 35% and 30% at 2 and 4 hours, and ALT was 126 plus minus 18 and 157.5 plus minus 36.6 Sigma units at 2 and 4 hours. ERD activity in BNF-treated mice was about 5 times that of the constitutive level determined in normal mice. Neither DADS nor NAC inhibited P450 1A1/1A2 induction as determined by their effect on the induction of ERD activity.In vitro assay indicates that DADS,but not NAC,was a potent inhibitor of ERD activity(IC(50) = 4.6&amp;mgr;m).CONCLUSION:A combined use of both DADS and NAC produced full protection in BNF treated mice against APAP hepatotoxicity.The mechanism is that DADS inhibits P450 1A1/1A2 activity, but not induction, which substantially reduces production of NAPQI, while NAC enhances liver detoxifying capability via serving as a precursor of GSH and stimulating GSH synthesis.}, }
@article {pmid11815436, year = {2002}, author = {Hirotani, S and Otsu, K and Nishida, K and Higuchi, Y and Morita, T and Nakayama, H and Yamaguchi, O and Mano, T and Matsumura, Y and Ueno, H and Tada, M and Hori, M}, title = {Involvement of nuclear factor-kappaB and apoptosis signal-regulating kinase 1 in G-protein-coupled receptor agonist-induced cardiomyocyte hypertrophy.}, journal = {Circulation}, volume = {105}, number = {4}, pages = {509-515}, doi = {10.1161/hc0402.102863}, pmid = {11815436}, issn = {1524-4539}, mesh = {Angiotensin II/pharmacology ; Animals ; Cardiomegaly/etiology ; Cell Size ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelin-1/pharmacology ; Heterotrimeric GTP-Binding Proteins/*metabolism ; I-kappa B Proteins/genetics ; Kinetics ; MAP Kinase Kinase Kinase 5 ; MAP Kinase Kinase Kinases/*physiology ; Mutation ; Myocardium/cytology/*metabolism/ultrastructure ; NF-kappa B/*physiology ; Phenylephrine/pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptors, Cell Surface/agonists ; Sarcomeres/ultrastructure ; }, abstract = {BACKGROUND: Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-kappaB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1), in G-protein-coupled receptor (GPCR) agonist (angiotensin II, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes.<br><br>METHODS AND RESULTS: Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-kappaB activation. Antioxidants such as N-acetyl cysteine, N-mercaptopropionyl glycine, and vitamin E attenuated the NF-kappaB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant of IkappaBalpha led to suppression of the hypertrophic responses. The GPCR agonists rapidly and transiently activated ASK1 in a dose-dependent manner. Infection of an adenovirus expressing a dominant-negative ASK1 attenuated the GPCR agonist-induced NF-kappaB activation and cardiac hypertrophy. Overexpression of a constitutively active mutant of ASK1 led to NF kappaB activation and cardiac hypertrophy. Activated ASK1-induced hypertrophy was abolished by inhibition of NF-kappaB activation.<br><br>CONCLUSIONS: These data indicate that GPCR agonist-induced cardiac hypertrophy is mediated through NF-kappaB activation via the generation of ROS. ASK1 is involved in GPCR agonist-induced NF-kappaB activation and resulting hypertrophy.}, }
@article {pmid11815388, year = {2002}, author = {Haddad, JJ and Land, SC}, title = {Redox/ROS regulation of lipopolysaccharide-induced mitogen-activated protein kinase (MAPK) activation and MAPK-mediated TNF-alpha biosynthesis.}, journal = {British journal of pharmacology}, volume = {135}, number = {2}, pages = {520-536}, pmid = {11815388}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Animals ; Culture Techniques ; Dose-Response Relationship, Drug ; Enzyme Activation ; Female ; Glutathione/metabolism ; Intracellular Signaling Peptides and Proteins ; Lipopolysaccharides/*pharmacology ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism/physiology ; Oxidation-Reduction ; Phosphorylation/drug effects ; Pregnancy ; Protein Serine-Threonine Kinases/metabolism ; Pulmonary Alveoli/cytology/drug effects/enzymology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/*biosynthesis ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Redox and ROS regulation of MAPK-mediated TNF-alpha biosynthesis is not well characterized. It was hypothesized that the involvement of the MAPK pathway in regulating LPS-mediated TNF-alpha secretion is redox-dependent, NF-kappaB-sensitive and attenuated by N-acetyl-L-cysteine (NAC) and other antioxidants. In alveolar epithelial cells, LPS induced a time- and dose-dependent phosphorylation of MAPK(p38). This was associated with the activation of MAPK-activated protein kinase, which phosphorylated the small heat-shock protein, Hsp27. MAPK(p38) inhibition (SB-203580) abrogated LPS-induced TNF-alpha production. MAPK(ERK) blockade (PD-98059) attenuated TNF-alpha secretion, an effect synergistically amplified in the presence of SB-203580. Regulation of NF-kappaB by selective inhibitors revealed that this pathway is partially involved in regulating LPS-mediated TNF-alpha secretion. Whereas the proteasome inhibitor, MG-132, had no effect on LPS-mediated TNF-alpha production, CAPE, sulfasalazine and SN-50, a cell-permeant NF-kappaB inhibitor, attenuated but did not abrogate TNF-alpha biosynthesis. LPS up-regulated ROS, an effect abrogated by 4'-hydroxy-3'-methoxy-acetophenone and NAC, which reduced TNF-alpha secretion, induced the accumulation of GSH, reduced the concentration of GSSG, and blockaded the phosphorylation/activation of MAPK(p38) pathway. ROS induced MAPK(p38) phosphorylation and selective antioxidants, including the permeant GSH precursor, gamma-GCE, reduced ROS-dependent MAPK(p38) phosphorylation. These results indicate that the MAPK pathway and MAPK-mediated regulation of TNF-alpha production is redox-dependent, GSH-mediated and requires, at least in part, a NF-kappaB/ROS-sensitive mechanism.}, }
@article {pmid11814705, year = {2002}, author = {Milchak, LM and Douglas Bricker, J}, title = {The effects of glutathione and vitamin E on iron toxicity in isolated rat hepatocytes.}, journal = {Toxicology letters}, volume = {126}, number = {3}, pages = {169-177}, doi = {10.1016/s0378-4274(01)00436-2}, pmid = {11814705}, issn = {0378-4274}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Combinations ; Ferrous Compounds/*toxicity ; Glutathione/*pharmacology ; Hepatocytes/*drug effects/metabolism/pathology ; Lipid Peroxidation/drug effects ; Male ; Rats ; Rats, Sprague-Dawley ; Vitamin E/*pharmacology ; }, abstract = {This study examined the acute toxicity of ferrous sulfate on rat hepatocyte suspensions, the correlation between lipid peroxidation and cell death, and the roles of glutathione and vitamin E in protecting against iron toxicity. Incubation with ferrous sulfate for 2 h produced lipid peroxidation, but did not decrease cell viability in the hepatocytes. When diethyl maleate (DEM) was added to deplete cellular glutathione concentrations, ferrous sulfate treatment (2.0-5.0 mM) did cause cell death and lipid peroxidation developed more extensively, suggesting that iron-mediated hepatotoxicity is influenced by glutathione content. Reduced glutathione (GSH), N-acetylcysteine (NAC) and alpha-tocopherol (vitamin E), alone and in combination, were added to hepatocyte suspensions in an attempt to protect cells against iron-induced damage. In iron-DEM-treated cells, GSH and NAC treatment increased viability by 43 and 36%, respectively, but only the combination of the two agents reduced lipid peroxidation (53% decrease). Vitamin E treatment reduced lipid peroxidation by 39% and also increased cell viability by 12%. The greatest protection against iron-induced lipid peroxidation occurred with the combination of GSH, NAC and vitamin E, which reduced lipid peroxidation by 94% in iron-treated cells, and by 98% in iron-DEM-treated cells. However, this combination did not prevent iron-induced cell death, although it did increase viability by 18%. These results suggest that iron-induced cell death may not be dependent upon lipid peroxidation, at least in short-term exposures. The results also suggest an interaction between GSH and vitamin E in protecting against lipid peroxidation.}, }
@article {pmid11814408, year = {2002}, author = {Walker, DG and Lue, LF and Beach, TG}, title = {Increased expression of the urokinase plasminogen-activator receptor in amyloid beta peptide-treated human brain microglia and in AD brains.}, journal = {Brain research}, volume = {926}, number = {1-2}, pages = {69-79}, doi = {10.1016/s0006-8993(01)03298-x}, pmid = {11814408}, issn = {0006-8993}, support = {AG018345/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/immunology/*metabolism/pathology ; Amyloid beta-Peptides/*pharmacology ; Brain/immunology/*metabolism/pathology ; Cells, Cultured ; Female ; Free Radicals/metabolism ; Gene Expression/drug effects/immunology ; Humans ; Male ; Microglia/cytology/*drug effects/immunology ; Oxidative Stress/physiology ; Receptors, Cell Surface/*genetics ; Receptors, Urokinase Plasminogen Activator ; Signal Transduction/physiology ; }, abstract = {The urokinase plasminogen-activator receptor (uPAR) is involved in many processes in inflammation including the migration of inflammatory-associated cells to sites of tissue damage. This receptor, also designated as CD87, is induced in response to a range of stimuli and is a marker of macrophage activation. Its role in inflammatory responses of microglia in Alzheimer's disease (AD) has not been previously investigated. In this study we demonstrate that uPAR mRNA and protein expression is induced following incubation of human post-mortem brain-derived microglia with fibrillar amyloid beta (Abeta) peptide. This response was stronger with Abeta peptide than with other tested pro-inflammatory agents. Induction of uPAR surface expression by microglia was inhibited by the antioxidant N-acetyl-cysteine, indicating that this gene may be induced as a result of oxidative stress-related mechanisms. The significance of these findings to AD was investigated. UPAR protein levels were significantly increased in human brain tissues from the hippocampus, superior frontal gyrus and inferior temporal gyrus of AD cases compared with similar tissues from non-demented cases. Increased uPAR expression was not demonstrated in AD cerebellum. Finally, increased uPAR immunoreactivity was demonstrated in activated microglia in AD brain samples using two different antibodies to uPAR. These results provide a connection between the induction of oxidative stress in AD and microglial activation, and establish a possible involvement of uPAR in AD pathogenesis.}, }
@article {pmid11813981, year = {2001}, author = {Nishinaka, Y and Nakamura, H and Okada, N and Okada, H and Yodoi, J}, title = {Redox control of EBV infection: prevention by thiol-dependent modulation of functional CD21/EBV receptor expression.}, journal = {Antioxidants &amp; redox signaling}, volume = {3}, number = {6}, pages = {1075-1087}, doi = {10.1089/152308601317203585}, pmid = {11813981}, issn = {1523-0864}, mesh = {Acetylcysteine/metabolism ; Antioxidants/chemistry/pharmacology ; Blotting, Northern ; CD4 Antigens/biosynthesis ; Cell Line ; Epstein-Barr Virus Nuclear Antigens/metabolism ; Flow Cytometry ; Glutathione/chemistry/metabolism ; Herpesvirus 4, Human/*metabolism ; Humans ; Mercaptoethanol/chemistry ; *Oxidation-Reduction ; Precipitin Tests ; RNA, Messenger/metabolism ; Receptors, Complement 3d/*biosynthesis ; Receptors, Interleukin-2/biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; Sulfhydryl Compounds/*chemistry ; T-Lymphocytes/metabolism ; Time Factors ; Viral Proteins ; }, abstract = {CD21 serves as a receptor for the Epstein-Barr virus (EBV). In this report, surface expression of CD21 on B and T cells was shown to be suppressed by a thiol-antioxidant, N-acetylcysteine (NAC), in a dose- and time-dependent manner. In contrast, expression of other surface markers, CD25 and CD4 for T cells and CD19 and surface IgM for B cells, was not affected by NAC. When an EBV-negative B-cell line B104 was treated with NAC, the cells were not susceptible to infection with B95-8-derived EBV. The effect of NAC was shown to be irrelevant to the transcriptional levels of CD21 mRNA and the intracellular glutathione levels. Immunoprecipitation study revealed that NAC causes a loss of anti-CD21 monoclonal antibody (HB5) binding to both membrane and soluble CD21, suggesting that NAC modulates the structure of CD21. Other thiol-antioxidants, such as 2-mercaptoethanol, pyrrolidine dithiocarbamate, and glutathione, showed similar effect to NAC on CD21 expression. These results suggest the possible modulation of EBV infection via thiol-dependent redox control of CD21, and thiol-antioxidants may be good candidates for controlling EBV infection.}, }
@article {pmid11812921, year = {2002}, author = {Park, J and Kamendulis, LM and Friedman, MA and Klaunig, JE}, title = {Acrylamide-induced cellular transformation.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {65}, number = {2}, pages = {177-183}, doi = {10.1093/toxsci/65.2.177}, pmid = {11812921}, issn = {1096-6080}, mesh = {Acetylcysteine/toxicity ; Acrylamide/*toxicity ; Animals ; Buthionine Sulfoximine/toxicity ; Carcinogens/*toxicity ; Cell Transformation, Neoplastic/*chemically induced ; Cells, Cultured/cytology/drug effects/enzymology ; Cricetinae ; Dose-Response Relationship, Drug ; Drug Combinations ; Embryo, Mammalian/cytology/*drug effects/metabolism ; Enzyme Inhibitors/toxicity ; Glutathione/metabolism ; Mesocricetus ; Triazoles/toxicity ; }, abstract = {Acrylamide is a monomer of polyacrylamide, whose products are used in biochemistry, the manufacture of paper, water treatment, and as a soil stabilizer. While polymeric acrylamide is nontoxic, the monomer can cause several toxic effects and has the potential for human occupational exposure. While acrylamide is not mutagenic in prokaryotic mutagenesis assays, chronic acrylamide treatment in rodents has been shown to produce tumors in both rats and mice. The mechanism for the induction of tumors by acrylamide is not known. In the present study, we examined the possibility that acrylamide might induce cellular transformation, using Syrian hamster embryo (SHE) cell morphological transformation as well as potential mechanisms for the cellular transformation. Results showed that treatment with 0.5 mM and higher concentrations of acrylamide continuously for 7 days induced morphological transformation. Cotreatment with acrylamide and N-acetyl-L-cysteine (NAC), a sulfhydryl group donor, resulted in the reduction of acrylamide-induced morphological transformation in SHE cells. Cotreatment with 1-aminobenzotriazole (ABT), a nonspecific P450 inhibitor, and acrylamide produced no change in morphological transformation when compared to acrylamide treatment only. Cotreatment with acrylamide and DL-buthionone-[S,R]-sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase, increased the percent of morphologically transformed colonies compared to acrylamide treatment alone. Acrylamide reduced GSH levels in SHE cells, and cotreatment with acrylamide and NAC prevented the acrylamide-induced reduction of GSH. BSO treatment with acrylamide enhanced the depletion of GSH. These results suggest that acrylamide itself, but not oxidative P450 metabolites of acrylamide appear to be involved in acrylamide-induced cellular transformation and that cellular thiol status (possibly GSH) is involved in acrylamide-induced morphological transformation.}, }
@article {pmid11807954, year = {2002}, author = {Hursting, SD and Shen, JC and Sun, XY and Wang, TT and Phang, JM and Perkins, SN}, title = {Modulation of cyclophilin gene expression by N-4-(hydroxyphenyl)retinamide: association with reactive oxygen species generation and apoptosis.}, journal = {Molecular carcinogenesis}, volume = {33}, number = {1}, pages = {16-24}, doi = {10.1002/mc.10020}, pmid = {11807954}, issn = {0899-1987}, mesh = {Antineoplastic Agents/*pharmacology ; *Apoptosis ; Blotting, Northern ; Breast Neoplasms/genetics/*metabolism ; Cyclophilins/biosynthesis/*genetics ; Fenretinide/*pharmacology ; Gene Expression Profiling ; Gene Expression Regulation/drug effects ; Humans ; Male ; Neoplasm Proteins/biosynthesis/genetics ; Polymerase Chain Reaction ; Prostatic Neoplasms/genetics/*metabolism ; RNA, Messenger/biosynthesis ; RNA, Neoplasm/biosynthesis ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured/drug effects ; }, abstract = {To explore the mechanisms underlying the pro-apoptotic effects of the synthetic retinoid N-4-(hydroxyphenyl)retinamide (4-HPR) on LNCaP human prostate cancer cells, we used the differential display-polymerase chain reaction (DD-PCR) technique to identify 4-HPR-responsive genes. RNA extracted from LNCaP cells that had been treated for 24 h with 4-HPR at a dose (2.5 microM) optimal for apoptosis induction was used for DD-PCR analysis using random primers. A differentially expressed 115 bp fragment was cloned and sequenced and then identified in GenBank as having a high degree of homology with several members of the cyclophilin gene family. Northern blot analyses using specific probes for cyclophilin A, cyclophilin D, and the cloned 115-bp fragment were performed on RNA extracted from LNCaP cells and MCF-7 human breast cancer cells treated with 4-HPR, N-acetylcysteine (NAC, an anti-oxidant), 4-HPR plus NAC, cyclosporin A, R-1881 (a synthetic androgen), dehydroepiandrosterone, all-trans retinoic acid, or prednisone. 4-HPR downregulated the transcript detected by the 115-bp fragment. Expression patterns detected by the 115-bp fragment and cyclophilin D probes were identical in response to each treatment; none of these treatments affected cyclophilin A expression. Furthermore, expression of mRNA transcripts detected by the 115-bp fragment and cyclophilin D probes correlated with the generation of reactive oxygen species (ROS), as detected by measurement of 2,7-dichlorofluorescein oxidation. Therefore, members of the cyclophilin gene family, such as cyclophilin D (a component of the mitochondrial permeability transition pore previously linked with oxidative stress and apoptosis), may play a role in the ROS-mediated apoptotic effects of 4-HPR.}, }
@article {pmid11807931, year = {2002}, author = {Tandon, SK and Prasad, S and Singh, S}, title = {Chelation in metal intoxication: influence of cysteine or N-acetyl cysteine on the efficacy of 2,3-dimercaptopropane-1-sulphonate in the treatment of cadmium toxicity.}, journal = {Journal of applied toxicology : JAT}, volume = {22}, number = {1}, pages = {67-71}, doi = {10.1002/jat.827}, pmid = {11807931}, issn = {0260-437X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cadmium/blood/*toxicity ; Chelating Agents/*pharmacology ; Cysteine/*pharmacology ; Drug Interactions ; Female ; Kidney/drug effects ; Liver/drug effects ; Metallothionein/analysis ; Rats ; Treatment Outcome ; Unithiol/*pharmacology ; }, abstract = {The influence of cysteine or N-acetyl cysteine administration on the efficacy of 2,3-dimercaptopropane-1-sulphonate (DMPS) in the treatment of cadmium intoxication was investigated in cadmium-pre-exposed rats. Cysteine, N-acetyl cysteine, DMPS, DMPS + cysteine or DMPS + N-acetyl cysteine were about equal in effectiveness in mobilizing hepatic cadmium mainly from its supernatant cytosolic fraction (SCF) and both of the combinations were more effective than either of them alone in mobilizing cadmium from its nuclear mitochondrial fraction (NMF). The DMPS was apparently more effective than cysteine or N-acetyl cysteine in mobilizing renal cadmium from its SCF or NMF and it was more effective than even their combinations in mobilizing cadmium from renal SCF. The treatment with cysteine or N-acetyl cysteine reduced cadmium-induced hepatic and renal metallothionein (MT) and the treatment with DMPS reduced renal MT only, probably due to removal of hepatic and renal SCF cadmium by these agents. However, MT levels were high in animals treated with DMPS + cysteine or DMPS + N-acetyl cysteine, despite lowering of cadmium in these tissues, suggesting a contribution of MT induced by cysteine or N-acetyl cysteine itself. The cadmium exposure increased hepatic and renal zinc and renal copper levels, probably as a result of cadmium-induced MT, and some of the levels were normalized considerably by the subsequent treatment with cysteine, DMPS or to a lesser extent N-acetyl cysteine and their combinations, showing their protective effects against cadmium toxicity. The increase in blood cadmium and the decrease in blood zinc and copper levels due to cadmium exposure also were reversed appreciably by some of these treatments. The results have shown a limited benefit of cysteine or N-acetyl cysteine administration on the efficacy of DMPS in the treatment of cadmium intoxication.}, }
@article {pmid11804668, year = {2002}, author = {Sindram, D and Rüdiger, HA and Upadhya, AG and Strasberg, SM and Clavien, PA}, title = {Ischemic preconditioning protects against cold ischemic injury through an oxidative stress dependent mechanism.}, journal = {Journal of hepatology}, volume = {36}, number = {1}, pages = {78-84}, doi = {10.1016/s0168-8278(01)00229-x}, pmid = {11804668}, issn = {0168-8278}, support = {DK54048/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Apoptosis ; Cold Temperature ; Cryopreservation ; *Ischemic Preconditioning ; Liver/*metabolism ; Liver Transplantation ; Male ; Oxidative Stress/physiology ; Rats ; Rats, Wistar ; Reperfusion Injury/*metabolism ; }, abstract = {BACKGROUND/AIMS: Ischemic injury in cold preserved livers is characterized by sinusoidal endothelial cell (SEC) detachment and matrix metalloproteinase activity. Upon reperfusion reversible ischemic injury becomes permanent with SEC rapidly undergoing apoptosis. Ischemic preconditioning prevents reperfusion injury after normothermic ischemia. We hypothesized that ischemic preconditioning, through an oxygen free radical burst, protects against injury during cold preservation and reperfusion.<br><br>METHODS: Ischemic preconditioning was achieved in rats by clamping blood supply to the left and median lobes for 10 min followed by 15 min of reperfusion prior to preservation in cold University of Wisconsin solution for 30 h. In a second set of experiments, rats were pretreated with N-acetyl-cysteine (NAC). SEC apoptosis upon reperfusion was assessed in an isolated perfused rat liver (IPRL) model.<br><br>RESULTS: SEC detachment and activities of matrix metalloproteinase were significantly reduced in preconditioned livers. A decrease of SEC apoptosis after 1h of reperfusion in the IPRL was noted in preconditioned livers compared to controls. Pretreatment with NAC reversed the beneficial effects of ischemic preconditioning on SEC detachment and apoptosis.<br><br>CONCLUSIONS: Ischemic preconditioning is an effective strategy to prevent injury during cold preservation and after reperfusion. The protective effect is possibly mediated by oxygen free radicals.}, }
@article {pmid11790356, year = {2000}, author = {Canesi, L and Ciacci, C and Betti, M and Gallo, G}, title = {Growth factor-mediated signal transduction and redox balance in isolated digestive gland cells from Mytilus galloprovincialis Lam.}, journal = {Comparative biochemistry and physiology. Toxicology &amp; pharmacology : CBP}, volume = {125}, number = {3}, pages = {355-363}, doi = {10.1016/s0742-8413(99)00120-6}, pmid = {11790356}, issn = {1532-0456}, mesh = {Acetylcysteine/pharmacology ; Animals ; Bivalvia/enzymology/*metabolism ; Buthionine Sulfoximine/pharmacology ; Copper/pharmacology ; Digestive System/*metabolism ; Epidermal Growth Factor/*metabolism/pharmacology ; Free Radical Scavengers/pharmacology ; Glutamate-Cysteine Ligase/drug effects/metabolism ; Glutathione/drug effects/metabolism ; Insulin-Like Growth Factor I/*metabolism/pharmacology ; Mitogen-Activated Protein Kinase Kinases ; Oxidation-Reduction ; Phosphofructokinase-1/drug effects/metabolism ; Pyruvate Kinase/drug effects/metabolism ; Signal Transduction/*physiology ; Time Factors ; }, abstract = {In mammalian cells, a growing body of evidence indicates a relationship between cellular redox balance and tyrosine kinase-mediated cell signalling. The phosphorylative cascade activated by extracellular signals is inhibited by reducing conditions and stimulated by oxidative stress, in particular at the level of mitogen activated protein kinase (MAPK) activation. The mussel Mytilus typically shows variations in antioxidant defence systems and decreases in glutathione content in response to both natural and contaminant environmental stressors. In isolated mussel digestive gland cells, both epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) have been recently demonstrated to activate tyrosine kinase receptors leading to multiple responses; among these, stimulation of the key glycolytic enzymes phosphofructokinase (PFK) and pyruvate kinase (PK). The present study investigates the possible relationship between the tyrosine kinase-mediated metabolic effects of growth factors and cellular redox balance in mussel cells. The results demonstrate that the effects of growth factors on glycolytic enzymes were abolished by cell pretreatment with the antioxidant N-acetyl-cysteine (NAC). On the other hand, in cells where the glutathione content and synthesis were lowered either in vitro (by cell pretreatment with buthionine sulfoximine (BSO)), or in vivo (by mussel exposure to Cu(2+)) the metabolic effects of growth factors were unaffected. Moreover, the results show that, in both control and glutathione-depleted cells, growth factors can also regulate the level of glutathione apparently by modulating, via phosphorylative mechanisms involving MAPK activation, the activity of gamma-glutamylcysteine synthetase (GCS), the rate limiting enzyme in GSH biosynthesis. Overall, this study extends the hypothesis that cell signalling is intimately related to redox balance in marine invertebrate cells.}, }
@article {pmid11782348, year = {2002}, author = {Yang, YM and Conaway, CC and Chiao, JW and Wang, CX and Amin, S and Whysner, J and Dai, W and Reinhardt, J and Chung, FL}, title = {Inhibition of benzo(a)pyrene-induced lung tumorigenesis in A/J mice by dietary N-acetylcysteine conjugates of benzyl and phenethyl isothiocyanates during the postinitiation phase is associated with activation of mitogen-activated protein kinases and p53 activity and induction of apoptosis.}, journal = {Cancer research}, volume = {62}, number = {1}, pages = {2-7}, pmid = {11782348}, issn = {0008-5472}, support = {P01 CA046535/CA/NCI NIH HHS/United States ; CA46535/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*pharmacology ; Animals ; Anticarcinogenic Agents/chemistry/*pharmacology ; Apoptosis/*drug effects/physiology ; Benzo(a)pyrene/antagonists &amp; inhibitors/toxicity ; Carcinogens/antagonists &amp; inhibitors/toxicity ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/biosynthesis/genetics ; Enzyme Activation ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Isothiocyanates/chemistry/*pharmacology ; Lung/drug effects/pathology ; Lung Neoplasms/chemically induced/metabolism/pathology/*prevention &amp; control ; Mice ; Mice, Inbred A ; Mitogen-Activated Protein Kinases/genetics/*metabolism ; NF-kappa B/metabolism ; Phosphorylation ; Proto-Oncogene Proteins/biosynthesis/genetics ; *Proto-Oncogene Proteins c-bcl-2 ; Transcription Factor AP-1/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; bcl-2-Associated X Protein ; }, abstract = {Recent studies in cell culture have shown that isothiocyanates (ITCs) induce apoptosis via activation of mitogen-activated protein (MAP) kinases and p53 pathways, suggesting a potential for ITCs or their conjugates to inhibit tumorigenesis during the postinitiation phase. To evaluate whether ITC compounds administered after carcinogen treatment inhibit lung tumorigenesis, we investigated in A/J mice the effects of the N-acetylcysteine (NAC) conjugates of benzyl (BITC-NAC) and phenethyl ITC (PEITC-NAC) in the diet (15 micromol/g) administered after a single dose of 20 micromol benzo(a)pyrene [B(a)P]. The formation of lung adenomas was examined 140 days after B(a)P dosing. Both the BITC-NAC and PEITC-NAC-treated groups showed a significant reduction in lung tumor multiplicity from 6.1 +/- 3.1 tumors/mouse in the B(a)P group fed the control diet to 3.7 +/- 2.9 and 3.4 +/- 2.7 tumors/mouse (P = 0.018 and 0.006, respectively). To investigate the mechanisms of tumor inhibition, lung tissues were obtained at 21, 84, and 140 days at interim sacrifices during the bioassay. These tissues showed a significant increase in apoptosis as determined by in situ end-labeling for both ITC-NAC-treated groups. The MAP kinase pathway was activated in the ITC-NAC-treated groups. The activation of c-Jun NH(2)-terminal kinase was higher in the BITC-NAC and PEITC-NAC groups when compared with B(a)P-treated control. The phosphorylation of p38 and extracellular signal-regulated kinases (ErKs) 1 and 2 was also induced by these treatments. To determine the downstream target of MAP kinases, activator protein-1 (AP-1) and nuclear factor-kappaB activities were evaluated by gel shift assay. The AP-1 binding activity was remarkably increased in lung tissue from both the BITC-NAC and PEITC-NAC groups. No change in nuclear factor-kappaB binding activity was found, however. Phosphorylation of p53 was also higher than the constitutive levels in both ITC-NAC-treated groups, but no induction of p53 expression was detected. This study demonstrates the chemopreventive efficacy of the NAC conjugates of PEITC and BITC administered in the diet after a single dose of B(a)P for lung tumorigenesis and provides the first in vivo evidence that activation of MAP kinases, AP-1 transcription factors, p53 phosphorylation, and the induction of apoptosis may be involved in the chemopreventive activity of these compounds.}, }
@article {pmid11780556, year = {2001}, author = {Kasacka, I and Skrzydlewska, E}, title = {Ethanol and N-acetylcysteine influence on the development of liver changes in experimental methanol intoxication.}, journal = {Roczniki Akademii Medycznej w Bialymstoku (1995)}, volume = {46}, number = {}, pages = {133-144}, pmid = {11780556}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Drug Synergism ; Ethanol/administration &amp; dosage/*toxicity ; Liver/*drug effects/pathology ; Male ; Methanol/administration &amp; dosage/antagonists &amp; inhibitors/*toxicity ; Microscopy, Electron ; Rats ; Rats, Wistar ; }, abstract = {The evaluation of ethanol and N-Acetylcysteine (NAC) influence on histopathological changes in rat liver intoxicated with 3 g of methanol/kg b.w. was conducted, based on morphological examinations in light and electron microscope. The rats received intragastrically 3.0 g of methanol/kg b.w. as a 50% solution, 10% ethanol for 24 hours before methanol and next 48 hours after methanol ingestion and NAC (150 mg/kg b.w.) after 15 min. methanol administrated. The results indicate that methanol intoxication causes pronounced morphological changes in the examined organ. Ethanol administered to methanol-intoxicated rats caused intensification of certain parameters of hepatocytes morphological damage. A simultaneous administration of methanol and NAC resulted in a lower degree of parenchymal damage.}, }
@article {pmid11769876, year = {2001}, author = {Moyad, MA}, title = {Results and lessons from clinical trials using dietary supplements for cancer: direct and indirect investigations.}, journal = {Seminars in urologic oncology}, volume = {19}, number = {4}, pages = {232-246}, pmid = {11769876}, issn = {1081-0943}, mesh = {Acetylcysteine/therapeutic use ; Amygdalin/adverse effects ; Antioxidants/therapeutic use ; Ascorbic Acid/pharmacology/therapeutic use ; *Dietary Supplements ; Disease Progression ; Humans ; Neoplasms/*drug therapy/prevention &amp; control ; Randomized Controlled Trials as Topic ; Selenium/therapeutic use ; Tissue Extracts/therapeutic use ; Vitamin A/therapeutic use ; Vitamin E/therapeutic use ; beta Carotene/therapeutic use ; }, abstract = {Randomized controlled trials are generally regarded as the standard of study designs to determine potential causality. The inclusion of a placebo group in these trials, when appropriate, is generally needed to access the efficacy of a drug or dietary supplement. The recent increasing use of dietary supplements and herbal medications by patients makes it imperative to reevaluate the past findings of clinical studies. Several large-scale trials of dietary supplements have been tested in various populations to determine their effect on cancer prevention. Other trials have focused on patients already diagnosed with cancer. In the latter case, it is difficult to involve a placebo because of the serious nature of the disease. Nevertheless, much has been gleaned from these trials directly and indirectly. Overall, when analyzing primary endpoints in these trials, the results have been discouraging and even support the nonuse of certain supplements because of potential adverse effects. Other secondary endpoints in these same trials have revealed some potential encouraging and discouraging data. Individuals who currently qualify for the potential use of dietary supplements for cancer may be restricted to those who have a deficiency in a certain compound despite adequate dietary sources or lifestyle changes. Those individuals with a smoking history or other unhealthy lifestyle seem to have the most to gain or lose from taking certain dietary supplements for cancer. The time seems more than ripe to evaluate past adequate trials with supplements, such as beta-carotene, N-acetyl-cysteine, selenium, shark cartilage, vitamin C, vitamin E, and others. Again, these studies have been disappointing, but they provide insight for the clinician and patient of what to potentially expect when using these supplements for cancer. In addition, indirect trials for other conditions (cardiovascular) may provide future insight into possible results for future cancer prevention trials.}, }
@article {pmid11755128, year = {2001}, author = {Kim, JA and Kang, YS and Park, SH and Kim, HW and Cho, SY and Lee, YS}, title = {Role of reactive oxygen species in apoptosis induced by N-ethylmaleimide in HepG2 human hepatoblastoma cells.}, journal = {European journal of pharmacology}, volume = {433}, number = {1}, pages = {1-6}, doi = {10.1016/s0014-2999(01)01420-0}, pmid = {11755128}, issn = {0014-2999}, mesh = {Apoptosis/*drug effects ; Chlorides/metabolism ; Ethylmaleimide/*pharmacology ; Hepatoblastoma/metabolism/*pathology ; Humans ; Liver Neoplasms/metabolism/*pathology ; NADPH Oxidases/physiology ; Potassium/metabolism ; *Reactive Oxygen Species ; Symporters/physiology ; K Cl- Cotransporters ; }, abstract = {We have previously reported that N-ethylmaleimide induces apoptosis through activation of K(+), Cl(-)-cotransport in HepG2 human hepatoblastoma cells. In this study, we investigated the role for reactive oxygen species as a mediator of the apoptosis induced by N-ethylmaleimide. N-ethylmaleimide induced a significant elevation of intracellular level of reactive oxygen species. Treatment with antioxidants (N-acetyl cysteine, N,N'-diphenyl-p-phenylenediamine) which markedly suppressed generation of reactive oxygen species, significantly inhibited the N-ethylmaleimide-induced activation of K(+), Cl(-)-cotransport and apoptosis. Inhibitors of NADPH oxidase (diphenylene iodonium, apocynin, D-(+)-neopterine) also significantly blunted the generation of reactive oxygen species, activation of K(+), Cl(-)-cotransport and apoptosis induced by N-ethylmaleimide. These results suggest that reactive oxygen species generated through activation of NADPH oxidase may play a role in the N-ethylmaleimide-induced stimulation of K(+), Cl(-)-cotransport and apoptosis in HepG2 cells.}, }
@article {pmid11751160, year = {2002}, author = {Bhatia, M and Brady, M and Kang, YK and Costello, E and Newton, DJ and Christmas, SE and Neoptolemos, JP and Slavin, J}, title = {MCP-1 but not CINC synthesis is increased in rat pancreatic acini in response to cerulein hyperstimulation.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {282}, number = {1}, pages = {G77-85}, doi = {10.1152/ajpgi.00031x.2002}, pmid = {11751160}, issn = {0193-1857}, mesh = {Acetylcysteine/pharmacology ; Amylases/metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Calcium/metabolism ; Cell Survival ; Cells, Cultured ; Ceruletide/*pharmacology ; Chelating Agents/pharmacology ; Chemokine CCL2/analysis/*biosynthesis ; *Chemokines, CXC ; Chemotactic Factors/analysis/*biosynthesis ; Egtazic Acid/*analogs &amp; derivatives/pharmacology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Growth Substances/analysis/*biosynthesis ; *Intercellular Signaling Peptides and Proteins ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Pancreas/chemistry/cytology/*metabolism ; Rats ; Rats, Wistar ; Serine Proteinase Inhibitors/pharmacology ; Thapsigargin/pharmacology ; Tosylphenylalanyl Chloromethyl Ketone/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Inflammatory mediators including chemokines play a critical role in acute pancreatitis. The precise nature of early inflammatory signals within the pancreas remains, however, unclear. We examined the ability of isolated pancreatic acini to synthesize CC chemokine monocyte chemotactic protein-1 (MCP-1) and CXC chemokine cytokine-induced neutrophil chemoattractant (CINC) and the response to the secretagogue cerulein at physiological and supraphysiological concentrations. Isolated rat pancreatic acini maintained in short-term (< or =48 h) primary culture constitutively synthesized MCP-1 and CINC. Cerulein (10(-7) M; supramaximal dose) increased production of MCP-1 but not CINC. Cerulein-induced increase in MCP-1 synthesis was accompanied by increase in nuclear factor (NF)-kappaB activation shown by EMSA. Pretreatment with NF-kappaB inhibitors N-acetylcysteine (NAC) and N-tosylphenyalanine chloromethyl ketone (TPCK) blocked cerulein-induced NF-kappaB activation and abolished cerulein's effect on MCP-1 synthesis. Pretreatment with calcium antagonist BAPTA-AM also blocked cerulein's effect on MCP-1 synthesis. These results indicate that isolated acini synthesize MCP-1 and CINC and support the idea of acinar-derived chemokines as early mediators of inflammatory response in acute pancreatitis. Although cerulein hyperstimulation increased MCP-1 synthesis by a calcium-dependent mechanism involving NF-kappaB activation, CINC synthesis was not affected. This suggests that regulation of CC and CXC chemokines within acinar cells may be quite different.}, }
@article {pmid11749846, year = {2001}, author = {Wei, YM and Ou, YX and Bai, H and Lu, JH and Zheng, RL}, title = {Down-regulation of four arsenic antagonists on apoptosis and telomerase activity induced by arsenic trioxide in three myelocytic leukemia cell lines.}, journal = {Acta pharmacologica Sinica}, volume = {22}, number = {8}, pages = {725-730}, pmid = {11749846}, issn = {1671-4083}, mesh = {Acetylcysteine/pharmacology ; Aminoquinolines/pharmacology ; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Arsenic/*antagonists &amp; inhibitors ; Arsenic Trioxide ; Arsenicals/*pharmacology ; Catalase/pharmacology ; Down-Regulation ; HL-60 Cells/pathology ; Humans ; K562 Cells/pathology ; Leukemia, Myeloid/enzymology/*pathology ; Oxides/*pharmacology ; Telomerase/*metabolism ; }, abstract = {AIM: To investigate regulative effects of thiol reagents, N-acetyl-l-cysteine (NAC) and natrii dimercaptosussinas (NDMS), catalase (CAT), and calcium chelator 2-[(2-bis-[carboxymethyl]-amino-5-methyl-phenoxy)-met]-6-methoxy-8-bis-[carboxy-methyl]-aminoquinoline (Quin 2) on apoptosis and telomerase activity induced by arsenic trioxide (As2O3) in three myelocytic leukemia cell lines.<br><br>METHODS: Flow cytometry was used to examine apoptosis and a PCR ELISA kit was used to detect telomerase activity.<br><br>RESULTS: As2O3 induced about 40 % - 60 % of apoptosis in NB4, K562, and HL-60 cells at the concentration of 0.6, 2.7, and 8.1 micromol/L respectively, as well as down-regulated telomerase activities in three cell lines. NAC 4 mmol/L, NDMS 200 micromol/L, CAT 80 kU/L, and Quin 2 20 micromol/L could down-regulate apoptosis variously induced by As2O3. NAC and CAT alone could decline telomerase activity in three cell lines and further decline telomerase activities that had been decreased by As2O3, whereas Quin 2 antagonized the decline in K562 and HL-60 cells.<br><br>CONCLUSION: Thiol activity loss, free radical alteration, intracellular calcium changes, and decline of telomerase activity might be involved in As2O3-induced apoptosis. NAC, NDMS, CAT, and Quin 2 antagonized in some extent the effect of As2O3 on the three tested cell lines.}, }
@article {pmid11748350, year = {2001}, author = {Kong, G and Lee, S and Kim, KS}, title = {Inhibition of rac1 reduces PDGF-induced reactive oxygen species and proliferation in vascular smooth muscle cells.}, journal = {Journal of Korean medical science}, volume = {16}, number = {6}, pages = {712-718}, doi = {10.3346/jkms.2001.16.6.712}, pmid = {11748350}, issn = {1011-8934}, mesh = {Adenoviridae/genetics ; Animals ; Aorta, Thoracic/cytology ; Cell Division/drug effects/physiology ; Cells, Cultured ; Gene Expression/physiology ; Gene Transfer Techniques ; Multienzyme Complexes/antagonists &amp; inhibitors ; Muscle, Smooth, Vascular/*cytology/*metabolism ; NADH, NADPH Oxidoreductases/antagonists &amp; inhibitors ; NADPH Oxidases/antagonists &amp; inhibitors ; Platelet-Derived Growth Factor/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; rac1 GTP-Binding Protein/*genetics/metabolism ; }, abstract = {In vascular smooth muscle cells, reactive oxygen species (ROS) were known to mediate platelet-derived growth factor (PDGF)-induced cell proliferation and NADH/NADPH oxidase is the major source of ROS. NADH/NADPH oxidase is controlled by rac1 in non-phagocytic cells. In this study, we examined whether the inhibition of rac1 by adenoviral-mediated gene transfer of a dominant negative rac1 gene product (Ad.N17rac1) could reduce the proliferation of rat aortic vascular smooth muscle cells (RASMC) stimulated by PDGF via decreasing intracellular ROS. RASMC were stimulated by PDGF (80 ng/mL) with or without N-acetylcysteine 1 mM or infected with 100 mutiplicity of infection of Ad.N17rac1. Intracellular ROS levels were measured at 12 hr using carboxyl-2', 7'-dichlorodihydrofluorescein diacetate confocal microscopy. At 72 hr, cellular proliferation was evaluated by cell number counting and XTT assay. Compared with control, ROS levels were increased by 2-folds by PDGF. NAC and Ad.N17rac1 inhibited PDGF-induced increase of ROS by 77% and 65%, respectively. Cell number was increased by PDGF by 1.6-folds compared with control. NAC and Ad.N17rac1 inhibited PDGF-induced cellular growth by 45% and 87%, respectively. XTT assay also showed similar results. We concluded that inhibition of rac1 in RASMCs could reduce intracellular ROS levels and cellular proliferation induced by PDGF.}, }
@article {pmid11744993, year = {2002}, author = {Hoare, GS and Chester, AH and Yacoub, MH and Marczin, N}, title = {Regulation of NF-kappaB and ICAM-1 expression in human airway epithelial cells.}, journal = {International journal of molecular medicine}, volume = {9}, number = {1}, pages = {35-44}, pmid = {11744993}, issn = {1107-3756}, mesh = {Acetylcysteine/metabolism ; Blotting, Western ; Cell Line ; Fluorescent Antibody Technique ; Gene Expression Regulation ; Humans ; Hydrogen Peroxide/metabolism ; Intercellular Adhesion Molecule-1/biosynthesis/*physiology ; Interleukin-1/physiology ; Microscopy, Confocal ; NF-kappa B/biosynthesis/*physiology ; Oxidants/*metabolism ; Oxidative Stress ; Respiratory Mucosa/*physiology ; Transcriptional Activation ; }, abstract = {The aim of this study was to elucidate the redox regulation of cytokine-induced NF-kappaB activation and NF-kappaB mediated gene induction in A549 cells and primary cultures of human airway epithelial cells. In A549 cells, Western blot analysis showed transient depletion of IkappaBalpha after 15 min IL-1beta treatment followed by its reappearance after 60 min, indicating efficient NF-kappaB-driven gene induction. A similar pattern was observed in primary epithelial cells however, the kinetics were slower and depletion was less. In primary airway epithelial cells IkappaBalpha levels were 59.8+/-8.5% of control following 30 min treatment with IL-1beta and in A549 cells 29.1+/-8.5% of control following 15 min IL-1beta treatment. Cytokine-induced IkappaBalpha depletion was associated with NF-kappaB nuclear accumulation and subsequent resynthesis of IkappaBalpha and upregulation of ICAM-1 in both cell types. The antioxidant, NAC (20 mM) had no effect on the kinetics of cytokine-induced IkappaBalpha depletion or NF-kappaB p65 nuclear translocation in either cell type and failed to influence kappaB dependent IkappaBalpha resynthesis. H2O2 treatment alone or in combination with cytokines had no significant effects on IkappaBalpha depletion, NF-kappaB p65 nuclear translocation or ICAM-1 expression in either cell type but did cause significant activation of p38 MAPK. These results suggest that cytokine-induced NF-kappaB activation in cultured human airway epithelial cells does not involve an NAC-sensitive oxidant stress and that H2O2-induced oxidant stress does not result in effective NF-kappaB activation and NF-kappaB mediated gene induction.}, }
@article {pmid11742581, year = {2001}, author = {Azad, A and Lall, SB and Mittra, S}, title = {Effect of N-acetylcysteine and L-NAME on aluminium phosphide induced cardiovascular toxicity in rats.}, journal = {Acta pharmacologica Sinica}, volume = {22}, number = {4}, pages = {298-304}, pmid = {11742581}, issn = {1671-4083}, mesh = {Acetylcysteine/*pharmacology ; Aluminum Compounds/antagonists &amp; inhibitors/*toxicity ; Animals ; Blood Pressure/drug effects ; Catalase/metabolism ; Drug Interactions ; Electrocardiography/drug effects ; Free Radical Scavengers/pharmacology ; Heart Rate/drug effects ; Male ; Malondialdehyde/*metabolism ; Myocardium/*metabolism ; NG-Nitroarginine Methyl Ester/*pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Phosphines/antagonists &amp; inhibitors/*toxicity ; Rats ; Rats, Wistar ; }, abstract = {AIM: To investigate the protective effects of N-acetylcysteine (NAC) and Nomega-Nitro-L-arginine methyl ester (L-NAME) on aluminium phosphide (AlP) poisoning induced hemodynamic changes, myocardial oxygen free radical injury and on survival time in rats.<br><br>METHODS: AlP (12.5 mg/kg) was administered intragastrically under urethane anaesthesia. The effect of pre- and post-treatment with NAC and L-NAME alone and in combination was studied on haemodynamic parameters [blood pressure (BP), heart rate (HR), and electrocardiogram (ECG)] and biochemical parameters (malonyldialdehyde, catalase, and glutathione peroxidase).<br><br>RESULTS: AlP caused significant hypotension, tachycardia, ECG abnormalities, and finally marked bradycardia. The mean survival time was (90 +/- 10) min. There was significant increase in myocardial malonyldialdehyde (MDA), and decrease in catalase and glutathione peroxidase (GSH Px) levels. NAC infusion (6.25 mg . kg-1 . min-1, iv for 30 min) caused insignificant hemodynamic and biochemical changes. Pre- and post-treatment of NAC with AlP significantly increased the survival time, stabilized BP, HR, and ECG, decreased MDA and increased GSH Px levels compared to AlP group. L-NAME infusion (1 mg . kg-1 . min-1, iv for 60 min) as such caused significant rise in BP but precipitated ECG abnormalities. Pre- and post-treatment of L-NAME with AlP neither improved the survival time nor the biochemical parameters despite significant rise in BP. Co-administration of both the drugs with AlP worsened the hemodynamic and biochemical parameters with reduction in the survival time as compared to AlP.<br><br>CONCLUSION: NAC increased the survival time by reducing myocardial oxidative injury whereas L-NAME showed no such protective effects in rats exposed to AlP.}, }
@article {pmid11742214, year = {2001}, author = {Rodríguez-Pallares, J and Rey, P and Soto-Otero, R and Labandeira-Garcia, JL}, title = {N-acetylcysteine enhances production of dopaminergic neurons from mesencephalic-derived precursor cells.}, journal = {Neuroreport}, volume = {12}, number = {18}, pages = {3935-3938}, doi = {10.1097/00001756-200112210-00016}, pmid = {11742214}, issn = {0959-4965}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain Tissue Transplantation ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Dopamine/*physiology ; Fetal Tissue Transplantation ; Fetus/cytology/drug effects ; Free Radical Scavengers/*pharmacology ; Interleukin-1/pharmacology ; Mesencephalon/cytology ; Neurons/*cytology/enzymology ; Rats ; Rats, Sprague-Dawley ; Stem Cells/*cytology/enzymology ; Tyrosine 3-Monooxygenase/analysis ; }, abstract = {Epidermal growth-factor-responsive rat mesencephalic precursor cells incubated in differentiation media produce only a small number of dopaminergic (DA) cells. Supplementation of the differentiation medium with N-acetylcysteine (NAC) induced a marked increase (approximately 400%) in the number of tyrosine hydroxylase (TH)-positive cells. Treatment with interleukin-1 alpha also induced a significant increase (approximately 300%) in the number of TH-positive cells. However, we did not find additive effects between these drugs. The results suggest that NAC is effective in the production of DA cells from precursors, and that this may be related to enhancement of generation and/or survival of DA cells.}, }
@article {pmid11741340, year = {2001}, author = {Shiffer, Z and Zurgil, N and Shafran, Y and Deutsch, M}, title = {Analysis of laser scattering pattern as an early measure of apoptosis.}, journal = {Biochemical and biophysical research communications}, volume = {289}, number = {5}, pages = {1320-1327}, doi = {10.1006/bbrc.2001.6127}, pmid = {11741340}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Annexin A5 ; *Apoptosis/drug effects ; *Cell Size/drug effects ; Dexamethasone/pharmacology ; Flow Cytometry ; Fluorescent Dyes ; In Vitro Techniques ; Kinetics ; Lasers ; Male ; Mice ; Mice, Inbred BALB C ; Scattering, Radiation ; T-Lymphocytes/cytology/drug effects ; }, abstract = {Light scattering pattern analysis (LSPA) was applied in the current study for accurate and sensitive detection of subtle changes in cell size, which occur in mouse thymocytes undergoing apoptosis. The decrease in cell diameter as measured by LSPA was found to be an early signal of apoptosis preceding the externalization of phosphatidylserine on the outer membrane. When apoptosis was induced by dexamethasone, the change in cell size was dose and time dependent, and could be blocked by pretreatment of the thymocytes with N-acetylcysteine (NAC). This implies that the scattering pattern, when combined with fluorescent markers such as annexine-V, may be a powerful tool for early detection of apoptosis. Another advantage gained by the use of this method is the ability to repeatedly trace the same cells and to monitor the kinetics of their size changes.}, }
@article {pmid11740866, year = {2002}, author = {Gu, Y and Xu, YC and Wu, RF and Souza, RF and Nwariaku, FE and Terada, LS}, title = {TNFalpha activates c-Jun amino terminal kinase through p47(phox).}, journal = {Experimental cell research}, volume = {272}, number = {1}, pages = {62-74}, doi = {10.1006/excr.2001.5404}, pmid = {11740866}, issn = {0014-4827}, support = {R01-HL61897/HL/NHLBI NIH HHS/United States ; R29-HL52591/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Cell Line ; Endothelium, Vascular/physiology ; Humans ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases/*physiology ; NADPH Oxidases/physiology ; Oxidants/metabolism ; Phagocytosis/physiology ; Phosphoproteins/*physiology ; Reactive Oxygen Species ; Signal Transduction/*drug effects/*physiology ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Reactive oxygen intermediates have been implicated in the transduction of TNFalpha signals, although the source of such oxidants has not been established. We found that activation of ECV-304 cells by TNFalpha was accompanied by a transient burst of oxidants and activation of JNK, both of which were suppressed by two distinct inhibitors of the phagocyte NADPH oxidase and the thiol antioxidant N-acetyl cysteine (NAC). We cloned partial and full-length cDNA sequences from ECV-304 cells and human umbilical vein endothelial cells (HUVEC), respectively, for p47(phox), demonstrating that these nonphagocytic cells express this adapter protein known to specifically initiate assembly of the NADPH oxidase in professional phagocytes. A mutant p47(phox), defective in the first Src homology 3 (SH3) domain (p47W(193)R), diminished JNK activation by TNFalpha. Surprisingly, p47(phox) resided entirely in the particulate, not cytosolic, fraction of cells. Immunostaining suggested partial colocalization with cytoskeletal elements, and cytoskeletal disrupters decreased both oxidant production and JNK activation by TNFalpha. A p47-GFP fusion protein localized to the cortical cytoskeleton in living cells; further, stimulation of cells with TNFalpha caused a marked concentration of p47-GFP in membrane ruffles, actin-rich structures associated with intense respiratory burst activity in stimulated neutrophils. We conclude that nonphagocytic cells express p47(phox), which appears to localize to the cytoskeleton and participate in TNFalpha signaling. We speculate that this physical targeting may prove important in conferring signal specificity and enhancing signaling efficiency of unstable oxidants.}, }
@article {pmid11740154, year = {2001}, author = {Yeh, LH and Kinsey, AM and Chatterjee, S and Alevriadou, BR}, title = {Lactosylceramide mediates shear-induced endothelial superoxide production and intercellular adhesion molecule-1 expression.}, journal = {Journal of vascular research}, volume = {38}, number = {6}, pages = {551-559}, doi = {10.1159/000051091}, pmid = {11740154}, issn = {1018-1172}, support = {DK-31722/DK/NIDDK NIH HHS/United States ; HL-54089/HL/NHLBI NIH HHS/United States ; }, mesh = {*Antigens, CD ; Cells, Cultured ; Endothelium, Vascular/cytology/drug effects/*metabolism ; Enzyme Inhibitors/pharmacology ; Galactosyltransferases/metabolism ; Humans ; Intercellular Adhesion Molecule-1/*metabolism ; Lactosylceramides/*pharmacology ; Morpholines/pharmacology ; Stress, Mechanical ; Superoxides/*metabolism ; }, abstract = {Laminar shear stress activates NADPH oxidase in vascular endothelial cells (ECs), and the generated superoxide radicals (O2(-.) are known to be involved in intercellular adhesion molecule (ICAM)-1 expression. In this study, the role of a glycosphingolipid (GSL), lactosylceramide (LacCer), as a second messenger in the shear-induced O2(-.) generation and ICAM-1 expression was examined. It is known that glucosylceramide synthase (GlcT-1) catalyzes the synthesis of glucosylceramide (GlcCer) from ceramide, and subsequently lactosylceramide synthase (GalT-2) synthesizes LacCer from GlcCer. We observed that exposing cultured human umbilical vein ECs (HUVECs) to fluid shear stress (20 dyn/cm(2) for 30 min) activated GalT-2. Shear stress also increased EC O2(-.) generation, that peaked at 30 min, and surface ICAM-1 protein expression at 6 h post-shear. EC preincubation with the antioxidant N-acetylcysteine (NAC; 20 mM for 2 h) completely abolished the shear-induced O2(-.) production and significantly inhibited ICAM-1 expression. EC preincubation with D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of the GSL glycosyltransferases GlcT-1 and GalT-2, abrogated the shear-induced activation of GalT-2. D-PDMP also abolished the shear-induced O2(-.) production and ICAM-1 expression. We conclude that laminar shear stress activates GalT-2 to produce LacCer. In turn, LacCer activates NADPH oxidase, which produces O2(-.), and O2(-.) mediates the shear-induced increase in ICAM-1 expression. Thus, LacCer may play an important role in hemodynamic force-induced pathological conditions, such as atherosclerosis and ischemia/reperfusion injury.}, }
@article {pmid11733013, year = {2001}, author = {Ohyama, K and Yuan, B and Bessho, T and Yamakawa, T}, title = {Progressive apoptosis in chorion laeve trophoblast cells of human fetal membrane tissues during in vitro incubation is suppressed by antioxidative reagents.}, journal = {European journal of biochemistry}, volume = {268}, number = {23}, pages = {6182-6189}, doi = {10.1046/j.0014-2956.2001.02573.x}, pmid = {11733013}, issn = {0014-2956}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/genetics ; Chorion/*cytology/*drug effects/metabolism ; DNA Fragmentation/drug effects ; Female ; Gene Expression/drug effects ; Humans ; In Vitro Techniques ; Labor, Obstetric ; Masoprocol/pharmacology ; Oxidative Stress ; Pregnancy ; Pyrrolidines/pharmacology ; RNA, Messenger/genetics/metabolism ; Superoxide Dismutase/genetics/metabolism ; Thiocarbamates/pharmacology ; Trophoblasts/*cytology/*drug effects/metabolism ; }, abstract = {Previously, we demonstrated apoptotic cell death in the chorion laeve trophoblast layer of human fetal membrane tissues during the late stages of pregnancy, the progression of apoptosis during incubation in vitro, and its suppression by a low concentration of glucocorticoid hormones. We now report examination of mRNA expression of inflammatory cytokines [interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha] and antioxidative enzyme genes [heme oxygenase 1, catalase, Mn-superoxide dismutase (SOD), Cu/Zn-SOD, glutathione S-transferase, glutathione reductase and glutathione peroxidase] and apoptosis-related genes during in vitro progression of apoptosis with or without glucocorticoid by a reverse transcription/PCR method. It was shown that the mRNA levels increased in chorion laeve tissue for each cytokine examined and for catalase, heme oxygenase 1 and Mn-SOD in direct correlation with the in vitro incubation period. By Western blotting the existence of Mn-SOD protein, and its slight increase with incubation time, was also shown. The investigation of the influence of antioxidative reagents [pyrrolidine dithiocarbamate (PDTC), N-acetyl-l-cysteine (NAC) and nordihydroguaiaretic acid (NDGA)] on DNA fragmentation showed that DNA fragmentation in chorion laeve tissues was inhibited by approximately 50% in the presence of 1 mm PDTC, 30 mm NAC and 1 mm NDGA. These results suggest that apoptotic cell death of the trophoblast layer of chorion tissues may be induced through intracellular oxidative stress at the stage of parturition.}, }
@article {pmid11719447, year = {2001}, author = {Albini, A and Morini, M and D'Agostini, F and Ferrari, N and Campelli, F and Arena, G and Noonan, DM and Pesce, C and De Flora, S}, title = {Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral N-acetylcysteine.}, journal = {Cancer research}, volume = {61}, number = {22}, pages = {8171-8178}, pmid = {11719447}, issn = {0008-5472}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Angiogenesis Inhibitors/*pharmacology ; Animals ; Cell Division/drug effects/physiology ; Cell Movement/drug effects ; Endothelial Growth Factors/antagonists &amp; inhibitors/biosynthesis/genetics ; Female ; Growth Inhibitors/pharmacology ; Humans ; Ki-67 Antigen/metabolism ; Lymphokines/antagonists &amp; inhibitors/biosynthesis/genetics ; Male ; Mice ; Mice, Nude ; Neovascularization, Pathologic/*drug therapy ; Proliferating Cell Nuclear Antigen/metabolism ; RNA, Messenger/biosynthesis/genetics ; Sarcoma, Kaposi/*blood supply/pathology ; Tumor Cells, Cultured ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; Xenograft Model Antitumor Assays ; }, abstract = {The thiol N-acetyl-L-cysteine (NAC), an analogue and precursor of reduced glutathione, has cancer chemopreventive properties attributable to its nucleophilicity, antioxidant activity, and a variety of other mechanisms. We demonstrated recently that NAC has anti-invasive, antimetastatic, and antiangiogenic effects in in vitro and in vivo test systems. In the present study, s.c. transplantation of KS-Imm cells in (CD-1)BR nude mice resulted in the local growth of Kaposi's sarcoma, a highly vascularized human tumor. The daily administration of NAC with drinking water, initiated after the tumor mass had become established and detectable, produced a sharp inhibition of tumor growth, with regression of tumors in half of the treated mice along with a markedly prolonged median survival time. The production of vascular endothelial growth factor (VEGF) and certain proliferation markers (proliferating cell nuclear antigen and Ki-67) were significantly lower in Kaposi's sarcomas from NAC-treated mice than from control mice. Treatment of KS-Imm cells with NAC in vitro resulted in a dose-dependent inhibition of chemotaxis and invasion through inhibition of gelatinase-A (matrix metalloproteinase-2, MMP-2) activity without altering MMP-2 or MMP-9 mRNA levels. NAC also significantly inhibited VEGF production but did not affect proliferation markers in vitro. Reverse transcription-PCR analysis indicated that total VEGF mRNAs were reduced by 10 mM NAC. Taken together, these findings provide evidence that NAC, the safety of which even at high doses has been established in almost 40 years of clinical use, in addition to its chemopreventive action, has a strong antiangiogenic potential that could be exploited for preventing cancer progression as well as used in cancer adjuvant therapy.}, }
@article {pmid11711574, year = {2001}, author = {Sanz-Alfayate, G and Obeso, A and Agapito, MT and González, C}, title = {Reduced to oxidized glutathione ratios and oxygen sensing in calf and rabbit carotid body chemoreceptor cells.}, journal = {The Journal of physiology}, volume = {537}, number = {Pt 1}, pages = {209-220}, pmid = {11711574}, issn = {0022-3751}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carotid Body/cytology/*physiology ; Catecholamines/metabolism ; Cattle ; Chemoreceptor Cells/cytology/*physiology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism ; Glutathione Disulfide/*metabolism ; Hypoxia/metabolism ; Ionomycin/pharmacology ; Ionophores/pharmacology ; Oxygen/*metabolism ; Potassium/pharmacology ; Rabbits ; }, abstract = {1. The aim of this work was to test the redox hypotheses of O(2) chemoreception in the carotid body (CB). They postulate that hypoxia alters the levels of reactive oxygen species (ROS) and the ratio of reduced to oxidized glutathione (GSH/GSSG), causing modifications to the sulfhydryl groups/disulfide bonds of K+ channel proteins, which leads to the activation of chemoreceptor cells. 2. We found that the GSH/GSSG ratio in normoxic calf CB (30.14 +/- 4.67; n = 12) and hypoxic organs (33.03 +/- 6.88; n = 10), and the absolute levels of total glutathione (0.71 +/- 0.07 nmol (mg tissue)(-1), normoxia vs. 0.76 +/- 0.07 nmol (mg tissue)(-1), hypoxia) were not statistically different. 3. N-Acetylcysteine (2 mM; NAC), a precursor of glutathione and ROS scavenger, increased normoxic glutathione levels to 1.03 +/- 0.06 nmol (mg tissue)(-1) (P < 0.02) and GSH/GSSG ratios to 59.05 +/- 5.05 (P < 0.001). 4. NAC (20 microM-10 mM) did not activate or inhibit chemoreceptor cells as it did not alter the normoxic or the hypoxic release of (3)H-catecholamines ((3)H-CAs) from rabbit and calf CBs whose CA deposits had been labelled by prior incubation with the natural CA precursor (3)H-tyrosine. 5. NAC (2 mM) was equally ineffective in altering the release of (3)H-CAs induced by stimuli (high external K+ and ionomycin) that bypass the initial steps of the hypoxic cascade of activation of chemoreceptor cells, thereby excluding the possibility that the lack of effect of NAC on normoxic and hypoxic release of (3)H-CAs results from a concomitant alteration of Ca(2+) channels or of the exocytotic machinery. 6. The present findings do not support the contention that O(2) chemoreception in the CB is linked to variations in the GSH/GSSG quotient as the redox models propose.}, }
@article {pmid11709424, year = {2001}, author = {Gurjar, MV and Deleon, J and Sharma, RV and Bhalla, RC}, title = {Role of reactive oxygen species in IL-1 beta-stimulated sustained ERK activation and MMP-9 induction.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {281}, number = {6}, pages = {H2568-74}, doi = {10.1152/ajpheart.2001.281.6.H2568}, pmid = {11709424}, issn = {0363-6135}, support = {HL-14388/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Extracellular Space/enzymology ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Enzymologic ; Gene Transfer Techniques ; Interleukin-1/*pharmacology ; MAP Kinase Signaling System/physiology ; Male ; Matrix Metalloproteinase 9/*genetics/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Muscle, Smooth, Vascular/cytology/*enzymology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Superoxide Dismutase/metabolism ; }, abstract = {We have recently demonstrated that interleukin-1 beta (IL-1 beta) stimulates matrix metalloproteinase-9 (MMP-9) induction. In this study we have investigated the roles of superoxide and extracellular signal-regulated kinase (ERK) activation in MMP-9 induction following exposure to IL-1 beta. IL-1 beta stimulated biphasic ERK activation in vascular smooth muscle (VSM) cells, a transient activation that reached a maximum at 15 min and declined to baseline levels within 1 h, and a second phase of sustained ERK activation lasting up to 8 h. To determine the role of ERK in IL-1 beta-stimulated MMP-9 induction, we treated cells with the specific ERK pathway inhibitor PD-98059 at different time intervals after IL-1 beta stimulation. Addition of PD-98059 up to 4 h after IL-1 beta stimulation significantly inhibited MMP-9 induction, suggesting a role for sustained ERK activation in MMP-9 induction. IL-1 beta treatment stimulated superoxide production in VSM cells that was inhibited by pretreatment of cells with the superoxide scavenger N-acetyl-L-cysteine (NAC) and also by overexpression of the human manganese superoxide dismutase (MnSOD) gene. Treatment of VSM cells with NAC selectively inhibited the sustained phase of ERK activation without influencing the transient phase, suggesting a role for reactive oxygen species in sustained ERK activation. In addition, both NAC treatment and MnSOD overexpression significantly inhibited IL-1 beta-stimulated MMP-9 induction (P < 0.05). The results demonstrate that IL-1 beta-dependent MMP-9 induction is mediated by superoxide-stimulated ERK activation.}, }
@article {pmid11708617, year = {2001}, author = {Studer, R and Baysang, G and Brack, C}, title = {N-Acetyl-L-Cystein downregulates beta-amyloid precursor protein gene transcription in human neuroblastoma cells.}, journal = {Biogerontology}, volume = {2}, number = {1}, pages = {55-60}, doi = {10.1023/a:1010065103073}, pmid = {11708617}, issn = {1389-5729}, mesh = {Acetylcysteine/*pharmacology ; Amyloid beta-Protein Precursor/*genetics ; Antioxidants/*pharmacology ; Down-Regulation/*drug effects ; Humans ; Neuroblastoma ; Oxidative Stress ; Transcription, Genetic/*drug effects ; Tumor Cells, Cultured ; }, abstract = {The causes for the sporadic form of Alzheimer's disease (AD) are still poorly understood, except from the fact that age is an important risk factor. The main component of the characteristic amyloid plaques in brains of AD patients are Abeta peptides, derivatives of the amyloid precursor protein APP. Oxidative stress may contribute to the aetiology of AD by dysregulation of APP metabolism. Overexpression of the APP gene could result in an increased secretion of neurotoxic Abeta peptides, while preventing the overexpression might be protective. We here report that the antioxidant N-Acetyl-L-Cystein (NAC) downregulates APP gene transcription in human neuroblastoma cells. The effect is reversible when cells are returned to NAC free medium. These results open up new possibilities for the development of therapeutic agents that intervene at the transcriptional level.}, }
@article {pmid11707430, year = {2002}, author = {Godbout, JP and Pesavento, J and Hartman, ME and Manson, SR and Freund, GG}, title = {Methylglyoxal enhances cisplatin-induced cytotoxicity by activating protein kinase Cdelta.}, journal = {The Journal of biological chemistry}, volume = {277}, number = {4}, pages = {2554-2561}, doi = {10.1074/jbc.M100385200}, pmid = {11707430}, issn = {0021-9258}, support = {CA-61931/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Annexin A5/pharmacology ; Antioxidants/pharmacology ; Apoptosis ; Blotting, Western ; Caspases/metabolism ; Cell Death ; Cell Survival ; Cisplatin/pharmacology/*toxicity ; Dose-Response Relationship, Drug ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Glutathione/metabolism ; Humans ; Isoenzymes/*metabolism ; Peroxides/metabolism ; Protein Binding ; Protein Kinase C/*metabolism ; Protein Kinase C-delta ; Proto-Oncogene Proteins c-abl/metabolism ; Pyruvaldehyde/*metabolism/pharmacology ; Reactive Oxygen Species ; Time Factors ; Tumor Cells, Cultured ; Up-Regulation ; }, abstract = {The cytotoxic side effects of anti-neoplastic drugs are increased in patients with either type 1 or type 2 diabetes mellitus by a mechanism that is not clearly defined. We report that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). We found that treatment of myeloma cells with the antioxidant N-acetylcysteine completely blocked cisplatin-dependent intracellular GSH oxidation, reactive oxygen species (ROS) generation, poly(ADP-ribose) polymerase cleavage, and apoptosis. Importantly, co-treatment of cells with the reactive carbonyl MGO and cisplatin increased apoptosis by 90% over the expected additive effect of combined MGO and cisplatin treatment. This same synergism was also observed when ROS generation was examined. MGO and cisplatin increased PKCdelta activity by 4-fold, and this effect was blocked by the PKCdelta inhibitor rottlerin but not by NAC. Furthermore, rottlerin blocked combined MGO and cisplatin-induced ROS generation and apoptosis. Finally, MGO and cisplatin induced c-Abl activation and c-Abl:PKCdelta association. Rottlerin blocked c-Abl activation, but the c-Abl inhibitor STI-571 increased MGO and cisplatin-induced apoptosis by 50%. Taken together these data indicate that MGO synergistically enhances cisplatin-induced apoptosis through activation of PKCdelta and that PKCdelta is critical to both cell death and cell survival pathways. These findings suggest that in the patient with diabetes mellitus heightened oxidative stress can enhance the cytotoxicity of agents that induce DNA damage.}, }
@article {pmid11707313, year = {2000}, author = {Nosál'ová, V and Cerná, S and Bauer, V}, title = {Effect of N-acetylcysteine on colitis induced by acetic acid in rats.}, journal = {General pharmacology}, volume = {35}, number = {2}, pages = {77-81}, doi = {10.1016/s0306-3623(01)00094-5}, pmid = {11707313}, issn = {0306-3623}, mesh = {Acetic Acid ; Acetylcysteine/*therapeutic use ; Animals ; Colitis/*drug therapy ; Dose-Response Relationship, Drug ; Glutathione/analysis ; Male ; Peroxidase/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; }, abstract = {(1) To verify the proposed role of reactive oxygen species (ROS) in ulcerative colitis, the effect of an antioxidant N-acetylcysteine (NAC) was studied in acetic acid (AA)-induced colonic inflammation. (2) Depending on the dose used, NAC administered intracolonically was found to reduce the extent of colonic damage, along with a decrease in myeloperoxidase (MPO) activity, colonic wet weight and wet/dry weight ratio. (3) NAC attenuated the enhanced vascular permeability and prevented the depletion of colonic reduced glutathione (GSH) caused by AA administration. (4) The findings indicate that NAC may prove beneficial in the treatment of colitis.}, }
@article {pmid11704536, year = {2001}, author = {Heunks, LM and Machiels, HA and de Abreu, R and Zhu, XP and van der Heijden, HF and Dekhuijzen, PN}, title = {Free radicals in hypoxic rat diaphragm contractility: no role for xanthine oxidase.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {281}, number = {6}, pages = {L1402-12}, doi = {10.1152/ajplung.2001.281.6.L1402}, pmid = {11704536}, issn = {1040-0605}, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Adenosine Triphosphate/metabolism ; Allopurinol/pharmacology ; Animals ; Diaphragm/*enzymology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Free Radicals/metabolism ; Hypoxia/*metabolism ; In Vitro Techniques ; Indicators and Reagents/pharmacology ; Isotonic Contraction/drug effects/*physiology ; Male ; Muscle Fatigue/drug effects/physiology ; Rats ; Rats, Wistar ; Xanthine Oxidase/antagonists &amp; inhibitors/*metabolism ; }, abstract = {Recent evidence indicates that hypoxia enhances the generation of oxidants. Little is known about the role of free radicals in contractility of the rat diaphragm during hypoxia. We hypothesized that antioxidants improve contractility of the hypoxic rat diaphragm and that xanthine oxidase (XO) is an important source of free radicals in the hypoxic diaphragm. The effects of N-acetylcysteine (NAC; 18 mM), Tiron (10 mM), and the XO inhibitor allopurinol (250 microM) were studied on isometric and isotonic force generation during hypoxia (PO(2) approximately 7 kPa). NAC and Tiron decreased maximal force generation, slowed the shortening velocity, and decreased the power output. Fatigue rate was decreased in the presence of either NAC or Tiron. Allopurinol did not alter the contractility or fatigability of the diaphragm. During hyperoxia (PO(2) approximately 85 kPa), neither NAC nor allopurinol affected the contractility or fatigability of the diaphragm. Thus free radicals play a significant role in diaphragm contractility during hypoxia. Whether antioxidants exert a beneficial or harmful effect on muscle performance depends on the contraction pattern of the muscle. Free radicals generated by XO do not play a role in diaphragm contractility during either hypoxia or hyperoxia.}, }
@article {pmid11697119, year = {2001}, author = {De la Fuente, M and Victor, VM}, title = {Ascorbic acid and N-acetylcysteine improve in vitro the function of lymphocytes from mice with endotoxin-induced oxidative stress.}, journal = {Free radical research}, volume = {35}, number = {1}, pages = {73-84}, doi = {10.1080/10715760100300611}, pmid = {11697119}, issn = {1071-5762}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Ascorbic Acid/*pharmacology ; Cell Adhesion/drug effects ; Cells, Cultured ; Chemotaxis/drug effects ; Escherichia coli/chemistry ; Female ; In Vitro Techniques ; Lipopolysaccharides ; Lymphocytes/*drug effects/*physiology ; Mice ; Mice, Inbred BALB C ; Oxidative Stress/physiology ; Phagocytosis/drug effects ; Reactive Oxygen Species/metabolism ; Shock, Septic/*drug therapy ; Tumor Necrosis Factor-alpha/biosynthesis/drug effects ; }, abstract = {Oxidative stress associated with reactive oxygen species (ROS) and cytokines produced by immune cells, which is involved in septic shock caused by endotoxin, can be controlled to a certain degree by antioxidants with free radical scavenging action. N-acetylcysteine (NAC) and ascorbic acid (AA) are ROS scavengers that improve the immune response, and modulate macrophage function in mice with endotoxin-caused oxidative stress. Therefore, we have investigated the in vitro effects of these antioxidants on the functions of lymphocytes from BALB/c mice with lethal endotoxic shock caused by intraperitoneal injection of E. coli lipopolysaccharide (LPS) (100 mg/kg). Adherence to tissues and chemotaxis (the earliest two functions of lymphocytes in the immune response), as well as ROS levels and TNF alpha production were determined in the presence or absence of NAC or AA (0.001, 0.01, 0.1, 1 and 2.5 mM) in lymphocytes from peritoneum, axillary nodes, spleen and thymus obtained at several times (2, 4, 12 and 24 hours) after LPS injection. Endotoxic shock decreases the chemotaxis of lymphocytes from all the above localizations and increases their adherence, TNF alpha and ROS production. These changes in lymphocyte function were counteracted by NAC and AA, bringing these functions to values near those of control animals. Our data suggest that lymphocytes are important targets of endotoxins contributing to oxidative stress by septic shock, and that antioxidants can preserve the function of lymphocytes, preventing the homeostatic disturbances caused by endotoxin.}, }
@article {pmid11697116, year = {2001}, author = {Kim, JA and Lee, YS}, title = {Role of reactive oxygen species generated by NADPH oxidase in the mechanism of activation of K(+)-Cl(-)-cotransport by N-ethylmaleimide in HepG2 human hepatoma cells.}, journal = {Free radical research}, volume = {35}, number = {1}, pages = {43-53}, doi = {10.1080/10715760100300581}, pmid = {11697116}, issn = {1071-5762}, mesh = {Carcinoma, Hepatocellular/*metabolism ; Chlorides/metabolism ; Enzyme Inhibitors/*pharmacology ; Ethylmaleimide/*pharmacology ; Genistein/pharmacology ; Humans ; Liver Neoplasms/*metabolism ; Marine Toxins ; NADPH Oxidases/*metabolism ; Oxazoles/pharmacology ; Potassium/metabolism ; Reactive Oxygen Species/*metabolism ; Symporters/*metabolism ; Tumor Cells, Cultured/drug effects ; K Cl- Cotransporters ; }, abstract = {K(+)-Cl(-)-cotransport (KCC) is ubiquitously present in all cells, and plays an essential role in ion and volume regulation. In this study we investigated the role of reactive oxygen species (ROS) in regulation of KCC in HepG2 human hepatoblastoma cells. N-ethylmaleimide (NEM), a KCC activator, induced Cl(-)-dependent K+ efflux, which was markedly prevented by KCC inhibitors (calyculin-A, genistein and BaCl2), indicating that KCC is activated by NEM in the HepG2 cells. Treatment with NEM also induced a sustained increase in the level of intracellular ROS assessed by 2',7'-dichlorofluorescein fluorescence. Antioxidants, N-acetyl cysteine or N,N'-diphenyl-p-phenylenediamine significantly inhibited both ROS generation and KCC activation induced by NEM. The NEM-induced ROS production was significantly suppressed by inhibitors of NADPH oxidase (diphenylene iodonium, apocynin and neopterine). These inhibitors also significantly inhibited the NEM-induced KCC activation. Taken together, these results suggest that ROS generated by NADPH oxidase may mediate the NEM-induced activation of KCC in human hepatoma cells.}, }
@article {pmid11696449, year = {2001}, author = {Hanigan, MH and Lykissa, ED and Townsend, DM and Ou, CN and Barrios, R and Lieberman, MW}, title = {Gamma-glutamyl transpeptidase-deficient mice are resistant to the nephrotoxic effects of cisplatin.}, journal = {The American journal of pathology}, volume = {159}, number = {5}, pages = {1889-1894}, pmid = {11696449}, issn = {0002-9440}, support = {ES 07827/ES/NIEHS NIH HHS/United States ; CA 57530/CA/NCI NIH HHS/United States ; R01 CA057530-09/CA/NCI NIH HHS/United States ; R01 ES007827/ES/NIEHS NIH HHS/United States ; R01 CA057530/CA/NCI NIH HHS/United States ; R56 CA057530/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*poisoning ; Blood Urea Nitrogen ; Body Weight ; Cisplatin/*poisoning ; Creatinine/blood ; Drug Resistance ; Female ; Kidney/*drug effects/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout/genetics ; Platinum/metabolism/urine ; Reference Values ; gamma-Glutamyltransferase/*deficiency/genetics ; }, abstract = {We have proposed that the nephrotoxicity of cisplatin, a widely used chemotherapy drug, is the result of the binding of cisplatin to glutathione and the subsequent metabolism of the cisplatin-glutathione complex via a gamma-glutamyl transpeptidase (GGT)-dependent pathway in the proximal tubules. To test the hypothesis that GGT activity is essential for the nephrotoxicity of cisplatin, the effects of cisplatin were examined in wild-type and GGT-deficient mice. Mice were treated with 15 mg cisplatin/kg. Five days after treatment, renal histopathology, blood urea nitrogen levels, serum creatinine, platinum excretion, and platinum accumulation in the kidney were examined. Half the mice were supplemented with N-acetylcysteine, which has been shown to correct low levels of tissue glutathione in GGT-deficient mice. The data show that cisplatin was nephrotoxic in wild-type mice but not in GGT-deficient mice. The wild-type mice, with and without N-acetylcysteine supplementation, had significantly elevated levels of blood urea nitrogen, serum creatinine, and renal tubular necrosis. There was no evidence of nephrotoxicity in the GGT-deficient mice regardless of N-acetyl cysteine supplementation. No differences in platinum excretion were seen comparing wild-type and GGT-deficient mice, nor was there any significant difference in renal platinum accumulation. These data suggest that renal cisplatin toxicity is dependent on GGT activity, and is not correlated with uptake. The results support our hypothesis that the nephrotoxicity of cisplatin is the result of the metabolism of the drug through a GGT-dependent pathway.}, }
@article {pmid11693264, year = {2001}, author = {Liu, J and Shen, HM and Ong, CN}, title = {Role of intracellular thiol depletion, mitochondrial dysfunction and reactive oxygen species in Salvia miltiorrhiza-induced apoptosis in human hepatoma HepG2 cells.}, journal = {Life sciences}, volume = {69}, number = {16}, pages = {1833-1850}, doi = {10.1016/s0024-3205(01)01267-x}, pmid = {11693264}, issn = {0024-3205}, mesh = {Apoptosis/*drug effects ; Caspase 3 ; Caspases/metabolism ; Cytochrome c Group/metabolism ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Flow Cytometry ; Glutathione/metabolism ; Hepatocytes/drug effects/*metabolism/pathology ; Intracellular Membranes/drug effects/metabolism ; Mitochondria/*drug effects/metabolism ; Permeability/drug effects ; Plant Extracts/*pharmacology ; Poly(ADP-ribose) Polymerases/metabolism ; Reactive Oxygen Species/*metabolism ; *Salvia miltiorrhiza ; Sulfhydryl Compounds/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Recent studies have demonstrated that induction of apoptosis is related to the cell growth inhibition potential of Salvia Miltiorrhiza (SM), a traditional herbal medicine. In the present study, we further explore the mechanistic pathway involved in SM-induced apoptosis in human hepatoma HepG2 cells. A rapid decline of intracellular glutathione (GSH) and protein thiol content was found in SM-treated cells. Moreover. SM exposure resulted in mitochondrial dysfunction as demonstrated by: (i) the onset of mitochondrial permeability transition (MPT); (ii) the disruption of mitochondrial membrane potential (MMP); and (iii) the release of cytochrome c from mitochondria into the cytosol. Subsequently, elevated level of intracellular reactive oxygen species (ROS) was observed prior to the onset of DNA fragmentation. However, no caspase-3 cleavage was observed throughout the whole period of SM treatment, while a caspase-3-independent poly(ADP-ribose) polymerase (PARP) cleavage was noted at the late stage in SM-induced apoptosis. Pretreatment of cells with N-acetylcysteine (NAC), the GSH synthesis precursor, conferred complete protection against MMP loss, ROS generation and apoptosis induced by SM. MPT inhibitors, cyclosporin A plus trifluoperazine, partially restored intracellular GSH content, and reduced SM-induced ROS formation and subsequently inhibited cell death. Moreover, antioxidants NAC, deferoxamine and catalase had little effect on GSH depletion and mitochondrial dysfunction, yet still were able to completely protect cells from SM-induced apoptosis. Taken together, our results suggest that SM deplete intracellular thiols, which, in turn, causes MPT and subsequent increase in ROS generation, and eventually apoptotic cell death.}, }
@article {pmid11692217, year = {2001}, author = {Taut, FJ and Breitkreutz, R and Zapletal, CM and Thies, JC and Babylon, A and Martin, E and Dröge, W}, title = {Influence of N-acetylcysteine on hepatic amino acid metabolism in patients undergoing orthotopic liver transplantation.}, journal = {Transplant international : official journal of the European Society for Organ Transplantation}, volume = {14}, number = {5}, pages = {329-333}, doi = {10.1007/s001470100335}, pmid = {11692217}, issn = {0934-0874}, mesh = {Acetylcysteine/*pharmacology ; Amino Acids/*metabolism ; Amino Acids, Aromatic/metabolism ; Amino Acids, Branched-Chain/metabolism ; Biological Transport ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Humans ; Liver/drug effects/*metabolism ; Liver Transplantation/*physiology ; Middle Aged ; Reperfusion Injury/prevention &amp; control ; Splanchnic Circulation/drug effects ; Urea/metabolism ; }, abstract = {Experimental treatment with the antioxidant and glutathione precursor N-acetylcysteine (NAC) has been performed in orthotopic liver transplantation (OLT) to reduce reperfusion injury. To investigate the effect of NAC on the hepatic and intestinal amino acid metabolism, intraoperative amino acid exchange rates were studied in liver transplant recipients with high dose NAC treatment (n = 10) and in control patients (n = 9). Treatment with NAC was found to cause a loss of amino acids and increased urea nitrogen release from the liver graft. The net balance of most amino acids was shifted to increased hepatic release or decreased hepatic uptake. The initial cumulative splanchnic release of all proteinogenic amino acids in the NAC treated group was significantly higher than in the control group. These findings are tentatively explained by an increased net protein catabolism in the liver. The increased hepatic urea and glutamine production rate of the NAC treated patients is expected to increase the energy and oxygen demand of the liver in this critical situation. Thus, NAC may have caused marked metabolic disturbances in the freshly implanted graft. The dosage of NAC should therefore be modified to avoid these disadvantages.}, }
@article {pmid11691805, year = {2001}, author = {Neuwelt, EA and Pagel, MA and Hasler, BP and Deloughery, TG and Muldoon, LL}, title = {Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model.}, journal = {Cancer research}, volume = {61}, number = {21}, pages = {7868-7874}, pmid = {11691805}, issn = {0008-5472}, support = {CA31770/CA/NCI NIH HHS/United States ; NS33618/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacokinetics/*pharmacology/toxicity ; Animals ; Antimetabolites/pharmacology ; Antineoplastic Agents, Alkylating/*adverse effects ; Aorta, Thoracic ; Blood-Brain Barrier ; Bone Marrow Diseases/chemically induced/*prevention &amp; control ; Brain/drug effects/metabolism ; Brain Neoplasms/drug therapy/metabolism ; Buthionine Sulfoximine/pharmacology ; Carcinoma, Small Cell/drug therapy/metabolism ; Dose-Response Relationship, Drug ; Drug Interactions ; Female ; Glutathione/*deficiency/metabolism ; Infusions, Intra-Arterial ; Lung Neoplasms/drug therapy/metabolism ; Rats ; Rats, Long-Evans ; Tissue Distribution ; Xenograft Model Antitumor Assays ; }, abstract = {Modulation of thiol levels may alter both the efficacy and toxicity of chemotherapeutic agents. We investigated cytoenhancement, using L-buthionine-[S,R]-sulfoximine (BSO) to reduce cellular glutathione levels prior to intracarotid alkylator administration. We also evaluated chemoprotection against chemotherapy-induced systemic toxicity when the thiol agents N-acetylcysteine (NAC) and sodium thiosulfate were administered into the descending aorta to limit brain delivery. BSO treatment reduced rat brain and intracerebral tumor glutathione levels by 50-65%, equivalent to the reduction in liver and s.c. tumor. BSO treatment significantly enhanced the toxicity of chemotherapy with carboplatin, melphalan, and etoposide phosphate against granulocytes, total white cells, and platelets. Intracarotid administration of NAC resulted in high delivery to the brain, whereas infusion via the descending aorta minimized brain delivery. When NAC, with or without sodium thiosulfate, was administered via aortic infusion prior to chemotherapy, the magnitude of the bone marrow toxicity nadir was minimized, even with BSO-enhanced myelosuppression. Thus, BSO depleted brain and brain tumor glutathione but thereby increased chemotherapy-induced myelosuppression. Surprisingly, although NAC was found to readily cross the blood-brain barrier when given into the carotid artery, aortic infusion of NAC resulted in minimal exposure to the central nervous system (CNS) vasculature because of rapid clearance. As a result, aortic infusion of NAC to perfuse bone marrow and minimize myelosuppression and toxicity to visceral organs could be performed without interfering with the CNS cytotoxicity of intracarotid alkylators, even after BSO depletion of CNS glutathione.}, }
@article {pmid11687721, year = {2001}, author = {Weinbroum, AA and Kidron, A and Hochhauser, E and Hochman, A and Rudick, V and Vidne, BA}, title = {Liver glutathione level influences myocardial reperfusion injury following liver ischemia-reperfusion.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {7}, number = {6}, pages = {1137-1144}, pmid = {11687721}, issn = {1234-1010}, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology ; Animals ; Glutathione/*metabolism ; In Vitro Techniques ; Ischemia/*metabolism ; Liver/*blood supply/*metabolism ; Male ; Myocardial Reperfusion Injury/metabolism/*prevention &amp; control ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: N-acetyl-L-cysteine (NAC) both replenishes reduced glutathione (GSH) and mitigates reperfusion injury. We hypothesized that liver content of GSH could affect remote myocardial reperfusion injury following liver ischemia-reperfusion.<br><br>MATERIAL AND METHODS: Following stabilization (30 min), isolated rat livers (6/group) were perfused with Krebs-Henseleit solution (two control groups) or made globally ischemic (two ischemia groups) for 120 min. Paired livers + paced hearts (Langendorff preparation) were then reperfused for 15 min after which the hearts were recirculated alone for 50 min. NAC was added to Krebs (2 mM) that perfused livers during stabilization and reperfusion phases in one control and one ischemia group.<br><br>RESULTS: GSH levels in the two control liver groups were identical (30.1 +/- 5.7 [SD] nmol/mg protein), and similar to that of the ischemia + NAC livers (28.6 +/- 2.8) but 2-fold that of the ischemia + 0 livers (15.8 +/- 2.4 nmol/mg protein, p<0.05). While hearts paired with control livers maintained unchanged their myocardial velocity of contraction, the contraction in the ischemia + NAC-paired hearts reduced, but was better than in the ischemia + 0-paired hearts (71 +/- 8% vs. 41 +/- 6% off baseline, p<0.05). Coronary flow also decreased dissimilarly in the two ischemia-associated groups of heart: 72 +/- 9% (ischemia + NAC) vs. 46 +/- 7% (ischemia + 0, p<0.05). Xanthine oxidase in the ischemia + 0 livers was 7.5-folds higher than in the ischemia-treated livers.<br><br>CONCLUSIONS: NAC treatment of ischemia-reperfused livers, associated with GSH replenishment, prevents remote myocardial reperfusion injury. The role of NAC and GSH in reducing liver-associated oxidative burst propagation is discussed.}, }
@article {pmid11681814, year = {2001}, author = {Grimble, RF}, title = {Nutritional modulation of immune function.}, journal = {The Proceedings of the Nutrition Society}, volume = {60}, number = {3}, pages = {389-397}, doi = {10.1079/pns2001102}, pmid = {11681814}, issn = {0029-6651}, mesh = {Animals ; Arginine/administration &amp; dosage ; Cytokines/metabolism ; Dietary Fats, Unsaturated/administration &amp; dosage ; Disease Models, Animal ; Fatty Acids, Omega-3/*administration &amp; dosage ; Glutamine/administration &amp; dosage ; Humans ; Immunity/*physiology ; Inflammation/*metabolism/*therapy ; Nucleotides/administration &amp; dosage ; Nutritional Physiological Phenomena/*physiology ; T-Lymphocytes/physiology ; }, abstract = {The inflammatory response to injury and infection, although an essential part of immune function, carries the risk of severe tissue depletion and immunosuppression. These outcomes increase morbidity and delay recovery. Evidence is accumulating that single-nucleotide polymorphisms in the genes controlling pro-inflammatory cytokine production adversely influence the response. Immunonutrition provides a means of modulating the inflammatory response to injury and infection, and thereby improves clinical outcome. n-3 Polyunsaturated fatty acids (n-3 PUFA), glutamine, arginine, S amino acids and nucleotides are important components of immunonutrient mixes. While animal model studies suggest that all these components may exert a beneficial effect in patients, the number of large randomized placebo-controlled trials utilizing immunonutrition is fairly limited and the observed effects are relatively small. Meta-analyses suggest that while immunonutrition may not reduce mortality rates, a reduction in hospital length of stay, decreased requirements for ventilation and lower infection rates are achieved by this mode of nutrition. The present paper discusses some underlying reasons for the difficulty in demonstrating the clinical efficacy of immunonutrition. Paramount among these reasons is the antioxidant status and genetic background of the patient. A number of studies suggest that there is an inverse relationship between inflammation and T-cell function. Immuno-enhancive effects have been shown in a number of studies in which n-3 PUFA, glutamine and N-acetyl cysteine have been employed. All these nutrients may exert their effects by suppressing inflammation; n-3 PUFA by direct suppression of the process and glutamine and N-acetyl cysteine by acting indirectly on antioxidant status. Glutamine and nucleotides exert a direct effect on lymphocyte proliferation. Preliminary data suggests that not all genotypes are equally sensitive to the effects of immunonutrition. When further studies have been conducted to discern the precise interaction between each individual's genotype of relevance to the response to injury and infection, and immunonutrients, the level of precision in the application of immunonutrition will undoubtedly improve.}, }
@article {pmid11680513, year = {2001}, author = {Hayashi, K and Takahata, H and Kitagawa, N and Kitange, G and Kaminogo, M and Shibata, S}, title = {N-acetylcysteine inhibited nuclear factor-kappaB expression and the intimal hyperplasia in rat carotid arterial injury.}, journal = {Neurological research}, volume = {23}, number = {7}, pages = {731-738}, doi = {10.1179/016164101101199252}, pmid = {11680513}, issn = {0161-6412}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Carotid Arteries/drug effects/metabolism/pathology ; Carotid Artery Injuries/*drug therapy/metabolism/pathology ; Carotid Stenosis/*drug therapy/physiopathology/prevention &amp; control ; Cell Division/drug effects/physiology ; Coronary Restenosis/drug therapy/physiopathology/prevention &amp; control ; Cytokines/biosynthesis/drug effects/genetics ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Hyperplasia/*drug therapy/physiopathology/prevention &amp; control ; Immunohistochemistry ; Inflammation/drug therapy/genetics/metabolism ; Male ; Muscle, Smooth, Vascular/*drug effects/metabolism/pathology ; NF-kappa B/*drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Tunica Intima/*drug effects/injuries/pathology ; }, abstract = {Neointima formation associated with vascular restenosis is a complex local inflammatory process actively involving the vascular smooth muscle cell (SMC) proliferation. Nuclear factor-kappaB (NF-kappaB) is a transactivator of a diverse group of genes whose activation has been strongly associated with the cellular response to inflammation. Since anti-oxidant N-acetylcysteine (NAC) inhibit NF-kappaB activity in vascular SMC in vitro, we examined the in vivo effect of the NAC on balloon-induced neointimal formation in the carotid artery of rats. Sprague-Dawley rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. One group of these rats (n = 9) were treated with daily intraperitoneal injection of NAC (200 mg kg(-1)) for 14 consecutive days, whereas the control group (n = 9) was treated with saline. Fourteen days after the injury, the left carotid arteries were removed and analyzed under microscope. Several rats underwent the same treatment as above and were sacrificed three days after injury for immunohistochemistry and Western blot studies. A morphometric analysis revealed that there were significant differences in intima/media ratio between the two groups. Immunohistochemical and Western blotting studies demonstrated that NAC suppressed the injury-induced NF-kappaB activity in the medial SMC layer. Treatment with NAC suppresses vascular NF-kappaB activation and this inhibition reduced the pathological thickening of the arterial wall. The NF-kappaB pathway, therefore, represents an attractive therapeutic target for strategies to prevent vascular restenosis.}, }
@article {pmid11678602, year = {2001}, author = {Qian, Y and Jiang, BH and Flynn, DC and Leonard, SS and Wang, S and Zhang, Z and Ye, J and Chen, F and Wang, L and Shi, X}, title = {Cr (VI) increases tyrosine phosphorylation through reactive oxygen species-mediated reactions.}, journal = {Molecular and cellular biochemistry}, volume = {222}, number = {1-2}, pages = {199-204}, pmid = {11678602}, issn = {0300-8177}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Aspirin/pharmacology ; Catalase/pharmacology ; Cell Line ; Chromium/*pharmacology ; Epithelial Cells/drug effects/enzymology ; Formates/pharmacology ; Hemostatics/pharmacology ; Humans ; Hydrogen Peroxide/*metabolism ; Hydroxyl Radical/*metabolism ; Lung/cytology/drug effects ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/*metabolism ; Time Factors ; }, abstract = {While Cr (VI)-containing compounds are well established carcinogens, the mechanisms of their action remain to be investigated. In this study we show that Cr (VI) causes increased tyrosine phosphorylation in human lung epithelial A549 cells in a time-dependent manner. N-acetyl-cysteine (NAC), a general antioxidant, inhibited Cr (VI)-induced tyrosine phosphorylation. Catalase, a scavenger of H2O2, sodium formate and aspirin, scavengers of hydroxyl radical (*OH), also inhibited the increased tyrosine phosphorylation induced by Cr (VI). SOD, an inhibitor of superoxide radical (O2*-), caused less inhibition. ESR study shows that incubation of Cr (VI) with the A549 cells generates *OH radical. The generation of radical was decreased by addition of catalase and sodium formate, while SOD did not have any inhibitory effect. Oxygen consumption measurements show that addition of Cr (VI) to A549 cells resulted in enhanced molecular oxygen consumption. These results indicate that Cr (VI) can induce an increase in tyrosine phosphorylation. H2O2 and *OH radicals generated during the process are responsible for the increased tyrosine phosphorylation induced by Cr (VI).}, }
@article {pmid11675123, year = {2001}, author = {Ni, L and Wen, Y and Peng, X and Jonakait, GM}, title = {Antioxidants N-acetylcysteine (NAC) and 2-mercaptoethanol (2-ME) affect the survival and differentiative potential of cholinergic precursors from the embryonic septal nuclei and basal forebrain: involvement of ras signaling.}, journal = {Brain research. Developmental brain research}, volume = {130}, number = {2}, pages = {207-216}, doi = {10.1016/s0165-3806(01)00238-3}, pmid = {11675123}, issn = {0165-3806}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Astrocytes/cytology/drug effects/metabolism ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Choline O-Acetyltransferase/metabolism ; Dose-Response Relationship, Drug ; Drug Synergism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Free Radical Scavengers/*pharmacology ; Mercaptoethanol/*pharmacology ; Mitogen-Activated Protein Kinases/metabolism ; Nerve Growth Factor/pharmacology ; Neurites/drug effects/metabolism ; Neurons/*drug effects/metabolism/ultrastructure ; Phosphorylation ; Rats ; Septal Nuclei/cytology/*embryology ; Signal Transduction/drug effects/physiology ; Stem Cells/cytology/drug effects ; ras Proteins/*metabolism ; }, abstract = {We investigated the effects of antioxidants N-acetylcysteine (NAC) and 2-mercaptoethanol (2-ME) on the expression of choline acetyltransferase (ChAT) in cultured cholinergic precursors from the embryonic rat septal nuclei and basal forebrain. Carboxy-dichlorofluorescein fluorescence confirmed that 2-ME inhibited intracellular oxidation. Low micromolar concentrations of 2-ME produce as much as a 12-fold increase in ChAT; this is enhanced further by inclusion of nerve growth factor (NGF). NAC effects are biphasic: 0.15 mM produces profound increases in ChAT while 1.5 mM has no effect. Immature (E16) cultures respond with increases in ChAT while more highly differentiated cultures (E18) do not. Labeling of single precursors with a lacZ-expressing retrovirus reveals that the increase in ChAT is due primarily to an increased number and size of clones, not an increase in cholinergic neurons per clone, suggesting an effect on precursor survival. Inhibition of ras farnesylation inhibits both 2-ME and NAC induction of ChAT suggesting a ras-mediated pathway. Inclusion of the MEK inhibitor PD98059 does not affect low doses of NAC, but at doses of NAC that fail to increase ChAT activity, inhibition of the pathway actually raises ChAT. Immunocytochemical investigation of the cultures indicates that cells exposed to low doses of NAC develop healthy neuronal arbors in the apparent absence of glial support. At higher concentrations of NAC, neurons were found in association with astrocytes, making contact via elaborate varicose fibers. Treatment of the cultures with PD98059 to inhibit MEK returned cultures to a 'low-dose' phenotype. These data suggest that redox status of basal forebrain precursors affect both their survival and differentiative potential.}, }
@article {pmid11673605, year = {2001}, author = {Adair, JC and Knoefel, JE and Morgan, N}, title = {Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease.}, journal = {Neurology}, volume = {57}, number = {8}, pages = {1515-1517}, doi = {10.1212/wnl.57.8.1515}, pmid = {11673605}, issn = {0028-3878}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Alzheimer Disease/*drug therapy ; Double-Blind Method ; Female ; Free Radical Scavengers/*administration &amp; dosage/adverse effects ; Humans ; Male ; Treatment Outcome ; }, abstract = {The antioxidant N-acetylcysteine (NAC) or placebo was administered in a double-blind fashion to patients who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD. Testing for efficacy occurred after 3 and 6 months of treatment. Comparison of interval change favored NAC treatment on nearly every outcome measure, although significant differences were obtained only for a subset of cognitive tasks.}, }
@article {pmid11672596, year = {2001}, author = {Lièvre, V and Becuwe, P and Bianchi, A and Bossenmeyer-Pourié, C and Koziel, V and Franck, P and Nicolas, MB and Dauça, M and Vert, P and Daval, JL}, title = {Intracellular generation of free radicals and modifications of detoxifying enzymes in cultured neurons from the developing rat forebrain in response to transient hypoxia.}, journal = {Neuroscience}, volume = {105}, number = {2}, pages = {287-297}, doi = {10.1016/s0306-4522(01)00189-0}, pmid = {11672596}, issn = {0306-4522}, mesh = {Animals ; Apoptosis/drug effects/*physiology ; Asphyxia Neonatorum/enzymology/pathology/physiopathology ; Catalase/genetics ; Cells, Cultured/drug effects/enzymology/pathology ; Fetus ; Fluoresceins/pharmacokinetics ; Fluorescent Dyes/pharmacokinetics ; Free Radical Scavengers/*metabolism ; Free Radicals/metabolism ; Glutathione Peroxidase/genetics ; Humans ; Hypoxia, Brain/embryology/*enzymology/physiopathology ; Infant, Newborn ; Intracellular Fluid/drug effects/*enzymology ; Neurons/drug effects/*enzymology/pathology ; Oxidative Stress/drug effects/physiology ; Prosencephalon/*enzymology/pathology/physiopathology ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*enzymology/pathology/physiopathology ; Rhodamines/pharmacokinetics ; Superoxide Dismutase/genetics ; Time Factors ; }, abstract = {To address the influence of oxidative stress and defense capacities in the effects of transient hypoxia in the immature brain, the time course of reactive oxygen species generation was monitored by flow cytometry using dihydrorhodamine 123 and 2',7'-dichlorofluorescein-diacetate in cultured neurons issued from the fetal rat forebrain and subjected to hypoxia/reoxygenation (6 h/96 h). Parallel transcriptional and activity changes of superoxide dismutases, glutathione peroxidase and catalase were analyzed, in line with cell outcome. The study confirmed hypoxia-induced delayed apoptotic death, and depicted increased mitochondrial and cytosolic productions of free radicals (+30%) occurring over the 48-h period after the restoration of oxygen supply, with sequential stimulations of superoxide dismutases. Whereas catalase mRNA levels and activity were augmented by cell reoxygenation, glutathione peroxidase activity was transiently repressed (-24%), along with reduced glutathione reductase activity (-27%) and intracellular glutathione depletion (-19%). Coupled with the neuroprotective effects of the glutathione precursor N-acetyl-cysteine (50 microM), these data suggest that hypoxia/reoxygenation-induced production of reactive oxygen species can overwhelm glutathione-dependent antioxidant capacity, and thus may contribute to the resulting neuronal apoptosis.}, }
@article {pmid11669166, year = {2001}, author = {Sambo, P and Amico, D and Giacomelli, R and Matucci-Cerinic, M and Salsano, F and Valentini, G and Gabrielli, A}, title = {Intravenous N-acetylcysteine for treatment of Raynaud's phenomenon secondary to systemic sclerosis: a pilot study.}, journal = {The Journal of rheumatology}, volume = {28}, number = {10}, pages = {2257-2262}, pmid = {11669166}, issn = {0315-162X}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Adult ; Cold Temperature ; Female ; Follow-Up Studies ; Free Radical Scavengers/*administration &amp; dosage/adverse effects ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Pilot Projects ; Plethysmography ; Raynaud Disease/diagnosis/*drug therapy/*etiology ; Scleroderma, Systemic/*complications ; Skin Ulcer/drug therapy/etiology ; Treatment Outcome ; }, abstract = {OBJECTIVE: To assess the efficacy and tolerability of N-acetylcysteine (NAC) in patients with Raynaud's phenomenon (RP) secondary to systemic sclerosis (scleroderma; SSc).<br><br>METHODS: Twenty-two patients with RP secondary to SSc were enrolled in a multicenter, open clinical trial lasting 11 weeks and conducted in winter. Primary outcome measures were frequency and severity of RP attacks, and number of digital ulcers. Secondary outcome measure was improvement in digital cold challenge test assessed by photoelectric plethysmography. Patients received a continuous 5 day intravenous infusion of NAC starting with a 2 h loading dose of 150 mg/kg subsequently adjusted to 15 mg/kg/h.<br><br>RESULTS: All 22 patients completed the 5 day infusion and 20 of them the posttreatment followup. Both frequency and severity of RP attacks decreased significantly compared to pretreatment values. Active ulcers were significantly less numerous at all followup visits (25.18% of baseline count on Day 33 from the beginning of infusion). In the cold challenge test mean recovery time fell by 69.56%, 67.70%, 71.42%, and 71.05% on Days 12, 19. 33, and 61 from the beginning of treatment. Side effects were minor, easily controlled, and reversible.<br><br>CONCLUSION: N-acetylcysteine appears to be safe for the treatment of RP secondary to SSc. These preliminary data warrant further controlled studies.}, }
@article {pmid11668049, year = {2001}, author = {Tian, J and Gong, X and Xie, Z}, title = {Signal-transducing function of Na+-K+-ATPase is essential for ouabain's effect on [Ca2+]i in rat cardiac myocytes.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {281}, number = {5}, pages = {H1899-907}, doi = {10.1152/ajpheart.2001.281.5.H1899}, pmid = {11668049}, issn = {0363-6135}, support = {HL-36573/HL/NHLBI NIH HHS/United States ; HL-63238/HL/NHLBI NIH HHS/United States ; }, mesh = {Age Factors ; Animals ; Calcium/*metabolism ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/*pharmacology ; MAP Kinase Signaling System/*drug effects/physiology ; Muscle Fibers, Skeletal/cytology/drug effects/*enzymology ; Myocardium/cytology/enzymology ; Ouabain/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Sodium-Potassium-Exchanging ATPase/*metabolism ; }, abstract = {We showed before that Na+-K+-ATPase is also a signal transducer in neonatal rat cardiac myocytes. Binding of ouabain to the enzyme activates multiple signal pathways that regulate cell growth. The aims of this work were to extend such studies to adult cardiac myocytes and to determine whether the signal-transducing function of Na+/K+-ATPase regulates the well-known effects of ouabain on intracellular Ca2+ concentration ([Ca2+]i). In adult myocytes, ouabain activated protein tyrosine phosphorylation and p42/44 mitogen-activated protein kinases (MAPKs), increased production of reactive oxygen species (ROS), and raised both systolic and diastolic [Ca2+]i. Pretreatment of myocytes with several Src kinase inhibitors, or overexpression of a dominant negative Ras, antagonized ouabain-induced activation of MAPKs and increases in [Ca2+]i. Treatment with PD-98059 (a MAPK kinase inhibitor) or overexpression of a dominant negative MAPK kinase 1 also ablated the effect of ouabain on MAPKs and [Ca2+]i. N-acetyl-cysteine, which blocks the effect of ouabain on ROS, did not prevent the ouabain-induced rise in [Ca2+]i. Clearly, the activation of the Ras/MAPK cascade, but not ROS generation, is necessary for ouabain-induced increases in [Ca2+]i in rat cardiac myocytes.}, }
@article {pmid11641438, year = {2001}, author = {Pombrio, JM and Giangreco, A and Li, L and Wempe, MF and Anders, MW and Sweet, DH and Pritchard, JB and Ballatori, N}, title = {Mercapturic acids (N-acetylcysteine S-conjugates) as endogenous substrates for the renal organic anion transporter-1.}, journal = {Molecular pharmacology}, volume = {60}, number = {5}, pages = {1091-1099}, doi = {10.1124/mol.60.5.1091}, pmid = {11641438}, issn = {0026-895X}, support = {DK48823/DK/NIDDK NIH HHS/United States ; ES01247/ES/NIEHS NIH HHS/United States ; ES06484/ES/NIEHS NIH HHS/United States ; ES07026/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/*metabolism ; Animals ; Humans ; Kidney/*metabolism ; Oocytes/metabolism ; Organic Anion Transport Protein 1/*metabolism ; Tritium ; Xenopus laevis ; p-Aminohippuric Acid/metabolism ; }, abstract = {Mercapturic acids are N-acetyl-L-cysteine S-conjugates that are formed from a range of endogenous and exogenous chemicals. Although the kidney is a major site for elimination of mercapturic acids, the transport mechanisms involved have not been identified. The present study examined whether mercapturic acids are substrates for the renal basolateral organic anion transporter-1 (Oat1) from rat kidney. This carrier mediates uptake of organic anions from the bloodstream in exchange for intracellular alpha-ketoglutarate. Uptake of [(3)H]p-aminohippuric acid (PAH) in Oat1-expressing Xenopus laevis oocytes was strongly inhibited by S-(2,4-dinitrophenyl)-N-acetyl-L-cysteine (DNP-NAC) and by all other mercapturic acids tested, including the endogenous mercapturic acid N-acetyl-leukotriene E(4). Inhibition by the mercapturic acids was competitive, which is consistent with the hypothesis that these compounds are substrates for Oat1. This conclusion was supported by the direct demonstration of saturable [(35)S]DNP-NAC uptake in Oat1-expressing oocytes. [(35)S]DNP-NAC uptake was inhibited by PAH and other mercapturic acids and was stimulated in oocytes preloaded with glutarate. The apparent K(m) value for DNP-NAC uptake was only 2 microM, indicating that this mercapturic acid is a high affinity substrate for Oat1. Together, these data indicate that clearance of endogenous mercapturic acids is an important function of the renal organic anion transporter.}, }
@article {pmid11641267, year = {2001}, author = {Sauer, H and Klimm, B and Hescheler, J and Wartenberg, M}, title = {Activation of p90RSK and growth stimulation of multicellular tumor spheroids are dependent on reactive oxygen species generated after purinergic receptor stimulation by ATP.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {15}, number = {13}, pages = {2539-2541}, doi = {10.1096/fj.01-0360fje}, pmid = {11641267}, issn = {1530-6860}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/*pharmacology ; Calcium/pharmacology ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Mitogen-Activated Protein Kinases/metabolism ; NADPH Oxidases/metabolism ; Phospholipases A/metabolism ; Phospholipases A2 ; Phosphorylation/drug effects ; Prostatic Neoplasms/metabolism/pathology ; *Purinergic Agonists ; Reactive Oxygen Species/*metabolism ; Receptors, Purinergic/physiology ; Ribosomal Protein S6 Kinases/*drug effects/metabolism ; Spheroids, Cellular/*drug effects/metabolism/pathology ; Thiourea/*analogs &amp; derivatives/pharmacology ; Tumor Cells, Cultured ; Vitamin E/pharmacology ; }, abstract = {Mitogenic stimulation by growth factors may be mediated through intracellular reactive oxygen species (ROS) acting as signaling molecules. Incubation of multicellular prostate tumor spheroids with adenosine 5' triphosphate (ATP) dose-dependently stimulated tumor growth. ATP, uridine 5'-triphosphate (UTP), adenosine 5'-diphosphate (ADP), and 2-methylthio-ATP (2-MeS-ATP) increased intracellular ROS levels significantly. ROS generation by ATP was inhibited by the P2 receptor antagonist suramin, by the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenylene iodonium chloride (DPI) and 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF), as well as by the Ca2+-dependent phospholipase A2 (PLA2) inhibitors indomethacin and methyl arachidonyl fluorophosphonate (MAFP). The generation of ROS was dependent on the intracellular Ca2+ response evoked by ATP. Exogenous ATP activated the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) pathway, which was blunted by the MAPK/ERK kinase 1/2 (MEK1/2) antagonist PD98059. The radical scavengers vitamin E, dimethyl thiourea (DMTU), and N-acetyl cysteine (NAC) failed to inhibit ERK1/2 activation but abolished p90 ribosomal S6 kinase (p90RSK) activation downstream of ERK1/2, as well as the growth stimulation of tumor spheroids. Our data indicate that p90RSK downstream of ERK1/2 is the molecular target for ROS generated through stimulation of purinergic receptors by ATP.}, }
@article {pmid11641239, year = {2001}, author = {Noda, T and Iwakiri, R and Fujimoto, K and Aw, TY}, title = {Induction of mild intracellular redox imbalance inhibits proliferation of CaCo-2 cells.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {15}, number = {12}, pages = {2131-2139}, doi = {10.1096/fj.01-0131com}, pmid = {11641239}, issn = {1530-6860}, support = {R01 DK044510/DK/NIDDK NIH HHS/United States ; R01 DK044510-08/DK/NIDDK NIH HHS/United States ; DK 44510/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Caco-2 Cells ; Carmustine/pharmacology ; *Cell Division/drug effects ; Cell Survival ; Cytoplasm/metabolism ; Diamide/pharmacology ; Epidermal Growth Factor/pharmacology ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Humans ; Kinetics ; Oxidation-Reduction ; *Oxidative Stress ; Reactive Oxygen Species/metabolism ; Sulfhydryl Reagents/pharmacology ; }, abstract = {Intracellular redox status plays a critical role in cell function, such as proliferation. Oxidative stress, which elicits redox imbalance, also affects cell growth. Therefore, it is often difficult to distinguish the effects of redox imbalance from those of oxidative stress. The objective of this study was to determine the role of redox imbalance independent of reactive oxygen species (ROS) production, in proliferation of human colonic CaCo-2 cells. Low concentrations of diamide plus 1,3-bis(2 chloroethyl)-1-nitrosourea (BCNU) increased intracellular GSSG and decreased GSH and the GSH:GSSG ratio. These changes occurred within 30 min, which preceded a decrease in thymidine incorporation at 6 and 24 h. ROS formation was not detected under these conditions. This suppression of cell proliferative activity was attenuated by N-acetyl cysteine, in parallel with restoration of the intracellular GSH redox status. dl-buthionine-[S, R]-sulfoximine (BSO) decreased intracellular GSH level, but did not change the GSH:GSSG ratio. BSO alone had no effect on cell proliferation, but its presence exaggerated the suppressive effect of diamide plus BCNU. Flow cytometric analysis showed that cells were arrested at G1-to-S transition and G2/M phase. Collectively, this study shows that mild intracellular redox imbalance inhibited cell proliferation independent of ROS generation. Moreover, cells with compromised cellular GSH were susceptible to redox imbalance-induced inhibition of proliferation.}, }
@article {pmid11603925, year = {2001}, author = {Yamamoto, S and Seta, K and Morisco, C and Vatner, SF and Sadoshima, J}, title = {Chelerythrine rapidly induces apoptosis through generation of reactive oxygen species in cardiac myocytes.}, journal = {Journal of molecular and cellular cardiology}, volume = {33}, number = {10}, pages = {1829-1848}, doi = {10.1006/jmcc.2001.1446}, pmid = {11603925}, issn = {0022-2828}, mesh = {Acetylcysteine/pharmacology ; Adenoviridae/genetics ; Alkaloids ; Animals ; Animals, Newborn ; Annexin A5/pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Benzophenanthridines ; Caspases/metabolism ; Cytosol/metabolism ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Genetic Vectors ; Glutathione/pharmacology ; Hydrogen Peroxide/pharmacology ; Immunoblotting ; In Situ Nick-End Labeling ; Injections, Intravenous ; Microscopy, Fluorescence ; Myocardium/*cytology/metabolism ; Necrosis ; Phenanthridines/*pharmacology ; Protein Isoforms ; Protein Kinase C/antagonists &amp; inhibitors/metabolism/physiology ; Rats ; Rats, Wistar ; *Reactive Oxygen Species ; Staurosporine/pharmacology ; Subcellular Fractions ; Tetradecanoylphorbol Acetate ; Time Factors ; }, abstract = {The role of protein kinase C (PKC) inhibition in cardiac myocyte apoptosis has not been well understood. We investigated the mechanism, by which chelerythrine, a commonly used PKC inhibitor, induces potent myocyte death. Chelerythrine (6-30 microm) rapidly induced pyknosis, shrinkage and subsequent cell death in cardiac myocytes. Chelerythrine-induced myocyte death was accompanied by nuclear fragmentation and activation of caspase-3 and -9, while it was prevented by XIAP, suggesting that the cell death is due to apoptosis. Higher concentrations of chelerythrine caused necrotic cell death where neither cell shrinkage nor caspase activation was observed. Intravenous injection of chelerythrine (5 mg/kg) also increased apoptosis in adult rat hearts in vivo. Downregulation of the phorbol 12-myristate 13-acetate (PMA)-sensitive PKC failed to affect chelerythrine-induced apoptosis, while anti-oxidants, including N-acetyl-L-cysteine (NAC) and glutathione, inhibited it, suggesting that generation of reactive oxygen species (ROS) rather than inhibition of PMA-sensitive PKC mediates chelerythrine-induced cardiac myocyte apoptosis. Chelerythrine caused cytochrome c release from mitochondria, which was significantly inhibited in the presence of NAC, suggesting that ROS mediates chelerythrine-induced cytochrome c release. Partial inhibition of cytochrome c release by Bcl-X(L) significantly reduced chelerythrine-induced apoptosis. These results suggest that chelerythrine rapidly induces cardiac myocyte apoptosis and that production of ROS, possibly H(2)O(2), and subsequent cytochrome c release from mitochondria play an important role in mediating chelerythrine-induced rapid cardiac myocyte apoptosis.}, }
@article {pmid11595380, year = {2001}, author = {Vairetti, M and Griffini, P and Pietrocola, G and Richelmi, P and Freitas, I}, title = {Cold-induced apoptosis in isolated rat hepatocytes: protective role of glutathione.}, journal = {Free radical biology &amp; medicine}, volume = {31}, number = {8}, pages = {954-961}, doi = {10.1016/s0891-5849(01)00670-0}, pmid = {11595380}, issn = {0891-5849}, mesh = {Acetylcysteine/*metabolism/pharmacology ; Animals ; Apoptosis/*physiology ; Buthionine Sulfoximine/metabolism/pharmacology ; Cold Temperature ; Glutathione/agonists/antagonists &amp; inhibitors/*metabolism ; Hepatocytes/*metabolism ; Hypothermia/*metabolism ; Lipid Peroxidation/physiology ; Male ; Maleates/metabolism/pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Rewarming ; }, abstract = {Liver conservation for transplantation is usually made at 2-4 degrees C. We studied the effect of rewarming to 37 degrees C for up to 3 h of rat hepatocytes kept at 4 degrees C for 20 h, modulating intracellular glutathione (GSH) concentration either with a GSH precursor (N-acetyl-L-cysteine, NAC), or with GSH depleting agents (diethylmaleate and buthionine sulfoximine, DEM/BSO). Untreated hepatocytes showed time-dependent production of reactive oxygen species (ROS), lipid peroxidation, chromatin condensation and membrane blebbing, decrease in GSH concentration, and protein sulfhydryl groups. Fluorochromatization with Propidium Iodide (PI) and Annexin V (AnxV) of cells rewarmed for 1 h caused an increase of AnxV-positive cells without PI staining and any observed lactate dehydrogenase leakage. TUNEL and DNA-laddering tests were negative for all times and treatments, indicating that apoptosis may occur without DNA fragmentation. Cold preservation and rewarming in the presence of NAC induced a significant improvement in the morphology, less oxidative stress and apoptosis. Conversely, DEM/BSO caused a marked deterioration of morphology, increase of oxidative stress and apoptosis. These results suggested that marked changes in GSH status might play a critical role in triggering apoptosis during cold preservation of isolated rat hepatocytes. NAC, added before rewarming, might represent a therapeutic approach for preventing the early events of apoptosis during cold storage.}, }
@article {pmid11591178, year = {2001}, author = {Pelisek, J and Armeanu, S and Nikol, S}, title = {Quiescence, cell viability, apoptosis and necrosis of smooth muscle cells using different growth inhibitors.}, journal = {Cell proliferation}, volume = {34}, number = {5}, pages = {305-320}, pmid = {11591178}, issn = {0960-7722}, mesh = {Animals ; Aorta ; Aphidicolin/pharmacology ; Apoptosis ; Cell Division/drug effects ; Cell Survival/*drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*cytology/drug effects ; Flow Cytometry ; Growth Inhibitors/*pharmacology ; Heparin/pharmacology ; Kinetics ; Muscle, Smooth, Vascular/*cytology/drug effects/pathology ; Necrosis ; Recombinant Proteins/biosynthesis ; Swine ; Transfection ; beta-Galactosidase/genetics ; }, abstract = {Smooth muscle cells and endothelial cells play an important role in cardiovascular diseases and may therefore be a potential target for gene therapy. Most in vitro experiments are performed using proliferating cell cultures. Nevertheless, non-dividing cells would represent more realistic in vivo conditions for gene therapy. Therefore, a simple method to achieve physiologically quiescence in cell cultures is needed for experiments. Growth to confluence is sufficient for endothelial cells to reach quiescence, in contrast to smooth muscle cells. Alternative techniques were investigated to achieve quiescence for smooth muscle cells. N-acetyl-cysteine, heparin, aphidicolin and serum-free medium are known inhibitors of smooth muscle cell proliferation and were tested for cell viability, necrosis and apoptosis. The inhibition status was evaluated counting cells in a cell counter. Toxicity, necrosis and apoptosis were determined using FACS analysis. Then, smooth muscle cells and endothelial cells were transfected with plasmid containing the beta-galactosidase gene using liposomes. Analysis of gene expression in transfected cells included a quantitative beta-galactosidase assay and X-gal staining. Growth inhibition was achieved with all agents tested. Using N-acetyl-cysteine, only slightly reduced growth rates were observed. Aphidicolin stopped cell growth almost immediately, but demonstrated enhanced toxicity. The amount of apoptotic and necrotic cells was lowest using heparin in the presence of foetal calf serum. Transfection experiments using stationary cultures of smooth muscle cells using heparin or aphidicolin demonstrated 5-10-fold lower transfection rates compared to transfected proliferating cell cultures serving as controls. Transfection experiments using stationary cultures of endothelial cells using growth inhibition through confluence demonstrated 40-fold lower transfection rates than transfected proliferating cell cultures. Transfer efficiency was much lower in endothelial cells compared to smooth muscle cells. In conclusion, quiescent cells simulate more realistically the in vivo situation and may therefore represent a better model for future in vivo experiments based on in vitro findings.}, }
@article {pmid11585706, year = {2001}, author = {Kumaran, C and Shivakumar, K}, title = {Superoxide-mediated activation of cardiac fibroblasts by serum factors in hypomagnesemia.}, journal = {Free radical biology &amp; medicine}, volume = {31}, number = {7}, pages = {882-886}, doi = {10.1016/s0891-5849(01)00656-6}, pmid = {11585706}, issn = {0891-5849}, mesh = {Animals ; Cell Division ; Collagen/biosynthesis ; Cysteine/metabolism/pharmacology ; Fibroblasts/*metabolism/pathology ; Fibrosis ; Magnesium Deficiency/*metabolism/pathology ; Myocardium/*metabolism/pathology ; Plasma/metabolism ; Rats ; Receptors, Neurokinin-1/*metabolism ; Superoxide Dismutase/metabolism/pharmacology ; Superoxides/*metabolism ; }, abstract = {Magnesium deficiency is known to produce myocardial fibrosis in different animal models, but the underlying mechanisms are unclear. However, circulating levels of pro-oxidant and mitogenic factors are reported to be elevated in a rodent model of acute magnesium deficiency, suggesting a role for humoral factors in the pathogenesis of the cardiovascular lesions. Probing the mechanism of cardiac fibrogenesis in magnesium deficiency, the present study furnished evidence that serum from magnesium-deficient rats has a more marked effect than serum from magnesium-sufficient rats on mitogenesis, net collagen production, and superoxide generation in cardiac fibroblasts from young adult rats. The enhanced mitogenic response was abolished by superoxide dismutase and N-acetyl cysteine, showing that it is mediated by superoxide anion. Further, a modest inhibitory effect of the neurokinin-1 receptor antagonist, spantide, suggested that factors acting via neurokinin-1 receptors may partly modulate cardiac fibroblast function in magnesium deficiency. The findings are consistent with the postulation that serum factors may activate cardiac fibroblasts via a superoxide-mediated mechanism and contribute to the fibrogenic response in the heart in magnesium deficiency.}, }
@article {pmid11582518, year = {2001}, author = {Sung, JH and Shin, SA and Park, HK and Montelaro, RC and Chong, YH}, title = {Protective effect of glutathione in HIV-1 lytic peptide 1-induced cell death in human neuronal cells.}, journal = {Journal of neurovirology}, volume = {7}, number = {5}, pages = {454-465}, pmid = {11582518}, issn = {1355-0284}, mesh = {AIDS Dementia Complex/drug therapy ; Acetylcysteine/pharmacology ; Amino Acid Sequence ; Amino Acid Substitution ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cell Death/drug effects ; Cells, Cultured ; Glutathione/analysis/*pharmacology ; HIV Envelope Protein gp41/chemistry/*toxicity ; HIV-1/*physiology ; Humans ; Intracellular Membranes/drug effects/physiology ; Membrane Potentials/drug effects ; Mitochondria/*drug effects/pathology ; Molecular Sequence Data ; Nerve Degeneration ; Neuroblastoma/pathology ; Neurons/chemistry/*drug effects/pathology ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidation-Reduction ; Peptide Fragments/chemistry/*toxicity ; Prodrugs/pharmacology ; Tumor Cells, Cultured ; }, abstract = {To elucidate the pathogenic mechanisms involved in neurodegeneration in AIDS patients with cognitive deficits, we have examined the toxic effect of the lentivirus lytic peptide 1 (LLP-1) corresponding to the carboxyl terminus of HIV-1 transmembrane glycoprotein gp41 on human neuronal and glial cell lines. LLP-1 induced a significant lactate dehydrogenase (LDH, a marker of cell death) release from these cells in a concentration- and time-dependent manner, while the noncytolytic LLP-1 analog 2 had little effect. Application of LLP-1 to SH-SY5Y, a well-characterized human neuronal cell line, caused the decline of intracellular glutathione (GSH) content that appeared to occur before a significant LDH release. Furthermore, LLP-1 elicited a significant loss of mitochondrial function as measured by mitochondrial transmembrane potential (MTP). Among the reducing agents and antioxidants tested, GSH and a GSH prodrug N-acetylcysteine (NAC) provided protection against LLP-1-induced neuronal cell death, evidently by restoring the intracellular GSH levels and blocking the disruption of mitochondrial integrity. Thus, gp41-derived LLP-1 may be a potential neurotoxic agent capable of causing the intracellular GSH depletion and disturbing the mitochondrial function, possibly contributing to the neurodegenerative cascade as seen in HIV-1-associated dementia. Our data indicate that restoring both GSH concentration and mitochondrial function may hold promise as possible therapeutic strategies for slowing disease progression of dementia in AIDS patients.}, }
@article {pmid11579333, year = {2001}, author = {Pinamonti, S and Venturoli, L and Leis, M and Chicca, M and Barbieri, A and Sostero, S and Ravenna, F and Daffonchio, L and Novellini, R and Ciaccia, A}, title = {Antioxidant activity of carbocysteine lysine salt monohydrate.}, journal = {Panminerva medica}, volume = {43}, number = {3}, pages = {215-220}, pmid = {11579333}, issn = {0031-0808}, mesh = {Aged ; Aged, 80 and over ; Antioxidants/*pharmacology ; Carbocysteine/*analogs &amp; derivatives/*pharmacology ; Cells, Cultured ; DNA Damage ; Female ; Glutathione/pharmacology ; Humans ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/metabolism ; }, abstract = {BACKGROUND: Reactive oxygen radicals are involved in many respiratory diseases, including chronic obstructive pulmonary disease (COPD). Carbocysteine lysine salt monohydrate (CLS) is a mucoactive drug effective in the treatment of bronchopulmonary diseases characterized by mucus alterations, including COPD. In the present study, the antioxidant activity of CLS was studied in vitro in three different oxygen radical producing systems, i.e. bronchoalveolar lavages (BAL) from patients affected by COPD, ultrasound treated human serum and cultured human lung endothelial cells challenged with elastase.<br><br>METHODS: BAL, exposed or not to different concentrations of CLS (1.5-30 mM), was assayed for free radical content by fluorometric analysis of DNA unwinding (FADU) or by cytochrome c reduction kinetics. Human serum was treated with ultrasound in the presence or absence of CLS (1.5, 2.5 mM) or N-acetyl cysteine (NAC; 4, 5 mM) and assayed for free radical content by FADU. Human endothelial cells cultured in vitro from pulmonary artery were incubated with elastase (0.3 IU/mL), in the presence or absence of glutathione (GSH; 0.65 mM) or CLS (0.16 mM). The supernatant was tested for cytochrome c reduction kinetics whereas cell homogenates were assessed for xanthine oxidase (XO) content by SDS-PAGE.<br><br>RESULTS: Results showed that CLS is more effective as an in vitro scavenger in comparison to GSH and NAC. CLS reduced the damage of DNA from healthy donors exposed to COPD-BAL and was able to quench clastogenic activity induced in human serum by exposure to ultrasound at concentrations as low as 2.5 mM. NAC protect DNA from radical damage, starting from 5 mM. In human lung endothelial cells cultured in presence of elastase, CLS (0.16 mM) decreased xanthine oxidase activity.<br><br>CONCLUSIONS: These results suggest that CLS could act by interfering with the conversion of xanthine dehydrogenase into superoxide-producing xanthine oxidase. The antioxidant activity of CLS could contribute to its therapeutic activity by reducing radical damage to different lung structures.}, }
@article {pmid11572767, year = {2001}, author = {Sasaki, M and Kobayashi, D and Watanabe, N}, title = {Augmented adriamycin sensitivity in cells transduced with an antisense tumor necrosis factor gene is mediated by caspase-3 downstream from reactive oxygen species.}, journal = {Japanese journal of cancer research : Gann}, volume = {92}, number = {9}, pages = {983-988}, pmid = {11572767}, issn = {0910-5050}, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/genetics/*pathology ; Antibiotics, Antineoplastic/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects/physiology ; Caspase 3 ; Caspase Inhibitors ; Caspases/*physiology ; Cysteine Proteinase Inhibitors/pharmacology ; Doxorubicin/*pharmacology ; Drug Resistance, Neoplasm/*physiology ; Genes, p53 ; Humans ; Neoplasm Proteins/antagonists &amp; inhibitors/*physiology ; Oligodeoxyribonucleotides, Antisense/*genetics ; Oligopeptides/pharmacology ; Oxidative Stress ; Pancreatic Neoplasms/genetics/*pathology ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; Transfection ; Tumor Cells, Cultured/drug effects ; Tumor Necrosis Factor-alpha/*genetics ; }, abstract = {While transduction of an antisense tumor necrosis factor (TNF) gene sequence can augment the cytotoxicity of adriamycin (ADM) in human cancer cells, the specific effect of introducing this sequence on the signal transduction pathway leading to cell death remains unclear. In ADM-resistant pancreatic carcinoma (PANC-1) cells, both the antioxidant N-acetyl-L-cysteine (NAC) and the caspase-3 inhibitor acetyl-L-aspartyl-L-methionyl-L-glutaminyl-L-aspartyl-aldehyde (Ac-DMQD-CHO) prevented ADM-induced cytotoxicity. NAC additionally inhibited caspase-3 activity induced by ADM treatment, while Ac-DMQD-CHO showed no suppressive effect on reactive oxygen species (ROS). Stable antisense-TNF transfectants showed higher ADM sensitivity and greater ADM-induced ROS production and caspase-3 activity than mock transfectant or parent cells. These results indicate that increased caspase-3 activity downstream from ROS production is among the mechanisms by which transduction of the antisense TNF sequence of augments ADM sensitivity of pancreatic carcinoma cells.}, }
@article {pmid11568534, year = {2001}, author = {Feghali, JG and Liu, W and Van De Water, TR}, title = {L-n-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity.}, journal = {The Laryngoscope}, volume = {111}, number = {7}, pages = {1147-1155}, doi = {10.1097/00005537-200107000-00005}, pmid = {11568534}, issn = {0023-852X}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Antineoplastic Agents/*toxicity ; Cells, Cultured ; Cisplatin/*toxicity ; Cochlear Nerve/*drug effects ; Deafness/chemically induced/prevention &amp; control ; Free Radical Scavengers/*pharmacology ; Hair Cells, Auditory, Inner/*drug effects ; Hearing/drug effects ; Humans ; Neurons/*drug effects ; Organ of Corti/drug effects ; Prospective Studies ; Rats ; Time Factors ; }, abstract = {OBJECTIVES: The aim of this study is to determine the efficacy of L-N-acetyl-cysteine (L-NAC) as a protectant for inner ear auditory sensory cells against the toxic effects of cisplatin.<br><br>STUDY DESIGN: Prospective laboratory study of the otoprotective effect of L-NAC on auditory neurons and hair cells in vitro.<br><br>METHODS: The study has two arms. The first arm evaluated the neuroprotective effect of L-NAC on early postpartum auditory ganglion cell cultures. Two culture media were used. The two media differed in that one of them was enhanced by the addition of neurotrophins (neurotrophin type 3 and brain-derived neurotrophic factor) and a growth factor (transforming growth factor-beta1). Then the survival of cisplatin-treated auditory neurons was studied before and after pretreatment with protective levels of L-NAC. The second arm of the study evaluated the effect of L-NAC on cisplatin damage initiated to auditory hair cells. Early-postpartum organ of Corti explants were grown in culture. Their rate of survival was studied after exposure to toxic levels of cisplatin. Then, survival of cisplatin-damaged hair cells was studied after they were pretreated with L-NAC.<br><br>RESULTS: Pretreatment of cultures with L-NAC protected both auditory neurons and hair cells from the effects of exposure to toxic levels of cisplatin. This observed otoprotective effect was dose dependent.<br><br>CONCLUSIONS: Our in vitro studies have demonstrated that L-NAC protected both auditory neurons and hair cells from the toxic effects of cisplatin. Because it protects both of these inner ear structures, L-NAC may be potentially useful in protecting hearing, in general, from cisplatin-induced damage. In addition, L-NAC has low systemic and mucosal toxicity. It also has a low molecular weight that may allow it to readily cross the round window membrane. All these characteristics make it potentially suitable for transtympanic application for the prevention of the ototoxicity of cisplatin in vivo.}, }
@article {pmid11562447, year = {2001}, author = {Guermonprez, L and Ducrocq, C and Gaudry-Talarmain, YM}, title = {Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitrite are differentially prevented by antioxidants.}, journal = {Molecular pharmacology}, volume = {60}, number = {4}, pages = {838-846}, pmid = {11562447}, issn = {0026-895X}, mesh = {Acetates/metabolism ; Acetylcholine/*antagonists &amp; inhibitors/biosynthesis ; Animals ; Antioxidants/*pharmacology ; Biological Transport/drug effects ; Carbon Radioisotopes ; Choline/metabolism ; Choline O-Acetyltransferase/antagonists &amp; inhibitors/*metabolism ; Drug Interactions ; Molsidomine/analogs &amp; derivatives/pharmacology ; Nitrates/*pharmacology ; Oxidants/*pharmacology ; Reducing Agents/pharmacology ; Torpedo ; Tyrosine/*analogs &amp; derivatives/*metabolism ; Uric Acid/pharmacology ; }, abstract = {Evidence of an overload of reactive oxygen species and peroxynitrite, a derivative of nitric oxide, in sporadic amyotrophic lateral sclerosis suggests that peroxynitrite could impair cholinergic functions. Because of the impossibility of obtaining synaptosomes from vertebrate neuromuscular junctions, we used cholinergic synaptosomes purified from Torpedo marmorata electroneurons to characterize the defects triggered by peroxynitrite in more detail. Addition of peroxynitrite or its donor 3-morpholinosydnonimine abolished high-affinity choline uptake and synthesis of acetylcholine from acetate. T. marmorata choline acetyltransferase (ChAT) was impaired to the same extent as bovine brain ChAT. A hallmark of peroxynitrite action is the nitration of tyrosine residues in proteins. Peroxynitrite induced a concentration-dependent appearance of nitrotyrosines in several neuronal proteins from synaptosomes and, more readily, from synaptic vesicles. Peroxynitrite also triggered tyrosine nitrations in purified ChAT. Peroxynitrite-dependent nitrations were impaired when synaptosomes were pretreated with thioreductants (glutathione, N-acetyl cysteine, dithiothreitol) or antioxidants (uric acid, melatonin, bovine serum albumin, desferrioxamine). Deleterious effects of peroxynitrite on choline transport and ChAT activity were prevented by the thioreductants but only partially by the antioxidants, suggesting a mechanism other than tyrosine nitration, which may involve cysteine oxidation. Further development of protective agents acting on choline transport and on ChAT activity may offer interesting therapeutic possibilities with respect to cholinergic dysfunction occurring in neurodegenerative diseases.}, }
@article {pmid11561726, year = {2001}, author = {Lee, KH and Kim, KC and Jung, YJ and Ham, YH and Jang, JJ and Kwon, H and Sung, YC and Kim, SH and Han, SK and Kim, CM}, title = {Induction of apoptosis in p53-deficient human hepatoma cell line by wild-type p53 gene transduction: inhibition by antioxidant.}, journal = {Molecules and cells}, volume = {12}, number = {1}, pages = {17-24}, pmid = {11561726}, issn = {1016-8478}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; *Apoptosis/drug effects ; Carcinoma, Hepatocellular ; Cell Survival ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-Dependent Kinases/metabolism ; Cyclins/genetics/*metabolism ; DNA Fragmentation ; Free Radical Scavengers/pharmacology ; *Genes, p53 ; Glutathione/pharmacology ; Humans ; In Situ Nick-End Labeling ; Liver Neoplasms ; Retroviridae/genetics/metabolism ; *Transduction, Genetic ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/*metabolism ; }, abstract = {We investigated the role of wild-type (wt)-p53 as an inducer of apoptotic cell death in human hepatoma cell lines. Following the retrovirus-mediated transduction of the wt-p53 gene, Hep3B cells lacking the endogenous p53 expression began to die through apoptosis in 4 h. They showed a maximal apoptotic death at 12 h, whereas HepG2 cells expressing endogenous p53 did not. However, the transduction of the wt-p53 gene elicited growth suppression of both Hep3B and HepG2 cells. P21(WAF1/CIP1), a p53-inducible cell cycle inhibitor, was induced, not only in Hep3B cells undergoing apoptosis, but also in HepG2 cells. The kinetics of the p21(WAF1/CIP1) induction, DNA fragmentation, and growth suppression of the Hep3B cells showed that DNA fragmentation and growth suppression progressed rapidly following p21(WAF1/CIP1) accumulation. N-acetyl-cysteine or glutathione, potent antioxidants, strongly inhibited the DNA fragmentation, but did not reduce the elevated level of p21(WAF1/CIP1). These findings suggested that p21(WAF1/CIP1) was not a critical mediator for the execution of p53-mediated apoptosis, although it contributed to the growth inhibition of cells undergoing apoptosis. Furthermore, p53-mediated apoptosis could be repressed by antioxidants.}, }
@article {pmid11557313, year = {2001}, author = {Christen, S and Schaper, M and Lykkesfeldt, J and Siegenthaler, C and Bifrare, YD and Banic, S and Leib, SL and Täuber, MG}, title = {Oxidative stress in brain during experimental bacterial meningitis: differential effects of alpha-phenyl-tert-butyl nitrone and N-acetylcysteine treatment.}, journal = {Free radical biology &amp; medicine}, volume = {31}, number = {6}, pages = {754-762}, doi = {10.1016/s0891-5849(01)00642-6}, pmid = {11557313}, issn = {0891-5849}, support = {NS-34028/NS/NINDS NIH HHS/United States ; NS-35902/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/*metabolism ; Cerebrospinal Fluid/microbiology ; Cyclic N-Oxides ; Disease Models, Animal ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/cerebrospinal fluid ; Meningitis, Pneumococcal/*metabolism ; Nitrogen Oxides/*pharmacology ; Oxidation-Reduction ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Streptococcus pneumoniae/growth &amp; development ; }, abstract = {Antioxidant treatment has previously been shown to be neuroprotective in experimental bacterial meningitis. To obtain quantitative evidence for oxidative stress in this disease, we measured the major brain antioxidants ascorbate and reduced glutathione, and the lipid peroxidation endproduct malondialdehyde in the cortex of infant rats infected with Streptococcus pneumoniae. Cortical levels of the two antioxidants were markedly decreased 22 h after infection, when animals were severely ill. Total pyridine nucleotide levels in the cortex were unaltered, suggesting that the loss of the two antioxidants was not due to cell necrosis. Bacterial meningitis was accompanied by a moderate, significant increase in cortical malondialdehyde. While treatment with either of the antioxidants alpha-phenyl-tert-butyl nitrone or N-acetylcysteine significantly inhibited this increase, only the former attenuated the loss of endogenous antioxidants. Cerebrospinal fluid bacterial titer, nitrite and nitrate levels, and myeloperoxidase activity at 18 h after infection were unaffected by antioxidant treatment, suggesting that they acted by mechanisms other than modulation of inflammation. The results demonstrate that bacterial meningitis is accompanied by oxidative stress in the brain parenchyma. Furthermore, increased cortical lipid peroxidation does not appear to be the result of parenchymal oxidative stress, because it was prevented by NAC, which had no effect on the loss of brain antioxidants.}, }
@article {pmid11557312, year = {2001}, author = {Childs, A and Jacobs, C and Kaminski, T and Halliwell, B and Leeuwenburgh, C}, title = {Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise.}, journal = {Free radical biology &amp; medicine}, volume = {31}, number = {6}, pages = {745-753}, doi = {10.1016/s0891-5849(01)00640-2}, pmid = {11557312}, issn = {0891-5849}, mesh = {Acetylcysteine/administration &amp; dosage/*adverse effects ; Adult ; Antioxidants/analysis ; Ascorbic Acid/administration &amp; dosage/*adverse effects ; Bleomycin ; Creatine Kinase/blood ; *Dinoprost/*analogs &amp; derivatives ; Double-Blind Method ; *Exercise ; F2-Isoprostanes/blood ; Glutathione Peroxidase/blood ; Humans ; Interleukin-6/blood ; Iron/blood ; L-Lactate Dehydrogenase/blood ; Lipid Peroxidation ; Lipid Peroxides/blood ; Male ; Muscle, Skeletal/*injuries/pathology ; Myoglobin/blood ; Myositis/etiology/*metabolism/pathology ; *Oxidative Stress ; Pain ; Peroxidase/blood ; Placebos ; Superoxide Dismutase/blood ; }, abstract = {There has been no investigation to determine if the widely used over-the-counter, water-soluble antioxidants vitamin C and N-acetyl-cysteine (NAC) could act as pro-oxidants in humans during inflammatory conditions. We induced an acute-phase inflammatory response by an eccentric arm muscle injury. The inflammation was characterized by edema, swelling, pain, and increases in plasma inflammatory indicators, myeloperoxidase and interleukin-6. Immediately following the injury, subjects consumed a placebo or vitamin C (12.5 mg/kg body weight) and NAC (10 mg/kg body weight) for 7 d. The resulting muscle injury caused increased levels of serum bleomycin-detectable iron and the amount of iron was higher in the vitamin C and NAC group. The concentrations of lactate dehydrogenase (LDH), creatine kinase (CK), and myoglobin were significantly elevated 2, 3, and 4 d postinjury and returned to baseline levels by day 7. In addition, LDH and CK activities were elevated to a greater extent in the vitamin C and NAC group. Levels of markers for oxidative stress (lipid hydroperoxides and 8-iso prostaglandin F2alpha; 8-Iso-PGF2alpha) and antioxidant enzyme activities were also elevated post-injury. The subjects receiving vitamin C and NAC had higher levels of lipid hydroperoxides and 8-Iso-PGF2alpha 2 d after the exercise. This acute human inflammatory model strongly suggests that vitamin C and NAC supplementation immediately post-injury, transiently increases tissue damage and oxidative stress.}, }
@article {pmid11555630, year = {2001}, author = {Santos, MM and Ohshima, K and Pandolfo, M}, title = {Frataxin deficiency enhances apoptosis in cells differentiating into neuroectoderm.}, journal = {Human molecular genetics}, volume = {10}, number = {18}, pages = {1935-1944}, doi = {10.1093/hmg/10.18.1935}, pmid = {11555630}, issn = {0964-6906}, support = {NS34192/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis/drug effects/genetics ; Cell Differentiation/drug effects/genetics ; Cell Division/drug effects/genetics ; DNA Fragmentation/drug effects ; DNA, Antisense/genetics ; Ectoderm/*cytology/drug effects/metabolism ; Free Radical Scavengers/pharmacology ; *Iron-Binding Proteins ; Microtubule-Associated Proteins/metabolism ; Myocardium/cytology/metabolism ; Nervous System/*cytology/drug effects/embryology ; Phosphotransferases (Alcohol Group Acceptor)/*deficiency/genetics/metabolism ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/pharmacology ; Time Factors ; Transfection ; Tretinoin/pharmacology ; Tumor Cells, Cultured ; Frataxin ; }, abstract = {Deficiency of the mitochondrial matrix protein frataxin causes Friedreich ataxia. Frataxin function is believed to be related to mitochondrial iron metabolism and free radical production. In Friedreich ataxia, loss of dorsal root ganglia neurons occurs early in life, suggesting a developmental process. In addition, frataxin knockout mice die during embryonic life, further suggesting that frataxin is necessary for normal development. In this study we examine the role of frataxin in neuronal differentiation by using the P19 embryonic carcinoma cell line as a model system. We produced stably transfected clones with antisense or sense frataxin constructs. During retinoic acid-induced neurogenesis of frataxin-deficient cells there was a striking rise in cell death, while cell division remained unaffected. However, frataxin deficiency does not affect cell survival in cells induced to differentiate into cardiomyocytes. Frataxin deficiency enhances apoptosis of retinoic acid-stimulated cells, and the number of neuronal-like cells expressing MAP2 was dramatically reduced in these clones. In addition, we found that antisense clones induced to differentiate into neuroectoderm with retinoic acid have increased production of reactive oxygen species, and that only cells non-committed to the neuronal lineages could be rescued by the addition of the antioxidant N-acetyl-cysteine (NAC). However, NAC treatment had no effect in increasing the number of terminally differentiated neuronal-like cells in frataxin-deficient clones. Our results suggest that frataxin deficiency may render cells susceptible to apoptosis after exposure to appropriate stimuli.}, }
@article {pmid11552643, year = {2001}, author = {Gamaleĭ, IA and Polozov, IuS and Kirpichnikova, KM and Aksenov, ND and Tararova, ND and Pospelova, TV}, title = {[Distribution of rat embryonal fibroblasts through cell cycle phases in the presence of inhibitors of active oxygen species formation and N-acetylcysteine].}, journal = {Tsitologiia}, volume = {43}, number = {7}, pages = {633-638}, pmid = {11552643}, issn = {0041-3771}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; *Cell Cycle ; Cells, Cultured ; Culture Media ; Embryo, Mammalian/*cytology ; Flow Cytometry ; Mice ; Onium Compounds/*pharmacology ; Rats ; *Reactive Oxygen Species ; Receptors, Growth Factor/metabolism ; Rotenone/*pharmacology ; Signal Transduction ; }, abstract = {Intracellular level of reactive oxygen species (ROS) and distribution of primary rat embryo fibroblast throughout the cell cycle have been studied. Serum-starved cells were activated by the addition of 10% serum to the culture medium in the presence on N-acetyl-cystein (NAC) and ROS-inhibitors, diphenileniodonium (DPI) and rothenone. It has been shown that serum starvation could block the cells at the G1/S boundary. Activation of serum-starved cells by the addition of serum reactivated the cell cycle and caused cell progression into S phase, which was paralleled with the increase in the intracellular level of ROS. Effects of NAC, PAI and rothenone, similar to that of serum starvation, blocked cell progression into S phase and decreased ROS formation due to the action of serum growth factors. The antiproliferative effect of NAC is discussed.}, }
@article {pmid11544433, year = {2001}, author = {Weigand, MA and Plachky, J and Thies, JC and Spies-Martin, D and Otto, G and Martin, E and Bardenheuer, HJ}, title = {N-acetylcysteine attenuates the increase in alpha-glutathione S-transferase and circulating ICAM-1 and VCAM-1 after reperfusion in humans undergoing liver transplantation.}, journal = {Transplantation}, volume = {72}, number = {4}, pages = {694-698}, doi = {10.1097/00007890-200108270-00023}, pmid = {11544433}, issn = {0041-1337}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Female ; Glutathione Transferase/*antagonists &amp; inhibitors ; Humans ; Intercellular Adhesion Molecule-1/*blood ; *Liver Transplantation ; Male ; Middle Aged ; Prospective Studies ; Reference Values ; *Reperfusion Injury/*drug therapy/*metabolism ; Time Factors ; Vascular Cell Adhesion Molecule-1/*blood ; }, abstract = {BACKGROUND: Oxidative stress and leukocyte-endothelial interactions contribute significantly to the reperfusion injury of the transplanted liver. Therefore, we investigated the effect of N-acetylcysteine (NAC) on reperfusion injury and circulating adhesion molecules during human liver transplantation.<br><br>METHODS: In a prospective study, 10 orthotopic liver transplantation patients were treated with high-dose NAC and 10 patients were treated with 5% glucose (placebo group) immediately before and during reperfusion of the donor liver. Parameters of hepatocellular injury, cellular oxygenation, plasma cytokines, and circulating adhesion molecules were determined at various time points during the liver transplantation.<br><br>RESULTS: NAC had no significant effect on the arterial lactate/pyruvate or hydroxybutyrate/acetoacetate ratio during the liver transplantation. At baseline, liver transplantation patients exhibited elevated levels of cytokines and circulating adhesion molecules compared with healthy volunteers (n=7). While no significant effect of NAC on circulating L- and P-selectin was observed, it significantly inhibited the increase in circulating ICAM-1 and VCAM-1 24 hr after reperfusion. There were no significant differences in maximal postoperative values of serum aspartate transaminase (peak AST) or alanine transaminase (peak ALT) between both groups. However, NAC significantly reduced the rise in alpha-glutathione S-transferase after reperfusion of the donor liver.<br><br>CONCLUSIONS: NAC attenuated the increase in alpha-glutathione S-transferase and circulating ICAM-1 and VCAM-1 after reperfusion of the donor liver, indicating possible cytoprotective effects of NAC.}, }
@article {pmid11543645, year = {2001}, author = {Vendemiale, G and Grattagliano, I and Caruso, ML and Serviddio, G and Valentini, AM and Pirrelli, M and Altomare, E}, title = {Increased oxidative stress in dimethylnitrosamine-induced liver fibrosis in the rat: effect of N-acetylcysteine and interferon-alpha.}, journal = {Toxicology and applied pharmacology}, volume = {175}, number = {2}, pages = {130-139}, doi = {10.1006/taap.2001.9234}, pmid = {11543645}, issn = {0041-008X}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Dimethylnitrosamine/*toxicity ; Free Radical Scavengers/therapeutic use ; Interferon-alpha/therapeutic use ; Liver Cirrhosis/*chemically induced/metabolism/pathology/*prevention &amp; control ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Oxidative stress may represent a common link between chronic liver damage and hepatic fibrosis. Antioxidants and interferon seem to protect against hepatic stellate cell (HSC) activation and liver fibrosis. This study evaluated (1) the effect of the profibrotic agent dimethylnitrosamine (DMN) on the hepatic oxidative balance in the rat; (2) the role played by the antioxidant agent N-acetylcysteine (NAC); and (3) the antifibrotic effects of two different types of interferon-alpha: recombinant alpha-2b (rIFN-alpha) and leukocyte alpha (LeIFN-alpha). Five groups of rats received: (1) saline; (2) DMN; (3) DMN + NAC; (4) DMN + rIFN-alpha; and (5) DMN + LeIFN-alpha. Oxidative balance was evaluated by hepatic glutathione, TBARs, protein carbonyl, and sulfhydryl determination. Fibrosis was determined by hepatic hydroxyproline content and fibronectin (FN) staining (immunohistochemistry). DMN rats showed a diffuse FN deposition, an impaired oxidative balance, and higher hepatic hydroxyproline levels compared to that of controls. NAC administration significantly reduced FN deposition, increased hepatic glutathione, and decreased TBARs and protein carbonyls. Administration of IFN-alpha exerted different effects according to the type used. Both IFNs decreased FN deposition; however, LeIFN-alpha significantly improved histology and oxidative parameters compared to those of untreated DMN and rats treated with rIFN-alpha. This study shows the role of free radicals in this model of hepatic fibrosis; the protective effect of NAC against liver fibrosis; and the antifibrotic effect exerted by IFN-alpha (particularly LeIFN-alpha) independent of its antiviral activity.}, }
@article {pmid11532857, year = {2001}, author = {Martin, KR and Trempus, C and Saulnier, M and Kari, FW and Barrett, JC and French, JE}, title = {Dietary N-acetyl-L-cysteine modulates benzo[a]pyrene-induced skin tumors in cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) mice.}, journal = {Carcinogenesis}, volume = {22}, number = {9}, pages = {1373-1378}, doi = {10.1093/carcin/22.9.1373}, pmid = {11532857}, issn = {0143-3334}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Benzo(a)pyrene/toxicity ; Carcinogens/toxicity ; Carcinoma, Squamous Cell/chemically induced/genetics/pathology/prevention &amp; control ; Cocarcinogenesis ; Crosses, Genetic ; Dietary Supplements ; Female ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Neoplastic ; Genes, p53/*genetics ; Genes, ras/*genetics ; Genetic Predisposition to Disease ; Haplotypes ; Male ; Mice ; Mice, Transgenic ; Skin Neoplasms/chemically induced/genetics/pathology/*prevention &amp; control ; Transgenes ; Tumor Suppressor Protein p53/biosynthesis/genetics ; }, abstract = {Epidemiologic studies support the protective role of dietary antioxidants in preventing cancer. However, emerging evidence from clinical trials and laboratory data suggest that in some cases individual antioxidant supplements may actually exacerbate carcinogenesis. Our goal was to explore these paradoxical activities in a rodent model that possesses genotypic characteristics of human cancers. We selected the p53 haploinsufficient Tg.AC (v-Ha-ras) mouse as a model, because it contains an activated, carcinogeninducible ras oncogene and an inactivated p53 tumor suppressor gene, which are frequent genetic alterations in human cancers. These mice develop chemically induced benign and malignant skin tumors rapidly which can easily be quantified. Mice were fed basal diets with or without 3% N-acetyl-L-cysteine (NAC), a well-recognized antioxidant, prior to, during and after topical application of the carcinogen benzo[a]pyrene (64 microg/mouse) applied twice per week for 7 weeks. Tumor incidence exceeded 90% for both groups, and NAC did not reduce tumor latency. Mice fed NAC displayed a 43% reduction (P < 0.05) in tumor multiplicity and delayed the appearance of lesions (P < 0.05). Dietary NAC also significantly (P < 0.05) improved group survival by 5 weeks. Total tumor yields were reduced in both dietary groups but malignant spindle cell tumors (SCT) increased by 25% in NAC-fed mice. The v-Ha-ras oncogene and p53 protein products were clearly co-expressed in both benign and malignant lesions from both dietary groups. In summary, dietary supplementation with NAC was chemopreventive, but the marginal increase in SCT suggests a paradoxical effect.}, }
@article {pmid11532081, year = {2001}, author = {Wilmer, WA and Dixon, CL and Hebert, C}, title = {Chronic exposure of human mesangial cells to high glucose environments activates the p38 MAPK pathway.}, journal = {Kidney international}, volume = {60}, number = {3}, pages = {858-871}, doi = {10.1046/j.1523-1755.2001.060003858.x}, pmid = {11532081}, issn = {0085-2538}, mesh = {Antioxidants/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Activation ; Glomerular Mesangium/*drug effects/enzymology ; Glucose/antagonists &amp; inhibitors/*pharmacology ; Humans ; Mannitol/pharmacology ; Mitogen-Activated Protein Kinases/*metabolism ; Osmotic Pressure ; Phorbol Esters/pharmacology ; Transcription Factor AP-1/metabolism ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {BACKGROUND: High glucose (HG) environments activate several protein kinase pathways in mesangial cells, including the mitogen-activated protein kinase (MAPK) pathway, ERK. The p38 MAPK pathway is activated by events that occur in the setting of diabetes, such as protein kinase C (PKC) up-regulation and cellular stresses (osmotic stress and redox changes). Substrates of activated p38 MAPK include transcription factors that are involved in the microvascular complications of diabetes. This current study investigated the mechanisms of HG-mediated activation of p38 MAPK in cultured human mesangial cells (HMCs) and the effects of p38 MAPK activation on the transcription factor activator protein-1 (AP-1).<br><br>METHODS: HMCs were cultured in 5 mmol/L D-glucose [normal glucose (NG)] or 30 mmol/L D-glucose (HG) for seven days. Cells were also treated with HG for brief periods of time (0.5 to 4 hours) to assess the acute effects of HG on p38 MAPK. Using Western blotting of HMC lysates, changes in the tyrosine and threonine phosphorylation of p38 MAPK were measured. The kinase activity of immunoprecipitated p38 MAPK was determined by an in vitro assay that measured the phosphorylation and activation of MAPKAP kinase-2, an intermediary signaling protein downstream of p38 MAPK. To investigate the role of osmotic stress in HG activation of p38 MAPK, cells were acutely treated with mannitol (25 to 250 mOsm/L x 5 to 60 min) or were grown seven days in media supplemented with mannitol at concentrations iso-osmotic to HG media. To investigate the role of PKC in HG-mediated p38 MAPK activation, HMCs were treated with the PKC inhibitors GF 109203X, Ro 32-0432, or rottlerin during the last several hours of HG treatment. HG conditioned cells were also treated with the antioxidants L-N-acetylcysteine (L-NAC) or diphenyliodonium (DPI) prior to harvest. To determine a functional significance of HG-mediated p38 MAPK activation, the DNA binding of the transcription factor complex AP-1 was measured by electrophoretic mobility shift assay.<br><br>RESULTS: The p38 MAPK pathway was not activated by the acute addition of HG to the HMCs. However, activation of p38 MAPK in HMCs grown seven days in HG was demonstrated by increased tyrosine and threonine phosphorylation of p38 MAPK proteins and increased kinase activity of immunoprecipitated p38 MAPK. As assessed by a kinase assay, p38 MAPK activity in cells grown in HG for seven days exceeded that of NG cells by more than 250%. This difference was not due to differences in the amount of p38 MAPK protein between the treatment groups. Acute osmotic activation of p38 MAPK occurred at extremely high mannitol concentrations (250 mOsm/L) that exceeded the osmotic stress of acute HG. Furthermore, in cells grown for seven days in mannitol at concentrations similar to HG, p38 MAPK activity was similar to control values. Phorbol ester (PMA) treatment stimulated a twofold increase in p38 MAPK activity. The addition of GFX or Ro 32-0432 to HG cells, at concentrations that inhibited PMA activation of p38 MAPK, did not inhibit the glucose-mediated p38 MAPK activation. Rottlerin, a PKC delta inhibitor, also failed to reverse the HG-mediated p38 MAPK activation. Treatment of HG cells with L-NAC or DPI inhibited the HG-mediated p38 MAPK phosphorylation. As we have previously shown, DNA binding of the transcription factor complex AP-1 was increased in HG cells. This binding was reversed by treatment of the HG cells with the p38 MAPK inhibitor SB 203580.<br><br>CONCLUSIONS: Chronic exposure of HMC to HG concentrations activates the p38 MAPK pathway. This activation appears to be independent of changes in the amount of total p38 MAPK produced by the cells, independent of chronic osmotic stress and independent of PKC activation. The reversal of p38 MAPK by L-NAC and DPI suggests the glucose-mediated p38 MAPK activation may occur via reactive oxygen species. The activity of AP-1, a transcription factor complex that regulates several genes involved in diabetic nephropathy, is reversed when the p38 MAPK pathway is inhibited. These findings suggest the p38 MAPK pathway may be an important pathway involved in diabetic complications.}, }
@article {pmid11516525, year = {2001}, author = {Cereser, C and Boget, S and Parvaz, P and Revol, A}, title = {Thiram-induced cytotoxicity is accompanied by a rapid and drastic oxidation of reduced glutathione with consecutive lipid peroxidation and cell death.}, journal = {Toxicology}, volume = {163}, number = {2-3}, pages = {153-162}, doi = {10.1016/s0300-483x(01)00401-2}, pmid = {11516525}, issn = {0300-483X}, mesh = {Acetylcysteine/pharmacology ; Adult ; Buthionine Sulfoximine/pharmacology ; Cell Death ; Cell Division/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Female ; Fibroblasts/*drug effects ; Fungicides, Industrial/*toxicity ; Glutathione/*metabolism ; Glutathione Disulfide/analysis ; Glutathione Reductase/analysis ; Humans ; Lipid Peroxidation ; Oxidation-Reduction ; Thiobarbituric Acid Reactive Substances/analysis ; Thiram/*toxicity ; }, abstract = {The toxic effect of thiram, a widely used dithiocarbamate fungicide, was investigated in cultured human skin fibroblasts. Cell survival assays demonstrated that thiram induced a dose-dependent decrease in the viable cell recovery. Thiram exposure resulted in a rapid depletion of intracellular reduced glutathione (GSH) content with a concomitant increase in oxidized glutathione (GSSG) concentration. Alteration of glutathione levels was accompanied by a dose-dependent decrease in the activity of glutathione reductase (GR), a key enzyme for the regeneration of GSH from GSSG. Thiram-exposed cells exhibited increased lipid peroxidation reflected by enhanced thiobarbituric acid reactive substances (TBARS) production, suggesting that GSH depletion and the lower GR activity gave rise to increased oxidative processes. To investigate the role of decreased GSH content in the toxicity of thiram, GSH levels were modulated prior to exposure. Pretreatment of fibroblasts with N-acetyl-L-cysteine (NAC), a GSH biosynthesis precursor, prevented both lipid peroxidation and cell death induced by thiram exposure. In contrast, thiram cytotoxicity was exacerbated by the previous depletion of cellular GSH by L-buthionine-(S,R)-sulfoximine (BSO). Taken together, these results strongly suggest that thiram induces GSH depletion, leading to oxidative stress and finally cell death.}, }
@article {pmid11514101, year = {2001}, author = {Tsai, SH and Hsieh, MS and Chen, L and Liang, YC and Lin, JK and Lin, SY}, title = {Suppression of Fas ligand expression on endothelial cells by arsenite through reactive oxygen species.}, journal = {Toxicology letters}, volume = {123}, number = {1}, pages = {11-19}, doi = {10.1016/s0378-4274(01)00373-3}, pmid = {11514101}, issn = {0378-4274}, mesh = {Acetylcysteine/pharmacology ; Arsenites/*toxicity ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*drug effects/metabolism ; Fas Ligand Protein ; Humans ; Membrane Glycoproteins/*biosynthesis ; Peroxides/metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Chronic exposure to arsenite is associated with vascular disease, such as arteriosclerosis. However, the cellular mechanisms for vascular disease in response to arsenic are not well known. The present study has demonstrated that arsenite not arsenate decreased the Fas ligand (FasL) expression on ECV304 cells through reactive oxygen species. Incubation of ECV304 cells with arsenite decreased the FasL expression and increased the intracellular peroxide levels. In addition, hydrogen peroxide was found to suppress FasL expression in a dose-dependent manner. The antioxidant, N-acetyl-cysteine, blocked the suppression of FasL expression in response to arsenite. These data suggested that arsenite initiates endothelium dysfunction, at least partly, by suppressing the FasL expression through activating reactive oxygen species sensitive endothelial cell signaling.}, }
@article {pmid11511177, year = {2001}, author = {Grillo, MP and Benet, LZ}, title = {Interaction of gamma-glutamyltranspeptidase with clofibryl-S-acyl-glutathione in vitro and in vivo in rat.}, journal = {Chemical research in toxicology}, volume = {14}, number = {8}, pages = {1033-1040}, doi = {10.1021/tx010039x}, pmid = {11511177}, issn = {0893-228X}, support = {GM36633/GM/NIGMS NIH HHS/United States ; }, mesh = {Acylation ; Animals ; Anticholesteremic Agents/*chemistry/pharmacokinetics ; Chromatography, High Pressure Liquid ; Clofibric Acid/*chemistry/pharmacokinetics ; Glutathione/analogs &amp; derivatives/*chemistry ; Kinetics ; Male ; Mass Spectrometry ; Rats ; Rats, Sprague-Dawley ; gamma-Glutamyltransferase/*metabolism ; }, abstract = {Clofibric acid (CA) is metabolized to chemically reactive acylating products that can transacylate glutathione to form clofibryl-S-acyl-glutathione (CA-SG) in vitro and in vivo. We investigated the first step in the degradation of CA-SG to the mercapturic acid conjugate, clofibryl-S-acyl-N-acetylcysteine (CA-SNAC), which is catalyzed by gamma-glutamyltranspeptidase (gamma-GT). After gamma-GT mediated cleavage of glutamate from CA-SG, the product clofibryl-S-acyl-cysteinylglycine (CA-S-CG) should undergo an intramolecular rearrangement reaction [Tate, S. S. (1975) FEBS Lett. 54, 319-322] to form clofibryl-N-acyl-cysteinylglycine (CA-N-CG). We performed in vitro studies incubating CA-SG with gamma-GT to determine the products formed, and in vivo studies examining the products excreted in urine after dosing rats with CA-SG or CA. Thus, CA-SG (0.1 mM) was incubated with gamma-GT (0.1 unit/mL) in buffer (pH 7.4, 25 degrees C) and analyzed for products formed by reversed-phase HPLC and electrospray mass spectrometry (ESI/MS). Results showed that CA-SG is degraded completely after 6 h of incubation leading to the formation of two products, CA-N-CG and its disulfide, with no detection of CA-S-CG thioester. After 36 h of incubation, only the disulfide remained in the incubation. Treatment of the disulfide with dithiothreitol led to the reappearance of CA-N-CG. ESI/LC/MS analysis of urine (16 h) extracts of CA-SG-dosed rats (200 mg/kg, iv) showed that CA-SG is degraded to CA-N-CG, CA-N-acyl-cysteine (CA-N-C) and their respective S-methylated products. The mercapturic acid conjugate (CA-SNAC) was found as a minor product. Analysis of urine extracts from CA-dosed rats (200 mg/kg, ip) resulted in the detection of clofibryl-N-acyl-cysteine (CA-N-C), but no evidence for the formation of CA-SNAC was obtained. These in vitro and in vivo experiments indicate that gamma-GT mediated degradation of clofibryl-S-acyl-glutathione leads primarily to the formation and excretion of clofibryl-N-acyl-cysteine products rather than the S-acyl-NAC conjugate.}, }
@article {pmid11510126, year = {2001}, author = {Attri, S and Rana, SV and Vaiphie, K and Katyal, R and Sodhi, CP and Kanwar, S and Singh, K}, title = {Protective effect of N-acetylcysteine in isoniazid induced hepatic injury in growing rats.}, journal = {Indian journal of experimental biology}, volume = {39}, number = {5}, pages = {436-440}, pmid = {11510126}, issn = {0019-5189}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/metabolism ; Free Radical Scavengers/metabolism ; Glutathione/metabolism ; Isoniazid/*antagonists &amp; inhibitors/toxicity ; Liver/*drug effects/injuries/metabolism/pathology ; Male ; Oxidants/toxicity ; Rats ; Rats, Wistar ; }, abstract = {Status of oxidative/antioxidative profile was the mechanistic approach to inumerate the nature of protection by N-acetylcysteine (NAC) in isoniazid (INH) exposed experimental animals. Analysis of lipid peroxidation, thiol levels, cytochrome P450, superoxide dismutase (SOD), catalase, glutathione peroxidase, reductase and transferase were estimated in liver along with the body and liver weight of animals and histological observations. Isoniazid exposure to animals resulted in no change in body and liver weights. Thiols, lipid peroxidation, catalase, SOD glutathione peroxidase, reductase, transferase and cytochrome P450 levels were altered with INH exposure. Supplementation of NAC with INH protected the animals against hepatotoxic reactions by minimizing the free radical induced tissue injury and overall maintenance of the endogenous scavengers of free radicals.}, }
@article {pmid11509553, year = {2001}, author = {Kim, KY and Rhim, T and Choi, I and Kim, SS}, title = {N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity.}, journal = {The Journal of biological chemistry}, volume = {276}, number = {44}, pages = {40591-40598}, doi = {10.1074/jbc.M100975200}, pmid = {11509553}, issn = {0021-9258}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Base Sequence ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/metabolism ; DNA Primers ; Enzyme Activation ; G1 Phase/*drug effects ; Liver/cytology/*drug effects/enzymology/metabolism ; Male ; Phosphorylation ; Protein Kinases/metabolism ; Rats ; Rats, Sprague-Dawley ; Sp1 Transcription Factor/metabolism ; Sulfhydryl Compounds/metabolism ; }, abstract = {Activation of hepatic stellate cells (HSC) has been identified as a critical step in hepatic fibrogenesis and is regulated by several factors including cytokines and oxidative stress. However, the molecular mechanism for HSC inactivation is not well understood. We investigated an N-acetyl-L-cysteine (NAC)-mediated signaling pathway involved in HSC inactivation. NAC, which acting through its reducing activity, induced cell arrest at G1 via the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway in a Ras-independent manner. The sustained activation of this extracellular signal-regulated kinase induced the expression of p21(Cip1/WAF1), a cell cycle-dependent kinase inhibitor, and mediated cell growth arrest through the Sp1 transcription activator-dependent mechanism. These effects of NAC were all reversed by treatment of HSC with MEK inhibitor PD98059 followed by culturing HSC on type I collagen-coated flasks. The collagen-mediated suppression of NAC-induced arrest may be due to an overriding of the cell cycle arrest through an acceleration of integrin-induced cell growth. NAC action is actually dependent on modulating the redox states of cysteine residues of target proteins such as Raf-1, MEK, and ERK. In conclusion, an understanding of the NAC signaling pathway in HSC should provide the theoretical basis for clinical approaches using antioxidant therapies in liver fibrosis.}, }
@article {pmid11509327, year = {2001}, author = {Harper, R and Wu, K and Chang, MM and Yoneda, K and Pan, R and Reddy, SP and Wu, R}, title = {Activation of nuclear factor-kappa b transcriptional activity in airway epithelial cells by thioredoxin but not by N-acetyl-cysteine and glutathione.}, journal = {American journal of respiratory cell and molecular biology}, volume = {25}, number = {2}, pages = {178-185}, doi = {10.1165/ajrcmb.25.2.4471}, pmid = {11509327}, issn = {1044-1549}, support = {ES06230/ES/NIEHS NIH HHS/United States ; ES09703/ES/NIEHS NIH HHS/United States ; HL35635/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Bronchi/*drug effects/*metabolism ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Cells, Cultured ; DNA/genetics/metabolism ; Epithelial Cells/drug effects/metabolism ; Gene Expression/drug effects ; Glutathione/*pharmacology ; Humans ; Interleukin-8/genetics ; NF-kappa B/*metabolism ; Oxidation-Reduction ; Thioredoxins/metabolism/*pharmacology ; Trachea/drug effects/metabolism ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Increasing evidence indicates that intracellular redox status modulates the activity of various transcriptional factors, including nuclear factor (NF)-kappa B and activator protein-1. Our laboratory has been interested in characterizing the role thioredoxin (TRX) plays in regulating cellular redox status in airway epithelium. TRX is a small, ubiquitous protein with two redox-active half-cysteine residues, -Cys-Gly-Pro-Cys, in its active center. Using primary passage-1 human tracheobronchial epithelial cell cultures and an immortalized human bronchial epithelial cell line, HBE1, we observed that tumor necrosis factor (TNF)-alpha enhanced NF-kappa B transcriptional activity. This observation was based on gel mobility shift assays and interleukin (IL)-8 promoter-reporter gene transfection studies. TNF-alpha activation coincided with translocation of NF-kappa B p65 from the cytoplasm to the nucleus. Pretreatment with N-acetyl-cysteine (NAC) (1 to 10 mM) or glutathione (1 to 10 mM) inhibited TNF-alpha-induced activation of NF-kappa B transcriptional activity and IL-8 promoter-mediated reporter gene expression. In contrast, elevated TRX protein levels in cells enhanced TNF-alpha-dependent NF-kappa B transcriptional activity and IL-8 promoter activity. This observation was independent of the manner in which TRX was elevated in cells (e.g., by cotransfection with a FLAG-TRX expression clone, or by direct exposure to commercially available human TRX protein). Localization of TRX protein by anti-TRX antibody indicated an accumulation of TRX protein in the nucleus after TNF-alpha treatment. The nuclear localization phenomenon was different from the major cytosolic accumulation of glutathione and NAC. This is the first known report demonstrating movement of TRX into the nucleus of airway epithelial cells after an inflammatory stress. These results suggest a compartment effect of thiol chemicals in the regulation of redox-dependent transcriptional activity.}, }
@article {pmid11506986, year = {2001}, author = {Conesa, EL and Valero, F and Nadal, JC and Fenoy, FJ and López, B and Arregui, B and Salom, MG}, title = {N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure.}, journal = {American journal of physiology. Regulatory, integrative and comparative physiology}, volume = {281}, number = {3}, pages = {R730-7}, doi = {10.1152/ajpregu.2001.281.3.R730}, pmid = {11506986}, issn = {0363-6119}, mesh = {Acetylcysteine/*pharmacology ; Acute Kidney Injury/complications/*drug therapy/physiopathology ; Animals ; Blood Flow Velocity/drug effects ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/*pharmacology ; Glomerular Filtration Rate/drug effects ; Kidney Medulla/*blood supply/*drug effects/physiopathology ; Laser-Doppler Flowmetry ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitrates/blood ; Nitrites/blood ; Rats ; Rats, Wistar ; Regional Blood Flow/drug effects ; Reperfusion ; Reperfusion Injury/complications/physiopathology ; Vena Cava, Inferior/physiology ; }, abstract = {This study evaluated the effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, and N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthesis inhibitor, on the changes in renal function, intrarenal blood flow distribution (laser-Doppler flowmetry), and plasma peroxynitrite levels during the acute renal failure (ARF) produced by inferior vena cava occlusion (IVCO; 45 min) in anesthetized rats. Renal blood flow fell on reperfusion (whole kidney by -45.7%; cortex -58.7%, outer medulla -62.8%, and papilla -47.7%); glomerular filtration rate (GRF) also decreased (-68.6%), whereas fractional sodium excretion (FE(Na%)) and peroxynitrite and NO/NO plasma levels increased (189.5, 46.5, and 390%, respectively) after ischemia. Pretreatment with L-NAME (10 microg. kg(-1). min(-1)) aggravated the fall in renal blood flow seen during reperfusion (-60%). Pretreatment with NAC (150 mg/kg bolus + 715 microg. kg(-1). min(-1) iv) partially prevented those changes in renal function (GFR only fell by -29.2%, and FE(Na%) increased 119.4%) and laser-Doppler blood flow, especially in the outer medulla, where blood flow recovered to near control levels during reperfusion. These beneficial effects seen in rats given NAC seem to be dependent on the presence of NO, because they were abolished in rats pretreated with L-NAME. Also, the antioxidant effects of NAC prevented the increase in plasma peroxynitrite after ischemia. In conclusion, NAC ameliorates the renal failure and the outer medullary vasoconstriction induced by ICVO, effects that seem to be dependent on the presence of NO and the scavenging of peroxynitrite.}, }
@article {pmid11506896, year = {2001}, author = {Turpaev, K and Litvinov, D and Dubovaya, V and Panasyuk, A and Ivanov, D and Prassolov, V}, title = {Induction of vascular endothelial growth factor by nitric oxide in cultured human articular chondrocytes.}, journal = {Biochimie}, volume = {83}, number = {6}, pages = {515-522}, doi = {10.1016/s0300-9084(01)01280-9}, pmid = {11506896}, issn = {0300-9084}, mesh = {Antioxidants/metabolism ; Catalase/metabolism ; Cells, Cultured ; Chondrocytes/drug effects/*metabolism ; Endothelial Growth Factors/genetics/*metabolism ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/metabolism ; Humans ; Lymphokines/genetics/*metabolism ; *MAP Kinase Kinase Kinase 1 ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Nitric Oxide/*metabolism ; Oxidation-Reduction/drug effects ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors/metabolism ; RNA, Messenger/genetics/metabolism ; Reactive Oxygen Species/metabolism ; S-Nitrosoglutathione/pharmacology ; Signal Transduction/drug effects ; Superoxide Dismutase/metabolism ; Up-Regulation/drug effects ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {We investigated the role of nitric oxide (NO) in the control of vascular endothelial growth factor A (VEGF) gene expression in cultured human articular chondrocytes. Cell treatment with the NO-generating compound nitrosoglutathione (GSNO) caused a significant accumulation of 4.4 kb VEGF mRNA, a major VEGF mRNA isoform expressing in chondrocytes. This is the first demonstration that NO can induce VEGF mRNA expression in chondrocytes. VEGF mRNA level was not affected in cells exposed to dibutyryl cGMP, a non-hydrolyzable analog of cGMP, suggesting that the cGMP system is not involved in NO-dependent transcriptional activation of VEGF gene. The GSNO-stimulated induction of VEGF mRNA was slightly attenuated by MAP protein kinase inhibitors PD98058 and SB203580, but was completely blocked in cells incubated with GSNO in the presence of catalase and superoxide dismutase, enzymes scavenging reactive oxygen species (ROS), or in the presence of thiol-containing antioxidants, N-acetyl cysteine and reduced glutathione. These results suggest that in articular chondrocytes the GSNO-induced VEGF gene transcriptional activation is dependent on endogenous ROS production and oxidative thiol modifications.}, }
@article {pmid11506803, year = {2001}, author = {Smith, WA and Freeman, JW and Gupta, RC}, title = {Effect of chemopreventive agents on DNA adduction induced by the potent mammary carcinogen dibenzo[a,l]pyrene in the human breast cells MCF-7.}, journal = {Mutation research}, volume = {480-481}, number = {}, pages = {97-108}, doi = {10.1016/s0027-5107(01)00173-7}, pmid = {11506803}, issn = {0027-5107}, support = {CA 77114/CA/NCI NIH HHS/United States ; ES07266/ES/NIEHS NIH HHS/United States ; }, mesh = {Anticarcinogenic Agents/pharmacology ; Antimutagenic Agents/*pharmacology ; Antineoplastic Agents/pharmacology ; Benzopyrenes/*toxicity ; Breast/cytology/*drug effects/metabolism ; Breast Neoplasms/drug therapy/metabolism ; Carcinogens/*toxicity ; Cell Line ; Chemoprevention/*methods ; Chlorophyllides/pharmacology ; DNA Adducts/*drug effects/metabolism ; Dose-Response Relationship, Drug ; Female ; Humans ; Pyrazines/pharmacology ; Thiones/pharmacology ; Thiophenes/pharmacology ; }, abstract = {Over 1500 structurally diverse chemicals have been identified which have potential cancer chemopreventive properties. The efficacy and mechanisms of this growing list of chemoprotective agents may be studied using short-term bioassays that employ relevant end-points of the carcinogenic process. In this study, we have examined the effects of eight potential chemopreventive agents, N-acetylcysteine (NAC), benzylisocyanate (BIC), chlorophyllin, curcumin, 1,2-dithiole-3-thione (D3T), ellagic acid, genistein, and oltipraz, on DNA adduction of the potent mammary carcinogen dibenzo[a,l]pyrene (DBP) using the human breast cell line MCF-7. Bioactivation of DBP by MCF-7 cells resulted in the formation of one predominant (55%) dA-derived and several other dA- or dG-derived DNA adducts. Three test agents, oltipraz, D3T, and chlorophyllin substantially (>65%) inhibited DBP-DNA adduction at the highest dose tested (30 microM). These agents also significantly inhibited DBP adduct levels at a lower dose of 15 microM, while oltipraz was effective even at the lowest dose of 5 microM. Two other agents, genistein and ellagic acid were moderate (45%) DBP-DNA adduct inhibitors at the highest dose tested, while NAC, curcumin, and BIC were ineffective. These studies indicate that the MCF-7 cell line is an applicable model to study the efficacy of cancer chemopreventive agents in a human setting. Moreover, this model may also provide information regarding the effect of the test agents on carcinogen bioactivation and detoxification enzymes.}, }
@article {pmid11504555, year = {2001}, author = {Lin, C and Zimmer, SG and Lu, Z and Holland, RE and Dong, Q and Chambers, TM}, title = {The involvement of a stress-activated pathway in equine influenza virus-mediated apoptosis.}, journal = {Virology}, volume = {287}, number = {1}, pages = {202-213}, doi = {10.1006/viro.2001.1010}, pmid = {11504555}, issn = {0042-6822}, mesh = {Animals ; *Apoptosis ; Carbazoles/pharmacology ; Carvedilol ; Cell Line ; Cytopathogenic Effect, Viral ; DNA Fragmentation ; Dogs ; Enzyme Activation ; In Situ Nick-End Labeling ; *Influenza A virus ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinases/*metabolism ; Oligodeoxyribonucleotides, Antisense/pharmacology ; Orthomyxoviridae Infections/*enzymology ; Oxidative Stress ; Propanolamines/pharmacology ; Signal Transduction ; Transforming Growth Factor beta/biosynthesis ; Virus Replication/drug effects ; }, abstract = {We have shown elsewhere that equine-2 influenza virus (EIV; subtype H3N8) induced pronounced cell death in infected cells through apoptosis as demonstrated by DNA fragmentation assay and a combined TUNEL and immunostaining scheme. In this study, we investigated the mechanism of EIV-mediated cytotoxicity on a permissive mammalian epithelial cell line, Madin-Darby canine kidney (MDCK) cells. EIV infection increased the cellular levels of oxidative stress and c-Jun/AP-1 protein (which is known to be affected by oxidative stress), as well as its DNA binding activity. Increased production of TGF-beta1, an inducer of c-Jun N-terminal kinase or stress-activated protein kinase (JNK/SAPK) activation, was also detected in EIV-infected MDCK cells. It has been reported that TGF-beta may initiate a signaling cascade leading to JNK/SAPK activation. Addition of c-Jun antisense oligodeoxynucleotide, antioxidant N-acetyl-cysteine (NAC), JNK/SAPK inhibitor carvedilol, or TGF-beta-neutralizing antibody effectively blocked c-Jun/AP-1 upregulation and TGF-beta1 production mediated by EIV infection. These treatments also attenuated EIV-induced cytopathogenic effects (CPE) and apoptosis. Our results suggest that a stress-activated pathway is involved in apoptosis mediated by EIV infection. It is likely that EIV infection turns on the JNK/SAPK cascade, which modulates the activity of apoptosis-promoting regulatory factor c-Jun/AP-1 and epithelial growth inhibitory cytokine TGF-beta.}, }
@article {pmid11504446, year = {2001}, author = {Akrishnan, VR and Menon, VP}, title = {Potential role of antioxidants during ethanol-induced changes in the fatty acid composition and arachidonic acid metabolites in male Wistar rats.}, journal = {Cell biology and toxicology}, volume = {17}, number = {1}, pages = {11-22}, doi = {10.1023/a:1010998929785}, pmid = {11504446}, issn = {0742-2091}, mesh = {Acetylcysteine/pharmacology ; Alprostadil/metabolism ; Animals ; Antioxidants/*pharmacology ; Arachidonic Acid/*metabolism ; Body Weight/drug effects ; Brain/metabolism ; Central Nervous System Depressants/*pharmacology ; Curcumin/pharmacology ; Dinoprost/metabolism ; Dinoprostone/metabolism ; Enzyme Inhibitors/pharmacology ; Ethanol/*pharmacology ; Fatty Acids/*metabolism ; Kidney/metabolism ; Liver/metabolism ; Male ; Phospholipids/metabolism ; Prostaglandin D2/metabolism ; Rats ; Rats, Wistar ; }, abstract = {Biochemical assessment of liver damage during ethanol-induced stress was done by measuring the activities of serum enzymes, viz., aspartate transaminase (AST) and alkaline phosphatase (ALP), which were significantly elevated in rats fed ethanol. Ethanol administration for a period of 60 days modifies the fatty acid composition, and the analysis of fatty acids showed that there was a significant increase in the concentrations of palmitic acid (16:0), stearic acid (18:0), and oleic acid (18:1) in liver, kidney, and brain, whereas the concentrations of palmitoleic (16:1) and arachidonic acid (20:4) were significantly decreased. The breakdown products of arachidonic acids (20:4), prostaglandins, were elevated. The antioxidants curcumin and N-acetylcysteine (NAC) decreased the activities of serum AST and ALP. Curcumin and NAC decreased the concentrations of fatty acids, viz., palmitic, stearic, and oleic acid, whereas arachidonic acid and palmitoleic acid were elevated. The prostaglandin concentrations were also decreased after curcumin and N-acetylcysteine treatment. Thus the present investigation shows that curcumin and N-acetylcysteine prevent the fatty acid changes produced by ethanol and also reduce the inflammatory response of ethanol by reducing the level of prostaglandins.}, }
@article {pmid11502591, year = {2001}, author = {López, B and Moreno, C and Salom, MG and Roman, RJ and Fenoy, FJ}, title = {Role of guanylyl cyclase and cytochrome P-450 on renal response to nitric oxide.}, journal = {American journal of physiology. Renal physiology}, volume = {281}, number = {3}, pages = {F420-7}, doi = {10.1152/ajprenal.2001.281.3.F420}, pmid = {11502591}, issn = {1931-857X}, support = {R37 HL036279/HL/NHLBI NIH HHS/United States ; HL-29587/HL/NHLBI NIH HHS/United States ; HL-36279/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/analogs &amp; derivatives/pharmacology ; Amidines/administration &amp; dosage/*pharmacology ; Animals ; Blood Pressure/drug effects ; Cytochrome P-450 Enzyme System/*metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Glomerular Filtration Rate/drug effects ; Guanylate Cyclase/*metabolism ; Infusions, Parenteral ; Kidney/drug effects/*physiology ; Male ; Methylene Blue/pharmacology ; NG-Nitroarginine Methyl Ester/pharmacology ; Natriuresis/drug effects ; Nitric Oxide/*physiology ; Nitric Oxide Donors/administration &amp; dosage/*pharmacology ; Oxadiazoles/administration &amp; dosage/pharmacology ; Rats ; Rats, Sprague-Dawley ; Renal Circulation/drug effects ; Triazoles/administration &amp; dosage/pharmacology ; }, abstract = {The present study evaluated whether inhibition of guanylyl cyclase (GC) with 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) and methylene blue (MB) or inhibition of the renal metabolism of arachidonic acid by cytochrome P-450 (CYP450) enzymes with 1-aminobenzotriazole (ABT) and N-hydroxy-N'-(4 butyl-2-methyl phenyl)formamidine (HET0016) alters the renal tubular and vascular effects of a nitric oxide (NO) donor in vivo. Intrarenal infusion of ODQ or MB at a dose of 170 nmol. kg(-1). min(-1) lowered renal blood flow (RBF) by 30 and 15%, respectively; glomerular filtration rate (GFR) by 26 and 18%, respectively; and sodium and water excretion by approximately 35%. In rats pretreated with nitro-L-arginine methyl ester (37 nmol. kg(-1). min(-1)) to block the endogenous production of NO, intrarenal infusion of the NO donor S-nitroso-N-acetylcysteine (S-NO-NAC; 50 nmol. kg(-1). min(-1)) increased RBF (18%), sodium (73%), and water excretion (61%). ODQ or MB administration blocked the effect of S-NO-NAC on RBF but not the diuretic and natriuretic response. Pretreatment of rats with ABT or HET0016 also abolished the renal vasodilatory response to the NO donor and reduced its diuretic and natriuretic effect. These results indicate that both activation of GC and inhibition of CYP450 enzymes contribute to the renal vascular actions of NO, whereas the natriuretic and diuretic actions of NO appear to be largely CYP450 dependent.}, }
@article {pmid11500943, year = {2001}, author = {Núñez, MT and Osorio, A and Tapia, V and Vergara, A and Mura, CV}, title = {Iron-induced oxidative stress up-regulates calreticulin levels in intestinal epithelial (Caco-2) cells.}, journal = {Journal of cellular biochemistry}, volume = {82}, number = {4}, pages = {660-665}, doi = {10.1002/jcb.1194}, pmid = {11500943}, issn = {0730-2312}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Caco-2 Cells ; Calcium-Binding Proteins/*biosynthesis/genetics ; Calreticulin ; Humans ; Intestinal Mucosa/*metabolism ; Iron/*pharmacology ; *Oxidative Stress ; Quercetin/pharmacology ; RNA, Messenger/biosynthesis ; Ribonucleoproteins/*biosynthesis/genetics ; Thiourea/analogs &amp; derivatives/pharmacology ; Up-Regulation ; }, abstract = {Calreticulin, a molecular chaperone involved in the folding of endoplasmic reticulum synthesized proteins, is also a shock protein induced by heat, food deprivation, and chemical stress. Mobilferrin, a cytosolic isoform of calreticulin, has been proposed to be an iron carrier for iron recently incoming into intestinal cells. To test the hypothesis that iron could affect calreticulin expression, we investigated the possible associations of calreticulin with iron metabolism. To that end, using Caco-2 cells as a model of intestinal epithelium, the mass and mRNA levels of calreticulin were evaluated as a function of the iron concentration in the culture media. Increasing the iron content in the culture from 1 to 20 microM produced an increase in calreticulin mRNA and a two-fold increase in calreticulin. Increasing iron also induced oxidative damage to proteins, as assessed by the formation of 4-hydroxy-2-nonenal adducts. Co-culture of cells with the antioxidants quercetin, dimethyltiourea and N-acetyl cysteine abolished both the iron-induced oxidative damage and the iron-induced increase in calreticulin. We postulate that the iron-induced expression of calreticulin is part of the cellular response to oxidative stress generated by iron.}, }
@article {pmid11499482, year = {2001}, author = {Campíns-Falcó, P and Molins-Legua, C and Sevillano-Cabeza, A and Tortajada Genaro, LA}, title = {o-Phthalaldelhyde-N-acetylcysteine polyamine derivatives: formation and stability in solution and in C18 supports.}, journal = {Journal of chromatography. B, Biomedical sciences and applications}, volume = {759}, number = {2}, pages = {285-297}, doi = {10.1016/s0378-4347(01)00236-5}, pmid = {11499482}, issn = {1387-2273}, mesh = {Acetylcysteine/*chemistry ; Chromatography, High Pressure Liquid ; Drug Stability ; Polyamines/*chemistry ; Sensitivity and Specificity ; Spectrophotometry, Ultraviolet ; o-Phthalaldehyde/*chemistry ; }, abstract = {A comparative study of different derivatization procedures has been performed in order to improve the stability of the reaction products o-phthalaldehyde-N-acetylcysteine (OPA-NAC) polyamines. Procedures such as solution derivatization, solution derivatization followed by retention on a packing support, derivatization on different packing supports and on-column derivatization, have been optimized and compared. The degradation rate constant (k) of the derivative was dependent on the procedure used and on the analyte. For the spermine (the most unstable isoindol tested) k was 8 +/- 2 x 10(-2) min(-1) in solution versus 7.7 +/- 1.1 x 10(-4) min(-1) on the (C18) solid support. The results obtained showed that forming the derivative on the packing support (C18) gave the best results following this procedure: conditioning the cartridges with borate buffer (1 ml, 0.5 M, pH 8), retention of the analyte, addition of 0.8 ml of OPA-NAC reagent, 0.2 ml borate buffer 0.8 M (pH 8) and elution of the isoindol with 3 ml of MeOH-borate buffer (9:1). The different derivatization procedures have been used to study the stability of the reaction products OPA-NAC polyamines formed in urine matrix using spermine as model compound. Similar results were obtained for standard solutions and urine samples.}, }
@article {pmid11498280, year = {2001}, author = {Du, J and Suzuki, H and Nagase, F and Akhand, AA and Ma, XY and Yokoyama, T and Miyata, T and Nakashima, I}, title = {Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process.}, journal = {Free radical biology &amp; medicine}, volume = {31}, number = {4}, pages = {469-478}, doi = {10.1016/s0891-5849(01)00611-6}, pmid = {11498280}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Activating Transcription Factor 2 ; Apoptosis/*drug effects ; Catalase/metabolism ; Cell Cycle/drug effects ; Chelating Agents/pharmacology ; Cyclic AMP Response Element-Binding Protein/metabolism ; Ditiocarb/pharmacology ; Enzyme Activation/drug effects ; Flow Cytometry ; Free Radical Scavengers/pharmacology ; Glutathione Transferase/chemistry ; Humans ; JNK Mitogen-Activated Protein Kinases ; Jurkat Cells/drug effects/metabolism ; *MAP Kinase Kinase 4 ; MAP Kinase Kinase Kinase 5 ; MAP Kinase Kinase Kinases/*metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Oxidation-Reduction ; Plasmids ; Pyruvaldehyde/*pharmacology ; Reactive Oxygen Species ; Signal Transduction ; Superoxide Dismutase/metabolism ; Superoxides/*metabolism ; Transcription Factors/metabolism ; Transfection ; }, abstract = {Methylglyoxal (MG) is a physiological metabolite, but it is known to be toxic, inducing stress and causing apoptosis. Our previous studies demonstrated that MG induced apoptosis in Jurkat cells by activating the c-Jun N-terminal kinase (JNK) signal transduction pathway, which induced an obvious decrease in mitochondrial membrane potential, followed by caspase-3 activation. Here, we observed that MG-induced apoptosis was associated with both rapid production of superoxide anion (O(2)(-)) followed by a marked increase in ROS and striking and temporal activation of ASK1. Overexpression of wild-type ASK1 could enhance the rate of apoptosis induced by MG, whereas the expression of the kinase-inactive form of ASK1 notably prevented cells from MG-induced death. NAC and PDTC blocked the activation of ASK1 and MG-induced apoptosis completely. Moreover, nonthiol antioxidants SOD-mimic MnTBAP and catalase together obviously inhibited MG-induced ASK1 activation and apoptosis induction. Correspondingly, MG-mediated ASK1 activation was enhanced by diethyldithiocarbamate (DDC). Addition of antioxidant into the culture of cells at a later stage (4-8 h after the initial MG treatment) failed to prevent their death. These results suggest that activating ASK1 at the early stage linking to production of O(2)(-) is crucial for subsequent progression of apoptosis in MG-treated Jurkat cells.}, }
@article {pmid11494135, year = {2001}, author = {Matroule, JY and Carthy, CM and Granville, DJ and Jolois, O and Hunt, DW and Piette, J}, title = {Mechanism of colon cancer cell apoptosis mediated by pyropheophorbide-a methylester photosensitization.}, journal = {Oncogene}, volume = {20}, number = {30}, pages = {4070-4084}, doi = {10.1038/sj.onc.1204546}, pmid = {11494135}, issn = {0950-9232}, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma/*pathology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Caspase 3 ; Caspases/metabolism ; Ceramides/physiology ; Chloroquine/pharmacology ; Colonic Neoplasms/*pathology ; Cytochrome c Group/metabolism ; Deuterium Oxide/pharmacology ; Endoplasmic Reticulum/metabolism ; Gene Expression Regulation, Neoplastic/drug effects/radiation effects ; Golgi Apparatus/metabolism ; Humans ; Lysosomes/metabolism ; Mannans/*pharmacology ; Mannosephosphates/*pharmacology ; Microscopy, Fluorescence ; Mitochondria/physiology ; NF-kappa B/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Oxygen/metabolism ; Phosphorylation ; Photochemistry ; Photosensitizing Agents/*pharmacology ; Proline/analogs &amp; derivatives/pharmacology ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Radiation Tolerance ; Radiation-Protective Agents/pharmacology ; Reactive Oxygen Species ; Second Messenger Systems ; Singlet Oxygen ; Thiocarbamates/pharmacology ; Tumor Cells, Cultured ; }, abstract = {Pyropheophorbide-a methylester (PPME) is a second generation of photosensitizers used in photodynamic therapy (PDT). We demonstrated that PPME photosensitization triggered apoptosis of colon cancer cells as measured by using several classical parameters such as DNA laddering, PARP cleavage, caspase activation and mitochondrial release of cytochrome c. Preincubation of cells with N-acetyl cysteine (NAC) or pyrolidine dithiocarbamate (PDTC) protected against apoptosis mediated by PPME photosensitization showing that reactive oxygen species (ROS) are involved as second messengers. On the other hand, photosensitization carried out in the presence of deuterium oxide (D2O) which enhances singlet oxygen (1O2) lifetime only increases necrosis without affecting apoptosis. Since PPME was localized in the endoplasmic reticulum (ER)/Golgi system and lysosomes, other messengers than ROS were tested such as calcium, Bid, Bap31, phosphorylated Bcl-2 and caspase-12 but none was clearly identified as being involved in triggering cytochrome c release from mitochondria. On the other hand, we demonstrated that the transduction pathways leading to NF-kappaB activation and apoptosis were clearly independent although NF-kappaB was shown to counteract apoptosis mediated by PPME photosensitization.}, }
@article {pmid11493938, year = {2001}, author = {Bailey, B and Lalkin, A and Kapur, BM and Koren, G}, title = {Is chronic poisoning with acetaminophen in children a frequent occurrence in Toronto?.}, journal = {The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique}, volume = {8}, number = {2}, pages = {96-101}, pmid = {11493938}, issn = {1198-581X}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Adolescent ; Analgesics, Non-Narcotic/*poisoning ; Child, Preschool ; Chronic Disease ; Free Radical Scavengers/therapeutic use ; Humans ; Ontario/epidemiology ; Retrospective Studies ; Treatment Outcome ; Urban Population ; }, abstract = {BACKGROUND: Acetaminophen is a common cause of poisoning in children. Recent American studies suggest that acetaminophen poisonings pose serious risks in children, particularly in the case of chronic poisoning caused by therapeutic error.<br><br>OBJECTIVE: To evaluate whether chronic acetaminophen poisoning in children is a frequent occurrence in a large, Canadian, urban population.<br><br>PATIENTS AND METHODS: Retrospective study. Charts of all patients admitted to The Hospital for Sick Children, Toronto, Ontario from January 1, 1990 to June 31, 1996 with an acetaminophen overdose were reviewed.<br><br>RESULTS: A total of 110 patients were admitted within the study period; only four of whom were preschool children (younger than five years of age). Among the preschool children, three had an acute overdose and one had possible chronic poisoning by therapeutic error. All preschool children were treated with N-acetylcysteine; one developed hepatotoxicity (aspartate aminotransferase or alanine aminotransferase greater than 1000 U/L) after presenting 24 h after acute ingestion. Of the remaining patients, all were adolescents; 102 had acute intentional overdose and four had staggered intentional overdoses. Fifty-three adolescents were treated with N-acetyl cysteine. Hepatotoxicity was present in 13 of 63 adolescents (21%). No patients required liver transplantation or died.<br><br>CONCLUSIONS: Contrary to American experience, chronic acetaminophen poisoning, including therapeutic error in children in Toronto, is a rare occurrence--most cases of acetaminophen poisonings are acute intentional ingestion in adolescents.}, }
@article {pmid11491169, year = {2001}, author = {Cortijo, J and Cerdá-Nicolás, M and Serrano, A and Bioque, G and Estrela, JM and Santangelo, F and Esteras, A and Llombart-Bosch, A and Morcillo, EJ}, title = {Attenuation by oral N-acetylcysteine of bleomycin-induced lung injury in rats.}, journal = {The European respiratory journal}, volume = {17}, number = {6}, pages = {1228-1235}, doi = {10.1183/09031936.01.00049701}, pmid = {11491169}, issn = {0903-1936}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Bleomycin/*toxicity ; Bronchoalveolar Lavage Fluid/chemistry ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Lung/drug effects/pathology ; Male ; Pulmonary Fibrosis/*chemically induced/pathology ; Rats ; Rats, Sprague-Dawley ; Taurine/metabolism ; }, abstract = {Antioxidant therapy may be useful in diseases with impaired oxidant-antioxidant balance such as pulmonary fibrosis. This study examines the effect of N-acetylcysteine (NAC) on bleomycin-induced lung fibrosis in rats. NAC (3 mmol x kg(-1); oral) was given daily from 1 week prior to a single intratracheal instillation of bleomycin (2.5 U x kg(-1)) or saline, until 14 days postinstillation. NAC partially decreased the augmented collagen deposition in bleomycin-exposed rats (hydroxyproline content was 4,354+/-386 and 3,416+/-326 microg x lung(-1) in vehicle-treated and NAC-treated rats, respectively; p < 0.05). The histological assessment using a semiquantitative score showed less collagen deposition and inflammatory cells in NAC-treated rats compared to those receiving bleomycin alone. NAC failed to inhibit the bleomycin-induced increases in lung wet weight and in cell counts and protein levels of bronchoalveolar lavage fluid, but significantly increased total glutathione and taurine levels in bronchoalveolar lavage fluid. These results indicate that oral N-acetylcysteine improves the pulmonary antioxidant protection and may be useful in reducing lung damage produced by bleomycin.}, }
@article {pmid11488539, year = {2001}, author = {Xu, J and Chen, S and Ku, G and Ahmed, SH and Xu, J and Chen, H and Hsu, CY}, title = {Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {21}, number = {6}, pages = {702-710}, doi = {10.1097/00004647-200106000-00008}, pmid = {11488539}, issn = {0271-678X}, support = {NS25545/NS/NINDS NIH HHS/United States ; NS28995/NS/NINDS NIH HHS/United States ; NS40525/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Amyloid beta-Peptides/*pharmacology ; Animals ; Brain/*blood supply ; Caspase 3 ; Caspase Inhibitors ; Caspases/*metabolism ; Cattle ; Cell Death/*drug effects ; Cell Line ; Cells, Cultured ; Cysteine Proteinase Inhibitors/pharmacology ; DNA Fragmentation ; DNA, Mitochondrial/analysis ; Endothelium, Vascular/enzymology/*ultrastructure ; Enzyme Activation ; Enzyme-Linked Immunosorbent Assay ; In Situ Nick-End Labeling ; Mice ; Mitochondria/*physiology ; }, abstract = {Amyloid beta peptide (A beta), a 39 to 43 amino acid fragment of the beta-amyloid precursor protein (betaAPP), forms insoluble fibrillar accumulation in neurofibrillary tangles and vascular plaques. A beta has been implicated in neuronal and vascular degeneration in brain regions susceptible to plaque formation because of its cytotoxic effect on neurons and endothelial cells (ECs). The authors used a murine cerebral endothelial cell (CEC) line and primary cultures of bovine CECs to explore the cytotoxic mechanism of A beta. A beta 1-40 and A beta 25-35 peptides caused cell death in a dose-dependent and time-dependent manner. Exposure to either A beta 25-35 or A beta 1-40 at 10 micromol/L for 48 hours caused at least 40% cell death. Cerebral endothelial cell death was characterized by nuclear condensation, mitochondrial dysfunction, and nuclear and mitochondrial DNA damage. A beta 25-35 activated both caspase-8 and caspase-3 in murine CECs. zVAD-fmk, a broad-spectrum caspase inhibitor, prevented A beta 25-35-induced increase in caspase-3 activity and CEC death. N-acetyl-cysteine, an antioxidant, also prevented A beta-induced cell death. Together, these findings indicate that A beta-mediated CEC death is an apoptotic process that is characterized by increased oxidative stress, caspase activation, mitochondrial dysfunction, and nuclear and mitochondrial DNA damage.}, }
@article {pmid11485373, year = {2001}, author = {Bergamini, S and Rota, C and Canali, R and Staffieri, M and Daneri, F and Bini, A and Giovannini, F and Tomasi, A and Iannone, A}, title = {N-acetylcysteine inhibits in vivo nitric oxide production by inducible nitric oxide synthase.}, journal = {Nitric oxide : biology and chemistry}, volume = {5}, number = {4}, pages = {349-360}, doi = {10.1006/niox.2001.0356}, pmid = {11485373}, issn = {1089-8603}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Citrulline/blood ; Electron Spin Resonance Spectroscopy ; Hemoglobins/*drug effects/metabolism ; Iron-Sulfur Proteins/drug effects/metabolism ; Lipopolysaccharides/*pharmacology ; Male ; Models, Animal ; Nitric Oxide/*antagonists &amp; inhibitors/biosynthesis ; Nitric Oxide Synthase/*antagonists &amp; inhibitors/genetics/metabolism ; Nitric Oxide Synthase Type II ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Urea/blood ; }, abstract = {This in vivo study evaluates the effect of N-acetylcysteine (NAC) administration on nitric oxide (NO) production by the inducible form of nitric oxide synthase (iNOS). NO production was induced in the rat by the ip administration of 2 mg/100 g lipopolysaccharide (LPS). This treatment caused: (1) a decrease in body temperature within 90 min, followed by a slow return to normal levels; (2) an increase in plasma levels of urea, nitrite/nitrate, and citrulline; (3) the appearance in blood of nitrosyl-hemoglobin (NO-Hb) and in liver of dinitrosyl-iron-dithiolate complexes (DNIC); and (4) increased expression of iNOS mRNA in peripheral blood mononuclear cells (PBMC). Rat treatment with 15 mg/100 g NAC ip, 30 min before LPS, resulted in a significant decrease in blood NO-Hb levels, plasma nitrite/nitrate and citrulline concentrations, and liver DNIC complexes. PBMC also showed a decreased expression of iNOS mRNA. NAC pretreatment did not modify the increased levels of plasma urea or the hypothermic effect induced by the endotoxin. The administration of NAC following LPS intoxication (15 min prior to sacrifice) did not affect NO-Hb levels. These results demonstrate that NAC administration can modulate the massive NO production induced by LPS. This can be attributed mostly to the inhibitory effect of NAC on one of the events leading to iNOS protein expression. This hypothesis is also supported by the lack of effect of late NAC administration.}, }
@article {pmid11481617, year = {2001}, author = {Higuchi, H and Adachi, M and Miura, S and Gores, GJ and Ishii, H}, title = {The mitochondrial permeability transition contributes to acute ethanol-induced apoptosis in rat hepatocytes.}, journal = {Hepatology (Baltimore, Md.)}, volume = {34}, number = {2}, pages = {320-328}, doi = {10.1053/jhep.2001.26380}, pmid = {11481617}, issn = {0270-9139}, mesh = {Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Caspase 3 ; Caspase 9 ; Caspases/chemistry/drug effects/metabolism/physiology ; Cells, Cultured ; Cyclosporine/pharmacology ; Cytochrome c Group/antagonists &amp; inhibitors ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Ethanol/*poisoning ; Hepatocytes/*drug effects/*physiology ; Male ; Mitochondria, Liver/*drug effects/*metabolism ; Permeability ; Rats ; Rats, Wistar ; Time Factors ; }, abstract = {Acute ethanol intoxication induces oxidative stress and apoptosis in primary cultured hepatocytes. Oxidative stress can trigger mitochondrial cytochrome c release initiating the mitochondrial pathway of apoptosis. Based on this information, we formulated the hypothesis that ethanol induced oxidative stress causes mitochondrial dysfunction resulting in apoptosis. In the present study, we found that the mitochondrial membrane permeability transition (MPT) is essential for induction of mitochondrial cytochrome c release and caspase activation of ethanol. The short-term incubation with ethanol (50 mmol/L) induced the MPT, cytochrome c release, caspase activation, and apoptosis of cultured rat hepatocytes. Hepatocyte apoptosis was prevented by caspase inhibitors (i.e., Z-VAD-fmk, DEVD-cho, and DMQD-cho). An MPT inhibitor, cyclosporin A, also prevented ethanol-induced cytochrome c release, caspase activation, and apoptosis, suggesting that acute ethanol-induced apoptosis is MPT dependent. Ethanol-induced MPT was also attenuated by N'N'-dimethylthiourea (DMTU, a scavenger of hydrogen peroxide, 10 mmol/L) and N-acetyl-cysteine (NAC, an antioxidant, 5 mmol/L). Preventing hepatocyte MPT by DMTU or NAC attenuated cytochrome c release as well as caspase activation, suggesting that ethanol-induced oxidative stress mediates the MPT. Thus, acute ethanol induces MPT via oxidative stress, and the MPT mediates mitochondrial pathway of apoptosis in hepatocytes exposed to acute ethanol.}, }
@article {pmid11481452, year = {2001}, author = {Gong, G and Waris, G and Tanveer, R and Siddiqui, A}, title = {Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {98}, number = {17}, pages = {9599-9604}, pmid = {11481452}, issn = {0027-8424}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Calcium/*metabolism ; *Calcium Signaling/drug effects ; Carcinoma, Hepatocellular/pathology ; Chelating Agents/pharmacology ; DNA-Binding Proteins/*metabolism ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Gallic Acid/analogs &amp; derivatives/pharmacology ; Gene Expression Regulation, Neoplastic ; Gene Expression Regulation, Viral/drug effects/*physiology ; Genes, Reporter ; Hepacivirus/genetics/*metabolism ; Humans ; Liver Neoplasms/pathology ; Luciferases/biosynthesis/genetics ; NF-kappa B/*metabolism ; Neoplasm Proteins/metabolism ; *Oxidative Stress/drug effects ; Pyrrolidines/pharmacology ; Reactive Oxygen Species ; Recombinant Fusion Proteins/biosynthesis/genetics ; STAT3 Transcription Factor ; Thiocarbamates/pharmacology ; Trans-Activators/*metabolism ; Transcription, Genetic/drug effects ; Transfection ; Tumor Cells, Cultured ; Viral Nonstructural Proteins/*physiology ; }, abstract = {The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus RNA genome is shown here to induce the activation of NF-kappaB and STAT-3 transcription factors from its cytoplasmic residence via oxidative stress. NS5A causes the disturbance of intracellular calcium. Ca2+ signaling triggers the elevation of reactive oxygen species in mitochondria, leading to the translocation of NF-kappaB and STAT-3 into the nucleus. Evidence is presented for the constitutive activation of STAT-3 by NS5A. In the presence of antioxidants [pyrrolidine dithiocarbamate (PDTC), N-acetyl l-cysteine (NAC)] or Ca2+ chelators (EGTA-AM, TMB-8), NS5A-induced activation of NF-kappaB and STAT-3 was eliminated. These results provide an insight into the mechanism by which NS5A can alter intracellular events relevant to liver pathogenesis associated with the viral infection.}, }
@article {pmid11477374, year = {2001}, author = {Hatton, MW and Day, S and Southward, SM and Dereske, M and Ross, B and Seidlitz, E and Singh, G and Richardson, M}, title = {Metabolism of rabbit angiostatin glycoforms I and II in rabbits: angiostatin-I leaves the intravascular space faster and appears to have greater anti-angiogenic activity than angiostatin-II.}, journal = {The Journal of laboratory and clinical medicine}, volume = {138}, number = {2}, pages = {83-93}, doi = {10.1067/mlc.2001.116679}, pmid = {11477374}, issn = {0022-2143}, mesh = {Angiostatins ; Animals ; Capillaries/metabolism ; Chick Embryo ; Endothelium, Vascular/metabolism ; Iodine Radioisotopes ; Isomerism ; Neovascularization, Physiologic/*drug effects ; Peptide Fragments/chemistry/isolation &amp; purification/*pharmacokinetics ; Plasminogen/chemistry/isolation &amp; purification/*pharmacokinetics ; Rabbits ; Species Specificity ; Tarsal Joints/metabolism ; }, abstract = {Plasminogen (PLG) exists in the circulation as two glycoforms, I and II. Angiostatin (AST) is a polypeptide that has been cleaved from the kringle region of PLG and has strong anti-angiogenic properties. AST-I and AST-II, which consisted only of kringles 1 through 3, were prepared by the action of urokinase on purified rabbit PLG-I and PLG-II, respectively, in the presence of N-acetyl cysteine, followed by affinity chromatography on lysine-Sepharose. Purified AST-I and AST-II were tested for functional activity with a chick chorioallantoic membrane (CAM) model; when similar amounts were applied to a 6-day CAM, AST-I was substantially more effective than AST-II in decreasing vascular supply to the CAM over a 72-hour period; this activity correlated with a loss of capillaries, probably through apoptosis of endothelial cells. Radiolabeled AST-I and AST-II (iodine 125 and iodine 131) were co-injected intravenously into healthy rabbits to determine their clearances from plasma measured over 3 days. Over a dose range of 0.08 to 2.7 microg/kg, the fractional catabolic rate within the intravascular space (j(3)) indicated that AST-I was cleared 3-fold to 4-fold more rapidly than AST-II (P < .001). The catabolic half-life of AST-I (2.01 +/- 0.19 days) was significantly less than that of AST-II (2.62 +/- 0.20 days). The faster clearance of AST-I from the intravascular space was matched by its more rapid passage than AST-II to the extravascular space of various organs over 60 minutes in vivo. This property of AST-I as compared with AST-II may partially explain its greater anti-angiogenic potential. From the plasma concentrations of PLG-I and PLG-II and their relative behaviors toward rabbit VX-2 lung tumors in vivo, we predict that substantially greater quantities of AST-II than AST-I may be released into the extravascular space of tumors.}, }
@article {pmid11477100, year = {2001}, author = {Li, L and Tao, J and Davaille, J and Feral, C and Mallat, A and Rieusset, J and Vidal, H and Lotersztajn, S}, title = {15-deoxy-Delta 12,14-prostaglandin J2 induces apoptosis of human hepatic myofibroblasts. A pathway involving oxidative stress independently of peroxisome-proliferator-activated receptors.}, journal = {The Journal of biological chemistry}, volume = {276}, number = {41}, pages = {38152-38158}, doi = {10.1074/jbc.M101980200}, pmid = {11477100}, issn = {0021-9258}, mesh = {Apoptosis/*physiology ; Fibroblasts/cytology ; GTP-Binding Proteins/metabolism ; Humans ; Immunohistochemistry ; Liver/*cytology ; *Oxidative Stress ; Prostaglandin D2/*analogs &amp; derivatives/*physiology ; Reactive Oxygen Species ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/*metabolism ; }, abstract = {Hepatic myofibroblasts (hMFs) play a key role in the development of liver fibrosis associated with chronic liver diseases. Apoptosis of these cells is emerging as a key process in the resolution of liver fibrosis. Here, we examined the effects of cyclopentenone prostaglandins on apoptosis of human hMFs. Cyclopentenone prostaglandins of the J series markedly reduced hMF viability, with 15-deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) being the most potent. This effect was independent of peroxisome-proliferator-activated receptors (PPARs), because PPARgamma and PPARalpha agonists did not affect hMF cell viability, and PPARgamma, the nuclear receptor for 15-d-PGJ2, was not expressed in hMFs. Moreover, 15-d-PGJ2 did not act via a cell surface G protein-coupled receptor, as shown in guanosine-5'-O-(3-thiotriphosphate) binding assays. Cell death resulted from an apoptotic process, because 15-d-PGJ2-treated hMFs exhibited condensed nuclei, fragmented DNA, and elevated caspase-3 activity. Moreover, the caspase inhibitor Z-Val-Ala-Asp(OCH3)-fluoromethyl ketone blocked the cytotoxic effect of 15-d-PGJ2. The apoptotic effects of 15-d-PGJ2 were reproduced by H2O2 and blocked by the antioxidants N-acetylcysteine (NAC), N-(2-mercapto-propionyl)-glycine (NMPG) and pyrrolidine dithiocarbamate (PDTC). Accordingly, 15-d-PGJ2 generated rapid production of reactive oxygen species in hMFs, via a NAC/NMPG/PDTC-sensitive pathway. In conclusion, 15-d-PGJ2 induces apoptosis of human hMFs via a novel mechanism involving oxidative stress and unrelated to activation of its nuclear receptor PPARgamma. These data underline the antifibrogenic potential of 15-d-PGJ2.}, }
@article {pmid11473058, year = {2001}, author = {Kowluru, RA and Tang, J and Kern, TS}, title = {Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy.}, journal = {Diabetes}, volume = {50}, number = {8}, pages = {1938-1942}, doi = {10.2337/diabetes.50.8.1938}, pmid = {11473058}, issn = {0012-1797}, support = {EY00300/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Chromans/pharmacology ; Diabetes Mellitus, Experimental/*metabolism/*physiopathology ; Diabetic Retinopathy/physiopathology/*prevention &amp; control ; Diet ; Dietary Supplements ; Galactosemias/*metabolism/physiopathology ; Male ; Pericytes/drug effects ; Rats ; Rats, Sprague-Dawley ; Retina/drug effects/*metabolism ; Retinal Diseases/etiology/*prevention &amp; control ; Selenium/pharmacology ; Vitamin E/pharmacology ; beta Carotene/pharmacology ; }, abstract = {Antioxidants were administered to diabetic rats and experimentally galactosemic rats to evaluate the ability of these agents to inhibit the development of diabetic retinopathy. Alloxan diabetic rats and nondiabetic rats that were fed 30% galactose randomly received standard diets or the diets supplemented with ascorbic acid and alpha-tocopherol (vitamins C+E diet) or a more comprehensive mixture of antioxidants (multi-antioxidant diet), including Trolox, alpha-tocopherol, N-acetyl cysteine, ascorbic acid, beta-carotene, and selenium. Diabetes or galactose feeding of at least 12 months resulted in pericyte loss, acellular capillaries, and basement membrane thickening. Compared with diabetic controls, the development of acellular capillaries was inhibited by 50% (P < 0.05) in diabetic rats that received supplemental vitamins C+E, and the number of pericyte ghosts tended to be reduced. The vitamins C+E supplement had no beneficial effect in galactosemic rats, but these rats consumed only approximately half as much of the antioxidants as the diabetic rats. The multi-antioxidant diet significantly inhibited (approximately 55-65%) formation of both pericyte ghosts and acellular capillaries in diabetic rats and galactosemic rats (P < 0.05 vs. controls), without affecting the severity of hyperglycemia. Parameters of retinal oxidative stress, protein kinase C activity, and nitric oxides remained elevated for at least 1 year of hyperglycemia, and these abnormalities were normalized by multi-antioxidant therapy. Thus, long-term administration of antioxidants can inhibit the development of the early stages of diabetic retinopathy, and the mechanism by which this action occurs warrants further investigation. Supplementation with antioxidants can offer an achievable and inexpensive adjunct therapy to help inhibit the development of retinopathy in diabetes.}, }
@article {pmid11472606, year = {2001}, author = {Bucuvalas, JC and Ryckman, FC and Krug, S and Alonso, MH and Balistreri, WF and Kotagal, U}, title = {Effect of treatment with prostaglandin E1 and N-acetylcysteine on pediatric liver transplant recipients: a single-center study.}, journal = {Pediatric transplantation}, volume = {5}, number = {4}, pages = {274-278}, doi = {10.1034/j.1399-3046.2001.005004274.x}, pmid = {11472606}, issn = {1397-3142}, mesh = {Acetylcysteine/*therapeutic use ; Alprostadil/*therapeutic use ; Chi-Square Distribution ; Drug Therapy, Combination ; Free Radical Scavengers/*therapeutic use ; Graft Rejection/prevention &amp; control ; Graft Survival/drug effects ; Humans ; Liver Transplantation/*physiology ; Pilot Projects ; Postoperative Complications/*prevention &amp; control ; Statistics, Nonparametric ; Treatment Outcome ; Vasodilator Agents/*therapeutic use ; }, abstract = {Prostaglandin E1 (PGE1) and N-acetylcysteine (NAC) have been used as single agents to decrease reperfusion injury and improve outcome after solid-organ transplantation (Tx). We hypothesized that combined treatment with NAC and PGE1 would be safe and reduce reperfusion injury. We therefore carried out a pilot study to assess the safety of this drug combination and gain information regarding the efficacy of treating pediatric liver transplant recipients with NAC and PGE1. The pilot study took the form of an open-label study incorporating 25 pediatric liver transplant recipients (12 children in the treatment group and 13 children as controls). NAC (70 mg/kg) was given intravenously over 1 h following reperfusion and then every 12 h for 6 days. PGE1 (0.4 mg/kg/h) was given as a continuous intravenous infusion for 6 days, starting after the first NAC dose. The primary outcome was the safety of combined treatment with NAC and PGE1. Patient survival, graft survival, allograft rejection within the first 90 days after Tx, peak post-transplant serum alanine aminotransferase (ALT) concentration, post-transplant length of hospitalization, and post-operative complications were secondary outcomes. Post-operative complications occurred at similar rates in both control and treated groups. No complications or adverse events occurred in the treated group as a result of study drugs. The 3-month patient survival rate was 100% for both groups. For the group treated with NAC and PGE1, peak serum ALT was lower and median length of stay was shorter but the differences did not reach statistical significance. The proportion of patients with allograft rejection was not significantly different between the two groups. However, rejection was more severe in the control group than in the treated group. In summary, infusions of NAC and PGE1 were safely administered to pediatric liver transplant recipients. However, a randomized controlled study is needed to determine the efficacy of treatment with NAC and PGE1.}, }
@article {pmid11463798, year = {2001}, author = {Lu, B and Ennis, D and Lai, R and Bogdanovic, E and Nikolov, R and Salamon, L and Fantus, C and Le-Tien, H and Fantus, IG}, title = {Enhanced sensitivity of insulin-resistant adipocytes to vanadate is associated with oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4).}, journal = {The Journal of biological chemistry}, volume = {276}, number = {38}, pages = {35589-35598}, doi = {10.1074/jbc.M106783200}, pmid = {11463798}, issn = {0021-9258}, mesh = {Acetylcysteine/pharmacology ; Adipocytes/*drug effects/metabolism ; Animals ; Buthionine Sulfoximine/pharmacology ; Electron Spin Resonance Spectroscopy ; Glucose/metabolism ; Glutathione/metabolism ; *Insulin Resistance ; Male ; Oxidation-Reduction ; *Oxidative Stress ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 1 ; Protein Tyrosine Phosphatases/antagonists &amp; inhibitors ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Receptor, Insulin/metabolism ; Recombinant Proteins/antagonists &amp; inhibitors ; Vanadates/*metabolism/*pharmacology ; }, abstract = {Vanadate (sodium orthovanadate), an inhibitor of phosphotyrosine phosphatases (PTPs), mimics many of the metabolic actions of insulin in vitro and in vivo. The potential of vanadate to stimulate glucose transport independent of the early steps in insulin signaling prompted us to test its effectiveness in an in vitro model of insulin resistance. In primary rat adipocytes cultured for 18 h in the presence of high glucose (15 mm) and insulin (10(-7) m), sensitivity to insulin-stimulated glucose transport was decreased. In contrast, there was a paradoxical enhanced sensitivity to vanadate of the insulin-resistant cells (EC(50) for control, 325 +/- 7.5 microm; EC(50) for insulin-resistant, 171 +/- 32 microm; p < 0.002). Enhanced sensitivity was also present for vanadate stimulation of insulin receptor kinase activity and autophosphorylation and Akt/protein kinase B Ser-473 phosphorylation consistent with more effective PTP inhibition in the resistant cells. Investigation of this phenomenon revealed that 1) depletion of GSH with buthionine sulfoximine reproduced the enhanced sensitivity to vanadate while preincubation of resistant cells with N-acetylcysteine (NAC) prevented it, 2) intracellular GSH was decreased in resistant cells and normalized by NAC, 3) exposure to high glucose and insulin induced an increase in reactive oxygen species, which was prevented by NAC, 4) EPR (electron paramagnetic resonance) spectroscopy showed a decreased amount of vanadyl (+4) in resistant and buthionine sulfoximine-treated cells, which correlated with decreased GSH and increased vanadate sensitivity, while total vanadium uptake was not altered, and 5) inhibition of recombinant PTP1B in vitro was more sensitive to vanadate (+5) than vanadyl (+4). In conclusion, the paradoxical increased sensitivity to vanadate in hyperglycemia-induced insulin resistant adipocytes is due to oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4). Thus, sensitivity of PTP inhibition and glucose transport to vanadate is regulated by cellular redox state.}, }
@article {pmid11461973, year = {2001}, author = {Junn, E and Mouradian, MM}, title = {Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases.}, journal = {Journal of neurochemistry}, volume = {78}, number = {2}, pages = {374-383}, doi = {10.1046/j.1471-4159.2001.00425.x}, pmid = {11461973}, issn = {0022-3042}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Apoptosis/drug effects/*physiology ; Biological Transport ; Caspase 3 ; Caspase 9 ; Caspases/*metabolism ; Cell Death/drug effects/physiology ; Cysteine Proteinase Inhibitors/pharmacology ; Cytochrome c Group/*metabolism ; Dopamine/metabolism/*pharmacology ; Humans ; Kinetics ; Mitogen-Activated Protein Kinases/*metabolism ; Neuroblastoma ; Nomifensine/pharmacology ; Oxidative Stress/*physiology ; Signal Transduction/drug effects/physiology ; Tumor Cells, Cultured ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Oxidative stress generated by dopamine (DA) oxidation could be one of the factors underlying the selective vulnerability of nigral dopaminergic neurons in Parkinson's diseases. Here we show that DA induces apoptosis in SH-SY5Y neuroblastoma cells demonstrated by activation of caspase-9 and caspase-3, cleavage of poly(ADP-ribose) polymerase as well as nuclear condensation. We also show that p38 mitogen-activated protein kinase is activated within 10 min of DA treatment, which precedes the onset of apoptosis because the potent p38 kinase inhibitor SB203580 protects against DA-induced cell death as well as against caspase-9 and caspase-3 activation. In addition, the antioxidant N-acetyl-L-cysteine (NAC) effectively blocks DA-induced p38 kinase activation, caspase-9 and caspase-3 cleavage and subsequent apoptosis, indicating that DA triggers apoptosis via a signaling pathway that is initiated by the generation of reactive oxygen species (ROS). Dopamine exerts its toxicity principally intracellularly as the DA uptake inhibitor, nomifensine significantly reduces DA-induced cell death as well as activation of p38 kinase and caspase-3. Furthermore, DA induces mitochondrial cytochrome c release, which is dependent on p38 kinase activation and precedes the cleavage of caspases. These observations indicate that DA induces apoptosis primarily by generating ROS, p38 kinase activation, cytochrome c release followed by caspase-9 and caspase-3 activation.}, }
@article {pmid11461774, year = {2001}, author = {Anuradha, CD and Kanno, S and Hirano, S}, title = {Oxidative damage to mitochondria is a preliminary step to caspase-3 activation in fluoride-induced apoptosis in HL-60 cells.}, journal = {Free radical biology &amp; medicine}, volume = {31}, number = {3}, pages = {367-373}, doi = {10.1016/s0891-5849(01)00591-3}, pmid = {11461774}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/metabolism ; Amino Acid Chloromethyl Ketones/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Caspase 3 ; Caspases/*metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; Glutathione/pharmacology ; HL-60 Cells ; Humans ; Lipid Peroxidation/drug effects/*physiology ; Lipid Peroxides/metabolism ; Malondialdehyde/metabolism ; Mitochondria/drug effects/*physiology ; Oxidative Stress/drug effects/*physiology ; Sodium Fluoride/*pharmacology ; }, abstract = {It has been suggested that oxidative stress plays a major role in various forms of cell death, including necrosis and apoptosis. We have previously reported that fluoride (NaF) induces apoptosis in HL-60 cells by caspase-3 activation. The main focus of this investigation was to arrive at a possible pathway of the apoptosis induced by NaF upstream of caspase-3, because the mechanism is still unknown. The present study showed that after exposure to NaF, there was an increase in MDA and 4-HNE and a loss of mitochondrial membrane potential (deltaPsi(m)) was also observed in NaF-treated cells. There was a significant increase in cytosolic cytochrome c, which is released from the mitochondria. We have reported a downregulation of Bcl-2 protein in NaF-treated cells. The antioxidants N-acetyl cysteine (NAC), glutathione (GSH) protected the cells from loss of deltaPsi(m), and there was no cytochrome c exit or Bcl-2 downregulation, and we suggest that these antioxidants prevent apoptosis induced by NaF. These results suggested that perhaps NaF induced apoptosis by oxidative stress-induced lipid peroxidation, causing loss of deltaPsi(m), and thereby releasing cytochrome c into the cytosol and further triggering the caspase cascade leading to apoptotic cell death in HL-60 cells.}, }
@article {pmid11461766, year = {2001}, author = {Peshenko, IV and Shichi, H}, title = {Oxidation of active center cysteine of bovine 1-Cys peroxiredoxin to the cysteine sulfenic acid form by peroxide and peroxynitrite.}, journal = {Free radical biology &amp; medicine}, volume = {31}, number = {3}, pages = {292-303}, doi = {10.1016/s0891-5849(01)00579-2}, pmid = {11461766}, issn = {0891-5849}, support = {EY04694/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Binding Sites ; Cattle ; Cysteine/analogs &amp; derivatives/*chemistry ; Hydrogen Peroxide/*chemistry ; Kinetics ; Nitrates/*chemistry ; Oxidants/*chemistry ; Oxidation-Reduction ; Peroxidases/*chemistry/metabolism ; Peroxiredoxins ; Recombinant Proteins/chemistry ; Spectrophotometry ; Sulfenic Acids/*chemistry ; tert-Butylhydroperoxide/chemistry ; }, abstract = {Peroxiredoxins are antioxidant enzymes whose peroxidase activity depends on a redox-sensitive cysteine residue at the active center. In this study we investigated properties of the active center cysteine of bovine 1-Cys peroxiredoxin using a recombinant protein (BRPrx). The only cysteine residue of the BRPrx molecule was oxidized rapidly by an equimolar peroxide or peroxynitrite to the cysteine sulfenic acid. Approximate rates of oxidation of BRPrx by different peroxides were estimated using selenium glutathione peroxidase as a competitor. Oxidation of the active center cysteine of BRPrx by H2O2 proceeded only several times slowly than that of the selenocysteine of glutathione peroxidase. The rate of oxidation varied depending on peroxides tested, with H2O2 being about 7 and 80 times faster than tert-butyl hydroperoxide and cumene hydroperoxide, respectively. Peroxynitrite oxidized BRPrx slower than H2O2 but faster than tert-butyl hydroperoxide. Further oxidation of the cysteine sulfenic acid of BRPrx to higher oxidation states proceeded slowly. Oxidized BRPrx was reduced by dithiothreitol, dihydrolipoic acid, and hydrogen sulfide, and demonstrated peroxidase activity (about 30 nmol/mg/min) with these reductants as electron donors. beta-Mercaptoethanol formed a mixed disulfide and did not support peroxidase activity. Oxidized BRPrx did not react with glutathione, cysteine, homocysteine, N-acetyl-cysteine, and mercaptosuccinic acid.}, }
@article {pmid11456129, year = {2001}, author = {Isuzugawa, K and Inoue, M and Ogihara, Y}, title = {Ca2+-Dependent caspase activation by gallic acid derivatives.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {24}, number = {7}, pages = {844-847}, doi = {10.1248/bpb.24.844}, pmid = {11456129}, issn = {0918-6158}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/drug effects ; Blotting, Western ; Calcium/*physiology ; Caspase Inhibitors ; Caspases/*metabolism ; Catalase/chemistry ; Dioxoles/*pharmacology ; Enzyme Activators/*pharmacology ; Enzyme Inhibitors/pharmacology ; Gallic Acid/*analogs &amp; derivatives/*pharmacology ; HL-60 Cells ; Humans ; Hydrogen Peroxide/chemistry ; Poly(ADP-ribose) Polymerases/metabolism ; }, abstract = {Gallic acid (GA) derivatives, 3,4-methylenedioxyphenyl 3,4,5-trihydroxybenzoate (GD-1) and S-(3,4-methylenedioxyphenyl)3,4,5-trihydroxythiobenzoate (GD-3), were previously reported to induce apoptosis in tumor cells with IC50s of 14.5 microm and 3.9 microm, respectively. To elucidate the mechanism by which these gallic acid derivatives (GDs) induce apoptosis, we studied whether GD-1 and GD-3 can activate caspases. When promyelocytic leukemia HL-60RG cells were treated with GD-1 and GD-3, poly(ADP-ribose)polymerase (PARP), a substrate of caspase-3, was cleaved into 85 kDa of degradative product with increasing incubation time. GA also activated PARP cleavage, which was inhibited by catalase, N-acetyl-L-cysteine (NAC), and intracellular Ca2+ chelator 1,2-bis(2-aminophenoxyethane)-N,N,N,N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), in addition to a caspase inhibitor, Z-VAD-FMK. Its inhibitory pattern was identical with that of hypoxanthine/xanthine oxidase. On the other hand, GD-1- and GD3-induced PARP cleavage was not suppressed by catalase or NAC, but by BAPTA-AM. This suggested that the GD-elicited signaling pathway is different from GA's. Taken together, GDs activated caspase-3 following intracellular Ca2+ elevation independent of reactive oxygen species. Thus, it became evident that the signaling pathway leading to apoptosis was regulated by GDs in a different manner from GA.}, }
@article {pmid11451199, year = {2001}, author = {Noda, S and Yoshimura, S and Sawada, M and Naganawa, T and Iwama, T and Nakashima, S and Sakai, N}, title = {Role of ceramide during cisplatin-induced apoptosis in C6 glioma cells.}, journal = {Journal of neuro-oncology}, volume = {52}, number = {1}, pages = {11-21}, pmid = {11451199}, issn = {0167-594X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Apoptosis/*physiology ; Caspase 3 ; Caspases/metabolism ; Ceramides/antagonists &amp; inhibitors/*physiology ; Cisplatin/*pharmacology ; Drug Synergism ; Endocannabinoids ; Endopeptidases/metabolism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Ethanolamines/pharmacology ; Glioma/*physiopathology/ultrastructure ; Glutathione/pharmacology ; Microscopy, Electron ; Oleic Acids ; Rats ; Tumor Cells, Cultured ; }, abstract = {Cisplatin is commonly used for the treatment of malignant brain tumors. However, the mechanisms of cell death by cisplatin are not fully understood. Therefore, the present study was designed to elucidate the apoptotic signaling pathway(s) activated by cisplatin in a C6 rat glioma cell line. C6 cells were treated with various concentrations of cisplatin (0.2-10 microg/ml) for 24-72 h. At 10 microg/ml cisplatin, over 90% of the cells became dead at 72 h. Apoptotic death was confirmed by condensation and fragmentation of nuclei, and DNA laddering. Even in cells treated with 1.5 microg/ml cisplatin, typical apoptotic cells were observed at 72 h. The intracellular level of ceramide, measured Escherichia coli diacylglycerol kinase markedly increased during 24-72 h after the addition of 10 microg/ml cisplatin. The activity of caspase-3(-like) proteases increased and reached a peak at 48 h. Inhibitors of caspases reduced the number of apoptotic cells. Pretreatment of C6 cells with glutathione or N-acetyl-cysteine, which are known to block the activation of neutral magnesium-dependent sphingomyelinase, inhibited ceramide formation, leading to suppression of both activation of caspase-3(-like) proteases and apoptosis by cisplatin. In contrast, pretreatment of the cells with N-oleoylethanolamine (OE), a ceramidase inhibitor, potentiated apoptosis induced by cisplatin. Furthermore, OE enhanced sensitivity of the cisplatin-resistant cells to cisplatin. These results suggest that ceramide is closely implicated in apoptosis of glioma cells by cisplatin through activation of caspase-3(-like) proteases.}, }
@article {pmid11448159, year = {2001}, author = {Gu, Y and Wu, RF and Xu, YC and Flores, SC and Terada, LS}, title = {HIV Tat activates c-Jun amino-terminal kinase through an oxidant-dependent mechanism.}, journal = {Virology}, volume = {286}, number = {1}, pages = {62-71}, doi = {10.1006/viro.2001.0998}, pmid = {11448159}, issn = {0042-6822}, support = {HL61897/HL/NHLBI NIH HHS/United States ; K14-HL03157/HL/NHLBI NIH HHS/United States ; R01 HL059785/HL/NHLBI NIH HHS/United States ; R29-52591//PHS HHS/United States ; R01-HL59785/HL/NHLBI NIH HHS/United States ; }, mesh = {Cell Line ; Enzyme Activation ; Gene Products, tat/*physiology ; HIV Infections/*virology ; HIV-1/*physiology ; Humans ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases/*physiology ; NADPH Oxidases/physiology ; Oxidation-Reduction ; Signal Transduction ; Virus Replication/physiology ; tat Gene Products, Human Immunodeficiency Virus ; }, abstract = {The HIV-1 accessory protein Tat has been found to exert profound effects on vascular cell behavior. Recently, Tat has been found to activate the c-Jun amino-terminal kinase (JNK1, SAPK) MAP kinase in lymphoid cells. We found that purified Tat rapidly activated JNK1 in human umbilical vein endothelial cells and ECV-304 cells, and coculture of ECV-304 cells with Tat-transfected HeLa cells resulted in persistent activation of JNK1. In addition, lower doses of Tat potentiated TNFalpha-induced JNK1 activation, although higher doses paradoxically diminished JNK1 activation by TNFalpha. Treatment of ECV-304 cells with Tat acutely increased intracellular oxidant levels, and Tat-induced oxidant activity was decreased by two structurally distinct NADPH oxidase inhibitors, diphenylene iodonium and apocynin. Both oxidase inhibitors and the thiol antioxidant N-acetyl cysteine decreased Tat-induced JNK1 activation in parallel with reduction in oxidant levels. Activation of JNK1 by Tat was also inhibited by cytochalasin B, suggesting that Tat signaling was dependent upon intact cytoskeletal function. Indeed, JNK1 activation by Tat was associated with actin microfilament rearrangement. We conclude that HIV Tat may cause acute and persistent activation of the JNK MAP kinase through activation of a specific oxidase.}, }
@article {pmid11446713, year = {2001}, author = {Cabassi, A and Dumont, EC and Girouard, H and Bouchard, JF and Le Jossec, M and Lamontagne, D and Besner, JG and de Champlain, J}, title = {Effects of chronic N-acetylcysteine treatment on the actions of peroxynitrite on aortic vascular reactivity in hypertensive rats.}, journal = {Journal of hypertension}, volume = {19}, number = {7}, pages = {1233-1244}, doi = {10.1097/00004872-200107000-00008}, pmid = {11446713}, issn = {0263-6352}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Aorta/drug effects/*physiopathology ; Drug Synergism ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Hypertension/*physiopathology ; In Vitro Techniques ; Isoproterenol/pharmacology ; Male ; Malondialdehyde/metabolism ; Nitrates/metabolism ; Nitroprusside/pharmacology ; Peroxynitrous Acid/*pharmacology ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Time Factors ; Tyrosine/metabolism ; Vasodilation ; Vasodilator Agents/pharmacology ; Vasomotor System/drug effects/*physiopathology ; }, abstract = {BACKGROUND: Peroxynitrite (ONOO-), the product of superoxide and nitric oxide, seems to be involved in vascular alterations in hypertension.<br><br>OBJECTIVES: To evaluate the effects of ONOO- on endothelium-dependent and independent aortic vascular responsiveness, oxidized/reduced glutathione balance (GSSG/GSH), malondialdehyde aortic content, and the formation of 3-nitrotyrosine (3-NT), a stable marker of ONOO-, in N-acetylcysteine (NAC)-treated normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).<br><br>RESULTS: In SHR only, NAC significantly reduced heart rate and systolic, but not diastolic, blood pressure. It also improved endothelium-dependent aortic relaxation in SHR, but not after exposure to ONOO-. Endothelium-dependent and independent aortic relaxations were markedly impaired by ONOO- in both strains of rat. NAC partially protected SHR against the ONOO- -induced reduction in endothelium-independent relaxation. Aortic GSSG/GSH ratio and malondialdehyde, which were higher in SHR than in WKY rats, showed a greater increase in SHR after exposure to ONOO-. NAC decreased GSSG/GSH and malondialdehyde in both strains of rat before and after exposure to ONOO-. The 3-NT concentration, which was similar in both strains of rat under basal conditions, was greater in SHR than in WKY rats after the addition of ONOO-, with a reduction only in NAC-treated SHR.<br><br>CONCLUSIONS: These findings suggest an increased vulnerability of SHR aortas to the effects of ONOO- as compared with those of WKY rats. The selective improvements produced by NAC, in systolic arterial pressure, heart rate, aortic endothelial function, ONOO- -induced impairment of endothelium-independent relaxation, aortic GSSG/GSH balance, malondialdehyde content and 3-NT formation in SHR suggest that chronic administration of NAC may have a protective effect against aortic vascular dysfunction in the SHR model of hypertension.}, }
@article {pmid11444723, year = {2001}, author = {Kozer, E and Koren, G}, title = {Management of paracetamol overdose: current controversies.}, journal = {Drug safety}, volume = {24}, number = {7}, pages = {503-512}, pmid = {11444723}, issn = {0114-5916}, mesh = {Acetaminophen/*adverse effects/metabolism/pharmacokinetics ; Acetylcysteine/therapeutic use ; Analgesics, Non-Narcotic/adverse effects/metabolism/pharmacokinetics ; *Chemical and Drug Induced Liver Injury ; Child ; Drug Interactions ; Drug Overdose ; Female ; Humans ; Liver Diseases/drug therapy ; Pregnancy ; Risk Factors ; }, abstract = {Paracetamol (acetaminophen) is one of the most frequently used analgesics, and is the most commonly used substance in self-poisoning in the US and UK. Paracetamol toxicity is manifested primarily in the liver. Treatment with N-acetyl-cysteine (NAC), if started within 10 hours from ingestion, can prevent hepatic damage in most cases. Pharmacokinetic data relating plasma paracetamol concentration to time after ingestion have been used to generate a 'probable hepatoxicity line' to predict which cases of paracetamol overdose will result in hepatotoxicity and should be treated with NAC. However, later studies use a 25% lower line as their 'possible hepatotoxicity line'. Although adopting the original line may save considerable resources, further studies are needed to determine whether such an approach is safe. On the basis of the metabolism of paracetamol, several risk factors for paracetamol toxicity have been proposed. These risk factors include long term alcohol (ethanol) ingestion, fasting and treatment with drugs that induce the cytochrome P450 2E1 enzyme system. Although some studies have suggested that these risk factors may be associated with worse prognosis, the data are inconclusive. However, until further evidence is available, we suggest that the lower line should be used when risk factors are present. In Canada and the UK, the intravenous regimen for NAC is used almost exclusively; in the US, an oral regimen is used. Both regimens have been shown to be effective. There is no large scale study with direct comparison between these 2 therapeutic protocols and controversy still exists as to which regimen is superior. During the last few years there has been an increase in the number of reports of liver failure associated with prolonged paracetamol administration for therapeutic reasons. The true incidence of this phenomenon is not known. We suggest testing liver enzyme levels if a child has received more than 75 mg/kg/day of paracetamol for more than 24 hours during febrile illness, and to treat with NAC when transaminase levels are elevated. Paracetamol overdose during pregnancy should be treated with either oral or intravenous NAC according to the regular protocols in order to prevent maternal, and potentially fetal, toxicity. Unless severe maternal toxicity develops, paracetamol overdose does not appear to increase the risk for adverse pregnancy outcome.}, }
@article {pmid11441839, year = {2001}, author = {Valdivia, AG and Martínez, A and Damián, FJ and Quezada, T and Ortíz, R and Martínez, C and Llamas, J and Rodríguez, ML and Yamamoto, L and Jaramillo, F and Loarca-Piña, MG and Reyes, JL}, title = {Efficacy of N-acetylcysteine to reduce the effects of aflatoxin B1 intoxication in broiler chickens.}, journal = {Poultry science}, volume = {80}, number = {6}, pages = {727-734}, doi = {10.1093/ps/80.6.727}, pmid = {11441839}, issn = {0032-5791}, mesh = {Acetylcysteine/*pharmacology ; Aflatoxin B1/*antagonists &amp; inhibitors/toxicity ; Alanine Transaminase/blood/drug effects ; Animal Feed ; Animals ; Aspartate Aminotransferases/blood/drug effects ; Blood Proteins/drug effects/metabolism ; Body Weight/drug effects ; Chemical and Drug Induced Liver Injury ; *Chickens ; Free Radical Scavengers/*pharmacology ; Glutathione/drug effects/metabolism ; Glutathione Transferase/drug effects/metabolism ; Kidney/drug effects/pathology ; Kidney Diseases/chemically induced/veterinary ; Liver/drug effects/metabolism/pathology ; Liver Diseases/veterinary ; Male ; Poultry Diseases/chemically induced/*prevention &amp; control ; Random Allocation ; Treatment Outcome ; }, abstract = {N-acetylcysteine (NAC) has been used safely in humans and in other mammals as an antidote against several toxic and carcinogenic agents, including aflatoxin B1 (AFB1). The aim of this study was to evaluate the capability of dietary supplementation with NAC to ameliorate the effects of subacute intoxication with AFB1 in broiler chickens. One hundred twenty male Hubbard 1-d-old chickens were allocated into one of four dietary treatments: 1) control group without treatment, 2) purified AFB1 added to diet (3 mg/kg of feed) for 21 d, 3) NAC (800 mg/kg BW, daily), or 4) AFB1 plus NAC at the same doses as Groups 2 and 3. Broilers treated with AFB1 plus NAC were shown to be partially protected against deleterious effects on BW (57.8%), daily weight gain (49.1%), feed conversion index (21.4%), plasma and hepatic total protein concentration (45.2, 66.7%), plasma alanine aminotransferase (67.4%), hepatic glutathione-S-transferase (18.8%), and reduced glutathione liver concentration (75.0%). In addition, they showed less intense liver fading, friable texture, and microvesicular steatosis. In the kidney, thickening of glomerular basement membrane was also less severe in NAC+AFB1-treated chickens than in AFB1-treated chickens. Our results suggest that NAC provided protection against negative effects on performance, liver and renal damage, and biochemical alterations induced by AFB1 in broiler chickens. Effects of NAC alone on chick performance were also evaluated. Addition of NAC to diet (800 mg/kg BW) did not negatively affect feed consumption, conversion index, or serum chemistry and did not induce structural changes in the liver or kidney.}, }
@article {pmid11440976, year = {2001}, author = {Su, B and Mitra, S and Gregg, H and Flavahan, S and Chotani, MA and Clark, KR and Goldschmidt-Clermont, PJ and Flavahan, NA}, title = {Redox regulation of vascular smooth muscle cell differentiation.}, journal = {Circulation research}, volume = {89}, number = {1}, pages = {39-46}, doi = {10.1161/hh1301.093615}, pmid = {11440976}, issn = {1524-4571}, support = {AR46126/AR/NIAMS NIH HHS/United States ; HL56091/HL/NHLBI NIH HHS/United States ; HL67331/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Calcium-Binding Proteins/metabolism ; Catalase/pharmacology ; Cell Differentiation ; Cell Division ; Cells, Cultured ; Humans ; MAP Kinase Signaling System ; Metalloporphyrins/pharmacology ; Microfilament Proteins ; Mitogen-Activated Protein Kinases/physiology ; Muscle, Smooth, Vascular/cytology/drug effects/*physiology ; Myosins/metabolism ; Oxidation-Reduction ; Phenotype ; Reactive Oxygen Species/*physiology ; p38 Mitogen-Activated Protein Kinases ; Calponins ; }, abstract = {Experiments were performed to determine the role of reactive oxygen species (ROS) in regulating vascular smooth muscle cell (VSMC) phenotype. After quiescence, cultured human VSMCs increased their expression of differentiation proteins (alpha-actin, calponin, and SM1 and SM2 myosin), but not beta-actin. ROS activity, determined using the H(2)O(2)-sensitive probe dichlorodihydrofluorescein (DCF), remained high in quiescent cells and was inhibited by catalase (3000 U/mL) or by N-acetylcysteine (NAC, 2 to 20 mmol/L). A superoxide dismutase mimic (SOD; MnTMPyP, 25 micromol/L) or SOD plus low concentrations of NAC (SODNAC2, 2 mmol/L) increased DCF fluorescence, which was inhibited by catalase or by NAC (10 to 20 mmol/L). Inhibition of ROS activity (by catalase or NAC) decreased the baseline expression of differentiation proteins, whereas elevation of ROS (by SOD or SODNAC2) increased expression of the differentiation markers. The latter effect was blocked by catalase or by NAC (10 to 20 mmol/L). None of the treatments altered beta-actin expression. SODNAC2-treated cells demonstrated contractions to endothelin that were absent in proliferating cells. p38 Mitogen-activated protein kinase (MAPK) activity was decreased when ROS activity was reduced (NAC, 10 mmol/L) and was augmented when ROS activity was increased (SODNAC2). Inhibition of p38 MAPK with pyridyl imidazole compound (SB202190, 2 to 10 micromol/L) reduced expression of differentiation proteins occurring under basal conditions and in response to SODNAC2. Transduction of VSMCs with an adenovirus encoding constitutively active MKK6, an activator of p38 MAPK, increased expression of differentiation proteins, whereas transduction with an adenovirus encoding dominant-negative p38 MAPK decreased expression of the differentiation proteins. These findings demonstrate that ROS can increase VSMC differentiation through a p38 MAPK-dependent pathway.}, }
@article {pmid11435212, year = {2001}, author = {Brown, LA and Harris, FL and Guidot, DM}, title = {Chronic ethanol ingestion potentiates TNF-alpha-mediated oxidative stress and apoptosis in rat type II cells.}, journal = {American journal of physiology. Lung cellular and molecular physiology}, volume = {281}, number = {2}, pages = {L377-86}, doi = {10.1152/ajplung.2001.281.2.L377}, pmid = {11435212}, issn = {1040-0605}, support = {R01-AA-11660/AA/NIAAA NIH HHS/United States ; R01-AA-12197/AA/NIAAA NIH HHS/United States ; }, mesh = {*Alcohol Drinking ; Animals ; Apoptosis/*physiology ; Biological Transport/drug effects ; Caspase 3 ; Caspases/metabolism ; Cytochrome c Group/metabolism ; Cytoplasm/metabolism ; Cytosol/metabolism ; Drug Synergism ; Glutathione/metabolism ; Lung/cytology/drug effects/*physiology ; Male ; Mitochondria/metabolism ; Oxidative Stress/*physiology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Time Factors ; Tumor Necrosis Factor-alpha/pharmacology/*physiology ; }, abstract = {In septic patients, chronic alcohol abuse increases the incidence of the acute respiratory distress syndrome (ARDS). Because alveolar type II cell viability is critical for epithelial repair, our objective was to determine if chronic ethanol ingestion increased the sensitivity of type II cells to the inflammatory mediators upregulated during sepsis. In rats chronically fed ethanol, type II cell mitochondrial GSH was depleted, and tumor necrosis factor-alpha (TNF-alpha)-induced generation of mitochondrial reactive oxygen species (ROS) and apoptosis were potentiated. When added to the ethanol diet, the GSH precursor (-)-2-oxo-4-thiazolidinecarboxylic acid (Procysteine; Pro) but not N-acetylcysteine (NAC) normalized type II cell mitochondrial GSH. Likewise, Pro but not NAC normalized TNF-alpha-induced mitochondrial ROS and apoptosis. This suggested that chronic ethanol ingestion potentiated TNF-alpha-induced apoptosis in type II cells via mitochondrial GSH depletion. This may be particularly relevant in ARDS when type II cell viability is critical to repair of the damaged alveolar epithelium and may have important ramifications for the treatment of ARDS patients with a history of alcohol abuse.}, }
@article {pmid11428623, year = {2000}, author = {Anderson, DR and Byers, SL and Vesely, KR}, title = {Treatment of sulfur mustard (HD)-induced lung injury.}, journal = {Journal of applied toxicology : JAT}, volume = {20 Suppl 1}, number = {}, pages = {S129-32}, doi = {10.1002/1099-1263(200012)20:1+&lt;::aid-jat670&gt;3.0.co;2-x}, pmid = {11428623}, issn = {0260-437X}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Bronchoalveolar Lavage ; Dermatologic Agents/*toxicity ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Lung/drug effects/immunology/*pathology ; Lung Diseases/*chemically induced/drug therapy/prevention &amp; control ; Male ; Mustard Gas/*toxicity ; Neutrophils ; Niacinamide/administration &amp; dosage/*pharmacology ; Rats ; gamma-Glutamyltransferase/analysis ; }, abstract = {An in vivo sulfur mustard (HD) vapor exposure model followed by bronchoalveolar lavage was developed previously in this laboratory to study biochemical indicators of HD-induced lung injury. This model was used to test two treatment compounds--niacinamide (NIA) and N-acetyl cysteine (NAC)--for their ability to ameliorate HD-induced biochemical changes. Anesthetized rats were intratracheally intubated and exposed to 0.35 mg of HD in 0.1 ml of ethanol or ethanol alone for 50 min. At the beginning of the exposure (t = 0), the rats were treated with either NIA (750 mg kg(-1)) or NAC (816 mg kg(-1)), i.p. At 24 h post-exposure, rats were euthanized and the lungs were lavaged with saline (three 5-ml washes). One milliliter of the recovered lavage fluid was analyzed for cellular components. The remaining fluid was centrifuged (10 min at 300 g) and the supernatant was assayed on a Cobas FARA clinical analyzer for lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), albumin (ALB), total protein (TP) and glutathione peroxidase (GP). The HD alone and HD+NIA treatment caused significant increases in all of the biochemical parameters compared with control levels. The NAC treatment yielded LDH, ALB and TP values that, although elevated, were not significantly different from the control. The GP levels were significantly higher than the control but significantly lower than the HD alone levels, indicating some protection compared with the HD alone group. The GGT levels were unaffected by NAC compared with HD alone. Cytological analysis of lavage fluid showed that the percentages of neutrophils were 5.3 +/- 1.0 (mean +/- SEM) for control, 46.6 +/- 4.5 for HD, 31.4 +/- 4.7 for HD + NIA and 21.6 +/- 4.7 for HD + NAC, respectively. The neutrophil counts were significantly higher for the three HD-exposed groups vs controls; however, the NAC-treated group had neutrophil counts lower than HD alone, indicating decreased inflammatory response. These results show that NAC may be useful as a potential treatment compound for HD-induced lung injury.}, }
@article {pmid11428622, year = {2000}, author = {Atkins, KB and Lodhi, IJ and Hurley, LL and Hinshaw, DB}, title = {N-acetylcysteine and endothelial cell injury by sulfur mustard.}, journal = {Journal of applied toxicology : JAT}, volume = {20 Suppl 1}, number = {}, pages = {S125-8}, doi = {10.1002/1099-1263(200012)20:1+&lt;::aid-jat671&gt;3.0.co;2-u}, pmid = {11428622}, issn = {0260-437X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Cattle ; Cytokines/biosynthesis ; Dermatologic Agents/*adverse effects ; Endothelium/pathology ; Gene Expression Regulation ; Glutathione/*biosynthesis ; Inflammation ; Mustard Gas/*adverse effects ; NF-kappa B/*pharmacology ; }, abstract = {Understanding the underlying mechanisms of cell injury and death induced by the chemical warfare vesicant sulfur mustard (HD) will be extremely helpful in the development of effective countermeasures to this weapon of terror. We have found recently that HD induces both apoptosis and necrosis in endothelial cells (Toxicol. Appl. Pharmacol. 1996; 141: 568-583). Pretreatment of the endothelial cells for 20 h with the redox-active agent N-acetyl-L-cysteine (NAC) selectively prevented apoptotic death induced by HD. In this study, we tested the hypotheses that pretreatment with NAC acts through two different pathways to minimize endothelial injury by HD: NAC pretreatment acts via a glutathione (GSH)-dependent pathway; and NAC pretreatment acts to suppress HD-induced activation of the nuclear transcription factor NFkappaB. We used a fluorescence microscopic assay of apoptotic nuclear features to assess viability and electrophoretic mobility shift assays (EMSAs) to assess the activity of NFkappaB following exposure to HD. The cells were treated with 0-10 mM GSH for 1 h prior to and during exposure to 0 or 500 microM HD for 5-6 h. Cells were also treated with 50 mM NAC or 200 microM buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, alone or in combination overnight prior to exposure to 0 or 500 microM HD for 5-6 h. Externally applied GSH up to a concentration of 5 mM had no toxic effect on the cells. Mild toxicity was associated with 10 mM GSH alone. There was a dose-related enhancement of viability when 2.5 and 5 mM GSH were present during the HD exposure. Pretreatment with BSO alone had no discernible toxicity. However, pretreatment with this inhibitor of GSH synthesis potentiated the toxicity of HD. Pretreatment with 50 mM NAC, as previously reported, provided substantial protection. Combining pretreatment with both BSO and NAC eliminated the protective effect of NAC pretreatment alone on HD injury. These observations are highly suggestive that NAC enhances endothelial survival via GSH-dependent effects and confirms and extends the work of others with different models that externally supplied GSH alone may be a fairly effective countermeasure against HD injury of endothelium. We next examined the hypothesis that HD may activate the nuclear transcription factor NFkappaB by performing EMSAs with nuclear extracts of endothelial cells following exposure to 0, 250 or 500 microM HD. This demonstrated an up to 2.5-fold increase (scanning densitometry) in activation of NFkappaB binding to its consensus sequence induced by 500 microM HD after 5 h of HD exposure. Paradoxically, treatment of the endothelial cells alone with 50 mM NAC activated NFkappaB, although HD-induced activation of NFkappaB was partially suppressed by NAC at 5 h. Factor NFkappaB is an important transcription factor for a number of cytokine genes (e.g. tumor necrosis factor, TNF), which can be activated following stress in endothelial cells. Taken together, these observations suggest that the protective effects of NAC may be mediated by enhanced GSH synthesis. The increased GSH may act to scavenge HD and also prevent oxidative activation of NFkappaB. Under some conditions, NAC may act as an oxidizing agent and thus increase NFkappaB activity. The NFkappaB-dependent gene expression may be important in inducing endothelial cell death as well as in generating a local inflammatory reaction associated with the release of endothelial-derived cytokines.}, }
@article {pmid11423095, year = {2001}, author = {Fonck, C and Baudry, M}, title = {Toxic effects of MPP(+) and MPTP in PC12 cells independent of reactive oxygen species formation.}, journal = {Brain research}, volume = {905}, number = {1-2}, pages = {199-206}, doi = {10.1016/s0006-8993(01)02551-3}, pmid = {11423095}, issn = {0006-8993}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/*pharmacology ; 1-Methyl-4-phenylpyridinium/*toxicity ; Animals ; Cell Differentiation/drug effects/physiology ; Cell Survival/drug effects/physiology ; Dopamine/metabolism/pharmacokinetics ; Dopamine Agents/*pharmacology ; Drug Interactions/physiology ; Free Radical Scavengers/pharmacology ; Herbicides/*toxicity ; Lipid Peroxidation/drug effects ; NAD/pharmacology ; Nerve Growth Factor/pharmacology ; Neurons/drug effects/metabolism ; Oxidopamine/pharmacology ; PC12 Cells/*drug effects/metabolism ; Parkinsonian Disorders/*metabolism/physiopathology ; Rats ; Reactive Oxygen Species/*metabolism ; Substantia Nigra/drug effects/metabolism/physiopathology ; Tritium/pharmacokinetics ; }, abstract = {MPTP is a toxin presumed to damage dopamine-secreting neurons by an oxygen free radical-mediated mechanism. Two steps in MPTP metabolism are the primary candidates for oxygen free radical generation: (a) MPTP oxidation to MPP(+) by a monoamine oxidase and (b) NADH dehydrogenase inhibition by MPP(+). In order to test the idea that MPTP toxicity is mediated by oxygen free radicals, we assessed lipid peroxidation and the effects of antioxidants in dopaminergic PC12 cells treated with MPTP or MPP(+). For comparison purposes, we also examined the effects of the pro-oxidant tert-butyl-hydroperoxide (TBHP) and of the dopaminergic toxin 6-hydroxydopamine (6-OHDA) in PC12 cells. MPTP and MPP(+), unlike TBHP, failed to induce lipid peroxidation in PC12 cells after a 4-h exposure. All toxins tested (MPTP, MPP(+), TBHP and 6-OHDA) caused a dose-dependent decrease in [(3)H]dopamine ((3)H-DA) uptake in PC12 cultures. The hydroperoxide scavengers glutathione and N-acetyl-cysteine and the superoxide and peroxide scavenger EUK-134 protected PC12 cells from TBHP- and 6-OHDA-induced decrease in (3)H-DA uptake. However, no protection by these antioxidants at various concentrations and time regimens was observed against MPTP- or MPP(+)-induced decreases in (3)H-DA uptake in PC12 cells. In addition, incubation of PC12 cells with the energy-rich substrate, NADH, attenuated MPP(+)-induced decrease in (3)H-DA uptake. These results suggest that MPTP-induced toxicity in dopaminergic PC12 cell cultures, does not involve oxygen free radical production, but rather may be caused by impairment in energy metabolism.}, }
@article {pmid11422213, year = {2001}, author = {Taut, FJ and Schmidt, H and Zapletal, CM and Thies, JC and Grube, C and Motsch, J and Klar, E and Martin, E}, title = {N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation.}, journal = {Clinical and experimental immunology}, volume = {124}, number = {2}, pages = {337-341}, pmid = {11422213}, issn = {0009-9104}, mesh = {Acetylcysteine/*pharmacology ; Adult ; E-Selectin/metabolism ; Free Radical Scavengers/*pharmacology ; Humans ; Intestines/blood supply/*drug effects ; Liver/blood supply/*drug effects ; Liver Transplantation/*physiology ; Middle Aged ; P-Selectin/metabolism ; Reperfusion Injury/drug therapy ; Selectins/*metabolism ; Splanchnic Circulation ; }, abstract = {In orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P < or = 0.02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment.}, }
@article {pmid11422207, year = {2001}, author = {Dobashi, K and Aihara, M and Araki, T and Shimizu, Y and Utsugi, M and Iizuka, K and Murata, Y and Hamuro, J and Nakazawa, T and Mori, M}, title = {Regulation of LPS induced IL-12 production by IFN-gamma and IL-4 through intracellular glutathione status in human alveolar macrophages.}, journal = {Clinical and experimental immunology}, volume = {124}, number = {2}, pages = {290-296}, pmid = {11422207}, issn = {0009-9104}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Humans ; Interferon-gamma/*pharmacology ; Interleukin-12/*metabolism ; Interleukin-4/*pharmacology ; Lipopolysaccharides/*immunology ; Macrophages, Alveolar/drug effects/*metabolism ; Monocytes/cytology ; Phenanthrenes ; }, abstract = {Interleukin-12 (IL-12) is secreted from monocytes and macrophages; it exerts pleiotropic effects on T cells and natural killer (NK) cells, and stimulates interferon-gamma (IFN-gamma) secretion. Glutathione tripeptide regulates the intracellular redox status and other aspects of cell physiology. We examined whether IFN-gamma and IL-4 affect the balance between intracellular reduced glutathione (GSH) and oxidized (GSSG) glutathione, as this may affect IL-12 production in human alveolar macrophages (AM). We used both AM from healthy non-smokers obtained by bronchoalveolar lavage and the monocytic THP-1 cell line in this study. Incubation of AM for 2 h with the GSH precursor N-acetylcysteine (NAC) increased the intracellular GSH/GSSG ratio, and enhanced lipopolysaccharide (LPS)-induced IL-12 secretion by AM. In THP-1 cells, NAC increased the GSH/GSSG ratio and the expression of LPS-induced IL-12 mRNA, whereas L-buthionine-[S,R]-sulphoximine (BSO) decreased these. NAC and BSO offset their own effects on the intracellular GSH/GSSG ratio and the expression of LPS-induced IL-12 mRNA. Furthermore, exposure of AM to the helper T cell type 1 (Th1) cytokine IFN-gamma or the helper T cell type 2 (Th2) cytokine IL-4 for 72 h increased and decreased the GSH/GSSG ratio, respectively. Lipopolysaccharide (LPS)-induced secretion of IL-12 in AM was enhanced by IFN-gamma but inhibited by IL-4. These results suggest that IFN-gamma and IL-4 oppositely affect the GSH/GSSG balance, which may regulate IL-12 secretion from AM in response to LPS.}, }
@article {pmid11421501, year = {2001}, author = {Kasielski, M and Nowak, D}, title = {Long-term administration of N-acetylcysteine decreases hydrogen peroxide exhalation in subjects with chronic obstructive pulmonary disease.}, journal = {Respiratory medicine}, volume = {95}, number = {6}, pages = {448-456}, doi = {10.1053/rmed.2001.1066}, pmid = {11421501}, issn = {0954-6111}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Analysis of Variance ; Breath Tests ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Hydrogen Peroxide/*metabolism ; Lipid Peroxidation/drug effects ; Lung Diseases, Obstructive/*drug therapy/metabolism ; Male ; Middle Aged ; Spectrometry, Fluorescence ; Statistics, Nonparametric ; Thiobarbituric Acid Reactive Substances/analysis ; Treatment Outcome ; }, abstract = {Patients with chronic obstructive pulmonary disease (COPD) exhale more hydrogen peroxide (H2O2) and lipid peroxidation products than healthy subjects. This may reflect oxidative stress in the airways that plays important role in the development and progression of COPD. N-acetylcysteine (NAC), a mucolytic drug, possesses antioxidant properties as it is a precursor of reduced glutathione that together with glutathione peroxidase may decompose H2O2 and lipid peroxides. We aimed to determine the effect of NAC, 600 mg effervescent tablets (Fluimucil), once a day for 12 months, and placebo on the concentration of H2O2 and thiobarbituric acid reactive substances (TBARs) in expired breath condensate and serum levels of two lipid peroxidation products (TBARs, lipid peroxides) in patients with COPD. The study was performed as a double-blind, double-dummy comparison between active drug and placebo in two parallel groups. Forty-four outpatients with stable COPD (22 in the NAC group and 22 in the placebo group) completed the study. Specimens of expired breath condensate and serum were collected at the randomization visit and then every 3 months over 1 year. The concentration of TBARs and H2O2 in expired breath condensate was measured spectrofluorimetrically by the thiobarbituric acid and homovanillic acid methods, respectively. Serum levels of lipid peroxides were determined spectrophotometrically after extraction with butanol and pyridine. Initially, H2O2 exhalation did not differ between the placebo and NAC groups up to 6 months of treatment. After this the significant differences were observed. After 9 and 12 months of treatment NAC group exhaled 2.3-fold (0.17+/-0.33 microM vs. 041+/-0.26 microM, P<0.04) [median 0.01 microM, quartile range (qr)=0.22 vs. median 0.15 microM, qr =0.43] and 2.6-fold (0.15+/-0.23 microM vs. 0.40+/-0.25 microN, P<0.05) median = 0.00 microM, qr = 0.23 vs. median = 0.36 microM, qr = 0.51] less H2O2 than placebo receivers, respectively. No significant effect of NAC administration on TBARs exhalation and serum levels of TBARs and lipid peroxides were noted over the whole treatment period. Also no significant associations between exhaled H2O2 and concentrations of lipid peroxidation products were noted in both treatment groups at any time-point. These results indicate that long-term oral administration of NAC attenuates H2O2 formation in the airways of COPD subjects and prove anti-oxidant action of drug. However, further studies are necessary to estimate the clinical significance of this finding.}, }
@article {pmid11409648, year = {2001}, author = {Kyaw, M and Yoshizumi, M and Tsuchiya, K and Kirima, K and Tamaki, T}, title = {Antioxidants inhibit JNK and p38 MAPK activation but not ERK 1/2 activation by angiotensin II in rat aortic smooth muscle cells.}, journal = {Hypertension research : official journal of the Japanese Society of Hypertension}, volume = {24}, number = {3}, pages = {251-261}, doi = {10.1291/hypres.24.251}, pmid = {11409648}, issn = {0916-9636}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Aorta, Thoracic/cytology ; Ascorbic Acid/pharmacology ; Cells, Cultured ; Chelating Agents/pharmacology ; Chromans/pharmacology ; Ditiocarb/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; *JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; MAP Kinase Signaling System/drug effects/physiology ; Male ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinase Kinases/*antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinases/*antagonists &amp; inhibitors/*metabolism ; Muscle, Smooth, Vascular/cytology/drug effects/*enzymology ; Onium Compounds/pharmacology ; Oxygen Consumption/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Vasoconstrictor Agents/*pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy, which results in several cardiovascular diseases. Ang II-induced cellular events have been mediated, in part, by reactive oxygen species (ROS) which also involve activation of mitogen-activated protein (MAP) kinases. Although it has been proposed that the therapeutic administration of antioxidants is useful for vascular diseases, the precise mechanisms which regulate ROS-sensitive signaling events have not been well characterized. Thus, we hypothesized that antioxidants may affect ROS-mediated MAP kinases activation induced by Ang II. The present findings showed that Ang II stimulated rapid and significant activation of ERK 1/2, JNK and p38 MAPK in cultured rat aortic smooth muscle cells (RASMC). Ang II-induced ERK 1/2 activation was not affected by all antioxidants examined, whereas JNK was sensitive to all antioxidants. In contrast, p38 MAPK activation was inhibited by DPI and ascorbic acid concentration-dependently, but by NAC only at high concentration. DETC and Trolox C had no effects on p38 MAPK activation by Ang II. We further examined the effects of antioxidants on Ang II-induced increases in oxygen consumption as an index of ROS generation in RASMC. DPI strongly inhibited Ang II-induced increases in oxygen consumption. DETC also inhibited Ang II-induced oxygen consumption, whereas ascorbic acid markedly augmented it. These findings suggest that the inhibitory effects of antioxidants on MAP kinases activation in VSMC are attributable, in part, to their modulating effects on ROS generation by Ang II in VSMC. Thus, inhibition of MAP kinases by antioxidants may imply their usefulness for relief of cardiovascular diseases.}, }
@article {pmid11405507, year = {2001}, author = {Decramer, M and Dekhuijzen, PN and Troosters, T and van Herwaarden, C and Rutten-van Mölken, M and van Schayck, CP and Olivieri, D and Lankhorst, I and Ardia, A}, title = {The Bronchitis Randomized On NAC Cost-Utility Study (BRONCUS): hypothesis and design. BRONCUS-trial Committee.}, journal = {The European respiratory journal}, volume = {17}, number = {3}, pages = {329-336}, doi = {10.1183/09031936.01.17303290}, pmid = {11405507}, issn = {0903-1936}, mesh = {Acetylcysteine/*therapeutic use ; Cost-Benefit Analysis ; Double-Blind Method ; Expectorants/*therapeutic use ; Female ; Follow-Up Studies ; Forced Expiratory Volume ; Functional Residual Capacity ; Humans ; Male ; Middle Aged ; Pulmonary Disease, Chronic Obstructive/*drug therapy/*economics/physiopathology ; Quality of Life ; Randomized Controlled Trials as Topic/methods ; Spirometry ; Vital Capacity ; }, abstract = {Chronic obstructive pulmonary disease (COPD) is an irreversible disorder characterized by airflow obstruction and a progressive decline in forced expiratory volume in one second (FEV1). At present, no treatment except quitting smoking appears to affect the progression of the disease. Oxidative stress has been implicated in its pathogenesis. The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS) is a phase III, randomized, double-blind, placebo-controlled, parallel group, multicentre study designed to assess the effectiveness of the antioxidant agent N-acetylcysteine (NAC) in altering the decline in FEV1, exacerbation rate, and quality of life in patients with moderate to severe COPD. In addition, cost-utility of the treatment will be estimated. Patients will be followed for 3 yrs and evaluated every 3 months. The necessary sample size to demonstrate an effect on the decline in FEV1 of 20 mL x yr(-1) was estimated to be 478 patients. Five hundred and twenty-three patients with moderate to severe COPD were recruited from 10 European countries from June 1, 1997-December 31, 1999. They were 63+/-8 yrs old and consisted of 243 (46%) current smokers and 280 (54%) exsmokers. Patients had on the average 4.9+/-1.6 exacerbations during the last 2 yrs. Postbronchodilator FEVI averaged 57+/-9% and the reversibility after 400 microg of Salbutamol averaged 4+/-4% predicted. The final results of the trial will be available in about 2 yrs. The study will provide objective data on the effects of N-acetylcysteine on outcome variables in chronic obstructive pulmonary disease.}, }
@article {pmid11408612, year = {2001}, author = {Biroccio, A and Benassi, B and Amodei, S and Gabellini, C and Del Bufalo, D and Zupi, G}, title = {c-Myc down-regulation increases susceptibility to cisplatin through reactive oxygen species-mediated apoptosis in M14 human melanoma cells.}, journal = {Molecular pharmacology}, volume = {60}, number = {1}, pages = {174-182}, doi = {10.1124/mol.60.1.174}, pmid = {11408612}, issn = {0026-895X}, mesh = {Antineoplastic Agents/*pharmacology ; *Apoptosis ; Camptothecin/pharmacology ; Caspase 1/metabolism ; Caspase 3 ; Caspases/metabolism ; Cisplatin/*pharmacology ; Down-Regulation ; Doxorubicin/pharmacology ; Enzyme Activation/drug effects ; Humans ; Melanoma/*metabolism ; Peptide Hydrolases/metabolism ; Poly (ADP-Ribose) Polymerase-1 ; Poly(ADP-ribose) Polymerases ; Proteins/metabolism ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Proto-Oncogene Proteins c-myc/*metabolism ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/biosynthesis ; bcl-2-Associated X Protein ; bcl-X Protein ; }, abstract = {Our aim in this work was to define the role of c-Myc in the susceptibility to cisplatin [cis-diamminedichloroplatinum(II) (CDDP)] in human melanoma cells. Two M14 melanoma cell clones obtained by transfection and expressing six to ten times lower c-Myc protein levels than the parental cells and the control clone were employed. Analysis of survival curves demonstrates an increase in CDDP sensitivity in c-Myc low-expressing clones if compared with the control clone and the parental line. The enhanced sensitivity is unrelated to the impairment in enzymatic DNA repair activity. Cell cycle analysis demonstrates that although the control clone is able to completely recover from the CDDP-induced S-G(2)/M block, this arrest is prolonged in c-Myc low-expressing clones and a fraction of cells undergoes apoptosis. Although no changes in P53, Bax, Bcl-2, and Bcl-x(L/S) protein levels are observed, apoptosis is associated with the formation of reactive oxygen species (ROS), activation of caspase-1, caspase-3 and cleavage of the specific caspase substrate poly-ADP-ribose polymerase. The use of the antioxidant N-acetyl cysteine and caspase inhibitors prevents CDDP-induced apoptosis in c-Myc low-expressing clones, demonstrating that ROS, caspase-1, and caspase-3 are required for apoptotic cell death. Moreover, ROS generation depends on caspase-1-like activation because the Ac-YVAD-cho inhibitor abrogates CDDP-induced ROS in the c-Myc low-expressing clones.}, }
@article {pmid11408342, year = {2001}, author = {De Flora, S and Izzotti, A and D'Agostini, F and Balansky, RM}, title = {Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points.}, journal = {Carcinogenesis}, volume = {22}, number = {7}, pages = {999-1013}, doi = {10.1093/carcin/22.7.999}, pmid = {11408342}, issn = {0143-3334}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anticarcinogenic Agents/*pharmacology ; Antimutagenic Agents/*pharmacology ; Humans ; Smoking/adverse effects/*genetics ; }, abstract = {Although smoking cessation is the primary goal for the control of cancer and other smoking-related diseases, chemoprevention provides a complementary approach applicable to high risk individuals such as current smokers and ex-smokers. The thiol N-acetylcysteine (NAC) works per se in the extracellular environment, and is a precursor of intracellular cysteine and glutathione (GSH). Almost 40 years of experience in the prophylaxis and therapy of a variety of clinical conditions, mostly involving GSH depletion and alterations of the redox status, have established the safety of this drug, even at very high doses and for long-term treatments. A number of studies performed since 1984 have indicated that NAC has the potential to prevent cancer and other mutation-related diseases. N-Acetylcysteine has an impressive array of mechanisms and protective effects towards DNA damage and carcinogenesis, which are related to its nucleophilicity, antioxidant activity, modulation of metabolism, effects in mitochondria, decrease of the biologically effective dose of carcinogens, modulation of DNA repair, inhibition of genotoxicity and cell transformation, modulation of gene expression and signal transduction pathways, regulation of cell survival and apoptosis, anti-inflammatory activity, anti-angiogenetic activity, immunological effects, inhibition of progression to malignancy, influence on cell cycle progression, inhibition of pre-neoplastic and neoplastic lesions, inhibition of invasion and metastasis, and protection towards adverse effects of other chemopreventive agents or chemotherapeutical agents. These mechanisms are herein reviewed and commented on with special reference to smoking-related end-points, as evaluated in in vitro test systems, experimental animals and clinical trials. It is important that all protective effects of NAC were observed under a range of conditions produced by a variety of treatments or imbalances of homeostasis. However, our recent data show that, at least in mouse lung, under physiological conditions NAC does not alter per se the expression of multiple genes detected by cDNA array technology. On the whole, there is overwhelming evidence that NAC has the ability to modulate a variety of DNA damage- and cancer-related end-points.}, }
@article {pmid11408093, year = {2001}, author = {Pocernich, CB and Cardin, AL and Racine, CL and Lauderback, CM and Butterfield, DA}, title = {Glutathione elevation and its protective role in acrolein-induced protein damage in synaptosomal membranes: relevance to brain lipid peroxidation in neurodegenerative disease.}, journal = {Neurochemistry international}, volume = {39}, number = {2}, pages = {141-149}, doi = {10.1016/s0197-0186(01)00012-2}, pmid = {11408093}, issn = {0197-0186}, support = {AG-05119/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; AG-12423/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Acrolein/*toxicity ; Animals ; Brain/*drug effects/metabolism ; Cell Membrane/drug effects/metabolism ; Electron Spin Resonance Spectroscopy ; Female ; Gerbillinae ; Glutathione/*metabolism ; *Lipid Peroxidation ; Nerve Tissue Proteins/*metabolism ; Neurodegenerative Diseases/*metabolism ; Synaptosomes/*drug effects/metabolism ; }, abstract = {Oxidative stress may be a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD) Huntington's, and Parkinson's diseases as well as amyotrophic lateral sclerosis. Acrolein is a highly reactive product of lipid peroxidation that is elevated in the brains of persons with AD. This alkenal potentially can react with proteins by Michael addition to alter their structure and function. In the present study, we used electron paramagnetic resonance in conjunction with a protein-specific spin label to monitor synaptosomal membrane protein conformational alterations induced by acrolein. A dose-dependent increased conformational alteration was observed. Consistent with this finding, protein carbonyl levels from protein-bound acrolein were significantly elevated. However, pretreatment of synaptosomes with glutathione ethyl ester (GEE) significantly ameliorated both the conformational alterations and protein carbonyls induced by acrolein. Based on this success, we tested the hypothesis that elevated levels of endogenous glutathione (GSH) would offer protection against acrolein-induced oxidative stress. In-vivo elevation of GSH (215% over control, P<0.04) was produced by i.p. injection of N-acetylcysteine (NAC), a known precursor of GSH. Synaptosomes were treated with vehicle or 2 nM acrolein, the level of this alkenal found in AD brain. In contrast to synaptosomes from control animals, which had significantly increased protein carbonyl levels following addition of 2 nM acrolein, synaptosomes that were isolated from NAC-treated rodents and treated with 2 nM acrolein showed no increased carbonyl levels compared to untreated controls. These results demonstrate protection by increased in-vivo GSH levels against acrolein-induced oxidative stress at levels found in AD brain and are consistent with the notion that methods to increase endogenous GSH levels in neurodegenerative diseases associated with oxidative stress may be promising.}, }
@article {pmid11401302, year = {2001}, author = {Liebes, L and Conaway, CC and Hochster, H and Mendoza, S and Hecht, SS and Crowell, J and Chung, FL}, title = {High-performance liquid chromatography-based determination of total isothiocyanate levels in human plasma: application to studies with 2-phenethyl isothiocyanate.}, journal = {Analytical biochemistry}, volume = {291}, number = {2}, pages = {279-289}, doi = {10.1006/abio.2001.5030}, pmid = {11401302}, issn = {0003-2697}, support = {CA 46535/CA/NCI NIH HHS/United States ; M01 RR000096/RR/NCRR NIH HHS/United States ; NCI-CN-55120/CI/NCPDCID CDC HHS/United States ; P01 CA046535/CA/NCI NIH HHS/United States ; CA-166081-21/CA/NCI NIH HHS/United States ; CRC-RR-00096/RR/NCRR NIH HHS/United States ; }, mesh = {Chromatography, High Pressure Liquid ; Clinical Trials, Phase I as Topic ; Diet ; Humans ; Isothiocyanates/*blood/chemistry/pharmacokinetics ; Regression Analysis ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {Dietary and pharmacologic isothiocyanates (ITCs) may play a role in reducing the risk of certain cancers. The quantification of ITCs in humans is important both for epidemiological and pharmacokinetic studies. We describe a modification of an HPLC-based assay of urinary ITCs for use with human plasma. The assay utilizes the cyclocondensation reaction of 1,2-benzenedithiol with ITCs present in human plasma, followed by a two-step hexane extraction and analysis by HPLC using UV detection at 365 nm. The method shows linearity and reproducibility with human plasma over a range of 49-3003 nM phenethyl isothiocyanate (PEITC) (r(2) = 0.996 +/- 0.003). A similar degree of linearity was seen with two other biologically occurring conjugates of PEITC: PEITC--N-acetylcysteine (PEITC--NAC) and PEITC--glutathione (PEITC--GSH). The recovery of PEITC assessed on multiple days was 96.6 +/- 1.5% and was 100% for PEITC--GSH and PEITC--NAC. The reproducibility of the assay on multiday samplings showed a mean %CV of 6.5 +/- 0.3% for PEITC, 6.4 +/- 4.3 for PEITC--NAC and 12.3 +/- 3.9 for PEITC--GSH. In clinical studies, mean plasma ITC level of 413 +/- 193 nM PEITC equivalents was determined for a non-dietary-controlled group of 23 subjects. Multiday analysis data from pharmacokinetic plasma sets of 3 subjects taking a single dose of PEITC at 40 mg showed a good CV (range: 16-21%). The applicability of the methodology to pharmacokinetic studies of PEITC in humans is demonstrated.}, }
@article {pmid11390188, year = {2001}, author = {Murley, JS and Kataoka, Y and Hallahan, DE and Roberts, JC and Grdina, DJ}, title = {Activation of NFkappaB and MnSOD gene expression by free radical scavengers in human microvascular endothelial cells.}, journal = {Free radical biology &amp; medicine}, volume = {30}, number = {12}, pages = {1426-1439}, doi = {10.1016/s0891-5849(01)00554-8}, pmid = {11390188}, issn = {0891-5849}, support = {R01 CA37435/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Blotting, Northern ; Catalase/pharmacology ; Cell Line, Transformed/drug effects ; Dimerization ; Endothelium, Vascular/*drug effects/metabolism ; Enzyme Induction/drug effects ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation/*drug effects ; Humans ; Hydrogen Peroxide/metabolism ; Intercellular Adhesion Molecule-1/biosynthesis/genetics ; Mercaptoethylamines/pharmacology ; NF-kappa B/antagonists &amp; inhibitors/*biosynthesis/chemistry/genetics ; Oxidation-Reduction ; Oxidative Stress ; Phosphorylation ; Prodrugs/metabolism ; Pyruvates/pharmacology ; RNA, Messenger/biosynthesis ; Radiation-Protective Agents/pharmacology ; Skin/blood supply ; Superoxide Dismutase/*biosynthesis/genetics ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The effect of nonprotein thiol (NPT) free radical scavengers WR-1065 (SH) and WR-33278 (SS), the active thiol and disulfide metabolites of amifostine, N-acetylcysteine (NAC; both L- and D- isomers), mesna, captopril, and dithiothreitol (DTT) on NFkappaB activation in human microvascular endothelial cells (HMEC) was investigated and contrasted to TNFalpha. The use of each of these NPTs at millimolar concentrations independent of oxidative damage-inducing agents resulted in a marked activation of NFkappaB, with the maximum effect observed between 30 min and 1 h after treatment. Only the SH and SS forms of amifostine, however, were effective in activating NFkappaB when administered at micromolar levels. Using a supershift assay, SH and SS equally affected the p50-p65 heterodimer, but not homodimers or heterodimers containing p52 or c-Rel subunits of NFkappaB. Neither catalase nor pyruvate when added to the culture medium to minimize hydrogen peroxide production had an effect on NFkappaB activation by SH. Thus, while oxidative damage is known to activate NFkappaB, the intracellular redox environment may also be affected by the addition of free radical scavenging agents such as NPT, and these in turn are capable of activating the redox sensitive transcription factor NFkappaB. There does not appear to be a significant role, if any, for the production of H(2)O(2) as an intermediate step in the activation of NFkappaB by either the SH or the SS form of amifostine. Rather, the underlying mechanism of action, especially for the SS form, may be related to the close structural and functional similarities of these agents to polyamines, which have been reported to be capable of activating NFkappaB. In contrast to TNFalpha, exposure of cells to either 40 microM or 4 mM of SH for 30 min did not induce intercellular adhesion molecule-1 (ICAM-1) gene expression, but did increase manganese superoxide dismutase (MnSOD) gene expression. MnSOD expression rose by 2-fold and remained elevated from 4 to 22 h following SH exposure.}, }
@article {pmid11388655, year = {2001}, author = {de Ceballos, ML and Brera, B and Fernández-Tomé, MP}, title = {beta-Amyloid-induced cytotoxicity, peroxide generation and blockade of glutamate uptake in cultured astrocytes.}, journal = {Clinical chemistry and laboratory medicine}, volume = {39}, number = {4}, pages = {317-318}, doi = {10.1515/CCLM.2001.049}, pmid = {11388655}, issn = {1434-6621}, mesh = {Acetylcysteine/pharmacology ; Amyloid beta-Peptides/*metabolism/pharmacology ; Astrocytes/*metabolism ; Catalase/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Dithiothreitol/pharmacology ; Dose-Response Relationship, Drug ; Free Radicals/metabolism ; Glutamic Acid/*pharmacokinetics ; Humans ; Neurons/metabolism ; Peptide Fragments/pharmacology ; Peroxides/*metabolism ; Time Factors ; Vitamin E/pharmacology ; }, abstract = {beta-Amyloid (betaA) is cytotoxic to neurons in culture by increasing hydrogen peroxide and altering calcium homeostasis. We have evaluated betaA-induced cytotoxicity, peroxide generation and glutamate (Glu) uptake in cultured astrocytes. Twenty-four hours after a single addition of either betaA25-35 or betaA1-40there was a concentration-dependent decrease in viability. Catalase or vitamin E showed no protective effect against betaA25-35 Dithiothreitol (DTT), N-acetylcysteine (NAC) and cyclosporine A significantly prevented the toxic effects of both betaA25-35 and peroxide, while inhibition of peroxide detoxifying enzymes enhanced toxicity. Exposure to betaA25-35 or betaA1-40 increased peroxides at 2 h and 24 h, which was prevented by DTT and NAC, but not vitamin E. betaA25-35 inhibited Glu uptake in astrocytes and neurons in culture. Following exposure of neurons to betaA for 24 h there was decreased uptake and increased Glu levels in the culture medium, that resulted in gradual excitotoxicity.}, }
@article {pmid11384840, year = {2001}, author = {Aubel, C and Dehez, S and Chabanon, H and Seva, C and Ferrara, M and Brachet, P}, title = {Activation of c-Jun N-terminal kinase 1 (JNK-1) after amino acid deficiency in HeLa cells.}, journal = {Cellular signalling}, volume = {13}, number = {6}, pages = {417-423}, doi = {10.1016/s0898-6568(01)00159-0}, pmid = {11384840}, issn = {0898-6568}, mesh = {Acetylcysteine/pharmacology ; Amino Acids/*deficiency ; Enzyme Activation ; Free Radical Scavengers/pharmacology ; HeLa Cells ; Humans ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases/*metabolism ; Oxidative Stress ; Precipitin Tests ; Substrate Specificity ; Time Factors ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Long-term amino acid starvation represents a form of metabolic stress which stimulates gene expression. Here we report that depriving HeLa cells for any one of a series of amino acids activates c-Jun N-terminal kinase-1 (JNK-1). In contrast, the other mitogen-activated protein kinases (MAPKs) ERK-1 and, to a lesser extent, p38 activities decreased under such conditions. In methionine- or leucine-deprived cells, JNK-1 activation occurred after 4 or 6 h, respectively, and reached a steady maximum of 5- to 7-fold over control cells afterwards. This activation was dependent on the amino acid concentration and it could be reversed by resupplying the complete medium. Limitation for all amino acids also augmented JNK-1 activity, whereas increased amino acid concentrations had an opposite effect. The free radical scavenging thiol antioxidant N-acetylcysteine (NAC) alleviated partially JNK-1 activation in amino acid-deprived cells. The data indicate that activation of JNK-1 by long-term amino acid deprivation may be mediated in part by oxidative stress.}, }
@article {pmid11383692, year = {2001}, author = {Liu, L and Yeh, YY}, title = {Water-soluble organosulfur compounds of garlic inhibit fatty acid and triglyceride syntheses in cultured rat hepatocytes.}, journal = {Lipids}, volume = {36}, number = {4}, pages = {395-400}, pmid = {11383692}, issn = {0024-4201}, mesh = {Acetates/metabolism ; Animals ; Carbon Radioisotopes ; Cells, Cultured ; Fatty Acids/*biosynthesis ; Garlic/*chemistry ; Liver/*metabolism ; Male ; *Plants, Medicinal ; Rats ; Rats, Sprague-Dawley ; Solubility ; Sulfur Compounds/chemistry/*pharmacology ; Triglycerides/*biosynthesis ; *Water ; }, abstract = {The putative hypolipidemic effect of garlic remains controversial. To gain further insight into the effect of garlic on lipid metabolism, the present study determined the inhibitory effects of water-soluble organosulfur compounds present in garlic on triglyceride (TG) and fatty acid synthesis in cultured rat hepatocytes. When incubated at 0.05 to 4.0 mmol/L with cultured hepatocytes, S-allyl cysteine (SAC) and S-propyl cysteine (SPC) decreased [2-14C]acetate incorporation into triglyceride in a concentration-dependent fashion achieving a maximal inhibition at 4.0 mmol/L of 43 and 51%, respectively. The rate of [2-14C]acetate incorporation into phosphlipids was depressed to a similar extent by SAC and SPC. SPC, SAC, S-ethyl cysteine (SEC), and gamma-glutamyl-S-methyl cysteine decreased [2-14C]acetate incorporation into fatty acid synthesis by 81, 59, 35, and 40%, respectively, at 2.0-4.0 mmol/L concentrations. Alliin, gamma-glutamyl-S-allyl cysteine, gamma-glutamyl-S-propyl cysteine S-allyl-N-acetyl cysteine, S-allylsulfonyl alanine, and S-methyl cysteine had no effect on fatty acid synthesis. The activities of lipogenic enzymes, fatty acid synthase (FAS), and glucose-6-phosphate dehydrogenase (G6PDH) were measured in cultured hepatocytes treated with the inhibitors. The activity of FAS in cells treated with 4.0 mmol/L SAC and SPC, respectively, was 32 and 27% lower than that of nontreated cells. Neither SAC nor SPC affected G6PDH activity. The results indicate that SAC, SEC, and SPC inhibit lipid biosynthesis in cultured rat hepatocytes, and further suggest that these S-alk(en)yl cysteines of garlic impair triglyceride synthesis in part due to decreased de novo fatty acid synthesis resulting from inhibition on FAS. Whether tissue concentrations of active garlic components can achieve levels required to inhibit TG synthesis in vivo warrants further investigation.}, }
@article {pmid11369649, year = {2001}, author = {Dvorakova, K and Waltmire, CN and Payne, CM and Tome, ME and Briehl, MM and Dorr, RT}, title = {Induction of mitochondrial changes in myeloma cells by imexon.}, journal = {Blood}, volume = {97}, number = {11}, pages = {3544-3551}, doi = {10.1182/blood.v97.11.3544}, pmid = {11369649}, issn = {0006-4971}, support = {CA 17094/CA/NCI NIH HHS/United States ; CA 23074/CA/NCI NIH HHS/United States ; CA09213/CA/NCI NIH HHS/United States ; CA7176/CA/NCI NIH HHS/United States ; }, mesh = {Acetone/analogs &amp; derivatives/pharmacology ; Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Cytochrome c Group/metabolism ; DNA Damage/drug effects ; DNA, Mitochondrial/drug effects ; Electron Transport Complex II ; Flow Cytometry ; Hexanones/*pharmacology ; Humans ; Leukemia, Promyelocytic, Acute ; Lymphocytes/drug effects ; Membrane Potentials/drug effects ; Microscopy, Electron ; Mitochondria/*drug effects/physiology/ultrastructure ; Multienzyme Complexes/antagonists &amp; inhibitors ; Multiple Myeloma/*ultrastructure ; Oxidative Stress ; Oxidoreductases/antagonists &amp; inhibitors ; Polymerase Chain Reaction ; Reactive Oxygen Species/metabolism ; Succinate Dehydrogenase/antagonists &amp; inhibitors ; Thiophenes/pharmacology ; Tumor Cells, Cultured ; }, abstract = {Imexon is a cyanoaziridine derivative that has antitumor activity in multiple myeloma. Previous studies have shown that imexon induces oxidative stress and apoptosis in the RPMI 8226 myeloma cell line. This study reports that imexon has cytotoxic activity in other malignant cell lines including NCI-H929 myeloma cells and NB-4 acute promyelocytic leukemia cells, whereas normal lymphocytes and U266 myeloma cells are substantially less sensitive. Flow cytometric experiments have shown that imexon treatment is associated with the formation of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (Deltapsi(m)) in imexon-sensitive myeloma cell lines and NB-4 cells. In contrast, reduction of Deltapsi(m) and increased levels of ROS were not observed in imexon-resistant U266 cells. Treatment of imexon-sensitive RPMI 8226 cells with the antioxidant N-acetyl-L-cysteine (NAC) protects cells against these effects of imexon. Mitochondrial swelling was observed by electron microscopy in RPMI 8226 myeloma cells treated with 180 microM imexon as early as 4 hours. Damage to mitochondrial DNA was detected by a semiquantitative polymerase chain reaction assay in imexon-treated RPMI 8226 cells; however, nuclear DNA was not affected. Finally, partial protection of RPMI 8226 cells against the imexon effects was achieved by treatment with theonyltrifluoroacetone, an inhibitor of superoxide production at mitochondrial complex II. These changes are consistent with mitochondrial oxidation and apoptotic signaling as mediators of the growth inhibitory effects of imexon. Interestingly, oxidative damage and decrease of Deltapsi(m) induced by imexon highly correlates with sensitivity to imexon in several myeloma cell lines and an acute promyelocytic leukemia cell line. (Blood. 2001;97:3544-3551)}, }
@article {pmid11366795, year = {1999}, author = {}, title = {NAC-boosting defenses against free radicals.}, journal = {TreatmentUpdate}, volume = {11}, number = {4}, pages = {7-9}, pmid = {11366795}, issn = {1181-7186}, mesh = {Acetylcysteine/administration &amp; dosage ; Anti-HIV Agents/administration &amp; dosage ; Erythrocytes/*metabolism ; Female ; Glutathione/*biosynthesis/*deficiency ; HIV Infections/*blood/drug therapy/physiopathology ; Humans ; Male ; }, }
@article {pmid11366543, year = {1998}, author = {}, title = {Hepatitis viral load correlates to glutathione levels.}, journal = {Positive health news}, volume = {}, number = {No 17}, pages = {14-15}, pmid = {11366543}, mesh = {Antigen Presentation ; Chlorophyll/*therapeutic use ; *Complementary Therapies ; Dietary Supplements ; Enema ; Glutamine/*therapeutic use ; Glutathione/*immunology ; Hepatitis B/*immunology ; Hepatitis C/*immunology ; Humans ; Viral Load ; }, }
@article {pmid11366023, year = {1999}, author = {}, title = {Study finds NAC fails to prevent Bactrim/Septra hypersensitivity.}, journal = {TreatmentUpdate}, volume = {11}, number = {1}, pages = {4-5}, pmid = {11366023}, issn = {1181-7186}, mesh = {AIDS-Related Opportunistic Infections/prevention &amp; control ; Acetylcysteine/*therapeutic use ; Anti-Infective Agents/*adverse effects/therapeutic use ; Drug Hypersensitivity/etiology/*prevention &amp; control ; Free Radical Scavengers/*therapeutic use ; Humans ; Pneumonia, Pneumocystis/prevention &amp; control ; Primary Prevention ; Toxoplasmosis/prevention &amp; control ; Trimethoprim, Sulfamethoxazole Drug Combination/*adverse effects/therapeutic use ; }, }
@article {pmid11364196, year = {1997}, author = {Lands, L}, title = {NAC, glutamine, and alpha lipoic acid. Interview by John S. James.}, journal = {AIDS treatment news}, volume = {}, number = {No 268}, pages = {2-7}, pmid = {11364196}, issn = {1052-4207}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; *Complementary Therapies ; Diet ; Drug Therapy, Combination ; Glutamine/*pharmacology/therapeutic use ; HIV Infections/*drug therapy ; Humans ; Thioctic Acid/*pharmacology/therapeutic use ; }, }
@article {pmid11364246, year = {1997}, author = {James, JS}, title = {Stanford NAC study: glutathione level predicts survival.}, journal = {AIDS treatment news}, volume = {}, number = {No 266}, pages = {1-5}, pmid = {11364246}, issn = {1052-4207}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Dose-Response Relationship, Drug ; Glutathione/*blood ; HIV Infections/blood/*drug therapy/mortality ; Humans ; Lymphocyte Subsets ; Placebos ; Survival Analysis ; }, }
@article {pmid11364276, year = {1997}, author = {Gilden, D and Cadman, J}, title = {A NAC for controversy.}, journal = {GMHC treatment issues : the Gay Men's Health Crisis newsletter of experimental AIDS therapies}, volume = {11}, number = {3}, pages = {7, 10-2}, pmid = {11364276}, issn = {1077-1824}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; CD4 Lymphocyte Count ; Clinical Trials, Phase I as Topic ; Disease Progression ; Female ; Glutathione/*biosynthesis/*pharmacology ; HIV Infections/*drug therapy ; Humans ; Male ; United States ; Viral Load ; }, }
@article {pmid11363915, year = {1996}, author = {}, title = {Pot shots.}, journal = {Notes from the underground (New York, N.Y.)}, volume = {}, number = {No 33}, pages = {6}, pmid = {11363915}, mesh = {AIDS-Related Opportunistic Infections/*therapy ; Acetylcysteine/*therapeutic use ; Animals ; Anti-Bacterial Agents/therapeutic use ; Antitubercular Agents/therapeutic use ; Antiviral Agents/therapeutic use ; CD4 Lymphocyte Count ; Cattle ; China/epidemiology ; Clarithromycin/therapeutic use ; Clinical Trials as Topic ; Clofazimine/*adverse effects/therapeutic use ; Cryptosporidiosis/*drug therapy ; Drug Combinations ; Ethambutol/therapeutic use ; Expectorants/*therapeutic use ; Glutathione/*biosynthesis ; Hepatitis B/epidemiology/*therapy ; Humans ; Immunoglobulins/*therapeutic use ; Interferon-alpha/*therapeutic use ; Italy ; Leprostatic Agents/*adverse effects/therapeutic use ; Mycobacterium avium-intracellulare Infection/*drug therapy ; Philippines ; Protease Inhibitors/*adverse effects ; Survival Rate ; Taiwan ; Thymosin/*therapeutic use ; Zidovudine/therapeutic use ; }, }
@article {pmid11363634, year = {1996}, author = {James, JS}, title = {NAC: first controlled trial, positive results.}, journal = {AIDS treatment news}, volume = {}, number = {no 250}, pages = {1-3}, pmid = {11363634}, issn = {1052-4207}, mesh = {Acetylcysteine/*therapeutic use ; Acquired Immunodeficiency Syndrome/*drug therapy/metabolism/mortality ; Controlled Clinical Trials as Topic ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Humans ; Survival Rate ; }, }
@article {pmid11362617, year = {1995}, author = {}, title = {NAC users: you can help NAC research.}, journal = {AIDS treatment news}, volume = {}, number = {no 226}, pages = {8}, pmid = {11362617}, issn = {1052-4207}, mesh = {AIDS-Related Opportunistic Infections/*therapy ; Acetylcysteine/adverse effects/*pharmacology/therapeutic use ; CD4 Lymphocyte Count/drug effects ; Clinical Trials as Topic/methods ; Data Collection/methods ; Double-Blind Method ; Drug Administration Schedule ; Humans ; *Patient Participation ; *Population Surveillance ; Research Design ; }, }
@article {pmid11362399, year = {1995}, author = {Lichtenstein, BS}, title = {Nutrition and HIV.}, journal = {STEP perspective}, volume = {7}, number = {1}, pages = {2-5}, pmid = {11362399}, mesh = {Acetylcysteine/therapeutic use ; Carotenoids/therapeutic use ; HIV Infections/*diet therapy/immunology ; Humans ; *Nutritional Physiological Phenomena ; Nutritional Requirements ; Selenium/therapeutic use ; Vitamins/therapeutic use ; beta Carotene ; }, }
@article {pmid11541458, year = {1995}, author = {Zhao, M and Bada, JL}, title = {Determination of alpha-dialkylamino acids and their enantiomers in geological samples by high-performance liquid chromatography after derivatization with a chiral adduct of o-phthaldialdehyde.}, journal = {Journal of chromatography. A}, volume = {690}, number = {}, pages = {55-63}, doi = {10.1016/0021-9673(94)00927-2}, pmid = {11541458}, issn = {0021-9673}, mesh = {Acetylcysteine/*chemistry ; Amino Acids/analysis/*isolation &amp; purification ; Aminoisobutyric Acids/analysis ; Chromatography, High Pressure Liquid/methods ; Geologic Sediments/analysis/*chemistry ; Geology/*methods ; Isomerism ; Time Factors ; Valine/analysis ; o-Phthalaldehyde/*chemistry ; }, abstract = {Derivatization with o-phthaldialdehyde (OPA) and the chiral thiol N-acetyl-L-cysteine (NAC) is a convenient and sensitive technique for the HPLC detection and resolution of protein amino acid enantiomers. The kinetics of the reaction of OPA-NAC with alpha-dialkylamino acids was investigated. The fluorescence yield of alpha-dialkylamino acids was only about 10% of that of protein amino acids when the derivatization was carried out at room temperature for 1-2 min, which is the procedure generally used for protein amino acid analyses. The fluorescence yield of alpha-dialkylamino acids can be enhanced by up to ten-fold when the derivatization reaction time is increased to 15 min at room temperature. The OPA-NAC technique was optimized for the detection and enantiomeric resolution of alpha-dialkylamino acids in geological samples which contain a large excess of protein amino acids. The estimated detection limit for alpha-dialkylamino acids is 1-2 pmol, comparable to that for protein amino acids.}, }
@article {pmid14229719, year = {1965}, author = {LAWSON, D and SAGGERS, BA}, title = {N.A.C. AND ANTIBIOTICS IN CYSTIC FIBROSIS.}, journal = {British medical journal}, volume = {1}, number = {5430}, pages = {317}, pmid = {14229719}, issn = {0007-1447}, mesh = {*Acetylcysteine ; *Ampicillin ; *Anti-Bacterial Agents ; *Antibiotics, Antitubercular ; *Cysteine ; *Cystic Fibrosis ; *Erythromycin ; *Fusidic Acid ; Humans ; *Penicillins ; *Pharmacology ; *Protein Synthesis Inhibitors ; *Tetracycline ; }, }
@article {pmid14005424, year = {1962}, author = {WEBB, WR}, title = {Clinical evaluaton of a new mucolytic agent, acetyl-cysteine.}, journal = {The Journal of thoracic and cardiovascular surgery}, volume = {44}, number = {}, pages = {330-343}, pmid = {14005424}, issn = {0022-5223}, mesh = {*Acetylcysteine ; *Bronchi ; *Bronchial Diseases ; Cysteine/analogs &amp; derivatives ; *Disease ; *Expectorants ; Humans ; Lung Abscess/*therapy ; }, }
@article {pmid11361037, year = {2001}, author = {Rivabene, R and Napolitano, M and Cantafora, A and Bravo, E}, title = {Redox-dependent modulation of lipid synthesis induced by oleic acid in the human intestinal epithelial cell line Caco-2.}, journal = {Experimental biology and medicine (Maywood, N.J.)}, volume = {226}, number = {3}, pages = {191-198}, doi = {10.1177/153537020122600306}, pmid = {11361037}, issn = {1535-3702}, mesh = {Acetylcysteine/pharmacology ; Aldehydes/metabolism ; Antioxidants/pharmacology ; Caco-2 Cells ; Copper Sulfate/pharmacology ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Humans ; Intestinal Mucosa/*metabolism ; Lipids/*biosynthesis ; Malondialdehyde/metabolism ; Oleic Acids/*metabolism ; Oxidants/pharmacology ; Oxidation-Reduction ; }, abstract = {The absorption, remodeling, and delivery of dietary lipids by intestinal cells are part of a complex multi-step process, the dynamics of which is influenced by the lipid composition of the diet and the physiological state of enterocytes. Emerging data indicate that, among the parameters known to modulate the cell functionality, the internal oxidative balance plays a pivotal role. In this study, we analyzed the effects of varying redox equilibria on the way in which the intestinal Caco-2 cell line utilize an exogenous lipid source such as oleic acid. Firstly, we manipulated the intracellular levels of soluble thiols (glutathione), and the amount of cell-associated products of lipid peroxidation, commonly regarded as two critical parameters characterizing the redox profile of the cells. Two different perturbants having opposite effects on the cell's redox profile were used: the pro-oxidizing agent CuSO4 (2.5 and 10 microM) and the antioxidant and thiol supplier N-acetylcysteine (NAC, 2.5 and 5 mM). The influence of these mild but critical manipulations on the incorporation of oleate (50 and 500 microM) into cholesterol, triacylglycerol, and phospholipid was then evaluated. We found that the emerging pro-oxidant condition induced by CuSO4 pre-exposure was associated with a significant up-regulation of phospholipid synthesis, while minor modifications were detected in that of triacylglycerols. Conversely, when a more reducing state was induced by NAC pre-treatment, there was a significant down-regulation of triacylglycerol synthesis, with minor modifications in that of phospholipids. In addition, the incorporation of oleic acid in the cholesteryl ester fraction appeared to be unmodified under all the redox conditions reported. On the whole, these results indicate that the pre-existing internal redox potential of the enterocytes is a critical factor that is able to differentially modulate lipid synthesis at the intestinal level. Thus, the adoption of a strategy designed to control/buffer the antioxidant capacity of the gastrointestinal tract could have important consequences for the modulation of lipid balance in the body.}, }
@article {pmid11358676, year = {2001}, author = {Bravo, E and Napolitano, M and Rivabene, R}, title = {Role of pre-existing redox profile of human macrophages on lipid synthesis and cholesteryl ester cycle in presence of native, acetylated and oxidised low density lipoprotein.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {77}, number = {1}, pages = {73-81}, doi = {10.1016/s0960-0760(01)00026-7}, pmid = {11358676}, issn = {0960-0760}, mesh = {Acetylcysteine/pharmacology ; Cells, Cultured ; Cholesterol Esters/*metabolism ; Copper Sulfate/pharmacology ; Humans ; Lipids/*biosynthesis ; Lipoproteins, LDL/*metabolism ; Macrophages/drug effects/*metabolism ; Oxidation-Reduction ; }, abstract = {The importance of the interactions of modified lipids and macrophages in foam cell generation is clear; however, little attention has been paid to the role of intra-macrophagic redox potential as a modulator of their lipid synthesis and metabolism. In this study, the effects of previously induced non-toxic manipulations of intracellular redox balance on lipid synthesis in human monocyte-derived macrophages (HMDM) was evaluated. Cells, pre-treated with 2.5 microM of the pro-oxidising agent CuSO(4) or with 5 mM of the antioxidant and thiol supplier N-acetylcysteine (NAC), were exposed to radiolabelled oleic acid alone or in combination with native low density lipoprotein (LDL) or modified LDL to evaluate the incorporation of radioactivity into cholesteryl ester, triacylglycerols and phospholipids. CuSO(4)-treated macrophages synthesised more lipids than NAC-treated cells in absence of exogenous lipid, and, generally, in the presence of native or acetylated, but oxidised LDL. In addition, the activities of the enzymes involved in cholesteryl ester storage were also influenced by the pro-oxidant condition. The ratio values between acyl-coenzyme A:cholesterol acyl transferase and cholesteryl ester hydrolase activity suggest that in CuSO(4)-treated macrophages the hydrolysis of cholesteryl ester is favoured with respect to esterification. The interaction of HMDM with oxidised LDL showed a significant different pattern in term of lipid synthesis with respect to those induced by native or acetylated LDL, disrespectful of the initial redox profile of the cells. On the whole, these results suggest that the pre-existing internal redox condition is a further parameter able to modulate the effects of native or acetylated LDL-cell interaction, influencing both HMDM lipid synthesis profile and cholesterol storage. Moreover, oxidised LDL represent a carrier of additional factor(s) able per se to introduce perturbation in the synthetic pathway of lipids, which is not influenced by the redox potential of the macrophage.}, }
@article {pmid11356710, year = {2001}, author = {Demary, K and Wong, L and Liou, JS and Faller, DV and Spanjaard, RA}, title = {Redox control of retinoic acid receptor activity: a novel mechanism for retinoic acid resistance in melanoma cells.}, journal = {Endocrinology}, volume = {142}, number = {6}, pages = {2600-2605}, doi = {10.1210/endo.142.6.8201}, pmid = {11356710}, issn = {0013-7227}, support = {CA-50459/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Blotting, Northern ; Blotting, Western ; Cell Hypoxia ; DNA/metabolism ; Dimerization ; *Drug Resistance, Neoplasm ; Gene Expression/drug effects ; Hydrogen Peroxide/pharmacology ; Luciferases/genetics ; Melanoma/drug therapy/*pathology ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Receptors, Retinoic Acid/genetics/metabolism/*physiology ; Recombinant Fusion Proteins ; Retinoid X Receptors ; Signal Transduction ; Transcription Factors/genetics/metabolism ; Transfection ; Tretinoin/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {Retinoic acid (RA) slows growth and induces differentiation of tumor cells through activation of RA receptors (RARs). However, melanoma cell lines display highly variable responsiveness to RA, which is a poorly understood phenomenon. By using Northern and Western blot analyses, we show that RA-resistant A375 and RA-responsive S91 melanoma cells express comparable levels of major components of RAR-signaling pathways. However, A375 cells have substantially higher intracellular reactive oxygen species (ROS) levels than S91 cells. Lowering ROS levels in A375 cells through hypoxic culture conditions restores RAR-dependent trans-activity, which could be further enhanced by addition of the antioxidant N-acetyl-cysteine. Hypoxia also enhances RAR activity in the moderately RA-responsive C32 cells, which have intermediate ROS levels. Conversely, increasing oxidative stress in highly RA-responsive S91 and B16 cells, which have low ROS levels, by treatment with H(2)O(2) impairs RAR activity. Consistent with these observations, RA more potently inhibited the proliferation of hypoxic A375 cells than that of normoxic cells. Oxidative states diminish, whereas reducing conditions enhance, DNA binding of retinoid X receptor/RAR heterodimers in vitro, providing a molecular basis for the observed inverse correlation between RAR activity and ROS levels. The redox state of melanoma cells provides a novel, epigenetic control mechanism of RAR activity and RA resistance.}, }
@article {pmid11354374, year = {2001}, author = {Oiry, J and Mialocq, P and Puy, JY and Fretier, P and Clayette, P and Dormont, D and Imbach, JL}, title = {NAC/MEA conjugate: a new potent antioxidant which increases the GSH level in various cell lines.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {11}, number = {9}, pages = {1189-1191}, doi = {10.1016/s0960-894x(01)00171-8}, pmid = {11354374}, issn = {0960-894X}, mesh = {Acetylcysteine/analogs &amp; derivatives/*chemical synthesis/*pharmacology ; Antioxidants/*chemical synthesis/*pharmacology ; Astrocytes/drug effects/metabolism ; CD4-Positive T-Lymphocytes/drug effects/metabolism ; Cell Line ; Cysteamine/analogs &amp; derivatives/*chemical synthesis/*pharmacology ; Glutathione/*metabolism ; HIV Infections/metabolism ; Humans ; Indicators and Reagents ; Macrophages/drug effects/metabolism ; Monocytes/drug effects/metabolism ; Prodrugs/*chemical synthesis/*pharmacology ; }, abstract = {I-152 is a prodrug of NAC and MEA with potent pro-GSH effects in human macrophages, astrocytes and lymphocytes. This molecule could be of interest in HIV infection in respect to its antioxidant and anti-HIV activities, but also in other diseases to counteract oxidative stress, that is, inflammation, cardiovascular diseases, and neurodegenerative diseases.}, }
@article {pmid11353799, year = {2001}, author = {Hirsch-Ernst, KI and Schlaefer, K and Bauer, D and Heder, AF and Kahl, GF}, title = {Repression of phenobarbital-dependent CYP2B1 mRNA induction by reactive oxygen species in primary rat hepatocyte cultures.}, journal = {Molecular pharmacology}, volume = {59}, number = {6}, pages = {1402-1409}, doi = {10.1124/mol.59.6.1402}, pmid = {11353799}, issn = {0026-895X}, mesh = {Acetylcysteine/pharmacology ; Amitrole/pharmacology ; Animals ; Cytochrome P-450 CYP2B1/*biosynthesis/drug effects/genetics ; Drug Interactions ; Enzyme Induction/drug effects ; Enzyme Inhibitors/pharmacology ; Excitatory Amino Acid Antagonists/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects ; Gene Silencing/physiology ; Hepatocytes/*drug effects/enzymology ; Hydrogen Peroxide/pharmacology ; In Vitro Techniques ; Male ; Phenobarbital/*pharmacology ; Promoter Regions, Genetic/drug effects ; RNA, Messenger/biosynthesis/drug effects ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*physiology ; Transcriptional Activation ; }, abstract = {Xenobiotic-metabolizing cytochrome P-450 (P-450) enzymes not only play a pivotal role in elimination of foreign compounds but also contribute to generation of toxic intermediates, including reactive oxygen species, that may elicit cellular damage if produced excessively. Expression of several xenobiotic-metabolizing P-450 enzymes is induced by phenobarbital (PB). Pronounced induction is observed for the rat CYP2B1 isoform. A primary rat hepatocyte culture system was used to investigate whether reactive oxygen species might modulate PB-dependent CYP2B1 induction. In cells cultivated for 3 days with 1.5 mM PB, substantial CYP2B1 mRNA induction was observed (100%). Addition of H(2)O(2) or of the catalase inhibitor 3-amino-1,2,4-triazole (AT) to the medium repressed induction to approximately 30% (at 1 mM H(2)O(2) and 2 mM AT, respectively). Accordingly, treatment of hepatocytes with PB and the glutathione precursor N-acetylcysteine (NAC) led to enhanced PB-dependent induction (to over 1000% at 10 mM NAC). In primary hepatocyte cultures transfected with a CYP2B1 promoter-luciferase construct containing approximately 2.7 kilobase pairs of the native CYP2B1 promoter sequence, PB-dependent reporter gene activation was repressed by AT and stimulated by N-acetylcysteine. Furthermore, a 263-base pair CYP2B1 promoter fragment encompassing the phenobarbital-responsive enhancer module conferred suppression of PB-dependent luciferase expression by AT and activation by NAC in a heterologous SV40-promoter construct. In summary, these data demonstrate a regulatory mechanism that is dependent on the cellular redox status, which modulates CYP2B1 mRNA induction by PB on the transcriptional level, thus representing a feedback mechanism preventing further P-450-dependent production of reactive oxygen intermediates under oxidative stress.}, }
@article {pmid11350834, year = {2001}, author = {Chan, ED and Riches, DW and White, CW}, title = {Redox paradox: effect of N-acetylcysteine and serum on oxidation reduction-sensitive mitogen-activated protein kinase signaling pathways.}, journal = {American journal of respiratory cell and molecular biology}, volume = {24}, number = {5}, pages = {627-632}, doi = {10.1165/ajrcmb.24.5.4280}, pmid = {11350834}, issn = {1044-1549}, support = {1K08HL036250-01/HL/NHLBI NIH HHS/United States ; HL 30068/HL/NHLBI NIH HHS/United States ; HL 52732/HL/NHLBI NIH HHS/United States ; HL 56263/HL/NHLBI NIH HHS/United States ; HL 56556/HL/NHLBI NIH HHS/United States ; HL 57144/HL/NHLBI NIH HHS/United States ; HL55549/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Proteins/*pharmacology ; Cell Line ; Electrophoresis, Polyacrylamide Gel ; Enzyme Activation/drug effects ; Immunoblotting ; JNK Mitogen-Activated Protein Kinases ; Lipopolysaccharides/pharmacology ; MAP Kinase Signaling System/*drug effects ; Macrophage Activation/drug effects/physiology ; Macrophages/cytology/drug effects/*metabolism ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Oxidation-Reduction/drug effects ; Phosphorylation/drug effects ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {The thiol reducing agent N-acetylcysteine (NAC) is commonly used as an "antioxidant" in studies examining gene expression, signaling pathways, and outcome in acute and chronic models of lung injury. It is less widely appreciated that NAC can also undergo auto-oxidation and behave as an oxidant. We showed previously that NAC can have opposite effects on the activation of nuclear factor-kappaB depending on whether or not serum is present, and that the effects of NAC in the absence of serum are mimicked by various oxidants. Here we show that in a serum-depleted environment (0.1% fetal bovine serum), NAC substantially inhibited lipopolysaccharide (LPS) activation of the mitogen-activated protein kinases (MAPKs), namely extracellular signal-regulated kinase (ERK), p38mapk, and c-Jun NH2-terminal kinase (JNK). By contrast, in the presence of 10% serum, NAC had no effect on LPS activation of p42 and p44 ERK and in fact enhanced LPS induction of p38mapk and JNK phosphorylation. Because serum can significantly alter the redox state, these findings highlight the importance of the local redox milieu in signal transduction.}, }
@article {pmid11350215, year = {2001}, author = {Panaretakis, T and Shabalina, IG and Grandér, D and Shoshan, MC and DePierre, JW}, title = {Reactive oxygen species and mitochondria mediate the induction of apoptosis in human hepatoma HepG2 cells by the rodent peroxisome proliferator and hepatocarcinogen, perfluorooctanoic acid.}, journal = {Toxicology and applied pharmacology}, volume = {173}, number = {1}, pages = {56-64}, doi = {10.1006/taap.2001.9159}, pmid = {11350215}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Caprylates/*pharmacology ; Carcinogens/pharmacology ; Carcinoma, Hepatocellular/*pathology ; Caspase 9 ; Caspases/metabolism ; Cyclosporine/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Flow Cytometry ; Fluorocarbons/*pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Kinetics ; Liver Neoplasms/*pathology ; Membrane Potentials ; Mitochondria, Liver/*physiology ; Reactive Oxygen Species/*metabolism ; Superoxides/metabolism ; Tumor Cells, Cultured ; }, abstract = {We have previously shown that one of the most potent rodent hepatocarcinogens, perfluorooctanoic acid (PFOA), induces apoptosis in human HepG2 cells in a dose- and time-dependent manner. In this study we have investigated the involvement of reactive oxygen species (ROS), mitochondria, and caspase-9 in PFOA-induced apoptosis. Treatment with 200 and 400 microM PFOA was found to cause a dramatic increase in the cellular content of superoxide anions and hydrogen peroxide after 3 h. Measurement of the mitochondrial transmembrane potential (Delta Psi(m)) after PFOA treatment showed a dissipation of Delta Psi(m) at 3 h. Caspase-9 activation was seen at 5 h after treatment with 200 microM PFOA. In order to evaluate the importance of these events in PFOA-induced apoptosis, cells were cotreated with PFOA and N-acetylcysteine (NAC), a precursor of glutathione, or Cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPT pore). NAC reduced Delta Psi(m) dissipation, caspase 9 activation, and apoptosis, indicating a role for PFOA-induced ROS. In addition, CsA also reduced Delta Psi(m) dissipation, caspase 9 activation, and apoptosis, indicating a role for PFOA-induced opening of the MPT pore. In summary, we have delineated a ROS and mitochondria-mediated pathway for induction of apoptosis by PFOA.}, }
@article {pmid11344087, year = {2001}, author = {Cuzzocrea, S and Mazzon, E and Dugo, L and Serraino, I and Ciccolo, A and Centorrino, T and De Sarro, A and Caputi, AP}, title = {Protective effects of n-acetylcysteine on lung injury and red blood cell modification induced by carrageenan in the rat.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {15}, number = {7}, pages = {1187-1200}, doi = {10.1096/fj.00-0526hyp}, pmid = {11344087}, issn = {0892-6638}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blotting, Western ; Carrageenan/toxicity ; DNA Damage/drug effects ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Erythrocytes/drug effects/ultrastructure ; Free Radical Scavengers/*pharmacology ; *I-kappa B Proteins ; Immunohistochemistry ; Intercellular Adhesion Molecule-1/metabolism ; Lung/pathology/*physiopathology ; Macrophages/drug effects/physiology ; Male ; Malondialdehyde/metabolism ; NF-KappaB Inhibitor alpha ; Neutrophils/physiology ; Nitrates/metabolism ; Nitric Oxide/metabolism ; P-Selectin/metabolism ; Peroxidase/metabolism ; Pleurisy/chemically induced/*drug therapy/pathology/physiopathology ; Poly(ADP-ribose) Polymerases/metabolism ; Rats ; Rats, Sprague-Dawley ; Tyrosine/*analogs &amp; derivatives/metabolism ; }, abstract = {Oxidative stress has been suggested as a potential mechanism in the pathogenesis of lung inflammation. The pharmacological profile of n-acetylcysteine (NAC), a free radical scavenger, was evaluated in an experimental model of lung injury (carrageenan-induced pleurisy). Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity that contained many neutrophils (PMNs), an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate, tumor necrosis factor alpha, and interleukin 1beta. All parameters of inflammation were attenuated by NAC treatment. Furthermore, carrageenan induced an up-regulation of the adhesion molecules ICAM-1 and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS), as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine, and PARS was reduced by NAC. In vivo NAC treatment significantly reduced peroxynitrite formation as measured by the oxidation of the fluorescent dihydrorhodamine-123, prevented the appearance of DNA damage, an decrease in mitochondrial respiration, and partially restored the cellular level of NAD+ in ex vivo macrophages harvested from the pleural cavity of rats subjected to carrageenan-induced pleurisy. A significant alteration in the morphology of red blood cells was observed 24 h after carrageenan administration. NAC treatment has the ability to significantly diminish the red blood cell alteration. Our results clearly demonstrate that NAC treatment exerts a protective effect and clearly indicate that NAC offers a novel therapeutic approach for the management of lung injury where radicals have been postulated to play a role.}, }
@article {pmid11341981, year = {2001}, author = {Galán, A and Troyano, A and Vilaboa, NE and Fernández, C and de Blas, E and Aller, P}, title = {Modulation of the stress response during apoptosis and necrosis induction in cadmium-treated U-937 human promonocytic cells.}, journal = {Biochimica et biophysica acta}, volume = {1538}, number = {1}, pages = {38-46}, doi = {10.1016/s0167-4889(00)00134-8}, pmid = {11341981}, issn = {0006-3002}, mesh = {Acetylcysteine ; Apoptosis ; Cadmium Chloride/*pharmacology ; Chaperonin 60/analysis ; DNA-Binding Proteins/metabolism ; Dose-Response Relationship, Drug ; Glutathione/deficiency ; HSP70 Heat-Shock Proteins/*biosynthesis/metabolism ; Heat Shock Transcription Factors ; *Hot Temperature ; Humans ; Methionine Sulfoximine/*analogs &amp; derivatives ; Monocytes/*drug effects ; Necrosis ; Proto-Oncogene Proteins/analysis ; Proto-Oncogene Proteins c-bcl-2/analysis ; RNA, Messenger/biosynthesis ; Transcription Factors ; Tumor Cells, Cultured ; bcl-2-Associated X Protein ; }, abstract = {Treatment for 2 h with 200 microM cadmium chloride, followed by recovery, caused apoptosis and induced heat-shock protein 70 (HSP70) expression in U-937 promonocytic cells. However, pre-incubation with the GSH depleting agent L-buthionine-[S,R]-sulfoximine (BSO, 1 mM for 24 h) caused necrosis instead of apoptosis and failed to induce HSP70 expression. This failure was a consequence of necrosis instead of GSH depletion, since BSO allowed or even potentiated HSP70 induction when used in combination with heat shock (2 h at 42.5 degrees C) or with 50 microM cadmium, which caused apoptosis. The administration of N-acetyl-L-cysteine (NAC) at the beginning of recovery after BSO/200 microM cadmium treatment prevented the execution of necrosis and restored the execution of apoptosis, but did not restore HSP70 induction, indicating that the inhibition by BSO of HSP70 expression is an early regulated event. This contrasted with the capacity of NAC to prevent the alterations caused by BSO/200 microM cadmium in other proteins, namely the suppression of Bax expression and the increase in Bcl-2 and HSP-60 expression. Finally, it was observed that treatment with 200 microM cadmium rapidly increased the HSP70 mRNA level and stimulated heat-shock factor 1 (HSF1) trimerization and binding, and that these effects were prevented by pre-incubation with BSO. Taken together, these results indicate that the stress response is compatible with apoptosis but not with necrosis in cadmium-treated promonocytic cells. The suppression of the stress response is specifically due to the early inhibition of HSF1 activation.}, }
@article {pmid11341511, year = {2001}, author = {Ghigliotti, G and Mereto, E and Eisenberg, PR and Martelli, A and Orsi, P and Sini, D and Spallarossa, P and Olivotti, L and Brunelli, C}, title = {N-acetyl-cysteine reduces neointimal thickening and procoagulant activity after balloon-induced injury in abdominal aortae of New Zealand white rabbits.}, journal = {Thrombosis and haemostasis}, volume = {85}, number = {4}, pages = {724-729}, pmid = {11341511}, issn = {0340-6245}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Aorta, Abdominal/drug effects/*injuries/pathology ; Catheterization/*adverse effects ; Cell Division ; Free Radical Scavengers/pharmacology/*therapeutic use ; Heparin/pharmacology/therapeutic use ; Hyperplasia ; Male ; Muscle, Smooth, Vascular/pathology ; Oxidative Stress ; Platelet Adhesiveness ; Rabbits ; Thromboplastin/*metabolism ; Tunica Intima/drug effects ; Wound Healing ; }, abstract = {BACKGROUND: Procoagulant activity and oxidative stress generated by balloon injury to normal vessels promote the migration of medial smooth muscle cells and their proliferation in the intima. We hypothesised that administering levo N-acetyl-cysteine (NAC) i.v. at the time of injury, and s.c. before and after injury would reduce neointimal formation 4 weeks later and would regulate procoagulant activity in vessels with neointima undergoing ballooning a second time.<br><br>METHODS AND RESULTS: at the time of injury rabbits received: NAC, unfractionated heparin (HEP) or both (NAC + HEP). Neointimal thickening at 28 days, calculated as the ratio between the intimal and medial area, was attenuated after NAC, HEP and NAC+HEP by 39%, 30% and 47% respectively when compared to untreated injured animals (CONTROLS) (p <0.05). At 28 days, bound thrombin activity and platelet adhesion 1 h after a repeated balloon injury decreased in animals receiving NAC, HEP and NAC+HEP bv 54%, 63% and 64% for thrombin activity (p <0.05 vs CONTROLS), and by 56%, 66% and 75% respectively for 111Indium-platelet deposition (p <0.05 vs CONTROLS).<br><br>CONCLUSIONS: NAC in-vivo was effective in reducing neointimal thickening and procoagulant response after balloon injury.}, }
@article {pmid11341102, year = {2001}, author = {Suwannaroj, S and Lagoo, A and Keisler, D and McMurray, RW}, title = {Antioxidants suppress mortality in the female NZB x NZW F1 mouse model of systemic lupus erythematosus (SLE).}, journal = {Lupus}, volume = {10}, number = {4}, pages = {258-265}, doi = {10.1191/096120301680416940}, pmid = {11341102}, issn = {0961-2033}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Adjuvants, Immunologic/pharmacology ; Animals ; Antioxidants/pharmacology/*therapeutic use ; Cysteamine/pharmacology/therapeutic use ; Female ; Free Radical Scavengers/pharmacology/therapeutic use ; Humans ; Lupus Erythematosus, Systemic/*drug therapy/immunology/mortality ; Mice ; Radiation-Protective Agents/pharmacology/therapeutic use ; T-Lymphocytes/drug effects/immunology ; }, abstract = {Inflammation produces reactive oxygen intermediates (ROI) that cause vascular damage and activate T lymphocytes. Conversely, antioxidants not only protect tissue from oxidative damage but also suppress immune reactivity. The objective of this study was to examine immunomodulatory effects of the non-enzymatic antioxidants, N-acetylcysteine (NAC) and cysteamine (CYST), on autoimmune disease, glomerulonephritis, and mortality in the female B/W mouse model of human systemic lupus erythematosus (SLE). The development of murine lupus was assessed during the lifespan of female B/W mice given NAC or CYST. Morbidity and mortality were assessed daily. At 6 week intervals mice were examined for weight change, albuminuria, serum BUN, antibodies to DNA, and IgG immunoglobulin levels. Serum prolactin, estrogen and progesterone were measured at 18 weeks of age. In a parallel study, NAC- and CYST-treated and control B/W mice were examined at 24 weeks of age for interval renal histopathology, lymphocyte adhesion molecule expression, and antibody titers and in vitro cytokine production in response to immunization with DNP-KLH. CYST significantly suppressed development of albuminuria and azotemia at 36 and 42 weeks of age compared to control and NAC-treated mice. NAC significantly suppressed anti-DNA antibody levels at 24 weeks. In contrast CYST significantly increased anti-DNA antibody levels at 18 weeks of age (P < 0.001 CYST vs control and NAC-treated mice). Kidneys of CYST-treated mice also had accelerated inflammatory histologic changes despite their lower incidence of albuminuria and azotemia. Mean (+/- s.e.m.) survival of control mice was 33 +/- 2 weeks compared to 38 +/- 2 weeks in NAC-treated mice (P < 0.05 vs control), and 48 +/- 2 weeks in the CYST-treated group (P < 0.01 vs control mice). The antioxidants, NAC and CYST, significantly improved mortality in the female B/W mouse model of SLE. NAC suppressed autoantibody formation and modestly prolonged survival. CYST, despite its augmentation of anti-DNA levels and renal inflammatory changes, inhibited the development of renal insufficiency and markedly improved survival. These findings suggest that ROIs play a role in the pathogenesis of lupus nephritis and that antioxidants reduce the damage causing renal insufficiency. Antioxidants may be a beneficial adjunctive therapy in the treatment of human SLE.}, }
@article {pmid11335071, year = {2001}, author = {Sha, SH and Taylor, R and Forge, A and Schacht, J}, title = {Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals.}, journal = {Hearing research}, volume = {155}, number = {1-2}, pages = {1-8}, doi = {10.1016/s0378-5955(01)00224-6}, pmid = {11335071}, issn = {0378-5955}, support = {R01 DC003685/DC/NIDCD NIH HHS/United States ; DC-03685/DC/NIDCD NIH HHS/United States ; }, mesh = {Animals ; Cell Survival/drug effects ; Free Radical Scavengers/pharmacology ; Free Radicals/toxicity ; Glutathione/metabolism/pharmacology ; Guinea Pigs ; Hair Cells, Auditory, Outer/*drug effects/injuries/pathology ; In Vitro Techniques ; Mannitol/pharmacology ; }, abstract = {The base of the cochlea is more vulnerable to trauma than the apex as seen in the pattern of hair cell damage by cisplatin or aminoglycosides. The differential vulnerability is maintained in organotypic cultures exposed directly to these drugs, suggesting there may be an intrinsic difference in sensitivity to damage along the cochlear spiral. We therefore investigated the survival capacity of isolated outer hair cells and strips dissected from different turns of the guinea pig organ of Corti in short-term culture. Cells were stained with fluorescent indicators of viable or dead cells, calcein-AM and ethidium homodimer. After 5 h at room temperature, up to 90% of outer hair cells from the apex survived, but less than 30% from the base. In contrast, basal inner hair cells remained viable, and supporting cells survived for at least 20 h. The difference in survival capacity between basal and apical outer hair cells coincided with a significantly lower level of the antioxidant glutathione in basal outer hair cells compared with apical outer hair cells. This suggested that basal outer hair cells may be more vulnerable to free-radical damage than apical outer hair cells. The survival of basal outer hair cells was significantly improved by addition of the radical scavengers n-acetyl cysteine, p-phenylenediamine, glutathione, mannitol or salicylate. The protection by antioxidants implies that the accelerated death of basal outer hair cells is due to free-radical damage. The results support an intrinsic susceptibility to free radicals that differs among cochlear cell populations. This differential provides a rational explanation for base-to-apex gradients observed in various forms of cochlear pathology.}, }
@article {pmid11330844, year = {2001}, author = {Vasdev, S and Ford, CA and Parai, S and Longerich, L and Gadag, V}, title = {Dietary vitamin C supplementation lowers blood pressure in spontaneously hypertensive rats.}, journal = {Molecular and cellular biochemistry}, volume = {218}, number = {1-2}, pages = {97-103}, pmid = {11330844}, issn = {0300-8177}, mesh = {Aldehydes/metabolism ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Blood Platelets/metabolism ; Blood Pressure/*drug effects ; Body Weight/drug effects ; Calcium/blood ; Dietary Supplements ; Drinking/drug effects ; Eating/drug effects ; Hyperplasia/pathology ; Hypertension/*drug therapy/pathology ; Liver/*drug effects/metabolism ; Organ Size/drug effects ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; }, abstract = {In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. Vitamin C can increase tissue cysteine and glutathione levels. The aim of the present study was to investigate whether a dietary supplementation of vitamin C can lower tissue aldehydes and blood pressure and normalize associated biochemical and histopathological changes in SHRs. Starting at 12 weeks of age, animals were divided into 3 groups of 6 animals each. Animals in the WKY-control group and SHR-control group were given a normal diet and the SHR-vitamin C group a diet supplemented with vitamin C (1000 mg/kg feed) for the next 9 weeks. After nine weeks, systolic blood pressure, platelet [Ca2+]i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared to WKY controls and the SHR-vitamin C group. SHR-controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin C supplementation in SHRs lowered the systolic blood pressure, tissue aldehyde conjugates and attenuated adverse renal vascular changes.}, }
@article {pmid11329937, year = {2000}, author = {Kusano, C and Takao, S and Noma, H and Yoh, H and Aikou, T and Okumura, H and Akiyama, S and Kawamura, M and Makino, M and Baba, M}, title = {N-acetyl cysteine inhibits cell cycle progression in pancreatic carcinoma cells.}, journal = {Human cell}, volume = {13}, number = {4}, pages = {213-220}, pmid = {11329937}, issn = {0914-7470}, mesh = {Acetylcysteine/*pharmacology ; Adenocarcinoma/*pathology ; Antineoplastic Agents/*pharmacology ; Cell Cycle/*drug effects ; Cell Line ; Depression, Chemical ; Humans ; Pancreatic Neoplasms/*pathology ; Tumor Cells, Cultured ; }, abstract = {The antioxidant N-acetyl cysteine (NAC) is a precursor of intracellular glutathione (GSH) and is also a well known as one of the chemopreventive agents which act through a variety of cellular mechanisms. We examined the effects of NAC on cell cycle progression in the pancreatic carcinoma cell lines, SW1990 and JHP1. Cells were incubated with or without NAC. Cell cycle distribution was analyzed by flow cytometry and immunoblotting. NAC suppressed cell proliferation in a concentration-dependent manner, whereas NAC increased intracellular glutathione content significantly in a dose-dependent manner. The percentage of cells in the G1 phase after treatment with NAC was significantly higher than the percentage seen for control cells. Cyclin D1 expression of carcinoma cells treated with NAC decreased remarkably compared with cells without NAC treatment. Thus, the antiproliferative effect of NAC by prolongation of the G1 phase in human pancreatic carcinoma cells shows its possible utility as an antitumor agent.}, }
@article {pmid11325872, year = {2001}, author = {Forbes, RA and Steenbergen, C and Murphy, E}, title = {Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism.}, journal = {Circulation research}, volume = {88}, number = {8}, pages = {802-809}, doi = {10.1161/hh0801.089342}, pmid = {11325872}, issn = {1524-4571}, support = {R01 HL039752/HL/NHLBI NIH HHS/United States ; R01-HL-39752/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cells, Cultured ; Diazoxide/*pharmacology ; Free Radical Scavengers/pharmacology ; Glycogen/metabolism ; Heart/*drug effects/physiology ; Hemodynamics/drug effects/physiology ; Hydrogen-Ion Concentration/drug effects ; In Vitro Techniques ; Ischemic Preconditioning, Myocardial/*methods ; Magnetic Resonance Spectroscopy ; Male ; Myocardial Contraction/drug effects ; Myocardium/cytology/*metabolism ; Oxidation-Reduction/drug effects ; Phosphates/metabolism ; Phosphocreatine/metabolism ; Phosphorus Isotopes ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Signal Transduction/*drug effects ; Vasodilator Agents/pharmacology ; Ventricular Function, Left/drug effects ; }, abstract = {Diazoxide, a selective opener of the mitochondrial ATP-sensitive potassium channel, has been shown to elicit tolerance to ischemia in cardiac myocytes and in perfused heart. However, the mechanism of this cardioprotection is poorly understood. Because reactive oxygen species (ROS) are recognized as important intracellular signaling molecules and have been implicated in ischemic preconditioning, we examined diazoxide-induced ROS production in adult cardiomyocytes. Cells treated with 50 micromol/L diazoxide showed a 173% increase in ROS production relative to baseline. 5-Hydroxydecanoate was found to attenuate the diazoxide-induced increase in ROS generation. The diazoxide-induced increase in ROS also was abrogated by the addition of either the antioxidant N-acetylcysteine (NAC) or N-mercaptopropionylglycine. We also examined the ability of NAC to block the protective effects of diazoxide in the perfused rat heart. After 20 minutes of global ischemia and 20 minutes of reflow, hearts perfused with 100 micromol/L diazoxide before ischemia showed significantly improved postischemic contractile function relative to untreated hearts (84% versus 29% of initial left ventricular developed pressure, respectively). Hearts treated with diazoxide in the presence of 4 mmol/L NAC recovered 53% of initial left ventricular developed pressure, whereas hearts treated with NAC alone recovered 46% of preischemic function. Using (31)P NMR spectroscopy, we found that, similar to preconditioning, diazoxide significantly attenuated ischemia-induced intracellular acidification and enhanced post- ischemic recovery of phosphocreatine levels, both of which were blocked by cotreatment with NAC. These data suggest that the cardioprotective actions of diazoxide are mediated by generation of a pro-oxidant environment.}, }
@article {pmid11322781, year = {2001}, author = {Shih, NL and Cheng, TH and Loh, SH and Cheng, PY and Wang, DL and Chen, YS and Liu, SH and Liew, CC and Chen, JJ}, title = {Reactive oxygen species modulate angiotensin II-induced beta-myosin heavy chain gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in neonatal rat cardiomyocytes.}, journal = {Biochemical and biophysical research communications}, volume = {283}, number = {1}, pages = {143-148}, doi = {10.1006/bbrc.2001.4744}, pmid = {11322781}, issn = {0006-291X}, mesh = {Angiotensin II/*pharmacology ; Angiotensin Receptor Antagonists ; Animals ; Animals, Newborn ; Antihypertensive Agents/pharmacology ; Antioxidants/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Fluoresceins ; Fluorescent Dyes ; Gene Expression/drug effects ; Mitogen-Activated Protein Kinase 1/genetics/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Myocardium/cytology/*metabolism ; Myosin Heavy Chains/*biosynthesis/genetics ; Phosphorylation/drug effects ; Proto-Oncogene Proteins c-raf/genetics/metabolism ; Rats ; Reactive Oxygen Species/*metabolism ; Receptor, Angiotensin, Type 1 ; Receptor, Angiotensin, Type 2 ; Signal Transduction/drug effects ; Transfection ; ras Proteins/genetics/metabolism ; }, abstract = {Angiotensin II (Ang II) causes cardiomyocytes hypertrophy. Cardiac beta-myosin heavy chain (beta-MyHC) gene expression can be altered by Ang II. The molecular mechanisms are not completely known. Reactive oxygen species (ROS) are involved in signal transduction pathways of Ang II. However, the role of ROS on Ang II-induced beta-MyHC gene expression remains unclear. Here we found that Ang II increased beta-MyHC promoter activity and it was blocked by Ang II type 1 receptor antagonist losartan. Ang II dose-dependently increased the intracellular ROS. Cardiomyocytes cotransfected with a dominant negative mutant of Ras (RasN17), Raf-1 (Raf301), or a catalytically inactive mutant of extracellular signal regulated kinase (mERK2) inhibited Ang II-induced beta-MyHC promoter activity, indicating Ras/Raf/ERK pathway was involved. Antioxidants such as catalase or N-acetyl-cysteine decreased Ang II-activated ERK phosphorylation and inhibited Ang II-induced beta-MyHC promoter activity. These data indicate that Ang II increases beta-MyHC gene expression in part via the generation of ROS.}, }
@article {pmid11322385, year = {2001}, author = {Chen, YC and Tsai, SH and Shen, SC and Lin, JK and Lee, WR}, title = {Alternative activation of extracellular signal-regulated protein kinases in curcumin and arsenite-induced HSP70 gene expression in human colorectal carcinoma cells.}, journal = {European journal of cell biology}, volume = {80}, number = {3}, pages = {213-221}, doi = {10.1078/0171-9335-00158}, pmid = {11322385}, issn = {0171-9335}, mesh = {Acetylcysteine/pharmacology ; Arsenites/*pharmacology ; Blotting, Northern ; Blotting, Western ; Colorectal Neoplasms/*metabolism ; Curcumin/*pharmacology ; Cyclooxygenase Inhibitors/pharmacology ; Dimerization ; Dose-Response Relationship, Drug ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; *Gene Expression Regulation, Neoplastic ; HSP70 Heat-Shock Proteins/*metabolism ; Humans ; Indomethacin/pharmacology ; MAP Kinase Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Phosphorylation ; Precipitin Tests ; Protein Binding ; Time Factors ; Transcription, Genetic ; Tumor Cells, Cultured ; }, abstract = {We have investigated the regulation mechanism of chemical stress-induced HSP70 gene expression in human colorectal carcinoma cells (COLO205 and HT29). Our data show that chemical treatments including sodium arsenite and curcumin, induced significant synthesis of HSP70 and its mRNA. The induced HSP70 gene expression appears to be increased at the transcriptional level. The increase in HSP70 gene expression by both chemicals is associated with an increase in HSF binding to HSE and induction of HSF1 di- or trimerization. Phosphorylation and activation of extracellular signal-regulated proteins (ERK1/2) were detected in sodium arsenite-treated COLO205 and HT29 cells, and the free radical scavenger N-acetyl-L-cysteine (NAC) was able to inhibit this ERK1/2 activation and HSP70 gene expression. MAPK blockade by the specific MEK1 inhibitor (PD98059) decreased the ability of sodium arsenite to increase HSP70 gene expression in a dose-dependent manner along with dephosphorylation of ERK1/2 proteins. In contrast to arsenite treatment, activation of ERK1/2 was not detected in curcumin-treated colorectal carcinoma cells, and NAC and PD98059 did not show any inhibitory effect on HSP70 gene expression induced by curcumin. Overexpression of a dominant negative mutant of mitogen-activated protein kinase kinase kinase 1 (MEKK1-DN) prevents arsenite-induced ERK1/2 phosphorylation and HSP70 protein synthesis. These results indicated that the ERK signaling pathway can participate in HSP70 gene expression induced by the prooxidant sodium arsenite, but not by the antioxidant curcumin.}, }
@article {pmid11320530, year = {2001}, author = {Wentzel, P and Wentzel, CR and Gäreskog, MB and Eriksson, UJ}, title = {Induction of embryonic dysmorphogenesis by high glucose concentration, disturbed inositol metabolism, and inhibited protein kinase C activity.}, journal = {Teratology}, volume = {63}, number = {5}, pages = {193-201}, doi = {10.1002/tera.1034}, pmid = {11320530}, issn = {0040-3709}, mesh = {Abnormalities, Drug-Induced ; Acetylcysteine/pharmacology ; Animals ; Diabetes Mellitus, Experimental/metabolism ; Dose-Response Relationship, Drug ; Embryo, Mammalian/abnormalities/*drug effects ; Embryonic and Fetal Development/*drug effects ; Enzyme Inhibitors/pharmacology ; Female ; Glucose/*pharmacology ; Indoles/pharmacology ; Inositol/*pharmacology ; Maleimides/pharmacology ; Models, Biological ; Models, Statistical ; Organ Culture Techniques ; Oxidative Stress ; Phospholipases A/biosynthesis ; Protein Kinase C/*antagonists &amp; inhibitors/biosynthesis ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; }, abstract = {BACKGROUND: Exposure to a diabetic environment causes excess reactive oxygen species (ROS), decreased prostaglandin E(2) (PGE(2)) concentration, and increased embryonic maldevelopment. The aim of the present work was to study whether embryonic dysmorphogenesis is also dependent on alterations of inositol and associated intracellular metabolites.<br><br>METHODS: Day 9 rat embryos were cultured for 24 or 48 hr and evaluated for gene expression. Day 10 and day 11 embryos from normal and diabetic rats were also examined. RT-PCR was used to study embryonic gene expression of protein kinase C (PKC) and cytosolic phospholipase A(2) (cPLA(2)).<br><br>RESULTS: Embryos exposed to 30 mmol/L glucose (30G), 500 or 750 micromol/L of scyllo-inositol (500SI or 750SI) had higher malformation score than control embryos cultured in 10 mmol/L glucose (10G). Adding 1.6 mmol/L inositol to the 30G or 750SI culture medium partly corrected these embryos, and completely normalized 500SI embryonic development. Adding 0.5 mmol/L N-acetylcysteine (NAC) or 280 nmol/L PGE(2) protected, and failed to protect, the SI-exposed embryos, respectively. 10G embryos exposed to the PKC inhibitor GF-109203X displayed dose-dependent dysmorphogenesis. Addition of 1.6 mmol/L inositol or 0.5 mmol/L NAC to the PKC-inhibitor-exposed 10G embryos largely normalized the outcome, whereas PGE(2) again failed to protect embryonic development. 30G culture tended to decrease the expression of cPLA(2) after 24 hr in vitro. We also found decreased mRNA levels of cPLA(2) in offspring of diabetic rats on gestational day 10 and of PKC on day 11, as compared with normal offspring.<br><br>CONCLUSIONS: High glucose concentration causes dysmorphogenesis in embryos by an interaction of oxidative stress and inositol depletion.}, }
@article {pmid11319613, year = {2001}, author = {Murakawa, M and Jung, SK and Iijima, K and Yonehara, S}, title = {Apoptosis-inducing protein, AIP, from parasite-infected fish induces apoptosis in mammalian cells by two different molecular mechanisms.}, journal = {Cell death and differentiation}, volume = {8}, number = {3}, pages = {298-307}, doi = {10.1038/sj.cdd.4400811}, pmid = {11319613}, issn = {1350-9047}, mesh = {Animals ; Anisakiasis/*metabolism/parasitology/veterinary ; Anisakis/physiology ; Apoptosis/*drug effects/physiology ; Apoptosis Regulatory Proteins/biosynthesis/genetics/isolation &amp; purification/*pharmacology ; Blotting, Western ; Caspase 3 ; Caspase 9 ; Caspases/metabolism ; Cell Line, Tumor ; Cytochromes c/metabolism ; Enzyme Activation ; Fish Diseases/*metabolism/parasitology/pathology ; HL-60 Cells ; Humans ; Hydrogen Peroxide/metabolism ; Lysine/deficiency/metabolism ; Mitochondria/metabolism ; Perciformes/*metabolism/parasitology ; Proto-Oncogene Proteins c-bcl-2/biosynthesis/physiology ; Recombinant Proteins/biosynthesis/genetics/isolation &amp; purification/pharmacology ; }, abstract = {AIP (apoptosis-inducing protein) is a protein purified and cloned from Chub mackerel infected with the larval nematode, Anisakis simplex, which induces apoptosis in various mammalian cells including human tumor cell lines. AIP has shown structural and functional homology to L-amino acid oxidase (LAO) which oxidizes several L-amino acids including L-lysine and AIP-induced apoptosis has been suggested to be mediated by H2O2 generated by LAO activity of AIP. In this study, we confirmed that recombinant AIP generated enough H2O2 in culture medium to induce rapid apoptosis in cells and this apoptosis was clearly inhibited by co-cultivation with antioxidants such as catalase and N-acetyl-cysteine. Surprisingly, however, we found that AIP still could induce H2O2-independent apoptosis more slowly than H2O2-dependent one in HL-60 cells even in the presence of antioxidants. In addition, the HL-60-derived cell line HP100-1, which is a H2O2-resistant variant, underwent apoptosis on treatment with AIP with a similar delayed time course. The latter apoptosis was completely blocked by addition of L-lysine to the culture medium, which is the best substrate of AIP as LAO, indicating that decreased concentration of L-lysine in the culture medium by AIP-treatment induced apoptosis. We also showed that the both apoptosis by AIP were associated with the release of cytochrome c from mitochondria and activation of caspase-9, and overexpressed Bcl-2 could inhibit both of the AIP-induced apoptosis. These results indicate that AIP induces apoptosis in cells by two distinct mechanisms; one rapid and mediated by H2O2, the other delayed and mediated by deprivation of L-lysine, both of which utilize caspase-9/cytochrome c system.}, }
@article {pmid11319275, year = {2000}, author = {Martin, KR and Kari, FW and Barrett, JC and French, JE}, title = {N-acetyl-L-cysteine simultaneously increases mitogenesis and suppresses apoptosis in mitogen-stimulated B-lymphocytes from p53 haploinsufficient Tg.AC (v-Ha-ras) mice.}, journal = {In vitro &amp; molecular toxicology}, volume = {13}, number = {4}, pages = {237-248}, pmid = {11319275}, issn = {1097-9336}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects/genetics/immunology ; B-Lymphocytes/cytology/*drug effects/immunology/metabolism ; Cell Survival/drug effects/genetics/immunology ; Cells, Cultured ; Concanavalin A/pharmacology ; Female ; Genes, p53/*genetics ; Genes, ras/*genetics ; Glutathione/metabolism ; Haplotypes/genetics ; Lipopolysaccharides/pharmacology ; Lymphocyte Activation/*drug effects/genetics ; Male ; Mice ; Mice, Transgenic ; Mitogens/*pharmacology ; Mitosis/*drug effects/immunology ; Oncogene Protein p21(ras)/genetics ; Oxidation-Reduction/drug effects ; Spleen/cytology/drug effects/immunology ; Tumor Suppressor Protein p53/*deficiency/genetics ; }, abstract = {Recent epidemiological evidence suggests that antioxidants may enhance carcinogenesis by promoting cellular proliferation and/or impeding programmed cell death. We examined the effect of N-acetyl-l-cysteine (NAC) on mitogenesis and apoptosis in splenocytes from p53 haploinsufficient Tg.AC (v-Ha-ras) mice. This model contains genetic lesions found frequently in human cancer and is predisposed to develop carcinogen-induced cancer. Splenocytes were incubated with NAC alone or with the B- and T-cell-specific mitogens Concanavalin A (Con A) and E. coli lipopolysaccharide (LPS), respectively. Mitogenesis increased 17-fold in mitogen-stimulated cultures and 10-fold in cultures incubated with NAC alone. Co-incubation with both NAC (1000 microg/mL) and mitogen increased mitogenesis by 33-fold without changing apoptosis rates. Strikingly, incubation with NAC and LPS attenuated LPS-induced apoptosis. Mitogen alone did not affect GSH levels but NAC-induced increases were significantly depleted by co-incubation with mitogen. Furthermore, NAC increased the number of CD45R+ B cells, but decreased CD3+ T cells showing enhanced survival of B cells under these conditions. These results demonstrate concurrent reduced apoptosis and increased mitogenesis in B lymphocytes that may favor clonal selection of preneoplastic cells.}, }
@article {pmid11311209, year = {2001}, author = {Opare Kennedy, D and Kojima, A and Hasuma, T and Yano, Y and Otani, S and Matsui-Yuasa, I}, title = {Growth inhibitory effect of green tea extract and (-)-epigallocatechin in Ehrlich ascites tumor cells involves a cellular thiol-dependent activation of mitogenic-activated protein kinases.}, journal = {Chemico-biological interactions}, volume = {134}, number = {2}, pages = {113-133}, doi = {10.1016/s0009-2797(00)00251-9}, pmid = {11311209}, issn = {0009-2797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/pharmacology ; Carcinoma, Ehrlich Tumor/*drug therapy/metabolism/pathology ; *Catechin/*analogs &amp; derivatives ; Cell Division/drug effects ; Cell Survival/drug effects ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Flavonoids/*pharmacology ; Kinetics ; Mice ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Phenols/pharmacology ; *Phytotherapy ; Plant Extracts/pharmacology ; Polymers/pharmacology ; Sulfhydryl Compounds/metabolism ; Tea/*therapeutic use ; Tumor Cells, Cultured ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {The effect of green tea extract (GTE) in Ehrlich ascites tumor cells (EATC) was studied with respect to changes in the intracellular kinase system involving mitogen-activated protein kinases (MAPKs) and cellular thiol. We have previously shown a reduction in viability of EATC and tyrosine phosphorylation of 42 and 45 kDa proteins by GTE and its polyphenolic component, Epigallocatechin (EGC) (D.O. Kennedy, S. Nishimura, T. Hasuma, Y. Yoshihisa, S. Otani, I. Matsui-Yuasa, Involvement of protein tyrosine phosphorylation in the effect of green tea polyphenols on Ehrlich ascites tumor cells in vitro, Chem. Biol. Interact. 110 (1998) 159-172). Furthermore, GTE and EGC significantly decreased both cellular non-protein and protein sulfhydryl levels in EATC, but replenishing thiol stores with N-acetylcysteine (NAC) caused a recovery in cell viability, and therefore SH groups were identified as a novel target of green tea cytotoxicity (D.O. Kennedy, M. Matsumoto, A. Kojima, I. Matsui-Yuasa, Cellular thiol status and cell death in the effect of green tea polyphenols in Ehrlich ascites tumor cells, Chem. Biol. Interact. 122 (1999) 59-71). In this study, we have observed the stimulation of three forms of MAPK, namely ERK1/2, JNK/SAPK and p38, by EGC, which were dose and time-dependent. These MAPK stimulations were found to be cellular thiol status-dependent events as NAC reversed these stimulations. Furthermore, inhibition of the p38 MAPK pathway using the p38 inhibitor SB203580 caused a marked dose-dependent reduction in the decrease in cell viability caused by EGC treatment. Inhibiting the Erk1/2 MAPK pathway using the MEK inhibitor PD098059 caused a slight change in the decrease in cell viability by EGC. These may suggest that the cytotoxicity associated with EGC was more associated with the other MAPKs than with ERK1/2. This may be the first study of its kind providing a novel evidence of a role for different forms of MAPKs in the antitumor effect of green tea polyphenols, especially EGC, in Ehrlich ascites tumor cells.}, }
@article {pmid11311048, year = {2001}, author = {Chiapponi, C and Carta, A and Petrucco, S and Maraini, G and Ottonello, S}, title = {Transcriptional up-regulation of the protooncogenes c-fos and c-jun following vitreous removal and short-term in vitro culture of bovine lenses.}, journal = {Experimental eye research}, volume = {72}, number = {5}, pages = {565-571}, doi = {10.1006/exer.2001.0982}, pmid = {11311048}, issn = {0014-4835}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cattle ; DNA Probes ; Dissection ; In Situ Hybridization ; Lens, Crystalline/anatomy &amp; histology/*physiology ; Organ Culture Techniques ; Proto-Oncogene Proteins c-fos/*physiology ; Proto-Oncogene Proteins c-jun/*physiology ; Transcriptional Activation/*physiology ; Vitreous Body/anatomy &amp; histology/*physiology ; }, abstract = {Chemical (mainly oxidative) and mechanical (anterior capsule injury) stresses have been reported to up-regulate the expression of the protooncogenes c-fos and c-jun in the lens. Another potentially stressful, yet largely unexplored condition, inherent to all experiments requiring the in vitro culturing of isolated lenses, is vitreous removal. Based on the results of an extensive RNA gel blot analysis conducted on epithelial/capsule preparations isolated from calf lenses dissected and cultured under different conditions, we show, here, that lens isolation and short-term culture (1-2.5 hr, without any significant GSH depletion) result in a strong and time-dependent up-regulation of the c-jun and c-fos mRNAs. This response, which relies on transcriptional protooncogene activation and is more intense for c-fos than for c-jun, is in part prevented by the preservation of the lens-vitreous contact, but not by the culture of vitreous-stripped lenses on a vitreous bed. Supplementation of the culture medium with the antioxidant N -acetyl-cysteine slightly reduced the c-jun, but not the c-fos response. Protooncogene up-regulation thus appears to be mainly determined by the disruption of critical lens-vitreous interactions. Since this response takes place in the epithelial cells, these data also point to the existence of a communication mechanism whereby a posteriorly applied mechanical stress is transmitted to, and perceived by, the anterior lens surface.}, }
@article {pmid11306435, year = {2001}, author = {Kawasaki, S and Takizawa, H and Takami, K and Desaki, M and Okazaki, H and Kasama, T and Kobayashi, K and Yamamoto, K and Nakahara, K and Tanaka, M and Sagai, M and Ohtoshi, T}, title = {Benzene-extracted components are important for the major activity of diesel exhaust particles: effect on interleukin-8 gene expression in human bronchial epithelial cells.}, journal = {American journal of respiratory cell and molecular biology}, volume = {24}, number = {4}, pages = {419-426}, doi = {10.1165/ajrcmb.24.4.4085}, pmid = {11306435}, issn = {1044-1549}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; *Benzene ; Bronchi/*cytology ; Cell Line ; Chemokine CCL5/metabolism ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/cytology/enzymology/immunology ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects/immunology ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Humans ; Imidazoles/pharmacology ; In Vitro Techniques ; Interleukin-8/*immunology ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/metabolism ; Pyridines/pharmacology ; Pyrrolidines/pharmacology ; RNA, Messenger/analysis ; T-Lymphocytes/immunology/metabolism ; Thiocarbamates/pharmacology ; Vehicle Emissions/*toxicity ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Epidemiologic and experimental studies suggest that diesel exhaust particles (DEPs) may be related to increasing respiratory mortality and morbidity. We have shown that DEPs augmented the production of inflammatory cytokines by human airway epithelial cells in vitro. To better understand the mechanisms of their proinflammatory activities, we studied the effects of several components extracted from DEPs on interleukin (IL)-8 expression in human bronchial epithelial cell line BEAS-2B and normal human airway epithelial cells obtained from very peripheral airways by an ultrathin bronchoscope. We used several agents active on signal transduction pathways in cytokine expression, such as the protein kinase C inhibitor staurosporin, antioxidant agents including N-acetyl cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. Benzene-extracted components showed effects mimicking DEPs on IL-8 gene expression, release of several cytokines (IL-8; granulocyte macrophage colony-stimulating factor; and regulated on activation, normal T cells expressed and secreted) and nuclear factor (NF)-kappa B activation. We also found that NAC, PDTC, and SB203580 suppressed the activities of DEPs and their benzene extracts, suggesting the roles of oxidants-mediated NF-kappa B activation and p38MAPK pathways. Finally, benzo[a]pyrene, one of the important compounds included in the benzene component, replicated the activities shown by DEPs.}, }
@article {pmid11304944, year = {2001}, author = {Lombardi, A and Drago, L and De Vecchi, E and Mombelli, B and Gismondo, MR}, title = {Antimicrobial activity of thiamphenicol-glycinate-acetylcysteinate and other drugs against Chlamydia pneumoniae.}, journal = {Arzneimittel-Forschung}, volume = {51}, number = {3}, pages = {264-267}, doi = {10.1055/s-0031-1300034}, pmid = {11304944}, issn = {0004-4172}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*pharmacology ; Cells, Cultured ; Chlamydophila pneumoniae/*drug effects ; Dietary Carbohydrates/metabolism ; Drug Combinations ; Food ; Humans ; Microbial Sensitivity Tests ; Thiamphenicol/analogs &amp; derivatives/*pharmacology ; }, abstract = {Chlamydia pneumoniae is responsible for respiratory tract infections of both upper and lower respiratory tract. Although this bacterium is one of the most wide-spread pathogens of man, there are limited data on the antibiotic treatment of C. pneumoniae infections. The aim of this study has been to evaluate the in vitro activity of thiamphenicol glycinate acetylcysteinate (TGA, CAS 20192-91-0) in comparison with molecules with established activity against C. pneumoniae, as well as macrolides and quinolones. The results have shown that TGA and clarithromycin (CAS 81103-11-9) are the most active drugs tested, but it is important to underline that the minimal inhibitory concentration (MIC) ranges of TGA are very much lower than the breakpoint of thlamphenicol for the respiratory pathogens. In conclusion, the good antimicrobial in vitro activity of TGA against C. pneumoniae together with its in vivo characteristics, in particular the high concentration reached in lung and the combination with the mucolytic agent N-acetylcysteine (NAC, CAS 616-91-1), can make a valid choice in the treatment of respiratory tract infections caused by C. pneumoniae. These findings need further evaluation by clinical studies.}, }
@article {pmid11303598, year = {2001}, author = {Pendyala, L and Schwartz, G and Bolanowska-Higdon, W and Hitt, S and Zdanowicz, J and Murphy, M and Lawrence, D and Creaven, PJ}, title = {Phase I/pharmacodynamic study of N-acetylcysteine/oltipraz in smokers: early termination due to excessive toxicity.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {10}, number = {3}, pages = {269-272}, pmid = {11303598}, issn = {1055-9965}, support = {N01-CN-55123/CN/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/*toxicity ; Adult ; Aged ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Therapy, Combination ; Fatigue/chemically induced ; Female ; Gastrointestinal Diseases/*chemically induced ; Humans ; Male ; Middle Aged ; Pyrazines/*administration &amp; dosage/*toxicity ; Reference Values ; Risk Assessment ; Smoking ; Thiones ; Thiophenes ; }, abstract = {An N-acetylcysteine (NAC)/oltipraz (OLZ) combination was studied in healthy volunteer smokers who received daily NAC (1200 mg/day) and were randomized to weekly placebo (Arm A), OLZ 200 mg (Arm B), or 400 mg (Arm C). Treatment was for 12 weeks with follow-up at 16 weeks. The objective was to study toxicity and the modulation of pharmacodynamic end points. After treatment of 19 of a planned 60 subjects, (Arm A, six; Arm B, four; and Arm C, nine), the study was closed because of toxicity. Eight subjects failed to complete 12 weeks of drug administration, (Arm A, two, and Arm C, six). The most frequent side effects were gastrointestinal, fatigue, conjunctival irritation, and skin rash. Pharmacodynamic end points were measured pretreatment and 48 h after the dose of OLZ at weeks 1, 5, and 12 and 4 weeks after the end of treatment. Glutathione (GSH) was measured in plasma and in peripheral blood lymphocytes (PBLs). Other end points measured in PBLs were the enzyme activities of total glutathione-S-transferase (GST), GSTpi, and NAD(P)H:quinone oxidoreductase; and the mRNA expression of gamma-glutamylcysteine synthetase gammaGCS), GSTpi, and NAD(P)H:quinone oxidoreductase. GSH in PBLs, GST (total), and the mRNA of gammaGCS showed increases at some time points in some subjects. Most consistent was the mRNA of gammaGCS, which showed a > or = 30% increase at one or more time points in 11 of 19 subjects. Other end points were unchanged. We concluded that NAC/OLZ modulates some end points related to GSH but is too toxic for chemoprevention at the doses used.}, }
@article {pmid11302009, year = {2000}, author = {Vasdev, S and Ford, CA and Parai, S and Longerich, L and Gadag, V}, title = {Dietary lipoic acid supplementation prevents fructose-induced hypertension in rats.}, journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD}, volume = {10}, number = {6}, pages = {339-346}, pmid = {11302009}, issn = {0939-4753}, mesh = {Aldehydes/metabolism ; Animals ; Aorta/drug effects/metabolism ; Blood Glucose/drug effects ; Blood Pressure/drug effects ; Dietary Supplements ; Disease Models, Animal ; Fructose/toxicity ; Hypertension/blood/chemically induced/*prevention &amp; control ; Insulin ; Kidney/drug effects/metabolism/pathology ; Rats ; Rats, Inbred WKY ; Thioctic Acid/*administration &amp; dosage/pharmacology/therapeutic use ; }, abstract = {BACKGROUND AND AIMS: In fructose-induced hypertension in Wistar-Kyoto (WKY) rats, excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, alter membrane Ca2+ channels and increase cytosolic free calcium and blood pressure. The thiol compound N-acetyl cysteine prevents such hypertension by binding these aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of this work was to investigate whether dietary supplementation of an endogenous fatty acid, alpha-lipoic acid, another thiol compound known to increase cysteine and glutathione, prevents this hypertension and its associated biochemical and histopathological changes.<br><br>METHODS AND RESULTS: Starting at seven weeks of age, animals were divided into three groups of six animals each and treated as follows: control (normal diet and normal drinking water); fructose (normal diet and 4% fructose in drinking water); fructose + lipoic acid (diet supplemented with lipoic acid 500 mg/kg feed and 4% fructose in drinking water). After 14 weeks, systolic blood pressure, platelet [Ca2+]i, plasma glucose and insulin and kidney and aortic aldehyde conjugates were significantly higher in the fructose group. These also displayed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys.<br><br>CONCLUSION: Dietary alpha-lipoic acid supplementation in fructose-treated WKY rats may prevent their increase in systolic blood pressure by normalizing cytosolic [Ca2+], blood glucose and insulin, kidney and aortic aldehyde conjugates and preventing adverse renal vascular changes.}, }
@article {pmid11299737, year = {2001}, author = {Kawakami, S and Kageyama, Y and Fujii, Y and Kihara, K and Oshima, H}, title = {Inhibitory effect of N-acetylcysteine on invasion and MMP-9 production of T24 human bladder cancer cells.}, journal = {Anticancer research}, volume = {21}, number = {1A}, pages = {213-219}, pmid = {11299737}, issn = {0250-7005}, mesh = {Acetylcysteine/*pharmacology ; Basement Membrane/metabolism ; Humans ; Matrix Metalloproteinase 9/*biosynthesis/genetics ; Matrix Metalloproteinase Inhibitors ; Neoplasm Invasiveness ; RNA, Messenger/biosynthesis ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Cells, Cultured ; Urinary Bladder Neoplasms/*enzymology/genetics/*pathology ; }, abstract = {BACKGROUND: MMPs play a crucial role in the process of cancer invasion and metastasis.<br><br>METHODS: The influence of NAC on invasion and MMP-9 production of human bladder cancer cell line T24 was investigated using an in vitro invasion assay, gelatin zymography, Western and Northern blot analyses and RT-PCR assays.<br><br>RESULTS: TPA increased the number of invading T24 cells through reconstituted basement membrane more than 10-fold compared to basal condition. NAC inhibited TPA-enhanced invasion dose-dependently. TPA increased the MMP-9 production by T24 cells without altering expression of TIMP-1 gene, while NAC suppressed TPA-enhanced production of MMP-9. Neither TPA nor NAC altered TIMP-1 mRNA level in T24 cells. In vitro experiments demonstrated that MMP-9 was directly inhibited by NAC but was not influenced by TPA.<br><br>CONCLUSION: NAC limits invasion of T24 human bladder cancer cells by inhibiting the MMP-9 production in addition to a direct inhibition of MMP-9 activity.}, }
@article {pmid11298119, year = {2001}, author = {Bengtsson, A and Lundberg, M and Avila-Cariño, J and Jacobsson, G and Holmgren, A and Scheynius, A}, title = {Thiols decrease cytokine levels and down-regulate the expression of CD30 on human allergen-specific T helper (Th) 0 and Th2 cells.}, journal = {Clinical and experimental immunology}, volume = {123}, number = {3}, pages = {350-360}, pmid = {11298119}, issn = {0009-9104}, mesh = {Acetylcysteine/pharmacology ; Clone Cells/drug effects ; Cytokines/*drug effects ; Dermatitis, Atopic/*immunology ; Dose-Response Relationship, Drug ; Down-Regulation ; Glutathione/pharmacology ; Humans ; Interleukin-4/pharmacology ; Ki-1 Antigen/*drug effects ; Sulfhydryl Compounds/*pharmacology ; T-Lymphocytes, Helper-Inducer/*immunology ; Th2 Cells/immunology ; }, abstract = {The thiol antioxidant N-acetyl- L-cysteine (NAC), known as a precursor of glutathione (GSH), is used in AIDS treatment trials, as a chemoprotectant in cancer chemotherapy and in treatment of chronic bronchitis. In vitro, GSH and NAC are known to enhance T cell proliferation, production of IL-2 and up-regulation of the IL-2 receptor. The 120-kD CD30 surface antigen belongs to the tumour necrosis factor (TNF) receptor superfamily. It is expressed by activated T helper (Th) cells and its expression is sustained in Th2 cells. We have analysed the effect of GSH and NAC on the cytokine profile and CD30 expression on human allergen-specific T cell clones (TCC). TCC were stimulated with anti-CD3 antibodies in the presence of different concentrations of GSH and NAC. Both thiols caused a dose dependent down-regulation of IL-4, IL-5 and IFN-gamma levels in Th0 and Th2 clones, with the most pronounced decrease of IL-4. Furthermore, they down-regulated the surface expression of CD30, and the levels of soluble CD30 (sCD30) in the culture supernatants were decreased. In contrast, the surface expression of CD28 or CD40 ligand (CD40L) was not significantly changed after treatment with 20 m M NAC. These results indicate that GSH and NAC favour a Th1 response by a preferential down-regulation of IL-4. In addition, the expression of CD30 was down regulated by GSH and NAC, suggesting that CD30 expression is dependent on IL-4, or modified by NAC. In the likely event that CD30 and its soluble counterpart prove to contribute to the pathogenesis in Th2 related diseases such as allergy, NAC may be considered as a future therapeutic agent in the treatment of these diseases.}, }
@article {pmid11292581, year = {2001}, author = {Pande, M and Mehta, A and Pant, BP and Flora, SJ}, title = {Combined administration of a chelating agent and an antioxidant in the prevention and treatment of acute lead intoxication in rats.}, journal = {Environmental toxicology and pharmacology}, volume = {9}, number = {4}, pages = {173-184}, doi = {10.1016/s1382-6689(01)00064-3}, pmid = {11292581}, issn = {1872-7077}, abstract = {The administration of chelating agents, meso 2,3-dimercaptosuccinic acid (DMSA), monoisoamyl DMSA (MiADMSA) either individually or in combination with an antioxidant, n-acetylcysteine (NAC) in the prevention and treatment of acute lead intoxication in rats, was investigated. The results suggest that concomitant oral supplementation of DMSA with lead was most effective in preventing the inhibition of lead sensitive blood delta-aminolevulinic acid dehydratase (ALAD) activity in blood, elevation of zinc protoporphyrin level and the alterations in hepatic reduced and oxidized glutathione (GSH and GSSG) contents. A number of other biochemical variables either remained insensitive to lead exposure or responded moderately to chelation treatment. Combined administrations of NAC plus DMSA was most effective when given during lead exposure or post exposure, followed by DMSA and MiADMSA alone or NAC plus MiADMSA treatment, in reducing the accumulation of lead in blood and liver. Administration of NAC alone was only mildly effective in preventing lead absorption in the blood and tissues. The results suggest that combined administration of DMSA and NAC could be a more effective treatment protocol for acute lead toxicity, keeping in view its beneficial effect on oxidative injury.}, }
@article {pmid11277202, year = {2001}, author = {Hill, AS and O'Neill, S and Rogers, QR and Christopher, MM}, title = {Antioxidant prevention of Heinz body formation and oxidative injury in cats.}, journal = {American journal of veterinary research}, volume = {62}, number = {3}, pages = {370-374}, doi = {10.2460/ajvr.2001.62.370}, pmid = {11277202}, issn = {0002-9645}, mesh = {Acetylcysteine/*pharmacology ; Anemia, Hemolytic/blood/prevention &amp; control/*veterinary ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cat Diseases/blood/*prevention &amp; control ; Cats ; Eating/drug effects ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/blood ; Heinz Bodies/*drug effects ; Hematocrit/veterinary ; Male ; Propylene Glycol/adverse effects ; Prospective Studies ; Random Allocation ; Specific Pathogen-Free Organisms ; Vitamin E/*pharmacology ; }, abstract = {OBJECTIVE: To determine the effectiveness of 3 antioxidants in preventing Heinz body anemia in cats.<br><br>DESIGN: Prospective study.<br><br>ANIMALS: 44 specific-pathogen-free healthy cats.<br><br>PROCEDURE: Cats were housed individually, divided randomly into 4 groups, and given the following orally every 12 hours: empty gelcaps (control cats), N-acetylcysteine (NAC, 100 mg/kg of body weight), vitamin E (d,l-alpha-tocopherol; 400 IU), or ascorbate (250 mg). After 2 weeks, Heinz bodies were induced by dietary onion powder (OP; 1% or 3% of dry matter) or propylene glycol (PG, 8% wt/vol in drinking water) for an additional 3 weeks. Intake of treated water or food was recorded daily. Body weight, PCV, Heinz body and reticulocyte percentages, reduced glutathione concentration, and total antioxidant status were measured twice weekly in all cats.<br><br>RESULTS: Heinz body percentage and degree of anemia did not differ significantly among cats receiving antioxidants and control cats except in cats that ingested water containing PG, in which antioxidant supplementation was associated with a decrease in water intake. Of cats that were fed a diet that contained OP, cats that received NAC had significantly higher reduced glutathione concentrations, compared with other cats in the experiment. Total antioxidant status did not consistently correlate with antioxidant supplementation or type of oxidant administered (ie, OP or PG).<br><br>Although the effect of antioxidant supplementation on Heinz body anemia in cats was minimal, antioxidants may have subclinical biochemical effects such as GSH sparing that may be important against milder forms of oxidative stress.}, }
@article {pmid11271461, year = {2001}, author = {Seko, Y and Pang, J and Tokoro, T and Ichinose, S and Mochizuki, M}, title = {Blue light-induced apoptosis in cultured retinal pigment epithelium cells of the rat.}, journal = {Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie}, volume = {239}, number = {1}, pages = {47-52}, doi = {10.1007/s004170000220}, pmid = {11271461}, issn = {0721-832X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*radiation effects ; Cells, Cultured ; Free Radical Scavengers/pharmacology ; In Situ Nick-End Labeling ; Light/*adverse effects ; Pigment Epithelium of Eye/drug effects/*radiation effects/ultrastructure ; Rats ; Rats, Long-Evans ; }, abstract = {BACKGROUND: We previously demonstrated that phagosome-free retinal pigment epithelium (RPE) cells in culture can be damaged directly by blue light (wavelength 440+/-10 nm) as observed by electron microscope. A low intensity (1.0 mW/cm2) of light induced only swelling of mitochondria, while a high intensity (4.0 mW/cm2) induced necrosis in the RPE. The aim of the present study was to investigate what intensity of blue light could induce apoptosis in cultured phagosome-free RPE.<br><br>METHODS: Primary cultured RPE cells, harvested from Long-Evans rats, that contained no phagosomes were exposed to a cool blue light (wavelength 440+/-10 nm). After exposure, transmission electron microscopy (TEM) and TdT-mediated dUTP nick-end labeling (TUNEL) staining were used to detect apoptosis in the RPE cells. To assess the relationship of oxidation to apoptosis by blue light, we added N-acetylcysteine (NAC) as a free radical scavenger and investigated its inhibitory effect on apoptosis.<br><br>RESULTS: In RPE cells exposed to blue light of 2.7 mW/cm2 for 24 h, apoptotic bodies were found by TEM. In RPE cells exposed to blue light of 2.0 mW/cm2 for 60 h, apoptotic bodies, nuclear condensation and nuclear segmentation were observed by TEM and some RPE cells showed positive TUNEL staining. When 30 mM of NAC was added, TUNEL staining was negative.<br><br>CONCLUSION: Our findings demonstrate that apoptotic cell death is induced by blue light exposure in cultured RPE cells in vitro. The findings of our previous experiments and those of the present study suggest that a higher intensity of blue light could induce necrosis, and moderately intense blue light could induce non-necrotic cell death or apoptosis, in RPE cells. Furthermore, it is suggested that blue light caused cell death by a free-radical-associated mechanism.}, }
@article {pmid11269657, year = {2001}, author = {Daum, G and Pham, J and Deou, J}, title = {Arsenite inhibits Ras-dependent activation of ERK but activates ERK in the presence of oncogenic Ras in baboon vascular smooth muscle cells.}, journal = {Molecular and cellular biochemistry}, volume = {217}, number = {1-2}, pages = {131-136}, pmid = {11269657}, issn = {0300-8177}, support = {HL18645/HL/NHLBI NIH HHS/United States ; HL30946/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Arsenites/*pharmacology ; Becaplermin ; Cells, Cultured ; Enzyme Activation ; Genetic Vectors ; Guanosine Triphosphate/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Muscle, Smooth, Vascular/drug effects/*enzymology ; Oxidation-Reduction ; Oxidative Stress ; Papio ; Phosphorylation ; Platelet-Derived Growth Factor/pharmacology ; Proto-Oncogene Proteins c-sis ; Retroviridae/genetics ; ras Proteins/genetics/*metabolism ; }, abstract = {Exposure to arsenical compounds enhances the risk of atherosclerosis. The reason is unknown but it might be because an effect of arsenite (As3+) on plaque smooth muscle cells (SMCs) activation of extracellular signal-regulated kinase (ERK), a crucial mediator of SMC function. We found that arsenite inhibits the activation of ERK by platelet-derived growth factor-BB (PDGF-BB). This inhibitory effect depends on the time of arsenite exposure, is reversible, and is attenuated by preincubation of SMCs with the antioxidant N-acetyl-cysteine. These observations are consistent with the assumption that oxidative stress is involved. The blockade of ERK by arsenite may be mediated by an inhibition of Ras as arsenite prevents GTP-loading of Ras in response to PDGF-BB. Moreover, the Ras blockade by arsenite is not specific for PDGF-BB because it was also observed following stimulation of SMCs with EGF. To address the role of Ras, we expressed constitutively active, GTP-bound Ha-Ras (V12Ras). Unexpectedly, in V12Ras expressing-SMCs, arsenite stimulates ERK, but still decreases ERK activity in the presence of PDGF-BB. Our data suggest that arsenite inhibits the Ras/ERK pathway in SMCs, and that arsenite may activate ERK in Ras-transformed cells by mechanisms different from those employed by growth factors.}, }
@article {pmid11261888, year = {2001}, author = {Chen, YJ and Shiao, MS and Wang, SY}, title = {The antioxidant caffeic acid phenethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HL-60 cells.}, journal = {Anti-cancer drugs}, volume = {12}, number = {2}, pages = {143-149}, doi = {10.1097/00001813-200102000-00008}, pmid = {11261888}, issn = {0959-4973}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Caffeic Acids/*pharmacology ; Catalase/metabolism ; Cell Cycle/drug effects ; Cytotoxins/*pharmacology ; DNA Damage/drug effects ; DNA, Neoplasm/analysis ; Glutathione/metabolism ; HL-60 Cells/*drug effects/metabolism ; Humans ; Hydrogen Peroxide/*metabolism ; Oxidation-Reduction ; Phenylethyl Alcohol/*analogs &amp; derivatives/*pharmacology ; Reactive Oxygen Species ; Superoxides/metabolism ; }, abstract = {Caffeic acid phenethyl ester (CAPE), an active component of propolis, has many biological and pharmacological activities including antioxidation and tumor cell cytotoxicity. We examined the type of cell death in human leukemic HL-60 cells after CAPE treatment in order to elucidate the relationship between CAPE-induced alterations of the redox state and apoptosis. CAPE treatment (6 microg/ml) resulted in marked growth inhibition up to 70.3+/-4.0% at day 2. This inhibition was partially blocked by pretreatment with N-acetyl-L-cycteine (NAC). Agarose gel electrophoresis showed evident DNA fragmentation after CAPE treatment. CAPE induced a significant decrease in mitochondrial transmembrane potential to about half of the untreated level after 6 h and a rapid depletion of intracellular glutathione (GSH) down to 41.7+/-6.0% after 1 h. Pretreatment of HL-60 cells with NAC reversed the GSH depletion and partially rescued cells from CAPE-induced apoptosis. With regard to intracellular reactive oxygen species, CAPE caused a fast and profound scavenging of H202 (19% of untreated cells after a 2-h treatment) but not of superoxide anion. These results suggest that apoptosis induced by CAPE is associated with mitochondrial dysfunction, GSH depletion and selective scavenging of H2O2 in human leukemic HL-60 cells.}, }
@article {pmid11256490, year = {2001}, author = {Lee, MG and Lee, KT and Chi, SG and Park, JH}, title = {Costunolide induces apoptosis by ROS-mediated mitochondrial permeability transition and cytochrome C release.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {24}, number = {3}, pages = {303-306}, doi = {10.1248/bpb.24.303}, pmid = {11256490}, issn = {0918-6158}, mesh = {Animals ; Antineoplastic Agents, Phytogenic/*pharmacology ; Apoptosis/*drug effects ; Blotting, Western ; Caspases/metabolism ; Cell Fractionation ; Cytochrome c Group/*metabolism ; Drug Screening Assays, Antitumor ; Enzyme Activation/drug effects ; Humans ; Membrane Potentials/drug effects ; Mitochondria/drug effects/enzymology/*metabolism ; Permeability/drug effects ; Rats ; Reactive Oxygen Species/*metabolism ; Sesquiterpenes/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {Costunolide is an active compound isolated from the root of Saussurea lappa Clarks, a Chinese medicinal herb, and is considered a therapeutic candidate for various types of cancers. Nevertheless, the pharmacological pathways of costunolide are still unknown. In this study, we investigate the effects of costunolide on the induction of apoptosis in HL-60 human leukemia cells and its putative pathways of action. Using apoptosis analysis, measurement of reactive oxygen species (ROS), and assessment of mitochondrial membrane potentials, we show that costunolide is a potent inducer of apoptosis, and facilitates its activity via ROS generation, thereby inducing mitochondrial permeability transition (MPT) and cytochrome c release to the cytosol. ROS production, mitochondrial alteration, and subsequent apoptotic cell death in costunolide-treated cells were blocked by the antioxidant N-acetylcystein (NAC). Cyclosporin A, a permeability transition inhibitor, also inhibited mitochondrial permeability transition and apoptosis. Our data indicate that costunolide induces the ROS-mediated mitochondrial permeability transition and resultant cytochrome c release. This is the first report on the mechanism of the anticancer effect of costunolide.}, }
@article {pmid11247927, year = {2001}, author = {Hoshikawa, Y and Ono, S and Suzuki, S and Tanita, T and Chida, M and Song, C and Noda, M and Tabata, T and Voelkel, NF and Fujimura, S}, title = {Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {90}, number = {4}, pages = {1299-1306}, doi = {10.1152/jappl.2001.90.4.1299}, pmid = {11247927}, issn = {8750-7587}, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Animals ; Antioxidants/pharmacology ; Chronic Disease ; Enzyme Inhibitors/pharmacology ; Hypertension, Pulmonary/*metabolism/pathology/physiopathology ; Hypertrophy, Right Ventricular/pathology/physiopathology ; Lung/metabolism ; Male ; *Oxidative Stress ; Oxygen/metabolism/*pharmacology ; Phosphatidylcholines/metabolism ; Pulmonary Artery/pathology ; Rats ; Rats, Sprague-Dawley ; Tunica Media/pathology ; Ventricular Function, Right ; Xanthine Oxidase/metabolism ; }, abstract = {Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with pulmonary vascular remodeling. Because hypoxia might promote generation of oxidative stress in vivo, we hypothesized that oxidative stress may play a role in the hypoxia-induced cardiopulmonary changes and examined the effect of treatment with the antioxidant N-acetylcysteine (NAC) in rats. NAC reduced hypoxia-induced cardiopulmonary alterations at 3 wk of hypoxia. Lung phosphatidylcholine hydroperoxide (PCOOH) increased at days 1 and 7 of the hypoxic exposure, and NAC attenuated the increase in lung PCOOH. Lung xanthine oxidase (XO) activity was elevated from day 1 through day 21, especially during the initial 3 days of the hypoxic exposure. The XO inhibitor allopurinol significantly inhibited the hypoxia-induced increase in lung PCOOH and pulmonary hypertension, and allopurinol treatment only for the initial 3 days also reduced the hypoxia-induced right ventricular hypertrophy and pulmonary vascular thickening. These results suggest that oxidative stress produced by activated XO in the induction phase of hypoxic exposure contributes to the development of chronic hypoxic pulmonary hypertension.}, }
@article {pmid11246305, year = {2001}, author = {Heller, AR and Groth, G and Heller, SC and Breitkreutz, R and Nebe, T and Quintel, M and Koch, T}, title = {N-acetylcysteine reduces respiratory burst but augments neutrophil phagocytosis in intensive care unit patients.}, journal = {Critical care medicine}, volume = {29}, number = {2}, pages = {272-276}, doi = {10.1097/00003246-200102000-00009}, pmid = {11246305}, issn = {0090-3493}, mesh = {APACHE ; Acetylcysteine/*pharmacology/*therapeutic use ; Adult ; Analysis of Variance ; Female ; Flow Cytometry ; Free Radical Scavengers/*pharmacology/*therapeutic use ; Hospital Mortality ; Humans ; Infusions, Intravenous ; Length of Stay/statistics &amp; numerical data ; Male ; Middle Aged ; Neutrophils/*drug effects/immunology ; Phagocytosis/*drug effects/immunology ; Prospective Studies ; Respiratory Burst/*drug effects/immunology ; Shock, Septic/blood/*drug therapy/immunology/mortality ; Survival Analysis ; Time Factors ; }, abstract = {OBJECTIVE: The antioxidant N-acetylcysteine (NAC) has been shown to attenuate septic tissue injury. To evaluate whether NAC affects host defense mechanisms in critically ill patients, thus predisposing to increased risk of infection, the current study focuses on neutrophil phagocytotic and burst activity after treatment with NAC.<br><br>DESIGN: Prospective, randomized, clinical trial.<br><br>SETTING: Twelve-bed operative intensive care unit in a university hospital.<br><br>PATIENTS: Thirty patients diagnosed with sepsis/systemic inflammatory response syndrome, or multiple trauma.<br><br>INTERVENTIONS: Patients were randomly assigned to receive either NAC (n = 15) for 4 days in increasing dosages (day 1: 6 g; day 2: 12 g; days 3 and 4: 18 g) or a mucolytic basis dosage of NAC (3 x 300 mg/day [control]; n = 15), respectively.<br><br>MEASUREMENTS AND MAIN RESULTS: Blood samples were taken before NAC high-dose infusion (day 1), after increasing doses of NAC (days 3 and 5) and 4 days after the last high-dose treatment (day 8). Neutrophil oxidative burst activity after stimulation with Escherichia coli and polymorphonuclear phagocytosis were determined in a flow cytometric assay. Baseline values of polymorphonuclear functions were comparable in both groups. NAC high-dose treatment resulted in a significantly improved phagocytosis activity compared with control patients. In contrast to this, polymorphonuclear burst activity was significantly reduced in the NAC high-dose treated group on day 3.<br><br>CONCLUSION: These findings suggest that infusion of NAC in high doses affects granulocyte functions in critically ill patients. Antimicrobial host defense requires the effective sequence of cell adhesion, phagocytosis, and bactericidal respiratory burst. The enhanced phagocytotic activity might be a compensatory mechanism in states of impaired respiratory burst to maintain tissue sterility. For certain mechanisms of disease, the effects observed might be favorable (e.g., ischemia/reperfusion, endothelial cell activation), for others (infection) this might be detrimental.}, }
@article {pmid11246218, year = {2001}, author = {Hoffmann, GR and Buccola, J and Merz, MS and Littlefield, LG}, title = {Structure-activity analysis of the potentiation by aminothiols of the chromosome-damaging effect of bleomycin in G0 human lymphocytes.}, journal = {Environmental and molecular mutagenesis}, volume = {37}, number = {2}, pages = {117-127}, doi = {10.1002/em.1019}, pmid = {11246218}, issn = {0893-6692}, mesh = {Bleomycin/*toxicity ; *Chromosome Aberrations ; Cysteamine/*pharmacology ; Drug Synergism ; Humans ; Lymphocytes/cytology/*drug effects ; Mercaptoethylamines/*pharmacology ; Micronucleus Tests ; Resting Phase, Cell Cycle ; Structure-Activity Relationship ; }, abstract = {The radioprotective aminothiols 2-[(aminopropyl)amino] ethanethiol (WR-1065) and cysteamine (CSM) potentiate the induction of chromosomal damage by the radiomimetic compound bleomycin (BLM) in G0 human lymphocytes. To investigate the mechanism of potentiation, we measured the clastogenic activity of BLM in the cytokinesis-block micronucleus assay in the presence and absence of amines, thiols, and aminothiols. The hydroxy analog of WR-1065, 2-(3-aminopropylamino) ethanol (WR-OH), potentiates BLM only slightly, indicating the critical nature of the thiol group. As thiols, WR-1065 and CSM may donate electrons for the activation of Fe(+2)-BLM or for the regeneration of Fe(+2)-BLM from inactive Fe(+3)-BLM. The amines putrescine, spermidine, and spermine all potentiate BLM, but they are weaker potentiators than the aminothiols, and they are effective only at high concentrations. Their activity, like that of WR-OH, is probably a consequence of conformational alteration of DNA. Dithioerythritol (DTE) and 2-mercaptoethanol (2-ME), thiols lacking an amino group, are less effective potentiators of BLM than are the aminothiols. The thiol group of WR-1065 and CSM is therefore essential, but insufficient, for explaining the strong enhancement of BLM activity. The cationic nature of CSM and WR-1065, conferred by the amino groups, evidently concentrates the active thiol function at the site of BLM action on DNA. As expected on this basis, the diamine WR-1065 is a more effective potentiator of BLM than is the monoamine CSM, whereas cysteine and N-acetylcysteine (NAC), which lack a net positive charge, potentiate BLM only weakly. These studies suggest that potentiation of the clastogenic action of BLM by aminothiols can be explained by the combination of a thiol-mediated redox mechanism and an amine-mediated targeting of the thiol function to DNA.}, }
@article {pmid11243251, year = {2000}, author = {Iciek, M and Polak, M and Włodek, L}, title = {Effect of thiol drugs on the oxidative hemolysis in human erythrocytes.}, journal = {Acta poloniae pharmaceutica}, volume = {57}, number = {6}, pages = {449-454}, pmid = {11243251}, issn = {0001-6837}, mesh = {Acetylcysteine/pharmacology ; Captopril/pharmacology ; Hemolysis/*drug effects ; Humans ; Methimazole/pharmacology ; Penicillamine/*analogs &amp; derivatives/pharmacology ; Reactive Oxygen Species ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {The effect of different thiol drugs and 2-methyl-thiazolidine-2,4-dicarboxylic acid on the oxidative stress, induced by hydrogen peroxide, was examined in human erythrocytes. The results indicated that captopril (CA), methimazole, N-acetylcysteine (NAC), penicillamine and precursor of L-cysteine 2-methyl-thiazolidine-2,4-dicarboxylic acid (CP) might protect the erythrocyte membrane against lipid peroxidation in the experimental conditions. Captopril, methimazole and penicillamine had the strongest antioxidative properties at the concentration level of 0.5 mM. The protective effects gradually decreased at higher and lower concentrations of these drugs. Contrary, the antioxidative properties of N-acetylcysteine increased with its levels growing in the reaction mixture, and only N-acetylpenicillamine did not protect erythrocytes against oxidative damages. The effect of 2-methyl-thiazolidine-2,4-dicarboxylic acid showed in these in vitro experimental conditions that it could act as an antioxidant at the concentration as high as 5 mM and higher.}, }
@article {pmid11237327, year = {2001}, author = {Harada, D and Naito, S and Kawauchi, Y and Ishikawa, K and Koshitani, O and Hiraoka, I and Otagiri, M}, title = {Determination of reduced, protein-unbound, and total concentrations of N-acetyl-L-cysteine and L-cysteine in rat plasma by postcolumn ligand substitution high-performance liquid chromatography.}, journal = {Analytical biochemistry}, volume = {290}, number = {2}, pages = {251-259}, doi = {10.1006/abio.2000.4980}, pmid = {11237327}, issn = {0003-2697}, mesh = {Acetylcysteine/analysis/*blood ; Animals ; Chromatography, High Pressure Liquid/*methods ; Cysteine/analysis/*blood ; Disulfides/blood/chemistry ; Ligands ; Male ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Sulfhydryl Compounds/blood ; }, abstract = {A high-performance liquid chromatographic assay was developed for the quantitative determination of the sulfur-containing amino acids N-acetyl-L-cysteine (NAC) and L-cysteine (Cys) in rat plasma. The thiols were separated by reverse-phase ion-pair chromatography, and the column eluent was continuously mixed with an iodoplatinate-containing solution. The substitution of sulfur of the thiol compound with iodide was quantitatively determined by measuring changes in the absorption at 500 nm. The low-molecular-weight disulfides and mixed disulfide conjugates of thiols with proteins were entirely reduced to the original reduced compounds by dithiothreitol. By reducing these two types of disulfides separately during sample pretreatment, the reduced, protein-unbound, and total thiol concentrations could also be determined. Validation testing was performed, and no problems were encountered. The limit of detection was approximately 20 pmol of thiol on the column. The present method was used to measure the plasma concentrations of NAC and Cys in the rat after a bolus intravenous administration of NAC, focusing on disulfide formation. The binding of NAC to protein through mixed disulfide formation proceeds in a time-dependent and reversible manner. Moreover, this "stable" covalent binding might limit total drug elimination, while the unbound NAC is rapidly eliminated. Consequently, the analytical method described in this study is very useful for the determination of plasma NAC and Cys, including disulfide conjugates derived from them.}, }
@article {pmid11237096, year = {2000}, author = {Koh, YH and Park, YS and Takahashi, M and Suzuki, K and Taniguchi, N}, title = {Aldehyde reductase gene expression by lipid peroxidation end products, MDA and HNE.}, journal = {Free radical research}, volume = {33}, number = {6}, pages = {739-746}, doi = {10.1080/10715760000301261}, pmid = {11237096}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Aldehyde Reductase/*biosynthesis/*genetics ; Aldehydes/*pharmacology ; Animals ; Aorta ; Calcium/pharmacology ; Cells, Cultured ; Enzyme Induction/drug effects ; Gene Expression/*drug effects ; *Lipid Peroxidation ; Malondialdehyde/*pharmacology ; Muscle, Smooth, Vascular/enzymology ; Phosphorylation ; Phosphotyrosine/metabolism ; Rats ; Rats, Wistar ; }, abstract = {Membrane lipid peroxidation results in the production of a variety of aldehydic compounds that play a significant role in aging, drug toxicity and the pathogenesis of a number of human diseases, such as atherosclerosis and cancer. Increased lipid peroxidation and reduced antioxidant status may also contribute to the development of diabetic complications. This study reports that lipid peroxidation end products such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) induce aldehyde reductase (ALR) gene expression. MDA and HNE induce an increase in intracellular peroxide levels; N-Acetyl-L-cysteine (NAC) suppressed MDA- and HNE-induced ALR gene expression. These results indicate that increased levels of intracellular peroxides by MDA and HNE might be involved in the upregulation of ALR.}, }
@article {pmid11230331, year = {2001}, author = {Ichiki, T and Takeda, K and Tokunou, T and Funakoshi, Y and Ito, K and Iino, N and Takeshita, A}, title = {Reactive oxygen species-mediated homologous downregulation of angiotensin II type 1 receptor mRNA by angiotensin II.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {37}, number = {2 Pt 2}, pages = {535-540}, doi = {10.1161/01.hyp.37.2.535}, pmid = {11230331}, issn = {1524-4563}, mesh = {Acetylcysteine/pharmacology ; Angiotensin II/antagonists &amp; inhibitors/*pharmacology ; Angiotensin II Type 1 Receptor Blockers ; Angiotensin II Type 2 Receptor Blockers ; Angiotensin Receptor Antagonists ; Animals ; Antioxidants/pharmacology ; Binding, Competitive ; Cells, Cultured ; Down-Regulation ; Enzyme Activation ; Flavonoids/pharmacology ; Gene Expression Regulation/drug effects ; Hydrogen Peroxide/pharmacology ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors ; Muscle, Smooth, Vascular/*metabolism ; RNA, Messenger/biosynthesis/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Receptor, Angiotensin, Type 1 ; Receptor, Angiotensin, Type 2 ; Receptors, Angiotensin/drug effects/genetics/*metabolism ; Transfection ; }, abstract = {Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of angiotensin (Ang) II through Ang II type 1 receptor (AT(1)-R). However, the role of ROS in the regulation of AT(1)-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT(1)-R by Ang II. Ang II (10(-6) mol/L) decreased AT(1)-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells. Preincubation of vascular smooth muscle cells with N:-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT(1)-R mRNA. The effect of NAC was due to stabilization of the AT(1)-R mRNA that was destabilized by Ang II. The Ang II-induced AT(1)-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as by PD98059. Exogenous H(2)O(2) also suppressed AT(1)-R mRNA. These results suggest that the production of ROS and the activation of ERK are critical for the downregulation of AT(1)-R mRNA. The generation of ROS through stimulation of AT(1)-R not only mediates signaling of Ang II but also may play a crucial role in the adaptation process of AT(1)-R to the sustained stimulation of Ang II.}, }
@article {pmid11230290, year = {2001}, author = {Greene, EL and Lu, G and Zhang, D and Egan, BM}, title = {Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {37}, number = {2}, pages = {308-312}, doi = {10.1161/01.hyp.37.2.308}, pmid = {11230290}, issn = {1524-4563}, support = {HL-07260/HL/NHLBI NIH HHS/United States ; K01-HL-03710/HL/NHLBI NIH HHS/United States ; P01-HL55782/HL/NHLBI NIH HHS/United States ; R01-HL-58794/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Analysis of Variance ; Androstadienes/pharmacology ; Angiotensin II/*pharmacology ; Animals ; Cell Movement/*drug effects ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; Indoles/pharmacology ; Maleimides/pharmacology ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism ; Muscle, Smooth, Vascular/cytology/*drug effects/metabolism ; Oleic Acid/*pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase C/antagonists &amp; inhibitors/metabolism ; Rats ; Signal Transduction/*drug effects ; Wortmannin ; }, abstract = {Obese hypertensive patients with cardiovascular risk factor clustering and increased risk for atherosclerotic disease have increased plasma nonesterified fatty acid levels, including oleic acid (OA), and a more active renin-angiotensin-aldosterone system. Vascular smooth muscle cell (VSMC) migration and proliferation participate in the development of atherosclerotic plaque. OA and angiotensin (Ang) II induce synergistic mitogenic responses in VSMCs through sequential signaling pathways dependent on the activation of protein kinase C (PKC), oxidants (reactive oxygen species, ROS), and extracellular signal-regulated kinase (ERK) activation. We tested the hypotheses that (1) OA and Ang II have additive or synergistic effects on VSMC migration and (2) PKC, ROS, and mitogen-activated protein kinase are critical signaling molecules. OA at 100 micromol/L increases VSMC migration 60+/-10% over control (P:<0.001). Ang II (10(-)(9) mol/L) increases VSMC migration by 62+/-13% and 73% over control, respectively (P:<0.01). Coincubation of cells with OA and Ang II produces a nearly additive increase in VSMC cell migration at 107+/-20% (P:<0.01). Increases in VSMC migration induced by OA alone and combined with Ang II were reduced by PKC inhibition and downregulation. VSMC migration in response to OA alone and with Ang II was also inhibited by N:-acetyl-cysteine, MEK inhibition, and ERK antisense. VSMC migration in response to OA alone or combined with Ang II is dependent on activation of PKC, ROS, and ERK activation, further raising the possibility that increased plasma nonesterified fatty acids and an activated renin-angiotensin-aldosterone system in subjects with the risk factor cluster contribute to accelerated atherosclerosis through a PKC, ROS, and ERK-dependent signaling pathway.}, }
@article {pmid11228747, year = {1999}, author = {Parinandi, NL and Scribner, WM and Vepa, S and Shi, S and Natarajan, V}, title = {Phospholipase D activation in endothelial cells is redox sensitive.}, journal = {Antioxidants &amp; redox signaling}, volume = {1}, number = {2}, pages = {193-210}, doi = {10.1089/ars.1999.1.2-193}, pmid = {11228747}, issn = {1523-0864}, support = {HL-47671/HL/NHLBI NIH HHS/United States ; HL-57260/HL/NHLBI NIH HHS/United States ; P01-HL-58064/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*metabolism/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cattle ; Cell Line ; Dose-Response Relationship, Drug ; Endothelium, Vascular/cytology/drug effects/*enzymology/metabolism ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Intracellular Fluid/metabolism ; Oxidation-Reduction ; Phospholipase D/*metabolism ; Phosphorylation/drug effects ; Phosphotyrosine/metabolism ; Pulmonary Artery ; Reactive Oxygen Species/physiology ; Sulfhydryl Compounds/pharmacology ; Sulfhydryl Reagents/pharmacology ; Thiourea/*analogs &amp; derivatives/pharmacology ; Tiopronin/pharmacology ; }, abstract = {Reactive oxygen species (ROS) are implicated in the pathophysiology of a number of vascular disorders, including atherosclerosis. Recent studies indicate that ROS modulate signal transduction in mammalian cells. Previously, we have shown that ROS (hydrogen peroxide, fatty acid hydroperoxide, diperoxovanadate, and 4-hydroxynonenal) enhance protein tyrosine phosphorylation and activate phospholipase D (PLD) in bovine pulmonary artery endothelial cells (BPAECs). In the present study, our aim was to investigate the role of exogenous thiol agents on ROS-induced PLD activation in conjunction with the role of cellular thiols--glutathione (GSH) and protein thiols--on PLD activation and protein tyrosine phosphorylation. Pretreatment of BPAECs with N-acetyl-L-cysteine (NAC) or 2-mercaptopropionylglycine (MPG) blocked ROS-induced changes in intracellular GSH and PLD activation. Also, pretreatment with NAC attenuated diperoxovanadate-induced protein tyrosine phosphorylation. Pretreatment of BPAECs with diamide or L-buthionine-(S,R)-sulfoximine (BSO), agents that lower intracellular GSH and thiols, enhanced PLD activity. Furthermore, NAC blocked diamide- or BSO-mediated changes in GSH levels, PLD activity, and protein tyrosine phosphorylation. NAC also attenuated diamide-induced tyrosine phosphorylation of proteins between 69 and 118 KDa. These results support the hypothesis that modulation of thiol-redox status (cellular nonprotein and protein thiols) may contribute to the regulation of ROS-induced protein tyrosine phosphorylation and PLD activation in vascular endothelium.}, }
@article {pmid11228746, year = {1999}, author = {Shrivastava, A and Aggarwal, BB}, title = {Antioxidants differentially regulate activation of nuclear factor-kappa B, activator protein-1, c-jun amino-terminal kinases, and apoptosis induced by tumor necrosis factor: evidence that JNK and NF-kappa B activation are not linked to apoptosis.}, journal = {Antioxidants &amp; redox signaling}, volume = {1}, number = {2}, pages = {181-191}, doi = {10.1089/ars.1999.1.2-181}, pmid = {11228746}, issn = {1523-0864}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Butylated Hydroxyanisole/pharmacology ; Butylated Hydroxytoluene/pharmacology ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Glutathione/pharmacology ; Humans ; Hydroxyl Radical/antagonists &amp; inhibitors ; JNK Mitogen-Activated Protein Kinases ; Lipid Peroxidation/drug effects ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; NF-kappa B/*metabolism ; Pyrrolidines/pharmacology ; Superoxides/antagonists &amp; inhibitors ; Thiocarbamates/pharmacology ; Transcription Factor AP-1/antagonists &amp; inhibitors/*metabolism ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*pharmacology/toxicity ; U937 Cells ; }, abstract = {Tumor necrosis factor (TNF) is known to mediate its signaling through generation of reactive oxygen species (ROS), but the type of TNF signal regulated by ROS and the nature of the ROS species involved are not fully understood. In this report, we investigated the effect of various superoxide radical quenchers--pyrrolidine dithiocarbamate (PDTC), N-acetyl-L-cysteine (NAC), and glutathione (GSH)--an hydroxyl radical quencher (mannitol), and lipid peroxide quenchers--butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA)--on TNF-induced activation of nuclear transcription factors-kappa B (NF-kappa B) and activator protein-1 (AP-1), c-jun amino-terminal kinase (JNK), and apoptosis in human monocytic U937 cells. TNF-induced NF-kappa B activation was inhibited by both superoxide and lipid peroxide quenchers but potentiated by an hydroxyl radical quencher. In contrast, none of the radical quenchers had any significant effect on TNF-induced AP-1 activation. TNF-induced JNK activation, similar to NF-kappa B, was inhibited by both superoxide and lipid peroxide quenchers but potentiated by hydroxyl radical quencher. TNF-induced activation of caspase activity was blocked by all three types of quenchers. TNF cytotoxicity, however, was potentiated by superoxide radical quenchers and suppressed by hydroxyl radical and lipid peroxide quenchers. Overall, these results suggest that hydroxyl radicals mediate TNF-induced apoptosis but not activation of NF-kappa B, AP-1, and JNK; superoxide radicals mediate NF-kappa B and JNK activation but potentiate apoptosis; and lipid peroxides are required for all the signals induced by TNF.}, }
@article {pmid11226137, year = {2001}, author = {Zaragoza, A and Díez-Fernández, C and Alvarez, AM and Andrés, D and Cascales, M}, title = {Mitochondrial involvement in cocaine-treated rat hepatocytes: effect of N-acetylcysteine and deferoxamine.}, journal = {British journal of pharmacology}, volume = {132}, number = {5}, pages = {1063-1070}, pmid = {11226137}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/physiology ; Caspase 3 ; Caspases/drug effects/metabolism ; Chelating Agents/pharmacology ; Cocaine/*toxicity ; Cytochrome c Group/*drug effects/metabolism ; DNA Fragmentation/drug effects/physiology ; Deferoxamine/pharmacology ; Dopamine Uptake Inhibitors/*toxicity ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; HSP20 Heat-Shock Proteins ; *Heat-Shock Proteins ; Hepatocytes/*drug effects/metabolism ; Male ; Membrane Potentials/drug effects/physiology ; Mitochondria, Liver/*drug effects/metabolism ; Muscle Proteins/*drug effects/metabolism ; Rats ; Rats, Wistar ; }, abstract = {The cytotoxicity of cocaine (0 - 1000 microM), was studied on parameters related to the mitochondrial role and the cascade of events that lead to apoptosis in hepatocyte cultures from phenobarbitone (PB) pretreated rats. Cytotoxicity was dose-dependent and LDH leakage was significantly enhanced above 100 microM cocaine. Apoptosis was visualized by DNA fragmentation on agarose gel, and appeared at 50 and 100 microM cocaine. Cocaine induced biphasic changes in mitochondrial transmembrane potential and significantly increased the mitochondrial release of cytochrome c, the caspase-3 like DEVDase activity and the level of 20 kDa subunit, a product of pro-caspase-3 cleavage. The protective effect of N-acetylcysteine (NAC) and deferoxamine (DFO) on all these parameters confirmed the involvement of oxygen radicals in cocaine-induced necrosis/apoptosis. We conclude: first, that the biphasic changes recorded in mitochondrial inner membrane potential by the effect of cocaine, were parallel to apoptosis; second, that caspase-3 activity and cleavage to it p20 subunit increased sharply in parallel to the translocation of cytochrome c from mitochondria to cytosol; and third, that the antioxidants, NAC or DFO exerted a noticeable protective role in counteracting the cytotoxicity of cocaine, these effects being more pronounced in the case of DFO than NAC. These findings demonstrate that cocaine cytotoxicity involves mitochondrial damage.}, }
@article {pmid11225730, year = {1999}, author = {Moldovan, L and Irani, K and Moldovan, NI and Finkel, T and Goldschmidt-Clermont, PJ}, title = {The actin cytoskeleton reorganization induced by Rac1 requires the production of superoxide.}, journal = {Antioxidants &amp; redox signaling}, volume = {1}, number = {1}, pages = {29-43}, doi = {10.1089/ars.1999.1.1-29}, pmid = {11225730}, issn = {1523-0864}, support = {GM053236-03/GM/NIGMS NIH HHS/United States ; HL52315/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Actins/*metabolism ; Animals ; Aorta/cytology ; Blotting, Western ; Cell Surface Extensions/metabolism ; Cells, Cultured ; Coronary Vessels/cytology ; Culture Media, Serum-Free ; Cytoskeleton/*metabolism ; Endothelium, Vascular/cytology/*metabolism/ultrastructure ; Fluorescent Dyes/metabolism ; Free Radical Scavengers/chemistry/metabolism/pharmacology ; Humans ; Metalloporphyrins/pharmacology ; Mice ; Microscopy, Confocal ; Microscopy, Fluorescence ; Recombinant Proteins/metabolism ; Superoxide Dismutase/chemistry/genetics/metabolism ; Superoxides/*metabolism ; Transfection ; rac1 GTP-Binding Protein/genetics/*metabolism ; }, abstract = {The small GTPase rac1 controls actin redistribution to membrane ruffles in fibroblasts and other cell types, as well as the activation of the NADPH oxidase in phagocytes. We explored the possibility that these two processes could be related. We used a replication-deficient adenoviral vector to overexpress the constitutively active form of rac1, racV12, in human and mouse aortic endothelial cells. We show here that, in addition to membrane ruffle formation, racV12 induced an increase in the total amount of F-actin within endothelial cells. Concurrently, racV12-overexpressing cells produced significantly higher amounts of free radicals, as detected by the fluorescent probe 5-(and-6)-chloromethyl-2',7'-dichloro-dihydrofluorescein diacetate, than cells infected with a control virus encoding the bacterial beta-galactosidase (Ad-betaGal). To assess the specific role of superoxide in racV12-induced actin reorganization, we co-expressed the human enzyme Cu,Zn-superoxide dismutase (SOD), by means of another adenoviral vector construct. Overexpressed SOD reduced the concentration of superoxide detected in Ad-racV12-transfected cells and reversed the effects of Ad-racV12 on the content of filamentous actin. MnTMPyP, an SOD mimetic, as well as the antioxidant N-acetyl cysteine, had similar effects, in that they reduced not only the free radicals production, but also ruffle formation and the concentration of F-actin within racV12-overexpressing endothelial cells. Our data support the hypothesis that superoxide is one of the important mediators acting downstream of rac1 on the pathway of actin cytoskeleton remodeling in endothelial cells.}, }
@article {pmid11222918, year = {2001}, author = {Kowluru, RA and Engerman, RL and Case, GL and Kern, TS}, title = {Retinal glutamate in diabetes and effect of antioxidants.}, journal = {Neurochemistry international}, volume = {38}, number = {5}, pages = {385-390}, doi = {10.1016/s0197-0186(00)00112-1}, pmid = {11222918}, issn = {0197-0186}, support = {EY00300/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*pharmacology ; Diabetes Mellitus, Experimental/*metabolism ; Glutamic Acid/*metabolism ; Male ; Nitric Oxide/metabolism ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Retina/drug effects/*metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Diabetes results in various biochemical abnormalities in the retina, but which of these abnormalities are critical in the development of retinopathy is not known. The aim of this study is to examine the effect of antioxidant supplementation on diabetes-induced alterations of retinal glutamate, and to explore the inter-relationship between alterations of retinal glutamate, oxidative stress, and nitric oxide (NO) in diabetes. Glutamate was measured in the retina at 2 months of diabetes in rats receiving diets supplemented with or without a mixture of antioxidants containing ascorbic acid, Trolox, DL alpha-tocopherol acetate, N-acetyl cysteine, beta-carotene and selenium. The relationship between glutamate, oxidative stress and NO was evaluated using both bovine retinal endothelial cells and normal rat retina. In diabetes, retinal glutamate was elevated by 40, thiobarbituric acid-reactive substances (TBARS) by 100, and NO by 70%, respectively. Administration of antioxidants inhibited the diabetes-induced increases in glutamate, TBARS and NO. Incubation of bovine retinal endothelial cells or normal rat retina with glutamate significantly increased TBARS and NO, and addition of either antioxidant (N-acetyl cysteine) or a NO synthase inhibitor prevented the glutamate-induced elevation in oxidative stress and NO. Incubation of retina with a glutamate agonist, likewise elevated oxidative stress and NO, and memantine inhibited such elevations. Thus, the alterations of retinal glutamate, oxidative stress and NO appear to be inter-related in diabetes, and antioxidant therapy may be a suitable approach to determine the roles of these abnormalities in the development of diabetic retinopathy.}, }
@article {pmid11218623, year = {2000}, author = {Neri, S and Ierna, D and Antoci, S and Campanile, E and D'Amico, RA and Noto, R}, title = {Association of alpha-interferon and acetyl cysteine in patients with chronic C hepatitis.}, journal = {Panminerva medica}, volume = {42}, number = {3}, pages = {187-192}, pmid = {11218623}, issn = {0031-0808}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Alanine Transaminase/blood ; Drug Interactions ; Drug Therapy, Combination ; Female ; Glutathione/blood ; Glutathione Peroxidase/blood ; Hepatitis C, Chronic/blood/*drug therapy/pathology ; Humans ; Interferon-alpha/administration &amp; dosage/*therapeutic use ; Linoleic Acid/blood ; Male ; Malondialdehyde/blood ; Middle Aged ; Oxidative Stress/drug effects ; Prospective Studies ; RNA, Viral/blood ; }, abstract = {BACKGROUND: Numerous experimental findings have underlined the relationships between liver damage and production of oxygen-derived free radicals during inflammation. In chronic hepatitis C liver disease this damage may be attributed to altered oxide-reductive balance and glutathione (GSH) depletion. Moreover, it may be linked to chronic inflammation provoked by the replicative activity of the hepatitis C virus and its relationships with immune system cells. Our aim was to assess the effects of combined IFN + NAC treatment to compare the effects of interferon alpha-n1 associated with N-acetyl cysteine treatment with the results observed using interferon therapy alone.<br><br>EXPERIMENTAL DESIGN: prospective randomised study.<br><br>SETTING: Ambulatory and hospitalised care.<br><br>PATIENTS: 77 selected patients affected by chronic C hepatitis.<br><br>INTERVENTIONS: our patients were investigated by laboratory tests (ALT values, RIBA test, HCV-RNA, oxide-reductive balance), liver biopsy and liver US. The recruited subjects were treated with interferon and N-acetyl cysteine or with interferon alone.<br><br>RESULTS: Our findings confirmed the presence of oxidative stress in patients with chronic hepatitis C and showed earlier relapse in patients treated with interferon alone. The difference between the results in patients treated with interferon and N-acetyl cysteine and those on interferon alone was significant.<br><br>CONCLUSIONS: The good results and absence of side effects in patients treated with interferon + N-acetyl cysteine recommend wider use of this association.}, }
@article {pmid11215758, year = {2000}, author = {Galili, R and Mosberg,  and Gil-Ad, I and Weizman, A and Melamed, E and Offen, D}, title = {Haloperidol-induced neurotoxicity--possible implications for tardive dyskinesia.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {107}, number = {4}, pages = {479-490}, doi = {10.1007/s007020070089}, pmid = {11215758}, issn = {0300-9564}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antipsychotic Agents/*adverse effects ; Apoptosis/*drug effects/physiology ; Brain ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Dyskinesia, Drug-Induced/*etiology/physiopathology ; Embryo, Mammalian ; Free Radical Scavengers/*pharmacology ; Haloperidol/*adverse effects ; Mice ; Mice, Inbred ICR ; Neurons/*drug effects/physiology ; PC12 Cells ; Rats ; Vitamin E/*pharmacology ; }, abstract = {Tardive dyskinesia (TD) is one of the major side effects of long term neuroleptic treatment. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. The traditional concept of supersensitivity of striatal dopamine receptors as the mechanism involved in the development of TD is not satisfying, and current studies have focused on the role of neuroleptic-induced neuronal toxicity in the development of TD. We performed a series of experiments to gain a better understanding on the mechanisms involved in induction of TD. We have evaluated the direct neurotoxic effect of haloperidol (HP), a widely--used neuroleptic drug, and its three metabolites, in mouse neuronal cultures and in PC-12 cells. We found that the features of HP-induced cell death were apoptotic rather than necrotic, as indicated by different DNA-staining methods and specific caspases inhibitors. Moreover, cotreatment with antioxidants such as vitamin E and N-acetylcysteine (NAC) significantly protected the cultures. Further studies on the mechanisms underlying HP-induced toxicity may lead to the development of new neuroprotective therapeutic strategies.}, }
@article {pmid11214823, year = {2000}, author = {Redondo, P and Jimenez, E and Perez, A and García-Foncillas, J}, title = {N-acetylcysteine downregulates vascular endothelial growth factor production by human keratinocytes in vitro.}, journal = {Archives of dermatological research}, volume = {292}, number = {12}, pages = {621-628}, doi = {10.1007/s004030000187}, pmid = {11214823}, issn = {0340-3696}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/pharmacology ; Antioxidants/pharmacology ; Cell Culture Techniques ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Down-Regulation/drug effects ; Endothelial Growth Factors/biosynthesis/metabolism ; Female ; Humans ; Keratinocytes/drug effects/*metabolism ; Lymphokines/biosynthesis/*drug effects/metabolism ; Quercetin/pharmacology ; Resveratrol ; Stilbenes/pharmacology ; Thymidine/pharmacokinetics ; Tritium ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {The present study was designed to evaluate the action of various antioxidants including N-acetylcysteine (NAC) and the flavonoids resveratrol and quercetin on the production of VEGF by human keratinocytes (HKC). NAC, resveratrol, and quercetin dose-dependently suppressed the incorporation of 3H-thymidine into HKC. Values of median inhibitory concentration for NAC, resveratrol, and quercetin were 10 mM, 55 microM, and 15 microM, respectively (P < 0.01). RT-PCR demonstrated VEGF 121 and VEGF 206 expression in all HKC samples. HKC showed baseline expression and a progressive gradual time-dependent increase in VEGF secretion (510+/-75 pg/ml at 24 h), and EGF (2.5-100 ng/ml) enhanced the secretion of VEGF in a dose-dependent fashion. HKC were incubated with NAC (2.5-20 mM) for 2 h prior to the addition of EGF (5 ng/ml) or PMA (10 ng/ml), and a significant decrease (P < 0.01) was found after 24 h of incubation with 2.5 mM NAC. However, neither resveratrol nor quercetin reduced the synthesis of this cytokine. In summary we conclude that NAC and the flavonoid antioxidants resveratrol and quercetin inhibit HKC proliferation regardless of the stage of differentiation and that NAC significantly inhibits VEGF secretion in basal and EGF- or PMA-treated HKC.}, }
@article {pmid11213077, year = {2001}, author = {Weinbroum, AA and Kluger, Y and Ben Abraham, R and Shapira, I and Karchevski, E and Rudick, V}, title = {Lung preconditioning with N-acetyl-L-cysteine prevents reperfusion injury after liver no flow-reflow: a dose-response study.}, journal = {Transplantation}, volume = {71}, number = {2}, pages = {300-306}, doi = {10.1097/00007890-200101270-00023}, pmid = {11213077}, issn = {0041-1337}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Glutathione/analysis ; Liver/*blood supply/enzymology ; *Lung/blood supply/chemistry ; *Lung Transplantation ; Rats ; Regional Blood Flow/physiology ; Reperfusion Injury/*prevention &amp; control ; Time Factors ; Transplantation Conditioning ; }, abstract = {BACKGROUND: Circulating xanthine oxidase activity and the generated oxidants have been linked to lung reperfusion injury from no flow-reflow conditions in other organs after organ transplantation or surgery. N-acetyl-1-cysteine (NAC), an oxidant scavenger, promotes glutathione in its reduced form (GSH) that is depleted during ischemia. We have recently demonstrated its efficacy in protecting lungs from reperfusion injury if administered during reperfusion of postischemic liver. We now investigated whether preconditioning of lungs with NAC could attenuate lung respiratory or vascular derangement after no flow-reflow (ischemia-reperfusion, IR) and if this depends on lung GSH levels.<br><br>METHODS: Rat isolated livers were stabilized and perfused with modified Krebs-Henseleit solution (KH) (control, n=12) or made ischemic (no flow, IR-0, n=12) for 2 hr. Meanwhile, lungs were isolated, ventilated, and stabilized (KH+bovine albumin 5%). Serial perfusion (15 min) of liver+lung pairs took place followed by lung only recirculation (45 min) with the accumulated solution. Another three controls and three ischemic groups included lungs treated during stabilization with NAC at 100 mg x kg(-1), 150 or 225 mg x kg(-1) (in 2.5, 3.7 or 5.5 mmol solutions, respectively). Results. Ischemic liver damage, expressed by circulating hepatocellular constituents, was associated with pulmonary artery and ventilatory pressure increases by 70-100% of baseline, abnormal wet-to-dry weight ratio, and abnormal bronchoalveolar lavage volume and content in the IR-0 (nontreated) and the IR-100 and IR-225 pretreated lungs. NAC-150 pretreatment afforded preservation for most parameters. GSH content in the IR-150 lung tissue was only 11% higher than that of IR-225, but 2-fold that in IR-0 and IR-100 GSH lungs.<br><br>CONCLUSION: Lung preconditioning with NAC prevents reperfusion injury but not in a dose-related manner. Although enhanced GSH tissue content explains lung protection, GSH-independent NAC activity is another possibility.}, }
@article {pmid11207438, year = {2001}, author = {Ottaviani, E and Barbieri, D and Malagoli, D and Franchini, A}, title = {Nitric oxide induces apoptosis in the fat body cell line IPLB-LdFB from the insect Lymantria dispar.}, journal = {Comparative biochemistry and physiology. Part B, Biochemistry &amp; molecular biology}, volume = {128}, number = {2}, pages = {247-254}, doi = {10.1016/s1096-4959(00)00311-0}, pmid = {11207438}, issn = {1096-4959}, mesh = {Acetylcysteine/pharmacology ; Amidines/pharmacology ; Animals ; *Apoptosis/drug effects ; Benzylamines/pharmacology ; Cell Death/drug effects ; Cell Line ; Densitometry ; Dose-Response Relationship, Drug ; Flow Cytometry ; Immunohistochemistry ; Insecta ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide/pharmacokinetics/*pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Nitric Oxide Synthase Type II ; Nitroprusside/pharmacology ; Time Factors ; }, abstract = {The presence of immunoreactive inducible nitric oxide synthase molecules (ir-iNOS) is demonstrated in the Lymantria dispar IPLB-LdFB cell line. The maximum ir-iNOS inducibility is observed 18 h after incubation with sodium nitroprusside (SNP). The increase in NO provoked by SNP in turn induces apoptosis. However, this phenomenon is observed only after 48 h. The NOS-inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME) and N-[3-(aminomethyl)-benzyl]acetamide (1400W) were both unable to block the SNP-induced apoptosis at all the concentrations used. Incubation with SNP plus N-acetyl-L-cysteine (NAC) further augmented the percentage of cell death with respect to SNP used alone, and this process is seen earlier, i.e. after 24 h. Moreover, the induction of apoptosis in the presence of NAC is time- and concentration-dependent. The high percentage of cell death with SNP+NAC suggests that NAC forms S-nitrosothiols with NO, resulting in an increase in the bioavailability of NO. In conclusion, these findings show the existence of a close relationship between mammalian and invertebrate cells with regards to SNP and NAC induction and the related NO response.}, }
@article {pmid11204554, year = {2000}, author = {Attri, S and Rana, SV and Vaiphei, K and Sodhi, CP and Katyal, R and Goel, RC and Nain, CK and Singh, K}, title = {Isoniazid- and rifampicin-induced oxidative hepatic injury--protection by N-acetylcysteine.}, journal = {Human &amp; experimental toxicology}, volume = {19}, number = {9}, pages = {517-522}, doi = {10.1191/096032700674230830}, pmid = {11204554}, issn = {0960-3271}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Body Weight/drug effects ; Catalase/metabolism ; Chemical and Drug Induced Liver Injury/blood/drug therapy/pathology/*prevention &amp; control ; Cytochrome P-450 Enzyme System/metabolism ; Drug Interactions ; Injections, Intraperitoneal ; Isoniazid/administration &amp; dosage/*toxicity ; Lipid Peroxidation/drug effects ; Liver/drug effects/enzymology/pathology ; Male ; *Oxidative Stress ; Rats ; Rats, Wistar ; Rifampin/administration &amp; dosage/*toxicity ; Superoxide Dismutase/metabolism ; }, abstract = {The role of N-acetylcysteine (NAC), a glutathione (GSH) precursor, was investigated in protection against isoniazid- (INH) and rifampicin- (RIF) induced oxidative hepatic injury in young Wistar rats. The hepatotoxic dose of INH and RIF was 50 mg kg(-1) day(-1) each and the hepatoprotective dose of NAC was 100 mg kg(-1) day(-1). All drugs were administered intraperitoneally (i.p.) in sterile water (4.0 ml kg(-1) day(-1)) over a period of 3 weeks. Status of oxidative/antioxidative profiles was the mechanistic approach to assess the hepatotoxicity and/or hepatoprotection. The oxidative injury in INH-RIF co-exposed animals was closely associated with significant decline of GSH and related thiols, as well as with compromised antioxidant enzyme system. The oxidative stress was further supported by increased lipid peroxidation observed in these animals. The co-administration of NAC prevented the induction of oxidative stress in INH-RIF co-exposed animals. The amelioration of oxidative stress by NAC was faithfully reflected as normal morphology in these animals, except the presence of mild degree of portal triaditis in one animal co-exposed to INH-RIF and NAC. In contrast, the animals co-exposed to INH-RIF alone showed histological lesions which ranged from intralobular inflammation to patchy necrosis. These results suggest that INH-RIF-induced oxidative injury can be prevented by supporting the cellular antioxidant defense mechanism by NAC.}, }
@article {pmid11201668, year = {2000}, author = {Michielsen, C and Boeren, S and Rietjens, I and van Mil, F and Vos, J and Bloksma, N}, title = {The mercapturic acid biotransformation pathway of hexachlorobenzene is not involved in the induction of splenomegaly, or skin and lung lesions in the Brown Norway rat.}, journal = {Archives of toxicology}, volume = {74}, number = {10}, pages = {609-617}, doi = {10.1007/s002040000166}, pmid = {11201668}, issn = {0340-5761}, mesh = {Acetylcysteine/*metabolism ; Animals ; Biotransformation ; Chromatography, High Pressure Liquid ; Female ; Fungicides, Industrial/*pharmacokinetics/*toxicity ; Hexachlorobenzene/*pharmacokinetics/*toxicity ; Liver/drug effects/pathology ; Lung/*drug effects/metabolism/pathology ; Mass Spectrometry ; Nitrobenzenes/pharmacokinetics/toxicity ; Organ Size/drug effects ; Rats ; Rats, Inbred Strains ; Skin/*drug effects/metabolism/pathology ; Spleen/drug effects/pathology ; Splenomegaly/*etiology/metabolism/pathology ; }, abstract = {Involvement of the mercapturic acid pathway in the induction of splenomegaly and skin and lung pathology by hexachlorobenzene (HCB) in the rat was investigated by seeking to determine whether pentachloronitrobenzene (PCNB) has the same inflammatory effects as HCB, since both compounds are directly conjugated to glutathione, and further processed into the same mercapturic acid metabolites which are excreted via the urine. Female Brown Norway (BN/SsNO1aHsd) rats at 3 to 4 weeks of age were orally exposed to diets with or without supplementation with 450 mg HCB or equimolar (467 mg) or higher (934 mg) amounts of PCNB per kilogram of diet over 4 weeks. Gross skin lesion development and body weight gains were assessed during exposure and spleen and liver weights as well as histopathologic changes in skin and lung were assessed after exposure. After 3 weeks of exposure, urinary metabolites of the mercapturic acid and oxidative biotransformation pathways were identified using high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). Oral exposure of the rats to 450 mg/kg HCB resulted in an increase in relative spleen and liver weights as well as in the development of skin and lung pathology in the absence of overall liver toxicity. Equimolar or higher concentrations of PCNB caused none of these effects. Urinary levels of the mercapturic acid N-acetyl-S-(pentachlorophenyl)-cysteine (PCP-NAC), were comparable in HCB- and PCNB-treated rats. Levels of closely related methylsulfide derivatives of PCP-NAC, also generated via the same mercapturic acid pathway, appeared to be significantly higher in PCNB- than in HCB-treated rats, whereas the reverse was true for the urinary levels of the oxidative metabolite pentachlorophenol (PCP). Thus, results indicate that metabolites of the mercapturic acid pathway are not involved in the induction of splenomegaly and skin and lung pathology caused by HCB exposure in BN rats and that the main urinary metabolite of HCB in these BN rats is PCP. Since PCP itself, as well as other cytochrome P450-derived metabolites from HCB, are not likely to be involved in the induction of splenomegaly and skin and lung pathology, it is suggested that either the parent compound HCB or as-yet-unidentified non-P450-generated metabolites are involved in these inflammatory effects of HCB.}, }
@article {pmid11198153, year = {2000}, author = {Camello, C and Camello, PJ and Pariente, JA and Salido, GM}, title = {Effects of antioxidants on calcium signal induced by cholecystokinin in mouse pancreatic acinar cells.}, journal = {Journal of physiology and biochemistry}, volume = {56}, number = {3}, pages = {173-180}, pmid = {11198153}, issn = {1138-7548}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Calcium/metabolism ; Calcium Signaling/*drug effects ; Free Radical Scavengers/*pharmacology ; Glutathione/pharmacology ; In Vitro Techniques ; Mice ; Pancreas/*cytology/drug effects ; Sincalide/*pharmacology ; }, abstract = {Digital imaging fluorescence microscopy was used to study the effect of two antioxidants, N-acetyl-cysteine (NAC) and glutathione, on the cytosolic free calcium concentration ([Ca2+]i) induced by cholecystokinin-octapeptide (CCK-8) of mouse pancreatic acinar cells. When acinar cells were preincubated with either NAC or glutathione, subsequent stimulation with CCK-8 in the presence of each antioxidant had no significant effect on the typical pattern of [Ca2+]i transient evoked by the gastrointestinal hormone. However, application of NAC to acinar cells pretreated for 60 min with the same antioxidant, strongly blocked the oscillatory pattern initiated by CCK-8, inhibiting both amplitude and frequency of calcium oscillations. By contrast, glutathione had no effect on the oscillatory pattern evoked by CCK-8. The present results allow us to speculate that during [Ca2+]i oscillation there is a production of oxidants that facilitate oscillations by enhancing release of calcium from internal stores.}, }
@article {pmid11195468, year = {2000}, author = {Witschi, H}, title = {Successful and not so successful chemoprevention of tobacco smoke-induced lung tumors.}, journal = {Experimental lung research}, volume = {26}, number = {8}, pages = {743-755}, doi = {10.1080/01902140150216792}, pmid = {11195468}, issn = {0190-2148}, support = {ES05707/ES/NIEHS NIH HHS/United States ; ES07499/ES/NIEHS NIH HHS/United States ; ES07908/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Anticarcinogenic Agents/*therapeutic use ; Aspirin/therapeutic use ; Chemoprevention ; Cyclohexenes ; Dexamethasone/administration &amp; dosage/therapeutic use ; Diet ; Disease Models, Animal ; Drug Therapy, Combination ; Inhalation Exposure ; Inositol/administration &amp; dosage/therapeutic use ; Isothiocyanates/therapeutic use ; Limonene ; Lung Neoplasms/etiology/pathology/*prevention &amp; control ; Mice ; Mice, Inbred A ; Organoselenium Compounds/therapeutic use ; Phytotherapy ; Tea/therapeutic use ; Terpenes/therapeutic use ; Tobacco Smoke Pollution/*adverse effects ; }, abstract = {Strain A/J mice underwent whole body exposure for 6 hours a day, 5 days a week, for 5 months to a mixture of cigarette sidestream and mainstream smoke (89%-11%; total suspended particulates 80-150 mg/m3), then were kept for another 4 months in air before being killed for scoring of lung tumors. In 7 independent experiments, lung tumor multiplicity was significantly increased in all 7 trials and lung tumor incidence in 5. When animals were kept for 9 months in smoke, lung tumor multiplicity was not significantly higher than in controls, although lung tumor incidence was. The following chemopreventive agents were evaluated: green tea, phenethyl isothiocyanate (PEITC), acetylsalicylic acid (ASA), N-acetylcysteine (NAC), p-XSC (1,4-phenylenebis[methylene]selenocyanate), d-limonene (DL), and a mixture of PEITC and BITC (benzyl isothiocyanate). In animals exposed to tobacco smoke, none of these agents reduced lung tumor multiplicity or incidence. As a control, the effects of the same agents were examined in A/J mice initiated with 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK) or urethane. In mice injected with NNK, green tea and ASA did not reduce lung tumor multiplicities and NAC had no effect on urethane-induced lung tumors, whereas PEITC, p-XSC and DL reduced NNK-induced tumor multiplicities to 20% to 50% of control values. On the other hand, dietary mixture of myoinositol and dexamethasone was not only highly protective against NNK, but reduced lung tumor multiplicities and incidence in smoke-exposed animals to control values. This effect was also seen when the animals were fed the myo-inositol-dexamethasone mixture once they were removed from smoke. It is concluded that in animal studies it might be preferable to evaluate the effectiveness of putative chemopreventive agents against full tobacco smoke rather than against selected model compounds. The observations made with myo-inositol-dexamethasone suggest that people who have recently quit smoking might benefit the most from active chemoprevention.}, }
@article {pmid11192539, year = {2000}, author = {Gon, Y and Hashimoto, S and Nakayama, T and Matsumoto, K and Koura, T and Takeshita, I and Horie, T}, title = {N-acetyl-L-cysteine inhibits bleomycin-induced interleukin-8 secretion by bronchial epithelial cells.}, journal = {Respirology (Carlton, Vic.)}, volume = {5}, number = {4}, pages = {309-313}, pmid = {11192539}, issn = {1323-7799}, mesh = {Acetylcysteine/*pharmacology ; Antimetabolites, Antineoplastic/*adverse effects ; Antioxidants/*pharmacology ; Bleomycin/*adverse effects ; Bronchi/*cytology/*drug effects ; Cell Line ; Drug Evaluation, Preclinical ; Enzyme-Linked Immunosorbent Assay ; Free Radical Scavengers/*pharmacology ; Humans ; Interleukin-8/analysis/*immunology/*metabolism ; Pyrrolidines/pharmacology ; Respiratory Distress Syndrome/*chemically induced/*immunology/prevention &amp; control ; Respiratory Mucosa/*drug effects/*metabolism ; Thiocarbamates/pharmacology ; }, abstract = {OBJECTIVE: Bleomycin (BLM) has proven effective for the treatment of cancers, but the most serious dose-limiting side-effect is the development of pulmonary toxicity. Although the precise mechanism in the pathogenesis of BLM-induced lung injury has not been determined, oxygen radicals and neutrophils are indicated to play a key role in it. Interleukin-8 (IL-8) is thought to be an important mediator of the pathogenesis of acute lung injury.<br><br>METHODOLOGY: The IL-8 production from bronchial epithelial cell line, BEAS-2B cells was measured by enzyme-linked immunosorbent assays for IL-8.<br><br>RESULTS: The concentrations of IL-8 were reportedly elevated in BLM-induced lung injury, suggesting the involvement of IL-8 in the pathogenesis of BLM-induced lung injury. In the present study, we showed that BLM induced the expression of IL-8 protein and mRNA in BEAS-2B cells, and N-acetyl-L-cysteine (NAC) inhibited IL-8 expression. In addition, the structurally unrelated antioxidant, pyrrolidine dithiocarbamate (PDTC) also effectively inhibited BLM-induced IL-8 production.<br><br>CONCLUSION: These results suggest that anti-oxidant-sensitive mechanism might be involved in the inhibition of IL-8 secretion by BLM-stimulated bronchial epithelial cells and that NAC might be useful for the treatment of BLM-induced lung injury.}, }
@article {pmid11181436, year = {2001}, author = {Serra, PA and Esposito, G and Delogu, MR and Migheli, R and Rocchitta, G and Miele, E and Desole, MS and Miele, M}, title = {Analysis of S-nitroso-N-acetylpenicillamine effects on dopamine release in the striatum of freely moving rats: role of endogenous ascorbic acid and oxidative stress.}, journal = {British journal of pharmacology}, volume = {132}, number = {4}, pages = {941-949}, pmid = {11181436}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/*physiology ; Corpus Striatum/*drug effects/metabolism ; Dopamine/*metabolism ; Iron/metabolism ; Male ; Microdialysis ; Nitric Oxide Donors/*pharmacology ; *Oxidative Stress ; Penicillamine/analogs &amp; derivatives/*pharmacology ; Rats ; Rats, Wistar ; S-Nitroso-N-Acetylpenicillamine ; }, abstract = {1. We showed previously that interaction between NO and iron(II), both released following decomposition of sodium nitroprusside (SNP), accounted for the late SNP-induced dopamine (DA) increase in dialysates from the striatum of freely moving rats. 2. In this study, intrastriatal infusion of the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) (0.2 mM for 180 min) induced a moderate increase in dialysate DA and decreases in ascorbic acid dialysate concentrations; in contrast, SNAP 1 mM infusion induced a long-lasting decrease in both DA and ascorbic acid dialysate concentrations. 3-Methoxy-tyramine (3-MT), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and uric acid levels were unaffected. 3. Co-infusion of ferrous sulphate [iron(II), 1 mM for 40 min] with SNAP either 1 or 0.2 mM (for 180 min), produced a significant increase in both DA and 3-MT dialysate concentrations, but it did not affect decreases in dialysate ascorbic acid levels. All other dialysate neurochemicals were unaffected. 4. Co-infusion of ascorbic acid (0.1 mM) with SNAP (1 mM) for 180 min did not modify SNAP-induced decreases in dialysate DA levels. In contrast, co-infusion of uric acid (1 mM) reversed SNAP-induced decreases in dialysate DA; co-infusion of a superoxide dismutase mimetic delayed SNAP-induced DA decreases for a short period, while co-infusion of the antioxidant N-acetylcysteine (NAC, 0.1 mM) significantly increased dialysate DA. 5. The results of this study show that SNAP induces concentration-related changes in DA dialysate levels. At higher concentrations, SNAP induces non-enzymatic DA oxidation, which is inhibited by uric acid and NAC; ascorbic acid failed to protect dialysate DA from oxidation, probably owing to its promoting effect on SNAP decomposition; exogenous iron(II) may react with NO generated from SNAP decomposition, with a consequent increase in dialysate DA and 3-MT, therefore mimicking SNP effects on striatal DA release.}, }
@article {pmid11181056, year = {2001}, author = {Kim, SH and Han, SI and Oh, SY and Chung, HY and Kim, HD and Kang, HS}, title = {Activation of heat shock factor 1 by pyrrolidine dithiocarbamate is mediated by its activities as pro-oxidant and thiol modulator.}, journal = {Biochemical and biophysical research communications}, volume = {281}, number = {2}, pages = {367-372}, doi = {10.1006/bbrc.2001.4376}, pmid = {11181056}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Butylated Hydroxytoluene/pharmacology ; Cell Line ; DNA-Binding Proteins/*drug effects/metabolism ; Dose-Response Relationship, Drug ; Fibroblasts/cytology/drug effects/metabolism ; Glutathione Disulfide/drug effects/metabolism ; Heat Shock Transcription Factors ; Heat-Shock Proteins/drug effects/metabolism ; Oxidants/*pharmacology ; Propyl Gallate/pharmacology ; Pyrrolidines/*pharmacology ; Sulfhydryl Compounds/*metabolism ; Thiocarbamates/*pharmacology ; Transcription Factors ; }, abstract = {Pyrrolidine dithiocarbamate (PDTC) is known to inhibit NF-kappa B, which plays a critical role(s) as an immediate early mediator of immune and inflammatory responses. Here we show that PDTC induces heat shock factor 1 (HSF1) activation and heat shock protein expression, while other antioxidants such as butylated hydroxytoluene (BHT), n-propylgallate (PG), ascorbic acid (AA), and N-acetyl-L-cysteine (NAC) do not. Since PDTC exerts other functions than antioxidant, e.g., a pro-oxidant, metal chelator, and thiol group modulator, we examined which of these activities is responsible for the PDTC-induced HSF1 activation. PDTC-induced HSF1 activation was not prevented by metal chelators, EDTAs, indicating that the metal chelating effect of PDTC is not linked to the HSF1 activation. PDTC increased intracellular GSSG level. In addition, PDTC-induced activation of HSF1 was significantly inhibited by NAC and a thiol-reducing agent dithiothreitol (DTT), while it was partially prevented by other antioxidants, AA, BHT, and PG. These results suggest that the activation of HSF1 by PDTC may be due to its activities as pro-oxidant and thiol group modulator rather than anti-oxidant.}, }
@article {pmid11177646, year = {2000}, author = {Atroshi, F and Biese, I and Saloniemi, H and Ali-Vehmas, T and Saari, S and Rizzo, A and Veijalainen, P}, title = {Significance of apoptosis and its relationship to antioxidants after ochratoxin A administration in mice.}, journal = {Journal of pharmacy &amp; pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques}, volume = {3}, number = {3}, pages = {281-291}, pmid = {11177646}, issn = {1482-1826}, mesh = {Animals ; Anticarcinogenic Agents/pharmacology ; Antioxidants/*pharmacology ; *Apoptosis ; Carcinogens/toxicity ; Drug Interactions ; Glutathione/metabolism ; Liver/cytology/*drug effects/metabolism ; Male ; Mice ; Ochratoxins/*toxicity ; Tamoxifen/pharmacology ; }, abstract = {A study of the appearance of liver apoptosis after ochratoxin A (OTA) administration was performed in male mice. Administration of OTA twice a week for one or two weeks period results in the occurrence of apoptosis in mice"s liver. The presence of intracellular apoptosis bodies was detected at two weeks after toxin treatment. Light microscopic examination demonstrated the presence of eosinophilic globules, often containing apoptotic bodies. They were found within the cytoplasm of intact hepatic cells. The number of apoptotic bodies was further enhanced at two weeks, resulting in 8 fold increases in liver over the control values. No evidence of cell necrosis could be observed by histological and biochemical analysis at one week. However, centrilobular necrosis was evident at two weeks. The ability of the combined antioxidants: Coenzyme Q 10 (CoQ 10), L-carnitine, Zn, Mg, N-acetyl cysteine, vitamin C, vitamin E and selenium or tamoxifen to intervene in apoptosis induced in livers of mice by OTA was also investigated. The inhibition by these scavengers was more clear in mice treated with OTA for one week than those mice treated for two weeks. Treatment with tamoxifen, known in restoration of tumor suppressor function and on induction of programmed cell death (apoptosis), after OTA administration, had no significant inhibition effect on the incidence of apoptotic bodies in liver. Because hepatic glutathione represents the major defence against toxic liver injury, we studied the activity of tissue reduced glutathione (GSH), known to inhibit apoptosis. Our finding showed that two weeks after treatment, OTA caused a decrease of the GSH activity. However, treatment of mice with the combined antioxidants could enhance hepatic antioxidant/detoxification system, as indicated by increase in hepatic reduced glutathione level. In the light of these results, apoptosis was observed after two weeks of OTA administration. We also suggest that use of the combined antioxidants may be of interest in conditions were certain toxin-mediated forms of cell death and/or apoptosis contribute significantly to toxicity.}, }
@article {pmid11173994, year = {2001}, author = {Kokura, S and Rhoads, CA and Wolf, RE and Yoshikawa, T and Granger, DN and Aw, TY}, title = {NF kappa b signaling in posthypoxic endothelial cells: relevance to E-selectin expression and neutrophil adhesion.}, journal = {Journal of vascular research}, volume = {38}, number = {1}, pages = {47-58}, doi = {10.1159/000051029}, pmid = {11173994}, issn = {1018-1172}, support = {P01-DK43785/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cell Adhesion ; Cell Hypoxia ; Cells, Cultured ; Chemotaxis, Leukocyte ; DNA-Binding Proteins/metabolism ; Diamide/pharmacology ; E-Selectin/*biosynthesis/genetics ; Endothelium, Vascular/*metabolism ; Gene Expression Regulation/*physiology ; Humans ; *I-kappa B Proteins ; NF-KappaB Inhibitor alpha ; NF-kappa B/*metabolism/*physiology ; Neutrophils/*cytology ; Oxidation-Reduction ; Phosphorylation ; Protein Kinase C/antagonists &amp; inhibitors/physiology ; Protein Processing, Post-Translational ; Protein Transport ; Protein Tyrosine Phosphatases/metabolism ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/physiology ; Transcription Factor RelA ; Umbilical Veins ; }, abstract = {Our previous studies have implicated the nuclear transcription factor kappa B (NF kappa B) in the regulation of adhesion molecule expression in endothelial cells exposed to anoxia-reoxygenation (A/R) or a redox imbalance. The objectives of this study were (1) to define the kinetics of NF kappa B activation by examining I kappa B alpha degradation and the nuclear translocation of p65 in response to A/R or redox imbalance (induced by treatment of cells with diamide and buthionine sulfoximine) and (2) to determine whether the signal for I kappa B alpha degradation, nuclear translocation of p65, and E-selectin-mediated neutrophil adhesion is related to the activity of protein tyrosine kinase (PTK), protein tyrosine phosphatase (PTPase) and/or protein kinase C (PKC). The results demonstrate that both A/R and redox imbalance led to I kappa B alpha degradation within 30 min and the concomitant appearance of p65 in the nucleus, consistent with rapid cytosolic activation of NF kappa B and subsequent nuclear translocation of the activated p65 subunit. Inhibition of PKC blocked I kappa B alpha degradation and p65 translocation in A/R-challenged, but not redox-altered, endothelial cells. However, both A/R- and redox-induced NF kappa B activation was blocked by inhibition of PTK. Similarly, A/R-induced E-selectin expression and neutrophil-endothelial cell adhesion were blocked by inhibition of PKC or PTK, while only PTK inhibited the redox-induced adhesion response. Pretreatment of cells with N-acetyl cysteine effectively blocked A/R- or redox-induced I kappa B degradation and significantly attenuated the respective neutrophil adhesion responses. Collectively, these findings indicate that A/R-induced E-selectin expression and neutrophil-endothelial cell adhesion are mediated by both PKC and PTK, which signal rapid activation of NF kappa B. This A/R-induced NF kappa B signaling response appears to be mediated, at least in part, by intracellular redox imbalance.}, }
@article {pmid11172608, year = {2001}, author = {Mantovani, G and Maccio, A and Madeddu, C and Massa, E and Mudu, MC and Mulas, C and Gramignano, G and Massidda, S and Murgia, V and Lusso, MR and Mura, L}, title = {Immunotherapy (recombinant interleukin 2), hormone therapy (medroxyprogesterone acetate) and antioxidant agents as combined maintenance treatment of responders to previous chemotherapy.}, journal = {International journal of oncology}, volume = {18}, number = {2}, pages = {383-391}, pmid = {11172608}, issn = {1019-6439}, mesh = {Aged ; Analysis of Variance ; Antineoplastic Agents, Hormonal/*therapeutic use ; Antioxidants/*therapeutic use ; Confidence Intervals ; Cytokines/*blood ; Disease-Free Survival ; Drug Therapy, Combination ; Female ; Hormone Replacement Therapy ; Humans ; Immunotherapy ; Interleukin-2/*therapeutic use ; Lung Neoplasms/blood/*drug therapy/psychology ; Lymphocyte Count ; Male ; Medroxyprogesterone Acetate/*therapeutic use ; Middle Aged ; Quality of Life/psychology ; Recombinant Proteins/therapeutic use ; Treatment Outcome ; }, abstract = {An open, non-randomized phase II study was carried out including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response or stable disease (SD) for more than three months, to receive maintenance treatment with recombinant interleukin-2 (rIL-2) plus medroxyprogesterone acetate (MPA) plus antioxidant agents alpha-lipoic acid (ALA) and N-acetyl cysteine (NAC). The main study endpoints were clinical outcome and toxicity. The secondary endpoints were effects of treatment on cancer-related anorexia/cachexia syndrome (CACS) symptoms, on serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin as well as the evaluation of quality of life (QL). rIL-2 was administered at a dose of 1.8 MIU subcutaneously three times/week on alternate days for the first two weeks of every month and MPA was given orally at a dose of 500 mg once a day at alternate days without interruption. ALA 300 mg/day orally and NAC 1800 mg/day orally were also administered. The treatment was administered until progression of disease or appearance of toxicity. From July 1998 to May 2000, 16 patients were enrolled in the study (M/F ratio: 15/1; mean age: 62 years, range 45-71). The median duration of maintenance treatment was 10 months (range 5-22). The response to maintenance treatment at September 2000 was: CR (persistent throughout the treatment) 4 patients (25%); SD 1 patient (6.2%); PD 11 patients (68.8%). The median duration of response was 9.8 months (range: 5-22+). The median follow-up duration was 19 months (range: 8-102). The median OS was not reached. The median PFS was 14 months (range 1-29). The 1-year survival rate was 25%. At September 2000, 9 patients are still surviving. No grade 3/4 toxicity was observed. One Grade 2 skin toxicity was observed and Grade 1: 2 fever, 2 thrombocytopenia, 1 neutropenia and 1 skin were observed. The ECOG PS did worsen significantly, the body weight and BMI increased significantly after treatment, whereas the appetite did not change significantly. The QL evaluation showed a significant amelioration of cognitive functions and a borderline significant amelioration of emotional functions after treatment, whereas a borderline worsening of dyspnea was observed. The absolute lymphocyte count increased significantly after the maintenance treatment, as well as the serum IL-2, TNFalpha decreased at borderline statistical significance; the serum levels of leptin did not change significantly. The evaluation of patient subgroups showed that responders/survivors had a pattern superimposable to that of whole patient population, the patients who rapidly progressed and died exhibited no significant changes of these parameters during treatment. The results of the present study suggest that the host immune response, evaluated by several parameters, after IL-2 administration, (e.g. lymphocytosis), are worth further study as potential markers for the major end points of cancer treatment, i.e. OS and QL, in an adequate number of patients.}, }
@article {pmid11168458, year = {2001}, author = {Müller, B and Oske, M and Hochscheid, R and Seifart, C and Barth, PJ and Garn, H and von Wichert, P}, title = {Effect of N-acetylcysteine treatment on NO2-impaired type II pneumocyte surfactant metabolism.}, journal = {European journal of clinical investigation}, volume = {31}, number = {2}, pages = {179-188}, doi = {10.1046/j.1365-2362.2001.00776.x}, pmid = {11168458}, issn = {0014-2972}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Cell Separation ; Cells, Cultured ; Choline ; Culture Techniques ; Glutathione/analysis ; Male ; Nitrogen Dioxide/*pharmacology ; Phosphatidylcholines/metabolism ; Phospholipids/analysis ; Pulmonary Alveoli/*cytology/*drug effects ; Pulmonary Surfactants/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Inhalation of nitrogen dioxide (NO2) is known to alter the composition of the bronchoalveolar lavage (BAL) and to impair the surfactant metabolism of type II pneumocytes. However, information is sparse as to whether application of the widely used antioxidant N-acetylcysteine (NAC) is capable of preventing or reducing these alterations. The aim of the study was to investigate if in vivo administration of NAC to NO2-inhaling rats protected BAL parameters and physiology of type II pneumocytes from impairment. For this purpose, rats were exposed to 720 p.p.m. h-1 NO2, that was applied continuously, intermittently or repeatedly. During inhalation one group of rats received saline and the other group received NAC antioxidant (200 mg kg-1, intraperitoneally) once a day. The BAL protein and phospholipid content increased most in the continuously and repeatedly NO2-exposed rats when compared to the controls, while the intermittent exposure did not change these parameters. Application of NAC led to a marked decrease of the protein elevation for the continuously and intermittently exposed groups, but exhibited no influence on the BAL phospholipid. Surprisingly, all NO2 exposure modes elevated the glutathione content (reduced and oxidized) in the BAL. Application of NAC clearly decreased the content of both forms of glutathione in the continuously and the repeatedly NO2-exposed groups. Phospholipid synthesis, measured by choline uptake into type II cells, was increased most after continuous NO2 inhalation. The NAC reduced this increase moderately. Whereas choline uptake by type II cells was obviously stimulated by NO2, the stimulated secretion of phosphatidylcholine from these cells was decreased by this oxidant. Only continuous exposure reduced this activity markedly. The NAC clearly restored the impaired secretion activity in the cells from the continuously NO2-exposed animals. Since the efficacy of NAC in the prevention of NO2-induced impairments in the surfactant system is striking mainly in the continuously exposed group, we suggest that administration of NAC to NO2-induced lung injury partially restores altered BAL components and the impaired physiology of type II pneumocytes.}, }
@article {pmid11167962, year = {2001}, author = {Hashimoto, S and Gon, Y and Matsumoto, K and Takeshita, I and MacHino, T and Horie, T}, title = {Intracellular glutathione regulates tumour necrosis factor-alpha-induced p38 MAP kinase activation and RANTES production by human bronchial epithelial cells.}, journal = {Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology}, volume = {31}, number = {1}, pages = {144-151}, pmid = {11167962}, issn = {0954-7894}, mesh = {Acetylcysteine/pharmacology ; Bronchi/cytology/metabolism ; Buthionine Sulfoximine/pharmacology ; Cell Line, Transformed ; Chemokine CCL5/*metabolism ; Enzyme Activation/drug effects ; Epithelial Cells/metabolism ; Gene Expression Regulation ; Glutathione/*pharmacology ; Humans ; Mitogen-Activated Protein Kinases/*metabolism ; Tumor Necrosis Factor-alpha/*pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {BACKGROUND: RANTES plays an important role in the production of allergic inflammation of the airway through its chemotactic activity for eosinophils. The cellular reduction and oxidation (redox) changes are involved in the activation of p38 mitogen-activated protein (MAP) kinase and the induction of cytokine expression. It has previously been shown that tumour necrosis factor (TNF)-MA activates p38 mitogen-activated protein (MAP) kinase to produce cytokine, including RANTES, that N-acetylcysteine (NAC) attenuates cytokine production by human bronchial epithelial cells (BECs), and that sensitivity to TNFalpha is inversely correlated with cellular redox state. However, a role of cellular redox regulated by intracellular glutathione (GSH) in TNFalpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs has not been determined.<br><br>OBJECTIVE: Human BECs were exposed to NAC or buthionine sulfoximine (BSO). TNFalpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs were then examined in order to clarify these issues.<br><br>RESULTS: The results showed that: NAC attenuated TNFalpha-induced p38 MAP kinase activation and RANTES production; SB 203580 as the specific inhibitor of p38 MAP kinase activity attenuated TNF-alpha-induced RANTES production; BSO facilitated TNF-alpha-induced p38 MAP kinase activation and RANTES production; SB 203580 attenuated BSO-mediated facilitation of TNF-alpha-induced RANTES production; and the intracellular GSH increased in NAC-treated cells, whereas the intracellular GSH was reduced in BSO-treated cells.<br><br>CONCLUSIONS: These results indicate that cellular redox regulated by GSH is critical for TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human BECs.}, }
@article {pmid11167669, year = {2001}, author = {Schmidt, LE and Dalhoff, K}, title = {Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning.}, journal = {British journal of clinical pharmacology}, volume = {51}, number = {1}, pages = {87-91}, pmid = {11167669}, issn = {0306-5251}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Non-Narcotic/*poisoning ; Child ; Denmark ; Drug Overdose/drug therapy ; Female ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Poisoning/*drug therapy ; Prognosis ; Risk Factors ; }, abstract = {AIMS: To identify risk factors in the development of side-effects to N-acetylcysteine (NAC) in patients with paracetamol poisoning.<br><br>METHODS: A retrospective study was carried out based upon the hospital charts of 529 consecutive patients admitted with paracetamol poisoning, all treated with NAC, at the Department of Hepatology, Copenhagen University Hospital (the tertiary care centre of liver disease in Denmark).<br><br>RESULTS: Forty-five patients (8.5%; 95% confidence intervals (CI) 6.4, 11%) developed side-effects to NAC and 18 patients (3.4%; 95% CI 2.1, 5.4%) developed systemic side-effects. Asthmatics were 2.9 times (95% CI 2.1, 4.7) more likely to develop side-effects (Chi-square: P = 0.004). Side-effects were of similar severity in asthmatics and nonasthmatics. A history of medical allergy was not a risk factor. Serum paracetamol was lower in patients with side-effects than in those without (Mann-Whitney: P = 0.00006).<br><br>CONCLUSIONS: Asthma must be considered a risk factor in the development of side-effects to NAC. However, the side-effects are easily managed and there is no reason to withhold NAC from any patient with paracetamol poisoning. Paracetamol itself seems to offer some protection against the development of side-effects to NAC.}, }
@article {pmid11162875, year = {2000}, author = {Farbiszewski, R and Witek, A and Skrzydlewska, E}, title = {N-acetylcysteine or trolox derivative mitigate the toxic effects of methanol on the antioxidant system of rat brain.}, journal = {Toxicology}, volume = {156}, number = {1}, pages = {47-55}, doi = {10.1016/s0300-483x(00)00333-4}, pmid = {11162875}, issn = {0300-483X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*analysis/pharmacology ; Ascorbic Acid/analysis ; Brain/*drug effects/metabolism ; Chromans/*pharmacology ; Glutathione/analysis ; Glutathione Peroxidase/metabolism ; Male ; Methanol/*toxicity ; Piperazines/*pharmacology ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {The effect of two compounds: N-acetylcysteine (NAC) and trolox derivative (U-83836E) on the methanol induced impairment of the antioxidant system of the rat brain was studied in male Wistar rats (approx. 250 g body weight). The animals were divided into six main groups: control group (0.5 ml of physiological saline intragastrically), NAC group (150 mg/kg intraperitoneally-i.p), U-83836E group (10 mg/kg i.p.), methanol group (3 g/kg intragastrically), NAC+methanol and U-83836E+methanol groups. In these particular groups the changes in antioxidant parameters were observed for 6,12,24,48 h and 5 and 7 days. The results proved that the use of methanol and N-acetylcysteine increased the activities of Cu,Zn-superoxide dismutase, glutathione peroxidase and glutathione reductase by about 15,15 and 41%, respectively, in comparison to the group of rats receiving methanol alone. Similarly, the level of GSH increased by about 17%, the concentration of ascorbate by 20%, while the thiobarbituric acid-reactive substances (TBA-rs) diminished to the values as in control group. The use of new antioxidant U8383E and methanol showed less beneficial effect in the measured parameters however, it serves as a better protector for the methanol induced decrease in GSH-content. These data suggest that NAC and U-83836E mitigate the toxic effects of methanol on the antioxidant system of the rat brain.}, }
@article {pmid11162779, year = {2001}, author = {Tran, A and Tréluyer, JM and Rey, E and Barbet, J and Ferracci, G and d'Athis, P and Vincent, J and Pons, G}, title = {Protective effect of stiripentol on acetaminophen-induced hepatotoxicity in rat.}, journal = {Toxicology and applied pharmacology}, volume = {170}, number = {3}, pages = {145-152}, doi = {10.1006/taap.2000.9091}, pmid = {11162779}, issn = {0041-008X}, mesh = {Acetaminophen/blood/toxicity/urine ; Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Area Under Curve ; Aspartate Aminotransferases/blood ; Chemical and Drug Induced Liver Injury/etiology/mortality/*prevention &amp; control ; Dioxolanes/*pharmacology ; Drug Combinations ; Drug Overdose ; Liver/drug effects/enzymology/pathology ; Male ; Rats ; Rats, Sprague-Dawley ; Time Factors ; }, abstract = {Acetaminophen (APAP) is mainly eliminated at a therapeutic dose through glucuronidation and sulfatation and a small fraction is oxidized by cytochromes P450 (CYP) 2E1, 3A4, and 1A2 to N-acetyl-p-benzoquinone-imine (NAPQI), a highly reactive metabolite further conjugated with glutathione into APAP-GSH, and then metabolized to APAP-cystein and APAP-mercapturate excreted in urine. After APAP overdose, the glucuronidation and sulfatation pathways are saturated and the production of NAPQI increases, causing hepatic injury. Stiripentol (STP); (200 mg/kg), an anticonvulsant drug inhibitor of CYP1A2 and CYP3A4 in vivo in humans was tested against APAP-induced toxicity in rat in comparison with N-acetylcysteine (NAC; 100 mg/kg). The mortality rates 24 h after APAP overdose (2 x 500 mg/kg) were 63% (control), 38% (NAC), 0% (STP), and 4% (STP + NAC). The mean plasma transaminase concentrations 5 and 24 h after overdose were significantly higher in control than in STP and NAC groups. The percentage of rats without microscopic liver necrosis 5 h after APAP overdose was significantly higher in rats receiving STP (100%), NAC (83%), or STP + NAC (83%) than controls (42%). In another experiment, four similar groups were administered 50 mg/kg APAP. Plasma AUC(0-5 h) for APAP-GSH, APAP-cystein, and APAP-mercapturate as well as urine APAP-mercapturate mean amounts were significantly lower in STP animals than in the other groups. STP (200 mg/kg) inhibited NAPQI synthesis through CYP inhibition, thus preventing both liver necrosis and mortality in rats.}, }
@article {pmid11159825, year = {2001}, author = {Xiao, CW and Ash, K and Tsang, BK}, title = {Nuclear factor-kappaB-mediated X-linked inhibitor of apoptosis protein expression prevents rat granulosa cells from tumor necrosis factor alpha-induced apoptosis.}, journal = {Endocrinology}, volume = {142}, number = {2}, pages = {557-563}, doi = {10.1210/endo.142.2.7957}, pmid = {11159825}, issn = {0013-7227}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*physiology ; Biological Transport/drug effects ; Cycloheximide/pharmacology ; Down-Regulation ; Drug Synergism ; Female ; Granulosa Cells/*drug effects/*physiology ; NF-kappa B/antagonists &amp; inhibitors/*physiology ; Peptides/pharmacology ; Proteins/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/*pharmacology ; X-Linked Inhibitor of Apoptosis Protein ; }, abstract = {Although X-linked inhibitor of apoptosis protein (Xiap) is an important intracellular suppressor of apoptosis in a variety of cell types and is present in ovary, its physiological role in follicular development remains unclear. The purpose of the present studies was to examine the modulatory role of Xiap in the proapoptotic action of tumor necrosis factor-alpha (TNFalpha) in rat granulosa cells. Granulosa cells from equine CG-primed immature rats were plated in RPMI 1640 medium containing 10% FCS and subsequently cultured in serum-free RPMI in the absence or presence of TNFalpha (20 ng/ml), the protein synthesis inhibitor cycloheximide (10 microM), and/or adenoviral Xiap sense or antisense complementary DNA. TNFalpha alone failed to induce granulosa cell death, but in the presence of cycloheximide, it markedly increased the number of apoptotic granulosa cells (as assessed by in situ terminal deoxynucleotidyl transferase-mediated deox-UTPbiotin end labeling and DNA fragmentation analysis). Western analysis indicated that TNFalpha alone increased the Xiap protein level, a response significantly reduced by adenoviral Xiap antisense expression. Down-regulation of Xiap expression by antisense complementary DNA induced granulosa cell apoptosis, which was potentiated by the cytokine. Inhibition of nuclear factor-kappaB activation by N-acetyl-cysteine and SN50 suppressed Xiap protein expression and enhanced apoptosis induced by TNFalpha. The latter phenomenon was readily attenuated by adenoviral Xiap sense expression. In conclusion, these findings suggest that Xiap is an important intracellular modulator of the TNFalpha death signaling pathway in granulosa cells. Its expression is regulated by the TNFalpha via a nuclear factor-kappaB-mediated mechanism.}, }
@article {pmid11156936, year = {2001}, author = {Takacs, P and Kauma, SW and Sholley, MM and Walsh, SW and Dinsmoor, MJ and Green, K}, title = {Increased circulating lipid peroxides in severe preeclampsia activate NF-kappaB and upregulate ICAM-1 in vascular endothelial cells.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {15}, number = {2}, pages = {279-281}, doi = {10.1096/fj.00-0549fje}, pmid = {11156936}, issn = {0892-6638}, mesh = {Antioxidants/pharmacology ; Cells, Cultured ; Endothelium, Vascular/drug effects/*physiology/physiopathology ; Female ; Humans ; Intercellular Adhesion Molecule-1/*genetics ; Lipid Peroxides/*blood ; NF-kappa B/*metabolism ; Pre-Eclampsia/*blood/physiopathology ; Pregnancy ; Umbilical Veins ; }, abstract = {Preeclampsia is a systemic disease of pregnancy characterized by maternal hypertension, proteinuria, and edema. These clinical pathological findings may be attributed to abnormalities in vascular endothelial activation secondary to increased oxidative stress. To test the hypothesis that increased circulating lipid peroxides in preeclamptic women activate vascular endothelial cells, we determined NF-kappaB transcriptional activity and ICAM-1 expression in human umbilical vein endothelial cells (HUVEC) cultured with plasma from women with severe preeclampsia (preeclamptic plasma, N = 12) or plasma from normal pregnancies (normal plasma, N = 12). Preeclamptic women had increased circulating lipid peroxides compared with normal pregnant women, as demonstrated by a 4.5-fold higher concentration of plasma malondialdehyde (PkB luciferase reporter construct transfected into HUVEC, preeclamptic plasma was found to up-regulate HUVEC NF-kappaB activity by 2.5-fold when compared with normal plasma (PkB activation in response to preeclamptic-plasma by 77% (PkB activation and ICAM-1 expression on HUVEC, which can be inhibited by vitamin E and N-acetyl-cysteine.}, }
@article {pmid10755539, year = {2000}, author = {Weinbroum, AA and Rudick, V and Ben-Abraham, R and Karchevski, E}, title = {N-acetyl-L-cysteine for preventing lung reperfusion injury after liver ischemia-reperfusion: a possible dual protective mechanism in a dose-response study.}, journal = {Transplantation}, volume = {69}, number = {5}, pages = {853-859}, doi = {10.1097/00007890-200003150-00031}, pmid = {10755539}, issn = {0041-1337}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Dose-Response Relationship, Drug ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Glutathione/metabolism ; Ischemia/*complications ; Liver/enzymology ; *Liver Circulation ; Lung/drug effects/enzymology/metabolism ; Lung Diseases/*prevention &amp; control ; Male ; Perfusion ; Pulmonary Circulation ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; Respiration ; Xanthine Oxidase/metabolism ; }, abstract = {BACKGROUND: Acute lung reperfusion injury (ALI) frequently follows an ischemic event in another organ, such as organ transplantation. We recently demonstrated that lung priming with N-acetyl-L-cysteine (NAC) prevented liver ischemia-reperfusion (IR)-induced ALI pending on reduced glutathione (GSH) amount of replenishment. We now assessed the therapeutic effect of NAC-in preventing ALI caused by liver IR-if administered to the lung during liver reperfusion.<br><br>PROCEDURES: Rat isolated livers were stabilized (30 min) and then perfused with modified Krebs-Henseleit solution (control, n=20) or made globally ischemic (IR, n=20) for 2 hr. Rat lungs were isolated separately, ventilated, and stabilized (30 min) with Krebs plus 5% bovine albumin. Pairs of liver and lung were then reperfused together for 15 min, followed by only lung recirculation with the liver effluent for another 45 min. Three more controls (n=20 each) and three ischemic groups (n=20 each) included lungs which were treated with 100, 150 or 225 mg x kg(-1) NAC (0.5, 0.74, or 1.1 mmol, respectively) during the 15-min liver and lung reperfusion period.<br><br>RESULTS: Pulmonary artery and ventilatory pressures and vascular resistance increased by 60-80% of baseline, compliance decreased, and bronchoalveolar lavage volume and content were abnormally high in the IR-nontreated and the IR-100 lungs. Most parameters in IR-150 and IR-225 lungs remained almost similar to controls. Postinsult GSH content in IR-100, -150, and -225 lungs was at 20%, 110%, and 90% above the IR-nontreated lungs, respectively.<br><br>CONCLUSIONS: Lung treatment with NAC during its reperfusion with IR liver effluent prevented ALI. Lung GSH replenishment accounted for lung protection, but its content did not correlate directly with grade of protection; NAC itself seemingly afforded lung protection as well.}, }
@article {pmid11156586, year = {2001}, author = {Hashimoto, S and Gon, Y and Matsumoto, K and Takeshita, I and Horie, T}, title = {N-acetylcysteine attenuates TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells.}, journal = {British journal of pharmacology}, volume = {132}, number = {1}, pages = {270-276}, pmid = {11156586}, issn = {0007-1188}, mesh = {Acetylcysteine/*pharmacology ; Blotting, Western ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cells, Cultured ; Endothelium, Vascular/cytology/drug effects/*metabolism ; Enzyme Activation ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Interleukin-8/*biosynthesis ; MAP Kinase Kinase 3 ; MAP Kinase Kinase 6 ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Muscle, Smooth, Vascular/cytology/drug effects/*metabolism ; Phosphorylation ; Protein-Tyrosine Kinases/metabolism ; Pulmonary Artery/cytology/drug effects/*metabolism ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {1. We have previously shown that tumour necrosis factor-alpha (TNF-alpha) activates p38 mitogen-activated protein (MAP) kinase to produce interleukin-8 (IL-8) by human pulmonary vascular endothelial cells. Reactive oxygen species (ROS) including H(2)O(2) generated by TNF-alpha can act as signalling intermediates for cytokine induction; therefore, scavenging ROS by anti-oxidants is important for the regulation of cytokine production. However, the effect of N-acetylcysteine (NAC), which acts as a precursor of glutathione (GSH) synthesis, on TNF-alpha-induced activation of p38 MAP kinase pathway and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells has not been determined. To clarify these issues, we examined the effect of NAC on TNF-alpha-induced activation of p38 MAP kinase, MAP kinase kinase (MKK) 3 and MKK6 which are upstream regulators of p38 MAP kinase, and p38 MAP kinase-mediated IL-8 production. 2. Human pulmonary vascular endothelial cells that had been preincubated with NAC were stimulated with TNF-alpha and then the activation of p38 MAP kinase and MKK3/MKK6 in the cells and IL-8 concentrations in the culture supernatants were determined. 3. Intracellular GSH levels increased in NAC-treated cells. 4. NAC attenuated TNF-alpha-induced activation of p38 MAP kinase and MKK3/MKK6. 5. NAC attenuated p38 MAP kinase-mediated IL-8 production by TNF-alpha-stimulated cells. 6. These results indicate that the cellular reduction and oxidation (redox) regulated by intracellular GSH is critical for TNF-alpha-induced activation of p38 MAP kinase pathway and p38 MAP kinase-mediated IL-8 production by human pulmonary vascular endothelial cells, and we emphasize that anti-oxidant therapy is an important strategy for the treatment of acute lung injury.}, }
@article {pmid11154075, year = {2000}, author = {Tobi, SE and Paul, N and McMillan, TJ}, title = {Glutathione modulates the level of free radicals produced in UVA-irradiated cells.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {57}, number = {2-3}, pages = {102-112}, doi = {10.1016/s1011-1344(00)00084-1}, pmid = {11154075}, issn = {1011-1344}, mesh = {Acetylcysteine/metabolism/pharmacology ; Antioxidants/*metabolism ; Dose-Response Relationship, Radiation ; Fluoresceins ; Fluorescent Dyes ; Free Radical Scavengers/metabolism/pharmacology ; Free Radicals/*metabolism ; Glutathione/*metabolism ; Humans ; Intracellular Fluid/metabolism ; Keratinocytes/radiation effects ; Oxidation-Reduction ; Rhodamines/pharmacology ; Tumor Cells, Cultured ; Ultraviolet Rays ; }, abstract = {We have developed an assay to detect reactive oxygen species (ROS) generated by UVA radiation utilising chemical probes which become fluorescent upon oxidation. Using a human bladder carcinoma cell line (MGH-U1) and spontaneously immortalised keratinocytes (HaCaT), we have shown a UVA (narrow band 365+/-5 nm) dose-dependent increase in fluorescence by flow cytometry following loading of the cells with either dihydrorhodamine 123 (DHR) or 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). The UVA response of both DHR and DCFH was enhanced by elevation of intracellular levels of the photosensitiser protoporphyrin IX by incubation for 2.5 h with 5-aminolaevulinic acid. Depletion of the antioxidant glutathione (GSH) using the inhibitor D,L-buthionine-sulphoximine (BSO), resulted in an increase in the UVA-induced fluorescence of DCF but not of rhodamine 123. Conversely, raising intracellular GSH levels with N-acetyl cysteine (NAC) had relatively little protective effect in terms of degree of induced fluorescence.}, }
@article {pmid11153725, year = {2001}, author = {Andrews, NP and Prasad, A and Quyyumi, AA}, title = {N-acetylcysteine improves coronary and peripheral vascular function.}, journal = {Journal of the American College of Cardiology}, volume = {37}, number = {1}, pages = {117-123}, doi = {10.1016/s0735-1097(00)01093-7}, pmid = {11153725}, issn = {0735-1097}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Adult ; Coronary Artery Disease/*drug therapy/physiopathology ; Coronary Circulation/*drug effects/physiology ; Dose-Response Relationship, Drug ; Drug Synergism ; Endothelium, Vascular/*drug effects/physiopathology ; Female ; Femoral Artery/drug effects/physiopathology ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Nitric Oxide/physiology ; Nitroglycerin/administration &amp; dosage ; Nitroprusside/administration &amp; dosage ; Vasodilation/*drug effects/physiology ; }, abstract = {OBJECTIVES: We investigated whether N-acetylcysteine (NAC), a reduced thiol that modulates redox state and forms adducts of nitric oxide (NO), improves endothelium-dependent vasomotion.<br><br>BACKGROUND: Coronary atherosclerosis is associated with endothelial dysfunction and reduced NO activity.<br><br>METHODS: In 16 patients undergoing cardiac catheterization, seven with and nine without atherosclerosis, we assessed endothelium-dependent vasodilation with acetylcholine (ACH) and endothelium-independent vasodilation with nitroglycerin (NTG) and sodium nitroprusside (SNP) before and after intracoronary NAC. In 14 patients femoral vascular responses to ACH, NTG and SNP were measured before and after NAC.<br><br>RESULTS: Intraarterial NAC did not change resting coronary or peripheral vascular tone. N-acetylcysteine potentiated ACH-mediated coronary vasodilation; coronary blood flow was 36 +/- 11% higher (p < 0.02), and epicardial diameter changed from -1.2 +/- 2% constriction to 4.7 +/- 2% dilation after NAC (p = 0.03). Acetylcholine-mediated femoral vasodilation was similarly potentiated by NAC (p = 0.001). Augmentation of the ACH response was similar in patients with or without atherosclerosis. N-acetylcysteine did not affect NTG-mediated vasodilation in either the femoral or coronary circulations and did not alter SNP responses in the femoral circulation. In contrast, coronary vasodilation with SNP was significantly greater after NAC (p < 0.05).<br><br>CONCLUSIONS: Thiol supplementation with NAC improves human coronary and peripheral endothelium-dependent vasodilation. Nitroglycerin responses are not enhanced, but SNP-mediated responses are potentiated only in the coronary circulation. These NO-enhancing effects of thiols reflect the importance of the redox state in the control of vascular function and may be of therapeutic benefit in treating acute and chronic manifestations of atherosclerosis.}, }
@article {pmid11153617, year = {2000}, author = {Rank, N and Michel, C and Haertel, C and Lenhart, A and Welte, M and Meier-Hellmann, A and Spies, C}, title = {N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study.}, journal = {Critical care medicine}, volume = {28}, number = {12}, pages = {3799-3807}, doi = {10.1097/00003246-200012000-00006}, pmid = {11153617}, issn = {0090-3493}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Aged ; Blood Flow Velocity/drug effects ; Coloring Agents/pharmacokinetics ; Double-Blind Method ; Female ; Free Radical Scavengers/pharmacology/*therapeutic use ; Hemodynamics/drug effects ; Humans ; Indocyanine Green/pharmacokinetics ; Infusions, Intravenous ; Injections, Intravenous ; Lidocaine/*analogs &amp; derivatives/blood ; Liver/*drug effects/metabolism ; Liver Circulation/*drug effects ; Liver Function Tests ; Male ; Metabolic Clearance Rate/drug effects ; Microsomes, Liver/drug effects/metabolism ; Middle Aged ; Oxygen Consumption/drug effects ; Prospective Studies ; Shock, Septic/*drug therapy/metabolism/microbiology/mortality/physiopathology ; Survival Analysis ; }, abstract = {OBJECTIVE: In septic shock, decreased splanchnic blood flow is reported, despite adequate systemic hemodynamics. Aacetylcysteine (NAC) was found to increase hepatosplanchnic blood flow in experimental settings. In septic shock patients, NAC improved the clearance of indocyanine green and the relationship of systemic oxygen consumption to oxygen demand. We investigated the influence of NAC on liver blood flow, hepatosplanchnic oxygen transport-related variables, and liver function during early septic shock.<br><br>DESIGN: Prospective, randomized, double-blind study.<br><br>SETTING: Septic shock patients admitted to an interdisciplinary surgical intensive care unit.<br><br>PATIENTS: We examined 60 septic shock patients within 24 hrs after onset of sepsis. They were conventionally resuscitated with volume and inotropes and were in stable condition. A gastric tonometer was inserted into the stomach and a catheter into the hepatic vein. Microsomal liver function was assessed by using the plasma appearance of monoethylglycinexylidide (MEGX).<br><br>INTERVENTIONS: Subjects randomly received either a bolus of 150 mg/kg iv NAC over 15 mins and a subsequent continuous infusion of 12.5 mg/kg/hr NAC over 90 mins (n = 30) or placebo (n = 30).<br><br>MEASUREMENTS AND MAIN RESULTS: Measurements were performed before (baseline) and 60 mins after beginning the infusion (infusion). After NAC, a significant increase in absolute liver blood flow index (2.7 vs. 3.3 L/min/m2; p = .01) and cardiac index (5.0 vs. 5.7 L/min/m2; p = .02) was observed. Fractional liver blood flow index (cardiac index-related liver blood flow index) did not change. The difference between arterial and gastric mucosal carbon dioxide tension decreased (p = .05) and MEGX increased (p = .04). Liver blood flow index and MEGX correlated significantly (r(s) = .57; p < or = .01).<br><br>CONCLUSIONS: After NAC treatment, hepatosplanchnic flow and function improved and may, therefore, suggest enhanced nutritive blood flow. The increase of liver blood flow index was not caused by redistribution to the hepatosplanchnic area, but by an increase of cardiac index. Because of its correlation with liver blood flow index, MEGX may be helpful in identifying patients who benefit from NAC treatment in early septic shock.}, }
@article {pmid11153595, year = {2000}, author = {Parmentier, M and Hirani, N and Rahman, I and Donaldson, K and MacNee, W and Antonicelli, F}, title = {Regulation of lipopolysaccharide-mediated interleukin-1beta release by N-acetylcysteine in THP-1 cells.}, journal = {The European respiratory journal}, volume = {16}, number = {5}, pages = {933-939}, doi = {10.1183/09031936.00.16593300}, pmid = {11153595}, issn = {0903-1936}, mesh = {Acetylcysteine/*pharmacology ; Cell Line ; Cycloheximide/pharmacology ; Enzyme Inhibitors/pharmacology ; Glutathione/*analogs &amp; derivatives/pharmacology ; Humans ; Interleukin-1/genetics/*metabolism ; Lipopolysaccharides/*pharmacology ; Macrophages/drug effects/metabolism ; NF-kappa B/metabolism/physiology ; Okadaic Acid/pharmacology ; Protein Isoforms/metabolism ; Protein Synthesis Inhibitors/pharmacology ; RNA, Messenger/metabolism ; }, abstract = {Increased levels of inflammatory cytokines such as interleukin (IL)-1 and IL-8 occur in the bronchoalveolar lavage fluid in various lung diseases. Cytokine gene expression is controlled by transcription factors such as nuclear factor-kappaB (NF-kappaB) which can be activated by a number of stimuli including the oxidants prevent. It was hypothesized that lipopolysaccharide (LPS)-induced IL-1beta secretion may be modulated by the intracellular thiol redox status of the cells. The effect of the antioxidant compound, N-acetyl-L-cysteine (NAC), on IL-1beta release and regulation of NF-kappaB in a human myelo-monocytic cell line (THP-1) differentiated into macrophages was studied. LPS (10 microg x mL(-1)) increased IL-1beta release at 24 h compared to control levels (p<0.001). NAC (5 mM) also enhanced LPS-induced IL-1beta release from THP-1 cells (p<0.001). In addition, treatment of cells with cycloheximide, an inhibitor of protein synthesis, inhibited the NAC-mediated IL-1beta release. Under the same conditions, NF-kappaB binding was activated by LPS and NAC increased this LPS-mediated effect. Western blot analysis revealed that NAC treatment leads to an increase in p50 and p65 protein synthesis. These data indicate that N-acetyl-L-cysteine modulates interleukin-1kappa release by increasing levels of the homo- and heterodimeric forms of nuclear factor-kappaB.}, }
@article {pmid11145996, year = {2001}, author = {Olivieri, G and Baysang, G and Meier, F and Müller-Spahn, F and Stähelin, HB and Brockhaus, M and Brack, C}, title = {N-acetyl-L-cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell cytotoxicity: effects on beta-amyloid secretion and tau phosphorylation.}, journal = {Journal of neurochemistry}, volume = {76}, number = {1}, pages = {224-233}, doi = {10.1046/j.1471-4159.2001.00090.x}, pmid = {11145996}, issn = {0022-3042}, mesh = {Acetylcysteine/*pharmacology ; Amyloid beta-Peptides/*metabolism/pharmacology ; Blotting, Western ; Cell Survival/drug effects/radiation effects ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Glutathione/metabolism ; Glutathione Reductase/antagonists &amp; inhibitors ; Humans ; Hydrogen Peroxide/pharmacology ; Neuroblastoma/*metabolism ; Oxidative Stress/*drug effects ; Peptide Fragments/metabolism/pharmacology ; Phosphorylation/drug effects/radiation effects ; Tetrazolium Salts/metabolism ; Thiazoles/metabolism ; Tumor Cells, Cultured ; Ultraviolet Rays ; tau Proteins/*metabolism ; }, abstract = {Redox changes within neurones are increasingly being implicated as an important causative agent in brain ageing and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). Cells have developed a number of defensive mechanisms to maintain intracellular redox homeostasis, including the glutathione (GSH) system and antioxidant enzymes. Here we examine the effects of N-acetyl-L-cysteine (NAC) on beta-amyloid (A beta) secretion and tau phosphorylation in SHSY5Y neuroblastoma cells after exposure to oxidative stress inducing/cytotoxic compounds (H(2)O(2), UV light and toxic A beta peptides). A beta and tau protein are hallmark molecules in the pathology of AD while the stress factors are implicated in the aetiology of AD. The results show that H(2)O(2), UV light, A beta 1-42 and toxic A beta 25-35, but not the inactive A beta 35-25, produce a significant induction of oxidative stress and cell cytotoxicity. The effects are reversed when cells are pre-treated with 30 mM NAC. Cells exposed to H(2)O(2), UV light and A beta 25-35, but not A beta 35-25, secrete significantly higher amounts of A beta 1-40 and A beta 1-42 into the culture medium. NAC pre-treatment increased the release of A beta 1-40 compared with controls and potentiated the release of both A beta 1-40 and A beta 1-42 in A beta 25-35-treated cells. Tau phosphorylation was markedly reduced by H(2)O(2) and UV light but increased by A beta 25-35. NAC strongly lowered phospho-tau levels in the presence or absence of stress treatment.}, }
@article {pmid11140748, year = {2000}, author = {Yang, EY and Campbell, A and Bondy, SC}, title = {Configuration of thiols dictates their ability to promote iron-induced reactive oxygen species generation.}, journal = {Redox report : communications in free radical research}, volume = {5}, number = {6}, pages = {371-375}, doi = {10.1179/135100000101535942}, pmid = {11140748}, issn = {1351-0002}, support = {AG 16794/AG/NIA NIH HHS/United States ; ES 7992/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/pharmacology ; Animals ; Antioxidants/chemistry/*pharmacology ; Cerebral Cortex/*metabolism ; Cysteine/chemistry/pharmacology ; Glutathione/chemistry/pharmacology ; Homocysteine/chemistry/pharmacology ; Indicators and Reagents ; Iron/*pharmacology ; Male ; Mice ; Mice, Inbred Strains ; Mitochondria/drug effects/*metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Structure-Activity Relationship ; Sulfhydryl Compounds/chemistry/*pharmacology ; Synaptosomes/drug effects/*metabolism ; }, abstract = {Iron catalyzes the production of reactive oxygen species (ROS) through the Fenton reaction. The modification of this phenomenon in the presence of various thiol compounds that are nominally reducing agents has been studied. Using the synaptosomal/mitochondrial (P2) fraction of rat cerebral cortex as a biological source of reactive oxygen species (ROS) production, we studied the influence of four compounds, glutathione (GSH), cysteine, N-acetyl-cysteine (NAC), and homocysteine on iron-induced ROS production. None of the thiol compounds alone, at the concentrations used, affected the basal rate of ROS production in the P2 fraction. GSH, homocysteine and NAC did not alter Fe-induced ROS generation, while cysteine greatly potentiated ROS formation. Measurement of the rate of ROS production in the presence of varying concentrations of cysteine together with 20 microM ferrous iron revealed a dose-response relationship. The mechanism whereby free cysteine, but not the cysteine-containing peptide GSH, homocysteine or NAC with a blocked amino group, exacerbates the pro-oxidant properties of ferrous iron probably involves formation of a complex between iron, a sulfhydryl and a free carboxyl residue located at a critical distance from the -SH group. Cysteine-iron interactions may, in part, account for the excessive toxicity of free cysteine in contrast to GSH and NAC.}, }
@article {pmid11135060, year = {2001}, author = {Vindis, C and Séguélas, MH and Lanier, S and Parini, A and Cambon, C}, title = {Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase.}, journal = {Kidney international}, volume = {59}, number = {1}, pages = {76-86}, doi = {10.1046/j.1523-1755.2001.00468.x}, pmid = {11135060}, issn = {0085-2538}, support = {NS35875-01/NS/NINDS NIH HHS/United States ; }, mesh = {*Adaptor Proteins, Signal Transducing ; *Adaptor Proteins, Vesicular Transport ; Animals ; Cell Division/physiology ; Cells, Cultured ; Dopamine/*pharmacology ; Enzyme Activation ; Hydrogen Peroxide/*metabolism ; Kidney Tubules, Proximal/cytology/drug effects/*enzymology/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Monoamine Oxidase/*metabolism ; Phosphorylation ; Proteins/metabolism ; Rats ; Rats, Sprague-Dawley ; Shc Signaling Adaptor Proteins ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; Substrate Specificity ; Thymidine/metabolism ; Tyramine/pharmacology ; Tyrosine/metabolism ; }, abstract = {BACKGROUND: The rat renal proximal tubule cells contain a large amount of monoamine oxidase, which catalyzes the oxidative deamination of catecholamines such as dopamine (DA). The aim of this study is to investigate the potential role of hydrogen peroxide (H2O2) produced by monoamine oxidase (MAO) isoform on regulation of cell signaling and function.<br><br>METHODS: Primary rat proximal tubular cells, which contain almost exclusively MAO-A, and human embryonic kidney 293 (HEK 293) cells stably transfected with human MAO-B cDNA were treated with DA or tyramine in the presence or the absence of some inhibitors. Then, Shc protein tyrosine phosphorylation and extracellular-regulated kinase (ERK) activation were evaluated by immunoprecipitation/immunoblot analysis and cell proliferation by [3H]thymidine incorporation or cell counting.<br><br>RESULTS: In rat proximal tubule cells, DA induced tyrosine phosphorylation of Shc, ERK activation, and a significant increase in DNA synthesis. The involvement of MAO-dependent H2O2 generation induced by DA (5 micromol/L) was supported by the demonstration that the DA effects were (1) fully prevented by cell pretreatment with the MAO inhibitor pargyline, the antioxydant N-acetylcysteine (NAC), and the DA uptake inhibitor GBR 12909; (2) not abrogated by the D1 and D2 receptor antagonists; (3) observed in HEK 293 MAO-B cells but not in HEK 293 wild-type cells, which do not express MAO; and (4) similar to those induced by another MAO substrate, tyramine.<br><br>CONCLUSIONS: Taken together, these results show that in addition to the effects related to receptor stimulation, DA, and probably the other catecholamines, may induce some of its effects through the MAO-dependent H2O2 production.}, }
@article {pmid11134896, year = {2001}, author = {Thibodeau, PA and Kocsis-Bédard, S and Courteau, J and Niyonsenga, T and Paquette, B}, title = {Thiols can either enhance or suppress DNA damage induction by catecholestrogens.}, journal = {Free radical biology &amp; medicine}, volume = {30}, number = {1}, pages = {62-73}, doi = {10.1016/s0891-5849(00)00446-9}, pmid = {11134896}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Copper/chemistry/pharmacology ; DNA Damage/*drug effects ; Dithiothreitol/pharmacology ; Drug Resistance, Neoplasm ; Estradiol/*analogs &amp; derivatives/chemistry/pharmacology ; Estrogens, Catechol/*pharmacology ; Glutathione/pharmacology ; Hydrogen Peroxide/metabolism ; Kinetics ; Methotrexate ; NAD/pharmacology ; Oxidation-Reduction ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/*pharmacology ; Thioctic Acid/*analogs &amp; derivatives/pharmacology ; }, abstract = {The estrogen metabolites catecholestrogens (or hydroxyestrogens) are involved in carcinogenesis and the development of resistance to methotrexate. This induction of drug resistance correlates with the relative efficiency of catecholestrogens in the generation of reactive oxygen species (ROS) and the induction of DNA strand breaks. Although antioxidants can neutralize ROS, the generation of these reactive species by catecholestrogens can be enhanced by electron donors like NADH. Therefore, this study was undertaken to determine the ability of different thiol agents (GSH, NAC, DTT, DHLA) to either inhibit or enhance the level of DNA damage induced by the H(2)O(2) generating system 4-hydroxyestradiol/Cu(II). Our results show that GSH, DTT, and DHLA inhibited the induction of the 4-hydroxyestradiol/Cu(II)-mediated DNA damage, with GSH showing the best potential. In contrast, the GSH precursor NAC at low concentrations was able to enhance the level of oxidative damage, as observed with NADH. NAC can reduce Cu(II) to Cu(I) producing the radical NAC&amp;z.rad;, which can generate the superoxide anion. However, the importance of this pathway appears to be relatively minor since the addition of NAC to the 4-hydroxyestradiol/Cu(II) system generates about 15 times more DNA strand breaks than NAC and Cu(II) alone. We suggest that NAC can perpetuate the redox cycle between the quinone and the semiquinone forms of the catecholestrogens, thereby enhancing the production of ROS. In conclusion, this study demonstrates the crucial importance of the choice of antioxidant as potential therapy against the negative biological effects of estrogens.}, }
@article {pmid11133820, year = {2000}, author = {Chung, FL and Conaway, CC and Rao, CV and Reddy, BS}, title = {Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate.}, journal = {Carcinogenesis}, volume = {21}, number = {12}, pages = {2287-2291}, doi = {10.1093/carcin/21.12.2287}, pmid = {11133820}, issn = {0143-3334}, support = {P01 CA046535/CA/NCI NIH HHS/United States ; CA46535/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Anticarcinogenic Agents ; Azoxymethane/toxicity ; Body Weight/drug effects ; Brassica ; Carcinogens/toxicity ; Colon/*drug effects/pathology ; Colonic Neoplasms/chemically induced/*prevention &amp; control ; Genotype ; Glutathione Transferase/genetics ; Humans ; Intestinal Mucosa/*drug effects/pathology ; Isothiocyanates/*pharmacology ; Male ; Rats ; Rats, Inbred F344 ; Sulfoxides ; Thiocyanates/*pharmacology ; Vegetables ; }, abstract = {Epidemiological studies have linked consumption of broccoli to a reduced risk of colon cancer in individuals with the glutathione S-transferase M1 (GSTM1) null genotype. GSTs are involved in excretion and elimination of isothiocyanates (ITCs), which are major constituents of broccoli and other cruciferous vegetables and have cancer chemopreventive potential, so it is speculated that ITCs may play a role in protection against human colon cancer. However, there is a lack of data from animal studies to support this. We carried out a bioassay to examine whether sulforaphane (SFN) and phenethyl isothiocyanate (PEITC), major ITCs in broccoli and watercress, respectively, and their corresponding N:-acetylcysteine (NAC) conjugates, show any chemopreventive activity towards azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in F344 rats. Groups of six male F344 rats were treated with AOM subcutaneously (15 mg/kg body wt) once weekly for 2 weeks. SFN and PEITC and their NAC conjugates were administered by gavage either three times weekly for 8 weeks (5 and 20 micromol, respectively) after AOM dosing (post-initiation stage) or once daily for 3 days (20 and 50 micromol, respectively) before AOM treatment (initiation stage). The bioassay was terminated on week 10 after the second AOM dosing and ACF were quantified. SFN, SFN-NAC, PEITC and PEITC-NAC all significantly reduced the formation of total ACF from 153 to 100-116 (P < 0.01) and multicrypt foci from 52 to 27-38 (more than four crypts/focus; P < 0.05) during the post-initiation treatment. However, only SFN and PEITC were effective during the initiation phase, reducing the total ACF from 153 to 109-115 (P < 0.01) and multicrypt foci from 52 to 35 (more than four crypts/focus; P < 0.05). The NAC conjugates were inactive as anti-initiators against AOM-induced ACF. These findings provide important laboratory evidence for a potential role of SFN and PEITC in the protection against colon cancer.}, }
@article {pmid11133225, year = {2001}, author = {Lee, YW and Kühn, H and Hennig, B and Neish, AS and Toborek, M}, title = {IL-4-induced oxidative stress upregulates VCAM-1 gene expression in human endothelial cells.}, journal = {Journal of molecular and cellular cardiology}, volume = {33}, number = {1}, pages = {83-94}, doi = {10.1006/jmcc.2000.1278}, pmid = {11133225}, issn = {0022-2828}, support = {P42 ES007380/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Arteriosclerosis/etiology ; Cells, Cultured/drug effects/metabolism ; Endothelium, Vascular/*drug effects/metabolism ; Genes, Reporter ; Humans ; Inflammation/metabolism ; Interleukin-4/antagonists &amp; inhibitors/*pharmacology ; Oxidative Stress/drug effects/*genetics ; Promoter Regions, Genetic ; Pyrrolidines/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Sp1 Transcription Factor/*physiology ; Thiocarbamates/pharmacology ; Transcription Factors/physiology ; Transcription, Genetic/drug effects ; Transfection ; Umbilical Veins ; Up-Regulation/*drug effects ; Vascular Cell Adhesion Molecule-1/*biosynthesis/genetics ; }, abstract = {Vascular cell adhesion molecule-1 (VCAM-1) is expressed in early stages of atherosclerosis; however, the mechanisms of its upregulation are not fully understood. In the present study, we examined the effects of interleukin-4 (IL-4) on VCAM-1 gene expression and its transcriptional regulatory mechanism in human umbilical vein endothelial cells (HUVEC). Reverse transcription-polymerase chain reaction showed that VCAM-1 mRNA was induced in IL-4-treated HUVEC in a time- and dose-dependent manner. Among known transcription factors that have binding sites in the promoter region of the VCAM-1 gene, IL-4 activated only SP-1. In contrast, nuclear factor- kappa B (NF- kappa B), activator protein-1 (AP-1) and interferon regulatory factor-1 (IRF-1), which also have consensus binding sequences in the 5'-flanking region of the human VCAM-1 gene, were not activated. The role of SP-1 in IL-4-induced VCAM-1 expression was confirmed in HUVEC transfected with a reporter construct of the VCAM-1 promoter with mutated SP-1 binding site. As IL-4 treatment of HUVEC enhanced the intracellular oxidizing potential, as indicated by an increase in 2',7'-dichlorofluorescein (DCF) fluorescence, we studied the effect of antioxidants on IL-4-induced VCAM-1 expression. Pretreatment of HUVEC with pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC) completely prevented IL-4-induced VCAM-1 expression. In addition, PDTC inhibited IL-4-related activation of SP-1. These results suggest that IL-4-induced oxidative stress upregulates the expression of VCAM-1 gene in HUVEC at transcriptional levels via activation of SP-1 transcription factor. In contrast, NF- kappa B, AP-1 or IRF-1 do not appear to be involved in the signal transduction cascade.}, }
@article {pmid11124650, year = {2000}, author = {Aihara, M and Dobashi, K and Akiyama, M and Naruse, I and Nakazawa, T and Mori, M}, title = {Effects of N-acetylcysteine and ambroxol on the production of IL-12 and IL-10 in human alveolar macrophages.}, journal = {Respiration; international review of thoracic diseases}, volume = {67}, number = {6}, pages = {662-671}, doi = {10.1159/000056297}, pmid = {11124650}, issn = {0025-7931}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Ambroxol/*therapeutic use ; Dose-Response Relationship, Drug ; Expectorants/*therapeutic use ; Female ; Humans ; Interleukin-10/*biosynthesis ; Interleukin-12/*biosynthesis ; Lipopolysaccharides ; Macrophages, Alveolar/*drug effects/metabolism ; Male ; Reference Values ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) and ambroxol (AMB) have recently been proposed as possible therapeutic agents in the treatment of pulmonary disorders. IL-12 plays an important role in host resistance to infection and the development of Th-1 cells. In contrast, IL-10 is involved in anti-inflammatory and immunoregulatory mechanisms.<br><br>OBJECTIVE: We investigated the effects of NAC and AMB on secretions of IL-12 and IL-10 from human alveolar macrophages.<br><br>METHODS: Alveolar macrophages were obtained from 7 healthy nonsmokers by bronchoalveolar lavage. The cells were first incubated with either NAC or AMB for 2 h and then cultured in lipopolysaccharide (LPS) solution for 24 h. IL-12 and IL-10 secretions were measured by ELISA.<br><br>RESULT: Both NAC and AMB enhanced LPS-induced secretion of IL-12. NAC also enhanced LPS-induced IL-10 secretion, while AMB did not. The ratio IL-12/IL-10 secretion was increased by AMB, but NAC did not affect it.<br><br>CONCLUSIONS: The results suggest that NAC enhances inflammatory and immune responses and prevents excessive responses reciprocally, through keeping local balance of IL-12 and IL-10 production in alveolar macrophages at inflammatory sites of bacterial pneumonia. AMB appears to strengthen inflammatory responses and cell-mediated immunity, facilitating the development of Th-1 cells, through shifting the local balance to IL-12 dominance.}, }
@article {pmid11124598, year = {2000}, author = {Rangan, GK and Wang, Y and Tay, YC and Harris, DC}, title = {Cytokine gene expression in Adriamycin nephropathy: effects of antioxidant nuclear factor kappaB inhibitors in established disease.}, journal = {Nephron}, volume = {86}, number = {4}, pages = {482-490}, doi = {10.1159/000045838}, pmid = {11124598}, issn = {1660-8151}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/*toxicity ; Antioxidants/*pharmacology ; Cytokines/*biosynthesis/genetics ; Doxorubicin/*toxicity ; Free Radical Scavengers/pharmacology ; Kidney Diseases/chemically induced/*metabolism ; Male ; NF-kappa B/*antagonists &amp; inhibitors ; Nuclear Proteins/biosynthesis/isolation &amp; purification ; Pyrrolidines/pharmacology ; RNA, Messenger/biosynthesis/genetics ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Thiocarbamates/pharmacology ; }, abstract = {BACKGROUND/AIM: Inhibition of nuclear factor kappaB with the antioxidant pyrrolidine dithiocarbamate (PDTC) reduced tubulointerstitial injury in Adriamycin nephropathy (AN), whereas N-acetylcysteine (NAC) was ineffective. Here we hypothesize that PDTC reduces the renal cortical expression of nuclear factor kappaB dependent cytokines in AN.<br><br>METHODS: Male Wistar rats received a single intravenous injection of doxorubicin hydrochloride (7.5 mg/kg). NAC (150 mg/kg twice daily i.p.), PDTC (50 mg/kg twice daily i.p.), or vehicle were commenced on day 14 and continued until day 30.<br><br>RESULTS: On day 30, mRNAs of selected cytokines were increased in AN (TNF-alpha 3.4-fold, MCP-1 5.1-fold, IL-10 2.7-fold, TGF-beta1 3.5-fold, all p < 0.05) as determined by RT-PCR. PDTC reduced IL-10 and TGF-beta1 mRNAs (p < 0.05), whereas the upregulation of MCP-1 and TNF-alpha mRNAs was not affected. In contrast, NAC increased TNF-alpha and IL-10 mRNAs (p < 0.05). Nuclear protein levels of activator protein-1 were increased in AN (4.4-fold, p < 0.01) and not significantly altered by PDTC (3.0-fold, p = 0.13) or NAC (5. 2-fold, p = 0.18).<br><br>CONCLUSIONS: The protective effects of PDTC in AN are not associated with a local reduction in TNF-alpha and MCP-1 gene expression. The latter may be due to continued transactivation by activator protein-1. These data also suggest that IL-10 and TGF-beta1 mRNA expressions are PDTC dependent and have a role in mediating tubulointerstitial injury.}, }
@article {pmid11118966, year = {2000}, author = {Bailey, B and Bussières, JF}, title = {Antidote availability in Quebec hospital pharmacies: impact of N-acetylcysteine and naloxone consumption.}, journal = {The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique}, volume = {7}, number = {4}, pages = {198-204}, pmid = {11118966}, issn = {1198-581X}, mesh = {Acetylcysteine/supply &amp; distribution ; Antidotes/economics/*standards/*supply &amp; distribution ; Drug Utilization Review ; Humans ; Naloxone/supply &amp; distribution ; Pharmacy Service, Hospital/*organization &amp; administration ; Quebec ; Surveys and Questionnaires ; }, abstract = {OBJECTIVES: To study the availability of 13 specific antidotes in hospitals and correlate the availability of those antidotes to the number of poisonings seen in hospitals using N-acetylcysteine and naloxone consumption as a surrogate.<br><br>METHODS: Pharmacy directors of hospitals with an emergency department were surveyed for number of adequately stocked antidotes (N-acetylcysteine, ethanol, cyanide antidote kit or hydroxycobalamine, deferoxamine, digoxin-immune FAB, dimercaprol, flumazenil, glucagon, methylene blue, naloxone, physostigmine, pralidoxime and pyridoxine).<br><br>RESULTS: Data were obtained from 96 of 112 (86%) of the pharmacies surveyed. Number of adequately stocked antidotes per hospital ranged from zero to nine of 13. There was a correlation between all hospital characteristics evaluated and the number of adequately stocked antidotes (P<0.05). Correlations between the number of adequately stocked antidotes and the amount of N-acetylcysteine and naloxone consumed were significant (rs=0.58, P<0.001; r(s)=0.53, P<0.001). The amount of N-acetylcysteine consumed, the number of annual visits to the emergency department and the number of hours of pharmacy coverage on weekends independently predicted the presence of adequately stocked antidotes.<br><br>CONCLUSIONS: Larger hospitals are more likely to have adequate stocks of antidotes. Adequate stocking of antidotes is significantly correlated with the amount of N-acetyl- cysteine and naloxone consumed. This suggests that hospitals more likely to see serious acetaminophen and opiate poisonings are more likely to maintain adequate stocks of antidotes.}, }
@article {pmid11118324, year = {2000}, author = {Straface, E and Matarrese, P and Gambardella, L and Forte, S and Carlone, S and Libianchi, E and Schmid, G and Malorni, W}, title = {N-Acetylcysteine counteracts erythrocyte alterations occurring in chronic obstructive pulmonary disease.}, journal = {Biochemical and biophysical research communications}, volume = {279}, number = {2}, pages = {552-556}, doi = {10.1006/bbrc.2000.3981}, pmid = {11118324}, issn = {0006-291X}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Erythrocytes/drug effects/*physiology/ultrastructure ; Glycophorins/metabolism ; Humans ; In Vitro Techniques ; Lung Diseases, Obstructive/*blood ; Microscopy, Electron, Scanning ; Reactive Oxygen Species/physiology ; Reference Values ; }, abstract = {A key role has been proposed for reactive oxygen species (ROS) in chronic obstructive pulmonary disease (COPD). Aim of the present work was to evaluate possible implications of ROS in the integrity and function of the cell type mainly involved in oxygen uptake and delivery to the peripheral tissues: the erythrocyte. Red blood cells (RBCs) were thus collected from blood samples from COPD patients. Furthermore, blood samples from the same patients treated with the antioxidizing drug of widespread use in such disease i.e., N-acetylcysteine (NAC), were also considered. Morphometric and analytical cytology studies were then conducted. We report herein that: (i) alterations of RBC ultrastructure were detectable in RBCs from COPD patients, that (ii) relevant changes of spectrin cytoskeleton and glycophorin expression were also found and that (iii) NAC treatment was capable of significantly counteracting these changes. These results are consistent with a reappraisal of the role of RBCs in this disease.}, }
@article {pmid11115065, year = {2000}, author = {Berger, SP and Hünger, M and Yard, BA and Schnuelle, P and Van Der Woude, FJ}, title = {Dopamine induces the expression of heme oxygenase-1 by human endothelial cells in vitro.}, journal = {Kidney international}, volume = {58}, number = {6}, pages = {2314-2319}, doi = {10.1046/j.1523-1755.2000.00415.x}, pmid = {11115065}, issn = {0085-2538}, mesh = {Antioxidants/pharmacology ; Ascorbic Acid/pharmacology ; Cardiotonic Agents/*pharmacology ; Cells, Cultured ; Dopamine/*pharmacology ; Dose-Response Relationship, Drug ; Endothelium, Vascular/cytology/drug effects/*enzymology ; Gene Expression Regulation, Enzymologic/drug effects ; Heme Oxygenase (Decyclizing)/analysis/*genetics ; Heme Oxygenase-1 ; Humans ; In Vitro Techniques ; Kidney Transplantation ; Membrane Proteins ; Oxidative Stress/drug effects/physiology ; RNA, Messenger/analysis ; Transplantation Conditioning/methods ; Umbilical Veins/cytology ; }, abstract = {BACKGROUND: In a retrospective study of the kidney transplantations performed at our institution, we found that the administration of dopamine (DA) to the organ donors resulted in a significant improvement of long-term organ survival of the retrieved kidneys. To study the mechanisms underlying the organ protection associated with the administration of DA prior to transplantation, we questioned whether DA induces the antioxidative enzyme heme oxygenase-1 (HO-1) in cultured endothelial cells.<br><br>METHODS: Human umbilical vein endothelial cells (HUVECs) in culture were incubated with varying concentrations of DA for different time periods. Cells were subsequently assessed for the expression of HO-1 by Western blot and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR).<br><br>RESULTS: The presence of DA resulted in a dose- and time-dependent up-regulation of HO-1 both on RNA and protein level, whereas HO-1 was barely detectable under basal conditions. RT-PCR indicated the increased presence of HO-1 messenger RNA after 2 hours of incubation with DA, which peaked after 24 hours. The induction of HO-1 antigen was detectable after eight hours, as visualized by Western blot analysis. The addition of the antioxidant agents ascorbic acid and N-acetyl-cysteine both lead to dose-dependent inhibition of DA-mediated HO-1 induction. DA-mediated up-regulation of HO-1 was not influenced by the addition of either the D2-receptor antagonist haloperidol or the D1-receptor antagonist SCH 23390.<br><br>CONCLUSION: We conclude that DA induces the expression of the protective enzyme HO-1 in cultured endothelial cells by an oxidative mechanism. These findings may explain the beneficial effect of DA administration to kidney donors and indicate the potential role of DA in organ preconditioning.}, }
@article {pmid11113600, year = {2000}, author = {Brewer, GJ}, title = {Neuronal plasticity and stressor toxicity during aging.}, journal = {Experimental gerontology}, volume = {35}, number = {9-10}, pages = {1165-1183}, doi = {10.1016/s0531-5565(00)00121-2}, pmid = {11113600}, issn = {0531-5565}, support = {1RO1AG12435/AG/NIA NIH HHS/United States ; }, mesh = {*Aging ; Amyloid beta-Peptides/*metabolism/pharmacology ; Animals ; Antioxidants/pharmacology ; Brain/drug effects/metabolism/pathology ; Calcium/metabolism ; Glutamates/*metabolism/pharmacology ; Humans ; Neuronal Plasticity/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Brain aging, Alzheimer disease and stroke share common elements of deficits in calcium regulation, declines in mitochondrial function, increases in generation of reactive oxygen species (ROS), accumulated damage from ROS and immune system dysfunction. The problem is to distinguish less significant side reactions, such as gray hair, from aspects of aging that contribute to disease. Toward establishing cause and effect relationships, a neuron cell culture system is described that allows comparisons with age under uniform environmental conditions. This neuron culture model indicates that susceptibility to death by apoptosis and consequences of the inflammatory response from beta-amyloid are age-related and an inherent characteristic of the neurons. Further mechanistic investigations are possible. New therapeutic approaches are suggested that combine inhibition of calcium overloads (calcium channel blockers), reduced ROS damage (melatonin, N-acetyl-cysteine), and bolstered mitochondrial function and energy generation (creatine). Together with newly demonstrated capabilities for adult and aged neuron regeneration and multiplication, i.e. plasticity, these approaches offer new hope toward reversing age-related decrements and damage from neurodegenerative disease.}, }
@article {pmid11112425, year = {2000}, author = {Harrison, PM and Farzaneh, F}, title = {Regulation of HGF/SF gene expression in MRC-5 cells by N-acetylcysteine.}, journal = {Biochemical and biophysical research communications}, volume = {279}, number = {1}, pages = {108-115}, doi = {10.1006/bbrc.2000.3904}, pmid = {11112425}, issn = {0006-291X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Base Sequence ; Cell Line ; Chloramphenicol O-Acetyltransferase/genetics ; DNA Primers ; Electrophoresis/methods ; Gene Expression Regulation/*drug effects ; Hepatocyte Growth Factor/*genetics ; Promoter Regions, Genetic ; RNA, Messenger/genetics ; }, abstract = {The effect of N-acetylcysteine (NAC) on levels of hepatocyte growth factor/scatter factor (HGF/SF) gene transcripts was investigated in the human lung embryonic fibroblast cell line, MRC-5. NAC increased expression of HGF/SF mRNA, in a dose- and time-dependent fashion, by a mechanism independent of glutathione synthesis but sensitive to oxidant stress induced by H(2)O(2). Using actinomycin D to block RNA synthesis, it was observed that NAC had no effect on the stability of the HGF/SF mRNA transcripts. NAC increased HGF/SF promoter activity in cells transiently transfected with chloramphenicol acetyltransferase (CAT) reporter genes driven by HGF/SF gene 5'-flanking sequences. Primer extension analysis demonstrated that NAC enhanced the expression of HGF/SF mRNA transcribed from the main transcription initiation site. Although the 5' flanking region of the HGF/SF gene contains a sequence at -1019 to -1011 with homology to the NF-kappaB response element, electrophoretic mobility shift assay demonstrated that this site did not bind nuclear factors in MRC-5 cells in the presence or absence of NAC. In contrast to the effect on HGF/SF mRNA, NAC did not increase HGF/SF protein production by MRC-5 cells.}, }
@article {pmid11112413, year = {2000}, author = {Yin, JH and Yang, DI and Ku, G and Hsu, CY}, title = {iNOS expression inhibits hypoxia-inducible factor-1 activity.}, journal = {Biochemical and biophysical research communications}, volume = {279}, number = {1}, pages = {30-34}, doi = {10.1006/bbrc.2000.3896}, pmid = {11112413}, issn = {0006-291X}, support = {28995//PHS HHS/United States ; 37230//PHS HHS/United States ; 40162//PHS HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Base Sequence ; Cell Line ; DNA Primers ; DNA-Binding Proteins/*antagonists &amp; inhibitors/metabolism ; Hypoxia-Inducible Factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit ; Nitric Oxide Synthase/genetics/*metabolism ; Nitric Oxide Synthase Type II ; Nuclear Proteins/*antagonists &amp; inhibitors/metabolism ; *Transcription Factors ; }, abstract = {Hypoxia-inducible factor-1 (HIF-1) activates genes important in vascular function such as vascular endothelial growth factor (VEGF), erythropoietin (EPO), and inducible nitric oxide synthase (iNOS). iNOS catalyzes the synthesis of nitric oxide (NO), a free radical gas that mediates a number of cellular processes, including regulation of gene expression, vasodilatation, and neurotransmission. Here we demonstrate that iNOS expression inhibits HIF-1 activity under hypoxia in C6 glioma cells transfected with an iNOS gene and a VEGF promoter-driven luciferase gene. HIF-1 induction of VEGF-luciferase activity in C6 cell is also inhibited by sodium nitroprusside (SNP). Furthermore, pretreatment of C6 cells with N-acetyl-l-cysteine (NAC), an antioxidant, nullified the inhibitory effect of iNOS on HIF-1 binding. These results demonstrate that NO generated by iNOS expression inhibits HIF-1 activity in hypoxic C6 cells and suggest a negative feedback loop in the HIF-1 --> iNOS cascade.}, }
@article {pmid11102554, year = {2000}, author = {Yang, KD and Chen, MZ and Teng, RJ and Yang, MY and Liu, HC and Chen, RF and Hsu, TY and Shaio, MF}, title = {A model to study antioxidant regulation of endotoxemia-modulated neonatal granulopoiesis and granulocyte apoptosis.}, journal = {Pediatric research}, volume = {48}, number = {6}, pages = {829-834}, doi = {10.1203/00006450-200012000-00021}, pmid = {11102554}, issn = {0031-3998}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/*pharmacology ; *Apoptosis/drug effects ; Cells, Cultured/drug effects ; DNA Fragmentation/drug effects ; Endotoxemia/*blood/immunology/physiopathology ; Endotoxins/pharmacology ; Fetal Blood/cytology/drug effects ; Granulocytes/drug effects/*pathology ; *Hematopoiesis/drug effects ; Humans ; Infant, Newborn ; Interleukin-8/pharmacology ; Oxidative Stress ; Reactive Oxygen Species ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors ; }, abstract = {Neonates with septicemia tend to develop granulocytopenia, which may, in part, be due to septic mediators such as oxygen free radicals and tumor necrosis factor alpha (TNF-alpha). Granulocytopenia may be caused by a decrease in granulocyte growth and/or an increase in granulocyte destruction. In the present study, we investigated antioxidant regulation of endotoxin-modulated neonatal granulopoiesis and granulocyte apoptosis. Using human umbilical cord blood (HUCB), we found that simulating endotoxemia in vitro elicited significant superoxide production within a few minutes. Endotoxin exposure suppressed colony-forming unit-granulocyte and monocyte formation in a dose-dependent fashion. Addition of antioxidants such as N-acetyl-cysteine could reverse the endotoxin suppression of colony-forming unit-granulocyte and monocyte formation (13 +/- 5 versus 75 +/- 5 colony-forming units/mL). Spontaneous in vitro granulocyte apoptosis in 6 h, as reflected by phosphatidylserine expression on the cell surface, was higher in granulocytes from HUCB than in those from adult blood (10.8 +/- 1.0% versus 5.6 +/- 1.2%). The addition of endotoxin or IL-8 to the cells in the in vitro model did not promote granulocyte apoptosis, but TNF-alpha, a major mediator of the effects of endotoxin, significantly induced granulocyte apoptosis in HUCB (control versus TNF-alpha: 8.9 +/- 1.2% versus 35.9 +/- 2.9%). Addition of the antioxidant N-acetyl-cysteine effectively blocked TNF-alpha-induced granulocyte apoptosis as demonstrated by DNA fragmentation. Results from these studies indicate that oxygen radicals are directly involved in endotoxin suppression of granulopoiesis, and indirectly promote granulocyte apoptosis, presumably through TNF-alpha-mediated action. Thus, under certain conditions, modulation of oxygen radical production in the blood may benefit neonates with granulocytopenia.}, }
@article {pmid11095909, year = {2000}, author = {Chévez-Barrios, P and Wiseman, AL and Rojas, E and Ou, CN and Lieberman, MW}, title = {Cataract development in gamma-glutamyl transpeptidase-deficient mice.}, journal = {Experimental eye research}, volume = {71}, number = {6}, pages = {575-582}, doi = {10.1006/exer.2000.0913}, pmid = {11095909}, issn = {0014-4835}, support = {ES-07827/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Cataract/drug therapy/*enzymology/etiology ; Cysteine/physiology ; Electrophoresis ; Free Radical Scavengers/therapeutic use ; Glutathione/physiology ; Lighting ; Mice ; Mice, Inbred C57BL ; gamma-Glutamyltransferase/*deficiency ; }, abstract = {The present study was undertaken to analyse the relationship of lens glutathione (GSH) and light to cataract development in mice deficient in gamma-glutamyl transpeptidase (GGT). These mice have reduced levels of cysteine and GSH in the eye and develop cataracts. GGT-deficient mice raised under normal vivarium conditions, showed no cataractous changes at birth, but by 1 week they had developed nuclear opacities. By 3 weeks more severe cataracts develop, and lens GSH levels are approximately 6-7% of wild type levels. By 6-11 weeks cataracts show nuclear and cortical involvement, liquefaction and calcification. Single cell DNA electrophoresis (comet assay) demonstrated mild DNA damage in the lens epithelium. GGT-deficient mice raised in the dark beginning the day after conception all developed cataracts, but these were less severe than those in GGT-deficient mice raised with normal vivarium lighting. Administration of N -acetyl cysteine (NAC) raises lens GSH and almost completely prevents cataract development. Our data indicate that cataract development in GGT-deficient mice is multifactorial and results from exogenous damage (exposure to light), reduced lens GSH levels, and nutritional effects secondary to low cysteine levels.}, }
@article {pmid11093939, year = {2000}, author = {Teshima, S and Kutsumi, H and Kawahara, T and Kishi, K and Rokutan, K}, title = {Regulation of growth and apoptosis of cultured guinea pig gastric mucosal cells by mitogenic oxidase 1.}, journal = {American journal of physiology. Gastrointestinal and liver physiology}, volume = {279}, number = {6}, pages = {G1169-76}, doi = {10.1152/ajpgi.2000.279.6.G1169}, pmid = {11093939}, issn = {0193-1857}, mesh = {Animals ; Antioxidants/pharmacology ; *Apoptosis/drug effects ; Caspases/metabolism ; Cells, Cultured ; Gastric Mucosa/enzymology/growth &amp; development/*physiology ; Guinea Pigs ; NADH, NADPH Oxidoreductases/biosynthesis/genetics/*physiology ; *NADPH Oxidases ; NF-kappa B/metabolism ; Neutrophils/metabolism ; Superoxides/metabolism ; Transcription, Genetic ; }, abstract = {We previously reported that primary cultures of guinea pig gastric pit cells expressed all of the phagocyte NADPH oxidase components (gp91-, p22-, p67-, p47-, and p40-phox) and could spontaneously release superoxide anion (O(2)(-)). We demonstrate here that pit cells express a nonphagocyte-specific gp91-phox homolog (Mox1) but not gp91-phox. Inclusion of catalase significantly inhibited [(3)H]thymidine uptake during the initial 2 days of culture. Pit cells, matured on day 2, slowly underwent spontaneous apoptosis. Scavenging O(2)(-) and related oxidants by superoxide dismutase plus catalase or N-acetyl cysteine (NAC) and inhibiting Mox1 oxidase by diphenylene iodonium activated caspase 3-like proteases and markedly enhanced chromatin condensation and DNA fragmentation. This accelerated apoptosis was completely blocked by a caspase inhibitor, z-Val-Ala-Asp-CH(2)F. Mox1-derived reactive oxygen intermediates constitutively activated nuclear factor-kappaB, and inhibition of this activity by nuclear factor-kappaB decoy oligodeoxynucleotide accelerated their spontaneous apoptosis. These results suggest that O(2)(-) produced by the pit cell Mox1 oxidase may play a crucial role in the regulation of their spontaneous apoptosis as well as cell proliferation.}, }
@article {pmid11091282, year = {2000}, author = {Rocksén, D and Lilliehöök, B and Larsson, R and Johansson, T and Bucht, A}, title = {Differential anti-inflammatory and anti-oxidative effects of dexamethasone and N-acetylcysteine in endotoxin-induced lung inflammation.}, journal = {Clinical and experimental immunology}, volume = {122}, number = {2}, pages = {249-256}, pmid = {11091282}, issn = {0009-9104}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Anti-Inflammatory Agents/administration &amp; dosage/*pharmacology ; Antioxidants/administration &amp; dosage/*pharmacology ; Bronchoalveolar Lavage Fluid/cytology ; Chemokines/genetics ; Cytokines/genetics ; Dexamethasone/administration &amp; dosage/*pharmacology ; Female ; Granulocytes/drug effects ; Lipopolysaccharides/toxicity ; Lung/drug effects/immunology/metabolism ; Mice ; Mice, Inbred C57BL ; Pneumonia/*drug therapy/immunology/metabolism ; RNA, Messenger/genetics/metabolism ; Respiratory Burst/drug effects ; }, abstract = {Inhalation of bacterial endotoxin induces an acute inflammation in the lower respiratory tract. In this study, the anti-inflammatory effects of the anti-oxidant N-acetylcysteine (NAC) and the glucocorticoid dexamethasone were investigated in mice exposed to aerosolized endotoxin (lipopolysaccharide (LPS)). Powerful reduction of neutrophils in bronchoalveolar lavage fluid (BALF) was obtained by a single i.p. injection of dexamethasone (10 mg/kg), whereas treatment with NAC only resulted in reduction of neutrophils when administered at a high dose (500 mg/kg). Measurement of cytokine and chemokine expression in lung tissue revealed a significant decrease of tumour necrosis factor-alpha, IL-1alpha, IL-1beta IL-6, IL- 12p40, and MIP-1alpha mRNA when mice where treated with dexamethasone but not when treated with NAC. Analysis of oxidative burst demonstrated a remarkable reduction of oxygen radicals in BALF neutrophils after treatment with dexamethasone, whereas the effect of NAC was not significantly different from that in untreated animals. In conclusion, dexamethasone exerted both anti-inflammatory and anti-oxidative effects in acute airway inflammation, probably by blocking early events in the inflammatory cascade. In contrast, treatment with NAC resulted in a weak reduction of the inflammatory response but no inhibition of proinflammatory cytokines or reduction of oxidative burst in neutrophils. These results demonstrate dramatic differences in efficiency and also indicate that the two drugs have different actions. Combined treatment with NAC and dexamethasone revealed an additive action but no synergy was observed.}, }
@article {pmid11084291, year = {2000}, author = {Neely, MD and Zimmerman, L and Picklo, MJ and Ou, JJ and Morales, CR and Montine, KS and Amaranth, V and Montine, TJ}, title = {Congeners of N(alpha)-acetyl-L-cysteine but not aminoguanidine act as neuroprotectants from the lipid peroxidation product 4-hydroxy-2-nonenal.}, journal = {Free radical biology &amp; medicine}, volume = {29}, number = {10}, pages = {1028-1036}, doi = {10.1016/s0891-5849(00)00411-1}, pmid = {11084291}, issn = {0891-5849}, support = {AG00774/AG/NIA NIH HHS/United States ; AG16835/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Aldehydes/*toxicity ; Animals ; Brain/drug effects/metabolism ; Cell Line ; Free Radical Scavengers/pharmacology ; Guanidines/*pharmacology ; In Vitro Techniques ; Lipid Peroxidation/drug effects ; Magnetic Resonance Spectroscopy ; Male ; Mitochondria/drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Increased generation of neurotoxic lipid peroxidation products is proposed to contribute to the pathogenesis of Alzheimer's disease (AD). Current antioxidant therapies are directed at limiting propagation of brain lipid peroxidation. Another approach would be to scavenge the reactive aldehyde products of lipid peroxidation. N(alpha)-acetyl-L-cysteine (NAC) and aminoguanidine (AG) react rapidly and irreversibly with 4-hydroxy-2-nonenal (HNE) in vitro, and both have been proposed as potential scavengers of HNE in biological systems. We have compared NAC, AG, and a series of congeners as scavengers of HNE and as neuroprotectants from HNE. Our results showed that while both NAC and AG had comparable chemical reactivity with HNE, only NAC and its congeners were able to block HNE-protein adduct formation in vitro and in neuronal cultures. Moreover, NAC and its congeners, but not AG, effectively protected brain mitochondrial respiration and neuronal microtubule structure from the toxic effects of HNE. We conclude that NAC and its congeners, but not AG, may act as neuroprotectants from HNE.}, }
@article {pmid11080051, year = {2000}, author = {Gannett, PM and Ye, J and Ding, M and Powell, J and Zhang, Y and Darian, E and Daft, J and Shi, X}, title = {Activation of AP-1 through the MAP kinase pathway: a potential mechanism of the carcinogenic effect of arenediazonium ions.}, journal = {Chemical research in toxicology}, volume = {13}, number = {10}, pages = {1020-1027}, doi = {10.1021/tx000068s}, pmid = {11080051}, issn = {0893-228X}, support = {CA 31611/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Animals ; Carcinogens/*toxicity ; Cell Line ; Diazonium Compounds/*toxicity ; Electron Spin Resonance Spectroscopy ; Enzyme Activation/drug effects/physiology ; Enzyme Activators/*toxicity ; Free Radical Scavengers/chemistry ; Indicators and Reagents ; Luciferases/genetics ; Mice ; Mice, Transgenic ; Mitogen-Activated Protein Kinases/metabolism/*physiology ; Phosphorylation ; Plasmids ; Protein Kinases/metabolism ; Transcription Factor AP-1/*physiology ; }, abstract = {Arenediazonium ions such as those found in the common mushroom Agaricus bisporus have been convincingly demonstrated to be tumorigenic. The specific mechanism of their tumorigenicity remains unclear. It has been shown that arenediazonium ions can be metabolized to aryl radicals, and that reaction of these aryl radicals with DNA produces aryl adducts. These metabolic processes also produce the reactive oxygen species superoxide and hydroxyl radicals which have been implicated in AP-1 activation. To further investigate the mechanism of tumorigenesis by arenediazonium ions, we studied the effect of a representative arenediazonium ion on AP-1 activation and phosphorylation of the signal transduction proteins ERK1, ERK2, JNK, and p38 kinase, both in vitro and in vivo. We also identified the specific radicals produced by spin trapping and ESR analysis. Here, it was found that p-methylbenzenediazonium ion (2a) induced a 16-fold increase in the extent of AP-1 activation at micromolar concentrations, and that this increase coincided with phosphorylation of the signaling kinases ERK1 and -2 and p38 kinase, but not JNK, in JB6 mouse epithelial cells. In vivo studies using AP-1 luciferase reporter-bearing transgenic mice supported the increase in the extent of AP-1 activation in 2a-treated mice over controls, and showed that this effect was different in different tissue types. The antioxidant N-acetylcysteine (NAC), a general antioxidant, showed an inhibitory effect on 2a-mediated AP-1 induction, while aspirin, a hydroxyl radical scavenger, had no effect. Spin trapping studies showed that while NAC suppressed radical formation from 2a, aspirin did not alter radical production from 2a. It appears that 3a, a carbon-centered radical formed from 2a, is responsible for AP-1-induced activation, and therefore, radical species that are not oxygen-centered are also capable of inducing AP-1. These results represent a step toward understanding the mechanism of tumorigenicity of arenediazonium ions.}, }
@article {pmid11079466, year = {2000}, author = {Origuchi, T and Migita, K and Nakashima, T and Honda, S and Yamasaki, S and Hida, A and Kawakami, A and Aoyagi, T and Kawabe, Y and Eguchi, K}, title = {Regulation of cyclooxygenase-2 expression in human osteoblastic cells by N-acetylcysteine.}, journal = {The Journal of laboratory and clinical medicine}, volume = {136}, number = {5}, pages = {390-394}, doi = {10.1067/mlc.2000.110369}, pmid = {11079466}, issn = {0022-2143}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Cyclooxygenase 2 ; Gene Expression Regulation, Enzymologic/*drug effects ; Humans ; Interleukin-1/pharmacology ; Isoenzymes/*genetics ; Membrane Proteins ; NF-kappa B/metabolism ; Osteoblasts/*metabolism ; Prostaglandin-Endoperoxide Synthases/*genetics ; Rabbits ; }, abstract = {Cyclooxygenase (COX) plays a pivotal role in the inflammatory process of inflammatory arthropathies. Inflammatory cytokines induce COX-2 expression in osteoblasts of inflamed joints, followed by osteoclast activation. The inhibition of COX-2 expression could help prevent prostaglandin E2 secretion, followed by osteoclast activation for bone destruction and resorption. We examined whether the antioxidant N-acetylcysteine (NAC) inhibited COX-2 expression induced in the human osteoblastic cell line MG63 by interleukin-1beta (IL-1beta). According to Western blot and reverse transcription-polymerase chain reaction (RT-PCR) test results, NAC inhibited IL-1beta-induced COX-2 expression in protein and messenger RNA. We also demonstrated immunohistochemically that NAC inhibited NFkappaB nuclear translocation. These results suggested that NAC inhibited both COX-2 expression and NFkappaB nuclear translocation in MG63, which in turn indicated that NAC could inhibit the inflammatory process involved in bone resorption by regulating COX-2 expression at the level of transcription.}, }
@article {pmid11078921, year = {2000}, author = {Lee, YS and Nam, DH and Kim, JA}, title = {Induction of apoptosis by capsaicin in A172 human glioblastoma cells.}, journal = {Cancer letters}, volume = {161}, number = {1}, pages = {121-130}, doi = {10.1016/s0304-3835(00)00608-x}, pmid = {11078921}, issn = {0304-3835}, mesh = {Apoptosis/*drug effects/physiology ; Brain Neoplasms/drug therapy/metabolism/*pathology ; Calcium/metabolism ; Capsaicin/*analogs &amp; derivatives/*pharmacology ; Dose-Response Relationship, Drug ; Glioblastoma/drug therapy/metabolism/*pathology ; Humans ; Kinetics ; Lipid Peroxidation/drug effects ; Reactive Oxygen Species/metabolism ; Receptors, Drug/physiology ; Tumor Cells, Cultured/drug effects ; }, abstract = {Capsaicin induced apoptosis of A172 human glioblastoma cells in a time- and dose-dependent manner. Neither capsazepine, a vanilloid receptor antagonist, nor bis-(o-aminophenoxy)-ethane-N,N,N', N'-tetraacetic acid/acetoxymethyl ester (BAPTA/AM), an intracellular Ca(2+) chelator, significantly inhibited the capsaicin-induced apoptosis, although capsaicin increased intracellular Ca(2+) level. Capsaicin markedly reduced the basal generation of reactive oxygen species (ROS) and lipid peroxidation. Exogenous application of H(2)O(2) significantly prevented the cells from the apoptosis by capsaicin. Treatment with N-acetyl cysteine alone induced both reduction of the basal production of ROS and apoptosis. Taken together, these results suggest that capsaicin induced apoptosis in A172 cells and that vanilloid receptors and intracellular Ca(2+) may not be involved in the apoptotic mechanism of capsaicin. Reduction of the basal generation of ROS may play a role in the induction of apoptosis by capsaicin.}, }
@article {pmid11078829, year = {2000}, author = {Wan, Y and Wang, Z and Shao, Y and Xu, Y and Voorhees, J and Fisher, G}, title = {UV-induced expression of GADD45 is mediated by an oxidant sensitive pathway in cultured human keratinocytes and in human skin in vivo.}, journal = {International journal of molecular medicine}, volume = {6}, number = {6}, pages = {683-688}, doi = {10.3892/ijmm.6.6.683}, pmid = {11078829}, issn = {1107-3756}, mesh = {Acetylcysteine/pharmacology ; Adult ; Cells, Cultured ; Dose-Response Relationship, Radiation ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/antagonists &amp; inhibitors ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects/radiation effects ; Humans ; Hydrogen Peroxide/pharmacology ; Interleukin-1/pharmacology ; Intracellular Signaling Peptides and Proteins ; Keratinocytes/drug effects/metabolism/*radiation effects ; Onium Compounds/pharmacology ; Oxidants/*physiology ; Proteins/*genetics ; RNA, Messenger/drug effects/metabolism/radiation effects ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Skin/drug effects/metabolism/*radiation effects ; Ultraviolet Rays ; GADD45 Proteins ; }, abstract = {The expression of GADD45 was examined in cultured skin keratinocytes and in human skin in vivo following UV irradiation. Northern blot analysis revealed that UV-induced the expression of GADD45 (alpha, beta, gamma) in a time- and dose-dependent manner. Messenger RNA of GADD45 (alpha, beta, gamma) increased within 30 min, peaked at 4 h and remained elevated for at least 8 h following UV irradiation in vitro and in vivo. Maximal induction of GADD45alpha was approximately 5-fold compared to the level in sham-irradiated controls. Similarly H2O2 and IL-1 also induced GADD45alpha expression in cultured human keratinocytes. The kinetics of induction of GADD45alpha by H2O2, IL-1beta and UV were very similar. Interestingly, UV-induced GADD45alpha expression was inhibited by diphenylene iodonium (DPI), an inhibitor of NADPH oxidase, and antioxidant, N-acetyl-L-cysteine (NAC), indicating the involvement of reactive oxygen species in UV signaling. Previously we have shown that EGF receptor activation by UV is prerequisite for subsequent activation of NADPH oxidase and generation of reactive oxygen species. We therefore examined the effect of EGF receptor inhibitor on UV-induced GADD45alpha expression. Our results showed that PD168393, a potent EGF receptor inhibitor, blocked UV-induced GADD45alpha expression. Collectively, our data suggest that UV-induced GADD45alpha expression occur via an EGF receptor-mediated oxidative pathway sensitive to antioxidant regulation.}, }
@article {pmid11076697, year = {2000}, author = {Kang, JL and Pack, IS and Hong, SM and Lee, HS and Castranova, V}, title = {Silica induces nuclear factor-kappa B activation through tyrosine phosphorylation of I kappa B-alpha in RAW264.7 macrophages.}, journal = {Toxicology and applied pharmacology}, volume = {169}, number = {1}, pages = {59-65}, doi = {10.1006/taap.2000.9039}, pmid = {11076697}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Enzyme Inhibitors/pharmacology ; Genistein/pharmacology ; I-kappa B Proteins/*metabolism ; Macrophage Activation/*drug effects/physiology ; Macrophages/*drug effects/metabolism ; Mice ; NF-kappa B/*metabolism ; Protein Tyrosine Phosphatases/antagonists &amp; inhibitors/*metabolism ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/metabolism ; Silicon Dioxide/*toxicity ; Superoxide Dismutase/pharmacology ; Thiocarbamates/pharmacology ; Tyrphostins/pharmacology ; }, abstract = {It was previously reported that protein tyrosine kinase (PTK) but not protein kinase C or A plays an important role in silica-induced activation of NF-kappa B in macrophages. The question is raised whether PTK stimulation and NF-kappa B activation in silica-stimulated macrophages are directly connected through tyrosine phosphorylation of I kappa B-alpha. Results indicate that stimulation of macrophages with silica led to NF-kappaB activation through tyrosine phosphorylation without serine phosphorylation. Specific inhibitors of protein tyrosine kinase, such as genistein and tyrophostin AG126, prevented tyrosine phosphorylation of I kappa B-alpha in response to silica. I kappa B-alpha protein levels remained relatively unchanged for up to 60 min after silica stimulation. Moreover, inhibition of proteasome proteolytic activity did not affect NF-kappa B activation by silica. Antioxidants, such as superoxide dismutase (SOD), N-acetylcysteine (NAC), and pyrrolidine dithiocarbamate (PDTC), blocked tyrosine phosphorylation of I kappa B-alpha induced by silica, suggesting reactive oxygen species (ROS) may be important regulatory molecules in NF-kappa B activation through tyrosine phosphorylation of I kappa B-alpha. The results suggest that tyrosine phosphorylation of I kappa B-alpha represents a proteasome proteolytic activity-independent mechanism for NF-kappa B activation that directly couples NF-kappa B to cellular tyrosine kinase in silica-stimulated macrophages. This proposed mechanism of NF-kappa B activation induced by silica could be used as a target for development of antiinflammatory and antifibrosis drugs.}, }
@article {pmid11075992, year = {2000}, author = {Dabrowski, A and Boguslowicz, C and Dabrowska, M and Tribillo, I and Gabryelewicz, A}, title = {Reactive oxygen species activate mitogen-activated protein kinases in pancreatic acinar cells.}, journal = {Pancreas}, volume = {21}, number = {4}, pages = {376-384}, doi = {10.1097/00006676-200011000-00008}, pmid = {11075992}, issn = {0885-3177}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cholecystokinin/pharmacology ; Enzyme Activation ; Hydrogen Peroxide/pharmacology ; Indoles/pharmacology ; *JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; Male ; Maleimides/pharmacology ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/*metabolism ; Pancreas/*enzymology ; Protein Kinase C/physiology ; Rats ; Rats, Wistar ; *Reactive Oxygen Species ; Vitamin K/pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {It has been recently reported that kinases that belong to the mitogen-activated protein kinase (MAPK) family are rapidly activated by cholecystokinin (CCK) in rat pancreas both in vitro and in vivo. It is known that reactive oxygen species (ROS) play an important role in the pathogenesis of acute pancreatitis induced by supraphysiologic stimulation with CCK analogue, cerulein. The aim of our study was to evaluate whether MAPKs are activated by ROS in pancreatic acini. The activity of MAPK, c-Jun amino-terminal kinase (JNK), and p38 MAPK was determined in isolated rat pancreatic acinar cells by means of Western blotting, with the use of specific antibody that recognizes active, dually phosphorylated kinases. Incubation of acini with ROS donors, hydrogen peroxide (H2O2) and/or menadione (MND), strongly activated all three kinases. Activation of these kinases by ROS, but not by CCK, was substantially inhibited by pretreatment of acini with antioxidant N-acetylo-L-cysteine (NAC). Whereas CCK-induced activation of MAPK or JNK was totally or partially blocked by protein kinase C (PKC) inhibitor GF-109203X, ROS-induced activation of MAPK, JNK, and p38 MAPK was PKC independent. In conclusion, ROS strongly activate MAPK, JNK, and p38 MAPK in pancreatic acinar cells. It may be of importance in acute pancreatitis, because ROS are involved in the pathogenesis of this disease.}, }
@article {pmid11074303, year = {2000}, author = {Kang, JL and Pack, IS and Lee, HS and Castranova, V}, title = {Enhancement of nuclear factor-kappaB activation and protein tyrosine phosphorylation by a tyrosine phosphatase inhibitor, pervanadate, involves reactive oxygen species in silica-stimulated macrophages.}, journal = {Toxicology}, volume = {151}, number = {1-3}, pages = {81-89}, doi = {10.1016/s0300-483x(00)00295-x}, pmid = {11074303}, issn = {0300-483X}, mesh = {Animals ; Blotting, Western ; Cell Line ; Cell Nucleus/drug effects/metabolism ; Electrophoresis ; Enzyme Inhibitors/*pharmacology ; Macrophages/drug effects/*metabolism ; Mice ; NF-kappa B/*metabolism ; Precipitin Tests ; Protein Tyrosine Phosphatases/*antagonists &amp; inhibitors ; Reactive Oxygen Species/*metabolism ; Silicon Dioxide/*toxicity ; Stimulation, Chemical ; Tyrosine/*metabolism ; Vanadates/*pharmacology ; }, abstract = {Reactive oxygen species (ROS) and phosphorylation events mediated by tyrosine kinase are involved in silica-induced nuclear factor-kappa B (NF-kappaB) activation. Protein tyrosine phosphatase (PTPase) acts to limit protein tyrosine phosphorylation. In the present study, we investigated the role of PTPase in NF-kappaB activation and tyrosine phosphorylation in silica-stimulated macrophages, and the involvement of ROS in these responses. Treatment of mouse peritoneal macrophages (RAW264.7 cells) with a PTPase inhibitor, pervanadate, markedly enhanced the DNA-binding activity of NF-kappaB in the presence or absence of silica. The stimulatory effect of pervanadate on NF-kappaB activation was also demonstrated in LPS-stimulated macrophages. A specific inhibitor of protein tyrosine kinase (PTK), genistein, prevented the NF-kappaB activation induced by pervanadate in the presence of silica while inhibitors of protein kinase A or C, such as staurosporine or H7, had no inhibitory effect on NF-kappaB activation. A variety of antioxidants, such as catalase, superoxide dismutase, N-acetyl cysteine (NAC), and pyrrolidine dithiocarbamate, inhibited NF-kappaB activation induced by pervanadate in the presence of silica. Furthermore, pervanadate markedly enhanced silica- or LPS-induced protein tyrosine phosphorylation in cells. Treatment of macrophages with NAC abolished the increase in tyrosine phosphorylation in cells stimulated with the combination of pervanadate and either silica or LPS or with silica alone. The results suggest that PTPase may play a crucial role in the negative regulation of silica-signaling pathways leading to NF-kappaB activation in macrophages. Furthermore, ROS appear to be involved in downstream signaling between PTPase inhibition and NF-kappaB activation.}, }
@article {pmid11072237, year = {2000}, author = {D'Agostini, F and Balansky, RM and Camoirano, A and de Flora, S}, title = {Interactions between N-acetylcysteine and ascorbic acid in modulating mutagenesis and carcinogenesis.}, journal = {International journal of cancer}, volume = {88}, number = {5}, pages = {702-707}, doi = {10.1002/1097-0215(20001201)88:5&lt;702::aid-ijc4&gt;3.0.co;2-3}, pmid = {11072237}, issn = {0020-7136}, mesh = {Acetylcysteine/*metabolism ; Animals ; Ascorbic Acid/*metabolism ; Carcinogenicity Tests ; Cell Transformation, Neoplastic/*metabolism ; Chromium/metabolism ; Drug Stability ; Female ; Lung Neoplasms/chemically induced/*metabolism ; Mice ; Mutagenesis/*physiology ; Urethane ; }, abstract = {Both ascorbic acid (AsA, vitamin C) and N-acetylcysteine (NAC), a precursor and analogue of glutathione, possess a broad array of biological properties underlying their protective role in a variety of pathophysiological conditions. However, under certain circumstances, AsA behaves as a pro-oxidant rather than an anti-oxidant and produces adverse effects. This prompted us to evaluate whether NAC could interact with AsA in preventing mutation and cancer. AsA significantly increased spontaneous revertants in the Salmonella typhimurium strains TA102 and TA104, which are sensitive to oxidative mutagens. In contrast, NAC lowered the spontaneous background in TA104 and neutralized the negative effects of AsA. Moreover, NAC and AsA showed additive effects in reducing chromium(VI) and in reverting its mutagenicity. A single i.p. injection of urethane (1 g/kg body weight) to 120 A/J mice resulted, after 4 months, in the formation of a total of 1,532 lung tumors, 425 in the 30 mice treated with the carcinogen only, 404 in those treated with urethane plus AsA, 365 in those treated with urethane plus NAC and 338 in those treated with urethane plus the combination of AsA and NAC (both given daily with drinking water at the dose of 1 g/kg body weight). Compared to positive controls, tumor multiplicity was poorly affected by AsA, whereas it was significantly decreased by NAC and even more so by its combination with AsA. The overall volumes of lung tumors in the 4 groups were 107.5, 89.3, 61.3 and 49.7 mm(3), respectively. Tumor sizes were slightly but significantly decreased in mice treated with AsA and more so in those treated with NAC and NAC plus AsA, their combination being significantly more effective than each individually. All protective effects elicited by combining the 2 drugs were additive. Therefore, NAC prevents the adverse effects of AsA on spontaneous mutagenicity; at the same time, this thiol behaves in an additive fashion with AsA, inhibiting the mutagenicity of chromium(VI) and the lung tumorigenicity of urethane in mice. These findings suggest that NAC and AsA could conveniently be combined in cancer chemoprevention and other pharmacological interventions.}, }
@article {pmid11071271, year = {2000}, author = {Cuzzocrea, S and Mazzon, E and De Sarro, A and Caputi, AP}, title = {Role of free radicals and poly(ADP-ribose) synthetase in intestinal tight junction permeability.}, journal = {Molecular medicine (Cambridge, Mass.)}, volume = {6}, number = {9}, pages = {766-778}, pmid = {11071271}, issn = {1076-1551}, mesh = {Animals ; Benzamides/pharmacology ; Cell Membrane Permeability/*drug effects ; Cells, Cultured ; Cytoskeletal Proteins/metabolism ; Enzyme Inhibitors/pharmacology ; Fluorescent Antibody Technique ; Free Radicals/*pharmacology ; Freeze Fracturing ; Hydrogen Peroxide/pharmacology ; Immunoenzyme Techniques ; Intestinal Absorption ; Intestine, Small/cytology/*drug effects/metabolism ; Kidney/cytology/*drug effects/metabolism ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Knockout ; Mitochondria/metabolism ; Nitrates/metabolism ; Nitric Oxide Synthase/genetics/metabolism ; Nitric Oxide Synthase Type II ; Occludin ; Oxidative Stress ; Phosphoproteins/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/*metabolism ; Tight Junctions/*metabolism ; *Trans-Activators ; Zonula Occludens-1 Protein ; Zymosan/pharmacology ; beta Catenin ; }, abstract = {BACKGROUND: Small intestine permeability is frequently altered in inflammatory bowel disease and may be caused by the translocation of intestinal toxins through leaky small intestine tight junctions (TJ) and adherence (1,2). The role of hydrogen peroxide (H2O2), and nitric oxide (NO) and PARS in the permeability and structure of small intestine TJ is not clearly understood.<br><br>MATERIALS AND METHODS: In vitro study, MDCK (Madin-Darby Canine Kidney) cells were exposed to H2O2 (100 microM for 2h), or zymosan (200 microl of stock solution 1 mg/ml for 4h), in the presence or absence of a treatment with poly(ADP-ribose) synthetase (PARS) inhibitor 3-aminobenzamide (3-AB: 3 mM) or with n-acetylcysteine (NAC 10 mM). In vivo study, wild-type mice (WT) and mice lacking (KO) of the inducible (or type 2) nitric oxide synthase (iNOS) were treated with zymosan (500 mg/kg, suspended in saline solution, i.p.). In addition INOSWT mice were treated with 3-AB (10 mg/kg, i.p.) or with NAC (40 mg/kg, i.p.) 1 hour and 6 h after zymosan administration.<br><br>RESULTS: Exposure of MDCK cells to hydrogen peroxide caused a significant impairment in mitochondrial respiration that was associated with a reduction of cells adherence as well as derangement of the junctional proteins. A significant increase of nitrate and nitrite levels, stable metabolites of nitric oxide (NO), were found in MDCK supernatant after zymosan incubation. NO production was associated with a significant reduction of cell adherence and impairment of occludin protein. Pre-treatment of the cells with 3-AB or with NAC caused a significant prevention of H2O2-mediated occludin junctional damage as well as reduced the NO-induced occludin damage. In addition, H2O2 and NO are able to induce a significant derangement of beta-catenin and Zonula Ocludence-1 (ZO-1). We found an increase of tight junctional permeability to lanthanum nitrate (molecular weight, 433) in the terminal ileal TJs in zymosan-treated iNOSWT mice compared with permeable TJ in the control animals. Zymosan-treated iNOSKO mice showed a significant increase of tight junctional permselectivity. There were no differences in strand count or strand depth in the ilea from control or treated animals. In addition, a significant disrupted immunofluorescence signal for occludin, ZO-1 and beta-catenin was observed in the terminal ilea of zymosan-treated iNOSWT mice. In ileal fragments from zymosan-treated iNOSKO mice, we found less irregular distribution patterns of occludin, ZO-1 and beta-catenin. Similarly NAC or 3-AB treatments were able to prevent zymosan-induced damage of junctional proteins in iNOSWT mice.<br><br>CONCLUSION: In conclusion, this study demonstrates that the alteration of permselectivity is most likely induced by ROS and PARS activation.}, }
@article {pmid11070462, year = {2000}, author = {Riise, GC and Qvarfordt, I and Larsson, S and Eliasson, V and Andersson, BA}, title = {Inhibitory effect of N-acetylcysteine on adherence of Streptococcus pneumoniae and Haemophilus influenzae to human oropharyngeal epithelial cells in vitro.}, journal = {Respiration; international review of thoracic diseases}, volume = {67}, number = {5}, pages = {552-558}, doi = {10.1159/000067473}, pmid = {11070462}, issn = {0025-7931}, mesh = {Acetylcysteine/*pharmacology ; Bacterial Adhesion/*drug effects ; Cells, Cultured ; Epithelial Cells ; Expectorants/*pharmacology ; Haemophilus influenzae/*drug effects ; Humans ; Mouth Mucosa/cytology ; Pharynx/cytology ; Streptococcus pneumoniae/*drug effects ; }, abstract = {BACKGROUND: Bacterial adherence to mucosal and epithelial cell structures is of importance for the persistence of bacteria in the airways. Cigarette smoking and chronic bronchitis are associated with increased bacterial adherence. N-Acetylcysteine (NAC) medication reduces the number of infectious exacerbations in patients with chronic bronchitis, and NAC medication has been associated with low intrabronchial bacterial numbers.<br><br>OBJECTIVE: We investigated whether NAC influences bacterial adherence as a possible mechanism behind its clinical effects.<br><br>METHODS: Highly adhering test strains of Streptococcus pneumoniae and Haemophilus influenzae were used to investigate the influence of four pharmacological compounds on adherence to oropharyngeal epithelial cells in vitro. Adhesion assays were performed both during short-term exposure to, as well as after long-time incubation with, NAC, lidocaine, hydrocortisone and terbutaline at concentrations not inhibiting bacterial growth.<br><br>RESULTS: Only NAC showed a significant inhibitory effect on adhesion of H. influenzae during short-term incubation. After long-term incubation, both NAC and hydrocortisone inhibited bacterial adhesion for both strains in a dose-dependent manner. When NAC's effect on three different strains of S. pneumoniae and four strains of H. influenzae was studied, inhibition of bacterial adhesion was found for three strains of each species.<br><br>CONCLUSIONS: NAC lowers bacterial adhesion in vitro to oropharyngeal epithelial cells in doses equivalent to that is being used clinically. This effect might be a contributory mechanism behind the reduction of infectious exacerbations in chronic bronchitis patients.}, }
@article {pmid11063914, year = {2000}, author = {Janiszewski, M and Pedro, MA and Scheffer, RC and van Asseldonk, JH and Souza, LC and da Luz, PL and Augusto, O and Laurindo, FR}, title = {Inhibition of vascular NADH/NADPH oxidase activity by thiol reagents: lack of correlation with cellular glutathione redox status.}, journal = {Free radical biology &amp; medicine}, volume = {29}, number = {9}, pages = {889-899}, doi = {10.1016/s0891-5849(00)00393-2}, pmid = {11063914}, issn = {0891-5849}, mesh = {Acridines ; Animals ; Blood Vessels/*drug effects/enzymology/*metabolism ; Carotid Arteries/drug effects/metabolism ; Electron Spin Resonance Spectroscopy ; Glutathione/*metabolism ; Iliac Artery/drug effects/metabolism ; In Vitro Techniques ; NADH, NADPH Oxidoreductases/*antagonists &amp; inhibitors ; Oxidation-Reduction ; Oxidative Stress ; Rabbits ; Sulfhydryl Reagents/*pharmacology ; }, abstract = {Vascular NAD(P)H oxidase activity contributes to oxidative stress. Thiol oxidants inhibit leukocyte NADPH oxidase. To assess the role of reactive thiols on vascular oxidase, rabbit iliac/carotid artery homogenates were incubated with distinct thiol reagents. NAD(P)H-driven enzyme activity, assessed by lucigenin (5 or 250 microM) luminescence, was nearly completely (> 97%) inhibited by the oxidant diamide (1mM) or the alkylator p-chloromercuryphenylsulfonate (pCMPS, 0.5mM). Analogous inhibition was also shown with EPR spectroscopy using DMPO as a spin trap. The oxidant dithionitrobenzoic acid (0.5mM) inhibited NADPH-driven signals by 92% but had no effect on NADH-driven signals. In contrast, the vicinal dithiol ligand phenylarsine oxide (PAO, 1 microM) induced minor nonsignificant inhibition of NADPH-driven activity, but significant stimulation of NADH-triggered signals. The alkylator N-ethyl maleimide (NEM, 0.5mM) or glutathione disulfide (GSSG, 3mM) had no effect with each substrate. Coincubation of N-acetylcysteine (NAC, 3mM) with diamide or pCMPS reversed their inhibitory effects by 30-60%, whereas NAC alone inhibited the oxidase by 52%. Incubation of intact arterial rings with the above reagents disclosed similar results, except that PAO became inhibitor and NAC stimulator of NADH-driven signals. Notably, the cell-impermeant reagent pCMPS was also inhibitory in whole rings, suggesting that reactive thiol(s) affecting oxidase activity are highly accessible. Since lack of oxidase inhibition by NEM or GSSG occurred despite significant cellular glutathione depletion, change in intracellular redox status is not sufficient to account for oxidase inhibition. Moreover, the observed differences between NADPH and NADH-driven oxidase activity point to complex or multiple enzyme forms.}, }
@article {pmid11062741, year = {2000}, author = {Aluigi, MG and De Flora, S and D'Agostini, F and Albini, A and Fassina, G}, title = {Antiapoptotic and antigenotoxic effects of N-acetylcysteine in human cells of endothelial origin.}, journal = {Anticancer research}, volume = {20}, number = {5A}, pages = {3183-3187}, pmid = {11062741}, issn = {0250-7005}, mesh = {Acetylcysteine/*pharmacology ; Angiogenesis Inhibitors/pharmacology ; Antimutagenic Agents/*pharmacology ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Cell Line ; Endothelium, Vascular/*drug effects ; Humans ; Paraquat/antagonists &amp; inhibitors/pharmacology ; Transforming Growth Factor beta/pharmacology ; }, abstract = {N-Acetylcysteine (NAC) is a drug bearing multiple preventive properties that can inhibit genotoxicity and carcinogenicity. NAC also inhibits invasion and metastasis of malignant cells, as well as tumor take. We recently demonstrated the effects of NAC on Kaposi's sarcoma cells supernatant-induced invasion in vitro and angiogenesis in vivo. Many anticancer agents act through cytotoxicity of rapidly proliferating cells and several antineoplastic drugs induce apoptosis of cancer cells. Since endothelial cells are the target for the inhibition of angiogenesis, we wanted to verify that NAC, while inhibiting tumor vascularization and endothelial cell invasion would not induce endothelial cell apoptosis. We tested the ability of NAC to modulate apoptosis and cytogenetic damage in vitro and to promote differentiation on a reconstituted basement membrane (matrigel) in two endothelial cell lines (EAhy926 and HUVE). Treatment with NAC protected endothelial cells from TGF-beta-induced apoptosis and paraquat-induced cytogenetic damage. Therefore, NAC acts as an antiangiogenic agent and, at the same time, appears to prevent apoptosis and oxygen-related genotoxicity in endothelial cells.}, }
@article {pmid11056417, year = {2000}, author = {}, title = {N-acetylcysteine.}, journal = {Alternative medicine review : a journal of clinical therapeutic}, volume = {5}, number = {5}, pages = {467-471}, pmid = {11056417}, issn = {1089-5159}, mesh = {Acetaminophen/poisoning ; Acetylcysteine/adverse effects/pharmacokinetics/pharmacology/*therapeutic use ; Antidotes/therapeutic use ; Expectorants/therapeutic use ; Heart Diseases/drug therapy ; Humans ; Neoplasms/drug therapy ; Respiratory Tract Diseases/drug therapy ; }, abstract = {N-acetylcysteine (NAC) is the acetylated precursor of both the amino acid L-cysteine and reduced glutathione (GSH). Historically it has been used as a mucolytic agent in chronic respiratory illnesses as well as an antidote for hepatotoxicity due to acetaminophen overdose. More recently, animal and human studies of NAC have shown it to be a powerful antioxidant and a potential therapeutic agent in the treatment of cancer, heart disease, HIV infection, heavy metal toxicity, and other diseases characterized by free radical oxidant damage. NAC has also been shown to be of some value in treating Sjogren's syndrome, smoking cessation, influenza, hepatitis C, and myoclonus epilepsy.}, }
@article {pmid11056005, year = {2000}, author = {Park, J and Liu, AY}, title = {Pervanadate induces the hyperphosphorylation but not the activation of human heat shock factor 1.}, journal = {Journal of cellular physiology}, volume = {185}, number = {3}, pages = {348-357}, doi = {10.1002/1097-4652(200012)185:3&lt;348::AID-JCP5&gt;3.0.CO;2-3}, pmid = {11056005}, issn = {0021-9541}, mesh = {DNA-Binding Proteins/*metabolism ; Enzyme Inhibitors/metabolism/*pharmacology ; HeLa Cells ; Heat Shock Transcription Factors ; Heat-Shock Proteins/metabolism ; Humans ; *JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Phosphorylation/drug effects ; Signal Transduction/drug effects ; Transcription Factors ; Vanadates/metabolism/*pharmacology ; }, abstract = {In this study, we evaluated the effects of pervanadate, a tyrosine phosphatase inhibitor, on the regulation and function of heat-shock factor 1 (HSF1) in HeLa cells. We showed that 50-100 microM pervanadate induced the hyperphosphorylation of the latent HSF1, as demonstrated by a retarded mobility of the HSF1 protein in SDS-polyacrylamide gel electrophoresis and as supported by the reversal of this mobility shift upon treatment of the cell extract with acid phosphatase. Pervanadate by itself had no effect on the monomeric stoichiometry and DNA-binding activity of HSF1. Upon heat shock, the pervanadate-induced hyperphosphorylated HSF1 formed DNA-binding trimers and translocated into the nuclear compartment. At high concentration (approximately 500 microM), pervanadate also induced the tyrosine phosphorylation of many cellular proteins and blunted the heat-induced transcription of hsp 70. N-acetyl cysteine inhibited these effects of pervanadate, suggesting a redox-based mechanism for its activity. Analysis of the activation of mitogen-activated protein kinases (MAPKs) using antibodies specific for the phospho-form (activated) of the kinases in Western blot showed that pervanadate activated extracellular signal-regulated kinase (ERK1/2), c-Jun-N-terminal kinase 1/2 (JNK1/2), and p-38 kinase. Pharmacological inhibitors of the ERK1/2 kinase pathway or the p38 kinase had little or no effect on the pervanadate-induced hyperphosphorylation of HSF1. Our results show that hyperphosphorylation of hHSF1 can occur prior to and independent of other events involved in the activation of hHSF1. The possibility that activation of the MAPK signaling cascade, notably JNK, may contribute to the hyperphosphorylation of human HSF1 (hHSF1) is discussed.}, }
@article {pmid11053946, year = {2000}, author = {Börjesson, A and Wang, X and Sun, Z and Wallén, R and Deng, X and Johansson, E and Andersson, R}, title = {Effects of N-acetylcysteine on pulmonary macrophage activity after intestinal ischemia and reperfusion in rats / with invited commentaries.}, journal = {Digestive surgery}, volume = {17}, number = {4}, pages = {379-87; discussion 387-9}, doi = {10.1159/000018882}, pmid = {11053946}, issn = {0253-4886}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Capillary Permeability/drug effects ; Epithelium/ultrastructure ; Extravascular Lung Water/metabolism ; Free Radical Scavengers/*pharmacology ; Intestines/*blood supply ; Lung/ultrastructure ; Macrophage Activation/drug effects ; Macrophages, Alveolar/drug effects/*physiology ; Male ; Phagocytosis/drug effects ; Pulmonary Circulation/drug effects ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/pathology/*physiopathology ; }, abstract = {BACKGROUND/AIMS: Intestinal ischemia and reperfusion (I/R) is considered to be a critical and triggering event in the development of distal organ dysfunction after a variety of insults. It appears that activated leukocytes, especially polymorphonuclear granulocytes (PMNs), and reactive oxygen species are important mediators in the process. In the present study, the aim was to evaluate the behavior of pulmonary macrophages, acute lung injury and pulmonary endothelial permeability after intestinal I/R, together with potential alterations in pulmonary endothelial and epithelial ultrastructure and cellular membrane system integrity.<br><br>METHODS: Intestinal ischemia for 40 min was followed by reperfusion for 12 h in the rat. Macrophage uptake of radiolabeled bacteria, levels of pulmonary blood content assessed by radiolabeled red blood cells and pulmonary endothelial permeability of radiolabeled albumin, as well as pulmonary endothelial and epithelial ultrastructure and cellular membrane system integrity by the use of scanning electron microscopy and a tracer was evaluated after 12 h reperfusion. Treatment with the free radical scavenger N-acetylcysteine (NAC) administered prior to reperfusion was evaluated.<br><br>RESULTS: Overactivation of pulmonary macrophages was noted after intestinal I/R, as was a significant decrease in pulmonary blood content. No increase in pulmonary albumin leakage or increase in pulmonary water content was found after intestinal I/R as compared to controls. Treatment with NAC prevented against intestinal I/R-induced overactivation of pulmonary macrophages and a decrease in pulmonary blood content.<br><br>CONCLUSION: Reactive oxygen species may be involved in the regulation of pulmonary macrophage function and pulmonary circulation after intestinal I/R.}, }
@article {pmid11053552, year = {2000}, author = {Rappeneau, S and Baeza-Squiban, A and Marano, F and Calvet, J}, title = {Efficient protection of human bronchial epithelial cells against sulfur and nitrogen mustard cytotoxicity using drug combinations.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {58}, number = {1}, pages = {153-160}, doi = {10.1093/toxsci/58.1.153}, pmid = {11053552}, issn = {1096-6080}, mesh = {Acetylcysteine/pharmacology ; Bronchi/cytology/*drug effects ; Cells, Cultured ; Citrulline/*analogs &amp; derivatives/pharmacology ; Cytoprotection/*drug effects ; Dose-Response Relationship, Drug ; Doxycycline/pharmacology ; Drug Combinations ; Drug Interactions ; Epithelial Cells/cytology/drug effects/metabolism ; Humans ; Mechlorethamine/*toxicity ; Mercaptoethylamines/pharmacology ; Methenamine/pharmacology ; Mustard Gas/*toxicity ; NG-Nitroarginine Methyl Ester/pharmacology ; Niacinamide/pharmacology ; Protective Agents/*pharmacology ; Radiation-Protective Agents/pharmacology ; Tetrazolium Salts/metabolism ; Thiourea/*analogs &amp; derivatives/pharmacology ; }, abstract = {The aim of this study was to test the efficacy of several candidate molecules against sulfur mustard (SM) and nitrogen mustard (HN2) using a human bronchial-epithelial cell line (16HBE14o-). Candidate molecules were chosen on the basis of the known cytotoxicity mechanisms of mustards or their efficacy previously observed on other cellular models. It included the sulfhydryl-containing molecules N-acetyl-cysteine (NAC) and WR-1065, the nucleophile hexamethylenetetramine (HMT), the energy-level stabilizer niacinamide (NC), the antioxidant dimethylthiourea (DMTU), L-arginine analogues such as L-thiocitrulline (L-TC) and L-nitroarginine methyl ester (L-NAME), and the anti-gelatinase doxycycline (DOX). Their efficacy was determined using 2-(4-[3-iodophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2Htetrazolium (WST-1) reduction by viable cells 24 h after initial exposure to 100 microM HN2 or SM. On individual immediate cotreatment, some molecules exhibited selective protection against only one mustard, such as DMTU and WR-1065 against HN2 and DOX against SM, whereas NAC and L-TC were effective against both SM and HN2 cytotoxicity. However, as the level of protection against SM was always weak compared to HN2, several combinations were investigated against SM to improve the protection. The effective combinations (L-TC + DOX, NAC + DOX, NAC + DMTU, NAC + HMT, NC + DOX) combined agents, reducing the bioavailability of the mustard with compounds possibly acting on the consequences of alkylation. One of these combinations, NAC + DOX, appeared to be the most interesting, as these agents are already used in human therapy. It exhibited good efficacy in delayed cotreatment (up to 90 min) against SM.}, }
@article {pmid11033420, year = {2000}, author = {Kim, H and Seo, JY and Roh, KH and Lim, JW and Kim, KH}, title = {Suppression of NF-kappaB activation and cytokine production by N-acetylcysteine in pancreatic acinar cells.}, journal = {Free radical biology &amp; medicine}, volume = {29}, number = {7}, pages = {674-683}, doi = {10.1016/s0891-5849(00)00368-3}, pmid = {11033420}, issn = {0891-5849}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cells, Cultured ; Cytokines/analysis/*genetics ; Gene Expression Regulation/drug effects/*immunology ; Hydrogen Peroxide/metabolism ; Kinetics ; Lipid Peroxidation/*drug effects ; Male ; NF-kappa B/*antagonists &amp; inhibitors ; Pancreas/drug effects/immunology/*physiology ; RNA, Messenger/genetics ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Time Factors ; Transcription, Genetic/drug effects ; }, abstract = {Reactive oxygen species (ROS), generated by infiltrating neutrophils, are considered as an important regulator in the pathogenesis and development of pancreatitis. A hallmark of the inflammatory response is the induction of cytokine gene expression, which may be regulated by oxidant-sensitive transcription factor, nuclear factor-kappaB (NF-kappaB). Present study aims to investigate whether neutrophils primed by 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA) affect the productions of H(2)O(2) and lipid peroxide (LPO), NF-kappaB activation and cytokine production in pancreatic acinar cells, and whether these alterations were inhibited by N-acetylcysteine (NAC) and superoxide dismutase (SOD). Neutrophils generated ROS by stimulation with PMA, which was inhibited by NAC and SOD. In acinar cells, PMA-primed neutrophils increased the productions of H(2)O(2), LPO, and cytokines both time and dose dependently. PMA-primed neutrophils resulted in the activation of two species of NF-kappaB dimers (a p50/p65 heterodimer and a p50 homodimer) in acinar cells. Both NAC and SOD inhibited neutrophil-induced, oxidant-mediated alterations in acinar cells. In conclusion, ROS, generated by neutrophils, activates NF-kappaB, resulting in upregulation of inflammatory cytokines in acinar cells. Antioxidants such as NAC might be useful antiinflammatory agents by inhibiting oxidant-mediated activation of NF-kappaB and decreasing cytokine production.}, }
@article {pmid11033253, year = {2000}, author = {Kopke, RD and Weisskopf, PA and Boone, JL and Jackson, RL and Wester, DC and Hoffer, ME and Lambert, DC and Charon, CC and Ding, DL and McBride, D}, title = {Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla.}, journal = {Hearing research}, volume = {149}, number = {1-2}, pages = {138-146}, doi = {10.1016/s0378-5955(00)00176-3}, pmid = {11033253}, issn = {0378-5955}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Audiometry ; Auditory Threshold/drug effects ; Cell Count ; Chinchilla ; Drug Combinations ; Hair Cells, Auditory/drug effects/pathology ; Hearing Loss, Noise-Induced/*drug therapy/physiopathology ; Salicylates/*therapeutic use ; }, abstract = {The effects of a combination of two antioxidant compounds were studied in a chinchilla model of noise-induced hearing loss. After obtaining baseline hearing thresholds using inferior colliculus evoked potentials, chinchillas were exposed for 6 h to octave band noise centered at 4 kHz (105 dB SPL). Post-noise thresholds were obtained 1 h after the noise exposure, and then animals received either saline or salicylate and N-L-acetylcysteine combination. Another group received antioxidant treatment 1 h prior to noise. Hearing was tested at 1, 2 and 3 weeks post-noise. Subsequently, the cochleae were harvested, and cytocochleograms were prepared. There was a 20-40 dB SPL threshold shift at 3 weeks for tested controls. Permanent threshold shifts (PTS) were significantly reduced (P<0.05) to approximately 10 dB for the pre-treatment group at week 3. The PTS for the post-treatment group at week 3 was similar to the pre-treatment group at 1 and 2 kHz (0-10 dB) but was intermediate between the control and pre-treatment groups at 4 and 8 kHz (23 dB). Animals pre-treated with antioxidant had a significant reduction in hair cell loss but those post-treated with antioxidant had no protection from hair cell loss. These findings demonstrate the feasibility of reduction of noise-induced hearing loss using clinically available antioxidant compounds.}, }
@article {pmid11033233, year = {2000}, author = {Afaq, F and Abidi, P and Rahman, Q}, title = {N-acetyl L-cysteine attenuates oxidant-mediated toxicity induced by chrysotile fibers.}, journal = {Toxicology letters}, volume = {117}, number = {1-2}, pages = {53-60}, doi = {10.1016/s0378-4274(00)00236-8}, pmid = {11033233}, issn = {0378-4274}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Asbestos, Serpentine/*toxicity ; Bronchoalveolar Lavage Fluid/chemistry ; Cell Count ; Female ; Free Radical Scavengers/*pharmacology ; Glucosephosphate Dehydrogenase/drug effects/metabolism ; Glutathione/drug effects/metabolism ; Glutathione Peroxidase/drug effects/metabolism ; Glutathione Reductase/drug effects/metabolism ; Hydrogen Peroxide/metabolism ; Lipid Peroxidation/drug effects ; Macrophages, Alveolar/cytology/drug effects/metabolism ; Oxidants/*metabolism ; Rats ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Chrysotile, an important commercial variety of asbestos, is known to cause oxidative stress by enhancing production of hydrogen peroxide (H(2)O(2)) and thiobarbituric acid reactive substances (TBARS), depleting glutathione (GSH) and altering levels of GSH redox system enzymes. N-acetyl L-cysteine (NAC), a compound that increases GSH levels, protects cells against chrysotile toxicity. In the present study, rats were exposed intratracheally to a single dose (5 mg/rat) of chrysotile. This was followed by a daily dose of NAC 50 mg/kg. b. wt., i.p. At 1, 4, 8 and 16 days post chrysotile exposure lung lavage fluid was collected to determine H(2)O(2) generation, TBARS production, GSH level and its redox system enzymes activities. A significant decrease in H(2)O(2) and TBARS, an increase in GSH content and its redox system enzymes was observed in chrysotile+NAC animals in comparison to chrysotile-exposed animals. In this preliminary study it appears that NAC may be protecting cells against oxidative damage. This protection may be due to its ability to maintain intracellular GSH/oxidative scavenging capability.}, }
@article {pmid11031216, year = {2000}, author = {De Castellarnau, C and Sánchez-Quesada, JL and Benítez, S and Rosa, R and Caveda, L and Vila, L and Ordóñez-Llanos, J}, title = {Electronegative LDL from normolipemic subjects induces IL-8 and monocyte chemotactic protein secretion by human endothelial cells.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {20}, number = {10}, pages = {2281-2287}, doi = {10.1161/01.atv.20.10.2281}, pmid = {11031216}, issn = {1524-4636}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants ; Cells, Cultured ; Chemokine CCL2/*biosynthesis ; Chromatography, Ion Exchange ; Dactinomycin/pharmacology ; Dose-Response Relationship, Drug ; Electrophoresis, Polyacrylamide Gel ; Endothelium, Vascular/*drug effects/metabolism ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Interleukin-8/*biosynthesis ; Lipoproteins, LDL/antagonists &amp; inhibitors/chemistry/*pharmacology ; Male ; Middle Aged ; Plasminogen Activator Inhibitor 1/biosynthesis ; Thiobarbiturates ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The presence in plasma of an electronegative LDL subfraction [LDL(-)] cytotoxic for endothelial cells (ECs) has been reported. We studied the effect of LDL(-) on the release by ECs of molecules implicated in leukocyte recruitment [interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1)] and in the plasminogen activator inhibitor-1 (PAI-1). LDL(-), isolated by anion-exchange chromatography, differed from nonelectronegative LDL [LDL(+)] in its higher triglyceride, nonesterified fatty acid, apoprotein E and apoprotein C-III, and sialic acid contents. No evidence of extensive oxidation was found in LDL(-); its antioxidant and thiobarbituric acid-reactive substances contents were similar to those of LDL(+). However, conjugated dienes were increased in LDL(-), which suggests that mild oxidation might affect these particles. LDL(-) increased, in a concentration-dependent manner, the release of IL-8 and MCP-1 by ECs and was a stronger inductor of both chemokines than oxidized LDL (oxLDL) or LDL(+). PAI-1 release increased slightly in ECs incubated with both LDL(-) and oxLDL but not with LDL(+). However, no cytotoxic effects of LDL(-) were observed on ECs. Actinomycin D inhibited the release of IL-8 and MCP-1 induced by LDL(-) and oxLDL by up to 80%, indicating that their production is mediated by protein synthesis. Incubation of ECs with N:-acetyl cysteine inhibited production of IL-8 and MCP-1 induced by LDL(-) and oxLDL by >50%. The free radical scavenger butylated hydroxytoluene slightly inhibited the effect of oxLDL but did not modify the effect of LDL(-). An antagonist (BN-50730) of the platelet-activating factor receptor inhibited production of both chemokines by LDL(-) and oxLDL in a concentration-dependent manner. Our results indicate that LDL(-) shows proinflammatory activity on ECs and may contribute to early atherosclerotic events.}, }
@article {pmid11029607, year = {2000}, author = {De Rosa, SC and Zaretsky, MD and Dubs, JG and Roederer, M and Anderson, M and Green, A and Mitra, D and Watanabe, N and Nakamura, H and Tjioe, I and Deresinski, SC and Moore, WA and Ela, SW and Parks, D and Herzenberg, LA and Herzenberg, LA}, title = {N-acetylcysteine replenishes glutathione in HIV infection.}, journal = {European journal of clinical investigation}, volume = {30}, number = {10}, pages = {915-929}, doi = {10.1046/j.1365-2362.2000.00736.x}, pmid = {11029607}, issn = {0014-2972}, support = {CA42509/CA/NCI NIH HHS/United States ; CA81543/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Antiviral Agents/*administration &amp; dosage ; Disease Progression ; Double-Blind Method ; Glutathione/*blood ; HIV Infections/*drug therapy/*metabolism/mortality ; Humans ; Male ; Survival Analysis ; }, abstract = {BACKGROUND: Glutathione (GSH) deficiency is common in HIV-infected individuals and is associated with impaired T cell function and impaired survival. N-acetylcysteine (NAC) is used to replenish GSH that has been depleted by acetaminophen overdose. Studies here test oral administration of NAC for safe and effective GSH replenishment in HIV infection.<br><br>DESIGN: Oral NAC administration in a randomized, 8-week double-blind, placebo-controlled trial followed by optional open-label drug for up to 24 weeks.<br><br>SUBJECTS: HIV-infected, low GSH, CD4 T cells < 500 micro L(-1), no active opportunistic infections or other debilitation; n = 81. Study conducted prior to introduction of protease inhibitors.<br><br>RESULTS: Whole blood GSH levels in NAC arm subjects significantly increased from 0.88 mM to 0.98 mM, bringing GSH levels in NAC-treated subjects to 89% of uninfected controls (P = 0.03). Baseline GSH levels in the placebo group (0.91) remained essentially the same during the 8 week placebo-controlled trial. T cell GSH, adjusted for CD4 T cell count and beta2-microglobulin levels, also increased in the NAC-treated subjects (P = 0.04). Adverse effects were minimal and not significantly associated with NAC ingestion.<br><br>CONCLUSION: NAC treatment for 8 weeks safely replenishes whole blood GSH and T cell GSH in HIV-infected individuals. Thus, NAC offers useful adjunct therapy to increase protection against oxidative stress, improve immune system function and increase detoxification of acetaminophen and other drugs. These findings suggest that NAC therapy could be valuable in other clinical situations in which GSH deficiency or oxidative stress plays a role in disease pathology, e.g. rheumatoid arthritis, Parkinson's disease, hepatitis, liver cirrhosis, septic shock and diabetes.}, }
@article {pmid11029606, year = {2000}, author = {Müller, F and Svardal, AM and Nordoy, I and Berge, RK and Aukrust, P and Frøland, SS}, title = {Virological and immunological effects of antioxidant treatment in patients with HIV infection.}, journal = {European journal of clinical investigation}, volume = {30}, number = {10}, pages = {905-914}, doi = {10.1046/j.1365-2362.2000.00727.x}, pmid = {11029606}, issn = {0014-2972}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Acquired Immunodeficiency Syndrome/*drug therapy/immunology/*metabolism ; Adult ; Antioxidants/*administration &amp; dosage/adverse effects ; Antiviral Agents/*administration &amp; dosage/adverse effects ; Apoptosis/immunology ; Ascorbic Acid/*administration &amp; dosage/adverse effects ; CD4-CD8 Ratio ; CD4-Positive T-Lymphocytes/cytology/drug effects/metabolism ; Cell Division/immunology ; Cysteine/blood ; Dipeptides/blood ; Drug Therapy, Combination ; Glutathione/blood ; Humans ; Interleukin-10/blood ; Lipopolysaccharide Receptors/analysis ; Male ; Middle Aged ; Monocytes/chemistry/drug effects/metabolism ; Neopterin/blood ; Oxidative Stress/drug effects ; Pilot Projects ; Receptors, Tumor Necrosis Factor/blood ; Solubility ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {BACKGROUND: Intracellular oxidative stress in CD4+ lymphocytes due to disturbed glutathione homeostasis may lead to impaired lymphocyte functions and enhanced HIV replication in patients with HIV infection, especially in those with advanced immunodeficiency. The aim of the present study was to assess whether short-term, high-dose antioxidant treatment might have effects on immunological and virological parameters in patients with HIV infection.<br><br>MATERIALS AND METHODS: In this pilot study, we examined virological and immunological effects of antioxidant combination treatment for 6 days with high doses of N-acetylcysteine (NAC) and vitamin C in 8 patients with HIV infection. The following were assayed before, during and after antioxidant treatment: HIV RNA plasma levels; numbers of CD4+, CD8+, and CD14+ leukocytes in blood; plasma thiols; intracellular glutathione redox status in CD4+ lymphocytes and CD14+ monocytes; lymphocyte proliferation; lymphocyte apoptosis and plasma levels of tumour necrosis factor (TNF)alpha; soluble TNF receptors and neopterin in plasma.<br><br>RESULTS: No significant changes in HIV RNA plasma levels or CD4+ lymphocyte counts in blood were noted during antioxidant treatment in the patient group. However, in the 5 patients with the most advanced immunodeficiency (CD4+ lymphocyte counts < 200 x 106 L(-1)), a significant rise in CD4+ lymphocyte count, a reduction in HIV RNA plasma level of 0.8 log, an enhanced lymphocyte proliferation and an increased level of intracellular glutathione in CD4+ lymphocytes were found. No change in lymphocyte apoptosis was noted.<br><br>CONCLUSIONS: Short-term, high-dose combination treatment with NAC and vitamin C in patients with HIV infection and advanced immunodeficiency lead to immunological and virological effects that might be of therapeutic value.}, }
@article {pmid11006087, year = {2000}, author = {Iseki, A and Kambe, F and Okumura, K and Niwata, S and Yamamoto, R and Hayakawa, T and Seo, H}, title = {Pyrrolidine dithiocarbamate inhibits TNF-alpha-dependent activation of NF-kappaB by increasing intracellular copper level in human aortic smooth muscle cells.}, journal = {Biochemical and biophysical research communications}, volume = {276}, number = {1}, pages = {88-92}, doi = {10.1006/bbrc.2000.3452}, pmid = {11006087}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Aorta/metabolism ; Cells, Cultured ; Copper/*metabolism ; Drug Antagonism ; Free Radical Scavengers/pharmacology ; Humans ; Muscle, Smooth, Vascular/*metabolism ; NF-kappa B/*metabolism ; Pyrrolidines/*pharmacology ; Thiocarbamates/*pharmacology ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Pyrrolidine dithiocarbamate (PDTC) is a metal-chelating compound that acts as antioxidant or pro-oxidant and is widely used to study redox regulation of cell function. In the present study, we investigated effects of PDTC and another antioxidant, N-acetyl-l-cysteine (NAC), on TNF-alpha-dependent activation of NF-kappaB in human aortic smooth muscle cells (HASMC). Treatment of the cells with TNF-alpha induced the activation of p65/p50 heterodimer NF-kappaB and increased the mRNA levels of monocyte chemoattractant protein (MCP)-1. Pretreatment with PDTC markedly suppressed the NF-kappaB activation and expression of MCP-1 by inhibiting IkappaB-alpha degradation. In contrast, NAC had no effect. PDTC concomitantly increased the intracellular levels of copper, and bathocuproinedisulfonic acid, a non-cell-permeable chelator of Cu(1+), inhibited the PDTC-induced increase in intracellular copper level and reversed the PDTC effects on IkappaB-alpha, NF-kappaB, and MCP-1. These results indicate that TNF-alpha-dependent expression of MCP-1 in HASMC is tightly regulated by NF-kappaB and that intracellular copper level is crucial for the TNF-alpha-dependent activation of NF-kappaB in HASMC.}, }
@article {pmid11003618, year = {2000}, author = {Will, Y and Fischer, KA and Horton, RA and Kaetzel, RS and Brown, MK and Hedstrom, O and Lieberman, MW and Reed, DJ}, title = {gamma-glutamyltranspeptidase-deficient knockout mice as a model to study the relationship between glutathione status, mitochondrial function, and cellular function.}, journal = {Hepatology (Baltimore, Md.)}, volume = {32}, number = {4 Pt 1}, pages = {740-749}, doi = {10.1053/jhep.2000.17913}, pmid = {11003618}, issn = {0270-9139}, support = {ES-00210/ES/NIEHS NIH HHS/United States ; ES-01978/ES/NIEHS NIH HHS/United States ; ES-09001/ES/NIEHS NIH HHS/United States ; }, mesh = {Adenosine Diphosphate/analysis ; Adenosine Triphosphate/analysis/biosynthesis ; Animals ; Glutathione/analysis/*metabolism ; Liver/cytology/ultrastructure ; Mice ; Mice, Knockout ; Microscopy, Electron ; Mitochondria, Liver/*physiology ; Oxygen Consumption ; gamma-Glutamyltransferase/*deficiency ; }, abstract = {gamma-Glutamyltranspeptidase (GGT)-deficient mice (GGT(-/-)) display chronic glutathione (GSH) deficiency, growth retardation, and die at a young age (<20 weeks). Using livers from these mice, we investigated the relationship between GSH content, especially mitochondrial, and mitochondrial and cellular function. We found that the GSH content of isolated liver mitochondria was diminished by >/=50% in GGT(-/-) mice when compared with wild-type mice. Respiratory control ratios (RCRs) of GGT(-/-) mice liver mitochondria were </=60% those of wild-type mice primarily as a result of impaired state 3 respiration. Mitochondrial adenine nucleotide content was decreased by >/=40% in mitochondria obtained from GGT(-/-) mice. We observed a strong correlation between mitochondrial GSH content and RCRs. Even moderate decreases (<50%) correlated with adverse effects with respect to respiration. Electron microscopy revealed that livers from GGT(-/-) knockout mice were deprived of fat and glycogen, and swollen mitochondria were observed in animals that were severely deprived of GSH. Thus, GGT(-/-) mice exhibit a loss of GSH homeostasis and impaired oxidative phosphorylation, which may be related to the rate of adenosine triphosphate (ATP) formation and subsequently leads to progressive liver injury, which characterizes the diseased state. We also found that supplementation of GGT(-/-) mice with N-acetylcysteine (NAC) partially restored liver GSH, but fully restored mitochondrial GSH and respiratory function. Electron microscopy revealed that the livers of NAC-supplemented GGT(-/-) mice contained fat and glycogen; however, slightly enlarged mitochondria were found in some livers. NAC supplementation did not have any beneficial effect on the parameters examined in wild-type mice.}, }
@article {pmid10993480, year = {2000}, author = {Kim, JA and Kang, YS and Lee, SH and Lee, YS}, title = {Inhibitors of Na+/Ca2+ exchanger prevent oxidant-induced intracellular Ca2+ increase and apoptosis in a human hepatoma cell line.}, journal = {Free radical research}, volume = {33}, number = {3}, pages = {267-277}, doi = {10.1080/10715760000301431}, pmid = {10993480}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Calcium/*metabolism ; Carcinoma, Hepatocellular/*metabolism ; Chelating Agents/pharmacology ; Egtazic Acid/*analogs &amp; derivatives/pharmacology ; Flow Cytometry ; Humans ; Liver Neoplasms/*metabolism ; Oxidants/*pharmacology ; Oxidative Stress ; Phenylenediamines/pharmacology ; Reactive Oxygen Species/metabolism ; Sodium/metabolism ; Sodium-Calcium Exchanger/*antagonists &amp; inhibitors/physiology ; Tumor Cells, Cultured ; tert-Butylhydroperoxide/pharmacology ; }, abstract = {Oxidative stress appears to be implicated in the pathogenesis of various diseases including hepatotoxicity. Although intracellular Ca2+ signals have been suggested to play a role in the oxidative damage of hepatocytes, the sources and effects of oxidant-induced intracellular Ca2+ increases are currently debatable. Thus, in this study we investigated the exact source and mechanism of oxidant-induced liver cell damage using HepG2 human hepatoma cells as a model liver cellular system. Treatment with 200 microM of tert-butyl hydroperoxide (tBOOH) induced a sustained increase in the level of intracellular reactive oxygen intermediates (ROI) and apoptosis, assessed by 2',7'-dichlorofluorescein fluorescence and flow cytometry, respectively. Antioxidants, N-acetyl cysteine (NAC) or N,N'-diphenyl-p-phenylenediamine significantly inhibited both the ROI generation and apoptosis. In addition, tBOOH induced a slow and sustained increase in intracellular Ca2+ concentration, which was completely prevented by the antioxidants. An intracellular Ca2+ chelator, bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid/cetoxymethyl ester significantly suppressed the tBOOH-induced apoptosis. These results imply that activation of an intracellular Ca2+ signal triggered by increased ROI may mediate the tBOOH-induced apoptosis. Both intracellular Ca2+ increase and induction of apoptosis were significantly inhibited by an extracellular Ca2+ chelator or Na+/Ca2+ exchanger blockers (bepridil and benzamil), whereas neither Ca2+ channel antagonists (verapamil and nifedipine) nor a nonselective cation channel blocker (flufenamic acid) had an effect. These results suggest that tBOOH may increase intracellular Ca2+ through the activation of reverse mode of Na+/Ca2+ exchanger. However, tBOOH decreased intracellular Na+ concentration, which was completely prevented by NAC. These results indicate that ROI generated by tBOOH may increase intracellular Ca2+ concentration by direct activation of the reverse mode of Na+/Ca2+ exchanger, rather than indirect elevation of intracellular Na+ levels. Taken together, these results suggest that the oxidant, tBOOH induced apoptosis in human HepG2 cells and that intracellular Ca2+ may mediate this action of tBOOH. These results further suggest that Na+/Ca2+ exchanger may be a target for the management of oxidative hepatotoxicity.}, }
@article {pmid10991774, year = {2000}, author = {Comhaire, FH and Christophe, AB and Zalata, AA and Dhooge, WS and Mahmoud, AM and Depuydt, CE}, title = {The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men.}, journal = {Prostaglandins, leukotrienes, and essential fatty acids}, volume = {63}, number = {3}, pages = {159-165}, doi = {10.1054/plef.2000.0174}, pmid = {10991774}, issn = {0952-3278}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Acrosome Reaction ; Adult ; Antioxidants/*administration &amp; dosage/*therapeutic use ; Cell Membrane/metabolism ; DNA/metabolism ; Fatty Acids, Essential/*therapeutic use ; Fatty Acids, Unsaturated/metabolism ; Female ; Free Radical Scavengers/administration &amp; dosage/therapeutic use ; Humans ; Infertility, Male/*therapy ; Male ; Phospholipids/metabolism ; Pilot Projects ; Pregnancy ; Pregnancy Rate ; Prospective Studies ; Reactive Oxygen Species ; Smoking ; Sperm Count ; Spermatozoa/*drug effects ; Time Factors ; Vitamin A/administration &amp; dosage/therapeutic use ; Vitamin E/administration &amp; dosage/therapeutic use ; }, abstract = {We evaluated the effects of combined conventional treatment, oral antioxidants (N-acetyl-cysteine or vitamins A plus E) and essential fatty acids (FA) on sperm biology in an open prospective study including 27 infertile men. The evaluation included sperm characteristics, seminal reactive oxygen species (ROS), FA of sperm membrane phospholipids, sperm oxidized DNA (8-OH-dG), and induced acrosome reaction (AR). Treatment did not improve sperm motility and morphology, nor decrease the concentration of round cells and white blood cells in semen. Sperm concentration increased in oligozoospermic men (7.4+/-1.3 to 12.5+/-1.9 million/ml). Treatment significantly reduced ROS (mean+/-SEM) (775.3+/-372.2 to 150.3+/-105.2 x 10(3)counts/10 second) and 8-OH-dG (45.3+/-10.4 to 16. 8+/-3.3 fmol/microg DNA). Treatment increased the AR (55.1+/-2.2 to 71.6+/-2.2%), the proportion of polyunsaturated FA of the phospholipids, and sperm membrane fluidity. The overall pregnancy rate was 4.5% in 134 months. The per month pregnancy rate tended to be higher in partners of (ex)-smokers (7.15%, n=14,70 months) than in never-smokers (1.6%, n=13,64 months) (OR:4.57, 95% Cl:0.55-38.1).}, }
@article {pmid10987854, year = {2000}, author = {Fontaine, MA and Geddes, JW and Banks, A and Butterfield, DA}, title = {Effect of exogenous and endogenous antioxidants on 3-nitropionic acid-induced in vivo oxidative stress and striatal lesions: insights into Huntington's disease.}, journal = {Journal of neurochemistry}, volume = {75}, number = {4}, pages = {1709-1715}, doi = {10.1046/j.1471-4159.2000.0751709.x}, pmid = {10987854}, issn = {0022-3042}, support = {AG-05119/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; AG-12423/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*metabolism/pharmacology ; Cerebral Cortex/drug effects/metabolism/pathology ; Corpus Striatum/*drug effects/metabolism/pathology ; Cyclic N-Oxides/pharmacology ; Electron Spin Resonance Spectroscopy ; Glutathione/metabolism/pharmacology ; Huntington Disease/*metabolism ; Male ; Membrane Proteins/analysis/metabolism ; Nitro Compounds ; *Oxidative Stress/drug effects ; Propionates/*administration &amp; dosage ; Rats ; Rats, Sprague-Dawley ; Synaptic Membranes/drug effects/metabolism ; Synaptosomes/drug effects/metabolism ; }, abstract = {3-Nitropropionic acid (3-NP) is an irreversible inhibitor of complex II in the mitochondria. 3-NP toxicity has gained acceptance as an animal model of Huntington's disease (HD). In the present study, we confirmed that rats injected with 3-NP (20 mg/kg, i.p., daily for 4 days) exhibit increased oxidative stress in both striatum and cortical synaptosomes as well as lesions in the striatum. Synaptosomal membrane proteins from rats injected with 3-NP exhibited a decrease in W/S ratio, the relevant electron paramagnetic resonance (EPR) parameter used to determine levels of protein oxidation, and western blot analysis for protein carbonyls revealed direct evidence of increased synaptosomal protein oxidation. Treatment of rats with the brain-accessible free radical spin trap 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO; 30 mg/kg, i.p., daily 2 h before 3-NP injection) or with N-acetylcysteine (NAC; 100 mg/kg, i.p., daily 2 h before 3-NP injection), a known glutathione precursor, before 3-NP treatments protects against oxidative damage induced by 3-NP as measured by EPR and western blot analysis for protein carbonyls. Furthermore, both DEMPMPO and NAC treatments before 3-NP administration significantly reduce striatal lesion volumes. These data suggest oxidative damage is a prerequisite for striatal lesion formation and that antioxidant treatment may be a useful therapeutic strategy against 3-NP neurotoxicity and perhaps against HD as well.}, }
@article {pmid10981515, year = {2000}, author = {Kim, H and Seo, JY and Kim, KH}, title = {NF-kappaB and cytokines in pancreatic acinar cells.}, journal = {Journal of Korean medical science}, volume = {15 Suppl}, number = {Suppl}, pages = {S53-4}, doi = {10.3346/jkms.2000.15.S.S53}, pmid = {10981515}, issn = {1011-8934}, mesh = {Acute Disease ; Chronic Disease ; Cytokines/*immunology ; Humans ; NF-kappa B/*metabolism ; Pancreas/cytology/*immunology/*metabolism ; Pancreatitis/immunology/metabolism ; }, abstract = {Reactive oxygen species (ROS), generated by infiltrating neutrophils, are considered as an important regulator in the pathogenesis and deveolpment of pancreatitis. A hallmark of the inflammatory response is the induction of cytokine gene expression, which may be regulated by oxidant-sensitive transcription factor, nuclear factor-kappaB (NF-KB). Present study aims to investigate whether neutrophils primed by 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA) affect the productions of H2O2 and lipid peroxide (LPO), NF-kappaB activation and cytokine production in pancreatic acinar cells, and whether these alterations were inhibited by N-acetylcysteine (NAC) and superoxide dismutase (SOD). ROS generation in neutrophils increased by PMA, which was inhibited by NAC and SOD. The productions of H2O2, LPO and TNF-alpha were increased with the amounts of PMA-primed neutrophils added to acinar cells while the productions of H2O2, LPO and cytokines increased with time. PMA-primed neutrophils resulted in the activation of two species of NF-kappaB dimers (a p50/p65 heterodimer and a p50 homodimer). Both NAC and SOD inhibited neutrophil-induced alterations in acinar cells. In conclusion, ROS, generated by neutrophils, activates NF-kappaB, resulting in upregulation of inflammatory cytokines in acinar cells. Antioxidants such as NAC might be clinically useful antiinflammatory agents by inhibiting oxidant-mediated activation of NF-KB and decreasing cytokine production.}, }
@article {pmid10976006, year = {2000}, author = {Park, CS and Park, WR and Sugimoto, N and Nakahira, M and Ahn, HJ and Hamaoka, T and Ohta, T and Kurimoto, M and Fujiwara, H}, title = {Differential effects of N-acetyl-l-cysteine on IL-2- vs IL-12-driven proliferation of a T cell clone: implications for distinct signalling pathways.}, journal = {Cytokine}, volume = {12}, number = {9}, pages = {1419-1422}, doi = {10.1006/cyto.2000.0722}, pmid = {10976006}, issn = {1043-4666}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Division/drug effects ; Cell Line ; Dexamethasone/pharmacology ; Dose-Response Relationship, Drug ; Down-Regulation ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Glucocorticoids/pharmacology ; Imidazoles/pharmacology ; Interleukin-12/*pharmacology ; Interleukin-2/*pharmacology ; Mice ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors ; Precipitin Tests ; Pyridines/pharmacology ; Recombinant Proteins/pharmacology ; *Signal Transduction ; T-Lymphocytes/cytology/*drug effects ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Using a T cell clone (2D6) capable of responding to IL-2 and IL-12, we compared the effects of NAC on IL-2 and IL-12-driven T cell proliferation. Addition of N-acetylcysteine (NAC) to 2D6 cultures did not affect IL-2 stimulated proliferation, but strikingly inhibited IL-12 stimulated proliferation. These differential NAC effects did not correlate with the patterns of the mitogen-activated protein kinase (MAPK) activation following cytokine stimulation and its regulation by NAC. Although a p38 MAPK inhibitor downregulated both IL-2- and IL-12-induced proliferation, this effect was seen at drug concentrations one order higher than those reportedly used to specifically inhibit p38 MAPK. The results suggest the existence of distinct signalling pathways and a common, indispensable signalling molecule in IL-2- and IL-12 driven T cell proliferation.}, }
@article {pmid10975858, year = {2000}, author = {Li, N and Venkatesan, MI and Miguel, A and Kaplan, R and Gujuluva, C and Alam, J and Nel, A}, title = {Induction of heme oxygenase-1 expression in macrophages by diesel exhaust particle chemicals and quinones via the antioxidant-responsive element.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {165}, number = {6}, pages = {3393-3401}, doi = {10.4049/jimmunol.165.6.3393}, pmid = {10975858}, issn = {0022-1767}, support = {AI34567/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Benzopyrenes/pharmacology ; Cell Line ; Enzyme Induction/drug effects ; Flavonoids/pharmacology ; Heme Oxygenase (Decyclizing)/*biosynthesis/genetics ; Heme Oxygenase-1 ; Hydroquinones/pharmacology ; Ketones/pharmacology ; Macrophages/*drug effects/*enzymology/metabolism ; Membrane Proteins ; Mice ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Phospholipid Ethers/metabolism/pharmacology ; Polycyclic Aromatic Hydrocarbons/pharmacology ; Promoter Regions, Genetic/drug effects ; Quinones/metabolism/*pharmacology ; Response Elements/*drug effects ; *Vehicle Emissions/adverse effects ; }, abstract = {Diesel exhaust particles (DEP) contain organic chemicals that contribute to the adverse health effects of inhaled particulate matter. Because DEP induce oxidative stress in the lung and in macrophages, effective antioxidant defenses are required. One type of defense is through the expression of the antioxidant enzyme, heme oxygenase I (HO-1). HO-1 as well as phase II detoxifying enzymes are induced via antioxidant response elements (ARE) in their promoters of that gene. We show that a crude DEP total extract, aromatic and polar DEP fractions, a benzo(a)pyrene quinone, and a phenolic antioxidant induce HO-1 expression in RAW264.7 cells in an ARE-dependent manner. N-acetyl cysteine and the flavonoid, luteolin, inhibited HO-1 protein expression. We also demonstrate that the same stimuli induce HO-1 mRNA expression in parallel with the activation of the SX2 enhancer of that gene. Mutation of the ARE core, but not the overlapping AP-1 binding sequence, disrupted SX2 activation. Finally, we show that biological agents, such as oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, could also induce HO-1 expression via an ARE-dependent mechanism. Prior induction of HO-1 expression, using cobalt-protoporphyrin, protected RAW264.7 cells against DEP-induced toxicity. Taken together, these data show that HO-1 plays an important role in cytoprotection against redox-active DEP chemicals, including quinones.}, }
@article {pmid10973800, year = {2000}, author = {Li, WQ and Dehnade, F and Zafarullah, M}, title = {Thiol antioxidant, N-acetylcysteine, activates extracellular signal-regulated kinase signaling pathway in articular chondrocytes.}, journal = {Biochemical and biophysical research communications}, volume = {275}, number = {3}, pages = {789-794}, doi = {10.1006/bbrc.2000.3385}, pmid = {10973800}, issn = {0006-291X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Blotting, Western ; Cartilage, Articular/cytology/*drug effects/enzymology/metabolism ; Cattle ; Cells, Cultured ; Chondrocytes/*drug effects/enzymology/metabolism ; Cysteine/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Activation/drug effects ; Flavonoids/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/pharmacology ; Humans ; MAP Kinase Signaling System/*drug effects ; Mitogen-Activated Protein Kinase Kinases/antagonists &amp; inhibitors/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation/drug effects ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/*metabolism/pharmacology ; Thiocarbamates/pharmacology ; Time Factors ; }, abstract = {Reactive oxygen species (ROS) generated during inflammation and aging contribute to the resorption of articular cartilage. Low antioxidant levels are a risk factor for arthritis because they protect cartilage from ROS. N-Acetylcysteine (NAC) is a ROS scavenger and, depending upon the concentration, an anti-inflammatory or prooxidant agent. Mechanisms of action for NAC were studied in primary human and bovine chondrocytes. NAC dose-dependently activated phosphorylation of extracellular signal-regulated kinases-mitogen-acivated protein kinases (ERK-MAPK). ERK activation peaked within 15 min and declined afterward up to 180 min. This activation was inhibited by the MAPKK inhibitor, PD098059. The induction was mimicked by other thiols, l-cysteine, reduced glutathione, and pyrrolidine dithiocarbamate (PDTC) but not by a nonthiol, N-acetylalanine. The total nonphosphorylated ERKs levels remained unaffected by these treatments. Activation of the ERK-MAPK pathway provides a mechanism for the reported promotion of chondrocyte survival by thiol antioxidants.}, }
@article {pmid10970698, year = {2000}, author = {MacKinnon, AC and Waters, C and Rahman, I and Harani, N and Rintoul, R and Haslett, C and Sethi, T}, title = {[Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) induces AP-1 transcription and sensitizes cells to chemotherapy.}, journal = {British journal of cancer}, volume = {83}, number = {7}, pages = {941-948}, pmid = {10970698}, issn = {0007-0920}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*pharmacology ; Antineoplastic Agents, Phytogenic/pharmacology ; Apoptosis/drug effects ; CHO Cells ; Carcinoma, Small Cell/drug therapy/pathology ; Cell Division/drug effects ; Cricetinae ; Drug Synergism ; Etoposide/pharmacology ; Free Radical Scavengers ; Glutathione/metabolism ; Growth Inhibitors/pharmacology ; *JNK Mitogen-Activated Protein Kinases ; Lipid Peroxidation/drug effects ; Lung Neoplasms/drug therapy/metabolism/pathology ; MAP Kinase Kinase 4 ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Oligopeptides/*pharmacology ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Stimulation, Chemical ; Transcription Factor AP-1/*biosynthesis/genetics/physiology ; Transcription, Genetic/drug effects ; Tumor Cells, Cultured ; }, abstract = {[Arg(6), D-Trp(7,9), N(me)Phe(8)]-substance P (6-11) (antagonist G) inhibits small cell lung cancer (SCLC) growth and is entering Phase II clinical investigation for the treatment of SCLC. As well as acting as a neuropeptide receptor antagonist, antagonist G stimulates c-jun-N-terminal kinase (JNK) activity and apoptosis in SCLC cells. We extend these findings and show that the stimulation of JNK and apoptosis by antagonist G is dependent upon the generation of reactive oxygen species (ROS) being inhibited either by anoxia or the presence of N-acetyl cysteine (n-AC). Antagonist G is not intrinsically a free radical oxygen donor but stimulates free radical generation specifically within SCLC cells (6.2-fold) and increases the activity of the redox-sensitive transcription factor AP-1 by 61%. In keeping with this, antagonist G reduces cellular glutathione (GSH) levels (38% reduction) and stimulates ceramide production and lipid peroxidation (112% increase). At plasma concentrations achieved clinically in the phase I studies, antagonist G augments, more than additively, growth inhibition induced by etoposide. Our results suggest that antagonist G may be particularly effective as an additional treatment with standard chemotherapy in SCLC. These novel findings will be important for the clinical application of this new and exciting compound and for the future drug development of new agents to treat this aggressive cancer.}, }
@article {pmid10968500, year = {2000}, author = {Stey, C and Steurer, J and Bachmann, S and Medici, TC and Tramèr, MR}, title = {The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review.}, journal = {The European respiratory journal}, volume = {16}, number = {2}, pages = {253-262}, doi = {10.1034/j.1399-3003.2000.16b12.x}, pmid = {10968500}, issn = {0903-1936}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects/therapeutic use ; Administration, Oral ; Bronchitis/*drug therapy ; Chronic Disease ; Expectorants/*administration &amp; dosage/adverse effects/therapeutic use ; Humans ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {The role of N-acetylcysteine (NAC) in the treatment of chronic bronchitis is unclear. Since a number of studies have been published on this topic, a systematic review of published studies seems justified. A systematic search (Medline, Embase, Cochrane Library, bibliographies, no language restriction) for published randomized trials comparing oral NAC with placebo in patients with chronic bronchitis was performed. Dichotomous data on prevention of exacerbation, improvement of symptoms and adverse effects were extracted from original reports. The relative benefit and number-needed-to-treat were calculated for both individual trials and combined data. Thirty-nine trials were retrieved; eleven (2,011 analysed patients), published 1976-1994, were regarded as relevant and valid according to preset criteria. In nine studies, 351 of 723 (48.5%) patients receiving NAC had no exacerbation compared with 229 of 733 (31.2%) patients receiving placebo (relative benefit 1.56 (95% confidence interval (CI) 1.37-1.77), number-needed-to-treat 5.8 (95% CI 4.5-8.1). There was no evidence of any effect of study period (12-24 weeks) or cumulative dose of NAC on efficacy. In five trials, 286 of 466 (61.4%) patients receiving NAC reported improvement of their symptoms compared with 160 of 462 (34.6%) patients receiving placebo (relative benefit 1.78 (95% CI 1.54-2.05), number-needed-to-treat 3.7 (95% CI 3.0-4.9)). With NAC, 68 of 666 (10.2%) patients reported gastrointestinal adverse effects compared with 73 of 671 (10.9%) taking placebo. With NAC, 79 of 1,207 (6.5%) patients withdrew from the study due to adverse effects, compared with 87 of 1,234 (7.1%) receiving placebo. In conclusion, with treatment periods of approximately 12-24 weeks, oral N-acetylcysteine reduces the risk of exacerbations and improves symptoms in patients with chronic bronchitis compared with placebo, without increasing the risk of adverse effects. Whether this benefit is sufficient to justify the routine and long-term use of N-acetylcysteine in all patients with chronic bronchitis should be addressed in further studies and cost-effectiveness analyses.}, }
@article {pmid10965357, year = {2000}, author = {Lepri, E and Gambelunghe, C and Fioravanti, A and Pedini, M and Micheletti, A and Rufini, S}, title = {N-acetylcysteine increases apoptosis induced by H(2)O(2) and mo-antiFas triggering in a 3DO hybridoma cell line.}, journal = {Cell biochemistry and function}, volume = {18}, number = {3}, pages = {201-208}, doi = {10.1002/1099-0844(200009)18:3&lt;201::AID-CBF873&gt;3.0.CO;2-A}, pmid = {10965357}, issn = {0263-6484}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibodies, Monoclonal/metabolism ; Antioxidants/pharmacology ; *Apoptosis ; Chromatography, High Pressure Liquid ; Fas Ligand Protein ; Flow Cytometry ; Glutathione/metabolism ; Hybridomas/*pathology ; Hydrogen Peroxide/*pharmacology ; Immunoglobulin G/metabolism ; Indicators and Reagents/pharmacology ; Kinetics ; Membrane Glycoproteins/metabolism ; Mice ; Necrosis ; Neutrophils/metabolism ; Oxidation-Reduction ; Propidium/pharmacology ; Time Factors ; Tumor Cells, Cultured ; fas Receptor/metabolism ; }, abstract = {N-Acetylcysteine (NAC) has been used as an antioxidant to prevent apoptosis triggered by different stimuli in different cell types. It is common opinion that cellular redox, which is largely determined by the ratio of oxidized and reduced glutathione (GSH), plays a significant role in the propensity of cells to undergo apoptosis. However, there are also contrasting opinions stating that intracellular GSH depletion or supplemented GSH alone are not sufficient to lead cells to apoptosis or conversely protect them. Unexpectedly, this study shows that NAC, even if it maintains the peculiar characteristics of an agent capable of reducing cell proliferation and increasing intracellular GSH content, increases apoptosis induced by H(2)O(2) treatment and mo-antiFas triggering in a 3DO cell line. We found that 24 h of NAC pre-treatment can shift cellular death from necrotic to apoptotic and determine an early expression of FasL in a 3DO cell line treated with H(2)O(2).}, }
@article {pmid10964610, year = {2000}, author = {Brera, B and Serrano, A and de Ceballos, ML}, title = {beta-amyloid peptides are cytotoxic to astrocytes in culture: a role for oxidative stress.}, journal = {Neurobiology of disease}, volume = {7}, number = {4}, pages = {395-405}, doi = {10.1006/nbdi.2000.0313}, pmid = {10964610}, issn = {0969-9961}, mesh = {Alzheimer Disease/physiopathology ; Amyloid beta-Peptides/*toxicity ; Animals ; Astrocytes/*drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Oxidative Stress/*drug effects/physiology ; Peptide Fragments/*toxicity ; Rats ; }, abstract = {beta-Amyloid is cytotoxic to neurons in culture by increasing hydrogen peroxide and altering calcium homeostasis. We have evaluated the cytotoxicty of beta-amyloid peptides (betaA(25-35) and betaA(1-40)) and generation of hydrogen peroxide on cortical cultured astrocytes. Twenty-four hours after a single addition of either betaA(25-35) or betaA(1-40) there was a concentration-dependent decrease in viability. This toxicity never exceeded 50% of the population independently of exposure time and concentrations. The subpopulation of astrocytes resistant to betaA(25-35) effects were also insensitive to peroxide. Catalase or vitamin E showed no protective effect against betaA(25-35) toxicity. Dithiothreitol (DTT), N-acetylcysteine (NAC), and cyclosporine A significantly prevented the toxic effects of both betaA(25-35) and peroxide. Inhibition of peroxide detoxifying enzymes increased betaA(25-35) and peroxide toxicity. Exposure to betaA(25-35) or betaA(1-40) increased peroxide production at 2 and 24 h, which was prevented by DTT and NAC, but not vitamin E. Despite the inability of added catalase to reduce betaA toxicity, these results suggest that betaA-induced cytotoxicity to astrocytes in culture is, as in neurons, mediated by generation of hydrogen peroxide.}, }
@article {pmid10964049, year = {2000}, author = {Ho, TJ and Chiang, CP and Hong, CY and Kok, SH and Kuo, YS and Yen-Ping Kuo, M}, title = {Induction of the c-jun protooncogene expression by areca nut extract and arecoline on oral mucosal fibroblasts.}, journal = {Oral oncology}, volume = {36}, number = {5}, pages = {432-436}, doi = {10.1016/s1368-8375(00)00031-2}, pmid = {10964049}, issn = {1368-8375}, mesh = {Areca/*adverse effects ; Arecoline/*adverse effects ; Carcinoma, Squamous Cell/*chemically induced/genetics ; Fibroblasts/*drug effects ; Gene Expression/drug effects ; Humans ; Mouth Mucosa/drug effects ; Mouth Neoplasms/*chemically induced/epidemiology/genetics ; Mutagenicity Tests ; *Plants, Medicinal ; Proto-Oncogene Proteins c-jun/*drug effects ; Taiwan/epidemiology/ethnology ; }, abstract = {To investigate the mechanisms of areca quid (AQ)-induced carcinogenesis, expression of c-fos and c-jun protooncogenes was examined in human oral mucosal fibroblasts after exposure to areca nut extracts (ANE) or arecoline. We found that treatment of cells with 200 microg/ml ANE or 10 microg/ml arecoline for 1 h induced about three-fold increase in c-jun mRNA levels. This increase was transient and the level of c-jun mRNAs returned rapidly to control levels thereafter. However, ANE and arecoline did not induce c-fos mRNA expression at detectable levels. During AQ chewing, oral mucosal cells are continuously stimulated by ANE and arecoline. Persistent induction of the c-jun protooncogene by ANE and arecoline may be one of the mechanisms in the carcinogenesis of oral squamous cell carcinoma in Taiwan. Furthermore, we observed that pre-incubation of cells with either N-acetyl-cysteine [a glutathione (GSH) precursor] or L-buthionine-S,R-sulfoximine (a specific inhibitor of GSH biosynthesis) had a minimal effect on arecoline-induced c-jun expression. Therefore, arecoline-induced c-jun expression is independent of GSH depletion.}, }
@article {pmid10963726, year = {2000}, author = {Cuzzocrea, S and Mazzon, E and Costantino, G and Serraino, I and De Sarro, A and Caputi, AP}, title = {Effects of n-acetylcysteine in a rat model of ischemia and reperfusion injury.}, journal = {Cardiovascular research}, volume = {47}, number = {3}, pages = {537-548}, doi = {10.1016/s0008-6363(00)00018-3}, pmid = {10963726}, issn = {0008-6363}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Aorta ; Fluorescent Antibody Technique, Indirect ; Free Radical Scavengers/*therapeutic use ; Ileum/blood supply/metabolism/pathology ; In Vitro Techniques ; Intercellular Adhesion Molecule-1/metabolism ; Leukocyte Count/drug effects ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/metabolism ; Nitrates/analysis/metabolism ; Nitrites/analysis ; P-Selectin/metabolism ; Peroxidase/metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/metabolism/pathology/*prevention &amp; control ; Splenic Artery ; Tyrosine/analogs &amp; derivatives/metabolism ; Vasodilation/drug effects ; }, abstract = {OBJECTIVE: Splanchnic artery occlusion shock (SAO) causes an enhanced formation of reactive oxygen species (ROS), which contribute to the pathophysiology of shock. Here we have investigated the effects of n-acetylcysteine (NAC), a free radical scavenger, in rats subjected to SAO shock.<br><br>METHODS AND RESULTS: Treatment of rats with NAC (applied at 20 mg/kg, 5 min prior to reperfusion, followed by an infusion of 20 mg/kg/h) attenuated the mean arterial blood and the migration of polymorphonuclear cells (PMNs) caused by SAO-shock. NAC also attenuated the ileum injury (histology) as well as the increase in the tissue levels of myeloperoxidase (MPO) and malondialdehyde (MDA) caused by SAO shock in the ileum. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine in the plasma of the SAO-shocked rats after reperfusion. Immunohistochemical analysis for nitrotyrosine and for poly(ADP-ribose) synthetase (PARS) revealed a positive staining in ileum from SAO-shocked rats. The degree of staining for nitrotyrosine and PARS were markedly reduced in tissue sections obtained from SAO-shocked rats which had received NAC. Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin, which was mainly localised in the vascular endothelial cells. Ileum tissue section obtained from SAO-shocked rats with anti-intercellular adhesion molecule (ICAM-1) antibody showed a diffuse staining. NAC treatment markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue section from SAO-shocked rats. In addition, in ex vivo studies in aortic rings from shocked rats, we found reduced contractions to noradrenaline and reduced responsiveness to a relaxant effect to acetylcholine (vascular hyporeactivity and endothelial dysfunction, respectively). NAC treatment improved contractile responsiveness to noradrenaline, enhanced the endothelium-dependent relaxations and significantly improved survival.<br><br>CONCLUSION: Taken together, our results clearly demonstrate that NAC treatment exert a protective effect and part of this effect may be due to inhibition of the expression of adhesion molecule and peroxynitrite-related pathways and subsequent reduction of neutrophil-mediated cellular injury.}, }
@article {pmid10954324, year = {2000}, author = {Saxena, NC}, title = {Inhibition of GABA(A) receptor (GABAR) currents by arachidonic acid in HEK 293 cells stably transfected with alpha1beta2gamma2 GABAR subunits.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {440}, number = {3}, pages = {380-392}, doi = {10.1007/s004240000289}, pmid = {10954324}, issn = {0031-6768}, support = {T32 DK07656/DK/NIDDK NIH HHS/United States ; }, mesh = {5,8,11,14-Eicosatetraynoic Acid/pharmacology ; Anticonvulsants/pharmacology ; Arachidonic Acid/*pharmacology ; Binding, Competitive ; Cells, Cultured ; Cyclooxygenase Inhibitors/pharmacology ; Diazepam/pharmacology ; Dose-Response Relationship, Drug ; Fatty Acids/pharmacology ; Fatty Acids, Monounsaturated/pharmacology ; GABA Antagonists/pharmacology ; GABA Modulators/pharmacology ; GABA-A Receptor Antagonists ; Humans ; Indomethacin/pharmacology ; Kidney/cytology ; Linoleic Acid/pharmacology ; Masoprocol/pharmacology ; Membrane Potentials/drug effects/physiology ; Patch-Clamp Techniques ; Pentobarbital/pharmacology ; Picrotoxin/pharmacology ; *Receptors, GABA-A/genetics/metabolism ; Recombinant Proteins/genetics ; Transfection ; Triazoles/pharmacology ; gamma-Aminobutyric Acid/pharmacology ; }, abstract = {Agonist-stimulated liberation of arachidonic acid and subsequent generation of active metabolites are established components of several signal transduction pathways including pathways that regulate ion channels. We evaluated the role of arachidonic acid and some related unsaturated and saturated fatty acids in the modulation of a stably expressed recombinant gamma-aminobutyric acidA receptor (GABAR) isoform, the alpha1beta2gamma2 isoform. Whole-cell currents evoked by 10 microM GABA were inhibited in a concentration-dependent manner by arachidonic acid (0.1-100 microM). This effect of arachidonic acid to inhibit GABAR currents was not reproduced by the non-metabolizable analog of arachidonic acid, 5,8,11,14-eicosatetraynoic acid (ETYA) or by other monounsaturated or saturated fatty acids. However, another polyunsaturated fatty acid, linoleic acid, which is an essential fatty acid and an effective reductant like arachidonic acid, inhibited GABAR currents in a manner similar to arachidonic acid. Nordihydroguaiaretic acid (NDGA), indomethacin and 1-amonibenzotriazole (1-ABT) did not block the inhibitory effect of arachidonic acid, suggesting that arachidonic acid metabolites of the lipoxygenase, cyclooxygenase or P-450 pathways are unlikely to play a major role in the inhibitory effect of arachidonic acid on GABAR currents. However, the antioxidant N-acetyl cysteine (NAC), a scavenger of active oxygen radicals, reduced the inhibitory effect of arachidonic acid on GABAR currents significantly (P<0.01), suggesting that active oxygen radicals might mediate inhibition of GABAR currents by arachidonic acid.}, }
@article {pmid10953313, year = {2000}, author = {Jiang, Y and Satoh, K and Kusama, K and Watanabe, S and Sakagami, H}, title = {Interaction between chlorogenic acid and antioxidants.}, journal = {Anticancer research}, volume = {20}, number = {4}, pages = {2473-2476}, pmid = {10953313}, issn = {0250-7005}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Chlorogenic Acid/*pharmacology ; Dose-Response Relationship, Drug ; Electron Spin Resonance Spectroscopy ; Free Radicals ; Humans ; }, abstract = {The interaction between chlorogenic acid (CGA) and antioxidants was investigated by two different parameters: radical intensity and cytotoxicity induction. ESR spectroscopy shows that CGA produced radicals under alkaline condition. The CGA radical was scavenged by 100-300-fold lower concentrations of sodium ascorbate or N-acetyl-l-cysteine (NAC), whereas the ascorbate radical was not completely scavenged by CGA. The cytotoxic activity of CGA against human oral tumor cells (HSC-2, HSG) was completely eliminated by lower concentrations of sodium ascorbate or NAC, whereas that of sodium ascorbate or NAC was only slightly reduced by CGA. The present study demonstrated that CGA induces cytotoxicity by its radical-mediated oxidation mechanism and suggests the applicability of ESR spectroscopy for the screening of drug to drug interaction.}, }
@article {pmid10951279, year = {2000}, author = {Wong, JW and Shi, B and Farboud, B and McClaren, M and Shibamoto, T and Cross, CE and Isseroff, RR}, title = {Ultraviolet B-mediated phosphorylation of the small heat shock protein HSP27 in human keratinocytes.}, journal = {The Journal of investigative dermatology}, volume = {115}, number = {3}, pages = {427-434}, doi = {10.1046/j.1523-1747.2000.00077.x}, pmid = {10951279}, issn = {0022-202X}, support = {ESO4699/ES/NIEHS NIH HHS/United States ; ESO7133/ES/NIEHS NIH HHS/United States ; HL47628/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cell Survival/radiation effects ; Cells, Cultured ; ErbB Receptors/physiology ; Free Radical Scavengers/pharmacology ; Heat-Shock Proteins/*metabolism ; Humans ; Keratinocytes/*chemistry/*cytology/metabolism ; Mitogen-Activated Protein Kinases/pharmacology ; Phosphorylation/drug effects/radiation effects ; Protein Isoforms/antagonists &amp; inhibitors/metabolism ; Protein Kinase C ; Subcellular Fractions/chemistry ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Exposure of human keratinocytes to environmental stress is known to induce changes in the expression, phosphorylation, and subcellular relocalization of the 27 kDa heat shock protein. This study demonstrates that ultraviolet B (280-320 nM) irradiation with physiologic doses induces a dose-dependent phosphorylation of 27 kDa heat shock protein, generating the more acidic 27 kDa heat shock protein B, C, and D isoforms. Ultraviolet B also induces perinuclear cytoplasmic relocation and nuclear translocation of 27 kDa heat shock protein and caused aggregation of cytoplasmic actin filaments into a broad perinuclear distribution. The ultraviolet B-induced phosphorylation is reversible, returning to baseline levels 4 h after exposure, and this coincides with the reversal of ultraviolet B-induced actin reorganization. The ultraviolet B-induced phosphorylation is not affected by the protein kinase C inhibitor, GF 109203X, is partially inhibited by epidermal growth factor receptor tyrosine kinase inhibitor, PD 153035, and is substantially inhibited by the specific p38 mitogen-activated protein kinase inhibitor, SB 203580. In addition, pretreatment of cells with the anti-oxidant N-acetyl cysteine partially inhibits ultraviolet B-and oxidant-induced 27 kDa heat shock protein phosphorylation. The p38 mitogen-activated protein kinase cascade is thus the major transduction pathway for ultraviolet B-induced 27 kDa heat shock protein phosphorylation, and reactive oxygen species generated in response to ultraviolet B also contribute to this phosphorylation. As 27 kDa heat shock protein phosphorylation and relocalization has been associated with increased cell survival after environmental insult, our data suggest that ultraviolet B, in addition to initiating recognized cytotoxic events in keratinocytes, also initiates a signaling pathway that may provide cellular protection against this ubiquitous environmental insult.}, }
@article {pmid10943709, year = {2000}, author = {Andreassen, OA and Dedeoglu, A and Klivenyi, P and Beal, MF and Bush, AI}, title = {N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis.}, journal = {Neuroreport}, volume = {11}, number = {11}, pages = {2491-2493}, doi = {10.1097/00001756-200008030-00029}, pmid = {10943709}, issn = {0959-4965}, mesh = {Acetylcysteine/*pharmacology ; Age Factors ; Amyotrophic Lateral Sclerosis/*drug therapy/genetics/physiopathology/prevention &amp; control ; Animals ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Motor Activity/*drug effects/physiology ; Mutation/physiology ; Superoxide Dismutase/genetics ; Survival Rate ; }, abstract = {Increasing evidence implicates oxidative damage as a major mechanism in the pathogenesis of amyotrophic lateral sclerosis (ALS). We examined the effect of preventative treatment with N-acetyl-L-cysteine (NAC), an agent that reduces free radical damage, in transgenic mice with a superoxide dismutase (SODI) mutation (G93A), used as an animal model of familial ALS. NAC was administered at 1% concentration in the drinking water from 4-5 weeks of age. The treatment caused a significantly prolonged survival and delayed onset of motor impairment in G93A mice treated with NAC compared to control mice. These results provide further evidence for the involvement of free radical damage in the G93A mice, and support the possibility that NAC, an over-the-counter antioxidant, could be explored in clinical trials for ALS.}, }
@article {pmid10942197, year = {2000}, author = {Lu, TH and Shan, Y and Pepe, J and Lambrecht, RW and Bonkovsky, HL}, title = {Upstream regulatory elements in chick heme oxygenase-1 promoter: a study in primary cultures of chick embryo liver cells.}, journal = {Molecular and cellular biochemistry}, volume = {209}, number = {1-2}, pages = {17-27}, pmid = {10942197}, issn = {0300-8177}, support = {DK38825/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Arsenites/pharmacology ; Base Sequence ; Binding Sites ; Cells, Cultured ; Chick Embryo ; Chickens ; Chloramphenicol O-Acetyltransferase/genetics ; Cobalt/pharmacology ; Consensus Sequence ; Enzyme Induction/drug effects ; Gene Expression Regulation, Enzymologic/drug effects ; Heme Oxygenase (Decyclizing)/biosynthesis/*genetics ; Heme Oxygenase-1 ; Liver/cytology/*enzymology ; Mammals ; Mutagenesis, Site-Directed ; *Promoter Regions, Genetic ; Recombinant Fusion Proteins/biosynthesis ; *Regulatory Sequences, Nucleic Acid ; Sodium Compounds/pharmacology ; Transfection ; beta-Galactosidase/genetics ; }, abstract = {Previously, chick heme oxygenase-1 (cHO-1) gene was cloned by us and two regions important for induction by sodium arsenite were identified. These two regions were found to contain consensus sequences of an AP-1 (-1580 to -1573) and a MRE/cMyc complex (-52 to -41). In the current study, the roles of these two elements in mediating the sodium arsenite or cobalt chloride dependent induction of cHO-1 were investigated further. DNA binding studies and site-directed mutagenesis studies indicated that both the AP-1 and MRE/cMyc elements are important for the sodium arsenite induction, while cobalt chloride induction involves only the AP-1 element. Electrophoretic mobility shift assays showed that nuclear protein binding to the AP-1 element was increased by both sodium arsenite or cobalt chloride treatment, whereas the binding of proteins to the MRE/cMyc element showed a high basal expression in untreated cells and the binding activity was only slightly increased by sodium arsenite treatment. Site-directed mutagenesis studies showed that, to completely abolish sodium arsenite induction, both the AP-1 and MRE/cMyc elements must be mutated; mutation of either element alone resulted in only a partial effect. In contrast, a single mutation at AP-1 element was sufficient to reduce the cobalt chloride induction almost completely. The MRE/cMyc complex plays a major role in the basal level expression, and shares some similarities to the upstream stimulatory factor element (USF) identified in the promoter regions of mammalian HO-1 genes and other stress regulated genes. Because sodium arsenite is known to cause oxidative stress and because activation of AP-1 proteins has been shown to be a key step in the oxidative stress response pathway, we also explored the possibility that the induction of the cHO-1 gene by sodium arsenite is mediated through oxidative stress pathway(s) by activation of AP-1 proteins. We found that pretreatment with antioxidants (N-acetyl cysteine or quercetin) reduced the induction of the endogenous cHO-1 message or cHO-1 reporter construct activities induced by sodium arsenite or cobalt chloride. These antioxidants also reduced the protein binding activities to the AP-1 element in the electrophoretic mobility shift assays. In summary, induction of the cHO-1 gene by sodium arsenite or cobalt chloride is mediated by activation of the AP-1 element located at -1,573 to -1,580 of the 5'UTR.}, }
@article {pmid10941151, year = {2000}, author = {Chen, SH and Liu, SH and Liang, YC and Lin, JK and Lin-Shiau, SY}, title = {Death signaling pathway induced by pyrrolidine dithiocarbamate-Cu(2+) complex in the cultured rat cortical astrocytes.}, journal = {Glia}, volume = {31}, number = {3}, pages = {249-261}, doi = {10.1002/1098-1136(200009)31:3&lt;249::aid-glia60&gt;3.0.co;2-l}, pmid = {10941151}, issn = {0894-1491}, mesh = {Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Astrocytes/cytology/*drug effects/metabolism ; Caspase 3 ; Caspases/drug effects/metabolism ; Cell Nucleus/drug effects/metabolism ; Cell Size/drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Copper/metabolism/*pharmacology ; Diploidy ; Drug Combinations ; Drug Interactions/*physiology ; Hydrogen Peroxide/metabolism ; Intracellular Fluid/drug effects/metabolism ; Intracellular Membranes/drug effects/metabolism ; Mitochondria/drug effects/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinases/drug effects/metabolism ; Oxidative Stress/drug effects/physiology ; Poly(ADP-ribose) Polymerases/drug effects/metabolism ; Pyrrolidines/*pharmacology ; Rats ; Rats, Wistar ; Signal Transduction/*drug effects/physiology ; Thiocarbamates/*pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {The chelating and antioxidant effects of pyrrolidine dithiocarbamate (PDTC) have been investigated extensively for preventing cell death induced by different insults. However, the toxic effects of PDTC have been studied only recently and fewer studies on the toxic effects on astrocytes have been reported. In our study, we demonstrated that both PDTC and Cu(2+) alone were rated as only weakly toxic in inducing cell death in cortical astrocytes with IC(50) of 300 microM and 180 microM, respectively. However, PDTC and Cu(2+) in the complex form markedly potentiated with each other by about 1,000-fold with IC(50) of 0.3 microM PDTC plus 10 microM Cu(2+). Other metals at concentrations of 3-10 microM (VO(4)(5+), Cr(6+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Zn(2+), Pb(2+), Bi(2+), Ba(2+), UO(2+), Cs(+), SeO(4)(2-), La(3+)) had no such potentiating effects on PDTC. Changes in morphology (nuclear condensation), apoptotic body formation, and hypodiploidity of DNA suggested that the PDTC-Cu(2+) complex induced cell death through an apoptotic process. Further studies showed that the PDTC-Cu(2+) complex decreased mitochondrial membrane potential, increased hydrogen peroxide production, and depleted GSH contents. After the increased oxidative stress, PDTC-Cu(2+) complex differentially activated JNKs, ERK, p38 and caspase 3, which caused PARP degradation in a time-dependent manner. All these effects were consistent with the increased cellular Cu contents. The nonpermeable copper-specific chelator bathocuproine disulfonate (BCPS), but not the permeable Cu(2+) chelator neocuproine, abolished all the observed effects. Antioxidants (N-acetylcysteine [NAC], vitamin C), catalase, and Cu(2+)-binding proteins (albumin, hemoglobin, and higher serum) reduced the cytotoxic effects of PDTC-Cu(2+) complex. We concluded that the death signaling pathway of PDTC-Cu(2+) complex was mediated by oxidative stress and subsequent JNK activation. These findings imply that PDTC, a widely used pesticide and medicine that is capable of penetrating the blood-brain barrier, may cause neurotoxicity through astrocyte dysfunction.}, }
@article {pmid10936175, year = {2000}, author = {Park, SA and Choi, KS and Bang, JH and Huh, K and Kim, SU}, title = {Cisplatin-induced apoptotic cell death in mouse hybrid neurons is blocked by antioxidants through suppression of cisplatin-mediated accumulation of p53 but not of Fas/Fas ligand.}, journal = {Journal of neurochemistry}, volume = {75}, number = {3}, pages = {946-953}, doi = {10.1046/j.1471-4159.2000.0750946.x}, pmid = {10936175}, issn = {0022-3042}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Nucleus/drug effects ; Cell Survival/drug effects ; Chromans/pharmacology ; Cisplatin/antagonists &amp; inhibitors/*toxicity ; DNA Fragmentation ; Fas Ligand Protein ; Ganglia, Spinal ; Hybrid Cells/cytology/*drug effects/physiology ; Kinetics ; Membrane Glycoproteins/metabolism ; Mice ; Neuroblastoma ; Neurons, Afferent/cytology/*drug effects/physiology ; Tumor Suppressor Protein p53/*metabolism ; fas Receptor/*metabolism ; }, abstract = {Peripheral neuropathy following cisplatin treatment is a major limiting factor in cisplatin chemotherapy of cancer patients. We investigated the pathomechanism underlying cisplatin neuropathy using a mouse dorsal root ganglion neuron-neuroblastoma hybrid cell line (N18D3) developed in our laboratory. DNA fragmentation, a characteristic feature of apoptosis, was induced in hybrid neurons following treatment with cisplatin. Accumulation of p53, Fas, and Fas ligand (Fas-L) was also demonstrated in these neurons. Preincubation with N-acetylcysteine (NAC), a precursor of glutathione, blocked cisplatin-induced apoptosis completely, whereas Trolox, a vitamin E analogue, blocked it partially. Cisplatin-induced p53 accumulation was suppressed by NAC treatment, whereas p53 accumulation was retarded by Trolox treatment. In contrast, neither NAC nor Trolox showed any inhibitory effect on cisplatin-induced Fas/Fas-L accumulation. These results suggest that the neuroprotective effects of antioxidants against cisplatin-induced neurotoxicity in hybrid neurons are mediated mainly through the inhibition of p53 accumulation but not of Fas/Fas-L accumulation by these antioxidants.}, }
@article {pmid10935502, year = {1999}, author = {Nargi, JL and Ratan, RR and Griffin, DE}, title = {p53-independent inhibition of proliferation and p21(WAF1/Cip1)-modulated induction of cell death by the antioxidants N-acetylcysteine and vitamin E.}, journal = {Neoplasia (New York, N.Y.)}, volume = {1}, number = {6}, pages = {544-556}, pmid = {10935502}, issn = {1522-8002}, support = {R01 NS018596/NS/NINDS NIH HHS/United States ; T32 ES007141/ES/NIEHS NIH HHS/United States ; R01-NS18596/NS/NINDS NIH HHS/United States ; T32-ES07141/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Division/drug effects ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/*physiology ; Humans ; Phosphorylation ; Reactive Oxygen Species/metabolism ; Retinoblastoma Protein/metabolism ; Tumor Suppressor Protein p53/*physiology ; Vitamin E/*pharmacology ; }, abstract = {Epidemiological evidence has suggested an association between diets rich in antioxidants and diminished risks of various types of cancer. Proposed mechanisms for protective effects of antioxidants have involved inhibition of free radical-mediated DNA damage. Recent data suggest that antioxidants may prevent or eliminate cancerous cells through their ability to inhibit proliferation or to induce programmed cell death (PCD). To begin to identify cell cycle and cell death regulatory factors involved in antioxidant-induced growth arrest and PCD, we have studied colorectal carcinoma cells (CRCs) that differ in expression of the tumor suppressor protein p53, and of the cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1). The antioxidants, N-acetylcysteine (NAC) and vitamin E either inhibited proliferation in a p53-independent manner without affecting cell viability or induced cell death. Growth arrest was not associated with upregulation of the CDK inhibitors p21(Waf1/Cip1), p18(ink4c) or p16(ink4a), but was associated with a decrease in reactive oxygen species (ROS). In contrast to previous observations, the absence of p21(Waf1/Cip1) increased susceptibility of CRCs to antioxidant-induced PCD. NAC decreased levels of retinoblastoma protein (Rb) phosphorylation in all cells tested, but Rb was cleaved only in cells which underwent NAC-induced death. Although NAC decreased ROS in all cells studied, cell lines in which PCD occurred had higher baseline levels of ROS than cell lines in which proliferation was blocked. These observations suggest that expression of p21(Waf1/Cip1) and basal levels of ROS are important determinants of outcome after antioxidant treatment.}, }
@article {pmid10933875, year = {2000}, author = {Shan, Y and Pepe, J and Lu, TH and Elbirt, KK and Lambrecht, RW and Bonkovsky, HL}, title = {Induction of the heme oxygenase-1 gene by metalloporphyrins.}, journal = {Archives of biochemistry and biophysics}, volume = {380}, number = {2}, pages = {219-227}, doi = {10.1006/abbi.2000.1921}, pmid = {10933875}, issn = {0003-9861}, support = {DK38825/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Cell Line ; Cells, Cultured ; Chick Embryo ; DNA Primers/genetics ; Enhancer Elements, Genetic ; Gene Expression/drug effects ; Genes, Reporter ; Heme/pharmacology ; Heme Oxygenase (Decyclizing)/*genetics ; Heme Oxygenase-1 ; Luciferases/genetics ; Metalloporphyrins/*pharmacology ; Mutagenesis, Site-Directed ; Promoter Regions, Genetic ; Protoporphyrins/pharmacology ; Transfection ; }, abstract = {Induction of expression of heme oxygenase-1 (HO-1) has been studied in primary cultures of chick embryo liver cells and in the LMH line of avian hepatoma cells. Cells were transiently transfected with selected constructs containing portions of the 5'-untranslated (promoter) region of the HO-1 gene linked to luciferase as reporter gene. LMH cells that had been stably transfected with selected wild type or mutant constructs were also studied. Metalloporphyrins, especially Fe protoporphyrin (heme) and Co protoporphyrin strongly induced luciferase expression in both types of transfected cells. Low concentrations of Zn mesoporphyrin, an inhibitor of HO activity, exerted a synergistic effect on heme-, but not Co protoporphyrin-dependent induction. The antioxidant and &amp;bond;SH donor N-acetyl cysteine had little effect on the metalloporphyrin-dependent inductions of HO-1, in contrast to its marked inhibitory effect on the sodium arsenite-dependent induction of the HO-1 gene. Deletional analysis showed that the key element(s) required for the metalloporphyrin-dependent induction of HO-1 is located between -3.6 and -5.6 kb upstream of the transcription starting point. Data from electrophoretic mobility shift and site-directed mutagenesis experiments excluded a role for consensus AP-1 binding elements at -1576, -3647, or -4578 in the inductions produced by heme or Co protoporphyrin.}, }
@article {pmid10930529, year = {2000}, author = {Dvorakova, K and Payne, CM and Tome, ME and Briehl, MM and McClure, T and Dorr, RT}, title = {Induction of oxidative stress and apoptosis in myeloma cells by the aziridine-containing agent imexon.}, journal = {Biochemical pharmacology}, volume = {60}, number = {6}, pages = {749-758}, doi = {10.1016/s0006-2952(00)00380-4}, pmid = {10930529}, issn = {0006-2952}, mesh = {Alkylation ; Antineoplastic Agents/*pharmacology ; *Apoptosis ; Cysteine/metabolism ; DNA/drug effects/metabolism ; Gene Expression/drug effects ; Glutathione/metabolism ; Hexanones/*pharmacology ; Humans ; Inhibitory Concentration 50 ; Multiple Myeloma/*drug therapy/pathology ; Oxidative Stress/*drug effects ; Proto-Oncogene Proteins c-bcl-2/biosynthesis/genetics ; Sulfhydryl Compounds/metabolism ; Thymoma/pathology ; Tumor Cells, Cultured ; }, abstract = {Imexon is an iminopyrrolidone derivative that has selective antitumor activity in multiple myeloma. The exact mechanism of imexon action is unknown. In human 8226 myeloma cells, the cytotoxicity of imexon was schedule-dependent, and long exposures (> or = 48 hr) to low concentrations of imexon were most effective at inducing cytotoxicity. Our data suggest that imexon does not affect DNA, but it can alkylate thiols by binding to the sulfhydryl group. We have also demonstrated by HPLC studies that in human 8226 myeloma cells, imexon depletes cellular stores of cysteine and glutathione. Oxidative stress in 8226 cells exposed to imexon was detected by immunohistochemical staining with a monoclonal antibody to 8-hydroxydeoxyguanosine (8-OHdG), followed by confocal microscopy. These images showed increased levels of 8-OHdG in the cytoplasm of cells treated with different concentrations of imexon at 8, 16, and 48 hr. Interestingly, 8-OHdG staining was not observed in the nuclei of imexon-treated cells, in contrast to the diffuse staining seen with t-butyl hydroperoxide. Myeloma cells exposed to imexon showed classic morphologic features of apoptosis upon electron microscopy, and increased levels of phosphatidylserine exposure, detected as Annexin-V binding, on the cell surface. To prevent depletion of thiols, 8226 myeloma cells exposed to imexon were treated with N-acetylcysteine (NAC). Simultaneous, as well as sequential, treatment with NAC before imexon exposure resulted in protection of myeloma cells against imexon-induced cytotoxicity. Conversely, the glutathione synthesis inhibitor buthionine sulfoximine increased imexon cytotoxicity. These data suggest that imexon perturbs cellular thiols and induces oxidative stress leading to apoptosis in human myeloma cells.}, }
@article {pmid10930308, year = {2000}, author = {Desaki, M and Takizawa, H and Kasama, T and Kobayashi, K and Morita, Y and Yamamoto, K}, title = {Nuclear factor-kappa b activation in silica-induced interleukin 8 production by human bronchial epithelial cells.}, journal = {Cytokine}, volume = {12}, number = {8}, pages = {1257-1260}, doi = {10.1006/cyto.2000.0704}, pmid = {10930308}, issn = {1043-4666}, mesh = {Analysis of Variance ; Antioxidants/pharmacology ; Bronchi/*drug effects/metabolism ; Chemotaxis/drug effects ; Electrophoresis ; Epithelial Cells/drug effects/metabolism ; Gene Expression/drug effects ; Humans ; Interleukin-8/*biosynthesis/genetics ; NF-kappa B/*metabolism ; Neutrophils/drug effects/physiology ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/metabolism ; Silicon Dioxide/*pharmacology ; }, abstract = {Recent studies indicate that interleukin 8 (IL-8) plays an important role in interstitial lung diseases including silica-induced lung inflammation. To investigate the regulation of IL-8 expression and production in human bronchial epithelial cells, we examined the effects of silica on NF-kappaB activation. Human bronchial epithelial cell line BET-1A was cultured with hormonally defined Ham's F12 medium. The administration of silica induced IL-8 production in BET-1A dose-dependently and time-dependently. Northern blot analysis demonstrated that silica upregulated IL-8 expression in BET-1A. Moreover, electrophoretic mobility shift assays revealed that NF-kappaB activation occurred in the presence of silica, which was inhibited by antioxidants such as N-acetylcysteine (NAC). These data suggest that reactive oxygen species may be involved in the activation of NF-kappaB induced by silica.}, }
@article {pmid10928950, year = {2000}, author = {Jordán, J and Galindo, MF and Calvo, S and González-García, C and Ceña, V}, title = {Veratridine induces apoptotic death in bovine chromaffin cells through superoxide production.}, journal = {British journal of pharmacology}, volume = {130}, number = {7}, pages = {1496-1504}, pmid = {10928950}, issn = {0007-1188}, mesh = {Animals ; *Apoptosis ; Calcium/metabolism ; Caspases/metabolism ; Cattle ; Cell Survival/drug effects ; Chromaffin Cells/cytology/*drug effects/enzymology/metabolism ; DNA Damage/drug effects ; Enzyme Activation ; In Vitro Techniques ; Neurons/drug effects/metabolism ; Superoxides/*metabolism ; Veratridine/*pharmacology ; }, abstract = {The molecular mechanisms involved in veratridine-induced chromaffin cell death have been explored. We have found that exposure to veratridine (30 microM, 1 h) produces a delayed cellular death that reaches 55% of the cells 24 h after veratridine exposure. This death has the features of apoptosis as DNA fragmentation can be observed. Calcium ions play an important role in veratridine-induced chromaffin cell death because the cell permeant Ca(2+) chelator BAPTA-AM and extracellular Ca(2+) removal completely prevented veratridine-induced toxicity. Following veratridine treatment, there is a decrease in mitochondrial function and an increase in superoxide anion production. Veratridine-induced increase in superoxide production was blocked by tetrodotoxin (TTX; 10 microM), extracellular Ca(2+) removal and the mitochondrial permeability transition pore blocker cyclosporine A (10 microM). Veratridine-induced death was prevented by different antioxidant treatments including catalase (100 IU ml(-1)), N-acetyl cysteine (100 microM), allopurinol (100 microM) or vitamin E (50 microM). Veratridine-induced DNA fragmentation was prevented by TTX (10 microM). Veratridine produced a time-dependent increase in caspase activity that was prevented by Ca(2+) removal and TTX (10 microM). In addition, calpain and caspases inhibitors partially prevented veratridine-induced death. These results indicate that chromaffin cells share with neurons the molecular machinery involved in apoptotic death and might be considered a good model to study neuronal death during neurodegeneration.}, }
@article {pmid10925209, year = {2000}, author = {Koren, R and Rocker, D and Kotestiano, O and Liberman, UA and Ravid, A}, title = {Synergistic anticancer activity of 1,25-dihydroxyvitamin D(3) and immune cytokines: the involvement of reactive oxygen species.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {73}, number = {3-4}, pages = {105-112}, doi = {10.1016/s0960-0760(00)00068-6}, pmid = {10925209}, issn = {0960-0760}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/*pharmacology ; Calcitriol/*pharmacology ; Cell Division/drug effects ; Drug Synergism ; Glutathione/pharmacology ; Humans ; Interleukin-1/*pharmacology ; Interleukin-6/*pharmacology ; Reactive Oxygen Species/*metabolism ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {It was previously shown that 1,25-dihydroxyvitamin D(3) (1, 25(OH)(2)D(3)) enhances the cytotoxic activity of tumor necrosis factor alpha (TNFalpha), doxorubicin and menadione. A feature shared by these anticancer agents is the involvement of reactive oxygen species (ROS) in their action. In this work we found that 1, 25(OH)(2)D(3) acted synergistically with interleukin 1 beta (IL-1beta) or interleukin 6 (IL-6) to inhibit the proliferation of MCF-7 breast cancer cells. The extent of the synergism was maximal at 1 nM, a concentration at which 1,25(OH)(2)D(3), acting singly, only marginally reduced the cell number. The thiol antioxidant, N-acetylcysteine (NAC) abolished the synergism between IL-1beta or IL-6 and 1,25(OH)(2)D(3), but had only a small protective effect when the cytokines acted alone. NAC and reduced glutathione (GSH) protected MCF-7 cells from cytotoxicity induced both by TNFalpha alone and by TNFalpha and 1,25(OH)(2)D(3). A two-day exposure to TNFalpha caused a 27.7+/-3.1% (mean +/- SEM) reduction in GSH content. This effect increased to 46.4+/-5.5% by co-treatment with 1, 25(OH)(2)D(3) which did not affect GSH levels on it own. We conclude that 1,25(OH)(2)D(3) can act synergistically with anticancer cytokines present in the tumor milieu and that ROS plays a mediatory role in this interaction.}, }
@article {pmid10924012, year = {2000}, author = {Guidot, DM and Brown, LA}, title = {Mitochondrial glutathione replacement restores surfactant synthesis and secretion in alveolar epithelial cells of ethanol-fed rats.}, journal = {Alcoholism, clinical and experimental research}, volume = {24}, number = {7}, pages = {1070-1076}, pmid = {10924012}, issn = {0145-6008}, support = {R01- AA11660-01A2/AA/NIAAA NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Central Nervous System Depressants/*pharmacology ; Epithelial Cells/*drug effects/metabolism ; Ethanol/*pharmacology ; Glutathione/*drug effects/metabolism ; Male ; Mitochondria/*drug effects/metabolism ; Pulmonary Alveoli/drug effects/metabolism ; Pulmonary Surfactants/biosynthesis/*drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Chronic alcohol abuse increases the incidence and severity of acute lung injury in critically ill patients. Previously we determined that ethanol ingestion in rats dramatically decreased alveolar epithelial cellular levels of glutathione and surfactant synthesis and secretion in vitro. Previous studies in alcoholic liver disease suggest that mitochondrial glutathione levels, and not cellular levels per se, are involved in the pathogenesis of ethanol-mediated hepatotoxicity. Therefore, we hypothesized that alveolar epithelial mitochondrial glutathione depletion mediates the observed defects in surfactant synthesis and secretion in ethanol-fed rats.<br><br>METHODS: Male Sprague-Dawley rats were fed the Lieber-DeCarli liquid diet with or without ethanol (36% of total calories) for 6 weeks. In some experiments, ethanol-fed rats were then switched to the control diet for 1 week, with or without glutathione supplementation with either N-acetylcysteine (NAC) or procysteine (PRO). Alveolar epithelial type II cells were then isolated and glutathione levels (cytosolic and mitochondrial) and surfactant production (synthesis and secretion) were determined.<br><br>RESULTS: Ethanol ingestion decreased (p < 0.05) mitochondrial and cytosolic levels of glutathione, and surfactant synthesis and secretion in isolated type II cells when compared to cells from control-fed rats. NAC treatment restored (p < 0.05) cytosolic but not mitochondrial glutathione levels (p > 0.05), and had no effect (p > 0.05) on surfactant synthesis and secretion in type II cells isolated from ethanol-fed rats. In contrast, PRO treatment restored (p < 0.05) cytosolic and mitochondrial glutathione levels, and normalized (p < 0.05) surfactant synthesis and secretion in type II cells isolated from ethanol-fed rats.<br><br>CONCLUSIONS: These results suggest that mitochondrial, and not simply cytosolic, replacement of glutathione is necessary to improve surfactant function in critically ill patients with a history of alcohol abuse.}, }
@article {pmid10923013, year = {2000}, author = {Fan, J and Shek, PN and Suntres, ZE and Li, YH and Oreopoulos, GD and Rotstein, OD}, title = {Liposomal antioxidants provide prolonged protection against acute respiratory distress syndrome.}, journal = {Surgery}, volume = {128}, number = {2}, pages = {332-338}, doi = {10.1067/msy.2000.108060}, pmid = {10923013}, issn = {0039-6060}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; *Chemokines, CXC ; Chemotactic Factors/genetics ; Drug Carriers ; Gene Expression Regulation/drug effects ; Growth Substances/genetics ; Hemorrhage/physiopathology ; Injections, Intravenous ; *Intercellular Signaling Peptides and Proteins ; Lipopolysaccharides/toxicity ; Liposomes ; Lung/drug effects/pathology/*physiopathology ; Male ; Neutrophils/drug effects/*physiology ; Peroxidase/analysis ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome/etiology/*physiopathology/*prevention &amp; control ; Resuscitation ; }, abstract = {BACKGROUND: We have previously shown that N-acetylcysteine (NAC), an antioxidant, in the resuscitation fluid after shock prevents lung injury in response to lipopolysaccharide (LPS) by inhibiting chemokine generation by alveolar macrophages in the lung. However, the protection was short-lived. We hypothesized that liposomal (Lip) NAC delivered intratracheally might be delivered directly to the target cells and exert prolonged effect.<br><br>METHODS: Sprague-Dawley rats were bled to a blood pressure of 40 mm Hg for 1 hour and resuscitated with shed blood and equal volume of Ringer's lactate. In some studies 500 mg/kg NAC was included in the resuscitation fluid. Thirty minutes later, 150 microl LipNAC (9.4 mg/kg NAC) was given intratracheally. One hour and 18 hours after resuscitation, LPS (30 microg/kg) or saline was given intratracheally. Lung injury was assessed by permeability to (125)I-albumin, bronchoalveolar lavage neutrophils and lung myeloperoxidase. The cytokine-induced neutrophil chemoattractant (CINC) expression in the lung was assessed by Northern blot.<br><br>RESULTS: At the early time point, both NAC and LipNAC protected the lung with the effects in significantly reducing the increases in transpulmonary albumin flux, neutrophil influx and myeloperoxidase in the lungs of shock/LPS rats. However, by the late time point, only LipNAC retained its salutary effect. This correlated well with persistent ability to prevent CINC increase. In addition, Lipalpha-tocopherol (alpha-T) and LipNAC/alpha-T were tested and determined to be effective to protect the lung.<br><br>CONCLUSIONS: Liposomal encapsulation of antioxidants at low dose provides long lasting protection against acute respiratory distress syndrome after shock. This may represent a novel treatment approach.}, }
@article {pmid10913623, year = {2000}, author = {Miralles, C and Busquets, X and Santos, C and Togores, B and Hussain, S and Rahman, I and MacNee, W and Agustí, AG}, title = {Regulation of iNOS expression and glutathione levels in rat liver by oxygen tension.}, journal = {FEBS letters}, volume = {476}, number = {3}, pages = {253-257}, doi = {10.1016/s0014-5793(00)01748-8}, pmid = {10913623}, issn = {0014-5793}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Base Sequence ; DNA Primers/genetics ; Enzyme Induction/drug effects ; Gene Expression Regulation, Enzymologic ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Hyperoxia/genetics/metabolism ; In Vitro Techniques ; Liver/*metabolism ; Male ; Nitric Oxide Synthase/biosynthesis/*genetics/*metabolism ; Nitric Oxide Synthase Type II ; Oxygen/*metabolism ; Perfusion ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {Molecular oxygen (O(2)) regulates the expression of a variety of genes. We hypothesized that O(2) tension may regulate iNOS expression in rat liver through the production of reactive oxygen species (ROS) and the reduction of intracellular glutathione (GSH) levels. To investigate this hypothesis, we determined the effects of hyperoxia upon iNOS induction (both at the protein and mRNA level) and the intracellular concentration of GSH in an isolated in vitro perfused rat liver preparation. To study the potential involvement of ROS in the intracellular signaling pathway linking changes in oxygen tension to gene expression, we repeated these determinations in the presence of the thiol antioxidant N-acetyl-L-cysteine (NAC). We found that 95% O(2) tension caused a significant induction of the iNOS protein and mRNA levels paralleled by a significant fall in intracellular GSH concentration. The addition of NAC (1 mM) to the perfusate during hyperoxia blocked the induction of iNOS and restored GSH levels. These results indicate that molecular O(2) regulates the expression of iNOS in rat liver at the transcriptional level, most likely through the production of ROS and the reduction of intracellular GSH levels.}, }
@article {pmid10908985, year = {2000}, author = {Ovesen, T and Felding, JU and Tommerup, B and Schousboe, LP and Petersen, CG}, title = {Effect of N-acetylcysteine on the incidence of recurrence of otitis media with effusion and re-insertion of ventilation tubes.}, journal = {Acta oto-laryngologica. Supplementum}, volume = {543}, number = {}, pages = {79-81}, doi = {10.1080/000164800454044}, pmid = {10908985}, issn = {0365-5237}, mesh = {Acetylcysteine/*therapeutic use ; Antioxidants/*therapeutic use ; Child ; Child, Preschool ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Incidence ; Infant ; Male ; Middle Ear Ventilation/*methods ; *Otitis Media with Effusion/drug therapy/epidemiology/surgery ; Recurrence ; Treatment Outcome ; }, abstract = {Previous studies have demonstrated the anti-inflammatory, anti-oxidant, and mucolytic nature of N-acetylcysteine (NAC). Theoretically, these properties make the substance ideal for therapeutic use against otitis media with effusion (OME). The disease is characterized as a sustained non-specific inflammation of the middle ear mucosa with secretory transformation of the epithelium resulting in accumulation of fluid in the middle ear space. To investigate the effects of instillation of NAC in the middle ear, a double-blind, placebo-controlled, randomized trial was carried out. A total of 75 children who were undergoing their first bilateral insertion of ventilation tubes (VT) due to OME were randomized to Mucomyst (NAC) or placebo (the vehicle) on one ear in relation to the VT insertion. The contralateral ear underwent VT insertion exclusively. Instillation of Mucomyst or placebo was repeated 3 and 7 days afterwards. The children were followed regularly for 11-39 months. Episodes of otorrhea, recurrence of OME after VT extrusion and re-insertion of VTs were registered as primary outcome parameters. The results demonstrated that Mucomyst significantly reduced the recurrence of OME and re-insertion of VTs (p < 0.025) and significantly increased the time until VT extrusion (p < 0.0167). In addition, the number of episodes of ear problems and visits at the ENT clinic were reduced significantly by NAC (p < 0.0383).}, }
@article {pmid10903958, year = {2000}, author = {Cuzzocrea, S and Mazzon, E and Costantino, G and Serraino, I and Dugo, L and Calabrò, G and Cucinotta, G and De Sarro, A and Caputi, AP}, title = {Beneficial effects of n-acetylcysteine on ischaemic brain injury.}, journal = {British journal of pharmacology}, volume = {130}, number = {6}, pages = {1219-1226}, pmid = {10903958}, issn = {0007-1188}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/drug effects/metabolism/pathology ; Brain Edema/pathology/prevention &amp; control ; Brain Ischemia/metabolism/physiopathology/*prevention &amp; control ; Free Radical Scavengers/*pharmacology ; Gerbillinae ; Male ; Malondialdehyde/metabolism ; Motor Activity/drug effects ; Nitric Oxide/metabolism ; Peroxidase/drug effects/metabolism ; Poly(ADP-ribose) Polymerases/drug effects/metabolism ; Reperfusion Injury/metabolism/physiopathology/*prevention &amp; control ; Time Factors ; Tyrosine/analogs &amp; derivatives/drug effects/metabolism ; }, abstract = {1. Nitric oxide (NO), peroxynitrite, formed from NO and superoxide anion, poly (ADP-ribole) synthetase have been implicated as mediators of neuronal damage following focal ischaemia. Here we have investigated the effects of n-acetylcysteine (NAC) treatment in Mongolian gerbils subjected to cerebral ischaemia. 2. Treatment of gerbils with NAC (20 mg kg(-1) 30 min before reperfusion and 1, 2 and 6 h after reperfusion) reduced the formation of post-ischaemic brain oedema, evaluated by water content. 3. NAC also attenuated the increase in the brain levels of malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischaemia. 4. Positive staining for nitrotyrosine was found in the hippocampus in Mongolian gerbils subjected to cerebral ischaemia. Hippocampus tissue sections from Mongolian gerbils subjected to cerebral ischaemia also showed positive staining for poly (ADP-ribose) synthetase (PARS). The degree of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received NAC. 5. NAC treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischaemia and reperfusion. 6. Histological observations of the pyramidal layer of CA1 showed a reduction of neuronal loss in animals that received NAC. 7. These results show that NAC improves brain injury induced by transient cerebral ischaemia.}, }
@article {pmid10903612, year = {2000}, author = {Ding, WX and Shen, HM and Ong, CN}, title = {Microcystic cyanobacteria extract induces cytoskeletal disruption and intracellular glutathione alteration in hepatocytes.}, journal = {Environmental health perspectives}, volume = {108}, number = {7}, pages = {605-609}, pmid = {10903612}, issn = {0091-6765}, mesh = {Animals ; Bacterial Toxins/*adverse effects ; Cell Culture Techniques ; Cyanobacteria/*chemistry ; Cytoskeleton/diagnostic imaging/*drug effects ; Glutathione/*metabolism ; Liver/cytology/*drug effects/pathology ; Microcystins ; Peptides, Cyclic/*adverse effects ; Rats ; Ultrasonography ; }, abstract = {Microcystins are a group of highly liver-specific toxins, although their exact mechanisms of action remain unclear. We examined the effects of microcystic cyanobacteria extract (MCE) collected from a contaminated water source on the organization of cellular microtubules (MTs) and microfilaments (MFs) in hepatocytes. We also investigated the effects on lactate dehydrogenase (LDH) leakage and intracellular glutathione (GSH). Primary cultured rat hepatocytes exposed to MCE (equivalent to 125 microg/mL lyophilized algae cells) showed a characteristic disruption of MTs and MFs in a time-dependent manner. Under these conditions, MCE caused aggregation of MTs and MFs and a severe loss of MTs in some cells. Moreover, MCE-induced cytoskeletal alterations preceded the LDH leakage. On the other hand, the treatment of cells with MCE led to a dose-dependent increase of intracellular GSH. However, time-course study showed a biphasic change of intracellular GSH levels with a significant increase in the initial stage followed by a decrease after prolonged treatment. Furthermore, pretreatment with N-acetylcystein (NAC), a GSH precursor, significantly enhanced the intracellular GSH level and decreased the MCE-induced cytotoxicity as well as cytoskeleton changes. In contrast, buthionine-(S, R)-sulfoximine, a specific GSH synthesis inhibitor, increased the cell susceptibility to MCE-induced cytotoxicity by depleting the intracellular GSH level. These findings suggest that intracellular GSH plays an important role in MCE-induced cytotoxicity and cytoskeleton changes in primary cultured rat hepatocytes. Increasing intracellular GSH levels protect cells from MCE-induced cytotoxicity and cytoskeleton changes.}, }
@article {pmid10903246, year = {2000}, author = {Hagiwara, SI and Ishii, Y and Kitamura, S}, title = {Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice.}, journal = {American journal of respiratory and critical care medicine}, volume = {162}, number = {1}, pages = {225-231}, doi = {10.1164/ajrccm.162.1.9903129}, pmid = {10903246}, issn = {1073-449X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Inhalation ; Animals ; Bleomycin/administration &amp; dosage ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Cell Count ; Chemokines/analysis ; Glutathione/analysis ; Hydroxyproline/analysis ; Lipid Peroxides/analysis ; Male ; Mice ; Mice, Inbred ICR ; Pulmonary Fibrosis/chemically induced/*drug therapy/pathology ; }, abstract = {Reactive oxygen species (ROS) play an important role in the pathogenesis of pulmonary fibrosis. We previously demonstrated that N-acetylcysteine (NAC), an antioxidant, inhibited adhesion molecule expression and cytokine production in lung cells. When NAC is inhaled into the alveolar space, it is expected to directly interact with inflammatory cells and to elevate glutathione levels in the epithelial lining fluids. We therefore examined whether inhaled NAC inhibits lung fibrosis induced by bleomycin (BLM). Male ICR mice were given a single intravenous injection of BLM (150 mg/ kg). Thirty milliliters of NAC (70 mg/ml) or saline were inhaled twice a day for 28 d using an ultrasonic nebulizer. In the inflammatory phase (Day 7), NAC administration attenuated the cellular infiltration in both bronchoalveolar lavage fluid (BALF) and alveolar tissues. At Day 28, the fibrotic changes estimated by Aschroft's criteria and hydroxyproline content in the NAC inhalation group were significantly decreased compared with the BLM-only group (p < 0.05). CXC chemokines, macrophage inflammatory protein-2 (MIP-2), cytokine-induced neutrophil chemoattractant (KC), and CC chemokines, macrophage inflammatory protein-1alpha (MIP-1alpha), in BALF were mostly elevated on Day 7 in the BLM-only group; however, these elevations were significantly repressed by NAC inhalation (p < 0.05). Lipid hydroperoxide (LPO) was also quantified in BALF. LPO was markedly increased on Day 3 in the BLM-only group, and this increase was significantly decreased by NAC inhalation (p < 0.05). These results revealed that aerosolized NAC ameliorated acute pulmonary inflammation induced by BLM injection via the repression of chemokines and LPO production, resulting in the attenuation of subsequent lung fibrosis. These findings are limited to the BLM-induced lung fibrosis animal model. However, NAC inhalation will be expected to be a potential therapy for patients with other interstitial pneumonias because ROS are involved in the pathogenesis of lung injury in most interstitial pneumonia.}, }
@article {pmid10901282, year = {2000}, author = {Cavallini, L and Alexandre, A}, title = {Oral N-acetyl-cysteome increases the production of anti HIV chemokines in peripheral blood mononuclear cells.}, journal = {Life sciences}, volume = {67}, number = {2}, pages = {147-154}, doi = {10.1016/s0024-3205(00)00610-x}, pmid = {10901282}, issn = {0024-3205}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Adult ; Antiviral Agents/*pharmacology ; Chemokine CCL3 ; Chemokine CCL4 ; Chemokine CCL5/metabolism ; Chemokines/*metabolism ; Female ; Glutathione/metabolism ; HIV/*immunology ; Humans ; In Vitro Techniques ; Leukocytes, Mononuclear/*drug effects/metabolism ; Macrophage Inflammatory Proteins/metabolism ; Male ; }, abstract = {The C-C chemokines MIP-1alpha, MIP-1beta and RANTES are specific and powerful inhibitors of HIV infectivity. They appear to work by blocking the interaction of the virus with the receptor (CCR5). The latter is utilized as a coreceptor for cell penetration by macrophage-tropic (R5) HIV strains responsible for the majority of HIV transmissions. A natural high capability to release such chemokines has been proposed as a protection factor against HIV infection in exposed uninfected individuals. We report that oral administration of N-acetyl-cysteine (NAC) to healthy volunteers increases the capability of their peripheral blood mononuclear cells (PBMC) to release such anti HIV chemokines upon stimulation. The data reported may explain at least in part the mechanism of action of NAC as an anti HIV therapeutic agent: By potentiating chemokine production NAC may decrease susceptibility to infection.}, }
@article {pmid10900173, year = {2000}, author = {Bogoyevitch, MA and Ng, DC and Court, NW and Draper, KA and Dhillon, A and Abas, L}, title = {Intact mitochondrial electron transport function is essential for signalling by hydrogen peroxide in cardiac myocytes.}, journal = {Journal of molecular and cellular cardiology}, volume = {32}, number = {8}, pages = {1469-1480}, doi = {10.1006/jmcc.2000.1187}, pmid = {10900173}, issn = {0022-2828}, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Antifungal Agents/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; *Electron Transport ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Fluorescent Antibody Technique ; Free Radicals ; Glutathione Transferase/metabolism ; Heart Ventricles/metabolism ; Hydrogen Peroxide/*pharmacology ; Immunoblotting ; *JNK Mitogen-Activated Protein Kinases ; MAP Kinase Kinase 4 ; Methacrylates ; Mitochondria/*metabolism/physiology ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Myocardium/*metabolism ; Osmotic Pressure ; Oxidative Stress ; Phenylephrine/pharmacology ; Phosphorylation ; Protein Kinases/metabolism ; Rats ; Signal Transduction ; Thiazoles/pharmacology ; Time Factors ; Tyrosine/metabolism ; Uncoupling Agents/pharmacology ; }, abstract = {Oxidative stress has been proposed as a mediator of cardiac injury during ischemia and reperfusion. We examined the signalling events initiated by short-term exposure of cardiac myocytes to oxidative stress elicited by hydrogen peroxide. A potent stimulation of tyrosine phosphorylation was observed within 1 to 2 min exposure to 1 m m hydrogen peroxide. Within 5 min, the ERK mitogen-activated protein kinases (ERK MAPKs) were activated. This activation of ERK MAPKs was blocked by N-acetylcysteine (NAC), implicating a role for free radicals in the signalling events. NAC failed to inhibit ERK MAPK activation by the hypertrophic agent, phenylephrine, or hyperosmotic shock. Myxothiazol, an inhibitor of complex III of the mitochondrial electron transport chain, also inhibited ERK MAPK activation by hydrogen peroxide, but not by 12- O -tetradecanoylphorbol-13-acetate (TPA) or hyperosmotic shock. Myxothiazol completely inhibited the increase in tyrosine phosphorylated proteins observed with hydrogen peroxide treatment. A variety of inhibitors which act at different levels of the mitochondrial electron transport chain (rotenone, theonyltrifluoroacetone, antimycin A, cyanide) also inhibited activation of the ERK MAPKs by hydrogen peroxide but not TPA or hyperosmotic shock. These studies suggest a novel mechanism of regulation of the ERK MAPK pathway and oxidative stress signalling by hydrogen peroxide.}, }
@article {pmid10897061, year = {2000}, author = {Grant, PR and Black, A and Garcia, N and Prieto, J and Garson, JA}, title = {Combination therapy with interferon-alpha plus N-acetyl cysteine for chronic hepatitis C: a placebo controlled double-blind multicentre study.}, journal = {Journal of medical virology}, volume = {61}, number = {4}, pages = {439-442}, doi = {10.1002/1096-9071(200008)61:4&lt;439::aid-jmv5&gt;3.0.co;2-l}, pmid = {10897061}, issn = {0146-6615}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Alanine Transaminase/blood ; Antiviral Agents/*therapeutic use ; Double-Blind Method ; Drug Therapy, Combination ; Hepacivirus/genetics/isolation &amp; purification ; Hepatitis C, Chronic/*drug therapy/pathology/virology ; Humans ; Interferon-alpha/*therapeutic use ; Italy ; Liver/drug effects/pathology ; Pilot Projects ; RNA, Viral/blood ; Spain ; Viremia/drug therapy ; }, abstract = {A small pilot study in patients with chronic hepatitis C (HCV) infection suggested that antiviral treatment with interferon (IFN) plus N-acetyl cysteine (NAC) was more effective than treatment with interferon alone [Beloqui et al. (1993) Journal of Interferon Research 13:279-282]. An attempt was made to confirm this by performing a placebo-controlled double-blind study at 8 medical centres in Spain and Italy. One-hundred forty-seven patients with chronic HCV infection were investigated, 73 received 3MU IFN-alpha thrice weekly plus NAC 1800 mg daily and 74 received IFN alone. Treatment was continued for 6 months and patients were followed up for a further 6 months. Amongst patients receiving IFN plus NAC, sustained virological responses were observed in 5.5%, transient responses in 26% and non-response in 68.5%. The figures for patients receiving IFN only were 4.1%, 24.3% and 71.6% respectively. Sustained virological response was significantly associated with non-type 1 genotypes (P = 0.045) and with low pre-treatment viraemia levels (P = 0.034). Biochemical response (serum ALT concentrations) correlated with virological outcome in 97% (n = 139) of cases. Patients who experienced a sustained virological response also showed reduction in the Knodell histological activity index. It is concluded that patients with chronic HCV infection are very unlikely to benefit from the addition of N-acetyl cysteine to conventional therapy with interferon-alpha.}, }
@article {pmid10893407, year = {2000}, author = {Ryu, J and Pyo, H and Jou, I and Joe, E}, title = {Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-kappa B.}, journal = {The Journal of biological chemistry}, volume = {275}, number = {39}, pages = {29955-29959}, doi = {10.1074/jbc.M001220200}, pmid = {10893407}, issn = {0021-9258}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carbazoles/pharmacology ; Cells, Cultured ; Cerebral Cortex/cytology ; Enzyme Induction ; Flavonoids/pharmacology ; Imidazoles/pharmacology ; Indoles/pharmacology ; Maleimides/pharmacology ; Microglia/cytology/*drug effects ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; NF-kappa B/*metabolism ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II ; Protein Kinase C/antagonists &amp; inhibitors/*metabolism ; Proteins/pharmacology ; Pyridines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptor, PAR-1 ; Receptors, Thrombin/agonists/metabolism ; Signal Transduction ; Thrombin/*pharmacology ; }, abstract = {Microglia, brain resident macrophages, become activated in brains injured due to trauma, ischemia, or neurodegenerative diseases. In this study, we found that thrombin treatment of microglia induced NO release/inducible nitric-oxide synthase expression, a prominent marker of activation. The effect of thrombin on NO release increased dose-dependently within the range of 5-20 units/ml. In immunoblot analyses, inducible nitric-oxide synthase expression was detected within 9 h after thrombin treatment. This effect of thrombin was significantly reduced by protein kinase C inhibitors, such as Go6976, bisindolylmaleimide, and Ro31-8220. Within 15 min, thrombin activated three subtypes of mitogen-activated protein kinases: extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase/stress-activated protein kinase. Inhibition of the extracellular signal-regulated kinase pathway and p38 reduced the NO release of thrombin-treated microglia. Thrombin also activated nuclear factor kappaB (NF-kappaB) within 5 min, and N-acetyl cysteine, an inhibitor of NF-kappaB, reduced NO release. However, thrombin receptor agonist peptide (an agonist of protease activated receptor-1 (PAR-1)), could not mimic the effect of thrombin, and cathepsin G, a PAR-1 inhibitor, did not reduce the effect of thrombin. These results suggest that thrombin can activate microglia via protein kinase C, mitogen-activated protein kinases, and NF-kappaB but that this occurs independently of PAR-1.}, }
@article {pmid10889310, year = {2000}, author = {Cole, AM and Wu, M and Kim, YH and Ganz, T}, title = {Microanalysis of antimicrobial properties of human fluids.}, journal = {Journal of microbiological methods}, volume = {41}, number = {2}, pages = {135-143}, doi = {10.1016/s0167-7012(00)00140-8}, pmid = {10889310}, issn = {0167-7012}, support = {AI40268/AI/NIAID NIH HHS/United States ; HL10181/HL/NHLBI NIH HHS/United States ; HL46809/HL/NHLBI NIH HHS/United States ; }, mesh = {Anti-Bacterial Agents/pharmacology ; Bacteria/drug effects/growth &amp; development ; *Bacteriological Techniques ; *Body Fluids ; Cell Cycle ; Colony Count, Microbial ; Humans ; Nasal Lavage Fluid ; Peptides/pharmacology ; }, abstract = {Host defense responses of animals and plants to pathogenic microbes are mediated in part by the release of antimicrobial substances into tissue fluids. Exploration of the antimicrobial properties of tissue fluids is often limited by their small quantity. We have developed assays of antimicrobial activity that require only 1 microl of fluid. Using normal nasal secretions as a model mucosal fluid we demonstrated that the kinetics of the 1 microl colony-forming unit (CFU) assays were equivalent to the larger CFU assays. The handling of viscous mucin-containing fluids was facilitated by pretreatment with N-acetylcysteine (NAC), a treatment that did not alter the performance of the assay. This low-volume assay will facilitate studies of the antimicrobial properties of scarce biological fluids.}, }
@article {pmid10888301, year = {2000}, author = {Aramaki, Y and Takano, S and Arima, H and Tsuchiya, S}, title = {Induction of apoptosis in WEHI 231 cells by cationic liposomes.}, journal = {Pharmaceutical research}, volume = {17}, number = {5}, pages = {515-520}, pmid = {10888301}, issn = {0724-8741}, mesh = {Animals ; Apoptosis/*drug effects ; B-Lymphocytes/*drug effects ; Cations ; Cell Line ; DNA/chemistry/metabolism ; DNA Fragmentation/drug effects ; Electrophoresis, Agar Gel ; Liposomes/*pharmacology ; Mice ; Microscopy, Fluorescence ; Reactive Oxygen Species/metabolism ; Spleen/cytology ; }, abstract = {PURPOSE: Liposomes are of considerable interest as drug carriers and immunoadjuvants. However, few investigators have studied the changes exerted by liposomes in the cells with which they interact. The purpose of this study was to investigate whether liposomes induce apoptosis in B cells.<br><br>METHODS: The mouse immature B cell line WEHI 231 cells and mouse splenic B cells were treated with liposomes, and the induction of apoptosis was evaluated by monitoring changes in DNA content, DNA fragmentation and chromatin condensation by flow cytometry, agarose gel electrophoresis and by morphological investigation.<br><br>RESULTS: Cationic liposomes induced apoptosis in WEHI 231 cells, but neutral and anionic liposomes did not. A contact time of 30 min between WEHI 231 cells and cationic liposomes was sufficient to induce apoptosis, and 80% of the cells showed hypodiploid DNA content. Apoptosis induced by cationic liposomes composed of stearylamine was inhibited by addition of the oxidant scavenger, N-acetyl-cysteine.<br><br>CONCLUSIONS: Cationic liposomes induced apoptosis in WEHI 231 cells, and the production of reactive oxygen species is important in the regulation of apoptosis induced by cationic liposomes. It is well known that cationic liposomes show cytotoxicity, and apoptosis may be one of the causes of this toxicity.}, }
@article {pmid10882622, year = {2000}, author = {Auer, M and Pfister, LA and Leppert, D and Täuber, MG and Leib, SL}, title = {Effects of clinically used antioxidants in experimental pneumococcal meningitis.}, journal = {The Journal of infectious diseases}, volume = {182}, number = {1}, pages = {347-350}, doi = {10.1086/315658}, pmid = {10882622}, issn = {0022-1899}, support = {NS-32553/NS/NINDS NIH HHS/United States ; NS-34028/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Deferoxamine/therapeutic use ; Disease Models, Animal ; Meningitis, Pneumococcal/*drug therapy/metabolism/pathology ; Neurons/drug effects/pathology ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Reactive oxygen intermediates mediate brain injury in bacterial meningitis. Several antioxidant drugs are clinically available, including N-acetylcysteine (NAC), deferoxamine (DFO), and trylizad-mesylate (TLM). The present study evaluated whether these antioxidants are beneficial in a model of pneumococcal meningitis. Eleven-day-old rats were infected intracisternally with Streptococcus pneumoniae and randomized to intraperitoneal treatment every 8 h with NAC (200 mg/kg), DFO (100 mg/kg), TLM (10 mg/kg), or saline (250 microL). TLM-treated animals showed a significantly reduced mortality compared with controls (P<.03). Meningitis led to extensive cortical injury at 22+/-2.2 h after infection (median, 14. 6% of cortex; range, 0-61.1%). Injury was significantly (P<.01) reduced to 1.1% (range, 0-34.6%) by NAC, to 2.3% (range, 0-19.6%) by DFO, and to 0.2% (range, 0-36.9%) by TLM (the difference was not significant among the 3 groups). None of the drugs reduced hippocampal injury. Thus, several clinically used antioxidants reduced cortical injury in experimental pneumococcal meningitis.}, }
@article {pmid10880232, year = {2000}, author = {Nathan, I and Dizdaroglu, M and Bernstein, L and Junker, U and Lee, C and Muegge, K and Durum, SK}, title = {Induction of oxidative DNA damage in u937 cells by TNF or anti-Fas stimulation.}, journal = {Cytokine}, volume = {12}, number = {7}, pages = {881-887}, doi = {10.1006/cyto.1999.0638}, pmid = {10880232}, issn = {1043-4666}, mesh = {Adenosine/metabolism ; Aphidicolin/pharmacology ; Apoptosis/drug effects ; DNA/drug effects ; *DNA Damage ; Enzyme Inhibitors/pharmacology ; Free Radicals ; Guanine/metabolism ; Humans ; Oxidation-Reduction ; Tumor Necrosis Factor-alpha/*metabolism/pharmacology ; U937 Cells ; fas Receptor/immunology/*metabolism ; }, abstract = {TNF and Fas signaling pathways are reported to induce mitochondrial damage associated with production of oxygen radicals. We examined whether such radical production elicited detectable nuclear DNA damage in U937 cells following treatment with TNF or with anti-Fas antibodies. Using GC-mass spectroscopy for analysing base oxidation, several oxidized species increased significantly following TNF treatment, whereas anti-Fas resulted in less detectable oxidative damage using this assay. Cytogenetic analysis showed that, in the presence of aphidicolin, which blocks several types of DNA repair, TNF induced extensive chromosomal damage. Aphidicolin also synergized with TNF and anti-Fas in inducing cell death which was prevented by reducing atmospheric oxygen or addition of n -acetyl cysteine, a scavenger of oxygen radicals. Thus, several lines of evidence point to the TNF and Fas pathways inducing extensive oxidative DNA damage and repair, and suggest potential roles for these pathways in mutagenesis and aging.}, }
@article {pmid10880090, year = {2000}, author = {Stanislawski, L and Soheili-Majd, E and Perianin, A and Goldberg, M}, title = {Dental restorative biomaterials induce glutathione depletion in cultured human gingival fibroblast: protective effect of N-acetyl cysteine.}, journal = {Journal of biomedical materials research}, volume = {51}, number = {3}, pages = {469-474}, doi = {10.1002/1097-4636(20000905)51:3&lt;469::aid-jbm22&gt;3.0.co;2-b}, pmid = {10880090}, issn = {0021-9304}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Composite Resins/adverse effects ; Culture Techniques ; Dental Materials/*adverse effects ; Dental Restoration, Permanent/adverse effects ; Fibroblasts/cytology/drug effects/metabolism ; Gingiva/cytology/*drug effects/*metabolism ; Glass Ionomer Cements/adverse effects ; Glutathione/deficiency/*metabolism ; Humans ; Materials Testing ; Sulfhydryl Compounds/pharmacology ; }, abstract = {Eight biomaterials eluted from four different types of dental restorative biomaterials, that is, from glass-ionomer cement (GIC: Ketac-fil and Fuji II), resin-modified glass ionomer cement (RM-GIC: Fuji II LC and Photac-fil), composite (Z100 MP and Tetric-flow), and compomer (Compoglass F and F-2000), were studied for their cytotoxic properties in relation to glutathione (GSH) content in cultured human gingival fibroblasts. Z100 MP, Tetric-flow, and Compoglass F were less cytotoxic than the others, with a toxic concentration of 50% (TC 50) > 24% (of eluate), as determined by the MTT test. F-2000, Tetric-flow, and the other biomaterials were relatively more cytotoxic (TC 50 = 9-16%). With the exception of Z100 MP, all the biomaterials induced a depletion of cellular glutathione (GSH) that was variable depending upon the biomaterial eluates. The strongest GSH depletion was with F-2000, Fuji II, and Photac-fil. GSH depletion, with Compoglass and F-2000, was rapid-detectable after one h of cell treatment and complete within 3 h-whereas a longer period of incubation was required for the other biomaterials. Interestingly, the drug cytotoxic effects induced by all the biomaterials were prevented by cell treatment with the antioxidant N-acetylcysteine (NAC). This study provides evidence that the cytotoxic property of dental restorative biomaterials is associated with depletion of the glutathione level in gingival fibroblasts. While the molecular mechanisms of this phenomenon require further investigations, our data suggest that NAC may be useful in preventing the cellular damage induced by dental restorative biomaterials.}, }
@article {pmid10878455, year = {2000}, author = {Nakano, H and Fujiwara, Y and Kitamura, N and Kumada, K and Matsumiya, A and Sakai, H and Hatakeyama, T and Yamaguchi, M and Jaeck, D}, title = {Susceptibility to lipopolysaccharide of cholestatic rat liver produced with bile duct ligation: assessments of the mitochondrial glutathione pool and the effects of N-acetylcysteine.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {32}, number = {3}, pages = {148-154}, doi = {10.1159/000008756}, pmid = {10878455}, issn = {0014-312X}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/analysis ; Animals ; Cholestasis/*metabolism ; Glutathione/*analysis ; Glutathione Disulfide/analysis ; Hydrogen Peroxide/metabolism ; Lipopolysaccharides/*toxicity ; Liver/*drug effects ; Male ; Mitochondria, Liver/*metabolism ; Neutrophils/physiology ; Oxidative Stress ; Rats ; }, abstract = {We investigated whether rats with obstructive jaundice produced with bile duct ligation for 2 weeks are more susceptible to the additional stress of lipopolysaccharide (LPS) administration than sham-operated rats and also examined the effects of N-acetylcysteine (NAC) on LPS stimulation in rats with bile duct ligation. The effects of LPS on the mitochondrial glutathione pool and on oxidative stress of polymorphonuclear leukocytes were investigated in cholestatic rats. Serum concentrations of alpha-glutathione S-transferase showed that lipopolysaccharide stimulation caused more severe hepatocellular injury in cholestatic rats than in sham-operated rats. In addition, concentrations of mitochondrial reduced and oxidized glutathione and hepatic adenosine triphosphate showed that LPS stimulation decreased mitochondrial function more in cholestatic rats than in sham-operated rats. Intraperitoneal administration of NAC for 2 weeks significantly improved mitochondrial function and decreased hepatocellular injury. However, the oxidative stress of polymorphonuclear leukocytes that had infiltrated hepatic tissue was increased by NAC. The present results indicate that the cholestatic liver is susceptible to the additional stress of LPS, that NAC suppresses the adverse effects of LPS in cholestatic livers, and that the oxidative stress of polymorphonuclear leukocytes is not significantly involved in mitochondrial dysfunction or hepatocellular injury in this model.}, }
@article {pmid10873716, year = {2000}, author = {Slim, R and Toborek, M and Robertson, LW and Lehmler, HJ and Hennig, B}, title = {Cellular glutathione status modulates polychlorinated biphenyl-induced stress response and apoptosis in vascular endothelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {166}, number = {1}, pages = {36-42}, doi = {10.1006/taap.2000.8944}, pmid = {10873716}, issn = {0041-008X}, support = {P42 ES007380/ES/NIEHS NIH HHS/United States ; 1 P42 ES 07380/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; *Apoptosis ; Caspase 3 ; Caspases/metabolism ; Endothelium, Vascular/*drug effects/enzymology/metabolism/pathology ; Environmental Pollutants/pharmacology ; Enzyme Activation ; Glutathione/*metabolism ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinases/metabolism ; Polychlorinated Biphenyls/*pharmacology ; Swine ; }, abstract = {Exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs), may severely compromise normal function of vascular endothelial cells (EC). We have previously shown that PCB 77 (3,3',4,4'-tetrachlorobiphenyl), an arylhydrocarbon receptor (AhR) agonist, can induce oxidative stress in cultured EC. We now show that PCB 77 can activate EC and induce a cellular stress response that is reflected by the activation of c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK). Our data also suggest that this PCB 77-mediated stress response can be modulated by the intracellular glutathione content. EC treated with buthionine-sulphoximine (BSO), an inhibitor of glutathione synthesis, further enhanced PCB-induced JNK/SAPK activity. This stress response was sustained only in the presence of BSO plus PCB 77. Media supplementation with the glutathione precursor N-acetyl-cysteine (NAC) reduced PCB 77-induced JNK/SAPK. Intracellular glutathione also may be implicated in PCB-induced EC apoptosis. Individual treatment with PCB, BSO, or linoleic acid induced activation of caspase 3. Compared to PCB 77 alone, annexin V activity was further amplified during combined treatment with BSO and PCB 77. DNA fragmentation was mostly observed when cells were treated with both BSO and PCB 77. The caspase 3-specific inhibitor DEVD-CHO protected cells against PCB 77/BSO-mediated apoptosis and inhibited the caspase activity without affecting JNK/SAPK activation or cellular glutathione levels. These results suggest that AhR ligands, such as PCB 77, cause vascular EC dysfunction by modulating intracellular glutathione, which subsequently leads to activation of stress-specific kinases. Furthermore, inhibition of glutathione synthesis by BSO can further potentiate the PCB 77-induced stress response and ultimately lead to apoptotic cell death.}, }
@article {pmid10871428, year = {2000}, author = {Ercal, N and Neal, R and Treeratphan, P and Lutz, PM and Hammond, TC and Dennery, PA and Spitz, DR}, title = {A role for oxidative stress in suppressing serum immunoglobulin levels in lead-exposed Fisher 344 rats.}, journal = {Archives of environmental contamination and toxicology}, volume = {39}, number = {2}, pages = {251-256}, doi = {10.1007/s002440010102}, pmid = {10871428}, issn = {0090-4341}, support = {R01 ES06065-OIAI/ES/NIEHS NIH HHS/United States ; R01HL51469/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antibody Formation/drug effects ; Body Weight/drug effects ; Catalase/metabolism ; Chromatography, High Pressure Liquid ; Immunodiffusion ; Immunoglobulins/blood/*drug effects ; *Immunosuppression Therapy ; Immunosuppressive Agents/*toxicity ; Lead/metabolism/*toxicity ; Lead Poisoning/*immunology ; Lipid Peroxidation/drug effects ; Liver/drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Monocytes/drug effects/metabolism ; *Oxidative Stress/physiology ; Rats ; Rats, Inbred F344 ; }, abstract = {Evidence implicating oxidative stress in toxicity during lead intoxication in vivo has opened new avenues for investigation of the mechanisms of lead-induced immunosuppression. The current study explores the possibility that lead-induced oxidative stress contributes to the immunosuppression observed during lead poisoning. Fisher 344 rats were exposed to 2,000 ppm lead acetate in their drinking water for 5 weeks. One week following removal of lead from the drinking water, significant reductions in serum levels of IgA, IgM, and IgG were detected. Significant increases in oxidative damage, based on malondialdehyde (MDA) content, were observed in peripheral blood mononuclear cells (PMCs) collected during the same experiments. In addition, MDA content increased in livers from lead-exposed rats. Following 5 weeks of lead exposure, administration of either 5.5 mmol/kg N-acetylcysteine (NAC) or 1 mmol/kg meso-2,3-dimercaptosuccinic acid (DMSA) in the drinking water for 1 week significantly reversed the inhibitory effects of lead on serum immunoglobulin (Ig) levels. Also, all parameters indicative of oxidative stress returned to control levels. These results suggest that oxidative stress contributes to suppressed serum Ig levels during lead intoxication in vivo, and that intervention with either a thiol antioxidant (NAC) or a metal chelator (DMSA) will alleviate this lead-induced suppression by correcting the prooxidant/antioxidant imbalance caused by lead exposure.}, }
@article {pmid10867640, year = {2000}, author = {Zhai, Q and Ji, H and Zheng, Z and Yu, X and Sun, L and Liu, X}, title = {Copper induces apoptosis in BA/F3beta cells: Bax, reactive oxygen species, and NFkappaB are involved.}, journal = {Journal of cellular physiology}, volume = {184}, number = {2}, pages = {161-170}, doi = {10.1002/1097-4652(200008)184:2&lt;161::AID-JCP3&gt;3.0.CO;2-N}, pmid = {10867640}, issn = {0021-9541}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects/physiology ; Cell Death/drug effects/physiology ; Cell Line ; Copper/*pharmacology ; Free Radical Scavengers/pharmacology ; Mice ; NF-kappa B/*drug effects/metabolism ; Proto-Oncogene Proteins/*drug effects/metabolism/physiology ; Proto-Oncogene Proteins c-bcl-2/pharmacology ; Reactive Oxygen Species/*metabolism ; Up-Regulation ; bcl-2-Associated X Protein ; }, abstract = {Copper, an essential trace element, can be toxic to some cells when present in excess. But thorough investigations into the cytotoxicity of copper and subsequent molecular mechanisms are rare, although the cytotoxicity of copper has been applied to cancer chemotherapy. The present study demonstrates that Cu(2+) inhibits [(3)H] thymidine incorporation in mouse pro-B cell line BA/F3beta and induces apoptosis. Apoptosis was mainly judged by morphology of cells, quantification of subdiploid DNA contents by flow cytometry, and detection of DNA fragmentation by gel electrophoresis. The apoptotic effect is dose and time dependent. Western blotting shows Bax is upregulated by Cu(2+). Bcl-2 overexpression can partially inhibit this apoptosis. Moreover, Cu(2+) increases the production of reactive oxygen species (ROS) in a dose-dependent manner. The antioxidant N-acetylcysteine (NAC) not only significantly inhibited copper-induced apoptosis but also totally blocked generation of ROS, while Bcl-2 overexpression has no effect on the generation of ROS. Furthermore, our results show that NFkappaB is downregulated by Cu(2+). Bcl-2 overexpression or NAC can sustain the activity of NFkappaB. These data indicate that Cu(2+) might induce apoptosis in BA/F3beta cells via upregulation of Bax and ROS and subsequent inactivation of NFkappaB.}, }
@article {pmid10864903, year = {2000}, author = {Serra, PA and Esposito, G and Enrico, P and Mura, MA and Migheli, R and Delogu, MR and Miele, M and Desole, MS and Grella, G and Miele, E}, title = {Manganese increases L-DOPA auto-oxidation in the striatum of the freely moving rat: potential implications to L-DOPA long-term therapy of Parkinson's disease.}, journal = {British journal of pharmacology}, volume = {130}, number = {4}, pages = {937-945}, pmid = {10864903}, issn = {0007-1188}, mesh = {3,4-Dihydroxyphenylacetic Acid/metabolism ; Acetylcysteine/pharmacology ; Animals ; Ascorbic Acid/metabolism ; Chlorides/pharmacology ; Chromatography, High Pressure Liquid ; Corpus Striatum/*drug effects/metabolism ; Dialysis Solutions/chemistry ; Dopamine/metabolism ; Homovanillic Acid/metabolism ; Infusion Pumps ; Levodopa/*metabolism/pharmacology/therapeutic use ; Male ; Manganese/*pharmacology ; Manganese Compounds/pharmacology ; Microdialysis ; Movement ; Oxidation-Reduction/drug effects ; Parkinson Disease/drug therapy ; Rats ; Rats, Wistar ; Time Factors ; Uric Acid/metabolism ; }, abstract = {We have previously shown that manganese enhances L-dihydroxyphenylanine (L-DOPA) toxicity to PC12 cells in vitro. The supposed mechanism of manganese enhancing effect [an increase in L-DOPA and dopamine (DA) auto-oxidation] was studied using microdialysis in the striatum of freely moving rats. Systemic L-DOPA [25 mg kg(-1) intraperitoneally (i.p.) twice in a 12 h interval] significantly increased baseline dialysate concentrations of L-DOPA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and uric acid, compared to controls. Conversely, DA and ascorbic acid concentrations were significantly decreased. A L-DOPA oxidation product, presumptively identified as L-DOPA semiquinone, was detected in the dialysate. The L-DOPA semiquinone was detected also following intrastriatal infusion of L-DOPA. In rats given L-DOPA i.p. , intrastriatal infusion of N-acetylcysteine (NAC) significantly increased DA and L-DOPA dialysate concentrations and lowered those of L-DOPA semiquinone; in addition, NAC decreased DOPAC+HVA and uric acid dialysate concentrations. In rats given L-DOPA either systemically or intrastriatally, intrastriatal infusion of manganese decreased L-DOPA dialysate concentrations and greatly increased those of L-DOPA semiquinone. These changes were inhibited by NAC infusion. These findings demonstrate that auto-oxidation of exogenous L-DOPA occurs in vivo in the rat striatum. The consequent reactive oxygen species generation may account for the decrease in dialysate DA and ascorbic acid concentrations and increase in enzymatic oxidation of xanthine and DA. L-DOPA auto-oxidation is inhibited by NAC and enhanced by manganese. These results may be of relevance to the L-DOPA long-term therapy of Parkinson's disease.}, }
@article {pmid10862121, year = {2000}, author = {Gopaul, SV and Farrell, K and Abbott, FS}, title = {Gas chromatography/negative ion chemical ionization mass spectrometry and liquid chromatography/electrospray ionization tandem mass spectrometry quantitative profiling of N-acetylcysteine conjugates of valproic acid in urine: application in drug metabolism studies in humans.}, journal = {Journal of mass spectrometry : JMS}, volume = {35}, number = {6}, pages = {698-704}, doi = {10.1002/1096-9888(200006)35:6&lt;698::AID-JMS996&gt;3.0.CO;2-S}, pmid = {10862121}, issn = {1076-5174}, mesh = {Acetylcysteine/analogs &amp; derivatives/metabolism/urine ; Adolescent ; Analysis of Variance ; Animals ; Anticonvulsants/metabolism/*urine ; Child ; Child, Preschool ; Chromatography, Liquid/methods ; Epilepsy/drug therapy/metabolism/urine ; Gas Chromatography-Mass Spectrometry/*methods/statistics &amp; numerical data ; Humans ; Mass Spectrometry/*methods/statistics &amp; numerical data ; Rats ; Valproic Acid/analogs &amp; derivatives/metabolism/*urine ; }, abstract = {We report a GC/NICI-MS assay and a LC/ESI-MS/MS assay for the analysis of N-acetylcysteine (NAC) conjugates of (E)-2,4-diene VPA (NAC I and NAC II) identified in humans. The assay also includes the analysis of the NAC conjugate of 4,5-epoxy VPA (NAC III), an identified metabolite in rats treated with 4-ene VPA for its use in metabolic studies in animals. The highly sensitive GC/MS assay was designed to monitor selectively the diagnostic and most abundant [M - 181](-) fragment anion of the di-PFB derivatives of NAC I, NAC II, and NAC IV, the internal standard (IS) and the PFB derivative of NAC III. The higher selectivity of LC/MS/MS methodology was the basis for an assay which could identify and quantitate the underivatized conjugates simultaneously using MRM of the diagnostic ions m/z 130 and 123 arising from the CID of their protonated molecular ions [MH](+). The GC/MS assay employed liquid-liquid extraction whereas the LC/MS/MS assay used a solid-phase extraction procedure. Linearity ranges of the calibration curves were 0.10-5.0microg ml(-1) by GC/MS and 0.10-1.0microg ml(-1) by LC/MS/MS for NAC I, NAC II and NAC III (r(2) = 0.999 or better). Both assays were validated for NAC I and NAC II and provided good inter- and intra-assay precision and accuracy for NAC I and NAC II. The LOQ by LC/MS/MS was 0.1microg ml(-1), representing 1 ng of NAC I and NAC II. The same LOQ (0.1microg ml(-1)) was observed by GC/MS and was equivalent to 100 pg of each metabolite. NAC III was detected at concentrations as low as 0.01 microg ml(-1) by both methods. The total urinary excretion of the NAC conjugates in four patients on VPA therapy was determined to be 0.004-0.088% of a VPA dose by GC/MS and 0.004-0. 109% of a VPA dose by LC/MS/MS.}, }
@article {pmid10861855, year = {2000}, author = {Umansky, V and Rocha, M and Breitkreutz, R and Hehner, S and Bucur, M and Erbe, N and Dröge, W and Ushmorov, A}, title = {Glutathione is a factor of resistance of Jurkat leukemia cells to nitric oxide-mediated apoptosis.}, journal = {Journal of cellular biochemistry}, volume = {78}, number = {4}, pages = {578-587}, doi = {10.1002/1097-4644(20000915)78:4&lt;578::aid-jcb7&gt;3.0.co;2-a}, pmid = {10861855}, issn = {0730-2312}, mesh = {Acridine Orange/metabolism ; Aminoacyltransferases/antagonists &amp; inhibitors ; Annexin A5/metabolism ; Apoptosis/*drug effects ; Buthionine Sulfoximine/pharmacology ; Cardiolipins/biosynthesis/metabolism ; Cell Separation ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Fluorescein-5-isothiocyanate/pharmacology ; Fluorescent Dyes/metabolism/pharmacology ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors ; Glutathione/*metabolism ; Humans ; Jurkat Cells ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Nitric Oxide/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; bcl-X Protein ; }, abstract = {We have previously reported that nitric oxide (NO) stimulates apoptosis in different human neoplastic lymphoid cell lines through mitochondrial damage (including degradation of cardiolipin, a major mitochondrial lipid) followed by activation of caspases. Here we demonstrate that Jurkat human leukemia cells which survive after 24 h treatment with NO form subpopulations with higher and lower cardiolipin content (designated as NAO(high) and NAO(low), respectively). Sorted NAO(high) cells were found to survive in culture whereas sorted NAO(low) cells died. Moreover, NAO(high) cells acquired an increased resistance to the exposure to NO donors which remained unchanged during long-term culture. These cells showed a similar cardiolipin content and expressed the same level of anti-apoptotic proteins Bcl-2 and Bcl-x(L) as APO-S unsorted cells but contained significantly higher concentration of the antioxidant glutathione. Depletion of glutathione in these cells with buthionine-sulfoximine (BSO) correlated with a significant stimulation of NO-mediated apoptosis whereas the exposure of NO-sensitive APO-S cells to the glutathione precursor N-acetylcysteine (NAC) resulted in a substantial suppression of this effect. Our data suggest a complex mechanism of the resistence to NO-induced apoptosis in Jurkat human leukemia cells in which glutathione plays an important role.}, }
@article {pmid10860633, year = {2000}, author = {Grandjean, EM and Berthet, PH and Ruffmann, R and Leuenberger, P}, title = {Cost-effectiveness analysis of oral N-acetylcysteine as a preventive treatment in chronic bronchitis.}, journal = {Pharmacological research}, volume = {42}, number = {1}, pages = {39-50}, doi = {10.1006/phrs.1999.0647}, pmid = {10860633}, issn = {1043-6618}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Bronchitis/*prevention &amp; control ; Chronic Disease ; Cost-Benefit Analysis ; Health Care Costs ; Hospitalization/economics ; Humans ; }, abstract = {UNLABELLED: Chronic bronchitis has a prevalence of approximately 11% in the population aged over 35 years and its frequent acute exacerbations (AECBs) are an important cause of morbidity and costs in health-care resources. Oral N -acetylcysteine (NAC) is administered during the winter months as a way of reducing AECBs. This cost-effectiveness analysis was done from the payers' point of view in the Swiss health-care system, based on a retrospective analysis of published placebo-controlled studies. The pooled data show that continuous administration of 400 mg day(-1)per os of NAC leads to a significant reduction in the number of AECBs (NAC: 16.2 vs 25.2% AECBs per month); a significantly smaller percentage of days of sick leave (NAC: 3.6 vs 5.3%) and a lower rate of hospitalizations (NAC: 1.5 vs 3.5% over a period of 6 months). Taking into account the poor compliance of these patients, calculations assumed a compliance of 80%. Direct costs were those of an NAC treatment, the management of an AECB (biological tests in 59%, X-rays in 65% and pulmonary function tests in 45%; antibiotics 70%, bronchodilators in 89%, corticosteroids in 24% and 'others' in 25% of the patients), and of hospitalizations (estimated at 10 days per case). Based on these figures, the mean direct costs of an untreated patient were CHF 869 vs CHF 700 in the NAC-treated patient. Univariate sensitivity analysis indicated that cost neutrality is reached with 0.6 (<0.25-1. 94, 95% CI) AECBs per 6 months. Indirect costs (based on sick leave) were also significantly different; the mean in untreated patients was CHF 1324 vs CHF 779 in the NAC-treated patients.<br><br>CONCLUSION: Treating chronic bronchitis patients with NAC during the winter months is cost-effective both from the payer's and a social point of view.}, }
@article {pmid10859157, year = {2000}, author = {Gopaul, SV and Farrell, K and Abbott, FS}, title = {Identification and characterization of N-acetylcysteine conjugates of valproic acid in humans and animals.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {28}, number = {7}, pages = {823-832}, pmid = {10859157}, issn = {0090-9556}, mesh = {Acetylcysteine/chemistry/*pharmacokinetics ; Animals ; Biotransformation ; Chromatography, Liquid ; Esters ; Guinea Pigs ; Humans ; Hydrolysis ; Mass Spectrometry ; Rats ; Valproic Acid/chemistry/*pharmacokinetics ; }, abstract = {Reactive and hepatotoxic metabolites formed from the biotransformation of valproic acid (VPA) are normally detoxified by conjugating with GSH and followed by mercapturic acid metabolism to produce their respective N-acetylcysteine (NAC) conjugates. Hence, the levels of NAC conjugates of VPA in human urine are an indirect measure of exposure of the liver toward reactive metabolites of the anticonvulsant drug. We report here the synthesis, identification, and characterization of a second NAC conjugate of (E)-2-propyl-2, 4-pentadienoic acid in the urine samples (n = 39) of humans on VPA therapy, namely, (E)-5-(N-acetylcystein-S-yl)-2-ene VPA by gas chromatography/mass spectrometry and liquid chromatography with tandem mass spectrometry. In this study, we were able to separate the diastereomers of (E)-5-(N-acetylcystein-S-yl)-3-ene VPA by HPLC. The NAC conjugate of 4,5-epoxy VPA, namely, 5-NAC-4-OH-VPA gamma-lactone, previously identified in rats treated with 2-propyl-4-pentenoic acid (4-ene VPA), was not detected in any of the human urine samples studied. This suggests that in humans, the P-450 metabolism of 4-ene VPA to the reactive epoxide is not a significant pathway. The excretion of the NAC conjugate of (E)-2, 4-diene VPA glucuronide in the urine of seven patients on VPA was also examined and was not detected. The limit of detection of 5-NAC-3-keto VPA and its decarboxylated product, 1-NAC-3-heptanone, was estimated at 25 ng (signal to noise ratio > 3). Neither 5-NAC-3-keto VPA nor 1-NAC-3-heptanone was detected in the urine of patients on VPA therapy or 4-ene VPA-treated guinea pigs, but 1-NAC-3-heptanone was detected in the urine of 4-ene VPA-treated rats.}, }
@article {pmid10857766, year = {2000}, author = {Flescher, E and Fingrut, O}, title = {Suppression of interleukin 2 biosynthesis by three modes of oxidative cellular stress: selective prevention by N-acetyl cysteine.}, journal = {Cytokine}, volume = {12}, number = {5}, pages = {495-498}, doi = {10.1006/cyto.1999.0571}, pmid = {10857766}, issn = {1043-4666}, mesh = {Acetylcysteine/*metabolism/pharmacology ; Antioxidants/*metabolism/pharmacology ; Cells, Cultured ; Humans ; Hydrogen Peroxide/pharmacology ; Interleukin-2/*biosynthesis ; *Oxidative Stress ; T-Lymphocytes/cytology/drug effects/metabolism ; }, abstract = {Acute stress induced by reagent hydrogen peroxide suppressed interleukin (IL-)2 biosynthesis in a dose-dependent fashion, reaching almost complete abolishment at 200 microM. Cells exposed to longitudinal oxidative stress and irradiation did not exhibit complete suppression of IL-2 biosynthesis, probably because intensities high enough to achieve such response would be lethal. These results suggest that suppression of IL-2 biosynthesis is a sensitive measure of acute oxidative stress. N-acetyl cysteine (NAC) prevented oxidative stress-induced suppression of IL-2 biosynthesis, except for that induced by acute stress at 100 microM and above. NAC was very efficient in preventing longitudinal and irradiation-induced stresses. Therefore, NAC appears to be a promising candidate for providing defence to individuals exposed to environmental conditions in which reactive oxygen intermediates are generated.}, }
@article {pmid10852765, year = {2000}, author = {Ortolani, O and Conti, A and De Gaudio, AR and Moraldi, E and Cantini, Q and Novelli, G}, title = {The effect of glutathione and N-acetylcysteine on lipoperoxidative damage in patients with early septic shock.}, journal = {American journal of respiratory and critical care medicine}, volume = {161}, number = {6}, pages = {1907-1911}, doi = {10.1164/ajrccm.161.6.9903043}, pmid = {10852765}, issn = {1073-449X}, mesh = {APACHE ; Acetylcysteine/*administration &amp; dosage/adverse effects ; Adult ; Aged ; Antioxidants/*administration &amp; dosage/adverse effects ; Critical Care ; Female ; Glutathione/*administration &amp; dosage/adverse effects ; Humans ; Infusions, Intravenous ; Lipid Peroxidation/*drug effects/physiology ; Male ; Middle Aged ; Shock, Septic/*drug therapy/mortality/physiopathology ; Survival Rate ; Treatment Outcome ; }, abstract = {Both the hyperproduction of oxygen free radicals (OFR) and the weakening of natural scavenging mechanisms have been implicated as contributors to multiple organ failure in septic shock. This study examined whether the antioxidants glutathione (GSH) and N-acetyl-L-cysteine (NAC) play a protective role against damage by OFR in early septic shock. We randomly entered 30 patients with septic shock into one of three groups within 24 h of diagnosis. All of the patients received septic shock therapy, including parenteral nutrition, antibiotics, and volume-expanding and inotropic agents. One group (Group B) also received 70 mg/kg/d of intravenous GSH, and a second group (Group C), 70 mg/kg/d of intravenous GSH and 75 mg/kg/d of intravenous NAC. The protection against OFR damage was evaluated by measuring expired ethane, plasma malondialdehyde, erythrocyte deformability, complement activation, and clinical scores at admission and on Days 3 and 5 of treatment. A significant decrease in peroxidative indexes was observed at Day 5 in Group B as compared with both the control group and basal values. The decrease in peroxidative indexes was even more marked in Group C. Clinical scores in this group were also significantly improved. In conclusion, the administration of high doses of NAC added to GSH significantly decreased the peroxidative stress of patients with septic shock.}, }
@article {pmid10851302, year = {2000}, author = {Nowzari, FB and Davidson, SD and Eshghi, M and Mallouh, C and Tazaki, H and Konno, S}, title = {Adverse effects of oxidative stress on renal cells and its prevention by antioxidants.}, journal = {Molecular urology}, volume = {4}, number = {1}, pages = {15-19}, pmid = {10851302}, issn = {1091-5362}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cell Line ; Cell Survival/drug effects ; HSP90 Heat-Shock Proteins/metabolism ; Hydrogen Peroxide/*toxicity ; Kidney Tubules, Proximal/cytology/drug effects/*physiology ; Kinetics ; Lipid Peroxidation/*drug effects ; Malondialdehyde/metabolism ; Mannitol/pharmacology ; Oxidative Stress/drug effects/*physiology ; Pyruvates/pharmacology ; Swine ; }, abstract = {BACKGROUND AND PURPOSE: Recent reports suggest that reactive oxygen species; e.g., hydrogen peroxide (H(2)O(2)), could be the primary cause of various drug-induced renal injuries. We investigated the effects of H(2)O(2) on renal cells to understand its mode of action and to explore cytoprotection from such a fatal injury.<br><br>MATERIALS AND METHODS: Renal proximal tubular LLC-PK(1) cells were exposed to various concentrations of H(2)O(2), and cell viability was determined at specified times. Lipid peroxidation assay and Western blot analysis of heat shock proteins (Hsp70 and Hsp90) were performed to assess the cellular effects.<br><br>RESULTS: The dose-response study showed that H(2)O(2) > or = 100 microM was severely cytotoxic. Even a 1-h exposure was sufficient to induce >95% cell death in 24 h. Lipid peroxidation was significantly (>50%) increased, while Hsp90, but not Hsp70, was partially degraded, to an approximately 85-kDa fragment, after a 3-h H(2)O(2) exposure. However, such cytotoxic cell death was remarkably (approximately 90%) prevented by the antioxidants pyruvate or N-acetylcysteine (NAC), and Hsp90 remained intact.<br><br>CONCLUSION: Hydrogen peroxide-induced renal cell death involves increased lipid peroxidation and partial degradation of Hsp90. Both pyruvate and NAC are capable of detoxifying H(2)O(2) to maintain cell viability and Hsp90 integrity. Acute renal injuries associated with oxidative stress might preventable by appropriate antioxidants.}, }
@article {pmid10846614, year = {1998}, author = {Vasdev, S and Ford, CA and Longerich, L and Parai, S and Gadag, V and Wadhawan, S}, title = {Aldehyde induced hypertension in rats: prevention by N-acetyl cysteine.}, journal = {Artery}, volume = {23}, number = {1}, pages = {10-36}, pmid = {10846614}, issn = {0098-6127}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Aldehydes/analysis ; Animals ; Arterioles/drug effects/pathology ; Blood Platelets/chemistry/drug effects ; Blood Pressure/drug effects ; Body Weight/drug effects ; Calcium/blood ; Carbohydrate Metabolism ; Diet ; Drinking/drug effects ; Eating/drug effects ; Energy Intake/drug effects ; Hyperplasia ; Hypertension/*chemically induced/prevention &amp; control ; Insulin Resistance ; Kidney/blood supply ; Male ; Muscle, Skeletal/chemistry ; Muscle, Smooth, Vascular/drug effects/pathology ; Nitrates/blood ; Nitric Oxide/blood ; Nitrites/blood ; Organ Size/drug effects ; Pyruvaldehyde/*toxicity ; Rats ; Rats, Inbred WKY ; Renal Artery/drug effects/pathology ; Viscera/chemistry ; }, abstract = {Methylglyoxal, a highly reactive endogenous aldehyde is formed in the tissue of humans and animals as an intermediate of glucose and fructose metabolism. N-acetyl cysteine (NAC), an analogue of the dietary amino acid cysteine, binds aldehydes thus preventing their damaging effect on physiological proteins. We measured systolic blood pressure (SBP), platelet [Ca2+]i, circulating nitric oxide levels, tissue aldehyde conjugates and renal vascular changes in chronic methyglyoxal treated Wistar-Kyoto (WKY) rats and examined the effect of NAC in the diet on these parameters. Animals, age seven weeks, were divided into three groups of six animals each and were treated as follows: WKY-control (chow diet and normal drinking water); WKY-methylglyoxal (chow diet and methyglyoxal in drinking water); WKY-methyglyoxal + NAC (1.5% NAC in diet and methylglyoxal in drinking water) for the next 18 weeks. Methylgyoxal in drinking water was given at a concentration of 0.2% during weeks 0-5; 0.4%, weeks 6-10; and 0.8%, weeks 11-18. After 18 weeks systolic blood pressure, platelet [Ca2+]i and kidney aldehyde conjugates were significantly higher and serum nitric oxide levels lower in methylglyoxal treated rats. Methylglyoxal treated rats also showed smooth muscle cell hyperplasia in the small artery and arterioles of the kidney. N-acetyl cysteine, an aldehyde binding thiol compound, prevented these changes.}, }
@article {pmid10844609, year = {2000}, author = {Cao, LC and Honeyman, T and Jonassen, J and Scheid, C}, title = {Oxalate-induced ceramide accumulation in Madin-Darby canine kidney and LLC-PK1 cells.}, journal = {Kidney international}, volume = {57}, number = {6}, pages = {2403-2411}, doi = {10.1046/j.1523-1755.2000.00099.x}, pmid = {10844609}, issn = {0085-2538}, support = {DK43184/DK/NIDDK NIH HHS/United States ; ES07864/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/pharmacology ; Ceramides/antagonists &amp; inhibitors/biosynthesis/*metabolism ; Dogs ; Epithelial Cells/metabolism ; Kidney/cytology/*metabolism ; LLC-PK1 Cells ; Oxalates/*pharmacology ; Oxidation-Reduction ; Phospholipases A/metabolism ; Phospholipases A2 ; Sphingomyelins/metabolism ; Swine ; }, abstract = {BACKGROUND: Oxalate exposure produces oxidant stress in renal epithelial cells leading to death of some cells and adaptation of others. The pathways involved in these diverse actions remain unclear, but appear to involve activation of phospholipase A2 (PLA2) and redistribution of membrane phospholipids. The present studies examined the possibility that oxalate actions may also involve increased accumulation of ceramide, a lipid-signaling molecule implicated in a variety of pathways, including those leading to apoptotic cell death.<br><br>METHODS: Ceramide accumulation was examined in renal epithelial cells from pig kidney (LLC-PK1 cells) and from dog kidney [Madin-Darby canine kidney (MDCK cells)] using the diacylglycerol kinase assay. Sphingomyelin degradation was assessed by monitoring the disappearance of 3H-sphingomyelin from cells that had been prelabeled with [3H]-choline. The effects of oxalate were compared with those of other oxidants (peroxide, xanthine/xanthine oxidase), other organic acids (formate and citrate), and a known activator of sphingomyelinase in these cells [tumor necrosis factor-alpha (TNF-alpha)]. Separate studies determined whether oxalate-induced accumulation of ceramide could be blocked by pretreatment with antioxidants [Mn (III) tetrakis (1-methyl-4-pyridyl) porphyrin (Mn TMPyP, a superoxide dismutase mimetic) or N-acetylcysteine (NAC; an antioxidant)], with an inhibitor of ceramide synthase [fumonisin B1 (FB1)] or with an inhibitor of PLA2 [arachidonyl trifluoromethylketone (AACOCF3)].<br><br>RESULTS: Oxalate exposure produced a significant time- and concentration-dependent increase in cellular ceramide. A reciprocal decrease in 3H-sphingomyelin was observed under these conditions. Increases in cellular ceramide levels were also observed after treatment with other oxidants (hydrogen peroxide, and xanthine/xanthine oxidase), activators of sphingomyelinase (TNF-alpha), exogenous sphingomyelinase, or arachidonic acid. Formate produced similar (albeit smaller) effects, and citrate did not. The oxidant-induced increases in ceramide were attenuated by pretreatment with NAC (a glutathione precursor) and MnTMPyP (a superoxide dismutase mimetic), suggesting a role for cellular redox states. The oxalate-induced increase in ceramide was also attenuated by pretreatment with AACOCF3, suggesting a role for PLA2. Pretreatment with FB1 produced a small but statistically insignificant attenuation of the response to oxalate.<br><br>CONCLUSIONS: Oxalate exposure produces a marked accumulation of ceramide in renal epithelial cells by a process that is redox sensitive and mediated in part by activation of PLA2. Since cellular sphingomyelin decreased as ceramide increased, it seems likely that oxalate actions are mediated, at least in part, by an increase in sphingomyelinase activity, although alterations in ceramide synthase are also possible. Further study is required to define the steps involved in oxalate actions and to determine the extent to which ceramide signaling mediates oxalate actions.}, }
@article {pmid10843427, year = {2000}, author = {Hashimoto, S and Gon, Y and Matsumoto, K and Takeshita, I and Asai, Y and Asai, Y and Machino, T and Horie, T}, title = {Regulation by intracellular glutathione of TNF-alpha-induced p38 MAP kinase activation and RANTES production by human pulmonary vascular endothelial cells.}, journal = {Allergy}, volume = {55}, number = {5}, pages = {463-469}, doi = {10.1034/j.1398-9995.2000.00455.x}, pmid = {10843427}, issn = {0105-4538}, mesh = {Acetylcysteine/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Chemokine CCL5/*analysis ; Endothelium, Vascular/drug effects/immunology/*metabolism ; Glutathione/*pharmacology ; Humans ; Imidazoles/pharmacology ; Immunoblotting ; Lung/blood supply ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Oxidation-Reduction ; Pyridines/pharmacology ; Time Factors ; Tumor Necrosis Factor-alpha/*pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {BACKGROUND: We have previously shown that p38 mitogen-activated protein (MAP) kinase regulates tumor necrosis factor-alpha (TNF-alpha)-induced RANTES production by human pulmonary vascular endothelial cells, and that sensitivity to TNF-alpha is inversely correlated with cellular reduction and oxidation (redox) state. However, a regulatory role of intracellular glutathione (GSH) in TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production has not been determined. In the present study, therefore, we extended our previous studies and focused on redox regulation on p38 MAP kinase activation.<br><br>METHODS: Human pulmonary vascular endothelial cells were exposed to N-acetylcysteine (NAC) or buthionine sulfoximine (BSO), and then TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production were determined.<br><br>RESULTS: The results showed that 1) NAC attenuated TNF-alpha-induced p38MAP kinase activation and RANTES production 2) SB 203580 as the specific inhibitor of p38 MAP kinase activity attenuated TNF-alpha-induced RANTES production 3) BSO facilitated TNF-alpha-induced p38 MAP kinase activation and RANTES production 4) SB 203580 attenuated BSO-mediated facilitation of TNF-alpha-induced RANTES production.<br><br>CONCLUSIONS: These results indicated that TNF-alpha-induced p38 MAP kinase activation and p38 MAP kinase-mediated RANTES production by human pulmonary vascular endothelial cells are inversely regulated by intracellular GSH levels.}, }
@article {pmid10842199, year = {2000}, author = {Mantovani, G and Macciò, A and Melis, G and Mura, L and Massa, E and Mudu, MC}, title = {Restoration of functional defects in peripheral blood mononuclear cells isolated from cancer patients by thiol antioxidants alpha-lipoic acid and N-acetyl cysteine.}, journal = {International journal of cancer}, volume = {86}, number = {6}, pages = {842-847}, doi = {10.1002/(sici)1097-0215(20000615)86:6&lt;842::aid-ijc13&gt;3.0.co;2-k}, pmid = {10842199}, issn = {0020-7136}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Antioxidants/*pharmacology ; Cell Cycle ; Cytokines/blood ; Flow Cytometry ; Humans ; Leukocytes, Mononuclear/*physiology ; Lymphocyte Activation ; Middle Aged ; Neoplasms/*immunology ; Nitric Oxide/physiology ; Receptors, Interleukin-2/analysis ; Thioctic Acid/*pharmacology ; fas Receptor/analysis ; }, abstract = {The ability of Alpha-Lipoic Acid (ALA) and N-Acetyl Cysteine (NAC), two active antioxidant agents, to correct in vitro the most significant functional defects of peripheral blood mononuclear cells (PBMC) isolated from advanced stage cancer patients was studied. The proliferative response of PBMC isolated from cancer patients to anti-CD3 monoclonal antibody (MAb) and the expression of CD25 (IL-2R) and CD95 (Fas) on unstimulated and anti-CD3 MAb-stimulated PBMC were studied, and the serum levels of proinflammatory cytokines IL-1, IL-6, TNFalpha as markers of pro-cachectic activity in cancer patients, and the serum levels of IL-2 and sIL-2R were assessed. Twenty patients (mean age 64.6 years) with cancer of lung, ovary, endometrium, and head and neck, all in advanced (III, IV) stage of disease, were studied. The serum levels of IL-1beta, IL-2, IL-6, TNFalpha, and sIL-2R were significantly higher in cancer patients than in normal subjects. The response of PBMC isolated from cancer patients to anti-CD3 MAb was significantly lower than that of controls. The addition of either ALA 0.001 mM or NAC 0.004 mM in the PBMC cultures stimulated with anti-CD3 MAb significantly increased the response of PBMC isolated from cancer patients and normal subjects. After 24 and 72 hr of culture with anti-CD3 MAb, the expression of CD25 and CD95 on PBMC isolated from cancer patients was significantly lower than that of PBMC isolated from normal subjects. The addition of either ALA or NAC into cultures of PBMC isolated from cancer patients significantly increased the percentage of cells expressing CD25 as well as those expressing CD95. The results of the present study show a favorable effect of antioxidant agents ALA and NAC on several important T-cell functions in vitro in advanced-stage cancer patients.}, }
@article {pmid10841796, year = {2000}, author = {Noszál, B and Visky, D and Kraszni, M}, title = {Population, acid-base, and redox properties of N-acetylcysteine conformers.}, journal = {Journal of medicinal chemistry}, volume = {43}, number = {11}, pages = {2176-2182}, doi = {10.1021/jm9909600}, pmid = {10841796}, issn = {0022-2623}, mesh = {Acetylcysteine/*chemistry/pharmacokinetics ; Acid-Base Equilibrium ; Disulfides/chemistry ; Free Radical Scavengers/*chemistry/pharmacokinetics ; Hydrogen-Ion Concentration ; Oxidation-Reduction ; Stereoisomerism ; Sulfhydryl Compounds/chemistry ; }, abstract = {Rotamers of N-acetyl-L-cysteine (NAC, the most popular mucolytic drug) are characterized in terms of populations, site- and conformer-specific acid-base properties, reducing strength, and molecular pharmacology. A new, general relationship between the bulk- and rotamer-specific basicities is introduced. NAC at high pH predominantly exists in a trans thiolate-carboxylate rotameric form, whereas protonation promotes the occurrence of intramolecular hydrogen bond-forming isomers. Distribution curves of the rotamers are depicted as a function of pH. Rotamer-dependent thiolate basicities differ by up to 0.5 log k units. Carboxylate basicities show slight conformation-dependence only. The membrane-penetrating capabilities from various compartments of the body are assessed on the basis of the pH-dependent charge of the molecule. The thiol-disulfide half-cell potential is calculated, using the correlation between the thiolate basicity and oxidizability. The oxidation-reduction properties of NAC are compared to those of other biological thiols in their definite microscopic forms. The pharmacokinetic behavior is interpreted in terms of the physicochemical parameters, providing molecular/submolecular explanation for several therapeutic properties of NAC.}, }
@article {pmid10839919, year = {2000}, author = {Welters, ID and Menzebach, A and Goumon, Y and Cadet, P and Menges, T and Hughes, TK and Hempelmann, G and Stefano, GB}, title = {Morphine inhibits NF-kappaB nuclear binding in human neutrophils and monocytes by a nitric oxide-dependent mechanism.}, journal = {Anesthesiology}, volume = {92}, number = {6}, pages = {1677-1684}, doi = {10.1097/00000542-200006000-00027}, pmid = {10839919}, issn = {0003-3022}, support = {DA09010/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Analgesics, Opioid/*pharmacology ; Cell Nucleus/drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Flow Cytometry ; Humans ; In Vitro Techniques ; Lipopolysaccharides ; Male ; Monocytes/drug effects/*metabolism ; Morphine/*pharmacology ; NF-kappa B/drug effects/*metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Naloxone/pharmacology ; Narcotic Antagonists/pharmacology ; Neutrophils/drug effects/*metabolism ; Nitric Oxide/*physiology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Protein Binding ; Receptors, Opioid, mu/drug effects/metabolism ; }, abstract = {BACKGROUND: The transcription factor NF-kappaB plays a pivotal role in gene expression of inflammatory mediators such as cytokines or adhesion molecules. NF-kappaB-mediated transcriptional activation of these genes is inhibited by nitric oxide (NO) in a variety of cells, including monocytes. Morphine mediates NO release in a naloxone antagonizable manner in monocytes and neutrophils.<br><br>METHODS: The influence of morphine on NF-kappaB activation was investigated in a whole-blood flow cytometric assay. A specific antibody against the p65 subunit of NF-kappaB was used and detected by fluoresceine-isothiocyanate-labeled anti-immunoglobulin G. Nuclei were stained with propidium iodide. Leukocyte subpopulations were evaluated by gating on neutrophils and monocytes. The median fluorescence channel was determined. Different morphine concentrations (50 nm, 50 microm, 1 mm) and incubation intervals (10-150 min) were used.<br><br>RESULTS: Morphine inhibits lipopolysaccharide-induced NF-kappaB nuclear binding in human blood neutrophils and monocytes in a time-, concentration-, and naloxone-sensitive-dependent manner. Similar effects were achieved with the NO donor S-nitroso-N-acetyl-pencillamine and the antioxidant N-acetyl-cysteine. The NO synthase inhibitors Nomega-nitro-l-arginine-methyl-esther and Nomega-nitro-l-arginine completely abolished the morphine-induced attenuation of NF-kappaB nuclear binding, demonstrating that the inhibitory action is mediated by NO release.<br><br>CONCLUSION: Morphine causes immunosuppression, at least in part, via the NO-stimulated depression of NF-kappaB nuclear binding.}, }
@article {pmid10837337, year = {2000}, author = {Gow, AJ and Chen, Q and Gole, M and Themistocleous, M and Lee, VM and Ischiropoulos, H}, title = {Two distinct mechanisms of nitric oxide-mediated neuronal cell death show thiol dependency.}, journal = {American journal of physiology. Cell physiology}, volume = {278}, number = {6}, pages = {C1099-107}, doi = {10.1152/ajpcell.2000.278.6.C1099}, pmid = {10837337}, issn = {0363-6143}, support = {AG-11542/AG/NIA NIH HHS/United States ; HL-54926/HL/NHLBI NIH HHS/United States ; P01-AG11542/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Death/drug effects/physiology ; Cell Differentiation ; Cell Line ; Cell Survival/drug effects ; Cyclic GMP/analogs &amp; derivatives/metabolism/pharmacology ; Hydrazines/pharmacology ; Molsidomine/analogs &amp; derivatives/pharmacology ; Necrosis ; Neurons/*cytology/drug effects/*physiology ; Nitrates/pharmacology ; Nitric Oxide/pharmacology/*physiology ; Nitric Oxide Donors/*pharmacology ; Oxidants/pharmacology ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {To better understand the mechanism(s) underlying nitric oxide (. NO)-mediated toxicity, in the presence and absence of concomitant oxidant exposure, postmitotic terminally differentiated NT2N cells, which are incapable of producing. NO, were exposed to PAPA-NONOate (PAPA/NO) and 3-morpholinosydnonimine (SIN-1). Exposure to SIN-1, which generated peroxynitrite in the range of 25-750 nM/min, produced a concentration- and time-dependent delayed cell death. In contrast, a critical threshold concentration (>440 nM/min) was required for. NO to produce significant cell injury. Examination of cells by electron microscopy shows a largely necrotic injury after peroxynitrite exposure but mainly apoptotic-like morphology after. NO exposure. Cellular levels of reduced thiols correlated with cell death, and pretreatment with N-acetylcysteine (NAC) fully protected from cell death in either PAPA/NO or SIN-1 exposure. NAC given within the first 3 h posttreatment further delayed cell death and increased the intracellular thiol level in SIN-1 but not. NO-exposed cells. Cell injury from. NO was independent of cGMP, caspases, and superoxide or peroxynitrite formation. Overall, exposure of non-. NO-producing cells to. NO or peroxynitrite results in delayed cell death, which, although occurring by different mechanisms, appears to be mediated by the loss of intracellular redox balance.}, }
@article {pmid10832073, year = {2000}, author = {Shen, H and Yang, C and Liu, J and Ong, C}, title = {Dual role of glutathione in selenite-induced oxidative stress and apoptosis in human hepatoma cells.}, journal = {Free radical biology &amp; medicine}, volume = {28}, number = {7}, pages = {1115-1124}, doi = {10.1016/s0891-5849(00)00206-9}, pmid = {10832073}, issn = {0891-5849}, mesh = {Acetylcysteine/toxicity ; Apoptosis/*drug effects ; Buthionine Sulfoximine/toxicity ; Carcinoma, Hepatocellular/*metabolism/*pathology ; Glutathione/*physiology/toxicity ; Growth Inhibitors/toxicity ; Humans ; Intracellular Fluid/drug effects/metabolism ; L-Lactate Dehydrogenase/metabolism ; Liver Neoplasms/*metabolism/*pathology ; Oxidative Stress/*drug effects ; Reactive Oxygen Species/metabolism ; Sodium Selenite/*toxicity ; Tumor Cells, Cultured ; }, abstract = {It is well known that glutathione, the major intracellular antioxidant, is closely involved in the metabolism and bioactivity of selenium. In the present study, glutathione was demonstrated to play a dual role on selenite (Se)-induced oxidative stress and apoptosis in human hepatoma HepG(2) cells. The experiment was carried out in two different modes to modulate intracellular reduced glutathione (GSH) content. In Mode A (pretreatment), cells were pretreated with N-acetylcysteine (NAC), buthionine sulfoximine (BSO), or GSH prior to Se exposure. In Mode B (simultaneous treatment), cells were treated with Se and NAC, BSO, or GSH simultaneously. It was found that Se-induced oxidative stress and apoptosis are closely related to the intracellular level of GSH. Both the increase and depletion of GSH content significantly enhanced Se-induced oxidative stress and apoptosis in HepG(2) cells. Results from this study clearly demonstrated that GSH has a dual role in the effects of Se on cancer cells: (i) GSH acts as a pro-oxidant, facilitating Se-induced oxidative stress, and (ii) GSH acts as an antioxidant, protecting against Se-induced oxidative stress and apoptosis. Understanding such a unique association between GSH and Se may help to explain the controversy in the literature over the complex relationship between selenium and glutathione, and ultimately the capability of selenium to prevent cancer.}, }
@article {pmid10830784, year = {2000}, author = {Ardite, E and Sans, M and Panés, J and Romero, FJ and Piqué, JM and Fernández-Checa, JC}, title = {Replenishment of glutathione levels improves mucosal function in experimental acute colitis.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {80}, number = {5}, pages = {735-744}, doi = {10.1038/labinvest.3780077}, pmid = {10830784}, issn = {0023-6837}, support = {AA09526/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Acute Disease ; Animals ; Colitis/*metabolism ; Ethanol/toxicity ; Glutathione/*physiology ; Inflammatory Bowel Diseases/etiology ; Intestinal Mucosa/drug effects/*physiology ; Male ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Time Factors ; Trinitrobenzenesulfonic Acid/toxicity ; }, abstract = {Because reactive oxygen species (ROS) have been implicated as mediators of inflammatory bowel disease (IBD), the purpose of the present work was to determine the functional role of mucosal GSH in the trinitrobenzenesulfonic acid in 50% ethanol (TNBS+ethanol)-induced colitis in rats. Mucosal samples were taken to evaluate the temporal relationship between the extent of injury, the levels of glutathione (GSH) during acute colitis induced by TNBS+ethanol, and the effect of N-acetylcysteine (NAC) administration. In vitro assays revealed the interaction of TNBS with GSH leading to the almost instantaneous disappearance of GSH, while the reductive metabolism of TNBS by GSSG reductase generated ROS. Mucosal samples from TNBS+ethanol-treated rats indicated a direct correlation between GSH depletion and injury detected as soon as 30 minutes after TNBS+ethanol administration that persisted 24 hours post treatment. Although, short term depletion of mucosal GSH per se by diethylmaleate did not result in mucosal injury, the oral administration of NAC (40 mM) 4 hours after TNBS+ethanol treatment increased GSH stores (2-fold), decreasing the extent of mucosal injury (60-70%) examined at 24 hours post treatment. However, an equimolar dose of dithiothreitol failed to increase GSH levels and protect mucosa from TNBS+ethanol-induced injury. Interestingly, GSH levels in TNBS+ethanol-treated rats recovered by 1-2 weeks, an effect that was accounted for by an increase of gamma-glutamylcysteine synthetase (gamma-GCS) activity due to an induction of gamma-GCS-heavy subunit chain mRNA. Thus, TNBS promotes two independent mechanisms of injury, GSH depletion and ROS generation, both being required for the manifestation of mucosal injury as GSH limitation renders intestine susceptible to the TNBS-induced ROS overgeneration. Accordingly, in vivo administration of NAC attenuates the acute colitis through increased mucosal GSH levels, suggesting that GSH precursors may be of relevance in the acute relapse of IBD.}, }
@article {pmid10828269, year = {2000}, author = {Boulares, AH and Giardina, C and Inan, MS and Khairallah, EA and Cohen, SD}, title = {Acetaminophen inhibits NF-kappaB activation by interfering with the oxidant signal in murine Hepa 1-6 cells.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {55}, number = {2}, pages = {370-375}, doi = {10.1093/toxsci/55.2.370}, pmid = {10828269}, issn = {1096-6080}, support = {GM31460/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/pharmacology ; Analgesics, Non-Narcotic/*pharmacology ; Animals ; Antioxidants/pharmacology ; Blotting, Western ; Carcinoma, Hepatocellular/metabolism ; DNA Probes/chemistry ; DNA-Binding Proteins/metabolism ; Fluoresceins/pharmacology ; Hydrogen Peroxide/pharmacology ; *I-kappa B Proteins ; Mice ; NF-KappaB Inhibitor alpha ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Oxidation-Reduction/drug effects ; Pyrrolidines/pharmacology ; Signal Transduction/drug effects ; Thiocarbamates/pharmacology ; Tumor Cells, Cultured ; }, abstract = {A toxic dose of acetaminophen (APAP) reduces the activity of NF-kappaB in mouse liver. NF-kappaB inactivation may be important for APAP toxicity, as this transcription factor can play a central role in maintaining hepatic viability. We recently reported that APAP likewise inhibits serum growth factor activation of NF-kappaB in a mouse hepatoma cell line (Hepa 1-6 cells). Here we present evidence that APAP's antioxidant activity may be involved in this NF-kappaB inhibition in Hepa 1-6 cells. Like the antioxidants N-acetylcysteine (NAC) and pyrrolidinedithiocarbamate (PDTC), APAP was found to suppress the H(2)O(2)-induced oxidation of an intracellular reactive oxygen species probe (dihydrodichlorofluorescein) in Hepa 1-6 cells. Treatment of Hepa 1-6 cells with H(2)O(2) was sufficient for NF-kappaB activation and IkappaBalpha degradation, and APAP was able to block both of these events. The APAP inhibition of NF-kappaB activation by serum growth factors may also be due to APAP's antioxidant activity, as the antioxidants NAC and PDTC likewise inhibit this activation. The potential role of NF-kappaB and oxidant-based growth factor signal transduction in APAP toxicity is discussed.}, }
@article {pmid10826560, year = {2000}, author = {Chun, TH and Itoh, H and Saito, T and Yamahara, K and Doi, K and Mori, Y and Ogawa, Y and Yamashita, J and Tanaka, T and Inoue, M and Masatsugu, K and Sawada, N and Fukunaga, Y and Nakao, K}, title = {Oxidative stress augments secretion of endothelium-derived relaxing peptides, C-type natriuretic peptide and adrenomedullin.}, journal = {Journal of hypertension}, volume = {18}, number = {5}, pages = {575-580}, doi = {10.1097/00004872-200018050-00010}, pmid = {10826560}, issn = {0263-6352}, mesh = {Acetylcysteine/pharmacology ; Adrenomedullin ; Animals ; Antioxidants/pharmacology ; Arteriosclerosis/physiopathology ; Base Sequence ; Cattle ; Cells, Cultured ; DNA Primers/genetics ; Endothelium, Vascular/drug effects/metabolism ; Gene Expression ; Humans ; Hydrogen Peroxide/toxicity ; Hypertension/physiopathology ; Natriuretic Peptide, C-Type/genetics/*metabolism ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II ; Nitric Oxide Synthase Type III ; Oxidative Stress/drug effects/genetics/*physiology ; Peptides/genetics/*metabolism ; RNA, Messenger/genetics/metabolism ; Vasodilation/physiology ; }, abstract = {OBJECTIVE: Excess oxidative stress is one of the major metabolic abnormalities on vascular walls in hypertension and atherosclerosis. In order to further elucidate the endothelial function under oxidative stress, the effect of hydrogen peroxide (H2O2) on expression of two novel endothelium-derived vasorelaxing peptides, C-type natriuretic peptide (CNP) and adrenomedullin (AM) from bovine carotid artery endothelial cells (BCAECs) was examined.<br><br>METHODS: BCAECs were treated with H2O2 (0.1-1.0 mmol/ l) and/or an antioxidant, N-acetylcysteine (NAC) (5-10 mmol/l), and incubated for 48 h. The concentrations of CNP and AM were measured with the specific radioimmuno assays that we originally developed. CNP and AM mRNA expressions were also examined by reverse transcription-polymerase chain reaction (RT-PCR).<br><br>RESULTS: Treatment of BCAECs with 0.5 and 1 mmol/l H2O2 induced 9-and 10-fold increases of CNP concentration in the media. Addition of 10 mmol/l NAC significantly suppressed the effect of H2O2 by 52%. RT-PCR analysis showed that CNP mRNA expression in BCAECs was also rapidly augmented within 1 h with H2O2 (1 mmol/l) treatment, and reached a peak at 3 h to show a 10-fold increase. AM secretion from BCAECs also increased to two-fold with exposure to 0.5 mmol/l H2O2, accompanied with the augmented level of AM mRNA. NAC 10 mmol/l completely suppressed the effect of H2O2 on AM secretion.<br><br>CONCLUSIONS: In this study, it has been demonstrated that H2O2 augments endothelial secretion of the two endothelium-derived relaxing peptides, CNP and AM. Our findings suggest the increased secretion of CNP and AM from endothelium under oxidative stress may function to compensate the impaired nitric oxide-dependent vasorelaxation in hypertension and atherosclerosis.}, }
@article {pmid10826559, year = {2000}, author = {Vasdev, S and Ford, CA and Parai, S and Longerich, L and Gadag, V}, title = {Dietary alpha-lipoic acid supplementation lowers blood pressure in spontaneously hypertensive rats.}, journal = {Journal of hypertension}, volume = {18}, number = {5}, pages = {567-573}, doi = {10.1097/00004872-200018050-00009}, pmid = {10826559}, issn = {0263-6352}, mesh = {Aldehydes/metabolism ; Animals ; Aorta/drug effects/metabolism/pathology ; Blood Glucose/metabolism ; Blood Platelets/drug effects/metabolism ; Blood Pressure/drug effects ; Calcium/blood ; *Dietary Supplements ; Hyperplasia ; Hypertension/*diet therapy/pathology/physiopathology ; Insulin/blood ; Kidney/blood supply/metabolism/pathology ; Liver/drug effects/metabolism/pathology ; Muscle, Smooth, Vascular/pathology ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Thioctic Acid/*administration &amp; dosage ; }, abstract = {BACKGROUND AND OBJECTIVES: In spontaneously hypertensive rats (SHRs), excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing cytosolic free calcium and blood pressure. The thiol compound, N-acetyl cysteine, normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes and normalizing membrane Ca2+ channels and cytosolic free calcium. The aim of the present study was to investigate whether a dietary supplementation of an endogenous fatty acid, alpha-lipoic acid, another thiol compound that is known to increase tissue cysteine and glutathione, can lower blood pressure and normalize associated biochemical and histopathological changes in SHRs.<br><br>METHODS AND RESULTS: Starting at 12 weeks of age, animals were divided into three groups of six animals each. Animals in the Wistar- Kyoto (WKY) rat control group and the SHR control group were given a normal diet, and the SHR-lipoic acid group was given a diet supplemented with lipoic acid (500 mg/kg feed) for the next 9 weeks. After 9 weeks, systolic blood pressure, platelet [Ca2+]i, plasma insulin and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls as compared with WKY rat controls and the SHR lipoic acid group. SHR controls also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys.<br><br>CONCLUSIONS: Dietary alpha-lipoic acid supplementation in SHRs lowered the systolic blood pressure, cytosolic [Ca2+]i, blood glucose and insulin levels, and tissue aldehyde conjugates, and attenuated adverse renal vascular changes.}, }
@article {pmid10814534, year = {2000}, author = {Kim, YH and Takahashi, M and Suzuki, E and Niki, E}, title = {Apoptosis induced by hydrogen peroxide under serum deprivation and its inhibition by antisense c-jun in F-MEL cells.}, journal = {Biochemical and biophysical research communications}, volume = {271}, number = {3}, pages = {747-752}, doi = {10.1006/bbrc.2000.2676}, pmid = {10814534}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Catalase/pharmacology ; Culture Media, Serum-Free ; DNA Fragmentation/drug effects ; DNA, Antisense/*pharmacology ; Flow Cytometry ; *Friend murine leukemia virus ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, jun/*genetics ; Hydrogen Peroxide/*pharmacology ; In Situ Nick-End Labeling ; *Leukemia, Erythroblastic, Acute ; Mice ; Proto-Oncogene Proteins c-jun/metabolism ; Tumor Cells, Cultured ; }, abstract = {Under serum deprivation F-MEL cells die by apoptosis. We previously showed that apoptosis induced by serum deprivation was suppressed by inhibition of c-jun expression using antisense c-jun transfected cell line, c-junAS. To elucidate the underlying mechanisms we examined the species which is responsible for apoptosis under serum deprivation. When catalase and N-acetyl-L-cysteine (NAC) were included in the medium, cell death under serum deprivation was effectively suppressed in F-MEL cells. Intracellular generation of hydrogen peroxide (H(2)O(2)) was also detected under serum deprivation in parental F-MEL cells, but it was suppressed in c-junAS (+) cells, in which antisense c-jun was expressed and c-Jun protein expression was inhibited as shown by Western blot. When H(2)O(2) was directly applied to F-MEL cells at 3 mM, apoptotic cell death was induced, whereas it was suppressed in c-junAS (+) cells. Induction of apoptosis by H(2)O(2) and its inhibition by antisense c-jun was confirmed by detection of internucleosomal fragmentation of DNA, TdT-mediated dUTP nick end labeling (TUNEL)-positive cells and morphological alteration of nuclei. These results indicate that apoptosis induced by serum deprivation in F-MEL cells is mediated by H(2)O(2) and c-jun expression is essential to apoptosis induced by H(2)O(2) in F-MEL cells.}, }
@article {pmid10813654, year = {2000}, author = {Fliege, R and Metzler, M}, title = {Electrophilic properties of patulin. N-acetylcysteine and glutathione adducts.}, journal = {Chemical research in toxicology}, volume = {13}, number = {5}, pages = {373-381}, doi = {10.1021/tx9901480}, pmid = {10813654}, issn = {0893-228X}, mesh = {Acetylcysteine/*chemistry ; Chromatography, High Pressure Liquid ; Glutathione/*chemistry ; Molecular Structure ; Mutagens/*chemistry ; Patulin/*chemistry ; }, abstract = {In our studies on the electrophilic properties of the mycotoxin patulin (PAT), we have now investigated the nonenzymatic reaction of PAT with the thiol-containing tripeptide glutathione and its metabolic degradation product N-acetyl-L-cysteine (NAC). Adduct formation in aqueous phosphate buffer (pH 7.4) was studied by analytical HPLC/DAD, and most of the products were isolated by preparative HPLC. Structure elucidation was carried out mainly by means of high-resolution NMR experiments and comparison of the data with those previously obtained for PAT adducts formed with simple model nucleophiles such as 4-bromothiophenol and 2-mercaptoethanol [Fliege, R., and Metzler, M. (2000) Chem. Res. Toxicol. 13, 363-372]. The assigned structures were confirmed by UV spectroscopy, formation of daughter products from isolated adducts, and partly FAB-MS. The reaction pathways of PAT with NAC were qualitatively the same as those previously observed for the aliphatic thiol model compound 2-mercaptoethanol. Due to the chiral nature of NAC and the new chiral center generated during the reaction with PAT, two diastereomers of each adduct were formed and observed in HPLC analysis. The major products formed in the reaction of PAT with GSH were of the same structural type as obtained with NAC. In addition, three cyclic adducts were formed with GSH, arising from the nucleophilic activity of the alpha-amino groups of the glutamic acid and the cysteine residue. In contrast, free cysteine yielded a markedly different adduct pattern, possibly due to the preferred formation of mixed thiol/amine-type adducts involving the alpha-amino group.}, }
@article {pmid10811998, year = {2000}, author = {Chiao, JW and Chung, F and Krzeminski, J and Amin, S and Arshad, R and Ahmed, T and Conaway, CC}, title = {Modulation of growth of human prostate cancer cells by the N-acetylcysteine conjugate of phenethyl isothiocyanate.}, journal = {International journal of oncology}, volume = {16}, number = {6}, pages = {1215-1219}, doi = {10.3892/ijo.16.6.1215}, pmid = {10811998}, issn = {1019-6439}, mesh = {Anticarcinogenic Agents/chemistry/pharmacology/*therapeutic use ; Cell Cycle/drug effects ; Cell Division/drug effects ; Humans ; Isothiocyanates/chemistry/pharmacology/*therapeutic use ; Male ; Prostatic Neoplasms/*drug therapy/pathology ; Tumor Cells, Cultured ; }, abstract = {There is growing evidence that thiol conjugates of isothiocyanates present in cruciferous vegetables are effective cancer chemopreventive and potentially active therapeutic agents. The effects of the N-acetylcysteine conjugate of phenethyl isothiocyanate (PEITC-NAC) on tumor cell growth were analyzed in human prostate cancer cell lines LNCaP, androgen-dependent, and DU-145, androgen-independent. Exposure of the cells to PEITC-NAC at high concentrations caused cytolysis, while at lower concentrations PEITC-NAC mediated a dose-dependent growth modulation, with reduction of DNA synthesis and growth rate, inhibition of clonogenicity and induction of apoptosis in both types of prostate cancer cells. PEITC-NAC decreased cells in S and G2M phases of cell cycle, blocking cells entering replicating phases. In parallel, a significant enhancement of cells expressing the cell cycle regulator p21 as well as its intensity was determined using a fluorescent antibody technique. The action of PEITC-NAC was time-dependent, with the magnitude of inhibition increasing to 50-65% after PEITC-NAC exposure for several days. Interaction of tumor cells with dissociation products of PEITC-NAC, PEITC and NAC, are proposed as the mechanism of growth regulation.}, }
@article {pmid10809266, year = {2000}, author = {Dötsch, J and Demirakça, S and Kratz, M and Repp, R and Knerr, I and Rascher, W}, title = {Comparison of methylene blue, riboflavin, and N-acetylcysteine for the reduction of nitric oxide-induced methemoglobinemia.}, journal = {Critical care medicine}, volume = {28}, number = {4}, pages = {958-961}, doi = {10.1097/00003246-200004000-00008}, pmid = {10809266}, issn = {0090-3493}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/*therapeutic use ; Erythrocytes/chemistry/drug effects ; Free Radical Scavengers/*therapeutic use ; Humans ; Methemoglobin/analysis/drug effects ; Methemoglobinemia/blood/chemically induced/*drug therapy ; Methylene Blue/*therapeutic use ; Nitric Oxide ; Riboflavin/*therapeutic use ; }, abstract = {OBJECTIVE: To investigate the treatment of nitric oxide (NO)-induced methemoglobinemia by methylene blue (MB), riboflavin, and N-acetylcysteine (NAC) in vitro.<br><br>DESIGN: Prospective, controlled in vitro study.<br><br>SETTING: Research laboratory in a university hospital.<br><br>PARTICIPANTS: Five healthy volunteers.<br><br>INTERVENTIONS: Generation of 16% to 18% of methemoglobin in red blood cells by NO and subsequent addition of MB, riboflavin, or NAC. Simultaneous NO (32 ppm) and MB or riboflavin exposure of red blood cells. Induction of 14% to 18% of methemoglobin in red blood cells by NO, subsequent addition of MB or riboflavin, and further incubation with NO (80 ppm).<br><br>MEASUREMENTS AND MAIN RESULTS: After discontinuation of NO, mean half-life for methemoglobin was significantly reduced by MB from 356 mins (controls) to 5 mins (10 microM) in a dose-dependent manner (p < .001). NAC did not alter the half-life for methemoglobin, and a reduction from 356 to 168 mins was seen for 120 microM riboflavin (p < .001). Methemoglobin formation after 3 hrs of NO exposure was 4.3%+/-0.7% in controls and 0.3%+/-0.1% with 10 microM MB (p < .001); 1 microM MB attenuated methemoglobin formation to 1.9%+/-0.1% (p < .01). With riboflavin (120 microM), methemoglobin was 2.2%+/-0.5% vs. 3.2%+/-0.6% in controls (p < .001). In the presence of high methemoglobin concentrations, further methemoglobin formation was inhibited by 1 and 10 microM MB (p < .001) and attenuated by 0.1 microM MB (p < .001) but not by riboflavin.<br><br>CONCLUSIONS: In vitro, NO-induced methemoglobin formation is significantly decreased by medium (1 microM) and high (10 microM) concentrations of MB and partially by high riboflavin concentrations (120 microM). NAC and low concentrations of riboflavin do not alter methemoglobin formation.}, }
@article {pmid10803710, year = {2000}, author = {del Olmo, M and Alonso-Varona, A and Castro, B and Calle, Y and Bilbao, P and Palomares, T}, title = {Effects of L-2-oxothiazolidine-4-carboxylate on the cytotoxic activity and toxicity of cyclophosphamide in mice bearing B16F10 melanoma liver metastases.}, journal = {Melanoma research}, volume = {10}, number = {2}, pages = {103-112}, pmid = {10803710}, issn = {0960-8931}, mesh = {Acrolein/pharmacokinetics/toxicity ; Alkylation/drug effects ; Animals ; Antineoplastic Agents, Alkylating/pharmacokinetics/*toxicity ; Biotransformation ; Cell Division/drug effects ; Cyclophosphamide/pharmacokinetics/*toxicity ; Cysteine/pharmacokinetics ; Disease Progression ; Drug Interactions ; Drug Screening Assays, Antitumor ; Female ; Glutathione/metabolism ; Leukopenia/chemically induced/*prevention &amp; control ; Liver Neoplasms/drug therapy/*secondary ; Melanoma, Experimental/drug therapy/*secondary ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction ; Prodrugs/pharmacokinetics/*therapeutic use ; Pyrrolidonecarboxylic Acid ; Thiazoles/pharmacokinetics/*therapeutic use ; Thiazolidines ; }, abstract = {Glutathione (GSH) is the major non-protein thiol in cells that plays a critical role against damage from electrophilic agents such as alkylating drugs. Selective therapeutic GSH elevation in normal but not in tumour cells has been suggested as a means of protecting host tissues against more intense doses of chemotherapy. The present study investigated the response of B16 melanoma to treatment with the cysteine pro-drug L-2-oxothiazolidine-4-carboxylate (OTZ), alone and in combination with cyclophosphamide (CY). We found that OTZ decreased the GSH levels and proliferation rate of B16 melanoma cells in vitro, sensitizing them to the cytotoxic action of the activated metabolite of CY, acrolein (AC). In contrast to OTZ, the cysteine deliverer N-acetylcysteine (NAC) enhanced B16 melanoma cell proliferation by increasing GSH levels, and markedly decreased the sensitivity of these tumour cells to AC. In vivo studies showed the antitumoral activity of OTZ in B16 melanoma liver metastasis-induced mice, increasing their life span. We also observed that, whereas with CY treatment the GSH levels in peripheral blood mononuclear cells (PBMCs) were reduced and a dose-dependent leukopenia was produced, OTZ significantly increased PBMC GSH content, reducing toxicity and enhancing the survival of mice bearing established melanoma liver metastases treated with lethal dose CY. These results suggest a critical role for OTZ in protecting against alkylator agent-induced immunosuppression, which may allow the dose escalation of these cytostatic drugs to improve their therapeutic benefit in the treatment of malignant melanoma.}, }
@article {pmid10800069, year = {2000}, author = {Ringdén, O and Remberger, M and Lehmann, S and Hentschke, P and Mattsson, J and Klaesson, S and Aschan, J}, title = {N-acetylcysteine for hepatic veno-occlusive disease after allogeneic stem cell transplantation.}, journal = {Bone marrow transplantation}, volume = {25}, number = {9}, pages = {993-996}, doi = {10.1038/sj.bmt.1702387}, pmid = {10800069}, issn = {0268-3369}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Child ; Cytokines/metabolism ; Female ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Hepatic Veno-Occlusive Disease/*drug therapy/*etiology/metabolism ; Humans ; Male ; Transplantation, Homologous ; }, abstract = {Three patients developed veno-occlusive disease of the liver (VOD) after allogeneic stem cell transplantation. On the day after diagnosis, N-acetylcysteine (NAC) was given, initially in loading doses and thereafter 50-150 mg/kg/day for 12 to 31 days. The maximum bilirubin levels were 137, 58 and 138 mmol/l in the three patients, respectively. After the introduction of NAC, bilirubin, aspartate aminotransferase, sIL-2 receptor and IL-8 decreased. All three patients achieved normal bilirubin levels and prothrombin times. To conclude, NAC may be useful for treatment of VOD.}, }
@article {pmid10792388, year = {2000}, author = {Takizawa, H and Abe, S and Ohtoshi, T and Kawasaki, S and Takami, K and Desaki, M and Sugawara, I and Hashimoto, S and Azuma, A and Nakahara, K and Kudoh, S}, title = {Diesel exhaust particles up-regulate expression of intercellular adhesion molecule-1 (ICAM-1) in human bronchial epithelial cells.}, journal = {Clinical and experimental immunology}, volume = {120}, number = {2}, pages = {356-362}, pmid = {10792388}, issn = {0009-9104}, mesh = {Bronchi/cytology ; Cell Adhesion ; Cell Line ; Flow Cytometry ; Gasoline/*adverse effects ; Humans ; Intercellular Adhesion Molecule-1/*genetics ; Neutrophils/physiology ; Respiratory Mucosa/cytology ; Solubility ; *Up-Regulation ; Vehicle Emissions/*adverse effects ; }, abstract = {Epidemiological and experimental studies suggest that diesel exhaust particles (DEP) may play an active role in the increased respiratory mortality and morbidity. We have shown that DEP augmented the production of inflammatory cytokines by human airway epithelial cells in vitro. ICAM-1 has been shown to play an important role in the local accumulation of inflammatory cells. We studied the effect of DEP on ICAM-1 gene expression and surface expression in human bronchial epithelial cell line BEAS-2B. DEP (5-50 microg/ml) showed a stimulatory effect on ICAM-1 mRNA levels as evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Flow cytometric analysis demonstrated an increased ICAM-1 expression on the epithelial cell surfaces. The soluble form of ICAM-1 molecules was also increased by the stimulation of DEP. In vitro neutrophil attachment onto DEP-stimulated epithelial cells was augmented, which was partially blocked by anti-ICAM-1 neutralizing antibody. Finally, these events were significantly inhibited by pretreatment with anti-oxidants pyrrolidine dithiocarbamate and N-acetyl cysteine, and p38 mitogen activated protein kinase (MAPK) inhibitor SB203580. These findings suggested that DEP induced up-regulation of ICAM-1 gene, and this process might be largely dependent on oxidant-mediated NF-kappaB activation and p38-MAPK pathways.}, }
@article {pmid10788610, year = {2000}, author = {Oka, S and Kamata, H and Kamata, K and Yagisawa, H and Hirata, H}, title = {N-acetylcysteine suppresses TNF-induced NF-kappaB activation through inhibition of IkappaB kinases.}, journal = {FEBS letters}, volume = {472}, number = {2-3}, pages = {196-202}, doi = {10.1016/s0014-5793(00)01464-2}, pmid = {10788610}, issn = {0014-5793}, mesh = {Acetylcysteine/*metabolism/pharmacology ; Biological Transport ; Cell Nucleus/metabolism ; Dithiothreitol/pharmacology ; Free Radical Scavengers/*metabolism/pharmacology ; HeLa Cells ; Humans ; I-kappa B Kinase ; NF-kappa B/*metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases/*antagonists &amp; inhibitors/metabolism ; Proteins/metabolism ; Receptors, Tumor Necrosis Factor/metabolism ; TNF Receptor-Associated Factor 1 ; TNF Receptor-Associated Factor 2 ; Tumor Necrosis Factor-alpha/*metabolism/pharmacology ; NF-kappaB-Inducing Kinase ; }, abstract = {Here, we used a reductant, N-acetyl-L-cysteine (NAC), to investigate the redox-sensitive step(s) in the signalling pathway from the tumor necrosis factor (TNF) receptor to nuclear factor kappaB (NF-kappaB). We found that NAC suppressed NF-kappaB activation triggered by TNF or by overexpression of either the TNF receptor-associated death domain protein, TNF receptor-associated factor 2, NF-kappaB-inducing kinase (NIK), or IkappaB kinases (IKKalpha and IKKbeta). NAC also suppressed the TNF-induced activation of IKKalpha and IKKbeta, phosphorylation and degradation of IkappaB, and nuclear translocation of NF-kappaB. Furthermore, NAC suppressed the activation of IKKalpha and IKKbeta triggered by the overexpression of NIK. These results indicate that IKKalpha and IKKbeta are subject to redox regulation in the cells, and that NAC inhibits NF-kappaB activation through the suppression of these kinases.}, }
@article {pmid10781801, year = {2000}, author = {Sarker, KP and Obara, S and Nakata, M and Kitajima, I and Maruyama, I}, title = {Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and caspase-3.}, journal = {FEBS letters}, volume = {472}, number = {1}, pages = {39-44}, doi = {10.1016/s0014-5793(00)01425-3}, pmid = {10781801}, issn = {0014-5793}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*physiology ; Arachidonic Acids/antagonists &amp; inhibitors/pharmacology/*physiology ; Caspase 3 ; Caspases/*metabolism ; Cell Survival ; Endocannabinoids ; PC12 Cells ; Polyunsaturated Alkamides ; Rats ; Superoxides/*metabolism ; }, abstract = {Anandamide (arachidonoylethanolamide), an endogenous cannabinoid receptor ligand has been suggested to have physiological role in mammalian nervous system. However, little is known about the role of anandamide on neuronal cells. Here, we demonstrate that anandamide causes death of PC-12 cells, showing marked DNA condensation and fragmentation, appearance of cells at sub-G(0)/G(1) and redistribution of phosphatidyl serine, the hallmark features of apoptosis. Anandamide raised intracellular superoxide level and CPP32-like protease activity in PC-12 cells markedly. Furthermore, antioxidant N-acetyl cysteine prevented anandamide-induced superoxide anion formation and cell death, implying that intracellular superoxide is a novel mediator of anandamide-induced apoptosis of PC-12 cells.}, }
@article {pmid10778915, year = {2000}, author = {van Overveld, FJ and Vermeire, PA and De Backer, WA}, title = {Induced sputum of patients with chronic obstructive pulmonary disease (COPD) contains adhesion-promoting, therapy-sensitive factors.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {49}, number = {1}, pages = {8-13}, doi = {10.1007/PL00000203}, pmid = {10778915}, issn = {1023-3830}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Inhalation ; Adrenal Cortex Hormones/administration &amp; dosage/*therapeutic use ; Cell Adhesion/*drug effects ; Cell Line ; Cross-Over Studies ; Double-Blind Method ; Endothelium/cytology ; Humans ; Lung Diseases, Obstructive/*drug therapy/metabolism ; Neutrophils/physiology ; Sputum/*metabolism ; Time Factors ; }, abstract = {OBJECTIVE: The aim of this study was to investigate whether sputum of COPD patients before and after treatment with inhaled corticosteroids (IHC) or N-acetylcysteine (NAC) exerts any effect on the adhesion of isolated polymorphonuclear cells (PMNs) to cultured endothelial cells.<br><br>METHODS: A human endothelial cell line was grown to confluence before use in adhesion experiments. PMNs were obtained from normal, non-smoking volunteers and preincubated (30 min, 37 degrees C) with diluted sputum sol obtained from COPD patients before the cells were put on the endothelial cells.<br><br>RESULTS: Basal adhesion of unstimulated PMNs after 30 min at 37 degrees C in 5% CO2 was 15.9+/-1.1% (mean +/- SEM, n = 9). A significant enhancement of the adhesion to 33.0+/-1.4% (n = 11, P<0.0001) was observed with sputum obtained from COPD patients before treatment with IHC, and 34.6+/-1.5% (n = 10, P<0.0001) before treatment with NAC. Administration of IHC for 8 weeks resulted in an adhesion of 27.7+/-2.4%, which is an inhibition of 31% (n = 11, P<0.05). However, treatment for 8 weeks with NAC showed no change in the adhesion of stimulated PMNs. Long-term treatment with NAC showed a gradual decrease of adhesion (n = 9, P<0.05), whereas long-term treatment with IHC lead to an increase in adhesion (n = 10, P<0.02).<br><br>CONCLUSIONS: These results indicate that factors locally produced in the airways of COPD patients may promote adhesion of neutrophils to endothelium. They further suggest that glucocorticoids may only have a short-term transient effect on adhesion, whereas NAC showed effects on the adhesion after administration for longer periods.}, }
@article {pmid10772898, year = {2000}, author = {Frank, GD and Motley, ED and Inagami, T and Eguchi, S}, title = {PYK2/CAKbeta represents a redox-sensitive tyrosine kinase in vascular smooth muscle cells.}, journal = {Biochemical and biophysical research communications}, volume = {270}, number = {3}, pages = {761-765}, doi = {10.1006/bbrc.2000.2505}, pmid = {10772898}, issn = {0006-291X}, support = {HL03320/HL/NHLBI NIH HHS/United States ; HL58205/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Aorta, Thoracic/cytology/enzymology ; Cells, Cultured ; Enzyme Activation ; Focal Adhesion Kinase 2 ; Hydrogen Peroxide/pharmacology ; Kinetics ; Male ; Muscle, Smooth, Vascular/cytology/*enzymology ; Oxidation-Reduction ; Phosphorylation ; Protein-Tyrosine Kinases/drug effects/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {In vascular smooth muscle cells (VSMCs), the focal adhesion kinase-related tyrosine kinase PYK2/CAKbeta is activated by vascular mitogens. Because reactive oxygen species (ROS) are assumed to mediate mitogenic signals by these agonists, we examined the possible link between ROS and PYK2 in cultured rat VSMCs. Here we present several lines of evidence showing that PYK2 is activated by ROS in VSMCs. The inhibitory effect of an antioxidant, N-acetyl-cysteine, on PYK2 activation by its specific agonists further suggests the pivotal role of PYK2 in vascular remodeling associated with enhanced ROS production.}, }
@article {pmid10771256, year = {2000}, author = {Ben-Menachem, E and Kyllerman, M and Marklund, S}, title = {Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies.}, journal = {Epilepsy research}, volume = {40}, number = {1}, pages = {33-39}, doi = {10.1016/s0920-1211(00)00096-6}, pmid = {10771256}, issn = {0920-1211}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Epilepsies, Myoclonic/blood/drug therapy/*enzymology/physiopathology ; Erythrocytes/enzymology ; Female ; Glutathione Peroxidase/*metabolism ; Humans ; Lafora Disease/blood/drug therapy/enzymology/physiopathology ; Male ; Reference Values ; Superoxide Dismutase/*metabolism ; Unverricht-Lundborg Syndrome/drug therapy/metabolism/physiopathology ; }, abstract = {Progressive myoclonic epilepsies (EPM) are difficult to treat and refractory to most antiepileptic drugs. Besides epilepsy, EPMs also involve continuous neurological deterioration. Oxidative stress is thought to be an important factor in this process. We therefore analyzed a series of antioxidant enzymes in the blood of patients and compared with healthy age matched controls. In addition patients were given high doses of N-acetylcysteine (NAC), a glutathione percursor to determine if symptoms of EPM would improve. Five patients, four with EPM 1 (Unverricht-Lundborg disease) and one patient with EPM2 (Lafora body disease) were treated with 6 g/day of NAC. Before treatment, plasma samples were analyzed for glutathione peroxidase activity, catalase activity, extracellular superoxide dismutase (SOD) and CuZn-SOD and compared with the controls. Erythrocyte CuZn-SOD was significantly lower in the EPM patients compared to controls. NAC improved markedly and stabilized the neurological symptoms in patients with EPM 1 but had a doubtful effect in the patient with EPM 2.}, }
@article {pmid10771087, year = {2000}, author = {Zaragoza, A and Díez-Fernández, C and Alvarez, AM and Andrés, D and Cascales, M}, title = {Effect of N-acetylcysteine and deferoxamine on endogenous antioxidant defense system gene expression in a rat hepatocyte model of cocaine cytotoxicity.}, journal = {Biochimica et biophysica acta}, volume = {1496}, number = {2-3}, pages = {183-195}, doi = {10.1016/s0167-4889(00)00036-7}, pmid = {10771087}, issn = {0006-3002}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*metabolism/pharmacology ; Catalase/genetics/metabolism ; Cells, Cultured ; Cocaine/toxicity ; Deferoxamine/*pharmacology ; Diploidy ; Dose-Response Relationship, Drug ; Flow Cytometry ; Gene Expression Regulation ; Gene Expression Regulation, Enzymologic/drug effects ; Glutathione Peroxidase/genetics/metabolism ; Hydrogen Peroxide/analysis ; Liver/*drug effects/enzymology/metabolism ; Male ; RNA, Messenger/analysis ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/metabolism ; }, abstract = {In the present study we investigated on cultures of hepatocytes from phenobarbital-pretreated rats, the effect of the antioxidants, 0.5 mM N-acetylcysteine (NAC) or 1.5 mM deferoxamine (DFO), previously incubated for 24 h and coincubated with cocaine (0-1000 microM) for another 24 h. Cocaine cytotoxicity was monitored by either the lysis of the cell membranes or apoptosis. Lysis of the cell membranes was evidenced by lactate dehydrogenase leakage, apoptosis was observed by detecting a hypodiploid peak (<2C) in DNA histograms obtained by flow cytometry, peroxide production was quantified with 2', 7'-dichlorodihydrofluorescein diacetate and gene expression of the antioxidant enzymes: Mn- and Cu,Zn-superoxide dismutases, catalase and glutathione peroxidase were measured by Northern blot analysis. NAC and DFO significantly decreased the extent of lysis of cell membranes and apoptosis, and the antiapoptotic effect was parallel to peroxide generation. By the effect of NAC and DFO, significant increases were detected in the levels of mRNA of catalase, manganese superoxide dismutase and glutathione peroxidase. From these results we conclude that NAC or DFO, when incubated in the presence of cocaine, exerted a protective effect against cocaine toxicity at the level of both lysis of the membranes and apoptosis. This protective effect, in the case of NAC, was directed towards an increase in antioxidant enzyme expression, and in the case of DFO against reactive oxygen species generation.}, }
@article {pmid10759444, year = {2000}, author = {Rubio, ML and Sanchez-Cifuentes, MV and Ortega, M and Peces-Barba, G and Escolar, JD and Verbanck, S and Paiva, M and González Mangado, N}, title = {N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats.}, journal = {The European respiratory journal}, volume = {15}, number = {3}, pages = {505-511}, doi = {10.1034/j.1399-3003.2000.15.13.x}, pmid = {10759444}, issn = {0903-1936}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bronchi/*drug effects/pathology/physiopathology ; Male ; Rats ; Rats, Wistar ; *Tobacco Smoke Pollution ; }, abstract = {This study investigated the effect of cigarette smoke exposure and the potential protection N-acetylcysteine (NAC) in rat lungs. Forty-eight rats were exposed to cigarette smoke (CS) for 10 weeks, without (CS group) or with (CS+NAC group) oral intake of NAC 200 mg x rat(-1) x day(-1), or to fresh air (Control). All rat lungs were assessed in terms of lung function, ventilation distribution (nitrogen, helium and sulphur hexafluoride phase III slopes), and morphometry (airway wall thickening of small, medium and large bronchi). The small bronchi, defined as the airways with an internal perimeter <1,000 microm showed significantly thicker airway walls in the CS than in the Control group. By contrast, no airway wall thickening was observed in the CS+NAC group with respect to Control. Except for decreased lung volumes and compliance in CS and CS+NAC groups, which were entirely attributable to smaller body weight gain, lung function was indistinguishable from Control. Phase III slopes were significantly increased only in the CS group. In conclusion, smoke-induced alterations in the rat lungs were reflected in wall thickening of the small bronchi and increased ventilation maldistribution. These smoke-induced morphometric and ventilation distribution alterations were prevented by N-acetylcysteine.}, }
@article {pmid10759030, year = {2000}, author = {Breitkreutz, R and Pittack, N and Nebe, CT and Schuster, D and Brust, J and Beichert, M and Hack, V and Daniel, V and Edler, L and Dröge, W}, title = {Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {78}, number = {1}, pages = {55-62}, doi = {10.1007/s001099900073}, pmid = {10759030}, issn = {0946-2716}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acquired Immunodeficiency Syndrome/blood/*drug therapy/immunology/virology ; Administration, Oral ; Adolescent ; Adult ; Antigens, CD/metabolism ; Double-Blind Method ; Female ; Glutamine/blood ; *HIV-1 ; Humans ; Interleukin-6/blood ; Killer Cells, Natural/metabolism ; Male ; Middle Aged ; Placebos ; Serum Albumin/metabolism ; T-Lymphocytes/metabolism ; Thioredoxins/blood ; Viral Load ; }, abstract = {To determine the therapeutic effect of sulfur amino acid supplementation in HIV infection we randomized 40 patients with antiretroviral therapy (ART; study 1) and 29 patients without ART (study 2) to treatment for 7 months with N-acetyl-cysteine or placebo at an individually adjusted dose according to a defined scheme. The main outcome measures were the change in immunological parameters including natural killer (NK) cell and T cell functions and the viral load. Both studies showed consistently that N-acetyl-cysteine causes a marked increase in immunological functions and plasma albumin concentrations. The effect of N-acetyl-cysteine on the viral load, in contrast, was not consistent and may warrant further studies. Our findings suggest that the impairment of immunological functions in HIV+ patients results at least partly from cysteine deficiency. Because immune reconstitution is a widely accepted aim of HIV treatment, N-acetyl-cysteine treatment may be recommended for patients with and without ART. Our previous report on the massive loss of sulfur in HIV-infected subjects and the present demonstration of the immunoreconstituting effect of cysteine supplementation indicate that the HIV-induced cysteine depletion is a novel mechanism by which a virus destroys the immune defense of the host and escapes immune elimination.}, }
@article {pmid10757551, year = {2000}, author = {Liu, L and Yeh, YY}, title = {Inhibition of cholesterol biosynthesis by organosulfur compounds derived from garlic.}, journal = {Lipids}, volume = {35}, number = {2}, pages = {197-203}, pmid = {10757551}, issn = {0024-4201}, mesh = {Acetates/metabolism ; Animals ; Anticholesteremic Agents/*pharmacology ; Carbon Radioisotopes ; Cells, Cultured ; Cholesterol/*biosynthesis ; Garlic/*chemistry ; Inhibitory Concentration 50 ; L-Lactate Dehydrogenase/drug effects/metabolism ; Liver/cytology/drug effects/metabolism ; Male ; *Plants, Medicinal ; Rats ; Rats, Sprague-Dawley ; Sulfur Compounds/*pharmacology ; Toxicity Tests ; }, abstract = {The study was undertaken to test the inhibitory potential on cholesterogenesis of organosulfur compounds derived from garlic. The primary rat hepatocytes maintained in Dulbecco's modified Eagle's medium were treated with [2-14C]acetate as substrate for cholesterol synthesis in the presence or absence of test compounds at 0.05 to 4.0 mmol/L. Eleven water-soluble and six lipid-soluble compounds of garlic were tested. Among water-soluble compounds, S-allyl cysteine (SAC), S-ethyl cysteine (SEC), and S-propyl cysteine (SPC) inhibited [2-14C]acetate incorporation into cholesterol in a concentration-dependent manner, achieving 42 to 55% maximal inhibition. Gamma-glutamyl-S-allyl cysteine, gamma-glutamyl-S-methyl cysteine, and gamma-glutamyl-S-propyl cysteine were less potent, exerting only 16 to 29% maximal inhibitions. Alliin, S-allyl-N-acetyl cysteine, S-allylsulfonyl alanine, and S-methyl cysteine had no effect on cholesterol synthesis. Of the lipid-soluble compounds, diallyl disulfide (DADS), diallyl trisulfide (DATS), and dipropyl disulfide (DPDS) depressed cholesterol synthesis by 10 to 25% at low concentrations (< or =0.5 mmol/L), and abolished the synthesis at high concentrations (> or =1.0 mmol/L). Diallyl sulfide, dipropyl sulfide, and methyl allyl sulfide slightly inhibited [2-14C]acetate incorporation into cholesterol only at high concentrations. The complete depression of cholesterol synthesis by DADS, DATS, and DPDS was associated with cytotoxicity as indicated by marked increase in cellular LDH release. There was no apparent increase in LDH secretion by water-soluble compounds except S-allyl mercaptocysteine, which also abolished cholesterol synthesis. Judging from maximal inhibition and IC50 (concentration required for 50% of maximal inhibition), SAC, SEC, and SPC are equally potent in inhibiting cholesterol synthesis.}, }
@article {pmid10754220, year = {2000}, author = {Blum, D and Torch, S and Nissou, MF and Benabid, AL and Verna, JM}, title = {Extracellular toxicity of 6-hydroxydopamine on PC12 cells.}, journal = {Neuroscience letters}, volume = {283}, number = {3}, pages = {193-196}, doi = {10.1016/s0304-3940(00)00948-4}, pmid = {10754220}, issn = {0304-3940}, mesh = {3T3 Cells ; Animals ; Cell Death/drug effects ; Cell Survival/drug effects ; Dose-Response Relationship, Drug ; Extracellular Space/*drug effects/metabolism ; Intracellular Fluid/drug effects/metabolism ; Mice ; Neurotoxins/metabolism ; Oxidation-Reduction/drug effects ; Oxidopamine/*toxicity ; PC12 Cells/*drug effects ; Rats ; Reactive Oxygen Species/physiology ; }, abstract = {6-hydroxydopamine (6-OHDA) is usually thought to cross cell membrane through dopamine uptake transporters, to inhibit mitochondrial respiration and to generate intracellular reactive oxygen species. In this study, we show that the anti-oxidants catalase, glutathione and N-acetyl-cysteine are able to reverse the toxic effects of 6-OHDA. These two latter compounds considerably slow down 6-OHDA oxidation in a cell free system suggesting a direct chemical interaction with the neurotoxin. Moreover, desipramine does not protect PC12 cells and 6-OHDA is also strongly toxic towards non-catecholaminergic C6 and NIH3T3 cells. These results thus suggest that 6-OHDA toxicity on PC12 cells mainly involves an extracellular process.}, }
@article {pmid10745022, year = {2000}, author = {Fan, J and Kapus, A and Li, YH and Rizoli, S and Marshall, JC and Rotstein, OD}, title = {Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: role of tumor necrosis factor.}, journal = {American journal of respiratory cell and molecular biology}, volume = {22}, number = {4}, pages = {412-421}, doi = {10.1165/ajrcmb.22.4.3857}, pmid = {10745022}, issn = {1044-1549}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/therapeutic use ; Blood Coagulation Disorders/*etiology ; Bronchoalveolar Lavage Fluid/cytology ; Capillary Leak Syndrome/prevention &amp; control ; Disseminated Intravascular Coagulation/*etiology/prevention &amp; control ; Fibrin/metabolism ; Fibrinolysis ; Gene Expression Regulation ; Lipopolysaccharides/toxicity ; Lipoproteins/physiology/therapeutic use ; Macrophage Activation ; Macrophages, Alveolar/metabolism ; Male ; Models, Biological ; NF-kappa B/physiology ; Neutrophils/immunology ; Oxidative Stress ; Plasminogen Activator Inhibitor 1/biosynthesis/genetics ; Pulmonary Alveoli/*metabolism/pathology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Respiratory Distress Syndrome/blood/etiology/*metabolism ; Shock, Hemorrhagic/blood/*complications ; Shock, Septic/blood/*complications ; Thromboplastin/biosynthesis/genetics/physiology ; Transcription, Genetic ; Tumor Necrosis Factor-alpha/adverse effects/pharmacology/*physiology ; }, abstract = {Hemorrhagic shock due to major trauma predisposes to the development of acute respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock might predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lipopolysaccharide (LPS), a clinically relevant "two-hit" model, was used to test this hypothesis. Resuscitated shock primed the lungs for an increased tissue factor and plasminogen activator (PA) inhibitor-1 gene expression in response to LPS, while the fibrinolytic PA was reduced. These alterations were recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF antibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not appear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemokine expression. However, treatment prevented albumin leak by preventing alveolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cysteine in the resuscitation fluid resulted in prevention of both the development of the net procoagulant state and lung neutrophil sequestration, suggesting a role for upstream oxidant effects in the priming process. These studies provide a cellular and molecular basis for lung fibrin deposition after resuscitated shock and demonstrate a divergence of pathways responsible for fibrin generation and neutrophil accumulation.}, }
@article {pmid10743980, year = {2000}, author = {Grandjean, EM and Berthet, P and Ruffmann, R and Leuenberger, P}, title = {Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials.}, journal = {Clinical therapeutics}, volume = {22}, number = {2}, pages = {209-221}, doi = {10.1016/S0149-2918(00)88479-9}, pmid = {10743980}, issn = {0149-2918}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Administration, Oral ; Antiviral Agents/administration &amp; dosage/adverse effects/*therapeutic use ; Bronchial Diseases/*drug therapy ; Controlled Clinical Trials as Topic ; Double-Blind Method ; Drug Administration Schedule ; Humans ; Lung Diseases, Obstructive/drug therapy ; }, abstract = {OBJECTIVE: This meta-analysis was performed to assess the possible prophylactic benefit of prolonged treatment with oral N-acetylcysteine (NAC) in chronic bronchitis (CB) based on qualifying clinical trials. Treatment of acute exacerbations with NAC was not investigated.<br><br>BACKGROUND: Prolonged treatment with oral NAC has been investigated in a number of studies of patients with CB. NAC prevented acute exacerbations and symptoms of CB in some but not all trials.<br><br>METHODS: The trials included in this analysis were selected from a MEDLINE search of the period from January 1, 1980, through June 30, 1995; references in the articles retrieved in the initial search; and consultation with 2 experts. Selection was based on the following criteria: published, double-blind, placebo-controlled, chronic bronchopulmonary disease, duration of therapy > or =2 months, and data sufficient to calculate an outcome variable permitting direct comparison of studies (effect size) for both NAC and placebo groups. The primary end point was the incidence of acute exacerbations in 7 of 8 trials and clinical assessment in the other. In 7 studies, inclusion criteria were based on Medical Research Council criteria for CB, with an additional criterion in some trials. For the meta-analysis, the end points of individual trials were transformed into an effect size as a common outcome.<br><br>RESULTS: Of 21 trials initially identified, 8 qualified for inclusion. References from the 8 papers and consultation with the experts produced 8 additional publications, 1 of which qualified for inclusion. NAC was administered orally at a daily dose of 400 mg (1 study), 600 mg (5 studies), or 1200 mg (1 study). One other trial used a dose of 600 mg 3 times per week. The duration of treatment was 3 months (1 study), > or =5 months (2 studies), or 6 months (7 studies). The results of this meta-analysis showed a statistically significant effect size for NAC compared with placebo. The overall value of effect size was -1.37 (95% CI, -1.5 to -1.25). Sensitivity analyses did not significantly alter these results. In a subset analysis of trials with the number of acute exacerbations as a clinical end point, a mean difference of -0.32 clinical event (95% CI, -0.50 to -0.18) was found (ie, a 23% decrease in the number of acute exacerbations compared with placebo).<br><br>CONCLUSION: These findings suggest that a prolonged course of oral NAC prevents acute exacerbations of CB, thus possibly decreasing morbidity and health care costs.}, }
@article {pmid10737618, year = {2000}, author = {Soto-Otero, R and Méndez-Alvarez, E and Hermida-Ameijeiras, A and Muñoz-Patiño, AM and Labandeira-Garcia, JL}, title = {Autoxidation and neurotoxicity of 6-hydroxydopamine in the presence of some antioxidants: potential implication in relation to the pathogenesis of Parkinson's disease.}, journal = {Journal of neurochemistry}, volume = {74}, number = {4}, pages = {1605-1612}, doi = {10.1046/j.1471-4159.2000.0741605.x}, pmid = {10737618}, issn = {0022-3042}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Cysteine/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Glutathione/pharmacology ; Hydrogen Peroxide/metabolism ; Neurons/drug effects/metabolism/pathology ; Oxidation-Reduction ; Oxidopamine/chemistry/metabolism/*toxicity ; Oxygen Consumption/physiology ; Parkinson Disease/etiology/*metabolism/*pathology ; Rats ; Rats, Sprague-Dawley ; Sympatholytics/chemistry/metabolism/*toxicity ; }, abstract = {6-Hydroxydopamine (6-OHDA) is a dopaminergic neurotoxin putatively involved in the pathogenesis of Parkinson's disease (PD). Its neurotoxicity has been related to the production of reactive oxygen species. In this study we examine the effects of the antioxidants ascorbic acid (AA), glutathione (GSH), cysteine (CySH), and N-acetyl-CySH (NAC) on the autoxidation and neurotoxicity of 6-OHDA. In vitro, the autoxidation of 6-OHDA proceeds rapidly with the formation of H2O2 and with the participation of the H2O2 produced in the reaction. The presence of AA induced a reduction in the consumption of O2 during the autoxidation of 6-OHDA and a negligible presence of the p-quinone, which demonstrates the efficiency of AA to act as a redox cycling agent. The presence of GSH, CySH, and NAC produced a significant reduction in the autoxidation of 6-OHDA. In vivo, the presence of sulfhydryl antioxidants protected against neuronal degeneration in the striatum, which was particularly remarkable in the case of CySH and was attributed to its capacity to remove the H2O2 produced in the autoxidation of 6-OHDA. These results corroborate the involvement of oxidative stress as the major mechanism in the neurotoxicity of 6-OHDA and the putative role of CySH as a scavenger in relation to PD.}, }
@article {pmid10736124, year = {2000}, author = {Tanen, DA and LoVecchio, F and Curry, SC}, title = {Failure of intravenous N-acetylcysteine to reduce methemoglobin produced by sodium nitrite in human volunteers: A randomized controlled trial.}, journal = {Annals of emergency medicine}, volume = {35}, number = {4}, pages = {369-373}, doi = {10.1016/s0196-0644(00)70056-4}, pmid = {10736124}, issn = {0196-0644}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Area Under Curve ; Cross-Over Studies ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Indicators and Reagents/adverse effects ; Infusions, Intravenous ; Male ; Methemoglobin/pharmacokinetics ; Methemoglobinemia/chemically induced/*drug therapy ; Sodium Nitrite/adverse effects ; Treatment Failure ; }, abstract = {STUDY OBJECTIVE: To determine whether intravenous N -acetylcysteine (NAC) produces a clinically significant decline in sodium nitrite-induced methemoglobinemia in human volunteers.<br><br>METHODS: We conducted a randomized, control crossover trial with each subject serving as his own control. Methemoglobinemia was induced with intravenous sodium nitrite (4 mg/kg) administered over 10 minutes starting at time 0. At time 30 minutes, subjects were randomly assigned to treatment with intravenous NAC for 100 minutes (150 mg/kg over 1 hour followed by 14 mg/kg per hour for 40 minutes) or administration of an equal volume of 5% dextrose in water. Each subject received the alternative treatment after an interval of at least 1 week. Blood methemoglobin concentrations were measured by multiwavelength co-oximetry at time 0, 15, 30, 50, 70, 90, 110, and 130 minutes. Area under the methemoglobin concentration-time curve (AUC) between 30 and 130 minutes was compared between groups using a 2-tailed, paired t test.<br><br>RESULTS: There were no statistically significant differences in the control and treatment groups with respect to baseline hemoglobin or methemoglobin concentrations, as well as nitrite-induced methemoglobin concentrations at the initiation of treatment (0.85+/-0.06 g/dL, 0.88+/-0.04 g/dL; mean+/-SEM; P =.31). Mean AUC for the control group (77.1+/-5.7 g x min/dL) was significantly lower than the mean AUC for the treatment group (84.5+/-4.7 g x min/dL); P =.01).<br><br>CONCLUSION: Intravenous NAC failed to enhance methemoglobin reduction in this model.}, }
@article {pmid10736123, year = {2000}, author = {Woo, OF and Mueller, PD and Olson, KR and Anderson, IB and Kim, SY}, title = {Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose.}, journal = {Annals of emergency medicine}, volume = {35}, number = {4}, pages = {363-368}, pmid = {10736123}, issn = {0196-0644}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Adolescent ; Adult ; Age Distribution ; Aged ; Analgesics, Non-Narcotic/blood/*poisoning ; Child ; Drug Overdose/drug therapy ; Emergency Service, Hospital ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Hospitals, Urban ; Humans ; Liver/drug effects/enzymology ; Male ; Middle Aged ; Retrospective Studies ; Sex Distribution ; Time Factors ; }, abstract = {STUDY OBJECTIVE: We sought to evaluate the safety and efficacy of a shorter N-acetylcysteine (NAC) regimen in the treatment of acute acetaminophen overdose.<br><br>METHODS: We performed a retrospective case series in a large urban county hospital. Of 305 patients identified through the emergency department, 75 patients met the criteria inclusion: an acute overdose ingestion, serum acetaminophen concentration in toxic range according to the Rumack-Matthew nomogram, and oral NAC treatment initiated within 24 hours of the ingestion. The regional poison control center recommended oral treatment with NAC 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours until the serum acetaminophen level was no longer detectable, rather than the standard 72-hour treatment regimen.<br><br>RESULTS: The primary outcome measure was the development of hepatotoxicity. Twenty-five (33.3%) patients were treated for a period of less than 24 hours, 25 (33.3%) were treated for 24 to 36 hours, and 25 (33.3%) were treated for 37 to 64 hours; the mean and median duration of treatment was 31 hours. None of the patients treated for less than 24 hours had evidence of hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] level >1,000 IU/L); hepatotoxicity developed in 2 (8%) patients treated for 24 to 36 hours and 4 (16%) patients treated for 37 to 64 hours. There were no deaths or patients who received liver transplantation. The overall incidence of hepatotoxicity in our patients was similar to that found in other protocols with administration of oral NAC for 72 hours or intravenous NAC for 20 or 48 hours.<br><br>CONCLUSION: This observational study suggests that a shorter course of oral NAC therapy in patients who do not show evidence of hepatotoxicity within 36 hours of an acute acetaminophen overdose is safe and effective.}, }
@article {pmid10731516, year = {2000}, author = {Nakatani, T and Tawaramoto, M and Opare Kennedy, D and Kojima, A and Matsui-Yuasa, I}, title = {Apoptosis induced by chelation of intracellular zinc is associated with depletion of cellular reduced glutathione level in rat hepatocytes.}, journal = {Chemico-biological interactions}, volume = {125}, number = {3}, pages = {151-163}, doi = {10.1016/s0009-2797(99)00166-0}, pmid = {10731516}, issn = {0009-2797}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Caspase 3 ; Caspases/drug effects/metabolism ; Cell Nucleus/drug effects/ultrastructure ; Chelating Agents/*pharmacology ; Drug Interactions ; Ethylenediamines/pharmacology ; Glutathione/*metabolism ; Liver/*cytology/drug effects/metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Zinc/*metabolism ; }, abstract = {Zn(2+) has multiple implications in cellular metabolism, including free radicals metabolism and cell death by apoptosis. In the present study, we examined the role of Zn(2+) in the regulation of apoptosis in cultured rat hepatocytes. The chelation of Zn(2+) by a membrane permeable metal ion chelator, N, N, N', N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), induced apoptosis. Addition of ZnSO(4) prevented TPEN-induced apoptosis. Unlike the effect of TPEN, a membrane impermeable metal ion chelator, diethylenetriamine pentaacetic acid (DTPA), did not induce apoptosis, indicating that chelation of intracellular Zn(2+) was required to trigger apoptosis. Caspase-3-like proteolytic activity, a general biochemical mediator of apoptosis in a variety of cells and tissues, was also activated with the treatment of TPEN but not DTPA. TPEN treatment, but not DTPA, also resulted in the depletion of intracellular reduced glutathione (GSH) but addition of Zn(2+) recovered the GSH level. N-acetyl-L-cysteine (NAC), a thiol antioxidant, prevented TPEN-induced apoptosis. These results taken together suggest that intracellular Zn(2+) interfere with the apoptosis process, possibly through the regulation of cellular redox potential involving GSH.}, }
@article {pmid10731097, year = {1999}, author = {Banzet, N and François, D and Polla, BS}, title = {Tobacco smoke induces mitochondrial depolarization along with cell death: effects of antioxidants.}, journal = {Redox report : communications in free radical research}, volume = {4}, number = {5}, pages = {229-236}, doi = {10.1179/135100099101534945}, pmid = {10731097}, issn = {1351-0002}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Antioxidants/*pharmacology ; Cell Death/drug effects ; Cells, Cultured ; Cysteine Proteinase Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Membrane Potentials/drug effects ; Mitochondria/*drug effects/physiology ; Monocytes/*drug effects/pathology/physiology/*ultrastructure ; Superoxide Dismutase/pharmacology ; Tobacco Smoke Pollution/*adverse effects ; }, abstract = {Smoking has been associated with a large number of diseases, in particular cancers. Among the many substances identified in tobacco smoke, reactive oxygen species (ROS) are major carcinogens. We have previously reported that exposure of mammalian cells to tobacco smoke induces the expression of stress proteins, as well as apoptosis (programmed cell death). Here we examined the effects of tobacco smoke on mitochondrial membrane potential (deltapsim), since mitochondria have been proposed to control the effector phase of apoptosis. We used normal human monocytes for these experiments, with the prospect for application of deltapsim as a biomarker of oxidative stress. Tobacco smoke induced mitochondrial depolarization at 3 h, and apoptosis (or necrosis for higher concentrations) after 16 h. Apoptosis was assessed by both a functional approach (annexin V binding) and morphological analysis (electron microscopy). N-acetyl-cysteine prevented tobacco smoke-induced deltapsim disruption and apoptosis, while the caspase inhibitor Z-VAD.Fmk did not affect deltapsim, though preventing apoptosis, and superoxide dismutase had no effect. Our data designate mitochondria as a target for ROS-mediated effects of tobacco smoke exposure.}, }
@article {pmid10730821, year = {2000}, author = {Chen, G and Wang, SH and Warner, TD}, title = {Regulation of iNOS mRNA levels in endothelial cells by glutathione, a double-edged sword.}, journal = {Free radical research}, volume = {32}, number = {3}, pages = {223-234}, doi = {10.1080/10715760000300231}, pmid = {10730821}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Carmustine/pharmacology ; Cell Line ; Cytokines/pharmacology ; DNA-Binding Proteins/analysis ; Endothelium, Vascular/drug effects ; Enzyme Stability/drug effects ; Gene Expression Regulation, Enzymologic/*drug effects ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Humans ; NF-kappa B/metabolism ; Nitric Oxide Synthase/*genetics/metabolism ; Nitric Oxide Synthase Type II ; RNA, Messenger/*metabolism ; }, abstract = {Both inducible nitric oxide synthase (iNOS) and glutathione are important mediators in various physiological and pathological conditions in humans. In human endothelial cells the intracellular glutathione levels were modulated by N-acetyl-L-cysteine (NAC), a precursor of glutathione and 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. BCNU significantly decreased reduced glutathione (GSH) but increased oxidized glutathione (GSSG) whereas NAC markedly elevated GSH with a relatively small increase in GSSG. Appropriate concentrations of GSH and GSSG increase the expression of iNOS gene. However, either GSH or GSSG at a too high concentration inhibits its expression, indicating that iNOS gene is fine tuned by the metabolites of glutathione cycle. The changes of iNOS mRNA steady state levels by the glutathione metabolites were associated with a similar alteration in its gene transcription and NF-kappaB activity. BCNU at high concentrations also shortens the half-life of iNOS mRNA, suggesting a role of GSSG in the stability of the iNOS gene. Thus, the change of glutathione levels in vitro can regulate iNOS mRNA steady state levels in a bi-phasic manner in human endothelial cells.}, }
@article {pmid10727416, year = {2000}, author = {Pani, G and Colavitti, R and Borrello, S and Galeotti, T}, title = {Endogenous oxygen radicals modulate protein tyrosine phosphorylation and JNK-1 activation in lectin-stimulated thymocytes.}, journal = {The Biochemical journal}, volume = {347 Pt 1}, number = {Pt 1}, pages = {173-181}, pmid = {10727416}, issn = {0264-6021}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; CD4 Antigens/physiology ; CD8 Antigens/physiology ; Cells, Cultured ; Concanavalin A/*pharmacology ; Enzyme Inhibitors/pharmacology ; Kinetics ; *Lymphocyte Activation ; Male ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase 8 ; Mitogen-Activated Protein Kinases/*metabolism ; Onium Compounds/pharmacology ; Phosphorylation ; Phosphotyrosine/metabolism ; Reactive Oxygen Species/*physiology ; Receptor-CD3 Complex, Antigen, T-Cell/physiology ; T-Lymphocytes/drug effects/*enzymology/immunology ; Tetradecanoylphorbol Acetate/pharmacology ; }, abstract = {Molecular events mediating the T-lymphocyte response to lectins are still incompletely understood, although much evidence suggests that both the mitogenic and the death-promoting effects of these agents involve the biochemical cascade initiated by the CD3/T-cell antigen receptor (TCR) complex. Reactive oxygen species (ROS) and in particular H(2)O(2) have been shown to have a role in cell response to cytokines and growth factors. Here we report that the proliferation of mouse thymocytes in response to the mitogenic lectin concanavalin A (ConA) is strongly and selectively inhibited by the intracellular ROS scavenger N-acetylcysteine (NAC) and by diphenyleneiodonium (DPI), a potent inhibitor of NADPH-dependent membrane oxidases activated by surface receptors. A rapid 'burst' of intracellular oxygen radicals was observed in mouse thymocytes stimulated by ConA, with kinetics that paralleled the appearance of tyrosine-phosphorylated proteins. This burst was abrogated by the pretreatment of cells with NAC or DPI. Only a modest increase in intracellular oxygen species was found in thymocytes stimulated by strong cross-linking of TCR together with CD4 or CD28. Pharmacological interference with ROS production in ConA-stimulated thymocytes resulted in a decreased tyrosine phosphorylation of multiple protein species, including a 38 kDa band able to recruit the adapter protein Grb2 and corresponding to the recently identified transducer LAT (linker for activation of T-cells), a molecule involved in linking activated TCR to the production of interleukin 2 and the proliferation of T-cells. Furthermore, ROS inhibition markedly attenuated the activation of stress-activated protein kinase/JNK-1 (c-Jun N-terminal kinase 1) in response to lectins. Taken together, these results identify ROS as important modulators of the signalling cascade initiated by mitogenic lectins in thymocytes and, by extension, as a novel class of mediators downstream of antigen receptors.}, }
@article {pmid10726110, year = {1999}, author = {Vasdev, S and Wadhawan, S and Ford, CA and Parai, S and Longerich, L and Gadag, V}, title = {Dietary vitamin B6 supplementation prevents ethanol-induced hypertension in rats.}, journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD}, volume = {9}, number = {2}, pages = {55-63}, pmid = {10726110}, issn = {0939-4753}, mesh = {Analysis of Variance ; Animals ; Blood Pressure Determination ; Dietary Supplements ; Disease Models, Animal ; Ethanol ; Female ; Hypertension/chemically induced/*drug therapy/pathology ; Male ; Pyridoxine/*administration &amp; dosage ; Rats ; Rats, Inbred WKY ; Reference Values ; }, abstract = {BACKGROUND AND AIMS: All known pathways of ethanol metabolism result in the production of acetaldehyde, a highly reactive compound. Acetaldehyde has been shown to deplete vitamin B6 in chronic alcoholics. It also binds with sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing vascular cytosolic free calcium, peripheral vascular resistance and blood pressure. The aldehyde-binding thiol compound, N-acetyl cysteine, attenuates elevated blood pressure and associated adverse changes in ethanol-induced hypertensive rats. Vitamin B6 supplementation increases the level of endogenous cysteine. Aim of this work was thus to investigate whether a dietary supplementation of vitamin B6 can prevent ethanol-induced hypertension and associated changes in Wistar-Kyoto (WKY) rats.<br><br>METHODS AND RESULTS: Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each. The control group received a normal vitamin B6 diet (regular chow) and normal drinking water, the ethanol group, the same diet plus 1% ethanol in the drinking water, and the ethanol + vitamin B6 group a high vitamin B6 diet (20 times normal diet) and 1% ethanol in the drinking water. After 14 weeks, systolic blood pressure, platelet [Ca2+]i and kidney and aortic aldehyde conjugate levels were significantly higher in the ethanol group. These rats also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin B6 supplementation prevented these changes.<br><br>CONCLUSIONS: Dietary vitamin B6 supplementation prevented ethanol-induced hypertension and associated changes in WKY rats by normalizing tissue aldehyde conjugate levels.}, }
@article {pmid10725743, year = {2000}, author = {Cadroy, Y and Dupouy, D and Boneu, B and Plaisancié, H}, title = {Polymorphonuclear leukocytes modulate tissue factor production by mononuclear cells: role of reactive oxygen species.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {164}, number = {7}, pages = {3822-3828}, doi = {10.4049/jimmunol.164.7.3822}, pmid = {10725743}, issn = {0022-1767}, mesh = {Adult ; Blood Coagulation/physiology ; Cell Communication/*physiology ; Cells, Cultured ; Female ; Humans ; Leukocyte Count ; Leukocytes, Mononuclear/*metabolism/physiology ; Lymphocyte Activation ; Male ; Middle Aged ; Neutrophil Activation/physiology ; Neutrophils/metabolism/*physiology ; RNA, Messenger/blood ; Reactive Oxygen Species/*physiology ; Thromboplastin/*biosynthesis/genetics ; Time Factors ; }, abstract = {To determine whether polymorphonuclear leukocytes (PMN) modulate the production of tissue factor (TF) by monocytes, PBMC were incubated with increasing concentrations of PMN. PMN did not express any procoagulant activity. After 20-h cocultures, PMN enhanced or inhibited the TF production of PBMC, and this effect depended on the PMN/PBMC ratio. When the ratio increased from 1/1000 to 1/5, without or with LPS, the TF activity of PBMC increased to peak at 2.5-fold the baseline value (p < 0.01). The TF Ag and TF mRNA also increased. This potentiating effect was mediated by reactive oxygen species (ROS) released by PMN during the coculture; it did not require direct cell contact between PMN and PBMC, it was enhanced when PMN were stimulated by fMLP (a chemotactic peptide), and it was inhibited by two antioxidants, N-acetyl cysteine and pyrrolidine dithiocarbamate. In contrast, when the PMN/PBMC ratio was further increased from 1/2 to 2/1, the PBMC TF activity, Ag, and mRNA decreased and were inhibited compared with those of PBMC cultured alone (p < 0.01). This inhibitory effect required direct cell contact between PMN and PBMC, and it was not due to a PMN-mediated cytotoxicity. To confirm the role of ROS, H2O2 enhanced then inhibited the TF activity of PBMC in a dose-dependent manner, similarly to PMN. Thus, PMN may play an important role in the pathogenesis of thrombosis and atherosclerosis by exerting concentration-dependent regulatory effects on the TF production by PBMC via the release of ROS.}, }
@article {pmid10722085, year = {2000}, author = {Vasanits, A and Kutlán, D and Sass, P and Molnár-Perl, I}, title = {Retention/quantitation properties of the o-phthaldialdehyde-3-mercaptopropionic acid and the o-phthaldialdehyde-N-acetyl-L-cysteine amino acid derivatives in reversed-phase high-performance liquid chromatography.}, journal = {Journal of chromatography. A}, volume = {870}, number = {1-2}, pages = {271-287}, doi = {10.1016/s0021-9673(99)00942-5}, pmid = {10722085}, issn = {0021-9673}, mesh = {3-Mercaptopropionic Acid/*chemistry ; Acetylcysteine/*chemistry ; Amino Acids/*chemistry ; Chromatography, High Pressure Liquid/*methods ; Fruit/chemistry ; Reproducibility of Results ; Spectrometry, Fluorescence ; o-Phthalaldehyde/*chemistry ; }, abstract = {The separation/identification of 25 amino acids as their o-phthaldialdehyde-3-mercaptopropionic acid (OPA/MPA) and o-phthaldialdehyde-N-acetyl-L-cysteine (OPA/NAC) derivatives have been optimized [paying particular attention to those amino acids which elute with more than one derivative (glycine, histidine, gamma-aminobutyric acid, beta-alanine, ornithine, lysine) and that are expected to be present in apples in their free form]. Optimum separation conditions are reported on six reversed-phase columns: Nucleosil 3 and 5 microm, 150(+20 guard)x4.0 mm; Gromsil 3 microm, 150(+10 guard)x4.0 mm; Hypersil 5 microm, 150(+20 guard)x4.0 mm and 200(+20 guard)x4.0 mm; and Hypersil 3 microm, 150(+20 guard)x4.0 mm. Elutions were followed, simultaneously, with photodiode array and fluorescence detectors connected in line. Optimization studies carried out in model solutions as a function of temperature (30-55 degrees C) and eluent flow-rate (0.8-2.5 mL/min) demonstrated that optimum resolutions are obtained with the highest flow-rate applicable (remaining on the safe side with a column pressure of << 3500 p.s.i.; 1 p.s.i.=6894.76 Pa) in the temperature range 30-50 degrees C. Twenty-five amino acids, eluting in 31 separate, characteristic derivatives, were determined on all six columns (the main component, asparagine, present in overwhelming excess, together with the minor constituents glutamine, beta-alanine, gamma-aminobutyric acid, homoserine, and homoarginine). Optimum conditions in the case of both derivatives were obtained on the same type of column (Hypersil, 5 microm), as follows: for the OPA/MPA amino acids with programmed flow-rate [1.3-2.3 ml/min; column, 200(+20 guard)x4 mm], at 50 degrees C, while, for the OPA/NAC amino acids at 2.1 ml/min flow rate, at 30 degrees C [column, 150(+20 guard)x4 mm], with 40 and 37 min run times, including equilibration. Responses of the corresponding amino acids proved to be independent of the column used; reproducibility in the concentration range 6-12,000 pmol, related to the injected amount of amino acids, was <3.4% RSD (average relative standard deviation percentage). The utility of the protocol was demonstrated in the quantitation of the free amino acid content of five apple varieties (Jonagored, Idared, Jonica, Florina, Freedom) on various harvesting dates and after different storage times. Derivatization of the apple pulp was performed with filtered samples, applying any special isolation processes.}, }
@article {pmid10720628, year = {2000}, author = {Martínez Banaclocha, M}, title = {N-acetylcysteine elicited increase in complex I activity in synaptic mitochondria from aged mice: implications for treatment of Parkinson's disease.}, journal = {Brain research}, volume = {859}, number = {1}, pages = {173-175}, doi = {10.1016/s0006-8993(00)02005-9}, pmid = {10720628}, issn = {0006-8993}, mesh = {Acetylcysteine/*pharmacology ; Aging/*physiology ; Animals ; Electron Transport Complex I ; Free Radical Scavengers/*pharmacology ; Mice ; Mitochondria/*drug effects/*metabolism ; NADH, NADPH Oxidoreductases/*drug effects/*metabolism ; Parkinson Disease/*drug therapy/*physiopathology ; Sulfhydryl Compounds/metabolism ; Synapses/*drug effects/*metabolism ; Synaptosomes/drug effects/metabolism ; }, abstract = {It has been suggested that thiolic groups are essential for complex I activity and other respiratory mitochondrial enzymes. Recent experiments showed that the thiolic antioxidant N-acetylcysteine (NAC) can protect against age-related decrease in complex I activity in mice hepatic mitochondria. The present paper shows that NAC enhances complex I activity in vitro in synaptic mitochondria isolated from old mice. The optimum NAC concentration for maximum complex I activity was 10 mM in old synaptic preparations. Our data suggest that mitochondrial thiolic groups, which are essentials to oxidative phosphorylation, are impaired by aging. Based on the finding of decreased mitochondrial complex I activity in the substantia nigra of patients with Parkinson's disease, we propose that the thiol-containing antioxidant NAC could be beneficial for treatment of the disease.}, }
@article {pmid10720201, year = {1999}, author = {Arora-Kuruganti, P and Lucchesi, PA and Wurster, RD}, title = {Proliferation of cultured human astrocytoma cells in response to an oxidant and antioxidant.}, journal = {Journal of neuro-oncology}, volume = {44}, number = {3}, pages = {213-221}, pmid = {10720201}, issn = {0167-594X}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Astrocytoma/genetics/metabolism/*pathology ; Blood Physiological Phenomena ; Cell Division/drug effects/physiology ; Culture Media, Serum-Free/pharmacology ; DNA/biosynthesis ; Humans ; Hydrogen Peroxide/pharmacology ; Oxidants/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {The role of reactive oxygen species (ROS) in initiation, promotion and progression of several (lung, skin, colon, bladder, breast) tumors is well-documented. Indirect evidence for ROS involvement in tumor proliferation is provided by numerous in vivo and in vitro studies that show antioxidants inhibit tumor proliferation. However, despite strong epidemiological and experimental support for ROS involvement in brain tumor proliferation, to date little is known about the role of ROS in brain tumor promotion at a cellular level. In the present study ROS involvement in proliferation of a cultured, human astrocytoma cell line (U373-MG) was tested by studying effects of an oxidant (hydrogen peroxide, H2O2), and an antioxidant (N-acetylcysteine, NAC) on astrocytoma on proliferation of these cultured cells. Proliferation was assessed by evaluating changes in cell counts and DNA synthesis. Results from these experiments clearly indicate that NAC inhibits tumor cell proliferation and DNA synthesis induced by both serum and H2O2 (10(-5) M). NAC alone did not have any significant effects on the proliferation of serum-starved cells. Thus, ROS are capable of inducing proliferation in cultured astrocytoma cells and antioxidants block ROS- and serum-induced proliferation. Further investigation using primary cultures and animal models will be needed to substantiate the therapeutic potential of antioxidants in future brain tumor therapy.}, }
@article {pmid10718115, year = {2000}, author = {Chong, IW and Lin, SR and Hwang, JJ and Huang, MS and Wang, TH and Tsai, MS and Hou, JJ and Paulauskis, JD}, title = {Expression and regulation of macrophage inflammatory protein-2 gene by vanadium in mouse macrophages.}, journal = {Inflammation}, volume = {24}, number = {2}, pages = {127-139}, pmid = {10718115}, issn = {0360-3997}, mesh = {Acetylcysteine/pharmacology ; Animals ; Chemokine CXCL2 ; Dose-Response Relationship, Drug ; Enzyme-Linked Immunosorbent Assay ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects ; Gene Expression Regulation/drug effects ; Macrophages/*chemistry ; Mice ; Monokines/*genetics/metabolism ; RNA Stability/drug effects ; RNA, Messenger/biosynthesis/drug effects ; Transcription, Genetic ; Tumor Cells, Cultured ; Vanadates/pharmacology ; Vanadium/*pharmacology ; }, abstract = {Environmental and occupational exposure to vanadium (V) dusts results in inflammation mainly confined to the respiratory tract. Macrophages apparently play an important role in mediating the inflammation via the production of many chemokines. In the current study, we investigated whether vanadium can regulate the gene expression of a CXC chemokine macrophage inflammatory protein-2 (MIP-2), and to determine the molecular mechanisms controlling MIP-2 gene expression. A mouse macrophage cell line RAW 264.7 was treated with sodium metavanadate (NaVO3) at the dose of 0.5, 5, or 10 microg/mi V. Northern blot analysis showed that induction of MIP-2 mRNA expression was in a dose-dependent manner. To define the time course of the inflammatory response, RAW 264.7 cells were exposed to 5 microg/ml V, MIP-2 mRNA in macrophages increased markedly as early as 1 h after treatment, maximally induced at 4 h and reduced to 2-fold above control levels by 6 and 8 h. The protein levels of MIP-2 in conditioned media, measured by enzyme-linked immunosorbent assay (ELISA), was well correlated with the levels of MIP-2 mRNA following all of the treatments in the study. In addition, the increase in MIP-2 mRNA expression by vanadium was attenuated by co-treatment with the antioxidant N-acetylcysteine (NAC), at the doses of 10 and 20 mM, suggesting that the induction of MIP-2 mRNA is mediated via the generation of reactive oxygen species (ROS). To further investigate transcriptional regulation of the MIP-2 gene expression by vanadium, we performed RNA decay assay by measuring the half-life of MIP-2 mRNA. Co-treatment of macrophages with the transcriptional inhibitor actinomycin D at 5 microg/ml following exposure to 5 microg/ml V for 4 h revealed complete stabilization of vanadium-induced MIP-2 mRNA and no sign of mRNA degradation, at least, for 6 h, in comparison to the half-life of MIP-2 mRNA was approximately 2.5 h by bacterial lipopolysaccharide (LPS) treatment, supporting post-transcriptional stabilization as the predominant role of MIP-2 gene expression. In conclusion, these observations demonstrate that in vitro vanadium can induce MIP-2 mRNA expression, mediating, at least in part, via the production of ROS. In addition, the increase in MIP-2 mRNA level involves, most likely, post-transcriptional control via increased mRNA stability.}, }
@article {pmid10718114, year = {2000}, author = {Hubbard, AK and Giardina, C}, title = {Regulation of ICAM-1 expression in mouse macrophages.}, journal = {Inflammation}, volume = {24}, number = {2}, pages = {115-125}, pmid = {10718114}, issn = {0360-3997}, support = {R15ES09433/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies, Monoclonal/pharmacology ; Female ; Free Radical Scavengers/pharmacology ; Intercellular Adhesion Molecule-1/*biosynthesis ; Macrophages/*chemistry ; Macrophages, Alveolar/chemistry ; Macrophages, Peritoneal/chemistry ; Mice ; Mice, Inbred C57BL ; Silicon Dioxide/pharmacology ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/immunology/pharmacology ; }, abstract = {In a mouse model of silica (SI) induced lung injury, SI exposure increases expression of intercellular adhesion molecule-1 (ICAM-1) on lung (alveolar/interstitial) macrophages and alveolar type II epithelial cells. To investigate the regulation of SI induced ICAM-1 expression on mouse macrophages, freshly isolated macrophages (alveolar, peritoneal) and macrophage cell lines (MH-S, RAW 264.7) were evaluated for ICAM-1 expression elicited by the particle silica (alpha quartz; 20 microg/ml; 6 microg/cm2) or the inflammatory cytokine, TNFalpha (20 ng/ml). TNFalpha significantly increased ICAM-1 expression in all cell types whereas SI elicited an increase in peritoneal macrophages (PM) and the cell line, MH-S. This pattern of increased expression was confirmed by immunocytochemistry. To investigate the regulation of ICAM-1 expression, PM were incubated with SI, TNFalpha or media concomitantly with anti-TNFalpha antibody, the antioxidant, NAC, or the iNOS synthase inhibitor, L-NAME. Both anti-TNFalpha and NAC, but not L-NAME, inhibited elicited (TNFalpha, SI) as well as constitutive (media) ICAM-1 expression. These data demonstrate that both inflammatory cytokines and inorganic particles can increase ICAM-1 expression on mouse macrophages and that this expression is mediated, in part, by TNFalpha and reactive oxygen species.}, }
@article {pmid10711676, year = {2000}, author = {Jiang, S and Wu, MW and Sternberg, P and Jones, DP}, title = {Fas mediates apoptosis and oxidant-induced cell death in cultured hRPE cells.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {41}, number = {3}, pages = {645-655}, pmid = {10711676}, issn = {0146-0404}, support = {ES09047/ES/NIEHS NIH HHS/United States ; EY06360/EY/NEI NIH HHS/United States ; EY07892/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Annexin A5/metabolism ; *Apoptosis/drug effects ; Blotting, Western ; Cell Death/drug effects ; Cells, Cultured ; Fas Ligand Protein ; Flow Cytometry ; Fluorescein-5-isothiocyanate ; Glutathione/pharmacology ; Humans ; Membrane Glycoproteins/*metabolism ; Microscopy, Confocal ; Pigment Epithelium of Eye/drug effects/*metabolism/pathology ; Recombinant Proteins ; Up-Regulation ; fas Receptor/*metabolism ; tert-Butylhydroperoxide/antagonists &amp; inhibitors/*pharmacology ; }, abstract = {PURPOSE: To investigate whether Fas ligand (FasL) and the Fas receptor system mediates apoptosis in cultured human retinal pigment epithelial (hRPE) cells and contributes to oxidant-induced death of hRPE cells.<br><br>METHODS: Expression of FasL and Fas in cultured hRPE cells was examined by Western blot analysis and flow cytometry. The susceptibility of hRPE cells to Fas-mediated apoptosis was determined by incubating cells with recombinant soluble Fas ligand (sFasL). Characteristics of apoptosis assessed included chromatin condensation, DNA cleavage, and phosphatidylserine exposure. To investigate the possible involvement of Fas-mediated apoptosis in oxidative killing of hRPE cells, the effects of the oxidant tert-butylhydroperoxide (tBH) on the expression of FasL and Fas were studied. The specificity of effects of oxidant was examined using the antioxidants glutathione and N-acetyl-L-cysteine (NAC). The requirement for the Fas pathway in tBH-induced apoptosis was investigated using an antagonistic anti-Fas antibody ZB4 that blocks the interaction between FasL and Fas.<br><br>RESULTS: Cultured hRPE cells constitutively expressed FasL and Fas. Ligation of Fas receptor with recombinant sFasL triggered apoptosis in hRPE cells. tBH treatment of hRPE cells resulted in increased expression of FasL and Fas. Glutathione and NAC completely abrogated tBH-induced increase in FasL and Fas expression and apoptosis. Blocking FasL and Fas interaction by ZB4 inhibited tBH-induced apoptosis, but only partially.<br><br>CONCLUSIONS: A functional Fas-mediated apoptotic pathway is present in cultured hRPE cells and can be activated with sFasL or by upregulation of FasL and Fas expression with an oxidant. The incomplete inhibition by blocking antibody indicates that the Fas pathway is involved in oxidant-induced apoptosis, but other triggering mechanisms are also important.}, }
@article {pmid10678679, year = {1999}, author = {Dröge, W and Breitkreutz, R}, title = {N-acetyl-cysteine in the therapy of HIV-positive patients.}, journal = {Current opinion in clinical nutrition and metabolic care}, volume = {2}, number = {6}, pages = {493-498}, doi = {10.1097/00075197-199911000-00011}, pmid = {10678679}, issn = {1363-1950}, mesh = {Acetylcysteine/pharmacokinetics/*therapeutic use ; Biological Availability ; Cysteine/deficiency/metabolism ; Glutathione/deficiency/metabolism ; HIV Seropositivity/*drug therapy ; Humans ; Sulfur/deficiency/metabolism ; }, abstract = {Randomly selected asymptomatic HIV-positive persons reveal, on average, a massive daily loss of sulphur, which appears to represent in first approximation the mean loss throughout the asymptomatic stage, and may explain the widely observed decrease in cyst(e)ine and glutathione levels. This sulphur loss is reasonably expected to lead, within a few years, to a life-threatening condition and may, therefore, contribute decisively to disease progression. Importantly, the rate of sulphur loss is not ameliorated by highly active antiretroviral therapy and may contribute to antiretroviral treatment failure. Several clinical trials on N-acetyl-cysteine treatment of HIV-positive patients have revealed various therapeutic effects, but did not meet the rigorous standards for approval by the health authorities.}, }
@article {pmid10708808, year = {2000}, author = {Sung, JY and Hong, JH and Kang, HS and Choi, I and Lim, SD and Lee, JK and Seok, JH and Lee, JH and Hur, GM}, title = {Methotrexate suppresses the interleukin-6 induced generation of reactive oxygen species in the synoviocytes of rheumatoid arthritis.}, journal = {Immunopharmacology}, volume = {47}, number = {1}, pages = {35-44}, doi = {10.1016/s0162-3109(99)00185-x}, pmid = {10708808}, issn = {0162-3109}, mesh = {Adenosine/pharmacology ; Arthritis, Rheumatoid/*metabolism/pathology ; Cell Culture Techniques ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; Humans ; Inflammation Mediators/antagonists &amp; inhibitors ; Interleukin-1/pharmacology ; Interleukin-6/biosynthesis/genetics/*pharmacology ; Knee Joint/pathology ; Methotrexate/*pharmacology ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/*metabolism ; Synovial Fluid/*cytology/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Various cytokines and reactive oxygen species (ROS) play a fundamental role in the inflammatory and immunologic processes of rheumatoid arthritis (RA). Methotrexate (MTX) is one of the disease-modifying anti-rheumatic drugs and its effect may be partly due to the modulation of immunologic or inflammatory reactions by some cytokines. In the present study, we investigated the effects of MTX on the gene expression and synthesis of interleukin-6 (IL-6), and the proliferative activity and the production of ROS in the fibroblast-like synoviocytes (FLSs) obtained from the patient of RA. The expression or production of IL-6 was induced spontaneously, and augmented by the addition of recombinant human IL-6 or recombinant human IL-1 beta and TNF-alpha in FLSs. These spontaneous and augmented IL-6 expressions or productions were suppressed by treatment with low-concentration of MTX (1 microg/ml). Also, IL-6 stimulated the proliferation of FLSs, and this IL-6 driven proliferation was inhibited with the treatment of MTX or N-acetylcysteine (NAC, 1 mM). Furthermore, ROS production in FLSs was increased significantly by IL-6, and its effect was also abrogated in the presence of MTX or NAC. These results suggest that inflammatory reaction in the synovium of RA patients could be augmented by the autocrine or other cytokine-induced production of IL-6 with subsequent generation of ROS in the synoviocytes, and the modulations of IL-6 synthesis and ROS production may contribute to the therapeutic effects of MTX for RA.}, }
@article {pmid10707932, year = {2000}, author = {Demols, A and Van Laethem, JL and Quertinmont, E and Legros, F and Louis, H and Le Moine, O and Devière, J}, title = {N-acetylcysteine decreases severity of acute pancreatitis in mice.}, journal = {Pancreas}, volume = {20}, number = {2}, pages = {161-169}, doi = {10.1097/00006676-200003000-00009}, pmid = {10707932}, issn = {0885-3177}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Amylases/blood ; Animals ; Chemokine CCL2/blood/metabolism ; Dose-Response Relationship, Drug ; Female ; Interleukin-6/blood/metabolism ; Lipase/blood ; Male ; Mice ; Mice, Inbred BALB C ; Pancreatitis/blood/metabolism/mortality/pathology/*prevention &amp; control ; Survival Rate ; }, abstract = {Oxidative stress plays a major role in the early stage of acute pancreatitis. This study assessed the effects of N-acetylcysteine (NAC), a reduced glutathione (GSH) provider and a direct scavenger of reactive oxygen intermediates, in the course of acute pancreatitis in mice. Acute pancreatitis (AP) was induced by intraperitoneal (i.p.) injections of cerulein. Mice received NAC (1,000 mg/kg, i.p.) every 3 h, starting either 1 h before the first cerulein injection (prophylactic group) or 1 h after the first cerulein injection (therapeutic group), or i.p. saline injections for controls. Severity of AP was evaluated by histology, serum hydrolase levels, and serum and intrapancreatic levels of MCP-1 and interleukin 6 (IL-6). Pancreatic conjugated dienes and intrapancreatic and intrahepatic GSH levels were measured to assess the local and systemic oxidative processes. Acute pancreatitis was also induced with a CDE diet in controls and mice receiving either both NAC ad libidum in drinking water and 1,000 mg/kg i.p. injection once daily. The severity of pulmonary lesions was assessed by arterial blood gases (pO2) and intrapulmonary myeloperoxidase (MPO content) measurements as well as the survival of mice. The severity of cerulein-induced AP was significantly decreased in the prophylactic group compared with the therapeutic and control groups. Prophylactic administration of NAC also decreased the intrapancreatic levels of conjugated dienes compared with controls. The intrapancreatic and systemic release of MCP- 1 and IL-6 was also decreased in the prophylactic group 3 and 6 hours after AP induction. In addition, NAC pretreatment also reduced hepatic IL-6 production at 3 and 6 hours after starting cerulein challenge. In CDE-induced AP, the severity of lung injury (hypoxemia, MPO content) was decreased, and survival was improved by NAC. NAC administered in a prophylactic protocol limits the severity of experimental acute pancreatitis in mice, as well as its systemic complications and related mortality.}, }
@article {pmid10706714, year = {2000}, author = {Kujime, K and Hashimoto, S and Gon, Y and Shimizu, K and Horie, T}, title = {p38 mitogen-activated protein kinase and c-jun-NH2-terminal kinase regulate RANTES production by influenza virus-infected human bronchial epithelial cells.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {164}, number = {6}, pages = {3222-3228}, doi = {10.4049/jimmunol.164.6.3222}, pmid = {10706714}, issn = {0022-1767}, mesh = {Acetylcysteine/pharmacology ; Bronchi/cytology/*enzymology/metabolism/*virology ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors/metabolism/*physiology ; Carbazoles/pharmacology ; Cell Line ; Chemokine CCL5/antagonists &amp; inhibitors/*biosynthesis ; Cytokines/physiology ; Enzyme Activation/drug effects/immunology ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/*enzymology/metabolism/*virology ; Flavonoids/pharmacology ; Humans ; Imidazoles/pharmacology ; Indoles/pharmacology ; Influenza A virus/drug effects/*immunology ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/metabolism/*physiology ; Phosphorylation/drug effects ; Pyridines/pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Airway epithelial cells which are the initial site of influenza virus (IV) infection are suggested to participate in airway inflammatory response by expressing various cytokines including RANTES; however, the intracellular signal that regulates RANTES expression has not been determined. In the present study, we examined the role of p38 mitogen-activated protein (MAP) kinase, extracellular signal-regulated kinase (Erk), and c-Jun-NH2-terminal kinase (JNK) in RANTES production by IV-infected human bronchial epithelial cells. The results showed that IV infection induced increases in p38 MAP kinase, and Erk and JNK phosphorylation and activity. SB 203580, PD 98059, and CEP-1347 attenuated IV-infection induced p38 MAP kinase activity, Erk activity, and JNK activity, respectively. SB 203580 and CEP-1347 attenuated RANTES production by 45.3% and 45.2%, respectively, but a combination of these inhibitors additively attenuated by 69.1%. In contrast, PD 98059 did not attenuate. Anti-IL-1alpha mAb, anti-IL-1beta mAb, anti-TNF-alpha mAb, anti-IL-8 mAb, anti-IFN-beta mAb, anti-RANTES mAb, and a combination of these mAbs did not affect IV infection-induced increases in p38 MAP kinase, Erk, and JNK phosphorylation, indicating that each cytokine neutralized by corresponding Ab was not involved in IV infection-induced phosphorylation of MAP kinases. N-acetylcysteine (NAC) did not affect IV infection-induced increases in MAP kinase phosphorylation, whereas NAC attenuated RANTES production by 18.2%, indicating that reactive oxygen species may act as a second messenger leading to RANTES production via p38 MAP kinase- and JNK-independent pathway. These results indicate that p38 MAP kinase and JNK, at least in part, regulate RANTES production by bronchial epithelial cells.}, }
@article {pmid10677603, year = {2000}, author = {Lockhart, B and Jones, C and Cuisinier, C and Villain, N and Peyroulan, D and Lestage, P}, title = {Inhibition of L-homocysteic acid and buthionine sulphoximine-mediated neurotoxicity in rat embryonic neuronal cultures with alpha-lipoic acid enantiomers.}, journal = {Brain research}, volume = {855}, number = {2}, pages = {292-297}, doi = {10.1016/s0006-8993(99)02372-0}, pmid = {10677603}, issn = {0006-8993}, mesh = {Animals ; Buthionine Sulfoximine/antagonists &amp; inhibitors/*toxicity ; Cell Death/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology ; Embryo, Mammalian ; Homocysteine/*analogs &amp; derivatives/antagonists &amp; inhibitors/toxicity ; Neurons/cytology/*drug effects ; Neurotoxins/*toxicity ; Rats ; Rats, Inbred Strains ; Stereoisomerism ; Thioctic Acid/chemistry/*pharmacology ; }, abstract = {In the present report, we have set out to investigate the potential capacity of both the oxidised and reduced forms of RS-alpha-lipoic acid, and its separate R-(+) and S-(-)enantiomers, to prevent cell death induced with L-homocysteic acid (L-HCA) and buthionine sulphoximine (BSO) in rat primary cortical and hippocampal neurons. L-HCA induced a concentration-dependent neurotoxic effect, estimated by cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction, in primary neurons, but was significantly more toxic for hippocampal (EC(50)=197 microM) compared with cortical neurons (EC(50)=1016 microM) whereas D-HCA demonstrated only moderate (<20%) toxicity. On the other hand, cortical and hippocampal cultures were equally susceptible (341 and 326 microM, respectively) to the neurotoxic action of BSO. Antioxidants including butylated hydroxyanisole, propyl gallate and vitamin E protected cells against the neurotoxic effect of L-HCA and BSO. However, N-acetyl-cysteine and tert-butylphenyl nitrone, although capable of abrogating L-HCA-mediated cell death showed no protective effect against BSO-mediated toxicity. RS-alpha-lipoic acid, RS-alpha-dihydrolipoic acid and the enantiomers R-alpha-lipoic acid and S-alpha-lipoic acid protected cells against L-HCA-mediated toxicity with EC(50) values between 3.1-8.3 microM in primary hippocampal neurons and 2.6-16.8 microM for cortical neurons. However, RS-alpha-lipoic acid, RS-alpha-dihydrolipoic acid, and S-alpha-lipoic acid failed to protect cells against the degeneration induced by prolonged exposure to BSO, whereas the natural form, R-alpha-lipoic, was partially active under the same conditions. The present results indicate a unique sensitivity of hippocampal neurons to the effect of L-HCA-mediated toxicity, and suggest that RS-alpha-lipoic acid, and in particular the R-alpha-enantiomeric form is capable of preventing oxidative stress-mediated neuronal cell death in primary cell culture.}, }
@article {pmid10694187, year = {2000}, author = {Cabassi, A and Bouchard, JF and Dumont, EC and Girouard, H and Le Jossec, M and Lamontagne, D and Besner, JG and de Champlain, J}, title = {Effect of antioxidant treatments on nitrate tolerance development in normotensive and hypertensive rats.}, journal = {Journal of hypertension}, volume = {18}, number = {2}, pages = {187-196}, doi = {10.1097/00004872-200018020-00009}, pmid = {10694187}, issn = {0263-6352}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Coronary Vessels/drug effects ; Drug Tolerance ; Endothelium, Vascular/drug effects/physiology ; Hypertension/*drug therapy/*physiopathology ; In Vitro Techniques ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/blood ; Melatonin/pharmacology ; Nitrates/*pharmacology ; Nitroprusside/pharmacology ; Perfusion ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Serotonin/pharmacology ; Vasodilation/drug effects ; }, abstract = {OBJECTIVES: To investigate the effect of chronic antioxidant treatments on the development of nitrate tolerance in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats by evaluating (i) coronary vascular reactivity, (ii) lipid peroxidation (malondialdehyde), and (iii) peroxynitrite formation (3-nitrotyrosine).<br><br>METHODS: Tolerance was induced in 16-week-old male SHR and WKY, by 4 days of continuous treatment with nitroglycerin patches. Two groups were orally pre-treated (2-weeks) with antioxidants: N-acetyl-L-cysteine (NAC) or melatonin. Effects of serotonin (5-HT) and sodium nitroprusside (SNP) perfusion were tested in isolated Langendorff-perfused hearts. 3-Nitrotyrosine levels were measured in coronary sinus effluent and malondialdehyde in plasma.<br><br>RESULTS: Nitrate tolerance reduced SNP-induced dilation in both strains. This alteration was differently improved by antioxidants: melatonin was effective in SHR, whereas NAC was effective in WKY. Tolerance also reduced 5-HT-mediated vasodilation in WKY, which was reversed by both antioxidants. By contrast, nitrate tolerance enhanced the vasoconstriction to 5-HT in SHR and both antioxidants prevented this response. Furthermore, tolerance was associated with higher malondialdehyde levels in both strains and with higher 3-nitrotyrosine levels in SHR. These changes were reversed by both antioxidants.<br><br>CONCLUSIONS: A participation of oxidative stress was suggested during nitrate tolerance development, since antioxidants prevented the increase in lipid peroxidation and improved vascular responses to SNP and 5HT. Differential effects of antioxidants on SNP-induced vasodilation in SHR and WKY may suggest distinct mechanisms of tolerance development in hearts from hypertensive and normotensive rats. An increased peroxynitrite generation, expressed by higher 3-nitrotyrosine levels, could contribute to nitrate tolerance in the coronary circulation of SHR.}, }
@article {pmid10688222, year = {2000}, author = {Kigawa, G and Nakano, H and Kumada, K and Kitamura, N and Takeuchi, S and Hatakeyama, T and Yamaguchi, M and Nagasaki, H and Boudjema, K and Jaeck, D}, title = {Improvement of portal flow and hepatic microcirculatory tissue flow with N-acetylcysteine in dogs with obstructive jaundice produced by bile duct ligation.}, journal = {The European journal of surgery = Acta chirurgica}, volume = {166}, number = {1}, pages = {77-84}, doi = {10.1080/110241500750009753}, pmid = {10688222}, issn = {1102-4151}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Cholestasis/*physiopathology ; Common Bile Duct/surgery ; Cyclic GMP/blood ; Dogs ; Glutathione/metabolism ; Ligation ; Liver/metabolism ; Liver Circulation/*drug effects ; Male ; Microcirculation/drug effects ; Portal Vein/*physiopathology ; Rats ; Rats, Wistar ; Regional Blood Flow/drug effects ; Stimulation, Chemical ; }, abstract = {OBJECTIVE: To find out if N-acetylcysteine (NAC) would improve hepatic circulation in dogs with obstructive jaundice.<br><br>DESIGN: Open laboratory study.<br><br>SETTING: University hospitals, Japan and France.<br><br>MATERIALS: 14 male beagle dogs and 10 male Wistar rats.<br><br>INTERVENTIONS: Obstructive jaundice was produced by ligation of the common bile duct (CBD) for 7 days in both dogs and rats. Either 5% dextrose (control group, n = 7) or NAC (NAC group, n = 7) was given to dogs. Sinusoidal endothelial cells were obtained from rats after ligation by elutriation, and varying amounts of NAC were given.<br><br>MAIN OUTCOME MEASURES: The volumes of portal blood flow and hepatic microcirculatory tissue flow were reduced after ligation of the CBD, but those increased after NAC had been given to dogs with obstructive jaundice. NAC increased the concentrations of plasma cyclic 3',5'-guanosine monophosphate (cGMP). It also increased concentrations of serum and hepatic-reduced glutathione, and hepatic adenosine triphosphate (ATP) in cholestatic dogs, and secretion of cGMP from sinusoidal endothelial cells from rats with obstructive jaundice.<br><br>CONCLUSION: These results suggest that NAC given intravenously effectively improves hepatic circulation and hepatic function in dogs with obstructive jaundice.}, }
@article {pmid10683711, year = {2000}, author = {Daels-Rakotoarison, DA and Seidel, V and Gressier, B and Brunet, C and Tillequin, F and Bailleul, F and Luyckx, M and Dine, T and Cazin, M and Cazin, JC}, title = {Neurosedative and antioxidant activities of phenylpropanoids from ballota nigra.}, journal = {Arzneimittel-Forschung}, volume = {50}, number = {1}, pages = {16-23}, doi = {10.1055/s-0031-1300158}, pmid = {10683711}, issn = {0004-4172}, mesh = {Animals ; Antioxidants/*pharmacology ; Catechols/isolation &amp; purification/*pharmacology ; Enzyme Activation/drug effects ; Female ; Humans ; Hypnotics and Sedatives/*pharmacology ; In Vitro Techniques ; Inositol 1,4,5-Trisphosphate/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Male ; N-Formylmethionine Leucyl-Phenylalanine/pharmacology ; Neutrophils/drug effects ; Plant Extracts/chemistry/pharmacology ; Plants, Medicinal/*chemistry ; Protein Kinase C/metabolism ; Rats ; Receptors, Dopamine/drug effects ; Receptors, GABA-A/drug effects ; Receptors, Opioid/drug effects ; Spectrophotometry, Ultraviolet ; Superoxides/metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; }, abstract = {Ballota nigra is a European plant known for its neurosedative properties. In this study, the ability of five phenylpropanoids (verbascoside, forsythoside B, arenarioside, ballotetroside, and caffeoyl malic acid) isolated from a hydroalcoholic extract, to bind to benzodiazepine, dopaminergic, and morphinic receptors was investigated. To carry out these studies, affinity tests with rat striata, entire brains and receptor rich preparations were employed. In addition, the phenolic aspect of these five phenylpropanoid esters led to investigate antioxidant activities using cell-free experiments and cellular experiments including isolated polymorphonuclear neutrophils (PMN). Effects of phenylpropanoid esters against reactive oxygen species as superoxide anion, peroxide hydrogen, hypochlorous acid and hydroxyl radical were tested. These molecules are liberated by PMN during inflammatory disorders, so that reproduction of this process in vitro stimulating PMN by chemical stimulants was undertaken. Results show that four of the five compounds are able to bind to the studied receptors. Inhibitory concentrations at 50% were determined and vary from 0.4 to 4.7 mg/ml. This may be in relation with the Ballota nigra known neurosedative activities. Results concerning antioxidant investigations evidence an ability to scavenge reactive oxygen species. Inhibitory concentrations at 50% obtained are comparable to those of known antioxidant drugs (mesna or N-acetyl cysteine). Moreover, the use of different stimuli having various pathways of action on PMN oxidative metabolism permits to establish that each phenylpropanoid ester has its own particular way of action by using proteine kinase C or phospholipase C pathways.}, }
@article {pmid10681368, year = {2000}, author = {Lai, WG and Gardner, I and Zahid, N and Uetrecht, JP}, title = {Bioactivation and covalent binding of hydroxyfluperlapine in human neutrophils: implications for fluperlapine-induced agranulocytosis.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {28}, number = {3}, pages = {255-263}, pmid = {10681368}, issn = {0090-9556}, mesh = {Acetylcysteine/chemistry/immunology/pharmacology ; Agranulocytosis/chemically induced ; Binding, Competitive ; Clozapine/chemistry/immunology/pharmacology ; Dibenzazepines/chemistry/metabolism/*pharmacology ; Glutathione/pharmacology ; Hemocyanins/chemistry/immunology ; Humans ; Hypochlorous Acid/metabolism ; Immune Sera/chemistry ; Immunoblotting ; Neutrophil Activation/drug effects ; Neutrophils/cytology/drug effects/*metabolism ; Oxidation-Reduction ; Peroxidase/metabolism ; Protein Binding ; }, abstract = {The use of fluperlapine and the structurally related clozapine has been associated with the induction of agranulocytosis in humans. Unlike clozapine, fluperlapine is relatively resistant to chemical and biochemical oxidations. In this study we demonstrated that 7-hydroxyfluperlapine, the major metabolite of fluperlapine in humans, is oxidized to a reactive intermediate by HOCl and by myeloperoxidase in the presence of H(2)O(2) and Cl(-). This reactive intermediate was identified as an iminoquinone species with a M + 1 ion at m/z 324 by mass spectrometry. The iminoquinone intermediate was trapped by N-acetyl-L-cysteine (NAC) as well as GSH. NMR spectra of the NAC adducts indicated that the NAC was bound to the 6 and 9 positions of the aromatic ring. This is the same orientation as the binding of nucleophiles to the reactive metabolite of clozapine. We were able to use an antibody against clozapine to demonstrate that 7-hydroxyfluperlapine, but not fluperlapine itself, covalently modifies human myeloperoxidase. Furthermore, we demonstrated that 7-hydroxyfluperlapine is metabolized by activated neutrophils to a reactive intermediate that covalently binds to neutrophils. In the presence of NAC or GSH, such covalent binding was inhibited and the NAC or GSH adducts were formed. Thus, the reactivity and even the orientation of the binding of the reactive metabolite of 7-hydroxyfluperlapine is very similar to that of clozapine. These results provide a mechanism for the formation of a reactive metabolite of fluperlapine similar to clozapine that may explain its ability to induce agranulocytosis.}, }
@article {pmid10680717, year = {2000}, author = {Shoeman, DW and Shirota, FN and DeMaster, EG and Nagasawa, HT}, title = {Reaction of nitroxyl, an aldehyde dehydrogenase inhibitor, with N-acetyl-L-cysteine.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {20}, number = {1}, pages = {55-59}, doi = {10.1016/s0741-8329(99)00056-7}, pmid = {10680717}, issn = {0741-8329}, mesh = {Acetylcysteine/*chemistry ; Aldehyde Dehydrogenase/antagonists &amp; inhibitors/*chemistry ; Hydroxamic Acids/*chemistry ; Nitrogen Oxides/*chemical synthesis ; Sulfonamides/*chemistry ; }, abstract = {Nitroxyl (HNO) is the aldehyde dehydrogenase (AIDH) inhibitor produced by catalase action on cyanamide. Incubation of N-acetyl-L-cysteine (NAC), a reagent with a free sulfhydryl group, with Piloty's acid (a nitroxyl generator) suggested that NAC was acting as a competitive "trap" for nitroxyl. Elucidation of the structure of this reaction product should give an insight as to how nitroxyl interacts with AIDH, a sulfhydryl enzyme. We now present evidence that the product formed is N-acetyl-L-cysteinesulfinamide (NACS). We have synthesized NACS and showed that this synthetic product was identical to the product formed in the trapping experiment. Both had identical RT values by reverse phase HPLC and identical RF values by TLC using three different solvent systems. The structural identification of this nitroxyl trapped product as a sulfinamide now allows the chemical confirmation of the active-site cysteine residue of AIDH as Cys-302.}, }
@article {pmid10677007, year = {1999}, author = {Oguri, S and Ohta, Y and Suzuki, C}, title = {Direct detection of endogenous histamine in rat peritoneal mast cells by in-capillary derivatization high-performance capillary electrophoresis.}, journal = {Journal of chromatography. B, Biomedical sciences and applications}, volume = {736}, number = {1-2}, pages = {263-271}, doi = {10.1016/s0378-4347(99)00468-5}, pmid = {10677007}, issn = {1387-2273}, mesh = {Animals ; Cell Count ; Electrophoresis, Capillary/*methods ; Histamine/*analysis ; Indicators and Reagents ; Male ; Mast Cells/*chemistry ; Peritoneal Cavity/*cytology ; Rats ; Rats, Wistar ; Reproducibility of Results ; Sodium Dodecyl Sulfate ; }, abstract = {A simple method for the detection of endogenous histamine in rat peritoneal mast cells was evaluated using on-line mode in-capillary derivatization high-performance capillary electrophoretic (ICD-HPCE) techniques, which were previously developed by our group [S. Oguri et al., J. Chromatogr. A, 787 (1997) 253-260]. The method involves a suspension of peritoneal mast cells (1 x 10(6) cells/ml of saline) collected from a male Wistar rat (eight weeks of age), which are directly introduced into the capillary tube from the anodic end by hydrostatic injection (at 25 cm height, for 2-20 s). When a high-voltage potential (25 kV) is applied to the capillary, which is already filled with the run buffer containing both a lysing reagent (SDS, sodium dodecyl sulfate,) and a derivatizing reagent (OPA, o-phthalaldehyde; NAC, N-acetylcysteine), histamine in the mast cells was detected at high-sensitivity level without further procedures. During ICD-HPCE, the mast cells injected in the capillary were lysed with the lysing reagent, free histamine released from the cell was labeled with the derivatizing reagent, and its derivative was electromigrated, separated and detected with a fluorescence detector (excitation wavelength at 340 nm, emission wavelength at 450 nm) in a fused-silica capillary (75 cm x effective length x 50 microm I.D.). The run buffer used was a 20 mM phosphate-borate buffer (pH 10) containing 20 mM SDS, 2 mM OPA and 2 mM NAC. This method was also examined with regard to the possibility of its use for determination of histamine at the single mast cell level.}, }
@article {pmid10676851, year = {2000}, author = {Pocernich, CB and La Fontaine, M and Butterfield, DA}, title = {In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain.}, journal = {Neurochemistry international}, volume = {36}, number = {3}, pages = {185-191}, doi = {10.1016/s0197-0186(99)00126-6}, pmid = {10676851}, issn = {0197-0186}, support = {AG-05119/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Brain/drug effects/*metabolism ; Ferrous Compounds/pharmacology ; Glutathione/*metabolism ; Hydrogen Peroxide/pharmacology ; Hydroxyl Radical/*pharmacology ; Male ; Nerve Tissue Proteins/*metabolism ; Oxidation-Reduction ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Synaptosomes/metabolism ; }, abstract = {Glutathione deficiency has been associated with a number of neurodegenerative diseases including Lou Gehrig's disease, Parkinson's disease, and HIV. A crucial role for glutathione is as a free radical scavenger. Alzheimer's disease (AD) brain is characterized by oxidative stress, manifested by protein oxidation, lipid oxidation, oxidized glutathione, and decreased activity of glutathione S-transferase, among others. Reasoning that elevated levels of endogenous glutathione would offer protection against free radical-induced oxidative stress, rodents were given in vivo injections of N-acetylcysteine (NAC), a known precursor of glutathione, to study the vulnerability of isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer. Protein carbonyls, a marker of protein oxidation, were measured. NAC significantly increased endogenous glutathione levels in cortical synaptosome cytosol (P < 0.01). As reported previously, protein carbonyl levels of the Fe2+/H2O2-treated synaptosomes were significantly higher compared to that of non-treated controls (P < 0.01), consistent with increased oxidative stress. In contrast, protein carbonyl levels in Fe2+/H2O2-treated synaptosomes isolated from NAC-injected animals were not significantly different from saline-injected non-treated controls, demonstrating protection against hydroxyl radical induced oxidative stress. These results are consistent with the notion that methods to increase endogenous glutathione levels in neurodegenerative diseases associated with oxidative stress, including AD, may be promising.}, }
@article {pmid10669958, year = {1999}, author = {Morini, M and Cai, T and Aluigi, MG and Noonan, DM and Masiello, L and De Flora, S and D'Agostini, F and Albini, A and Fassina, G}, title = {The role of the thiol N-acetylcysteine in the prevention of tumor invasion and angiogenesis.}, journal = {The International journal of biological markers}, volume = {14}, number = {4}, pages = {268-271}, doi = {10.1177/172460089901400413}, pmid = {10669958}, issn = {0393-6155}, mesh = {Acetylcysteine/*pharmacology ; Angiogenesis Inhibitors/*pharmacology ; Animals ; Doxorubicin/pharmacology ; Endothelium, Vascular/drug effects/pathology ; Humans ; Mice ; Neoplasm Invasiveness/*prevention &amp; control ; Neoplasm Metastasis ; }, abstract = {We have extensively studied the effects of N-acetylcysteine (NAC), a cytoprotective drug that can prevent in vivo carcinogenesis. Here we review our findings NAC completely inhibits gelatinolytic activity of metalloproteases and chemotactic and invasive activities of tumor cells. In addition, NAC reduces the number of lung metastases when malignant murine melanoma cells are injected into nude mice. NAC treatment decreases the weight of primary tumors and produces a dose-related increase in tumor latency. Moreover, oral administration of NAC reduces the formation of spontaneous metastases. In experimental metastasis assays, we have found a synergistic reduction in the number of lung metastases after treatment with doxorubicin (DOX) and NAC in nude mice. In tumorigenicity and spontaneous metastasis assays, the combined administration of DOX and oral NAC again has shown synergistic effects on the frequency and weight of primary tumors and local recurrences and completely prevented the formation of lung metastases. The addition of NAC to endothelial cells strongly reduces their invasive activity in response to angiogenic stimuli. NAC inhibited the degradation and release of radiolabeled type IV collagen by activated endothelial cells, indicating that NAC blocks gelatinase activity. Oral administration of NAC reduces the angiogenic response induced by KS tumor cell products, confirming the ability of NAC to inhibit the invasive activity of endothelial cells in vivo and thereby blocking angiogenesis.}, }
@article {pmid10667587, year = {2000}, author = {Goldman, Y and Peled, A and Shinitzky, M}, title = {Effective elimination of lung metastases induced by tumor cells treated with hydrostatic pressure and N-acetyl-L-cysteine.}, journal = {Cancer research}, volume = {60}, number = {2}, pages = {350-358}, pmid = {10667587}, issn = {0008-5472}, mesh = {Acetylcysteine/*pharmacology ; Adenosine/*analogs &amp; derivatives/pharmacology ; Animals ; CD4 Antigens/analysis ; CD8 Antigens/analysis ; Female ; Humans ; *Hydrostatic Pressure ; Hypersensitivity, Delayed ; Lung/drug effects/pathology ; Lung Neoplasms/immunology/*pathology/*prevention &amp; control/secondary ; Lymphocyte Culture Test, Mixed ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasm Metastasis/prevention &amp; control ; Spleen/drug effects/*immunology ; }, abstract = {In previous studies, we have demonstrated that application of high hydrostatic pressure (P) to tumor cells in the presence of a slow-reacting membrane-impermeable cross-linker (CL), 2'-3'-adenosine dialdehyde, can rearrange cell surface proteins into immunogenic clusters. Here, we present evidence indicating that subsequent reduction of surface protein disulfides with N-acetyl-L-cysteine (NAC) further augments the immunogenic potential of PCL-modified tumor cells both in vitro and in vivo. Immunotherapy with PCL+NAC-modified 3LL-D122 Lewis lung carcinoma cells plus i.v. delivery of NAC in mice bearing established lung metastases provoked an antitumor response capable of eradicating the metastatic nodules as demonstrated by restoration of normal lung weight and histology. In addition, immunization with PCL+NAC-modified tumor cells gave rise to a strong delayed-type hypersensitivity recall response against parental D122 cells. We propose that this novel two-prong strategy, based on local immunization with autologous PCL+NAC-modified tumor cells and systemic boosting with NAC, could provide a practical, effective immunotherapeutic regimen for the treatment of human cancer.}, }
@article {pmid10666292, year = {2000}, author = {Yang, CF and Shen, HM and Ong, CN}, title = {Ebselen induces apoptosis in HepG(2) cells through rapid depletion of intracellular thiols.}, journal = {Archives of biochemistry and biophysics}, volume = {374}, number = {2}, pages = {142-152}, doi = {10.1006/abbi.1999.1574}, pmid = {10666292}, issn = {0003-9861}, mesh = {Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Azoles/*pharmacology ; Carcinoma, Hepatocellular ; Cell Survival/*drug effects ; Glutathione/*metabolism ; Humans ; In Situ Nick-End Labeling ; Isoindoles ; Kinetics ; Liver Neoplasms ; Neoplasm Proteins/metabolism ; Organoselenium Compounds/*pharmacology ; Sulfhydryl Compounds/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Ebselen, 2-phenyl-1,2-benzisoselenazol-3(2H)-one, is a synthetic seleno-organic compound with antioxidant capability. In the present study, we systematically examined the ability of ebselen to induce apoptosis in a human hepatoma cell line, HepG(2). Ebselen-induced apoptosis was evaluated by (i) TdT-mediated dUTP nick end labeling assay; (ii) analysis of sub-G1 cells; (iii) cell morphology, including cell size and granularity examination; and (iv) DNA gel electrophoresis. The results showed that ebselen was able to induce typical apoptosis in HepG(2) cells in a dose- and time-dependent manner. In order to explore the possible mechanisms involved in ebselen-induced apoptosis, the effect of ebselen on intracellular thiol concentrations including reduced glutathione (GSH) and protein thiols and the effect of N-acetylcysteine (NAC) and buthionine sulfoximine (BSO) pretreatment on ebselen-induced apoptosis were investigated. It was found that (i) ebselen rapidly depleted intracellular GSH and protein thiols, moreover, the depletion preceded the occurrence of apoptosis; (ii) NAC, a precursor of intracellular GSH synthesis, significantly alleviated ebselen-induced apoptosis; and (iii) BSO, a specific inhibitor of intracellular GSH synthesis, augmented ebselen-induced apoptosis significantly. Taken together, the present study demonstrates that ebselen is able to induce apoptosis in HepG(2) cells, most probably through rapid depletion of intracellular thiols.}, }
@article {pmid10663636, year = {2000}, author = {Dizdar, N and Kullman, A and Kågedal, B}, title = {Comparison of N-acetylcysteine and l-2-oxothiazolidine-4-carboxylate as cysteine deliverers and glutathione precursors in human malignant melanoma transplants in mice.}, journal = {Cancer chemotherapy and pharmacology}, volume = {45}, number = {3}, pages = {192-198}, doi = {10.1007/s002800050029}, pmid = {10663636}, issn = {0344-5704}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cysteine/drug effects/*metabolism ; Cysteinyldopa/drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Glutathione/drug effects/*metabolism ; Humans ; Melanoma/*metabolism/pathology ; Melanoma, Experimental/metabolism/pathology ; Mice ; Mice, Nude ; Microdialysis ; Neoplasm Transplantation ; Protein Precursors/metabolism ; Pyrrolidonecarboxylic Acid ; Thiazoles/metabolism/*pharmacology ; Thiazolidines ; Transplantation, Heterologous ; Tumor Cells, Cultured ; }, abstract = {PURPOSE: Glutathione is an important cellular compound which affects detoxification of electrophiles and may have direct or indirect effects on pigment formation. It is therefore of importance to study interstitial concentrations in melanoma tissue while decreasing its formation with an enzyme inhibitor and increasing its amount with cysteine deliverers.<br><br>METHOD: Glutathione formation was inhibited by intraperitoneal (i.p.) injection of BSO. N-Acetylcysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) were then given i.p. to subgroups of the animals. Intratumoral microdialysis was performed during BSO treatment, during BSO treatment combined with NAC or OTC and after discontinuation of BSO but ongoing NAC or OTC treatment.<br><br>RESULTS: Glutathione formation was inhibited during BSO treatment. The dialysate concentrations of both glutathione and cysteine decreased during concomitant treatment with BSO and NAC or OTC. Recovery of the amounts of the two compounds was seen in both groups after discontinuation of BSO treatment. In the NAC group we also observed an acute increase in dialysate concentrations of cysteine after NAC injection. The 5-S-cysteinyldopa concentrations were unaffected by variations in glutathione and cysteine concentrations.<br><br>CONCLUSIONS: 5-S-Cysteinyldopa in melanoma is not formed from glutathione in vivo to any appreciable extent. The intracellular amount of cysteine is probably not a limiting factor for cysteinyldopa formation. It seems that both NAC and OTC can be used as cysteine deliverers to melanoma cells in vivo to produce recovery of glutathione levels after synthesis inhibition by BSO treatment.}, }
@article {pmid10661865, year = {1999}, author = {Fernandez, PC and Machado, J and Heussler, VT and Botteron, C and Palmer, GH and Dobbelaere, DA}, title = {The inhibition of NF-kappaB activation pathways and the induction of apoptosis by dithiocarbamates in T cells are blocked by the glutathione precursor N-acetyl-L-cysteine.}, journal = {Biological chemistry}, volume = {380}, number = {12}, pages = {1383-1394}, doi = {10.1515/BC.1999.178}, pmid = {10661865}, issn = {1431-6730}, mesh = {Acetylcysteine/*pharmacology ; Activating Transcription Factor 2 ; Apoptosis/*drug effects ; Base Sequence ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cell Division/drug effects ; Cell Line, Transformed ; Cyclic AMP Response Element-Binding Protein/metabolism ; DNA/metabolism ; DNA Primers ; Disulfiram/antagonists &amp; inhibitors/pharmacology ; Enzyme Activation ; JNK Mitogen-Activated Protein Kinases ; Mitogen-Activated Protein Kinases/metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Pyrrolidines/antagonists &amp; inhibitors/*pharmacology ; T-Lymphocytes/cytology/*drug effects/metabolism ; Thiocarbamates/antagonists &amp; inhibitors/*pharmacology ; Transcription Factors/metabolism ; Transcription, Genetic/drug effects ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Nuclear factor-kappaB regulates genes that control immune and inflammatory responses and are involved in the pathogenesis of several diseases, including AIDS and cancer. It has been proposed that reactive oxygen intermediates participate in NF-kappaB activation pathways, and compounds with putative antioxidant activity such as N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) have been used interchangeably to demonstrate this point. We examined their effects, separately and combined, on different stages of the NF-kappaB activation pathway, in primary and in transformed T cells. We show that NAC, contrary to its reported role as an NF-kappaB inhibitor, can actually enhance rather than inhibit IkappaB degradation and, most importantly, show that in all cases NAC exerts a dominant antagonistic effect on PDTC-mediated NF-kappaB inhibition. This was observed at the level of IkappaB degradation, NF-kappaB DNA binding, and HIV-LTR-driven reporter gene expression. NAC also counteracted growth arrest and apoptosis induced by dithiocarbamates. Antagonistic effects were further observed at the level of jun-NH2-terminal kinase, p38 and ATF-2 activation. Our findings argue against the widely accepted assumption that NAC inhibits all NF-kappaB activation pathways and shows that two compounds, previously thought to function through a common inhibitory mechanism, can also have antagonistic effects.}, }
@article {pmid10660096, year = {1999}, author = {Estensen, RD and Levy, M and Klopp, SJ and Galbraith, AR and Mandel, JS and Blomquist, JA and Wattenberg, LW}, title = {N-acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyps.}, journal = {Cancer letters}, volume = {147}, number = {1-2}, pages = {109-114}, doi = {10.1016/s0304-3835(99)00281-5}, pmid = {10660096}, issn = {0304-3835}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adenomatous Polyps/pathology/*prevention &amp; control ; Administration, Oral ; Age Factors ; Biopsy ; Chemoprevention ; Cohort Studies ; Colonic Polyps/pathology/*prevention &amp; control ; Colorectal Neoplasms/pathology/*prevention &amp; control ; Diet ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Intestinal Mucosa/drug effects/metabolism/pathology ; Mitotic Index/*drug effects ; Proliferating Cell Nuclear Antigen/metabolism ; Sex Factors ; }, abstract = {This investigation is part of an effort to develop chemoprevention for carcinogenesis of the large bowel. The agent investigated is N-acetylcysteine (NAC). We used as a predictive biomarker, the proliferative index (PI), in a short-term human study. Patients with previous adenomatous colonic polyps are a cohort with increased risk for colon cancer and an increased PI of colonic crypts. They were randomly assigned to an experimental group given 800 mg/day of NAC for 12 weeks or a placebo group. Using proliferative cell nuclear antigen immunostaining, the PI of colonic crypts was measured prior to and after the treatments. The PI of the NAC group was decreased significantly (P < 0.02) while the placebo group showed no difference (P > 0.45). Since this decrease in PI may be an indicator of decreased risk of colon cancer, more extensive studies of the potential of NAC as a chemopreventive agent for colon cancer appear warranted.}, }
@article {pmid10659406, year = {1999}, author = {}, title = {Acetylcysteine. Fluimucil, Mucomyst, N-acetylcysteine, NAC, NSC 111180.}, journal = {Drugs in R&amp;D}, volume = {2}, number = {4}, pages = {265-266}, doi = {10.2165/00126839-199902040-00011}, pmid = {10659406}, issn = {1174-5886}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Antiviral Agents/administration &amp; dosage/*therapeutic use ; Clinical Trials as Topic ; Drug Synergism ; Drug Therapy, Combination ; HIV Infections/drug therapy ; Hepatitis C/*drug therapy ; Humans ; Interferon-alpha/administration &amp; dosage/*therapeutic use ; }, }
@article {pmid10657911, year = {2000}, author = {Khuri, FR and Lippman, SM}, title = {Lung cancer chemoprevention.}, journal = {Seminars in surgical oncology}, volume = {18}, number = {2}, pages = {100-105}, doi = {10.1002/(sici)1098-2388(200003)18:2&lt;100::aid-ssu3&gt;3.0.co;2-9}, pmid = {10657911}, issn = {8756-0437}, mesh = {Antineoplastic Agents/therapeutic use ; Clinical Trials, Phase III as Topic ; Humans ; Lung Neoplasms/*prevention &amp; control ; Randomized Controlled Trials as Topic ; Retinoids/therapeutic use ; Selenium/therapeutic use ; Vitamin E/therapeutic use ; }, abstract = {Lung cancer is the leading cause of cancer death in the United States. The persisting grim lung cancer incidence and mortality figures argue powerfully for new approaches such as chemoprevention for controlling this disease. Retinoids are among the most intensively studied cancer chemoprevention agents, including in the lung. Several randomized clinical or translational chemoprevention trials (e.g., of retinoids, beta-carotene, or combined folic acid and vitamin B(12)) have been conducted in lung pre-malignancy. Retinoid studies have produced important data on molecular/cellular markers of lung carcinogenesis, e.g., loss of heterozygosity (LOH) at 3p and 9p and retinoic acid receptor-beta (RAR-beta). Two large randomized trials with a lung cancer endpoint, the Alpha-Tocopherol, Beta-Carotene (ATBC) Prevention Study and the Beta-Carotene and Retinol Efficacy Trial (CARET), found that beta-carotene (+/- retinol) was harmful (in smokers). Recently completed lung-second-primary-tumor-prevention trials include the retinoids retinyl palmitate and 13-cis-retinoic acid (13cRA) and N-acetylcysteine (NAC). Vitamin E and selenium show promise for lung cancer prevention, based on positive secondary/subset analyses of three large-scale, randomized National Cancer Institute (NCI) cancer prevention trials. Future directions of lung cancer chemoprevention include the study of molecular markers of risk and drug activity, molecular targeting study, improved imaging techniques (e.g., molecular imaging) and new drug delivery systems.}, }
@article {pmid10654448, year = {2000}, author = {Cortelezzi, A and Cattaneo, C and Sarina, B and Cristiani, S and Pomati, M and Silvestris, I and Motta, M and Ibatici, A and Gornati, G and Volpe, AD and Maiolo, AT}, title = {Efficacy of N-acetylcysteine and all-trans retinoic acid in restoring in vitro effective hemopoiesis in myelodysplastic syndromes.}, journal = {Leukemia research}, volume = {24}, number = {2}, pages = {129-137}, doi = {10.1016/s0145-2126(99)00165-4}, pmid = {10654448}, issn = {0145-2126}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Aged, 80 and over ; Apoptosis ; Bone Marrow Cells/drug effects/pathology ; Female ; Hematopoiesis/*drug effects ; Humans ; Male ; Middle Aged ; Myelodysplastic Syndromes/*pathology ; Tretinoin/*pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {We evaluated the in vitro effect on clonogenic potential (CFU-GM) and apoptosis in myelodysplastic syndromes (MDS) progenitors of an anti-oxidant (N-acetylcysteine, NAC) and/or a differentiating (all-trans retinoic acid, ATRA) agent. NAC significantly reduced apoptosis, both NAC and ATRA induced an increase in CFU-GM, but NAC seemed to be particularly effective in the high risk (HR) MDS. NAC + ATRA conferred a significant advantage in terms of CFU-GM with respect to NAC and ATRA alone. Tumor Necrosis Factor-alpha (TNF-alpha) levels decreased after incubation with NAC in the MDS samples. This study shows that ineffective hemopoiesis in MDS could benefit from both NAC and ATRA, suggesting that anti-oxidant treatment may play a role in guaranteeing MDS cell survival, predisposing them towards differentiation.}, }
@article {pmid10653978, year = {2000}, author = {Chen, KD and Lai, MT and Cho, JH and Chen, LY and Lai, YK}, title = {Activation of p38 mitogen-activated protein kinase and mitochondrial Ca(2+)-mediated oxidative stress are essential for the enhanced expression of grp78 induced by the protein phosphatase inhibitors okadaic acid and calyculin A.}, journal = {Journal of cellular biochemistry}, volume = {76}, number = {4}, pages = {585-595}, pmid = {10653978}, issn = {0730-2312}, mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium/*pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Carrier Proteins/genetics/*metabolism ; Egtazic Acid/analogs &amp; derivatives/pharmacology ; Endoplasmic Reticulum Chaperone BiP ; Enzyme Inhibitors/pharmacology ; *Heat-Shock Proteins ; Imidazoles/pharmacology ; Marine Toxins ; Mitochondria/*metabolism ; *Mitogen-Activated Protein Kinases ; Molecular Chaperones/genetics/*metabolism ; Okadaic Acid/*pharmacology ; Oxazoles/*pharmacology ; Oxidative Stress/*drug effects ; Phosphoprotein Phosphatases/*antagonists &amp; inhibitors ; Proline/analogs &amp; derivatives/pharmacology ; Promoter Regions, Genetic ; Pyridines/pharmacology ; RNA, Messenger/metabolism ; Rats ; Ruthenium Red/pharmacology ; Thiocarbamates/pharmacology ; Transcriptional Activation/genetics ; Tumor Cells, Cultured ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {We have reported that treatment with okadaic acid, a potent protein phosphatase inhibitor, has the ability to enhance the synthesis of the 78-kDa glucose-regulated protein (GRP78). This article reports our investigation of another protein phosphatase inhibitor, calyculin A, demonstrating the signaling pathways elicited by the protein phosphatase inhibitors that lead to the induction of grp78. Our data showed that the induction process is abolished by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38(MAPK)). Phosphorylation-activation of p38(MAPK) in the treated cells was indicated by its own phosphorylation, as shown by double Western blotting analyses and directly confirmed by the in vitro kinase assay using MAPK-activated protein kinase-2, a well-known downstream effector of p38(MAPK), as a substrate. The involvement of p38(MAPK) in this process is further substantiated by using transient transfection assays with a plasmid, pGRP78-Luc, which contains a 0.72-kbp stretch of the grp78 promoter. By exploiting the same transfection assay, we demonstrated that the up-regulation of the grp78 promoter by the protein phosphatase inhibitors is suppressed in the presence of the cytoplasmic calcium chelator bis(aminophenoxy)ethane N,N'-tetraacetic acid, the mitochondria calcium uniporter inhibitor ruthenium red as well as the antioxidants N-acetyl cysteine and pyrrolidinedithiocarbamate. Taken together, our results lead us to conclude that treatment with the protein phosphatase inhibitors would activate the signaling pathways involving p38(MAPK) and mitochondrial calcium-mediated oxidative stress and that these pathways must act in concert in order to confer the induction of grp78 by okadaic acid and calyculin A.}, }
@article {pmid10653697, year = {2000}, author = {Schmitz, S and Clayton, J and Nongthomba, U and Prinz, H and Veigel, C and Geeves, M and Sparrow, J}, title = {Drosophila ACT88F indirect flight muscle-specific actin is not N-terminally acetylated: a mutation in N-terminal processing affects actin function.}, journal = {Journal of molecular biology}, volume = {295}, number = {5}, pages = {1201-1210}, doi = {10.1006/jmbi.1999.3407}, pmid = {10653697}, issn = {0022-2836}, mesh = {Acetylation ; Acetylcysteine/metabolism ; Actins/*chemistry/genetics/*metabolism ; Actomyosin/metabolism ; Animals ; *Drosophila melanogaster ; Electrophoresis, Gel, Two-Dimensional ; Flight, Animal ; Genes, Insect/genetics/physiology ; Isoelectric Point ; Mass Spectrometry ; Methionine/metabolism ; Methylation ; Methylcellulose/metabolism ; Mutation/*genetics ; Phenotype ; Protein Isoforms/chemistry/genetics/metabolism ; *Protein Processing, Post-Translational ; Viscosity ; }, abstract = {Many eukaryotic proteins are co and post-translationally modified at their N termini by removal of one or two amino acid residues and N(alpha)-acetylation. Actins show two different forms of N-terminal processing dependent on their N-terminal sequence. In class II actins, which include muscle actins, the common primary sequence of Met-Cys-Asp-actin is processed to acetyl-Asp-actin. The functional significance of this in vivo is unknown. We have studied the indirect flight muscle-specific actin, ACT88F, of Drosophila melanogaster. Our results show that ACT88F is N-terminally processed in vivo as a class II actin by removal of the first two amino acid residues (Met and Cys), but that uniquely the N terminus is not acetylated. In addition we show that ACT88F is methylated, probably at His73. Flies carrying the mod(-) mutation fail to complete post-translational processing of ACT88F. We propose that the mod gene product is normally responsible for removing N-acetyl-cysteine from actin. The biological significance of this process is demonstrated by observations that retention of the N-acetyl-cysteine in ACT88F affects the flight muscle function of mod(-) flies. This suggests that the extreme N terminus affects actomyosin interactions in vivo, a proposal we have examined by in vitro motility assays of ACT88F F-actin from mod(-) flies. The mod(-) actin only moves in the presence of methylcellulose, a viscosity-enhancing agent, where it moves at velocities slightly, but significantly, reduced compared to wild-type. These data confirm that N-acetyl-cysteine at the N terminus affects actomyosin interactions, probably by reducing formation of the initial actomyosin collision complex, a process known to involve the actin N terminus.}, }
@article {pmid10653482, year = {2000}, author = {Kobayashi, MS and Han, D and Packer, L}, title = {Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity.}, journal = {Free radical research}, volume = {32}, number = {2}, pages = {115-124}, doi = {10.1080/10715760000300121}, pmid = {10653482}, issn = {1071-5762}, mesh = {Animals ; Antioxidants/*pharmacology ; Cell Death/drug effects ; Cell Line ; Excitatory Amino Acid Antagonists/*pharmacology ; Flavonoids/*pharmacology ; Free Radical Scavengers/pharmacology ; Ginkgo biloba/chemistry ; Glutamic Acid/*pharmacology ; Glutathione/metabolism ; Neurodegenerative Diseases/therapy ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; *Plant Extracts ; Plants, Medicinal ; Rats ; Sulfhydryl Compounds/pharmacology ; Vitamin E/pharmacology ; }, abstract = {Antioxidant therapy has been shown to be beneficial in neurological disorders including Alzheimer's disease and cerebral ischemia. Glutamate-induced cytotoxicity in HT-4 neuronal cells has been previously demonstrated to be due to oxidative stress caused by depletion of cellular glutathione (GSH). The present study demonstrates that a wide variety of antioxidants inhibit glutamate-induced cytotoxicity in HT-4 neuronal cells. Low concentrations of alpha-tocopherol and its analogs were highly effective in protecting neuronal cells against cytotoxicity. Purified flavonoids and herbal extracts of Gingko biloba (EGb 761) and French maritime pine bark (Pycnogenol) were also effective. We have previously shown that pro-glutathione agents can spare GSH and protect cells from glutamate insult in a C6 glial cell model. The protective effects of nonthiol-based antioxidants tested in the HT-4 line were not mediated via GSH level modulation. In contrast, protective effects of thiol-based pro-glutathione agents alpha-lipoic acid (LA) and N-acetyl cysteine (NAC) corresponded with a sparing effect on GSH levels in glutamate-treated HT-4 cells. Glutamate-induced cytotoxicity in HT-4 cells is a useful model system for testing compounds or mixtures for antioxidant activity.}, }
@article {pmid10653436, year = {2000}, author = {Omara, FO and Fournier, M and Vincent, R and Blakley, BR}, title = {Suppression of rat and mouse lymphocyte function by urban air particulates (Ottawa dust) is reversed by N-acetylcysteine.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {59}, number = {2}, pages = {67-85}, doi = {10.1080/009841000156989}, pmid = {10653436}, issn = {1528-7394}, mesh = {Acetylcysteine/agonists/*pharmacology ; Air Pollutants/antagonists &amp; inhibitors/*toxicity ; Animals ; Calcium/metabolism ; Cell Survival/drug effects ; Cells, Cultured ; Dust ; Free Radical Scavengers/agonists/*pharmacology ; Interleukin-2/metabolism/pharmacology ; Lymphocyte Activation/drug effects ; Lymphocytes/*drug effects/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Ontario ; Rats ; Rats, Inbred F344 ; Receptors, Interleukin-2/metabolism ; Receptors, Transferrin/metabolism ; Spleen/cytology/drug effects/immunology ; }, abstract = {Epidemiology studies have demonstrated increased pulmonary morbidity such as allergy and infection with episodes of high particulate air pollution (size range 0.1-10 microm diameter, PM10), but the mechanism(s) for this association is not yet well defined. The present study was undertaken to evaluate the effects of EHC-93 urban particles (Ottawa dust) on immune functions of peripheral blood mononuclear cells (PBMCs) and splenocytes from male Fischer 344 rats and C57Bl/6 mice. Immune function endpoints evaluated included cell viability, lymphocyte blastogenesis stimulated by T-cell mitogen (concanavalin A, Con A) or B-cell mitogens [lipopolysaccharide (LPS) or LPS/dextran sulfate], intracellular Ca2+ concentration, interleukin 2 (IL-2) production, and expression of receptors for transferrin (TfR) and IL-2 (IL-2R). In addition, the effect of N-acetylcysteine (NAC), an antioxidant, on the toxicity of EHC-93 particles was evaluated. Total EHC-93 particles, water leachate of EHC-93, and washed EHC-93 suppressed proliferation of PBMCs and splenocytes to T- and B-cell mitogens. Treatment of splenocytes with EHC-93 particles did not alter intracellular Ca2+ concentration or mitogen-induced expression of TfR and IL-2R expression, but increased IL-2 production assayed by enzyme-linked immunosorbent assay (ELISA). In spite of an increase in IL-2 production, exogenous IL-2 when added to cultures was able to reverse the suppression of Con A-induced lymphocyte proliferation by EHC-93 particles. Furthermore, the suppressive effect of EHC-93 particles on mitogen-induced lymphocyte proliferation was completely abolished by addition of the antioxidant NAC to cultures, suggesting a possible role of oxidative factors for the toxicity of EHC-93 particles.}, }
@article {pmid10651168, year = {1998}, author = {Tate, Y and Kawasaki, K and Ishibashi, S and Ikeda, U and Shimada, K}, title = {Effects of N-acetylcysteine on nitroglycerin-induced relaxation and protein phosphorylation of porcine coronary arteries.}, journal = {Heart and vessels}, volume = {13}, number = {6}, pages = {263-268}, pmid = {10651168}, issn = {0910-8327}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Coronary Vessels/*drug effects ; Desmin/drug effects ; Drug Synergism ; Drug Tolerance ; Muscle, Smooth, Vascular/*drug effects ; Myosin Light Chains/drug effects ; Nitroglycerin/*pharmacology ; Phosphorylation/drug effects ; Swine ; Vasodilator Agents/*pharmacology ; }, abstract = {We investigated the effects of the sulfhydryl-donor, N-acetylcysteine (NAC), on nitroglycerin (NTG)-induced relaxation of the vascular smooth muscle. Addition of histamine to isolated porcine coronary arteries induced an initial rapid contraction followed by a gradual decrease in tonic contraction. NTG applied to the coronary artery strips before histamine caused relaxation of the histamine-induced rapid (3 min) and tonic (48 min) contraction. The inhibition of the tonic contraction by NTG was less at 48 min than at 3 min. Application of NAC (NTG-NAC) enhanced the relaxing effects of NTG on the histamine-induced tonic contraction rather than the acute contraction. In phosphorylation studies, changes in the phosphorylation of an intermediate filament, desmin, were parallel with changes in contraction in NTG-treated and NTG-NAC samples at 48 min. These phosphorylation changes of desmin at 48 min, which might be responsible for tonic phase contraction, were more extensive than those of myosin light chain (MLC) phosphorylation at 3 min, which might be responsible for acute contraction. These results suggest that treatment with the sulfhydryl donor, NAC, inhibited the phosphorylation of desmin associated with the enhancement of NTG-induced relaxation, which might be related to the mechanisms of recovery from NTG tolerance by sulfhydryl groups.}, }
@article {pmid10650135, year = {2000}, author = {Martínez, M and Hernández, AI and Martínez, N}, title = {N-Acetylcysteine delays age-associated memory impairment in mice: role in synaptic mitochondria.}, journal = {Brain research}, volume = {855}, number = {1}, pages = {100-106}, doi = {10.1016/s0006-8993(99)02349-5}, pmid = {10650135}, issn = {0006-8993}, mesh = {Acetylcysteine/*pharmacology ; Aging/*drug effects/physiology ; Animals ; Avoidance Learning/drug effects ; Behavior, Animal/drug effects ; Female ; Free Radical Scavengers/*pharmacology ; Memory Disorders/*drug therapy ; Mice ; Mice, Inbred Strains ; Mitochondria/*physiology ; Oxidative Stress/drug effects/physiology ; Regression Analysis ; Synapses/*physiology ; }, abstract = {Mitochondrial oxidative damage is implicated in brain aging and in age-related neurodegenerative diseases. Since N-acetylcysteine (NAC) has recently been shown to prevent apoptotic death in neuronal cells and protect synaptic mitochondria proteins from oxidative damage in aged mice, we have investigated whether dietary administration of this thiolic antioxidant retards age-related memory loss. At 48 weeks of age, a control female OF-1 mice group was fed standard food pellets and another group received pellets containing 0.3% (w/w) of NAC. After 23 weeks of this diet, the NAC had partially restored the memory deficit associated with aging in mice. Moreover, the lipid peroxide and protein carbonyl contents of the synaptic mitochondria were significantly decreased in the NAC-supplemented animals in comparison with their age-matched controls. The antioxidant properties and probable action on mitochondrial bioenergetic ability in the synaptic terminals may explain, at least partially, the beneficial action of NAC administration.}, }
@article {pmid10645973, year = {2000}, author = {Morshead, CM and van der Kooy, D}, title = {A cell-survival factor (N-acetyl-L-cysteine) alters the in vivo fate of constitutively proliferating subependymal cells in the adult forebrain.}, journal = {Journal of neurobiology}, volume = {42}, number = {3}, pages = {338-346}, doi = {10.1002/(sici)1097-4695(20000215)42:3&lt;338::aid-neu5&gt;3.0.co;2-k}, pmid = {10645973}, issn = {0022-3034}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Cell Division/drug effects ; Cell Survival/drug effects ; Cerebral Ventricles/*cytology/drug effects/physiology ; Ependyma/*cytology ; Gene Transfer Techniques ; Infusions, Parenteral ; Male ; Mice ; Neurons/*cytology/drug effects ; Retroviridae ; beta-Galactosidase/analysis/genetics ; }, abstract = {The adult mouse brain contains a population of constitutively proliferating subependymal cells that surround the lateral ventricle and are the direct progeny of the neural stem cell. Constitutively proliferating cells divide rapidly; 6 days after labeling, 60% of their progeny undergo cell death, 25% migrate to the olfactory bulbs, and 15% continue to proliferate within the subependyma. We have intraventricularly infused a cell survival factor N-acetyl-L-cysteine (NAC), which is known to have survival effects without concomitant proliferative effects on cells in vitro, and examined the resulting fate of cells spared from the normally occurring cell death. NAC infusion for 5 days results in a five-fold increase in the number of retrovirally labeled subependymal cells compared to saline-infused controls. The increase in the number of subependymal cells is directly proportional to the amount of time during which NAC is present and is not due to increased proliferation. While NAC is able to keep all the normally dying progeny alive, the cells spared from death remain confined to the subependyma lining the lateral ventricles and do not migrate to the olfactory bulbs (one normal fate of constitutively proliferating progeny) or into the surrounding brain parenchyma. When animals survive for an additional 6 days following NAC infusion, the number of retrovirally labeled subependymal cells returns to control values, indicating that the continued presence of NAC is necessary for cell survival. These data suggest that preventing cell death is not sufficient to keep all of the progeny of these cells in a proliferative mode.}, }
@article {pmid10640916, year = {1999}, author = {Kanazawa, H and Hirata, K and Yoshikawa, J}, title = {Administration of SIN-1 induces guinea pig airway hyperresponsiveness through inactivation of airway neutral endopeptidase.}, journal = {International archives of allergy and immunology}, volume = {120}, number = {4}, pages = {317-322}, doi = {10.1159/000024285}, pmid = {10640916}, issn = {1018-2438}, mesh = {Animals ; Bronchial Hyperreactivity/*chemically induced ; Bronchoconstriction/drug effects ; Endothelin-1/pharmacology ; Enzyme Activation/drug effects ; Glycopeptides/pharmacology ; Guinea Pigs ; Male ; Molsidomine/administration &amp; dosage/*analogs &amp; derivatives ; Neprilysin/*metabolism ; Nitrates/pharmacology ; Oxidants/pharmacology ; Protease Inhibitors/pharmacology ; Respiratory System/enzymology ; Substance P/pharmacology ; Trachea/enzymology ; Vasodilator Agents/administration &amp; dosage ; }, abstract = {BACKGROUND: Peroxynitrite plays an important role in the pathogenesis of airway inflammation. We have already found that peroxynitrite may contribute to decreased beta(2)-adrenoceptor responses in airway smooth muscle. However, it is not known whether peroxynitrite can alter neutral endopeptidase (EC 3.4.24.11; NEP) activity in the airways. This study was designed to determine whether peroxynitrite induces airway hyperresponsiveness to substance P (SP) and endothelin-1 (ET-1) through the inactivation of airway NEP.<br><br>METHODS: We examined whether the administration of S-morpholinosydnonimine (SIN-1), a compound that releases peroxynitrite, increased bronchoconstrictor responses to SP and ET-1 in anesthetized guinea pigs. In addition, we assayed NEP activity in the airways of SIN-1-exposed guinea pigs.<br><br>RESULTS: Though SIN-1 (10(-7) M) alone had no effect on pulmonary resistance, pretreatment with SIN-1 significantly enhanced SP- and ET-1-induced bronchoconstriction. Pretreatment with phosphoramidon, an NEP inhibitor, also enhanced SP- and ET-1-induced bronchoconstriction. However, simultaneous administration of phosphoramidon and SIN-1 had no additive effect on SP- and ET-1-induced bronchoconstriction. Peroxynitrite formation by SIN-1 was completely inhibited by N-acetylcysteine (NAC) and glutathione (GSH) in vitro, and pretreatment with NAC and GSH significantly reversed the potentiation by SIN-1 of SP-induced bronchoconstriction. In addition, the NEP activity of the trachea after SIN-1 exposure was significantly reduced compared to the level in control guinea pigs (solvent for SIN-1: 30.0+/-4.2 fmol.min(-1).mg tissue(-1); 10(-7) M SIN-1; 15.5+/-4.5 fmol.min(-1).mg tissue(-1), p<0.05).<br><br>CONCLUSIONS: These findings suggest that peroxynitrite induces airway hyperresponsiveness to SP and ET-1 through the inactivation of airway NEP, and that peroxynitrite is an important mediator of the alterations in airway functions.}, }
@article {pmid10640773, year = {2000}, author = {Takeyama, K and Dabbagh, K and Jeong Shim, J and Dao-Pick, T and Ueki, IF and Nadel, JA}, title = {Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor: role of neutrophils.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {164}, number = {3}, pages = {1546-1552}, doi = {10.4049/jimmunol.164.3.1546}, pmid = {10640773}, issn = {0022-1767}, support = {HL-24136/HL/NHLBI NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology ; Cell-Free System/drug effects/immunology ; Enzyme Activation/drug effects/immunology ; Enzyme Inhibitors/pharmacology ; ErbB Receptors/antagonists &amp; inhibitors/genetics/*metabolism ; Glycoconjugates/metabolism ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors/pharmacology ; In Situ Hybridization ; Ligands ; MAP Kinase Signaling System/drug effects/immunology ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Mucin 5AC ; Mucins/antagonists &amp; inhibitors/*biosynthesis/genetics ; Neutrophil Activation/drug effects/immunology ; Neutrophils/drug effects/*immunology/metabolism ; Oxidative Stress/drug effects/*immunology ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/metabolism ; RNA, Messenger/biosynthesis ; Transcriptional Activation/drug effects/*immunology ; Tumor Cells, Cultured ; Up-Regulation/drug effects/immunology ; }, abstract = {Oxidative stress has been implicated in the pathogenesis of inflammatory diseases of airways. Here we show that oxidative stress causes ligand-independent activation of epidermal growth factor receptors (EGFR) and subsequent activation of mitogen-activated protein kinase kinase (MEK)-p44/42 mitogen-activated protein kinase (p44/42mapk), resulting in mucin synthesis in NCI-H292 cells. Exogenous hydrogen peroxide and neutrophils activated by IL-8, FMLP, or TNF-alpha increased EGFR tyrosine phosphorylation and subsequent activation of p44/42mapk and up-regulated the expression of MUC5AC at both mRNA and protein levels in NCI-H292 cells. These effects were blocked by selective EGFR tyrosine kinase inhibitors (AG1478, BIBX1522) and by a selective MEK inhibitor (PD98059), whereas a selective platelet-derived growth factor receptor tyrosine kinase inhibitor (AG1295), a selective p38 MAPK inhibitor (SB203580), and a negative compound of tyrosine kinase inhibitors (A1) were without effect. Neutrophil supernatant-induced EGFR tyrosine phosphorylation, activation of p44/42mapk, and MUC5AC synthesis were inhibited by antioxidants (N-acetyl-cysteine, DMSO, dimethyl thiourea, or superoxide dismutase); neutralizing Abs to EGFR ligands (EGF and TGF-alpha) were without effect, and no TGF-alpha protein was found in the neutrophil supernatant. In contrast, the EGFR ligand, TGF-alpha, increased EGFR tyrosine phosphorylation, activation of p44/42mapk, and subsequent MUC5AC synthesis, but these effects were not inhibited by antioxidants. These results implicate oxidative stress in stimulating mucin synthesis in airways and provide new therapeutic approaches in airway hypersecretory diseases.}, }
@article {pmid10638663, year = {2000}, author = {Ortolani, O and Conti, A and De Gaudio, AR and Masoni, M and Novelli, G}, title = {Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome.}, journal = {Shock (Augusta, Ga.)}, volume = {13}, number = {1}, pages = {14-18}, doi = {10.1097/00024382-200013010-00003}, pmid = {10638663}, issn = {1073-2322}, mesh = {APACHE ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Aged ; Breath Tests ; Bronchoalveolar Lavage Fluid/chemistry ; Ethane/analysis ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Glutathione/analysis ; Glutathione Disulfide/analysis ; Humans ; Infusions, Intravenous ; Lipid Peroxidation/*drug effects ; Lung/drug effects/physiopathology ; Male ; Malondialdehyde/analysis ; Middle Aged ; Respiratory Distress Syndrome/*drug therapy/mortality/*physiopathology ; Respiratory Mucosa/*drug effects/physiopathology ; Rutin/administration &amp; dosage/*therapeutic use ; Time Factors ; }, abstract = {This study investigates the effects of N-acetylcysteine (NAC) and rutin on the lung oxidative burden of patients with early adult respiratory distress syndrome (ARDS). The protection was evaluated by measuring expired ethane and malondialdehyde (MDA), and oxidized (GSSG) and reduced glutathione (GSH) in the epithelial lining fluid of 36 patients who developed ARDS less than 24 hours before enrollment in the study. The patients were randomly assigned to 3 groups, receiving 250 mL 5% dextrose in water (group 1), NAC 50 mg/kg body weight in 5% dextrose (group 2), and NAC 50 mg/kg + rutin 5 mg/kg in 5% dextrose (group 3). Ethane and MDA concentrations were significantly reduced in the treatment groups after day 6. GSH was 30% increased in the treatment groups. No significant variations were observed in the control group until day 9. The trial confirms that NAC and rutin are efficient in protecting the lungs of patients with ARDS.}, }
@article {pmid10637512, year = {1999}, author = {Gonin, S and Diaz-Latoud, C and Richard, MJ and Ursini, MV and Imbo, A and Manero, F and Arrigo, AP}, title = {p53/T-antigen complex disruption in T-antigen transformed NIH3T3 fibroblasts exposed to oxidative stress: correlation with the appearance of a Fas/APO-1/CD95 dependent, caspase independent, necrotic pathway.}, journal = {Oncogene}, volume = {18}, number = {56}, pages = {8011-8023}, doi = {10.1038/sj.onc.1203319}, pmid = {10637512}, issn = {0950-9232}, mesh = {3T3 Cells ; Acetylcysteine/pharmacology ; Animals ; Antibodies/pharmacology ; Antigens, Polyomavirus Transforming/*genetics/*metabolism ; Antioxidants/pharmacology ; Apoptosis/*physiology ; Cell Survival/drug effects ; *Cell Transformation, Neoplastic ; Mice ; Necrosis ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; Simian virus 40/genetics ; Tumor Suppressor Protein p53/*metabolism ; Vitamin K/pharmacology ; fas Receptor/drug effects/*physiology ; }, abstract = {Simian Virus 40 Large T-antigen expressed in NIH3T3 cells increases p53 level and interacts with this tumor suppressor to form large nuclear complexes. We show here that T-antigen sensitizes NIH3T3 cells to low doses of the oxidative stress inducer menadione. This oxidant increased p53 accumulation and disrupted p53/T-antigen interaction, but not T-antigen/pRb, T-antigen/Hsc70 and p53/Hsc70 complexes; a phenomenon inhibited by the anti-oxidant N-acetyl-cysteine. Analysis of several p53 downstream gene products revealed that the level of Fas receptor, which was sharply reduced by T-antigen expression, was drastically increased in response to menadione treatment. Menadione also induced a T-antigen dependent cleavage of Fas ligand. Analysis performed with Fas receptor antagonist antibody and metalloproteinases inhibitor revealed that menadione triggers a Fas-dependent death of a fraction of T-antigen expressing cells. This Fas pathway does not activate caspase 8 or 3, probably because of the inhibition induced by T-antigen, and leads to a necrotic cell death which contributes at least in part to the hypersensitivity of T-antigen transformed cells to oxidative stress.}, }
@article {pmid10635453, year = {1999}, author = {Montanini, S and Sinardi, D and Praticò, C and Sinardi, AU and Trimarchi, G}, title = {Use of acetylcysteine as the life-saving antidote in Amanita phalloides (death cap) poisoning. Case report on 11 patients.}, journal = {Arzneimittel-Forschung}, volume = {49}, number = {12}, pages = {1044-1047}, doi = {10.1055/s-0031-1300549}, pmid = {10635453}, issn = {0004-4172}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Alanine Transaminase/blood ; *Amanita ; Antidotes/*therapeutic use ; Aspartate Aminotransferases/blood ; Biomarkers ; Child ; Child, Preschool ; Female ; Humans ; L-Lactate Dehydrogenase/blood ; Liver Failure, Acute/chemically induced/drug therapy/surgery ; Liver Function Tests ; Liver Transplantation ; Male ; Middle Aged ; Mushroom Poisoning/*drug therapy/therapy ; Renal Insufficiency/chemically induced/drug therapy/metabolism ; Time Factors ; }, abstract = {alpha-Amanitin is an amatoxin known to produce deleterious effects on the liver and the kidneys, when circulating in the blood. It is produced by a particular kind of mushroom called amanita phalloides. Therapeutic options employed to treat mushroom intoxication, such as haemodiaperfusion on activated charcoal, high dosages of penicillin G, oral charcoal, etc., very often failed to act properly and liver transplantation (when a graft is available) appeared to be the only solution. In recent years, as suggest by some authors, it has been postulated that the oxidant effects of alpha-amanitin could be counteracted by the use of antioxidants such as silibinin. High dosages of N-acetyl-cysteine (CAS 616-91-1, NAC), already used as antioxidant in paracetamol poisoning, were successfully used in our Intensive Care Unit (ICU) in the treatment of Amanita phalloides poisoning. In the last two years, 11 patients (mean age of 5-72 = 38.5) were treated for Amanita phalloides poisoning of various degrees, with a protocol (haemodiaperfusion on activated charcoal, high dosages of penicillin G, etc.) further comprehending NAC (fluimucil). All the patients recovered successfully but one (bearing precedent liver disease) needed liver transplantation. Daily monitoring of liver enzymes, creatinine, coagulation, LDH, blood and urinary alpha-amanitin were used to screen the progresses of the patients.}, }
@article {pmid10634007, year = {1999}, author = {Wu, ML and Tsai, WJ and Deng, JF and Yang, CC}, title = {Hemodialysis as adjunctive therapy for severe acetaminophen poisoning: a case report.}, journal = {Zhonghua yi xue za zhi = Chinese medical journal; Free China ed}, volume = {62}, number = {12}, pages = {907-913}, pmid = {10634007}, issn = {0578-1337}, mesh = {Acetaminophen/*poisoning ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Drug Overdose ; Female ; Humans ; *Renal Dialysis ; }, abstract = {Acetaminophen overdose is a common intoxication in daily practice the standard treatment is N-acetylcysteine (NAC) antidotal therapy for possible poisoning. However, dialysis procedures can remove the drug from the body effectively. We describe a case of acetaminophen overdose that was treated with both hemodialysis (HD) and NAC due to severe intoxication and slow drug clearance. A 37-year-old woman attempted suicide by ingestion of 100 tablets (500 mg each) of acetaminophen, and presented with vomiting, hematemesis and abdominal pain. The patient had elevated liver enzymes, coagulation defects, thrombocytopenia a high serum acetaminophen level (201 mg/l at 12 hours post-ingestion) with a prolonged half-life. Oral NAC was given; however, it was ineffective due to severe vomiting and hematemesis. HD as adjunctive therapy was initiated at 19 hours post-ingestion. HD reduced the serum acetaminophen level from 102.77 to 35.77 mg/l. Severe hepatic injury, bacteremia and pancytopenia were noted in the following days. The patient later recovered after treatment with NAC, HD and intensive supportive care. HD removed 66% of the total acetaminophen body burden during a single four-hour session, increased the clearance by 2.75-fold and shortened the half-life from 7.2 hours to 2.6 hours during HD. Through NAC therapy is the standard regimen for acetaminophen poisoning, in the severely poisoned patient who cannot tolerate NAC therapy, HD may be used as adjunctive therapy to enhance the elimination of acetaminophen.}, }
@article {pmid11115795, year = {2000}, author = {Dröge, W and Breitkreutz, R}, title = {Glutathione and immune function.}, journal = {The Proceedings of the Nutrition Society}, volume = {59}, number = {4}, pages = {595-600}, doi = {10.1017/s0029665100000847}, pmid = {11115795}, issn = {0029-6651}, mesh = {Acetylcysteine/*therapeutic use ; Cysteine/administration &amp; dosage/*deficiency/physiology ; Glutathione/administration &amp; dosage/*deficiency/physiology ; HIV Infections/*drug therapy/etiology ; Humans ; Immunity/drug effects/*physiology ; Lymphocytes/metabolism ; }, abstract = {The immune system works best if the lymphoid cells have a delicately balanced intermediate level of glutathione. Even moderate changes in the intracellular glutathione level have profound effects on lymphocyte functions. Certain functions, such as the DNA synthetic response, are exquisitely sensitive to reactive oxygen intermediates and, therefore, are favoured by high levels of the antioxidant glutathione. Certain signal pathways, in contrast, are enhanced by oxidative conditions and favoured by low intracellular glutathione levels. The available evidence suggests that the lymphocytes from healthy human subjects have, on average, an optimal glutathione level. There is no indication that immunological functions such as resistance to infection or the response to vaccination may be enhanced in healthy human subjects by administration of glutathione or its precursor amino acid cysteine. However, immunological functions in diseases that are associated with a cysteine and glutathione deficiency may be significantly enhanced and potentially restored by cysteine supplementation. This factor has been studied most extensively in the case of human immunodeficiency virus (HIV)-infected patients who were found to experience, on average, a massive loss of S equivalent to a net loss of approximately 4 g cysteine/d. Two randomized placebo-controlled trials have shown that treatment of HIV-infected patients with N-acetyl-cysteine caused in both cases a significant increase in all immunological functions under test, including an almost complete restoration of natural killer cell activity. It remains to be tested whether cysteine supplementation may be useful also in other diseases and conditions that are associated with a low mean plasma cystine level and impaired immunological functions.}, }
@article {pmid10628776, year = {1999}, author = {Rahman, Q and Abidi, P and Afaq, F and Schiffmann, D and Mossman, BT and Kamp, DW and Athar, M}, title = {Glutathione redox system in oxidative lung injury.}, journal = {Critical reviews in toxicology}, volume = {29}, number = {6}, pages = {543-568}, doi = {10.1080/10408449991349276}, pmid = {10628776}, issn = {1040-8444}, mesh = {Antioxidants/*pharmacology ; Gene Expression Regulation ; Genes, fos/genetics ; Genes, jun/genetics ; Glutathione/biosynthesis/*pharmacology ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Glutathione Transferase/metabolism ; Humans ; Lung Diseases/*chemically induced/enzymology/physiopathology ; Oxidation-Reduction ; *Oxidative Stress ; Xenobiotics/adverse effects ; }, abstract = {Glutathione (GSH) is a ubiquitous intracellular thiol present in all tissues, including lung. Besides maintaining cellular integrity by creating a reduced environment, GSH has multiple functions, including detoxification of xenobiotics, synthesis of proteins, nucleic acids, and leukotrienes. Present in high concentrations in bronchoalveolar lavage fluid (BALF), GSH provides protection to the lung from oxidative injury induced by different endogenous or exogenous pulmonary toxicants. Its depletion in the lung has been associated with the increased risk of lung damage and disease. The redox system of GSH consists of primary and secondary antioxidants, including glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and glucose 6-phosphate dehydrogenase (G6PD). Alterations in the activities of these enzymes may reflect reduced cellular defense and may serve as surrogate markers of many lung diseases. As GSH is also involved in the regulation of expression of protooncogenes and apoptosis (programmed cell death), the development of diseases such as cancer and human immune deficiency may be affected by depleting or elevating cellular GSH levels. Exogenous delivery of GSH or its precursor N-acetyl cysteine (NAC) is being used as chemotherapeutic approach.}, }
@article {pmid10625575, year = {2000}, author = {Bassirat, M and Khalil, Z}, title = {Endothelin and free radicals modulate microvascular responses in streptozotocin-induced diabetic rats.}, journal = {Microvascular research}, volume = {59}, number = {1}, pages = {88-98}, doi = {10.1006/mvre.1999.2209}, pmid = {10625575}, issn = {0026-2862}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antihypertensive Agents/pharmacology ; Diabetes Mellitus, Experimental/chemically induced/*physiopathology ; Electric Stimulation ; Endothelin Receptor Antagonists ; Endothelins/*physiology ; Free Radicals/metabolism ; Laser-Doppler Flowmetry ; Male ; Microcirculation/drug effects/*metabolism ; Nitroprusside/pharmacology ; Oligopeptides/pharmacology ; Peptides, Cyclic/pharmacology ; Piperidines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptor, Endothelin A ; Receptor, Endothelin B ; Sciatic Nerve ; Skin/blood supply/drug effects ; Streptozocin ; Substance P/pharmacology ; Superoxide Dismutase/pharmacology ; Vasodilator Agents/pharmacology ; }, abstract = {The quantitative contribution of endothelin and free radicals in modulating peripheral endothelial and smooth muscle-dependent vascular responses in 4 weeks streptozotocin-induced diabetic rats was investigated. Skin blood flow was monitored in base of blisters raised on the hind footpad. Smooth muscle-dependent vasodilation was tested using sodium nitroprusside (SNP). Endothelial-mediated inflammatory responses were induced via either electrical stimulation (ES) of the sciatic nerve or substance P (SP) perfusion over the blister base. Role of endothelin and free radicals was examined using ET-A or ET-B receptor antagonists (BQ-123 or BQ-788) and superoxide anions or hydroxyl radicals scavengers (superoxide dismutase (SOD) or N-acetyl cysteine (NAC)). Diabetic rats showed a significant reduction (75%) in SNP responses that coincided with a 70 and 60% reduction in responses to ES and SP. Their basal plasma extravasation (PE) was significantly higher while PE response to SP was significantly reduced. BQ-788, was more potent than BQ-123, improving responses to ES and SP in diabetic rats by 85%. Likewise, NAC was more potent than SOD normalizing the ES response and improving SP response by 85%. Combined treatment with BQ-123 and SOD normalized all vasodilatation responses in diabetic rats. BQ-123 and BQ-788 were equally potent normalizing the PE responses to SP whereas SOD and NAC had no effect. We conclude that endothelin and free radicals play a role in altering microvascular function in diabetes and that their effect could be reversed early in the disease.}, }
@article {pmid10625218, year = {2000}, author = {Kowluru, RA and Engerman, RL and Kern, TS}, title = {Diabetes-induced metabolic abnormalities in myocardium: effect of antioxidant therapy.}, journal = {Free radical research}, volume = {32}, number = {1}, pages = {67-74}, doi = {10.1080/10715760000300071}, pmid = {10625218}, issn = {1071-5762}, support = {EY00300/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*pharmacology ; Body Weight ; Cardiomyopathies/*prevention &amp; control ; Diabetes Mellitus, Experimental/complications/*drug therapy/*metabolism ; Eating ; Galactose/pharmacology ; Galactosemias/*metabolism ; Hyperglycemia/metabolism ; Lipid Metabolism ; Myocardium/*metabolism ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Effects of hyperglycemia (both diabetes and experimental galactosemia) on cardiac metabolism have been determined. In addition, the effect of supplemental antioxidants on these hyperglycemia-induced abnormalities of cardiac metabolism has been investigated. Diabetes or experimental galactosemia of 2 months duration in rats significantly increased oxidative stress in myocardium, as demonstrated by elevation of thiobarbituric acid reactive substances (TBARS) and lipid fluorescent products in left ventricle. Activity of protein kinase C (PKC) was elevated in the myocardium, and the activities of (Na,K)-ATPase and calcium ATPases were subnormal. Administration of supplemental antioxidants containing a mixture of ascorbic acid, Trolox; alpha-tocopherol acetate, N-acetyl cysteine, beta-carotene, and selenium prevented both the diabetes-induced and galactosemia-induced elevation of oxidative stress and PKC activity, and inhibited the decreases of myocardial (Na,K)-ATPase and calcium ATPases. The results show that these metabolic abnormalities are not unique to diabetes per se, but are secondary to elevated blood hexose levels, and supplemental antioxidants inhibit these metabolic abnormalities. Our findings suggest that antioxidants inhibit abnormal metabolic processes that may contribute to the development of cardiac disease in diabetes, and offer a potential clinical means to inhibit cardiac abnormalities in diabetes.}, }
@article {pmid10619832, year = {2000}, author = {Hashimoto, S and Gon, Y and Takeshita, I and Matsumoto, K and Jibiki, I and Takizawa, H and Kudoh, S and Horie, T}, title = {Diesel exhaust particles activate p38 MAP kinase to produce interleukin 8 and RANTES by human bronchial epithelial cells and N-acetylcysteine attenuates p38 MAP kinase activation.}, journal = {American journal of respiratory and critical care medicine}, volume = {161}, number = {1}, pages = {280-285}, doi = {10.1164/ajrccm.161.1.9904110}, pmid = {10619832}, issn = {1073-449X}, mesh = {Acetylcysteine/*pharmacology ; Blotting, Western ; Bronchi/cytology/*drug effects/metabolism ; Cells, Cultured ; Chemokine CCL5/*biosynthesis ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Epithelial Cells/*drug effects/metabolism ; Humans ; Imidazoles/pharmacology ; Interleukin-8/*biosynthesis ; Mitogen-Activated Protein Kinases/antagonists &amp; inhibitors/*metabolism ; Oxidation-Reduction/drug effects ; Phosphorylation/drug effects ; Pyridines/pharmacology ; Signal Transduction/drug effects ; Threonine/metabolism ; Tyrosine/metabolism ; Vehicle Emissions/*toxicity ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Air pollutants including diesel exhaust particles (DEPs) have been shown to enhance allergic responses. DEPs stimulate airway epithelial cells to produce various cytokines; however, the intracellular signal transduction pathway and the involvement of reduction and oxidation (redox) control in DEP-activated signaling have not been determined. In the present study, we therefore examined the role of p38 mitogen-activated protein (MAP) kinase in DEP-induced interleukin 8 (IL-8) and RANTES production by human bronchial epithelial cells (BECs) in order to clarify the intracellular signal transduction pathway that regulates IL-8 and RANTES production. In addition, we also examined the effect of a thiol-reducing agent, N-acetylcysteine (NAC), on DEP-induced p38 MAP kinase activation and cytokine production in order to clarify the redox control mechanism in DEP-induced p38 MAP kinase activation and IL-8 and RANTES production. The results showed that DEP induced IL-8 and RANTES production and the threonine and tyrosine phosphorylation of p38 MAP kinase, reflecting the activation of p38 MAP kinase in BECs. SB 203580, as the specific inhibitor of p38 MAP kinase activity, inhibited DEP-induced IL-8 and RANTES production. NAC inhibited DEP-induced p38 MAP kinase activation and IL-8 and RANTES production. These results indicate that p38 MAP kinase plays an important role in the DEP-activated signaling pathway that regulates IL-8 and RANTES production by BECs and that the cellular redox state is critical for DEP-induced p38 MAP kinase activation leading to IL-8 and RANTES production.}, }
@article {pmid10619702, year = {1999}, author = {Víctor, VM and Guayerbas, N and Garrote, D and Del Río, M and De la Fuente, M}, title = {Modulation of murine macrophage function by N-acetylcysteine in a model of endotoxic shock.}, journal = {BioFactors (Oxford, England)}, volume = {10}, number = {4}, pages = {347-357}, doi = {10.1002/biof.5520100405}, pmid = {10619702}, issn = {0951-6433}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Adhesion/drug effects ; Chemotaxis/drug effects ; Disease Models, Animal ; Escherichia coli ; Female ; In Vitro Techniques ; Lipopolysaccharides/toxicity ; Macrophages, Peritoneal/*drug effects/physiology ; Mice ; Mice, Inbred BALB C ; N-Formylmethionine Leucyl-Phenylalanine/pharmacology ; Phagocytosis/drug effects ; Shock, Septic/*physiopathology ; Superoxides/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {In previous studies we have observed changes in several functions of peritoneal macrophages from BALB/c mice with irreversible endotoxic shock caused by intraperitoneal injection of E. coli lipopolysaccharide (LPS) (100 mg/kg), which were associated with a high production of superoxide anion. Since antioxidants, such as N-acetylcysteine (NAC), are free radical scavengers that improve the immune response, in the present work we have studied different functions of peritoneal macrophages from BALB/c mice suffering the endotoxic shock above indicated and administered N-acetylcysteine (150 mg/kg i.p.) at 30 minutes after LPS injection. In the peritoneal macrophages obtained at 2, 4, 12 and 24 h after LPS injection, the following functions were studied: adherence to substrate, mobility, ingestion of particles, and production of superoxide anion and tumour necrosis factor (TNF alpha). The increase in adherence, ingestion and superoxide anion and TNF alpha production shown by macrophages from animals with endotoxic shock was counteracted by NAC injection. Moreover, the survival time of mice with endotoxic shock was increased in the presence of NAC. These data suggest that NAC, administered intraperitoneally, may be useful for the treatment of irreversible endotoxic shock by modulation of the function of macrophages with decreased superoxide anion and TNF alpha production and concomitant increase of survival time.}, }
@article {pmid10617314, year = {1999}, author = {Skrzydlewska, E and Farbiszewski, R}, title = {Protective effect of N-acetylcysteine on reduced glutathione, reduced glutathione-related enzymes and lipid peroxidation in methanol intoxication.}, journal = {Drug and alcohol dependence}, volume = {57}, number = {1}, pages = {61-67}, doi = {10.1016/s0376-8716(99)00040-x}, pmid = {10617314}, issn = {0376-8716}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Free Radical Scavengers/*pharmacology ; Glutathione/blood/*drug effects ; Glutathione Peroxidase/drug effects/metabolism ; Glutathione Reductase/drug effects/metabolism ; Lipid Peroxidation/drug effects ; Liver/*drug effects/metabolism ; Male ; Malondialdehyde/metabolism ; Methanol/metabolism/*poisoning ; Rats ; Solvents/metabolism/*poisoning ; }, abstract = {The primary metabolic appropriation of methanol is oxidation to formaldehyde and then to formate. These processes are accompanied by formation of superoxide anion and hydrogen peroxide. This paper reports data on the effect of N-acetylcysteine (NAC) on reduced glutathione (GSH) and on activity of some GSH-metabolising enzymes in the liver, erythrocytes and serum of rats intoxicated with methanol (3 g/kg b.w.) during 7 days after intoxication. Methanol administration, increasing concentration of the lipid peroxidation products, decreased the liver glutathione-peroxidase and glutathione reductase (GSSG-R) activities, GSH concentration and total antioxidant status (TAS). The use of NAC after methanol ingestion apparently diminished lipid peroxidation, elevated the GSH level in the liver and erythrocytes, and increased activity of GSH-related enzymes in the serum, erythrocytes and in the liver. These results suggest that NAC exerts its protective effect by acting as a precursor for glutathione, the main low molecular antioxidant and as a free radical scavenger.}, }
@article {pmid10614498, year = {1999}, author = {Dobbelaere, D and Fernandez, P and Machado, J and Botteron, C and Heussler, V}, title = {Interference by the intracellular parasite Theileria parva with T-cell signal transduction pathways induces transformation and protection against apoptosis.}, journal = {Veterinary immunology and immunopathology}, volume = {72}, number = {1-2}, pages = {95-100}, doi = {10.1016/s0165-2427(99)00121-x}, pmid = {10614498}, issn = {0165-2427}, mesh = {Animals ; Apoptosis/immunology ; Cattle ; Immunosuppressive Agents/immunology ; Lymphocyte Activation/*immunology ; NF-kappa B/immunology ; Signal Transduction/*immunology ; T-Lymphocytes/*immunology ; Theileria parva/*immunology ; Theileriasis/*immunology ; }, abstract = {The intracellular parasite Theileria parva transforms bovine T-lymphocytes, inducing uncontrolled proliferation. Upon infection, cells cease to require antigenic stimulation and exogenous growth factors to proliferate. Earlier studies have shown that pathways triggered via stimulation of the T-cell receptor are silent in transformed cells. This is reflected by a lack of phosphorylation of key signalling molecules and the fact that proliferation is not inhibited by immunosuppressants such as cyclosporin and ascomycin that target calcineurin. This suggests that the parasite bypasses the normal T-cells activation pathways to induce proliferation. Among the MAP-kinase pathways, ERK and p38 are silent, and only Jun N-terminal kinase is activated. This appears to suffice to induce constitutive activation of the transcription factor AP-1. More recently, it could be shown that the presence of the parasite in the host cell cytoplasm also induces constitutive activation of NF-kappaB, a transcription factor involved in proliferation and protection against apoptosis. Activation is effectuated by parasite-induced degradation of IkappaBs, the cytoplasmic inhibitors which sequester NF-kappaB in the cytoplasm. NF-kappaB activation is resistant to the antioxidant N-acetyl cysteine and a range of other reagents, suggesting that activation might occur in an unorthodox manner. Studies using inhibitors and dominant negative mutants demonstrate that the parasite activates a NF-kappaB-dependent anti-apoptotic mechanism that protects the transformed cell form spontaneous apoptosis and is essential for maintaining the transformed state of the parasitised cell.}, }
@article {pmid10609881, year = {1999}, author = {Molina-Holgado, F and Hernanz, A and De la Fuente, M and Guaza, C}, title = {N-Acetyl-cysteine inhibition of encephalomyelitis Theiler's virus-induced nitric oxide and tumour necrosis factor-alpha production by murine astrocyte cultures.}, journal = {BioFactors (Oxford, England)}, volume = {10}, number = {2-3}, pages = {187-193}, doi = {10.1002/biof.5520100215}, pmid = {10609881}, issn = {0951-6433}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Astrocytes/drug effects/*physiology/*virology ; Cardiovirus Infections/*physiopathology ; Cells, Cultured ; Cerebral Cortex/physiopathology/virology ; Disease Models, Animal ; Mice ; Mice, Inbred BALB C ; Mice, Inbred Strains ; Multiple Sclerosis ; Nitric Oxide/*biosynthesis ; Nitrites/metabolism ; *Theilovirus ; Tumor Necrosis Factor-alpha/*biosynthesis ; }, abstract = {The pathological mechanisms that cause central nervous system (CNS) dysfunction in most neurological diseases are not well established. Theiler's murine encephalomyelitis virus (TMEV) is known to interact with cells of the CNS and its intracerebral inoculation to susceptible mice strains causes neurological disorders resembling multiple sclerosis (MS). In this study, we reported that primary astrocyte cultures from SJL/J susceptible mice when infected with TMEV released important amounts of nitrites (NO2-) to the culture medium, as measured in the supernatants 24 hours after infection. In addition, we observed an increment in the production of tumour necrosis factor alpha (TNF-alpha) by susceptible SJL/J strain derived astrocytes infected with TMEV. The treatment with the thiolic antioxidant N-acetyl-cysteine partially suppressed the virus-stimulated production of nitric oxide and TNF-alpha, in a dose response fashion. These results indicate that during viral infection astrocytes are an important cellular source of nitric oxide and TNF-alpha, substances which play important roles during CNS inflammatory events. The effects of the antioxidant N-acetyl-cysteine, modulating the production of the above compounds by TMEV-infected astrocytes may be a significant factor in preventing CNS demyelination.}, }
@article {pmid10609880, year = {1999}, author = {Blanco, B and Ferrández, MD and Correa, R and Del Rio, M and Guaza, C and Hernanz, A and De la Fuente, M}, title = {Changes in several functions of murine peritoneal macrophages by N-acetylcysteine and thioproline ingestion. Comparative effect between two strains of mice.}, journal = {BioFactors (Oxford, England)}, volume = {10}, number = {2-3}, pages = {179-185}, doi = {10.1002/biof.5520100214}, pmid = {10609880}, issn = {0951-6433}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/administration &amp; dosage/*pharmacology ; Cell Adhesion/drug effects ; Chemotaxis/drug effects ; Dietary Supplements ; Female ; In Vitro Techniques ; Interleukin-1/biosynthesis ; Macrophages, Peritoneal/cytology/drug effects/*physiology ; Mice ; Mice, Inbred BALB C ; Phagocytosis/*drug effects ; Species Specificity ; Superoxides/metabolism ; Thiazoles/administration &amp; dosage/*pharmacology ; Thiazolidines ; }, abstract = {The administration of the thiol compounds, N-acetylcysteine (NAC) and in particular thioproline (thiazolidine-4-carboxylic acid) at 0.1% w/w concentration in the diet, improves lymphocyte functions in old female Swiss mice, as has been shown in our previous studies. In the present work, adult mice from two different strains, namely BALB/c (an inbred strain) and OF1-Swiss (noninbred strain), were fed a diet supplemented with the above dose of each thiol compound jointly for five weeks. At 28 weeks of age, peritoneal cell suspensions were obtained and different steps of the phagocytic process, the most representative activity of macrophages, as well as interleukin-1beta (IL-1beta) production, were studied. Thus, adherence to substrate, mobility directed to a chemoattractant gradient (chemotaxis), ingestion of inert particles and superoxide anion production were analysed. The results show that diet supplementation with NAC plus thioproline increased all macrophage functions studied with the exception of superoxide anion production, which was decreased. These effects were more evident in macrophages from Swiss mice, whereas in BALB/c mice the stimulation of phagocytosis and IL-1beta production was lower and no differences were seen after treatment in adherence and superoxide anion production. These data suggest that immune function can be improved in adult mice by administration of the above thiol compounds, especially in the noninbred strain of OF1-Swiss mice.}, }
@article {pmid10602391, year = {1999}, author = {Akbay, A and Cinar, K and Uzunalimoğlu, O and Eranil, S and Yurdaydin, C and Bozkaya, H and Bozdayi, M}, title = {Serum cytotoxin and oxidant stress markers in N-acetylcysteine treated thioacetamide hepatotoxicity of rats.}, journal = {Human &amp; experimental toxicology}, volume = {18}, number = {11}, pages = {669-676}, doi = {10.1191/096032799678839518}, pmid = {10602391}, issn = {0960-3271}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biomarkers/blood ; *Chemical and Drug Induced Liver Injury ; Cytotoxins/*blood ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Liver Diseases/*blood/enzymology/physiopathology ; Male ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Thioacetamide/*toxicity ; }, abstract = {N-acetylcysteine (NAC) is a glutathione precursor used to treat several clinical conditions where intracellular oxidant-antioxidant balance is disturbed, among which, acetaminophen induced hepatotoxicity may be counted. In this study, administering thioacetamide (TAA) as a hepatotoxic agent, a rat model of hepatotoxicity has been established, to investigate some of the immune mediated basic oxidant-antioxidant homeostatic mechanisms involved, and potential serum markers for follow-up of disease and treatment. To do this, four experimental groups receiving saline/saline, saline/NAC, saline/TAA and NAC/TAA as intraperitoneal injections, have been formed. Rat serum tumor necrosis factor-alpha (TNF-alpha), Interleukin1-beta (IL1-beta), malondialdehyde (MDA) as a measure of final oxidant damage and the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) have been assayed. Hepatocellular damage has been measured via the biochemical estimates ALT, AST and LDH as well as histopathological grading. It was found that both TNF-alpha and IL1-beta were significantly elevated in saline/TAA receivers (P<0.01) when compared to NAC/TAA receivers. Serum MDA was also increased in TAA receivers in addition to SOD (P<0.05) and GSH-Px (P<0.05). Serum nitrite levels have also been assayed to give an estimate of nitric oxide that is suggested as a counter-balancer of oxidant stress. NAC/saline receivers had the highest levels of nitrites in the serum (P<0.05). Our results indicate that part of the hepatocellular injury to rat liver, induced by TAA is mediated by oxidative stress caused by the action of cytokines imparted by the enzymatic SOD and GSH-Px and non-enzymatic gaseous nitric oxide mechanisms causing an alleviation on administration of NAC. In addition, TNF-alpha, IL1-beta, MDA, SOD, GSH-Px and nitrites are potential candidates of serum indicators for monitorization of pathophysiological stage of liver disease.}, }
@article {pmid10601882, year = {1999}, author = {Floyd, RA}, title = {Antioxidants, oxidative stress, and degenerative neurological disorders.}, journal = {Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)}, volume = {222}, number = {3}, pages = {236-245}, doi = {10.1046/j.1525-1373.1999.d01-140.x}, pmid = {10601882}, issn = {0037-9727}, support = {NS35747/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/metabolism ; Animals ; Antioxidants/*pharmacology ; Brain/metabolism ; Cyclic N-Oxides ; Free Radicals ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; Neurodegenerative Diseases/drug therapy/*etiology ; Neuroprotective Agents/*pharmacology ; Nitrogen Oxides/*pharmacology/therapeutic use ; *Oxidative Stress ; Signal Transduction/drug effects ; Vitamin E/pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Recently, clinical trials of several neurodegenerative diseases have increasingly targeted the evaluation of the effectiveness of various antioxidants. The results so far are encouraging but variable and thus confusing. Rationale for the possible clinical effectiveness of antioxidants in several degenerative conditions has arisen out of the many years of basic science generally showing that reactive oxygen species (ROS) and oxidative damage are important factors in the processes involved. Aging is one of the most significant risk factors for degenerative neurological disorders. Basic science efforts in our laboratory have centered on exploring the role of ROS and oxidative stress in neurodegenerative processes. The present review brings together some of the basic concepts we have learned by following this approach for the last 20 years and specifically the results we have obtained by following up on our serendipitous findings that a nitrone-based free radical trap, alpha-phenyl-tert-butylnitrone (PBN), has neuroprotective activity in several experimental neurodegenerative models. The mechanistic basis of the neuroprotective activity of PBN does not appear to rely on its general free radical trapping or antioxidant activity per se, but its activity in mediating the suppression of genes induced by pro-inflammatory cytokines and other mediators associated with enhanced neuroinflammatory processes. Neuroinflammatory processes, induced in part by pro-inflammatory cytokines, yield enhanced ROS and reactive nitric oxide species (RNS) as well as other unknown components that have neurotoxic properties. Neurotoxic amounts of RNS are formed by the activity of inducible nitric oxide synthase (iNOS). The demonstration of enhanced 3-nitro-tyrosine formation in affected regions of the Alzheimer's brain, in comparison to age-matched controls, reinforces the importance of neuroinflammatory processes. iNOS induction involves activation by phosphorylation of the MAP kinase p38 and can be induced in cultured astrocytes by IL-1beta or H2O2. The action of PBN and N-acetyl cysteine to suppress the activation of p38 was demonstrated in cultured astrocytes. The demonstration of activated p38 in neurons surrounding amyloid plaques in affected regions of the Alzheimer's brain attest to enhanced signal transduction processes in this neurodegenerative condition. The major themes of ROS and RNS formation associated with neuroinflammation processes and the suppression of these processes by antioxidants and PBN continue to yield promising leads for new therapies. Outcomes of clinical trials on antioxidants will become less confusing as more knowledge is amassed on the basic processes involved.}, }
@article {pmid10600775, year = {1999}, author = {Wu, QD and Wang, JH and Fennessy, F and Redmond, HP and Bouchier-Hayes, D}, title = {Taurine prevents high-glucose-induced human vascular endothelial cell apoptosis.}, journal = {The American journal of physiology}, volume = {277}, number = {6}, pages = {C1229-38}, doi = {10.1152/ajpcell.1999.277.6.C1229}, pmid = {10600775}, issn = {0002-9513}, mesh = {Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Arsenites/pharmacology ; Calcium/metabolism ; Cells, Cultured ; DNA Fragmentation/drug effects ; Diabetic Angiopathies/drug therapy/metabolism ; Diuretics, Osmotic/pharmacology ; Dose-Response Relationship, Drug ; Endothelium, Vascular/drug effects/*metabolism/pathology ; Enzyme Inhibitors/pharmacology ; Glucose/*pharmacology ; Homeostasis/drug effects ; Humans ; Ionophores/pharmacology ; Mannitol/pharmacology ; Necrosis ; Osmolar Concentration ; Reactive Oxygen Species/metabolism ; Sodium Compounds/pharmacology ; Taurine/*pharmacology ; Umbilical Veins/cytology ; }, abstract = {Elevated blood glucose in uncontrolled diabetes is causally correlated with diabetic microangiopathy. Hyperglycemia-triggered accelerated endothelial cell apoptosis is a critical event in the process of diabetes-associated microvascular disease. The conditionally semiessential amino acid taurine has been previously shown to protect against human endothelial cell apoptosis. Therefore, this study was designed to investigate the role of taurine in the prevention of high-glucose-mediated cell apoptosis in human umbilical vein endothelial cells (HUVEC) and the mechanisms involved. Exposure of HUVEC to 30 mM glucose for 48 h (short-term) and 14 days (long-term) resulted in a significant increase in apoptosis, compared with normal glucose (5.5 mM; P < 0.05). High-glucose-induced DNA fragmentation preferentially occurred in the S phase cells. Mannitol (as osmotic control) at 30 mM failed to induce HUVEC apoptosis. Taurine prevented high-glucose-induced HUVEC apoptosis, which correlates with taurine attenuation of high-glucose-mediated increased intracellular reactive oxygen species (ROS) formation and elevated intracellular Ca(2+) concentration ([Ca(2+)](i)) level. Antioxidants, DMSO, N-acetyl cysteine, and glutathione, only partly attenuated high-glucose-induced HUVEC apoptosis. Glucose at 30 mM did not cause HUVEC necrosis. However, both glucose and mannitol at 60 mM caused HUVEC necrosis as represented by increased lactate dehydrogenase release and cell lysis. Taurine failed to prevent hyperosmolarity-induced cell necrosis. These results demonstrate that taurine attenuates hyperglycemia-induced HUVEC apoptosis through ROS inhibition and [Ca(2+)](i) stabilization and suggest that taurine may exert a beneficial effect in preventing diabetes-associated microangiopathy.}, }
@article {pmid10595823, year = {1999}, author = {Xiong, Y and Peterson, PL and Lee, CP}, title = {Effect of N-acetylcysteine on mitochondrial function following traumatic brain injury in rats.}, journal = {Journal of neurotrauma}, volume = {16}, number = {11}, pages = {1067-1082}, doi = {10.1089/neu.1999.16.1067}, pmid = {10595823}, issn = {0897-7151}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Brain Injuries/*drug therapy/metabolism ; Free Radical Scavengers/*therapeutic use ; Glutathione/*drug effects/metabolism ; Male ; Mitochondria/*drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Efficacy of N-acetylcysteine (NAC) in traumatic brain injury (TBI)-induced mitochondrial dysfunction was evaluated following controlled cortical impact injury in rats. Respiratory function and calcium transport of rat forebrain mitochondria from injured and uninjured hemispheres were examined. NAC significantly restored mitochondrial electron transfer, energy coupling capacity, calcium uptake activity and reduced calcium content absorbed to brain mitochondrial membranes when examined 12 h post-TBI if NAC was administered i.p. 5 min before injury or 30 min or 1 h postinjury. Glutathione (reduced form, GSH) levels in brain tissues were decreased at all time points examined over a 14-day observation period, while mitochondrial GSH levels significantly decreased only at 3 days and 14 days following TBI. NAC treatment given within 1 h greatly restored brain GSH levels from 1 h to 14 days and mitochondrial GSH levels from 12 h to 14 days post-TBI. NAC did not show protective effects when given 2 h postinjury. Our data indicate that NAC administered postinjury at an early stage can effectively restore TBI-induced mitochondrial dysfunction and the protective effect of NAC may be related to its restoration of GSH levels in the brain.}, }
@article {pmid10592316, year = {1999}, author = {Brennan, RJ and Schiestl, RH}, title = {The aromatic amine carcinogens o-toluidine and o-anisidine induce free radicals and intrachromosomal recombination in Saccharomyces cerevisiae.}, journal = {Mutation research}, volume = {430}, number = {1}, pages = {37-45}, doi = {10.1016/s0027-5107(99)00118-9}, pmid = {10592316}, issn = {0027-5107}, mesh = {Aniline Compounds/*toxicity ; Carcinogens/*toxicity ; Chromosomes/*drug effects/metabolism ; DNA, Fungal/drug effects/genetics ; Dose-Response Relationship, Drug ; Free Radicals/metabolism ; Mutagenicity Tests ; Recombination, Genetic/*drug effects ; Saccharomyces cerevisiae/drug effects/*genetics/*metabolism ; Salmonella/genetics ; Toluidines/*toxicity ; }, abstract = {Aniline-based aromatic amine carcinogens are poorly detected in short-term mutagenicity assays such as the Salmonella reverse mutation (Ames) assay. More information on the mechanism of toxicity of such Salmonella-negative carcinogens is needed. Aniline and o-toluidine are negative in the Ames assay, but induce deletions (DEL) due to intrachromosomal recombination in Saccharomyces cerevisiae with an apparent threshold. We show here that the DEL assay also detects the genotoxic activity of another aromatic amine carcinogen, o-anisidine, which is also negative in the Salmonella assay. We also show that the DEL assay distinguishes between o-anisidine and its non-carcinogenic structural analog 2, 4-dimethoxyaniline. We have investigated whether the ability of the DEL assay to detect the carcinogens and to distinguish between the carcinogen/non-carcinogen pair is linked to rises in intracellular free radical species following exposure to the carcinogens. Toxicity induced by all three compounds was reduced in the presence of the free radical scavenger and antioxidant N-acetyl cysteine, recombination induced by o-anisidine and o-toluidine was also reduced by N-acetyl cysteine. All three compounds induced oxidation of the free radical-sensitive reporter compound dichlorofluorescin diacetate. Superoxide dismutase-deficient strains, however, were hypersensitive to cytotoxicity induced by o-toluidine and o-anisidine but not by the non-carcinogen 2,4-dimethoxyaniline, indicating a different potential for generating superoxide radical between the carcinogens and the non-carcinogen analog. The results indicate that the yeast DEL assay is a useful tool for investigating the genotoxic activity of aromatic amine carcinogens.}, }
@article {pmid10588366, year = {1999}, author = {Cameron, NE and Cotter, MA}, title = {Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes.}, journal = {Diabetes research and clinical practice}, volume = {45}, number = {2-3}, pages = {137-146}, doi = {10.1016/s0168-8227(99)00043-1}, pmid = {10588366}, issn = {0168-8227}, mesh = {Animals ; Antioxidants/*pharmacology ; Diabetes Mellitus, Experimental/*physiopathology ; Diabetic Angiopathies/*physiopathology ; Diabetic Neuropathies/*physiopathology ; Fatty Acids, Essential/metabolism ; Humans ; Neural Conduction/drug effects ; Rats ; Reactive Oxygen Species/physiology ; }, abstract = {Reactive oxygen species (ROS) are elevated by metabolic changes in diabetes, including autoxidation and increased advanced glycation. Endogenous protection by the glutathione redox cycle is also compromised by the competing NADPH requirement of elevated polyol pathway flux. Antioxidant treatment strategies prevent or reverse nerve conduction velocity (NCV) deficits in diabetic rats. These include lipophilic scavengers such as butylated hydroxytoluene, probucol and vitamin E, more hydrophilic agents like alpha-lipoic acid and acetyl cysteine, and transition metal chelators that inhibit autoxidation. In the long-term, elevated ROS cause cumulative damage to neurons and Schwann cells, however, they also have a deleterious effect on nerve blood flow in the short term. This causes endoneurial hypoxia, which is responsible for early NCV deficits. Antioxidant treatment corrects the blood flow deficit and promotes normal endoneurial oxygenation. ROS cause antioxidant-preventable vascular endothelium abnormalities, neutralizing nitric oxide mediated vasodilation and increasing reactivity to vasoconstrictors. Unsaturated fatty acids are a major target for ROS and essential fatty acid metabolism is impaired by diabetes. Gamma-linolenic acid stimulates vasodilator prostanoid production, and there are marked synergistic interactions between gamma-linolenic acid and antioxidants. This has encouraged the development of novel drugs such as ascorbyl-gamma-linolenic acid and gamma-linolenic acid-lipoic acid with enhanced therapeutic potential.}, }
@article {pmid10587478, year = {1999}, author = {Nawrocka, A and Papierz, W and Bialasiewicz, P and Stolarek, R and Komos, J and Nowak, D}, title = {N-acetylcysteine and ambroxol inhibit endotoxin-induced phagocyte accumulation in rat lungs.}, journal = {Pulmonary pharmacology &amp; therapeutics}, volume = {12}, number = {6}, pages = {369-375}, doi = {10.1006/pupt.1999.0219}, pmid = {10587478}, issn = {1094-5539}, mesh = {Acetylcysteine/*pharmacology ; Ambroxol/*pharmacology ; Animals ; Endotoxins/*pharmacology ; Escherichia coli/metabolism ; Expectorants/*pharmacology ; Humans ; Lipopolysaccharides/*pharmacology ; Luminescent Measurements ; Lung/*cytology/drug effects ; Macrophages, Alveolar/drug effects ; Male ; Neutrophils/drug effects ; Phagocytes/*drug effects ; Pulmonary Alveoli/cytology/drug effects ; Rats ; Rats, Wistar ; }, abstract = {UNLABELLED: We have investigated whether pretreatment with N-acetylcysteine (NAC) and/or ambroxol (Amb), drugs known as reactive oxygen species (ROS) scavengers, would minimize lipopolysaccharide (LPS)-induced leucocyte accumulation in rat lung microvasculature and protect lungs from damage and the effect of these drugs on chemotactic peptide (fMLP)-induced chemiluminescence of human polymorphonuclear leukocytes (PMNs). Animals were injected ip with NAC (27.6 mg/kg, n=8), ambroxol (70 mg/kg, n=8), combination NAC+ambroxol (n=8), or 1 ml buffer alone (n=8), once a day for 3 consecutive days. Then animals were injected with LPS (17 mg/kg), and killed 3 h later. In each of another four groups eight rats were used as a control, and received the same drug treatment but LPS was replaced with 0.9% NaCl. PMNs and macrophages (Ms) were counted in histologic slides of lung tissue. Using computer image analysis we measured the area of alveolar profiles. Luminol-enhanced chemiluminescence was measured in PMNs suspensions obtained from healthy volunteers. Chemiluminescence intensity was measured in resting and fMLP-stimulated cells, and compared between cells incubated with Amb, NAC or distilled water. We observed significant differences in the number of PMNs and Ms, alveolar profile area between control and LPS-treated animals (P<0.01). PMNs and Ms were numerous in lungs of LPS-administered animals (PMNs: Median (M)=137.5 per 6 high power fields range (r)=54.0; Ms: M=123.0 r=11.0), less numerous in ambroxol-treated group (PMNs: M=101.5 r=32.0 and Ms:53.5 r=36.0), not abundant in NAC (PMNs:M=56.0 r=28.0 and Ms:M=20.5 r=13.0) and in NAC+ambroxol treated rats (PMNs:M=53.5 r=21.0 and Ms:M=29.0 r=9.0), and rare in LPS+drugs-untreated control group (PMNs:M=40.5 r=19.0 and Ms:M=18.5 r=15.0). Chemiluminescence assay revealed that 100 micro;M ambroxol stimulated fMLP-induced PMNs chemiluminescence and NAC of the same concentration had no significant effect.<br><br>CONCLUSION: In our experiment we showed that pretreatment with NAC and ambroxol may inhibit phagocyte influx to rat lung and may protect it from damage. We also revealed that NAC at dose 27.6 mg/kg has stronger protective properties than ambroxol at dose 70 mg/kg and this may result from enhancing effect of ambroxol on fMLP-provoked PMNs chemiluminescence.}, }
@article {pmid10585590, year = {2000}, author = {Shatrov, VA and Ameyar, M and Bouquet, C and Cai, Z and Stancou, R and Haddada, H and Chouaib, S}, title = {Adenovirus-mediated wild-type-p53-gene expression sensitizes TNF-resistant tumor cells to TNF-induced cytotoxicity by altering the cellular redox state.}, journal = {International journal of cancer}, volume = {85}, number = {1}, pages = {93-97}, doi = {10.1002/(sici)1097-0215(20000101)85:1&lt;93::aid-ijc17&gt;3.0.co;2-i}, pmid = {10585590}, issn = {0020-7136}, mesh = {Acetylcysteine/pharmacology ; Adenoviridae/*genetics ; Breast Neoplasms/enzymology/genetics/pathology/virology ; Cytopathogenic Effect, Viral ; Down-Regulation/drug effects ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Expression/*drug effects ; Genetic Vectors/genetics/*pharmacology ; Humans ; Oxidation-Reduction ; Oxidative Stress/drug effects/genetics ; RNA, Messenger/biosynthesis ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Transfection ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*pharmacology ; Tumor Suppressor Protein p53/antagonists &amp; inhibitors/biosynthesis/*genetics ; }, abstract = {We have shown that the loss of p53 function contributed to resistance of tumor cells to TNF-induced cytotoxicity. In the present study, we evaluated the effect of wild-type p53 (wt-p53) expression on TNF sensitivity, by introducing wt-p53 into MCF7/Adr cells in which p53 was deleted, via a recombinant adenovirus encoding p53 (Ad-p53). Our results indicate that infection with Ad-p53 (50-100 viral particles per cell) resulted in pronounced cytotoxicity, whereas infection with 10 viral particles per cell, which was weakly toxic for the MCF7/Adr cells, sensitized these cells to TNF-induced cell death. Moreover, expression of wt-p53 in MCF7/Adr cells induced the production of reactive oxygen intermediates (ROIs) and caused glutathione (GSH) depletion, indicating disturbances in the cellular redox state. Additional treatment of cells with the anti-oxidant and glutathione (GSH) precursor N-acetylcysteine (NAC) resulted in inhibition of p53-induced ROIs production and in partial restoration of intracellular GSH levels, which was associated with the ability of NAC to inhibit p53-modulated TNF-induced cytotoxicity. Interestingly, Ad-p53 was able to inhibit TNF-induced MnSOD mRNA expression in MCF7/Adr cells, which might contribute to the sensitization of cells to the cytotoxic action of TNF. Taken together, our data strongly suggest that wt-p53 expression sensitizes TNF-resistant MCF7 cells with p53 deletion to TNF-induced cell death by a pathway that is dependent on ROIs production.}, }
@article {pmid10584588, year = {1999}, author = {Buckley, NA and Whyte, IM and O'Connell, DL and Dawson, AH}, title = {Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning?.}, journal = {Journal of toxicology. Clinical toxicology}, volume = {37}, number = {6}, pages = {759-767}, doi = {10.1081/clt-100102453}, pmid = {10584588}, issn = {0731-3810}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*administration &amp; dosage/adverse effects ; Administration, Oral ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Charcoal/therapeutic use ; Chemical and Drug Induced Liver Injury ; Child ; Child, Preschool ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*administration &amp; dosage/adverse effects ; Humans ; Infant ; Injections, Intravenous ; Liver Diseases/blood/pathology ; Male ; Middle Aged ; Poisoning/*drug therapy ; Transaminases/blood ; }, abstract = {BACKGROUND: The optimal route and duration of administration for N-acetyl-cysteine in the management of acetaminophen (paracetamol) poisoning are controversial. It has been stated on the basis of a selected post-hoc analysis that oral N-acetylcysteine is superior to intravenous N-acetylcysteine in presentations later than 15 hours.<br><br>AIM OF STUDY: To investigate the efficacy of intravenous or oral N-acetylcysteine.<br><br>PATIENTS AND METHODS: We analyzed a series of acetaminophen poisonings treated with a protocol including activated charcoal and intravenous N-acetylcysteine. The outcomes assessed included use of N-acetylcysteine, adverse effects of intravenous N-acetylcysteine, and the occurrence of hepatotoxicity (transaminase > 1000 U/L). We incorporated these results in a meta-analysis of previously reported series of acetaminophen poisonings to compare the outcomes from intravenous and oral N-acetylcysteine use.<br><br>RESULTS: Of 981 patients admitted over 10 years, 4% (40) presented later than 24 hours and 10% (100) had concentrations of acetaminophen that indicated a probable or high risk of hepatotoxicity. The 30 patients who developed hepatotoxicity presented later, took larger amounts, had higher concentrations, and received N-acetylcysteine later than those who did not. No patients received a liver transplant but 2 patients died (one after referral to a transplant unit and one just before). Adverse reactions to intravenous N-acetylcysteine occurred in 6% (12/205) of patients but none prevented completion of the treatment. In the meta-analysis, those with probable or high risk concentrations had similar outcomes with intravenous (pooled n = 341) and oral N-acetylcysteine (pooled n = 1462) administration. Rates of hepatotoxicity for those treated within 10 hours (3 and 6%), late (10-24 hours: 30 and 26%), and overall (0-24 hours: 16 and 19%) were all similar. The proportion of patients classified as presenting later than 10 hours is much greater in the oral N-acetylcysteine studies (64%) than in many of the intravenous N-acetylcysteine studies (38%, 44%, and 63%).<br><br>CONCLUSIONS: The differences claimed between oral and intravenous N-acetylcysteine regimes are probably artifactual and relate to inappropriate subgroup analysis. A shorter hospital stay, patient and doctor convenience, and the concerns over the reduction in bioavailability of oral N-acetylcysteine by charcoal and vomiting make intravenous N-acetylcysteine preferable for most patients with acetaminophen poisoning.}, }
@article {pmid10580429, year = {1999}, author = {Kaneto, H and Kajimoto, Y and Miyagawa, J and Matsuoka, T and Fujitani, Y and Umayahara, Y and Hanafusa, T and Matsuzawa, Y and Yamasaki, Y and Hori, M}, title = {Beneficial effects of antioxidants in diabetes: possible protection of pancreatic beta-cells against glucose toxicity.}, journal = {Diabetes}, volume = {48}, number = {12}, pages = {2398-2406}, doi = {10.2337/diabetes.48.12.2398}, pmid = {10580429}, issn = {0012-1797}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Blood Glucose/drug effects/*metabolism ; Body Weight ; Diabetes Mellitus, Type 2/drug therapy/pathology/*physiopathology ; Female ; *Insulin Resistance ; Islets of Langerhans/*drug effects/pathology/physiopathology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Vitamin E/*pharmacology ; }, abstract = {Oxidative stress is produced under diabetic conditions and possibly causes various forms of tissue damage in patients with diabetes. The aim of this study was to examine the involvement of oxidative stress in the progression of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate the potential usefulness of antioxidants in the treatment of type 2 diabetes. We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine [NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects were evaluated at 10 and 16 weeks of age. According to an intraperitoneal glucose tolerance test, the treatment with NAC retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels. Vitamins C and E were not effective when used alone but slightly effective when used in combination with NAC. No effect on insulin secretion was observed when the same set of antioxidants was given to nondiabetic control mice. Histologic analyses of the pancreases revealed that the beta-cell mass was significantly larger in the diabetic mice treated with the antioxidants than in the untreated mice. As a possible cause, the antioxidant treatment suppressed apoptosis in beta-cells without changing the rate of beta-cell proliferation, supporting the hypothesis that in chronic hyperglycemia, apoptosis induced by oxidative stress causes reduction of beta-cell mass. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA, making the extent of insulin degranulation less evident. Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), a beta-cell-specific transcription factor, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. In conclusion, our observations indicate that antioxidant treatment can exert beneficial effects in diabetes, with preservation of in vivo beta-cell function. This finding suggests a potential usefulness of antioxidants for treating diabetes and provides further support for the implication of oxidative stress in beta-cell dysfunction in diabetes.}, }
@article {pmid10579837, year = {1999}, author = {Oiry, J and Puy, JY and Mialocq, P and Clayette, P and Fretier, P and Jaccard, P and Dereuddre-Bosquet, N and Dormont, D and Imbach, JL}, title = {Synthesis and in vitro anti-HIV activity in human monocyte-derived macrophages of 2-oxothiazolidine-4(R)-carboxylic acid derivatives.}, journal = {Journal of medicinal chemistry}, volume = {42}, number = {23}, pages = {4733-4740}, doi = {10.1021/jm980289j}, pmid = {10579837}, issn = {0022-2623}, mesh = {Anti-HIV Agents/*chemical synthesis/chemistry/pharmacology ; HIV-1/*drug effects ; Humans ; Macrophages/*drug effects/virology ; Monocytes/*drug effects/virology ; Pyrrolidonecarboxylic Acid ; Structure-Activity Relationship ; Thiazoles/*chemical synthesis/chemistry/pharmacology ; Thiazolidines ; }, abstract = {Oxidative stress and glutathione (GSH) deficit may play an important role in HIV infection pathogenesis, and oral administration of GSH-replenishing drugs such as N-acetylcysteine (NAC) and 2-oxothiazolidine-4(R)-carboxylic acid (OTC) may be associated with an increased survival rate of HIV-infected patients. Nevertheless, beneficial effects of these molecules are restricted in vivo by the high concentrations that are necessary to obtain biological effects, rapid extracellular metabolization, and low availability and plasma concentrations. We synthesized OTC derivatives that are more lipophilic than OTC and theoretically able to overcome these limitations and to generate, in addition to cysteine, other substrates of the gamma-glutamyl cycle. Their antiviral effects were investigated in human HIV-1/Ba-L-infected monocyte-derived macrophages. In our experimental conditions, OTC exhibited anti-HIV-1 effects and little cytotoxicity at high doses. None of the nine tested derivatives showed higher cytotoxicity than OTC, nor anti-HIV-1/Ba-L activity.}, }
@article {pmid10549609, year = {1999}, author = {Walther, M and Kaffenberger, W and Van Beuningen, D}, title = {Influence of clinically used antioxidants on radiation-induced expression of intercellular cell adhesion molecule-1 on HUVEC.}, journal = {International journal of radiation biology}, volume = {75}, number = {10}, pages = {1317-1325}, doi = {10.1080/095530099139485}, pmid = {10549609}, issn = {0955-3002}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Biological Assay ; Cell Adhesion ; Cells, Cultured ; Endothelium, Vascular/metabolism/*radiation effects ; Flow Cytometry ; Humans ; In Vitro Techniques ; Intercellular Adhesion Molecule-1/analysis/*biosynthesis ; Neutrophils/cytology ; Pyrrolidines/pharmacology ; Radiation Tolerance/drug effects ; Radiation-Protective Agents/pharmacology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {PURPOSE: The effects of antioxidants (N-acetyl-L-cysteine [NAC] and pyrrolidine dithiocarbamate [PDTC]) on radiation-induced ICAM-1 expression on human umbilical vein endothelial cells (HUVEC) were investigated.<br><br>MATERIALS AND METHODS: The expression of ICAM-1 on HUVEC was determined by flow cytometry up to 72 h after X-irradiation. Functional competence of induced ICAM-1 was assessed by adhesion experiments with human polymorphonuclear neutrophils on irradiated HUVEC.<br><br>RESULTS: Preincubation of cells with both or either NAC and PDTC was unable to reduce radiation-induced ICAM-1 expression on HUVEC. In fact, by themselves, these antioxidants induced a significant increase of ICAM-1 expression, which in comparison with a radiation dose of 7 Gy after 24h was nine times higher for PDTC, and more than double for NAC. Treatment with NAC clearly restrained TNF-alpha-induced ICAM expression on HUVEC, while preincubation of cells with PDTC showed synergistic effects.<br><br>CONCLUSIONS: The role of reactive oxygen intermediates in signal transduction pathways leading to ICAM-1 expression should be investigated further. Furthermore, antioxidants may exert a pro-inflammatory role, as revealed by the induction of ICAM-1 expression on endothelial cells. The inhibition of TNF-alpha-induced ICAM-1 expression by NAC might have clinical implications because this substance is used as a radioprotector in radiotherapy.}, }
@article {pmid10541281, year = {1999}, author = {Jonassen, JA and Cooney, R and Kennington, L and Gravel, K and Honeyman, T and Scheid, CR}, title = {Oxalate-induced changes in the viability and growth of human renal epithelial cells.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {10 Suppl 14}, number = {}, pages = {S446-51}, pmid = {10541281}, issn = {1046-6673}, support = {R01 DK43184/DK/NIDDK NIH HHS/United States ; R01 ES07864/ES/NIEHS NIH HHS/United States ; }, mesh = {Cell Division/drug effects ; Cell Membrane Permeability/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; DNA-Binding Proteins/genetics ; Dose-Response Relationship, Drug ; Early Growth Response Protein 1 ; Epithelial Cells/drug effects ; Humans ; *Immediate-Early Proteins ; Kidney Tubules, Proximal/cytology/*drug effects ; Oxalates/*toxicity ; RNA, Messenger/analysis ; Transcription Factors/genetics ; }, abstract = {Previous studies on the porcine renal epithelial LLC-PK1 cell line demonstrated that oxalate exposure produces concentration-dependent effects on renal cell growth and viability via process(es) involving free radicals. The present studies were conducted to determine whether these findings could be extended to a renal proximal tubular epithelial cell line derived from the human kidney. These studies examined oxalate-induced changes in membrane integrity after short-term exposure (4 h) and changes in cell survival after longer-term exposure (24 to 72 h). Oxalate-induced changes were also assessed in the expression of two genes: egr-1, a zinc-finger transcription factor, and osteopontin, a protein associated with tissue remodeling. The present studies also determined whether oxalate-induced changes in either cell viability or gene expression depended on free radicals. Oxalate at a concentration > or = 175 microM (free) produced membrane damage within 4 h. This effect was inhibited by Mn(III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP), a superoxide dismutase mimetic, but not by N-acetyl cysteine, a glutathione precursor, or by deferoxamine, an iron chelator. Acute oxalate-induced injury was followed by cell loss within 24 h, an effect maintained at 48 and 72 h at high concentrations of oxalate. Oxalate also promoted DNA synthesis. This mitogenic effect offset cell loss at lower oxalate concentrations (88 microM) leading to a small but significant increase in cell number at 72 h. Treatment with oxalate also increased expression of egr-1 mRNA within 1 h, a response that was attenuated by MnTMPyP; oxalate treatment for 8 h also increased abundance of osteopontin mRNA. These studies suggest that oxalate exposure produces changes in human renal cell growth and viability via a process(es) dependent on reactive oxygen intermediates. Such changes may play a role in the development and/or progression of renal disease via generation of reactive oxygen intermediates.}, }
@article {pmid10575333, year = {1999}, author = {Pela, R and Calcagni, AM and Subiaco, S and Isidori, P and Tubaldi, A and Sanguinetti, CM}, title = {N-acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD.}, journal = {Respiration; international review of thoracic diseases}, volume = {66}, number = {6}, pages = {495-500}, doi = {10.1159/000029447}, pmid = {10575333}, issn = {0025-7931}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Aged ; Bronchodilator Agents/administration &amp; dosage ; Drug Administration Schedule ; Drug Therapy, Combination ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Humans ; Lung Diseases, Obstructive/diagnosis/*drug therapy/physiopathology ; Male ; Middle Aged ; Patient Satisfaction ; Probability ; Respiratory Function Tests ; Secondary Prevention ; Severity of Illness Index ; Statistics, Nonparametric ; Treatment Outcome ; }, abstract = {OBJECTIVE: This study was performed to confirm the efficacy of a 6-month therapy with a formulation of N-acetylcysteine (NAC; 600 mg/day p.o.) on frequency and severity of exacerbations in patients suffering from chronic obstructive pulmonary disease (COPD).<br><br>METHODS: One hundred sixty-nine patients attending five Italian centres were recruited in an open, randomized, controlled study. The patients were randomly allocated to standard therapy plus NAC 600 mg once a day or standard therapy alone over a 6-month period. At baseline, medical history was evaluated, and physical examination was performed; occurrence and severity of exacerbations and side effects of NAC were analyzed after 3 and 6 months.<br><br>RESULTS: The results showed a decreased number of exacerbations (by 41%) in the group of patients treated with NAC and standard treatment: 46 patients had at least one exacerbation as compared with 63 patients of the group treated with standard therapy alone. Also the number of the patients with two or more exacerbations was lower in the NAC group (26%) than in the standard-therapy group (49%). The number of sick days was less (82) in the NAC group as compared with the standard-therapy group (155). There was a small but significant improvement in FEV(1) and MEF(50) in the NAC group. NAC once a day was well tolerated. There were no differences in the number of side effects reported in both groups.<br><br>CONCLUSIONS: These data confirm results of previous studies which reported a reduction in the number of exacerbations in patients having moderate to severe COPD treated with the antioxidant NAC. Further, the once-daily formulation is well tolerated and is likely to improve patient compliance with the prescribed regimen.}, }
@article {pmid10574475, year = {1999}, author = {Grzybowski, AE}, title = {In vitro effect of glutathione precursors on cytotoxicity of amino acids to human mesothelial cells.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {50}, number = {3}, pages = {463-475}, pmid = {10574475}, issn = {0867-5910}, mesh = {Acetylcysteine/pharmacology ; Amino Acids/*toxicity ; Biological Transport/drug effects ; Cell Membrane/pathology ; Cells, Cultured ; Epithelial Cells/cytology/drug effects/metabolism ; Glutathione/*pharmacology ; Growth Inhibitors/toxicity ; Humans ; Intracellular Fluid/drug effects/metabolism ; Peritoneum/*cytology ; Potassium/metabolism ; Protein Precursors/*pharmacology ; Pyrrolidonecarboxylic Acid ; Rubidium Radioisotopes/metabolism ; Thiazoles/pharmacology ; Thiazolidines ; }, abstract = {Amino acids (AA) which were proposed as an alternative osmotically active agents in dialysates are toxic to human peritoneal mesothelial cells (HPMC) due to disturbance of the antioxidant-oxidant balance in cells by reducing level of glutathione. We assessed if the addition intracellular glutathione precursors: N-acetyl-cysteine (NAC), tioproline (TP), L--2-oxo--4-thiazolidine acid (PC), and glutathione (GSH) could reduce the cytotoxicity of AA, as measured by inhibition of cells proliferation and disorders of intracellular 86Rb transport. HPMC were obtained from omentum from nonuremic donors and cultured in in vitro conditions. The HPMC proliferation capacity was assessed indirectly by the 3H-methyl-thymidine incorporation assay. The injury to HPMC membrane integrity was assessed by the release of radioisotope molecules of 86Rb from the prelabelled cells. We have found that AA diminished the intracellular potassium (86Rb) influx. Supplementation of AA mixture with NAC enhanced the total 86Rb influx into HMC. Other precursors of intracellular glutathione (TP,PC,GSH) tested in the presence of AA significantly stimulated intracellular transport of 86Rb via Na,K-ATPase dependent channel, but the total intracellular transport of 86Rb was still lower than in control. HMC proliferation was significantly inhibited by AA what was measured by incorporation of H-metyl-tymidine. In the presence of NAC inhibition of HMC proliferation caused by AA was weaker. Our results suggest that some of intracellular glutathione precursors may reduce the disturbances of the HMC function caused by AA.}, }
@article {pmid10573084, year = {1999}, author = {Colombo, AA and Alessandrino, EP and Bernasconi, P and Arcese, GW and Rabusin, M and Bacigalupo, A and Bernasconi, C}, title = {N-acetylcysteine in the treatment of steroid-resistant acute graft-versus-host-disease: preliminary results. Gruppo Italiano Trapianto di Midollo Osseo (GITMO).}, journal = {Transplantation}, volume = {68}, number = {9}, pages = {1414-1416}, doi = {10.1097/00007890-199911150-00031}, pmid = {10573084}, issn = {0041-1337}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Adolescent ; Adrenal Cortex Hormones/*therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Drug Resistance ; Female ; Graft vs Host Disease/*drug therapy ; Humans ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Acute graft-versus-host disease (GVHD) results from reactivity of donor immunocompetent cells versus host tissues. Its pathogenesis involves co-stimulatory molecules, cytokines, free radicals, and oxidative stress products. N-Acetylcysteine (NAC) is an antioxidant that inhibits the B7-1/CD28 expression in vitro, and it may contrabalance the effects of free radicals and oxidative stress; it has been tested in eight patients with steroid-resistant acute GVHD.<br><br>METHODS: NAC was given at the dose of 150 mg/kg bolus intravenously, followed by 50 mg/kg intravenous continuous infusion over 3 weeks or less up, to clinical GVHD resolution. In four patients, flow cytometric analysis of co-stimulatory molecules was performed on peripheral mononuclear cells before and after NAC therapy.<br><br>RESULTS: We achieved prompt response in six patients: four had complete response, two partial response. Two patients died of acute GVHD, and four of intercurrent disease. We noticed significant decrease in CD80, CD25, and CD8+ cells after NAC therapy.<br><br>CONCLUSION: NAC therapy is feasible; it may give response in steroid-resistant acute GVHD. More extensive studies are needed to confirm these data.}, }
@article {pmid10569383, year = {1999}, author = {Bond, GR and Hite, LK}, title = {Population-based incidence and outcome of acetaminophen poisoning by type of ingestion.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {6}, number = {11}, pages = {1115-1120}, doi = {10.1111/j.1553-2712.1999.tb00113.x}, pmid = {10569383}, issn = {1069-6563}, mesh = {Acetaminophen/*poisoning/therapeutic use ; Adult ; Aged ; Analgesics, Non-Narcotic/*poisoning/therapeutic use ; Confidence Intervals ; Drug Overdose/epidemiology/therapy ; Emergency Service, Hospital/*statistics &amp; numerical data ; Female ; Hospitalization/*statistics &amp; numerical data ; Humans ; Incidence ; Male ; Middle Aged ; Population Surveillance ; Prognosis ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Sex Distribution ; United States/epidemiology ; }, abstract = {OBJECTIVES: 1) To determine, in a population-based sample, the observed frequency of acetaminophen overdose-related ED evaluation and hospitalization. 2) To examine the relative frequency of hospitalization by pattern of ingestion, the outcome of each group, and the presence or absence of postulated risk factors.<br><br>METHODS: This study was a 46-month, retrospective chart review of all acetaminophen-related visits, by patients at least 10 years of age, to either of the two hospitals that serve a four-county region of central Virginia.<br><br>RESULTS: Of 636 charts identified for review, only 137 involved acute or chronic acetaminophen overdose. One hundred twenty-six patients presented after an acute ingestion; 122 of these patients gave a history of a single, supratherapeutic ingestion of acetaminophen. Twenty-five patients were hospitalized for treatment. Eighteen of these were treated with N-acetylcysteine (NAC) based on the Rumack-Matthew nomogram; one suffered significant hepatic injury. The other seven presented at least 18 hours after ingestion, with no measurable serum acetaminophen. Two of these suffered significant hepatic injury. Four additional patients presented after multiple ingestions within 24 hours. Three were hospitalized, but none experienced significant injury. Only 11 patients were evaluated for chronic acetaminophen overmedication for pain (more than 6 g/day over a period of more than 24 hours). Four were admitted for treatment; three suffered significant hepatic injury. Thus, the observed incidence of acute acetaminophen ingestion in this region was 21.4/100,000/yr (95% CI = 17.7 to 25.2). The observed incidence of hospitalization for acute acetaminophen toxicity was 4.8/100,000/yr (95% CI = 3.0 to 6.5). The observed incidence of hospitalization for all acetaminophen poisoning was 5.5/100,000/yr (95% CI = 4.1 to 7.0). High ethanol consumption was present more frequently in those who suffered hepatic injury.<br><br>CONCLUSIONS: Most patients evaluated for acetaminophen ingestion present early following acute single overdose. Relatively few of these patients require hospitalization and, for those hospitalized, the outcome is good. More significantly, acetaminophen overdose patients whose risk cannot be estimated using the Rumack-Matthew nomogram represented 44% of those hospitalized and 83% of those who suffered significant hepatic injury. Emergency physicians need to determine how they can impact the outcome of these patients. Efforts should be directed at further characterizing historical, physical, and biochemical markers of risk and at determining in which circumstances hospitalization for NAC or other therapies is justified.}, }
@article {pmid10569195, year = {1999}, author = {Vasdev, S and Ford, CA and Parai, S and Longerich, L and Gadag, V}, title = {Dietary vitamin B6 supplementation attenuates hypertension in spontaneously hypertensive rats.}, journal = {Molecular and cellular biochemistry}, volume = {200}, number = {1-2}, pages = {155-162}, pmid = {10569195}, issn = {0300-8177}, mesh = {Aldehydes/metabolism ; Animals ; Antihypertensive Agents/*administration &amp; dosage ; Aorta/drug effects/metabolism ; Blood Platelets/metabolism ; Blood Pressure/drug effects ; Calcium/blood ; Hypertension/*drug therapy/pathology/physiopathology ; Kidney/drug effects/metabolism/pathology ; Liver/drug effects/metabolism ; Organ Size/drug effects ; Pyridoxine/*administration &amp; dosage ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; }, abstract = {In spontaneously hypertensive rats (SHRs) excess endogenous aldehydes bind sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels, increasing cytosolic free calcium and blood pressure. N-acetyl cysteine normalizes elevated blood pressure in SHRs by binding excess endogenous aldehydes. It is known that dietary vitamin B6 supplementation can increase the level of endogenous cysteine. Our objective was to investigate whether a dietary supplementation of vitamin B6 can prevent hypertension and associated changes in SHRs. Starting at 7 weeks of age, animals were divided into three groups of six animals each. Animals in WKY-control group and SHR-control group were given a normal vitamin B6 diet; and SHR-vitamin B6 group, a high vitamin B6 diet (20 times the recommended dietary intake; RDA) for the next 14 weeks. After 14 weeks, systolic blood pressure, platelet [Ca2+]i and liver, kidney and aortic aldehyde conjugates were significantly higher in SHR controls compared to WKY controls. These animals also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin B6 supplementation attenuated the increase in systolic blood pressure, tissue aldehyde conjugates and associated changes. These results further support the hypothesis that aldehydes are involved in increased systolic blood pressure in SHRs and suggest that vitamin B6 supplementation may be an effective antihypertensive.}, }
@article {pmid10568698, year = {1999}, author = {Lawrence, BP and Meyer, M and Reed, DJ and Kerkvliet, NI}, title = {Role of glutathione and reactive oxygen intermediates in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced immune suppression in C57Bl/6 mice.}, journal = {Toxicological sciences : an official journal of the Society of Toxicology}, volume = {52}, number = {1}, pages = {50-60}, doi = {10.1093/toxsci/52.1.50}, pmid = {10568698}, issn = {1096-6080}, support = {ES00040/ES/NIEHS NIH HHS/United States ; ES00210/ES/NIEHS NIH HHS/United States ; ES05667/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Cells, Cultured ; Female ; Glutathione/*physiology ; Immunosuppressive Agents/*toxicity ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Oxidative Stress/drug effects ; Polychlorinated Dibenzodioxins/*toxicity ; Reactive Oxygen Species/*metabolism ; Spleen/drug effects/metabolism ; }, abstract = {Recent developments in basic immunology have revealed the importance of glutathione (GSH) and cellular redox balance in the generation of an immune response. In the liver, it has been shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters cellular GSH and reactive oxygen intermediate (ROI) production. We have tested the hypothesis that TCDD mediates the suppression of the cytotoxic T lymphocyte (CTL) response to alloantigen by increasing oxidative stress. Total cellular GSH, GSSG, and GSH-protein adducts were analyzed by HPLC. Changes in intracellular GSH and ROI were simultaneously measured in isolated hepatocytes and individual subpopulations of spleen cells (CD4+, CD8+, B220+, and Mac-1+) following in vivo exposure to TCDD and antigenic challenge with P815 mastocytoma cells. Monochlorobimane was utilized to measure GSH levels, and two fluorescent probes were used to evaluate ROI levels: dichlorofluoroscein diacetate to monitor peroxides and dihydroethidine to assess superoxide anion. In hepatocytes, in vivo treatment with TCDD resulted in a transient, 2-fold increase in GSH, a 50% decrease in peroxide levels and a small (20-40%) decrease in superoxide anion levels. Although alloantigen challenge resulted in increased GSH and peroxide in spleen cells, in vivo exposure to TCDD had no effect on splenic ROI levels, nor did it consistently alter GSH levels in any subpopulation of spleen cells examined. Moreover, in vivo treatment with the antioxidant N-acetyl cysteine failed to affect the immune suppression caused by TCDD. These results suggest to us that although TCDD perturbs cellular redox balance in the liver, it does not exacerbate or diminish the normal increased GSH and ROI which occur in the spleen in response to antigenic challenge.}, }
@article {pmid10567914, year = {2000}, author = {Isowa, N and Yoshimura, T and Kosaka, S and Liu, M and Hitomi, S and Yodoi, J and Wada, H}, title = {Human thioredoxin attenuates hypoxia-reoxygenation injury of murine endothelial cells in a thiol-free condition.}, journal = {Journal of cellular physiology}, volume = {182}, number = {1}, pages = {33-40}, doi = {10.1002/(SICI)1097-4652(200001)182:1&lt;33::AID-JCP4&gt;3.0.CO;2-5}, pmid = {10567914}, issn = {0021-9541}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Cell Adhesion/drug effects ; *Cell Hypoxia ; Cell Line ; Cell Size/drug effects ; Cell Survival/drug effects ; Cytokines/pharmacology ; *Cytoprotection ; Dose-Response Relationship, Drug ; Endothelium/*cytology/drug effects/metabolism ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Mice ; Mice, Inbred Strains ; Neoplasm Proteins/pharmacology ; Oxidants/metabolism ; Oxidation-Reduction/drug effects ; Oxygen/*metabolism ; Sulfhydryl Compounds/*physiology ; Thioredoxins/*pharmacology ; }, abstract = {The adult T cell leukemia-derived factor (ADF), or human thioredoxin (hTRX), has a radical scavenging effect similar to that of N-acetyl cysteine (NAC). We have recently shown that ADF/hTRX protects the lung and the heart from ischemia-reperfusion induced injury. To elucidate mechanisms of the protective effect, a hypoxia-reoxygenation (H-R) injury model was developed using a murine endothelial cell line, cultured in a thiol-free medium. In this condition, cells became much more vulnerable to H-R injury. The viability of cells decreased significantly after 1 h of hypoxic incubation followed by 1 h of reoxygenation. The injury was reduced by ADF/hTRX (100 microM) or NAC (10 mM). These two agents also demonstrated an additive protective effect. When cells were cultured in thiol-free medium for 2 h in a normoxic condition, intracellular hydrogen peroxide production was increased, which was associated with a decrease in glutathione level. NAC (10 mM) attenuated these changes whereas ADF/hTRX (100 microM) did not. These results suggest that although both ADF/hTRX and NAC protected cells from H-R injury, the underlying mechanisms are different. Because the cytoprotective effect of ADF/hTRX occurs in the thiol-free condition, it must be mediated via a novel mechanism other than enhancing thiol uptake. The additive cytoprotective effect between ADF/hTRX and NAC suggests that we should combine these two agents clinically.}, }
@article {pmid10566875, year = {1999}, author = {Aruoma, OI and Spencer, JP and Mahmood, N}, title = {Protection against oxidative damage and cell death by the natural antioxidant ergothioneine.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {37}, number = {11}, pages = {1043-1053}, doi = {10.1016/s0278-6915(99)00098-8}, pmid = {10566875}, issn = {0278-6915}, mesh = {Animals ; Antioxidants/*pharmacology ; Cattle ; Cell Death/drug effects ; Cell Line ; Cell Survival/drug effects ; DNA/metabolism ; DNA Damage/drug effects ; Ergothioneine/*pharmacology ; Humans ; Hybridomas ; Hydrogen Peroxide/antagonists &amp; inhibitors/toxicity ; Mice ; Neurons/cytology/drug effects/metabolism ; Nitrates/antagonists &amp; inhibitors/toxicity ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Rats ; }, abstract = {The natural antioxidant ergothioneine (EGT) was tested for its ability to inhibit cell death caused by hydrogen peroxide (H2O2) and to inhibit DNA oxidation by peroxynitrite (ONOO-) in human neuronal hybridoma cell line (N-18-RE-105). High concentrations of EGT (5 mM) were tolerated by the N-18-RE-105 cells. N-acetylcysteine (NAC) was not well tolerated by the cells at concentrations greater than 3 mM (cell viability averaged 50%). Increasing concentrations of EGT increases cell viability in the presence of NAC. EGT at concentrations up to 2 mM weakly improved cell viability in the presence of H2O2. NAC at concentrations up to 2 mM weakly decreased, but not significantly, the viability of the cells. At a higher concentration of 5 mM, NAC weakly protected the neuronal cells against the H2O2-induced cell death. The protection was significantly enhanced by preincubation with EGT. Ergothioneine inhibited ONOO(-)-induced oxidative damage in isolated calf thymus DNA and DNA in N-18-RE-105 cells. The concentration of EGT in human and mammalian tissue has been estimated to be 1-2 mM, which suggests that EGT may serve as a non-toxic thiol buffering antioxidant in vivo and may find applications in pharmaceutical preparations where oxidative stability is desired.}, }
@article {pmid10564823, year = {1999}, author = {Seo, MS and Lee, MS and Lim, IK}, title = {Expression of rat BTG(3) gene, Rbtg3, is regulated by redox changes.}, journal = {Gene}, volume = {240}, number = {1}, pages = {165-173}, doi = {10.1016/s0378-1119(99)00415-1}, pmid = {10564823}, issn = {0378-1119}, mesh = {3' Untranslated Regions ; 3T3 Cells ; 5' Untranslated Regions ; Acetylcysteine/pharmacology ; Amino Acid Sequence ; Animals ; Base Sequence ; Brain/metabolism ; Cell Line ; Cycloheximide/pharmacology ; DNA, Complementary/chemistry/genetics ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects/*genetics ; *Genes, Tumor Suppressor ; Hydrogen Peroxide/pharmacology ; Immediate-Early Proteins/drug effects/genetics/metabolism ; Mice ; Molecular Sequence Data ; *Oxidation-Reduction ; PC12 Cells ; Proteins/*genetics ; RNA/genetics/metabolism ; RNA, Messenger/drug effects/genetics/metabolism ; Rats ; Rats, Sprague-Dawley ; Sequence Alignment ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Suppressor Proteins ; }, abstract = {The Rbtg3 gene was isolated by PCR (polymerase chain reaction) cloning from the cDNA library of Rat1 fibroblasts that were stimulated with TPA (12-O-tetradecanoylphorbol-13-acetate) or various growth factors for 3h and was found to be a rat homologue of mouse BTG3 and human ANA genes. The Rbtg3 gene had unique DNA sequences in the 5'-UTR and 3'-UTR that contained four ATTTA and one TTATTTA(T/A)(T/A) nonamer motif, and also a polyA addition site. Nucleotide homology of Rbtg3 with BTG3 and ANA was 88.5 and 76.6%, respectively. Expression of Rbtg3 was investigated in SD rats as well as cell lines derived from mouse--SW3T3, NIH3T3 fibroblasts--and rat--Rat1, 3Y1 fibroblasts and PC12--cells. Rbtg3 was highly expressed in brain but barely in lung, kidney, thymus and spleen. The constitutive expression level was high in SW3T3, Rat1 and 3Y1 fibroblasts, but very low in NIH3T3 fibroblast and PC12 cells. However, in all cells tested, Rbtg3 was proved to be one of the primary response genes superinduced by TPA (50ng/ml)+cycloheximide (CHX, 10 microgram/ml). Expression of Rbtg3 was induced by H(2)O(2) (500mM) up to fourfold in PC12 cells and was blocked by pretreatment of NAC (N-acetyl-L-cysteine, 10mM). The induction was ninefold in 3Y1 fibroblasts by menadione (25mM) treatment for 1h, whereas it was reduced to a third of the control level in SW3T3 fibroblast by the same treatment. Rbtg3 was not expressed in NIH3T3 cells but minimally regulated by redox changes as compared with rapid and strong induction of TIS21/BTG2 mRNAs after TPA or H(2)O(2) stimulation. The above results indicate that Rbtg3 is one of many redox-regulated genes as well as a primary response gene.}, }
@article {pmid10564243, year = {1999}, author = {Rangan, GK and Wang, Y and Tay, YC and Harris, DC}, title = {Inhibition of NFkappaB activation with antioxidants is correlated with reduced cytokine transcription in PTC.}, journal = {The American journal of physiology}, volume = {277}, number = {5}, pages = {F779-89}, doi = {10.1152/ajprenal.1999.277.5.F779}, pmid = {10564243}, issn = {0002-9513}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Catalase/pharmacology ; Cell Survival/drug effects ; Cytokines/*genetics ; Deferoxamine/pharmacology ; Hydrogen Peroxide/pharmacology ; Kidney Tubules, Proximal/cytology/*drug effects/*metabolism/physiology ; L-Lactate Dehydrogenase/metabolism ; Lipopolysaccharides/pharmacology ; Male ; NF-kappa B/*antagonists &amp; inhibitors ; Pyrrolidines/pharmacology ; Quercetin/pharmacology ; Rats ; Rats, Wistar ; Thiocarbamates/pharmacology ; Transcription, Genetic/*drug effects ; }, abstract = {We recently reported that inhibition of the transcription factor nuclear factor-kappaB (NFkappaB) with pyrrolidinedithiocarbamate (PDTC) reduced interstitial monocyte infiltration in rats with proteinuric tubulointerstitial disease, whereas N-acetylcysteine (NAC) was not effective. Here we investigate the effects of antioxidants (PDTC, NAC, and quercetin) on NFkappaB activation and cytokine transcription in primary cultured rat proximal tubular epithelial cells (PTC) stimulated with lipopolysaccharide. Antioxidant-mediated inhibition of NFkappaB activation (PDTC, 20-100 microM; NAC, 100 mM; and quercetin, 50 microM) diminished the induction of both pro- [interleukin (IL)-1beta, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1alpha, and MIP-2] and anti-inflammatory (IL-10, transforming growth factor-beta1) cytokine transcription in PTC (RT-PCR analysis). PDTC and quercetin did not affect PTC viability, but NAC (100 mM) caused a threefold increase in lactate dehydrogenase leakage (P < 0.001). We conclude that NAC is unable to suppress NFkappaB activation in PTC at subtoxic and physiologically relevant concentrations. Furthermore, antioxidant-mediated inhibition of NFkappaB is correlated with the nonselective reduction of cytokine transcription in activated tubular cells. These data might explain the protective effects of PDTC-mediated NFkappaB inhibition in tubulointerstitial disease in vivo.}, }
@article {pmid10564154, year = {1999}, author = {Hoare, GS and Marczin, N and Chester, AH and Yacoub, MH}, title = {Role of oxidant stress in cytokine-induced activation of NF-kappaB in human aortic smooth muscle cells.}, journal = {The American journal of physiology}, volume = {277}, number = {5}, pages = {H1975-84}, doi = {10.1152/ajpheart.1999.277.5.H1975}, pmid = {10564154}, issn = {0002-9513}, mesh = {Antioxidants/pharmacology ; Aorta/cytology/drug effects/*metabolism ; Cells, Cultured ; Chelating Agents/pharmacology ; Flow Cytometry ; Humans ; Hydrogen Peroxide/pharmacology ; Interleukin-1/*pharmacology ; Intracellular Membranes/metabolism ; Metals/metabolism ; Muscle, Smooth, Vascular/cytology/drug effects/*metabolism ; NF-kappa B/*physiology ; Oxidants/pharmacology ; Oxidative Stress/*physiology ; Sulfhydryl Compounds/metabolism ; }, abstract = {The transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated in inflammatory and proliferative vascular mechanisms. Activated NF-kappaB has been documented in human atherosclerotic lesions, and its activation in human vascular smooth muscle cells (SMC) by cytokines has been reported. However, intracellular mechanisms mediating NF-kappaB activation in human SMC are poorly understood. The aim of this study was to explore the potential role of reactive oxygen species and oxidant stress as signaling events in cytokine-induced NF-kappaB activation. Western blot analysis revealed the presence of inhibitory protein I-kappaBalpha in resting human aortic SMC, which was rapidly phosphorylated and degraded on exposure to interleukin-1beta (IL-1beta) followed by NF-kappaB translocation to the nucleus. IL-1beta had no effect on two measures of intracellular oxidant stress, fluorescence generated by the oxidation of 2',7'-dichlorodihydrofluorescin to dichlorofluorescein (DCF) or changes in intracellular sulfhydryl content. N-acetylcysteine (NAC) a membrane-permeant antioxidant, which augmented intracellular sulfhydryl content and inhibited H(2)O(2)-induced DCF fluorescence, had no effect on cytokine-induced NF-kappaB activation. In contrast to NAC, the metal chelators pyrrolidine dithiocarbamate and diethyldithiocarbamate attenuated IL-1beta-induced NF-kappaB activation but had no effect on intracellular sulfhydryl content. Treatment of the cells with the oxidant H(2)O(2) caused an increase in DCF fluorescence and decreased intracellular sulfhydryl content but had no effect on I-kappaBalpha or NF-kappaB. In conclusion, this study suggests that oxidant stress may not play a major role in cytokine-induced activation of NF-kappaB in human aortic SMC and that oxidants may not be primary activators of NF-kappaB in these cells.}, }
@article {pmid10563527, year = {1999}, author = {Idéo, G and Bellobuono, A and Tempini, S and Mondazzi, L and Airoldi, A and Benetti, G and Bissoli, F and Cestari, C and Colombo, E and Del Poggio, P and Fracassetti, O and Lazzaroni, S and Marelli, A and Paris, B and Prada, A and Rainer, E and Roffi, L}, title = {Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study.}, journal = {European journal of gastroenterology &amp; hepatology}, volume = {11}, number = {11}, pages = {1203-1207}, doi = {10.1097/00042737-199911000-00003}, pmid = {10563527}, issn = {0954-691X}, mesh = {Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Antiviral Agents/*therapeutic use ; Drug Therapy, Combination ; Female ; Hepacivirus/isolation &amp; purification ; Hepatitis C, Chronic/blood/*drug therapy/virology ; Humans ; Interferon-alpha/*therapeutic use ; Male ; Middle Aged ; Prospective Studies ; RNA, Viral/blood ; Treatment Failure ; Vitamin E/*therapeutic use ; }, abstract = {OBJECTIVE: After non-response to the initial course of therapy, retreatment with alpha-interferon is not effective. The aim of this study was to ascertain whether the administration of N-acetyl cysteine and vitamin E could increase the response rate to retreatment with alpha-interferon.<br><br>DESIGN: Prospective, multicentre clinical trial.<br><br>SETTING: Twelve hospitals in Lombardy, Italy.<br><br>PARTICIPANTS: 120 consecutive patients affected by biopsy-proven chronic hepatitis C who had been non-responders to a previous course of alpha-interferon, administered at the dosage of 3-6 million units (MU) three times a week (tiw) for 6 months.<br><br>INTERVENTIONS: The patients were randomly assigned to one of two groups of treatment: group A, natural interferon-alphaN3, 6 or 9 MU tiw, when the body weight was < 60 kg or > or = 60 kg, respectively; group B, the same dosage of natural interferon-alphaN3 in association with oral administration of N-acetyl cysteine 1200 mg/day and vitamin E 600 mg/day. The period of treatment was 6 months in both groups.<br><br>RESULTS: Neither end-therapy biochemical response nor sustained biochemical response rates were improved by the combination treatment, and in no case was clearance of the virus from serum observed.<br><br>CONCLUSIONS: In this randomized study carried out on 120 patients with chronic hepatitis C not responsive to alpha-interferon, oral supplementation with N-acetyl cysteine and vitamin E did not improve the poor efficacy of retreatment with alpha-interferon alone.}, }
@article {pmid10561806, year = {1999}, author = {Flora, SJ}, title = {Arsenic-induced oxidative stress and its reversibility following combined administration of N-acetylcysteine and meso 2,3-dimercaptosuccinic acid in rats.}, journal = {Clinical and experimental pharmacology &amp; physiology}, volume = {26}, number = {11}, pages = {865-869}, doi = {10.1046/j.1440-1681.1999.03157.x}, pmid = {10561806}, issn = {0305-1870}, mesh = {3,4-Methylenedioxyamphetamine/metabolism ; 5-Aminolevulinate Synthetase/metabolism ; Acetylcysteine/*therapeutic use ; Animals ; Arsenic Poisoning/*metabolism ; Brain/drug effects/metabolism ; Chelating Agents/*therapeutic use ; Erythrocytes/drug effects/metabolism ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Liver/drug effects/metabolism ; Male ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Succimer/*therapeutic use ; }, abstract = {1. The present study examined whether arsenic induces oxidative stress in liver, brain and erythrocytes (RBC) based on the investigation of certain selected parameters. It also explored the possibility that combined administration of N-acetylcysteine (NAC) and meso 2,3-dimercaptosuccinic acid (DMSA) was capable of achieving better reversibility in the parameters indicative of arsenic-induced oxidative stress than individual treatment with either of these drugs. 2. Male rats were exposed to 100 p.p.m. sodium arsenite in their drinking water for 12 weeks (equivalent to 12 mg/kg As). The arsenic was then removed and rats were given NAC (1 mmol/kg per day), DMSA (1 mmol/kg per day) or a combination of the two, orally, once daily for 5 days. Animals not given arsenic and those given arsenic but not NAC or DMSA served as negative and positive controls, respectively. 3. Twelve weeks of arsenic exposure was found to deplete glutathione (GSH) levels, increase oxidized glutathione (GSSG) and promote malondialdehyde (MDA) production in both liver and brain samples. In addition to a significant reduction in RBC delta-aminolevulinic acid dehydratase (ALAD) activity and GSH levels, a marked elevation in MDA production may also contribute to arsenic-induced oxidative stress. 4. Treatment with either NAC or DMSA alone partially reversed arsenic-induced alterations in hepatic GSH and MDA, while only brain MDA levels responded favourably to these drugs. Only DMSA appeared to restore blood ALAD, while RBC MDA levels responded favourably to both drugs. Treatment with DMSA also produced an effective depletion of blood and hepatic arsenic concentrations. In the liver, most of these parameters were more effectively reversed by combined treatment with NAC and DMSA compared with the effects of either drug alone. 5. These results provide in vivo evidence of arsenic-induced oxidative stress in liver, brain and RBC and indicate that these effects can be mitigated by pharmacological intervention that encompasses combined treatment with NAC and DMSA.}, }
@article {pmid10553087, year = {1999}, author = {Hiura, TS and Kaszubowski, MP and Li, N and Nel, AE}, title = {Chemicals in diesel exhaust particles generate reactive oxygen radicals and induce apoptosis in macrophages.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {163}, number = {10}, pages = {5582-5591}, pmid = {10553087}, issn = {0022-1767}, support = {AI-34567/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects/immunology ; Cell Death/drug effects/immunology ; Cell Line ; Enzyme Activation/drug effects ; Free Radicals/toxicity ; JNK Mitogen-Activated Protein Kinases ; Macrophages/cytology/*drug effects/enzymology/*metabolism ; Macrophages, Alveolar/cytology/drug effects ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Phagocytosis/drug effects ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; Vehicle Emissions/analysis/*toxicity ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {There is increasing evidence that particulate air pollutants, such as diesel exhaust particles (DEP), potentiate chronic inflammatory processes as well as acute symptomatic responses in the respiratory tract. The mechanisms of action as well as the cellular targets for DEP remain to be elucidated. We show in this paper that the phagocytosis of DEP by primary alveolar macrophages or macrophage cell lines, RAW 264.7 and THP-1, leads to the induction of apoptosis through generation of reactive oxygen radicals (ROR). This oxidative stress initiates two caspase cascades and a series of cellular events, including loss of surface membrane asymmetry and DNA damage. The apoptotic effect on macrophages is cell specific, because DEP did not induce similar effects in nonphagocytic cells. DEP that had their organic constituents extracted were no longer able to induce apoptosis or generate ROR. The organic extracts were, however, able to induce apoptosis. DEP chemicals also induced the activation of stress-activated protein kinases, which play a role in cellular apoptotic pathways. The injurious effects of native particles or DEP extracts on macrophages could be reversed by the antioxidant, N-acetyl-cysteine. Taken together, these data suggest that organic compounds contained in DEP may exert acute toxic effects via the generation of ROR in macrophages.}, }
@article {pmid10548500, year = {1999}, author = {Mazière, C and Conte, MA and Degonville, J and Ali, D and Mazière, JC}, title = {Cellular enrichment with polyunsaturated fatty acids induces an oxidative stress and activates the transcription factors AP1 and NFkappaB.}, journal = {Biochemical and biophysical research communications}, volume = {265}, number = {1}, pages = {116-122}, doi = {10.1006/bbrc.1999.1644}, pmid = {10548500}, issn = {0006-291X}, mesh = {Arachidonic Acid/metabolism ; Cell Line ; Culture Media ; Fatty Acids, Unsaturated/*pharmacology ; Fibroblasts/drug effects/metabolism ; Humans ; Kinetics ; NF-kappa B/*metabolism ; Oleic Acid/pharmacology ; Oxidative Stress/drug effects/*physiology ; Reactive Oxygen Species/metabolism ; Transcription Factor AP-1/*metabolism ; Vitamin E/*pharmacology ; }, abstract = {A 48-h incubation of cultured human fibroblasts with 5 x 10(-5) M oleic acid or polyunsaturated fatty acids (PUFA) from the (n-6) (linoleic, gamma-linolenic and arachidonic acids) or (n-3) (alpha-linolenic and eicosapentaenoic acids) series resulted in an enrichment of the cells with the introduced fatty acid. Cell enrichment with PUFA initiated a rise in the intracellular level of reactive oxygen species (ROS) and lipid peroxidation products (thiobarbituric reactive substances TBARS). Simultaneously, cell enrichment with all the studied PUFA induced an increase in AP1 and NFkappaB binding activity measured by electrophoretic mobility shift assay, whereas no significant effect was observed with the monounsaturated oleic acid. Furthermore, the antioxidants vitamin E (alpha-tocopherol) and N-acetyl cysteine prevented both the arachidonic acid-induced increase in intracellular ROS and TBARS, and the activation of AP1 and NFkappaB. These results indicate that the accumulation of PUFA from (n-6) and (n-3) series elicited an intracellular oxidative stress, resulting in the activation of oxidative stress-responsive transcription factors such as AP1 and NFkappaB.}, }
@article {pmid10545417, year = {1999}, author = {Kramer-Stickland, K and Edmonds, A and Bair, WB and Bowden, GT}, title = {Inhibitory effects of deferoxamine on UVB-induced AP-1 transactivation.}, journal = {Carcinogenesis}, volume = {20}, number = {11}, pages = {2137-2142}, doi = {10.1093/carcin/20.11.2137}, pmid = {10545417}, issn = {0143-3334}, support = {CA-27502/CA/NCI NIH HHS/United States ; }, mesh = {Antioxidants/pharmacology ; Cell Line ; Chlorides ; Deferoxamine/*pharmacology ; Ferric Compounds/pharmacology ; Humans ; Iron Chelating Agents/*pharmacology ; Reactive Oxygen Species ; Transcription Factor AP-1/*genetics ; Transcriptional Activation/*drug effects/radiation effects ; *Ultraviolet Rays ; }, abstract = {Production of reactive oxygen species (ROS) by iron can contribute directly to DNA and protein damage and may contribute to cell signaling and proliferation. We have examined the effects of the iron(III) chelator deferroxamine (DFO) and iron (FeCl(3)) on UVB (290-320 nm)-induced activator protein 1 (AP-1) signaling. The ability of DFO to inhibit UVB-induced AP-1 transactivation was tested in a human keratinocyte cell line stably transfected with a luciferase reporter driven by a single AP-1 element. DFO treatment 24 h prior to UVB irradiation reduced UVB-induced AP-1 transactivation by approximately 80%, with the effect of DFO diminishing as pre-treatment time was shortened. Treatment with FeCl(3) a minimum of 6 h prior to UVB potentiated the UVB induction of AP-1 transactivation by 2-3-fold. DFO was able to ablate both the UVB induction of AP-1 transactivation as well as the potentiation by FeCl(3). The antioxidants Trolox and N-acetyl cysteine were both able to inhibit UVB-induced AP-1 transactivation and Trolox was able to inhibit the potentiation of UVB-induced AP-1 by FeCl(3). These results indicate that UVB-induced AP-1 activation may be in part due to oxidant effects of UVB and intercellular iron.}, }
@article {pmid10533675, year = {1999}, author = {Khalak, R and Huyck, HL and Pryhuber, GS}, title = {Antagonistic effects of pyrrolidine dithiocarbamate and N-acetyl-L-cysteine on surfactant protein A and B mRNAs.}, journal = {Experimental lung research}, volume = {25}, number = {6}, pages = {479-493}, doi = {10.1080/019021499270088}, pmid = {10533675}, issn = {0190-2148}, mesh = {Acetylcysteine/*pharmacology ; Blotting, Northern ; Carmustine/pharmacology ; Cell Line ; Clusterin ; Drug Synergism ; Epithelial Cells/*drug effects/metabolism ; Gene Expression Regulation ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Glutathione Reductase/antagonists &amp; inhibitors ; Glycoproteins/drug effects/genetics/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Lung/*drug effects/metabolism ; *Molecular Chaperones ; Proteolipids/*antagonists &amp; inhibitors/biosynthesis/genetics ; Pulmonary Surfactant-Associated Protein A ; Pulmonary Surfactant-Associated Proteins ; Pulmonary Surfactants/*antagonists &amp; inhibitors/biosynthesis/genetics ; Pyrrolidines/*pharmacology ; RNA, Messenger/*antagonists &amp; inhibitors/metabolism ; Ribonucleases/metabolism ; Thiocarbamates/*pharmacology ; }, abstract = {Pulmonary surfactant, a mixture of phospholipids and specific associated proteins, reduces surface tension at the air-liquid interface of the lung and protects the large epithelial surface of the lung from infectious organisms. Surfactant proteins, SP-A and SP-B, are required for normal surfactant function. In the current work, increased levels of oxidized glutathione (GSSG) are demonstrated at doses of pyrrolidine dithiocarbamate (PDTC) which decrease SP-A and SP-B mRNAs, suggesting that cellular oxidation reduces surfactant protein expression. Similarly, reduction of SP-A and SP-B mRNA levels following accumulation of GSSG induced by glutathione reductase inhibitor 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), supports the hypothesis that surfactant protein synthesis is reduced in response to oxidation of pulmonary epithelial glutathione. Concurrent induction of apolipoprotein J (apoJ) mRNA by PDTC demonstrates the selectivity of pulmonary gene regulation by the dithiocarbamate. In contrast, the glutathione precursor N-acetyl-l-cysteine (NAC) prevented PDTC-dependent increase in GSSG/GSH ratio, inhibition of SP-A and -B mRNAs, and induction of apoJ. Insufficiency of SP-A and -B, which occurs in inflammatory lung diseases, may result from the exposure of the pulmonary epithelium to oxidant stress and may be reversed by the antioxidant NAC.}, }
@article {pmid10531305, year = {1999}, author = {Cross, JV and Deak, JC and Rich, EA and Qian, Y and Lewis, M and Parrott, LA and Mochida, K and Gustafson, D and Vande Pol, S and Templeton, DJ}, title = {Quinone reductase inhibitors block SAPK/JNK and NFkappaB pathways and potentiate apoptosis.}, journal = {The Journal of biological chemistry}, volume = {274}, number = {44}, pages = {31150-31154}, doi = {10.1074/jbc.274.44.31150}, pmid = {10531305}, issn = {0021-9258}, support = {CA-66134/CA/NCI NIH HHS/United States ; HL-09249-01/HL/NHLBI NIH HHS/United States ; HL-57940/HL/NHLBI NIH HHS/United States ; }, mesh = {*Apoptosis ; Cells, Cultured ; Dicumarol/pharmacology ; Dose-Response Relationship, Drug ; Drug Synergism ; Enzyme Activation/drug effects ; Humans ; Hydroquinones/pharmacology ; JNK Mitogen-Activated Protein Kinases ; Kidney/cytology ; Leukocytes, Mononuclear/drug effects ; Mitogen-Activated Protein Kinases/*metabolism ; Models, Biological ; NAD(P)H Dehydrogenase (Quinone)/*antagonists &amp; inhibitors ; NF-kappa B/*metabolism ; Osmotic Pressure ; Oxidation-Reduction ; Phytohemagglutinins/pharmacology ; Signal Transduction/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {A variety of environmental stresses stimulate the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEKK) > stress-activated protein kinase (SAPK)-ERK kinase (SEK) > SAPK/c-Jun NH(2)-terminal kinase (JNK) stress-activated protein kinase cascade and coordinately activate the transcription factor NFkappaB. Mechanisms of stress activation upstream of MEKK1 have not been precisely determined. Redox mechanisms involving sulfhydryls are likely because N-acetyl-cysteine at millimolar concentrations blocks stress signals. Because intracellular sulfhydryl concentrations can be regulated through redox cycling involving reactive quinones (1), we tested the ability of quinone reductase inhibitors to alter stress signaling. Several quinone reductases are inhibited by dicoumarol, a coumarin derivative. Dicoumarol prevented SAPK activation in vivo by chemical cell stressors and also prevented SAPK activation induced by expression of the tumor necrosis factor alpha (TNFalpha) receptor-associated protein TRAF2 but not by expression of truncated active MEKK1. Other coumarin derivatives failed to block SAPK activation, but other inhibitors of quinone reductases, particularly menadione, similarly blocked SAPK activation. Cells deficient in a major quinone reductase, NQO1, displayed hypersensitivity to dicoumarol stress inhibition, whereas SAPK in cells reconstituted with the NQO1 gene displayed relative dicoumarol resistance. Consistent with the proposed role of overlapping upstream signaling cascades in activation of NFkappaB, dicoumarol also blocked NFkappaB activation in primary macrophages stimulated with either lipopolysaccharide or TNFalpha. In addition, dicoumarol strongly potentiated TNFalpha-induced apoptosis in HeLa cells, probably by blocking the anti-apoptotic effect of NFkappaB. The ability of dicoumarol to simultaneously inhibit SAPK and NFkappaB activation and to potentiate apoptotic cell death suggests that SAPK is not an obligate participant in apoptosis. Dicoumarol, currently in clinical use as an oral anticoagulant, represents a potential therapeutic inhibitor of the SAPK and NFkappaB response.}, }
@article {pmid10530792, year = {1999}, author = {Ferrández, MD and Correa, R and Del Rio, M and De la Fuente, M}, title = {Effects in vitro of several antioxidants on the natural killer function of aging mice.}, journal = {Experimental gerontology}, volume = {34}, number = {5}, pages = {675-685}, doi = {10.1016/s0531-5565(99)00009-1}, pmid = {10530792}, issn = {0531-5565}, mesh = {Acetylcysteine/pharmacology ; Aging/*immunology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Killer Cells, Natural/drug effects/*immunology ; Lymph Nodes/growth &amp; development/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Peritoneum ; Spleen/growth &amp; development/immunology ; Thiazoles/pharmacology ; Thiazolidines ; Thymus Gland/growth &amp; development/immunology ; Vitamin E/pharmacology ; }, abstract = {The aim of the present work is to study the change with aging in the effect in vitro of several antioxidants: thiazolidine-4-carboxylic acid or thioproline, N-acetylcysteine (NAC), ascorbic acid (AA), and alpha-tocopherol (vitamin E, VE) on the natural killer (NK) activity in mononuclear cells from axillary nodes, spleen, thymus and peritoneal leukocytes from BALB/c male mice. Young (8+/-2 weeks), adult (24+/-2 weeks). mature (48+/-2 weeks), and old (72+/-2 weeks) animals were studied. A nonradioactive cytotoxic assay with cells from the murine lymphoma YAC-1 as target cells and a relation effector cells/target cells of 10/1 were used. The concentrations of the different antioxidants were: 1 mM for thioproline and N-acetylcysteine and 5 microM for ascorbic acid and alpha-tocopherol, which induced a maximum effect in our previous dose-response experiments. The results show that, in general, the above antioxidants cause an enhancement of the NK activity at all ages studied, this stimulation being higher with thioproline and N-acetylcysteine than with ascorbic acid and alpha-tocopherol. The effects were similar for the three lymphoid organs and the peritoneum. This stimulation of the NK activity by antioxidants is an important favorable response, especially in old mice, in which age results in a decrease in NK function and, therefore, in a higher incidence of neoplasia.}, }
@article {pmid10527705, year = {1999}, author = {Ramakrishna, V and Hu, J and Lei, J and Li, X and Gorczynski, RM}, title = {Alterations in chemokine mRNA expression in animals receiving portal vein immunization and renal allo- or xenotransplantation precede altered cytokine production.}, journal = {The Journal of surgical research}, volume = {87}, number = {1}, pages = {62-72}, doi = {10.1006/jsre.1999.5744}, pmid = {10527705}, issn = {0022-4804}, mesh = {Acetylcysteine/pharmacology ; Animals ; Chemokine CCL2/physiology ; Chemokines/*genetics ; Cytokines/*biosynthesis ; Graft Survival ; Immunization ; *Kidney Transplantation ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Portal Vein/*immunology ; RNA, Messenger/*analysis ; Rats ; Rats, Inbred Lew ; Reperfusion Injury/immunology ; Transplantation, Heterologous ; Transplantation, Homologous ; }, abstract = {We have analyzed chemokine mRNA expression in graft tissue of C3H/HEJ mice receiving allogeneic (C57BL/6) or xenogeneic [Lewis (LEW) rat donors] kidney grafts and correlated this with graft survival. Since donor-specific portal vein (pv) immunization is known to increase allo- and xenograft survival, in some cases recipients also received pretransplant pv or intravenous (iv) immunization; other animals received the antioxidant N-acetylcysteine (NAc) to examine the role of ischemia/reperfusion injury in the changes observed. Graft tissue and lymph nodes draining the respective grafts were obtained at various times posttransplantation and used for quantitative polymerase chain reaction analysis of mRNAs for different chemokines. In addition, lymphocytes were restimulated in culture with donor antigen and supernatants assayed for different cytokines. We observed that early increases in mRNA for MCP-1 preceded a polarization to type 2 cytokine production. Infusion of NAc twice daily for 4 days following transplantation further altered chemokine mRNA expression (increased MCP-1 and RANTES; decreased CINC); led to more enhanced type 2 cytokine production relative to control animals; and further increased xenograft survival. By use of heteroantibodies to different chemokines, anti-MCP-1 alone, but not antibodies to MIP-1alpha or RANTES, abolished this early polarization in cytokine production, implying a causal link between MCP-1 production and polarization in cytokine production. We conclude that manipulation of chemokine production early after transplantation might indirectly modify graft outcome by modifying cytokine production.}, }
@article {pmid10527647, year = {1999}, author = {Ventura, P and Panini, R and Pasini, MC and Scarpetta, G and Salvioli, G}, title = {N -Acetyl-cysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion.}, journal = {Pharmacological research}, volume = {40}, number = {4}, pages = {345-350}, doi = {10.1006/phrs.1999.0519}, pmid = {10527647}, issn = {1043-6618}, mesh = {Acetylcysteine/*administration &amp; dosage/blood/urine ; Aged ; Aged, 80 and over ; Cysteine/blood/*drug effects/urine ; Female ; Free Radical Scavengers/*administration &amp; dosage/blood/urine ; Homocysteine/blood/*drug effects/urine ; Humans ; Hyperhomocysteinemia/drug therapy ; Male ; Middle Aged ; }, abstract = {A decrease of plasma homocysteine (Hcy) may represent a therapeutic promise for reducing the impact of atherosclerosis. N -Acetyl-cysteine (NAC) is a thiol-containing compound interfering with endogenous thiols, cysteine (Cys) and Hcy, by forming with them mixed disulphides with a possibly more efficient renal clearance. The aim of this work was to assess the effect of NAC intravenous infusion on plasma levels of different forms of Hcy and particularly to verify the effect on Hcy renal excretion. We collected basal blood samples at 0.5, 1, 2, 5, 8 and 24 h after the beginning of NAC infusion (50 mg kg(-1)body wt.) and also 24-h urine samples of the day of NAC infusion and of the day before and of the day after the infusion in ten healthy subjects (mean age 73+/-15). Urinary and plasma thiols (Hcy, Cys and NAC) were assayed by HPLC. Both total plasma Hcy (approx. 69%vs basal values) and Cys (approx. 40%vs basal values) fell progressively, reaching a minimum 5 h after infusion start; total free (i.e. not bound to proteins) Hcy (2.2+/-1.8 down from 4.4+/-4.2 nmol ml(-1)) and Cys (70.4+/-39.8 down from 113. 3+/-61.2 nmol ml(-1)) decreased as well. Reduced (thiolic-free form) Hcy and Cys decreased during infusion, though not as pronounced as for the other forms. Percentagewise, out of the total plasma levels, Hcy and Cys total free form and reduced form tended to increase over infusion as well as their difference (i.e. the plasma mixed disulphide moiety), thus supporting the idea that excess NAC displaces thiols from their plasma binding sites forming mixed disulphides. Urinary total Cys and Hcy excretion significantly increased at the end of the day of NAC infusion (tenfold for Cys and fivefold for Hcy) and reduced appreciably on the following day. Also urinary excretion of the free form of Cys and Hcy increased at the end of the day of NAC infusion, although in a lower amount with respect of total amounts, meaning a reduction of percentage Cys and Hcy excreted as the free form; for none of the patients had proteinuria, the 'free' form of urine thiols has to be identified in the 'reduced' form, the difference between the total and free form reflecting the 'mixed disulphide' moiety. NAC intravenous administration induces an efficient and rapid reduction of plasma thiols, particularly of Hcy; our data support the hypothesis that NAC displaces thiols from their binding protein sites and forms, in excess of plasma NAC, mixed disulphides (NAC-Hcy) with an high renal clearance. This effect may represent the start of an alternative approach in the treatment of hyperhomocysteinaemic conditions.}, }
@article {pmid10526120, year = {1999}, author = {Martínez Banaclocha, M and Martínez, N}, title = {N-acetylcysteine elicited increase in cytochrome c oxidase activity in mice synaptic mitochondria.}, journal = {Brain research}, volume = {842}, number = {1}, pages = {249-251}, doi = {10.1016/s0006-8993(99)01819-3}, pmid = {10526120}, issn = {0006-8993}, mesh = {Acetylcysteine/*pharmacology ; Aging/metabolism ; Animals ; Electron Transport Complex IV/*metabolism ; Male ; Mice ; Mitochondria/drug effects/*enzymology ; Oxidative Phosphorylation/drug effects ; Synapses/drug effects/*enzymology ; }, abstract = {It has been suggested that thiolic groups are essential for cytochrome c oxidase (COX) activity and other respiratory mitochondrial enzymes. Recent experiments showed that the thiolic antioxidant N-acetylcysteine (NAC) can protect against age-related impairment in COX activity in mice hepatic mitochondria. The present paper shows that NAC enhances COX activity in vitro in synaptic mitochondria isolated from young and old mice. The optimum NAC concentration for maximum COX activity was 5 mM in young and 10 mM in old synaptic preparations. Our data suggest that mitochondrial thiolic groups, which are essentials to oxidative phosphorylation, are impaired by aging.}, }
@article {pmid10525424, year = {1999}, author = {Tejero-Taldo, MI and Caffrey, JL and Sun, J and Mallet, RT}, title = {Antioxidant properties of pyruvate mediate its potentiation of beta-adrenergic inotropism in stunned myocardium.}, journal = {Journal of molecular and cellular cardiology}, volume = {31}, number = {10}, pages = {1863-1872}, doi = {10.1006/jmcc.1999.1020}, pmid = {10525424}, issn = {0022-2828}, support = {HL50441/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adrenergic beta-Agonists/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Drug Synergism ; Energy Metabolism ; Glucose/metabolism ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Guinea Pigs ; Heart/*drug effects/physiology/physiopathology ; In Vitro Techniques ; Isoproterenol/*pharmacology ; Myocardial Contraction/drug effects/*physiology ; Myocardial Reperfusion ; Myocardial Stunning/*physiopathology ; Myocardium/*metabolism ; Pyruvic Acid/*pharmacology ; }, abstract = {UNLABELLED: This study tested the hypothesis that pyruvate's antioxidant actions, particularly its enhancement of the endogenous glutathione system, mediate its potentiation of beta-adrenergic inotropism in stunned myocardium. Isolated working guinea pig hearts, metabolizing 10 m M glucose and stunned by 45 min of low flow ischemia, were treated with 5 m M pyruvate, 5 m M N-acetylcysteine (NAC) and/or 2 n M isoproterenol beginning 15 min after reperfusion. The antioxidant NAC alone did not increase cardiac power (mJ/min/g wet: 11 +/- 1 in untreated and 15 +/- 2 in NAC treated stunned hearts), but NAC potentiated the increase in power produced by 2 n M isoproterenol (isoproterenol alone: 50+/-10; NAC plus isoproterenol: 133 +/- 24). Addition of NAC doubled cyclic AMP content but lowered cytosolic phosphorylation potential by 32% in isoproterenol-stimulated hearts. Stunning decreased the glutathione antioxidant ratio (GSH/GSSG) by 68%. The antioxidant ratio was completely restored by pyruvate alone or in combination with isoproterenol, but only partially restored by isoproterenol alone. Combining isoproterenol and NAC increased the GSH/GSSG ratio by an additional 36%. The combined treatment of pyruvate and isoproterenol increased the NADPH/NADP(+) ratio almost three-fold, and produced the greatest accumulation of glucose-6-phosphate of any treatment.<br><br>CONCLUSIONS: like pyruvate, the antioxidant NAC potentiated beta-adrenergic inotropism of stunned myocardium. Unlike pyruvate, NAC did not increase cellular energy reserves, thus effectively limiting its potentiation of beta-adrenergic stimulation. Thus, pyruvate's potentiation of beta-adrenergic stimulation in stunned myocardium is most likely the result of the combined effects of its antioxidant and energetic properties.}, }
@article {pmid10517313, year = {1999}, author = {Look, MP and Gerard, A and Rao, GS and Sudhop, T and Fischer, HP and Sauerbruch, T and Spengler, U}, title = {Interferon/antioxidant combination therapy for chronic hepatitis C--a controlled pilot trial.}, journal = {Antiviral research}, volume = {43}, number = {2}, pages = {113-122}, doi = {10.1016/s0166-3542(99)00041-8}, pmid = {10517313}, issn = {0166-3542}, mesh = {Acetylcysteine/therapeutic use ; Adult ; Antioxidants/*therapeutic use ; Drug Therapy, Combination ; Female ; Glutathione/blood ; Hepacivirus/genetics/isolation &amp; purification ; Hepatitis C, Chronic/*drug therapy/virology ; Humans ; Interferon alpha-2 ; Interferon-alpha/*therapeutic use ; Male ; Middle Aged ; Oxidative Stress ; Peroxidase/blood ; Pilot Projects ; RNA, Viral/blood ; Recombinant Proteins ; Sodium Selenite/blood/therapeutic use ; Thiobarbituric Acid Reactive Substances/analysis ; Treatment Outcome ; Vitamin E/blood/therapeutic use ; }, abstract = {The effects of two forms of antioxidative co-therapy were analyzed in 24 interferon-alpha (IFN)-naive patients with chronic hepatitis C who were randomized to either receive IFN monotherapy (3 x 4.5 million units IFN-alpha 2a per week), (group A), or IFN and N-acetylcysteine (N-acetylcysteine (NAC) 1.800 mg/day) plus sodium selenite (400 microg/day) supplementation (group B), or treatment as in group B plus vitamin E (544 IU/day) (group C), over 24 weeks. Changes in histology, normalization of ALT, reduction of viral RNA, serum levels of glutathione, selenium, vitamin E, erythrocyte glutathione peroxidase, trolox equivalent antioxidative capacity (TEAC), thiobarbituric acid reactive substances (TBARS) and protein carbonyl groups were measured. Low baseline TEAC and elevated TBARS indicated increased oxidative stress before therapy, which was not affected by antioxidant supplementation. At the end of treatment complete responses were found in 3/8, 2/8 and 6/8 patients in groups A, B and C, respectively, but liver histology had not significantly improved. Vitamin E treated patients had a 2.4 greater chance (95% CI: 1.05-5.5) of obtaining a complete response and had significantly greater reduction in viral load (P = 0.028) than patients without vitamin E. Relapses, i.e. re-appearance of detectable hepatitis C virus (HCV) RNA and/or re-elevation of ALT-activity occurred in 7 out of the 11 responders within 6 months after termination of therapy (group A: 2/3, group B: 1/2 and group C: 4/6). Thus, no overall beneficial effect of antioxidant/IFN therapy was detected. However, the apparent trend towards a more favorable outcome with vitamin E supplementation warrants to further study this substance as an adjuvant to IFN therapy in chronic hepatitis C.}, }
@article {pmid10513606, year = {1999}, author = {Cheng, JJ and Wung, BS and Chao, YJ and Hsieh, HJ and Wang, DL}, title = {Cyclic strain induces redox changes in endothelial cells.}, journal = {The Chinese journal of physiology}, volume = {42}, number = {2}, pages = {103-111}, pmid = {10513606}, issn = {0304-4920}, mesh = {Cells, Cultured ; Endothelium, Vascular/cytology/enzymology/*metabolism ; Gene Expression Regulation/physiology ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Glutathione Peroxidase/metabolism ; Heme Oxygenase (Decyclizing)/genetics ; Heme Oxygenase-1 ; Humans ; Intracellular Membranes/metabolism ; Lipid Peroxides/biosynthesis ; Membrane Proteins ; Oxidation-Reduction ; Periodicity ; Reactive Oxygen Species/metabolism ; Stress, Mechanical ; Superoxide Dismutase/metabolism ; Transcriptional Activation ; }, abstract = {Our previous studies have shown that cyclic strain to endothelial cells (ECs) increases reactive oxygen species (ROS) that act as second messengers. The potential impact of these enhanced ROS levels on ECs was examined by studying the antioxidant activities and heme oxygenase-1 (HO-1) expression in strained ECs. Cyclic strain to ECs increased lipid peroxidation and augmented oxidation of low-density lipoproteins. ECs subjected to strain increased their superoxide dismutase activities. Concomitantly, glutathione peroxidase activities increased in 3 to 6 hr and returned to basal level 24 hr after continuous cyclic strain treatment. A decrease of glutathione (GSH) was accompanied with an increase of oxidized glutathione (GSSH) level in ECs 3 to 6 hr after strain treatment. This was followed with a return of both GSH and GSSH to basal levels in 24 hr. Consistently, H2O2 treatment of ECs decreased the GSH/GSSG ratio. ECs pretreated with catalase abolished the strain-induced change in GSH/GSSG. Strain treatment, similar to H2O2 exposure, induced HO-1 expression in a time-dependent manner. This induction was inhibited after treating ECs with catalase or free radical scavenger. ECs treated with N-acetyl-cysteine abolished HO-1 gene induction. Our results suggest that cyclic strain-induced ROS cause a transient increase of glutathione peroxidase activity that results in a decrease of GSH level in ECs and that this decrease is crucial to HO-1 induction.}, }
@article {pmid10508890, year = {1999}, author = {Yildiz, D and Liu, YS and Ercal, N and Armstrong, DW}, title = {Comparison of pure nicotine- and smokeless tobacco extract-induced toxicities and oxidative stress.}, journal = {Archives of environmental contamination and toxicology}, volume = {37}, number = {4}, pages = {434-439}, doi = {10.1007/s002449900537}, pmid = {10508890}, issn = {0090-4341}, mesh = {3,4-Methylenedioxyamphetamine/metabolism ; Acetylcysteine/metabolism ; Animals ; CHO Cells ; Catalase/metabolism ; Cell Survival/drug effects ; Cricetinae ; Glutathione/metabolism ; L-Lactate Dehydrogenase/metabolism ; Nicotine/*toxicity ; Oxidative Stress/*drug effects ; Plant Extracts/toxicity ; *Plants, Toxic ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/metabolism ; Tobacco, Smokeless/*toxicity ; }, abstract = {The toxicities and oxidative stress-inducing actions of (-)-nicotine and smokeless tobacco extract (STE), containing equivalent amounts of nicotine, were studied. Toxicities were determined by colony formation assays using Chinese hamster ovary (CHO) cells. Results indicated that nicotine is less toxic than smokeless tobacco extract that contained the same amount of nicotine. The generation of reactive oxygen species, following treatment with smokeless tobacco extract and nicotine, was assessed by measurement of changes in glutathione (GSH) and malondialdehyde (MDA) levels. CHO cells (5 x 10(5) cells/5 ml media) were incubated with 4, 0.8, and 0.08 mg of nicotine and STE containing the same amounts of nicotine. All preparations of smokeless tobacco extract significantly decreased GSH levels and increased MDA generation. However, 0.08 mg of nicotine treatment did not result in a significant change in GSH level, and only 4 mg of nicotine were sufficient to increase MDA generation. Addition of free radical scavenging enzymes, superoxide dismutase (SOD) and catalase (CAT), and an intracellular GSH precursor, N-acetyl-L-cysteine (NAC), replenished the GSH levels in nicotine-treated cells. GSH levels in cells exposed to smokeless tobacco extract containing 4 and 0.8 mg nicotine remained significantly lower than the control with the addition of SOD and CAT. However, co-addition of NAC with smokeless tobacco extract preparations returned the GSH levels to the control level. Lactate dehydrogenase (LDH) activities were measured in the media to establish the membrane damage following exposure to smokeless tobacco extract and nicotine. Treatment of cells with 4 mg nicotine caused a significant increase in LDH activity, which was returned to control level in the presence of the antioxidant enzymes and NAC. Smokeless tobacco extract did not change the LDH activity. http://link.springer-ny. com/link/service/journals/00244/bibs/37n4p434.html</++ +HEA}, }
@article {pmid10506589, year = {1999}, author = {Ho, E and Chen, G and Bray, TM}, title = {Supplementation of N-acetylcysteine inhibits NFkappaB activation and protects against alloxan-induced diabetes in CD-1 mice.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {13}, number = {13}, pages = {1845-1854}, pmid = {10506589}, issn = {0892-6638}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Alloxan/*pharmacology ; Animals ; Blood Glucose/analysis ; Cyclic N-Oxides ; Diabetes Mellitus, Experimental/*prevention &amp; control ; Diabetes Mellitus, Type 1/*etiology ; Dose-Response Relationship, Drug ; Electron Spin Resonance Spectroscopy ; Free Radicals ; Glutathione/pharmacology ; Male ; Mice ; NF-kappa B/*metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/analysis ; Nitric Oxide Synthase Type II ; Nitrogen Oxides/pharmacology ; Pancreas/*drug effects/enzymology/metabolism ; }, abstract = {Reactive oxygen species (ROS) are involved in the destruction of pancreatic beta cells and the development of insulin-dependent diabetes mellitus (IDDM). However, the cellular mechanism responsible for beta cell death is still unclear. We hypothesize that activation of NFkappaB by ROS is the key cellular signal in initiating a cascade of events leading to beta cell death. Thus, enhancement of pancreatic GSH, a known antioxidant and key regulator of NF-kappaB, should protect against IDDM. Weanling CD1 mice (n=5) were injected with alloxan (50 mg/kg i.v.) to induce IDDM. Using EPR spin trapping techniques, we demonstrated that alloxan generated ROS in the pancreas 15 min after administration. Activation of NFkappaB in pancreatic nuclear extracts was observed 30 min after alloxan injection, as assessed by an electrophoretic mobility shift assay. Fasting blood glucose levels were monitored for 14 days. Supplementation with N-acetylcysteine (NAC, 500 mg/kg), a GSH precursor, inhibited alloxan-induced NFkappaB activation and reduced hyperglycemia. Thus, NFkappaB activation by ROS may initiate a sequence of events leading to IDDM. Inhibition of NF-kappaB activation by NAC attenuated the severity of IDDM. This research will contribute to the understanding of the etiology of IDDM and may lead to the development of better strategies for disease prevention.}, }
@article {pmid10506578, year = {1999}, author = {Thévenod, F and Friedmann, JM}, title = {Cadmium-mediated oxidative stress in kidney proximal tubule cells induces degradation of Na+/K(+)-ATPase through proteasomal and endo-/lysosomal proteolytic pathways.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {13}, number = {13}, pages = {1751-1761}, doi = {10.1096/fasebj.13.13.1751}, pmid = {10506578}, issn = {0892-6638}, mesh = {Ammonium Chloride/pharmacology ; Animals ; Biological Transport ; Cadmium/*toxicity ; Cell Line ; Cell Membrane/enzymology ; Chloroquine/pharmacology ; Cysteine Endopeptidases ; Endosomes ; Enzyme Stability ; Kidney Tubules, Proximal/cytology/*drug effects ; Leupeptins/pharmacology ; Lysosomes ; Models, Biological ; Multienzyme Complexes ; Oxidative Stress/*physiology ; Proteasome Endopeptidase Complex ; Rats ; Rats, Inbred WKY ; Reactive Oxygen Species/metabolism ; Serine Proteinase Inhibitors/pharmacology ; Sodium-Potassium-Exchanging ATPase/*metabolism ; Ubiquitins/metabolism ; }, abstract = {The mechanisms of cadmium (Cd)-dependent nephrotoxicity were studied in a rat proximal tubule (PT) cell line. CdCl(2) (5 microM) increased the production of reactive oxygen species (ROS), as determined by oxidation of dihydrorhodamine 123 to fluorescent rhodamine 123. The levels of ubiquitin-conjugated cellular proteins were increased by Cd in a time-dependent fashion (maximum at 24-48 h). This was prevented by coincubation with the thiol antioxidant N-acetylcysteine (NAC, 15 mM). Cd also increased apoptosis (controls: 2.4+/-1.6%; Cd: 8.1+/-1.9%), but not necrosis (controls: 0.5 +/- 0.3%; Cd: 1.4+/- 2.5%). Exposure of PT cells with Cd decreased protein levels of the catalytic subunit (alpha1) of Na+/K(+)-ATPase, a long-lived membrane protein (t(1/2)>48 h) that drives reabsorption of ions and nutrients through Na(+)-dependent transporters in PT. Incubation of PT cells for 48 h with Cd decreased Na+/K(+)-ATPase alpha1-subunit, as determined by immunoblotting, by approximately 50%, and NAC largely prevented this effect. Inhibitors of the proteasome such as MG-132 (20 microM) or lactacystin (10 microM), as well as lysosomotropic weak bases such as chloroquine (0.2 mM) or NH(4)Cl (30 mM), significantly reduced the decrease of Na(+)/K(+)-ATPase alpha1-subunit induced by Cd, and in combination abolished the effect of Cd on Na+/K(+)-ATPase. Immunofluorescence labeling of Na+/K(+)-ATPase showed a reduced expression of the protein in the plasma membrane of Cd-exposed cells. After addition of lactacystin and chloroquine to Cd-exposed PT cells, immunoreactive material accumulated into intracellular vesicles. The data indicate that micromolar concentrations of Cd can increase ROS production and exert a toxic effect on PT cells. Oxidative damage increases the degradation of Na+/K(+)-ATPase through both the proteasomal and endo-/lysosomal proteolytic pathways. Degradation of oxidatively damaged Na+/K(+)-ATPase may contribute to the 'Fanconi syndrome'-like Na(+)-dependent transport defects associated with Cd-nephrotoxicity.}, }
@article {pmid10506163, year = {1999}, author = {Sun, H and Li, H and Harvey, I and Sadler, PJ}, title = {Interactions of bismuth complexes with metallothionein(II).}, journal = {The Journal of biological chemistry}, volume = {274}, number = {41}, pages = {29094-29101}, doi = {10.1074/jbc.274.41.29094}, pmid = {10506163}, issn = {0021-9258}, mesh = {Acetylcysteine/chemistry ; Animals ; Anti-Ulcer Agents/*chemistry ; Binding, Competitive ; Bismuth/*chemistry ; Cadmium/chemistry ; Glutathione/chemistry ; Kinetics ; Magnetic Resonance Spectroscopy ; Metallothionein/*chemistry ; Organometallic Compounds/chemistry ; Protein Binding ; Rabbits ; Spectrum Analysis ; Zinc/chemistry ; }, abstract = {Bismuth complexes are widely used as anti-ulcer drugs and can significantly reduce the side effects of platinum anti-cancer drugs. Bismuth is known to induce the synthesis of metallothionein (MT) in the kidney, but there are few chemical studies on the interactions of bismuth complexes with metallothionein. Here we show that Bi(3+) binds strongly to metallothionein with a stoichiometry bismuth:MT = 7:1 (Bi(7)MT) and can readily displace Zn(2+) and Cd(2+). Bismuth is still bound to the protein even in strongly acidic solutions (pH 1). Reactions of bismuth citrate with MT are faster than those of [Bi(EDTA)](-), and both exhibit biphasic kinetics. (1)H NMR data show that Zn(2+) is displaced faster than Cd(2+), and that both Zn(2+) and Cd(2+) in the beta-domain (three metal cluster) of MT are displaced by Bi(3+) much faster than from the alpha-domain (four metal cluster). The extended x-ray absorption fine structure spectrum of Bi(7)MT is very similar to that for the glutathione and N-acetyl-L-cysteine complexes [Bi(GS)(3)] and [Bi(NAC)(3)] with an inner coordination sphere of three sulfur atoms and average Bi-S distances of 2.55 A. Some sites appear to contain additional short Bi-O bonds of 2.2 A and longer Bi-S bonds of 3.1 A. The Bi(3+) sites in Bi(7)MT are therefore highly distorted in comparison with those of Zn(2+) and Cd(2+).}, }
@article {pmid10502497, year = {1999}, author = {Latour, I and De Ros, E and Denef, JF and Buc Calderon, P}, title = {Protein S-thiolation can mediate the inhibition of protein synthesis induced by tert-butyl hydroperoxide in isolated rat hepatocytes.}, journal = {Toxicology and applied pharmacology}, volume = {160}, number = {1}, pages = {1-9}, doi = {10.1006/taap.1999.8757}, pmid = {10502497}, issn = {0041-008X}, mesh = {Animals ; Cell Membrane/drug effects ; Glutathione/metabolism/pharmacology ; Glutathione Disulfide/metabolism ; Liver/cytology/*drug effects/metabolism ; Male ; Oxidative Stress ; Protein Synthesis Inhibitors/*pharmacology ; Proteins/*metabolism ; Rats ; Rats, Wistar ; Sulfhydryl Compounds/*metabolism ; tert-Butylhydroperoxide/*pharmacology ; }, abstract = {A rapid inhibition of protein synthesis is observed when isolated rat hepatocytes are incubated in the presence of 0.25-0.5 mM of tert-butyl hydroperoxide (tBOOH). Such an inhibition occurs in the absence of a cytolytic effect by tBOOH. Iron chelators (o-phenanthroline and desferrioxiamine), protected against oxidative cell death, but they did not modify the inhibition of protein synthesis caused by tBOOH (0.5 mM), suggesting that free radicals are less implicated in such an impairment. Electron micrographs of hepatocytes under oxidative stress show disaggregation of polyribosomes but not oxidative alterations, such as blebs or mitochondrial swelling. Protein synthesis inhibition is accompanied by a decrease in reduced glutathione (GSH) and an increase in glutathione disulfide (GSSG) and the level of protein S-thiolation (protein mixed disulfides formation). Such an increase of GSSG appears as a critical event since diethylmaleate (DEM) at 0.2 mM reduced GSH content by more than 50% but did not affect either GSSG content or protein synthesis. The addition of exogenous GSH and N-acetylcysteine (NAC) to tBOOH-treated hepatocytes significantly reduced the formation of protein mixed disulfides and restored the depressed protein synthesis either completely or partially. We suggest that S-thiolation of some key proteins may be involved in protein synthesis inhibition by tBOOH.}, }
@article {pmid10498608, year = {1999}, author = {Wedi, B and Straede, J and Wieland, B and Kapp, A}, title = {Eosinophil apoptosis is mediated by stimulators of cellular oxidative metabolisms and inhibited by antioxidants: involvement of a thiol-sensitive redox regulation in eosinophil cell death.}, journal = {Blood}, volume = {94}, number = {7}, pages = {2365-2373}, pmid = {10498608}, issn = {0006-4971}, mesh = {Acetylcysteine/pharmacology ; Antibodies, Monoclonal/pharmacology ; Antigens, CD/immunology/physiology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/physiology ; Arsenites/pharmacology ; Cell Death/drug effects ; Cell Survival ; Cells, Cultured ; Dimethyl Sulfoxide/pharmacology ; Eosinophils/*cytology/drug effects/*physiology ; Glutathione/pharmacology ; Humans ; Interleukin-3/pharmacology ; Kinetics ; Luminescent Measurements ; Oxidants/*pharmacology ; Oxidation-Reduction ; Sodium Compounds/pharmacology ; Taurine/pharmacology ; fas Receptor/immunology/physiology ; }, abstract = {The mechanisms for induction of eosinophil apoptosis remain uncertain. The role of oxidative stress has not been investigated. The present study was undertaken to determine the role of reactive oxygen species (ROS) and selective antioxidants in eosinophil apoptosis. Eosinophils were cultured with sodium arsenite (SA) known to induce intracellular oxidative metabolites. There was a significant increase in the rate of eosinophil apoptosis with low concentrations of arsenite, whereas high concentrations showed rates of apoptosis similar to control medium. Investigating the role of intracellular oxidants by flow cytometry, we found that while inducing apoptosis, SA more than anti-Fas resulted in a significant dose-dependent production of intracellular H(2)O(2). In contrast, the extracellular release of superoxide decreased after stimulation with SA or anti-Fas as assessed by lucigenin-dependent chemiluminescence. Coincubation experiments demonstrated that arsenite-induced apoptosis can be nearly completely prevented by selective antioxidants such as glutathione (GSH) and N-acetyl-cysteine (NAC), but not dimethyl sulfoxide (DMSO) or taurine (TAUR). Moreover, GSH and NAC significantly reduced eosinophil apoptosis mediated by a monoclonal antibody directed to Fas antigen. Next it was shown that GSH and NAC, but not DMSO or TAUR, were able to significantly delay spontaneous apoptosis in unstimulated eosinophils. Taken together, these data point to an important role of oxygen-dependent mechanisms in the regulation of eosinophil survival and apoptosis. We propose that eosinophil apoptosis may be related to the ability of the cell to maintain an appropriate oxidant-antioxidant balance.}, }
@article {pmid10497373, year = {1999}, author = {Konstan, MW and Butler, SM and Schidlow, DV and Morgan, WJ and Julius, JR and Johnson, CA}, title = {Patterns of medical practice in cystic fibrosis: part II. Use of therapies. Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis.}, journal = {Pediatric pulmonology}, volume = {28}, number = {4}, pages = {248-254}, doi = {10.1002/(sici)1099-0496(199910)28:4&lt;248::aid-ppul3&gt;3.0.co;2-n}, pmid = {10497373}, issn = {8755-6863}, mesh = {Adolescent ; Adrenal Cortex Hormones/therapeutic use ; Adult ; Anti-Bacterial Agents/therapeutic use ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Child ; Child, Preschool ; Combined Modality Therapy ; Cystic Fibrosis/diagnosis/*therapy ; Drainage, Postural/methods ; Evaluation Studies as Topic ; Female ; Humans ; Male ; Nutritional Physiological Phenomena ; Patient Care/*standards/statistics &amp; numerical data ; *Practice Patterns, Physicians' ; Prognosis ; Respiratory Function Tests ; Sampling Studies ; }, abstract = {This report describes the prescribing pattern of therapeutic interventions in the management of patients with cystic fibrosis (CF), as observed in the Epidemiologic Study of Cystic Fibrosis (ESCF). Use of 20 therapies by 12,622 patients was recorded from each health care encounter (53,024 outpatient visits and 8,561 hospitalizations) during a 1-year period (1995), and analyzed by gender, age, severity of lung disease, and presence of any Pseudomonas species in the respiratory tract. The percentage of patients using the following pulmonary therapies was observed (in descending order): airway clearance techniques (88.2%); inhaled bronchodilators (82.2%); oral antibiotics (excluding quinolones) (68. 2%); dornase alfa (52.9%); intravenous antibiotics (34.4%); oral quinolones (34.4%); inhaled antibiotics (34.3%); mast cell stabilizers (29.5%); inhaled corticosteroids (25.9%); oral corticosteroids (17.1%); oral bronchodilators (16.2%); oxygen (8. 1%); inhaled mucolytic agent acetyl cysteine (6.5%); and diuretics (1.4%). The percentage of patients using nutritional therapies was: pancreatic enzymes (96%); oral nutritional supplements (31.1%); enteral nutrition (7.3%); and parenteral nutrition (0.7%). The percentage of patients using other therapies was: nonsteroidal anti-inflammatory drugs (7.9%); and insulin or oral hypoglycemic agents (6.1%). The general trend was for therapies to be used more by older patients, those with lower pulmonary function, and by those with Pseudomonas in their respiratory tract. Exceptions to this trend occurred for airway clearance, oral antibiotics, mast cell stabilizers, and pancreatic enzymes. Four therapies (oral nutritional supplements, parenteral nutrition, diuretics, and pancreatic enzymes) were used more by males than females. However, there was no gender difference for this group of therapies on pulmonary or nutritional status.}, }
@article {pmid10496534, year = {1999}, author = {Cai, T and Fassina, G and Morini, M and Aluigi, MG and Masiello, L and Fontanini, G and D'Agostini, F and De Flora, S and Noonan, DM and Albini, A}, title = {N-acetylcysteine inhibits endothelial cell invasion and angiogenesis.}, journal = {Laboratory investigation; a journal of technical methods and pathology}, volume = {79}, number = {9}, pages = {1151-1159}, pmid = {10496534}, issn = {0023-6837}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Chemoprevention ; Endothelium, Vascular/*drug effects/pathology ; Gelatinases/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Invasiveness ; *Neovascularization, Pathologic ; }, abstract = {The thiol N-acetylcysteine (NAC) is a chemopreventive agent that acts through a variety of mechanisms and can prevent in vivo carcinogenesis. We have previously shown that NAC inhibits invasion and metastasis of malignant cells as well as tumor take. Neovascularization is critical for tumor mass expansion and metastasis formation. We investigated whether a target of the anti-cancer activity of NAC could be the inhibition of the tumor angiogenesis-associated phenotype in vitro and in vivo using the potent angiogenic mixture of Kaposi's sarcoma cell products as a stimulus. Two endothelial (EAhy926 and human umbilical vein endothelial [HUVE]) cell lines were utilized in a panel of assays to test NAC ability in inhibiting chemotaxis, invasion, and gelatinolytic activity in vitro. NAC treatment of EAhy926 and HUVE cells in vitro dose-dependently reduced their ability to invade a reconstituted basement membrane, an indicator of endothelial cell activation. Invasion of HUVE cells was inhibited with an ID50 of 0.24 mM NAC, whereas inhibition of chemotaxis required a 10 fold higher doses, indicating that invasion is a preferential target. NAC inhibited the enzymatic activity and conversion to active forms of the gelatinase produced by endothelial cells. The matrigel in vivo assay was used for the evaluation of angiogenesis; NAC strongly inhibited neovascularization of the matrigel sponges in response to Kaposi's sarcoma cell products. NAC prevented angiogenesis while preserving endothelial cells, implying that it could be safely used as an anti-angiogenic treatment.}, }
@article {pmid10494766, year = {1999}, author = {Sarker, KP and Abeyama, K and Nishi, J and Nakata, M and Tokioka, T and Nakajima, T and Kitajima, I and Maruyama, I}, title = {Inhibition of thrombin-induced neuronal cell death by recombinant thrombomodulin and E5510, a synthetic thrombin receptor signaling inhibitor.}, journal = {Thrombosis and haemostasis}, volume = {82}, number = {3}, pages = {1071-1077}, pmid = {10494766}, issn = {0340-6245}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Sequence ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects/physiology ; Cell Line ; Fatty Acids, Monounsaturated/*pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Mice ; Neurons/*cytology/*drug effects/physiology ; Peptide Fragments/chemistry/pharmacology ; Receptors, Thrombin/agonists/drug effects ; Recombinant Proteins/pharmacology ; Signal Transduction/drug effects ; Thrombin/*antagonists &amp; inhibitors/*pharmacology/physiology ; Thrombomodulin/*physiology ; }, abstract = {Thrombin, a serine protease generated by the activation of the blood coagulation cascade following vessel injury, converts fibrinogen to fibrin, activates platelets and several coagulation factors, and plays a pivotal role in thrombosis and haemostasis. Thrombin acts as a mitogen and apoptosis inducer in a dose-dependent fashion. We have previously shown that thrombin caused proliferation of vascular smooth muscle cells (VSMCs). Here, we show that a low concentration of thrombin caused proliferation of mouse neuroblastoma (Neuro-2a) and human neuroblastoma (NB-1) cells, while higher concentrations affected cell viability in a time-dependent manner. Similar effects were observed when thrombin receptor agonist peptide (SFLLRNPNDKYEPF, TRAP) was applied. The dying cells showed nuclear condensation and fragmentation, suggesting that cell death occurred by apoptosis. The extent to which thrombin induced cell death was significantly attenuated by recombinant thrombomodulin (rTM), or by a minimum functional domain of TM, termed E456. Furthermore, a synthetic compound that inhibits signaling from the thrombin receptor, 4-cyano-5,5-bis (4-methoxyphenyl)-4-pentanoic acid (E5510), and the antioxidant N-acetyl L-cysteine (NAC), efficiently prevented thrombin-induced Neuro-2a cell death. Thus, thrombin inhibitors and antioxidant appear to neutralize thrombin toxicity.}, }
@article {pmid10490916, year = {1999}, author = {Lai, WG and Zahid, N and Uetrecht, JP}, title = {Metabolism of trimethoprim to a reactive iminoquinone methide by activated human neutrophils and hepatic microsomes.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {291}, number = {1}, pages = {292-299}, pmid = {10490916}, issn = {0022-3565}, mesh = {Acetylcysteine/pharmacology ; Animals ; Drug Interactions ; Free Radical Scavengers/pharmacology ; Humans ; Hypochlorous Acid/pharmacology ; In Vitro Techniques ; Magnetic Resonance Spectroscopy ; Male ; Microsomes, Liver/*metabolism ; Neutrophils/drug effects/*metabolism ; Oxidation-Reduction ; Peroxidase/metabolism ; Quinones/metabolism ; Rats ; Rats, Sprague-Dawley ; Trimethoprim/*metabolism/pharmacology ; Tritium ; }, abstract = {The antibacterial agent, trimethoprim, is normally used synergistically with sulfonamides. Its use is associated with idiosyncratic reactions including liver toxicity and agranulocytosis. In this study, we demonstrated that trimethoprim was oxidized by activated human neutrophils, as well as a combination of myeloperoxidase/hydrogen peroxide/chloride or hypochlorous acid, to a reactive pyrimidine iminoquinone methide intermediate with a protonated molecular ion of m/z 289 as detected by mass spectrometry. In the presence of N-acetyl-L-cysteine (NAC), the pyrimidine iminoquinone methide could be trapped as three NAC adducts. The three NAC adducts were separable on HPLC, but showed the same protonated molecular ion of m/z 452. The proton NMR spectrum of the major adduct showed that the NAC group was at the 6 position of the pyrimidine ring. The mass spectra of the two minor NAC adducts indicated that they were the two diastereomers in which NAC was attached to the exo-cyclic prechiral carbon of the pyrimidine iminoquinone methide. Incubation of trimethoprim with isolated hepatic microsomes, both human and rat, in presence of NAC gave the same set of trimethoprim-NAC adducts. We propose that the formation of this pyrimidine iminoquinone methide by both hepatic microsomes and neutrophils may be responsible for trimethoprim-induced idiosyncratic hepatotoxicity and agranulocytosis.}, }
@article {pmid10490237, year = {1999}, author = {Ginsburg, I and Sadovnic, M and Varani, J and Tirosh, O and Kohen, R}, title = {Hemolysis of human red blood cells induced by the combination of diethyldithiocarbamate (DDC) and divalent metals: modulation by anaerobiosis, certain antioxidants and oxidants.}, journal = {Free radical research}, volume = {31}, number = {2}, pages = {79-91}, doi = {10.1080/10715769900301591}, pmid = {10490237}, issn = {1071-5762}, support = {CA60958/CA/NCI NIH HHS/United States ; }, mesh = {Anaerobiosis ; Antioxidants/*pharmacology ; Cations, Divalent ; Cobalt/pharmacology ; Copper/pharmacology ; Ditiocarb/*pharmacology ; Erythrocytes/*drug effects ; Hemolysis/*drug effects ; Humans ; Hydrogen Peroxide/metabolism ; Metals/*pharmacology ; Oxidants/*pharmacology ; Spectrophotometry ; Temperature ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The objective of the present communication is to describe the role played by combinations between diethydithiocarbamate (DDC) and divalent metals in hemolysis of human RBC. RBC which had been treated with DDC (10-50 microM) were moderately hemolyzed (about 50%) upon the addition of subtoxic amounts of Cu2+ (50 microM). However, a much stronger and a faster hemolysis occurred either if mixtures of RBC-DDC were immediately treated either by Co2+ (50 microM) or by a premixture of Cu2+ and Co2+ (Cu:Co) (50 microM). While Fe2+ and Ni2+, at 50 microM, initiated 30-50% hemolysis when combined with DDC (50 microM), on a molar basis, Cd2+ was at least 50 fold more efficient than any of the other metals in the initiation of hemolysis by DDC. On the other hand, neither Mn2+ nor Zn2+, had any hemolysis-initiating effects. Co2+ was the only metal which totally blocked hemolysis if added to DDC prior to the addition of the other metals. Hemolysis by mixtures of DDC + (Cu:Co) was strongly inhibited by anaerobiosis (flushing with nitrogen gas), by the reducing agents glutathione, N-acetyl cysteine, mercaptosuccinate, ascorbate, TEMPO, and alpha-tocopherol, by the PLA2 inhibitorbromophenacylbromide (BrPACBr), by tetracycline as well as by phosphatidyl choline, cholesterol and by trypan blue. However, TEMPO, BrPACBr and PC were the only agents which inhibited hemolysis induced by DDC: Cd2+ complexes. On the other hand, none of the classical scavengers of reactive oxygen species (ROS) employed e.g dimethylthiourea, catalase, histidine, mannitol, sodium benzoate, nor the metal chelators desferal and phenanthroline, had any appreciable inhibitory effects on hemolysis induced by DDC + (Cu:Co). DDC oxidized by H2O2 lost its capacity to act in concert either with Cu2+ or with Cd2+ to hemolyze RBC. While either heating RBC to temperatures greater than 37 degrees C or exposure of the cells to glucose-oxidase-generated peroxide diminished their susceptibility to hemolysis, exposure to the peroxyl radical from AAPH, enhanced hemolysis by DDC + (Cu:Co). The cyclovoltammetry patterns of DDC were drastically changed either by Cu2+, Co2+ or by Cd2+ suggesting a strong interaction of the metals with DDC. Also, while the absorbance spectrum of DDC at 280 nm was decreased by 50% either by Co2+, Cd2+ or by H2O2, a 90% reduction in absorbance occurred if DDC + H2O2 mixtures were treated either by Cu2+ or by Co2+, but not by Cd2+. Taken together, it is suggested that DDC-metal chelates can induce hemolysis by affecting the stability and the integrity of the RBC membrane, and possibly also of the cytoskeleton and the role played by reducing agents as inhibitors might be related to their ability to deplete oxygen which is also supported by the inhibitory effects of anaeobiosis.}, }
@article {pmid10489835, year = {1999}, author = {Gosset, P and Wallaert, B and Tonnel, AB and Fourneau, C}, title = {Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages.}, journal = {The European respiratory journal}, volume = {14}, number = {1}, pages = {98-105}, doi = {10.1034/j.1399-3003.1999.14a17.x}, pmid = {10489835}, issn = {0903-1936}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antimetabolites/*pharmacology ; Antioxidants/pharmacology ; Buthionine Sulfoximine/*pharmacology ; Cells, Cultured ; DNA Primers/chemistry ; Female ; Glutathione/metabolism/pharmacology ; Humans ; Interleukin-6/*biosynthesis/genetics ; Interleukin-8/*biosynthesis/genetics ; Intracellular Fluid/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages, Alveolar/drug effects/*metabolism ; Male ; Polymerase Chain Reaction ; RNA, Messenger/biosynthesis/*genetics ; Tumor Necrosis Factor-alpha/*biosynthesis/genetics ; }, abstract = {Reactive oxygen intermediates exert signalling functions and modulate gene transcription, particularly for pro-inflammatory cytokines. Since exogenous as well as endogenous thiols could be potent inhibitors of the production of cytokines, the effects of N-acetylcysteine (NAC), glutathione (GSH) and modulated GSH synthesis on the production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8 by human alveolar macrophages (AMs) was evaluated, as well as the potential role of intracellular GSH depletion on the effect of exogenous thiols. AMs were stimulated with lipopolysaccharide (LPS) and cytokine production was measured by evaluating messenger ribonucleic acid (mRNA) expression and protein secretion. Depletion of intracellular GSH by treatment with buthionine sulphoximine (BSO) reached 45.2% after 3 h and was nearly complete at 24 h. Whereas a 24-h preincubation of AMs with BSO significantly increased LPS-induced secretion of TNF-alpha and IL-8, a 3-h preincubation only enhanced LPS-stimulated production of IL-8 (p<0.05). Treatment with NAC and GSH did not significantly increase intracellular content of GSH even after a 48-h incubation. Addition of GSH and NAC significantly reduced the secretion of TNF-alpha (mean+/-SEM 21.2+/-5 and 44.7+/-4.4% inhibition, respectively) as well as LPS-induced IL-6 and IL-8 (p<0.05). Similarly, NAC inhibited the production of TNF-alpha, IL-6 and IL-8 in GSH-depleted AMs obtained by BSO pretreatment. In conclusion, N-acetylcysteine and glutathione inhibit the production of tumour necrosis factor-alpha, interleukin-8 and interleukin-6 by alveolar macrophages by a mechanism independent of glutathione metabolism. However, total depletion of glutathione within alveolar macrophages significantly increases tumour necrosis factor-alpha and interleukin-8 synthesis whereas it does not modulate interleukin-6 secretion.}, }
@article {pmid10486756, year = {1999}, author = {Jaworska, M and Szulińska, G and Wilk, M and Tautt, J}, title = {Capillary electrophoretic separation of N-acetylcysteine and its impurities as a method for quality control of pharmaceuticals.}, journal = {Journal of chromatography. A}, volume = {853}, number = {1-2}, pages = {479-485}, doi = {10.1016/s0021-9673(99)00727-x}, pmid = {10486756}, issn = {0021-9673}, mesh = {Acetylcysteine/*analysis/chemical synthesis ; Chromatography, High Pressure Liquid/methods ; Drug Contamination ; Drug Industry ; Electrophoresis, Capillary/*methods ; Expectorants/analysis/chemical synthesis ; Hydrogen-Ion Concentration ; Quality Control ; }, abstract = {Capillary electrophoresis has been applied to separate and determine N-acetylcysteine (NAC) and related impurities. Determination conditions were found to be optimum with 100 mmol/l borate as the buffer, pH 8.40. The limit of detection was established for each substance examined. The method has been validated by examining linearity ranges, precision and repeatability. The method was used to determine the content of NAC in, and purity of, pharmaceutical preparations. The major impurities (N,N-diacetylcystine, N,S-diacetylcysteine and cystine) were determined at levels of 0.1%.}, }
@article {pmid10486128, year = {1999}, author = {Mastrangelo, AJ and Zou, S and Hardwick, JM and Betenbaugh, MJ}, title = {Antiapoptosis chemicals prolong productive lifetimes of mammalian cells upon Sindbis virus vector infection.}, journal = {Biotechnology and bioengineering}, volume = {65}, number = {3}, pages = {298-305}, pmid = {10486128}, issn = {0006-3592}, mesh = {Animals ; Apoptosis/*drug effects ; Cell Survival/*drug effects ; Chloramphenicol O-Acetyltransferase/genetics ; Electrophoresis, Agar Gel ; *Genetic Vectors ; Male ; Prostatic Neoplasms/pathology/virology ; Rats ; Sindbis Virus/*genetics ; Tumor Cells, Cultured ; }, abstract = {Viral expression systems allow for the rapid production of large amounts of recombinant protein in cell culture. In particular, Sindbis virus vectors now exist that make possible the expression of a variety of heterologous proteins in mammalian culture systems. Unfortunately, infection of cultured cells with Sindbis virus vectors typically results in apoptotic cell death, as demonstrated in the current study by DNA laddering and fluorescence microscopy. Fortunately, it has recently been demonstrated that apoptosis can be inhibited in vitro by certain chemical reagents that are capable of blocking specific steps during the cell death cascade. In this study, a rat prostate carcinomal cell line, AT3-neo, was infected with a Sindbis virus vector containing the gene for chloramphenicol acetyltransferase (dsSV-CAT) in the presence of several representative antiapoptotic chemicals and analyzed for cell viability as well as recombinant protein production. N-acetylcysteine (NAC), pyrrolidine dithiocarbamate (PDTC), bongkrekic acid (BA), and N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD.fmk) all exhibited the capacity to limit apoptosis in the infected cells. In fact, after just 1 day, percentage viabilities of the cells exposed to chemical reagents were between 72% and 91%, compared with 44% for the untreated controls. Furthermore, cells maintained on these agents were able to survive the infection from 1 to 3 days longer than the control samples. In addition to providing gains in cell viability, chemical treatment allowed for higher levels of recombinant protein production in most cases. Maximum chloramphenicol acetyltransferase (CAT) productivities in cells maintained on BA, NAC, and Z-VAD.fmk were 1.7-, 2.2-, and 3.9-fold higher than those obtained from the untreated cultures. Consequently, the addition of chemical reagents to culture media as a means of inhibiting apoptosis may be a valuable tool in the cell culture industry, where cell death severely limits productivity levels and adds significantly to production costs.}, }
@article {pmid10485916, year = {1999}, author = {Tanaka, Y and Gleason, CE and Tran, PO and Harmon, JS and Robertson, RP}, title = {Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {96}, number = {19}, pages = {10857-10862}, pmid = {10485916}, issn = {0027-8424}, support = {R01 DK038325/DK/NIDDK NIH HHS/United States ; R56 DK038325/DK/NIDDK NIH HHS/United States ; DK 38325/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Age Factors ; Animals ; Cell Line ; Diabetes Mellitus, Type 2/*etiology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/*pharmacology ; Free Radical Scavengers/*pharmacology ; Glucose/*toxicity ; Glucose Tolerance Test ; Guanidines/*pharmacology ; *Homeodomain Proteins ; Insulin/genetics/metabolism ; Islets of Langerhans/metabolism ; Male ; Mice ; *Oxidative Stress ; Promoter Regions, Genetic ; RNA, Messenger/metabolism ; Rats ; Rats, Zucker ; Trans-Activators/metabolism ; }, abstract = {Chronic exposure of pancreatic islets to supraphysiologic concentrations of glucose causes adverse alterations in beta cell function, a phenomenon termed glucose toxicity and one that may play a secondary pathogenic role in type 2 diabetes. However, no mechanism of action has been definitively identified for glucose toxicity in beta cells. To ascertain whether chronic oxidative stress might play a role, we chronically cultured the beta cell line, HIT-T15, in medium containing 11.1 mM glucose with and without the antioxidants, N-acetyl-L-cysteine (NAC) or aminoguanidine (AG). Addition of NAC or AG to the culture medium at least partially prevented decreases in insulin mRNA, insulin gene promoter activity, DNA binding of two important insulin promoter transcription factors (PDX-1/STF-1 and RIPE-3b1 activator), insulin content, and glucose-induced insulin secretion. These findings suggested that one mechanism of glucose toxicity in the beta cell may be chronic exposure to reactive oxygen species, i.e., chronic oxidative stress. To ascertain the effects of these drugs on diabetes, NAC or AG was given to Zucker diabetic fatty rats, a laboratory model of type 2 diabetes, from 6 through 12 weeks of age. Both drugs prevented a rise in blood oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde + 4-hydroxy-2-nonenal), and partially prevented hyperglycemia, glucose intolerance, defective insulin secretion as well as decrements in beta cell insulin content, insulin gene expression, and PDX-1 (STF-1) binding to the insulin gene promoter. We conclude that chronic oxidative stress may play a role in glucose toxicity, which in turn may worsen the severity of type 2 diabetes.}, }
@article {pmid10483360, year = {1999}, author = {Bush, JA and Ho, VC and Mitchell, DL and Tron, VA and Li, G}, title = {Effect of N-acetylcysteine on UVB-induced apoptosis and DNA repair in human and mouse keratinocytes.}, journal = {Photochemistry and photobiology}, volume = {70}, number = {3}, pages = {329-333}, pmid = {10483360}, issn = {0031-8655}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects/radiation effects ; Cell Survival/drug effects/radiation effects ; Cells, Cultured ; DNA/*radiation effects ; DNA Damage ; DNA Repair/*drug effects/radiation effects ; Glutathione/metabolism ; Humans ; Keratinocytes/*drug effects/metabolism/physiology/radiation effects ; Mice ; Mice, Inbred C57BL ; *Ultraviolet Rays ; }, abstract = {The incidence of skin cancer is increasing rapidly, particularly in the Caucasian population. Epidemiological and experimental studies demonstrated that ultraviolet radiation (UVR) is the primary cause for the increasing incidence of skin cancer. It is well known that UV irradiation induces DNA damage. If the damage is not repaired or removed in time, it can lead to mutations and skin carcinogenesis. N-acetylcysteine (NAC) has been shown to be an effective protector against UVB-induced immunosuppression and to modulate the expression of some oncogenes and tumor suppressor genes. To test further the protective effect of NAC against UVR, we used both in vitro and in vivo models to investigate the effect of NAC on UVB-induced apoptosis and repair of DNA damage in human and mouse keratinocytes. Our data indicate that the intracellular glutathione level was increased after treatment with NAC at 10-20 mM but decreased with 40 mM NAC treatment due to the toxicity. At concentrations up to 20 mM NAC did not have a significant effect on UVB-induced apoptosis of cultured human keratinocytes. In addition, in an in vivo mouse model, topical application of NAC (3 mumol cm-2) that has been shown to inhibit UVB-induced immunosuppression did not have any effect on UVB-induced apoptosis and did not reduce the formation or enhance the repair of UVB-induced cyclobutane pyrimidine dimers and (6-4) photoproducts. Our results indicate that NAC is ineffective in preserving the genomic stability of keratinocytes against UVB irradiation.}, }
@article {pmid10480618, year = {1999}, author = {Jain, SK and McVie, R}, title = {Hyperketonemia can increase lipid peroxidation and lower glutathione levels in human erythrocytes in vitro and in type 1 diabetic patients.}, journal = {Diabetes}, volume = {48}, number = {9}, pages = {1850-1855}, doi = {10.2337/diabetes.48.9.1850}, pmid = {10480618}, issn = {0012-1797}, mesh = {3-Hydroxybutyric Acid/blood ; Acetoacetates/blood ; Acetone/blood ; Child ; Diabetes Mellitus, Type 1/*blood ; Erythrocytes/*metabolism ; Glutathione/*blood ; Humans ; In Vitro Techniques ; Ketone Bodies/*blood ; Lipid Peroxidation/*physiology ; Reference Values ; }, abstract = {Recent studies have suggested that elevated cellular lipid peroxidation may play a role in the development of cellular dysfunction and other complications of diabetes. People with type 1 diabetes frequently encounter elevated levels of the ketone bodies acetoacetate (AA), beta-hydroxybutyrate (BHB), and acetone (ACE). This study was undertaken to test the hypothesis that ketosis might increase lipid peroxidation and lower glutathione (GSH) levels of red blood cells (RBCs) in diabetic patients. This study demonstrates that incubation of AA with normal RBCs in phosphate-buffered saline (37 degrees C for 24 h) resulted in marked GSH depletion, oxidized glutathione accumulation, hydroxyl radical generation, and increased membrane lipid peroxidation. Increases in oxygen radicals and lipid peroxidation and depletion of GSH in RBCs were not observed with BHB or ACE treatments. Similarly, there was a significant generation of superoxide ion radicals even in a cell-free buffer solution of AA, but not in that of BHB. The presence of BHB together with AA did not influence the capacity of AA to generate oxygen radicals in a cell-free solution or the increase in lipid peroxidation of RBCs incubated with AA. The antioxidants vitamin E and N-acetylcysteine (NAC) blocked increase in lipid peroxidation in AA-treated RBCs. To examine the effects of ketone bodies in vivo, studies were performed that showed a significant decrease in GSH and an increase in lipid peroxidation levels in RBCs of hyperketonemic diabetic patients, but not in normoketonemic type 1 diabetic patients, when compared with age-matched normal subjects. This study demonstrates that elevated levels of the ketone body AA can increase lipid peroxidation and lower GSH levels of RBCs in people with type 1 diabetes.}, }
@article {pmid10477716, year = {1999}, author = {Vlahopoulos, S and Boldogh, I and Casola, A and Brasier, AR}, title = {Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation.}, journal = {Blood}, volume = {94}, number = {6}, pages = {1878-1889}, pmid = {10477716}, issn = {0006-4971}, support = {1 RO1 55630//PHS HHS/United States ; 1 RO1 AI40218/AI/NIAID NIH HHS/United States ; ES06676/ES/NIEHS NIH HHS/United States ; }, mesh = {Antioxidants/*pharmacology ; Base Sequence ; Binding Sites ; Cell Nucleus/*physiology ; DNA Primers ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation, Neoplastic/drug effects/*physiology ; Humans ; Interleukin-8/*genetics ; Kinetics ; Monocytes ; NF-kappa B/*metabolism ; Reactive Oxygen Species/*physiology ; Recombinant Proteins/biosynthesis/pharmacology ; Transcription Factor RelA ; Transfection ; Tumor Necrosis Factor-alpha/*pharmacology ; U937 Cells ; }, abstract = {Tumor necrosis factor alpha (TNFalpha) is a pluripotent activator of inflammation by inducing a proinflammatory cytokine cascade. This phenomenon is mediated, in part, through inducible expression of the CXC chemokine, interleukin-8 (IL-8). In this study, we investigate the role of TNFalpha-inducible reactive oxygen species (ROS) in IL-8 expression by "monocyte-like" U937 histiocytic lymphoma cells. TNFalpha is a rapid activator of IL-8 gene expression by U937, producing a 50-fold induction of mRNA within 1 hour of treatment. In gene transfection assays, the effect of TNFalpha requires the presence of an inducible nuclear factor-kappaB (NF-kappaB) (Rel A) binding site in the IL-8 promoter. TNFalpha treatment induces a rapid translocation of the 65 kD transcriptional activator NF-kappaB subunit, Rel A, whose binding in the nucleus occurs before changes in intracellular ROS. Pretreatment (or up to 15 minutes posttreatment) relative to TNFalpha with the antioxidant dimethyl sulfoxide (DMSO) (2% [vol/vol]) blocks 80% of NF-kappaB-dependent transcription. Surprisingly, however, DMSO has no effect on inducible Rel A binding. Similar selective effects on NF-kappaB transcription are seen with the unrelated antioxidants, N-acetylcysteine (NAC) and vitamin C. These data indicate that TNFalpha induces a delayed ROS-dependent signalling pathway that is required for NF-kappaB transcriptional activation and is separable from that required for its nuclear translocation. Further definition of this pathway will yield new insights into inflammation initiated by TNFalpha signalling.}, }
@article {pmid10475615, year = {1999}, author = {Kennedy, DO and Matsumoto, M and Kojima, A and Matsui-Yuasa, I}, title = {Cellular thiols status and cell death in the effect of green tea polyphenols in Ehrlich ascites tumor cells.}, journal = {Chemico-biological interactions}, volume = {122}, number = {1}, pages = {59-71}, doi = {10.1016/s0009-2797(99)00114-3}, pmid = {10475615}, issn = {0009-2797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carcinoma, Ehrlich Tumor/*metabolism/pathology ; Cell Death/*drug effects ; Cell Survival/drug effects ; *Flavonoids ; Glutathione/metabolism ; Liver/cytology/drug effects ; Molecular Structure ; Phenols/*pharmacology ; Plant Extracts/*pharmacology ; Polymers/*pharmacology ; Polyphenols ; Sulfhydryl Compounds/*metabolism ; *Tea ; Tumor Cells, Cultured ; }, abstract = {Epidemiological studies suggest that the consumption of green tea may help prevent cancers in humans, and also breast and prostate cancers in animal models are reduced by green tea, and several mechanisms have been proposed for these effects. In this study the relationship between cellular sulfhydryl (SH) groups and the cytotoxicity of green tea polyphenols in Ehrlich ascites tumor cells was examined. It was found that in the presence of green tea extract (GTE) (100 microg/ml) and one of its polyphenolic components, epigallocatechin (EGC; 100 microM), both cellular non-protein (GSH) and protein-sulfhydryl (PSH) levels were significantly decreased and this was associated with a decrease in cell viability. Replenishing the thiol levels by using N-acetylcysteine (NAC) caused a recovery in cell viability, but this recovery was dependent on the time of thiol replenishment in the presence of EGC (initial 15 min). These results identify SH groups as a novel target of green tea polyphenols cytotoxicity in tumor cells, and a regulatory role for green tea in terms of reducing sulfhydryls in tumor inhibition.}, }
@article {pmid10471400, year = {1999}, author = {Sharma, M and Slocum, HK}, title = {Prevention of quinone-mediated DNA arylation by antioxidants.}, journal = {Biochemical and biophysical research communications}, volume = {262}, number = {3}, pages = {769-774}, doi = {10.1006/bbrc.1999.1290}, pmid = {10471400}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/*pharmacology ; Chromatography, High Pressure Liquid/methods ; DNA Adducts/*drug effects/*metabolism ; Diethylstilbestrol/*metabolism/*pharmacology ; Horseradish Peroxidase ; Hydrogen Peroxide/pharmacology ; Male ; Salmon ; Tamoxifen/*analogs &amp; derivatives/pharmacology ; Testis ; }, abstract = {High performance liquid chromatographic (HPLC) analysis showed that the prototype antioxidant ascorbate (vitamin C) inhibits the DNA adducts induced by synthetic estrogen diethylstilbestrol (DES) and the antiestrogen metabolite 4-hydroxytamoxifen (4-OHTam). Treatment of salmon testes DNA with 4-OHTam quinone or 4-OHTam in the presence of horseradish peroxidase and hydrogen peroxide (H(2)O(2)) generated the same DNA adduct profile. Vitamin C and N-acetylcysteine (NAC) inhibited the formation of 4-OHTam-dG adducts in a dose-dependent manner. To determine whether the same antioxidants also protect cellular DNA, HL-60 cells were used as cell culture model. Cells treated with 10 microM 4-OHTam in the presence of 1 microM H(2)O(2)for 24 h gave 4-OHTam-dG adducts approximately 4 x 10(-7), n = 3. Treatment of the cells with 100 microM 4-OHTam, without H(2)O(2), produced the same level of adducts. Supplementation of the incubation media with vitamin C (2.5 mM) or NAC (5 mM) inhibited the formation of DNA adducts. Thus, antioxidants may protect susceptible cells from genotoxicity associated with 4-OHTam activation.}, }
@article {pmid10469636, year = {1999}, author = {Liu, M and Wikonkal, NM and Brash, DE}, title = {Induction of cyclin-dependent kinase inhibitors and G(1) prolongation by the chemopreventive agent N-acetylcysteine.}, journal = {Carcinogenesis}, volume = {20}, number = {9}, pages = {1869-1872}, doi = {10.1093/carcin/20.9.1869}, pmid = {10469636}, issn = {0143-3334}, support = {CA55737/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anticarcinogenic Agents/*pharmacology ; Antioxidants/*pharmacology ; Cell Cycle/drug effects ; Cell Line/drug effects/metabolism ; Chromans/pharmacology ; Cyclin-Dependent Kinase Inhibitor p16/*biosynthesis ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins/*biosynthesis/genetics ; Fibroblasts/drug effects/metabolism ; Free Radical Scavengers/pharmacology ; G1 Phase/drug effects ; Gene Expression Regulation/*drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Genes, p16/*drug effects ; Glutathione/physiology ; Humans ; Keratinocytes/drug effects/metabolism ; Mice ; Models, Biological ; Neoplasm Proteins/biosynthesis/genetics ; Papilloma/pathology ; Skin Neoplasms/pathology ; Tumor Cells, Cultured/drug effects/metabolism ; Tumor Suppressor Protein p53/physiology ; }, abstract = {Cyclin-dependent kinase (cdk) inhibitors, such as p16(INK4a) and p21(WAF1/CIP1), often inhibit G(1) cyclin kinases and result in G(1) arrest. It has been suggested that p21(WAF1/CIP1) may also play a role in other chemopreventive activities such as DNA repair, slowdown of DNA replication and induction of cellular differentiation. In this report we demonstrate that the antioxidant N-acetylcysteine (NAC), a well-known chemopreventive agent, induces p16(INK4a) and p21(WAF1/CIP1) gene expression and prolongs cell-cycle transition through G(1) phase. A portion of the G(1) arrest by NAC is governed by p16(INK4a); it is independent of p53. NAC's usual mechanism of increasing intracellular glutathione level is not required for the G(1) arrest. An antioxidant whose action is limited to scavenging radicals, Trolox, does not induce G(1) arrest. Taken together, these results suggest a potential novel molecular basis for chemoprevention by NAC.}, }
@article {pmid10464319, year = {1999}, author = {Iordanov, MS and Magun, BE}, title = {Different mechanisms of c-Jun NH(2)-terminal kinase-1 (JNK1) activation by ultraviolet-B radiation and by oxidative stressors.}, journal = {The Journal of biological chemistry}, volume = {274}, number = {36}, pages = {25801-25806}, doi = {10.1074/jbc.274.36.25801}, pmid = {10464319}, issn = {0021-9258}, support = {CA-39360/CA/NCI NIH HHS/United States ; ES-08456/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Cells, Cultured ; Enzyme Activation/radiation effects ; Fibroblasts ; JNK Mitogen-Activated Protein Kinases ; *Mitogen-Activated Protein Kinases ; Oxidative Stress ; Rats ; Ultraviolet Rays ; }, abstract = {Irradiation of mammalian cells with ultraviolet-B radiation (UV-B) triggers the activation of a group of stress-activated protein kinases known as c-Jun NH(2)-terminal kinases (JNKs). UV-B activates JNKs via UV-B-induced ribotoxic stress. Because oxidative stress also activates JNKs, we have addressed the question of whether the ribotoxic and the oxidative stress responses are mechanistically similar. The pro-oxidants sodium arsenite, cadmium chloride, and hydrogen peroxide activated JNK1 with slow kinetics, whereas UV-B potentiated the activity of JNK1 rapidly. N-acetyl cysteine (a scavenger of reactive oxygen intermediates) abolished the ability of all oxidative stressors tested to activate JNK1, but failed to affect the activation of JNK1 by UV-B or by another ribotoxic stressor, the antibiotic anisomycin. In contrast, emetine, an inhibitor of the ribotoxic stress response, was unable to inhibit the activation of JNK1 by oxidative stressors. Although UV-A and long wavelength UV-B are the spectral components of the ultraviolet solar radiation that cause significant oxidative damage to macromolecules, the use of a filter to eliminate the radiation output from wavelengths below 310 nm abolished the activation of JNK1 by UV. Our results are consistent with the notion that UV-B and oxidative stressors trigger the activation of JNK1 through different signal transduction pathways.}, }
@article {pmid10463948, year = {1999}, author = {Hogaboam, CM and Bone-Larson, CL and Steinhauser, ML and Lukacs, NW and Colletti, LM and Simpson, KJ and Strieter, RM and Kunkel, SL}, title = {Novel CXCR2-dependent liver regenerative qualities of ELR-containing CXC chemokines.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {13}, number = {12}, pages = {1565-1574}, doi = {10.1096/fasebj.13.12.1565}, pmid = {10463948}, issn = {0892-6638}, support = {1P50HL56402/HL/NHLBI NIH HHS/United States ; 1P50HL60289/HL/NHLBI NIH HHS/United States ; CA66180/CA/NCI NIH HHS/United States ; }, mesh = {Acetaminophen/toxicity ; Acetylcysteine/pharmacology ; Animals ; Aspartate Aminotransferases/blood ; Cell Division/drug effects ; Cells, Cultured ; Chemokine CXCL2 ; Chemokine CXCL5 ; Chemokines, CXC/*pharmacology ; Chemotactic Factors/pharmacology ; Female ; Hepatocyte Growth Factor/pharmacology ; Interleukin-8/*analogs &amp; derivatives/*pharmacology ; Liver/cytology/drug effects/pathology/*physiology ; Liver Regeneration/drug effects/*physiology ; Mice ; Monokines/*pharmacology ; Receptors, Chemokine/*physiology ; Receptors, Interleukin/*physiology ; Receptors, Interleukin-8B ; }, abstract = {Severe acute liver injury due to accidental or intentional acetaminophen overdose presents a major clinical dilemma often requiring liver transplantation. In the present study, liver regeneration after profound liver injury in mice challenged with acetaminophen was facilitated by the exogenous addition of ELR-containing CXC chemokines such as macrophage inflammatory protein-2 (MIP-2), epithelial neutrophil-activating protein-78 (ENA-78), or interleukin 8. Intravenous administration of ELR-CXC chemokines or N-acetyl-cysteine (NAC) immediately after acetaminophen challenge in mice significantly reduced histological and biochemical markers of hepatic injury. However, when the intervention was delayed until 10 h after acetaminophen challenge, only ELR-CXC chemokines significantly reduced liver injury and mouse mortality. The delayed addition of ELR-CXC chemokines to cultured hepatocytes maintained the proliferation of these cells in a CXCR2-dependent fashion after acetaminophen challenge whereas delayed NAC treatment did not. These observations demonstrate that ELR-CXC chemokines represent novel hepatic regenerative factors that exhibit prolonged therapeutic effects after acetaminophen-induced hepatotoxicity.}, }
@article {pmid10459834, year = {1999}, author = {Sprietsma, JE}, title = {Cysteine, glutathione (GSH) and zinc and copper ions together are effective, natural, intracellular inhibitors of (AIDS) viruses.}, journal = {Medical hypotheses}, volume = {52}, number = {6}, pages = {529-538}, doi = {10.1054/mehy.1997.0689}, pmid = {10459834}, issn = {0306-9877}, mesh = {Amino Acid Sequence ; Anti-HIV Agents/*pharmacology ; *Antimicrobial Cationic Peptides ; Copper/*pharmacology ; Cysteine/*pharmacology ; Glutathione/*pharmacology ; HIV-1/*drug effects ; Humans ; In Vitro Techniques ; Models, Chemical ; Molecular Sequence Data ; Peptides/pharmacology ; Zinc/*pharmacology ; }, abstract = {Sufficient essential nutrients such as methionine, cysteine, copper, selenium, zinc and vitamins C and E are indispensable for the maintenance of optimal (immune) cell functions. Parasitic organisms such as protozoa, fungi, bacteria and viruses also depend on these essential nutrients for their multiplication and functioning. An evolutionarily developed optimal distribution of available nutrients between host (cells) and parasitic organisms normally prevents diseases, the nature of which will depend on genetic and environmental factors. The way in which the right amount of cysteine, glutathione (GSH), and copper and zinc ions made available in the right place at the right time and in the right form can prevent an unchecked multiplication of (AIDS) viruses in a more passive or active way forms the basis for the AIDS zinc-deficiency hypothesis (A-Z hypothesis) presented in this article. Zinc and copper ions stimulate/inhibit/block in a concentration-dependent way the (intracellular) activation of essential protein-splitting enzymes such as HIV proteases. Zinc and copper ions as 'passive' virus inhibitors. Apart from this, zinc ions directly or indirectly regulate, via zinc finger protein molecular structures, the activities of virus-combating Th-1 cells such as cytotoxic T-cells (CTLs). Zinc ions as regulators of the active, virus-combating Th-1 cells. Zinc and copper ions that remain available in sufficient amounts via cysteine/GSH are effective natural inhibitors/combaters of (AIDS) viruses and thereby prevent the development of chronic virus diseases that can lead to AIDS, autoimmune diseases, (food) allergies and/or cancer. A safe, relatively inexpensive and extensively tested medicine such as N-acetylcysteine (NAC) can help in supplying extra cysteine. The anti-HIV peptide T22, synthesized on the basis of two natural peptides from the Tachypleus tridentatus and Limnus polyphemus crabs, appears to be able to serve as supplier/carrier molecule of cysteine and zinc and/or to hinder the entry of HIVs into cells by way of the CD4 receptor.}, }
@article {pmid10459557, year = {1999}, author = {Jain, SK and Palmer, M and Chen, Y}, title = {Effect of vitamin E and N-acetylcysteine on phosphatidylserine externalization and induction of coagulation by high-glucose-treated human erythrocytes.}, journal = {Metabolism: clinical and experimental}, volume = {48}, number = {8}, pages = {957-959}, doi = {10.1016/s0026-0495(99)90189-0}, pmid = {10459557}, issn = {0026-0495}, mesh = {Acetylcysteine/*pharmacology ; *Blood Coagulation ; Erythrocyte Membrane/metabolism ; Erythrocytes/drug effects/*physiology ; Glucose/*pharmacology ; Humans ; Lipid Peroxidation ; Phosphatidylserines/*metabolism ; Vitamin E/*pharmacology ; }, abstract = {This study examines the effect of high glucose levels on the markers of oxidative stress, phosphatidylserine (PS) externalization, and induction of coagulation by high-glucose-treated red blood cells (RBCs). Washed normal RBCs were suspended to 15% hematocrit in phosphate-buffered saline and incubated with different concentrations of glucose for 24 hours in a shaking water bath at 37 degrees C. This treatment caused depletion of vitamin E and accumulation of vitamin E-quinone and malondialdehyde ([MDA] an end product of lipid peroxidation), externalization of PS in the membrane bilayer, and induction of coagulation by RBCs. Pretreatment of RBCs with N-acetylcysteine (NAC) and vitamin E reduced membrane lipid peroxidation, PS externalization, and the tendency of high-glucose-treated RBCs to clot plasma. This study provides further evidence for the increased oxidative stress in RBCs exposed to high glucose levels. In addition, it suggests a role for membrane lipid peroxidation in the PS externalization in the membrane bilayer and in the induction of clotting by RBCs exposed to hyperglycemia. It also suggests that certain antioxidants can decrease cellular damage and restore certain cellular functions in diabetes.}, }
@article {pmid10459534, year = {1999}, author = {Manika, A and Trinh, T and Lagacé, G and Dugas, MA and Proulx, F and Lepage, G and Champagne, J and Lavoie, JC and Cousineau, J and Russo, P and Chartrand, C and Yandza, T}, title = {N-acetylcysteine in pig liver transplantation from non-heart-beating donors.}, journal = {Transplantation}, volume = {68}, number = {3}, pages = {327-330}, doi = {10.1097/00007890-199908150-00002}, pmid = {10459534}, issn = {0041-1337}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Aspartate Aminotransferases/metabolism ; Female ; Glutathione/analysis ; Graft Survival/drug effects ; Injections, Intravenous ; Liver/anatomy &amp; histology/chemistry/pathology ; *Liver Transplantation/pathology ; Swine ; *Tissue Donors ; Tissue and Organ Procurement/methods ; }, abstract = {Lipid peroxidation due to oxygen free radicals (OFR) seems to play a major role in loss of liver graft viability after warm ischemia, preservation, and transplantation. N-acetylcysteine (NAC) is an antioxidant that has a direct effect on OFR, and is also a glutathione precursor, another antioxidant. This study was designed to evaluate the efficacy of NAC in preventing ischemia-reperfusion damage of liver grafts harvested from non-heart-beating donors. Liver transplantation was performed on pigs divided into five groups: group 1 (control group; n=5) received livers from heart-beating donors; livers were subjected to 30 min of warm ischemia in groups 2 (n=3, no NAC) and group 3 (n=3; NAC treatment); warm ischemia time lasted 60 min in groups 4 (n=4; no NAC) and 5 (n=5; NAC treatment). Studied parameters included graft survival for more than 3 days, aspartate aminotransferase plasma levels, liver histology, and hepatic total glutathione concentrations. Graft survival was 100% in groups 1, 2, and 3, 0% in group 4, and 20% in group 5. NAC treatment did not influence initial mean aspartate aminotransferase release which was greater in warm ischemic livers than in controls. NAC treatment had no effect on liver hepatic total glutathione after reperfusion of animals receiving warm ischemic grants. Finally, no effect on liver histology was observed with NAC treatment. Our study suggests that in liver transplantation from non-heart-beating donors, NAC has no effect in both graft viability and lipid peroxidation. The role of OFR in primary dysfunction of transplanted warm ischemic livers remains controversial.}, }
@article {pmid10456252, year = {1999}, author = {Dröge, W}, title = {Cysteine and glutathione in catabolic conditions and immunological dysfunction.}, journal = {Current opinion in clinical nutrition and metabolic care}, volume = {2}, number = {3}, pages = {227-233}, doi = {10.1097/00075197-199905000-00006}, pmid = {10456252}, issn = {1363-1950}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Cysteine/*blood ; Glutathione/*blood ; Humans ; Immune System Diseases/*blood/drug therapy/physiopathology ; }, abstract = {The conspicuous increase in the plasma cysteine disulphide/thiol ratio in elderly persons and cancer patients indicates a shift of the plasma redox state. The most important redox buffers in skeletal muscle tissue and blood plasma, i.e. glutathione and albumin, respectively, are significantly decreased in different models of cachexia. Treatment with N-acetyl cysteine, i.e. a thiol-containing antioxidant, was found to increase the plasma albumin level and to ameliorate the loss of body cell mass in cancer patients and healthy individuals. The treatment of HIV infection with N-acetyl cysteine, in contrast, serves mainly as a tool to ameliorate the physiological and immunological consequences of the virus-induced cysteine deficiency.}, }
@article {pmid10452837, year = {1998}, author = {Cappelletti, G and Maggioni, MG and Maci, R}, title = {Apoptosis in human lung epithelial cells: triggering by paraquat and modulation by antioxidants.}, journal = {Cell biology international}, volume = {22}, number = {9-10}, pages = {671-678}, doi = {10.1006/cbir.1998.0305}, pmid = {10452837}, issn = {1065-6995}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/*physiology ; Ascorbic Acid/pharmacology ; Cell Line ; Epithelial Cells/cytology/drug effects/metabolism ; Humans ; Lung/*cytology/*drug effects/metabolism ; Models, Biological ; Paraquat/*toxicity ; Reactive Oxygen Species/metabolism ; }, abstract = {Recent results have shown that apoptosis is an important feature of the normal and injured lung epithelium, but little conclusive evidence is available about the exact intracellular mechanisms involved. In this work, we studied apoptotic cell death in the established human lung epithelial cell line, A549, by evaluating the ability of the pulmonary toxin, paraquat (1,1'-dimethyl-4, 4'-bipyridylium dichloride), to act as a trigger, and assessing the ability of ascorbic acid and N-acetyl-cysteine (NAC) to modulate the process. The analysis of nuclear and cellular morphology along with TUNEL staining showed that paraquat is an inducer of apoptosis. A549 cells incubated with sublethal doses of paraquat for up to 24 h showed no apoptotic features but, their following incubation in paraquat-free medium resulted in a time-dependent appearance of apoptosis. The antioxidants, ascorbic acid and NAC, proved effective in reducing paraquat-induced apoptosis, and therefore were seen as protective agents. Finally, we propose an experimental model for investigating some of the key steps in the apoptotic programme in alveolar cells.}, }
@article {pmid10449535, year = {1999}, author = {Schrader, M and Wodopia, R and Fahimi, HD}, title = {Induction of tubular peroxisomes by UV irradiation and reactive oxygen species in HepG2 cells.}, journal = {The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society}, volume = {47}, number = {9}, pages = {1141-1148}, doi = {10.1177/002215549904700906}, pmid = {10449535}, issn = {0022-1554}, mesh = {Acetylcysteine/pharmacology ; Diglycerides/pharmacology ; Dose-Response Relationship, Drug ; Fluorescent Antibody Technique, Indirect ; Humans ; Hydrogen Peroxide/pharmacology ; Indoles/pharmacology ; Maleimides/pharmacology ; Microbodies/drug effects/*metabolism/radiation effects ; Oxygen/physiology ; Partial Pressure ; Protein Kinase C/antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism/*physiology ; Tumor Cells, Cultured ; *Ultraviolet Rays ; }, abstract = {Peroxisomes in the human hepatoblastoma cell line HepG2 exhibit a high degree of plasticity. Whereas in confluent cultures they appear as small (0.1-0.3 micrometer) spherical particles, they undergo dramatic changes, forming elongated tubules measuring up to 5 micrometer on separation of cells and cultivation at low density. We recently showed that several growth factors, including nerve growth factor (NGF), induce the formation of tubular peroxisomes and that this induction is sensitive to K 252b, a specific tyrosine kinase inhibitor, suggesting the involvement of this signal transduction pathway. Because tyrosine kinase is also involved in signal transduction via the reactive oxygen species (ROS), we have analyzed in this study the effects of UV irradiation, H(2)O(2), and oxygen on tubulation of peroxisomes. UVC irradiation induced a significant increase in formation of tubular peroxisomes (40-50% of cells) and this effect was dose-dependently inhibited by pretreatment with N-acetyl cysteine, confirming the involvement of ROS in the UV effect. Furthermore, H(2)O(2) also directly induced the tubulation of peroxisomes, although to a lesser extent. Finally, cultivation under hypoxic conditions (1.5% O(2)) drastically reduced the inducing effect of fetal calf serum on tubulation of peroxisomes, suggesting the involvement of oxygen-mediated signaling. Taken together, our observations indicate that ROS induce the tubulation of peroxisomes in HepG2 cells. Because peroxisomes harbor most of the enzymes for catabolism of ROS, the tubulation and expansion of the peroxisome compartment could have a cell rescue function against the destructive effects of ROS.}, }
@article {pmid10448899, year = {1999}, author = {Bagchi, S and Bhaumik, G and Raha, S}, title = {Thrombin releases calcium from internal stores of ultraviolet C-treated V79 fibroblasts independent of phosphatidylinositol bisphosphate hydrolysis: role of oxidative stress.}, journal = {Molecular and cellular biochemistry}, volume = {196}, number = {1-2}, pages = {23-30}, pmid = {10448899}, issn = {0300-8177}, mesh = {Animals ; Calcium/*metabolism ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cells, Cultured ; Cricetinae ; Cricetulus ; Cyclooxygenase Inhibitors/pharmacology ; Fibroblasts/metabolism/radiation effects ; Genistein/pharmacology ; Glycogen Synthase Kinase 3 ; Hydrolysis ; Lipoxygenase Inhibitors/pharmacology ; Lung/cytology/metabolism ; *Oxidative Stress ; Phosphatidylinositol 4,5-Diphosphate/*metabolism ; Sulfhydryl Compounds/metabolism ; Thrombin/*metabolism ; Ultraviolet Rays ; }, abstract = {V79 fibroblasts were treated with ultraviolet (UV) C radiation alone as well as in conjunction with chronic oxidative stress. The effects of these treatments on calcium signaling were observed at 30 min post-irradiation. In the absence of extracellular calcium, thrombin released calcium from internal stores of UVC-irradiated V79 fibroblasts even after exposure to neomycin. In neomycin-treated control and chronic oxidative stress cells, no calcium release by thrombin was observed after chelation of external calcium. Calcium release by thrombin from internal stores of UV-irradiated and neomycin-treated cells was completely abolished by pretreatment with N-acetyl cysteine and dexamethasone. Cellular total soluble thiol content which is a good indicator of cellular reduced glutathione (GSH) level was significantly elevated 30 min after ultraviolet radiation, indicating an adaptive response after oxidative stress. Chronic oxidative stress alone resulted in a much smaller increase in GSH but chronic oxidative stress in conjunction with UVC produced a very prominent elevation in GSH levels. Our data suggest that thrombin can cause calcium release from internal stores of ultraviolet-irradiated fibroblasts which is independent of phosphatidylinositol bisphosphate hydrolysis and is directly related to the level of oxidative stress. Involvement of phospholipase A2 and a role for its products as possible mediators of calcium release from intracellular stores, is strongly indicated.}, }
@article {pmid10448097, year = {1999}, author = {Qin, S and Ding, J and Takano, T and Yamamura, H}, title = {Involvement of receptor aggregation and reactive oxygen species in osmotic stress-induced Syk activation in B cells.}, journal = {Biochemical and biophysical research communications}, volume = {262}, number = {1}, pages = {231-236}, doi = {10.1006/bbrc.1999.1079}, pmid = {10448097}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; B-Lymphocytes/cytology/drug effects/*enzymology/*metabolism ; Cell Line ; Cell Size/drug effects ; Drug Synergism ; Enzyme Activation/drug effects ; Enzyme Precursors/*metabolism ; Glutathione/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Intracellular Signaling Peptides and Proteins ; Osmolar Concentration ; *Oxidative Stress/drug effects ; Phosphorylation/drug effects ; Phosphotyrosine/metabolism ; Potassium Chloride/pharmacology ; Protein-Tyrosine Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; *Receptor Aggregation/drug effects ; Sodium Chloride/pharmacology ; Suramin/pharmacology ; Swine ; Syk Kinase ; }, abstract = {Syk has been shown to be activated by osmotic stress, however, the mechanisms involved are largely unknown. In this study, we demonstrated that cell shrinkage, rather than osmolarity, was responsible for osmotic stress-induced Syk activation. Osmotic stress-induced Syk activation depended partly upon aggregation of surface receptors. Moreover, intracellular reactive oxygen species were involved in mediating osmotic stress-induced Syk activation, with osmotic stress-induced Syk activation being inhibited by the pretreatment of cells with N-acetyl-cysteine and reduced glutathione. When cells were treated with the combination of sodium chloride and hydrogen peroxide, there was a synergistic activation of Syk. In conclusion, osmotic stress-induced Syk activation required suramin-inhibitable surface receptor aggregation and accumulation of intracellular reactive oxygen species.}, }
@article {pmid10444522, year = {1999}, author = {Lee, SL and Wang, WW and Finlay, GA and Fanburg, BL}, title = {Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion.}, journal = {The American journal of physiology}, volume = {277}, number = {2}, pages = {L282-91}, doi = {10.1152/ajplung.1999.277.2.L282}, pmid = {10444522}, issn = {0002-9513}, support = {HL-32723/HL/NHLBI NIH HHS/United States ; }, mesh = {1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors/drug effects/*metabolism ; Cattle ; Cell Line ; Cricetinae ; Cricetulus ; Enzyme Activation ; Fibroblasts/drug effects/physiology ; Ginkgo biloba/chemistry ; Lung/cytology/drug effects/physiology ; Muscle, Smooth, Vascular/cytology/drug effects/physiology ; Phosphorylation/drug effects ; Plant Extracts/pharmacology ; Plants, Medicinal ; Pulmonary Artery/cytology/drug effects/physiology ; Serotonin/*pharmacology ; Superoxides/*metabolism ; }, abstract = {Our previous studies have shown that, through an active transport process, serotonin (5-HT) rapidly elevates O(-)(2). formation, stimulates protein phosphorylation, and enhances proliferation of bovine pulmonary artery smooth muscle cells (SMCs). We presently show that 1 microM 5-HT also rapidly elevates phosphorylation and activation of the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase (ERK) 1 and ERK2 of SMCs, and the enhanced phosphorylation is blocked by the antioxidants Tiron, N-acetyl-L-cysteine (NAC), and Ginkgo biloba extract. Inhibition of MAP kinase with PD-98059 failed to block enhanced O(-)(2). formation by 5-HT. Chinese hamster lung fibroblasts (CCL-39 cells), which demonstrate both 5-HT transporter and receptor activity, showed a similar response to 5-HT (i.e., enhanced mitogenesis, O(-)(2). formation, and ERK1 and ERK2 phosphorylation and activation). Unlike SMCs, they also responded to 5-HT receptor agonists. We conclude that downstream signaling of MAP kinase is a generalized cellular response to 5-HT that occurs secondary to O(-)(2). formation and may be initiated by either the 5-HT transporter or receptor depending on the cell type.}, }
@article {pmid10443929, year = {1999}, author = {Liu, Z and Lu, Y and Lebwohl, M and Wei, H}, title = {PUVA (8-methoxy-psoralen plus ultraviolet A) induces the formation of 8-hydroxy-2'-deoxyguanosine and DNA fragmentation in calf thymus DNA and human epidermoid carcinoma cells.}, journal = {Free radical biology &amp; medicine}, volume = {27}, number = {1-2}, pages = {127-133}, doi = {10.1016/s0891-5849(99)00058-1}, pmid = {10443929}, issn = {0891-5849}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Animals ; Carcinoma, Squamous Cell ; Cattle ; DNA/*drug effects/*radiation effects ; *DNA Damage ; DNA Fragmentation ; Deoxyguanosine/*analogs &amp; derivatives/biosynthesis ; Humans ; Methoxsalen/*pharmacology ; Reactive Oxygen Species ; Thymus Gland ; Tumor Cells, Cultured ; *Ultraviolet Rays ; }, abstract = {The objective of this study is to investigate if 8-methoxy-psoralen (8-MOP) plus ultraviolet A (UVA) radiation (PUVA) induces oxidative DNA damage. When calf thymus DNA was incubated with 8-MOP and irradiated with UVA (335-400 nm), the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was substantially increased by approximately 6-fold. Formation of 8-OHdG proportionally correlated with both UVA fluence and 8-MOP concentrations. Human epidermoid carcinoma cells were incubated with 10 microg 8-MOP per milliliter, followed by irradiation of 25 kJ/m2 UVA. The level of 8-OHdG increased by nearly 3-fold in PUVA-treated cells compared to 8-MOP and UVA controls. The formation of 8-OHdG correlated with DNA fragmentation as determined by spectrofluorometry. To investigate the reactive oxygen species (ROS) involved in PUVA-induced oxidative DNA damage, less or more specific ROS quenchers were added to DNA solution prior to PUVA treatment. The results showed that only sodium azide and genistein significantly quenched PUVA-induced 8-OHdG, whereas catalase, superoxide dismutase, and mannitol exhibited no effect. The quencher study with cultured cells indicated that N-acetyl-cysteine and genistein protected oxidative DNA damage as well as DNA fragmentation by PUVA treatment. Our studies show that PUVA treatment is able to induce the formation of 8-OHdG in purified DNA and cultured cells and suggest that singlet oxygen is the principle reactive oxygen species involved in oxidative DNA damage by PUVA treatment.}, }
@article {pmid10441525, year = {1999}, author = {Hur, GM and Ryu, YS and Yun, HY and Jeon, BH and Kim, YM and Seok, JH and Lee, JH}, title = {Hepatic ischemia/reperfusion in rats induces iNOS gene transcription by activation of NF-kappaB.}, journal = {Biochemical and biophysical research communications}, volume = {261}, number = {3}, pages = {917-922}, doi = {10.1006/bbrc.1999.1143}, pmid = {10441525}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Dimerization ; *Gene Expression/drug effects ; Ischemia/*enzymology ; Kinetics ; Liver/*blood supply ; NF-kappa B/*metabolism ; Nitric Oxide Synthase/*genetics/metabolism ; Nitric Oxide Synthase Type II ; Oxidative Stress ; RNA, Messenger/metabolism ; Rats ; Rats, Sprague-Dawley ; *Reperfusion ; }, abstract = {It has been known that many immediately early genes are expressed during ischemia/reperfusion (I/R) injury. Here, employing a model of hepatic I/R, we show that inducible nitric oxide synthase (iNOS) is induced via the activation of nuclear factor kappaB (NF-kappaB) after I/R in rat liver. When liver was subjected to ischemia followed by reperfusion, but not ischemia alone, an NF-kappaB complex composed of p50/p65 heterodimer and p50 homodimer was rapidly activated within 1 h and remained elevated for up to 3 h, and then tended to decline after 5 h of reperfusion. Also, the expression of iNOS mRNA was initiated after 1 h and continued to increase after 5 h of reperfusion during the time course studied. This upregulated iNOS mRNA expression coincides with increased iNOS enzyme activity and NF-kappaB binding activity after hepatic I/R. Administration of N-acetylcysteine (NAC, 20 mg/kg i.v. 10 min before reperfusion), an antioxidant, not only significantly inhibited the expression of iNOS mRNA but also blocked upregulated NF-kappaB binding activity after reperfused liver. These results suggest that NF-kappaB is activated by oxidative stress during hepatic I/R and may play a significant role in the induction of the iNOS gene.}, }
@article {pmid10438654, year = {1999}, author = {Barrett, EG and Johnston, C and Oberdörster, G and Finkelstein, JN}, title = {Antioxidant treatment attenuates cytokine and chemokine levels in murine macrophages following silica exposure.}, journal = {Toxicology and applied pharmacology}, volume = {158}, number = {3}, pages = {211-220}, doi = {10.1006/taap.1999.8716}, pmid = {10438654}, issn = {0041-008X}, support = {ES01247/ES/NIEHS NIH HHS/United States ; ES04872/ES/NIEHS NIH HHS/United States ; ES07026/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antidotes/pharmacology ; Antioxidants/*pharmacology ; Cell Death/drug effects ; Cells, Cultured ; Chemokines/*biosynthesis ; Cytokines/*biosynthesis ; Dimethyl Sulfoxide/pharmacology ; Enzyme-Linked Immunosorbent Assay ; Free Radical Scavengers/pharmacology ; Glutathione/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Macrophages/drug effects/enzymology/*metabolism ; Male ; Mice ; Oxidative Stress/drug effects ; Ribonucleases/metabolism ; Silicon Dioxide/*toxicity ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {Alveolar macrophages play a key role in the development of silicosis by releasing a host of mediators, such as, cytokines and chemokines, which contribute to a complex network of interactions that result in the onset of lung injury, inflammation, and potentially fibrosis. Using a murine macrophage cell line, RAW 264.7, we exposed the cells to cristobalite-silica (35 micrograms/cm(2)) in the presence or absence of antioxidants and various modifiers of cellular antioxidant status. Treatment with dimethyl sulfoxide, extracellular glutathione, or N-acetyl-L-cysteine (NAC) decreased cristobalite-induced tumor necrosis factor (TNF)-alpha mRNA levels by 40%, 20%, and 42%, respectively. TNF-alpha protein levels were decreased by 90%, 32%, and 53%, respectively. Cristobalite-induced macrophage inflammatory protein (MIP)-2 mRNA levels were reduced by 52%, 38%, and 57%, with DMSO, GSH, and NAC treatment, respectively. Both MIP-1alpha and MIP-1beta mRNA levels were reduced at a magnitude similar to the reduction in TNF-alpha mRNA levels, whereas monocyte chemotactic protein (MCP)-1 mRNA levels were reduced at a magnitude similar to the reduction in MIP-2 mRNA levels following antioxidant treatment. These results suggests that the macrophage response to cristobalite exposure is mediated at least in part by oxidant stress.}, }
@article {pmid10435037, year = {1999}, author = {Cheng, TH and Shih, NL and Chen, SY and Wang, DL and Chen, JJ}, title = {Reactive oxygen species modulate endothelin-I-induced c-fos gene expression in cardiomyocytes.}, journal = {Cardiovascular research}, volume = {41}, number = {3}, pages = {654-662}, doi = {10.1016/s0008-6363(98)00275-2}, pmid = {10435037}, issn = {0008-6363}, mesh = {Animals ; Blotting, Northern ; Cells, Cultured ; Dose-Response Relationship, Drug ; Endothelin-1/*pharmacology ; Gene Expression/drug effects ; *Genes, fos ; Microscopy, Confocal ; Myocardium/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*physiology ; *Second Messenger Systems ; }, abstract = {OBJECTIVES: Recent evidence indicates that reactive oxygen species (ROS) may act as second messengers in receptor-mediated signaling pathways. The possible role of ROS during Et-1 stimulation in cardiomyocytes was therefore investigated.<br><br>METHODS: Intracellular ROS levels were measured with fluorescence probe 2',7'-dichlorofluorescin diacetate by confocal microscopy in cultured neonatal rat cardiomyocytes. The ROS-inducible c-fos expression was analyzed by Northern blotting and promoter activity.<br><br>RESULTS: Et-1 applied to cardiomyocytes dose-dependently increased intracellular ROS levels. The increase of ROS levels was attenuated by pretreating cardiomyocytes with Et-A receptor antagonist-BQ485, but not with Et-B receptor antagonist. Cardiomyocytes pretreated with catalase or an antioxidant N-acetylcysteine (NAC) reduced Et-1-induced ROS levels. Et-1 or H2O2 treatment of cardiomyocytes rapidly induced the expression of an immediate early gene c-fos. Et-1-treated cardiomyocytes enhanced the c-fos gene expression as revealed by functional analysis using a reporter gene construct containing c-fos promoter region (-2.25 kb) and reporter gene chloramphenicol acetyltransferase. The induction of mRNA levels and the promoter activities of c-fos gene by Et-1 or H2O2 were abolished by pretreating cardiomyocytes with catalase or NAC. Cells transiently transfected with the dominant positive mutant of p21ras (RasL61) led to a significant increase in intracellular ROS. Concomitantly, the mRNA levels and the promoter activities of c-fos were also induced. In contrast, cells transfected with the dominant negative mutant of Ras (RasN17) inhibited Et-1-induced ROS. Consistently, the increase of c-fos mRNA levels and promoter activities by Et-1 were also inhibited.<br><br>CONCLUSIONS: These findings clearly indicate that Et-1 treatment to cardiomyocytes can induce ROS via Ras pathway and the increased ROS are involved in the increase of c-fos expression. Our studies thus emphasize the importance of ROS as second messengers in Et-1-induced responses on cardiomyocytes.}, }
@article {pmid10434788, year = {1999}, author = {Schmidt, LE and Dalhoff, KP}, title = {[Side-effects of N-acetylcysteine treatment in patients with paracetamol poisoning].}, journal = {Ugeskrift for laeger}, volume = {161}, number = {18}, pages = {2669-2672}, pmid = {10434788}, issn = {0041-5782}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/administration &amp; dosage/*adverse effects ; Female ; Humans ; Male ; Retrospective Studies ; }, abstract = {Treatment of paracetamol intoxication with N-acetylcysteine (NAC) is standard in Denmark. NAC is considered safe with relatively few side effects. It is recommended that all patients be treated irrespective of paracetamol dose or time from intoxication to treatment start. Consequently a higher number of patients will be treated with NAC than with previous regimens based on plasma concentrations of paracetamol. In this retrospective study we evaluated the incidence of side effects of NAC in 310 patients admitted to the Department of Hepatology, Rigshospitalet, Copenhagen, over a four-year period (1.1.1994-31.12.1997). Twenty-six (8.4%) patients developed side effects. Side effects were anaphylactoid, mainly from skin (25 rash, pruritus or flushing), in rare cases more serious (four bronchospasm, three angioedema, one hypotension). None were life-threatening and all patients received the full course of NAC. In all cases the recommended treatment with antihistamine or steroids against adverse effects was administered. We conclude that treatment with NAC is safe. Accordingly we find no reason to change the recommendation for treatment of paracetamol intoxication in Denmark.}, }
@article {pmid10433156, year = {1999}, author = {Nakayama, M and Izumi, G and Nemoto, Y and Shibata, K and Hasegawa, T and Numata, M and Wang, K and Kawaguchi, Y and Hosoya, T}, title = {Suppression of N(epsilon)-(carboxymethyl)lysine generation by the antioxidant N-acetylcysteine.}, journal = {Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis}, volume = {19}, number = {3}, pages = {207-210}, pmid = {10433156}, issn = {0896-8608}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Collagen ; Glycation End Products, Advanced/*metabolism ; In Vitro Techniques ; Lysine/*analogs &amp; derivatives/metabolism ; Oxidative Stress ; Peritoneal Dialysis, Continuous Ambulatory ; Serum Albumin, Bovine ; }, abstract = {OBJECTIVE: Accumulated evidence suggests that N(epsilon)-(carboxymethyl)lysine (CML), which is a dominant antigen of advanced glycation end-products (AGEs), is generated in the peritoneal cavity of patients undergoing continuous ambulatory peritoneal dialysis (CAPD), and that this process may be involved in the pathophysiology of the peritoneal injury found with CAPD treatment. Since CML is a sequential product of glycation and oxidation processes, CML generation could be suppressed by antioxidants. The aim of this in vitro study was to clarify the effect of N-acetylcysteine (NAC), an antioxidant, on CML generation from proteins under high glucose settings mimicking peritoneal dialysis solutions.<br><br>DESIGN: Test proteins (bovine serum albumin/type I collagen) were incubated continuously for 16 weeks in glucose solutions (200 mmol/L) with or without NAC (2 mmol/L), and the generation time courses (8 and 16 weeks) of CML and furosine (the biomarker of the glycation products of the early Maillard reaction) were determined.<br><br>RESULTS: In both proteins, furosine and CML were progressively generated in accordance with the duration of the incubation period. No apparent differences were found between solutions with and without NAC in furosine levels at the 8th and 16th weeks. However, the generation of CML was lower in the solution with NAC throughout the test periods.<br><br>CONCLUSION: The results showed that NAC could suppress the generation of CML. This indicates the therapeutic potential of antioxidants for the glycoxidative stress-related peritoneal injury occurring during CAPD.}, }
@article {pmid10430495, year = {1999}, author = {Castagné, V and Lefèvre, K and Natero, R and Clarke, PG and Bedker, DA}, title = {An optimal redox status for the survival of axotomized ganglion cells in the developing retina.}, journal = {Neuroscience}, volume = {93}, number = {1}, pages = {313-320}, doi = {10.1016/s0306-4522(99)00138-4}, pmid = {10430495}, issn = {0306-4522}, mesh = {Acetylcysteine/pharmacokinetics/pharmacology ; Animals ; Antioxidants/pharmacology ; Axotomy ; Azulenes ; Cell Count ; Cell Survival/drug effects/physiology ; Chick Embryo ; Cyclic N-Oxides ; Eye/metabolism ; Neuroprotective Agents/pharmacokinetics/pharmacology ; Nitrogen Oxides/pharmacokinetics/pharmacology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Retina/*cytology/drug effects/*growth &amp; development ; Retinal Degeneration/physiopathology/prevention &amp; control ; Retinal Ganglion Cells/drug effects/*physiology ; Sesquiterpenes/pharmacokinetics/pharmacology ; Thiourea/analogs &amp; derivatives/pharmacokinetics/pharmacology ; }, abstract = {The neuronal redox status influences the expression of genes involved in neuronal survival. We previously showed that antioxidants may reduce the number of dying ganglion cells following axotomy in chick embryos. In the present study, we show that various antioxidants, including the new spin trap azulenyl nitrone and 1,3-dimethyl-2-thiourea, protect axotomized ganglion cells, confirming that neuronal death involves an imbalance of the cellular redox status towards oxidation. However, high concentrations of antioxidants did not protect ganglion cells, suggesting that excessive reduction is detrimental for neurons. Simultaneous injections of two different antioxidants gave results only partly supporting this view. Combinations of azulenyl nitrone and N-acetyl cysteine in fact gave greater protection than either antioxidant alone, whereas N-acetyl cysteine lost its neuroprotective effects and diminished those of alpha-phenyl-N-tert-butyl nitrone when the two compounds were injected simultaneously. The results of the combined treatments suggest that azulenyl nitrone and alpha-phenyl-N-tert-butyl nitrone do not have the same chemical effects within the ganglion cells. Moreover, N-acetyl cysteine's own antioxidant properties enhance the spin trapping effects of azulenyl nitrone but potentiate the toxicity of alpha-phenyl-N-tert-butyl nitrone. Our main conclusion is that neuronal survival requires the maintenance of the redox status near an optimal set-point. "Reductive stress" may be as dangerous as oxidative stress.}, }
@article {pmid10429960, year = {1999}, author = {Chavez-Cartaya, R and Jamieson, NV and Ramirez, P and Marin, J and Pino-Chavez, G}, title = {Free radical scavengers to prevent reperfusion injury following experimental warm liver ischaemia. Is there a real physiological benefit?.}, journal = {Transplant international : official journal of the European Society for Organ Transplantation}, volume = {12}, number = {3}, pages = {213-221}, doi = {10.1007/s001470050213}, pmid = {10429960}, issn = {0934-0874}, mesh = {Acetylcysteine/therapeutic use ; Allopurinol/therapeutic use ; Animals ; Free Radical Scavengers/*therapeutic use ; Galactose/pharmacokinetics ; Ischemia/*complications ; Liver/*blood supply/metabolism ; Liver Function Tests ; Male ; Microcirculation ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*prevention &amp; control ; Superoxide Dismutase/metabolism ; Vitamin E/therapeutic use ; }, abstract = {Free radical scavengers have been utilized to prevent the consequences of ischemia, however, results do not seem conclusive. In our study we analyzed the blood flow, function, and histology of rat liver tissue after warm liver ischemia, in order to assess the effect of free radicals in liver reperfusion injury. N-acetyl cysteine (NAC), tocopherol, allopurinol, and superoxide dismutase (SOD), pharmacological agents expected to protect from injury mediated by free radicals, were investigated. Laser Doppler flowmetry and photometry were utilized to measure post-ischemic microcirculatory changes as an expression of ischemia-reperfusion injury in a model of segmental liver ischemia in the rat, with an ischemic time of 45 min. Galactose elimination capacity, ALT and histology were used to assess the functional and morphological consequences of ischemia after 24 h of reperfusion. The overall mean blood flow over 1 hour after reperfusion was of 33.9% (SD 11.2) of the normal, non-ischemic control. NAC (31.2% SD 10.9) did not show any protective effect and in some cases the effect seemed to be negative. Tocopherol (41.7% SD 5.1) marginally improved post ischemic liver tissue blood flow. Treatment with allopurinol did not show any beneficial effects (37.5% SD 14.2). Only animals treated with SOD showed an improvement of the post ischemic liver microcirculation (57.9% SD 14.4)(P < 0.001) and function. Only SOD produced statistically significant differences in galactose elimination capacity, compared with those of the ischemic control group. This moderately protective effect of SOD is encouraging, however, the relevance of all these compounds in a broader pathophysiological setting remains unproven.}, }
@article {pmid10428064, year = {1999}, author = {Yoshimura, S and Banno, Y and Nakashima, S and Hayashi, K and Yamakawa, H and Sawada, M and Sakai, N and Nozawa, Y}, title = {Inhibition of neutral sphingomyelinase activation and ceramide formation by glutathione in hypoxic PC12 cell death.}, journal = {Journal of neurochemistry}, volume = {73}, number = {2}, pages = {675-683}, doi = {10.1046/j.1471-4159.1999.0730675.x}, pmid = {10428064}, issn = {0022-3042}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/metabolism ; Caspase 3 ; Caspases/metabolism ; Cell Death/drug effects ; Cell Differentiation/physiology ; Cell Hypoxia/drug effects ; Ceramides/*biosynthesis ; Enzyme Activation/physiology ; Free Radical Scavengers/pharmacology ; Glutathione/*metabolism/pharmacology ; L-Lactate Dehydrogenase/metabolism ; Neurons/*cytology/enzymology ; PC12 Cells ; Rats ; Signal Transduction/physiology ; Sphingomyelin Phosphodiesterase/antagonists &amp; inhibitors/*metabolism ; Sphingosine/*analogs &amp; derivatives/pharmacology ; }, abstract = {Reduced glutathione (GSH) and N-acetylcysteine (NAC), but not other antioxidative or reducing agents, were found to inhibit cell death, both apoptosis and necrosis, induced by hypoxia in naive and nerve growth factor-differentiated PC12 cells. The level of intracellular total GSH decreased time-dependently during hypoxia, but exogenously added GSH prevented such a decrease in GSH. Pretreatment of cells with exogenous GSH or NAC resulted in inhibition of both neutral sphingomyelinase (SMase) activation and ceramide formation during hypoxia. In the in vitro assay system, neutral SMase activity was inhibited dose-dependently by GSH and NAC. Activation of caspase-3 induced by hypoxia was also inhibited by either GSH or NAC. NAC but not GSH inhibited caspase-3 activation induced by C2-ceramide. These results suggest that GSH protects cells from hypoxic injury by direct inhibition of neutral SMase activity and ceramide formation, resulting in inhibition of caspase-3 activation, and that NAC exerts an additional inhibitory effect(s) downstream of ceramide.}, }
@article {pmid10426797, year = {1999}, author = {Balansky, RM and D' Agostini, F and De Flora, S}, title = {Induction, persistence and modulation of cytogenetic alterations in cells of smoke-exposed mice.}, journal = {Carcinogenesis}, volume = {20}, number = {8}, pages = {1491-1497}, doi = {10.1093/carcin/20.8.1491}, pmid = {10426797}, issn = {0143-3334}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; *Chromosome Aberrations ; Erythrocytes ; Female ; Free Radical Scavengers/administration &amp; dosage ; Macrophages, Alveolar ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; *Micronuclei, Chromosome-Defective ; Micronucleus Tests ; Tobacco Smoke Pollution/*adverse effects ; }, abstract = {In spite of the major role played by smoking tobacco in the epidemiology of chronic degenerative diseases, it is difficult to mimic the genotoxic and carcinogenic effects of this complex mixture in animal models. We undertook an experimental study evaluating the time-course induction, persistence and modulation of cytogenetic alterations induced in BDF(1) mice exposed whole-body to mainstream cigarette smoke. The animals were divided into five groups, including: (i) 72 sham-exposed mice; (ii) 72 mice exposed to smoke for up to 3 weeks; (iii) 72 mice treated daily with the thiol N-acetylcysteine (NAC, 0.5 g/kg body weight) with drinking water; (iv) 72 mice exposed to smoke and treated daily with NAC, starting 5 days before exposure to smoke; and (v) 48 mice exposed to smoke and treated daily with NAC, starting 1 day after discontinuation of exposure to smoke. After 1, 2, 3, 4, 5, 6, 7, 10 and 14 weeks since the start of exposure to cigarette smoke, eight mice per group were killed, and cytogenetic parameters were evaluated. Exposure to smoke induced a high frequency of micronucleated and binucleated (BN) pulmonary alveolar macrophages, which persisted for at least 14 weeks. The frequency of micronuclei increased early in bone marrow polychromatic erythrocytes, but declined to background levels upon discontinuation of exposure to smoke. By comparison, their induction in circulating normochromatic erythrocytes (NCE) was slightly delayed, less intense but still significant, and persisting for an additional 3 weeks. Administration of NAC, throughout duration of the experiment, strongly inhibited the smoke-induced formation of micronuclei in alveolar macrophages and had some transiently significant effect on the induction of BN macrophages. NAC did not significantly decrease the smoke-induced formation of micronuclei in bone marrow cells, whereas it attenuated the formation of micronuclei in peripheral blood NCE. When given after discontinuation of exposure to cigarette smoke, NAC did not affect the cytogenetic alterations but normalized the altered bronchoalveolar lavage cellularity. The present data provide a detailed analysis of time-related cytogenetic alterations in smoke-exposed mice, both in the respiratory tract and at a systemic level, and show the effects of NAC on these parameters and on the pulmonary inflammatory response.}, }
@article {pmid10425820, year = {1999}, author = {Montoya-Cabrera, MA and Escalante-Galindo, P and Nava-Juárez, A and Terroba-Larios, VM and Terán-Hernández, JA}, title = {[Evaluation of the efficacy of N-acetylcysteine administered alone or in combination with activated charcoal in the treatment of acetaminophen overdoses].}, journal = {Gaceta medica de Mexico}, volume = {135}, number = {3}, pages = {239-243}, pmid = {10425820}, issn = {0016-3813}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*therapeutic use ; Charcoal/*therapeutic use ; Child ; Child, Preschool ; Combined Modality Therapy ; Drug Overdose ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Infant ; Male ; Prospective Studies ; }, abstract = {STUDY OBJECTIVE: To evaluate the efficacy of N-acetylcysteine (N-AC) alone or combined with multiple-dose activated charcoal (AC) in the treatment of acetaminophen (ACT) overdose.<br><br>DESIGN: Prospective observational case series of 14 consecutive pediatric patients. Group A (n = 7) were treated only with N-AC and group B (n = 7) with N-AC combined with AC. Plasma ACT concentrations were measured at 0.0, 24 and 48 h. As a measure of ACT disappearance, half-life of elimination (t1/2 beta) and exogenous body clearance (ClB) were calculated.<br><br>RESULTS: Group A, Initial and final mean ACT plasmatic levels were 27 micrograms/mL and 4 micrograms/mL; t1/2 beta of 17 h and ClB 0.640 mL.kg.min. Group B, 27 micrograms/mL and 0.66 microgram/mL; t1/2 beta of 10 h and ClB 1.092 mL.kg.min. For both t1/2 beta and ClB differences, p < 0.05 (SS).<br><br>CONCLUSION: N-AC significantly decreased the plasma ACT levels in both treatments; however, there were several advantages with the combined therapy: AC enhanced the efficacy of N-AC according with the higher eliminati&#xf3;n of the overdosed drug (97.6% vs. 85.2%), the t1/2 beta decreased 42%, and the ClB increased 70% in relation to the group A. Data of this study suggested that N-AC plus AC is more effective than N-AC alone in enhancing ACT elimination in overdosed patients and that it provided additional hepatoprotective benefit.}, }
@article {pmid10416620, year = {1999}, author = {Ushmorov, A and Hack, V and Dröge, W}, title = {Differential reconstitution of mitochondrial respiratory chain activity and plasma redox state by cysteine and ornithine in a model of cancer cachexia.}, journal = {Cancer research}, volume = {59}, number = {14}, pages = {3527-3534}, pmid = {10416620}, issn = {0008-5472}, mesh = {Acetylcysteine/pharmacology/therapeutic use ; Adenosine Triphosphate/metabolism ; Animals ; Biomarkers ; Blood Glucose/analysis ; Cachexia/drug therapy/etiology/*metabolism ; Cysteine/*pharmacology/therapeutic use ; Cystine/blood ; Electron Transport/*drug effects ; Energy Metabolism/*drug effects ; Fibrosarcoma/*complications/metabolism/physiopathology ; Free Radical Scavengers ; Glutathione/deficiency/metabolism ; Glycolysis ; Insulin Resistance ; Mice ; Mice, Inbred C57BL ; Mitochondria/*drug effects ; Models, Biological ; Muscle, Skeletal/metabolism/pathology ; Ornithine/*pharmacology/therapeutic use ; Oxidation-Reduction ; Oxidative Phosphorylation/drug effects ; Oxidative Stress ; Plasma/chemistry ; Receptor, Insulin/drug effects/metabolism ; Serum Albumin/deficiency ; Spermine/physiology ; Sulfhydryl Compounds/blood ; }, abstract = {The mechanism of wasting, as it occurs in malignant diseases and various etiologically unrelated conditions, is still poorly understood. We have, therefore, studied putative cause/effect relationships in a murine model of cancer cachexia, C57BL/6 mice bearing the fibrosarcoma MCA-105. The plasma of these mice showed decreased albumin and increased glutamate levels, which are typically found in practically all catabolic conditions. Skeletal muscles from tumor-bearing mice were found to have an abnormally low mitochondrial respiratory chain activity (mito.RCA) and significantly decreased glutathione (GSH) levels. The decrease in mito.RCA was correlated with an increase in the i.m. GSH disulfide/GSH ratio, the plasma cystine/thiol ratio, and the GSH disulfide/GSH ratio in the bile. This is indicative of a generalized shift in the redox state extending through different body fluids. Treatment of tumor-bearing mice with ornithine, a precursor of the radical scavenger spermine, reversed both the decrease in mito.RCA and the change in the redox state, whereas treatment with cysteine, a GSH precursor, normalized only the redox state. Treatment of normal mice with difluoromethyl-ornithine, a specific inhibitor of ornithine decarboxylase and spermine biosynthesis, inhibited the mito.RCA in the skeletal muscle tissue, thus illustrating the importance of the putrescine/spermine pathway in the maintenance of mito.RCA. Ornithine, cysteine, and N-acetyl-cysteine (NAC) also reconstituted the abnormally low concentrations of the GSH precursor glutamate in the skeletal muscle tissue of tumor-bearing mice. Higher doses, however, enhanced tumor growth and increased the plasma glucose level in normal mice. In the latter, cysteine and NAC also decreased i.m. catalase and GSH peroxidase activities. Taken together, our studies on the effects of ornithine, cysteine, and NAC illuminate some of the mechanistic pathways involved in cachexia and suggest targets for therapeutic intervention.}, }
@article {pmid10411685, year = {1999}, author = {Rangan, GK and Wang, Y and Tay, YC and Harris, DC}, title = {Inhibition of nuclear factor-kappaB activation reduces cortical tubulointerstitial injury in proteinuric rats.}, journal = {Kidney international}, volume = {56}, number = {1}, pages = {118-134}, doi = {10.1046/j.1523-1755.1999.00529.x}, pmid = {10411685}, issn = {0085-2538}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Movement/drug effects ; Doxorubicin ; Kidney/drug effects/metabolism/pathology/physiopathology ; Kidney Cortex/*pathology ; Kidney Tubules/*pathology ; Lipid Peroxides/metabolism ; Macrophages/physiology ; Male ; Monocytes/physiology ; NF-kappa B/drug effects/*physiology ; Nephrosis/chemically induced/physiopathology ; Proteinuria/chemically induced/*pathology/physiopathology ; Pyrrolidines/pharmacology ; Rats ; Rats, Wistar ; Thiocarbamates/pharmacology ; Time Factors ; }, abstract = {BACKGROUND: Protein-induced chemokine expression in proximal tubular cells is mediated by the transcription factor nuclear factor-kappa B (NF-kappaB). We hypothesized that in vivo inhibition of renal NF-kappaB activation would reduce interstitial monocyte infiltration in a rat model of nonimmune proteinuric tubulointerstitial inflammation.<br><br>METHODS: Male Wistar rats received a single intravenous injection of doxorubicin hydrochloride [adriamycin (ADR), 7.5 mg/kg] and were studied 7, 14, 21, and 28 days later. In a second study, inhibitors of NF-kappaB [N-acetylcysteine (NAC; 150 mg/kg, b.i.d., i.p.), pyrrolidine dithiocarbamate (PDTC, 50 mg/kg, b. i.d., i.p.)] or vehicle were commenced on day 14 after the onset of proteinuria and were continued until day 30.<br><br>RESULTS: Rats injected with ADR had increased proteinuria (UpV, day 28, 474 +/- 57; control, 18 +/- 2 mg/day; P < 0.01) and cortical tubulointerstitial injury [tubule cell atrophy, interstitial volume, and monocyte/macrophage (ED-1) infiltration]. Electrophoretic mobility shift assay of nuclear extracts from whole cortex of ADR rats demonstrated that NF-kappaB activation (p50/65, p50/c-Rel) increased from day 7 (4.7 +/- 0.2 fold-increase above control; P < 0.01) was maximal at day 28 (6.2 +/- 0.7; P < 0.01) and correlated with UpV (r = 0.63; P < 0.05) and interstitial ED-1 infiltration (r = 0.67; P < 0.01). Chronic treatment of ADR rats with PDTC suppressed NF-kappaB activation (by 73%; P < 0.05) without any effect on UpV. NF-kappaB inhibition with PDTC was accompanied by a reduction in tubule cell atrophy (59%; P < 0.01), interstitial volume (49%; P < 0.05) and ED-1 infiltration (48%; P < 0.01), and cortical lipid peroxidation (41%; P < 0.05) compared with vehicle-treated ADR rats. In contrast NAC had no effect on NF-kappaB activation, tubulointerstitial injury, or UpV in ADR rats.<br><br>CONCLUSION: The activation of NF-kappaB may have an important role in mediating cortical interstitial monocyte infiltration and tubular injury in nonimmune proteinuric tubulointerstitial inflammation.}, }
@article {pmid10408905, year = {1999}, author = {Chatterjee, A and Deb, S}, title = {Genotoxic effect of arecoline given either by the peritoneal or oral route in murine bone marrow cells and the influence of N-acetylcysteine.}, journal = {Cancer letters}, volume = {139}, number = {1}, pages = {23-31}, doi = {10.1016/s0304-3835(98)00364-4}, pmid = {10408905}, issn = {0304-3835}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Animals ; Arecoline/*administration &amp; dosage/*toxicity ; Bone Marrow Cells/ultrastructure ; Cell Cycle/drug effects ; *Chromosome Aberrations ; Free Radical Scavengers/pharmacology ; Injections, Intraperitoneal ; Kinetics ; Male ; Mice ; Nicotinic Agonists/administration &amp; dosage/pharmacology ; Sister Chromatid Exchange/drug effects ; Time Factors ; }, abstract = {The carcinogenic potentiality of the major alkaloid of betel nut, arecoline (ARC), is well established. This study was undertaken to determine the differences in genotoxic effects of ARC when given by two different routes (oral administration (OA) and intraperitoneal injection (IP)) in mouse bone marrow cells (BMC) since ARC carcinogenicity was observed only when ARC was given orally. The data indicate that ARC-OA induced a higher frequency of cancers, a greater delay in the cell cycle and greater sister chromatid exchanges than ARC-IP. The presence of N-acetyl cysteine along with ARC-OA significantly reduced the effect of ARC.}, }
@article {pmid10397212, year = {1999}, author = {Molnár, Z and Shearer, E and Lowe, D}, title = {N-Acetylcysteine treatment to prevent the progression of multisystem organ failure: a prospective, randomized, placebo-controlled study.}, journal = {Critical care medicine}, volume = {27}, number = {6}, pages = {1100-1104}, doi = {10.1097/00003246-199906000-00028}, pmid = {10397212}, issn = {0090-3493}, mesh = {APACHE ; Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Adult ; Aged ; Critical Care ; Double-Blind Method ; Female ; Free Radical Scavengers/administration &amp; dosage/adverse effects/*therapeutic use ; Humans ; Infusions, Intravenous ; Intensive Care Units ; Male ; Middle Aged ; Multiple Organ Failure/*drug therapy/mortality ; Time Factors ; }, abstract = {OBJECTIVES: To investigate whether prolonged infusion of N-acetylcysteine (NAC) that is commenced immediately after admission to the intensive care unit could ameliorate the development or progression of multisystem organ failure and improve mortality.<br><br>DESIGN: Prospective, randomized, double-blinded clinical trial.<br><br>SETTING: Six-bed intensive care unit in a teaching hospital.<br><br>PATIENTS: Of the 100 patients recruited (14 withdrew), 86 patients were studied.<br><br>INTERVENTIONS: After randomization, the treatment group (n = 41) received NAC (150 mg/kg bolus followed by a continuous infusion of 12 mg/kg/hr) and the placebo group (n = 45) received 5% dextrose, from a minimum of 3 days up to a maximum of 5 days.<br><br>MEASUREMENTS AND MAIN RESULTS: There was no statistically significant difference between the two groups regarding outcome as indicated by mortality and the required days of inotropic support, mechanical ventilation, and intensive care. The time interval between hospital and intensive care unit admission showed great variability, with a median of 24 hrs for the whole sample. By splitting the groups with this median value, the effect of NAC was examined on patients admitted within 24 hrs and after 24 hrs of arrival to the hospital. There was a nonsignificant difference in mortality in favor of NAC. Patients admitted after 24 hrs of hospital admission had a significantly worse mortality in the NAC-treated group (61% vs. 32% for controls; p = .05).<br><br>CONCLUSIONS: We found a nonsignificant difference in outcome between NAC and placebo-treated patients. Our results suggest that the initiation of NAC treatment >24 hrs after hospital admission may potentially be harmful, and further studies should be undertaken to investigate the clinical use of the early application of NAC in critically ill patients.}, }
@article {pmid10395951, year = {1999}, author = {Stefanelli, C and Pignatti, C and Tantini, B and Stanic, I and Bonavita, F and Muscari, C and Guarnieri, C and Clo, C and Caldarera, CM}, title = {Nitric oxide can function as either a killer molecule or an antiapoptotic effector in cardiomyocytes.}, journal = {Biochimica et biophysica acta}, volume = {1450}, number = {3}, pages = {406-413}, doi = {10.1016/s0167-4889(99)00045-2}, pmid = {10395951}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/drug effects/*physiology ; *Caspase Inhibitors ; Cells, Cultured ; Chick Embryo ; Glutathione/analogs &amp; derivatives/pharmacology ; Heart/embryology/*physiology ; Nitric Oxide/antagonists &amp; inhibitors/*physiology ; Nitro Compounds/pharmacology ; Penicillamine/analogs &amp; derivatives/pharmacology ; Staurosporine/pharmacology ; }, abstract = {Caspase enzymes are a family of cysteine proteases that play a central role in apoptosis. Recently, it has been demonstrated that caspases can be S-nitrosylated and inhibited by nitric oxide (NO). The present report shows that in chick embryo heart cells (CEHC), NO donor molecules such as S-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione, spermine-NO or sodium nitroprusside inhibit caspase activity in both basal and staurosporine-treated cells. However, the inhibitory effect of NO donors on caspase activity is accompanied by a parallel cytotoxic effect, that precludes NO to exert its antiapoptotic capability. N-Acetylcysteine (NAC) at a concentration of 10 mM blocks depletion of cellular glutathione and cell death in SNAP-treated CEHC, but it poorly affects the ability of SNAP to inhibit caspase activity. Consequently, in the presence of NAC, SNAP attenuates not only caspase activity but also cell death of staurosporine-treated CEHC. These data show that changes in the redox environment may inhibit NO-mediated toxicity, without affecting the antiapoptotic capability of NO, mediated by inhibition of caspase enzymes. NO may thus be transformed from a killer molecule into an antiapoptotic agent.}, }
@article {pmid10395401, year = {1999}, author = {Silbergleit, R and Haywood, Y and Fiskum, G and Rosenthal, RE}, title = {Lack of a neuroprotective effect from N-acetylcysteine after cardiac arrest and resuscitation in a canine model.}, journal = {Resuscitation}, volume = {40}, number = {3}, pages = {181-186}, doi = {10.1016/s0300-9572(99)00027-1}, pmid = {10395401}, issn = {0300-9572}, support = {R01 NS34152-02/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Brain Ischemia/*prevention &amp; control ; Cardiopulmonary Resuscitation/*methods ; Cerebrovascular Circulation/*drug effects ; Disease Models, Animal ; Dogs ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Heart Arrest/*drug therapy/therapy ; Reference Values ; Time Factors ; Ventricular Fibrillation ; }, abstract = {OBJECTIVE: Oxygen free radicals cause brain injury following resuscitation from cardiac arrest. In preclinical trials, some free radical scavenging drugs reduce oxidative neuronal damage after ischemia and reperfusion, but these drugs are generally not yet available for clinical testing or use. N-Acetylcysteine (NAC), a commonly used antidote in acetaminophen poisoning, is also a potent free radical scavenger that can ameliorate oxidative injury following ischemia and reperfusion in neuronal cell culture. We hypothesized that treatment with NAC would improve neurological outcome after cardiac arrest and resuscitation.<br><br>METHODS: In 16 adult female beagles, 10 min of ventricular fibrillation was followed by 3 min of open-chest CPR, and defibrillation. Immediately following return of spontaneous circulation, animals randomly received either 150 mg/kg NAC (3% solution) (n = 8) or an equivalent volume of normal saline (n = 8). Twenty-three hours later, neurological deficit was scored (0 = normal, 100 = brain death).<br><br>RESULTS: All animals were successfully resuscitated, and there were no apparent adverse effects to the administration of NAC in post resuscitative animals. There was, however, no significant difference in neurological deficit in the animals receiving NAC (40 +/- 12.9, mean +/- SD) compared to control animals (44 +/- 6.5, P = 0.73).<br><br>CONCLUSION: No neuroprotective effect was found from the administration of NAC at currently used clinical dosages, to dogs subjected to 10 min of global cerebral ischemia from cardiac arrest and resuscitation.}, }
@article {pmid10393400, year = {1999}, author = {Sajkowska, A and Wykretowicz, A and Szczepanik, A and Kempa, M and Minczykowski, A and Wysocki, H}, title = {Fibrinolytic therapy and n-acetylocysteine in the treatment of patients with acute myocardial infarction: its influence on authentic plasma hydroperoxide levels and polymorphonuclear neutrophil oxygen metabolism.}, journal = {Cardiology}, volume = {91}, number = {1}, pages = {60-65}, doi = {10.1159/000006878}, pmid = {10393400}, issn = {0008-6312}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Drug Therapy, Combination ; Female ; Humans ; Hydrogen Peroxide/*blood ; Lipid Peroxides/blood ; Male ; Middle Aged ; Myocardial Infarction/blood/*drug therapy ; Neutrophils/*drug effects ; Oxidative Stress/drug effects ; Oxygen Consumption/drug effects ; Streptokinase/*administration &amp; dosage ; *Thrombolytic Therapy ; }, abstract = {Recently it has been demonstrated that the administration of n-acetylocysteine (NAC), in combination with streptokinase, significantly diminished oxidative stress in patients with myocardial infarction. The aim of our study was to assess the influence of NAC treatment, as adjunct therapy in an evolving myocardial infarction, on the polymorphonuclear count, superoxide anion and hydrogen peroxide levels and nitric oxide production by PMNs and authentic plasma hydroperoxide (ROOH). Treatment of patients with NAC in addition to reperfusion therapy was accompanied by a significant decrease in the number of circulating polymorphonuclear neutrophils. However, the oxygen metabolism of PMNs was not affected by NAC administration. The concentration of authentic plasma hydroperoxide was significantly reduced by the administration of NAC which suggests diminished oxidative stress during acute myocardial infarction.}, }
@article {pmid10391097, year = {1999}, author = {Miyajima, A and Nakashima, J and Tachibana, M and Nakamura, K and Hayakawa, M and Murai, M}, title = {N-acetylcysteine modifies cis-dichlorodiammineplatinum-induced effects in bladder cancer cells.}, journal = {Japanese journal of cancer research : Gann}, volume = {90}, number = {5}, pages = {565-570}, pmid = {10391097}, issn = {0910-5050}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/antagonists &amp; inhibitors/*therapeutic use ; Cisplatin/antagonists &amp; inhibitors/*therapeutic use ; DNA Fragmentation ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Humans ; In Situ Nick-End Labeling ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; Urinary Bladder Neoplasms/*drug therapy/metabolism ; }, abstract = {We previously demonstrated a role of reactive oxygen species (ROS) in cytotoxicity induced by cis-dichlorodiammineplatinum (CDDP) in combination with glutathione (GSH) depletors in bladder cancer cells. However, the relationship between CDDP and ROS is still unclear, although many mechanisms of drug resistance have been well characterized. The present study was undertaken to investigate the effects of N-acetylcysteine (NAC), a GSH precursor, on the CDDP-induced effects in bladder cancer cells (KU1). The cytotoxic effects of CDDP were significantly blunted by NAC (1 mM) in KU1 cells. The IC50 of CDDP only (10.2+/-1.2 microM) is significantly lower than that of CDDP with NAC (IC50: 20.3+/-1.6 microM) in KU1 cells. NAC also significantly increased the intracellular concentration of GSH in KU1 cells (37.2+/-1.6 nmol/10(6) cells), compared to controls (15.9+/-7.6 nmol/10(6) cells). While CDDP produced a significant increase in ROS as measured in terms of dichlorofluorescein (DCF) production in KU1 cells in a time-dependent manner, pretreatment with NAC significantly reduced CDDP-induced intracellular DCF in KU1 cells. Moreover, TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay showed that CDDP-induced apoptosis (31.1+/-3.8%) was significantly inhibited by pretreatment with NAC in KU1 cells (11.2+/-2.6%). These results demonstrated that NAC scavenges CDDP-induced ROS and inhibits CDDP-induced cytotoxicity, suggesting that ROS mediate the CDDP-induced cytotoxicity in bladder cancer cells.}, }
@article {pmid10385654, year = {1999}, author = {Hentze, H and Künstle, G and Volbracht, C and Ertel, W and Wendel, A}, title = {CD95-Mediated murine hepatic apoptosis requires an intact glutathione status.}, journal = {Hepatology (Baltimore, Md.)}, volume = {30}, number = {1}, pages = {177-185}, doi = {10.1002/hep.510300111}, pmid = {10385654}, issn = {0270-9139}, mesh = {Acetylcysteine/pharmacology ; Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Butylated Hydroxytoluene/pharmacology ; Caspase 3 ; Caspases/metabolism ; Catalase/pharmacology ; Cysteine Proteinase Inhibitors/pharmacology ; DNA Fragmentation ; Glutathione/antagonists &amp; inhibitors/*metabolism ; Glutathione Disulfide/metabolism ; Glutathione Transferase/metabolism ; Humans ; Ketones/*pharmacology ; Liver/*cytology/pathology/physiology ; Male ; Mice ; Mice, Inbred BALB C ; Vitamin E/pharmacology ; fas Receptor/immunology/*physiology ; }, abstract = {Agonistic engagement of the cytokine receptor CD95 in mice leads to activation of hepatic caspases, followed by massive hepatocyte apoptosis, acute liver failure, and death. This mechanism of cell death is thought to be associated with several human liver disorders. Because hepatic glutathione represents the major defense against toxic liver injury, we investigated its role in CD95-mediated liver failure, which represents a model for hyperinflammatory organ destruction. As a tool for modulating the liver glutathione status of mice in vivo, we used the GSH transferase substrate, phorone, which rapidly depleted hepatic glutathione in a dose-dependent manner. When GSH was depleted, CD95-initiated hepatic caspase-3-like activity and DNA fragmentation were completely blocked, and animals were protected from liver injury dose-dependently as assessed by histological examination and determination of liver enzymes in plasma. Conversely, repletion of hepatic glutathione by treatment with the permeable glutathione monoethylester restored susceptibility of GSH-depleted mice toward CD95-mediated liver injury. In contrast, the antioxidants, GSH, N-acetyl cysteine, alpha-tocopherol, butyl-hydroxytoluene, and catalase failed to do so. Animals treated once with phorone survived for more than 3 months after an otherwise lethal injection of the activating anti-CD95 antibody. We investigated the thiol sensitivity of recombinant caspase-3 in vitro and observed that its activity was dependent on the presence of a reducing agent such as GSH, while GSSG attenuated proteolytic activity. Based on our finding that CD95-mediated hepatocyte apoptosis requires an intact intracellular glutathione status, we propose that the activation of apoptosis-executing caspases is controlled by reduced glutathione.}, }
@article {pmid10383443, year = {1999}, author = {Xie, Z and Kometiani, P and Liu, J and Li, J and Shapiro, JI and Askari, A}, title = {Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes.}, journal = {The Journal of biological chemistry}, volume = {274}, number = {27}, pages = {19323-19328}, doi = {10.1074/jbc.274.27.19323}, pmid = {10383443}, issn = {0021-9258}, support = {HL-36573/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Calcium/metabolism ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cardiomegaly/*genetics ; Cardiotonic Agents/pharmacology ; Cells, Cultured ; Enzyme Activation ; Genetic Markers ; Heart/drug effects ; Myocardium/*enzymology ; Ouabain/pharmacology ; Proto-Oncogene Proteins c-fos/metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*metabolism ; Rubidium/pharmacokinetics ; Sodium-Potassium-Exchanging ATPase/*metabolism ; Transcription Factor AP-1/metabolism ; Vitamin E/pharmacology ; }, abstract = {We showed before that in cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophy and transcriptional regulations of growth-related marker genes through multiple Ca2+-dependent signal pathways many of which involve Ras and p42/44 mitogen-activated protein kinases. The aim of this work was to explore the roles of intracellular reactive oxygen species (ROS) in these ouabain-initiated pathways. Ouabain caused a rapid generation of ROS within the myocytes that was prevented by preexposure of cells to N-acetylcysteine (NAC) or vitamin E. These antioxidants also blocked or attenuated the following actions of ouabain: inductions of the genes of skeletal alpha-actin and atrial natriuretic factor, repression of the gene of the alpha3-subunit of Na+/K+-ATPase, activation of mitogen-activated protein kinases, activation of Ras-dependent protein synthesis, and activation of transcription factor NF-kappaB. Induction of c-fos and activation of AP-1 by ouabain were not sensitive to NAC. Ouabain-induced inhibition of active Rb+ uptake through Na+/K+-ATPase and the resulting rise in intracellular Ca2+ were also not prevented by NAC. A phorbol ester that also causes myocyte hypertrophy did not increase ROS generation, and its effects on marker genes and protein synthesis were not affected by NAC. We conclude the following: (a) ROS are essential second messengers within some but not all signal pathways that are activated by the effect of ouabain on Na+/K+-ATPase; (b) the ROS-dependent pathways are involved in ouabain-induced hypertrophy; (c) increased ROS generation is not a common response of the myocyte to all hypertrophic stimuli; and (d) it may be possible to dissociate the positive inotropic effect of ouabain from its growth-related effects by alteration of the redox state of the cardiac myocyte.}, }
@article {pmid10381639, year = {1999}, author = {Friesen, C and Fulda, S and Debatin, KM}, title = {Induction of CD95 ligand and apoptosis by doxorubicin is modulated by the redox state in chemosensitive- and drug-resistant tumor cells.}, journal = {Cell death and differentiation}, volume = {6}, number = {5}, pages = {471-480}, doi = {10.1038/sj.cdd.4400512}, pmid = {10381639}, issn = {1350-9047}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Down-Regulation ; Doxorubicin/*metabolism/pharmacology ; Drug Resistance ; Fas Ligand Protein ; Glutathione/metabolism/pharmacology ; Membrane Glycoproteins/*biosynthesis/genetics ; Oxidation-Reduction ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; bcl-X Protein ; fas Receptor/metabolism ; }, abstract = {Induction of CD95 ligand (CD95-L) may contribute to drug-induced apoptosis in chemosensitive leukemias and solid tumors. Here we report that induction of CD95-L and apoptosis by doxorubicin in leukemic and neuroblastoma cells is regulated by the redox state and reactive oxygen species (ROS). Preincubation of chemosensitive cells with antioxidants such as N-acetyl-cysteine (NAC) or glutathione (GSH), significantly reduced doxorubicin-induced apoptosis, hyperexpression of ROS, loss of mitochondrial membrane potential (DeltaPsim) and upregulation of CD95-L expression. Doxorubicin-resistant cells exhibited higher levels of GSH in comparison to chemosensitive cells and were deficient in hyperproduction of ROS, loss of DeltaPsim and upregulation of CD95-L in response to cytotoxic drugs. Downregulation of intracellular GSH concentrations reversed deficient drug-induced hyperproduction of ROS and CD95-L upregulation. In addition, overexpression of Bcl-XL in CEM cells blocked doxorubicin-triggered ROS and CD95-L expression. These findings suggest that induction of CD95-L by cytotoxic drugs is modulated by the cellular redox state and mitochondria derived ROS.}, }
@article {pmid10381628, year = {1999}, author = {Heussler, VT and Fernandez, PC and Machado, J and Botteron, C and Dobbelaere, DA}, title = {N-acetylcysteine blocks apoptosis induced by N-alpha-tosyl-L-phenylalanine chloromethyl ketone in transformed T-cells.}, journal = {Cell death and differentiation}, volume = {6}, number = {4}, pages = {342-350}, doi = {10.1038/sj.cdd.4400501}, pmid = {10381628}, issn = {1350-9047}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Annexin A5/metabolism ; Apoptosis/*drug effects ; Cell Division/drug effects ; Cell Line, Transformed/cytology/drug effects/parasitology ; Cysteine/pharmacology ; DNA-Binding Proteins/metabolism ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; Humans ; I-kappa B Proteins ; Jurkat Cells/*cytology/drug effects/parasitology ; NF-kappa B/metabolism ; Phosphorylation ; Serine Proteinase Inhibitors/*pharmacology ; Theileria parva ; Theileriasis/immunology ; Tosylphenylalanyl Chloromethyl Ketone/*pharmacology ; Transcriptional Activation/drug effects ; }, abstract = {The serine protease inhibitor N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) can interfere with cell-cycle progression and has also been shown either to protect cells from apoptosis or to induce apoptosis. We tested the effect of TPCK on two transformed T-cell lines. Both Jurkat T-cells and Theileria parva-transformed T-cells were shown to be highly sensitive to TPCK-induced growth arrest and apoptosis. Surprisingly, we found that the thiol antioxidant, N-acetylcysteine (NAC), as well as L- or D-cysteine blocked TPCK-induced growth arrest and apoptosis. TPCK inhibited constitutive NF-kappaB activation in T. parva-transformed T-cells, with phosphorylation of IkappaBalpha and IkappaBbeta being inhibited with different kinetics. TPCK-mediated inhibition of IkappaB phosphorylation, NF-kappaB DNA binding and transcriptional activity were also prevented by NAC or cysteine. Our observations indicate that apoptosis and NF-kappaB inhibition induced by TPCK result from modifications of sulphydryl groups on proteins involved in regulating cell survival and the NF-kappaB activation pathway(s).}, }
@article {pmid10378449, year = {1999}, author = {Yusof, M and Yildiz, D and Ercal, N}, title = {N-acetyl-L-cysteine protects against delta-aminolevulinic acid-induced 8-hydroxydeoxyguanosine formation.}, journal = {Toxicology letters}, volume = {106}, number = {1}, pages = {41-47}, doi = {10.1016/s0378-4274(99)00014-4}, pmid = {10378449}, issn = {0378-4274}, support = {1R15ES09497-01/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Aminolevulinic Acid/*toxicity ; Animals ; CHO Cells ; Catalase/pharmacology ; Cricetinae ; DNA Damage ; Guanosine/*analogs &amp; derivatives/metabolism ; Oxidation-Reduction ; Superoxide Dismutase/pharmacology ; }, abstract = {5-Aminolevulinic acid (ALA) is a heme precursor that accumulates in acute intermittent porphyria and lead poisoning. It has been shown that ALA induces free radical generation and may cause damage to proteins and DNA. In the present study, the effects of ALA on DNA damage and its prevention by N-acetyl-L-cysteine (NAC) and the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) are investigated. Oxidative damage to DNA was quantitated by measuring the increase in 8-hydroxy-2'-deoxyguanosine (oh8dG) formation. The time-course study demonstrated that ALA causes a linear increase in oh8dG levels in Chinese hamster ovary (CHO) cells. However, direct lead exposure did not cause any measurable increase in oh8dG levels. In the presence of either NAC (1 mM) or antioxidant enzymes (10 u/ml SOD and 10 u/ml CAT), oh8dG levels returned to the corresponding control levels. This suggests a protective role for NAC and the antioxidant enzymes. To determine the effect of ALA on cell proliferation, cell numbers were counted at the end of 24 h of incubation in the presence and absence of ALA at different concentrations. Results showed that levels of ALA up to 5 mM do not inhibit cell proliferation.}, }
@article {pmid10375166, year = {1999}, author = {Sakaguchi, N and Inoue, M and Isuzugawa, K and Ogihara, Y and Hosaka, K}, title = {Cell death-inducing activity by gallic acid derivatives.}, journal = {Biological &amp; pharmaceutical bulletin}, volume = {22}, number = {5}, pages = {471-475}, doi = {10.1248/bpb.22.471}, pmid = {10375166}, issn = {0918-6158}, mesh = {Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Death/*drug effects ; DNA Fragmentation ; Drug Screening Assays, Antitumor ; Gallic Acid/analogs &amp; derivatives/*pharmacology ; HL-60 Cells ; Humans ; Inhibitory Concentration 50 ; Signal Transduction ; }, abstract = {In this study, the cytotoxic activity of gallic acid derivatives (GDs) was studied using some cancer cell lines. Among them, 3,4-methylenedioxyphenyl 3,4,5-trihydroxybenzoate (GD-1) and S-(3,4-methylenedioxyphenyl)-3,4,5-trihydroxy-thiobenzoate (GD-3) were found to induce cell death in cancer cell lines with IC50s ranging from 2.9 to 114.4 microM, a concentration comparable with or lower than that of gallic acid. On the other hand, although gallic acid did not show any cytotoxicity against primary cultured rat hepatocytes and human keratinocytes, GD-1 and -3 showed slightly higher sensitivity against such normal cells, when compared with gallic acid. The cell death induced by gallic acid and GD-1 was accompanied by internucleosomal DNA fragmentation characteristic of apoptosis, whereas only smear DNA degradation was detected following GD-3 treatment. When the mechanism by which GD-1 and -3 caused cell death in HL-60RG cells was examined, GD-1 and -3-induced cell death was inhibited by the intracellular Ca2+ chelator, bis-(o-aminophenoxy)-N,N,N,N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM), calmodulin inhibitor, W-7, and the Ca2+/Mg2+ -dependent endonuclease inhibitor zinc sulfate. In contrast, catalase, N-acetylcysteine (NAC), and ascorbic acid inhibited gallic acid-induced apoptosis in HL-60RG cells, whereas they had no effect on GD-1- and -3-induced cell death. This result suggests that GD-1 and -3 induced cell death in a different manner to gallic acid. In conclusion, esterification of gallic acid with a 3,4-methylenedioxyphenyl group yielded potent agents to treat cancer with a different signaling pathway from gallic acid, although selectivity was lost.}, }
@article {pmid10368658, year = {1999}, author = {Takenaga, M and Igarashi, R and Nakayama, T and Mizushima, Y}, title = {Lecithinized ascorbic acid (PC-AS) effectively inhibits murine pulmonary metastasis.}, journal = {Anticancer research}, volume = {19}, number = {2A}, pages = {1085-1091}, pmid = {10368658}, issn = {0250-7005}, mesh = {Animals ; Antioxidants/pharmacology ; Ascorbic Acid/pharmacokinetics/pharmacology/*therapeutic use ; Dose-Response Relationship, Drug ; Female ; Lung Neoplasms/prevention &amp; control/*secondary ; Male ; Mice ; Mice, Inbred BALB C ; Nitric Oxide/analysis ; Phosphatidylcholines/pharmacokinetics/pharmacology/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Tumor Cells, Cultured ; }, abstract = {In order to enhance the lipophilicity and develop the efficacy of ascorbic acid (ASA), we synthesized lecithinized ascorbic acid (PC-AS), in which a lecithin was covalently bound to ASA. Its pharmacological activity was also evaluated. The IC50 value of scavenge superoxide anions generated from hypoxanthine in combination with xanthine oxidase, indicated that the antioxidative activity of PC-AS (IC50; 22.19 microM) was about 60% of that shown by ASA (IC50; 13.35 microM). Also, PC-AS suppressed in vitro cell growth of Meth A-T, a highly metastatic cell line established by us. Although its potency (IC50; 110.0 microM) was a little lower than that of ASA, dramatic suppression was observed under serum-free culture conditions (IC50; 13.0 microM). In addition, N-acetylcysteine (NAC), an antioxidant, showed an additive inhibitory effect on cell growth in combination with PC-AS and ASA. Biodistribution studies revealed that PC-AS persisted longer in the blood (AUC0-240 min; 182.8 nmole min ml-1) than ASA (AUC0-240 min; 79.35 nmole min ml-1). It should be noted that intravenous preadministration of PC-AS significantly and dose-dependently reduced the number of colony formation in an experimental murine pulmonary metastasis model. ASA had little effect. [3H]-labeled Meth A-T cells predominantly accumulated in the lung, metastatic target organ, which was reduced by PC-AS. Our in vivo study showed that PC-AS could not totally prevent pulmonary invasion of Meth A-T cells, however, PC-AS effectively inhibited the number of metastatic colony formation. PC-AS's potency was superior to that of unmodified ASA. These findings might be in part ascribed to changes to lecithinization-induced biodistribution, antioxidative activity and cytotoxicity.}, }
@article {pmid10368077, year = {1999}, author = {Thompson, CD and Barthen, MT and Hopper, DW and Miller, TA and Quigg, M and Hudspeth, C and Montouris, G and Marsh, L and Perhach, JL and Sofia, RD and Macdonald, TL}, title = {Quantification in patient urine samples of felbamate and three metabolites: acid carbamate and two mercapturic acids.}, journal = {Epilepsia}, volume = {40}, number = {6}, pages = {769-776}, doi = {10.1111/j.1528-1157.1999.tb00777.x}, pmid = {10368077}, issn = {0013-9580}, support = {T326M07055//PHS HHS/United States ; }, mesh = {Acetylcysteine/*urine ; Aldehydes/*urine ; Animals ; Anticonvulsants/*metabolism/*urine ; Carbamates/urine ; Chromatography, High Pressure Liquid ; Epilepsy/drug therapy/metabolism ; Felbamate ; Humans ; Mass Spectrometry ; Phenylcarbamates ; Propylene Glycols/*metabolism/*urine ; Radioisotope Dilution Technique ; Rats ; }, abstract = {PURPOSE: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine.<br><br>METHODS: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population.<br><br>RESULTS: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured.<br><br>CONCLUSIONS: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.}, }
@article {pmid10365774, year = {1999}, author = {White, AC and Maloney, EK and Lee, SL and Lanzillo, JJ and Fanburg, BL}, title = {Reduction of endothelial cell related TGFbeta activity by thiols.}, journal = {Endothelium : journal of endothelial cell research}, volume = {6}, number = {3}, pages = {231-239}, doi = {10.3109/10623329909053413}, pmid = {10365774}, issn = {1062-3329}, support = {HL42376/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cattle ; Cells, Cultured ; Culture Media, Conditioned ; Cysteine/pharmacology ; Dose-Response Relationship, Drug ; Endothelium, Vascular/cytology/*metabolism ; Glutathione/metabolism/pharmacology ; Glutathione Disulfide/metabolism/pharmacology ; Oxidation-Reduction ; Pulmonary Artery/cytology ; Sulfhydryl Compounds/*metabolism/pharmacology ; Swine ; Transforming Growth Factor beta/genetics/*metabolism ; }, abstract = {Transforming growth factor beta (TGFbeta) may play an important role in diseases characterized by pulmonary fibrosis. We have previously demonstrated that thiols inhibit the pro-oxidant effects of TGFbeta1 in bovine pulmonary artery endothelial cells (BPAEC). To help define the mechanism of this observation we have examined the effect of reduced (GSH) and oxidized (GSSG) glutathione, N-acetyl cysteine (NAC) and cysteine (CYS) on the biological activity of a) TGFbeta released by bovine pulmonary artery endothelial cells (BPAEC) into culture medium, and b) commercially available porcine platelet TGFbeta1. The biological activity of TGFbeta (following activation) released into the medium from cultured BPAEC was significantly reduced when the cells were cultured in the presence of 10 mM GSH or 10 mM NAC for 24 h (10 mM GSH: 85.7 +/- 50 pg/ml/10(6) cells and 10 mM NAC: 127.3 +/- 35 pg/ml/10(6) cells, compared with control: 541 +/- 8.9 pg/ml/10(6) cells; p < 0.05). Thiols (10 mM GSH, 10 mM NAC and 5 mM cysteine), added directly to cell-free conditioned medium or to a commercially available preparation of porcine platelet TGFbeta1 for 6-24 h had a similar inhibitory effect on the biological activity of TGFbeta and altered the structure of porcine platelet TGFbeta1 as determined by mass spectroscopy. These thiols failed to reduce the expression of TGFbeta mRNA in BPAEC as measured by a competitive polymerase chain reaction assay. Incubating endothelial cells or cell-free conditioned medium with GSSG did not alter the biological activity of TGFbeta. Lower doses of thiols (0.1-1 mM), that we have shown inhibit the antiproliferative and pro-oxidant effects of exogenous TGFbeta1 on BPAEC, had no direct effect on TGFbeta bioactivity. In summary, thiols are capable of reducing the effects of TGFbeta in biological systems through a direct effect on the TGFbeta molecule. However, this action appears to be dose-dependent, and at low doses (0.1-1 mM) thiols may also inhibit the actions of exogenous TGFbeta1 in cell culture through a mechanism involving the cellular redox status.}, }
@article {pmid10365635, year = {1999}, author = {Berkovitch, M and Eshel, G and Lushkov, G and Reznik, S and Chen-Levy, Z and Pinto, O and Koren, G}, title = {The effect of diazepam in the recovery of rabbits from acute acetaminophen intoxication.}, journal = {Therapeutic drug monitoring}, volume = {21}, number = {3}, pages = {267-273}, doi = {10.1097/00007691-199906000-00002}, pmid = {10365635}, issn = {0163-4356}, mesh = {Acetaminophen/blood/*poisoning ; Acute Disease ; Administration, Oral ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/blood/*therapeutic use ; Animals ; Aspartate Aminotransferases/blood ; Creatinine/blood ; Diazepam/*therapeutic use ; Drug Evaluation, Preclinical ; Male ; Rabbits ; Survival Rate ; Treatment Outcome ; Urea/blood ; }, abstract = {We have recently shown that diazepam can reduce mortality of acute iron overdose in rats. The mechanism for that effect is not yet defined. Our objective in the present study was to assess whether diazepam can similarly reduce mortality of experimental acute acetaminophen intoxication. Survival of rabbits was compared among four groups receiving 3 g/kg (body weight) of acetaminophen (LD40) orally each, followed by: 1) nothing (group I), 2) one oral dose of 140 mg/kg N-acetylcystein (NAC) an hour later (group II), 3) intramuscular injection of 7 mg/kg diazepam (group III), 4) intramuscular injection of 7 mg/kg diazepam and one oral dose of 140 mg/kg NAC an hour later (group IV). 37.5% of rabbits in group I died after 16 hours, whereas none of the rabbits in group III died, (p = 0.04). No animal died during the 96-hour observation period in groups II and IV. Two and four hours post drug administration, acetaminophen plasma concentrations (APC) were significantly lower among rabbits in group III than in group I (p = 0.0007 and 0.01, respectively) and significantly lower among rabbits in group IV than in those in group II (p<0.0001 and p = 0.03, respectively). Acetaminophen plasma concentrations 2 hours after drug administration were also significantly lower among rabbits in group III than in those in group II (p = 0.0002). Seven and 24 hours after dosage, APC tended to be higher among rabbits in group III than in those in group I, but not significantly so. Administration of diazepam without NAC did not prevent liver and renal dysfunction. We conclude that early administration of diazepam in acute experimental acetaminophen overdose in rabbits reduced APC and mortality, probably by slowing intestinal motility, which resulted in delayed acetaminophen absorption from the gastrointestinal tract.}, }
@article {pmid10362111, year = {1999}, author = {MacKinnon, AC and Armstrong, RA and Waters, CM and Cummings, J and Smyth, JF and Haslett, C and Sethi, T}, title = {[Arg6,D-Trp7,9,NmePhe8]-substance P (6-11) activates JNK and induces apoptosis in small cell lung cancer cells via an oxidant-dependent mechanism.}, journal = {British journal of cancer}, volume = {80}, number = {7}, pages = {1026-1034}, pmid = {10362111}, issn = {0007-0920}, mesh = {3T3 Cells ; Animals ; Antineoplastic Agents/*pharmacology ; *Apoptosis ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Carcinoma, Small Cell/*drug therapy/pathology ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Edema/chemically induced ; Enzyme Activation/drug effects ; GTP-Binding Proteins/metabolism ; Humans ; JNK Mitogen-Activated Protein Kinases ; Lung Neoplasms/*drug therapy/pathology ; Mice ; *Mitogen-Activated Protein Kinases ; Neuropeptides/pharmacology ; Oligopeptides/*pharmacology ; Rabbits ; Reactive Oxygen Species/physiology ; Tumor Cells, Cultured ; }, abstract = {[Arg6,D-Trp7,9,NmePhe8]-substance P (6-11) (antagonist G) is a novel class of anti-cancer agent that inhibits small-cell lung cancer (SCLC) cell growth in vitro and in vivo and is entering phase II clinical investigation for the treatment of SCLC. Although antagonist G blocks SCLC cell growth (IC50 = 24.5 +/- 1.5 and 38.5 +/- 1.5 microM for the H69 and H510 cell lines respectively), its exact mechanism of action is unclear. This study shows that antagonist G stimulates apoptosis as assessed by morphology (EC50 = 5.9 +/- 0.1 and 15.2 +/- 2.7 microM for the H69 and H510 cell lines respectively) and stimulates c-jun-N-terminal kinase (JNK) activity in SCLC cells (EC50 = 3.2 +/- 0.1 and 15.2 +/- 2.7 microM). This activity is neuropeptide-independent, but dependent on the generation of reactive oxygen species (ROS) and is inhibited by the free radical scavenger n-acetyl cysteine. Furthermore, antagonist G itself induces inflammation (59% increase in oedema volume compared to control) and potentiates (by 35-40%) bradykinin-induced oedema formation in vivo. In view of these results we show that, as well as acting as a 'broad-spectrum' neuropeptide antagonist, antagonist G stimulates basal G-protein activity in SCLC cell membranes (81 +/- 12% stimulation at 10 microM), thereby displaying a unique ability to stimulate certain signal transduction pathways by activating G-proteins. This novel activity may be instrumental for full anti-cancer activity in SCLC cells and may also account for antagonist G activity in non-neuropeptide-dependent cancers.}, }
@article {pmid10362048, year = {1999}, author = {Ekberg-Jansson, A and Larson, M and MacNee, W and Tunek, A and Wahlgren, L and Wouters, EF and Larsson, S}, title = {N-isobutyrylcysteine, a donor of systemic thiols, does not reduce the exacerbation rate in chronic bronchitis.}, journal = {The European respiratory journal}, volume = {13}, number = {4}, pages = {829-834}, doi = {10.1034/j.1399-3003.1999.13d22.x}, pmid = {10362048}, issn = {0903-1936}, mesh = {Administration, Oral ; Bronchitis/*drug therapy ; Chronic Disease ; Cysteine/administration &amp; dosage/*analogs &amp; derivatives/therapeutic use ; Double-Blind Method ; Female ; Humans ; Life Tables ; Male ; Middle Aged ; Spirometry ; Sulfhydryl Compounds ; }, abstract = {N-isobutyrylcysteine (NIC), a new thiol compound that is not rapidly hydrolysed to give higher levels of free thiols in the body than N-acetylcysteine (NAC), was used to test if the effect of NAC on exacerbations in chronic bronchitis was an effect of the unhydrolysed thiol compound. Smokers or exsmokers with chronic bronchitis forced expiratory volume in one second (FEV1) >40% and reversibility < or = 10% predicted were treated with oral NIC 300 mg b.i.d. or placebo for 24 weeks. Steroids, NAC, antibiotics, and nonsteroid anti-inflammatory drugs use were restricted. Exacerbations were recorded by a respiratory symptom diary card and the time to onset of the first exacerbation after the start of treatment was measured using life-table analysis. Spirometry was performed at each visit. Six hundred and thirty-seven patients were randomized to treatment with NIC (n=316) or placebo (n=321). NIC did not prolong the time to first exacerbation (life-table analysis, p=0.59) and no increase in FEV1 or forced vital capacity was observed. Altered taste perception, taste loss and anosmia occurred more often in the NIC group (p<0.001). In conclusion, N-isobutyrylcysteine, a N-acetylcysteine-like drug with a greater bioavailability has, contrary to N-acetylcysteine, no effect on exacerbations in chronic bronchitis. This suggests that the effect of N-acetylcysteine on exacerbations in chronic bronchitis is not due to the relatively low free thiol levels (other than glutathione) produced by N-acetylcysteine therapy.}, }
@article {pmid10361279, year = {1999}, author = {Wanke, V and Accorsi, K and Porro, D and Esposito, F and Russo, T and Vanoni, M}, title = {In budding yeast, reactive oxygen species induce both RAS-dependent and RAS-independent cell cycle-specific arrest.}, journal = {Molecular microbiology}, volume = {32}, number = {4}, pages = {753-764}, doi = {10.1046/j.1365-2958.1999.01391.x}, pmid = {10361279}, issn = {0950-382X}, mesh = {Acetylcysteine/pharmacology ; Cell Cycle/*genetics ; Cell Division/drug effects/genetics ; Cyclin-Dependent Kinases/metabolism ; Cyclins/genetics ; DNA/analysis ; Gene Expression Regulation, Fungal/drug effects ; *Genes, Fungal ; *Genes, ras ; Glutathione/metabolism ; Interphase/genetics ; Maleates/pharmacology ; Oxidative Stress/genetics ; Reactive Oxygen Species/*metabolism ; Saccharomyces cerevisiae/*genetics ; }, abstract = {The role of mild oxidative stresses elicited by diethylmaleate (DEM)-induced glutathione depletion in the progression of the yeast cell cycle has been investigated. We found that different wild-type strains are sensitive to oxidative stresses induced by similar DEM doses: approximately 1 mM on YPD plates, 5-10 mM in shaken flasks. At lower doses, DEM caused a transient decrease in growth rate, largely because of a decreased G1-to-S transition. Treatment with higher DEM doses leads to complete growth arrest, with most cells found in the unbudded G1 phase of the cell cycle. DEM treatment resulted in transcriptional induction of stress-responsive element (STRE)-controlled genes and was relieved by treatment with the antioxidant N-acetyl cysteine. Reciprocal shift experiments with cdc25 and cdc28 mutants showed that the major cell cycle arrest point was located in the Start area, at or near the CDC25-mediated step, before the step mediated by the CDC28 cyclin-dependent kinase. The DEM-induced G1 arrest requires a properly regulated RAS pathway and can be bypassed by overexpressing the G1-specific cyclin CLN2. However, cells with either a deregulated RAS pathway or overexpressing CLN2 failed to grow and arrested as budded cells, indicating that a second DEM-sensitive cell cycle step exists.}, }
@article {pmid10344471, year = {1999}, author = {Miyake, K and Kaise, T and Hosoe, H and Akuta, K and Manabe, H and Ohmori, K}, title = {The effect of erdosteine and its active metabolite on reactive oxygen species production by inflammatory cells.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {48}, number = {4}, pages = {205-209}, doi = {10.1007/s000110050447}, pmid = {10344471}, issn = {1023-3830}, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Dose-Response Relationship, Drug ; Eosinophils/*drug effects/metabolism ; Expectorants/metabolism/pharmacology ; Guinea Pigs ; Humans ; Male ; Neutrophils/*drug effects/metabolism ; Peritoneal Lavage ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; Thioglycolates/metabolism/*pharmacology ; Thiophenes/metabolism/*pharmacology ; }, abstract = {OBJECTIVE: We examined the effect of erdosteine (KW-9144), an expectorant, and related compounds on inflammatory cell-derived reactive oxygen species which are involved in airway inflammation.<br><br>METHODS: Neutrophils were isolated from peritoneal lavages of casein-injected rats and from peripheral blood of healthy human donors. Eosinophils were isolated from peritoneal lavages of horse serum-injected guinea pigs. These cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and the production of reactive oxygen species was measured with luminol-dependent chemiluminescence (LDCL).<br><br>RESULTS: M1, an active metabolite of erdosteine, significantly inhibited PMA-induced LDCL of the all cell populations with treatment before stimulation. The effects of S-carboxymethylcysteine (S-CMC), ambroxol and N-acetylcysteine (NAC) on the LDCL response were weaker than those of M1. Furthermore, PMA-induced LDCL was decreased by posttreatment with M1.<br><br>CONCLUSION: These results suggest that M (an active metabolite of erdosteine) may exert an antiinflammatory effect by scavenging inflammatory cells-derived reactive oxygen species.}, }
@article {pmid10335374, year = {1999}, author = {Friedman, M}, title = {Lysinoalanine in food and in antimicrobial proteins.}, journal = {Advances in experimental medicine and biology}, volume = {459}, number = {}, pages = {145-159}, doi = {10.1007/978-1-4615-4853-9_10}, pmid = {10335374}, issn = {0065-2598}, mesh = {Animals ; Anti-Bacterial Agents/*chemistry ; Bacteriocins ; Caseins/chemistry ; *Food-Processing Industry ; Hot Temperature ; Humans ; Hydrogen-Ion Concentration ; Kidney/pathology ; Lysinoalanine/*chemistry ; Maillard Reaction ; Nisin/chemistry ; Nutritive Value ; *Peptides, Cyclic ; Phosphorylation ; Rats ; Soybean Proteins/chemistry ; Subtilisins/chemistry ; Sulfhydryl Compounds/chemistry ; Sulfites/chemistry ; Time Factors ; }, abstract = {Heat and alkali treatment of food proteins widely used in food processing results in the formation of crosslinked amino acids such as lysinoalanine, ornithinoalanine, lanthionine, and methyl-lanthionine and concurrent racemization of L-amino acid isomers to D-analogues. The mechanism of lysinoalanine formation is a two-step process: first, hydroxide ion-catalyzed elimination of cysteine and serine residues to a dehydroalanine intermediate; second, reaction of the double bond of dehydroalanine with the epsilon-NH2 group of lysine to form a lysinoalanine crosslink. The corresponding elimination-addition reaction of threonine produces methyl-dehydroalanine, which then reacts with the NH2 and SH groups to form methyl-lysinoalanine and methyl-lanthionine, respectively. The crosslinked amino acids lanthionine and methyl-lanthionine are formed by analogous nucleophilic addition reactions of the SH group of cysteine to dehydroalanine and methyl-dehydroalanine, respectively. Processing conditions that favor these transformations include high pH, temperature and exposure time. Factors which minimize lysinoalanine formation include the presence of SH-containing amino acids such as cysteine, N-acetyl-cysteine, and glutathione, dephosphorylation of O-phosphoryl esters, and acylation of epsilon-NH2 groups of lysine side chains. The presence of lysinoalanine residues along a protein chain decreases digestibility and nutritional quality in rodents but enhances nutritional quality in ruminants. Protein-bound and free lysinoalanines are reported to induce enlargement of nuclei of rat kidney cells. All of the mentioned dehydro and crosslinked amino acids also occur naturally in certain peptide and protein antibiotics. These include duramycin, cinnamycin, epidermin, subtilin and the widely used food preservative nisin. Mechanistic rationalizations are offered for the observed antimicrobial activities of these compounds in relation to their structures. The cited findings and new research to better define the chemistry and dietary and antimicrobial roles of lysinoalanine and related compounds should lead to better and safer foods.}, }
@article {pmid10331420, year = {1999}, author = {Marumo, T and Schini-Kerth, VB and Busse, R}, title = {Vascular endothelial growth factor activates nuclear factor-kappaB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells.}, journal = {Diabetes}, volume = {48}, number = {5}, pages = {1131-1137}, doi = {10.2337/diabetes.48.5.1131}, pmid = {10331420}, issn = {0012-1797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cattle ; Chemokine CCL2/*biosynthesis/genetics ; Endothelial Growth Factors/*pharmacology ; Endothelium, Vascular/*metabolism ; Gene Expression ; Kinetics ; Lymphokines/*pharmacology ; Microcirculation/metabolism ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; RNA, Messenger/metabolism ; Retinal Vessels/*metabolism ; Tosyllysine Chloromethyl Ketone/pharmacology ; Transcription Factor AP-1/metabolism ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; }, abstract = {Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathogenesis of diabetic vascular complications. In the present study, we investigated whether expression of monocyte chemoattractant protein-1 (MCP-1), a chemokine that has been proposed to recruit leukocytes to sites of inflammation, neovascularization, and vascular injury, can be modulated by VEGF in bovine retinal microvascular endothelial cells (BRECs). VEGF induced expression of MCP-1 mRNA in BRECs in a concentration- and time-dependent manner. Secretion of MCP-1 into the culture medium of BRECs treated with VEGF for 24 h was increased by 2.2-fold compared with the control. Inhibitors of transcription factor NF-kappaB, N-alpha-tosyl-L-lysine chloromethylketone (TLCK) and N-acetylcysteine (NAC), as well as an inhibitor of the extracellular signal-regulated kinase (ERK) pathway, PD 98059, attenuated VEGF-induced expression of MCP-1 mRNA. Using electrophoretic gel mobility shift assay, we observed that VEGF stimulated binding activity of NF-kappaB. VEGF-induced NF-kappaB activation was inhibited by TLCK and NAC, but not by PD 98059. Binding activity of transcription factor AP-1, which is suggested to regulate induction of the MCP-1 gene together with NF-kappaB, was also stimulated by VEGF. PD 98059 inhibited the VEGF-induced activation of AP-1. These results indicate that VEGF induces MCP-1 expression in BRECs most likely by activating NF-kappaB and AP-1 via ERK-independent and -dependent pathways. Activation of NF-kappaB and induction of MCP-1 by VEGF in microvascular endothelial cells may contribute to the development of diabetic vascular complications.}, }
@article {pmid10329958, year = {1999}, author = {Mohan, S and Mohan, N and Valente, AJ and Sprague, EA}, title = {Regulation of low shear flow-induced HAEC VCAM-1 expression and monocyte adhesion.}, journal = {The American journal of physiology}, volume = {276}, number = {5}, pages = {C1100-7}, doi = {10.1152/ajpcell.1999.276.5.C1100}, pmid = {10329958}, issn = {0002-9513}, support = {F32-HL-09694-01AL/HL/NHLBI NIH HHS/United States ; HL-52218/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antibodies/pharmacology ; Antioxidants/pharmacology ; Aorta ; Cell Adhesion/drug effects/*physiology ; Cells, Cultured ; Endothelium, Vascular/cytology/*metabolism ; *Gene Expression Regulation/drug effects ; Humans ; Monocytes/*cytology ; NF-kappa B/physiology ; Pyrrolidines/pharmacology ; *Rheology ; Thiocarbamates/pharmacology ; Vascular Cell Adhesion Molecule-1/*genetics/immunology/physiology ; }, abstract = {We recently reported that prolonged exposure of human aortic endothelial cells (HAEC) to low shear stress flow patterns is associated with a sustained increase in the activated form of the transcriptional regulator nuclear factor-kappaB (NF-kappaB). Here we investigate the hypothesis that low shear-induced activation of NF-kappaB is responsible for enhanced expression of vascular cell adhesion molecule (VCAM-1) resulting in augmented endothelial cell-monocyte (EC-Mn) adhesion and that this activation is dependent on intracellular oxidant activity. Before exposure to low shear (2 dyn/cm2) for 6 h, HAEC were preincubated with or without the antioxidants pyrrolidine dithiocarbamate (PDTC) or N-acetyl-L-cysteine (NAC). PDTC strongly inhibited low shear-induced activation of NF-kappaB, expression of VCAM-1, and EC-Mn adhesion. Paradoxically, NAC exerted a positive effect on low shear-induced VCAM-1 expression and EC-Mn adhesion and only slightly downregulated NF-kappaB activation. However, cytokine-induced NF-kappaB activation and VCAM-1 expression are blocked by both PDTC and NAC. These data suggest that NF-kappaB plays a key role in low shear-induced VCAM-1 expression and that pathways mediating low shear- and cytokine-induced EC-Mn adhesion may be differentially regulated.}, }
@article {pmid10328827, year = {1999}, author = {Thongphasuk, J and Oberley, LW and Oberley, TD}, title = {Induction of superoxide dismutase and cytotoxicity by manganese in human breast cancer cells.}, journal = {Archives of biochemistry and biophysics}, volume = {365}, number = {2}, pages = {317-327}, doi = {10.1006/abbi.1999.1179}, pmid = {10328827}, issn = {0003-9861}, support = {P01-CA66081/CA/NCI NIH HHS/United States ; P50 DE-10758/DE/NIDCR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Breast Neoplasms ; Cell Survival/*drug effects ; Chlorides/*pharmacology/toxicity ; Citrate (si)-Synthase/metabolism ; Cyclic N-Oxides/pharmacology ; Cycloheximide/pharmacology ; Enzyme Induction ; Female ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Enzymologic ; *Gene Expression Regulation, Neoplastic ; Humans ; Kinetics ; Manganese Compounds/*pharmacology ; Manganese Poisoning ; RNA, Messenger/genetics ; Superoxide Dismutase/*biosynthesis/*genetics/metabolism ; Transcription, Genetic/drug effects ; Tumor Cells, Cultured ; }, abstract = {MnCl2 induced manganese-containing superoxide dismutase (MnSOD) expression (mRNA, immunoreactive protein, and enzyme activity) in human breast cancer Hs578T cells. The induction of MnSOD immunoreactive protein in Hs578T cells was inhibited by tiron (a metal chelator and superoxide scavenger), pyruvate (a hydrogen peroxide scavenger), or 2-deoxy-d-glucose (DG, an inhibitor of glycolysis and the hexose monophosphate shunt), but not by 5,5-dimethyl-1-pyrroline-1-oxide (a superoxide scavenger), N-acetyl cysteine (a scavenger for reactive oxygen species and precursor of glutathione), diphenylene iodonium (an inhibitor of flavoproteins such as NADPH oxidase and nitric oxide synthase), or SOD (a superoxide scavenger). Northern blotting demonstrated that tiron or DG affected at the mRNA level, while pyruvate affected Mn-induced MnSOD expression at both the mRNA and protein levels. These results demonstrate that Mn can induce MnSOD expression in cultured human breast cancer cells. Mn also induced apoptosis and necrosis in these cells. Since inhibitors of Mn-induced MnSOD induction did not affect cell viability, MnSOD induction is probably not the cause of the Mn-induced cell killing.}, }
@article {pmid10328814, year = {1999}, author = {Robinson, KA and Stewart, CA and Pye, Q and Floyd, RA and Hensley, K}, title = {Basal protein phosphorylation is decreased and phosphatase activity increased by an antioxidant and a free radical trap in primary rat glia.}, journal = {Archives of biochemistry and biophysics}, volume = {365}, number = {2}, pages = {211-215}, doi = {10.1006/abbi.1999.1178}, pmid = {10328814}, issn = {0003-9861}, support = {NS 35747/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Cells, Cultured ; Cerebral Cortex/cytology/metabolism ; Cyclic N-Oxides ; Enzyme Activation ; Free Radical Scavengers/pharmacology ; Hydrogen Peroxide/pharmacology ; Kinetics ; Nerve Tissue Proteins/metabolism ; Neuroglia/cytology/drug effects/*metabolism ; Nitrogen Oxides/*pharmacology ; Phosphoprotein Phosphatases/*metabolism ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; }, abstract = {Reversible protein phosphorylation regulates a wide array of cellular functions. Cells respond to cytokines and various stressors via phosphorylation and thus activation of one or more of the mitogen-activated protein kinase (MAPK) pathways. Involvement of these signal transduction pathways has been implicated in numerous pathologies, including inflammation. Using a primary glia cell culture, we show here that the antioxidant N-acetylcysteine (NAC) and the nitrone-based free radical trap, alpha-phenyl-N-tert-butyl nitrone (PBN), reduce total basal protein phosphorylation in a concentration-dependent manner as assessed by phosphotyrosine analysis and by [gamma-32P]ATP transfer radioassay. In addition we show that NAC inhibits H2O2-induced phosphatase inactivation in glia cell lysate. The PBN- and NAC-induced reduction in protein phosphorylation is accompanied by an increase in phosphatase activity, suggesting that PBN and NAC reduce protein phosphorylation by globally augmenting oxidant-sensitive phosphatase activities. These results partly explain why certain antioxidants also possess anti-inflammatory actions.}, }
@article {pmid10328471, year = {1999}, author = {Tariq, M and Morais, C and Sobki, S and Al Sulaiman, M and Al Khader, A}, title = {N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats.}, journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association}, volume = {14}, number = {4}, pages = {923-929}, doi = {10.1093/ndt/14.4.923}, pmid = {10328471}, issn = {0931-0509}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cyclosporine/*toxicity ; Drug Antagonism ; Free Radical Scavengers/*pharmacology ; Immunosuppressive Agents/*toxicity ; Kidney/*drug effects/*physiopathology ; Male ; Organ Transplantation ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Cyclosporin (CsA) has played an important role in the improvement of solid-organ transplant patients and graft survival. However, nephrotoxicity due to CsA remains an important clinical challenge. The renal toxicity of CsA is attributed to reduced renal blood flow which leads to hypoxia reoxygenation injury accompanied by excessive generation of oxygen-derived free radicals (ODFR). N-acetyl-L-cysteine (NAC) is a highly potent antioxidant that has been shown to reduce ODFR injury. In this study an attempt was made to assess the effect of NAC on CsA-induced lipid peroxidation and nephrotoxicity.<br><br>METHODS: Adult Sprague-Dawley rats were treated orally with CsA (25 and 50 mg/kg) alone and in combination with different doses of NAC (10, 20 and 40 mg/kg) for a period of 3 weeks. Twenty-four hours after the last treatment, animals were sacrificed and blood was analysed for blood urea nitrogen (BUN) and serum creatinine (SCr), and kidney samples were analysed for lipid hydroperoxides, conjugated dienes and glutathione, and histopathological changes.<br><br>RESULTS: Treatment of rats with CsA produced a significant increase in BUN and SCr level and histological abnormalities. CsA-induced impairment of renal toxicity was accompanied by significant increase in renal oxidative stress. NAC treatment significantly protected animals against CsA-induced structural and functional impairment of kidney.<br><br>CONCLUSIONS: CsA-induced nephrotoxicity was significantly attenuated by NAC. This study clearly suggests the role of oxidative stress in the pathogenesis of CsA-induced nephrotoxicity. Concomitant use of antioxidants such as NAC to minimize CsA-induced nephrotoxicity in humans warrant further studies.}, }
@article {pmid10320817, year = {1999}, author = {Newton, CJ and Drummond, N and Burgoyne, CH and Speirs, V and Stalla, GK and Atkin, SL}, title = {Functional inactivation of the oestrogen receptor by the antioestrogen, ZM 182780, sensitises tumour cells to reactive oxygen species.}, journal = {The Journal of endocrinology}, volume = {161}, number = {2}, pages = {199-210}, doi = {10.1677/joe.0.1610199}, pmid = {10320817}, issn = {0022-0795}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/antagonists &amp; inhibitors/*pharmacology ; Antioxidants/pharmacology ; Cell Death/drug effects ; DNA Fragmentation ; Dose-Response Relationship, Drug ; Estradiol/*analogs &amp; derivatives/pharmacology ; Estrogen Antagonists/*pharmacology ; Fulvestrant ; Hydrogen Peroxide/pharmacology ; Membrane Potentials/drug effects ; Mitochondria/physiology ; Pituitary Neoplasms/*pathology ; Rats ; Reactive Oxygen Species/*physiology ; Receptors, Estrogen/*antagonists &amp; inhibitors ; Tumor Cells, Cultured/drug effects ; }, abstract = {Reactive oxygen species (ROS) play a fundamental role in both apoptotic and necrotic cell death. Their importance is highlighted by studies showing that they mediate cell death in response to radiotherapy and to some forms of chemotherapy. Here we provide the first evidence for a role of ROS in response to an antiendocrine agent currently undergoing clinical trials. Using the oestrogen receptor (ER) containing rat pituitary GH3 cell line, we show that cell death is induced by the pure steroidal antioestrogen, ZM 182780, and that this is blocked by the antioxidant, N-acetyl cysteine (NAC). By flow cytometry, we show that, prior to the onset of DNA breakdown measured by ELISA, ZM 182780 exposure has no significant effect on intracellular oxidant concentrations. In contrast, ZM 182780 exposure greatly increases sensitivity to oxidants generated by blocking cellular antioxidant pathways and from exogenous administration of hydrogen peroxide (H2O2). As both necrosis and apoptosis are controlled by mitochondrial function, further experiments conducted to determine mitochondrial membrane potential (Delta|gWm) have indicated that the ZM 182780-induced loss of ER function increases the ease with which oxidants collapse mitochondrial activity and, as a consequence, cell death.}, }
@article {pmid10319281, year = {1999}, author = {Danfour, M and Schorah, CJ and Evans, SW}, title = {Changes in sensitivity of a human myeloid cell line (U937) to metal toxicity after glutathione depletion.}, journal = {Immunopharmacology and immunotoxicology}, volume = {21}, number = {2}, pages = {277-293}, doi = {10.3109/08923979909052763}, pmid = {10319281}, issn = {0892-3973}, mesh = {Buthionine Sulfoximine/pharmacology ; Cell Count ; Glutathione/analysis/*physiology ; Humans ; Metals/*toxicity ; U937 Cells ; }, abstract = {Glutathione (GSH) concentrations have been determined in the human myeloid cell line U937. The effects of modulating GSH concentration on sensitivity to metal toxicity has also been examined. Intracellular concentrations of GSH increased as the cells entered into the cell cycle, reaching a maximum level after 24 hours of cell culture, after which levels declined. Cell concentration was also observed to influence intracellular GSH concentrations. A reciprocal relationship was observed with higher maximum intracellular GSH concentrations being measured in cultures initiated with smaller cell number. The relative toxicity's determined for five metal chlorides were mercury > cadmium > cobalt > zinc > gold. Treatment of cells with N-acetylcysteine (NAC) increased intracellular GSH but had little effect on the absolute or relative toxicity's of the metals. Treatment of cells with L-buthionine-(S-R)-sulfoximine (BSO) depleted intracellular GSH and resulted in increased sensitivity of the cells to gold, 40 fold, cadmium 8 fold and mercury 3 fold.}, }
@article {pmid10234300, year = {1999}, author = {Kawaguchi, M and Nakamura, A and Tsurusawa, M}, title = {[The role of mitochondria in apoptosis in U937 and Molt-4 cells: difference in order of mitochondrial membrane potential (delta psi m) reduction and interleukin-1 beta-converting enzyme (ICE) on signal transduction pathway in each cell type].}, journal = {Gan to kagaku ryoho. Cancer &amp; chemotherapy}, volume = {26}, number = {5}, pages = {679-685}, pmid = {10234300}, issn = {0385-0684}, mesh = {*Apoptosis ; Caspase 1/*physiology ; DNA Fragmentation ; Etoposide/pharmacology ; Humans ; Leukemia, Myeloid/pathology ; Leukemia, T-Cell/pathology ; Membrane Potentials ; Mitochondria/*physiology ; Signal Transduction/*physiology ; Tumor Cells, Cultured ; U937 Cells ; }, abstract = {Time-course-analysis of two apoptotic events of DNA fragmentation and delta psi m reduction revealed that delta psi m reduction preceded DNA fragmentation in U937 and Molt-4 cells treated with etoposide (ETP). DNA fragmentation and delta psi m reduction were inhibited by N-acetylcysteine (NAC) in both cell lines treated with ETP. These findings suggest that DNA fragmentation was inhibited through maintenance of delta psi m. Z-Asp-CH2-DCB, interleukin-1 beta-converting enzyme (ICE) specific inhibitor, inhibited ETP-induced DNA fragmentation and delta psi m reduction in U937 cells. This suggests that activation of ICE is an earlier event than delta psi m reduction. On the other hand, in Molt-4 cells, Z-Asp-CH2-DCB inhibited ETP-induced DNA fragmentation but not delta psi m reduction, suggesting that delta psi m reduction occurs earlier than activation of ICE.}, }
@article {pmid10231542, year = {1999}, author = {Garant, MJ and Kole, S and Maksimova, EM and Bernier, M}, title = {Reversible change in thiol redox status of the insulin receptor alpha-subunit in intact cells.}, journal = {Biochemistry}, volume = {38}, number = {18}, pages = {5896-5904}, doi = {10.1021/bi982844p}, pmid = {10231542}, issn = {0006-2960}, mesh = {Acetylcysteine/pharmacology ; Animals ; CHO Cells ; Carcinoma, Hepatocellular ; Cricetinae ; Culture Media ; Glutathione/metabolism/pharmacology ; Humans ; Oxidation-Reduction ; Protein Binding/drug effects ; Rats ; Receptor, Insulin/*chemistry/*metabolism/physiology ; Sulfhydryl Compounds/*chemistry/*metabolism ; Time Factors ; Tumor Cells, Cultured ; }, abstract = {In this study, we used maleimidobutyrylbiocytin to examine possible alteration that may occur in the redox state of the insulin receptor (IR) sulfhydryl groups in response to reduced glutathione (GSH) or N-acetyl-L-cysteine (NAC). Short-term treatment of intact cells expressing large numbers of IR with GSH or NAC led to a rapid and reversible reduction of IR alpha-subunit disulfides, without affecting the receptor beta-subunit thiol reactivity. The overall integrity of the oligomeric structure of IR was maintained, indicating that neither class I nor class II disulfides were targeted by these agents. Similar findings were obtained in cells transfected with IR mutants lacking cysteine524, one of the class I disulfides that link the two IR alpha-subunits. Membrane-associated thiols did not participate in GSH- or NAC-mediated reduction of IR alpha-subunit disulfides. No difference in insulin binding was observed in GSH-treated cells; however, ligand-mediated increases in IR autophosphorylation, tyrosine phosphorylation of cellular substrates, and dual phosphorylation of the downstream target mitogen-activated protein kinase were inhibited at concentrations of GSH (10 mM or greater) that yielded a significant increase in IR alpha-subunit thiol reactivity. GSH did not affect IR signaling in the absence of insulin. Our results provide the first evidence that the IR alpha-subunit contains a select group of disulfides whose redox status can be rapidly altered by the reducing agents GSH and NAC.}, }
@article {pmid10229264, year = {1999}, author = {Zheng, CH and Ahmed, K and Rikitomi, N and Martinez, G and Nagatake, T}, title = {The effects of S-carboxymethylcysteine and N-acetylcysteine on the adherence of Moraxella catarrhalis to human pharyngeal epithelial cells.}, journal = {Microbiology and immunology}, volume = {43}, number = {2}, pages = {107-113}, doi = {10.1111/j.1348-0421.1999.tb02381.x}, pmid = {10229264}, issn = {0385-5600}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Asthma/pathology ; Bacterial Adhesion/*drug effects ; Bronchiectasis/pathology ; Bronchitis/pathology ; Carbocysteine/metabolism/*pharmacology ; Epithelial Cells/drug effects/microbiology/ultrastructure ; Expectorants/*pharmacology ; Female ; Humans ; Male ; Middle Aged ; Moraxella catarrhalis/*drug effects/physiology ; Pharynx/cytology/*microbiology ; Pulmonary Emphysema/pathology ; Sputum/metabolism ; }, abstract = {We investigated the effects of two mucoregulating drugs, S-carboxymethylcysteine (S-CMC) and N-acetylcysteine (NAC), on the attachment of Moraxella catarrhalis (M. catarrhalis) to pharyngeal epithelial cells. The attachment of M. catarrhalis decreased (33-57%) significantly (P<0.01) in a dose-dependent manner in cells treated with mucoregulating drugs as compared to the control. There was a significant (P<0.01) decrease (35-45%) in the attachment of M. catarrhalis to pharyngeal cells after oral administration of S-CMC. By electron microscopic observation, it was found that there was a fine, granular, electron-dense, ruthenium red-positive layer on the surface of pharyngeal epithelial cells; this layer was absent on cell surfaces treated with mucoregulating drugs. Possibly, this layer contained the portion of M. catarrhalis receptor which is responsible for the attachment of this bacteria to pharyngeal epithelial cells. From the above results, it may be concluded that one of the mechanisms of mucoregulating drugs to decrease the episode of respiratory infections in patients with chronic respiratory diseases is by inhibiting the attachment of bacteria to the upper respiratory tract.}, }
@article {pmid10224484, year = {1999}, author = {Tashiro, K and Makita, Y and Shike, T and Shirato, I and Sato, T and Cynshi, O and Tomino, Y}, title = {Detection of cell death of cultured mouse mesangial cells induced by oxidized low-density lipoprotein.}, journal = {Nephron}, volume = {82}, number = {1}, pages = {51-58}, doi = {10.1159/000045367}, pmid = {10224484}, issn = {1660-8151}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Death/drug effects ; Cell Line, Transformed ; Cells, Cultured ; Female ; Glomerular Mesangium/*cytology/drug effects ; Glutathione/analogs &amp; derivatives/pharmacology ; Lipoproteins, LDL/blood/isolation &amp; purification/*pharmacology ; Mice ; Rabbits ; Simian virus 40 ; Tumor Necrosis Factor-alpha/pharmacology ; Vitamin E/pharmacology ; }, abstract = {The objectives of the present study using cultured mouse mesangial cells (MMC) were (1) to evaluate the type of cytotoxicity induced by oxidized (ox) LDL, i.e. apoptosis, necrosis and types of other cell death and (2) to investigate the pathway of cell death under incubation with antioxidants or scavenger receptor (SR) antagonists. LDH release and a morphological examination were used in this study. Trypan blue staining of MMC was performed to detect dead cells in culture. Cytotoxicity of ox-LDL in MMC was found to be dose- and time-dependent. In the morphological study of electron microscopy, three different types of cell death in ox-LDL-treated MMC were identified. In the morphological study with semithin sections, these three types of dead cells were identified at different dosages of ox-LDL. Type 1 or type 2 dead cells were observed in low dose ox-LDL or in middle-dose ox-LDL-treated MMC, respectively. Type 3 dead cells were marked in high dose ox-LDL-treated MMC. It appears that the cells were apoptotic (type 1), necrotic (type 3) and other types (type 2). The cytotoxicity of ox-LDL was not mediated by cellular internalization of ox-LDL via SRs. On the other hand, the cytotoxicity of ox-LDL was inhibited by antioxidants such as alpha-tocopherol, probucol, N-acetyl-cysteine or glutathione ethyl ester. It is indicated that the pathways of ox-LDL induced cell death were distinct from the pathway via SRs.}, }
@article {pmid10224123, year = {1999}, author = {Arakaki, N and Kajihara, T and Arakaki, R and Ohnishi, T and Kazi, JA and Nakashima, H and Daikuhara, Y}, title = {Involvement of oxidative stress in tumor cytotoxic activity of hepatocyte growth factor/scatter factor.}, journal = {The Journal of biological chemistry}, volume = {274}, number = {19}, pages = {13541-13546}, doi = {10.1074/jbc.274.19.13541}, pmid = {10224123}, issn = {0021-9258}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis ; Cell Division/*physiology ; Cell Line ; Dogs ; Hepatocyte Growth Factor/*physiology ; Oxidative Stress ; Reactive Oxygen Species ; Sarcoma, Experimental/*pathology ; Tumor Cells, Cultured ; }, abstract = {In this study, we show that N-acetylcysteine (NAC), a precursor of glutathione and an intracellular free radical scavenger, almost completely prevented hepatocyte growth factor (HGF)-suppressed growth of Sarcoma 180 and Meth A cells, and HGF-induced apoptosis, assessed by DNA fragmentation, and increase in caspase-3 activity, in Sarcoma 180 cells. The reduced form of glutathione also prevented HGF-suppressed growth of the cells as effective as NAC. Ascorbic acid partially prevented the effect of HGF, but other antioxidants such as superoxide dismutase, catalase, and vitamin E, and the free radical spin traps N-t-butyl-alpha-phenylnitrone and 3,3,5, 5-tetramethyl-1-pyrroline-1-oxide did not have protective effects. HGF caused morphological changes of the cells, many cells showing condensation and rounding, and enhanced the generation of intracellular reactive oxygen species (ROS) as judged by flow cytometric analysis using 2',7'-dichlorofluorescein diacetate. NAC completely prevented both HGF-induced morphological changes and the enhancement of ROS generation in the cells. However, NAC did not prevent the HGF-induced scattering of Madin-Darby canine kidney cells. To our knowledge, this is the first report that HGF stimulates the production of ROS, and our results suggest the involvement of oxidative stress in the mechanism by which HGF induces growth suppression of tumor cells.}, }
@article {pmid10220113, year = {1999}, author = {Robinson, KA and Stewart, CA and Pye, QN and Nguyen, X and Kenney, L and Salzman, S and Floyd, RA and Hensley, K}, title = {Redox-sensitive protein phosphatase activity regulates the phosphorylation state of p38 protein kinase in primary astrocyte culture.}, journal = {Journal of neuroscience research}, volume = {55}, number = {6}, pages = {724-732}, doi = {10.1002/(SICI)1097-4547(19990315)55:6&lt;724::AID-JNR7&gt;3.0.CO;2-9}, pmid = {10220113}, issn = {0360-4012}, support = {NS 35747/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Antioxidants/pharmacology ; Astrocytes/cytology/drug effects/*metabolism ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Cells, Cultured ; Cerebral Cortex/*metabolism ; Cyclic N-Oxides ; Hydrogen Peroxide/metabolism ; Interleukin-1/*pharmacology ; Kinetics ; *Mitogen-Activated Protein Kinases ; Nitrogen Oxides/*pharmacology ; Oxidation-Reduction ; Phosphoprotein Phosphatases/*metabolism ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/physiology ; Sorbitol/pharmacology ; Spin Labels ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {Reactive oxygen species (ROS) have been implicated as second messengers that activate protein kinase cascades, although the means by which ROS regulate signal transduction remains unclear. In the present study, we show that interleukin 1beta (IL1beta), H2O2, and sorbitol-induced hyperosmolarity mediate a 5- to 10-fold increase in phosphorylation (activation) of the p38 protein kinase in rat primary glial cells as measured by analyses of Western blots using an antibody directed against the dually phosphorylated (active) p38. Additionally, IL1beta was found to elicit H2O2 synthesis in these cells. Concurrent with p38 phosphorylation, all three stimulation paradigms caused an inhibition of protein phosphatase activity. Phenyl-tert-butyl nitrone (PBN), a nitrone-based free radical trap and N-acetyl-cysteine (NAC), a thiol reducing agent, were examined for their effects on the phosphorylation of p38 as well as phosphatase activity. Pretreatment of cells with either PBN or NAC at 1.0 mM suppressed IL1beta H2O2, and sorbitol-mediated activation of p38 and significantly increased phosphatase activity. These data suggest that ROS, particularly H2O2, are used as second messenger substances that activate p38 in part via the transient inactivation of regulatory protein phosphatases.}, }
@article {pmid10216087, year = {1999}, author = {Sattler, M and Winkler, T and Verma, S and Byrne, CH and Shrikhande, G and Salgia, R and Griffin, JD}, title = {Hematopoietic growth factors signal through the formation of reactive oxygen species.}, journal = {Blood}, volume = {93}, number = {9}, pages = {2928-2935}, pmid = {10216087}, issn = {0006-4971}, support = {CA01730/CA/NCI NIH HHS/United States ; CA36167/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Cycle/drug effects/*physiology ; Cell Line ; Cell Survival/drug effects ; Culture Media, Conditioned ; Genes, fos/drug effects ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Hematopoietic Cell Growth Factors/*pharmacology/physiology ; Humans ; Hydrogen Peroxide/pharmacology ; Interleukin-3/pharmacology ; Kinetics ; Megakaryocytes ; Mercaptoethanol/pharmacology ; Mice ; Proto-Oncogene Proteins c-fos/genetics ; Pyrrolidines ; Reactive Oxygen Species/*chemistry ; Recombinant Proteins/pharmacology ; Signal Transduction/drug effects/*physiology ; Stem Cell Factor/pharmacology ; Thiocarbamates/pharmacology ; Thrombopoietin/pharmacology ; }, abstract = {Hematopoietic growth factors (HGFs) stimulate growth, differentiation, and prevent apoptosis of progenitor cells. Each growth factor has a specific cell surface receptor, which activates both unique and shared signal transduction pathways. We found that several HGFs, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), steel factor (SF), and thrombopoietin (TPO) induce a rapid increase in reactive oxygen species (ROS) in quiescent cells. In an effort to understand the potential biochemical and biological consequences of increased ROS in these cells, we exposed growth factor-deprived cells to hydrogen peroxide (H2O2) at concentrations that increased intracellular ROS. H2O2 induced a dose-dependent increase in tyrosine phosphorylation, including increased tyrosine phosphorylation of the GM-CSF receptor beta chain (betac), STAT5, and other signaling proteins. H2O2 also induced expression of the early response gene c-FOS, and G1- to S-phase transition, but not S- to G2/M-phase transition of MO7e cells. The cell permeable antioxidant pyrrolidine dithiocarbamate (PDTC) decreased the intracellular levels of ROS and inhibited tyrosine phosphorylation induced by GM-CSF in MO7e cells, suggesting that ROS generation plays an important role in GM-CSF signaling. Consistent with this notion, PDTC and two other antioxidants, N-acetyl cysteine and 2-mercaptoethanol, reduced growth and viability of MO7e cells. These results suggest that generation of ROS in response to HGFs may contribute to downstream signaling events, especially those involving tyrosine phosphorylation.}, }
@article {pmid10213169, year = {1999}, author = {Gasparini, L and Benussi, L and Bianchetti, A and Binetti, G and Curti, D and Govoni, S and Moraschi, S and Racchi, M and Trabucchi, M}, title = {Energy metabolism inhibition impairs amyloid precursor protein secretion from Alzheimer's fibroblasts.}, journal = {Neuroscience letters}, volume = {263}, number = {2-3}, pages = {197-200}, doi = {10.1016/s0304-3940(99)00155-x}, pmid = {10213169}, issn = {0304-3940}, mesh = {Acetylcysteine/pharmacology ; Alzheimer Disease/*metabolism ; Amyloid beta-Protein Precursor/biosynthesis/*metabolism ; Antioxidants/*pharmacology ; Cells, Cultured ; Energy Metabolism/*drug effects ; Fibroblasts/drug effects/metabolism/pathology ; Glucose/metabolism ; Glutathione/pharmacology ; Humans ; Hypoglycemia ; Lipid Peroxidation/drug effects ; Reference Values ; Skin/drug effects/*metabolism/pathology ; Sodium Azide/*pharmacology ; }, abstract = {The present study investigates the influence of aglycemia and sodium azide (a Cytochrome c Oxidase inhibitor) on sAPP secretion from skin fibroblasts derived from sporadic AD patients and control subjects. Aglycemia reduced sAPP release in the medium of both AD and control fibroblasts to a similar extent after 2 h incubation. Treatment for 2 h with increasing azide concentrations (1 microM-100 mM) under glucose deprivation did not significantly affect sAPP secretion from control fibroblasts, but was able to significantly inhibit sAPP secretion from AD fibroblasts (maximal inhibition 51%). The failure of antioxidants like glutathione (GSH) or N-acetylcysteine (NAC) to antagonize the azide effect on AD fibroblasts and lipoperoxidation data seemed to rule out the possibility that oxidative stress could mediate the sodium azide effect on sAPP release from AD fibroblasts.}, }
@article {pmid10203358, year = {1999}, author = {Kitamura, M}, title = {The antioxidant N-acetylcysteine induces mesangial cells to create three-dimensional cytoarchitecture that underlies cellular differentiation.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {10}, number = {4}, pages = {746-751}, doi = {10.1681/ASN.V104746}, pmid = {10203358}, issn = {1046-6673}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Blotting, Northern ; Cell Differentiation/drug effects ; Cells, Cultured/cytology/drug effects ; Diamide/pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Free Radical Scavengers/*pharmacology ; Glomerular Mesangium/cytology/*drug effects/*ultrastructure ; Glutathione/*pharmacology ; Male ; Rats ; Rats, Sprague-Dawley ; Reference Values ; Vitamin K/pharmacology ; }, abstract = {Prolonged culture of mesangial cells produces multifocal nodular structures, i.e., "hillocks," consisting of cells and extracellular matrix. Hillock formation is associated with induction of a differentiated phenotype of mesangial cells, with suppressed mitogenesis and downregulation of alpha-smooth muscle actin (alpha-SMA). Currently, little is understood regarding physiologically relevant factors that facilitate this cytodifferentiation. This study explores whether and how the cellular redox state modulates hillock formation. Exposure of confluent rat mesangial cells to the antioxidant N-acetylcysteine (NAC), an inducer of glutathione, dramatically facilitated hillock formation. This effect was mimicked by external addition of the reduced form of glutathione ethyl ester. In contrast, the oxidizing agents diamide and menadione inhibited the development of hillocks triggered by either NAC, glutathione, or prolonged culture. The induction of hillocks by NAC was correlated with downregulation of alpha-SMA as well as attenuated activity of the CArG box element (the cis-element relevant to the expression of the alpha-SMA gene and growth-associated genes). These results indicate that, by a redox-sensitive mechanism, NAC induces mesangial cells to create three-dimensional cytoarchitecture that underlies cellular differentiation.}, }
@article {pmid10202994, year = {1999}, author = {Gibbs, BF and Schmutzler, W and Vollrath, IB and Brosthardt, P and Braam, U and Wolff, HH and Zwadlo-Klarwasser, G}, title = {Ambroxol inhibits the release of histamine, leukotrienes and cytokines from human leukocytes and mast cells.}, journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]}, volume = {48}, number = {2}, pages = {86-93}, doi = {10.1007/s000110050421}, pmid = {10202994}, issn = {1023-3830}, mesh = {Ambroxol/*pharmacology ; Anti-Inflammatory Agents/*pharmacology ; Cytokines/*metabolism ; Histamine Release/*drug effects ; Humans ; Leukocytes/*drug effects/metabolism ; Leukotrienes/*metabolism ; Mast Cells/*drug effects/metabolism ; }, abstract = {OBJECTIVES AND DESIGN: The effects of the mucolytic agents ambroxol and N-acetylcystein (NAC) were studied on the release of histamine, leukotrienes, cytokines and superoxide anions from a variety of cells involved in the pathogenesis of allergic inflammation.<br><br>SUBJECTS: Mast cells were isolated from human adenoids and skin (n = 5-6). Basophils, monocytes and granulocytes were obtained from Buffy-coat blood obtained from healthy blood donors (n = 4-7) and enriched by density centrifugation.<br><br>TREATMENT AND METHODS: Ambroxol or NAC were added to the cells for different periods before stimulation with various immunological and non-immunological secretagogues. Histamine release from mast cells, basophils and monocytes was assayed either by radioimmunoassay or spectrofluorometrically. LTC4 (basophils), LTB4 (neutrophil/eosinophil granulocytes or monocytes), IL-4 and IL-13 (basophils) were measured by ELISA.<br><br>RESULTS: Ambroxol inhibited histamine release by more than 50% from human adenoidal mast cells (1000 microM ambroxol) and skin mast cells (100 microM ambroxol) stimulated by Con A and compound 48/80, respectively. Ambroxol (100 microM) strikingly inhibited anti-IgE induced release of both histamine, LTC4, IL-4 and IL-13 from basophils and reduced both histamine and LTB4 release induced by C5a or Zymosan in monocytes. The drug also reduced LTB4 and superoxide anion production in granulocytes stimulated by zymosan or fMLP. In all cell types studied, ambroxol was more efficacious following a short preincubation (5-15 min) of the drug with the cells before stimulation. In contrast, NAC produced no clear effects on any of the different cell types studied, regardless of the preincubation period, the concentration or the stimulus employed.<br><br>CONCLUSIONS: Unlike NAC, ambroxol is able to not only inhibit acute mediator release from mast cells and leukocytes but also reduce immunomodulatory cytokine generation from basophils and may have beneficial effects in the treatment of allergic respiratory diseases.}, }
@article {pmid10193576, year = {1999}, author = {Chang, KH and Kim, KS and Kim, JH}, title = {N-acetylcysteine increases the biosynthesis of recombinant EPO in apoptotic Chinese hamster ovary cells.}, journal = {Free radical research}, volume = {30}, number = {2}, pages = {85-91}, doi = {10.1080/10715769900300091}, pmid = {10193576}, issn = {1071-5762}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Butyrates/antagonists &amp; inhibitors/pharmacology ; CHO Cells ; Cell Division/drug effects ; Cell Membrane/drug effects ; Cell Size/drug effects ; Cell Survival/drug effects ; Cricetinae ; DNA Fragmentation/drug effects ; Drug Synergism ; Erythropoietin/*biosynthesis ; Recombinant Proteins/*biosynthesis ; Time Factors ; Vacuoles/drug effects ; }, abstract = {Sodium butyrate (NaBu) is known to enhance the rate of biosynthesis of recombinant proteins in Chinese hamster ovary cells (CHO). Here we demonstrate that supplementation with NaBu during rapid growth brings about abrupt death of the cells. The death of the cells is due to apoptosis, as assessed by intranucleosomal DNA fragmentation. The promotion of apoptotic death of the cells could be partially blocked by treatment with the well-known antioxidant, N-acetylcysteine (NAC). Strikingly, the NAC treatment enhanced the production of recombinant EPO two-fold compared with that of the culture without NAC supplementation. These results showed that NaBu treatment supplemented with NAC not only inhibits apoptosis, but also exerts a synergistic effect on the biosynthesis of recombinant EPO.}, }
@article {pmid10192917, year = {1999}, author = {Oda, T and Iwaoka, J and Komatsu, N and Muramatsu, T}, title = {Involvement of N-acetylcysteine-sensitive pathways in ricin-induced apoptotic cell death in U937 cells.}, journal = {Bioscience, biotechnology, and biochemistry}, volume = {63}, number = {2}, pages = {341-348}, doi = {10.1271/bbb.63.341}, pmid = {10192917}, issn = {0916-8451}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Antioxidants/metabolism/*pharmacology ; Apoptosis/*drug effects/physiology ; Buthionine Sulfoximine/pharmacology ; Caspase 3 ; Caspase Inhibitors ; Cell Survival/drug effects/physiology ; DNA Fragmentation/drug effects/physiology ; Dose-Response Relationship, Drug ; Electrophoresis, Agar Gel ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/metabolism/*pharmacology ; Glutathione/pharmacology/physiology ; Humans ; Microscopy, Fluorescence ; Oxidative Stress/drug effects/physiology ; Protein Synthesis Inhibitors/pharmacology ; Ricin/*metabolism ; U937 Cells ; }, abstract = {We have found that the antioxidant N-acetylcysteine (NAC) strongly inhibited ricin-induced apoptotic cell death in U937 cells (human myeloid leukemia), as judged by cytotoxicity, nuclear morphological change, and DNA fragmentation. Consistent with these observations, a significant depletion of cellular glutathione was observed in ricin-treated cells, and NAC prevented the decrease in cellular glutathione. On the other hand, among the caspase inhibitors tested, Z-Asp-CH2-DCB, which inhibited ricin cytotoxicity, also suppressed ricin-mediated glutathione depletion, while NAC did not affect the generation of caspase-3 like activity in ricin-treated cells. These results suggest that glutathione loss takes place downstream from caspase activation during the ricin-induced apoptotic process. Treatment with a specific inhibitor of glutathione biosynthesis, buthionine sulfoximine (BSO) failed to induce apoptosis, and had no effect on the overall extent of ricin-induced apoptosis, even though the glutathione level was decreased to less than 5% of the control level. However, NAC still protected against ricin-induced apoptosis in the BSO-treated cells. We conclude that glutathione loss is one of several apoptotic changes caused by ricin, but is not a sufficient factor for the progress of apoptosis. NAC may prevent ricin-induced apoptosis through maintaining an intracellular reducing condition by acting as a thiol supplier.}, }
@article {pmid10188993, year = {1999}, author = {Bernareggi, M and Radice, S and Rossoni, G and Oriani, G and Chiesara, E and Berti, F}, title = {Hyperbaric oxygen increases plasma exudation in rat trachea: involvement of nitric oxide.}, journal = {British journal of pharmacology}, volume = {126}, number = {3}, pages = {794-800}, pmid = {10188993}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Animals ; Anti-Asthmatic Agents/pharmacology ; Blood Pressure/drug effects/physiology ; Blotting, Western ; Capillary Permeability/drug effects/*physiology ; Enzyme Inhibitors/pharmacology ; Fluocinolone Acetonide/analogs &amp; derivatives/pharmacology ; Free Radical Scavengers/pharmacology ; Heart Rate/drug effects/physiology ; Hemodynamics/drug effects/physiology ; *Hyperbaric Oxygenation ; Indomethacin/pharmacology ; Male ; NG-Nitroarginine Methyl Ester/chemistry/pharmacology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism ; Nitric Oxide Synthase Type II ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; Trachea/drug effects/enzymology/*physiopathology ; }, abstract = {This study investigates the microvascular permeability changes in tracheal tissue of rats exposed to hyperbaric oxygen (HBO). Rats, following exposure to HBO or ambient air (control animals) for 1.5, 3 and 6 h, were prepared for recording of nitric oxide exhaled (FENO) in air using a chemiluminescence analyser. The level of FENO was not statistically different in the two groups. Plasma exudation, evaluated by measuring the leakage of Evans blue (EB) dye into the tracheal tissue, was significantly elevated (48, 86 and 105% at 1.5, 3 and 6 h, respectively) in HBO-treated rats. Plasma exudation in the trachea of control rats was significantly increased (42%, P<0.05) by NG-nitro-L-arginine methyl ester (L-NAME), whereas it was significantly reduced (31%, P<0.05) in rats exposed to HBO for 3 h. N-acetylcysteine (NAC) and flunisolide significantly prevented the increase in plasma leakage in HBO-treated rats. In contrast, indomethacin was devoid of anti-exudative activity in these experiments. Western immunoblot showed a significant increase in the level of inducible nitric oxide synthase (iNOS) protein in the tracheal homogenates of HBO-treated rats, as compared to basal levels. These results indicate that nitric oxide (NO) is involved in the maintenance of microvascular permeability in tracheal tissue of rats. The protective effect observed with the steroid seems to support this hypothesis. Furthermore, the beneficial action of NAC underlines that reactive oxygen species participate in the microvascular permeability changes observed in tracheal tissue of rats exposed to HBO.}, }
@article {pmid10102970, year = {1999}, author = {Simmonds, NJ and Millar, AD and Blake, DR and Rampton, DS}, title = {Antioxidant effects of aminosalicylates and potential new drugs for inflammatory bowel disease: assessment in cell-free systems and inflamed human colorectal biopsies.}, journal = {Alimentary pharmacology &amp; therapeutics}, volume = {13}, number = {3}, pages = {363-372}, doi = {10.1046/j.1365-2036.1999.00484.x}, pmid = {10102970}, issn = {0269-2813}, mesh = {Adrenal Cortex Hormones/pharmacology ; Adult ; Aged ; Aminosalicylic Acid/pharmacology ; Aminosalicylic Acids/pharmacology ; Anti-Infective Agents/pharmacology ; Anti-Inflammatory Agents/pharmacology ; Anti-Ulcer Agents/*pharmacology ; Antioxidants/*pharmacology ; Cell-Free System ; Colitis/*metabolism ; Female ; Humans ; In Vitro Techniques ; Inflammatory Bowel Diseases/*drug therapy ; Luminescent Measurements ; Male ; Mesalamine/*pharmacology ; Metronidazole/pharmacology ; Middle Aged ; Phenylhydrazines ; Proctitis/*metabolism ; Steroids ; }, abstract = {BACKGROUND: The therapeutic efficacy of 5-aminosalicylic acid in inflammatory bowel disease may be related to its antioxidant properties.<br><br>AIM: To compare in vitro the antioxidant effects of conventional drugs (5-aminosalicylic acid, corticosteroids, metronidazole), with new aminosalicylates (4-aminosalicylic acid, balsalazide) and other potential therapies (ascorbate, N-acetylcysteine, glutathione, verapamil).<br><br>METHODS: Compounds were assessed for efficacy in reducing the in vitro production of reactive oxygen species by cell-free systems (using xanthine/xanthine oxidase, with or without myeloperoxidase) and by colorectal biopsies from patients with ulcerative colitis using luminol-amplified chemiluminescence.<br><br>RESULTS: 5-aminosalicylic acid and balsalazide were more potent antioxidants than 4-aminosalicylic acid or N-acetyl-5-aminosalicylic acid in cell-free systems. 5-aminosalicylic acid (20 mM) and balsalazide (20 mM) inhibited rectal biopsy chemiluminescence by 93% and 100%, respectively, compared with only 59% inhibition by 4-aminosalicylic acid (20 mM). Hydrocortisone, metronidazole and verapamil had no significant effect on chemiluminescence in any system. Ascorbate (20 mM) inhibited chemiluminescence by 100% in cell-free systems and by 60% in rectal biopsies. N-acetyl cysteine (10 mM), and both oxidized and reduced glutathione (10 mM), completely inhibited chemiluminescence in cell-free systems, but not with rectal biopsies.<br><br>CONCLUSIONS: The antioxidant effects of compounds varies between cell-free systems and inflamed colorectal biopsies. The effect of drugs on the chemiluminescence produced by these two assay systems is useful for screening potentially new antioxidant treatments for inflammatory bowel disease. Ascorbate seems worth further study as a novel therapy.}, }
@article {pmid10102698, year = {1999}, author = {Wentzel, P and Welsh, N and Eriksson, UJ}, title = {Developmental damage, increased lipid peroxidation, diminished cyclooxygenase-2 gene expression, and lowered prostaglandin E2 levels in rat embryos exposed to a diabetic environment.}, journal = {Diabetes}, volume = {48}, number = {4}, pages = {813-820}, doi = {10.2337/diabetes.48.4.813}, pmid = {10102698}, issn = {0012-1797}, mesh = {Abnormalities, Drug-Induced ; Animals ; Congenital Abnormalities/*etiology ; Cyclooxygenase 1 ; Cyclooxygenase 2 ; Diabetes Mellitus, Experimental/*complications/physiopathology ; Dinoprost/analogs &amp; derivatives/metabolism ; Dinoprostone/*metabolism ; Embryo, Mammalian/anatomy &amp; histology/metabolism/*physiology ; Embryonic and Fetal Development/physiology ; F2-Isoprostanes ; Female ; Gene Expression/*physiology ; Indomethacin/pharmacology ; Isoenzymes/*genetics ; Lipid Peroxides/metabolism ; Membrane Proteins ; Pregnancy ; Pregnancy Complications/*physiopathology ; Prostaglandin-Endoperoxide Synthases/*genetics ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Previous experimental studies suggest that diabetic embryopathy is associated with an excess of radical oxygen species (ROS), as well as with a disturbance of prostaglandin (PG) metabolism. We aimed to investigate the relationship between these pathways and used hyperglycemia in vitro (embryo culture for 24-48 h) and maternal diabetes in vivo to affect embryonic development. Subsequently, we assessed lipid peroxidation and gene expression of cyclooxygenase (COX)-1 and -2 and measured the concentration of prostaglandin E2 (PGE2) in embryos and membranes. Both hyperglycemia in vitro and maternal diabetes in vivo caused embryonic dysmorphogenesis and increased embryonic levels of 8-epi-PGF2alpha, an indicator of lipid peroxidation. Addition of N-acetylcysteine (NAC) to the culture medium normalized the morphology and 8-epi-PGF2alpha concentration of the embryos exposed to high glucose. Neither hyperglycemia nor diabetes altered COX-1 expression, but embryonic COX-2 expression was diminished on gestational day 10. The PGE2 concentration of day 10 embryos and membranes was decreased after exposure to high glucose in vitro or diabetes in vivo. In vitro addition of NAC to high glucose cultures largely rectified morphology and restored PGE2 concentration, but without normalizing the COX-2 expression in embryos and membranes. Hyperglycemia/diabetes-induced downregulation of embryonic COX-2 gene expression may be a primary event in diabetic embryopathy, leading to lowered PGE2 levels and dysmorphogenesis. Antioxidant treatment does not prevent the decrease in COX-2 mRNA levels but restores PGE2 concentrations, suggesting that diabetes-induced oxidative stress aggravates the loss of COX-2 activity. This may explain in part the antiteratogenic effect of antioxidant treatment.}, }
@article {pmid10101259, year = {1999}, author = {Koppal, T and Drake, J and Butterfield, DA}, title = {In vivo modulation of rodent glutathione and its role in peroxynitrite-induced neocortical synaptosomal membrane protein damage.}, journal = {Biochimica et biophysica acta}, volume = {1453}, number = {3}, pages = {407-411}, doi = {10.1016/s0925-4439(99)00014-9}, pmid = {10101259}, issn = {0006-3002}, support = {AG-05119/AG/NIA NIH HHS/United States ; AG-10836/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Cerebral Cortex/*drug effects/metabolism ; Electron Spin Resonance Spectroscopy ; Gerbillinae ; Glutathione/*metabolism/therapeutic use ; Male ; Membrane Proteins/chemistry/*metabolism ; Nitrates/*pharmacology ; *Oxidative Stress ; Protein Conformation ; Synaptic Membranes/*drug effects/metabolism/pathology ; }, abstract = {Peroxynitrite, formed by the reaction between nitric oxide and superoxide, leads to the oxidation of proteins, lipids, and DNA, and nitrates thiols such as cysteine and glutathione, and amino acids like tyrosine. Previous in vitro studies have shown glutathione to be an efficient scavenger of peroxynitrite, protecting synaptosomal membranes from protein oxidation, the enzyme glutamine synthetase from inactivation, and preventing the death of hippocampal neurons in culture. The current study was undertaken to see if in vivo modulation of glutathione levels would affect brain cortical synaptosomal membrane proteins and their subsequent reaction with peroxynitrite. Glutathione levels were depleted, in vivo, by injecting animals with 2-cyclohexen-1-one (CHX, 100 mg/kg body weight), and levels of glutathione were enhanced by injecting animals with N-acetylcysteine (NAC, 200 mg/kg body weight), which gets metabolized to cysteine, a precursor of glutathione. Changes in membrane protein conformation and structure in synaptosomes subsequently isolated from these animals were examined using electron paramagnetic resonance, before and after in vitro addition of peroxynitrite. The animals injected with the glutathione depletant CHX showed greater damage to the membrane proteins both before and after peroxynitrite treatment, compared to the non-injected controls. The membrane proteins from animals injected with NAC were comparable to controls before peroxynitrite treatment and were partially protected against peroxynitrite-induced damage. This study showed that modulation of endogenous glutathione levels can affect the degree of peroxynitrite-induced brain membrane damage and may have potential therapeutic significance for oxidative stress-associated neurodegenerative disorders.}, }
@article {pmid10095130, year = {1999}, author = {Yih, LH and Lee, TC}, title = {Effects of exposure protocols on induction of kinetochore-plus and -minus micronuclei by arsenite in diploid human fibroblasts.}, journal = {Mutation research}, volume = {440}, number = {1}, pages = {75-82}, doi = {10.1016/s1383-5718(99)00008-x}, pmid = {10095130}, issn = {0027-5107}, mesh = {Acetylcysteine/pharmacology ; Arsenites/administration &amp; dosage/metabolism/*toxicity ; Carcinogens/administration &amp; dosage/metabolism/*toxicity ; Catalase/pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Diploidy ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Fibroblasts/drug effects/metabolism ; Humans ; Kinetochores/*drug effects ; Micronuclei, Chromosome-Defective/*drug effects ; Micronucleus Tests ; Oxidative Stress ; Sodium Compounds/administration &amp; dosage/metabolism/*toxicity ; }, abstract = {Arsenic, widely distributed in the environment, is a potent human carcinogen. Arsenite genotoxicity has been observed in a variety of cells and animal systems. However, the underlying mechanism is not completely clear. In this study, human fibroblasts (HFW) were treated with 1.25-10 microM arsenite for 24 h (low dose and long exposure) and 5-80 microM for 4 h (high dose and short exposure), and the arsenite accumulation, cytotoxicity, and micronucleus (MN) induction were examined. By these two different protocols, HFW cells showed equivalent levels of arsenite accumulation, but exhibited different kinetics of cell killing and different types of MN generation. Arsenite induced mainly kinetochore-positive MN (K+-MN) in HFW cells by low dose exposure whereas mainly kinetochore-negative MN (K--MN) was induced by high dose exposure. Catalase reduced both K+- and K--MN induced by these two exposure protocols. Except for the case of K+-MN induction by the high dose exposure protocol, N-acetyl-cysteine (NAC) in both low and high dose protocols was also shown to effectively reduce arsenite-induced MN. The present results imply that oxidative stress is involved in arsenite-induced MN in diploid human fibroblasts. However, different protocols for arsenite exposure may result in different cellular damage.}, }
@article {pmid10091258, year = {1999}, author = {Domenighetti, G and Quattropani, C and Schaller, MD}, title = {[Therapeutic use of N-acetylcysteine in acute lung diseases].}, journal = {Revue des maladies respiratoires}, volume = {16}, number = {1}, pages = {29-37}, pmid = {10091258}, issn = {0761-8425}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Free Radical Scavengers/*therapeutic use ; Humans ; Lung Diseases/*drug therapy/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Oxidants play a key role in disease processes, particularly in the detrimental mechanisms leading to tissue damage in certain forms of acute lung injury. A number of mediators contribute to the pathologic response in ARDS, SIRS or hyperoxia-induced pulmonary damage. One of the most important detrimental factors is the generation and activation of highly reactive oxygen species which are leading factors implicated in the process of tissue damage. N-acetylcysteine (NAC) is a free radical scavenger and might access the endothelial cell thus increasing intracellular glutathione (GSH) stores. Different studies have demonstrated that NAC might be a promising compound either for the prevention or the treatment of acute lung damages such as ARDS. However, the true beneficial effect so far reported in several clinical and experimental studies contrasts with some contradictory and intriguing aspects, probably because the significance of a direct in vivo antioxidative effect of this compound remains to be established in humans. Thus, the mode of action of NAC may not be the same in different pathologies and clinical situations. More research into the mechanisms of action of this unique xenobiotic substance may offer a clue for elucidating these controversies.}, }
@article {pmid10086329, year = {1999}, author = {Wadsworth, TL and Koop, DR}, title = {Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages.}, journal = {Biochemical pharmacology}, volume = {57}, number = {8}, pages = {941-949}, doi = {10.1016/s0006-2952(99)00002-7}, pmid = {10086329}, issn = {0006-2952}, support = {AA08608/AA/NIAAA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Line ; Cytokines/*biosynthesis/genetics ; Gene Expression Regulation/drug effects ; Macrophages/*drug effects/metabolism ; Mice ; NF-kappa B/metabolism ; Nitric Oxide Synthase/biosynthesis/genetics ; Nitric Oxide Synthase Type II ; Quercetin/*pharmacology ; RNA, Messenger/biosynthesis ; Resveratrol ; Stilbenes/*pharmacology ; Tumor Necrosis Factor-alpha/biosynthesis/genetics ; *Wine ; }, abstract = {The beneficial effects of moderate red wine consumption have been attributed, in part, to the presence of antioxidant components. Oxidant stress is an activating stimulus for the NF (nuclear factor)-KB/Rel family of transcription factors, which have binding sites in the promoter regions of many genes involved in inflammatory and immune responses. The effect of lipopolysaccharide (LPS)-stimulated activation of NF-KB and the subsequent production of tumor necrosis factor alpha (TNF-alpha) and NO was determined in the macrophage cell line RAW 264.7. Unexpectedly, the wine polyphenolics quercetin and resveratrol and the antioxidant N-acetylcysteine (NAC) did not inhibit LPS-induced activation of the NF-KB complex p50/65, as determined by mobility shift. Quercetin inhibited LPS-induced p50/50. Northern blot analysis indicated that quercetin (0.1 and 0.2 mM) inhibited LPS-dependent production of inducible nitric oxide synthase (iNOS) mRNA and decreased NO release, as measured by the Griess reaction. This flavonoid had no effect on LPS-induced TNF-alpha mRNA, but decreased LPS-stimulated TNF-alpha release, as measured by ELISA. Resveratrol (0.05 and 0.1 mM) posttranscriptionally decreased LPS-induced nitrite release. It increased basal levels of TNF-alpha mRNA and protein and enhanced LPS-induced TNF-alpha mRNA and cytokine release. Our results do not support the view that wine antioxidants inhibit LPS-induced NF-KB activation but instead that they have a more selective action on genes activated by LPS.}, }
@article {pmid10082136, year = {1999}, author = {Hossain, MZ and Jagdale, AB and Ao, P and Boynton, AL}, title = {Mitogen-activated protein kinase and phosphorylation of connexin43 are not sufficient for the disruption of gap junctional communication by platelet-derived growth factor and tetradecanoylphorbol acetate.}, journal = {Journal of cellular physiology}, volume = {179}, number = {1}, pages = {87-96}, doi = {10.1002/(SICI)1097-4652(199904)179:1&lt;87::AID-JCP11&gt;3.0.CO;2-K}, pmid = {10082136}, issn = {0021-9541}, support = {CA 57064/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Becaplermin ; Calcium-Calmodulin-Dependent Protein Kinases/*physiology ; Carcinogens/*pharmacology ; Cell Communication/*drug effects/physiology ; Connexin 43/*metabolism ; Enzyme Activation/drug effects ; Epithelial Cells/drug effects/metabolism ; Fluorescent Dyes/metabolism ; Gap Junctions/*drug effects/physiology ; Humans ; Hydrogen Peroxide/pharmacology ; Isoquinolines/metabolism ; Liver/cytology ; Phosphorylation ; Platelet-Derived Growth Factor/antagonists &amp; inhibitors/*pharmacology ; Protein Kinase C/physiology ; Protein Processing, Post-Translational ; Proto-Oncogene Proteins c-sis ; Rats ; Recombinant Fusion Proteins/pharmacology ; Tetradecanoylphorbol Acetate/antagonists &amp; inhibitors/*pharmacology ; Transfection ; }, abstract = {Disruption of gap junctional communication (GJC) by various compounds, including growth factors and tumor promoters, is believed to be modulated by the phosphorylation of a gap junctional protein, connexin43 (Cx43). We have previously demonstrated a platelet-derived growth factor (PDGF)-induced blockade of GJC and phosphorylation of Cx43 in T51B rat liver epithelial cells expressing wild-type PDGF receptor beta (PDGFr beta). Both of these actions of PDGF required participation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). Similar requirements of MAPK were suggested in the modulation of GJC by other agents, including epidermal growth factor (EGF) and lysophosphatidic acid (LPA). Since many of these agents activate additional protein kinases, our present study examined whether activation of MAPK was sufficient for Cx43 phosphorylation and GJC blockade. By utilizing a variety of MAPK activators, we now show that activation of MAPK is not always associated with either Cx43 phosphorylation or disruption of GJC, which suggests a requirement for additional factors. Furthermore, pretreatment with hydrogen peroxide (H2O2), a potent MAPK activator but inefficient GJC/Cx43 modulator, abrogated PDGF- or TPA-induced disruption of GJC. While a 5 min H2O2 pretreatment abolished both PDGF- and TPA-induced Cx43 phosphorylation and GJC blockade, a simultaneous H2O2 treatment interfered only with GJC closure but not with the phosphorylation of Cx43 induced by PDGF and TPA. This finding indicates that, in addition to the Cx43 phosphorylation step, inhibition of GJC requires interaction with other components. H2O2-mediated abrogation of PDGF/TPA signaling can be neutralized by the antioxidant N-acetylcysteine (NAC) or by the tyrosine kinase inhibitor genistein. Taken together, our results suggest that disruption of GJC is not solely mediated by either activated MAPK or Cx43 phosphorylation but requires the participation of additional kinases and regulatory components. This complex mode of regulation is perhaps essential for the proposed functional role of GJC.}, }
@article {pmid10072497, year = {1999}, author = {Verhasselt, V and Vanden Berghe, W and Vanderheyde, N and Willems, F and Haegeman, G and Goldman, M}, title = {N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {162}, number = {5}, pages = {2569-2574}, pmid = {10072497}, issn = {0022-1767}, mesh = {Acetylcysteine/*pharmacology ; CD40 Ligand ; Cells, Cultured ; Cytokines/biosynthesis ; Dendritic Cells/*drug effects/physiology ; Glutathione/analysis ; HLA-DR Antigens/analysis ; Humans ; Lipopolysaccharides/pharmacology ; Membrane Glycoproteins/pharmacology ; NF-kappa B/*antagonists &amp; inhibitors ; T-Lymphocytes/*drug effects/physiology ; }, abstract = {N-acetyl-L-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-kappaB. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.}, }
@article {pmid10063910, year = {1999}, author = {Shimada, T and Watanabe, N and Hiraishi, H and Terano, A}, title = {Redox regulation of interleukin-8 expression in MKN28 cells.}, journal = {Digestive diseases and sciences}, volume = {44}, number = {2}, pages = {266-273}, pmid = {10063910}, issn = {0163-2116}, mesh = {Acetylcysteine/pharmacology ; Blotting, Northern ; Dimethyl Sulfoxide/pharmacology ; Electrophoresis ; Enzyme-Linked Immunosorbent Assay ; Gastric Mucosa/*metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Interleukin-1/pharmacology ; Interleukin-8/*biosynthesis ; NF-kappa B/pharmacology ; Oxidation-Reduction ; RNA, Messenger/analysis ; Reactive Oxygen Species/*metabolism ; Transcription Factors/analysis ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Recent evidence suggests a role of reactive oxygen intermediates (ROI) in intracellular signaling and regulation of gene expression. We examined whether expression of interleukin-8 (IL-8), a key cytokine in the inflammatory responses of gastric epithelial cells, is sensitive to antioxidants and oxidative stress. IL-8 secretion was quantified by IL-8 enzyme-linked immunosorbent assay, and IL-8 mRNA expression was determined by northern blot analysis. Electrophoretic mobility shift assay was performed to detect the transcription factor, nuclear factor kappaB (NF-kappaB). N-Acetylcysteine (NAC) or dimethylsulfoxide inhibited IL-8 expression induced by tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta). Externally applied H2O2 significantly up-regulated IL-8 expression. TNF-alpha-induced activation of NF-kappaB activity was suppressed by NAC, and H2O2 caused significant activation of NF-kappaB. Since ROI production is increased in the inflamed gastric mucosa, for example, in H. pylori-associated gastritis, the present results suggest that ROI may be an important modulator of IL-8 expression in gastric mucosal cells.}, }
@article {pmid10048759, year = {1999}, author = {Shaikh, ZA and Zaman, K and Tang, W and Vu, T}, title = {Treatment of chronic cadmium nephrotoxicity by N-acetyl cysteine.}, journal = {Toxicology letters}, volume = {104}, number = {1-2}, pages = {137-142}, doi = {10.1016/s0378-4274(98)00358-0}, pmid = {10048759}, issn = {0378-4274}, support = {ES03187/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Cadmium Poisoning/enzymology/pathology/*prevention &amp; control ; Female ; Free Radical Scavengers/*therapeutic use ; Kidney Diseases/chemically induced/pathology/*prevention &amp; control ; L-Lactate Dehydrogenase/metabolism ; Rats ; Rats, Sprague-Dawley ; Time Factors ; }, abstract = {Chronic cadmium (Cd)-induced nephrotoxicity is believed to be irreversible at advanced stages and no treatment is currently available. This study examined the beneficial effect of N-acetyl cysteine (NAC) on Cd-induced nephrotoxicity. Female Sprague-Dawley rats were injected s.c. with 5 micromol CdCl2/kg per day, five times/week for up to 26 weeks. Nephrotoxicity was detected after 10 weeks by elevation in urinary lactate dehydrogenase activity and protein. NAC co-administration from week 13 prevented the progression of nephrotoxicity. In these animals, with low-level nephrotoxicity, discontinuation of Cd exposure at the end of week 22 resulted in gradual recovery over the next several weeks, without the need for treatment with NAC. On the other hand, discontinuation of NAC co-treatment at the end of week 22 resulted in quick progression of nephrotoxicity, indicating that NAC protection was short-lived. Resumption of NAC treatment and cessation of Cd exposure after 26 weeks resulted in rapid recovery from advanced nephrotoxicity. It is concluded that protection from Cd-induced nephrotoxicity is possible by continued co-administration of NAC and that recovery from advanced nephrotoxicity can also be achieved with NAC, provided that Cd exposure is stopped.}, }
@article {pmid10028407, year = {1998}, author = {Langenberg, JP and van der Schans, GP and Spruit, HE and Kuijpers, WC and Mars-Groenendijk, RH and van Dijk-Knijnenburg, HC and Trap, HC and van Helden, HP and Benschop, HP}, title = {Toxicokinetics of sulfur mustard and its DNA-adducts in the hairless guinea pig.}, journal = {Drug and chemical toxicology}, volume = {21 Suppl 1}, number = {}, pages = {131-147}, doi = {10.3109/01480549809007407}, pmid = {10028407}, issn = {0148-0545}, mesh = {Administration, Cutaneous ; Administration, Inhalation ; Animals ; Chromatography, Gas ; DNA Adducts/*pharmacokinetics/*toxicity ; Guanine/*metabolism ; Guinea Pigs ; Immunoassay ; Injections, Intravenous ; Male ; Mass Spectrometry ; Mustard Gas/adverse effects/*pharmacokinetics/*toxicity ; }, abstract = {In order to provide a quantitative basis for pretreatment and therapy of intoxications with sulfur mustard (SM) the toxicokinetics of this agent as well as its major DNA-adduct were studied in male hairless guinea pigs for the intravenous, respiratory and percutaneous routes. The study comprised measurement of the concentration-time course of SM in blood and measurement of the concentrations of intact SM and its adduct to guanine in various tissues at several time points after administration of, or exposure to SM. SM was analyzed in blood and tissues by gas chromatography with automated thermodesorption injection and mass-spectrometric detection. DNA-adducts were measured via an immuno-slot-blot method. In contrast with nerve agents of the phosphofluoridate type, SM partitions strongly to various organs, especially the lung, spleen, liver and bone marrow. The respiratory toxicity of SM appears to be local, rather than systemic. Surprisingly, the maximum concentration of SM in blood upon percutaneous exposure to 1 LCt50 (10,000 mg.min.m-3, estimated) is approximately 6-fold higher than that for nose--only exposure to 3 LCt50 (2,400 mg.min.m-3). Pretreatment of hairless guinea pigs with the potential scavengers N-acetyl cysteine or cysteine isopropyl ester did not significantly increase the LCt50-value for nose--only exposure to SM vapor.}, }
@article {pmid10027856, year = {1999}, author = {Särnstrand, B and Jansson, AH and Matuseviciene, G and Scheynius, A and Pierrou, S and Bergstrand, H}, title = {N,N'-Diacetyl-L-cystine-the disulfide dimer of N-acetylcysteine-is a potent modulator of contact sensitivity/delayed type hypersensitivity reactions in rodents.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {288}, number = {3}, pages = {1174-1184}, pmid = {10027856}, issn = {0022-3565}, mesh = {Acetylcysteine/analogs &amp; derivatives ; Adjuvants, Immunologic/*pharmacology ; Animals ; CD8-Positive T-Lymphocytes ; Cystine/*analogs &amp; derivatives/pharmacology ; Dermatitis, Contact/etiology/*immunology ; Dinitrofluorobenzene ; Ear ; Female ; Fluorescein-5-isothiocyanate ; Foot ; Granuloma/etiology/immunology ; Hypersensitivity, Delayed/etiology/*immunology ; Immunohistochemistry ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred Strains ; Oxazolone ; Rabbits ; Serum Albumin, Bovine ; }, abstract = {Oral N-acetyl-L-cysteine (NAC) is used clinically for treatment of chronic obstructive pulmonary disease. NAC is easily oxidized to its disulfide. We show here that N,N'-diacetyl-L-cystine (DiNAC) is a potent modulator of contact sensitivity (CS)/delayed type hypersensitivity (DTH) reactions in rodents. Oral treatment of BALB/c mice with 0.003 to 30 micromol/kg DiNAC leads to enhancement of a CS reaction to oxazolone; DiNAC is 100 to 1000 times more potent than NAC in this respect, indicating that it does not act as a prodrug of NAC. Structure-activity studies suggest that a stereochemically-defined disulfide element is needed for activity. The DiNAC-induced enhancement of the CS reaction is counteracted by simultaneous NAC-treatment; in contrast, the CS reaction is even more enhanced in animals treated with DiNAC together with the glutathione-depleting agent buthionine sulfoximine. These data suggest that DiNAC acts via redox processes. Immunohistochemically, ear specimens from oxazolone-sensitized and -challenged BALB/c mice treated with DiNAC display increased numbers of CD8(+) cells. DiNAC treatment augments the CS reaction also when fluorescein isothiocyanate is used as a sensitizer in BALB/c mice; this is a purported TH2 type of response. However, when dinitrofluorobenzene is used as a sensitizer, inducing a purported TH1 type of response, DiNAC treatment reduces the reaction. Treatment with DiNAC also reduces a DTH footpad-swelling reaction to methylated BSA. Collectively, these data indicate that DiNAC in vivo acts as a potent and effective immunomodulator that can either enhance or reduce the CS or DTH response depending on the experimental conditions.}, }
@article {pmid10026227, year = {1999}, author = {Rao, GN and Katki, KA and Madamanchi, NR and Wu, Y and Birrer, MJ}, title = {JunB forms the majority of the AP-1 complex and is a target for redox regulation by receptor tyrosine kinase and G protein-coupled receptor agonists in smooth muscle cells.}, journal = {The Journal of biological chemistry}, volume = {274}, number = {9}, pages = {6003-6010}, doi = {10.1074/jbc.274.9.6003}, pmid = {10026227}, issn = {0021-9258}, mesh = {Acetylcysteine/pharmacology ; Animals ; Base Sequence ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cells, Cultured ; Chloramphenicol O-Acetyltransferase/genetics ; DNA Primers ; Enzyme Activation ; GTP-Binding Proteins/*metabolism ; Male ; Muscle, Smooth, Vascular/cytology/enzymology/*metabolism ; Onium Compounds/pharmacology ; Oxidation-Reduction ; Proto-Oncogene Proteins c-jun/*metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor Protein-Tyrosine Kinases/*metabolism ; Transcription Factor AP-1/*metabolism ; }, abstract = {To understand the role of redox-sensitive mechanisms in vascular smooth muscle cell (VSMC) growth, we have studied the effect of N-acetylcysteine (NAC), a thiol antioxidant, and diphenyleneiodonium (DPI), a potent NADH/NADPH oxidase inhibitor, on serum-, platelet-derived growth factor BB-, and thrombin-induced ERK2, JNK1, and p38 mitogen-activated protein (MAP) kinase activation; c-Fos, c-Jun, and JunB expression; and DNA synthesis. Both NAC and DPI completely inhibited agonist-induced AP-1 activity and DNA synthesis in VSMC. On the contrary, these compounds had differential effects on agonist-induced ERK2, JNK1, and p38 MAP kinase activation and c-Fos, c-Jun, and JunB expression. NAC inhibited agonist-induced ERK2, JNK1, and p38 MAP kinase activation and c-Fos, c-Jun, and JunB expression except for platelet-derived growth factor BB-induced ERK2 activation. In contrast, DPI only inhibited agonist-induced p38 MAP kinase activation and c-Fos and JunB expression. Antibody supershift assays indicated the presence of c-Fos and JunB in the AP-1 complex formed in response to all three agonists. In addition, cotransfection of VSMC with expression plasmids for c-Fos and members of the Jun family along with the AP-1-dependent reporter gene revealed that AP-1 with c-Fos and JunB composition exhibited a higher transactivating activity than AP-1 with other compositions tested. All three agonists significantly stimulated reactive oxygen species production, and this effect was inhibited by both NAC and DPI. Together, these results strongly suggest a role for redox-sensitive mechanisms in agonist-induced ERK2, JNK1, and p38 MAP kinase activation; c-Fos, c-Jun, and JunB expression; AP-1 activity; and DNA synthesis in VSMC. These results also suggest a role for NADH/NADPH oxidase activity in some subset of early signaling events such as p38 MAP kinase activation and c-Fos and JunB induction, which appear to be important in agonist-induced AP-1 activity and DNA synthesis in VSMC.}, }
@article {pmid10025562, year = {1999}, author = {Dringen, R and Hamprecht, B}, title = {N-acetylcysteine, but not methionine or 2-oxothiazolidine-4-carboxylate, serves as cysteine donor for the synthesis of glutathione in cultured neurons derived from embryonal rat brain.}, journal = {Neuroscience letters}, volume = {259}, number = {2}, pages = {79-82}, doi = {10.1016/s0304-3940(98)00894-5}, pmid = {10025562}, issn = {0304-3940}, mesh = {Acetylcysteine/*metabolism ; Animals ; Brain/*cytology/embryology ; Cells, Cultured ; Cysteine/*metabolism ; Female ; Glutathione/*biosynthesis ; Methionine/*metabolism ; Neurons/cytology/*metabolism ; Pregnancy ; Pyrrolidonecarboxylic Acid ; Rats ; Rats, Wistar ; Thiazoles/*metabolism ; Thiazolidines ; }, abstract = {The ability of neurons to metabolize sulfur-containing compounds to cysteine was investigated using as indicator the glutathione content in neuron-rich primary cultures derived from the brains of embryonal rats. The-glutathione content of these cultures was doubled during a 4-h incubation in a minimal medium containing cysteine, glutamine and glycine. In contrast, absence of cysteine or replacement of cysteine by methionine or 2-oxothiazolidine-4-carboxylate failed to increase the glutathione content of cultured neurons. Besides cysteine, N-acetylcysteine (NAC) also caused in the millimolar range, a concentration-dependent increase in the neuronal glutathione content during a 4-h incubation. These data suggest that neurons in culture, contain an acylase activity which allows them to generate from extracellular NAC as precursor intracellular cysteine in concentrations sufficient for glutathione synthesis. In contrast, generation of cysteine from 2-oxothiazolidine-4-carboxylate by the reaction of 5-oxoprolinase or from methionine by the transsulfuration pathway appears not to take place in these cultured neurons.}, }
@article {pmid10022994, year = {1999}, author = {Ward, NE and Fan, G and O'Brian, CA}, title = {Differential non-redox inhibitory effects of glutathione against protein kinase C isozyme family members.}, journal = {Oncology reports}, volume = {6}, number = {2}, pages = {307-310}, doi = {10.3892/or.6.2.307}, pmid = {10022994}, issn = {1021-335X}, support = {CA74831/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Enzyme Inhibitors/pharmacology ; Glutathione/*pharmacology ; Humans ; Isoenzymes/*antagonists &amp; inhibitors ; Kinetics ; Oxidation-Reduction ; Protein Kinase C/*antagonists &amp; inhibitors ; Protein Kinase C beta ; Protein Kinase C-epsilon ; Recombinant Proteins/antagonists &amp; inhibitors ; }, abstract = {Glutathione (GSH) and the GSH metabolic precursor N-acetylcysteine (NAC) are potent antioxidants that have clear potential either as cancer chemopreventive agents or as lead compounds for new cancer chemopreventive agents. The potential efficacy of GSH and NAC in clinical cancer chemoprevention is suggested by their antagonism of tumor promotion in animal models. Protein kinase C (PKC) is an isozyme family that plays a critical role in phorbol ester-mediated tumor promotion. We recently found that GSH and NAC exert direct inhibitory effects against a purified PKC isozyme mixture by a mechanism that did not involve their antioxidant properties. In this report, we characterize non-redox inhibitory effects of glutathiones on PKC isozymes that have been shown to produce partially or fully transformed phenotypes in mammalian cells. We show that GSH, NAC, and oxidized GSH analogs exert potent inhibition of the isozyme cPKC-ç and are somewhat less effective against cPKC- 1. In contrast, the oncogenic isozyme nPKC-â was unaffected by NAC, and it was inhibited by GSH and oxidized GSH analogs very modestly. Our results suggest that the potential impact of non-redox GSH/NAC-mediated PKC inhibition on cellular responses to tumor promoters and indeed, on cell growth regulation in general, may depend upon the pattern of PKC isozyme expression in the cells.}, }
@article {pmid9990295, year = {1999}, author = {Giardina, C and Boulares, H and Inan, MS}, title = {NSAIDs and butyrate sensitize a human colorectal cancer cell line to TNF-alpha and Fas ligation: the role of reactive oxygen species.}, journal = {Biochimica et biophysica acta}, volume = {1448}, number = {3}, pages = {425-438}, doi = {10.1016/s0167-4889(98)00156-6}, pmid = {9990295}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antibodies/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/genetics ; Butyrates/*pharmacology ; Colorectal Neoplasms/*drug therapy/*metabolism/prevention &amp; control ; Fas Ligand Protein ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Indomethacin/pharmacology ; Membrane Glycoproteins/antagonists &amp; inhibitors/*metabolism ; NF-kappa B/metabolism ; Reactive Oxygen Species/*metabolism ; Salicylic Acid/pharmacology ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {The nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin and salicylic acid and the short chain fatty acid butyrate are effective colon cancer chemopreventive agents that increase reactive oxygen species (ROS) generation in colon cancer cells. Here we demonstrate that these agents sensitize the normally resistant human HT-29 colon cancer cell line to apoptosis induced by TNF-alpha or a Fas ligating antibody. The role of ROS in this sensitization is supported by the finding that direct exposure of the cells to H2O2 is sufficient for sensitization. Neither TNF-alpha nor Fas ligation alter basal or chemopreventive agent-activated ROS generation, suggesting that the death ligands and chemopreventive agents act in a complementary fashion. The dual chemopreventive agent/death ligand treatments do not increase Fas, TNF receptor 1, Bak or c-myc expression (although salicylic acid moderately induces of Fas expression). Cell death does correlate with alterations in NF-kappa B activity: the NSAIDs, butyrate and H2O2 enhance c-Rel complex formation by TNF-alpha and provide an overall enhancement of NF-kappa B activation by Fas. The antioxidant N-acetylcysteine (NAC) blocks cell death and NF-kappa B activation induced by Fas ligation, suggesting a potential role for NF-kappa B in Fas-induced apoptosis in these cells. The effects of NAC on TNF-alpha-induced cell death are more complex, with NAC being marginally protective and itself enhancing the formation of c-Rel containing complexes at higher concentrations (25 mM). The influence of NSAIDs and butyrate on ROS generation and death ligand sensitivity may be relevant to their ability to suppress colon carcinogenesis.}, }
@article {pmid9973469, year = {1999}, author = {Furuke, K and Shiraishi, M and Mostowski, HS and Bloom, ET}, title = {Fas ligand induction in human NK cells is regulated by redox through a calcineurin-nuclear factors of activated T cell-dependent pathway.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {162}, number = {4}, pages = {1988-1993}, pmid = {9973469}, issn = {0022-1767}, mesh = {Antibodies, Monoclonal/pharmacology ; Calcineurin/*physiology ; Calcineurin Inhibitors ; Cells, Cultured ; Culture Media, Conditioned ; DNA-Binding Proteins/antagonists &amp; inhibitors/*physiology ; Enzyme Activation/drug effects/immunology ; Fas Ligand Protein ; Humans ; Hydrogen Peroxide/pharmacology ; Interleukin-2/pharmacology ; Intracellular Fluid/metabolism ; Killer Cells, Natural/drug effects/enzymology/*immunology ; Ligands ; Lymphocyte Activation/*immunology ; Membrane Glycoproteins/antagonists &amp; inhibitors/*biosynthesis/genetics ; NFATC Transcription Factors ; *Nuclear Proteins ; Oxidation-Reduction ; Peroxides/metabolism ; RNA, Messenger/antagonists &amp; inhibitors/metabolism ; Receptors, IgG/immunology ; Sulfhydryl Compounds/metabolism ; T-Lymphocytes/*immunology ; Time Factors ; Transcription Factors/antagonists &amp; inhibitors/*physiology ; fas Receptor/*metabolism ; }, abstract = {Fas ligand (FasL) on cytotoxic lymphocytes is important for mediating apoptosis of activated lymphocytes and other target cells. We have reported that NK cell functions, such as proliferation, cell death, and killing activity, are subject to regulation by cellular redox status. Here, we report that expression of FasL protein and mRNA in activated NK cells is also regulated by redox. Ligation of CD16 on IL-2-preactivated NK cells resulted in reduction of intracellular peroxide level as well as induction of FasL expression. This CD16-induced FasL expression was suppressed by oxidative stress, including thiol deprivation or treatment with hydrogen peroxide (H2O2). Addition of thiol-reducing compounds, such as L-cystine, 2-ME, or N-acetyl cysteine, restored FasL expression. These data suggest that CD16 stimulation requires cellular reducing status for FasL induction in NK cells. Because FasL gene activation following CD16 cross-linking is regulated by the NF of activated T cells (NFAT), we examined the effect of oxidative stresses on NFAT activation. Electrophoretic mobility shift assays revealed that both thiol insufficiency and H2O2 treatment suppressed DNA-binding activity of NFAT and that addition of thiol-reducing compounds reversed or even enhanced it. Furthermore, these oxidative stresses inhibited activity of calcineurin, a serine/threonine phosphatase that regulates NFAT activation. These results suggest that suppression of calcineurin and NFAT activation is a mechanism by which oxidative stress inhibits FasL induction in activated NK cells and further support the hypothesis that thiol-reducing compounds might be required for maintenance of optimal NK functions under physiologic oxidative conditions.}, }
@article {pmid9933417, year = {1999}, author = {Tsuji, F and Miyake, Y and Aono, H and Kawashima, Y and Mita, S}, title = {Effects of bucillamine and N-acetyl-L-cysteine on cytokine production and collagen-induced arthritis (CIA).}, journal = {Clinical and experimental immunology}, volume = {115}, number = {1}, pages = {26-31}, pmid = {9933417}, issn = {0009-9104}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antibodies/blood ; Arthritis, Experimental/chemically induced/*drug therapy ; Cholesterol/blood ; *Collagen/immunology ; Cysteine/*analogs &amp; derivatives/pharmacology ; Humans ; Male ; Mice ; Mice, Inbred DBA ; NF-kappa B/metabolism ; Phospholipids/blood ; Rats ; Rats, Wistar ; Triglycerides/blood ; Tumor Cells, Cultured/drug effects/metabolism ; }, abstract = {We investigated the effects of bucillamine and N-acetyl-L-cysteine (NAC) on cytokine production and CIA. Bucillamine and NAC inhibited NF-kappaB activation and tumour necrosis factor-alpha (TNF-alpha) mRNA expression in human monocytic leukaemia cell line THP-1, and cytokine production from monocyte cell lines at concentrations >10-3 M. They also inhibited cytokine production and CIA in mice at a dose of 500 mg/kg. These results suggest that NF-kappaB inhibitors such as bucillamine and NAC may inhibit cytokine-related diseases, including arthritis.}, }
@article {pmid9927752, year = {1999}, author = {Partington, GA and Patient, RK}, title = {Phosphorylation of GATA-1 increases its DNA-binding affinity and is correlated with induction of human K562 erythroleukaemia cells.}, journal = {Nucleic acids research}, volume = {27}, number = {4}, pages = {1168-1175}, doi = {10.1093/nar/27.4.1168}, pmid = {9927752}, issn = {0305-1048}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Cell Differentiation ; DNA/*metabolism ; DNA-Binding Proteins/*metabolism ; Enzyme Inhibitors/pharmacology ; Erythroid-Specific DNA-Binding Factors ; GATA1 Transcription Factor ; Humans ; K562 Cells ; Leukemia, Erythroblastic, Acute ; Mice ; Nuclear Proteins/*metabolism ; Okadaic Acid/pharmacology ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Transcription Factors/*metabolism ; }, abstract = {We have investigated by electrophoretic mobility shift assay (EMSA) the level of GATA-1 DNA-binding activity in nuclear extracts prepared from the human erythroleukaemic cell line, K562, after erythroid induction by hemin, sodium butyrate (NaB) or Trichostatin A or treatment with N -acetylcysteine (NAC). Relative to extract from untreated cells, GATA-1 binding activity increased markedly in all cases. However, immunoblot analysis revealed unchanged levels of GATA-1 protein after induction. Incubation of induced but not uninduced K562 extracts with phosphatase prior to EMSA weakened the binding activity, suggesting that the increase in GATA-1 binding following induction of K562 cells was a consequence of phosphorylation. When the mouse erythroleukaemic cell line MEL was induced with dimethylsulphoxide (DMSO), NaB or NAC, GATA-1 binding activity fell with DMSO, rose significantly with NaB and remained at about the same level in NAC-induced cells. In this case immunoblotting revealed that GATA-1 protein levels were in accord with the EMSA data. The DNA-binding activities of induced and uninduced MEL cell nuclear extracts were decreased by incubation with phosphatase, showing that phosphoryl-ation and DNA binding of GATA-1 are already optimalin these cells. The DNA-binding activity of affinity-purified GATA-1 from MEL cells was also reduced by phosphatase treatment, showing that phosphorylation/dephosphorylation is directly affecting the factor. Furthermore, when a comparison was made by EMSA of nuclear extracts prepared from K562 and MEL cells untreated or incubated with okadaic acid, a phosphatase inhibitor, GATA-1 binding was seen to increase with K562 cells, whereas with MEL cells there was no change in GATA-1 binding. Overall the results suggest that the level of GATA-1 phosphorylation increases after the induction of K562, but not MEL cells, where GATA-1 is already highly phosphorylated. Furthermore, phosphorylation increases the binding affinity of GATA-1 for a canonical binding site.}, }
@article {pmid9925989, year = {1998}, author = {Grdina, DJ and Murley, JS and Roberts, JC}, title = {Effects of thiols on topoisomerase-II alpha activity and cell cycle progression.}, journal = {Cell proliferation}, volume = {31}, number = {5-6}, pages = {217-229}, pmid = {9925989}, issn = {0960-7722}, support = {CA37435/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; Antigens, Neoplasm ; CHO Cells ; Captopril/pharmacology ; Cell Cycle/*drug effects ; Cell Extracts ; Cricetinae ; *DNA Topoisomerases, Type II/*metabolism ; DNA, Kinetoplast/metabolism ; DNA-Binding Proteins ; Dithiothreitol/pharmacology ; Flow Cytometry ; Isoenzymes/antagonists &amp; inhibitors/*metabolism ; Stereoisomerism ; Sulfhydryl Compounds/*pharmacology ; Time Factors ; Topoisomerase II Inhibitors ; }, abstract = {Thiol containing compounds exhibiting antioxidant properties are currently being evaluated for use in cytoprotection and chemoprevention. Many of these have also been found to be effective in inhibiting cell cycle progression and cellular proliferation. N-Acetyl-L-cysteine (L-NAC), along with its nonmetabolically active stereoisomer N-acetyl-D-cysteine (D-NAC), together with captopril and dithiothreitol (DTT) were investigated to assess their effects on cell cycle progression as determined by flow cytometry. Topoisomerase-IIa (topo-II alpha) activity, an enzyme involved in DNA synthesis, was also monitored as a function of drug dose using a kinetoplast DNA (kDNA) decatenation assay. Chinese hamster ovary (CHO) AA8 cells were exposed to each thiol at concentrations ranging from 4 microM to 4 mM for a period of 3 h. Following the removal of the thiols, cell cultures were followed for an additional 5 h to assess changes in cell cycle progression. L-NAC, which also serves as a precursor for glutathione (GSH) synthesis, effectively inhibited topo-IIa activity by at least 50% at all concentrations tested. Associated with this reduction in enzyme activity was a sixfold increase in the relative number of cells accumulating in G2phase. D-NAC, which is unable to participate in GSH synthesis, was only half as effective as L-NAC at each concentration tested in inhibiting topo-IIa activity as well as perturbing cell progression through G2. In comparison, captopril, an inhibitor of angiotensin converting enzyme (ACE), had little effect on the progression of cells into G2 phase. In contrast to the repressive effects of L-NAC and D-NAC, it enhanced topo-IIa activity over control values by approximately 20%. DTT, a well characterized thiol known to be capable of reducing disulphides in proteins, was observed to be relatively ineffective in either perturbing cell cycle progression or affecting topo-IIa activity. This suggests an involvement of a mechanism(s) in addition to thiol mediated affects on reduction/oxidation processes. The inhibitory effects of L-NAC and D-NAC on topo-IIa activity, in contrast to the other two thiols, may be due in part to the presence of amine groups which could allow for their participation in polyamine related processes. The difference in the magnitude of the effect exhibited by L-NAC, as compared to D-NAC, on the repression topo-IIa activity also suggests a role for GSH in this process. Inhibition of cellular progression and proliferation by thiols can therefore be mediated by diverse mechanisms which include both cycle-phase specific (i.e. L-NAC and D-NAC) and non cell cycle specific (i.e. captopril) processes.}, }
@article {pmid9924848, year = {1998}, author = {Beltrame, JF and Zeitz, CJ and Unger, SA and Brennan, RJ and Hunt, A and Moran, JL and Horowitz, JD}, title = {Nitrate therapy is an alternative to furosemide/morphine therapy in the management of acute cardiogenic pulmonary edema.}, journal = {Journal of cardiac failure}, volume = {4}, number = {4}, pages = {271-279}, doi = {10.1016/s1071-9164(98)90232-9}, pmid = {9924848}, issn = {1071-9164}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Diuretics/*therapeutic use ; Drug Tolerance ; Female ; Free Radical Scavengers/*therapeutic use ; Furosemide/*therapeutic use ; Humans ; Male ; Morphine/therapeutic use ; Nitroglycerin/*therapeutic use ; Prospective Studies ; Pulmonary Edema/*drug therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Nitrates are superior to furosemide in the management of acute pulmonary edema associated with myocardial infarction; however, their role in the absence of infarction is unclear.<br><br>METHODS AND RESULTS: A randomized comparison was undertaken of the relative effectiveness of primary therapy with either intravenous morphine/furosemide (men/women; n = 32) or nitroglycerin/N-acetylcysteine (NTG/NAC; n = 37) in consecutive patients with acute pulmonary edema. The primary end point was change in PaO2/FIO2 over the first 60 minutes of therapy. Secondary end points were needed for mechanical respiratory assistance (ie, continuous positive airway pressure via mask or intubation and ventilation) and changes in other gas exchange parameters. Both treatment groups showed improvement in oxygenation after 60 minutes of therapy; however, this reached statistical significance only with NTG/NAC therapy. There was no significant difference between groups in the assessed parameters (95% CI for differences in Pao2/FIO2: furosemide/morphine -12 to 23 and NTG/NAC 4 to 44), a finding also confirmed in 32 patients presenting with respiratory failure. Only 11% of the study group required mechanical ventilatory assistance (continuous positive airway pressure in 4 patients and intubation and ventilation in 3 patients).<br><br>CONCLUSIONS: NTG/NAC therapy is as effective as furosemide/morphine in the initial management of acute pulmonary edema, regardless of the presence or absence of respiratory failure. The necessity for mechanical ventilatory assistance is infrequent in these patients, regardless of the initial medical treatment regimen.}, }
@article {pmid9924804, year = {1998}, author = {Madesh, M and Benard, O and Balasubramanian, KA}, title = {Glutathione modulates lipid composition of human colon derived HT-29 cells.}, journal = {The international journal of biochemistry &amp; cell biology}, volume = {30}, number = {12}, pages = {1345-1352}, doi = {10.1016/s1357-2725(98)00097-1}, pmid = {9924804}, issn = {1357-2725}, mesh = {Acetylcysteine/pharmacology ; Antimetabolites, Antineoplastic/pharmacology ; Buthionine Sulfoximine/pharmacology ; Cholesterol Esters/metabolism ; Colon/drug effects/*metabolism ; Diglycerides/metabolism ; Glutathione/*physiology ; HT29 Cells ; Humans ; *Lipid Metabolism ; Maleates/pharmacology ; Sulfhydryl Compounds/metabolism ; Triglycerides/metabolism ; }, abstract = {Glutathione (GSH) is important in maintaining intracellular thiol status. The present study looked at the effect of GSH depletion on lipid composition of colon-derived HT-29 cells. GSH was depleted in HT-29 cells by incubation either with buthionine-S, R-sulfoximine (BSO) or diethylmaleate (DEM). GSH was restored during early periods of cells growth by supplementation of growth medium with either GSH ester or N-acetyl cysteine (NAC). Lipids were analysed following GSH depletion and supplementation. Among the neutral lipids, an increase in free cholesterol and diacylglycerol and decrease in cholesteryl ester and triacylglycerol were seen in GSH-depleted cells as compared to control cells. There were no detectable free fatty acids either in control or GSH-depleted cells. Among the phospholipids, a decrease in phosphatidylcholine and phosphatidylinositol and an increase in phosphatidylethanolamine were observed. These changes were a completely reversed by supplementation of BSO-treated cells with GSH ester and partially reversed by N-acetyl cysteine. These results suggest that the GSH status of the cell plays an important role in the lipid composition of the cells.}, }
@article {pmid9916320, year = {1998}, author = {Accinni, R and Campolo, J and Bartesaghi, S and De Leo, G and Lucarelli, C and Cursano, CF and Parodi, O}, title = {High-performance liquid chromatographic determination of total plasma homocysteine with or without internal standards.}, journal = {Journal of chromatography. A}, volume = {828}, number = {1-2}, pages = {397-400}, doi = {10.1016/s0021-9673(98)00661-x}, pmid = {9916320}, issn = {0021-9673}, mesh = {Chromatography, High Pressure Liquid/*methods ; Homocysteine/*blood ; Humans ; Reference Standards ; Reproducibility of Results ; Spectrometry, Fluorescence ; }, abstract = {Hyperhomocysteinemia is an independent risk factor for atherosclerosis and vascular occlusive disease. Assessment of total plasma concentration of homocysteine (tHcys) requires accurate and reproducible measurements. The aim of this study was to test a rapid isocratic HPLC method for tHcys analysis with an internal standard (I.S.) of alpha-mercaptopropionylglycine (MPG), 2-mercaptoethylamine (ME), or N-acetylcysteine (NAC) or without I.S., and to verify whether the use of an I.S. improves the precision. The method without I.S. showed an excellent linearity (y = 1.59x - 0.15, r = 1), recovery (100%) and a within-assay relative standard deviation (R.S.D.) of 1.2%. Instead, in our hands, the presence of I.S.s decreased the reproducibility (within-assay R.S.D. ranged from 4.5 to 6.5%) and lengthened the chromatogram by up to four to five times. In conclusion, HPLC measurement of plasma tHcys without I.S. improves accuracy with respect to determination with I.S.; moreover, this approach allows to routinely process larger amounts of plasma samples.}, }
@article {pmid9915780, year = {1999}, author = {Pollman, MJ and Hall, JL and Gibbons, GH}, title = {Determinants of vascular smooth muscle cell apoptosis after balloon angioplasty injury. Influence of redox state and cell phenotype.}, journal = {Circulation research}, volume = {84}, number = {1}, pages = {113-121}, doi = {10.1161/01.res.84.1.113}, pmid = {9915780}, issn = {0009-7330}, mesh = {Acetylcysteine/pharmacology ; Angioplasty, Balloon/*adverse effects ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/*physiology ; Enzyme Activation ; Glutathione/metabolism ; Kinetics ; Male ; Muscle, Smooth, Vascular/injuries/pathology/*physiology ; Oxidation-Reduction ; Oxidative Stress ; Protein Kinases/metabolism ; Pyrrolidines/pharmacology ; Rabbits ; Signal Transduction ; Thiocarbamates/pharmacology ; Time Factors ; Tunica Media/injuries/pathology/physiology ; }, abstract = {We have observed that acute medial cell loss is an initial event in the response to vascular injury induced by balloon-catheter distention of the rabbit carotid artery. Numerous apoptotic medial cells were observed as early as 30 minutes after balloon inflation, and a 70% loss of cellularity was evident by 90 minutes. Balloon injury was associated with oxidative stress as reflected by a fall in glutathione levels by 63% within 30 minutes after injury. We hypothesized that balloon injury activated a redox-sensitive signaling pathway coupled to the regulation of apoptosis. Indeed, the activity of the proapoptotic signal mediator, stress-activated protein kinase, was increased severalfold within 10 minutes after injury. Moreover, modifying the vascular redox state by the administration of 1 of 2 structurally dissimilar antioxidants, N-acetyl cysteine or pyrrolidine dithiocarbamate, markedly attenuated both stress-activated protein kinase activation and the induction of apoptosis at 30 minutes. We hypothesized further that the induction of vascular smooth muscle cell apoptosis is modulated by phenotype. In contrast to medial cells, we observed that neointimal cells were relatively resistant to apoptotic death induced by angioplasty injury. This resistance to balloon injury-induced death was associated with an upregulation of the antiapoptotic mediator bcl-xL. This study suggests that acute apoptotic cell death after vascular injury is a highly regulated process governed by cellular redox state and the relative expression of antiapoptotic genes. Angioplasty-induced vascular cell apoptosis may be an important determinant of vascular remodeling and restenosis.}, }
@article {pmid9895238, year = {1999}, author = {Biagioli, MC and Kaul, P and Singh, I and Turner, RB}, title = {The role of oxidative stress in rhinovirus induced elaboration of IL-8 by respiratory epithelial cells.}, journal = {Free radical biology &amp; medicine}, volume = {26}, number = {3-4}, pages = {454-462}, doi = {10.1016/s0891-5849(98)00233-0}, pmid = {9895238}, issn = {0891-5849}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Epithelial Cells/metabolism/*physiology ; Humans ; Hydrogen Peroxide/pharmacology ; Interleukin-8/*biosynthesis ; Lung/cytology/*metabolism ; NF-kappa B/metabolism ; Oxidative Stress/*physiology ; Rhinovirus/*physiology ; Signal Transduction/physiology ; Stimulation, Chemical ; }, abstract = {A direct correlation has been reported between the severity of symptoms associated with rhinovirus infection and the concentration of interleukin-8 in nasal secretions. The purpose of these studies was to examine the mechanism of rhinovirus-induced IL-8 elaboration. Rhinovirus infection induced oxidative stress in Beas-2b cells and the concentration of H2O2 in supernatant media from rhinovirus challenged cells was 12.5 +/- 6.1 microM 1 h after challenge compared to 0.7 +/- 0.3 microM in supernatant from control cells. N-acetyl cysteine inhibited RV-induced NF-kappaB activation and IL-8 elaboration. IL-8 concentrations were 36 +/- 2 pg/ml and 10 +/- 1 pg/ml 6 h after virus challenge in untreated and NAC-treated (30 mM NAC) cells, respectively. Despite the effects of NAC on IL-8 elaboration and NF-kappaB activation, RV stimulated increases in supernatant H2O2 were not altered by NAC. These data suggest that RV stimulation of IL-8 in respiratory epithelium is mediated through production of oxidative species and the subsequent activation of NF-kappaB.}, }
@article {pmid9895229, year = {1999}, author = {Kowluru, RA and Engerman, RL and Kern, TS}, title = {Abnormalities of retinal metabolism in diabetes or experimental galactosemia. VI. Comparison of retinal and cerebral cortex metabolism, and effects of antioxidant therapy.}, journal = {Free radical biology &amp; medicine}, volume = {26}, number = {3-4}, pages = {371-378}, doi = {10.1016/s0891-5849(98)00210-x}, pmid = {9895229}, issn = {0891-5849}, support = {EY00300/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*therapeutic use ; Catalase/metabolism ; Cerebral Cortex/*metabolism ; Diabetes Mellitus, Experimental/*metabolism ; Dietary Supplements ; Galactosemias/*metabolism ; Glutathione Reductase/metabolism ; Male ; Oxidative Stress/physiology ; Rats ; Rats, Sprague-Dawley ; Retina/*metabolism ; Superoxide Dismutase/metabolism ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Metabolic abnormalities observed in retina and in cerebral cortex were compared in diabetic rats and experimentally galactosemic rats. Diabetes or experimental galactosemia of 2 months duration significantly increased oxidative stress in retina, as shown by elevation of retinal thiobarbituric acid reactive substances (TBARS) and subnormal activities of antioxidant defense enzymes, but had no such effect in the cerebral cortex. Activities of sodium potassium adenosine triphosphatase [(Na,K)-ATPase] and calcium ATPase became subnormal in retina as well as in cerebral cortex. In contrast, protein kinase C (PKC) activity was elevated in retina but not in cerebral cortex in the same hyperglycemic rats. Dietary supplementation with an antioxidant mixture (containing ascorbic acid, Trolox, alpha-tocopherol acetate, N-acetyl cysteine, beta-carotene, and selenium) prevented the diabetes-induced and galactosemia-induced elevation of retinal oxidative stress, the elevation of retinal PKC activity and the decrease of retinal ATPases. In cerebral cortex, administration of the antioxidant diet also prevented the diabetes-induced decreases in (Na,K)-ATPase and calcium ATPases, but had no effect on TBARS and activities of PKC and antioxidant-defense enzymes. The results indicate that retina and cerebral cortex differ distinctly in their response to elevation of tissue hexose, and that cerebral cortex is more resistant than retina to diabetes-induced oxidative stress. The greater resistance to oxidative stress in cerebral cortex, as compared to retina, is consistent with the resistance of cerebral cortex to microvascular disease in diabetes, and with a hypothesis that oxidative stress contributes to microvascular disease in diabetes. Dietary supplementation with these antioxidants offers a means to inhibit multiple hyperglycemia-induced retinal metabolic abnormalities.}, }
@article {pmid9893136, year = {1999}, author = {Holt, S and Marley, R and Fernando, B and Harry, D and Anand, R and Goodier, D and Moore, K}, title = {Acute cholestasis-induced renal failure: effects of antioxidants and ligands for the thromboxane A2 receptor.}, journal = {Kidney international}, volume = {55}, number = {1}, pages = {271-277}, doi = {10.1046/j.1523-1755.1999.00252.x}, pmid = {9893136}, issn = {0085-2538}, mesh = {Acetylcysteine/pharmacology ; Acute Kidney Injury/drug therapy/*etiology/*metabolism ; Animals ; Antioxidants/*pharmacology ; Carbazoles/pharmacology ; Cholestasis/*complications/drug therapy/*metabolism ; Dinoprost/urine ; Glutathione/metabolism ; Ligands ; Lipid Peroxidation ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, Thromboxane/antagonists &amp; inhibitors/*metabolism ; Sodium/urine ; Sulfonamides/pharmacology ; Thioctic Acid/pharmacology ; Thromboxane B2/urine ; }, abstract = {BACKGROUND: Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F2-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA2 receptor could improve renal function.<br><br>METHODS: The effects on renal function of acute bile duct ligation (BDL) in the rat were studied for two days. The consequences of administration of N-acetylcysteine (NAC), alpha-lipoic acid (LA), the TX receptor antagonist (TXRA) BAYu3405, or placebo were then examined.<br><br>RESULTS: BDL caused a reduction in creatinine clearance from 1.10 +/- 0.05 to 0.55 +/- 0.05 ml/min and sodium excretion from 52 +/- 3 to 17 +/- 3 micromol/hr. Urinary F2-isoprostanes increased from 14 +/- 2 to 197 +/- 22 pg/ml following BDL. Renal functional changes were ameliorated by NAC (creatinine clearance 0.73 +/- 0.05 ml/min), LA (0.64 +/- 0.03 ml/min), and a TXRA (0.90 +/- 0.15 ml/min); P < 0.05. Similarly, sodium excretion was increased from 17 +/- 3 micromol/hr (placebo) to 34 +/- 3 micromol/hr (NAC), 29 +/- 3 micromol/hr (LA), and 38 +/- 5 micromol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 +/- 0.3 micromol/g (normal liver) to 8.8 +/- 0.5 micromol/g (NAC) and 7.7 +/- 0.3 micromol/g (LA), P < 0.01. However, only LA markedly inhibited F2-isoprostane formation (197 +/- 22 to 36 +/- 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB2 excretion was elevated after BDL (2.2 +/- 0.5 to 111.1 +/- 20.3 pg/min) but was unaffected by NAC and LA.<br><br>CONCLUSION: NAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.}, }
@article {pmid9892811, year = {1999}, author = {Mosley, K and Waddington, SN and Ebrahim, H and Cook, T and Cattell, V}, title = {Inducible nitric oxide synthase induction in Thy 1 glomerulonephritis is complement and reactive oxygen species dependent.}, journal = {Experimental nephrology}, volume = {7}, number = {1}, pages = {26-34}, doi = {10.1159/000020581}, pmid = {9892811}, issn = {1018-7782}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Base Sequence ; Complement System Proteins/*metabolism ; DNA Primers/genetics ; Disease Models, Animal ; Enzyme Induction ; Glomerulonephritis/drug therapy/*immunology/*metabolism ; In Vitro Techniques ; Interleukin-1/biosynthesis/genetics ; Male ; Nitric Oxide Synthase/*biosynthesis/genetics ; Nitric Oxide Synthase Type II ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Inbred Lew ; Reactive Oxygen Species/*metabolism ; Receptors, Complement/administration &amp; dosage ; *Thy-1 Antigens ; Tumor Necrosis Factor-alpha/biosynthesis/genetics ; }, abstract = {Thy 1 glomerulonephritis (GN) is a rat model of complement-dependent immune mesangial injury with induced glomerular nitric oxide (NO) synthesis. To examine mechanisms of inducible nitric oxide synthase (iNOS) induction, we studied the effects of treatment with the antioxidant N-acetyl-cysteine (NAC) and soluble complement receptor 1 (sCR1). Thy 1 GN was induced by intravenous anti-Thy 1 antibody. Glomeruli were isolated and kidney tissue taken from 30 min to 24 h after induction. Nitrite (NO-2) synthesis, luminol chemiluminescence for reactive oxygen species (ROS), and iNOS and cytokine mRNA were assayed in isolated glomeruli. Mesangial injury (mesangiolysis) and leucocyte infiltration were quantitated on tissue sections. NAC (i.p. 1,000 mg/kg, 1 h prior to anti-Thy 1) reduced glomerular NO-2 synthesis (3.5 +/- 0.66 vs. untreated 8.2 +/- 1.1, p = 0.02), and iNOS mRNA expression, and abolished enhanced chemiluminescence. In vitro incubation of nephritic glomeruli with 20 mM NAC also suppressed nitrite production (4.7 +/- 0.8 vs. untreated 12.2 +/- 0. 7 nmol NO-2/2,000 glomeruli/48 h, p = 0.003), and chemiluminescence. In NAC-treated animals, neutrophil infiltration (0.5 +/- 0 vs. untreated 9.6 +/- 1.6 glomerulus, p = 0.0005), and macrophage infiltration (1.7 +/- 0.4 vs. untreated 12.0 +/- 0.1, p = 0.006) were abolished, and mesangiolysis was significantly reduced (45.9 +/- 1.3 vs. untreated 34.4 +/- 2.1 cells/glomerulus, p = 0.009). NAC did not inhibit anti-Thy 1 antibody deposition. C1q was unaffected, but C3 was reduced. sCR1 treatment prevented iNOS mRNA induction, the enhanced chemiluminescence, and the neutrophil infiltration at 1 h. IL-1beta and TNFalpha mRNAs were not affected by either NAC or sCR1. These results show that NAC inhibits iNOS induction and NO synthesis in this model, and suppresses ROS synthesis and injury. They suggest that complement-dependent ROS generation is the critical initiating event that follows fixation of anti-Thy 1 antibody.}, }
@article {pmid9890652, year = {1999}, author = {Saliou, C and Kitazawa, M and McLaughlin, L and Yang, JP and Lodge, JK and Tetsuka, T and Iwasaki, K and Cillard, J and Okamoto, T and Packer, L}, title = {Antioxidants modulate acute solar ultraviolet radiation-induced NF-kappa-B activation in a human keratinocyte cell line.}, journal = {Free radical biology &amp; medicine}, volume = {26}, number = {1-2}, pages = {174-183}, doi = {10.1016/s0891-5849(98)00212-3}, pmid = {9890652}, issn = {0891-5849}, support = {DK50430/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cell Line ; Free Radicals/metabolism ; Gene Expression/drug effects/radiation effects ; Humans ; Keratinocytes/*drug effects/metabolism/*radiation effects ; NF-kappa B/*metabolism ; Radiation-Protective Agents/pharmacology ; Silymarin/pharmacology ; Skin/drug effects/metabolism/radiation effects ; Skin Diseases/prevention &amp; control ; Thioctic Acid/pharmacology ; Transcription Factor AP-1/metabolism ; Ultraviolet Rays/*adverse effects ; }, abstract = {Exposure of the human skin to ultraviolet radiation (UVR) leads to depletion of cutaneous antioxidants, regulation of gene expression and ultimately to the development of skin diseases. Although exogenous supplementation of antioxidants prevents UVR-induced photooxidative damage, their effects on components of cell signalling pathways leading to gene expression has not been clearly established. In the present study, the effects of the antioxidants alpha-lipoic acid, N-acetyl-L-cysteine (NAC) and the flavonoid extract silymarin were investigated for their ability to modulate the activation of the transcription factors nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1) in HaCaT keratinocytes after exposure to a solar UV simulator. The activation of NF-kappaB and AP-1 showed a similar temporal pattern: activation was detected 2 h after UV exposure and maintained for up to 8 h. To determine the capacity of activated NF-kappaB to stimulate transcription, NF-kappaB-dependent gene expression was measured using a reporter gene assay. The effects of the antioxidants on NF-kappaB and AP-1 activation were evaluated 3 h after exposure. While a high concentration of NAC could achieve a complete inhibition, low concentrations of alpha-lipoic acid and silymarin were shown to significantly inhibit NF-kappaB activation. In contrast, AP-1 activation was only partially inhibited by NAC, and not at all by alpha-lipoic acid or silymarin. These results indicate that antioxidants such as alpha-lipoic acid and silymarin can efficiently modulate the cellular response to UVR through their selective action on NF-kappaB activation.}, }
@article {pmid9888413, year = {1999}, author = {Khan, J and Iiboshi, Y and Cui, L and Wasa, M and Okada, A}, title = {Role of intestinal mucus on the uptake of latex beads by Peyer's patches and on their transport to mesenteric lymph nodes in rats.}, journal = {JPEN. Journal of parenteral and enteral nutrition}, volume = {23}, number = {1}, pages = {19-23}, doi = {10.1177/014860719902300119}, pmid = {9888413}, issn = {0148-6071}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Membrane Permeability/drug effects ; Free Radical Scavengers ; Ileum/drug effects/metabolism ; Intestinal Mucosa/*drug effects/metabolism ; Lymph Nodes/metabolism ; Male ; Microspheres ; Permeability/drug effects ; Peyer's Patches/*drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: The effects of N-acetylcysteine (NAC) as a mucolytic agent on the uptake of fluorescent polystyrene microparticles by Peyer's patches, on intestinal permeability, and on subsequent transport to mesenteric lymph nodes (MLNs) were investigated to establish the role of mucus gel layer in this process.<br><br>METHODS: Twenty rats were divided into two groups: control (n = 10) and NAC (n = 10). Fluorescent polystyrene latex beads of 3.2+/-0.2 microm in diameter were used as a probe for measuring the previously mentioned parameters. The solution of latex beads (0.1 mL) was injected into a 2-cm length of ileal loop containing Peyer's patches, with 0.1 mL of saline (control group) or with 0.1 mL of NAC solution (NAC group) within 10 cm proximal from the ileocaecal valve. Intestinal loops, portal blood, and neighboring MLNs were taken within 1 hour of injection. Intestinal sections were stained by periodic acid-Schiff reagent. Peyer's patches and MLNs were analyzed for the count of particles by image analysis using a confocal laser scanning microscope.<br><br>RESULTS: Morphologically, periodic acid-Schiff positive uniform mucus gel was present in front of Peyer's patches of the control group, and mucus gel layer was disrupted and noncontinuous in the NAC group. The number of particles within Peyer's patches and MLNs in the NAC group was significantly higher than that in the control group (p<.001). Intestinal permeability of latex beads in the NAC group was significantly higher than that in the control group (p<.001).<br><br>CONCLUSIONS: These data suggest that the mucus gel layer located in front of Peyer's patches is one of the important factors for the uptake of noxious macromolecules, and this in turn plays a major role on small intestinal permeability and subsequent translocation to MLNs.}, }
@article {pmid9881991, year = {1998}, author = {Tucker, JR}, title = {Late-presenting acute acetaminophen toxicity and the role of N-acetylcysteine.}, journal = {Pediatric emergency care}, volume = {14}, number = {6}, pages = {424-426}, doi = {10.1097/00006565-199812000-00013}, pmid = {9881991}, issn = {0749-5161}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Acute Disease ; Adult ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/*therapeutic use ; *Chemical and Drug Induced Liver Injury ; Child ; Clinical Protocols ; Drug Overdose/complications/drug therapy ; Humans ; Liver Diseases/prevention &amp; control ; Risk Factors ; Time Factors ; }, abstract = {NAC is an effective antidote for APAP toxicity. NAC has been shown to be effective for early toxicity and is gaining acceptance for late toxicity. As the knowledge of APAP toxicity advances, the duration and route of NAC administration may be clarified.}, }
@article {pmid9877282, year = {1998}, author = {Vulcano, M and Rosa, MF and Breyer, I and Isturiz, MA}, title = {Hydroxyl radical scavengers inhibit TNF-alpha production in mononuclear cells but not in polymorphonuclear leukocytes.}, journal = {International journal of immunopharmacology}, volume = {20}, number = {12}, pages = {709-722}, doi = {10.1016/s0192-0561(98)00055-1}, pmid = {9877282}, issn = {0192-0561}, mesh = {Adult ; Animals ; Antioxidants/*pharmacology ; Free Radical Scavengers/*pharmacology ; Humans ; Hydroxyl Radical/*pharmacology ; L Cells ; Leukocytes, Mononuclear/drug effects/*metabolism ; Male ; Mice ; Mice, Inbred BALB C ; NADPH Oxidases/physiology ; Neutrophils/drug effects/*metabolism ; Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors/biosynthesis ; }, abstract = {The hydroxyl radical (HO*) scavengers dimethylthiourea (DMTU), tetramethylthiourea (TMTU), dimethylsulfoxide (DMSO) and deferoxamine (DFX), the latter being an iron chelator which prevents HO* formation by blocking the Fenton reaction, were found to inhibit TNF-alpha production in LPS-stimulated human PBMC but not in PMN. Furthermore, this effect was not LPS-specific, as TNF-alpha production was reduced by HO* radical scavengers to a similar extent upon stimulation of PBMC with immune complexes (IC), concanavalin A (Con A) and phorbol myristate acetate (PMA). Other scavengers such as glutathione (GSH), N-acetylcysteine (NAC), ascorbic acid (ASC) and mannitol (MAN) do not have effect on the production of TNF-alpha either in PBMC or PMN. These results provide evidence that the participation of ROI in the regulation of TNF-alpha production differ in different cell types. Particularly, the data presented in this work indicate that HO* radicals have a central role in the production of this inflammatory cytokine by human PBMC.}, }
@article {pmid9875558, year = {1998}, author = {Anderson, ME and Luo, JL}, title = {Glutathione therapy: from prodrugs to genes.}, journal = {Seminars in liver disease}, volume = {18}, number = {4}, pages = {415-424}, doi = {10.1055/s-2007-1007174}, pmid = {9875558}, issn = {0272-8087}, mesh = {Animals ; *Genetic Therapy ; Glutathione/*deficiency/genetics/*therapeutic use ; Humans ; *Prodrugs ; }, abstract = {Glutathione (GSH; L-gamma-glutamyl-L-cysteineglycine) is found in almost all mammalian cells, and liver has very high intracellular levels of GSH. It has many cellular functions, such as being a coenzyme, maintaining thiol/disulfide status, protection against toxic compounds and oxidative stress. GSH levels have been reported to be low in a number of pathological conditions; thus methods for increasing GSH levels are desirable. GSH may be increased by supplying its amino acid precursor cysteine, in the form of prodrugs, such as N-acetylcysteine (NAC) and 2-oxothiazolidine-4-carboxylate (OTC). It may also be increased by giving gamma-glutamylcysteine, a dipeptide precursor GSH monoester and GSH diester are effective GSH delivery drugs. Such compounds may be therapeutically useful. Gene therapy may be useful for longer term therapy of GSH deficiency.}, }
@article {pmid9874183, year = {1998}, author = {Ross, DA and Kish, P and Muraszko, KM and Blaivas, M and Strawderman, M}, title = {Effect of dietary vitamin A or N-acetylcysteine on ethylnitrosourea-induced rat gliomas.}, journal = {Journal of neuro-oncology}, volume = {40}, number = {1}, pages = {29-38}, pmid = {9874183}, issn = {0167-594X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain Neoplasms/chemically induced/*drug therapy/mortality ; Carcinogens ; Ethylnitrosourea ; Female ; Free Radical Scavengers/*pharmacology ; Glioma/chemically induced/*drug therapy/mortality ; Neuroectodermal Tumors/chemically induced/drug therapy/mortality ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Survival Analysis ; Vitamin A/*pharmacology ; }, abstract = {It is our hypothesis that low grade gliomas are the glial counterparts of other precancerous lesions such as colon polyps and, therefore, suitable targets for chemoprevention. Steps in the molecular progression of gliomas have been described, indicating that an accumulation of abnormalities is required for progression to a high grade and interruption of this progression might be possible. An animal model of chemical glial carcinogenesis was used to test this hypothesis. Pregnant rats were injected intravenously with ENU (ethylnitrosourea) on the 18th day of gestation to induce gliomas in the offspring, which were randomized to receive control diet, diet supplemented with vitamin A palmitate, or diet supplemented with N-acetylcysteine. Animals exposed to ENU and receiving a control diet developed brain tumors and had a shortened life expectancy compared with rats unexposed to ENU. The animals treated with NAC showed no statistically significant delay in the time to tumor and no change in the histologic grade of the tumors when compared with animals receiving control diet, but the time to death from any cause of NAC treated animals differed significantly from untreated animals. Animals receiving high dose VA had statistically significantly prolonged time to tumor, survived significantly longer than untreated animals, but had no reduction in the total number of tumors or change in the histologic grade of their tumors. The theoretical basis of these results is likely due to the putative mechanism of action of these agents. These data indicate that glioma chemoprevention is possible and deserves further exploration.}, }
@article {pmid9870400, year = {1998}, author = {Oguri, S and Tsukamoto, A and Yura, A and Miho, Y}, title = {Development of a simple high-performance capillary electrophoretic method with on-line mode in capillary derivatization for the determination of spermidine.}, journal = {Electrophoresis}, volume = {19}, number = {16-17}, pages = {2986-2990}, doi = {10.1002/elps.1150191631}, pmid = {9870400}, issn = {0173-0835}, mesh = {Buffers ; Electrophoresis, Capillary/instrumentation/*methods ; Humans ; Spermidine/*blood ; }, abstract = {A new high-performance capillary electrophoretic (HPCE) method with an on-line mode in-capillary derivatization (ICD) procedure for determinations of some amines using 20 mmol/L sodium dodecyl sulfate (SDS) - 2 mmol/L o-phthalaldehyde (OPA) - 2 mmol/L N-acetylcysteine (NAC) - 20 mmol/L phosphate-borate buffer [9] has previously been shown. Although this technique offers direct fluorescence detection of free amines without any derivatization procedures before or after HPCE separation, the presence of spermidine (Spd) is difficult to detect due to low fluorescence intensity. The purpose of this study is to improve the detection sensitivity of Spd by reoptimizing this method with regard to the run buffer; the reoptimized method was applied to the determination of Spd in human plasma. To enhance the fluorescence intensity of the Spd signal, it is effective to use the run buffer in the presence of both beta-cyclodextrin (beta-CD: 8.8 mmol/L) and NAC at high concentration (16 mmol/L). By contrast, the intensity was remarkably decreased when SDS was used in the presence of beta-CD. After ultrafiltrating (UF) spiked human plasma with Spd, UF plasma was directly analyzed using the reoptimized method. Spd peak was detected and separated from the other peaks of blank plasma. The present method gave good linearity (r = 0.999), reproducibility (3.85% coefficient of variation at 5 micromol/L level; n = 10) and specificity. The detection limit and lower limit of quantitation is for 0.2 micromol/L and 1 micromol/L, respectively.}, }
@article {pmid9860045, year = {1998}, author = {Emonet-Piccardi, N and Richard, MJ and Ravanat, JL and Signorini, N and Cadet, J and Béani, JC}, title = {Protective effects of antioxidants against UVA-induced DNA damage in human skin fibroblasts in culture.}, journal = {Free radical research}, volume = {29}, number = {4}, pages = {307-313}, doi = {10.1080/10715769800300341}, pmid = {9860045}, issn = {1071-5762}, mesh = {Acetylcysteine/pharmacology ; Adult ; Antioxidants/*pharmacology ; Breast ; Cells, Cultured ; Chlorides/pharmacology ; DNA Damage/*drug effects ; Electrophoresis, Agar Gel ; Female ; Fibroblasts/drug effects ; Humans ; Skin/cytology/*drug effects/radiation effects ; Sodium Selenite/pharmacology ; *Ultraviolet Rays ; Zinc Compounds/pharmacology ; }, abstract = {Ultraviolet A radiation (UVA, 320-400 nm) is mutagenic and induces genomic damage to skin cells. N-acetyl-cysteine (NAC), selenium and zinc have been shown to have antioxidant properties and to exhibit protective effects against UVA cytotoxicity. The present work attempts to delineate the effect of these compounds on genomic integrity of human skin fibroblasts exposed to UVA radiation using the single cell gel electrophoresis (SCGE) or Comet assay. The cells were incubated with NAC (5 mM), sodium selenite (0.6 microM) or zinc chloride (100 microM). Then cells were embedded in low melting point agarose, and immediately submitted to UVA fluences ranging from 1 to 6J/cm2. In the Comet assay, the tail moment increased by 45% (1 J/cm2) to 89% (6J/cm2) in non-supplemented cells (p)<0.01). DNA damage was significantly prevented by NAC, Se and Zn, with a similar efficiency from 1 to 4J/cm2 (p < 0.05). For the highest UVA dose (6J/cm2), Se and Zn were more effective than NAC (p < 0.01).}, }
@article {pmid9853298, year = {1998}, author = {Mortola, E and Okuda, M and Ohno, K and Watari, T and Tsujimoto, H and Hasegawa, A}, title = {Inhibition of apoptosis and virus replication in feline immunodeficiency virus-infected cells by N-acetylcysteine and ascorbic acid.}, journal = {The Journal of veterinary medical science}, volume = {60}, number = {11}, pages = {1187-1193}, doi = {10.1292/jvms.60.1187}, pmid = {9853298}, issn = {0916-7250}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects ; Ascorbic Acid/*pharmacology ; Cats ; Cell Line ; DNA Fragmentation ; DNA, Viral/drug effects ; Fibroblasts/virology ; Free Radical Scavengers/*pharmacology ; Humans ; Immunodeficiency Virus, Feline/*physiology ; Lentivirus Infections/*veterinary/virology ; Recombinant Proteins/pharmacology ; T-Lymphocytes/*virology ; Virus Replication/*drug effects ; }, abstract = {Infection of feline immunodeficiency virus (FIV) has been shown to induce apoptosis that might be associated with the lymphocyte depletion in the infected cats. To investigate the inhibitory effect of antioxidants on FIV-induced apoptosis, we examined the effect of N-acetylcysteine (NAC) and ascorbic acid (AA) on apoptosis and virus replication in feline lymphoblastoid (Fel-039) and fibroblastoid (CRFK) cell lines infected with FIV. The treatment with NAC or AA induced a significant inhibition of viral replication and apoptosis in Fel-039 cells and tumor necrosis factor alpha (TNF-alpha)-treated CRFK cells infected with FIV. Both cell lines in the presence of noncytotoxic concentrations of NAC or AA showed in increase of intracellular glutathione (GSH) level, which might protect the cells against oxidative stresses exerted by FIV infection and TNF-alpha treatment. On the basis of these in vitro results, we suggest that antioxidant therapies aimed at restoring depleted GSH level might be effective for inhibition of viral replication and cell death associated with the development of immunodeficiency.}, }
@article {pmid9845106, year = {1998}, author = {Tuttle, S and Horan, AM and Koch, CJ and Held, K and Manevich, Y and Biaglow, J}, title = {Radiation-sensitive tyrosine phosphorylation of cellular proteins: sensitive to changes in GSH content induced by pretreatment with N-acetyl-L-cysteine or L-buthionine-S,R-sulfoximine.}, journal = {International journal of radiation oncology, biology, physics}, volume = {42}, number = {4}, pages = {833-838}, doi = {10.1016/s0360-3016(98)00331-9}, pmid = {9845106}, issn = {0360-3016}, support = {CA-44982/CA/NCI NIH HHS/United States ; CA-49498/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism/*pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; CHO Cells/metabolism/radiation effects ; Cricetinae ; Cysteine/metabolism ; Free Radical Scavengers/metabolism/*pharmacology ; Glutathione/*metabolism ; Hydrogen Peroxide/pharmacology ; Phosphorylation ; Proto-Oncogene Proteins/*metabolism/radiation effects ; Proto-Oncogene Proteins c-fyn ; Radiation Tolerance ; Radiation-Protective Agents/pharmacology ; Radiation-Sensitizing Agents/pharmacology ; Reactive Oxygen Species/*metabolism ; Signal Transduction/*drug effects ; }, abstract = {PURPOSE: At relatively high concentrations, ie., > 20 mM, N-acetyl-L-cysteine (NAC) scavenges reactive oxygen species produced by ionizing radiation in aqueous solution. Therefore, the ability of NAC to block signal transduction reactions in vivo, has lead to the suggestion that ROS are necessary for the normal propagation of these signals. In this paper we investigate the mechanism by which NAC alters signal transduction in whole cells.<br><br>RESULTS: Exposing CHO-K1 cells to ionizing radiation results in elevated pp59fyn kinase activity. Moreover, we observe changes in the phosphotyrosine content of multiple cellular proteins, including one prominent phosphotyrosyl protein with a Mr of 85 kDa. Both the radiation-induced changes in pp59fyn kinase activity and the changes in phosphotyrosine content of pp85 were not affected by exposing K1 cells to NAC during the time of irradiation, suggesting that ROS generated extracellularly are not involved in the radiation-induced changes observed in phosphotyrosyl proteins. We also demonstrate that the cell membrane is an effective barrier against negatively charged NAC. Therefore, it seems unlikely that NAC's ability to block signal transduction reactions is related to scavenging of ROS intracellularly. Chronic exposure, ie., 1 h, to 20 mM NAC lead to a twofold elevation in GSH levels and resulted in a 17% decrease in the phosphotyrosine content of pp85 after exposure to 10 Gy. Moreover, pretreatment with L-buthionine-S,R-sulfoximine (BSO) decreased GSH levels and resulted in elevated phosphotyrosine levels in pp85 isolated from irradiated CHO-K1 cells.<br><br>CONCLUSIONS: Since many signaling molecules contain redox sensitive cysteine residues that regulate enzyme activity, we suggest that the effects of NAC on radiation-induced signal transduction are due to its ability to alter the intracellular reducing environment, and not related to direct scavenging of ROS.}, }
@article {pmid9843778, year = {1998}, author = {Gukovsky, I and Gukovskaya, AS and Blinman, TA and Zaninovic, V and Pandol, SJ}, title = {Early NF-kappaB activation is associated with hormone-induced pancreatitis.}, journal = {The American journal of physiology}, volume = {275}, number = {6}, pages = {G1402-14}, doi = {10.1152/ajpgi.1998.275.6.G1402}, pmid = {9843778}, issn = {0002-9513}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; *Ceruletide/pharmacology ; Chemokines ; Cytokines/genetics ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation/drug effects/physiology ; I-kappa B Proteins ; Interleukin-6/genetics ; Isomerism ; Kinetics ; Male ; NF-kappa B/antagonists &amp; inhibitors/*metabolism/physiology ; Pancreas/drug effects ; Pancreatitis/*chemically induced/*metabolism ; Rats ; Rats, Sprague-Dawley ; Sincalide/analogs &amp; derivatives/pharmacology ; Tumor Necrosis Factor-alpha/physiology ; }, abstract = {Inflammation and cell death are critical to pathogenesis of acute pancreatitis. Here we show that transcription factor nuclear factor-kappaB (NF-kappaB), which regulates these processes, is activated and plays a role in rat cerulein pancreatitis. NF-kappaB was strongly activated in the pancreas within 30 min of cerulein infusion; a second phase of NF-kappaB activation was prominent at 3-6 h. This biphasic kinetics could result from observed transient degradation of the inhibitory protein IkappaBalpha and slower but sustained degradation of IkappaBbeta. The hormone also caused NF-kappaB translocation and IkappaB degradation in vitro in dispersed pancreatic acini. Both p65/p50 and p50/p50, but not c-Rel, NF-kappaB complexes were manifest in pancreatitis and in isolated acini. Coinfusion of CCK JMV-180, which abolishes pancreatitis, prevented cerulein-induced NF-kappaB activation. The second but not early phase of NF-kappaB activation was inhibited by a neutralizing tumor necrosis factor-alpha antibody. Antioxidant N-acetylcysteine (NAC) blocked NF-kappaB activation and significantly improved parameters of pancreatitis. In particular, NAC inhibited intrapancreatic trypsin activation and mRNA expression of cytokines interleukin-6 and KC, which were dramatically induced by cerulein. The results suggest that NF-kappaB activation is an important early event that may contribute to inflammatory and cell death responses in acute pancreatitis.}, }
@article {pmid9840292, year = {1998}, author = {Malorni, W and Rivabene, R and Lucia, BM and Ferrara, R and Mazzone, AM and Cauda, R and Paganelli, R}, title = {The role of oxidative imbalance in progression to AIDS: effect of the thiol supplier N-acetylcysteine.}, journal = {AIDS research and human retroviruses}, volume = {14}, number = {17}, pages = {1589-1596}, doi = {10.1089/aid.1998.14.1589}, pmid = {9840292}, issn = {0889-2229}, mesh = {Acetylcysteine/*pharmacology ; Acquired Immunodeficiency Syndrome/immunology/*physiopathology ; Adult ; Antioxidants/*pharmacology ; Cells, Cultured ; Disease Progression ; Female ; Humans ; Leukocytes, Mononuclear/cytology/drug effects/metabolism/virology ; Lipid Peroxidation ; Male ; Middle Aged ; Oxidative Stress/*physiology ; Sulfhydryl Compounds ; }, abstract = {In this study we investigate the redox profile of HIV+ patients at different stages of disease with regard to immunological parameters, i.e., the number of circulating CD4+ and CD8+ lymphocytes. For this purpose, peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, HIV+ patients in the asymptomatic phase, long-term nonProgressors (LTNPs), and AIDS patients have been considered. Cells have been exposed in vitro to the prooxidizing agent menadione, which is able to induce superoxide anion formation, and the susceptibility of the cells to the induced oxidative stress was estimated. Moreover, the possibility that the susceptibility of the cells to oxidative stress might be reduced by preexposing them to the antioxidizing agent N-acetylcysteine (NAC) has also been analyzed. The results obtained can be summarized as follows: (1) treatment with the prooxidant agent is capable of inducing massive morphological alterations in PBMCs. In particular, a significant correlation was found between the decrease in number of CD4+ lymphocytes in patients at different stages of disease and the susceptibility of their PBMCs to oxidative stress; (2) preincubation with NAC was able to preserve partially the ultrastructural characteristics of PBMCs isolated from HIV+ patients. In particular, a direct relationship was found between the efficacy of NAC protection and CD4 counts; (3) evaluation of the plasma index of peroxidation and the number of circulating CD4 lymphocytes indicates the existence of a positive correlation between "systemic" oxidative imbalance and stage of the disease; and (4) cells from LTNPs display either oxidative susceptibility or oxidative markers similar to those of healthy donor cells. Our study suggests that the redox profile of patients may be considered a predictive marker of AIDS progression and that the acute infection and the asymptomatic phase of the disease may represent a useful period in which the combined use of antiretroviral and antioxidant drugs may be beneficial.}, }
@article {pmid9837855, year = {1998}, author = {Lizard, G and Gueldry, S and Sordet, O and Monier, S and Athias, A and Miguet, C and Bessede, G and Lemaire, S and Solary, E and Gambert, P}, title = {Glutathione is implied in the control of 7-ketocholesterol-induced apoptosis, which is associated with radical oxygen species production.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {12}, number = {15}, pages = {1651-1663}, doi = {10.1096/fasebj.12.15.1651}, pmid = {9837855}, issn = {0892-6638}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/metabolism/pharmacology ; *Apoptosis ; Caspases/metabolism ; Cycloheximide/pharmacology ; Cytochrome c Group/metabolism ; DNA Fragmentation ; Enzyme Activation ; Enzyme Precursors/metabolism ; Etoposide/pharmacology ; Fatty Acids, Unsaturated/metabolism ; Free Radicals ; Glutathione/*metabolism/pharmacology ; Humans ; Ketocholesterols/*pharmacology ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; U937 Cells ; }, abstract = {In a number of experimental systems, inhibition of apoptosis by antioxidants has led to the production of radical oxygen species (ROS) in certain apoptotic forms of cell death. Since antioxidant therapies can reduce vascular dysfunctions in hypercholesterolemic patients who frequently have increased plasma levels of oxysterols constituting potent inducers of apoptosis, we speculate that oxysterol-induced apoptosis could involve oxidative stress. Here, we tested the protective effects of the aminothiols glutathione (GSH) and N-acetylcysteine (NAC), which are two potent antioxidants, on apoptosis induced by 7-ketocholesterol in U937 cells, and we present evidence indicating that oxidative processes are involved in 7-ketocholesterol-induced cell death. Thus, GSH and NAC prevented phenomenona linked to apoptosis such as reduction of cell growth, increase cellular permeability to propidium iodide, and occurrence of nuclear condensation and/or fragmentation, and they delayed internucleosomal DNA fragmentation. In addition, cell treatment with GSH impaired cytochrome c release into the cytosol and degradation of caspase-8 occurring during cell death. During 7-ketocholesterol-induced apoptosis, we also observed a rapid decrease in cellular GSH content, oxidation of polyunsaturated fatty acids, and a production of ROS by flow cytometry with the use of the dye 2', 7'-dichlorofluorescin-diacetate; both phenomena were inhibited by GSH. Prevention of cell death by GSH and NAC does not seem to be a general rule since these antioxidants impaired etoposide (but not cycloheximide) -induced apoptosis. Taken together, our data demonstrate that GSH is implied in the control of 7-ketocholesterol-induced apoptosis associated with the production of ROS.}, }
@article {pmid9826354, year = {1998}, author = {Denning, GM and Wollenweber, LA and Railsback, MA and Cox, CD and Stoll, LL and Britigan, BE}, title = {Pseudomonas pyocyanin increases interleukin-8 expression by human airway epithelial cells.}, journal = {Infection and immunity}, volume = {66}, number = {12}, pages = {5777-5784}, pmid = {9826354}, issn = {0019-9567}, support = {AI34954/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors/metabolism ; Cells, Cultured ; Chemokine CCL5/biosynthesis ; Drug Synergism ; Epithelial Cells/cytology/immunology ; Humans ; Interleukin-8/*biosynthesis/genetics ; Lung/cytology/*immunology ; Oxidants/metabolism ; Protein Kinase C/antagonists &amp; inhibitors ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/metabolism ; *Pseudomonas ; Pyocyanine/*pharmacology ; RNA, Messenger/analysis ; Signal Transduction ; Tumor Necrosis Factor-alpha/biosynthesis ; }, abstract = {Pseudomonas aeruginosa, an opportunistic human pathogen, causes acute pneumonia in patients with hospital-acquired infections and is commonly associated with chronic lung disease in individuals with cystic fibrosis (CF). Evidence suggests that the pathophysiological effects of P. aeruginosa are mediated in part by virulence factors secreted by the bacterium. Among these factors is pyocyanin, a redox active compound that increases intracellular oxidant stress. We find that pyocyanin increases release of interleukin-8 (IL-8) by both normal and CF airway epithelial cell lines and by primary airway epithelial cells. Moreover, pyocyanin synergizes with the inflammatory cytokines tumor necrosis factor alpha and IL-1alpha. RNase protection assays indicate that increased IL-8 release is accompanied by increased levels of IL-8 mRNA. The antioxidant n-acetyl cysteine, general inhibitors of protein tyrosine kinases, and specific inhibitors of mitogen-activated protein kinases diminish pyocyanin-dependent increases in IL-8 release. Conversely, inhibitors of protein kinases C (PKC) and PKA have no effect. In contrast to its effects on IL-8 expression, pyocyanin inhibits cytokine-dependent expression of the monocyte/macrophage/T-cell chemokine RANTES. Increased release of IL-8, a potent neutrophil chemoattractant, in response to pyocyanin could contribute to the marked infiltration of neutrophils and subsequent neutrophil-mediated tissue damage that are observed in Pseudomonas-associated lung disease.}, }
@article {pmid9823769, year = {1998}, author = {Steinhauser, ML and Kunkel, SL and Hogaboam, CM and Evanoff, H and Strieter, RM and Lukacs, NW}, title = {Macrophage/fibroblast coculture induces macrophage inflammatory protein-1alpha production mediated by intercellular adhesion molecule-1 and oxygen radicals.}, journal = {Journal of leukocyte biology}, volume = {64}, number = {5}, pages = {636-641}, doi = {10.1002/jlb.64.5.636}, pmid = {9823769}, issn = {0741-5400}, support = {A136302//PHS HHS/United States ; HL35276/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Cell Communication ; Coculture Techniques ; Cytokines/physiology ; Fibroblasts/cytology/*physiology ; Fibrosis ; Free Radicals ; Gene Expression Regulation ; Inflammation ; Intercellular Adhesion Molecule-1/genetics/*physiology ; Macrophages, Peritoneal/cytology/*metabolism ; Mice ; Mice, Inbred CBA ; Mice, Knockout ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Specific Pathogen-Free Organisms ; Stromal Cells/physiology ; }, abstract = {This study examined the cell-to-cell interaction between fibroblasts and macrophages as a possible contributor to the chronic inflammatory state. In a coculture system, consisting of macrophages layered over confluent fibroblasts, there was a significant increase in macrophage inflammatory protein 1alpha (MIP-1alpha) compared with control cultures. ICAM-1 adhesion was identified as an important stimulus of MIP-1alpha production by using ICAM-1-specific monoclonal antibodies. Furthermore, fibroblasts from ICAM-1 knockout mice induced significantly less MIP-1alpha production from peritoneal macrophages when compared to control fibroblasts. In addition, it appeared that oxygen radicals functioned as activating molecules during cellular interaction and production of MIP-1alpha, as the addition of the antioxidant N-acetylcysteine (NAC) prevented MIP-1alpha secretion. Thus, the ICAM-1 and oxygen radical-mediated induction of MIP-1alpha associated with a macrophage/fibroblast coculture system provides one possible mechanism by which immune/inflammatory cell interactions may augment chemokine production and exacerbate chronic inflammatory diseases.}, }
@article {pmid9815188, year = {1998}, author = {Kleiner, HE and Rivera, MI and Pumford, NR and Monks, TJ and Lau, SS}, title = {Immunochemical detection of quinol--thioether-derived protein adducts.}, journal = {Chemical research in toxicology}, volume = {11}, number = {11}, pages = {1283-1290}, doi = {10.1021/tx980134e}, pmid = {9815188}, issn = {0893-228X}, support = {ES07247/ES/NIEHS NIH HHS/United States ; ES07359/ES/NIEHS NIH HHS/United States ; GM39338/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Antibody Specificity ; Blotting, Western ; Cattle ; Cytosol/metabolism ; Enzyme-Linked Immunosorbent Assay ; Hydroquinones/*chemistry ; Immunochemistry ; Kidney/enzymology/metabolism ; Male ; Proteins/*chemistry ; Rabbits ; Rats ; Rats, Inbred F344 ; Subcellular Fractions/enzymology/metabolism ; Sulfides/*chemistry ; }, abstract = {Glutathione (GSH) conjugates of hydroquinone (HQ) and 2-bromohydroquinone (2-BrHQ) produce severe renal proximal tubular necrosis in rats. Since the reactivity of quinones lies, in part, in their ability to alkylate proteins, our goal was to develop an immunochemical method with which to investigate the role of protein adduct formation in quinone-thioether-mediated toxicity. An immunogen was synthesized by coupling 2-bromo-6-(N-acetylcystein-S-yl)hydroquinone (2-BrHQ-NAC) to keyhole-limpet hemocyanin (KLH). Anti-2-BrHQ-NAC-KLH antibodies were raised in rabbits and purified by affinity chromatography. Antibody binding to the 2-BrHQ-NAC epitope was confirmed by competitive enzyme-linked immunosorbent assay (ELISA) with a bovine serum albumin conjugate of 2-BrHQ-NAC. Affinity-purified anti-2-BrHQ-NAC-KLH antibodies recognized adducted proteins in the kidneys of rats treated with HQ, 2-BrHQ, 2-bromo-bis(glutathion-S-yl)hydroquinone, 2-(glutathion-S-yl)hydroquinone, 2, 5-bis(glutathion-S-yl)hydroquinone, and 2,3, 5-tris(glutathion-S-yl)hydroquinone. Immunoreactive proteins were found in all renal subcellular fractions of 2-BrHQ-treated rats, and the distribution of adducts was similiar to that obtained by quantifying 2-Br[14C]HQ covalent adducts. Western blot analysis revealed that three proteins, at 42, 46, and 79 kDa, were adducted by all the compounds examined. The identification of these adducted proteins will be required to assess their significance in quinol-thioether-mediated nephrotoxicity.}, }
@article {pmid9806160, year = {1998}, author = {Witschi, H and Espiritu, I and Yu, M and Willits, NH}, title = {The effects of phenethyl isothiocyanate, N-acetylcysteine and green tea on tobacco smoke-induced lung tumors in strain A/J mice.}, journal = {Carcinogenesis}, volume = {19}, number = {10}, pages = {1789-1794}, doi = {10.1093/carcin/19.10.1789}, pmid = {9806160}, issn = {0143-3334}, support = {ES007908/ES/NIEHS NIH HHS/United States ; ES05707/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anticarcinogenic Agents/*pharmacology ; Female ; Isothiocyanates/*pharmacology ; Lung Neoplasms/etiology/*prevention &amp; control ; Male ; Mice ; Plants, Toxic ; Smoke/*adverse effects ; *Tea ; Nicotiana ; }, abstract = {Male and female strain A/J mice were exposed to a mixture of cigarette sidestream and mainstream smoke at a chamber concentration of total suspended particulates of 82.5 mg/m3. Exposure time was 6 h/day, 5 days/week for 5 months. The animals were allowed to recover for another 4 months in filtered air before sacrifice and lung tumor count. Male animals were fed either 0.2% N-acetylcysteine (NAC) or 0.05% phenethyl isothiocyanate (PEITC) in diet AIN-76A with 5% corn oil added. Female animals received normal laboratory chow and were given a 1.25% extract of green tea in the drinking water. Corresponding control groups were fed diets without NAC or PEITC or given plain tap water. Exposure to tobacco smoke increased lung tumor multiplicity to 1.1-1.6 tumors/lung, significantly higher than control values (0.5-1.0 tumors/lung). None of the putative chemopreventive agents (NAC, PEITC or green tea extract) had a protective effect. In positive control experiments, PEITC significantly reduced both lung tumor multiplicity and incidence in mice treated with the tobacco smoke-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In mice treated with three different doses of urethan and fed NAC in the diet, a significant reduction in lung tumor multiplicity was found only at one dose level. Green tea extract did not reduce lung tumor multiplicity in animals treated with a single dose of NNK. It was concluded that successful chemoprevention of tobacco smoke-induced lung tumorigenesis might require administration of several chemopreventive agents rather than just a single one.}, }
@article {pmid9803334, year = {1998}, author = {Schmidt, W and Walther, A and Gebhard, MM and Martin, E and Schmidt, H}, title = {Influence of N-acetylcysteine treatment on endotoxin-induced microcirculatory disturbances.}, journal = {Intensive care medicine}, volume = {24}, number = {9}, pages = {967-972}, pmid = {9803334}, issn = {0342-4642}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Flow Velocity/drug effects ; Capillary Permeability/*drug effects ; Cell Adhesion/drug effects ; Endotoxemia/blood/*physiopathology ; Erythrocytes/*drug effects ; Leukocytes/*drug effects ; Male ; Prospective Studies ; Random Allocation ; Rats ; Rats, Wistar ; Venules/*drug effects ; }, abstract = {OBJECTIVES: To determine the influence of N-acetylcysteine (NAC) in a treatment model, its effects on endotoxin-induced leukocyte-endothelial cell adhesion, vascular leakage, and venular microhemodynamics in postcapillary venules of rat mesentery.<br><br>DESIGN: Prospective, randomized, controlled, experimental study.<br><br>SETTING: Animal research laboratory.<br><br>SUBJECTS: 40 male Wistar rats.<br><br>INTERVENTIONS: The rats randomly received one of four treatments: infusion of saline (SAL) or Escherichia coli lipopolysaccharides (LPS) followed by treatment with saline (SAL) or NAC (150 mg.kg-1 body weight) 30 min after induction of endotoxemia.<br><br>MEASUREMENTS AND MAIN RESULTS: Leukocyte adherence, red blood cell velocity, and vessel diameters in postcapillary venules of rat mesentery were evaluated every 30 min over a period of 120 min using in vivo videomicroscopy. Vascular permeability was determined by measuring the extravasation of fluorescence-labeled albumin. Venular wall shear rate was calculated from red cell velocity, and vessel diameter. NAC in rats without endotoxemia (SAL + NAC group) compared to the control group (SAL + SAL) did not change microcirculatory parameters in postcapillary venules of rat mesentery. In both LPS-treated groups (LPS + SAL and LPS + NAC), leukocyte adherence increased after just 30 min. NAC treatment prevented a further increase in leukocyte adherence and attenuated the extravasation of fluorescence-labeled albumin during endotoxemia. Venular diameters remained unchanged, while erythrocyte velocity decreased in the LPS + SAL group. This led to a lower venular wall shear rate in this group.<br><br>CONCLUSIONS: Treatment with NAC attenuates endotoxin-induced leukocyte adherence and macromolecular leakage in postcapillary venules of rat mesentery, showing that NAC is also effective after the onset of endotoxemia.}, }
@article {pmid9795082, year = {1998}, author = {Van den Broeke, LT and Gräslund, A and Nilsson, JL and Wahlberg, JE and Scheynius, A and Karlberg, AT}, title = {Free radicals as potential mediators of metal-allergy: Ni2+- and Co2+-mediated free radical generation.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {6}, number = {4}, pages = {279-286}, doi = {10.1016/s0928-0987(97)10024-0}, pmid = {9795082}, issn = {0928-0987}, mesh = {Acetylcysteine/pharmacology ; Adult ; Ascorbic Acid/metabolism ; Carnosine/pharmacology ; Cells, Cultured ; Cobalt/*toxicity ; Cysteine/pharmacology ; Dermatitis, Allergic Contact/*physiopathology ; Electron Spin Resonance Spectroscopy ; Female ; Free Radical Scavengers/pharmacology ; *Free Radicals/analysis ; Glutathione/pharmacology ; Histidine/pharmacology ; Humans ; Hydrogen Peroxide/chemistry ; Middle Aged ; Monocytes/drug effects/metabolism ; Nickel/*toxicity ; }, abstract = {The generation of free radicals by Ni(2+) and Co(2+) was studied at physiological pH in H(2)O(2)-containing solutions in the absence and presence of various radical-mediating ligands and in human peripheral blood mononuclear cell (PBMC) cultures. With ESR spectroscopy, free radical species were identified and quantitated by spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Co(2+) generated hydroxyl radicals from H(2)O(2) in PBS solutions containing glutathione (GSH) or histidine (His). Omission of GSH or His from the reaction mixture significantly reduced the ESR-signal, indicating the importance of metal-chelation in free radical generation. Carnosine did not significantly enhance the reactivity of Co(2+) toward H(2)O(2), whereas cysteine (Cys) and N-acetylcysteine (NAC) suppressed free radical generation. Under identical reaction conditions, Ni(2+) was markedly less reactive toward H(2)O(2) in comparison with Co(2+). GSH, His, Cys and NAC did not enhance free radical generation of Ni(2+) from H(2)O(2). However, in the presence of carnosine weak but significantly enhanced ESR intensities were found. Incubation of PBMC cultures from healthy subjects with Co(2+) (10-50 microM) yielded the DMPO-.OH adduct, suggesting Co(2+)-mediated hydroxyl radical generation. In contrast, incubation of PBMC cultures with Ni(2+) (10-50 microM) did not produce a detectable ESR-signal. Ascorbic acid efficiently inhibited Co(2+)-mediated free radical generation in PBS solutions and PBMC cultures. The observed difference in free radical generating capacity between Ni(2+) and Co(2+) is of interest with respect to the absence of cross-reactivity between the two metal-ions in experimental allergic contact dermatitis.}, }
@article {pmid9786425, year = {1998}, author = {Furuke, K and Bloom, ET}, title = {Redox-sensitive events in Fas-induced apoptosis in human NK cells include ceramide generation and protein tyrosine dephosphorylation.}, journal = {International immunology}, volume = {10}, number = {9}, pages = {1261-1272}, doi = {10.1093/intimm/10.9.1261}, pmid = {9786425}, issn = {0953-8178}, mesh = {Acetylcysteine/pharmacology ; Antibodies, Monoclonal/pharmacology ; Apoptosis/drug effects/*physiology ; Buthionine Sulfoximine/pharmacology ; Caspase 3 ; Caspases/metabolism ; Cells, Cultured ; Ceramides/*biosynthesis ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; Fas Ligand Protein ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors ; Glutathione/biosynthesis ; Humans ; Interleukin-2/pharmacology ; Killer Cells, Natural/*cytology/drug effects/*metabolism ; Membrane Glycoproteins/genetics/physiology ; Oxidation-Reduction ; Phosphoproteins/*metabolism ; Phosphorylation ; Signal Transduction/physiology ; Sulfhydryl Compounds/metabolism/pharmacology ; Transfection ; Tyrosine/metabolism ; fas Receptor/*physiology ; }, abstract = {We previously reported that intracellular oxidation-reduction (redox) regulates NK cell functions and that IL-2-activated NK cells undergo apoptosis upon contact with NK-sensitive target cells. We now report that apoptosis in activated human NK cells is also regulated by redox. Thiol deprivation increased apoptosis in NK cells induced by anti-Fas mAb or Fas ligand-transfected cells, and pretreatment of cells with N-acetyl cysteine, which increased intracellular glutathione, partially inhibited the apoptosis and reversed the effect of thiol-deficient medium, suggesting that Fas-induced apoptosis in NK cells is also redox sensitive. Thiol deprivation did not alter cell surface Fas expression, but did increase ceramide generation following Fas engagement. Although exogenous ceramides induced apoptosis of NK cells, thiol depletion had no effect on this apoptosis. Thiol deprivation increased CPP32 activation induced by Fas engagement, but not by ceramides. These findings suggest that, if ceramide is required for Fas-induced apoptosis, thiol deprivation affects the Fas-mediated signaling pathway at the generation of ceramide and/or upstream thereof. Though tyrosine phosphorylation following Fas engagement was not significantly affected by thiol deprivation, tyrosine dephosphorylation was delayed, suggesting that tyrosine phosphatases may also be redox sensitive. The notion that dephosphorylation is important in the Fas signaling pathway is supported by the finding that tyrosine phosphatase inhibitors significantly enhanced both CPP32 activity and apoptosis following Fas ligation. We conclude that events downstream of tyrosine phosphorylation and upstream of CPP32 activation, including tyrosine dephosphorylation and possibly ceramide generation, are sensitive to regulation by redox in human NK cells, requiring a reducing environment for optimal protection from apoptosis induced by Fas ligation.}, }
@article {pmid9786244, year = {1998}, author = {Lucas, JH and Wheeler, DG and Emery, DG and Mallery, SR}, title = {The endogenous antioxidant glutathione as a factor in the survival of physically injured mammalian spinal cord neurons.}, journal = {Journal of neuropathology and experimental neurology}, volume = {57}, number = {10}, pages = {937-954}, doi = {10.1097/00005072-199810000-00006}, pmid = {9786244}, issn = {0022-3069}, support = {NS-29683/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*metabolism ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Dendrites/drug effects/metabolism/physiology ; Glutathione/agonists/antagonists &amp; inhibitors/*metabolism ; Lasers ; Mice ; Microscopy, Electron ; Neuroglia/drug effects/metabolism/ultrastructure ; Neurons/drug effects/*metabolism/ultrastructure ; Spinal Cord/cytology/*metabolism/ultrastructure ; }, abstract = {Glutathione is part of the system of cellular defenses against lipid peroxidation and other free radical-mediated damage. An established in vitro trauma model was utilized to evaluate whether glutathione is a factor in the survival of mammalian spinal cord neurons following physical injury. Cultured murine spinal neurons were subjected to a standard lesion: transection of a primary dendrite 100 microm from the perikaryon. Prior reduction of glutathione with ethacrynic acid or buthionine sulfoximine caused a dose-dependent decrease in neuronal survival 24 hours after dendrotomy. Prior glutathione augmentation with gamma-glutamylcysteine or L-2-oxo-4-thiazolidine carboxylic acid significantly increased survival, but N-acetyl-cysteine was not protective. Gamma glutamylcysteine effected the most rapid increase in glutathione (peak at 10 min), and survival was 72% +/- 10 when 0.2 mM gamma-glutamylcysteine was added immediately after dendrotomy compared with 38% +/- 4 in the control group (p < 0.0001). These results indicate that the level of glutathione is a factor in spinal cord neuron survival after physical trauma, and that glutathione augmentation may be an effective acute phase spinal cord injury (SCI) intervention strategy.}, }
@article {pmid9784841, year = {1998}, author = {Zhang, J and Yoneda, M and Naruse, K and Borgeld, HJ and Gong, JS and Obata, S and Tanaka, M and Yagi, K}, title = {Peroxide production and apoptosis in cultured cells carrying mtDNA mutation causing encephalomyopathy.}, journal = {Biochemistry and molecular biology international}, volume = {46}, number = {1}, pages = {71-79}, doi = {10.1080/15216549800203572}, pmid = {9784841}, issn = {1039-9712}, mesh = {Acetylcysteine/pharmacology ; *Apoptosis ; Cell Line ; DNA, Mitochondrial/*genetics ; Free Radical Scavengers/pharmacology ; Humans ; Hybrid Cells ; MELAS Syndrome/genetics/*metabolism/*pathology ; Oxygen/pharmacology ; Peroxides/*metabolism ; *Point Mutation ; Reactive Oxygen Species/metabolism ; }, abstract = {When cybrids with a point mutation, which locates in the tRNALeu(UUR) gene of mtDNA and causes a mitochondrial encephalomyopathy (MELAS syndrome), were exposed to a high concentration of oxygen (95%), the peroxide production markedly increased by 6 h of oxygen exposure, whereas the peroxide production was similar among the cybrids under a normal concentration of oxygen. The peroxide production by oxygen exposure was enhanced particularly in cybrids with high proportions of the mutant mtDNA and low respiratory capacities. The appearance of apoptotic cells by oxygen exposure was high in cybrids with the impaired respiratory function due to the mutation. An antioxidant NAC successfully suppressed both the peroxide production and apoptosis. These results imply that the peroxide production plays an important role in inducing apoptosis in cells carrying the mtDNA mutation causing encephalomyopathy.}, }
@article {pmid9774922, year = {1998}, author = {Lopez, BL and Snyder, JW and Birenbaum, DS and Ma, XI}, title = {N-acetylcysteine enhances endothelium-dependent vasorelaxation in the isolated rat mesenteric artery.}, journal = {Annals of emergency medicine}, volume = {32}, number = {4}, pages = {405-410}, doi = {10.1016/s0196-0644(98)70167-2}, pmid = {9774922}, issn = {0196-0644}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Calcimycin/pharmacology ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*drug effects ; Glutathione/pharmacology ; In Vitro Techniques ; Mesenteric Arteries/drug effects ; Methionine/analogs &amp; derivatives/pharmacology ; Rats ; Vasodilation/*drug effects ; Vasodilator Agents/pharmacology ; }, abstract = {STUDY HYPOTHESIS: Previous studies have suggested that N-acetylcysteine (NAC) may confer additional protection in acetaminophen (APAP) overdose by improving hepatic microcirculation. We hypothesize that NAC enhances release of nitric oxide (NO) from the vasculature.<br><br>METHODS: Sprague-Dawley rat superior mesenteric artery rings were suspended in oxygenated Krebs-Henseleit tissue baths and contracted with U-46619 (a thromboxane A2-mimetic). In part 1, the effect of NAC on endothelial cell (EC) release of NO was assessed by measurement of vasorelaxation induced by acetylcholine (ACh, an EC-dependent vasorelaxor) in the presence and absence of NAC. In part 2, the effect of glutathione (a major component of NAC hepatoprotection) was examined by measuring ACh-induced vasorelaxation in rings from rats treated with L-buthionine sulfoxamine (BSO, a glutathione synthesis inhibitor). Data were analyzed by repeated-measures ANOVA.<br><br>RESULTS: Addition of 15 to 30 mmol/L NAC after ring contraction had no direct vasodilatory effect. By contrast, pretreatment of rings with NAC (15 mmol/L) enhanced vasorelaxation induced by ACh (95.0% +/- 7.9% versus 62.3% +/- 7.6% for control; ACh dose, 1 mumol/L; P < .001) or by A23187, a receptor-independent, NO-mediated vasodilator (91.6% +/- 9.6% versus 68.3% +/- 12.1% for control; A23187 dose, 1 mumol/L; P < .001). In rings from BSO-treated rats, NAC also enhanced vasorelaxation (76.5% +/- 7.1%; P < .001 versus control), but to a lesser degree than in nontreated rats.<br><br>CONCLUSION: NAC enhances endothelium-dependent vasodilation in an isolated rat mesenteric artery ring preparation. In addition to its antioxidant effects, NAC may decrease APAP hepatotoxicity by stimulating NO production and improving microvascular circulation.}, }
@article {pmid9766835, year = {1998}, author = {Wagner, R and Heckman, HM and Myers, RR}, title = {Wallerian degeneration and hyperalgesia after peripheral nerve injury are glutathione-dependent.}, journal = {Pain}, volume = {77}, number = {2}, pages = {173-179}, doi = {10.1016/S0304-3959(98)00091-8}, pmid = {9766835}, issn = {0304-3959}, support = {F32-NS10071-02/NS/NINDS NIH HHS/United States ; NS18715-13/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies ; Female ; Glutathione/*metabolism ; Heme Oxygenase (Decyclizing)/analysis/immunology/metabolism ; Heme Oxygenase-1 ; Hot Temperature ; Hyperalgesia/metabolism/*physiopathology ; Nerve Fibers, Myelinated/chemistry/metabolism ; Nociceptors/drug effects/physiology ; Oxidative Stress/physiology ; Pain Measurement ; Rats ; Rats, Sprague-Dawley ; Reaction Time/physiology ; Sciatic Nerve/*injuries/metabolism/physiopathology ; Wallerian Degeneration/metabolism/*physiopathology ; }, abstract = {Experimental inflammatory compression injury to the sciatic nerve (chronic constriction injury, CCI) induces Wallerian degeneration of axons and damages non-neuronal cells at the injury site in association with the development of exaggerated pain-like behavior, or hyperalgesia, to noxious thermal stimuli in the affected anatomical area. We examined whether glutathione, one of whose many functions is an important endogenous antioxidant, influenced resulting neuropathology and hyperalgesia following CCI. Dietary supplementation of the amino acid N-acetyl-cysteine (NAC), a rate-limiting component of glutathione production, beginning 1 day prior to CCI significantly diminished both Wallerian degeneration, measured by quantitative morphometry of myelinated fibers, and thermal hyperalgesia. NAC treatment raised nerve glutathione levels compared to untreated nerves, as indicated using hemeoxygenase-1 (hsp32) immunoreactivity as a marker of glutathione depletion. Because NAC is also known to have antioxidant abilities, studies simultaneously inhibited glutathione synthesis, and results demonstrated no significant reduction in resulting neuropathology or hyperalgesia. Delaying NAC administration to post-injury times consistently decreased hyperalgesia, although not significantly. This study identifies glutathione levels, and presumably oxidative stress, as important determinants of the neuropathological and behavioral consequences of nerve injury, and suggests that dietary supplementation of NAC constitutes an effective pre-emptive therapeutic strategy for situations involving painful nerve injury, such as occurs during surgery.}, }
@article {pmid9765355, year = {1998}, author = {Wispriyono, B and Matsuoka, M and Igisu, H and Matsuno, K}, title = {Protection from cadmium cytotoxicity by N-acetylcysteine in LLC-PK1 cells.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {287}, number = {1}, pages = {344-351}, pmid = {9765355}, issn = {0022-3565}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cadmium/pharmacokinetics/*toxicity ; Cell Survival/drug effects ; Dactinomycin/pharmacology ; Glutathione/physiology ; Kidney/drug effects/metabolism ; LLC-PK1 Cells ; Proto-Oncogene Proteins c-fos/analysis ; Swine ; }, abstract = {N-acetylcysteine (NAC) has been known not only to stimulate synthesis of glutathione but also to affect the gene regulation. In our study, effects of NAC on the cytotoxicity of cadmium (Cd) were examined in LLC-PK1 cells. Preincubation and subsequent incubation with 1 mM NAC almost completely suppressed Cd-induced cellular damage evaluated either by trypan blue exclusion or lactate dehydrogenase leakage. This almost complete protection required the presence of NAC during Cd exposure. Treatment with 1 mM NAC increased the intracellular glutathione level approximately 2-fold. Inhibition of this increase by buthionine sulfoximine did not abolish the protection by NAC. One mM NAC also suppressed Cd-induced increase of c-Fos protein although NAC alone did not change the protein content. The inhibition of transcriptions by actinomycin D did not affect the protection by NAC. Thus, NAC-induced protection appeared to be independent of glutathione level or the transcriptional activation of genes including c-fos. However, treatment with NAC markedly lowered the uptake of Cd into cells although it did not affect the efflux clearly. Addition of NAC during the exposure to Cd suppressed Cd-induced cellular damage but the suppression decreased when the duration of the exposure without NAC increased. These results suggest that NAC-induced protection against Cd cytotoxicity is mainly due to the lowered uptake of Cd into the cells.}, }
@article {pmid9762833, year = {1998}, author = {Binet, H and Simonart, T and Van Vooren, JP and Heenen, M and Liesnard, C and Delforge, ML and Farber, CM and Parent, D}, title = {Porphyria cutanea tarda in a human immunodeficiency virus-infected patient: treatment with N-acetyl-cysteine.}, journal = {International journal of dermatology}, volume = {37}, number = {9}, pages = {718-719}, doi = {10.1046/j.1365-4362.1998.00481.x}, pmid = {9762833}, issn = {0011-9059}, mesh = {Acetylcysteine/*therapeutic use ; Acquired Immunodeficiency Syndrome/*complications ; Adult ; Antiviral Agents/therapeutic use ; Fatal Outcome ; Homosexuality, Male ; Humans ; Male ; Porphyria Cutanea Tarda/complications/*drug therapy/virology ; Treatment Outcome ; }, }
@article {pmid9756554, year = {1998}, author = {Nielsen, HB and Secher, NH and Kappel, M and Pedersen, BK}, title = {N-acetylcysteine does not affect the lymphocyte proliferation and natural killer cell activity responses to exercise.}, journal = {The American journal of physiology}, volume = {275}, number = {4}, pages = {R1227-31}, doi = {10.1152/ajpregu.1998.275.4.R1227}, pmid = {9756554}, issn = {0002-9513}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antigens, CD/blood ; Double-Blind Method ; Exercise/*physiology ; Exercise Test ; Humans ; Killer Cells, Natural/drug effects/*physiology ; Lymphocyte Activation/drug effects/*physiology ; Lymphocyte Count/drug effects ; Lymphocyte Subsets/drug effects/*immunology ; Male ; }, abstract = {This study evaluated whether N-acetylcysteine (NAC) attenuates the reduced lymphocyte proliferation and natural killer (NK) cell activity responses to exercise in humans. Fourteen oarsmen were double-blind randomized to either NAC (6 g daily for 3 days) or placebo groups. During 6-min "all-out" ergometer rowing, the concentration of lymphocytes in the peripheral blood increased, with no significant difference between NAC and placebo as reflected in lymphocyte subsets: CD4(+), CD8(+), CD16(+), and CD19(+) cells. The phytohemagglutinin-stimulated lymphocyte proliferation decreased from 9,112 +/- 2,865 to 5,851 +/- 1,588 cpm (P < 0.05), but it was not affected by NAC. During exercise, the NK cell activity was elevated from 17 +/- 3 to 38 +/- 4% and it decreased to 7 +/- 1% below the resting value 2 h into recovery. Yet, when evaluated as lytic units per CD16(+) cell, the NK cell activity decreased during and after exercise without a significant effect of NAC. We conclude that NAC does not attenuate the reduction in lymphocyte proliferation and NK cell activity associated with intense exercise.}, }
@article {pmid9756488, year = {1998}, author = {Hinchman, CA and Rebbeor, JF and Ballatori, N}, title = {Efficient hepatic uptake and concentrative biliary excretion of a mercapturic acid.}, journal = {The American journal of physiology}, volume = {275}, number = {4}, pages = {G612-9}, doi = {10.1152/ajpgi.1998.275.4.G612}, pmid = {9756488}, issn = {0002-9513}, support = {DK-48823/DK/NIDDK NIH HHS/United States ; ES-01247/ES/NIEHS NIH HHS/United States ; ES-06484/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives/blood/pharmacokinetics ; Amino Acids/pharmacology ; Animals ; Bile/*metabolism ; Biological Transport/drug effects ; Biotransformation ; Carrier Proteins/metabolism ; Chromatography, High Pressure Liquid ; Glutathione/analogs &amp; derivatives/isolation &amp; purification/pharmacokinetics ; In Vitro Techniques ; Infusions, Intravenous ; Liver/*metabolism ; Male ; Metabolic Clearance Rate ; Perfusion ; Rats ; Rats, Sprague-Dawley ; Sodium/pharmacology ; Time Factors ; }, abstract = {The role of the liver in the disposition of circulating mercapturic acids was examined in anesthetized rats and in the isolated perfused rat liver using S-2,4-dinitrophenyl-N-acetylcysteine (DNP-NAC) as the model compound. When DNP-NAC was infused into the jugular vein (150 or 600 nmol over 60 min) it was rapidly and nearly quantitatively excreted as DNP-NAC into bile (42-36% of the dose) and urine (48-62% of dose). Some minor metabolites were detected in bile (<4%), with the major metabolite coeluting on HPLC with the DNP conjugate of glutathione (DNP-SG). Isolated rat livers perfused single pass with 3 microM DNP-NAC removed 72 +/- 9% of this mercapturic acid from perfusate. This rapid DNP-NAC uptake was unaffected by sodium omission, or by L-cysteine, L-glutamate, L-cystine, or N-acetylated amino acids, but was decreased by inhibitors of hepatic sinusoidal organic anion transporters (oatp), indicating that DNP-NAC is a substrate for these transporters. The DNP-NAC removed from perfusate was promptly excreted into bile, eliciting a dose-dependent choleresis. DNP-NAC itself constituted approximately 75% of the total dose recovered in bile, reaching a concentration of 9 mM when livers were perfused in a recirculating mode with an initial DNP-NAC concentration of 250 microM. Other biliary metabolites included DNP-SG, DNP-cysteinylglycine, and DNP-cysteine. DNP-SG was likely formed by a spontaneous retro-Michael reaction between glutathione and DNP-NAC. Subsequent degradation of DNP-SG by biliary gamma-glutamyltranspeptidase and dipeptidase activities accounts for the cysteinylglycine and cysteine conjugates, respectively. These findings indicate the presence of efficient hepatic mechanisms for sinusoidal uptake and biliary excretion of circulating mercapturic acids in rat liver and demonstrate that the liver plays a role in their whole body elimination.}, }
@article {pmid9755056, year = {1998}, author = {Voskoboinik, I and Söderholm, K and Cotgreave, IA}, title = {Ascorbate and glutathione homeostasis in vascular smooth muscle cells: cooperation with endothelial cells.}, journal = {The American journal of physiology}, volume = {275}, number = {4}, pages = {C1031-9}, doi = {10.1152/ajpcell.1998.275.4.C1031}, pmid = {9755056}, issn = {0002-9513}, mesh = {Acetylcysteine/metabolism ; Ascorbic Acid/*metabolism ; Cells, Cultured ; Coculture Techniques ; Cystine/metabolism ; Dehydroascorbic Acid/metabolism ; Endothelium, Vascular/cytology/*physiology ; Glutathione/*metabolism ; Homeostasis ; Humans ; Kinetics ; Methionine/metabolism ; Muscle, Smooth, Vascular/cytology/*physiology ; Oxidation-Reduction ; Phloretin/pharmacology ; Umbilical Veins/cytology/*physiology ; }, abstract = {Human umbilical vein smooth muscle cells (HUVSMCs) utilize extracellular cystine, glutathione (GSH), and N-acetylcysteine (NAC) to synthesize cellular GSH. Extracellular cystine was effective from 5 microM, whereas GSH and NAC were required at 100 microM for comparable effects. The efficacy of extracellular GSH was dependent on de novo GSH synthesis, indicating a dependence on cellular gamma-glutamyltransferase (glutamyl transpeptidase). Coculture of syngenetic HUVSMCs and corresponding human umbilical vein endothelial cells (HUVECs) on porous supports restricted cystine- or GSH-stimulated synthesis of HUVSMC GSH when supplied on the "luminal" endothelial side. Thus HUVSMC GSH rapidly attained a steady-state level below that achieved in the absence of interposed HUVECs. HUVSMCs also readily utilize both reduced ascorbate (AA) and oxidized dehydroascorbate (DHAA) over the range 50-500 microM. Phloretin effectively blocked both AA- and DHAA-stimulated assimilation of intracellular AA, indicating a role for a glucose transporter in their transport. Uptake of extracellular AA was also sensitive to extracellular, but not intracellular, thiol depletion. When AA was applied to the endothelial side of the coculture model, assimilation of intracellular AA in HUVSMCs was restricted to a steady-state level below that achieved by free access.}, }
@article {pmid9750041, year = {1998}, author = {Gürer, H and Ozgünes, H and Neal, R and Spitz, DR and Erçal, N}, title = {Antioxidant effects of N-acetylcysteine and succimer in red blood cells from lead-exposed rats.}, journal = {Toxicology}, volume = {128}, number = {3}, pages = {181-189}, doi = {10.1016/s0300-483x(98)00074-2}, pmid = {9750041}, issn = {0300-483X}, support = {R01 HL51469/HL/NHLBI NIH HHS/United States ; R15 ES08016/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Blood Cell Count/drug effects ; Erythrocytes/drug effects/enzymology/*metabolism ; Glutathione/blood ; Lead/blood/*toxicity ; Male ; Malondialdehyde/blood ; Oxidative Stress/drug effects ; Rats ; Rats, Inbred F344 ; Succimer/*pharmacology ; }, abstract = {This study examined whether lead-induced alterations in selected parameters that are indicative of oxidative stress accompany the toxic effects of lead in red blood cells (RBCs) in vivo. It also explored the possibility that treatment with N-acetylcysteine (NAC) or succimer (meso-2,3-dimercaptosuccinic acid) was capable of reversing parameters indicative of lead-induced oxidative stress. Fisher 344 rats were given 2000 ppm lead acetate in their drinking water for 5 weeks. The lead was then removed and the animals were given NAC (800 mg/kg/day) or succimer (90 mg/kg/day) in their drinking water for 1 week, after which the RBCs were harvested. Animals not given lead and those given lead, but not NAC or succimer, served as negative and positive controls, respectively. At the end of the experiment, blood-lead levels were 35 +/- 4 microg/dl in lead-treated animals, which were reduced to 2.5 +/- 1 microg/dl by treatment with succimer and to 25 +/- 3 microg/dl by treatment with NAC. Lead-exposed animals demonstrated signs of anemia as evidenced by anisocytosis, poikilocytosis, and alterations in hemoglobin, hematocrit, and mean corpuscular volume. Lipid peroxidation, as evidenced by increased malondialdehyde (MDA) content, as well as decreases in reduced glutathione (GSH) and increases in catalase and glucose 6-phosphate dehydrogenase (G6PD) activity were noted in RBCs from lead-treated rats, suggesting that the lead induced oxidative stress. In addition, a significant reduction in blood delta-aminolevulinic acid dehydratase (ALAD) activity suggested that accumulation and autooxidation of delta-aminolevulinic acid might contribute to lead-induced oxidative stress. Treatment with either NAC or succimer reversed lead-induced alterations in MDA and GSH content, but only succimer appeared to partially restore ALAD activity. These results provide in vivo evidence supporting the hypothesis that lead induces oxidative stress in RBCs, which is reversible by treatment with a thiol antioxidant (NAC), as well as a chelating agent (succimer).}, }
@article {pmid9747602, year = {1998}, author = {Stringer, B and Kobzik, L}, title = {Environmental particulate-mediated cytokine production in lung epithelial cells (A549): role of preexisting inflammation and oxidant stress.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {55}, number = {1}, pages = {31-44}, doi = {10.1080/009841098158601}, pmid = {9747602}, issn = {1528-7394}, support = {NIEHS-00002/EH/NCEH CDC HHS/United States ; P01-ES0-8129/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenocarcinoma, Bronchiolo-Alveolar ; Air Pollution/*adverse effects ; Antioxidants/pharmacology ; Carbon/toxicity ; Chromans/pharmacology ; Coal Ash ; Dose-Response Relationship, Drug ; Epithelial Cells/drug effects/*immunology/pathology ; Flow Cytometry ; Fluoresceins/chemistry ; Free Radical Scavengers/pharmacology ; Humans ; Industrial Waste/adverse effects ; Interleukin-8/*biosynthesis ; Lung/drug effects/*immunology/pathology ; Lung Neoplasms ; *Oxidative Stress ; Particle Size ; Particulate Matter ; Petroleum/toxicity ; Piperazines/pharmacology ; Pneumonia/*immunology/pathology ; Quartz/chemistry/toxicity ; Titanium/chemistry/toxicity ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Epidemiologic data show that air pollution particulates cause adverse pulmonary health effects, especially in individuals with preexisting lung disease. We sought to model in vitro preexisting lung inflammation in order to investigate the hypothesis that "primed" lung epithelial cells will exhibit enhanced phlogistic responses [e.g., interleukin-8 (IL-8) production] to particulate air pollution. Exposure of tumor necrosis factor alpha (TNF-alpha) primed or control A549 cells to the air pollution particulates, residual oil fly ash (ROFA), and the known pathogenic dust alpha-quartz, but not inert TiO2, caused increased IL-8 production in primed cells compared to normal cells in a concentration-dependent manner (particle concentration range 0-200 microg/ml). We hypothesized that oxidant mechanisms may be involved in the cellular response to particulates. Addition of the antioxidant N-acetylcysteine (NAC, 1.0 mM) decreased ROFA and alpha-quartz-mediated IL-8 production by approximately 50% in normal and TNF-alpha-primed A549 cells. In addition, exposure of A549 cells to ROFA caused a substantial (and NAC inhibitable) increase in oxidant levels as measured by fluorometry (DCFH oxidation). These data suggest that (1) lung epithelial cells primed by inflammatory mediators can show enhanced cytokine production after exposure to air pollution particulates, and (2) oxidant stress is a key mechanism for this response.}, }
@article {pmid9747510, year = {1998}, author = {Takahashi, S and Takahashi, Y and Yoshimi, T and Miura, T}, title = {Oxygen tension regulates heme oxygenase-1 gene expression in mammalian cell lines.}, journal = {Cell biochemistry and function}, volume = {16}, number = {3}, pages = {183-193}, doi = {10.1002/(SICI)1099-0844(199809)16:3&lt;183::AID-CBF784&gt;3.0.CO;2-0}, pmid = {9747510}, issn = {0263-6484}, mesh = {Animals ; Antioxidants/pharmacology ; Cell Line ; Cell Survival ; Cycloheximide/pharmacology ; Dactinomycin/pharmacology ; Dose-Response Relationship, Drug ; *Gene Expression Regulation, Enzymologic ; Heme Oxygenase (Decyclizing)/*biosynthesis/genetics ; Heme Oxygenase-1 ; Humans ; Membrane Proteins ; Mice ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Oxidants/pharmacology ; Oxygen/*pharmacology ; Protein Synthesis Inhibitors/pharmacology ; RNA, Messenger/analysis ; Rats ; }, abstract = {The gene expression of heme oxygenase-1 (HO-1) was studied in mammalian cell lines exposed to hyperoxia. Northern blot analysis demonstrated that hyperoxic exposure increased the HO-1 mRNA levels in various types of cells, including human hepatoma (HepG2) cells. This increase was time- and dose-dependent, and reversible. The HO-1 mRNA levels in HepG2 cells were increased to 2.3- and 4.2-fold of the control by hyperoxic exposure of 6 and 23 h, respectively. Cycloheximide and actinomycin D inhibited the increases in the HO-1 mRNA level produced by hyperoxia, indicating that response to hyperoxia is dependent on de novo protein synthesis and mRNA transcription. Antioxidants, desferrioxamine (DES) and o-phenanthroline (OP) partially inhibited the HO-1 mRNA elevation by hyperoxia. In addition to hyperoxia, sodium arsenite (NaAsO2), cadmium chloride (CdCl(2)) and hydrogen peroxide (H2O2), which are reactive oxygen intermediates (ROI) generators, increased the HO-1 mRNA level by 11-, 22- and 2.5-fold, respectively. OP, an antioxidant and a bivalent metal chelator, blocked the HO-1 mRNA elevation induced either by hyperoxia or by the three ROI generators. In contrast to OP, N-acetylcysteine (NAC), an antioxidant and membrane-permeable reducing reagent, enhanced the HO-1 mRNA elevation induced by hyperoxia, although NAC inhibited the mRNA elevation induced by NaAsO2, CdCl2 and H2O2. These results indicate that oxygen tension regulates HO-1 gene expression and suggest that hyperoxia-specific and redox-sensitive regulators may be involved in hyperoxia-mediated HO-1 gene expression.}, }
@article {pmid9747437, year = {1998}, author = {Venditti, P and Balestrieri, M and De Leo, T and Di Meo, S}, title = {Free radical involvement in doxorubicin-induced electrophysiological alterations in rat papillary muscle fibres.}, journal = {Cardiovascular research}, volume = {38}, number = {3}, pages = {695-702}, doi = {10.1016/s0008-6363(98)00034-0}, pmid = {9747437}, issn = {0008-6363}, mesh = {Acetylcysteine/pharmacology ; Action Potentials/drug effects ; Animals ; Antibiotics, Antineoplastic/*pharmacology ; Antioxidants/*pharmacology ; Doxorubicin/*pharmacology ; Electrophysiology ; Free Radicals/metabolism ; Heart/*drug effects/physiology ; Heart Rate/drug effects ; In Vitro Techniques ; Lipid Peroxidation ; Liver/chemistry/drug effects ; Male ; Oxidative Stress ; Papillary Muscles/drug effects ; Rats ; Rats, Wistar ; Vitamin E/analysis/blood/pharmacology ; }, abstract = {OBJECTIVE: This work was designed to determine whether the doxorubicin-induced changes in heart electrical activity are due to increased free radical production and membrane oxidative damage.<br><br>METHODS: Four groups of rats (60 days old) were used. One group was untreated and the others were treated with doxorubicin (DXR), DXR and vitamin E, and DXR and N-acetylcysteine (NAC), respectively. DXR was administered by single i.p. injection (20 mg/kg b.wt.). Vitamin E was administered by ten daily i.m. injections (100 mg/kg), while NAC (100 mg/kg) was injected i.p. 1 h before and 7 h after DXR. The effectiveness of the drug in inducing oxidative stress in different tissues and of the antioxidants in offering protection was established by determining antioxidant capacity, susceptibility to oxidative stress, and lipid peroxidation in heart, liver, and blood. The drug effect on heart electrical activity was determined by measuring the heart rate in vivo and action potential configuration in papillary muscle fibres in vitro. Heart lipid peroxidation and electrical activity were also examined in both vitamin E and NAC-treated rats.<br><br>RESULTS: DXR treatment decreased antioxidant capacity and increased lipid peroxidation and susceptibility to oxidative stress in heart and blood, but not in liver. DXR administration to rats treated with antioxidants did not produce significant changes in antioxidant capacity and susceptibility to oxidative stress even in heart and blood. Furthermore, lipid peroxidation in heart and liver from DXR- and vitamin E-treated rats, and in liver from DXR- and NAC-treated rats was lower than in untreated controls. DXR treatment also increased the duration of ventricular action potentials in untreated rats, but not in antioxidant-treated rats. The treatment of control animals with the antioxidants affected lipid peroxidation, but not cardiac electrical activity.<br><br>CONCLUSIONS: The protection offered by antioxidants against electrophysiological alterations indicates a free radical involvement in such alterations. In contrast, although electrical modifications are associated with increased peroxidative processes and both are prevented by the antioxidants, it is not yet clear whether a causative relationship exists between them.}, }
@article {pmid9744525, year = {1998}, author = {Waleh, NS and Calaoagan, J and Murphy, BJ and Knapp, AM and Sutherland, RM and Laderoute, KR}, title = {The redox-sensitive human antioxidant responsive element induces gene expression under low oxygen conditions.}, journal = {Carcinogenesis}, volume = {19}, number = {8}, pages = {1333-1337}, doi = {10.1093/carcin/19.8.1333}, pmid = {9744525}, issn = {0143-3334}, support = {CA20329/CA/NCI NIH HHS/United States ; CA57692/CA/NCI NIH HHS/United States ; CA67116/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Butylated Hydroxyanisole/pharmacology ; Cell Hypoxia ; Chloramphenicol O-Acetyltransferase/antagonists &amp; inhibitors/genetics/*metabolism ; Free Radical Scavengers/pharmacology ; *Gene Expression Regulation, Enzymologic ; Genes, Reporter ; Humans ; Mice ; NAD(P)H Dehydrogenase (Quinone)/genetics/*metabolism ; Oxidation-Reduction ; Trans-Activators/*physiology ; Tumor Cells, Cultured ; }, abstract = {Transient transfection studies of human HepG2 and mouse Hepa hepatocarcinoma cells with a reporter gene construct regulated by a human antioxidant responsive element (ARE) from the NQO1 gene demonstrated that the element is responsive to low oxygen conditions. The antioxidant N-acetyl L-cysteine (NAC) strongly inhibited basal aerobic reporter gene activity in HepG2 cells without obviously affecting the hypoxic induction, as is consistent with ARE sensitivity to oxidative stress in aerobic cultures. Electrophoretic mobility shift (EMS) assays of nuclear extracts of HepG2 and Hepa cells lysed under aerobic or hypoxic conditions or after exposure to the phenolic compound 3-(2)-tert-butyl-4-hydroxyanisole (BHA), showed specific and constitutive protein binding to the ARE under all of these conditions. Taken together, these findings show that the ARE can mediate gene expression in response to low oxygen conditions. Co-ordinately regulated expression of ARE-dependent genes, such as phase II detoxification enzymes, may be an important phenotype of solid tumors containing significant regions of pathophysiological hypoxia.}, }
@article {pmid9741582, year = {1998}, author = {Jackson, RM and Parish, G and Helton, ES}, title = {Peroxynitrite modulates MnSOD gene expression in lung epithelial cells.}, journal = {Free radical biology &amp; medicine}, volume = {25}, number = {4-5}, pages = {463-472}, doi = {10.1016/s0891-5849(98)00101-4}, pmid = {9741582}, issn = {0891-5849}, support = {HL 57801/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Blotting, Northern ; Cell Line ; Epithelial Cells/enzymology ; Gene Expression/*drug effects ; Humans ; Hydrogen Peroxide/pharmacology ; Luciferases/genetics ; Lung/*enzymology ; Molsidomine/analogs &amp; derivatives/pharmacology ; Nitrates/*pharmacology ; Nitric Oxide/pharmacology ; Nitrites/pharmacology ; RNA, Messenger/biosynthesis ; Rats ; Recombinant Fusion Proteins/metabolism ; Superoxide Dismutase/*genetics ; }, abstract = {Peroxynitrite (ONOO-) is a strong oxidant derived from nitric oxide ('NO) and superoxide (O2.-), reactive nitrogen (RNS) and oxygen species (ROS) present in inflamed tissue. Other oxidant stresses, e.g., TNF-alpha and hyperoxia, induce mitochondrial, manganese-containing superoxide dismutase (MnSOD) gene expression. These experiments tested whether ONOO regulated MnSOD gene expression in human lung epithelial (A549) cells. 3-morpholinosydnonimine HCI (SIN-1) (10 or 1000 microM) increased MnSOD mRNA, but did not change hypoxanthine guanine phosphoribosyl transferase (HPRT) mRNA. Authentic peroxynitrite (ONOO) (100-500 microM) also increased MnSOD mRNA but did not change constitutive HPRT mRNA expression. ONOO stimulated luciferase gene expression driven by a 2.5 kb fragment of the rat MnSOD gene 5' promoter region. MnSOD gene induction due to ONOO- was inhibited effectively by L-cysteine (10 mM) and partially inhibited by N-acetyl cysteine (50 mM) or pyrrole dithiocarbamate (10 mM). .NO from 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazine) (PAPA NONOate) (100 or 1000 microM) did not change MnSOD or HPRT mRNA. Neither H202 nor NO2-, breakdown products of SIN-1 and ONOO , had any effect on MnSOD mRNA expression; however, ONOO- and SIN-1 did not increase MnSOD protein content detectable by western blots, nor did they increase MnSOD enzymatic activity. Increased steady state [O2.-] in the presence of .NO yields ONOO , and ONOO has direct, stimulatory effects on MnSOD transcript expression.}, }
@article {pmid9734707, year = {1998}, author = {Del Rio, M and Ruedas, G and Medina, S and Victor, VM and De la Fuente, M}, title = {Improvement by several antioxidants of macrophage function in vitro.}, journal = {Life sciences}, volume = {63}, number = {10}, pages = {871-881}, doi = {10.1016/s0024-3205(98)00344-0}, pmid = {9734707}, issn = {0024-3205}, mesh = {Animals ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Cell Migration Inhibition ; Chemotaxis, Leukocyte/drug effects ; Female ; Immune Adherence Reaction ; Indicators and Reagents ; Macrophages, Peritoneal/*drug effects/immunology/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Nitroblue Tetrazolium ; Phagocytosis/drug effects ; Superoxides/metabolism ; Vitamin E/pharmacology ; }, abstract = {The toxic effects of oxygen radicals produced by immune cells can be controlled to certain degree by endogenous antioxidants, because of their scavenger action. This control is specially important in a type of immune cell, i.e.: the phagocyte, which needs oxygen free radicals and uses antioxidants in order to support its functions. Previous studies have shown an stimulation of the immune system with an antioxidant enriched diet. In the present work, we have studied the effects in vitro of several antioxidants: alpha-tocopherol or vitamin E (VE), ascorbic acid (AA), glutathione (GSH), N-acetylcysteine (NAC) and thioproline or thiazolidine-4-carboxylic acid (TCA), at different concentrations, on the various steps of the phagocytic process of murine peritoneal macrophages, i.e.: adherence to substrate, migration (random migration and directed migration or chemotaxis), ingestion and superoxide anion production. The results show an antioxidant-induced stimulation of the phagocytic process of macrophages. Thus, the adherence to substrate was raised, after short incubation times, by a-tocopherol and ascorbic acid. Random migration, chemotaxis, ingestion and superoxide anion production were increased by all the antioxidants used.}, }
@article {pmid9733280, year = {1998}, author = {Pelle, E and Ingrassia, M and Mammone, T and Marenus, K and Maes, D}, title = {Protection against cigarette smoke-induced damage to intact transformed rabbit corneal cells by N-acetyl-L-cysteine.}, journal = {Cell biology and toxicology}, volume = {14}, number = {4}, pages = {253-259}, doi = {10.1023/a:1007478823798}, pmid = {9733280}, issn = {0742-2091}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antidotes/pharmacology ; Biological Assay/methods ; Buthionine Sulfoximine/pharmacology ; Cell Line, Transformed ; *Cornea/cytology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/pharmacology ; *Plants, Toxic ; Rabbits ; *Smoke/adverse effects ; *Nicotiana ; }, abstract = {In order to assess cigarette smoke-induced oxidative damage to intact cells, an assay was developed to measure cell detachment and protection. Due to the complex nature of cigarette smoke, which contains molecules that can interfere with conventional spectrophotometric and fluorometric biochemical assays, transformed rabbit corneal cells were radiolabeled with tritiated thymidine and then subjected to direct stream smoke. As a result, cell damage in response to the smoke from only two cigarettes could be measured in a time-dependent manner. When cells were prelabeled with N-acetyl-L-cysteine (NAC), a substrate for glutathione synthesis, a significant reduction in damage was measured. Additionally, when buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, was incubated with cells, a reduction in the effectiveness of NAC was observed, although NAC still retained some activity. Furthermore, vitamin E conferred no protection to cells in this system nor was NAC active in a separate assay that appears to favor peroxyl radical generation. From these results we conclude that cigarette smoke damage can easily be determined at the cellular level with this technique and that NAC acted to prevent this damage in two ways: first, as glutathione precursor and, secondly, as an antioxidant capable of scavenging non-peroxyl radicals.}, }
@article {pmid9731560, year = {1998}, author = {Fernando, B and Marley, R and Holt, S and Anand, R and Harry, D and Sanderson, P and Smith, R and Hamilton, G and Moore, K}, title = {N-acetylcysteine prevents development of the hyperdynamic circulation in the portal hypertensive rat.}, journal = {Hepatology (Baltimore, Md.)}, volume = {28}, number = {3}, pages = {689-694}, doi = {10.1002/hep.510280314}, pmid = {9731560}, issn = {0270-9139}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dinoprost/urine ; Hemodynamics/*drug effects ; Hypertension, Portal/*metabolism ; Male ; Nitrates/blood ; Nitric Oxide/biosynthesis ; Nitrites/blood ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Partial portal vein ligation (PPVL) leads to the development of a hyperdynamic circulation. It is associated with elevated levels of tumor necrosis factor (TNF-alpha) and nitric oxide (NO) production, both of which can result in oxidant injury. In this study, we have investigated whether PPVL is associated with the development of oxidative stress, by measuring urinary F2-isoprostanes. In addition, we have examined whether N-acetylcysteine (NAC) can ameliorate oxidant injury and prevent the development of the hyperdynamic circulation. Urinary excretion of F2-isoprostanes increased sixfold following PPVL together with a significant increase in plasma nitrite and nitrate. Treatment with NAC inhibited the formation of F2-isoprostanes as well as the increase in plasma nitrite and nitrate. Hemodynamic studies in anesthetized rats showed that following PPVL, cardiac output and portal pressure increased, and systemic vascular resistance decreased, consistent with the development of a hyperdynamic circulation. These changes were prevented by chronic administration of NAC. We conclude that NAC prevents the development of the hyperdynamic circulation and that the formation of reactive oxygen species may be important in the pathogenesis of these hemodynamic changes.}, }
@article {pmid9728048, year = {1998}, author = {Rahman, A and Kefer, J and Bando, M and Niles, WD and Malik, AB}, title = {E-selectin expression in human endothelial cells by TNF-alpha-induced oxidant generation and NF-kappaB activation.}, journal = {The American journal of physiology}, volume = {275}, number = {3}, pages = {L533-44}, doi = {10.1152/ajplung.1998.275.3.L533}, pmid = {9728048}, issn = {0002-9513}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Base Sequence ; Binding Sites ; Cell Nucleus/drug effects/physiology ; Cells, Cultured ; E-Selectin/biosynthesis/*genetics ; Endothelium, Vascular/drug effects/*immunology/physiology ; Humans ; NF-kappa B/*metabolism ; Oligodeoxyribonucleotides/chemistry ; Oxidants/metabolism ; Pulmonary Artery ; Pyrrolidines/pharmacology ; Reactive Oxygen Species/metabolism ; Recombinant Proteins/pharmacology ; Signal Transduction ; Thiocarbamates/pharmacology ; *Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/*pharmacology/physiology ; }, abstract = {Because reactive oxygen species (ROS) can function as second messengers and regulate the activation of the transcription factor nuclear factor (NF)-kappaB, we investigated the possible role of tumor necrosis factor-alpha (TNF-alpha)-induced ROS generation in endothelial cells in signaling E-selectin gene transcription. We demonstrated that stimulation of human pulmonary artery endothelial cells with TNF-alpha (100 U/ml) resulted in ROS production using the oxidant-sensitive dye 5 (and 6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate bis(acetoxymethyl)ester. Pretreatment with N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC) for 0.5 h inhibited TNF-alpha-induced generation of ROS as well as activation of NF-kappaB and E-selectin mRNA and the cell surface protein expression. These findings indicate that TNF-alpha induces NF-kappaB activation and the resultant E-selectin gene expression by a pathway that involves formation of ROS and that E-selectin expression can be inhibited by the antioxidant action of NAC or PDTC. The results support the hypothesis that generation of ROS in endothelial cells induced by proinflammatory cytokines such as TNF-alpha is a critical signal mediating E-selectin expression.}, }
@article {pmid9726778, year = {1998}, author = {Goldsmith, CA and Imrich, A and Danaee, H and Ning, YY and Kobzik, L}, title = {Analysis of air pollution particulate-mediated oxidant stress in alveolar macrophages.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {54}, number = {7}, pages = {529-545}, doi = {10.1080/009841098158683}, pmid = {9726778}, issn = {1528-7394}, support = {NIHES0001/ES/NIEHS NIH HHS/United States ; P01ES08129/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Air Pollutants/*adverse effects ; Animals ; Cell Line ; Chelating Agents ; Chemokines, CC ; Cricetinae ; Cytokines/metabolism ; Deferoxamine ; Environmental Exposure/*adverse effects ; Fluoresceins ; Free Radical Scavengers/pharmacology ; *Macrophage Inflammatory Proteins ; Macrophages, Alveolar/*drug effects/pathology ; Oxidative Stress/*drug effects ; Particle Size ; RNA/metabolism ; Reactive Oxygen Species/metabolism ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/biosynthesis ; }, abstract = {Adverse health effects of urban air pollution particulates may be attributable to particle-mediated oxidant stress and inflammation. Intracellular oxidant production in normal hamster alveolar macrophages (AMs) was measured upon exposure to concentrated ambient particulates (CAPs), residual oil fly ash (ROFA), and their water-soluble and particulate fractions. ROFA and CAPs caused increases in dichlorofluorescin (DCFH) oxidation, a fluorescent measure of intracellular reactive oxygen species (ROS) production, comparable to the positive control, phorbol myristate acetate (PMA). The water-soluble component of both CAPs and ROFA (CAPs, S and ROFA, S) significantly increased AM oxidant production over negative control. CAPs samples and components showed substantial day-to-day variability in their oxidant effects. Metal chelation by desferrioxamine (DF, 1 mM) caused significant inhibition of particulate-induced AM oxidant production. ROFA exposure resulted in increased macrophage inflammatory protein-2 (MIP-2) message in AMs and in increased tumor necrosis factor alpha (TNF-alpha) production by the monocyte-macrophage cell line, RAW 264.7. TNF-alpha production was inhibitable by the antioxidant N-acetylcysteine (NAC). The data suggest that metal components adsorbed to urban air pollution particulates can significantly contribute to particulate ability to cause oxidant stress and cytokine production in AMs.}, }
@article {pmid9726007, year = {1998}, author = {Brennan, RJ and Schiestl, RH}, title = {Free radicals generated in yeast by the Salmonella test-negative carcinogens benzene, urethane, thiourea and auramine O.}, journal = {Mutation research}, volume = {403}, number = {1-2}, pages = {65-73}, doi = {10.1016/s0027-5107(98)00050-5}, pmid = {9726007}, issn = {0027-5107}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzene/toxicity ; Benzophenoneidum/toxicity ; Carcinogens/*toxicity ; Fluoresceins/metabolism ; Fluorescent Dyes/metabolism ; Free Radical Scavengers/pharmacology ; Free Radicals/metabolism ; Mutagenicity Tests ; Mutagens/*toxicity ; Oxidation-Reduction ; Oxidative Stress/drug effects/genetics ; Recombination, Genetic/drug effects ; Saccharomyces cerevisiae/*drug effects/genetics/*metabolism ; Salmonella/drug effects/genetics ; Superoxide Dismutase/metabolism ; Thiourea/toxicity ; Urethane/toxicity ; }, abstract = {A large fraction of carcinogens score negative in short-term genotoxicity assays such as the Salmonella reverse mutation (Ames) assay. More information is needed about the mechanism of action of such Salmonella-negative carcinogens. Many Salmonella-negative carcinogens induce deletions due to intrachromosomal recombination in Saccharomyces cerevisiae with an apparent threshold. We have previously shown that the Salmonella-negative carcinogens cadmium, aniline, chloroform and carbon tetrachloride generate free radical species in S. cerevisiae. We have further investigated the possible generation of intracellular free radical species by the diverse Salmonella-negative carcinogens benzene, urethane, thiourea and auramine O. The toxicity and recombinagenicity of thiourea and auramine O was reduced in the presence of the free radical scavenger N-acetyl cysteine. N-acetyl cysteine did not protect against toxicity or recombination induced by the Salmonella-positive carcinogens ethyl methane sulfonate, methyl methane sulfonate or nitroquinoline-N-oxide. A strain deficient in the enzyme superoxide dismutase, which catalyses the dismutation of superoxide anion radical, was hypersensitive to killing by benzene, urethane and thiourea. The sod- strain was only slightly more sensitive to the Salmonella-positive carcinogens. Intracellular oxidation of the free radical-sensitive reporter compound dichlorofluorescin diacetate was increased in yeast cultures exposed to benzene, urethane and auramine O; again, the Salmonella mutagens had no effect on oxidation of the dye. These data show that free radical species are produced in Saccharomyces cerevisiae following exposure to benzene, urethane, thiourea and auramine O, and suggest a possible role for oxidative stress is recombination induced by these carcinogens.}, }
@article {pmid9722042, year = {1998}, author = {Moriuchi, H and Zaha, M and Fukumoto, T and Yuizono, T}, title = {Activation of polymorphonuclear leukocytes in oleic acid-induced lung injury.}, journal = {Intensive care medicine}, volume = {24}, number = {7}, pages = {709-715}, pmid = {9722042}, issn = {0342-4642}, mesh = {Acetylcysteine/*pharmacology ; Amino Acid Chloromethyl Ketones/*pharmacology ; Animals ; Capillary Permeability/*drug effects ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Female ; Free Radical Scavengers/*pharmacology ; Guinea Pigs ; Leukocyte Elastase/drug effects/immunology ; Male ; Neutrophils/*immunology ; *Oleic Acid ; Prospective Studies ; Pulmonary Circulation/*drug effects ; Rats ; Respiratory Distress Syndrome/*chemically induced/drug therapy/*immunology ; Serine Proteinase Inhibitors/*pharmacology ; Superoxides/immunology ; }, abstract = {OBJECTIVE: Oleic acid (OA) can produce a lung injury similar to the adult respiratory distress syndrome (ARDS). Elastase and superoxides are thought to have an effect in ARDS. However, the effect that elastase and superoxide have in OA lung injury is unclear. To examine their involvement in OA lung injury, we tested the effects of methoxysuccinyl-alanyl-alanyl-prolyl-valyl chloromethyl ketone (MAAPVCK), an elastase inhibitor, and N-acetyl-L-cysteine (NAC), an active oxygen scavenger, on the increase in pulmonary vascular permeability caused by OA. We also examined whether OA stimulated elastase and/or superoxide release from polymorphonuclear leukocytes (PMNs).<br><br>DESIGN: Prospective trial.<br><br>SETTING: University laboratory.<br><br>INTERVENTIONS: (1) Guinea pigs were anesthetized. MAAPVCK (2.5 mg/ kg) or NAC (150 mg/kg) was infused over OA (15 microl/kg) injection. Evans blue was used to measure vascular permeability. (2) PMNs were isolated from the blood of guinea pigs and rats. Elastase release was measured with MeO-Suc-Ala-Ala-Pro-Val-7-amino-4-methylcoumarin. Superoxide production was measured by the ferricytochrome c reduction method.<br><br>MEASUREMENTS AND RESULTS: OA caused pulmonary hemorrhage and an increase in vascular permeability. MAAPVCK and NAC significantly attenuated the increase in vascular permeability in distal bronchus and trachea, respectively. OA induced superoxide production from PMNs in guinea pigs, but elastase release from PMNs was not detected.<br><br>CONCLUSIONS: These results suggest that elastase and superoxide are involved in OA lung injury.}, }
@article {pmid9721806, year = {1998}, author = {Hultén, LM and Lindmark, H and Scherstén, H and Wiklund, O and Nilsson, FN and Riise, GC}, title = {Butylated hydroxytoluene and N-acetylcysteine attenuates tumor necrosis factor-alpha (TNF-alpha) secretion and TNF-alpha mRNA expression in alveolar macrophages from human lung transplant recipients in vitro.}, journal = {Transplantation}, volume = {66}, number = {3}, pages = {364-369}, doi = {10.1097/00007890-199808150-00014}, pmid = {9721806}, issn = {0041-1337}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antioxidants/*pharmacology ; Butylated Hydroxytoluene/*pharmacology ; Female ; Gene Expression/drug effects ; Graft Survival/drug effects/immunology ; Heart Transplantation/*immunology ; Heart-Lung Transplantation/*immunology ; Humans ; In Vitro Techniques ; Lipopolysaccharides/immunology ; Macrophage Activation/drug effects/immunology ; Macrophages, Alveolar/*drug effects/immunology ; Male ; Middle Aged ; RNA, Messenger/genetics ; Tumor Necrosis Factor-alpha/genetics/*metabolism ; }, abstract = {BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide cytokine principally produced by macrophages/monocytes and commonly associated with inflammatory conditions. The present study was designed to investigate whether the antioxidants butylated hydroxytoluene (BHT) and N-acetylcysteine (NAC) modified TNF-alpha production in stimulated and unstimulated alveolar macrophages from lung transplant recipients in vitro.<br><br>METHODS: The effects of BHT and NAC on TNF-alpha production were studied both with and without lipopolysaccharide (LPS) activation of alveolar macrophages from bronchoalveolar lavage fluid. TNF-alpha was quantitated in cell culture medium using an enzyme-linked immunosorbent assay. TNF-alpha mRNA expression was analyzed by quantitative reverse transcription-polymerase chain reaction on total RNA extracted from the incubated alveolar macrophages.<br><br>RESULTS: In unstimulated alveolar macrophages, TNF-alpha levels were significantly reduced by incubation with BHT or NAC. When alveolar macrophages from patients with cytomegalovirus infection were incubated with BHT, TNF-alpha secretion was significantly lowered. A significant reduction of TNF-alpha levels in LPS-stimulated alveolar macrophages was obtained in the presence of BHT or NAC. Our data from quantitative reverse transcription-polymerase chain reaction showed that the observed decrease in protein levels of TNF-alpha was associated with a decrease in TNF-alpha mRNA expression.<br><br>CONCLUSIONS: Our results indicate that antioxidant treatment may be an effective step to lower the inflammatory process caused by cytomegalovirus infection or in endotoxin (LPS)-activated macrophages. The therapeutic use of antioxidant compounds could, therefore, be of interest in conditions such as lung transplantation, in which oxidative stress and inflammation can contribute significantly to the loss of allograft function.}, }
@article {pmid9721071, year = {1998}, author = {Demir, S and Inal-Erden, M}, title = {Pentoxifylline and N-acetylcysteine in hepatic ischemia/reperfusion injury.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {275}, number = {2}, pages = {127-135}, doi = {10.1016/s0009-8981(98)00078-3}, pmid = {9721071}, issn = {0009-8981}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Catalase/metabolism ; Female ; Free Radical Scavengers/*pharmacology ; Free Radicals/metabolism ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Glutathione Reductase/metabolism ; Ischemia/*metabolism ; Lipid Peroxidation/drug effects ; Liver/blood supply/*drug effects/enzymology/metabolism ; Malondialdehyde/metabolism ; Pentoxifylline/*pharmacology ; Rats ; Rats, Wistar ; Reperfusion Injury/*metabolism ; Superoxide Dismutase/metabolism ; Vasodilator Agents/*pharmacology ; }, abstract = {This study was designed to clarify the effects of pentoxifylline (PTX) and N-acetylcysteine (NAC) on hepatic reperfusion injury in rats. Rats were pretreated with NAC, or PTX, or combination of the drugs. In each rat, liver was isolated after twenty minutes reperfusion following thirty minutes ischemia. Plasma alanine amino transferase (ALT) activity, liver tissue glutathione (GSH) and malondialdehyde (MDA) levels, glutathione peroxidase (GPx), glutathione reductase (GSSGR), superoxide dismutase (SOD) and catalase (CAT) activities were determined. Plasma ALT activity was higher in ischemia/reperfusion groups than in control. It was decreased in the groups given NAC. Administration of NAC maintained tissue GSH levels, whereas the levels were decreased in both the ischemia/reperfusion groups treated (P < 0.05) and untreated with PTX (P < 0.01). Increases in liver MDA concentration in ischemia/reperfusion (P < 0.01) and PTX-treated groups (P < 0.05) were mitigated by administration of NAC. GPx and CAT activities were increased in the ischemia/reperfusion (P < 0.01, P < 0.05) and PTX-treated groups (P < 0.05, P < 0.001). GSSGR activities were increased in the NAC (P < 0.001) and NAC-PTX-treated groups (P < 0.01). SOD activities were higher in the ischemia/reperfusion (P < 0.01) and the PTX-treated (P < 0.01) and the NAC-PTX-treated groups (P < 0.01). In conclusion, short-term liver ischemia/reperfusion diminished GSH, increased MDA and induced some antioxidant enzymes. While we could not find any useful effects with PTX as we expected, our findings indicate that NAC might be useful to prevent tissue damage in hepatic ischemia/reperfusion injury.}, }
@article {pmid9720938, year = {1998}, author = {Deng, X and Sun, Z and Lasson, A and Wang, X and Andersson, R}, title = {Alterations in the functions of the reticuloendothelial and protease-antiprotease systems after intraperitoneal injection of zymosan in rats.}, journal = {The European journal of surgery = Acta chirurgica}, volume = {164}, number = {8}, pages = {605-615}, doi = {10.1080/110241598750005714}, pmid = {9720938}, issn = {1102-4151}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Dimethyl Sulfoxide/pharmacology ; Endopeptidases/blood/*drug effects ; Escherichia coli/drug effects/pathogenicity ; Injections, Intraperitoneal ; Iodine Radioisotopes ; Male ; Mononuclear Phagocyte System/*drug effects/physiology ; *Protease Inhibitors/blood ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Splanchnic Circulation/drug effects ; Time Factors ; Zymosan/*administration &amp; dosage ; }, abstract = {OBJECTIVE: To evaluate alterations in the function of the reticuloendothelial system (RES) and potential protective effects of pretreatment with the antioxidants: N-acetyl-L-cysteine (NAC) or dimethyl sulphoxide (DMSO), after intraperitoneal injection of zymosan (0.50 mg/g body weight) in rats.<br><br>DESIGN: Experimental study.<br><br>SETTING: University hospital, Sweden.<br><br>ANIMALS: 81 male Sprague-Dawley rats.<br><br>INTERVENTION: Intraperitoneal injection of either 4 ml saline or zymosan suspension (0.50 mg/g body weight). One hour before the intraperitoneal injection, 1 ml of saline, or a solution of NAC (150 mg/kg) or DMSO (80 mg/kg) were given intravenously.<br><br>MAIN OUTCOME MEASURES: Systemic arterial pressure, packed cell volume, concentrations of plasma proteins and plasma protease inhibitors, uptake of 125I-labelled Escherichia coli in organs, blood clearance and body uptake rate of radiolabelled E. coli, and blood flow in organs at 3, 6, and 12 hours after injection.<br><br>RESULTS: The uptake of radiolabelled E. coli in the liver, spleen and lungs decreased significantly from 3 hours onwards after zymosan challenge (p <(0.05). Blood clearance and body uptake rate also decreased significantly from 3 hours onwards (p < 0.05), but this did not correlate with the reduction in organ blood flow. Significant falls in plasma concentrations of prekallikrein (p < 0.01) and protease inhibitors (p <0.05) suggested possible contact-phase activation and activation of the kallikrein-kinin and fibrinolytic system. Pretreatment with NAC, and to a less extent DMSO, significantly prevented these alterations in RES function.<br><br>CONCLUSION: Zymosan induced an impairment in RES function that was not initially associated with a reduction in blood flow. Plasma proteolytic activity seems to be involved in the impaired RES function. Pretreatment with NAC or DMSO effectively improved RES function.}, }
@article {pmid9715438, year = {1998}, author = {Zhao, C and Shichi, H}, title = {Prevention of acetaminophen-induced cataract by a combination of diallyl disulfide and N-acetylcysteine.}, journal = {Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics}, volume = {14}, number = {4}, pages = {345-355}, doi = {10.1089/jop.1998.14.345}, pmid = {9715438}, issn = {1080-7683}, support = {EY04694/EY/NEI NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*pharmacology ; Alanine Transaminase/metabolism ; Allyl Compounds/*pharmacology ; Animals ; Antimutagenic Agents/*pharmacology ; Benzoquinones/metabolism ; Cataract/chemically induced/pathology/*prevention &amp; control ; Ciliary Body/drug effects/pathology ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP2B1/metabolism ; Disulfides/*pharmacology ; Drug Therapy, Combination ; Garlic ; Glutathione/metabolism ; Imines/metabolism ; Lens, Crystalline/*drug effects/pathology ; Liver/drug effects/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Microsomes, Liver/drug effects/enzymology ; Plants, Medicinal ; }, abstract = {Injection of acetaminophen (APAP) (350 mg/kg body weight) into C57BL/6 mice in which cytochrome P450 (CYP) 1A1/1A2 had been induced produced acute cataract and other ocular tissue damage. Treatment of APAP-injected mice with one of the major organosulfides in garlic oil, diallyl disulfide (DADS) (200 mg/kg body weight), prevented cataract development and prolonged survival time. N-acetyl L-cysteine (NAC) (500 mg/kg body weight), a prodrug that stimulates glutathione synthesis, also prolonged survival time but was effective only weakly to prevent cataract formation. A combination of DADS and NAC completely prevented cataractogenesis, and all of the treated animals survived APAP toxicity. Neither DADS nor NAC inhibited CYP 1A1/1A2 induction as determined by their effect on the induction of hepatic microsomal ethoxyresorufin O-dealkylase (ERD) activity. However, in the in vitro enzyme assay, DADS, but not NAC, was a potent inhibitor of ERD activity (IC50 = 3.5 mM). Treatment with DADS or NAC slowed but did not stop the decrease of hepatic glutathione (GSH) content. At 4 hours after APAP injection, hepatic GSH began to increase only when DADS and NAC were administered together. These results suggest that the protective effect of DADS is due to its inhibition of biotransformation of APAP to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) by CYP 1A1/1A2 enzymes and that NAC provides protection by increasing cellular cysteine level and GSH synthesis, thus facilitating detoxification of NAPQI by glutathione conjugation. Assay of plasma glutamate-pyruvate transaminase activity, an indicator of liver necrosis, showed that treatment with DADS and NAC together effectively protected the liver. Therefore, the decrease of GSH as much as 30% of normal concentration, by itself, is not responsible for liver damage. The primary cause of hepatic necrosis is rapid accumulation of NAPQI.}, }
@article {pmid9715255, year = {1998}, author = {Lange, RW and Germolec, DR and Foley, JF and Luster, MI}, title = {Antioxidants attenuate anthralin-induced skin inflammation in BALB/c mice: role of specific proinflammatory cytokines.}, journal = {Journal of leukocyte biology}, volume = {64}, number = {2}, pages = {170-176}, doi = {10.1002/jlb.64.2.170}, pmid = {9715255}, issn = {0741-5400}, mesh = {Acetylcysteine/pharmacology ; Administration, Topical ; Animals ; *Anthralin ; *Anti-Inflammatory Agents ; Antioxidants/*pharmacology ; Chemokine CXCL2 ; Chemotactic Factors/genetics/immunology ; Cytokines/*immunology ; Dermatitis/*immunology ; Ear ; Female ; Free Radical Scavengers/pharmacology ; Free Radicals/immunology ; Gene Expression/immunology ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics/immunology ; Interleukin-6/genetics/immunology ; Irritants ; Mice ; Mice, Inbred BALB C ; Monokines/genetics/immunology ; RNA, Messenger/analysis ; Skin/*immunology ; Superoxide Dismutase/pharmacology ; Tumor Necrosis Factor-alpha/genetics/immunology ; Vitamin E/pharmacology ; }, abstract = {Anthralin is the most common therapeutic agent among a small number of pro-oxidant, 9-anthrones effective in the topical treatment of psoriasis. However, the usefulness of this drug is diminished by toxic side effects, including skin irritation and inflammation. The activities of anthralin are believed to be mediated by the generation of reactive oxygen intermediates and anthrone radicals produced in the skin. In this study, the dermal inflammatory response to anthralin was determined using a mouse ear swelling test. Maximum ear swelling induced by anthralin coincided with the elevation of cytokine mRNA expression in the skin, including interleukin-6, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein-2, and tumor necrosis factor alpha at 24 h post challenge. The role of free radical generation in ear swelling and cytokine modulation were examined by systemic administration of cell permeable and impermeable antioxidants before anthralin challenge. Superoxide dismutase and alpha-tocopherol acetate, but not the glutathione precursor N-acetyl cysteine, were effective inhibitors of anthralin-induced ear swelling and cytokine elevation. Maximum inflammatory cell infiltration occurred 72-96 h post anthralin challenge and was also reduced by antioxidants. These data suggest that oxidative stress, generated at the site of anthralin treatment, alters the expression of dermal chemokines and other cytokines resulting in the recruitment of inflammatory cells. Systemic antioxidant administration may provide opportunities for therapeutic intervention against anthralin-associated toxicities.}, }
@article {pmid9714697, year = {1998}, author = {Tsuyuki, S and Yamauchi, A and Nakamura, H and Kinoshita, K and Gomi, T and Tanaka, K and Inamoto, T and Yamaoka, Y}, title = {Possible availability of N-acetylcysteine as an adjunct to cytokine therapy for hepatocellular carcinoma.}, journal = {Clinical immunology and immunopathology}, volume = {88}, number = {2}, pages = {192-198}, doi = {10.1006/clin.1998.4574}, pmid = {9714697}, issn = {0090-1229}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Adult ; Aged ; Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology ; Cytokines/*therapeutic use ; Cytotoxicity, Immunologic/drug effects ; Female ; Glutathione/biosynthesis ; Humans ; Interleukin-2/pharmacology ; Leukocytes, Mononuclear/drug effects/immunology/metabolism ; Liver/cytology/drug effects/metabolism ; Liver Neoplasms/*drug therapy/metabolism/pathology ; Male ; Middle Aged ; Recombinant Proteins/pharmacology ; }, abstract = {To examine the possibility of immunotherapy for activating liver-associated mononuclear cells (liver MNC) in hepatocellular carcinoma (HCC), we evaluated the cytotoxicity of liver MNC and peripheral blood mononuclear cells (PBMNC) in HCC patients and examined how they can be activated by cytokines and how this activation is modulated by reduction/oxidation. Cytotoxicity of liver MNC but not PBMNC in HCC patients was significantly decreased compared with that of controls, despite no alteration in the subpopulation of liver MNC between the two groups. We next measured intracellular glutathione (GSH), which is required for the enhancement of the cytotoxicity by interleukin-2 (IL-2). Intracellular GSH levels of liver MNC in HCC were significantly lower than that of controls. In vitro administration of N-acetylcysteine (NAC) not only restored intracellular GSH levels but also enhanced the IL-2-stimulated cytotoxicity of liver MNC in HCC patients. This suggests that intracellular GSH of liver MNC in HCC may participate in the modulation of cytotoxicity of liver MNC in vitro and that NAC may be effective as an adjunct to immunotherapy for HCC.}, }
@article {pmid9713511, year = {1998}, author = {D'Alessandro, N and Flugy, A and Tolomeo, M and Dusonchet, L}, title = {The apoptotic signaling of TNF-alpha in multidrug resistant Friend leukemia cells.}, journal = {Anticancer research}, volume = {18}, number = {4C}, pages = {3065-3072}, pmid = {9713511}, issn = {0250-7005}, mesh = {Animals ; Antibiotics, Antineoplastic/pharmacology ; Apoptosis/*drug effects/physiology ; Doxorubicin/pharmacology ; *Drug Resistance, Multiple ; *Friend murine leukemia virus ; Humans ; Leukemia, Erythroblastic, Acute/*drug therapy/metabolism/pathology ; Mice ; Signal Transduction/*drug effects/physiology ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Drug resistance, especially in its multiple forms (multidrug resistance, MDR), is a major and difficult problem to resolve in cancer therapy. Certain cytokines might be capable of bypassing this process and here we report on the in vitro effects of Tumor Necrosis Factor alpha, (TNF) on a MDR variant (FLC/DOX) of Friend leukemia. Drug resistance of FLC/DOX is associated with at least two mechanisms, i.e. overexpression of P-glycoprotein and increase in glutathione-related detoxifying activities. Nevertheless, TNF exerts more cytotoxicity in FLC/DOX than in its parental, drug-sensitive, counterpart and this effect is related to the induction of apoptosis. In contrast, Doxorubicin (DOX) never induces apoptosis in FLC/DOX, even when applied at high, fully cytotoxic, concentrations. We have tried to elucidate TNF signaling in FLC/DOX. The results have indicated that in this cell line TNF-triggered apoptosis exhibits some distinct features. It occurs mostly through type I (p55) TNF receptors, probably involves a calphostin-C sensitive protein kinase C activity and requires synthesis of proteins (it is inhibited by actinomycin D or cycloheximide) and of inducible nitric oxide (NO) synthase (it is inhibited by NG-methyl-L-arginine or aminoguanidine). Further, it is not influenced by agents which increase or decrease cell sulfhydryl groups, such as N-acetylcysteine or buthionine sulfoximine, respectively. These steps appeared to be either not or dissimilarly involved in the resistance to DOX of the same cells. In particular, DOX activity was stimulated by calphostin C and buthionine sulfoximine, and reduced by N-acetyl-cysteine. These findings illustrate that TNF may activate fresh cytotoxic pathways in tumor cells which are multidrug resistant, also owing to multifactorial causes.}, }
@article {pmid9707512, year = {1998}, author = {Dong, W and Simeonova, PP and Gallucci, R and Matheson, J and Flood, L and Wang, S and Hubbs, A and Luster, MI}, title = {Toxic metals stimulate inflammatory cytokines in hepatocytes through oxidative stress mechanisms.}, journal = {Toxicology and applied pharmacology}, volume = {151}, number = {2}, pages = {359-366}, doi = {10.1006/taap.1998.8481}, pmid = {9707512}, issn = {0041-008X}, mesh = {Animals ; Antioxidants/pharmacology ; Cadmium Chloride/*toxicity ; Cells, Cultured ; Chemotaxis/drug effects ; Cytokines/*biosynthesis/metabolism ; Humans ; Inflammation Mediators/*metabolism ; L Cells ; Liver/cytology/drug effects ; Mice ; Mice, Inbred C57BL ; Neutrophils/drug effects ; *Oxidative Stress ; Rats ; Rats, Inbred F344 ; Reactive Oxygen Species ; Vanadium Compounds/*toxicity ; }, abstract = {Hepatocytes, as well as nonparenchymal cells, secrete proinflammatory cytokines and chemokines that are involved in the pathology of many liver diseases. In particular, tumor necrosis factor-alpha (TNFalpha), as well as members of the CXC family of chemokines, including interleukin (IL)-8 in humans and macrophage inflammatory protein (MIP)-2 in rodents, have been implicated in both damage and repair processes associated with various hepatotoxins. In the liver, cytokine secretion is usually associated with nonparenchymal cells, particularly Kupffer cells. In the present studies, cytokine gene expression and secretion were investigated in hepatocytes treated with cadmium chloride (CdCl2) or vanadium pentoxide (V2O5). Using human Hep G2 cells and freshly isolated rodent hepatocytes, it was demonstrated that metals increase gene expression and secretion of CXC chemokines and TNFalpha. IL-8 and MIP-2 secretion induced either by the metals or H2O2 were inhibited by antioxidants such as tetramethyl-thiourea and N-acetyl-cysteine. In vitro neutralization experiments with TNFalpha and in vivo studies with TNFalpha receptor knockout mice indicated that the metals directly stimulate CXC chemokine secretion without the need for TNFalpha. Taken together these studies indicate that, in addition to other inflammatory mediators and acute phase proteins, cytokines and chemokines are produced by hepatocytes, which may participate in hepatotoxic responses. The events responsible for their expression involve cellular redox changes.}, }
@article {pmid9699515, year = {1998}, author = {Keogh, B and Allen, RG and Tresini, M and Furth, JJ and Cristofalo, VJ}, title = {Antioxidants stimulate transcriptional activation of the c-fos gene by multiple pathways in human fetal lung fibroblasts (WI-38).}, journal = {Journal of cellular physiology}, volume = {176}, number = {3}, pages = {624-633}, doi = {10.1002/(SICI)1097-4652(199809)176:3&lt;624::AID-JCP19&gt;3.0.CO;2-Z}, pmid = {9699515}, issn = {0021-9541}, support = {AG00131/AG/NIA NIH HHS/United States ; AG00378/AG/NIA NIH HHS/United States ; AG00523/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Blotting, Northern ; Carcinogens/pharmacology ; Chromans/pharmacology ; Enzyme Inhibitors/pharmacology ; Fetus/enzymology ; Fibroblasts/cytology/drug effects ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/drug effects ; Glutathione/metabolism ; Humans ; Lung/*cytology ; Masoprocol/pharmacology ; Naphthalenes/pharmacology ; Protein Kinase C/metabolism ; Proto-Oncogene Proteins c-fos/*genetics ; RNA, Messenger/analysis ; Signal Transduction/physiology ; Tetradecanoylphorbol Acetate/pharmacology ; Transcriptional Activation/*drug effects ; }, abstract = {We have examined the effects of three structurally distinct antioxidants (N-acetylcysteine [NAC], Trolox C [a water-soluble vitamin E derivative], and nordihydroguaiaretic acid [NGA]) on the expression of the c-fos gene over a 2-hour period. Determination of cellular glutathione concentration (the primary determinant of the cellular redox state) over the same time-course verifies that all the compounds studied cause an increase in cellular reduction potential. The level of c-fos messenger RNA increased rapidly in response to micromolar concentrations of these compounds, reaching a peak in 30-60 minutes. Induction of c-fos expression by these antioxidants is at least partly due to an increase in transcription, as determined by nuclear run-on assay. Down regulation of protein kinase C (PKC) by pretreatment for 24 hours with 500 nm PMA prevents induction by subsequent stimulation with either PMA or NGA. NAC induction of c-fos is unaffected by PMA pretreatment, while Trolox C superinduced c-fos following PMA pretreatment. None of these treatments stimulated translocation of PKC-alpha from the cytosol to the membrane. These results suggest that increasing the intracellular reducing potential induces c-fos expression through multiple pathways.}, }
@article {pmid9699154, year = {1998}, author = {Chong, YH and Seoh, JY and Park, HK}, title = {Increased activity of matrix metalloproteinase-2 in human glial and neuronal cell lines treated with HIV-1 gp41 peptides.}, journal = {Journal of molecular neuroscience : MN}, volume = {10}, number = {2}, pages = {129-141}, pmid = {9699154}, issn = {0895-8696}, mesh = {Acetylcysteine/pharmacology ; Amyloid beta-Protein Precursor/pharmacology ; Animals ; Anti-Inflammatory Agents/pharmacology ; Antiviral Agents/pharmacology ; Cell Line ; Culture Media, Conditioned ; Dexamethasone/pharmacology ; Gelatinases/*metabolism ; Glutathione/pharmacology ; HIV Envelope Protein gp41/*pharmacology ; *HIV-1 ; Humans ; Indomethacin/pharmacology ; Matrix Metalloproteinase 2 ; Metalloendopeptidases/*metabolism ; Mice ; Molecular Weight ; Neuroglia/drug effects/*enzymology ; Neurons/drug effects/*enzymology ; Recombinant Proteins/pharmacology ; Tumor Cells, Cultured ; }, abstract = {Part of the neurodegenerative cascade in AIDS dementia may involve overexpression of matrix metalloproteinases (MMPs). Here, we examined the possible effect of HIV-1 gp41, which has been shown as a key determinant associated with pathogenesis of AIDS dementia, on the activity of MMPs using human neuronal and glial cell lines. Zymographic analysis revealed that treatment with the gp41 peptide (aa 583-599) for 24 h markedly elevated the activity of MMP with Mr 66 kDa in the cultured media of glioblastoma cell line T98G in a concentration-dependent manner as well as of neuroblastoma cell line SK-N-SH despite of lower magnitude of the activity. In contrast, the immediately adjacent gp41 peptide (aa 598-613) as well as the reverse peptide (aa 598-583) had a little effect. Recombinant gp41 protein containing extracellular domain also elicited a similar effect, although with a lesser extent. This 66 kDa MMP was confirmed as gelatinase A (MMP-2) based on the results of its activity dependent on Ca2+ and inhibited in the presence of 1,10-phenanthroline or EDTA, as well as its specific immunoreactivity on the Western blot. N-acetyl cysteine (NAC) downregulated this gp41 peptide-induced MMP-2 activity in T98G. The soluble form of amyloid precursor protein (sAPP), which is synthesized in the Escherichia coli system, also inhibited the MMP-2 activity in vitro. Taken together, these results implicate that high production of HIV-1 gp41 or its metabolites containing aa 583-599 within central nervous system (CNS) could result in the increased activity of MMP-2 and that the extracellular deficiency of reducing agent or decreased level of sAPP within CNS could exacerbate this gp41-induced MMP-2 activity.}, }
@article {pmid9699004, year = {1998}, author = {Obrador, E and Navarro, J and Mompo, J and Asensi, M and Pellicer, JA and Estrela, JM}, title = {Regulation of tumour cell sensitivity to TNF-induced oxidative stress and cytotoxicity: role of glutathione.}, journal = {BioFactors (Oxford, England)}, volume = {8}, number = {1-2}, pages = {23-26}, doi = {10.1002/biof.5520080105}, pmid = {9699004}, issn = {0951-6433}, mesh = {Animals ; Carcinoma, Ehrlich Tumor/*pathology/physiopathology ; Cell Survival/drug effects/physiology ; Glutathione/*metabolism ; Glutathione Disulfide/metabolism ; Humans ; Mice ; Oxidative Stress/drug effects/*physiology ; Recombinant Proteins/toxicity ; Superoxides/metabolism ; Tumor Necrosis Factor-alpha/*toxicity ; }, abstract = {Glutathione (GSH) and the rate of cellular proliferation determine tumour cell sensitivity to tumour necrosis factor (TNF). Buthionine sulphoximine (BSO), a selective inhibitor of GSH synthesis, inhibits tumour growth and increases recombinant human TNF (rhTNF)-alpha cytoxicity in vitro. Administration of sublethal doses of rhTNF-alpha to Ehrlich ascites-tumour (EAT)-bearing mice induces oxidative stress (as measured by increases in intracellular peroxide levels, O2.- generation and mitochondrial GSSG). ATP-induced selective GSH depletion, when combined with rhTNF-alpha administration, affords a 61% inhibition of tumour growth and results in a significant extent of host survival. Administration of N-acetylcysteine (NAC) or GSH ester abolishes the rhTNF-alpha and ATP-induced effects on tumour growth by maintaining high GSH levels in the cancer cells. TNF-induced mitochondria GSH depletion appears critical in the cascade of events that lead to cell death.}, }
@article {pmid9697667, year = {1998}, author = {Salahudeen, A and Poovala, V and Parry, W and Pande, R and Kanji, V and Ansari, N and Morrow, J and Roberts, J}, title = {Cisplatin induces N-acetyl cysteine suppressible F2-isoprostane production and injury in renal tubular epithelial cells.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {9}, number = {8}, pages = {1448-1455}, doi = {10.1681/ASN.V981448}, pmid = {9697667}, issn = {1046-6673}, support = {DK 48837/DK/NIDDK NIH HHS/United States ; GM 42056/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Cisplatin/*toxicity ; Dinoprost/*biosynthesis ; Epithelial Cells/drug effects/metabolism ; Free Radicals/metabolism ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/metabolism ; Kidney Tubules, Proximal/*drug effects/injuries/metabolism ; LLC-PK1 Cells ; Lipid Metabolism ; Models, Biological ; Swine ; }, abstract = {In the low intracellular chloride milieu, chloride ions of cisplatin may exchange for cellular SH moieties resulting in glutathione depletion, H2O2 accumulation, and lipid peroxidation. Cisplatin-induced lipid peroxidation, in addition to causing direct cellular injury, may further contribute to cisplatin-induced renal dysfunction by generating vasoconstrictive E2- and F2-isoprostanes. The aim of this study was to determine whether cisplatin-induced renal epithelial (LLC-PK1 and primary human proximal tubular) cell injury is associated with increased production of isoprostanes, and whether this can be suppressed with a thiol donor, N-acetyl cysteine. It was confirmed that incubation of renal epithelial cells with cisplatin resulted in N-acetyl cysteine-inhibitable glutathione depletion, H2O2 accumulation, lipid degradation, and lactate dehydrogenase release. In additional experiments, incubation of cells with cisplatin for 48 h was accompanied by a dose-related increase in total (free plus esterified) F2-isoprostanes. An increase in F2-isoprostanes was discernible at 16.5 microM cisplatin and doubled at 66.0 microM. N-Acetyl cysteine at 50 microM concentration effectively suppressed 66.0 microM cisplatin-induced increase in isoprostanes. Similar findings were also obtained in human cells. Thus, cisplatin-induced tubular cell injury is accompanied by increased isoprostane production through a mechanism involving thiol depletion. On the basis of this new finding, it is hypothesized that these arachidonic acid peroxidation products may be partially responsible for the cisplatin-induced renal vasoconstriction demonstrable in the in vivo models.}, }
@article {pmid9692114, year = {1998}, author = {Matsumoto, K and Hashimoto, S and Gon, Y and Nakayama, T and Takizawa, H and Horie, T}, title = {N-acetylcysteine inhibits IL-1 alpha-induced IL-8 secretion by bronchial epithelial cells.}, journal = {Respiratory medicine}, volume = {92}, number = {3}, pages = {512-515}, doi = {10.1016/s0954-6111(98)90300-6}, pmid = {9692114}, issn = {0954-6111}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Bronchi/cytology/*drug effects/metabolism ; Butylated Hydroxyanisole/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Epithelial Cells/*drug effects/metabolism ; Free Radical Scavengers/*pharmacology ; Humans ; Interleukin-1/antagonists &amp; inhibitors/*pharmacology ; Interleukin-8/*metabolism ; Pyrrolidines/pharmacology ; Thiocarbamates/pharmacology ; }, abstract = {The protective effects of N-acetylcysteine (NAC) have been documented in experimental and clinical acute lung injury. However, the effect of NAC on the secretion of interleukin-8-(IL-8), which is an important mediator of the pathogenesis of acute lung injury through the recruitment of neutrophils, has not been determined. In the present study, therefore, we examined the effect of NAC on IL-8 secretion by IL-1 alpha-stimulated bronchial epithelial cells. NAC inhibited IL-8 secretion by bronchial epithelial cells in a dose-dependent manner. In addition, the structurally unrelated antioxidants, butylated hydroxyanisole (BHA) and pyrrolidine dithiocarbamate (PDTC) also effectively inhibited secretion. These results indicated that an antioxidant-sensitive mechanism might be involved in inhibition of IL-8 secretion by IL-1 alpha-stimulated bronchial epithelial cells. The protective effects of NAC on acute lung injury have been suggested to be due to scavenging reactive oxygen intermediates (ROIs) and stimulation of glutathione synthesis. In addition to this, our results may provide an alternative explanation for the efficacy of NAC on acute lung injury.}, }
@article {pmid9690915, year = {1998}, author = {Rattan, AK and Arad, Y}, title = {Temporal and kinetic determinants of the inhibition of LDL oxidation by N-acetylcysteine (NAC).}, journal = {Atherosclerosis}, volume = {138}, number = {2}, pages = {319-327}, doi = {10.1016/s0021-9150(98)00041-0}, pmid = {9690915}, issn = {0021-9150}, mesh = {Acetylcysteine/metabolism/*pharmacology ; Free Radical Scavengers/metabolism/*pharmacology ; Humans ; Lipid Peroxidation/*drug effects ; Lipoproteins, LDL/*metabolism ; Oxidation-Reduction ; }, abstract = {We investigated the ability of NAC to inhibit in vitro LDL oxidation, and the effects of the timing of NAC addition, repeated additions of NAC, and the presence of preoxidized LDL, on the oxidation reaction. NAC inhibited in vitro LDL oxidation induced by copper sulfate, 2,2'-azobis(2-amidinopropane) dihydrochloride, and UV light, and protected LDL against depletion of antioxidant vitamins. Glutathione was similarly effective against copper-mediated LDL oxidation. NAC's effectiveness was inversely related to the timing of its addition. Sequential NAC additions prolonged the lag phase more effectively than initial addition of the same total dose. NAC reduced CD formation during the oxidation of native LDL by oxidized LDL. NAC's effectiveness as an inhibitor of in vitro LDL oxidation is dependent on the temporal sequence of the oxidation reaction, sequential additions, and the presence of previously oxidized LDL.}, }
@article {pmid9685387, year = {1998}, author = {Singh, I and Pahan, K and Khan, M and Singh, AK}, title = {Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases.}, journal = {The Journal of biological chemistry}, volume = {273}, number = {32}, pages = {20354-20362}, doi = {10.1074/jbc.273.32.20354}, pmid = {9685387}, issn = {0021-9258}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; NS-37766/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adrenoleukodystrophy/physiopathology ; Amitrole/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/physiology ; Brain/drug effects/*metabolism ; Cells, Cultured ; Ceramides/*biosynthesis ; Cytokines/*pharmacology ; DNA Fragmentation/drug effects ; Diamide/metabolism ; Glutathione/physiology ; Glutathione Disulfide/metabolism ; Hydrogen Peroxide/pharmacology ; Inflammation/physiopathology ; Interleukin-1/pharmacology ; Multiple Sclerosis/physiopathology ; Oxidation-Reduction ; Pyrrolidines/pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Sphingomyelins/metabolism ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The present study underlines the importance of reactive oxygen species in cytokine-mediated degradation of sphingomyelin (SM) to ceramide. Treatment of rat primary astrocytes with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta led to marked alteration in cellular redox (decrease in intracellular GSH) and rapid degradation of SM to ceramide. Interestingly, pretreatment of astrocytes with N-acetylcysteine (NAC), an antioxidant and efficient thiol source for glutathione, prevented cytokine-induced decrease in GSH and degradation of sphingomyelin to ceramide, whereas treatment of astrocytes with diamide, a thiol-depleting agent, alone caused degradation of SM to ceramide. Moreover, potent activation of SM hydrolysis and ceramide generation were observed by direct addition of an oxidant like hydrogen peroxide or a prooxidant like aminotriazole. Similar to NAC, pyrrolidinedithiocarbamate, another antioxidant, was also found to be a potent inhibitor of cytokine-induced degradation of SM to ceramide indicating that cytokine-induced hydrolysis of sphingomyelin is redox-sensitive. Besides astrocytes, NAC also blocked cytokine-mediated ceramide production in rat primary oligodendrocytes, microglia, and C6 glial cells. Inhibition of TNF-alpha- and diamide-mediated depletion of GSH, elevation of ceramide level, and DNA fragmentation (apoptosis) in primary oligodendrocytes by NAC, and observed depletion of GSH, elevation of ceramide level, and apoptosis in banked human brains from patients with neuroinflammatory diseases (e.g. X-adrenoleukodystrophy and multiple sclerosis) suggest that the intracellular level of GSH may play a critical role in the regulation of cytokine-induced generation of ceramide leading to apoptosis of brain cells in these diseases.}, }
@article {pmid9679454, year = {1998}, author = {Steenvoorden, DP and Beijersburgen van Henegouwen, GM}, title = {Glutathione synthesis is not involved in protection by N-acetylcysteine against UVB-induced systemic immunosuppression in mice.}, journal = {Photochemistry and photobiology}, volume = {68}, number = {1}, pages = {97-100}, pmid = {9679454}, issn = {0031-8655}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Buthionine Sulfoximine/pharmacology ; Glutathione/*biosynthesis ; Immune Tolerance/*drug effects/physiology/*radiation effects ; Male ; Mice ; Mice, Inbred BALB C ; Photobiology ; Radiation-Protective Agents/pharmacology ; Skin/drug effects/metabolism/radiation effects ; Ultraviolet Rays/*adverse effects ; }, abstract = {Irradiation of the skin with ultraviolet-B (UVB) radiation causes a local and systemic suppression of T-cell-mediated immune responses. Recently, N-acetylcysteine (NAC) was found to protect against UVB-induced immunosuppression and several other types of UV damage. The protective effects appeared to be based on the ability of NAC to increase glutathione (GSH) levels by promoting GSH synthesis. In this study, it was investigated whether topical application of NAC was still effective against UVB-induced suppression of contact hypersensitivity if GSH synthesis was blocked. Mice were pretreated with buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, which succeeded in blocking the increase in epidermal GSH after topical application of NAC. Whereas the non-BSO-treated animals showed an increase to around 155% of the control GSH level for all NAC doses tested, only a slight (nonsignificant) increase in epidermal GSH was observed in the BSO-treated animals. Surprisingly, the protective efficacy of NAC against UVB-induced immunosuppression was not affected by the BSO pretreatment. No significant difference between the protective efficacy of NAC in the two groups was observed. Apparently, the antioxidant effect of NAC itself was sufficient to provide protection against UVB-immunosuppression, independent of GSH synthesis.}, }
@article {pmid9676716, year = {1998}, author = {Nishikawa, Y and Kanki, H and Ogawa, S}, title = {Differential effects of N-acetylcysteine on nitroglycerin- and nicorandil-induced vasodilation in human coronary circulation.}, journal = {Journal of cardiovascular pharmacology}, volume = {32}, number = {1}, pages = {21-28}, doi = {10.1097/00005344-199807000-00004}, pmid = {9676716}, issn = {0160-2446}, mesh = {Acetylcysteine/*pharmacology ; Coronary Circulation/*drug effects ; Coronary Disease/pathology ; Coronary Vessels/drug effects/pathology ; Female ; Free Radical Scavengers/*pharmacology ; Hemodynamics/drug effects ; Humans ; Male ; Middle Aged ; Niacinamide/*analogs &amp; derivatives/pharmacology ; Nicorandil ; Nitroglycerin/*pharmacology ; Vasodilation/*drug effects ; Vasodilator Agents/*pharmacology ; }, abstract = {We investigated the role of the availability of sulfhydryl groups during vasodilation of the human coronary circulation induced by nitroglycerin and nicorandil. In patients with normal coronary arteries (n = 29) or with coronary artery disease (CAD; n = 26), coronary blood flow (CBF) and epicardial coronary artery diameter after intracoronary administration of 50 microg nitroglycerin or 0.5 mg nicorandil were measured, before and after the intravenous infusion of saline or 100 mg/kg of N-acetylcysteine (NAC). In normal subjects, saline infusion did not alter the nitroglycerin- and nicorandil-induced vasodilation in large epicardial coronary artery. In contrast, NAC potentiated both nitroglycerin- and nicorandil-induced vasodilation. In patients with CAD, nitroglycerin and nicorandil induced less dilation than in normal subjects. NAC augmented the nitroglycerin- and nicorandil-induced vasodilation in the small epicardial coronary artery, but not in the large epicardial segments. In both groups, NAC potentiated the increase in CBF in response to nitroglycerin. However, NAC had no effects on the CBF response to nicorandil. Sulfhydryl availability is at least one determinant of the in vivo responsiveness to nitroglycerin of conductance and resistance vessels in normal human coronary circulation. In patients with CAD, external augmentation of sulfhydryl availability did not affect the depressed response to nitroglycerin in the large epicardial coronary artery. Although nicorandil acts as an NO donor, similar to nitroglycerin, in dilating the epicardial coronary artery, other effects, such as the opening of K(ATP) channel, play a more important role in the nicorandil-induced vasodilation of resistance vessels.}, }
@article {pmid9675657, year = {1998}, author = {Cimino, L and Belisario, MA and Intrieri, M and D'Ascoli, B and Sacchetti, L and Salvatore, F and Budillon, G}, title = {Effect of N-acetyl-cysteine on lymphomonocyte glutathione and response to interferon treatment in C-virus chronic hepatitis.}, journal = {Italian journal of gastroenterology and hepatology}, volume = {30}, number = {2}, pages = {189-193}, pmid = {9675657}, issn = {1125-8055}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Analysis of Variance ; Antiviral Agents/*administration &amp; dosage ; Chromatography, Liquid ; Drug Therapy, Combination ; Female ; Glutathione/blood/*drug effects ; Hepatitis C, Chronic/blood/*drug therapy ; Humans ; Interferon-beta/*administration &amp; dosage ; Lymphocytes/chemistry/drug effects ; Male ; Middle Aged ; Reference Values ; }, abstract = {BACKGROUND/AIM: Much controversy exists concerning effect of N-acetyl-cysteine, a precursor of glutathione, on the response to interferon treatment in patients with C-virus chronic hepatitis. The aim of this study was to evaluate the efficacy of interferon therapy with and without oral N-acetyl-cysteine. We also measured glutathione concentrations in lymphomonocytes of 25 patients with chronic C-virus hepatitis before and after interferon treatment and correlated the results with treatment response.<br><br>METHODS: Glutathione was extracted from lymphomonocytes and measured with a modified high performance liquid chromatographic method in the 25 hepatitis patients and 12 healthy controls.<br><br>RESULTS/CONCLUSIONS: 1) Hepatitis patients and controls had similar basal concentrations of lymphomonocytic glutathione; 2) neither interferon nor N-acetyl-cysteine significantly affected glutathione concentrations in patients; and 3) N-acetyl-cysteine did not affect response to interferon.}, }
@article {pmid9671543, year = {1998}, author = {Uttamsingh, V and Keller, DA and Anders, MW}, title = {Acylase I-catalyzed deacetylation of N-acetyl-L-cysteine and S-alkyl-N-acetyl-L-cysteines.}, journal = {Chemical research in toxicology}, volume = {11}, number = {7}, pages = {800-809}, doi = {10.1021/tx980018b}, pmid = {9671543}, issn = {0893-228X}, support = {ES03127/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemical synthesis/*chemistry ; Alkylation ; Amidohydrolases/isolation &amp; purification/*metabolism ; Animals ; Catalysis ; Dealkylation ; Kidney/enzymology ; Kinetics ; Male ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Swine ; }, abstract = {The aminoacylase that catalyzes the hydrolysis of N-acetyl-L-cysteine (NAC) was identified as acylase I after purification by column chromatography and electrophoretic analysis. Rat kidney cytosol was fractionated by ammonium sulfate precipitation, and the proteins were separated by ion-exchange column chromatography, gel-filtration column chromatography, and hydrophobic interaction column chromatography. Acylase activity with NAC and N-acetyl-L-methionine (NAM), a known substrate for acylase I, as substrates coeluted during all chromatographic steps. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the protein was purified to near homogeneity and had a subunit Mr of 43 000, which is identical with the Mr of acylase I from porcine kidney and bovine liver. n-Butylmalonic acid was a slow-binding inhibitor of acylase I and inhibited the deacetylation of NAC with a Ki of 192 +/- 27 microM. These results show that acylase I catalyzes the deacetylation of NAC. The acylase I-catalyzed deacetylation of a range of S-alkyl-N-acetyl-L-cysteines, their carbon and oxygen analogues, and the selenium analogue of NAM was also studied with porcine kidney acylase I. The specific activity of the acylase I-catalyzed deacetylation of these substrates was related to their calculated molar volumes and log P values. The S-alkyl-N-acetyl-L-cysteines with short (C0-C3) and unbranched S-alkyl substituents were good acylase I substrates, whereas the S-alkyl-N-acetyl-L-cysteines with long (>C3) and branched S-alkyl substituents were poLr acylase I substrates. The carbon and oxygen analogues of S-methyl-N-acetyl-L-cysteine and the carbon analogue of S-ethyl-N-acetyl-L-cysteine were poor acylase I substrates, whereas the selenium analogue of NAM was a good acylase I substrate.}, }
@article {pmid9670954, year = {1998}, author = {Kumar, A and Manna, SK and Dhawan, S and Aggarwal, BB}, title = {HIV-Tat protein activates c-Jun N-terminal kinase and activator protein-1.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {161}, number = {2}, pages = {776-781}, pmid = {9670954}, issn = {0022-1767}, mesh = {Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Cell Line ; Enzyme Activation/drug effects/immunology ; Free Radicals/immunology/metabolism ; Gene Products, tat/genetics/*pharmacology/physiology ; Genes, tat/immunology ; HIV-1/genetics/*immunology ; Humans ; JNK Mitogen-Activated Protein Kinases ; Jurkat Cells ; Kinetics ; Mitogen-Activated Protein Kinase Kinases ; *Mitogen-Activated Protein Kinases ; Protein Kinases/metabolism ; Transcription Factor AP-1/*metabolism ; Transfection/immunology ; tat Gene Products, Human Immunodeficiency Virus ; }, abstract = {Human immunodeficiency virus-1 tat (HIV-tat) protein, like other proinflammatory cytokines (such as TNF), activates a wide variety of cellular responses, some of which play a critical role in progression of HIV infection. Whether HIV-tat, like TNF, also activates c-Jun N-terminal kinase (JNK) and the transcription factor activator protein (AP)-1 is not known. We show that treatment of human histiocytic lymphoma U937 cells with the HIV-tat protein causes activation of JNK and AP-1 in a time- and dose-dependent manner. Transfection of a T cell line, H9 cells with the HIV-tat gene also resulted in an activation of JNK that was not further increased by treatment of cells with exogenous HIV-tat protein. Neutralizing Ab against HIV-tat inhibited the HIV-tat-mediated JNK activation. The activation of JNK by HIV-tat appears to be mediated through generation of free radical species, since pretreatment of cells with N-acetylcysteine (NAC) abolished the effect. Overall our results demonstrate that HIV-tat activates JNK and AP-1, which may contribute to the pathogenesis of AIDS.}, }
@article {pmid9668065, year = {1998}, author = {Barber, LA and Spandau, DF and Rathman, SC and Murphy, RC and Johnson, CA and Kelley, SW and Hurwitz, SA and Travers, JB}, title = {Expression of the platelet-activating factor receptor results in enhanced ultraviolet B radiation-induced apoptosis in a human epidermal cell line.}, journal = {The Journal of biological chemistry}, volume = {273}, number = {30}, pages = {18891-18897}, doi = {10.1074/jbc.273.30.18891}, pmid = {9668065}, issn = {0021-9258}, support = {HL43403/HL/NHLBI NIH HHS/United States ; K08AR1993/AR/NIAMS NIH HHS/United States ; }, mesh = {Apoptosis/drug effects/*radiation effects ; Cell Line ; Epidermis/drug effects/radiation effects ; Humans ; Platelet Activating Factor/analogs &amp; derivatives/metabolism/pharmacology ; Platelet Membrane Glycoproteins/*biosynthesis/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; *Receptors, Cell Surface ; *Receptors, G-Protein-Coupled ; Skin/drug effects/*radiation effects ; *Ultraviolet Rays ; }, abstract = {Recent studies have demonstrated that ultraviolet B radiation (UVB) damages human keratinocytes in part by inducing oxidative stress and cytokine production. Severe UVB damage to the keratinocyte can also result in apoptosis or programmed cell death. Although the lipid mediator platelet-activating factor (PAF) is synthesized in response to epidermal cell damage and epidermal cells express PAF receptors, it is not known whether PAF is involved in UVB-induced epidermal cell apoptosis. These studies examined the role of the PAF system in UVB-induced epidermal cell apoptosis using a novel model system created by retroviral-mediated transduction of the PAF receptor-negative human epidermal cell line KB with the human PAF receptor (PAF-R). Expression of the PAF-R in KB cells did not affect base-line growth or apoptosis, yet resulted in a decrease in the lag time between treatment of the cells and the induction of apoptosis following irradiation with 400 J/m2 UVB. This effect was inhibited by pretreatment with the PAF-R antagonists WEB 2086 and A-85783, confirming involvement of the PAF-R in this process. At lower doses (100-200 J/m2) of UVB, only KB cells that expressed the PAF-R became apoptotic. Treatment of PAF-R-expressing KB clones with the metabolically stable PAF-R agonist 1-hexadexyl-2-N-methylcarbamoyl-3-glycerophosphocholine (CPAF) alone did not induce apoptosis but augmented the degree of apoptosis observed if CPAF was used in combination with lower doses (200 J/m2) of UVB irradiation. Interestingly, UVB irradiation was found to stimulate PAF synthesis only in PAF-R-expressing KB cell clones. The antioxidants N-acetyl cysteine, 1,1,3,3-tetramethyl-2-thiourea, and vitamin E inhibited both UVB-induced PAF biosynthesis as well as the augmentation of UVB-induced apoptosis in PAF-R-expressing KB clones, suggesting the possibility that UVB stimulates the production of oxidized lipid species with PAF-R agonistic activity in this model system. Thus, these studies indicate that a component of UVB-induced epidermal cell cytotoxicity can be modulated by PAF-R activation through the production of PAF and PAF-like species.}, }
@article {pmid9665023, year = {1998}, author = {Thies, JC and Teklote, J and Clauer, U and Töx, U and Klar, E and Hofmann, WJ and Herfarth, C and Otto, G}, title = {The efficacy of N-acetylcysteine as a hepatoprotective agent in liver transplantation.}, journal = {Transplant international : official journal of the European Society for Organ Transplantation}, volume = {11 Suppl 1}, number = {}, pages = {S390-2}, doi = {10.1007/s001470050505}, pmid = {9665023}, issn = {0934-0874}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Humans ; *Liver Transplantation ; Middle Aged ; Pilot Projects ; Prospective Studies ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {One of the most common complications after liver transplantation is primary graft dysfunction which results from severe deterioration of the microcirculation. The data obtained from our experimental studies indicate that N-acetylcysteine (NAC) is able to reduce the severity of ischemia/reperfusion injury and improves postoperative graft function after liver transplantation in rats. The aim of this pilot study was to evaluate the efficacy of NAC as a hepatoprotective agent under clinical conditions. A group of 30 liver transplanted patients were treated with NAC, and 30 patients (control group) were treated with a 5% solution of glucose only. In the NAC group we observed a distinct reduction in ischemia/reperfusion injury and improved liver function with less elevated peak transaminases, better macrocirculation, improved liver synthesis function and a lower incidence of primary nonfunction compared with the control group. We conclude that NAC is a very promising substance for reducing graft dysfunction in clinical liver transplantation.}, }
@article {pmid9664114, year = {1998}, author = {D'Agostini, F and Bagnasco, M and Giunciuglio, D and Albini, A and De Flora, S}, title = {Inhibition by oral N-acetylcysteine of doxorubicin-induced clastogenicity and alopecia, and prevention of primary tumors and lung micrometastases in mice.}, journal = {International journal of oncology}, volume = {13}, number = {2}, pages = {217-224}, doi = {10.3892/ijo.13.2.217}, pmid = {9664114}, issn = {1019-6439}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Alopecia/chemically induced/*prevention &amp; control ; Animals ; Antibiotics, Antineoplastic/administration &amp; dosage/*antagonists &amp; inhibitors/toxicity ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use/*toxicity ; Body Weight/drug effects ; Doxorubicin/administration &amp; dosage/*antagonists &amp; inhibitors/toxicity ; Drug Synergism ; Erythrocytes/drug effects/ultrastructure ; Female ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Lung Neoplasms/*prevention &amp; control/*secondary ; Melanoma, Experimental/*prevention &amp; control/secondary ; Mice ; Mice, Inbred C57BL ; Micronuclei, Chromosome-Defective/drug effects ; Mutagens/*toxicity ; Neoplasm Transplantation ; }, abstract = {The thiol N-acetylcysteine (NAC), an analog and precursor of glutathione, displays cancer preventive properties not only in early stages of the carcinogenesis process but also in its advanced stages. NAC inhibited type-IV collagenase activity as well as invasion, tumor take, and metastasis of malignant cells in murine models. Previously, we provided evidence for synergistic effects of oral NAC with intravenously injected doxorubicin (DOX). In the present study B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice. The animals were divided into 5 groups: i) untreated mice; ii) mice receiving daily NAC with drinking water (12.25 mmol/kg body weight) starting 16 h after injection of cancer cells; iii) mice receiving a single i.v. injection of DOX (2 micromol/kg body weight) 24 h after injection of cancer cells; iv) mice receiving a combination of NAC and DOX, with NAC treatment starting 72 h before injection of cancer cells; and v) mice treated as in iv) but with NAC treatment starting 16 h after injection of cancer cells. Both NAC and DOX, either individually or in combination, significantly enhanced the survival time as compared to controls. The weight of local primary tumors was significantly decreased by either drug, and was further decreased to a significant extent, compared to the individual treatments, in the two groups of mice receiving combinations of NAC and DOX. No lung micrometastases, evaluated by immunohistochemistry as S-100-positive foci of melanocytic cells, were detectable in the two groups of mice receiving the combined treatments. NAC significantly, attenuated the time-related increase of micronucleated polychromatic erythrocytes in the peripheral blood of DOX-treated mice. All mice individually treated with DOX developed a partial but well evident alopecia, diffusely affecting their back hair, which was totally prevented by NAC, irrespective of the combination schedule. Thus, besides preventing DOX cardiotoxicity, as extensively documented in the literature, oral NAC protects mice from DOX-induced myelogenotoxicity and alopecia, and at the same time interacts with this cytotoxic agent in inhibiting cancer cell invasion and metastasis.}, }
@article {pmid9661638, year = {1998}, author = {Erkkilä, K and Hirvonen, V and Wuokko, E and Parvinen, M and Dunkel, L}, title = {N-acetyl-L-cysteine inhibits apoptosis in human male germ cells in vitro.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {83}, number = {7}, pages = {2523-2531}, doi = {10.1210/jcem.83.7.4949}, pmid = {9661638}, issn = {0021-972X}, mesh = {Acetylcysteine/*pharmacology ; Aged ; Aged, 80 and over ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Blotting, Southern ; Cells, Cultured ; Culture Media, Serum-Free ; DNA Fragmentation ; Free Radical Scavengers/*pharmacology ; Humans ; Male ; Microscopy, Electron ; Middle Aged ; Spermatozoa/cytology/*drug effects ; Testosterone/pharmacology ; }, abstract = {Antioxidant defenses play a critical role in the regulation of programmed cell death, even when death is induced by nonoxidative stimuli. During spermatogenesis, most of the testicular germ cells degenerate by an apoptotic process that is under hormonal control. However, the exact mechanisms by which hormonal signals are transduced within the cells to direct their life, and whether other effectors of the apoptotic pathway, for example antioxidants, take part in the control of human germ cell survival, are not known. In the present study, testosterone and N-acetyl-L-cysteine (NAC), which is an antioxidant, an inhibitor of apoptosis in several systems, and a survival factor in human semen, were found to suppress programmed cell death in human testicular germ cells in vitro. The samples came from adult men undergoing orchidectomy for prostate cancer. Germ cell death was induced by incubating segments of seminiferous tubules under serum-free culture conditions. This apoptosis, detected by Southern blot analysis of DNA fragmentation, by DNA labeling in situ, and by morphological analysis under the electron microscope, was significantly inhibited by testosterone at concentrations of 10(-6) and 10(-7) mol/L. NAC concentrations of 125, 100, 50, and 25 mmol/L suppressed germ cell death in a dose-dependent manner. This inhibition was effective during 4, 24, and 48 h of incubation. Apoptotic cells were identified mainly as spermatocytes and early spermatids. Programmed cell death was also demonstrated in late spermatids. We conclude that NAC, which is an antioxidant, plays an important role in germ cell survival in the human seminiferous tubules in vitro. We also suggest NAC as a possible new therapeutic factor for some men with idiopathic oligospermia.}, }
@article {pmid9661124, year = {1998}, author = {Shattuck, KE and Rassin, DK and Grinnell, CD}, title = {N-acetylcysteine protects from glutathione depletion in rats exposed to hyperoxia.}, journal = {JPEN. Journal of parenteral and enteral nutrition}, volume = {22}, number = {4}, pages = {228-233}, doi = {10.1177/0148607198022004228}, pmid = {9661124}, issn = {0148-6071}, support = {2SO7-RR05427-30/RR/NCRR NIH HHS/United States ; P-30-HD27841/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Amino Acids/metabolism ; Animals ; Bile/metabolism ; Glutathione/*deficiency/metabolism ; Hyperoxia/*complications ; Liver/metabolism ; Male ; Proteins/metabolism ; Rats ; Rats, Sprague-Dawley ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) may protect against oxidative injury by providing cysteine for glutathione (GSH) biosynthesis or by direct reactions with electrophiles. We have recently shown that hyperoxic exposure of rats prior to liver perfusion is associated with significant decreases in hepatic GSH and significant changes in biliary amino acid concentrations. We hypothesized that NAC administration during hyperoxic exposure would prevent depletion of hepatic GSH by providing cysteine for GSH biosynthesis.<br><br>METHODS: NAC was administered during two conditions known to induce GSH depletion: hyperoxic exposure and biochemical inhibition of GSH synthesis using buthionine sulfoximine (BSO). After 48 hours, GSH concentrations in bile, liver and perfusate and biliary amino acid concentrations were determined using isolated perfused liver preparations.<br><br>RESULTS: Administration of NAC to rats maintained in normoxic or hyperoxic conditions, prior to liver perfusion, resulted in dose-dependent increases in GSH concentrations in bile, liver and perfusate, increases in bile flow rates and changes in biliary amino acid concentrations. When BSO was given concurrently with NAC in normal or hyperoxic conditions, these effects were not observed, and oxidant stress was evident.<br><br>CONCLUSIONS: NAC prevents oxidant stress during hyperoxic exposure, most likely by supplying cysteine as a precursor for GSH synthesis.}, }
@article {pmid9660850, year = {1998}, author = {Ju, C and Uetrecht, JP}, title = {Oxidation of a metabolite of indomethacin (Desmethyldeschlorobenzoylindomethacin) to reactive intermediates by activated neutrophils, hypochlorous acid, and the myeloperoxidase system.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {26}, number = {7}, pages = {676-680}, pmid = {9660850}, issn = {0090-9556}, mesh = {Anti-Inflammatory Agents, Non-Steroidal/*metabolism ; Dexamethasone/*metabolism ; Humans ; Hypochlorous Acid/*pharmacology ; Neutrophils/*metabolism ; Oxidation-Reduction ; Peroxidase/*physiology ; }, abstract = {The use of indomethacin is associated with a relatively high incidence of adverse reactions such as agranulocytosis. Many other drugs associated with agranulocytosis are metabolized to reactive metabolites by activated neutrophils. Therefore, we studied the oxidation of indomethacin and its metabolites by activated neutrophils, myeloperoxidase (MPO) (the major oxidizing enzyme in neutrophils), and HOCl (the major oxidant produced by activated neutrophils). No oxidation of indomethacin by activated neutrophils was observed. However, desmethyldeschlorobenzoylindomethacin (DMBI), a major metabolite of indomethacin, was oxidized to a reactive iminoquinone that could be trapped with glutathione (GSH) or N-acetylcysteine (NAC) to form conjugates, with MH+ ions at m/z 511 and 367, respectively. No metabolism was detected in neutrophils that had not been activated, and the oxidation was inhibited by azide (which inhibits MPO) and by catalase (which catalyzes the breakdown of H2O2). In reactions with HOCl, the same reactive intermediate was formed; its mass spectrum, with a MH+ ion at m/z 204, was obtained by using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into the mass spectrometer. The same GSH and NAC conjugates were also observed when DMBI was oxidized by HOCl or by the MPO system, followed by addition of GSH or NAC. NMR data for the NAC conjugate indicated that the sulfur was substituted in the 4-position on the aromatic ring. The reactive intermediate generated from DMBI by activated neutrophils may be responsible for indomethacin-induced agranulocytosis.}, }
@article {pmid9659525, year = {1998}, author = {Gillissen, A and Nowak, D}, title = {Characterization of N-acetylcysteine and ambroxol in anti-oxidant therapy.}, journal = {Respiratory medicine}, volume = {92}, number = {4}, pages = {609-623}, doi = {10.1016/s0954-6111(98)90506-6}, pmid = {9659525}, issn = {0954-6111}, mesh = {Acetylcysteine/*therapeutic use ; Ambroxol/*therapeutic use ; Animals ; Expectorants/*therapeutic use ; Free Radical Scavengers/*therapeutic use ; Humans ; Lung/metabolism ; Lung Diseases/*drug therapy/metabolism ; }, abstract = {Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) or cystic fibrosis (CF). They can originate from endogenous processes or can be part of exogenous exposures (e.g. ozone, cigarette smoke, asbestos fibres). Consequently, therapeutic enhancement of anti-oxidant defence mechanisms in these lung disorders seems a rational approach. In this regard, N-acetyl-L-cysteine (NAC) and ambroxol have both been frequently investigated. Because of its SH group, NAC scavenges H2O2 (hydrogen peroxide), .OH (hydroxol radical), and HOCl (hypochlorous acid). Furthermore, NAC can easily be deacetylated to cysteine, an important precursor of cellular glutathione synthesis, and thus stimulate the cellular glutathione system. This is most evident in pulmonary diseases characterized by low glutathione levels and high oxidant production by inflammatory cells (e.g. in IPF and ARDS). NAC is an effective drug in the treatment of paracetamol intoxication and may even be protective against side-effects of mutagenic agents. In addition NAC reduces cellular production of pro-inflammatory mediators (e.g. TNF-alpha, IL-1). Also, ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexane hydrochloride] scavenges oxidants (e.g. .OH, HOCl). Moreover, ambroxol reduces bronchial hyperreactivity, and it is known to stimulate cellular surfactant production. In addition, ambroxol has anti-inflammatory properties owing to its inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. For both substances effective anti-oxidant and anti-inflammatory function has been validated when used in micromolar concentrations. These levels are attainable in vivo in humans. This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of anti-oxidant augmentation therapy to the lung by using NAC or ambroxol.}, }
@article {pmid9635865, year = {1998}, author = {Müller, T and Gebel, S}, title = {The cellular stress response induced by aqueous extracts of cigarette smoke is critically dependent on the intracellular glutathione concentration.}, journal = {Carcinogenesis}, volume = {19}, number = {5}, pages = {797-801}, doi = {10.1093/carcin/19.5.797}, pmid = {9635865}, issn = {0143-3334}, mesh = {3T3 Cells ; Acetylcysteine/pharmacology ; Aldehydes/chemistry ; Animals ; Gene Expression Regulation ; Genes, fos ; Glutathione/*metabolism ; HeLa Cells ; Humans ; Mice ; *Oxidative Stress ; Smoke/*adverse effects ; Water ; }, abstract = {Mainstream cigarette smoke (CS) trapped in phosphate-buffered saline solutions (smoke-bubbled PBS) has been shown to induce a strong stress response in cultured cells. This is reflected, for example, by the expression of stress genes such as c-fos and haem oxygenase, a transient decrease in the translation efficiency and the induction of cell cycle arrest. In these studies, peroxynitrite, the reaction product of nitric oxide (NO) and superoxide (O2-.), was identified as an active principle formed by CS in aqueous solutions. In the present study, we show that the CS-induced stress response is critically dependent on the intracellular glutathione (GSH) content which itself becomes diminished in cells exposed to smoke-bubbled PBS. Investigations using c-fos expression as a measure for cellular stress revealed a direct correlation between the smoke-bubbled PBS concentration necessary for stress-dependent c-fos expression and the intracellular GSH concentration observed in different cell lines. Correspondingly, 3T3 fibroblasts artificially depleted of GSH by pretreatment with buthionine-sulphoximine (BSO), an inhibitor of GSH synthesis, require significantly lower amounts of smoke-bubbled PBS to obtain a detectable c-fos expression, whereas, supplementation of the medium with N-acetyl-cysteine is an efficient treatment for the inhibition of a CS-induced c-fos response. We also show that the smoke-bubbled PBS-dependent loss of intracellular GSH is mainly attributable to the aldehyde fraction of CS, although these aldehydes by themselves cannot induce c-fos in these cells. The smoke-bubbled PBS-dependent c-fos response can, however, be mimicked when peroxynitrite and CS-related aldehydes, at the concentrations calculated to appear in smoke-bubbled PBS, are used in combination for cell exposure. Taken together, these results suggest that in cells exposed to aqueous extracts of CS, smoke-related aldehydes decrease the intracellular GSH content significantly, allowing peroxynitrite to interfere with specific target molecules resulting in the stress-specific expression of c-fos.}, }
@article {pmid9655897, year = {1998}, author = {Salminen, WF and Voellmy, R and Roberts, SM}, title = {Effect of N-acetylcysteine on heat shock protein induction by acetaminophen in mouse liver.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {286}, number = {1}, pages = {519-524}, pmid = {9655897}, issn = {0022-3565}, support = {ES07213/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/metabolism/*toxicity ; Acetylcysteine/*pharmacology ; Analgesics, Non-Narcotic/*pharmacology ; Animals ; HSP70 Heat-Shock Proteins/*biosynthesis ; *Heat-Shock Proteins ; Liver/*drug effects/metabolism ; Male ; Mice ; Molecular Chaperones ; Neoplasm Proteins/*biosynthesis ; Protein Binding ; }, abstract = {It was previously shown that a necrogenic dose of acetaminophen (APAP) induced the 25- and 70-kDa heat shock proteins (hsp25 and hsp70i) in mouse liver, whereas nonnecrogenic doses failed to alter the level of either hsp. A strong correlation between the intralobular sites of APAP arylation of protein and hsp induction suggested that APAP-induced protein denaturation may play a role in triggering hsp induction. This study was conducted to determine whether APAP arylation of protein without concurrent toxicity could cause hsp induction. APAP (250 mg/kg i.p.) hepatotoxicity was eliminated using N-acetylcysteine (NAC, 300 mg/kg i.p.) or the cytochrome P-450 inhibitor diallyl sulfide (200 mg/kg p.o.). NAC did not inhibit APAP arylation of protein when administered 1 or 3 hr after the APAP dose but decreased binding by approximately 50% when administered at the same time as the APAP dose. Even though APAP hepatotoxicity was blocked by NAC administered 0 or 1 hr after the APAP dose, NAC did not inhibit the induction of hsp25 or hsp70i, indicating that APAP arylation of protein may play a key role in triggering hsp induction. Diallyl sulfide blocked APAP arylation of protein, hepatotoxicity, and induction of both hsps. These data are consistent with the hypothesis that toxicant adduction of protein triggers hsp induction.}, }
@article {pmid9650568, year = {1998}, author = {Balansky, RM and De Flora, S}, title = {Chemoprevention by N-acetylcysteine of urethane-induced clastogenicity and lung tumors in mice.}, journal = {International journal of cancer}, volume = {77}, number = {2}, pages = {302-305}, doi = {10.1002/(sici)1097-0215(19980717)77:2&lt;302::aid-ijc21&gt;3.0.co;2-b}, pmid = {9650568}, issn = {0020-7136}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Anticarcinogenic Agents/*pharmacology ; Antimutagenic Agents/*pharmacology ; Body Weight ; Carcinogens ; Lung Neoplasms/*chemically induced/prevention &amp; control ; Male ; Mice ; Mice, Inbred BALB C ; *Micronuclei, Chromosome-Defective ; Time Factors ; Urethane/*antagonists &amp; inhibitors ; }, abstract = {A major goal in pre-clinical cancer chemoprevention research is to assess the predictive value of intermediate biomarker modulation towards tumor prevention. With this aim, BALB/c mice were treated with 10 daily i.p. injections of urethane (ethyl carbamate), each of 400 mg/kg body weight. Groups of mice received with drinking water either a drug containing the thiol N-acetylcysteine (NAC), at 0.1 or 0.5 g/kg body weight, or its excipient, starting 27 days before the first injection of the carcinogen until the end of the experiment. Out of the 30 mice, 10 per group were identified and individually monitored for 8 sequential times in order to assess the course of micronucleated normochromatic erythrocytes in peripheral blood. This systemic genotoxicity biomarker increased during the 10-day period of treatment with urethane, reached a peak 2 to 6 days after the last injection, and was still significantly higher than the baseline after 10 additional days. Clastogenicity was significantly inhibited by NAC, with a dose-related effect, but not by the drug excipient. As evaluated 4 months after the first injection of urethane, most mice developed lung tumors, whose multiplicity was not affected by the drug excipient but was significantly decreased in the presence of NAC. Correlation between the frequency of micronucleated normochromatic erythrocytes at peak levels and lung-tumor multiplicity was highly significant when evaluated in the context of all 40 mice undergoing cytogenetic analyses (r = 0.561, p = 0.0002). It was similarly high, but did not reach the significance threshold, within each treatment group, due to the lower number of animals and some deviations from the regression line. Therefore, the prediction of lung-tumor yield based on the intensity of the early genotoxicity biomarker is justified when formulated within a sufficiently large group of animals, but is not absolute at individual level.}, }
@article {pmid9650013, year = {1998}, author = {Look, MP and Rockstroh, JK and Rao, GS and Barton, S and Lemoch, H and Kaiser, R and Kupfer, B and Sudhop, T and Spengler, U and Sauerbruch, T}, title = {Sodium selenite and N-acetylcysteine in antiretroviral-naive HIV-1-infected patients: a randomized, controlled pilot study.}, journal = {European journal of clinical investigation}, volume = {28}, number = {5}, pages = {389-397}, doi = {10.1046/j.1365-2362.1998.00301.x}, pmid = {9650013}, issn = {0014-2972}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Adult ; Erythrocytes/enzymology ; Female ; Glutathione/blood ; Glutathione Disulfide/blood ; Glutathione Peroxidase/blood ; HIV Infections/blood/*drug therapy/virology ; HIV-1/*drug effects ; Humans ; Male ; Middle Aged ; Pilot Projects ; Prospective Studies ; Reference Values ; Selenium/blood ; Sodium Selenite/*therapeutic use ; T-Lymphocyte Subsets/drug effects ; Viral Load ; }, abstract = {BACKGROUND: The aim of this work was to study the effects of combined oral administration of N-acetylcysteine (NAC) and sodium selenite (Se) on plasma glutathione (GSH), lymphocyte subpopulations and viral load in asymptomatic human immunodeficiency virus (HIV)-infected patients.<br><br>METHODS: We used a prospective, randomized and controlled therapy trial with partial crossover. Twenty-four antiretroviral-naive HIV-infected outpatients at Centers for Disease Control (CDC)'93 stages I and II were randomized to receive the antioxidant combination NAC 600 mg t.i.d. and Se 500 micrograms per day for either 24 weeks (group A, n = 13) or from the end of week 12 (group B, n = 11) until the end of week 24. Thus, group B served as untreated control during the first 12 weeks.<br><br>RESULTS: There was (a) a trend towards an increase in the percentage of CD4+ lymphocytes after 6 weeks (P = 0.08); (b) an increase in the CD4/CD8 ratio after 6 and 12 weeks (P = 0.02 and P = 0.04 respectively); and (c) a decrease in the absolute CD8/CD38 count and percentage of lymphocytes after 6 weeks (P = 0.002 and P = 0.033 respectively) and 12 weeks (P = 0.033, P = 0.1 respectively) in group A compared with the control period of group B. The effects observed in group A were, however, not paralleled to the same extent by group B after crossing-over to treatment after 12 weeks. In addition, erythrocyte glutathione peroxidase (GSH-Px) activity and GSH, glutathionedisulphide (GSSG) concentrations and the reduced/total GSH ratio were not affected by the treatment. Serum selenium levels increased significantly (P < 0.001) upon treatment. Viral load was not altered.<br><br>CONCLUSIONS: The changes in lymphocyte subsets after NAC/Se treatment were not comparable to those after standard antiretroviral drug therapy. This, however, does not preclude per se possible benefits of antioxidant supplementation in HIV disease.}, }
@article {pmid9648531, year = {1998}, author = {Steenvoorden, DP and Hasselbaink, DM and Beijersbergen van Henegouwen, GM}, title = {Protection against UV-induced reactive intermediates in human cells and mouse skin by glutathione precursors: a comparison of N-acetylcysteine and glutathione ethylester.}, journal = {Photochemistry and photobiology}, volume = {67}, number = {6}, pages = {651-656}, pmid = {9648531}, issn = {0031-8655}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Glutathione/*analogs &amp; derivatives/metabolism/pharmacology ; Humans ; Jurkat Cells/drug effects/metabolism/radiation effects ; Male ; Methoxsalen ; Mice ; Mice, Inbred BALB C ; Radiation-Protective Agents/*pharmacology ; Skin/drug effects/metabolism/*radiation effects ; *Ultraviolet Rays ; }, abstract = {Because glutathione (GSH) plays a central part in the endogenous defense against UV radiation, an increase in GSH might provide photoprotection. Two agents that increase GSH levels were investigated. Cultured human cells and mouse skin were treated with N-acetylcysteine (NAC) and glutathione ethylester (GSH-Et). After 30 min, the GSH level was determined by HPLC. Photoprotection was assessed by testing the ability of the thiols to scavenge UV-induced reactive intermediates in the same models. As compared to control cells, NAC and GSH-Et increased intracellular GSH in vitro to maximally 144% and 174% respectively. In vitro protection (maximum 23% for NAC and 21% for GSH-Et) did not correlate to the intracellular GSH level but to the concentration of the thiols in the medium. In vivo, epidermal GSH was increased to maximally 163% of the control level by NAC and 1234% by GSH-Et. The maximum in vivo photoprotection provided by GSH-Et was 55%, similar to what was found previously for NAC. Again, the protection seemed more closely correlated to the thiol dose than to the GSH level. The study showed that the protection against UV-induced reactive intermediates depends on a general antioxidant action of these thiols, rather than only on their role as GSH precursors.}, }
@article {pmid9647554, year = {1998}, author = {Hughes, CM and Lewis, SE and McKelvey-Martin, VJ and Thompson, W}, title = {The effects of antioxidant supplementation during Percoll preparation on human sperm DNA integrity.}, journal = {Human reproduction (Oxford, England)}, volume = {13}, number = {5}, pages = {1240-1247}, doi = {10.1093/humrep/13.5.1240}, pmid = {9647554}, issn = {0268-1161}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Ascorbic Acid/pharmacology ; Cell Separation/methods ; DNA/*drug effects/*metabolism/radiation effects ; DNA Damage ; Humans ; In Vitro Techniques ; Infertility, Male/genetics/metabolism/therapy ; Male ; Povidone ; Reactive Oxygen Species/metabolism ; Reproductive Techniques ; Silicon Dioxide ; Spermatozoa/*drug effects/*metabolism/radiation effects ; Uric Acid/pharmacology ; Vitamin E/pharmacology ; }, abstract = {The integrity of sperm DNA is crucial for the maintenance of genetic health. A major source of damage is reactive oxygen species (ROS) generation; therefore, antioxidants may afford protection to sperm DNA. The objectives of the study were, first, to measure the effects of antioxidant supplementation in vitro on endogenous DNA damage in spermatozoa using the single cell gel electrophoresis (comet) assay and, second, to assess the effect of antioxidant supplementation given prior to X-ray irradiation on induced DNA damage. Spermatozoa from 150 patients were prepared by Percoll centrifugation in the presence of ascorbic acid (300, 600 microM), alpha tocopherol (30, 60 microM), urate (200, 400 microM), or acetyl cysteine (5, 10 microM). DNA damage was induced by 30 Gy X-irradiation. DNA strand breakage was measured using the comet assay. Sperm DNA was protected from DNA damage by ascorbic acid (600 microM), alpha tocopherol (30 and 60 microM) and urate (400 microM). These antioxidants provided protection from subsequent DNA damage by X-ray irradiation. In contrast, acetyl cysteine or ascorbate and alpha tocopherol together induced further DNA damage. Supplementation in vitro with the antioxidants ascorbate, urate and alpha tocopherol separately has beneficial effects for sperm DNA integrity.}, }
@article {pmid9647254, year = {1998}, author = {Fan, J and Marshall, JC and Jimenez, M and Shek, PN and Zagorski, J and Rotstein, OD}, title = {Hemorrhagic shock primes for increased expression of cytokine-induced neutrophil chemoattractant in the lung: role in pulmonary inflammation following lipopolysaccharide.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {161}, number = {1}, pages = {440-447}, pmid = {9647254}, issn = {0022-1767}, mesh = {Acetylcysteine/pharmacology ; Albumins/metabolism ; Animals ; Biological Transport/drug effects/immunology ; Chemokine CXCL2 ; Chemokines, CXC/biosynthesis/physiology ; Chemotactic Factors/*biosynthesis/physiology ; Cytokines/*pharmacology ; Growth Substances/*biosynthesis/physiology ; Immune Sera/pharmacology ; *Intercellular Signaling Peptides and Proteins ; Lipopolysaccharides/*toxicity ; Lung/*immunology/metabolism/*pathology ; Macrophages, Alveolar/immunology/metabolism ; Male ; NF-kappa B/metabolism ; Neutrophils/*immunology/pathology ; Oxidants/pharmacology ; Rats ; Rats, Sprague-Dawley ; Shock, Hemorrhagic/*immunology/metabolism/pathology ; }, abstract = {Recent studies have suggested that hemorrhagic shock followed by resuscitation renders patients more susceptible to lung injury by priming for an exaggerated response to a second stimulus, the so-called "two-hit" hypothesis. We investigated the role of C-X-C chemokines in mediating the augmented lung inflammation in response to LPS following resuscitated shock. In a rodent model, animals exposed to antecedent shock exhibited enhanced lung neutrophil sequestration and transpulmonary albumin flux in response to intratracheal LPS. This effect correlated with an exaggerated expression of cytokine-induced neutrophil chemoattractant (CINC) protein and mRNA, but not macrophage-inflammatory protein 2. Strategies designed to inhibit CINC, both anti-CINC Ab and supplementation with the antioxidant N-acetyl-cysteine, prevented the enhanced neutrophil sequestration, suggesting that CINC played a central role in the enhanced leukocyte accumulation following shock plus LPS treatment. Shock alone increased lung nuclear factor-kappaB expression and augmented the response to LPS. Prevention of this effect by N-acetylcysteine supplementation of the resuscitation fluid implicates a role for oxidant stress in the priming for lung inflammation following shock. Finally, alveolar macrophages recovered from shock-resuscitated animals released more CINC protein in vitro in response to LPS than macrophages from sham animals. Considered together, these findings show that augmented release of CINC, in part from primed alveolar macrophages, contributes significantly to the enhanced lung leukosequestration and transpulmonary albumin flux in response to LPS following resuscitated shock.}, }
@article {pmid9645393, year = {1998}, author = {Izzotti, A and Orlando, M and Gasparini, L and Scatolini, L and Cartiglia, C and Tulimiero, L and De Flora, S}, title = {In vitro inhibition by N-acetylcysteine of oxidative DNA modifications detected by 32P postlabeling.}, journal = {Free radical research}, volume = {28}, number = {2}, pages = {165-178}, doi = {10.3109/10715769809065802}, pmid = {9645393}, issn = {1071-5762}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cattle ; Chromatography, Thin Layer ; Copper Sulfate/pharmacology ; DNA/drug effects ; DNA Adducts/*analysis ; *DNA Damage ; DNA Fragmentation ; Free Radical Scavengers/*pharmacology ; Hydrogen Peroxide/*pharmacology ; Hydroxyl Radical/*pharmacology ; Isotope Labeling/methods ; Oxidation-Reduction ; Phosphorus Radioisotopes ; *Reactive Oxygen Species ; }, abstract = {Reactive oxygen species are involved in the pathogenesis of cancer and other chronic degenerative diseases through a variety of mechanisms, including DNA damage. We investigated by 32p and 33P postlabeling analyses the nucleotidic modifications induced in vitro by treating calf thymus DNA with H2O2 and CuSO4, interacting in a Fenton type reaction. Six different enrichment procedures and three chromatographic systems were comparatively assayed. The chromatographic system using phosphate/urea, which is more suitable for detecting bulky DNA adducts, was rather insensitive. In contrast, the system using acetic acid/ammonium formate revealed high levels of mononucleotidic modifications. In terms of ratio of adduct levels in treated and untreated DNA, the enrichment procedures ranked as follows: nuclease P1 (19.6), no enrichment (18.3), digestion to trinucleotides (17.6), digestion to monophosphate mononucleotides (8.4), digestion to dinucleotides (3.4), and extraction with butanol (<1.0). The system using formic acid/ammonium formate was quite efficient in detecting 8-hydroxy-2'-deoxyguanosine. Labeling with 33p further enhanced the sensitivity of the method. The oxidative damage was so intense to produce a strong DNA fragmentation detectable by agarose gel electrophoresis, and nucleotidic modifications were more intense when DNA fragmentation was greater. The DNA alterations produced by H2O2 alone were significantly lower than those produced following reaction of H2O2 with CuSO4. The thiol N-acetylcysteine (NAC) was quite efficient in inhibiting both nucleotidic modifications and DNA fragmentation produced in vitro by either H2O2 or the .OH generating system. These results support at a molecular level the findings of previous studies showing the ability of NAC to inhibit the genotoxicity of peroxides and of reactive oxygen species generated by electron transfer reactions.}, }
@article {pmid9641697, year = {1998}, author = {Galis, ZS and Asanuma, K and Godin, D and Meng, X}, title = {N-acetyl-cysteine decreases the matrix-degrading capacity of macrophage-derived foam cells: new target for antioxidant therapy?.}, journal = {Circulation}, volume = {97}, number = {24}, pages = {2445-2453}, doi = {10.1161/01.cir.97.24.2445}, pmid = {9641697}, issn = {0009-7322}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aortic Diseases/metabolism ; Arteriosclerosis/*metabolism ; Collagenases/*metabolism ; Foam Cells/*drug effects/*metabolism ; Free Radical Scavengers/*pharmacology ; Gelatinases/metabolism ; Hypercholesterolemia ; Matrix Metalloproteinase 2 ; Matrix Metalloproteinase 9 ; Metalloendopeptidases/metabolism ; Rabbits ; }, abstract = {BACKGROUND: Atherosclerotic plaque destabilization triggers clinical cardiovascular disease and thus represents an attractive therapeutic target. Weakening of tissue through the action of matrix-degrading enzymes, called matrix metalloproteinases (MMPs), released by resident macrophages was previously implicated in unstable vascular syndromes.<br><br>METHODS AND RESULTS: We used a hypercholesterolemic rabbit model of atherosclerosis to investigate the gelatinolytic activity associated with macrophage-derived foam cells (FCs). Gelatinolytic activity and expression of MMP-9 but not of MMP-2 cosegregated with macrophage FCs in aortic lesions. Macrophage-derived gelatinases were further investigated in vitro. MMP-9 was identified as the main macrophage-derived gelatinase in cells isolated from aortic lesions and from granuloma induced in the same rabbits to increase cell yield. Importantly, detection of activated MMP-9 in the FC culture medium supports the notion that these cells can independently initiate processing of secreted MMP zymogens to active enzymes. We further examined whether FC gelatinolytic activity is dependent on the presence of reactive oxygen species (ROS). We found that treatment (1 to 5 days) with 1 to 10 mmol/L N-acetyl-L-cysteine (NAC), an ROS scavenger, decreased not only gelatinolytic activity but also gelatinase expression by FCs. Similarly, NAC treatment of explanted lesions abolished in situ gelatinolytic activity and MMP-9 expression.<br><br>CONCLUSIONS: Macrophage FCs are an abundant source of gelatinolytic activity that can be inhibited in vitro and in situ by NAC. This newly described action of antioxidant therapy might prove useful to inhibit matrix degradation and to improve vascular stability.}, }
@article {pmid9639500, year = {1998}, author = {Hack, V and Breitkreutz, R and Kinscherf, R and Röhrer, H and Bärtsch, P and Taut, F and Benner, A and Dröge, W}, title = {The redox state as a correlate of senescence and wasting and as a target for therapeutic intervention.}, journal = {Blood}, volume = {92}, number = {1}, pages = {59-67}, pmid = {9639500}, issn = {0006-4971}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*metabolism ; Cell Death ; Child ; Child, Preschool ; Cystine/blood ; Female ; Free Radical Scavengers/*administration &amp; dosage/therapeutic use ; Humans ; Male ; Middle Aged ; Neoplasms/drug therapy/*metabolism/physiopathology ; *Oxidation-Reduction/drug effects ; Serum Albumin/metabolism ; Sulfhydryl Compounds/blood ; }, abstract = {The loss of body cell mass (bcm) in senescence and wasting is poorly understood. We now show that the plasma cystine/acid soluble thiol ratio, ie, an indicator of the redox state, is increased in old age and cancer patients and correlated with a decrease in bcm and plasma albumin. A cause/effect relationship was suggested by two independent studies with N-acetyl-cysteine (NAC). NAC caused an increase in the bcm of healthy persons with high plasma cystine/thiol ratios, and treatment of cancer patients with NAC plus interleukin-2 caused an increase in bcm, plasma albumin, and functional capacity. Albumin levels below 680 micromol/L were associated with an increase in body water. Our studies suggest that the shift in the redox state may contribute to the loss of bcm and may provide a quantitative guideline for therapeutic intervention. Treatment of cancer patients with thiol-containing antioxidants may improve the quality of life.}, }
@article {pmid9593830, year = {1998}, author = {Hoover-Plow, J and Skocir, P}, title = {Enzymatic and chemical modifications of lipoprotein(a) selectively alter its lysine-binding functions.}, journal = {Biochimica et biophysica acta}, volume = {1392}, number = {1}, pages = {73-84}, doi = {10.1016/s0005-2760(98)00022-8}, pmid = {9593830}, issn = {0006-3002}, support = {HL 18577/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Amidines/pharmacology ; Binding Sites ; Chromatography, Affinity ; Copper Sulfate/pharmacology ; Homocysteine/pharmacology ; Immunoassay ; Lipoprotein(a)/drug effects/*metabolism ; Lysine/*metabolism ; Oxidation-Reduction ; Phospholipases A/pharmacology ; Phospholipases A2 ; }, abstract = {The pathogenicity of lipoprotein(a) [Lp(a)] as a risk factor for cardiovascular disease may depend upon its lysine binding sites (LBS) which impart unique functions to Lp(a) not shared with low density lipoprotein. Biologically relevant modifications of Lp(a) were tested for alterations of LBS activity using two previously described functional assays, a LBS-Lp(a) immunoassay and a lysine-Sepharose bead assay. In the LBS-Lp(a) immunoassay, minimal changes in the LBS activity of Lp(a) were observed after modification with lipoprotein lipase, sphingomyelinase, or phospholipase C. In contrast, a significant (p<0.003) increase in the LBS activity of Lp(a) occurred after phospholipase A2 (PLA2) treatment, and this increase was confirmed using the lysine-Sepharose bead assay. The increase depended upon the release of fatty acids from Lp(a) by PLA2. A decrease in the LBS activity of Lp(a) occurred after oxidation of Lp(a) with 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) (44% decrease), but CuSO4 oxidation increased LBS activity (210%). N-acetylcysteine (NAC) treatment of Lp(a) decreased (48%) LBS activity while homocysteine treatment had no (89%) effect. Thus, modification of phospholipids and protein moieties can alter the LBS-activity of Lp(a). Such enzymatic and chemical modifications may contribute to the variability in LBS function of Lp(a) seen within the population.}, }
@article {pmid9631802, year = {1998}, author = {Spapen, H and Zhang, H and Demanet, C and Vleminckx, W and Vincent, JL and Huyghens, L}, title = {Does N-acetyl-L-cysteine influence cytokine response during early human septic shock?.}, journal = {Chest}, volume = {113}, number = {6}, pages = {1616-1624}, doi = {10.1378/chest.113.6.1616}, pmid = {9631802}, issn = {0012-3692}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Antigens, CD/analysis ; Double-Blind Method ; Female ; Hemodynamics ; Humans ; Infusions, Intravenous ; Interleukin-10/blood ; Interleukin-6/blood ; Interleukin-8/blood ; Interleukins/*blood ; Lactic Acid/blood ; Lung Compliance ; Male ; Middle Aged ; Oxygen Consumption ; Prospective Studies ; Receptors, Tumor Necrosis Factor/analysis ; Receptors, Tumor Necrosis Factor, Type I ; Shock, Septic/blood/*drug therapy/physiopathology ; Tumor Necrosis Factor-alpha/*analysis ; }, abstract = {STUDY OBJECTIVE: To assess the effects of adjunctive treatment with N-acetyl-L-cysteine (NAC) on hemodynamics, oxygen transport variables, and plasma levels of cytokines in patients with septic shock.<br><br>DESIGN: Prospective, randomized, double-blind, placebo-controlled study.<br><br>SETTING: A 24-bed medicosurgical ICU in a university hospital.<br><br>PATIENTS: Twenty-two patients included within 4 h of diagnosis of septic shock.<br><br>INTERVENTIONS: Patients were randomly allocated to receive either NAC (150 mg/kg bolus, followed by a continuous infusion of 50 mg/kg over 4 h; n= 12) or placebo (n=10) in addition to standard therapy.<br><br>MEASUREMENTS: Plasma concentrations of tumor necrosis factor-alpha (TNF), interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor-alpha receptor-p55 (sTNFR-p55) were measured by sensitive immunoassays at 0, 2, 4, 6 and 24 h. Pulmonary artery catheter-derived hemodynamics, blood gases, hemoglobin, and arterial lactate were measured at baseline, after infusion (4 h), and at 24 h.<br><br>RESULTS: NAC improved oxygenation (PaO2/FIO2 ratio, 214+/-97 vs 123+/-86; p<0.05) and static lung compliance (44+/-11 vs 31+/-6 L/cm H2O; p<0.05) at 24 h. NAC had no significant effects on plasma TNF, IL-6, or IL-10 levels, but acutely decreased IL-8 and sTNFR-p55 levels. The administration of NAC had no significant effect on systemic and pulmonary hemodynamics, oxygen delivery, and oxygen consumption. Mortality was similar in both groups (control, 40%; NAC, 42%) but survivors who received NAC had shorter ventilator requirement (7+/-2 days vs 20+/-7 days; p<0.05) and were discharged earlier from the ICU (13+/-2 days vs 32+/-9 days; p<0.05).<br><br>CONCLUSION: In this small cohort of patients with early septic shock, short-term IV infusion of NAC was well-tolerated, improved respiratory function, and shortened ICU stay in survivors. The attenuated production of IL-8, a potential mediator of septic lung injury, may have contributed to the lung-protective effects of NAC.}, }
@article {pmid9630353, year = {1998}, author = {Gordge, MP and Hothersall, JS and Noronha-Dutra, AA}, title = {Evidence for a cyclic GMP-independent mechanism in the anti-platelet action of S-nitrosoglutathione.}, journal = {British journal of pharmacology}, volume = {124}, number = {1}, pages = {141-148}, doi = {10.1038/sj.bjp.0701821}, pmid = {9630353}, issn = {0007-1188}, mesh = {Cell Membrane/metabolism ; Cyclic AMP/metabolism ; Cyclic GMP/*metabolism ; Glutathione/*analogs &amp; derivatives/pharmacology ; Humans ; Hydrazines/pharmacology ; In Vitro Techniques ; Nitric Oxide/metabolism ; Nitrogen Oxides ; Nitroso Compounds/*pharmacology ; Oxadiazoles/pharmacology ; Phenanthrolines/pharmacology ; Platelet Aggregation Inhibitors/*pharmacology ; Quinoxalines/pharmacology ; S-Nitrosoglutathione ; Sulfhydryl Compounds/metabolism ; }, abstract = {1. We have measured the ability of a range of NO donor compounds to stimulate cyclic GMP accumulation and inhibit collagen-induced aggregation of human washed platelets. In addition, the rate of spontaneous release of NO from each donor has been measured spectrophotometrically by the oxidation of oxyhaemoglobin to methaemoglobin. The NO donors used were five s-nitrosothiol compounds: S-nitrosoglutathione (GSNO), S-nitrosocysteine (cysNO), S-nitroso-N-acetyl-DL-penicillamine (SNAP), S-nitroso-N-acetyl-cysteine (SNAC), S-nitrosohomocysteine (homocysNO), and two non-nitrosothiol compounds: diethylamine NONOate (DEANO) and sodium nitroprusside (SNP). 2. Using 10 microM of each donor compound, mean+/-s.e.mean rate of NO release ranged from 0.04+/-0.001 nmol min(-1) (for SNP) to 3.15+/-0.29 nmol min(-1) (for cysNO); cyclic GMP accumulation ranged from 0.43+/-0.05 pmol per 10(8) platelets (for SNP) to 2.67+/-0.31 pmol per 10(8) platelets (for cysNO), and inhibition of platelet aggregation ranged from 40+/-6.4% (for SNP) to 90+/-3.8% (for SNAC). 3. There was a significant positive correlation between the rate of NO release and the ability of the different NO donors to stimulate intra-platelet cyclic GMP accumulation (r = 0.83; P = 0.02). However, no significant correlation was observed between the rate of NO release and the inhibition of platelet aggregation by the different NO donors (r= -0.17), nor was there a significant correlation between cyclic GMP accumulation and inhibition of aggregation by the different NO donor compounds (r = 0.34). 4. Comparison of the dose-response curves obtained with GSNO, DEANO and 8-bromo cyclic GMP showed DEANO to be the most potent stimulator of intraplatelet cyclic GMP accumulation (P < 0.001 vs both GSNO and 8-bromo cyclic GMP), but GSNO to be the most potent inhibitor of platelet aggregation (P < 0.01 vs DEANO, and P < 0.001 vs 8-bromo cyclic GMP). 5. The rate of NO release from GSNO, and its ability both to stimulate intra-platelet cyclic GMP accumulation and to inhibit platelet aggregation, were all significantly diminished by the copper (I) (Cu+) chelating agent bathocuproine disulphonic acid (BCS). In contrast, BCS had no effect on either the rate of NO release, or the anti-platelet action of the non-nitrosothiol compound DEANO. 6. Cyclic GMP accumulation in response to GSNO (10(-9) 10(-5) M) was undetectable following treatment of platelets with ODQ (100 microM), a selective inhibitor of soluble guanylate cyclase. Despite this abolition of guanylate cyclase stimulation, GSNO retained some ability to inhibit aggregation, indicating the presence of a cyclic GMP-independent component in its anti-platelet action. However, this component was abolished following treatment of platelets with a combination of both ODQ and BCS, suggesting that Cu+ ions were required for the cyclic GMP-independent pathway to operate. 7. The cyclic GMP-independent action of GSNO, observed in ODQ-treated platelets, could not be explained by an increase in intra-platelet cyclic AMP. 8. The impermeable thiol modifying agent p-chloromercuriphenylsulphonic acid (CMPS) produced a concentration-dependent inhibition of aggregation of ODQ-treated platelets, accompanied by a progressive loss of detectable platelet surface thiol groups. Additional treatment with GSNO failed to increase the degree of aggregation inhibition, suggesting that a common pathway of thiol modification might be utilized by both GSNO and CMPS to elicit cyclic GMP-independent inhibition of platelet aggregation. 9. We conclude that NO donor compounds mediate inhibition of platelet aggregation by both cyclic GMP-dependent and -independent pathways. Cyclic GMP generation is related to the rate of spontaneous release of NO from the donor compound, but transfer of the NO signal to the cyclic GMP-independent pathway may depend upon a cellular system which involves both copper (I) (Cu+) ions and surface membrane thiol groups. The potent anti-platelet action of GSNO}, }
@article {pmid9625012, year = {1998}, author = {Salom, MG and Ramírez, P and Carbonell, LF and López Conesa, E and Cartagena, J and Quesada, T and Parrilla, P and Fenoy, FJ}, title = {Protective effect of N-acetyl-L-cysteine on the renal failure induced by inferior vena cava occlusion.}, journal = {Transplantation}, volume = {65}, number = {10}, pages = {1315-1321}, doi = {10.1097/00007890-199805270-00006}, pmid = {9625012}, issn = {0041-1337}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/*pharmacology ; Acute Kidney Injury/*etiology/physiopathology/*prevention &amp; control ; Animals ; Constriction ; Dogs ; Enzyme Inhibitors/pharmacology ; Female ; Free Radical Scavengers/*pharmacology ; Injections, Intra-Arterial ; Ischemia/physiopathology ; Kidney/drug effects/physiopathology ; Male ; NG-Nitroarginine Methyl Ester/pharmacology ; Renal Circulation/physiology ; Reperfusion ; Vena Cava, Inferior/*physiopathology ; }, abstract = {BACKGROUND: Renal ischemia is produced during orthotopic liver transplantation when the inferior vena cava is clamped above the renal veins (inferior vena cava occlusion [IVCO]), and it often leads to postoperative renal failure. Although free radicals and nitric oxide (NO) have been implicated in the pathogenesis of ischemic renal failure, the effect of free radical scavengers in this model is unknown.<br><br>METHODS: The effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, on the acute renal failure that follows IVCO were evaluated in pentobarbital-anesthetized dogs. The effect of NO synthesis inhibition with NG-nitro-L-arginine methyl ester (NAME) was also studied. Renal vascular endothelial function was tested by infusing acetylcholine (Ach) into the renal artery before the ischemia and during reperfusion.<br><br>RESULTS: Renal failure developed during IVCO and persisted during reperfusion in all groups. However, in NAC-pretreated dogs, the glomerular filtration rate recovered progressively, reaching 31% of basal preischemic values 150 min after reperfusion. During reperfusion, fractional excretion of sodium increased above preischemic values only in the control group, which indicates a beneficial effect of NAC and NAME on the tubular dysfunction observed during reperfusion. The renal response to Ach was abolished in control dogs and in animals given NAME during reperfusion, which indicates endothelial dysfunction. However, in NAC-pretreated dogs, the renal response to Ach was preserved during reperfusion.<br><br>CONCLUSIONS: These results demonstrate that NAC ameliorates the renal failure and renal endothelial dysfunction induced by IVCO. This protective effect was abolished by NAME, which suggests that NO is involved in the beneficial effects of NAC. These data also suggest that the use of NAC could be beneficial in ameliorating the acute renal failure observed after orthotopic liver transplantation.}, }
@article {pmid9624310, year = {1998}, author = {Bailey, B and McGuigan, MA}, title = {Management of anaphylactoid reactions to intravenous N-acetylcysteine.}, journal = {Annals of emergency medicine}, volume = {31}, number = {6}, pages = {710-715}, doi = {10.1016/s0196-0644(98)70229-x}, pmid = {9624310}, issn = {0196-0644}, mesh = {Acetaminophen/poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects ; Anaphylaxis/*chemically induced/physiopathology/therapy ; Anti-Allergic Agents/therapeutic use ; Diphenhydramine/therapeutic use ; Free Radical Scavengers/administration &amp; dosage/*adverse effects ; Histamine H1 Antagonists/*therapeutic use ; Humans ; Infusions, Intravenous ; Practice Guidelines as Topic ; Prospective Studies ; Retrospective Studies ; }, abstract = {STUDY OBJECTIVE: To develop management guidelines for the treatment of anaphylactoid reactions to intravenous N-acetylcysteine (NAC) and to assess the safety of restarting the infusion after a reaction.<br><br>METHODS: In phased 1, we used a 6-year retrospective case series of hospitalized patients and a review of the literature to develop the management guidelines for anaphylactoid reactions to intravenous NAC. In phase 2, these guidelines were evaluated prospectively in our poison-control center.<br><br>RESULTS: In phase 1, the charts of 11 patients with anaphylactoid reactions (9 cutaneous and 2 systemic) were reviewed. In most cases, no treatment or treatment with diphenhydramine alone or with salbutamol was sufficient to continue or restart NAC infusion safely. On the basis of our findings in those patients and on published experience, we concluded that anaphylactoid reactions to intravenous NAC are dose-related and the antihistamines are useful in controlling and in preventing recurrence of anaphylactoid symptoms. We developed the following guidelines: flushing requires no treatment, urticaria should be treated with diphenhydramine, and NAC infusion should be continued in both cases. Angioedema and respiratory symptoms each require the administration of diphenhydramine and symptomatic therapy. In these cases, NAC infusion should be stopped but, when necessary, can be started 1 hour after the administration of diphenhydramine in the absence of symptoms. In phase 2, 50 patients (31 cutaneous and 19 systemic reactions) were treated prospectively with the use of these guidelines. Recurrence of symptoms occurred in only one case involving a deviation from the guidelines. The NAC infusion was restarted immediately after the administration of diphenhydramine in a patient who sustained a systemic reaction.<br><br>CONCLUSION: Non-life-threatening anaphylactoid reactions to intravenous NAC are treated easily and the infusion may be continued or restarted safely after the administration of diphenhydramine.}, }
@article {pmid9622162, year = {1998}, author = {De Keulenaer, GW and Chappell, DC and Ishizaka, N and Nerem, RM and Alexander, RW and Griendling, KK}, title = {Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase.}, journal = {Circulation research}, volume = {82}, number = {10}, pages = {1094-1101}, doi = {10.1161/01.res.82.10.1094}, pmid = {9622162}, issn = {0009-7330}, support = {HL-38206/HL/NHLBI NIH HHS/United States ; HL-58863/HL/NHLBI NIH HHS/United States ; }, mesh = {Arteriosclerosis/metabolism ; Cells, Cultured ; Endothelium, Vascular/*metabolism ; Free Radicals ; Gene Expression Regulation, Enzymologic ; Heme Oxygenase (Decyclizing)/genetics/metabolism ; Heme Oxygenase-1 ; Hemorheology ; Humans ; Membrane Proteins ; Multienzyme Complexes/*metabolism ; NADH, NADPH Oxidoreductases/*metabolism ; Oxidation-Reduction ; Stress, Mechanical ; Superoxide Dismutase/genetics/metabolism ; Superoxides/*metabolism ; }, abstract = {Atherosclerotic lesions are found opposite vascular flow dividers at sites of low shear stress and oscillatory flow. Since endothelial proinflammatory genes prominent in lesions are regulated by oxidation-sensitive transcriptional control mechanisms, we examined the redox state of cultured human umbilical vein endothelial cells after either oscillatory or steady laminar fluid shear stress. Endothelial oxidative stress was assessed by measuring activity of the superoxide (O2.-)-producing NADH oxidase (a major source of reactive oxygen species in vascular cells), intracellular O2.- levels, induction of the redox-sensitive gene heme oxygenase-1 (HO-1), and abundance of Cu/Zn superoxide dismutase (Cu/Zn SOD), an antioxidant defense enzyme whose level of expression adapts to changes in oxidative stress. When cells were exposed to oscillatory shear (+/-5 dyne/cm2, 1 Hz) for 1, 5, and 24 hours, NADH oxidase activity and the amount of HO-1 progressively increased up to 174+/-16% (P<0.05) and 505+/-111% (P<0.05) versus static conditions, respectively, whereas levels of Cu/Zn SOD remained unchanged. This upregulation of HO-1 was completely blocked by the antioxidant N-acetylcysteine (NAC, 20 mmol/L). In contrast, steady laminar shear (5 dyne/cm2) induced NADH oxidase activity and NAC-sensitive HO-1 mRNA expression only at 1 and 5 hours, a transient response that returned toward baseline at 24 hours. Levels of Cu/Zn SOD mRNA and protein were increased after 24 hours of steady laminar shear. Furthermore, intracellular O2.-, as measured by dihydroethidium fluorescence, was higher in cells exposed to oscillatory than to laminar shear. These data are consistent with the hypothesis that continuous oscillatory shear causes a sustained activation of pro-oxidant processes resulting in redox-sensitive gene expression in human endothelial cells. Steady laminar shear stress initially activates these processes but appears to induce compensatory antioxidant defenses. We speculate that differences in endothelial redox state, orchestrated by different regimens of shear stress, may contribute to the focal nature of atherosclerosis.}, }
@article {pmid9620673, year = {1998}, author = {Nakamura, M and Nakashima, S and Katagiri, Y and Nozawa, Y}, title = {Involvement of tyrosine phosphorylation in inhibition of fMLP-induced PLD activation by N-acetyl-L-cysteine in differentiated HL60 cells.}, journal = {Journal of leukocyte biology}, volume = {63}, number = {6}, pages = {781-789}, doi = {10.1002/jlb.63.6.781}, pmid = {9620673}, issn = {0741-5400}, mesh = {Acetylcysteine/*pharmacology ; Androstadienes/pharmacology ; Cell Differentiation/drug effects ; Chelating Agents/pharmacology ; Cysteine/pharmacology ; Dithiothreitol/pharmacology ; Enzyme Activation/drug effects ; Free Radical Scavengers/*pharmacology ; HL-60 Cells/cytology/drug effects/enzymology ; Humans ; Inositol Phosphates/metabolism ; N-Formylmethionine Leucyl-Phenylalanine/*antagonists &amp; inhibitors/*pharmacology ; Oxidants/pharmacology ; Phosphodiesterase Inhibitors/pharmacology ; Phospholipase D/drug effects/*metabolism ; Phosphorylation ; Sulfhydryl Reagents/pharmacology ; Tyrosine/*metabolism ; Unithiol/pharmacology ; Wortmannin ; }, abstract = {N-acetyl-L-cysteine (NAC), which is known as a multipotential agent; an antioxidant, a thiol reagent, or a tyrosine kinase inhibitor, inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced phospholipase D (PLD) activation in HL60 cells in a concentration-dependent manner (IC50 = 2 mM). Its inhibitory mechanism was examined in this study to gain insight into the regulation of PLD activity. NAC had no direct effect on membrane PLD activity in an in vitro assay system. fMLP-induced formation of inositol phosphates via phospholipase C (PLC) was not affected by the drug, suggesting that the receptor-G protein coupling was not inhibited. H2O2, which is known to induce PLD activation in several types of cells, failed to activate PLD in HL60 cells. Pretreatment of 3-amino-1,2,4-triazole (ATZ), a catalase inhibitor, did not enhance fMLP-induced PLD activation. NAC inhibited fMLP-induced tyrosine phosphorylation of several protein bands (42, 44, 64, and 138 kDa) in a concentration-dependent manner. The temporal and concentration-dependent inhibitory profiles for tyrosine phosphorylation of 64- and 138-kDa proteins were well correlated with PLD activation. However, thiol reagents, 1 mM 2,3-dimercapto-l-propanol (2,3-DMP), 1 mM dithiothreitol (DTT), and 2 mM cysteine also did not suppress protein tyrosine phosphorylation or PBut formation by fMLP. Wortmannin, a selective phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, inhibited these two tyrosine phosphorylation bands. These results suggest that NAC inhibits fMLP-induced PLD activation through blockage of protein tyrosine phosphorylation, which is located at the downstream of PI-3 kinase.}, }
@article {pmid9618303, year = {1998}, author = {Rezaul, K and Sada, K and Yamamura, H}, title = {Involvement of reactive oxygen intermediates in lectin-induced protein-tyrosine phosphorylation of Syk in THP-1 cells.}, journal = {Biochemical and biophysical research communications}, volume = {246}, number = {3}, pages = {863-867}, doi = {10.1006/bbrc.1998.8691}, pmid = {9618303}, issn = {0006-291X}, mesh = {Antioxidants/pharmacology ; Cell Line ; Concanavalin A/*pharmacology ; Enzyme Precursors/*metabolism ; Intracellular Signaling Peptides and Proteins ; Isoenzymes/metabolism ; Monocytes/cytology/*drug effects ; Phospholipase C gamma ; Phosphorylation ; Protein-Tyrosine Kinases/*metabolism ; Reactive Oxygen Species/*metabolism ; Receptors, IgG/metabolism ; Signal Transduction/drug effects ; Superoxides/metabolism ; Syk Kinase ; Type C Phospholipases/metabolism ; Tyrosine/metabolism ; }, abstract = {Oxidative stress (H2O2) has been shown to be associated with tyrosine phosphorylation and activation of protein-tyrosine kinase Syk. In the present study, we examined the possibility that reactive oxygen intermediates (ROI) were involved in concanavalin A (Con A)-induced tyrosine phosphorylation in THP-1 cells. Rapid tyrosine phosphorylations of Syk, Fc gamma receptor(s) and phospholipase C gamma 2 (PLC gamma 2) were induced by Con A treatment in THP-1 cells. Pretreatment of cells with antioxidants N-acetylcysteine (NAC) and glutathione (GSH) almost completely blocked tyrosine phosphorylations of Syk, Fc gamma receptor(s) and PLC gamma 2. In addition, THP-1 cells showed significant levels of ROI from the early period of Con A treatment and the levels of ROI were inhibited by antioxidant treatment. These data suggest that ROI have an important role in Con A-induced protein-tyrosine kinase(s) signaling pathways.}, }
@article {pmid9592085, year = {1998}, author = {Yan, CY and Greene, LA}, title = {Prevention of PC12 cell death by N-acetylcysteine requires activation of the Ras pathway.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {18}, number = {11}, pages = {4042-4049}, pmid = {9592085}, issn = {0270-6474}, mesh = {Acetylcysteine/*pharmacology ; Androstadienes/pharmacology ; Animals ; Apoptosis/*drug effects ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors/metabolism ; Cell Cycle/drug effects/physiology ; Cell Survival/drug effects ; Chromones/pharmacology ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Free Radical Scavengers/*pharmacology ; Gene Expression Regulation/drug effects ; Genes, Immediate-Early/genetics ; Humans ; Mitogen-Activated Protein Kinase 3 ; *Mitogen-Activated Protein Kinases ; Morpholines/pharmacology ; Neurons/*cytology/drug effects/enzymology ; Nitric Oxide Synthase/antagonists &amp; inhibitors/metabolism ; PC12 Cells ; Rats ; Signal Transduction/drug effects ; Wortmannin ; ras Proteins/*metabolism ; }, abstract = {We have shown that N-acetylcysteine (NAC) promotes survival of sympathetic neurons and pheochromocytoma (PC12) cells in the absence of trophic factors. This action of NAC was not related to its antioxidant properties or ability to increase intracellular glutathione levels but was instead dependent on ongoing transcription and seemed attributable to the action of NAC as a reducing agent. Here, we investigate the mechanism by which NAC promotes neuronal survival. We show that NAC activates the Ras-extracellular signal-regulated kinase (ERK) pathway in PC12 cells. Ras activation by NAC seems necessary for survival in that it is unable to sustain serum-deprived PC12 MM17-26 cells constitutively expressing a dominant-negative form of Ras. Promotion of PC12 cell survival by NAC is totally blocked by PD98059, an inhibitor of the ERK-activating MAP kinase/ERK kinase, suggesting a required role for ERK activation in the NAC mechanism. In contrast, LY294002 and wortmannin, inhibitors of phosphatidylinositol 3-kinase (PI3K) that partially block NGF-promoted PC12 cell survival, have no effect on prevention of death by NAC. We hypothesized previously that the ability of NAC to promote survival correlates with its antiproliferative properties. However, although NAC does not protect PC12 MM17-26 cells from loss of trophic support, it does inhibit their capacity to synthesize DNA. Thus, the antiproliferative effect of NAC does not require Ras activation, and inhibition of DNA synthesis is insufficient to mediate NAC-promoted survival. These findings highlight the role of Ras-ERK activation in the mechanism by which NAC prevents neuronal death after loss of trophic support.}, }
@article {pmid9609383, year = {1998}, author = {Vermeulen, NP and Commandeur, JN and Groot, EJ and Wormhoudt, LW and Ramnatshing, S and Li, QJ and Brakenhoff, JP}, title = {Toxicity of fotemustine in rat hepatocytes and mechanism-based protection against it.}, journal = {Chemico-biological interactions}, volume = {110}, number = {3}, pages = {139-158}, doi = {10.1016/s0009-2797(98)00004-0}, pmid = {9609383}, issn = {0009-2797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*toxicity ; Antioxidants/*pharmacology ; Cell Survival/drug effects ; Cells, Cultured ; Glutathione/*metabolism/pharmacology ; Glutathione Disulfide/metabolism ; Kinetics ; L-Lactate Dehydrogenase/analysis ; Lipid Peroxidation/drug effects ; Liver/*drug effects/metabolism/pathology ; Male ; Nitrosourea Compounds/*toxicity ; Organophosphorus Compounds/*toxicity ; Rats ; Rats, Wistar ; Sulfhydryl Reagents/*pharmacology ; Vitamin E/*pharmacology ; }, abstract = {Fotemustine is a relatively novel DNA-alkylating 2-chloroethyl-substituted N-nitrosourea (CENU) drug, clinically used for the treatment of disseminated malignant melanoma in different visceral and non-visceral tissues. Thrombocytopenia has been observed in patients treated with fotemustine and liver and renal toxicities as well. In this study, firstly the metabolism of fotemustine was investigated in vitro and secondly the undesired cytotoxicity of fotemustine as well as different ways of protection against it. In rat hepatocytes, chosen as a model system, fotemustine was shown to cause lactate dehydrogenase (LDH) leakage, glutathione (GSH) depletion, GSSG-formation and lipid peroxidation (LPO). A reactive metabolite, DEP-isocyanate, is most likely responsible for these undesired cytotoxic effects. Based on the observed cytotoxicity mechanisms, chemoprotection with several sulfhydryl-containing nucleophiles and antioxidants was investigated. The sulfhydryl nucleophiles; GSH, N-acetyl-L-cysteine (NAC) and glutathione isopropylester (GSH-IP) protected almost completely against fotemustine-induced LDH-leakage and LPO. NAC and GSH protected partly against fotemustine-induced GSH-depletion. The antioxidant, vitamin E protected completely against fotemustine-induced LPO, but only partly against fotemustine-induced LDH-leakage and not against GSH-depletion. Ebselen, a peroxidase-mimetic organoselenium compound, did not show protective effects against the cytotoxicity of fotemustine, possibly because GSH is required for the bioactivation of ebselen. It is concluded that co-administration of sulfhydryl nucleophiles, in particular NAC and GSH-IP, possibly in combination with antioxidants, such as vitamin E, are effective against the toxicity of fotemustine in vitro. It might, therefore, be worthwhile to investigate the cytoprotective potency of these agents against undesired toxicities of fotemustine in vivo as well.}, }
@article {pmid9596687, year = {1998}, author = {Gibson, XA and Shartava, A and McIntyre, J and Monteiro, CA and Zhang, Y and Shah, A and Campbell, NF and Goodman, SR}, title = {The efficacy of reducing agents or antioxidants in blocking the formation of dense cells and irreversibly sickled cells in vitro.}, journal = {Blood}, volume = {91}, number = {11}, pages = {4373-4378}, pmid = {9596687}, issn = {0006-4971}, support = {3P60 HL38639/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Actins/metabolism ; Anemia, Sickle Cell/*blood ; Antioxidants/*pharmacology ; Centrifugation, Density Gradient ; Dithiothreitol/pharmacology ; Erythrocyte Aggregation/*drug effects ; Erythrocyte Count/drug effects ; Glutathione/metabolism ; Humans ; In Vitro Techniques ; Reducing Agents/*pharmacology ; }, abstract = {We show that N-acetylcysteine (NAC) has the ability to cause statistically significant diminishment in the in vitro formation of irreversibly sickled cells (ISCs) at concentrations greater than 250 micromol/L. Other antioxidants, approved for human use (cysteamine, succimer, dimercaprol), were not efficacious. NAC had the ability to cause statistically significant conversion of ISCs formed in vivo back to the biconcave shape. NAC was also shown to reduce the formation of dense cells and increase the available thiols in beta-actin. We showed that diminishing reduced glutathione (GSH), by treatment with 1-chloro-2,4-dinitrobenzene, resulted in increased dense cells. We conclude the NAC blocks dense cell formation and ISC formation by targeting channels involved in cellular dehydration and beta-actin, respectively. The efficacy of NAC is probably due to its combined antioxidant activity and ability to increase intracellular GSH.}, }
@article {pmid9603282, year = {1998}, author = {Grossman, N and Schneid, N and Reuveni, H and Halevy, S and Lubart, R}, title = {780 nm low power diode laser irradiation stimulates proliferation of keratinocyte cultures: involvement of reactive oxygen species.}, journal = {Lasers in surgery and medicine}, volume = {22}, number = {4}, pages = {212-218}, doi = {10.1002/(sici)1096-9101(1998)22:4&lt;212::aid-lsm5&gt;3.0.co;2-s}, pmid = {9603282}, issn = {0196-8092}, mesh = {Acetates/pharmacology ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Catalase/pharmacology ; Cell Count ; Cell Division/drug effects/radiation effects ; Cells, Cultured ; Enzyme Inhibitors/pharmacology ; Follow-Up Studies ; Free Radical Scavengers/pharmacology ; Histidine/pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Hydroxyl Radical/pharmacology ; Keratinocytes/cytology/drug effects/metabolism/*radiation effects ; *Lasers ; Lipid Peroxidation ; Mannitol/pharmacology ; Radiopharmaceuticals ; Reactive Oxygen Species/*physiology ; Sodium Azide/pharmacology ; Superoxide Dismutase/pharmacology ; Superoxides/pharmacology ; Thymidine/metabolism ; Tritium ; Vitamin E/pharmacology ; }, abstract = {BACKGROUND AND OBJECTIVE: The purpose of this study was to determine irradiation parameters of a 780 nm low power CW diode laser (6.5 mW) leading to enhanced proliferation of cultured normal human keratinocytes (NHK). The possible role of reactive oxygen species (ROS) in this response was evaluated.<br><br>NHK were exposed to a single dose of 0 to 3.6 J/cm2 (0-180 sec) of irradiation. Proliferation parameters studied were: incorporation of 3H-thymidine during 6-24 hr following irradiation; percentage of dividing cells and number of cells, 24 hr and 48 hr following irradiation, respectively.<br><br>RESULTS: Proliferation of NHK exposed to 0.45-0.95 J/cm2 was significantly enhanced by 1.3-1.9-folds relative to sham-irradiated controls, as inferred from parameters studied. Exposure to other energy densities was considerably less effective in enhancing proliferation parameters. Added enzymatic antioxidants, superoxide dismutase or catalase, scavenging superoxide anions and H2O2, suppressed this enhanced proliferation. Added scavengers (alpha-tocopherol acetate, scavenging lipid peroxidation, or sodium azide, histidine, mannitol, scavenging singlet oxygen, superoxide anions, and hydroxyl radicals, respectively), or N-acetyl cysteine, the thiol-reducing agent, suppressed the response, but to different extents.<br><br>CONCLUSIONS: The results indicate that 780 nm low power diode laser irradiation enhanced keratinocytes proliferation in vitro, with an apparent involvement of ROS in this response, and comparably, might be used to promote their proliferation in vivo to enhance wound healing.}, }
@article {pmid9602121, year = {1998}, author = {Carroll, JE and Howard, EF and Hess, DC and Wakade, CG and Chen, Q and Cheng, C}, title = {Nuclear factor-kappa B activation during cerebral reperfusion: effect of attenuation with N-acetylcysteine treatment.}, journal = {Brain research. Molecular brain research}, volume = {56}, number = {1-2}, pages = {186-191}, doi = {10.1016/s0169-328x(98)00045-x}, pmid = {9602121}, issn = {0169-328X}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Antioxidants/pharmacology ; Cerebral Arteries ; Cerebral Infarction/metabolism/pathology ; Injections, Intraperitoneal ; Ischemic Attack, Transient/*metabolism ; Male ; NF-kappa B/analysis/*antagonists &amp; inhibitors/biosynthesis ; Rats ; Rats, Wistar ; Reperfusion Injury/*metabolism ; }, abstract = {We examined activation of the transcription factor, nuclear factor-kappaB (NF-kappaB), which participates in the upregulation of endothelial cell adhesion proteins, during reperfusion after temporary middle cerebral artery occlusion (TMCAO). We hypothesized that N-acetylcysteine (NAC), an antioxidant which inhibits NF-kappaB activation, would alter events in brain reperfusion injury. We used a rat model of TMCAO. The left sides of the brains were rendered ischemic for 2 h, and then the area was allowed to reperfuse. The animals were treated with NAC (150 mg/kg) or saline placebo, sacrificed, and activated NF-kappaB was assessed in both the left and right hemispheres, all at varying intervals. Cerebral infarction volume was also measured in each of the hemispheres collected from a separate group of animals. Activated NF-kappaB, consisting of p65 and p50 Rel proteins, was significantly increased 15 min after reperfusion in the affected hemisphere. The activation at 15 min was completely abolished with NAC treatment. NAC treatment 1 h prior to the end of occlusion and at 24 h reduced the percentage infarction volume of the affected hemispheres from 35.5+/-2.8% (S.E.) to 18. 1+/-2.1% (p<0.01). NAC treatment at 1 h after the occlusion (after the NF-kappaB peak) and again at 24 h also significantly reduced the percentage infarction volume from 34.8+/-3.8% to 24.6+/-3.8% (p<0. 05). Thus, while NAC inhibited activation of NF-kappaB at 15 min after reperfusion, the drug acted to reduce cerebral infarction by additional, undefined mechanisms. These results bring into question the various roles of NF-kappaB in cerebral infarction followed by reperfusion.}, }
@article {pmid9601681, year = {1998}, author = {Noel, F and Tofilon, PJ}, title = {Astrocytes protect against X-ray-induced neuronal toxicity in vitro.}, journal = {Neuroreport}, volume = {9}, number = {6}, pages = {1133-1137}, doi = {10.1097/00001756-199804200-00032}, pmid = {9601681}, issn = {0959-4965}, support = {CA16672/CA/NCI NIH HHS/United States ; CA50207/CA/NCI NIH HHS/United States ; CA72156/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Astrocytes/*physiology ; Cell Communication ; Cells, Cultured ; Cerebral Cortex/*physiology/radiation effects ; Free Radical Scavengers/pharmacology ; Neurons/*radiation effects ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The role of neuronal damage in the radiation-induced CNS injury resulting from brain tumor therapy remains poorly understood. To begin to define the radioresponse of neurons, the survival of rat cortical neuron cultures was investigated. Neuronal survival was reduced by approximately 40% 24-48 h after irradiation with 3.5 Gy. The addition of the free radical scavenger NAC after irradiation increased neuronal survival. Neurons were also significantly less sensitive to radiation in co-cultures with astrocytes or in the presence of astrocyte-conditioned medium. Medium conditioned on astrocytes was found to acquire significant free radical scavenging capability. However, this antioxidant property does not appear to be responsible for neuronal radioprotection. The ability of astrocytes to reduce radiation-induced neuronal toxicity appears to be mediated by a soluble protein(s) of mol. wt > 10 kDa.}, }
@article {pmid9600699, year = {1998}, author = {Smith, WA and Arif, JM and Gupta, RC}, title = {Effect of cancer chemopreventive agents on microsome-mediated DNA adduction of the breast carcinogen dibenzo[a,l]pyrene.}, journal = {Mutation research}, volume = {412}, number = {3}, pages = {307-314}, doi = {10.1016/s1383-5718(97)00203-9}, pmid = {9600699}, issn = {0027-5107}, support = {ES07266/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Antineoplastic Agents/*pharmacology ; Benzopyrenes/*metabolism/toxicity ; Biotransformation ; Carcinogens/*metabolism/toxicity ; Chemoprevention ; DNA Adducts/*drug effects ; Female ; Mammary Neoplasms, Experimental/chemically induced/drug therapy ; Microsomes, Liver/*drug effects ; Rats ; }, abstract = {Due to the large and expanding number of potential cancer chemopreventive agents, there is an increasing need for short term tests to study the efficacy and mechanisms of these agents. In this study, we have employed a microsome-mediated test system to study the effect of several suspected chemopreventive agents on the DNA adduct formation capacity of the potent mammary carcinogen, dibenzo[a,l]pyrene (DBP). Bioactivation of DBP by Aroclor 1254-induced rat liver microsomes in the presence of calf thymus DNA (300 microg/ml) resulted in the formation of one major and six other prominent DNA adducts (324 adducts/10(7) nucleotides). These adducts were previously determined to be deoxyadenosine (dA) and deoxyanosine (dG)-derivatives of both anti- and syn-DBP-11,12-diol-13,14-epoxides (DBPDE). Intervention with ellagic acid, chlorophyllin, benzyl isocyanate (BIC), oltipraz or genistein (150 microM) strongly diminished DBP-DNA adduction by > or = 75%. Linoleic acid, curcumin and butylated hydroxytoluene (BHT) also significantly inhibited DBP DNA adduction (26-46%) while N-acetylcysteine (NAC) had no effect. Moreover, nonenzymatic studies with anti- and syn-DBPDE isomers revealed that chlorophyllin, ellagic acid, BIC and BHT may be inhibiting DBP-DNA adduction in an enzymatic-independent manner since these agents diminished DBPDE-DNA adduction by 30-75%. Genistein, oltipraz and curcumin did not diminish DBPDE-DNA adduction and therefore most likely require the presence of the microsomal subcellular fraction to inhibit DBP-DNA adduction.}, }
@article {pmid9593012, year = {1998}, author = {Mastronarde, JG and Monick, MM and Mukaida, N and Matsushima, K and Hunninghake, GW}, title = {Activator protein-1 is the preferred transcription factor for cooperative interaction with nuclear factor-kappaB in respiratory syncytial virus-induced interleukin-8 gene expression in airway epithelium.}, journal = {The Journal of infectious diseases}, volume = {177}, number = {5}, pages = {1275-1281}, doi = {10.1086/515279}, pmid = {9593012}, issn = {0022-1899}, support = {HL-38121/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cell Line ; Cell Nucleus/metabolism ; Chloramphenicol O-Acetyltransferase/biosynthesis ; Cyclic N-Oxides/pharmacology ; Dimethyl Sulfoxide/pharmacology ; Epithelial Cells ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Interleukin-8/*biosynthesis ; Lung Neoplasms ; NF-kappa B/*metabolism ; Recombinant Proteins/biosynthesis ; Respiratory Syncytial Viruses/drug effects/*physiology ; Transcription Factor AP-1/*metabolism ; Transfection ; Tumor Cells, Cultured ; }, abstract = {The role of "oxidant-sensitive" transcription factors activator protein (AP)-1, nuclear factor (NF)-kappaB, and NF-IL6 in respiratory syncytial virus (RSV)-induced interleukin (IL)-8 gene expression in A549 epithelial cells was evaluated. RSV infection resulted in increased binding of each of these transcription factors. Transfection of A549 cells with plasmids containing serial truncations of the 5'-flanking region of the IL-8 gene revealed a positive cooperative effect of the binding sites for AP-1 and NF-kappaB. Mutation of either region markedly diminished responsiveness of the promoter to RSV. Mutation of the NF-IL6 site had minimal effect in the presence of intact binding sites for NF-kappaB and AP-1. The antioxidants NAC (N-acetylcysteine), DMSO, and DMPO (5,5-dimethyl-1-pyrroline N-oxide) did not inhibit RSV-induced binding of NF-kappaB; however, binding of AP-1 and NF-IL6 was inhibited. These observations suggest that AP-1 may be the preferred transcription factor (over NF-IL6) for cooperative interaction with NF-kappaB in RSV-induced IL-8 production.}, }
@article {pmid9586816, year = {1998}, author = {Lee, SL and Wang, WW and Fanburg, BL}, title = {Superoxide as an intermediate signal for serotonin-induced mitogenesis.}, journal = {Free radical biology &amp; medicine}, volume = {24}, number = {5}, pages = {855-858}, doi = {10.1016/s0891-5849(97)00359-6}, pmid = {9586816}, issn = {0891-5849}, support = {HL 32723/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Biological Transport, Active/drug effects ; Cattle ; Cell Division/drug effects ; Luminescent Measurements ; Mitosis/*drug effects ; Muscle, Smooth, Vascular/cytology/*drug effects/metabolism ; Phosphorylation ; Serotonin/*pharmacology ; Signal Transduction/*physiology ; Stimulation, Chemical ; Superoxides/*metabolism ; }, abstract = {Serotonin (5-HT) stimulates tyrosine phosphorylation and proliferation of bovine pulmonary artery smooth muscle cells (SMC) through its active transport (Lee et al, 1991). The present studies show that 5-HT also rapidly elevates O2.- formation by these cells within 10 minutes as measured by a lucigenin-enhanced chemiluminescence assay. The O2.- free radical quencher, Tiron, and N-acetyl-cysteine, a substrate for glutathione, block both the 5-HT-induced formation of O2.- and cellular proliferation. Similarly, inhibition of 5-HT transport with imipramine or treatment of cells with diphenyliodonium, a NAD(P)H oxidase inhibitor, block both 5-HT-induced elevation of O2.- and cellular proliferation. Alpha-hydroxyfarnesylphosphonic acid, an inhibitor of p21ras, also blocks 5-HT-induced proliferation. Endothelial cells from the same vessel show neither 5-HT-induced proliferation nor stimulation of O2.- formation. We conclude that 5-HT induced cellular proliferation of SMC through signaling pathways that utilize its transport system and O2.- formation.}, }
@article {pmid9581775, year = {1998}, author = {DeLuca, C and Kwon, H and Pelletier, N and Wainberg, MA and Hiscott, J}, title = {NF-kappaB protects HIV-1-infected myeloid cells from apoptosis.}, journal = {Virology}, volume = {244}, number = {1}, pages = {27-38}, doi = {10.1006/viro.1998.9085}, pmid = {9581775}, issn = {0042-6822}, mesh = {*Apoptosis ; DNA-Binding Proteins/metabolism ; HIV-1/*physiology ; Humans ; *I-kappa B Proteins ; Jurkat Cells ; Monocytes/pathology/*virology ; NF-KappaB Inhibitor alpha ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Tumor Cells, Cultured ; bcl-2-Associated X Protein ; }, abstract = {HIV-1 infection of primary monocytic cells and myeloid cell lines results in sustained NF-kappaB activation. Recently, NF-kappaB induction has been shown to play a role in protecting cells from programmed cell death. In the present study, we sought to investigate whether constitutive NF-kappaB activity in chronically HIV-1-infected promonocytic U937 (U9-IIIB) and myeloblastic PLB-985 (PLB-IIIB) cells affects apoptotic signaling. TNFalpha and cycloheximide caused infected cells to undergo apoptosis more rapidly than parental U937 and PLB-985 cells. Inhibition of TNFalpha-induced NF-kappaB activation using the antioxidant N-acetylcysteine (NAC) resulted in increased apoptosis in both U937 and U9-IIIB cells, while preactivation of NF-kappaB with the non-apoptotic inducer IL-1beta caused a relative decrease in apoptosis. Inhibition of constitutive NF-kappaB activity in U9-IIIB and PLB-IIIB cells also induced apoptosis, suggesting that NF-kappaB protects cells from a persistent apoptotic signal. TNFalpha plus NAC treatment resulted in a marked decrease in Bcl-2 protein levels in HIV-1-infected cells, coupled with an increase in Bax protein compared to uninfected cells, suggesting that the difference in susceptibility to TNFalpha-induced apoptosis may relate to the differences in relative levels of Bcl-2 and Bax. The protective role of NF-kappaB in blocking TNFalpha- and HIV-1-induced apoptosis was supported by studies in Jurkat T cells engineered to express IkappaB alpha repressor mutants (TD-IkappaB) under the control of a tetracycline-responsive promoter. Cells underwent apoptosis in response to TNFalpha only when NF-kappaB activation was inhibited by TD-IkappaB expression. As was observed for the U9-IIIB cells, TNFalpha treatment also induced a marked decrease in Bcl-2 protein levels in TD-IkappaB expressing cells. These experiments demonstrate that apoptotic signaling is perturbed in HIV-1-infected U9-IIIB cells and indicate that NF-kappaB activation may play an additional protective role against HIV-1-induced apoptosis in myeloid cells.}, }
@article {pmid9581680, year = {1998}, author = {Kawada, N and Seki, S and Inoue, M and Kuroki, T}, title = {Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells.}, journal = {Hepatology (Baltimore, Md.)}, volume = {27}, number = {5}, pages = {1265-1274}, doi = {10.1002/hep.510270512}, pmid = {9581680}, issn = {0270-9139}, mesh = {Actins/genetics/metabolism ; Animals ; Antioxidants/*pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cell Cycle/drug effects ; Cell Division/drug effects ; Gene Expression Regulation/drug effects ; Inositol Phosphates/metabolism ; Kupffer Cells/*drug effects ; Liver/cytology/*drug effects ; Male ; Nitric Oxide/metabolism ; Phosphotyrosine/metabolism ; Quercetin/*pharmacology ; RNA, Messenger/genetics ; Rats ; Rats, Wistar ; Resveratrol ; Stilbenes/*pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Effects of antioxidants, resveratrol, quercetin, and N-acetylcysteine (NAC) on the functions of cultured rat hepatic stellate cells and Kupffer cells were studied. These compounds dose-dependently suppressed serum-dependent proliferation of stellate cells as determined by [3H]thymidine and 5-bromo-2'-deoxyuridine uptake. Expression of smooth muscle alpha-actin was suppressed by a high dose of resveratrol and quercetin. These phenolic compounds also suppressed inositol phosphate metabolism, tyrosine phosphorylation, and mitogen-activated protein (MAP) kinase activation in platelet-derived growth factor/BB-stimulated stellate cells. Moreover, the phenolic compounds selectively reduced the level of cell cycle protein cyclin D1 in stellate cells. Thus, resveratrol and quercetin might inhibit stellate cell activation by perturbing signal transduction pathway and cell cycle protein expression, whereas mechanism of potent antiproliferative effect of NAC remains to be elucidated. On the other hand, kinetic analysis showed that production of nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) by lipopolysaccharide-stimulated Kupffer cells was strongly inhibited by resveratrol and quercetin but not by NAC. Although expression of messenger RNAs for inducible NO synthase and TNF-alpha was not affected by the phenolic compounds, cellular levels of inducible NO synthase and TNF-alpha secretion were suppressed significantly, indicating the posttranscriptional process of generating these proteins might be affected predominantly by these phenolic compounds. Thus, NAC and these phenolic compounds may have therapeutic potential against liver injury by regulating functions of hepatic stellate cells and Kupffer cells.}, }
@article {pmid9577247, year = {1998}, author = {Kelly, GS}, title = {Clinical applications of N-acetylcysteine.}, journal = {Alternative medicine review : a journal of clinical therapeutic}, volume = {3}, number = {2}, pages = {114-127}, pmid = {9577247}, issn = {1089-5159}, mesh = {Acetylcysteine/adverse effects/pharmacology/*therapeutic use ; Antiviral Agents/therapeutic use ; Expectorants/therapeutic use ; Free Radical Scavengers/adverse effects/pharmacology/*therapeutic use ; Glutathione/biosynthesis ; Humans ; Poisoning/drug therapy ; }, abstract = {N-acetylcysteine (NAC), the acetylated variant of the amino acid L-cysteine, is an excellent source of sulfhydryl (SH) groups, and is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification, and acting directly as free radical scavengers. Administration of NAC has historically been as a mucolytic agent in a variety of respiratory illnesses; however, it appears to also have beneficial effects in conditions characterized by decreased GSH or oxidative stress, such as HIV infection, cancer, heart disease, and cigarette smoking. An 18-dose oral course of NAC is currently the mainstay of treatment for acetaminophen-induced hepatotoxicity. N-acetylcysteine also appears to have some clinical usefulness as a chelating agent in the treatment of acute heavy metal poisoning, both as an agent capable of protecting the liver and kidney from damage and as an intervention to enhance elimination of the metals.}, }
@article {pmid9572162, year = {1998}, author = {Rebbeor, JF and Wang, W and Clifton, D and Ballatori, N}, title = {Glutathione S-conjugate formation and metabolism in HepG2 cells: a cell model of mercapturic acid biosynthesis.}, journal = {Journal of toxicology and environmental health. Part A}, volume = {53}, number = {8}, pages = {651-663}, doi = {10.1080/009841098159097}, pmid = {9572162}, issn = {1528-7394}, support = {ES01247/ES/NIEHS NIH HHS/United States ; ES06484/ES/NIEHS NIH HHS/United States ; ES07026/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/analogs &amp; derivatives/metabolism/*pharmacokinetics ; Biological Transport ; Carcinoma, Hepatocellular ; Cysteine/chemistry ; Dinitrochlorobenzene/metabolism ; Glutathione/*metabolism ; Humans ; Inactivation, Metabolic ; Liver Neoplasms ; Models, Biological ; Tumor Cells, Cultured ; }, abstract = {Mercapturic acid biosynthesis is mediated by a series of at least four enzymatic steps and three cell membrane transport events, and is believed to require the interorgan shuttling of the various metabolic intermediates. To identify a single cell type that can carry out all of these metabolic and transport steps, the present study examined whether HepG2 cells, a human hepatoma-derived cell line, can convert an electrophilic chemical (1-chloro-2,4-dinitrobenzene, CDNB) to its corresponding mercapturic acid (S-dinitrophenyl-N-acetylcysteine, DNP-NAC). The results demonstrate that HepG2 cells are able to convert CDNB to DNP-NAC in a dose- and time-dependent fashion. Intracellular conjugation with glutathione occurred rapidly, and the resulting glutathione S-conjugate was promptly transported into the culture medium, where it was sequentially degraded to the cysteinylglycine and cysteine S-conjugates. The cysteine conjugate was then presumably reabsorbed, and N-acetylated intracellularly to form the mercapturic acid. The mercapturic acid was found to accumulate slowly in the culture medium, such that after 4 h of incubation, 4-10% of the CDNB dose was recovered as the mercapturic acid. These data provide the first demonstration that a single cell type can carry out all of the transport and enzymatic steps required for mercapturic acid biosynthesis. HepG2 cells may provide a useful model system for studying this important detoxification pathway.}, }
@article {pmid9571990, year = {1998}, author = {Sekharam, M and Trotti, A and Cunnick, JM and Wu, J}, title = {Suppression of fibroblast cell cycle progression in G1 phase by N-acetylcysteine.}, journal = {Toxicology and applied pharmacology}, volume = {149}, number = {2}, pages = {210-216}, doi = {10.1006/taap.1997.8361}, pmid = {9571990}, issn = {0041-008X}, support = {T32 DA 07245/DA/NIDA NIH HHS/United States ; }, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors/metabolism ; Cell Cycle/*drug effects ; Cell Death/drug effects ; Cell Division/drug effects ; Cyclin D1/antagonists &amp; inhibitors/biosynthesis ; DNA/biosynthesis ; Enzyme Activation/drug effects ; Enzyme Inhibitors/pharmacology ; Flavonoids/pharmacology ; Flow Cytometry ; Free Radical Scavengers/*pharmacology ; G1 Phase/drug effects ; MAP Kinase Kinase 1 ; Mice ; *Mitogen-Activated Protein Kinase Kinases ; Proliferating Cell Nuclear Antigen/metabolism ; Protein Serine-Threonine Kinases/antagonists &amp; inhibitors ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors ; }, abstract = {The antioxidant N-acetyl-L-cysteine (NAC) has been increasingly used as an experimental tool to assess involvement of reactive oxygen species in cell signaling and is being evaluated as a preventive and therapeutic agent for cancer and pulmonary diseases related to inflammation and oxidative stress. However, a detailed characterization of the effect of NAC on cell cycle progression has not been reported. In the present study, modulation of cell cycle progression by NAC was analyzed in mouse fibroblast NIH3T3 cells grown in 10% fetal bovine serum. Complete inhibition of NIH3T3 cell proliferation was obtained with 20 mM NAC. Inhibition of cell proliferation by NAC (at or below 20 mM) was not due to cell death, and the antiproliferative effect of NAC was reversible. Flow cytometric analysis of cell cycle phase distribution indicated that NAC blocked the cell cycle in the G1 phase. Consistent with this observation, NAC inhibited DNA synthesis. After releasing the G1-block by NAC, S phase re-entry occurred between 8 and 12 h, suggesting that NAC blocked the cell cycle in early to mid-G1 phase. NAC prevented activation of mitogen-activated protein (MAP) kinases p42MAPK and p44MAPK and inhibited expression of cyclin D1, but had no effect on the levels of proliferating cell nuclear antigen. Incubation of cells with PD98059, a specific inhibitor of MAP kinase kinase 1, partially arrested the cell cycle in the G1 phase. These results indicate that the antiproliferative effect of NAC is linked in part to inhibition of the MAP kinase pathway.}, }
@article {pmid9568703, year = {1998}, author = {Wentzel, P and Eriksson, UJ}, title = {Antioxidants diminish developmental damage induced by high glucose and cyclooxygenase inhibitors in rat embryos in vitro.}, journal = {Diabetes}, volume = {47}, number = {4}, pages = {677-684}, doi = {10.2337/diabetes.47.4.677}, pmid = {9568703}, issn = {0012-1797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Arachidonic Acid/metabolism/pharmacology ; Aspirin/pharmacology ; Culture Techniques ; Cyclooxygenase Inhibitors/*pharmacology ; Dinoprostone/metabolism/pharmacology ; *Embryo, Mammalian/abnormalities/drug effects/metabolism ; Embryonic and Fetal Development/*drug effects ; Glucose/*toxicity ; Indomethacin/pharmacology ; Prostaglandin-Endoperoxide Synthases/*metabolism ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/pharmacology ; }, abstract = {Previous studies have suggested that the metabolism of arachidonic acid and radical oxygen species (ROS) are altered in diabetes and that these disturbances may induce severe embryonic dysmorphogenesis in diabetic pregnancy. We tested this hypothesis by studying whether an inhibition of the rate-limiting enzyme of prostaglandin biosynthesis, cyclooxygenase (COX), caused developmental disturbances analogous to those seen in embryos exposed to high glucose concentration. Whether antioxidants could prevent such developmental alterations was also investigated. Whole embryo culture was used in which day-9 embryos were exposed to high concentrations of glucose, arachidonic acid, prostaglandin (PG)E2, COX inhibitors, and antioxidants for 48 h. Increased glucose concentration (from 10 to 30 mmol/l) caused embryonic dysmorphogenesis, and addition of either 60 pmol/l arachidonic acid or 280 nmol/l PGE2 largely protected the embryo from this maldevelopment. Furthermore, exposure to the COX inhibitors indomethacin (200 micromol/l) or acetylsalicylic acid (700 micromol/l) in 10 mmol/l glucose concentration yielded embryonic dysmorphogenesis similar to that caused by 30 mmol/l glucose. Supplementation of either arachidonic acid or PGE2 to the culture medium with COX inhibitors in low glucose rectified the embryonic development, and PGE2 supplementation also normalized the development of embryos cultured with COX inhibitors in high glucose concentration. Interestingly, the antioxidants superoxide dismutase (SOD) and N-acetylcysteine (NAC) were each able to diminish the dysmorphogenesis induced by the COX inhibitors, at doses previously shown to diminish glucose-induced embryonic damage in the same in vitro culture system. In conclusion, the present study shows that a high glucose concentration disturbs embryonic development and that this disturbance may be partly mediated via altered metabolism of arachidonic acid and ROS in the embryo.}, }
@article {pmid9568320, year = {1997}, author = {Konukoğlu, D and Cetinkale, O and Bulan, R}, title = {Effects of N-acetylcysteine on lung glutathione levels in rats after burn injury.}, journal = {Burns : journal of the International Society for Burn Injuries}, volume = {23}, number = {7-8}, pages = {541-544}, doi = {10.1016/s0305-4179(97)00059-4}, pmid = {9568320}, issn = {0305-4179}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Burns/*drug therapy/metabolism ; Culture Techniques ; Disease Models, Animal ; Free Radical Scavengers/*pharmacology ; Glutathione/*analysis ; Injections, Intraperitoneal ; Lipid Peroxidation/drug effects ; Lung/drug effects/*metabolism ; Male ; Malondialdehyde/*analysis ; Rats ; Rats, Wistar ; Reference Values ; }, abstract = {This study was designed to determine the effect of N-acetyl-cysteine (NAC, a natural hydroxyl radical scavenger) treatment on levels of pulmonary malondialdehyde (MDA, the end product of lipid peroxidation) and glutathione (GSH, a natural antioxidant) in thermally injured rats. Severe skin scald injury (30 percent TBSA) caused a significant decrease in GSH levels, and a significant increase in MDA levels in lung tissue both at 1 h and 1 day postburn injury. Treatment of rats with NAC (15 mg/kg intraperitoneally, 15 min and 12 h following the burn) significantly improved GSH levels, and decreased ongoing lipid peroxidation at 1 day. This study showed that thermal injury resulted in increased pulmonary lipid peroxidation, and this remote organ injury was decreased by treatment with NAC. In addition NAC, a scavenger of hydroxyl radicals, improved GSH levels in the lungs. The higher level of GSH in the lungs of the burned rats treated with NAC could be due to either a decrease in the rate of degradation of GSH or to an increase in its synthesis. No data about these possibilities are provided.}, }
@article {pmid9565804, year = {1998}, author = {Molnar, Z and MacKinnon, KL and Shearer, E and Lowe, D and Watson, ID}, title = {The effect of N-acetylcysteine on total serum anti-oxidant potential and urinary albumin excretion in critically ill patients.}, journal = {Intensive care medicine}, volume = {24}, number = {3}, pages = {230-235}, pmid = {9565804}, issn = {0342-4642}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Albuminuria/etiology/*urine ; Antioxidants/*metabolism ; Cardiotonic Agents/therapeutic use ; Creatinine/urine ; Critical Illness ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Length of Stay ; Male ; Middle Aged ; Multiple Organ Failure/complications/*drug therapy/metabolism ; Prospective Studies ; Respiration, Artificial ; Treatment Outcome ; }, abstract = {OBJECTIVE: To investigate the effects of N-acetylcysteine (NAC) when given as an early treatment to critically ill patients on the serum total anti-oxidant potential (TAP) and urine micro-albumin:creatinine (M:Cr) ratio.<br><br>DESIGN: Prospective, placebo controlled double blinded clinical trial.<br><br>SETTING: General intensive care unit in a teaching hospital.<br><br>PATIENTS: Sixty critically ill patients were recruited but ten were withdrawn due to less than 48 h of ICU stay.<br><br>INTERVENTIONS: After envelope randomisation, patients received either NAC (n = 23): a bolus of 150 mg/kg in 250 ml of 5% dextrose followed by a continuous infusion of 12 mg/kg per h in 500 ml of 5% dextrose over 24 h or, as controls (n = 27), the equal volume of placebo. Treatment lasted for a minimum of 3, up to a maximum of 5, days. Blood and urine samples were collected on admission (0 h) and then 6 hourly up 18 h.<br><br>MEASUREMENTS AND RESULTS: There was no significant difference between NAC and placebo groups regarding the required length of inotropic support, mechanical ventilation and ICU stay. There was no significant difference in TAP or M:Cr ratio over 18 h or between the groups.<br><br>CONCLUSIONS: Our results suggest that NAC had no significant effects on the progress of the TAP and the urinary albumin excretion in our patients, which may suggest that NAC at the given dose has no clinical relevance as an early treatment in the critically ill.}, }
@article {pmid9565778, year = {1998}, author = {Testa, R and Ghia, M and Mattioli, F and Borzone, S and Caglieris, S and Mereto, E and Giannini, E and Risso, D}, title = {Effects of reduced glutathione and n-acetylcysteine on lidocaine metabolism in cimetidine treated rats.}, journal = {Fundamental &amp; clinical pharmacology}, volume = {12}, number = {2}, pages = {220-224}, doi = {10.1111/j.1472-8206.1998.tb00945.x}, pmid = {9565778}, issn = {0767-3981}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Anesthetics, Local/administration &amp; dosage/*metabolism ; Animals ; Cimetidine/administration &amp; dosage/*pharmacology ; Drug Interactions ; Fluorescence Polarization Immunoassay ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glutathione/administration &amp; dosage/*pharmacology ; Histamine H2 Antagonists/administration &amp; dosage/*pharmacology ; Injections, Intraperitoneal ; Lidocaine/administration &amp; dosage/analogs &amp; derivatives/*blood ; Rats ; Rats, Sprague-Dawley ; Time Factors ; }, abstract = {The aim of this work was to evaluate the effects of exogenous glutathione (GSH) and N-acetylcysteine (NAC) on the formation of monoethylglycinexylidide (MEGX) from lidocaine in rats with and without the administration of cimetidine. GSH and NAC were administered intraperitoneally (i.p.) (1 mmol/kg) 1 hour before treatment with cimetidine (0.5 mmol/kg) or saline, and 1 hr later all rats were injected i.p. with lidocaine (1 mg/kg). Blood samples were drawn 30 min after the lidocaine injection. MEGX and lidocaine serum concentrations were determined by means of fluorescence polarization immuno-assay using the TDX system. Cimetidine produced a decrease in MEGX levels (from 210 +/- 18 to 164 +/- 13 ng/mL) and a parallel increase in lidocaine levels (from 73 +/- 22 to 172 +/- 47 ng/mL), consistent with cytochrome P-450 3A inhibition. Both GSH and NAC produce a significant decrease in MEGX levels (151 +/- 16 and 139 +/- 14 ng/mL, respectively), but no significant increase in lidocaine levels were found. As compared to the cimetidine group, pre-treatment using either GSH or NAC with cimetidine produced a marked decrease in lidocaine levels (37 +/- 27 and 63 +/- 28 ng/mL, respectively) and no modification of MEGX levels (155 +/- 12 and 165 +/- 22 ng/mL, respectively). These results suggest that GSH and NAC might accelerate the lidocaine metabolism while counteracting the inhibitory effect of cimetidine.}, }
@article {pmid9563752, year = {1998}, author = {Sprong, RC and Winkelhuyzen-Janssen, AM and Aarsman, CJ and van Oirschot, JF and van der Bruggen, T and van Asbeck, BS}, title = {Low-dose N-acetylcysteine protects rats against endotoxin-mediated oxidative stress, but high-dose increases mortality.}, journal = {American journal of respiratory and critical care medicine}, volume = {157}, number = {4 Pt 1}, pages = {1283-1293}, doi = {10.1164/ajrccm.157.4.9508063}, pmid = {9563752}, issn = {1073-449X}, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Animals ; Antioxidants/*administration &amp; dosage/pharmacology ; Cell Line ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/blood ; Infusions, Intravenous ; Lipopolysaccharides/*toxicity ; Lung/metabolism/pathology ; Male ; Monocytes/metabolism ; NF-kappa B/metabolism ; *Oxidative Stress ; Rats ; Rats, Wistar ; Serine/administration &amp; dosage/analogs &amp; derivatives ; Survival Rate ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on oxidative stress, lung damage, and mortality induced by an endotoxin (lipopolysaccharide, or LPS) in the rat. Continuous intravenous infusion of 275 mg NAC/kg in 48 h, starting 24 h before LPS challenge, decreased hydrogen peroxide (H2O2) concentrations in whole blood (p < 0.01). This decrease was accompanied by fewer histologic abnormalities of the lung and decreased mortality (p < 0.025), compared with rats receiving LPS alone. N-Acetylserine, which has no sulfhydryl group, did not protect rats against LPS toxicity. Improved survival was not associated with an increase in pulmonary reduced glutathione, nor with inhibition of serum tumor necrosis factor (TNF) activity. In vitro, TNF production and DNA binding of nuclear factor kappa B (NF-kappaB) in human Mono Mac 6 cells was only inhibited at concentrations of NAC above 20 mM. High-dose NAC treatment (550 and 950 mg/kg in 48 h) decreased lung GSH (p < 0.05) and resulted in a significantly smaller number of surviving animals when compared with the low-dose NAC group (p < 0.025). In vitro, NAC increased hydroxyl radical generation in a system with Fe(III)-citrate and H2O2 by reducing ferric iron to its catalytic, active Fe2+ form. We conclude that low-dose NAC protects against LPS toxicity by scavenging H2O2, while higher doses may have the opposite effect.}, }
@article {pmid9562236, year = {1998}, author = {Vasdev, S and Ford, CA and Longerich, L and Gadag, V and Wadhawan, S}, title = {Role of aldehydes in fructose induced hypertension.}, journal = {Molecular and cellular biochemistry}, volume = {181}, number = {1-2}, pages = {1-9}, pmid = {9562236}, issn = {0300-8177}, mesh = {Acetylcysteine/*pharmacology ; Aldehydes/*analysis ; Animals ; Blood Platelets/chemistry ; Blood Pressure/drug effects ; Body Weight ; Calcium/blood ; Diet ; Drinking ; Eating ; Fructose/*pharmacology ; Hypertension/blood/chemically induced/*metabolism ; Kidney/chemistry ; Lipofuscin/analysis ; Organ Size ; Rats ; Rats, Inbred WKY ; }, abstract = {Aldehydes are formed in tissues of humans and animals as intermediates of glucose and fructose metabolism and due to lipid peroxidation. N-acetyl cysteine (NAC), an analogue of the dietary amino acid cysteine, binds aldehydes thus preventing their damaging effect on physiological proteins. We measured systolic blood pressure (SBP), platelet cytosolic free calcium [Ca2+]i and tissue aldehyde conjugates in fructose induced hypertensive Wistar-Kyoto (WKY) rats and examined the effect of NAC in the diet on these parameters. Animals age 7 weeks were divided into three groups of 6 animals each and were treated as follows: WKY-control (chow diet and normal drinking water); WKY-Fructose (chow diet and 4% fructose in drinking water); WKY-Fructose+NAC (1.5% NAC in chow diet and 4% fructose in drinking water). After 11 weeks, systolic blood pressure, platelet [Ca2+]i and kidney aldehyde conjugates were all significantly higher in fructose treated rats. NAC treatment prevented these changes. These results suggest that aldehydes may be the cause of fructose induced hypertension and elevated cytosolic free calcium.}, }
@article {pmid9559908, year = {1998}, author = {Muller, B and Kleschyov, AL and Malblanc, S and Stoclet, JC}, title = {Nitric oxide-related cyclic GMP-independent relaxing effect of N-acetylcysteine in lipopolysaccharide-treated rat aorta.}, journal = {British journal of pharmacology}, volume = {123}, number = {6}, pages = {1221-1229}, doi = {10.1038/sj.bjp.0701737}, pmid = {9559908}, issn = {0007-1188}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta, Thoracic/*drug effects/physiology ; Cyclic GMP/*physiology ; In Vitro Techniques ; Iron Compounds/metabolism ; Lipopolysaccharides/*pharmacology ; Male ; Muscle Relaxation/drug effects ; Nitric Oxide/*physiology ; Rats ; Rats, Wistar ; }, abstract = {1. We have recently demonstrated the formation of protein-bound dinitrosyl-iron complexes (DNIC) in rat aortic rings exposed to lipopolysaccharide (LPS) and shown that N-acetylcysteine (NAC) can promote vasorelaxation in these arteries, possibly via the release of nitric oxide (NO) as low molecular weight DNIC from these storage sites. The aim of the present study was to investigate further the mechanism of the relaxation induced by NAC in LPS-treated vessels. 2. In rings incubated with LPS (10 microg ml(-1) for 18 h) and precontracted with noradrenaline (NA, 3 microM) plus N(omega)-nitro-L-arginine methylester (L-NAME, 3 mM), the relaxation evoked by NAC (0.1 to 10 mM) was abolished by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 microM, a selective inhibitor of soluble guanylyl cyclase) but not affected by Rp-8-bromoguanosine 3'5'-cyclic monophosphorothioate (Rp-8BrcGMPS, 60 microM a selective inhibitor of cyclic GMP-dependent protein kinase). Tetrabutylammonium (TBA, 3 mM, as a non selective K+ channels blocker) or elevated concentration of external KCl (25 or 50 mM) significantly attenuated the NAC-induced relaxation. Selective K+ channels blockers (10 microM glibenclamide, 0.1 microM charybdotoxin, 0.5 microM apamin or 3 mM 4-aminopyridine) did not affect the NAC-induced relaxation. The relaxing effect of NAC (10 mM) was not associated with an elevation of guanosine 3':5' cyclic monophosphate (cyclic GMP) in LPS-treated rings. 3. In aortic rings precontracted with NA (0.1 microM), low molecular weight DNIC (with thiosulphate as ligand, 1 nM to 10 microM) evoked a concentration-dependent relaxation which was antagonized by ODQ (1 microM) and Rp-8BrcGMPS (150 microM) but not significantly affected by TBA (3 mM) or by the use of KCl (50 mM) as preconstricting agent. The relaxation produced by DNIC (0.1 microM) was associated with an 11 fold increase in aortic cyclic GMP content, which was completely abolished by ODQ (1 microM). 4. Taken together with our previous data, the main finding of the present study is that the vascular relaxation induced by NAC in LPS-treated aorta, although probably related to NO through an interaction via preformed NO stores, was not mediated by activation of the cyclic GMP pathway. It may involve the activation of TBA-sensitive K+ channels. The differences in the mechanism of relaxation induced by NAC and by exogenous DNIC suggest that the generation of low molecular weight DNIC from protein-bound species does not play a major role in the NAC-induced relaxation observed in LPS-treated rat aorta. In addition, it is suggested that ODQ may display other properties than the inhibition of soluble guanylyl cyclase.}, }
@article {pmid9559879, year = {1998}, author = {Chau, YP and Shiah, SG and Don, MJ and Kuo, ML}, title = {Involvement of hydrogen peroxide in topoisomerase inhibitor beta-lapachone-induced apoptosis and differentiation in human leukemia cells.}, journal = {Free radical biology &amp; medicine}, volume = {24}, number = {4}, pages = {660-670}, doi = {10.1016/s0891-5849(97)00337-7}, pmid = {9559879}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; *Apoptosis ; Ascorbic Acid/pharmacology ; Cell Differentiation/*drug effects ; DNA Fragmentation ; Drug Resistance ; Enzyme Inhibitors/*pharmacology ; Glutathione/metabolism ; Humans ; Hydrogen Peroxide/*metabolism ; Leukemia, Promyelocytic, Acute/*pathology ; Monocytes ; Naphthoquinones/*pharmacology ; Proto-Oncogene Proteins c-bcl-2/physiology ; *Topoisomerase I Inhibitors ; Tumor Cells, Cultured ; Vitamin E/pharmacology ; }, abstract = {Beta-Lapachone a novel topoisomerase inhibitor, has been found to induce apoptosis in various human cancer cells. In this study we report that a dramatic elevation of hydrogen peroxide (H2O2) in human leukemia HL-60 cells following 1 microM beta-lapachone treatment and that this increase was effectively inhibited by treatment with antioxidant N-acetyl-L-cysteine (NAC), ascorbic acid, alpha-tocopherol. NAC strongly prevented beta-lapachone-induced apoptotic characteristics such as DNA fragmentation and apoptotic morphology. However, treatment of HL-60 cells with another topoisomerase inhibitor camptothecin (CPT) did not induce H2O2 production as compared to untreated cells. NAC also failed to block CPT-induced apoptosis. Correlated with these findings, we found that cancer cell lines K562, MCF-7, and SW620, contained high level of intracellular glutathione (GSH), were not elevated in H2O2 and were resistant to apoptosis after treatment with beta-lapachone. In contrast, cancer cell lines such as, HL-60, U937, and Molt-4 which have lower level of GSH, were readily increased of H2O2 and were sensitive to this drug. Furthermore, ectopic overexpression of Bcl-2 in HL-60 cells also attenuated beta-lapachone-induced H2O2 and conferred resistance to beta-lapachone-induced cell death. Beta-Lapachone at the concentration as low as 0.25 microM effectively induced HL-60 cells to undergo monocytic differentiation, as evidenced by CD14 antigenicity and alpha-naphthyl acetate esterase activity. Again, the beta-lapachone-induced monocytic differentiation was suppressed by NAC. These results suggest that intracellular H2O2 generation plays a crucial role in beta-lapachone-induced cell death and differentiation.}, }
@article {pmid9551743, year = {1998}, author = {Mulier, B and Rahman, I and Watchorn, T and Donaldson, K and MacNee, W and Jeffery, PK}, title = {Hydrogen peroxide-induced epithelial injury: the protective role of intracellular nonprotein thiols (NPSH).}, journal = {The European respiratory journal}, volume = {11}, number = {2}, pages = {384-391}, doi = {10.1183/09031936.98.11020384}, pmid = {9551743}, issn = {0903-1936}, mesh = {Acetylcysteine/pharmacology ; Bronchi/cytology/*drug effects/metabolism ; Cell Line ; Drug Administration Schedule ; Epithelial Cells/cytology/drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Glutathione/pharmacology ; Humans ; Hydrogen Peroxide/administration &amp; dosage/*pharmacology ; Intracellular Membranes/*metabolism ; L-Lactate Dehydrogenase/metabolism ; Oxidants/*pharmacology ; Pulmonary Alveoli/cytology/*drug effects/metabolism ; Sulfhydryl Compounds/*physiology ; }, abstract = {Injury to the alveolar region is a hallmark of the adult respiratory distress syndrome (ARDS) whereas injury to the epithelium of the conducting airways is a characteristic of asthma. Reactive oxygen species have been implicated as mediators of lung injury in both of these conditions. We have investigated the relationship between intracellular nonprotein thiols (NPSH), and the release of the cytosolic enzyme lactate dehydrogenase (LDH), as an index of cell injury, following treatment of the human alveolar type II-like epithelial cell line (A549 cells) or the human bronchial epithelial cell line (16HBE140-) with hydrogen peroxide (H2O2). We have also assessed the protective effects of pre-incubation of both of these cells lines with H2O2 or enhancement of intracellular NPSH against H2O2-induced cell injury. Exposure of A549 and 16HBE140- cells to H2O2 (0.1 mM and 1 mM respectively for 16 h) produced the release of 40% of the total cellular LDH. H2O2 exposure produced an initial dose-dependent decrease in NPSH in A549 cells, with a subsequent increase to above control values. 16HBE140- cells also showed a dose-dependent decrease in NPSH following exposure to H2O2. Pretreatment of A549 cells with 0.1 mM H2O2 followed by subsequent exposure to H2O2 did not protect against H2O2-induced LDH release in this epithelial cell line. Pre-incubation with 2 mM N-acetylcysteine (NAC) increased NPSH but not intracellular reduced glutathione and resulted in total inhibition of H2O2-induced LDH release in both cell types. Pretreatment with reduced glutathione protected both cell types against the injurious effects of H2O2, whereas glutathione monethyl ester (GSHMEE) only partially protected A549 cells and had no effect in 16HBE140- cells. Intracellular cysteine levels were increased in both cell lines following NAC exposure but not sufficiently to account for the increase in NPSH levels. These observations raise the possibility that a critical concentration of nonprotein thiols may be necessary to protect pulmonary epithelial cells against hydrogen peroxide-induced injury.}, }
@article {pmid9546365, year = {1998}, author = {Ballatori, N and Wang, W and Lieberman, MW}, title = {Accelerated methylmercury elimination in gamma-glutamyl transpeptidase-deficient mice.}, journal = {The American journal of pathology}, volume = {152}, number = {4}, pages = {1049-1055}, pmid = {9546365}, issn = {0002-9440}, support = {DK48823/DK/NIDDK NIH HHS/United States ; ES06484/ES/NIEHS NIH HHS/United States ; ES07827/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Brain/metabolism ; Female ; Glutathione/metabolism ; Kidney/metabolism ; Liver/metabolism ; Male ; Mercury/pharmacokinetics ; Metabolic Clearance Rate/drug effects ; Methylmercury Compounds/administration &amp; dosage/blood/*pharmacokinetics ; Mice ; Mice, Knockout ; Tissue Distribution ; gamma-Glutamyltransferase/deficiency/*physiology ; }, abstract = {The disposition and toxicity of methylmercury, a ubiquitous environmental pollutant, is modulated by binding to the endogenous tripeptide glutathione (GSH) and metabolism of the resulting methylmercury-glutathione complex by the ectoproteins gamma-glutamyl transpeptidase (GGT) and dipeptidase. To evaluate the role of GGT in the whole-body disposition of methylmercury, we compared the elimination of [203Hg]methylmercury in GGT-deficient mice with that in wild-type mice and mice heterozygous for this deficiency. The effects of N-acetylcysteine (NAC), a drug used to maintain the cysteine and GSH levels of GGT-deficient mice, were also examined. Female mice were treated with either 0.5 or 25 micromol of CH3 203HgCl/kg body weight, in the presence and absence of 10 mg/ml NAC in the drinking water. There were no differences in methylmercury excretion between the wild-type and heterozygous mice; however, the GGT-deficient mice excreted methylmercury more rapidly at both dose levels. Wild-type and heterozygous mice excreted from 11 to 24% of the dose in the first 48 hours, whereas the GGT-deficient mice excreted 55 to 66% of the dose, with most of the methylmercury being excreted in urine. Urinary methylmercury excretion was further accelerated in mice that received NAC. In contrast to methylmercury, the whole-body elimination of inorganic mercury was not affected by GGT deficiency, although the tissue distribution of inorganic mercury was markedly different in GGT-deficient male mice, with only 13% of the 203Hg body burden in the kidneys of GGT-deficient mice versus approximately 50% in kidneys of wild-type male mice. These findings provide direct evidence for a major role of GGT in regulating the tissue distribution and elimination of methylmercury and inorganic mercury and provide additional support for the use of NAC as an antidote in methylmercury poisoning.}, }
@article {pmid9545559, year = {1998}, author = {Abe, T and Yamamura, K and Gotoh, S and Kashimura, M and Higashi, K}, title = {Concentration-dependent differential effects of N-acetyl-L-cysteine on the expression of HSP70 and metallothionein genes induced by cadmium in human amniotic cells.}, journal = {Biochimica et biophysica acta}, volume = {1380}, number = {1}, pages = {123-132}, doi = {10.1016/s0304-4165(97)00144-x}, pmid = {9545559}, issn = {0006-3002}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Amnion ; Cadmium/*toxicity ; Cell Line ; Dose-Response Relationship, Drug ; Gene Expression/drug effects ; Glutathione/metabolism ; HSP70 Heat-Shock Proteins/*genetics ; Humans ; Lipid Peroxidation/drug effects ; Metallothionein/*genetics ; RNA, Messenger/genetics/metabolism ; }, abstract = {Cadmium induces the expression of the 70 kDa heat shock protein (HSP70) and metallothionein (MT), both of which are considered to be associated with intracellular glutathione (GSH) metabolism in the cellular protection mechanism against cadmium-induced cellular injury. We determined the effects of N-acetyl-L-cysteine (NAC), which increases the intracellular GSH levels, on the induction of HSP70 and MT gene expression in a cultured cell line of human amniotic cells (WISH) exposed to CdCl2. The mRNA level of MT-II, a major isoform of MT genes, was more prominently increased than that of HSP70 when WISH cells were exposed to CdCl2 (5-15 microM, for 6 h). The treatment of WISH cells with 1.5 and 30 mM NAC for 2 h increased the intracellular GSH levels by 1.4- and 3.1-fold, respectively. Pretreatment of cells with 30 mM NAC significantly reduced both HSP70 and MT-II mRNA levels in the cells exposed to 50 microM CdCl2. This concentration of NAC also efficiently suppressed the cadmium-induced lethality. On the contrary, pretreatment with 1.5 mM NAC suppressed only the induction of HSP70 gene expression in the 50 microM CdCl2-treated cells, and did not inhibit the metal toxicity. However, this low concentration of NAC efficiently suppressed lipid peroxidation which was increased by 50 microM CdCl2. Furthermore, this low concentration of NAC also decreased the CdCl2-induced gene expression of HSP32 which represents a general response to oxidative stress. Taken together, NAC seems to have at least two concentration-dependent functions in WISH cells exposed to CdCl2; the low concentration of NAC can suppress the induction of HSP70 gene expression as well as the increase of lipid peroxidation via an antioxidant pathway, while the high concentration of NAC can suppress the induction of MT-II mRNA as well as cadmium-induced cell death. Our present data suggest that changes in intracellular redox status, as reflected by GSH concentration, have more important effects on the induction of HSP70 mRNA rather than that of MT-II mRNA in human amniotic cells exposed to cadmium.}, }
@article {pmid9544582, year = {1998}, author = {Fox, ES and Leingang, KA}, title = {Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-kappaB translocation and requires protein synthesis.}, journal = {Journal of leukocyte biology}, volume = {63}, number = {4}, pages = {509-514}, doi = {10.1002/jlb.63.4.509}, pmid = {9544582}, issn = {0741-5400}, support = {DK44305/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blotting, Northern ; Blotting, Western ; Cells, Cultured ; Cycloheximide/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Kupffer Cells/drug effects/*immunology/physiology ; Lipopolysaccharides/pharmacology ; *Macrophage Activation ; Male ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Okadaic Acid/pharmacology ; Proto-Oncogene Proteins/metabolism ; RNA, Messenger/analysis ; Rats ; Rats, Sprague-Dawley ; Transcription Factor RelB ; *Transcription Factors ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Activation of the resident hepatic macrophage population, Kupffer cells, leads to production of mediators that initiate, potentiate, and modulate hepatic injury. Recent studies have shown that activation of the pluripotent transcription factor nuclear factor-kappaB (NF-kappaB) is an important step in the induction of inflammatory cytokines, chemokines, growth factors, cell adhesion proteins, and cytokine receptors, thus efforts have been focused to modulate its activity. A common observation in diverse experimental systems is that oxidant stress activates NF-kappaB and antioxidant drugs prevent activation and subsequent inflammatory gene transcription. However, we have recently shown that the inhibitory effect of N-acetylcysteine (NAC) is independent of its role as a substrate of glutathione synthesis and NAC can inhibit Kupffer cell activation at points beyond the initiation of activation. The goal of this study was to characterize the mechanism for NAC-mediated inhibition of Kupffer cell activation. We show for the first time that this process requires a cellular synthetic response to prevent both NF-kappaB and tumor necrosis factor alpha (TNF-alpha) mRNA activation. Furthermore, NAC-mediated inhibition occurs after degradation of IkappaB-alpha and nuclear translocation of NF-kappaB. These data suggest that inhibition of Kupffer cell activation by NAC is a nuclear event and offers a potential approach to modulate Kupffer cell activation during hepatic injury.}, }
@article {pmid9537722, year = {1998}, author = {Nagasaki, H and Nakano, H and Boudjema, K and Jaeck, D and Alexandre, E and Baek, Y and Kitamura, N and Yamaguchi, M and Kumada, K}, title = {Efficacy of preconditioning with N-acetylcysteine against reperfusion injury after prolonged cold ischaemia in rats liver in which glutathione had been reduced by buthionine sulphoximine.}, journal = {The European journal of surgery = Acta chirurgica}, volume = {164}, number = {2}, pages = {139-146}, doi = {10.1080/110241598750004805}, pmid = {9537722}, issn = {1102-4151}, mesh = {Acetylcysteine/*therapeutic use ; Adenosine Triphosphate/biosynthesis ; Animals ; Buthionine Sulfoximine/*pharmacology ; Cold Temperature ; Enzyme Inhibitors/*pharmacology ; Free Radical Scavengers/*therapeutic use ; Glutathione/*metabolism ; In Vitro Techniques ; Ischemic Preconditioning/*methods ; Liver/*blood supply/enzymology/*metabolism ; Male ; Oxidation-Reduction ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {OBJECTIVE: To investigate the ability of N-acetylcysteine (NAC) to prevent cold ischaemic-reperfusion injury and improve hepatic integrity in a glutathione-depleted condition.<br><br>DESIGN: Open laboratory study.<br><br>SETTING: University hospitals, Japan and France.<br><br>MATERIALS: 40 male Wistar rats.<br><br>INTERVENTIONS: To produce a glutathione-depleted liver, buthionine sulphoximine (BSO) was injected intraperitoneally 2 hours before either NAC or 5% dextrose was infused 15 minutes before the liver was harvested. We used an isolated perfused rat liver model that had undergone prolonged hypothermic ischaemia, cold-storage for 48 hours and reperfusion for 120 minutes.<br><br>MAIN OUTCOME MEASURES: Concentrations of hepatic enzymes released into samples of perfusate, concentration of adenosine triphosphate in liver tissue, concentrations of reduced and oxidized glutathione in perfusate, and bile production.<br><br>RESULTS: The concentrations of the hepatocellular enzymes and oxidised glutathione in the perfusate samples were significantly reduced in the NAC group compared with the 5% dextrose group. Bile production improved significantly in the NAC group compared with the 5% dextrose group. The concentration of reduced glutathione in liver tissue was not increased by NAC.<br><br>CONCLUSION: In a glutathione-depleted liver NAC prevented hepatic injury and improved liver integrity after a cold ischaemic-reperfusion injury, by acting not as a substrate for glutathione synthesis but as a direct free radical scavenger.}, }
@article {pmid9525474, year = {1998}, author = {Hsieh, HJ and Cheng, CC and Wu, ST and Chiu, JJ and Wung, BS and Wang, DL}, title = {Increase of reactive oxygen species (ROS) in endothelial cells by shear flow and involvement of ROS in shear-induced c-fos expression.}, journal = {Journal of cellular physiology}, volume = {175}, number = {2}, pages = {156-162}, doi = {10.1002/(SICI)1097-4652(199805)175:2&lt;156::AID-JCP5&gt;3.0.CO;2-N}, pmid = {9525474}, issn = {0021-9541}, mesh = {Acetylcysteine/metabolism ; Amitrole/pharmacology ; Antioxidants/metabolism ; Catalase/metabolism ; Chelating Agents/pharmacology ; Deferoxamine/pharmacology ; Endothelium, Vascular/*physiology ; Fluoresceins/metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/*genetics ; Genes, fos/*genetics ; Hemodynamics/physiology ; Humans ; Hydrogen Peroxide/metabolism ; RNA/analysis ; Reactive Oxygen Species/*metabolism ; Thiourea/analogs &amp; derivatives/pharmacology ; Umbilical Cord ; }, abstract = {Intracellular reactive oxygen species (ROS) may participate in cellular responses to various stimuli including hemodynamic forces and act as signal transduction messengers. Human umbilical vein endothelial cells (ECs) were subjected to laminar shear flow with shear stress of 15, 25, or 40 dynes/cm2 in a parallel plate flow chamber to demonstrate the potential role of ROS in shear-induced cellular response. The use of 2',7'-dichlorofluorescin diacetate (DCFH-DA) to measure ROS levels in ECs indicated that shear flow for 15 minutes resulted in a 0.5- to 1.5-fold increase in intracellular ROS. The levels remained elevated under shear flow conditions for 2 hours when compared to unsheared controls. The shear-induced elevation of ROS was blocked by either antioxidant N-acetyl-cysteine (NAC) or catalase. An iron chelator, deferoxamine mesylate, also significantly reduced the ROS elevation. A similar inhibitory effect was seen with a hydroxyl radical (.OH) scavenger, 1,3-dimethyl-2-thiourea (DMTU), suggesting that hydrogen peroxide (H202), .OH, and possibly other ROS molecules in ECs were modulated by shear flow. Concomitantly, a 1.3-fold increase of decomposition of exogenously added H2O2 was observed in extracts from ECs sheared for 60 minutes. This antioxidant activity, abolished by a catalase inhibitor (3-amino-1,2,4-triazole), was primarily due to the catalase. The effect of ROS on intracellular events was examined in c-fos gene expression which was previously shown to be shear inducible. Decreasing ROS levels by antioxidant (NAC or catalase) significantly reduced the induction of c-fos expression in sheared ECs. We demonstrate for the first time that shear force can modulate intracellular ROS levels and antioxidant activity in ECs. Furthermore, the ROS generation is involved in mediating shear-induced c-fos expression. Our study illustrates the importance of ROS in the response and adaptation of ECs to shear flow.}, }
@article {pmid9523930, year = {1998}, author = {Wright, RO and Woolf, AD and Shannon, MW and Magnani, B}, title = {N-acetylcysteine reduces methemoglobin in an in-vitro model of glucose-6-phosphate dehydrogenase deficiency.}, journal = {Academic emergency medicine : official journal of the Society for Academic Emergency Medicine}, volume = {5}, number = {3}, pages = {225-229}, doi = {10.1111/j.1553-2712.1998.tb02617.x}, pmid = {9523930}, issn = {1069-6563}, mesh = {Acetylcysteine/*pharmacology ; Androsterone ; Antidotes/*pharmacology ; Free Radical Scavengers/*pharmacology ; Glucosephosphate Dehydrogenase Deficiency/*metabolism ; Humans ; Methemoglobin/*metabolism ; Methemoglobinemia/drug therapy ; Methylene Blue ; }, abstract = {OBJECTIVE: To determine whether N-acetylcysteine (NAC) reduces methemoglobin (MHB) in an in-vitro model of glucose-6-phosphate dehydrogenase (G6PD) deficiency, given that methylene blue is an ineffective MHB antidote in G6PD deficiency.<br><br>METHODS: Five volunteers donated blood, which was divided equally into 2 test tubes, centrifuged, and washed with Tris-Mopps buffer (pH 7.4, 15 mmol/L glucose). Both tubes were incubated with epiandrosterone (EA) (400 micromol), a specific inhibitor of G6PD. After 75 microL of 0.18 mol hydroxylamine (HA) was added to induce MHB formation, 150 microL of NAC (20 mg/mL) was added to tube 1 and 150 microL of phosphate-buffered saline (PBS) was added to tube 2 as a volume control. Serial MHB levels are reported as a percentage of total hemoglobin (Hb). G6PD activity was measured at baseline, 15 minutes after EA, and at 5 hours.<br><br>RESULTS: Mean G6PD activity at baseline was 9.2+/-2.9 U/g Hb (normal >4.6 U/g Hb); 15 minutes after EA was 3.0+/-1.0 U/g Hb; and at experiment's end was 2.3+/-0.7 U/g Hb. The mean (+/-SD) areas under the concentration-time curves (AUCs) of NAC-EA-HA and PBS-EA-HA samples were compared using an unpaired t-test and were significantly different: PBS-EA-HA, 20,400+/-1,100 % min, vs NAC-EA-HA, 10,400+/-1,000 % min, respectively (p < 0.05).<br><br>CONCLUSION: In this in-vitro model of G6PD deficiency, NAC efficiently reduced MHB.}, }
@article {pmid9521863, year = {1998}, author = {Lee, JS and Kypreos, KE and Sonenshein, GE}, title = {Synchronization of cultured vascular smooth muscle cells following reversal of quiescence induced by treatment with the antioxidant N-acetylcysteine.}, journal = {Experimental cell research}, volume = {239}, number = {2}, pages = {447-453}, doi = {10.1006/excr.1997.3919}, pmid = {9521863}, issn = {0014-4827}, support = {HL07429/HL/NHLBI NIH HHS/United States ; HL13262/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Aorta/cytology ; Cattle ; Cell Cycle/drug effects ; *Cell Cycle Proteins ; Cell Division/drug effects ; Cells, Cultured ; Cyclin D1/biosynthesis/genetics ; DNA Replication ; DNA-Binding Proteins/biosynthesis/genetics ; Gene Expression Regulation/drug effects ; Growth Inhibitors/pharmacology ; Humans ; Muscle, Smooth, Vascular/*drug effects ; *Trans-Activators ; Transcription Factors/biosynthesis/genetics ; }, abstract = {Smooth muscle cell (SMC) proliferation plays an important role in the pathogenesis of vascular diseases such as atherosclerosis and postangioplasty restenosis. Recently we demonstrated the thiol antioxidant N-acetylcysteine (NAC) inhibits constitutive NF-kappa B/Rel activity and growth of vascular SMCs. Here we show that treatment of human and bovine aortic SMC with the thiol antioxidant NAC causes cells to exit the cell cycle and remain quiescent as determined by a greatly reduced incorporation of [3H]thymidine and G0/G1 DNA content. Removal of NAC from the culture medium stimulates SMCs to synchronously reenter the cell cycle as judged by induction of cyclin D1 and B-myb gene expression during mid and late G1 phase, respectively, and induction of histone gene expression and [3H]thymidine incorporation during S phase. The time course of cyclin D1, B-myb, and histone gene expression after NAC removal was similar to that of serum-deprived cells induced to resume cell cycle progression by the addition of fetal bovine serum to the culture medium. Taken together, these results indicate that NAC treatment causes SMCs to enter a reversible G0 quiescent, growth-arrested state. Thus, NAC provides an important new method for synchronizing SMCs in culture.}, }
@article {pmid9520359, year = {1998}, author = {Ballatori, N and Lieberman, MW and Wang, W}, title = {N-acetylcysteine as an antidote in methylmercury poisoning.}, journal = {Environmental health perspectives}, volume = {106}, number = {5}, pages = {267-271}, pmid = {9520359}, issn = {0091-6765}, support = {DK48823/DK/NIDDK NIH HHS/United States ; ES06484/ES/NIEHS NIH HHS/United States ; ES07827/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Animals ; Antidotes/*therapeutic use ; Female ; Male ; Methylmercury Compounds/*poisoning/urine ; Mice ; Mice, Inbred C57BL ; Time Factors ; }, abstract = {Methylmercury is a ubiquitous environmental pollutant and potent neurotoxin. Treatment of methylmercury poisoning relies almost exclusively on the use of chelating agents to accelerate excretion of the metal. The present study demonstrates that oral administration of N-acetylcysteine (NAC), a widely available and largely nontoxic amino acid derivative, produces a profound acceleration of urinary methylmercury excretion in mice. Mice that received NAC in the drinking water (10 mg/ml) starting at 48 hr after methylmercury administration excreted from 47 to 54% of the 203Hg in urine over the subsequent 48 hr, as compared to 4-10% excretion in control animals. When NAC-containing water was given from the time of methylmercury administration, it was even more effective at enhancing urinary methylmercury excretion and at lowering tissue mercury levels. In contrast, excretion of inorganic mercury was not affected by oral NAC administration. The ability of NAC to enhance methylmercury excretion when given orally, its relatively low toxicity, and is wide availability in the clinical setting indicate that it may be an ideal therapeutic agent for use in methylmercury poisoning.}, }
@article {pmid9518145, year = {1997}, author = {Eskinja, M and Lamprecht, G and Scherer, G and Schmid, ER}, title = {Assay of S-ethyl-N-acetyl-l-cysteine in urine by high-performance liquid chromatography using post-column reaction detection.}, journal = {Journal of chromatography. B, Biomedical sciences and applications}, volume = {704}, number = {1-2}, pages = {159-165}, doi = {10.1016/s0378-4347(97)00437-4}, pmid = {9518145}, issn = {1387-2273}, mesh = {Acetylation ; Acetylcysteine/*analogs &amp; derivatives/urine ; Carcinogens/metabolism ; Chromatography, High Pressure Liquid/*methods ; Chromatography, Ion Exchange ; Ethyl Chloride/metabolism ; Formates ; Humans ; Mercaptoethanol ; Methanol ; Sensitivity and Specificity ; Solvents ; o-Phthalaldehyde ; }, abstract = {The assay of the ethyl chloride metabolite S-ethyl-N-acetyl-L-cysteine in human urine by HPLC is described. The compound is enriched by adsorption on a non-polar adsorbent of graphitized non-porous carbon, and then stripped from positively charged compounds by application onto a strong acid cation-exchanger. Subsequently, an enzymatic deacetylation is carried out and the acylase is removed by centrifugal ultrafiltration. Separation of the sample is performed by cation-exchange chromatography applying an eluent of a very low elution strength (diluted formic acid). In the column effluent S-ethyl-L-cysteine is derivatized by o-phthaldialdehyde and the reaction product is detected by fluorescence measurement. In human urine a detection limit in the low ppb range is achieved.}, }
@article {pmid9516568, year = {1998}, author = {Steib, A and Freys, G and Collin, F and Launoy, A and Mark, G and Boudjema, K}, title = {Does N-acetylcysteine improve hemodynamics and graft function in liver transplantation?.}, journal = {Liver transplantation and surgery : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society}, volume = {4}, number = {2}, pages = {152-157}, doi = {10.1002/lt.500040204}, pmid = {9516568}, issn = {1074-3022}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Female ; Hemodynamics/*drug effects ; Humans ; Liver/drug effects/*physiology ; Liver Function Tests ; *Liver Transplantation ; Male ; Middle Aged ; Prospective Studies ; Time Factors ; }, abstract = {The release of toxic oxidative free radicals induced by ischemia and reperfusion may jeopardize liver graft function. N-acetylcysteine (NAC) has shown protective effects on hypothermic and warm ischemia reperfusion liver injury in animals. NAC improves hemodynamics and survival rates in patients with fulminant hepatic failure. The aim of this study was to investigate whether intraoperative treatment with NAC would improve hemodynamics and postoperative graft function in liver transplantation. Sixty patients with chronic end-stage liver disease were included in a prospective randomized placebo-controlled study. NAC or the same volume of 5% glucose was started during the anhepatic phase. Hemodynamic data and calculated tissue oxygenation parameters were compared throughout the procedure. Postoperative graft function was assessed by measurements of aminotransferases, prothrombin time, and monoethylglycinexylidide test over the 3 first postoperative days. Patient demographics were similar before the infusion of NAC or glucose. Hemodynamic parameters, oxygen consumption, oxygen delivery, oxygen extraction ratio, and lactates were not different throughout the procedure. One hour after the revascularization of the hepatic artery, the oxygen extraction ratio by the liver was similar (17% +/- 7.6% v 17% +/- 6.2%) in both groups. Postoperative graft function was comparable within the 3 first postoperative days. This study failed to show any beneficial effect of the intraoperative administration of NAC on hemodynamics and graft function in liver transplantation in patients with chronic liver disease.}, }
@article {pmid9513793, year = {1998}, author = {Tripathi, Y and Hegde, BM}, title = {Effect of N-acetylcysteine on myocardial infarct size following ischemia and reperfusion in dogs.}, journal = {Indian journal of physiology and pharmacology}, volume = {42}, number = {1}, pages = {50-56}, pmid = {9513793}, issn = {0019-5499}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Blood Pressure/drug effects ; Coronary Vessels/physiology ; Dogs ; Free Radical Scavengers/*therapeutic use ; Glutathione/metabolism ; Lipid Peroxidation/drug effects ; Male ; Myocardial Infarction/*drug therapy/etiology/*pathology ; Myocardial Ischemia/*pathology ; Myocardial Reperfusion Injury/*pathology ; Superoxide Dismutase/metabolism ; }, abstract = {The present study was designed to examine the role of N-acetylcysteine (NAC) on free radical mediated reperfusion injury in canine model. Fourteen dogs underwent 90 min of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfusion. Treated animals received loading dose of NAC (250 mg/kg) at the time of reperfusion upto 1 h followed by maintenance dose (70 mg/kg) for remaining 3 h through left atrial line. Infarct size, myocardial tissue lipid peroxidation, superoxide dismutase (SOD) and glutathione (GSH) levels were measured at the end of reperfusion in treated (n = 7) and untreated animals (n = 7). Left ventricular end diastolic pressure was significantly lower in treated animals compared to untreated group. SOD and GSH levels in myocardial tissue at risk and in infarcted zone were similar in both groups. However, in NAC treated animals the lipid peroxidation was significantly lower in comparison to untreated control animals. Infarct size in the area at risk, percent left ventricular necrosis and myocardial tissue preservation were not significantly different in treated and untreated animals. These results suggests that N-acetylcysteine infusion at the time of reperfusion following 90 min of ischemia and 4 h of reperfusion fails to offer significant cardioprotection against free radical damage but it can improve ventricular performance by decreasing pre load.}, }
@article {pmid9500196, year = {1998}, author = {Conaway, CC and Jiao, D and Kelloff, GJ and Steele, VE and Rivenson, A and Chung, FL}, title = {Chemopreventive potential of fumaric acid, N-acetylcysteine, N-(4-hydroxyphenyl) retinamide and beta-carotene for tobacco-nitrosamine-induced lung tumors in A/J mice.}, journal = {Cancer letters}, volume = {124}, number = {1}, pages = {85-93}, doi = {10.1016/s0304-3835(97)00454-0}, pmid = {9500196}, issn = {0304-3835}, support = {1-CN-85095/CN/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Animals ; Anticarcinogenic Agents/*therapeutic use ; Carcinogens/*toxicity ; Dose-Response Relationship, Drug ; Female ; Fenretinide/therapeutic use ; Fumarates/therapeutic use ; Lung Neoplasms/*chemically induced/*prevention &amp; control ; Mice ; Mice, Inbred A ; Nitrosamines/*toxicity ; Plants, Toxic ; Nicotiana/chemistry ; beta Carotene/therapeutic use ; }, abstract = {Four agents, fumaric acid (FA), N-acetylcysteine (NAC), N-(4-hydroxyphenyl) retinamide (4-HPR) and beta-carotene (beta-CT), were evaluated for potential chemopreventive activity using the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumor model in female A/J mice. The agents were evaluated in both 16-week and 52-week bioassays at two dose levels corresponding to 0.8 maximum tolerated dose (MTD) and 0.4 MTD administered throughout the bioassay either in the diet (FA, 160 and 80 mmol/kg diet; NAC, 160 and 80 mmol/kg diet; 4-HPR, 4 and 2 mmol/kg diet) or by subcutaneous injection twice a week (beta-CT, 32 and 16 mg/kg b.w.). Mice were treated with a single i.p. dose of 10 micromol NNK in saline 1 week after administration of test agent. Lung adenomas were evaluated in the 16-week bioassay, whereas both adenomas and adenocarcinomas of the lung were determined in the 52-week bioassay. Both bioassays showed that all four agents did not significantly inhibit the total tumor incidence and multiplicity of the lung. However, the incidence of adenocarcinomas was reduced (P < 0.01) at 52 weeks in NNK groups given either 0.8 MTD NAC or 0.8 MTD beta-CT compared with the NNK control group. The decreases in adenocarcinomas were accompanied by corresponding increases in adenomas in these treatment groups. Thus, this study showed that FA, NAC, 4-HPR and beta-CT did not inhibit the total tumor formation, however, at the higher doses both NAC and beta-CT significantly retarded the malignant progression in the lung of NNK-treated A/J mice.}, }
@article {pmid9506822, year = {1998}, author = {Elferink, JG and de Koster, BM}, title = {N-acetylcysteine causes a transient stimulation of neutrophil migration.}, journal = {Immunopharmacology}, volume = {38}, number = {3}, pages = {229-236}, doi = {10.1016/s0162-3109(97)00056-8}, pmid = {9506822}, issn = {0162-3109}, mesh = {Acetylcysteine/antagonists &amp; inhibitors/*pharmacology ; Animals ; Calcium/metabolism ; Cell Movement/drug effects ; Cyclic GMP/metabolism ; Cyclic GMP-Dependent Protein Kinase Type I ; Cyclic GMP-Dependent Protein Kinases/antagonists &amp; inhibitors ; Cysteine/pharmacology ; Free Radical Scavengers/*pharmacology ; Guanylate Cyclase/antagonists &amp; inhibitors ; Macrophage-1 Antigen/biosynthesis ; N-Formylmethionine Leucyl-Phenylalanine/pharmacology ; Neutrophils/*drug effects/immunology/physiology ; Peritoneal Cavity/cytology ; Rabbits ; }, abstract = {Random migration of rabbit peritoneal neutrophils was enhanced in a chemokinetic way by N-acetylcysteine (NAC) in a small concentration range (10-400 microM). The enhancement was due to the cysteine moiety in the molecule, because cysteine equally caused a stimulation of random migration. The stimulating effect of NAC or cysteine largely disappeared when cells were preincubated with NAC or cysteine for 30 min before submission to chemotaxis, indicating that desensitization occurs. The stimulating effect of NAC was dependent on extracellular calcium. Because the Ca2+-dependence of migration by electroporated cells differed from that of intact cells, and because calcium channel blockers inhibited the effect of NAC, the calcium-dependent target is probably located inside the cell rather than on the cell surface. In contrast with fMLP, NAC did not cause an upregulation of CD11b expression of cells in suspension. Inhibitors of guanylate cyclase and of cGMP-dependent protein kinase (G-kinase) inhibited stimulation of migration by NAC, suggesting that cGMP played a decisive role in the stimulatory effect of NAC.}, }
@article {pmid9486129, year = {1998}, author = {Tyagi, SC}, title = {Homocysteine redox receptor and regulation of extracellular matrix components in vascular cells.}, journal = {The American journal of physiology}, volume = {274}, number = {2}, pages = {C396-405}, doi = {10.1152/ajpcell.1998.274.2.C396}, pmid = {9486129}, issn = {0002-9513}, support = {GM-46366/GM/NIGMS NIH HHS/United States ; HL-51971/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Actins/biosynthesis ; Amino Acid Sequence ; Cell Division ; Collagen/biosynthesis ; Extracellular Matrix Proteins/*physiology ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Homocysteine/*physiology ; Homocystine/*physiology ; Humans ; Molecular Sequence Data ; Muscle, Smooth, Vascular/drug effects/*physiology ; Oxidation-Reduction ; Receptors, Cell Surface/drug effects/*physiology ; }, abstract = {Dynamic changes in the reduction-oxidation (redox) state of the tissue lead to the pathophysiological condition. Reduced homocysteine causes dysfunctions in endothelium. The proliferation of smooth muscle cells may lead to occlusive vascular disease, ischemia, and heart failure, but whether fibrosis and hypertension are a consequence of smooth muscle proliferation is unclear. Redox changes during hyper-homocyst(e)inemia may be one of the causes of premature atherosclerotic heart disease. To examine the effect of homocystine on human vascular smooth muscle cells (HVSMC), we isolated HVSMC from idiopathic dilated cardiomyopathic hearts. Coronaries in these hearts were apparently normal. HVSMC numbers in culture were measured by hemocytometer in the presence and absence of homocystine. Results show that homocystine induced cellular proliferation. This proliferation was reversed by the addition of the antioxidant N-acetylcysteine (NAC). Homocystine induces collagen expression in a dose- and time-dependent manner, as measured by Northern blot (mRNA) analysis. The 50% inhibitory concentration of 5 microM for collagen was estimated. The induction of collagen was reversed by the addition of NAC and reduced glutathione. To localize the receptor for homocystine on HVSMC, we synthesized fluorescamine-labeled homocystine conjugate. Incubation of labeled homocystine with HVSMC demonstrated membrane and cytosol localization of homocystine binding. The receptor-ligand binding was disrupted by NAC. Based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis fluorography, we observed a 40- to 25-kDa homocystine redox receptor in HVSMC. Our results suggested that the redox homocysteine induces HVSMC proliferation by binding to the redox receptor and may exacerbate atherosclerotic lesion formation by inducing collagen expression.}, }
@article {pmid9482701, year = {1998}, author = {Iikura, M and Takaishi, T and Hirai, K and Yamada, H and Iida, M and Koshino, T and Morita, Y}, title = {Exogenous nitric oxide regulates the degranulation of human basophils and rat peritoneal mast cells.}, journal = {International archives of allergy and immunology}, volume = {115}, number = {2}, pages = {129-136}, doi = {10.1159/000023892}, pmid = {9482701}, issn = {1018-2438}, mesh = {Acetylcysteine/pharmacology ; Animals ; Basophils/*physiology ; Calcimycin/antagonists &amp; inhibitors/pharmacology ; Cell Degranulation/*drug effects ; Dose-Response Relationship, Drug ; Down-Regulation ; Histamine/metabolism ; Histamine Release/drug effects ; Immunoglobulin E/immunology ; Male ; Mast Cells/*physiology ; Nitric Oxide/*pharmacology ; Nitroprusside/pharmacology ; Peritoneal Cavity/cytology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {This study was designed to investigate whether anti-IgE-induced or ionophore A23187-induced histamine release from human basophils is regulated by exogenous nitric oxide (NO), and to assess some similarities between the effect of NO on basophils and that on rat peritoneal mast cells (RPMC). The NO donor, sodium nitroprusside (SNP), inhibited A23187-induced histamine release from crude human basophils and crude RPMC in a dose-dependent fashion. This downregulation was still observed when SNP was washed out just before the cell stimulation, indicating that the effect of SNP was irreversible. The downregulation disappeared in both purified cell populations after the removal of contaminating cells. However, when purified cells were preincubated with SNP in the presence of 5 mM N-acetylcysteine (NAC), increasing the bioavailability of NO, the downregulation was recovered. The presence of NAC significantly augmented the downregulation of SNP on A23187-induced histamine release from both crude cell populations. In contrast, SNP had no effect on anti-IgE-induced histamine release from either crude or purified basophil preparation in the absence of NAC, and SNP plus NAC inhibited anti-IgE-induced histamine release from both cell preparations. The same results were obtained with crude and purified RPMC preparations under the same conditions. These results show that SNP similarly downregulated exocytosis of basophils and RPMC, and acquired the potent effect in the presence of NAC, indicating that exogenous NO plays a part in the regulation of basophil and mast cell activation.}, }
@article {pmid9480824, year = {1998}, author = {Kletsas, D and Barbieri, D and Stathakos, D and Botti, B and Bergamini, S and Tomasi, A and Monti, D and Malorni, W and Franceschi, C}, title = {The highly reducing sugar 2-deoxy-D-ribose induces apoptosis in human fibroblasts by reduced glutathione depletion and cytoskeletal disruption.}, journal = {Biochemical and biophysical research communications}, volume = {243}, number = {2}, pages = {416-425}, doi = {10.1006/bbrc.1997.7975}, pmid = {9480824}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*physiology ; Cell Adhesion Molecules/analysis ; Cell Count/drug effects ; Chromatin/drug effects ; Cytoskeleton/*drug effects ; Deoxyribose/*pharmacology/toxicity ; Fibroblasts ; Flow Cytometry ; Glutathione/analysis/*deficiency ; Humans ; Integrins/analysis ; Microscopy, Fluorescence ; Mitochondria/drug effects ; Oxidative Stress/drug effects ; Protein Synthesis Inhibitors/pharmacology ; }, abstract = {2-deoxy-D-Ribose (dRib), the most reducing sugar, induces apoptosis in normal human fibroblasts, as judged by cytoplasmic shrinkage, chromatin condensation, DNA fragmentation and mitochondrial depolarization. This effect is independent from culture conditions, such as cell density and the presence or absence of serum in the culture milieu, suggesting that dRib-induced apoptosis is cell cycle-independent. dRib was found also to provoke disruption of the actin filament network and detachment from the substratum, while at the same time, interestingly, it increases the expression of several integrins and cell adhesion molecules. Furthermore, dRib was found to reduce the intracellular levels of reduced glutathione (GSH). The apoptotic process was not affected by the macromolecular-synthesis inhibitors cycloheximide and actinomycin D. On the contrary, the antioxidant N-acetyl-L-cysteine (NAC) fully blocks the dRib-induced apoptosis by preventing GSH depletion, while it also inhibits actin-filament-network disruption and mitochondrial depolarization. The above indicate that dRib induces apoptosis in human fibroblasts by a mechanism involving glutathione metabolism and oxidative stress, as well as disturbance of cytoskeletal integrity and cell adhesion.}, }
@article {pmid9476910, year = {1998}, author = {Camhi, SL and Alam, J and Wiegand, GW and Chin, BY and Choi, AM}, title = {Transcriptional activation of the HO-1 gene by lipopolysaccharide is mediated by 5' distal enhancers: role of reactive oxygen intermediates and AP-1.}, journal = {American journal of respiratory cell and molecular biology}, volume = {18}, number = {2}, pages = {226-234}, doi = {10.1165/ajrcmb.18.2.2910}, pmid = {9476910}, issn = {1044-1549}, support = {R01DK43135/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Cell Extracts ; Cell Line ; Cell Nucleus ; Dimethyl Sulfoxide/pharmacology ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation, Enzymologic/genetics ; Genes, fos/genetics ; Genes, jun/genetics ; Heme Oxygenase (Decyclizing)/*genetics ; Heme Oxygenase-1 ; Lipopolysaccharides/*pharmacology ; Macrophages ; Membrane Proteins ; Mice ; RNA, Messenger/analysis ; Reactive Oxygen Species/*physiology ; Regulatory Sequences, Nucleic Acid/genetics ; Sequence Deletion ; Transcription Factor AP-1/physiology ; Transcriptional Activation/drug effects/*genetics ; }, abstract = {Heme oxygenase-1 (HO-1) is a stress-response protein, the expression of which is transcriptionally regulated by agents that cause oxidative stress. We have previously shown that lipopolysaccharide (LPS)-induced HO-1 gene transcription in RAW 264.7 macrophage cells is mediated by a distal enhancer called SX2, located 4 kb upstream from the HO-1 transcription initiation site (Am. J. Respir. Cell Mol. Biol. 1995;13:387-398). We have recently identified a second distal enhancer, called AB1, located 6 kb upstream from the SX2 distal enhancer (J. Biol. Chem. 1995;270:11977-11984). Here we report the extension of our studies to investigate whether the AB1 distal enhancer and/or other potential regulatory elements in the entire 5' distal flanking sequences (11-kb region) of the HO-1 gene may also mediate HO-1 gene transcription in response to LPS. Using deletional analysis, we found that the AB1 enhancer also mediates LPS-induced HO-1 gene transcription. Mutational analysis of the AB1 enhancer and electrophoretic-mobility-shift assays of nuclear extracts from LPS-treated cells further demonstrated that the transcription factor activator protein-1 (AP-1) is critical for AB1-mediated HO-1 gene activation by LPS. We also found increased expression of AP-1 family members c-fos and c-jun by Northern blot analyses after treatment with LPS. Further, we observed that LPS-treated RAW 264.7 cells produced high levels of reactive oxygen intermediates (ROI) as measured through flow-cytometric analysis of dichlorofluoroscein (DCF)-stained cells. Treatment of cells with the antioxidants N-acetyl-L-cysteine (NAC) and dimethyl sulfoxide (DMSO) not only blunts LPS-induced production of ROI, but also significantly attenuates LPS-induced HO-1 messenger RNA (mRNA) expression and gene transcription. Taken together, these data suggest that LPS regulates HO-1 gene transcription in part by inducing the production of ROI, which initiate signal-transduction pathway(s) leading to the activation of AP-1-dependent HO-1 gene transcription.}, }
@article {pmid9470017, year = {1998}, author = {Perry, HE and Shannon, MW}, title = {Efficacy of oral versus intravenous N-acetylcysteine in acetaminophen overdose: results of an open-label, clinical trial.}, journal = {The Journal of pediatrics}, volume = {132}, number = {1}, pages = {149-152}, doi = {10.1016/s0022-3476(98)70501-3}, pmid = {9470017}, issn = {0022-3476}, mesh = {Acetaminophen/*adverse effects ; Acetylcysteine/*administration &amp; dosage/therapeutic use ; Administration, Oral ; Adolescent ; Analgesics, Non-Narcotic/*adverse effects ; Chemical and Drug Induced Liver Injury/drug therapy/etiology ; Drug Overdose/drug therapy ; *Drugs, Investigational/therapeutic use ; Female ; Free Radical Scavengers/*administration &amp; dosage/therapeutic use ; Humans ; Injections, Intravenous ; Male ; Statistics, Nonparametric ; }, abstract = {We compared the clinical course of pediatric patients (n = 25) with acetaminophen poisoning treated with an investigational intravenous preparation of N-acetylcysteine (IV-NAC) with that of historical control subjects (n = 29) treated with conventional oral NAC (O-NAC) therapy. Patients received IV-NAC for 52 hours; historical control subjects received O-NAC (72 hours). There were no significant intergroup differences between treatment groups in age (15.5 vs 15.9 years), gender (88% vs 90% female) or distribution of risk categories (probable risk, 12 vs 15; high risk; 13 vs 14). The peak prothrombin time was significantly higher in the IV-NAC group (14.2 vs 13.6 seconds; p = 0.048). Mean treatment delay was significantly longer in the IV-NAC group (14.4 vs 10.4 hours; p = 0.001). Hepatoxicity was noted in two (8.0%) patients in the IV-NAC treatment group and two (6.9%) patients in the O-NAC group. All patients recovered. Our results indicate that 52 hours of intravenous NAC is as effective as 72 hours of oral NAC.}, }
@article {pmid9459113, year = {1997}, author = {Domenighetti, G and Suter, PM and Schaller, MD and Ritz, R and Perret, C}, title = {Treatment with N-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlled clinical study.}, journal = {Journal of critical care}, volume = {12}, number = {4}, pages = {177-182}, doi = {10.1016/s0883-9441(97)90029-0}, pmid = {9459113}, issn = {0883-9441}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Aged ; Blood Coagulation ; Double-Blind Method ; Expectorants/administration &amp; dosage/*therapeutic use ; Female ; Hemodynamics ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Oxygen/blood ; Pulmonary Gas Exchange ; Respiration, Artificial ; Respiratory Distress Syndrome/*drug therapy/*mortality/physiopathology ; }, abstract = {PURPOSE: Intravenous N-acetylcysteine (NAC) has been reported to improve systemic oxygenation and reduce the need for ventilatory support in patients with an acute lung injury. In the more serious form, namely established adult respiratory distress syndrome (ARDS) (PaO2/FIO2 < or = 200 mm Hg), we tested the hypothesis that treatment with intravenous NAC may be beneficial.<br><br>MATERIALS AND METHODS: Respiratory dysfunction was graded daily according to the need for mechanical ventilation and FIO2 and to the evolution of the lung injury score (LIS) and the PaO2/FIO2 ratio in 42 patients with established ARDS receiving either NAC 190 mg/kg/day or placebo as a continuous intravenous infusion over the first 3 days of their clinical course.<br><br>RESULTS: NAC and placebo groups (22 and 20 patients, respectively) were comparable for demographic characteristics, ARDS categories, severity of illness (simplified acute physiology score [SAPS II]) LIS and PaO2/FIO2 ratio. Mortality rate was 32% for the NAC and 25% for the placebo group (difference not significant). At admission (day 1), 91% of patients in the NAC and 95% in the placebo group required ventilatory support; at days 2, 3, 5, and 7 after admission, the percentage of patients receiving ventilatory support was not significantly reduced for both groups in comparison with day 1. Moreover, there were no differences between the two groups at the same observation days. In both groups, the FIO2 was significantly lower and the PaO2/FIO2 ratio was significantly higher than the initial values during the evolution (FiO2 at day 3, P < .01 for NAC and P < .05 for placebo; PaO2/FIO2 at day 3: P < .01 for NAC and P < .02 for placebo), but this improvement was similar for both groups and, moreover, the between-group comparison was never significantly different at the various collection days. The LIS decreased significantly in NAC group between days 1 and 3 (2.23 +/- 0.62 v 1.76 +/- 0.17; P < .05), whereas no changes were observed in the placebo group; at day 5, there was a significant difference between the two groups (1.53 +/- 0.21 for the NAC v 2.15 +/- 0.19 for the placebo group; P < .05). In the prevalent sepsis category (10 patients in the NAC and 9 in the placebo group), the mortality rate, the need of ventilatory support, the intensive care unit stay, and the PaO2/FIO2 evolution did not differ significantly in both subgroups.<br><br>CONCLUSIONS: In this relatively small group of patients presenting with an established ARDS subsequent to a variety of underlying diseases, intravenous NAC treatment during 72 hours neither improved systemic oxygenation nor reduced the need for ventilatory support.}, }
@article {pmid9348433, year = {1997}, author = {Reed, M and Thompson, DC}, title = {Immunochemical visualization and identification of rat liver proteins adducted by 2,6-di-tert-butyl-4-methylphenol (BHT).}, journal = {Chemical research in toxicology}, volume = {10}, number = {10}, pages = {1109-1117}, doi = {10.1021/tx970124y}, pmid = {9348433}, issn = {0893-228X}, support = {ES06016/ES/NIEHS NIH HHS/United States ; }, mesh = {Alkylation ; Animals ; Antioxidants/*metabolism ; Butylated Hydroxytoluene/*metabolism ; Immune Sera/immunology ; Immunochemistry ; Liver/*metabolism ; Male ; Molecular Weight ; Proteins/*metabolism ; Rabbits ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Several alkylphenols (e.g., 2,6-di-tert-butyl-4-methylphenol, BHT) form reactive quinone methide intermediates (e.g., 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone, BHT-QM) upon oxidation by cellular enzymes. In order to pursue the role of protein alkylation in alkylphenol toxicity, we used an immunochemical approach to identify protein targets alkylated by BHT. Synthetic BHT-N-acetylcysteine (BHT-NAC) was coupled to keyhole limpet hemocyanin and used as an antigen from which polyclonal antibodies were raised in New Zealand white rabbits. Rabbit serum contained an antibody which was highly specific for BHT-NAC, as determined by competitive ELISA. The BHT antibody was used as a probe to look for the presence of BHT-protein adducts in in vitro incubations with rat liver microsomes or tissue slices and also in vivo in liver tissue from male Sprague-Dawley rats exposed to BHT. Western blotting of protein gels revealed BHT-dependent protein alkylation over a wide molecular weight range. Prominent recurrent bands were observed at approximately 34.5, 52, 64.5, 74, and 97 kDa. Detection of adducts was inhibited in microsomal incubations by cytochrome P450 inhibitors, deuterated BHT, and the omission of NADPH. Similar protein alkylation patterns were observed in rat liver microsomes exposed to synthetically prepared BHT-QM as in the enzyme-mediated incubations. In rats gavaged with up to 1000 mg/kg BHT, the amount of protein alkylation observed was maximal at 24 h postdosing and was dose-dependent. Two alkylated proteins were isolated and identified by N-terminal sequencing: a mitochondrial beta-oxidation enzyme, enoyl-CoA hydratase, and a plasma membrane/cytoskeletal linker protein from the ezrin/moesin/radixin family.}, }
@article {pmid9452125, year = {1998}, author = {Bellezzo, JM and Leingang, KA and Bulla, GA and Britton, RS and Bacon, BR and Fox, ES}, title = {Modulation of lipopolysaccharide-mediated activation in rat Kupffer cells by antioxidants.}, journal = {The Journal of laboratory and clinical medicine}, volume = {131}, number = {1}, pages = {36-44}, doi = {10.1016/s0022-2143(98)90075-0}, pmid = {9452125}, issn = {0022-2143}, support = {DK-41816/DK/NIDDK NIH HHS/United States ; DK-44305/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cell Nucleus/metabolism ; DNA-Binding Proteins/metabolism ; Kupffer Cells/*drug effects ; Lipopolysaccharides/*pharmacology ; Liver Diseases/prevention &amp; control ; Macrophage Activation/*drug effects ; Male ; NF-kappa B/metabolism ; Pyrrolidines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Vitamin E/*pharmacology ; }, abstract = {Activation of Kupffer cells, the resident macrophage population of the liver, has been implicated in the pathogenesis of several types of liver injury. The aim of this study was to investigate whether the antioxidants N-acetylcysteine (NAC) and alpha-tocopherol succinate (alpha-TOC) suppress lipopolysaccharide (LPS)-induced activation of rat Kupffer cells. LPS activated NF-kappaB in Kupffer cells, and this response was inhibited by NAC and alpha-TOC. NAC and alpha-TOC also markedly suppressed LPS-induced tumor necrosis factor-alpha (TNF-alpha) mRNA levels and secretion. We further show that LPS was unable to increase TNF-alpha mRNA in drug-treated cells even when stimulation occurred after NAC or alpha-TOC were removed. These results indicate that antioxidants persistently suppress LPS activation in Kupffer cells, and suggest that the mechanism responsible for this involves more than mere quenching of free radical production. The demonstration that NAC and alpha-TOC have inhibitory effects on LPS-mediated Kupffer cell activation suggests that these compounds may have a beneficial effect in liver injury involving oxidative stress and endotoxemia.}, }
@article {pmid9447249, year = {1997}, author = {Brack, C and Bechter-Thüring, E and Labuhn, M}, title = {N-acetylcysteine slows down ageing and increases the life span of Drosophila melanogaster.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {53}, number = {11-12}, pages = {960-966}, doi = {10.1007/pl00013199}, pmid = {9447249}, issn = {1420-682X}, mesh = {Acetylcysteine/*pharmacology ; *Aging ; Animals ; Antioxidants/*pharmacology ; Drosophila melanogaster/*physiology ; Gene Expression/drug effects ; Longevity ; RNA, Messenger/genetics ; RNA, Ribosomal/metabolism ; }, abstract = {Ageing can be defined as the time-dependent decline of physiological functions of an organism. The molecular causes for the ageing process are multiple, involving both genetic and environmental factors. It has been proposed that antioxidants may positively influence the ageing process, protecting the organism against free radical-induced damage. Here we show that the antioxidant N-acetylcysteine (NAC) has a life-extending effect on Drosophila melanogaster. Dietary uptake of NAC results in a dose-dependent increase in median and maximum life span. Flies fed on 1 mg/ml NAC food live 16.6% longer; at 10 mg/ml, life span increases by 26.6%. We have examined the effect of NAC treatment on protein and RNA levels: we observe an NAC-dependent increase in absolute amounts of total RNA and ribosomal RNA, but no differences in protein levels. The NAC effect on longevity may involve differential expression of specific mRNA genes, as suggested by RNA finger-printing experiments.}, }
@article {pmid9443171, year = {1997}, author = {Vriesman, MF and Haenen, GR and Westerveld, GJ and Paquay, JB and Voss, HP and Bast, A}, title = {A method for measuring nitric oxide radical scavenging activity. Scavenging properties of sulfur-containing compounds.}, journal = {Pharmacy world &amp; science : PWS}, volume = {19}, number = {6}, pages = {283-286}, pmid = {9443171}, issn = {0928-1231}, mesh = {Electrochemistry ; Free Radical Scavengers/*chemistry ; Free Radicals/analysis ; Kinetics ; Nitric Oxide/*analysis/chemistry ; Sulfhydryl Compounds/chemistry ; Sulfur Compounds/*chemistry ; }, abstract = {A new method for the quantification of the nitric oxide (.NO) scavenging activity of compounds in aqueous solutions is described using an amperometric .NO sensor. After correction for the spontaneous degradation of .NO, second-order rate kinetics of the scavenging reaction are observe. The rate constant for hemoglobin found with this method is comparable with that found with an established spectrophotometric method. To demonstrate the capability of the method, several sulfur-containing compounds were tested (GSH, GSSG, S-methyl glutathione, N-acetyl cysteine, lipoic acid and dihydrolipoic acid). Of these compounds, only those that contained a thiol group displayed a considerable .NO scavenging activity.}, }
@article {pmid9440542, year = {1997}, author = {Yanagihara, Y and Basaki, Y and Kajiwara, K and Ikizawa, K}, title = {A thiol antioxidant regulates IgE isotype switching by inhibiting activation of nuclear factor-kappaB.}, journal = {The Journal of allergy and clinical immunology}, volume = {100}, number = {6 Pt 2}, pages = {S33-8}, doi = {10.1016/s0091-6749(97)70002-2}, pmid = {9440542}, issn = {0091-6749}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; B-Lymphocytes/*metabolism ; CD40 Antigens/physiology ; Gene Expression Regulation, Developmental/drug effects ; *Genes, Immunoglobulin ; Genes, Switch ; Humans ; Immunoglobulin E/*genetics ; Interleukin-4/pharmacology ; NF-kappa B/*antagonists &amp; inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; STAT6 Transcription Factor ; Trans-Activators/metabolism ; Transcription, Genetic/drug effects ; Tumor Cells, Cultured ; }, abstract = {The binding site for nuclear factor-kappaB (NF-kappaB) is present at the promoter region of the germline Cepsilon gene, but there is little information on whether this factor is involved in regulating IgE synthesis by human B cells. Accordingly, we studied the role of NF-kappaB in germline Cepsilon transcription by using two human Burkitt's lymphoma B cell lines, DND39 and DG75. In both cell lines, n-acetyl-L-cysteine (NAC), a potent thiol antioxidant, inhibited the triggering of the nuclear expression of NF-kappaB by IL-4 and by anti-CD40 monoclonal antibody. Although IL-4 activated signal transducers and activators of transcription (STAT) 6 in addition to NF-kappaB, NAC treatment or the transfection of decoy oligodeoxynucleotides for NF-kappaB or STAT6 only partly blocked IL-4-induced germline Cepsilon transcription. However, these two decoy oligodeoxynucleotides together almost completely abrogated IL-4-induced germline Cepsilon transcription. Of note, CD40-mediated enhancement of IL-4-driven germline Cepsilon transcription was markedly decreased by NAC or by a decoy oligodeoxynucleotide for NF-kappaB. The effect of NAC was also examined on deletional switch recombination underlying the isotype switch to IgE. NAC inhibited the generation of Smu/Sepsilon switch fragments in normal human B cells costimulated with IL-4 and anti-CD40 monoclonal antibody. It also abolished IL-4-induced upregulation of CD40 but promoted upregulation of CD23. These results suggest that coordination of NF-kappaB and STAT6 may be required for induction of germline Cepsilon transcription by IL-4, and that CD40-mediated NF-kappaB activation may be important in regulating both enhancement of germline Cepsilon transcription and class switching to IgE.}, }
@article {pmid9438563, year = {1998}, author = {Jareño, EJ and Bosch-Morell, F and Fernández-Delgado, R and Donat, J and Romero, FJ}, title = {Serum malondialdehyde in HIV seropositive children.}, journal = {Free radical biology &amp; medicine}, volume = {24}, number = {3}, pages = {503-506}, doi = {10.1016/s0891-5849(97)00168-8}, pmid = {9438563}, issn = {0891-5849}, mesh = {Adolescent ; Antioxidants/analysis ; CD4 Lymphocyte Count ; CD4-CD8 Ratio ; Child ; Child, Preschool ; Female ; HIV Seropositivity/*blood ; Humans ; Infant ; Infant, Newborn ; Male ; Malondialdehyde/*blood ; Oxidative Stress ; }, abstract = {Human immunodeficiency virus (HIV) infection is associated with oxidative stress as it has been demonstrated in adult seropositive individuals. We show in this study that serum malondialdehyde (MDA) concentration of HIV infected children was significantly higher than in control children. Moreover, a statistically significant decreased serum antioxidant status was detected in HIV infected children when compared with controls. No correlation was found in HIV infected children between their clinical or immunological categories, CD4+ lymphocyte count or CD4+/CD8+ ratio, and MDA concentration or serum antioxidant status. Newborn from HIV seropositive mothers had also a higher MDA concentration in cord blood serum than their corresponding controls from HIV seronegative mothers, whereas no difference could be established in the serum antioxidant status between both groups. No apparent correlation could be established between birth weight, gestational age or APGAR test values, and MDA in any of these groups. The results presented, (i.e., the increase of MDA concentration in HIV seropositive infants and children, and the decrease in serum total antioxidants in HIV seropositive children) confirm the involvement of oxidative stress in the pathophysiology of this infection also in childhood. Because of the importance of oxidative stress and antioxidants for HIV viral replication, the adequacy of an adjuvant therapy with antioxidants should be considered; an adequate candidate for it could be N-acetyl-cysteine.}, }
@article {pmid9438554, year = {1998}, author = {Higuchi, Y and Matsukawa, S}, title = {Active oxygen-mediated chromosomal 1-2 Mbp giant DNA fragmentation into internucleosomal DNA fragmentation in apoptosis of glioma cells induced by glutamate.}, journal = {Free radical biology &amp; medicine}, volume = {24}, number = {3}, pages = {418-426}, doi = {10.1016/s0891-5849(97)00273-6}, pmid = {9438554}, issn = {0891-5849}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; *Apoptosis ; Ascorbic Acid/pharmacology ; Catalase/pharmacology ; Chromosomes/*chemistry ; DNA Fragmentation/*drug effects ; Deferoxamine/pharmacology ; Free Radical Scavengers/pharmacology ; Glioma/metabolism/*ultrastructure ; Glutamic Acid/*pharmacology ; Glutathione/metabolism ; Hydrogen Peroxide/metabolism ; Iron Chelating Agents/pharmacology ; Oxidation-Reduction ; Oxygen/*pharmacology ; Phenanthrolines/pharmacology ; Rats ; Tumor Cells, Cultured ; }, abstract = {C6 glioma cells treated with 10 mM glutamate reduced intracellular GSH to one-seventh of the initial level, and induced cytolysis accompanied by apoptosis. The treated cells produced extracellular H2O2. The cytolysis of the C6 cells induced by glutamate was prevented by antioxidants such as N-acetylcysteine (NAC), ascorbic acid (ASC), catalase, and NaN3, iron chelators such as deferoxamine and 1,10-phenanthroline, and oxygen radical scavengers such as 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) and alpha-phenyl-tert-butyl nitrone (PBN). The effect of these antioxidants, iron chelators, and oxygen radical scavengers on the cytolysis of C6 cells was dependent on the dose and the intracellular GSH level. Furthermore, 1-2 Mbp chromosomal DNA (giant DNA) fragments were observed during cytolysis. The giant DNA fragments were further cleaved into smaller DNA fragments of 200-800 kbp, and then to fragments of less than 300 kbp in size including chromosomal ladder DNA fragments. Such serial chromosomal DNA degradations induced by glutamate were also inhibited by addition of these antioxidants, iron chelators, and oxygen radical scavengers. These findings suggest that glutamate induces GSH depletion, and consequently, apoptosis through endogenously produced active oxygen species in C6 glioma cells and that the apoptosis is accompanied by 1-2 Mbp giant DNA fragmentation prior to the internucleosomal DNA fragmentation.}, }
@article {pmid9437207, year = {1997}, author = {Chiu, JJ and Wung, BS and Shyy, JY and Hsieh, HJ and Wang, DL}, title = {Reactive oxygen species are involved in shear stress-induced intercellular adhesion molecule-1 expression in endothelial cells.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {17}, number = {12}, pages = {3570-3577}, doi = {10.1161/01.atv.17.12.3570}, pmid = {9437207}, issn = {1079-5642}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Catalase/metabolism ; Cells, Cultured ; Endothelium, Vascular/*cytology ; Humans ; Intercellular Adhesion Molecule-1/*metabolism ; Monocytes/cytology ; Reactive Oxygen Species/*physiology ; Rheology ; Transcription, Genetic ; }, abstract = {Vascular endothelial cells (ECs) are constantly subjected to flow-induced shear stress. Although the effects of shear stress on ECs are well known, the intracellular signal mechanisms remain largely unclear. Reactive oxygen species (ROS) have recently been suggested to act as intracellular second messengers. The potential role of ROS in shear-induced gene expression was examined in the present study by subjecting ECs to a shear force using a parallel-plate flow chamber system. ECs under shear flow increased their intracellular ROS as indicated by superoxide production. This superoxide production was maintained at an elevated level as shear flow remained. Sheared ECs, similar to TNF(alpha)-, PMA-, or H2O2-treated cells, increased their intercellular adhesion molecule-1 (ICAM-1) mRNA levels in a time-dependent manner. Pretreatment of ECs with an antioxidant, N-acetyl-cysteine (NAC) or catalase, inhibited this shear-induced or oxidant-induced ICAM-1 expression. ROS that were involved in the shear-induced ICAM-1 gene expression were further substantiated by functional analysis using a chimera containing the ICAM-1 promoter region (-850 bp) and the reporter gene luciferase. Shear-induced promoter activities were attenuated by pretreating sheared ECs with NAC and catalase. Flow cytometric analysis and monocytic adhesion assay confirmed the inhibitory effect of NAC and catalase on the shear-induced ICAM-1 expression on ECs. These results clearly demonstrate that shear flow to ECs can induce intracellular ROS generation that may result in an increase of ICAM-1 mRNA levels via transcriptional events. Our findings thus support the importance of intracellular ROS in modulating hemodynamically induced endothelial responses.}, }
@article {pmid9436612, year = {1998}, author = {Pahan, K and Sheikh, FG and Namboodiri, AM and Singh, I}, title = {N-acetyl cysteine inhibits induction of no production by endotoxin or cytokine stimulated rat peritoneal macrophages, C6 glial cells and astrocytes.}, journal = {Free radical biology &amp; medicine}, volume = {24}, number = {1}, pages = {39-48}, doi = {10.1016/s0891-5849(97)00137-8}, pmid = {9436612}, issn = {0891-5849}, support = {NS-22576/NS/NINDS NIH HHS/United States ; NS-34741/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Astrocytes/drug effects/metabolism ; Cells, Cultured ; Cytokines/*antagonists &amp; inhibitors ; Enzyme Inhibitors/pharmacology ; Lipopolysaccharides/*antagonists &amp; inhibitors ; Macrophages, Peritoneal/drug effects/metabolism ; NF-kappa B/metabolism ; Neuroglia/drug effects/metabolism ; Nitric Oxide/*biosynthesis ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Nitric Oxide Synthase Type II ; Pyrrolidines/pharmacology ; Rats ; Thiocarbamates/pharmacology ; Tumor Cells, Cultured ; }, abstract = {The present study underscores the importance of N-acetyl cysteine (NAC), a potent antioxidant, in inhibiting the induction of NO production by lipopolysaccharides (LPS) and cytokines in peritoneal macrophages, C6 glial cells and primary astrocytes. LPS, interleukin-1 beta (IL-1beta), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) alone or in combinations induced the production of NO to different degrees. NAC when added 2 h earlier to the addition of these stimuli potentially blocked the increase in NO production in macrophages, astrocytes and C6 glial cells. The decrease in NO production by NAC was accompanied by a decrease in inducible nitric oxide synthase (iNOS) activity, in iNOS protein detected by immunoblot analysis with antibodies against iNOS, and in iNOS mRNA determined by reverse-transcriptase coupled polymerase chain reaction (RT-PCR). Time course studies show that inhibition was maximum when NAC was added 2 h prior to the addition of LPS and the degree of inhibition decreased progressively with the increase in time interval when NAC was added after the addition of LPS. In addition to NAC, another antioxidant pyrrolidine dithiocarbamate (PDTC) was also found to inhibit the induction of NO production effectively. Since activation of NF-kappaB is necessary for the induction of iNOS, we examined the effect of NAC on the activation of NF-kappaB. Inhibition of LPS-induced activation of NF-kappaB by NAC in rat peritoneal macrophages suggests that the inhibitory effect of NAC on the induction of iNOS is due to the inhibition of NF-kappaB. Besides NO, NAC also blocked the production of TNF-alpha in rat peritoneal macrophages activated with endotoxin. These results suggest that expression of iNOS and TNF-alpha in macrophages do involve oxygen radicals. The importance of these results in relation to controlling various harmful effects of cytokines released by activated macrophages and glial cells is discussed.}, }
@article {pmid9425274, year = {1997}, author = {Katoh, S and Mitsui, Y and Kitani, K and Suzuki, T}, title = {Hyperoxia induces the differentiated neuronal phenotype of PC12 cells by producing reactive oxygen species.}, journal = {Biochemical and biophysical research communications}, volume = {241}, number = {2}, pages = {347-351}, doi = {10.1006/bbrc.1997.7514}, pmid = {9425274}, issn = {0006-291X}, mesh = {Animals ; Antioxidants/pharmacology ; Cell Differentiation/drug effects ; Neurites ; Neurons/cytology/*drug effects ; Oxygen/*pharmacology ; PC12 Cells ; Rats ; Reactive Oxygen Species/*metabolism ; Signal Transduction ; }, abstract = {Neurite extension of PC12 cells induced by nerve growth factor (NGF) is a well-known model of neuronal differentiation. In this study, the incubation of PC12 cells in a 50% O2 atmosphere (hyperoxia) caused neurite extension. In these cells, amounts of differentiation-marker proteins, tyrosine hydroxylase and neurofilament M increased. The effects of hyperoxia were inhibited by ascorbic acid or N-acetyl-cysteine, antioxidant reagents, suggesting the involvement of reactive oxygen species (ROS). In support of this, artificial generation of free radicals induced the same effects as hyperoxia. In these cells, total phosphorylation of cellular proteins was enhanced similar to NGF-treated cells. These results suggest that hyperoxia enhances the signal for neuronal differentiation by producing ROS, resulting in the induction of the differentiated neuronal phenotype of PC12 cells.}, }
@article {pmid9383989, year = {1997}, author = {Steenvoorden, DP and Beijersbergen van Henegouwen, GM}, title = {Cysteine derivatives protect against UV-induced reactive intermediates in human keratinocytes: the role of glutathione synthesis.}, journal = {Photochemistry and photobiology}, volume = {66}, number = {5}, pages = {665-671}, doi = {10.1111/j.1751-1097.1997.tb03204.x}, pmid = {9383989}, issn = {0031-8655}, mesh = {Buthionine Sulfoximine/pharmacology ; Cells, Cultured ; Cysteine/*analogs &amp; derivatives/metabolism/pharmacology ; Free Radical Scavengers/pharmacology ; Glutathione/biosynthesis ; Humans ; Keratinocytes/*drug effects/metabolism/*radiation effects ; Photobiology ; Ultraviolet Rays/adverse effects ; }, abstract = {Several recent studies have shown cysteine derivatives can protect against negative effects of UV exposure. In this study, an attempt was made to correlate cellular bioavailability and metabolism of cysteine derivatives with protection against UV-induced reactive intermediates. Human keratinocytes were treated with cysteine, N-acetylcysteine (NAC), cysteine-ethylester (CYSET) and N-acetylcysteine-ethylester. The uptake of the compounds and their metabolism to cysteine and eventually to glutathione (GSH) was measured. Large differences in uptake were observed, with CYSET resulting in the highest and NAC in the lowest intracellular thiol levels. The increase in intracellular GSH was similar for all derivatives with a maximum of 23-54% over the control level. Protective efficacy of the derivatives was measured as the inhibition of binding of UV-induced reactive intermediates from 8-methoxypsoralen. There was only a small difference between the compounds, with maximum protection of 25-31%. No relation was found between total intracellular thiol and protection. However, for NAC, there was a linear relation between GSH level and protective efficacy (r = 0.94). Even though this was not clear for the other derivatives (r = 0.55 for CYS; r = 0.60 for CYSET; r = 0.70 for NACET), it indicates that GSH synthesis is an important factor. This was confirmed by experiments using cells with irreversibly inhibited GSH synthesis. Even though the total intracellular thiol level was comparable to uninhibited cells, protection was decreased. We conclude that the intracellular GSH increase is the most important factor in photoprotection by cysteine derivatives.}, }
@article {pmid9375974, year = {1997}, author = {Dent, G and Rabe, KF and Magnussen, H}, title = {Augmentation of human neutrophil and alveolar macrophage LTB4 production by N-acetylcysteine: role of hydrogen peroxide.}, journal = {British journal of pharmacology}, volume = {122}, number = {4}, pages = {758-764}, doi = {10.1038/sj.bjp.0701428}, pmid = {9375974}, issn = {0007-1188}, mesh = {Acetylcysteine/*pharmacology ; Catalase/metabolism ; Female ; Humans ; Hydrogen Peroxide/*pharmacology ; Leukotriene B4/*biosynthesis ; Macrophages, Alveolar/*drug effects/enzymology/metabolism ; Male ; Neutrophils/*drug effects/enzymology/metabolism ; Reference Values ; Superoxide Dismutase/metabolism ; }, abstract = {1. The actions of N-acetylcysteine (NAC) on hydrogen peroxide (H2O2) and leukotriene B4 (LTB4) production by human resting and stimulated peripheral blood neutrophils and alveolar macrophages were investigated. 2. At a concentration of 100 microM, NAC significantly (P < 0.01) suppressed the accumulation of H2O2 in the incubation medium of resting and opsonized zymosan (OZ; 0.5 mg ml[-1])- or N-formylmethionyl-leucyl-phenylalanine (fMLP; 1 microM)-stimulated neutrophils and of resting and OZ-stimulated macrophages. At concentrations of 10 microM and above, NAC augmented significantly the level of LTB4 in the supernatants of OZ- and fMLP-stimulated neutrophils (P < 0.01 and P < 0.05, respectively) and OZ-stimulated macrophages (P < 0.05 at 10 microM, P < 0.01 at 100 microM NAC). 3. NAC (100 microM) caused a significant (P < 0.01) reduction in the quantity of measurable H2O2 when incubated with exogenous H2O2 concentrations equivalent to those released from OZ-stimulated neutrophils and macrophages. At no concentration did NAC affect quantitites of measurable LTB4 when incubated with exogenous LTB4. 4. Superoxide dismutase (SOD), which catalyzes the conversion of superoxide anion to H2O2 had no significant effect on LTB4 production by human neutrophils. In contrast, catalase, which catalyzes the conversion of H2O2 to H2O and O2, caused a pronounced, statistically significant (P < 0.01) increase in the levels of LTB4 measured in the supernatants of OZ- and fMLP-stimulated neutrophils. 5. H2O2 (12.5 microM and 25 microM, concentrations equivalent to those measured in the supernatants of activated neutrophils and alveolar macrophages, respectively) caused a small (13%) decrease in the quantity of measurable LTB4 (P = 0.051 and P < 0.05 at 12.5 microM and 25 microM, respectively) that was inhibited by NAC (100 microM) but not by catalase (400 u ml[-1]). 6. In conclusion, the anti-oxidant drug, NAC, increases LTB4 production by human neutrophils and alveolar macrophages, probably through the elimination of cell-derived H2O2. LTB4 undergoes a H2O2-dependent oxidation that is inhibited by NAC but this is unlikely to account fully for the increased levels of LTB4, suggesting that NAC may increase LTB4 production by blocking the H2O2-dependent inhibition of a synthetic enzyme, such as 5-lipoxygenase.}, }
@article {pmid9421857, year = {1997}, author = {Davreux, CJ and Soric, I and Nathens, AB and Watson, RW and McGilvray, ID and Suntres, ZE and Shek, PN and Rotstein, OD}, title = {N-acetyl cysteine attenuates acute lung injury in the rat.}, journal = {Shock (Augusta, Ga.)}, volume = {8}, number = {6}, pages = {432-438}, pmid = {9421857}, issn = {1073-2322}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Animals ; Antioxidants/therapeutic use ; Bronchoalveolar Lavage Fluid/cytology/immunology ; CD11 Antigens/blood/drug effects ; Capillary Permeability/drug effects ; Cell Count/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Endotoxins/toxicity ; Glutathione/analysis/drug effects ; Hemorrhage/chemically induced ; Lipid Peroxidation/drug effects ; Lipopolysaccharides/pharmacology ; Liver/chemistry ; Lung/chemistry/*drug effects ; Lung Diseases/chemically induced/drug therapy/prevention &amp; control ; *Lung Injury ; Male ; Neutrophil Activation/drug effects ; Neutrophils/drug effects/immunology/metabolism ; Peroxidase/drug effects/metabolism ; Pulmonary Edema/chemically induced ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha/drug effects/metabolism ; }, abstract = {The development of the adult respiratory distress syndrome (ARDS) in the critically ill patient is associated with a significant morbidity and mortality. The pulmonary dysfunction in ARDS is largely secondary to neutrophil-mediated oxidant injury. The purpose of these studies is to examine the effect of the antioxidant N-acetyl cysteine (NAC) on a rodent model of lung injury. We postulated that NAC might attenuate lung injury following intratracheal challenge with endotoxin (lipopolysaccharide; LPS). Male Sprague-Dawley rats were administered NAC systemically either before or after intratracheal administration of LPS. Lung injury was assessed by measuring the transpulmonary leakage of 125I-labeled albumin, pulmonary myeloperoxidase content, bronchoalveolar lavage fluid cell counts, pulmonary lipid peroxidation and histology. NAC administration significantly attenuated the LPS-induced increases in lung permeability (LPS: .24 +/- .08 vs. LPS + NAC: .12 +/- .03, p < .05) and reduced the LPS-dependent increase in lipid peroxidation. However, total and differential bronchoalveolar lavage cell counts and myeloperoxidase content were not affected by NAC pretreatment. Although neutrophil influx was unaffected, neutrophil activation as assessed by surface CD11b expression and chemiluminescence was significantly down-regulated by NAC. Importantly, NAC administration up to 2 h after endotoxin challenge was still able to significantly ameliorate LPS-induced lung injury. Our data suggests that the attenuation of acute lung injury by NAC in our rodent model is related to free radical scavenging and inhibition of the neutrophil oxidative burst, rather than by an effect on inflammatory cell migration. These results suggest novel approaches for therapeutic interventions in acute lung injury.}, }
@article {pmid9412572, year = {1997}, author = {Behr, J and Maier, K and Degenkolb, B and Krombach, F and Vogelmeier, C}, title = {Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression.}, journal = {American journal of respiratory and critical care medicine}, volume = {156}, number = {6}, pages = {1897-1901}, doi = {10.1164/ajrccm.156.6.9706065}, pmid = {9412572}, issn = {1073-449X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Antioxidants/*metabolism ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Female ; Glutathione/metabolism ; Glutathione Disulfide/metabolism ; Humans ; Immunosuppressive Agents/*therapeutic use ; Lung/metabolism ; Male ; Methionine/analogs &amp; derivatives/metabolism ; Middle Aged ; Oxidative Stress ; Prospective Studies ; Pulmonary Fibrosis/*drug therapy/metabolism ; }, abstract = {In fibrosing alveolitis (FA), activated phagocytes cause excessive oxidative stress in the lower respiratory tract. Additionally, levels of glutathione, a major antioxidant of the human lung, are markedly reduced. Since N-acetylcysteine (NAC) is a known precursor for glutathione synthesis, we investigated the effect of NAC on redox balance and lung function in FA. Eighteen patients with an established diagnosis of FA were treated with 600 mg NAC three times daily for 12 wk in addition to their latest immunosuppressive therapy. Before and after NAC therapy, pulmonary function tests (PFTs) and bronchoalveolar lavage (BAL) were performed. BAL fluid was analyzed with regard to cell differential, glutathione status, and methionine sulfoxide content of BAL proteins (Met(O)), as an indicator of oxidative stress at the alveolar surface. There was an increase of total glutathione (GSHt = GSH +/- 2 x GSSG: 3.43 +/- 0.30 microM versus 4.20 +/- 0.66 microM, p < 0.05) and of reduced glutathione (GSH: 2.58 +/- 0.24 microM versus 3.42 +/- 0.54 microM, p < 0.005) in native BAL fluid and in the epithelial lining fluid (GSHt: 267.3 +/- 26.0 microM versus 367.1 +/- 36.0 microM, p < 0.005; GSH: 204.5 +/- 20.7 microM versus 302.9 +/- 32.2 microM, p < 0.005). The increase of GSH was accompanied by a decrease of Met(O) (6.83 +/- 0.71% versus 4.60 +/- 0.40%, p < 0.005). PFTs significantly improved during NAC treatment. We conclude that high-dose NAC significantly improved the antioxidant screen of the lungs by elevating GSH levels. Moreover, the decrease of Met(O) levels indicated an antioxidant effect at the alveolar surface. These biochemical changes were accompanied by an improvement of PFTs in patients under maintenance immunosuppression. NAC supplementation should, therefore, be considered as an adjunct therapy for FA.}, }
@article {pmid9372677, year = {1997}, author = {Travaline, JM and Sudarshan, S and Roy, BG and Cordova, F and Leyenson, V and Criner, GJ}, title = {Effect of N-acetylcysteine on human diaphragm strength and fatigability.}, journal = {American journal of respiratory and critical care medicine}, volume = {156}, number = {5}, pages = {1567-1571}, doi = {10.1164/ajrccm.156.5.96-09133}, pmid = {9372677}, issn = {1073-449X}, mesh = {Acetylcysteine/*pharmacology ; Action Potentials ; Adult ; Diaphragm/drug effects/*physiology ; Double-Blind Method ; Electric Stimulation ; Free Radical Scavengers/*pharmacology ; Humans ; Muscle Contraction/drug effects ; Muscle Fatigue/*drug effects ; Muscle Relaxation/drug effects ; }, abstract = {Free radical injury is believed to be important in diaphragm dysfunction. N-Acetylcysteine (NAC) is a potent free radical scavenger shown in animal models to attenuate diaphragm fatigue; however, its effects on human diaphragm function are unknown. We assessed diaphragm function by electrophrenic twitch stimulation (PdiT) and twitch occlusion (to yield Pdimax) in four healthy subjects 35 +/- 3 yr of age (mean +/- SD). We intravenously administered NAC (150 mg/kg in 250 ml D5W) or placebo (CON) (250 ml D5W) in a randomized manner after subjects were premedicated with antihistamines. There were no significant side effects with the infusion. After infusion, we measured baseline Pdimax and PdiT at FRC. Diaphragm fatigue was then induced by subjects breathing through an inspiratory resistive load. Pdimax and PdiT were then measured at 15 to 30 min and 1, 2, 3, 4, and 20-25 h after fatigue. Times to fatigue were 13 +/- 4 min (CON) and 21 +/- 6 min (NAC) (p = 0.04). At 15 min after fatigue, PdiT was reduced to 40% (CON) compared with 30% (NAC) initial PdiT value (p = 0.05). Other twitch characteristics (maximal rate of relaxation and maximal contraction rate) were reduced to a greater degree after placebo compared with NAC. There were no significant differences in the rate of recovery between CON and NAC. Pdimax at 30 min after fatigue was significantly greater with NAC; however, at 1 h after fatigue, Pdimax for CON and NAC were not different, suggesting similar rates of recovery in high-frequency fatigue. These data suggest that NAC may attenuate low-frequency human diaphragm fatigue.}, }
@article {pmid9403174, year = {1997}, author = {Kassahun, K and Davis, M and Hu, P and Martin, B and Baillie, T}, title = {Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: identification of phase I metabolites and glutathione conjugates.}, journal = {Chemical research in toxicology}, volume = {10}, number = {11}, pages = {1228-1233}, doi = {10.1021/tx970080t}, pmid = {9403174}, issn = {0893-228X}, support = {ES055500/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Bile/chemistry ; Biotransformation ; Glutathione/*pharmacokinetics ; Glutathione Transferase/metabolism ; Isothiocyanates ; Magnetic Resonance Spectroscopy ; Male ; Rats ; Rats, Sprague-Dawley ; Spectrophotometry, Ultraviolet ; Sulfoxides ; Thiocyanates/*pharmacokinetics/urine ; }, abstract = {Sulforaphane (SFN) is a naturally occurring isothiocyanate present in cruciferous vegetables, such as broccoli, that has been identified as a potent inducer of glutathione S-transferase activities in laboratory animals. The present studies were carried out to elucidate the metabolic fate of SFN in the rat. Particular emphasis was placed on glutathione (GSH)-dependent pathways because conjugation with GSH is a major route by which many isothiocyanates are eliminated in mammals. Male Sprague-Dawley rats were administered a single dose of SFN (50 mg kg-1 ip), and bile and urine were collected over ascorbic acid. Analysis of biological fluids was carried out by ionspray LC-MS/MS using the neutral loss (129 Da) and precursor ion (m/z 164) scan modes to detect GSH and N-acetylcysteine (NAC) conjugates, respectively. In bile, five thiol conjugates (designated M1-M5) were detected. Metabolites M2 and M4 were identified as the GSH conjugates of SFN and erucin (ERN, the sulfide analog of SFN), respectively, by comparing their LC-MS/MS properties with those of standards obtained by synthesis. M1 was characterized as the GSH conjugate of a desaturated metabolite of SFN (tentatively assigned the structure of delta 1-SFN), suggesting that the parent compound also undergoes oxidative metabolism. Metabolites M3 and M5 were identified as the NAC conjugates of SFN and ERN, respectively, and together with the NAC conjugate of delta 1-SFN, these species also were detected in urine. Quantitative determination of the former two mercapturates in urine indicated that approximately 60% and approximately 12% of a single dose of SFN is eliminated in 24 h as the NAC conjugates of SFN and ERN, respectively. The corresponding figures in rats dosed with ERN were approximately 67% and approximately 29%. When the GSH conjugate of SFN was incubated with phosphate buffer (pH 7.4, 37 degrees C), < 1% of the conjugate dissociated to liberate free SFN. On the other hand, the conjugate underwent a facile thiol exchange reaction (> 70% conversion) when incubated in the presence of excess cysteine, thereby acting as an effective carbamoylating agent. It is concluded that SFN undergoes metabolism by S-oxide reduction and dehydrogenation and that GSH conjugation is the major pathway by which the parent compound and its phase I metabolites are eliminated in the rat.}, }
@article {pmid9397498, year = {1997}, author = {Greenberg, MI and Grazioso, H and DiSandro, D and Stiller, S and Ferko, AP}, title = {Rectal administration of N-acetylcysteine in swine: a pilot study.}, journal = {Veterinary and human toxicology}, volume = {39}, number = {6}, pages = {329-331}, pmid = {9397498}, issn = {0145-6296}, mesh = {Absorption ; Acetylcysteine/*administration &amp; dosage/pharmacokinetics ; Administration, Rectal ; Animals ; Female ; Swine ; }, abstract = {The purpose of this pilot study was to determine if N-acetylcysteine (NAC) administered via the rectal route in swine is absorbed into the systemic circulation. Fasting swine were anesthetized, intubated, monitored and i.v. access was obtained by femoral cutdown. NAC was administered into the rectal vault (2.0 g/kg) via a balloon-tipped Foley catheter inserted into the animals' rectum. NAC administered via the rectal route resulted in systemic absorption as determined by spectrophotometric methods in 5 of the 7 study animals. This study provides important information regarding the development of a potential alternative route for the administration of NAC.}, }
@article {pmid9397238, year = {1997}, author = {Fenoy, FJ and Tornel, J and Madrid, MI and López, E and García-Salom, G}, title = {Effects of N omega-nitro-L-arginine and N-acetyl-L-cysteine on the reversal of one-kidney, one-clip hypertension.}, journal = {American journal of hypertension}, volume = {10}, number = {11}, pages = {1208-1215}, doi = {10.1016/s0895-7061(97)00223-9}, pmid = {9397238}, issn = {0895-7061}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Pressure/drug effects ; Enzyme Inhibitors/*pharmacology ; Free Radical Scavengers/*pharmacology ; Heart Rate/drug effects ; Hemodynamics/drug effects ; Hypertension, Renovascular/*drug therapy/physiopathology ; Kidney Function Tests ; Male ; Nitric Oxide Synthase/*antagonists &amp; inhibitors ; Nitroarginine/*pharmacology ; Rats ; Rats, Wistar ; }, abstract = {The present study evaluated whether nitric oxide (NO) synthesis blockade or potentiation (with N omega-nitro-L-arginine or N-acetyl-L-cysteine, respectively) modulates the systemic and renal responses to unclipping in anesthetized one-kidney, one-clip hypertensive rats (1K-1C). Cardiac output was measured by thermodilution. In time-control rats, mean arterial pressure (MAP) decreased from 197 +/- 8 mm Hg to 139 +/- 4 mm Hg 3 h after unclipping, and cardiac index (CI) decreased by 35%, with a transient rise in sodium and water excretion and no changes in total peripheral resistance (TPR), glomerular filtration rate (GFR), or renal plasma flow (RPF). Administration of N omega-nitro-L-arginine methyl ester (NAME, 10 micrograms/kg/ min) blunted the hypotensive (from 190 +/- 6 mm Hg to 157 +/- 3 mm Hg), diuretic and natriuretic responses and potentiated the decrease in CI (40%) observed after unclipping, whereas TPR increased by 103%. Also, in rats given NAME, GFR and RPF decreased by 20% and 45%, respectively, at the end of the experiment. The effect of N-acetyl-L-cysteine (NAC, 300 mg/kg), a sulfhydryl group donor that may protect NO from free radical destruction by forming an S-nitrosothiol compound, was also evaluated. NAC potentiated the depressor response to unclipping (from 180 +/- 5 mm Hg to 97 +/- 3 mm Hg), and GFR and RPF increased by 80% and 35%, respectively. These effects of NAC appear to be NO dependent, as they were blocked by simultaneous administration of NAME. However, no significant differences were observed among groups in cumulative excretion of sodium and water, demonstrating that the hemodynamic effects of NAME and NAC after unclipping are due to mechanisms other than renal excretory changes. The results of the present study indicate that the cardiovascular depressor effects of unclipping are modulated by endothelium-derived nitric oxide.}, }
@article {pmid9389904, year = {1997}, author = {Triguero, A and Barber, T and García, C and Puertes, IR and Sastre, J and Viña, JR}, title = {Liver intracellular L-cysteine concentration is maintained after inhibition of the trans-sulfuration pathway by propargylglycine in rats.}, journal = {The British journal of nutrition}, volume = {78}, number = {5}, pages = {823-831}, doi = {10.1079/bjn19970198}, pmid = {9389904}, issn = {0007-1145}, mesh = {Acetylcysteine/pharmacology ; Alkynes/*pharmacology ; Animals ; Cystathionine/blood/*metabolism ; Cystathionine gamma-Lyase/*antagonists &amp; inhibitors ; Cysteine/blood/*metabolism ; Depression, Chemical ; Glutathione/*metabolism ; Glycine/*analogs &amp; derivatives/pharmacology ; Liver/*metabolism ; Male ; Methionine/blood ; Rats ; Rats, Wistar ; Urea/urine ; }, abstract = {To study the fate of L-cysteine and amino acid homeostasis in liver after the inhibition of the trans-sulfuration pathway, rats were treated with propargylglycine (PPG). At 4 h after the administration of PPG, liver cystathionase (EC 4.4.1.1) activity was undetectable, L-cystathionine levels were significantly higher, L-cysteine was unchanged and GSH concentration was significantly lower than values found in livers from control rats injected intraperitoneally with 0.15 M-NaCl. The hepatic levels of amino acids that are intermediates of the urea cycle, L-ornithine, L-citrulline and L-arginine and blood urea were significantly greater. Ura excretion was also higher in PPG-treated rats when compared with control rats. These data suggest a stimulation of ureagenesis in PPG-treated rats. The inhibition of gamma-cystathionase was reflected in the blood levels of amino acids, because the L-methionine: L-cyst(e)ine ratio was significantly higher in PPG-treated rats than in control rats; blood concentration of cystathionine was also greater. Histological examination of liver and kidney showed no changes in PPG-treated rats when compared with controls. The administration of N-acetylcysteine (NAC) to PPG-treated rats reversed the changes in blood urea and in liver GSH. These data suggest that when liver L-cysteine production was impaired by the blockage of the trans-sulfuration pathway, the concentration of this amino acid was maintained mainly by an increase in protein degradation and by a depletion in GSH concentration that may spare L-cysteine.}, }
@article {pmid9367889, year = {1997}, author = {Ishizuka, S and Nagashima, Y and Numata, M and Yano, T and Hagiwara, K and Ozasa, H and Sone, M and Nihei, H and Horikawa, S}, title = {Regulation and immunohistochemical analysis of stress protein heme oxygenase-1 in rat kidney with myoglobinuric acute renal failure.}, journal = {Biochemical and biophysical research communications}, volume = {240}, number = {1}, pages = {93-98}, doi = {10.1006/bbrc.1997.7573}, pmid = {9367889}, issn = {0006-291X}, mesh = {Acetylcysteine/administration &amp; dosage ; Acute Kidney Injury/chemically induced/*enzymology/pathology ; Animals ; Enzyme Induction/drug effects ; Glutathione/metabolism ; Glycerol/administration &amp; dosage ; Heme Oxygenase (Decyclizing)/biosynthesis/*metabolism ; Heme Oxygenase-1 ; Immunohistochemistry ; Injections, Intramuscular ; Kidney/*enzymology/metabolism/pathology ; Male ; Myoglobinuria/*enzymology/metabolism ; Rats ; Rats, Wistar ; Stress, Physiological/enzymology ; }, abstract = {Intramuscular injection of hypertonic glycerol solution to rats results in acute renal injury. In this model, the proximal tubules are characteristically damaged. After glycerol injection renal glutathione (GSH) levels drastically decreased. On the other hand, stress protein heme oxygenase-1 (HO-1) was induced. When N-acetyl cysteine was administered to rats before 1 h glycerol injection, renal function was obviously improved. In this condition, the renal GSH content were sustained in the normal levels and HO-1 protein levels were decreased compared with those of glycerol-treated rats. Induction of HO-1 was accompanied by reduced renal GSH content. In addition, to investigate whether the location of HO-1 protein induced by glycerol injection is restricted to injured region or not in the kidney, we determined the localization of HO-1 protein using immunohistochemical staining. HO-1 protein was identified in the epithelia of the distal tubules, Henle's loop and collecting ducts, but not in the injured proximal tubules.}, }
@article {pmid9358747, year = {1997}, author = {Khachigian, LM and Collins, T and Fries, JW}, title = {N-acetyl cysteine blocks mesangial VCAM-1 and NF-kappa B expression in vivo.}, journal = {The American journal of pathology}, volume = {151}, number = {5}, pages = {1225-1229}, pmid = {9358747}, issn = {0002-9440}, support = {HL 35716/HL/NHLBI NIH HHS/United States ; HL 45462/HL/NHLBI NIH HHS/United States ; P01 36028//PHS HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antimetabolites/pharmacology ; Buthionine Sulfoximine/pharmacology ; Drug Synergism ; Female ; Free Radical Scavengers/*pharmacology ; Glomerular Mesangium/cytology/drug effects/*metabolism ; Lipopolysaccharides/pharmacology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred Strains ; NF-kappa B/*metabolism/physiology ; Promoter Regions, Genetic/physiology ; Vascular Cell Adhesion Molecule-1/genetics/*metabolism ; }, abstract = {Inducible vascular cell adhesion molecule-1 (VCAM-1) in glomerular mesangial cells (GMC) exposed to lipopolysaccharide (LPS) in vitro involves the activation of nuclear factor-kappa B (NF-kappa B) and its interaction with the proximal VCAM-1 promoter. We used a murine model to assess the effect of the antioxidant, N-acetyl cysteine on GMC activation in vivo. Single intraperitoneal administration of N-acetyl cysteine completely suppressed LPS-induced VCAM-1 expression on the GMC surface. When an oligonucleotide spanning the NF-kappa B binding region of the VCAM-1 promoter was incubated with extracts from the renal cortex of LPS-treated animals, a single nucleoprotein complex formed. This complex was composed of p50 and p65, but not p52, c-Rel, or RelB, and its formation was dramatically inhibited by pretreatment with N-acetyl cysteine, D,L-Buthionine-[S,R]-sulfoximide, a compound that depletes glutathione, augmented VCAM-1 expression inducible with a suboptimal amount of LPS to levels comparable with using 50 micrograms of LPS alone, D,L-Buthionine-[S,R]-sulfoximide also potentiated the p50-p65 binding activity induced with a suboptimal amount of LPS. These data provide a redox-sensitive, transcriptional link between NF-kappa B and VCAM-1 in GMC in vivo and implicate oxidative stress as an important regulatory signal in the pathogenesis of glomerular mesangial cell disorders.}, }
@article {pmid9354348, year = {1997}, author = {Akerlund, B and Tynell, E and Bratt, G and Bielenstein, M and Lidman, C}, title = {N-acetylcysteine treatment and the risk of toxic reactions to trimethoprim-sulphamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected patients.}, journal = {The Journal of infection}, volume = {35}, number = {2}, pages = {143-147}, doi = {10.1016/s0163-4453(97)91578-4}, pmid = {9354348}, issn = {0163-4453}, mesh = {AIDS-Related Opportunistic Infections/*prevention &amp; control ; Acetylcysteine/*therapeutic use ; Adult ; Anti-Infective Agents/*adverse effects ; Cysteine/deficiency ; Exanthema/chemically induced/prevention &amp; control ; Female ; Fever/chemically induced/prevention &amp; control ; Glutathione/blood ; Humans ; Male ; *Pneumocystis ; Pneumonia, Pneumocystis/*prevention &amp; control ; Trimethoprim, Sulfamethoxazole Drug Combination/*adverse effects ; }, abstract = {In a randomized double blind placebo controlled trial, HIV sero-positive patients with CD4+ cell count less than 200 x 10(6)/l or an AIDS diagnosis were evaluated for drug reactions to trimethoprim-sulphamethoxazole (TMP-SMX) during treatment, including pretreatment, with N-acetylcysteine (NAC) 800 mg daily or placebo. TMP-SMX (one double-strength tablet containing 160 mg of trimethoprim and 800 mg of sulphamethoxazole) was given three times weekly as primary Pneumocystis carinii (PCP) prophylaxis. Thirty percent (n = 15) of the patients experienced adverse reactions 8-20 (mean 12.7) days after starting with TMP-SMX. At entry, low cysteine and glutathione levels in plasma were found in the HIV-positive patients. Age, sex, CD4+ count, plasma cysteine and glutathione levels were not risk factors for adverse reactions to TMP-SMX. However, concomitant therapy with nucleoside analogues was associated with increased risk for TMP-SMX reactions. Oral NAC 800 mg daily was well tolerated, but replenished neither cysteine nor glutathione levels in plasma. NAC 800 mg/day did not significantly decrease the risk of adverse reactions to TMP-SMX in this study, and could thus not be recommended for this purpose. A prolonged pretreatment period and/or higher dose of NAC may be necessary for clinical effect.}, }
@article {pmid9352320, year = {1997}, author = {Kröger, H and Miesel, R and Dietrich, A and Ohde, M and Altrichter, S and Braun, C and Ockenfels, H}, title = {Suppression of type II collagen-induced arthritis by N-acetyl-L-cysteine in mice.}, journal = {General pharmacology}, volume = {29}, number = {4}, pages = {671-674}, doi = {10.1016/s0306-3623(96)00570-8}, pmid = {9352320}, issn = {0306-3623}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Arthritis/chemically induced/*drug therapy ; *Collagen ; Dose-Response Relationship, Drug ; Luminescent Measurements ; Male ; Mice ; Mice, Inbred DBA ; }, abstract = {1. The antiarthritic and anti-inflammatory efficacy of N-acetyl-L-cysteine (NAC) was tested in male DBA/1 hybrid mice suffering from type II collagen-induced arthritis. Parameters including the arthritis index and the phagocytic responses recorded by chemiluminescence in unseparated blood were used for the assessment of disease activity. 2. Mice were immunized by subdermal injection of bovine type II collagen in Freund's complete adjuvant. The treatment with NAC started at day 42 after immunization and was continued over a period of six weeks: in doses ranging up to 50 mg/kg, a dose-dependent suppression of arthritis was noted; between 50 and 200 mg/kg, the inhibition curve had a plateau [ED50 = 50 mg/(kg x day)]. 3. The arthritis index correlated positively with the generation of chemiluminescence by reactive oxygen species (ROS) produced in neutrophils and monocytes activated by 12-O-tetradecanoylphorbol 13-acetate. 4. After treatment with 100 mg/kg of NAC from day 42 after immunization over a period of six weeks, the ROS production was reduced to levels occurring in whole blood of healthy animals. 5. It is concluded that low-molecular-weight antioxidants such as NAC may be adequate for controlling oxidative stress-derived damage in rheumatic diseases by modulation of ROS-dependent signal transduction pathways.}, }
@article {pmid9351437, year = {1997}, author = {Wen, Y and Scott, S and Liu, Y and Gonzales, N and Nadler, JL}, title = {Evidence that angiotensin II and lipoxygenase products activate c-Jun NH2-terminal kinase.}, journal = {Circulation research}, volume = {81}, number = {5}, pages = {651-655}, doi = {10.1161/01.res.81.5.651}, pmid = {9351437}, issn = {0009-7330}, support = {P01 HL-55798/HL/NHLBI NIH HHS/United States ; R01 DK-39721/DK/NIDDK NIH HHS/United States ; }, mesh = {Angiotensin II/*metabolism/pharmacology ; Animals ; CHO Cells ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Cricetinae ; Enzyme Activation ; Gene Transfer Techniques ; Humans ; JNK Mitogen-Activated Protein Kinases ; Lipoxygenase/*metabolism ; *Mitogen-Activated Protein Kinases ; Rats ; Receptors, Angiotensin/genetics/*metabolism ; *Signal Transduction ; }, abstract = {The effect of angiotensin II (Ang II) to activate c-Jun amino-terminal kinase (JNK) was studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type-1a Ang II receptor (CHO-AT1a). Ang II treatment induced a time-dependent activation of JNK. Ang II (10(-7) mol/L) activated JNK activity, with a peak at 30 minutes (9.39 +/- 2.52-fold, n = 7, P < .02 versus control), which was maintained until 3 hours (2.7 +/- 0.65-fold, n = 3, P < .02 versus control). Ang II-induced JNK activation at 30 minutes was inhibited by a specific lipoxygenase (LO) pathway inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (1 mumol/L) by 87.5% (n = 4, P < .01 versus Ang II-induced JNK activity). The direct addition of 12-HETE also induced a time-dependent JNK activation. 12-HETE (10(-7) mol/L) activated JNK activity, with a peak at 10 minutes (3.43 +/- 0.87-fold, n = 6, P < .02 versus control), which remained elevated until 1 hour. These results suggest that the LO pathway is a mediator of Ang II-induced JNK activation. 15-HETE can also activate JNK at 5 minutes, but this activity was reduced at 30 minutes and could not be seen at 1 hour, indicating that the time course was different from that seen with 12-HETE. N-Acetylcysteine (NAC), an antioxidant, was used to perturb intracellular reactive oxygen intermediate (ROI) levels to assess the role of endogenous ROIs in regulating JNK activity. Pretreatment of cells with 500 mumol/L NAC for 1 hour attenuated approximately 50% of Aug II-induced JNK activation, suggesting that ROIs, at least partially, mediate Ang II-induced JNK activation. Furthermore, 12-HETE-induced JNK activation was reduced by approximately 90% by NAC. Finally, pertussis toxin completely blocked 12-HETE-induced JNK activation, suggesting that Gi-protein signaling participates in 12-HETE-induced effects. These results suggest that LO activation plays a role in mediating Ang II-induced JNK activation in part by altering the redox tone and Gi-protein signaling of cells.}, }
@article {pmid9350434, year = {1997}, author = {Legrand-Poels, S and Zecchinon, L and Piret, B and Schoonbroodt, S and Piette, J}, title = {Involvement of different transduction pathways in NF-kappa B activation by several inducers.}, journal = {Free radical research}, volume = {27}, number = {3}, pages = {301-309}, doi = {10.3109/10715769709065768}, pmid = {9350434}, issn = {1071-5762}, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology ; Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Base Sequence ; Binding Sites ; Cell Line ; Enzyme Inhibitors/pharmacology ; Humans ; Hydrogen Peroxide/*pharmacology ; Kinetics ; Molecular Sequence Data ; NF-kappa B/*metabolism ; Oligodeoxyribonucleotides/chemistry/metabolism ; Protein Kinase Inhibitors ; Reactive Oxygen Species ; *Signal Transduction/drug effects ; Staurosporine/pharmacology ; T-Lymphocytes ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Double-stimulation was used to demonstrate that, in a T lymphocytic cell line (CEM), phorbol myristate acetate (PMA) rapidly induced NF-kappa B through a signaling pathway which did not involve reactive oxygen species (ROS) and was different from the activation triggered by either H2O2 or tumor necrosis factor-alpha (TNF-alpha). Since these latter compounds were known to activate NF-kappa B translocation in a redox-sensitive way, we have demonstrated that NF-kappa B activation by PMA was resistant to antioxidant N-acetyl-L-cysteine (NAC) and sensitive to kinase inhibitors staurosporine and H7 while activation by H2O2 or TNF-alpha were not.}, }
@article {pmid9344715, year = {1997}, author = {van der Laan, L and Oyen, WJ and Verhofstad, AA and Tan, EC and ter Laak, HJ and Gabreels-Festen, A and Hendriks, T and Goris, RJ}, title = {Soft tissue repair capacity after oxygen-derived free radical-induced damage in one hindlimb of the rat.}, journal = {The Journal of surgical research}, volume = {72}, number = {1}, pages = {60-69}, doi = {10.1006/jsre.1997.5167}, pmid = {9344715}, issn = {0022-4804}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/metabolism ; Dermatitis/*enzymology ; Free Radicals ; Glutathione Peroxidase/metabolism ; Hindlimb ; Hydrogen Peroxide/metabolism ; Immunoglobulin G ; Male ; Muscle, Skeletal/blood supply/metabolism/pathology ; Myositis/*enzymology ; Organotechnetium Compounds ; Oxidative Stress/*physiology ; Oxygen/metabolism ; Peroxides/pharmacology ; Radionuclide Imaging ; Rats ; Rats, Wistar ; Skin Temperature ; tert-Butylhydroperoxide ; }, abstract = {Oxygen-derived free radicals are suspected to play an important role in the pathogenesis of inflammation and ischemia/reperfusion of an extremity. In this study we investigated the repair capacity of a free radical-damaged hindlimb of the rat and the effect of the anti-oxidant N-acetyl-L-cysteine (NAC). In nonanesthetized rats (n = 39), the left hindlimb was continuously infused intra-arterially (1 ml/hr) for 24 hr with the free radical donor tert-butylhydroperoxide (tert-BuOOH, 25 mM). Subsequently the infusion system was disconnected and the repair of soft tissue damage was observed with special attention to various pain tests, vascular permeability ((99m)Tc-IgG scintigraphy), and histology for a maximum period of 6 weeks. In 12 of these tert-BuOOH-infused rats the antioxidant NAC was injected intraperitoneally. Six of the NAC-treated rats were killed after 24 hr of infusion, while the remaining 6 rats were disconnected, reinjected with NAC, and observed for 1 week. Tert-BuOOH infusion for 24 hr led to significantly increased pain sensations, vascular permeability, and histological damage. Treatment with NAC significantly reduced pain sensations and vascular permeability, though not to control levels. One week after disconnection, tissue damage was almost completely repaired in the NAC-treated rats. In the untreated rats, repair took longer but histology and vascular permeability were completely normalized within the observation period. Soft tissue damage, induced by 24-hr infusion of the free radical donor tert-BuOOH, showed spontaneous repair within 6 weeks. The antioxidant NAC significantly reduced the soft tissue damage and shortened the repair period.}, }
@article {pmid9316488, year = {1997}, author = {van Klaveren, RJ and Dinsdale, D and Pype, JL and Demedts, M and Nemery, B}, title = {N-acetylcysteine does not protect against type II cell injury after prolonged exposure to hyperoxia in rats.}, journal = {The American journal of physiology}, volume = {273}, number = {3 Pt 1}, pages = {L548-55}, doi = {10.1152/ajplung.1997.273.3.L548}, pmid = {9316488}, issn = {0002-9513}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Body Weight ; Bronchoalveolar Lavage Fluid/cytology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Hyperoxia/*pathology/physiopathology/prevention &amp; control ; Lung/drug effects/*pathology/ultrastructure ; Macrophages/pathology ; Male ; Organ Size ; Putrescine/metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; }, abstract = {Although the antioxidant properties of N-acetylcysteine (NAC) in vitro are widely accepted, the efficacy of NAC in the prevention of O2 toxicity in vivo is poorly documented. The aim of our study was to investigate the presumed protective effect of NAC on hyperoxic lung injury, focusing on gamma-glutamyltransferase (gamma-GT) activity and glutathione (GSH) levels in lung tissue, epithelial lining fluid (ELF), and isolated rat type II cells immediately after their isolation and 48 h later when kept in culture in normoxia. Thirty-four male Wistar rats were divided in three groups (n = 10-14) and were exposed to air or to 60 or 85% O2 for 7 days. One-half of the rats in each group received 200 mg/kg NAC intraperitoneally one time per day from 3 days before exposure until the end of the experiment, and the other one-half received the vehicle. In the 85% O2-exposed animals, NAC led to more respiratory distress and weight loss. NAC did not prevent the rise in bronchoalveolar lavage lactate dehydrogenase and alkaline phosphatase, but it did prevent the rise in calculated ELF volume. NAC decreased GSH levels (1.4-fold) and gamma-GT activity (1.8-fold) in the air-exposed type II cells. In the 60% O2-exposed group, no effects of NAC were seen (except for a decrease in gamma-GT mRNA expression), but, in the 85% O2-exposed group, NAC gave rise to higher GSH (2.6-fold) and higher gamma-GT activity (2.9-fold) in the ELF and lower GSH (6.9-fold) and higher gamma-GT activity (3.6-fold) in the type II cells. Even in culture, GSH levels remained 1.5-fold lower than in the cells from the air-exposed animals and 2-fold lower than in the cells from the 85% O2-exposed animals. There was increased DNA damage (as assessed by thymidine incorporation) and apoptosis after hyperoxia, especially after 60% O2, and this effect was amplified after NAC treatment. Although protective at the endothelial side, NAC treatment led to adverse effects at the epithelial side, despite, or probably because of, restoration of the ELF GSH levels in the presence of high O2 levels. Because NAC is rapidly metabolized to cysteine, it is plausible that the effects of NAC are manifested through the toxic effects of cysteine.}, }
@article {pmid9316024, year = {1997}, author = {Wüllner, U and Weller, M and Groscurth, P and Löschmann, PA and Schulz, JB and Müller, I and Klockgether, T}, title = {Evidence for an active type of cell death with ultrastructural features distinct from apoptosis: the effects of 3-acetylpyridine neurotoxicity.}, journal = {Neuroscience}, volume = {81}, number = {3}, pages = {721-734}, doi = {10.1016/s0306-4522(97)00181-4}, pmid = {9316024}, issn = {0306-4522}, mesh = {Animals ; *Apoptosis ; Cell Death ; Cerebellum/cytology/drug effects ; Cycloheximide/pharmacology ; Dactinomycin/pharmacology ; Glutathione/metabolism ; Immunohistochemistry ; Microscopy, Electron ; Mitochondria/physiology ; Nerve Degeneration ; Neurons/drug effects/ultrastructure ; Neurotoxins/*pharmacology ; Protein Synthesis Inhibitors/pharmacology ; Pyridines/antagonists &amp; inhibitors/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; }, abstract = {3-Acetylpyridine is a niacinamide antagonist with potent neurotoxic properties in vitro and in vivo. 3-Acetylpyridine neurotoxicity was associated with positive DNA end-labelling and displayed features of active cell death without the ultrastructural changes of apoptotic cell death. After systemic administration in rats (70 mg/kg), we detected labelled nuclei in the inferior olive using in situ DNA end-labelling. However, the conventional chromatin stain did not show chromatin condensation or fragmentation and electron microscopy studies failed to reveal features of apoptosis. Although areas of condensed chromatin were present in some nuclei, cytoplasmic damage with extensive organelle swelling was the most prominent finding. In vitro, 3-acetylpyridine (0.1-1 mM) induced degeneration of cerebellar granule neurons in a concentration- and time-dependent manner. The protein synthesis inhibitor cycloheximide (10 micrograms/ml) and the transcriptional inhibitor actinomycin D (10 microM) protected against 3-acetylpyridine toxicity. In contrast, neither the free radical scavenger alpha-phenyl-N-tertbutylnitron (100 microM), nor glutathione ethyl ester (10-100 microM), N-acetyl-cysteine (10-200 microM) or 3-aminobenzamide (0.1-4 mM), an inhibitor of poly(ADP-ribose) synthesis, were effective. 3-Acetylpyridine-induced neuronal death in vitro was associated with positive in situ DNA labelling. However, DNA fragmentation could not be demonstrated prior to neuronal cell loss and no DNA "laddering" was detected by DNA gel electrophoresis. Correspondingly, no apoptotic nuclei were revealed upon electron microscopy but organelle swelling and extensive vacuolization, changes similar to autophagocytosis. In conclusion, 3-acetylpyridine induces an active form of cell death that required de novo protein synthesis but is distinct from apoptosis. A loss of glutathione accompanies, but does not precede, cell death.}, }
@article {pmid9314602, year = {1997}, author = {Pinot, F and el Yaagoubi, A and Christie, P and Dinh-Xuan, AT and Polla, BS}, title = {Induction of stress proteins by tobacco smoke in human monocytes: modulation by antioxidants.}, journal = {Cell stress &amp; chaperones}, volume = {2}, number = {3}, pages = {156-161}, doi = {10.1379/1466-1268(1997)002&lt;0156:iospbt&gt;2.3.co;2}, pmid = {9314602}, issn = {1355-8145}, mesh = {Adult ; Antioxidants/*pharmacology ; Female ; Heat-Shock Proteins/*biosynthesis/drug effects ; Humans ; Hydroxyl Radical/pharmacology ; Male ; Middle Aged ; Monocytes/drug effects/*metabolism ; Nitrates/pharmacology ; Nitric Oxide/antagonists &amp; inhibitors/biosynthesis ; Reactive Oxygen Species/physiology ; Tobacco Smoke Pollution/*adverse effects ; }, abstract = {Tobacco smoke (TS) induced in human monocytes the synthesis of both the classical heat shock proteins (HSP) (Hsp70, Hsp90, Hsp110) and the oxidation-specific stress protein (SP) heme oxygenase (HO). To determine the role of reactive oxygen species in SP induction by TS, we incubated the monocytes with various antioxidants before exposure to TS. Quercetin and N-acetylcysteine (NAC) both prevented the induction of HO by TS but not, or less so, than that of the classical HSP, while the nitric oxide synthase inhibitor L-nitroarginine had no effect. Thus, at least two mechanisms appear involved in SP induction by TS; (i) the induction of HO (oxidation-dependent), which was prevented by quercetin and NAC; and (ii) the induction of Hsp70, which was, at least in part, oxidation-independent. SP induction might represent an adequate biosensor for TS and other radical-mediated environmental exposures.}, }
@article {pmid9311486, year = {1997}, author = {Agustí, AG and Togores, B and Ibañez, J and Raurich, JM and Maimó, A and Bergada, J and Marse, P and Jorda, R}, title = {Effects of N-acetylcysteine on tissue oxygenation in patients with multiple organ failure and evidence of tissue hypoxia.}, journal = {The European respiratory journal}, volume = {10}, number = {9}, pages = {1962-1966}, doi = {10.1183/09031936.97.10091962}, pmid = {9311486}, issn = {0903-1936}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Aged ; Cross-Over Studies ; Hemodynamics/drug effects ; Humans ; Hydrogen-Ion Concentration ; Hypoxia/*blood ; Infusions, Intravenous ; Middle Aged ; Multiple Organ Failure/*metabolism/physiopathology ; Oxygen/*blood ; Oxygen Consumption/*drug effects ; Prospective Studies ; }, abstract = {Covert tissue hypoxia, particularly of the splanchnic region, appears important in the pathogenesis of multiple organ failure (MOF). This investigation evaluates the effects of N-acetylcysteine (NAC) upon several measures of tissue oxygenation in 10 patients with severe MOF and evidence of splanchnic hypoxia (as suggested by a pathologically low value (< 7.32) of the pH of the gastric mucosa (pHi)). Patients were studied following a prospective, randomized, placebo-controlled, cross-over design. Measurements included pulmonary and systemic haemodynamics, cardiac output by thermodilution, arterial and mixed venous blood gas values, blood lactate concentration, whole-body oxygen uptake by analysis of the expired gases, and pHi by tonometry. A complete set of measurements was obtained before and 45 min after the infusion of NAC (150 mg.kg-1 in 250 mL of saline) and, also, before and 45 min after the infusion of an equivalent volume of saline. NAC increased the cardiac index and vasodilated the systemic circulation (p < 0.01). However, O2 delivery to the tissues did not increase because the arterial oxygen content fell after NAC (p < 0.01). Mean O2 extraction or lactate concentration did not change after NAC, and pHi fell slightly (from 7.11 +/- 0.21 to 7.07 +/- 0.21; p < 0.05). The infusion of saline did not modify any variable significantly. The O2 extraction fraction increased exponentially in those patients with reduced O2 transport to the tissues. These results argue against a beneficial effect of N-acetylcysteine upon tissue oxygenation in patients with severe multiple organ failure and evidence of splanchnic hypoxia. Furthermore, they suggest that the mechanisms controlling the extraction of oxygen by the peripheral tissues in these patients were not impaired.}, }
@article {pmid9305680, year = {1997}, author = {Bonkovsky, HL}, title = {Therapy of hepatitis C: other options.}, journal = {Hepatology (Baltimore, Md.)}, volume = {26}, number = {3 Suppl 1}, pages = {143S-151S}, doi = {10.1002/hep.510260725}, pmid = {9305680}, issn = {0270-9139}, support = {DK38825/DK/NIDDK NIH HHS/United States ; }, mesh = {Adjuvants, Immunologic/therapeutic use ; Antioxidants/therapeutic use ; Antiviral Agents/therapeutic use ; Cytokines/therapeutic use ; Hepatitis C/blood/*therapy ; Humans ; Iron/blood ; Phlebotomy ; Sulfhydryl Compounds/therapeutic use ; Transferrin/analysis ; }, abstract = {Because current standard therapy of chronic hepatitis C with alpha interferon is less than ideal, numerous other approaches have been studied. Iron in the liver, particularly that found in vascular endothelial cells of portal tracts, has been associated with decreased responsiveness to alpha interferon therapy. Iron reduction alone, generally achieved by therapeutic phlebotomy, regularly has been associated with biochemical improvement (decrease in serum alanine aminotransferase), but not with virological improvement. Iron reduction has been reported to increase the therapeutic response to alpha interferon. Most studies of this combination have been conducted in patients who had not responded to interferon alone; in these patients, improved responsiveness has been observed in some, but not all studies. In patients not previously treated, iron reduction was found in a recent trial to improve the sustained biochemical and virological response rate from 5% to 29%. Hepatic iron and chronic hepatitis C increase oxidative stress in the liver and are associated with decreases in hepatic glutathione levels. In one report, administration of N-acetyl cysteine, a sulfhydryl donor, led to improved response to interferon in chronic hepatitis C. Several cytokines and immunomodulators have undergone limited study; perhaps the most promising of these is thymosin alpha-1. In one small study, amantadine was found to produce some response in patients who previously had failed to respond to interferon. Ursodiol improves serum aminotransferase levels in chronic hepatitis C but has no antiviral effect, nor has it been found to improve histologic abnormalities. The future of therapy of chronic hepatitis C will likely include measures to decrease oxidative stress and injury and multidrug combinations, including inhibitors of the hepatitis C viral protease and RNA polymerase.}, }
@article {pmid9303501, year = {1997}, author = {Colell, A and García-Ruiz, C and Morales, A and Ballesta, A and Ookhtens, M and Rodés, J and Kaplowitz, N and Fernández-Checa, JC}, title = {Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine.}, journal = {Hepatology (Baltimore, Md.)}, volume = {26}, number = {3}, pages = {699-708}, doi = {10.1002/hep.510260323}, pmid = {9303501}, issn = {0270-9139}, support = {AA09526/AA/NIAAA NIH HHS/United States ; DK 46357/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/pharmacology ; Alcoholism/*metabolism ; Animals ; Ethanol/*pharmacology ; Fluorescence Polarization ; Glutathione/*metabolism ; Intracellular Membranes/drug effects/*metabolism ; Kinetics ; Male ; Membrane Fluidity/drug effects ; Mitochondria, Liver/drug effects/*metabolism ; Rats ; Rats, Sprague-Dawley ; S-Adenosylmethionine/*pharmacology ; }, abstract = {Ethanol intake depletes the mitochondrial pool of reduced glutathione (GSH) by impairing the transport of GSH from cytosol into mitochondria. S-Adenosyl-L-methionine (SAM) supplementation of ethanol-fed rats restores the mitochondrial pool of GSH. The purpose of the current study was to determine the effect of ethanol feeding on the kinetic parameters of mitochondrial GSH transport, the fluidity of mitochondria, and the effect of SAM on these changes. Male Sprague-Dawley rats were fed ethanol-liquid diet for 4 weeks supplemented with either SAM or N-acetylcysteine (NAC). SAM-supplementation of ethanol-fed rats restored the mitochondrial GSH pool but NAC administration did not. Kinetic studies of GSH transport in isolated mitochondria revealed two saturable, adenosine triphosphate (ATP)-stimulated components that were affected significantly by chronic ethanol feeding: lowering Vmax (0.22 and 1.6 in ethanol case vs. 0.44 and 2.7 nmol/15 sec/mg protein in controls) for both low and high affinity components with the latter showing an increased Km (15.5 vs. 8.9, mmol/L in ethanol vs. control). Mitochondria from SAM-supplemented ethanol-fed rats showed kinetic features of GSH transport similar to control mitochondria. Determination of membrane fluidity revealed an increased order parameter in ethanol compared with control mitochondria, which was restricted to the polar head groups of the bilayer and was prevented by SAM but not NAC supplementation of ethanol-fed rats. The changes elicited in mitochondria by ethanol were confined to the inner membrane; mitoplasts from ethanol-fed rats showed features similar to those of intact mitochondria such as impaired transport of GSH and increased order parameter. A different mitochondrial transporter, adenosine diphosphate (ADP)/ATP translocator, was unaffected by ethanol feeding. Furthermore, fluidization of mitochondria or mitoplasts from ethanol-fed rats by treatment with a fatty acid derivative restored their ability to transport GSH to control levels. Thus, ethanol-induced impaired transport of GSH into mitochondria is selective, mediated by decreased fluidity of the mitochondrial inner membrane, and prevented by SAM treatment.}, }
@article {pmid9303498, year = {1997}, author = {Nakano, H and Nagasaki, H and Barama, A and Boudjema, K and Jaeck, D and Kumada, K and Tatsuno, M and Baek, Y and Kitamura, N and Suzuki, T and Yamaguchi, M}, title = {The effects of N-acetylcysteine and anti-intercellular adhesion molecule-1 monoclonal antibody against ischemia-reperfusion injury of the rat steatotic liver produced by a choline-methionine-deficient diet.}, journal = {Hepatology (Baltimore, Md.)}, volume = {26}, number = {3}, pages = {670-678}, doi = {10.1053/jhep.1997.v26.pm0009303498}, pmid = {9303498}, issn = {0270-9139}, mesh = {Acetylcysteine/*pharmacology ; Acid Phosphatase/analysis ; Alanine Transaminase/analysis ; Animals ; Antibodies, Monoclonal/*pharmacology ; Aspartate Aminotransferases/analysis ; Bile/metabolism ; *Choline Deficiency ; Fatty Liver/complications/pathology/*physiopathology ; In Vitro Techniques ; Intercellular Adhesion Molecule-1/immunology/*physiology ; Ischemia/pathology/physiopathology ; L-Lactate Dehydrogenase/analysis ; Liver/blood supply/*pathology/ultrastructure ; Male ; Malondialdehyde/analysis ; Methionine/*deficiency ; Microscopy, Electron ; Neutrophils/physiology ; Perfusion ; Rats ; Rats, Wistar ; Reperfusion Injury/pathology/*physiopathology ; }, abstract = {Abundant fat in the liver has been implicated in poor outcome after liver transplantation or liver surgery, but the reasons for this association are still unclear. The aim of the present study was to examine mechanisms that may be involved in hepatic dysfunction after ischemia-reperfusion (I/R) of the steatotic rat liver. Steatosis was produced by a choline-methionine-deficient (CMDD) diet. In the first experiment, isolated perfused rat livers, subjected to 24-hour cold storage followed by 120-minute reperfusion, were used to investigate hypothermic I/R injury of the steatotic rat liver. In the second experiment, livers were subjected to 60-minute partial left lobar vascular clamping to allow study of normothermic I/R injury. In the first experiment, compared with normal nonsteatotic liver, steatotic livers showed significantly greater injury, as assessed by amounts of hepatic enzymes released into the perfusate, bile production, the concentrations of reduced glutathione (GSH) in the perfusate, as well as in the livers themselves, and electron microscopic findings of sinusoidal microcirculatory injury. The addition of N-acetylcysteine (NAC), a precursor of glutathione, to the liver before cold storage significantly improved these parameters in steatotic livers. The second experiment showed that, compared with nonsteatotic livers, steatotic livers had lower concentrations of GSH and impaired rates of bile production. There was also evidence of increased oxidative stress in polymorphonuclear leukocytes (PMNLs) in liver or peripheral blood of rats with fatty livers. An anti-rat intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody inhibited neutrophil infiltration into pericentral sinusoids and improved these parameters in the steatotic rats. We conclude that sinusoidal microcirculatory injury is involved in hypothermic I/R injury, that oxidative stress produced by PMNLs is involved in normothermic I/R injury, and that NAC and anti-rat ICAM-1 monoclonal antibody restore liver integrity in I/R injury.}, }
@article {pmid9298175, year = {1997}, author = {Hashimoto, S and Gon, Y and Nakayama, T and Yoshida, S and Hayashi, S and Maruoka, S and Yodoi, J and Horie, T}, title = {N-acetylcysteine attenuates TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression in human monocytes.}, journal = {Allergy}, volume = {52}, number = {9}, pages = {909-913}, doi = {10.1111/j.1398-9995.1997.tb01250.x}, pmid = {9298175}, issn = {0105-4538}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Cells, Cultured ; Free Radical Scavengers/*pharmacology ; Humans ; Interleukin-4/*immunology ; Monocytes/*drug effects/immunology ; Pyrrolidines/pharmacology ; Receptors, IgE/*analysis/*drug effects/genetics ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/*drug effects/immunology ; }, abstract = {We have previously shown that tumor necrosis factor-alpha (TNF-alpha) reduces interleukin-4 (IL-4)-induced Fc epsilon RII expression in human monocytes. It has been shown that TNF-alpha activates nuclear transcriptional factors through the generation of reactive oxygen intermediates (ROIs), and antioxidant N-acetylcysteine (NAC) inhibits TNF-alpha-induced activation of nuclear transcriptional factors. Therefore, we hypothesized that TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression in monocytes might be mediated through the ROIs-activated mechanism. In the present study, to test our hypothesis, we examined the effect of NAC on TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression in human monocytes. NAC attenuated TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression by attenuating TNF-alpha-dependent reduction of Fc epsilon RII mRNA expression. Similarly, the structurally unrelated antioxidant, pyrrolidine dithiocarbamate (PDTC), also effectively attenuated this-reduction. These results indicate that an ROIs-activated and antioxidant-sensitive mechanism might be involved in TNF-alpha-dependent reduction of IL-4-induced Fc epsilon RII expression in monocytes.}, }
@article {pmid9231700, year = {1997}, author = {Al-Mustafa, ZH and Al-Ali, AK and Qaw, FS and Abdul-Cader, Z}, title = {Cimetidine enhances the hepatoprotective action of N-acetylcysteine in mice treated with toxic doses of paracetamol.}, journal = {Toxicology}, volume = {121}, number = {3}, pages = {223-228}, doi = {10.1016/s0300-483x(97)00069-3}, pmid = {9231700}, issn = {0300-483X}, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Acetylcysteine/administration &amp; dosage/*pharmacology/therapeutic use ; Administration, Oral ; Alanine Transaminase/blood ; Analgesics, Non-Narcotic/administration &amp; dosage/*toxicity ; Animals ; Aspartate Aminotransferases/blood ; Cimetidine/administration &amp; dosage/*pharmacology/therapeutic use ; Free Radical Scavengers/administration &amp; dosage/*pharmacology/therapeutic use ; Glutathione/metabolism ; Histamine H2 Antagonists/administration &amp; dosage/*pharmacology/therapeutic use ; Liver/*drug effects/enzymology/pathology ; Liver Diseases/mortality/pathology/prevention &amp; control ; Male ; Mice ; Microsomes, Liver/drug effects/enzymology ; Necrosis ; Survival Rate ; }, abstract = {Paracetamol, in toxic doses, is associated with extensive liver damage. This represents one of the common causes of morbidity and mortality in drug poisoning cases. This study was undertaken to investigate the possible potentiation of the hepatoprotective action of N-acetylcysteine (NAC) by cimetidine (CMD), an inhibitor of hepatic microsomal oxidative enzymes. The effects of NAC, cimetidine and the two in combination, administered 2 h post-paracetamol dose, on mortality, plasma glutamic oxaloacetic (GOT) and glutamic pyruvic (GPT) transaminase activities and hepatic reduced glutathione (GSH) levels were investigated in mice 24 h after treatment with a single oral dose of paracetamol (400 mg/kg). Both NAC and cimetidine caused a partial improvement of survival rate, plasma GOT and GPT activities. In addition, they prevented the depletion of hepatic GSH contents. However, concomitant administration of NAC and cimetidine produced a 100% survival rate and a marked reduction in plasma GOT and GPT activities to within the normal range, while significantly raising hepatic GSH concentrations to values close to those measured in saline-treated control animals. It is therefore concluded that cimetidine and N-acetylcysteine may have an additive hepatoprotective action in the treatment of paracetamol overdose.}, }
@article {pmid9287988, year = {1997}, author = {Tacchini, L and Recalcati, S and Bernelli-Zazzera, A and Cairo, G}, title = {Induction of ferritin synthesis in ischemic-reperfused rat liver: analysis of the molecular mechanisms.}, journal = {Gastroenterology}, volume = {113}, number = {3}, pages = {946-953}, doi = {10.1016/s0016-5085(97)70191-4}, pmid = {9287988}, issn = {0016-5085}, mesh = {Animals ; Electrophoresis, Polyacrylamide Gel ; Ferritins/*biosynthesis/genetics ; In Vitro Techniques ; Iron-Regulatory Proteins ; Iron-Sulfur Proteins/metabolism ; Ischemia/*metabolism ; Liver/*metabolism ; *Liver Circulation ; Male ; RNA, Messenger/metabolism ; RNA-Binding Proteins/metabolism ; Rats ; Rats, Wistar ; Receptors, Interleukin-1/antagonists &amp; inhibitors ; *Reperfusion ; }, abstract = {BACKGROUND &amp; AIMS: Iron may catalyze the production of reactive oxygen species (ROS) during postischemic reoxygenation. Ferritin, a cellular iron storage protein, can either represent a source of iron or perform a cytoprotective action against ROS. The aim of this study was to address the role of ferritin in postischemic reperfusion.<br><br>METHODS: Transcriptional and posttranscriptional mechanisms controlling ferritin gene expression were studied in reperfused rat livers.<br><br>RESULTS: Proteolysis reduced ferritin levels 2 hours after reperfusion, but a concomitant increase of synthesis, accompanied by enhanced transcription and accumulation of H and L ferritin subunit messenger RNAs (mRNAs), almost re-established normal ferritin content at 4 hours. Pretreatment with interleukin 1 receptor antagonist (IL-1RA) did not prevent the rise of ferritin mRNAs. RNA bandshift assays showed that the activity of the iron regulatory proteins (IRPs), which control ferritin mRNA translation, declined early after reperfusion and recovered progressively thereafter. Pretreatment with either the antioxidant N-acetyl cysteine or IL-1RA was sufficient to prevent almost completely down-regulation of IRP activity.<br><br>CONCLUSIONS: Postischemic reperfusion causes degradation of ferritin, possibly increasing iron levels. However, induction of ferritin gene transcription, possibly mediated by ferritin-derived iron and ROS-mediated inactivation of IRP, which allows translation of ferritin mRNAs, counteracts this effect and concurs to reestablish the amount of ferritin, which may thus act to limit reperfusion damage.}, }
@article {pmid9284951, year = {1997}, author = {Qiu, L and Welk, JF and Jurivich, DA}, title = {Ultraviolet light attenuates heat-inducible gene expression.}, journal = {Journal of cellular physiology}, volume = {172}, number = {3}, pages = {314-322}, doi = {10.1002/(SICI)1097-4652(199709)172:3&lt;314::AID-JCP5&gt;3.0.CO;2-R}, pmid = {9284951}, issn = {0021-9541}, support = {AG00509/AG/NIA NIH HHS/United States ; AR30692/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors/metabolism ; DNA/metabolism ; DNA-Binding Proteins/genetics/*metabolism ; Dose-Response Relationship, Radiation ; Gene Expression Regulation/*radiation effects ; HSP70 Heat-Shock Proteins/genetics/metabolism ; HeLa Cells ; Heat Shock Transcription Factors ; Heat-Shock Proteins/*genetics/metabolism ; Heat-Shock Response/*genetics/radiation effects ; Hot Temperature ; Humans ; Phosphorylation ; Protein Kinases/metabolism ; Transcription Factors ; *Ultraviolet Rays ; }, abstract = {Ultraviolet light (UV) induces a stress response mediated through transcription factors such as NF-kB and AP-1, yet little is known about its effect on other transactivators of stress gene expression such as heat shock factor (HSF1). Analysis of UV-treated HeLa cells unexpectedly revealed uncoupling of the heat shock response. UV weakly induced HSF1 into its DNA bound state and markedly attenuated heat-inducible gene expression. HSF1 was further analyzed as a potential target for the uncharacteristic uncoupling of the thermal stress response by another type of stress. Heat-inducible multimerization and nuclear translocation of HSF1 were found to be intact in UV-treated cells; however, the monomeric rather than the multimeric form of HSF1 become hyperphosphorylated by UV. This effect could be partially abolished by the antioxidant N-acetyl cysteine with partial reconstitution of hs gene expression. The reported role of a MAP kinase blockade of HSF1 transactivating properties could not be confirmed by an inhibitor of the MAP kinase pathway. Fibroblasts defective in SAP kinase activity also did not exhibit resistance to UV-inducible phosphorylation of HSF1. Two-dimensional phosphopeptide mapping of HSF1 revealed a single tryptic peptide to be affected by UV, but no new pattern of phosphorylation was evident relative to tryptic phosphopeptide profile observed in control cells. These data suggest that UV uncoupling of the hs response possibly involves steps in addition to those associated with phosphorylation the monomeric form of HSF1.}, }
@article {pmid9281616, year = {1997}, author = {Kuo, ML and Chau, YP and Wang, JH and Lin, PJ}, title = {The role of Src kinase in the potentiation by ethanol of cytokine- and endotoxin-mediated nitric oxide synthase expression in rat hepatocytes.}, journal = {Molecular pharmacology}, volume = {52}, number = {3}, pages = {535-541}, doi = {10.1124/mol.52.3.535}, pmid = {9281616}, issn = {0026-895X}, mesh = {Animals ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cells, Cultured ; Drug Synergism ; Enzyme Activation ; Enzyme Induction ; Ethanol/*pharmacology ; Lipopolysaccharides/*pharmacology ; Liver/*drug effects/*enzymology ; Male ; Mice ; Nitric Oxide/biosynthesis ; Nitric Oxide Synthase/*biosynthesis/metabolism ; Proto-Oncogene Proteins pp60(c-src)/metabolism ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; Stimulation, Chemical ; Tumor Necrosis Factor-alpha/*pharmacology ; src-Family Kinases/*physiology ; }, abstract = {This study demonstrates that exposure of primary rat hepatocytes or mouse BNL Cl.2 liver cell line to ethanol causes potentiation of tumor necrosis factor-alpha (TNF-alpha)- and lipopolysaccharide (LPS)-stimulated nitrite accumulation. The potentiating effect of ethanol (0.02-2 mM) appears to be time and concentration dependent. Consistent with nitrite production, the amount of inducible nitric oxide synthase (iNOS) mRNA and protein is initially detected at 4 hr after treatment with TNF-alpha/LPS/ethanol. Furthermore, the capability of these agents to induce iNOS expression is primarily determined by the age of the animals. Interestingly, antioxidants such as N-acetylcysteine (NAC), ascorbic acid, or alpha-tocopherol fail to inhibit TNF-alpha/LPS/ethanol-induced increase in iNOS protein. In addition, several kinase inhibitors, including staurosporine, genistein, curcumin, and herbimycin A, were used to examine their effects on this induction. Among them, only herbimycin A potently inhibits the accumulation of nitrite and iNOS expression. In vitro kinase assay verifies that Src tyrosine kinase is rapidly activated with a peak at 1 hr after treatment with TNF-alpha/LPS/ethanol but is not activated by these agents singly or doubly. As expected, herbimycin A can block Src kinase activity under circumstances in which iNOS expression is also inhibited. However, our results do not indicate that the mitogen-activated protein kinase is activated after treatment with these agents. The study results suggest that Src tyrosine kinase plays a prominent role in transducing the signal to induce iNOS expression in hepatocytes treated with TNF-alpha/LPS/ethanol.}, }
@article {pmid9299415, year = {1997}, author = {Yoo, YC and Watanabe, R and Koike, Y and Mitobe, M and Shimazaki, K and Watanabe, S and Azuma, I}, title = {Apoptosis in human leukemic cells induced by lactoferricin, a bovine milk protein-derived peptide: involvement of reactive oxygen species.}, journal = {Biochemical and biophysical research communications}, volume = {237}, number = {3}, pages = {624-628}, doi = {10.1006/bbrc.1997.7199}, pmid = {9299415}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Cattle ; DNA Fragmentation ; DNA, Neoplasm/drug effects ; Diploidy ; Female ; Glutathione/pharmacology ; Humans ; Kinetics ; Lactoferrin/*analogs &amp; derivatives/isolation &amp; purification/pharmacology ; Leukemia, Monocytic, Acute ; Milk/*chemistry ; Reactive Oxygen Species/*metabolism ; Tumor Cells, Cultured ; }, abstract = {We examined the activity of bovine lactoferricin (Lfcin-B), a peptide derived from a bovine milk protein lactoferrin (LF-B), to induce apoptosis in THP-1 human monocytic leukemic cells. Treatment with Lfcin-B at up to 50 micrograms/ml induced cell death in THP-1 cells in dose- and time-dependent manner, showing apparent morphological changes, hypodiploid forms of genomic DNA and apoptotic DNA fragmentation, whereas LF-B was inactive even at a high dose (500 micrograms/ml). The apoptosis-inducing effect of Lfcin-B increased with reduction of serum concentration, but was inhibited by addition of Zn2+, a inhibitor of Ca2+/Mg(2+)-dependent endonucleases in a dose-dependent manner. Furthermore, Lfcin-B-induced apoptosis in THP-1 cells was completely abolished by addition of antioxidants such as N-acetyl-L-cysteine (NAC) and glutathione (GSH), but not by various cytokines and mitogen which can activate monocytic cells. In addition, THP-1 cells treated with Lfcin-B, but not LF-B, showed high levels of intracellular reactive oxygen species (ROS) from the early period (20 min) of Lfcin-B treatment. And the production of ROS by Lfcin-B was dependent upon the dose of Lfcin-B added. These results suggested that Lfcin-B, a LF-B-derived peptide, but not LF-B itself, is able to induce apoptosis in THP-1 human monocytic tumor cells, and that its apoptosis-inducing activity is related to the pathway mediated by production of the intracellular ROS and activation of Ca2+/Mg(2+)-dependent endonucleases.}, }
@article {pmid9268159, year = {1997}, author = {Lee, R and Beauparlant, P and Elford, H and Ponka, P and Hiscott, J}, title = {Selective inhibition of l kappaB alpha phosphorylation and HIV-1 LTR-directed gene expression by novel antioxidant compounds.}, journal = {Virology}, volume = {234}, number = {2}, pages = {277-290}, doi = {10.1006/viro.1997.8642}, pmid = {9268159}, issn = {0042-6822}, mesh = {Antioxidants/*pharmacology ; DNA-Binding Proteins/genetics/*metabolism ; Gene Expression Regulation, Viral/*drug effects ; HIV Infections/metabolism/*virology ; HIV-1/*drug effects/*genetics ; Humans ; *I-kappa B Proteins ; Jurkat Cells ; NF-KappaB Inhibitor alpha ; NF-kappa B/antagonists &amp; inhibitors/*genetics ; Repetitive Sequences, Nucleic Acid/*genetics ; Transcriptional Activation ; }, abstract = {Oxidative stress activates the NF-kappaB/Rel transcription factors which are involved in the activation of numerous immunoregulatory genes and the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). In the present study, we examined the effects of established and novel compounds including antioxidants, ribonucleotide reductase inhibitors, and iron chelators on NF-kappaB activation and HIV LTR-mediated gene expression induced by TNF-alpha. N-Acetylcysteine (NAC), pyrrolidinedithiocarbamate (PDTC), and Trimidox (TD) at various concentrations inhibited TNF-alpha-induced NF-kappaB binding in Jurkat cells. Pretreatment of cells with these compounds prior to stimulation prevented I kappaB alpha degradation. Phosphorylation of I kappaB alpha, a prerequisite for its signal-induced degradation, was abrogated in these cells, indicating that oxidative stress is an essential step in the NF-kappaB activation pathway. On the other hand, iron chelators desferrioxamine, pyridoxal isonicotinoyl hydrazone (PIH), and salicylaldehyde isonicotinoyl hydrazone (SIH) showed no inhibition of TNF-alpha-induced NF-kappaB DNA-binding activity. Synergistic induction of HIV-1 LTR-mediated gene expression by TNF-alpha and the HIV-1 transactivator Tat in Jurkat cells was significantly suppressed in the presence of NAC and TD, but not PDTC. The inhibition of NAC and TD on LTR-directed gene expression was diminished when NF-kappaB-binding sites in the LTR were deleted, indicating that these compounds affected the NF-kappaB component of the synergism. Iron chelators PIH and SIH also showed some inhibitory effect on LTR-mediated gene activation, presumably through an NF-kappaB-independent mechanism. These experiments demonstrate that TD, at concentration 50 times lower than the effective concentration of NAC, potently inhibits NF-kappaB activity and suppresses HIV LTR expression.}, }
@article {pmid9350419, year = {1997}, author = {Ginsburg, I and Yedgar, S and Varani, J}, title = {Diethyldithiocarbamate and nitric oxide synergize with oxidants and with membrane-damaging agents to injure mammalian cells.}, journal = {Free radical research}, volume = {27}, number = {2}, pages = {143-164}, doi = {10.3109/10715769709097847}, pmid = {9350419}, issn = {1071-5762}, support = {GH29707/GH/CGH CDC HHS/United States ; HL 31963/HL/NHLBI NIH HHS/United States ; }, mesh = {Adolescent ; Amidines/toxicity ; Animals ; Antioxidants/pharmacology ; Aorta ; *Bacterial Proteins ; CHO Cells ; Cattle ; Cell Death/drug effects ; Cell Membrane/*drug effects/pathology ; Cells, Cultured ; Cricetinae ; Cyanides/toxicity ; Ditiocarb/*toxicity ; Drug Synergism ; Endothelium, Vascular/*drug effects/pathology ; Haplorhini ; Humans ; Hydrogen Peroxide/toxicity ; Male ; Nitric Oxide/*toxicity ; Nitroprusside/toxicity ; Oxidants/*toxicity ; Peroxides/toxicity ; Rats ; Skin/*drug effects/pathology ; Streptolysins/pharmacology ; Vitamin K/pharmacology ; Xanthine Oxidase/toxicity ; }, abstract = {The effect of diethyldithiocarbamate (DDC) and sodium nitroprusside (SNP) on the killing of endothelial cells and on the release of arachidonate by mixtures of oxidants and membrane-damaging agents was studied in a tissue culture model employing bovine aortic endothelial cells labeled either with 51Chromium or 3arachidonic acid. While exposure to low, subtoxic concentrations of oxidants (reagent H2O2, glucose-oxidase generated peroxide, xanthine xanthine oxidase, AAPH-generated peroxyl radical, menadione-generated oxidants) did not result either in cell death or in the loss of membrane-associated arachidonic acid, the addition of subtoxic amounts of a variety of membrane-damaging agents (streptolysin S, PLA2, histone, taurocholate, wheatgerm agglutinin) resulted in a synergistic cell death. However, no significant amounts of arachidonate were released unless proteinases were also present. The addition to these reaction mixtures of subtoxic amounts of DDC (an SOD inhibitor and a copper chelator) not only very markedly enhanced cell death but also resulted in the release of large amounts of arachidonate (in the complete absence of added proteinases). Furthermore, the inclusion in DDC-containing reaction mixtures of subtoxic amounts of SNP, a generator of NO, further enhanced, in a synergistic manner, both cell killing and the release of arachidonate. Cell killing and the release of arachidonate induced by the DDC and SNP-containing mixtures of agonists were strongly inhibited by catalase, glutathione, N-acetyl cysteine, vitamin A, and by a nonpenetrating PLA2 inhibitor as well as by tetracyclines. A partial inhibition of cell killing was also obtained by 1,10-phenanthroline and by antimycin. It is suggested that DDC might amplify cell damage by forming intracellular, loosely-bound complexes with copper and probably also by depleting antioxidant thiols. It is also suggested that "cocktails" containing oxidants, membrane-damaging agents, DDC, and SNP might be beneficial for killing of tumor cells in vivo and for the assessment of the toxicity of xenobiotics in vitro.}, }
@article {pmid9350418, year = {1997}, author = {Baeuml, H and Behrends, U and Peter, RU and Mueller, S and Kammerbauer, C and Caughman, SW and Degitz, K}, title = {Ionizing radiation induces, via generation of reactive oxygen intermediates, intercellular adhesion molecule-1 (ICAM-1) gene transcription and NF kappa B-like binding activity in the ICAM-1 transcriptional regulatory region.}, journal = {Free radical research}, volume = {27}, number = {2}, pages = {127-142}, doi = {10.3109/10715769709097846}, pmid = {9350418}, issn = {1071-5762}, support = {AR41206/AR/NIAMS NIH HHS/United States ; AR42687/AR/NIAMS NIH HHS/United States ; }, mesh = {Binding Sites ; Cell Line ; Cell Nucleus/metabolism ; Cell Survival/radiation effects ; Cesium Radioisotopes ; Chloramphenicol O-Acetyltransferase/biosynthesis ; Exons ; HeLa Cells ; Humans ; Intercellular Adhesion Molecule-1/*biosynthesis/*genetics ; NF-kappa B/*metabolism ; Oligodeoxyribonucleotides ; Radiation, Ionizing ; *Reactive Oxygen Species ; Recombinant Fusion Proteins/biosynthesis ; Regulatory Sequences, Nucleic Acid/*radiation effects ; TATA Box ; Transcription, Genetic/*radiation effects ; Transfection ; }, abstract = {Ionizing radiation produces reactive oxygen intermediates in mammalian tissues and may serve as a model system for the investigation of the biologic effects of free radicals. We have previously shown that the adhesion molecule ICAM-1 is induced by ionizing radiation, and here we have investigated the molecular mechanisms responsible. ICAM-1 mRNA and cell surface expression was induced in HeLa and HaCaT cells after exposure to ionizing radiation. This induction was blocked by preincubation with the antioxidants PDTC and N-acetyl cysteine. ICAM-1 promoter activity was assessed by transiently transfecting HeLa cells with CAT-reporter gene constructs containing sequential ICAM-1 5' deletions. ICAM-1 5' fragments -1162/+1 (relative to the transcription start site) and -277/+1 displayed increased promoter activity when cells were exposed to ionizing radiation, but no induction was seen in a -182/+1 construct associating positions -277 to around -182 with inducibility by ionizing radiation. Nuclear extracts from HaCaT cells were tested in mobility shift assays using an NF kappa B-like binding site of the ICAM-1 5' region (positions -186/-177). There was marked enhancement of DNA-protein complex forming in extracts from irradiated versus untreated cells. Incubation of cells with antioxidants prior to irradiation prevented the radiation-dependent increase in complex formation. We conclude that reactive oxygen intermediates are involved in ICAM-1 induction by ionizing radiation. The ionizing radiation-induced, antioxidant-inhibitable binding at the ICAM-1 NF kappa B-like binding site is consistent with the view that NF kappa B is a pro-oxidant transcription factor.}, }
@article {pmid9305490, year = {1997}, author = {Jones, AL and Jarvie, DR and Simpson, D and Hayes, PC and Prescott, LF}, title = {Pharmacokinetics of N-acetylcysteine are altered in patients with chronic liver disease.}, journal = {Alimentary pharmacology &amp; therapeutics}, volume = {11}, number = {4}, pages = {787-791}, doi = {10.1046/j.1365-2036.1997.00209.x}, pmid = {9305490}, issn = {0269-2813}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacokinetics ; Adult ; Aged ; Area Under Curve ; Biological Availability ; Expectorants/*pharmacokinetics ; Female ; Half-Life ; Humans ; Injections, Intravenous ; Liver Cirrhosis/*metabolism ; Male ; Metabolic Clearance Rate ; Middle Aged ; }, abstract = {BACKGROUND: The threshold plasma paracetamol concentration at which N-acetylcysteine (NAC) treatment is recommended to treat paracetamol poisoning in a patient with induced liver enzymes (for example, with chronic liver disease or taking anticonvulsant drugs) is 50% lower than in a patient without induced liver enzymes. More patients with chronic liver disease might therefore be expected to be exposed to NAC treatment than previously. In addition, there is increasing use of NAC in patients with chronic liver disease for multiorgan failure or hepatorenal syndrome. Little is known of NAC's pharmacokinetic properties in patients with cirrhosis.<br><br>AIM: The aim was to determine if the pharmacokinetics of NAC are altered by chronic liver disease.<br><br>SUBJECTS AND METHODS: NAC was given intravenously in a dose of 600 mg over 3 min to nine patients with biopsy-proven cirrhosis (Child's grade; 1 A, 4 B, 4 C: aetiology: 7 alcohol-related, 1 primary biliary cirrhosis, 1 secondary biliary stenosis) and six healthy matched controls. Venous blood was taken at 20, 40, 60 and 90 min then at 2, 3, 4, 6, 8 and 10 h after NAC administration. Serum NAC was estimated by HPLC. The data were normalized to a standard body weight of 70 kg.<br><br>RESULTS: The area under the serum concentration-time curve was increased (152.34 mg/L.h +/- 50.38 s.d.) in cirrhotics compared with normal controls (93.86 mg/L.h +/- 9.60 s.d.) (P < 0.05). The clearance of NAC was reduced in patients with chronic liver disease (4.52 L/h +/- 1.87 s.d.) compared with controls (6.47 L/h +/- 0.78: P < 0.01).<br><br>CONCLUSIONS: Increased vigilance for untoward anaphylactoid reactions is necessary in cirrhotics as they may have higher plasma NAC concentrations. Further studies to determine the optimum dosage regimen in such patients are required.}, }
@article {pmid9301047, year = {1997}, author = {Emonet, N and Leccia, MT and Favier, A and Beani, JC and Richard, MJ}, title = {Thiols and selenium: protective effect on human skin fibroblasts exposed to UVA radiation.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {40}, number = {1}, pages = {84-90}, doi = {10.1016/s1011-1344(97)00041-9}, pmid = {9301047}, issn = {1011-1344}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cell Survival/drug effects/radiation effects ; Cells, Cultured ; Cysteine/*analogs &amp; derivatives/*pharmacology ; Dose-Response Relationship, Radiation ; Female ; Fibroblasts/cytology/drug effects/radiation effects ; Glutathione/*metabolism ; Humans ; Pyrrolidonecarboxylic Acid ; *Radiation-Protective Agents ; Skin/cytology/drug effects/*radiation effects ; Sodium Selenite/*pharmacology ; Surgery, Plastic ; Thiazoles/pharmacology ; Thiazolidines ; Thiophenes/pharmacology ; *Ultraviolet Rays ; }, abstract = {The sensitivity of human dermal fibroblasts to UVA radiation has been linked to a decrease in intracellular glutathione (GSH) levels. GSH (gamma-glutamyl-cysteinyl-glycine) is a radical scavenger and a cofactor for protective enzymes such as selenium-dependent GSH peroxidases. In this study, we examine the possibility of a cooperative interaction between three cysteine delivery systems and selenium in protecting human cultured fibroblast exposed to UVA radiation. Cells were irradiated (9, 15 and 20 J cm-2) following incubation with N-acetyl-cysteine (NAC, 5 mM), N-acetyl-homocysteine-thiolactone (citiolone (CIT), 1 mM) or L-2-oxothiazolidine-4-carboxylate (OTC, 1 mM). The modulation of the intracellular GSH levels by the addition of the different compounds was determined by enzymatic and separative methods. Cells were harvested for survival analysis by measuring the ability of the cell to adhere and proliferate. Treatments with NAC and CIT resulted in a significant rise in GSH levels compared with control cells, with protection against UVA radiation. OTC did not induce any rise in GSH level; nevertheless, the protective effect afforded by OTC is similar to that observed with NAC and CIT. Moreover, selenium (0.1 mg 1-1), as sodium selenite, significantly increased the protective efficiency of NAC and CIT, but not of OTC. Although the precise mechanism is not known, thiol molecules can inhibit the deleterious effects of UVA radiation. These results provide evidence that compounds capable of inducing GSH synthesis can act with selenium to protect cells against UVA damage.}, }
@article {pmid9293482, year = {1997}, author = {Dizdar, N and Kullman, A and Kågedal, B and Arstrand, K}, title = {Effects on interstitial glutathione, cysteine and 5-S-cysteinyldopa of buthionine sulphoximine in human melanoma transplants.}, journal = {Melanoma research}, volume = {7}, number = {4}, pages = {322-328}, doi = {10.1097/00008390-199708000-00007}, pmid = {9293482}, issn = {0960-8931}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimetabolites, Antineoplastic/*pharmacology ; Buthionine Sulfoximine/*pharmacology ; Cysteine/*metabolism ; Cysteinyldopa/*biosynthesis/metabolism ; Drug Interactions ; Enzyme Inhibitors/*pharmacology ; Glutathione/*metabolism ; Humans ; Melanoma/*drug therapy/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microdialysis ; Neoplasm Transplantation ; Pyrrolidonecarboxylic Acid ; Thiazoles/pharmacology ; Thiazolidines ; }, abstract = {Using microdialysis of human melanoma transplants in athymic mice we have shown that interstitial glutathione levels decreased during treatment with buthionine sulphoximine (BSO) and recovered after cessation of treatment. The cysteine concentrations also decreased, while 5-S-cysteinyldopa tended to increase during BSO treatment. Restoration of the glutathione levels was not seen after either N-acetylcysteine (NAC) or L-2-oxothiazolidine-4-carboxylate (OTC) injections, given on the third day of BSO treatment. These results were to be expected since NAC and OTC were given during the BSO treatment, and BSO is a specific and potent inhibitor of glutathione synthesis. Cysteine levels, however, increased after the NAC injection but remained unaltered after the OTC injection, while 5-S-cysteinyldopa remained unaltered after both the NAC and the OTC injections.}, }
@article {pmid9288612, year = {1997}, author = {Pastor, A and Collado, PS and Almar, M and González-Gallego, J}, title = {Antioxidant enzyme status in biliary obstructed rats: effects of N-acetylcysteine.}, journal = {Journal of hepatology}, volume = {27}, number = {2}, pages = {363-370}, doi = {10.1016/s0168-8278(97)80183-3}, pmid = {9288612}, issn = {0168-8278}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cholestasis/*metabolism ; Glutathione/metabolism ; Lipid Peroxides/metabolism ; Liver/metabolism ; Male ; Membrane Fluidity/drug effects ; Oxidoreductases/*metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; }, abstract = {BACKGROUND/AIMS: N-acetylcysteine (NAC) is a modulator of thiol levels that protects against hepatotoxic agents. The aim of this study was to investigate whether NAC might improve hepatic antioxidant defenses in chronically biliary obstructed rats.<br><br>METHODS: Secondary biliary cirrhosis was induced by 28 days of bile-duct obstruction. Groups of control and cirrhotic animals received NAC (50 mumol .kg-1.d-1 i.m.) through the experimental period.<br><br>RESULTS: Bile-duct obstruction resulted in decreased liver glutathione concentrations. Dichlorofluorescein (DCF) and thiobarbituric acid reactive substances (TBARS) concentrations, measured as markers of production of reactive oxygen species and lipid peroxidation, respectively, were significantly increased. Microsomal and mitochondrial membrane fluidity and the activities of catalase, cytosolic and mitochondrial superoxide dismutase (SOD), glutathione S-transferase, and cytosolic and mitochondrial Se-dependent and Se-independent glutathione peroxidase (GPx) were significantly reduced. NAC corrected the reduction in glutathione concentration and partially prevented the increases in DCF and TBARS concentrations. In addition, NAC treatment resulted in significant preservation of membrane fluidity and of the activities of catalase, mitochondrial SOD and the different forms of GPx.<br><br>CONCLUSIONS: Our data indicate that NAC maintains antioxidant defenses in biliary obstructed rats. These effects of NAC suggest that it may be a useful agent to preserve liver function in patients with biliary obstruction.}, }
@article {pmid9278255, year = {1997}, author = {Li, DW and Spector, A}, title = {Hydrogen peroxide-induced expression of the proto-oncogenes, c-jun, c-fos and c-myc in rabbit lens epithelial cells.}, journal = {Molecular and cellular biochemistry}, volume = {173}, number = {1-2}, pages = {59-69}, pmid = {9278255}, issn = {0300-8177}, support = {EY 00423/EY/NEI NIH HHS/United States ; EY 11372/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Carcinogens/pharmacology ; Cell Line ; Epithelial Cells/drug effects ; Free Radical Scavengers/pharmacology ; Gene Expression/drug effects/genetics ; Gene Expression Regulation/drug effects/genetics ; Gene Expression Regulation, Neoplastic/drug effects/genetics ; Hydrogen Peroxide/*pharmacology ; Lens, Crystalline/*cytology/*drug effects ; Oxidants/*pharmacology ; Proto-Oncogene Proteins c-fos/drug effects/*genetics ; Proto-Oncogene Proteins c-jun/drug effects/*genetics ; Proto-Oncogene Proteins c-myc/drug effects/*genetics ; Pyrrolidines/pharmacology ; RNA, Messenger/drug effects/metabolism ; Rabbits ; Tetradecanoylphorbol Acetate/pharmacology ; Thiocarbamates/pharmacology ; Transcription Factor AP-1/drug effects/metabolism ; }, abstract = {The involvement of H2O2 in cataract development has been established in both human patients and animal models. At the molecular level H2O2 has been observed to cause damage to DNA, protein and lipid. To explore the oxidative stress response of the lens system at the gene expression level, we have examined the effects of H2O2 on the mRNA change of the proto-oncogenes, c-jun, c-fos and c-myc in a rabbit lens cell line, N/N1003A. H2O2 treatment of the rabbit lens epithelial cells for 60 min induces quick up-regulation of both c-jun and c-fos mRNAs. The maximal induction is 38 fold for c-jun at 150 microM and 72 fold for c-fos at 250 microM H2O2. Treatment of N/N1003A cells with 50-250 microM H2O2 for 60 min leads to a 2-5 fold increase of the c-myc mRNA level. H2O2 also induces an up-regulation in transactivity of the activating protein-1 (AP-1) as shown with a reporter gene driven by a prolactin gene promoter with 4 copies of AP-1 binding sites inserted in the upstream of the promoter. Maximal induction occurs with 150 microM H2O2. In the same system, the antioxidants, N-acetyl-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) at concentrations shown to up-regulate the mRNAs of both c-jun and c-fos, also enhance the transactivity of AP-1. NAC and PDTC have different effects in modulating the induction of AP-1 activity by H2O2 and TPA. These results reveal that oxidative stress regulates expression of various regulatory genes in lens systems, which likely affects cell proliferation, differentiation and viability and thus affect normal lens functions.}, }
@article {pmid9277499, year = {1997}, author = {Faruqi, RM and Poptic, EJ and Faruqi, TR and De La Motte, C and DiCorleto, PE}, title = {Distinct mechanisms for N-acetylcysteine inhibition of cytokine-induced E-selectin and VCAM-1 expression.}, journal = {The American journal of physiology}, volume = {273}, number = {2 Pt 2}, pages = {H817-26}, doi = {10.1152/ajpheart.1997.273.2.H817}, pmid = {9277499}, issn = {0002-9513}, support = {HL-34727/HL/NHLBI NIH HHS/United States ; M01-RR-00210/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Cell Adhesion/drug effects ; Cell Membrane/metabolism ; Cells, Cultured ; Cytokines/*antagonists &amp; inhibitors/*pharmacology ; E-Selectin/genetics/*metabolism ; Endothelium, Vascular/cytology ; Gene Expression Regulation/drug effects ; Genes/drug effects ; Glutathione/analogs &amp; derivatives/metabolism ; Glutathione Disulfide ; Humans ; Interleukin-1/pharmacology ; Monocytes/drug effects/physiology ; NF-kappa B/metabolism/pharmacology ; Transcription, Genetic/drug effects ; Vascular Cell Adhesion Molecule-1/genetics/*metabolism ; }, abstract = {We have examined the effects of N-acetyl-L-cysteine (NAC), a well-characterized, thiol-containing antioxidant, on agonist-induced monocytic cell adhesion to endothelial cells (EC). NAC inhibited interleukin-1 (IL-1 beta)-induced, but not basal, adhesion with 50% inhibition at approximately 20 mM. Monocytic cell adhesion to EC in response to tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), alpha-thrombin, or phorbol 12-myristate 13-acetate (PMA) was similarly inhibited by NAC. Unlike published studies with pyrrolidinedithiocarbamate, which specifically inhibited vascular cell adhesion molecule 1 (VCAM-1), NAC inhibited IL-1 beta-induced mRNA and cell surface expression of both E-selectin and VCAM-1. NAC had no effect on the half-life of E-selectin or VCAM-1 mRNA. Although NAC reduced nuclear factor-kappa B (NF-kappa B) activation in EC as measured by gel-shift assays using an oligonucleotide probe corresponding to the consensus NF-kappa B binding sites of the VCAM-1 gene (VCAM-NF-kappa B), the antioxidant had no appreciable effect when an oligomer corresponding to the consensus NF-kappa B binding site of the E-selectin gene (E-selectin-NF-kappa B) was used. Because NF-kappa B has been reported to be redox sensitive, we studied the effects of NAC on the EC redox environment. NAC caused an expected dramatic increase in the reduced glutathione (GSH) levels in EC. In vitro studies demonstrated that whereas the binding affinity of NF-kappa B to the VCAM-NF-kappa B oligomer peaked at a GSH-to-oxidized glutathione (GSSG) ratio of approximately 200 and decreased at higher ratios, the binding to the E-selectin-NF-kappa B oligomer appeared relatively unaffected even at ratios > 400, i.e., those achieved in EC treated with 40 mM NAC. These results suggest that NF-kappa B binding to its consensus sequences in the VCAM-1 and E-selectin gene exhibits marked differences in redox sensitivity, allowing for differential gene expression regulated by the same transcription factor. Our data also demonstrate that NAC increases the GSH-to-GSSG ratio within the EC suggesting one possible mechanism through which this antioxidant inhibits agonist-induced monocyte adhesion to EC.}, }
@article {pmid9242544, year = {1997}, author = {Delneste, Y and Jeannin, P and Potier, L and Romero, P and Bonnefoy, JY}, title = {N-acetyl-L-cysteine exhibits antitumoral activity by increasing tumor necrosis factor alpha-dependent T-cell cytotoxicity.}, journal = {Blood}, volume = {90}, number = {3}, pages = {1124-1132}, pmid = {9242544}, issn = {0006-4971}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Adjuvants, Immunologic/*pharmacology/therapeutic use ; Animals ; Antineoplastic Agents/*pharmacology/therapeutic use ; Cells, Cultured ; Cytotoxicity, Immunologic/drug effects ; Gene Expression Regulation/drug effects ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Leukemia L1210/drug therapy/immunology/pathology ; Mice ; Mice, Inbred BALB C ; Neoplasm Proteins/biosynthesis/genetics ; Neoplasm Transplantation ; Receptors, Tumor Necrosis Factor/biosynthesis/genetics ; T-Lymphocytes, Cytotoxic/*drug effects/immunology ; Tumor Necrosis Factor-alpha/biosynthesis/genetics/*physiology ; }, abstract = {Because of its anticarcinogenic and antimutagenic properties, N-acetyl-L-cysteine (NAC) has been proposed for cancer treatment. Here we present a mechanism of action for NAC in cancer. Our data show that NAC (1) induces an early and sustained increase of membrane tumor necrosis factor alpha (TNF alpha) expression on human stimulated-peripheral blood (PB) T cells and (2) increases membrane TNF-RI and TNF-RII on tumoral cell lines and on T cells after stimulation. These effects result from an early inhibition of both TNF alpha and TNF-R shedding, as well as a later increase of the respective mRNA expression. Consequently, NAC confers cytotoxic properties to human PB T cells through a membrane TNF alpha-dependent pathway. In vivo, NAC given orally inhibits tumor appearance in more than a third (18 out of 50) B6D2F1 mice injected with L1210 lymphoma cells. Spleen cells from protected mice killed L1210 lymphoma cells in vitro in a membrane TNF alpha-dependent manner. Furthermore these mice were resistant to a second inoculation of L1210 cells without further treatment with NAC. Thus, NAC exhibits a potent antitumoral activity by modulating TNF alpha and TNF-R processing without showing any in vitro and in vivo toxicity.}, }
@article {pmid9220453, year = {1997}, author = {Offen, D and Ziv, I and Barzilai, A and Gorodin, S and Glater, E and Hochman, A and Melamed, E}, title = {Dopamine-melanin induces apoptosis in PC12 cells; possible implications for the etiology of Parkinson's disease.}, journal = {Neurochemistry international}, volume = {31}, number = {2}, pages = {207-216}, doi = {10.1016/s0197-0186(96)00150-7}, pmid = {9220453}, issn = {0197-0186}, mesh = {Animals ; Antioxidants/pharmacology ; *Apoptosis ; Dopamine/pharmacology ; Drug Synergism ; Iron/pharmacology ; Melanins/*pharmacology ; Neurotoxins/pharmacology ; PC12 Cells/*drug effects ; Parkinson Disease/*etiology ; Rats ; Solubility ; }, abstract = {The function of neuromelanin (NM), the oxidized dopamine (DA) polymer, within the DA-producing cells in the human and primate substantia nigra (SN), is still an enigma. Some studies show that the vulnerability of nigral neurons in Parkinson's disease is correlated to their toxic NM content, while others suggest that it contributes to cellular protection. We showed recently that DA, the endogenous nigral neurotransmitter, triggers apoptosis, an active program of cellular self-destruction, in neuronal cultures. In the present study, we exposed cells to synthetic dopamine-melanin (DA-M) and analysed the cellular and genetic changes. We found that exposure of PC12 cells to DA-M (0.5 mg/ml for 24 h) caused 50% cell death, as indicated by trypan blue exclusion assay and 3H-thymidine incorporation. Gel electrophoresis DNA analysis of PC12 cells treated with DA-M showed the typical apoptotic DNA ladder, indicating inter-nucleosomal DNA degradation. The DNA fragmentation also was visualized histochemically in situ by DNA end-labeling staining (the TUNEL method). The FeCl2 (0.05 mM) significantly increased DA-M toxicity, while desferrioxamine, an iron chelator, totally abolished the additive toxicity of iron. The contribution of oxidative stress in this model of DA-M-induced cell death was examined using various antioxidants. In contrast to DA, inhibition of DA-M toxicity antioxidants by reduced glutathione (GSH), N-acetyl cysteine, catalase and Zn/Cu superoxide dismutase (SOD) was very limited. In conclusion, we found that DA-M may induce typical apoptotic death in PC12 cells. Our findings support a possible role of NM in the vulnerability of the dopaminergic neural degeneration in Parkinson's disease. The differential protective effect by antioxidants against toxicity of DA and DA-M may have implications for future neuroprotective therapeutic approaches for this common neurological disorder.}, }
@article {pmid9220449, year = {1997}, author = {Desole, MS and Sciola, L and Delogu, MR and Sircana, S and Migheli, R and Miele, E}, title = {Role of oxidative stress in the manganese and 1-methyl-4-(2'-ethylphenyl)-1,2,3,6-tetrahydropyridine-induced apoptosis in PC12 cells.}, journal = {Neurochemistry international}, volume = {31}, number = {2}, pages = {169-176}, doi = {10.1016/s0197-0186(96)00146-5}, pmid = {9220449}, issn = {0197-0186}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/*analogs &amp; derivatives/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Ascorbic Acid/pharmacology ; Cell Survival/drug effects ; Manganese/*pharmacology ; *Oxidative Stress ; PC12 Cells/*drug effects/*physiology ; Rats ; }, abstract = {Oxidative stress is thought to play a key role in the apoptotic death of several cellular systems, including neurons. Oxidative stress is proposed also as a mechanism of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and manganese (Mn)-induced neuronal death. We have recently shown that Mn and the MPTP analogue 1-methyl-4-(2'-ethylphenyl)-1,2,3,6-tetrahydropyridine (2'Et-MPTP), which is metabolized by MAO-A to 1-methyl-4-(2'-ethylphenyl)-pyridinium ion, induce apoptosis in PC12 cells. In the present study, we evaluated the effects of deprenyl and the antioxidant drugs N-acetylcysteine (NAC) and ascorbic acid (AA) on Mn- and 2'Et-MPTP-induced apoptosis in PC12 cells. Apoptosis was tested by terminal deoxynucleotidyl transferase-mediated 2'-deoxy-uridine-5'-triphosphate nick end labelling (TUNEL) technique, flow cytometry and fluorescence microscopy. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Mn-induced apoptosis and decrease in cell viability was inhibited by the antioxidants NAC and AA. Deprenyl failed to inhibit the above Mn effects. Neither NAC, AA nor deprenyl were able to inhibit both 2'Et-MPTP-induced apoptosis and decrease in cell viability. These results confirm that apoptosis may be an important mechanism of cell death in MPTP- and Mn-induced parkinsonism. However, an oxidative stress mechanism may be recognized, at least in vitro, only in the Mn-induced apoptosis.}, }
@article {pmid9240427, year = {1997}, author = {Nishio, E and Watanabe, Y}, title = {Cigarette smoke extract inhibits plasma paraoxonase activity by modification of the enzyme's free thiols.}, journal = {Biochemical and biophysical research communications}, volume = {236}, number = {2}, pages = {289-293}, doi = {10.1006/bbrc.1997.6961}, pmid = {9240427}, issn = {0006-291X}, mesh = {Aryldialkylphosphatase ; Dithionitrobenzoic Acid/chemistry ; Esterases/antagonists &amp; inhibitors/*blood/chemistry ; Humans ; Lipoproteins, LDL/*metabolism ; Oxidation-Reduction ; *Plants, Toxic ; Smoke ; Sulfhydryl Compounds/metabolism ; Sulfhydryl Reagents ; *Nicotiana ; }, abstract = {Cigarette smoking is associated with an increased incidence of premature atherosclerosis. Minimal information is available at the molecular level concerning the mechanism of action of cigarette smoke. Recent work has shown that paraoxonase (PON) protects low density lipoprotein against oxidation by Cu2+. The goal of the present study was to investigate the effect of cigarette smoke extract (CSE) on human plasma paraoxonase activity. The activity of paraoxonase was inhibited by the CSE in a dose- and time-dependent manner. The inhibition of PON activity by the CSE was reversed by the addition of glutathione or N-acetyl cysteine. Furthermore, we tested to see whether sulfhydryl compounds prevented the inhibition of PON activity caused by CSE. Sulfhydryl compounds prevented the inhibition of PON activity caused by CSE. But any amino compounds, such as N-acetyl lysine, N-acetyl arginine and aminoguanidine, failed to protect PON activity, indicating a specificity with regard to the ability of free thiols to buffer the deleterious components of CSE which inhibited PON activity. The observed inhibition of PON activity by CSE may account for the increased incidence of cardiovascular disease known to be present in smokers through the oxidative process of low density lipoprotein and its subsequent uptake by macrophage.}, }
@article {pmid9212229, year = {1997}, author = {Lubet, RA and Steele, VE and Eto, I and Juliana, MM and Kelloff, GJ and Grubbs, CJ}, title = {Chemopreventive efficacy of anethole trithione, N-acetyl-L-cysteine, miconazole and phenethylisothiocyanate in the DMBA-induced rat mammary cancer model.}, journal = {International journal of cancer}, volume = {72}, number = {1}, pages = {95-101}, doi = {10.1002/(sici)1097-0215(19970703)72:1&lt;95::aid-ijc14&gt;3.0.co;2-9}, pmid = {9212229}, issn = {0020-7136}, support = {N01-CN-25454-02/CN/NCI NIH HHS/United States ; N01-CN-95156-04/CN/NCI NIH HHS/United States ; }, mesh = {9,10-Dimethyl-1,2-benzanthracene ; Acetylcysteine/*pharmacology ; Anethole Trithione/*pharmacology ; Animals ; Anticarcinogenic Agents/*pharmacology ; Body Weight/drug effects ; Female ; Isothiocyanates/*pharmacology ; Mammary Neoplasms, Experimental/chemically induced/*prevention &amp; control ; Miconazole/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Time Factors ; }, abstract = {The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter carcinogen metabolism, was examined in the dimethylbenzanthracene (DMBA) mammary carcinogenesis model. In this protocol, animals were exposed to non-toxic doses of the chemopreventives in the diet beginning 7 days prior to DMBA administration and then continuously throughout the duration of the assay (100 days post carcinogen). Miconazole, an antifungal agent with relatively broad inhibitory activity toward a variety of cytochromes P450, increased mammary tumor latency, decreased tumor incidence at the highest dose and decreased tumor multiplicity up to 60%. Anethole trithione, a substituted dithiolthione and an analog of the relatively broad-spectrum chemopreventive oltipraz, was administered in the diet and significantly inhibited mammary cancer multiplicity but not cancer incidence. NAC, an antimucolytic agent, failed to inhibit DMBA-induced mammary tumorigenesis. Surprisingly, treatment with DMBA plus PEITC, a potent inhibitor of cytochrome P450 2E1, actually increased the multiplicity of tumors relative to that observed with DMBA alone.}, }
@article {pmid9483174, year = {1997}, author = {Polack, B and Pernod, G and Barro, C and Doussière, J}, title = {Role of oxygen radicals in tissue factor induction by endotoxin in blood monocytes.}, journal = {Haemostasis}, volume = {27}, number = {4}, pages = {193-200}, doi = {10.1159/000217456}, pmid = {9483174}, issn = {0301-0147}, mesh = {Drug Synergism ; Endotoxins/blood/*pharmacology ; Enzyme Inhibitors/pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Monocytes/drug effects/*immunology ; NADPH Oxidases/antagonists &amp; inhibitors/pharmacology ; Nitric Oxide/chemical synthesis/pharmacology ; Nitric Oxide Synthase/antagonists &amp; inhibitors/pharmacology ; Reactive Oxygen Species/*physiology ; Superoxides/pharmacology ; Thromboplastin/antagonists &amp; inhibitors/*biosynthesis ; }, abstract = {In response to bacterial endotoxin (lipopolysaccharide, LPS) monocytes synthesize and express on their surface tissue factor (TF) which triggers the blood coagulation cascade. Since LPS stimulates active oxygen species production by these cells, we investigated the roles of superoxide anion and nitric oxide in the induction of TF in human blood monocytes. Scavengers of reactive oxygen intermediates such as N-acetyl cysteine or pyrrolidine dithiocarbamate were able to block TF induction. In addition, inhibition of NADPH oxidase and/or NO synthase which are major sources of active oxygen species in phagocytes also blocked TF induction. The restoration of TF expression, in monocytes treated with inhibitors of reactive oxygen production, by N,N'-dimethyl-gamma, gamma'-dipyridylium dichloride and/or sodium nitrosylpentacyanoferrate (III), which generate respectively O2- and NO, suggests that these two radicals participate in the induction of TF at the surface of blood monocytes stimulated by LPS.}, }
@article {pmid9237764, year = {1997}, author = {Brennan, RJ and Schiestl, RH}, title = {Aniline and its metabolites generate free radicals in yeast.}, journal = {Mutagenesis}, volume = {12}, number = {4}, pages = {215-220}, doi = {10.1093/mutage/12.4.215}, pmid = {9237764}, issn = {0267-8357}, mesh = {Acetaminophen/metabolism/toxicity ; Aminophenols/toxicity ; Aniline Compounds/*metabolism/*toxicity ; Bacterial Proteins/drug effects/genetics/metabolism ; Carcinogens/metabolism/toxicity ; Dose-Response Relationship, Drug ; Escherichia coli/*drug effects/genetics/metabolism ; *Escherichia coli Proteins ; Ethyl Methanesulfonate/toxicity ; Fluoresceins/pharmacology ; Free Radicals/metabolism ; Recombination, Genetic/drug effects ; Saccharomyces cerevisiae/*drug effects/genetics/metabolism ; Sequence Deletion ; Superoxide Dismutase/drug effects/metabolism ; *Trans-Activators ; Transcription Factors/drug effects/genetics/metabolism ; beta-Galactosidase/drug effects/genetics/metabolism ; }, abstract = {The carcinogen aniline is negative in the Ames Salmonella mutagenicity assay. Aniline does, however, induce intrachromosomal recombination between repeated sequences in Saccharomyces cerevisiae, resulting in deletion (DEL) of intervening sequences. We have investigated whether the generation of oxidative free radical species by aniline and/ or its metabolites may be responsible for its recombinagenic activity in yeast. The toxicity and recombinagenicity of aniline in yeast were greatly reduced in the presence of the free radical scavenger N-acetyl cysteine. Aniline cytotoxicity was many-fold increased in strains of S.cerevisiae lacking the antioxidant enzyme superoxide dismutase. Aniline also induced oxidation of the intracellular free radical-sensitive reporter compound 2,4-dichlorofluorescin diacetate to its fluorescent derivative 2,4-dichlorofluorescein in vivo in S.cerevisiae. The aniline metabolites 4-aminophenol and 2-aminophenol were significantly more potent inducers of DEL recombination in yeast than aniline. In contrast, the secondary metabolite 4-acetamidophenol (acetaminophen) was non-toxic and non-recombinagenic in yeast. 4-Aminophenol and 2-aminophenol were also significantly more toxic than aniline in a superoxide dismutase deficient yeast strain. 4-aminophenol was a significantly more potent oxidizer of 2,4-dichlorofluorescin diacetate than aniline. The Escherichia coli soxS promoter, which is induced in the presence of redox cycling agents like paraquat, was induced weakly by aniline at toxic doses. The soxS promoter was strongly induced by 4-aminophenol and 2-aminophenol. The results indicate a role for oxidative stress, mediated by generation of superoxide radical, in the toxicity and recombinagenicity of aniline. The increased activity of 4-aminophenol and 2-aminophenol suggests that ring hydroxylation may be an important activating step in this process.}, }
@article {pmid9230243, year = {1997}, author = {De Flora, S and Grassi, C and Carati, L}, title = {Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment.}, journal = {The European respiratory journal}, volume = {10}, number = {7}, pages = {1535-1541}, doi = {10.1183/09031936.97.10071535}, pmid = {9230243}, issn = {0903-1936}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Aged ; Antiviral Agents/administration &amp; dosage/*therapeutic use ; Drug Administration Schedule ; Female ; Humans ; Immunity, Cellular/drug effects ; Incidence ; *Influenza A virus ; Influenza, Human/epidemiology/immunology/*prevention &amp; control ; Italy/epidemiology ; Male ; Seasons ; Time Factors ; }, abstract = {N-acetylcysteine (NAC), an analogue and precursor of reduced glutathione, has been in clinical use for more than 30 yrs as a mucolytic drug. It has also been proposed for and/or used in the therapy and/or prevention of several respiratory diseases and of diseases involving an oxidative stress, in general. The objective of the present study was to evaluate the effect of long-term treatment with NAC on influenza and influenza-like episodes. A total of 262 subjects of both sexes (78% > or = 65 yrs, and 62% suffering from nonrespiratory chronic degenerative diseases) were enrolled in a randomized, double-blind trial involving 20 Italian Centres. They were randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 months. Patients suffering from chronic respiratory diseases were not eligible, to avoid possible confounding by an effect of NAC on respiratory symptoms. NAC treatment was well tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. Frequency of seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected subjects under NAC treatment developed a symptomatic form, versus 79% in the placebo group. Evaluation of cell-mediated immunity showed a progressive, significant shift from anergy to normoergy following NAC treatment. Administration of N-acetylcysteine during the winter, thus, appears to provide a significant attenuation of influenza and influenza-like episodes, especially in elderly high-risk individuals. N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clinically apparent disease.}, }
@article {pmid9228372, year = {1997}, author = {Bernard, GR and Wheeler, AP and Arons, MM and Morris, PE and Paz, HL and Russell, JA and Wright, PE}, title = {A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The Antioxidant in ARDS Study Group.}, journal = {Chest}, volume = {112}, number = {1}, pages = {164-172}, doi = {10.1378/chest.112.1.164}, pmid = {9228372}, issn = {0012-3692}, support = {HL 07123/HL/NHLBI NIH HHS/United States ; HL 19153/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/therapeutic use ; Bilirubin/blood ; Bronchoalveolar Lavage Fluid/cytology ; Cardiac Output ; Cysteine/blood ; Double-Blind Method ; Free Radical Scavengers/*therapeutic use ; Glutathione/blood ; Humans ; Middle Aged ; Prospective Studies ; Pyrrolidonecarboxylic Acid ; Respiration, Artificial ; Respiratory Distress Syndrome/*drug therapy/physiopathology/therapy ; Thiazoles/*therapeutic use ; Thiazolidines ; Time Factors ; }, abstract = {OBJECTIVE: To determine the levels of glutathione and cysteine in patients with ARDS and examine the effect of treatment with N-acetylcysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (Procysteine; Clintec Technologies Inc; Chicago [OTZ]) on these levels and on common physiologic abnormalities, and organ dysfunction associated with ARDS.<br><br>DESIGN: Randomized, double-blind, placebo-controlled, prospective clinical trial.<br><br>SETTING: ICUs in five clinical centers in the United States and Canada.<br><br>PATIENTS: Patients meeting a predetermined definition of ARDS and requiring mechanical ventilation.<br><br>INTERVENTION: Standard care for ARDS and I.V. infusion, every 8 h for 10 days, of one of the following: NAC (70 mg/kg, n=14), OTZ (63 mg/kg, n=17), or placebo (n=15).<br><br>MAIN RESULTS: Both antioxidants effectively repleted RBC glutathione gradually over the 10-day treatment period (47% and 49% increases from baseline values for NAC and OTZ, respectively). There was no difference in mortality among groups (placebo, 40%; NAC, 36%; OTZ, 35%). However, the number of days of acute lung injury was decreased and there was also a significant increase in cardiac index in both treatment groups (NAC/OTZ [+]14%; placebo [-]6%).<br><br>CONCLUSIONS: Our findings suggest that repletion of glutathione may safely be accomplished with NAC or OTZ in patients with acute lung injury/ARDS. Such treatment may shorten the duration of acute lung injury, but larger studies are needed to confirm this.}, }
@article {pmid9209234, year = {1997}, author = {Cetaruk, EW and Dart, RC and Hurlbut, KM and Horowitz, RS and Shih, R}, title = {Tylenol Extended Relief overdose.}, journal = {Annals of emergency medicine}, volume = {30}, number = {1}, pages = {104-108}, doi = {10.1016/s0196-0644(97)70120-3}, pmid = {9209234}, issn = {0196-0644}, mesh = {Acetaminophen/*administration &amp; dosage/blood/pharmacokinetics/*poisoning ; Adolescent ; Adult ; Analgesics, Non-Narcotic/*administration &amp; dosage/blood/pharmacokinetics/*poisoning ; Drug Overdose ; Female ; Half-Life ; Humans ; Intestinal Absorption ; Male ; }, abstract = {In this report we describe the toxicokinetics of the Tylenol Extended Relief (TER) preparation of acetaminophen in human overdose. We collected 41 cases of TER overdose from five regional poison centers. Patients who met the following criteria were studied: a single ingestion of TER alone; confirmed time of ingestion; at least four acetaminophen determinations; and normal concentrations of liver function enzymes. With the exception of standard decontamination measures, treatment with N-acetylcysteine (NAC) if any acetaminophen level was above the treatment line of the Rumack-Matthew nomogram, and additional acetaminophen determinations, no interventions were recommended. Our study group comprised 13 patients, 12 female and 1 male, with single overdoses of 10.4 to 65 g TER. The acetaminophen elimination half-life was 3.1 +/- .8 hours (mean +/- SD; range, 1.3 to 4.0 hours; n = 12). The elimination phase for patients 2, 3, 4, 6, 8, 9, 11, 13 was delayed until 8.0 +/- 2.8 hours (range, 5 to 14 hours) after ingestion. Patients 3, 8, and 11--who had initial acetaminophen levels below the "possible toxicity" line of the Rumack-Matthew nomogram--later had acetaminophen levels above this line. No patient demonstrated a late or second acetaminophen peak. We conclude that the elimination half-life of TER acetaminophen is similar to that reported in overdose of immediate-release acetaminophen overdose. In a subgroup of patients, drug absorption continued beyond the 2 to 4 hours previously reported in immediate-release acetaminophen overdose. On the basis of our data, the use of a single 4-hour acetaminophen determination may lead to failure to recognize patients with potentially toxic TER ingestion. Until more toxicokinetic data are available, a reasonable approach would be to obtain at least one additional acetaminophen determination at least 4 to 6 hours after the first, if the first is obtained 4 to 8 hours after ingestion. NAC treatment should be initiated if either level is above the nomogram line but not if both levels fall below the nomogram line.}, }
@article {pmid9207456, year = {1997}, author = {Lee, JW and Beckham, C and Michel, BR and Rosen, H and Deeg, HJ}, title = {HLA-DR-mediated signals for hematopoiesis and induction of apoptosis involve but are not limited to a nitric oxide pathway.}, journal = {Blood}, volume = {90}, number = {1}, pages = {217-225}, pmid = {9207456}, issn = {0006-4971}, support = {CA18029/CA/NCI NIH HHS/United States ; CA18221/CA/NCI NIH HHS/United States ; HL36444/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Apoptosis/*immunology ; Cell Line ; Dogs ; HLA-DR Antigens/*immunology/metabolism ; Hematopoiesis/*immunology ; Humans ; Mice ; Monocytes/immunology/*pathology ; Nitric Oxide/*metabolism ; Oxidative Stress ; }, abstract = {Cross-linking of major histocompatibility complex (MHC) class II antigens by anti-HLA-DR monoclonal antibody (MoAb; H81.9; IgG2a) results in inhibition of hematopoiesis in canine and human models. Inhibition of hematopoiesis is associated with apoptosis in a proportion of marrow cells. Since in murine macrophages class II cross-linking triggers nitric oxide (NO) production, and NO is thought to affect regulation of hematopoiesis, we investigated whether NO was involved in our models. In murine J774 monocytes/macrophages, MoAb H81.9 did induce NO. NO production was blocked by N(G)-monomethyl-L-arginine (NMMA), an inhibitor of NO synthase (NOS), and by the antioxidant N-acetylcysteine (NAC). In human and canine long-term marrow cultures (LTMCs) and in enriched marrow monocytes, however, no measurable increase in NO production was noted after H81.9 exposure. Nevertheless, NAC protected LTMCs against H81.9 induced inhibition of hematopoiesis. Therefore, we determined the effect of an exogenous NO donator, sin-1 (3-morpholinosydnonimine), on canine and human LTMCs and on apoptosis. Sin-1 at concentrations > or =100 microg/mL inhibited LTMCs and induced apoptosis; at low concentrations (1 microg/mL), however, sin-1 stimulated the generation of colony-forming unit granulocyte-macrophage. Combined treatment with sin-1 at 100 microg/mL and MoAb H81.9 resulted in profound inhibition of hematopoiesis in both canine and human LTMCs, and had an additive effect on apoptosis. At 1 microg/mL sin-1 counteracted the effect of H81.9 on hematopoiesis. The effect of sin-1 on apoptosis and hematopoiesis in LTMC was largely prevented by NAC. These results are consistent with the hypothesis that HLA-DR mediated apoptosis and inhibition of hematopoiesis involve oxidative stress. However, the biphasic response of hematopoiesis to sin-1 suggests a complex regulatory network possibly related to differences in NO sensitivity of distinct subpopulations of cells. Signals in addition to NO appear to be involved in the effect of anti-HLA-DR MoAb on hematopoiesis.}, }
@article {pmid9202959, year = {1997}, author = {van Klaveren, RJ and Pype, JL and Demedts, M and Nemery, B}, title = {Decrease in gamma-glutamyltransferase activity in rat type II cells exposed in vitro to hyperoxia: effects of the 21-aminosteroid U-74389G.}, journal = {Experimental lung research}, volume = {23}, number = {4}, pages = {347-359}, doi = {10.3109/01902149709039231}, pmid = {9202959}, issn = {0190-2148}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Glutathione Peroxidase/metabolism ; Hyperoxia/*enzymology ; In Vitro Techniques ; Male ; Pregnatrienes/*pharmacology ; Pulmonary Alveoli/drug effects/*enzymology ; RNA, Messenger/metabolism ; Rats ; Rats, Wistar ; Superoxide Dismutase/metabolism ; gamma-Glutamyltransferase/genetics/*metabolism ; }, abstract = {Although the effect of hyperoxia on antioxidant enzymes is well known, the effect of subtoxic levels of hyperoxia on gamma-glutamyltransferase (gamma-GT), involved in the degradation and uptake of extracellular GSH for intracellular GSH synthesis, is unknown. The aim of the study was to investigate (1) the effects of in vitro hyperoxia on gamma-GT activity of type II cells and (2) the effects of the lazaroid U-74389G and N-acetylcysteine (NAC) on the hyperoxia-induced changes in gamma-GT and antioxidant enzyme activities. At 48 h after isolation, rat type II cells were exposed for 2 days to air, 60% O2 or 85% O2 with or without 30 microM U-74389G or 100 microM NAC. After the exposure, the cells were harvested and assayed for superoxide dismutase (SOD), glutathione peroxidase (GPx), gamma-GT activity, and GSH levels. In another series of experiments 85% O2-exposed cells, with or without U-74389G, were used for Northern blotting of gamma-GT mRNA. Exposure to 60% O2 decreased gamma-GT and GSH by -47 and -34%, respectively, while SOD and GPx activities remained unchanged. After 85% O2-exposure gamma-GT decreased by -55%, SOD and GPx increased by +55 and +87%, respectively, while GSH decreased by -35%. NAC treatment decreased gamma-GT activity by -42% in the air-exposed cells. After 60% O2, U-74389G led to significantly higher gamma-GT (+117%) and GSH (+26%) while NAC only led to higher GSH (+28%) compared to the oxygen-exposed cells not treated with NAC or U-74389G. After 85% O2 U-74389G increased gamma-GT, SOD, and GSH by +72, +58, and +68%, respectively, while NAC only increased SOD (+49%) and GSH (+26%) compared to the oxygen-exposed cells not treated with NAC or U-74389G. The 85% O2 exposure, with or without U-74389G, had no effect on gamma-GT mRNA levels. The results show that hyperoxia decreases rat type II cell gamma-GT activity in vitro. This effect was not related to an altered regulation at mRNA level and it was not associated with the hyperoxia-induced decrease in intracellular GSH, since restoration of the GSH levels by NAC did not restore gamma-GT activity. The lazaroid U-74389G with vitamin E-like properties effectively prevented the decrease in gamma-GT and GSH, so that direct inactivation of the membrane-bound gamma-GT by hyperoxia is the most likely mechanism.}, }
@article {pmid9201021, year = {1997}, author = {Wung, BS and Cheng, JJ and Hsieh, HJ and Shyy, YJ and Wang, DL}, title = {Cyclic strain-induced monocyte chemotactic protein-1 gene expression in endothelial cells involves reactive oxygen species activation of activator protein 1.}, journal = {Circulation research}, volume = {81}, number = {1}, pages = {1-7}, doi = {10.1161/01.res.81.1.1}, pmid = {9201021}, issn = {0009-7330}, mesh = {Acetylcysteine/pharmacology ; Base Sequence ; Blotting, Northern ; Catalase/pharmacology ; Cells, Cultured ; Chemokine CCL2/*genetics ; Data Interpretation, Statistical ; Electrophoresis ; Endothelium, Vascular/cytology/drug effects/*metabolism ; Free Radical Scavengers/pharmacology ; Gene Expression ; Hemodynamics ; Humans ; Luminescent Measurements ; Molecular Sequence Data ; Promoter Regions, Genetic ; RNA/isolation &amp; purification ; Reactive Oxygen Species/*physiology ; Stress, Mechanical ; Superoxides/analysis ; Tissue Plasminogen Activator/*metabolism ; Transcription Factor AP-1/*metabolism ; }, abstract = {Endothelial cells (ECs) are constantly exposed to blood pressure-induced mechanical strain. We have previously demonstrated that cyclic strain can induce gene expression of monocyte chemotactic protein-1 (MCP-1). The molecular mechanisms of gene induction by strain, however, remain unclear. Recent evidence indicates that intracellular reactive oxygen species (ROS) can act as a second messenger for signal transduction and thus affect gene expression. The potential role of ROS in strain-induced MCP-1 expression was investigated. ECs under cyclic strain induced a sustained elevated production of intracellular superoxide. ECs under strain or pretreated with either H2O2 or xanthine oxidase/hypoxanthine induced MCP-1 expression. Strain- or oxidant-induced MCP-1 mRNA levels could be inhibited by treating ECs with catalase or antioxidant N-acetyl-cysteine (NAC). Functional analysis of MCP-1 promoter and site-specific mutations indicates that the proximal tissue plasminogen activator-responsive element (TRE) in the -60-bp promoter region is sufficient for strain or H2O2 inducibility. Electrophoretic mobility shift assays demonstrated an increase of nuclear proteins binding to TRE sequences from ECs subsequent to strain or H2O2 treatment. NAC or catalase pretreatment of ECs inhibited the strain- or H2O2-induced AP-1 binding. These results clearly indicate that cyclic strain inducibility of MCP-1 in ECs uses the interaction of AP-1 proteins with TRE sites via the elevation of intracellular ROS levels in strained ECs. These findings emphasize the importance of intracellular ROS in the modulation of hemodynamic force-induced gene expression in vascular ECs.}, }
@article {pmid9237628, year = {1997}, author = {Vansuyt, G and Lopez, F and Inzé, D and Briat, JF and Fourcroy, P}, title = {Iron triggers a rapid induction of ascorbate peroxidase gene expression in Brassica napus.}, journal = {FEBS letters}, volume = {410}, number = {2-3}, pages = {195-200}, doi = {10.1016/s0014-5793(97)00587-5}, pmid = {9237628}, issn = {0014-5793}, mesh = {Abscisic Acid/pharmacology ; Ascorbate Peroxidases ; Brassica/enzymology/*genetics ; Citric Acid ; Cotyledon ; Enzyme Induction ; Ferrous Compounds/pharmacology ; *Gene Expression Regulation, Enzymologic ; *Gene Expression Regulation, Plant ; Iron/*pharmacology ; Oxidative Stress ; Peroxidases/biosynthesis/*genetics ; RNA, Messenger/metabolism ; }, abstract = {In plants, only ferritin gene expression has been reported to be iron-dependent. Here it is demonstrated that an iron overload of Brassica napus seedlings causes a large and rapid accumulation of ascorbate peroxidase transcripts, a plant-specific hydrogen peroxide-scavenging enzyme. This result documents a novel link between iron metabolism and oxidative stress. The ascorbate peroxidase mRNA abundance was not modified by reducing agents like N-acetyl cysteine, glutathione and ascorbate or by pro-oxidants such as hydrogen peroxide or diamide. Furthermore, the iron-induced ascorbate peroxidase mRNA accumulation was not antagonized by N-acetyl cysteine. Abscisic acid had no effect on the ascorbate peroxidase gene expression. Taken together these results suggest that iron-mediated expression of ascorbate peroxidase gene occurs through a signal transduction pathway apparently different from those already described for plant genes responsive to oxidative stress.}, }
@article {pmid9188453, year = {1997}, author = {Bhunia, AK and Han, H and Snowden, A and Chatterjee, S}, title = {Redox-regulated signaling by lactosylceramide in the proliferation of human aortic smooth muscle cells.}, journal = {The Journal of biological chemistry}, volume = {272}, number = {25}, pages = {15642-15649}, doi = {10.1074/jbc.272.25.15642}, pmid = {9188453}, issn = {0021-9258}, support = {1-P50 HL47212/HL/NHLBI NIH HHS/United States ; R01-DK31722/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; *Antigens, CD ; Antioxidants/pharmacology ; Buthionine Sulfoximine/metabolism ; Calcium-Calmodulin-Dependent Protein Kinases/metabolism ; Cell Division ; Cells, Cultured ; Enzyme Inhibitors/metabolism ; Glutathione/metabolism ; Guanosine Triphosphate/metabolism ; Humans ; Lactosylceramides/*metabolism ; Mitogen-Activated Protein Kinase 3 ; *Mitogen-Activated Protein Kinases ; Multienzyme Complexes/metabolism ; Muscle, Smooth, Vascular/*metabolism ; NADH, NADPH Oxidoreductases/metabolism ; NADPH Oxidases/metabolism ; Onium Compounds/metabolism ; Oxidation-Reduction ; Phosphorylation ; Protein Kinase C/metabolism ; Proto-Oncogene Proteins c-fos/metabolism ; *Signal Transduction ; Superoxide Dismutase/metabolism ; Superoxides/metabolism ; Xanthine Oxidase/metabolism ; }, abstract = {Previously, our laboratory reported that lactosylceramide (LacCer) stimulated human aortic smooth muscle cell proliferation via specific activation of p44 mitogen-activated protein kinase (MAPK) in the p21(ras)/Raf-1/MEK2 pathway and induced expression of the transcription factor c-fos downstream to the p44 MAPK signaling cascade (Bhunia A. K., Han, H., Snowden, A., and Chatterjee S. (1996) J. Biol. Chem. 271, 10660-10666). In the present study, we explored the role of free oxygen radicals in LacCer-mediated induction of cell proliferation. Superoxide levels were measured by the lucigenin chemiluminescence method, MAPK activity was measured by immunocomplex kinase assays, and Western blot analysis and c-fos expression were measured by Northern blot assay. We found that LacCer (10 microM) stimulates endogenous superoxide production (7-fold compared with control) in human aortic smooth muscle cells specifically by activating membrane-associated NADPH oxidase, but not NADH or xanthine oxidase. This process was inhibited by an inhibitor of NADPH oxidase, diphenylene iodonium (DPI), and by antioxidants, N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate. NAC and DPI both abrogated individual steps in the signaling pathway leading to cell proliferation. For example, the p21(ras).GTP loading, p44 MAPK activity, and induction of transcription factor c-fos all were inhibited by NAC and DPI as well as an antioxidant pyrrolidine dithiocarbamate or reduced glutathione (GSH). In contrast, depletion of GSH by L-buthionine (S, R)-sulfoximine up-regulated the above described signaling cascade. In sum, LacCer, by virtue of activating NADPH oxidase, produces superoxide (a redox stress signaling molecule), which mediates cell proliferation via activation of the kinase cascade. Our findings may explain the potential role of LacCer in the pathogenesis of atherosclerosis involving the proliferation of aortic smooth muscle cells.}, }
@article {pmid9201273, year = {1997}, author = {Abt, G and Vaghef, H and Gebhart, E and Dahlgren, CV and Hellman, B}, title = {The role of N-acetylcysteine as a putative radioprotective agent on X-ray-induced DNA damage as evaluated by alkaline single-cell gel electrophoresis.}, journal = {Mutation research}, volume = {384}, number = {1}, pages = {55-64}, doi = {10.1016/s0921-8777(97)00013-x}, pmid = {9201273}, issn = {0027-5107}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Animals ; DNA Damage/*drug effects/radiation effects ; DNA Mutational Analysis/*methods ; Electrophoresis, Agar Gel/methods ; Humans ; Hydrogen-Ion Concentration ; Lymphocytes/radiation effects ; Male ; Mice ; Middle Aged ; Mutagenicity Tests/*methods ; *Radiation-Protective Agents ; X-Rays ; }, abstract = {Samples of human whole blood from 8 different donors were incubated with physiological saline or N-acetyl-L-cysteine (NAC, 1 x 10(-3) M) before being irradiated in vitro with high-energy X-rays (0.7 or 2.0 Gy). Primary DNA damage was evaluated in isolated lymphocytes using alkaline single-cell gel electrophoresis. Whereas the lymphocytes from non-irradiated blood samples showed a similar 'background level' of damage, there was a difference in sensitivity towards the radiation-induced DNA damage, especially at 2.0 Gy. When the data were pooled there was a clear and dose-related increase (p < 0.001) in damage, both in the absence and presence of NAC. Using the two most sensitive 'comet parameters' for DNA damage, i.e., the tail inertia and tail moment, the radiation-induced damage was found to be significantly increased already at 0.7 Gy in the samples that had been irradiated without NAC. Overall, NAC was found to be without radioprotective effects. Instead, the incubation with NAC itself was found to be associated with a slightly increased level of DNA damage. If the present findings are relevant also in an in vivo situation using peripheral lymphocytes as a surrogate for non-malignant cells in the body, NAC seems to be of limited value as a radioprotective agent in the clinic, at least when it comes to the acute DNA-damaging effects of therapeutic doses of high-energy X-rays.}, }
@article {pmid9239448, year = {1997}, author = {Rossoni, G and Radice, S and Bernareggi, M and Polvani, G and Oriani, G and Chiesara, E and Berti, F}, title = {Influence of acetylcysteine on aggravation of ischemic damage in ex vivo hearts of rats exposed to hyperbaric oxygen.}, journal = {Arzneimittel-Forschung}, volume = {47}, number = {6}, pages = {710-715}, pmid = {9239448}, issn = {0004-4172}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta, Thoracic/drug effects/metabolism ; Coronary Circulation/drug effects ; Dinoprost/metabolism ; Endothelin-1/pharmacology ; Free Radical Scavengers/*pharmacology ; Hyperbaric Oxygenation/*adverse effects ; In Vitro Techniques ; Male ; Muscle Contraction/drug effects ; Muscle Relaxation/drug effects ; Muscle, Smooth, Vascular/drug effects/metabolism/physiology ; Myocardial Reperfusion Injury/*metabolism/*physiopathology ; Myocardium/metabolism ; Rats ; Rats, Sprague-Dawley ; Ventricular Pressure/drug effects ; }, abstract = {Rats were exposed to hyperbaric oxygen (HBO = 100% oxygen; 2.5 atmospheres absolute pressure) for 6 h. Isovolumic left heart preparations from these animals were subjected to global low flow-ischemia (perfusion rate from 12 ml/min to 2 ml/min for 40 min) and reperfusion. Hearts from rats not exposed to HBO underwent the same ischemic-reperfusion procedure (controls). As compared to control, HBO treatment caused in ex vivo hearts a significant aggravation of cardiac ischemic picture as indicated by a marked increase in left ventricular end diastolic pressure (LVEDP) and reduced post ischemic left ventricular developed pressure (LVDP). At the end of the ischemic and reperfusion periods LVEDP values were 6.8 (p < 0.001) and 8 (p < 0.001) times higher than the corresponding control values. Moreover, LVDP and coronary perfusion pressure (CPP) values were decreased (2.8 times; p < 0.001) and increased (56%; p < 0.001), respectively, as compared to control preparations. These events were also associated with a considerable impairment of the cardiac tissue to generate 6-keto-PGF1 alpha. Treatments of rats with different doses of acetylcysteine (N-acetylcysteine, CAS 616-91-1, NAC; 0.25-0.5-1 g/kg p.o.) before HBO displayed a clear-cut and dose-related protective activity in hearts subjected to ischemia-reperfusion. Also the generating capacity of 6-keto-PGF1 alpha from these hearts were restored according to the dose of NAC employed. When aortic rings from rats exposed to HBO were considered, they showed a reduced capacity to release 6-keto-PGF1 alpha and an increased sensitivity to endothelin-1. At the same time, the relaxant activity of acetylcholine in these tissues was almost lost. Again, NAC treatment of the animals before HBO restored in a dose-dependent way the capacity of the aortic rings to generate 6-keto-PGF1 alpha. This event was paralleled by normalized responses of the preparations to endothelin-1 and acetylcholine. Taken together these results clearly indicate that acute HBO treatment of the rats markedly aggravates the ischemic-reperfusion damage in ex vivo hearts. This event is coupled with a compromised integrity of cardiac and extracardiac endothelial cell functions. The protective activity of NAC observed in this study once more emphasises its therapeutic role in increasing antioxidant defence mechanisms.}, }
@article {pmid9180899, year = {1997}, author = {Gilbert, M and Knox, S}, title = {Influence of Bcl-2 overexpression on Na+/K(+)-ATPase pump activity: correlation with radiation-induced programmed cell death.}, journal = {Journal of cellular physiology}, volume = {171}, number = {3}, pages = {299-304}, doi = {10.1002/(SICI)1097-4652(199706)171:3&lt;299::AID-JCP8&gt;3.0.CO;2-J}, pmid = {9180899}, issn = {0021-9541}, support = {CA68149/CA/NCI NIH HHS/United States ; }, mesh = {*Apoptosis/radiation effects ; Humans ; Lymphoma, B-Cell/metabolism/pathology ; Membrane Potentials ; Proto-Oncogene Proteins c-bcl-2/*biosynthesis ; Sodium-Potassium-Exchanging ATPase/*metabolism ; Tumor Cells, Cultured ; }, abstract = {Bcl-2 overexpression in transfected PW cells is associated with inhibition of radiation-induced programmed cell death (PCD). We have previously reported that there is a relationship between inhibition of radiation-induced PCD and membrane hyperpolarization in these cells. In this article, we report that Na+/ K(+)-ATPase pump activity, as measured by the uptake of Rubidium-86 (86Rb+), is significantly higher in Bcl-2 overexpressing PW cells than in control PW cells, and that pump activity following irradiation with doses > or = 500 cGy was reduced to a lesser extent in the Bcl-2 transfectants than in the control cells. When PW-Bcl-2 cells were incubated with a dose of ouabain (1 microM) that decreased pump activity significantly, but did not induce PCD, the previously reported protection from radiation-induced PCD associated with overexpression of Bcl-2 no longer existed. In order to demonstrate that reactive oxygen species (ROS) affected Na+/ K(+)-ATPase pump activity, cells were incubated with N-acetyl cysteine (NAC) prior to irradiation, or treated with the ROS generating drug buthionine sulphoxamine (BSO). 86Rb+ uptake was significantly higher in irradiated cells incubated with NAC compared to cells irradiated in the absence of NAC, while BSO resulted in lower levels of 86Rb+ uptake, suggesting that the effects of radiation on the Na+/K(+)-ATPase pump were due to ROS. Furthermore, the resting cell membrane potential of cells exposed to NAC were slightly hyperpolarized compared to control PW cells, whereas cells exposed to BSO were depolarized in comparison to control PW cells. In summary, this data suggests that Bcl-2 affects Na+/K(+)-ATPase pump activity, which is associated with the resting membrane potential and the level of susceptibility to radiation-induced PCD.}, }
@article {pmid9217237, year = {1997}, author = {Neal, R and Yang, P and Fiechtl, J and Yildiz, D and Gurer, H and Ercal, N}, title = {Pro-oxidant effects of delta-aminolevulinic acid (delta-ALA) on Chinese hamster ovary (CHO) cells.}, journal = {Toxicology letters}, volume = {91}, number = {3}, pages = {169-178}, doi = {10.1016/s0378-4274(97)03887-3}, pmid = {9217237}, issn = {0378-4274}, support = {1R15ES08016-01/ES/NIEHS NIH HHS/United States ; }, mesh = {Aminolevulinic Acid/*pharmacology ; Animals ; CHO Cells/*drug effects/metabolism ; Catalase/metabolism ; Cell Survival/drug effects ; Chromatography, High Pressure Liquid ; Cricetinae ; Cricetulus ; Glutathione/analogs &amp; derivatives/metabolism ; Glutathione Disulfide ; L-Lactate Dehydrogenase/metabolism ; Oxidative Stress/drug effects ; }, abstract = {delta-Aminolevulinic Acid (delta-ALA) is a heme precursor accumulated in lead poisoning and acute intermittent porphyria. Although no single mechanism for lead toxicity has yet been defined, recent studies suggest at least some of the lead-induced damage may originate from delta-ALA-induced oxidative stress. The present study was designed to test the hypothesis that delta-ALA accumulation in Chinese hamster ovary (CHO) cells contributes to the cumulative oxidative challenge of lead poisoning as indicated by the oxidative stress parameters glutathione (GSH), glutathione disulfide (GSSG), malondialdehyde equivalents (MDA), and catalase (CAT). It will also examine the possibility that this oxidative challenge can be reversed by treatment with an antioxidant such as N-acetylcysteine (NAC). First in vitro administration of delta-ALA to CHO cells was found to have a concentration-dependent inhibitory effect on colony formation and cell survival. NAC administration was shown to alleviate this inhibition in CHO survival. The oxidative status of CHO cell cultures exposed to increasing concentrations of delta-ALA was then examined. Decreases in GSH levels (P < 0.05) were observed in the delta-ALA-treated cultures as compared to the controls, while GSSG and MDA levels were significantly increased in delta-ALA-treated cells (P < 0.05). CAT activity was not significantly affected. NAC administration concurrent with delta-ALA exposure resulted in GSH and GSSG levels similar to the control levels, while no significant improvement in MDA was observed. These results indicate a state of oxidative stress and suggest that the delta-ALA- induced inhibitory effect on CHO colony formation may be due to its pro-oxidant effect. To assess whether this oxidative challenge would induce antioxidant increases during extended exposure to delta-ALA, CHO cells were exposed to 5 mM delta-ALA for increasing time periods. The GSH and GSSG levels were measured and a rebound effect was observed after 12 h of delta-ALA exposure.}, }
@article {pmid9152014, year = {1997}, author = {Gong, Q and Hart, BA}, title = {Effect of thiols on cadmium-induced expression of metallothionein and other oxidant stress genes in rat lung epithelial cells.}, journal = {Toxicology}, volume = {119}, number = {3}, pages = {179-191}, doi = {10.1016/s0300-483x(96)03608-6}, pmid = {9152014}, issn = {0300-483X}, support = {ES 03098/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Buthionine Sulfoximine/*pharmacology ; Cadmium Chloride/*toxicity ; Carcinogens/*toxicity ; Cell Death/drug effects ; Cell Line ; DNA Probes/chemistry ; Dose-Response Relationship, Drug ; Epithelium/drug effects/metabolism ; Gene Expression/drug effects ; Glutathione/metabolism ; Glutathione Transferase/biosynthesis/genetics ; Heme Oxygenase (Decyclizing)/biosynthesis/genetics ; Kinetics ; Lung/drug effects/*metabolism ; Metallothionein/*biosynthesis/genetics ; Oxidoreductases/*biosynthesis/genetics ; RNA, Messenger/metabolism ; Rats ; }, abstract = {This study examined cadmium-induced alterations in metallothionein-1 (MT), glutathione-S-transferase Ya (GST), and heme oxygenase-1 (HO) gene expression in an adult rat lung epithelial cell line. Elevations in MT mRNA and HO mRNA occurred as early as 1 h after exposure to a sub-toxic concentration of CdCl(2) (10 microM) whereas GST expression did not increase significantly until 4 h after Cd addition. At t = 8 h, levels of GST, MT, and HO mRNA were elevated 9-fold, 27-fold, and 44-fold, respectively, over basal expression. By 24 h, MT expression was almost back to baseline levels. GST mRNA and HO mRNA were also reduced, compared to 8 h, but to a lesser extent than MT expression. The MT gene was more responsive to low Cd concentrations (5 microM) than the genes for HO or GST whereas HO was induced more than the others at higher Cd doses (10-20 microM). Pro-oxidant conditions play a role in Cd-induced gene expression, as suggested by the rapid decline (15-30 min) in glutathione (GSH), amounting to 25-30% of baseline, that occurred after exposure to 10 microM CdCl(2). This was followed by resynthesis of GSH to a concentration higher than the initial. Depleting GSH by treatment of cells with buthionine sulfoximine (BSO) enhanced Cd-induced expression of MT, GST, and HO whereas thiol supplementation, by treatment with N-acetyl cysteine (NAC), had an attenuating effect. BSO and NAC pretreatment had no effect on basal gene expression or Cd uptake. In summary, this study has shown that: (1) Cd increases MT, GST, and HO gene expression in a time- and dose-dependent fashion: (2) MT gene expression appears to be most sensitive to Cd whereas the HO gene is most inducible at higher Cd concentrations; (3) Cd-induced expression is enhanced by GSH depletion and suppressed by thiol supplementation.}, }
@article {pmid9216683, year = {1997}, author = {Satoh, K and Sakagami, H}, title = {Effect of cysteine, N-acetyl-L-cysteine and glutathione on cytotoxic activity of antioxidants.}, journal = {Anticancer research}, volume = {17}, number = {3C}, pages = {2175-2179}, pmid = {9216683}, issn = {0250-7005}, mesh = {Acetylcysteine/*pharmacology ; Amino Acids/*pharmacology ; Amino Acids, Essential/pharmacology ; Antineoplastic Agents/metabolism/toxicity ; Antioxidants/metabolism/*toxicity ; Ascorbic Acid/analogs &amp; derivatives/toxicity ; Benzylidene Compounds/toxicity ; Caffeic Acids/toxicity ; Cell Survival/*drug effects ; Cysteine/*pharmacology ; Electron Spin Resonance Spectroscopy ; Free Radicals/metabolism ; Gallic Acid/toxicity ; Glutathione/*pharmacology ; HL-60 Cells/drug effects ; Humans ; Kinetics ; }, abstract = {The effect of twenty amino acids on the radical intensity of four antioxidants (sodium L-ascorbate, sodium 5,6-benzylidene-L-ascorbate, gallic acid, caffeic acid) was investigated, using ESR spectroscopy. Methionine and methional did not significantly affect the radical intensity of these antioxidants. Methionine sulfoxide slightly enhanced the radical intensity of sodium ascorbate and sodium 5,6-benzylidene-L-ascorbate, but did not that of gallic acid and caffeic acid. Cysteine, N-acetyl cysteine and glutathione significantly reduced the radical intensity and cytotoxic activity of these antioxidants except for sodium 5,6-benzylidene-L-ascorbate. The other amino acids were inactive. The present study further supports that these antioxidants induce cytotoxicity via their pro-oxidant action.}, }
@article {pmid9197915, year = {1997}, author = {Oeda, T and Henkel, R and Ohmori, H and Schill, WB}, title = {Scavenging effect of N-acetyl-L-cysteine against reactive oxygen species in human semen: a possible therapeutic modality for male factor infertility?.}, journal = {Andrologia}, volume = {29}, number = {3}, pages = {125-131}, doi = {10.1111/j.1439-0272.1997.tb00305.x}, pmid = {9197915}, issn = {0303-4569}, mesh = {Acetylcysteine/*pharmacology ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*pharmacology ; Humans ; Infertility, Male/*therapy ; Male ; Reactive Oxygen Species/*metabolism ; Semen/*drug effects/metabolism ; Spermatozoa/drug effects/physiology ; Time Factors ; }, abstract = {A new approach to reduce the level of reactive oxygen species (ROS) in human semen by using N-acetyl-L-cysteine (NAC) was evaluated. Semen samples were incubated with or without NAC (1.0 mg ml-1) at room temperature. The chemiluminescent signal of the oxidation of luminol was detected by means of an MTP reader after 0, 20, 40, 60 and 120 min, respectively, using 200 microM luminol. In addition, the dose-dependent action of NAC (0.1, 1.0 and 5.0 mg ml-1) and the influence of NAC on functional sperm parameters (motility and acrosome reaction) were studied. ROS levels decreased significantly after 20 min incubation with NAC. This reduction was greater in the high ROS group (> 30000 counts/10(7) viable sperm at t = 0) than in the low ROS group (< 30000). In addition, a marked dose-dependence of NAC was observed. Concerning sperm function, total sperm motility improved after incubation with NAC, but no significant change was observed with respect to the acrosome reaction. NAC (at concentrations of 1.0 mg ml-1) significantly reduced ROS in human semen and showed the possibility of improving impaired sperm function. After further testing NAC might be useful for the treatment of male infertility patients.}, }
@article {pmid9188292, year = {1997}, author = {Stewart, S and Ryan, C and Poropat, S}, title = {Managing patients with acute myocardial ischemia and reperfusion injury with N-acetylcysteine.}, journal = {Dimensions of critical care nursing : DCCN}, volume = {16}, number = {3}, pages = {122-131}, doi = {10.1097/00003465-199705000-00002}, pmid = {9188292}, issn = {0730-4625}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Aged ; Critical Care ; Drug Monitoring ; Free Radical Scavengers/*therapeutic use ; Humans ; Male ; Myocardial Ischemia/*drug therapy ; Myocardial Reperfusion Injury/*drug therapy ; Nursing Assessment ; }, abstract = {Previously administered in cases of acetaminophen toxicity, N-Acetylcysteine (NAC) is now also being used in the management of acute myocardial ischemia and reperfusion injury. NAC potentiates the beneficial effects of nitrates such as nitroglycerin and reduces oxidative stress on the heart. The critical care nurse plays an important role in optimizing the therapeutic benefits of NAC and minimizing its potential harmful effects.}, }
@article {pmid9177840, year = {1997}, author = {Giblin, MF and Jurisson, SS and Quinn, TP}, title = {Synthesis and characterization of rhenium-complexed alpha-melanotropin analogs.}, journal = {Bioconjugate chemistry}, volume = {8}, number = {3}, pages = {347-353}, doi = {10.1021/bc9700291}, pmid = {9177840}, issn = {1043-1802}, mesh = {Animals ; Drug Stability ; Isotope Labeling ; Magnetic Resonance Spectroscopy ; Mice ; Receptors, Pituitary Hormone/metabolism ; Rhenium/*chemistry/metabolism ; alpha-MSH/*chemistry/metabolism ; }, abstract = {Receptor binding peptides labeled with medically important radionuclides such as technetium and rhenium are an important tool for the imaging and treatment of many forms of cancer. This paper describes a method of labeling peptides with rhenium using a natural amino acid chelating moiety. The structural characteristics of this chelate moiety, N-acetyl-cysteine-glycine-cysteine-glycine (NAc-CGCG) complexed with nonradioactive rhenium, have been investigated. The stability of this peptide-metal complex has been evaluated on the tracer level using radioactive rhenium-186. The rhenium-bound peptide has been appended to the N termini of receptor binding alpha-melanocyte stimulating hormone (alpha-MSH, NAc-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) fragments via solid phase peptide synthesis. Bioassays and receptor binding studies of the resulting complexes demonstrate that the fragments retained biological activity and exhibited receptor binding constants ranging from 0.3 to 1.1 nM. This method could provide a general means of labeling bioactive peptide fragments that would simplify product purification and characterization.}, }
@article {pmid9175256, year = {1997}, author = {Vossen, RC and Persoons, MC and Slobbe-van Drunen, ME and Bruggeman, CA and van Dam-Mieras, MC}, title = {Intracellular thiol redox status affects rat cytomegalovirus infection of vascular cells.}, journal = {Virus research}, volume = {48}, number = {2}, pages = {173-183}, doi = {10.1016/s0168-1702(96)01439-6}, pmid = {9175256}, issn = {0168-1702}, mesh = {Acute Disease ; Animals ; Cell Line ; Cytomegalovirus/drug effects/*metabolism/pathogenicity ; Cytomegalovirus Infections/*metabolism ; Endothelium, Vascular/chemistry/*metabolism/pathology/*virology ; Glutathione/metabolism/pharmacology ; Heart/virology ; Immunosuppression Therapy/adverse effects ; Intracellular Fluid/metabolism/virology ; Muscle, Smooth, Vascular/pathology/virology ; Myocardium/cytology ; Oxidation-Reduction ; Rats ; Sulfhydryl Compounds/*metabolism/physiology ; }, abstract = {There is increasing evidence for cytomegalovirus (CMV) induced vascular pathology during acute infection in the immunocompromised host. Inflammation is involved in such processes, which is frequently associated with increased levels of oxidative mediators and reduced anti-oxidant protection. A relation between viral infection and oxidative stress has been recognized for human immunodeficiency virus and herpes simplex virus-1 infections, but little is known in this respect for CMV infections. We investigated if there is a relation between CMV infection of vascular cells and the intracellular redox status using an in vitro rat model. We measured intracellular glutathione levels and rat CMV (RCMV) permissiveness of rat heart endothelial cell lines (RHEC), rat smooth muscle cells (RSMC), and compared these with fully CMV-permissive rat fibroblasts (REF and Rat 2). In addition, the effects of the anti-oxidant N-acetylcysteine (NAC) and the glutathione synthesis inhibitor buthionine sulfoximide (BSO) on CMV permissiveness and replication were investigated in these cell lines. Finally, we investigated infection of vascular cells under inflammatory conditions in an in vivo rat model for acute CMV infection. The results show a very high endogenous glutathione level in RHEC compared to REF, Rat 2 cells and RSMC. This is associated with a low CMV permissiveness in RHEC as opposed to full permissiveness in REF, Rat 2 cells and RSMC in vitro. In addition, modulation of the intracellular thiol redox status affected CMV infection and replication only in RHEC, but not in RSMC and Rat 2 cells. During acute infection in vivo under immunosuppressed conditions rat endothelial cells first become activated and subsequently infected leading to vascular damage and pathology. This study suggests that a high endogenous thiol redox status may contribute to the apparent barrier function of endothelial cells with respect of CMV infection and that oxidative stress may facilitate CMV infection of the vascular wall.}, }
@article {pmid9157963, year = {1997}, author = {Mietus-Snyder, M and Friera, A and Glass, CK and Pitas, RE}, title = {Regulation of scavenger receptor expression in smooth muscle cells by protein kinase C: a role for oxidative stress.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {17}, number = {5}, pages = {969-978}, doi = {10.1161/01.atv.17.5.969}, pmid = {9157963}, issn = {1079-5642}, support = {HL-47660/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Cell Line ; Enzyme Inhibitors/pharmacology ; *Gene Expression Regulation ; Humans ; Hydrogen Peroxide/pharmacology ; Luciferases/genetics ; *Membrane Proteins ; Muscle, Smooth, Vascular/*metabolism ; *Oxidative Stress ; Protein Kinase C/antagonists &amp; inhibitors/*physiology ; RNA, Messenger/biosynthesis ; Rabbits ; Reactive Oxygen Species ; Receptors, Immunologic/*genetics ; *Receptors, Lipoprotein ; Receptors, Scavenger ; Recombinant Fusion Proteins ; Scavenger Receptors, Class B ; Tetradecanoylphorbol Acetate/pharmacology ; Transfection ; Up-Regulation ; }, abstract = {Phorbol esters increase scavenger-receptor mRNA expression and receptor activity in smooth muscle cells (SMCs). Our present results demonstrate that activation of protein kinase C (PKC) mediates this increase in receptor expression. This conclusion is based on the findings that (1) phorbol esters induced translocation of PKC-alpha from the cytosol to the membrane fraction; (2) PKC inhibitors blocked the effect of phorbol esters on receptor expression; (3) diacylglycerol, a physiological PKC agonist, enhanced scavenger-receptor activity; and (4) in cotransfected human SMCs, constitutively active PKC-alpha stimulated the expression of a reporter gene under control of the scavenger-receptor promoter. Phorbol ester treatment of SMCs increased intracellular reactive oxygen, and the increase in receptor activity was reduced 30% by the antioxidant N-acetyl cysteine (NAC), suggesting a role for reactive oxygen in phorbol ester-mediated receptor regulation. Furthermore, direct treatment of SMCs with reactive oxygen species increased scavenger-receptor activity. In rabbit SMCs, 100 micromol/L H2O2 alone slightly increased scavenger-receptor mRNA and protein expression. In combination, 100 micromol/L H2O2 and 10 micromol/L vanadate, which promotes formation of OH and enhances the inhibition of protein tyrosine phosphatase by H2O2, increased scavenger-receptor mRNA expression 25-fold in rabbit SMCs and 8-fold in human SMCs. NAC reduced the effect of H2O2 and vanadate by 93%. The increase in SMC scavenger-receptor expression occurs at the level of gene transcription. Receptor mRNA half-life was unchanged after treatment with either phorbol esters or reactive oxygen (approximately 14.5 hours), and induction by phorbol esters increased SMC scavenger-receptor mRNA transcription, as determined by nuclear run-on assay. Multiple cytokines and growth factors that contribute to the generation of reactive oxygen species are present in atherosclerotic lesions. These factors may all contribute to the upregulation of SMC scavenger-receptor activity and therefore to the formation of smooth muscle foam cells.}, }
@article {pmid9152363, year = {1997}, author = {Hu, P and Jin, L and Baillie, TA}, title = {Studies on the metabolic activation of disulfiram in rat. Evidence for electrophilic S-oxygenated metabolites as inhibitors of aldehyde dehydrogenase and precursors of urinary N-acetylcysteine conjugates.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {281}, number = {2}, pages = {611-617}, pmid = {9152363}, issn = {0022-3565}, support = {ES05500/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry/*urine ; Alcohol Deterrents/*pharmacokinetics ; Aldehyde Dehydrogenase/*antagonists &amp; inhibitors ; Animals ; Biotransformation ; Chromatography, Liquid/methods ; Disulfiram/*pharmacokinetics ; Male ; Mass Spectrometry/methods ; Oxygen/chemistry ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Recent studies on the mechanism by which disulfiram inhibits aldehyde dehydrogenase have provided evidence for the formation of reactive intermediates that are thought to carbamoylate, and thereby inactivate the enzyme. In our study, rats were dosed with either disulfiram (0.25 mmol kg-1 i.p.) or its reduced metabolite diethyldithiocarbamate (DDTC; 0.5 mmol kg-1 i.p.) and urine was collected for the analysis of metabolites derived from putative reactive intermediates. By means of ionspray LC-MS/MS, two novel N-acetylcysteine (NAC) conjugates, i.e., N-acetyl-S-(N, N-diethylcarbamoyl)cysteine and N-acetyl-S-(N, N-diethylthiocarbamoyl)cysteine, were identified in urine specimens. Quantitative analyses indicated that, over the 0- to 24-hr period after drug administration, urinary excretion of N-acetyl-S-(N, N-diethylcarbamoyl)cysteine accounted for 7.5 +/- 4.0 and 6.2 +/- 1.0%, respectively, of the dose of disulfiram and diethyldithiocarbamate, while the corresponding thiocarbamoyl conjugate, N-acetyl-S-(N, N-diethylthiocarbamoyl)cysteine, accounted for a further 0.5 +/- 0.3 and 0.3 +/- 0.1%, respectively, of the dose. These conjugates are believed to derive from reactive sulfoxide and sulfone metabolites of disulfiram, namely S-methyl-N, N-diethylthiocarbamate sulfoxide (DETC-MeSO), S-methyl-N, N-diethylthiocarbamate sulfone (DETC-MeSO2), S-methyl-N, N-diethyldithiocarbamate sulfoxide (DDTC-MeSO) and S-methyl-N, N-diethyldithiocarbamate sulfone (DDTC-MeSO2), which were found to carbamoylate N-acetylcysteine in vitro with the following rank order of reactivity: DDTC-MeSO2 > DETC-MeSO2 > DDTC-MeSO > DETC-MeSO. In vitro experiments with aldehyde dehydrogenase showed that all four S-oxygenated metabolites inhibited the enzyme effectively. Furthermore, inclusion of NAC in incubation media attenuated significantly the inhibition by DDTC-MeSO2, DETC-MeSO2 and DDTC-MeSO, but had little effect on that by DETC-MeSO. Our results are consistent with the hypothesis that disulfiram and diethyldithiocarbamate undergo activation by a sequence of metabolic reactions leading to the formation of electrophilic S-methyl sulfoxides and sulfones that carbamoylate, and thereby inhibit, aldehyde dehydrogenase and possibly other enzymes.}, }
@article {pmid9135001, year = {1997}, author = {Liu, Y and Naumovski, L and Hanawalt, P}, title = {Nucleotide excision repair capacity is attenuated in human promyelocytic HL60 cells that overexpress BCL2.}, journal = {Cancer research}, volume = {57}, number = {9}, pages = {1650-1653}, pmid = {9135001}, issn = {0008-5472}, support = {CA44349/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Apoptosis ; Cell Survival/radiation effects ; DNA Fragmentation ; *DNA Repair ; DNA Replication/radiation effects ; HL-60 Cells ; Humans ; Proto-Oncogene Proteins c-bcl-2/*physiology ; Pyrimidine Dimers ; Recombinant Proteins ; Ultraviolet Rays ; }, abstract = {We investigated the effect of the BCL2 overexpression on nucleotide excision repair (NER) and DNA replication in UV-irradiated HL60 cells. Forty-eight h after 10 J/m2 irradiation, only 4% of the cyclobutane pyrimidine dimers were removed in the BCL2-overexpressing cells, in contrast to 38% removal in control cells. However, the repair of 6-4 pyrimidine pyrimidone photoproducts was not affected by BCL2 overexpression. Eight h after irradiation, DNA replication recovered to 60% of normal in the BCL2-overexpressing cells, whereas little DNA replication recovered in control cells. The antioxidant N-acetyl cysteine also attenuated cyclobutane pyrimidine dimer removal but did not enhance the recovery of DNA replication. Both BCL2-overexpressing and NAC-treated cells were more resistant to UV. Our data suggest that Bcl2 may promote mutagenesis and genomic instability in surviving cells.}, }
@article {pmid10495789, year = {1997}, author = {Satriano, JA and Banas, B and Luckow, B and Nelson, P and Schlondorff, DO}, title = {Regulation of RANTES and ICAM-1 expression in murine mesangial cells.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {8}, number = {4}, pages = {596-603}, doi = {10.1681/ASN.V84596}, pmid = {10495789}, issn = {1046-6673}, support = {DK-22036/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Anti-Inflammatory Agents/pharmacology ; Antioxidants/pharmacology ; Blotting, Northern ; Chemokine CCL5/genetics/*metabolism ; Colforsin/pharmacology ; Cyclic AMP/metabolism ; Dexamethasone/pharmacology ; Down-Regulation/drug effects ; Enzyme-Linked Immunosorbent Assay ; Free Radical Scavengers/metabolism ; Glomerular Mesangium/cytology/*metabolism ; Glucocorticoids/pharmacology ; Immunoglobulin G/*metabolism ; Intercellular Adhesion Molecule-1/genetics/*metabolism ; Mice ; Proline/analogs &amp; derivatives/pharmacology ; RNA, Messenger/drug effects ; Reactive Oxygen Species/*metabolism ; Thiocarbamates/pharmacology ; Thiourea/analogs &amp; derivatives/pharmacology ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Chemokines and adhesion molecules play a pivotal role in leukocyte infiltration during tissue injury. RANTES (regulated upon activation, normal T cell expressed and secreted) is a monocyte chemoattractant that induces the expression of CD11/CD18 integrins on leukocytes for which intercellular adhesion molecule-1 (ICAM-1) is the ligand. Both RANTES and ICAM-1 can be expressed by mesangial cells (MC) in culture and in glomeruli during immune injury. In this study, the role of reactive oxygen species (ROS) in the activation of RANTES and ICAM-1 in murine MC was examined. Tumor necrosis factor alpha (TNF-alpha) and aggregated immunoglobulin (aggr. Ig) G, which enhance ROS formation in MC, increased mRNA transcripts of both RANTES and ICAM-1. Thiol-containing free-radical scavengers N-acetyl cysteine, dimethyl- and tetramethylthiourea, or pyrrolidinedithiocarbamate abrogated the increase in mRNA for RANTES and ICAM-1 in response to TNF-alpha or IgG. Hydroxy-methoxy acetophenone, an inhibitor of NADPH-dependent oxidase, also attenuated RANTES and ICAM-1 in response to TNF-alpha or IgG. ROS generated by addition of xanthine oxidase and hypoxanthine induced RANTES and ICAM-1 expression, whereas hydrogen peroxide caused no response. Because cAMP can interfere with gene activation in MC, the effects of 8-Br-cAMP, forskolin, and prostaglandin E2 on mRNA levels were examined for RANTES and ICAM-1. These agents attenuated the response to IgG aggregates and also to superoxide generation. Finally, the effect of glucocorticoids, which are frequently used in glomerular immune injury, was examined. Dexamethasone decreased mRNA for both RANTES and ICAM-1 after stimulation with aggr. IgG or TNF-alpha. Both forskolin and dexamethasone also reduced the amount of RANTES protein secreted by MC in response to aggr. IgG. Only dexamethasone decreased RANTES secretion in response to TNF-alpha stimulation. The inhibitory effects of cAMP and dexamethasone may explain the beneficial effects of cAMP mimetics, such as prostaglandin E2 and glucocorticoid administration on glomerular inflammatory processes.}, }
@article {pmid9154446, year = {1997}, author = {Lailey, AF}, title = {Oral N-acetylcysteine protects against perfluoroisobutene toxicity in rats.}, journal = {Human &amp; experimental toxicology}, volume = {16}, number = {4}, pages = {212-216}, doi = {10.1177/096032719701600410}, pmid = {9154446}, issn = {0960-3271}, mesh = {Acetylcysteine/blood/*pharmacology ; Administration, Oral ; Animals ; Bronchoalveolar Lavage Fluid/chemistry ; Cysteine/analysis/blood/drug effects ; Female ; Fluorocarbons/*toxicity ; Glutathione/analysis/blood/drug effects ; Lung/chemistry/*drug effects/pathology ; Pulmonary Edema/chemically induced/drug therapy/*prevention &amp; control ; Rats ; Rats, Wistar ; }, abstract = {1. Perfluoroisobutene, a pyrolysis product of polyetrafluoroethene may cause pulmonary oedema and death when inhaled. Oral N-acetylcysteine has shown protection against inhalation of perfluoroisobutene and in this study we have tried to elucidate the mechanism by which protection is mediated. 2. Protection against the lethal effects of inhaled perfluoroisobutene has been shown when N-acetylcysteine has been orally administered 4, 6 or 8 h before gas exposure. 3. Plasma levels of cysteine, glutathione and N-acetylcysteine were increased for up to 7 h following oral administration of Nac. 4. N-acetylcysteine was not detected in the bronchioalveolar lavage fluid following oral administration. 5. Duration of protection in vivo has been related to the duration of increased thiol levels in the plasma.}, }
@article {pmid9152962, year = {1997}, author = {Allameh, A and Vansoun, EY and Zarghi, A}, title = {Role of glutathione conjugation in protection of weanling rat liver against acetaminophen-induced hepatotoxicity.}, journal = {Mechanisms of ageing and development}, volume = {95}, number = {1-2}, pages = {71-79}, doi = {10.1016/s0047-6374(97)01862-9}, pmid = {9152962}, issn = {0047-6374}, mesh = {Acetaminophen/*metabolism/pharmacokinetics/*toxicity ; Acetylcysteine/pharmacology ; Aging/metabolism ; Analgesics, Non-Narcotic/*metabolism/pharmacokinetics/*toxicity ; Animals ; Glutathione/*metabolism ; Inactivation, Metabolic ; Liver/*drug effects/*metabolism ; Male ; Rats ; }, abstract = {The rate of glutathione (GSH) conjugate formation to acetaminophen (APAP) in livers of weanling and adult rats treated with a single i.p. dose of APAP was compared. HPLC analysis of cytosolic fractions revealed that rate of conjugation in weanling rat is 24-times greater than that of adults. Increased rate of GSH conjugation was independent of of the age-related difference observed in liver GSH content. The normal level of liver GSH in weanling rat was 57% of adult level. APAP treatment depleted GSH more significantly in weanling rats as compared to that in adults. N-acetylcystein (NAC) alone had little influence on liver GSH levels. However it was successful in reducing GSH depletion in tissues of growing rats. A 32% repletion in hepatic GSH level in NAC-treated weanling rats was associated with a further 13-fold increase in the rate of GSH conjugate formation. These data together with histopathological results, clearly showed that the inducible GSH system in weanling rat liver act as a safe guard against APAP toxicity. A surge in the rate of APAP-GSH conjugation in growing liver may function in compensation of other detoxification pathways which are saturated more readily at this age.}, }
@article {pmid9149379, year = {1997}, author = {Morgan, DL and Mahler, JF and Wilson, RE and Moorman, MP and Price, HC and Patrick, KR and Richards, JH and O'Connor, RW}, title = {Effects of various pretreatments on the hepatotoxicity of inhaled styrene in the B6C3F1 mouse.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {27}, number = {4}, pages = {401-411}, doi = {10.1080/004982597240550}, pmid = {9149379}, issn = {0049-8254}, mesh = {Adipose Tissue/metabolism ; Administration, Inhalation ; Animals ; Body Weight/physiology ; Chemical and Drug Induced Liver Injury/enzymology/*pathology ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/metabolism ; Enzyme Induction/drug effects ; Epoxide Hydrolases/antagonists &amp; inhibitors/biosynthesis/metabolism ; Glutathione/metabolism ; Liver/metabolism ; Liver Function Tests ; Male ; Mice ; Mice, Inbred Strains ; Microsomes, Liver/enzymology ; Organ Size/physiology ; Styrenes/administration &amp; dosage/pharmacokinetics/*toxicity ; }, abstract = {1. The roles of cytochrome P450 monooxygenases (P450) and glutathione (GSH) in styrene hepatotoxicity were investigated in mice by pretreating with either phenobarbital (PB; P450 inducer), SKF 525A (P450 inhibitor), N-acetylcysteine (NAC; GSH precursor), or saline (vehicle control) prior to a 6-h exposure to either 500 ppm styrene on air. 2. Styrene caused hepatocellular degeneration or necrosis in all groups; these changes were more extensive and severe in mice pretreated with PB. Styrene significantly increased relative liver weights and serum ALT and SDH levels only in mice pretreated with PB. NAC did not prevent GSH depletion or hepatotoxicity. 3. In the fat of SKF 525A-pretreated mice a slight but statistically significant increase in styrene levels was observed, suggesting that metabolism was decreased; the SO/styrene ratio in the fat of PB-pretreated mice showed a slight, but statistically significant, increase indicating a slight increase in styrene metabolism. Neither SKF 525A nor PB caused changes in microsomal enzyme activity in vitro. 4. These results suggest that styrene may be activated by a pathway not totally dependent upon P450 enzyme activity, or more likely that PB and SKF 525A are not specific for the P450 enzymes involved in activation and detoxification of styrene.}, }
@article {pmid9142907, year = {1997}, author = {Salomons, H and Keaveny, AP and Henihan, R and Offner, G and Sengupta, A and Lamorte, WW and Afdhal, NH}, title = {Nitric oxide and gallbladder motility in prairie dogs.}, journal = {The American journal of physiology}, volume = {272}, number = {4 Pt 1}, pages = {G770-8}, doi = {10.1152/ajpgi.1997.272.4.G770}, pmid = {9142907}, issn = {0002-9513}, mesh = {Animals ; Bethanechol/pharmacology ; Blotting, Western ; Cholecystokinin/pharmacology ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Female ; Gallbladder/drug effects/*physiology ; Immunohistochemistry ; Methylene Blue/pharmacology ; Muscle Contraction/drug effects/*physiology ; Muscle Tonus/drug effects ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide/*physiology ; Nitric Oxide Synthase/metabolism ; Sciuridae ; }, abstract = {In this study we evaluated the role of nitric oxide (NO) on gallbladder motility in the normal prairie dog by 1) immunohistochemistry, 2) an enzymatic assay for NO synthase (NOS), and 3) an in vivo model to measure whole gallbladder tone and contractility. NOS was localized to gallbladder mucosal cells by NADPH-diaphorase and polyclonal antibodies to a constitutive brain NOS. Gallbladder mucosal homogenates demonstrated total NOS activity in the range of 578 +/- 115 pmol x mg protein(-1) x 30 min(-1). Blockade of NOS activity in vivo using N(omega)-nitro-L-arginine methyl ester resulted in an up to 80% increase in gallbladder tone from basal. A 40% increase in tone was seen with methylene blue, suggesting that tone was maintained by both NO activation of guanylate cyclase and possibly direct effects on Ca2+ channels. An exogenous nitrosothiol, S-nitroso-N-acetyl-cysteine, abolished cholecystokinin (CCK) octapeptide and bethanechol-stimulated gallbladder contraction. We conclude that the prairie dog gallbladder contains constitutive NOS and synthesizes NO, which is important for the maintenance of basal gallbladder tone and is an inhibitor of the contractile response of the gallbladder to agonists such as CCK and bethanechol.}, }
@article {pmid9105321, year = {1997}, author = {Murrell, KD and Slotved, HC and Eriksen, L and Bjerregaard, J and Nansen, P and Roepstorff, A}, title = {Improved method for the recovery of Ascarus suum larvae from pig intestinal mucosa.}, journal = {The Journal of parasitology}, volume = {83}, number = {2}, pages = {321-324}, pmid = {9105321}, issn = {0022-3395}, mesh = {Acetylcysteine/metabolism ; Animals ; Ascariasis/parasitology/*veterinary ; Ascaris suum/*isolation &amp; purification ; Cecum/parasitology ; Colon/parasitology ; Cysteine/metabolism ; Female ; Free Radical Scavengers/metabolism ; Intestinal Diseases, Parasitic/parasitology/*veterinary ; Intestinal Mucosa/metabolism/*parasitology ; Larva ; Oxidation-Reduction ; Pepsin A/metabolism ; Solubility ; Swine ; Swine Diseases/*parasitology ; }, abstract = {In the course of a comprehensive study on the population biology of Ascaris suum, it became necessary to determine quantitatively the migration of the larvae (L2) through the pig intestine. Because no satisfactory methods for recovering these larvae from the intestinal mucosa were apparently available in the literature, we undertook the development of such a procedure. Direct Baermannization of the intestine proved inadequate, so a series of studies was undertaken to find a method to solubilize the mucosa and free the larvae. Both pepsin digestion and mucus reduction with N-acetyl cysteine were evaluated. The highest recovery rates were obtained with short-term pepsin digestion (45-90 min), followed by a specific settling and washing procedure. A third alternative, migration of larvae out of agar-gel, was also tested. Although the recovery efficiency was low (10% of pepsin digestion), the larvae recovered were clean, with good motility. The agar-gel procedure could be useful when L2 larvae are needed for other purposes, such as antigen preparation or cultivation.}, }
@article {pmid9104848, year = {1997}, author = {Supinski, GS and Stofan, D and Ciufo, R and DiMarco, A}, title = {N-acetylcysteine administration alters the response to inspiratory loading in oxygen-supplemented rats.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {82}, number = {4}, pages = {1119-1125}, doi = {10.1152/jappl.1997.82.4.1119}, pmid = {9104848}, issn = {8750-7587}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Gas Analysis ; Blood Pressure/drug effects/physiology ; Electromyography ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Isometric Contraction/drug effects/physiology ; Muscle Contraction/drug effects/physiology ; Muscle, Skeletal/drug effects/metabolism ; Rats ; Respiratory Mechanics/drug effects/*physiology ; Survival Rate ; Tidal Volume/physiology ; }, abstract = {Based on recent studies, it has been suggested that free radicals are elaborated in the respiratory muscles during strenuous contractions and contribute to the development of muscle fatigue. If this theory is correct, then it should be possible to attenuate the development of diaphragm fatigue and/or delay the onset of respiratory failure during loaded breathing by administering a free radical scavenger. The purpose of the present experiment was, therefore, to examine the effect of N-acetylcysteine (NAC), a free radical scavenger and glutathione precursor, on the evolution of respiratory failure in decerebrate unanesthetized rats breathing against a large inspiratory resistive load. We compared the inspiratory volume and pressure generation over time in animals pretreated with either saline or NAC (150 mg/kg) and then loaded until respiratory arrest. After arrest, the diaphragm was excised, and samples were assayed for reduced (GSH) and oxidized glutathione. As a control, we also assessed respiratory function and glutathione concentrations in groups of nonloaded saline- and NAC-treated animals. We found that NAC-treated animals were able to tolerate loading better than the saline-treated group, maintaining higher inspiratory pressures and sustaining higher inspired volumes. Administration of NAC also increased the time that animals could tolerate loading before the development of respiratory arrest. In addition, although saline-treated loaded animals had significant reductions in diaphragmatic GSH levels compared with unloaded controls, the magnitude of this reduction was blunted by NAC administration (i.e., GSH averaged 965 +/- 113, 568 +/- 83, 907 +/- 39, and 784 +/- 61 nmol/g for unloaded-saline, loaded-saline, unloaded-NAC, and loaded-NAC groups, P < 0.05, with the value for the loaded-saline group lower than the values for the two unloaded groups; GSH for the loaded-NAC group was not different, however, from unloaded controls). These data demonstrate that administration of NAC, a free radical scavenger, slows the rate of development of respiratory failure during inspiratory resistive loading.}, }
@article {pmid9125224, year = {1997}, author = {Tanaka, C and Kamata, H and Takeshita, H and Yagisawa, H and Hirata, H}, title = {Redox regulation of lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) gene expression mediated by NF kappa B and AP-1 in human astrocytoma U373 cells.}, journal = {Biochemical and biophysical research communications}, volume = {232}, number = {2}, pages = {568-573}, doi = {10.1006/bbrc.1997.6264}, pmid = {9125224}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Astrocytoma/*genetics/metabolism ; Buthionine Sulfoximine/pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Interleukin-8/biosynthesis/*genetics ; Lipopolysaccharides/*pharmacology ; NF-kappa B/antagonists &amp; inhibitors/*pharmacology ; Oxidation-Reduction ; Transcription Factor AP-1/antagonists &amp; inhibitors/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {LPS-induced expression of the IL-8 gene was markedly enhanced by H2O2 or by deprivation of the cellular antioxidant glutathione by L-buthionine-(S,R)-sulfoximine (BSO) in human astrocytoma U373 cells. In contrast, it was markedly suppressed by the reductant N-acetyl-L-cysteine (NAC) and other antioxidants. Transient expression analysis using the chloramphenicol acetyltransferase assay revealed that activation of the IL-8 promoter by LPS was stimulated by BSO and was suppressed by NAC; likewise LPS-induced activation of both NF kappa B and AP-1 was enhanced by BSO and inhibited by NAC. These results suggest that LPS-induced IL-8 gene expression is regulated by cellular redox via modulation of these transcription factors.}, }
@article {pmid9138685, year = {1997}, author = {Huwiler, A and van Rossum, G and Wartmann, M and Pfeilschifter, J}, title = {Stimulation by extracellular ATP and UTP of the stress-activated protein kinase cascade in rat renal mesangial cells.}, journal = {British journal of pharmacology}, volume = {120}, number = {5}, pages = {807-812}, doi = {10.1038/sj.bjp.0700979}, pmid = {9138685}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/*pharmacology ; Amino Acid Sequence ; Animals ; Calcium-Calmodulin-Dependent Protein Kinases/antagonists &amp; inhibitors/chemistry/*metabolism ; Cells, Cultured ; Enzyme Activation ; Genistein ; Glomerular Mesangium/cytology/*drug effects/enzymology ; Isoflavones/pharmacology ; JNK Mitogen-Activated Protein Kinases ; *Mitogen-Activated Protein Kinases ; Molecular Sequence Data ; Pertussis Toxin ; Protein Kinase C/metabolism ; Rats ; Uridine Triphosphate/*pharmacology ; Virulence Factors, Bordetella/pharmacology ; p38 Mitogen-Activated Protein Kinases ; }, abstract = {1. Extracellular adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) have been shown to activate a nucleotide receptor (P2U receptor) in rat mesangial cells that mediates phosphoinositide and phosphatidylcholine hydrolysis by phospholipases C and D, respectively. This is followed by an increased activity of the mitogen-activated protein kinase cascade and cell proliferation. Here we show that ATP and UTP potently stimulate the stress-activated protein kinase pathway and phosphorylation of the transcription factor c-Jun. 2. Both nucleotides stimulated a rapid (within 5 min) and concentration-dependent activation of stress-activated protein kinases as measured by the phosphorylation of c-Jun in a solid phase kinase assay. 3. When added at 100 microM the rank order of potency of a series of nucleotide analogues for stimulation of c-Jun phosphorylation was UTP > ATP = UDP = ATP gamma S > 2-methylthio-ATP > beta gamma-imido-ATP = ADP > AMP = UMP = adenosine = uridine. Activation of stress-activated protein kinase activity by ATP and UTP was dose-dependently attenuated by suramin. 4. Down-regulation of protein kinase C-alpha, -delta and -epsilon isoenzymes by 24 h treatment of the cells with 12-O-tetradecanoylphorbol 13-acetate did not inhibit ATP- and UTP-induced activation of c-Jun phosphorylation. Furthermore, the specific protein kinase C inhibitors, CGP 41251 and Ro 31-8220, did not inhibit nucleotide-stimulated c-Jun phosphorylation, suggesting that protein kinase C is not involved in ATP- and UTP-triggered stress-activated protein kinase activation. 5. Pretreatment of the cells with pertussis toxin or the tyrosine kinase inhibitor, genistein, strongly attenuated ATP- and UTP-induced c-Jun phosphorylation. Furthermore, N-acetyl-cysteine completely blocked the activation of stress-activated protein kinase in response to extracellular nucleotide stimulation. 6. In summary, these results suggest that ATP and UTP trigger the activation of the stress-activated protein kinase module in mesangial cells by a pathway independent of protein kinase C but requiring a pertussis toxin-sensitive G-protein and tyrosine kinase activation.}, }
@article {pmid9135855, year = {1997}, author = {Gillissen, A and Jaworska, M and Orth, M and Coffiner, M and Maes, P and App, EM and Cantin, AM and Schultze-Werninghaus, G}, title = {Nacystelyn, a novel lysine salt of N-acetylcysteine, to augment cellular antioxidant defence in vitro.}, journal = {Respiratory medicine}, volume = {91}, number = {3}, pages = {159-168}, doi = {10.1016/s0954-6111(97)90052-4}, pmid = {9135855}, issn = {0954-6111}, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemistry/*pharmacology ; *Antioxidants ; Cell-Free System ; Cells, Cultured ; Depression, Chemical ; *Free Radical Scavengers ; Glutathione/biosynthesis ; Humans ; Hydrogen Peroxide/metabolism ; Hydrogen-Ion Concentration ; Lysine/*analogs &amp; derivatives/chemistry/pharmacology ; Neutrophils/drug effects/metabolism ; Reactive Oxygen Species/metabolism ; }, abstract = {Nacystelyn (NAL), a recently-developed lysine salt of N-acetylcysteine (NAC), and NAG, both known to have excellent mucolytic capabilities, were tested for their ability to enhance cellular antioxidant defence mechanisms. To accomplish this, both drugs were tested in vitro for their capacity: (1) to inhibit O2- and H2O2 in cell-free assay systems; (2) to reduce O2- and H2O2 released by polymorphonuclear leukocytes (PMN); and (3) for their cellular glutathione (GSH) precursor effect. In comparison with GSH, NAL and NAC inhibited H2O2, but not O2-, in cell-free, in vitro test systems in a similar manner. The anti-H2O2 effect of these drugs was as potent as that of GSH, an important antioxidant in mammalian cells. To enhance cellular GSH levels, increasing concentrations (0-2 x 10(-4) mol l-1) of both substances were added to a transformed alveolar cell line (A549 cells). After NAC administration (2 x 10(-4) mol l-1), total intracellular GSH (GSH + 2GSSG) levels reached 4.5 +/- 1.1 x 10(-6) mol per 10(6) cells, whereas NAL increased GSH to 8.3 +/- 1.6 x 10(-6) mol per 10(6) cells. NAC and NAL administration also induced extracellular GSH secretion; about two-fold (NAC), and 1.5-fold (NAL), respectively. The GSH precursor potency of cystine was about two-fold higher than that of NAL and NAC, indicating that the deacetylation process of NAL and NAC slows the ability of both drugs to induce cellular glut production and secretion. Buthionine-sulphoximine, which is an inhibitor of GSH synthetase, blocked the cellular GSH precursor effect of all substances. In addition, these data demonstrate that NAC and NAL reduce H2O2 released by freshly-isolated cultured blood PMN from smokers with chronic obstructive pulmonary disease (COPD) (n = 10) in a similar manner (about 45% reduction of H2O2 activity by NAC or NAL at 4 x 10(-6) mol l-1). In accordance with the results obtained from cell-free, in vitro assays, O2- released by PMN was not affected. Ambroxol (concentrations: 10(-9)-10(-3) mol l-1) did not reduce activity levels of H2O2 and O2- in vitro. Due to the basic effect of dissolved lysine, which separates easily in solution from NAL, the acidic function of the remaining NAC molecule is almost completely neutralized [at concentration 2 x 10(-4) M: pH 3.6 (NAC), pH 6.4 (NAL)]. Due to their function as H2O2 scavengers, and due to their ability to enhance cellular glutathione levels, NAL and NAC both have potent antioxidant capabilities in vitro. The advantage of NAL over NAC is two-fold; it enhances intracellular GSH levels twice as effectively, and it forms neutral pH solutions whereas NAC is acidic. Concluding from these in vitro results, NAL could be an interesting alternative to enhance the antioxidant capacity at the epithelial surface of the lung by aerosol administration.}, }
@article {pmid9087670, year = {1997}, author = {DiMari, J and Megyesi, J and Udvarhelyi, N and Price, P and Davis, R and Safirstein, R}, title = {N-acetyl cysteine ameliorates ischemic renal failure.}, journal = {The American journal of physiology}, volume = {272}, number = {3 Pt 2}, pages = {F292-8}, doi = {10.1152/ajprenal.1997.272.3.F292}, pmid = {9087670}, issn = {0002-9513}, support = {R01-CA-65861/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Genes, fos/drug effects ; Genes, jun/drug effects ; Ischemia/pathology/*physiopathology ; JNK Mitogen-Activated Protein Kinases ; Kidney/*blood supply/drug effects/pathology ; Kidney Tubules, Proximal/drug effects/pathology ; Male ; *Mitogen-Activated Protein Kinases ; Necrosis ; Proto-Oncogene Proteins c-fos/biosynthesis ; Proto-Oncogene Proteins c-jun/biosynthesis ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Renal Insufficiency/*drug therapy/pathology/*physiopathology ; Reperfusion ; Transcription, Genetic/drug effects ; }, abstract = {Recovery from ischemic renal injury is accompanied by enhanced DNA synthesis and a typical immediate early (IE) gene response. These two processes occur in distinct cell populations, suggesting that the IE gene response does not serve a proliferative function directly. As cellular stress induces an IE response through activation of the stress-activated protein kinases (SAPK) that is not proliferative and can be inhibited by N-acetyl-L-cysteine (NAC), we determined whether the Jun NH2-terminal kinases (JNK), members of the SAPKs, are activated during ischemia and whether NAC administration reduces the IE response and/or the induction of JNK activity. NAC (6 mM/kg body wt) infused 1 h prior to and 1 h following renal ischemia reduced c-fos and c-jun expression by 50 and 70%, respectively. Ischemia increased JNK activity, and this increase was inhibited by NAC. NAC infused animals had a higher glomerular filtration rate at 1 day (NAC, 0.9 +/- 0.2, vs. control, 0.05 +/- 0.01 ml/min, P < 0.001) and 7 days (NAC, 2.0 +/- 0.1, vs. control, 1.2 +/- 0.1, P < 0.001) after the induction of ischemia. NAC did not reduce the extent of proximal tubule necrosis at 24 h after reperfusion but improved histological appearance of the kidney at 7 days. The mechanism by which NAC ameliorates the loss of renal function is unknown but may involve its general properties as an antioxidant or a possible interaction with NAC and NO. We conclude that the IE gene response of the kidney to ischemia reperfusion is a consequence of the stress-activated kinase pathway and that part of the response is deleterious to kidney function and cellular integrity.}, }
@article {pmid9070319, year = {1997}, author = {Yanagihara, Y and Basaki, Y and Ikizawa, K and Kajiwara, K}, title = {Possible role of nuclear factor-kappa B activity in germline C epsilon transcription in a human Burkitt lymphoma B cell line.}, journal = {Cellular immunology}, volume = {176}, number = {1}, pages = {66-74}, doi = {10.1006/cimm.1996.1071}, pmid = {9070319}, issn = {0008-8749}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; B-Lymphocytes/drug effects/immunology/*metabolism ; Burkitt Lymphoma ; CD40 Antigens/immunology ; Cell Nucleus/metabolism ; Enzyme Activation ; Gene Expression Regulation ; Humans ; Immunoglobulin Constant Regions/*genetics ; Interleukin-4/immunology ; Isoenzymes/metabolism ; NF-kappa B/*physiology ; Phosphatidylinositol 3-Kinases ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Protein Kinase C/metabolism ; *Transcription, Genetic ; Tumor Cells, Cultured ; }, abstract = {Nuclear factor-kappa B (NF-kappa B) plays a broad role in gene regulation, but it is not evident whether NF-kappa B acts as a messenger system for germline C epsilon transcription. We report here that the signaling cascade triggered by interleukin-4 (IL-4) or anti-CD40 monoclonal antibody (mAb) participates in NF-kappa B activation responsible for germline C epsilon transcription in a human Burkitt lymphoma B cell line, DND39. Both IL-4 and anti-CD40 mAb induced activation of phosphatidylinositol 3-kinase (PI3-kinase), translocation of a zeta isoform of protein kinase C, and nuclear expression of NF-kappa B. All such events were abrogated by treatment with LY294002, a specific inhibitor of PI3-kinase. In addition, N-acetyl-L-cysteine (NAC), a potent antioxidant, decreased NF-kappa B activation caused by IL-4, anti-CD40 mAb, or their combination. NAC was also effective in diminishing germline C epsilon transcription, and its potency was higher in cultures costimulated with IL-4 and anti-CD40 mAb than in those stimulated with IL-4 alone. These results indicate that IL-4 and ligation of CD40 induce NF-kappa B expression via at least a mechanism dependent on the PI3-kinase pathway and suggest that NF-kappa B sensitive to NAC may play a role in regulating germline C epsilon transcription.}, }
@article {pmid9057130, year = {1997}, author = {Ceruti, S and Barbieri, D and Veronese, E and Cattabeni, F and Cossarizza, A and Giammarioli, AM and Malorni, W and Franceschi, C and Abbracchio, MP}, title = {Different pathways of apoptosis revealed by 2-chloro-adenosine and deoxy-D-ribose in mammalian astroglial cells.}, journal = {Journal of neuroscience research}, volume = {47}, number = {4}, pages = {372-383}, doi = {10.1002/(sici)1097-4547(19970215)47:4&lt;372::aid-jnr2&gt;3.0.co;2-b}, pmid = {9057130}, issn = {0360-4012}, mesh = {2-Chloroadenosine/*pharmacology ; Animals ; Apoptosis/drug effects/*physiology ; Astrocytes/*drug effects/ultrastructure ; Cells, Cultured ; DNA/metabolism ; Deoxyribose/*pharmacology ; Flow Cytometry ; Immunohistochemistry ; Membrane Potentials/physiology ; Microscopy, Electron, Scanning ; Mitochondria/drug effects/physiology ; Oxidative Stress/physiology ; Poly Adenosine Diphosphate Ribose/physiology ; Rats ; }, abstract = {Both the adenosine analogue 2-chloro-adenosine (2-CA) and the reducing sugar deoxy-D-ribose (dRib) induce apoptosis of astroglial cells in rat brain primary cultures (Abbracchio et al.: Biochem Biophys Res Commun 213:908-915, 1995). The present study was undertaken to elucidate by both morphological and cytofluorimetric analyses the intracellular mechanism(s) involved in induction of apoptosis by these two agents. The poly(ADP-ribose)polymerase (PARP) inhibitor 3-aminobenzamide did not prevent either 2-CA- or dRib-induced cell death, suggesting that activation of PARP is not critically important for induction of apoptosis in astrocytes. The radical scavenger N-acetyl-cysteine (NAC) strongly inhibited dRib- but not 2-CA-induced cell death, suggesting a differential role for radical formation in apoptosis by these two agents. A time-dependent increase of cells with depolarized mitochondria was observed in dRib-, and to a lesser extent, in 2-CA-treated cultures. NAC also prevented dRib- but not 2-CA-induced mitochondrial changes. We conclude that, in mammalian astrocytes, apoptosis can proceed through diverse and multiple pathways, depending upon the apoptotic stimulus. For dRib, apoptosis likely proceeds through generation of radicals and mitochondrial involvement. An adenosine extracellular receptor linked to an as yet unidentified signaling pathway may instead mediate 2-CA-induced cell death, which may have intriguing implications for both nervous system development and brain response to trauma and ischemia.}, }
@article {pmid9039941, year = {1997}, author = {Muraoka, K and Shimizu, K and Sun, X and Zhang, YK and Tani, T and Hashimoto, T and Yagi, M and Miyazaki, I and Yamamoto, K}, title = {Hypoxia, but not reoxygenation, induces interleukin 6 gene expression through NF-kappa B activation.}, journal = {Transplantation}, volume = {63}, number = {3}, pages = {466-470}, doi = {10.1097/00007890-199702150-00023}, pmid = {9039941}, issn = {0041-1337}, mesh = {Animals ; Gene Expression Regulation/*immunology ; Hypoxia/etiology/genetics/*metabolism ; Interleukin-6/*genetics ; L Cells ; Mice ; NF-kappa B/*metabolism ; Oxygen/*metabolism ; Reactive Oxygen Species/physiology ; Reperfusion Injury/genetics/*immunology/*metabolism ; Transcription, Genetic/*immunology ; Transcriptional Activation ; }, abstract = {Interleukin (IL) 6 is one of major mediators of inflammation, and IL-6 gene activation during hypoxia/reoxygenation has been implicated in the pathogenesis of ischemia/reperfusion injury. However, molecular events involved in IL-6 gene expression during hypoxia/reoxygenation remain to be identified. We have previously shown that NF-kappa B plays an essential and indispensable role in the transcriptional activation of the IL-6 gene induced by various stimuli, including IL-1 and tumor necrosis factor-alpha. We show here that hypoxia, but not reoxygenation, induces the activation of NF-kappa B through the degradation of a major inhibitor of NF-kappa B, I kappa B alpha. This hypoxia-induced NF-kappa B activation resulted in the kappa B-dependent transcriptional activation of the IL-6 gene. Interestingly, the time course of hypoxia-induced NF-kappa B activation was rather slow as compared with those of NF-kappa B activation induced by other stimuli, such as IL-1: a significant NF-kappa B activation was not observed before 1 hr of hypoxia treatment and persisted for up to 7 hr of hypoxia treatment. However, hypoxia-induced NF-kappa B activation was not inhibited by cycloheximide, which indicates that hypoxia directly triggers NF-kappa B activation. Furthermore, while hypoxia is unlikely to generate reactive oxygen intermediates, pretreatment of cells with antioxidants such as N-acetyl cysteine and alpha-tocopherol inhibited NF-kappa B activation induced by hypoxia. Thus, we discuss possible implications of these results for a postulated role of reactive oxygen intermediates in NF-kappa B activation.}, }
@article {pmid9115810, year = {1997}, author = {Harakeh, S and Jariwalla, RJ}, title = {NF-kappa B-independent suppression of HIV expression by ascorbic acid.}, journal = {AIDS research and human retroviruses}, volume = {13}, number = {3}, pages = {235-239}, doi = {10.1089/aid.1997.13.235}, pmid = {9115810}, issn = {0889-2229}, mesh = {Acetylcysteine/pharmacology ; Ascorbic Acid/*pharmacology ; Cell Line ; HIV/*drug effects/physiology ; Humans ; Hydrogen Peroxide/pharmacology ; NF-kappa B/*metabolism ; T-Lymphocytes/virology ; Tetradecanoylphorbol Acetate/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; Virus Latency ; Virus Replication/*drug effects ; }, abstract = {Ascorbic acid (ascorbate or vitamin C) has been shown to suppress the induction of HIV in latently infected T lymphocytic cells following stimulation with a tumor promoter (PMA) and inflammatory cytokine (TNF-alpha). To assess whether this inhibition was mediated via modulation of the cellular transcription factor, NF-kappa B, we carried out gel shift analysis on nuclear extracts prepared under different conditions of cell stimulation in the presence or absence of ascorbate, N-acetylcysteine (NAC), or zidovudine (AZT). Pretreatment of ACH-2 T cells by NAC followed by stimulation with PMA, TNF-alpha, or hydrogen peroxide (H2O2) resulted in strong suppression of NF-kappa B activation. In contrast, neither ascorbate nor AZT affected NF-kappa B activity under all three induction conditions in the ACH-2 cell line. Ascorbate and AZT also had no effect on NF-kappa B activation following TNF-alpha- or PMA-induced stimulation of U1 promonocytic cells. These results suggest that the molecular mechanism of HIV inhibition by ascorbate is not mediated via NF-kappa B inhibition, unlike that seen with other antioxidants.}, }
@article {pmid9051121, year = {1997}, author = {Hissink, AM and Dunnewijk, R and van Ommen, B and van Bladeren, PJ}, title = {Kinetics and metabolism of 1,4-dichlorobenzene in male Wistar rats: no evidence for quinone metabolites.}, journal = {Chemico-biological interactions}, volume = {103}, number = {1}, pages = {17-33}, doi = {10.1016/s0009-2797(96)03746-5}, pmid = {9051121}, issn = {0009-2797}, mesh = {Administration, Oral ; Animals ; Area Under Curve ; Benzoquinones/*metabolism ; Bile/chemistry ; Biotransformation ; Carcinogens/*pharmacokinetics ; Chlorobenzenes/blood/*pharmacokinetics ; Cytochrome P-450 CYP2E1/analysis/biosynthesis ; Enzyme Induction ; Male ; Rats ; Rats, Wistar ; }, abstract = {The biotransformation and kinetics of 1,4-dichlorobenzene (1,4-DCB) were studied in male Wistar rats at three oral dose levels (10, 50 and 250 mg/kg). The effect of induction of CYP2E1 by isoniazid on the kinetics and biotransformation was determined. Excretion was predominantly via the urine (78-85%) and to a small extent via the faeces (2-5%). The relative contributions of these routes were not dose dependent. Excretion via the bile ranged from less than 5% at the low dose level to 30% at the high dose level. The major biliary metabolite was the glucuronide of 2,5-dichlorophenol (2,5-DCP). The time point at which the plasma concentrations of the parent compound and the metabolites were maximal (TCmax) as well as the maximum concentrations (Cmax) increased with higher dose level. Induction by isoniazid resulted in a faster urinary elimination, whereas TCmax and Cmax were lower for induced rats. In addition, the area under the blood curve (AUC) was smaller and total clearance was higher for induced rats. 1,4-DCB was mainly metabolized to 2,5-DCP (ca. 90%), which was detected in the urine as its sulfate (50-60%), glucuronide (20-30%) and the free form (5-10%). Minor metabolites were the N-acetyl-cysteine-S-dihydro-hydroxy-1,4-dichlorobenzene and the corresponding dehydrated N-acetyl-cysteine-S-1,4-dichlorobenzene, which comprised ca. 10% of total metabolites. No hydroquinones were observed for the male Wistar rat, not even under conditions of induced oxidative metabolism.}, }
@article {pmid9020524, year = {1997}, author = {Omara, FO and Blakley, BR and Bernier, J and Fournier, M}, title = {Immunomodulatory and protective effects of N-acetylcysteine in mitogen-activated murine splenocytes in vitro.}, journal = {Toxicology}, volume = {116}, number = {1-3}, pages = {219-226}, doi = {10.1016/s0300-483x(96)03520-2}, pmid = {9020524}, issn = {0300-483X}, mesh = {Acetylcysteine/*pharmacology ; Adjuvants, Immunologic/*pharmacology ; Animals ; Cell Death/drug effects ; Cells, Cultured ; Female ; Lymphocyte Activation/*drug effects ; Lymphocytes/cytology/*drug effects ; Mice ; Mice, Inbred C57BL ; Mitogens/*toxicity ; Spleen/cytology/drug effects ; }, abstract = {N-Acetylcysteine (NAC) is a pro-glutathione drug used to treat chronic lung disorders and because of its anti-AIDS virus activity in vitro, has been proposed for AIDS therapy. The effect of NAC on mitogen-activated-lymphocyte blastogenesis in C57B1/6 mouse splenocytes and ability of NAC to protect lymphocytes against mitogen-induced cytotoxicity was examined in vitro. NAC increased splenocyte proliferation in the presence of optimal and suboptimal concentrations of concanavalin A (Con A) and lipopolysaccharide (LPS). Stimulatory and costimulatory effects of NAC on mitogen-induced responses were also evident. The dose-response relationship describing the effects of NAC on lymphocyte proliferation with Con A-induced responses were enhanced in a dose-dependent manner, whereas the corresponding LPS-induced responses increased to a maximum level followed by decline in responses at higher concentrations of NAC. When splenocytes were incubated with inhibitory supraoptimal concentrations of Con A (10 microg/ml) or LPS (150 microg/ml), NAC partially enhanced the Con A-induced response but completely prevented the inhibitory effect of supraoptimal concentrations of LPS on splenocyte blastogenesis. Optimal and supraoptimal concentrations of Con A caused activation-induced cell death in the splenocytes whereas comparable concentrations of LPS did not produce a similar effect. Splenocyte cell death produced by the optimal mitogenic concentrations of Con A was completely blocked by the addition of NAC to cultures. Immunomodulation and protective effects of NAC were observed in mitogen-activated lymphocytes in vitro.}, }
@article {pmid9588818, year = {1997}, author = {Anning, PB and Grocott-Mason, RM and Lewis, MJ}, title = {Effects of sulphydryl- and non-sulphydryl-containing ACE inhibitors on left ventricular relaxation in the isolated guinea pig heart.}, journal = {Endothelium : journal of endothelial cell research}, volume = {5}, number = {4}, pages = {265-275}, doi = {10.3109/10623329709052591}, pmid = {9588818}, issn = {1062-3329}, mesh = {Acetylcysteine/pharmacology ; Angiotensin-Converting Enzyme Inhibitors/chemistry/classification/*pharmacology ; Animals ; Bradykinin/analogs &amp; derivatives/pharmacology/physiology ; Bradykinin Receptor Antagonists ; Captopril/*analogs &amp; derivatives/chemistry/*pharmacology ; Diastole/drug effects ; Female ; Free Radical Scavengers/pharmacology ; Guinea Pigs ; Heart Ventricles/*drug effects ; Hemoglobins/pharmacology ; Isoquinolines/chemistry/*pharmacology ; Lisinopril/chemistry/*pharmacology ; Male ; Muscle Relaxation/drug effects ; Nitric Oxide/physiology ; Receptor, Bradykinin B2 ; Simethicone/pharmacology ; Stroke Volume/*drug effects ; Sulfhydryl Compounds/*pharmacology ; Superoxide Dismutase/pharmacology ; Systole/drug effects ; *Tetrahydroisoquinolines ; Ventricular Dysfunction, Left/drug therapy/physiopathology ; }, abstract = {ACE inhibitors exert both acute and chronic beneficial effects on cardiac function (e.g remodelling, diastolic dysfunction). We have previously reported that the ACE inhibitor captopril induces selective left ventricular (LV) relaxant effects in the isolated ejecting guinea pig heart. The aim of the present study was to further investigate the mechanism of the captopril-induced changes in early LV relaxation by comparing the effects of two sulphydryl and two non-sulphydryl containing ACE inhibitors in the same experimental preparation. Isolated ejecting guinea pig hearts were studied under conditions of constant loading and heart rate. LV pressure was monitored by a 2F micromanometer-tipped catheter transducer inserted in the LV cavity. The sulphydryl-containing ACE inhibitors captopril and zofenaprilat enhanced early LV relaxation, whereas the non-sulphydryl-containing ACE inhibitors lisinopril and quinaprilat did not. The effects of captopril and zofenaprilat were attenuated both by the nitric oxide-scavenger haemoglobin and the bradykinin B2-kinin receptor antagonist HOE 140. Neither the oxygen free-radical scavenger superoxide dismutase nor the sulphydryl-containing compound N-acetyl cysteine administered together with lisinopril had any effect on LV relaxation. These data demonstrate that inhibition of intra-cardiac ACE activity may acutely modulate LV relaxation through increased activity of the bradykinin-nitric oxide pathway. The presence of a sulphydryl group on the relevant ACE inhibitor appears to be essential for this LV relaxant effect.}, }
@article {pmid9588817, year = {1997}, author = {Nagy, J and Demaster, EG and Wittmann, I and Shultz, P and Raij, L}, title = {Induction of endothelial cell injury by cigarette smoke.}, journal = {Endothelium : journal of endothelial cell research}, volume = {5}, number = {4}, pages = {251-263}, doi = {10.3109/10623329709052590}, pmid = {9588817}, issn = {1062-3329}, mesh = {Animals ; Antioxidants/pharmacology ; Aorta ; Bradykinin/pharmacology ; Calcimycin/pharmacology ; Calcium/physiology ; Cell Adhesion/drug effects ; Cells, Cultured ; Cyclic GMP/metabolism ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*drug effects/metabolism/pathology ; Formaldehyde/analysis ; Free Radicals ; Gases ; Glutathione/metabolism ; Guanylate Cyclase/metabolism ; Ionophores/pharmacology ; Nitric Oxide/metabolism ; Nitroprusside/pharmacology ; *Plants, Toxic ; Smoke/*adverse effects/analysis ; Sulfhydryl Compounds/pharmacology ; Swine ; Nicotiana/*adverse effects ; }, abstract = {Cigarette smoke contains different populations of free radicals which may be responsible for endothelial cell (EC) injury of smokers. The purpose of this study was to examine the effects of gas-phase cigarette smoke on EC endothelium-derived relaxing factor (EDRF)/NO-guanylate cyclase (GC)-cGMP pathway and on EC detachment-type injury after incubation with smoke. Furthermore, we examined whether different kind of antioxidants can prevent smoke-caused EC injury. We measured cGMP pathway using direct (sodium nitroprusside, SNP) and indirect (A23187, the calcium ionophore and bradykinin, BK) activators of GC. Directly and indirectly stimulated EC cGMP production dose-dependently decreased and EC detachment increased after incubation with smoke. Externally added thiols (glutathione, GSH; D-Penicillamine, DP; N-acetylcysteine, NAC) protected EC from damage of cGMP production and cell detachment. Other antioxidants (catalase, deferoxamine and superoxide dismutase) were ineffective. These results suggest that the thiol containing GC in EC is destroyed or inactivated or thiol like species responsible for activation of GC is incomplete in EC after incubation with smoke. It is also possible that externally added thiols bind an unknown component of smoke and this way, EC is protected. EC injury may contribute to vascular diseases associated with cigarette smoking.}, }
@article {pmid9561100, year = {1997}, author = {Goldman, R and Moshonov, S and Chen, X and Berchansky, A and Fürstenberger, G and Zor, U}, title = {Crosstalk between elevation of [Ca2+]i, reactive oxygen species generation and phospholipase A2 stimulation in a human keratinocyte cell line.}, journal = {Advances in experimental medicine and biology}, volume = {433}, number = {}, pages = {41-45}, doi = {10.1007/978-1-4899-1810-9_7}, pmid = {9561100}, issn = {0065-2598}, mesh = {Arachidonic Acids/*metabolism ; Calcimycin/pharmacology ; Calcium/*metabolism ; Cell Line ; Enzyme Activation ; Epidermal Growth Factor/pharmacology ; Humans ; Keratinocytes/drug effects/*metabolism ; Kinetics ; Phospholipases A/*metabolism ; Phospholipases A2 ; Reactive Oxygen Species/*physiology ; Signal Transduction ; Thapsigargin/pharmacology ; }, abstract = {The aim of the study was to explore the possible interrelationship between reactive oxygen species (ROS) formation and cPLA2 activation and the mediator role that [Ca2+]i may play in these processes in the human keratinocyte cell line, HaCaT. HaCaT cells can be invoked to transiently produce ROS by epidermal growth factor (EGF), thapsigargin (TPG) and the Ca(2+)-ionophore, A23187. These 3 agonists transiently increase [Ca2+]i with characteristic kinetics and magnitude. TPG and A23187 each activates on its own [3H]AA release from prelabeled cells, whereas EGF on its own has no effect on [3H]AA release. However, EGF augments [3H]AA release invoked by TPG or A23187 several fold. EGF activates MAP kinase cascades in HaCaT cells, leads to ROS formation and induces relatively small (1.6 fold) elevation in [Ca2+]i, whereas A23187 and TPG lead to a substantial elevation in [Ca2+]i (2.5 to 5 fold) and to ROS formation. Both have a minor effect on MAP kinase activation. The synergism in PLA2 activation by EGF and TPG or A23187, and the sensitivity of [3H]AA release to N-acetylcysteine (NAC) and dithiothreitol (DTT) (potent reducing agents) or to DPI (an inhibitor of FAD-dependent oxidases) lead to the suggestion that ROS formation, elevation of [Ca2+]i and PLA2 activation are causally related. Since we show that elevation of [Ca2+]i is a prerequisite for both ROS and PLA2 activation, it is possible that these processes contribute to the toxicity (apoptosis) exerted by chronic elevation of [Ca2+]i.}, }
@article {pmid9452788, year = {1997}, author = {Urban, T and Akerlund, B and Jarstrand, C and Lindeke, B}, title = {Neutrophil function and glutathione-peroxidase (GSH-px) activity in healthy individuals after treatment with N-acetyl-L-cysteine.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {51}, number = {9}, pages = {388-390}, doi = {10.1016/s0753-3322(97)89431-0}, pmid = {9452788}, issn = {0753-3322}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Analysis of Variance ; Free Radical Scavengers/administration &amp; dosage/*pharmacology ; Glutathione Peroxidase/*metabolism ; Healthy Worker Effect ; Humans ; Middle Aged ; Neutrophils/*physiology ; Phagocytosis/drug effects ; Volunteers ; }, abstract = {The objective of this study was to evaluate the effect of N-acetyl-L-cysteine (NAC) on neutrophilic functions and as an antioxidant. NAC, 600 mg daily, given orally to healthy individuals for a period of 2 weeks, affected some functions of human neutrophilic granulocytes when tested in vitro. NAC treatment caused a decrease in the production of superoxide anions by stimulated neutrophils and the improvement of their phagocytic capacity although it did not affect their random or chemotactic migration. The level of glutathione peroxidase (GSH-px) in thrombocytes of the NAC-treated individuals was increased in comparison with the activity before treatment. These results suggest that NAC might act as a scavenger of oxygen-derived free radicals released by stimulated neutrophils and thereby protect the tissue against the radical caused injury as well as optimize phagocytosis.}, }
@article {pmid9269467, year = {1997}, author = {Aoki, T and Suzuki, Y and Nishio, K and Suzuki, K and Miyata, A and Oyamada, Y and Mori, M and Fujita, H and Yamaguchi, K}, title = {Effect of antioxidants on hyperoxia-induced ICAM-1 expression in human endothelial cells.}, journal = {Advances in experimental medicine and biology}, volume = {411}, number = {}, pages = {503-511}, doi = {10.1007/978-1-4615-5865-1_63}, pmid = {9269467}, issn = {0065-2598}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Biological Transport, Active ; Catalase/pharmacology ; Cells, Cultured ; Endothelium, Vascular/cytology/*drug effects/*metabolism ; Glutathione/analogs &amp; derivatives/metabolism ; Glutathione Disulfide ; Humans ; Hyperoxia/*metabolism ; Intercellular Adhesion Molecule-1/*metabolism ; Lung/metabolism ; Oxidation-Reduction ; Pneumonia/metabolism ; Pulmonary Artery/cytology/drug effects/metabolism ; Superoxide Dismutase/pharmacology ; Umbilical Veins/cytology/drug effects/metabolism ; Up-Regulation ; }, abstract = {The regulating mechanism of hyperoxia-induced ICAM-1 expression has not been elucidated. We studied the effect of antioxidants, including superoxide dismutase (SOD), catalase and N-acetylcysteine (NAC), on hyperoxia-induced ICAM-1 expression in human pulmonary artery endothelial cells (HPAEC) and human umbilical vein endothelial cells (HUVEC). Cells were cultured to confluence and exposed to either hyperoxic or normoxic gas with or without various kinds of antioxidants. The levels of ICAM-1 expression in the endothelial cells and the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the media were examined by flow cytometry and by spectrophotometry, respectively. After 48-hour exposure to hyperoxia, ICAM-1 expression was increased (HPAEC; 161 +/- 21% and HUVEC; 163 +/- 16%) and total glutathione concentration in the media was decreased as compared with normoxia. SOD did not change the GSH and GSSG concentrations in the media. Catalase dose-dependently decreased the supernatant GSSG concentration in both HPAEC and HUVEC, while the GSH concentration was nearly constant. NAC dose-dependently increased the supernatant GSH concentrations in both HPAEC and HUVEC. There was no difference in the supernatant GSSG concentrations between the NAC-treated HPAEC and HUVEC. There was no difference in ICAM-1 expression in either HPAEC or HUVEC with SOD treatment. ICAM-1 expressions in 100 U/ml (236 +/- 20%) and 1,000 U/ml (315 +/- 36%) of catalase were increased in HPAEC, and that in 1,000 U/ml (440 +/- 209%) of catalase was increased in HUVEC. Five and 10 U/ml of NAC decreased ICAM-1 expression in HPAEC (141 +/- 26% and 113 +/- 11%) and HUVEC (119 +/- 23% and 106 +/- 7%), respectively. These results suggest that extracellular glutathione may play a role in regulating hyperoxia-induced ICAM-1 expression in HPAEC and HUVEC.}, }
@article {pmid9230566, year = {1997}, author = {Casey, PB and Tracey, JA}, title = {N-acetylcysteine (NAC)--a safe antidote in paracetamol poisoning?.}, journal = {Irish medical journal}, volume = {90}, number = {1}, pages = {38}, pmid = {9230566}, issn = {0332-3102}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/adverse effects/*therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/adverse effects/*therapeutic use ; Drug Overdose/drug therapy ; Humans ; }, }
@article {pmid9195551, year = {1997}, author = {Gillissen, A and Bartling, A and Schoen, S and Schultze-Werninghaus, G}, title = {Antioxidant function of ambroxol in mononuclear and polymorphonuclear cells in vitro.}, journal = {Lung}, volume = {175}, number = {4}, pages = {235-242}, doi = {10.1007/pl00007570}, pmid = {9195551}, issn = {0341-2040}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Adult ; Ambroxol/*pharmacology ; Antioxidants/*pharmacology ; Catalase/pharmacology ; Expectorants/pharmacology ; Female ; Free Radical Scavengers/*pharmacology ; Glutathione/pharmacology ; Humans ; In Vitro Techniques ; Leukocytes, Mononuclear/*drug effects ; Lysine/analogs &amp; derivatives/pharmacology ; Male ; Neutrophils/*drug effects ; *Reactive Oxygen Species ; Superoxide Dismutase/pharmacology ; }, abstract = {This study quantifies the antioxidant function of ambroxol (2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine) in vitro. Polymorphonuclear cells (PMN) and mononuclear cells were isolated from the blood of healthy volunteers (n = 46) to determine reactive oxygen species (ROS) by luminol-enhanced chemiluminescence. Ambroxol or the controls N-acetylcysteine (NAC), nacystelyn (NAL), glutathione (GSH), superoxide dismutase (SOD), catalase, and the combination of SOD/catalase were incubated for 1 or 2 h with zymosan-activated cells in vitro using concentrations ranging from 10(-6) to 10(-3) mol/liter. Reduction of ROS-mediated luminescence was similar within the cell types. Ambroxol (10(-4) mol/liter) reduced ROS about 75% (1-h incubation) and 98% (2-h incubation), respectively (p < 0.001). SOD and SOD/catalase, but not the H2O2-catalyzing substances (NAC, NAL, GSH, and catalase), reduced cellular ROS. This indicates that inflammatory cells predominantly generate O2-, which can be scavenged by ambroxol. The antioxidant function of ambroxol with increasing incubation time suggests additional cellular antiinflammatory properties of this substance. Our results indicate that good antioxidant function of ambroxol is related mainly to direct scavenger function of reactive oxygen metabolites such as O2-. However, an antioxidative effect of ambroxol may also be associated with the reduction of prooxidative metabolism in inflammatory cells. Concluding from this observation, and because of the well known high affinity of ambroxol for lung tissue, ambroxol may be an alternative in antioxidant augmentation therapy, particularly in pulmonary diseases characterized by an overburden of toxic oxygen metabolites.}, }
@article {pmid9162285, year = {1997}, author = {Zabrodskiĭ, PF and Gryzunov, AV}, title = {[The effect of acetylcysteine and dipyroxime on the immune reactions in acute dichloroethane poisoning].}, journal = {Eksperimental'naia i klinicheskaia farmakologiia}, volume = {60}, number = {1}, pages = {47-49}, pmid = {9162285}, issn = {0869-2092}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Animals ; Antibody Formation/drug effects ; Antidotes/*therapeutic use ; Cholinesterase Reactivators/*therapeutic use ; Drug Evaluation, Preclinical ; Ethylene Dichlorides/*poisoning ; Immunity, Cellular/drug effects ; Immunity, Innate/drug effects ; Mice ; Mice, Inbred CBA ; Poisoning/drug therapy/immunology ; Rats ; Trimedoxime/*therapeutic use ; }, abstract = {It was established in experiments on CBA mice and outbred rats that acute dichloroethane (0.75 LD50) intoxication leads to decrease of antiinfectious immunological and nonspecific resistance of the organism, antibody production, and cell immune response evaluated according to the delayed-type hypersensitivity (DTH) reaction. Administration of the antidote acetyl-cysteine increased suppression of the reactions under study (with the exception of DTH), while dipiroxim weakened it. The dipiroxim effects are associated with reactivation of immunocyte alpha-naphthyl-AS-acetatesterase by this compound (and possibly also of other types of esterases of immunocompetent cells).}, }
@article {pmid9110073, year = {1997}, author = {Chen, P and Bauer, G and Mitchell, J and Factor, R and Markham, R and Schwartz, DH}, title = {N-acetyl-cysteine and L-2-oxothiazolidine-4-carboxylic acid enhance contact-dependent growth of HIV in resting peripheral blood mononuclear cells (PBMC) in vitro and increase recovery of HIV from human-PBMC SCID mice.}, journal = {AIDS (London, England)}, volume = {11}, number = {1}, pages = {33-41}, doi = {10.1097/00002030-199701000-00006}, pmid = {9110073}, issn = {0269-9370}, support = {DA09717/DA/NIDA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anti-HIV Agents/*pharmacology ; CD2 Antigens/analysis ; Cell Division ; Cells, Cultured ; Coculture Techniques ; Down-Regulation ; Female ; HIV-1/*physiology ; Humans ; Intercellular Adhesion Molecule-1/analysis ; Leukocytes, Mononuclear/*virology ; Male ; Mice ; Mice, SCID ; Monocytes/cytology/virology ; Peritoneal Cavity/cytology/virology ; Pyrrolidonecarboxylic Acid ; Thiazoles/*pharmacology ; Thiazolidines ; Virus Replication/*drug effects ; Zidovudine/pharmacology ; }, abstract = {OBJECTIVES: To ascertain the effects of N-acetyl-cysteine (NAC) and L-2-oxothiazolidine-4-carboxylic acid (OTC) on HIV replication in resting T lymphocytes mixed with chronically infected U1 promonocytic cells; examine the phenotypes of NAC- and OTC-treated cells; and monitor HIV recovery from hu-PBMC SCID mice (SCID mice infected with HIV-1BaL reconstituted with human peripheral blood mononuclear cells) treated with oral OTC.<br><br>DESIGN AND METHODS: Unstimulated PBMC from uninfected donors preincubated for 2 days with pH-adjusted NAC or OTC were cultured at a concentration of 1 x 10(6) cells/ml with 100 U1 cells that were chronically infected with HIV-1IIIB. HI-1 production in the presence or absence of zidovudine was measured by p24 assay at 1-3 weeks, and results were compared with values from the same cell cultures maintained without NAC or OTC exposure. In some experiments U1 cells were separated from PBMC by a 0.4 micron membrane. NAC-treated and -untreated cells were subjected to FACS analysis of multiple-cell-surface adhesion and activation molecules and the results were compared. Hu-PBMC SCID mice were fed OTC for 3 days prior to infection with HIV-1BaL and for the next 3 weeks. Mice were then sacrificed and peritoneal lavage cells were cultured for virus analysis.<br><br>RESULTS: Unstimulated, non-dividing PBMC supported high levels of HIV replication when in direct contact with U1 cells in the presence of NAC or OTC; CD2 and CD54 (I-CAM1) were down-regulated on NAC-treated PBMC; and OTC-treated mice produced significantly higher yields of HIV-1 from peritoneal cells than did untreated mice.<br><br>CONCLUSIONS: At concentrations < or = 5 mM, NAC and OTC potentiate HIV growth in unstimulated PBMC in vitro and in SCID mice. Caution in the use of these agents as antiviral monotherapies is advisable.}, }
@article {pmid9110071, year = {1997}, author = {Cossarizza, A and Mussini, C and Mongiardo, N and Borghi, V and Sabbatini, A and De Rienzo, B and Franceschi, C}, title = {Mitochondria alterations and dramatic tendency to undergo apoptosis in peripheral blood lymphocytes during acute HIV syndrome.}, journal = {AIDS (London, England)}, volume = {11}, number = {1}, pages = {19-26}, doi = {10.1097/00002030-199701000-00004}, pmid = {9110071}, issn = {0269-9370}, mesh = {Acetylcarnitine/pharmacology ; Acetylcysteine/pharmacology ; Acute Disease ; Adult ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; CD4 Lymphocyte Count ; CD8-Positive T-Lymphocytes ; Cells, Cultured ; Female ; HIV Core Protein p24/blood ; HIV Infections/*immunology ; Humans ; Intracellular Membranes ; Lymphocyte Count ; Lymphocytes/*pathology ; Male ; Membrane Potentials ; Mitochondria/*physiology ; Niacinamide/pharmacology ; Tumor Necrosis Factor-alpha/analysis ; }, abstract = {OBJECTIVE: To study alterations of mitochondrial membrane potential (delta psi) and the propensity to undergo apoptosis in peripheral blood lymphocytes (PBL) from subjects with acute HIV syndrome; and to evaluate possible modulations of these phenomena by antioxidants that can be used in therapy, such as N-acetyl-cysteine (NAC), nicotinamide (NAM), or L-acetyl-carnitine (LAC).<br><br>METHODS: Mitochondrial function and the tendency of PBL to undergo spontaneous apoptosis were studied on freshly collected PBL from patients with symptomatic, acute HIV-1 primary infection, which were cultured for different durations in the presence of absence of NAC. NAM or LAC. By a cytofluorimetric method allowing analysis of delta psi in intact cells, we studied the function of these organelles under the different conditions. PBL apoptosis was evaluated by the classic cytofluorimetric method of propidium iodide staining, capable of revealing the typical DNA hypodiploid peak.<br><br>RESULTS: Significant delta psi alterations and tendency to undergo apoptosis were present in PBL from the subjects we studied. Indeed, when cultured even for a few hours in the absence of any stimulus, a consistent number of cells died. However, the presence of even different levels of NAC, NAM or LAC was able to rescue most of them from apoptosis. Both a fall in delta psi and apoptosis were evident in PBL collected in the earliest phases of the syndrome (before seroconversion), and changed significantly after a few days. A significant correlation was found between spontaneous apoptosis and tumour necrosis factor (TNF)-alpha or p24 plasma levels, as well as between apoptosis and the percentages of circulating CD4+ or CD8+ T cells.<br><br>CONCLUSIONS: PBL from patients with acute HIV syndrome are characterized by both significant mitochondrial alterations and a dramatic tendency to undergo apoptosis. The use of NAC, NAM or LAC seems to rescue cells through a protective effect on mitochondria, a well-known target for the action of TNF-alpha and for reactive oxygen species, the production of which is strongly induced by this cytokine. Thus, our data could provide the rationale for the use of such agents in addition to antiviral drugs in primary infection.}, }
@article {pmid9089888, year = {1997}, author = {Gillissen, A and Schärling, B and Jaworska, M and Bartling, A and Rasche, K and Schultze-Werninghaus, G}, title = {Oxidant scavenger function of ambroxol in vitro: a comparison with N-acetylcysteine.}, journal = {Research in experimental medicine. Zeitschrift fur die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie}, volume = {196}, number = {6}, pages = {389-398}, doi = {10.1007/BF02576864}, pmid = {9089888}, issn = {0300-9130}, mesh = {Acetylcysteine/*pharmacology ; Ambroxol/*pharmacology ; Antioxidants/*pharmacology ; Expectorants/*pharmacology ; Free Radical Scavengers/*chemistry ; Glutathione/pharmacology ; Hydrogen Peroxide/chemistry ; Hydroxides/chemistry ; Hypochlorous Acid/chemistry ; In Vitro Techniques ; Superoxides/chemistry ; }, abstract = {Highly reactive oxygen metabolites play an important role in inflammatory processes in the lung. Ambroxol (2-amino-3,5-dibromo-N-[trans-4- hydroxycyclohexyl]benzylamine) has been shown to reduce oxidant-mediated cell damage. However, the mechanism of this effect remains unclear. In order to evaluate oxidant scavenger function increasing concentrations of ambroxol (0-10(-3) mol/l) were compared with equimolar concentrations of N-acetylcysteine (NAC) and glutathione (GSH) in vitro to reduce OH. (hydroxyl radical), HOC1 (hypochlorous acid), O-2 (superoxide anion) and H2O2 (hydrogen peroxide). OH. was measured spectrophotometrically (deoxyribose assay); O-2 (xanthine/x-oxidase), H2O2 and HOC1 (HOC1/OC1-) were determined by chemiluminescence. Ambroxol, NAC and reduced GSH scavenged OH. significantly at 10(-3) mol/l, while HOC1 was inhibited at concentrations > or = 10(-4) mol/l completely (P < 0.01). NAC and GSH had no anti-O-2 function, while ambroxol (10(-4) mol/l) reduced O-2 by 14.3 +/- 6.7%. In contrast, GSH and NAC scavenged H2O2 at > 10(-6) mol/l (P < 0.01), while ambroxol had no anti-H2O2 effect. Our data demonstrate direct oxidant-reducing capabilities of ambroxol, which may be directly related to the aromatic moiety of the molecule. However, high concentrations (micromolar concentrations) are needed. Due to differences in direct oxidant scavenger function, a combination of ambroxol and NAC could be beneficial in antioxidant therapy.}, }
@article {pmid9043953, year = {1997}, author = {Déas, O and Dumont, C and Mollereau, B and Métivier, D and Pasquier, C and Bernard-Pomier, G and Hirsch, F and Charpentier, B and Senik, A}, title = {Thiol-mediated inhibition of FAS and CD2 apoptotic signaling in activated human peripheral T cells.}, journal = {International immunology}, volume = {9}, number = {1}, pages = {117-125}, doi = {10.1093/intimm/9.1.117}, pmid = {9043953}, issn = {0953-8178}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/*immunology ; Buthionine Sulfoximine/pharmacology ; CD2 Antigens/*drug effects/physiology ; Cells, Cultured ; Cycloheximide/pharmacology ; Dactinomycin/pharmacology ; Female ; Glutathione/analogs &amp; derivatives/biosynthesis/drug effects/pharmacology ; Humans ; Lymphocyte Activation/*drug effects ; Male ; Signal Transduction/drug effects/*immunology ; Sulfhydryl Compounds/*pharmacology ; T-Lymphocytes/*drug effects/immunology ; fas Receptor/*drug effects/physiology ; }, abstract = {Fas and CD2 receptors can transduce apoptotic signals through two independent biochemical pathways. In this study, we first evaluated the role of intracellular GSH in these signaling pathways by inducing variations in the GSH pool of activated peripheral T lymphocytes. Increasing the concentration of intracellular GSH by means of N-acetyl-L-cysteine (NAC) and GSH ethyl ester (OEt) resulted in total protection against cell death, while inhibiting GSH synthesis with buthionine sulfoximine (BSO) greatly enhanced cell sensitivity to Fas and CD2 apoptotic signaling. The protection exerted by NAC and GSH OEt was essentially based on their capacity to establish an intracellular reducing environment as it still occurred in BSO-treated cells. Thiol-containing compounds (cysteine, captopril, D-penicillamine and 2-mercaptoethanol) inhibited apoptosis while a series of non-thiol antioxidants (including catalase and vitamin E) failed to do so, suggesting that protection was secondary to thiols/disulfides exchange reactions at the level of cysteine residues in proteins and not to detoxification of reactive oxygen intermediates. This conclusion was further supported by the finding that no enhanced generation of O.-2 and H2O2 could be detected in cells experiencing early stages of apoptosis such as a decreased concentration of intracellular GSH and cell shrinkage. Also, protection occurred in the presence of protein synthesis inhibitors, indicating that it was due to post-translational sulfhydryl redox regulation of critical molecules involved in the apoptotic cascade. These data suggest that GSH, the most abundant intracellular thiol antioxidant, may be important in counteracting Fas- and CD2-mediated apoptosis of T lymphocytes.}, }
@article {pmid9043100, year = {1997}, author = {Garmyn, M and Degreef, H}, title = {Suppression of UVB-induced c-fos and c-jun expression in human keratinocytes by N-acetylcysteine.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {37}, number = {1-2}, pages = {125-130}, doi = {10.1016/s1011-1344(96)07340-x}, pmid = {9043100}, issn = {1011-1344}, mesh = {Acetylcysteine/*pharmacology ; Cadmium Chloride/pharmacology ; DNA Replication/radiation effects ; Gene Expression Regulation/*radiation effects ; *Genes, fos ; *Genes, jun ; Humans ; Keratinocytes/*drug effects/radiation effects ; *Ultraviolet Rays ; }, abstract = {Irradiation of human keratinocytes with UVB results in the early induction of proto-oncogenes c-fos and c-jun, members of the AP-1 protein family of transcription factors. To explore a possible involvement of oxidant stress in triggering this UVB-induced early gene response, we investigated in human keratinocytes the effect of N-acetylcysteine (NAC), a thiocompound with antioxidant activities, on UVB-induced c-fos, and c-jun expression. Normal human keratinocytes were irradiated with either 16 or 32 mJ cm-2 UVB, which induces a temporary inhibition of DNA synthesis, without compromising cell survival. Preincubation with 1 and 3 mM NAC suppressed c-jun and c-fos induction by UVB in a dose-dependent fashion. These applied concentrations of NAC were not toxic to the keratinocytes, as determined by Trypan Blue exclusion assay and completely suppressed c-jun and c-fos induction by the chemical cadmium chloride (oxidative stress). These results indicate that oxidative stress, at least in part, mediates the transcriptional activation of c-fos and c-jun in human keratinocytes after UVB irradiation.}, }
@article {pmid9024731, year = {1997}, author = {Pizzulli, L and Hagendorff, A and Zirbes, M and Jung, W and Lüderitz, B}, title = {N-acetylcysteine attenuates nitroglycerin tolerance in patients with angina pectoris and normal left ventricular function.}, journal = {The American journal of cardiology}, volume = {79}, number = {1}, pages = {28-33}, doi = {10.1016/s0002-9149(96)00671-6}, pmid = {9024731}, issn = {0002-9149}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Angina Pectoris/*drug therapy/physiopathology ; Blood Pressure/drug effects ; Blood Volume/drug effects ; Drug Tolerance ; Female ; Free Radical Scavengers/*therapeutic use ; Hematocrit ; Hemodynamics/drug effects ; Humans ; Male ; Middle Aged ; Nitroglycerin/*therapeutic use ; *Ventricular Function, Left ; }, abstract = {The aim of this study was to assess whether N-acetylcysteine (NAC) is able to prevent tolerance to a 48-hour infusion of nitroglycerin (NTG) in the setting of normal left ventricular function. In 16 patients, the hemodynamic response to 0.8 mg sublingual (s.l.) NTG was assessed by measuring mean arterial, pulmonary artery, pulmonary capillary wedge and right atrial pressures, cardiac output, and calculation of the systemic and pulmonary vascular resistances. The parameters were obtained at baseline and 1 to 10 minutes after the s.l. NTG application (day 1). NTG was started at 1.5 microg/kg/min; concomitantly, a bolus of 2,000 mg of NAC was administered, followed by an infusion of 5 mg/kg/hour. Both infusions were continued for 48 hours, and the hemodynamic study was repeated (day 3). The same measurements were obtained in a matched control group of 15 patients with NTG infusion alone. Plasma renin activity, aldosterone, and norepinephrine were measured before and after the infusion period. The first s.l. NTG infusion (day 1) caused a significant decrease in mean arterial (p <0.01), pulmonary artery (p <0.001), and right atrial pressures (p <0.001), and in systemic (p <0.01) and pulmonary vascular resistances (p <0.001) in both groups. After the 48-hour infusion (day 3), there was a total loss of nitrate-mediated vasodilation (pressure values and vascular resistances day 3 > day 1) in 5 of 16 patients (NAC nonresponders), whereas in the other 11 of 16 patients (NAC responders), there was significant vasodilation throughout the infusion period. Tolerance had developed in 14 of 15 patients with NTG infusion alone. The same difference (responder vs nonresponder vs NTG alone) held true regarding the response to the second s.l. NTG infusion after 48 hours. The neurohormonal counter-regulation and intravascular volume expansion (increase in plasma renin activity, p <0.001, and norepinephrine, p <0.05; decrease in aldosterone, p <0.01) did not differ between responders and nonresponders. We conclude that NAC attenuates tolerance development to a continuous NTG infusion in a specific patient subgroup and that this occurs despite the same amount of neurohormonal counter-regulation and intravascular volume expansion compared with patients with tolerance development.}, }
@article {pmid9000534, year = {1997}, author = {Nottet, HS and Moelans, II and de Vos, NM and de Graaf, L and Visser, MR and Verhoef, J}, title = {N-acetyl-L-cysteine-induced up-regulation of HIV-1 gene expression in monocyte-derived macrophages correlates with increased NF-kappaB DNA binding activity.}, journal = {Journal of leukocyte biology}, volume = {61}, number = {1}, pages = {33-39}, doi = {10.1002/jlb.61.1.33}, pmid = {9000534}, issn = {0741-5400}, mesh = {Acetylcysteine/*pharmacology ; Anti-HIV Agents/*pharmacology ; Cells, Cultured ; Chloramphenicol O-Acetyltransferase/genetics/metabolism ; DNA, Viral/*metabolism ; Genes, Reporter/drug effects ; Genetic Vectors ; HIV Long Terminal Repeat/drug effects/genetics ; HIV-1/*drug effects/genetics/physiology ; Humans ; Jurkat Cells ; Macrophages/*drug effects/metabolism/virology ; NF-kappa B/*metabolism ; Transcription, Genetic/drug effects ; Transfection ; Up-Regulation/drug effects ; Virus Replication/*drug effects ; }, abstract = {Nuclear factor kappaB (NF-kappaB) is an important cellular regulator of human immunodeficiency virus (HIV) gene expression. In T cells, N-acetyl-L-cysteine (NAC) inhibits the induction of NF-kappaB and transcription of HIV-1. However, NAC up-regulates HIV-1 replication in monocyte-derived macrophages (MDM). In this study we demonstrate that NAC treatment of MDM transfected with a chloramphenicol acetyltransferase (CAT) construct under transcriptional control of the HIV-1 long terminal repeat resulted in an up-regulation of CAT activity. Furthermore, MDM transfected with a HIV-1-NF-kappaB-CAT construct also produced increased CAT activity after NAC treatment. In addition, electrophoretic mobility shift assays revealed that nuclei of NAC-treated MDM contained increased binding activity to wild-type, but not mutant, kappaB oligonucleotides. Components of the binding activity were identified with antibodies as the NF-kappaB subunits p50 and p65. These data indicate that NAC-induced enhancement of HIV-1 replication in MDM is regulated at the level of viral gene expression and mediated by NF-kappaB.}, }
@article {pmid8981050, year = {1997}, author = {Hoffer, E and Shenker, L and Baum, Y and Tabak, A}, title = {Paraquat-induced formation of leukotriene B4 in rat lungs: modulation by N-acetylcysteine.}, journal = {Free radical biology &amp; medicine}, volume = {22}, number = {3}, pages = {567-572}, doi = {10.1016/s0891-5849(96)00385-1}, pmid = {8981050}, issn = {0891-5849}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Arachidonic Acid/metabolism ; Bronchoalveolar Lavage Fluid/chemistry ; Female ; Leukotriene B4/*biosynthesis ; Lung/drug effects/*metabolism/pathology ; Lung Diseases/*chemically induced/metabolism/pathology ; Macrophages, Alveolar/drug effects/metabolism ; Neutrophils/pathology ; Paraquat/*toxicity ; Pulmonary Alveoli/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The present work is focused on the formation of the inflammatory mediator leukotriene B4 (LTB4) in the lungs of paraquat (PQ)-intoxicated rats. The levels of LTB4 and the number of neutrophils in lung lavages of PQ-intoxicated rats, measured 12 h after 30 mg/kg PQ, increased significantly compared with those of control animals; administration of 50 mg/kg IP N-acetylcysteine (NAC), 8 h after PQ, inhibited this effect. The release of LTB4 from alveolar macrophages (AM) or alveolar epithelial type II cells from healthy animals incubated with PQ and/or NAC did not offer' an explanation for the effect of these chemicals on LTB4 in the bronchoalveolar lavage fluid (BALF). The PQ-enhanced, NAC-inhibited release of arachidonic acid (AA) by alveolar epithelial type II cells did, however, explain our in vivo results, when one assumes that the AM synthesize their 5-lipoxygenase products from alveolar epithelial cell-derived AA, an hypothesis demonstrated already by other researchers.}, }
@article {pmid8895810, year = {1997}, author = {Cotgreave, IA}, title = {N-acetylcysteine: pharmacological considerations and experimental and clinical applications.}, journal = {Advances in pharmacology (San Diego, Calif.)}, volume = {38}, number = {}, pages = {205-227}, pmid = {8895810}, issn = {1054-3589}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Antioxidants/*pharmacology/therapeutic use ; Humans ; }, abstract = {The diversity of application of the thiol drug NAC in both the experimental setting, as a tool for the study of the mechanisms and consequences of oxidative stress, and the clinical setting, as a therapeutic agent, clearly reflects the central role played by the redox chemistries of the group XVI elements, oxygen and sulfur, in biology. As our understanding of such redox processes increases, particularly their roles in specific pathophysiological processes, new avenues will open for the use of NAC in the clinical setting. As a drug, NAC represents perhaps the ideal xenobiotic, capable of directly entering endogenous biochemical processes as a result of its own metabolism. Thus, it is hoped that the experience gained with this unique agent will help in future efforts to design antioxidants and chemoprotective principles which are able to more accurately utilize endogenous biochemical processes for cell- or tissue-specific therapy.}, }
@article {pmid8955147, year = {1996}, author = {Kamata, H and Tanaka, C and Yagisawa, H and Matsuda, S and Gotoh, Y and Nishida, E and Hirata, H}, title = {Suppression of nerve growth factor-induced neuronal differentiation of PC12 cells. N-acetylcysteine uncouples the signal transduction from ras to the mitogen-activated protein kinase cascade.}, journal = {The Journal of biological chemistry}, volume = {271}, number = {51}, pages = {33018-33025}, doi = {10.1074/jbc.271.51.33018}, pmid = {8955147}, issn = {0021-9258}, mesh = {Acetylcysteine/pharmacology ; Animals ; Calcium-Calmodulin-Dependent Protein Kinases/*physiology ; Cell Differentiation ; Gene Expression Regulation, Developmental ; Genes, fos ; Nerve Growth Factors/*physiology ; Neurons/*cytology ; Oxidation-Reduction ; PC12 Cells/*cytology ; Phosphorylation ; Protein Biosynthesis ; Protein Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-raf ; Proto-Oncogene Proteins p21(ras)/physiology ; RNA, Messenger/genetics ; Rats ; Signal Transduction ; Transcription, Genetic ; }, abstract = {The cellular redox state is thought to play an important role in a wide variety cellular signaling pathways. Here, we investigated the involvement of redox regulation in the nerve growth factor (NGF) signaling pathway and neuronal differentiation in PC12 cells. N-acetyl-L-cysteine (NAC), which acts as a reductant in cells both by its direct reducing activity and by increasing the synthesis of the cellular antioxidant glutathione, inhibited neuronal differentiation induced by NGF or by the expression of oncogenic ras in PC12 cells. NAC suppressed NGF-induced c-fos gene expression and AP-1 activation. These results suggest that neuronal differentiation and NGF signaling are subject to regulation by the cellular redox state. NAC also suppressed the NGF-induced activation of mitogen-activated protein kinases (MAPKs) and decreased the amount of tyrosine phosphorylation of MAPKs. The suppression of MAPK by NAC was independent of glutathione synthesis. In parallel with the suppression of MAPK, the activation of MAPK kinase kinase activity was also suppressed in the presence of NAC. In contrast, NGF-induced activation of Ras was not inhibited by NAC. The inhibitory effect of NAC on the MAPK cascade was independent of transcription and translation. Thus, NAC suppresses NGF-induced neuronal differentiation by uncoupling the signal transduction from Ras to the MAP kinase cascade in PC12 cells.}, }
@article {pmid8955144, year = {1996}, author = {Banki, K and Hutter, E and Colombo, E and Gonchoroff, NJ and Perl, A}, title = {Glutathione levels and sensitivity to apoptosis are regulated by changes in transaldolase expression.}, journal = {The Journal of biological chemistry}, volume = {271}, number = {51}, pages = {32994-33001}, doi = {10.1074/jbc.271.51.32994}, pmid = {8955144}, issn = {0021-9258}, support = {R01 DK 49221/DK/NIDDK NIH HHS/United States ; }, mesh = {*Apoptosis ; Glucosephosphate Dehydrogenase/metabolism ; Glutathione/*metabolism ; Humans ; Pentose Phosphate Pathway ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/metabolism ; Transaldolase/*metabolism ; Tumor Cells, Cultured ; fas Receptor/metabolism ; }, abstract = {Transaldolase (TAL) is a key enzyme of the reversible nonoxidative branch of the pentose phosphate pathway (PPP) that is responsible for the generation of NADPH to maintain glutathione at a reduced state (GSH) and, thus, to protect cellular integrity from reactive oxygen intermediates (ROIs). Formation of ROIs have been implicated in certain types of apoptotic cell death. To evaluate the role of TAL in this process, Jurkat human T cells were permanently transfected with TAL expression vectors oriented in the sense or antisense direction. Overexpression of TAL resulted in a decrease in glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities and NADPH and GSH levels and rendered these cells highly susceptible to apoptosis induced by serum deprivation, hydrogen peroxide, nitric oxide, tumor necrosis factor-alpha, and anti-Fas monoclonal antibody. In addition, reduced levels of TAL resulted in increased glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities and increased GSH levels with inhibition of apoptosis in all five model systems. The effect of TAL expression on susceptibility to apoptosis through regulating the PPP and GSH production is consistent with an involvement of ROIs in each pathway tested. Production of ROIs in Fas-mediated cell death was further substantiated by measurement of intracellular ROI production with oxidation-sensitive fluorescent probes, by the protective effects of GSH precursor, N-acetyl cysteine, free radical spin traps 5,5-dimethyl-1-pyrroline-1-oxide and 3,3,5,5-tetramethyl-1-pyrroline-1-oxide, the antioxidants desferrioxamine, nordihydroguaiaretic acid, and Amytal, and by the enhancing effects of GSH depletion with buthionine sulfoximine. The results provide definitive evidence that TAL has a role in regulating the balance between the two branches of PPP and its overall output as measured by GSH production and thus influences sensitivity to cell death signals.}, }
@article {pmid9003392, year = {1996}, author = {Neuschwander-Tetri, BA and Bellezzo, JM and Britton, RS and Bacon, BR and Fox, ES}, title = {Thiol regulation of endotoxin-induced release of tumour necrosis factor alpha from isolated rat Kupffer cells.}, journal = {The Biochemical journal}, volume = {320 (Pt 3)}, number = {Pt 3}, pages = {1005-1010}, pmid = {9003392}, issn = {0264-6021}, support = {DK41816/DK/NIDDK NIH HHS/United States ; DK44305/DK/NIDDK NIH HHS/United States ; DK50178/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Blotting, Northern ; Buthionine Sulfoximine/pharmacology ; Electrophoresis, Polyacrylamide Gel ; Endotoxins/*pharmacology ; Glutathione/analogs &amp; derivatives/analysis/metabolism/pharmacology ; Kupffer Cells/*metabolism ; Lipopolysaccharides/pharmacology ; Liver/enzymology ; Male ; Nuclear Proteins/metabolism ; RNA/metabolism ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/*pharmacology ; Tumor Necrosis Factor-alpha/*metabolism ; }, abstract = {Proinflammatory cytokines released by hepatic macrophages (Kupffer cells) have a central role in the pathogenesis of liver injury and the cardiovascular abnormalities of sepsis. Because cytokine release is controlled primarily at the level of gene expression, intracellular signalling mechanisms that control the transcription of cytokine genes are critical links to organ injury. Oxidant stress up-regulates and antioxidants down-regulate the pleiotropic transcription factor NF-kappa B, a DNA-binding protein that induces the expression of cytokines and vascular adhesion molecules. Thiol-bearing molecules are also important inhibitors of NF-kappa B activation, but whether this inhibition represents an antioxidant effect is unknown. This study was undertaken to determine whether important endogenous and pharmacological thiols modulate the activation of NF-kappa B and the release of tumour necrosis factor alpha (TNF-alpha) from Kupffer cells and to ascertain whether these effects are mediated through glutathione. Exposure of rat Kupffer cells to a physiologically relevant concentration of lipopolysaccharide (10 ng/ml) activated NF-kappa B within 1 h and induced the release of TNF-alpha over 5 h. Cellular glutathione content remained unchanged after lipopolysaccharide exposure, but both glutathione monoethyl ester and N-acetyl-L-cysteine increased cellular glutathione levels, blocked NF-kappa B activation and inhibited the release of TNF-alpha. Inhibition of glutathione synthesis prevented the NAC-induced increase in Kupffer cell glutathione, yet it did not prevent the inhibition of TNF-alpha release by NAC. Thus the inhibition of NF-kappa B activation by pharmacological thiols such as NAC might reflect a more general role of the intracellular thiol redox status in NF-kappa B regulation rather than the antioxidant properties of these agents.}, }
@article {pmid8981478, year = {1996}, author = {Lin, X and Bulleit, RF}, title = {Cell intrinsic mechanisms regulate mouse cerebellar granule neuron differentiation.}, journal = {Neuroscience letters}, volume = {220}, number = {2}, pages = {81-84}, doi = {10.1016/s0304-3940(96)13214-6}, pmid = {8981478}, issn = {0304-3940}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Cell Differentiation ; Cerebellum/*cytology/physiology ; DNA-Binding Proteins/*genetics ; Gene Expression ; Insulin-Like Growth Factor I/pharmacology ; MEF2 Transcription Factors ; Mice ; Myogenic Regulatory Factors ; Neurons/cytology ; Receptors, GABA-A/*genetics ; Transcription Factors/*genetics ; }, abstract = {Cerebellar granule cells isolated from postnatal day 7 mice, and cultured in minimal medium containing only insulin-like growth factor-I (IGF-I), both survive and differentiate. This differentiation is marked by neurite growth and expression of genes associated with terminal differentiation, the myocyte-specific enhancer factor 2A (MEF2A) and the alpha 6 subunit of the gamma-aminobutyric acidA receptor (GABAA alpha 6). Percoll gradient purified granule cells maintained without IGF-I, in minimal medium alone or in medium containing the antioxidant N-acetylcysteine (NAC), also express MEF2A and GABAA alpha 6. Thus, cultured granule neurons can differentiate to some extent cell-autonomously and IGF-I may not be a critical factor for this process.}, }
@article {pmid9216175, year = {1996}, author = {Kitamura, S}, title = {[Pathophysiology of acute lung injury].}, journal = {Nihon Kyobu Shikkan Gakkai zasshi}, volume = {34 Suppl}, number = {}, pages = {1-7}, pmid = {9216175}, issn = {0301-1542}, mesh = {Acute Disease ; Animals ; Biomarkers ; Capillary Permeability ; Cell Adhesion Molecules/physiology ; Clinical Trials as Topic ; Glycine/analogs &amp; derivatives/therapeutic use ; Humans ; Leukocyte Elastase/physiology ; Lung/blood supply/*physiopathology ; Lung Diseases/*physiopathology ; Nitric Oxide/physiology ; Reactive Oxygen Species/physiology ; Serine Proteinase Inhibitors/therapeutic use ; Sulfonamides/therapeutic use ; }, abstract = {Almost all respiratory diseases except benign lung tumors and lung dysplasia entail acute lung injury. The many clinical conditions associated with acute lung injury include aspiration pneumonia, bacterial pneumonia, and sepsis. The fundamental cause of acute lung injury is pulmonary vascular hyperpermeability. Pulmonary vascular hyperpermeability can be attenuated by nitric oxide and cyclic GMP, and potentiated by oxygen radicals and elastase released from neutrophils. Adhesion molecule inhibition could become an effective therapy against acute lung injury, because the adhesion molecules are very important in the pathogenesis of this condition. Adhesion molecules could also be useful markers of disease activity in various lung diseases. Neutrophil elastase inhibitors may become important as therapeutic agents against acute exacerbations of idiopathic interstitial pneumonia, because this pathological condition is a type of acute lung injury. Similarly, N-acetyl cysteine could also become a useful therapeutic agent against idiopathic interstitial pneumonia, because it is a precursor of glutathione, which is the major antioxidant in the fluid lining of the bronchial epithelium.}, }
@article {pmid9006111, year = {1996}, author = {Parfett, CL and Pilon, R and Caldeira, AA}, title = {Asbestos promotes morphological transformation and elevates expression of a gene family invariably induced by tumor promoters in C3H/10T1/2 cells.}, journal = {Carcinogenesis}, volume = {17}, number = {12}, pages = {2719-2726}, doi = {10.1093/carcin/17.12.2719}, pmid = {9006111}, issn = {0143-3334}, mesh = {Animals ; Antioxidants/pharmacology ; Asbestos/*toxicity ; Asbestos, Crocidolite/toxicity ; Carcinogens/*toxicity ; Cell Line ; Cell Transformation, Neoplastic/*chemically induced ; Gene Expression Regulation/*drug effects ; Glycoproteins/*genetics ; Intercellular Signaling Peptides and Proteins ; Mice ; Mice, Inbred C3H ; Prolactin ; RNA, Messenger/analysis ; Tetradecanoylphorbol Acetate/toxicity ; }, abstract = {The murine proliferin gene family, which has been shown to respond consistently to tumor promoters and other cellular pro-oxidant agents in C3H/10T1/2 cells, was used to monitor responses after treatment of these cell cultures with toxic, pro-oxidant asbestos fibres. Proliferin mRNA levels were increased by amosite, crocidolite or chrysotile asbestos fibres, especially in the presence of fresh serum and at low cell densities. Promotion of morphological transformation was confirmed in two-stage focus formation assays using crocidolite at a fibre density that induced proliferin expression. Asbestos-induced gene expression was inhibited by millimolar levels of N-acetylcysteine (NAC), supporting a linkage between: (i) induced oxidant stress that was sufficient to promote morphological transformation; (ii) induction of proliferin expression. Other anti-oxidant compounds (dithiothreitol and pyrrolidine dithiocarbamate) or enzymes (superoxide dismutase and catalase) did not inhibit induced expression. Non-fibrous powders (titanium dioxide, quartz or silica gel) were also effective inducers of proliferin mRNA accumulation. Latex beads and activated charcoal were effective at higher particle densities, implying that ubiquitous particle-induced surface membrane effects can lead to an NAC-reversible step necessary for proliferin induction. The results showed that asbestos resembled all other promoters of morphological transformation in C3H/10T1/2 cells in that an antioxidant-sensitive induction of the proliferin gene family occurred following treatment.}, }
@article {pmid8977294, year = {1996}, author = {Delneste, Y and Jeannin, P and Sebille, E and Aubry, JP and Bonnefoy, JY}, title = {Thiols prevent Fas (CD95)-mediated T cell apoptosis by down-regulating membrane Fas expression.}, journal = {European journal of immunology}, volume = {26}, number = {12}, pages = {2981-2988}, doi = {10.1002/eji.1830261225}, pmid = {8977294}, issn = {0014-2980}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects/immunology ; Down-Regulation/*drug effects ; Humans ; Jurkat Cells ; Membrane Proteins/*biosynthesis ; T-Lymphocytes/*drug effects ; fas Receptor/*biosynthesis/*drug effects ; }, abstract = {Thiol antioxidants have been shown to protect cells against apoptosis. Based on the role of Fas in T cell apoptosis, we investigated the effect of thiols on Fas expression. We report that the thiol N-acetyl-L-cysteine (NAC) prevents the induction of Fas on human peripheral blood T cells in a dose-dependent manner. It also down-regulates in a time- and dose-dependent manner Fas expression on Fas-expressing T cells. Although these effects were not mediated through de novo glutathione synthesis, only compounds with a free thiol group decreased membrane Fas expression. The decrease of Fas expression induced by NAC was not associated with a modulation of Fas mRNA transcription nor with an internalization, suggesting that NAC may affect the processing of Fas. Indeed, a soluble immunoreactive form of Fas was detected by ELISA and by Western blotting in the supernatants of Fas-expressing T cells treated with NAC. As a functional consequence, NAC partly protected Jurkat cells against Fas-mediated apoptotic cell death. Thus, this study shows that, by regulating Fas expression, the cytoprotective properties of NAC can be extended to Fas-mediated cell death.}, }
@article {pmid8975783, year = {1996}, author = {Dabrowska, MI and Becks, LL and Lelli, JL and Levee, MG and Hinshaw, DB}, title = {Sulfur mustard induces apoptosis and necrosis in endothelial cells.}, journal = {Toxicology and applied pharmacology}, volume = {141}, number = {2}, pages = {568-583}, doi = {10.1006/taap.1996.0324}, pmid = {8975783}, issn = {0041-008X}, mesh = {Acetylcysteine/pharmacology ; Adenosine Triphosphate/analysis ; Animals ; Apoptosis/*drug effects ; Cattle ; Cell Adhesion/drug effects ; Cells, Cultured ; Chemical Warfare Agents/*toxicity ; Cytoskeleton/drug effects ; Dose-Response Relationship, Drug ; Endothelium, Vascular/*drug effects/pathology ; GTP-Binding Proteins/analysis ; Microtubules/drug effects ; Mustard Gas/*toxicity ; Necrosis ; }, abstract = {Sulfur Mustard (SM) is a vesicant or blistering chemical warfare agent, for which there still is no effective therapy. Endothelial cells are one of the major cellular targets for SM. The mechanism of endothelial cell death during SM injury is poorly understood. We studied the effect of exposure of endothelial cells to 0-1000 microM SM over the time course of 2-24 hr to determine the role of apoptotic and necrotic patterns of cell death in endothelial injury induced by SM. SM concentrations < or = 250 microM induced exclusively apoptosis which was observed after 5 hr in 30% of endothelial cells. Exposure to SM concentrations > or = 500 microM caused apoptosis and necrosis to the same extent in 60-85% of all cells after 5 to 6 hr. Necrosis was accompanied by a significant (approximately 50%) depletion of intracellular ATP, while in apoptotic cells ATP remained at the level similar to healthy cells. Interestingly, disruption of the long actin filament stress fibers and rounding of cells preceded other features of apoptosis--DNA fragmentation, membrane budding, and apoptotic body formation. In apoptotic cells, microfilaments formed constricted perinuclear bands, which were not observed in necrotic cells. Pretreatment with 50 mM N-acetyl-L-cysteine (NAC), a sulfhydryl donor and antioxidant, nearly eliminated the apoptotic features of cell death but did not prevent necrosis in response to SM. NAC pretreatment alone induced reorganization of actin filaments into an enhanced network of long stress fibers instead of a dominant cortical band of actin. NAC pretreatment prevented loss of cell adherence and cell rounding following exposure to 250 microM SM. The effect of NAC on cytoskeletal organization and its ability to eliminate SM-induced apoptosis suggests that actin filament organization may be an important element in cellular susceptibility to apoptotic stimuli.}, }
@article {pmid8922414, year = {1996}, author = {Henderson, JT and Javaheri, M and Kopko, S and Roder, JC}, title = {Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-L-cysteine.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {16}, number = {23}, pages = {7574-7582}, pmid = {8922414}, issn = {0270-6474}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Facial Nerve/drug effects/ultrastructure ; Forelimb ; Free Radical Scavengers/*pharmacology ; Glutathione Peroxidase/metabolism ; Mice ; Mice, Neurologic Mutants/*physiology ; Motor Neurons/*drug effects/physiology ; Muscle, Skeletal/anatomy &amp; histology/drug effects/physiology ; Neck ; Nerve Degeneration/*drug effects ; Spinal Cord/drug effects/pathology ; }, abstract = {The murine mutant wobbler is a model of lower motoneuron degeneration with associated skeletal muscle atrophy. This mutation most closely resembles Werdnig-Hofmann disease in humans and shares some of the clinical features of amyotrophic lateral sclerosis (ALS). It has been suggested that reactive oxygen species (ROS) may play a role in the pathogenesis of disorders such as ALS. To examine the relationship between ROS and neural degeneration, we have studied the effects of agents such as N-acetyl-L-cysteine (NAC), which reduce free radical damage. Litters of wobbler mice were given a 1% solution of the glutathione precursor NAC in their drinking water for a period of 9 weeks. Functional and neuroanatomical examination of these animals revealed that wobbler mice treated with NAC exhibited (1) a significant reduction in motor neuron loss and elevated glutathione peroxidase levels within the cervical spinal cord, (2) increased axon caliber in the medial facial nerve, (3) increased muscle mass and muscle fiber area in the triceps and flexor carpi ulnaris muscles, and (4) increased functional efficiency of the forelimbs, as compared with untreated wobbler littermates. These data suggest that reactive oxygen species may be involved in the degeneration of motor neurons in wobbler mice and demonstrate that oral administration of NAC effectively reduces the degree of motor degeneration in wobbler mice. This treatment thus may be applicable in the treatment of other lower motor neuropathies.}, }
@article {pmid8984750, year = {1996}, author = {Clemmesen, JO and Ott, P and Dalhoff, KP and Astrup, LB and Tage-Jensen, U and Poulsen, HE}, title = {[Recommendations for treatment of paracetamol poisoning. Danish Medical Society, Study of the Liver].}, journal = {Ugeskrift for laeger}, volume = {158}, number = {48}, pages = {6892-6895}, pmid = {8984750}, issn = {0041-5782}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Analgesics, Non-Narcotic/*poisoning ; Antidotes/administration &amp; dosage/*therapeutic use ; Chemical and Drug Induced Liver Injury/drug therapy/*etiology ; Denmark ; Humans ; Infusions, Intravenous ; Poisoning/*drug therapy ; }, abstract = {Based on recent reports concerning the efficacy of N-acetylcysteine (NAC) in paracetamol (acetaminophen) poisoning, guidelines for treatment and control of these patients are reviewed by a study group under the Danish Association for the Study of the Liver. It is recommended that NAC-treatment is initiated immediately after referral and continued for 36 hours in all cases. Further NAC-treatment should not be discontinued before a decrease in INR has been observed.}, }
@article {pmid8950200, year = {1996}, author = {Homandberg, GA and Hui, F and Wen, C}, title = {Fibronectin fragment mediated cartilage chondrolysis. II. Reparative effects of anti-oxidants.}, journal = {Biochimica et biophysica acta}, volume = {1317}, number = {2}, pages = {143-148}, doi = {10.1016/s0925-4439(96)00045-2}, pmid = {8950200}, issn = {0006-3002}, support = {AR39239-03/AR/NIAMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cartilage, Articular/cytology/*metabolism ; Catalase/pharmacology ; Cattle ; Chymopapain/pharmacology ; Culture Techniques ; Dimethyl Sulfoxide/pharmacology ; Fibronectins/chemistry/*physiology ; Glutathione/pharmacology ; Interleukin-1/pharmacology ; Peptide Fragments ; Proteoglycans/*metabolism ; Superoxide Dismutase/pharmacology ; Trypsin/pharmacology ; }, abstract = {In an accompanying manuscript, it was shown that the cartilage chondrolytic activities of fibronectin fragments (Fn-f), which are mediated through catabolic cytokines such as TNF-alpha, IL-1 and IL-6, could be suppressed by anti-oxidants (AOs). The AOs neutralized reactive oxygen species (ROS) which are known to mediate catabolic cytokine action. The objective in this work was to test whether AOs would promote restoration of proteoglycan (PG) in Fn-f treated cartilage, since under normal culturing conditions, PG is not restored after removal of the Fn-f. Cartilage was first cultured with an amino-terminal 29-kDa Fn-f to cause loss of about half of the total PG and then treated with NAC (1 and 10 mM) or glutathione (10 microM) or DMSO (0.1 or 1%). Treatment with NAC and glutathione maximally caused restoration of PG within 14 days to normal or supernormal levels, while DMSO was less effective. Catalase, but not superoxide dismutase, enhanced PG content to a small but significant extent. The restoration of PG in Fn-f treated cartilage occurred throughout the full depth of the cartilage slices as shown by histochemical analysis. However, removal of the AO allowed a subsequent decrease in PG content suggesting that the AOs had not blocked cytokine expression but had merely suppressed cytokine activities. Addition of NAC to IL-1 treated cartilage promoted a restoration of PG, while addition to chymopapain or trypsin treated cartilage was not very effective, suggesting that the effect of AOs requires a cytokine driven damage system. We conclude that the AOs promote a restoration of PG in the Fn-f treated cartilage by suppressing the effects of catabolic cytokines. The data suggest a potential for AOs in reversing tissue damage caused by cytokines.}, }
@article {pmid8950199, year = {1996}, author = {Homandberg, GA and Hui, F and Wen, C}, title = {Fibronectin fragment mediated cartilage chondrolysis. I. Suppression by anti-oxidants.}, journal = {Biochimica et biophysica acta}, volume = {1317}, number = {2}, pages = {134-142}, doi = {10.1016/s0925-4439(96)00046-4}, pmid = {8950199}, issn = {0006-3002}, support = {AR39239-03/AR/NIAMS NIH HHS/United States ; }, mesh = {Allopurinol/pharmacology ; Animals ; Antioxidants/*pharmacology ; Cartilage, Articular/*metabolism ; Catalase/metabolism ; Cattle ; Collagen/*metabolism ; Culture Techniques ; Enzyme Inhibitors/pharmacology ; Fibronectins/chemistry/*metabolism ; Glutathione/metabolism ; Humans ; Interleukin-1/pharmacology ; Matrix Metalloproteinase 3/metabolism ; Peptide Fragments ; Proteoglycans/*metabolism ; Sulfates/metabolism ; Superoxide Dismutase/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; Xanthine Oxidase/antagonists &amp; inhibitors ; }, abstract = {Fibronectin fragments damage cartilage in vitro by greatly enhancing metalloproteinases and suppressing proteoglycan (PG) synthesis which results in severe cartilage PG depletion. Since reactive oxygen species (ROS) have been implicated in catabolic cytokine action and preliminary data suggested that catabolic cytokines such as TNF-alpha, IL-1 alpha, IL-1 beta and IL-6 are responsible for fibronectin fragment mediated damage, selected anti-oxidants (AOs) were tested as inhibitors of cytokine. ROS and fibronectin fragment activity. Damage was measured by depletion of cartilage PG during tissue culture. The AO, N-acetylcysteine (NAC), decreased the extent of cartilage PG depletion caused by TNF-alpha and IL-1 alpha and by the ROS, hydrogen peroxide and superoxide anion, confirming that the cytokines operate through ROS and that ROS can initiate cartilage PG depletion. NAC at 0.1 and 1 mM, totally suppressed PG depletion caused by a highly potent amino-terminal 29-kDa fibronectin fragment (Fn-f) for 14 days in culture. NAC at 10 mM totally blocked Fn-f mediated PG depletion for 21 days and increased the cartilage PG content by 30% above normal levels. Glutathione (10 microM) and DMSO (1%) were also totally effective while catalase and superoxide decreased Fn-f mediated damage only during the first week and superoxide dismutase alone caused damage after 1 wk. The AOs caused protection by reducing the major catabolic activities of the Fn-f: enhanced release of stromelysin-1 (MMP-3) and suppression of PG and protein synthesis. NAC also decreased normal rates of PG degradation and increased the half-lives of labeled PG in both control and Fn-f treated cartilage. We conclude that the Fn-f mediates cartilage chondrolysis through ROS, consistent with the involvement of catabolic cytokines in the Fn-f mechanism, and that AOs greatly reduce Fn-f mediated cartilage chondrolysis. In an accompanying manuscript we also report that AOs promote reparative responses in Fn-f and cytokine treated cartilage.}, }
@article {pmid8947498, year = {1996}, author = {Saxena, M and Henderson, GB}, title = {MOAT4, a novel multispecific organic-anion transporter for glucuronides and mercapturates in mouse L1210 cells and human erythrocytes.}, journal = {The Biochemical journal}, volume = {320 (Pt 1)}, number = {Pt 1}, pages = {273-281}, pmid = {8947498}, issn = {0264-6021}, support = {CA23970/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; Anion Transport Proteins ; Carrier Proteins/antagonists &amp; inhibitors/*metabolism ; Erythrocytes/*metabolism ; Glucuronates/*metabolism ; Glutathione/analogs &amp; derivatives/metabolism ; Humans ; Ion Transport ; Kinetics ; Leukemia L1210/*metabolism/pathology ; Mice ; }, abstract = {Glucuronides and mercapturates were examined as possible high-affinity substrates for a low-affinity ATP-dependent transport system for 2,4-dinitrophenyl S-glutathione (DNP-SG) in mouse L1210 cells. Initial inhibitor studies with inside-out vesicles revealed that the low-affinity transport of [3H]DNP-SG (Km 450 microM) exhibits a high sensitivity to N-acetyl 2,4-dinitrophenyl cysteine (NAc-DNP-Cys) (Ki 5.0 microM) and alpha-naphthyl beta-D-glucuronide (naphthyl glucuronide) (Ki 8.5 microM). Direct transport measurements showed the presence of ATP-dependent uptake activities for NAc-DNP-[35S]Cys and naphthyl [14C] glucuronide, and Km values for half-maximal transport were comparable to the Ki values of these compounds for inhibition of [3H]DNP-SG transport. Transport of [3H]DNP-SG, NAc-DNP-[35S]Cys and naphthyl [14C]glucuronide each showed the same sensitivity to various anions and anion conjugates. Inhibition was competitive and was most potent for bilirubin ditaurate, indoprofen, 4-biphenylacetic acid, 4-acridine 4 beta-D-glucuronide, N-acetyl leukotriene E4, 17 beta-oestradiol 3 beta-D-glucuronide and taurolithocholate 3-sulphate. Inside-out vesicles from human erythrocytes contain a comparable ATP-dependent transport system. These results show that NAc-DNP-Cys and naphthyl glucuronide are high-affinity substrates for a single system identified previously as a low-affinity transporter of DNP-SG. Substrate and inhibitor studies identify this system as a novel multispecific organic-anion transport system (MOAT4) that accommodates glucuronides and mercapturates and is distinct from other MOAT transporters. Human erythrocytes contain an additional ATP-dependent system for NAc-DNP-Cys (Km 33 microM) that does not transport monoglucuronides.}, }
@article {pmid8932258, year = {1996}, author = {Fukuse, T and Hirata, T and Ueda, M and Hitomi, S and Wada, H}, title = {Effects of Euro-Collins, University of Wisconsin, and new extracellular-type trehalase-containing Kyoto solutions in an ex vivo rat lung preservation model.}, journal = {Transplantation}, volume = {62}, number = {9}, pages = {1212-1217}, doi = {10.1097/00007890-199611150-00004}, pmid = {8932258}, issn = {0041-1337}, mesh = {Adenosine ; Allopurinol ; Animals ; Gluconates ; Glutathione ; Hydroxyethyl Starch Derivatives ; Hypertonic Solutions ; Insulin ; *Lung ; *Lung Transplantation ; Male ; Organ Preservation/*methods ; *Organ Preservation Solutions ; Phosphates ; Raffinose ; Rats ; Rats, Inbred Lew ; Trehalose ; }, abstract = {BACKGROUND: We have previously reported the effects of trehalose-based extracellular-type Kyoto (ET-K) solution in lung preservation. Now, we have developed a new ET-K solution by adding three substances--N-acetyl cysteine, dibutyryl cyclic AMP, and nitroglycerin, to ET-K solution. We studied the effects of new ET-K solution in lung preservation, and compare it with Euro-Collins (EC) and University of Wisconsin (UW) solutions using an ex vivo rat reperfusion model.<br><br>METHODS: The perfusion circuit was initiated by 30 ml of fresh mixed venous blood obtained from three haparinized rats. By means of a double-head roller pump, the blood passed from the venous blood reservoir through the pulmonary artery to be perfused in the examined lung. The lung effluent was returned at the same flow rate to the deoxygenator fresh lung. Four experimental groups were allocated. In group 1 (fresh group, n=6), lung was flushed with saline and reperfused immediately. In the other groups (group 2: new ET-K group, n=6; group 3: UW group, n=6; and group 4: EC group, n=6), lung was flushed with the new ET-K and prostanglandin E1 (PGE1), UW and PGE1, and EC and PGE1, respectively. After 17-hr preservation, the preserved lung was reperfused.<br><br>RESULTS: In all six animals of the EC group, ventilation of the experimental lung was discontinued at 20 min after reperfusion because of the exudate in the endotracheal tube that resulted from pulmonary edema. The shunt fraction, pulmonary arterial pressure, and peak inspiratory pressure in the new ET-K and UW groups were significantly better than those in the EC group, but were almost equal to those in the fresh group.<br><br>CONCLUSION: The postpreservation pulmonary functions with the new ET-K solution were better than those with the EC solution, and were equal to those with the UW solution. This new solution is expected to contribute to the increase in donor lungs for clinical lung transplantation. In addition, this ex vivo rat reperfusion model is simple and highly reliable, and can be widely used in the studies of pulmonary preservation.}, }
@article {pmid9027951, year = {1996}, author = {Ellis, A and Wendon, J}, title = {Circulatory, respiratory, cerebral, and renal derangements in acute liver failure: pathophysiology and management.}, journal = {Seminars in liver disease}, volume = {16}, number = {4}, pages = {379-388}, doi = {10.1055/s-2007-1007251}, pmid = {9027951}, issn = {0272-8087}, mesh = {*Blood Circulation ; Brain Edema/therapy ; Cardiovascular Diseases/complications ; Cerebrovascular Circulation ; Hemodynamics ; Humans ; Hypotension/drug therapy/etiology/physiopathology ; *Liver Failure, Acute/complications/physiopathology/therapy ; Renal Insufficiency/therapy ; }, abstract = {Many of the hemodynamic abnormalities seen in acute liver failure (ALF) have now been characterized. A lowered systemic vascular resistance with a raised cardiac output are prominent features, which in part are modulated by nitric oxide (NO). At a cellular level, oxygen supply and utilization are impaired by changes in vascular tone, plugging of nutritive vessels, and pathological shunting. The use of N-acetylcysteine (NAC) and prostacyclin, a vasodilator, have been shown to increase oxygen utilization in the microcirculation. NAC may act by enhancing the effect of NO on guanylate cyclase, increasing the formation of cyclic 3',5'-guanosine monophosphate (cGMP), and thereby resulting in vasodilatation. This suggests that despite overproduction of NO in ALF, there is a short-age/ failure of utilization at a cellular level. Appropriate management of these patients should be based on a good knowledge of the underlying pathophysiology, and thus on monitoring, during the course of the disease.}, }
@article {pmid8969987, year = {1996}, author = {Brandwene, EL and Williams, SR and Tunget-Johnson, C and Turchen, SG and Manoguerra, AS and Clark, RF}, title = {Refining the level for anticipated hepatotoxicity in acetaminophen poisoning.}, journal = {The Journal of emergency medicine}, volume = {14}, number = {6}, pages = {691-695}, doi = {10.1016/s0736-4679(96)00177-1}, pmid = {8969987}, issn = {0736-4679}, mesh = {Acetaminophen/*poisoning/toxicity ; Acetylcysteine/therapeutic use ; Adolescent ; Adult ; Clinical Protocols ; Drug Overdose/drug therapy ; Female ; Humans ; Infant ; Liver/*drug effects ; Male ; Pilot Projects ; Retrospective Studies ; Time Factors ; }, abstract = {Treatment of an acetaminophen overdose with N-acetyl cysteine usually is based on the position of the 4-h acetaminophen (APAP) level on the Rumack-Matthew nomogram; however, there is disagreement on the level at which clinically relevant hepatotoxicity occurs. A retrospective review of all acute adult formulation APAP exposures reported to our poison center between 1986 and 1993 was performed and cases corresponding to the "possible risk or toxicity" range on the nomogram were identified. Our current poison center protocol for APAP poisoning does not recommend treatment with N-acetylcysteine (NAC) in low-risk patients if the 4-h serum APAP level or the extrapolated equivalent falls within the possible toxicity range on the nomogram. Seventeen cases met the inclusion criteria for the study and received no NAC; six additional patients met inclusion criteria but received one or two doses of NAC before therapy was discontinued. No patients in either group demonstrated clinical evidence of hepatotoxicity. This pilot study suggests that patients with no risk factors and APAP levels in the "possible risk" range may not require NAC therapy.}, }
@article {pmid8968058, year = {1996}, author = {Conaway, CC and Jiao, D and Chung, FL}, title = {Inhibition of rat liver cytochrome P450 isozymes by isothiocyanates and their conjugates: a structure-activity relationship study.}, journal = {Carcinogenesis}, volume = {17}, number = {11}, pages = {2423-2427}, doi = {10.1093/carcin/17.11.2423}, pmid = {8968058}, issn = {0143-3334}, support = {CA46535/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/metabolism ; Enzyme Inhibitors/*pharmacology ; Isoenzymes/*antagonists &amp; inhibitors/metabolism ; Isothiocyanates/*pharmacology ; Liver/drug effects/*enzymology ; Male ; Rats ; Rats, Inbred F344 ; Structure-Activity Relationship ; }, abstract = {A series of arylalkyl and alkyl isothiocyanates, and their glutathione, cysteine, and N-acetylcysteine conjugates were used to study their inhibitory activity toward the dealkylation of ethoxyresorufin (EROD), pentoxyresorufin (PROD), and methoxyresorufin (MROD) in liver microsomes obtained from the 3-methylcholanthrene or phenobarbital-treated rats. These reactions are predominantly mediated by cytochrome P450 (P450) isozymes 1A1 and 1A2, 2B1 and 1A2, respectively. All isothiocyanates inhibited PROD more readily than EROD. Increases in the alkyl chain length of arylalkyl isothiocyanates to C6 resulted in an increased inhibitory potency in these assays; at longer alkyl chain lengths (C8-C10) the inhibitory potency declined. The IC50s for phenethyl isothiocyanate (PEITC) were 47, 46 and 1.8 microM for EROD, MROD and PROD, respectively. Substitution of an additional phenyl group on PEITC also increased the inhibitory potency; the IC50s for 1,2-diphenylethyl isothiocyanate (1,2-DPEITC) and 2,2-diphenylethyl isothiocyanate (2,2-DPEITC) were 0.9 and 0.26 microM for EROD, and 0.045 and 0.13 microM for PROD, respectively. The relative inhibitory potency of PEITC and its conjugates was N-acetylcysteine-PEITC (PEITC-NAC) < glutathione-PEITC (PEITC-GSH) < cysteine-PEITC (PEITC-CYS) < PEITC. The observations that the parent isothiocyanates were more potent inhibitors than the conjugates suggest that dissociation of the conjugate is required for activity. Naturally occurring alkyl isothiocyanates, sulforaphane (SFO) and allyl isothiocyanate (AITC), were very weak inhibitors in the assays. These results suggest the potential of isothiocyanates as structural probes for studying P450 isozymes. In addition, the inhibitory activity of isothiocyanates for PROD correlated with the previously demonstrated tumor inhibitory potency in (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced A/J mouse lung tumor bioassays, which supports earlier findings that P450 2B1 is one of the major isozymes involved in NNK activation and that inhibition of this isozyme is an important mechanism for the chemopreventive activity of isothiocyanates.}, }
@article {pmid8950741, year = {1996}, author = {Iiboshi, Y and Nezu, R and Khan, J and Chen, K and Cui, L and Yoshida, H and Wasa, M and Fukuzawa, M and Kamata, S and Takagi, Y and Okada, A}, title = {Developmental changes in distribution of the mucous gel layer and intestinal permeability in rat small intestine.}, journal = {JPEN. Journal of parenteral and enteral nutrition}, volume = {20}, number = {6}, pages = {406-411}, doi = {10.1177/014860719602000606}, pmid = {8950741}, issn = {0148-6071}, mesh = {Acetylcysteine/pharmacology ; Animals ; Dextrans/metabolism ; Epithelium/metabolism ; Fluorescein-5-isothiocyanate/analogs &amp; derivatives/metabolism ; Gels ; Intestinal Mucosa/drug effects/*growth &amp; development/metabolism ; Intestine, Small/drug effects/*growth &amp; development/metabolism ; Male ; Mucus/*metabolism ; Permeability ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Fluorescence ; }, abstract = {BACKGROUND: From the developmental aspects, the distribution of fluorescein isothiocyanate dextran 70,000 (FTTC-dextran) and mucous gel across the lumen of small intestine was observed as an investigation into the role of mucous gel on intestinal permeability. Furthermore, the effect of N-acetyl cysteine (NAC), a mucolytic agent, on intestinal permeability was examined.<br><br>METHODS: In suckling and weaned rats, FTTC-dextran (750 mg/kg body wt) was gavage-fed. After 3 hours, blood samples were taken by cardiac puncture to analyze plasma FTTC-dextran by fluorescence spectrometry. Samples of small intestine with luminal contents were frozen and sectioned in a cryostat for fluorescence microscopy; the same sections were placed in a 0.2% celloidin solution to preserve mucous gel and were stained by periodic acid-Schiff reaction for light microscopy. In weaned rats, intestinal permeability was examined with different concentrations of intraluminally instilled NAC.<br><br>RESULTS: The plasma level of FTTC-dextran showed a significant increase (p < .01) in suckling rats compared with the weaned rats. Morphologic findings were similar in both the jejunum and ileum: The spaces between villi were not entirely filled with mucus but filled with FTTC-dextran in suckling rats, whereas the spaces were filled with mucus and not filled with FTTC-dextran in weaned rats. Intestinal permeability in groups with NAC were significantly higher (p < .01) than that in group without NAC.<br><br>CONCLUSIONS: These results suggest that an increase in the mucous gel layer that coats the epithelial lining according to the maturation of the gastrointestinal tract is one of the most important factors for a restriction in intestinal permeability.}, }
@article {pmid8937852, year = {1996}, author = {Matthews, AM and Roberts, DW and Hinson, JA and Pumford, NR}, title = {Acetaminophen-induced hepatotoxicity. Analysis of total covalent binding vs. specific binding to cysteine.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {24}, number = {11}, pages = {1192-1196}, pmid = {8937852}, issn = {0090-9556}, support = {GM48749/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/immunology/metabolism/*toxicity ; Animals ; Binding Sites ; Blotting, Western ; Cysteine/*metabolism ; Immune Sera ; Liver/*drug effects/metabolism ; Mice ; }, abstract = {Acetaminophen-induced hepatotoxicity is believed to be mediated by covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to essential proteins in liver. It has been shown that the primary reaction of this metabolite with hepatic proteins is the formation of 3-(cysteine-S-yl)-acetaminophen adducts. The importance of covalent binding to other amino acids that may be formed by reaction of N-acetyl-p-benzoquinone imine with protein is unclear. Previously, we developed immunochemical assays for the acetaminophen cysteine adducts by immunizing animals with the conjugate 3-(N-acetylcystein-S-yl)acetaminophen-keyhole limpet hemocyanin, wherein the carboxyl group of the N-acetyl-cysteine moiety was coupled to amino groups on the protein. A very sensitive and specific immunochemical assay was developed for acetaminophen specifically bound to cysteine groups on protein [3-(cystein-S-yl)acetaminophen protein adducts]. Analysis of protein adducts indicated that after toxic doses, acetaminophen covalently bound at high levels to cysteine residues on a relatively small number of hepatic proteins. In the present work, a new antiacetaminophen antiserum was prepared by immunizing mice with 4-acetamidobenzoic acid coupled to keyhole limpet hemocyanin. Competitive ELISA data indicate that the resulting antiserum has excellent recognition of acetaminophen and related arylacetamide derivatives. Using this new antiserum, Western blot analyses of liver proteins from acetaminophen-intoxicated mouse livers were performed and compared with similar assays using the anti-3-(cystein-S-yl)acetaminophen antiserum. Visual and densitometric analyses of the Western blots indicate that the two antisera detect the same primary acetaminophen protein adducts; however, minor differences in the intensity of certain bands were observed. These differences may represent either differences in antibody accessibility to 3-(cystein-S-yl)acetaminophen adducts or differences in the proportion of acetaminophen bound to cysteine vs. binding to other amino acids.}, }
@article {pmid8937735, year = {1996}, author = {Muller, B and Kleschyov, AL and Stoclet, JC}, title = {Evidence for N-acetylcysteine-sensitive nitric oxide storage as dinitrosyl-iron complexes in lipopolysaccharide-treated rat aorta.}, journal = {British journal of pharmacology}, volume = {119}, number = {6}, pages = {1281-1285}, pmid = {8937735}, issn = {0007-1188}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta, Thoracic/*drug effects/metabolism ; Electron Spin Resonance Spectroscopy ; In Vitro Techniques ; Iron/*metabolism ; Lipopolysaccharides/*pharmacology ; Male ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide/*metabolism ; Rats ; Rats, Wistar ; Vasoconstriction/drug effects ; }, abstract = {1. The aim of this study was to assess whether or not vasoactive nitric oxide (NO) stores exist within vascular tissue after lipopolysaccharide (LPS)-treatment. 2. Rat thoracic aortic rings (for contraction experiments) or whole thoracic aortae (for electron paramagnetic resonance (e.p.r.) spectroscopy) were incubated for 18 h at 37 degrees C in the absence (control) or in the presence of LPS (10 micrograms ml-1), with or without L-arginine (L-Arg, 1 mM), the substrate of NO synthase (NOS) or N omega-nitro-L-arginine methyl ester (L-NAME, 1 mM), an inhibitor of NOS. 3. Incubation of rat aortic rings with LPS and L-Arg resulted in a significant decrease of the maximum contractile response to noradrenaline (NA, 3 microM). Addition of L-NAME (3 mM) enhanced contraction towards control values. After precontraction with NA and L-NAME, addition of N-acetyl-L-cysteine (NAC, 0.1 to 10 mM) evoked a concentration-dependent relaxation in rings incubated with LPS and L-Arg, but not in control rings, rings incubated with LPS in the absence of L-Arg or rings incubated with LPS in the presence of L-Arg and L-NAME. Removal of the endothelium did not significantly modify the relaxation induced by NAC. Methylene blue (3 microM), an inhibitor of the activation of guanylyl cyclase by NO, completely abolished the relaxing effect of NAC. 4. The presence of protein-bound dinitrosyl non-haem iron complexes (DNIC) was detected by e.p.r. spectroscopy in aortae incubated with LPS and L-Arg, but not in control aortae. Furthermore in LPS-treated aortae, addition of NAC (20 mM) gave rise to the appearance of an e.p.r. signal characteristic of low molecular weight DNIC. 5. These results provide evidence that, within vascular tissue, NO generated from L-Arg by LPS-induced NOS activity can be stored as protein-bound DNIC in non-endothelial cells. Upon addition of NAC, low molecular weight DNIC are released from these storage sites and induce vascular relaxation probably through guanylyl cyclase activation.}, }
@article {pmid8929554, year = {1996}, author = {Watson, RW and Redmond, HP and Wang, JH and Bouchier-Hayes, D}, title = {Mechanisms involved in sodium arsenite-induced apoptosis of human neutrophils.}, journal = {Journal of leukocyte biology}, volume = {60}, number = {5}, pages = {625-632}, doi = {10.1002/jlb.60.5.625}, pmid = {8929554}, issn = {0741-5400}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Arsenites/*pharmacology ; Catalase/pharmacology ; Dimethyl Sulfoxide/pharmacology ; Gene Expression Regulation/drug effects ; Glutathione/pharmacology ; Humans ; Macrophage-1 Antigen/biosynthesis/genetics ; Neutrophils/*drug effects ; Reactive Oxygen Species ; Receptors, IgG/biosynthesis/genetics ; Respiratory Burst/*drug effects ; Sodium Compounds/*pharmacology ; Taurine/pharmacology ; }, abstract = {Apoptosis is a distinct mechanism by which eukaryotic cells die. Factors governing the induction of polymorphonuclear leukocyte (PMN) apoptosis should be important in understanding resolution of acute inflammation. The mechanisms for induction of PMN apoptosis remain uncertain; however, oxidative stress has been suggested. The aims of this study were to determine whether reactive oxygen intermediates play a role in PMN apoptosis and to investigate inhibition of this process by selective use of antioxidants. PMN were isolated from 10 healthy volunteers. PMN (1 x 10(6) PMN/mL) were cultured in 40, 80, and 160 microM of arsenite for 2, 6, 12, 18, and 24 h. Apoptosis was assessed qualitatively by morphology and gel electrophoresis and quantitatively by CD16 receptor expression and propidium iodide DNA staining. There was a significant (P < 0.05) increase in the rate of apoptosis on incubation with arsenite (80 and 160 microM). To investigate the mechanism of this process, intracellular respiratory burst activity was measured following arsenite culture. We found that arsenite-induced PMN apoptosis correlated with an increase in intracellular respiratory burst. To further investigate the role of oxidative injury in inducing apoptosis, the antioxidants catalase, dimethyl sulfoxide (DMSO), glutathione (GSH), N-acetylcysteine (NAC), and taurine were investigated and we demonstrated that GSH, NAC, and taurine were significantly protective against arsenite-induced apoptosis. However, catalase and DMSO failed to induce protection. This study demonstrates that arsenite induces PMN apoptosis through an oxygen-dependent mechanism that can be prevented through selective antioxidants.}, }
@article {pmid8909441, year = {1996}, author = {Hurd, RW and Wilder, BJ and Helveston, WR and Uthman, BM}, title = {Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine.}, journal = {Neurology}, volume = {47}, number = {5}, pages = {1264-1268}, doi = {10.1212/wnl.47.5.1264}, pmid = {8909441}, issn = {0028-3878}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Anticonvulsants/*therapeutic use ; Epilepsies, Myoclonic/*drug therapy/physiopathology ; Evoked Potentials, Somatosensory/drug effects ; Female ; Humans ; Male ; }, abstract = {The finding of increased activity of the enzyme extracellular superoxide dismutase in four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type (PME-UL) prompted the addition of antioxidants to these patients' treatment regimen. After 6 months treatment with vitamin E, selenium, riboflavin, and zinc, there was some improvement in patient awareness and speech. N-acetylcysteine (NAC) is a sulfhydryl antioxidant that increases cellular glutathione and the activity levels of several antioxidant enzymes and has additional actions that contribute to its demonstrated efficacy in preventing or decreasing damage in models of neuronal toxicity. We treated the affected siblings with 4 to 6 grams a day of NAC in addition to the other antioxidants and magnesium. There has been a marked decrease in myoclonus and some normalization of somatosensory evoked potentials with NAC treatment. The patients were treated with NAC for up to 30 months with continued beneficial effects. NAC may prevent further deterioration in the clinical course of patients with PME-UL and may be indicated in other neurodegenerative conditions where excess free radical activity may contribute to disease progression.}, }
@article {pmid8909270, year = {1996}, author = {Wright, RO and Magnani, B and Shannon, MW and Woolf, AD}, title = {N-acetylcysteine reduces methemoglobin in vitro.}, journal = {Annals of emergency medicine}, volume = {28}, number = {5}, pages = {499-503}, doi = {10.1016/s0196-0644(96)70112-9}, pmid = {8909270}, issn = {0196-0644}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Free Radical Scavengers/*pharmacology ; Hemoglobins/drug effects/metabolism ; Humans ; In Vitro Techniques ; Methemoglobin/*drug effects/metabolism ; Oxidation-Reduction ; Sodium Nitrite/toxicity ; }, abstract = {STUDY OBJECTIVE: To determine whether N-acetylcysteine (NAC reduces methemoglobin.<br><br>METHODS: We carried out an in vitro laboratory experiment in which five healthy adult volunteers donated blood. Each sample was divided equally among three test tubes. Tube 1 served as a negative control. Sodium nitrite .18 mol/L with dextrose .23 mol/L was added to tube 2 and to tube 3. Next, phosphate-buffered saline solution (PBS) was added to tube 2 and NAC (200 mg/mL) to tube 3. Serial methemoglobin levels were measured over 5.5 hours.<br><br>RESULTS: Maximum methemoglobin levels were observed at 1.5 hours for both the NAC-nitrite and the PBS-nitrite sample (62.7% +/- 8.1% and 65.1% +/- 7.0%, respectively; data expressed as mean +/- SD). The mean difference in methemoglobin between NAC-nitrite and PBS-nitrite was significant at 4.5 hours (29.3% +/- 23.0%, P = .046). The mean rate of methemoglobin decline in NAC-nitrite samples was also different from that of PBS-nitrite samples (10.7% +/- 1.0% versus 2.9% +/- 2.3%, P = .002). The rate of decline was linea (zero order) in the NAC nitrite samples and represented by the equation: % change methemoglobin = .18 x time in minutes. Area under the concentration-time curve was also different among groups (P < .05).<br><br>CONCLUSION: In this in vitro model, NAC reduced chemically induced methemoglobin.}, }
@article {pmid8908200, year = {1996}, author = {Mitchell, J and Jiang, H and Berry, L and Meyrick, B}, title = {Effect of antioxidants on lipopolysaccharide-stimulated induction of mangano superoxide dismutase mRNA in bovine pulmonary artery endothelial cells.}, journal = {Journal of cellular physiology}, volume = {169}, number = {2}, pages = {333-340}, doi = {10.1002/(SICI)1097-4652(199611)169:2&lt;333::AID-JCP12&gt;3.0.CO;2-A}, pmid = {8908200}, issn = {0021-9541}, support = {HL 34208/HL/NHLBI NIH HHS/United States ; HL 45151/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Animals ; Antioxidants/*pharmacology ; Blotting, Northern ; Cattle ; Cell Nucleus ; Cell Size/drug effects ; Cells, Cultured ; Dimethyl Sulfoxide/pharmacology ; Endothelium/metabolism ; Gene Expression Regulation/genetics ; Lipopolysaccharides/*pharmacology ; Microscopy ; Pulmonary Artery ; Reactive Oxygen Species/metabolism ; Superoxide Dismutase/genetics/*metabolism ; }, abstract = {Generation of reactive oxygen species (ROS) is a common event in the pathogenesis of acute lung injury. Endothelial cells may be both a target and a source of the ROS. Exposure of bovine pulmonary endothelial cells (BPAEC) to lipopolysaccharide (LPS) has been shown to result in intracellular generation of both ROS and the antioxidant enzyme, mangano superoxide dismutase (MnSOD). The present study investigates whether alterations in intracellular oxidant state affect LPS-stimulated cytotoxicity and induction of MnSOD mRNA. BPAEC were pretreated with either the free radical scavenger, dimethylsulfoxide (DMSO), the xanthine oxidase inhibitor, allopurinol, or N-acetylcysteine (a cysteine derivate capable of increasing glutathione stores) prior to exposure to LPS (0.1 microgram/ml) for either 4, 8 or 18 hours. We found that pretreatment of BPAEC with DMSO blocked both LPS-induced cytotoxicity and induction of the MnSOD gene. Nuclear run-off experiments demonstrated that LPS-stimulated induction of the MnSOD mRNA occurred at the transcriptional level and that DMSO blocked this event. Pretreatment with allopurinol also prevented the cytotoxicity associated with LPS but, in contrast to DMSO, did not alter induction of MnSOD mRNA. N-acetylcysteine did not affect the LPS-stimulated cytotoxicity but resulted in an early and transient reduction in induction of the MnSOD gene. We conclude that LPS stimulates generation of intracellular ROS that regulate induction of the MnSOD gene at the transcriptional level further, we conclude that LPS-stimulated cytotoxicity involves both the xanthine oxidase pathway and perhaps intracellular generation of hydroxyl radicals. The difference in the protective effect between DMSO, NAC and allopurinol suggest that upregulation of the MnSOD gene does not contribute to LPS-induced cytotoxicity.}, }
@article {pmid8908193, year = {1996}, author = {Wang, TS and Kuo, CF and Jan, KY and Huang, H}, title = {Arsenite induces apoptosis in Chinese hamster ovary cells by generation of reactive oxygen species.}, journal = {Journal of cellular physiology}, volume = {169}, number = {2}, pages = {256-268}, doi = {10.1002/(SICI)1097-4652(199611)169:2&lt;256::AID-JCP5&gt;3.0.CO;2-N}, pmid = {8908193}, issn = {0021-9541}, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Arsenites/*pharmacology/toxicity ; CHO Cells ; Cell Count/drug effects ; Chelating Agents/pharmacology ; Chromans ; Cricetinae ; Cycloheximide/pharmacology ; DNA Damage/drug effects ; Electrophoresis, Agar Gel ; Flow Cytometry ; Fluoresceins/metabolism ; G1 Phase/drug effects ; G2 Phase/drug effects ; Hydrogen Peroxide/metabolism/pharmacology ; Reactive Oxygen Species/*metabolism ; }, abstract = {Arsenic, a human carcinogen, possesses a serious environmental threat but the mechanism of its toxicity remains unclear. Knowledge of how arsenic induces cell death and how cells escape the death path may help to understand arsenic carcinogenesis. We have investigated the nature of sodium arsenite-induced cell death in Chinese hamster ovary K1 cells. Following phosphate-citric acid buffer extraction, apoptotic cells with lower DNA content than the G1 cells were detected by flow cytometry. Immediately after 4 h of 40 microM arsenite treatment, no appreciable fraction of cells with sub-G1 DNA content was detected; however, the sub-G1 cell fraction increased with postarsenite incubation time, and detectable increase started at 8 h of incubation, whereas the intracellular peroxide level as measured by the fluorescent intensity of 2',7'-dichlorofluorescein increased immediately following a 4-h arsenite treatment. Simultaneous treatment with arsenite plus antioxidant (N-acetyl-cysteine, Trolox, and Tempo); copper ion chelator (neocuproine); protein kinase inhibitor (H-7) or protein synthesis inhibitor (cycloheximide) reduced the fraction of sub-G1 cell and internucleosomal DNA degradation. Trolox, neocuproine, or cycloheximide given after arsenite treatment also effectively reduced apoptosis. These results lead to a working hypothesis that arsenite-induced apoptosis in CHO-K1 cells is triggered by the generation of hydrogen peroxide, followed by a copper-mediated Fenton reaction that catalyzes the production of hydroxyl radicals, which selectively activates protein kinase through de novo synthesis of macromolecules.}, }
@article {pmid8896414, year = {1996}, author = {Muñoz, C and Pascual-Salcedo, D and Castellanos, MC and Alfranca, A and Aragonés, J and Vara, A and Redondo, JM and de Landázuri, MO}, title = {Pyrrolidine dithiocarbamate inhibits the production of interleukin-6, interleukin-8, and granulocyte-macrophage colony-stimulating factor by human endothelial cells in response to inflammatory mediators: modulation of NF-kappa B and AP-1 transcription factors activity.}, journal = {Blood}, volume = {88}, number = {9}, pages = {3482-3490}, pmid = {8896414}, issn = {0006-4971}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cells, Cultured ; Endothelium, Vascular/*metabolism ; Free Radical Scavengers/pharmacology ; *Gene Expression Regulation ; Granulocyte Colony-Stimulating Factor/*biosynthesis/genetics ; Humans ; Interleukin-6/*biosynthesis/genetics ; Interleukin-8/*biosynthesis/genetics ; NF-kappa B/genetics ; Pyrrolidines/*pharmacology ; Thiocarbamates/*pharmacology ; Transcription Factor AP-1/*genetics ; }, abstract = {Endothelial cells (EC) play a key role in the inflammatory response, both by the production of proinflammatory cytokines and by their interaction with leukocytes. Molecular genetic analysis has demonstrated that functional NF-kappa B sites are involved in the transcription of interleukin-6 (IL-6), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes in response to inflammatory mediators. Thus, we have explored the effect of two inhibitors of the NF-kappa B activation, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), on the production of these cytokines by EC. Both PDTC and NAC inhibited, in a dose-dependent manner, the synthesis of IL-6, IL-8, and GM-CSF induced by tumor necrosis factor (TNF)-alpha or bacterial lipopolysaccharides (LPS) in human umbilical vein endothelial cells (HUVEC). PDTC appeared to prevent IL-6, IL-8, and GM-CSF gene transcription, as it blocked the induction of specific mRNA by TNF-alpha or LPS. The TNF-alpha mediated transcriptional activation of a chloramphenicol acetyltransferase (CAT) plasmid containing three copies of the -72 kappa B binding site from the IL-6 promoter was abrogated by PDTC. According to transfection experiments, electrophoretic mobility shift assays (EMSA) demonstrated that the antioxidant prevented the induction of NF-kappa B DNA-binding activity by TNF-alpha. Under the same conditions, PDTC by itself or in combination with TNF-alpha, enhanced the DNA-binding activity of AP-1, as well as c-fos and c-jun mRNA levels. Altogether, these results indicate that the antioxidant PDTC specifically inhibits the transcription of IL-6, IL-8, and GM-CSF genes through the inhibition of the NF-kappa B activation, while increasing the expression of AP-1. Our data make evident the antiinflammatory and immunoregulatory potential of the pharmacological inhibition of the NF-kappa B activation. In addition, PDTC and related molecules may be a useful tool to explore the expression of genes involved in the inflammatory response.}, }
@article {pmid8953175, year = {1996}, author = {Ercal, N and Oztezcan, S and Hammond, TC and Matthews, RH and Spitz, DR}, title = {High-performance liquid chromatography assay for N-acetylcysteine in biological samples following derivatization with N-(1-pyrenyl)maleimide.}, journal = {Journal of chromatography. B, Biomedical applications}, volume = {685}, number = {2}, pages = {329-334}, doi = {10.1016/s0378-4347(96)00196-x}, pmid = {8953175}, issn = {1572-6495}, support = {R01HL51469/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*analysis/chemistry/pharmacokinetics ; Animals ; Calibration ; Chromatography, High Pressure Liquid/*methods ; Drug Stability ; Free Radical Scavengers/administration &amp; dosage/*analysis/chemistry/pharmacokinetics ; Linear Models ; Male ; Maleimides/*chemistry ; Rats ; Rats, Sprague-Dawley ; Reproducibility of Results ; Sensitivity and Specificity ; Sulfhydryl Reagents/*chemistry ; Tissue Distribution ; }, abstract = {N-Acetylcysteine is a thiol antioxidant with expanding clinical importance. A sensitive, rapid method for determining reduced N-acetylcysteine (NAC) concentration in biological samples has been developed which uses a modified reversed-phase high-performance liquid chromatography (HPLC) technique in conjunction with the derivatizing agent N-(1-pyrenyl)maleimide (NPM). The NAC-NPM adduct was analyzed by HPLC with fluorescence detection. The calibration curve for NAC was linear over the range 8-2500 nM and the coefficient of variation obtained for the within-run precision and the between-run precision for 0.5 mM NAC was 1.5% and 2.7%, respectively. Relative recovery of NAC from biological materials ranged between 86% and 96% and the limit of quantitation from biological samples was 32 nM. These results suggest practical advantages relative to other widely-accepted methods of NAC measurement.}, }
@article {pmid8871608, year = {1996}, author = {Breithaupt, TB and Vazquez, A and Baez, I and Eylar, EH}, title = {The suppression of T cell function and NF(kappa)B expression by serine protease inhibitors is blocked by N-acetylcysteine.}, journal = {Cellular immunology}, volume = {173}, number = {1}, pages = {124-130}, doi = {10.1006/cimm.1996.0258}, pmid = {8871608}, issn = {0008-8749}, support = {G12 RR003050/RR/NCRR NIH HHS/United States ; S06 GM008239/GM/NIGMS NIH HHS/United States ; 1-S06-RR08239/RR/NCRR NIH HHS/United States ; 1G12RR03050/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; DNA/metabolism ; Humans ; Interferon-gamma/immunology ; Interleukin-2/immunology ; Interleukin-6/immunology ; Mitogens/pharmacology ; NF-kappa B/*immunology ; Serine Proteinase Inhibitors/pharmacology ; T-Lymphocytes/drug effects/*immunology ; Tosyllysine Chloromethyl Ketone/pharmacology ; Tosylphenylalanyl Chloromethyl Ketone/pharmacology ; }, abstract = {Direct evidence that N-acetylcysteine (NAC) enhances the immune response of peripheral blood T cells at the level of NF(kappa)B is presented. In addition, NAC blocks the suppression of T cell mitogenesis and cytokine production by protease inhibitors such as N-tosylphenylalanine chloromethyl ketone (TPCK). The proliferative responses of purified CD4+ or CD8+ T cells are suppressed more strongly by TPCK when anti-CD28 rather than the phorbol ester PMA is used as the mitogenic coactivator. Cytokine (IL-2, IL-6, INF-gamma) production is inhibited 95-100% by concentrations of TPCK that totally suppress the mitogenesis of CD4+ or CD8+ cells. Using electrophoretic mobility shift assays, we find that TPCK virtually abolishes (to less than 1%) the levels of NF(kappa)B (but not Oct-1) found in nuclear and whole cell extracts of activated T cells. Strikingly, the immunosuppressive effects of TPCK are blocked when T cells are pretreated for 15 min with 5 mM NAC. NAC not only blocks the effect of TPCK but enhances mitogenesis and cytokine production (>2.5-fold in some cases) upon activation of unsuppressed T cells. Our data support the notion that NF(kappa)B and I(kappa)B proteases play obligate roles in T cell activation and mitogenesis, roles that are enhanced significantly by NAC.}, }
@article {pmid9112277, year = {1996}, author = {He, D and Behar, S and Roberts, JE and Lim, HW}, title = {The effect of L-cysteine and N-acetylcysteine on porphyrin/heme biosynthetic pathway in cells treated with 5-aminolevulinic acid and exposed to radiation.}, journal = {Photodermatology, photoimmunology &amp; photomedicine}, volume = {12}, number = {5}, pages = {194-199}, doi = {10.1111/j.1600-0781.1996.tb00199.x}, pmid = {9112277}, issn = {0905-4383}, mesh = {Acetylcysteine/*pharmacology ; Aminolevulinic Acid/*pharmacology ; Cells, Cultured ; Cysteine/*pharmacology ; Endothelium, Vascular/cytology/drug effects/radiation effects ; Ferrochelatase/drug effects/metabolism/radiation effects ; Heme/*biosynthesis/radiation effects ; Humans ; Porphyrins/*biosynthesis/metabolism/radiation effects ; Ultraviolet Rays ; }, abstract = {The effects of L-cysteine (LC) and N-acetylcysteine (NAC) on porphyrin accumulation in a human dermal microvascular endothelial cell line (HMEC-1) and a human epidermoid carcinoma cell line (A431) loaded with 5-aminolevulinic acid (ALA) and exposed to ultraviolet A (UVA) and blue light radiation were determined. Porphyrin accumulation was decreased in the presence of 0.1-7.5 mM LC (24.8%-31.4% suppression in HMEC-1 cell; 35.8%-48.9% suppression in A431 cells), and in the presence of 0.1-10.0 mM NAC (30.9%-58.0% suppression in HMEC-1 cells; 8.5%-45.3% in A431 cells). The suppression occurred in a LC or NAC dose-dependent fashion. The above was associated with partial reversal of suppression of ferrochelatase (FeC) activity in HMEC-1 cells and in A431 cells. As compared to FeC activity in cells treated with ALA and irradiation, enzyme activity was higher (by 31.9%-62.1%) in the presence of LC (1.0 mM or 5.0 mM) and in the presence of NAC (1.0 mM or 5.0 mM). These data indicate that LC and NAC have protective effects on porphyrin- and irradiation-induced diminution of FeC activity in HMEC-1 cells and A341 cells in vitro.}, }
@article {pmid9029823, year = {1996}, author = {Benard, O and Balasubramanian, KA}, title = {Effect of enterotoxin on glutathione status in the intestinal mucosa.}, journal = {Indian journal of biochemistry &amp; biophysics}, volume = {33}, number = {5}, pages = {409-413}, pmid = {9029823}, issn = {0301-1208}, mesh = {Animals ; Buthionine Sulfoximine/pharmacology ; Cholera Toxin/toxicity ; Cysteine/metabolism ; Endotoxins/*toxicity ; Glutathione/analogs &amp; derivatives/*metabolism ; Glutathione Disulfide ; Intestinal Mucosa/*drug effects/*metabolism ; Maleates/pharmacology ; Rats ; Sulfhydryl Compounds/metabolism ; }, abstract = {The effect of luminal exposure of enterotoxins on the intestinal mucosal glutathione (GSH) was studied in rat. Cholera toxin induced fluid secretion and decreased mucosal GSH by 35% without altering oxidized glutathione (GSSG) level. Toxin induced fluid secretion was tested after mucosal GSH depletion by compounds such as diethyl maleate (DEM) and buthionine sulfoximine (BSO) and thiol supplementation with N-Acetyl cysteine (NAC). Fluid secretion was not altered by prior thiol depletion or supplementation. Exposure of intestinal lumen to bacterial endotoxin resulted in 25% decrease in mucosal GSH with two fold increase in GSSG. Luminal exposure of Shiga toxin did not alter the mucosal thiol. The level of other low molecular weight thiols, cysteine and cystine was not altered by luminal exposure of any of these toxins. These results show that although cholera toxin decreased the mucosal GSH level, prior modulation of thiol status of the mucosa may not have any effect on toxin-induced fluid secretion.}, }
@article {pmid8943716, year = {1996}, author = {Gulbins, E and Brenner, B and Schlottmann, K and Welsch, J and Heinle, H and Koppenhoefer, U and Linderkamp, O and Coggeshall, KM and Lang, F}, title = {Fas-induced programmed cell death is mediated by a Ras-regulated O2- synthesis.}, journal = {Immunology}, volume = {89}, number = {2}, pages = {205-212}, pmid = {8943716}, issn = {0019-2805}, support = {CA64268/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects/*physiology ; Cyclic N-Oxides ; Gene Expression Regulation ; Humans ; Jurkat Cells/*physiology ; Nitrogen Oxides/pharmacology ; Oncogene Protein p21(ras)/*genetics ; Reactive Oxygen Species/*metabolism ; Transfection ; fas Receptor/*pharmacology ; }, abstract = {Fas induces apoptosis in lymphocytes via a poorly defined intracellular signalling cascade. Previously, we have demonstrated the involvement and significance of a signalling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in Fas-induced apoptosis. Here we demonstrate rapid and transient synthesis of reactive oxygen intermediates (ROI) via activation of Ras after Fas. Genetic inhibition of Ras by transfection of transdominant inhibitory N17Ras blocked Fas-mediated ROI synthesis and programmed cell death. Likewise, the antioxidants N-acetyl-cysteine and N-t-butyl-phenylnitrone abolished Fas-induced cell death, pointing to an important role for Ras-triggered ROI synthesis in Fas-mediated programmed cell death.}, }
@article {pmid8921427, year = {1996}, author = {Sakurada, S and Kato, T and Okamoto, T}, title = {Induction of cytokines and ICAM-1 by proinflammatory cytokines in primary rheumatoid synovial fibroblasts and inhibition by N-acetyl-L-cysteine and aspirin.}, journal = {International immunology}, volume = {8}, number = {10}, pages = {1483-1493}, doi = {10.1093/intimm/8.10.1483}, pmid = {8921427}, issn = {0953-8178}, mesh = {Acetylcysteine/*pharmacology ; Arthritis, Rheumatoid/drug therapy/*metabolism ; Aspirin/*pharmacology/therapeutic use ; Cells, Cultured ; Cytokines/*antagonists &amp; inhibitors/*biosynthesis ; Fibroblasts/*metabolism ; Humans ; Intercellular Adhesion Molecule-1/*biosynthesis/*drug effects ; Interleukin-1/antagonists &amp; inhibitors/pharmacology ; NF-kappa B/*antagonists &amp; inhibitors/*pharmacology ; Synovial Membrane/cytology/*metabolism ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/pharmacology ; }, abstract = {The role of transcription factor NF-kappa B in the induction of cytokines and ICAM-1 upon stimulation with proinflammatory cytokines, IL-1 and tumor necrosis factor (TNF)-alpha was investigated in primary synovial fibroblasts obtained from patients with rheumatoid arthritis (RA). Nuclear translocation of NF-kappa B was demonstrated after 30 min of treatment with IL-1 or TNF-alpha. Thereafter, the production of several cytokines including granulocyte macrophage colony stimulating factor, IL-6 and IL-8, that are known to be abundantly produced in the synovial cavity of RA patients, was greatly augmented. Similarly, cell surface expression of ICAM-1 was induced by the IL-1 or TNF-alpha treatment. Since expression of these genes is induced in rheumatoid synovial tissue, this experimental system is considered to represent the in vivo situation of RA pathophysiology. Using this cell culture system we attempted to modulate the intracellular signaling cascade for NF-kappa B activation and examined the effects of N-acetyl-L-cysteine (NAC) and acetylsalicylic acid (aspirin), which were previously reported to inhibit NF-kappa B activation. Pretreatment of the primary synovial fibroblasts with NAC inhibited nuclear translocation of NF-kappa B. Subsequently, the induction of these cytokines and ICAM-1 was considerably suppressed. On the other hand, pretreatment with aspirin blocked these phenomena only partially. These observations indicate the pivotal role of NF-kappa B in RA pathogenesis thus highlighting the possibility of a novel therapeutic strategy.}, }
@article {pmid8915955, year = {1996}, author = {Schmidt, AM and Weidman, E and Lalla, E and Yan, SD and Hori, O and Cao, R and Brett, JG and Lamster, IB}, title = {Advanced glycation endproducts (AGEs) induce oxidant stress in the gingiva: a potential mechanism underlying accelerated periodontal disease associated with diabetes.}, journal = {Journal of periodontal research}, volume = {31}, number = {7}, pages = {508-515}, doi = {10.1111/j.1600-0765.1996.tb01417.x}, pmid = {8915955}, issn = {0022-3484}, support = {A600602//PHS HHS/United States ; HL21006/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Animals ; *Diabetes Complications ; Diabetes Mellitus/*metabolism ; Diabetes Mellitus, Experimental/chemically induced/complications/metabolism ; Enzyme-Linked Immunosorbent Assay ; Gingiva/metabolism ; Glycation End Products, Advanced/administration &amp; dosage/blood/*metabolism ; Heme Oxygenase (Decyclizing)/biosynthesis ; Humans ; Mice ; Oxidative Stress/*physiology ; Periodontitis/*etiology/metabolism ; Streptozocin ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {We hypothesized that one mechanism underlying advanced periodontal disease in diabetes may involve oxidant stress in the gingiva, induced by the effects of Advanced Glycation Endproducts (AGEs), the irreversible products of non-enzymatic glycation and oxidation of proteins and lipids which accumulate in diabetic plasma and tissue. Infusion of AGE albumin, a prototypic ligand, into mice resulted in increased generation of thiobarbituric acid reactive substances (TBARS) compared with infusion of non-glycated albumin in the gingiva, as well as in the lung, kidney and brain. Pretreatment of the animals with the antioxidants probucol or N-acetylcysteine (NAC) prevented the generation of TBARS in the gingiva. Affinity-purified antibody to AGEs demonstrated increased immunoreactivity for AGEs in the vasculature and connective tissues of the gingiva in streptozotocin-induced diabetic mice compared to non-diabetic controls. Increased immunoreactivity for AGEs was also demonstrated in the gingiva of diabetic humans compared with non-diabetic individuals via immunohistochemistry and ELISA. Consistent with these data, immunohistochemistry for heme oxygenase-1, a marker of enhanced oxidant stress, was increased in the gingival vasculature of diabetic mice and humans compared with non-diabetic controls. These data suggest that AGEs present in diabetic gingiva may be associated with a state of enhanced oxidant stress, a potential mechanism for accelerated tissue injury.}, }
@article {pmid8911862, year = {1996}, author = {Koch, T and Heller, S and Heissler, S and Breil, I and Schiefer, HG and van Ackern, K and Neuhof, H}, title = {Effects of N-acetylcysteine on bacterial clearance.}, journal = {European journal of clinical investigation}, volume = {26}, number = {10}, pages = {884-892}, doi = {10.1111/j.1365-2362.1996.tb02134.x}, pmid = {8911862}, issn = {0014-2972}, mesh = {Acetylcysteine/*toxicity ; Animals ; Bacterial Infections/*immunology ; Blood Bactericidal Activity/*drug effects ; Female ; Hemodynamics/drug effects ; Leukocyte Count ; Male ; Neutrophils/*drug effects/physiology ; Rabbits ; Respiratory Burst ; }, abstract = {The aim of this study was to investigate whether the oxygen radical scavenger N-acetylcysteine (N-AC) impairs bacterial clearance, thus predisposing the host to increased risk of disease. Blood clearance of Escherichia coli and organ colonization were investigated in anaesthetized rabbits after pretreatment with N-AC (250 mg kg-1 body weight, n = 16) and in sham-operated animals (n = 12). To enable quantification of the clearance process, defined numbers of exogenous E. coli [1.3 x 108 colony-forming units (CFUs)] were injected intravenously. Parameters monitored were kinetics of bacterial elimination from the blood, and polymorphonuclear leucocyte (PMN) oxidative burst activity. Samples of liver, kidney, spleen and lung were collected for bacterial counts. Compared with controls, pretreatment with N-AC resulted in delayed bacterial elimination from blood and higher organ colonization with increased numbers of E. coli in liver, lung and kidney (P < 0.05). N-AC treatment was associated with a suppressed PMN oxidative burst activity. Impaired bacterial clearance and enhanced organ colonization in N-AC-treated animals correlated with reduced oxidative burst activity, suggesting impaired granulocyte-dependent bacterial killing due to N-AC application.}, }
@article {pmid8925935, year = {1996}, author = {Merin, JP and Matsuyama, M and Kira, T and Baba, M and Okamoto, T}, title = {Alpha-lipoic acid blocks HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable transformants.}, journal = {FEBS letters}, volume = {394}, number = {1}, pages = {9-13}, doi = {10.1016/0014-5793(96)00919-2}, pmid = {8925935}, issn = {0014-5793}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Cell Line ; Drug Resistance ; Gene Expression Regulation, Viral/*drug effects ; HIV Core Protein p24/analysis/genetics ; HIV Long Terminal Repeat/*genetics ; HIV-1/*genetics ; Humans ; Hygromycin B/*pharmacology ; Macrophages/drug effects/virology ; NF-kappa B/antagonists &amp; inhibitors/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism ; Plasmids ; Promoter Regions, Genetic ; Tetrazolium Salts/metabolism ; Thiazoles/metabolism ; Thioctic Acid/*pharmacology ; Transfection ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Gene expression of human immunodeficiency virus (HIV) depends on a host cellular transcription factors including nuclear factor-kappaB (NF-kappaB). The involvement of reactive oxygen intermediates (ROI) has been implicated as intracellular messengers in the inducible activation of NF-kappaB. In this study, we compared the efficacy of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), which are widely recognized NF-kappaB inhibitors. Here, we demonstrate that LA has a more potent activity in inhibiting NF-KappaB-mediated gene expression in THP-1 cells that have been stably transfected with a plasmid bearing a hygromycin B resistance gene under the control of HIV-1 long terminal repeat (LTR) promoter. The spontaneous activation of NF-kappaB in this cell culture system leads to expression of the hygromycin phosphotransferase gene hence rendering the cells resistance to hygromycin B. In this study, the effect of the test compounds against transcriptional activity of HIV-1 LTR was evaluated based on the degree of cellular toxicity due to the inhibitory activity on the expression of hygromycin B resistance gene in the presence of hygromycin B. We also found that 0.2 mM LA could cause 40% reduction in the HIV-1 expression from the TNF-alpha-stimulated OM 10.1, a cell line latently infected with HIV-1. On the other hand, 10 mM NAC was required to elicit the same effect. Furthermore, the initiation of HIV-1 induction by TNF-alpha was completely abolished by 1 mM LA. These findings confirm the involvement of ROI in NF-kappaB-mediated HIV gene expression as well as the efficacy of LA as a therapeutic regimen for HIV infection and acquired immunodeficiency syndrome (AIDS). Moreover, this study validates the applicability of our present assay system which we primarily designed for the screening of candidate drugs against HIV-1 gene expression.}, }
@article {pmid8858872, year = {1996}, author = {Castagné, V and Clarke, PG}, title = {Axotomy-induced retinal ganglion cell death in development: its time-course and its diminution by antioxidants.}, journal = {Proceedings. Biological sciences}, volume = {263}, number = {1374}, pages = {1193-1197}, doi = {10.1098/rspb.1996.0175}, pmid = {8858872}, issn = {0962-8452}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/*physiology ; Axons/pathology ; Chick Embryo ; Cyclic N-Oxides ; Embryo, Nonmammalian/*pathology/physiology ; Free Radical Scavengers/pharmacology ; Glutathione/analogs &amp; derivatives/pharmacology ; Nitrogen Oxides/pharmacology ; Oxidative Stress ; Retinal Ganglion Cells/*pathology ; Time Factors ; }, abstract = {Developing neurons die when deprived of trophic support from their axonal target. Although this is generally attributed to the programmed expression of suicide proteins, recent data suggest that a less orderly mechanism involving oxidative stress may also be involved. We have studied retinal ganglion cell death in the chick embryo after a contralateral tectal lesion. The kinetics of cell death, as judged from counts of pyknotic cells, are described. In addition, we show that the pyknotic counts are reduced following intraocular injections of the protein synthesis inhibitor cycloheximide or the antioxidants N-t-butyl-alpha-phenylnitrone and N-acetyl cysteine. Our results suggest that target deprivation-induced ganglion cell death involves oxidative stress.}, }
@article {pmid8824557, year = {1996}, author = {De Flora, S and D'Agostini, F and Masiello, L and Giunciuglio, D and Albini, A}, title = {Synergism between N-acetylcysteine and doxorubicin in the prevention of tumorigenicity and metastasis in murine models.}, journal = {International journal of cancer}, volume = {67}, number = {6}, pages = {842-848}, doi = {10.1002/(SICI)1097-0215(19960917)67:6&lt;842::AID-IJC14&gt;3.0.CO;2-3}, pmid = {8824557}, issn = {0020-7136}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology ; Disease Models, Animal ; Doxorubicin/*pharmacology ; Drug Screening Assays, Antitumor ; Drug Synergism ; Female ; Lung Neoplasms/*prevention &amp; control/*secondary ; Melanoma, Experimental/*prevention &amp; control/*secondary ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Survival Analysis ; }, abstract = {The thiol N-acetylcysteine (NAC) is a promising cancer chemopreventive agent which acts through a variety of mechanisms, including its nucleophilic and antioxidant properties. We have recently shown that NAC inhibits type-IV collagenase activity as well as invasion, tumor take and metastasis of malignant cells in mice. NAC is also known to attenuate the cardiotoxicity of the cytostatic drug doxorubicin (DOX, Adriamycin). The present study was designed to evaluate whether the combination of NAC and DOX treatments in mice injected with cancer cells could affect their tumorigenic and metastatic properties. Six separate experiments were carried out, using a total of 291 adult female mice. In experimental metastasis assays, in which B16-F10 melanoma cells were injected i.v. into (CD-1)BR nude mice, DOX significantly reduced the number of lung metastases when administered i.v. at a dose of 10 mg/kg body weight, 3 days after the i.v. injection of cancer cells. NAC inhibited lung metastases when added to the medium of cancer cells before their i.v. injection. The combined treatment with DOX and NAC, under various experimental conditions, was highly effective, showing a synergistic reduction in the number of mestastases. In tumorigenicity and spontaneous metastasis assays, in which B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice, DOX decreased the number of lung metastases when given i.p. at 2 mg/kg body weight. Oral NAC exerted significant protective effects, and considerably prolonged survival of mice. The combined treatment with DOX and NAC again showed synergistic effects on the frequency and weight of primary tumors and local recurrences, and completely prevented the formation of lung metastases in the experiment in which these end-points were evaluated at fixed times. While injection of DOX 7 days after implantation of cancer cells failed to improve the cancer-protective effects of NAC, its injection after I day resulted in a striking inhibition of lung metastases. These findings demonstrate an evident synergism between DOX (given parenterally) and NAC (given with drinking water) in preventing tumorigenicity and metastases. The indications of these animal studies warrant further evaluation in clinical trials.}, }
@article {pmid8805638, year = {1996}, author = {Williams, MS and Henkart, PA}, title = {Role of reactive oxygen intermediates in TCR-induced death of T cell blasts and hybridomas.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {157}, number = {6}, pages = {2395-2402}, pmid = {8805638}, issn = {0022-1767}, mesh = {Animals ; Antioxidants/pharmacology ; Cell Death/drug effects ; Fas Ligand Protein ; Humans ; Hybridomas/drug effects/*metabolism ; Ligands ; *Lymphocyte Activation/drug effects ; Membrane Glycoproteins/biosynthesis ; Mice ; Oxygen/antagonists &amp; inhibitors ; Reactive Oxygen Species/metabolism/*physiology ; Receptors, Antigen, T-Cell/drug effects/*physiology ; Sulfhydryl Compounds/pharmacology ; T-Lymphocytes/drug effects/*metabolism ; fas Receptor/drug effects ; }, abstract = {The functional role of reactive oxygen intermediates (ROI) in activation-induced death of mature T lymphocytes and hybridomas was tested using antioxidants and inhibitors of enzymes that generate oxidants. These agents were shown to inhibit TCR-triggered death in a concentration-dependent manner, suggesting a possible role of ROI in this death. Since the TCR-induced death of both human T blasts and the murine T cell hybridoma 2B4 involve an initial step of TCR-induced Fas ligand (FasL) up-regulation followed by a lethal step induced by Fas cross-linking, both steps were examined separately for ROI dependence. The thiol antioxidants N-acetyl cysteine and glutathione blocked Fas-induced death triggered via cross-linking either by IgM anti-Fas or cell-bound FasL, while the other inhibitors of activation-induced death did not block this late lethal step. None of the agents used blocked early events after TCR ligation, as seen by the lack of inhibition of IL-2 secretion or CD69 up-regulation. However, the nonthiol agents that blocked activation-induced death all blocked FasL up-regulation induced by TCR signals in the hybridoma, as measured by a functional assay. Agents inhibiting FasL up-regulation also inhibited activation-induced ROI generation in the hybridoma, as detected by flow cytometry using dihydrorhodamine oxidation. Furthermore, a good correlation was found between the extent of ROI generation and functional FasL expression in 2B4 cells. Thus, while ROI do not appear to act as downstream mediators of apoptotic death induced by steroid or Fas cross-linking in T cells, they are generated by TCR signaling and appear to participate in FasL up-regulation.}, }
@article {pmid8806670, year = {1996}, author = {Miyazaki, Y and Shinomura, Y and Tsutsui, S and Yasunaga, Y and Zushi, S and Higashiyama, S and Taniguchi, N and Matsuzawa, Y}, title = {Oxidative stress increases gene expression of heparin-binding EGF-like growth factor and amphiregulin in cultured rat gastric epithelial cells.}, journal = {Biochemical and biophysical research communications}, volume = {226}, number = {2}, pages = {542-546}, doi = {10.1006/bbrc.1996.1391}, pmid = {8806670}, issn = {0006-291X}, mesh = {Acetylcysteine/pharmacology ; Amphiregulin ; Animals ; Cell Line ; EGF Family of Proteins ; Epidermal Growth Factor/*genetics ; Gastric Mucosa/drug effects/enzymology/*metabolism ; *Gene Expression Regulation/drug effects ; Glycoproteins/*genetics ; Growth Substances/*genetics ; Heparin-binding EGF-like Growth Factor ; Hydrogen Peroxide/pharmacology ; *Intercellular Signaling Peptides and Proteins ; *Oxidative Stress ; Protein Kinase C/antagonists &amp; inhibitors ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors ; RNA, Messenger/genetics/metabolism ; Rats ; }, abstract = {We investigated the effects of oxidative stress on mRNA levels of heparin-binding epidermal growth factor-like growth factor (HB-EGF) and amphiregulin (AR) in rat gastric epithelial RGM1 cells. In response to stimulation with hydrogen peroxide (100-400 microM), gene expression of HB-EGF and AR increased in a dose-dependent manner, peaked at 3 h, and returned to the base line at 7 h. Hydrogen peroxide-induced HB-EGF and AR gene expression was blocked by pretreatment with an antioxidant N-acetyl-cysteine. In addition, it was significantly inhibited by pretreatment with EGF receptor-specific tyrphostin AG1478, but not by depletion of protein kinase C. These data indicate that oxidative stress upregulates expression of EGF-related polypeptides and the possible involvement of EGF receptor in this process.}, }
@article {pmid8951657, year = {1996}, author = {Deng, X and Wang, X and Andersson, R}, title = {Influence of anti-inflammatory and antioxidant agents on endothelial permeability alterations induced by bradykinin.}, journal = {Journal of investigative surgery : the official journal of the Academy of Surgical Research}, volume = {9}, number = {5}, pages = {337-349}, doi = {10.3109/08941939609021275}, pmid = {8951657}, issn = {0894-1939}, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Antioxidants/*pharmacology ; Body Water/physiology ; Bradykinin/*pharmacology ; Endothelium, Vascular/drug effects/*physiology/physiopathology ; Erythrocytes/drug effects/metabolism ; Free Radical Scavengers/pharmacology ; Humans ; Ibuprofen/pharmacology ; Indomethacin/pharmacology ; Inflammation ; Iodine Radioisotopes ; Male ; Microcirculation/drug effects/*physiology ; Permeability ; Rats ; Rats, Sprague-Dawley ; Serum Albumin/*pharmacokinetics ; Tissue Distribution ; Vasodilation/drug effects ; }, abstract = {Increased vascular permeability to plasma proteins and altered hemodynamics at the site of inflammation are characteristics of inflammation. In the present study, alterations in endothelial barrier permeability were evaluated in different organs/tissues 6 h after a systemic inflammatory response induced by intravenous injection of bradykinin (BK; 1.7 mg/kg). The effect of intravenous pretreatment with indomethacin or ibuprofen (cyclooxygenase inhibitors), N-acetyl-L-cysteine (NAC, an oxygen free radical scavenger), and allopurinol (a xanthine oxidase inhibitor) was determined. Endothelial permeability was evaluated by determining tissue water content (TWC), 125I-labeled human serum albumin (HSA) flux, and albumin leakage index (ALI) in various organs/tissues. The vasodilation in the local tissues was reflected by tissue blood content (TBC), measured by 51Cr-labeled red blood cells. The results indicate that albumin flux significantly increased in the peritoneum, pancreas, stomach, PSI, DSI, colon, kidneys, liver, lungs, and brain, TBC significantly increased in the kidneys, liver, lungs, and heart, as well as in the intestine, and an increased ALI, assaying endothelial permeability considering local hemodynamic alterations was noted in the pancreas, kidneys, liver, lungs, PSI, and DSI in the group with BK alone. These changes were to varying degrees reversed by pretreatment with indomethacin, ibuprofen, N-acetyl-L-cysteine, or allopurinol, where the protective effect tended to be organ-dependent.}, }
@article {pmid8905424, year = {1996}, author = {De Backer, WA and Amsel, B and Jorens, PG and Bossaert, L and Hiemstra, PS and van Noort, P and van Overveld, FJ}, title = {N-acetylcysteine pretreatment of cardiac surgery patients influences plasma neutrophil elastase and neutrophil influx in bronchoalveolar lavage fluid.}, journal = {Intensive care medicine}, volume = {22}, number = {9}, pages = {900-908}, pmid = {8905424}, issn = {0342-4642}, mesh = {Acetylcysteine/*therapeutic use ; Aged ; Bronchoalveolar Lavage Fluid/cytology ; Cardiac Surgical Procedures/*adverse effects ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; Humans ; Leukocyte Elastase/blood/*drug effects ; Male ; Middle Aged ; Neutrophils/*drug effects ; *Premedication ; Respiratory Distress Syndrome/blood/etiology/immunology ; }, abstract = {OBJECTIVE: Study of leukocyte activation and release of toxic mediators during extracorporeal circulation (ECC). ECC can be used to study the potential protective effect of a pharmacon against neutrophil-mediated lung injury. Clinical studies have indicated that N-acetylcysteine (NAC) may improve systemic oxygenation and reduce the need for ventilatory support when given to patients with acute lung injury.<br><br>DESIGN: Cardiac surgery patients were pretreated with high-dose NAC in order to assess the potential role of NAC to interfere with neutrophil-mediated inflammation and lung injury.<br><br>PATIENTS: 18 patients who underwent ECC: group 1 (n = 8) no premedication (only placebo); group 2 (n = 10) NAC (72 mg/kg i.v. as a bolus, later 72 mg/kg over 12 h).<br><br>MEASUREMENTS AND RESULTS: In group 2, the partial pressure of oxygen in arterial blood/fractional inspired oxygen 4 h after surgery was significantly higher than in group 1 (213 +/- 31 vs 123 +/- 22; p = 0.044). NAC pretreatment prevented an increase in plasma neutrophil elastase activity (18.9 +/- 6.9 vs 49.9 +/- 5.6 ng/ml in group 1 at the end of ECC; p = 0.027). Release of myeloperoxidase (MPO) was not affected (group 1:1105 +/- 225 ng/ml vs group 2:1127 +/- 81 at the end of ECC; p = 0.63). At the end of ECC, total antigenic human neutrophil elastase (group 1:671 +/- 72 ng/ml vs group 2:579 +/- 134; p = 0.37) and complex formation between elastase and alpha 1-proteinase inhibitor were no different in the two groups. There were no significant difference in cellular composition and mediators in the lavage fluid, although values for total number of neutrophils, elastase, MPO and interleukin-8 were lower in group 2.<br><br>CONCLUSION: Pretreatment with NAC may prevent lung injury by diminishing elastase activity. Since the release of mediators, especially MPO, is not affected, this diminished activity of elastase may be achieved by enhanced inactivation by antiproteases after initial treatment.}, }
@article {pmid8898929, year = {1996}, author = {Mazor, D and Golan, E and Philip, V and Katz, M and Jafe, A and Ben-Zvi, Z and Meyerstein, N}, title = {Red blood cell permeability to thiol compounds following oxidative stress.}, journal = {European journal of haematology}, volume = {57}, number = {3}, pages = {241-246}, doi = {10.1111/j.1600-0609.1996.tb01370.x}, pmid = {8898929}, issn = {0902-4441}, mesh = {Acetylcysteine/pharmacokinetics/pharmacology ; Adult ; Cell Membrane Permeability/drug effects ; Erythrocytes/*cytology ; Glutathione/pharmacology ; Humans ; Infant, Newborn ; Methemoglobin/metabolism ; Oxidative Stress/*physiology ; Sulfhydryl Compounds/pharmacology ; }, abstract = {The permeability of red blood cells (RBCs) to thiol containing compounds, reduced glutathione (GSH) and N-acetyl cysteine (NAC), has been studied in control adult and neonatal cells and after oxidative stress. NAC penetrates the cell membrane easily while GSH hardly permeates. We measured their capacity to enhance intracellular non-protein thiols (NPSH), after inducing damage to the membrane by formation of defects. Diamide, phenazine methosulfate (PMS) and t-butyl hydroperoxide (BHP) were chosen as exogenous oxidants, each inducing damage by a different mechanism. Our data indicate that although neonatal cells are more sensitive to oxidative stress, only membrane damage induced by diamide, renders adult and neonatal cells permeable to GSH. NAC treatment enhances thiol levels in cells exposed to oxidizing agents, as well as in control cells.}, }
@article {pmid8878448, year = {1996}, author = {Umemura, T and Hasegawa, R and Sai-Kato, K and Nishikawa, A and Furukawa, F and Toyokuni, S and Uchida, K and Inoue, T and Kurokawa, Y}, title = {Prevention by 2-mercaptoethane sulfonate and N-acetylcysteine of renal oxidative damage in rats treated with ferric nitrilotriacetate.}, journal = {Japanese journal of cancer research : Gann}, volume = {87}, number = {9}, pages = {882-886}, pmid = {8878448}, issn = {0910-5050}, mesh = {8-Hydroxy-2'-Deoxyguanosine ; Acetylcysteine/*therapeutic use ; Aldehydes/metabolism ; Animals ; Antioxidants/*therapeutic use ; Carcinogens/*toxicity ; DNA/drug effects/metabolism ; DNA Damage ; Deoxyguanosine/analogs &amp; derivatives/metabolism ; Ferric Compounds/*toxicity ; Kidney/drug effects/metabolism ; Kidney Diseases/*chemically induced/metabolism/*prevention &amp; control ; Kidney Tubules, Proximal/drug effects/metabolism ; Lipid Peroxidation ; Male ; Mesna/*therapeutic use ; Nitrilotriacetic Acid/*analogs &amp; derivatives/toxicity ; Oxidative Stress/physiology ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Ferric nitrilotriacetate (Fe-NTA) is a renal toxicant and carcinogen in rats and mice. We found that its administration results in formation of 4-hydroxy-2-nonenal (HNE) in the renal proximal tubule cells of rats, and 8-hydroxydeoxyguanosine (8-OHdG) adducts in their DNA, suggesting a role for oxidative stress. Since 2-mercaptoethane sulfonate (MESNA) and N-acetylcysteine (NAC), administered orally, have been shown to increase the kidney levels of free thiol groups, their influence on the renal toxicity and carcinogenicity induced by Fe-NTA was examined in the present study. Male Wistar rats were intraperitoneally injected with Fe-NTA (12 mg Fe/kg), and MESNA (100 mg/kg) or NAC (200 mg/kg) was given orally 1 h before and 1 h after this treatment. The animals were killed for tissue analyses 3 h after the Fe-NTA exposure. In accord with our previous reports, HNE-modified protein was detected in the proximal tubules of Fe-NTA-treated rats by means of immunohistochemistry. Likewise, levels of 8-OHdG in the renal nuclear DNA, lipid peroxides as thiobarbituric acid-reactive substances in the kidneys, and blood urea nitrogen and creatinine in the serum were significantly increased by the Fe-NTA treatment. All of these changes were completely inhibited by oral administration of MESNA or NAC. These results suggest that both of these compounds can prevent the oxidative stress induced by Fe-NTA.}, }
@article {pmid8877589, year = {1996}, author = {Lawson, DL and Haught, WH and Mehta, P and Mehta, JL}, title = {Studies of vascular tolerance to nitroglycerin: effects of N-acetylcysteine, NG-monomethyl L-arginine, and endothelin-1.}, journal = {Journal of cardiovascular pharmacology}, volume = {28}, number = {3}, pages = {418-424}, doi = {10.1097/00005344-199609000-00011}, pmid = {8877589}, issn = {0160-2446}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta/drug effects/physiology ; Cyclic GMP/metabolism ; Drug Tolerance ; Endothelin-1/*pharmacology ; Enzyme Inhibitors/*pharmacology ; Free Radical Scavengers/*pharmacology ; In Vitro Techniques ; Muscle Relaxation/drug effects ; Muscle, Smooth, Vascular/*drug effects/*physiology ; Nitric Oxide Synthase/*antagonists &amp; inhibitors ; Nitroglycerin/*pharmacology ; Rats ; Vasodilator Agents/*pharmacology ; omega-N-Methylarginine/*pharmacology ; }, abstract = {Development of vascular tolerance to nitroglycerin (NTG) has been attributed to sulfhydryl (SH) depletion, guanylate cyclase desensitization, or both. Controversy regarding the precise contribution of these mechanisms may be due to variations in experimental design. To examine further the biochemical basis of NTG tolerance, norepinephrine (NE)-precontracted rat aortic rings were exposed to NTG (10(-5)M), which resulted in 84 +/- 6% relaxation. Other rings were first superfused with NTG (10(-6)M) and then contracted with NE. These rings showed a marked tolerance to the vasorelaxant effects of NTG (maximal relaxation 20 +/- 5%, n = 15, p < 0.001 vs. control rings). Similar tolerance to NTG was observed when the vascular rings were first superfused with acetylcholine (ACh 10(-6)M), indicating cross-tolerance between ACh and NTG. Treatment of NTG-tolerant rings with N-acetylcysteine (NAC) (10(-5)M) did not restore vascular smooth muscle (VSM) relaxation in response to NTG (maximal relaxation 23 +/- 5%, n = 8), suggesting that SH depletion may not be the basis of NTG tolerance in these experiments. Parallel sets of NTG-tolerant aortic rings were contracted with endothelin-1 (ET-1, n = 5) or the endothelium-derived relaxing factor (EDRF) synthase inhibitor NG-monomethyl L-arginine (L-NMMA, 10(-4)M, n = 8). In both ET-1- and L-NMMA-contracted rings, vascular relaxation in response to NTG was preserved (80 +/- 6 and 88 +/- 8% relaxation, respectively). Measurement of cyclic GMP in aortic rings showed marked accumulation on initial exposure of tissues to NTG (310 +/- 10 fmol/mg), whereas the NTG-tolerant rings showed much less cyclic GMP accumulation (48 +/- 29 fmol/mg). Rings contracted with L-NMMA or ET-1, but not NE, accumulated cyclic GMP when exposed to NTG (280 +/- 20 fmol/mg). These data indicate that NTG tolerance develops on exposure of vascular rings superfused with NTG or ACh and is probably not related to tissue SH depletion. Contraction of NTG-tolerant rings with ET-1 or L-NMMA restores NTG-mediated relaxation.}, }
@article {pmid8877583, year = {1996}, author = {Chirkov, YY and Horowitz, JD}, title = {N-Acetylcysteine potentiates nitroglycerin-induced reversal of platelet aggregation.}, journal = {Journal of cardiovascular pharmacology}, volume = {28}, number = {3}, pages = {375-380}, doi = {10.1097/00005344-199609000-00005}, pmid = {8877583}, issn = {0160-2446}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Angina Pectoris/drug therapy/*physiopathology ; Aspirin/administration &amp; dosage ; Blood Platelets/*drug effects ; Drug Synergism ; Female ; Free Radical Scavengers/pharmacology ; Humans ; Male ; Middle Aged ; Nitroglycerin/*pharmacology ; Platelet Aggregation Inhibitors/*pharmacology ; }, abstract = {N-Acetylcysteine (N-AC) potentiates the systemic and coronary hemodynamic and antianginal effects of nitroglycerin (NGT) in humans; NTG/N-AC reduces the incidence of acute myocardial infarction in patients with unstable angina pectoris. Although previous studies have demonstrated that NTG exerts antiaggregatory effects on platelets, little information is available concerning the possible potentiation by N-AC of NTG antiplatelet effects. In the present study, we examined the in vitro effects of NTG and the combination of NTG with N-AC on reversal of ADP-induced aggregation in platelet-rich plasma (PRP) obtained from normal subjects and patients with stable angina pectoris. We also examined the potential effect of background aspirin therapy on this interaction. NTG, added to platelets 0.5 min after the beginning of aggregation, suppressed the incipient aggregation and provoked the appearance of a disaggregation phase, resulting in a concentration-dependent reversal of platelet aggregation. Platelet responsiveness to NTG was significantly less (p < 0.01) in both groups of patients (receiving and not receiving aspirin) as compared with normal subjects. N-AC (10(-5) M), which did not in itself affect aggregation, induced a threefold potentiation (p < 0.05) of the antiaggregating effect of NTG that was similar in degree for all tested groups of individuals. This potentiation of the antiplatelet effects of NTG by N-AC may contribute to the efficacy of combined NTG/N-AC therapy in patients with acute ischemic syndromes.}, }
@article {pmid8812214, year = {1996}, author = {Macrides, TA and Naylor, LM and Kalafatis, N and Shihata, A and Wright, PF}, title = {Hepatoprotective effects of the shark bile salt 5beta-scymnol on acetaminophen-induced liver damage in mice.}, journal = {Fundamental and applied toxicology : official journal of the Society of Toxicology}, volume = {33}, number = {1}, pages = {31-37}, doi = {10.1006/faat.1996.0140}, pmid = {8812214}, issn = {0272-0590}, mesh = {Acetaminophen ; Acetylcysteine/therapeutic use ; Alanine Transaminase/blood ; Animals ; Bile Acids and Salts/chemistry/*therapeutic use ; Chemical and Drug Induced Liver Injury ; Cholestanols/chemistry/*therapeutic use ; Injections, Intraperitoneal ; L-Lactate Dehydrogenase/metabolism ; Liver/pathology ; Liver Diseases/enzymology/pathology/*prevention &amp; control ; Male ; Mice ; Necrosis ; }, abstract = {The hepatoprotective effect of the shark bile salt 5beta-scymnol has been studied in the model of acute hepatotoxicity induced by administration of acetaminophen (APAP, paracetamol). 5beta-Scymnol at doses of 20, 35, and 70 mg/kg intraperitoneally (ip) decreased significantly the serum activity of alanine aminotransferase, sorbitol dehydrogenase, and lactate dehydrogenase (p < 0.05) caused by APAP treatment (350 mg/kg ip) alone. The highest dose of 5beta-scymnol remained hepatoprotective when administered 4 hr after the APAP overdose. N-Acetylcysteine (NAC) is protective against APAP-induced hepatotoxicity at 250 and 500 mg/kg (ip) when administered up to 3 hr after APAP overdose, as shown by a significant reduction in serum enzyme activity. Coadministration of 5beta-scymnol (70 mg/kg) and NAC (250 mg/kg) also reduced serum enzyme levels and histopathological effects; however, a similar level of hepatoprotection was conferred by 5beta-scymnol treatment alone. In addition, 5beta-scymnol has potent hydroxyl radical quenching activity as it markedly inhibited deoxyribose degradation in a ferrous/ascorbate Fenton reaction system. These results indicate a possible role for the use of 5beta-scymnol, either alone or concomitant with NAC, in the prevention of hepatic necrosis following toxic doses of APAP.}, }
@article {pmid8810635, year = {1996}, author = {Aoki, T and Suzuki, Y and Suzuki, K and Miyata, A and Oyamada, Y and Takasugi, T and Mori, M and Fujita, H and Yamaguchi, K}, title = {Modulation of ICAM-1 expression by extracellular glutathione in hyperoxia-exposed human pulmonary artery endothelial cells.}, journal = {American journal of respiratory cell and molecular biology}, volume = {15}, number = {3}, pages = {319-327}, doi = {10.1165/ajrcmb.15.3.8810635}, pmid = {8810635}, issn = {1044-1549}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Catalase/pharmacology ; Cattle ; Cell Adhesion/immunology ; Endothelium, Vascular/cytology/*drug effects/enzymology ; Glutathione/drug effects/*pharmacology ; Humans ; Hyperoxia/*metabolism ; Intercellular Adhesion Molecule-1/biosynthesis/drug effects/*metabolism ; L-Lactate Dehydrogenase/drug effects/metabolism ; Neutrophils/cytology ; Pulmonary Artery/cytology ; Superoxide Dismutase/pharmacology ; Umbilical Veins/cytology ; }, abstract = {To investigate the mechanisms regulating hyperoxia-induced intercellular adhesion molecule-1 (ICAM-1) expression, we studied the effects of antioxidants on ICAM-1 expression, and the relationship between ICAM-1 expression and extracellular glutathione levels in human pulmonary artery endothelial cells (HPAEC) and human umbilical vein endothelial cells (HUVEC). Cells were cultured to confluence and exposed to hyperoxia (90% O2) for 48 h with or without various antioxidants, including superoxide dismutase (SOD), catalase, N-acetylcysteine (NAC), and glutathione. The levels of ICAM-1 expression in the endothelial cells and the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the media were examined by flow cytometry and spectrophotometry, respectively. After exposure to hyperoxia, ICAM-1 expression was increased, and the supernatant total glutathione was decreased as compared with those at normoxia. SOD did not change ICAM-1 expression. The hyperoxia-induced increase in ICAM-1 expression was even greater with the addition of catalase. The ICAM-1 expression was decreased and the GSH concentration was increased with the addition of NAC. There were negative relationships between the level of ICAM-1 expression and the supernatant total glutathione concentration in catalase-treated HPAEC (R = 0.822, P < 0.0005) and HUVEC (R = 0.567, P < 0.01). Negative relationships were also demonstrated between the level of ICAM-1 expression and the total extracellular glutathione concentrations in NAC-treated HPAEC (R = 0.877, P < 0.0005) and HUVEC (R = 0.727, P < 0.0005). Exogenous GSH decreased ICAM-1 expression in both hyperoxia-exposed HPAEC and HUVEC, while exogenous GSSG did not. These results suggest that extracellular GSH plays a role in regulating hyperoxia-induced ICAM-1 expression in HPAEC and HUVEC.}, }
@article {pmid8797665, year = {1996}, author = {Offen, D and Ziv, I and Sternin, H and Melamed, E and Hochman, A}, title = {Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson's disease.}, journal = {Experimental neurology}, volume = {141}, number = {1}, pages = {32-39}, doi = {10.1006/exnr.1996.0136}, pmid = {8797665}, issn = {0014-4886}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/pharmacology ; Apoptosis/*drug effects ; Dithiothreitol/*pharmacology ; Dopamine/*pharmacology ; Glutathione/*pharmacology ; Neuroprotective Agents/pharmacology ; PC12 Cells/drug effects ; Parkinson Disease/*drug therapy ; Rats ; Sulfhydryl Compounds/pharmacology ; }, abstract = {We have recently shown that dopamine (DA) can trigger apoptosis, an active program of cellular self-destruction, in various neuronal cultures and proposed that inappropriate activation of apoptosis by DA and or its oxidation products may initiate nigral cell loss in Parkinson's disease (PD). Since DA toxicity may be mediated via generation of oxygen-free radical species, we examined whether DA-induced cell death in PC12 cells may be inhibited by antioxidants. We have found that the thiol containing compounds, reduced glutathione (GSH), N-acetyl-cysteine (NAC), and dithiothreitol (DTT) were markedly protective, while vitamins C and E had lesser or no effect. The thiol antioxidants and vitamin C but not vitamin E, prevented dopamine autooxidation and production of dopamine-melanin. Their protective effect has also manifested by inhibiting DA-induced apoptosis; DNA fragmentation was prevented as was shown histochemically by the in situ end-labeled DNA technique (TUNEL). Intracellular GSH and other thiols constitute an important natural defense against oxidative stress. We have found that depletion of cellular GSH by the addition of phoron, a substrate of glutathione transferase, and buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl transpeptidase, significantly enhanced DA toxicity. Cotreatment with NAC rescued the cells from the toxic effect of BSO+DA, and phoron+ DA, while addition of GSH provided only partial protection from BSO+DA toxicity. Our data indicate that the thiol family of antioxidants, but not vitamins C and E, are highly effective in rescuing cells from DA-induced apoptosis. Further study of the mechanisms underlying the unique protective capacity of thiol antioxidants may lead to the development of new neuroprotective therapeutic strategies for PD.}, }
@article {pmid8781560, year = {1996}, author = {Chakraborty, AK and Funasaka, Y and Slominski, A and Ermak, G and Hwang, J and Pawelek, JM and Ichihashi, M}, title = {Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B.}, journal = {Biochimica et biophysica acta}, volume = {1313}, number = {2}, pages = {130-138}, doi = {10.1016/0167-4889(96)00063-8}, pmid = {8781560}, issn = {0006-3002}, mesh = {Acetylcysteine/pharmacology ; Adrenocorticotropic Hormone/metabolism ; Base Sequence ; Bucladesine/pharmacology ; Cells, Cultured ; Cyclic AMP/*physiology ; Cytokines/pharmacology ; DNA Primers/chemistry ; Endothelins/pharmacology ; Gene Expression/drug effects/radiation effects ; Humans ; Keratinocytes/*physiology ; Melanocyte-Stimulating Hormones/metabolism ; Melanocytes/*physiology ; Molecular Sequence Data ; Pro-Opiomelanocortin/*metabolism ; RNA, Messenger/genetics ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Cells, Cultured ; *Ultraviolet Rays ; }, abstract = {It is demonstrated that ultraviolet B (UVB) radiation stimulates increased expression of the proopiomelanocortin (POMC) gene which is accompanied by production and release of alpha-melanocyte stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH) by both normal and malignant human melanocytes and keratinocytes. The production and release of both peptides are also stimulated by dibutyryl cyclic adenosine monophosphate (dbcAMP) and interleukin 1 alpha (IL-1 alpha) but not by endothelin-1 (ET-1) or tumor necrosis factor-alpha (TNF-alpha). N-acetyl-cysteine (NAC), a precursor of glutathione (GSH), an intracellular free radical scavenger, abolishes the UVB-stimulated POMC peptide production and secretion. Conclusions are as follows: (1) Cultured human cells of cutaneous origin, namely keratinocytes and melanocytes, can produce and express POMC; (2) POMC expression is enhanced by exposure to UVB, possibly through a cyclic AMP-dependent pathway; and (3) The action of UVB on POMC production may involve a cellular response to oxidative stress.}, }
@article {pmid8814364, year = {1996}, author = {Durand, P and Fortin, LJ and Lussier-Cacan, S and Davignon, J and Blache, D}, title = {Hyperhomocysteinemia induced by folic acid deficiency and methionine load--applications of a modified HPLC method.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {252}, number = {1}, pages = {83-93}, doi = {10.1016/0009-8981(96)06325-5}, pmid = {8814364}, issn = {0009-8981}, mesh = {Adult ; Animals ; Arteriosclerosis/complications ; Chromatography, High Pressure Liquid/*methods ; Cricetinae ; Cysteine/blood ; Female ; Folic Acid Deficiency/*blood/complications ; Glutathione/blood ; Homocysteine/*blood ; Humans ; Male ; Methionine/*toxicity ; Middle Aged ; Rats ; Sensitivity and Specificity ; }, abstract = {The increasing possibility that homocysteine might be involved in atherosclerosis in non-homocysteinuric subjects has required the measurement of low concentrations of this aminothiol in biological samples. The procedure described here represents an improvement of different HPLC methods. We utilized an isocratic HPLC system with fluorescence detection of plasma total homocysteine derivatized after reaction with ammonium 7-fluoro-benzo-2-oxa-1,3-diazole-4-sulphonate. With the help of the rapidly eluting internal standard N-acetyl-cysteine, the method ensures very good recovery (approximately 100%), reproducibility and precision (within-assay: 2.31%; day-to-day: 2.8%) in the physiological concentration range. This procedure allowed us to validate various animal models of hyperhomocysteinemia such as dietary folic acid deficiency in rat and acute methionine loads in rat and hamster. Using this method, we also confirmed that men have higher plasma total homocysteine levels than women. Due to its simplicity and reliability, our procedure is suitable for routine analysis of total homocysteine and other aminothiols (cysteine, cysteinyl-glycine and glutathione) in biological samples, as required in clinical and research laboratories.}, }
@article {pmid8759749, year = {1996}, author = {Blackwell, TS and Blackwell, TR and Holden, EP and Christman, BW and Christman, JW}, title = {In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {157}, number = {4}, pages = {1630-1637}, pmid = {8759749}, issn = {0022-1767}, support = {HL07123/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use ; Antioxidants/*pharmacology/therapeutic use ; Base Sequence ; *Chemokines, CXC ; Chemotactic Factors/*biosynthesis/genetics ; Chemotaxis, Leukocyte/drug effects ; Dinoprost/analogs &amp; derivatives/biosynthesis ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Endotoxins/*toxicity ; F2-Isoprostanes ; Gene Expression Regulation/drug effects ; Glutathione/biosynthesis/genetics ; Growth Substances/*biosynthesis/genetics ; Inflammation ; *Intercellular Signaling Peptides and Proteins ; Leukocyte Count ; Lung/drug effects/metabolism ; Lung Diseases/etiology/immunology/*prevention &amp; control ; Male ; Molecular Sequence Data ; NF-kappa B/*antagonists &amp; inhibitors ; Neutrophils/*physiology ; RNA, Messenger/biosynthesis/genetics ; Rats ; Rats, Sprague-Dawley ; Respiratory Distress Syndrome/drug therapy ; Sepsis/chemically induced/complications ; }, abstract = {We hypothesized that endotoxin injection in rats would stimulate in vivo nuclear factor-kappa B (NF-kappa B) activation in lung tissue and that antioxidant treatment before endotoxin injection would attenuate endotoxin-induced NF-kappa B activation, chemokine gene expression, and neutrophilic lung inflammation. We studied NF-kappa B activation in rat lung tissue following a single i.p. injection of endotoxin (6 mg/kg). After in vivo endotoxin treatment, lung NF-kappa B activation peaked at 2 h and temporally correlated with the expression of cytokine-induced neutrophil chemoattractant mRNA in lung tissue. Treatment with the antioxidant N-acetylcysteine (NAC) 1 h before endotoxin resulted in decreased lung NF-kappa B activation in a dose-dependent manner (from 200-1000 mg/kg) and diminished cytokine-induced neutrophil chemoattractant mRNA expression in lung tissue. Treatment with NAC significantly suppressed endotoxin-induced neutrophilic alveolitis. The average total lung lavage neutrophil count was 5.5 x 10(6) with endotoxin treatment vs 0.9 x 10(6) with NAC treatment before endotoxin. The NF-kappa B pathway represents an attractive therapeutic target for strategies to control neutrophilic inflammation and lung injury.}, }
@article {pmid8769100, year = {1996}, author = {Cheng, JJ and Chao, YJ and Wung, BS and Wang, DL}, title = {Cyclic strain-induced plasminogen activator inhibitor-1 (PAI-1) release from endothelial cells involves reactive oxygen species.}, journal = {Biochemical and biophysical research communications}, volume = {225}, number = {1}, pages = {100-105}, doi = {10.1006/bbrc.1996.1136}, pmid = {8769100}, issn = {0006-291X}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Catalase/metabolism ; Cells, Cultured ; Culture Techniques/methods ; Endothelium, Vascular/cytology/drug effects/*physiology ; Humans ; Kinetics ; Membranes, Artificial ; Plasminogen Activator Inhibitor 1/*biosynthesis/metabolism ; Pressure ; Reactive Oxygen Species/*metabolism ; Stress, Mechanical ; Time Factors ; Umbilical Cord ; }, abstract = {The molecular mechanisms of the endothelial fibrinolytic activities modulated by mechanical strain are not clear. Endothelial cells (ECs) grown on a flexible membrane base were deformed with sinusoidal negative pressures to produce an average strain of 12%. Cyclic strain induced PAI-1 release in a time-dependent manner. Strain cells resulted in a 5-fold increase in PAI-1 release. Strain induced a sustained elevated level in intracellular reactive oxygen species (ROS). Concomitantly, a sustained increase of catalase activity was observed. Both ROS and catalase activity returned to basal levels with the removal of strain. ECs pretreated with antioxidant, N-acetyl-cysteine, abolished the strain-induced ROS generation as well as strained-induced PAI-1 release. Our results indicate that cyclic strain-induced PAI-1 secretion may be mediated by an increase in ROS generation and thus emphasizes the importance of intracellular ROS in the modulation of hemodynamic force-induced cellular response of ECs.}, }
@article {pmid9125279, year = {1996}, author = {Vanderbist, F and Maes, P and Nève, J}, title = {In vitro comparative assessment of the antioxidant activity of nacystelyn against three reactive oxygen species.}, journal = {Arzneimittel-Forschung}, volume = {46}, number = {8}, pages = {783-788}, pmid = {9125279}, issn = {0004-4172}, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemistry ; Antioxidants/*chemistry ; Captopril/chemistry ; Free Radical Scavengers/chemistry ; Hydrogen Peroxide ; Hydroxyl Radical ; Hypochlorous Acid ; Kinetics ; Lysine/*analogs &amp; derivatives/chemistry ; *Reactive Oxygen Species ; }, abstract = {Thiol-containing molecules possess antioxidant properties that are of interest in the pharmacological inactivation of reactive oxygen species (ROS), particularly in the treatment of chronic inflammatory respiratory diseases. In the present study, the in vitro antioxidant activity of a new agent was examined and compared with other thiol containing molecules, N-acetylcysteine (NAC) and captopril. Nacystelyn (CAS 89344-48-9, NAL) is a L-lysine salt of NAC having demonstrated several advantages as compared to NAC. The deoxyribose assay used for assessing the scavenging effect of drugs against hydoxyl radicals (.OH) first showed a prooxidant effect for thiols at relatively low concentrations that was attributed to a reduction of Fe(III) ions added in the system. This interference could be corrected by increasing ascorbate concentration. Second order rate constants for reaction with OH were calculated by extrapolation of the linear part of competition plots. Both NAL and NAC appeared as potent .OH scavengers (Ks > 10(10) mol-1 s-1) and reacted faster than captopril. The horseradish peroxidase assay for assessing the activity of thiols against H202 could not be used because thiol derivatives were substrates for the enzyme. By using the dithio-bis-nitrobenzoic acid (DTNB) assay, first order rate constants for reaction with H2O2 were obtained showing that both NAL and NAC reacted quite slowly with this species (K approximately equal to 0.03 min-1) although faster than captopril. Finally, the elastase-alpha 1-antiproteinase assay for assessing the activity of thiols against HClO again demonstrated the superiority of NAC and NAL over captopril, but this time, NAL was more efficient in maintaining the protease/antiprotease balance than NAC. This last observation may be of importance and deserves further investigation as HClO has been implicated in lung tissue damages during inflammatory respiratory diseases.}, }
@article {pmid8899667, year = {1996}, author = {Vyth, A and Timmer, JG and Bossuyt, PM and Louwerse, ES and de Jong, JM}, title = {Survival in patients with amyotrophic lateral sclerosis, treated with an array of antioxidants.}, journal = {Journal of the neurological sciences}, volume = {139 Suppl}, number = {}, pages = {99-103}, doi = {10.1016/0022-510x(96)00071-8}, pmid = {8899667}, issn = {0022-510X}, mesh = {Acetylcysteine/administration &amp; dosage ; Administration, Oral ; Amyotrophic Lateral Sclerosis/*drug therapy/*mortality ; Antioxidants/*administration &amp; dosage ; Capsules ; Chelating Agents/administration &amp; dosage ; Dithioerythritol/administration &amp; dosage ; Dithiothreitol/administration &amp; dosage ; Free Radical Scavengers/administration &amp; dosage ; Gastric Juice/chemistry ; Humans ; Injections, Subcutaneous ; Methionine/administration &amp; dosage/analogs &amp; derivatives ; Succimer/administration &amp; dosage ; Sulfhydryl Reagents/administration &amp; dosage ; Survival Analysis ; }, abstract = {Between 1983 and 1988 we treated 36 patients with sporadic amyotrophic lateral sclerosis (ALS) by an array of antioxidants and added other drugs to the regimen whenever a patient reported deterioration. Our customary prescription sequence was N-acetylcysteine (NAC); vitamins C and E; N-acetylmethionine (NAM); and dithiothreitol (DTT) or its isomer dithioerythritol (DTE). Patients with a history of heavy exposure to metal were also given meso 2,3-dimercaptosuccinic acid (DMSA). NAC, NAM, DTT, and DTE were administered by subcutaneous injection or by mouth or by both routes, the other vitamins and DMSA by mouth alone. The hospital pharmacy supplied NAC and NAM injections fluid as 100 ml bottles of 5.0 and 5.85% solutions, respectively. DTT was delivered in special double-walled capsules of 200 mg. DTT/DTE injection fluid was added to the NAC and NAM bottles, the final DTT/DTE concentrations never exceeding 0.5%. DMSA was provided in 250 mg capsules. All of the 36 patients used NAC and DTT/DTE; 29 also used vitamins C and E; 21 also used NAM; and 7 also used DMSA, DMSA, NAM, vitamins C and E were tolerated well. In many patients, DTT, DTE, NAC and NAM induced pain, redness and swelling at the injection sites in that order of decreasing frequency. DTT and DTE did often and NAC did sometimes cause gastric pain, nausea and other abdominal discomfort. Comparison of survival in the treated group and in a cohort of untreated historical controls, disclosed a median survival of 3.4 years (95% confidence interval: 3.0-4.2) in the treated and of 2.8 (95% confidence interval 2.2-3.1) years in the control patients. This difference may be explained by self-selection of our highly motivated treated group and by its initial survival of diagnosis for an average of 8.5 months before onset of treatment. We conclude that antioxidants neither seem to harm ALS patients, nor do they seem to prolong survival.}, }
@article {pmid8869666, year = {1996}, author = {Skjelbakken, T and Valen, G and Vaage, J}, title = {Perfusing isolated rat hearts with hydrogen peroxide: an experimental model of cardiac dysfunction caused by reactive oxygen species.}, journal = {Scandinavian journal of clinical and laboratory investigation}, volume = {56}, number = {5}, pages = {431-439}, doi = {10.3109/00365519609088798}, pmid = {8869666}, issn = {0036-5513}, mesh = {Animals ; Disease Models, Animal ; Heart/*drug effects ; Heart Diseases/*chemically induced ; Hydrogen Peroxide/administration &amp; dosage/*toxicity ; In Vitro Techniques ; Male ; Perfusion ; Rats ; Rats, Wistar ; Reactive Oxygen Species/*metabolism ; }, abstract = {A model of cardiac dysfunction induced by reactive oxygen species (ROS) was established by adding hydrogen peroxide (H2O2) to the perfusate of isolated, Langendorff-perfused rat hearts, and the mechanism of functional injury was investigated. The following groups were included: 1 (n = 7), control perfusion; 2 (n = 11), perfusion with H2O2 (180 mumol 1(-1) for 10 min followed by recovery for 50 min; 3 (n = 4), control perfusion with N-acetylcysteine (NAC, 100 mumol 1(-1); 4 (n = 7), perfusion with H2O2 and NAC; 5 (n = 4), control perfusion with thiourea (15 mmol 1(-1), 6 (n = 7), H2O2 and thiourea together; 7 (n = 4), control perfusion with catalase (150 U ml-1); 8 (n = 7), catalase and H2O2, 9 (n = 4), control perfusion with deferoxamine (5 mmol 1(-1); and 10 (n = 7), deferoxamine and H2O2. coronary flow (CF), left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and heart rate (HR) were measured. All values are mean +/- SEM. When given alone, catalase, thiourea, NAC and deferoxamine did not influence left ventricular pressures, but NAC, catalase and thiourea increased CF. H2O2 increased CF (maximum 146 +/- 6% of baseline value after 5 min, p < 0.001 compared to group 1), decreased LVDP (minimum 14 +/- 5% of baseline value after 10 min, p < 0.0004), and increased LVEDP (from 0 mmHg to a maximum of 54 +/- 7 mmHg after 5 min recovery, p < 0.0003). All these changes gradually reversed during recovery. Catalase and thiourea both inhibited the H2O2-induced effects, but catalase inhibition was more complete. Neither NAC nor deferoxamine had any effect on H2O2-induced cardiac dysfunction. In conclusion, H2O2 perfusion is a convenient and reversible model of ROS-induced functional injury to isolated rat hearts. H2O2, rather than the hydroxyl radical, seems to be the main injurious ROS in this model.}, }
@article {pmid8863995, year = {1996}, author = {Weiss, L and Hildt, E and Hofschneider, PH}, title = {Anti-hepatitis B virus activity of N-acetyl-L-cysteine (NAC): new aspects of a well-established drug.}, journal = {Antiviral research}, volume = {32}, number = {1}, pages = {43-53}, doi = {10.1016/0166-3542(95)00977-9}, pmid = {8863995}, issn = {0166-3542}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/pharmacology ; Antiviral Agents/*pharmacology ; Base Sequence ; Cell Division/drug effects ; Cell Line ; Chloramphenicol O-Acetyltransferase/genetics ; DNA Primers/genetics ; DNA Replication/drug effects ; DNA, Viral/metabolism ; Genes, Reporter ; Genes, Viral/genetics ; Hepatitis B/drug therapy ; Hepatitis B virus/*drug effects/genetics/physiology ; Humans ; Promoter Regions, Genetic/drug effects ; Reactive Oxygen Species/metabolism ; Virus Replication/drug effects ; }, abstract = {N-acetyl-L-cysteine (NAC) is commonly administered as an antidote against acetaminophen intoxication and is the preferred agent in the treatment of pulmonary diseases. It is furthermore commonly considered that it restrains human immunodeficiency virus (HIV) replication by scavenging reactive oxygen intermediates (ROI) and thus suppressing activation of nuclear factor kappa B (NF kappa B). We show here that NAC is in addition able to inhibit hepatitis B virus (HBV) replication, but by a mechanism independent of the intracellular level of reactive oxygen intermediates. Treatment of HBV-producing cell lines with NAC resulted in an at least 50-fold reduction of viral DNA in the tissue culture supernatant within 48 h. This decrease of viral DNA and thus of virions in the tissue culture supernatant is caused by a disturbance of the virus assembly, rather than by a reduction of viral transcripts. Our data strongly suggest a potential use of this well-established, non-toxic drug for the treatment of HBV infection. Since NAC, in contrast to interferon, exerts its anti-HBV activity at a posttranscriptional level, a combination of NAC with the established interferon therapy could also be considered.}, }
@article {pmid8863052, year = {1996}, author = {Buylaert, W and Calle, P and De Paepe, P and Verstraete, A and Samyn, N and Vogelaers, D and Vandenbulcke, M and Belpaire, F}, title = {Hepatotoxicity of N, N-dimethylformamide (DMF) in acute poisoning with the veterinary euthanasia drug T-61.}, journal = {Human &amp; experimental toxicology}, volume = {15}, number = {8}, pages = {607-611}, doi = {10.1177/096032719601500801}, pmid = {8863052}, issn = {0960-3271}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Amides/*poisoning/toxicity ; Animals ; *Chemical and Drug Induced Liver Injury ; Dimethylformamide/pharmacokinetics/*poisoning/toxicity ; Drug Combinations ; Free Radical Scavengers/*therapeutic use ; Humans ; L-Iditol 2-Dehydrogenase/blood ; Liver Diseases/blood/*prevention &amp; control ; Male ; Quaternary Ammonium Compounds/*poisoning/toxicity ; Rats ; Rats, Wistar ; Suicide, Attempted ; Tetracaine/*poisoning/toxicity ; }, abstract = {1. We report on a patient who was resuscitated after a suicide attempt with the veterinary euthanasia product T-61 and treated with N-acetylcysteine (NAC) to prevent hepatotoxicity from N,N-dimethylformamide (DMF), the solvent of T-61. 2. Serum concentrations of DMF were high as compared with values published on occupational exposure. 3. The patient showed only a transient increase in liver enzymes with eventually a full recovery. 4. The hepatoprotective effect of NAC was studied in a rat model using the rise in serum sorbitol dehydrogenase (SDH) as a marker for DMF-induced hepatotoxicity. 5. Four series of randomized, controlled and double-blind experiments were carried out and consistently showed a lower increase in SDH in NAC-treated animals in each series. The difference was statistically significant only when the data of the 4 series were pooled. This is probably due to the large interindividual variations in the effect of DMF. 6. We hypothesize that in the rat NAC may have a protective effect. Whether NAC is also protective in patients, in which it is administered after exposure to DMF, cannot be concluded from the present experiments.}, }
@article {pmid8837043, year = {1996}, author = {Hussain, S and Slikker, W and Ali, SF}, title = {Role of metallothionein and other antioxidants in scavenging superoxide radicals and their possible role in neuroprotection.}, journal = {Neurochemistry international}, volume = {29}, number = {2}, pages = {145-152}, doi = {10.1016/0197-0186(95)00114-x}, pmid = {8837043}, issn = {0197-0186}, mesh = {Acetylcysteine/metabolism ; Animals ; Antioxidants/*metabolism/pharmacology ; Brain Chemistry ; Cysteine/metabolism ; Electrophoresis, Polyacrylamide Gel ; *Free Radical Scavengers ; Glutathione/metabolism ; Male ; Metallothionein/isolation &amp; purification/*metabolism/pharmacology ; Mice ; Mice, Inbred C57BL ; Nervous System Diseases/*prevention &amp; control ; Nitrites/antagonists &amp; inhibitors/metabolism ; Superoxides/*metabolism ; }, abstract = {Based on the inhibition of nitrite formation by generating superoxide from xanthine/xanthine oxidase (X/XO) reaction system, metallothionein (MT) and other sulfhydryl containing amino acids have been selected to test their abilities to scavenge superoxide radicals. Different concentrations of metallothionein and other sulfhydryl containing molecules e.g. cysteine, N-acetyl-cysteine and glutathione, were used to assess superoxide scavenging properties. Metallothionein scavenges superoxide radical in a dose-dependent manner with increasing concentrations as evidenced by the inhibition of nitrite formation. Similar abilities to scavenge superoxide radicals were shown by cysteine, N-acetyl-cysteine. Glutathione also scavenges superoxide radical in a dose-dependent manner. In vitro experiments demonstrated that metallothionein is superior in scavenging superoxide radicals compared to other sulfhydryl molecules such as cysteine, N-acetyl-cysteine and even glutathione. The data, further, suggest that metallothionein-II has a 6-fold higher capacity to scavenge superoxide radical than metallothionein-I. In addition, metallothionein-like protein was isolated from different regions of mouse brain treated with zinc. Brain metallothionein-like protein inhibits nitrite formation as demonstrated by other scavengers; however, the extent of inhibition is different by this protein isolated from different brain regions. The present study suggests that metallothioneins and metallothionein-like proteins isolated from mouse brain act as neuroprotective agents by scavenging superoxide radicals.}, }
@article {pmid8799319, year = {1996}, author = {Tang, W and Abbott, FS}, title = {Characterization of thiol-conjugated metabolites of 2-propylpent-4-enoic acid (4-ene VPA), a toxic metabolite of valproic acid, by electrospray tandem mass spectrometry.}, journal = {Journal of mass spectrometry : JMS}, volume = {31}, number = {8}, pages = {926-936}, doi = {10.1002/(SICI)1096-9888(199608)31:8&lt;926::AID-JMS383&gt;3.0.CO;2-P}, pmid = {8799319}, issn = {1076-5174}, mesh = {Animals ; Anticonvulsants/*pharmacokinetics ; Bile/chemistry ; Biotransformation ; Chromatography, Liquid ; Fatty Acids, Monounsaturated/chemical synthesis/*chemistry ; Liver/chemistry ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry ; Online Systems ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/chemical synthesis/*chemistry ; Valproic Acid/*pharmacokinetics ; }, abstract = {The hepatotoxicity of the anticonvulsant drug valproic acid (VPA) is most likely associated with the bioactivation of its metabolite 2-propylpent-4-enoic acid (4-ene VPA), which is known to induce hepatic microvesicular steatosis in rats. This paper presents an on-line liquid chromatographic/tandem mass spectrometric (LC/MS/MS) identification of new glutathione (GSH)-related conjugates of the reactive metabolites of 4-ene VPA. Bile samples collected from male Sprague-Dawley rats dosed intraperitoneally with 4-ene VPA or its [2H7]-analogue (100 mg kg-1) were injected on to an ODS column interfaced to a LC/MS/MS instrument using electrospray ionization. LC was developed such that no overlapping of peaks occurred among those metabolites which may potentially produce common fragment ions of interest. Subsequent comparison of LC retention times and MS/MS full fragment ion spectra generated for putative metabolites with that of authentic reference compounds made available by chemical synthesis confirmed the presence of the GSH, cysteinylglycine, cysteine and N-acetylcysteine (NAC) conjugates of 2-(2'-carboxypentanyl)oxirane (4,5-epoxy VPA) and (E)-2-propylpenta-2,4-dienoic acid ((E)-2,4-diene VPA), respectively. Quantitatively, the biliary thiol conjugates accounted for 5% of the dose. This observation is novel for 4-ene VPA metabolism in terms of the degradation of GSH conjugates to the corresponding mercapturic acids possibly occurring within the liver as opposed to an inter-organ process which involves the kidney. In addition, the GSH- and NAC-glucuronide di-conjugates of (E)-2,4-diene VPA were also identified as the biliary metabolites with the GSH-glucuronide di-conjugate being 10% of the corresponding mono-GSH conjugate. Taken together, these data clearly indicate that reactive metabolites of VPA can react with hepatic GSH via several different metabolic pathways and may subsequently produce depletion of GSH that leads to toxic consequences.}, }
@article {pmid8756297, year = {1996}, author = {Vemuri, GS and McMorris, FA}, title = {Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival.}, journal = {Development (Cambridge, England)}, volume = {122}, number = {8}, pages = {2529-2537}, doi = {10.1242/dev.122.8.2529}, pmid = {8756297}, issn = {0950-1991}, support = {NS 26119/NS/NINDS NIH HHS/United States ; NS 32122/NS/NINDS NIH HHS/United States ; NS 32394/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Androstadienes/pharmacology ; Apoptosis/physiology ; Ascorbic Acid/pharmacology ; Blood ; Cell Survival/*physiology ; Chromones/pharmacology ; Ciliary Neurotrophic Factor ; Enzyme Inhibitors/pharmacology ; Fibroblast Growth Factor 2/pharmacology ; Insulin-Like Growth Factor I/pharmacology ; Morpholines/pharmacology ; Nerve Growth Factors/pharmacology ; Nerve Tissue Proteins/pharmacology ; Neurotrophin 3 ; Oligodendroglia/*cytology/drug effects/enzymology ; Phosphatidylinositol 3-Kinases ; Phosphotransferases (Alcohol Group Acceptor)/antagonists &amp; inhibitors/*metabolism ; Platelet-Derived Growth Factor/pharmacology ; Signal Transduction/*physiology ; Stem Cells/cytology ; Vitamin E/pharmacology ; Wortmannin ; }, abstract = {Signal transduction in response to several growth factors that regulate oligodendrocyte development and survival involves the activation of phosphatidylinositol 3-kinase, which we detect in oligodendrocytes and their precursors. To investigate the role of this enzyme activity, we analyzed cell survival in cultures of oligodendrocytes treated with wortmannin or LY294002, two potent inhibitors of phosphatidylinositol 3-kinase. Cell survival was inhibited by 60-70% in these cultures within 24 hours, as quantitated by a tetrazolium staining assay for viable cells and by measurement of DNA content. Similar results were obtained with oligodendrocyte precursor cells. Nuclei of the dying cells contained fragmented DNA, as revealed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays, indicating that the cells were dying by apoptosis. Moreover, a significant increase in the number of cells with fragmented nuclear DNA was detected as early as 4 hours, well before any significant differences could be detected in glucose transport or cell viability. Exogenous addition of insulin-like growth factor-I, neurotrophin-3, platelet-derived growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, N-acetyl cysteine, vitamin C, vitamin E, progesterone or serum did not prevent cell death in the presence of wortmannin or LY294002. These findings indicate that survival of oligodendrocytes and their precursors depends on a phosphatidylinositol 3-kinase mediated signaling pathway. Inhibition of this critical enzyme activity induces apoptotic cell death, even in the presence of exogenous growth factors or serum.}, }
@article {pmid8844707, year = {1996}, author = {Hess, DC and Thompson, Y and Sprinkle, A and Carroll, J and Smith, J}, title = {E-selectin expression on human brain microvascular endothelial cells.}, journal = {Neuroscience letters}, volume = {213}, number = {1}, pages = {37-40}, doi = {10.1016/0304-3940(96)12837-8}, pmid = {8844707}, issn = {0304-3940}, mesh = {Allopurinol/pharmacology ; Cells, Cultured/chemistry/drug effects/metabolism ; Dexamethasone/pharmacology ; E-Selectin/*biosynthesis ; Electrophoresis ; Endothelium, Vascular/*chemistry/drug effects/metabolism ; Enzyme Inhibitors/pharmacology ; Glucocorticoids/pharmacology ; Humans ; Interleukin-1/pharmacology ; Lipopolysaccharides/pharmacology ; Microcirculation/physiology ; NF-kappa B/metabolism ; Temporal Lobe/*blood supply/cytology ; Tumor Necrosis Factor-alpha/pharmacology ; Umbilical Veins/cytology ; Up-Regulation/drug effects ; }, abstract = {E-Selectin is an endothelial adhesion molecule involved in binding and targeting of neutrophils. Little is known of its expression in the brain. We examined the expression of E-selectin on cultured human brain microvascular endothelial cells (HBMEC). There was no basal expression of E-selectin on HBMEC but with I1-1b, tumor necrosis factor (TNF), or lipopolysaccharide (LPS) stimulation there was surface expression at 4 h. The expression was quantitatively less than on cultured human umbilical vein endothelial cells (HUVEC). The cytokine-induced upregulation was partially inhibited with the glutathione donor, N-acetylcysteine (NAC), the free radical scavenger, dimethylthiourea (DMTU; 15 mM) and dexamethasone (1 microM). Allopurinol (100 microM) had no effect. TNF activated nuclear factor kappa B (NF kappa B) in HBMEC. This activation could be attenuated by prior treatment with NAC and dexamethasone. Thiol donors and corticosteroids could play a role in inhibiting potentially deleterious neutrophil-endothelial interactions in inflammatory conditions involving the brain.}, }
@article {pmid8841951, year = {1996}, author = {Kinscherf, R and Hack, V and Fischbach, T and Friedmann, B and Weiss, C and Edler, L and Bärtsch, P and Dröge, W}, title = {Low plasma glutamine in combination with high glutamate levels indicate risk for loss of body cell mass in healthy individuals: the effect of N-acetyl-cysteine.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {74}, number = {7}, pages = {393-400}, pmid = {8841951}, issn = {0946-2716}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aerobiosis/physiology ; Anaerobiosis/physiology ; Body Weight/*drug effects/physiology ; Cachexia/metabolism ; Cystine/blood/metabolism ; Exercise/physiology ; Female ; Glutamic Acid/*blood/metabolism ; Glutamine/*blood/metabolism ; Glycine/blood/metabolism ; Humans ; Male ; Middle Aged ; Tyrosine/blood/metabolism ; }, abstract = {Skeletal muscle catabolism, low plasma glutamine, and high venous glutamate levels are common among patients with cancer or human immunodeficiency virus infection. In addition, a high glycolytic activity is commonly found in muscle tissue of cachectic cancer patients, suggesting insufficient mitochondrial energy metabolism. We therefore investigated (a) whether an "an-aerobic physical exercise" program causes similar changes in plasma amino acid levels, and (b) whether low plasma glutamine or high glutamate levels are risk factors for loss of body cell mass (BCM) in healthy human subjects, i.e., in the absence of a tumor or virus infection. Longitudinal measurements from healthy subjects over longer periods suggest that the age-related loss of BCM occur mainly during episodes with high venous glutamate levels, indicative of decreased muscular transport activity for glutamate. A significant increase in venous glutamate levels from 25 to about 40 microM was seen after a program of "anaerobic physical exercise." This was associated with changes in T lymphocyte numbers. Under these conditions persons with low baseline levels of plasma glutamine, arginine, and cystine levels also showed a loss of BCM. This loss of BCM was correlated not only with the amino acid levels at baseline examination, but also with an increase in plasma glutamine, arginine, and cystine levels during the observation period, suggesting that a loss of BCM in healthy individuals terminates itself by adjusting these amino acids to higher levels that stabilize BCM. To test a possible regulatory role of cysteine in this context we determined the effect of N-acetyl-cysteine on BCM in a group of subjects with relatively low glutamine levels. The placebo group of this study showed a loss of BCM and an increase in body fat, suggesting that body protein had been converted into other forms of chemical energy. The decrease in mean BCM/body fat ratios was prevented by N-acetyl-cysteine, indicating that cysteine indeed plays a regulatory role in the physiological control of BCM.}, }
@article {pmid8836257, year = {1996}, author = {Kretzschmar, M and Klein, U and Palutke, M and Schirrmeister, W}, title = {Reduction of ischemia-reperfusion syndrome after abdominal aortic aneurysmectomy by N-acetylcysteine but not mannitol.}, journal = {Acta anaesthesiologica Scandinavica}, volume = {40}, number = {6}, pages = {657-664}, doi = {10.1111/j.1399-6576.1996.tb04506.x}, pmid = {8836257}, issn = {0001-5172}, mesh = {Acetylcysteine/*administration &amp; dosage ; Aged ; Aortic Aneurysm, Abdominal/*surgery ; Epoprostenol/blood ; Free Radical Scavengers/*administration &amp; dosage ; Hemodynamics ; Humans ; Mannitol/*administration &amp; dosage ; Middle Aged ; Oxidative Stress ; Pilot Projects ; *Postoperative Complications ; Reperfusion Injury/blood/etiology/physiopathology/*prevention &amp; control ; Thromboxane A2/blood ; }, abstract = {BACKGROUND: Abdominal aortic aneurysmectomy results in a general ischemia-reperfusion syndrome accompanied by an acute rise in mean pulmonary artery pressure (MPAP). Severe and sometimes fatal postoperative cardiopulmonary complications have been described.<br><br>METHODS: This pilot study examined whether N-acetyl-cysteine (NAC), a precursor of the most important physiological antioxidant glutathione (reduced form: GSH; oxidized form: GSSG), or the hydroxyl radical scavenger mannitol (MAN) modifies these events. The patients received 150 mg/ kg b.m.NAC (n = 9) 30 minutes before infrarenal aortic clamping or 500 mg/kg b.m. MAN (n = 10) 10 minutes before declamping. 11 patients had no additional treatment (control).<br><br>RESULTS: In the control group, a significant increase in plasma levels of oxidized glutathione and lipid peroxides was observed after declamping. Additionally, a significant increase in plasma levels of the stable metabolites of thromboxane (TXB2) and prostacyclin (6-keto-PGF1 alpha) was measureable after declamping. There was a transient increase in MPAP and pulmonary vascular resistance (PVR), both of which returned to normal values within 20 minutes. Six hours after surgery, pulmonary dysfunction was manifest by increase in the intrapulmonary shunt fraction. Relative to the control group, NAC pretreatment led to a complete lack of changes in plasma lipid peroxide, thromboxane and prostacyclin levels after declamping; there was a significant increase in plasma GSH concentration persisting over a period of 12 hours. MPAP, PVR and Qs/QT values were unchanged. MAN pretreatment showed similar effects on the parameters obtained in the acute phase after declamping like the control group.<br><br>CONCLUSIONS: Pretreatment with NAC, but not mannitol, may help prevent ischemia-reperfusion syndrome following aortic clamping.}, }
@article {pmid8813651, year = {1996}, author = {Koeppel, TA and Thies, JC and Lehmann, T and Gebhard, MM and Herfarth, C and Otto, G and Post, S}, title = {Improvement of hepatic microhemodynamics by N-acetylcysteine after warm ischemia.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {28}, number = {4}, pages = {270-277}, doi = {10.1159/000129466}, pmid = {8813651}, issn = {0014-312X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Adhesion ; Free Radical Scavengers/*pharmacology ; Ischemia/*physiopathology ; Leukocytes/physiology ; Liver/*blood supply ; Liver Circulation/*drug effects ; Male ; Phagocytosis ; Rats ; Rats, Wistar ; }, abstract = {In this study we investigated the influence of N-acetylcysteine (NAC) on the hepatic microcirculation after warm ischemia by intravital fluorescence microscopy. Clamping of the left liver lobe was performed in 20 male Wistar rats for 70 min. The treatment group (n = 10) received 400 mg NAC/kg body weight 20 min prior to clamping. After reperfusion, acinar and sinusoidal perfusions were observed as well as the leukocyte-endothelium interaction. Phagocytic activity was assessed after application of latex beads. NAC reduced the number of nonperfused sinusoids in all acinar zones. A reduction in zone 1 (portal) was achieved from 15.5 to 7.1% (p < 0.0001), in zone 2 (midzonal) from 14.6 to 6.1% (p < 0.0001) and in zone 3 (central) from 11.9 to 2.9% (p < 0.0001). There were no significant differences in leukocyte adherence as well as in phagocytic activity detectable. We conclude that NAC improves hepatic microcirculation after warm ischemia by increasing sinusoidal blood flow.}, }
@article {pmid8813648, year = {1996}, author = {Nakano, H and Boudjema, K and Jaeck, D and Alexandre, E and Imbs, P and Chenard, MP and Nagasaki, H and Kumada, K and Wolf, P and Cinqualbre, J}, title = {Amelioration of hepatocellular integrity and inhibition of sinusoidal oxidative stress by N-acetylcysteine pretreatment in cold ischemia-reperfusion injury of rat liver.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {28}, number = {4}, pages = {245-255}, doi = {10.1159/000129463}, pmid = {8813648}, issn = {0014-312X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Buthionine Sulfoximine/pharmacology ; Glutathione/analysis ; Ischemia/*metabolism ; Liver/blood supply/*drug effects/metabolism ; Liver Transplantation ; Male ; Organ Preservation ; Oxidative Stress/*drug effects ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {Further improvements of donor liver preservation are still required in liver transplantation. In the present study, we investigated whether intraportal injection of N-acetylcysteine (NAC) 15 min before flush-out of UW solution (NAC pretreatment) improves liver dysfunction after cold preservation or has a protective effect on sinusoidal oxidative stress. The effect of NAC pretreatment was examined using an isolated perfused rat liver model. The NAC pretreatment significantly reduced sinusoidal oxidative stress relative to a control dextrose 5% injection. Under a glutathione-depleted condition produced by L-buthionine-[S-R]-sulfoximine, the NAC pretreatment also significantly reduced hepatocellular as well as sinusoidal oxidative stress, resulting in improvement of hepatocelllar integrity relative to a control dextrose 5% injection.}, }
@article {pmid8683994, year = {1996}, author = {Hedley, DW and McCulloch, EA}, title = {Generation of reactive oxygen intermediates after treatment of blasts of acute myeloblastic leukemia with cytosine arabinoside: role of bcl-2.}, journal = {Leukemia}, volume = {10}, number = {7}, pages = {1143-1149}, pmid = {8683994}, issn = {0887-6924}, mesh = {Antimetabolites, Antineoplastic/*pharmacology ; Apoptosis/drug effects ; Blast Crisis/metabolism/*pathology ; Calcium/metabolism ; Cell Membrane/metabolism ; Cytarabine/*pharmacology ; Flow Cytometry ; Glutathione/metabolism ; Humans ; Leukemia, Myeloid, Acute/metabolism/*pathology ; Lipid Peroxidation ; Neoplastic Stem Cells/drug effects/metabolism/pathology ; Oxidation-Reduction ; Oxidative Stress ; Proto-Oncogene Proteins/*physiology ; Proto-Oncogene Proteins c-bcl-2 ; Reactive Oxygen Species/*metabolism ; Transfection ; Tumor Cells, Cultured/drug effects/metabolism/pathology ; Tumor Stem Cell Assay ; }, abstract = {Cytosine arabinoside is usually considered to be lethal by incorporation into DNA followed by chain termination. Recently, we have reported that the radical scavenger N-acetyl-cysteine (NAC) protects cultured clonogenic AML blast cells from the lethal affects of Ara-C if given before the drug. This observation provides indirect evidence that toxic reactive oxygen intermediates (ROI) are generated in AML blast cells following Ara-C-induced damage to DNA. In the present paper we present evidence in support of this hypothesis. Using flow cytometry and multiple fluorescent probes for live cell function, we have mapped a sequence of discrete stages that occur during Ara-C cytotoxicity. An early event was the increased generation of ROI. Initially this oxidative stress was countered by an increase in the cellular content of reduced glutathione (GSH), but cells then underwent an abrupt transition to a state characterized by low GSH and very high ROI generation indicative of collapse of cellular redox balance. Next, the capacity to maintain low intracellular ionized calcium was lost, probably due to lipid peroxidation at membrane sites of calcium regulation. Finally, surface membrane integrity was lost. Concurrent measurements of clonogenic cell survival insured the relevance of these flow cytometry measurements to the stem cell population. We used OCI/AML-2 cells transfected with bcl-2 to look for the place in this sequence where bcl-2 protein protects cells against apoptosis; bcl-2 transfectants showed an increase in ROI generation similar to controls, but were able to maintain GSH levels in the face of this oxidative stress. We conclude that oxidative stress plays a major role in Ara-C toxicity, and that bcl-2 protein protects cells by maintaining cellular redox balance in a reducing state. These studies complement previous work showing how regulators of AML growth affect the sensitivity of blast cells to Ara-C by changing the concentration or stability of bcl-2 protein.}, }
@article {pmid8662787, year = {1996}, author = {Pinkus, R and Weiner, LM and Daniel, V}, title = {Role of oxidants and antioxidants in the induction of AP-1, NF-kappaB, and glutathione S-transferase gene expression.}, journal = {The Journal of biological chemistry}, volume = {271}, number = {23}, pages = {13422-13429}, doi = {10.1074/jbc.271.23.13422}, pmid = {8662787}, issn = {0021-9258}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Base Sequence ; Butylated Hydroxyanisole/pharmacology ; Catalase/pharmacology ; Cell Line ; Gene Expression/drug effects ; Glutathione/pharmacology ; Glutathione Transferase/*genetics ; Humans ; Hydroquinones/pharmacology ; Molecular Sequence Data ; NF-kappa B/*genetics ; Oligodeoxyribonucleotides/genetics ; Oxidants/pharmacology ; Oxidative Stress ; Pyrrolidines/pharmacology ; Rats ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism ; Thiocarbamates/pharmacology ; Transcription Factor AP-1/*genetics ; }, abstract = {Transcription factors AP-1 and NF-kappaB have been implicated in the inducible expression of a variety of genes in response to oxidative stress. Recently, based on the observation that butylated hydroxyanisole (BHA) and pyrrolidine dithiocarbamate (PDTC) induce AP-1 binding activity and AP-1-dependent gene expression and assuming that these compounds exert an antioxidant effect, it was claimed that AP-1 is an antioxidant-responsive factor. To determine whether AP-1 can be responsive to both oxidant and antioxidant, we examined the nature of BHA and PDTC inducing activity. Using EPR spectroscopy to detect semiquinone radicals, we demonstrate the autoxidation of BHA metabolite tert-butylhydroquinone (TBHQ) to tert-butylquinone. The kinetics of TBHQ-mediated generation of .OH radicals were monitored in intact hepatoma HepG2 cells by EPR spin trapping technique. Exogenous catalase inhibited the rate and amount of .OH radical formation and the induction of AP-1-mediated glutathione S-transferase (GST) Ya gene expression by BHA and TBHQ, thus indicating the intermediate formation of H2O2 in the metabolism of these chemicals. Furthermore, we show that the induction of AP-1 and NF-kappaB activities and GST Ya gene expression by BHA and TBHQ is due to a pro-oxidant activity, since this induction was inhibited by thiol compounds N-acetyl cysteine and GSH. Similarly, induction of AP-1 and GST Ya gene expression by PDTC was inhibited by N-acetyl cysteine and GSH. The present findings do not support the notion that the induction of AP-1 by BHA, TBHQ, or PDTC is an antioxidant response and demonstrate that both AP-1 and NF-kappaB activities are induced by oxygen radicals.}, }
@article {pmid8942228, year = {1996}, author = {Chan, TY and Chan, AY and Critchley, JA}, title = {Factors responsible for continuing morbidity after paracetamol poisoning in Chinese patients in Hong Kong.}, journal = {Singapore medical journal}, volume = {37}, number = {3}, pages = {275-277}, pmid = {8942228}, issn = {0037-5675}, mesh = {Acetaminophen/*poisoning/therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Non-Narcotic/*poisoning/therapeutic use ; *Asian People ; *Chemical and Drug Induced Liver Injury ; Chronic Disease ; Female ; Hong Kong/epidemiology ; Humans ; Liver Diseases/*epidemiology/physiopathology ; Male ; Middle Aged ; Morbidity ; Prevalence ; Prognosis ; Risk Factors ; }, abstract = {To determine those factors responsible for continuing prevalence of liver damage after paracetamol poisoning, 222 Chinese patients presenting to the Prince of Wales Hospital, Hong Kong from 1988 to 1993 were studied. Of the 27 patients with plasma paracetamol concentrations above the recommended "treatment line", 13 developed liver damage. Time elapsed between ingestion and treatment with intravenous N-acetylcysteine (NAC) was the most important prognostic factor. Failure to give NAC appropriately (50%) and late presentation (23%) were the main reasons for the continuing morbidity. Liver damage in some of the remaining patients (30%) could have been prevented if NAC was started in the Emergency Department within 8-15 hours of ingestion. Liver damage after paracetamol poisoning remains common (5.9%) in Hong Kong because of the failure to give NAC appropriately or late presentation. We hope to improve patient management by repeatedly emphasising the importance of adherence to the standard protocols and having the toxic plasma level results phoned directly to the duty registrars.}, }
@article {pmid8873236, year = {1996}, author = {Kim, HS and Lee, JH and Kim, IK}, title = {Intracellular glutathione level modulates the induction of apoptosis by delta 12-prostaglandin J2.}, journal = {Prostaglandins}, volume = {51}, number = {6}, pages = {413-425}, doi = {10.1016/0090-6980(96)00047-0}, pmid = {8873236}, issn = {0090-6980}, mesh = {Acetylcysteine/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Arsenites/pharmacology ; Buthionine Sulfoximine/pharmacology ; Carcinoma, Hepatocellular/drug therapy/metabolism/pathology ; Cell Division/drug effects ; Cycloheximide/pharmacology ; DNA Fragmentation/drug effects ; Electrophoresis, Agar Gel ; Enzyme Inhibitors/pharmacology ; Glutathione/drug effects/*metabolism ; Humans ; Liver Neoplasms/drug therapy/metabolism/pathology ; Prostaglandin D2/metabolism/*pharmacology ; Sodium Compounds/pharmacology ; Structure-Activity Relationship ; Sulfhydryl Compounds/chemistry ; Tumor Cells, Cultured ; }, abstract = {We studied the effect of intracellular glutathione (GSH), which was known to conjugate readily with an alpha, beta-unsaturated carbonyl of 9-deoxy-delta 9,12-13,14-dihydroPGD2 (delta 12-PGJ2), on the cytotoxicity of delta 12-PGJ2. delta 12-PGJ2 caused DNA fragmentation in human hepatocellular carcinoma Hep 3B cells, which was blocked by cycloheximide (CHX). The delta 12-PGJ2-induced apoptosis was augmented by GSH depletion resulted from pretreatment with buthioninine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor of cysteine, elevated the GSH level and protected cells from initiating apoptosis by delta 12-PGJ2. Sodium arsenite, a thiol-reactive agent, also induced apoptosis, which was potentiated or attenuated by BSO or NAC treatment respectively. These results suggest that the apoptosis-inducing activity of delta 12-PGJ2 is due to thiol-reactivity and intracellular GSH modulates the delta 12-PGJ2-induced apoptosis by regulating the accessibility of delta 12-PGJ2 to target proteins containing thiol groups.}, }
@article {pmid8727227, year = {1996}, author = {Dean, BS and Bricker, JD and Krenzelok, EP}, title = {Outpatient N-acetylcysteine treatment for acetaminophen poisoning: an ethical dilemma or a new financial mandate?.}, journal = {Veterinary and human toxicology}, volume = {38}, number = {3}, pages = {222-224}, pmid = {8727227}, issn = {0145-6296}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adolescent ; Adult ; Ambulatory Care ; Analgesics, Non-Narcotic/*poisoning ; Female ; Follow-Up Studies ; Free Radical Scavengers/administration &amp; dosage/*therapeutic use ; Humans ; Length of Stay ; Liver/*drug effects/metabolism ; Male ; Patient Compliance ; Poison Control Centers ; Poisoning/drug therapy ; Retrospective Studies ; Self Administration ; }, abstract = {The mainstay of treatment for acetaminophen-induced hepatotoxicity, produced by the accumulation of the toxic metabolite N-acetylbenzoquinoneimine, is an enteral 18-dose course of N-acetylcysteine (NAC). However, absence of characteristic symptomatology is a frequent reason for premature cessation of NAC and early discharge of the toxic acetaminophen poisoned patient. We report a series of confirmed acetaminophen poisonings who were discharged early with NAC and instructions to self-administer. All cases of acute acetaminophen poisoning without concomitant drugs, reported to a certified Regional Poison Information Center for a 3-mo period of time, were reviewed. Inclusion criteria included patients who were discharged with orders to complete the course of NAC outside of a hospital, despite toxic serum acetaminophen concentrations. Data parameters evaluated included age, amount taken, symptoms, laboratory results, treatment, and medical outcome. 131 cases of confirmed toxic acetaminophen poisoning yielded 6 patients who received 4 to 6 doses of NAC during hospitalization, but were discharged to home with the remaining 11-13 doses. Patients' ages ranged from 16-28 y (mean 20.0 y). Serum acetaminophen concentrations measured at 4 h post-ingestion ranged from 171-198 mcg/ml (mean 182 mcg/ml). Follow-up by the certified Regional Poison Information Center at 1-3 w post-discharge determined dosing compliance to be 83%. All 6 patients remained asymptomatic with normal liver function testing. Since health care reform encourages practitioners to reconsider established approaches to the delivery of health care, perhaps home delivery of NAC would not only be clinically preferred to premature cessation of the antidote, but also offer cost savings. Self-administration of NAC in the home setting may be representative of a new era in America's health care delivery system.}, }
@article {pmid8665049, year = {1996}, author = {Hida, W and Shindoh, C and Satoh, J and Sagara, M and Kikuchi, Y and Toyota, T and Shirato, K}, title = {N-acetylcysteine inhibits loss of diaphragm function in streptozotocin-treated rats.}, journal = {American journal of respiratory and critical care medicine}, volume = {153}, number = {6 Pt 1}, pages = {1875-1879}, doi = {10.1164/ajrccm.153.6.8665049}, pmid = {8665049}, issn = {1073-449X}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Antioxidants/*pharmacology ; Diabetes Mellitus, Experimental/*physiopathology ; Diaphragm/*drug effects/*physiopathology ; Dose-Response Relationship, Drug ; Male ; Muscle Contraction/drug effects ; Muscle Relaxation/drug effects ; Rats ; Rats, Wistar ; Streptozocin/*antagonists &amp; inhibitors ; Time Factors ; }, abstract = {We examined whether streptozotocin (STZ)-induced diabetic rats have an impairment in diaphragm contractility, and if so, whether N-acetylcysteine (NAC), a nonspecific antioxidant, prevents this impairment. First, diaphragm contractility, assessed by tension-frequency relationships and twitch kinetics in in vitro diaphragm strip preparations of Wistar rats, was obtained on Days 3 and 7 after administration of STZ of 30 or 60 mg/kg body weight, and compared with that of the control group. Second, NAC at 500 mg/kg body weight or vehicle solution was administered orally every day in rats treated with STZ at 60 mg/kg body weight, and diaphragm function on Day 7 after starting NAC treatment was compared between vehicle control and STZ-treated groups. We found that diaphragm function in STZ-treated rats, which had hyperglycemia, decreased in a dose- and time-dependent manner. NAC inhibited the decrease in diaphragm contractility in STZ-treated rats without reducing blood glucose. These findings suggest that the loss of diaphragm function in STZ-induced diabetic rats is not directly related to hyperglycemia. The data are consistent with secondary alterations of normal cytokine signaling or changes in the redox state of the cell, both of which could be affected by NAC treatment.}, }
@article {pmid8655601, year = {1996}, author = {Phelan, MW and Faller, DV}, title = {Hypoxia decreases constitutive nitric oxide synthase transcript and protein in cultured endothelial cells.}, journal = {Journal of cellular physiology}, volume = {167}, number = {3}, pages = {469-476}, doi = {10.1002/(SICI)1097-4652(199606)167:3&lt;469::AID-JCP11&gt;3.0.CO;2-#}, pmid = {8655601}, issn = {0021-9541}, support = {HL45940/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Bradykinin/pharmacology ; Cattle ; *Cell Hypoxia ; Cells, Cultured ; Cobalt/pharmacology ; Dactinomycin/pharmacology ; Endothelin-1 ; Endothelins/analysis/genetics ; Endothelium, Vascular/cytology/*metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Nitric Oxide Synthase/genetics/*metabolism ; Oxygen/pharmacology ; Proline/analogs &amp; derivatives/pharmacology ; Protein Precursors/analysis/genetics ; RNA, Messenger/genetics/*metabolism ; Suppression, Genetic/genetics ; Thiocarbamates/pharmacology ; Umbilical Veins ; }, abstract = {Endothelial cell-generated nitric oxide (NO) accounts in large part for the labile vasodilator termed endothelium-derived relaxing factor. Two distinct types of NO synthase exist: a "constitutive' type (cNOS), found in endothelial cells, and an "inducible' enzyme. Endothelial cells sense pO2 levels in the range of 70-20 torr and respond to this hypoxia by inducing transcription of genes which encode the vasoactive proteins PDGF-B and endothelin-1. Exposure of human or bovine endothelial cells to low oxygen tensions results in a profound decrease in the transcript for cNOS and a corresponding fall in cNOS protein levels. The ability of endothelial cells exposed to hypoxia to produce NO in response to bradykinin, a stimulator of cNOS activity, was coordinately impaired. Cobalt inhibited the expression of cNOS transcripts, suggesting a mechanism comparable to that by which oxygen tension regulates expression of other vasoregulatory genes. In the presence of actinomycin-D, hypoxia had no effect on cNOS transcripts, suggesting that new gene transcription is required for cNOS suppression. The reducing agents PDTC and N-Ac did not mimic cNOS gene suppression by hypoxia, suggesting that this suppression is not related to the redox state of the intracellular environment. Thus, regulation of cNOS function in response to environmental factors can occur at the level of gene expression as well as at the level of enzyme activation.}, }
@article {pmid8793082, year = {1996}, author = {Smalheiser, NR and Dissanayake, S and Kapil, A}, title = {Rapid regulation of neurite outgrowth and retraction by phospholipase A2-derived arachidonic acid and its metabolites.}, journal = {Brain research}, volume = {721}, number = {1-2}, pages = {39-48}, doi = {10.1016/0006-8993(96)00134-5}, pmid = {8793082}, issn = {0006-8993}, support = {HD 09402/HD/NICHD NIH HHS/United States ; NS 26055/NS/NINDS NIH HHS/United States ; }, mesh = {Actins/metabolism ; Antioxidants/pharmacology ; Arachidonic Acid/biosynthesis/*physiology ; Down-Regulation/drug effects ; Histocytochemistry ; Indomethacin/pharmacology ; Lipoxygenase Inhibitors/pharmacology ; Lysophospholipids/pharmacology ; Neurites/drug effects/*physiology/ultrastructure ; Oxidation-Reduction ; Phospholipases A/antagonists &amp; inhibitors/metabolism/*physiology ; Phospholipases A2 ; Protein Kinase C/biosynthesis ; Tumor Cells, Cultured ; }, abstract = {Arachidonic acid and lipoxygenase metabolites have been proposed to act as retrograde synaptic messengers and as early mediators of neuronal injury, but few studies have analyzed their roles in controlling neurite behavior within a time window of minutes to hours. Phospholipase A2 inhibitors (BPB, ONO-RS-082, quinacrine and AACOCF3) and the lipoxygenase inhibitor AA861 delayed the initial outgrowth of NG108-15 cell neurites on laminin. Inhibitors of diacylglycerol lipase (RHC 80267), cyclooxygenase (indomethacin) and free radicals (N-acetyl cysteine and vitamin E) did not produce similar effects. Phospholipase A2 and lipoxygenase inhibitors also prevented acute neurite retraction in response to lysophosphatidic acid and eight other agents tested, and decreased F-actin staining at cell margins. Conversely, exogenous arachidonic acid (1 microM) enhanced the responses of neurites in outgrowth and retraction assays. Phospholipase A2 and lipoxygenase pathways appear to have a general role in maintaining the ability of neurites to respond rapidly to external stimuli, possibly via regulating the ability of the cytoskeleton to remodel.}, }
@article {pmid8629304, year = {1996}, author = {Koeppel, TA and Lehmann, TG and Thies, JC and Gehrcke, R and Gebhard, MM and Herfarth, C and Otto, G and Post, S}, title = {Impact of N-acetylcysteine on the hepatic microcirculation after orthotopic liver transplantation.}, journal = {Transplantation}, volume = {61}, number = {9}, pages = {1397-1402}, doi = {10.1097/00007890-199605150-00020}, pmid = {8629304}, issn = {0041-1337}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cold Temperature ; Free Radical Scavengers/*pharmacology ; Ischemia ; Liver Circulation/*drug effects ; *Liver Transplantation ; Male ; Microcirculation/drug effects ; Organ Preservation/methods ; Rats ; Rats, Inbred Lew ; Reperfusion Injury/prevention &amp; control ; }, abstract = {Recent observations showed an improvement of hepatic macro- and microhemodynamics as well as survival rates after warm ischemia of the liver following treatment with N-acetylcysteine (NAC). In this study we assessed the influence of NAC on the hepatic microcirculation after orthotopic liver transplantation (OLT) using intravital fluorescence microscopy. OLT with simultaneous arterialization was performed in 16 male Lewis rats following cold storage in University of Wisconsin solution for 24 hr. Within the experimental group (n = 8) donors received NAC (400 mg/kg) 25 min before hepatectomy. In addition, high-dose treatment of recipients with NAC (400 mg/kg) was started with reperfusion. Control animals (n = 8) received an equivalent amount of Ringer's solution. Intravital fluorescence microscopy was performed 30-90 min after reperfusion assessing acinar and sinusoidal perfusion, leukocyte-endothelium interaction, and phagocytic activity. Treatment with NAC reduced the number of nonperfused sinusoid from 52.4 +/- 0.8% to 15.7 +/- 0.5% (p = 0.0001) (mean +/- SEM). Furthermore, we achieved a significant reduction of leukocytes adhering to sinusoidal endothelium (per mm2 liver surface) from 351.9 +/- 13.0 in controls to 83.6 +/- 4.2 in the experimental group (P = 0.0001). In postsinusoidal venules, treatment with NAC decreased the number of sticking leukocytes (per mm2 endothelium) from 1098.5 +/- 59.6 to 425.9 +/- 37.7 (P = 0.0001). Moreover, bile flow was significantly increased after therapy with NAC (4.3 +/- 1.2 vs. 2.2 +/- 0.7 ml/90 min x 100g liver) (P < 0.05). Phagocytic activity was not influenced by application of NAC. We conclude that high-dose therapy with NAC in OLT attenuates manifestations of microvascular perfusion failure early after reperfusion and should be considered as a means to reduce reperfusion injury.}, }
@article {pmid8645333, year = {1996}, author = {Weltin, D and Aupeix, K and Iltis, C and Cuillerot, JM and Dufour, P and Marchal, J and Bischoff, P}, title = {N-acetylcysteine protects lymphocytes from nitrogen mustard-induced apoptosis.}, journal = {Biochemical pharmacology}, volume = {51}, number = {9}, pages = {1123-1129}, doi = {10.1016/0006-2952(96)83389-2}, pmid = {8645333}, issn = {0006-2952}, mesh = {Acetylcysteine/pharmacokinetics/*pharmacology ; Animals ; Apoptosis/*drug effects ; Concanavalin A/pharmacology ; Lymphocytes/cytology/*drug effects ; Mechlorethamine/antagonists &amp; inhibitors/*pharmacology ; Mice ; Mice, Inbred C3H ; Poly Adenosine Diphosphate Ribose/metabolism ; Spleen/cytology/drug effects ; }, abstract = {The ability of the antioxidant N-acetylcysteine to prevent apoptosis induced in lymphocytes by nitrogen mustard (HN2) was investigated. HN2 caused a concentration-dependent induction of apoptosis on C3H murine spleen cells, as identified by two criteria: morphological features revealed by microscopical observations and DNA fragmentation visualized by the characteristic "ladder" pattern observed upon agarose gel electrophoresis, as well as by hypodiploid DNA-containing cells revealed by the flow cytometric analysis of propidium iodide labelled cells. The antioxidant N-acetylcysteine (NAC) was found to markedly reduce the occurrence of HN2-induced apoptosis in these cells. This protective effect will still obtained when NAC was added 30 min after HN2. In contrast, the pretreatment of spleen cells with this antioxidant did not provide any significant protection. We also showed that lymphocytes protected by NAC are still able to respond to a mitogenic stimulation. To gain some insight into the mechanisms underlying the cytoprotective action of NAC against HN2, we tested whether or not poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30), a nuclear enzyme that participates in the triggering of apoptosis induced by alkylating agents, is involved. We report that 6(5H)-phenanthridinone, a potent PARP inhibitor, did not affect the ability of NAC to prevent HN2-induced apoptosis under our experimental conditions. Thus, the exact mechanism by which NAC protects lymphocytes from HN2 cytotoxicity has yet to be determined.}, }
@article {pmid8763412, year = {1996}, author = {Laursen, JB and Boesgaard, S and Poulsen, HE and Aldershvile, J}, title = {Nitrate tolerance impairs nitric oxide-mediated vasodilation in vivo.}, journal = {Cardiovascular research}, volume = {31}, number = {5}, pages = {814-819}, doi = {10.1016/0008-6363(96)00027-2}, pmid = {8763412}, issn = {0008-6363}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Arginine/analogs &amp; derivatives/pharmacology ; Drug Tolerance ; Female ; NG-Nitroarginine Methyl Ester ; Nitrates/*metabolism ; Nitric Oxide/antagonists &amp; inhibitors/*physiology ; Nitric Oxide Synthase/antagonists &amp; inhibitors ; Nitroglycerin/pharmacology ; Nitroprusside/pharmacology ; Rats ; Rats, Wistar ; Vasodilation/drug effects/*physiology ; }, abstract = {OBJECTIVES: Nitroglycerin (NTG) is metabolized to nitric oxide (NO) in vascular smooth muscle cells. It is currently not clear whether prolonged exposure to NTG and tolerance development directly affects endogenous NO-mediated vasodilation in vivo. This study investigates NO-mediated vasodilation in conscious chronically catheterized rats before and after development of nitrate tolerance. The effect of the thiol compound N-acetylcysteine (NAC), which may affect NTG responsiveness, was also studied.<br><br>METHODS: Nitrate tolerance was induced by a 72-h intravenous infusion of NTG and confirmed by a 65-68% reduction in the hypotensive response to NTG (P < 0.05). The hypotensive effects of acetylcholine (ACh) and sodium nitroprusside, (SNP) and possible NAC-mediated changes in the responses to these compounds were examined in nontolerant and nitrate-tolerant rats. Furthermore, the hypertensive response to the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) was measured.<br><br>RESULTS: Nitrate tolerance was associated with a significantly attenuated hypotensive response to ACh (before 24 +/- 1 mmHg; after 17 +/- 2 mmHg, n = 7, P < 0.05). Similarly, the response to SNP was reduced from 32 +/- 1 mmHg to 26 +/- 3 mmHg (n = 7, P < 0.05). NTG-vehicle (placebo) did not affect the response to ACh and SNP (P > 0.05). NAC augmented the effect of NTG, ACh and SNP in both nontolerant and nitrate-tolerant animals (P < 0.05). The hypertensive response to L-NAME (n = 8), was reduced by 67% (from 34 +/- 6 mmHg to 11 +/- 1 mmHg, P < 0.05) after induction of nitrate tolerance.<br><br>CONCLUSIONS: The results suggest (1) that nitrate tolerance in vivo is associated with cross tolerance to NO-mediated vasodilation produced by both exogenous and endogenous nitrovasodilators and (2) that also responses to nitrovasodilator agents other than NTG are improved by the addition of NAC.}, }
@article {pmid8718938, year = {1996}, author = {Malorni, W and Matarrese, P and Rivabene, R and Paradisi, S and Donelli, G}, title = {Antioxidant N-acetyl-cysteine increasing cell adhesion capability could facilitate the biocompatibility processes.}, journal = {Biomaterials}, volume = {17}, number = {9}, pages = {921-928}, doi = {10.1016/0142-9612(96)83288-1}, pmid = {8718938}, issn = {0142-9612}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; *Biocompatible Materials ; Cell Adhesion/*drug effects ; Cell Line ; Cytoskeletal Proteins/metabolism ; Epithelial Cells ; Epithelium/drug effects/metabolism ; Extracellular Matrix Proteins/metabolism ; Humans ; Hyaluronan Receptors/metabolism ; Integrin alpha3beta1 ; Integrin alpha6beta1 ; Integrins/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; Materials Testing ; Microscopy, Fluorescence ; Receptors, Collagen ; }, abstract = {Cell adhesion plays an important role in several cell processes and functions, including differentiation, proliferation and death. An important role for cell attachment to medical devices in biocompatibility studies has also been hypothesized. In this paper we report that the use of the antioxidant drug N-acetyl-cysteine is capable of increasing the adhesion properties of epithelial cells in culture. This is associated with a modification of specific cytoskeletal element assembly, such as microfilament system molecules. In contrast, no quantitative alterations in the expression of certain surface receptors for extracellular matrix molecules, such as VLA2, VLA3 and VLA6, are found. These data seem to indicate that intracellular oxidative balance, in particular of thiol groups, could play a key role in the cell adhesion properties and that N-acetyl-cysteine treatment, acting as 'thiol supply', could be of importance in several circumstances, including biocompatibility of medical devices.}, }
@article {pmid8647183, year = {1996}, author = {McLaughlin, KA and Osborne, BA and Goldsby, RA}, title = {The role of oxygen in thymocyte apoptosis.}, journal = {European journal of immunology}, volume = {26}, number = {5}, pages = {1170-1174}, doi = {10.1002/eji.1830260531}, pmid = {8647183}, issn = {0014-2980}, support = {GM47922/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anaerobiosis/drug effects ; Animals ; Apoptosis/*drug effects/radiation effects ; Calcimycin/pharmacology ; Cell Death/drug effects ; DNA-Binding Proteins/genetics ; Enterotoxins/pharmacology ; Female ; Gene Expression Regulation/drug effects ; Male ; Mercaptoethanol/pharmacology ; Mice ; Mice, Inbred BALB C ; Nuclear Receptor Subfamily 4, Group A, Member 1 ; Organ Culture Techniques ; Oxygen/pharmacology/*physiology ; Receptors, Antigen, T-Cell, alpha-beta ; Receptors, Cytoplasmic and Nuclear ; Receptors, Steroid ; Staphylococcus aureus ; T-Lymphocytes/*drug effects/physiology ; Tetradecanoylphorbol Acetate/pharmacology ; Thymus Gland/*drug effects ; Transcription Factors/genetics ; }, abstract = {Signals generated by T cell receptor (TCR) cross-linking (or phorbol 12-myristate-13-acetate + Ca2+ ionophore), glucocorticoids or ionizing radiation all stimulate apoptotic cell death in thymocytes by signals that are initially distinct from each other. However, when these stimuli were administered to thymocyte cultures that were maintained under an atmosphere containing less than 20 ppm oxygen as opposed to one that contained 18.5% molecular oxygen, cell death was inhibited or abrogated, suggesting that the induction of death by all three different stimuli depend on the presence of molecular oxygen. Studies of the effects of the cysteine analog N-acetyl cysteine (NAC) with normal thymocytes demonstrated that this antioxidant inhibited the induction of death by each of the different stimuli in a manner the paralleled anaerobiosis. Furthermore, studies with thymocytes demonstrated that the induction of nur77, a gene shown to be involved in thymocyte apoptosis signaled through the TCR or its surrogates, is not inhibited by NAC or dependent upon molecular oxygen. The possible implications for negative selection of NAC-mediated inhibition of TCR-signaled thymocyte cell death was examined in thymic organ culture. Treatment of these cultures with NAC provided significant protection against staphylococcal enterotoxin B-mediated deletion of V beta 8-expressing thymocytes.}, }
@article {pmid8647182, year = {1996}, author = {Chiba, T and Takahashi, S and Sato, N and Ishii, S and Kikuchi, K}, title = {Fas-mediated apoptosis is modulated by intracellular glutathione in human T cells.}, journal = {European journal of immunology}, volume = {26}, number = {5}, pages = {1164-1169}, doi = {10.1002/eji.1830260530}, pmid = {8647182}, issn = {0014-2980}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects/immunology ; Buthionine Sulfoximine ; Culture Media, Conditioned ; Cycloheximide/pharmacology ; Cysteine/immunology ; Cytotoxicity, Immunologic/drug effects ; Glutathione/antagonists &amp; inhibitors/*pharmacology ; Humans ; Immunity, Innate/drug effects ; Intracellular Fluid/immunology ; Killer Cells, Lymphokine-Activated/immunology ; Leukemia, T-Cell/immunology/metabolism ; Lymphocyte Activation/drug effects ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; T-Lymphocytes/*drug effects/immunology ; Tumor Cells, Cultured ; fas Receptor/immunology/*pharmacology ; }, abstract = {Fas antigen is a member of the tumor necrosis factor receptor family that transduces a lethal signal to the Fas-sensitive cells. We previously established the Fas-resistant variant cell lines LAC2D1R and JKT2D1R from the parental Fas-sensitive cell lines, SUPT13 and Jurkat, respectively. Recently, we isolated the Fas-resistant variant CEM2D1R from CCRF-CEM. All of the variants were Fas+ but resistant to Fas-mediated apoptosis. Further biochemical analysis revealed that the intracellular glutathione (GSH) content of the Fas-resistant variants was higher than in the original cells. When the Fas-resistant variants were incubated with buthionine sulfoximine (BSO) or in GSH-free/cysteine-free medium to deplete GSH, Fas resistance was reversed. Incubation of the cells with cycloheximide also decreased intracellular GSH and reversed the Fas resistance. Furthermore, incubation of activated peripheral blood lymphocytes with BSO enhanced Fas-mediated apoptosis. When the Fas-sensitive cells were incubated with N-acetylcysteine (NAC), intracellular GSH was increased and Fas-mediated apoptosis was blocked. In contrast, Fas-resistant variants, as well as Fas-sensitive cells pre-treated with NAC remained susceptible to allogeneic lymphokine-activated killer cells, most likely due to perforin-dependent killing. The results suggest that Fas-mediated apoptosis, but not perforin-dependent killing, is modulated by intracellular GSH in human T lymphocytes.}, }
@article {pmid8644118, year = {1996}, author = {Ercal, N and Treeratphan, P and Lutz, P and Hammond, TC and Matthews, RH}, title = {N-actylcysteine protects Chinese hamster ovary (CHO) cells from lead-induced oxidative stress.}, journal = {Toxicology}, volume = {108}, number = {1-2}, pages = {57-64}, doi = {10.1016/s0300-483x(95)03273-i}, pmid = {8644118}, issn = {0300-483X}, support = {R01ESO6065-01A1/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; CHO Cells ; Cell Survival/drug effects ; Cricetinae ; Environmental Pollutants ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Lead/*antagonists &amp; inhibitors/toxicity ; Lipid Peroxidation ; Malondialdehyde/metabolism ; Organometallic Compounds/*antagonists &amp; inhibitors/toxicity ; Oxidative Stress/drug effects ; }, abstract = {In vitro administration of lead acetate (PbA) to cultures of Chinese hamster ovary (CHO) cells had a concentration-dependent inhibitory effect on colony formation. Colony formation was returned to control levels in lead-treated cultures that were supplemented with 1 mM N-actylcysteine (NAC), a well-documented synthetic antioxidant. In order to investigate the nature of NAC's protective effect, we measured L-gamma-glutamyl-L-cysteinylglycine (GSH), oxidized glutathione (GSSG), malondialdehyde (MDA) and catalase activity both in the presence and absence of NAC in lead-exposed CHO cells. Increases in both MDA levels (p < 0.05) and catalase activity (P < 0.05) were observed in cultures that received only PbA, but supplementation with NAC returned these measures to pretreatment levels. The ratio of GSH to GSSG increased in lead-exposed cells incubated in NAC-enhanced media, but declined in cultures treated with PbA only. Our results suggest that NAC can confer protection against lead-induced oxidative stress to CHO cells, possibly through the enhancement of the cell's own antioxidant defense mechanisms.}, }
@article {pmid9173679, year = {1996}, author = {Berg-Candolfi, M and Candolfi, E and Benet, LZ}, title = {Suppression of intestinal and hepatic cytochrome P4503A in murine Toxoplasma infection. Effects of N-acetylcysteine and N(G)-monomethyl-L-arginine on the hepatic suppression.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {26}, number = {4}, pages = {381-394}, doi = {10.3109/00498259609046717}, pmid = {9173679}, issn = {0049-8254}, support = {GM-26691/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibodies, Monoclonal/immunology ; Arginine/*analogs &amp; derivatives/pharmacology ; *Aryl Hydrocarbon Hydroxylases ; Cyclosporine/metabolism ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System/*metabolism ; Erythromycin/metabolism ; Interferon-gamma/immunology/physiology ; Intestinal Mucosa/drug effects/*enzymology ; Jejunum/drug effects/enzymology ; Macrophages, Peritoneal/metabolism ; Male ; Mice ; Mice, Inbred CBA ; Microsomes/drug effects/enzymology ; Microsomes, Liver/drug effects/*enzymology ; Nitrites/metabolism ; Oxidoreductases, N-Demethylating/antagonists &amp; inhibitors/*metabolism ; Toxoplasmosis, Animal/*enzymology ; }, abstract = {1. Cytochrome P4503A (CYP3A) expression was studied in a murine model of infection. Mice were infected with a cystogenic strain of Toxoplasma gondii and microsomes were prepared for liver homogenates and jejunum villus tip enterocytes on day 10 postinfection. Total cytochrome P450 (CYP) and CYP3A were quantitated, and CYP3A activity was determined. 2. In the infected mouse, total CYP and CYP3A contents fell in the liver (-39 and - 49% respectively) and intestine (-43 and - 48 % respectively), as did the rate of metabolism of erythromycin (Ery) and cyclosporine A (CyA), two markers of CYP3A activity (-36 and -26% in the liver, -35 and -58% in the intestine). 3. To determine the mechanism(s) involved in the depression of hepatic CYP3A, infected mice were treated on day 7.5 post-infection with a monoclonal antibody raised against interferon-gamma (anti-IFN-gamma, or from days 7.5 to 10 post-infection with either N(G)-monomethyl-L-arginine (NMMA), an inhibitor of reactive nitrogen intermediates (RNI) production, or N-acetylcysteine (NAC), a reactive oxygen intermediates (ROI) scavenger. 4. Total CYP content was restored in the liver of infected mice treated with anti-IFN-gamma, but with marked interindividual variability. NAC treatment led to a recovery in the liver of total CYP content (+35 %), CYP3A content (total recovery), and the rates of Ery (+59%) and CyA (+87%) metabolism, whereas inconsistent results were obtained with NMMA. These results suggest that NAC, but probably not NMMA, partially protects hepatic CYP3A from Toxoplasma-mediated suppression in mouse.}, }
@article {pmid8901051, year = {1996}, author = {Gatherer, D and Woodland, HR}, title = {N-acetyl-cysteine causes a late re-specification of the anteroposterior axis in the Xenopus embryo.}, journal = {Developmental dynamics : an official publication of the American Association of Anatomists}, volume = {205}, number = {4}, pages = {395-409}, doi = {10.1002/(SICI)1097-0177(199604)205:4&lt;395::AID-AJA4&gt;3.0.CO;2-D}, pmid = {8901051}, issn = {1058-8388}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Axis, Cervical Vertebra/*growth &amp; development ; Cell Division ; Ectoderm ; Gastrula/drug effects ; Glutathione/pharmacology ; Lithium/pharmacology ; Phenotype ; Suramin/pharmacology ; Tretinoin/pharmacology ; Ultraviolet Rays ; Xenopus/anatomy &amp; histology/embryology/*growth &amp; development ; }, abstract = {N-acetyl cysteine is an agent which has been shown to interrupt signal transduction processes linking a wide range of stimuli to the activation of NF-kappa B in mammalian cells. We have investigated its effect on the early development of Xenopus embryos by injecting it into blastulae, using concentrations comparable to those effective on cultured cells. High concentrations at the late blastula or early gastrula stage suppress posterior and enhance anterior development, yielding embryos with enlarged cement glands and otherwise consisting of little except head in extreme cases. Reducing the amount of N-acetyl cysteine injected leads to progressively more posterior structures developing. Injection into one- or two-cell embryos gives similar phenotypes, but of reduced severity and the cement gland is not so enlarged. Explants of animal cap cells taken several hours after injection develop to give large amounts of cement gland material. We have examined the expression of a number of genes in the anteriorised embryos. Posterior markers and Xsna are reduced. Noggin and Goosecoid mRNA are up-regulated through the gastrula and persist at these levels until at least the late neurula stage, whereas in controls Noggin is much lower and Goosecoid is absent at these stages. The most anteriorised phenotype may be a consequence of this changed expression.}, }
@article {pmid8777989, year = {1996}, author = {Suzuki, N and Svensson, K and Eriksson, UJ}, title = {High glucose concentration inhibits migration of rat cranial neural crest cells in vitro.}, journal = {Diabetologia}, volume = {39}, number = {4}, pages = {401-411}, pmid = {8777989}, issn = {0012-186X}, mesh = {Animals ; Brain/*embryology ; Cell Movement/drug effects ; Cells, Cultured ; Congenital Abnormalities/genetics ; Crosses, Genetic ; Dose-Response Relationship, Drug ; Female ; Glucose/*pharmacology ; Male ; Microscopy, Electron, Scanning ; Neural Crest/cytology/drug effects/*physiology ; Neurons/drug effects/*physiology/ultrastructure ; Pregnancy ; Rats ; Rats, Mutant Strains ; Rats, Sprague-Dawley ; }, abstract = {Cranial neural crest cells give rise to a large part of the facial structures, and disturbed development of these cells may therefore cause congenital malformations affecting the head and face. We studied the effects of increased glucose concentration on the migration and development of cranial neural crest cells, maintained in vitro for 48 h. Pre-migratory cranial neural crest cells were removed from embryos of normal and diabetic rats on gestational day 9. After 24 h in 10 mmol/l glucose the cells were exposed to glucose concentrations of 10, 30, or 50 mmol/l for another 24 h. The cultures were photographed at 24 h and 48 h in a phase-contrast microscope to evaluate cell morphology, cell number, and cell migration. Exposure to 50 mmol/l glucose reduced the total number of neural crest cells, their mean migratory distance and migratory area expansion compared to cells cultured in 10 mmol/l glucose. To investigate the effect of antioxidant agents, high glucose cultures were studied after addition of N-acetylcysteine (NAC), or superoxide dismutase (SOD). Addition of NAC diminished the inhibitory effect of high glucose, whereas SOD did not offer any improvement in cell development. Neural crest cell culture from embryos of diabetic rats showed reduced cell migration in vitro at all glucose concentrations compared to normal cells. In addition, the cells from embryos of diabetic rats showed reduced migratory area expansion after culture in the basal 10 mmol/l glucose concentration, indicating that maternal diabetes permanently influences the future development of premigratory cranial neural crest cells. These findings indicate that high glucose concentration inhibits cranial neural crest development in vitro, and that antioxidant therapy may diminish this inhibition. Free radical oxygen species may be involved in the induction of malformations and antioxidants may therefore have a role in future attempts to block the teratogenic effects of diabetic pregnancy.}, }
@article {pmid8740084, year = {1996}, author = {Cogo, A and Chieffo, A and Farinatti, M and Ciaccia, A}, title = {Efficacy of topical tuaminoheptane combined with N-acetyl-cysteine in reducing nasal resistance. A double-blind rhinomanometric study versus xylometazoline and placebo.}, journal = {Arzneimittel-Forschung}, volume = {46}, number = {4}, pages = {385-388}, pmid = {8740084}, issn = {0004-4172}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Intranasal ; Adult ; Airway Resistance/*drug effects ; Amines/administration &amp; dosage/*pharmacology ; Double-Blind Method ; Drug Combinations ; Female ; Forced Expiratory Flow Rates/drug effects ; Humans ; Imidazoles/administration &amp; dosage/*pharmacology ; Male ; Manometry ; Middle Aged ; Nasal Cavity/*physiology ; Nasal Decongestants/administration &amp; dosage/*pharmacology ; Respiratory Mechanics/physiology ; }, abstract = {The aim of this study was to functionally evaluate the decongestant effect of a topical intranasal drug (Rhinofluimucil consisting of tuaminoheptane sulphate (CAS 6411-75-2, THS), a vasoconstrictor, combined with N-acetyl-cysteine (CAS 616-91-1, NAC). This was a double-blind randomized study, versus both xylometazoline and placebo. 18 subjects (8M and 10F, aged 20-47 years), unaffected by any rhinitic pathology, underwent anterior rhinomanometry. Following the basal evaluation (T0), subjects were randomly divided into three groups and subjected, in a double-blind manner, to nasal instillations (2 puffs per nostril) of THS/NAC (R), xylometazoline (O) and saline solution (P), respectively. Rhinomanometry was repeated after 5, 10 and 20 min (T5, T10, T20). Resistance and flow were measured in both nostrils at a pressure gradient of 150 Pa. After R and O nasal resistance significantly decreased from 0.30 Pa to 0.19 Pa and from 0.31 Pa to 0.17 Pa, respectively, and flow significantly increased; no effects were observed with placebo. In this study, THS/NAC showed rapid decongestant properties, with a significant decrease of resistance and increase of inspiratory flow. The same finding was observed with xylometazoline, but not with the placebo. The decongestant effect was rapid: it could already be observed at T5, and remained constant up to T20 without any rebound effect.}, }
@article {pmid8730112, year = {1996}, author = {Stucki, G and Brühlmann, P and Stoll, T and Stucki, S and Willer, B and Michel, BA}, title = {Low serum creatine kinase activity is associated with muscle weakness in patients with rheumatoid arthritis.}, journal = {The Journal of rheumatology}, volume = {23}, number = {4}, pages = {603-608}, pmid = {8730112}, issn = {0315-162X}, mesh = {Adrenal Cortex Hormones/therapeutic use ; Aged ; Arthritis, Rheumatoid/drug therapy/*enzymology/physiopathology ; Biomarkers/blood ; Creatine Kinase/*blood ; Cross-Sectional Studies ; Exercise ; Female ; Humans ; Isometric Contraction/physiology ; Longitudinal Studies ; Male ; Middle Aged ; Muscle Weakness/drug therapy/*enzymology/physiopathology ; Muscle, Skeletal/physiology ; Regression Analysis ; Retrospective Studies ; }, abstract = {OBJECTIVE: In rheumatoid arthritis (RA) serum creatine kinase (CK) is reduced in association with inflammatory response variables. Our objective was to examine whether low CK is associated with muscle weakness and to what extent the hypothesized relationship between CK and muscle weakness can be explained by anthropometric and sociodemographic variables and/or disease variables.<br><br>METHODS: Cross sectional and longitudinal retrospective analyses of clinical, radiological, and biochemical data of a prospective cohort of consecutive patients with RA. Isometric muscle strength was measured with a validated muscle strength index (MSI); CK was measured with an enzymatic assay (N-acetyl-cysteine, 37 degrees C).<br><br>RESULTS: 65 patients were enrolled in the study and we obtained complete one year followup data from 47. In cross sectional analysis, CK was a significant, moderate correlate of the MSI (r = 0.43, p < 0.01). CK remained a significant explanatory variable of the MSI in multivariate models that controlled for demographic variables and lean body mass, corticosteroid use, and biochemical, clinical, and radiological disease variables. In longitudinal dichotomous analyses, worsening in CK was weakly but significantly associated with decreased muscle strength, whereas in linear analyses the association did not reach significance.<br><br>CONCLUSION: In patients with RA, low CK activity is associated with muscle weakness. Demographic, anthropometric, and disease variables related to muscle mass or muscle atrophy explain only part of this association. Our findings support the hypothesis that muscle weakness may be partly caused by a disease related reduction of CK activity independent of muscle atrophy.}, }
@article {pmid8726363, year = {1996}, author = {Tyagi, SC and Kumar, S and Borders, S}, title = {Reduction-oxidation (redox) state regulation of extracellular matrix metalloproteinases and tissue inhibitors in cardiac normal and transformed fibroblast cells.}, journal = {Journal of cellular biochemistry}, volume = {61}, number = {1}, pages = {139-151}, doi = {10.1002/(sici)1097-4644(19960401)61:1&lt;139::aid-jcb15&gt;3.0.co;2-j}, pmid = {8726363}, issn = {0730-2312}, support = {GM-48595/GM/NIGMS NIH HHS/United States ; }, mesh = {Antineoplastic Agents/metabolism ; Ascorbic Acid/pharmacology ; Blood Proteins/pharmacology ; Blotting, Northern ; Cell Division/drug effects ; Cell Line, Transformed ; Cell Size/drug effects ; Cells, Cultured ; Extracellular Matrix/*enzymology ; Fibroblasts/metabolism ; Gene Expression Regulation ; Glutathione/pharmacology ; Humans ; Metalloendopeptidases/antagonists &amp; inhibitors/*metabolism ; Myocardium/enzymology/*metabolism ; Oxidation-Reduction ; Promoter Regions, Genetic/drug effects ; Protease Inhibitors/metabolism ; Proteins/*metabolism ; Pyrrolidines/pharmacology ; RNA, Messenger/analysis ; Thiocarbamates/pharmacology ; Tissue Inhibitor of Metalloproteinase-2 ; }, abstract = {Latent matrix metalloproteinases (MMPs) in normal myocardium are activated in end-stage heart failure. In vitro oxidized glutathione (GSSG) activates myocardial MMPs which contains a cysteine residue. In vivo GSSG induce the collagen lysis and cardiac dilatation. To assess whether thiol and non-thiol reducing agents have direct effect on the interstitial human heart fibroblast (HHF) proliferation and MMP expression, HHF and polyoma virus transformed fibroblast cells were cultured with or without the thiol-containing reduced (GSH) or oxidized (GSSG) glutathiones, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), and non-thiol ascorbic acid. After 100 micrograms/ml (approximately 0.3 mM) GSH or PDTC treatment the proliferative (synthetic) phenotype of transformed fibroblast cells was changed to quiescent (contractile) phenotype. Also, after GSH, PDTC, and ascorbic acid treatment the medium was then analyzed for MMP activity by zymography. The results indicate reduction in MMP expression in transformed fibroblast cells after GSH and PDTC treatments and no effect after ascorbic acid treatment. Based on reverse zymography, we observed the level of tissue inhibitor of metalloproteinase (TIMP) at a decreased level in transformed cells. The effect of the reducing agent at the gene transcription was measured by estimating mRNA (Northern blot analysis) of MMP and of TIMP in the cells that were cultured in medium in the presence and absence of GSH. These results indicate that GSH induces MMP-2 and MMP-1 expression in normal HHF and that GSH reduces MMP-2 and MMP-1 in transformed fibroblast cells. After the treatment, the TIMP-2 level was repressed in normal HHF and TIMP-2 level increased in transformed fibroblast cells. These events are dependent on the nuclear transcription factor activity on the collagenase promoter in normal HHF cells. On the other hand, in polyoma transform fibroblast cells these events are not dependent on this collagenase promoter. These results suggest that oxidative environment induces normal HHF cell proliferation, and the reducing agent decreases normal HHF cell proliferation by inducing MMP and repressing TIMP gene transcription. In transformed cells reducing agents inhibit MMP expression and increase TIMP levels, which suggests a role of antioxidants in preventing tumorigenesis.}, }
@article {pmid8702052, year = {1996}, author = {Spies, C and Giese, C and Meier-Hellmann, A and Specht, M and Hannemann, L and Schaffartzik, W and Reinhart, K}, title = {[The effect of prophylactically administered n-acetylcysteine on clinical indicators for tissue oxygenation during hyperoxic ventilation in cardiac risk patients].}, journal = {Der Anaesthesist}, volume = {45}, number = {4}, pages = {343-350}, doi = {10.1007/s001010050270}, pmid = {8702052}, issn = {0003-2417}, mesh = {Acetylcysteine/*therapeutic use ; Cardiac Output/drug effects/physiology ; Female ; Free Radical Scavengers/*therapeutic use ; Heart Diseases/*prevention &amp; control/therapy ; Hemodynamics/drug effects ; Humans ; Hyperoxia/*metabolism ; Male ; Middle Aged ; Oxygen Consumption/drug effects ; Prospective Studies ; Respiration, Artificial/*adverse effects ; Risk Factors ; }, abstract = {UNLABELLED: Hyperoxic ventilation, used to prevent hypoxia during potential periods of hypoventilation, has been reported to paradoxically decrease whole-body oxygen consumption (VO2). Reduction in nutritive blood flow due to oxygen radical production is one possible mechanism. We investigated whether pretreatment with the sulfhydryl group donor and O2 radical scavenger N-acetylcysteine (NAC) would preserve VO2 and other clinical indicators of tissue oxygenation in cardiac risk patients.<br><br>METHODS: Thirty patients, requiring hemodynamic monitoring (radial and pulmonary artery catheters) because of cardiac risk factors, were included in this randomized investigation. All patients exhibited stable clinical conditions (hemodynamics, body temperature, hemoglobin, F1O2 < 0.5). Cardiac output was determined by thermodilution and VO2 by cardiovascular Fick. After baseline measurements, patients randomly received either 150 mg kg-1 NAC (n = 15) or placebo (n = 15) in 250 ml 5% dextrose i.v. over a period of 30 min. Measurements were repeated 30 min after starting NAC or placebo infusion, 30 min after starting hyperoxia (F1O2 = 1.0), and 30 min after resetting the original F1O2.<br><br>RESULTS: There were no significant differences between groups in any of the measurements before treatment and after the return to baseline F1O2 at the end of the study, respectively. NAC, but not placebo infusion, caused a slight but not significant increase in cardiac index (CI), left ventricular stroke work index (LVSWI) and a decrease in systemic vascular resistance. Significant differences between groups during hyperoxia were: VO2 (NAC: 108 +/- 38 ml min-1m-2 vs placebo: 79 +/- 22 ml min-1m-2; P < or = 0.05), CI (NAC: 4.6 +/- 1.0 vs placebo: 3.7 +/- 1.11 min-1m-2; P < or = 0.05) and LVSWI (NAC: 47 +/- 12 vs placebo: 38 +/- 9; P < or = 0.05). The mean decrease of VO2 was 22% in the NAC group vs 47% in the placebo group (P < or = 0.05) and the mean difference between groups in venoarterial carbon dioxide gradient (PvaCO2) was 14% (P < or = 0.05). ST segment depression (> 0.2 mV) was significantly less marked in the NAC group (NAC: -0.02 +/- 0.17 vs placebo: -0.23 +/- 0.15; P < or = 0.05).<br><br>CONCLUSIONS: NAC helped preserve VO2, oxygen delivery, CI, LVSWI and PvaCO2 during brief hyperoxia in cardiac risk patients. Clinical signs of myocardial ischemia did not occur such as ST-depression if patients were prophylactically treated with NAC. This suggests that pretreatment with NAC could be considered to attenuate impaired tissue oxygenation and to preserve myocardial performance better in cardiac risk patients during hyperoxia.}, }
@article {pmid8733110, year = {1996}, author = {Keogh, BP and Tresini, M and Cristofalo, VJ and Allen, RG}, title = {Effects of cellular aging on the induction of c-fos by antioxidant treatments.}, journal = {Mechanisms of ageing and development}, volume = {86}, number = {3}, pages = {151-160}, doi = {10.1016/0047-6374(95)01689-9}, pmid = {8733110}, issn = {0047-6374}, support = {AG00131/AG/NIA NIH HHS/United States ; AG00378/AG/NIA NIH HHS/United States ; AG00523/AG/NIA NIH HHS/United States ; }, mesh = {Aging/*metabolism ; Antioxidants/*pharmacology ; Blotting, Northern ; Cells, Cultured ; Cysteine/pharmacology ; Humans ; Proto-Oncogene Mas ; Proto-Oncogene Proteins c-fos/*metabolism ; }, abstract = {The proto-oncogene c-fos (the cellular homolog of v-fos, Finkel-Biskis-Jenkins (FBJ) murine osteogenic sarcoma virus) encodes a major component of the activator protein-1 (AP-1) transcription factor. Serum stimulation as well as oxidizing treatments induce transitory increases in c-fos mRNA abundance. The induction of c-fos by serum stimulation is also known to decline during proliferative senesence. In this study, we examined the effects of two classes of antioxidants on the induction of c-fos in early and late passage human fetal lung fibroblasts (WI-38). N-acetyl cysteine (NAC) induces c-fos transcription in both early and late passage cells, while nordihydroguaiaretic acid (NGA) induced c-fos transcription in early passage cells but fails to stimulate it in late passage cells. Since we had previously observed an age-related decline in protein kinase C (PKC) translocation from the cytosol to the membrane, following its activation, and because PKC activation appears to be involved in the NGA induction of c-fos we examined the relative protein abundances of several PKC isoforms in early and late passage cells. Additionally, we examined the protein abundance of several members of the MAP kinase pathway which could play a role in c-fos induction by the PKC-dependent pathway. We were unable to detect PKC-beta or theta in early or late passage cells. Late passage cells contained a slightly greater abundance of PKC alpha, gamma and epsilon than cells at an early passage. No other differences in PKC isoforms or in members of the MAP kinase family were observed in early or late passage cells. These results clearly demonstrate that at least some pathways leading to c-fos induction remain intact in late passage cells. While we were unable to detect any decreases in PKC isoforms or MAP kinase proteins we cannot exclude the possibility that functional decrements accumulate in these proteins during senesence.}, }
@article {pmid8607802, year = {1996}, author = {Borrello, S and De Leo, ME and Landriscina, M and Palazzotti, B and Galeotti, T}, title = {Diethyldithiocarbamate treatment up regulates manganese superoxide dismutase gene expression in rat liver.}, journal = {Biochemical and biophysical research communications}, volume = {220}, number = {3}, pages = {546-552}, doi = {10.1006/bbrc.1996.0441}, pmid = {8607802}, issn = {0006-291X}, mesh = {Animals ; Blotting, Western ; Chelating Agents/pharmacology ; Ditiocarb/*pharmacology ; Gene Expression Regulation, Enzymologic/*drug effects ; Kinetics ; Liver/drug effects/*enzymology ; Male ; Rats ; Rats, Wistar ; Superoxide Dismutase/analysis/*biosynthesis/metabolism ; Time Factors ; }, abstract = {In vivo experiments demonstrate that rat liver manganese-containing superoxide dismutase (MnSOD) is up-regulated at the transcriptional level following the inactivation of copper-zinc superoxide dismutase (CuZnSOD). CuZnSOD activity was inhibited by the administration of the copper chelating agent diethyldithiocarbamate (DDC). This CuZnSOD inactivation is likely associated with an intracellular oxidative stress. Indeed the antioxidant N-acetyl-cysteine (NAC) completely prevents the MnSOD mRNA up-regulation observed after DDC administration. Evidence is also provided that an approximately 50% diminution of the total iron content in the tissue, which follows the in vivo administration of the iron chelator desferrioxamine (DESF), reduces the amount of MnSOD induction achieved by DDC treatment. Both NAC and DESF significantly down-regulate MnSOD gene expression also in normal untreated rat liver. While the observed inhibitory effect of NAC in MnSOD mRNA up-regulation can be ascribed mainly to its antioxidant property, iron chelation could act with an antioxidant effect and/or affecting some iron-dependent factor(s) possibly involved in MnSOD gene regulation. It is proposed that this metal could have a role among factors that sense and/or trigger transcription of the MnSOD gene.}, }
@article {pmid8881338, year = {1996}, author = {Hemelaar, PJ and Beijersbergen van Henegouwen, GM}, title = {The protective effect of N-acetylcysteine on UVB-induced immunosuppression by inhibition of the action of cis-urocanic acid.}, journal = {Photochemistry and photobiology}, volume = {63}, number = {3}, pages = {322-327}, doi = {10.1111/j.1751-1097.1996.tb03034.x}, pmid = {8881338}, issn = {0031-8655}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dermatitis, Contact/immunology ; Immune Tolerance/*drug effects/*radiation effects ; Male ; Mice ; Mice, Inbred BALB C ; Sunscreening Agents/*pharmacology ; Ultraviolet Rays/*adverse effects ; Urocanic Acid/*antagonists &amp; inhibitors/pharmacology ; }, abstract = {A recent study has shown that N-acetylcysteine (NAC) not only has sun-protective properties but also inhibits the UVB-induced suppression of contact hypersensitivity (CHS) in mice. Because NAC does not absorb any UVA (320-400 nm radiation) or UVB (290-320 nm radiation) we have studied the underlying mechanism of protection. Irradiation of solutions of plasmid DNA with UVC (200-290 nm radiation) (10 J m-2) resulted in the formation of cyclobutane pyrimidine dimers, but the extent to which this occurred was not affected by the presence of NAC as was determined by an in vitro T4 endonuclease assay. N-acetylcysteine proved not to have any effect on the photoisomerization of trans-urocanic acid (UCA) to its cis-form in vitro; at equilibrium, approximately 55% cis-UCA was formed. The same percentage was also found in vivo on exposure of mice to UVB (15 kJ m-2). Topical application of NAC 30 min prior to irradiation did not have any influence as well on the photoisomerization of trans- to cis-UCA. These in vivo experiments were performed under the same conditions used previously to show the protective effect of NAC against UVB-induced suppression of CHS. We conclude that this protection of NAC is at least partly based on interference in the role of cis-UCA in UVB-induced suppression of CHS. This conclusion is supported by the observation that NAC completely inhibits the suppression of CHS by cis-UCA administered to mice that were always kept in the dark. In the same range of doses as used in the present study, it was shown in our previous study that NAC alone does not affect the CHS response.}, }
@article {pmid8839216, year = {1996}, author = {Young, RJ and Critchley, JA and Young, KK and Freebairn, RC and Reynolds, AP and Lolin, YI}, title = {Fatal acute hepatorenal failure following potassium permanganate ingestion.}, journal = {Human &amp; experimental toxicology}, volume = {15}, number = {3}, pages = {259-261}, doi = {10.1177/096032719601500313}, pmid = {8839216}, issn = {0960-3271}, mesh = {Accidents, Home ; Acute Kidney Injury/*chemically induced ; Administration, Oral ; Adult ; Fatal Outcome ; Female ; Hepatorenal Syndrome/chemically induced ; Humans ; Liver Failure, Acute/*chemically induced ; Potassium Permanganate/administration &amp; dosage/*poisoning ; }, abstract = {Potassium permanganate (KMnO4), a powerful oxidizing agent, is readily available without prescription. Tissue contact produces coagulation necrosis and the lethal consequences of oral ingestion are well described, with most deaths because of airway oedema and obstruction or circulatory collapse. Whilst systemic toxicity is reported, its mechanism is unclear. We describe a case of suicidal ingestion of KMnO4 followed by acute hepatorenal toxicity resulting in the death of the patient. The clinical course bore close resemblance to that of severe paracetamol overdose. We discuss the pathogenesis of the systemic toxicity of KMnO4 and postulate that it is due to oxidative injury from free radicals generated by the absorbed permanganate ion. We recommend that N-acetyl cysteine be given within the first few hours to all patients with potassium permanganate poisoning.}, }
@article {pmid8832978, year = {1996}, author = {Sato, M and Miyazaki, T and Nagaya, T and Murata, Y and Ida, N and Maeda, K and Seo, H}, title = {Antioxidants inhibit tumor necrosis factor-alpha mediated stimulation of interleukin-8, monocyte chemoattractant protein-1, and collagenase expression in cultured human synovial cells.}, journal = {The Journal of rheumatology}, volume = {23}, number = {3}, pages = {432-438}, pmid = {8832978}, issn = {0315-162X}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Arthritis, Rheumatoid/drug therapy ; Cells, Cultured/chemistry/drug effects/enzymology ; Chemokine CCL2/*genetics ; Collagenases/*genetics ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Enzymologic/drug effects/immunology ; Humans ; Hydrogen Peroxide/metabolism ; Interleukin-8/*genetics ; NF-kappa B/genetics ; Pyrrolidonecarboxylic Acid ; RNA, Messenger/metabolism ; Synovial Membrane/cytology ; Thiazoles/pharmacology ; Thiazolidines ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {OBJECTIVE: To study whether the induction of mRNA for interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and collagenase by tumor necrosis factor-alpha (TNF-alpha) is suppressed by antioxidants in human synovial cells. TNF-alpha has been shown to exert some of its effects by stimulating production of reactive oxygen intermediates in some cell lines other than synovial cells.<br><br>METHODS: Amounts of mRNA for IL-8, MCP-1, and collagenase were determined by Northern blot analysis. Electrophoretic mobility shift assays were performed for the detection of a transcription factor, nuclear factor-kappa B(NF-kappa B). The concentration of IL-8 in the medium was determined by ELISA.<br><br>RESULTS: TNF-alpha increased the expression of IL-8, MCP-1, and collagenase mRNA in human synovial cells. NF-KB known to induce IL-8 gene transcription was also increased in nuclear extracts from the synovial cells treated with TNF-alpha. Prior addition of antioxidant, N-acetyl-L-cysteine (NAC) or 2-oxothiazolidine-4-carboxylate (OTC), suppressed TNF-alpha stimulated expressions of IL-8, MCP-1, and collagenase mRNA in a dose dependent manner. Treatment with NAC also suppressed TNF-alpha induced increase in NF-kappa B. The changes of IL-8 in the medium reflected the mRNA levels. Hydrogen peroxide (H2O2) induced the expression of mRNA for the cytokines but not collagenase mRNA, and NAC suppressed the effect of H2O2.<br><br>CONCLUSION: Our data suggest that TNF-alpha induces expression of proinflammatory cytokines such as IL-8 and MCP-1 through generation of reactive oxygen intermediates and subsequent activation of NF-kappa B in human synovial cells, and the antioxidants may inhibit, at least in part, the activation of NF-kappa B by TNF-alpha. These results indicate that antioxidants such as NAC may be useful in treating rheumatoid arthritis.}, }
@article {pmid8721770, year = {1996}, author = {Sagara, M and Satoh, J and Wada, R and Yagihashi, S and Takahashi, K and Fukuzawa, M and Muto, G and Muto, Y and Toyota, T}, title = {Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine.}, journal = {Diabetologia}, volume = {39}, number = {3}, pages = {263-269}, pmid = {8721770}, issn = {0012-186X}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Animals ; Blood Glucose/drug effects/metabolism ; Body Weight/drug effects ; Diabetes Mellitus, Experimental/blood/*physiopathology ; Diabetic Neuropathies/blood/*prevention &amp; control ; Free Radical Scavengers/*pharmacology ; Lipopolysaccharides/pharmacology ; Motor Neurons/drug effects/physiology ; Neural Conduction/*drug effects ; Rats ; Rats, Wistar ; Reference Values ; Time Factors ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*biosynthesis ; }, abstract = {N-acetylcysteine (NAC) is a precursor of glutathione (GSH) synthesis, a free radical scavenger and an inhibitor of tumour necrosis factor alpha (TNF). Because these functions might be beneficial in diabetic complications, in this study we examined whether NAC inhibits peripheral neuropathy. Motor nerve conduction velocity (MNCV) was significantly decreased in streptozotocin-induced-diabetic Wistar rats compared to control rats. Oral administration of NAC reduced the decline of MNCV in diabetic rats. Structural analysis of the sural nerve disclosed significant reduction of fibres undergoing myelin wrinkling and inhibition of myelinated fibre atrophy in NAC-treated diabetic rats. NAC treatment had no effect on blood glucose levels or on the nerve glucose, sorbitol and cAMP contents, whereas it corrected the decreased GSH levels in erythrocytes, the increased lipid peroxide levels in plasma and the increased lipopolysaccharide-induced TNF activity in sera of diabetic rats. Thus, NAC inhibited the development of functional and structural abnormalities of the peripheral nerve in streptozotocin-induced diabetic rats.}, }
@article {pmid8676540, year = {1996}, author = {Iiboshi, Y and Nezu, R and Cui, L and Chen, K and Khan, J and Yoshida, H and Sando, K and Kamata, S and Takagi, Y and Okada, A}, title = {Adhesive mucous gel layer and mucus release as intestinal barrier in rats.}, journal = {JPEN. Journal of parenteral and enteral nutrition}, volume = {20}, number = {2}, pages = {98-104}, doi = {10.1177/014860719602000298}, pmid = {8676540}, issn = {0148-6071}, mesh = {Acetylcysteine/*pharmacology ; Adhesiveness ; Animals ; Cell Membrane Permeability/drug effects ; Colchicine/*pharmacology ; Dextrans/metabolism ; Fluorescein-5-isothiocyanate/analogs &amp; derivatives/metabolism ; Gels ; Intestinal Mucosa/drug effects/*physiology ; Intestine, Small/anatomy &amp; histology/physiology ; Male ; Microscopy, Fluorescence ; Mucus/*metabolism ; Periodic Acid-Schiff Reaction ; Rats ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Although it has been reported that total parenteral nutrition induces an increased intestinal permeability and a decreased mucous gel layer covering the intestinal epithelium, the role of mucous gel on intestinal permeability has not been well understood. We examined the in vivo effects of N-acetyl cysteine (NAC) as mucolytic agent and colchicine as suppressant of the mucus production on the intestinal transmission of fluorescein isothiocyanate dextran 70,000 (FITC-dextran).<br><br>METHODS: Rats were divided into four groups. In each group, FITC-dextran (750 mg/kg) with or without NAC (3000 mg/kg) was injected into the small intestinal lumen 3 hours after intraperitoneal injection of saline or colchicine (Col, 10 mg/kg). Thirty minutes after injection of FITC-dextran, blood samples were taken from portal vein to analyze plasma fluorescein concentration by fluorescence spectrometry. Samples of small intestine were sectioned in a cryostat for fluorescence microscopy, and the identical sections were stained by periodic acid-Schiff reaction.<br><br>RESULTS: Plasma FITC-dextran level in NAC group was higher than that in control group (p < .01), that in Col + NAC group was higher than that in Col group (p < .01) and that in Col + NAC group was higher than that in NAC group (p < .05). The spaces between villi were filled with mucous gel in the control and Col groups, whereas those were not entirely filled with mucous gel in NAC and Col + NAC groups. FITC-dextran and mucous gel showed complementary distribution in all rats. The villous interstitial edema was recognized in NAC group and the villi were disrupted in Col + NAC group.<br><br>CONCLUSIONS: These results suggest that intestinal permeability is possibly affected not only by the mucous gel covering the intestinal epithelium but also by mucus release from goblet cells of the small intestine.}, }
@article {pmid8670069, year = {1996}, author = {Guyton, KZ and Xu, Q and Holbrook, NJ}, title = {Induction of the mammalian stress response gene GADD153 by oxidative stress: role of AP-1 element.}, journal = {The Biochemical journal}, volume = {314 (Pt 2)}, number = {Pt 2}, pages = {547-554}, pmid = {8670069}, issn = {0264-6021}, mesh = {Arsenites/pharmacology ; Base Sequence ; *CCAAT-Enhancer-Binding Proteins ; Cell Line, Transformed ; DNA-Binding Proteins/*genetics ; *Gene Expression Regulation ; HeLa Cells ; Humans ; Hydrogen Peroxide/pharmacology ; Molecular Sequence Data ; Oligodeoxyribonucleotides ; Oxidants/pharmacology ; *Oxidative Stress ; Promoter Regions, Genetic ; RNA, Messenger/genetics ; Sulfhydryl Compounds/metabolism ; Transcription Factor AP-1/*metabolism ; Transcription Factor CHOP ; Transcription Factors/*genetics ; Transcriptional Activation ; Ultraviolet Rays ; }, abstract = {GADD153 is a CCAAT/enhancer-binding-protein-related gene that may function to control cellular growth in response to stress signals. In this study, a variety of oxidant treatments were shown to stimulate endogenous GADD153 mRNA expression and to transcriptionally activate a GADD153 promoter-reporter gene construct in transfected HeLa cells. Both commonalities and distinctions in the induction of GADD153 by H2O2 and the thiol-reactive compound arsenite were demonstrated. GADD153 mRNA induction by both H2O2 and arsenite was potentiated by GSH depletion, and completely inhibited by N-acetyl-cysteine. o-Phenanthroline and mannitol blocked GADD153 induction by H2O2, indicating that iron-generated hydroxyl radical mediates this induction. Concordantly, GSH peroxidase overexpression in WI38 cells attenuated GADD153 mRNA induction by H2O2. However, GADD153 induction by arsenite was only modestly reduced in the same cells, suggesting a lesser contribution of peroxides to gene activation by arsenite. We also demonstrated that oxidative stress participates in the induction of GADD153 by UVC (254 nm) irradiation. Finally, both promoter-deletion analysis and point mutation of the AP-1 site in an otherwise intact promoter support a significant role for AP-1 in transcriptional activation of GADD153 by UVC or oxidant treatment. Indeed, exposure of cells to oxidants or UVC stimulated binding of Fos and Jun to the GADD153 AP-1 element. Together, these results demonstrate that both free-radical generation and thiol modification can transcriptionally activate GADD153, and that AP-1 is critical to oxidative regulation of this gene. This study further supports a role for the GADD153 gene product in the cellular response to oxidant injury.}, }
@article {pmid8642856, year = {1996}, author = {Quillet-Mary, A and Mansat, V and Duchayne, E and Come, MG and Allouche, M and Bailly, JD and Bordier, C and Laurent, G}, title = {Daunorubicin-induced internucleosomal DNA fragmentation in acute myeloid cell lines.}, journal = {Leukemia}, volume = {10}, number = {3}, pages = {417-425}, pmid = {8642856}, issn = {0887-6924}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists &amp; inhibitors ; Acetylcysteine/pharmacology ; Antibiotics, Antineoplastic/*pharmacology ; Antioxidants/pharmacology ; Apoptosis/drug effects ; Buthionine Sulfoximine ; Cell Differentiation ; *DNA Damage ; DNA Nucleotidylexotransferase/metabolism ; DNA, Neoplasm/*drug effects/metabolism ; Daunorubicin/*pharmacology ; Free Radical Scavengers/pharmacology ; Humans ; Leukemia, Myeloid, Acute/*metabolism/pathology ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Nucleosomes/drug effects/metabolism ; Pyrrolidines/pharmacology ; Thiocarbamates/pharmacology ; Tumor Cells, Cultured/drug effects/metabolism/pathology ; Verapamil/pharmacology ; }, abstract = {The study was designed to evaluate the implication of apoptosis in myeloid leukemic cell death induced by daunorubicin (DNR) and to identify the possible factors which may influence this process. DNR-induced apoptosis was characterized by morphology and DNA fragmentation in six leukemic myeloid cell lines which expressed different differentiation phenotypes. In phenotypically mature HL-60 and U937 cells, DNR induced typical apoptosis with characteristic morphological changes and intense internucleosomal DNA fragmentation within a narrow concentration range (0.5-2 microM). When these cells were treated with higher doses of DNR, large DNA fragments (100 kbp), but not internucleosomal fragments, were identified. DNR-induced DNA fragmentation in HL-60 and U937 was inhibited by antioxidants such as N-acetylcysteine (N-ac) or pyrrolidine-dithiocarbamate (PDTC). In the phenotypically immature KG1a, KG1, HEL and ML1 cell lines DNR induced no characteristic apoptotic morphological features as well as very low levels of internucleosomal DNA fragmentation, whereas large DNA fragments (200 kbp) were observed in KG1a treated with 7 microM DNR. Since the latter expressed P-glycoprotein (P-gp), the role of P-gp in the lack of apoptotic response to DNR was investigated. One P-gp inhibitor (verapamil) slightly improved DNR-induced DNA fragmentation in KG1a cells whereas the combination of verapamil and buthionine-sulfoximine (BSO), which depletes glutathion store, further increased internucleosomal DNA fragmentation. In conclusion, DNR induced internucleosomal DNA fragmentation in some but not all AML cells; the magnitude of this process being influenced by both intracellular drug concentration and oxidative balance.}, }
@article {pmid8602587, year = {1996}, author = {Hennig, B and Toborek, M and Joshi-Barve, S and Barger, SW and Barve, S and Mattson, MP and McClain, CJ}, title = {Linoleic acid activates nuclear transcription factor-kappa B (NF-kappa B) and induces NF-kappa B-dependent transcription in cultured endothelial cells.}, journal = {The American journal of clinical nutrition}, volume = {63}, number = {3}, pages = {322-328}, doi = {10.1093/ajcn/63.3.322}, pmid = {8602587}, issn = {0002-9165}, support = {P42 ES007380/ES/NIEHS NIH HHS/United States ; 1P01 HL36552/HL/NHLBI NIH HHS/United States ; M01 RR02602-08/RR/NCRR NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Calcium/metabolism ; Cells, Cultured ; Endothelium, Vascular/drug effects/*metabolism ; Glutathione/metabolism ; Linoleic Acid ; Linoleic Acids/*pharmacology ; Lipid Peroxidation/drug effects ; Molecular Sequence Data ; NF-kappa B/*physiology ; Pulmonary Artery ; Swine ; Transcription, Genetic/*drug effects ; }, abstract = {High dietary intakes of unsaturated fats may be atherogenic by disrupting normal functions of the vascular endothelium, due in part to the ability of linoleic acid (18:2n-6) to contribute to an increase in cellular oxidative stress and related injurious events. Exposing endothelial cells to 90 micromol linoleic acid/L for 6 h resulted in a significant increase in lipid hydroperoxides that coincided wih an increase in intracellular calcium concentrations. Treatment with this fatty acid caused an initial decrease in glutathione concentrations, which was followed by an increase at later time points. Most importantly, a significant activation of the oxidative stress-sensitive nuclear transcription factor-kappa B (NF-kappa B) was achieved after a 6-h exposure to 18:2n-6, which is the time point at which maximal depletion of cellular glutathione was observed. The fatty acid-mediated NF-kappa B activation was accompanied by induction of NF-kappa B-dependent transcription, as measured by chloramphenicol acetyltransferase (CAT) assay of an NF-kappa B-responsive promoter construct. Pretreatment of endothelial cells with vitamin E and N-acetyl cysteine inhibited the fatty acid-induced activation of NF-kappa B and formation of lipid hydroperoxides. These data suggest that oxidative stress-induced cellular changes are critical early events in fatty acid-mediated endothelial cell dysfunction.}, }
@article {pmid8626753, year = {1996}, author = {Guyton, KZ and Liu, Y and Gorospe, M and Xu, Q and Holbrook, NJ}, title = {Activation of mitogen-activated protein kinase by H2O2. Role in cell survival following oxidant injury.}, journal = {The Journal of biological chemistry}, volume = {271}, number = {8}, pages = {4138-4142}, doi = {10.1074/jbc.271.8.4138}, pmid = {8626753}, issn = {0021-9258}, mesh = {3T3 Cells ; Animals ; Aorta/cytology/drug effects/physiology ; Blotting, Western ; Calcium-Calmodulin-Dependent Protein Kinases/*metabolism ; Cell Survival/*drug effects ; Cells, Cultured ; Enzyme Activation ; Free Radicals/analysis/metabolism ; Gene Expression/drug effects ; Genes, fos ; Genes, jun ; HeLa Cells ; Humans ; Hydrogen Peroxide/*pharmacology ; Kinetics ; Luciferases/analysis/biosynthesis ; Mice ; Muscle, Smooth, Vascular/cytology/*drug effects/physiology ; PC12 Cells ; Phosphoproteins/isolation &amp; purification/metabolism ; Phosphotyrosine/analysis ; Rats ; Recombinant Proteins/analysis/biosynthesis ; Transfection ; }, abstract = {The mitogen-activated protein kinase (MAPK) family is comprised of key regulatory proteins that control the cellular response to both proliferation and stress signals. In this study we investigated the factors controlling MAPK activation by H2O2 and explored the impact of altering the pathways to kinase activation on cell survival following H2O2 exposure. Potent activation (10-20-fold) of extracellular signal-regulated protein kinase (ERK2) occurred within 10 min of H2O2 treatment, whereupon rapid inactivation ensued. H2O2 activated ERK2 in several cell types and also moderately activated (3-5-fold) both c-Jun N-terminal kinase and p38/RK/CSBP. Additionally, H2O2 increased the mRNA expression of MAPK-dependent genes c-jun, c-fos, and MAPK phosphatase-1. Suramin pretreatment completely inhibited H2O2 stimulation of ERK2, highlighting a role for growth factor receptors in this activation. Further, ERK2 activation by H2O2 was blocked by pretreatment with either N-acetyl-cysteine, o-phenanthroline, or mannitol, indicating that metal-catalyzed free radical formation mediates the initiation of signal transduction by H2O2. H2O2-stimulated activation of ERK2 was abolished in PC12 cells by inducible or constitutive expression of the dominant negative Ras-N-17 allele. Interestingly, PC12/Ras-N-17 cells were more sensitive than wild-type PC12 cells to H2O2 toxicity. Moreover, NIH 3T3 cells expressing constitutively active MAPK kinase (MEK, the immediate upstream regulator of ERK) were more resistant to H2O2 toxicity, while those expressing kinase-defective MEK were more sensitive, than cells expressing wild-type MEK. Taken together, these studies provide insight into mechanisms of MAPK regulation by H2O2 and suggest that ERK plays a critical role in cell survival following oxidant injury.}, }
@article {pmid8631978, year = {1996}, author = {Tsai, JC and Jain, M and Hsieh, CM and Lee, WS and Yoshizumi, M and Patterson, C and Perrella, MA and Cooke, C and Wang, H and Haber, E and Schlegel, R and Lee, ME}, title = {Induction of apoptosis by pyrrolidinedithiocarbamate and N-acetylcysteine in vascular smooth muscle cells.}, journal = {The Journal of biological chemistry}, volume = {271}, number = {7}, pages = {3667-3670}, pmid = {8631978}, issn = {0021-9258}, support = {CA49749/CA/NCI NIH HHS/United States ; GM53249/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Aorta ; Apoptosis/*drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Chromatin/drug effects/physiology/ultrastructure ; Culture Media, Serum-Free ; DNA/drug effects ; Dose-Response Relationship, Drug ; Endothelium, Vascular/cytology/drug effects/physiology ; Epidermal Growth Factor/pharmacology ; Fibroblast Growth Factor 2/pharmacology ; Humans ; Insulin/pharmacology ; Kinetics ; Male ; Muscle, Smooth, Vascular/cytology/*drug effects/physiology ; PC12 Cells ; Proto-Oncogene Proteins/biosynthesis ; Proto-Oncogene Proteins c-bcl-2 ; Pyrrolidines/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Thiocarbamates/*pharmacology ; Time Factors ; }, abstract = {Pyrrolidinedithiocarbamate (PDTC) and N-acetylcysteine (NAC) have been used as antioxidants to prevent apoptosis in lymphocytes, neurons, and vascular endothelial cells. We report here that PDTC and NAC induce apoptosis in rat and human smooth muscle cells. In rat aortic smooth muscle cells, PDTC induced cell shrinkage, chromatin condensation, and DNA strand breaks consistent with apoptosis. In addition, overexpression of Bcl-2 suppressed vascular smooth muscle cell death caused by PDTC and NAC. The viability of rat aortic smooth muscle cells decreased within 3 h of treatment with PDTC and was reduced to 30% at 12 h. The effect of PDTC and NAC on smooth muscle cells was not species specific because PDTC and NAC both caused dose-dependent reductions in viability in rat and human aortic smooth muscle cells. In contrast, neither PDTC nor NAC reduced viability in human aortic endothelial cells. The use of antioxidants to induce apoptosis in vascular smooth muscle cells may help prevent their proliferation in arteriosclerotic lesions.}, }
@article {pmid8631012, year = {1996}, author = {Chung, FL and Kelloff, G and Steele, V and Pittman, B and Zang, E and Jiao, D and Rigotty, J and Choi, CI and Rivenson, A}, title = {Chemopreventive efficacy of arylalkyl isothiocyanates and N-acetylcysteine for lung tumorigenesis in Fischer rats.}, journal = {Cancer research}, volume = {56}, number = {4}, pages = {772-778}, pmid = {8631012}, issn = {0008-5472}, support = {N01-85096-06//PHS HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Analysis of Variance ; Animals ; Anticarcinogenic Agents/*therapeutic use ; Body Weight/drug effects ; Carcinogens ; Chi-Square Distribution ; Diet ; Free Radical Scavengers/*therapeutic use ; Incidence ; Isothiocyanates/*therapeutic use ; Leukemia, Experimental/chemically induced/prevention &amp; control ; Leydig Cell Tumor/chemically induced/prevention &amp; control ; Lung Neoplasms/chemically induced/*prevention &amp; control ; Lymphoma/chemically induced/prevention &amp; control ; Male ; Nitrosamines ; Pancreatic Neoplasms/chemically induced/prevention &amp; control ; Plants, Toxic ; Rats ; Rats, Inbred F344 ; Survival Rate ; Testicular Neoplasms/chemically induced/prevention &amp; control ; Nicotiana ; }, abstract = {The purpose of this study is to evaluate the efficacy of three promising sulfur-containing compounds, 6-phenylhexyl isothiocyanate (PHITC), phenethyl isothiocyanate (PEITC), and N-acetylcysteine (NAC), as chemopreventive agents in a long-term bioassay for lung tumorigenesis in F344 rats. PEITC occurs as a constituent of certain cruciferous vegetables, PHITC is a synthetic homologue, and NAC is an endogenous substance. Male F344 rats were treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by s.c. injection at a dose of 1.5 mg/kg body weight three times weekly for 20 weeks. This dose regimen induced a 67% tumor incidence in the lung, a major target organ of NNK. PHITC or PEITC administered in the diet for 22 weeks, a period covering from 1 week before to 1 week after the NNK treatment, exhibited significant inhibition of lung tumorigenesis induced by NNK. The lung tumor incidences in the NNK-treated groups, fed a diet containing 4 mmol/kg (876 ppm) or 2 mmol/kg (438 ppm) PHITC, were 24 and 19% and were 9 and 17% in groups fed PEITC at concentrations of 8 mmol/kg (1304 ppm) or 4 mmol/kg (652 ppm), respectively. In contrast to isothiocyanates, NAC given in the diet at 80 mmol/kg (13056 ppm) or 40 mmol/kg (6528 ppm) exerted no inhibitory effects on the NNK-induced lung tumorigenesis. At the dose studied, NNK did not induce liver and pancreatic tumors in the treated animals, but a significant increase of nasal cavity tumor incidence was observed in the NNK-treated group. However, none of the test compounds showed any effect on the tumorigenesis in this tissue. This study demonstrated that PHITC and PEITC were potent chemopreventive agents for the NNK-induced lung tumorigenesis in F344 rats, whereas NAC was not active at all. These results support further evaluation of these compounds in chemoprevention studies.}, }
@article {pmid8849369, year = {1996}, author = {Fujisawa, K and Aono, H and Hasunuma, T and Yamamoto, K and Mita, S and Nishioka, K}, title = {Activation of transcription factor NF-kappa B in human synovial cells in response to tumor necrosis factor alpha.}, journal = {Arthritis and rheumatism}, volume = {39}, number = {2}, pages = {197-203}, doi = {10.1002/art.1780390205}, pmid = {8849369}, issn = {0004-3591}, mesh = {Acetylcysteine/pharmacology ; Base Sequence ; Cell Division/drug effects ; Cells, Cultured ; Humans ; Molecular Sequence Data ; NF-kappa B/antagonists &amp; inhibitors/*physiology ; Synovial Membrane/cytology/drug effects/*physiology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {OBJECTIVE: To examine whether nuclear factor kappaB (NF-kappaB) is activated in cultured synovial cells in response to tumor necrosis factor alpha (TNFalpha) and to investigate the correlation between NF-kappaB activation and synovial cell proliferation.<br><br>METHODS: Activation of NF-kappaB was detected by electrophoretic mobility shift assay. The transcription of several NF-kappaB-dependent genes was evaluated by reverse transcriptase polymerase chain reaction and transient expression assay using human immunodeficiency virus-long terminal repeat chloramphenicol acetyltransferase. Proliferative activity was determined by measurement of 3H-thymidine incorporation.<br><br>RESULTS: Stimulation of synovial cells with TNFalpha activated NF-kappaB and subsequent transcription of several genes. Treatment of synovial cells with N-acetyl-L-cysteine (NAC), an antioxidant agent, inhibited TNFalpha-induced NF-kappaB activation and transcription. Moreover, NAC also inhibited synovial cell proliferation induced by TNFalpha.<br><br>CONCLUSION: Our results suggest that NF-kappaB plays a pivotal role in synovial cell activation by TNFalpha. Thus, suppression of NF-kappaB could be a potential therapeutic modality for synovitis such as that of rheumatoid arthritis.}, }
@article {pmid8669050, year = {1996}, author = {Baier, JE and Neumann, HA and Moeller, T and Kissler, M and Borchardt, D and Ricken, D}, title = {[Radiation protection through cytokine release by N-acetylcysteine].}, journal = {Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]}, volume = {172}, number = {2}, pages = {91-98}, pmid = {8669050}, issn = {0179-7158}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Blood/drug effects/*radiation effects ; Cytokines/*blood ; Enzyme-Linked Immunosorbent Assay ; Humans ; In Vitro Techniques ; Interferon-gamma/blood ; Interleukin-1/blood ; Interleukin-2/blood ; Phytohemagglutinins/pharmacology ; *Radiation-Protective Agents ; Stimulation, Chemical ; Tumor Necrosis Factor-alpha/analysis ; }, abstract = {BACKGROUND: Interleukin-1, tumornecrosisfactor-alpha and interferon-gamma endogenously provide protection of the hematopoietic system against radiation. Thiols have already been used successfully as radioprotective agents. In this study the effect von N-acetylcysteine (NAC) on the release of interleukin-1 alpha and beta (IL-1), interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and tumornecrosisfactor-alpha (TNF-alpha) was assessed in an in vitro assay.<br><br>PATIENTS AND METHODS: Whole blood samples from 8 healthy volunteers were stimulated with 7.5 micrograms/ml PHA. NAC was added at concentrations of 0.6, 6, 12 and 24 mmol/l. Subsequently the samples were irradiated with a dose of 18 Gy according to preceding validation experiments.<br><br>RESULTS: IL-1 alpha, IL-1 beta b and IL-2: In comparison to stimulation and radiation alone the addition of 0.6 and 6 mmol/l, with IL-2 also 12 mmol/l, NAC resulted in a significant increase of the cytokine-concentrations. The highest concentration of 24 mmol/l NAC, however, resulted in a decrease beyond control levels. IFN-gamma and TNF-alpha: Until 12 mmol/l NAC no changes were observed. 24 mmol/l NAC resulted in a significant decrease, too.<br><br>CONCLUSION: N-acetylcysteine is capable to co-stimulate radioprotective cytokines like IL-1 alpha and IL-1 beta and to enhance IL-2 in vitro, whereas higher doses result in a suppression.}, }
@article {pmid8645365, year = {1996}, author = {Bostom, AG and Shemin, D and Yoburn, D and Fisher, DH and Nadeau, MR and Selhub, J}, title = {Lack of effect of oral N-acetylcysteine on the acute dialysis-related lowering of total plasma homocysteine in hemodialysis patients.}, journal = {Atherosclerosis}, volume = {120}, number = {1-2}, pages = {241-244}, doi = {10.1016/0021-9150(95)05705-6}, pmid = {8645365}, issn = {0021-9150}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Adult ; Aged ; Arteriosclerosis/blood/etiology/*prevention &amp; control ; Female ; Homocysteine/*blood ; Humans ; Kidney Failure, Chronic/*blood/complications/therapy ; Male ; Middle Aged ; *Renal Dialysis ; }, abstract = {Hyperhomocysteinemia refractory to standard B-vitamin supplementation treatment persists in > or = 75% of maintenance dialysis patients, potentially increasing their risk for atherothrombotic sequelae. We examined whether predialysis administration of oral N-acetylcysteine (NAC), which acutely increases the non-protein bound, dialyzable fraction of plasma homocysteine, might augment the homocysteine-lowering effect of dialysis therapy. Predialysis and postdialysis total plasma homocysteine levels were determined on a control day, and on a day in which oral NAC (1200 mg) was administered predialysis in n = 11 maintenance hemodialysis patients. Although NAC treatment had no significant effect on hemodialysis removal of plasma homocysteine (P = 0.594), we observed a 16% reduction (P = 0.033) in non-fasting prehemodialysis total plasma homocysteine on the NAC treatment vs. non-treatment day. Longer term, placebo-controlled confirmation of this finding will be required to evaluate the possible chronic homocysteine-lowering efficacy of NAC treatment in hemodialysis patients.}, }
@article {pmid8596698, year = {1996}, author = {Köttgen, M and Busch, AE and Hug, MJ and Greger, R and Kunzelmann, K}, title = {N-Acetyl-L-cysteine and its derivatives activate a Cl- conductance in epithelial cells.}, journal = {Pflugers Archiv : European journal of physiology}, volume = {431}, number = {4}, pages = {549-555}, pmid = {8596698}, issn = {0031-6768}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacology ; Animals ; Bronchi/cytology/drug effects ; Cells, Cultured/drug effects ; Chloride Channels/*drug effects/*physiology ; Colonic Neoplasms/pathology ; Cystic Fibrosis/physiopathology ; Electric Conductivity ; Epithelial Cells ; Humans ; Hydrogen-Ion Concentration ; Oocytes/physiology ; Respiratory System/cytology ; Tumor Cells, Cultured/drug effects ; Xenopus ; }, abstract = {N-Acetyl-L-cysteine (NAC) is a widely used mucolytic drug in patients with a variety of respiratory disorders including cystic fibrosis (CF). The beneficial effects of NAC are empirical and the exact mechanism of action in the airways remains obscure. In the present study we examined the effects on whole-cell (wc) conductance (Gm) and voltage (Vm) of NAC and the congeners S-carboxymethyl-L-cysteine (CMC) and S-carbamyl-L-cysteine (CAC) and L-cysteine in normal and CF airway epithelial cells. L-Cysteine (1 mmol/l) had no detectable effect. The increase in Gm (delta Gm) by the other compounds was concentration dependent and was (all substances at 1 mmol/l) 3.8 +/- 1.4 nS (NAC; n = 11), 4.2 +/- 1.0 nS (CMC; n = 16) and 3.8 +/- 1.6 nS (CAC; n = 18), respectively. The changes in Gm were paralleled by an increased depolarization (delta Vm) when extracellular Cl- concentration was reduced to 34 mmol/l: under control conditions = -4.1 +/- 2.1 versus 10.2 +/- 2.1 mV in the presence of NAC, CMC, CAC (n = 36). In the presence of NAC, CMC and CAC, the reduction in Cl- concentration was paralleled by a reduction of Gm by 2.1 +/- 0.4 nS (n = 35), indicating that all substances acted by increasing the Cl- conductance. Analysis of intracellular pH did not reveal any changes by any of the compounds (1 mmol/l). A Cl- conductance was also activated in HT29 colonic carcinoma and CF tracheal epithelial (CFDE) cells but not in CFPAC-1 cells, which do not express detectable levels of delta F508-CFTR, suggesting that the presence of CFTR may be a prerequisite for the induction of Cl- currents. Next we examined the ion currents in Xenopus oocytes microinjected with CFTR-cRNA. Water-injected oocytes did not respond to activation by forskolin and 3-isobutyl-1-methylxanthine (IBMX) (delta Gm = 0.08 +/- 0.04 microS; n = 10) and no current was activated when these oocytes were exposed to NAC or CMC. In contrast, in CFTR-cRNA-injected oocytes Gm was enhanced when intracellular adenosine 3',5'-cyclic monophosphate (cAMP) was increased by forskolin and IBMX (Gm = 4.5 +/- 1.3 microS; n = 8). Gm was significantly increased by 0.74 +/- 0.2 microS (n = 11) and 0.46 +/- 0.1 microS (n = 10) when oocytes were exposed to NAC and CMC, respectively (both 1 mmol/l). In conclusion, NAC and its congeners activate Cl- conductances in normal and CF airway epithelial cells and hence induce electrolyte secretion which may be beneficial in CF patients. CFTR appears to be required for this response in an as yet unknown fashion.}, }
@article {pmid8929261, year = {1996}, author = {Wiklund, O and Fager, G and Andersson, A and Lundstam, U and Masson, P and Hultberg, B}, title = {N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels.}, journal = {Atherosclerosis}, volume = {119}, number = {1}, pages = {99-106}, doi = {10.1016/0021-9150(95)05635-1}, pmid = {8929261}, issn = {0021-9150}, mesh = {Acetylcysteine/*administration &amp; dosage ; Cross-Over Studies ; Double-Blind Method ; Female ; Free Radical Scavengers/*administration &amp; dosage ; Homocysteine/*blood ; Humans ; Hyperlipoproteinemias/blood/*drug therapy ; Lipoprotein(a)/*blood ; Male ; }, abstract = {High levels of lipoprotein(a) (Lp(a)) or homocysteine in plasma have both been associated with an increased risk for premature cardiovascular disease. For both components, the plasma levels are primarily genetically determined, and they have been very restintant to therapeutic approaches. It has been suggested that N-acetylcysteine (NAC) breaks disulphide bonds in Lp(a) as well as between homocysteine and plasma proteins. In the present study we analyze if this mechanism, in vivo, could be used to lower plasma concentrations of Lp(a) and homocysteine. Treatment with NAC and placebo was performed in a double blind cross over design with 2 weeks wash-out between treatments. Eleven subjects with high plasma Lp(a) (> 0.3 milligram) were recruited from the Lipid Clinic at Sahlgren's Hospital, Göteborg, Sweden. Main outcome measures were treatment effects on plasma Lp(a) and plasma amino thiols (homocysteine, cysteine and cysteinyl glycine). There was no significant effect on plasma Lp(a) levels. Plasma thiols were significantly reduced during treatment with NAC: homocysteine by 45% (P < 0.0001), cysteinyl glycine by 24% (P < 0.0001) and cysteine by 11% (P = 0.0002). The high dose of NAC was well tolerated. In conclusion NAC has no effect on plasma Lp(a) levels while the reduction in homocysteine is considerable and might be of clinical significance in cases with high plasma homocysteine levels.}, }
@article {pmid9027604, year = {1996}, author = {De Flora, S and Camoirano, A and Bagnasco, M and Bennicelli, C and van Zandwijk, N and Wigbout, G and Qian, GS and Zhu, YR and Kensler, TW}, title = {Smokers and urinary genotoxins: implications for selection of cohorts and modulation of endpoints in chemoprevention trials.}, journal = {Journal of cellular biochemistry. Supplement}, volume = {25}, number = {}, pages = {92-98}, pmid = {9027604}, issn = {0733-1959}, support = {ES06052/ES/NIEHS NIH HHS/United States ; N01-CN-25437/CN/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Adult ; Anticarcinogenic Agents/*therapeutic use ; Biomarkers, Tumor/*analysis ; Chemoprevention ; China ; Clinical Trials, Phase II as Topic ; Cohort Studies ; DNA Repair ; Female ; Humans ; Lung Neoplasms/chemistry/etiology/*prevention &amp; control ; Male ; Middle Aged ; Mutagenicity Tests ; Mutagens/*analysis ; Netherlands ; Pyrazines/therapeutic use ; Research Design ; Smoking/adverse effects/*urine ; Thiones ; Thiophenes ; }, abstract = {Urinary genotoxicity assays measure the internal dose of genotoxic carcinogens, thereby providing a particularly sensitive endpoint for selecting cohorts of individuals exposed to cigarette smoke or other mutagens excreted with urines, as well as for evaluating the modulation of this parameter after administration of chemopreventive agents. Mutagenicity of urines was investigated in smoking Italian volunteers, who received oral N-acetylcysteine (NAC) at the same doses which are usually prescribed for the long-term treatment of chronic bronchitis. The daily excretion of mutagens, concentrated on XAD-2 columns and tested in Salmonella typhimurium YG1024 with S9 mix, was significantly and remarkably decreased by NAC in the majority of the subjects examined so far. Time-course experiments showed that this effect starts since the first day of drug administration and reverses when treatment is withdrawn. In addition, NAC administration almost totally prevented urinary genotoxicity in one subject whose concentrated urines induced a differential lethality in Escherichia coli strains having distinctive DNA repair capacities. The decrease of urinary genotoxicity produced by NAC in the majority of smokers correlates with the ability of this thiol to prevent tumors and to affect a variety of intermediate biomarkers in animal models. Modulation of the urinary excretion of mutagens is one of the biomarkers evaluated in two ongoing Phase II chemoprevention trials. One study involves the oral administration of NAC in Dutch smokers. The pretreatment urine samples of all the subjects so far recruited are clearly mutagenic. The other study involves the oral administration of the dithiolethione oltipraz to individuals living in the Qidong County of the People's Republic of China, an area of high endemy for HBV infection and of high exposure to aflatoxins. Additionally, a large proportion of the recruited male subjects are smokers. A total of 500 urine specimens will be assayed from 240 subjects according to a complex protocol arranged in three consecutive phases.}, }
@article {pmid8923039, year = {1996}, author = {De Flora, S and Balansky, R and Scatolini, L and Di Marco, C and Gasparini, L and Orlando, M and Izzotti, A}, title = {Adducts to nuclear DNA and mitochondrial DNA as biomarkers in chemoprevention.}, journal = {IARC scientific publications}, volume = {}, number = {139}, pages = {291-301}, pmid = {8923039}, issn = {0300-5038}, mesh = {Animals ; Biomarkers, Tumor/*metabolism ; Cell Nucleus/metabolism ; Chemoprevention/*methods ; DNA/*metabolism ; DNA Adducts/*metabolism ; DNA, Mitochondrial/*metabolism ; Humans ; Rats ; }, abstract = {DNA adducts are biomarkers evaluating the biologically effective dose of carcinogens, which reflects, more realistically than the external exposure dose, an enhanced risk of developing cancer. Likewise, inhibition of DNA adduct formation can be assumed as an indicator of decreased risk. Molecular dosimetry techniques can be exploited in anticarcinogenicity studies in animal models as well as in Phase II clinical chemoprevention trials. We have extensively used these end points in animal studies using individual carcinogens and complex mixtures. As assessed by 32P-postlabelling, DNA adducts were formed in the liver of rats fed a diet supplemented with 2-acetylaminofluorene. DNA adducts were detected by synchronous fluorescence spectrophotometry (SFS) in rat liver, lung, heart and testis following intratracheal (l.t) instillations of benzo[a]pyrene. The whole-body exposure of rats to mainstream cigarette smoke resulted in the appearance of DNA adducts in lung, heart, aorta and kidney, whereas adducts were not detected by SFS in liver, brain, oesophagus and testis. Moreover, typical diagonal radioactive zones and multiple DNA adducts were revealed by 32P-postlabelling in the tracheal epithelium, nasal mucosa, aorta and testis of smoke-exposed rats. Formation of adducts to lung DNA, as assessed by both 32P-postlabelling and SFS, also occurred in rats receiving i.t. instillations of air particulate extracts from polluted urban and rural areas. The oral administration of the thiol N-acetylcysteine (NAC) significantly inhibited the formation of DNA adducts in all organs of the rats exposed to the aforementioned carcinogens, which correlated with the parallel inhibition of biochemical, cytogenetic and histopathological alterations as well as with inhibition of preneoplastic and neoplastic lesions in rodents. Our working hypothesis is that DNA adducts in trachea/lung, heart and aorta may be associated with lung cancer, cardiomyopathies and atherosclerosis, respectively. DNA adducts were consistently detectable in the DNA of smooth muscle cells from abdominal aorta specimens taken at surgery from atherosclerotic patients. Even broader are the consequences of mitochondrial (mt) DNA impairment, which has been associated with aging, cancer, and other degenerative diseases. Our data show that adduct levels are consistently higher in mtDNA than in the nuclear DNA in different organs of rats exposed either to benzo[a]pyrene, 2-acetylaminofluorene or cigarette smoke. NAC significantly decreased the formation of adducts to mtDNA when administered with drinking-water. Inhibition of adducts to nuclear DNA is one of the end points evaluated in ongoing Phase II chemoprevention trials in high-risk individuals.}, }
@article {pmid8911827, year = {1996}, author = {Atalay, M and Marnila, P and Lilius, EM and Hänninen, O and Sen, CK}, title = {Glutathione-dependent modulation of exhausting exercise-induced changes in neutrophil function of rats.}, journal = {European journal of applied physiology and occupational physiology}, volume = {74}, number = {4}, pages = {342-347}, pmid = {8911827}, issn = {0301-5548}, mesh = {Animals ; Cell Count/drug effects ; Glutathione/*pharmacology ; Male ; Neutrophils/*physiology ; Physical Conditioning, Animal/*physiology ; Rats ; Rats, Wistar ; }, abstract = {Reduced glutathione (GSH) plays a central role in maintaining an effective synergism between various physiological and exogenous antioxidants. We tested the effects of GSH and N-acetylcysteine (NAC, a pro-GSH clinical drug), intraperitoneal (i.p.) supplementation and GSH deficiency on exercise-induced leucocyte margination and neutrophil oxidative burst activity. GSH, NAC (1g.kg-1) or placebo saline was i.p. injected (one or eight times) to male rats (n > or = seven per group). The GSH-deficient rats were prepared by i.p. injections of L-buthionine-[SR]-sulphoximine (BSO, 6 mmol.l-1.kg-1) twice daily for 4 days. Exercised animals were subjected to treadmill run to exhaustion. Exhausting treadmill exercise significantly decreased peripheral blood leucocyte count in the controls (P < 0.001). Such exercise-associated leucocyte margination was prevented by GSH supplementation. Peripheral blood neutrophil counts were significantly higher (P < 0.02) in the GSH-supplemented groups compared to the placebo control groups. Exercise-induced increase in peripheral blood neutrophil oxidative burst activity as measured by luminol-enhanced chemiluminescence per volume of blood tended to be higher in the GSH-supplemented group (P < 0.10), and lower in the GSH-deficient rats (P < 0.02). In these experiments, for the first time we have shown that GSH supplementation can induce neutrophil mobilization and decrease exercise-induced leucocyte margination, and that exogenous and endogenous GSH can regulate exercise-induced stimulation of the neutrophil oxidative burst.}, }
@article {pmid8876661, year = {1996}, author = {Gogu, SR and Agrawal, KC}, title = {The protective role of zinc and N-acetylcysteine in modulating zidovudine induced hematopoietic toxicity.}, journal = {Life sciences}, volume = {59}, number = {16}, pages = {1323-1329}, doi = {10.1016/0024-3205(96)00457-2}, pmid = {8876661}, issn = {0024-3205}, support = {AI 25909/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antidotes/pharmacology/*therapeutic use ; Bone Marrow/*drug effects ; Cell Survival/drug effects ; Female ; Hematopoietic Stem Cells/cytology ; Mice ; Zidovudine/*adverse effects ; Zinc/pharmacology/*therapeutic use ; }, abstract = {The role of zinc and N-acetylcysteine (NAC) has been investigated in protecting the hematopoietic progenitor cells from zidovudine (AZT)-induced toxicity. Murine bone marrow progenitor cells (BMPC, 1x10(6)) were exposed to various concentrations (0.1-50 microM) of AZT in the presence and absence of zinc acetate (100 microM) or NAC (100 microM). The cell survival was determined by the colony forming assays of erythroid (CFU-E) and granulocytic (CFU-GM) lineage. The IC50 values of AZT in the presence of zinc were increased approximately 3-fold (from 3.0 to 9.5 microM) in the CFU-E assay and 7-fold (from 4.3 to 28.8 microM) in the CFU-GM assay whereas in the presence of NAC, the IC50 values were increased by 2- and 4-fold, respectively. To delineate the mechanism of significant protection of BMPC by zinc, the mRNA levels of metallothionein (MT) were monitored by using a 31-mer cDNA probe. Zinc produced a concentration-dependent increase in the MT mRNA levels in BMPC. These results suggest that zinc and NAC dietary supplementation can be conveniently used to reduce AZT-induced bone marrow toxicity.}, }
@article {pmid8870953, year = {1996}, author = {Lock, EA and Sani, Y and Moore, RB and Finkelstein, MB and Anders, MW and Seawright, AA}, title = {Bone marrow and renal injury associated with haloalkene cysteine conjugates in calves.}, journal = {Archives of toxicology}, volume = {70}, number = {10}, pages = {607-619}, doi = {10.1007/s002040050319}, pmid = {8870953}, issn = {0340-5761}, mesh = {Animals ; Bone Marrow/*drug effects/*pathology ; Butadienes/toxicity ; Cattle ; Cysteine/*analogs &amp; derivatives/metabolism/*toxicity ; Female ; Fungicides, Industrial/toxicity ; Hydrocarbons, Halogenated/metabolism/*toxicity ; Kidney/*drug effects/*pathology ; Male ; }, abstract = {Almost 40 years ago, it was reported that cattle-feed which had been extracted with hot trichloroethylene and then fed to calves produced renal injury and a fatal aplastic anaemia. The toxic factor was subsequently identified as S-(1,2-dichlorovinyl)-L-cysteine (DCVC). These original findings have been confirmed, a single intravenous dose of DCVC at 4 mg/kg, or 0.4 mg/kg intravenously per day administered for 10 days to calves produced aplastic anaemia, and renal injury after a single dose of 4 mg/kg. The toxicity to calves of a number of other haloalkene cysteine conjugates has been examined to ascertain whether, like DCVC, they produce bone marrow and renal injury. Intravenous administration of the N-acetyl cysteine conjugate of DCVC produced renal but not bone marrow injury at a molar equivalent dose to DCVC, indicating that the calf can deacetylate the mercapturic acid and further that sufficient chemical had reached the kidney to be a substrate for the enzyme cysteine conjugate beta-lyase. However, intravenous administration of the alpha-methyl analogue of DCVC, which cannot undergo metabolism via the enzyme cysteine conjugate beta-lyase, was without toxicity at doses about five-fold higher than DCVC. These latter findings provide strong evidence that metabolism of DCVC via the enzyme beta-lyase is necessary for bone marrow and renal injury to occur. The cysteine conjugates of perchloroethylene and hexachloro-1,3-butadiene(HCBD) when given intravenously to calves at molar equivalent doses to DCVC, or above, did not produce either bone marrow or renal injury. In contrast, intravenous administration of the cysteine conjugate of tetrafluoroethylene (TFEC) produced severe renal tubular injury in calves without affecting the bone marrow. In vitro studies with these haloalkene cysteine conjugates showed, like DCVC, that they were good substrates for calf renal cysteine conjugate beta-lyase and toxic to renal cells as judged by their ability to reduce organic anion and cation transport by slices of calf renal cortex and inhibit the renal enzyme glutathione reductase. Calves were also dosed either orally or intravenously with HCBD to assess its toxicity. HCBD at higher molar equivalent doses than DCVC produced mid-zonal necrosis in the liver, renal tubular necrosis but no bone marrow injury in calves. The key findings emerging from these studies are (1) that none of the other cysteine conjugates, at molar equivalent doses to DCVC and above, produce bone marrow injury in calves, (2) TFEC produced only renal injury, suggesting that sufficient of the other conjugates had not reached the kidney for metabolism by beta-lyase to produce cytotoxicity and (3) that HCBD itself is more toxic than its cysteine or mercapturic acid conjugate, suggesting that pharmaco-kinetics and disposition are important factors in determining the toxicity of these conjugates to calves. Further studies are needed to understand the basis for the selective toxicity of DCVC to the bone marrow of calves.}, }
@article {pmid8869738, year = {1996}, author = {Keppler, D and Leier, I and Jedlitschky, G and Mayer, R and Büchler, M}, title = {The function of the multidrug resistance proteins (MRP and cMRP) in drug conjugate transport and hepatobiliary excretion.}, journal = {Advances in enzyme regulation}, volume = {36}, number = {}, pages = {17-29}, doi = {10.1016/0065-2571(95)00011-9}, pmid = {8869738}, issn = {0065-2571}, mesh = {ATP-Binding Cassette Transporters/chemistry/genetics/*metabolism ; Amino Acid Sequence ; Animals ; Anion Transport Proteins ; Bile/metabolism ; Carrier Proteins/metabolism ; Drug Resistance, Multiple/*physiology ; Etoposide/metabolism ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Leukotriene C4/metabolism ; Liver/metabolism ; Membrane Proteins/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Multidrug Resistance-Associated Proteins ; Pharmaceutical Preparations/*metabolism ; Rats ; Rats, Inbred Strains ; Substrate Specificity ; Transfection/genetics ; }, abstract = {The MRP gene encodes a 190-kDa integral membrane glycoprotein which functions as a primary-active ATP-dependent export pump for amphiphilic anions. The MRP gene-encoded conjugate export pump and its canalicular isoform represent the transport activity which has been described earlier as multispecific organic anion transporter, non-bile acid organic anion transporter, glutathione S-conjugate export pump, or leukotriene export pump. Analyses of the substrate specificity of the human MRP pump were performed in plasma membrane vesicles from MRP-overexpressing drug-selected cells (7) and cells transfected with an MRP expression vector (8). Substrates for MRP include thioether-linked conjugates of lipophilic compounds with glutathione, cysteinyl glycine, cysteine, and N-acetyl cysteine, but also glutathione disulfide, and glucuronate conjugates such as etoposide glucuronide. This broad-specificity ATP-dependent export pump is not only overexpressed in several multidrug resistant tumor cells and tissues, but is also present in most normal cells and tissues. The expression of cMRP and MRP in human liver and of cMrp and its homolog Mrp in rat liver was demonstrated by reverse transcription PCR, cDNA sequencing, and immunoblotting (13). The important function of the cMRP gene-encoded broad-specificity conjugate export pump in hepatobiliary excretion is illustrated by the selective absence of this canalicular isoform from the hepatocyte canalicular membrane in transport-deficient mutant rats. This altered lack of cMrp is the basis for the hereditary detect of the hepatobiliary excretion of anionic conjugates in the mutant animals (13). The absence of this canalicular Mrp in the mutants is analogous to the defect in the human Dubin-Johnson syndrome which is characterized by an impaired excretion of conjugated anions across the canalicular membrane.}, }
@article {pmid8858271, year = {1996}, author = {Akerlund, B and Jarstrand, C and Lindeke, B and Sönnerborg, A and Akerblad, AC and Rasool, O}, title = {Effect of N-acetylcysteine(NAC) treatment on HIV-1 infection: a double-blind placebo-controlled trial.}, journal = {European journal of clinical pharmacology}, volume = {50}, number = {6}, pages = {457-461}, doi = {10.1007/s002280050140}, pmid = {8858271}, issn = {0031-6970}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Antiviral Agents/*therapeutic use ; CD4 Lymphocyte Count ; Cysteine/blood ; Double-Blind Method ; Female ; Free Radical Scavengers/*therapeutic use ; HIV Infections/blood/*drug therapy/immunology ; *HIV-1 ; Humans ; Male ; Middle Aged ; Neutrophils/metabolism ; Nitroblue Tetrazolium ; Superoxides/analysis ; Tumor Necrosis Factor-alpha/analysis ; }, abstract = {OBJECTIVE: In a double-blind placebo-controlled trial, human immunodeficiency virus (HIV)-seropositive patients with a CD4 lymphocyte cell count of more than 200 x 10(6) . l-1 were randomised to receive either 800 mg N-acetylcysteine (NAC) or placebo for 4 months. Before treatment low plasma cysteine levels, high free radical activity in neutrophils in the presence of autologous plasma-measured by the nitroblue tetrazolium (NBT) test- and increased tumor necrosis factor (TNF)-alpha levels were found in the HIV positive patients.<br><br>RESULTS: After treatment the low plasma cysteine level in the NAC group increased to normal, and the decline of the CD4+ lymphocyte count before the study start, was less steep in the NAC group than in the placebo group after treatment. There was also a reduction in TNF-alpha level. However, NAC had no effect on the radical production by neutrophils, and although it did not increase the CD4+ cell count, it may have decreased the decline in CD4+ cells.<br><br>CONCLUSION: Further controlled trials with NAC are needed to determine whether it has a beneficial effect in the treatment of asymptomatic HIV-infected individuals.}, }
@article {pmid8828094, year = {1996}, author = {Gonzalez, PK and Zhuang, J and Doctrow, SR and Malfroy, B and Benson, PF and Menconi, MJ and Fink, MP}, title = {Role of oxidant stress in the adult respiratory distress syndrome: evaluation of a novel antioxidant strategy in a porcine model of endotoxin-induced acute lung injury.}, journal = {Shock (Augusta, Ga.)}, volume = {6 Suppl 1}, number = {}, pages = {S23-6}, pmid = {8828094}, issn = {1073-2322}, support = {1 R41 HL55053-01/HL/NHLBI NIH HHS/United States ; 2 R01 GM37631-11/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Adult ; Animals ; Catalase/therapeutic use ; Disease Models, Animal ; Endotoxins/toxicity ; Ethylenediamines/therapeutic use ; Free Radical Scavengers/therapeutic use ; Humans ; Lipopolysaccharides/toxicity ; Lung/pathology ; *Lung Injury ; Organometallic Compounds/therapeutic use ; *Oxidative Stress ; Reactive Oxygen Species/physiology ; Respiratory Distress Syndrome/etiology/*physiopathology/prevention &amp; control ; Superoxide Dismutase/therapeutic use ; Swine ; Thiourea/analogs &amp; derivatives/therapeutic use ; }, abstract = {Reactive oxygen metabolites (ROMs) are thought to play a key role in the pathogenesis of the adult respiratory distress syndrome (ARDS). Accordingly, the use of ROM scavengers, such as N-acetyl-cysteine or dimethylthiourea, as therapeutic adjuncts to prevent oxidant-mediated damage to the lung have been evaluated extensively in animal models of ARDS. Results with this approach have been quite variable among studies. Another strategy that has been examined in animal models of ARDS is the administration of various enzymes, particularly superoxide dismutase (SOD) or catalase (CAT), in an effort to promote the conversion of ROMs to inactive metabolites. In theory, this strategy should be more effective than the use of ROM scavengers since a single molecule of a catalytically active molecule can neutralize a large number of molecules of a reactive species, whereas most scavengers act in a stoichiometric fashion to neutralize radicals on a mole-for-mole basis. This notion is supported by studies showing that prophylactic treatment with CAT provides impressive protection against acute lung injury induced in experimental animals by the administration of lipopolysaccharide (LPS). Results with SOD have been more variable. Recently, we have utilized a porcine model of LPS-induced ARDS to investigate the therapeutic potential of EUK-8, a novel, synthetic, low molecular salen-manganese complex that exhibits both SOD-like and CAT-like activities in vitro. Using both pre- and post-treatment designs, we have documented that treatment with EUK-8 significantly attenuates many of the features of LPS-induced acute lung injury, including arterial hypoxemia, pulmonary hypertension, decreased dynamic pulmonary compliance, and pulmonary edema. These findings support the view that salen-manganese complexes warrant further evaluation as therapeutic agents for treatment or prevention of sepsis-related ARDS in humans.}, }
@article {pmid8826530, year = {1996}, author = {Noble, M and Mayer-Próschel, M}, title = {On the track of cell survival pharmaceuticals in the oligodendrocyte type-2 astrocyte lineage.}, journal = {Perspectives on developmental neurobiology}, volume = {3}, number = {2}, pages = {121-131}, pmid = {8826530}, issn = {1064-0517}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Cell Survival/drug effects ; *Drug Design ; Glutamic Acid/pharmacology ; Humans ; Nerve Growth Factors/pharmacology ; Neuroprotective Agents/pharmacology ; Oligodendroglia/*drug effects/*physiology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The identification of compounds that can protect cells against death induced by exposure to noxious stimuli and against programmed cell death (apoptosis) associated with exposure to inadequate amounts of trophic factors is of great interest in contemporary biology. We have found that N-acetyl-L-cysteine (NAC) is able to promote cell survival in these two distinct experimental paradigms of, respectively, "death by murder" and "death by neglect." In the former case, NAC prevented the death of oligodendrocytes induced by glutamate or tumor necrosis factor-alpha (TNF-alpha), and also prevented TNF-alpha-induced death of L929 cells. NAC also acted in synergy with ciliary neurotrophic factor (CNTF) to prevent killing of oligodendrocytes by TNF-alpha. In analysis of "death by neglect," NAC markedly enhanced the extent of spinal ganglion neuron survival obtained with suboptimal concentrations of nerve growth factor and of oligodendrocyte survival obtained with suboptimal concentrations of CNTF or insulin-like growth factor-1. Surprisingly, significant rescue of oligodendrocytes from apoptosis was also observed with combinations of NAC with progesterone, vitamin C, or Trolox, a water-soluble vitamin E analogue, although not with any of these compounds applied individually. These results demonstrate that cocktails of small molecules such as those we have studied may have beneficial effects not predictable from the action of any individual member of the cocktail. In light of the long clinical history of therapeutic use of NAC and the other compounds identified in our studies, we suggest that it may be of interest to examine use of NAC alone, or combinations of NAC with the other small molecules we have studied, in conditions in which certain toxin-mediated forms of cell death or apoptosis contribute significantly to disease.}, }
@article {pmid8818630, year = {1996}, author = {Ercal, N and Treeratphan, P and Hammond, TC and Matthews, RH and Grannemann, NH and Spitz, DR}, title = {In vivo indices of oxidative stress in lead-exposed C57BL/6 mice are reduced by treatment with meso-2,3-dimercaptosuccinic acid or N-acetylcysteine.}, journal = {Free radical biology &amp; medicine}, volume = {21}, number = {2}, pages = {157-161}, doi = {10.1016/0891-5849(96)00020-2}, pmid = {8818630}, issn = {0891-5849}, support = {R01HL51469/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/metabolism ; Cysteine/metabolism ; Glutathione/metabolism ; Lead/blood/metabolism/*toxicity ; Liver/metabolism ; Male ; Malondialdehyde/metabolism ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction ; Oxidative Stress/*drug effects ; Succimer/*pharmacology ; }, abstract = {Knowledge of lead's capacity to disrupt the prooxidant/antioxidant balance within mammalian tissues suggests that definitive therapy for chronic lead poisoning should encompass both chelating and antioxidant actions. The dithiol meso-2,3-Dimercaptosuccinic Acid (DMSA) is the first orally administered metal chelating agent to receive U.S. Food and Drug Administration (FDA) approval for the treatment of childhood plumbism and possesses the potential to function as an antioxidant by removing lead from the site of deleterious oxidation reactions. Five weeks of lead exposure was found to deplete glutathione (GSH) levels, increase oxidized glutathione (GSSG), and promote malondialdehyde (MDA) production in both liver and brain samples taken from C57BL/6 mice. GSH levels increased and GSSG and MDA levels decreased in groups of lead-exposed mice that received 1 mmol/kg DMSA or 5.5 mmol/kg N-acetylcysteine (NAC) for 7 d prior to sacrifice. Treatment with DMSA caused a reduction in blood, liver, and brain lead levels consistent with its function as a chelating agent, while treatment with NAC did not reduce these lead levels. However, NAC did cause a reduction in indices of oxidative stress in both brain and liver samples, which implies that this synthetic thiol-containing antioxidant is capable of abrogating lead-induced oxidative stress in vivo. Overall, these results suggest that lead-induced oxidative stress in vivo can be mitigated by pharmacologic interventions, which encompass both chelating as well as thiol-mediated antioxidant functions.}, }
@article {pmid8720913, year = {1996}, author = {Bisby, RH and Johnson, SA and Parker, AW}, title = {Quenching of reactive oxidative species by probucol and comparison with other antioxidants.}, journal = {Free radical biology &amp; medicine}, volume = {20}, number = {3}, pages = {411-420}, doi = {10.1016/0891-5849(95)02094-2}, pmid = {8720913}, issn = {0891-5849}, mesh = {Acetylcysteine ; Antimutagenic Agents ; *Antioxidants ; Ascorbic Acid/analogs &amp; derivatives ; Benzophenones ; Benzoquinones ; Free Radicals ; Oxidation-Reduction ; Photolysis ; *Probucol ; Reactive Oxygen Species/*chemistry ; Spectrophotometry ; Spectrum Analysis, Raman/methods ; Thioctic Acid/analogs &amp; derivatives ; Vitamin E ; }, abstract = {One-electron oxidation of the antiatherogenic and antiatherosclerotic drug probucol has been studied in relation to its activity as an antioxidant. Oxidation by triplet excited states of duroquinone and benzophenone, and by the inorganic radicals Br2.- and N3., lead to the formation of a transient absorption at 500 nm. This was identified by time-resolved resonance Raman spectroscopy as the phenoxyl radical from probucol, formed by hydrogen atom or electron plus proton loss from one of the phenolic groups of probucol. The reactivity of probucol with triplet duroquinone and triplet benzophenone, and as a quencher of singlet oxygen, was compared with the reactivities of other antioxidants (alpha-tocopherol, palmitoyl ascorbic acid, dihydrolipoic acid and N-acetyl cysteine). In quenching of the triplet states the reactivity of probucol was comparable with that of alpha-tocopherol, whereas as a quencher of singlet oxygen probucol (k < 10(6) M-1 s-1) was less effective than alpha-tocopherol (k = 2.0 x 10(8) M-1 s-1) by more than two orders of magnitude. This difference in reactivity may allow the contribution of singlet oxygen towards oxidative stress to be quantified separately.}, }
@article {pmid8630680, year = {1996}, author = {Kobrinsky, NL and Hartfield, D and Horner, H and Maksymiuk, A and Minuk, GY and White, DF and Feldstein, TJ}, title = {Treatment of advanced malignancies with high-dose acetaminophen and N-acetylcysteine rescue.}, journal = {Cancer investigation}, volume = {14}, number = {3}, pages = {202-210}, doi = {10.3109/07357909609012140}, pmid = {8630680}, issn = {0735-7907}, mesh = {Acetaminophen/*administration &amp; dosage/adverse effects ; Acetylcysteine/pharmacokinetics/*therapeutic use ; Adult ; Aged ; Antineoplastic Agents/*administration &amp; dosage ; Carcinoma, Small Cell/drug therapy ; Drug Combinations ; Female ; Humans ; Lung Neoplasms/drug therapy/secondary ; Male ; Middle Aged ; Neoplasms/*drug therapy ; Time Factors ; }, abstract = {High-dose acetaminophen (HDAC) produces hepatocellular necrosis and cytotoxic changes in other tissues that express mixed-function-oxidase (MFO) activity. N-acetylcysteine (NAC), administered within 8 hr of HDAC exposure, replenishes reduced glutathione and prevents these effects. Numerous cell culture and animal studies have demonstrated that NAC may differentially protect normal cells compared with malignant cells from the toxic effects of chemotherapeutic agents and radiation. It was therefore proposed that HDAC with NAC rescue may be effective in malignancies that express MFO activity. To test this hypothesis, a phase I trial of HDAC with NAC rescue was conducted on 19 patients with advanced cancer. HDAC was escalated from 6 to 20 g/m2 PO using a standard IV NAC rescue regimen. A total of 78 treatments were administered. Moderate fatigue, anorexia, and weight loss were the main toxicities observed. Transient grade 3 liver toxicity was noted following 1 treatment. Alopecia and renal and hematological toxicities were not observed. Responses after 4 courses administered weekly were as follows: response in at least 1 site-8 (partial 3, improved 3, mixed 2); stable disease-3; progressive disease-3; inevaluable-5. In conclusion, HDAC was tolerated with moderate fatigue, anorexia, and weight loss but few other effects using a standard IV NAC rescue regimen. A maximum tolerated dose was not reached at 20 g/m2. A 3/19 (15.8%) partial response rate was observed.}, }
@article {pmid8549180, year = {1996}, author = {Laurent, T and Markert, M and Feihl, F and Schaller, MD and Perret, C}, title = {Oxidant-antioxidant balance in granulocytes during ARDS. Effect of N-acetylcysteine.}, journal = {Chest}, volume = {109}, number = {1}, pages = {163-166}, doi = {10.1378/chest.109.1.163}, pmid = {8549180}, issn = {0012-3692}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acridines ; Antioxidants/*metabolism ; Double-Blind Method ; Female ; Glutathione/metabolism ; Granulocytes/drug effects/enzymology/*metabolism ; Humans ; Indicators and Reagents ; Infusions, Intravenous ; Leukocyte Elastase ; Luminescent Measurements ; Luminol ; Male ; Middle Aged ; Oxidants/*metabolism ; Pancreatic Elastase/blood ; Placebos ; Reactive Oxygen Species/metabolism ; Respiratory Distress Syndrome/*drug therapy/*metabolism ; }, abstract = {The production of cytotoxic oxygen radicals by activated granulocytes is a proposed mechanism of lung injury in ARDS. Protective effects of N-acetylcysteine (NAC) have been described in experimental and clinical ARDS. NAC could act in part by replenishing the intracellular stores of glutathione (GSH) in activated granulocytes, leading to detoxification of oxygen radicals produced by these cells. To test this hypothesis, 16 patients in the early phase of ARDS were randomized to receive either NAC (n = 8) or placebo (n = 8); granulocyte GSH, granulocyte oxygen radical production, and plasma levels of granulocyte elastase were measured in blood samples drawn sequentially within 8 h after the onset of ARDS (day 0), and then 24 (day 1), 72 (day 3), and 120 h (day 5) after the first sample; treatment with NAC or placebo was started immediately after day 0 and stopped just after day 3. Granulocyte GSH was significantly higher on days 1 and 3 when NAC was received by the patient. Unstimulated oxygen radical production, as measured ex vivo by luminol- and lucigenin-amplified chemiluminescence (CL), was higher in granulocytes from ARDS patients than from healthy control subjects, but was not influenced by NAC. The plasma levels of granulocyte elastase were five to eight times above the upper normal limit on day 0, decreased steadily until day 5, and were uninfluenced by NAC. In summary, parenteral NAC treatment started within 8 h of diagnosis increases the intracellular GSH in the granulocytes of ARDS patients without decreasing spontaneous oxidant production by these cells. The mechanisms of the protective effects of this drug previously reported in experimental and clinical ARDS remain to be established.}, }
@article {pmid8546677, year = {1996}, author = {Xia, C and Hu, J and Ketterer, B and Taylor, JB}, title = {The organization of the human GSTP1-1 gene promoter and its response to retinoic acid and cellular redox status.}, journal = {The Biochemical journal}, volume = {313 (Pt 1)}, number = {Pt 1}, pages = {155-161}, pmid = {8546677}, issn = {0264-6021}, mesh = {Base Sequence ; Gene Expression Regulation, Enzymologic/drug effects/*physiology ; Glutathione Transferase/*genetics/*metabolism ; HeLa Cells ; Humans ; Molecular Sequence Data ; NF-kappa B/metabolism ; Neoplasms/enzymology/genetics/metabolism ; Oxidation-Reduction ; *Promoter Regions, Genetic ; Receptors, Retinoic Acid/metabolism ; Transcription Factor AP-1/metabolism ; Transfection ; Tretinoin/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {High levels of expression of GSTP1-1 are associated with cell proliferation, embryogenesis and malignancy. Given the role of glutathione S-transferase (GST) in detoxication, it is possible that GSTP1-1 evolved specifically to protect proliferating cells and share regulatory mechanisms with other cellular genes which are involved in cell division and tumorigenesis. We have previously shown that the expression of GSTP1 is suppressed by retinoic acid (RA) in the presence of the retinoic acid receptor (RAR) as a result of decreased transcription from its promoter. Through deletion analysis, we show here that the RA-RAR-dependent repression is mediated by the region -73 to +8. Further mutation analysis of this region indicates that the DNA sequence required for RA-RAR-dependent repression co-localizes with a consensus activator protein-1 (AP1) site essential for the promoter activity. The degree of repression correlates with the residual activity of the AP1 site. There are two adjacent G/C boxes. The one immediately downstream from the AP1 site is not essential for the promoter activity, but mutation of the second, further downstream, impairs the promoter. On the other hand, mutation of either of these two G/C boxes has little effect on RA-RAR suppression. We also show that the expression of GSTP1 is regulated by the redox status of the cell. Using the chloramphenicol acetyltransferase assay system, we have demonstrated that treatment with H2O2 induced transcription from the promoter and that this effect can be blocked by pre-incubation with N-acetylcysteine (NAC). It was shown that the induction by H2O2 is mediated by trans-acting factor NF-kappa B (nuclear factor kappa B), via a putative NF-kappa B site, 'GGGACCCTCC', located from -96 to -86. Co-transfection with an NF-kappa B (p65) expression construct increased the promoter activity, an effect which could be blocked by co-transfection with an I kappa B (MAD-3) expression construct. Deletion of the NF-kappa B site abolished the effect of both H2O2 and co-transfection of NF-kappa B. Interestingly, NAC is also an inducer for GSTP1. The effect of NAC was shown to be mediated largely by the AP1 site, since mutation of this site abolished the induction by NAC.}, }
@article {pmid8819180, year = {1995}, author = {Tomkiewicz, RP and App, EM and De Sanctis, GT and Coffiner, M and Maes, P and Rubin, BK and King, M}, title = {A comparison of a new mucolytic N-acetylcysteine L-lysinate with N-acetylcysteine: airway epithelial function and mucus changes in dog.}, journal = {Pulmonary pharmacology}, volume = {8}, number = {6}, pages = {259-265}, doi = {10.1006/pulp.1995.1035}, pmid = {8819180}, issn = {0952-0600}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacology ; Administration, Inhalation ; Animals ; Bronchi/drug effects ; Dogs ; Expectorants/*pharmacology ; Female ; Lysine/*analogs &amp; derivatives/pharmacology ; Male ; Mucociliary Clearance/*drug effects ; Mucus/metabolism/physiology ; Trachea/drug effects ; Viscosity/drug effects ; }, abstract = {A newly synthesized mucolytic agent, N-acetylcysteine L-lysinate (Nacystelyn) was studied. Tracheal mucus velocity (TMV), transepithelial potential difference (PD), rheological properties, and ion content of collected airway secretions were evaluated in six healthy mongrel dogs after placebo, Nacystelyn (NAL) and acetylcysteine (NAC) metered dose inhaler (MDI) aerosols. Although TMV was increased and viscoelasticity decreased after both treatments, the treatment effect with NAL was significantly greater. Furthermore, NAL increased the negative PD and CI- content of secretions in the trachea, an effect not observed after NAC. Both compounds increased ciliary beat frequency (CBF) on the frog palate at a concentration range similar to that approximated in dog airways. The increased mucociliary clearance could be partially explained by favourable rheological changes combined with stimulation of CBF. Since both compounds break disulfide bonds in mucus polymers, the greater change in mucus rheology and clearance rate after NAL, without change in water content, could be explained by the increase in CI- content. Nacystelyn appears to combine different modes of action which synergistically cause an increase in the clearance rate of airway secretions.}, }
@article {pmid8542991, year = {1995}, author = {Taramelli, D and Basilico, N and Pagani, E and Grande, R and Monti, D and Ghione, M and Olliaro, P}, title = {The heme moiety of malaria pigment (beta-hematin) mediates the inhibition of nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide-stimulated macrophages.}, journal = {Experimental parasitology}, volume = {81}, number = {4}, pages = {501-511}, doi = {10.1006/expr.1995.1143}, pmid = {8542991}, issn = {0014-4894}, mesh = {Animals ; Dose-Response Relationship, Drug ; Female ; Heme/*pharmacology ; Hemeproteins/*pharmacology ; Lipopolysaccharides/pharmacology ; Macrophages, Peritoneal/*drug effects/metabolism ; Malaria/*metabolism ; Mice ; Microglia/drug effects ; Nitric Oxide/*biosynthesis ; Sulfhydryl Compounds/pharmacology ; Tumor Necrosis Factor-alpha/*biosynthesis ; }, abstract = {To investigate the effect of the heme moiety of malaria pigment, hemozoin, on phagocyte functions, mouse macrophages were fed with insoluble beta-hematin, the synthetic heme-polymer chemically identical to the native pigment, or the soluble monomer, hematin. Production of inflammatory cytokines, interleukin 1 (IL1), tumor necrosis factor alpha (TNF alpha), and nitric oxide (NO) was assayed in the supernatants after stimulation with lipopolysaccharide. The results indicate that both beta-hematin and hematin induce a dose-dependent inhibition of macrophage production of TNF alpha and NO, but not of IL1. One-hour pretreatment with soluble hematin inhibited production of cytotoxic mediators by more than 50% compared to controls, while 6-hr exposure was necessary for insoluble beta-hematin to induce the same level of inhibition. However, the same treatment did not modify the production of TNF alpha and NO by mouse microglia cell lines. The inhibition was partially counterbalanced by adding sulphydryl group donors such as 2-mercaptoethanol, glutathione, or N-acetyl-cysteine during the preincubation time. The results of the present study confirm the inhibitory role of malaria pigment and show that such effect is due to the heme moiety and may be selective for the production of cytotoxic mediators by specific phagocytes. The implications of these findings in the control of malaria infection and disease and in the pathogenesis of severe malaria are discussed.}, }
@article {pmid8522579, year = {1995}, author = {Lin, KI and Lee, SH and Narayanan, R and Baraban, JM and Hardwick, JM and Ratan, RR}, title = {Thiol agents and Bcl-2 identify an alphavirus-induced apoptotic pathway that requires activation of the transcription factor NF-kappa B.}, journal = {The Journal of cell biology}, volume = {131}, number = {5}, pages = {1149-1161}, pmid = {8522579}, issn = {0021-9525}, support = {5T32HD07428/HD/NICHD NIH HHS/United States ; DA-00266/DA/NIDA NIH HHS/United States ; MH-00926/MH/NIMH NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Apoptosis ; Base Sequence ; Cell Nucleus/metabolism ; Chelating Agents/pharmacology ; DNA ; Dithiothreitol/pharmacology ; Iron ; Lipid Peroxidation/drug effects ; Male ; Mercaptoethanol/pharmacology ; Mice ; Molecular Sequence Data ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Neuroblastoma/pathology ; Prostatic Neoplasms/pathology ; Proto-Oncogene Proteins/*metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Pyrrolidines/pharmacology ; Rats ; Sindbis Virus/*physiology ; Sulfhydryl Reagents/*pharmacology ; Thiocarbamates/pharmacology ; Tumor Cells, Cultured ; }, abstract = {Oxidative stress has been proposed as a common mediator of apoptotic death. To investigate further the role of oxidants in this process we have studied the effects of antioxidants on Sindbis virus (SV)-induced apoptosis in two cell lines, AT-3 (a prostate carcinoma line) and N18 (a neuroblastoma line). The thiol antioxidant, N-acetylcysteine (NAC), at concentrations above 30 mM, completely abrogates SV-induced apoptosis in AT-3 and N18 cells. The effects of NAC cannot be attributed to inhibition of viral entry or viral replication, changes in extracellular osmolarity or to increases in cellular glutathione levels, nor can they be mimicked by chelators of trace metals, inhibitors of lipid peroxidation or peroxide scavengers. In contrast, other thiol agents including pyrrolidine dithiocarbamate (PDTC, 75 microM) are protective. Because NAC and PDTC are among the most effective inhibitors of the transcription factor NF-kappa B, we examined SV's ability to activate NF-kappa B before the onset of morphologic or biochemical evidence of apoptosis. Within hours of infection, SV induced a robust increase in nuclear NF-kappa B activity in AT-3 and N18 cells; this activation was suppressible by NAC and PDTC. Over-expression of bcl-2 in AT-3 cells, which has been shown to inhibit SV-induced apoptosis, also inhibits SV-induced NF-kappa B activation. To determine if NF-kappa B activation is necessary for SV-induced apoptosis in these cells, we used double stranded oligonucleotides with consensus NF-kappa B sequences as transcription factor decoys (TFDs) to inhibit NF-kappa B binding to native DNA sites. Wild-type, but not mutant, TFDs inhibit SV-induced apoptosis in AT-3 cells. In contrast, TFD inhibition of NF-kappa B nuclear activity in N18 cells did not prevent SV-induced apoptosis. Taken together, these observations define a cell type-specific, transcription factor signaling pathway necessary for SV-induced apoptosis. Understanding the precise mechanism by which Bcl-2 and thiol agents inhibit SV-induced nuclear NF-kappa B activity in AT-3 cells may provide insights into the pluripotent antiapoptotic actions of these agents.}, }
@article {pmid7594708, year = {1995}, author = {Roberts, RL and Aroda, VR and Ank, BJ}, title = {N-acetylcysteine enhances antibody-dependent cellular cytotoxicity in neutrophils and mononuclear cells from healthy adults and human immunodeficiency virus-infected patients.}, journal = {The Journal of infectious diseases}, volume = {172}, number = {6}, pages = {1492-1502}, doi = {10.1093/infdis/172.6.1492}, pmid = {7594708}, issn = {0022-1899}, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Adult ; Antibody-Dependent Cell Cytotoxicity/*drug effects ; Antioxidants/*pharmacology ; Carmustine/pharmacology ; Child ; Child, Preschool ; Female ; Glutathione/physiology ; Granulomatous Disease, Chronic/immunology ; HIV Infections/*immunology ; Humans ; Infant ; Leukocytes, Mononuclear/*drug effects/immunology ; Male ; Neutrophils/*drug effects/immunology ; }, abstract = {Patients with AIDS have decreased levels of the intracellular antioxidant, glutathione, in their circulating lymphocytes and plasma. N-acetylcysteine (NAC) increases intracellular stores of glutathione and has direct antioxidant properties. In this study, the effects of glutathione and NAC on the cytotoxicity of neutrophils and mononuclear cells were tested using cells from healthy controls and human immunodeficiency virus (HIV)-infected patients. NAC (1 and 5 mM) enhanced the antibody-dependent cellular cytotoxicity (ADCC) of neutrophils from healthy adult controls and HIV-infected adults and children. The antineoplastic drug, 1,3 bis(2-chloroethyl)-1-nitrosourea (BCNU), which depletes intracellular glutathione, inhibited the ADCC of neutrophils; the addition of NAC partially reversed this inhibition. Similar effects of BCNU and NAC were seen when the cytotoxicity of mononuclear cells was tested using CEM tumor cells bearing the HIV gp120 antigen as targets. Thus, NAC enhances various forms of cytotoxicity and may be beneficial to AIDS patients whose defects in leukocyte cytotoxicity may be due to glutathione depletion.}, }
@article {pmid7500023, year = {1995}, author = {Jeannin, P and Delneste, Y and Lecoanet-Henchoz, S and Gauchat, JF and Life, P and Holmes, D and Bonnefoy, JY}, title = {Thiols decrease human interleukin (IL) 4 production and IL-4-induced immunoglobulin synthesis.}, journal = {The Journal of experimental medicine}, volume = {182}, number = {6}, pages = {1785-1792}, pmid = {7500023}, issn = {0022-1007}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antibody Formation/drug effects ; Antioxidants/*pharmacology ; B-Lymphocytes/physiology ; CD40 Antigens/genetics ; Cells, Cultured ; Gene Expression/drug effects ; Genes, Immunoglobulin ; Humans ; Immunoglobulins/*biosynthesis ; Interleukin-4/*biosynthesis/genetics ; Lymphocyte Activation/drug effects ; Mice ; Mice, Inbred C57BL ; Palatine Tonsil/cytology ; RNA, Messenger/genetics ; Receptors, Complement 3d/genetics ; Sulfhydryl Compounds/*pharmacology ; T-Lymphocyte Subsets/*immunology ; }, abstract = {N-Acetyl-L-cysteine (NAC) is an antioxidant precursor of intracellular glutathione (GSH), usually given in human as a mucolytic agent. In vitro, NAC and GSH have been shown to act on T cells by increasing interleukin (IL) 2 production, synthesis and turnover of IL-2 receptors, proliferation, cytotoxic properties, and resistance to apoptosis. We report here that NAC and GSH decrease in a dose-dependent manner human IL-4 production by stimulated peripheral blood T cells and by T helper (Th) 0- and Th2-like T cell clones. This effect was associated with a decrease in IL-4 messenger RNA transcription. In contrast, NAC and GSH had no effect on interferon gamma and increased IL-2 production and T cell proliferation. A functional consequence was the capacity of NAC and GSH to selectively decrease in a dose-dependent manner IL-4-induced immunoglobulin (Ig) E and IgG4 production by human peripheral blood mononuclear cells. Interestingly, NAC and GSH also acted directly on purified tonsillar B cells by decreasing the mature epsilon messenger RNA, hence decreasing IgE production. In contrast, IgA and IgM production were not affected. At the same time, B cell proliferation was increased in a dose-dependent manner. Not all antioxidants tested but only SH-bearing molecules mimicked these properties. Finally, when given orally to mice, NAC decreased both IgE and IgG1 antibody responses to ovalbumin. These results demonstrate that NAC, GSH, and other thiols may control the production of both the Th2-derived cytokine IL-4 and IL-4-induced Ig in vitro and in vivo.}, }
@article {pmid7586252, year = {1995}, author = {Arstall, MA and Yang, J and Stafford, I and Betts, WH and Horowitz, JD}, title = {N-acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction. Safety and biochemical effects.}, journal = {Circulation}, volume = {92}, number = {10}, pages = {2855-2862}, doi = {10.1161/01.cir.92.10.2855}, pmid = {7586252}, issn = {0009-7322}, mesh = {Acetylcysteine/*administration &amp; dosage/toxicity ; Cardiac Catheterization ; Drug Synergism ; Drug Therapy, Combination ; Female ; Fibrinolytic Agents/*administration &amp; dosage ; Free Radical Scavengers/*administration &amp; dosage/toxicity ; Hemodynamics/drug effects ; Humans ; Male ; Middle Aged ; Myocardial Infarction/*drug therapy ; Myocardial Reperfusion ; Nitroglycerin/*administration &amp; dosage ; Oxidative Stress/drug effects ; Streptokinase/*administration &amp; dosage ; Time Factors ; Vasodilator Agents/*administration &amp; dosage ; }, abstract = {BACKGROUND: N-acetylcysteine (NAC) has been shown to potentiate the effects of nitroglycerin (NTG) and to have antioxidant activity. This is the first study to assess the safety and effect of NAC in the treatment of evolving acute myocardial infarction (AMI).<br><br>METHODS AND RESULTS: Patients with AMI received either 15 g NAC infused over 24 hours (n = 20) or no NAC (n = 7), combined with intravenous NTG and streptokinase. Peripheral venous plasma malondialdehyde (MDA), reduced (GSH) and oxidized (GSSG) glutathione concentrations, and rate of reperfusion (using continuous ST-segment analysis) were measured. Cardiac catheterization was performed between days 2 and 5. No significant adverse events occurred. Less oxidative stress occurred in patients treated with NAC than in patients not receiving NAC (GSH to GSSG ratio 44 +/- 25 versus 19 +/- 13 at 4 hours, P < .05). NAC concentration (mean 172 +/- 79 mumol/L at 4 hours) was correlated to GSH concentration (P = .006). MDA concentrations were lower (P = .001) over the first 8 hours of treatment with NAC. There was a trend toward more rapid reperfusion (median 58 minutes, 95% confidence interval [CI] 48 to 98 minutes versus median 95 minutes, 95% CI 59 to 106 minutes; P = .17) and better preservation of left ventricular function (cardiac index 3.4 +/- 0.8 versus 2.6 +/- 0.27 L.min.m2, P = .009) with NAC treatment.<br><br>CONCLUSIONS: NAC in combination with NTG and streptokinase appeared to be safe for the treatment of evolving AMI and was associated with significantly less oxidative stress, a trend toward more rapid reperfusion, and better preservation of left ventricular function.}, }
@article {pmid7592924, year = {1995}, author = {Yan, CY and Ferrari, G and Greene, LA}, title = {N-acetylcysteine-promoted survival of PC12 cells is glutathione-independent but transcription-dependent.}, journal = {The Journal of biological chemistry}, volume = {270}, number = {45}, pages = {26827-26832}, doi = {10.1074/jbc.270.45.26827}, pmid = {7592924}, issn = {0021-9258}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Cell Survival/*drug effects ; DNA/biosynthesis ; Dimercaprol/pharmacology ; Gene Expression/drug effects ; Glutathione/*metabolism ; Mitosis/drug effects ; Oxidation-Reduction ; PC12 Cells ; Rats ; Transcription, Genetic/drug effects ; }, abstract = {Our prior work established that comparable concentrations of N-acetylcysteine (NAC) both block the proliferation of PC12 cells and prevent death of trophic factor-deprived sympathetic neurons and PC12 cells. The present work addresses several aspects of the mechanisms of these actions. NAC increases intracellular levels of glutathione (GSH) by approximately 10-fold in PC12 cells. However, blockade of this increase by treatment with buthionine sulfoximine did not affect either promotion of survival or inhibition of DNA synthesis. Thus, these actions of NAC are independent of its effects on intracellular GSH. NAC's actions in our system do not appear to be dependent on its anti-oxidant/radical scavenger properties, but may be due to its activity as a reductant. Consistent with this, several other reducing agents, the most effective of which was 2,3-dimercaptopropanol, mimicked NAC in blocking DNA synthesis and suppressing death of PC12 cells and sympathetic neurons. Finally, we observed that in striking contrast to nerve growth factor and a number of other trophic agents, the survival-promoting effects of NAC on PC12 cells are blocked by actinomycin D. This suggests that NAC may act by inducing specific gene expression.}, }
@article {pmid11023411, year = {1995}, author = {Khalife, J and Godin, C and Capron, A}, title = {Transcriptional regulation of Schistosoma mansoni calreticulin: possible role of AP-1.}, journal = {Parasitology}, volume = {111 (Pt 4)}, number = {}, pages = {469-475}, doi = {10.1017/s0031182000065975}, pmid = {11023411}, issn = {0031-1820}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Base Sequence ; Calcium-Binding Proteins/biosynthesis/*genetics ; Calreticulin ; Cell Line ; *Gene Expression Regulation ; Genes, Reporter ; Humans ; Luciferases/biosynthesis/genetics ; Molecular Sequence Data ; Oxidants/pharmacology ; Promoter Regions, Genetic ; Protein Binding ; Recombinant Fusion Proteins/biosynthesis ; Ribonucleoproteins/biosynthesis/*genetics ; Schistosoma mansoni/*genetics ; T-Lymphocytes ; Transcription Factor AP-1/*metabolism ; *Transcription, Genetic ; Transfection ; }, abstract = {Little is known about the regulation and control of Schistosoma mansoni gene expression. In order to study such mechanisms a gene reporter expression vector construction, under the control of a promoter region derived from the S. mansoni calreticulin gene was used to transfect the human Jurkat T cell line. The promoter region contains potential TATA and CAAT boxes as well as an AP-1 core element. We show here that transcriptional factors of eucaryotic cells may induce a gene reporter activity under the control of a S. mansoni promoter region. Treatment of stably transfected cells with N-acetyl cysteine (NAC), a well-characterized antioxidant which counteracts the effects of reactive oxygen intermediates, enhanced the AP-1 dependent transactivation. This effect was abolished when the SmCaR promoter region was deleted in the AP-1 site. Electrophoretic Mobility Shift Assays showed that the AP-1 sequence of S. mansoni bound to both S. mansoni extracts and in nuclear extracts from Jurkat cells, thus explaining possible activation of AP-1 by NAC. Finally treatment of S. mansoni schistosomula and adult worms with NAC induced an increased synthesis of calreticulin protein suggesting a possible role of redox mechanisms in the regulation of a calreticulin gene transcription process in S. mansoni.}, }
@article {pmid8847091, year = {1995}, author = {Maes, RF}, title = {Detection of human IgG antibodies against free N-acetyl-L-cysteine.}, journal = {Immunology letters}, volume = {48}, number = {1}, pages = {49-52}, doi = {10.1016/0165-2478(95)02441-7}, pmid = {8847091}, issn = {0165-2478}, mesh = {Acetylcysteine/*immunology ; Autoantibodies/*isolation &amp; purification ; HIV Seropositivity/blood ; Humans ; Immunocompromised Host ; Immunoconjugates ; Immunoglobulin G/*isolation &amp; purification ; Nitric Oxide/immunology ; Sensitivity and Specificity ; Serum Albumin, Bovine ; Tuberculosis/immunology ; }, abstract = {Human antibodies of the IgG type reacting with free N-acetyl-cysteine are detectable with an appropriate immunoconjugate. Free cysteine, homocysteine and glutathione, but not cystine, interfere with the antibodies. The interference with cysteine and homocysteine is frequently reduced after nitrosylation of these amino acids. The interference with glutathione is frequently amplified after nitrosylation of this oligopeptide. The antibodies react weakly with whole red blood cells. Autoantibodies of this type may explain the wasting observed in untreated tuberculosis patients and in AIDS patients.}, }
@article {pmid8788130, year = {1995}, author = {van Leuken, RG and Duchateau, AL and Kwakkenbos, GT}, title = {Thermospray liquid chromatography/mass spectrometry study of diastereomeric isoindole derivatives of amino acids and amino acid amides.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {13}, number = {12}, pages = {1459-1464}, doi = {10.1016/0731-7085(95)01580-9}, pmid = {8788130}, issn = {0731-7085}, mesh = {Acetylcysteine ; Amino Acids/*analysis ; Chromatography, High Pressure Liquid ; Chromatography, Liquid ; Gas Chromatography-Mass Spectrometry ; Hydrolysis ; Indicators and Reagents ; Indoles/*analysis ; Spectrophotometry, Ultraviolet ; Stereoisomerism ; Temperature ; o-Phthalaldehyde ; }, abstract = {A thermospray liquid chromatography/mass spectrometry (TSP-LC/MS) method is described for determination of the enantiomeric excess of alpha-amino acids and alpha-amino acid amides as their o-phthalaldehyde/N-acetyl-L-cysteine (OPA/NAC) derivatives. The source temperature is an important factor in optimizing the sensitivity of the TSP-LC/MS analysis, whereas the repeller voltage is of minor importance. On-column mass spectra were acquired for the OPA/NAC derivatives of several alpha-amino acids and alpha-amino acid amides. For the main fragment ions, mass spectra fragmentation pathways are proposed. The applicability of the method is demonstrated by means of the enantiomeric excess determination of valine in a sample from an enzymatic hydrolysis experiment. Using single ion monitoring, the detection limit of D-valine in the presence of excess L-valine is 10 pmol. The present TSP-LC/MS method is useful for validating the results obtained from LC/UV or LC/fluorescence methods for the enantiomeric excess determination of alpha-amino acids and alpha-amino acid amides.}, }
@article {pmid8747803, year = {1995}, author = {Boesgaard, S}, title = {Thiol compounds and organic nitrates.}, journal = {Danish medical bulletin}, volume = {42}, number = {5}, pages = {473-484}, pmid = {8747803}, issn = {0907-8916}, mesh = {Animals ; Drug Interactions ; Drug Tolerance ; Hemodynamics/drug effects ; Nitrates/metabolism/*therapeutic use ; Substance-Related Disorders ; Sulfhydryl Compounds/*therapeutic use ; }, abstract = {Organic nitrates are widely used in the treatment of ischemic heart disease. The magnitude and duration of their circulatory and ischemic effects are, however, rapidly reduced during continuous treatment. The specific mechanisms underlying this tolerance development are not clear. According to the most widely accepted theory, tolerance is due to an intracellular depletion of thiol compounds (GSH and/or cysteine) involved in the conversion of nitrates to vasoactive intermediates. This presentation deals with aspects of in vivo thiol/nitrate interactions in different experimental and clinical conditions. The major results and conclusions are: The acute hypotensive effect of NTG is decreased by lowering of intracellular GSH levels. This finding emphasizes that normal intracellular thiol levels are required for optimal conversion of nitrates. Thus, intracellular GSH plays a critical role in the metabolism of NTG. Despite development of tolerance to the hypotensive effect of NTG, arterial and venous thiol levels are similar in nitrate tolerant and non-tolerant animals, suggesting that depletion of vascular thiol compounds may not be the cause of nitrate tolerance in vivo. The effect of exogenous thiol administration on intravascular thiol levels are different in nitrate tolerant and non-tolerant conscious rats. Exogenous thiol compounds (e.g. NAC) augments the hypotensive effect of NTG by a tolerance nonspecific mechanism. This effect is most likely mediated by an extracellular and/or membrane-related nitrate/thiol interaction and formation of NO. N-acetylcysteine inhibits angiotensin converting enzyme and counteracts nitrate-induced stimulation of the renin angiotensin system in vivo. Therefore, in addition to an effect on nitrate metabolism, thiol compounds may modify tolerance development by attenuating nitrate-induced counter-regulatory mechanisms. In the clinical setting, co-administration of NAC and ISDN delays and partially prevents tolerance to the antianginal and antiischemic effects normally seen in patients with stable angina pectoris during treatment with ISDN. N-acetylcysteine treatment in humans, potentiates and preserves nitrate induced venodilation and augments the effect of nitrates on small resistance vessels without affecting the response to nitrates in larger sized arteries. Thus, administration of NAC may change the normal vasodilator profile of nitrates. In conclusion, changes in cellular thiol levels may modify the hemodynamic effect of organic nitrates and the cellular handling of thiols and/or thiol related enzymes is altered after development of nitrate tolerance. In addition, a tolerance unrelated thiol/nitrate interaction, potentiating the effect of nitrates, may occur after administration of exogenous thiol compounds. In the clinical setting administration of thiols results in a characteristic change in the vasodilator profile of nitrates and an attenuation of the nitrate-induced stimulation of the renin-angiotensin system. The combination of these effects probably contributes to the improvement in antianginal and antiischemic parameters which may be seen during continuous and prolonged treatment with nitrates and thiol compounds.}, }
@article {pmid8585668, year = {1995}, author = {Rumbeiha, WK and Lin, YS and Oehme, FW}, title = {Comparison of N-acetylcysteine and methylene blue, alone or in combination, for treatment of acetaminophen toxicosis in cats.}, journal = {American journal of veterinary research}, volume = {56}, number = {11}, pages = {1529-1533}, pmid = {8585668}, issn = {0002-9645}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*therapeutic use ; Animals ; Antidotes/*therapeutic use ; *Cat Diseases ; Cats ; Drug Therapy, Combination ; Female ; Humans ; Liver Failure/chemically induced/mortality/veterinary ; Male ; Methylene Blue/*therapeutic use ; Poisoning/*veterinary ; Sex Characteristics ; }, abstract = {Acetaminophen is widely used in human beings for analgesic purposes, but is one of the most frequent causes of poisoning in cats. Acetaminophen-poisoned cats develop methemoglobinemia and sometimes hepatic failure. To determine the benefit of using methylene blue, a treatment for methemoglobinemia, along with N-acetylcysteine (NAC), the recommended treatment for acetaminophen-poisoned cats, groups of 3 male and 3 female cats each were given methylene blue NAC, or both after administration of acetaminophen (120 mg/kg of body weight, PO). Male cats seemed more susceptible than female cats to acetaminophen toxicosis, because 3 males died of hepatic failure (2 cats given acetaminophen/methylene blue and 1 given acetaminophen/NAC/methylene blue). Although NAC alone seemed to elicit the best overall response, methylene blue, alone or in combination with NAC, may be useful in female cats.}, }
@article {pmid8583705, year = {1995}, author = {Hoshikawa, Y and Ono, S and Tanita, T and Sakuma, T and Noda, M and Tabata, T and Ueda, S and Ashino, Y and Fujimura, S}, title = {[Contribution of oxidative stress to pulmonary hypertension induced by chronic hypoxia].}, journal = {Nihon Kyobu Shikkan Gakkai zasshi}, volume = {33}, number = {11}, pages = {1168-1173}, pmid = {8583705}, issn = {0301-1542}, mesh = {Acetylcysteine/pharmacology ; Animals ; Chronic Disease ; Free Radical Scavengers/pharmacology ; Hypertension, Pulmonary/etiology/*metabolism ; Hypoxia/*complications ; Male ; *Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Chronic hypoxia causes pulmonary hypertension and right ventricular hypertrophy associated with media wall thickening of pulmonary arteries in rats. Platelet-activating factor plays an important role in the pulmonary vascular remodeling induced by chronic hypoxia, and reactive oxygen species are involved in tissue injury induced by platelet activating factor. We therefore hypothesized that reactive oxygen species contribute to the pulmonary hypertension induced by chronic hypoxia, and examined the effect of N-acetyl-L-cysteine (NAC), a free radical scavenger and the precursor of glutathione sulfhydryl (GSH), on hypoxia-induced pulmonary hypertension. We used a chemiluminescence-HPLC assay to measure the levels of phosphatidylcholine hydroperoxide (PCOOH) in the rat lungs exposed to hypoxia. Three weeks of normobaric hypoxia (FiO2 = 0.1) with NAC significantly reduced pulmonary hypertension, right ventricular hypertrophy, and media wall thickening of the pulmonary arteries. NAC had no effect on the hematocrit of normoxic or chronically normobaric hypoxic rats. Lung PCOOH levels were significantly higher in the hypoxic rats than in the control rats, and those in the NAC-treated rats were significantly lower than those in the hypoxic rats that were not given NAC. Lung PCOOH levels were significantly higher in the hypoxic rats than in the control rats, and those in the NAC-treated rats were significantly lower than those in the hypoxic rats that were not given NAC. These results indicate that hypoxia induces oxidative stress in the lung tissue, and that oxidative stress may have a role in the development of pulmonary hypertension induced by chronic hypoxia in rats.}, }
@article {pmid7593644, year = {1995}, author = {Bellas, RE and Lee, JS and Sonenshein, GE}, title = {Expression of a constitutive NF-kappa B-like activity is essential for proliferation of cultured bovine vascular smooth muscle cells.}, journal = {The Journal of clinical investigation}, volume = {96}, number = {5}, pages = {2521-2527}, pmid = {7593644}, issn = {0021-9738}, support = {CA 36355/CA/NCI NIH HHS/United States ; HL 13262/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Cattle ; Cell Division ; Cells, Cultured ; Cytomegalovirus/*genetics ; Gene Expression Regulation, Viral ; Molecular Sequence Data ; Muscle, Smooth, Vascular/*cytology/*metabolism ; NF-kappa B/*biosynthesis/genetics ; Promoter Regions, Genetic/genetics ; Transfection ; }, abstract = {We have recently discovered bovine and human vascular smooth muscle cells (SMCs) express a novel constitutive Nuclear Factor-kappa B (NF-kappa B)/Rel-like activity (Lawrence, R., L.-J. Chang, U. Siebenlist, P. Bressler, and G.E. Sonenshein. 1994. J. Biol. Chem. 269:28913-28918), here termed SMC-Rel. Since cytomegalovirus (CMV) infection of human vascular SMCs has been implicated in aberrant SMC proliferation during post-angioplasty restenosis, we tested the role of NF-kappa B/Rel activity in transactivation of the CMV immediate early (ie) promoter. The basal CMV ie promoter linked to three wild-type, but not mutant, copies of its NF-kappa B element was active in bovine aortic SMCs. The anti-oxidants N-acetyl cysteine (NAC) or pentoxifylline (PTX), which are used clinically to reduce NF-kappa B/Rel activity, inhibited NF-kappa B driven promoter transactivation, and SMC-Rel binding activity. Treatment with either NAC or PTX was observed to slow the growth of the SMCs in a dose dependent fashion. Microinjection of either purified I kappa B-alpha, a naturally occurring specific inhibitor of NF-kappa B/Rel activity, or double-stranded oligonucleotides harboring wild type, but not non-binding mutants of NF-kappa B elements selectively inhibited SMC proliferation. Thus constitutive NF-kappa B/Rel activity appears essential for proliferation of vascular SMCs and might be a novel target for therapeutic intervention for restenosis.}, }
@article {pmid7588208, year = {1995}, author = {Kwon, G and Corbett, JA and Rodi, CP and Sullivan, P and McDaniel, ML}, title = {Interleukin-1 beta-induced nitric oxide synthase expression by rat pancreatic beta-cells: evidence for the involvement of nuclear factor kappa B in the signaling mechanism.}, journal = {Endocrinology}, volume = {136}, number = {11}, pages = {4790-4795}, doi = {10.1210/endo.136.11.7588208}, pmid = {7588208}, issn = {0013-7227}, support = {DK-06181/DK/NIDDK NIH HHS/United States ; T32-DK007296/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; Base Sequence ; Ditiocarb/pharmacology ; Enzyme Activation ; Enzyme Inhibitors/pharmacology ; *Gene Expression ; Genistein ; Insulinoma ; Interleukin-1/*pharmacology ; Islets of Langerhans/*enzymology/ultrastructure ; Isoflavones/pharmacology ; Male ; Molecular Sequence Data ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Nitric Oxide Synthase/*genetics ; Pancreatic Neoplasms ; Protein-Tyrosine Kinases/antagonists &amp; inhibitors/metabolism ; Rats ; Rats, Sprague-Dawley ; *Signal Transduction ; Tumor Cells, Cultured ; }, abstract = {Recent evidence indicates that overproduction of nitric oxide mediates cytokine-induced inhibition of insulin secretion by pancreatic islets. The current studies were designed to characterize signaling events involving the transcriptional factor NFkappaB in interleukin-1 (IL-1)-induced expression of inducible nitric oxide synthase (iNOS) by primary and transformed rat pancreatic beta-cells. Due to limitations of cell numbers of purified primary beta-cells, biochemical and molecular studies were performed primarily using the insulinoma cell line, RINm5F. Inhibitors of NFkappaB, diethyldithiocarbamate, pyrrolidine dithiocarbamate, and N-acetyl cysteine prevent IL-1-induced iNOS expression at the level of messenger RNA, protein, and nitrite generation. IL-1 induces a time-dependent translocation of NFkappaB from cytosol to nucleus, with maximal translocation observed approximately 15-30 min after IL-1 treatment, as determined by electrophoretic mobility shift assays. The specificity of the band containing the NF kappa B DNA-protein complex was shown by competition with a 150-fold excess of nonradiolabeled NF kappa B oligonucleotide. Supershift assays using immunoglobulins G against NF kappa b subunits p50 an p65 indicate that the protein complex contains a heterodimer of p50 and p65. IL-1-induced translocation of NF kappa B was blocked by 100 microns 100 microM diethyldithiocarbamate or 100 microM pyrrolidine dithiocarbamate, further establishing a critical role for NF kappa B in the induction of iNOS by IL-1 in rat pancreatic beta-cells. Activation of tyrosine kinase appears to precede NF kappa B activation, as the tyrosine kinase inhibitor genistein (100 microM) blocks IL-1-induced translocation of NF kappa B. An understanding of the signal transduction pathway of cytokine-induced nitric oxide generation by beta-cells will provide strategies of intervention to further evaluate the role of nitric oxide in mediating beta-cell dysfunction.}, }
@article {pmid7491977, year = {1995}, author = {Das, KC and Lewis-Molock, Y and White, CW}, title = {Activation of NF-kappa B and elevation of MnSOD gene expression by thiol reducing agents in lung adenocarcinoma (A549) cells.}, journal = {The American journal of physiology}, volume = {269}, number = {5 Pt 1}, pages = {L588-602}, doi = {10.1152/ajplung.1995.269.5.L588}, pmid = {7491977}, issn = {0002-9513}, support = {1 P50 HL-46481/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Base Sequence ; Dithiothreitol/metabolism ; Gene Expression Regulation, Enzymologic/*drug effects ; Humans ; Hydrogen Peroxide/metabolism ; Mercaptoethanol/metabolism ; Molecular Probes/genetics ; Molecular Sequence Data ; NF-kappa B/*physiology ; Oxidation-Reduction ; Rats ; Reactive Oxygen Species/metabolism ; Sulfhydryl Compounds/metabolism/*pharmacology ; Superoxide Dismutase/*genetics ; Transcription Factor AP-1/physiology ; Tumor Cells, Cultured ; }, abstract = {The effect of reducing agents, including N-acetylcysteine (NAC), dithiothreitol (DTT), and 2-mercaptoethanol (2-ME) on nuclear transcription factor-kappa B (NF-kappa B) activation and manganese superoxide dismutase (MnSOD) expression was investigated in a pulmonary adenocarcinoma (A549) cell line. NAC, DTT, and 2-ME each activated the transcription factor NF-kappa B and increased steady-state levels of MnSOD mRNA and enzyme activity in these cells. In addition, NAC, DTT, and 2-ME increased chloramphenicol acetyltransferase (CAT) activity in cells transfected with a construct containing the CAT gene under the control of the rat MnSOD promoter. SOD and catalase (500 U/ml) plus ethanol (1 mM) did not inhibit activation of NF-kappa B or elevation of steady-state MnSOD mRNA levels by NAC, DTT, or 2-ME. Controls in which comparable amounts of O2-. to those produced by thiols were generated by hypoxanthine and xanthine oxidase, or in which H2O2 was added directly, had neither activated NF-kappa B nor elevated MnSOD mRNA. This shows that reactive oxygen intermediates, which may be formed during autooxidation, may not contribute to activation of NF-kappa B. Because the MnSOD promoter also contains potential binding sites for other transcription factors, such as promoter-selective transcription factor-1 (SP-1), activator protein-1 (AP-1), AP-2, adenosine 3',5'-cyclic monophosphate-regulator element binding factor (CREB), and transcription factor IID complex (TFIID), the effect of thiols on their activation also were evaluated. In contrast to findings with NF-kappa B, there was only minor activation of AP-1 by thiols, and none of the other transcription factors were activated by thiols. AP-1 activation was inhibited by catalase (500 U/ml) plus SOD plus ethanol (1 mM). Addition of 700 microM H2O2 also activated AP-1, and catalase at 500 U/ml prevented this activation. This indicates that H2O2 produced as a result of autooxidation of thiols can activate AP-1 but not NF-kappa B. Thus a close association between exposure to reducing agents, activation of NF-kappa B, and elevation of MnSOD gene expression is demonstrated.}, }
@article {pmid7473856, year = {1995}, author = {Manautou, JE and Khairallah, EA and Cohen, SD}, title = {Evidence for common binding of acetaminophen and bromobenzene to the 58-kDa acetaminophen-binding protein.}, journal = {Journal of toxicology and environmental health}, volume = {46}, number = {3}, pages = {263-269}, doi = {10.1080/15287399509532034}, pmid = {7473856}, issn = {0098-4108}, support = {ES07163/ES/NIEHS NIH HHS/United States ; GM31460/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*metabolism ; Animals ; Bromobenzenes/administration &amp; dosage/*metabolism ; Carrier Proteins/*metabolism ; Liver/*metabolism ; Male ; Mice ; Mice, Inbred ICR ; Molecular Weight ; Selenium-Binding Proteins ; }, abstract = {Acetaminophen (APAP) toxicity has been closely associated with covalent binding to a cytosolic protein of approximately 58 kDa (58-ABP). To determine if metabolites of other toxicants might also selectively target this protein, studies were conducted with bromobenzene (BrB). Mice were given phenobarbital (80 mg/kg/d x 4 d) and were killed 4 h after challenge with 800 mg BrB/kg. Liver cytosols from BrB-treated or naive mice were incubated with an APAP activating system. Cytosolic fractions were analyzed for APAP binding by Western blotting with anti-APAP antibody. Binding to 58-ABP was selectively decreased in liver cytosol from BrB-treated mice while binding to other targets was minimally affected. Western blotting of the same samples with anti-58-ABP antisera showed that this decrease in binding did not result from diminished 58-ABP content. HPLC analysis of APAP-N-acetyl cysteine conjugate formation in vitro indicates that APAP activation was not altered in the incubates with cytosol from BrB-treated mice. These results suggest that the 58-ABP may be a common target for electrophiles in reactive intermediate toxicity.}, }
@article {pmid7592595, year = {1995}, author = {Ren, Y and Smith, A}, title = {Mechanism of metallothionein gene regulation by heme-hemopexin. Roles of protein kinase C, reactive oxygen species, and cis-acting elements.}, journal = {The Journal of biological chemistry}, volume = {270}, number = {41}, pages = {23988-23995}, doi = {10.1074/jbc.270.41.23988}, pmid = {7592595}, issn = {0021-9258}, support = {DK-37463/DK/NIDDK NIH HHS/United States ; }, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; Animals ; Base Sequence ; Carcinoma, Hepatocellular ; Cell Line ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation/*drug effects ; Heme/*pharmacology ; Hemopexin/isolation &amp; purification/*pharmacology ; Hydrogen Peroxide/pharmacology ; Isoquinolines/pharmacology ; Kinetics ; Liver Neoplasms ; Metallothionein/*biosynthesis/*genetics ; Mice ; Molecular Sequence Data ; Piperazines/pharmacology ; *Promoter Regions, Genetic ; Protein Kinase C/antagonists &amp; inhibitors/*metabolism ; RNA, Messenger/analysis/biosynthesis ; Rabbits ; Reactive Oxygen Species/*pharmacology ; Sequence Deletion ; *Sulfonamides ; Tetradecanoylphorbol Acetate/pharmacology ; Transcription, Genetic/drug effects ; Tumor Cells, Cultured ; Xanthine ; Xanthines/pharmacology ; }, abstract = {Heme-hemopexin or cobalt protoporphyrin (CoPP)-hemopexin (a model ligand for hemopexin receptor occupancy) is shown to increase transcription of the metallothionein-1 (MT-1) gene by activation of a signaling pathway. Promoter deletion analysis followed by transient transfection assays show that 110 base pairs (-153 to -43) of 5'-flanking region of the murine MT-1 promoter are sufficient for increasing transcription in response to heme-hemopexin or to CoPP-hemopexin in mouse hepatoma cells. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), prevented the increase in MT-1 transcription by heme-hemopexin, CoPP-hemopexin, or phorbol 12-myristate 13-acetate, but the protein kinase A inhibitor, HA1004, was without effect. N-Acetylcysteine (NAC) and glutathione, as well as superoxide dismutase and catalase, inhibited both the increase in endogenous MT-1 mRNA and the activation of reporter gene activity by heme-hemopexin, CoPP-hemopexin, and phorbol 12-myristate 13-acetate. In sum, these data suggest that reactive oxygen intermediates are generated by heme-hemopexin via events associated with receptor binding, including protein kinase C activation. Induction of heme oxygenase-1 expression, in contrast to MT-1, is significantly less sensitive to NAC. Deletion and mutation analyses of the MT-1 proximal promoter revealed that the sequence 5'-GTGACTATGC-3' (from -98 to -89 base pairs) is, in part, responsible for the hemopexin-mediated regulation of MT-1 which is inhibited by H7. Regulation via this element is also induced by H2O2 showing that it is an antioxidant response element. Heme itself acts via more distal elements on the MT-1 promoter. In contrast to NAC and glutathione, diethyl dithiocarbamate and pyrrolidine dithiocarbamate, which inactivate reactive oxygen intermediates and chelate Zn(II), synergistically augment the induction of MT-1 mRNA levels and reporter gene activity in response to heme-hemopexin via the antioxidant response element by both metal-responsive element-dependent and -independent mechanisms.}, }
@article {pmid7487999, year = {1995}, author = {Mass, H and Pirazzi, B and Gonzalez, P and Collazo, V and Fitzovich, D and Avakian, E}, title = {N-acetylcysteine diminishes injury induced by balloon angioplasty of the carotid artery in rabbits.}, journal = {Biochemical and biophysical research communications}, volume = {215}, number = {2}, pages = {613-618}, doi = {10.1006/bbrc.1995.2508}, pmid = {7487999}, issn = {0006-291X}, support = {RR 03050/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Angioplasty, Balloon, Coronary/*adverse effects ; Animals ; Carotid Arteries/drug effects/pathology ; *Carotid Artery Injuries ; Female ; Male ; Rabbits ; }, abstract = {The effect of N-acetylcysteine (NAC) on preventing or ameliorating the injury associated with percutaneous transluminal angioplasty was investigated in rabbits. Carotid artery angioplasty (CA) was performed on 8 control (vehicle-treated) rabbits and 7 rabbits treated with NAC, 250 mg/kg, administered orally in Nutrical paste for 10 days prior to and 10 days following CA. Single blind histologic evaluation of the angioplasty sites demonstrated a significant reduction in the incidence in vessel: 1) inflammation; 2) endothelial damage; 3) thrombus formation; 4) elastic lamina damage in the NAC rabbits. The percentage of control versus NAC treated animals exhibiting damage in each category were: inflammation: 75% vs 14%; endothelial damage: 88% vs 57%; thrombus formation: 88% vs 43%; laminal damage: 63% vs 14%. The results suggest that NAC treatment may be a valuable therapeutic agent in effectively preventing or reducing angioplasty-induced vessel damage.}, }
@article {pmid11361419, year = {1995}, author = {}, title = {NAC found to be ineffective.}, journal = {AIDS patient care}, volume = {9}, number = {5}, pages = {259}, pmid = {11361419}, issn = {0893-5068}, mesh = {Acetylcysteine/adverse effects/*pharmacology ; Acquired Immunodeficiency Syndrome/*drug therapy ; Complementary Therapies ; Humans ; }, }
@article {pmid8847707, year = {1995}, author = {Thielemann, LE and Rodrigo, RA and Oberhauser, EW and Rosenblut, G and Videla, LA}, title = {N-acetyl-L-cysteine abolishes the bromoethylamine-induced choline incorporation into renal papillary tissue.}, journal = {Journal of biochemical toxicology}, volume = {10}, number = {5}, pages = {251-257}, doi = {10.1002/jbt.2570100505}, pmid = {8847707}, issn = {0887-2082}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Choline/*metabolism ; Ethylamines/*antagonists &amp; inhibitors/toxicity ; Female ; Free Radical Scavengers/*pharmacology ; Kidney Medulla/drug effects/*metabolism/pathology ; Lysophosphatidylcholines/metabolism ; Membranes/drug effects/metabolism ; Necrosis ; Phosphatidylcholines/metabolism ; Rats ; Rats, Sprague-Dawley ; Regeneration/drug effects ; Sphingomyelins/metabolism ; }, abstract = {The role of regenerative processes in the protective effect of N-acetyl-L-cysteine (NAC) against bromoethylamine-induced renal papillary necrosis was assessed in rats given bromoethylamine (BEA)(1.2 mmol/kg), N-acetylcysteine (6 mmol/kg), or N-acetyl-cysteine plus BEA. Renal papillary slices were dissected after 15 hours of treatment, and 14C-choline incorporation into total phospholipid, lysophosphatidylcholine, sphingomyelin, and phosphatidylcholine was measured. Bromoethylamine elicited an increase in the incorporation of 14C-choline into choline-containing phospholipid, an effect that was abolished when N-acetylcysteine was administered prior to bromoethylamine. These studies indicate that the defensive mechanism of N-acetylcysteine against bromoethylamine-induced renal papillary necrosis is not related to regenerative processes and that N-acetylcysteine abolishes the bromoethylamine-induced choline incorporation into papillary phospholipid.}, }
@article {pmid8801863, year = {1995}, author = {Toborek, M and Barger, SW and Mattson, MP and McClain, CJ and Hennig, B}, title = {Role of glutathione redox cycle in TNF-alpha-mediated endothelial cell dysfunction.}, journal = {Atherosclerosis}, volume = {117}, number = {2}, pages = {179-188}, doi = {10.1016/0021-9150(95)05568-h}, pmid = {8801863}, issn = {0021-9150}, support = {P42 ES007380/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine ; Calcium/metabolism ; Cell Membrane Permeability ; Endothelium, Vascular/*metabolism/physiology ; Glutathione/*metabolism ; Lipid Peroxides/metabolism ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Oxidation-Reduction ; Swine ; Tumor Necrosis Factor-alpha/pharmacology/*physiology ; }, abstract = {Modulation of the glutathione redox cycle may influence tumor necrosis factor-alpha (TNF)-mediated disturbances of endothelial integrity. To test this hypothesis, normal endothelial cells or cells with either increased or decreased glutathione levels were exposed to 100 ng (500 U) TNF/ml. Increased glutathione levels were achieved by exposure to 0.2 mM N-acetyl-L-cysteine (NAC) and decreased glutathione levels by exposure to 25 microM buthionine sulfoximine (BSO). Several components of the glutathione redox cycle as well as markers of endothelial integrity, such as cytoplasmic free calcium and transendothelial albumin transfer, were measured in the treated cells. Exposure to TNF for 3 and 6 h decreased total glutathione levels, which was followed by an increase at later time points. Moreover, treatment with TNF resulted in an increase in the ratio of oxidized to reduced glutathione, intracellular free calcium, albumin transfer across endothelial monolayers and lipid hydroperoxides. However, an increase in lipid hydroperoxides was seen only when endothelial cell cultures were supplemented with iron. BSO treatment increased susceptibility of endothelial cells to TNF-mediated metabolic disturbances. On the other hand, NAC partially protected against TNF-induced injury to endothelial monolayers. Our results demonstrate the important role of the glutathione redox cycle in TNF-mediated disturbances of the vascular endothelium and indicate that modulation of glutathione levels may potentiate the injurious effects of this inflammatory cytokine.}, }
@article {pmid8584524, year = {1995}, author = {Jaworska, M and Gillissen, A and Schärling, B and Wickenburg, D and Schultze-Werninghaus, G}, title = {[N-acetylcysteine: a functional oxygen radical scavenger in vitro and ex vivo in monocytes and neutrophilic granulocytes of patients with COPD].}, journal = {Pneumologie (Stuttgart, Germany)}, volume = {49}, number = {10}, pages = {539-545}, pmid = {8584524}, issn = {0934-8387}, mesh = {Acetylcysteine/*therapeutic use ; Cells, Cultured ; Dose-Response Relationship, Drug ; Free Radical Scavengers/*therapeutic use ; Free Radicals ; Glutathione/therapeutic use ; Humans ; Lung Diseases, Obstructive/*drug therapy/immunology ; Monocytes/*drug effects/immunology ; Neutrophils/*drug effects/immunology ; Reactive Oxygen Species/*metabolism ; }, abstract = {In order to develop an efficient antioxidant therapeutic regime for inflammatory disease in the lung N-acetylcysteine (NAC) and reduced glutathione (GSH) were tested to inhibit O2 and H2O2 in vitro and ex vivo. NAC and GSH inhibited both at > or equal to 10(-4)M significantly H2O2 (5 x 10(-8)) mol/ml; p < 0.05). In contrast, in an assay consisting of xanthine/xanthine oxidase/ferricytochrome c Cu++/Zn++ superoxide dismutase (SOD), but not NAC and GSH had an anti-O2 effect (SOD: at > or equal to 10(-5)M, p < 0.01 when compared with 0). In accordance with these results, NAC and GSH had good anti-H2O2 efficacy in freshly isolated and ex vivo cultured mononuclear (MN) and polymorphonuclear cells (PMN) derived from patients with COPD (smoker, n = 30). Both drugs reduced H2O2 significantly when used in concentrations already at > or equal to 10(-9)M (p < 0.05). However, neither GSH nor NAC influenced O2 produced by these inflammatory cells effectively. Antioxidative properties of NAC are well explained by the SH-group within the molecular structure which can be oxidized by certain oxygen radicals. Good H2O2 scavenger function ex vivo, which seems to contradict the results obtained in vitro, illustrates additional cellular GSH-precursor efficacy of both substances in cell dependent assay systems. Thus, to achieve direct anti-H2O2 efficacy in vivo high local NAC concentrations (10(-4)M)) are necessary.}, }
@article {pmid7590404, year = {1995}, author = {Pace, GW and Leaf, CD}, title = {The role of oxidative stress in HIV disease.}, journal = {Free radical biology &amp; medicine}, volume = {19}, number = {4}, pages = {523-528}, doi = {10.1016/0891-5849(95)00047-2}, pmid = {7590404}, issn = {0891-5849}, mesh = {Antioxidants ; HIV/physiology ; *HIV Infections/etiology/immunology/metabolism/virology ; Humans ; *Oxidative Stress ; Virus Replication ; }, abstract = {Evidence has accumulated suggesting that HIV-infected patients are under chronic oxidative stress. Perturbations to the antioxidant defense system, including changes in levels of ascorbic acid, tocopherols, carotenoids, selenium, superoxide dismutase, and glutathione, have been observed in various tissues of these patients. Elevated serum levels of hydroperoxides and malondialdehyde also have been noted and are indicative of oxidative stress during HIV infection. Indications of oxidative stress are observed in asymptomatic HIV-infected patients early in the course of the disease. Oxidative stress may contribute to several aspects of HIV disease pathogenesis, including viral replication, inflammatory response, decreased immune cell proliferation, loss of immune function, apoptosis, chronic weight loss, and increased sensitivity to drug toxicities. Glutathione may play a role in these processes, and thus, agents that replete glutathione may offer a promising treatment for HIV-infected patients. Clinical studies are underway to evaluate the efficacy of the glutathione-repleting agents, L-2-oxothiazolidine-4-carboxylic acid (OTC) and N-acetylcysteine (NAC), in HIV-infected patients.}, }
@article {pmid7573115, year = {1995}, author = {Pacht, ER and Abernathy, F}, title = {Prevention of intracellular adenosine triphosphate depletion after sublethal oxidant injury to rat type II alveolar epithelial cells with exogenous glutathione and N-acetylcysteine.}, journal = {The American journal of the medical sciences}, volume = {310}, number = {4}, pages = {133-137}, doi = {10.1097/00000441-199510000-00001}, pmid = {7573115}, issn = {0002-9629}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/*metabolism ; Animals ; Glutathione/*pharmacology ; Hydrogen Peroxide/*toxicity ; Hypochlorous Acid/*toxicity ; Male ; Pulmonary Alveoli/*metabolism ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The alveolar epithelial cells of the lower respiratory tract are exposed continuously to injurious agents, including oxygen radicals. The type II alveolar epithelial cell is critically important to the normal function of the lung, because it is responsible for synthesis of surfactant and other essential duties. In the current investigation, the authors documented the loss of intracellular adenosine triphosphate (ATP) after exposure of the cells to sublethal concentrations of hydrogen peroxide (H2O2) and hypochlorous acid. Subsequent experiments attempted to alleviate or prevent this oxidant mediated loss of ATP by preincubating the cells with either glutathione or N-acetylcysteine (NAC). Initially, it was determined that exposure of the type II cells to 250 microM hypochlorous acid or 250 microM H2O2 for 1 hour each would cause significant loss of type II cell ATP. However, preincubation with glutathione (1,000 microM) inhibited the loss of ATP after both exposure to 250 microM H2O2 (24 +/- 3% loss of ATP without glutathione compared with 13 +/- 2% loss with glutathione, P < 0.05), and 250 microM hypochlorous acid (12 +/- 2% loss of ATP without glutathione compared with 1 +/- 1% increase of ATP with glutathione). Similar results were obtained using NAC (2 mg/mL) after exposure to 250 microM H2O2 (23 +/- 2% loss of ATP without NAC compared with a 4 +/- 3% loss of ATP with NAC). This study demonstrates that exogenous glutathione and NAC are able to protect type II cells from oxidant mediated sublethal injury and loss of intracellular ATP stores.}, }
@article {pmid7501621, year = {1995}, author = {Staikowsky, F and Uzan, D and Grillon, N and Pevirieri, F and Hafi, A and Michard, F}, title = {[Voluntary drug poisoning cases admitted to an emergency care unit].}, journal = {Presse medicale (Paris, France : 1983)}, volume = {24}, number = {28}, pages = {1296-1300}, pmid = {7501621}, issn = {0755-4982}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Analgesics/*toxicity ; Anti-Anxiety Agents/*toxicity ; Anticonvulsants/*toxicity ; Benzodiazepines ; Charcoal/therapeutic use ; Emergency Medicine ; Female ; Gastric Lavage/methods ; Humans ; Male ; Middle Aged ; Poisoning/*therapy ; Psychotropic Drugs/*toxicity ; Retrospective Studies ; Suicide, Attempted ; }, abstract = {OBJECTIVES: The aim of this study was to ascertain the specific nature of voluntary drug intoxications seen in emergency wards receiving adult patients.<br><br>METHODS: From July 1992 to June 1993, all patients presenting at the emergency room with voluntary drug intoxication were assessed retrospectively. There were 727 patients (482 females and 245 males, mean age 33.3 +/- 12 years, age range 15-92) admitted for 804 episodes of voluntary drug intoxication.<br><br>RESULTS: A past history of psychiatric problems or drug abuse was found in 42.8 and 9.1% of the patients respectively. The time laps between ingestion and consultation was noted for 43% (5 h 30 +/- 9 h, range 15-4320 min). The drug ingested was identified in 89% of the cases and 1.7 drugs were ingested per episode (range 1-8). Generally, only 1 (52%) or 2 (21%) drugs were ingested. Nonbarbituric psychotropic agents were ingested in 79.7% of the cases. Alcohol had also been consumed in 36.5% of the cases. Treatment was gastric lavage in 34.4%, activated carbon in 16.7%, flumazenil in 16.9%, naloxone and N-acetyl-cysteine in 3.4%. Twelve patients required intubation. Patients were admitted to a medical (n = 156) or psychiatric (n = 67) ward or an intensive care unit (n = 61). Nearly 25% of the patients left hospital either against medical advice or left without notice.<br><br>CONCLUSION: Voluntary drug intoxications seen in emergency rooms require care by a well coordinated team of clinicians and psychiatrists.}, }
@article {pmid8653090, year = {1995}, author = {Sokal, A and Walkowiak, B and Kałuzna, A and Król, K and Cieślak, M and Rychlik, B and Sychowski, R and Bartosz, G}, title = {Stimulation of erythrocyte membrane Mg(2+)-ATPase activity by glutathione S-conjugates.}, journal = {Biochemistry and molecular biology international}, volume = {37}, number = {1}, pages = {73-79}, pmid = {8653090}, issn = {1039-9712}, mesh = {Acetylcysteine/*analogs &amp; derivatives/chemical synthesis/pharmacology ; Adenosine Triphosphatases/drug effects/*metabolism ; Animals ; Chromatography, High Pressure Liquid ; Erythrocyte Membrane/*drug effects/*enzymology/metabolism ; Glutathione/*analogs &amp; derivatives/*pharmacology ; Kinetics ; Magnesium/*metabolism ; Solubility ; Structure-Activity Relationship ; Substrate Specificity ; Swine ; }, abstract = {Pig erythrocyte membrane Mg2+-ATPase activity was stimulated by various glutathione S-conjugates. For alkyl S-conjugates, the Km for the stimulation was lower, the more hydrophobic was the conjugate. 2,4-Dinitrophenyl-S-(N-acetyl)cysteine also stimulated the Mg2+-ATPase activity, suggesting a low specificity of the ¿glutathione S-conjugate pump¿. The Km values for the stimulation by 2,4-dinitrophenyl conjugates were lower than predictable on the basis of hydrophobicity which indicates a high affinity of the transporter for these conjugates.}, }
@article {pmid7665977, year = {1995}, author = {Seno, K and Joh, T and Yokoyama, Y and Itoh, M}, title = {Role of mucus in gastric mucosal injury induced by local ischemia/reperfusion.}, journal = {The Journal of laboratory and clinical medicine}, volume = {126}, number = {3}, pages = {287-293}, pmid = {7665977}, issn = {0022-2143}, mesh = {Acetylcysteine/pharmacology ; Alcian Blue ; Animals ; Chromium Radioisotopes ; Diterpenes/pharmacology ; Edetic Acid/metabolism ; Gastric Mucosa/*blood supply ; Hexosamines/metabolism ; *Ischemia ; Male ; Mucus/*physiology ; Periodic Acid-Schiff Reaction ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*physiopathology ; }, abstract = {The role of gastric mucus was evaluated in a rat model of gastric epithelial damage induced by local ischemia/reperfusion (I/R) stress. In this model, blood-to-lumen chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) clearance served as an index of injury. Tetraprenyl acetone (TPA; 100 mg, 200 mg/kg IP) was used to stimulate mucus production. Administration of TPA increased both the hexosamine content in gastric tissue and the amount of alcian blue-periodic acid Schiff (AB-PAS) stained mucus in the mucosa in a dose-dependent manner. Increases in 51Cr-EDTA clearance induced by I/R were significantly attenuated by TPA in a dose-dependent manner. N-acetyl-L-cysteine (NAC; 0.6%, 0.8%) was perfused into the gastric lumen to assess the effect of reduction in mucus on the injury induced by I/R. Although mean values of hexosamine content were increased by perfusion with NAC, AB-PAS-stained mucus in the mucosa was significantly decreased in a dose-dependent manner. Perfusion of NAC did not change basal 51Cr-EDTA clearance but significantly exacerbated the increase in clearance induced by I/R in a dose-dependent manner. These results indicate that gastric mucus protects the gastric mucosa against I/R stress in vivo.}, }
@article {pmid7664840, year = {1995}, author = {Cossarizza, A and Franceschi, C and Monti, D and Salvioli, S and Bellesia, E and Rivabene, R and Biondo, L and Rainaldi, G and Tinari, A and Malorni, W}, title = {Protective effect of N-acetylcysteine in tumor necrosis factor-alpha-induced apoptosis in U937 cells: the role of mitochondria.}, journal = {Experimental cell research}, volume = {220}, number = {1}, pages = {232-240}, doi = {10.1006/excr.1995.1311}, pmid = {7664840}, issn = {0014-4827}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Benzimidazoles ; Carbocyanines ; Cycloheximide/pharmacology ; DNA Damage ; Flow Cytometry ; Fluorescent Dyes ; Homeostasis ; Humans ; Leukemia, Myelomonocytic, Acute ; Membrane Potentials ; Mitochondria/*physiology ; Monocytes/drug effects/ultrastructure ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {The existence of two different pathways for cell death has been postulated. In addition to the passive and traumatic process leading to necrosis, an active program characterized by organelle integrity and called apoptosis has been described. A positive correlation between the apoptotic cell death process and oxidative imbalance has been demonstrated. In fact, the antioxidant N-acetylcysteine (NAC) seems to be capable of impairing the apoptotic program, replenishing intracellular reduced glutathione content in cells exposed to tumor necrosis factor-alpha (TNF) as apoptotic inducer. Moreover, protein synthesis inhibitors such as cycloheximide (CHX) can facilitate apoptotic triggering by TNF, and mitochondrial function was suggested to be essential in the TNF-mediated apoptotic process. With this in mind, a specific analysis using the JC-1 probe, a fluorescent dye which is capable of indicating mitochondrial membrane potential (delta psi m) changes, was carried out. Our results show that TNF exposure is capable of altering the mitochondria and that NAC protection from CHX + TNF-induced apoptosis could be due to a direct effect of the drug on mitochondrial integrity and function.}, }
@article {pmid7663783, year = {1995}, author = {Meyer, A and Buhl, R and Kampf, S and Magnussen, H}, title = {Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals.}, journal = {American journal of respiratory and critical care medicine}, volume = {152}, number = {3}, pages = {1055-1060}, doi = {10.1164/ajrccm.152.3.7663783}, pmid = {7663783}, issn = {1073-449X}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Aged ; Bronchoalveolar Lavage Fluid/chemistry ; Case-Control Studies ; Epithelium/chemistry ; Female ; Glutathione/*analysis ; Humans ; Lung/*chemistry ; Male ; Middle Aged ; Pulmonary Fibrosis/*drug therapy ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) is characterized by a huge alveolar oxidant burden and a deficiency of glutathione, a major antioxidant, in the pulmonary epithelial lining fluid (ELF). Therefore, a rational therapeutic strategy is to increase lung glutathione to augment the pulmonary antioxidant protective screen. To evaluate this concept, different doses of N-acetylcysteine (NAC), a glutathione precursor, were administered intravenously to eight patients with pulmonary fibrosis and six control subjects. In patients, bronchoalveolar lavage fluid (BALF) total glutathione increased significantly from 0.99 +/- 0.25 microM to 1.79 +/- 0.37 microM within 3 h following 1.8 g NAC, whereas 4.8 g NAC had no additional effect (1.47 +/- 0.34 microM). In the control subjects, NAC did not significantly alter BALF total glutathione (baseline: 0.79 +/- 0.17 microM, 600 mg NAC: 0.92 +/- 0.33 microM, 1.8 g NAC: 1.39 +/- 0.41 microM, 4.8 g NAC: 1.33 +/- 0.46 microM). The same was true in ELF, 1.8 g NAC significantly raised ELF total glutathione in patients from 186 +/- 47 microM to near normal levels (373 +/- 103 microM), with no further increase following 4.8 g NAC (293 +/- 62 microM). In the control subjects, ELF total glutathione remained unchanged independent of the NAC dose (baseline: 342 +/- 91 microM, 600 mg NAC: 385 +/- 135 microM, 1.8 g NAC: 633 +/- 220 microM, 4.8 g NAC: 646 +/- 263 microM). The increases in total glutathione were almost entirely due to increased levels of reduced glutathione, the form functional as an antioxidant. No adverse effects were noted.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7557548, year = {1995}, author = {Bustamante, J and Slater, AF and Orrenius, S}, title = {Antioxidant inhibition of thymocyte apoptosis by dihydrolipoic acid.}, journal = {Free radical biology &amp; medicine}, volume = {19}, number = {3}, pages = {339-347}, doi = {10.1016/0891-5849(95)00045-y}, pmid = {7557548}, issn = {0891-5849}, mesh = {Animals ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Cell Survival ; Cells, Cultured ; Chromatin/drug effects/ultrastructure ; Etoposide/pharmacology ; Glutathione/analogs &amp; derivatives/metabolism ; Glutathione Disulfide ; Male ; Methylprednisolone/pharmacology ; Microscopy, Confocal ; Rats ; Rats, Sprague-Dawley ; Thioctic Acid/*analogs &amp; derivatives/pharmacology ; Thymus Gland/cytology/drug effects/*physiology ; }, abstract = {Recent findings suggest that intracellular oxidants are involved in the induction of apoptosis, and that this type of cell death can be inhibited by various thiol-containing antioxidants such as N-acetyl cysteine. To study the effects of a physiologically important thiol reductant, rat thymocytes were preincubated with either lipoic acid, dihydrolipoic acid, or lipoamide and then exposed to methylprednisolone or etoposide, two stimuli known to induce apoptosis in these cells. Dihydrolipoic acid and lipoamide both exerted an inhibitory effect on apoptosis induced by the two stimuli, while lipoic acid was inactive. Inhibition of apoptosis was evident as (a) reduced formation of condensed, pyknotic nuclei; (b) a prevention of cell shrinkage; and (c) decreased chromatin degradation. Furthermore, the depletion of reduced glutathione that occurs as thymocytes undergo apoptosis was also prevented in the presence of DHLA. Investigation of the pattern of chromatin fragmentation revealed that DNA in the antioxidant-loaded thymocytes remained above 50 kb pairs in size, indicating that inhibition by DHLA was operative at an early step in the apoptotic pathway. These results suggest that intracellular oxidation is an obligate, early component of thymocyte apoptosis.}, }
@article {pmid7554060, year = {1995}, author = {McLellan, LI and Lewis, AD and Hall, DJ and Ansell, JD and Wolf, CR}, title = {Uptake and distribution of N-acetylcysteine in mice: tissue-specific effects on glutathione concentrations.}, journal = {Carcinogenesis}, volume = {16}, number = {9}, pages = {2099-2106}, doi = {10.1093/carcin/16.9.2099}, pmid = {7554060}, issn = {0143-3334}, mesh = {Acetylcysteine/*pharmacokinetics/pharmacology ; Animals ; Bone Marrow/drug effects/metabolism ; Bone Marrow Cells ; Carbon Radioisotopes ; Glutathione/*metabolism ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred CBA ; Tissue Distribution ; Urinary Bladder/drug effects/metabolism ; }, abstract = {Modulation of cellular thiols has been used to ameliorate the toxic side effects associated with cancer chemotherapy and is currently being investigated as a novel therapeutic strategy in cancer treatment. One of the most extensively studied modulators of thiol levels is N-acetylcysteine (NAC), a cytoprotective drug with multiple therapeutic applications, including use as an adjunct to cancer chemotherapy. Tissue-specific protective effects have previously been observed when NAC has been used in conjunction with chemotherapeutic alkylating agents, but the basis for this was unknown. In view of the contrasting cytoprotective effects of NAC in bladder and bone marrow we examined the effect of this compound on mouse liver, bladder and bone marrow glutathione (GSH) levels, as well as the disposition of 14C-labelled NAC. Radiolabelled NAC was taken up by the majority of tissues at varying rates and levels, except for the brain and spinal cord. The bladder, bone marrow and liver all took up the drug or its metabolites within 15 min of injection. NAC was not found to alter GSH concentrations in the liver, but increased GSH levels in the bladder approximately 2-fold. In contrast, the GSH content of bone marrow was found to decrease by 70-50% after NAC administration. When separate bone marrow cell populations were examined the decrease in GSH was associated with granulocytes, as opposed to lymphocytes, whose GSH levels remained unchanged. These findings provide a possible explanation for the differential cytoprotective effects of NAC.}, }
@article {pmid7547057, year = {1995}, author = {Bromley, PN and Cottam, SJ and Hilmi, I and Tan, KC and Heaton, N and Ginsburg, R and Potter, DR}, title = {Effects of intraoperative N-acetylcysteine in orthotopic liver transplantation.}, journal = {British journal of anaesthesia}, volume = {75}, number = {3}, pages = {352-354}, doi = {10.1093/bja/75.3.352}, pmid = {7547057}, issn = {0007-0912}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Antioxidants/therapeutic use ; Blood Pressure/drug effects ; Cardiac Output/drug effects ; Double-Blind Method ; Free Radical Scavengers/*therapeutic use ; Graft Rejection/prevention &amp; control ; Humans ; Intraoperative Care ; *Liver Transplantation ; Oxygen Consumption ; Prospective Studies ; Treatment Outcome ; Vascular Resistance/drug effects ; }, abstract = {N-acetylcysteine (NAC) is an antioxidant agent which has been shown to benefit patients with fulminant hepatic failure. We have examined its effect in patients with chronic liver disease undergoing orthotopic liver transplantation by giving NAC during operation. In a prospective, randomized, double-blind, placebo-controlled study of 50 patients, NAC appeared to induce mild vasodilatation, improve oxygen delivery and consumption, and reduce base deficit, but data interpretation was difficult. There were no significant effects on mortality, morbidity or postoperative graft function.}, }
@article {pmid7485927, year = {1995}, author = {Konrad, F and Schoenberg, MH and Wiedmann, H and Kilian, J and Georgieff, M}, title = {[The application of n-acetylcysteine as an antioxidant and mucolytic in mechanical ventilation in intensive care patients. A prospective, randomized, placebo-controlled, double-blind study].}, journal = {Der Anaesthesist}, volume = {44}, number = {9}, pages = {651-658}, doi = {10.1007/s001010050200}, pmid = {7485927}, issn = {0003-2417}, mesh = {APACHE ; Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Bronchoalveolar Lavage Fluid ; *Critical Care ; Double-Blind Method ; Expectorants/*therapeutic use ; Female ; Follow-Up Studies ; Free Radical Scavengers/*therapeutic use ; Glutathione/blood/metabolism ; Humans ; Lipid Peroxidation/drug effects ; Male ; Middle Aged ; Prospective Studies ; *Respiration, Artificial ; Respiratory Function Tests ; }, abstract = {Oxygen radicals and oxygen radial mediators are thought to be important components in the development of acute lung injury, sepsis, and multiple organ failure. Injured patients, patients with pulmonary diseases, and multiple trauma patients also showed an elevated lipid peroxidation, indicating increased oxidant stress. N-Acetylcysteine (NAC) has been used as an antioxidant in a wide variety of experiments. NAC has been suggested to act by raising concentrations of cysteine, and hence glutathione, and by scavenging of oxidant species [1, 11, 17, 29]. The present study was designed to investigate whether the application of NAC in intubated patients has an effect on concentrations of reduced glutathione in plasma and bronchoalveolar lavage fluid (BAL) and on the lipid peroxidation products malondialdehyde and conjugated dienes. Because NAC has been widely used as a mucolytic drug for the treatment of lung diseases, the influence on tracheobronchial mucus was studied, too. METHODS. In a randomized, double-blind, placebo-controlled study, a total of 38 long-term ventilated patients of a surgical intensive care unit were investigated. Patients were treated for 5 days with either 3 g NAC/day or placebo. The plasma concentration of reduced glutathione, malondialdehyde, and conjugated dienes were measured on admission and on the 3rd and 5th days of treatment [8, 34, 48]. Additionally, the numbers of tracheobronchial suctionings were registered and chest radiographs were evaluated. A fibre-bronchoscopy was performed on admission and on the 3rd day of treatment. The amount and viscidity of tracheobronchial secretions were examined semiquantitatively, and glutathione levels were measured in the unconcentrated BAL. The study was approved by the ethics committee of the University of Ulm. RESULTS. The two groups were comparable with respect to age, sex, APACHE II score and diagnosis (Table 1). We found no significant differences in reduced glutathione levels in the plasma or in the BAL (Figs. 1, 2). Plasma concentrations of malondialdehyde were similar (Fig. 3). Only the levels of conjugated dienes were significantly higher on the 5th treatment day in the placebo group (Fig. 4). The organ function of the lung (FiO2, PEEP, PaO2), liver (SGOT, bilirubin), and kidney (creatinine) and coagulation parameters (PTT, prothrombin time, platelet count) were similar in the two groups during the time of investigation. We observed no clinically relevant differences in the tracheobronchial mucus (Table 2). CONCLUSION. The present data do not support routine use of NAC in ventilated patients, either as an antioxidant or as a mucolytic agent. Intravenous administration of 3 g NAC/day had no clinically relevant effect on glutathione levels, lipid peroxidation products, tracheobronchial mucus, and clinical condition.}, }
@article {pmid7654778, year = {1995}, author = {Bielicki, JK and Forte, TM and McCall, MR}, title = {Gas-phase cigarette smoke inhibits plasma lecithin-cholesterol acyltransferase activity by modification of the enzyme's free thiols.}, journal = {Biochimica et biophysica acta}, volume = {1258}, number = {1}, pages = {35-40}, doi = {10.1016/0005-2760(95)00092-q}, pmid = {7654778}, issn = {0006-3002}, support = {HL07279/HL/NHLBI NIH HHS/United States ; HL18574/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Binding Sites ; Cross-Linking Reagents ; Dithionitrobenzoic Acid/pharmacology ; Glutathione/pharmacology ; Humans ; Lipoproteins, HDL/blood ; Phosphatidylcholine-Sterol O-Acyltransferase/*antagonists &amp; inhibitors/blood/*chemistry ; *Plants, Toxic ; *Smoke ; Smoking/adverse effects ; Sulfhydryl Compounds/*chemistry ; *Nicotiana ; }, abstract = {Cigarette smoking is associated with an increased risk of premature atherosclerosis. The underlying mechanisms responsible for this association are unknown. Recent work from this laboratory has shown that ex vivo exposure to plasma to gas-phase cigarette smoke (CS) produces a rapid inhibition of lecithin-cholesterol acyltransferase (LCAT) activity and crosslinking of HDL-apolipoproteins. The goal of the present study was to investigate the mechanism(s) by which CS inhibited LCAT and modified HDL. When dialyzed human plasma (12 ml) was exposed to the gas-phase of an equivalent of 1/8 of a cigarette (one 'puff') at 15 min intervals for 3 h, LCAT activity was reduced by 76 +/- 1% compared to controls; supplementation of plasma with glutathione produced a dose-dependent protection of LCAT activity where at the highest concentration (1 mM) 78% protection was observed. A similar protection was obtained with N-acetyl cysteine (1 mM). In addition to LCAT inhibition, HDL-apolipoproteins were crosslinked after 3 h exposure of plasma to CS; crosslinking was reduced by the addition of either glutathione or N-acetyl cysteine to plasma. The amino compounds N-acetyl lysine, N-acetyl arginine, and aminoguanidine failed to protect LCAT and HDL indicating a specificity with regard to the ability of free thiols to buffer the deleterious components of CS which inhibited LCAT and crosslinked HDL-apolipoproteins. Since LCAT contains two free cysteine residues (Cys-31 and -184) near the active site of the enzyme, we tested whether pretreatment of plasma with the reversible sulfhydryl modifying compound, 5,5'-dithiobis-2-nitrobenzoic acid (DTNB), could protect LCAT from CS-induced inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7543016, year = {1995}, author = {Chiao, C and Carothers, AM and Grunberger, D and Solomon, G and Preston, GA and Barrett, JC}, title = {Apoptosis and altered redox state induced by caffeic acid phenethyl ester (CAPE) in transformed rat fibroblast cells.}, journal = {Cancer research}, volume = {55}, number = {16}, pages = {3576-3583}, pmid = {7543016}, issn = {0008-5472}, mesh = {Acetylcysteine/pharmacology ; Animals ; Apoptosis/*drug effects ; Caffeic Acids/*pharmacology ; Catalase/metabolism ; Cell Cycle/drug effects ; Cell Line ; Cell Transformation, Neoplastic/*pathology ; DNA Damage/drug effects ; Glutathione/metabolism ; Hydrogen Peroxide/pharmacology ; Oxidation-Reduction ; Phenylethyl Alcohol/*analogs &amp; derivatives/pharmacology ; Proto-Oncogene Proteins/physiology ; Proto-Oncogene Proteins c-bcl-2 ; Rats ; Rats, Inbred F344 ; }, abstract = {Caffeic acid phenethyl ester (CAPE), which is derived from the propolis of bee hives, was shown previously to block tumor promoter- and carcinogen-generated oxidative processes in several assays and to engender differential toxicity to some transformed cells. To study the mechanisms of CAPE-induced differential cytotoxicity, nontumorigenic rat embryo fibroblasts (CREF) and adenovirus (type 5)-transformed CREF cells (Wt3A) were used. As shown by nucleosomal-length DNA degradation, morphological alterations by electron microscopy, in situ labeling of 3'-OH ends, and the appearance of a hypodiploid cell population by bivariant flow cytometry, cell death induced by CAPE in the transformed Wt3A cells was apoptosis. Under the same CAPE treatment conditions, CREF cells transiently growth arrested. Both CREF and Wt3A cells were radioresistant, suggesting deficiencies in the proteins controlling the G1 checkpoint. To explore possible mechanisms of CAPE-induced apoptosis, it was determined whether CAPE-induced toxicity was influenced by the redox state of the cells. Depletion of cellular glutathione (GSH) with buthionine sulfoximine before CAPE treatment caused CREF sensitive to CAPE-induced cell death. GSH levels were also determined in CAPE-treated CREF and Wt3A cells. The GSH level in the CREF cells was unaffected by CAPE, whereas the Wt3A cells showed a significant reduction. When the GSH levels were increased in Wt3A cells by treatment with the reducing agent, N-acetyl-cysteine before CAPE treatment, the Wt3A cells were partially rescued. Furthermore, Bcl2, which protects cells from oxidative stress, had a protective effect against CAPE-induced apoptosis in Wt3A cells. Finally, the sensitivity of Wt3A cells to a known oxidant, hydrogen peroxide (H2O2), was examined. Wt3A cells were killed by H2O2-induced apoptosis, whereas CREF cells remained resistant. When Wt3A cells were treated with catalase, a cellular enzyme that inactivates H2O2, CAPE-induced apoptosis in Wt3A cells was reduced, further proving that Wt3A cells were more sensitive than CREF cells to oxidative stress. These results suggest that CAPE can modulate the redox state of cells. Sensitivity of cells to CAPE-induced cell death may be determined by the loss of normal redox state regulation in transformed cells.}, }
@article {pmid7638759, year = {1995}, author = {Mendez, C and Garcia, I and Maier, RV}, title = {Antioxidants attenuate endotoxin-induced activation of alveolar macrophages.}, journal = {Surgery}, volume = {118}, number = {2}, pages = {412-420}, doi = {10.1016/s0039-6060(05)80353-8}, pmid = {7638759}, issn = {0039-6060}, support = {GM-07037/GM/NIGMS NIH HHS/United States ; GM-45873/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Blood Coagulation Factors/metabolism ; Dinoprostone/biosynthesis ; Endotoxins/*pharmacology ; Macrophages, Alveolar/*drug effects/*physiology ; Male ; Rabbits ; Tumor Necrosis Factor-alpha/biosynthesis ; Vitamin E/*pharmacology ; }, abstract = {BACKGROUND: Endotoxin (lipopolysaccharide [LPS]) stimulation of tissue-fixed macrophages induces the generation of toxic oxidants. However, recent studies also implicate redox changes in both the signal transduction pathways for cytokine genes and the generation of physiologically active arachidonic acid metabolites. Because cytokines and arachidonic acid metabolites initiate and perpetuate deleterious systemic inflammatory responses, we tested whether macrophage activation could be modulated by antioxidants.<br><br>METHODS: Rabbit alveolar macrophages were obtained by bronchoalveolar lavage, isolated, treated with the antioxidants vitamin E or N-acetylcysteine (NAC), and stimulated with an optimal dose of LPS (10 ng/ml). Assays were performed for tumor necrosis factor (TNF), procoagulant activity, and prostaglandin E2. Total cellular RNA was extracted for Northern blot analysis of TNF messenger RNA.<br><br>RESULTS: Exposure of the macrophage to the antioxidants vitamin E and NAC inhibited TNF production, accumulation of TNF messenger RNA, procoagulant activity expression, and prostaglandin E2 production.<br><br>CONCLUSIONS: Macrophage signal transduction of LPS is dependent on the generation of reactive oxygen intermediates that can be blocked both at the level of the lipid membrane (vitamin E) and at the intracellular level (NAC). This suggests a potential therapeutic role for antioxidants is disease states such as adult respiratory distress syndrome and multiple organ failure syndrome, which are characterized by excessive macrophage activation.}, }
@article {pmid7635422, year = {1995}, author = {Nakano, H and Boudjema, K and Alexandre, E and Imbs, P and Chenard, MP and Wolf, P and Cinqualbre, J and Jaeck, D}, title = {Protective effects of N-acetylcysteine on hypothermic ischemia-reperfusion injury of rat liver.}, journal = {Hepatology (Baltimore, Md.)}, volume = {22}, number = {2}, pages = {539-545}, pmid = {7635422}, issn = {0270-9139}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acid Phosphatase/metabolism ; Alanine Transaminase/metabolism ; Animals ; Aspartate Aminotransferases/metabolism ; Buthionine Sulfoximine ; *Cold Temperature ; Cysteine/metabolism ; Glutathione/metabolism ; L-Lactate Dehydrogenase/metabolism ; Liver/*blood supply/metabolism ; Male ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Oxidation-Reduction ; Rats ; Rats, Wistar ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {We investigated whether intraportal injection of 150 mg/kg N-acetylcysteine (NAC) into rats reduced hepatic ischemia-reperfusion injury after 48 hours of cold storage and 2 hours of reperfusion. The organ was isolated and perfused to evaluate liver function. The control group received an intraportal injection of 5% dextrose. NAC increased L-cysteine concentrations 15 minutes after injection (1.29 +/- 0.11 mumol/g vs. 2.68 +/- 0.4 mumol/g, P < .05). However, neither treatment modified glutathione liver concentrations relative to preinjection values. After 48 hours of cold storage and 2 hours of reperfusion, livers from NAC-treated rats produced larger amounts of bile than those in the control group (5.04 +/- 1.92 vs. 0.72 +/- 0.37 microL/g liver; P < .05), and showed a significant reduction in liver injury, as indicated by reduced release of lactate dehydrogenase (679.4 +/- 174.4 vs. 1891.3 +/- 268.3 IU/L/g; P < .01), aspartate transaminase (AST) (13.94 +/- 3.5 vs. 38.75 IU/L/g; P < .01), alanine transaminase ALT) (14.92 +/- 4.09 vs. 45.91 +/- 10.58 IU/L/g; P < .05), and acid phosphatase, a marker of Kupffer cell injury (344.4 +/- 89.6 vs. 927.3 +/- 150.8 IU/L/g; P < .01) in the perfusate. Reduced glutathione concentrations in the perfusate were similar in the two groups (805 +/- 69 vs. 798 +/- 252 nmol/L/g), whereas oxidized glutathione (GSSG) concentrations were higher in the control group (967 +/- 137 vs. 525 +/- 126 nmol/L/g; P < .05). Reduced glutathione (GSH) concentrations in liver tissue collected at the end of perfusion were significantly higher in the NAC group (7.3 +/- 0.9 vs. 4.1 +/- 1.0 mumol/g; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7623839, year = {1995}, author = {Sun, X and Shimizu, H and Yamamoto, K}, title = {Identification of a novel p53 promoter element involved in genotoxic stress-inducible p53 gene expression.}, journal = {Molecular and cellular biology}, volume = {15}, number = {8}, pages = {4489-4496}, pmid = {7623839}, issn = {0270-7306}, mesh = {Animals ; Anticarcinogenic Agents/*pharmacology ; Base Sequence ; Cells, Cultured ; DNA-Binding Proteins/metabolism ; *Gene Expression Regulation ; Humans ; Mice ; Molecular Sequence Data ; Mutagens/*pharmacology ; NF-kappa B/metabolism ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic/*genetics ; Tumor Suppressor Protein p53/*genetics ; }, abstract = {p53 is recruited in response to DNA-damaging genotoxic stress and plays an important role in maintaining the integrity of the genome. We show that exposure of cells to various genotoxic agents, including anticancer drugs such as mitomycin and 5-fluorouracil, results in an increase in p53 mRNA levels and in p53 promoter activation, indicating that the p53 genotoxic stress response is partly regulated at the transcriptional level. The results of the p53 promoter analysis show that a novel p53 promoter element, termed a p53 core promoter element (from -70 to -46), is essential for basal p53 promoter activity and promoter activation induced by genotoxic agents such as anticancer drugs and UV. Although a kappa B motif partially overlaps with this element and those genotoxic agents activate NF-kappa B, it does not play a major role in p53 genotoxic stress response: NF-kappa B p65 expression did not induce significant p53 promoter activation, and NF-kappa B inhibitors (N-acetyl cysteine and I kappa B alpha) did not inhibit genotoxic stress-inducible p53 promoter activation. Finally, we characterized nuclear factors, the binding of which to the p53 core promoter element is essential for basal p53 promoter activity and p53 promoter activation induced by genotoxic agents.}, }
@article {pmid7614726, year = {1995}, author = {Chen, W and Gabel, S and Steenbergen, C and Murphy, E}, title = {A redox-based mechanism for cardioprotection induced by ischemic preconditioning in perfused rat heart.}, journal = {Circulation research}, volume = {77}, number = {2}, pages = {424-429}, doi = {10.1161/01.res.77.2.424}, pmid = {7614726}, issn = {0009-7330}, support = {R01 HL039752/HL/NHLBI NIH HHS/United States ; R01-HL-39752/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Biochemical Phenomena ; Biochemistry ; Coronary Circulation ; Creatine Kinase/metabolism ; Energy Metabolism ; Glutathione/*metabolism ; Heart/*drug effects ; Heart Rate ; Hydrogen-Ion Concentration ; In Vitro Techniques ; Magnetic Resonance Spectroscopy ; Male ; *Myocardial Ischemia ; *Myocardial Reperfusion ; Myocardium/*metabolism ; *Oxidation-Reduction ; Perfusion ; Rats ; Time Factors ; }, abstract = {Recent studies have suggested that mild redox alterations can regulate cell function. Therefore, we tested the hypothesis that alteration in the thiol redox state might be responsible for the cardioprotective effects conferred by ischemic preconditioning in the perfused rat heart. We find that preconditioning with four 5-minute periods of ischemia, each separated by 5 minutes of reflow, is associated with a significant loss of glutathione (3.98 +/- 0.32 mumol/g dry wt, n = 8) compared with no preconditioning (6.38 +/- 0.24 mumol/g dry wt, n = 14). We further find that the addition of N-acetylcysteine (NAC, a glutathione precursor and antioxidant) during the preconditioning protocol not only blocks the loss of glutathione (5.60 +/- 0.31 mumol/g dry wt, n = 9) but also blocks the protective effects of preconditioning. It is observed that after 20 minutes of ischemia followed by 20 minutes of reflow, untreated hearts recover 38 +/- 7% (n = 5) of their initial preischemic contractile function, whereas preconditioned hearts recover 91 +/- 11% (n = 7). Hearts preconditioned in the presence of NAC recover 24 +/- 3% (n = 7) of their preischemic function. Similarly, the addition of NAC reverses the protective effect of preconditioning on creatine kinase release. On reflow after 60 minutes of ischemia, creatine kinase release from control hearts was 271 +/- 20 IU.20 min-1.g dry wt-1 (n = 5), whereas preconditioned hearts release only 170 +/- 26 IU.20 min-1.g dry wt-1 (n = 6), and hearts preconditioned in the presence of NAC release 361 +/- 30 IU.20 min-1.g dry wt-1 (n = 5). We also find that hearts preconditioned in the presence of NAC have less attenuation of the decline in pHi than hearts preconditioned in the absence of drug. Thus, a redox-sensitive mechanism may be involved in the protection afforded by ischemic preconditioning.}, }
@article {pmid7550076, year = {1995}, author = {Rivabene, R and Viora, M and Matarrese, P and Rainaldi, G and D'Ambrosio, A and Malorni, W}, title = {N-acetyl-cysteine enhances cell adhesion properties of epithelial and lymphoid cells.}, journal = {Cell biology international}, volume = {19}, number = {8}, pages = {681-686}, doi = {10.1006/cbir.1995.1117}, pmid = {7550076}, issn = {1065-6995}, mesh = {Acetylcysteine/*pharmacology ; Antioxidants/*pharmacology ; Carcinoma, Squamous Cell ; Cell Adhesion/*drug effects ; Cell Line ; Cells, Cultured ; Cytoskeleton/drug effects/physiology/ultrastructure ; Cytotoxicity, Immunologic/drug effects ; Epithelium/drug effects/physiology ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Humans ; Killer Cells, Natural/drug effects/*immunology ; Lymphocytes/drug effects/*physiology ; Tumor Cells, Cultured ; }, abstract = {In this paper, we show that the antioxidant N-acetyl-cysteine (NAC) is capable of enhancing the adhesion properties of the epithelial cell line A431 and of the lymphocytic cells with cytotoxic activity from human peripheral blood: the natural killer (NK) cells. This effect leads to an increased efficiency of A431 cells to form a monolayer and of NK cells to kill their targets. In both cases a specific effect of NAC was found in the distribution of those molecules of the cytoskeleton which are generally involved in cell substrate and cell-to-cell contact region formation, e.g., the actin microfilaments. NAC could thus behave as a drug influencing certain cytoskeleton-dependent cell processes in a non-histotype dependent manner.}, }
@article {pmid7663656, year = {1995}, author = {Rey, C and Ajzenberg, N and Tchernia, G and Alvin, P and Dreyfus, M}, title = {[Acute liver failure caused by paracetamol: should treatment with N-acetylcysteine be prolonged?].}, journal = {Archives de pediatrie : organe officiel de la Societe francaise de pediatrie}, volume = {2}, number = {7}, pages = {662-665}, doi = {10.1016/0929-693x(96)81222-x}, pmid = {7663656}, issn = {0929-693X}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adolescent ; Dose-Response Relationship, Drug ; Female ; Humans ; Injections, Intravenous ; Liver Failure, Acute/*chemically induced/*drug therapy ; }, abstract = {BACKGROUND: Some cases of paracetamol-induced acute hepatic failure may require liver transplantation but the present shortage of graft urges the search for an alternate therapeutic approach.<br><br>CASE REPORT: A 17 year-old girl was admitted for sleepingness and vomiting after about 15 hours of voluntary but denied absorption of paracetamol. Plasma paracetamol concentration was 120 mg/l; factors VII+X level were 55% and factor V 106%. The patient was given IV N-acetylcysteine, 150 mg/kg/30 min, then 50 mg/kg/4 hours. Further decrease in facteur VII level led to pursue administration of N-acetylcysteine (total dose: 350 mg/kg/2 hours). While indication of liver transplantation was considered, clinical and laboratory findings definitely improved.<br><br>CONCLUSIONS: N-acetylcysteine may be effective even if administered late. Repeated determination of factor VII could be a good means for managing such a severe condition.}, }
@article {pmid7559241, year = {1995}, author = {Supinski, GS and Stofan, D and Ciufo, R and DiMarco, A}, title = {N-acetylcysteine administration and loaded breathing.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {79}, number = {1}, pages = {340-347}, doi = {10.1152/jappl.1995.79.1.340}, pmid = {7559241}, issn = {8750-7587}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Decerebrate State ; Diaphragm/*drug effects/*physiology ; Glutathione/analogs &amp; derivatives/metabolism ; Glutathione Disulfide ; Male ; Muscle Contraction ; Muscle Fatigue/*drug effects ; Osmolar Concentration ; Rats ; *Respiration ; Respiratory Insufficiency/*prevention &amp; control ; *Work of Breathing ; }, abstract = {Recent work has shown that loaded breathing produces alterations in diaphragmatic glutathione metabolism. Moreover, it has been suggested that alterations in glutathione levels may be related to the development of respiratory muscle fatigue and respiratory failure during loading. The purpose of this study was to determine whether it was possible to augment diaphragmatic stores of reduced glutathione (GSH) and thereby delay the development of respiratory failure during loaded breathing by administering N-acetylcysteine (NAC), a glutathione precursor. We compared the effects of massive inspiratory loading on saline- and NAC-treated groups of decerebrate unanesthetized rats with loading continuing until respiratory arrest occurred. As controls, we also studied unloaded saline- and NAC-treated animals. After arrest, diaphragms were excised, measurement was made of diaphragmatic GSH and oxidized glutathione (GSSG) concentrations, and assessment was made of in vitro diaphragmatic contractility (i.e., the force-frequency relationship and in vitro fatigability). We found that loading of saline-treated animals produced reductions in the diaphragmatic force-frequency curve, reductions in GSH, and increases in GSSG levels. NAC administration blunted loading-induced decreases in diaphragmatic GSH levels and reduced the in vitro fatigability of excised diaphragm muscle strips. NAC did not significantly alter the time to respiratory arrest, however, and also failed to alter the effect of loaded breathing on the diaphragmatic force-frequency relationship. These findings suggest that free radical-mediated GSH depletion is not the limiting factor determining the development of respiratory failure in this model of loaded breathing.}, }
@article {pmid7548749, year = {1995}, author = {Tang, W and Borel, AG and Fujimiya, T and Abbott, FS}, title = {Fluorinated analogues as mechanistic probes in valproic acid hepatotoxicity: hepatic microvesicular steatosis and glutathione status.}, journal = {Chemical research in toxicology}, volume = {8}, number = {5}, pages = {671-682}, doi = {10.1021/tx00047a006}, pmid = {7548749}, issn = {0893-228X}, mesh = {Animals ; Anticonvulsants/*toxicity ; Fatty Acids, Monounsaturated/metabolism/*toxicity ; Fatty Liver/*chemically induced/pathology ; Gas Chromatography-Mass Spectrometry ; Glutathione/*metabolism ; Liver/chemistry/*drug effects/metabolism/pathology ; Male ; Mitochondria, Liver/metabolism ; Pentanoic Acids/metabolism/*toxicity ; Rats ; Rats, Sprague-Dawley ; Valproic Acid/analogs &amp; derivatives/metabolism/*toxicity ; }, abstract = {It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis (> 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg) and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.}, }
@article {pmid7775104, year = {1995}, author = {Tate, DJ and Miceli, MV and Newsome, DA}, title = {Phagocytosis and H2O2 induce catalase and metallothionein gene expression in human retinal pigment epithelial cells.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {36}, number = {7}, pages = {1271-1279}, pmid = {7775104}, issn = {0146-0404}, support = {EY06677/EY/NEI NIH HHS/United States ; EY06782/EY/NEI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Base Sequence ; Catalase/*biosynthesis/genetics ; Cells, Cultured ; Child ; Child, Preschool ; Gene Expression Regulation/physiology ; Humans ; Hydrogen Peroxide/metabolism/*pharmacology ; Metallothionein/*biosynthesis/genetics ; Middle Aged ; Molecular Sequence Data ; NF-kappa B/chemistry/metabolism ; Oligonucleotides/chemistry ; *Phagocytosis/physiology ; Pigment Epithelium of Eye/cytology/drug effects/*metabolism ; RNA, Messenger/biosynthesis ; Transcription Factor AP-1/chemistry/metabolism ; }, abstract = {PURPOSE: Reactive oxygen intermediates have been implicated in the aging process and degenerative diseases of the eye, including retinopathy of prematurity, cataractogenesis, and macular degeneration. The purpose of this study was to investigate the effect of phagocytosis of photoreceptor outer segments and the addition of exogenous H2O2 on catalase and metallothionein expression in human retinal pigment epithelial cells.<br><br>METHODS: Confluent RPE cells were treated with bovine photoreceptor outer segments or H2O2 for either 6 or 18 hours. Slot blot hybridization was used to assess catalase and metallothionein gene expression after 6 hours. Catalase enzyme activity and metallothionein content were measured after 18 hours.<br><br>RESULTS: Phagocytosis or the addition of H2O2 increased catalase enzyme activity and metallothionein twofold above control levels. The addition of n-acetyl cysteine abrogated the inductive effect caused by either stress. Catalase and metallothionein gene expression, measured by slot blot hybridization, also were measurably induced by either stress. Phagocytosis of photoreceptor outer segments increased extracellular H2O2 concentration nine times above control.<br><br>CONCLUSIONS: The response of the retinal pigment epithelial cells to phagocytosis was indistinguishable from the response observed after the addition of exogenous H2O2. The generation of H2O2 during phagocytosis may act as an intracellular signal in retinal pigment epithelial cells that leads to increased levels of key antioxidant enzymes and other proteins important for protecting the cells from oxidative damage.}, }
@article {pmid7646922, year = {1995}, author = {Bongers, V and de Jong, J and Steen, I and de Vries, N and Bast, A and Snow, GB and Braakhuis, BJ}, title = {Antioxidant-related parameters in patients treated for cancer chemoprevention with N-acetylcysteine.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {31A}, number = {6}, pages = {921-923}, doi = {10.1016/0959-8049(94)00508-7}, pmid = {7646922}, issn = {0959-8049}, mesh = {Aged ; Aged, 80 and over ; Cystine/*analogs &amp; derivatives/pharmacokinetics/therapeutic use ; Erythrocytes/metabolism ; Female ; Glutathione/metabolism ; Humans ; Male ; Middle Aged ; Mouth Mucosa/metabolism ; Neoplasms/metabolism/*prevention &amp; control ; Reactive Oxygen Species/*metabolism ; }, abstract = {N-acetylcysteine (NAC) is an antioxidant, possibly effective in the early steps of carcinogenesis, and is applied to prevent second primary tumours in the upper aerodigestive tract and the lungs. In this study, we evaluated the pharmacodynamic profile of 600 mg NAC treatment, given daily for 3 months. Treatment caused a significant increase of the non-protein-SH concentration in blood plasma (38%) and erythrocytes (31%). Glutathione levels in exfoliated buccal mucosa cells appeared not to be influenced by treatment. The total radical-trapping ability parameter (TRAP) of blood plasma showed no change. In vitro, the addition of glutathione, but not of NAC did increase the TRAP value. In addition, when peroxyl radicals were generated in vitro, NAC was shown to be consumed more rapidly than glutathione. This suggests that NAC prevents early damage, while glutathione functions over a longer time period.}, }
@article {pmid7591713, year = {1995}, author = {Włodek, L and Grabowska, A and Marcinkiewicz, J}, title = {The modulation of IL-2 dependent proliferation of CTLL-2 cells by 2-methyl-thiazolidine-2,4-dicarboxylic acid.}, journal = {Immunopharmacology}, volume = {30}, number = {1}, pages = {51-58}, doi = {10.1016/0162-3109(95)00004-d}, pmid = {7591713}, issn = {0162-3109}, mesh = {Adjuvants, Immunologic/*pharmacology ; Animals ; B-Lymphocytes/drug effects ; Cell Division/drug effects ; Cell Line ; Cell Survival/drug effects ; Cysteine/analogs &amp; derivatives/pharmacology/physiology ; Extracellular Space/drug effects ; Interleukin-2/*physiology ; Intracellular Fluid/drug effects ; Lymphoma, T-Cell ; Mice ; Sulfhydryl Compounds/metabolism/pharmacology ; T-Lymphocytes, Cytotoxic/cytology/*drug effects ; Thiazoles/metabolism/*pharmacology ; Thiazolidines ; Tumor Cells, Cultured ; }, abstract = {It is known that cysteine and other thiol compounds are able to modulate the immune response. The extracellular concentration of cysteine was shown to determine the intracellular level of glutathione (GSH). Thus cysteine, by enhancing GSH production, is able to affect some T-cell functions like IL-2 dependent cell proliferation and the generation of cytotoxic T cells. However, physiologically blood plasma cysteine is maintained at a very low concentration. The use of cysteine as a therapeutic compound in vivo is strongly limited due to its cytotoxicity. Recent studies demonstrate that N-acetyl-cysteine (NAC) as well as a variety of thiazolidine derivatives (TDs), which are the products of the reaction of L-cysteine with carbonyl compounds, could serve as a 'delivery' system for cysteine into the cell. In the present study, we have shown that 2-methyl-thiazolidine-2,4,-dicarboxylic acid (CP), the product of condensation of L-cysteine and pyruvate, strongly increases the proliferation of one particular cell line, IL-2 dependent CTLL-2 cells. We have also shown that this compound significantly increases the intracellular level of non-protein sulfhydryls (NPSH), but we did not find any correlation between NPSH levels and cell viability and proliferation. In contrast to CP, free cysteine showed its toxic properties by affecting cell viability of different cell lines and also by cancelling the influence of CP on the proliferation of CTLL cells.}, }
@article {pmid7663972, year = {1995}, author = {O'Connor, E and Devesa, A and García, C and Puertes, IR and Pellín, A and Viña, JR}, title = {Biosynthesis and maintenance of GSH in primary astrocyte cultures: role of L-cystine and ascorbate.}, journal = {Brain research}, volume = {680}, number = {1-2}, pages = {157-163}, doi = {10.1016/0006-8993(95)00257-q}, pmid = {7663972}, issn = {0006-8993}, mesh = {Amino Acids/physiology ; Animals ; Ascorbic Acid/*physiology ; Astrocytes/cytology/*metabolism ; Cells, Cultured ; Cystine/*physiology ; Glutathione/*metabolism ; Methionine/metabolism ; Osmolar Concentration ; Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {We have studied the optimal conditions to maintain the astrocyte GSH levels under normal and oxidative stress conditions. The rate of GSH synthesis from L-methionine was statistically lower than from L-cystine or N-acetyl-cysteine in astrocytes treated with diethyl-maleate, which is a substrate of GSH S-transferases. This is in accordance with the fact that cystathionase activity was not detectable. The transport of L-cystine mediated by the Na(+)-independent system Xc- is the limiting step in GSH synthesis in astrocytes. Incubation with tert-butyl hydroperoxide (t-booH) reduced GSH concentration in astrocytes. This reduction was ameliorated in part by the addition of ascorbate or dehydroascorbate. When L-cystine and ascorbate were added together to the t-booH-treated astrocytes, the GSH concentration was indistinguishable from controls. Electron micrographs of astrocytes treated with t-booH showed an increased number of vacuoles and mitochondrial swelling. This was prevented by ascorbate and dehydroascorbate. The physiological implications of the availability of GSH precursors and ascorbate in the maintenance of GSH in astrocytes are discussed.}, }
@article {pmid7728902, year = {1995}, author = {Malorni, W and Rivabene, R and Matarrese, P}, title = {The antioxidant N-acetyl-cysteine protects cultured epithelial cells from menadione-induced cytopathology.}, journal = {Chemico-biological interactions}, volume = {96}, number = {2}, pages = {113-123}, doi = {10.1016/0009-2797(94)03576-t}, pmid = {7728902}, issn = {0009-2797}, mesh = {Acetylcysteine/*pharmacology ; Antimetabolites/toxicity ; Buthionine Sulfoximine ; Carcinoma, Squamous Cell/pathology ; Cell Adhesion/drug effects ; Epithelium/drug effects/pathology/ultrastructure ; Glutamate-Cysteine Ligase/antagonists &amp; inhibitors ; Humans ; Methionine Sulfoximine/analogs &amp; derivatives/toxicity ; Microscopy, Electron, Scanning ; Microscopy, Fluorescence ; Oxidative Stress/*drug effects ; Tumor Cells, Cultured ; Vitamin K/*toxicity ; }, abstract = {The effects of the antioxidant N-acetyl-cysteine (NAC) were assessed after short term exposure of A431 epithelial cells. The drug was able to protect, at least partially, the cells from the oxidative stress induced by the quinone menadione. In particular, the oxidizing agent-induced cell rounding and detachment from the substrate were strongly impaired by pre-exposure to the compound. The mechanism of such an effect seems to be ascribable to a target effect of the drug on the adhesion properties of the cells. In fact, a modification of morphological features of NAC-exposed cells and of their ability to adhere to different coated substrates was found. These changes resulted in a significant improvement of the A431 tumor cell adhesion pattern which was associated with a noticeable rearrangement of some cytoskeletal components, mainly of the microfilament system. These data add new importance to the subcellular activity of NAC and seem to indicate that the redox status of the cells, i.e. the intracellular balance between proxidants and antioxidants, could also play a role in their adhesive properties.}, }
@article {pmid7753847, year = {1995}, author = {Kwak, HS and Yim, HS and Chock, PB and Yim, MB}, title = {Endogenous intracellular glutathionyl radicals are generated in neuroblastoma cells under hydrogen peroxide oxidative stress.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {92}, number = {10}, pages = {4582-4586}, pmid = {7753847}, issn = {0027-8424}, mesh = {Acetylcysteine/pharmacology ; Cell Line ; Cyclic N-Oxides ; Electron Spin Resonance Spectroscopy ; Free Radicals/*metabolism ; Glucose ; Glucose Oxidase ; Glutathione/*metabolism ; Horseradish Peroxidase/pharmacology ; Humans ; Hydrogen Peroxide/*pharmacology ; Kinetics ; NF-kappa B/metabolism ; Neuroblastoma/*metabolism ; Oxidative Stress ; Spin Labels ; Superoxide Dismutase/pharmacology ; Tumor Cells, Cultured ; }, abstract = {We report the detection of endogenous intracellular glutathionyl (GS.) radicals in the intact neuroblastoma cell line NCB-20 under oxidative stress. Spin-trapping and electron paramagnetic resonance (EPR) spectroscopic methods were used for monitoring the radicals. The cells incubated with the spin trap 5,5-dimethyl-1-pyrroline 1-oxide (DMPO) were challenged with H2O2 generated by the enzymic reaction of glucose/glucose oxidase. These cells exhibit the EPR spectrum of the GS. radical adduct of DMPO (DMPO-.SG) without exogenous reduced glutathione (GSH). The identity of this radical adduct was confirmed by observing hyperfine coupling constants identical to previously reported values in in vitro studies, which utilized known enzymic reactions, such as horseradish peroxidase and Cu/Zn superoxide dismutase, with GSH and H2O2 as substrates. The formation of the GS. radicals required viable cells and continuous biosynthesis of GSH. No significant effect on the resonance amplitude by the addition of a membrane-impermeable paramagnetic broadening agent indicated that these radicals were located inside the intact cell. N-Acetyl-L-cysteine (NAC)-treated cells produced NAC-derived free radicals (NAC.) in place of GS. radicals. The time course studies showed that DMPO-.SG formation exhibited a large increase in its concentration after a lag period, whereas DMPO-NAC. formation from NAC-treated cells did not show this sudden increase. These results were discussed in terms of the limit of antioxidant enzyme defenses in cells and the potential role of the GS. radical burst in activation of the transcription nuclear factor NF-kappa B in response to oxidative stress.}, }
@article {pmid7769841, year = {1995}, author = {Hu, ZB and Yang, GS and Li, M and Miyamoto, N and Minden, MD and McCulloch, EA}, title = {Mechanism of cytosine arabinoside toxicity to the blast cells of acute myeloblastic leukemia: involvement of free radicals.}, journal = {Leukemia}, volume = {9}, number = {5}, pages = {789-798}, pmid = {7769841}, issn = {0887-6924}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/pharmacology ; Base Sequence ; Blotting, Northern ; Cytarabine/*toxicity ; Down-Regulation/drug effects ; Drug Interactions ; Drug Screening Assays, Antitumor ; Free Radicals/metabolism/toxicity ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Hydrocortisone/pharmacology ; Hydrogen Peroxide/metabolism/*toxicity ; Leukemia, Myeloid, Acute/*drug therapy/metabolism/pathology ; Lymphocyte Activation ; Lymphocytes/*drug effects ; Molecular Sequence Data ; Polymerase Chain Reaction ; Proto-Oncogene Mas ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Transcription, Genetic/drug effects ; Tretinoin/pharmacology ; Tumor Cells, Cultured/drug effects ; }, abstract = {Retinoic acid and hydrocortisone (HC) have been shown to regulate the drug sensitivity of the blast cells of acute myeloblastic leukemia (AML). We asked if the proto-oncogene bcl-2 played a role in this regulation. As target cells we used the continuous lines, OCI/AML-1, OCI/AML-2 or OCI/AML-5; expression of bcl-2 can be detected by Northern analysis of RNA from OCI/AML-2 or OCI/AML-5 cells; bcl-2 expression can be found in OCI/AML-1 cells only by using RT-PCR. Exposure of OCI/AML-2 or OCI/AML-5 cells to retinoic acid (all-trans retinoic acid, ATRA) led to a down-regulation of bcl-2 expression that was first seen after 2 h of exposure and was complete after a day. The down-regulation could be prevented by exposing the cells to ara-C either before or after ATRA; decrease in bcl-2 protein was moderate and only obvious after 36 h of ATRA treatment. Nuclear run-on experiments provided evidence that bcl-2 down-regulation was occurring at transcriptional and post-translational levels. Since bcl-2 is considered to have anti-oxidant activity, we tested the sensitivity of the three cell lines to H2O2; we found that OCI/AML-1, the line with very low bcl-2 expression, was a 100-fold more H2O2-sensitive than OCI/AML-2 or OCI/AML-5, where bcl-2 expression can be detected readily. We then asked if H2O2 sensitivity could be regulated. We found that exposure of cells to HC before H2O2 was protective while ATRA after peroxide treatment increased killing; this is the same pattern of regulation observed when AML blasts are exposed to HC before, or ATRA after ara-C. Finally, we asked whether N-acetylcysteine (NAC), a known radical scavenger would protect cells against ara-C killing. Significant protection was observed when NAC was given before drug, but not if given after drug. NAC protection against ara-C killing was seen for OCI/AML-1 and 2 cells, but not for OCI/AML-5 cells. We interpret the results as follows: ara-C kills cells in two ways: first, directly, by incorporation into DNA and chain termination; second, indirectly, by inducing the production of toxic radicals. Bcl-2 reduces the oxidant activity of such radicals, and is protective. ATRA regulates ara-C toxicity by its action on bcl-2. Left unexplained are the action of HC, which does not affect bcl-2 expression and the mechanism by which ara-C prevents down-regulation of bcl-2 by ATRA.}, }
@article {pmid7750344, year = {1995}, author = {van Zandwijk, N}, title = {N-acetylcysteine for lung cancer prevention.}, journal = {Chest}, volume = {107}, number = {5}, pages = {1437-1441}, doi = {10.1378/chest.107.5.1437}, pmid = {7750344}, issn = {0012-3692}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Humans ; Lung Neoplasms/*prevention &amp; control ; }, abstract = {Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well recognized causes. Apart from oxidants, cigarette smoke contains several precarcinogens, and it is surprising that not every heavy smoker becomes a victim of malignant disease. This points to the interindividual variability in susceptibility to carcinogens and there are several lines of evidence that metabolic factors are involved in such variability. Metabolism of carcinogens and also the subsequent multisteps of carcinogenesis are affected by host factors and governed by the balance between opposite forces, such as metabolic activation and detoxification, formation, and scavenging of radicals and DNA damage and repair. This implies that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione plays a crucial role in the detoxification of xenobiotics. N-acetylcysteine (NAC), an aminothiol and precursor of intracellular cysteine and glutathione, has been shown not only to be an efficient antidote in acetaminophen poisoning but also to possess important chemopreventive properties. In this article, sites and mechanisms of the therapeutic action of NAC are reviewed with special reference to its chemopreventive characteristics.}, }
@article {pmid7738358, year = {1995}, author = {Alena, F and Dixon, W and Thomas, P and Jimbow, K}, title = {Glutathione plays a key role in the depigmenting and melanocytotoxic action of N-acetyl-4-S-cysteaminylphenol in black and yellow hair follicles.}, journal = {The Journal of investigative dermatology}, volume = {104}, number = {5}, pages = {792-797}, doi = {10.1111/1523-1747.ep12606994}, pmid = {7738358}, issn = {0022-202X}, mesh = {Animals ; Cell Death/drug effects ; Cysteamine/*analogs &amp; derivatives/pharmacology ; Dose-Response Relationship, Drug ; Glutathione/analysis/*physiology ; Hair/chemistry/*drug effects ; Hair Color/drug effects ; Melanins/analysis ; Melanocytes/*cytology ; Mice ; Mice, Inbred C57BL ; Phenols/*pharmacology ; Pigmentation/*drug effects ; Skin/chemistry ; }, abstract = {This study examined the effect of glutathione on the in vivo depigmenting potency of N-acetyl-4-S-cysteaminylphenol (N-acetyl-4-S-CAP) in black and yellow mice after multiple intraperitoneal injections on 10 consecutive days. In black mice (C57BL/6J, a/a), N-acetyl-4-S-CAP showed dose-dependent depigmenting potency (0.5, 1.0, and 2.0 mmol/kg), which was in parallel to the tissue eumelanin content (98%, 28%, and 3% of controls, respectively) and to the tissue glutathione content (94%, 85%, and 76%, respectively). In lethal yellow mice (C57BL/6J, Ay/a), only a dose of 2.0 mmol/kg showed the color change of hair to dark, not to white as seen in black mice. This was reflected by the decrease of pheomelanin content (56%) and the increase of eumelanin content (28% of black mice). The simultaneous administration of N-acetyl-cysteine, which up-regulated glutathione content, completely abolished the depigmenting potency of N-acetyl-4-S-CAP, whereas administration of buthionine sulfoximine, which depleted the tissue glutathione content, enhanced the depigmenting potency of N-acetyl-4-S-CAP in black hair. In yellow mice, the darkening of hair follicles by 2.0 mmol/kg of N-acetyl-4-S-CAP was completely abolished by the combined administration of N-acetyl-cysteine, with the resulting hair color the same as in controls, whereas combined administration with buthionine sulfoximine caused some whitening of yellow hair follicles. Our data indicate that the tissue content of glutathione regulates melanocytotoxicity and depigmenting potency of N-acetyl-4-S-CAP and that this alteration of glutathione content may switch the melanogenesis type from pheomelanin to eumelanin.}, }
@article {pmid7599285, year = {1995}, author = {Täger, M and Ittenson, A and Franke, A and Frey, A and Gassen, HG and Ansorge, S}, title = {gamma-Glutamyl transpeptidase-cellular expression in populations of normal human mononuclear cells and patients suffering from leukemias.}, journal = {Annals of hematology}, volume = {70}, number = {5}, pages = {237-242}, pmid = {7599285}, issn = {0939-5555}, mesh = {Adult ; Bone Marrow/enzymology ; Female ; Glutathione/pharmacology ; Humans ; Leukemia/blood/*enzymology ; Leukocytes, Mononuclear/*enzymology ; Male ; Middle Aged ; Mitogens/pharmacology ; gamma-Glutamyltransferase/*biosynthesis ; }, abstract = {The expression of the ectoenzyme gamma-glutamyl transpeptidase (EC2.3.2.2., gamma GT) was investigated by flow cytometry on populations of peripheral blood mononuclear cells (PBMC) from healthy subjects and patients suffering from several types of leukemia before and under chemotherapy. In unstimulated PBMC, 28% of these cells were found to be gamma GT positive. The highest expression was measured on monocytes (CD14/gamma GT+ cells: 60%). Within the subsets of T lymphocytes (CD3/gamma GT+ cells: 18%) we saw no clear differences between CD4+ and CD8+ cells. B lymphocytes, NK cells, and activated cells showed low expressions (up to 10%). Treatment of PBMC with mitogens, alpha-IFN, IL-2, and GM-CSF did not affect the enzyme expression on normal mononuclear cells (MNC). However, a rapid increase of gamma GT+ cells was found in the presence of glutathione (GSH) and n-acetyl cysteine (nAC), particularly on monocytes, B cells, and NK cells. Comparing 40 healthy subjects and untreated patients suffering from leukemias, a significantly higher expression of gamma GT+ cells in the total MNC populations (B-CLL: 57%, CML: 62% gamma GT+ cells) was observed in B-chronic lymphocytic leukemia (B-CLL) and chronic myelogenous leukemia (CML), whereas other leukemias did not show clear differences. Most interestingly, the gamma GT expression was diminished in all populations of CML cells after 5 h of incubation in the presence of 10 units/ml IFN-alpha. These data suggest a possible protective role of gamma GT in MNC and a regulatory function of this enzyme in the development of CML.}, }
@article {pmid7491847, year = {1995}, author = {De Groote, J and Van Steenbergen, W}, title = {Paracetamol intoxication and N-acetyl-cysteine treatment.}, journal = {Acta gastro-enterologica Belgica}, volume = {58}, number = {3-4}, pages = {326-334}, pmid = {7491847}, issn = {1784-3227}, mesh = {Acetaminophen/metabolism/*poisoning ; Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Anaphylaxis/chemically induced ; Humans ; Poisoning/drug therapy ; }, abstract = {N-acetylcysteine is a good and reasonable specific antidotum in case of paracetamol intoxication. It is very active when administered within eight hours after intoxication. It can be used as well as in intravenous as peroral administration. There are few side effects.}, }
@article {pmid7738404, year = {1995}, author = {Van den Broeke, LT and Beijersbergen van Henegouwen, GM}, title = {UV radiation protecting efficacy of cysteine derivatives, studies with UVA-induced binding of 8-MOP and CPZ to rat epidermal biomacromolecules in vivo.}, journal = {International journal of radiation biology}, volume = {67}, number = {4}, pages = {411-420}, doi = {10.1080/09553009514550471}, pmid = {7738404}, issn = {0955-3002}, mesh = {Administration, Topical ; Animals ; Biological Availability ; Chlorpromazine/*metabolism ; Cysteine/*analogs &amp; derivatives/pharmacokinetics/*pharmacology ; Electrochemistry ; Female ; Macromolecular Substances ; Methoxsalen/*metabolism ; Oxidation-Reduction ; Radiation-Protective Agents/pharmacokinetics/*pharmacology ; Rats ; Rats, Wistar ; Skin/drug effects/*metabolism/*radiation effects ; Time Factors ; *Ultraviolet Rays ; }, abstract = {With the aim of optimizing the UV radiation protecting efficacy of N-acetylcysteine (NAC), the following topically applied cysteine derivatives were investigated: N-acetylcysteine ethylester (NACET), S-acetylcysteine ethylester (SACET), cysteine ethylester (CYSET), N,S-diacetylcysteinamide (SNACA), N,S-diacetylcysteine (SNAC) and N,S-diacetylcysteine ethylester (SNACET). As a measure for protection the inhibition of in vivo irreversible photobinding of the labelled phototoxic drugs chlorpromazine (CPZ) and 8-methoxypsoralen (8-MOP) to rat epidermal biomacromolecules was used. The duration of protection of the cysteine derivatives was shortened by S-acetylation, N-acetylation and carboxyl derivatization. Compounds with a free thiol group showed a long-lasting presence in the stratum corneum, probably by the formation of mixed disulphides with proteins. The intrinsic protecting efficacy with respect to the total epidermis increased in the order CYSET < SNACET,SNACA,SACET < NACET, SNAC,NAC. The results of this study are discussed in view of susceptibility to oxidation, epidermal bioavailability and metabolic activation. With respect to the viable epidermis we postulate that NACET and SNAC have the most promising properties as UV protective agents.}, }
@article {pmid7675271, year = {1995}, author = {Pelaia, P and Rocco, M and De Blasi, RA and Spadetta, G and Alampi, D and Araimo, FS and Nicolucci, S}, title = {[Assessment of lipid peroxidation in hyperbaric oxygen therapy: protective role of N-acetylcysteine].}, journal = {Minerva anestesiologica}, volume = {61}, number = {4}, pages = {133-139}, pmid = {7675271}, issn = {0375-9393}, mesh = {Acetylcysteine/*therapeutic use ; Humans ; *Hyperbaric Oxygenation ; *Lipid Peroxidation ; }, abstract = {OBJECTIVE: To verify and quantify lipidic peroxidation by means of tiobarbituric-acid reactive substance (TBARS) dosage in patients treated daily with HBO. To verify if a potentiated glutathione enzymatic system, with N-acetylcisteine (NAC) treatment, may determine higher HBO tolerance and reduced lipidic peroxidation.<br><br>DESIGN: Randomised study on patients treated with 20 HBO 2.2 ATA (90' oxygen) sessions.<br><br>SETTING: Hyperbaric Medical Centre.<br><br>PATIENTS: Seventeen patients divided, at random, into two groups; group A: 10 patients treated with only HBO; group B: 7 patients treated with NAC antioxidant therapy (Fluimucil, Zambon Group, Italy) 1800 mg/day in addition to HBO.<br><br>INTERVENTIONS: None.<br><br>MEASUREMENTS AND MAIN RESULTS: TBARS on blood sample at T0 (basal) T1 (at the end of the 1st HBO session) T2 (at the beginning of the 20th HBO session) T3 (at the end of the 20th). The group A TBARS analysis at the different study time has shown significant data (p < 0.01) as the difference between TBARS values of the two groups at T2 (p < 0.01).<br><br>CONCLUSIONS: HBO induces a lipidic peroxidation even if the therapeutical protocol cannot determine lung or cerebral oxygen toxicity symptoms. The NAC administration, during HBO treatment, determines a protection against the HBO radicalic stress.}, }
@article {pmid7606199, year = {1995}, author = {Pendyala, L and Creaven, PJ}, title = {Pharmacokinetic and pharmacodynamic studies of N-acetylcysteine, a potential chemopreventive agent during a phase I trial.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {4}, number = {3}, pages = {245-251}, pmid = {7606199}, issn = {1055-9965}, support = {N01-CN-85102-02/CN/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacokinetics/toxicity ; Administration, Oral ; Adult ; Aged ; Cohort Studies ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Glutathione/blood ; Glutathione Reductase/blood ; Humans ; Intestinal Absorption/physiology ; Male ; Middle Aged ; Neoplasm Recurrence, Local/*blood/prevention &amp; control ; Precancerous Conditions/*blood/prevention &amp; control ; Risk Factors ; }, abstract = {A Phase I, pharmacokinetic and pharmacodynamic study of N-acetylcysteine (NAC), a potential chemopreventive agent, given daily p.o. for 6 months was carried out in 26 volunteers at higher than normal risk of malignancy. The goals of the study were to define the highest nontoxic dose, the toxicity profile, and the pharmacokinetics and pharmacodynamics of NAC. The pharmacodynamic end points studied included glutathione (GSH) in plasma, RBC and peripheral blood lymphocytes (PBL), cysteine in plasma, and two GSH-metabolizing enzymes glutathione S-transferase and oxidized glutathione reductase in PBL. The study was carried out in 2 stages. The first stage consisted of an inter- and intrasubject dose escalation; the second, an assessment of a single daily dose. Starting doses for the first 4 cohorts of 3 subjects were 400, 800, 1600, and 3200 mg/m2/day in divided doses doubled at the end of each month in the absence of toxicity to a final dose of 6400 mg/m2/day. The total planned period on NAC for each subject was 6 months. Pharmacokinetic and pharmacodynamic measurements were carried out at the beginning of the study and at the end of each month. The second stage of the study consisted of a daily dose of 800 mg/m2/day. During this part of the study, NAC in plasma and GSH and oxidized glutathione reductase (GRD) in PBL were measured on day 1 and again at the end of first, second, and sixth month on NAC. Major toxicities were bad taste and gastrointestinal disturbances. The highest nontoxic dose was 800 mg/m2/day in most of the subjects.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7705924, year = {1995}, author = {Albini, A and D'Agostini, F and Giunciuglio, D and Paglieri, I and Balansky, R and De Flora, S}, title = {Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine.}, journal = {International journal of cancer}, volume = {61}, number = {1}, pages = {121-129}, doi = {10.1002/ijc.2910610121}, pmid = {7705924}, issn = {0020-7136}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; Carcinoma, Lewis Lung/drug therapy/pathology/secondary ; Cell Movement/drug effects ; Gelatinases/*antagonists &amp; inhibitors/*metabolism ; Glutathione/analogs &amp; derivatives/pharmacology ; Glutathione Disulfide ; Humans ; Lung Neoplasms/*drug therapy/*secondary ; Melanoma/*drug therapy/*enzymology/pathology ; Melanoma, Experimental/*drug therapy/enzymology/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Invasiveness ; Sarcoma, Experimental/*drug therapy/enzymology/pathology ; Tumor Cells, Cultured ; }, abstract = {The thiol N-acetylcysteine (NAC) is currently considered one of the most promising cancer chemopreventive agents by virtue of its multiple and coordinated mechanisms affecting the process of chemical carcinogenesis. Recent studies have shown that an unpaired cysteine residue in the propeptide plays a key role in inactivation of latent metastasis-associated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of malignant cells. As assessed by zymographic analysis, NAC completely inhibited the gelatinolytic activity of type-IV collagenases in the cells tested (gelatinases A and B). Moreover, NAC was efficient in inhibiting the chemotactic and invasive activities of tumor cells of human (A2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, which are predictive of the invasive and metastatic properties. Reduced glutathione (GSH) had a similar, although less effective activity. The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAC. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAC. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol.}, }
@article {pmid7896007, year = {1995}, author = {Voelkel, NF and Lobel, K and Westcott, JY and Burke, TJ}, title = {Nitric oxide-related vasoconstriction in lungs perfused with red cell lysate.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {9}, number = {5}, pages = {379-386}, doi = {10.1096/fasebj.9.5.7896007}, pmid = {7896007}, issn = {0892-6638}, support = {R01 HL43180/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Arginine/pharmacology ; Catalase/pharmacology ; Cyclic GMP/metabolism ; Dialysis ; Ethylmaleimide/pharmacology ; *Hemolysis ; In Vitro Techniques ; Indoles/pharmacology ; Lung/*blood supply/drug effects/metabolism ; Meclofenamic Acid/pharmacology ; Nitric Oxide/antagonists &amp; inhibitors/biosynthesis/*physiology ; Nitroprusside/pharmacology ; Oxygen Consumption ; Perfusion ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/pharmacology ; Vasoconstriction/drug effects/*physiology ; }, abstract = {The present study in isolated rat lungs demonstrates that nitric oxide gas (.NO, 70 nM) added to the perfusate containing a small amount of hemolysate [175 microliters of lysed red blood cells (RBC) per 50 ml of Earle's balanced salt solution (EBSS)] triggered profound and sustained vasoconstriction. Vasoconstriction was not observed when .NO was added to lungs perfused with washed intact rat or human RBC or with oxyhemoglobin (Hgb 20 microM). The presence of hemolysate in the perfusate also caused vasoconstriction in response to n-acetylcysteine (50 microM), glutathione (10(-4) M), or ascorbic acid (10(-4) M) and potentiated greatly the vasoconstrictor response to 5 mM KCl. Not only .NO, but also nitroprusside (SNP) or L-arginine and paradoxically three .NO synthesis inhibitors, including N-monomethyl L-arginine, L-NAME, and nitroblue tetrazolium, which have different mechanisms of action, each caused in the presence of hemolysate large vasoconstrictive responses. Hemolysate itself enhanced O2 consumption by slices of lung; no effects of this dose of .NO on lung slice respiration were seen in the absence of hemolysate. Both Hgb and hemolysate lowered perfusate cGMP levels to the same degree suggesting that the vasoconstrictive response was not due to unique effects of hemolysate on guanylyl cyclase. Addition of superoxide dismutase (SOD) and catalase (CAT) to the hemolysate containing perfusate, or addition of a cyclooxygenase or 5-lipoxygenase inhibitor, virtually abolished the .NO induced vasoconstriction. The latter data are consistent with the concept that exposure of the vasculature to hemolysate may result in the formation of peroxynitrite. However, SOD and CAT did not abolish the pulmonary vasoconstriction induced by L-arginine or by NAC. Our data indicate that hemolysate has profound effects on lung vessel tone regulation and on lung tissue mitochondrial function, yet the precise molecular mechanisms responsible for the action of hemolysate are likely to be very complex.}, }
@article {pmid7881669, year = {1995}, author = {Reinhart, K and Spies, CD and Meier-Hellmann, A and Bredle, DL and Hannemann, L and Specht, M and Schaffartzik, W}, title = {N-acetylcysteine preserves oxygen consumption and gastric mucosal pH during hyperoxic ventilation.}, journal = {American journal of respiratory and critical care medicine}, volume = {151}, number = {3 Pt 1}, pages = {773-779}, doi = {10.1164/ajrccm/151.3_Pt_1.773}, pmid = {7881669}, issn = {1073-449X}, mesh = {Acetylcysteine/*therapeutic use ; Female ; Gastric Mucosa/*drug effects/metabolism ; Humans ; Hydrogen-Ion Concentration ; Hyperoxia/*physiopathology ; Male ; Middle Aged ; Oxygen Consumption/*drug effects ; Premedication ; Prospective Studies ; *Respiration, Artificial ; Systemic Inflammatory Response Syndrome/metabolism/*therapy ; }, abstract = {Hyperoxic ventilation, used to prevent hypoxemia during potential periods of hypoventilation, has been reported to paradoxically decrease whole body oxygen consumption (VO2). Reduction in nutritive blood flow due to oxygen radical production is one possible mechanism. We investigated whether pretreatment with the sulfhydryl group donor and O2 radical scavenger N-acetylcysteine (NAC) would preserve whole body VO2 and prevent deterioration of oxygenation in gastric mucosal tissue during hyperoxia. Thirty-eight patients, requiring hemodynamic monitoring (radial and pulmonary artery catheters) due to sepsis syndrome, were included in this randomized experiment. All patients exhibited stable clinical conditions (hemodynamics, body temperature, hemoglobin, FIO2 < 0.5). A gastric tonometer was placed to measure the gastric intramucosal pH (pHi), which indirectly assesses nutritive blood flow to the mucosa. Cardiac output was determined by thermodilution and VO2 by cardiovascular Fick. After baseline measurements, patients randomly received either 150 mg.kg-1 NAC (n = 19) or placebo (n = 19) in 250 ml 5% dextrose intravenously over a period of 15 min. Measurements were repeated 30 min after starting NAC or placebo infusion, 30 min after starting hyperoxia (FIO2 = 1.0), and 60 min after resetting the original FIO2. There were no significant differences between groups in any of the measurements before treatment and after the return to baseline FIO2 at the end of the study. NAC, but not placebo infusion, caused a slight but significant increase in cardiac output and decrease in systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7881668, year = {1995}, author = {Sciuto, AM and Strickland, PT and Kennedy, TP and Gurtner, GH}, title = {Protective effects of N-acetylcysteine treatment after phosgene exposure in rabbits.}, journal = {American journal of respiratory and critical care medicine}, volume = {151}, number = {3 Pt 1}, pages = {768-772}, doi = {10.1164/ajrccm.151.3.7881668}, pmid = {7881668}, issn = {1073-449X}, support = {HL-83543/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Antioxidants/pharmacology ; Glutathione/metabolism ; Leukotrienes/metabolism ; Lipid Peroxidation/drug effects ; Lung/drug effects/metabolism ; Male ; Oxidation-Reduction ; Phosgene/*poisoning ; Pulmonary Edema/*chemically induced/*prevention &amp; control ; Rabbits ; Time Factors ; }, abstract = {We examined the effects of treatment with N-acetylcysteine (NAC) on pulmonary edema formation in isolated perfused rabbit lungs following in vivo phosgene exposure. This study focused on posttreatment intratracheal administration of NAC after exposure. Rabbits, 2 to 3 kg, were exposed to a cumulative dose of phosgene to attain a concentration x time exposure effect of 1,500 ppm/min. Lungs were perfused with Krebs-Henseleit buffer at 40 ml/min from 70 to 150 min after exposure. Pulmonary artery pressure (Ppa), tracheal pressure (Pt), and the rate of lung weight gain (LWG) were measured continuously. Perfusate concentration of peptide leukotrienes LTC4, D4, and E4 were measured every 20 min during perfusion. At the conclusion of the experiment, lung tissue was analyzed for reduced and oxidized glutathione (GSH and GSSG) and lipid peroxidation (thiobarbituric acid-reactive substances, TBARS). Exposure to phosgene significantly increased Pt, LWG, LTC4, D4, and E4, TBARS, and GSSG over time compared with controls. Compared with phosgene, intratracheal NAC lowered Ppa, LWG, LTC4, D4, and E4, TBARS, and GSSG. We conclude that NAC protected against phosgene-induced lung injury by acting as an antioxidant by maintaining protective levels of glutathione, reducing both lipid peroxidation and production of arachidonic acid metabolites.}, }
@article {pmid7875767, year = {1995}, author = {Fenoy, FJ and Ferrer, P and Carbonell, L and García-Salom, M}, title = {Role of nitric oxide on papillary blood flow and pressure natriuresis.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {25}, number = {3}, pages = {408-414}, doi = {10.1161/01.hyp.25.3.408}, pmid = {7875767}, issn = {0194-911X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Arginine/analogs &amp; derivatives/pharmacology ; Blood Pressure/*physiology ; Kidney Medulla/*blood supply ; Laser-Doppler Flowmetry ; NG-Nitroarginine Methyl Ester ; Natriuresis/*physiology ; Nitric Oxide/antagonists &amp; inhibitors/*physiology ; Rats ; Rats, Wistar ; Regional Blood Flow/physiology ; }, abstract = {This study examined whether nitric oxide synthesis blockade or potentiation (with N omega-nitro-L-arginine methyl ester [L-NAME] or N-acetylcysteine, respectively) can shift the relations between sodium excretion, papillary blood flow, and renal perfusion pressure. Papillary blood flow was measured by laser Doppler flowmetry. A low dose of L-NAME (3.7 nmol/kg per minute) reduced papillary blood flow only at high arterial pressure (140 mm Hg), but it had no effect on pressure natriuresis. Infusion of 37 nmol/kg per minute L-NAME reduced cortical blood flow by 9% at all perfusion pressures studied, lowered papillary blood flow by 8% and 19% at 120 and 140 mm Hg, respectively, and blunted the pressure-natriuresis response. The administration of 185 nmol/kg per minute L-NAME reduced cortical blood flow by 30% and decreased papillary blood flow by 25% in the range of 100 to 140 mm Hg of arterial pressure. Blockade of nitric oxide synthesis with L-NAME at all doses studied reduced papillary blood flow only at high renal perfusion pressures, but papillary blood flow remained essentially unchanged at low perfusion pressures, thus restoring papillary blood flow autoregulation. N-Acetyl-cysteine (1.8 mmol/kg) increased papillary blood flow by 9% and shifted the relations between papillary blood flow, sodium excretion, and renal perfusion pressure toward lower pressures. This effect of N-acetylcysteine on papillary blood flow was blocked by subsequent L-NAME administration.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7720826, year = {1995}, author = {Colton, CA and Pagan, F and Snell, J and Colton, JS and Cummins, A and Gilbert, DL}, title = {Protection from oxidation enhances the survival of cultured mesencephalic neurons.}, journal = {Experimental neurology}, volume = {132}, number = {1}, pages = {54-61}, doi = {10.1016/0014-4886(95)90058-6}, pmid = {7720826}, issn = {0014-4886}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Survival/drug effects ; Cells, Cultured ; Glutathione Peroxidase/*pharmacology ; Mesencephalon/*cytology/*metabolism ; Neurons/cytology/enzymology ; Oxidative Stress ; Oxygen/*metabolism ; Rats ; Reactive Oxygen Species/*pharmacology ; Superoxide Dismutase/*pharmacology ; Tyrosine 3-Monooxygenase/metabolism ; }, abstract = {Oxidative stress has been linked to the destruction of dopaminergic neurons in the substantia nigra and may be a significant factor in both Parkinson's disease and MPTP toxicity. Using primary cultures of embryonic rat mesencephalon and standard immunocytochemical techniques, we have examined the survival of tyrosine hydroxylase-containing (TH+) neurons cultured in the presence of antioxidants and/or in an environment of low oxygen partial pressure. The number of TH+ neurons increased approximately twofold if superoxide dismutase, glutathione peroxidase (GP), or N-acetyl cysteine (NAC) were added to the culture media. Exposure of the neurons to a 5% oxygen environment (38 torr, i.e., 38 mm Hg) also increased the survival of TH+ neurons by about twofold. A dramatic enhancement of survival, however, was seen when NAC was used in combination with the 5% oxygen environment. In this case, the number of TH+ neurons increased fourfold from nontreated controls. Morphological changes were also noted. GP increased the average neurite length while NAC increased the average area of the cell body in the TH+ neuron. These results suggest that manipulation of oxidative conditions by changing the ambient O2 tension or the level of antioxidants promotes survival of TH+ neurons in culture and may have implications for transplantation therapies in Parkinson's disease.}, }
@article {pmid7697831, year = {1995}, author = {Izzotti, A and Balansky, R and Scatolini, L and Rovida, A and De Flora, S}, title = {Inhibition by N-acetylcysteine of carcinogen-DNA adducts in the tracheal epithelium of rats exposed to cigarette smoke.}, journal = {Carcinogenesis}, volume = {16}, number = {3}, pages = {669-672}, doi = {10.1093/carcin/16.3.669}, pmid = {7697831}, issn = {0143-3334}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Anticarcinogenic Agents/*pharmacology ; DNA Adducts/*drug effects ; Epithelium/drug effects/metabolism ; Humans ; Male ; Plants, Toxic ; Rats ; Rats, Sprague-Dawley ; Smoke/*adverse effects ; Nicotiana ; Trachea/*drug effects/metabolism ; }, abstract = {The ability of the aminothiol N-acetylcysteine (NAC) to prevent the formation of carcinogen-DNA adducts in tracheal epithelial cells was investigated in Sprague-Dawley rats exposed whole-body to mainstream cigarette smoke for either 40 or 100 consecutive days. 32P-Postlabelling analyses showed the occurrence of DNA adducts (12.49 adducts/10(8) nucleotides) after 40 days of exposure, with a trend to formation of characteristic diagonal radioactive zones. Total adduct levels were not further enhanced after 100 days of exposure to smoke, although significant changes occurred in the amounts of individual adducts. NAC, given by gavage in the 40 day study and in drinking water in the 100 day study, significantly inhibited the formation of smoke-related carcinogen-DNA adducts in the tracheal epithelium, to such an extent that adduct levels were not significantly higher than those detected in sham-exposed control rats. Together with a variety of other molecular, clastogenicity, metabolic, cytological and histopathological end-points investigated in rodents and with the preliminary evidence arising from a study in humans, these results document the considerable efficacy of oral NAC in inhibiting smoke-related carcinogen-DNA adducts.}, }
@article {pmid7558175, year = {1995}, author = {Jones, DP and Maellaro, E and Jiang, S and Slater, AF and Orrenius, S}, title = {Effects of N-acetyl-L-cysteine on T-cell apoptosis are not mediated by increased cellular glutathione.}, journal = {Immunology letters}, volume = {45}, number = {3}, pages = {205-209}, doi = {10.1016/0165-2478(95)00004-o}, pmid = {7558175}, issn = {0165-2478}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/*drug effects/immunology ; Cells, Cultured ; DNA Damage/immunology ; Glutathione/antagonists &amp; inhibitors/biosynthesis/*drug effects ; Hybridomas/drug effects ; Mice ; Oxidation-Reduction/drug effects ; T-Lymphocytes/*drug effects/metabolism ; }, abstract = {Thiol-containing antioxidants such as N-acetyl-L-cysteine (NAC) are known to inhibit apoptosis, although it is unclear whether this effect is direct or mediated through modulation of intracellular glutathione (GSH). In the present study, NAC treatment of the murine T-cell hybridoma DO-11.10 was found to inhibit apoptosis triggered by anti-CD3 antibody but enhance the process when induced by 6-alpha- methylprednisolone. HPLC measurements showed that these effects were not correlated with the levels of GSH or glutathione disulfide (GSSG) in the cells. Similar effects on DNA fragmentation were obtained when the experiments were repeated in the presence either of a specific inhibitor of GSH biosynthesis (buthionine sulfoximine) or the isomer N-acetyl-D-cysteine which cannot be enzymatically converted into GSH. We conclude that NAC can have divergent effects on apoptosis independent of changes in either the amount or redox state of intracellular GSH.}, }
@article {pmid7873605, year = {1995}, author = {Esposito, F and Cuccovillo, F and Morra, F and Russo, T and Cimino, F}, title = {DNA binding activity of the glucocorticoid receptor is sensitive to redox changes in intact cells.}, journal = {Biochimica et biophysica acta}, volume = {1260}, number = {3}, pages = {308-314}, doi = {10.1016/0167-4781(94)00209-l}, pmid = {7873605}, issn = {0006-3002}, mesh = {Base Sequence ; Cell Line ; DNA/*metabolism ; HeLa Cells ; Humans ; Molecular Sequence Data ; Oligodeoxyribonucleotides ; Oxidants/pharmacology ; Oxidation-Reduction ; Receptors, Glucocorticoid/*metabolism ; Transcriptional Activation ; }, abstract = {The effect of changes of redox conditions on glucocorticoid receptor (GR) activity in intact cells has been studied using two approaches. One was to evaluate the GR-DNA binding in extracts of COS2 cells transiently overexpressing GR and in which reactive oxygen intermediates (ROI) accumulate as a consequence of glutathione (GSH) depletion. GR-DNA binding was significantly decreased in COS2 cells treated with diethylmaleate (DEM), which causes GSH depletion by forming GSH-DEM complexes. A similar effect was observed for Sp1, another Zn-finger transcription factor, whereas no difference was observed for the C/EBP transcription factor, which is known to be unaffected by redox changes in vitro. N-Acetylcysteine (NAC), which counteracts the effects of DEM by increasing GSH biosynthesis, prevents the decrease of GR-DNA binding in cells treated with DEM. The GR-DNA binding efficiency was similarly decreased using extracts from H2O2-treated COS2 cells and from COS2 cells treated with buthionine sulphoximine, which causes GSH depletion via a mechanism different from that of DEM. The other approach was to evaluate the efficiency of a GR-regulated promoter under different redox conditions. In HeLa cells, transfected with a plasmid containing the CAT gene under the control of the glucocorticoid responsive element (GRE) within the mouse mammary tumor virus promoter, and treated with dexamethasone to activate GR, exposure to DEM significantly impaired the activation of CAT gene expression induced by dexamethasone. Also in this case NAC treatment inhibited the effects of DEM.}, }
@article {pmid7849291, year = {1995}, author = {Brisseau, GF and Dackiw, AP and Cheung, PY and Christie, N and Rotstein, OD}, title = {Posttranscriptional regulation of macrophage tissue factor expression by antioxidants.}, journal = {Blood}, volume = {85}, number = {4}, pages = {1025-1035}, pmid = {7849291}, issn = {0006-4971}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Cells, Cultured ; Female ; Fluorescent Antibody Technique ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation/*drug effects ; Humans ; Kinetics ; Lipopolysaccharides/pharmacology ; Macrophages, Peritoneal/drug effects/*metabolism ; Mice ; Monocytes/drug effects/*metabolism ; NF-kappa B/metabolism ; Pyrrolidines/*pharmacology ; RNA Processing, Post-Transcriptional/*drug effects ; RNA, Messenger/analysis/biosynthesis ; Thiocarbamates/*pharmacology ; Thromboplastin/*biosynthesis ; Transcription Factor AP-1/metabolism ; Transcription Factors/metabolism ; }, abstract = {Tissue factor (TF) expression by cells of monocyte/macrophage lineage represents an important mechanism underlying the initiation of fibrin deposition at sites of extravascular inflammation. Recent evidence suggests a role for oxidant stress in the signalling pathway of various cell types by virtue of its ability to induce DNA binding of various transcription factors, including nuclear factor kappa B and AP-1. The effect of antioxidant treatment on lipopolysaccharide (LPS)-induced TF expression was examined in murine peritoneal macrophages and human monocytes. Both pyrrolidine dithiocarbamate, an oxidant scavenger, and N-acetyl-cysteine, a precursor of the endogenous antioxidant glutathione, inhibited stimulation of macrophage procoagulant activity by LPS. Northern blot analysis showed that neither of these agents reduced LPS-stimulated TF mRNA accumulation, thereby suggesting a posttranscriptional mechanism for the effect. Immunofluorescence studies of human monocytes using polyclonal anti-TF antibody showed that N-acetyl-cysteine treatment prevented the characteristic plasmalemmal localization of TF antigen that occurs in response to LPS. Western blot analysis showed that N-acetyl-cysteine reduced the accumulation of the 47-kD mature glycoprotein in LPS-treated cells, a finding consistent with the results of the immunofluorescence studies. Furthermore, these conditions did not result in an accumulation of the less mature forms of TF. When considered together, these data suggest that antioxidants exert their effects by impairing translation and/or by causing degradation of newly translated protein. The effect of antioxidants on tumor necrosis factor appeared to be species specific, with no effect on LPS-induced tumor necrosis factor in murine cells, but with inhibition in human monocytes. The posttranscriptional effect of antioxidants on TF expression data suggests a novel mechanism whereby these agents might modulate monocyte/macrophage activation.}, }
@article {pmid7857277, year = {1995}, author = {Hall, TJ and Schaeublin, M and Jeker, H and Fuller, K and Chambers, TJ}, title = {The role of reactive oxygen intermediates in osteoclastic bone resorption.}, journal = {Biochemical and biophysical research communications}, volume = {207}, number = {1}, pages = {280-287}, doi = {10.1006/bbrc.1995.1184}, pmid = {7857277}, issn = {0006-291X}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Animals, Newborn ; Antioxidants/*pharmacology ; *Bone Resorption ; Cell Survival/drug effects ; Cells, Cultured ; Deferoxamine/pharmacology ; Free Radical Scavengers/pharmacology ; NF-kappa B/antagonists &amp; inhibitors/*metabolism ; Osteoclasts/cytology/drug effects/*physiology ; Pyrrolidines/*pharmacology ; Rats ; Reactive Oxygen Species/*metabolism ; Thiocarbamates/*pharmacology ; }, abstract = {Osteoclasts have been shown to produce reactive oxygen intermediates (ROI) and it has been suggested that ROI are involved in the process of bone resorption. ROI have also been shown to play a central role in the activation of the multisubunit transcription factor NF-kappa B that enhances the transcription of genes encoding defence and signaling proteins. Therefore, we have assessed the effect of pyrrolidine dithiocarbamate (PDTC), an oxygen-radical scavenger and metal chelator that is a selective and potent inhibitor of NF-kappa B activation, on osteoclastic bone resorption in the bone slice assay. PDTC (0.001-0.1 mM) dose-dependently and non-cytotoxically inhibited osteoclast activity with an IC50 of 0.01 mM. PDTC (0.01 mM) caused no change in the ratio of resorption pit area to resorption pit depth as measured by Lasertec confocal microscopy, indicating that ROI are not involved in the resorptive process per se. This view is supported by time-course studies showing that addition of PDTC or N-acetyl cysteine (NAC; an ROI scavenger, but not metal chelator), 6 hr after the start of the assay had no significant effect on subsequent bone resorption. Desferal (100 microM), a chelator of iron and other metal ions, had no significant effect on bone resorption, indicating (along with the results with NAC) that ROI-scavenging rather than metal chelation is responsible for inhibition of osteoclastic bone resorption by PDTC. Taken together these results indicate that ROI produced by osteoclasts in the bone slice assay are not involved in the process of bone resorption, but are important during osteoclast activation for bone resorption, possibly being involved in activation of the transcription factor NF-kappa B.}, }
@article {pmid7853180, year = {1995}, author = {Dantzler, WH and Evans, KK and Wright, SH}, title = {Kinetics of interactions of para-aminohippurate, probenecid, cysteine conjugates and N-acetyl cysteine conjugates with basolateral organic anion transporter in isolated rabbit proximal renal tubules.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {272}, number = {2}, pages = {663-672}, pmid = {7853180}, issn = {0022-3565}, support = {HL-07249/HL/NHLBI NIH HHS/United States ; NS-07309/NS/NINDS NIH HHS/United States ; P01-DK-41006/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacology ; Animals ; Anion Transport Proteins ; Carrier Proteins/*metabolism ; Cysteine/*analogs &amp; derivatives/pharmacology ; In Vitro Techniques ; Kidney Tubules, Proximal/drug effects/*metabolism ; Mercuric Chloride/pharmacology ; Probenecid/*pharmacology ; Rabbits ; p-Aminohippuric Acid/*pharmacokinetics ; }, abstract = {Kinetics of the first 15 s of para-aminohippurate (PAH) uptake across the basolateral membrane of single isolated S2 segments of rabbit proximal renal tubules and the effects of probenecid and cysteine conjugates on them were determined. For PAH uptake in control tubules, Kt (the concentration of PAH at 1/2 Jmax) was about 110 microM and Jmax (maximal rate of PAH transport) was about 6.5 pmol min-1 nl-1. In tubules preloaded with alpha-ketoglutarate (alpha-KG), thereby stimulating PAH/alpha-KG countertransport, Jmax doubled with little change in Kt. Probenecid cis-inhibited PAH uptake with an apparent Ki of about 13 to 15 microM whether or not the tubules were preloaded with alpha-KG. High probenecid concentrations cis-inhibited PAH uptake by > 98%, indicating that essentially all movement of PAH across the basolateral membrane is carrier mediated. Zwitterionic nephrotoxic cysteine conjugate, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and nontoxic cysteine conjugate, S-(2-benzothiazole)-L-cysteine (BTC) cis-inhibited PAH uptake (apparent Ki: approximately 86 microM for DCVC; approximately 37 microM for BTC) at least as effectively as their negatively charged N-acetyl derivatives (NAC-DCVC and NAC-BTC) (apparent Ki: approximately 310 microM for NAC-DCVC; approximately 35 microM for NAC-BTC). The inhibition by both DCVC and NAC-DCVC was competitive in nature. NAC-DCVC also cis-inhibited net transepithelial secretion of PAH by isolated, perfused S2 segments. The presence of DCVC and NAC-DCVC, as well as PAH itself, in the bathing medium trans-stimulated the 15 s efflux of PAH across the basolateral membrane of single S2 segments with oil-filled lumens. These data indicate that these cysteine conjugates and their N-acetyl derivatives, not only interact competitively with the PAH transporter, but are transported by it.}, }
@article {pmid7828222, year = {1995}, author = {Särnstrand, B and Tunek, A and Sjödin, K and Hallberg, A}, title = {Effects of N-acetylcysteine stereoisomers on oxygen-induced lung injury in rats.}, journal = {Chemico-biological interactions}, volume = {94}, number = {2}, pages = {157-164}, doi = {10.1016/0009-2797(94)03332-3}, pmid = {7828222}, issn = {0009-2797}, mesh = {Acetylcysteine/administration &amp; dosage/blood/*pharmacology/therapeutic use ; Administration, Oral ; Animals ; Cysteine/blood ; Disease Models, Animal ; Glutathione/blood ; Hyperemia/drug therapy ; Infusion Pumps, Implantable ; Infusions, Intravenous ; Lung/*drug effects/pathology ; Male ; Osmosis ; Oxygen/*toxicity ; Pulmonary Edema/drug therapy ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; }, abstract = {The effects of the stereoisomers of N-acetylcysteine (L-NAC and D-NAC) on oxygen-induced lung oedema have been studied in rats. The NAC-isomers were given by an osmotic minipump in order to attain continuous administration, either intravenously or intragastrically. In some experiments, plasma concentrations of NAC, cysteine and glutathione (total concentrations, i.e., concentrations obtained after reduction of the samples with dithiothreitol) were recorded. Exposure to oxygen induced an almost two-fold increase of the lung wet weight. When L-NAC or D-NAC were given intravenously, in dose of 1.1 mmol/day/kg body weight, the increase of lung wet weight was prevented by 40-50%. The plasma concentrations were approximately 40 microM (L-NAC) and approximately 90 microM (D-NAC). Following intragastrical administration of the same doses, plasma concentrations of L-NAC and D-NAC reached approximately 3 and approximately 60 microM, respectively. Using this method of administration, only D-NAC significantly diminished the increase of the lung wet weight. The difference in plasma concentrations of the NAC isomers, particularly after intragastric administration, most likely reflects the fact that L-NAC is effectively hydrolysed in most tissues, while D-NAC is resistant to enzymatic hydrolysis, thus penetrating largely intact into the systemic circulation. The data presented shows that NAC, regardless of stereoconfiguration, will protect the lung against oxygen toxicity, provided sufficient systemic levels are obtained. Since D-NAC is not a precursor of L-cysteine, formation of glutathione cannot explain the protective effects of this isomer. L- and D-NAC may therefore act via direct antioxidant/radical scavenging mechanisms and not necessarily as precursors of glutathione in this model.}, }
@article {pmid7701469, year = {1995}, author = {Dekhuijzen, PN and Van Herwaarden, CL}, title = {Effect of N-acetyl cysteine on thiol levels.}, journal = {Thorax}, volume = {50}, number = {2}, pages = {215}, pmid = {7701469}, issn = {0040-6376}, mesh = {Acetylcysteine/*therapeutic use ; Humans ; Lung Diseases, Obstructive/*drug therapy ; Sulfhydryl Compounds/*metabolism ; }, }
@article {pmid7621808, year = {1995}, author = {Ramos, O and Carrizales, L and Yáñez, L and Mejía, J and Batres, L and Ortíz, D and Díaz-Barriga, F}, title = {Arsenic increased lipid peroxidation in rat tissues by a mechanism independent of glutathione levels.}, journal = {Environmental health perspectives}, volume = {103 Suppl 1}, number = {Suppl 1}, pages = {85-88}, pmid = {7621808}, issn = {0091-6765}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Arsenic/*toxicity ; Buthionine Sulfoximine ; Female ; Glutamate-Cysteine Ligase/*antagonists &amp; inhibitors ; Glutathione/*metabolism ; Lipid Peroxidation/*drug effects ; Methionine Sulfoximine/*analogs &amp; derivatives/pharmacology ; Rats ; Rats, Wistar ; }, abstract = {The role of lipid peroxidation in the mechanism of arsenic toxicity was investigated in female rats pretreated with N-acetylcysteine (NAC, a glutathione [GSH] inducer) or with buthionine sulfoximine (BSO, a GSH depletor). Rats were challenged with sodium arsenite, and sacrificed 1 hr after this treatment. Results showed that arsenic decreased GSH levels and increased lipid peroxidation in liver, kidney, and heart, with a larger effect at 18.2 mg/kg than at 14.8 mg/kg for lipid peroxidation induction. In the liver of rats treated with arsenic, pretreatment with NAC increased the levels of GSH and decreased lipid peroxidation. In kidney and heart, NAC pretreatment protected the tissues against arsenic-induced depletion of GSH levels, but the same degree of protection was not found for lipid peroxidation induction. In its turn, BSO had an additive effect with arsenic in lowering the levels of GSH in the liver and kidney, but an inverse correlation between GSH levels and lipid peroxidation was found only in liver. Arsenic content in tissues of rats pretreated with NAC was lower than in rats treated only with arsenic. In rats with depleted levels of GSH (BSO-pretreated rats), a shift in arsenic tissue distribution was found, with higher levels in skin and lower levels in kidney. A clear tendency for a positive correlation between arsenic concentration and lipid peroxidation levels was found in liver, kidney, and heart.}, }
@article {pmid7895867, year = {1995}, author = {Yamanaka, T and Hishinuma, A}, title = {[Different effects of anticancer drugs on two human thyroid cell lines with different stages of differentiation].}, journal = {Nihon Naibunpi Gakkai zasshi}, volume = {71}, number = {1}, pages = {73-86}, doi = {10.1507/endocrine1927.71.1_73}, pmid = {7895867}, issn = {0029-0661}, mesh = {Adenoma/*pathology ; Adult ; Antineoplastic Agents/*pharmacology ; Carcinoma, Papillary/*pathology ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Female ; Free Radicals/metabolism ; Humans ; Middle Aged ; Thyroid Neoplasms/*pathology ; Time Factors ; Tumor Cells, Cultured/drug effects ; }, abstract = {We established two human thyroid tumor cell lines. One cell line (hPTC) was established from the tissue of a papillary thyroid carcinoma surgically excised from a 27-year-old female patient. The other cell line (hAG) was established from the tissue of an adenomatous goiter excised from a 59-year old female patient. Synthesis of cAMP by hPTC and hAG increased when they were stimulated by TSH. hPTC and hAG continued to divide as a monolayer in a tissue culture for three years and two years, respectively. We assessed the efficacy of anticancer drugs (doxorubicin:ADR, cisplatin:CDDP, nimustine:ACNU, bleomycin:BLM, cyclophosphamide:CPA, aclarubicin:ACR) with resard to hPTC. The hPTC cells were cultured in 24-well plates in the presence of the anticancer drugs for 48 hours, and the cellular DNA of the live cells was measured with diaminobenzoic acid. ADR had the lowest ED50 (0.029 mu g/ml) and the clinical blood concentration was 13.8 times that of the ED50. The clinical blood concentration divided by ED50 for the other anticancer drugs are, in order of higher values, 2.3 for CPA, 1.7 for BLM, 1.2 for CDDP, 0.5 for ACR, and less than 0.1 for ACNU. ADR showed time-independent effects since a 2-hour exposure of ADR to the hPTC cells resulted in the significant reduction of the cellular DNA content of the live cells even after 48 hours. The effects of the other anticancer drugs were time-dependent. We then studied the difference of the effects of ADR on hPTC and hAG. ED50 for hPTC was significantly low (0.035 mu g/ml) compared to that for hAG (0.460 mu g/ml). Since free radical formation is one of the major anticancer mechanisms of ADR the effects of free radicals on ED50's for hPTC and hAG were measured by adding glutathione (GSH), N-acetylcystein (NAC), buthionine sulfoximine (BSO), and alpha-tocopherol (alpha-toco) into the culture media. GSH catches up with free radicals in the extracellular fluid. NAC promotes production of GSH in the cytoplasm, but BSO interferes with the production of GSH in the cytoplasm. alpha-toco catches up with free radicals on the plasma membrane. GSH and alpha-toco did not effect ED50 for hPTC and hAG. However, NAC increased ED50 for hPTC and hAG, and BSO reduced ED50 for hPTC and hAG. The effects of NAC and BSO on ED50 for hPTC were greater than those for hAG.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid7839430, year = {1995}, author = {Fukuzawa, K and Emre, S and Senyuz, O and Acarli, K and Schwartz, ME and Miller, CM}, title = {N-acetylcysteine ameliorates reperfusion injury after warm hepatic ischemia.}, journal = {Transplantation}, volume = {59}, number = {1}, pages = {6-9}, doi = {10.1097/00007890-199501150-00002}, pmid = {7839430}, issn = {0041-1337}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/metabolism ; Animals ; Aspartate Aminotransferases/metabolism ; Bile/metabolism ; Glutathione/*metabolism ; Hot Temperature ; Ischemia/*metabolism ; L-Lactate Dehydrogenase/metabolism ; Liver/*blood supply/metabolism ; Oxidative Stress ; Reperfusion Injury/metabolism/*prevention &amp; control ; Swine ; }, abstract = {Glutathione is important in cellular defense against oxidative stress. We postulated that administration of N-acetylcysteine (NAC), a glutathione precursor, might help maintain or replenish hepatic glutathione stores, thereby reducing reperfusion injury in liver grafts after warm ischemia. Eighteen pigs were subjected to 2 hr of warm hepatic ischemia and divided into a control group (group A, n = 6), a preischemia treatment group (group B, n = 6: NAC, 150 mg/kg, continuous i.v. infusion 1 hr before ischemia), and a postischemia treatment group (group C, n = 6: NAC, 150 mg/kg continuous i.v., begun 20 min before reperfusion and continued for 1 hr). At initiation of laparotomy, we measured hepatic levels of reduced glutathione (GSH), its oxidized form (GSSG), ATP, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). Before reperfusion, after 2 hr of warm ischemia, GSH, GSSG, and ATP were measured. One hour after reperfusion, we measured GSH, GSSG, ATP, AST, and LDH. Bile output was recorded every 10 min. Postoperfusion AST and LDH were significantly lower in both treatment groups than in controls. In group B, hepatic glutathione was maintained at significantly higher levels than in controls, even after ischemia (P < 0.05). In group C, although hepatic GSH levels fell until reperfusion, after administration of NAC, hepatic GSH reached the level of the preischemia treatment group. In both treatment groups, GSH 1 hr after reperfusion was significantly higher than in the controls (P < 0.01): regeneration of glutathione was seen in all 6 animals in group C, compared with 2/6 in group B and none in the control group. ATP recovery, bile output, and survival were all better in the treatment groups than in the control group. Pretreatment with NAC helps maintain hepatic glutathione during warm ischemia; given after ischemia, NAC is effective in replenishing depleted glutathione stores. Adjunctive use of NAC was associated with improved glutathione homeostasis, improved bile output and ATP regeneration, and increased survival.}, }
@article {pmid8001675, year = {1995}, author = {Vallé, A and Kinet, JP}, title = {N-acetyl-L-cysteine inhibits antigen-mediated Syk, but not Lyn tyrosine kinase activation in mast cells.}, journal = {FEBS letters}, volume = {357}, number = {1}, pages = {41-44}, doi = {10.1016/0014-5793(94)01329-y}, pmid = {8001675}, issn = {0014-5793}, mesh = {Acetylcysteine/*pharmacology ; Antigens/metabolism ; Calcium/metabolism ; Cell Line ; Enzyme Activation/drug effects ; Enzyme Precursors/*antagonists &amp; inhibitors ; Exocytosis/drug effects ; Intracellular Signaling Peptides and Proteins ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/*antagonists &amp; inhibitors/*metabolism ; Receptors, IgE/*metabolism ; Syk Kinase ; *src-Family Kinases ; }, abstract = {High affinity IgE receptors (alpha beta gamma 2) mediate the activation of the non-receptor tyrosine kinases Lyn and Syk. Here we show that the antioxidant drug N-acetyl-L-cysteine (NAC) inhibits antigen-mediated Syk activation whereas Lyn activation and phosphorylation of beta and gamma is maintained. Furthermore, NAC inhibits antigen-mediated calcium mobilization and exocytosis in a dose-dependent manner, but does not inhibit ionomycin-induced exocytosis. These data support a model in which the activation of Lyn is responsible for receptor phosphorylation and precedes the activation of Syk. The inhibition of Syk activation by NAC may be relevant to B and T cell antigen receptors, which are also linked to Syk/ZAP70 tyrosine kinases.}, }
@article {pmid8866668, year = {1995}, author = {Flugy, A and Borsellino, N and D'Alessandro, N}, title = {TNF-induced apoptosis in multidrug resistant friend erythroleukemia is not influenced by the P-glycoprotein and glutathione status of the cell line.}, journal = {Oncology research}, volume = {7}, number = {10-11}, pages = {559-564}, pmid = {8866668}, issn = {0965-0407}, mesh = {ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism ; Acetylcysteine/pharmacology ; Animals ; Antibiotics, Antineoplastic/pharmacology ; Antimetabolites, Antineoplastic/pharmacology ; Apoptosis/*drug effects/physiology ; Buthionine Sulfoximine/pharmacology ; Cell Differentiation/drug effects ; Diuretics/pharmacology ; Doxorubicin/pharmacology ; *Drug Resistance, Multiple ; Drug Synergism ; Enzyme Inhibitors/pharmacology ; Ethacrynic Acid/pharmacology ; *Friend murine leukemia virus ; Glutathione/*metabolism ; Interferon-gamma/pharmacology ; Leukemia, Erythroblastic, Acute/*drug therapy/*metabolism/virology ; Mice ; Recombinant Proteins ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {The effects that TNF-alpha exerts on Friend erythroleukemia (FLC) and on one multidrug resistant variant (FLC-DXR) of the cell line were studied. Resistance to doxorubicin of FLC-DXR entails two mechanisms: overexpression of P-glycoprotein; and increased glutathione-related activities. Both these might also decrease the effects of the cytokine. Nonetheless, TNF caused even greater cytotoxicity and apoptosis, with no induction of differentiation markers, in FLC-DXR. In addition, TNF produced minor changes of the levels of reduced and oxidized glutathione in the cell lines, and its cytotoxic effects were not inluenced by agents that modify the cell glutathione content such as buthionine sulfoximine, ethacrynic acid, or N-acetyl cysteine. We can exclude that the mechanisms of drug resistance of FLC-DXR prevent the response to the cytokine.}, }
@article {pmid8833231, year = {1995}, author = {Vasdev, S and Mian, T and Longerich, L and Prabhakaran, V and Parai, S}, title = {N-acetyl cysteine attenuates ethanol induced hypertension in rats.}, journal = {Artery}, volume = {21}, number = {6}, pages = {312-316}, pmid = {8833231}, issn = {0098-6127}, mesh = {Acetaldehyde/blood ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Aorta/drug effects/metabolism ; Blood Platelets/drug effects/metabolism ; Blood Pressure/*drug effects ; Body Weight/drug effects ; Calcium/blood ; Cytosol/metabolism ; Energy Intake ; Ethanol/*pharmacology ; Heart/anatomy &amp; histology/drug effects ; Hypertension/chemically induced/*prevention &amp; control ; Kidney/anatomy &amp; histology/drug effects ; Lipid Peroxidation/drug effects ; Liver/anatomy &amp; histology/drug effects ; Male ; Muscle, Smooth, Vascular/drug effects/metabolism ; Myocardium/pathology ; Organ Size/drug effects ; Rats ; Rats, Inbred WKY ; Renal Circulation/drug effects ; Thiobarbituric Acid Reactive Substances/analysis ; }, abstract = {All known pathways of ethanol metabolism result in the production of acetaldehyde, a highly reactive compound. N-acetyl cysteine, an analogue of the dietary amino acid cysteine, binds acetaldehyde, thus preventing its damaging effect on physiological proteins. This study examined the effect of oral N-acetyl cysteine on the increased blood pressure, platelet cytosolic free calcium, blood acetaldehyde and adverse renal vascular changes induced by chronic ethanol treatment in rats. Twenty-four male Wistar-Kyoto (WKY) rats, age 7 weeks were divided into four groups of six animals each. Animals in group I were given water and group II 5% ethanol in water for the next 14 weeks. Animals in group III were given 5% ethanol + 1% N-acetyl cysteine for 4 weeks followed by 5% ethanol + 2% N-acetyl cysteine for the next 10 weeks. Animals in group IV were given 5% ethanol for 7 weeks; at that time ethanol was withdrawn and animals were placed on water with 2% N-acetyl cysteine for the next 7 weeks. After 14 weeks systolic blood pressure and platelet cytosolic free calcium were all significantly higher (p<0.001) in rats given ethanol as compared to rats in other groups. N-acetyl cysteine treatment, along with ethanol, significantly (p<0.001) attenuated the increased blood pressure and platelet cytosolic free calcium and adverse renal vascular changes. Discontinuation of ethanol treatment for 7 weeks along with N-acetyl cysteine supplementation also significantly lowered the blood pressure and platelet cytosolic free calcium and attenuated adverse renal vascular changes. There was no significant difference in aortic malonaldehyde among four groups. Increase in blood acetaldehyde with ethanol treatment was significantly attenuated with N-acetyl cysteine treatment. These results suggest that acetaldehyde may be the cause of ethanol-induced hypertension and elevated cytosolic free calcium and renal vascular changes.}, }
@article {pmid8574146, year = {1995}, author = {Eylar, EH and Báez, I and Vázquez, A and Yamamura, Y}, title = {N-acetylcysteine (NAC) enhances interleukin-2 but suppresses interleukin-4 secretion from normal and HIV+ CD4+ T-cells.}, journal = {Cellular and molecular biology (Noisy-le-Grand, France)}, volume = {41 Suppl 1}, number = {}, pages = {S35-40}, pmid = {8574146}, issn = {0145-5680}, support = {1-G-12RR03050/RR/NCRR NIH HHS/United States ; 1-S06-RR08239/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Antibodies, Monoclonal/pharmacology ; CD28 Antigens/physiology ; Concanavalin A/pharmacology ; HIV Infections/*immunology ; Hispanic or Latino ; Humans ; Interleukin-2/*metabolism ; Interleukin-4/*metabolism ; Lymphocyte Activation ; Muromonab-CD3/pharmacology ; Tetradecanoylphorbol Acetate/pharmacology ; Th1 Cells/*drug effects/metabolism ; Th2 Cells/*drug effects/metabolism ; }, abstract = {We find that purified CD4+ T cells from 30 HIV+ individuals have a suppressed Interleukin-4 (IL-4) production compared to normal controls regardless of activator (anti-CD3 or Con A) or co-activator [phorbol ester (PMA or anti-CD28)], generally by 2-4 fold. In every case, the cells producing IL-4 respond more strongly to anti-CD28 co-activation than to PMA, ie, 1150 pg/ml compared to 2070 pg/ml for controls and 398 pg/ml compared to 1250 pg/ml for HIV+ cells, respectively. In contrast, anti-CD3 with PMA gives a more vigorous IL-2 response than with anti-CD28, ie, 37.3 ng/ml compared to 12.3 ng/ml for controls and 28.5 ng/ml versus 15.1 ng/ml for HIV+ cells, respectively. These data are not compatible with the TH1/TH2 switch hypothesis since IL-4 production is decreased, not increased for CD4+ HIV+ T-cells and while IL-2 production is decreased with PMA, it is not decreased significantly with anti-CD28. Interestingly, 5 mM N-acetylcysteine (NAC) acts as an immunoenhancer; mitogenesis was enhanced 2 fold or more in general for control and HIV+ CD4+ T-cells and IL-2 production was enhanced 2-3 fold for anti-CD3 (with PMA or anti-CD28) for both controls and HIV+ CD4+ cells. However, NAC suppressed IL-4 production induced by anti-CD3 and anti-CD28 in both control and HIV+ CD4+ T cells. In the other cases, it produced in general no significant change.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8538208, year = {1995}, author = {De Flora, S and Cesarone, CF and Balansky, RM and Albini, A and D'Agostini, F and Bennicelli, C and Bagnasco, M and Camoirano, A and Scatolini, L and Rovida, A}, title = {Chemopreventive properties and mechanisms of N-Acetylcysteine. The experimental background.}, journal = {Journal of cellular biochemistry. Supplement}, volume = {22}, number = {}, pages = {33-41}, doi = {10.1002/jcb.240590806}, pmid = {8538208}, issn = {0733-1959}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anticarcinogenic Agents/*therapeutic use ; Biomarkers/chemistry ; Cricetinae ; Cytoplasm/drug effects ; Humans ; Inactivation, Metabolic ; Mice ; Mutagenicity Tests ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Rats ; }, abstract = {The thiol N-acetylcysteine (NAC), now under clinical trial for cancer chemoprevention both in Europe (project Euroscan) and in the US (National Cancer Institute), has been shown during the past decade to exert protective effects in a variety of experimental test systems. NAC inhibited spontaneous mutagenicity and that induced by a number of chemical compounds and complex mixtures. Moreover, NAC significantly decreased the incidence of neoplastic and preneoplastic lesions induced by several chemical carcinogens in rodents (mice, rats, hamsters), e.g., in lung, trachea, colon, liver, mammary gland, Zymbal gland, bladder and skin. Our studies provided evidence that multiple mechanisms contribute to NAC antimutagenicity and anticarcinogenicity. They include extracellular mechanisms, such as detoxification of reactive compounds due to the nucleophilic and antioxidant properties of NAC, inhibition of nitrosation products, and enhancement of thiol concentration in intestinal bacteria; trapping and enhanced detoxification of carcinogens in long-lived non-target cells, such as erythrocytes and bronchoalveolar lavage cells; mechanisms working in the cytoplasm of target cells, such as replenishment of GSH stores, modulation of metabolism of mutagens/carcinogens, blocking of electrophiles, and scavenging of reactive oxygen species; and nuclear effects, such as inhibition of DNA adduction by metabolites of carcinogens, inhibition of "spontaneous" mutations, attenuation of carcinogen-induced DNA damage, and protection of nuclear enzymes, such as poly(ADP-ribose) polymerase.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8538205, year = {1995}, author = {van Zandwijk, N}, title = {N-acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer.}, journal = {Journal of cellular biochemistry. Supplement}, volume = {22}, number = {}, pages = {24-32}, doi = {10.1002/jcb.240590805}, pmid = {8538205}, issn = {0733-1959}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Anticarcinogenic Agents/adverse effects/*therapeutic use ; Antidotes/therapeutic use ; Antioxidants/adverse effects/*therapeutic use ; Expectorants/therapeutic use ; Glutathione/adverse effects/*therapeutic use ; Humans ; Lung Neoplasms/*prevention &amp; control ; Smoking/*adverse effects ; }, abstract = {Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well-recognized causes. Apart from oxidants (free radicals), cigarette smoke contains such a multitude of (pre)carcinogens that it is astonishing that not every heavy smoker becomes a victim of malignancy. This points to the interindividual variability in susceptibility to carcinogens; several lines of evidence suggest that metabolic factors are involved in such variability. Metabolism of carcinogens as well as the subsequent (multi)steps of carcinogenesis are affected by host factors and governed by the balance between opposing forces, such as metabolic activation and detoxification, formation and scavenging of radicals, and DNA damage and repair, which seem to imply that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione (GSH) plays a crucial role in the detoxification of xenobiotics. N-Acetylcysteine (NAC), an aminothiol and synthetic precursor of intracellular cysteine and GSH, has been used for many years in Europe as a mucolytic drug. Clinically, it is a safe agent without major side effects and has been considered to have a place in cancer prevention, too. The antimutagenic and anticarcinogenic properties of NAC could be ascribed to multiple protective mechanisms, such as NAC nucleophilicity, antioxidant activity, its ability to act as a precursor of intracellular reduced GSH, modulation of detoxification, and DNA repair processes. On these grounds, NAC has emerged as a most promising cancer chemopreventive agent.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7856740, year = {1995}, author = {Blanco, FJ and Ochs, RL and Schwarz, H and Lotz, M}, title = {Chondrocyte apoptosis induced by nitric oxide.}, journal = {The American journal of pathology}, volume = {146}, number = {1}, pages = {75-85}, pmid = {7856740}, issn = {0002-9440}, support = {AG07996/AG/NIA NIH HHS/United States ; }, mesh = {Adult ; Aged ; Apoptosis/drug effects/*physiology ; Cartilage/*cytology/drug effects ; Cells, Cultured ; DNA Damage ; Flow Cytometry ; Humans ; Interleukin-1/pharmacology ; Middle Aged ; Nitric Oxide/*physiology ; Reactive Oxygen Species/pharmacology ; }, abstract = {Chondrocytes stimulated with IL-1 produce high levels of nitric oxide (NO), which inhibits proliferation induced by transforming growth factor-beta or serum. This study analyzes the role of NO and IL-1 in the induction of chondrocyte cell death. NO generated from sodium nitroprusside induced apoptosis in cultured chondrocytes as demonstrated by electron microscopy, 4',6-dianidino-2-phenylindole dihydrochloride staining, FACS analysis, and histochemical detection of DNA fragmentation. Similar results were obtained with two other NO donors, 3-morpholinosynonimide-hydrochloride and s-nitroso-N-acetyl-D-L-penicillamine. In contrast, oxygen radicals generated by hypoxanthine/xanthine oxidase caused necrosis but did not induce chondrocyte apoptosis. To analyze whether endogenously generated NO induces apoptosis, chondrocytes were stimulated with IL-1, but there was no evidence for apoptotic changes. Combinations of NO inducers such as IL-1, lipopolysaccharide, tumor necrosis factor, and interferon-gamma also failed to trigger apoptosis. IL-1-stimulated chondrocytes are known to produce oxygen radicals that react with NO to form products that can induce cell death in other systems. We thus tested IL-1 in combination with the oxygen radical scavengers N-acetyl cysteine, dimethyl sulfoxide, or 5,5'-dimetylpyrroline 1-oxide. Under these conditions IL-1 was able to induce apoptosis, which was inhibited in a dose-dependent manner by the NO synthase inhibitor N-monomethyl L-arginine. Conversely, endogenous oxygen radicals induced by inflammatory mediators caused necrosis under conditions in which the simultaneous production of NO was reduced. These results suggest that NO, but not oxygen radicals, is the primary inducer of apoptosis in human articular chondrocytes.}, }
@article {pmid7795309, year = {1995}, author = {Andersen, LW and Thiis, J and Kharazmi, A and Rygg, I}, title = {The role of N-acetylcystein administration on the oxidative response of neutrophils during cardiopulmonary bypass.}, journal = {Perfusion}, volume = {10}, number = {1}, pages = {21-26}, doi = {10.1177/026765919501000105}, pmid = {7795309}, issn = {0267-6591}, mesh = {Acetylcysteine/*pharmacology ; *Cardiopulmonary Bypass ; Double-Blind Method ; Humans ; Luminescent Measurements ; Middle Aged ; Neutrophils/*drug effects/metabolism ; Oxidation-Reduction/drug effects ; Superoxides/blood ; }, abstract = {The role of N-acetylcystein (NAC) administration on the oxidative response of neutrophils during cardiopulmonary bypass (CPB) was evaluated in a double-blind study. Twenty-four adult patients undergoing coronary artery bypass were included in the study. Twelve patients received NAC as a bolus of 100 mg/kg followed by a continuous infusion of 20 mg/kg/h in the bypass circuit from the beginning to the end of bypass. A further 12 patients received placebo. Citrated blood samples for measurement of oxidative burst response of neutrophils were obtained at different time points during bypass. The oxidative burst response of neutrophils in the patients receiving NAC was significantly low at all times during bypass. Based on these findings NAC appears to act as an oxygen free radical scavenger during open-heart surgery.}, }
@article {pmid7734187, year = {1995}, author = {Witschi, A and Junker, E and Schranz, C and Speck, RF and Lauterburg, BH}, title = {Supplementation of N-acetylcysteine fails to increase glutathione in lymphocytes and plasma of patients with AIDS.}, journal = {AIDS research and human retroviruses}, volume = {11}, number = {1}, pages = {141-143}, doi = {10.1089/aid.1995.11.141}, pmid = {7734187}, issn = {0889-2229}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acquired Immunodeficiency Syndrome/blood/*drug therapy ; Adult ; Cysteine/blood ; Female ; Glutathione/*blood ; Humans ; Lymphocytes/metabolism ; Male ; Middle Aged ; }, abstract = {Because glutathione (GSH) in plasma and lymphocytes of HIV-infected patients is low, adjunct therapy with N-acetylcysteine (NAC) to restore GSH homeostasis has been proposed. To investigate the effect of NAC on the GSH status we treated six patients with AIDS with 1.8 g/day of NAC for 2 weeks. During treatment the plasma concentration of cysteine, a precursor for GSH synthesis, increased significantly. Nevertheless, there was no significant increase in GSH in plasma and peripheral blood mononuclear cells. The failure of sulfhydryl supplementation to increase GSH suggests that the low concentrations of the tripeptide are not the result of an increased consumption secondary to an oxidant stress, but rather the consequence of a decreased rate of synthesis of GSH in HIV infection.}, }
@article {pmid7734123, year = {1995}, author = {McNeil, CJ and Athey, D and Ho, WO}, title = {Direct electron transfer bioelectronic interfaces: application to clinical analysis.}, journal = {Biosensors &amp; bioelectronics}, volume = {10}, number = {1-2}, pages = {75-83}, doi = {10.1016/0956-5663(95)96796-2}, pmid = {7734123}, issn = {0956-5663}, mesh = {Cytochrome c Group/*chemistry ; Electrochemistry ; Electrodes ; Electron Transport ; *Electronics, Medical ; Enzymes, Immobilized ; Free Radicals ; Gold ; Horseradish Peroxidase/*chemistry ; Humans ; Immunoassay ; Neutrophils/metabolism ; Signal Transduction/physiology ; Superoxides/metabolism ; }, abstract = {Bioelectronic interfaces based on direct electron transfer to proteins and enzymes immobilised at functional electrode surfaces are currently under development and the potential of two such systems for application to clinical measurement will be outlined. The first is the detection of free radical production via direct electrochemistry of cytochrome c immobilised covalently at modified gold electrodes. The redox protein cytochrome c has been immobilised covalently to gold electrodes surface-modified with N-acetyl cysteine via carbodiimide condensation. The electrodes thus produced were used to measure directly the enzymatic and cellular production of the superoxide anion radical (O2(-). The superoxide radical reduced the immobilised cytochrome c which was immediately re-oxidised by the surface-modified gold electrode poised at a potential of +25 mV (vs Ag/AgCl). The electron transfer rate constant (ket) of this process was 3.4 +/- 1.2 s(-1). The rate of current generation was directly proportional to the rate of O2(-) production. The essentially reagentless system produced was designed to be applied ultimately to continuous monitoring of free radical activity in vivo since there is evidence that oxygen-derived free radical species act as mediators which cause and perpetuate inflammation in disease states, including rheumatoid arthritis and neurodegenerative disorders. The second systems are pseudo-homogeneous immunoassays based on direct electron transfer to horseradish peroxidase. Horseradish peroxidase enzyme electrodes based on activated carbon (HRP-ACE) have been constructed by simple passive adsorption.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7651057, year = {1995}, author = {Baas, P and van Mansom, I and van Tinteren, H and Stewart, FA and van Zandwijk, N}, title = {Effect of N-acetylcysteïne on Photofrin-induced skin photosensitivity in patients.}, journal = {Lasers in surgery and medicine}, volume = {16}, number = {4}, pages = {359-367}, doi = {10.1002/lsm.1900160407}, pmid = {7651057}, issn = {0196-8092}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Dihematoporphyrin Ether/administration &amp; dosage/*adverse effects ; Edema/chemically induced/prevention &amp; control ; Erythema/chemically induced/prevention &amp; control ; Esophageal Neoplasms/radiotherapy ; Female ; Follow-Up Studies ; Free Radicals/adverse effects ; Glutathione/metabolism ; Humans ; Lung Neoplasms/drug therapy ; Male ; Middle Aged ; Photochemotherapy/adverse effects ; Photosensitivity Disorders/chemically induced/*prevention &amp; control ; Reactive Oxygen Species/adverse effects ; Skin/*drug effects/metabolism/*radiation effects ; }, abstract = {BACKGROUND AND OBJECTIVE: One of the major side effects of photodynamic therapy (PDT) employing Photofrin as the sensitizer is enhanced photosensitivity of the skin. The basic mechanism in PDT damage is believed to be the formation of singlet oxygen and radical species. N-acetylcysteïne (NAC) increases glutathione levels and is known to prevent pathology elicited by radicals and reactive species.<br><br>NAC was tested in a randomized, open label study for its protective effect on skin photosensitivity. Twenty-seven patients treated with PDT for central obstructive lung cancer or esophageal cancer received either "early" or "delayed" NAC, starting 5 or 10 days after Photofrin, in a dose of 3 x 600 mg per day for 5 days. Light, obtained from a halogen lamp (fluence rate 200 mW.cm-2) was used to illuminate skin patches of 2.5 cm2 on the back (10, 25, and 50 J.cm-2). Skin response was measured by using a visual scoring system and by measuring the redness using a reflectance meter.<br><br>RESULTS: Skin responses varied from no changes at 10 J.cm-2 to redness with edema at energies of 50 J.cm-2. In the absence of edema, measurements with the reflectance meter appeared to be more sensitive than visual scoring.<br><br>CONCLUSION: In a limited number of patients, there was a trend for decreased sensitivity after NAC, but statistical analysis failed to show any significant protective effect of this short course of NAC.}, }
@article {pmid7589000, year = {1995}, author = {Zhang, H and Spapen, H and Nguyen, DN and Rogiers, P and Bakker, J and Vincent, JL}, title = {Effects of N-acetyl-L-cysteine on regional blood flow during endotoxic shock.}, journal = {European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes}, volume = {27}, number = {5}, pages = {292-300}, doi = {10.1159/000129412}, pmid = {7589000}, issn = {0014-312X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dogs ; Femoral Artery/physiopathology ; Free Radical Scavengers/*pharmacology ; Hemodynamics/drug effects ; Mesenteric Arteries/physiopathology ; Oxygen/blood ; Regional Blood Flow/*drug effects ; Renal Artery/physiopathology ; Shock, Septic/blood/*physiopathology ; }, abstract = {We previously reported that N-acetyl-L-cysteine (NAC), an oxygen free-radical scavenger, can increase the oxygen extraction capabilities during endotoxic shock when blood flow is progressively reduced. In the present study, we investigated whether the protective effects of NAC are related to an improvement in regional blood flow following endotoxemia. Fourteen anesthetized, saline-infused and ventilated dogs were divided into two groups: 7 dogs received NAC (150 mg/kg, followed by a 20 mg/kg.h infusion), and the other 7 dogs served as a control time-matching group. Thirty minutes later all the dogs received Escherichia coli endotoxin (2 mg/kg) i.v. A saline infusion was started 30 min after endotoxin challenge to restore pulmonary artery occlusion pressure to baseline and maintain it constant. Regional blood flow was measured by ultrasonic volume flowmeter. In the control group, arterial pressure, left ventricular stroke work index and systemic vascular resistance remained lower than baseline. Mesenteric, renal and femoral arterial blood flow increased but only femoral blood flow returned to baseline levels. In the NAC group, cardiac index and left ventricular stroke work index remained higher and systemic and pulmonary vascular resistance were lower than in the control group. Blood flow in mesenteric, renal and especially femoral arteries was higher than in the control group. Fractional blood flow increased only in the femoral artery. PaO2 and PvO2 had similar courses in the two groups. A higher venous admixture was associated with a higher cardiac index and a lower pulmonary vascular resistance in the NAC group. Oxygen delivery and oxygen-uptake were higher in the NAC-treated than in the control animals throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7546156, year = {1995}, author = {Walcher, F and Marzi, I and Flecks, U and Larsen, R}, title = {N-acetylcysteine failed to improve early microcirculatory alterations of the rat liver after transplantation.}, journal = {Transplant international : official journal of the European Society for Organ Transplantation}, volume = {8}, number = {4}, pages = {317-323}, doi = {10.1007/BF00346887}, pmid = {7546156}, issn = {0934-0874}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Adhesion ; Female ; Glutathione/analogs &amp; derivatives/drug effects/metabolism ; Glutathione Disulfide ; Leukocytes/cytology ; Liver/*blood supply ; Liver Transplantation/*physiology ; Microcirculation/drug effects ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/*prevention &amp; control ; }, abstract = {The application of radical scavengers reduces reperfusion injury of liver grafts despite the natural occurrence of cellular defense mechanisms enabling the cell to tolerate moderate oxidant stress without further cell damage. The glutathione peroxidase mechanism of the liver serves to reduce hydroxyl radical-induced lipid peroxidation by releasing reduced glutathione from intracellular stores. There is evidence that the application of cysteine-providing amino acids for glutathione synthesis could maintain or even increase liver glutathione. Therefore, the purpose of this study was to evaluate the effect of N-acetylcysteine (NAC) on oxidative stress-induced reperfusion injury after liver transplantation. This was done by applying intravital microscopy. Livers from female Sprague-Dawley rats weighing 220-260 g were stored for 20 h in University of Wisconsin (UW) solution and transplanted orthotopically using the cuff technique. Donors were given 150 mg/kg body weight NAC i.v. or placebo in a blind, random fashion 6 h prior to harvesting, followed by two injections of 50 mg/kg body weight, 4 and 2 h before explantation. In additional experimental groups, recipients were given a bolus of 83 mg/kg body weight NAC or placebo at the beginning of the recipient operations, 1 min prior to reperfusion, and 60 min after surgery. Ninety minutes after transplantation, intravital microscopy was applied and five liver lobules were recorded for 30 s after injection of acridine orange, a fluorescent leukocyte marker. Sinusoidal perfusion, sinusoidal width, and leukocyte adhesion, as well as reduced and oxidized glutathione, were determined in all livers.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7998983, year = {1994}, author = {Rizzardini, M and Carelli, M and Cabello Porras, MR and Cantoni, L}, title = {Mechanisms of endotoxin-induced haem oxygenase mRNA accumulation in mouse liver: synergism by glutathione depletion and protection by N-acetylcysteine.}, journal = {The Biochemical journal}, volume = {304 (Pt 2)}, number = {Pt 2}, pages = {477-483}, pmid = {7998983}, issn = {0264-6021}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Buthionine Sulfoximine ; Dose-Response Relationship, Drug ; Escherichia coli ; Glutathione/antagonists &amp; inhibitors/*metabolism ; Heme Oxygenase (Decyclizing)/*genetics ; Lipopolysaccharides/*pharmacology ; Liver/drug effects/*enzymology ; Male ; Methionine Sulfoximine/administration &amp; dosage/analogs &amp; derivatives/pharmacology ; Mice ; Oxidative Stress ; RNA, Messenger/*metabolism ; S-Adenosylmethionine/pharmacology ; }, abstract = {In in vitro systems haem oxygenase-1 (HO-1) mRNA increases after exposure to agents causing oxidative stress. We lowered cellular antioxidant defence systems in vivo by giving mice increasing doses (0.15 g/kg-1.6 g/kg) of DL-buthionine-(S,R)-sulphoximine (BSO), a specific inhibitor of glutathione synthesis. Maximum glutathione depletion (80%) coincided with maximum hepatic HO-1 mRNA accumulation (about 20 times), whereas with 50% depletion, accumulation was only doubled. It has been suggested that reactive oxygen and nitrogen intermediates are involved in hepatic toxicity of endotoxin (lipopolysaccharide, LPS); LPS even at low doses [0.1 mg/kg, intraperitoneally (i.p.)] induces HO-1 mRNA about 25-fold after 1 h. Hepatic glutathione depletion (respectively 40% and 80%) after a low (0.3 g/kg) or a high (1.6 g/kg) BSO dose, resulted in potentiation of the HO-1 mRNA accumulation induced by LPS (0.1 mg/kg, i.p.). In the absence of BSO, N-acetylcysteine (NAC) (1 g/kg orally) reduced LPS-induced HO-1 mRNA accumulation to one fourth. Under the same experimental conditions S-adenosylmethionine (SAM) was not effective. NAC also reduced HO-1 mRNA accumulation when administered to mice in which glutathione was depleted and its synthesis blocked by BSO (1.6 g/kg). Thus reactive oxygen intermediates are likely mediators of LPS-induced HO-1 mRNA accumulation, and glutathione content appears to be one of the factors regulating this accumulation in the liver. Our findings are compatible with the theory that HO-1 induction might have a protective function in vivo when defence mechanisms against oxidants are challenged.}, }
@article {pmid7996046, year = {1994}, author = {Nottet, HS and van Asbeck, BS and de Graaf, L and de Vos, NM and Visser, MR and Verhoef, J}, title = {Role for oxygen radicals in self-sustained HIV-1 replication in monocyte-derived macrophages: enhanced HIV-1 replication by N-acetyl-L-cysteine.}, journal = {Journal of leukocyte biology}, volume = {56}, number = {6}, pages = {702-707}, doi = {10.1002/jlb.56.6.702}, pmid = {7996046}, issn = {0741-5400}, mesh = {Acetylcysteine/antagonists &amp; inhibitors/*pharmacology ; Drug Interactions ; Ferrous Compounds/metabolism ; Free Radical Scavengers ; Glutathione/pharmacology ; HIV-1/*drug effects/metabolism/*physiology ; Humans ; Hydroxyl Radical/metabolism ; Macrophages/drug effects/metabolism/*virology ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Stimulation, Chemical ; Thiourea/analogs &amp; derivatives/pharmacology ; Urea/pharmacology ; Virus Replication/*drug effects/*physiology ; }, abstract = {N-acetyl-L-cysteine (NAC) has been proposed as a therapeutic agent for AIDS patients because it reduces human immunodeficiency virus type 1 (HIV-1) replication in stimulated T cells. However, NAC and glutathione enhanced acute HIV-1 replication in monocyte-derived macrophages. Buthionine sulfoximine did not affect NAC-mediated enhanced HIV-1 replication, indicating that the NAC-mediated effects are glutathione-independent. Superoxide dismutase and the hydroxyl radical scavengers dimethylthiourea and thiourea, but not urea, inhibited acute HIV-1 replication in macrophages. NAC reduced ferricytochrome c and increased dose-dependently Fe(III)-citrate and Fe(III)-EDTA-catalyzed hydroxyl radical formation in a system using glucose and glucose oxidase. Dimethylthiourea and thiourea, but not urea and superoxide dismutase, dose-dependently inhibited NAC-mediated enhancement of HIV-1 replication. These data suggest that oxygen radicals play an important role in self-sustained HIV-1 replication in macrophages and that oxygen radical scavengers other than NAC should be considered as therapeutic agents for AIDS patients.}, }
@article {pmid7989604, year = {1994}, author = {Reid, MB and Stokić, DS and Koch, SM and Khawli, FA and Leis, AA}, title = {N-acetylcysteine inhibits muscle fatigue in humans.}, journal = {The Journal of clinical investigation}, volume = {94}, number = {6}, pages = {2468-2474}, pmid = {7989604}, issn = {0021-9738}, support = {HL-45721/HL/NHLBI NIH HHS/United States ; RR-05425/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/*pharmacology ; Adult ; Ankle/physiology ; Antioxidants/adverse effects/*pharmacology ; Cross-Over Studies ; Electric Stimulation ; Humans ; Male ; Muscle Contraction/physiology ; Muscle Fatigue/*drug effects ; }, abstract = {N-acetylcysteine (NAC) is a nonspecific antioxidant that selectively inhibits acute fatigue of rodent skeletal muscle stimulated at low (but not high) tetanic frequencies and that decreases contractile function of unfatigued muscle in a dose-dependent manner. The present experiments test the hypothesis that NAC pretreatment can inhibit acute muscular fatigue in humans. Healthy volunteers were studied on two occasions each. Subjects were pretreated with NAC 150 mg/kg or 5% dextrose in water by intravenous infusion. The subject then sat in a chair with surface electrodes positioned over the motor point of tibialis anterior, an ankle dorsiflexor of mixed-fiber composition. The muscle was stimulated to contract electrically (40-55 mA, 0.2-ms pulses) and force production was measured. Function of the unfatigued muscle was assessed by measuring the forces produced during maximal voluntary contractions (MVC) of ankle dorsiflexor muscle groups and during electrical stimulation of tibialis anterior at 1, 10, 20, 40, 80, and 120 Hz (protocol 1). Fatigue was produced using repetitive tetanic stimulations at 10 Hz (protocol 1) or 40 Hz (protocol 2); intermittent stimulations subsequently were used to monitor recovery from fatigue. The contralateral leg then was studied using the same protocol. Pretreatment with NAC did not alter the function of unfatigued muscle; MVC performance and the force-frequency relationship of tibialis anterior were unchanged. During fatiguing contractions stimulated at 10 Hz, NAC increased force output by approximately 15% (P < 0.0001), an effect that was evident after 3 min of repetitive contraction (P < 0.0125) and persisted throughout the 30-min protocol. NAC had no effect on fatigue induced using 40 Hz stimuli or on recovery from fatigue. N-acetylcysteine pretreatment can improve performance of human limb muscle during fatiguing exercise, suggesting that oxidative stress plays a causal role in the fatigue process and identifying antioxidant therapy as a novel intervention that may be useful clinically.}, }
@article {pmid7963551, year = {1994}, author = {Flescher, E and Ledbetter, JA and Schieven, GL and Vela-Roch, N and Fossum, D and Dang, H and Ogawa, N and Talal, N}, title = {Longitudinal exposure of human T lymphocytes to weak oxidative stress suppresses transmembrane and nuclear signal transduction.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {153}, number = {11}, pages = {4880-4889}, pmid = {7963551}, issn = {0022-1767}, support = {DE09311/DE/NIDCR NIH HHS/United States ; DE10863/DE/NIDCR NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Adult ; Base Sequence ; CD3 Complex/immunology ; Calcium/metabolism ; DNA/metabolism ; Electrophoresis, Polyacrylamide Gel/methods ; Female ; Gene Expression Regulation ; Humans ; Interleukin-2/*biosynthesis ; Male ; Middle Aged ; Molecular Sequence Data ; Oxidative Stress/*physiology ; Oxidoreductases Acting on CH-NH Group Donors/metabolism ; Polymerase Chain Reaction ; Protein-Tyrosine Kinases/physiology ; RNA, Messenger ; Signal Transduction/*physiology ; Spermidine/metabolism ; T-Lymphocytes/*immunology ; Polyamine Oxidase ; }, abstract = {Products of polyamine oxidase activity, at micromolar levels and during a period of 2 to 3 days, down-regulate IL-2 mRNA levels and activity in human lymphocytes. We studied whether this suppression was associated with signal transduction abnormalities. We found that polyamine oxidase activity suppresses both anti-CD3-induced IL-2 production and protein tyrosine phosphorylation. Polyamine oxidase activity also caused a reduction in intracellular calcium mobilization after mitogenic stimulation. The most distal step of CD3-mediated signal transduction is dependent upon transcription factors that regulate a set of genes, including IL-2. We found that polyamine oxidase-treated cells exhibited very low DNA binding activity of two such factors: NFAT and NF-kappa B. On the other hand, AP-1 DNA binding activity was enhanced in polyamine oxidase-treated cells, suggesting a possible role for AP-1 in the human lymphocyte stress response. In accordance with the oxidation dependence of this suppressive mechanism, N-acetylcysteine (NAC; an antioxidant) significantly reversed the polyamine oxidase effects on lymphokine production and signal transduction. These results suggest that NAC contributes, under oxidizing conditions, to the preservation of immune function. In summary, our data suggest that chronic low-level oxidative stress, via suppression of mitogen-induced transmembrane signaling (protein-tyrosine phosphorylation and calcium mobilization), causes a decrease in the DNA binding activity of transcription factors that regulate the IL-2 gene. This results in decreased IL-2 production.}, }
@article {pmid7889134, year = {1994}, author = {Bakker, J and Zhang, H and Depierreux, M and van Asbeck, S and Vincent, JL}, title = {Effects of N-acetylcysteine in endotoxic shock.}, journal = {Journal of critical care}, volume = {9}, number = {4}, pages = {236-243}, doi = {10.1016/0883-9441(94)90003-5}, pmid = {7889134}, issn = {0883-9441}, mesh = {Acetylcysteine/blood/*therapeutic use ; Analysis of Variance ; Animals ; Blood Pressure/drug effects ; Cardiac Output/drug effects ; Disease Models, Animal ; Dogs ; Lactates/blood ; Random Allocation ; Respiratory Function Tests ; Shock, Septic/*drug therapy/metabolism ; Tumor Necrosis Factor-alpha/drug effects/metabolism ; Vasodilator Agents/blood/*therapeutic use ; }, abstract = {PURPOSE: The release of oxygen-free radicals has been implicated in both peripheral vascular and myocardial alterations of septic shock. N-Acetylcysteine (N-AC), a substrate for the production of glutathione, has potent antioxidant effects. As a nitrosothiol, it may also improve capillary blood flow. We studied the effects of N-AC in a dog model of endotoxic shock.<br><br>METHODS: Ten pentobarbital-anesthetized, mechanically ventilated dogs were randomly assigned to receive either N-AC (150 mg/kg loading dose in 1 hour, followed by 20 mg/kg.h maintenance dose) or D5W. After the loading dose, each dog received 3 mg/kg Escherichia coli endotoxin intravenously. After 30 minutes, saline infusion was started to restore and maintain baseline filling pressures.<br><br>RESULTS: The loading dose of N-AC increased DO2 significantly (from 661 +/- 54 to 914 +/- 190 mL/min, P < .05), but VO2 remained stable. After the administration of endotoxin, fluid challenge restored cardiac output to baseline, in both groups. Hemoglobin and, thus, DO2 were slightly lower in the N-AC-treated dogs, but VO2 was similar in both groups. At the end of the study, O2ER was significantly higher in the N-AC-treated dogs than in the control dogs. Blood lactate levels fell more rapidly in the N-AC dogs than in the control dogs. Blood lactate levels returned to normal in the N-AC dogs but not in the control dogs. Tumor necrosis factor (TNF) also decreased significantly in the N-AC dogs but remained elevated in the control dogs.<br><br>CONCLUSION: These data indicate that N-AC administration in endotoxic shock is well tolerated, may increase oxygen availability to the tissues, and is associated with an attenuation of TNF release.}, }
@article {pmid7867976, year = {1994}, author = {de Toranzo, EG and Castro, JA}, title = {Reaction of 4-hydroxynonenal with some thiol-containing radioprotective agents or their active metabolites.}, journal = {Free radical biology &amp; medicine}, volume = {17}, number = {6}, pages = {605-607}, doi = {10.1016/0891-5849(94)90100-7}, pmid = {7867976}, issn = {0891-5849}, support = {DK 13195-23/DK/NIDDK NIH HHS/United States ; }, mesh = {Aldehydes/*chemistry ; Cysteine/chemistry ; Glutathione/chemistry ; Kinetics ; Radiation-Protective Agents/*chemistry ; Sulfhydryl Compounds/chemistry ; }, abstract = {The rate of reaction of several radioprotective agents or their active metabolites with 4-hydroxynonenal (4HNE) was studied and compared to the rate of reaction with cysteine (Cys) and glutathione (GSH). The agents studied were: mercapto ethylamine (MEA); 2(3-aminopropyl) aminoethanethiol (WR1065); S-2-aminoethylisothiouronium bromide-hydrobromide (AET); 1,4-dithiothreitol (DTT); 1,4-dithioerythritol (DTE); N-2(2-mercaptopropionyl)-glycine (MPG); penicillamine hydrochloride (PA); N-acetylcysteine (NAC); 2-3 dimercapto-1 propane sulfonic acid (DMPS); 2,3-dimercaptopropanol (BAL), and meso 2,3 dimercapto succinic acid (DMS). All of them reacted with 4HNE. MEA and WR1065 were the most reactive thiols, and PA and DMS were the least reactive thiols. All the others reacted at rates comparable to or higher than that of cysteine or GSH. The potential role of this type of interactions in the protective action of these drugs against deleterious effects of radiation or carbon tetrachloride is analyzed.}, }
@article {pmid7853119, year = {1994}, author = {van den Broeke, LT and Beijersbergen, GM and van Henegouwen, B}, title = {The effect of N-acetylcysteine on the UVB-induced inhibition of epidermal DNA synthesis in rat skin.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {26}, number = {3}, pages = {271-276}, doi = {10.1016/1011-1344(94)07042-3}, pmid = {7853119}, issn = {1011-1344}, mesh = {Acetylcysteine/*pharmacology ; Animals ; DNA/biosynthesis/drug effects/*radiation effects ; DNA Replication/drug effects/radiation effects ; Dose-Response Relationship, Radiation ; Female ; Rats ; Rats, Wistar ; Skin/drug effects/metabolism/*radiation effects ; *Ultraviolet Rays ; }, abstract = {The effect of N-acetylcysteine (NAC), on the UVB-induced inhibition of epidermal DNA synthesis in rat skin was investigated. Topical application of NAC, 30 min prior to UVB irradiation (20 kJ m-2), significantly reduced the UVB-induced inhibition of the epidermal (methyl-1',2'-3H)-thymidine uptake. These results indicate that NAC affords protection against at least some of the damaging effects of UVB radiation on epidermal DNA, probably by neutralization of UVB induced reactive species.}, }
@article {pmid7721335, year = {1994}, author = {Malorni, W and D'Ambrosio, A and Rainaldi, G and Rivabene, R and Viora, M}, title = {Thiol supplier N-acetylcysteine enhances conjugate formation between natural killer cells and K562 or U937 targets but increases the lytic function only against the latter.}, journal = {Immunology letters}, volume = {43}, number = {3}, pages = {209-214}, doi = {10.1016/0165-2478(94)90225-9}, pmid = {7721335}, issn = {0165-2478}, mesh = {Acetylcysteine/*pharmacology ; Actins/metabolism ; Cell Membrane/metabolism ; *Cytotoxicity, Immunologic ; Humans ; Killer Cells, Natural/drug effects/*metabolism/ultrastructure ; Membrane Glycoproteins/metabolism ; *Microfilament Proteins ; Microscopy, Fluorescence ; Monocytes/metabolism ; Sulfhydryl Compounds ; Tumor Cells, Cultured/metabolism ; }, abstract = {In this in vitro study, an evaluation of the importance of intracellular oxidative balance on cell-mediated cytotoxicity was performed by analyzing the effects of the antioxidant N-acetylcysteine (NAC), a specific thiol supplier, on natural killer (NK) cell-mediated cytotoxicity. The results obtained indicate that an enhancement of target cell (TC) killing can be detected when a pre-exposure of effector cells (EC) to NAC was performed. However, this effect seems to depend upon the TC type used. In fact, the increase of EC activity was detected against the differentiated U937 TC while no changes were detected by the same effectors against K562 cells. The mechanism of this enhancement seems to be ascribable to an increased ability of NAC-exposed NK cells to form conjugates (binding) which, in turn, appears to be due to a specific effect of NAC on actin microfilaments. A role for NAC as a cytoskeleton thiol-modifier contributing to the activation of effector cells can thus be hypothesized.}, }
@article {pmid7986199, year = {1994}, author = {Bessho, R and Matsubara, K and Kubota, M and Kuwakado, K and Hirota, H and Wakazono, Y and Lin, YW and Okuda, A and Kawai, M and Nishikomori, R}, title = {Pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kappa B (NF-kappa B) activation, prevents apoptosis in human promyelocytic leukemia HL-60 cells and thymocytes.}, journal = {Biochemical pharmacology}, volume = {48}, number = {10}, pages = {1883-1889}, doi = {10.1016/0006-2952(94)90586-x}, pmid = {7986199}, issn = {0006-2952}, mesh = {Acetylcysteine/pharmacology ; Apoptosis/*drug effects ; Base Sequence ; Cytarabine/pharmacology ; Endonucleases/antagonists &amp; inhibitors ; Etoposide/pharmacology ; Humans ; Leukemia, Promyelocytic, Acute/*pathology ; Molecular Sequence Data ; NF-kappa B/*antagonists &amp; inhibitors ; Oligodeoxyribonucleotides ; Phenanthrolines/pharmacology ; Pyrrolidines/*pharmacology ; T-Lymphocytes/cytology/*drug effects ; Thiocarbamates/*pharmacology ; Thymus Gland/cytology ; Tumor Cells, Cultured ; }, abstract = {We examined the effect of pyrrolidine dithiocarbamate (PDTC), which potently blocks the activation of nuclear factor kappa B (NF-kappa B), on the induction of apoptosis by a variety of agents. Treatment of a human promyelocytic leukemia cell line, HL-60, with 10 micrograms/mL etoposide or 2 microM 1-beta-D-arabinofuranosylcytosine induced NF-kappa B activation within 1 hr and subsequently caused apoptosis within 3-4 hr. The simultaneous addition of 50-500 microM PDTC with these agents blocked NF-kappa B activation and completely abrogated both morphologically apoptotic changes and internucleosomal DNA fragmentation for up to 6 hr. However, PDTC failed to inhibit the endonuclease activity contained in the whole cell lysates. The inhibitory effect of PDTC was also observed in etoposide- and dexamethasone-induced apoptosis in human thymocytes at a concentration of 1-10 microM. Since PDTC has both antioxidant and metal-ion chelating activities, we tested the effects of N-acetyl-L-cysteine (NAC) (antioxidant) or o-phenanthroline (OP) (metal-ion chelator) on the induction of apoptosis. Pretreatment of HL-60 cells or thymocytes with 100-500 microM OP for 2 hr, but not 10-60 mM NAC, suppressed subsequent occurrence of apoptosis induced by etoposide. These results suggest that the activation of NF-kappa B plays an important role in the apoptotic process of human hematopoietic cells.}, }
@article {pmid7974515, year = {1994}, author = {Rafeiro, E and Barr, SG and Harrison, JJ and Racz, WJ}, title = {Effects of N-acetylcysteine and dithiothreitol on glutathione and protein thiol replenishment during acetaminophen-induced toxicity in isolated mouse hepatocytes.}, journal = {Toxicology}, volume = {93}, number = {2-3}, pages = {209-224}, doi = {10.1016/0300-483x(94)90079-5}, pmid = {7974515}, issn = {0300-483X}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Buthionine Sulfoximine ; Dithiothreitol/*pharmacology ; Glutathione/*metabolism ; L-Lactate Dehydrogenase/metabolism ; Liver/cytology/*drug effects/metabolism ; Male ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Mice ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Isolated mouse hepatocytes were incubated with 1.0 mM acetaminophen (AA) for 1.5 h to initiate glutathione (GSH) and protein thiol (PSH) depletion and cell injury. Cells were subsequently washed to remove non-covalently bound AA and resuspended in medium containing N-acetylcysteine (NAC, 2.0 mM) or dithiothreitol (DTT, 1.5 mM). The effects of these agents on the replenishment of GSH and total PSH content were related to the development of cytotoxicity. When cells exposed to AA were resuspended in medium containing NAC or DTT, both agents replenished GSH and total PSH content to levels observed in untreated cells but only DTT was able to attenuate cytotoxicity. Addition of the GSH synthesis inhibitor, buthionine sulfoximine (BSO, 1.0 mM, 1.5 h), to cells in incubation medium containing AA, enhanced GSH and total PSH depletion and potentiated cytotoxicity. Resuspension of these cells in medium containing NAC did not alter the potentiating effects of BSO; GSH and PSH levels were not replenished and no cytoprotective effects were observed. However, when cells exposed to AA and BSO were resuspended in medium containing DTT, PSH content was replenished but GSH levels were not restored. In addition, DTT was able to delay the development of cytotoxicity. It appears that DTT, unlike NAC, has a GSH-independent mechanism of PSH replenishment. These observations suggest that while replenishment of GSH and total PSH content does not result in cytoprotection, the regeneration of critical PSH by DTT may play an important role in the maintenance of proper cell structure and/or function.}, }
@article {pmid8082235, year = {1994}, author = {Klee, S and Nürnberger, MC and Ungemach, FR}, title = {The consequences of nitrofurantoin-induced oxidative stress in isolated rat hepatocytes: evaluation of pathobiochemical alterations.}, journal = {Chemico-biological interactions}, volume = {93}, number = {2}, pages = {91-102}, doi = {10.1016/0009-2797(94)90089-2}, pmid = {8082235}, issn = {0009-2797}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carmustine/pharmacology ; Deferoxamine/pharmacology ; Dithiothreitol/pharmacology ; Glutathione/metabolism ; Glutathione Reductase/antagonists &amp; inhibitors ; L-Lactate Dehydrogenase/metabolism ; Liver/*drug effects ; Male ; Malondialdehyde/metabolism ; Nitrofurantoin/*pharmacology ; Oxidation-Reduction ; Rats ; Rats, Wistar ; Stress, Physiological/*chemically induced/metabolism ; }, abstract = {Oxidative stress was induced in isolated rat hepatocytes by incubation with nitrofurantoin in the absence and presence of the GSSG reductase inhibitor BCNU. In both cases nitrofurantoin markedly reduced glutathione but exerted cytotoxicity as measured by LDH release and loss of intracellular potassium only in BCNU pretreated cells. The onset of cytotoxicity was accompanied by an increase of lipid peroxidation. Oxidation of protein thiols, however, could not be detected in the early phase of cell damage. The cytoprotective activity of N-acetyl-cysteine > dithiothreitol = deferoxamine revealed the substantial importance of glutathione for cellular defence and the sensitivity of not yet identified thiol-dependent targets of oxidative stress.}, }
@article {pmid7868466, year = {1994}, author = {Diaz, PT and Brownstein, E and Clanton, TL}, title = {Effects of N-acetylcysteine on in vitro diaphragm function are temperature dependent.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {77}, number = {5}, pages = {2434-2439}, doi = {10.1152/jappl.1994.77.5.2434}, pmid = {7868466}, issn = {8750-7587}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Diaphragm/*drug effects/physiology ; Electric Stimulation ; In Vitro Techniques ; Muscle Contraction/*drug effects ; Muscle Fatigue/*drug effects ; Rats ; Rats, Sprague-Dawley ; Temperature ; }, abstract = {Recent evidence has shown that systemic administration of N-acetylcysteine (NAC), a compound structurally similar to the intracellular antioxidant glutathione, inhibits skeletal muscle fatigue. To further elucidate the actions of NAC, we studied its effects on in vitro rat diaphragm contractile function. Rat diaphragm strips were incubated in tissue baths containing physiological salt solution (n = 29) or physiological salt solution containing 4 mg/ml of NAC (n = 29). Strips were stimulated by either indirect or direct means. After determination of baseline contractile characteristics, strips were fatigued for 4 min at 20 Hz (1 train/s, 0.33 ms train duration). Force-frequency relationships were then studied over a 60-min recovery period. We found that 1) NAC had significant effects on the baseline force-frequency relationship; treated strips had increased peak tension but diminished twitch tension and accelerated twitch kinetics; 2) NAC had significant fatigue-sparing effects that were magnified at 37 degrees C; and 3) NAC treatment did not improve postfatigue recovery. The effects of NAC were generally independent of the stimulation method. We conclude that NAC has direct temperature-dependent effects on diaphragm function. These effects are consistent with the properties of NAC as an antioxidant and suggest important but complex effects of oxidant stress on skeletal muscle.}, }
@article {pmid7868431, year = {1994}, author = {Sen, CK and Atalay, M and Hänninen, O}, title = {Exercise-induced oxidative stress: glutathione supplementation and deficiency.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {77}, number = {5}, pages = {2177-2187}, doi = {10.1152/jappl.1994.77.5.2177}, pmid = {7868431}, issn = {8750-7587}, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine ; Glutathione/deficiency/*metabolism/pharmacology ; Heart/drug effects ; Injections, Intraperitoneal ; Kidney/drug effects/metabolism ; Lipid Peroxides/metabolism ; Liver/drug effects/metabolism ; Lung/drug effects/metabolism ; Male ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Muscle, Skeletal/drug effects/metabolism ; Myocardium/metabolism ; Oxidative Stress/drug effects/*physiology ; Physical Exertion/*physiology ; Random Allocation ; Rats ; Rats, Wistar ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {Glutathione (GSH) plays a central role in coordinating the synergism between different lipid- and aqueous-phase antioxidants. We documented 1) how exogenous GSH and N-acetylcysteine (NAC) may affect exhaustive exercise-induced changes in tissue GSH status, lipid peroxides [thiobarbituric acid-reactive substances (TBARS)], and endurance and 2) the relative role of endogenous GSH in the circumvention of exercise-induced oxidative stress by using GSH-deficient [L-buthionine-(S,R)-sulfoximine (BSO)-treated] rats. Intraperitoneal injection of GSH remarkably increased plasma GSH; exogenous GSH per se was an ineffective delivery agent of GSH to tissues. Repeated administration of GSH (1 time/day for 3 days) increased blood and kidney total GSH [TGSH; GSH+oxidized GSH (GSSG)]. Neither GSH nor NAC influenced endurance to exhaustion. NAC decreased exercise-induced GSH oxidation in the lung and blood. BSO decreased TGSH pools in the liver, lung, blood, and plasma by approximately 50% and in skeletal muscle and heart by 80-90%. Compared with control, resting GSH-deficient rats had lower GSSG in the liver, red gastrocnemius muscle, heart, and blood; similar GSSG/TGSH ratios in the liver, heart, lung, blood, and plasma; higher GSSG/TGSH ratios in the skeletal muscle; and more TBARS in skeletal muscle, heart, and plasma. In contrast to control, exhaustive exercise of GSH-deficient rats did not decrease TGSH in the liver, muscle, or heart or increase TGSH of plasma; GSSG of muscle, blood, or plasma; or TBARS of plasma or muscle. GSH-deficient rats had approximately 50% reduced endurance, which suggests a critical role of endogenous GSH in the circumvention of exercise-induced oxidative stress and as a determinant of exercise performance.}, }
@article {pmid7857697, year = {1994}, author = {Lailey, AF and Upshall, DG}, title = {Thiol levels in rat bronchio-alveolar lavage fluid after administration of cysteine esters.}, journal = {Human &amp; experimental toxicology}, volume = {13}, number = {11}, pages = {776-780}, doi = {10.1177/096032719401301106}, pmid = {7857697}, issn = {0960-3271}, mesh = {Animals ; Bronchoalveolar Lavage Fluid/*chemistry ; Cysteine/administration &amp; dosage/analogs &amp; derivatives/*pharmacology ; Esters/administration &amp; dosage/pharmacology ; Female ; Injections, Intraperitoneal ; Rats ; Sulfhydryl Compounds/blood/*metabolism ; }, abstract = {1. The intraperitoneal administration of cysteine, N-acetylcysteine, the methyl, isopropyl, cyclo pentyl, neo pentyl, cyclo hexyl and tertiary butyl esters of cysteine and of cystine dimethyl ester increased the levels of total non-protein sulphydryls and cysteine in the bronchioalveolar lavage fluid and plasma of rats. In all cases the non-protein sulphydryl levels reflected the increased cysteine levels. 2. Cysteine, N-acetylcysteine, the cysteine esters and cystine dimethyl ester raised the levels of non-protein sulphydryls and hence cysteine in the bronchioalveolar lining fluid as follows: CIPE > CCPE > CME > CDME > CneoPE > CCHE > Nac > CySH > CTBE. 3. Plasma levels of NPSH were increased as follows: Nac > CySH > CCPE > CCHE > CneoPE > CIPE > CME > CDME > CTBE. 4. All except CTBE have been shown to protect against the lethal effects of inhaled perfluoroisobutene, a pyrolysis product of polytetrafluoroethene which induces a fulminating pulmonary oedema. 5. This study showed that by raising the levels of thiols in the bronchioalveolar lavage fluid (BALF), the epithelial cells lining the bronchiolar, alveolar regions of the lung could be protected against inhaled toxicants. 6. It is proposed that increased thiol levels in the BALF may contribute to the overall protection induced by these compounds by reacting with inhaled electrophiles to prevent or reduce damage to tissue in close proximity to the airways.}, }
@article {pmid7857693, year = {1994}, author = {Wilde, PE and Upshall, DG}, title = {Cysteine esters protect cultured rodent lung slices from sulphur mustard.}, journal = {Human &amp; experimental toxicology}, volume = {13}, number = {11}, pages = {743-748}, doi = {10.1177/096032719401301102}, pmid = {7857693}, issn = {0960-3271}, mesh = {Animals ; Cells, Cultured ; Cysteine/analogs &amp; derivatives/*therapeutic use ; Dose-Response Relationship, Drug ; Esters/therapeutic use ; In Vitro Techniques ; Lung/*drug effects/metabolism ; Male ; Mustard Gas/*toxicity ; Rats ; }, abstract = {1. In previous studies an in vitro rat lung slice system was used to investigate the metabolic and structural changes after exposure to known lung toxicants. 2. In this study, the same system was used to identify the ability of cysteine esters to protect against sulphur mustard toxicity. 3. The cyclopentyl (CCPE), cyclohexyl (CCHE), isopropyl (CIPE), methyl (CME) esters of cysteine, cystine dimethyl ester (CDME), cysteine (CySH) and N-acetyl cysteine (NAc) were all non-toxic to cultured rat lung slices at 5 mM (equivalent cysteine concentration) after a pretreatment time of 30 min. 4. Pretreatment with the isopropyl, cyclohexyl, cyclopentyl and methyl esters of cysteine at concentrations higher than 1 mM protected against an IC50 of sulphur mustard, however, neither cysteine nor N-acetylcysteine protected. 5. We propose that the extent of protection is directly related to increased levels of intracellular cysteine provided by the esters of cysteine.}, }
@article {pmid7533847, year = {1994}, author = {Lockhart, BP and Benicourt, C and Junien, JL and Privat, A}, title = {Inhibitors of free radical formation fail to attenuate direct beta-amyloid25-35 peptide-mediated neurotoxicity in rat hippocampal cultures.}, journal = {Journal of neuroscience research}, volume = {39}, number = {4}, pages = {494-505}, doi = {10.1002/jnr.490390416}, pmid = {7533847}, issn = {0360-4012}, mesh = {Allopurinol/pharmacology ; Alzheimer Disease/metabolism/pathology ; Amino Acid Oxidoreductases/antagonists &amp; inhibitors ; Amyloid beta-Peptides/*pharmacology ; Animals ; Arginine/analogs &amp; derivatives/pharmacology ; Catalase/pharmacology ; Cell Death/drug effects ; Cells, Cultured ; Embryo, Mammalian ; Free Radical Scavengers/*pharmacology ; Free Radicals/antagonists &amp; inhibitors/metabolism ; Hippocampus/*metabolism ; Humans ; Indomethacin/pharmacology ; Masoprocol/pharmacology ; Neurons/cytology/drug effects/*metabolism ; Neurotoxins/*pharmacology ; Nitric Oxide Synthase ; Nitroarginine ; Oxypurinol/pharmacology ; Peptide Fragments/*pharmacology ; Quinacrine/pharmacology ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/pharmacology ; Xanthine Oxidase/antagonists &amp; inhibitors ; omega-N-Methylarginine ; }, abstract = {The direct neurotoxic action of the beta-amyloid protein, the major constituent of senile plaques, may represent the underlying cause of neuronal degeneration observed in Alzheimer's disease. The apoptotic-mediated neuronal death induced by beta-amyloid appears to reside in its ability to form Ca(2+)-permeable pores in neuronal membranes resulting in an excessive influx of Ca2+ and the induction of neurotoxic cascades. It is possible that during beta-amyloid exposure a Ca(2+)-mediated increase in free radical generation may exceed the defensive capacity of cells and thus lead to cell death. Consequently, in the present study we have investigated the effect of a panoply of antioxidants and inhibitors of free radical formation on the development of beta-amyloid neurotoxicity. Acute exposure of rat hippocampal neurons to "aged" beta-amyloid25-35 peptide (5-50 microM) induced a slow, concentration-dependent apoptotic neurotoxicity (25-85%) during a 6 day exposure. Co-incubation of cultures with beta-amyloid25-35 peptide (25 microM) and inhibitors of nitric oxide synthase and/or xanthine oxidase (NG-monomethyl-L-arginine [1 mM), N omega-nitro-L-arginine [1 mM], oxypurinol [100 microM], allopurinol [100 microM]), important mediators of nitric oxide, superoxide, and hydroxyl radical formation, did not attenuate beta-amyloid neurotoxicity. Similarly, a reduction in free radical generation by selective inhibition of phospholipase-A2 cyclooxygenase, and lipoxygenase activities with quinacrine (0.5 microM), indomethacin (50 microM), and nor-dihydroguaiaretic acid (0.5 microM), respectively, did not reduce the proclivity of beta-amyloid to induce cell death. Exposure of cultures to catalase (25 U/ml) and/or superoxide dismutase (10 U/ml) as well as the free radical scavengers vitamin E (100 microM), vitamin C (100 microM), glutathione (100 microM), L-cysteine (100 microM), N-acetyl-cysteine (100 microM), deferoxamine (5 microM), or haemoglobin (35 micrograms/ml) failed to attenuate the neurotoxic action of beta-amyloid. On the other hand, pre-treatment of cultures with subtoxic concentrations of beta-amyloid peptide significantly increased the vulnerability of neurons to H2O2 exposure and suggest that beta-amyloid peptide renders neurons more sensitive to free radical attack. However, a potential beta-amyloid-mediated increase in free radical formation is not a proximate cause of the neurotoxic mechanism of beta-amyloid in vitro.}, }
@article {pmid7957773, year = {1994}, author = {Egawa, K and Yoshiwara, M and Nose, K}, title = {Effect of radical scavengers on TNF alpha-mediated activation of the uPA in cultured cells.}, journal = {Experientia}, volume = {50}, number = {10}, pages = {958-962}, pmid = {7957773}, issn = {0014-4754}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line, Transformed ; Endothelium, Vascular/*enzymology ; Enzyme Activation ; Enzyme Induction ; Fluorescent Dyes ; Free Radical Scavengers/*pharmacology ; Glutathione/metabolism ; Humans ; Mice ; Microscopy, Confocal ; Oxidation-Reduction ; Pyrrolidines/pharmacology ; RNA, Messenger/metabolism ; Thiocarbamates/pharmacology ; Tumor Necrosis Factor-alpha/*pharmacology ; Urokinase-Type Plasminogen Activator/genetics/*metabolism ; }, abstract = {Active oxygen, produced by cultured cells following stimulation with various growth factors, seems to be involved in signal transduction leading to cellular responses such as gene expression and growth modulation. In the present study, the intracellular oxidation state was measured in immortalized human endothelial cells (ECV304) after treatment with tumor necrosis factor (TNF) alpha, using a fluorescent dye and a laser-scanning confocal microscope. The intracellular oxidation state was increased 60 min after the addition of TNF alpha, and this increase was abolished by a radical scavenger, N-acetylcysteine (NAC), which is also a precursor of glutathione, and by pyrrolidine dithiocarbamate (PDTC). TNF alpha increased the steady state level of urokinase-type plasminogen activator (uPA), and NAC inhibited this increase at a dose that also inhibited the increase in the intracellular oxidation state. PDTC, on the other hand, did not affect the induction of the uPA gene by TNF alpha. These results suggest that intracellular glutathione level rather than the oxidation state is necessary for the induction of the uPA gene by TNF alpha.}, }
@article {pmid7926024, year = {1994}, author = {Shibanuma, M and Kuroki, T and Nose, K}, title = {Inhibition by N-acetyl-L-cysteine of interleukin-6 mRNA induction and activation of NF kappa B by tumor necrosis factor alpha in a mouse fibroblastic cell line, Balb/3T3.}, journal = {FEBS letters}, volume = {353}, number = {1}, pages = {62-66}, doi = {10.1016/0014-5793(94)01014-5}, pmid = {7926024}, issn = {0014-5793}, mesh = {3T3 Cells ; Acetylcysteine/*pharmacology ; Animals ; Base Sequence ; Binding Sites ; Cell Line ; Interleukin-6/*genetics ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; NF-kappa B/*metabolism ; RNA, Messenger/*biosynthesis ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {Redox-based modulation plays a role in transcriptional control of gene expression. In the present study, we investigated the possible role of reactive oxygen species in the induction of interleukin-6 (IL-6) mRNA and in increases in NF kappa B binding activity by tumor necrosis factor (TNF) alpha using a mouse fibroblastic cell line, Balb/3T3. Expression of IL-6 mRNA is known to be dependent upon NF kappa B that binds to the 5'-flanking region of the IL-6 gene. We found that: (i) TNF alpha increased IL-6 mRNA levels and this increase was inhibited by N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species. (ii) NF kappa B binding activity in this cell line was also increased by TNF alpha, and the increase was inhibited in the presence of NAC. (iii) The treatment of cells with low doses of hydrogen peroxide increased the NF kappa B binding activity. (iv) Expression of a reporter gene in which the chloramphenicol acetyltransferase (CAT) gene was under the control of NF kappa B binding sites was induced by hydrogen peroxide. These results suggest that the induction of IL-6 mRNA is regulated by a mechanism involving reactive oxygen species and that NF kappa B, whose activity is sensitive to the cellular redox state, plays an important role in this induction in a fibroblastic cell line, Balb/3T3, stimulated with TNF alpha.}, }
@article {pmid7923887, year = {1994}, author = {Qasim, FJ and Mathieson, PW and Thiru, S and Oliveira, DB}, title = {Use of methyl prednisolone and antioxidants in mercuric chloride-induced experimental vasculitis.}, journal = {Clinical and experimental immunology}, volume = {98}, number = {1}, pages = {66-70}, pmid = {7923887}, issn = {0009-9104}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Autoimmune Diseases/chemically induced/*drug therapy/pathology ; Basement Membrane/immunology ; Enzyme-Linked Immunosorbent Assay ; Immunoglobulin E/immunology ; Intestines/immunology/pathology ; Kidney Glomerulus/immunology ; Mercuric Chloride ; Methylprednisolone/*therapeutic use ; Peroxidase/immunology ; Rats ; Rats, Inbred BN ; Vasculitis/chemically induced/*drug therapy/*pathology ; Vitamin E/therapeutic use ; }, abstract = {The systemic vasculitides are characterized by necrotizing inflammation of blood vessels. Neutrophils are implicated in tissue damage by their presence at the site of injury. They can mediate injury by release of cellular contents including proteinases, cytokines and reactive oxygen species. Antioxidants such as vitamin E and N-acetyl cysteine (NAC) may therefore be predicted to ameliorate oxidative damage in vivo and could be a cheap and non-toxic form of therapy. We examined this hypothesis in an experimental model of vasculitis which has some similarities to human disease, and in which depletion of neutrophils ameliorates tissue injury. Mercuric chloride (HgCl2) treatment induces an autoimmune syndrome and necrotizing leucocytoclastic vasculitis in the Brown Norway (BN) rat; anti-myeloperoxidase (MPO) and anti-glomerular basement (GBM) antibodies are present, and vasculitis is reduced by antimicrobials. Methyl prednisolone given intravenously was effective in reducing tissue injury, demonstrating that the model was responsive to a treatment used in man. Vitamin E and NAC were given as daily injections intraperitoneally to BN rats either before, during or after HgCl2 administration. Serial blood samples were taken for anti-MPO and IgE antibodies, which were assayed by ELISA. Necropsies were performed on animals killed at peak disease. At doses of 50-200 mg/kg per day vitamin E had no beneficial effect on tissue injury, regardless of timing of treatment. NAC at 100 or 200 mg/kg also had no significant protective effect on vasculitis. Autoantibody and IgE levels were not affected by either methyl prednisolone or the antioxidants. The lack of benefit of vitamin E and NAC suggests that oxidative damage, whether generated by neutrophils or other cells, does not play a major role in the pathogenesis of vasculitis, and that antioxidant therapy is unlikely to be of benefit in systemic vasculitis in man.}, }
@article {pmid7900412, year = {1994}, author = {Klos, C and Dekant, W}, title = {Comparative metabolism of the renal carcinogen 1,4-dichlorobenzene in rat: identification and quantitation of novel metabolites.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {24}, number = {10}, pages = {965-976}, doi = {10.3109/00498259409043294}, pmid = {7900412}, issn = {0049-8254}, mesh = {Acetylcysteine/urine ; Animals ; Biotransformation ; Carbon Radioisotopes ; Carcinogens/*metabolism ; Chlorobenzenes/*metabolism/pharmacokinetics/urine ; Chromatography, High Pressure Liquid ; Feces/chemistry ; Female ; Gas Chromatography-Mass Spectrometry ; Hydroquinones/urine ; Kidney Neoplasms/*chemically induced ; Kinetics ; Male ; Rats ; Rats, Inbred F344 ; Tissue Distribution ; }, abstract = {1. The metabolism of 1,4-dichlorobenzene has been studied in the male and female Fisher 344 rat over 72 h after oral administration of 14C-1,4-dichlorobenzene (900 mg = 96.8 microCi/kg). No covalent binding of radioactivity could be detected in samples of liver, kidney, lung and spleen. The major route of excretion was with urine accounting for 41.3% of the dose for male and 37.8% of the dose for female rat within 72 h after dosing. 2. Urinary metabolites of 1,4-dichlorobenzene were identified and quantified. The major metabolites identified in the urine of both the male and female rat, were the sulphate and glucuronide of 2,5-dichlorophenol. Minor amounts of 2,5-dichlorohydroquinone were excreted as an unidentified conjugate. 3. 2-(N-acetyl-cysteine-S-yl)-1,4-dichlorobenzene and 2-(N-acetyl-cysteine-S-yl)-2,3-dihydro-3-hydroxy-1,3-hydroxy-1,4-dich lorobenzen e were minor metabolites excreted in the urine of both sexes. 4. A novel biotransformation pathway for 1,4-dichlorobenzene may be postulated, leading to the urinary excretion of a mercapturic acid of chlorophenol. 5. No marked differences in the distribution and excretion of metabolites of 1,4-dichlorobenzene were observed between the male and female Fisher 344 rat.}, }
@article {pmid7809573, year = {1994}, author = {Hultberg, B and Andersson, A and Masson, P and Larson, M and Tunek, A}, title = {Plasma homocysteine and thiol compound fractions after oral administration of N-acetylcysteine.}, journal = {Scandinavian journal of clinical and laboratory investigation}, volume = {54}, number = {6}, pages = {417-422}, doi = {10.3109/00365519409085464}, pmid = {7809573}, issn = {0036-5513}, mesh = {Acetylcysteine/*pharmacology ; Homocysteine/*blood ; Humans ; Sulfhydryl Compounds/*blood ; }, abstract = {The total concentration of the atherogenic aminothiol acid homocysteine in plasma of healthy volunteers was decreased after oral administration of N-acetylcysteine (NAC), whereas the reduced and free (non-protein bound) fractions of homocysteine were increased. The decrease of the total fraction varied between 20 and 50% and was dose-related. Cysteinylglycine was also decreased after the administration of NAC, whereas cysteine did not change. Administration of high amounts of NAC probably displaces homocysteine and cysteinylglycine from their protein binding sites by disulfide interchange reactions. This leads to the formation of mixed low molecular-weight cysteine and NAC disulfides with high renal clearance and possibly also increased metabolic bio-availability, thereby eliminating homocysteine and cysteinylglycine from plasma. Since only a small amount of additional urinary homocysteine was recovered it is likely that this aminothiol acid is taken up by the tubular cells and further metabolized.}, }
@article {pmid7521369, year = {1994}, author = {Moynagh, PN and Williams, DC and O'Neill, LA}, title = {Activation of NF-kappa B and induction of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 expression in human glial cells by IL-1. Modulation by antioxidants.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {153}, number = {6}, pages = {2681-2690}, pmid = {7521369}, issn = {0022-1767}, mesh = {Antioxidants/pharmacology ; Base Sequence ; Cell Adhesion Molecules/*biosynthesis ; Cell Survival/drug effects ; Electrophoresis/methods ; Humans ; Intercellular Adhesion Molecule-1 ; Interleukin-1/*physiology ; Molecular Sequence Data ; NF-kappa B/*metabolism ; Neuroglia/*metabolism ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; Vascular Cell Adhesion Molecule-1 ; }, abstract = {The infiltration of leukocytes into the central nervous system is associated with many pathologic conditions of the brain. The mechanisms by which these immune cells can penetrate the blood-brain barrier and remain within the brain are not understood. However, elevated brain levels of the pro-inflammatory cytokine IL-1 appear to accompany pathogenesis. The present study provides the first evidence that IL-1 can induce the expression of adhesion molecules for leukocytes on glial cells and suggests a role for the transcription factor NF-kappa B in the induction process. Human rIL-1 alpha was found to induce the expression of the cell adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) but not E-selectin in human 1321N1 astrocytoma. Both VCAM-1 and ICAM-1 were detectable from 3 h and remained sustained for up to 72 h. Induction was inhibited by the IL-1 receptor antagonist. IL-1 alpha was also shown to induce the expression of VCAM-1 and ICAM-1 in a receptor-dependent fashion in human A172 glioblastoma. Activation of the transcription factor NF-kappa B was also observed in 1321N1 astrocytoma in response to IL-1 alpha treatment and was similarly abolished by pretreatment of cells with antagonist. Activated NF-kappa B was apparent from 20 min and remained for up to 24 h. N-acetylcysteine (NAC) and pyrollidinedithiocarbamate (PDTC), which were shown to inhibit activation of NF-kappa B in Jurkat E6.1 lymphoblasts and EL4.NOB-1 thymoma, failed to block IL-1 activation of NF-kappa B in 1321N1 astrocytoma. However, both of these antioxidants demonstrated complex modulatory effects on the induction of cell adhesion molecule expression by IL-1. The induction of VCAM-1 but not of ICAM-1 proved susceptible to inhibition by both PDTC and NAC. The expression of adhesion molecules for leukocytes on glial cells in response to IL-1 may represent an important mechanism for retention of immune cells in the central nervous system that may be a prologue to inflammatory conditions in the brain.}, }
@article {pmid8092321, year = {1994}, author = {Ruiz, FJ and Salom, MG and Inglés, AC and Quesada, T and Vicente, E and Carbonell, LF}, title = {N-acetyl-L-cysteine potentiates depressor response to captopril and enalaprilat in SHRs.}, journal = {The American journal of physiology}, volume = {267}, number = {3 Pt 2}, pages = {R767-72}, doi = {10.1152/ajpregu.1994.267.3.R767}, pmid = {8092321}, issn = {0002-9513}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Pressure/*drug effects ; Captopril/*pharmacology ; Drug Synergism ; Enalaprilat/*pharmacology ; Hypertension/*physiopathology ; Male ; Rats ; Rats, Inbred SHR ; }, abstract = {Recently, in vivo and in vitro studies have implicated nitric oxide as a mediator of the vascular effects of angiotensin-converting enzyme inhibitors (ACEIs). In the present study we hypothesized that N-acetyl-L-cysteine (NAC), by increasing the availability of reduced sulfhydryl groups, would enhance the antihypertensive response to the ACEIs captopril and enalaprilat by a mechanism dependent on nitric oxide. The experiments were performed on instrumented, indomethacin-pretreated, awake spontaneously hypertensive rats (SHRs). Thirty minutes after a bolus of captopril (10 mg/kg iv) was administered, blood pressure decreased from 167 +/- 5 to 147 +/- 6 mmHg (n = 8). The pretreatment with the donor of thiol groups NAC (300 mg/kg iv) potentiated the depressor response to captopril because blood pressure decreased from 172 +/- 3 to 139 +/- 4 mmHg (n = 6). At the dose of 60 micrograms/kg iv, the ACEI enalaprilat did not acutely modify the blood pressure of SHRs (from 172 +/- 5 to 167 +/- 4 mmHg; n = 6). However, when the SHRs were pretreated with NAC, the same dose of enalaprilat significantly reduced blood pressure from 176 +/- 5 to 151 +/- 5 mmHg (n = 6). This potentiation of the depressor response to ACEIs, due to NAC, was not observed when SHRs were pretreated with the nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 50 micrograms.kg-1.min-1 iv). The results of this study suggest that NAC, a donor of sulfhydryl groups, potentiates the antihypertensive response to captopril and enalaprilat in SHR by a nitric oxide-dependent mechanism.}, }
@article {pmid7814537, year = {1994}, author = {Zwadyk, P and Down, JA and Myers, N and Dey, MS}, title = {Rendering of mycobacteria safe for molecular diagnostic studies and development of a lysis method for strand displacement amplification and PCR.}, journal = {Journal of clinical microbiology}, volume = {32}, number = {9}, pages = {2140-2146}, pmid = {7814537}, issn = {0095-1137}, mesh = {Acetylcysteine ; *Bacteriolysis ; Base Sequence ; Buffers ; Containment of Biohazards/*methods ; DNA, Bacterial/*isolation &amp; purification ; Disinfectants/pharmacology ; Feasibility Studies ; Hot Temperature ; Humans ; Molecular Sequence Data ; Mycobacterium/chemistry/genetics/*isolation &amp; purification ; Mycobacterium Infections/*microbiology ; *Nucleic Acid Amplification Techniques ; *Polymerase Chain Reaction ; Safety ; Sensitivity and Specificity ; Sodium Hydroxide ; Time Factors ; }, abstract = {Two criteria must be met before mycobacterial specimens can be tested by DNA amplification methods: (i) the sample must be rendered noninfectious, and (ii) the organisms must be lysed to free the DNA. Previous publications reporting DNA amplification of mycobacteria have concentrated on lysis and amplification procedures and have not addressed the issue of sample safety. We have shown that heating of samples below 100 degrees C may not consistently kill mycobacteria; however, heating at 100 degrees C in a boiling-water bath or a forced-air oven for a minimum of 5 min kills mycobacteria, including Mycobacterium thermoresistibile. Furthermore, heating at 100 degrees C for 30 min consistently lyses mycobacteria to produce short fragments of DNA that are suitable for amplification by PCR and strand displacement amplification. This procedure works with clinical samples digested by the n-acetyl cysteine-NaOH method as well as with suspensions of organisms in phosphate buffer. This paper also demonstrates the feasibility of using strand displacement amplification with clinical specimens.}, }
@article {pmid8091167, year = {1994}, author = {Zala, G and Flury, R and Wüst, J and Meyenberger, C and Ammann, R and Wirth, HP}, title = {[Omeprazole/amoxicillin: improved eradication of Helicobacter pylori in smokers because of N-acetylcysteine].}, journal = {Schweizerische medizinische Wochenschrift}, volume = {124}, number = {31-32}, pages = {1391-1397}, pmid = {8091167}, issn = {0036-7672}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Aged ; Amoxicillin/therapeutic use ; Drug Therapy, Combination/*therapeutic use ; Female ; Gastric Mucosa/drug effects ; Helicobacter Infections/*drug therapy/microbiology ; Helicobacter pylori/drug effects ; Humans ; Male ; Middle Aged ; Omeprazole/therapeutic use ; Prospective Studies ; }, abstract = {Colonization of Helicobacter pylori (HP) beneath the protective film of gastric mucus enables the organism to survive in the hostile environment of the gastric mucosa. N-acetylcysteine (NAC), a sulfhydryl compound with potent mucolytic activity, induces a reduction of gastric barrier mucus thickness of about 75% and reduces mucus viscoelasticity. We therefore tested the hypothesis whether better eradication results could be achieved by addition of NAC to omeprazole/amoxicillin (OME/AMOX). 34 HP positive outpatients with endoscopically documented recurrent duodenal ulcer were included in an ongoing, prospective, randomized trial. Exclusion criteria were: alcoholism, previous gastric surgery, or intake of antibiotics, OME, bismuth salts, corticosteroids or NSAIDs within 4 weeks before study entry. Patients currently smoking > 10 cigarettes/day were classified as smokers. HP infection was confirmed by histology (3 biopsy specimens from gastric antrum and 2 from gastric body; H&amp;E, Giemsa) and at least positive rapid urease test or culture. All 34 patients underwent ulcer therapy with OME (20 mg per day) for 20 days (d 1-20). Group A: in 17 patients (5 females, 12 males, mean age 46 [29-74] years; 8 smokers, 9 nonsmokers) the subsequent eradication therapy, consisting of oral OME (40 mg bid) and AMOX solute (750 mg tid) for 10 days, was combined with NAC solute (2 x 600 mg bid (d 21-30). Group B: 17 patients (2 females, 15 males, mean age 39 [19-70] years; 11 smokers, 6 nonsmokers) underwent eradication therapy without NAC (d 21-30). Control endoscopy was done after a minimal interval of 30 days from the end of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7914368, year = {1994}, author = {Mayer, M and Noble, M}, title = {N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {91}, number = {16}, pages = {7496-7500}, pmid = {7914368}, issn = {0027-8424}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Apoptosis/drug effects ; Cell Death/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Ciliary Neurotrophic Factor ; Fibroblasts/cytology ; Ganglia, Spinal/cytology ; Glutamates/pharmacology ; Glutamic Acid ; Models, Biological ; Nerve Growth Factors/*pharmacology ; Nerve Tissue Proteins/*pharmacology ; Nervous System/cytology/*drug effects ; Neurons, Afferent/cytology ; Oligodendroglia/cytology/drug effects ; Rats ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {We have discovered that N-acetyl-L-cysteine (NAC) protects cells against death induced by exposure to noxious stimuli and against programmed cell death (apoptosis) associated with exposure to inadequate amounts of trophic factors. NAC prevented glutamate-induced death of oligodendrocytes and tumor necrosis factor alpha (TNF-alpha)-induced death of oligodendrocytes and L929 fibroblasts. Moreover, suboptimal doses of NAC plus ciliary neurotrophic factor (which also protects oligodendrocytes against TNF-alpha-mediated killing) acted synergistically to protect oligodendrocytes against TNF-alpha-induced death. Protection against death by growth factor deprivation was provided by the combination of (i) NAC, vitamin C, or Trolox (a water-soluble analogue of vitamin E) with suboptimal concentrations of protein trophic factors, (ii) NAC, vitamin C, or Trolox with progesterone, and (iii) NAC with either vitamin C or Trolox; these latter experiments suggest that the addition of tyrosine kinase stimulators is not required to promote cell survival. In all paradigms, NAC was either equally or more effective than the other compounds examined. In light of the long history of therapeutic application of NAC, we suggest that use of this compound may be of interest in conditions where certain toxin-mediated forms of cell death and/or apoptosis contribute significantly to disease.}, }
@article {pmid8051494, year = {1994}, author = {Oddera, S and Silvestri, M and Sacco, O and Eftimiadi, C and Rossi, GA}, title = {N-acetylcysteine enhances in vitro the intracellular killing of Staphylococcus aureus by human alveolar macrophages and blood polymorphonuclear leukocytes and partially protects phagocytes from self-killing.}, journal = {The Journal of laboratory and clinical medicine}, volume = {124}, number = {2}, pages = {293-301}, pmid = {8051494}, issn = {0022-2143}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Blood Bactericidal Activity/*drug effects ; Cell Death/drug effects/physiology ; Cell Survival/drug effects/physiology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Female ; Humans ; Hydrogen Peroxide/metabolism ; In Vitro Techniques ; Macrophages, Alveolar/*cytology/drug effects/physiology ; Male ; Neutrophils/*cytology/physiology ; Phagocytes/*cytology/metabolism/physiology ; Phagocytosis/drug effects/*physiology ; Staphylococcus aureus/drug effects/*physiology ; }, abstract = {The processes of phagocytosis and intracellular killing of bacteria by alveolar macrophages (AMs) and polymorphonuclear leukocytes (PMNs) result in the production of reactive oxygen species that can induce self-damage to the phagocytic cells. N-Acetylcysteine (NAC), a mucolytic agent used to treat chronic respiratory inflammatory disorders, possesses antioxidant properties and has therefore been used for the prevention of damage induced by oxygen radicals. This study was designed to evaluate whether NAC can interfere with the processes of phagocytosis and intracellular killing of bacteria and protect the phagocytic cells from self-killing. Human AM, obtained by bronchoalveolar lavage, and peripheral blood PMNs were cultured with Staphylococcus aureus (American Type Culture Collection 25923 strain) in the presence of different concentrations of NAC (1, 10, and 100 mg/L) and two chromophores (4',6'-diamidino-2-phenylindole dihydrochloride and propidium iodide), which identify live or dead bacteria and dead phagocytes. As compared with PMNs, AMs were more effective in ingesting bacteria (p < 0.05) and were equally effective as intracellular killers (p > 0.05), but were susceptible to a significantly higher rate of self-killing (p < 0.01). The presence of NAC in the cell cultures at the highest dose tested (100 mg/L) induced a significant enhancement of the bactericidal activity of both AMs (p < 0.05) and PMNs (p < 0.05). This increased intracellular killing was not associated with increased proportions of dead phagocytes either in AMs or PMNs cultures (p > 0.05, each comparison), suggesting a protective effect of NAC on damage induced by toxic products generated during phagocytosis.}, }
@article {pmid8035787, year = {1994}, author = {Ausserer, WA and Bourrat-Floeck, B and Green, CJ and Laderoute, KR and Sutherland, RM}, title = {Regulation of c-jun expression during hypoxic and low-glucose stress.}, journal = {Molecular and cellular biology}, volume = {14}, number = {8}, pages = {5032-5042}, pmid = {8035787}, issn = {0270-7306}, support = {CA 20329/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Base Sequence ; Gene Expression Regulation ; Genes, fos ; *Genes, jun ; Glucose/*metabolism ; Humans ; Hypoxia/*genetics ; Molecular Sequence Data ; Oligodeoxyribonucleotides/chemistry ; Protein Kinase C/metabolism ; Proto-Oncogene Mas ; RNA, Messenger/genetics/metabolism ; Transcription, Genetic ; }, abstract = {Hypoxic stress in tumor cells has been implicated in malignant progression and in the development of therapeutic resistance. We have investigated the effects of acute hypoxic exposure on regulation of the proto-oncogene c-jun in SiHa cells, a human squamous carcinoma cell line. Hypoxic exposure produced increased levels of c-jun mRNA resulting from both message stabilization and transcriptional activation. A superinduction of c-jun message resulted during simultaneous oxygen and glucose deprivation, with several characteristics of an induction mediated by oxidative-stress pathways. This superinduction was blocked by preincubation of cells with the glutathione precursor N-acetyl cysteine or with phorbol 12-myristate 13-acetate, which indicates redox control of c-jun expression and probable involvement of protein kinase C. By gel retardation assay, no increase in AP-1 DNA binding activity was found to be concomitant with the transcriptional activation of c-jun. A lack of increased DNA binding was observed for the consensus AP-1 sequence and for the two AP-1 sequence variants found within the c-Jun promoter. Additionally, hypoxic and low-glucose stress produced no activation of stably transfected AP-1 reporter sequences. Taken together, these results indicate that the transcriptional activation of c-jun during hypoxic and low-glucose stress involves redox control and is unlikely to be mediated by AP-1 recognition elements within the c-jun promoter.}, }
@article {pmid7972979, year = {1994}, author = {Hansen, NC and Skriver, A and Brorsen-Riis, L and Balsløv, S and Evald, T and Maltbaek, N and Gunnersen, G and Garsdal, P and Sander, P and Pedersen, JZ}, title = {Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis.}, journal = {Respiratory medicine}, volume = {88}, number = {7}, pages = {531-535}, doi = {10.1016/s0954-6111(05)80337-3}, pmid = {7972979}, issn = {0954-6111}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Aged ; Bronchitis/*drug therapy/psychology ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Psychiatric Status Rating Scales ; *Quality of Life ; Surveys and Questionnaires ; }, abstract = {Oral N-acetylcysteine (NAC) exerts a beneficial action in chronic bronchitis by reducing the number of exacerbations. There have been few studies of the effect of NAC (or of any other drug) on general well-being in chronic bronchitis. We used an established psychiatric instrument (General Health Questionnaire; GHQ) and a visual analogue scale (VAS) to measure well-being in a 22-week, placebo-controlled, double-blind, parallel-group study of NAC administered as sustained release tablets 600 mg b.i.d., including during the winter months, to patients with mild chronic bronchitis. One hundred and fifty-three patients were accepted for randomized treatment, 129 finished the study (59 NAC, 70 placebo), and well-being was measured in 105 (46 NAC, 59 placebo). The number of observed exacerbations was unexpectedly low in both groups. The number was lowest in the NAC group, however, the difference did not reach statistical significance in the present study (P = 0.08). There were no statistically significant differences between NAC and placebo in subjective symptom scores, FEV1 or FVC. The distribution of GHQ score at baseline was uneven, but NAC was significantly superior to placebo in terms of a favourable effect on GHQ score. GHQ score correlated with the number of exacerbations, and VAS correlated with GHQ score. This study therefore demonstrates the validity of measuring general well-being in patients with mild chronic bronchitis. Future studies of the treatment of chronic bronchitis should use a battery of more specifically adapted instruments which are now becoming available to measure well-being.}, }
@article {pmid7967350, year = {1994}, author = {Shan, Z and Tan, D and Satriano, J and Silbiger, S and Schlondorff, D}, title = {Intracellular glutathione influences collagen generation by mesangial cells.}, journal = {Kidney international}, volume = {46}, number = {2}, pages = {388-395}, doi = {10.1038/ki.1994.286}, pmid = {7967350}, issn = {0085-2538}, support = {R01 DK41566/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimetabolites/pharmacology ; Buthionine Sulfoximine ; Cell Transformation, Viral ; Cells, Cultured ; Collagen/*biosynthesis/genetics ; Culture Media ; Glomerular Mesangium/cytology/drug effects/*metabolism ; Glucose/pharmacology ; Glutathione/*metabolism ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Mice ; Oxidation-Reduction ; RNA, Messenger/metabolism ; Transcription, Genetic ; Transforming Growth Factor beta/metabolism ; }, abstract = {The cellular redox state is altered in a number of pathological conditions, including various forms of glomerular injury and diabetes. For example, glucose, via the pentose phosphate pathway generates NADPH, which maintains glutathione (GSH) (part of a major intracellular reducing system) in its reduced state. GSH in turn influences the activity of transcription factors on gene expression. We therefore examined whether changes in cellular GSH influence total collagen synthesis and mRNA levels for collagen I, collagen IV and TGF-beta in SV-40 transformed mouse mesangial cells (MC) maintained in either 5 or 25 mM glucose media. Total intracellular GSH was increased by N-acetylcysteine (NAC; 10 mM) or decreased with the GSH synthesis inhibitor buthionine sulfoximine (BSO; 0.2 mM) in MC. NAC increased 3H-proline incorporation into collagenase-sensitive protein while BSO decreased it under both glucose conditions. The presence of BSO did not reverse the increased collagen synthesis seen in the NAC stimulated cells. Northern blot analysis showed increased mRNA levels for collagen I, collagen IV and TGF-beta in cells grown in high glucose (25 mM). NAC increased the mRNA for all three compounds while BSO alone had no effect on these mRNA levels. However, BSO reversed the increased mRNA levels for collagen I, IV and TGF-beta seen in the presence of NAC. These findings suggest that the cellular redox state may influence gene transcription in MC, and may have implications in explaining injury-associated alterations of mesangial matrix generation.}, }
@article {pmid7953744, year = {1994}, author = {Hori, K and Katayama, M and Sato, N and Ishii, K and Waga, S and Yodoi, J}, title = {Neuroprotection by glial cells through adult T cell leukemia-derived factor/human thioredoxin (ADF/TRX).}, journal = {Brain research}, volume = {652}, number = {2}, pages = {304-310}, doi = {10.1016/0006-8993(94)90241-0}, pmid = {7953744}, issn = {0006-8993}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimetabolites, Antineoplastic/pharmacology ; Astrocytoma/metabolism ; Blotting, Western ; Brain Neoplasms/metabolism ; Buthionine Sulfoximine ; Cell Survival/drug effects ; Cerebral Cortex/cytology/drug effects ; *Cytokines ; Glutathione/biosynthesis ; Growth Substances/*pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Mercaptoethanol/pharmacology ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Mice ; Mice, Inbred Strains ; Neoplasm Proteins/*pharmacology ; Neuroglia/*drug effects/metabolism ; Thioredoxins/*pharmacology ; Tumor Cells, Cultured ; }, abstract = {Adult T cell leukemia-derived factor (ADF) is a human homologue of thioredoxin (TRX) with many biological functions and is induced by various stimuli and stress. In the central nervous system (CNS), expression of ADF/TRX occurs in glial cells during ischemia and reperfusion. We showed that ADF/TRX was actively released from U251 astrocytoma cells upon exposure to a low concentration of H2O2. The addition of conditioned medium from H2O2-stimulated U251 cells or recombinant ADF (rADF) to the culture medium promoted the survival of neurons from embryonic mouse cortex and striatum, but the addition of mutant ADF (mADF), which has no reducing activity, did not. In addition to rADF, incubation with two other thiol compounds, 2-mercaptoethanol (2-ME) and N-acetyl-L-cysteine (NAC), also increased the neuronal cell survival rate. In contrast, L-buthionine-(S,R)-sulfoximine (BSO), which inhibited the synthesis of glutathione (GSH), decreased the neuronal cell survival rate. Intracellular GSH was increased by incubation with rADF for 24 h, as it is with 2-ME and NAC. Redox active molecules such as thiol compounds may be survival factors for central neurons in vitro, and this capacity may be supplied by endogenous molecules, such as ADF/TRX and glutathione, under certain pathologic conditions in vivo.}, }
@article {pmid7946509, year = {1994}, author = {Chan, TY and Critchley, JA}, title = {Adverse reactions to intravenous N-acetylcysteine in Chinese patients with paracetamol (acetaminophen) poisoning.}, journal = {Human &amp; experimental toxicology}, volume = {13}, number = {8}, pages = {542-544}, doi = {10.1177/096032719401300806}, pmid = {7946509}, issn = {0960-3271}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/administration &amp; dosage/*adverse effects/therapeutic use ; Adolescent ; Adult ; Asian People ; Chlorpheniramine/administration &amp; dosage/adverse effects ; Dose-Response Relationship, Drug ; Female ; Humans ; Injections, Intravenous ; Male ; }, abstract = {The incidence of adverse reactions to intravenous N-acetylcysteine (NAC) was studied in 56 Chinese patients with paracetamol (acetaminophen) poisoning. Eight (14%) patients developed a skin rash (n = 7) or fever (n = 1) mostly during the initial high dose infusion of the antidote. In four subjects (three with toxic plasma paracetamol levels), the infusion was continued without a worsening of the adverse reaction. NAC was discontinued in the remaining four subjects in whom the paracetamol levels were subsequently found to be non-toxic. Intravenous chlorpheniramine was given to six subjects. All eight subjects completely recovered. In the dose that is recommended for the treatment of acute paracetamol poisoning, intravenous NAC is generally safe in Chinese but mild side effects are common. We recommend that the initial loading dose is given over 60 rather than 15 min.}, }
@article {pmid7835407, year = {1994}, author = {Li, WC and Wang, GM and Wang, RR and Spector, A}, title = {The redox active components H2O2 and N-acetyl-L-cysteine regulate expression of c-jun and c-fos in lens systems.}, journal = {Experimental eye research}, volume = {59}, number = {2}, pages = {179-190}, doi = {10.1006/exer.1994.1096}, pmid = {7835407}, issn = {0014-4835}, support = {F32 EY006542/EY/NEI NIH HHS/United States ; EY00423/EY/NEI NIH HHS/United States ; EY00759/EY/NEI NIH HHS/United States ; EY07105/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cataract/genetics ; Dose-Response Relationship, Drug ; Down-Regulation ; Gene Expression Regulation ; *Genes, fos/drug effects ; *Genes, jun/drug effects ; Hydrogen Peroxide/*pharmacology ; Lens, Crystalline/*metabolism ; Oxidation-Reduction ; Phosphoprotein Phosphatases/antagonists &amp; inhibitors ; Protein Kinase Inhibitors ; RNA, Messenger/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Transcription Factor AP-1/biosynthesis ; Transcriptional Activation ; }, abstract = {Hydrogen peroxide (H2O2) is implicated in human cataract development. At the molecular level H2O2 has been observed to cause damage to DNA, protein and lipid. It is now demonstrated, for the first time in a lens system, that H2O2 at concentrations found in cataract patients induces expression of both c-jun and c-fos. At optimal concentrations of H2O2, mRNA accumulation of c-jun and c-fos in the rat lenses is induced 20- and 18-fold above normal levels respectively, but with distinct kinetics. This induction occurs at the transcriptional level. H2O2 also induces transactivation by activating protein-1 (AP-1) in rabbit lens epithelial cells. The antioxidant N-acetyl-cysteine (NAC) has a dual effect on the induction of c-jun and c-fos. Preincubation of rat lenses with 5 mM NAC inhibits the induction by H2O2, while 30 mM and 50 mM NAC induce expression of these genes and mask the H2O2 effect. H7 (50 microM), genistein (2 microM) and okadaic acid (20 nM), all block the induction of c-jun and c-fos mRNA accumulation in the H2O2-treated rat lenses. These results suggest that H2O2 activates protein kinase and phosphatase dependent signal transduction pathways to induce c-jun and c-fos expression which may regulate lens crystallin genes and other genes containing AP-1 binding sites.}, }
@article {pmid7811547, year = {1994}, author = {Raju, PA and Herzenberg, LA and Herzenberg, LA and Roederer, M}, title = {Glutathione precursor and antioxidant activities of N-acetylcysteine and oxothiazolidine carboxylate compared in in vitro studies of HIV replication.}, journal = {AIDS research and human retroviruses}, volume = {10}, number = {8}, pages = {961-967}, doi = {10.1089/aid.1994.10.961}, pmid = {7811547}, issn = {0889-2229}, support = {AI-31770/AI/NIAID NIH HHS/United States ; CA-42509/CA/NCI NIH HHS/United States ; LM-04836/LM/NLM NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Antimetabolites/pharmacology ; Antioxidants/pharmacology ; Antiviral Agents/pharmacology ; Buthionine Sulfoximine ; Cells, Cultured ; Free Radical Scavengers/pharmacology ; Gene Expression Regulation, Viral/drug effects ; Genes, Reporter ; Glutathione/*biosynthesis ; HIV Long Terminal Repeat/genetics ; HIV-1/*drug effects/physiology ; Humans ; Leukocytes, Mononuclear/virology ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Monocytes/virology ; Prodrugs/pharmacology ; Pyrrolidonecarboxylic Acid ; Thiazoles/*pharmacology ; Thiazolidines ; Tumor Necrosis Factor-alpha/pharmacology ; Virus Replication/*drug effects ; }, abstract = {N-Acetyl-L-cysteine (NAC) and L-2-oxothiazolidine 4-carboxylate (OTC) are pro-GSH drugs that been proposed for AIDS therapy. In this article we compare the antiviral activities of these compounds in various in vitro HIV infection models. Although both compounds blocked cytokine induction of HIV in acute and chronic infection models, and in HIV-LTR reporter cell systems, NAC was far more effective than OTC, even at suboptimal doses. To test whether this difference is due to GSH conversion efficacies of these compounds, we measured GSH restoration by NAC or OTC in GSH-depleted peripheral blood mononuclear cells (PBMCs), using flow cytometry. In isolated PBMCs, NAC fully replenishes depleted intracellular GSH whereas OTC only minimally replenishes GSH. This ability to replenish GSH in vitro and its ability to scavenge free radicals directly explain why NAC has more potent antiviral activities in vitro.}, }
@article {pmid7728586, year = {1994}, author = {Abello, PA and Fidler, SA and Buchman, TG}, title = {Thiol reducing agents modulate induced apoptosis in porcine endothelial cells.}, journal = {Shock (Augusta, Ga.)}, volume = {2}, number = {2}, pages = {79-83}, doi = {10.1097/00024382-199408000-00001}, pmid = {7728586}, issn = {1073-2322}, support = {GM 00581/GM/NIGMS NIH HHS/United States ; GM 48095/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta ; Apoptosis/*drug effects ; Blotting, Western ; Cell Survival ; Cells, Cultured ; Dithiothreitol/*pharmacology ; Dose-Response Relationship, Drug ; Endothelium, Vascular/cytology/*drug effects/physiology ; Female ; Free Radical Scavengers/pharmacology ; Glutathione/metabolism ; Heat-Shock Proteins/biosynthesis ; Kinetics ; Lipopolysaccharides/pharmacology ; Swine ; }, abstract = {When cultured porcine endothelial cells are exposed first to endotoxin (lipopolysaccharide (LPS)) followed by standard inducers of the heat shock response in vitro (heat or sodium arsenite), these cells aberrantly execute programmed cell death. This cell death is dependent upon two distinct events: the LPS-priming step and the heat shock-induced activation step. Prior work demonstrated that the LPS-priming step could be blocked by the prior application of cell-permeable hydroxyl radical scavengers, suggesting a role for this reactive oxygen species as an important intracellular signal mediating the first step. In these present experiments, we evaluated the potential role of reduction-oxidation mechanisms in the heat shock activation step. The thiol reducing agents reduced glutathione (GSH), n-acetylcysteine (NAC), and dithiothreitol (DTT) were evaluated for their ability to block programmed cell death in LPS-primed porcine aortic endothelial cells. Both DTT and NAC, agents that augment intracellular reduced glutathione levels, were protective against cell death when applied prior to heat shock induction with sodium arsenite (As) in endothelial cells treated previously with LPS. The less cell permeable agent GSH was not protective. Delayed application of DTT or NAC could block progression to cell death for up to 1.5 h after initiation of the heat shock response with As. These data show that heat shock-induced programmed cell death in LPS-primed endothelial cells can be arrested, at least in its early stages, by agents that augment or stabilize the reducing potential of the cell.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8066561, year = {1994}, author = {Bridgeman, MM and Marsden, M and Selby, C and Morrison, D and MacNee, W}, title = {Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue.}, journal = {Thorax}, volume = {49}, number = {7}, pages = {670-675}, pmid = {8066561}, issn = {0040-6376}, mesh = {Acetylcysteine/administration &amp; dosage/blood/*pharmacology ; Adult ; Aged ; Bronchoalveolar Lavage Fluid/*chemistry ; Bronchoscopy ; Carcinoma, Bronchogenic/*metabolism ; Drug Administration Schedule ; Female ; Glutathione/*analysis/blood ; Humans ; Lung/*chemistry/drug effects ; Lung Diseases, Obstructive/*metabolism ; Lung Neoplasms/*metabolism ; Male ; Middle Aged ; Pneumonectomy ; }, abstract = {BACKGROUND: Oxidant/antioxidant imbalance may occur in the lungs of patients with chronic obstructive pulmonary disease (COPD). Glutathione is an important extracellular and intracellular thiol oxidant in the lungs. These studies were carried out to determine the effect of N-acetyl cysteine on thiol concentrations in plasma, bronchoalveolar lavage fluid, and lung tissue.<br><br>METHODS: Studies were carried out on normal subjects, patients with COPD, and those undergoing lung resection. In the first study N-acetyl cysteine was given to three groups; healthy subjects (600 mg once daily by mouth) and two groups of patients with COPD. In the first group of patients with COPD the dose was 600 mg once daily and in the second 600 mg thrice daily, all for five days. The latter dosage regimen was also given to six patients before bronchoscopy and to 11 patients before lung resection. Lung glutathione (GSH) levels in bronchoalveolar lavage fluid or lung tissue were compared with the same numbers of patients who did not receive N-acetyl cysteine.<br><br>RESULTS: N-acetyl cysteine was detected in plasma after a single 600 mg dose in normal subjects and patients with COPD up to 1.5 hours after the drug was given. Plasma cysteine concentrations increased in normal subjects on both days 1 and 5, and in patients with COPD on day 5. Glutathione concentrations in plasma increased on day 1 in normal subjects but not in patients with COPD given 600 mg N-acetyl cysteine daily. With the higher dose of 600 mg thrice daily, however, there was a sustained elevation of GSH concentrations in plasma in patients with COPD. In patients undergoing routine diagnostic bronchoscopy and bronchoalveolar lavage those who were given N-acetyl cysteine (600 mg) thrice daily for five days had higher concentrations of cysteine in the plasma, but no significant differences in cysteine concentrations in bronchoalveolar lavage or epithelial lining fluid compared with a control group; nor were there any differences in reduced glutathione concentrations in plasma, bronchoalveolar lavage or epithelial lining fluids between the control and treated groups. Moreover, in patients undergoing lung resection those treated with N-acetyl cysteine (600 mg thrice daily for five days) had similar concentrations of cysteine and glutathione in both plasma and lung tissue when compared with a control untreated group.<br><br>CONCLUSIONS: These data suggest that, even when given in high oral doses, N-acetyl cysteine does not produce a sustained increase in glutathione levels sufficient to increase the antioxidant capacity of the lungs.}, }
@article {pmid8022202, year = {1994}, author = {Jabbar, SA and Hoffbrand, AV and Wickremasinghe, RG}, title = {Redox reagents and staurosporine inhibit stimulation of the transcription regulator NF-kappa B following tumour necrosis factor treatment of chronic B-leukaemia cells.}, journal = {Leukemia research}, volume = {18}, number = {7}, pages = {523-530}, doi = {10.1016/0145-2126(94)90090-6}, pmid = {8022202}, issn = {0145-2126}, mesh = {Acetylcysteine/pharmacology ; Alkaloids/*pharmacology ; Base Sequence ; Butylated Hydroxytoluene/pharmacology ; DNA-Binding Proteins/metabolism ; Humans ; In Vitro Techniques ; Leukemia, B-Cell/*physiopathology ; Leukemia, Hairy Cell/*physiopathology ; Molecular Sequence Data ; NF-kappa B/*metabolism ; Oligodeoxyribonucleotides/metabolism ; Oxidation-Reduction ; Staurosporine ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Necrosis Factor-alpha/*pharmacology ; }, abstract = {B-chronic lymphocytic leukaemia (B-CLL) and hairy cell leukaemia cells (HCL) are refractory to stimulation by several cytokines which activate normal B-cells. However, tumour necrosis factor (TNF) promotes the proliferation of these cells. TNF regulates some of its cellular responses via the transcription factor NF-kappa B. Using an electrophoretic mobility shift assay, we demonstrate that TNF treatment of B-CLL and HCL cells in vitro resulted in the augmentation of NF-kappa B levels. In haemopoietic cell lines, TNF induction of NF-kappa B is mediated via the generation of reactive oxygen intermediates and by the activation of protein kinase C (PKC). We have used activators and inhibitors of these pathways to unravel TNF signalling in the cells of ten patients with B-CLL and two with HCL, using the increase in NF-kappa B levels following TNF treatment as an end point. Raising glutathione levels with N-acetyl cysteine substantially reduced NF-kappa B induction by TNF in two of four samples tested. These data suggest that redox mechanisms are involved in TNF signalling in these cells. Treatment with the PKC activator phorbol myristate acetate failed to activate NF-kappa B suggesting that this enzyme does not mediate the induction of NF-kappa B in these cells. However, the protein kinase inhibitor staurosporine inhibited TNF induction of NF-kappa B in four of five samples, suggesting that staurosporine-sensitive protein kinases (other than PKC) are involved in the signalling pathway. Our results suggest that PKC-independent pathways, including pathways sensitive to redox reagents, mediate the induction of NF-kappa B by TNF in chronic B-leukaemia cells. Additionally, these data suggest that defects in PKC-mediated pathways may contribute to the general reluctance of B-CLL and HCL cells to respond to mitogenic signals.}, }
@article {pmid8016303, year = {1994}, author = {Held, KD and Biaglow, JE}, title = {Mechanisms for the oxygen radical-mediated toxicity of various thiol-containing compounds in cultured mammalian cells.}, journal = {Radiation research}, volume = {139}, number = {1}, pages = {15-23}, pmid = {8016303}, issn = {0033-7587}, support = {CA42167/CA/NCI NIH HHS/United States ; CA44982/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/toxicity ; Animals ; Cell Line ; Cell Survival/*drug effects ; Copper/toxicity ; Cricetinae ; Cricetulus ; Dithiothreitol/toxicity ; Dose-Response Relationship, Drug ; Glutathione/toxicity ; *Hydrogen Peroxide ; Kinetics ; Lung ; Mercaptoethylamines/toxicity ; Oxidation-Reduction ; Penicillamine/toxicity ; Radiation-Protective Agents/*toxicity ; Sulfhydryl Compounds/*chemistry/*toxicity ; *Superoxides ; }, abstract = {When Chinese hamster V79 cells are exposed to various thiol compounds in phosphate-buffered saline (PBS), some compounds cause toxicity (loss of colony formation), although the dependence on drug concentration and the magnitude of the cell killing vary between the different thiols. For example: dithiothreitol (DTT) and WR-1065 cause a biphasic toxicity whereby cell killing occurs at about 0.2 to 1.0 mM thiol, but is not seen at higher or lower drug concentrations; N-acetylcysteine (NAC) is toxic only at concentrations > or = 2 mM and shows no biphasic pattern; and glutathione (GSH) and penicillamine are only minimally toxic at all concentrations. The effect of the addition of 1 microM Cu2+ to the thiol also depends on the particular thiol: e.g., Cu2+ increases cell killing in the biphasic pattern with WR-1065; it increases the toxicity of NAC only at high thiol concentrations; and it elicits a slight toxicity in the biphasic pattern by GSH and penicillamine. In all cases tested, if the thiol is toxic, the cell killing can be decreased or prevented by addition of catalase, consistent with the hypothesis that the toxicity is mediated through H2O2 produced during the thiol oxidation. However, when the oxidation rates of the various thiols in PBS without and with Cu2+ were measured, the data did not show a simple correlation between the toxicity of the various thiols and their oxidation rates. The rate of the reaction of the various thiols with H2O2 was also determined and showed a better, but still not good, correlation with toxicity. However, cell killing by the various thiols correlated better with the ratio between the half-lives for thiol oxidation and reaction of thiol with H2O2 than with either reaction rate alone. This suggests that the toxicity pattern and magnitude of cell killing in V79 cells by various thiols depend on the interplay between the rate of thiol oxidation and the rate of reaction between the thiol and the H2O2 produced in the thiol oxidation.}, }
@article {pmid8006594, year = {1994}, author = {Newman, GW and Balcewicz-Sablinska, MK and Guarnaccia, JR and Remold, HG and Silberstein, DS}, title = {Opposing regulatory effects of thioredoxin and eosinophil cytotoxicity-enhancing factor on the development of human immunodeficiency virus 1.}, journal = {The Journal of experimental medicine}, volume = {180}, number = {1}, pages = {359-363}, pmid = {8006594}, issn = {0022-1007}, support = {AI-28525/AI/NIAID NIH HHS/United States ; AI-31006/AI/NIAID NIH HHS/United States ; HL-435110/HL/NHLBI NIH HHS/United States ; }, mesh = {Cells, Cultured ; Cytokines/*pharmacology ; *Cytotoxicity, Immunologic ; Eosinophils/*immunology ; HIV-1/*drug effects/growth &amp; development ; Humans ; Macrophages/microbiology ; Recombinant Proteins/pharmacology ; Thioredoxins/metabolism/*pharmacology ; }, abstract = {Exogenous recombinant human thioredoxin (rTRX, > or = 500 nM), a dithiol reductase enzyme, inhibited the expression of human immunodeficiency virus (HIV) 1BaL in human macrophages (M phi) by 71% (range, 26-100%), as evaluated by p24 antigen production and the integration of provirus at 14 d after infection. The stoichiometric reducing agent N-acetylcysteine (NAC) also inhibited HIV production, but to a lesser degree, and only at 30,000-fold higher concentrations. Exogenous rTRX is cleaved by M phi to generate the inflammatory cytokine, eosinophil cytotoxicity-enhancing factor (ECEF). In contrast to rTRX, rECEF (concentrations from 50 pM to 2 microM) enhanced the production of HIV by 67% (range, 33-92%). Thus, whereas TRX is a potent inhibitor of the expression of HIV in human M phi, cleavage of TRX to ECEF creates a mediator with the opposite effect. TRX also inhibited the expression of integrated provirus in the chronically infected OM 10.1 cell line, showing that it can act at a step subsequent to viral infection and integration.}, }
@article {pmid7961253, year = {1994}, author = {Khawli, FA and Reid, MB}, title = {N-acetylcysteine depresses contractile function and inhibits fatigue of diaphragm in vitro.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {77}, number = {1}, pages = {317-324}, doi = {10.1152/jappl.1994.77.1.317}, pmid = {7961253}, issn = {8750-7587}, support = {HL-45721/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/toxicity ; Animals ; Antioxidants/pharmacology ; Diaphragm/cytology/*drug effects/metabolism ; In Vitro Techniques ; Isometric Contraction/drug effects ; Male ; Muscle Contraction/drug effects ; Muscle Fatigue/*drug effects ; Muscle Fibers, Skeletal/drug effects ; Oxidation-Reduction ; Oxidative Stress/physiology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {We have previously shown that antioxidant enzymes (superoxide dismutase and catalase) depress contractility of unfatigued diaphragm fiber bundles and inhibit development of acute fatigue. In the present study, we tested for similar effects of N-acetyl-cysteine (NAC), a nonspecific antioxidant approved for clinical use. Diaphragms were excised from deeply anesthetized rats. Fiber bundles were removed, mounted isometrically at 37 degrees C, and stimulated directly using supramaximal current intensity. Studies of unfatigued muscle showed that 10 mM NAC reduced peak twitch stress (P < 0.0001), shortened time to peak twitch stress (P < 0.002), and shifted the stress-frequency curve down and to the right (P < 0.05). Fiber bundles incubated in 0.1-10 mM NAC exhibited a dose-dependent decrease in relative stresses developed during 30-Hz contraction (P < 0.0001) with no change in maximal tetanic (200 Hz) stress. NAC (10 mM) also inhibited acute fatigue. Throughout 10 min of intermittent contraction at 30-40 Hz, treated bundles developed higher stresses than time-matched control bundles (P < 0.0001). NAC concentrations > or = 30 mM were toxic, causing a prompt irreversible decrease in maximal tetanic stress (P < 0.0001). Because NAC effects mimic the effects of other antioxidant agents with different mechanisms of action, we conclude that exogenous antioxidants exert stereotypical effects on contractile function that differ between unfatigued and fatiguing muscle. Unlike antioxidant enzymes, however, NAC has been approved for clinical use and may be used in future studies of human muscle fatigue.}, }
@article {pmid7941647, year = {1994}, author = {De Caterina, R}, title = {[Nitrates as thrombocyte function inhibitors].}, journal = {Zeitschrift fur Kardiologie}, volume = {83}, number = {7}, pages = {463-473}, pmid = {7941647}, issn = {0300-5860}, mesh = {Animals ; Bleeding Time ; Blood Platelets/*drug effects/physiology ; Coronary Circulation/drug effects ; Humans ; Myocardial Infarction/blood/*drug therapy ; Nitrates/*therapeutic use ; Nitric Oxide/physiology ; Platelet Aggregation/drug effects ; Platelet Aggregation Inhibitors/*therapeutic use ; Vascular Resistance/drug effects ; }, abstract = {Besides their well-known relaxing effects on smooth muscle cells--the basis for vasodilation in peripheral arteries and veins and in epicardial coronary arteries--nitrates also exert effects on blood platelets. These occur by the same mechanisms operating in blood vessels, a penetration of the parent molecule or its active metabolites through the plasma membrane, the release of the reactive free radical NO, the stimulation of guanylate cyclase and the consequent increase of cytosolic levels of cyclic guanosinemonophosphate (cGMP). As a consequence, platelets become unspecifically less reactive to a variety of aggregating stimuli. When added to platelet suspensions nitrates indeed inhibit platelet aggregation by virtually all known stimuli. These in vitro anti-platelet effects require high concentrations of the drugs; however, recent evidence has been gathered that such inhibition of platelet function also occurs during the in vivo administration of nitrates. Such evidence derives from direct ex vivo studies with platelet aggregometry, from experiments showing synergism of nitrates with prostacyclin and the amplification of ex vivo effects with sulfhydryl group donors such as N-acetyl-cysteine, and, finally, from studies on the bleeding time. The effects of nitrates on blood platelets may be an explanation for the protection from death and reinfarction inferred on the basis of metaanalysis of several studies in acute myocardial infarction.}, }
@article {pmid7917503, year = {1994}, author = {Meulenbelt, J and van Bree, L and Dormans, JA and Sangster, B}, title = {No beneficial effect of N-acetylcysteine treatment on broncho-alveolar lavage fluid variables in acute nitrogen dioxide intoxicated rats.}, journal = {Human &amp; experimental toxicology}, volume = {13}, number = {7}, pages = {472-477}, doi = {10.1177/096032719401300704}, pmid = {7917503}, issn = {0960-3271}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bronchoalveolar Lavage Fluid/*chemistry/cytology ; Female ; Nitric Oxide/*poisoning ; Poisoning/drug therapy ; Protein Biosynthesis ; Rats ; Rats, Wistar ; }, abstract = {1. In previous studies a rat inhalation model was developed to investigate the efficacy of treatment in acute NO2 intoxication. 2. N-acetylcysteine (NAC) was administered intravenously to study its effect on biochemical variables in broncho-alveolar lavage fluid in acute NO2 intoxicated rats. It was decided to start the intravenous administration of NAC 24 h before the exposure to NO2 to induce higher intracellular glutathione (GSH) levels in lung cells of NAC-treated rats compared to not NAC-treated rats. Because, on theoretical grounds, the therapeutic effect of NAC may be expected to be especially marked during the first 24 h after exposure, the rats were observed for a period of 24 h and were then killed for investigation. A loading dose of 85 mg kg-1 h-1 or 170 mg kg-1 h-1 was followed by a continuous infusion (until autopsy) with a dose of 225 mg kg-1 24 h-1 or 450 mg kg-1 24 h-1 respectively. 3. Twenty four hours after exposure to 175 ppm NO2 (1 ppm is 1.88 mg m-3) for 10 min, NAC did not reduce the increase of variables in broncho-alveolar lavage fluid which reflect the severity of lung damage. 4. The protein and albumin concentration and the activities of angiotensin converting enzyme and alkaline phosphatase in broncho-alveolar lavage fluid after NO2 exposure were even more increased in the NAC-treated than in the saline-treated rats, but none of the differences was statistically significant. 5. In sham exposed rats no effect of NAC was observed.}, }
@article {pmid8207209, year = {1994}, author = {Yim, CY and Hibbs, JB and McGregor, JR and Galinsky, RE and Samlowski, WE}, title = {Use of N-acetyl cysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {152}, number = {12}, pages = {5796-5805}, pmid = {8207209}, issn = {0022-1767}, support = {CA42014/CA/NCI NIH HHS/United States ; U01-CA58248/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Animals ; Cytotoxicity, Immunologic/drug effects ; Female ; Fibrosarcoma/immunology/metabolism/*therapy ; Glutathione/*metabolism ; Immunotherapy ; In Vitro Techniques ; Interleukin-2/administration &amp; dosage/*therapeutic use ; Killer Cells, Lymphokine-Activated/drug effects/immunology/metabolism ; Lymphocyte Activation/drug effects ; Lymphocytes/drug effects/immunology/metabolism ; Male ; Mice ; Mice, Inbred C3H ; Phenotype ; }, abstract = {IL-2 therapy can induce marked oxidative stress via reactive oxygen and nitrogen intermediates. Glutathione, the major intracellular reductant, may become rate limiting to cytotoxic lymphocyte activation and proliferation under these circumstances. N-Acetyl cysteine (NAc-cys) was used to increase intracellular glutathione levels during lymphokine-activated killer (LAK) cell activation by IL-2. Incubation of splenocytes with NAc-cys (0.6 to 1.0 mM) resulted in significant changes in intracellular reduced and total glutathione (92% and 58% increase, respectively) at 96 h. These levels correlated with markedly enhanced cell proliferation (threefold) and cytolytic effector cell generation (> fivefold increase in LU/10(6) cells) induced by the combination of NAc-cys with IL-2. IL-2 exposure by itself unexpectedly increased intracellular reduced glutathione by 43%. IL-2 and NAc-cys were synergistic in increasing glutathione levels (reduced glutathione: 292% increase; total: 251% increase). Inhibition of glutathione synthesis, using L-buthionine-(S,R)-sulfoximine reversed the effects of NAc-cys on intracellular glutathione, as well as cellular proliferation and cytotoxicity. This experiment established that the effects of NAc-cys required de novo glutathione synthesis. In conjunction with IL-2/LAK treatment, oral NAc-cys administration (260 to 900 mg/kg/day for 7 days) significantly decreased tumor progression in a refractory s.c. tumor model. A small fraction of mice (11 to 17%) had complete tumor regressions. NAc-cys may be useful as an adjunct to increase the antitumor activity of IL-2/LAK therapy.}, }
@article {pmid8205670, year = {1994}, author = {Mehra, A and Shotan, A and Ostrzega, E and Hsueh, W and Vasquez-Johnson, J and Elkayam, U}, title = {Potentiation of isosorbide dinitrate effects with N-acetylcysteine in patients with chronic heart failure.}, journal = {Circulation}, volume = {89}, number = {6}, pages = {2595-2600}, doi = {10.1161/01.cir.89.6.2595}, pmid = {8205670}, issn = {0009-7322}, support = {MO1-RR-43/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*administration &amp; dosage/pharmacology ; Adult ; Aged ; Atrial Natriuretic Factor/blood ; Catecholamines/blood ; Chronic Disease ; Drug Synergism ; Drug Therapy, Combination ; Female ; Heart Failure/*drug therapy/physiopathology ; Humans ; Isosorbide Dinitrate/administration &amp; dosage/pharmacology/*therapeutic use ; Male ; Middle Aged ; Renin/blood ; }, abstract = {BACKGROUND: Supply of sulfhydryl groups with the administration of N-acetylcysteine (NAC) has been reported to reverse tolerance to nitroglycerin but not to isosorbide dinitrate (ISDN). Lack of interaction between NAC and ISDN was suggested as an explanation for these findings. The present study was therefore designed to further evaluate this hypothesis. For this purpose, we compared the hemodynamic and hormonal effects of ISDN when given alone and in combination with NAC.<br><br>METHODS AND RESULTS: We performed a randomized, cross-over design evaluation of the hemodynamic and hormonal effects of ISDN and ISDN + NAC in 14 patients with chronic congestive heart failure due to left ventricular systolic dysfunction. The findings of this study demonstrated a substantial NAC-mediated potentiation of ISDN effect on mean right atrial pressure (-11 +/- 21% versus -38 +/- 27%, -17 +/- 20% versus -34 +/- 27%, and -7 +/- 20% versus -25 +/- 26% at 2, 3, and 4 hours, respectively; all P < .05), mean pulmonary artery wedge pressure (-18 +/- 16% versus -33 +/- 14%, -15 +/- 25% versus -33 +/- 19%, -14 +/- 22% versus -25 +/- 22%, and -16 +/- 16% versus -26 +/- 16% at 2, 3, 4, and 5 hours, respectively; all P < .05), mean pulmonary artery pressure (-8 +/- 11% versus -20 +/- 15% at 3 hours, P < .05), and cardiac output (an increase of 2 +/- 16% versus 25 +/- 20% at 4 hours, P < .05). Although there were no significant changes in serum catecholamine levels and plasma renin concentration with both regimens, ISDN + NAC resulted in a greater fall in plasma levels of atrial natriuretic peptide (296 +/- 251 pg/mL after ISDN versus 202 +/- 118 pg/mL after ISDN + NAC, P < .05).<br><br>CONCLUSIONS: The results of this study provide strong evidence for the existence of an interaction between thiols and ISDN and further support the role of sulfhydryl groups in the activation and therapeutic action of organic nitrates. The discrepancy between the results of this study demonstrating NAC-induced potentiation of ISDN effects and a previous study showing failure to reverse ISDN tolerance with NAC may suggest that ISDN-NAC interaction requires normal intracellular levels of sulfhydryl groups and does not occur after intracellular sulfhydryl group depletion.}, }
@article {pmid8200134, year = {1994}, author = {Sagara, M and Satoh, J and Zhu, XP and Takahashi, K and Fukuzawa, M and Muto, G and Muto, Y and Toyota, T}, title = {Inhibition with N-acetylcysteine of enhanced production of tumor necrosis factor in streptozotocin-induced diabetic rats.}, journal = {Clinical immunology and immunopathology}, volume = {71}, number = {3}, pages = {333-337}, doi = {10.1006/clin.1994.1094}, pmid = {8200134}, issn = {0090-1229}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Diabetes Mellitus, Experimental/*metabolism ; Fructosamine ; Hexosamines/blood ; Rats ; Rats, Wistar ; Serum Albumin/analysis ; Time Factors ; Triglycerides/blood ; Tumor Necrosis Factor-alpha/*biosynthesis ; }, abstract = {We previously reported that the in vivo production of the tumor necrosis factor alpha (TNF) was significantly enhanced after the onset of diabetes in spontaneous type 1 and 2 diabetic animals. In this report we confirmed the enhanced production of TNF in streptozotocin (STZ)-induced diabetes and then attempted to suppress the enhanced TNF production with N-acetylcysteine (NAC), a precursor of glutathione synthesis. The lipopolysaccharide-induced serum TNF activities were significantly enhanced in STZ-induced diabetic rats (6-18 weeks of age) compared with those of nondiabetic rats throughout the 12-week experiment. A single, oral administration of NAC (200 or 1000 mg/kg body wt) significantly suppressed the enhanced TNF production in the diabetic rats compared with that in untreated rats in a dose-dependent manner. On the other hand, in the long-term (6 or 12 weeks) administrations, smaller doses of NAC (50 or 200 mg/kg/day) also significantly inhibited the enhanced production of TNF regardless of the dose of NAC. NAC administration, however, did not suppress the TNF production of nondiabetic rats. The long-term NAC administration affected neither body weight nor levels of serum glucose, fructosamine, albumin, and triglyceride. These results show that NAC administration significantly suppressed the enhanced TNF production in diabetic rats and indicate that NAC might be useful in preventing TNF-mediated pathological conditions in diabetes.}, }
@article {pmid8194136, year = {1994}, author = {Simon, G and Moog, C and Obert, G}, title = {Effects of glutathione precursors on human immunodeficiency virus replication.}, journal = {Chemico-biological interactions}, volume = {91}, number = {2-3}, pages = {217-224}, doi = {10.1016/0009-2797(94)90042-6}, pmid = {8194136}, issn = {0009-2797}, mesh = {Acetylcysteine/*pharmacology ; Cell Line ; Colorimetry ; Gene Expression Regulation, Viral/drug effects ; Glutathione/*metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; HIV/*drug effects/genetics/physiology ; HIV Long Terminal Repeat/drug effects ; Homocysteine/*pharmacology ; Humans ; Interleukin-6/pharmacology ; Prodrugs/pharmacology ; Pyrrolidonecarboxylic Acid ; Tetradecanoylphorbol Acetate/pharmacology ; Thiazoles/*pharmacology ; Thiazolidines ; Tumor Cells, Cultured ; Virus Replication/drug effects ; beta-Galactosidase/biosynthesis ; }, abstract = {Asymptomatic human immunodeficiency virus (HIV)-seropositive individuals have reduced glutathione (GSH) levels. This has led to the suggestion that elevated intracellular thiols levels may inhibit HIV replication and progression of the disease. We confirmed that N-acetyl-L-cysteine (NAC), a cysteine prodrug which maintains intracellular GSH levels during oxidative stress, inhibits in the chronically infected U1 cells, the stimulation of HIV replication induced by phorbol 12-myristate 13-acetate (PMA), interleukin-6 (IL-6) or granulocyte-macrophage colony stimulating factor (GM-CSF). However, we found no significant inhibition of PMA-mediated long terminal repeat (LTR)-directed beta-galactosidase expression in transiently transfected Jurkat T-cells. We have compared NAC effects with the effects of other GSH precursors on HIV expression. Treatment of the U1 cell line by L-2-oxo-4-thiazolidine carboxylic acid (OTC), which is converted to cysteine by 5-oxoprolinase, or by homocysteine (HC), a natural cysteine precursor, reduced the PMA-induced HIV expression, but surprisingly, markedly stimulated the expression mediated by IL-6 and GM-CSF. Several experiments to investigate the effect of OTC on LTR transactivation were carried out, but beta-galactosidase activity was never modified in a significant fashion in PMA-induced Jurkat T-cells after OTC treatment. Furthermore, HC stimulated the PMA-mediated HIV-LTR transactivation in Jurkat T-cells. GSH assays showed that treatment of U937 and Jurkat T-cells with NAC and OTC moderately increased the GSH level, while HC led to a significantly higher increase of the thiol level. In conclusion, it appeared that an increase of the GSH intracellular level did not lead solely to an inhibition of HIV replication but could also lead to an activation of viral expression. This seemed the case when HIV replication was stimulated by compounds which act mainly at a post-transcriptional level.}, }
@article {pmid8194133, year = {1994}, author = {Favier, A and Sappey, C and Leclerc, P and Faure, P and Micoud, M}, title = {Antioxidant status and lipid peroxidation in patients infected with HIV.}, journal = {Chemico-biological interactions}, volume = {91}, number = {2-3}, pages = {165-180}, doi = {10.1016/0009-2797(94)90037-x}, pmid = {8194133}, issn = {0009-2797}, mesh = {Acquired Immunodeficiency Syndrome/drug therapy/*metabolism ; Adult ; Analysis of Variance ; Antioxidants/*metabolism ; Female ; Free Radicals ; HIV Infections/drug therapy/*metabolism ; Humans ; *Lipid Peroxidation ; Male ; }, abstract = {Deficiency in antioxidant micronutrients have been observed in patients with AIDS. These observations concerning only some isolated nutrients demonstrate a defect in zinc, selenium, and glutathione. An increase in free radical production and lipid peroxidation has been also found in these patients, and takes a great importance with recent papers presenting an immunodeficiency and more important an increase in HIV-1 replication secondary to free radicals overproduction. We have assessed different studies, trying to obtain a global view of the antioxidant status of these patients. In adults we observe a progressive decrease for zinc, selenium, and vitamin E with the severity of disease, except that selenium remains normal at stage II. However, the main dramatic decrease concerns carotenoids whose level at stage II is only half the normal value. To understand if these decreases in antioxidant and increases in oxidative stress occur secondary to the aggravation of the disease or, conversely, are responsible for it, we undertook a longitudinal survey of asymptotic patients. The preliminary results of this evaluation are presented. Paradoxically, lipid peroxidation is higher at stage II than at stage IV. This may be consecutive to a more intense overproduction of oxygen free radicals by more viable polymorphonuclear (PMN) at the asymptomatic stage. The free radicals production and lipid peroxidation seem secondary to a direct induction by the virus of PMN stimulation and cytokines secretion. N-Acetyl cysteine or ascorbate have been demonstrated in cell culture to be capable of blocking the expression of HIV-1 after oxidative stress and N-acetyl cysteine inhibits in vitro TNF-induced apoptosis of infected cells. In regard to all these experimental data, few serious and large trials of antioxidants have been conducted in HIV-infected patients, although some preliminary studies using zinc or selenium have been performed. In our opinion it is now time to evaluate in humans the beneficial effect of antioxidants. The more promising candidates for presenting synergistic effects when associated with N-acetyl cysteine seem to be beta-carotene, selenium and zinc.}, }
@article {pmid7928885, year = {1994}, author = {Sen, CK and Rankinen, T and Väisänen, S and Rauramaa, R}, title = {Oxidative stress after human exercise: effect of N-acetylcysteine supplementation.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {76}, number = {6}, pages = {2570-2577}, doi = {10.1152/jappl.1994.76.6.2570}, pmid = {7928885}, issn = {8750-7587}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Anaerobic Threshold/physiology ; DNA Damage ; Exercise/*physiology ; Exercise Test ; Free Radical Scavengers ; Glutathione/blood/metabolism ; Humans ; Leukocytes/metabolism ; Male ; *Oxidative Stress ; Thiobarbituric Acid Reactive Substances/metabolism ; }, abstract = {The association between exercise intensity and related oxidative stress was investigated in nine men who exercised for 30 min at their aerobic (AeT) and anaerobic (AnaeT) thresholds. We also tested the effect of oral N-acetylcysteine (NAC) on exercise-associated rapid blood glutathione (GSH) oxidation in subjects performing two identical maximal bicycle ergometer exercise (Max) tests. Before the second test (Max with NAC supplementation [Max(NAC)]), the men took 200 x 4 mg/day of NAC tablets for 2 days and an additional 800 mg on the test morning. Blood samples were drawn before, immediately after, and 24 h after the tests. Total and oxidized GSH levels in blood were determined. Plasma thiobarbituric acid-reactive substances and net peroxyl radical scavenging capacity (PSC) were assayed. Exercise-associated damage in leukocyte DNA was estimated by fluorometric analysis of DNA unwinding. A single bout of exercise at Max, AeT, and AnaeT resulted in a significant increase in blood GSH oxidation but did not influence net PSC of plasma. Although an association between a single bout of exercise and leukocyte DNA damage was apparent, this study suggests that the parameter may not serve as a sensitive index to assess the role of exercise intensity in the extent of exercise-associated oxidative stress. Plasma thiobarbituric acid-reactive substances did not change after either Max or Max(NAC) tests. NAC supplementation resulted in an increase in preexercise PSC, indicating a higher net antioxidant capacity of the plasma, but did not affect blood GSH.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7521193, year = {1994}, author = {Kalebic, T and Schein, PS}, title = {Organic thiophosphate WR-151327 suppresses expression of HIV in chronically infected cells.}, journal = {AIDS research and human retroviruses}, volume = {10}, number = {6}, pages = {727-733}, doi = {10.1089/aid.1994.10.727}, pmid = {7521193}, issn = {0889-2229}, mesh = {Amifostine/analogs &amp; derivatives/*pharmacology ; Cell Line/drug effects/microbiology ; Cytokines/pharmacology ; HIV Infections/*drug therapy ; HIV Reverse Transcriptase ; HIV-1/*drug effects ; Organothiophosphorus Compounds/*pharmacology ; RNA-Directed DNA Polymerase/metabolism ; Sulfhydryl Compounds/pharmacology ; }, abstract = {Reducing agents such as glutathione (GSH), glutathione ester (GSE), and N-acetylcysteine (NAC) have been shown to suppress the induction of HIV expression in chronically infected cells stimulated by cytokines. We present data which show the effects of the organic thiophosphate WR-151327 on the expression of latent HIV in U1 cells. The chronically infected promonocytic cell line U1 constitutively expresses low levels of HIV that can be increased by 13-phorbol 12-myristate acetate (PMA), tumor necrosis factor alpha (TNF-alpha), and granulocyte/monocyte colony-stimulating factor (GM-CSF). WR-151327 suppressed, in dose-dependent fashion, the reverse transcriptase (RT) activity induced by TNF-alpha, GM-CSF, and PMA. The maximal decrease in RT activity was 70, 80, and 50%, respectively. Pretreatment with WR-151327 also suppressed the induction of total HIV protein synthesis, as shown by Western blot analysis. In addition, WR-151327 suppressed HIV-LTR-CAT activity in transfected human rhabdomyosarcoma cells (RD). Suppression of HIV expression by WR-151327 was observed in the absence of a cytotoxic or cytostatic effect. Incubation of WR-151327 with human recombinant TNF-alpha for 6 hr at 37 degrees C did not alter the capacity of TNF-alpha to induce the expression of HIV. Our observations further support the hypothesis that reducing agents are important in the control of HIV replication and that the clinical evaluation of WR-151327 may be indicated.}, }
@article {pmid8203575, year = {1994}, author = {Zhang, H and Spapen, H and Nguyen, DN and Benlabed, M and Buurman, WA and Vincent, JL}, title = {Protective effects of N-acetyl-L-cysteine in endotoxemia.}, journal = {The American journal of physiology}, volume = {266}, number = {5 Pt 2}, pages = {H1746-54}, doi = {10.1152/ajpheart.1994.266.5.H1746}, pmid = {8203575}, issn = {0002-9513}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Animals ; Blood Pressure/drug effects ; Cardiac Tamponade/physiopathology ; Dogs ; Endotoxins/antagonists &amp; inhibitors/*toxicity ; Escherichia coli ; Female ; Heart Rate/drug effects ; Hematocrit ; Hemodynamics/*drug effects/physiology ; Lactates/blood ; Male ; Oxygen Consumption/drug effects ; Pulmonary Artery/drug effects/physiopathology ; Pulmonary Circulation/drug effects ; Sepsis/*physiopathology/prevention &amp; control ; Stroke Volume/drug effects ; Time Factors ; Vascular Resistance/drug effects ; Ventricular Function, Left/drug effects ; Ventricular Function, Right/drug effects ; }, abstract = {Because oxygen free radicals have been implicated in the endothelial cell damage and in the myocardial depression occurring during severe sepsis, we investigated whether N-acetyl-L-cysteine (NAC) could influence the oxygen extraction capabilities during an acute reduction in blood flow induced by cardiac tamponade after endotoxin challenge. Sixteen anesthetized, saline-infused, and ventilated dogs received Escherichia coli endotoxin (2 mg/kg) 30 min before tamponade was induced by repeated bolus injections of warm saline into the pericardial space. Thirty minutes before endotoxin administration, nine dogs received NAC (150 mg/kg, followed by a 20 mg.kg-1.h-1 infusion); the other seven dogs served as a control group. The NAC group maintained higher cardiac index, oxygen delivery (DO2), and left ventricular stroke work index, but lower systemic and pulmonary vascular resistance, than the control group. The oxygen uptake (VO2) levels at critical DO2 (DO2crit) were identical in the two groups. However, DO2crit was significantly lower in the NAC than in the control group (8.1 +/- 1.7 vs. 10.8 +/- 1.8 ml.kg-1.min-1, P < 0.01). Critical oxygen extraction ratio and the slope of the VO2-to-DO2-dependent line were higher in the NAC than in the control group (72 +/- 14 vs. 53 +/- 15% and 0.80 vs. 0.56, respectively; both P < 0.05). The peak lactate and the maximal tumor necrosis factor (TNF) levels were lower in the NAC than in the control group (5.2 +/- 0.4 vs. 7.6 +/- 0.4 mM, and 0.14 +/- 0.03 vs. 1.21 +/- 0.58 ng/ml, respectively; both P < 0.01). NAC significantly increased glutathione peroxidase activity.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8174437, year = {1994}, author = {Monto, GL and Scheuer, PJ and Hansing, RL and Burroughs, AK}, title = {Attenuation of acetaminophen hepatitis by prostaglandin E2. A histopathological study.}, journal = {Digestive diseases and sciences}, volume = {39}, number = {5}, pages = {957-960}, pmid = {8174437}, issn = {0163-2116}, mesh = {16,16-Dimethylprostaglandin E2/*therapeutic use ; Acetaminophen/*toxicity ; Acetylcysteine/therapeutic use ; Acute Disease ; Animals ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology/pathology ; Liver/pathology ; Male ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Acute acetaminophen hepatitis was produced in three groups of five rats given 1600 mg/kg by gavage. The protective effect of 16,16-dimethyl prostaglandin E2, 200 micrograms/kg administered subcutaneously 30 min later, was compared to the protective effect of N-acetylcysteine 1 g/kg similarly administered. All animals were killed at 24 hr, and liver tissues were compared histologically to the damage found in acetaminophen-treated controls and untreated anatomic controls. Serum transaminase values at 24 hr exceeded 1000 units in the acetaminophen control group, averaged 658 units in the acetylcysteine treated group, and were near normal (75 units) in the prostaglandin treated group (P < 0.02). Liver samples (1 cm3) were removed terminally at 24 hr. Liver damage was assessed without reference to precedent history. Histopathologically, damage was most severe in the acetaminophen control group, mainly in pericentral lobular zones. The prostaglandin-treated group showed considerably less damage, which was confined to the hepatic vein area. The acetylcysteine-treated group showed an intermediate degree of damage. We conclude that dmPGE2, given 30 min after ingestion of acetaminophen was found to be more effective in limiting liver damage than NAC in this rat model.}, }
@article {pmid8042190, year = {1994}, author = {Leerink, CB and van Ham, AD and Heeres, A and Duif, PF and Bouma, BN and van Rijn, HJ}, title = {Sulfhydryl compounds influence immunoreactivity, structure and functional aspects of lipoprotein(a).}, journal = {Thrombosis research}, volume = {74}, number = {3}, pages = {219-232}, doi = {10.1016/0049-3848(94)90110-4}, pmid = {8042190}, issn = {0049-3848}, mesh = {Dithiothreitol/pharmacology ; Electrophoresis, Polyacrylamide Gel ; Enzyme-Linked Immunosorbent Assay ; Humans ; Lipoprotein(a)/chemistry/*drug effects/physiology ; Oxidation-Reduction ; Plasminogen Inactivators/pharmacology ; Protein Binding ; Structure-Activity Relationship ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {Human plasma Lp(a) is susceptible to various sulfhydryl compounds. In this study we present evidence indicating that after treatment of Lp(a) with sulfhydryl compounds, immunoreactivity is changed, structural changes occur and functional characteristics regarding the numerous kringle structures in apo(a) disappear. Purified Lp(a) was subjected to variable concentrations (0.01-10 mM) of various sulfhydryl compounds: DTT, 2-mercapto-ethanol (BME), N-acetylcysteine (NAC) and homocysteine (HCys). Free SH groups were blocked by iodoacetamide. Reduced and alkylated Lp(a) was tested in two ELISAs, one detecting apo(a) alone and one detecting apo(a)-apoB complexes. In both ELISAs polyclonal antibodies were used. For comparison a commercial apo(a) IRMA utilizing two monoclonal antibodies was used. The results indicate that a similar decrease in response of both ELISAs is observed, whereas the IRMA response is less affected. Western blotting of "DTT treated" Lp(a) after SDS-PAGE under nonreducing conditions showed that separate apo(a) and apoB-100 bands became detectable at 1 mM DTT. Native PAGE (2.5-16%) indicated structural changes of Lp(a) beginning to occur at 0.03 mM DTT. Epsilon-aminocaproic acid-inhibitable binding of "DTT-treated" Lp(a) to Desafib-X decreased with increasing DTT concentrations in concert with a loss of the capacity of Lp(a) to inhibit plasminogen activation upon treatment with DTT. The observed immunological and functional changes of Lp(a) indicate that apo(a) kringle function is severely affected by sulfhydryl compounds.}, }
@article {pmid8178341, year = {1994}, author = {Dunne, JB and Davenport, M and Williams, R and Tredger, JM}, title = {Evidence that S-adenosylmethionine and N-acetylcysteine reduce injury from sequential cold and warm ischemia in the isolated perfused rat liver.}, journal = {Transplantation}, volume = {57}, number = {8}, pages = {1161-1168}, doi = {10.1097/00007890-199404270-00004}, pmid = {8178341}, issn = {0041-1337}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aspartate Aminotransferases/metabolism ; Bile/physiology ; Cold Temperature ; Hot Temperature ; Ischemia/drug therapy ; Liver/*blood supply/chemistry/enzymology ; Male ; Oxygen/isolation &amp; purification/metabolism ; Oxygen Consumption ; Rats ; Rats, Inbred Lew ; Regional Blood Flow ; Reperfusion Injury/*prevention &amp; control ; S-Adenosylmethionine/*pharmacology ; Time Factors ; }, abstract = {S-Adenosylmethionine (SAMe) and N-acetylcysteine (NAC), two agents with known benefit for reducing hepatic injury, were used to treat ischemic injury in a rat liver perfusion model. We compared cold ischemic injury with sequential periods of cold and warm ischemia that equate to episodes during the storage and implantation of liver grafts. The additional period of 20 min warm ischemia after 24 hr cold ischemia profoundly impaired initial (15 min) mean blood flow (1.8 +/- 0.1 vs. 2.7 +/- 0.4 ml/min/g liver for cold ischemia, P < 0.001) and bile flow (2.31 +/- 0.74 vs. 10.6 +/- 3.96 mg/hr/g liver for cold ischemia, P < 0.001) and increased the oxygen extraction ratio (OER) (0.53 +/- 0.03 vs. 0.29 +/- 0.08 for cold ischemia, P < 0.01) and acid release from glycolysis (0.18 +/- 0.02 vs. 0.11 +/- 0.02 mmol/g liver for cold ischemia, P < 0.05). Impairment of blood flow, bile flow, and OER was sustained throughout the 3-hr perfusion. In the same model, SAMe restored hepatic blood flow to control values when administered to the donor, included in the UW, and added as a bolus to the perfusate on reperfusion. SAMe also improved OER (P < 0.001 vs. sequential cold and warm ischemia) and initial bile flow (9.63 +/- 2.01 mg/hr/g liver, P < 0.01), returning values to control levels by 3 hr. SAMe reduced the initial release of glucose upon reperfusion (P < 0.01) and improved subsequent glucose uptake, but corresponding benefits on enzyme release from damaged hepatocytes (AST) or endothelial cells (purine nucleoside phosphorylase) were not observed. Equimolar concentrations of NAC induced transitory improvements in blood and bile flow but these were not sustained beyond 30 min of reperfusion.}, }
@article {pmid8209319, year = {1994}, author = {Boberg, KM and Schrumpf, E and Rogstad, B and Berg, KJ and Ganes, T and Bergan, A}, title = {[Treatment of paracetamol poisoning. An indication for liver transplantation?].}, journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke}, volume = {114}, number = {10}, pages = {1199-1203}, pmid = {8209319}, issn = {0029-2001}, mesh = {Acetaminophen/*poisoning ; Adolescent ; Adult ; Female ; Hepatic Encephalopathy/chemically induced/mortality/*surgery ; Humans ; *Liver Transplantation ; Prognosis ; Suicide ; Suicide, Attempted ; }, abstract = {Development of metabolic acidosis (pH < 7.30) or the combination of encephalopathy grade III-IV, coagulopathy (PT > 100s) and oliguric renal failure are associated with a poor prognosis in paracetamol-induced fulminant liver failure. It is important to administer N-acetylcysteine as soon as possible after the overdose, but N-acetyl-cysteine also seems to improve survival when given 36-80h following ingestion. Liver transplantation has been performed in some patients with paracetamol-induced fulminant liver failure, but convincing evidence that transplantation improves survival in this group of patients is still lacking. We discuss the difficulties met in deciding if and when to perform liver transplantation. Renal failure may develop some days after paracetamol poisoning, even in the absence of severe liver damage, and haemofiltration and haemodialysis may be necessary.}, }
@article {pmid8144975, year = {1994}, author = {Van Dervort, AL and Yan, L and Madara, PJ and Cobb, JP and Wesley, RA and Corriveau, CC and Tropea, MM and Danner, RL}, title = {Nitric oxide regulates endotoxin-induced TNF-alpha production by human neutrophils.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {152}, number = {8}, pages = {4102-4109}, pmid = {8144975}, issn = {0022-1767}, mesh = {Acetylcysteine/pharmacology ; Cyclic GMP/metabolism ; Gene Expression/drug effects ; Humans ; In Vitro Techniques ; Interferon-gamma/pharmacology ; Lipopolysaccharides/pharmacology ; Macrophages/metabolism ; Neutrophils/drug effects/*metabolism ; Nitric Oxide/*pharmacology ; Nitroprusside/pharmacology ; RNA, Messenger/genetics ; Tumor Necrosis Factor-alpha/*biosynthesis/genetics ; }, abstract = {We studied the effect of nitric oxide on LPS-induced TNF-alpha production by human neutrophils. Human neutrophils exposed to LPS and IFN-gamma did not show measurable increases in intracellular cyclic GMP (cGMP). However, cGMP increased upto 30-fold (p < 0.01) in neutrophils incubated with both sodium nitroprusside (SNP), an exogenous source of nitric oxide, and N-acetylcysteine (NAC), which increases the bioavailability of nitric oxide; this increase indicates that neutrophils contain a nitric oxide-sensitive guanylate cyclase. SNP, with or without NAC, did not increase TNF-alpha production in human neutrophils cultured in medium alone. However, LPS-dependent TNF-alpha production was increased by exposure to SNP (p < 0.05); this effect was further increased by the addition of NAC (p < 0.02). IFN-gamma greatly increased LPS-mediated TNF-alpha production by human neutrophils (p < 0.01), and SNP plus NAC was found to further augment this production (p < 0.01). The up-regulation of TNF-alpha production by nitric oxide was not associated with increased amounts of LPS-induced TNF-alpha mRNA, and was not reproduced by exposing neutrophils to cGMP analogues. These data suggest that nitric oxide released by endothelial and vascular smooth muscle cells may exert a paracrine effect on human neutrophils and augment the inflammatory response in sepsis by increasing the production of cytokines. Although the mechanism of this effect remains unknown, it does not seem to be dependent on cGMP or increased levels of TNF-alpha mRNA.}, }
@article {pmid8137327, year = {1994}, author = {Izzotti, A and D'Agostini, F and Bagnasco, M and Scatolini, L and Rovida, A and Balansky, RM and Cesarone, CF and De Flora, S}, title = {Chemoprevention of carcinogen-DNA adducts and chronic degenerative diseases.}, journal = {Cancer research}, volume = {54}, number = {7 Suppl}, pages = {1994s-1998s}, pmid = {8137327}, issn = {0008-5472}, mesh = {2-Acetylaminofluorene/toxicity ; Acetylcysteine/*pharmacology ; Animals ; Anticarcinogenic Agents/*pharmacology ; Aorta, Abdominal/pathology ; Arteriosclerosis/*etiology/pathology/prevention &amp; control ; Carcinogens/*metabolism/*toxicity ; Cricetinae ; DNA/drug effects/*metabolism ; Diet ; Humans ; Male ; Mice ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Smoke/adverse effects ; Smoking/adverse effects ; }, abstract = {Molecular dosimetry techniques were exploited in order to assess the efficacy of experimental chemoprevention assays and to evaluate the involvement of DNA alterations, not only in cancer but also in other chronic degenerative diseases. In agreement with other protective effects previously observed in the same animal models, the thiol N-acetylcysteine (NAC) totally prevented or significantly reduced the formation of carcinogen-DNA adducts in three experimental systems in rats. Thus, as assessed by 32P postlabeling, supplement of the diet with NAC decreased both deoxyguanosine-C8-aminofluorene adducts (butanol enrichment) and deoxyguanosine-N2-acetylaminofluorene adducts (nuclease P1 enrichment) formed in rat liver following dietary administration of 2-acetylaminofluorene for 3 weeks. DNA adducts were detected by synchronous fluorescence spectrophotometry in rat liver, lung, heart, and testis following a daily i.t. instillation of benzo(a)pyrene for 3 consecutive days. The whole-body exposure of rats to mainstream cigarette smoke for 40 consecutive days resulted in the appearance of DNA adducts in heart, lung, and aorta, whereas no adduct was detected by synchronous fluorescence spectrophotometry in liver, brain, and testis. Multiple DNA adducts in the aorta were also measured by 32P postlabeling. Administration of NAC by gavage inhibited the formation of DNA adducts in all organs of rats treated with benzo(a)pyrene or exposed to cigarette smoke. It is of interest that a single chemopreventive agent can display a broad-spectrum protective ability. The selective localization of DNA adducts in different organs depends on pharmacokinetics, metabolic capacity, DNA repair efficiency, and cell proliferation rate. Whereas inhibition by NAC of DNA adducts in testis can be correlated with its demonstrated ability to prevent dominant lethal mutations, we raise the hypothesis that DNA adducts in lung, heart, and aorta may be pathogenetically associated with lung cancer, cardiomyopathies, and arteriosclerosis, respectively. In order to explore the involvement of molecular and biochemical alterations in human arteriosclerosis, we started an extensive collaborative project and report here preliminary data showing the presence of DNA adducts in aorta smooth muscle cells obtained from arteriosclerotic patients.}, }
@article {pmid8059534, year = {1994}, author = {Sahali, Y and Jett, CM and Murphy, JJ}, title = {Metabolic fate of S,S,S-tributyl phosphorotrithioate (DEF) in the lactating goat.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {24}, number = {4}, pages = {301-313}, doi = {10.3109/00498259409045894}, pmid = {8059534}, issn = {0049-8254}, mesh = {Animals ; Biotransformation ; Carbon Radioisotopes ; Chromatography, High Pressure Liquid ; Defoliants, Chemical/*metabolism ; Female ; Goats/*metabolism ; Lactation/*metabolism ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Milk/metabolism ; Organothiophosphates/*metabolism/pharmacokinetics/urine ; Scintillation Counting ; Tissue Distribution ; }, abstract = {1. Metabolism of [1-14C] DEF (S,S,S-1-14C-tributyl phosphorotrithioate, 1) in the lactating goat has been investigated. A goat was dosed orally by capsule on 3 consecutive days at a rate of 0.82 mg/kg body weight/day based on 25 times the maximum DEF residue anticipated in animal feed. 2. Urine and milk were collected throughout the study. The goat was killed 21 h following the last treatment, and kidney, liver and composite samples of muscle and fat were collected. The radioactive residue levels (following the three doses) were 3.45 ppm in liver, 0.35 ppm in kidney, 0.19 ppm in fat, 0.06 ppm in muscle and 0.12 ppm in milk collected at the final 16 h and prior to killing. 3. Urinary metabolic profile indicated that DEF was efficiently metabolized to many metabolites. Tissue and milk extracts also indicated that DEF was extensively metabolized. 4. DEF comprised 31 and 5% of the total radioactive residue in fat and milk, respectively. The amount of DEF in liver, kidney and muscle represented < 1% of the total radioactive residue. 5. A major metabolite, 3-hydroxybutylmethyl sulphone (HBM sulphone, UP3), was found in tissue, milk and urine. The identification of this metabolite was accomplished by a combination of MS, nmr and comparison with an authentic standard. The glucuronide (UP1) and sulphate (UP2) conjugates of HBM sulphone were found in urine, and the sulphate conjugate was a major metabolite in kidney. 6. The hydrolytic products of DEF, S,S-dibutyl phosphorodithioate (Dibufos, U16) and S-butyl phosphorothiate (Bufos, U8), were identified as minor components in urine, comprising 5 and 4% of the total radioactive residue, respectively. Butyl mercaptan was not found, but mixed disulphides of butyl mercaptan with either glutathione (U10, 3%) or N-acetyl cysteine (U13, 2%) were found. 7. Direct evidence for the incorporation of DEF residue into natural constituents was also established. Fatty acids from milk and fat were isolated and shown to be radioactive.}, }
@article {pmid8022887, year = {1994}, author = {Baas, P and Oppelaar, H and van der Valk, MA and van Zandwijk, N and Stewart, FA}, title = {Partial protection of photodynamic-induced skin reactions in mice by N-acetylcysteine: a preclinical study.}, journal = {Photochemistry and photobiology}, volume = {59}, number = {4}, pages = {448-454}, doi = {10.1111/j.1751-1097.1994.tb05063.x}, pmid = {8022887}, issn = {0031-8655}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Female ; Mice ; Mice, Inbred BALB C ; Photochemotherapy/*adverse effects ; Photosensitivity Disorders/etiology/*prevention &amp; control ; Ranitidine/pharmacology ; Skin/drug effects/pathology ; }, abstract = {The major side effect of photodynamic therapy (PDT) using Photofrin is enhanced skin sensitivity for sunlight, which persists for 3-8 weeks after injection. Formation of singlet oxygen and radicals is believed to be involved in the basic mechanism of inducing skin damage. Reducing this side effect would make PDT more widely acceptable, particularly for palliative use. Hairless dorsal skin patches of mice, injected with 10 mg kg-1 photofrin intraperitoneally (i.p.) 24 h before illumination, were used to evaluate the effect of increasing light doses. The light was obtained from a halogen lamp and transmitted via a fiber optic to illuminate a field of 2.5 cm2. After establishing a dose-response relationship for single or fractionated light dose illumination of the skin, drugs known to scavenge radicals, quench singlet oxygen or interfere with histamine release were tested for their protective effect. N-acetyl-cysteine (NAC), a radical scavenger, administered i.p. (1000 and 2000 mg kg-1) 1 h before illumination produced a significant decrease in skin damage at light doses > 50 J cm-2 (protection factor of 1.3-1.8). When NAC was administered in a dose of 500 mg kg-1, no protection was observed. Fractionated illumination experiments in combination with multiple injections of NAC (1000 mg kg-1) also failed to show any protection. The addition of Ranitidine, a histamine blocking agent (25-100 mg kg-1), given prior to illumination, resulted in a limited protection at higher light doses. From this study we conclude that NAC could be of value in amelioration of the photosensitivity in patients treated with PDT.}, }
@article {pmid7915123, year = {1994}, author = {Aillet, F and Gougerot-Pocidalo, MA and Virelizier, JL and Israël, N}, title = {Appraisal of potential therapeutic index of antioxidants on the basis of their in vitro effects on HIV replication in monocytes and interleukin 2-induced lymphocyte proliferation.}, journal = {AIDS research and human retroviruses}, volume = {10}, number = {4}, pages = {405-411}, doi = {10.1089/aid.1994.10.405}, pmid = {7915123}, issn = {0889-2229}, mesh = {Acetylcysteine/pharmacology ; Antioxidants/administration &amp; dosage/*pharmacology ; Base Sequence ; Butylated Hydroxyanisole/pharmacology ; CD4-Positive T-Lymphocytes/microbiology ; Cell Line ; DNA, Viral/genetics ; HIV Infections/drug therapy ; HIV-1/*drug effects/genetics/physiology ; Humans ; Interleukin-2/pharmacology ; Lymphocyte Activation/drug effects ; Molecular Sequence Data ; Monocytes/microbiology ; NF-kappa B/metabolism ; Virus Replication/*drug effects ; }, abstract = {Antioxidant molecules have been suggested to be of therapeutic value in the treatment of HIV-infected patients. To evaluate this possibility, we examined in vitro the effects of two types of antioxidant molecules in terms of inhibition of HIV replication in monocytes, one of the main reservoirs of HIV, and also in terms of modulation of the immune competence as measured by PBMC proliferation. We tested the effects of BHA, a phenolic, lipid-soluble, chain-breaking antioxidant, and NAC, a known glutathione precursor with some direct free-radical scavenging properties as well, on the regulation of HIV-1 expression in latently infected U1 cells and in productively and chronically infected U937 cells. Both antioxidants inhibited TNF- or PMA-induced NF-kappa B activity in U1 cells, as well as the sustained NF-kappa B activity permanently induced by the virus itself in chronically HIV-infected U937 cells. This resulted in only a partial inhibition of TNF- or PMA-induced HIV replication in U1 cells, and no detectable effect on HIV replication in chronically infected U937 cells. This may be the first limitation to potential antiviral effects of antioxidant therapies. Another limitation is that antioxidant concentrations high enough to block NK-kappa B activation were shown to have a suppressive effect on immune functions in vitro, because NAC and BHA blocked IL-2-induced PBMC proliferation. These data warrant prudence in the design of antioxidant-based therapies aimed at suppressing HIV replication.}, }
@article {pmid7909525, year = {1994}, author = {Kinscherf, R and Fischbach, T and Mihm, S and Roth, S and Hohenhaus-Sievert, E and Weiss, C and Edler, L and Bärtsch, P and Dröge, W}, title = {Effect of glutathione depletion and oral N-acetyl-cysteine treatment on CD4+ and CD8+ cells.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {8}, number = {6}, pages = {448-451}, pmid = {7909525}, issn = {0892-6638}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Adult ; CD4-Positive T-Lymphocytes/*drug effects ; CD8 Antigens/*analysis ; Double-Blind Method ; Glutathione/*analysis ; Humans ; Leukocyte Count/drug effects ; Male ; Middle Aged ; T-Lymphocytes/*drug effects ; }, abstract = {HIV-infected individuals and SIV-infected rhesus macaques have, on the average, decreased plasma cysteine and cystine concentrations and decreased intracellular glutathione levels. We show that the cysteine supply and the intracellular glutathione levels have a strong influence on the T cell system. A study of healthy human subjects revealed that persons with intracellular glutathione levels of 20-30 nmol/mg protein had significantly higher numbers of CD4+ T cells than persons with either lower or higher glutathione levels. Persons who moved during a 4-week observation period from the optimal to the suboptimal range (10-20 nmol/mg) experienced, on the average, a 30% decrease in CD4+ T cell numbers. This decrease was prevented by treatment with N-acetyl-cysteine (NAC). NAC caused this relative increase of CD4+ T cell numbers in spite of decreasing glutathione levels and not by increasing the glutathione level. Our studies suggest that the immune system may be exquisitely sensitive not only against a cysteine and glutathione deficiency but also against an excess of cysteine.}, }
@article {pmid8168173, year = {1994}, author = {Kassahun, K and Hu, P and Grillo, MP and Davis, MR and Jin, L and Baillie, TA}, title = {Metabolic activation of unsaturated derivatives of valproic acid. Identification of novel glutathione adducts formed through coenzyme A-dependent and -independent processes.}, journal = {Chemico-biological interactions}, volume = {90}, number = {3}, pages = {253-275}, doi = {10.1016/0009-2797(94)90014-0}, pmid = {8168173}, issn = {0009-2797}, support = {GM 32165/GM/NIGMS NIH HHS/United States ; TW 04607/TW/FIC NIH HHS/United States ; }, mesh = {Acetylcysteine/urine ; Animals ; Biotransformation ; Chromatography, Liquid ; Coenzyme A/*metabolism ; Fatty Acids, Monounsaturated/*metabolism/toxicity ; Glutathione/*metabolism ; Liver/drug effects/*metabolism ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry ; Mitochondria, Liver/drug effects/metabolism ; Rats ; Rats, Sprague-Dawley ; Triglycerides/metabolism ; Valproic Acid/toxicity ; }, abstract = {The ability of 2-n-propyl-4-pentenoic acid (delta 4-VPA) and 2-n-propyl-2(E)-pentenoic acid ([E]-delta 2-VPA), two unsaturated metabolites of valproic acid (VPA), to form reactive intermediates, deplete hepatic glutathione (GSH) and cause accumulation of liver triglycerides was investigated in the rat. With the aid of ionspray liquid chromatography-tandem mass spectrometry (LC-MS/MS), three GSH adducts were detected in the bile of delta 4-VPA-treated animals and were identified as 4-hydroxy-5-glutathion-S-yl-VPA-gamma-lactone, 5-glutathion-S-yl-(E)-delta 3-VPA and 3-oxo-5-glutathion-S-yl-VPA. A fourth conjugate was identified tentatively as 4-glutathion-S-yl-5-hydroxy-VPA. Quantitative analysis of the corresponding N-acetyl-cysteine (NAC) conjugates in urine indicated that metabolism of delta 4-VPA via the GSH-dependent pathways accounted for approximately 20% of an acute dose (100 mg kg-1 i.p.). In contrast, when rats were given an equivalent dose of (E)-delta 2-VPA, only one GSH adduct (5-glutathion-S-yl-(E)-delta 3-VPA) was detected at low concentrations in bile. In vitro experiments with rat liver mitochondria demonstrated that delta 4-VPA undergoes coenzyme A- and ATP-dependent metabolic activation in this organelle via the beta-oxidation pathway to intermediates which bind covalently to proteins. When liver homogenates and hepatic mitochondria from rats injected with delta 4-VPA, (E)-delta 2-VPA or VPA were analyzed for GSH content, it was found that only delta 4-VPA depleted GSH pools significantly. Treatment of rats with delta 4-VPA and (to a lesser extent) VPA led to an accumulation of liver triglycerides, whereas (E)-delta 2-VPA had no measurable effect. It is concluded that delta 4-VPA undergoes metabolic activation by both microsomal cytochrome P-450-dependent and mitochondrial coenzyme A-dependent processes, and that the resulting electrophilic intermediates, which are trapped in part by GSH, may mediate the hepatotoxic effects of this compound. In contrast, (E)-delta 2-VPA is not transformed to any appreciable extent to reactive metabolites, which thus accounts for the apparent lack of hepatotoxicity of this positional isomer in the rat.}, }
@article {pmid8140593, year = {1994}, author = {Valles, EG and de Castro, CR and Castro, JA}, title = {N-acetyl cysteine is an early but also a late preventive agent against carbon tetrachloride-induced liver necrosis.}, journal = {Toxicology letters}, volume = {71}, number = {1}, pages = {87-95}, doi = {10.1016/0378-4274(94)90202-x}, pmid = {8140593}, issn = {0378-4274}, support = {DK 13195-20/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Carbon Tetrachloride/metabolism/*toxicity ; Lipid Peroxidation/drug effects ; Liver/drug effects/*pathology ; Male ; Microsomes, Liver/drug effects/metabolism ; Necrosis/chemically induced/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; }, abstract = {N-Acetyl cysteine (NAC) treatment 30 min before or 6 or 10 h after carbon tetrachloride (CCl4) administration significantly prevented the liver necrosis produced by the hepatotoxin at 24 h. NAC pretreatment was able to partially decrease the covalent binding of CCl4 reactive metabolites at 1 and 3 h of poisoning and, to a small extent, the concentration of CCl4 reaching the liver at 3 h. NAC also diminished partially the CCl4-promoted increases in lipid peroxidation at 3 h, but had an enhancing effect of its own of small intensity. Results suggest that early and late protective effects of NAC might be attributable to its prior conversion to cysteine and glutathione.}, }
@article {pmid8133151, year = {1994}, author = {Faggioni, R and Gatti, S and Demitri, MT and Delgado, R and Echtenacher, B and Gnocchi, P and Heremans, H and Ghezzi, P}, title = {Role of xanthine oxidase and reactive oxygen intermediates in LPS- and TNF-induced pulmonary edema.}, journal = {The Journal of laboratory and clinical medicine}, volume = {123}, number = {3}, pages = {394-399}, pmid = {8133151}, issn = {0022-2143}, mesh = {Acetylcysteine/pharmacology ; Allopurinol/pharmacology ; Animals ; Interferon-gamma/physiology ; Interleukin-1/physiology ; *Lipopolysaccharides ; Male ; Mice ; Mice, Inbred BALB C ; Pulmonary Edema/*chemically induced/*metabolism ; Reactive Oxygen Species/*metabolism ; *Tumor Necrosis Factor-alpha/physiology ; Xanthine Oxidase/antagonists &amp; inhibitors/*metabolism ; }, abstract = {We studied the role of reactive oxygen intermediates (ROI) in lipopolysaccharide (LPS)-induced pulmonary edema. LPS treatment (600 micrograms/mouse, IP) was associated with a marked induction of the superoxide-generating enzyme xanthine oxidase (XO) in serum and lung. Pretreatment with the antioxidant N-acetylcysteine (NAC)--1 gm/kg orally, 45 minutes before LPS--or with the XO inhibitor allopurinol (AP)--50 mg/kg orally at -1 hour and +3 hours--was protective. On the other hand nonsteroidal antiinflammatory drugs (ibuprofen, indomethacin, and nordihydroguaiaretic acid) were ineffective. These data suggested that XO might be involved in the induction of pulmonary damage by LPS. However, treatment with the interferon inducer polyriboinosylic-polyribocytidylic acid, although inducing XO to the same extent as LPS, did not cause any pulmonary edema, indicating that XO is not sufficient for this toxicity of LPS. To define the possible role of cytokines, we studied the effect of direct administration of LPS (600 micrograms/mouse, IP), tumor necrosis factor (TNF, 2.5 or 50 micrograms/mouse, IV), interleukin-1 (IL-1 beta, 2.5 micrograms/mouse, IV), interferon-gamma (IFN-gamma, 2.5 micrograms/mouse, IV), or their combination at 2.5 micrograms each. In addition to LPS, only TNF at the highest dose induced pulmonary edema 24 hours later. LPS-induced pulmonary edema was partially inhibited by anti-IFN-gamma antibodies but not by anti-TNF antibodies, anti-IL-1 beta antibodies, or IL-1 receptor antagonist (IL-1Ra).}, }
@article {pmid8131544, year = {1994}, author = {Vecchiarelli, A and Dottorini, M and Pietrella, D and Cociani, C and Eslami, A and Todisco, T and Bistoni, F}, title = {Macrophage activation by N-acetyl-cysteine in COPD patients.}, journal = {Chest}, volume = {105}, number = {3}, pages = {806-811}, doi = {10.1378/chest.105.3.806}, pmid = {8131544}, issn = {0012-3692}, mesh = {Acetylcysteine/*therapeutic use ; Bronchoalveolar Lavage Fluid/cytology ; Candida albicans/immunology ; Female ; Humans ; In Vitro Techniques ; Leukocytes, Mononuclear/drug effects ; Lung Diseases, Obstructive/*drug therapy/immunology ; Lung Neoplasms/drug therapy/immunology ; Macrophage Activation/*drug effects ; Macrophages, Alveolar/*drug effects ; Male ; Middle Aged ; Neutrophils/drug effects ; Phagocytosis/*drug effects ; }, abstract = {The effect of in vivo and in vitro N-acetylcysteine (NAC) treatment on destructive activity of macrophages against Candida from COPD patients has been evaluated. Patients received NAC (600 mg) or placebo orally 3 times a day for 15 days and bronchoalveolar lavage (BAL) fluid and peripheral blood were collected before and at the conclusion of treatment. In our system, NAC treatment was not able to modulate antifungal activity of alveolar macrophages, peripheral blood monocytes (PBM), and polymorphonuclear leukocytes. On the contrary, in vitro NAC treatment at appropriate doses (10 micrograms/ml) significantly enhanced antifungal activity of PBM from COPD patients. This phenomenon is mediated by augmented phagocytic activity and phagosome-lysosome fusion. The lack of correlation between in vivo and in vitro studies could be ascribed to differences in the intracellular concentration of the drug that in vivo does not reach levels capable of inducing macrophage activation. We speculate that in COPD patients who undergo long-term NAC treatment, appropriate schedules and doses of the drug could augment resistance against microbial infections which are often life-threatening in these patients.}, }
@article {pmid8120657, year = {1994}, author = {Banks, MF and Stipanuk, MH}, title = {The utilization of N-acetylcysteine and 2-oxothiazolidine-4-carboxylate by rat hepatocytes is limited by their rate of uptake and conversion to cysteine.}, journal = {The Journal of nutrition}, volume = {124}, number = {3}, pages = {378-387}, doi = {10.1093/jn/124.3.378}, pmid = {8120657}, issn = {0022-3166}, mesh = {Acetylcysteine/*metabolism ; Animals ; Cells, Cultured ; Culture Media ; Cysteine/*metabolism ; Glutathione/*metabolism ; Liver/cytology/*metabolism ; Male ; Pyrrolidonecarboxylic Acid ; Rats ; Rats, Sprague-Dawley ; Selenium Radioisotopes ; Thiazoles/*metabolism ; Thiazolidines ; }, abstract = {N-Acetyl-L-cysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (OTC) are converted enzymatically to cysteine and have been used to stimulate hepatic glutathione synthesis. Using hepatocytes isolated from male Sprague-Dawley rats and 35S-labeled substrates, the uptake and metabolism of these cysteine precursors was measured and compared with those for cells provided with an equimolar amount of cysteine. Cysteine was utilized more rapidly than NAC or OTC for sulfate and taurine production and more rapidly than OTC for glutathione production. N-Acetyl-L-cysteine itself was taken up slowly by hepatocytes, but deacetylation of NAC to cysteine seemed to occur extracellularly. Utilization of OTC seemed to be limited by a low rate of uptake and slow intracellular conversion to cysteine. The rate of accumulation of [35S]glutathione from OTC was low compared to that from other substrates, but glutathione production accounted for 78% of the measured OTC metabolism. Although the rate of accumulation of [35S]glutathione was similar for hepatocytes incubated with [35S]cysteine or [35S]NAC, glutathione synthesis accounted for a higher percentage of NAC metabolism than of cysteine metabolism (62-81% vs. 46%). The apparent preferential distribution of OTC and NAC to glutathione vs. taurine and sulfate can be partly explained by a lower rate of substrate availability, but another unknown mechanism also appears to favor the conversion of NAC to glutathione.}, }
@article {pmid8018747, year = {1994}, author = {Sandberg, JW and Lau, C and Jacomino, M and Finegold, M and Henning, SJ}, title = {Improving access to intestinal stem cells as a step toward intestinal gene transfer.}, journal = {Human gene therapy}, volume = {5}, number = {3}, pages = {323-329}, doi = {10.1089/hum.1994.5.3-323}, pmid = {8018747}, issn = {1043-0342}, support = {DK-44646/DK/NIDDK NIH HHS/United States ; HD-14094/HD/NICHD NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Buffers ; Dithiothreitol/*pharmacology ; Epithelial Cells ; Expectorants/*pharmacology ; *Gene Transfer Techniques ; Intestinal Mucosa/drug effects ; Intestines/*cytology/drug effects ; Ligation ; Male ; Pilocarpine/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Muscarinic/drug effects ; Stem Cells/*cytology ; }, abstract = {In previous studies exploring the intestinal epithelium as a potential site for somatic gene therapy, we concluded that the mucus lining the intestine constitutes a significant barrier to any attempts at gene transfer via the lumenal route. The mucus problem is aggravated by the fact that the epithelial stem cells, which are the logical target for gene transfer, are located deep in the intestinal crypts. The goals of the current study were to develop procedures that would improve accessibility to the intestinal stem cells and which would effect in vivo mucus removal without damaging the underlying epithelium. Initial experiments involved evaluation of the use of distension to improve accessibility to the intestinal crypts and the use of the mucolytic agents dithiothreitol (DTT) and N-acetyl-cysteine (NAC) versus a control solution of phosphate-buffered saline (PBS) for mucus removal. Catheters were inserted in each end of 3-cm terminal ileal segments in anesthetized rats. Two milliliters of agent was instilled into the clamped segment for 2 min, removed, and repeated. Lumenal distension resulted in shortened villi with wider intervillus spacing, thereby improving crypt access. Both NAC and DTT washes removed significant mucus between the villi but failed to reach the crypt lumen. To enhance mucus release from the crypt lumen, pilocarpine was selected due to its cholinergic properties and preferential binding to muscarinic receptors on crypt goblet cells. Pilocarpine given intraperitoneally 30 min prior to the mucolytic or PBS wash resulted in significant eradication of mucus down into the crypt lumen. This effect was still evident 3-4 hr later provided the intestine remained undisturbed.}, }
@article {pmid8013597, year = {1994}, author = {Meyer, A and Buhl, R and Magnussen, H}, title = {The effect of oral N-acetylcysteine on lung glutathione levels in idiopathic pulmonary fibrosis.}, journal = {The European respiratory journal}, volume = {7}, number = {3}, pages = {431-436}, doi = {10.1183/09031936.94.07030431}, pmid = {8013597}, issn = {0903-1936}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Bronchoalveolar Lavage Fluid/chemistry ; Epithelium/metabolism ; Female ; Glutathione/*metabolism ; Humans ; Lung/*metabolism ; Male ; Middle Aged ; Pulmonary Fibrosis/*drug therapy/metabolism ; }, abstract = {Idiopathic pulmonary fibrosis (IPF) is characterized by an increased oxidant burden and by a deficiency of glutathione, a major antioxidant, in the lung epithelial lining fluid (ELF). Therefore, a rational therapeutic approach is to reverse the imbalance between oxidants and antioxidants in the lung by enhancing the antioxidant screen. With this background, the aim of our study was to evaluate oral N-acetylcysteine (NAC) as a strategy to augment lung glutathione levels in patients with IPF. Concentrations of total glutathione in bronchoalveolar lavage fluid (BALF) were quantified spectrophotometrically, before and following oral therapy with 3 x 600 mg NAC per day for 5 days, in 17 nonsmoking patients with biopsy-proven IPF. The volume of ELF recovered by BAL was determined using the urea method. Pretherapy, total glutathione levels in ELF in IPF patients were significantly less than normal (187 +/- 36 vs 368 +/- 60 microM), in contrast to levels in BALF (0.99 +/- 0.12 vs 1.18 +/- 0.19 microM). Following therapy with oral NAC, glutathione levels in BALF were 1.54 +/- 0.24 microM (a significant increase compared to pretherapy), whereas the increase in ELF levels (319 +/- 92 microM) did not reach significance. The therapy was well-tolerated, and all routine clinical and bronchoscopic parameters remained unchanged. It is thus feasible and safe to augment deficient lung glutathione levels in patients with IPF; thereby, potentially augmenting pulmonary antioxidant protection.}, }
@article {pmid7519084, year = {1994}, author = {Hatchett, RJ and Gryglewski, RJ and Młochowski, J and Zembowicz, A and Radziszewski, W}, title = {Carboxyebselen a potent and selective inhibitor of endothelial nitric oxide synthase.}, journal = {Journal of physiology and pharmacology : an official journal of the Polish Physiological Society}, volume = {45}, number = {1}, pages = {55-67}, pmid = {7519084}, issn = {0867-5910}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/pharmacology ; Amino Acid Oxidoreductases/*antagonists &amp; inhibitors ; Animals ; Aorta, Thoracic/drug effects/metabolism ; Azoles/antagonists &amp; inhibitors/*pharmacology ; Cattle ; Cerebellum/enzymology ; Endothelium, Vascular/drug effects/*enzymology ; Female ; Glutathione/pharmacology ; Glutathione Peroxidase/metabolism ; In Vitro Techniques ; Isoindoles ; Male ; Mice ; Muscle Relaxation/drug effects ; Muscle, Smooth, Vascular/drug effects ; Nitric Oxide Synthase ; Organoselenium Compounds/antagonists &amp; inhibitors/*pharmacology ; Rabbits ; Spleen/enzymology ; Sulfhydryl Compounds/metabolism ; Swine ; }, abstract = {Ebselen (Ebs) a glutathione peroxidase like agent has been recently described as an inhibitor of nitric oxide synthase (NOS). Presently, we report that carboxyebselen (HOOC-Ebs), a hydrophyllic derivative of Ebs inhibits NOS present in enzymatic preparations from bovine endothelium, porcine cerebella, and murine spleen, however, it is both more potent and more selective for the constitutive endothelial NOS than Ebs. Unlike Ebs, HOOC-Ebs (0.1-30 microM) causes a concentration-dependent endothelium-independent relaxations of rings of rabbit aorta. The mechanism of this relaxation remains unknown and it is attenuated by glutathione (GSH, 30-300 microM) and N-acetyl-L-cysteine (NAC, 30-300 microM). The vasorelaxant activity of acetylcholine (Ach, 0.1-1 microM) in aortic rings exposed to low concentrations of HOOC-Ebs (0.1-1 microM) or rings exposed to 10 microM HOOC-Ebs after their pretreatment with GSH or NAC (30-300 microM) remained unchanged. The lack of activity of HOOC-Ebs as a NOS inhibitor in intact endothelial cells contrasts the effectiveness of Ebs in this respect.}, }
@article {pmid8300856, year = {1994}, author = {Lehmann, D and Karussis, D and Misrachi-Koll, R and Shezen, E and Ovadia, H and Abramsky, O}, title = {Oral administration of the oxidant-scavenger N-acetyl-L-cysteine inhibits acute experimental autoimmune encephalomyelitis.}, journal = {Journal of neuroimmunology}, volume = {50}, number = {1}, pages = {35-42}, doi = {10.1016/0165-5728(94)90212-7}, pmid = {8300856}, issn = {0165-5728}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Acute Disease ; Animals ; Dose-Response Relationship, Drug ; Encephalomyelitis, Autoimmune, Experimental/etiology/*prevention &amp; control ; Female ; *Free Radical Scavengers ; Free Radicals ; Lipopolysaccharides/pharmacology ; Lymphocyte Activation/drug effects ; Mice ; Time Factors ; }, abstract = {The prevention of acute experimental autoimmune encephalomyelitis (EAE) by N-acetyl-L-cysteine (NAC), a potent free radical scavenger, is described. Administrated ad libitum to SJL/J mice at a dosage of 0.2-2 mg/ml in drinking water from the day of the encephalitogenic injection, the agent significantly inhibited the induction of acute EAE. The improvement in clinical condition was dose-dependent. A complete protective effect required administration of the agent at an early stage. Examination of lymphocytes from NAC-treated EAE mice showed that at early stages (days 9 and 15) post encephalitogenic injection the anti-oxidant enhanced the specific lymphocyte proliferative response to the immunizing antigens. Examination of the mitogenic stimulation of lymphocytes from naive animals in the presence of NAC in vitro indicated that the scavenger enhanced the stimulative effect of LPS in a dose-dependent manner. The immunomodulative capacity of the anti-oxidant NAC suggests that free radicals are involved in the pathogenesis of acute EAE.}, }
@article {pmid8299097, year = {1994}, author = {Mizutani, Y and Yoshida, O}, title = {Overcoming tumor necrosis factor-alpha resistance of human renal and ovarian carcinoma cells by combination treatment with buthionine sulfoximine and tumor necrosis factor-alpha. Role of tumor necrosis factor-alpha mRNA down-regulation in tumor cell sensitization.}, journal = {Cancer}, volume = {73}, number = {3}, pages = {730-737}, doi = {10.1002/1097-0142(19940201)73:3&lt;730::aid-cncr2820730338&gt;3.0.co;2-x}, pmid = {8299097}, issn = {0008-543X}, mesh = {Acetylcysteine/pharmacology ; Antimetabolites, Antineoplastic/*administration &amp; dosage/pharmacology ; Blotting, Northern ; Buthionine Sulfoximine ; Carcinoma, Renal Cell/*pathology ; Down-Regulation ; Drug Resistance ; Drug Synergism ; Female ; Glutathione/pharmacology ; Humans ; Kidney Neoplasms/*pathology ; Methionine Sulfoximine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Ovarian Neoplasms/*pathology ; RNA, Messenger/*metabolism ; Tumor Cells, Cultured/drug effects ; Tumor Necrosis Factor-alpha/*administration &amp; dosage/*genetics/pharmacology ; }, abstract = {BACKGROUND: Previous studies have reported the glutathione plays a central role in a wide range of cellular functions, including protection, detoxification, transport, and metabolism. Buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamyl-cysteine synthetase, depletes intracellular glutathione. The study investigates the cytotoxic effect of BSO and tumor necrosis factor-alpha (TNF-alpha) used in combination on TNF-alpha-resistant human renal and ovarian cancer cells.<br><br>METHODS: Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. TNF-alpha mRNA was examined by Northern blot analysis.<br><br>RESULTS: Combination treatment of TNF-alpha-resistant R4 and R11 human renal cell carcinoma cells with BSO and TNF-alpha overcame their resistance to TNF-alpha. In addition, the combination of BSO and TNF-alpha resulted in a synergistic cytotoxic effect on TNF-alpha-resistant OVC-8 and C30 human ovarian cancer cells. Treatment of R4, R11, and OVC-8 cells with TNF-alpha in combination with glutathione or N-acetyl-cysteine (NAC) showed an antagonistic cytotoxic effect. A possible mechanism of resistance to TNF-alpha in tumor cells is the expression of TNF-alpha mRNA or protein. R4 cells and OVC-8 cells constitutively expressed mRNA for TNF-alpha. Treatment of R4 cells or OVC-8 cells with BSO down-regulated the expression of TNF-alpha mRNA; however, treatment with TNF-alpha up-regulated the expression of TNF-alpha mRNA. When BSO was used in combination with TNF-alpha, the level of TNF-alpha mRNA enhanced by TNF-alpha was markedly reduced. Incubation of R4 cells with glutathione or NAC also down-regulated the expression of TNF-alpha mRNA. R11 and C30 cells did not constitutively express mRNA for TNF-alpha, and the BSO treatment had no effect on the TNF-alpha mRNA level.<br><br>CONCLUSIONS: This study demonstrates that the combination of BSO and TNF-alpha can overcome the TNF-alpha resistance of tumor cells and that depletion of intracellular glutathione and down-regulation of TNF-alpha mRNA by BSO may play a role in the enhanced cytotoxicity seen with the combination of BSO and TNF-alpha. There may not be always a correlation between the expression of TNF-alpha mRNA in tumor cells and their resistance to TNF-alpha. The synergistic effect obtained with established renal cell carcinoma cells and ovarian cancer cells suggests that combination treatment with TNF-alpha and BSO could have clinical application in the therapy of TNF-alpha-resistant tumors.}, }
@article {pmid7906736, year = {1994}, author = {Gaston, B and Drazen, JM and Jansen, A and Sugarbaker, DA and Loscalzo, J and Richards, W and Stamler, JS}, title = {Relaxation of human bronchial smooth muscle by S-nitrosothiols in vitro.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {268}, number = {2}, pages = {978-984}, pmid = {7906736}, issn = {0022-3565}, support = {HL19170/HL/NHLBI NIH HHS/United States ; HL40411/HL/NHLBI NIH HHS/United States ; HL48743/HL/NHLBI NIH HHS/United States ; }, mesh = {Bronchi/*drug effects/physiology ; Cyclic GMP/analysis ; Dose-Response Relationship, Drug ; Enzyme Activation ; Female ; Guanylate Cyclase/physiology ; Humans ; Male ; *Mercaptoethanol ; Middle Aged ; Muscle Relaxation/*drug effects ; Muscle, Smooth/drug effects/physiology ; Nitroso Compounds/*pharmacology ; *S-Nitrosothiols ; }, abstract = {S-Nitrosothiols (RS-NO) relax tracheal smooth muscle from a variety of animal species, and may have physiological relevance. We therefore studied their effects on human bronchial smooth muscle. S-Nitroso adducts of glutathione, cysteine, N-acetylcysteine and bovine serum albumin relaxed tissues contracted with methacholine with mean IC50 +/- S.E.M. of 3.3 (+/- 14), 22 (+/- 45), 25 (+/- 22) and 36 (+/- 7.1) microM, respectively; they were more potent as inhibitory agonists than the corresponding reduced thiol, NaNO2, or theophylline, but less potent than isoproterenol (P < .001). Despite large differences in their molecular weights and dissociation kinetics, the IC50 of these RS-NO did not differ significantly from one another, from nitric oxide (NO.) or from sodium nitroprusside. Consistent with the role of cyclic GMP (cGMP) in mediating relaxation responses, S-nitroso-N-acetyl cysteine (S-NO-AC) (100 microM) increased tissue cGMP levels 4-fold, and 8-bromo-cGMP caused modest tissue relaxation which was potentiated by the phosphodiesterase inhibitor, dipyridamole (1 microM). However, the guanylyl cyclase inhibitors, methylene blue (100 microM) and LY 83583 (50 microM), failed to modify the relaxation response to S-NO-AC (sodium nitroprusside and NO.), while altering the accumulation of cGMP. Further, hemoglobin (100 microM) failed to inhibit relaxation by S-NO-AC.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid7507967, year = {1994}, author = {Sandstrom, PA and Mannie, MD and Buttke, TM}, title = {Inhibition of activation-induced death in T cell hybridomas by thiol antioxidants: oxidative stress as a mediator of apoptosis.}, journal = {Journal of leukocyte biology}, volume = {55}, number = {2}, pages = {221-226}, doi = {10.1002/jlb.55.2.221}, pmid = {7507967}, issn = {0741-5400}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Apoptosis/drug effects/*physiology ; Cells, Cultured ; Hybridomas/*cytology/drug effects/immunology ; Lectins ; *Lymphocyte Activation ; Myelin Basic Protein/immunology/pharmacology ; Oxidation-Reduction ; Rats ; Rats, Inbred Lew ; Stress, Physiological ; T-Lymphocytes/*cytology/drug effects/immunology ; Thymoma ; Tumor Cells, Cultured ; }, abstract = {N-Acetylcysteine (NAC) is a well established thiol antioxidant which, after uptake, deacylation and conversion to glutathione functions as both a redox buffer and a reactive oxygen intermediate scavenger. We report here that NAC completely blocks activation induced death and associated DNA fragmentation of myelin basic protein (MBP) specific T cell hybridomas. Conversely, NAC had very little effect on the antigen driven proliferation of a MBP specific T cell line similar to that from which the hybridomas were derived. NAC displayed an analogous absolute inhibition of mitogen mediated activation induced death, even if added up to 3 h post activation. Although glutathione was as efficient as NAC at blocking activation induced death, dithiothreitol displayed minimal inhibition while L-cysteine had no effect at all. The observation that certain thiol antioxidants such as NAC and glutathione can completely block the activation induced death of T cell hybridomas implicates redox regulation in this process.}, }
@article {pmid8310451, year = {1994}, author = {Gomez, MR and Benzick, AE and Rogers, LK and Heird, WC and Smith, CV}, title = {Attenuation of acetaminophen hepatotoxicity in mice as evidence for the bioavailability of the cysteine in D-glucose-L-cysteine in vivo.}, journal = {Toxicology letters}, volume = {70}, number = {1}, pages = {101-108}, doi = {10.1016/0378-4274(94)90149-x}, pmid = {8310451}, issn = {0378-4274}, support = {GM44263/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Alanine Transaminase/blood ; Animals ; Biological Availability ; Cysteine/administration &amp; dosage/*analogs &amp; derivatives/*pharmacokinetics/pharmacology ; Drug Interactions ; Glucose/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Injections, Intraperitoneal ; Liver/*drug effects ; Male ; Mice ; Mice, Inbred ICR ; }, abstract = {A substantial fraction of the cysteine added to total parenteral nutrition (TPN) solutions is converted to the corresponding thiazolidine derivative, while in solution with relatively large concentrations of glucose typical of TPN (700 mM and higher). It was recently reported (Roberts et al. (1987) J. Med. Chem. 30, 1891-1896) that this thiazolidine, D-glucose-L-cysteine (DGC), offered no significant protection against the hepatic injury caused by 5 mmol/kg of acetaminophen in mice, suggesting that the cysteine present as DGC is poorly bioavailable in vivo. In the present study, fasted male ICR mice given 1.6 or 2.6 mmol/kg of acetaminophen sustained hepatic injury, estimated by elevations in plasma alanine aminotransferase (ALT) activities. Administration of 2.5 mmol/kg of N-acetylcysteine (NAC) 1 h before acetaminophen given i.p. prevented the rise in plasma ALT activities, apparently through support of glutathione (GSH) synthesis. Administration of 2.5 mmol/kg of DGC prior to acetaminophen resulted in slightly lower mean plasma ALT activities than were observed in animals given saline before acetaminophen, but the effect was not statistically significant. When DGC was given 1 h before p.o. administration of 1.6 or 2.6 mmol/kg of acetaminophen, the protective effects of DGC were statistically significant (P < 0.01, 0.025, respectively), although NAC afforded significantly greater protection than did DGC at the higher dose of acetaminophen. Given 4 h before acetaminophen, DGC attenuated acetaminophen-induced increases in plasma ALT activities significantly, whereas NAC was without effect. These results indicate that the cysteine in DGC is at least partially bioavailable in vivo and, further, that DGC may function as a slow release formulation of cysteine.}, }
@article {pmid8275731, year = {1994}, author = {Suter, PM and Domenighetti, G and Schaller, MD and Laverrière, MC and Ritz, R and Perret, C}, title = {N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study.}, journal = {Chest}, volume = {105}, number = {1}, pages = {190-194}, doi = {10.1378/chest.105.1.190}, pmid = {8275731}, issn = {0012-3692}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Aged ; Double-Blind Method ; Female ; Humans ; Lung/*drug effects/physiopathology ; *Lung Injury ; Male ; Middle Aged ; Oxygen Consumption/physiology ; Oxygen Inhalation Therapy ; Placebos ; Respiration, Artificial ; Respiratory Distress Syndrome/physiopathology/*prevention &amp; control ; Risk Factors ; Severity of Illness Index ; Survival Rate ; Time Factors ; Treatment Outcome ; }, abstract = {OBJECTIVE: To determine the effects of intravenous N-acetylcysteine (NAC) on the development of severe adult respiratory distress syndrome (ARDS) and mortality rate in patients with mild-to-moderate acute lung injury and to analyze the duration of ventilatory support and FIO2 required as well as the evolution of the lung injury score.<br><br>SETTING: Three university hospital ICUs and one regional ICU in Switzerland.<br><br>PATIENTS: Sixty-one adult patients presenting with mild-to-moderate acute lung injury and various predisposing factors for ARDS received either NAC, 40 mg/kg/d, or placebo intravenously for 3 days.<br><br>MEASUREMENTS: Respiratory dysfunction was assessed daily according to the need for mechanical ventilation and FIO2, the evolution of the lung injury score, and the PaO2/FIO2 ratio. The cardiovascular state, liver function, and kidney function were also monitored. Data were collected at admission (day 0), during the first 3 days, and on the day of discharge from the ICU.<br><br>RESULTS: The NAC and placebo groups (32 and 29 patients, respectively) were comparable at ICU admission for severity of illness assessed by the simplified acute physiology score (SAPS) (10.8 +/- 4.6 vs 10.9 +/- 4.8) and lung injury score (LIS) (1.39 +/- 0.95 vs 1.11 +/- 1.08) (mean +/- SD). Three patients in each group developed ARDS. The 1-month mortality rate was 22 percent for the NAC group and 35 percent for the placebo group (difference not statistically significant). At admission, 22 of 32 patients (69 percent) in the NAC group were mechanically ventilated compared with 22 of 29 (76 percent) in the placebo group. At the end of the treatment period (day 3), 5 of 29 (17 percent) in the NAC group and 12 of 25 (48 percent) in the placebo group were still receiving ventilatory support (p = 0.01), The FIO2 was 0.37 less than admission value (day 0) in the NAC group, and 0.20 less in the placebo group (p < 0.04); the oxygenation index (PaO2/FIO2) improved significantly (p < 0.05) from day 0 to day 3 only in the NAC-treated group. The LIS showed a significant regression (p = 0.003) in the NAC-treated group during the first 10 days of treatment: no change was observed in the placebo group. No adverse effects were observed during the treatment with NAC.<br><br>CONCLUSIONS: Intravenous NAC treatment during 72 h improved systemic oxygenation and reduced the need for ventilatory support in patients presenting with mild-to-moderate acute lung injury subsequent to a variety of underlying diseases. Development of ARDS and mortality were not reduced significantly by this therapy.}, }
@article {pmid8208062, year = {1994}, author = {Sastre, J and Asensi, M and Rodrigo, F and Pallardó, FV and Vento, M and Viña, J}, title = {Antioxidant administration to the mother prevents oxidative stress associated with birth in the neonatal rat.}, journal = {Life sciences}, volume = {54}, number = {26}, pages = {2055-2059}, doi = {10.1016/0024-3205(94)00714-4}, pmid = {8208062}, issn = {0024-3205}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Animals, Newborn/*physiology ; Antioxidants/administration &amp; dosage/*pharmacology ; Female ; Glutathione/analogs &amp; derivatives/*metabolism ; Glutathione Disulfide ; Liver/drug effects/embryology/*metabolism ; *Maternal-Fetal Exchange ; Pregnancy ; Rats ; Rats, Wistar ; Stress, Physiological/prevention &amp; control ; }, abstract = {In the fetal-to-neonatal transition, important circulatory and respiratory changes ensue which lead to oxidative stress evidenced by changes in glutathione status. Administration of N-Acetyl-Cysteine (NAC), a glutathione precursor, to the mother might be a rational approach to protect the fetus against oxidative stress. We have found that NAC administration to pregnant rats partially prevents the change in hepatic GSSG that occurs in the fetal-neonatal transition: GSSG increased 11-fold (from 1 to 12 nmol/g) in controls and less than two-fold (from 5 to 9 nmol/g) in animals exposed to NAC in utero. The GSH/GSSG ratio in liver of NAC-treated newborns was 411 +/- 216 and in liver of controls it was 283 +/- 176. Thus, the oxidative stress that occurs in the fetal-to-neonatal transition is partially prevented by oral NAC administration.}, }
@article {pmid8179480, year = {1994}, author = {Donnelly, PJ and Walker, RM and Racz, WJ}, title = {Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity.}, journal = {Archives of toxicology}, volume = {68}, number = {2}, pages = {110-118}, pmid = {8179480}, issn = {0340-5761}, mesh = {Acetaminophen/administration &amp; dosage/*toxicity ; Acetylcysteine/pharmacology ; Alanine Transaminase/blood ; Animals ; Chemical and Drug Induced Liver Injury ; Liver Diseases/enzymology/pathology ; Male ; Mice ; Mice, Inbred Strains ; Mitochondria, Liver/*drug effects ; Oxygen Consumption/drug effects ; }, abstract = {Morphological changes in mitochondria are observed early in the course of acetaminophen (AA)-induced hepatotoxicity, and mitochondrial dysfunction has been observed both in vivo and in vitro following exposure to AA. This study examined the early effects of AA exposure in vivo on mitochondrial respiration and evaluated the effectiveness of N-acetyl-L-cysteine (NAC) in protecting against respiratory dysfunction. Mitochondria were isolated from the livers of fasted, male CD-1 mice 0, 0.5, 1, 1.5 or 2 h after administration of a hepatotoxic dose of AA (750 mg/kg). Glutamate- and succinate-supported mitochondrial respiration were subsequently assessed by polarographic measurement of state 3 (ADP-stimulated) and state 4 (resting) rates of oxygen consumption and determination of the corresponding respiratory control ratios (RCR: state 3/state 4) and ADP:O ratios. Hepatotoxicity was assessed histologically and by measuring plasma alanine aminotransferase (ALT) activity. The earliest sign of mitochondrial dysfunction observed in this study was a significant decrease in the ADP:O ratio for the oxidation of glutamate 1 h post-dosing. At 1.5 and 2 h post-dosing the RCRs for both glutamate- and succinate-supported respiration were significantly decreased. All of the respiratory parameters measured in this study were significantly decreased, with the exception of succinate-supported state 4 respiration which was significantly increased, 2 h after AA administration. Thus, inhibition of mitochondrial respiration preceded overt hepatic necrosis, indicated by an elevation of ALT activity, which was not observed until 3 and 4 h post-dosing. In addition, mitochondrial respiratory dysfunction correlated with morphological alterations.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8148219, year = {1994}, author = {Godfrey, EG and Stewart, J and Dargie, HJ and Reid, JL and Dominiczak, M and Hamilton, CA and McMurray, J}, title = {Effects of ACE inhibitors on oxidation of human low density lipoprotein.}, journal = {British journal of clinical pharmacology}, volume = {37}, number = {1}, pages = {63-66}, pmid = {8148219}, issn = {0306-5251}, mesh = {Acetylcysteine/*pharmacology ; Analysis of Variance ; Angiotensin-Converting Enzyme Inhibitors/*pharmacology ; Captopril/*pharmacology ; Copper/pharmacology ; Female ; Humans ; Isoquinolines/*pharmacology ; Lipoproteins, LDL/*blood ; Oxidation-Reduction ; *Tetrahydroisoquinolines ; }, abstract = {Oxidation of low density lipoprotein (LDL) may be instrumental in the development of atherosclerosis. We have examined the effect of the angiotensin converting enzyme (ACE) inhibitors captopril and quinaprilat and the -SH containing compound N-acetylcysteine on LDL oxidation. Oxidation of isolated human LDL was initiated with CuCl2. Conjugated diene formation (monitored spectrophotometrically at 234 nm) gave a measure of LDL oxidation. Captopril inhibited LDL oxidation but quinaprilat did not. The lag phase to the rapid increase in absorbance at 234 nm determined was 109 (65-157) min median and range for control samples and rose to 209 (168-305) min with captopril 10 microM, a ratio of 2.1:1 for drug to control (P = 0.01). N-acetylcysteine had a similar effect to captopril (drug to control lag time ratio 2.0:1, with NAC 10 microM), i.e. suggesting resistance to oxidation was due to the -SH group of both drugs. Captopril may have a potentially anti-atherosclerotic property not shared by other ACE inhibitors.}, }
@article {pmid8143838, year = {1994}, author = {Riise, GC and Larsson, S and Larsson, P and Jeansson, S and Andersson, BA}, title = {The intrabronchial microbial flora in chronic bronchitis patients: a target for N-acetylcysteine therapy?.}, journal = {The European respiratory journal}, volume = {7}, number = {1}, pages = {94-101}, doi = {10.1183/09031936.94.07010094}, pmid = {8143838}, issn = {0903-1936}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Inhalation ; Adult ; Aged ; Bacterial Infections/complications ; Bronchi/*microbiology ; Bronchitis/complications/drug therapy/*microbiology ; Chronic Disease ; Haemophilus influenzae/drug effects ; Humans ; Immunoglobulins/analysis ; Lung Diseases, Obstructive/complications/drug therapy/microbiology ; Middle Aged ; Smoking/adverse effects ; Streptococcus pneumoniae/drug effects ; }, abstract = {Chronic bronchitis is common among smokers, often together with recurrent infectious exacerbations. Streptococcus pneumoniae and Haemophilus influenzae are the pathogens traditionally considered most important. N-acetylcysteine (NAC) treatment has been shown to reduce the number of infectious exacerbations in patients with chronic bronchitis. The mechanism behind this is unknown. We attempted to characterize the intrabronchial bacterial flora in patients with chronic bronchitis in an infection-free interval, and to determine whether pharmacological and immunological factors effected the bacterial occurrence. Twenty two smokers with non-obstructive chronic bronchitis, 19 smokers with chronic bronchitis and chronic obstructive pulmonary disease (COPD) and 14 healthy nonsmokers underwent bronchoscopy. To obtain uncontaminated intrabronchial samples, a protected specimen brush was used. Quantitative bacterial cultures and virus isolations were performed. Significantly positive bacterial cultures (> 1,000 colony-forming units (cfu).ml-1) were found only in the patients. S. pneumoniae and H. influenzae were found in five patients, and only in the patients without NAC treatment. The most common bacterium was alpha-haemolytic streptococcus. Negative cultures were more common in the healthy controls. Of the various factors examined, only NAC medication had an influence on bacterial numbers. Significantly fewer patients with NAC medication had positive cultures (3 out of 16) than in the group of patients without NAC therapy (15 out of 21). Our results confirm that chronic bronchitis in smokers leads to increased intrabronchial bacterial colonization. We could also confirm that 1,000 cfu.ml-1 is an adequate cut-off level for significant bacterial growth when using the protected specimen brush. NAC medication was associated with low bacterial numbers.}, }
@article {pmid8143836, year = {1994}, author = {Tomkiewicz, RP and App, EM and Coffiner, M and Fossion, J and Maes, P and King, M}, title = {Mucolytic treatment with N-acetylcysteine L-lysinate metered dose inhaler in dogs: airway epithelial function changes.}, journal = {The European respiratory journal}, volume = {7}, number = {1}, pages = {81-87}, doi = {10.1183/09031936.94.07010081}, pmid = {8143836}, issn = {0903-1936}, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives/*pharmacology ; Animals ; Bronchi/*drug effects ; Dogs ; Epithelium/drug effects ; In Vitro Techniques ; Lysine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Mucociliary Clearance/*drug effects ; Mucus/drug effects/physiology ; Nebulizers and Vaporizers ; Rana pipiens ; Rheology ; Trachea/*drug effects ; }, abstract = {N-acetylcysteine L-lysinate Nacystelyn (L-NAC) is a newly synthesized mucolytic agent, of which the action in vivo has not been well defined. In six healthy mongrel dogs, the rheological properties of mucus, its mucociliary and cough clearability, and the transepithelial potential difference (PD) of the tracheobronchial epithelium were evaluated after placebo and L-NAC metered dose inhaler (MDI) aerosols. The principal index of mucus rigidity, log G*, decreased at all airway sites with L-NAC administration, i.e. the mucus became less rigid and more deformable (the overall change in G* was 0.29 log units, i.e. ca. twofold decrease). The viscoelasticity-derived mucus transportability parameters, mucociliary (MCI) and cough (CCI) clearability indices, increased with L-NAC MDI, particularly CCI, which predicts the effect of mucus rheology on cough clearability. PD increased significantly with L-NAC administration at all measurement sites, which appears to be a novel effect for a direct acting mucolytic agent. Tracheal mucus linear velocity (TMV) increased after L-NAC compared with placebo, as did the normalized frog palate transport rate (NFPTR). The increase in NFPTR was greater than that predicted from the mucus rheological properties alone, suggesting that L-NAC still resident in the collected mucus stimulated the frog palate cilia. The index of mucus flux, the collection rate in mg.min-1, was higher with L-NAC compared with placebo. From our results, we conclude that L-NAC shows potential benefit in terms of improving mucus rheological properties and clearability. It may act, in part, by stimulating the fresh secretion of mucus of lower viscoelasticity. The stimulation of mucociliary clearance could be related to ion flux changes, as indicated by the increase in PD.}, }
@article {pmid7854494, year = {1994}, author = {Konstantinov, S and Topashka-Ancheva, M and Karaivanova, M and Zoneva, G and Galova, I}, title = {Antitumor, nephrotoxic and clastogenic effect of cis-DDP with DDTC or NAC.}, journal = {Neoplasma}, volume = {41}, number = {5}, pages = {253-258}, pmid = {7854494}, issn = {0028-2685}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Animals ; Antineoplastic Combined Chemotherapy Protocols/*pharmacology/toxicity ; Cisplatin/administration &amp; dosage/*pharmacology/*toxicity ; Creatinine/blood ; Ditiocarb/administration &amp; dosage/*therapeutic use ; Kidney Diseases/blood/*chemically induced/*prevention &amp; control ; Leukemia L1210/drug therapy ; Melanoma, Experimental/drug therapy ; Mice ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Mutagens/*toxicity ; Neoplasm Transplantation ; Urea/blood ; }, abstract = {Diethyldithiocarbamate (DDTC) and N-acetylcysteine (NAC) are nucleophile sulfur-containing compounds which can protect the platinum-induced nephrotoxicity. Combinations of cis-diamminedichloroplatinum(II) (cis-DDP) and DDTC or NAC were tested on the leukemia L1210 and melanoma B 16 tumor models. Nephrotoxicity of cis-DDP alone and in combination with DDTC or NAC was evaluated. On both of the investigated tumor models clastogenic effects in bone marrow cells were detected. DNA synthetic and mitotic activity of L1210 cells in vivo were evaluated by 3H-thymidine incorporation and cytogenetic analysis. Amelioration of the platinum induced nephrotoxicity and preservation of the antitumor activity of cis-DDP through combined application with DDTC or NAC were obtained at the L1210 model. Maximal inhibition of the DNA synthesis in L1210 cells was detected with the cis-DDP treatment. The sulfurcontaining nucleophiles DDTC or NAC could modulate the inhibitory effect of cis-DDP on the incorporation of 3H-thymidine into the nuclei of L1210 cells. Enhanced mitotic activity was detected during cytotoxic therapy with cis-DDP. Cis-DDP alone and in combination with DDTC or NAC caused a significant growth inhibition on the s.c. tumor of the melanoma B16 bearing mice. Two times better therapeutic results at this model were obtained with cis-DDP alone (T/C = 234.09%, T/C = 136.36% for cis-DDP+DDTC and T/C = 151.14% for cis-DDP+NAC). The usefulness of DDTC or NAC as adjuvants in the platinum based chemotherapy of human cancers have been discussed. Clastogenic effect and antitumor activity are probably connected and it is supposed that the reduction of the genotoxicity could lead to a decreased antitumor activity of the platinum complex.}, }
@article {pmid7511731, year = {1994}, author = {Jaraki, O and Strauss, WE and Francis, S and Loscalzo, J and Stamler, JS}, title = {Antiplatelet effects of a novel antianginal agent, nicorandil.}, journal = {Journal of cardiovascular pharmacology}, volume = {23}, number = {1}, pages = {24-30}, doi = {10.1097/00005344-199401000-00024}, pmid = {7511731}, issn = {0160-2446}, mesh = {Acetylcysteine/pharmacology ; Adenosine Diphosphate/pharmacology ; Analysis of Variance ; Binding Sites ; Blood Platelets/*drug effects/metabolism ; Cyclic GMP/blood ; Dose-Response Relationship, Drug ; Drug Tolerance ; Fibrinogen/metabolism ; Guanylate Cyclase/blood ; Humans ; Niacinamide/*analogs &amp; derivatives/pharmacology ; Nicorandil ; Platelet Aggregation/*drug effects ; Platelet Aggregation Inhibitors/*pharmacology ; Potassium Channels/drug effects/physiology ; Radioimmunoassay ; Vasodilator Agents/*pharmacology ; }, abstract = {Nicorandil (nicotinamidoethyl nitrate) is a novel vasodilator. Its vasodilator properties are related both to the nicotinamide and nitrate moieties. Classic nitrates such as nitroglycerin (NTG) and isosorbide dinitrate demonstrate in vitro inhibition of ADP-induced platelet aggregation. Such effects have been shown to occur in a dose-related manner, are potentiated by reduced thiols and by increasing preincubation time, and are associated with increases in intracellular cyclic GMP. We explored the effect of nicorandil on ADP-induced human platelet aggregation and the role of reduced thiol N-acetylcysteine (NAC) in modulating this response. Nicorandil significantly inhibited aggregation to ADP dose dependently (IC50 3.0 mM). These effects were associated with inhibition of fibrinogen binding to the platelet surface (IC50 2 mM). Addition of nicorandil after maximal ADP-induced aggregation was achieved resulted in disaggregation. Addition of a source of reduced thiol (NAC) potentiated the antiaggregatory effects of nicorandil threefold (p < 0.05). Platelet inhibition by nicorandil was also augmented by increase in duration of preincubation, with maximal effects observed at 180 min. Preincubation of platelets with 10 mM nicorandil resulted in attenuated inhibition of platelet aggregation on gel filtration and subsequent exposure to additional nicorandil, indicative of tolerance induction. Methylene blue (MB), an inhibitor of guanylate cyclase, significantly reversed nicorandil-induced inhibition of platelet aggregation. Moreover, in accordance with this mechanism, nicorandil increased intracellular platelet cyclic GMP levels. Although the antiplatelet effect of nicotinamide was partially reversed by the K+ channel inhibitor iberotoxin, preincubation with iberotoxin had no impact on inhibition of platelet aggregation by nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8143355, year = {1993}, author = {David, M and Horvath, G and Schimke, I and Nagy, I and Mueller, MM}, title = {Comparative drug influence on peroxide mediated increase of cytosolic calcium in human endothelial cells.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {223}, number = {1-2}, pages = {1-7}, doi = {10.1016/0009-8981(93)90057-b}, pmid = {8143355}, issn = {0009-8981}, mesh = {Antioxidants/pharmacology ; Benzene Derivatives/antagonists &amp; inhibitors ; Calcium/*metabolism ; Cells, Cultured ; Cytosol/*drug effects/metabolism ; Endothelium, Vascular/*drug effects/metabolism ; Humans ; Hydrogen Peroxide/antagonists &amp; inhibitors ; Peroxides/*antagonists &amp; inhibitors/pharmacology ; Umbilical Veins/cytology ; }, abstract = {The increase of cytosolic free calcium in human umbilical vein endothelial cells caused by peroxides was used as a model to determine and compare the putative cytoprotective properties of substances known to interfere with the generation or metabolism of reactive oxygen species. Hydrophilic hydrogen peroxide and lipophilic cumene hydroperoxide were used as sources of reactive oxygen. [Ca2+]i in endothelial cells was measured by the FURA method and the resting level was found to be 129.3 +/- 14.1 nM. Both peroxides were found to increase cytosolic calcium with dependence on the concentration and on the presence of extracellular calcium. Among the substances tested, only catalase and N-acetyl-cysteine were able to exhibit a significant cytoprotective effect.}, }
@article {pmid8306888, year = {1993}, author = {Vernet, M and Cavard, C and Zider, A and Fergelot, P and Grimber, G and Briand, P}, title = {In vitro manipulation of early mouse embryos induces HIV1-LTRlacZ transgene expression.}, journal = {Development (Cambridge, England)}, volume = {119}, number = {4}, pages = {1293-1300}, doi = {10.1242/dev.119.4.1293}, pmid = {8306888}, issn = {0950-1991}, mesh = {Animals ; Autoradiography ; Cells, Cultured ; Electrophoresis, Polyacrylamide Gel ; Gene Expression Regulation/*physiology ; Genes, Viral/*genetics ; HIV-1/*genetics ; Lac Operon/*genetics ; Mice ; Mice, Transgenic/embryology/genetics ; Oxidation-Reduction ; Transcription, Genetic ; }, abstract = {We report here that the transcriptional activity of early mouse embryos is affected by their manipulation and culture in vitro, using transgenic embryos that express the reporter gene lacZ. We examined the pattern of expression of the lacZ gene fused to the human immunodeficiency virus type 1 long terminal repeat during the preimplantation stages. Transgene expression is induced as early as the two-cell stage in embryos developed in vitro, while there is no constitutive expression at the same stage in embryos developed in vivo. We have established a relation between this inducible expression occurring in vitro and an oxidative stress phenomenon. Indeed, when the culture medium is supplemented with antioxidants such N-acetyl-cysteine or CuZn-superoxide dismutase the transgene expression is markedly reduced. We also present evidence that the transgene expression in vitro coincides with the onset of the embryonic genome activation as attested by the synthesis of the 70 x 10(3) M(r) protein complex. Therefore, this transgene expression could prove to be a useful tool in our understanding of the molecular mechanisms involved in this crucial developmental event.}, }
@article {pmid8298817, year = {1993}, author = {Salvemini, D and Pistelli, A and Anggard, E}, title = {Vascular and anti-platelet actions of 1,2- and 1,3-glyceryl dinitrate.}, journal = {British journal of pharmacology}, volume = {110}, number = {3}, pages = {937-942}, pmid = {8298817}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Animals ; Benzoates/pharmacology ; Biotransformation ; Blood Platelets/*drug effects/metabolism ; Cattle ; Drug Synergism ; Endothelium, Vascular/*drug effects/metabolism ; Humans ; In Vitro Techniques ; Muscle, Smooth, Vascular/*drug effects/metabolism ; Nitric Oxide/metabolism ; Nitrites/analysis ; Nitroglycerin/*analogs &amp; derivatives/metabolism/pharmacokinetics/pharmacology ; Platelet Aggregation/drug effects ; Platelet Aggregation Inhibitors/metabolism/pharmacology ; Rabbits ; Sulfhydryl Compounds ; Thimerosal ; Vasodilator Agents/*metabolism/pharmacokinetics/*pharmacology ; }, abstract = {1. The aim of this study was to investigate whether two metabolites of glyceryl trinitrate (GTN), 1,2 and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN) could account for the pharmacological effects of GTN. To this end the formation of nitric oxide (NO) from 1,2- and 1,3-GDN in the presence of bovine aortic smooth muscle cells (SMC) or endothelial cells (EC) was studied. The effects of various thiols on NO formation from these dinitrates was also evaluated. 2. 1,2-GDN or 1,3-GDN (10(-10)-10(-5) M) caused a dose-dependent relaxation of rabbit aortic strips denuded of endothelium and precontracted with phenylephrine. The dinitrates were less than one tenth as potent as GTN. 3. Incubation of 1,2-GDN or 1,3-GDN (75-2400 microM) with SMC for 30 min led to a concentration-dependent increase in nitrite (NO2-) formation but this increase was less than that produced from GTN. Likewise incubation of 1,2-GDN or 1,3-GDN with N-acetylcysteine (NAC), glutathione (GSH) or thiosalicylic acid (TSA) (all at 1 mM) for 30 min at 37 degrees C produced a concentration-dependent increase in NO2- formation. 4. Platelet aggregation induced by thrombin (40 mu ml-1) was not modified by high concentrations of 1,2-GDN or 1,3-GDN (175-700 microM). However, aggregation was inhibited when platelets were exposed to 1,2-GDN or 1,3-GDN (700 microM) in the presence of SMC (0.24-1.92 x 10(5) cells) or EC (0.8-3.2 x 10(5) cells). These effects were abrogated by co-incubation with oxyhaemoglobin (OxyHb, 10 microM) indicating that they were due to NO release. The concentrations of the dinitrates required to inhibit platelet aggregation by 50% were about 15 times higher than for GTN in the presence of the same numbers of SMC or EC.5. When NAC or TSA (both at 0.5 mM) were co-incubated with platelets for 3 min in the presence of1,2-GDN or 1,3-GDN, a concentration-dependent inhibition of platelet aggregation was observed. These anti-platelet effects were abolished by co-incubation with OxyHb (10 microM). Glutathione had no potentiating effects.6. Thus the dinitrate metabolites of GTN are metabolized to NO by SMC or EC and are acted upon by thiols to form NO at concentrations about 10 times higher than those of GTN. In vivo, after oral or intravenous GTN, GDN levels are reached which are more than 10 times higher than those of GTN.These data support the notion that part of the effects of GTN are due to the generation of NO from 1,2-GDN and 1,3-GDN by the cells of the vascular wall.}, }
@article {pmid8238538, year = {1993}, author = {Leff, JA and Wilke, CP and Hybertson, BM and Shanley, PF and Beehler, CJ and Repine, JE}, title = {Postinsult treatment with N-acetyl-L-cysteine decreases IL-1-induced neutrophil influx and lung leak in rats.}, journal = {The American journal of physiology}, volume = {265}, number = {5 Pt 1}, pages = {L501-6}, doi = {10.1152/ajplung.1993.265.5.L501}, pmid = {8238538}, issn = {0002-9513}, support = {HL-40784/HL/NHLBI NIH HHS/United States ; HL-45582/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/blood/*pharmacology ; Animals ; Disease Models, Animal ; Glutathione/analogs &amp; derivatives/blood ; Glutathione Disulfide ; Humans ; Hydrogen Peroxide/analysis ; Interleukin-1/*toxicity ; Lung/drug effects/*pathology/physiology ; Male ; Neutrophils/drug effects/*physiology ; Pulmonary Artery ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/toxicity ; Respiration ; Respiratory Distress Syndrome/pathology ; }, abstract = {We found that intratracheal administration of interleukin-1 alpha (IL-1) rapidly (5 h) increased leak of 125I-labeled albumin from the blood into the lung (lung leak), influx of neutrophils into lung lavages, lung oxidized glutathione (GSSG) levels, breath hydrogen peroxide (H2O2) concentrations, and lung histological abnormalities in intact rats. Since N-acetyl-L-cysteine (NAC) increases glutathione (GSH) levels in vivo and scavenges oxygen radicals in vitro, we tested the effect of NAC given intravenously on lung changes following intratracheal IL-1 administration. We found that administration of NAC immediately before or 2.5 h after intratracheal administration of IL-1 decreased lung leak, neutrophil influx into lung lavages, and defects in lung histology. NAC treatment also increased blood acid soluble sulfhydryl levels, reduced lung GSSG increases, and decreased breath H2O2 levels in rats given IL-1 intratracheally. The latter findings are consistent with the possibility that NAC is enhancing GSH or other sulfhydryls and, as a result, reducing oxidative stress due to H2O2 or H2O2-derived products. Since postinsult treatment with NAC is effective in this relevant intact animal model of acute lung injury, we speculate that NAC may have promise in the treatment of patients with the adult respiratory distress syndrome.}, }
@article {pmid8133789, year = {1993}, author = {Doyle, CE and Mackay, JM and Ashby, J}, title = {Failure of N-acetylcysteine to protect the mouse bone marrow against the clastogenicity of 7,12-dimethylbenzanthracene.}, journal = {Mutagenesis}, volume = {8}, number = {6}, pages = {583-584}, doi = {10.1093/mutage/8.6.583}, pmid = {8133789}, issn = {0267-8357}, mesh = {9,10-Dimethyl-1,2-benzanthracene/antagonists &amp; inhibitors/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Antimutagenic Agents/*pharmacology ; Bone Marrow/*drug effects/ultrastructure ; Erythroblasts/drug effects/ultrastructure ; Male ; Mice ; Mice, Inbred C57BL ; Micronucleus Tests ; Sulfhydryl Compounds/pharmacology ; }, abstract = {De Flora et al. (1991a) have demonstrated a marked protective effect afforded by N-acetylcysteine (NAC) to the liver and lung of rats exposed to benzo[a]pyrene (BP) by intratracheal injection. Due to the protocol used by De Flora et al., BP was inactive in the bone marrow micronucleus assay and, consequently, the possible protective effect of NAC in this tissue could not be assessed. In the present study, three daily administrations of 7,12-dimethylbenzanthracene (DMBA; 15 or 25 mg/kg/day via oral gavage) resulted in the expected increased in micronucleated polychromatic erythrocytes (MPE) in the bone marrow of male C57BL/6 mice 24 h after the final dose. Pretreatment of similar groups of mice with NAC (1 g/kg/day via oral gavage) 5 h before each administration of DMBA had no effect on MPE frequencies. It is concluded that NAC does not have a protective effect on the mouse bone marrow.}, }
@article {pmid7997760, year = {1993}, author = {Timenetsky, J and Curcio, M}, title = {[Staphylococcal coagglutination reaction in the identification of mycoplasma].}, journal = {Revista do Instituto de Medicina Tropical de Sao Paulo}, volume = {35}, number = {6}, pages = {551-555}, pmid = {7997760}, issn = {0036-4665}, mesh = {Agglutination ; Animals ; Humans ; Mice ; Mycoplasma/*isolation &amp; purification ; Rabbits ; Rats ; Staphylococcus/*immunology ; }, abstract = {Staphylococcal Coagglutination was used as method for a rapid identification of mycoplasmas that could be performed by non specialized laboratories. Suspensions of Staphylococcus aureus (Cowan I) sensitized with rabbit antibodies against NCTC mycoplasma strains have identified these microorganisms and the strains isolated from humans, cell cultures rats and mice in concentrated suspensions from cultures of 4.0 ml. Fourty eight strains of M.pulmonis, 6 of M. arthritidis, 8 of M.arginini, 3 of M.orale, 15 of A.laidlawii, 8 of M.hominis and 3 of M.pneumoniae were identified by staphylococcal coagglutination and confirmed by Growth Inhibition Test. Optimal parameters of coagglutination were established and the stability of the conjugates were preserved for 90 days when added with acetyl cysteine. The reaction was visualized without optical resources. The sera were previously absorbed with heterologous NCTC strains and with the pellet of the sterile broth.}, }
@article {pmid8372431, year = {1993}, author = {Laughlin, MA and Zeichner, S and Kolson, D and Alwine, JC and Seshamma, T and Pomerantz, RJ and Gonzalez-Scarano, F}, title = {Sodium butyrate treatment of cells latently infected with HIV-1 results in the expression of unspliced viral RNA.}, journal = {Virology}, volume = {196}, number = {2}, pages = {496-505}, doi = {10.1006/viro.1993.1505}, pmid = {8372431}, issn = {0042-6822}, support = {NS 07180/NS/NINDS NIH HHS/United States ; NS 27405/NS/NINDS NIH HHS/United States ; T32-AI07278/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Butyrates/*pharmacology ; Butyric Acid ; Chloramphenicol O-Acetyltransferase/biosynthesis/genetics ; Cystine/analogs &amp; derivatives/pharmacology ; DNA Mutational Analysis ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Viral/*drug effects ; HIV Long Terminal Repeat/*genetics ; HIV-1/*genetics/growth &amp; development ; Humans ; Novobiocin/pharmacology ; RNA Splicing/*drug effects ; RNA, Viral/biosynthesis ; Recombinant Fusion Proteins/biosynthesis ; Rhabdomyosarcoma ; Tumor Cells, Cultured ; Virus Replication/drug effects ; }, abstract = {To investigate potential mechanisms for HIV-1 proviral latency, we generated a set of chronically HIV-1 infected and stably long terminal repeat-chloramphenicol acetyl transferase (LTR-CAT)-transfected TE671/RD cells, and studied both their virus production and LTR-driven reporter gene expression. Established tissue culture models of retroviral latency in lymphoid and monocytoid cell lines have demonstrated that the induction of virus production is associated with a shift in HIV-1-specific mRNA from a predominance of singly and multiply spliced mRNA's to the production of full-length HIV-1 RNA. We found a similar pattern in TE671/RD cells, but in contrast to U1 and ACH2 cells, could not induce viral replication by exposure to phorbol myristate acetate (PMA) alone. We demonstrated instead that production of full-length viral RNA, viral replication, and LTR-driven CAT expression could be induced by exposure to sodium butyrate. The most proximate effect of sodium butyrate is inhibition of cellular histone deacetylase(s) which results in disruption of nucleosomes relieving one level of restriction to gene expression. Consistent with this mechanism of action, we further found that sodium butyrate's effects: (i) act synergistically with PMA and TNF-alpha; (ii) are independent of protein synthesis; (iii) do not affect the constitutively expressed creatine phosphokinase gene; (iv) do not map to a discrete sequence motif in the viral LTR; and (v) are not blocked by N-acetyl cysteine but (vi) are blocked by novobiocin, an inhibitor of cellular topoisomerase II. These data show that a similar pattern of restricted viral RNA expression exists in this nonlymphoid cellular model of HIV-1 latency. In contrast however, these results suggest that in these cells there is an additional block to viral gene expression, which is overcome with sodium butyrate. These results are discussed in the context of histone-mediated repression of HIV-1 gene expression.}, }
@article {pmid8212000, year = {1993}, author = {Thornton-Manning, JR and Nichols, WK and Manning, BW and Skiles, GL and Yost, GS}, title = {Metabolism and bioactivation of 3-methylindole by Clara cells, alveolar macrophages, and subcellular fractions from rabbit lungs.}, journal = {Toxicology and applied pharmacology}, volume = {122}, number = {2}, pages = {182-190}, doi = {10.1006/taap.1993.1186}, pmid = {8212000}, issn = {0041-008X}, support = {HL02119/HL/NHLBI NIH HHS/United States ; HL13645/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Animals ; Biotransformation ; Cell Survival/drug effects ; Chromatography, High Pressure Liquid ; Cytosol/metabolism ; Glutathione/metabolism ; In Vitro Techniques ; Lung/cytology/drug effects/*metabolism ; Macrophages, Alveolar/metabolism ; Male ; Microsomes/metabolism ; Rabbits ; Skatole/*metabolism/toxicity ; }, abstract = {3-Methylindole (3MI), a fermentation product of tryptophan produced by intestinal and ruminal microflora, has been shown to cause pneumotoxicity in several species subsequent to cytochrome P450-mediated biotransformation. Among several species studied, rabbits are comparatively resistant to 3MI-induced pneumotoxicity, especially when compared to goats or mice. In this study, rabbit pulmonary cells and subcellular fractions were used to examine the metabolism and bioactivation of 3MI. A covalent-binding metabolite was produced in 3MI incubations by both Clara cells and macrophages. The addition of the cytochrome P450 inhibitor, 1-aminobenzotriazole, to these incubations inhibited the production of covalent-binding metabolite(s) by 94% in Clara cells and only 24% in macrophages. In incubations of Clara cells or macrophages with 3MI and N-acetylcysteine (NAC), a polar conjugate was detected and tentatively identified as an adduct of 3-hydroxy-3-methylindolenine (3H3MIN). Also identified were 3[(N-glutathione-S-yl)-methyl]-indole (3MI-GSH) and 3-methyloxindole (3MOI). In rabbit lung microsomal incubations with 3MI and glutathione (GSH), 3MI-GSH, 3MOI, indole-3-carbinol, and a GSH adduct of 3H3MIN were identified. The addition of cytosol to the microsomal incubations with GSH did not increase the rate of formation of the GSH adducts, indicating that cytosolic GSH-S-transferases are not essential in the formation of these metabolites. GSH significantly decreased the covalent binding of an electrophilic metabolite in microsomal incubations. These data suggest that GSH may be important in the mitigation of 3MI toxicity. Furthermore, the comparison of 3MI bioactivation to electrophilic intermediates in Clara cells and alveolar macrophages suggests that 3MI is metabolized by different oxidative pathways in the two different cell types, although the same metabolites were produced by the two cell types. This study shows that rabbit pulmonary enzymes are capable of bioactivating 3MI to reactive intermediates which become covalently bound to cellular macromolecules. This indicates that the relative resistance of rabbits to 3MI-induced pneumotoxicity is probably not due to differences in metabolic enzymes which convert 3MI to reactive intermediates.}, }
@article {pmid8108311, year = {1993}, author = {Franceschini, G and Werba, JP and Safa, O and Gikalov, I and Sirtori, CR}, title = {Dose-related increase of HDL-cholesterol levels after N-acetylcysteine in man.}, journal = {Pharmacological research}, volume = {28}, number = {3}, pages = {213-218}, doi = {10.1006/phrs.1993.1124}, pmid = {8108311}, issn = {1043-6618}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Cholesterol, HDL/*blood ; Dose-Response Relationship, Drug ; Female ; Humans ; Hyperlipidemias/blood ; Lipoprotein(a)/blood ; Male ; Middle Aged ; Stimulation, Chemical ; Triglycerides/blood ; }, abstract = {Changes in plasma lipid-lipoprotein levels were evaluated in 10 hyperlipidemic patients during treatment with progressive doses (from 1200 mg day-1 to 3600 mg day-1) of N-acetylcysteine (NAC). Plasma total cholesterol and triglyceride levels, as well as those of lipoprotein (a) did not change to an appreciable extent, even with the highest dosage. However, the HDL-cholesterol levels showed a significant, dose-related rise, the mean absolute increase, with the highest NAC dose, being of approximately 10 mg dl-1 (16.2%). The rise of HDL-cholesterol was independent of changes in other lipid-lipoprotein parameters, suggesting a possible direct effect of NAC on the HDL system.}, }
@article {pmid7901297, year = {1993}, author = {Sölen, G}, title = {Radioprotective effect of N-acetylcysteine in vitro using the induction of DNA breaks as end-point.}, journal = {International journal of radiation biology}, volume = {64}, number = {4}, pages = {359-366}, doi = {10.1080/09553009314551541}, pmid = {7901297}, issn = {0955-3002}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Cricetinae ; Cricetulus ; DNA/*drug effects/*radiation effects ; *DNA Damage ; In Vitro Techniques ; Radiation-Protective Agents/*pharmacology ; }, abstract = {Cultures of Chinese hamster cells were treated with N-acetylcysteine (NAC) and irradiated under hypoxic or aerobic conditions. Protection factors (PFs) were calculated using the yield of DNA breaks as a measure of the radiation response. With NAC up to 50 mmol dm-3, the PF values were smaller for aerobically- than for hypoxically-irradiated cells. In contrast with NAC concentrations > 100 mmol dm-3, the PF values for aerobically-irradiated cells were larger than those for hypoxic cells. This reversal is in agreement with the predictions of a modified competition model, the 'X-model'. The value of X (the ratio of reparable to non-reparable damage) was calculated to be close to 5 for the NAC-treated cells, i.e. about 18% of the radiation damage was not reparable. The increase of the total non-protein bound thiols (NPSH) and GSH content after NAC treatment was measured both in whole cells and isolated nuclei. Measurement of the cellular NPSH content showed a continuous increase with increasing NAC concentrations in the medium, independent of treatment time. In contrast, the amount of intracellular and intranuclear GSH increased with prolonged incubation time with NAC. No quantitative relationship was found between PF values and cellular NPSH or GSH content.}, }
@article {pmid7691889, year = {1993}, author = {Marui, N and Offermann, MK and Swerlick, R and Kunsch, C and Rosen, CA and Ahmad, M and Alexander, RW and Medford, RM}, title = {Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells.}, journal = {The Journal of clinical investigation}, volume = {92}, number = {4}, pages = {1866-1874}, pmid = {7691889}, issn = {0021-9738}, support = {P01 HL48667/HL/NHLBI NIH HHS/United States ; }, mesh = {Antioxidants/*pharmacology ; Base Sequence ; Binding Sites ; Blotting, Northern ; Cell Adhesion Molecules/analysis/*biosynthesis/*genetics ; Cell Nucleus/metabolism ; Cells, Cultured ; DNA Probes ; E-Selectin ; Endothelium, Vascular/drug effects/*metabolism ; Enzyme-Linked Immunosorbent Assay ; Gene Expression/drug effects ; Gene Expression Regulation/drug effects/*physiology ; Glyceraldehyde-3-Phosphate Dehydrogenases/biosynthesis ; Humans ; Intercellular Adhesion Molecule-1 ; Interleukin-1/*pharmacology ; Molecular Sequence Data ; NF-kappa B/metabolism ; Oligodeoxyribonucleotides/chemical synthesis/metabolism ; Promoter Regions, Genetic ; RNA, Messenger/drug effects/metabolism ; Recombinant Proteins/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; Umbilical Veins ; Vascular Cell Adhesion Molecule-1 ; }, abstract = {Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. Regulation of VCAM-1 gene expression may be coupled to oxidative stress through specific reduction-oxidation (redox) sensitive transcriptional or posttranscriptional regulatory factors. In cultured human umbilical vein endothelial (HUVE) cells, the cytokine interleukin 1 beta (IL-1 beta) activated VCAM-1 gene expression through a mechanism that was repressed approximately 90% by the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC). Furthermore, PDTC selectively inhibited the induction of VCAM-1, but not intercellular adhesion molecule-1 (ICAM-1), mRNA and protein accumulation by the cytokine tumor necrosis factor-alpha (TNF alpha) as well as the noncytokines bacterial endotoxin lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). PDTC also markedly attenuated TNF alpha induction of VCAM-1-mediated cellular adhesion. In a distinct pattern, PDTC partially inhibited E-selectin gene expression in response to TNF alpha but not to LPS, IL-1 beta, or PIC. TNF alpha and LPS-mediated transcriptional activation of the human VCAM-1 promoter through NF-kappa B-like DNA enhancer elements and associated NF-kappa B-like DNA binding proteins was inhibited by PDTC. These studies suggest a molecular linkage between an antioxidant sensitive transcriptional regulatory mechanism and VCAM-1 gene expression that expands on the notion of oxidative stress as an important regulatory signal in the pathogenesis of atherosclerosis.}, }
@article {pmid8250542, year = {1993}, author = {Pani, A and Marongiu, ME and La Colla, P}, title = {Modulatory effect of N-acetyl-L-cysteine on the HIV-1 multiplication in chronically and acutely infected cell lines.}, journal = {Antiviral research}, volume = {22}, number = {1}, pages = {31-43}, doi = {10.1016/0166-3542(93)90084-v}, pmid = {8250542}, issn = {0166-3542}, mesh = {Acetylcysteine/*pharmacology ; Acquired Immunodeficiency Syndrome/drug therapy ; Antiviral Agents/*pharmacology ; Cell Division/drug effects ; Cell Fusion/physiology ; Cell Line ; Dextran Sulfate/pharmacology ; HIV-1/*drug effects/growth &amp; development/*physiology ; Humans ; Lymphoid Tissue/cytology/microbiology ; T-Lymphocytes/drug effects/*microbiology ; Virus Replication/*drug effects ; Zidovudine/pharmacology ; }, abstract = {N-acetyl-L-cysteine (NAC) is known to antagonize the PMA- or cytokine-stimulated HIV-1 replication in latently and acutely infected monocytic and lymphocytic cell lines, and to reduce the virus multiplication in acutely infected, PHA-stimulated PBMC. We here report on the modulatory effects of NAC on the HIV-1 multiplication in both chronically and acutely infected lymphocytes that produce high virus levels independently from cytokine activation. In both cases, NAC doses of 0.12 and 0.25 mM decreased, whereas doses of 0.5-2 mM increased the infectious HIV-1 yield. At these concentrations, the modulatory effect of NAC on the HIV-1 multiplication paralleled that on cell proliferation, suggesting a close correlation between the two phenomena; in fact, under conditions where NAC could not modulate the cell growth, the drug also failed to modulate the HIV-1 multiplication. High NAC concentrations (4-16 mM), which were able to increase the proliferative rate of both chronically infected H9/IIIB and normal T lymphocytes, increased up to 6-fold the virus multiplication in H9/IIIB cells but were inhibitory to HIV-1 in acutely infected cells. This inhibition was due to the fact that, like dextran sulfate, NAC interfered with an early event in the virus growth cycle. The finding that high NAC doses were also capable of preventing syncytium formation in H9/IIIB and C8166 (or MT-4) cocultures further indicated an interference of the drug with receptor-binding-related events.}, }
@article {pmid7902253, year = {1993}, author = {Borel, AG and Abbott, FS}, title = {Identification of carbamoylated thiol conjugates as metabolites of the antineoplastic 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, in rats and humans.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {21}, number = {5}, pages = {889-901}, pmid = {7902253}, issn = {0090-9556}, mesh = {Acetylcysteine/metabolism ; Animals ; Biotransformation ; Carbamates/chemical synthesis/*metabolism ; Chromatography, High Pressure Liquid ; Glutathione/metabolism ; Humans ; Lomustine/*metabolism/pharmacokinetics/toxicity ; Mass Spectrometry ; Rats ; Sulfhydryl Compounds/chemical synthesis/*metabolism ; }, abstract = {The metabolic fate of 1-(2-chloroethyl)-3-cyclohexyl)-nitrosourea (CCNU) in rats and humans was investigated with a view to characterizing the nature of the carbamoylating species released upon in vivo transformation of the drug. CCNU undergoes oxidation in vivo to afford 4-hydroxy and 3-hydroxy CCNU which, along with the parent drug, decomposes to the corresponding isocyanates. Although the highly reactive nature of the isocyanate species precludes their identification in vivo, their existence as electrophilic intermediates was detected in the likeness of trapped glutathione (GSH) and N-acetylcysteine (NAC) conjugates. Conjugated thiol metabolites were purified by HPLC from the bile and urine of CCNU-dosed rats, and the urine of a patient on CCNU therapy. The metabolites were identified by atmospheric pressure chemical ionization LC/MS and LC/MS/MS. In addition, LC/MS and LC/MS/MS spectra of synthesized authentic standards corroborated the identity of the metabolites. In rats, 4-hydroxycyclohexyl, 3-hydroxycyclohexyl, and cyclohexyl isocyanate were identified as their GSH conjugates in bile and NAC conjugates in urine. In the case of the patient, the NAC conjugates of 4-hydroxycyclohexyl and 3-hydroxycyclohexyl isocyanate were identified as urinary metabolites. The identification of GSH and NAC conjugates reported herein marks a significant advance in the assessment of the in vivo carbamoylating activity of CCNU and its phase I metabolites.}, }
@article {pmid8353285, year = {1993}, author = {Schieven, GL and Kirihara, JM and Myers, DE and Ledbetter, JA and Uckun, FM}, title = {Reactive oxygen intermediates activate NF-kappa B in a tyrosine kinase-dependent mechanism and in combination with vanadate activate the p56lck and p59fyn tyrosine kinases in human lymphocytes.}, journal = {Blood}, volume = {82}, number = {4}, pages = {1212-1220}, pmid = {8353285}, issn = {0006-4971}, support = {R01 CA-42633/CA/NCI NIH HHS/United States ; R01 CA-51425/CA/NCI NIH HHS/United States ; R29 CA-4211/CA/NCI NIH HHS/United States ; }, mesh = {Base Sequence ; Calcium/metabolism ; Cells, Cultured ; Humans ; Hydrogen Peroxide/pharmacology ; Inositol 1,4,5-Trisphosphate/metabolism ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ; Lymphocytes/metabolism ; Molecular Sequence Data ; NF-kappa B/*metabolism ; Protein-Tyrosine Kinases/*metabolism ; Proto-Oncogene Proteins/*metabolism ; Proto-Oncogene Proteins c-fyn ; Reactive Oxygen Species/*pharmacology ; *Signal Transduction ; Vanadates/*pharmacology ; }, abstract = {We have previously observed that ionizing radiation induces tyrosine phosphorylation in human B-lymphocyte precursors by stimulation of unidentified tyrosine kinases and this phosphorylation is substantially augmented by vanadate. Ionizing radiation generates reactive oxygen intermediates (ROI). Because H2O2 is a potent ROI generator that readily crosses the plasma membrane, we used H2O2 to examine the effects of ROI on signal transduction. We now provide evidence that the tyrosine kinase inhibitor herbimycin A and the free radical scavenger N-acetyl-cysteine inhibit both radiation-induced and H2O2-induced activation of NF-kappa B, indicating that activation triggered by ROI is dependent on tyrosine kinase activity. H2O2 was found to stimulate Ins-1,4,5-P3 production in a tyrosine kinase-dependent manner and to induce calcium signals that were greatly augmented by vanadate. The synergistic induction of tyrosine phosphorylation by H2O2 plus vanadate included physiologically relevant proteins such as PLC gamma 1. Although treatment of cells with H2O2 alone did not affect the activity of src family kinases, treatment with H2O2 plus vanadate led to activation of the p56lck and p59fyn tyrosine kinases. The combined inhibition of phosphatases and activation of kinases provides a potent mechanism for the synergistic effects of H2O2 plus vanadate. Induction of tyrosine phosphorylation by ROI may thus lead to many of the pleiotropic effects of ROI in lymphoid cells, including downstream activation of PLC gamma 1 and NF-kappa B.}, }
@article {pmid8344990, year = {1993}, author = {Koong, AC and Giaccia, AJ and Hahn, GM and Saad, AH}, title = {Activation of potassium channels by hypoxia and reoxygenation in the human lung adenocarcinoma cell line A549.}, journal = {Journal of cellular physiology}, volume = {156}, number = {2}, pages = {341-347}, doi = {10.1002/jcp.1041560217}, pmid = {8344990}, issn = {0021-9541}, support = {CA03353/CA/NCI NIH HHS/United States ; CA32827/CA/NCI NIH HHS/United States ; NRSA 5T32 1A 09302/NR/NINR NIH HHS/United States ; }, mesh = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; Acetylcysteine/pharmacology ; Adenocarcinoma/*pathology/*physiopathology/ultrastructure ; Alkaloids/pharmacology ; Free Radical Scavengers ; Humans ; Hypoxia/*physiopathology ; Isoquinolines/pharmacology ; Lung Neoplasms/*pathology/*physiopathology/ultrastructure ; Oxidation-Reduction ; Oxygen/metabolism ; Piperazines/pharmacology ; Potassium Channels/drug effects/*physiology ; Protein Kinase Inhibitors ; Protein Kinases/physiology ; Staurosporine ; Tetradecanoylphorbol Acetate/pharmacology ; Tetraethylammonium ; Tetraethylammonium Compounds/pharmacology ; Time Factors ; Tumor Cells, Cultured ; }, abstract = {Active oxygen species are generated in cells during pathophysiologic conditions such as inflammation and postischemic reperfusion. If oxygen radical scavengers are added before reperfusion, then the magnitude of injury is reduced. We investigated whether free radicals generated following exposure to hypoxia and reoxygenation activate voltage-dependent K+ ion channels in tumor cells in vitro. Using the technique of whole cell voltage clamping, we recorded currents from two families of potassium (K+) channels that were activated following reoxygenation. One of these groups possessed the electrophysical characteristics of a tetraethylammonium (TEA)-sensitive delayed rectifier channel and the other possessed characteristics of a Tea-insensitive slow inactivating channel. We present evidence which suggests that K+ channels are activated following reoxygenation but not during the hypoxia phase. The K+ currents decayed with time following reoxygenation. The decay characteristics of the K+ currents depended on the duration and level of hypoxia to which the cells were exposed. To determine whether activation of K+ channels by reoxygenation was initiated by free radicals, we pretreated cells with N-Acetyl L-Cysteine (NAC), a free radical scavenger, and found that this pretreatment abolished the currents induced by reoxygenation. We also present evidence that free radicals do not directly act on the channel itself, but activate a protein kinase which, in turn, activates the K+ channels. Taken together, these results indicate that one of the early responses to oxidative stress is the activation of K+ currents.}, }
@article {pmid8266197, year = {1993}, author = {Chan, TY and Chan, AY and Critchley, JA}, title = {Paracetamol poisoning and hepatotoxicity in Chinese--the Prince of Wales Hospital (Hong Kong) experience.}, journal = {Singapore medical journal}, volume = {34}, number = {4}, pages = {299-302}, pmid = {8266197}, issn = {0037-5675}, mesh = {Acetaminophen/administration &amp; dosage/antagonists &amp; inhibitors/blood/*poisoning ; Acetylcysteine/administration &amp; dosage/therapeutic use ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alanine Transaminase/blood ; China/ethnology ; Drug Combinations ; Drug Overdose/drug therapy ; Female ; Hong Kong ; Humans ; Liver/*drug effects/enzymology ; Male ; Middle Aged ; Nausea/etiology ; Time Factors ; Vomiting/etiology ; }, abstract = {From 1989 to 1991, 104 Chinese patients were admitted to the Prince of Wales Hospital with paracetamol poisoning. Only 11 subjects had a plasma paracetamol concentration above the published treatment line. Intravenous N-acetylcysteine (NAC) was completely effective when given within 8 hours (3 patients), while late treatment with NAC at 16 and 26 hours after overdose (2 patients) was ineffective in preventing liver damage as evidenced by elevations in plasma alanine transaminase concentrations. Of the 6 patients receiving NAC between 10 to 15 hours, two had liver damage. Two other subjects who presented late or in whom a plasma paracetamol concentration was not measured also developed liver damage. Fortunately, none of these 6 subjects developed hepatic encephalopathy. We recommend that a standard protocol be readily available for junior hospital staff to use when treating patients with paracetamol overdosage.}, }
@article {pmid8228388, year = {1993}, author = {Beloqui, O and Prieto, J and Suárez, M and Gil, B and Qian, CH and García, N and Civeira, MP}, title = {N-acetyl cysteine enhances the response to interferon-alpha in chronic hepatitis C: a pilot study.}, journal = {Journal of interferon research}, volume = {13}, number = {4}, pages = {279-282}, doi = {10.1089/jir.1993.13.279}, pmid = {8228388}, issn = {0197-8357}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Chronic Disease ; Drug Synergism ; Drug Therapy, Combination ; Female ; Glutathione/blood ; Hepatitis C/blood/*drug therapy ; Humans ; Interferon-alpha/*therapeutic use ; Leukocytes, Mononuclear/drug effects/metabolism ; Male ; Middle Aged ; Pilot Projects ; }, abstract = {Hepatitis C virus (HCV) is an RNA virus that replicates in both the liver and lymphoid cells. Interferon-alpha (IFN-alpha) is a useful treatment of chronic hepatitis C (CHC) although resistance to this drug occurs frequently. The mechanisms underlying resistance to IFN remain unknown. In this work, we have measured the levels of glutathione in plasma and peripheral lymphoid cells from 15 healthy controls and 24 CHC patients, 10 of whom were without treatment and 14 showed high serum alanine aminotransferase (ALT) values despite therapy with lymphoblastoid IFN for more than 4 months. In all patients, glutathione levels in plasma and in mononuclear cells were depressed in comparison to controls. In IFN-unresponsive patients, the addition of 600 mg tid of oral N-acetyl cysteine (NAC), a glutathione precursor, resulted in a steady decrease of ALT values in all patients, with complete normalization in 41% of cases after 5-6 months of combined therapy. Administration of NAC alone for 1 month was without effect in the 10 patients that were not receiving IFN. Supplementation of IFN with NAC induced a near normalization of intralymphocytic glutathione, but plasma levels were only moderately increased. HCV replication was markedly inhibited in lymphocytes and viremia was cleared in one of the 8 patients tested. In conclusion, NAC enhances the response to IFN in CHC. Controlled studies are needed to ascertain whether antioxidant therapy might act in synergy with IFN in chronic viral hepatitis.}, }
@article {pmid7692178, year = {1993}, author = {Collis, CS and Davies, MJ and Rice-Evans, C}, title = {Comparison of N-methyl hexanoylhydroxamic acid, a novel antioxidant, with desferrioxamine and N-acetyl cysteine against reperfusion-induced dysfunctions in isolated rat heart.}, journal = {Journal of cardiovascular pharmacology}, volume = {22}, number = {2}, pages = {336-342}, doi = {10.1097/00005344-199308000-00025}, pmid = {7692178}, issn = {0160-2446}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Antioxidants/*therapeutic use ; Cardiovascular Agents/*therapeutic use ; Deferoxamine/*therapeutic use ; Heart/drug effects ; Heart Rate/drug effects ; Hydroxamic Acids/*therapeutic use ; In Vitro Techniques ; Male ; Myocardial Reperfusion Injury/physiopathology/*prevention &amp; control ; Perfusion ; Rats ; Rats, Wistar ; Ventricular Function, Left/drug effects ; Ventricular Pressure/drug effects ; }, abstract = {The effects of a novel free radical scavenger, N-methyl hexanoylhydroxamic acid (NMHH) on ischaemia and reperfusion-induced dysfunction were compared with those of desferrioxamine (DFO) and N-acetyl cysteine (NAC) in isolated Langendorff-perfused rat heart. NMHH (150 microM) produced significant improvement in recovery of left ventricular developed pressure (LVDP) as compared with that of control hearts (35 +/- 8%) when included in the perfusate both before ischaemia and on reperfusion (68 +/- 6%) and on reperfusion alone (61 +/- 6%). In contrast, neither DFO (52 +/- 9%) nor NAC (54 +/- 12%), at the same concentration, produced a significant increase in recovery of LVDP when applied on reperfusion alone. Only DFO (77 +/- 5%), not NAC (54 +/- 12%), had a significant effect on recovery of LVDP when added to the perfusate before ischaemia and reperfusion. NAC applied before ischaemia produced significant improvement in recovery of heart rate (HR). The improved recovery of LVDP obtained with NMHH applied on reperfusion as compared with that obtained with controls and equimolar concentrations of DFO or NAC suggests that the novel hydroxamate NMHH is the more effective in attenuating reperfusion injury of contractile function in this model.}, }
@article {pmid7687566, year = {1993}, author = {Malorni, W and Rivabene, R and Santini, MT and Donelli, G}, title = {N-acetylcysteine inhibits apoptosis and decreases viral particles in HIV-chronically infected U937 cells.}, journal = {FEBS letters}, volume = {327}, number = {1}, pages = {75-78}, doi = {10.1016/0014-5793(93)81043-y}, pmid = {7687566}, issn = {0014-5793}, mesh = {Acetylcysteine/*pharmacology ; Apoptosis/*drug effects ; Bisbenzimidazole ; Cell Death/drug effects ; Cell Line ; DNA Damage/drug effects ; Glutathione/metabolism ; HIV Core Protein p24/metabolism ; HIV-1/*drug effects/growth &amp; development ; Humans ; Leukocytes, Mononuclear/microbiology ; Microscopy, Fluorescence ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {Apoptosis or programmed cell death (PCD) is a type of death occurring in various physiological processes. Several data suggest that: (1) apoptosis may play a critical role in AIDS pathogenesis; (2) an increase of endocellular free radical levels can be associated with activation of previously latent HIV virus. Tumor necrosis factor (TNF), a cytokine capable of inducing oxygen free radicals and apoptosis, appears also to be involved in HIV activation. The present findings, which elucidate a relationship between the percentage of apoptotic cells, reduced glutathione (GSH) depletion and an increase of p24 antigenemia, suggest that pretreatment with N-acetylcysteine (NAC) is capable of decreasing the above-mentioned phenomena in HIV-infected U937 cells.}, }
@article {pmid8374041, year = {1993}, author = {LaLonde, RT and Xie, S}, title = {Glutathione and N-acetylcysteine inactivations of mutagenic 2(5H)-furanones from the chlorination of humics in water.}, journal = {Chemical research in toxicology}, volume = {6}, number = {4}, pages = {445-451}, doi = {10.1021/tx00034a010}, pmid = {8374041}, issn = {0893-228X}, mesh = {Acetylcysteine/*chemistry ; Animals ; Chlorides/chemistry ; Chromatography, Thin Layer ; Circular Dichroism ; Furans/*chemistry/toxicity ; Glutathione/*chemistry ; Humic Substances/*chemistry ; In Vitro Techniques ; Kinetics ; Magnetic Resonance Spectroscopy ; Molecular Conformation ; Mutagenicity Tests ; Mutagens/*chemistry/toxicity ; Rats ; Salmonella typhimurium/drug effects/genetics ; Spectrophotometry, Ultraviolet ; Water Supply/*analysis ; X-Ray Diffraction ; }, abstract = {The mutagenic 2(5H)-furanones resulting from the chlorination of lignohumic substances in water disinfection and paper pulp bleaching are known to be inactivated by thiols. The objectives of the present study were to characterize the kinetics of an inactivating reaction, isolate and characterize products, and determine their mutagenicity in relation to the starting, mutagenic 2(5H)-furanones. The Salmonella typhimurium (TA100) mutagenicity of mucochloric acid (MCA) had a mean value of 2800 revertants/mumol from four assays and was twice as potent as the C-5 isopropyl ether of MCA (MCA-IPE), whose mutagenicity was determined in the same four assays. A second-order reaction of MCA with GSH at pH 7 was observed. The major product, making up 70% of the total product mixture, was identified as a 1.5:1 mixture of two diastereomers formed by sulfur displacement of the C-4 Cl atom from MCA. The major diastereomer was isolated from the 1.5:1 mixture. Connectivity of GSH to the MCA moiety in the product was established by 2D long-range coupling NMR and fully coupled 13C NMR. On the basis of circular dichroism, the major diastereomer had the S configuration at the hydroxyl-bearing, C-5 ring carbon. MCA-IPE reacted with GSH and N-acetylcysteine (NAC), giving 1:1 mixtures of two diastereomers, again by displacement of the C-4 Cl atom from MCA. A single diastereomer was isolated from the 1:1 MCA-IPE plus NAC reaction. Its structure, determined by X-ray crystallography, had the 5R,8R configuration and was in agreement with the ross structure deduced from the NMR analysis.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8299004, year = {1993}, author = {Gross, CL and Innace, JK and Hovatter, RC and Meier, HL and Smith, WJ}, title = {Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard.}, journal = {Cell biology and toxicology}, volume = {9}, number = {3}, pages = {259-267}, pmid = {8299004}, issn = {0742-2091}, mesh = {Acetylcysteine/pharmacology ; Alkylation ; Buthionine Sulfoximine ; Cell Death/drug effects ; Glutathione/*metabolism ; Humans ; In Vitro Techniques ; Intracellular Fluid/metabolism ; Lymphocytes/cytology/*drug effects/*metabolism ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Mustard Gas/*toxicity ; }, abstract = {Glutathione (GSH) is the major nonprotein thiol that can protect cells from damage due to electrophilic alkylating agents by forming conjugates with the agent. Sulfur mustard (HD) is an electrophilic alkylating agent that has potent mutagenic, carcinogenic, cytotoxic, and vesicant properties. Compounds that elevate or reduce intracellular levels of GSH may produce changes in cytotoxicity induced by sulfur mustard. Pretreatment of human peripheral blood lymphocytes (PBL) for 72 hr with 1 mM buthionine sulfoximine (BSO), which reduces intracellular GSH content to approximately 26% of control, appears to sensitize these in vitro cells to the cytotoxic effects of 10 microM HD but not to higher HD concentrations. Pretreatment of PBL for 48 hr with 10 mM N-acetyl cysteine (NAC), which elevates intracellular glutathione levels to 122% of control, appears to partially protect these in vitro cells from the cytotoxic effects of 10 microM HD but not to higher HD concentrations. Augmentation of intracellular levels of glutathione may provide partial protection against cytotoxicity of sulfur mustard.}, }
@article {pmid8389858, year = {1993}, author = {Boesgaard, S and Aldershvile, J and Poulsen, HE and Christensen, S and Dige-Petersen, H and Giese, J}, title = {N-acetylcysteine inhibits angiotensin converting enzyme in vivo.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {265}, number = {3}, pages = {1239-1244}, pmid = {8389858}, issn = {0022-3565}, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Adult ; Angiotensin I/pharmacology ; Angiotensin II/blood/pharmacology ; Angiotensin-Converting Enzyme Inhibitors/*pharmacology ; Animals ; Blood Pressure/drug effects ; Drug Interactions ; Female ; Heart Rate/drug effects ; Humans ; Isosorbide Dinitrate/pharmacology ; Kidney/drug effects/enzymology ; Male ; Peptidyl-Dipeptidase A/blood/metabolism ; Rats ; Rats, Wistar ; Renin/blood ; }, abstract = {Nitrate tolerance has been explained by 1) a direct loss of pharmacological effect due to reduced bioconversion and 2) an indirect effect due to activation of the renin/angiotensin system and counter-regulatory vasoconstriction. The sulfhydryl compound N-acetylcysteine (NAC) has been shown to attenuate and partly counteract tolerance to nitrates, and this effect has been attributed to a nitrate/sulfhydryl interaction and increased production of vasoactive intermediates. The effect of NAC on counter-regulatory mechanisms is, however, unknown. This study examined whether NAC modulates the function of the renin/angiotensin system in normal rats and in nitrate-tolerant healthy volunteers. Animal study: Conscious rats received NAC (5 mmol/kg/hr i.v., n = 8) or placebo (N-acetylserine, n = 8). Two hours of NAC infusion significantly reduced the pressor effect of angiotensin I (ANG I) by 39 +/- 14% (mean +/- SEM) and reduced angiotensin converting enzyme activity by 31% in plasma (N-acetylserine: 74 +/- 9 nmol/min/mg, NAC: 51 +/- 7) and 43% in kidney (N-acetylserine: 0.9 +/- 0.3, NAC: 0.5 +/- 0.1 nmol/min/mg protein) (P < .05). Clinical study: Isosorbide dinitrate (5 mg/hr) was infused into six male volunteers for 48 hr. NAC (2 g i.v. followed by 5 mg/kg/hr) was co-infused from 24 to 48 hr. Plasma angiotensin II (ANG II) increased during the first 24 hr of isosorbide dinitrate infusion and decreased from 28 +/- 4 to 14 +/- 2 ng/l after 2 hr of NAC infusion (P < .05). The results suggest that sulfhydryl supplementation modifies the function of the renin/angiotensin system in vivo, an effect probably mediated by inhibition of angiotensin converting enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8358544, year = {1993}, author = {Salvemini, D and Pistelli, A and Mollace, V}, title = {Release of nitric oxide from glyceryl trinitrate by captopril but not enalaprilat: in vitro and in vivo studies.}, journal = {British journal of pharmacology}, volume = {109}, number = {2}, pages = {430-436}, pmid = {8358544}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Animals ; Captopril/*pharmacology ; Cattle ; Enalapril/*pharmacology ; Endothelium, Vascular/cytology/drug effects ; Glutathione/pharmacology ; Humans ; In Vitro Techniques ; Isosorbide Dinitrate/analogs &amp; derivatives/pharmacology ; Male ; Muscle, Smooth, Vascular/cytology/drug effects ; Nitric Oxide/*metabolism ; Nitrites/metabolism ; Nitroglycerin/*metabolism ; Platelet Aggregation/drug effects ; Rats ; Rats, Wistar ; Vasodilator Agents/pharmacology ; }, abstract = {1. The hypotensive effects of glyceryl trinitrate (GTN, 0.5 mg kg-1) but not of 3-morpholino-sydnonimine (SIN-1, 0.125 mg kg-1) in anaesthetized rats were attenuated following a seven day (using a q.i.d. dosing schedule) oral treatment with isosorbide-5-mononitrate (IS-5-MN; 5 mg kg-1) indicative of the induction of tolerance to GTN but not to SIN-1. The hypotensive effects of GTN did not decline when the sulphydryl (SH) containing angiotensin converting enzyme inhibitor (ACE-1), captopril (CPT, 5 mg kg-1) or the structurally unrelated SH-containing, N-acetylcysteine (NAC, 10 mg kg-1) but not the non-SH-containing ACE-I, enalaprilat (ENA, 5 mg kg-1) were given together with IS-5-MN for the seven days treatment. 2. The attenuated hypotensive effects of GTN (0.5 mg kg-1) in rats treated with IS-5-MN were also restored when CPT (1 mg kg-1) or NAC (2.5 mg kg-1) but not ENA (1 mg kg-1) was administered intraperitoneally (i.p.) 30 min before GTN. Furthermore, in control rats, CPT or NAC but not ENA given i.p. 30 min before GTN, potentiated its haemodynamic effects. These effects were blocked by methylene blue (10 mg kg-1). At the same doses, CPT or NAC did not affect the hypotensive effects of SIN-1. 3. The reduced ability of cultured tolerant smooth muscle cells (SMC, 24 x 103 cells) or endothelial cells(EC, 40 x 103 cells) to potentiate the anti-platelet effects of GTN (44 microM) was restored by CPT or NAC but not by ENA or glutathione (all at 0.5 mM). Potentiation of the anti-platelet effects of tolerant SMC or EC by CPT or NAC was abolished by co-incubation with oxyhaemoglobin (Oxy-Hb, 10 microM)indicative of nitric oxide (NO) formation.4. When GTN (150-2400 microM) was incubated with CPT, NAC or glutathione but not ENA (all at 0.1 mM) for 30 min in Krebs buffer at 37 degrees C a concentration-dependent increase in nitrite (NO2-)formation was observed. 5. The antiplatelet effects of GTN (5.5-352 microM) were potentiated by co-incubation with CPT or NAC but not with ENA or glutathione (all at 0.5 mM). The concentration of GTN required to inhibit platelet aggregation by 50% (IC50) was 110 +/- 2 microM for GTN alone, 14 +/- 2 microM for GTN in the presence of NAC and 30 +/- 2 microM for GTN in the presence of CPT. The potentiation of the effects of GTN by CPT or NAC was inhibited by co-incubation with Oxy-Hb (10 microM). By themselves, CPT or NAC did not inhibit platelet aggregation.6. The ability of CPT to restore (a) the haemodynamic effects of GTN in tolerant rats and (b) the reduced capacity of tolerant SMC or EC to potentiate the anti-platelet effects of GTN is not related to its ACE inhibitory activity.7. CPT also potentiated the hypotensive effects of GTN in non-tolerant rats, and in vitro CPT released NO from GTN in the absence of a GTN to NO converting cell, so that it is unlikely that reversal of tolerance by CPT is due to the replenishment of intracellular thiols. Rather it can be explained by the ability of CPT to release NO from GTN in the extracellular space. This extracellular formation of NO from GTN by CPT would then compensate for the impaired enzymic biotransformation of GTN to NO that develops during tolerance as was originally proposed for NAC.}, }
@article {pmid8511501, year = {1993}, author = {Poulsen, HE and Vilstrup, H and Almdal, T and Dalhoff, K}, title = {No net splanchnic release of glutathione in man during N-acetylcysteine infusion.}, journal = {Scandinavian journal of gastroenterology}, volume = {28}, number = {5}, pages = {408-412}, doi = {10.3109/00365529309098240}, pmid = {8511501}, issn = {0036-5521}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Adult ; Female ; Glutathione/*blood/metabolism ; Humans ; Infusions, Intravenous ; Liver/metabolism ; Liver Circulation/physiology ; Liver Cirrhosis, Alcoholic/metabolism ; Male ; Middle Aged ; Splanchnic Circulation/physiology ; }, abstract = {Glutathione and amino acid concentrations were measured in arterial and hepatic vein plasma in four healthy volunteers and two patients with cirrhosis. There was no significant splanchnic efflux of glutathione (95% confidence limits, -0.501 to 0.405 mumol/min). After infusion of N-acetylcysteine (NAC) in a high dose (150 mg/kg body weight primer plus 15 mg/(h x kg BW), corresponding to treatment of acetaminophen overdose, there was no change in the splanchnic glutathione efflux (95% confidence limits, -0.531 to 0.375 mumol/min). NAC increased hepatic plasma flow rate from 0.90 +/- 0.531 min-1 to 0.97 +/- 0.11 (mean +/- SEM; p < 0.05). The effects of NAC treatment on plasma amino acids corresponded to an increased load on hepatic metabolic N conversion and transamination among nonessential amino acids. Splanchnic uptake of serine, alanine, cystine, isoleucine, and phenylalanine increased after NAC compatible with stimulated hepatic glutathione synthesis. In contrast to the rat, plasma glutathione in man probably originates mainly from extrahepatic tissues.}, }
@article {pmid8496812, year = {1993}, author = {Sargent, CA and Sleph, PG and Dzwonczyk, S and Smith, MA and Normandin, D and Antonaccio, MJ and Grover, GJ}, title = {Cardioprotection in ischemic rat hearts with the SH-containing angiotensin-converting enzyme inhibitor zofenopril: possible involvement of the ATP-sensitive potassium channel.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {265}, number = {2}, pages = {609-618}, pmid = {8496812}, issn = {0022-3565}, mesh = {Adenosine Triphosphate/*metabolism ; Angiotensin-Converting Enzyme Inhibitors/*pharmacology ; Animals ; Captopril/*analogs &amp; derivatives/pharmacology ; Coronary Vessels/drug effects ; Male ; Myocardial Contraction/drug effects ; Myocardial Ischemia/physiopathology/*prevention &amp; control ; Potassium Channels/*drug effects ; Rats ; Rats, Inbred WKY ; Rats, Sprague-Dawley ; Stereoisomerism ; }, abstract = {The SH-containing angiotensin-converting enzyme (ACE) inhibitors zofenopril and captopril have been shown to protect the ischemic myocardium independently of ACE inhibition. Zofenopril (30-100 microM) enhanced reperfusion contractile function and reduced lactate dehydrogenase release. The cardioprotective activity of zofenopril was stereoselective in isolated globally ischemic rat hearts (S, S,R stereoisomer of zofenopril was inactive). The role of ATP-sensitive potassium channel (KATP) activation was investigated using two structurally different KATP blockers, 1 microM glyburide and 100 microM sodium 5-hydroxydecanoate. The cardioprotective activity of 100 microM zofenopril was abolished by both KATP blockers. Cardioprotection with the SH-containing compound n-acetyl cysteine (300 microM) was also reversed by glyburide, further demonstrating that ACE inhibition is not a prerequisite. Isobolographic analysis demonstrated that cotreatment with zofenopril and the KATP opener cromakalim resulted in a super-additive response in the ischemic myocardium. KB analysis demonstrated glyburide was a noncompetitive antagonist in the presence of zofenopril and a competitive antagonist in the presence of cromakalim. Zofenopril has been reported to cause relaxation in aortic smooth muscle rings via an endothelium-dependent component. This relaxation was shifted to the right by both glyburide and sodium 5-hydroxydecanoate. Isobolographic analysis of zofenopril and cromakalim in smooth muscle also demonstrated a super-additive response. These results demonstrate for the first time a link between the cardioprotective effects of the SH-containing compounds zofenopril and n-acetyl cysteine and the KATP. The activity appears to be a receptor-mediated event which occurs in a manner different from classical KATP openers such as cromakalim.}, }
@article {pmid8390113, year = {1993}, author = {Hoffer, E and Avidor, I and Benjaminov, O and Shenker, L and Tabak, A and Tamir, A and Merzbach, D and Taitelman, U}, title = {N-acetylcysteine delays the infiltration of inflammatory cells into the lungs of paraquat-intoxicated rats.}, journal = {Toxicology and applied pharmacology}, volume = {120}, number = {1}, pages = {8-12}, doi = {10.1006/taap.1993.1080}, pmid = {8390113}, issn = {0041-008X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bronchoalveolar Lavage Fluid/metabolism ; Chemotactic Factors/metabolism ; Chemotaxis, Leukocyte/*drug effects/physiology ; Inflammation/prevention &amp; control ; Liver/metabolism ; Lung Diseases/*chemically induced/*immunology/metabolism/prevention &amp; control ; Male ; Neutrophils/*drug effects/physiology ; Paraquat/*toxicity ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/metabolism ; Superoxides/metabolism ; }, abstract = {We investigated a possible role for N-acetylcysteine (NAC), a well-known antioxidant and free radical scavenger, against oxidative lung damage as observed in the in vivo model of paraquat-intoxicated rats. The administration of two ip doses of 50 mg/kg NAC to paraquat-intoxicated animals did not change the glutathione status of the lungs, as determined by the measurement of nonprotein sulfhydryl (NP-SH) groups. The administration of NAC did however suppress the paraquat-induced release of chemoattractants for neutrophils in the bronchoalveolar fluid when the lavage was carried out 12 hr after the administration of 30 mg/kg paraquat. Also, in the intoxicated NAC-treated animals, the infiltration of inflammatory cells was significantly reduced, as demonstrated by the examination of the cell composition of the bronchoalveolar lavage (BAL), 24 hr after paraquat. Phorbol myristate acetate-stimulated superoxide anion production from the AM isolated from the BAL of paraquat-intoxicated nontreated animals was lower than that of controls, whereas in the NAC-treated animals, it was close to that of the controls. The obtained results indicate that NAC has a protective effect against oxidative lung damage by delaying inflammation. It also prevents the paraquat-induced reduction of superoxide anion production by stimulated AM. In the present model, however, the NAC administration regimen did not affect the survival rate of paraquat-intoxicated rats.}, }
@article {pmid8318660, year = {1993}, author = {Davis, MR and Kassahun, K and Jochheim, CM and Brandt, KM and Baillie, TA}, title = {Glutathione and N-acetylcysteine conjugates of 2-chloroethyl isocyanate. Identification as metabolites of N,N'-bis(2-chloroethyl)-N-nitrosourea in the rat and inhibitory properties toward glutathione reductase in vitro.}, journal = {Chemical research in toxicology}, volume = {6}, number = {3}, pages = {376-383}, doi = {10.1021/tx00033a020}, pmid = {8318660}, issn = {0893-228X}, support = {ES 05500/ES/NIEHS NIH HHS/United States ; RR 05543/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*metabolism ; Animals ; Carmustine/pharmacology ; Cross-Linking Reagents ; Cyanates/*metabolism ; Drug Stability ; Ethylnitrosourea/*analogs &amp; derivatives/metabolism/pharmacology ; Glutathione/analogs &amp; derivatives/chemistry/*metabolism ; Glutathione Reductase/*antagonists &amp; inhibitors ; *Isocyanates ; Liver/drug effects/enzymology ; Male ; Rats ; Rats, Sprague-Dawley ; Solutions ; }, abstract = {The antitumor agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU) is known to be unstable in aqueous solution, and to degrade spontaneously to reactive alkylating and carbamoylating intermediates. Whereas the alkylating component is believed to be responsible for the antitumor effects of this drug, it has been speculated that the carbamoylating species 2-chloroethyl isocyanate (CEIC) may mediate some of the serious adverse effects of BCNU therapy. In order to determine whether CEIC is released from BCNU in vivo, rats were administered an ip injection of the drug and a targeted search was made by ionspray LC-MS/MS techniques for the glutathione (GSH) conjugate of CEIC in bile and for the corresponding N-acetylcysteine (NAC) adduct in urine. Both of these S-linked conjugates were identified on the basis of their HPLC and MS/MS characteristics, which were identical to those of the respective reference compounds prepared by synthesis. Quantitative studies indicated that, following an ip dose of BCNU (24 mg kg-1), excretion of the GSH conjugate in bile over 4 h accounted for 3.90 +/- 0.64% of the administered dose, while excretion of the mercapturic acid derivative in urine over 24 h accounted for a further 18.1 +/- 3.3% (n = 4). Experiments conducted in vitro demonstrated that the S-linked conjugates of CEIC were of limited stability under simulated physiological conditions, decomposing to generate free GSH and NAC. In addition, both adducts inhibited rat liver glutathione reductase in vitro, when they were essentially equipotent to BCNU.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8314459, year = {1993}, author = {Ornaghi, F and Ferrini, S and Prati, M and Giavini, E}, title = {The protective effects of N-acetyl-L-cysteine against methyl mercury embryotoxicity in mice.}, journal = {Fundamental and applied toxicology : official journal of the Society of Toxicology}, volume = {20}, number = {4}, pages = {437-445}, doi = {10.1006/faat.1993.1054}, pmid = {8314459}, issn = {0272-0590}, mesh = {Abnormalities, Drug-Induced/prevention &amp; control ; Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Body Weight/drug effects ; Embryo, Mammalian/*drug effects ; Female ; Fetal Resorption/chemically induced/prevention &amp; control ; Injections, Intravenous ; Methylmercury Compounds/*antagonists &amp; inhibitors/toxicity ; Mice ; Mice, Inbred Strains ; Organ Size/drug effects ; Pregnancy ; }, abstract = {N-Acetyl-L-cysteine (NAC) has been widely used in the protection against the toxic effects produced by several chemicals because of its radical scavenger properties and because NAC is a precursor of glutathione, one of the most important intracellular defenses against oxidants. The aim of this investigation was to verify the potential protective activity of NAC against the well-known embryotoxicity induced by methyl mercuric chloride (MMC) in mice. Three experimental approaches were carried out. In the first investigation, acute treatment of MMC (25 mg/kg po) was given in CD female mice on Day 10 of pregnancy, and was followed immediately and/or after 24, 48, and 72 hr by administrations of NAC (800 mg/kg i.v.). The embryolethal effects caused by MMC poisoning were completely antagonized by just a single administration of NAC, while the incidence of palatoschisis was reduced in relation to the number of NAC administrations. In the second experiment MMC was chronically gavaged (3 mg/kg/day po) during the period of organogenesis on Days 5 to 14 of gestation. During the same period of time some of these females were also exposed to 1% NAC dissolved in drinking water. MMC poisoning reduced the body weight of viable fetuses and induced many cases of palatoschisis. The body weight of fetuses from MMC-poisoned mothers treated with NAC was improved and the incidence of palatoschisis was in the normal range. In the last experiment the treatment with NAC (400 mg/kg i.v., during the period of organogenesis) drastically reduced the severe embryolethality induced by MMC (6 mg/kg/day po) administered during the same period of time.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8484801, year = {1993}, author = {Hobbs, MJ and Butterworth, M and Cohen, GM and Upshall, DG}, title = {Structure-activity relationships of cysteine esters and their effects on thiol levels in rat lung in vitro.}, journal = {Biochemical pharmacology}, volume = {45}, number = {8}, pages = {1605-1612}, doi = {10.1016/0006-2952(93)90301-c}, pmid = {8484801}, issn = {0006-2952}, mesh = {Animals ; Cysteine/*analogs &amp; derivatives/metabolism/pharmacology ; Esters/metabolism/*pharmacology ; Female ; In Vitro Techniques ; Liver/metabolism ; Lung/*metabolism ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; Sulfhydryl Compounds/*metabolism ; Time Factors ; }, abstract = {Pretreatment with cysteine esters increases cysteine (CySH) levels in rat lung and protects against the lethal effects of inhaled perfluoroisobutene in vivo. There are marked differences in the duration of protection achieved with different cysteine esters. In this study we have compared the uptake and metabolism of CySH, N-acetyl cysteine (NAc), cysteine esters and cystine esters in vitro using rat lung and liver homogenates and lung slices. Liver homogenates metabolized CySH and cysteine esters faster than lung homogenates. The half life (T1/2) of CySH in lung was 58.8 +/- 17.3 min and in liver was 14.0 +/- 1.6 min (mean +/- SEM). T1/2 of the esters in lung ranged between 6.5 and 12.1 min and in liver between 1.9 and 5.3 min. Cysteine tertiary butyl ester, which does not protect in vivo, was not hydrolysed to CySH by lung or liver homogenates. All esters increased and prolonged intracellular CySH concentrations in lung slices to a much greater extent than CySH itself. NAc did not raise intracellular CySH above that of the controls and no NAc appeared within the slice. After CySH incubation intracellular CySH was 0.9 +/- 0.1 nmol/mg wet wt at 10 min whereas after incubation with the esters it ranged between 2.60 and 3.65 nmol/mg wet wt. Cysteine cyclohexyl ester prolonged the increase of CySH the longest and cysteine methyl ester the shortest. CySH levels with cysteine cyclohexyl ester were 2.74 +/- 0.15 and 4.13 +/- 0.37 nmol/mg wet wt at 10 and 60 min, respectively, whereas with cysteine methyl ester, CySH levels were 2.60 +/- 0.5 and 1.25 +/- 0.08 nmol/mg wet wt at similar times. Cystine esters increased intracellular concentrations of both cystine and CySH. CySH concentrations ranged between 2.92 and 3.19 nmol/mg wet wt and cystine between 1.39 and 1.47 nmol/mg wet wt at 60 min. The elevation and duration of CySH in lung slices is well correlated with the duration of protection against perfluoroisobutene achieved in vivo.}, }
@article {pmid8492774, year = {1993}, author = {Feddersen, CO and Barth, P and Püchner, A and von Wichert, P}, title = {[N-acetylcysteine decreases functional and structural, ARDS-typical lung changes in endotoxin-treated rats].}, journal = {Medizinische Klinik (Munich, Germany : 1983)}, volume = {88}, number = {4}, pages = {197-206}, pmid = {8492774}, issn = {0723-5003}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Endotoxins/*pharmacology ; Lung/pathology ; Perfusion ; Rats ; *Reactive Oxygen Species ; Respiratory Distress Syndrome/*pathology ; *Salmonella enteritidis ; Ventilation-Perfusion Ratio/*drug effects ; }, abstract = {Oxygen radicals and oxygen radical mediators derived from activated granulocytes are important components in the development of acute lung injury, namely the adult respiratory distress syndrome ARDS. N-acetylcysteine (NAC) is one important substance for endogenous production of reduced glutathion, which is known to be an intra- and extracellular reducing agent also found in lung tissue. We evaluated the effect of exogenous NAC on the endotoxin induced development and course of ARDS in rats. ARDS-like injury was induced in rats via intraperitoneal injection of Salmonella enteritidis endotoxin 30 mg/kg body weight. NAC or solvent was injected intraperitoneally 30 min prior to, at the time of and 30 min after injection of endotoxin respectively with 150 mg/kg body weight each dose. Endotoxin injection in rats resulted in 80% mortality within 72 hours, increased lung wet weight, severe ultrastructural lung damage as measured by histological methods. In isolated, ventilated, with physiological salt solution perfused rat lungs vasocontractility was severely blunted, lung albumin leakage was increased, thromboxane B2 (TXB2) and 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) perfusate levels were increased. NAC treatment significantly improved survival of endotoxin treated rats, ameliorated structural lung damage, diminished lung wet weight and lung albumin leakage, lowered lung perfusate TXB2 and 6-keto-PGF1 alpha levels and slightly improved vasocontractility in isolated perfused lungs. Therefore, NAC significantly ameliorates ARDS-like lung injury in rats, when given in vivo.}, }
@article {pmid8512745, year = {1993}, author = {Staal, FJ and Roederer, M and Raju, PA and Anderson, MT and Ela, SW and Herzenberg, LA and Herzenberg, LA}, title = {Antioxidants inhibit stimulation of HIV transcription.}, journal = {AIDS research and human retroviruses}, volume = {9}, number = {4}, pages = {299-306}, doi = {10.1089/aid.1993.9.299}, pmid = {8512745}, issn = {0889-2229}, support = {CA42509/CA/NCI NIH HHS/United States ; R0I AI31770/AI/NIAID NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Antioxidants/*pharmacology ; Cells, Cultured ; Gene Expression Regulation, Viral/drug effects ; Glutathione/pharmacology ; HIV/*drug effects/genetics/physiology ; HIV Long Terminal Repeat ; Humans ; NF-kappa B/metabolism ; Serine/analogs &amp; derivatives/pharmacology ; Transcription, Genetic/*drug effects ; Virus Replication/drug effects ; }, abstract = {In studies presented here, we demonstrate that antioxidants regulate NF-kappa B activation and signal transduction pathways leading to HIV expression. We show (1) that N-acetyl-L-cysteine (NAC), an antioxidant and an efficient glutathione (GSH) precursor, inhibits NF-kappa B activation and HIV expression under conditions in which GSH is depleted and NAC cannot be converted to GSH, (2) that the D-stereoisomer of NAC and a wide variety of chemically unrelated antioxidants also inhibit NF-kappa B activation and/or transcription directed by the HIV LTR, and (3) that depletion of GSH, the principal intracellular antioxidant, augments HIV production in an acute infection model. Taken together, these findings suggest direct antioxidant action as the mechanism for inhibition of HIV transcription by NAC. They also confirm that GSH, acting in its capacity as an antioxidant, regulates HIV expression and that exogenous antioxidants can potentiate this regulation.}, }
@article {pmid8096862, year = {1993}, author = {van den Broeke, LT and Beyersbergen van Henegouwen, GM}, title = {UV-radiation protecting efficacy of thiols, studied with UVA-induced binding of 8-MOP and CPZ to rat epidermal biomacromolecules in vivo.}, journal = {International journal of radiation biology}, volume = {63}, number = {4}, pages = {493-500}, doi = {10.1080/09553009314550651}, pmid = {8096862}, issn = {0955-3002}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Captopril/therapeutic use ; Chlorpromazine/metabolism ; Cysteamine/therapeutic use ; Epidermis/drug effects/metabolism/radiation effects ; Ergothioneine/therapeutic use ; Female ; Mesna/therapeutic use ; Methoxsalen/metabolism ; Penicillamine/therapeutic use ; Radiation-Protective Agents/*therapeutic use ; Rats ; Rats, Wistar ; Sulfhydryl Compounds/*therapeutic use ; Tiopronin/therapeutic use ; *Ultraviolet Rays ; }, abstract = {The following topically-applied thiols were investigated with regard to their possible UV-radiation protective properties: captopril, cysteamine, ergothioneine, mesna, mercaptopropionylglycine, N-acetyl-cysteine and penicillamine. As a measure for protection the inhibition of in vivo irreversible photobinding of the labelled phototoxic drugs chlorpromazine (CPZ) and 8-methoxypsoralen (8-MOP) to rat epidermal biomacromolecules was used. Ergothioneine, mesna and penicillamine did not show any effect; probably, as a result of their charge they are not able to enter the stratum corneum. Captopril, cysteamine, mercaptopropionylglycine and N-acetylcysteine showed a considerable inhibition of CPZ and 8-MOP photobinding. Captopril and N-acetylcysteine were clearly the most potent whereas cysteamine was the least effective. Captopril, mercaptopropionylglycine and N-acetylcysteine appeared to have a wider action range and to be a more effective protector than dl-alpha-tocopherol and di-butyl-hydroxytoluene. Cysteamine and mercaptopropionylglycine were only capable of protecting the stratum corneum. Captopril and N-acetylcysteine on the other hand showed an additional dose-dependent inhibition of photobinding to the viable epidermis. Gradually with increasing time after application, the protecting efficacy with regard to the viable layer of the epidermis decreased; the duration of protection depending on the dose.}, }
@article {pmid8487592, year = {1993}, author = {Gressier, B and Cabanis, A and Lebegue, S and Brunet, C and Dine, T and Luyckx, M and Cazin, M and Cazin, JC}, title = {Comparison of in vitro effects of two thiol-containing drugs on human neutrophils hydrogen peroxide production.}, journal = {Methods and findings in experimental and clinical pharmacology}, volume = {15}, number = {2}, pages = {101-105}, pmid = {8487592}, issn = {0379-0355}, mesh = {Acetylcysteine/*pharmacology ; Humans ; Hydrogen Peroxide/*metabolism ; Mesna/*pharmacology ; Neutrophils/*drug effects/metabolism ; Oxidation-Reduction ; }, abstract = {During inflammatory disorders, potentially destructive reactive oxygen species, especially hydrogen peroxide, are produced by activated phagocytic cells. It was demonstrated in vitro that mesna and N-acetylcysteine (NAC), mucolytic thiols, have antioxidant properties. An estimation was made of the 50% inhibitory concentration (IC50) of mesna and NAC for PMA-induced H2O2 production by human neutrophils, the results being 70 mcM and 77 mcM, respectively. The mechanism which governs mesna and NAC reactions results from a scavenging effect of H2O2: the calculated IC50s of this effect were 30 mcM and 42 mcM, respectively, in free cellular experimentation. The results suggest that mesna and NAC might be used as antioxidants in aerosols to prevent tissue damage inflicted by this reactive oxygen species, especially in the lungs.}, }
@article {pmid8472835, year = {1993}, author = {Sala, R and Moriggi, E and Corvasce, G and Morelli, D}, title = {Protection by N-acetylcysteine against pulmonary endothelial cell damage induced by oxidant injury.}, journal = {The European respiratory journal}, volume = {6}, number = {3}, pages = {440-446}, pmid = {8472835}, issn = {0903-1936}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Alveolitis, Extrinsic Allergic/*drug therapy/immunology ; Animals ; Antigen-Antibody Complex/immunology ; Endothelium/metabolism ; *Free Radical Scavengers ; Glutathione/biosynthesis ; Lung/*metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/*adverse effects ; Serotonin/metabolism ; }, abstract = {The protective effect of N-acetylcysteine (NAC) against oxidant lung injury was investigated in a model of acute immunological alveolitis in the rat. Intrapulmonary immune complex deposition into rat lungs, induced by intratracheal infusion of immunoglobulin G (IgG) anti-bovine serum albumin (BSA) antibodies and intravenous injection of the antigen, caused lung damage associated with a marked decrease in [14C]5-hydroxytryptamine ([14C]5HT) uptake capacity, taken as a biochemical marker of endothelial cell function. The oral administration of a single dose of NAC (2 mmol.kg-1) 60 min before antigen/antibody (Ag/Ab) treatment was effective in preventing pulmonary endothelial cell [14C]5HT uptake loss induced by immune complex deposition. The mechanisms involved in this lung protective action of NAC were investigated by studying the antioxidant activity of NAC on hypoxanthine/xanthine oxidase-induced lung damage in vitro, and the effectiveness of the drug as lung glutathione (reduced form) (GSH) precursor in diethylmaleate-depleted rats. The results obtained provide further evidence on the ability of NAC to reduce the susceptibility of lung tissue to free radical-induced damage, by potentiating the antioxidant defence systems.}, }
@article {pmid8460697, year = {1993}, author = {Barreto, JC and Smith, GS and Tornwall, MS and Miller, TA}, title = {Protective action of oral N-acetylcysteine against gastric injury: role of hypertonic sodium.}, journal = {The American journal of physiology}, volume = {264}, number = {3 Pt 1}, pages = {G422-6}, doi = {10.1152/ajpgi.1993.264.3.G422}, pmid = {8460697}, issn = {0002-9513}, support = {DK-25838/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Female ; Gastric Mucosa/drug effects/injuries/pathology ; Hypertonic Solutions ; Rats ; Rats, Sprague-Dawley ; Serine/administration &amp; dosage/analogs &amp; derivatives/pharmacology ; Sodium/*physiology ; Stomach Diseases/pathology/physiopathology/*prevention &amp; control ; Stomach Ulcer/prevention &amp; control ; }, abstract = {N-acetylcysteine (NAC), when administered orally as a 20% solution, is a potent protective agent against gastric injury in the rat stomach induced by absolute ethanol. The present study was undertaken to define the means by which this protection is mediated. The notion that NAC acts as a glutathione precursor was excluded when N-acetylserine (NAS) was noted to be equally protective against alcohol injury. The NAS molecule contains a hydroxyl moiety at the site where NAC contains a sulfhydryl. To orally administer 20% NAC at a neutral pH, NaOH is added to the free acid form to keep NAC in solution. We determined by titration that a sodium concentration of 1.2 M results. Thus it became apparent that the protective effect of NAC might be mediated through the sodium employed to titrate NAC. Accordingly, we examined various sodium salts and assessed their relative protective effects against alcohol injury. Both sodium acetate and sodium chloride in 1 M solutions were found to be equally effective in preventing alcohol injury with the same efficiency as 1 M sodium solutions of NAC and NAS, excluding the acetate portion of NAC and NAS as being of primary importance for protection to occur. Further study, using different concentrations of sodium chloride (i.e., 150-1,000 mM) revealed that the 1 M solution was most optimal in preventing alcohol injury. One molar sodium by itself and when administered as part of the NAC solution also prevented gastric injury by concentrated acid and base.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8443968, year = {1993}, author = {Gatti, S and Faggioni, R and Echtenacher, B and Ghezzi, P}, title = {Role of tumour necrosis factor and reactive oxygen intermediates in lipopolysaccharide-induced pulmonary oedema and lethality.}, journal = {Clinical and experimental immunology}, volume = {91}, number = {3}, pages = {456-461}, pmid = {8443968}, issn = {0009-9104}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antibodies, Monoclonal ; Bronchoalveolar Lavage Fluid/immunology ; Chlorpromazine/pharmacology ; Dexamethasone/pharmacology ; Disease Models, Animal ; Endotoxins ; Lipopolysaccharides ; Male ; Mice ; Mice, Inbred BALB C ; Neutrophils/immunology ; Pulmonary Edema/etiology/*immunology ; Reactive Oxygen Species/*pharmacology ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/biosynthesis/*physiology ; }, abstract = {The purpose of this study was to characterize the role of tumour necrosis factor (TNF) and neutrophils (PMN) in the pathogenesis of pulmonary oedema induced by endotoxin (lipopolysaccharide (LPS)). Intraperitoneal administration to BALB/c mice of 0.6-1 mg of LPS caused pulmonary oedema and lethality. This was associated with production of TNF in serum and bronchoalveolar lavage fluid and with accumulation of PMN in the lung. In this experimental model, we could block TNF production by different means: pretreatment 30 min before LPS with 4 mg/kg of i.p. chlorpromazine (CPZ), 3 mg/kg of i.p. dexamethasone (DEX), 1 g/kg p.o. of N-acetylcysteine (NAC, an antioxidant precursor of glutathione), or an anti-TNF MoAb. CPZ, DEX and anti-TNF completely prevented LPS lethality but not pulmonary oedema or pulmonary PMN infiltration, indicating that: (i) lung oedema is not the main cause of death after LPS; and (ii) lung oedema induced by LPS is not mediated by TNF. Pretreatment with NAC not only inhibited TNF production but also protected against LPS-induced pulmonary oedema, indicating that reactive oxygen intermediates are implicated. NAC also blocked TNF production in blood and in bronchoalveolar lavage. We also tested the effect of PMN depletion induced with cyclophosphamide (CP) or 5-fluorouracil (5-FU). While no pulmonary PMN infiltrate was observed in PMN-depleted mice, neutropenia did not prevent LPS lethality or oedema, indicating PMN do not play an important role in the toxic effects of LPS in this experimental model.}, }
@article {pmid8319635, year = {1993}, author = {De Flora, S and Izzotti, A and D'Agostini, F and Rossi, GA and Balansky, RM}, title = {Pulmonary alveolar macrophages in molecular epidemiology and chemoprevention of cancer.}, journal = {Environmental health perspectives}, volume = {99}, number = {}, pages = {249-252}, pmid = {8319635}, issn = {0091-6765}, mesh = {7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/analysis ; Acetylcysteine/pharmacology ; Adolescent ; Adult ; Aged ; Animals ; Benzo(a)pyrene/toxicity ; DNA/analysis ; *DNA Adducts ; Female ; Humans ; Macrophages, Alveolar/chemistry/*drug effects/ultrastructure ; Male ; Micronuclei, Chromosome-Defective/drug effects/ultrastructure ; Middle Aged ; Neoplasms/*prevention &amp; control ; Rats ; Rats, Sprague-Dawley ; Smoking/pathology ; }, abstract = {In addition to possessing an extraordinary sweeping activity, pulmonary alveolar macrophages (PAM) are equipped with the biochemical mechanisms involved in the metabolism of carcinogens, which were found to be inducible in humans by cigarette smoke. Moreover, several defense processes were stimulated in rat PAM after in vivo administration of the anticarcinogen N-acetylcysteine (NAC). Benzo[a]pyrene diol epoxide (BPDE)-DNA adducts, as revealed by synchronous fluorescence spectrophotometry, were selectively detected in PAM of smokers and persisted up to 6 months. The amount of adducts was significantly correlated with the number of currently smoked cigarettes but not with the cigarettes smoked in a lifetime (pack-years). Nevertheless, deviations from the regression line pointed out the role of interindividual variability factors in adduct formation. Probably due to the low mitotic rate of PAM in the respiratory lumen, the frequency of micronuclei was not enhanced in smokers. However, parallel assays in rats showed that micronuclei can be enhanced after massive intratracheal administration of benzo[a]pyrene or whole-body exposure to high amounts of mainstream cigarette smoke, which also induced BPDE-DNA adducts in lung cells and other organs, including the heart. All these adverse effects were markedly inhibited by the oral administration of NAC, which provides the premise and rationale for a future study on the protective effects of oral NAC in heavy smokers.}, }
@article {pmid8452559, year = {1993}, author = {Langley, SC and Kelly, FJ}, title = {N-acetylcysteine ameliorates hyperoxic lung injury in the preterm guinea pig.}, journal = {Biochemical pharmacology}, volume = {45}, number = {4}, pages = {841-846}, doi = {10.1016/0006-2952(93)90167-u}, pmid = {8452559}, issn = {0006-2952}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Catalase/metabolism ; Disease Models, Animal ; Female ; Glutathione/analysis/pharmacology ; Glutathione Peroxidase/metabolism ; Guinea Pigs ; Humans ; Infant, Newborn ; Infant, Premature, Diseases/*prevention &amp; control ; Lung/*drug effects/metabolism/pathology ; Lung Diseases/*prevention &amp; control ; Oxygen/*toxicity ; Proteins/analysis ; Ventilators, Mechanical/adverse effects ; }, abstract = {The therapeutic efficacy of N-acetylcysteine (NAC) in the management of hyperoxia-induced lung injury was assessed using the preterm guinea pig model of prematurity. Preterm guinea pig pups were delivered by Caesarean section 3 days preterm, and exposed to either 21 or 95% oxygen for 72 hr. NAC (200 mg/kg body weight) or saline was injected twice daily. Bronchoalveolar lavage fluid (BALF) from hyperoxia-exposed pups contained significantly higher protein concentrations and an increased number of neutrophils. NAC partly ameliorated lung injury, preventing the increase in BALF protein concentration, which is generally associated with oedema. There was no effect on the movement of neutrophils into the lung airspaces in response to oxygen. Treatment with NAC had no effect on lung or liver glutathione (reduced) (GSH) concentrations either after 2 hr post-administration, or over the full 72 hr experimental period. An apparent resistance of the lung to increased synthesis or uptake of GSH was demonstrated by the lack of effect of direct administration of GSH, its isopropyl ester or 2-oxo-4-thiazolidine carboxylic acid. Oxygen exposure alone (95%) increased lung concentrations by 60-70%. It would, therefore, appear from this data that NAC may have potential as a future component of antioxidant therapy, although its effects are not mediated through increased GSH levels.}, }
@article {pmid8430104, year = {1993}, author = {Kuo, SS and Saad, AH and Koong, AC and Hahn, GM and Giaccia, AJ}, title = {Potassium-channel activation in response to low doses of gamma-irradiation involves reactive oxygen intermediates in nonexcitatory cells.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {90}, number = {3}, pages = {908-912}, pmid = {8430104}, issn = {0027-8424}, support = {5T32 CA 09302/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Cell Line ; Dose-Response Relationship, Radiation ; Electric Conductivity ; Free Radical Scavengers ; Free Radicals ; *Gamma Rays ; Hydrogen Peroxide/pharmacology ; Microelectrodes ; Oxygen/*metabolism ; Potassium/*metabolism ; Potassium Channels/drug effects/metabolism/*radiation effects ; Protein Kinase C/metabolism ; }, abstract = {Active oxygen species are generated during pathophysiologic conditions such as inflammation and ionizing radiation exposure. We tested the hypothesis that an early cellular event in response to these species involves regulation of ion channels. We exposed cells to gamma-irradiation or treated them with hydrogen peroxide, xanthine/xanthine oxidase, or [3H]thymidine and then monitored channel activity by the technique of whole-cell voltage clamping. Recordings showed that both normal and tumor cells exhibit an increase in K+ currents after treatment with radiation, H2O2, and xanthine/xanthine oxidase but not with high specific activity [3H]thymidine, suggesting that the signal for K+ channel activation originates at the cell membrane. A single noncytotoxic dose of 10 cGy induced measurable levels of K+ currents, suggesting that the induction of currents regulates biochemical changes in response to stress. To test whether channel activity is sensitive to active oxygen species, we pretreated cells with N-acetyl-L-cysteine (NAC) to increase cellular pools of free radical scavengers before radiation. In NAC-pretreated cells, K+ channel activation by gamma-irradiation was abolished. It has previously been shown that protein kinase C (PKC) is activated by ionizing radiation and can regulate K+ channels in some cells. However, the effect of radiation on induction of K+ channel activity was independent of PKC, since cells chronically exposed to phorbol esters still produced K+ currents after radiation. These results suggest that an early cellular response to oxidative stress is the activation of K+ channels.}, }
@article {pmid8425299, year = {1993}, author = {Boesgaard, S and Poulsen, HE and Aldershvile, J and Loft, S and Anderson, ME and Meister, A}, title = {Acute effects of nitroglycerin depend on both plasma and intracellular sulfhydryl compound levels in vivo. Effect of agents with different sulfhydryl-modulating properties.}, journal = {Circulation}, volume = {87}, number = {2}, pages = {547-553}, doi = {10.1161/01.cir.87.2.547}, pmid = {8425299}, issn = {0009-7322}, mesh = {Animals ; Aorta/*metabolism ; Buthionine Sulfoximine ; Cysteine/metabolism ; Female ; Glutathione/metabolism ; Intracellular Membranes/*metabolism ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Nitroglycerin/*pharmacology ; Rats ; Rats, Wistar ; Sulfhydryl Compounds/*blood/metabolism ; Time Factors ; Vena Cava, Superior/*metabolism ; }, abstract = {BACKGROUND: Changes in sulfhydryl (SH) compound availability may alter the hemodynamic effect of nitroglycerin (NTG). Data on the relation between NTG effect and thiol levels are, however, limited to in vitro experiments. The present study investigates how intracellular and extracellular changes in SH group concentrations (cysteine and glutathione [GSH]) affect the responsiveness to NTG in vivo.<br><br>METHODS AND RESULTS: GSH and cysteine levels in plasma, vena cava, and aorta were measured after administration of N-acetylserine (placebo, n = 6), N-acetylcysteine (NAC, extracellular and intracellular SH donor, n = 6), oxothiazolidine (OXO, intracellular SH donor, n = 6), buthionine sulfoximine (BSO, intracellular GSH-depleting agent, n = 6), BSO+NAC (n = 6), and BSO+OXO (n = 6) in chronically catheterized conscious rats. In addition, the effect of 2.5 mg NTG/kg i.v. on mean arterial pressure (MAP) was determined before and after the same treatment. NAC (5 mmol/kg i.v. for 2 hours) significantly (p < 0.05) increased extracellular cysteine and GSH levels and potentiated the hypotensive effect of NTG (from 26 +/- 3 to 31 +/- 4 mm Hg [mean +/- SEM], p < 0.05). OXO (5 mmol.kg-1 x hr-1 i.v. for 2 hours) significantly increased intracellular cysteine and GSH levels but had no effect on NTG responsiveness (p > 0.05). BSO (1 g i.p. three times within 24 hours) significantly decreased intracellular GSH levels (p < 0.05) and attenuated the effect of NTG (from 28 +/- 3 to 16 +/- 2 mm Hg).<br><br>CONCLUSIONS: The results suggest that the acute hypotensive effect of NTG in vivo is: 1) increased by high extracellular GSH and/or cysteine levels (NAC), 2) decreased by low intracellular GSH levels (BSO), and 3) unaffected by high intracellular levels of cysteine and GSH (OXO).}, }
@article {pmid7679409, year = {1993}, author = {Lioy, J and Ho, WZ and Cutilli, JR and Polin, RA and Douglas, SD}, title = {Thiol suppression of human immunodeficiency virus type 1 replication in primary cord blood monocyte-derived macrophages in vitro.}, journal = {The Journal of clinical investigation}, volume = {91}, number = {2}, pages = {495-498}, pmid = {7679409}, issn = {0021-9738}, support = {MH 47422/MH/NIMH NIH HHS/United States ; NS 27405/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Cell Survival/drug effects ; Cells, Cultured ; Fetal Blood/*microbiology ; Glutathione/*pharmacology ; HIV Reverse Transcriptase ; HIV-1/*drug effects/pathogenicity ; Humans ; Infant, Newborn ; Macrophages/*microbiology ; RNA-Directed DNA Polymerase/analysis ; Virus Replication/*drug effects ; }, abstract = {We investigated the effects of glutathione (GSH), the major naturally occurring thiol, and a pharmacologic thiol precursor of GSH, N-acetyl cysteine (NAC), on the expression of human immunodeficiency type 1 (HIV-1) in primary cord blood and adult donor monocyte-derived macrophages (MDM). HIV-1 infection of cord blood and adult MDM was accomplished after incubating 10-15-d-old cultures for 4 h with a monocyte-tropic strain of HIV-1 (Bal). After 1 wk in culture cell supernatants were tested for reverse transcriptase (RT) activity. MDM were exposed to 5, 10 and 20 mM concentrations of both GSH and NAC before infection, during infection, and after infection was established. GSH and NAC suppressed the replication of HIV-1 in both primary cord blood and adult donor MDM in a concentration dependent fashion. These suppressive effects were more pronounced in cord-derived cells than in adult-derived cells. In cells treated with GSH or NAC before infection, there was no significant rise in RT activity as compared with controls. Similarly, when cells were treated with GSH and NAC and simultaneously infected, there was also no significant rise in RT activity after 1 wk in culture. In cells treated after infection was established, RT values were suppressed 80-90% that of untreated controls. This effect persisted for 1-2 wk after exposure to GSH and NAC. Untreated controls demonstrated syncytium formation and lost characteristics of spreading and elongation 2 wk after HIV-1 infection, whereas most of the treated cells remained free of syncytium and retained cytoplasmic spreading, adherence, and elongation. These data are consistent with other studies of thiol suppression of HIV-1 replication and demonstrate a similar observation for primary cultured cord MDM. These results may offer new approaches toward cellular protection after infection with HIV-1.}, }
@article {pmid8442009, year = {1993}, author = {MacFarlane, M and Schofield, M and Parker, N and Roelandt, L and David, M and Lock, EA and King, LJ and Goldfarb, PS and Gibson, GG}, title = {Dose-dependent induction or depression of cysteine conjugate beta-lyase in rat kidney by N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine.}, journal = {Toxicology}, volume = {77}, number = {1-2}, pages = {133-144}, doi = {10.1016/0300-483x(93)90144-h}, pmid = {8442009}, issn = {0300-483X}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives/toxicity ; Animals ; Blood Urea Nitrogen ; Blotting, Western ; Butadienes/administration &amp; dosage/*toxicity ; *Carbon-Sulfur Lyases ; Cytosol/enzymology ; Depression, Chemical ; Dose-Response Relationship, Drug ; Enzyme Induction/drug effects ; Enzyme-Linked Immunosorbent Assay ; Female ; Injections, Intraperitoneal ; Kidney/*drug effects/*enzymology ; Lyases/analysis/*biosynthesis ; Mitochondria/enzymology ; RNA, Messenger/analysis ; Rats ; Transaminases/analysis ; }, abstract = {The influence of N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine (NAc-PCBD) on cysteine conjugate beta-lyase in female rat kidney has been examined. After a single, non-nephrotoxic dose of NAc-PCBD (3 mg/kg), cytosolic beta-lyase enzyme activity was increased 1.5 to 3-fold commensurate with a corresponding increase in enzyme protein levels as assessed by both Western blot and ELISA analyses. Using a cDNA probe for beta-lyase, this induction was found to be accompanied by an increase in the cognate mRNA. In contrast, a higher, nephrotoxic dose of NAc-PCBD (10 mg/kg) decreased all the above parameters. These effects appeared to be specific to the cytosolic form of the enzyme as no changes in kidney mitochondrial beta-lyase or enzyme protein levels were observed. Repeated dosing with the lower dose level (3 mg/kg) resulted in either no change, or in some instances, a reduction in the above parameters, suggesting an accumulation of the xenobiotic and a masking of the induction phenomenon. The molecular mechanisms underlying these observations are discussed in terms of the nephrotoxicity of halogenated xenobiotics.}, }
@article {pmid8469780, year = {1993}, author = {Appenroth, D and Winnefeld, K}, title = {Role of glutathione for cisplatin nephrotoxicity in young and adult rats.}, journal = {Renal failure}, volume = {15}, number = {2}, pages = {135-139}, doi = {10.3109/08860229309046144}, pmid = {8469780}, issn = {0886-022X}, mesh = {Acetylcysteine/pharmacology ; Aging/*drug effects/metabolism ; Animals ; Antimetabolites/pharmacology ; Buthionine Sulfoximine ; Cisplatin/*toxicity ; Drug Interactions ; Female ; Glutathione/antagonists &amp; inhibitors/*drug effects/metabolism ; Kidney/*drug effects/metabolism ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Rats ; Rats, Wistar ; }, abstract = {Investigations were done in 10- and 55-day-old Wistar rats. Glutathione (GSH) level in kidney was decreased by 8 mmol buthionine sulfoximine (BSO)/100 g BW. There was no effect on the renal function and nephrotoxicity of cisplatin (0.6 mg CP/100 g BW) in adult rats. In young rats BSO treatment was followed by nephrotoxic effects. Pt concentration remained unaffected by BSO in young and adult rats. GSH concentration in kidney was increased by 100 mg acetyl-cysteine (accys)/100 g BW. CP nephrotoxicity was lower in young as well as in adult ac-cys-treated rats. Pt levels in renal tissue were significantly decreased in rats from both age groups. From our results we conclude that the beneficial effect of high GSH concentration in renal tissue on CP nephrotoxicity is the result of decreased Pt concentration in kidney.}, }
@article {pmid8453693, year = {1993}, author = {Benjamin, RS and Legha, SS and Patel, SR and Nicaise, C}, title = {Single-agent ifosfamide studies in sarcomas of soft tissue and bone: the M.D. Anderson experience.}, journal = {Cancer chemotherapy and pharmacology}, volume = {31 Suppl 2}, number = {}, pages = {S174-9}, pmid = {8453693}, issn = {0344-5704}, mesh = {Acetylcysteine/therapeutic use ; Bone Neoplasms/*drug therapy ; Fluid Therapy ; Humans ; Ifosfamide/adverse effects/*therapeutic use ; Mesna/therapeutic use ; Randomized Controlled Trials as Topic ; Sarcoma/*drug therapy ; Soft Tissue Neoplasms/*drug therapy ; Treatment Outcome ; Urinary Bladder Diseases/chemically induced/*prevention &amp; control ; }, abstract = {We have used ifosfamide to treat patients with sarcomas in four completed single-agent protocols and one pilot study since 1985. All the studies have used either N-acetyl-L-cysteine (NAC) or mesna as a uroprotective agent, except in one arm of one study where hydration alone was employed. Mesna has proven superior to NAC in providing protection against ifosfamide-induced hematuria. Mesna given as a loading dose followed by continuous 24-h infusion has been effective and most practical in this regard. Ifosfamide has demonstrated clinically useful antitumor activity in our hands against most sarcoma subtypes. Our studies suggest a dose-response relationship for ifosfamide. At a total dose of 6 g/m2 per course, the overall response rate was 10%; at 10 g/m2 per course, it rose to 21%. Future clinical trials will determine ifosfamide's role in combination chemotherapy and more clearly define the best schedule or schedules for the uroprotective administration of mesna.}, }
@article {pmid8443125, year = {1993}, author = {Eylar, E and Rivera-Quinones, C and Molina, C and Báez, I and Molina, F and Mercado, CM}, title = {N-acetylcysteine enhances T cell functions and T cell growth in culture.}, journal = {International immunology}, volume = {5}, number = {1}, pages = {97-101}, doi = {10.1093/intimm/5.1.97}, pmid = {8443125}, issn = {0953-8178}, support = {1-G-12RR03050/RR/NCRR NIH HHS/United States ; 1-S06-RR08239/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology/toxicity ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; CD3 Complex/immunology ; Cell Adhesion/immunology ; Cell Division/immunology ; Cell Survival/drug effects ; Cells, Cultured ; Concanavalin A/immunology ; Humans ; Interleukin-2/biosynthesis ; Lymphocyte Activation/drug effects ; Middle Aged ; Mitosis/drug effects ; T-Lymphocytes/cytology/*drug effects/immunology/physiology ; }, abstract = {N-Acetylcysteine (NAC) is highly nontoxic for peripheral blood T cells and immunostimulatory enhancing T cell functions such as mitogenesis, interleukin-2 (IL-2) production, and growth in culture. NAC has been proposed for the treatment of AIDS based on its inhibition of human immunodeficiency virus (HIV) replication in cultured cells. Therefore its effect on normal T cells from 10 young donors and one elderly donor has been investigated as a prelude to clinical consideration. T cell function was evaluated in the presence and absence of accessory cells. With concanavalin A and anti-CD3 activation, NAC enhanced mitogenesis by approximately 2- to 2.5-fold at 5-10 mM. Mitogenesis of purified T cells with anti-CD2 was not affected by NAC; in the presence of accessory cells, NAC enhanced mitogenesis by approximately 2-fold at 1-10 mM. Importantly, NAC levels above 10 mM completely inhibited activation of peripheral blood mononuclear cells by anti-CD2. IL-2 secreted by T cells was also enhanced by NAC, approximately 1.5-fold, but IL-2 secreted by cells from old donors was enhanced by 3-fold. In cultures of peripheral blood T cells, NAC (10 mM) stimulated growth by at least 4- to 6-fold after two passages. These results show that NAC, nontoxic even at 20 mM, is an effective enhancer of T cell function and a remarkable enhancer of growth. Results from other laboratories show that NAC, which increases glutathione levels, suppresses HIV replication presumably via suppression of the activation of transcriptional factor NF-kappa B.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8441757, year = {1993}, author = {Dröge, W}, title = {Cysteine and glutathione deficiency in AIDS patients: a rationale for the treatment with N-acetyl-cysteine.}, journal = {Pharmacology}, volume = {46}, number = {2}, pages = {61-65}, doi = {10.1159/000139029}, pmid = {8441757}, issn = {0031-7012}, mesh = {Acetylcysteine/*therapeutic use ; Acquired Immunodeficiency Syndrome/blood/*drug therapy/immunology ; Amino Acids/blood ; Cysteine/*deficiency ; Glutathione/*deficiency ; Humans ; T-Lymphocytes/metabolism ; }, abstract = {A series of clinical studies and laboratory investigations suggests that the acquired immunodeficiency syndrome (AIDS) may be the consequence of a virus-induced cysteine deficiency. HIV-infected persons at all stages of the disease were found to have decreased plasma cystine and cysteine concentrations and decreased intracellular glutathione levels. In rhesus macaques, cysteine levels decrease already within 1-2 weeks after infection with the closely related virus SIVmac. HIV-infected persons and SIV-infected rhesus macaques have also, on the average, substantially increased plasma glutamate levels. Increased glutamate levels aggravate the cysteine deficiency by inhibiting the membrane transport of cystine. Even moderately elevated extracellular glutamate levels as they occur in HIV-infected persons cause a substantial decrease of intracellular cysteine levels. Clinical studies revealed that individual cystine and glutamate levels are correlated with the individual lymphocyte reactivity and T4+ cell counts but not T8+ cell counts. This phenomenon was demonstrated not only in HIV-infected persons but also in healthy human individuals. The cellular cysteine supply affects amongst others the intracellular glutathione level and IL-2-dependent proliferation of T cells and (inversely) also the activation of the transcription factor NF-kappa B. The cysteine deficiency of HIV-infected persons is, therefore, possibly responsible not only for the cellular dysfunction but also for the overexpression of tumor necrosis factor-alpha (TNF-alpha), interleukin-2 receptor alpha-chain, and and beta 2-microglobulin. All the corresponding genes are associated with kappa-like enhancer sequences.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid8412205, year = {1993}, author = {De Vries, N and De Flora, S}, title = {N-acetyl-l-cysteine.}, journal = {Journal of cellular biochemistry. Supplement}, volume = {17F}, number = {}, pages = {270-277}, doi = {10.1002/jcb.240531040}, pmid = {8412205}, issn = {0733-1959}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Anticarcinogenic Agents/*therapeutic use ; Antioxidants/pharmacology ; Humans ; Laryngeal Neoplasms/prevention &amp; control ; Lung Neoplasms/prevention &amp; control ; Mouth Neoplasms/prevention &amp; control ; }, abstract = {The most commonly used chemopreventive agents in the prevention of oral leukoplakia, head and neck cancer, and lung cancer are beta-carotene, vitamin A, and other retinoids. One of the few chemopreventive agents not in this group and presently being used in a clinical trial is N-acetyl-l-cysteine (NAC). NAC, an antioxidant, is used in EUROSCAN, a European Organization of Research and Treatment of Cancer (EORTC) chemoprevention study in curatively treated patients with oral, laryngeal, or lung cancer. The rationale for choosing NAC is based on a variety of experimental data showing its ability to exert protective effects, including extracellular inhibition of mutagenic agents from exogenous and endogenous sources, inhibition of genotoxicity of reactive oxygen species, modulation of metabolism coordinated with blocking of reactive metabolites, protection of DNA and nuclear enzymes, and prevention of the formation of carcinogen-DNA adducts. NAC has also demonstrated an effect on mutagen-induced chromosomal sensitivity assays, and on anticarcinogenicity in experimental animal models. In addition, preliminary data from EUROSCAN show good compliance in treated patients and a low frequency of side effects.}, }
@article {pmid8381319, year = {1993}, author = {Salvemini, D and Pistelli, A and Vane, J}, title = {Conversion of glyceryl trinitrate to nitric oxide in tolerant and non-tolerant smooth muscle and endothelial cells.}, journal = {British journal of pharmacology}, volume = {108}, number = {1}, pages = {162-169}, pmid = {8381319}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Animals ; Aorta, Thoracic ; Cyclic GMP/metabolism ; Endothelium, Vascular/cytology/drug effects/*metabolism ; Humans ; In Vitro Techniques ; Male ; Metyrapone/pharmacology ; Muscle, Smooth, Vascular/cytology/drug effects/*metabolism ; Nitric Oxide/*metabolism ; Nitrites/*metabolism ; Nitroglycerin/*metabolism/pharmacology ; Platelet Aggregation/drug effects ; Platelet Aggregation Inhibitors/pharmacology ; Proadifen ; Rabbits ; Sulfobromophthalein/pharmacology ; }, abstract = {1. Exposure of smooth muscle cells (SMC) to glyceryl trinitrate (GTN, 75-600 microM) for 30 min led to a concentration-dependent increase in nitrite (NO2-), one of the breakdown products of nitric oxide (NO). This was not affected by 30 min pretreatment of the cells with 0.5 mM of sulphobromophthalein (SBP) an inhibitor of glutathione-S-transferase (GST), by metyrapone or SKF-525A inhibitors of cytochrome P450. These experiments were confirmed by organ bath studies using rabbit aortic strips denuded of endothelium and contracted with phenylephrine. Thus, a 30 min incubation of the strips with 0.5 mM SPB, metyrapone or SKF-525A did not affect the relaxations in response to GTN (10(-10)-10(-6) M). 2. Potentiation of the anti-platelet effect of GTN (44 microM) by endothelial cells (EC, 40 x 10(3) cells) was not affected by prior incubation of EC with SBP, metyrapone or SKF-525A (all at 0.5 mM). 3. Potentiation of the antiplatelet activity of GTN (11-352 microM) by small numbers of SMC (24 x 10(3) cells) or EC (40 x 10(3) cells) treated with indomethacin (10 microM) was attenuated when the SMC or EC were treated in culture with a high concentration of GTN (600 microM) for 18 h beforehand (referred to as 'tolerant' cells). In addition, tolerant SMC produced far less NO2- than non-tolerant SMC. 4. Exposure of non-tolerant SMC or EC (10(5) cells) to GTN (200 microM) for 3 min increased (3-4 fold) the levels of guanosine 3':5'-cyclic monophosphate (cyclic GMP). This increase was much less (< I fold) in the tolerant SMC or EC (105 cells). The basal levels of cyclic GMP were similar in normal or tolerant SMC or EC. Sodium nitroprusside (80 JAM) or atrial natriuretic factor (ANF, I0- M) increased the levels of cyclic GMP in normal or tolerant SMC or EC to the same extent.5 The anti-platelet effects of GTN (44 JM) were potentiated by the sulphydryl donor N-acetylcysteine(NAC, 0.5mM). Incubation of GTN (150-1200fJM) for 30min with NAC (0.1-1mM) led to aconcentration-dependent increase in N02- formation. The reduced ability of tolerant SMC or EC to potentiate the anti-platelet activity of GTN was restored by NAC (0.5 mM). These anti-aggregatory effects were abolished by concurrent co-incubation with oxyhaemoglobin (10 JM) indicating that they were due to NO release.6 Thus, in SMC or EC, metabolism of GTN to NO does not depend on glutathione-S-transferase or the cytochrome P450 system. Furthermore, when compared to normal cells, tolerant SMC or EC metabolize GTN to NO less effectively as assessed by the reduced capacity to potentiate the antiplatelet effects of GTN, to release NO2- and to increase the level of cyclic GMP. This decrease in NO formation shows that tolerance to GTN is mainly due to impaired biotransformation of GTN to NO. NAC, by directly forming NO from GTN, compensates for this failing mechanism.}, }
@article {pmid8148757, year = {1993}, author = {Jankowska, R and Passowicz-Muszyńska, E and Medrala, W and Banaś, T and Marcinkowska, A}, title = {[The influence of n-acetylcysteine on chemiluminescence of granulocytes in peripheral blood of patients with chronic bronchitis].}, journal = {Pneumonologia i alergologia polska}, volume = {61}, number = {11-12}, pages = {586-591}, pmid = {8148757}, issn = {0867-7077}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Female ; Granulocytes/*drug effects ; Humans ; Luminescent Measurements ; Lung Diseases, Obstructive/*drug therapy/physiopathology ; Male ; Middle Aged ; Reference Values ; Spirometry ; }, abstract = {The effect of NAC on exacerbation of chronic obstructive pulmonary disease (COPD) may be due to its mucolytic properties due to the thiol group of NAC and to its reducing and antioxidant properties. It has been postulated that NAC may protect lung cells from inhaled oxidants or oxidants produced by inflammatory leukocytes by increasing intra and extra cellular GSH. The FMLP induced granulocyte chemiluminescence (CL) in 6 healthy and 12 patients with COPD was determined. Peripheral blood polymorphonuclear leukocytes were incubated with NAC. The results obtained show a significant decrease of CL after incubation with NAC in both groups. We also found higher CL in healthy subjects than patients with COPD. This study showed a significant increase of FVC, FEV1 and a significant decrease of granulocyte CL after treatment with oral NAC 200 mg three times daily for 3 weeks.}, }
@article {pmid7508225, year = {1993}, author = {Barale, R and Micheletti, R and Sbrana, C and Glussich, I and Scapoli, C and Barrai, I}, title = {N-acetylcysteine inhibits diesel extract mutagenicity in the Ames test and SCE induction in human lymphocytes.}, journal = {Basic life sciences}, volume = {61}, number = {}, pages = {149-160}, doi = {10.1007/978-1-4615-2984-2_14}, pmid = {7508225}, issn = {0090-5542}, mesh = {Acetylcysteine/*pharmacology ; Antimutagenic Agents/*pharmacology ; Fossil Fuels/*toxicity ; Humans ; Lymphocytes/cytology/*drug effects/physiology ; Mutagenicity Tests ; Mutagens/isolation &amp; purification/*toxicity ; Pyrenes/toxicity ; Salmonella typhimurium/*drug effects ; Sister Chromatid Exchange/*drug effects ; *Vehicle Emissions ; }, abstract = {N-Acetylcysteine (NAC) has been reported to decrease genotoxicity induced by several mutagens. In this paper, the desmutagenic effect of NAC on a complex mixture, such as diesel extract, has been analyzed. Studies have been carried out in vitro with the Ames test (reverse mutations on TA98, TA100, and TA104 strains) and sister chromatid exchanges assay (SCE) in human lymphocytes. NAC inhibits diesel genotoxicity in both assays. NAC also inhibits the mutagenicity of 1,8-dinitropyrene (1,8-DNP) and 1-nitropyrene (1-NP) known to be present in diesel exhaust and to be activated by cellular O-transacetylases and nitropyrene reductases. NAC inhibits also the induction of SCE in human lymphocytes by diesel extract. These results, and those obtained by the preincubation of NAC with cells, suggest that the inhibition also takes place inside the cell.}, }
@article {pmid7506126, year = {1993}, author = {Trizna, Z and Schantz, SP and Lee, JJ and Spitz, MR and Goepfert, H and Hsu, TC and Hong, WK}, title = {In vitro protective effects of chemopreventive agents against bleomycin-induced genotoxicity in lymphoblastoid cell lines and peripheral blood lymphocytes of head and neck cancer patients.}, journal = {Cancer detection and prevention}, volume = {17}, number = {6}, pages = {575-583}, pmid = {7506126}, issn = {0361-090X}, support = {PC1-CA-52021/PC/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Anticarcinogenic Agents/*pharmacology ; Antimutagenic Agents/*pharmacology ; Ascorbic Acid/pharmacology ; Bleomycin/*adverse effects ; Cell Line/drug effects ; Chromosome Aberrations ; Head and Neck Neoplasms/*blood ; Humans ; Lymphocytes/*drug effects/ultrastructure ; Tretinoin/pharmacology ; Vitamin E/pharmacology ; }, abstract = {The protective effects of ascorbic acid (AA), n-acetyl-l-cysteine (NAC), alpha-tocopherol acid (ATA), alpha-tocopherol-acid succinate (TAS), and 13-cis-retinoic acid (CRA) on mutagen-induced chromosomal breakage were studied. Mutagen-sensitivity was determined by the bleomycin assay in human lymphoblastoid cell lines (LCLs) and cultures of peripheral blood lymphocytes (PBLs) from head and neck cancer patients. Preincubation with chemopreventive agents statistically significantly decreased mutagen-induced chromatid breakage in LCLs and PBLs in a dose-related manner. As the concentration of the agents was increased in tenfold increments in the study range, mean breakage rates were reduced by 3.0 to 7.7% in LCLs and by 6.0 to 11.1% in PBLs. The effective concentrations are comparable to those achieved in clinical applications and found in human dietary studies. A similar phenomenon in vivo, if identified, may explain the differences in occurrence of head and neck and other cancers between populations with different dietary habits. The bleomycin assay may be used for studying compounds with presumed chemopreventive properties.}, }
@article {pmid7337295, year = {1981}, author = {Gaunt, SD and Baker, DC and Green, RA}, title = {Clinicopathologic evaluation N-acetylcysteine therapy in acetaminophen toxicosis in the cat.}, journal = {American journal of veterinary research}, volume = {42}, number = {11}, pages = {1982-1984}, pmid = {7337295}, issn = {0002-9645}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Animals ; Cat Diseases/blood/chemically induced/*drug therapy/pathology ; Cats ; Glutathione/blood ; Heinz Bodies ; Hematocrit ; Methemoglobin/analysis ; }, abstract = {Acute acetaminophen (ACM) toxicosis was induced in cats and the therapeutic benefit of N-acetylcysteine (NAC) was demonstrated. Groups of 4 adult cats were treated as follows: group A-given ACM only; group B- given ACM and then treated with NAC, starting at 0 hour; group C-given ACM and then treated with NAC, starting at 4 hours; and group D-treated with NAC only. Acetaminophen was given as a single oral dose or 143 mg/kg, and the NAC regimen consisted of 4 oral doses (200 mg/kg, given 3 times and 100 mg/kg, given once) with 2 hours between doses. Group A cats developed increased methemoglobin concentration, depletion of erythrocyte reduced glutathione, and increased Heinz body formation. Group B cats also developed methemoglobinemia, depletion of glutathione, and increased Heinz body formation, but the magnitude of these changes was significantly less (P less than 0.05) than in group A. In group C, the findings were similar to group A through 4 hours, but thereafter, significant hematologic improvement was noted. The level of Heinz bodies in group C was intermediate between the values for groups A and B. In group D cats, no significant changes from base line were noted. Evidence of hepatotoxicity was not seen in any group as based on daily determinations of plasma alanine aminotransferase and sorbitol dehydrogenase activities.}, }
@article {pmid7275534, year = {1981}, author = {Pfister, RR and Nicolaro, ML and Paterson, CA}, title = {Sodium citrate reduces the incidence of corneal ulcerations and perforations in extreme alkali-burned eyes--acetylcysteine and ascorbate have no favorable effect.}, journal = {Investigative ophthalmology &amp; visual science}, volume = {21}, number = {3}, pages = {486-490}, pmid = {7275534}, issn = {0146-0404}, support = {EY 02018/EY/NEI NIH HHS/United States ; }, mesh = {Acetylcysteine/therapeutic use ; Administration, Topical ; Alkalies ; Animals ; Ascorbic Acid/therapeutic use ; Burns, Chemical/complications/*drug therapy ; Citrates/*therapeutic use ; Citric Acid ; Corneal Ulcer/complications/*prevention &amp; control ; Eye Burns/complications/*drug therapy ; Rabbits ; }, abstract = {Alkali-burned eyes (45 sec, 12 mm, 4N NaOH) were subjected to topical treatment with 10% ascorbate, 20% acetylcysteine, 10% ascorbate together with 20% acetylcysteine, 10% citrate, or Adsorbotear vehicle. Only citrate-treated eyes showed a significant decrease in corneal ulcerations and perforations (17%) compared with ascorbate (88%), acetylcysteine (81%), ascorbate/acetyl-cysteine (100%), or Adsorbotear (75%). In the citrate-treated eyes there was a significantly reduced incidence of band keratopathy (17%) but an increased incidence of hyphema (100%). Both groups receiving acetylcysteine developed acellular corneal caps, the result of peripheral ulceration undermining the central cornea. Polymorphonuclear neutrophils (PMN) were substantially increased at the base of the cap in the acetylcysteine- and acetylcysteine/ascorbate-treated eyes at day 56. At the end of the experiment, citrate-treated eyes showed substantially fewer stromal PMN than any other group. These results show that topical citrate has a most favorable effect on the incidence of corneal ulceration and perforation after alkali burning.}, }
@article {pmid7286849, year = {1981}, author = {Kogi, K and Saito, T and Kasé, Y and Hitoshi, T}, title = {[Pharmacological effects of N-acetyl-L-cysteine on the respiratory tract. (I). Quantitative and qualitative changes in respiratory tract fluid and sputum (author's transl)].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {77}, number = {6}, pages = {569-578}, pmid = {7286849}, issn = {0015-5691}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bronchi/*metabolism ; Rabbits ; Rats ; Sputum/analysis/drug effects/*metabolism ; Viscosity ; }, abstract = {The following three experiments were performed to determine the effects of N-acetyl-L-cysteine (NAC) on the quantity and quality of respiratory tract fluid (RTF) and sputum. All drugs used were administered into the stomach through a gastric tube. 1) Indirect measurement of bronchial secretion in rats, which was expressed by the amounts of dye excreted into the respiratory tract, was carried out according the the Sakuno's method, with some modification. Some expectorants of the secretomotor type, such as bromhexine and pilocarpine, significantly increased the secretion, even at low doses. On the other hand, mucolytic agents such as NAC augmented the secretion only in doses of 500 to 1500 mg/kg. 2)As a direct method of measurements, Kasé's modification of Perry and Boyd's method was used to collect RTF, quantitatively, from rabbits. The RTF of healthy rabbits was colorless and watery. The administration of NAC in doses of 500 to 1500 mg/kg augmented the output volume and RTF became slightly turbid, probably due to an increase in the viscous mucus. 3) Rabbits with subacute bronchitis were prepared by long-term exposure to air contaminated with SO2 gas and sputa were collected before and after administration of NAC, respectively, according to the Kase's method. The sputa were opalescent and viscous gel included nodular masses. The administration of NAC, 1000 and 1500 mg/kg resulted in a dose dependent decrease in the relative viscosity. The percent-decreased in viscosity with NAC was statistically correlated with that in amounts of dry matter, those in protein and polysaccharide in the sputa. From the results described above, it was concluded that NAC given into the stomach can liquefy sputum by splitting mucoprotein disulphide linkages, that is, altering the rheological characteristics of sputum to facilitate expectoration.}, }
@article {pmid7272464, year = {1981}, author = {Feil, VJ and Bakke, JE and Larsen, GL and Gustafsson, BE}, title = {A new metabolite of propachlor isolated from germfree rat excreta.}, journal = {Biomedical mass spectrometry}, volume = {8}, number = {1}, pages = {1-4}, doi = {10.1002/bms.1200080102}, pmid = {7272464}, issn = {0306-042X}, mesh = {Acetanilides/isolation &amp; purification/*metabolism/urine ; Animals ; Anti-Bacterial Agents/pharmacology ; Feces/analysis ; Germ-Free Life ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Rats ; }, abstract = {2-[S-(N-Acetyl)cysteine]-isopropylacetanilide sulfoxide was isolated from the excreta of germfree rats given oral doses of 2-chloro-N-isopropylacetanilide. The metabolite was characterized by mass and nuclear magnetic resonance spectrometry on samples isolated from rats dosed with [1-14C]-and [2-13C]-2-chloro-N-iso-propylacetanilide. Artifact formation upon reaction of the sulfoxide with alcoholic HCl is discussed.}, }
@article {pmid7441509, year = {1980}, author = {Olson, RD and MacDonald, JS and vanBoxtel, CJ and Boerth, RC and Harbison, RD and Slonim, AE and Freeman, RW and Oates, JA}, title = {Regulatory role of glutathione and soluble sulfhydryl groups in the toxicity of adriamycin.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {215}, number = {2}, pages = {450-454}, pmid = {7441509}, issn = {0022-3565}, support = {GM-00058/GM/NIGMS NIH HHS/United States ; GM-15431/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Cysteamine/pharmacology ; Doxorubicin/*toxicity ; Glutathione/*physiology ; Heart/drug effects ; Male ; Mice ; Myocardium/metabolism ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Adriamycin (ADR) has been shown to produce free radicals in NADPH microsomal systems, to increase oxygen consumption of both hepatic microsomes and heart sarcosomes and to stimulate superoxide formation in cardiac, submitochondria particles. These reactive products could produce the cardiotoxicity of ADR by oxidizing various membrane structures, especially if the heart lacks sufficient protective reducing substances such as thiols. We examined 1) the effect of ADR on reduced glutathione (G-SH) levels in various tissues including heart, 2) the ability of the sulfhydryl (SH) donor, cysteamine, to alter soluble SH levels in heart tissue after ADR administration and 3) the effects of SH donors (cysteamine and N-acetyl cysteine and G-SH depletion by diethyl maleate on ADR-induced lethality in Swiss ICR-HA mice. A single injection of ADR (15 mg/kg i.p.) elicited a statistically significant fall in liver (P < .05), heart (P < .02) and erythrocyte (P < .01) G-SH levels. Treatment with cysteamine protected against the fall in soluble SH groups in heart tissue. Cysteamine (50 mg/kg, i.p., every 8 hr for 6 days) or N-acetylcysteine (100 mg/kg, i.p., 1 hr before and 7 hr after ADR) protected against ADR-induced lethality and decreased the appearance of microscopic myocardial lesions. When endogenous levels of G-SH were depleted by diethyl maleate (300 mg/kg i.p., every 8 hr for 4 days), ADR lethality was markedly potentiated. Diethyl maleate alone did not cause death. We conclude 1) ADR significantly lowers G-SH levels in erythrocytes, liver and heart tissue, 2) the lowering of cardiac SH groups by ADR can be prevented by cysteamine and 3) ADR toxicity can be potentiated by diethyl maleate, a G-SH depletor, and reduced by cysteamine or N-acetyl cysteine, SH donors. These results suggest that the G-SH system may be involved in the modulation of ADR-induced toxicity.}, }
@article {pmid7386356, year = {1980}, author = {Bailey, BO}, title = {Acetaminophen hepatotoxicity and overdose.}, journal = {American family physician}, volume = {22}, number = {1}, pages = {83-87}, pmid = {7386356}, issn = {0002-838X}, mesh = {Acetaminophen/metabolism/poisoning/therapeutic use/*toxicity ; Acetylcysteine/therapeutic use ; Humans ; Liver/*drug effects ; }, abstract = {Acetaminophen is a widely available and frequently recommended over-the-counter analgesic and antipyretic. Chronic doses in excess of 5 Gm. per day and acute doses of as little as 7 Gm. have caused hepatic damage in adults. Larger doses may be fatal. The hepatotoxicity, which is due to metabolic transformation of the acetaminophen to an alkylating agent, can be palliated or avoided by prompt treatment. Blood levels over 200 micrrograms per mL. four hours after ingestion correlate with severe hepatotoxicity. Clinical trials have shown N-acetylcysteine (NAC) to be a specific antidote when administered within eight hours of an acute ingestion.}, }
@article {pmid7414175, year = {1980}, author = {Saraiva, PA and Giovani, L and Giordan, EA and Leitão, FB}, title = {[Prolonged use of N-acetyl-cysteine by oral route].}, journal = {Revista do Hospital das Clinicas}, volume = {35}, number = {2}, pages = {56-59}, pmid = {7414175}, issn = {0041-8781}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; *Respiration, Artificial ; Respiratory Insufficiency/physiopathology/*therapy ; }, }
@article {pmid7353286, year = {1980}, author = {Burlina, A}, title = {Improved electrophoretic separation of creatine kinase isoenzymes.}, journal = {Clinical chemistry}, volume = {26}, number = {2}, pages = {317-320}, pmid = {7353286}, issn = {0009-9147}, mesh = {Blood Protein Electrophoresis/*methods ; Creatine Kinase/*blood ; Female ; Humans ; Isoenzymes ; Male ; Myocardial Infarction/enzymology ; Temperature ; }, abstract = {Creatine kinase isoenzymes are separated electrophoretically on cellulose acetate, with use of an improved procedure for reactivation and visualization of enzymic activity. N-Acetyl cysteine is used as the reactivator and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide for visualization in a tetrazolium-coupled system. This test, both practical and reliable, is a suitable alternative to chromatographic or immunochemical assay. The method allows: (a) detection of the MB isoenzyme on the basis of its electrophoretic migration, (b) confirmation of results obtained with other methods, particularly by immunoinhibition, and (c) detection of atypical bands of possible diagnostic significance in addition to the recognized fractions.}, }
@article {pmid1360651, year = {1992}, author = {Tobias, JD and Gregory, DF and Deshpande, JK}, title = {Ondansetron to prevent emesis following N-acetylcysteine for acetaminophen intoxication.}, journal = {Pediatric emergency care}, volume = {8}, number = {6}, pages = {345-346}, doi = {10.1097/00006565-199212000-00010}, pmid = {1360651}, issn = {0749-5161}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Adolescent ; Female ; Humans ; Infusions, Intravenous ; Ipecac/therapeutic use ; Ondansetron/*therapeutic use ; Poisoning/drug therapy ; Recurrence ; Vomiting/chemically induced/*prevention &amp; control ; }, abstract = {We present a 17-year-old girl who developed persistent vomiting following acetaminophen overdose. Because of the amount of drug ingested (300 mg/kg acetaminophen) and the four-hour postingestion level (256 micrograms/ml), administration of N-acetylcysteine (NAC) was indicated. Emesis occurred immediately following the first three doses of NAC despite administering the drug by continuous nasogastric drip over one hour. Prior to the next attempt, ondansetron (0.15 mg/kg) was administered intravenously as an antiemetic. Thirty minutes following ondansetron, NAC was tolerated without further emesis. Although several antiemetics may have prevented further emesis, we chose ondansetron since, as a serotonin antagonist, it does not cause extrapyramidal side effects or sedation. In patients with potentially toxic drug ingestions, these side effects may be confused with or mask the adverse effects of the ingested drug, thereby interfering with the ongoing evaluation of the patient. Although not previously administered for this indication, ondansetron has several advantages over other antiemetic agents in the setting of an acute drug ingestion.}, }
@article {pmid1343225, year = {1992}, author = {Bijlmer-Iest, JC and Baart de la Faille, H and van Asbeck, BS and van Hattum, J and van Weelden, H and Marx, JJ and Koningsberger, JC}, title = {Protoporphyrin photosensitivity cannot be attenuated by oral N-acetylcysteine.}, journal = {Photodermatology, photoimmunology &amp; photomedicine}, volume = {9}, number = {6}, pages = {245-249}, pmid = {1343225}, issn = {0905-4383}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Double-Blind Method ; Erythrocytes/metabolism ; Glutathione/metabolism ; Glutathione Reductase/metabolism ; Humans ; Photosensitivity Disorders/complications/*pathology ; Porphyria, Hepatoerythropoietic/complications/*drug therapy/metabolism ; Protoporphyrins/metabolism ; }, abstract = {The photodermatosis in erythropoietic protoporphyria (EPP) is caused by the accumulation of photosensitizing protoporphyrin (PP) in the skin, due to a defect in ferrochelatase, the enzyme that inserts ferrous iron into PP to form heme. Hydroxyl radical (.OH) and singlet oxygen generation with subsequent lipid peroxidation are thought to play a major role in the pathogenesis of the photodermatosis in EPP. Hydrogen peroxide (H2O2) can generate .OH in the Haber-Weiss as well as the Fenton reaction, and is thus a potentially harmful intermediate in the photoreduction of O2. The use of oxyradical scavengers, such as beta-carotene, has been reported to be beneficial in the treatment of EPP photodermatosis. In this study, N-acetylcysteine (NAC) 1800 mg/day was used for 3 reasons: (i) its -SH groups directly scavenge H2O2; (ii) ferrochelatase can be activated by sulfhydryl groups; (iii) NAC was reported to upregulate the glutathione redox system, which is a major endogenous anti-oxidant system. However, in a double-blind crossover placebo controlled study on 6 EPP patients, we could neither demonstrate an effect through photosensitivity tests, nor on light hypersensitivity as reported by the patients. This dosage of NAC could not increase reduced glutathione and did not affect the red blood cell PP content nor the excretion of PP in the feces. Neither were adverse effects observed. We conclude that the oral administration of NAC, in the relatively low dose used here, is not effective in the treatment of photodermatosis in EPP.}, }
@article {pmid1282593, year = {1992}, author = {Vincent, J and Kongpatanakul, S and Blaschke, TF and Hoffman, BB}, title = {Desensitization of nitrate-induced venodilation: reversal with oral N-acetylcysteine in humans.}, journal = {Journal of cardiovascular pharmacology}, volume = {20}, number = {6}, pages = {907-912}, doi = {10.1097/00005344-199212000-00010}, pmid = {1282593}, issn = {0160-2446}, support = {AG05627/AG/NIA NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Adult ; Blood Pressure Determination ; Dose-Response Relationship, Drug ; Drug Tolerance ; Female ; Hand/blood supply ; Humans ; Isosorbide Dinitrate/*pharmacology ; Male ; Nitroglycerin/pharmacology ; Regional Blood Flow/drug effects ; Vasodilation/*drug effects ; }, abstract = {The objective of this study was to determine whether the dorsal hand vein could be used as a model to study tolerance to oral nitrates, and whether oral N-acetylcysteine (NAC) could reverse tolerance if present. Dose-response curves to nitroglycerin were constructed for 11 normotensive volunteers before and during treatment with a sustained-release formulation of isosorbide dinitrate, 80 mg, three times daily for 7 days and followed by concurrent treatment with NAC at a mean dose of 150 mg/kg/day, in divided doses, for 2 days. In separate studies, dose-response curves were constructed for seven normotensive volunteers before and after treatment with oral NAC at the same dose for 2 days. Nitroglycerin's Emax was significantly attenuated from 115 +/- 36 to 77 +/- 22% after treatment with isosorbide dinitrate alone (p < 0.009). Concurrent treatment with NAC reversed this decrease, as nitroglycerin's Emax of 108 +/- 26% during coadministration of isosorbide dinitrate and NAC was not different from its Emax in the control period. There was also no difference in the dose of phenylephrine required to cause 80% of maximal venoconstriction throughout the study. These studies demonstrate that smooth muscle tolerance to nitrates can be demonstrated in medium-sized veins in humans. In addition, high-dose oral NAC can reverse existing tolerance to oral nitrates in human veins. These results indicate that the dorsal hand vein compliance technique is a good model for the clinical investigation of tolerance to nitrates in humans.}, }
@article {pmid1423892, year = {1992}, author = {Izzotti, A and Balansky, RM and Coscia, N and Scatolini, L and D'Agostini, F and De Flora, S}, title = {Chemoprevention of smoke-related DNA adduct formation in rat lung and heart.}, journal = {Carcinogenesis}, volume = {13}, number = {11}, pages = {2187-2190}, doi = {10.1093/carcin/13.11.2187}, pmid = {1423892}, issn = {0143-3334}, mesh = {7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Carcinogens/toxicity ; DNA/*drug effects ; Heart/*drug effects ; Lung/*drug effects ; Male ; Neoplasms, Experimental/*prevention &amp; control ; Plants, Toxic ; Rats ; Rats, Sprague-Dawley ; Smoke ; Nicotiana ; }, abstract = {The formation of smoke-related DNA adducts and their chemoprevention were investigated in tissues of male Sprague-Dawley rats, by testing a total of 132 DNA samples by synchronous fluorescence spectrophotometry (SFS), which mainly detects benzo[a]pyrene diolepoxide (BPDE)-DNA adducts. Groups of six animals each were exposed whole-body to mainstream cigarette smoke, once daily, for up to 40 consecutive days. No adduct was revealed in liver DNA, whereas smoke-related DNA adducts were detectable in the lung from the 8th day of exposure and continued to increase until the 40th day. Adducts to heart DNA, which were monitored after 28 and 40 days of exposure, attained even higher levels than those detected in the lungs of the same animals. A high correlation existed between the amounts of smoke-related DNA adducts measured in these two organs. The daily administration by gavage of the thiol N-acetyl-L-cysteine (NAC), an effective mutation and cancer chemopreventive agent, which had been previously shown to inhibit the formation of SFS-positive DNA adducts in rats receiving intratracheal instillations of benzo[a]pyrene, significantly prevented occurrence of the same adducts in both heart and lungs of smoke-exposed rats. No fluorescence signal was observed in liver, lung, or heart DNA of sham-exposed animals. The findings of this molecular dosimetry study complement the results of parallel histopathologic, cytogenetic, biochemical and metabolic analyses of tissues and cells from the same rats, providing evidence for a variety of significant alterations produced by exposure to cigarette smoke and for the specific protective role of NAC.}, }
@article {pmid1335155, year = {1992}, author = {Maasilta, P and Holsti, LR and Blomqvist, P and Kivisaari, L and Mattson, K}, title = {N-acetylcysteine in combination with radiotherapy in the treatment of non-small cell lung cancer: a feasibility study.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {25}, number = {3}, pages = {192-195}, doi = {10.1016/0167-8140(92)90267-x}, pmid = {1335155}, issn = {0167-8140}, mesh = {Acetylcysteine/*administration &amp; dosage/adverse effects ; Adult ; Aged ; Carcinoma, Non-Small-Cell Lung/*drug therapy/*radiotherapy ; Combined Modality Therapy ; Feasibility Studies ; Humans ; Lung/diagnostic imaging/radiation effects ; Lung Neoplasms/*radiotherapy ; Middle Aged ; Radiation Injuries/diagnostic imaging/prevention &amp; control ; Radiation-Protective Agents/*administration &amp; dosage/adverse effects ; Radiotherapy Dosage ; Tomography, X-Ray Computed ; }, abstract = {N-Acetylcysteine (NAC) is a free radical scavenger and could therefore act as a radioprotector. To test the feasibility of administering NAC in combination with radiotherapy, we studied 10 patients with inoperable non-small cell lung cancer who were receiving hyperfractionated radiotherapy (RT) of 1.25 Gy B.I.D. (6-h interval) up to a total dose of 60 Gy/48 fractions/32 days. They were given NAC concomitantly with RT: 100 mg/kg i.v. 30 min before the first RT session followed by 30 mg/kg as an i.v. infusion over 7 h; and 600 mg inhaled 30 min before and after each RT session. The patients were assessed by serial CT scans and lung function studies during a 1-year follow-up period. The treatment regime was feasible, but expensive in time and resources. Normal tissue reactions and tumour responses were similar to those in a control group.}, }
@article {pmid1455612, year = {1992}, author = {Mrvos, R and Schneider, SM and Dean, BS and Krenzelok, EP}, title = {Orthotopic liver transplants necessitated by acetaminophen-induced hepatotoxicity.}, journal = {Veterinary and human toxicology}, volume = {34}, number = {5}, pages = {425-427}, pmid = {1455612}, issn = {0145-6296}, mesh = {Acetaminophen/*adverse effects ; Adolescent ; Adult ; Drug Overdose ; Female ; Hepatic Encephalopathy/*chemically induced/*surgery ; Humans ; *Liver Transplantation ; }, abstract = {BACKGROUND: Acetaminophen-induced hepatotoxicity has been recognized since 1966. Patients experiencing a massive hepatic insult due to acetaminophen (APAP) may recover with minimal residual complications or develop fulminant hepatic necrosis. We report 3 patients with hepatic failure due to an APAP overdose who received orthotopic liver transplants and survived.<br><br>CASE REPORTS: An 18-y-o female ingested 60 500 mg APAP tablets (30 g). She presented with tachycardia and lethargy stating that she had taken amoxipine, carbamazepine, and lorazepam. She began to recover but on day 2 experienced an upper gastrointestinal bleed and became hypotensive and hyperpyrexic. She developed hepatic encephalopathy and it was then determined she had ingested APAP. Her APAP level was 13 micrograms/ml 96 h post-ingestion. She was successfully transplanted 19 d post-ingestion with recovery. A 40-y-o female was admitted for flu-like symptoms persisting for 7 d. She was jaundiced, hyperventilating and hypotensive. She admitted ingesting approximately 17 g APAP over 36 h. Her APAP level was 12.2 micrograms/ml. Her condition worsened and on day 3 she was in grade IV coma. She was successfully transplanted 4 d post-arrival with recovery. A 16-y-o female ingested an unknown amount of APAP. She presented approximately 24 h post-ingestion with a serum APAP level of 130 micrograms/ml. Her condition deteriorated and she became encephalopathic with grade IV coma. She was successfully transplanted on day 7 post-arrival.<br><br>DISCUSSION: Hepatotoxicity can occur as a result of either acute or chronic APAP overdose. Although n-acetylcysteine (NAC) is effective antidotal therapy, it must be used within 8-12 h post-ingestion to be optimally effective. Inaccurate patient histories may prevent NAC administration resulting in hepatotoxicity.<br><br>CONCLUSION: Liver transplantation is a viable option to be considered in those APAP overdose patients who experience rapidly progressing encephalopathy, hemolysis, and hepato-renal failure.}, }
@article {pmid1452401, year = {1992}, author = {Calabresi, A and Perito, S and Romani, L and Bistoni, F}, title = {Drug-induced modulation of IL-2 production in experimental murine trypanosomiasis.}, journal = {International journal of immunopharmacology}, volume = {14}, number = {7}, pages = {1165-1173}, doi = {10.1016/0192-0561(92)90051-l}, pmid = {1452401}, issn = {0192-0561}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Female ; In Vitro Techniques ; Indomethacin/*pharmacology ; Interleukin-2/*biosynthesis ; Male ; Mice ; Receptors, Interleukin-2/drug effects/metabolism ; Spleen/drug effects/immunology ; T-Lymphocytes, Regulatory/drug effects/immunology ; Trypanosomiasis/*drug therapy/*immunology ; }, abstract = {In this study we evaluated the effects of N-acetyl-cysteine and indomethacin in restoring IL-2 producing ability in vitro of splenocytes from mice infected with Trypanosoma equiperdum. Spleen cells from these mice were found to produce significantly lower levels of interleukin-2 (IL-2) in response to mitogen stimulation than spleen cells from uninfected control mice. This was accompanied by considerable suppression of IL-2-receptor expression, which was not attributable to the elimination of a particular T-cell subset. Impairment of IL-2 production was not due to a primary defect in L3T4+ T-cells, but rather to the presence of both adherent and non-adherent suppressor cells that apparently acted via prostaglandin-independent and dependent mechanisms. In fact, the IL-2-producing ability of lymphocytes from infected mice could be efficiently restored by in vitro exposure to N-acetyl-cysteine or indomethacin.}, }
@article {pmid1394619, year = {1992}, author = {Chan, HM and Tabarrok, R and Tamura, Y and Cherian, MG}, title = {The relative importance of glutathione and metallothionein on protection of hepatotoxicity of menadione in rats.}, journal = {Chemico-biological interactions}, volume = {84}, number = {2}, pages = {113-124}, doi = {10.1016/0009-2797(92)90072-s}, pmid = {1394619}, issn = {0009-2797}, support = {ES00210/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine ; Calcium/metabolism ; *Chemical and Drug Induced Liver Injury ; Cytosol/metabolism ; Glutathione/*physiology ; In Vitro Techniques ; L-Lactate Dehydrogenase/metabolism ; Liver/drug effects/metabolism ; Male ; Metallothionein/*physiology ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Phenobarbital/pharmacology ; Potassium/metabolism ; Rats ; Rats, Sprague-Dawley ; Sulfates/pharmacology ; Vitamin K/*toxicity ; Zinc/pharmacology ; Zinc Sulfate ; }, abstract = {The effects of induction of metallothionein (MT) on the toxicity of menadione were investigated in rat liver slices. The protective role of hepatic glutathione (GSH) was also studied and compared to that of MT. A 3-h incubation of rat liver slices with menadione (100-300 microM) containing medium (37 degrees C, pH 7.4, 95%O2:5%CO2) resulted in cellular toxicity, as shown by changes in cytosolic K, Ca and GSH concentrations and lactate dehydrogenase (LDH) leakage. A dose-dependent decrease in cytosolic K and GSH was observed concomitant with an increase in cytosolic Ca and LDH leakage after incubation with menadione. Pretreatment of rats with zinc sulphate (ZnSO4) (30 mg/kg body wt.) increased MT levels in liver slices and suppressed the toxicity of menadione. Intracellular GSH concentrations in liver slices were either depleted or increased by injection of rats with buthionine sulfoximine (BSO), (4 mmol/kg body wt.) and N-acetyl-L-cysteine (NAC) (1.6 g/kg body wt.), respectively. Intracellular GSH was found to be crucial in protection against menadione toxicity. Menadione toxicity was increased when the rats were injected with sodium phenobarbital (PB) (4 x 80 mg/kg body wt.). Pretreatment with Zn provided partial protection against menadione toxicity in liver slices from both BSO- and PB-injected rats. These findings suggest that induction of MT synthesis does protect against quinone-induced toxicity, but the role may be secondary to that of GSH. The mechanisms by which MT protect against menadione toxicity are still unclear but may involve protection of both redox cycling and sulphydryl arylation.}, }
@article {pmid1447987, year = {1992}, author = {Brotodihardjo, AE and Batey, RG and Farrell, GC and Byth, K}, title = {Hepatotoxicity from paracetamol self-poisoning in western Sydney: a continuing challenge.}, journal = {The Medical journal of Australia}, volume = {157}, number = {6}, pages = {382-385}, doi = {10.5694/j.1326-5377.1992.tb137246.x}, pmid = {1447987}, issn = {0025-729X}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/administration &amp; dosage/adverse effects/therapeutic use ; Chemical and Drug Induced Liver Injury/*etiology/physiopathology ; Drug Overdose/epidemiology/mortality/therapy ; Female ; Humans ; Infusions, Intravenous ; Liver Function Tests ; Male ; New South Wales/epidemiology ; Patient Admission/statistics &amp; numerical data ; Prognosis ; Retrospective Studies ; }, abstract = {OBJECTIVE: To determine the annual incidence of admissions for paracetamol overdosage in the years 1985 to 1990, morbidity and mortality rates, predictors of poor prognosis and the most appropriate use of N-acetylcysteine (NAC).<br><br>DESIGN: A retrospective review of case records of all patients with a discharge diagnosis of paracetamol overdosage.<br><br>SETTING: A 900-bed tertiary referral teaching hospital in western Sydney with a busy accident and emergency department.<br><br>PATIENTS: 306 patient records were reviewed and details of the overdose and admission were recorded.<br><br>INTERVENTIONS: NAC infusion in patients with possible paracetamol hepatotoxicity.<br><br>MAIN OUTCOME MEASURES: Blood paracetamol levels; elevated alanine aminotransferase levels; prolonged prothrombin time; severe liver injury; and NAC side effects.<br><br>RESULTS: Annual admission rate was constant at circa 55 per annum. Female to male ratio was 2:1. Predictors of liver injury included paracetamol dose over 10 g, presentation more than 10 hours after the overdose and chronic ingestion of more than 80 g alcohol per day. There were no deaths. Fifty-five patients (18%) had toxic paracetamol levels, 51% received treatment with NAC, including 40% of those with non-toxic levels, and 11% of those treated with NAC experienced side effects.<br><br>CONCLUSION: Paracetamol overdosage continues to be a significant cause of hospital admissions in western Sydney. Severe hepatic damage occurs infrequently and the prognosis for liver injury, when it occurs, is good. Treatment with NAC should be reserved for patients with definite indications for the drug.}, }
@article {pmid1520492, year = {1992}, author = {Phelps, DT and Deneke, SM and Daley, DL and Fanburg, BL}, title = {Elevation of glutathione levels in bovine pulmonary artery endothelial cells by N-acetylcysteine.}, journal = {American journal of respiratory cell and molecular biology}, volume = {7}, number = {3}, pages = {293-299}, doi = {10.1165/ajrcmb/7.3.293}, pmid = {1520492}, issn = {1044-1549}, support = {HL07053/HL/NHLBI NIH HHS/United States ; HL42376/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Amino Acids/metabolism ; Animals ; Biological Transport/drug effects ; Cattle ; Cells, Cultured ; Cysteine/metabolism ; Cystine/metabolism ; Endothelium, Vascular/cytology/*drug effects/metabolism ; Glutathione/*metabolism ; Oxidation-Reduction ; Pulmonary Artery/cytology/*drug effects/metabolism ; }, abstract = {N-Acetylcysteine (NAC), a cysteine derivative with chemoprotective and radioprotective effects, was found to elevate bovine pulmonary artery endothelial cell (EC) glutathione after in vitro incubation. The elevation in glutathione was associated with enhanced uptake of radioactivity of cystine from the medium. Because cystine in medium was converted rapidly to cysteine and cysteinyl-NAC in the presence of NAC and given that cysteine has a higher affinity for uptake by EC than cystine, we conclude that the enhanced uptake of radioactivity was in the form of cysteine and at least part of the stimulatory effect of NAC on EC glutathione was due to a formation of cysteine by a mixed disulfide reaction of NAC with cystine similar to that previously reported for Chinese hamster ovarian cells (R. D. Issels et al. 1988. Biochem. Pharmacol. 37:881-888). However, NAC was more effective than cysteine in elevating cellular glutathione at equimolar concentrations, and at higher concentrations of NAC an elevation of EC glutathione occurred even in the absence of cystine in the medium through a currently unknown mechanism. Thus, at least two mechanisms are operative in the elevation of endothelial cellular glutathione by NAC. NAC may be a useful compound for elevating glutathione of the pulmonary vasculature for protection against oxidant stress.}, }
@article {pmid1519854, year = {1992}, author = {Van Surell, C and Boczkowski, J and Pasquier, C and Du, Y and Franzini, E and Aubier, M}, title = {Effects of N-acetylcysteine on diaphragmatic function and malondialdehyde content in Escherichia coli endotoxemic rats.}, journal = {The American review of respiratory disease}, volume = {146}, number = {3}, pages = {730-734}, doi = {10.1164/ajrccm/146.3.730}, pmid = {1519854}, issn = {0003-0805}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bacteremia/blood/*drug therapy/physiopathology ; Diaphragm/*drug effects/physiopathology ; Drug Evaluation, Preclinical ; Endotoxins/*blood ; *Escherichia coli ; Escherichia coli Infections/blood/*drug therapy/physiopathology ; Lipid Peroxidation/drug effects ; Male ; Malondialdehyde/*metabolism ; Muscle Contraction/drug effects ; Rats ; Rats, Inbred Strains ; Time Factors ; }, abstract = {We evaluated the effects of sublethal Escherichia coli endotoxemia with or without concomitant administration of N-acetylcysteine, an antioxidant agent, on diaphragmatic strength, endurance, and malondialdehyde (MDA) content in rats. One hundred ninety rats were inoculated subcutaneously on 2 successive days with 0.6 and 1.2 mg/100 g body weight of E. coli lipopolysaccharide respectively (E animals, n = 100) or saline (C group, n = 90). E and C animals were divided into two groups based on administration of endotoxin or saline alone (E group, n = 55; C group, n = 47, respectively) or endotoxin or saline plus N-acetylcysteine (1 g/kg body weight/day intraperitoneally) (E-NAC group, n = 45; C-NAC group, n = 43, respectively). Diaphragmatic strength was assessed in vivo 48 h after the first endotoxin or saline administration by measuring the transdiaphragmatic pressure (Pdl) generated during electrical stimulation of the phrenic nerves at 0.5, 10, 20, 30, 50, and 100 Hz. Endurance index was calculated as the percent ratio of Pdl generated after 30 s of phrenic stimulation at 10 Hz divided by the initial force. Diaphragmatic MDA (fluorometric technique) was measured 0, 6, 18, 30, 42, and 48 h after the first dose of endotoxin or saline. Pdl for 50 and 100 Hz was significantly reduced in Group E as compared with group C. This phenomenon was associated with a reduced endurance performance as assessed by a lower diaphragmatic endurance index in E as compared with C animals (90.9 +/- 4.2 versus 114.3 +/- 4.1 respectively; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1446000, year = {1992}, author = {LaLonde, RT and Xie, S}, title = {A study of inactivation reactions of N-acetylcysteine with mucochloric acid, a mutagenic product of the chlorination of humic substances in water.}, journal = {Chemical research in toxicology}, volume = {5}, number = {5}, pages = {618-624}, doi = {10.1021/tx00029a005}, pmid = {1446000}, issn = {0893-228X}, mesh = {Acetylcysteine/*chemistry ; Borohydrides/chemistry ; Furans/chemistry/*toxicity ; Mutagenicity Tests ; Mutagens/chemistry/*toxicity ; Salmonella typhimurium/drug effects/genetics ; }, abstract = {The Salmonella typhimurium (TA100) mutagenic compound, mucochloric acid [3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA)], was inactivated by in vitro N-acetylcysteine (NAC). The reaction of MCA with NAC at pH7 was second order and gave products 4, 5, and 6a that resulted from the displacement of chlorine from C-3 or C-4 of MCA. The sodium borohydride treatment of product 4 gave the same product (7) as was obtained by treating 3,4-dichloro-2(5H)-furanone with NAC. The treatment of MCA with (R)-(+)-cysteine gave the bicyclic product 9a, in which the two chlorine atoms of MCA were still present. This product was slightly more mutagenic than MCA, whereas product 5 was less mutagenic than MCA and product 4 was nonmutagenic in the Salmonella typhimurium (TA100) assay.}, }
@article {pmid1355413, year = {1992}, author = {Münzel, T and Mülsch, A and Holtz, J and Just, H and Harrison, DG and Bassenge, E}, title = {Mechanisms of interaction between the sulfhydryl precursor L-methionine and glyceryl trinitrate.}, journal = {Circulation}, volume = {86}, number = {3}, pages = {995-1003}, doi = {10.1161/01.cir.86.3.995}, pmid = {1355413}, issn = {0009-7322}, mesh = {Animals ; Aorta/cytology/metabolism ; Cells, Cultured ; Coronary Circulation/drug effects ; Cysteine/pharmacology ; Dogs ; Drug Interactions ; Guanylate Cyclase/metabolism ; Methionine/metabolism/*pharmacology ; Muscle, Smooth, Vascular/cytology/metabolism ; Nitroglycerin/*pharmacology ; Pericardium ; Prodrugs/pharmacology ; Sulfhydryl Compounds/*metabolism ; Vascular Resistance/drug effects ; Vasodilation/drug effects ; Wakefulness ; }, abstract = {BACKGROUND: L-Methionine potentiates systemic hemodynamic effects of intravenous glyceryl trinitrate (GTN) in tolerant and nontolerant patients to a similar extent as N-acetylcysteine (NAC). This potentiation of GTN action by L-methionine has been attributed to enhanced intracellular formation of nitrosothiols, known to be potent stimulators of soluble guanylyl cyclase. This study was performed to analyze directly the effects of L-methionine on GTN-induced dilation of large epicardial arteries and the venous capacitance system of the dog in the tolerant and nontolerant states. Cultured rat aortic vascular smooth muscle cells and purified guanylyl cyclase were used to study potential intracellular and extracellular mechanisms responsible for this interaction.<br><br>METHODS AND RESULTS: In awake nontolerant dogs, L-methionine (100 mg/kg) potentiated the tachycardic response to GTN (5.0 and 15 micrograms/kg/min) and enhanced the hypotensive action of GTN (1.5 and 5.0 micrograms/kg/min) in anesthetized, nonreflexic dogs. In nontolerant and tolerant dogs, however, L-methionine did not alter the dose-response of large epicardial artery dilation to intravenous GTN challenges and did not modify nitrate tolerance of the low pressure system of the dog. The infusion of L-methionine (100 mg/kg) significantly increased plasma methionine levels (from 52 +/- 12 to 1,141 +/- 239 microM), cystine levels (from 12 +/- 4 to 26 +/- 7 microM), but not homocystine levels. In vitro, the L-methionine conversion product L-cysteine (0.1-1.0 mM) but not homocysteine significantly enhanced the augmentation of purified guanylyl cyclase activity by GTN (100 microM). Incubation of cultured rat aortic smooth muscle cells with L-methionine (10 microM or 1 mM) did not result in a significant increase of free intracellular sulfhydryl group content.<br><br>CONCLUSIONS: The L-methionine conversion product L-cysteine mediates tolerance independent the potentiation of GTN action. This may result from an L-cysteine-induced formation of a vasoactive metabolite of GTN (nitric oxide) or nitrosothiol. This effect occurs primarily in the resistance vessel circulation, not in large epicardial arteries and veins. The lack of effect of L-methionine on sulfhydryl group content in large conductance vessels indicates that hepatic L-methionine metabolism constitutes the significant source of L-cysteine. These findings strongly suggest that administration of sulfhydryl-group precursor L-methionine does not represent a therapeutic alternative to a nitrate-free interval to restore nitrate sensitivity in tolerant large epicardial arteries and veins.}, }
@article {pmid1298650, year = {1992}, author = {Edwards, AS and Wedzicha, BL}, title = {Kinetics and mechanism of the reaction between 3-deoxyhexosulose and thiols.}, journal = {Food additives and contaminants}, volume = {9}, number = {5}, pages = {461-469}, doi = {10.1080/02652039209374098}, pmid = {1298650}, issn = {0265-203X}, mesh = {Acetylcysteine/chemistry ; Brassica ; Chromatography, High Pressure Liquid ; Deoxyglucose/*analogs &amp; derivatives/chemistry ; Glutathione/chemistry ; Kinetics ; Mercaptoethanol/chemistry ; Sulfhydryl Compounds/*chemistry ; }, abstract = {The kinetics of the reaction of 3-deoxyhexosulose, DH, with mercaptoethanol, ME, and glutathione, GSH, resemble those of the DH-sulphite reaction, but the stoichiometry of the DH-thiol reaction is 1:2 unlike that of the DH-sulphite reaction which is 1:1. However, the rate determining step in all these reactions is the spontaneous conversion of DH to a reactive intermediate, followed by a rapid reaction of this intermediate with the nucleophile. This is also true of the reaction between DH and N-acetylcysteine, NAC, but this thiol is less reactive than ME or GSH and less than one mole of NAC reacts with each mole of DH. Evidence for instability of NAC at pH 5.5 is presented. Aminothiols (cysteine, homocysteine, cysteamine) undergo a fast reaction with DH followed by a slow release of thiol. The initial reaction is probably formation of a thiazolidine. In the case of cysteine and homocysteine it is suggested that the subsequent slow step is a Strecker degradation reaction. The kinetic behaviour of thiols in cabbage homogenates is reported.}, }
@article {pmid1510734, year = {1992}, author = {Pritsos, CA and Sokoloff, M and Gustafson, DL}, title = {PZ-51 (Ebselen) in vivo protection against adriamycin-induced mouse cardiac and hepatic lipid peroxidation and toxicity.}, journal = {Biochemical pharmacology}, volume = {44}, number = {4}, pages = {839-841}, doi = {10.1016/0006-2952(92)90427-k}, pmid = {1510734}, issn = {0006-2952}, support = {CA-43660/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Antioxidants/*pharmacology ; Azoles/*pharmacology ; Body Weight/drug effects ; *Chemical and Drug Induced Liver Injury ; Creatine Kinase/blood ; Doxorubicin/antagonists &amp; inhibitors/*toxicity ; Drug Interactions ; Female ; Heart Diseases/*chemically induced/prevention &amp; control ; Isoindoles ; Lipid Peroxidation/*drug effects ; Liver Diseases/prevention &amp; control ; Mice ; Mice, Inbred BALB C ; Organoselenium Compounds/*pharmacology ; }, abstract = {Adriamycin (Adr)-induced cardiotoxicity occurs most likely via an oxidative mechanism of action. Moderation of this activity may result in an improved therapeutic index for this compound. PZ-51, 2-phenyl-1,2-benzoisoselenazol-3(2H)-one, is a selenoorganic compound with thiol-dependent, peroxidase-like activity. We tested this compound alone and in combination with N-acetylcysteine (NAC) for its effect on Adr-induced in vivo toxicity in Balb/c mice. These studies demonstrated that PZ-51 protects against Adr-induced lipid peroxidation in heart and liver tissue and Adr-induced toxicity in general, as measured by total serum creatine kinase activity and body weight.}, }
@article {pmid1428725, year = {1992}, author = {Munshi, NC and Loehrer, PJ and Williams, SD and Langefeld, C and Sledge, G and Nichols, CR and Roth, BJ and Neuman, A and Walsh, WB and Einhorn, LH}, title = {Comparison of N-acetylcysteine and mesna as uroprotectors with ifosfamide combination chemotherapy in refractory germ cell tumors.}, journal = {Investigational new drugs}, volume = {10}, number = {3}, pages = {159-163}, pmid = {1428725}, issn = {0167-6997}, support = {MOI-RROO 750-06/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use ; Cisplatin/administration &amp; dosage ; Dysgerminoma/*drug therapy ; Etoposide/administration &amp; dosage ; Hematuria/chemically induced/*prevention &amp; control ; Humans ; Ifosfamide/*adverse effects ; Male ; Mesna/*therapeutic use ; Severity of Illness Index ; Vinblastine/administration &amp; dosage ; }, abstract = {From January 1983 through August 1988, 318 consecutive patients with refractory germ cell neoplasms were treated with ifosfamide-containing combination chemotherapy. The patients received ifosfamide at 1.2 gm/m2/day with cis-platin 20 mg/m2/day for 5 days and etoposide 75 mg/m2/day for 5 days or vinblastine 0.11 mg/kg on days 1 and 2 for each cycle. Of 277 evaluable patients, NAC was used as an uroprotector in the initial 86 patients while the latter 191 consecutive patients received mesna to reduce urothelial toxicity. Dosages of NAC was 2.0 gm po q 6 hr and for mesna 120 mg/m2 IV push prior to ifosfamide and then 1200 mg/m2/day as continuous infusion of 5 consecutive days. All patients received 3.0 liters of normal saline per day. The number of courses of chemotherapy given in the two groups were similar. Twenty-four of the 86 patients (27.9%) receiving NAC developed hematuria (13 patients - grade 1, 4 patients - grade 2, and 7 patients - grade 3 toxicity). While 8 out of 191 (4.2%) mesna patients developed hematuria (6 - grade 1 and 2 - grade 3) (p < 0.0001). The incidence of severity of renal toxicity was similar in the two groups. Ifosfamide dosage was reduced solely for urothelial toxicity in 11 patients receiving NAC compared with none of the patients receiving mesna (p < 0.0001). Chemotherapy response was similar in the two groups. In conclusion, mesna provides better urothelial protection from ifosfamide-induced toxicity than NAC and allows better maintenance of the drug dosage.}, }
@article {pmid1639069, year = {1992}, author = {Meyer, M and Caselmann, WH and Schlüter, V and Schreck, R and Hofschneider, PH and Baeuerle, PA}, title = {Hepatitis B virus transactivator MHBst: activation of NF-kappa B, selective inhibition by antioxidants and integral membrane localization.}, journal = {The EMBO journal}, volume = {11}, number = {8}, pages = {2991-3001}, pmid = {1639069}, issn = {0261-4189}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Base Sequence ; Blotting, Western ; Cell Line ; Cell Membrane/metabolism ; Chloramphenicol O-Acetyltransferase/genetics/metabolism ; Fluorescent Antibody Technique ; HeLa Cells ; Hepatitis B Surface Antigens/genetics/*metabolism ; Hepatitis B virus/drug effects/*genetics ; Humans ; Molecular Sequence Data ; NF-kappa B/*metabolism ; Oligodeoxyribonucleotides ; Protein Kinase C/antagonists &amp; inhibitors ; Pyrrolidines/*pharmacology ; Recombinant Fusion Proteins/metabolism ; Thiocarbamates/*pharmacology ; Trans-Activators/genetics/*metabolism ; Transfection ; }, abstract = {C-terminal truncation of the middle surface antigen from hepatitis B virus (MHBs) gives rise to a novel transactivating protein, called MHBst. In this study we show that MHBst like the HBx protein of HBV, can cause nuclear appearance of NF-kappa B DNA binding activity and induce various kappa B-controlled reporter genes. While an inhibitor of protein kinase C could not block gene induction by MHBst, the antioxidants N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) could potently suppress transactivation at mM and microM concentrations, respectively. Also, kappa B-dependent gene induction by the transactivator HBx was blocked. The effects were selective because PDTC did not interfere with MHBst and HBx-induced activation of the c-fos promoter/enhancer, nor with the basal activity of several other reporter genes lacking functional NF-kappa B binding motifs. Our data suggest that induction of a prooxidant state is crucial for the activation of NF-kappa B by MHBst and HBx and might be related to the hepatocarcinogenic potential of the viral proteins. MHBst had a subcellular localization unusual for a viral transactivator: it appeared to be an integral membrane protein of the endoplasmic reticulum.}, }
@article {pmid1628651, year = {1992}, author = {Huwyler, J and Aeschlimann, D and Christen, U and Gut, J}, title = {The kidney as a novel target tissue for protein adduct formation associated with metabolism of halothane and the candidate chlorofluorocarbon replacement 2,2-dichloro-1,1,1-trifluoroethane.}, journal = {European journal of biochemistry}, volume = {207}, number = {1}, pages = {229-238}, doi = {10.1111/j.1432-1033.1992.tb17042.x}, pmid = {1628651}, issn = {0014-2956}, mesh = {Animals ; Cell Fractionation ; *Chlorofluorocarbons ; Chlorofluorocarbons, Ethane ; Chlorofluorocarbons, Methane/*metabolism ; Halothane/*metabolism ; Hydrocarbons, Halogenated/*metabolism ; Kidney/drug effects/*metabolism/ultrastructure ; Liver/metabolism ; Male ; Microsomes/drug effects/*metabolism/ultrastructure ; Microsomes, Liver/metabolism ; Phenobarbital/pharmacology ; Protein Binding ; Proteins/analysis/*metabolism ; Rats ; Rats, Inbred Strains ; }, abstract = {Hydrochlorofluorocarbons (HCFCs) have been identified as chemical replacements of the widely used chlorofluorocarbons (CFCs) that are implicated in stratospheric ozone depletion. Many HCFCs are structural analogues of the anesthetic agent halothane and may follow a common pathway of biotransformation and formation of adducts to protein-centered and other cellular nucleophiles. Exposure of rats to a single dose of halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) or of the candidate CFC substitute HCFC 123 (2,2-dichloro-1,1,1-trifluoroethane) led to the formation of trifluoroacetylated protein adducts (CF3CO-proteins) not only in the liver, but also in the kidney as a novel target tissue for protein trifluoroacetylation. CF3CO-proteins in the kidney amounted to about 5% of those formed in the liver of the same animal. The amount of CF3CO-proteins formed within the kidney was roughly reflected by the capacity of metabolism of halothane or HCFC 123 by rat kidney microsomes in vitro which amounted to about 10% of that observed with liver microsomes. By immunohistochemistry, CF3CO-proteins in the kidney were mainly localized in the tubular segments of the cortex. In the liver, the density of CF3CO-proteins decreased from the central vein towards the portal triad. In vitro incubation of rat liver microsomes with halothane or HCFC 123 resulted in extensive formation of CF3CO-proteins and reproduced faithfully the pattern of liver CF3CO-proteins obtained in vivo. CF3CO-proteins generated in vitro were immunochemically not discernible from those generated in vivo. Glutathione (5 mM) and cysteine (5 mM) virtually abolished CF3CO-protein formation; the release of Br- from halothane and Cl- from HCFC 123 was reduced to much lesser a degree. S-Methyl-glutathione, N-acetyl-cysteine, methionine, and N-acetyl-methionine only slightly affected the formation of CF3CO-proteins or metabolism of either substrate. The data suggest that metabolism and concomitant CF3CO-protein formation of halothane or of candidate CFC replacements like HCFC 123 is not restricted to the liver but also takes place in the kidney. Furthermore, an in vitro system for CF3CO-protein formation has been developed and used to show that protein-centered and glutathione-centered nucleophilic sites compete for intermediates of metabolism of halothane or of HCFC 123.}, }
@article {pmid1529808, year = {1992}, author = {Brumas, V and Hacht, B and Filella, M and Berthon, G}, title = {Can N-acetyl-L-cysteine affect zinc metabolism when used as a paracetamol antidote?.}, journal = {Agents and actions}, volume = {36}, number = {3-4}, pages = {278-288}, pmid = {1529808}, issn = {0065-4299}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/blood/pharmacokinetics/*pharmacology ; Antidotes/*pharmacology ; Computer Simulation ; Digestive System Physiological Phenomena ; Hydrogen-Ion Concentration ; Potentiometry ; Zinc/*metabolism ; }, abstract = {N-Acetyl-L-cysteine (NAC) has long been used in the treatment of chronic lung diseases. Inhalation and oral administration of the drug are both effective in reducing mucus viscosity. In addition, NAC oral therapy allows to restore normal mucoprotein secretion in the long term. Although displaying heavy metal-complexing potential, NAC exerts no detectable influence on the metabolism of essential trace metals when used in the above context (i.e. at doses near 600 mg day-1). However, this may no longer be the case when NAC is used as an oxygen radical scavenger, like in the treatment of paracetamol poisoning. In the latter case, intravenous doses as high as 20 g day-1 are administered, which may induce excessive zinc urinary excretion. In order to allow a better appreciation of the risk of zinc depletion during NAC therapy, the present work addresses the role of this drug towards zinc metabolism at the molecular level. First, formation constants for zinc-NAC complexes have been determined under physiological conditions. Then, computer simulations for blood plasma and gastrointestinal fluid have been run to assess the influence of NAC and its metabolites (e.g. cysteine and glutathione) on zinc excretion and absorption. Blood plasma simulations reveal that NAC can effectively mobilise an important fraction of zinc into urinary excretable complexes as from concentrations of 10(-3) mol dm-3 (which corresponds to a dose of about 800 mg). This effect can still be enhanced by the action of NAC metabolites, among which cysteine is the most powerful zinc sequestering agent. In contrast, simulations relative to gastrointestinal conditions suggest that NAC should tend to increase zinc absorption, regardless of its dose.}, }
@article {pmid1529807, year = {1992}, author = {Le Guen, CA and Bain, S and Barnett, AH and Lunec, J}, title = {Captopril inhibits the fluorescence development associated with glycation of proteins.}, journal = {Agents and actions}, volume = {36}, number = {3-4}, pages = {264-270}, pmid = {1529807}, issn = {0065-4299}, mesh = {Albumins/immunology/metabolism ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Captopril/*pharmacology ; Chromatography, High Pressure Liquid ; Copper ; Fluorescence ; Free Radical Scavengers ; Gamma Rays ; Glucose/*chemistry ; Hydrogen Peroxide ; Immunoglobulin G/immunology/metabolism ; Proteins/*chemistry/drug effects/radiation effects ; Spectrophotometry, Ultraviolet ; }, abstract = {Albumin and immunoglobulin G (IgG) show increased visible fluorescence in diabetic patients, IgG fluorescence being correlated with the presence of diabetic retinopathy. Captopril, an angiotensin converting enzyme (ACE) inhibitor, has free radical scavenging ability, attributable to its thiol group. We compared the scavenging effect of captopril (at doses between 0.5 and 100 microM) with perindoprilat, enalapril and enalaprilat (ACE inhibitors without scavenging ability) and two thiol-containing compounds, mercaptopropionylglycine (MPG) and N-acetylcysteine (NAC) (scavengers with no effect on ACE). Three systems were used to generate visible fluorescence in albumin and IgG; glycation, exposure to copper/hydrogen peroxide and gamma radiation. All three thiol-containing compounds inhibited fluorescence development in IgG and albumin, when fluorescence was generated by glycation or gamma radiation. Other ACE inhibitors had no effect with IgG. Enalapril and perindoprilat showed less effect than captopril with albumin; enalaprilat had no effect. No compound had any effect on fluorescence generation by copper/hydrogen peroxide. Captopril may have an additional antioxidant effect compared to other ACE inhibitors.}, }
@article {pmid1520537, year = {1992}, author = {Ho, WZ and Douglas, SD}, title = {Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte/macrophages in vitro.}, journal = {AIDS research and human retroviruses}, volume = {8}, number = {7}, pages = {1249-1253}, doi = {10.1089/aid.1992.8.1249}, pmid = {1520537}, issn = {0889-2229}, support = {500-18S-11PG/PG/OAPP OPHS HHS/United States ; MH 47422/MH/NIMH NIH HHS/United States ; NS 27405/NS/NINDS NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Glutathione/*pharmacology ; HIV-1/*drug effects/physiology ; Humans ; Kinetics ; Macrophages/*microbiology ; Monocytes/*microbiology ; Virus Replication/drug effects ; }, abstract = {Glutathione (GSH), its derivatives and N-acetylcysteine (NAC) inhibit the induction of HIV-1 expression in a chronically HIV-1-infected promonocytic cell line (U1/HIV) and peripheral blood mononuclear cells (PBMC). We have examined the effects of GSH and NAC on HIV-1 replication in human primary monocyte/macrophages cultured in vitro. Ficoll-gradient purified human monocytes were cultivated in vitro for 7-10 days and then infected with HIV-1 (Bal and Ada-M). Infection was blocked or substantially reduced by GSH or NAC (5-20 mM). Significant reduction (greater than or equal to 90%) in the amount of virus released, as determined by measuring supernatant reverse transcriptase activity and secreted p24 protein, was obtained when the cells were treated for 4 h with greater than or equal to 10 mM of GSH or NAC. The inhibitory effects of GSH and NAC were concentration dependent. This anti-HIV-1 effect persisted in these cultures for at least 35 days without evidence of significant increase in HIV-1 expression. Thus, a single pulse exposure of HIV-1-infected monocyte/macrophages with GSH or NAC led to a sustained, concentration-dependent decrease in HIV-1 p24 antigen levels, as well as, reverse transcriptase activity without producing detectable cellular toxicity in monocyte/macrophages.}, }
@article {pmid1391618, year = {1992}, author = {Wang, M and Nishikawa, A and Chung, FL}, title = {Differential effects of thiols on DNA modifications via alkylation and Michael addition by alpha-acetoxy-N-nitrosopyrrolidine.}, journal = {Chemical research in toxicology}, volume = {5}, number = {4}, pages = {528-531}, doi = {10.1021/tx00028a011}, pmid = {1391618}, issn = {0893-228X}, support = {CA-44377/CA/NCI NIH HHS/United States ; CA-51830/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/chemistry ; Aldehydes/chemistry ; Alkylation ; DNA/*chemistry ; Glutathione/chemistry ; Guanine/analysis ; Mesna/chemistry ; N-Nitrosopyrrolidine/*analogs &amp; derivatives/chemistry ; Sulfhydryl Compounds/*chemistry ; }, abstract = {The hepatocarcinogen NPYR is metabolically activated by alpha-hydroxylation mediated by cytochrome P-450 enzymes to yield a 4-oxobutylating agent and 2-butenal (crotonaldehyde). Both are reactive intermediates capable of modifying DNA with guanine either by simple alkylation or by Michael type addition, respectively. In order to assess the roles of these pathways in NPYR tumorigenesis, we are interested in identifying agents which can selectively modify one of these two pathways. In this study, we examined the effects of three thiols--(mesna), glutathione (Glu), and N-acetylcysteine (Nac)--on DNA adduct formation by alpha-acetoxyNPYR, a stable precursor of alpha-hydroxyNPYR. Calf thymus DNA isolated from incubation of alpha-acetoxyNPYR with or without thiol was hydrolyzed and analyzed for the adducts formed by alkylation (adducts 1 and 2) and Michael addition (adducts 3-5). The results showed that the addition of mesna completely blocked the formation of the crotonaldehyde-derived adducts 3-5, whereas it exerted little effect on the formation of the alkylated adducts 1 and 2. These results indicate the preferential conjugation of mesna with crotonaldehyde. In contrast, Nac had little selectivity on adduct formation; levels of adducts 1 to 5 were were reduced by 36-75%. These results suggest that Nac conjugated with both alkylating agent and crotonaldehyde. Similar to mesna, Glu blocked the formation of the crotonaldehyde-derived adducts (adducts 3-5) efficiently. However, unlike mesna, Glu inhibited the formation of adduct 1, while it did not inhibit the formation of adduct 2, although both adducts are presumably derived from the 4-oxobutylating agent.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1326880, year = {1992}, author = {Ohman, L and Dahlgren, C and Follin, P and Lew, D and Stendahl, O}, title = {N-acetylcysteine enhances receptor-mediated phagocytosis by human neutrophils.}, journal = {Agents and actions}, volume = {36}, number = {3-4}, pages = {271-277}, pmid = {1326880}, issn = {0065-4299}, mesh = {Acetylcysteine/*pharmacology ; Catalase/pharmacology ; Granulomatous Disease, Chronic/enzymology/metabolism ; Humans ; In Vitro Techniques ; Luminescent Measurements ; Neutrophils/*drug effects ; Phagocytosis/*drug effects ; Receptors, Cell Surface/drug effects/*physiology ; Saccharomyces cerevisiae/immunology/metabolism ; Stimulation, Chemical ; }, abstract = {The effect of the sulphur compound N-acetylcysteine (NAC) on certain receptor-mediated cellular functions [chemiluminescence (CL), phagocytosis and degranulation] in human neutrophils was studied, to evaluate how a scavenger of certain toxic oxygen product can protect the phagocyte and the bystander tissue cells from oxidative damage. When using IgG-opsonized yeast particles as stimulating agent, preincubating the neutrophils with NAC (0.25 mg/ml = 1.5 mM) increased both the CL response and phagocytosis. Higher concentrations of NAC (0.50-1.00 mg/ml = 3-6 mM) decreased the CL response, whereas the phagocytic capacity was still enhanced. This effect was more pronounced with adherent neutrophils than with neutrophils in suspension. No increased CL or phagocytic activity was, however, induced by NAC when C3bi-opsonized particles were used as a prey. From the fact that NAC (i) inhibited extracellularly localized myeloperoxidase dependent activities, and (ii) had no effect on neutrophils from patients with chronic granulomatous disease (CGD), we conclude that the scavenger effect of NAC not only reduces the accumulation of oxidative metabolites per se, but also enhances receptor-mediated phagocytosis by protecting Fc(IgG)-receptors from oxidative damage mediated by myeloperoxidase (MPO) and hydrogen peroxide (H2O2). Since NAC can increase phagocytosis and reduce the extracellularly produced oxidative metabolites, we furthermore conclude that NAC possesses some ideal properties as an anti-inflammatory agent.}, }
@article {pmid1611595, year = {1992}, author = {Balansky, RB and D'Agostini, F and Zanacchi, P and De Flora, S}, title = {Protection by N-acetylcysteine of the histopathological and cytogenetical damage produced by exposure of rats to cigarette smoke.}, journal = {Cancer letters}, volume = {64}, number = {2}, pages = {123-131}, doi = {10.1016/0304-3835(92)90072-4}, pmid = {1611595}, issn = {0304-3835}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Atmosphere Exposure Chambers ; Body Weight ; Bone Marrow/drug effects/ultrastructure ; Bronchitis/etiology/prevention &amp; control ; Bronchoalveolar Lavage Fluid/cytology/*pathology ; Cell Survival/drug effects ; Emphysema/etiology/prevention &amp; control ; Erythrocytes/drug effects/ultrastructure ; Lung/drug effects/*pathology ; Macrophages, Alveolar/drug effects/ultrastructure ; Male ; Micronucleus Tests ; Neutrophils/drug effects ; *Plants, Toxic ; Rats ; Rats, Inbred Strains/growth &amp; development ; Smoke/*adverse effects ; *Nicotiana ; Tobacco Smoke Pollution/*adverse effects ; }, abstract = {Adult male Sprague-Dawley rats were exposed whole-body to mainstream cigarette smoke (CS) once daily for 40 consecutive days. Such a treatment resulted in a significant decrease of body weight growth and in intense histopathological changes of terminal airways, including a severe inflammation of bronchial and bronchiolar mucosae, with multiple hyperplastic and metaplastic lesions and foci of micropapillomatous growth as well as emphysema, with extensive disruption of alveolar walls. All histopathological changes were efficiently prevented by the daily administration of the thiol N-acetyl-L-cysteine (NAC) by gavage. Cytological and cytogenetical changes were monitored in bronchoalveolar lavage (BAL) fluid and bone marrow cells of groups of rats killed after 1, 3, 8, 28, or 40 days of treatment. From the first day of exposure, CS significantly enhanced the proportion of polymorphonucleates among BAL cells and the frequency of micronucleated (MN) bone marrow polychromatic erythrocytes. After 8 days, a reduction was observed in the polychromatic/normochromatic erythrocytes ratio and an increase in the frequency of MN pulmonary alveolar macrophages (PAM) was also recorded, followed, after 28 days, by an increase of binucleated PAM. All these alterations immediately reached a plateau and persisted unchanged until the end of the experiment. NAC administration exhibited a significant and considerable protective effect towards the CS-induced alterations of BAL cellularity, the increase of MN PAM and bone marrow cytotoxicity.}, }
@article {pmid1611284, year = {1992}, author = {Stewart, S}, title = {Current theories and therapies relating to acute myocardial infarction and reperfusion injury.}, journal = {Intensive &amp; critical care nursing}, volume = {8}, number = {2}, pages = {104-112}, doi = {10.1016/0964-3397(92)90039-m}, pmid = {1611284}, issn = {0964-3397}, mesh = {Electrocardiography ; Humans ; Myocardial Infarction/nursing/physiopathology/*therapy ; Myocardial Reperfusion/adverse effects/*methods ; Myocardial Reperfusion Injury/*etiology/nursing/physiopathology ; }, abstract = {Acute myocardial infarction (AMI) was previously treated with conservative strategies that allowed the process of ischaemia to proceed uninterrupted. The resultant myocardial necrosis and reduced ventricular function were accepted outcomes. The emergence of thrombolytic agents such as streptokinase and tissue plasminogen activator (tPA) revolutionised the management of coronary artery occlusion, yet the spectre of further myocardial necrosis and ventricular dysfunction remains. The concept of 'reperfusion injury', an acute process described as occurring after thrombolysis of a coronary artery occlusion and referring to an unexpected loss of ventricular function, has been extensively researched. Current research papers describing the mechanisms involved appear either to emphasise those processes that occur within the actual myocytes, or those events within the coronary vasculature. In most papers however, oxygen free radicals (OFRs) are accepted as mediators of cellular injury; despite the debate surrounding their primary source. Efforts to minimise the effects of primary ischaemia and subsequent 'reperfusion injury', appear to be focused upon restoring cardioprotection against the increased levels of these damaging molecules. Scavenging agents such as N-acetylcysteine (NAC) which can also assist in dilating coronary vessels as well as preventing further platelet aggregation, when combined with glyceryl trinitrate (GTN), are being closely scrutinised. Despite the advances made, the processes within the myocardium remain somewhat a mystery and the search continues for more effective strategies to ensure myocardial viability and long-term function. Critical care nurses need not only to be aware of the aim of these new strategies, but should also be conscious of their effect on the patients receiving them.}, }
@article {pmid1530678, year = {1992}, author = {Ammon, HP and Müller, PH and Eggstein, M and Wintermantel, C and Aigner, B and Safayhi, H and Stützle, M and Renn, W}, title = {Increase in glucose consumption by acetylcysteine during hyperglycemic clamp. A study with healthy volunteers.}, journal = {Arzneimittel-Forschung}, volume = {42}, number = {5}, pages = {642-645}, pmid = {1530678}, issn = {0004-4172}, mesh = {Acetylcysteine/adverse effects/pharmacokinetics/*pharmacology ; Adult ; Blood Glucose/*metabolism ; Female ; Glucose/*metabolism ; Glutathione/blood ; Half-Life ; Humans ; Insulin/blood ; Male ; Models, Biological ; }, abstract = {Thiols have been shown to be related to insulin secretion and to uptake of glucose into tissues. In the present study the effects of i.v. administration of acetylcysteine (N-acetylcysteine, NAC, CAS 616-91-1) on glucose consumption and plasma free thiols were studied in young healthy volunteers during hyperglycemic clamp. NAC (0.5-2.0 mg/kg) significantly increased glucose consumption. This effect was not obvious at higher doses of NAC. Plasma free NAC depended on the dose of NAC injected. The t1/2 of NAC was 11 min. NAC produced significant increases of plasma cysteine concentrations, and a slight but insignificantly increase of plasma glutathione. These data suggest that a moderate increase in plasma thiols augments glucose consumption during hyperglycemic clamp.}, }
@article {pmid1544168, year = {1992}, author = {Peristeris, P and Clark, BD and Gatti, S and Faggioni, R and Mantovani, A and Mengozzi, M and Orencole, SF and Sironi, M and Ghezzi, P}, title = {N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production.}, journal = {Cellular immunology}, volume = {140}, number = {2}, pages = {390-399}, doi = {10.1016/0008-8749(92)90205-4}, pmid = {1544168}, issn = {0008-8749}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cells, Cultured ; Corticosterone/blood ; Dactinomycin/pharmacology ; Glutathione/*metabolism ; Interleukin-1/biosynthesis ; Interleukin-6/biosynthesis ; Lipopolysaccharides/toxicity ; Macrophages/drug effects/immunology ; Male ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Mice ; Mice, Inbred Strains ; Serum Amyloid A Protein/analysis/drug effects ; Tumor Necrosis Factor-alpha/*biosynthesis ; }, abstract = {TNF is a major mediator in the pathogenesis of endotoxic shock, and its inhibition has a protective effect in various animal models of sepsis or endotoxin (lipopolysaccharide, LPS) toxicity. LPS treatment also induces an oxidative damage mediated by increased production of reactive oxygen intermediates. N-Acetylcysteine (NAC) is an antioxidant and a precursor of the synthesis of glutathione (GSH) and was reported to protect against LPS toxicity and LPS-induced pulmonary edema. In this study we investigated the effect of NAC on TNF production and LPS lethality in mice. The results indicated that oral administration of NAC protects against LPS toxicity and inhibits the increase in serum TNF levels in LPS-treated mice. The inhibition was not confined to the released form of TNF, since NAC also inhibited LPS-induced spleen-associated TNF. On the other hand, the inhibitor of GSH synthesis, DL-buthionine-(SR)-sulfoximine (BSO), had the opposite effect of potentiating LPS-induced TNF production, and this was associated with a decrease in liver GSH levels. Repletion of liver GSH with NAC reversed this effect. NAC was also active in inhibiting TNF production and hepatotoxicity in mice treated with LPS in association with a sensitizing dose of Actinomycin D. These data indicate that GSH can be an endogenous modulator of TNF production in vivo. On the other hand, NAC pretreatment did not inhibit other effects of LPS, particularly induction of serum IL-6, spleen IL-1 alpha, and corticosterone, in the same experimental model, suggesting that the observed effect could be specific for TNF.}, }
@article {pmid1544167, year = {1992}, author = {Levy, EM and Wu, J and Salibian, M and Black, PH}, title = {The effect of changes in thiol subcompartments on T-cell colony formation and cell cycle progression: relevance to AIDS.}, journal = {Cellular immunology}, volume = {140}, number = {2}, pages = {370-380}, doi = {10.1016/0008-8749(92)90203-2}, pmid = {1544167}, issn = {0008-8749}, mesh = {Acetylcysteine/*pharmacology ; Acquired Immunodeficiency Syndrome/*immunology ; Buthionine Sulfoximine ; Cell Compartmentation ; Cell Cycle/drug effects ; Cells, Cultured ; Colony-Forming Units Assay ; Cyclohexanones/pharmacology ; Humans ; Mercaptoethanol/*pharmacology ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Protein Kinase C/metabolism ; Sulfhydryl Compounds/*metabolism ; T-Lymphocytes/cytology/drug effects/*immunology ; }, abstract = {Recently, it has been shown that intra- and extracellular thiol levels are significantly lower than normal even in the relatively early stages of human immunodeficiency virus (HIV) infection. It is plausible that this deficiency could contribute both to the loss of T-cell function and the ability to replenish T cells associated with HIV infection. We had previously reported that the T-cell colony-forming cell (T-CFC) is impaired in HIV infection and that it can be enhanced with the thiol compounds 2-mercaptoethanol (2-ME) and N-acetylcysteine (NAC). In this study, the effect of the thiol-depleting reagents buthionine sulfoximine, cyclohexene-1-one, and copper phenanthroline on T-CFC formation and cell cycle progression was determined in HIV+ subject and/or controls. All three reagents inhibited T-CFC formation and cell cycle progression with a suggestion that colony formation by cells from HIV+ subjects was more sensitive to the effects of thiol depletion. 2-ME and NAC enhanced effect of NAC did not appear to involve increased protein kinase C translocation. Our results suggest that oxidation of membrane thiols, as well as depletion of intracellular glutathione, inhibits T-CFC formation as well as cell cycle progression for mitogen-stimulated cells in bulk culture.}, }
@article {pmid1340573, year = {1992}, author = {Brahm, J and Silva, G and Palma, R}, title = {[Paracetamol overdose: a new form of suicide in Chile and the value of N-acetylcysteine administration].}, journal = {Revista medica de Chile}, volume = {120}, number = {4}, pages = {427-429}, pmid = {1340573}, issn = {0034-9887}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/*therapeutic use ; Adolescent ; Chile ; Drug Overdose/drug therapy ; Female ; Humans ; Middle Aged ; Suicide, Attempted ; }, abstract = {Overdose of paracetamol is associated to varying degrees of hepatic necrosis and may lead to severe hepatic failure. In this paper, we report 2 patients with paracetamol overdose for suicidal purposes who were successfully treated using the antidote N-acetyl-cysteine orally. A brief analysis of the literature follows.}, }
@article {pmid1554394, year = {1992}, author = {Traber, J and Suter, M and Walter, P and Richter, C}, title = {In vivo modulation of total and mitochondrial glutathione in rat liver. Depletion by phorone and rescue by N-acetylcysteine.}, journal = {Biochemical pharmacology}, volume = {43}, number = {5}, pages = {961-964}, doi = {10.1016/0006-2952(92)90599-e}, pmid = {1554394}, issn = {0006-2952}, mesh = {Acetylcysteine/*pharmacology ; Alloxan/pharmacology ; Animals ; Calcium/*metabolism ; Glutathione/*metabolism ; Injections, Intraperitoneal ; Ketones/*pharmacology ; Liver/drug effects/*metabolism ; Male ; Mitochondria, Liver/drug effects/metabolism ; Nucleotides/metabolism ; Peroxides/pharmacology ; Rats ; Rats, Inbred Strains ; tert-Butylhydroperoxide ; }, abstract = {The aim of the present work was to modulate in vivo the level of hepatic mitochondrial glutathione (GSH). Rats were given phorone (diisopropylidene acetone), which in vivo becomes enzymatically conjugated to GSH, and were subsequently treated with N-acetylcysteine (NAC) to rescue GSH. In liver homogenate, a rapid and biphasic (T1/2 less than or equal to 15 min and 1.5 hr) drop of GSH was observed upon phorone administration. NAC treatment led to a restoration (T1/2 about 1 hr) of GSH in the homogenate above control values within 3 hr. The mitochondrial GSH level decreased with T1/2 of about 1.5 hr upon phorone treatment, and was 75% restored by NAC treatment within 3 hr. Hydroperoxide-induced mitochondrial pyridine nucleotide oxidation and Ca2+ release were impeded in GSH-depleted organelles, and NAC treatment restored these processes. The GSH status had no influence on mitochondrial pyridine nucleotide oxidation and Ca2+ released induced by alloxan, which reacts directly and non-enzymatically with pyridine nucleotides. It is concluded that NAC is able to rescue mitochondrial GSH in vivo and restore important mitochondrial functions. The data suggest that NAC may be a useful antidote in oxidative stress-related diseases.}, }
@article {pmid1587147, year = {1992}, author = {Epstein, DL and Hooshmand, LB and Epstein, MP}, title = {Thiol adducts of ethacrynic acid increase outflow facility in enucleated calf eyes.}, journal = {Current eye research}, volume = {11}, number = {3}, pages = {253-258}, doi = {10.3109/02713689209001776}, pmid = {1587147}, issn = {0271-3683}, support = {R01 EY01894/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; Anterior Chamber/drug effects ; Aqueous Humor/*metabolism ; Cattle ; Cysteamine/analogs &amp; derivatives/pharmacology ; Cysteine/analogs &amp; derivatives/pharmacology ; Ethacrynic Acid/*pharmacology ; Eye Enucleation ; Glutathione/analogs &amp; derivatives/pharmacology ; Perfusion ; }, abstract = {Ethacrynic acid (ECA), a sulfhydryl (SH)-reactive diuretic drug, has been shown to increase outflow facility (C) both in living monkey eyes and in the calf eye, in vitro (Epstein et al. 1987). In an attempt to increase the therapeutic index of this drug for potential clinical use in glaucoma, we explored the effect of various thiol adducts of ECA on C in the calf eye in vitro. These adducts might be expected to liberate ECA by a reversible retro-Michael type reaction. Enucleated calf eyes were perfused at 25 degrees C at 15 mm Hg for 5 hours with various ECA-thiol adducts. ECA-cysteine at 0.25 mM (for each) increased outflow facility 104% compared to 38% in sham manipulated eyes (n-10; p less than .005). A dose response effect was demonstrated from 0.01 mM to 0.25 mM. A relative potency table (for increasing C) was established for several ECA-thiol adducts: Cysteine = cysteamine greater than glutathione greater than N-Acetyl cysteine greater than thiosalicylic acid greater than N-Acetyl cysteamine. This study identifies the potential of utilizing various derivatives of ECA as outflow pathway acting agents.}, }
@article {pmid1623211, year = {1992}, author = {Benvenuto, JA and Ayele, W and Legha, SS and Raber, MN and Nicaise, C and Newman, RA}, title = {Clinical pharmacokinetics of ifosfamide in combination with N-acetylcysteine.}, journal = {Anti-cancer drugs}, volume = {3}, number = {1}, pages = {19-23}, doi = {10.1097/00001813-199202000-00004}, pmid = {1623211}, issn = {0959-4973}, mesh = {Acetylcysteine/blood/pharmacokinetics/urine ; Agranulocytosis/drug therapy ; Bone Marrow/drug effects ; Humans ; Ifosfamide/blood/*pharmacokinetics/urine ; Sarcoma/*drug therapy ; }, abstract = {The pharmacokinetics of ifosfamide were studied in 20 patients with soft tissue and bone sarcomas. Drug was administered as a 30-60 min i.v. infusion at 1.2 or 2.0 mg/m2/day for five consecutive days. Some patients also received 1.5 g/m2 of N-acetylcysteine (NAC) administered 3 times per day during the course of therapy. NAC had no effect on ifosfamide pharmacokinetics. There were significant differences in plasma half-life, area under the concentration-time curve and plasma clearance on day 1 versus day 5 of ifosfamide administration. Myelosuppression and granulocytopenia correlated better with day 1 versus day 5 ifosfamide pharmacokinetics suggesting that the alteration of ifosfamide pharmacology with multiple dosing has a significant effect on drug activity.}, }
@article {pmid1540408, year = {1992}, author = {Roederer, M and Ela, SW and Staal, FJ and Herzenberg, LA and Herzenberg, LA}, title = {N-acetylcysteine: a new approach to anti-HIV therapy.}, journal = {AIDS research and human retroviruses}, volume = {8}, number = {2}, pages = {209-217}, doi = {10.1089/aid.1992.8.209}, pmid = {1540408}, issn = {0889-2229}, support = {CA42509/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Acquired Immunodeficiency Syndrome/*drug therapy/metabolism ; Animals ; Cytokines/metabolism ; Glutathione/*metabolism ; HIV/metabolism ; Humans ; Lymphocytes/metabolism ; Oxygen Consumption/drug effects ; Sulfhydryl Compounds/metabolism ; }, abstract = {Several investigators have implicated depletion of glutathione (GSH) and production of reactive oxygen intermediates (ROIs) in the regulation of the human immunodeficiency virus (HIV). We have shown directly that N-acetylcysteine (NAC) blocks HIV expression in chronic and acute infection models, and HIV replication in normal peripheral blood mononuclear cells. NAC is a cysteine prodrug which maintains intracellular thiol levels during oxidative stress and replenishes depleted GSH. The observed antiviral effect of NAC is due to inhibition of viral stimulation by ROIs, which are produced in response to inflammatory cytokines. We have also shown that HIV-infected individuals have decreased intracellular GSH levels in their circulating T cells. Since GSH is the major protection against the production of ROIs, we hypothesize that the observed decrease is due to a chronic oxidative stress induced by continual exposure to elevated levels of inflammatory cytokines. Together, these results provide a rationale for clinical trials testing the efficacy of GSH-replenishing drugs such as NAC in the treatment of AIDS. NAC is different than many other antiviral drugs in that it inhibits host-mediated stimulation of viral replication arising in normal immune responses, and may thereby extend latency. In addition, it inhibits the action of inflammatory cytokines which may mediate cachexia, thereby raising the possibility that it may alleviate the deleterious wasting that accompanies late stage AIDS.}, }
@article {pmid1510833, year = {1992}, author = {D'Agostini, F and Scatolini, L and Maggiani, M and Balansky, R}, title = {[Chemoprevention of genotoxic damage in lung cells of rats exposed to cigarette smoke].}, journal = {Bollettino della Societa italiana di biologia sperimentale}, volume = {68}, number = {2}, pages = {137-142}, pmid = {1510833}, issn = {0037-8771}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bronchoalveolar Lavage Fluid/cytology ; Cell Nucleus/drug effects ; Macrophages, Alveolar/*drug effects/ultrastructure ; Male ; Micronucleus Tests ; Rats ; Rats, Inbred Strains ; Time Factors ; Tobacco Smoke Pollution/*adverse effects ; }, abstract = {Male Sprague-Dawley rats were exposed to cigarette smoke (CS) according to a complex protocol which lasted 40 days. Some of the groups were pre-treated with N-acetyl-L-cysteine (NAC) by gavage (1 g/kg b.w.) 5 h before each exposure. Bronchoalveolar lavage was performed in each animal at the end of each exposure period in order to recover pulmonary alveolar macrophages (PAM). Cells were identified and counted under the microscope, and the number of micronucleated (MN) and binucleated (BN) PAM was registered. The results showed an increase in the number of MN PAM, which was already evident after 8 days of CS exposure; this increase remained constant after 28 and 40 days of exposure. A significant decrease in the number of MN PAM was observed in the animals pre-treated with NAC. BN PAM were significantly increased after 28 and 40 days of exposure; again, a slight yet not significant decrease was detected in NAC-pre-treated animals. On the whole, this study demonstrates that CS is clearly clastogenic to alveolar macrophages and that NAC can efficiently prevent this cytogenetic damage.}, }
@article {pmid1309791, year = {1992}, author = {Romero, FJ and Ordoñez, I and Arduini, A and Cadenas, E}, title = {The reactivity of thiols and disulfides with different redox states of myoglobin. Redox and addition reactions and formation of thiyl radical intermediates.}, journal = {The Journal of biological chemistry}, volume = {267}, number = {3}, pages = {1680-1688}, pmid = {1309791}, issn = {0021-9258}, support = {ES05423/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Catalase/metabolism ; Disulfides/*pharmacology ; Electron Spin Resonance Spectroscopy ; Free Radicals ; Horses ; Metmyoglobin/chemistry/metabolism ; Myoglobin/*chemistry/metabolism ; Oxidation-Reduction ; Protein Conformation ; Spectrophotometry ; *Sulfhydryl Compounds/*pharmacology ; }, abstract = {The reactivity of several thiols, including glutathione, dihydrolipoic acid, cysteine, N-acetyl cysteine, and ergothioneine, as well as several disulfides, toward different redox states of myoglobin, mainly met-myoglobin (HX-FeIII) and ferrylmyoglobin (HX-FeIV=O), was evaluated by optical spectral analysis, product formation, and thiyl free radical generation. Only dihydrolipoic acid reduced met-myoglobin to oxy-myoglobin, whereas all the other thiols tested did not interact with met-myoglobin. Although the redox transitions involved in the former reduction were expected to yield the dihydrolipoate thiyl radical, the reaction was EPR silent. Conversely, all thiols interacted to different extent with the high oxidation state of myoglobin, i.e. ferrylmyoglobin, via two processes. First, direct electron transfer to heme iron in ferrylmyoglobin (HX-FeIV=O) with formation of met-myoglobin (HX-FeIII) or oxymyoglobin (HX-FeIIO2); the former transition was effected by all thiols except dihydrolipoate, which facilitated the latter, i.e. the formation of the two-electron reduction product of ferrylmyoglobin. Second, nucleophilic addition onto a pyrrole in ferrylmyoglobin with subsequent formation of sulfmyoglobin. The contribution of either direct electron transfer to the heme iron or nucleophilic addition depended on the physicochemical properties of the thiol involved and on the availability of H2O2 to reoxidize met-myoglobin to ferrylmyoglobin. The thiyl radicals of glutathione, cysteine, and N-acetylcysteine were formed during the interaction of the corresponding thiols with ferrylmyoglobin and detected by EPR in conjunction with the spin trap 5,5'-dimethyl-1-pyroline-N-oxide. The intensity of the EPR signal was insensitive to superoxide dismutase and it was decreased, but not suppressed, by catalase. The disulfides of glutathione and cysteine did not react with ferrylmyoglobin, but the disulfide bridge in lipoic acid interacted efficiently with the ferryl species by either reducing directly the heme iron to form met-myoglobin or adding onto a pyrrole ring to form sulfmyoglobin; either process depended on the presence or absence of catalase (to eliminate the excess of H2O2) in the reaction mixture, respectively. The biological significance of the above results is discussed in terms of the occurrence and distribution of high oxidation states of myoglobin, its specific participation in cellular injury, and its potential interaction with biologically important thiols leading to either recovery of myoglobin or generation of nonfunctional forms of the hemoprotein as sulfmyoglobin.}, }
@article {pmid1733359, year = {1992}, author = {Mercer, DW and Ritchie, WP and Dempsey, DT}, title = {Do sensory neurons mediate adaptive cytoprotection of gastric mucosa against bile acid injury?.}, journal = {American journal of surgery}, volume = {163}, number = {1}, pages = {12-7; discussion 17-8}, doi = {10.1016/0002-9610(92)90245-m}, pmid = {1733359}, issn = {0002-9610}, mesh = {Acetylcysteine/pharmacology ; Adaptation, Physiological/physiology ; Animals ; Bile Acids and Salts/*adverse effects ; DNA/metabolism ; Gastric Mucosa/drug effects/*physiology ; Lidocaine/pharmacology ; Mucus/metabolism ; Neurons, Afferent/*physiology ; Rats ; Rats, Inbred Strains ; Taurocholic Acid/adverse effects ; }, abstract = {Pretreatment with the mild irritant 1 mmol acidified taurocholate protects the gastric mucosa from the injury induced by the subsequent application of 5 mmol acidified taurocholate, a phenomenon referred to as "adaptive cytoprotection." How this occurs remains an enigma. The purpose of this study was to investigate the role of sensory neurons and mucus secretion in this phenomenon. Prior to injury with 5 mmol acidified taurocholate (pH 1.2), the stomachs of six groups of rats were subjected to the following protocol. Two groups were topically pretreated with either saline or the mild irritant 1 mmol acidified taurocholate. Two other groups received the topical anesthetic 1% lidocaine prior to pretreatment with either saline or 1 mmol acidified taurocholate. The last two groups got the mucolytic agent 10% N-acetylcysteine (NAC) after pretreatment with either saline or 1 mmol acidified taurocholate. Injury was assessed by measuring net transmucosal ion fluxes, luminal appearance of deoxyribonucleic acid (DNA), and gross and histologic injury. Pretreatment with the mild irritant 1 mmol acidified taurocholate significantly decreased bile acid-induced luminal ion fluxes and DNA accumulation, suggesting mucosal protection (corroborated by gross and histologic injury analysis). This effect was negated by lidocaine but not by NAC. Thus, it appears that sensory neurons, and not increased mucus secretion, play a critical role in adaptive cytoprotection.}, }
@article {pmid1728663, year = {1992}, author = {Ou, YH and Lin, JK}, title = {Biotransformation of butachlor through mercapturic acid pathway in rat tissue homogenates.}, journal = {Journal of toxicology and environmental health}, volume = {35}, number = {1}, pages = {19-28}, doi = {10.1080/15287399209531590}, pmid = {1728663}, issn = {0098-4108}, mesh = {Acetanilides/*metabolism ; Animals ; Chromatography, High Pressure Liquid ; Chromatography, Thin Layer ; Herbicides/*metabolism ; Kidney/*metabolism ; Liver/*metabolism ; Rats ; Spectrum Analysis ; }, abstract = {The metabolism of butachlor was studied in rat liver and kidney homogenates. In vitro incubation of butachlor with liver fractions (S9, microsome, and cytosolic fractions) formed a considerable amount of butachlor glutathione conjugate (BGSC), while the conjugating activity was not efficient for the kidney S9 fraction. There is a sex difference in the distribution of glutathione S-transferase in the liver. It seems that more enzyme activity is detected in the female liver microsome, while this is not the case in its cytosolic fraction. Further biotransformation of BGSC to mercapturate was not observed in the liver S9 fraction. This metabolite was further transformed to butachlor acetyl cysteine conjugate (BACC) in the presence of acetyl CoA, but to butachlor cysteine conjugate (BCC) in the absence of acetyl CoA. These findings demonstrated that butachlor is initially conjugated with GSH to form BGSC by the enzyme glutathione S-transferase in the liver. This metabolite is apparently transported to the kidneys, where it is transformed to the mercapturate.}, }
@article {pmid1728443, year = {1992}, author = {Boesgaard, S and Aldershvile, J and Poulsen, HE}, title = {Preventive administration of intravenous N-acetylcysteine and development of tolerance to isosorbide dinitrate in patients with angina pectoris.}, journal = {Circulation}, volume = {85}, number = {1}, pages = {143-149}, doi = {10.1161/01.cir.85.1.143}, pmid = {1728443}, issn = {0009-7322}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Angina Pectoris/*drug therapy/physiopathology ; Double-Blind Method ; Drug Combinations ; Drug Tolerance ; Exercise Test ; Hemodynamics ; Humans ; Injections, Intravenous ; Isosorbide Dinitrate/*therapeutic use ; Middle Aged ; Rest ; }, abstract = {BACKGROUND: Development of tolerance to organic nitrates may be related to depletion of sulfhydryl groups in vascular smooth muscle. N-Acetylcysteine (NAC), a sulfhydryl donor, has been reported to potentiate the effect of nitroglycerin and reverse tolerance in humans. However, its ability to prevent or delay the development of nitrate tolerance in patients with angina pectoris has not been established.<br><br>METHODS AND RESULTS: Ten patients with stable angina pectoris were treated with intravenous isosorbide dinitrate (ISDN; 5 mg/hr) combined with NAC (2 g i.v. over 15 minutes followed by 5 mg/kg/hr) or matching placebo for 30 hours in a double-blind, randomized, crossover study with a washout interval of 8 days. Bicycle exercise tests were performed before and at 1 1/2, 8, 20, 24, and 30 hours after start of treatment. After 24 hours of infusion, exercise parameters were not significantly different from pretreatment values (p greater than 0.05) during ISDN plus placebo, indicating development of tolerance to ISDN. In contrast, time to onset of angina, time to 1-mm ST segment depression, and total amount of ST segment depression were still significantly improved after 24-hour infusion of ISDN plus NAC (p less than 0.05). In addition, compared with placebo, a significant difference (p less than 0.05) in favor of NAC was observed regarding time to angina (507 +/- 63 versus 445 +/- 69 seconds, mean +/- SEM), time to 1-mm ST segment depression (435 +/- 43 versus 407 +/- 45 seconds), and total ST segment depression (1.8 +/- 0.9 versus 3.1 +/- 0.4 mm).<br><br>CONCLUSIONS: These results suggest that infusion of high doses of NAC in combination with ISDN for 30 hours affects and partially prevents the development of tolerance to antianginal effects normally observed during infusion with ISDN.}, }
@article {pmid1581851, year = {1992}, author = {Peterson, TC and Brown, IR}, title = {Cysteamine in combination with N-acetylcysteine prevents acetaminophen-induced hepatotoxicity.}, journal = {Canadian journal of physiology and pharmacology}, volume = {70}, number = {1}, pages = {20-28}, doi = {10.1139/y92-004}, pmid = {1581851}, issn = {0008-4212}, mesh = {Acetaminophen/*antagonists &amp; inhibitors/metabolism/toxicity ; Acetylcysteine/*administration &amp; dosage ; Alanine Transaminase/blood ; Animals ; Cysteamine/*administration &amp; dosage ; Cytochrome P-450 Enzyme System/metabolism ; Drug Interactions ; Liver/*drug effects/metabolism/pathology ; Male ; Mice ; }, abstract = {N-Acetylcysteine (NAC) is protective against acetaminophen-induced hepatotoxicity primarily by providing precursor for the glutathione synthetase pathway, while cysteamine has been demonstrated to alter the cytochrome P-450 dependent formation of toxic acetaminophen metabolite. Mice administered acetaminophen (500 mg/kg) had elevations of serum alanine aminotransferase (ALT) to 273.0 +/- 37.5 and 555.8 +/- 193.4 U/mL at 12 and 24 h, respectively, after injection. Administration of cysteamine (100 mg/kg) or NAC (500 mg/kg) significantly reduced serum ALT activity (p less than 0.001). Reducing the dose of NAC or cysteamine by 50% greatly reduced their hepatoprotective effect while the co-administration of the reduced doses of NAC (250 mg/kg) and cysteamine (50 mg/kg) following acetaminophen overdose prevented elevation of serum ALT activity (39.2 +/- 1.17 and 32.5 +/- 5.63 U/mL at 12 and 24 h post-injection, p less than 0.001) and preserved normal mouse hepatic histology. Neither NAC (500 mg/kg), cysteamine (100 mg/kg), or the lower doses in combination of both agents were found to alter the half-life or peak levels of acetaminophen. Liver microsomal aryl hydrocarbon hydroxylase activity measured 24 h after drug administration was not significantly different between treatment groups and controls receiving only saline. These results indicate a possible role for the concomitant use of NAC and cysteamine in the prevention of hepatic necrosis following toxic doses of acetaminophen. Neither decrease in plasma acetaminophen levels nor depression of cytochrome P-450 enzyme activity appears to be the mechanism of protection when these doses of NAC, cysteamine, or both drugs together are administered with a toxic dose of acetaminophen in mice.}, }
@article {pmid1514928, year = {1992}, author = {Brambilla, G and Carlo, P and Finollo, R}, title = {Effect of ten thiocompounds on rat liver DNA damage induced by a small dose of N-nitrosodimethylamine.}, journal = {Archives of toxicology}, volume = {66}, number = {4}, pages = {286-290}, pmid = {1514928}, issn = {0340-5761}, mesh = {Administration, Oral ; Animals ; Cell Nucleus/drug effects ; DNA Damage/*drug effects ; Dimethylnitrosamine/*antagonists &amp; inhibitors ; Free Radical Scavengers ; Liver/*drug effects/pathology ; Male ; Rabbits ; Rats ; Rats, Inbred Strains ; Sulfur/*pharmacology ; Viscosity ; }, abstract = {The use in a chemoprevention study of high doses of the genotoxic agent might result in erroneous information because of possible nonlinearity of pharmacokinetic processes and toxicity-induced derangement of physiological defense mechanisms. According to these premises ten thiocompounds, potentially active as inhibitors of metabolic activation and/or scavengers, were examined for their capability of reducing the frequency of liver DNA lesions induced by a very small dose of N-nitrosodimethylamine (NDMA). This was accomplished by means of a viscometric technique previously found suitable to detect a minimal amount of DNA fragmentation. Rats were injected i.p. or i.v. with 1 mmol/kg of thiocompound, 0.2 mg/kg NDMA given by gavage 1 h afterwards, and killed for DNA damage assessment 14 h later. Statistically significant changes of viscometric parameters, which are considered indicative of a protective activity, were produced by disulfiram (DSF), and to a lower extent by diethyldithiocarbamate (DEDTC). Any modification of NDMA-induced DNA damage was absent in rats pretreated with glutathione reduced form (GSH) and dimethyl sulfoxide (DMSO). Allyl disulfide (ADS), L-cysteine (CYS), N-acetylcysteine (NAC), alpha-mercaptopropionylglycine (MPG), ethylxanthic acid (PEX), and 2-mercaptoethane sulfonic acid (MESNA) increased in various degree the frequency of DNA-strand breaks. In subsequent experiments the protective activity of DSF was found to be dose-related, dependent on the time of administration, and greater by oral route. Taken as a whole, these results suggest that several putative anticarcinogens might be ineffective against the DNA-damage produced by the low doses encountered in human exposure.}, }
@article {pmid1505789, year = {1992}, author = {Udupi, V and Rice-Evans, C}, title = {Thiol compounds as protective agents in erythrocytes under oxidative stress.}, journal = {Free radical research communications}, volume = {16}, number = {5}, pages = {315-323}, doi = {10.3109/10715769209049184}, pmid = {1505789}, issn = {8755-0199}, mesh = {Acetylcysteine/pharmacology ; Anemia, Sickle Cell/blood/*drug therapy ; Antioxidants/*pharmacology ; Erythrocytes/*drug effects/metabolism ; Humans ; Oxidation-Reduction ; Thiomalates/pharmacology ; Tiopronin/pharmacology ; }, abstract = {The potential for the thiol-containing drugs, N-acetyl cysteine and N-mercaptopropionyl glycine, to act as antioxidants intracellularly has been studied in erythrocytes under oxidative stress. The effects have been compared with that of the glutathione peroxidase inhibitor, mercaptosuccinate. The results show differential responses of sickle and normal erythrocytes to the thiol compounds. N-acetyl cysteine is the more efficacious with no toxic effects in these systems. N-Mercaptopropionyl glycine is not only limited in its ability to demonstrate antioxidant capacity in erythrocytes but also exerts deleterious effects.}, }
@article {pmid1482288, year = {1992}, author = {Na, KJ and Jeong, SY and Lim, CH}, title = {The role of glutathione in the acute nephrotoxicity of sodium dichromate.}, journal = {Archives of toxicology}, volume = {66}, number = {9}, pages = {646-651}, pmid = {1482288}, issn = {0340-5761}, mesh = {Animals ; Ascorbic Acid/pharmacology ; Chromates/metabolism/*toxicity ; Glutathione/pharmacology/*physiology ; Kidney/pathology ; Kidney Diseases/chemically induced/*pathology ; Male ; Oxidation-Reduction ; Rats ; Rats, Sprague-Dawley ; Sulfhydryl Compounds/pharmacology ; }, abstract = {Ascorbate treatment 30 min prior to sodium dichromate (20 or 30 mg/kg, s.c.) shows higher potency than that of glutathione (GSH) in protecting against both the metabolic disturbance and nephrotoxicity induced by dichromate. However, ascorbate treatment after 2 h of dichromate intoxication had no effect on dichromate-induced blood urea nitrogen (BUN) elevation 3 days after intoxication. In contrast, dichromate-induced glucosuria, which reached maximum levels at 3 days after treatment, was significantly decreased by GSH or N-acetyl cysteine (NAC) treatment, even if its administration was after 24 h of dichromate intoxication. Pretreatment with GSH depletors such as diethyl maleate (DEM) and buthionine sulfoximine (BSO) had no effect on dichromate-induced nephrotoxicity. GSH levels in the liver and kidney were not affected at 3 h after dichromate treatment. However, dichromate significantly increased tissue GSH levels with a marked increase in liver per kidney GSH ratio at 24 h after treatment, if food was withheld subsequent to dichromate treatment, indicating that GSH biosynthesis resulted from the accelerated protein breakdown. These results suggest that GSH-mediated dichromate reduction is not a kinetically favorable pathway in vivo; however, GSH plays an important role in protection against dichromate-induced nephrotoxicity. In addition, the cellular metabolism of dichromate in the early period after treatment is important in the pathogenesis of its nephrotoxicity.}, }
@article {pmid1359663, year = {1992}, author = {Gandy, J and Bates, HK and Conder, LA and Harbison, RD}, title = {Effects of reproductive tract glutathione enhancement and depletion on ethyl methanesulfonate-induced dominant lethal mutations in Sprague-Dawley rats.}, journal = {Teratogenesis, carcinogenesis, and mutagenesis}, volume = {12}, number = {2}, pages = {61-70}, doi = {10.1002/tcm.1770120203}, pmid = {1359663}, issn = {0270-3211}, mesh = {Acetylcysteine/pharmacology ; Animals ; Ethyl Methanesulfonate/toxicity ; Fetal Resorption/chemically induced/*prevention &amp; control ; Genitalia, Male/*chemistry ; Glutathione/analysis/*physiology ; Ketones/pharmacology ; Male ; Mutagens ; *Mutation ; Rats ; Rats, Sprague-Dawley ; }, abstract = {The effects of altering glutathione (GSH) levels in the male reproductive tract have been studied in an attempt to establish a link between chemical-induced perturbations in glutathione and susceptibility of spermatozoa to chemical insult. Tissue GSH levels were enhanced by a treatment regimen of N-acetylcysteine (NAC) (250 mg/kg, 4 treatments at 2 h intervals). With this treatment, GSH levels in liver, testis, caput epididymis, and cauda epididymis were elevated to 126%, 110%, 178%, and 136% of control values. Sexually mature male rats were then treated with NAC and challenged with a dose of EMS (100 mg/kg) to determine if enhanced tissue GSH would protect against EMS-induced dominant lethal mutations. Pretreatment with NAC significantly decreased the post-implantation loss from 7.05 +/- 0.57 with EMS alone to 5.28 +/- 0.47. Conversely, a dominant lethal assay was conducted using different doses of phorone pretreatment to determine the relative contribution of hepatic versus reproductive tract GSH in protecting against EMS-induced dominant lethal resorptions. Doses of 100 mg/kg and 250 mg/kg phorone significantly lowered both hepatic and reproductive tract GSH while 25 mg/kg lowered only hepatic GSH. These three dose levels were used as pretreatments in a dominant lethal study followed by a challenge administration of EMS (50 mg/kg), which is a threshold dose of EMS for producing dominant lethal mutations. Comparison against controls demonstrated a significant potentiation of fetal resorptions in all groups receiving phorone pretreatment, including the 25 mg/kg pretreatment group which only lowered hepatic GSH prior to EMS challenge. The results of these experiments indicate that GSH reserves in the male reproductive tract are insufficient to protect developing spermatozoa from damage by alkylating agents in the absence of hepatic GSH.}, }
@article {pmid1305285, year = {1992}, author = {Ballke, EH and Wiersbitzky, S and Mahner, B and König, A}, title = {The effect of N-acetyl-cysteine (Mucosolvin) on the transmural potential difference of the mucosa in children.}, journal = {Padiatrie und Grenzgebiete}, volume = {31}, number = {2}, pages = {97-101}, pmid = {1305285}, issn = {0030-932X}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Administration, Rectal ; Asthma/*drug therapy/physiopathology ; Child ; Cystic Fibrosis/*drug therapy/physiopathology ; Female ; Humans ; Intestinal Mucosa/drug effects/physiopathology ; Male ; Membrane Potentials/*drug effects/physiology ; Mouth Mucosa/drug effects/physiopathology ; Mucous Membrane/*drug effects/physiopathology ; Nasal Mucosa/drug effects/physiopathology ; Reference Values ; }, abstract = {The mucosa of the respiratory and gastrointestinal tract produces an active transepithelial (or transmural) electric potential difference (tpd), which can be measured (in millivolts, mV). In CF-children receiving oral N-acetyl-cysteine treatment, the tpd of the buccal mucosa is largely the same as that in non-CF-children; the tpd of the nasal mucosa is significantly higher in CF-children. Given orally, N-acetyl-cysteine also provokes a significant decrease in the rectal mucosa tpd in CF-children. We suggest the effect is caused either by an osmotic effect of N-acetyl-cysteine (local), and/or by alteration of the factors regulating basal electrolyte transport/conductance of epithelia (chloride secretion? leaky junction?).}, }
@article {pmid1285017, year = {1992}, author = {Kinter, AL and Poli, G and Fauci, AS}, title = {N-acetyl-cysteine is a potent suppressor of human immunodeficiency virus transcription in persistently infected cells.}, journal = {Transactions of the Association of American Physicians}, volume = {105}, number = {}, pages = {36-43}, pmid = {1285017}, issn = {0066-9458}, mesh = {Acetylcysteine/*pharmacology ; Cell Line ; HIV Long Terminal Repeat/drug effects ; HIV Reverse Transcriptase ; HIV-1/*drug effects/genetics/physiology ; Humans ; Reverse Transcriptase Inhibitors ; Tetradecanoylphorbol Acetate/pharmacology ; Transcription, Genetic/drug effects ; Transfection ; Tumor Necrosis Factor-alpha/pharmacology ; Virus Replication/drug effects ; }, }
@article {pmid1798273, year = {1991}, author = {Brigham, KL}, title = {Oxygen radicals--an important mediator of sepsis and septic shock.}, journal = {Klinische Wochenschrift}, volume = {69}, number = {21-23}, pages = {1004-1008}, pmid = {1798273}, issn = {0023-2173}, support = {HL 07123/HL/NHLBI NIH HHS/United States ; HL 19153/HL/NHLBI NIH HHS/United States ; R01 HL 34208/HL/NHLBI NIH HHS/United States ; }, mesh = {Antioxidants/therapeutic use ; Endothelium, Vascular/drug effects/physiopathology ; Free Radicals ; Humans ; Lipopolysaccharides/immunology ; Oxygen/*physiology ; Respiratory Distress Syndrome/drug therapy/*physiopathology ; Sepsis/drug therapy/*physiopathology ; Shock, Septic/drug therapy/*physiopathology ; }, abstract = {There is considerable evidence to implicate aggressive species of oxygen in the pathogenesis of organ dysfunction consequent to sepsis and septic shock. The inflammatory process appears to participate ubiquitously in this setting. A characteristic of inflammation is the involvement of activated neutrophils and their generation of aggressive oxygen species. Such species may both directly injure cells proximal to the oxidant generating cells, and may inactivate any proteolytic mechanisms normally protective against proteolytic injury caused by neutrophil elastase and other proteolytic enzymes released during inflammation. The offending agent in sepsis is most commonly envisioned as bacterial lipopolysaccharide, or endotoxin. Infusion of endotoxin into animals can reproduce much of the pathophysiology of sepsis and septic shock. In addition, administration of endotoxin to cultured cells, particularly endothelial cells, can cause responses consistent with a sequence of events that occurs in intact animals and humans. In both experimental models, it appears that aggressive oxygen species are important actors in the scenario eventuating in cell or organ injury. Of importance, the toxic consequences of these free radicals probably occurs in relatively protected spaces, including microenvironments created by close adherence between inflammatory cells and endothelial cells and the cell interior. For those reasons, the potential for antioxidants as therapy should include consideration of the volume of distribution of such substances. It is probably important that antioxidants access excluded spaces including cell interiors in order to have their maximum effect in this setting. We have studied ina preliminary way the effects of n-acetyl-cysteine, a highly permeable free radical scavenger and anti-oxidant, in patients with established ARDS.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1808834, year = {1991}, author = {Dulaney, MD and Brumley, M and Willis, JT and Hume, AS}, title = {Protection against cyanide toxicity by oral alpha-ketoglutaric acid.}, journal = {Veterinary and human toxicology}, volume = {33}, number = {6}, pages = {571-575}, pmid = {1808834}, issn = {0145-6296}, mesh = {Acetylcysteine/therapeutic use ; Administration, Oral ; Animals ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Ketoglutaric Acids/administration &amp; dosage/*therapeutic use ; Male ; Mice ; Mice, Inbred ICR ; Potassium Cyanide/antagonists &amp; inhibitors/*toxicity ; }, abstract = {The efficacy of orally administered alpha-ketoglutarate (AKG), alone and in combination with n-acetyl-cysteine (NAC), in reducing the lethal effects of injected potassium cyanide was examined in the mouse. A behavioral scoring system was developed to monitor and measure the signs of toxicity associated with cyanide exposure. AKG significantly reduced the lethality of KCN (6.7 mg/kg ip) in a dose-related manner. The protective effect of AKG was observed if given between 10 and 30 min prior to cyanide exposure. NAC increased the protective effect of AKG but did not alter the time course of protection. AKG alone or in combination with NAC significantly reduced the duration of the toxicity associated with cyanide exposure. This study identifies AKG as an orally effective cyanide antagonist. The protective effect of AKG is enhanced by concomitant administration of NAC. Our work also describes a scoring system which quantifies the signs of toxicity associated with cyanide poisoning.}, }
@article {pmid1768285, year = {1991}, author = {Lailey, AF and Hill, L and Lawston, IW and Stanton, D and Upshall, DG}, title = {Protection by cysteine esters against chemically induced pulmonary oedema.}, journal = {Biochemical pharmacology}, volume = {42 Suppl}, number = {}, pages = {S47-54}, doi = {10.1016/0006-2952(91)90391-h}, pmid = {1768285}, issn = {0006-2952}, mesh = {Acetylcysteine/pharmacology ; Animals ; Buthionine Sulfoximine ; Chromatography, High Pressure Liquid ; Cysteine/*analogs &amp; derivatives/analysis/blood/pharmacology ; Cystine/*analogs &amp; derivatives/pharmacology ; DNA/analysis ; Female ; Fluorocarbons/administration &amp; dosage/toxicity ; Glutathione/analysis ; Liver/drug effects ; Lung/*drug effects/metabolism/pathology ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Perfusion ; Pulmonary Edema/chemically induced/*prevention &amp; control ; Rats ; Sulfhydryl Compounds/blood ; Time Factors ; }, abstract = {Perfluoroisobutene (PFIB) is a hydrophobic reactive gas produced by the pyrolysis of polytetrafluoroethane which induces pulmonary oedema similar to that induced by phosgene when inhaled. When a lethal dose is inhaled by Porton strain rats total non-protein thiol (NPSH) and glutathione (GSH) in the lung are reduced by between 30 and 49%, respectively. If the endogenous levels of thiols in the lung are reduced by pretreatment with buthionine sulfoximine (BSO) 16 hr before exposure to PFIB, the rats become more susceptible to the effects of the gas. The effect of BSO pretreatment on toxicity was prevented by pretreatment 30 min before exposure, with 5 mmol/kg N-acetylcysteine (NAc). NAc increased the levels of cysteine (CySH) in the lung by 150% and GSH was unaffected. Similarly pretreatment with 3 mmol/kg CySH also protected against toxicity and raised CySH levels by 100%. A series of cysteine esters and cystine dimethyl ester (CDME) have been synthesised which selectively raise lung levels of CySH in the rat lungs after intraperitoneal (i.p.) injection. The methyl ester and CDME raised lung levels of CySH by 4000 and 2000%, respectively, 10 min after i.p. injection whilst GSH levels remained unchanged. Cysteine isopropyl ester raised lung levels of CySH by 10,600% but liver levels by only 1400%. All esters except the t-butyl ester (CTBE) also raised maximal plasma levels of NPSH by up to 500%; however, when NAc was injected plasma levels increased by over 1500%. Rats treated with these esters at 3 mmol/kg and with NAc at 5 mmol/kg were protected against lethal doses of PFIB in all cases except when CTBE was used. It appears that these cysteine esters may distribute preferentially into the lung, unlike NAc. The selective enhancement of pulmonary CySH levels may provide a method for the protection of lungs against inhaled reactive toxicants by increasing intracellular CySH. Levels of CySH may also be raised in epithelial lining fluid thus reducing access of gaseous toxicants to pulmonary tissue.}, }
@article {pmid1836221, year = {1991}, author = {Kroon, AA and Demacker, PN and Stalenhoef, AF}, title = {N-acetylcysteine and serum concentrations of lipoprotein(a).}, journal = {Journal of internal medicine}, volume = {230}, number = {6}, pages = {519-526}, doi = {10.1111/j.1365-2796.1991.tb00483.x}, pmid = {1836221}, issn = {0954-6820}, mesh = {Acetylcysteine/*pharmacology/therapeutic use ; Adult ; Aged ; Female ; Humans ; Hyperlipidemias/blood/*drug therapy ; Immunoassay ; In Vitro Techniques ; Lipoprotein(a) ; Lipoproteins/*blood/*drug effects ; Male ; Middle Aged ; }, abstract = {A high plasma concentration of lipoprotein(a) [Lp(a)], a complex of low-density lipoprotein linked by disulphide bridges to apoprotein(a), is correlated with premature atherosclerosis. We determined whether the serum Lp(a) concentration could be decreased in vitro and in vivo by the reducing agent N-acetylcysteine (NAC), a drug used as a mucolytic agent, which acts by cleaving disulphide bonds. High concentrations of NAC (greater than or equal to 8 mg ml-1) resulted in dissociation of the Lp(a) antigen in vitro. However, the plasma level of Lp(a) was not changed by administration of NAC 1.2 g d-1 for 4 weeks in 7 subjects with a median Lp(a) concentration of 14.3 mg dl-1 (range 2.1-21.0 mg dl-1) or by doubling the dose to 2.4 g d-1 for a further 2 weeks. In 12 subjects with a high plasma level of Lp(a), median 87.0 mg dl-1 (range 42.0-201.6 mg dl-1), a small but significant decrease in Lp(a) concentration of 7% (P = 0.02) was observed after administration of NAC in a dose of 1.2 g d-1 for 6 weeks. These results indicate that NAC has only a limited capacity to reduce the concentration of Lp(a), which is not clinically significant.}, }
@article {pmid1720598, year = {1991}, author = {Harakeh, S and Jariwalla, RJ}, title = {Comparative study of the anti-HIV activities of ascorbate and thiol-containing reducing agents in chronically HIV-infected cells.}, journal = {The American journal of clinical nutrition}, volume = {54}, number = {6 Suppl}, pages = {1231S-1235S}, doi = {10.1093/ajcn/54.6.1231s}, pmid = {1720598}, issn = {0002-9165}, mesh = {Acetylcysteine/*pharmacology ; Ascorbic Acid/*pharmacology ; Cell Division/drug effects ; Cells, Cultured ; Glutathione/*pharmacology ; HIV/*drug effects/growth &amp; development/metabolism ; Humans ; RNA-Directed DNA Polymerase/biosynthesis ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {To elucidate the action of vitamin C on pathogenic human retroviruses, we investigated and compared the effects of noncytoxic concentrations of ascorbic acid (AA), its calcium salt (Ca-ascorbate), and two thiol-based reducing agents [glutathione (GSH) and N-acetyl-L-cysteine (NAC)] against human immunodeficiency virus (HIV)-1 replication in chronically infected T lymphocytes. Ca-ascorbate reduced extracellular HIV reverse transcriptase (RT) activity by about the same magnitude as the equivalent dose of AA. Long-term experiments showed that continuous presence of ascorbate was necessary for HIV suppression. NAC (10 mmol/L) caused less than twofold inhibition of HIV RT and conferred a synergistic effect (approximately eightfold inhibition) when tested simultaneously with AA (0.426 mmol/L). In contrast, nonesterified GSH (less than or equal to 1.838 mmol/L) had no effect on RT concentrations and did not potentiate the anti-HIV effect of AA. These results further support the potent antiviral activity of ascorbate and suggest its therapeutic value in controlling HIV infection in combination with thiols.}, }
@article {pmid1770755, year = {1991}, author = {Ruffmann, R and Wendel, A}, title = {GSH rescue by N-acetylcysteine.}, journal = {Klinische Wochenschrift}, volume = {69}, number = {18}, pages = {857-862}, pmid = {1770755}, issn = {0023-2173}, mesh = {Acetylcysteine/*administration &amp; dosage ; Acquired Immunodeficiency Syndrome/physiopathology/*therapy ; Glutathione/*deficiency/physiology ; Humans ; Pulmonary Fibrosis/physiopathology/*therapy ; Respiratory Distress Syndrome/physiopathology/*therapy ; }, abstract = {Reduced glutathione (GSH) is the main intracellular low molecular weight thiol. GSH acts as a nucleophilic scavenger and as an enzyme-catalyzed antioxidant in the event of electrophilic/oxidative tissue injury. Therefore, GSH has a major role as a protector of biological structures and functions. GSH depletion has been recognized as a hazardous condition during paracetamol intoxication. Conversely, GSH rescue, meaning recovery of the protective potential of GSH by early administration of N-acetylcysteine (NAC), has been found to be life-saving. Lack of GSH and electrophilic/oxidative injury have been identified among the causes of the adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and the acquired immunodeficiency syndrome (AIDS). Experimental and early clinical data (in ARDS) point to the role of NAC in the treatment of these conditions. Recently, orally given NAC has been shown to enhance the levels of GSH in the liver, in plasma, and notably in the bronchoalveolar lavage fluid. Rescue of GSH through NAC needs to be appreciated as an independent treatment modality for an array of different disease, all of which have one feature in common: pathogenetically relevant loss of GSH.}, }
@article {pmid1957322, year = {1991}, author = {Jurima-Romet, M and Huang, HS and Paul, CJ and Thomas, BH}, title = {Enalapril cytotoxicity in primary cultures of rat hepatocytes. II. Role of glutathione.}, journal = {Toxicology letters}, volume = {58}, number = {3}, pages = {269-277}, doi = {10.1016/0378-4274(91)90038-8}, pmid = {1957322}, issn = {0378-4274}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antimetabolites/pharmacology ; Buthionine Sulfoximine ; Cell Survival/drug effects ; Cells, Cultured ; Drug Synergism ; Enalapril/*toxicity ; Glutathione/*physiology ; Glutathione Reductase/metabolism ; Glutathione Transferase/metabolism ; L-Lactate Dehydrogenase/metabolism ; Liver/*drug effects/enzymology ; Male ; Maleates/pharmacology ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Rats ; Rats, Inbred F344 ; }, abstract = {The cytotoxicity of enalapril maleate (EN) in primary cultures of rat hepatocytes, at concentrations of 0.5 mM or greater, was measured by the release of lactate dehydrogenase (LDH) into the culture medium. Pretreatment of the hepatocytes with L-buthionine-(S,R)-sulfoximine (BSO) and diethyl maleate (DEM) potentiated the toxicity whereas N-acetyl-L-cysteine (NAC) provided protection. EN produced a dose-dependent reduction in intracellular glutathione (GSH) concentration. This was an early effect, apparent after only 1 h of exposure to the drug, whereas loss of cell viability occurred after 6-18 h. These results suggest that the mechanism of EN cytotoxicity involves a GSH-dependent detoxification pathway.}, }
@article {pmid1957313, year = {1991}, author = {Monks, TJ and Jones, TW and Hill, BA and Lau, SS}, title = {Nephrotoxicity of 2-bromo-(cystein-S-yl) hydroquinone and 2-bromo-(N-acetyl-L-cystein-S-yl) hydroquinone thioethers.}, journal = {Toxicology and applied pharmacology}, volume = {111}, number = {2}, pages = {279-298}, doi = {10.1016/0041-008x(91)90031-9}, pmid = {1957313}, issn = {0041-008X}, support = {ES 04662/ES/NIEHS NIH HHS/United States ; ES 05436/ES/NIEHS NIH HHS/United States ; GM 39338/GM/NIGMS NIH HHS/United States ; }, mesh = {Aminooxyacetic Acid/pharmacology ; Animals ; Cysteine/adverse effects/*analogs &amp; derivatives/metabolism ; Hydroquinones/*adverse effects/metabolism ; Kidney/drug effects/pathology ; Kidney Diseases/*chemically induced/pathology ; Male ; Necrosis ; Probenecid/pharmacology ; Rats ; Rats, Inbred Strains ; }, abstract = {The in vivo toxicity of isomeric cystein-S-yl and N-acetylcystein-S-yl conjugates of 2-bromohydroquinone was determined in male Sprague-Dawley rats. 2-Bromo-(dicystein-S-yl)hydroquinone [2-Br-(diCYS)HQ] and 2-bromo-(di-N-acetyl-L-cystein-S-yl)hydroquinone [2-Br-(diNAC)HQ] were considerably more nephrotoxic than their corresponding monosubstituted thioethers and 2-Br-(diCYS)HQ was more nephrotoxic than 2-Br-(diNAC)HQ. 2-Br-(diCYS)HQ caused elevations in blood urea nitrogen (BUN) concentrations and increases in the urinary excretion of glucose, lactate dehydrogenase (LDH), and gamma-glutamyl transpeptidase (gamma-GT) at a dose of 25 mumol/kg (iv). In contrast, 2-Br-(diNAC)HQ caused significant elevations in BUN at 100 mumol/kg and glucosuria and enzymuria at 50 mumol/kg. 2-Br-3-(CYS)HQ and 2-Br-5&amp;6-(CYS)HQ caused increases in the biochemical indices of nephrotoxicity at doses between 50 and 150 mumol/kg whereas 2-Br-5-(NAC)HQ and 2-Br-6-(NAC)HQ required doses of 150-200 mumol/kg to cause smaller, though significant increases in urinary glucose, gamma-GT, and LDH excretion. The histological alterations caused by each thioether were qualitatively similar; only differences in the extent of the renal proximal tubular damage were observed. The initial lesion appears to involve the cells of the medullary ray and the S3M within the outer stripe of the outer medulla. The in vivo nephrotoxicity of 2-Br-(DiCYS)HQ, 2-Br-(diNAC)HQ, and the most potent monosubstituted thioethers, 2-Br-5&amp;6-(CYS)HQ and 2-Br-6-(NAC)HQ, was investigated further. Pretreatment of animals with aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase (beta-lyase), had no effect on the toxicity of 2-Br-(diCYS)HQ, partially inhibited the toxicity of 2-Br-5&amp;6-(CYS)HQ, and almost completely protected against the toxicity of both 2-Br-6-(NAC)HQ and 2-Br-(diNAC)HQ. Thus, the nephrotoxicity of 2-Br-5&amp;6-(CYS)HQ, 2-Br-6-(NAC)HQ, and 2-Br-(diNAC)HQ may be mediated, in part, via their processing by beta-lyase. Pretreatment of animals with probenecid, an inhibitor of renal organic anion transport, completely protected against the toxicity of 2-Br-(diNAC)HQ but had no effect on the toxicity of the other thioethers.}, }
@article {pmid1940584, year = {1991}, author = {Bertolatus, JA and Klinzman, D and Bronsema, DA and Ridnour, L and Oberley, LW}, title = {Evaluation of the role of reactive oxygen species in doxorubicin hydrochloride nephrosis.}, journal = {The Journal of laboratory and clinical medicine}, volume = {118}, number = {5}, pages = {435-445}, pmid = {1940584}, issn = {0022-2143}, support = {R01-CA41267/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Catalase/metabolism/pharmacology ; Cells, Cultured ; Dimethyl Sulfoxide/metabolism/pharmacology ; Dose-Response Relationship, Drug ; Doxorubicin ; Epithelium/drug effects/metabolism/pathology ; Female ; Free Radical Scavengers ; Glomerular Mesangium/drug effects/metabolism/pathology ; Glutathione/analysis/metabolism ; Kidney Cortex/chemistry/metabolism ; Male ; Malondialdehyde/analysis/metabolism ; Nephrosis/chemically induced/metabolism/*physiopathology ; Oxygen/metabolism/*physiology ; Platelet Activation/drug effects/physiology ; Polyethylene Glycols/metabolism/pharmacology ; Proteinuria/metabolism/physiopathology ; Rats ; Rats, Inbred Strains ; Superoxide Dismutase/metabolism/pharmacology ; Thrombin/metabolism/pharmacology ; }, abstract = {In subcellular systems, doxorubicin hydrochloride (ADR) leads to the generation of reactive oxygen species such as superoxide anion. Because reactive oxygen species have been shown to be important mediators of glomerular injury in several animal models, we sought to determine whether reactive oxygen species play a significant role in the pathogenesis of ADR-induced nephrotic syndrome in the rat. Rats pretreated with a variety of free radical scavengers (superoxide dismutase conjugated to polyethylene glycol [PEGSOD], catalase, catalase plus PEGSOD, dimethylsulfoxide, desferoxamine, or n-acetyl cysteine) had no significant reduction in proteinuria at 3 weeks after ADR administration when compared with rats receiving ADR in the absence of scavengers. No evidence was seen of increased lipid peroxidation or depletion of reduced glutathione in renal cortex tissue obtained up to 24 hours after administration of ADR. No changes were seen in the renal cortical levels of either enzyme activity or immunoreactive protein for the endogenous antioxidant enzymes superoxide dismutase (either the Mn or CuZn forms) or catalase after ADR. Total and MnSOD activities in glomeruli isolated from rats after ADR administration fell significantly, though CuZnSOD activity was increased. The effect of ADR on cultured rat mesangial or epithelial cells was also evaluated. ADR inhibited growth of both cell types at concentrations of approximately 5 to 10 mumol/L, an order of magnitude below the reported Michaelis-Menten constant for ADR-induced superoxide production. The growth inhibitory effect could not be prevented in either cell type by treatment with PEGSOD, catalase, or PEGSOD plus catalase. This combination of results from in vivo and in vitro studies provides no evidence for an important role of reactive oxygen species in ADR nephrosis and suggests that other known mechanisms of ADR cytotoxicity, such as interference with DNA metabolism, mediate the glomerular injury.}, }
@article {pmid1928876, year = {1991}, author = {Selden, BS and Curry, SC and Clark, RF and Johnson, BC and Meinhart, R and Pizziconi, VB}, title = {Transplacental transport of N-acetylcysteine in an ovine model.}, journal = {Annals of emergency medicine}, volume = {20}, number = {10}, pages = {1069-1072}, doi = {10.1016/s0196-0644(05)81354-x}, pmid = {1928876}, issn = {0196-0644}, mesh = {Acetylcysteine/blood/*metabolism ; Animals ; Female ; Fetal Blood ; Infusions, Intravenous ; *Maternal-Fetal Exchange ; Models, Biological ; Pregnancy ; Sheep ; }, abstract = {STUDY OBJECTIVE: Acetaminophen freely crosses the placenta, and acetaminophen ingestion is the most frequent intentional overdose in pregnancy. Although most patients do well after maternal treatment with the antidote N-acetylcysteine (NAC), fetal death with massive hepatic necrosis has occurred. It has never been shown whether NAC crosses the placenta to yield fetal plasma levels equal to those associated with hepatoprotective effects in human beings. Our study objective was to evaluate this in a widely accepted large animal model for maternal-fetal research. DESIGN AND TYPE OF PARTICIPANTS: A nonblinded experiment was performed using four domestic sheep at near-term gestation.<br><br>INTERVENTIONS: NAC 150 mg/kg IV was administered to the ewe over 15 minutes. After induction of anesthesia, the fetal head was delivered surgically and a neck vein cannulated for blood sampling. Maternal and fetal blood samples were obtained at the end of NAC infusion, at 30- and then at 60-minute intervals for four hours. Plasma NAC levels were determined by gas chromatography/mass spectroscopy (detection limit, 2 micrograms/mL; quantification limit, 5 micrograms/mL).<br><br>RESULTS: Maternal peak plasma NAC levels were 619, 631, 1,757, and 2,512, micrograms/mL, respectively, within 30 minutes of infusion. However, NAC was only minimally detectable in plasma of two fetal animals and transiently reached quantifiable levels in two others. None of the fetal animals attained serial plasma NAC levels that equalled those associated with therapeutic dosing or hepatoprotective effects in human beings.<br><br>CONCLUSION: Transplacental transport of NAC is clinically insignificant in a mammalian model resembling the human being. These findings suggest that the human fetal liver is not protected from acetaminophen toxicity by maternal NAC therapy.}, }
@article {pmid1928874, year = {1991}, author = {Smilkstein, MJ and Bronstein, AC and Linden, C and Augenstein, WL and Kulig, KW and Rumack, BH}, title = {Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol.}, journal = {Annals of emergency medicine}, volume = {20}, number = {10}, pages = {1058-1063}, doi = {10.1016/s0196-0644(05)81352-6}, pmid = {1928874}, issn = {0196-0644}, mesh = {Acetaminophen/blood/*poisoning ; Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Child ; Drug Overdose/drug therapy ; Female ; Humans ; Injections, Intravenous ; Liver/drug effects ; Male ; Prospective Studies ; Risk Factors ; Time Factors ; }, abstract = {STUDY OBJECTIVE: To determine the safety and efficacy of a 48-hour IV N-acetylcysteine (IV NAC) treatment protocol for acute acetaminophen overdose.<br><br>DESIGN: Nonrandomized trial open to all eligible patients.<br><br>SETTING: Multicenter; hospitals included moderate- and high-volume private, university, and municipal hospitals in urban and suburban settings.<br><br>TYPE OF PARTICIPANTS: Two hundred twenty-three patients were entered. Of these, 179 met inclusion criteria: acute acetaminophen overdose, plasma acetaminophen concentration above the treatment nomogram line, treatment with IV NAC according to the protocol, and sufficient data to determine outcome.<br><br>INTERVENTIONS: IV NAC treatment consisted of a loading dose of 140 mg/kg followed by 12 doses of 70 mg/kg every four hours.<br><br>MEASUREMENTS AND MAIN RESULTS: Patients were grouped for analysis according to risk group based on the initial plasma acetaminophen concentration. Hepatotoxicity (aspartate aminotransferase or alanine aminotransferase of more than 1,000 IU/L) developed in 10% (five of 50) of patients at "probable risk" when IV NAC was started within ten hours of acetaminophen ingestion and in 27.1% (23 of 85) when therapy was begun after ten to 24 hours. Among "high-risk" patients first treated 16 to 24 hours after overdose, hepatotoxicity occurred in 57.9% (11 of 19). There were two deaths (two of 179, 1.1%). Adverse reactions resulting from NAC occurred in 32 of 223 cases (14.3%), consisting in 29 of 32 patients (91% of reactions) of transient, patchy, skin erythema or mild urticaria during the loading dose that did not require discontinuation of therapy.<br><br>CONCLUSION: This 48-hour IV NAC protocol is safe and effective antidotal therapy for acetaminophen overdose. Based on available data, it is equal to 72-hour oral and 20-hour IV treatment protocols when started early and superior to the 20-hour IV regimen when treatment is delayed. Further study will be required to determine its relative efficacy in the high-risk patient treated very late.}, }
@article {pmid1793738, year = {1991}, author = {Watanabe, H and Fujita, Y and Sugahara, K and Kodama, H and Ohmori, S}, title = {Identification of NAc-HCPC and NAc-beta-CEC, and qualitative analyses of sulphur amino acids in the urine of a patient with cystathioninuria using liquid chromatography/atmospheric pressure ionization mass spectrometry.}, journal = {Biological mass spectrometry}, volume = {20}, number = {10}, pages = {602-608}, doi = {10.1002/bms.1200201005}, pmid = {1793738}, issn = {1052-9306}, mesh = {Acetylcysteine/*analogs &amp; derivatives/urine ; Adult ; Amino Acid Metabolism, Inborn Errors/*urine ; Amino Acids, Sulfur/*urine ; Chromatography, Liquid ; Cystathionine/*urine ; Female ; Humans ; In Vitro Techniques ; Mass Spectrometry ; }, abstract = {Standard sulphur amino acids and various cystathionine metabolites in the urine of a patient with cystathioninuria were analysed using liquid chromatography/mass spectrometry with an atmospheric pressure ionization interface system. Very intense quasi-molecular ions ([M + H]+) of synthetic cystathionine, N-monoacetylcystathionine, perhydro-1,4-thiazepine-3,5-dicarboxylic acid, S-(3-hydroxy-3-carboxy-n-propyl)cysteine, S-(2-carboxyethyl) cysteine, S-(2-hydroxy-2-carboxyethyl)homocysteine, S-(carboxymethyl)homocysteine, N-acetyl-S-(3-hydroxy-3-carboxy-n-propyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine were observed by this method. Quasi-molecular ions ([M + H]+) of these sulphur amino acids were observed in the urine sample of the patient with cystathioninuria, and N-acetyl-HCPC and N-acetyl-beta-CEC as N-substituted sulphur amino acids were also identified in the urine of the same patient.}, }
@article {pmid1752389, year = {1991}, author = {Komuro, Y and Ishihara, K and Ohara, S and Saigenji, K and Hotta, K}, title = {A new method of separation and quantitation of mucus glycoprotein in rat gastric mucus gel layer and its application to mucus secretion induced by 16,16-dimethyl PGE2.}, journal = {Gastroenterologia Japonica}, volume = {26}, number = {5}, pages = {582-587}, pmid = {1752389}, issn = {0435-1339}, mesh = {Animals ; Epithelium/drug effects/pathology ; Gastric Mucosa/*drug effects/pathology ; Glycoproteins/*analysis ; Male ; Mucus/*metabolism ; Prostaglandins E, Synthetic/*pharmacology ; Rats ; Rats, Inbred Strains ; }, abstract = {A method was established for recovering the mucus gel layer of rat gastric mucosa without damage to underlying surface epithelium. The mucus gel was solubilized by stirring the gastric mucosa in a solution of N-acetylcysteine (NAC), a mucolytic agent. Optimal mucus gel solubilization was possible by treatment with 2% NAC for 5 minutes at room temperature. Mucus glycoprotein was quantitatively extracted and measured from the mucus gel sample obtained by the NAC treatment. This treatment caused no damage to surface epithelial cells, as observed by a light microscope. Besides NAC, pronase solution was also adequate for solubilizing the mucus gel layer without any damage to the surface epithelium. However, extraction and measurement of mucus glycoprotein from the pronase-treated mucus gel sample was not possible due to contamination by high molecular hexose-containing substances which were eluted along with the mucus glycoprotein from the column of Bio-Gel A-1.5m. This NAC method was used to examine changes in mucus glycoprotein content in the mucus gel at one hour following the oral administration of 16,16-dimethyl prostaglandin E2. A significant increase in mucus glycoprotein of the gel was brought about by the prostaglandin treatment. Thus, the present method was suitable for estimating the amount of mucus secreted in to the mucus gel layer.}, }
@article {pmid1719835, year = {1991}, author = {Trizna, Z and Schantz, SP and Hsu, TC}, title = {Effects of N-acetyl-L-cysteine and ascorbic acid on mutagen-induced chromosomal sensitivity in patients with head and neck cancers.}, journal = {American journal of surgery}, volume = {162}, number = {4}, pages = {294-298}, doi = {10.1016/0002-9610(91)90134-y}, pmid = {1719835}, issn = {0002-9610}, mesh = {Acetylcysteine/*pharmacology ; Ascorbic Acid/*pharmacology ; Bleomycin/toxicity ; Cell Line ; *Chromosome Fragility ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Head and Neck Neoplasms/*genetics/prevention &amp; control ; Humans ; In Vitro Techniques ; Lymphocytes/drug effects ; Tumor Cells, Cultured ; }, abstract = {The protective effect of N-acetyl-L-cysteine (NAC) and ascorbic acid on mutagen-induced chromosomal breakage was determined using human lymphoblastoid cell lines as well as freshly cultured lymphocytes from patients with head and neck malignancies and healthy control subjects. Mutagen sensitivity was determined using the previously described bleomycin exposure assay. The toxicities of different concentrations of NAC and ascorbic acid, as well as both the preincubation and dose-dependent protective effects of these two agents, were analyzed. Both test drugs proved to be effective in diminishing mutagen-induced chromatid breakage in established lymphocyte cell lines. In freshly cultured lymphocytes, NAC given in doses ranging from 0.1 to 10 mmol/L decreased the number of mutagen-induced breaks per cell in a range from 23% to 73%, and ascorbic acid decreased chromosomal breakage by 21% to 58% in a dose range from 0.01 to 1 mmol/L. The results of this study demonstrate the protective effect mediated in vitro by both NAC and ascorbic acid against mutagen-induced chromosomal damage. A similar in vivo phenomenon may explain the differences in occurrence of head and neck cancer between populations with different dietary backgrounds.}, }
@article {pmid1928201, year = {1991}, author = {Horowitz, JD}, title = {Thiol-containing agents in the management of unstable angina pectoris and acute myocardial infarction.}, journal = {The American journal of medicine}, volume = {91}, number = {3C}, pages = {113S-117S}, doi = {10.1016/0002-9343(91)90293-7}, pmid = {1928201}, issn = {0002-9343}, mesh = {Acetylcysteine/*administration &amp; dosage ; Angina, Unstable/*drug therapy ; Drug Therapy, Combination ; Humans ; Myocardial Infarction/*drug therapy ; Nitroglycerin/*administration &amp; dosage ; Platelet Aggregation/drug effects ; Sulfhydryl Compounds/*therapeutic use ; }, abstract = {The development of unstable angina pectoris and acute myocardial infarction is a process of platelet aggregation and thrombus formation associated with local coronary vasoconstriction. Regional deficiencies in endothelial vasodilator function, due to reduced formation of endothelium-derived relaxing factor (EDRF), may predispose to platelet aggregation and coronary vasoconstriction. Nitroglycerin (NTG), frequently utilized in the management of unstable angina pectoris and acute myocardial infarction, undergoes bioconversion, via a sulfhydryl-dependent process, to nitric oxide, which is identical or closely related to EDRF. Other products of the nitrate bioconversion "cascade" are various S-nitrosothiols, which, like nitric oxide, activate soluble guanylate cyclase, inducing increased formation of cyclic guanosine monophosphate. NTG potentially may act to correct a localized deficiency of EDRF effect, at both the vasculature and platelet levels. In patients with unstable angina, hemodynamic effects and therapeutic efficacy of intravenously infused NTG may be attenuated within hours. Combined therapy with NTG and intravenously infused N-acetylcysteine (NAC) results in potentiation of hemodynamic responses to NTG, markedly augments the effects of NTG on platelet aggregation, and reduces the incidence of acute myocardial infarction in patients with severe unstable angina pectoris. The combination of NTG with intermittent NAC infusion may increase the risk of hypotensive episodes in such patients, whereas continuous coinfusion of the drugs is better tolerated. The combination of NTG with thiol-containing agents, such as NAC, may be of therapeutic value in unstable angina pectoris and in evolving acute myocardial infarction. This is currently under investigation.}, }
@article {pmid1928200, year = {1991}, author = {Abrams, J}, title = {Interactions between organic nitrates and thiol groups.}, journal = {The American journal of medicine}, volume = {91}, number = {3C}, pages = {106S-112S}, doi = {10.1016/0002-9343(91)90292-6}, pmid = {1928200}, issn = {0002-9343}, mesh = {Animals ; Drug Tolerance ; Heart Diseases/drug therapy/metabolism ; Humans ; Muscle, Smooth, Vascular/*drug effects/metabolism ; Nitrates/*metabolism/therapeutic use ; Sulfhydryl Compounds/*physiology ; Vasodilation/drug effects ; }, abstract = {Nitroglycerin and the organic nitrates (RONO2) can be considered prodrugs that require conversion to an active intracellular moiety that initiates vascular smooth muscle relaxation. Vasodilation of veins and arteries occurs when the enzyme guanylate cyclase (GC) is activated, initiating the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP); this is the final pathway for vascular dilation caused by the nitrovasodilators (organic nitrates, sodium nitroprusside, and molsidomine) as well as endothelium-derived relaxing factor (EDRF). The common denominator appears to be the intracellular production of nitric oxide (NO), which is the activated product of organic nitrate denitration. Nitrate tolerance has been associated with a relative depletion or unavailability of thiol groups that are involved in the initial step of denitration of RONO2. Sulfhydryl groups (SH) are oxidized during this process; with continuous nitrate exposure, decreased nitrate metabolism within the vascular smooth muscle cell occurs as a direct result of the depletion of reduced SH groups. Thus, less NO is formed and cGMP production is diminished, with a subsequent decrease or absence of vasodilation. In addition, SH groups or thiols are required for the production of S-nitrosothiols (RSNO). These short-lived compounds have been identified as an end product of organic nitrate metabolism and as possibly obligatory for the induction of GC. It is unclear, however, as to whether S-nitrosothiols are a necessary by-product of NO production from organic nitrates. It appears that RSNO can be formed outside the cell membrane and may be able to induce vasorelaxation after penetrating the cell and initiating GC activation. Exogenous SH donors, particularly N-acetylcysteine (NAC), have been employed to provide intracellular thiols in efforts to prevent or reverse nitrate tolerance. Nitrate physiologic actions are accentuated following NAC administration in the absence of tolerance. Although controversial, the concept that NAC or other thiols might be able to prevent the development of nitrate tolerance is being actively studied in laboratories around the world. Methionine has also been utilized as an SH donor with some success. Not all data are consistent, however, and the ultimate role of thiol donors for the prevention or reversal of nitrate tolerance remains uncertain. Finally, there has been considerable interest in supplying thiols by use of the SH-containing angiotensin converting enzyme inhibitors, such as captopril. This approach does not seem promising, probably because insufficient thiol can be supplied by therapeutic dosages of these drugs.}, }
@article {pmid1930267, year = {1991}, author = {Chong, S and Fung, HL}, title = {Biochemical and pharmacological interactions between nitroglycerin and thiols. Effects of thiol structure on nitric oxide generation and tolerance reversal.}, journal = {Biochemical pharmacology}, volume = {42}, number = {7}, pages = {1433-1439}, doi = {10.1016/0006-2952(91)90456-f}, pmid = {1930267}, issn = {0006-2952}, support = {GM42850/GM/NIGMS NIH HHS/United States ; HL22273/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Aorta ; Benzoates/pharmacology ; Blood ; Buffers ; Culture Media ; Culture Techniques ; Cysteine/pharmacology ; Drug Tolerance ; Hot Temperature ; Humans ; Nitric Oxide/*metabolism ; Nitroglycerin/pharmacokinetics/*pharmacology ; Rats ; Structure-Activity Relationship ; Sulfhydryl Compounds/*pharmacology ; Thimerosal ; }, abstract = {Co-administration of N-acetylcysteine (NAC) with nitroglycerin (NTG) has been shown to partially reverse nitrate tolerance and to potentiate the hypotensive effect of NTG in humans. However, a high clinical dose of NAC was required for this pharmacologic interaction resulting in the production of unwanted side-effects. Therefore, sulfhydryl compounds more active than NAC need to be identified if this interaction is to be exploited clinically. We previously suggested that the effect of sulfhydryl compounds on NTG may be mediated by the formation of S-nitrosothiol or nitric oxide (NO) extracellularly to the vascular smooth muscle cell (e.g. in plasma) (Fung et al., J. Pharmacol Exp Ther 245: 524-530, 1988). In an attempt to understand the structural features which govern this thiol-catalyzed NO generation from NTG, nineteen different aliphatic and ten aromatic sulfhydryl compounds were examined with respect to their catalytic activity to generate NO from NTG in plasma. Significantly enhanced production of NO was observed with most sulfhydryl compounds examined when compared to buffer control. Among the aliphatic thiols, only mercaptosuccinic acid was more potent than NAC (2x), whereas among the aromatic thiols, both thiosalicylic acid (TSA, 10x) and TSA-methyl ester (3x) were more potent than NAC. Comparative in vitro relaxation studies were carried out using isolated (and nitrate-tolerant) rat aortic rings with NTG/TSA and NTG/NAC, in the presence of 0.5% (v/v) plasma. Under these conditions, partial reversal of NTG tolerance could be achieved with TSA, but not with NAC. These data are consistent with the view that extracellular production of NO or S-nitrosothiol serves as a tolerance-reversing mechanism of thiols on NTG. TSA appears to be a more potent sulfhydryl compound than NAC in this biochemical and pharmacologic interaction.}, }
@article {pmid1944365, year = {1991}, author = {De Flora, S and D'Agostini, F and Izzotti, A and Balansky, R}, title = {Prevention by N-acetylcysteine of benzo[a]pyrene clastogenicity and DNA adducts in rats.}, journal = {Mutation research}, volume = {250}, number = {1-2}, pages = {87-93}, doi = {10.1016/0027-5107(91)90165-k}, pmid = {1944365}, issn = {0027-5107}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Benzo(a)pyrene/*antagonists &amp; inhibitors ; Bone Marrow Cells ; Cell Division/drug effects ; DNA Damage/*drug effects ; Macrophages/cytology ; Male ; Mutagenicity Tests ; Rats ; Rats, Inbred Strains ; }, abstract = {The daily i.t. administration of benzo[a]pyrene (BP) to Sprague-Dawley rats, for 3 consecutive days, did not cause any toxicity or clastogenicity in bone marrow cells, as evaluated by monitoring the ratio of polychromatic to normochromatic erythrocytes and the frequency of micronucleated polychromatic erythrocytes. However, BP produced a considerable enhancement of binucleated and micronucleated pulmonary alveolar macrophages, as well as a significant increase in polymorphonucleates recovered by bronchoalveolar lavage. These effects were prevented by administering the thiol N-acetylcysteine (NAC) by gavage 5 h before each BP instillation. In addition, the i.t. treatment with BP resulted in the formation of BP diolepoxide (BPDE)-DNA adducts in lungs and liver, as assessed by synchronous fluorescence spectrophotometry, with fluorescence peaks of similar magnitude in the 2 tissues. Pretreatment with NAC by gavage completely prevented BPDE adducts to liver DNA and significantly decreased those to lung DNA.}, }
@article {pmid1909757, year = {1991}, author = {Boesgaard, S and Petersen, JS and Aldershvile, J and Poulsen, HE and Flachs, H}, title = {Nitrate tolerance: effect of thiol supplementation during prolonged nitroglycerin infusion in an in vivo rat model.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {258}, number = {3}, pages = {851-856}, pmid = {1909757}, issn = {0022-3565}, mesh = {Animals ; Consciousness ; Drug Administration Schedule ; Drug Interactions ; Drug Tolerance ; Female ; Hemodynamics/drug effects ; Infusions, Intravenous ; Nitroglycerin/administration &amp; dosage/*pharmacology ; Rats ; Rats, Inbred Strains ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {Depletion of intracellular sulfhydryl groups has been considered a main reason for the development of nitrate tolerance during sustained nitrate therapy. Although administration of N-acetyl-cysteine, a sulfhydryl donor, potentiates the acute hypotensive effect of nitroglycerin (NTG), its role in the reversal of nitrate tolerance is controversial. In the present study, we developed a conscious in vivo rat model to study nitrate tolerance and nitrate-thiol interactions. Tolerance to NTG, as assessed by the blood pressure reduction in response to i.v. NTG bolus doses, developed after 24 h of i.v. NTG infusion. After 3 and 5 days of 0.2 mg/h NTG i.v., the dose-response relations for NTG-induced reduction in blood pressure were shifted to 25-fold higher doses (P less than .01). Infusion of N-acetylcysteine (0.245, 1.225 and 6.125 mmol/kg/h for 4 h) and, to a lesser extent, equimolar doses of reduced glutathione, but not N-acetylserine, significantly potentiated the hypotensive effect of NTG, in a dose-dependent manner (P less than .05). However, complete reversal of tolerance was not achieved. This animal model of nitrate tolerance is suitable for further investigations of nitrate-thiol interactions and shares similarities with nitrate tolerance development in humans. The results suggest that sulfhydryl supplementation may enhance the hypotensive effect of NTG in a dose-dependent manner. This effect is more likely to be achieved with N-acetylcysteine than with glutathione and may be related to differences in membrane permeability.}, }
@article {pmid1810343, year = {1991}, author = {Perrone, MC and Serra, D and D'Agostini, F and Cesarone, CF}, title = {[Evaluation of blood chemistry parameters of rats treated with 2-acetylaminofluorene and N-acetylcysteine].}, journal = {Bollettino della Societa italiana di biologia sperimentale}, volume = {67}, number = {9}, pages = {875-879}, pmid = {1810343}, issn = {0037-8771}, mesh = {2-Acetylaminofluorene/*toxicity ; Acetylcysteine/*toxicity ; Animals ; Blood Proteins/analysis ; Chemical and Drug Induced Liver Injury/*blood/enzymology ; Lipids/blood ; Liver Function Tests ; Male ; Rats ; Rats, Inbred Strains/blood ; }, abstract = {Male wistar rats were treated with a diet supplemented with 0.05% 2-acetylaminofluorene (2AAF) and/or 0.2% N-acetylcysteine (NAC) according to the protocol of Teebor and Becker. Eleven haematochemical parameters were evaluated at the third week of the first two cycles. The results showed a slight yet significant decrease in total proteins and triglycerides, and an increase in total bilirubin, gamma-glutamyltranspeptidase and alkaline phosphatase, as compared to untreated controls. Co-treatment with NAC slightly attenuated the alterations induced by 2AAF. On the whole, these results demonstrate that 2AAF is poorly necrotic to hepatocytes, and hence its known ability to damage the liver appears to mainly depend on nuclear effects rather than on cytoplasmic changes.}, }
@article {pmid1716310, year = {1991}, author = {Mollace, V and Salvemini, D and Sessa, WC and Vane, JR}, title = {Inhibition of human platelet aggregation by endothelium-derived relaxing factor, sodium nitroprusside or iloprost is potentiated by captopril and reduced thiols.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {258}, number = {3}, pages = {820-823}, pmid = {1716310}, issn = {0022-3565}, mesh = {Acetylcysteine/pharmacology ; Blood Platelets/drug effects/metabolism ; Captopril/*pharmacology ; Drug Synergism ; Enalaprilat/pharmacology ; Endothelium, Vascular/cytology/physiology ; Humans ; Iloprost/*pharmacology ; Nitric Oxide/*pharmacology ; Nitroprusside/*pharmacology ; Nucleotides, Cyclic/blood ; *Platelet Aggregation Inhibitors ; Sulfhydryl Compounds/*pharmacology ; Teprotide/pharmacology ; Thrombin/pharmacology ; }, abstract = {We have examined whether inhibitors of angiotensin-converting enzyme-containing sulfhydryl groups such as, captopril (CPT) or SQ 14,534, the nonsulfhydryl-containing angiotensin-converting enzyme inhibitors, teprotide (TPR) or enalaprilat (ENA) and other structurally unrelated sulfhydryl-containing compounds, N-2-mercaptopropionylglycine (MPG) or N-acetyl-L-cysteine (NAC), could influence platelet aggregation. Incubation of human washed platelets with CPT, SQ 14,534, TPR, ENA, MPG or NAC (0.1-0.5 mM) did not modify their aggregatory responses to thrombin. However, the antiaggregatory properties of endothelial cells cultured from bovine aorta were potentiated by CPT, SQ 14,534, MPG or NAC but not by TPR or ENA (40-100 microM). CPT (100-500 microM) or NAC (50-200 microM) but not ENA (100 and 500 microM) also potentiated the antiaggregatory effects of sodium nitroprusside (1.0 microM) or iloprost (0.2 nM). The ability of the thiol-containing compounds (CPT or NAC) to potentiate the antiaggregatory effects of sodium nitroprusside or iloprost was not associated with an elevation of platelet cyclic GMP or cyclic AMP levels, respectively. Thus, CPT and other sulfhydryl-containing compounds can synergize with antiplatelet compounds, thereby enhancing the ability of endothelial-derived autocoids to inhibit platelet aggregation. The mechanism responsible for this potentiating effect of thiols on platelet aggregation is not known, but may relate to the ability of thiol-containing compounds to act as intracellular scavengers of oxygen-derived free radicals.}, }
@article {pmid1665295, year = {1991}, author = {Caccese, RG and DiJoseph, JF and Skotnicki, JS and Borella, LE and Adams, LM}, title = {Inhibition of interleukin-1 (IL-1) induced neutral proteases from rabbit articular chondrocytes by WY-46,135 and WY-48,989.}, journal = {Agents and actions}, volume = {34}, number = {1-2}, pages = {223-225}, pmid = {1665295}, issn = {0065-4299}, mesh = {*Acetylcysteine/*analogs &amp; derivatives ; Animals ; Benzothiazoles ; Cartilage, Articular/*enzymology/pathology ; Cysteine/*analogs &amp; derivatives/pharmacology ; Endopeptidases/analysis/biosynthesis ; Enzyme Induction/drug effects ; Hindlimb ; In Vitro Techniques ; Interleukin-1/*pharmacology ; Male ; Microbial Collagenase/analysis ; Protease Inhibitors/*pharmacology ; Pyrazoles/*pharmacology ; Rabbits ; }, abstract = {The effects of potential anti-osteoarthritic compounds both on the direct inhibition of collagenase and neutral protease activities and on IL-1 induced release of neutral proteases from rabbit articular chondrocytes were investigated. WY-46,135 ((+)-N-[[[(5-chloro-2-benzothiazolyl)thio]phenyl]acetyl]-L- cysteine) directly inhibited collagenase activity (IC50 = 15.4 microM). This inhibition was reversible upon dialysis. WY-46,135 also directly inhibited neutral protease activity (IC50 = 16.8 microM) but did not significantly block bacterial collagenase activity at a concentration of 80 microM. In contrast, WY-48,989 (4-[[2-(7-chloro-2-phenyl-2H-pyrazolo[4,3-c]quinolin-4- yl)ethyl]amino]benzonitrile) did not directly inhibit either collagenase (10 microM) or neutral protease (100 microM) activity. Both WY-48,989 and WY-46,135 inhibited IL-1 stimulated release of neutral proteases (IC50 = 3 microM). The activities of these compounds represents two potential approaches for the treatment of osteoarthritis. WY-46,135 combines direct metalloprotease inhibitory activity with the inhibition of IL-1 stimulated neutral protease release from articular chondrocytes while WY-48,989 selectively inhibits the IL-1 induced release of metalloproteases.}, }
@article {pmid1941835, year = {1991}, author = {Hansen, RM and Varma, RR and Hanson, GA}, title = {Gold induced hepatitis and pure red cell aplasia. Complete recovery after corticosteroid and N-acetylcysteine therapy.}, journal = {The Journal of rheumatology}, volume = {18}, number = {8}, pages = {1251-1253}, pmid = {1941835}, issn = {0315-162X}, mesh = {Acetylcysteine/*therapeutic use ; Adrenal Cortex Hormones/*therapeutic use ; Chemical and Drug Induced Liver Injury/*drug therapy/etiology ; Gold/administration &amp; dosage/*adverse effects/therapeutic use ; Hepatitis/*drug therapy/etiology ; Humans ; Injections ; Male ; Middle Aged ; Red-Cell Aplasia, Pure/*chemically induced/*drug therapy ; }, abstract = {A 54-year-old man developed severe cholestatic jaundice and pure red cell aplasia shortly after beginning treatment with gold sodium thiomalate. Although the hepatic toxicity began to spontaneously improve, the pure red cell aplasia was progressive. Treatment with prednisone and N-acetylcysteine (NAC) infusions was followed by prompt and complete hematologic recovery. Gold induced pure red cell aplasia should be added to the list of gold induced hematologic toxicities that can be potentially reversed with NAC infusion therapy.}, }
@article {pmid2068120, year = {1991}, author = {Lopez, RA and Tornwall, MS and Henagan, JM and Smith, GS and Miller, TA}, title = {N-acetyl-cysteine: protective agent or promoter of gastric damage?.}, journal = {Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)}, volume = {197}, number = {3}, pages = {273-278}, doi = {10.3181/00379727-197-43255}, pmid = {2068120}, issn = {0037-9727}, support = {DK 25838/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology/toxicity ; Administration, Oral ; Animals ; Blood Pressure/drug effects ; Ethanol/toxicity ; Female ; Gastric Mucosa/*drug effects ; Glutathione/analysis ; Injections, Intraperitoneal ; Male ; Rats ; Rats, Inbred Strains ; }, abstract = {N-acetyl-cysteine (NAC), when given orally, has been shown to prevent gastric damage induced by ethanol, but when administered intraperitoneally, it appears to potentiate such damage. In an effort to resolve these seemingly discordant findings, fasted rats (six per group) received 1 ml of saline or 20% NAC orally or intraperitoneally (ip). Two hours or 15 min later, they received 1 ml of 100% ethanol orally. At sacrifice 5 min later, rats receiving oral pretreatment with 20% NAC at both 15 and 120 min prior to ethanol exposure demonstrated a significant reduction in the magnitude of gastric injury when compared with saline controls. In contrast, actual promotion of ethanol damage was noted when NAC was given intraperitoneally, but was more pronounced when NAC was administered 15 min prior to exposing the mucosa to 100% ethanol. In all animals receiving intraperitoneal NAC, large amounts of peritoneal fluid (4-6 ml/rat) were recovered at the time of sacrifice, most of which occurred within 15 min of NAC administration; these more pronounced peritoneal effects at 15 min after NAC correlated with the more severe injury from ethanol at this time period compared to 120 min after intraperitoneal NAC. Saline controls had no peritoneal fluid. Mucosal glutathione (GSH) levels generally paralleled these results in that a significant decrease in tissue GSH occurred at 15 min following intraperitoneal NAC when compared with controls; at 120 min after intraperitoneal NAC, GSH levels were similar to control values. Additional experiments demonstrated that within 15 min following NAC administration, systemic blood pressure dropped by approximately 20% and basically remained unchanged over the next 2 hr; intraperitoneal saline had no sustained adverse effects on blood pressure. It was concluded that the inability of NAC to prevent ethanol injury when given intraperitoneally in contrast to orally is related to the drop in blood pressure secondary to NAC's peritoneal irritant effects, which presumably altered gastric mucosal blood flow, thus obivating its ability to prevent ethanol damage under these conditions. Furthermore, the decreased levels in mucosal GSH following the hypotension induced by intraperitoneal NAC suggest that perturbations in GSH metabolism may also have contributed to the decreased resistance to ethanol injury.}, }
@article {pmid1918880, year = {1991}, author = {Bramley, PN and Rathbone, BJ and Forbes, MA and Cooper, EH and Losowsky, MS}, title = {Serum hyaluronate as a marker of hepatic derangement in acute liver damage.}, journal = {Journal of hepatology}, volume = {13}, number = {1}, pages = {8-13}, doi = {10.1016/0168-8278(91)90856-7}, pmid = {1918880}, issn = {0168-8278}, mesh = {Acetaminophen/toxicity ; Acute Disease ; Adolescent ; Adult ; Alanine Transaminase/blood ; Biomarkers/blood ; Child ; Female ; Humans ; Hyaluronic Acid/*blood ; Liver/drug effects/pathology/physiology ; Liver Diseases/*blood/diagnosis/epidemiology ; Liver Function Tests ; Longitudinal Studies ; Male ; Middle Aged ; }, abstract = {Twenty patients with paracetamol(acetaminophen)-induced acute liver damage of varying severity were studied longitudinally with assessment of clinical state, standard liver function tests and radiometric hyaluronate (HYA) assay (Pharmacia). In patients (n = 6) who developed coma, HYA rose rapidly with clinical deterioration to reach a median value of 27,510 micrograms/l, 7 days post-ingestion, which was significantly higher (p less than 0.005) than in patients (n = 7) who exhibited only marked derangement of liver function tests without evidence of encephalopathy, HYA median value of 3240 micrograms/l. These peak values showed no correlation to the peak values of serum alanine aminotransferase (ALT). A third group of patients (n = 7) who were treated with N-acetyl cysteine, did not exhibit any evidence of liver failure and showed no significant rise in levels of HYA or ALT. The data demonstrate that HYA is a rapidly changing marker of liver derangement which appears to follow the clinical course of the patient. The increase to extremely high levels in patients with hepatic encephalopathy, suggests that there is a reversible defect in the hepatic endothelial cell HYA receptor, possibly due to endothelial cell damage or release of toxins from the necrotic liver.}, }
@article {pmid1912338, year = {1991}, author = {Lindqvist, T and Kenne, L and Lindeke, B}, title = {On the chemistry of the reaction between N-acetylcysteine and 4-[(4-ethoxyphenyl)imino]-2,5-cyclohexadien-1-one, a 4-ethoxyaniline metabolite formed during peroxidase reactions.}, journal = {Chemical research in toxicology}, volume = {4}, number = {4}, pages = {489-496}, doi = {10.1021/tx00022a014}, pmid = {1912338}, issn = {0893-228X}, mesh = {Acetylcysteine/*metabolism ; Benzoquinones/*metabolism ; Glutathione/metabolism ; Hydrogen-Ion Concentration ; Oxidation-Reduction ; Peroxidases/*pharmacology ; Phenetidine/*metabolism ; }, abstract = {4-Ethoxyaniline (p-phenetidine) is oxidized by peroxidases to form several products, one of which is 4-[(4-ethoxyphenyl)imino]-2,5-cyclohexadien-1-one (1). This compound reacts with N-acetylcysteine (NAC) in methanol-phosphate buffers, generating at least four different products. Four major products, 4-[(4-ethoxyphenyl)amino]phenol (2), 3-(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)amino]phenol (3), 2,5-bis(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)-amino]phenol (4), and 2,5-bis(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)imino]-2,5- cyclohexadien-1-one (5), were isolated and identified by NMR spectroscopy and mass spectrometry. The relative ratio between the formed products depends on the pH, the concentration of NAC, and the reaction time. Compound 2, which is the reduced form of 1, was the dominating product when the reaction took place at pH 3, whereas formation of the mono conjugate (3) was more extensive at a neutral pH. Under alkaline conditions 2 and 3 were oxidized by 1 or O2. The oxidized form of 3 was subsequently attacked by a second molecule of NAC, generating the bis conjugate (4). Unless an excess of NAC was present, compound 4 underwent rapid oxidation to 5. Quinone imines, like 1, generating mono conjugates, which are more reactive than the quinone imines per se, are likely to inflict an increased toxic potential and an increased stress on the endogenous thiol pool, resulting in an overall greater toxicity.}, }
@article {pmid1720100, year = {1991}, author = {Shahzeidi, S and Sarnstrand, B and Jeffery, PK and McAnulty, RJ and Laurent, GJ}, title = {Oral N-acetylcysteine reduces bleomycin-induced collagen deposition in the lungs of mice.}, journal = {The European respiratory journal}, volume = {4}, number = {7}, pages = {845-852}, pmid = {1720100}, issn = {0903-1936}, mesh = {Acetylcysteine/chemistry/*therapeutic use ; Animals ; Bleomycin ; Collagen/*analysis ; Lung/*chemistry/pathology ; Mice ; Mice, Inbred Strains ; Microscopy, Electron ; Pulmonary Fibrosis/chemically induced/*drug therapy/pathology ; }, abstract = {N-acetylcysteine (NAC) has been employed in the treatment of acute lung injury but its therapeutic value is as yet unproven. In the present study we examined the effect of both L- and D-forms of NAC as inhibitors of bleomycin-induced fibrosis in mice. We hypothesized that, because of the D-form is not metabolized, it may be more effective than the L-form in ameliorating lung injury and fibrosis. Both drugs were given daily in the drinking water at a dose of approximately 400 mg.kg-1 body weight commencing one week prior to a single intratracheal instillation of bleomycin at a dose of 6 mg.kg-1 body weight. Lung injury was assessed 35 days later by measuring total lung collagen content, lung wet weight and examination of tissues by light and electron microscopy. Total collagen content and lung wet weight of animals receiving bleomycin together with L-NAC were 2.90 +/- 0.03 mg and 0.23 +/- 0.01 g, respectively. The values for collagen content, but not wet weight, were significantly less (p less than 0.05) than those given for bleomycin alone (3.90 +/- 0.02 mg and 0.260 +/- 0.005 g, respectively), but greater than (p less than 0.05) controls (2.10 +/- 0.01 mg and 0.160 +/- 0.002 g, respectively). Values for collagen content and wet weight of animals given bleomycin together with D-NAC (3.10 +/- 0.02 mg and 0.21 +/- 0.01 mg, respectively) were both significantly greater than values for control animals but lower than animals given bleomycin alone.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1659478, year = {1991}, author = {Zhu, Y}, title = {[Experimental study of the protective effects of N-acetylcysteine on endotoxin-induced acute lung injury].}, journal = {Zhonghua yi xue za zhi}, volume = {71}, number = {7}, pages = {373-7, 26}, pmid = {1659478}, issn = {0376-2491}, mesh = {Animals ; Cystine/*analogs &amp; derivatives/therapeutic use ; Endotoxins ; Escherichia coli ; Female ; Lipid Peroxides/metabolism ; Lung Diseases/etiology/*prevention &amp; control ; Lymph/metabolism ; Sheep ; Toxemia/*complications ; }, abstract = {The purpose of this study was to investigate the effects of NAC (N-acetylcysteine) on endotoxin induced acute lung injury in unanesthetized sheep. The results showed that NAC attenuated the responses to endotoxemia, and the rise in pulmonary artery pressure was significantly diminished, and the rise of TXB2 and 6-keto-PGF1 alpha in plasma and lung lymph was less significantly for NAC + E than for E alone. The QL (lung lymph flow), PC (lung lymph protein clearance) and PS (pulmonary capillary surface permeability area) were significantly decreased in NAC + E group. The lipid peroxide contents in artery plasma and lung lymph were not increased in NAC-treated group. We conclude that NAC is capable of attenuating all pathophysiologic changes after endotoxin infusion, blocking the reaction of oxygen free radicals, and protecting lungs from oxidant damage.}, }
@article {pmid2069595, year = {1991}, author = {Commandeur, JN and Stijntjes, GJ and Wijngaard, J and Vermeulen, NP}, title = {Metabolism of L-cysteine S-conjugates and N-(trideuteroacetyl)-L-cysteine S-conjugates of four fluoroethylenes in the rat. Role of balance of deacetylation and acetylation in relation to the nephrotoxicity of mercapturic acids.}, journal = {Biochemical pharmacology}, volume = {42}, number = {1}, pages = {31-38}, doi = {10.1016/0006-2952(91)90677-w}, pmid = {2069595}, issn = {0006-2952}, mesh = {Acetylation ; Acetylcysteine/*pharmacokinetics/urine ; Amidohydrolases/metabolism ; Animals ; Arylamine N-Acetyltransferase/metabolism ; Bile/metabolism ; *Chlorofluorocarbons ; Cysteine/pharmacokinetics/urine ; Deuterium ; Ethylenes/*pharmacokinetics/urine ; Gas Chromatography-Mass Spectrometry ; Hydrocarbons, Fluorinated/*pharmacokinetics/toxicity/urine ; Hydrocarbons, Halogenated/pharmacokinetics ; Kidney/metabolism ; Kidney Diseases/chemically induced/*urine ; Liver/metabolism ; Male ; Rats ; Rats, Inbred Strains ; Subcellular Fractions/metabolism ; }, abstract = {The relationship between the relative nephrotoxicity of the mercapturic acids (NAc) of the fluorinated ethylenes tetrafluoroethylene (TFE), chlorotrifluoroethylene (CTFE), 1,1-dichloro-2,2-difluoroethylene (DCDFE) and 1,1-dibromo-2,2-difluoroethylene (DBDFE), and the biotransformation by activating (N-deacetylase and beta-lyase) and inactivating (N-acetyltransferase) enzymes was studied in the rat. After intraperitoneal (i.p.) administration of 50 mumol/kg of N-(trideuteroacetyl)-labeled mercapturic acids of DCDFE and DBDFE to rats, significant amounts of the dose were excreted unchanged: with DCDFE-NAc, 17% of the dose, and DBDFE-NAc, 31% of the dose. In contrast, the corresponding deuterium-labeled mercapturic acids of TFE and CTFE were excreted unchanged at less than 1% of the dose. With DCDFE-NAc and DBDFE-NAc, also high amounts of unlabeled mercapturic acids were excreted, respectively 48% and 28% of the dose, indicating extensive N-deacetylation followed by reacetylation in vivo. Only small amounts (less than 2%) of unlabeled mercapturic acids were excreted with TFE-NAc and CTFE-NAc. After administration of the cysteine S-conjugates DCDFE-Cys and DBDFE-Cys to rats, high amounts of the corresponding mercapturic acids were detected in urine, respectively 57% and 45% of the dose. After administration of TFE-Cys and CTFE-Cys, however, only small amounts were excreted as the corresponding mercapturic acid, approximately 4% of the dose. The strongly different amounts of mercapturic acids in urine may be attributed to the strong differences in N-deacetylation activities which were found in rat renal fractions. The threshold dose of the mercapturic acids to cause nephrotoxicity in male Wistar rats increased in the order: CTFE-NAc (25 mumol/kg) less than TFE-NAc (50 mumol/kg) less than DCDFE-NAc (75 mumol/kg) less than DBDFE-NAc (100 mumol/kg). A higher ratio of N-deacetylation and N-acetylation activities, resulting in a higher availability of cysteine S-conjugate, in addition to a higher specific activity of cysteine S-conjugate beta-lyase, probably explains the higher nephrotoxicity of TFE-NAc and CTFE-NAc when compared to DCDFE-NAc and DBDFE-NAc. The much lower activities of N-deacetylation and beta-lyase which are observed in hepatic fractions may explain the lack of hepatotoxicity of the mercapturic acids studied.}, }
@article {pmid2064885, year = {1991}, author = {O'Connell, MJ and Snape, SD and Nunn, JF}, title = {An early marker of hyperoxic lung injury in the rat and its pharmacological modulation.}, journal = {British journal of anaesthesia}, volume = {66}, number = {6}, pages = {697-702}, doi = {10.1093/bja/66.6.697}, pmid = {2064885}, issn = {0007-0912}, mesh = {Allopurinol/pharmacology ; Animals ; Antioxidants/pharmacology ; Cystine/analogs &amp; derivatives/pharmacology ; Dimethyl Sulfoxide/pharmacology ; Female ; Lung/*drug effects/metabolism ; Mitochondria/drug effects/*metabolism ; Oxygen/metabolism/*toxicity ; Rats ; Rats, Inbred Strains ; Time Factors ; }, abstract = {Of three possible early biochemical changes which were investigated in rats after hyperoxia, one was shown to be a useful marker of damage in this species. Mitochondrial oxygen uptake measured in lung homogenates has already been reported to be impaired after 24 h. With a purified mitochondrial fraction, we found significant impairment after only 3 h exposure to 100% oxygen. To our knowledge, this is the earliest significant change reported in this species. The antioxidants N-acetyl cysteine, dimethyl sulphoxide and allopurinol were found to ameliorate the injury. This suggests a possible link with the pulmonary damage and survival of rats in hyperoxia, which may be modulated also by antioxidant therapy.}, }
@article {pmid1889500, year = {1991}, author = {Drost, E and Lannan, S and Bridgeman, MM and Brown, D and Selby, C and Donaldson, K and MacNee, W}, title = {Lack of effect of N-acetylcysteine on the release of oxygen radicals from neutrophils and alveolar macrophages.}, journal = {The European respiratory journal}, volume = {4}, number = {6}, pages = {723-729}, pmid = {1889500}, issn = {0903-1936}, mesh = {Acetylcysteine/*pharmacology ; Administration, Oral ; Adult ; Animals ; Bronchoalveolar Lavage Fluid/cytology ; Cysteine/metabolism ; Free Radicals ; Glutathione/metabolism ; Humans ; Macrophages/*drug effects/metabolism ; Neutrophils/*drug effects/metabolism ; Oxygen/*metabolism ; Pulmonary Alveoli/*cytology ; Rats ; }, abstract = {N-acetylcysteine (NAC) is rapidly de-acetylated in vivo to cysteine (CYSH), a precursor of glutathione (GSH) which is an antioxidant in cells and body fluids. We investigated the effect of oral administration of N-acetyl cysteine for 5 days on the spontaneous and stimulated generation of hydrogen peroxide (H2O2) and superoxide anion (O2-) from human and rat phagocytic leucocytes. Alveolar macrophages (AM) were obtained by bronchoalveolar lavage (BAL) in control rats and rats given NAC in their drinking water. Neutrophils (PMNL) were harvested from whole blood in normal nonsmoking volunteers before and after NAC was given by mouth. The stimulated release of H2O2 and O2 from both rat AM and human PMN was not changed by administration of NAC. However, a small but significant increase was observed in both the spontaneous generation of O2- from rat AM and the spontaneous generation of H2O2 from human PMNL. Administration of NAC significantly increased cysteine levels in human plasma and rat BAL, but the levels in human PMNL and rat AM after NAC did not differ from control levels. GSH levels were not altered significantly by NAC.}, }
@article {pmid1714011, year = {1991}, author = {Boesgaard, S and Aldershvile, J and Pedersen, F and Pietersen, A and Madsen, JK and Grande, P}, title = {Continuous oral N-acetylcysteine treatment and development of nitrate tolerance in patients with stable angina pectoris.}, journal = {Journal of cardiovascular pharmacology}, volume = {17}, number = {6}, pages = {889-893}, doi = {10.1097/00005344-199106000-00005}, pmid = {1714011}, issn = {0160-2446}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Aged ; Angina Pectoris/*drug therapy ; Double-Blind Method ; Drug Tolerance ; Exercise Test ; Hemodynamics/drug effects ; Humans ; Isosorbide Dinitrate/therapeutic use ; Male ; Middle Aged ; Nitrates/*therapeutic use ; Time Factors ; }, abstract = {The presence of sulfhydryl (SH) groups appears to be fundamental to nitrate-induced vasodilation and N-acetylcysteine (NAC), a sulfhydryl (SH)-donor substance, potentiates hemodynamic responsiveness to nitrates. We investigated the effect of simultaneous administration of NAC and isosorbide dinitrate (ISDN) on development of nitrate tolerance. In a double-blind, randomized, placebo-controlled cross-over study, seven patients with stable angina pectoris were treated for two 8-day periods with ISDN (40 mg four times daily, q.i.d.) together with NAC (controlled release 600 mg q.i.d.) or matching placebo. Bicycle exercise tests were performed before treatment was started, 1 h after treatment was started, and at day 8. After 8-day treatment with ISDN + placebo, responses determined by exercise testing were diminished as compared with responses obtained during acute therapy and did not differ from baseline values, suggesting development of tolerance to ISDN. During treatment with ISDN + NAC, time to 1-mm ST depression was significantly prolonged (441 +/- 44 vs. 381 +/- 40 s, mean +/- SEM) and total ST segment depression significantly reduced (1.9 +/- 0.7 vs. 3.5 +/- 0.8 mm) as compared with baseline values. The reduction in ST segment depression was significantly more pronounced during ISDN + NAC (46%) as compared with ISDN + placebo (23%). Although exercise time and time to angina pectoris were unaffected. NAC augmented the antiischemic effects of ISDN as assessed by ECG. This finding may suggest that development of nitrate tolerance is modified by chronic oral high-dose NAC administration.}, }
@article {pmid1646324, year = {1991}, author = {Goldschmidt, JE and Tallarida, RJ}, title = {Pharmacological evidence that captopril possesses an endothelium-mediated component of vasodilation: effect of sulfhydryl groups on endothelium-derived relaxing factor.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {257}, number = {3}, pages = {1136-1145}, pmid = {1646324}, issn = {0022-3565}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Captopril/*pharmacology ; Cyclic GMP/metabolism ; Enalaprilat/pharmacology ; Endothelium, Vascular/*physiology ; Glutathione/pharmacology ; In Vitro Techniques ; Nitric Oxide/*physiology ; Norepinephrine/pharmacology ; Pyrogallol/pharmacology ; Rabbits ; Structure-Activity Relationship ; Sulfhydryl Compounds/*pharmacology ; Superoxide Dismutase/pharmacology ; Tiopronin/pharmacology ; Vasodilation/drug effects/*physiology ; }, abstract = {Captopril, an angiotensin-converting enzyme inhibitor, reportedly can scavenge superoxide anion (O2-), a property attributed to its sulfhydryl group. The present investigation, using rabbit aortic rings precontracted with either norepinephrine or clonidine, was designed to determine whether captopril possesses an endothelium-dependent component of vasodilation related to its ability to protect endothelium-derived relaxing factor (EDRF) from superoxide-mediated destruction. Also studied were enalaprilat, a nonsulfhydryl angiotensin-converting enzyme-inhibitor, superoxide dismutase, and the sulfhydryl compounds glutathione (GSH), N-2-mercaptopropionylglycine (MPG) and N-acetylcysteine (NAC). Captopril, but not enalaprilat, caused dose-dependent relaxations in preconstricted aortic rings containing an intact endothelium. Rings denuded of endothelium were unresponsive to any dose of captopril. Captopril's vasodilation was not related to prostaglandin influence but was associated with an increase in cyclic GMP. Superoxide dismutase, GSH, MPG and NAC also produced endothelium-dependent relaxations similar to captopril. It was also demonstrated that endothelium-dependent relaxations to acetylcholine were enhanced by captopril, GSH, MPG and NAC but not by enalaprilat. In another set of experiments, the ability of captopril to inhibit superoxide-mediated inactivation of EDRF was examined. Pyrogallol, a potent generator of O2-, and superoxide dismutase, a scavenger of O2-, were used as a basis for comparing a possible scavenging effect of captopril. In preconstricted rings, pyrogallol elicited endothelium-dependent contractions that were attenuated by both captopril and superoxide dismutase. Similar effects were found with GSH, MPG and NAC but not with enalaprilat. These results suggest that captopril's endothelium-dependent vasodilation is due to its sulfhydryl group and the ability of the latter to scavenge O2-, thereby protecting EDRF.}, }
@article {pmid2029748, year = {1991}, author = {Romert, L and Swedmark, S and Jenssen, D}, title = {Thiol-enhanced decomposition of MNNG, ENNG, and nitrosocimetidine: relationship to mutagenicity in V79 Chinese hamster cells.}, journal = {Carcinogenesis}, volume = {12}, number = {5}, pages = {847-853}, doi = {10.1093/carcin/12.5.847}, pmid = {2029748}, issn = {0143-3334}, mesh = {Animals ; Carcinogens/*metabolism ; Cell Line ; Cimetidine/*analogs &amp; derivatives/chemistry ; Cricetinae ; Cricetulus ; Methylnitronitrosoguanidine/*analogs &amp; derivatives/*chemistry ; Mutagenicity Tests ; Mutation ; Sulfhydryl Compounds/*chemistry ; Thioguanine ; }, abstract = {The nitrosated form of cimetidine (Tagamet), nitrosocimetidine (NC), belongs to a group of nitrosoamidines in which the mutagenic and carcinogenic properties of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) have been studied in detail. The common mechanism of action of these compounds is that nucleophilic atoms can attack their iminocarbon, thereby leading to the formation of alkyldiazohydroxide and, subsequently of an alkylating and mutagenic diazonium ion. A competitive, non-mutagenic pathway involves denitrosation, which is strongly dependent on pH and can be enhanced by glutathione transferase. The influence of different thiols (e.g. glutathione and the L- and D-forms of N-acetylcysteine (L-NAC and D-NAC respectively] at different extra- and intracellular concentrations on the mutagenicity of these nitrosoamidines in V79 cells has been studied in the present investigation. The results demonstrate that the mutagenicity of MNNG and ENNG is highly dependent on where their reaction with thiols takes place. Thus, an increase in the intracellular glutathione level in combination with treatment with MNNG (or ENNG) in thiol-free medium elevated the mutagenicity, whereas treatment with thiols in the medium reduced mutagenicity. The mutagenicity of NC was, on the other hand, only slightly affected by increasing extra- or intracellular thiol levels. The dependence of NC-induced mutagenicity on thiols was indicated, however, by the finding that depletion of intracellular glutathione reduced this mutagenicity almost completely. The effects of treatments with thiols alone or in combination with glutathione transferases suggest that, under our assay conditions (e.g. physiological pH and thiol levels, in combination with low levels of the nitrosoamidines), no denitrosation occurs. On the contrary, our results indicate that intracellular thiols, and possibly glutathione transferases, potentiate the production of mutagenic species from these nitrosamidines.}, }
@article {pmid2020974, year = {1991}, author = {Skiles, GL and Smith, DJ and Appleton, ML and Carlson, JR and Yost, GS}, title = {Isolation of a mercapturate adduct produced subsequent to glutathione conjugation of bioactivated 3-methylindole.}, journal = {Toxicology and applied pharmacology}, volume = {108}, number = {3}, pages = {531-537}, doi = {10.1016/0041-008x(91)90099-z}, pmid = {2020974}, issn = {0041-008X}, support = {HL02119/HL/NHLBI NIH HHS/United States ; HL13645/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*isolation &amp; purification/metabolism ; Animals ; Biotransformation ; Chromatography, High Pressure Liquid ; Glutathione/*metabolism ; Goats ; Male ; Mass Spectrometry ; Mice ; Rats ; Skatole/metabolism/*pharmacokinetics ; }, abstract = {Bioactivation of the pneumotoxin 3-methylindole (3MI) to a methylene imine intermediate has been demonstrated previously by trapping the electrophile with glutathione in goat lung microsomal incubations. To determine whether the same bioactivation process occurs in whole animals, 3MI was administered to goats, mice, and rats, and the urinary metabolites from these three species were analyzed by HPLC for the presence of the mercapturate that would be expected as the processed and excreted form of the 3MI-glutathione adduct. The mercapturate, 3-[(N-acetylcysteine-S-yl)-methyl]indole (3MI-NAC), was identified in the urine from all three species and was isolated from rat urine for structural identification by uv, NMR, and mass spectrometry. Synthetic 3MI-NAC had uv, NMR, and chromatographic characteristics identical to the isolated metabolite. The presence of this mercapturate in the urine of treated animals unequivocally demonstrates that 3MI is bioactivated to the methylene imine in vivo and that the glutathione adduct is also formed, presumably to detoxify the methylene imine.}, }
@article {pmid2018563, year = {1991}, author = {Ravindranath, V and Boyd, MR}, title = {Effect of modulators of glutathione synthesis on the hepatotoxicity of 2-methylfuran.}, journal = {Biochemical pharmacology}, volume = {41}, number = {9}, pages = {1311-1318}, doi = {10.1016/0006-2952(91)90102-b}, pmid = {2018563}, issn = {0006-2952}, mesh = {Alanine Transaminase/blood ; Animals ; Antimetabolites/administration &amp; dosage/*pharmacology ; Buthionine Sulfoximine ; Chemical and Drug Induced Liver Injury/etiology/*metabolism ; Cystine/blood ; Drug Interactions ; Furans/antagonists &amp; inhibitors/*toxicity ; Glutathione/*biosynthesis ; Male ; Maleates/pharmacology ; Methionine Sulfoximine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Pyrrolidonecarboxylic Acid ; Rats ; Rats, Inbred Strains ; Thiazoles/pharmacology ; Thiazolidines ; }, abstract = {Treatment of male Sprague-Dawley rats with buthionine sulfoximine (BSO), prior to administration of carbon-14(14C)-labelled 2-methylfuran (2MF) caused a marked decrease in the covalent binding of 14C-labelled 2MF metabolites to both DNA and protein, although there was no apparent change in the distribution of the labelled parent 2MF. BSO pretreatment also protected against hepatotoxicity of 2MF, as indicated by lower serum glutamic pyruvic transaminase (GPT) levels. Pretreatment with BSO offered protection only if administered 1.5 hr before 2MF dosage. Administration of 2MF, 4 and 6 hr after BSO resulted in manifestation of the hepatotoxicity of 2MF. Prior treatment with diethylmaleate (DEM), increased covalent binding of [14C]2MF to liver proteins and also elevated serum GPT levels. Thus, depletion of tissue glutathione (GSH) by two different chemicals acting by different mechanisms produced opposite effects on the covalent binding and toxicity of 2MF. Pretreatment with L-2-oxothiazolidine-4-carboxylate (OTZ), a promoter of GSH biosynthesis, increased the hepatic covalent binding of [14C]2MF and potentiated hepatotoxicity. However, administration of OTZ and BSO prior to an i.p. dose of 100 mg/kg of 2MF, decreased the hepatic covalent binding of [14C]2MF and decreased the hepatoxicity. The marked instability of the GSH conjugate of the reactive metabolite of 2MF may account for the potentiation of hepatotoxicity of 2MF by OTZ. A single s.c. dose of BSO, caused a transient increase in plasma cystine levels concurrent with the depletion of liver GSH. Administration of 2MF, 1.5 hr after BSO, significantly decreased plasma cystine levels as compared to control animals that received vehicle alone. Pretreatment with BSO also resulted in increased excretion of urinary metabolites in 2MF treated animals as compared to animals receiving 2MF alone. Thus, BSO probably protects against hepatoxicity of 2MF by indirectly causing more detoxification of the reactive metabolite of 2MF, as it does not alter the distribution of unmetabolized 2MF and does not have any apparent effect on the microsomal mixed-function oxidase which mediates the activation of 2MF. The enhanced detoxification of 2MF in BSO treated animals appears independent of the depleted GSH levels; it may result from increased availability of a better alternative nucleophile (i.e. cysteine), capable of conjugating with acetyl acrolein. Acetyl acrolein (AA) appears to be the principal reactive metabolite of 2MF which binds covalently to tissues. Previous in vitro studies have shown that cysteine is a better trapping agent of AA than GSH or N-acetyl-cysteine.}, }
@article {pmid1936757, year = {1991}, author = {De Caterina, R}, title = {[Antiplatelet effects of nitrate derivatives].}, journal = {Giornale italiano di cardiologia}, volume = {21}, number = {5}, pages = {529-541}, pmid = {1936757}, issn = {0046-5968}, mesh = {Animals ; Blood Platelets/*drug effects ; Humans ; Nitrates/*pharmacology ; Platelet Aggregation Inhibitors/*pharmacology ; }, abstract = {Nitrates are among the most widely prescribed drugs in cardiovascular disease. They are able to prevent and to interrupt episodes of myocardial ischaemia, alleviate anginal symptoms, and exert favourable effects in acute myocardial infarction and in congestive heart failure. Most of these effects can be explained by their ability to relax smooth muscle cells: peripheral vasodilation, in veins and in arteries, reduces cardiac workload, thereby decreasing oxygen consumption; furthermore, nitrates dilate coronary arteries directly, thereby increasing myocardial oxygen supply. However, nitrates also exert effects on blood platelets. These occur by the same mechanisms operating on blood vessels, a stimulation of soluble guanylate cyclase and a consequent increase in cytosolic levels of cyclic GMP. When added to platelet suspensions nitrates inhibit platelet aggregation by almost all known stimuli. Such effects in vitro generally require high concentrations of drugs; evidence has been obtained, however, that nitrates may inhibit platelet function also in vivo. Such evidence derives from ex vivo studies with platelet aggregometry, from experiments showing the synergism of nitrates and prostacyclin and the requirement for nitrate action of sulphydryl group donors such as N-acetyl-cysteine, and from studies on bleeding time. Antiplatelet effects of nitrates may be an explanation for the protection from death and reinfarction, inferred on the basis of meta-analysis of several studies in acute myocardial infarction.}, }
@article {pmid1907460, year = {1991}, author = {Mihm, S and Ennen, J and Pessara, U and Kurth, R and Dröge, W}, title = {Inhibition of HIV-1 replication and NF-kappa B activity by cysteine and cysteine derivatives.}, journal = {AIDS (London, England)}, volume = {5}, number = {5}, pages = {497-503}, doi = {10.1097/00002030-199105000-00004}, pmid = {1907460}, issn = {0269-9370}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Base Sequence ; Cell Line ; Cysteine/*pharmacology ; Gene Expression Regulation/drug effects ; Gene Products, gag/analysis ; Glutathione/metabolism ; HIV Antigens/analysis ; HIV Core Protein p24 ; HIV-1/*drug effects/physiology ; Humans ; Molecular Sequence Data ; Monocytes/microbiology ; NF-kappa B/*drug effects ; T-Lymphocytes/microbiology ; Transcription, Genetic/drug effects ; Tumor Cells, Cultured ; Viral Core Proteins/analysis ; Virus Replication/drug effects ; }, abstract = {HIV-1 proviral DNA contains two binding sites for the transcription factor NF-kappa B. HIV-1-infected individuals have, on average, abnormally high levels of tumour necrosis factor alpha (TNF alpha) and abnormally low plasma cysteine levels. We therefore investigated the effects of cysteine and related thiols on HIV-1 replication and NF-kappa B expression. The experiments in this report show that cysteine or N-acetylcysteine (NAC) raise the intracellular glutathione (GSH) level and inhibit HIV-1 replication in persistently infected Molt-4 and U937 cells. However, inhibition of HIV-1 replication appears not to be directly correlated with GSH levels. Cysteine and NAC also inhibit NF-kappa B activity as determined by electrophoretic mobility shift assays and chloramphenicol acetyl-transferase (CAT) gene expression under control of NF-kappa B binding sites in uninfected cells. This suggests that the cysteine deficiency in HIV-1-infected individuals may cause an over-expression of NF-kappa B-dependent genes and enhance HIV-1 replication. NAC may be considered for the treatment of HIV-1-infected individuals.}, }
@article {pmid1674384, year = {1991}, author = {Girardi, G and Elias, MM}, title = {Effectiveness of N-acetylcysteine in protecting against mercuric chloride-induced nephrotoxicity.}, journal = {Toxicology}, volume = {67}, number = {2}, pages = {155-164}, doi = {10.1016/0300-483x(91)90139-r}, pmid = {1674384}, issn = {0300-483X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Glutathione/analysis/metabolism ; Kidney/chemistry/*drug effects/physiology ; Lipid Peroxidation ; Liver/chemistry/drug effects/metabolism ; Male ; Maleates/pharmacology ; Mercuric Chloride/*toxicity ; Mercury/analysis ; Rats ; Rats, Inbred Strains ; Sulfhydryl Compounds/analysis/metabolism ; gamma-Glutamyltransferase/urine ; }, abstract = {Mercuric chloride (HgCl2)-induced nephrotoxicity, as measured by functional and biochemical parameters was evaluated in rats at different kidney non-protein sulfhydryls (NPS) levels. Diethylmaleate (DEM) induced a 75% of NPS diminution 1 h after the administration. Renal function (clearance) and biochemical measurements (gamma-glutamyltranspeptidase activity in urine, and lipoperoxides in kidney tissue) were impaired when the animals were HgCl2-treated. Values were highly impaired when the kidneys were NPS-depleted and were improved when NPS pools were previously increased although they were not similar to control values. DEM treatment promoted a higher accumulation of HgCl2 in both kidney and liver while NAC-treatment reduced significantly the metal content in these organs. These data are in favour of a positive relationship among mercury content and organ injury. On the other hand, mercury content increased while NPS levels diminished. NPS might play a role in the HgCl2 detoxification and thus avoids mercury accumulation and mercury effects.}, }
@article {pmid1907641, year = {1991}, author = {Devasagayam, TP and Sundquist, AR and Di Mascio, P and Kaiser, S and Sies, H}, title = {Activity of thiols as singlet molecular oxygen quenchers.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {9}, number = {1}, pages = {105-116}, doi = {10.1016/1011-1344(91)80008-6}, pmid = {1907641}, issn = {1011-1344}, mesh = {Glutathione/chemistry ; Oxidation-Reduction ; Oxygen/*chemistry ; Photochemistry ; Singlet Oxygen ; Sulfhydryl Compounds/*chemistry ; }, abstract = {Singlet molecular oxygen O2(1 delta g) arising from the thermodissociation of the endoperoxide of 3,3'-(1,4-naphthylidene) dipropionate (NDPO2) was used to assess the quenching ability of various thiols and related compounds in sodium phosphate buffer in D2O at 37 degrees C. The overall quenching ability decreases in the sequence ergothioneine, methionine, cysteine, beta,beta-dimethyl cysteine (penicillamine), mercaptopropionylglycine, mesna, glutathione (GSH), dithiothreitol, N-acetyl cysteine and captopril. Cystine, glutathione disulphide, dimesna, methionine sulphone and methionine sulphoxide have no quenching effect. Comparison of the rate constants for physical (kq) with chemical (kr) quenching by thiols indicates that chemical reactivity accounts fully for their ability to quench O2(1 delta g), and pD dependence indicates that the thiolate anion reacts with O2(1 delta g). Loss of thiol groups, as exemplified by GSH, is not affected by the free radical scavengers superoxide dismutase and mannitol. However, sodium azide, a scavenger of O2(1 delta g), completely prevents NDPO2-induced thiol depletion. Depletion of GSH by NDPO2 is accompanied by the formation of its disulphide, sulphinate, sulphonate, sulphoxide and other products.}, }
@article {pmid1863605, year = {1991}, author = {Belda, FJ and Fernández, J and Esteban, G and García, M and Luquin, M and Ausina, V}, title = {[Evaluation of 2 culture systems for the isolation of opportunistic mycobacteria].}, journal = {Enfermedades infecciosas y microbiologia clinica}, volume = {9}, number = {3}, pages = {145-147}, pmid = {1863605}, issn = {0213-005X}, mesh = {*Bacteriological Techniques ; Evaluation Studies as Topic ; Humans ; Mycobacterium Infections, Nontuberculous/*microbiology ; Nontuberculous Mycobacteria/*isolation &amp; purification ; Opportunistic Infections/*microbiology ; Retrospective Studies ; }, abstract = {The increment of infections produced by opportunist environmental mycobacteria (OEM) raises the question about the appropriateness of the conventional culture methods since they were initially designed to isolate M. tuberculosis. In this study we have comparatively evaluated the yield of a conventional culture (Löwenstein-Jensen) with respect to that of Middlebrook 7H12 (Bactec) in 396 selected samples in which OEM were isolated. Samples with commensal flora were previously subjected to a chemical homogenization-decontamination process with alkaline N-acetyl-cysteine. All cultures were sown with standard inoculates obtained from centrifugate material. The 7H12 culture showed a more rapid detection (mean: 17-18 days) and a greater effectiveness in the isolation of eventually pathogenic mycobacteria than the conventional Löwenstein-Jensen culture. The 7H12/LJ ratio for the species with high clinical relevance was: 1.3 for M. kansasii, 1.0 for M. marinum, 1.8 for M. scrofulaceum, 1.3 for M. xenopi, 1.5 for M. avium-intracellulare, 0.5 for M. chelonae, and 2.0 for M. fortuitum.}, }
@article {pmid1711602, year = {1991}, author = {Lawson, DL and Nichols, WW and Mehta, P and Mehta, JL}, title = {Captopril-induced reversal of nitroglycerin tolerance: role of sulfhydryl group vs. ACE-inhibitory activity.}, journal = {Journal of cardiovascular pharmacology}, volume = {17}, number = {3}, pages = {411-418}, doi = {10.1097/00005344-199103000-00009}, pmid = {1711602}, issn = {0160-2446}, mesh = {Acetylcholine/pharmacology ; Acetylcysteine/pharmacology ; Animals ; Aorta/chemistry ; Captopril/*pharmacology ; Cyclic GMP/analysis ; Drug Tolerance ; Enalaprilat/pharmacology ; Nitroglycerin/*pharmacology ; Rats ; Rats, Inbred Strains ; Sulfhydryl Compounds/*pharmacology ; Vasodilation/*drug effects ; }, abstract = {The angiotensin-converting enzyme (ACE) inhibitor captopril has been shown to reverse vascular tolerance to nitroglycerin (NTG). Whether captopril reverses NTG tolerance by providing sulfhydryl (SH) groups or by inhibiting ACE is not clear. To examine this issue, we treated rat aortic rings with buffer, captopril (SH +, ACE inhibitory activity +), enalaprilat (SH-, ACE inhibitory activity +), or N-acetylcysteine (NAC, SH+, ACE inhibitory activity-) prior to their contraction with epinephrine and subsequent relaxation with NTG. Previous exposure of NTG-treated rings resulted in marked resistance to the vasorelaxant effect of a subsequent exposure to NTG in buffer-treated rings. Both NAC and captopril, but not enalaprilat, potentiated the vasorelaxant effects of NTG during the first exposure of vascular rings to NTG and also prevented the development of tolerance to NTG during a second exposure. Buffer-treated rings showed an inability to accumulate cyclic guanosine monophosphate (GMP) in response to a second exposure to NTG. In contrast, both NAC and captopril-pretreated rings demonstrated a persistence of cyclic GMP accumulation during the second NTG exposure. The endothelium-dependent vasodilator acetylcholine (ACh) caused relaxation of the NTG-tolerant rings and also induced cyclic GMP accumulation in these rings. In other experiments, we found that prior exposure of vascular rings to ACh did not cause resistance to the subsequent vasorelaxant effects of ACh. NAC, captopril, and enalaprilat did not modulate the effects of ACh during either the first or subsequent exposures to ACh. In addition, indomethacin did not influence the "protective" effects of NAC or captopril against NTG tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1676665, year = {1991}, author = {Kassahun, K and Farrell, K and Abbott, F}, title = {Identification and characterization of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {19}, number = {2}, pages = {525-535}, pmid = {1676665}, issn = {0090-9556}, mesh = {Acetylcysteine/*metabolism ; Animals ; Fatty Acids, Unsaturated/analysis/chemical synthesis/*metabolism ; Gas Chromatography-Mass Spectrometry ; Glutathione/*metabolism ; Humans ; Magnetic Resonance Spectroscopy ; Male ; Rats ; Rats, Inbred Strains ; Valproic Acid/*metabolism ; }, abstract = {The severe hepatotoxicity of valproic acid (VPA) is believed to be mediated through reactive metabolites. The formation of glutathione (GSH) and N-acetylcysteine (NAC) adducts of reactive intermediates derived from VPA and two of its metabolites, 2-propyl-4-pentenoic acid (4-ene-) and 2-propyl-2,4-pentadienoic acid [(E)-2,4-diene VPA], was investigated in the rat. Rats were dosed ip with 100 mg/kg of VPA, 4-ene-, or 2,4-diene-VPA, and methylated bile and urine extracts were analyzed by LC/MS/MS and GC/MS, respectively. The GSH conjugate of (E)-2,4-diene VPA was detected in the bile of rats treated with 4-ene- and (E)-2,4-diene VPA. The NAC conjugate was a major urinary metabolite of rats given (E)-2,4-diene VPA and was a prominent urinary metabolite of those animals given 4-ene VPA. The NAC conjugate was also found to be a metabolite of VPA in patients. Both the GSH and NAC adducts were chemically synthesized and their structures established to be 5-(glutathion-S-yl)3-ene VPA and 5-(N-acetylcystein-S-yl)3-ene VPA by NMR and mass spectrometry. In contrast to the very slow reaction of the free acid of (E)-2,4-diene VPA with GSH, the methyl ester reacted rapidly with GSH to yield the adduct. In vivo it appears the diene forms an intermediate with enhanced electrophilic reactivity to GSH as indicated by the facile reaction of the diene with GSH in vivo [about 40% of the (E)-2,4-diene VPA administered to rats was excreted as the NAC conjugate in 24 hr]. The characterization of the GSH and NAC (in humans and rats) conjugates of (E)-2,4-diene VPA suggests that VPA is metabolized to a chemically reactive intermediate that may contribute to the hepatotoxicity of the drug.}, }
@article {pmid1364825, year = {1991}, author = {Tang, LD and Sun, JZ and Wu, K and Sun, CP and Tang, ZM}, title = {Beneficial effects of N-acetylcysteine and cysteine in stunned myocardium in perfused rat heart.}, journal = {British journal of pharmacology}, volume = {102}, number = {3}, pages = {601-606}, pmid = {1364825}, issn = {0007-1188}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Arrhythmias, Cardiac/prevention &amp; control ; Coronary Circulation ; Cystamine/pharmacology ; Cysteine/*pharmacology ; Female ; Hydroxyl Radical/metabolism ; Male ; Myocardial Stunning/*physiopathology ; Perfusion ; Rats ; Rats, Wistar ; Superoxides/metabolism ; }, abstract = {1. The objective of this study was to evaluate the effects of three sulphydryl (SH) compounds, N-acetylcysteine (NAC), cysteine (Cys) and cystamine, on functional recovery and ventricular arrhythmias (VF) in stunned myocardium in the isolated perfused heart of the rat. 2. Hearts (n = 7-8 per group) were perfused by the Langendorff procedure for 20 min to stabilize and then assigned to one of five groups: saline, sham, NAC, Cys and cystamine. After the stabilizing period, the drugs (at 3.6 microM min-1) or their vehicle (saline) were infused into coronary vessels throughout the experimental period. Ten min after administration of drugs, the left anterior descending coronary artery (LAD) was ligatured for 20 min and then untied to reperfuse for 30 min. In the sham group, a ligature was placed around the LAD but not tied. 3. NAC and Cys had a significant effect in attenuating myocardial stunning: the percentage recovery of rate-pressure product measured 30 min after reperfusion as an index of heart function, was improved with the NAC (98.3 +/- 4.5) and Cys groups (104.0 +/- 6.5) compared with the saline (only 73.6 +/- 3.8, P < 0.01) group. Cystamine did not show these beneficial effects. This may be due to the difference in chemical structure between NAC, Cys and cystamine since the latter does not have a free SH group with a disulphide bond formed. This phenomenon suggests that a free SH group is essential for the protective effects of compounds like NAC and Cys in myocardial injury. 4. NAC and Cys prevented the fall in coronary flow during the LAD occlusion and enhanced coronary flow during reperfusion but cystamine did not have such a beneficial effect. 5. The incidence of VF in the saline, cystamine, Cys and NAC groups was 6/8 (75.0%), 4/7 (57.1%), 3/8 (37.5%) and 2/7 (28.6%), respectively, and no significant differences (P > 0.05) were noted between the saline- and drug-treated groups. 6. An in vitro study with electron spin resonance indicated that Cys effectively scavenged the hydroxyl radical (-OH) generated by Fenton's reaction but did not scavenge superoxide generated in an irradiated riboflavin system. NAC and cystamine showed a scavenging effect on -OH to a certain extent but this effect did not reach statistical significance (P > 0.05 vs saline). 7. Our results demonstrate that NAC and Cys treatment before ischaemia and reperfusion can reduce myocardial stunning. This beneficial effect may be mainly due to their ability to preserve and enhance coronary flow during coronary occlusion and reperfusion and in part due to scavenging -OH and/or replenishing intracellular glutathione. The results also indicate that the condition of coronary perfusion can produce a great impact on postischaemic ventricular performance.}, }
@article {pmid1990978, year = {1991}, author = {Brown, PC and Dulik, DM and Jones, TW}, title = {The toxicity of menadione (2-methyl-1,4-naphthoquinone) and two thioether conjugates studied with isolated renal epithelial cells.}, journal = {Archives of biochemistry and biophysics}, volume = {285}, number = {1}, pages = {187-196}, doi = {10.1016/0003-9861(91)90348-m}, pmid = {1990978}, issn = {0003-9861}, support = {R01 ES05436-01/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; Cricetinae ; Epithelium/drug effects ; In Vitro Techniques ; Kidney/*drug effects/metabolism ; Male ; Microsomes/drug effects/enzymology ; Mitochondria/metabolism ; Models, Biological ; NADH Dehydrogenase/metabolism ; Oxidation-Reduction ; Quinones/metabolism ; Rats ; Rats, Inbred F344 ; Structure-Activity Relationship ; Sulfides/*pharmacology ; Vitamin K/chemical synthesis/*toxicity ; }, abstract = {Menadione (2-methyl-1,4-naphthoquinone) was used as a model compound to test the hypothesis that thioether conjugates of quinones can be toxic to tissues associated with their elimination through a mechanism involving oxidative stress. Unlike menadione, the glutathione (2-methyl-3-(glutathion-S-yl)-1,4-naphthoquinone; MGNQ) and N-acetyl-L-cysteine (2-methyl-3-(N-acetylcysteine-S-yl)-1,4-naphthoquinone; M(NAC)NQ) thioether conjugates were not able to arylate protein thiols but were still able to redox cycle with cytochrome c reductase/NADH and rat kidney microsomes and mitochondria. Interestingly, menadione and M(NAC)NQ were equally toxic to isolated rat renal epithelial cells (IREC) while MGNQ was nontoxic. The toxicity of both menadione and M(NAC)NQ was preceded by a rapid depletion of soluble thiols and was associated with a depletion of soluble thiols and was associated with a depletion of protein thiols. Treatment of IREC with the glutathione reductase inhibitor, 1,3-bis(2-chloroethyl)-1-nitrosourea, potentiated the thiol depletion and toxicity observed with menadione and M(NAC)NQ indicating the involvement of oxidative stress in this model of renal cell toxicity. The lack of MGNQ toxicity can be attributed to an intramolecular cyclization reaction which destroys the quinone nucleus and therefore eliminates its ability to redox cycle. These findings have important implications with regard to our understanding of the toxic potential of quinone thioether conjugates and of quinone toxicity in general.}, }
@article {pmid2058179, year = {1991}, author = {Poulsen, HE and Ranek, L and Jørgensen, L}, title = {The influence of disulfiram on acetaminophen metabolism in man.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {21}, number = {2}, pages = {243-249}, doi = {10.3109/00498259109039466}, pmid = {2058179}, issn = {0049-8254}, mesh = {Acetaminophen/blood/*pharmacokinetics/urine ; Adult ; Aged ; Alcoholism/drug therapy ; Disulfiram/*pharmacology/therapeutic use ; Drug Interactions ; Female ; Humans ; Liver Cirrhosis, Alcoholic/metabolism ; Male ; Metabolic Clearance Rate ; Middle Aged ; }, abstract = {1. Acetaminophen clearance and its partial clearance to its major metabolites has been determined before and after 5 days treatment with the anti-alcohol abuse agent disulfiram (200 mg daily). The study was conducted in 10 subjects, five without liver disease and five with alcoholic cirrhosis of the liver. Acetaminophen was given i.v. at a dose of 500 mg. Plasma samples were obtained up to 8 h after injection and urine collected for 24 h. 2. Across all subjects acetaminophen plasma clearance was reduced from 0.249 +/- 0.061 to 0.217 +/- 0.066 l/min after disulfiram treatment (mean +/- SD, P less than 0.05). Thus no change in acetaminophen dosage would be required in patients treated with disulfiram. 3. The partial clearance of acetaminophen to its glucuronide, sulphate and glutathione derivatives (i.e. cysteine and N-acetyl cysteine) was not significantly changed by disulfiram treatment. Thus it seems unlikely that the previously observed protective effects of disulfiram against acetaminophen-induced hepatotoxicity in animals due to inhibition of metabolism will be seen in man.}, }
@article {pmid1704137, year = {1991}, author = {Kalebic, T and Kinter, A and Poli, G and Anderson, ME and Meister, A and Fauci, AS}, title = {Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {88}, number = {3}, pages = {986-990}, pmid = {1704137}, issn = {0027-8424}, support = {2 R37 DK-12034/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; *Antiviral Agents ; Cell Line ; Glutathione/analogs &amp; derivatives/*pharmacology ; HIV/drug effects/genetics/*physiology ; Humans ; Interleukin-6/pharmacology ; Kinetics ; RNA, Messenger/genetics ; Reverse Transcriptase Inhibitors ; Tetradecanoylphorbol Acetate/pharmacology ; Tumor Necrosis Factor-alpha/pharmacology ; }, abstract = {The effects of glutathione (GSH), glutathione ester (GSE), and N-acetyl-L-cysteine (NAC) on the induction of human immunodeficiency virus (HIV) expression were investigated in the chronically infected monocytic U1 cell line, a previously described cellular model for HIV latency. U1 cells constitutively express low levels of virus, which can be increased by phorbol 12-myristate 13-acetate (PMA), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and other inducers. GSH, GSE, and NAC suppressed in a dose-dependent fashion the induction of HIV expression mediated by PMA, TNF-alpha, and IL-6, in the absence of cytotoxic or cytostatic effects. Reverse transcriptase activity, inducible by PMA, TNF-alpha, or IL-6, was decreased by 80-90% after pretreatment with GSH, GSE, or NAC. The induction of total HIV protein synthesis was also decreased appreciably after pretreatment with GSH, GSE, or NAC. The accumulation of HIV mRNA was substantially suppressed after pretreatment with NAC but to a lesser extent after pretreatment with GSH or GSE. Although PMA induces the expression of TNF-alpha in U1 cells, the suppressive effect of GSH, GSE, and NAC on PMA-induced HIV expression in U1 cells was not associated with the inhibition of TNF-alpha expression. The present findings, which elucidate relationships between cellular GSH and HIV expression, suggest that therapy with thiols may be of value in the treatment of HIV infection.}, }
@article {pmid1670844, year = {1991}, author = {Gavish, D and Breslow, JL}, title = {Lipoprotein(a) reduction by N-acetylcysteine.}, journal = {Lancet (London, England)}, volume = {337}, number = {8735}, pages = {203-204}, doi = {10.1016/0140-6736(91)92161-t}, pmid = {1670844}, issn = {0140-6736}, mesh = {Acetylcysteine/*pharmacology ; Antibodies/analysis ; Arteriosclerosis/blood ; Diet ; Drug Evaluation ; Humans ; In Vitro Techniques ; Lipoprotein(a) ; Lipoproteins/blood/immunology/*metabolism ; Molecular Weight ; }, abstract = {Lipoprotein(a), a complex of low-density lipoprotein linked by disulphide bridges with apo(a), is associated with atherosclerotic disease when present at very high plasma concentrations. In vitro, N-acetylcysteine (NAC) dissociates this complex. In two patients with high Lp(a) levels NAC lowered plasma Lp(a) from 58 to 20 mg/dl and from 59 to 18 mg/dl: reductions of this order have not hitherto been achieved either by drugs or by diet.}, }
@article {pmid2026726, year = {1991}, author = {Longo, A and Di Toro, M and Galimberti, C and Carenzi, A}, title = {Determination of N-acetylcysteine in human plasma by gas chromatography-mass spectrometry.}, journal = {Journal of chromatography}, volume = {562}, number = {1-2}, pages = {639-645}, doi = {10.1016/0378-4347(91)80614-i}, pmid = {2026726}, mesh = {Acetylcysteine/*blood ; Autoanalysis ; Cysteine/analogs &amp; derivatives/analysis ; Gas Chromatography-Mass Spectrometry ; Half-Life ; Humans ; Indicators and Reagents ; }, abstract = {An automatic mass spectrometric method for the quantitation of N-acetylcysteine (NAC) in human plasma has been developed. NAC was extracted from plasma with ethyl acetate and derivatized in two steps with 2-propanol and pentafluoropropionic anhydride. The volatile derivative obtained was ideal for gas chromatographic-mass spectrometric analysis. Data obtained by analysing the plasma of healthy volunteers to whom 600 mg of NAC had been orally given are reported.}, }
@article {pmid1941902, year = {1991}, author = {Thielemann, LE and Rosenblut, G and Cerda, MC and Oberhauser, EW and De Geyter, MA and Videla, LA}, title = {Effect of different amino acidic pretreatments that protect the kidney against papillary necrosis induced by bromoethylamine on differential distribution of renal nonprotein sulfhydryls.}, journal = {Journal of biochemical toxicology}, volume = {6}, number = {2}, pages = {155-159}, doi = {10.1002/jbt.2570060210}, pmid = {1941902}, issn = {0887-2082}, mesh = {Acetylcysteine/pharmacology ; Amino Acids/*pharmacology ; Animals ; Cystine/metabolism ; *Ethylamines ; Glutamine/metabolism ; Glycine/metabolism ; Kidney/drug effects/*metabolism ; Kidney Cortex/drug effects/metabolism ; Kidney Medulla/drug effects/metabolism ; Kidney Papillary Necrosis/chemically induced/*prevention &amp; control ; Rats ; Sulfhydryl Compounds/*metabolism ; }, abstract = {Content of nonprotein sulfhydryls (NPSH) was found to be higher in rat renal cortex than in external medulla and papilla. Administration of bromoethylamine (BEA), at a dose that produces extensive papillary necrosis and minor effects in the other renal segments, induced a significant reduction in NPSH levels of renal cortex and external medulla, with no changes in the papilla. Treatment with N-acetyl-L-cysteine (NAC) elicited an increase in papillary NPSH and a decrease in the cortex, with opposite changes being observed with an amino acid mixture of glutamine, glycine, and cystine (AM). Similar results were found in animals pretreated with NAC or AM prior to BEA intoxication. These pretreatments protect the cortex, external medulla, and papilla from the necrosis induced by BEA. It is suggested that protection of BEA-induced renal necrosis by NAC or AM pretreatments might be due to different mechanisms, with NPSH playing direct or indirect roles, respectively.}, }
@article {pmid1929851, year = {1991}, author = {Commandeur, JN and Boogaard, PJ and Mulder, GJ and Vermeulen, NP}, title = {Mutagenicity and cytotoxicity of two regioisomeric mercapturic acids and cysteine S-conjugates of trichloroethylene.}, journal = {Archives of toxicology}, volume = {65}, number = {5}, pages = {373-380}, pmid = {1929851}, issn = {0340-5761}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*toxicity ; Animals ; Cysteine/*analogs &amp; derivatives/toxicity ; In Vitro Techniques ; Kidney Tubules, Proximal/*drug effects/metabolism ; Male ; Mutagenicity Tests ; *Mutagens ; Rats ; Rats, Inbred Strains ; Salmonella typhimurium/drug effects ; Stereoisomerism ; Trichloroethylene/*metabolism ; }, abstract = {The mutagenicity, cytotoxicity and metabolism of two regioisomic L-cysteine- and N-acetyl-L-cysteine-S-conjugates of trichloroethylene were studied. The 1,2-dichlorovinyl(1,2-DCV) isomers of both the cysteine conjugate and the mercapturate were much stronger mutagens in the Ames test with Salmonella typhimurium TA2638 when compared to the corresponding 2,2-dichlorovinyl (2,2-DCV) isomers. Similarly, the 1,2-DCV isomers were more cytotoxic towards isolated rat kidney proximal tubular cells, as assessed by inhibition of alpha-methylglucose uptake, than the 2,2-DCV isomers. The 3-4-fold higher rate of beta-lyase-dependent activation of S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCV-Cys) when compared to S-(1,2-dichlorovinyl)-L-cysteine (2,2-DCV-Cys) as well as the different nature of the reactive intermediates formed is probably responsible for these structure-dependent effects. The cytotoxicity of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCV-NAc) toward isolated kidney cells showed a delayed time course as compared to that of 1,2-DCV-Cys, probably due to the relatively low rate of deacetylation of 1,2-DCV-NAc. The time course of cytotoxicity of N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCV-NAc), however, parallelled that of 2,2-DCV-Cys. Due to the relatively high rate of N-acetylation and low rate of beta-lyase activation, for 2,2-DCV-Nac the beta-lyase activation step may be rate limiting. Different rates of cellular uptake also may play a role in time course of toxicity of the cysteine conjugates and the mercapturic acids in the renal cells.}, }
@article {pmid1906786, year = {1991}, author = {Gustafson, DL and Pritsos, CA}, title = {Inhibition of mitomycin C's aerobic toxicity by the seleno-organic antioxidant PZ-51.}, journal = {Cancer chemotherapy and pharmacology}, volume = {28}, number = {3}, pages = {228-230}, pmid = {1906786}, issn = {0344-5704}, support = {CA-43660/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Aerobiosis/drug effects ; Animals ; Antineoplastic Agents/*antagonists &amp; inhibitors/toxicity ; Antioxidants/*pharmacology ; Azoles/*pharmacology ; Cell Hypoxia/drug effects ; Cell Line ; Dimethyl Sulfoxide/pharmacology ; Dose-Response Relationship, Drug ; Isoindoles ; Mice ; Mitomycin ; Mitomycins/*antagonists &amp; inhibitors/toxicity ; *Organoselenium Compounds ; Porfiromycin/toxicity ; Selenium/*pharmacology ; Tumor Cells, Cultured/drug effects/metabolism ; }, abstract = {Mitomycin C (MMC) is a bioreductive alkylating agent that is capable of generating oxygen radicals. Porfiromycin (PM) is an analog to MMC that generates oxygen radicals at a significantly lower level than the parent compound. Under aerobic conditions, the toxicity of MMC to EMT6 cells is 2.5-fold that of PM, whereas hypoxically the two are equitoxic. In the present studies, the protective effect of PZ-51 in combination with NAC was assessed against the dose-dependent toxicity of either MMC or PM under both aerobic and hypoxic conditions. Aerobically, the PZ-51 and NAC combination inhibited the toxicity of MMC at concentrations of between 0.25 and 2 microM but had no effect on PM toxicity. Under hypoxic conditions, the PZ-51 and NAC combination had no effect on either MMC or PM toxicity. These findings support a role for oxygen radical generation in the aerobic toxicity of MMC at clinically relevant doses.}, }
@article {pmid1897703, year = {1991}, author = {Millán Guevara, J and Bernal Pascual, MA and Gaitero del Hoyo, MJ and Romero Alvira, D and Royo López, J}, title = {[Ambulatory aerosol therapy in the treatment of chronic pathology of the O.R.L. region].}, journal = {Anales otorrinolaringologicos ibero-americanos}, volume = {18}, number = {3}, pages = {231-238}, pmid = {1897703}, issn = {0303-8874}, mesh = {Acetylcysteine/administration &amp; dosage ; *Aerosols ; Ambulatory Care ; Cefotaxime/administration &amp; dosage ; Drug Evaluation ; Humans ; Methylprednisolone/administration &amp; dosage ; Otitis Media with Effusion/*drug therapy ; Paranasal Sinus Diseases/*drug therapy ; Time Factors ; }, abstract = {This study considers the efficacity of the ambulatory aerosol therapy in chronic cases of the ENT area. A nebulizer, air-jet type, of 4 microns MMAD, was the device employed, and an ample spectre antibiotic (cefotaxime) a mucolytic (N-acetyl-cysteine) plus a corticoid (methyl-prednisolone) the associated drugs. The antibiotic was discarded when otitis were the problem. The results have been favourable in 75 percent of the cases whilst negative in the resting 24 percent of the treated subjects.}, }
@article {pmid1835247, year = {1991}, author = {Tang, LD and Tang, ZM}, title = {[Protective effects of SH-compounds on ischemia reperfusion induced arrhythmias in the isolated rat heart].}, journal = {Yao xue xue bao = Acta pharmaceutica Sinica}, volume = {26}, number = {2}, pages = {91-95}, pmid = {1835247}, issn = {0513-4870}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Arrhythmias, Cardiac/etiology/*prevention &amp; control ; Coronary Circulation/drug effects ; Cysteamine/*therapeutic use ; Cysteine/*therapeutic use ; Dihydropyridines/*pharmacology ; *Dimaprit/*analogs &amp; derivatives ; Female ; In Vitro Techniques ; Male ; Myocardial Reperfusion Injury/*complications ; Rats ; Rats, Inbred Strains ; Thiourea/*therapeutic use ; }, abstract = {Protective effects of cysteine (Cys), N-acetylcysteine (NAC), cysteamine (MEA), cystamine (CSSC) and aminopropylmethylisothiourea (APMT) on ischemia/reperfusion induced arrhythmias were studied in isolated Langendorff perfused rat hearts. The arrhythmias were caused by ligation of the anterior descending branch of the left coronary artery for 10 min and reperfused for 5 min. The drugs were dissolved in saline (NS) and perfused through a peristaltic pump system at 0.1, 0.6 or 3.6 mumol/min (n = 10), starting from 10 min before ligation up to 5 min after reperfusion. The control hearts were perfused with NS. The results showed that Cys, NAC and MEA pursued at 0.6-3.6 mumol/min significantly reduced the incidence of ventricular fibrillation (VF), which were 80-90% in control and 0-20% in 3 treated groups, with P less than 0.01-0.001. The duration of ventricular tachycardia (VT) + VF was 3.0 +/- 1.6 min in control and were 0.2 +/- 0.2, 0.2 +/- 0.1 and 1.2 +/- 2.1 min in Cys, NAC and MEA groups, respectively (with P less than 0.01-0.001). Coronary flow (CF) were remarkably reduced to about 50% during ligation in NS, but remained at normal levels in three treated groups. There were no significant protective effects on arrhythmias in CSSC and APMT perfused hearts. CF of CSSC and APMT groups were even less than those of control. The structure-activity analysis suggested that the SH group may play a crucial role in the protective effect of SH compounds on ischemia/reperfusion induced arrhythmias. The mechanism of protection was briefly discussed in this paper.}, }
@article {pmid1725675, year = {1991}, author = {Hong, XJ and Francker, A and Diamant, B}, title = {Effects of N-acetylcysteine on histamine release by sodium fluoride and compound 48/80 from isolated rat mast cells.}, journal = {International archives of allergy and applied immunology}, volume = {96}, number = {4}, pages = {338-343}, doi = {10.1159/000235518}, pmid = {1725675}, issn = {0020-5915}, mesh = {Acetylcysteine/*pharmacology ; Adenosine Triphosphate/analysis ; Animals ; Calcium/pharmacology ; Female ; Free Radicals/metabolism ; Histamine Release/*drug effects ; Mast Cells/chemistry/*metabolism ; Peritoneal Cavity/cytology ; Rats ; Rats, Inbred Strains ; Sodium Fluoride/*metabolism ; p-Methoxy-N-methylphenethylamine/*metabolism/pharmacology ; }, abstract = {N-acetylcysteine (NAC) enhances the release of histamine induced by the fluoride-calcium system but not by compound 48/80. After preincubation of the cells for 2 h at room temperature (RT) as well as at 37 degrees C, NAC was found to enhance histamine release also when induced by compound 48/80. Both fluoride treatment and prolonged incubation at 37 degrees C (but not at RT) for 2 h decreased the ATP content of the cells. NAC was found to counteract the fall in ATP caused by prolonged incubation of the cells at 37 degrees C but not when induced by exposure to sodium fluoride. The results do not favor the concept that free radicals generated by fluoride treatment are responsible for the subsequent sensitivity of the cells to the secretory action of calcium. On the other hand, it cannot be excluded that free radicals generated during prolonged incubation of the cells at 37 degrees C might be involved in the decrease of the sensitivity of the cells to the secretory action of the fluoride-calcium system and of compound 48/80. This is supported by the finding that the presence of NAC not only activated the secretory response but also counteracted the decrease of the cellular ATP content noted following preincubation of the cells for 2 h at 37 degrees C.}, }
@article {pmid2123045, year = {1990}, author = {Estep, JE and Lamé, MW and Jones, AD and Segall, HJ}, title = {N-acetylcysteine-conjugated pyrrole identified in rat urine following administration of two pyrrolizidine alkaloids, monocrotaline and senecionine.}, journal = {Toxicology letters}, volume = {54}, number = {1}, pages = {61-69}, doi = {10.1016/0378-4274(90)90056-r}, pmid = {2123045}, issn = {0378-4274}, support = {ES-03343/ES/NIEHS NIH HHS/United States ; ES-04699/ES/NIEHS NIH HHS/United States ; RR-01460/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/urine ; Animals ; Antineoplastic Agents, Phytogenic/isolation &amp; purification/*pharmacokinetics/urine ; Chromatography, High Pressure Liquid ; Liver/metabolism ; Male ; Monocrotaline ; Pyrrolizidine Alkaloids/isolation &amp; purification/*pharmacokinetics/*urine ; Rats ; Rats, Inbred Strains ; }, abstract = {This report demonstrates that an Ehrlich-reagent-positive metabolite of monocrotaline and senecionine is excreted in the urine of male rats as an N-acetylcysteine conjugate of (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (NAC-DHP). Isolation of the metabolite employed an initial organic extraction followed by HPLC separation of remaining urinary components using a reverse-phase, polymer-based, PRP-1 column. Fast-atom-bombardment tandem mass spectrometry was used to identify the metabolite. This finding suggests that reactive metabolites of pyrrolizidine alkaloids generated in the liver can survive the aqueous environment of the circulatory system as glutathione conjugates or mercapturic acids.}, }
@article {pmid2278610, year = {1990}, author = {Bernard, GR}, title = {Potential of N-acetylcysteine as treatment for the adult respiratory distress syndrome.}, journal = {The European respiratory journal. Supplement}, volume = {11}, number = {}, pages = {496s-498s}, pmid = {2278610}, issn = {0904-1850}, support = {HL 19153/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Double-Blind Method ; Free Radicals ; Glutathione/blood ; Humans ; Lymphocyte Activation ; Methylprednisolone/*therapeutic use ; Respiratory Distress Syndrome/*drug therapy ; Sheep ; }, abstract = {The adult respiratory distress syndrome (ARDS), often referred to as non-cardiac pulmonary oedema, is now regarded as a very complicated inflammatory process with oedema being only one facet. In recognition of this, pharmacologic therapy with anti-inflammatory corticosteroids was used widely until the completion of randomized clinical trials. Unfortunately, corticosteroids have not been proved to be useful in preventing ARDS in septic patients nor in patients with established ARDS and this has led to investigations with pharmacologic agents which are safer and more specifically targeted to certain parts of the inflammatory process. We have examined the role of the glutathione anti-oxidant system in the sheep model of ARDS as well as in patients with established ARDS through use of intravenous N-acetylcysteine (NAC). We have found that the response to endotoxin is markedly blunted in sheep treated with NAC. In our controlled clinical trials with NAC we found that patients with ARDS have depressed plasma and red cell glutathione concentrations, that these levels are substantially increased by therapy with intravenous NAC and there are measurable clinical responses to treatment with regard to increased oxygen delivery, improved lung compliance and resolution of pulmonary oedema.}, }
@article {pmid2089383, year = {1990}, author = {Medina Hernández, MJ and García Alvarez-Coque, MC and Bonet Domingo, E and Villanueva Camañas, RM}, title = {FIA-spectrophotometric assay of N-acetylcysteine by o-phthalaldehyde derivatization.}, journal = {Die Pharmazie}, volume = {45}, number = {10}, pages = {745-747}, pmid = {2089383}, issn = {0031-7144}, mesh = {Acetylcysteine/*analysis ; Indicators and Reagents ; Powders ; Solutions ; Spectrophotometry ; o-Phthalaldehyde/chemistry ; }, abstract = {A flow injection-spectrophotometric procedure is proposed for the determination of N-acetylcysteine (NAC). The procedure is based on the rapid reaction of the thiol group with o-phthalaldehyde and isoleucine at pH 9.5 to give an 1-alkylthio-2-alkyl-substituted isoindole which shows maximum absorbance at 335 nm. The linear dynamic range is 16-160 micrograms/ml, with a 0.6% relative standard deviation for 100 micrograms/ml. The sampling rate is 126 samples/h. The method is applied successfully to the evaluation of NAC in commercial formulations.}, }
@article {pmid2112750, year = {1990}, author = {Roederer, M and Staal, FJ and Raju, PA and Ela, SW and Herzenberg, LA and Herzenberg, LA}, title = {Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {87}, number = {12}, pages = {4884-4888}, pmid = {2112750}, issn = {0027-8424}, support = {AI07290/AI/NIAID NIH HHS/United States ; CA42509/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; *Antiviral Agents ; Cell Line ; HIV/*drug effects/genetics/physiology ; Humans ; Recombinant Fusion Proteins/metabolism ; Repetitive Sequences, Nucleic Acid/drug effects ; Tetradecanoylphorbol Acetate/*pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/antagonists &amp; inhibitors/*pharmacology ; Virus Replication/*drug effects ; beta-Galactosidase/genetics/metabolism ; }, abstract = {We show that the stimulation of human immunodeficiency virus (HIV) brought about by tumor necrosis factor alpha and phorbol 12-myristate 13-acetate can be inhibited by adding N-acetyl-L-cysteine (NAC). NAC, which replenishes intracellular glutathione, effectively inhibits the tumor necrosis factor alpha- or phorbol ester-stimulated replication of HIV in acutely infected cell cultures. NAC also inhibits the cytokine-enhanced HIV long terminal repeat-directed expression of beta-galactosidase in in vitro HIV model systems. These results show that intracellular thiol levels influence HIV production. Furthermore, because NAC reverses tumor necrosis factor alpha toxicity both in cells and in animals and is a well-known drug that can be administered orally without known toxicity in humans, these results suggest that NAC is a possible therapeutic agent in AIDS.}, }
@article {pmid2361912, year = {1990}, author = {Shindoh, C and DiMarco, A and Thomas, A and Manubay, P and Supinski, G}, title = {Effect of N-acetylcysteine on diaphragm fatigue.}, journal = {Journal of applied physiology (Bethesda, Md. : 1985)}, volume = {68}, number = {5}, pages = {2107-2113}, doi = {10.1152/jappl.1990.68.5.2107}, pmid = {2361912}, issn = {8750-7587}, support = {HL-38926/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Diaphragm/*drug effects/physiology ; Electric Stimulation ; Fatigue/drug therapy/physiopathology/prevention &amp; control ; Isometric Contraction/*drug effects/physiology ; Male ; Muscle Contraction/*drug effects ; Organelles/drug effects/physiology ; Rabbits ; }, abstract = {It has recently been postulated that diaphragm fatigue may be due, at least in part, to a form of low-grade injury to subcellular organelles. Moreover, several studies have shown that thiol-containing compounds can protect cardiac and striated skeletal muscle organelles from the deleterious effects of a number of physiological stresses. The purpose of the present study was to determine whether pretreatment with N-acetylcysteine (NAC), a thiol-containing compound, would attenuate the rate of development of diaphragmatic fatigue. Studies were performed with the use of an in situ rabbit diaphragm strip preparation that permitted direct and continuous measurement of diaphragm tension development. Diaphragm fatigue was induced by rhythmically stimulating strips to contract at 30/min (20-Hz trains) for 20 min. The diaphragm force-frequency relationship (10-, 20-, 50-, and 100-Hz stimuli) was assessed immediately before and after fatigue trials and then again 20 min into the period of recovery. Half the animals were treated with intravenous NAC before fatigue, whereas the remaining animals were given intravenous saline. The rate of development of fatigue was markedly greater in saline-treated control than in NAC-treated animals, with reductions in tension of 55 +/- 3 and 34 +/- 3%, respectively, in these two groups of animals over 20 min (P less than 0.001). Although rhythmic stimulation resulted in a downward shift in the force-frequency relationship in both NAC- and saline-treated animals, the magnitude of this shift was substantially greater in saline-treated animals (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1966701, year = {1990}, author = {Commandeur, JN and Vermeulen, NP}, title = {Identification of N-acetyl(2,2-dichlorovinyl)- and N-acetyl(1,2-dichlorovinyl)-L-cysteine as two regioisomeric mercapturic acids of trichloroethylene in the rat.}, journal = {Chemical research in toxicology}, volume = {3}, number = {3}, pages = {212-218}, doi = {10.1021/tx00015a005}, pmid = {1966701}, issn = {0893-228X}, mesh = {Acetylation ; Acetylcysteine/*analogs &amp; derivatives/chemical synthesis ; Animals ; Carbon Isotopes ; Cysteine/analogs &amp; derivatives/metabolism ; Gas Chromatography-Mass Spectrometry ; Isomerism ; Kinetics ; Magnetic Resonance Spectroscopy/methods ; Male ; Protons ; Rats ; Rats, Inbred Strains ; Trichloroethylene/*metabolism ; }, abstract = {The regioselectivity of glutathione conjugation to trichloroethylene (TRI) and the metabolism of its cysteine and N-acetyl-L-cysteine conjugates were investigated in the rat. Intraperitoneal (ip) administration of TRI to rats at a dose of 400 mg/kg resulted in excretion in urine of small amounts of the two distinct regioisomers N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (1,2-DCV-NAC) and N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine (2,2-DCV-NAC). The vicinal (vic) isomer was excreted in a 2 times higher amount (16 nmol) than the geminal (gem) isomer (8 nmol). Intraperitoneal administration of a 1:1 mixture (2.5 mumol/kg each) of the two regioisomers of S-(dichlorovinyl)-L-cysteine (DCVC) to the rat resulted in excretion of the corresponding mercapturic acids in urine, the main fractions being excreted within 8 h after administration. The gem-dichlorovinyl isomer appeared to be acetylated to a higher extend than the 1,2-dichlorovinyl isomer; 73% vs 50% of the dose administered. Intraperitoneal administration of a 1:1 mixture (12.5 mumol/kg each) of the two regioisomers of N-(trideuterioacetyl)-S-(dichlorovinyl)-L-cysteine (DCV-NAC-d3) resulted in excretion of both deuterium-labeled and unlabeled mercapturic acids in urine. The vic isomer was excreted unchanged at a significantly higher percentage, 34% of dose (i.e., still deuterium labeled), than the gem isomer, 17% of the dose. This suggests less efficient metabolism of the vic isomer when compared to the gem isomer. Both regioisomers of DCV-NAC-d3 were excreted in urine unlabeled at 40% of the dose, which indicates that for both isomers deacetylation, followed by reacetylation (resulting in unlabeled DCV-NAC), is an important metabolic pathway.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2384071, year = {1990}, author = {Critchley, JA and Beeley, JM and Clark, RJ and Summerfield, M and Bell, S and Spurlock, MS and Edginton, JA and Buchanan, JD}, title = {Evaluation of N-acetylcysteine and methylprednisolone as therapies for oxygen and acrolein-induced lung damage.}, journal = {Environmental health perspectives}, volume = {85}, number = {}, pages = {89-94}, pmid = {2384071}, issn = {0091-6765}, mesh = {Acrolein/administration &amp; dosage/*toxicity ; Administration, Inhalation ; Aldehydes/*toxicity ; Animals ; Cystine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology/therapeutic use ; Disease Models, Animal ; Injections, Intravenous ; Lung Diseases/chemically induced/*drug therapy/pathology ; Methylprednisolone/administration &amp; dosage/pharmacology/*therapeutic use ; Organ Size/drug effects ; Oxygen/administration &amp; dosage/*toxicity ; Rats ; Rats, Inbred Strains ; }, abstract = {Reactive oxidizing species are implicated in the etiology of a range of inhalational pulmonary injuries. Consequently, various free radical scavengers have been tested as potential prophylactic agents. The sulfydryl compound, N-acetylcysteine (NAC) is the only such compound clinically available for use in realistic dosages, and it is well established as an effective antidote for the hepatic and renal toxicity of paracetamol. Another approach in pulmonary injury prophylaxis is methylprednisolone therapy. We evaluated NAC and methylprednisolone in two rat models of inhalational injury: 40-hr exposure to greater than 97% oxygen at 1.1 bar and 15-min exposure to acrolein vapor (210 ppm). For oxygen toxicity, NAC (80 mg) or methylprednisolone (10 mg) were given IP every 2 or 6 hr, respectively. For acrolein, single doses of NAC (1 g/kg) and methylprednisolone (30 mg/kg) were given intravenously 15 min before exposure. In sham-exposed control animals, neither treatment favorably effected mortality, lung wet/dry weight ratios, or pulmonary histology. The increases in lung wet/dry weight ratios, seen with both oxygen and acrolein toxicity were reduced with both treatments. However, with oxygen, NAC therapy was associated with considerably increased mortality and histological changes. Furthermore, IP NAC administration resulted in large volumes of ascitic fluid. With acrolein, IV, NAC had no significant effect on mortality or pulmonary histological damage. Methylprednisolone had no beneficial effects on either the mortality or histological damage observed in either toxicity model. We caution against the ad hoc use of NAC in the management of inhalational pulmonary injury.}, }
@article {pmid2356705, year = {1990}, author = {Tiffany, JM}, title = {Measurement of wettability of the corneal epithelium. I. Particle attachment method.}, journal = {Acta ophthalmologica}, volume = {68}, number = {2}, pages = {175-181}, doi = {10.1111/j.1755-3768.1990.tb01900.x}, pmid = {2356705}, issn = {0001-639X}, mesh = {Acetylcysteine/pharmacology ; Adhesiveness ; Animals ; Cornea/drug effects/*physiology ; Dimethyl Sulfoxide/pharmacology ; Epithelium/physiology ; Methods ; Mucus/drug effects/physiology ; Polystyrenes/pharmacology ; Rabbits ; Solutions ; Spores, Bacterial ; Surface Tension ; }, abstract = {Surface wettability of the adult rabbit cornea, as indicated by the epithelium/air surface tension, was estimated from the attachment of particles of several different types from suspension in dimethyl sulphoxide-saline bathing solutions. The mean surface tension of corneas where mucus had been removed by rinsing with N-acetyl cysteine was 67.5 +/- 0.6 mN/m, and for corneas retaining their native covering of mucus was 68.3 +/- 0.8 mN/m. Thus the wettability of the normal cornea does not depend on the presence of mucus to overcome its previously-supposed hydrophobicity. Removal of mucus by wiping gave a damaged surface for which no surface tension could be determined within the range of solution surface tensions studied.}, }
@article {pmid2350394, year = {1990}, author = {Dehnen, W}, title = {A study on urinary thioethers by detecting N-acetylcysteine and thiophenol after alkaline hydrolysis.}, journal = {Zentralblatt fur Hygiene und Umweltmedizin = International journal of hygiene and environmental medicine}, volume = {189}, number = {5}, pages = {441-451}, pmid = {2350394}, issn = {0934-8859}, mesh = {Acetylcysteine/*urine ; Animals ; Benzene/pharmacokinetics ; Female ; Humans ; Hydrolysis ; Maleates/pharmacokinetics ; Phenols/*urine ; Rats ; Reproducibility of Results ; Smoking/*urine ; *Sulfhydryl Compounds ; }, abstract = {A method is described for the selective determination of thiol compounds liberated by alkaline hydrolysis of urine. It is based on the procedure described by Newton et al. Two thiol compounds were detected selectively: N-acetylcysteine and thiophenol. The following results were obtained: 1. On alkaline hydrolysis (at room temperature) among other thiols N-acetylcysteine is released. The amount of NAC increases after administration to rats of compounds, which directly or after metabolisation are bound by glutathione conjugation, such as diethylmaleate. 2. In these cases the amount of total thiols and NAC released by alkaline hydrolysis are closely related to each other. 3. Monitoring urines of smokers and non-smokers revealed a significant difference between non-smokers and smokers of the released NAC. So it may be concluded that exposure to certain electrophilic agents reacting with GSH increases the NAC as well as total thiols detected after alkaline hydrolysis of urine. 2. On alkaline hydrolysis (at 95 degrees C) thiophenol can be detected. Evidence is presented that thiophenol is derived from the benzene metabolite S-phenyl-N-acetyl-cysteine: 1. after treatment with radioactive benzene of rats the peak of the thiophenol-derivative elutes together with a radioactive peak; 2. inhalation of benzene increases the peak of the thiophenol-derivative in the urine of a human volunteer. 3. The amount of thiophenol detected by the described method in the urines of smokers is increased in comparison to non-smokers. This is in accordance with the observation that the benzene concentration is elevated in the blood of smokers.}, }
@article {pmid2200749, year = {1990}, author = {Mendis, AH and Venaille, TJ and Robinson, BW}, title = {Study of human epithelial cell detachment and damage: effects of proteases and oxidants.}, journal = {Immunology and cell biology}, volume = {68 (Pt 2)}, number = {}, pages = {95-105}, doi = {10.1038/icb.1990.14}, pmid = {2200749}, issn = {0818-9641}, mesh = {Amnion/*drug effects/pathology ; Basement Membrane/*drug effects/pathology ; Cell Adhesion/drug effects ; Epithelium/drug effects/pathology ; Female ; Humans ; Hydrolases/pharmacology ; In Vitro Techniques ; Kinetics ; Neutrophils/enzymology ; Oxidation-Reduction ; Peptide Hydrolases/*pharmacology ; Pregnancy ; Protease Inhibitors/pharmacology ; }, abstract = {Polymorphonuclear leucocyte (PMN) accumulation is associated with damage to airways epithelial cells in bronchitis, bronchiectasis and some forms of asthma. PMNs release several molecules which may mediate this damage, particularly proteases and oxidants. Using an in vitro model of intact human amnionic epithelial cells (EC) attached to native basement membrane (BM), we evaluated the capacity of several proteases and oxidants to induce detachment of EC from the BM. Maximum desquamation was observed with collagenase, elastase and trypsin, with minimum effective concentrations required to produce 50% EC-desquamation (MEC50) for highly purified collagenase, pancreatic elastase, human leucocyte elastase, human leucocyte cathepsin-G (Cath-G), trypsin, and kallikrein being 3616 +/- 989 U/mL, 32.3 +/- 14.7 U/mL, 85.8 +/- 26.7 U/mL, 360 +/- 20 U/mL, 340 +/- 49 BAEE U/mL and 300 +/- 23 U/mL, respectively. Urokinase (20 U/mL) and plasmin (500 U/mL) produced no desquamation in this system. Relatively high concentrations of oxidants also produced detachment (MEC50 for H2O2 and HOCl being 0.59 +/- 0.006 mol/L and 0.015 +/- 0.009 mol/L, respectively) and pretreatment of EC membranes with non-detaching concentrations of H2O2 rendered them 10-fold more susceptible to protease-induced desquamation, suggesting synergism. Reduced glutathione (GSH), N-acetyl cysteine (NAC), ethylenediamine tetra-acetic acid (EDTA) and 1,10 phenanthroline ablated collagenase induced EC-detachment. Elastase induced detachment was sensitive to inhibition by phenyl methyl sulfonyl fluoride (PMSF) and alpha 1-anti-proteinase (alpha 1-AP) and, to a lesser extent by aprotinin; trypsin-induced detachment was ablated by PMSF, alpha 1-AP and soybean trypsin inhibitor (SBTI) but not by 1,10 phenanthroline or EDTA. Cath-G induced detachment was profoundly inhibited by SBTI, GSH and NAC. These data demonstrate that human EC can be detached from intact BM by several PMN products, including collagenase, Cath-G and elastase, and that PMN-mediated detachment can be prevented by Cath-G and collagenase inhibitors. The data suggest a role for proteases, particularly Cath-G and collagenase, plus oxidants in synergism with proteases, in mediating PMN-induced EC detachment.}, }
@article {pmid2113825, year = {1990}, author = {Newman, CM and Warren, JB and Taylor, GW and Boobis, AR and Davies, DS}, title = {Rapid tolerance to the hypotensive effects of glyceryl trinitrate in the rat: prevention by N-acetyl-L- but not N-acetyl-D-cysteine.}, journal = {British journal of pharmacology}, volume = {99}, number = {4}, pages = {825-829}, pmid = {2113825}, issn = {0007-1188}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Pressure/*drug effects ; Drug Tolerance ; Male ; Nitroglycerin/*pharmacology ; Nitroprusside/pharmacology ; Rats ; Rats, Inbred Strains ; Stereoisomerism ; }, abstract = {1. A new model of tolerance to the hypotensive effect of organic nitrates has been developed in the rat. 2. The fall in mean arterial pressure (MAP) in response to bolus doses of sodium nitroprusside (NP) (4 micrograms kg-1) and glyceryl trinitrate (GTN) (10 micrograms kg-1) was recorded both before and after a 60 min infusion of either 0.9% saline, NP (20 micrograms kg-1 min-1) or GTN (40 micrograms kg-1 min-1). 3. The hypotensive effects of NP or GTN were unchanged following saline infusion, but were reduced in both cases by approximately 40% following the infusion of NP. 4. Infusion of GTN for 60 min virtually abolished the hypotensive effect of a GTN bolus (i.e. nitrate tolerance), whilst the effect of a NP bolus was reduced only to a similar extent (30%) as after an infusion of NP. This latter effect is attributed to a degree of non-specific cross-tolerance between GTN and NP. 5. Co-treatment of a group of rats with N-acetyl-L-cysteine (L-NAC) prevented the development of nitrate tolerance, confirming the role of thiols in this phenomenon, whereas N-acetyl-D-cysteine (D-NAC) did not. 6. The stereospecificity in the effect of NAC in preventing this specific tolerance to GTN suggests that the interaction between GTN and NAC and/or cysteine involves an enzyme-dependent step. 7. NAC was unable to prevent the non-specific cross-tolerance to NP which followed infusion of GTN, suggesting that the mechanism does not directly involve NAC and/or cysteine.}, }
@article {pmid2340888, year = {1990}, author = {Robinson, N and Brattsand, R and Dahlbäck, M}, title = {Effect of oral N-acetylcysteine (NAC) on volume and albumin content of respiratory tract fluid but not on epithelial secretory cell number in "smoking" rats.}, journal = {The European respiratory journal}, volume = {3}, number = {3}, pages = {304-310}, pmid = {2340888}, issn = {0903-1936}, mesh = {Administration, Oral ; Albumins/*analysis ; Animals ; Bronchi/*drug effects/pathology ; Bronchitis/metabolism/*pathology ; Cell Count ; Cystine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Epithelium/drug effects/pathology ; Male ; Mucus/*drug effects ; Rats ; Rats, Inbred Strains ; Tobacco Smoke Pollution ; }, abstract = {This study was designed to look at the effect of N-acetylcysteine (NAC) on epithelial secretory cells and the respiratory tract fluid volume and albumin content from the lower airways of "bronchitic" rats. Rats were exposed either to tobacco smoke (TS), TS and NAC, or NAC alone. TS caused a significant increase in epithelial secretory cell number which was not reduced by concomitant NAC administration; NAC alone had no effect on cell numbers. TS increased respiratory tract fluid volume and albumin content by a small but non-significant amount, whereas TS and NAC increased the volume and albumin content by a greater and significant amount; NAC alone was also shown to significantly increase both fluid volume and albumin content.}, }
@article {pmid2328298, year = {1990}, author = {Borgström, L and Kågedal, B}, title = {Dose dependent pharmacokinetics of N-acetylcysteine after oral dosing to man.}, journal = {Biopharmaceutics &amp; drug disposition}, volume = {11}, number = {2}, pages = {131-136}, doi = {10.1002/bdd.2510110205}, pmid = {2328298}, issn = {0142-2782}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacokinetics ; Administration, Oral ; Adult ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Humans ; Male ; Middle Aged ; }, abstract = {The pharmacokinetics after oral administration of 200, 600 or 1200 mg of N-acetylcysteine (NAC) were studied in 10 healthy subjects. Normalized maximal plasma concentration was significantly higher after a 600 mg dose than after a 200 mg dose. Bioavailability of NAC significantly increased with increasing dose. Time for maximal plasma concentration also increased with increasing dose. The observations can be explained by a capacity-limited presystemic elimination of NAC. In an extension of the study, 600 mg of NAC was given twice a day for 5 days and the plasma concentrations were followed after the morning dose on day 6. No differences in the pharmacokinetic parameters were observed in comparison with the single 600 mg dose. This indicates that the beneficial clinical effects observed after repeated dosing can not be ascribed to an accumulation of NAC in plasma.}, }
@article {pmid2328520, year = {1990}, author = {Coetzee, WA and Owen, P and Dennis, SC and Saman, S and Opie, LH}, title = {Reperfusion damage: free radicals mediate delayed membrane changes rather than early ventricular arrhythmias.}, journal = {Cardiovascular research}, volume = {24}, number = {2}, pages = {156-164}, doi = {10.1093/cvr/24.2.156}, pmid = {2328520}, issn = {0008-6363}, mesh = {Action Potentials/drug effects ; Animals ; Arrhythmias, Cardiac/*etiology ; Calcium/pharmacology ; Catalase/pharmacology ; Diltiazem/pharmacology ; Dose-Response Relationship, Drug ; Free Radicals ; Guinea Pigs ; Heart/physiology ; Heart Ventricles ; Hydrogen Peroxide/pharmacology ; In Vitro Techniques ; Myocardial Reperfusion Injury/*complications ; Oxygen ; Rats ; Superoxide Dismutase/pharmacology ; Verapamil/pharmacology ; }, abstract = {STUDY OBJECTIVE - The aim of the study was to reassess the role of reactive oxygen species in causing reperfusion arrhythmias, which they might do either by directly generating free oxygen radicals or by using scavengers of free oxygen radicals. DESIGN - Ventricular arrhythmias were studied in isolated rat hearts (n = 8-15 per experiment) subjected to regional ischaemia and treated with various free radical scavengers and spin trap agents. Reoxygenation automaticity was similarly studied in isolated guinea pig papillary muscles (n = 6-13 per experiment). MEASUREMENTS and RESULTS - In isolated rat hearts early reperfusion ventricular arrhythmias were unaltered by superoxide dismutase (1 X 10(5) IU.litre-1), catalase (1 X 10(6) IU.litre-1), N-tert-butyl-alpha-phenylnitrone (30 mumols.litre-1), 5,5-dimethyl-1-pyrroline-N-oxide (1 mmol.litre-1), or the combination of superoxide dismutase 1 X 10(5) IU.litre-1, catalase 1 X 10(6) IU.litre-1, and mannitol 10 mol.litre-1, or by the generation of the free radical .OH (Fe:ADP plus dihydroxyfumerate). In the isolated reoxygenated guinea pig papillary muscle, the incidence of reoxygenation automaticity was significantly reduced by verapamil 5 mumols.litre-1 but not by the following free oxygen radical scavengers: reduced glutathione (0.5 mmol.litre-1), N-acetyl cysteine (1 mmol.litre-1), the combination of superoxide dismutase (3 X 10(4) IU.litre-1) and catalase (5 X 10(3) IU.litre-1), or by pretreatment with allopurinol (30 mg.kg-1). Generating systems of .O2- or .OH induced relatively slow electrophysiological changes, including a decreased action potential duration. Reperfusion ventricular fibrillation in the rat heart was increased by increasing the extracellular calcium concentration from 1.25 to 1.9 or 2.5 mmol.litre-1, or by prolongation of the ischaemic time. CONCLUSIONS - Because of (a) the lack of an arrhythmogenic effect of free radical generating systems or of scavengers of free radicals, (b) the calcium sensitivity of reperfusion arrhythmias, and (c) the relatively slow time course of electrophysiological changes induced by free radical generating systems, we propose that free radicals are unlikely to be the prime cause of early ventricular arrhythmias in the systems that we tested. The mechanism of such arrhythmias is more likely to be a calcium sensitive process. The relatively slow electrophysiological changes mediated by free radicals suggest that these agents can cause delayed membrane change.}, }
@article {pmid2377577, year = {1990}, author = {Karg, E and Tunek, A and Brötell, H and Rosengren, E and Rorsman, H}, title = {Alteration of glutathione level in human melanoma cells: effect of N-acetyl-L-cysteine and its analogues.}, journal = {Pigment cell research}, volume = {3}, number = {1}, pages = {11-15}, doi = {10.1111/j.1600-0749.1990.tb00256.x}, pmid = {2377577}, issn = {0893-5785}, mesh = {Acetylcysteine/*analogs &amp; derivatives/*pharmacology/toxicity ; Cell Survival/drug effects ; Glutathione/*metabolism ; Humans ; Melanoma/*metabolism ; Time Factors ; Tumor Cells, Cultured ; }, abstract = {The effects of N-acetyl-L-cysteine (L-NAC), N,N-diacetyl-L-cystine (oxidized form of L-NAC) and N-acetyl-D-cysteine on the intracellular glutathione (GSH) level and their toxicity were investigated in the human melanoma cell culture IGR1. L-NAC applied in 3 mM concentration for 24 hr decreased; when applied for 48 hr it did not alter the intracellular GSH level. Treatment with 1 mM L-NAC for 24 hr had no effect on cellular glutathione, whereas the same concentration applied for 48 hr resulted in an increase in the level of GSH. Both concentrations also induced cell injury as determined by protein assay and trypan blue staining. N,N-diacetyl-L-cystine (0.5 and 1.5 mM, 24 hr) induced a decrease in cellular glutathione content without any apparent cell toxicity. D-NAC (1 and 3 mM, 24 hr) did not influence the GSH level of the melanoma cells; however, it had toxic effects resulting in cell loss.}, }
@article {pmid2308909, year = {1990}, author = {Lalitha, T and Kerem, D and Yannai, S}, title = {Effect of N-acetyl-cysteine, D-penicillamine and buthionine sulfoximine on glutathione levels and CNS oxygen toxicity in rats.}, journal = {Pharmacology &amp; toxicology}, volume = {66}, number = {1}, pages = {56-61}, doi = {10.1111/j.1600-0773.1990.tb00703.x}, pmid = {2308909}, issn = {0901-9928}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Animals ; Brain/*drug effects/metabolism ; Buthionine Sulfoximine ; Drinking ; Electrocardiography ; Glutathione/biosynthesis/*metabolism ; Glutathione Peroxidase/metabolism ; Injections, Intraperitoneal ; Male ; Methionine Sulfoximine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology ; Penicillamine/administration &amp; dosage/*pharmacology ; Rats ; Rats, Inbred Strains ; }, abstract = {The effect of glutathione (GSH) synthesis modulators - L-buthionine sulfoximine (BSO), N-acetyl cysteine (NAC) and D-penicillamine (DPA) - on the susceptibility of rat CNS to O2 toxicity was investigated. The animals were given 5% sucrose or 40 mM solutions of BSO, NAC or DPA in 5% sucrose as drinking water for one week and sacrificed prior to or after exposure to 4.5 ATA O2. The GSH content in brain, liver, lung and blood, and the activity of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PD) and superoxide dismutase (SOD) in brain and lungs were measured. The brain GSH content and the enzyme activities were not changed by any of the drugs. BSO decreased the GSH content in all the other tissues; NAC and DPA treatments increased the GSH content in lungs, blood and/or liver. The CNS toxicity threshold as measured by the time of appearance of first electrical discharge (FED) on ECoG recording was not changed by NAC or DPA, but BSO brought about a significant delay in FED time. It is suggested that increased extracerebral GSH levels do not protect against CNS oxygen toxicity, and that BSO provides some protection, probably via a glutathione-independent mechanism.}, }
@article {pmid2276385, year = {1990}, author = {Hjortsø, E and Fomsgaard, JS and Fogh-Andersen, N}, title = {Does N-acetylcysteine increase the excretion of trace metals (calcium, magnesium, iron, zinc and copper) when given orally?.}, journal = {European journal of clinical pharmacology}, volume = {39}, number = {1}, pages = {29-31}, pmid = {2276385}, issn = {0031-6970}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Adult ; Calcium/pharmacokinetics ; Copper/pharmacokinetics ; Female ; Humans ; Iron/pharmacokinetics ; Magnesium/pharmacokinetics ; Male ; Middle Aged ; Trace Elements/*pharmacokinetics ; Zinc/pharmacokinetics ; }, abstract = {N-Acetylcysteine (NAC) is known to decrease the exacerbation rate in patients with chronic bronchitis. It has also been shown that NAC has both an oxygen-radical scavenger and a heavy-metal chelating effect in high intravenous doses. In a study lasting 5 weeks, 10 healthy volunteers were treated with NAC 200 mg t.d.s. for two weeks. The concentrations of trace metals (Ca, Mg, Fe, Zn &amp; Cu) in plasma were measured weekly and daily in a morning spot urine during the investigation. No significant change in plasma concentration or excretion was found during the two weeks of treatment, implying that additional administration of trace metals is unnecessary for patients treated perorally with a therapeutic dose of NAC.}, }
@article {pmid2183167, year = {1990}, author = {Lubec, G}, title = {[Paracetamol hepatotoxicity].}, journal = {Padiatrie und Padologie}, volume = {25}, number = {1}, pages = {39-41}, pmid = {2183167}, issn = {0030-9338}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage ; Chemical and Drug Induced Liver Injury/drug therapy/*etiology ; Child ; Child, Preschool ; Humans ; Infant ; }, abstract = {A potential side effect of paracetamol is its hepatotoxicity. This side effect can be found in excessive overdosages exceeding the therapeutical dosage significantly. There is a specific antidot: N-acetyl-cysteine. Liver diseases are not absolute contraindication against paracetamol medication.}, }
@article {pmid2147665, year = {1990}, author = {Schürer-Maly, CC and Haussner, V and Halter, F}, title = {Effect of 16.16 dimethyl prostaglandin E2, N-acetyl-cysteine and the proton pump inhibitor BY 831-78 on hydrogen peroxide-induced mucosal damage in the rat stomach.}, journal = {Digestion}, volume = {46}, number = {2}, pages = {97-106}, doi = {10.1159/000200338}, pmid = {2147665}, issn = {0012-2823}, mesh = {16,16-Dimethylprostaglandin E2/*pharmacology ; Acetylcysteine/*pharmacology ; Adenosine Triphosphatases/*antagonists &amp; inhibitors/pharmacology ; Animals ; *Benzimidazoles ; Gastric Juice/drug effects ; Gastric Mucosa/*drug effects ; Gastritis/chemically induced/*prevention &amp; control ; *Hydrogen Peroxide ; Male ; Mucus/drug effects ; Rats ; Rats, Inbred Strains ; }, abstract = {Reactive oxygen species are noxious to gastrointestinal mucosa and contribute to a variety of gastrointestinal diseases. We examined whether 16.16 dimethyl prostaglandin E2 (PG) is protective against the oxidizing action of 6% H2O2 causing gross hemorrhagic lesions in rat gastric mucosa. Male Wistar rats were treated with PG, 0.005-5 micrograms/kg, either intragastrically (i.g.) or subcutaneously, 30 min prior to i.g. administration of 6% H2O2, 0.5 ml/100 g. Further animals received 25 mg of the mucus dissolvent N-acetyl-cystein (NAC) following oral PG treatment or 30 mumol/kg of the H+K(+)-ATPase inhibitor BY 831-78 (BY), 4 h before onset of the experiments. Volume, pH and beta-N-acetyl-glucosaminidase and lactate dehydrogenase as parameters of cell damage were determined in the gastric juice. i.g. PG treatment achieved 60 and 55% reduction of the mucosal lesions in doses between 5 and 0.05 micrograms/kg, respectively. i.p. PG administration was effective in all doses tested. Gastric juice volume was only slightly and enzymes were not significantly affected by PG treatment. NAC did not diminish PG efficacy or aggravate mucosal lesions. Gastric acid suppression did not increase PG-induced protection but was strongly protective by itself, reducing damage by 75%. Low-dose PG treatment achieves an effective protection against oxidative damage in gastric mucosa, which is not the result of dilution or enhanced mucus production.}, }
@article {pmid2074045, year = {1990}, author = {Villani, F and Galimberti, M and Monti, E and Piccinini, F and Lanza, E and Rozza, A and Favalli, L and Poggi, P and Zunino, F}, title = {Effect of glutathione and N-acetylcysteine on in vitro and in vivo cardiac toxicity of doxorubicin.}, journal = {Free radical research communications}, volume = {11}, number = {1-3}, pages = {145-151}, doi = {10.3109/10715769009109677}, pmid = {2074045}, issn = {8755-0199}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cardiomyopathies/*chemically induced ; Doxorubicin/*toxicity ; Female ; Glutathione/*pharmacology ; Heart Atria/drug effects ; Myocardial Contraction/drug effects ; Organ Culture Techniques ; Rats ; Rats, Inbred Strains ; Sulfhydryl Compounds/analysis ; }, abstract = {The effects of two sulfhydryl compounds, glutathione (GSH) and N-acetylcysteine (NAC), on the cardiotoxicity of doxorubicin (DXR) were tested on in vitro and in vivo models. DXR was administered to rats as 4 weekly i.v. doses of 3 mg/kg. GSH (1.5 mmoles/kg), given i.v. 10 min before and 1 hr after DXR, was found to prevent the development of the delayed cardiotoxic effects of DXR, as assessed by electrocardiographic and mechanical parameters, as well as by histological examination of left ventricular preparations. In contrast, equimolar oral doses of NAC (1 hr before and 2 hrs after DXR) were found to be ineffective. Both GSH and NAC prevented the negative inotropic effect produced by DXR on isolated rat atria. A good correlation exists between the cardioprotective effects of the two agents and their ability to enhance the non-protein sulfhydryl group content of the myocardium. Differences observed in vivo between GSH and NAC might be accounted for by pharmacokinetic factors.}, }
@article {pmid1980407, year = {1990}, author = {Imberti, R and Mapelli, A and Colombo, P and Richelmi, P and Bertè, F and Bellomo, G}, title = {1,2-Dichloropropane (DCP) toxicity is correlated with DCP-induced glutathione (GSH) depletion and is modulated by factors affecting intracellular GSH.}, journal = {Archives of toxicology}, volume = {64}, number = {6}, pages = {459-465}, pmid = {1980407}, issn = {0340-5761}, mesh = {5'-Nucleotidase/blood ; Acetylcysteine ; Alanine Transaminase/blood ; Alkaline Phosphatase/blood ; Animals ; Antimetabolites/pharmacology ; Aspartate Aminotransferases/blood ; Buthionine Sulfoximine ; Chromatography, High Pressure Liquid ; Glutathione/deficiency/*metabolism ; Hemolysis/drug effects ; Male ; Methionine Sulfoximine/analogs &amp; derivatives ; Propane/*analogs &amp; derivatives/toxicity ; Rats ; Rats, Inbred Strains ; gamma-Glutamyltransferase/blood ; }, abstract = {Acute 1,2-dichloropropane (DCP) poisoning in humans is relatively frequent in Italy, where DCP is widely diffused as a constituent of commercial solvents and dry cleaners. In this study we have investigated the effects of DCP on intracellular glutathione (GSH) content in main target tissues of male Wistar rats, i.e. liver, kidney and blood, in order to establish if a correlation between DCP-induced GSH depletion and tissue damage exists. Administration of DCP (2 ml/kg body weight orally) caused a dramatic loss of tissue GSH occurring 24 h after DCP intoxication, followed by a slow restoration approaching physiological levels after 96 h. GSH depletion was associated with a marked increase in serum GOT, GPT, 5'-nucleotidase, gamma-glutamyl transpeptidase, alkaline phosphatase, urea and creatinine, and a significant degree of hemolysis. When animals were pretreated with a GSH depleting agent, buthionine-sulfoximine (BSO) (0.5 g/kg body weight) i.p. 4 h before DCP intoxication, an increase of overall mortality was found, significantly different from the group of animals treated with DCP alone. On the contrary, the administration of a GSH precursor, N-acetylcysteine (NAC) i.p. (250 mg/kg body weight) 2 and 16 h after DCCP intoxication prevented the dramatic loss of cellular GSH and reduced the extent of injury in target tissues, as demonstrated by laboratory indices. Furthermore, statistical analysis of the data revealed a correlation between: (1) depletion of liver GSH and increase in serum GOT, GPT, 5'-nucleotidase, (2) depletion of kidney GSH and increase in serum urea and creatinine and (3) depletion of blood GSH and the occurrence of hemolysis.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid1970779, year = {1990}, author = {Chong, S and Fung, HL}, title = {Thiol-mediated catalysis of nitroglycerin degradation by serum proteins. Increase in metabolism was not accompanied by S-nitrosothiol production.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {18}, number = {1}, pages = {61-67}, pmid = {1970779}, issn = {0090-9556}, support = {GM-42850/GM/NIGMS NIH HHS/United States ; HL 22273/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/metabolism ; Blood Proteins/*metabolism ; Catalysis ; Humans ; *Mercaptoethanol ; Nitroglycerin/*blood ; Nitroso Compounds/*metabolism ; Protein Binding ; *S-Nitrosothiols ; Serum Albumin/metabolism ; Sulfhydryl Compounds/*metabolism ; }, abstract = {In vitro degradation of nitroglycerin (NTG) in human plasma has been shown to be accelerated significantly by sulfhydryl compounds. The interaction between NTG and N-acetyl-1-cysteine (NAC) in human plasma produces a pharmacologically active S-nitrosothiol, which may be responsible, at least in part, for the in vivo nitrate tolerance-reversing effect of NAC. The mechanism of this thiol-mediated NTG degradation in plasma has not been identified. In this report, we examined the catalytic activity of various plasma proteins toward NAC-mediated NTG degradation and found human serum albumin (HSA) to have the highest catalytic activity among the proteins tested. However, the dinitrate metabolite distribution ratio found with HSA (favoring the 1,3- over the 1,2-isomer) was substantially different from that observed with human plasma (where equal amounts of both dinitrates were produced). In addition, the HSA-catalyzed degradation of NTG did not lead to enhanced formation of S-nitrosothiol. These findings therefore argue against a predominant role exerted by HSA in the thiol-mediated NTG metabolism in plasma. The HSA-mediated catalysis of NTG was partially blocked by pretreatment with NAC followed by a thiol-alkylating agent, suggesting that the catalytic mechanism was due, in part, to the conversion of disulfide linkages within the HSA structure to reactive sulfhydryl groups.}, }
@article {pmid2768860, year = {1989}, author = {Badawy, AH and Abdel Aal, SF and Samour, SA}, title = {Liver injury associated with N-acetylcysteine administration.}, journal = {Journal of the Egyptian Society of Parasitology}, volume = {19}, number = {2}, pages = {563-571}, pmid = {2768860}, issn = {1110-0583}, mesh = {Acetylcysteine/*toxicity ; Animals ; *Chemical and Drug Induced Liver Injury ; Dose-Response Relationship, Drug ; Liver Function Tests ; Male ; Rats ; }, abstract = {90 adult male albino rats, were divided into two groups each comprising 45 rats out of which 15 were used as controls. N-acetylcysteine was given orally in a doses of 300 and 600 mg/Kg body weight respectively for three weeks. At the end of each week 10 rats from each experimental group as well as 5 rats from control animals were sacrificed and biochemical and pathological studies for hepatic functions and structure were performed. NAC in the high dose group induced significant changes in the liver function tests suggestive of liver dysfunction and damage. Histopathological studies revealed cell ballooning portal dilatation with round cell infiltration, portal tract fibrosis and proliferations. It was concluded that NAC in small dose is safe and can be used, while in large dose it has a hepatotoxic potential.}, }
@article {pmid2688231, year = {1989}, author = {Evald, T and Hansen, M and Balsløv, S and Brorson-Riis, L and Hansen, NC and Maltbaek, N and Thorshauge, H}, title = {[Steroid response after long-term treatment with oral N-acetylcysteine in patients with chronic obstructive bronchitis].}, journal = {Ugeskrift for laeger}, volume = {151}, number = {46}, pages = {2076-2078}, pmid = {2688231}, issn = {0041-5782}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Bronchitis/*drug therapy/physiopathology ; Clinical Trials as Topic ; Double-Blind Method ; Humans ; Lung Diseases, Obstructive/*drug therapy/physiopathology ; Middle Aged ; Prednisone/therapeutic use ; }, abstract = {The significance of long-term treatment with N-acetylcystein (NAC) for the steroid response on pulmonary function and general symptoms was investigated in patients with chronic bronchitis and moderate respiratory obstruction. All of the patients had received preliminary treatment with oral NAC in a dosage of 1,200 mg daily (Mucomyst Retard) or a placebo for 22 weeks in a double-blind design. After the conclusion of the long-term treatment but before the code was revealed, 37 non-allergic patients with irreversible respiratory obstruction participated in a follow-up investigation with 30 mg prednisone daily for 14 days. The peak flow was measured twice daily and the symptoms of bronchitis were registered by completion of 13 visual analogue scales. Pulmonary function was measured by means of spirometry on days 0, 7 and 14, respectively. In both of the treated groups, slight increase in the daily registered peak flow was found but no changes in the results of spirometry or the symptoms. Comparison between the groups revealed a significantly greater increase in the evening peak flow in the group which had received preliminary treatment with NAC. It is concluded that, in this investigation, no clinically relevant effect of long-term preliminary treatment with NAC on the results of a steroid test was observed in patients with chronic bronchitis and moderate respiratory obstruction.}, }
@article {pmid2591988, year = {1989}, author = {Rygnestad, T}, title = {A comparative prospective study of self-poisoned patients in Trondheim, Norway between 1978 and 1987: epidemiology and clinical data.}, journal = {Human toxicology}, volume = {8}, number = {6}, pages = {475-482}, doi = {10.1177/096032718900800607}, pmid = {2591988}, issn = {0144-5952}, mesh = {Adult ; Antidotes/therapeutic use ; Diuresis ; Female ; Hospitalization ; Humans ; Hypotension/chemically induced/physiopathology ; Male ; Middle Aged ; Norway ; Poisoning/*epidemiology ; Prospective Studies ; *Suicide ; }, abstract = {1. In a prospective study of patients hospitalized for deliberate self-poisoning between 1978 and 1987 the number of admissions increased from 303 to 425. The annual incidence increased significantly for both women (P less than 0.05) and men (P less than 0.01). The mean age decreased significantly in the male group (P less than 0.05), but increased in the female group (P less than 0.05). 2. The median latency time for patients presenting at the hospital was short; 3.7 h in 1978 and 2.9 h in 1987. 3. There was a significant reduction in the percentage using barbiturates (9% in 1978 and 1% in 1987; P less than 0.001) and the use of benzodiazepines increased (18% in 1978 and 32% in 1987; P less than 0.05). The percentage of unconscious patients did not change significantly. 4. In 1987 N-acetyl-cysteine was the most frequently used antidote. Physostigmine has almost been abandoned since 1978. 5. Significantly more patients were hypotensive in 1978: 24% vs 11% in 1987; (P less than 0.001) and significantly less patients needed treatment in the central intensive care unit (2% in 1987 and 5% in 1978; P less than 0.05). Complications were few (8-10%) and the mortality low (approximately 1%) in both years studied. 6. The mean duration of hospitalization in 1978 was 65 h vs 30 h in 1987, (P less than 0.001).}, }
@article {pmid2532606, year = {1989}, author = {Rogers, DF and Turner, NC and Marriott, C and Jeffery, PK}, title = {Oral N-acetylcysteine or S-carboxymethylcysteine inhibit cigarette smoke-induced hypersecretion of mucus in rat larynx and trachea in situ.}, journal = {The European respiratory journal}, volume = {2}, number = {10}, pages = {955-960}, pmid = {2532606}, issn = {0903-1936}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Carbocysteine/*pharmacology ; Cysteine/*analogs &amp; derivatives ; Fucose/analysis ; Hexoses/analysis ; Larynx/*drug effects/metabolism ; Male ; Mucus/analysis/*metabolism ; Plants, Toxic ; Rats ; Rats, Inbred Strains ; Serum Albumin/analysis ; Smoke/*adverse effects ; Specific Pathogen-Free Organisms ; Nicotiana ; Trachea/*drug effects/metabolism ; }, abstract = {Two weeks exposure of rats to cigarette smoke (CS) significantly (p less than 0.05) increased the secretion of fucose-containing glycoconjugates above normal in an in situ preparation of larynx and trachea. After equilibration mean basal secretion in CS-exposed rats was 24 micrograms (per 30 min collection) which was 8 times higher than that of unexposed animals (p less than 0.01). N-acetylcysteine (NAC) or S-carboxymethylcysteine (SCMC) given as 1% of the drinking water, before and after daily exposure to CS, significantly inhibited the development of the CS-induced increase in fucose secretion reducing the mean for basal secretion in each group to 7 and 5 micrograms, respectively (p less than 0.05). Neither NAC nor SCMC had significant effects on baseline glycoconjugate secretion in control animals. Albumin was inconsistently present in the secretions of both control and CS-exposed animals, whereas in those exposed to CS and also given one of the two cysteine derivatives there was a consistent increase in albumin transudation.}, }
@article {pmid2515966, year = {1989}, author = {Holtz, J and Münzel, T and Stewart, DJ and Bassenge, E}, title = {Nitrate action on epicardial coronary arteries and tolerance: new aspects based on longterm glyceryl trinitrate infusions in dogs.}, journal = {European heart journal}, volume = {10 Suppl F}, number = {}, pages = {127-133}, doi = {10.1093/eurheartj/10.suppl_f.127}, pmid = {2515966}, issn = {0195-668X}, mesh = {Acetylcysteine/pharmacology ; Animals ; Coronary Vessels/*drug effects ; Dogs ; Drug Administration Schedule ; Drug Interactions ; Drug Tolerance ; Endothelium, Vascular/drug effects ; Hemodynamics/drug effects ; Infusions, Intravenous ; Nitroglycerin/administration &amp; dosage/*pharmacology ; Vasodilation/*drug effects ; }, abstract = {Continuous application of organic nitrates in patients causes a well-documented attenuation of their antianginal efficacy. N-acetylcysteine (NAC) is assumed to reverse this nitrate tolerance by replenishing depleted intracellular sulphydryl groups, but data on NAC application in patients are controversial. Therefore, we studied the effect of NAC on epicardial artery vasomotion under nitrate tolerance, and we examined under these conditions the epicardial artery dilations induced by glyceryl trinitrate (GTN) and those mediated by the endothelium, since the activation of soluble guanylate cyclase is a common mechanism of these two reactions. Tolerance was induced in chronically instrumented dogs by long-term GTN infusion (1.5 micrograms kg-1 min-1 i.v. for 5 to 6 days) and shifted the GTN dose response curve of epicardial arteries to 17- to 20-fold higher doses. However, there was no alteration of epicardial artery dilations induced by SIN-1, another activator of guanylate cyclase, or of endothelium-mediated dilations. Furthermore, NAC (100 mg kg-1 i.v.) did not alter the dose-response relation of GTN under tolerance. In vitro, however, NAC potentiated the activation of purified soluble guanylate cyclase by GTN, while NAC without GTN was ineffective. In non-tolerant dogs, NAC slightly (1.5- to 2-fold) augmentated dilations induced by 0.5-1.5 micrograms kg-1 min-1 GTN, and a similar small augmentation of GTN dilations by NAC is observed in patients, regardless whether they are tolerant to nitrates or not. We conclude: (1) a step prior to the guanylate cyclase activation is responsible for GTN-specific tolerance of epicardial arteries in vivo. (2) NAC does not reverse GTN-specific tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2684829, year = {1989}, author = {Baur, X}, title = {[Treatment of the severe asthma attack and status asthmaticus].}, journal = {Fortschritte der Medizin}, volume = {107}, number = {30}, pages = {627-629}, pmid = {2684829}, issn = {0015-8178}, mesh = {Airway Resistance/drug effects ; Albuterol/administration &amp; dosage ; Asthma/*drug therapy ; Drug Therapy, Combination ; Fenoterol/administration &amp; dosage ; Humans ; Prednisolone/administration &amp; dosage ; Status Asthmaticus/*drug therapy ; Theophylline/administration &amp; dosage ; }, abstract = {For the treatment of severe attacks of asthma, too, inhalable beta 2-sympathomimetic agents form the basis of drug therapy. It is, further, necessary to apply these agents systemically together with theophylline, the best approach to pre-status and status asthmaticus being continuous i.v. application following a bolus administration (dose of beta 2-sympathomimetic 0.04 mg/kg x min, for theophylline 10-15 micrograms/kg x min). Furthermore, 50-200 mg prednisolone equivalent are administered i.v. Secretolysis and increased expectoration are ensured by a copious supply of liquids, inhalation of saline mists, administration of acetyl cysteine or ambroxol, together with physical-therapeutic measures. Also important is the administration of oxygen and the calming of the anxious, agitated patient by adopting a relaxed, calm approach and devoting the patient sufficient attention. The uncritical use of sedatives (cave: depressive effect on respiration) is to be rejected. If, despite increasing the dose of the beta 2-sympathomimetic agent (approx. 0.06 micrograms/kg x min), no improvement is seen after 1-2 hours, or if global respiratory failure develops or exhaustion of the respiratory musculature is threatening, intensive monitoring and care should be initiated. If necessary, the patient is intubated and ventilated; in therapy-refractory situations, bronchoalveolar lavage should be employed as an adjunctive measure.}, }
@article {pmid2811861, year = {1989}, author = {Commandeur, JN and De Kanter, FJ and Vermeulen, NP}, title = {Bioactivation of the cysteine-S-conjugate and mercapturic acid of tetrafluoroethylene to acylating reactive intermediates in the rat: dependence of activation and deactivation activities on acetyl coenzyme A availability.}, journal = {Molecular pharmacology}, volume = {36}, number = {4}, pages = {654-663}, pmid = {2811861}, issn = {0026-895X}, mesh = {Acetyl Coenzyme A/*metabolism ; Acetylcysteine/*metabolism ; Acylation ; Animals ; Biotransformation ; *Carbon-Sulfur Lyases ; Cysteine/*metabolism ; Fluorocarbons/*metabolism ; Gas Chromatography-Mass Spectrometry ; Kidney/*metabolism ; Liver/*metabolism ; Lyases/metabolism ; Magnetic Resonance Spectroscopy ; Male ; Rats ; Rats, Inbred Strains ; Subcellular Fractions/metabolism ; Time Factors ; }, abstract = {The beta-lyase-dependent bioactivation of S-conjugates of tetrafluoroethylene by subcellular fractions from rat liver and rat kidney was studied. Incubation of both hepatic and renal cytosol with S-(1,2,2,2-tetrafluoroethyl)-l-cysteine (TFE-Cys) resulted in the formation of previously unidentified difluorothionamides, indicating difluorothionoacyl fluoride as the main reactive intermediate derived from the beta-lyase-dependent bioactivation of TFE-Cys. The presence of N-difluorothionoacetyl-S-(1,1,2,2-tetrafluoroethyl)-l-cystei ne (TFE-PMS) and difluoroacetic acid in urine of rats treated with N-acetyl-S-(1,1,2,2-tetrafluoroethyl)-l-cysteine (TFE-NAC) points to a similar mechanism of bioactivation in vivo. When TFE-NAC was incubated with 11,000 X g supernatants of rat kidney and liver in the absence of exogenous acetyl coenzyme A (acetyl-CoA), N-deacetylation and subsequent beta-lyase-dependent activation to difluorothionoacyl fluoride could be observed. Both the N-deacetylation of TFE-NAC and the beta-lyase-dependent activation of TFE-Cys were much faster in rat kidney then in rat liver. When TFE-Cys was incubated with 11,000 X g supernatants of rat kidney and rat liver, formation of TFE-NAC could only be observed in the presence of 2 mM exogenous acetyl-CoA; the initial rate of N-acetylation was 5-fold higher in renal then in hepatic fractions. Under these conditions, formation of TFE-PMS was very low. The low urinary excretion of unchanged TFE-NAC (3-5% of dose) upon administration of TFE-NAC points to a high N-deacetylation/N-acetylation ratio in vivo. Due to a very high turn-over of TFE-NAC/TFE-Cys, the availability of the cofactor for N-acetylation, acetyl-CoA, might be rate limiting in the kidney, resulting in accumulation of TFE-Cys followed by increasing beta-lyase-dependent bioactivation of TFE-Cys to reactive intermediates.}, }
@article {pmid2511910, year = {1989}, author = {Hogan, JC and Lewis, MJ and Henderson, AH}, title = {N-acetylcysteine fails to attenuate haemodynamic tolerance to glyceryl trinitrate in healthy volunteers.}, journal = {British journal of clinical pharmacology}, volume = {28}, number = {4}, pages = {421-426}, pmid = {2511910}, issn = {0306-5251}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Blood Pressure/drug effects ; Double-Blind Method ; Drug Tolerance ; Heart Rate/drug effects ; Hemodynamics/*drug effects ; Humans ; Male ; Nitroglycerin/blood/*pharmacology ; Randomized Controlled Trials as Topic ; }, abstract = {1. The effects of chronic dosing with N-acetylcysteine (NAC), on nitrate-induced haemodynamic changes during the acute and chronic treatment of healthy volunteers with glyceryl trinitrate (GTN) patches (Transiderm nitro) has been investigated. 2. Seven volunteers were treated in a double-blind randomised crossover manner for two periods of 4 days with 20 mg of transdermal GTN/24 h together with NAC (200 mg three times daily) or matching placebo. There was a washout period of greater than 3 days between treatment periods. 3. Haemodynamic measurements (blood pressure (BP); heart rate (HR] at rest and following maximal treadmill exercise were performed before treatment and 4 h after starting treatment on days 1 and 4. 4. Significant haemodynamic changes as evidenced by a fall in BP and rise in HR, were seen on day 1 in both the NAC and placebo phases. By day 4 the haemodynamic changes had returned towards the pre-treatment values during both the NAC and placebo phases suggesting the development of tolerance in both treatment groups. 5. These findings suggest that concurrent administration of NAC fails to prevent the development of tolerance to GTN.}, }
@article {pmid2507878, year = {1989}, author = {Magnusson, I and Ekman, L and Wångdahl, M and Wahren, J}, title = {N-acetyl-L-tyrosine and N-acetyl-L-cysteine as tyrosine and cysteine precursors during intravenous infusion in humans.}, journal = {Metabolism: clinical and experimental}, volume = {38}, number = {10}, pages = {957-961}, doi = {10.1016/0026-0495(89)90005-x}, pmid = {2507878}, issn = {0026-0495}, mesh = {Acetylcysteine/metabolism/*pharmacokinetics ; Adult ; Amino Acids, Essential/metabolism ; Biological Availability ; Cysteine/*metabolism ; Female ; Humans ; Infusions, Intravenous ; Kidney/metabolism ; Male ; Parenteral Nutrition, Total ; Tyrosine/*metabolism/pharmacokinetics ; }, abstract = {The usefulness of N-acetyl-L-tyrosine (NAT) and N-acetyl-L-cysteine (NAC) as tyrosine and cysteine precursors during intravenous infusion was investigated in humans. Plasma levels and urinary excretion of NAT, tyrosine, NAC, and total cysteine were determined, and the site of deacetylation was examined by measuring the splanchnic and renal balances. Eleven healthy volunteers were given 5 g of either NAT or NAC as a 4-hour intravenous infusion. Plasma levels of NAT and NAC increased rapidly, accompanied by a 25% increase in tyrosine levels and a 35% decrease in total cysteine. Urinary excretion of NAT and NAC in 4 hours accounted for 56% and 11% of the infused amount, respectively. No net production of tyrosine or cysteine was found from the splanchnic area, but from the kidneys there was a small release of both tyrosine (10 +/- 3 mumol/min) and cysteine (64 +/- 3 mumol/min). We conclude that under these conditions the usefulness of NAT and NAC as precursors for the corresponding amino acids in humans is not apparent.}, }
@article {pmid2584315, year = {1989}, author = {Hisaka, A and Kasamatsu, S and Takenaga, N and Ohtawa, M}, title = {Quantification of L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (NB-355) by high-performance liquid chromatography using o-phthalaldehyde/N-acetyl-L-cysteine derivatization.}, journal = {Journal of chromatography}, volume = {494}, number = {}, pages = {183-189}, doi = {10.1016/s0378-4347(00)82667-5}, pmid = {2584315}, mesh = {Acetylcysteine ; Animals ; Biological Availability ; Carbidopa/pharmacology ; Chromatography, High Pressure Liquid/*methods ; Dogs ; Levodopa/*analogs &amp; derivatives/blood ; Male ; Prodrugs/*analysis ; o-Phthalaldehyde ; }, abstract = {A new and rapid high-performance liquid chromatographic assay has been developed for the determination of L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (NB-355,I), a novel prodrug of L-DOPA. The method involves precolumn derivatization of the drug in biological samples with o-phthalaldehyde (OPA) and N-acetyl-L-cysteine (NAC) in a triethanolamine buffer (pH 8.0), giving a fluorescent compound that is stable for 2 h at 4 degrees C. Use of an internal standard improved the assay in accuracy and reliability. A programmable injector allowed automatic derivatization of large numbers of samples. Chromatographic separation was performed on a reversed-phase column (Capcell Pak C18) in which the silica gel was coated with silicone polymer. The peaks corresponding to compound I and the internal standard were eluted within 16 min with a mobile phase of acetonitrile-phosphate buffer (pH 7.1). The reliable limit of quantification was 0.5 pmol per injection (0.05 micrograms equivalents of L-DOPA per ml in plasma). The method was successfully applied for the measurements of dog plasma concentrations after oral dosing of compound I.}, }
@article {pmid2802671, year = {1989}, author = {Saxena, S and Abdel-Rahman, MS}, title = {Pharmacodynamics of benzyl chloride in rats.}, journal = {Archives of environmental contamination and toxicology}, volume = {18}, number = {5}, pages = {669-677}, pmid = {2802671}, issn = {0090-4341}, mesh = {Animals ; Benzyl Compounds/*pharmacokinetics/toxicity ; *Hazardous Substances ; Liver/*drug effects/metabolism/pathology ; Male ; Pancreas/*drug effects/metabolism/pathology ; Rats ; Rats, Inbred Strains ; }, abstract = {In today's world of high industrialization, toxicity and pollution have become common terms of references. Both laymen and experts are becoming increasingly concerned about various health hazards created by occupational and industrial wastes dumped in and around public places. Benzyl chloride (BCl) was one of the chemicals dumped by Hooker Chemicals in Love Canal, N.Y. Benzyl chloride (BCl) is extensively used in industry in the manufacture of dyes, perfumes, resins, and synthetic tannins. It has been found at various dump sites and industrial wastes, which has led to potential hazards to health. This study was conducted to investigate the pharmacodynamics of BCl in rats. Rats were given 14C-BCl in corn oil by gavage. The peak plasma level was reached at 30 min and began to decline. BCl elimination pattern follows a two compartment model. The distribution half-life (alpha-phase) was 1.3 hr while the half-life of elimination (beta-phase) was 58.53 hr. Distribution studies after 48 hr of BCl administration revealed that the concentration of radioisotopes was highest in the stomach, gastric content, ileum, and duodenum followed by liver, adrenal, bone marrow, whole blood, pancreas, lung, esophagus, skin, kidney, heart, thymus, fat, testes, spleen, brain, and carcass. Approximately 76% of the initial dose was excreted by kidney during the 72 hr studies. About 7% was detected in expired air as 14CO2, while less than 1.3% was present as 14C-BCl or 14C-BCl metabolites in expired air during 72 hr. Metabolism studies revealed that S-benzyl-N-acetyl cysteine, benzyl alcohol, and benzaldehyde were the metabolites present in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2775309, year = {1989}, author = {Lambert, C and Park, BK and Kitteringham, NR}, title = {Activation of mianserin and its metabolites by human liver microsomes.}, journal = {Biochemical pharmacology}, volume = {38}, number = {17}, pages = {2853-2858}, doi = {10.1016/0006-2952(89)90441-3}, pmid = {2775309}, issn = {0006-2952}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Biotransformation ; Chromatography, High Pressure Liquid ; Humans ; In Vitro Techniques ; Mass Spectrometry ; Mianserin/*metabolism ; Microsomes, Liver/*metabolism ; Models, Biological ; Protein Binding ; }, abstract = {Human liver microsomes metabolise mianserin to the stable 8-hydroxymianserin, desmethylmianserin and mianserin-2-oxide and in addition to one or more chemically reactive metabolites which bind, irreversibly, to microsomal protein. The stable metabolites were isolated by HPLC and characterized by mass spectrometry. The generation of each of these metabolites showed substantial inter-individual variation between eight sets of human liver microsomes studied. Inhibition of irreversible binding was observed with SKF-525A together with concomitant decrease in the formation of 8-hydroxymianserin and desmethylmianserin but not mianserin-2-oxide. Methimazole inhibited binding and the formation of each of the metabolites at a low concentration. Quinidine did not significantly inhibit irreversible binding but did inhibit the formation of 8-hydroxymianserin. Sulphaphenazole had no effect on irreversible binding or metabolism. The irreversible binding of mianserin was inhibited by ascorbic acid, glutathione and N-acetyl cysteine, whereas N-acetyl lysine and trichloropropane oxide had no effect. The irreversible binding of mianserin, 8-hydroxymianserin and desmethylmianserin was of the same order of magnitude however significantly greater binding was observed with the desmethyl metabolite. Incubations with [10-3H/14C]mianserin showed no change in the 3H/14C ratio when irreversible binding occurred. Inhibition of irreversible binding was demonstrated with sodium cyanide at concentrations which did not inhibit total metabolism, which suggest that metabolic activation by the cytochrome P-450 enzyme system may lead to the formation of a reactive iminium intermediate that can bind to nucleophilic groups on proteins.}, }
@article {pmid2763302, year = {1989}, author = {Zhang, GH and Stevens, JL}, title = {Transport and activation of S-(1,2-dichlorovinyl)-L-cysteine and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine in rat kidney proximal tubules.}, journal = {Toxicology and applied pharmacology}, volume = {100}, number = {1}, pages = {51-61}, doi = {10.1016/0041-008x(89)90091-4}, pmid = {2763302}, issn = {0041-008X}, support = {GM-39604/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*analogs &amp; derivatives/pharmacokinetics/toxicity ; Animals ; Biological Transport ; Biotransformation ; Cysteine/*analogs &amp; derivatives/metabolism/pharmacokinetics/toxicity ; Drug Interactions ; In Vitro Techniques ; Kidney Tubules, Proximal/drug effects/*metabolism ; Male ; Probenecid/pharmacology ; Rats ; Rats, Inbred Strains ; Sulfur Radioisotopes ; }, abstract = {An important step in understanding the mechanism underlying the tubular specificity of the nephrotoxicity of toxic cysteine conjugates is to identify the rate-limiting steps in their activation. The rate-limiting steps in the activation of toxic cysteine conjugates were characterized using isolated proximal tubules from the rat and 35S-labeled S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAC-DCVC) as model compounds. The accumulation by tubules of 35S radiolabel from both DCVC and NAC-DCVC was time and temperature dependent and was mediated by both Na+-dependent and independent processes. Kinetic studies with DCVC in the presence of sodium revealed the presence of two components with apparent Km and Vmax values of (1) 46 microM and 0.21 nmol/mg min and (2) 2080 microM and 7.3 nmol/mg.min. NAC-DVVC uptake was via a single system with apparent Km and Vmax values of 157 microM and 0.65 nmol/mg.min, respectively. Probenecid, an inhibitor of the renal organic anion transport system, inhibited accumulation of radiolabel from NAC-DCVC, but not from DCVC. The covalent binding of 35S label to cellular macromolecules was much greater from [35S]DCVC than from NAC-[35S]DCVC. Analysis of metabolites showed that a substantial amount of the cellular NAC-[35S]DCVC was unmetabolized while [35S]DCVC was rapidly metabolized to bound 35S-labeled material and unidentified products. The data suggest that DCVC is rapidly metabolized following transport, but that activation of NAC-DCVC depends on a slower rate of deacetylation. The results are discussed with regard to the segment specificity of cysteine conjugate toxicity and the role of disposition in vivo in the nephrotoxicity of glutathione conjugates.}, }
@article {pmid2768393, year = {1989}, author = {Rashed, MS and Nelson, SD}, title = {Use of thermospray liquid chromatography-mass spectrometry for characterization of reactive metabolites of 3'-hydroxyacetanilide, a non-hepatotoxic regioisomer of acetaminophen.}, journal = {Journal of chromatography}, volume = {474}, number = {1}, pages = {209-222}, doi = {10.1016/s0021-9673(01)93916-0}, pmid = {2768393}, support = {GM25418/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*metabolism/pharmacology/urine ; Acetylcysteine/metabolism ; Animals ; Chemical Phenomena ; Chemistry ; Chromatography, High Pressure Liquid/methods ; Cysteine/metabolism ; Isomerism ; Liver/*drug effects ; Magnetic Resonance Spectroscopy ; Male ; Mass Spectrometry/methods ; Mice ; }, abstract = {3'-Hydroxyacetanilide (AMAP) is a non-hepatotoxic regioisomer of acetaminophen that nonetheless does form reactive metabolites that are trapped as glutathione thioether adducts. These reactive intermediates are, 4-acetamido-o-benzoquinone, 2-acetamido-p-benzoquinone and N-acetyl-3-methoxy-p-benzoquinone. Thermospray liquid chromatography mass spectrometry (TSP LC-MS) was used to characterize products of reactions of these reactive compounds with cysteine or N-acetyl-cysteine. The TSP spectra of the mono- and bis-thioether adducts showed protonated molecular ions and characteristic fragmentation patterns. The chromatographic resolution together with the MS selectivity allowed for unequivocal identification of these conjugates in the urine of mice treated with AMAP.}, }
@article {pmid2556228, year = {1989}, author = {Mahlis, E and Christophidis, N}, title = {Modulation of the iodination reaction in normal human neutrophils and in whole blood by penicillamine, congeners and intracellular enzyme catalase and superoxide dismutase.}, journal = {Clinical and experimental rheumatology}, volume = {7}, number = {4}, pages = {365-371}, pmid = {2556228}, issn = {0392-856X}, mesh = {Catalase/*metabolism ; Copper/pharmacology ; Glutathione/pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Iodine/*metabolism ; Iodine Radioisotopes ; Neutrophils/*enzymology ; Oxidation-Reduction ; Penicillamine/metabolism/*pharmacology ; Peroxidase/metabolism ; Superoxide Dismutase/*metabolism ; }, abstract = {We have demonstrated that penicillamine (PSH) has the capacity to effect phagocytic cells by its interaction with the myeloperoxidase-halide system (MPOHS). We have undertaken studies at the cellular level, measuring the activity of the MPOHS through quantitation of I125 uptake (free and bound), known as the iodination reaction (i.e., in isolated polymorphonuclear leukocytes (PMN) and in whole blood). In contrast to other studies investigating the effects of PSH on isolated myeloperoxidase (MPO), we have shown that PSH scavenges the H2O2 produced by phagocytic cells, thereby reducing the availability of H2O2 for conversion to HOI125 by myeloperoxidase. This was observed as a reduction in the level of iodination. This finding is supported by our having obtained similar results in PMN and whole blood with catalase (C), glutathione (GSH) and N-acetylcysteine (NAC) but not with penicillamine disulphide (PSSP) or superoxide dismutase. Cu2+ (8 microM) when incubated with PSH reduced the level of inhibition of the iodination reaction by the oxidation of PSH to PSSP, illustrating the importance of the free sulphydryl group for this action. Incubation of PMN or whole blood for 0 to 2 hours with PSH, with a subsequent washing of PMN prior to stimulation, showed that PSH (free) requires to be present during stimulation of phagocytic cells to have this effect on the iodination reaction. Superoxide dismutase (SOD) produced increases in the iodination reaction in stimulated PMN by increasing the availability of H2O2. In conclusion, PSH inhibits the myeloperoxidase-halide system at a cellular level by scavenging H2O2 rather than by oxidation of the myeloperoxidase enzyme. This was observed at clinically relevant concentrations of PSH.}, }
@article {pmid2527652, year = {1989}, author = {Wu, J and Levy, EM and Black, PH}, title = {2-Mercaptoethanol and n-acetylcysteine enhance T cell colony formation in AIDS and ARC.}, journal = {Clinical and experimental immunology}, volume = {77}, number = {1}, pages = {7-10}, pmid = {2527652}, issn = {0009-9104}, support = {AI23409/AI/NIAID NIH HHS/United States ; }, mesh = {AIDS-Related Complex/immunology ; Acetylcysteine/*pharmacology ; Acquired Immunodeficiency Syndrome/*immunology ; Cell Division/drug effects ; Cells, Cultured ; Humans ; Mercaptoethanol/*pharmacology ; T-Lymphocytes/cytology/*drug effects ; T-Lymphocytes, Regulatory/drug effects ; }, abstract = {One contributing factor to the loss of T cells in AIDS may be the impaired ability of T cell precursors to expand, as reflected in a decreased ability of patient cells to form T cell colonies in agar. We and others have noted such a defect in people with AIDS and ARC, and have found that suppressor cells and suppressive plasma contribute to decreased T-CFC formation. We report here that the reducing agents 2-mercaptoethanol (2-ME) and n-acetyl cysteine (NAC) can enhance colony formation in vitro. In part, 2-ME can reverse the defect in T cell colony-forming cells (T-CFC) formation by overcoming the effect of suppressor cells. In a group of 46 AIDS patients, T-CFC formation was initially 42 +/- 8% (mean +/- s.e.) that of control levels. 2-ME caused an increase of 401 +/- 76% in T-CFC formation which was significantly greater than the increase in control T-CFC formation; it also significantly enhanced T-CFC formation by cells from ARC patients. Suppressor cell activity from ten AIDS patients decreased from 58 +/- 21% to 12 +/- 10% when 2-ME was added. Similar data were obtained from 14 ARC patients. NAC, a related antioxidant with low toxicity, also enhanced T-CFC in cells of AIDS and ARC patients. Vitamin C generally did not increase T-CFC formation. The data suggest that certain antioxidants such as 2-ME and NAC may be useful in treatment protocols to enhance T cell numbers in patients with AIDS or ARC.}, }
@article {pmid2499418, year = {1989}, author = {Seitz, DE and Katterjohn, CJ and Rinzel, SM and Pearce, HL}, title = {Thermodynamic analysis of the reaction of phosphoramide mustard with protector thiols.}, journal = {Cancer research}, volume = {49}, number = {13}, pages = {3525-3528}, pmid = {2499418}, issn = {0008-5472}, mesh = {Acetylcysteine ; Alkylation ; Animals ; Cell Survival/drug effects ; Cyclophosphamide/analogs &amp; derivatives ; Dose-Response Relationship, Drug ; In Vitro Techniques ; Mesna ; *Phosphoramide Mustards/pharmacology ; *Sulfhydryl Compounds ; Thermodynamics ; }, abstract = {The systemic use of thiol-containing uroepithelial protecting agents, e.g., N-acetylcysteine (NAC) or mesna, in conjunction with the alkylating agent cyclophosphamide is predicated on the assumption that the toxic metabolic by-products will be consumed by thiol without diminishing the cytotoxicity of the active alkylating intermediate, phosphoramide mustard. Studies in murine tumor systems have been with either a single dose or two equally divided doses of thiol, administered within 30 min of the addition of cyclophosphamide, without an observed adverse effect on antitumor activity; however, the relatively short serum half-life of thiol relative to alkylating agent in humans weakens the clinical relevance of these results. This study presents a thermodynamic model for the chemical reaction of phosphoramide mustard with either NAC or mesna. The gas phase thermodynamic parameters for these reactions, enthalpy (H) and entropy (S), were calculated using the semiempirical quantum mechanical method AM1 and were used to predict the free energy (delta G) for these processes. For the reaction of phosphoramide mustard with NAC or mesna, delta G = +3.82 and 2.29 kcal/mol, respectively. In the absence of enzyme catalysis, these results suggest that such reactions are not favored. In order to assess the validity of this gas phase thermodynamic model, the cellular cytotoxicity of phosphoramide mustard in the presence or absence of either NAC or mesna was studied using CCRF-CEM cells in culture. In these experiments the 50% effective dose of phosphoramide mustard was 1.7 micrograms/ml; this result was unchanged in the presence of 10 micrograms/ml concentration of either thiol. This study supports the conclusion that phosphoramide mustard and protector thiols are compatible.}, }
@article {pmid2503018, year = {1989}, author = {Hogan, JC and Lewis, MJ and Henderson, AH}, title = {Glyceryl trinitrate and platelet aggregation: effects of N-acetyl-cysteine.}, journal = {British journal of clinical pharmacology}, volume = {27}, number = {5}, pages = {617-619}, pmid = {2503018}, issn = {0306-5251}, mesh = {Acetylcysteine/blood/*pharmacology ; Adenosine Diphosphate/pharmacology ; Adult ; Double-Blind Method ; Humans ; Male ; Nitroglycerin/*pharmacology ; Platelet Aggregation/*drug effects ; Platelet Aggregation Inhibitors ; Random Allocation ; }, abstract = {The concentration range of GTN causing inhibition of platelet aggregation in vitro is much higher than the plasma concentrations achieved clinically. This action is potentiated by the sulphydryl donor N-acetylcysteine. We have investigated the effects of GTN given with and without N-acetylcysteine on ex vivo platelet aggregation in man. In a double-blind randomised crossover trial eight healthy volunteers were treated with 20 mg of transdermal GTN/24 h, together with N-acetylcysteine 200 mg three times daily or matching placebo. Platelet aggregation, measured ex vivo by whole blood impedance aggregometry in response to adenosine diphosphate, was not significantly altered by GTN acutely or after 4 days' treatment with or without N-acetylcysteine. Platelet cyclic guanosine monophosphate levels were not significantly altered by GTN either in the absence or presence of N-acetylcysteine. This result implies that previously reported beneficial effects of GTN in myocardial infarction or unstable angina are unlikely to be attributable to direct pharmacological inhibition of platelet aggregation.}, }
@article {pmid2499991, year = {1989}, author = {Bodemann, T and Langescheid, C and Hochrein, H}, title = {[Nitrate tolerance and its management by N-acetylcysteine (studies of patients with severe chronic heart failure)].}, journal = {Zeitschrift fur Kardiologie}, volume = {78}, number = {5}, pages = {328-334}, pmid = {2499991}, issn = {0300-5860}, mesh = {Acetylcysteine/*administration &amp; dosage ; Cardiomyopathy, Dilated/drug therapy ; Coronary Disease/drug therapy ; Drug Therapy, Combination ; Drug Tolerance ; Female ; Heart Failure/*drug therapy ; Hemodynamics/*drug effects ; Humans ; Hypertension/drug therapy ; Infusions, Intravenous ; Male ; Middle Aged ; Nitroglycerin/*administration &amp; dosage ; }, abstract = {The mechanisms responsible for the development of nitrate tolerance are not completely clear, and their clinical importance remains controversial. This study examined the possible development of nitrate tolerance under the continuous infusion of high doses (10 mg/h) of nitroglycerine (NTG) and the effect of an additional N-acetylcysteine (NAC) injection in respect of hemodynamic changes. Eighteen patients with severe chronic heart failure (NYHA stages III-IV) were investigated. In 16 patients, NTG produced a marked improvement of the hemodynamic parameters; in two patients it caused a moderate amelioration only. In 13 patients there was a complete loss of the initial hemodynamic effect of NTG within 12 to 36 h. NAC reversed the NTG tolerance in 11 out of the 13 patients. In the two patients who showed a milder response to NTG and who did not develop a tolerance, NAC improved the effectiveness of NTG significantly. There was no additional NAC effect in the three patients without NTG tolerance. NAC itself produced no hemodynamic changes. These results confirm the relevance of the depletion of sulfhydryl-groups for the development of nitrate tolerance under the continuous infusion of NTG.}, }
@article {pmid2660373, year = {1989}, author = {Jepsen, S and Nielsen, PH and Klaerke, A and Johansen, K}, title = {[The effect of systemic N-acetylcysteine on postoperative expectoration. A prospective, randomized double-blind study].}, journal = {Ugeskrift for laeger}, volume = {151}, number = {17}, pages = {1055-1057}, pmid = {2660373}, issn = {0041-5782}, mesh = {Clinical Trials as Topic ; Cough/*drug therapy/etiology ; Cystine/*analogs &amp; derivatives/therapeutic use ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Postoperative Complications/*drug therapy ; Prospective Studies ; Random Allocation ; }, abstract = {A material of 110 consecutive patients submitted to elective upper abdominal laparotomy participated in a randomized double-blind investigation of the effect of N-acetylcysteine (Mucomyst) administered systemically in the recommended dosage on postoperative expectoration. As an effect variable the quantity of expectorate and the viscosity as assessed subjectively by the physiotherapists in the department on a visual analog scale was employed. N-acetyl-cysteine was not found to have any effect on the postoperative expectoration as assessed by the quantity and the viscosity.}, }
@article {pmid2658458, year = {1989}, author = {Jepsen, S and Klaerke, A and Nielsen, PH and Nielsen, ST and Simonsen, O}, title = {Systemic administration of N-acetylcysteine has no effect on postoperative lung function following elective upper laparotomy in lung healthy patients.}, journal = {Acta anaesthesiologica Scandinavica}, volume = {33}, number = {3}, pages = {219-222}, doi = {10.1111/j.1399-6576.1989.tb02894.x}, pmid = {2658458}, issn = {0001-5172}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Forced Expiratory Volume ; Humans ; Injections, Intravenous ; Laparotomy/*adverse effects ; Lung/*physiology ; Male ; Middle Aged ; Placebos ; Pulmonary Atelectasis/*prevention &amp; control ; Random Allocation ; Ventilation-Perfusion Ratio/drug effects ; Vital Capacity/drug effects ; }, abstract = {In a randomized, double-blind study, 131 consecutive patients, subjected to elective upper laparotomy, were prophylactically given the recommended dose of N-acetylcysteine (NAC) (Mucomyst, ASTRA) (200 mg x 3) or placebo against postoperative pulmonary complications. The effect was evaluated by lung function tests (VC and FEV1), arterial blood gas analyses and chest x-ray. No benefit could be demonstrated, either to postoperative pulmonary function or in the frequency of atelectasis in the recommended dose. However, no patients with preoperative bronchopulmonary disease demanding treatment with bronchodilatators were included in the study. A positive effect of NAC in this category of patients could not be excluded.}, }
@article {pmid2499923, year = {1989}, author = {Wosiewitz, U and Güldütuna, S and Fischer, H and Leuschner, U}, title = {Pigment gallstone dissolution in vitro. Solubilization of brown bilirubinate and black polybilirubinate stone material by buffered solvents containing ethylenediaminetetraacetic acid, bile salts, and reducing thiols.}, journal = {Scandinavian journal of gastroenterology}, volume = {24}, number = {3}, pages = {373-380}, doi = {10.3109/00365528909093062}, pmid = {2499923}, issn = {0036-5521}, mesh = {Bile Acids and Salts/administration &amp; dosage ; Bile Pigments/*analysis ; Buffers ; Cholelithiasis/analysis/*therapy ; Detergents/administration &amp; dosage ; Drug Synergism ; Edetic Acid/administration &amp; dosage ; Humans ; In Vitro Techniques ; Solubility ; Solvents/*administration &amp; dosage ; Sulfhydryl Compounds/administration &amp; dosage ; }, abstract = {The efficacy of a buffered 1% ethylenediaminetetraacetic acid (EDTA)-2Na solution (pH 9.2) in solubilizing carefully pulverized material from brown bilirubinate and black polybilirubinate pigment stones can be intensified stepwise by admixtures of detergents and mucolytic active thiols. Solubilization effects were quantified either photometrically by measuring the dissolved calcium bilirubinate or gravimetrically by measuring the total weight loss of solids after a defined incubation period. Maximum effects were achieved when using a buffered solvent with 1 g/dl disodium-EDTA, 1 g/dl sodium taurocholate (NaTCA), and 2 g/dl N-acetylcysteine (NAC). Whereas admixtures of NAC enhanced the solubilization of brown bilirubinate stone material additionally by an average of 21.3% (related to the effect of an EDTA/NaTCA-containing solvent), black polybilirubinate material responded rather poorly and inconsistently to NAC (mean, 8.4 +/- 11.7%).}, }
@article {pmid2757663, year = {1989}, author = {De Caro, L and Ghizzi, A and Costa, R and Longo, A and Ventresca, GP and Lodola, E}, title = {Pharmacokinetics and bioavailability of oral acetylcysteine in healthy volunteers.}, journal = {Arzneimittel-Forschung}, volume = {39}, number = {3}, pages = {382-386}, pmid = {2757663}, issn = {0004-4172}, mesh = {Acetylcysteine/blood/*pharmacokinetics/urine ; Administration, Oral ; Adult ; Biological Availability ; Female ; Gas Chromatography-Mass Spectrometry ; Humans ; Injections, Intravenous ; Male ; }, abstract = {The plasma pharmacokinetics of oral acetylcysteine(N-acetylcysteine, NAC) after the administration of single 600 mg and repeated 200 mg doses and the relative bioavailability of the two regimens were studied in 12 adult subjects. On two different occasions in a cross-over, balanced fashion the subjects were administered orally either a single dose of NAC 600 mg as effervescent tablets or 4 repeated doses of NAC as granules in sachets at the regimen of 200 mg t.i.d. Venous blood samples were obtained just before dosing and 20, 40 min, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 h after the administration of NAC 600 mg; with the 1st, the 2nd and the 4th doses of NAC 200 mg samples were taken just before dosing and after 20, 40 min, 1, 1.5, 2, 3, 4, 6 and 8 h, the last sampling after the 1st dose being the one before the 2nd dose. A detailed description of the assaying methods of NAC is given in the text. As indexes of bioavailability Cmax' tmax and AUC of NAC plasma concentrations were considered and MRT was taken as an estimate of its persistence in plasma. NAC was quickly absorbed without any significant difference in tmax among the doses. With the 600 mg dose Cmax' AUC and MRT were greater than with a single 200 mg dose; after summing up the values of these parameters for the 200 mg doses no significant differences were observed in comparison to the single 600 mg dose in Cmax and AUC, while MRT resulted significantly higher.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid2729871, year = {1989}, author = {Williamson, J and Davidson, DF and Boag, DE}, title = {Contamination of a specimen with N-acetyl cysteine infusion: a cause of spurious ketonaemia and hyperglycaemia.}, journal = {Annals of clinical biochemistry}, volume = {26 (Pt 2)}, number = {}, pages = {207}, doi = {10.1177/000456328902600227}, pmid = {2729871}, issn = {0004-5632}, mesh = {Acetylcysteine/*blood ; Acidosis/diagnosis ; Adult ; False Positive Reactions ; Female ; Humans ; Hyperglycemia/*diagnosis ; Ketone Bodies/*blood ; Reagent Strips ; }, }
@article {pmid2659384, year = {1989}, author = {Ueno, O and Lee, LN and Wagner, PD}, title = {Effect of N-acetylcysteine on gas exchange after methacholine challenge and isoprenaline inhalation in the dog.}, journal = {The European respiratory journal}, volume = {2}, number = {3}, pages = {238-246}, pmid = {2659384}, issn = {0903-1936}, support = {HL 17731/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; *Airway Resistance ; Animals ; Dogs ; Hemodynamics ; Isoproterenol/administration &amp; dosage/*therapeutic use ; Methacholine Chloride ; Methacholine Compounds ; Pulmonary Gas Exchange/*drug effects ; Respiratory Function Tests ; Time Factors ; Ventilation-Perfusion Ratio/drug effects ; }, abstract = {N-acetylcysteine (NAC) has antioxidant and possibly mucolytic properties. To determine whether NAC could be of benefit in acute bronchoconstriction induced by methacholine, 12 of 24 anaesthetized dogs (group 1) received NAC i.v. (loading dose 150 mg.kg-1, then 20 mg.kg-1.hr-1). The other 12 (group 2) received diluent. Nebulized methacholine (1%) was then inhaled until arterial oxygen tension (PaO2) fell to a mean of 5.5 kPa, after which isoprenaline 0.5% was inhaled in six dogs of each group to reverse bronchoconstriction. Over the next 3 h we measured total lung resistance, functional residual capacity (FRC), haemodynamic variables, and pulmonary gas exchange for respiratory and inert gases. After methacholine challenge, lung resistance increased and then fell similarly for both groups, but PaO2 was higher in the NAC group (by 0.6-1.9 kPa) throughout the observation period. The ventilation-perfusion distribution measured by inert gas elimination also showed less abnormality in the NAC treated dogs over this time. Mucus was visible during post-mortem in the large airways in about half of the dogs in both groups, with no significant differences between them. These results show that NAC produces a measurable improvement in gas exchange following methacholine challenge (both with and without subsequent isoprenaline therapy) by mechanisms that remain to be determined.}, }
@article {pmid2659383, year = {1989}, author = {Stafanger, G and Koch, C}, title = {N-acetylcysteine in cystic fibrosis and Pseudomonas aeruginosa infection: clinical score, spirometry and ciliary motility.}, journal = {The European respiratory journal}, volume = {2}, number = {3}, pages = {234-237}, pmid = {2659383}, issn = {0903-1936}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Child ; Cilia/*drug effects/physiology ; Clinical Trials as Topic ; Cystic Fibrosis/complications/drug therapy/*physiopathology ; Double-Blind Method ; Female ; Humans ; Male ; Pseudomonas Infections/complications/drug therapy/*physiopathology ; Respiration/*drug effects ; Respiratory Function Tests ; Time Factors ; }, abstract = {The effect of peroral N-acetylcysteine (NAC) in patients with cystic fibrosis (CF) and chronic pulmonary Pseudomonas aeruginosa infection was studied in 52 patients in a double-blind, placebo-controlled, cross-over trial of two, 3 month durations. Active treatment consisted of NAC, 200 mg x 3 daily (patients weighing less than 30 kg) or 400 mg x 2 daily (greater than 30 kg). The effect was evaluated by a subjective clinical score, weight, sputum bacteriology, blood leucocyte count, sedimentation rate, titres of specific antimicrobial antibodies, lung function parameters and measurement of nasal ciliary function in vitro. 31 patients completed the study. No significant differences in lung function or subjective clinical scores were seen between NAC and placebo for the study group as a whole. Patients with peak expiratory flow rate (PEFR) below 70% of predicted normal values showed a satisfactory significant increase in PEFR, forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) during NAC treatment. No effect of NAC on ciliary activity was observed.}, }
@article {pmid2652239, year = {1989}, author = {Unger, P and Bethume, P and Berkenboom, G and Degré, S}, title = {[Tolerance of nitrate derivatives: pharmacologic and clinical aspects].}, journal = {Revue medicale de Bruxelles}, volume = {10}, number = {3}, pages = {82-88}, pmid = {2652239}, issn = {0035-3639}, mesh = {Acetylcysteine/pharmacology ; Drug Tolerance ; Humans ; Muscle, Smooth, Vascular/*drug effects/metabolism ; Nitrates/antagonists &amp; inhibitors/pharmacokinetics/*pharmacology ; Sulfhydryl Compounds/metabolism ; }, abstract = {The authors emphasize the importance of the phenomenon of vascular tolerance to organic nitrates. Its mechanisms remain controversial but there are compelling evidences supporting the role of the availability of sulfhydryl groups in vascular smooth muscle cells. Nitrate tolerance can be avoided or minimized with dosing strategies that use intermittent administration of nitrates, using the smallest effective dose and providing a nitrate-free interval. The preventive role of N-acetyl-cysteine is briefly discussed as well as the absence of cross-tolerance observed with sydnonimines.}, }
@article {pmid2915120, year = {1989}, author = {Zimmerman, RJ and Marafino, BJ and Chan, A and Landre, P and Winkelhake, JL}, title = {The role of oxidant injury in tumor cell sensitivity to recombinant human tumor necrosis factor in vivo. Implications for mechanisms of action.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {142}, number = {4}, pages = {1405-1409}, pmid = {2915120}, issn = {0022-1767}, mesh = {Acetylcysteine/administration &amp; dosage ; Animals ; Female ; Free Radicals ; Glutathione/metabolism ; Humans ; Lipid Peroxides/toxicity ; Maleates/administration &amp; dosage ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasm Transplantation ; Neoplasms, Experimental/*metabolism/pathology/therapy ; Oxygen/*toxicity ; Rats ; Rats, Inbred Strains ; Recombinant Proteins/*administration &amp; dosage ; Tumor Necrosis Factor-alpha/*administration &amp; dosage ; }, abstract = {The intracellular glutathione levels of two human tumor lines and seven murine tumor lines were determined in order to investigate the role of oxidant injury in tumor cell sensitivity to human rTNF (rhTNF). Correlations were found between high intracellular glutathione levels and in vivo tumor resistance to rhTNF, and on the other hand, low glutathione levels and rhTNF sensitivity. The transplantable murine fibrosarcoma, Meth A, a TNF-sensitive line in vivo, was less sensitive to rhTNF and host toxicity was reduced when the hosts were pretreated with uric acid, a major reactive oxygen scavenger in humans and certain other primates. Conversely, pretreatment of the tumor-bearing hosts with DL-buthionine-(S,R)-sulfoximine, an inhibitor of GSH biosynthesis, resulted in an increased sensitivity of Meth A to rhTNF. This effect was not limited to tumor-bearing mice, as rats pretreated with diethyl maleate, a compound which irreversibly binds glutathione, were more sensitive to rhTNF toxicity than control rats. On the other hand, pretreatment with N-acetyl cysteine, an oxidant scavenger, reduced the toxicity of rhTNF treatment in rats. The data are consistent with the hypothesis that tumor cell sensitivity to rhTNF in vivo is dependent on its capacity to buffer oxidative attack. In addition, host toxicity is also related to the production of reactive oxygen species. Activated effector cells such as granulocytes and macrophages are hypothesized to produce most of this damage by their respiratory burst and oxidant release, although the direct action of rhTNF may also contribute to oxidative injury in vivo.}, }
@article {pmid2703040, year = {1989}, author = {Wagner, PD and Mathieu-Costello, O and Bebout, DE and Gray, AT and Natterson, PD and Glennow, C}, title = {Protection against pulmonary O2 toxicity by N-acetylcysteine.}, journal = {The European respiratory journal}, volume = {2}, number = {2}, pages = {116-126}, pmid = {2703040}, issn = {0903-1936}, support = {HL 17731/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/pharmacology/*therapeutic use ; Administration, Oral ; Animals ; Antioxidants/administration &amp; dosage/pharmacology/*therapeutic use ; Dogs ; Free Radicals ; Glutathione/biosynthesis/metabolism ; Lung Diseases/chemically induced/*drug therapy/physiopathology ; Oxygen/*toxicity ; Respiratory Distress Syndrome/physiopathology ; Respiratory Function Tests ; }, abstract = {N-acetylcysteine (NAC) is a known antioxidant. We therefore investigated NAC as an agent protective against O2 toxicity in the lung. Twelve dogs were anaesthetized with sodium pentobarbital and ventilated with 100% O2 for 54 h. Five were given diluent and 7 intravenous NAC (loading dose prior to 100% O2 ventilation of 150 mg.kg-1 and maintenance dose of 20 mg.kg-1.h-1). Every 6 h, physiological evaluation of the pulmonary circulation, mechanical properties, and gas exchange was performed. Post-mortem evaluation consisted of gross examination and weighing followed by light and electron microscopy. By both functional and structural criteria, NAC protected against the effects of 100% O2. The NAC group developed significantly less increase in pulmonary vascular resistance, arterial carbon dioxide tension (PaCO2) and lung wet weight, while dynamic compliance was greater. NAC also delayed the development of abnormal ventilation-perfusion relationships and was associated with reduced pulmonary white cell accumulation, with less evidence of alveolar and interstitial oedema. NAC may well be worthy of evaluation as a therapeutic agent in human diseases characterized by oxidant damage.}, }
@article {pmid2538005, year = {1989}, author = {Pascale, R and Daino, L and Garcea, R and Frassetto, S and Ruggiu, ME and Vannini, MG and Cozzolino, P and Feo, F}, title = {Inhibition by ethanol of rat liver plasma membrane (Na+,K+)ATPase: protective effect of S-adenosyl-L-methionine, L-methionine, and N-acetylcysteine.}, journal = {Toxicology and applied pharmacology}, volume = {97}, number = {2}, pages = {216-229}, doi = {10.1016/0041-008x(89)90327-x}, pmid = {2538005}, issn = {0041-008X}, mesh = {Acetaldehyde/pharmacology ; Acetylcysteine/*pharmacology ; Animals ; Ca(2+) Mg(2+)-ATPase/analysis ; Cell Membrane/enzymology ; Ethanol/*pharmacology ; Female ; Glutathione/analysis/biosynthesis ; Liver/*enzymology ; Methionine/*pharmacology ; Rats ; Rats, Inbred Strains ; S-Adenosylmethionine/analysis/*pharmacology ; Sodium-Potassium-Exchanging ATPase/analysis/*antagonists &amp; inhibitors ; }, abstract = {(Na+,K+)ATPase activity of rat liver plasma membranes was evaluated in female rats feeding an ethanol containing diet for 46 days (total ethanol ingested, 59.7 g/100 g body wt). Determinations were performed at the end of ethanol treatment or at various times after stopping treatment. (Na+,K+)ATPase and 5'-nucleotidase activities exhibited a 8- and 1.4-fold decrease, respectively, at the end of ethanol ingestion. In contrast no modifications of Mg2+-ATPase activity were observed. There also occurred, in ethanol-treated rats, release of sorbitol dehydrogenase into the blood, fat accumulation in liver cells, and decrease in reduced glutathione (GSH) liver content. A decrease in (Na+,K+)ATPase activity was also found in plasma membranes isolated from hepatocyte suspensions after a 2-hr incubation with 50 mM ethanol or 1 mM acetaldehyde (ACA), in conditions that caused a great fall in hepatocyte GSH content but did not cause cell death. After the cessation of ethanol administration, there occurred a progressive recovery of (Na+,K+)ATPase activity, GSH and triacylglycerol content, and release of sorbitol dehydrogenase. These parameters reached control values 12 hr after ethanol withdrawal. S-Adenosyl-L-methionine (SAM), L-methionine, and N-acetylcysteine (NAC), given to rats during ethanol treatment, prevented the decrease in (Na+,K+)ATPase activity and GSH content. They also reduced steatosis and liver necrosis. The efficiency of these compounds decreased in this order: SAM, methionine, NAC. SAM accelerated the recovery of all parameters studied after ethanol withdrawal, and also protected (Na+,K+)ATPase activity and GSH content of isolated hepatocytes from the deleterious effect of ethanol. These SAM effects were prevented by 1-chloro-2,4-dinitro-benzene, a compound which depletes cell GSH. Treatment of isolated hepatocytes with [35S]SAM led to the synthesis of labeled GSH. The total amount and specific activity of labeled GSH underwent a significant increase, in the presence of 2 mM ethanol or 0.5 mM ACA, which indicates a marked stimulation of GSH synthesis by ethanol and ACA. These data indicate that ethanol intoxication may inhibit (Na+,K+)ATPase activity; an effect that does not seem to depend on cell necrosis. SAM, methionine, and NAC exert various degrees of protection toward ethanol-induced cell injury, which are related to the efficiency of these compounds in maintaining a high GSH pool.}, }
@article {pmid2537647, year = {1989}, author = {Paulsen, O and Forsgren, A}, title = {Effects of N-acetylcysteine on human polymorphonuclear leukocytes.}, journal = {APMIS : acta pathologica, microbiologica, et immunologica Scandinavica}, volume = {97}, number = {2}, pages = {115-119}, doi = {10.1111/j.1699-0463.1989.tb00764.x}, pmid = {2537647}, issn = {0903-4641}, mesh = {Acetylcysteine/*pharmacology ; Blood Bactericidal Activity/drug effects ; Chemotaxis, Leukocyte/drug effects ; Humans ; Luminescent Measurements ; Neutrophils/*drug effects/physiology ; Superoxides/metabolism ; }, abstract = {N-acetylcysteine (NAC) at concentrations from 0.39 micrograms/ml to 100 micrograms/ml did not affect chemotaxis under agarose of human polymorphonuclear leukocytes (PMNLs). No reduction of phagocytic or bactericidal capacity was found in PMNLs exposed to NAC at the same concentrations. At high concentrations of NAC (25-100 micrograms/ml) a distinct inhibition of the chemiluminescent response to formylmetionyl-leucyl-phenylalanine (fMLP) known to be associated with mainly extracellular metabolic processes, was observed, consistent with the well known scavenger effects of the drug. The response to opsonized zymosan, which reflects mainly intracellular metabolic activity, was less marked. At a still higher concentration of NAC (500 micrograms/ml), a distinct effect on both intra- and extracellularly generated chemiluminescence could be demonstrated. The lack of inhibitory effects on phagocytosis and intracellular killing in spite of the effects on chemiluminescence indicates that NAC has no negative influence on the antimicrobial activity of PMNLs.}, }
@article {pmid2468964, year = {1989}, author = {Svendsen, JH and Klarlund, K and Aldershvile, J and Waldorff, S}, title = {N-acetylcysteine modifies the acute effects of isosorbide-5-mononitrate in angina pectoris patients evaluated by exercise testing.}, journal = {Journal of cardiovascular pharmacology}, volume = {13}, number = {2}, pages = {320-323}, doi = {10.1097/00005344-198902000-00022}, pmid = {2468964}, issn = {0160-2446}, mesh = {Acetylcysteine/adverse effects/*therapeutic use ; Administration, Sublingual ; Adult ; Angina Pectoris/*drug therapy/physiopathology ; Clinical Trials as Topic ; Delayed-Action Preparations ; Double-Blind Method ; Exercise Test ; Humans ; Isosorbide Dinitrate/administration &amp; dosage/adverse effects/*analogs &amp; derivatives/therapeutic use ; Male ; Middle Aged ; Nitroglycerin/administration &amp; dosage/adverse effects/therapeutic use ; Random Allocation ; }, abstract = {Nitrates are well established in the treatment of angina pectoris and the presence of sulfhydryl groups seems to be fundamental to nitrate-induced vasodilatation. The present study was performed to elucidate if large oral doses of N-acetylcysteine (NAC, 2,400 mg X 2), a donor of sulfhydryl groups, given together with a single oral dose of the long-acting nitrate, isosorbide-5-mononitrate (5-ISMN, 60 mg), would modify the nitrate effect evaluated by exercise testing before and after additional sublingual doses of nitroglycerin (NTG). Ten patients with angina pectoris and angiographically proven significant coronary artery disease were included. All patients received a baseline therapy with beta blockers. None of the patients had developed nitrate tolerance at inclusion. NAC/5-ISMN treatment significantly prolonged the total exercise time as compared with placebo/5-ISMN (7.7 +/- 2.1 min vs. 6.8 +/- 1.7 min, p less than 0.05). This increase was of such magnitude that no further effect was obtained after additional NTG doses. This study demonstrated that increased availability of sulfhydryl groups can increase the exercise capacity in angina pectoris patients treated with 5-ISMN without nitrate tolerance.}, }
@article {pmid2727045, year = {1989}, author = {Lu, SC and Kuhlenkamp, J and Robert, A and Kaplowitz, N}, title = {Role of glutathione status in protection against ethanol-induced gastric lesions.}, journal = {Pharmacology}, volume = {38}, number = {1}, pages = {57-60}, doi = {10.1159/000138519}, pmid = {2727045}, issn = {0031-7012}, mesh = {Acetylcysteine/pharmacology ; Animals ; Cysteamine/pharmacology ; Ethanol/*antagonists &amp; inhibitors ; Gastric Mucosa/analysis/metabolism ; Glutathione/*physiology ; Male ; Maleates/pharmacology ; Pyrrolidonecarboxylic Acid ; Rats ; Rats, Inbred Strains ; Stomach Ulcer/physiopathology/*prevention &amp; control ; Thiazoles/pharmacology ; Thiazolidines ; }, abstract = {The role of glutathione status in gastric mucosal cytoprotection has been a subject of controversy. Cysteamine, an exogenous sulfhydryl agent and diethyl maleate (DEM), an endogenous glutathione (GSH) depletor both appear to protect rats from ethanol-induced gastric lesions. In this study, we used various agents to alter gastric mucosal GSH levels and assessed the effects on susceptibility to ethanol injury. We found that DEM and buthionine sulfoximine both depleted gastric GSH but only DEM protected against ethanol-induced gastric lesions. L-Oxothiazolidine-4-carboxylate (OXT) and N-acetyl-L-cysteine (NAC) both potentiated ethanol-induced gastric lesions even though only NAC significantly raised the GSH level. The depletion of GSH by DEM was reversed by supplying cysteine in the form of OXT or NAC so that the net result was a GSH level close to normal control. The potentiation of ethanol injury by NAC and OXT was still apparent. These experiments show no relation between gastric GSH levels and susceptibility to ethanol injury.}, }
@article {pmid2721538, year = {1989}, author = {Burgunder, JM and Varriale, A and Lauterburg, BH}, title = {Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration.}, journal = {European journal of clinical pharmacology}, volume = {36}, number = {2}, pages = {127-131}, pmid = {2721538}, issn = {0031-6970}, mesh = {Acetaminophen/*pharmacology ; Acetylcysteine/*pharmacology ; Adult ; Chromatography, High Pressure Liquid ; Cysteine/*blood ; Glutathione/*blood ; Half-Life ; Humans ; Male ; Sulfhydryl Compounds/blood ; }, abstract = {The effect of oral N-acetyl-L-cysteine (NAC) on plasma sulphhydryls has been studied in healthy volunteers. Following NAC 30 mg.kg-1, total NAC in plasma (i.e. free NAC and NAC as disulphides) reached a median peak concentration of 67 nmol.ml-1 within 45 to 60 min, and disappeared with an apparent half-life of 1.3 h. Only a fraction of total NAC (AUC 163 nmol.ml-1.h) was in the form of free NAC (AUC 12 nmol.ml-1.h, peak concentration 9 nmol.ml-1). Free cysteine was markedly increased (peak increment 49 nmol.ml-1; AUC 80 nmol.ml-1.h). Total cysteine and free and total glutathione in plasma were unchanged. Following the administration of 2 g paracetamol plasma cysteine and glutathione decreased (median decrement in AUC over 3 h was 5.1 nmol.ml-1.h and 3.8 nmol.ml-1.h, respectively). In contrast, the administration of 2 g NAC together with paracetamol resulted in an increase in the AUC of cysteine (+29.2 nmol.ml-1.h) and glutathione (+4.6 nmol.ml-1.h). The data show that NAC leads to a marked increase in circulating cysteine, in part by reacting with cystine and thereby forming mixed disulphides with cysteine and releasing free cysteine as shown in vitro. NAC had no effect on plasma glutathione in the absence of increased stress on the glutathione pools. However, NAC supports glutathione synthesis when the demand for glutathione is increased, as during the metabolism of paracetamol.}, }
@article {pmid2718141, year = {1989}, author = {Fantel, AG and Juchau, MR and Tracy, JW and Burroughs, CJ and Person, RE}, title = {Studies of mechanisms of niridazole-elicited embryotoxicity: evidence against a major role for covalent binding.}, journal = {Teratology}, volume = {39}, number = {1}, pages = {63-74}, doi = {10.1002/tera.1420390108}, pmid = {2718141}, issn = {0040-3709}, support = {HD 00836/HD/NICHD NIH HHS/United States ; HD 12717/HD/NICHD NIH HHS/United States ; HD 16727/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; Autoradiography ; Binding, Competitive ; Biotransformation ; Chromatography, High Pressure Liquid ; Culture Media ; Culture Techniques ; Fetal Proteins/analysis ; Glutathione/analysis ; Microsomes, Liver/drug effects ; Niridazole/pharmacokinetics/*toxicity ; *Teratogens ; Yolk Sac/analysis ; }, abstract = {Studies reported here were designed to examine the hypothesis that covalent binding of reactive intermediates to macromolecules of the conceptus represents a major mechanism for the embryotoxicity of niridazole (NDZ). The roles of embryonic thiol content and oxygenation on: 1) malformation incidence; 2) reductive metabolism; and 3) covalent binding to embryonic macromolecules of metabolites resulting from reductive biotransformation of NDZ were studied. Results were compared with those from studies with the nondysmorphogenic analog of NDZ, 4'-methylniridazole (MNDZ). Day 10 rat embryos were pretreated for 5 hours in vitro with either L-buthionine-S, R-sulfoximine (BSO) or N-acetylcysteine (NAC) to modulate their glutathione (GSH) content. BSO reduced GSH levels, but NAC was ineffective. Following pretreatment, embryos were cultured for an additional 15 hours in the presence of [14C]NDZ or [14C]MNDZ with an initial oxygen concentration of 5%. At the end of the culture period (day 11, AM), those embryos with active heartbeat and vitelline circulation were examined for asymmetric malformations. Drug metabolites were subjected to multiple extractions from the culture medium and subjected to quantitative high-performance liquid chromatography (HPLC) analysis. Homogenates of the embryos were extracted with trichloroacetic acid (TCA) to estimate the covalent binding of radiolabeled parent compound/metabolites. Autoradiographic analyses were performed on other embryos. BSO pretreatment, which reduces embryonic GSH tissue levels, dramatically increased both the conversion of NDZ to 1-thiocarbamoyl-2-imidazolidinone (TCI) (generated via reductive metabolism of NDZ) and covalently bound label but failed to increase embryotoxicity. NAC, by contrast, did not significantly affect embryonic GSH levels, TCI generation, or covalent binding. Because both rates of metabolism of NDZ to TCI and covalent binding could vary independently of malformation incidence, we concluded that they do not represent critical mechanistic factors for the embryotoxicity of NDZ and related nitroheterocycles.}, }
@article {pmid2682864, year = {1989}, author = {Maayan, C and Bar-Yishay, E and Yaacobi, T and Marcus, Y and Katznelson, D and Yahav, Y and Godfrey, S}, title = {Immediate effect of various treatments on lung function in infants with cystic fibrosis.}, journal = {Respiration; international review of thoracic diseases}, volume = {55}, number = {3}, pages = {144-151}, doi = {10.1159/000195725}, pmid = {2682864}, issn = {0025-7931}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Administration, Inhalation ; Albuterol/administration &amp; dosage/therapeutic use ; Combined Modality Therapy ; Cystic Fibrosis/*therapy ; Humans ; Infant ; Methods ; Physical Therapy Modalities ; Respiratory Function Tests ; }, abstract = {The immediate effect of four different modes of treatment was assessed by lung function tests on 19 infants with cystic fibrosis (CF) during the first year of life. The regimens were applied in a randomized fashion and consisted of aerosol inhalation of salbutamol (n = 8; SAL), aerosol inhalation of N-acetyl cysteine (n = 5; AC), chest physiotherapy (n = 6; CPT), and combined treatment with aerosol inhalation of SAL and AC followed by CPT (n = 6; COMB). Pulmonary function was measured before and shortly after therapy with each mode of treatment. Thoracic gas volume (Vtg) and specific airway conductance (SGaw) were measured by an infant whole body plethysmograph, and forced expiratory flow at resting lung volume (VmaxFRC) was determined with a thoraco-abdominal squeeze jacket. There was no correlation between baseline lung function and changes in any parameter due to treatment. Overall group comparison showed that the combined therapy resulted in a significant improvement in lung function when compared to any of the three treatments applied separately. There was no significant change in lung volumes in any individual group, but SGaw and VmaxFRC showed a small but significant improvement following the COMB treatment when compared with AC or CPT.}, }
@article {pmid2598977, year = {1989}, author = {De Bernardi di Valserra, M and Mautone, G and Barindelli, E and Lualdi, P and Feletti, F and Galmozzi, MR}, title = {Bioavailability of suckable tablets of oral N-acetylcysteine in man.}, journal = {European journal of clinical pharmacology}, volume = {37}, number = {4}, pages = {419-421}, pmid = {2598977}, issn = {0031-6970}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacokinetics ; Administration, Oral ; Adult ; Biological Availability ; Drug Compounding ; Female ; Humans ; Male ; Middle Aged ; Tablets ; }, abstract = {The pharmacokinetics and bioavailability of suckable tablets and granules of N-acetylcysteine (NAC) have been compared after oral administration of 400 mg doses to 10 healthy volunteers. The oral bioavailability of the NAC tablets was 103%. In a multiple dosing study of the same tablets in the same subjects, a high maintenance plasma level of NAC was revealed.}, }
@article {pmid2555979, year = {1989}, author = {Schneider, W and Hawlicek, J and Kirsten, N and Kober, G and Krause, A and Weyenmeyer, T and Satter, P and von Loh, D and Kalenbach, M}, title = {[Isolated human venous segments as a model for the study of problems of nitrate tolerance].}, journal = {Zeitschrift fur Kardiologie}, volume = {78 Suppl 2}, number = {}, pages = {33-7; discussion 64-7}, pmid = {2555979}, issn = {0300-5860}, mesh = {Acetylcysteine/pharmacology ; Coronary Artery Bypass ; Cyclic GMP/metabolism ; Dose-Response Relationship, Drug ; Humans ; Isosorbide Dinitrate/*pharmacology ; Muscle, Smooth, Vascular/*drug effects ; Nitroglycerin/*pharmacology ; Saphenous Vein/drug effects/transplantation ; Vascular Resistance/*drug effects ; Vasodilation/drug effects ; }, abstract = {Concentration-dependent relaxation (6-70%) of segments of human saphenous veins under isometric conditions could be demonstrated with cumulative concentrations of isosorbide dinitrate (ISDN) and Glycerol trinitrate GTN (10(-9)-10(-5) M). Vein segments were obtained during coronary by-pass surgery. Nitrate (GTN)-induced relaxation was accompanied by a 2- to 3-fold increase of cyclic GMP content in the vessel walls. However, no change of concentrations in the vessel walls could be determined for the metabolites of prostaglandines: (PG E2, PG F2 alpha, TX B2, 6-keto-PGF1 alpha). Pretreatment of patients with 40 mg ISDN (standard release formulation) 4 times daily for 1 week prior to surgery with the last dose 1 hour before harvesting the vein segments did not influence relaxation. by ISDN. Immersion of vein segments for 1 hour in buffer solution containing 10(-6) M ISDN (= therapeutic concentration) prior to relaxation with cumulative concentrations of ISDN did not influence relaxation either. Induction of in vitro tolerance required ISDN concentrations which exceeded the range achieved under therapeutic conditions: 4.4 x 10(-4) M. This in vitro tolerance could be widely reversed by 10 mM N-Acetylcysteine (NAC) suggesting involvement of sulfhydril (SH) groups. Since tolerance in this experimental model was not seen under concentrations achieved in patients it seems likely that clinical tolerance is caused by activation of counterregulatory forces.}, }
@article {pmid2531111, year = {1989}, author = {Barbey, MM and Fels, LM and Soose, M and Poelstra, K and Gwinner, W and Bakker, W and Stolte, H}, title = {Adriamycin affects glomerular renal function: evidence for the involvement of oxygen radicals.}, journal = {Free radical research communications}, volume = {7}, number = {3-6}, pages = {195-203}, doi = {10.3109/10715768909087942}, pmid = {2531111}, issn = {8755-0199}, support = {1P 30 ES 03828/02/ES/NIEHS NIH HHS/United States ; }, mesh = {Adenosine Triphosphatases/metabolism ; Animals ; Doxorubicin/*toxicity ; Free Radicals ; Hagfishes ; Heart/drug effects ; In Vitro Techniques ; Kidney Diseases/chemically induced ; Kidney Glomerulus/*drug effects/enzymology ; Lipid Peroxidation/drug effects ; Liver/drug effects ; Oxygen/*metabolism ; Perfusion ; }, abstract = {The early nephrotoxic effect of the antitumor drug adriamycin (ADR) is suggested to be related to the generation of oxygen free radicals. Therefore the O2-dependence and the influence of free radical scavengers were studied in the model of the isolated perfused single glomerulus of Myxine glutinosa and by histochemical demonstration of the glomerular ATP-ase. In Myxine, the glomerular ATP-ase activity was decreased after injection of ADR (5 mg/kg, i.v.). Both ADR-treated Myxine and controls were exposed for 48 h to an artificial atmosphere of 20% O2/80% N2 or 80% O2/20% N2, respectively. After 10 days a significant decrease of the hydraulic conductivity (k) was measured in the experimental group exposed to 80% O2 (k-values expressed as nl/s.mm Hg.mm2: controls (7): 0.059 +/- 0.017; ADR (7): 0.033 +/- 0.026). The reduction of k following the administration of ADR (20 mg/kg) could be prevented by the sulphydryl donor N-acetylcysteine (NAC). The sieving coefficient for albumin (phi) was significantly increased in ADR-treated animals, showing no O2-dependence (phi x 10(-2): controls (7) 1.3 +/- 0.2; ADR 20% O2 (8): 8.1 +/- 9.6; ADR 80% O2 (7): 6.9 +/- 6.7). phi was not affected by NAC. The lipid peroxide levels in liver, kidney and heart of Myxine increased after the administration of ADR, peaking by day 2 to 5. The circulation disorders of ADR-treated Myxine were not due to an accumulation of the drug in the heart, but rather to a lack of the intracellular antioxidant glutathione. It is concluded that the early nephrotoxic effect of ADR, as reflected by a decreased glomerular ATP-ase activity, is mediated by free radical formation. Oxidative stress on membrane compounds seems to reduce the water permeability of the glomerular barrier, while the ADR-induced sieving defect may be due to oxygen independent pathological mechanisms.}, }
@article {pmid2511688, year = {1989}, author = {Münzel, T and Holtz, J and Mülsch, A and Stewart, DJ and Bassenge, E}, title = {Failure of the sulfhydryl donor N-acetylcysteine (NAC) to reverse nitrate tolerance in large epicardial arteries and the venous capacitance system of the dog.}, journal = {Zeitschrift fur Kardiologie}, volume = {78 Suppl 2}, number = {}, pages = {26-8; discussion 64-7}, pmid = {2511688}, issn = {0300-5860}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Coronary Circulation/*drug effects ; Coronary Vessels/drug effects ; Dogs ; Dose-Response Relationship, Drug ; Drug Tolerance ; Muscle, Smooth, Vascular/*drug effects ; Nitroglycerin/*pharmacology ; Sulfhydryl Compounds/*metabolism ; Vascular Resistance/*drug effects ; Venous Pressure/*drug effects ; }, abstract = {NAC has been thought to reverse nitrate tolerance by replenishing depleted intracellular sulfhydryl groups, however data on interactions between N-acetylcysteine and nitrates in patients with stable angina are controversial and disappointing. Therefore, we studied the effect of NAC on nitrate responsiveness of epicardial arteries and of the venous system (assessed as changes in effective vascular compliance) in dogs (n = 12) during long-term nitroglycerine (GTN)-treatment (1.5 micrograms/kg/min for 5 to 6 days). In dogs with GTN-specific tolerance (shift of venous or epicardial artery dilation with 15- to 17-fold higher dosages), NAC (100 mg/kg i.v.) had no dilator effect and did not alter the dose response relations of nitroglycerin. However, in nontolerant dogs (n = 7) NAC augmented (1.5- to 2-fold) the reduction of peripheral vascular resistance induced by 0.5-1.5 microgram/kg/min GTN. In vitro, the augmentation of purified guanylate cyclase activity by GTN (100 microM) was potentiated by NAC (0.01-1.0 mM) in saline or in canine plasma, whereas NAC alone was ineffective. Therefore, NAC does not restore GTN-responsiveness in epicardial arteries or veins in vivo and a small, tolerance-independent augmentation of GTN-induced dilation may result from NAC-induced extracellular formation of a stimulant of guanylate cyclase from GTN.}, }
@article {pmid3202890, year = {1988}, author = {Commandeur, JN and Brakenhoff, JP and De Kanter, FJ and Vermeulen, NP}, title = {Nephrotoxicity of mercapturic acids of three structurally related 2,2-difluoroethylenes in the rat. Indications for different bioactivation mechanisms.}, journal = {Biochemical pharmacology}, volume = {37}, number = {23}, pages = {4495-4504}, doi = {10.1016/0006-2952(88)90665-x}, pmid = {3202890}, issn = {0006-2952}, mesh = {*Acetylcysteine/*analogs &amp; derivatives ; Animals ; Biotransformation ; Cysteine/*analogs &amp; derivatives/toxicity ; Dose-Response Relationship, Drug ; Fluoroacetates/urine ; Glycosuria/urine ; Hydrocarbons, Fluorinated/*toxicity ; Hydrocarbons, Halogenated/*toxicity ; Kidney Diseases/*chemically induced/metabolism ; Organ Size/drug effects ; Proteinuria/urine ; Pyruvates/urine ; Pyruvic Acid ; Rats ; Structure-Activity Relationship ; Urea/blood ; }, abstract = {The biotransformation and the hepato- and nephrotoxicity of the mercapturic acids (N-acetyl-1-cysteine S-conjugates) of three structurally related 2,2-difluoroethylenes were investigated in vivo in the rat. All mercapturic acids appeared to cause nephrotoxicity, without any measureable effect on the liver. The mercapturic acid of tetrafluoroethylene (TFE-NAC) appeared to be the most potent nephrotoxin, causing toxicity upon an i.p. dose of 50 mumol/kg. The mercapturic acids of 1,1-dichloro-2,2-difluoroethylene (DCDFE-NAC) and 1,1-dibromo-2,2-difluoroethylene (DBDFE-NAC) were nephrotoxic at slightly higher doses, i.e. at 75 and 100 mumol/kg, respectively. In the urine of TFE-NAC-treated rats significant amounts of difluoroacetic acid (DFAA) could be detected. With increasing doses, the relative amount of DFAA in urine increased progressively (5-18% of dose). In urine of rats treated with DCDFE-NAC and DBDFE-NAC, however, the corresponding dihaloacetic acids, dichloroacetic acid and dibromoacetic acid, could not be detected. Formation of DFAA and pyruvate could also be observed during in vitro metabolism of the cysteine conjugate of tetrafluoroethylene (TFE-CYS) by rat renal cytosol. Inhibition by aminooxyacetic acid (AOA) pointed to a beta-lyase dependency for the DFAA-formation. Next to DFAA and pyruvate, also formation of hydrogen sulfide and thiosulfate could be detected. These results suggest that TFE-CYS is bioactivated to a significant extent to difluorothionacyl fluoride, which most likely is subsequently hydrolysed to difluorothio(no)acetic acid and difluoroacetic acid. According to formation of pyruvate, the cysteine conjugates derived from DCDFE-NAC and DBDFE-NAC also were efficiently metabolized by rat renal beta-lyase. However, the formation of corresponding dihaloacetic acids, dichloroacetic acid and dibromoacetic acid, could not be detected in vitro at all. Only very small amounts of hydrogen sulfide and thiosulfate were detected. These results suggest that bioactivation of the latter two conjugates to a dichloro- or dibromothionoacyl fluoride represents only a minor route. Because of better leaving group abilities of chloride and bromide compared to fluoride, rearrangement of the initially formed ethanethiol to a thiirane might be favoured. Based on the present in vivo and in vitro data, it is concluded that the nephrotoxicity of the structurally related mercapturic acids of 2,2-difluoroethylenes is dependent on halogen substitution and presumably the result of at least two different mechanisms of bioactivation.}, }
@article {pmid3196357, year = {1988}, author = {Bruno, MK and Cohen, SD and Khairallah, EA}, title = {Antidotal effectiveness of N-acetylcysteine in reversing acetaminophen-induced hepatotoxicity. Enhancement of the proteolysis of arylated proteins.}, journal = {Biochemical pharmacology}, volume = {37}, number = {22}, pages = {4319-4325}, doi = {10.1016/0006-2952(88)90613-2}, pmid = {3196357}, issn = {0006-2952}, support = {GM 31460/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Aspartate Aminotransferases/metabolism ; Glutathione/metabolism ; Liver/*drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; }, abstract = {The post-arylative mechanisms by which N-acetylcysteine (NAC) reduces the severity of the hepatotoxicity induced by acetaminophen (APAP) were investigated in primary cultures of mouse hepatocytes. When administered at selected times immediately following removal of medium containing 10 mM APAP, 2.0 mM NAC was shown to restore glutathione levels through 16 hr of APAP pretreatment and to minimize the leakage of glutamate-oxaloacetate transaminase resulting from the first 8 hr of drug exposure. This temporal difference defined a critical period in which cells were responsive to NAC and permitted the investigation of potential post-arylative mechanisms of the antidote. In the absence of NAC during the recovery period, the cellular loss of covalently-bound APAP could be accounted for by the appearance of arylated proteins in the medium without any apparent degradation of APAP-bound proteins. By contrast, when NAC was present during the recovery period, there was a decrease in intracellular protein-bound APAP which could not be accounted for by that detected in the medium. Since during the recovery period the low residual intracellular concentration of APAP could not contribute significantly to any additional covalent binding in this system, NAC could not merely be acting as a nucleophilic trap for the reactive electrophile. Furthermore, NAC is not likely to dissociate covalently bound APAP from proteins. Hence, the overall decrease in covalent binding observed in cultures previously exposed to APAP for up to 8 hr must have arisen from an NAC-dependent enhancement of the degradation of the arylated proteins. However, after a more prolonged exposure to APAP, the ineffectiveness of NAC may have resulted from APAP-induced irreparable damage to the intracellular proteolytic system. These data suggest that the post-arylative efficacy of NAC may reside in the ability of the antidote to restore the functional capacity of the proteolytic system to rid the cells of arylated proteins.}, }
@article {pmid3242706, year = {1988}, author = {Tomer, KB and Guenat, C and Dino, JJ and Deterding, LJ}, title = {Applications of fast atom bombardment and tandem mass spectrometry.}, journal = {Biomedical &amp; environmental mass spectrometry}, volume = {16}, number = {1-12}, pages = {473-476}, doi = {10.1002/bms.1200160194}, pmid = {3242706}, issn = {0887-6134}, mesh = {Acetylcysteine/analysis ; Carcinogens/analysis ; Cysteine/analysis ; Glutathione/analysis ; Mass Spectrometry/*instrumentation ; Oligonucleotides/analysis ; Peptides/analysis ; Toxins, Biological/analysis ; }, abstract = {The application of fast atom bombardment combined with tandem mass spectrometry to the structure elucidation of carcinogen-modified oligonucleotides, glutathione, cysteine and N-acetyl cysteine conjugates of exogenous toxins and chemically modified peptides is described.}, }
@article {pmid3071772, year = {1988}, author = {Bais, R and Conyers, RA and Rofe, AM and Tormet, RI and Geary, TD}, title = {Creatine kinase reference intervals determined from a multi-centre data pool.}, journal = {Pathology}, volume = {20}, number = {4}, pages = {367-372}, doi = {10.3109/00313028809085221}, pmid = {3071772}, issn = {0031-3025}, mesh = {Australia ; Creatine Kinase/*blood ; Data Interpretation, Statistical ; Female ; Humans ; Male ; Multicenter Studies as Topic ; Numerical Analysis, Computer-Assisted ; Reference Values ; Sex Factors ; }, abstract = {Reference intervals for creatine kinase assayed at 37 degrees C using N-acetyl cysteine-activated methods have been determined on data obtained from 10 laboratories throughout Australia. The pooled distributions for males and females are skewed towards higher values and cannot be transformed to Gaussian distributions. The reference interval for females was calculated to be 34 to 180 U/l and for males it was 46 to 300 U/l. However, if creatine kinase is to be used in the diagnosis of myocardial infarction, the upper limit of the reference interval for males is considered to be too high. It is concluded that for males, the upper limit may need to be determined on specific populations such as hospital inpatients.}, }
@article {pmid2852604, year = {1988}, author = {Eklund, A and Eriksson, O and Håkansson, L and Larsson, K and Ohlsson, K and Venge, P and Bergstrand, H and Björnson, A and Brattsand, R and Glennow, C}, title = {Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: correlation to effects on cellular variables.}, journal = {The European respiratory journal}, volume = {1}, number = {9}, pages = {832-838}, pmid = {2852604}, issn = {0903-1936}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Adult ; Biomarkers/*analysis ; Blood Proteins/analysis ; Bronchoalveolar Lavage Fluid/*cytology ; Endotoxins/analysis ; Eosinophil Granule Proteins ; Humans ; Lactoferrin/analysis ; Male ; Muramidase/analysis ; Pancreatic Elastase/analysis ; Peroxidase/analysis ; Protease Inhibitors/analysis ; *Ribonucleases ; Serum Albumin/analysis ; Smoking/*metabolism ; }, abstract = {Bronchoalveolar lavage (BAL) was performed on eleven healthy smokers before and after eight weeks of oral treatment with N-acetylcysteine (NAC) 200 mg t.i.d. The concentrations of selected eosinophil and neutrophil granule constituents and of selected proteases and protease inhibitors, albumin and endotoxin were determined in the recovered BAL fluid and in plasma or serum samples. In addition, in vitro chemotactic activities for neutrophils and eosinophils were assessed in the BAL fluid. Significant reductions in BAL fluid content of lactoferrin (LF), eosinophil cationic protein (ECP), antichymotrypsin (ACT) and chemotactic activity for neutrophils were recorded after NAC treatment. The levels of other examined markers tended to be reduced or were not affected. In serum/plasma, the concentrations of myeloperoxidase (MPO) and elastase were reduced after NAC treatment whereas concentrations of other constituents examined were unaltered. These data, together with previously reported findings, suggest that oral NAC may influence the activity of "inflammatory" cells in the bronchoalveolar space of smokers.}, }
@article {pmid3198299, year = {1988}, author = {De Bernardi, M and Feletti, F and Gazzani, G and Fregnan, GB}, title = {Human pharmacokinetics of erythromycin propionate-N-acetylcysteinate: comparative evaluation with erythromycin stearate and N-acetylcysteine.}, journal = {International journal of clinical pharmacology, therapy, and toxicology}, volume = {26}, number = {9}, pages = {444-447}, pmid = {3198299}, issn = {0174-4879}, mesh = {Acetylcysteine/*analogs &amp; derivatives/blood/*pharmacokinetics ; Adult ; Biological Availability ; Erythromycin/*analogs &amp; derivatives/blood/pharmacokinetics ; Female ; Half-Life ; Humans ; Male ; Metabolic Clearance Rate ; Middle Aged ; }, abstract = {The pharmacokinetic pattern of erythromycin propionate-N-acetylcysteinate (EPAC) (erythromycin stinoprate I.N.N.), a new derivative, was studied on 12 healthy volunteers after single and multiple oral treatments. Microbiological and/or HPLC analytical methods were used to titer either erythromycin as base, propionate and total or N-acetylcysteine (NAC). In the acute experiment, a comparative evaluation was performed with erythromycin stearate (ES) and with N-acetylcysteine, according to a randomized-multi-crossover design. EPAC showed a better bioavailability than ES with longer-lasting serum levels of active antibiotic. NAC concentrations in the serum after EPAC were practically identical to those found after an oral administration of NAC alone. The multiple treatment study, performed in the same 12 volunteers with only EPAC, indicated that the pharmacokinetic pattern is somewhat different from that observed after a single dose, since higher concentrations were present at the steady state conditions.}, }
@article {pmid3197987, year = {1988}, author = {Lauterburg, BH and Velez, ME}, title = {Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity.}, journal = {Gut}, volume = {29}, number = {9}, pages = {1153-1157}, pmid = {3197987}, issn = {0017-5749}, support = {GM34120/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/*adverse effects/metabolism ; Alcoholism/*complications/metabolism ; Chemical and Drug Induced Liver Injury/*etiology/metabolism ; Cysteine/urine ; Glutathione/blood/*deficiency/metabolism ; Humans ; Liver/metabolism ; Male ; Risk Factors ; }, abstract = {Patients chronically abusing ethanol are more susceptible to the hepatotoxic effects of paracetamol. This could be due to an increased activation of the drug to a toxic metabolite or to a decreased capacity to detoxify the toxic metabolite by conjugation with glutathione (GSH). To test these hypotheses paracetamol 2 g was administered to five chronic alcoholics without clinical evidence of alcoholic liver disease and five control subjects. The urinary excretion of cysteine- plus N-acetyl-cysteine-paracetamol, the two major products of detoxification of the reactive metabolite of paracetamol, was not significantly higher in chronic alcoholics arguing against a substantially increased metabolic activation of paracetamol. Chronic alcoholics had significantly lower plasma concentrations of GSH than healthy volunteers, however (4.35 (1.89) microM v 8.48 (2.68) microM, p less than 0.05) before the administration of paracetamol, and plasma GSH reached lower concentrations in the alcoholics after paracetamol (2.40 (1.36) v 6.26 (2.96) microM). In a group of patients with alcoholic hepatitis intrahepatic GSH was significantly lower than in patients with chronic persistent hepatitis and patients with non-alcoholic cirrhosis, suggesting that low plasma GSH in alcoholics reflects low hepatic concentrations of GSH. The data indicate that low GSH may be a risk factor for paracetamol hepatotoxicity in alcoholics because a lower dose of paracetamol will be necessary to deplete GSH below the critical threshold concentration where hepatocellular necrosis starts to occur.}, }
@article {pmid3136944, year = {1988}, author = {Rotstein, JB and Slaga, TJ}, title = {Effect of exogenous glutathione on tumor progression in the murine skin multistage carcinogenesis model.}, journal = {Carcinogenesis}, volume = {9}, number = {9}, pages = {1547-1551}, doi = {10.1093/carcin/9.9.1547}, pmid = {3136944}, issn = {0143-3334}, support = {CA 43278-02/CA/NCI NIH HHS/United States ; RR5511-25/RR/NCRR NIH HHS/United States ; }, mesh = {9,10-Dimethyl-1,2-benzanthracene ; Acetylcysteine/pharmacology ; Animals ; Antioxidants/pharmacology ; Carcinoma/*chemically induced ; Disulfiram/pharmacology ; Free Radicals ; Glutathione/*pharmacology ; Mice ; Oxidation-Reduction ; Papilloma/pathology ; Precancerous Conditions/*pathology ; Skin Neoplasms/*chemically induced ; }, abstract = {Oxidative stress has been suggested to play an integral role in the cancer process. It may be particularly significant during tumor progression, where there is likely to be a large amount of free radicals generated by infiltrating inflammatory cells and dying tumor cells. In order to test this hypothesis, a variety of free radical scavengers and antioxidants were assessed for their ability to inhibit tumor progression. The murine skin multistage carcinogenesis model was used to generate papillomas, which are a population of putative precancerous lesions. Various test agents were applied topically to papillomas in order to determine if they would decrease the incidence of the malignant lesion, squamous cell carcinoma. The agents tested included: reduced glutathione (GSH), butylated hydroxyanisole, vitamin E, copper(II) (3,5-diisopropylsalicylate)2, sodium benzoate, N-acetyl cysteine and disulfiram. Under the conditions of our experiments, only GSH and disulfiram inhibited tumor progression to a significant degree. Additional studies indicated that GSH prevented cancer development in a dose-dependent manner. Another experiment demonstrated that when papillomas received repeated topical applications of diethylmaleate, a GSH-depleting agent, tumor progression was enhanced. Collectively these data suggest that sufficient glutathione levels may be important in preventing cancer formation.}, }
@article {pmid3067458, year = {1988}, author = {Bakke, JE and Larsen, GL and Struble, C and Feil, VJ and Brandt, I and Brittebo, EB}, title = {Metabolism of 2,6-dichlorobenzonitrile, 2,6-dichlorothiobenzamide in rodents and goats.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {18}, number = {9}, pages = {1063-1075}, doi = {10.3109/00498258809042229}, pmid = {3067458}, issn = {0049-8254}, mesh = {Amides/*pharmacokinetics ; Animals ; Autoradiography ; Bile/metabolism ; Carbon Radioisotopes ; Chromatography, Gas ; Chromatography, High Pressure Liquid ; Female ; Goats/*metabolism ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Nitriles/metabolism/*pharmacokinetics ; Radioisotope Dilution Technique ; Rats ; Rats, Inbred Strains ; Species Specificity ; Thioamides/metabolism/*pharmacokinetics ; Tissue Distribution ; }, abstract = {1. Twelve 14C-labelled metabolites were isolated from either urine or bile from either rats (11 metabolites) or goats (7 metabolites) given single oral doses of 2,6-dichlorobenzo[14C]nitrile (DCBN). Five of these metabolites were also excreted in urine from rats dosed orally with 2,6-dichlorothiobenz[14C]-amide (DCTBA). 2. All metabolites from either DCBN or DCTBA were benzonitriles with the following ring substituents: Cl2, OH (three isomers); Cl2, (OH)2; Cl, (OH)2; Cl, OH, SH; Cl, OH, SCH3; SCH3, SOCH3, OH; Cl2, S-(N-acetyl)cysteine; Cl, S-(N-acetyl)cysteine; Cl, OH, S-(N-acetyl)cysteine. 3. The thiobenzamide moiety of DCTBA was converted to the nitrile in all the excreted urinary metabolites. No hydrolysis of the nitrile in DCBN to either an amide or an acid was detected. 4. Urine was the major route for excretion; however, enterohepatic circulation occurred. 5. Whole-body autoradiography of 14C-DCBN and 14C-DCTBA in mice showed the presence of bound residues in the mucosa of the nasal cavity, trachea, tongue, oesophagus, the kidney, liver and the intestinal contents.}, }
@article {pmid3042286, year = {1988}, author = {Broner, CW and Shenep, JL and Stidham, GL and Stokes, DC and Hildner, WK}, title = {Effect of scavengers of oxygen-derived free radicals on mortality in endotoxin-challenged mice.}, journal = {Critical care medicine}, volume = {16}, number = {9}, pages = {848-851}, doi = {10.1097/00003246-198809000-00006}, pmid = {3042286}, issn = {0090-3493}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Endotoxins ; Escherichia coli ; Female ; Free Radicals ; Mice ; Mice, Inbred Strains ; Sepsis/*drug therapy/mortality ; Superoxide Dismutase/*therapeutic use ; }, abstract = {Oxygen-derived free radicals have been implicated as mediators of cellular injury in several model systems. Recently, a role for free radicals has been proposed in the mortality associated with Gram-negative bacterial sepsis. To determine if pretreatment with free radical scavengers can prevent endotoxin-induced mortality, mice rendered sensitive to endotoxin with actinomycin D were treated with either superoxide dismutase (SOD), N-acetylcysteine (NAC) or saline and were then challenged with a dose of endotoxin calculated to cause a mortality of greater than 80%. Mortality was assessed at 12-h intervals after challenge. Increased survival was seen in the SOD-treated group compared to the control group (p less than or equal to .05). In contrast, survival in mice treated with NAC, another potential scavenger, was not significantly different from the control group. These results support the hypothesis that superoxide and hydroxyl radicals contribute to mortality in Gram-negative bacterial sepsis.}, }
@article {pmid2464108, year = {1988}, author = {Berkenboom, G and Fontaine, J and Degre, S}, title = {Persistence of the response to SIN1 on isolated coronary arteries rendered tolerant to nitroglycerin in vitro or in vivo.}, journal = {Journal of cardiovascular pharmacology}, volume = {12}, number = {3}, pages = {345-349}, doi = {10.1097/00005344-198809000-00013}, pmid = {2464108}, issn = {0160-2446}, mesh = {Adolescent ; Adult ; Animals ; Antihypertensive Agents/*pharmacology ; Coronary Vessels/drug effects ; Dogs ; Drug Tolerance ; Humans ; In Vitro Techniques ; Middle Aged ; Molsidomine/*analogs &amp; derivatives/pharmacology ; Muscle, Smooth, Vascular/*drug effects ; Nitroglycerin/*pharmacology ; }, abstract = {Experiments were performed on isolated canine and human coronary arteries to provide more insight into the mechanisms responsible for the vascular tolerance to nitroglycerin that is induced under in vitro or in vivo conditions. In vitro tolerance was produced after an incubation of coronary ring segments with nitroglycerin (10 microM for 30 min at physiological pH). After elevation of tone with KCl (15 mM), dose-response curves were constructed for nitroglycerin or SIN1 (3-morpholino-syndnonimin) on control and tolerant rings. On canine tolerant rings the dose-response curve for nitroglycerin-induced relaxations was significantly (p less than 0.001) shifted to the right, and 50% of the maximal relaxation (ED50) increased from 55 +/- 9 nM to 1.2 +/- 0.2 microM. Pretreatment of tolerant rings with N-acetylcysteine (NAC, 10 microM 10 min before KCl-induced contraction) partially restored the responsiveness to nitroglycerin, with ED50 reducing to 0.56 +/- 0.03 microM (p less than 0.02). On the other hand, the dose-response curves to SIN1 were not significantly altered. Similar results were obtained on human preparations. On isolated canine coronary rings rendered tolerant in vivo by subcutaneous injections of 15 mg/kg nitroglycerin (two times daily for 4 consecutive days), ED50 for nitroglycerin was 0.67 +/- 0.08 microM (p less than 0.001 versus control rings), and NAC again partially restored the responsiveness to nitroglycerin. As for the in vitro tolerance, the relaxations to SIN1 were not significantly altered on these canine rings rendered nitrate tolerant in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid3220208, year = {1988}, author = {Fisher, GD and Kilgore, WW}, title = {Mercapturic acid excretion by rats following inhalation exposure to 1,3-dichloropropene.}, journal = {Fundamental and applied toxicology : official journal of the Society of Toxicology}, volume = {11}, number = {2}, pages = {300-307}, doi = {10.1016/0272-0590(88)90155-8}, pmid = {3220208}, issn = {0272-0590}, support = {ES07059-08/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetylcysteine/*urine ; Administration, Inhalation ; Allyl Compounds/administration &amp; dosage/*toxicity ; Animals ; Atmosphere Exposure Chambers ; Hydrocarbons, Chlorinated ; Male ; Rats ; Rats, Inbred Strains ; }, abstract = {Rats were exposed to 1,3-dichloropropene (DCP), a commonly used agricultural nematicide, by inhalation to assess the relationship between DCP concentration and the urinary excretion of the mercapturic acid of cis-DCP (3C-NAC). The nose-only exposure system that was used for simultaneously exposing up to four rodents is described. This apparatus provided for generation and monitoring of relative humidity and test vapor concentration. Animals were exposed for 1 hr to concentrations of up to 789 ppm DCP. Urine was collected for 24 hr after exposure. The quantity of 3C-NAC contained in the urine collections exhibited an exposure concentration-dependent increase from 0 to 284 ppm DCP. However, the amount of 3C-NAC was no greater for animals exposed to 398 or 789 ppm DCP than for animals exposed to 284 ppm DCP.}, }
@article {pmid3188573, year = {1988}, author = {Davison, KL and Bakke, JE}, title = {Intermediary metabolism of 2,6-dichlorobenzonitrile (dichlobenil) in chickens and growth of chickens fed dichlobenil.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {18}, number = {8}, pages = {941-948}, doi = {10.3109/00498258809167517}, pmid = {3188573}, issn = {0049-8254}, mesh = {Animals ; Bile/metabolism ; Chickens/growth &amp; development/*metabolism ; Chromatography, Gas ; Eating/drug effects ; Feces/analysis ; Glutathione/metabolism ; Kidney/anatomy &amp; histology/metabolism ; Liver/anatomy &amp; histology ; Male ; Mass Spectrometry ; Molecular Structure ; Nitriles/*metabolism/pharmacology/urine ; Organ Size/drug effects ; Weight Gain/drug effects ; }, abstract = {1. Ten 14C-labelled metabolites were isolated from either bile (6 metabolites) or urine (7 metabolites) from chickens given single oral doses of 2,6-dichlorobenzo[14C]nitrile (14C-dichlobenil). All metabolites were benzonitriles with the following ring substituents: two Cl, OH (two isomers); Cl, two OH; Cl, OH, SH; Cl, OH, S-glutathione; Cl, OH, S-cysteinylglycine; Cl, OH, S-cysteine; and Cl, OH, S-(N-acetyl)cysteine. 2. 2-(S-Glutathionyl)-3-hydroxy-6-chlorobenzo[14C]nitrile perfused through chicken kidneys in situ was excreted in urine from the perfused kidney (44% dose) as 2-mercapto-3-hydroxy-6-chlorobenzonitrile. 3. Dichlobenil (2,6-dichlorobenzonitrile) was fed at 0, 75, 150 or 225 p.p.m. in the diet to broiler and laying strains of cockerels to determine biological activity. Feed consumption and growth were not affected, but liver and kidney weights were higher in chicks fed the dichlobenil. The percentage of lipid or nitrogen in the livers and kidneys from chicks fed dichlobenil did not differ from controls and histological or ultrastructural changes were not observed in these tissues.}, }
@article {pmid3383404, year = {1988}, author = {Forman, MB and Puett, DW and Cates, CU and McCroskey, DE and Beckman, JK and Greene, HL and Virmani, R}, title = {Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.}, journal = {Circulation}, volume = {78}, number = {1}, pages = {202-213}, doi = {10.1161/01.cir.78.1.202}, pmid = {3383404}, issn = {0009-7322}, support = {AM26657-W/AM/NIADDK NIH HHS/United States ; R29-HL-38294/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Animals ; *Coronary Circulation ; Dogs ; Female ; Glutathione Peroxidase/*metabolism ; Heart/drug effects/*physiopathology ; Heart Ventricles ; Hemodynamics ; Male ; Myocardial Infarction/drug therapy/enzymology/pathology/*physiopathology ; Oxidation-Reduction ; }, abstract = {Glutathione peroxidase is an important enzyme in the degradative cascade of reactive oxygen free radicals. N-Acetylcysteine (NAC) is a low molecular weight compound that has been used clinically to replenish glutathione. To assess the role of the glutathione redox pathway on reperfusion injury, 23 animals underwent 90 minutes of proximal left anterior descending coronary artery occlusion followed by 24 hours of reperfusion with the administration of NAC (n = 11) or saline (n = 12) beginning 30 minutes into occlusion and continuing for 3 hours after reperfusion. Regional ventricular function was measured with contrast ventriculography, and regional myocardial blood flow was determined with microspheres. At 24 hours, the area at risk was defined in vivo with Monastral Blue, and the area of necrosis was defined by incubation in triphenyltetrazolium. Biopsies were taken from the ischemic and nonischemic zones to determine levels of total glutathione, superoxide dismutase and glutathione peroxidase activity, and reactivity to thiobarbituric acid, an index of lipid peroxidation. The rate-pressure product and myocardial blood flow were similar in the two groups throughout the study. No significant differences were noted in infarct size expressed as a percentage of the area at risk (28.6 +/- 5.3% vs. 36.6 +/- 6.0%) and of the total left ventricle (14.4 +/- 3.2% vs. 16.5 +/- 3.1%), and no differences were noted between the two groups on examination of the ischemic subendocardium by light and electron microscopy. Both groups exhibited similar degrees of dyskinesis during occlusion; however, treated animals showed significant improvement in regional radial shortening at 3 hours (3.4 +/- 2.4% vs. -2.4 +/- 2.1%, p less than 0.02) and 24 hours (9.2 +/- 2.2% vs. -2.5 +/- 6.3%, p less than 0.001) after reperfusion. No differences were present in total glutathione, thiobarbituric acid reactivity, or superoxide dismutase and glutathione peroxidase activity in the ischemic zones of the two groups. This study suggests that N-acetylcysteine treatment before reperfusion may reduce myocardial stunning but does not limit myocyte death after reperfusion.}, }
@article {pmid3140711, year = {1988}, author = {Dorr, RT and Alberts, DS and Liddil, JD}, title = {Mitomycin C toxicity and pharmacokinetics in mice given sulfur nucleophiles.}, journal = {Anticancer research}, volume = {8}, number = {4}, pages = {733-737}, pmid = {3140711}, issn = {0250-7005}, support = {CA 17094/CA/NCI NIH HHS/United States ; CA 23074/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antidotes/*pharmacology ; Colony-Forming Units Assay ; Leukemia P388/drug therapy ; Male ; Mice ; Mice, Inbred DBA ; Mitomycin ; Mitomycins/pharmacokinetics/therapeutic use/*toxicity ; Thiosulfates/*pharmacology ; }, abstract = {The sulfur nucleophiles, sodium thiosulfate (Na2S2O3) and N-acetylcysteine (NAC) given in maximally tolerated doses did not reduce the hematologic toxicity of high dose mitomycin C (MMC) in normal mice. In addition, neither sulfur nucleophile significantly altered the antileukemic activity of MMC. Pharmacokinetic studies of MMC in normal mice, demonstrated rapid plasma elimination (T1/2 beta = 0.53 hrs) and substantial drug distribution to the bone marrow which was enhanced by NAC. These results demonstrate a lack of MMC antidotal activity for Na2S2O3 and NAC.}, }
@article {pmid2846345, year = {1988}, author = {Linden, M and Wieslander, E and Eklund, A and Larsson, K and Brattsand, R}, title = {Effects of oral N-acetylcysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers.}, journal = {The European respiratory journal}, volume = {1}, number = {7}, pages = {645-650}, pmid = {2846345}, issn = {0903-1936}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Bronchoalveolar Lavage Fluid/*cytology ; Cell Count/drug effects ; Cell Survival/drug effects ; Female ; Humans ; Leukotriene B4/biosynthesis ; Macrophages/*drug effects ; Male ; Phagocytosis/drug effects ; Pulmonary Alveoli/cytology ; Smoking/*drug therapy/pathology ; }, abstract = {Bronchoalveolar lavage (BAL) was performed in fourteen healthy non-smokers and eleven healthy smokers. In smokers BAL was performed before and after eight weeks' treatment with N-acetylcysteine (NAC; 200 mg t.i.d.). Cell number, composition and viability were determined in the BAL fluid. Alveolar macrophages (AMs) were cultured before examination of their phagocytic capacity and their ability to produce leukotriene B4 (LTB4). BAL fluid from smokers contained more cells than that from non-smokers (p less than 0.001). This was mainly attributable to increases in both proportion and absolute number of AMs (p less than 0.001) and to an increase in absolute number of neutrophils (p less than 0.05). However, there was a decrease in proportion of lymphocytes in BAL fluid from smokers (p less than 0.001). Phagocytic capacity of adherent cells and capacity of AMs to generate LTB4 after stimulation with opsonized zymosan (OZy) were decreased in smokers (p less than 0.05 and p less than 0.01 respectively). NAC treatment of smokers did not affect cell number but resulted in an increased proportion of lymphocytes in BAL fluid (p less than 0.05). The phagocytic capacity of AMs was not significantly altered but was improved in five of eleven smokers after NAC treatment. NAC also enhanced the decreased LTB4 secretion by smokers' AMs (p less than 0.05). We conclude that smoking leads to reduced phagocytic capacity and LTB4 secretion of AMs and that oral NAC treatment may improve the function of AMs.}, }
@article {pmid2459531, year = {1988}, author = {Kennedy, TP and Gordon, GB and Paky, A and McShane, A and Adkinson, NF and Peters, SP and Friday, K and Jackman, W and Sciuto, AM and Gurtner, GH}, title = {Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs.}, journal = {Journal of cardiovascular pharmacology}, volume = {12}, number = {1}, pages = {23-36}, doi = {10.1097/00005344-198807000-00004}, pmid = {2459531}, issn = {0160-2446}, mesh = {Amiodarone/*toxicity ; Animals ; Antioxidants/*pharmacology ; Arachidonate 5-Lipoxygenase/metabolism ; Arachidonic Acids/metabolism ; Glutathione/metabolism ; In Vitro Techniques ; Lung/*drug effects/metabolism/physiology ; Male ; Oxidation-Reduction ; Perfusion ; Prostaglandin-Endoperoxide Synthases/metabolism ; Pulmonary Edema/chemically induced ; Rabbits ; Superoxides/metabolism ; }, abstract = {Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean +/- SEM) (from 13.6 +/- 1.2 to 40.6 +/- 9.5 mm Hg, p less than 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 microM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (delta W) of 5.7 +/- 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (delta W = 0.7 +/- 0.3 g/min, p less than 0.05), pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., delta W = 0.05 +/- 0.02 g/min, p less than 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, delta W = 0.6 +/- 0.2 g/min, p less than 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, delta W = 0.1 +/- 0.08 g/min, p less than 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2-), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.}, }
@article {pmid3395714, year = {1988}, author = {Parker, CE and de Wit, JS and Smith, RW and Gopinathan, MB and Hernandez, O and Tomer, KB and Vestal, CH and Sanders, JM and Bend, JR}, title = {Analysis of glutathione conjugates and related compounds by thermospray mass spectrometry.}, journal = {Biomedical &amp; environmental mass spectrometry}, volume = {15}, number = {11}, pages = {623-633}, doi = {10.1002/bms.1200151108}, pmid = {3395714}, issn = {0887-6134}, mesh = {Chemical Phenomena ; Chemistry ; Chromatography, High Pressure Liquid ; Glutathione/*analysis ; Mass Spectrometry ; Molecular Weight ; }, abstract = {A series of 17 cysteine, N-acetyl cysteine, glutathione, and N-trifluoroacetyl glutathione conjugates have been prepared, and their thermospray (TSP) spectra have been recorded in the positive and negative ion modes. The compounds undergo extensive fragmentation, which primarily occurs at the carbon-sulfur bonds. For most of the compounds, positive ion TSP is more sensitive than negative ion thermospray. Probably due to the thermal lability of these adducts, the quality of the spectra obtained are dependent on source conditions, requiring fine control of the vaporization/desolvation process.}, }
@article {pmid3048003, year = {1988}, author = {Bach, PH and Kwizera, EN}, title = {Nephrotoxicity: a rational approach to target cell injury in vitro in the kidney.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {18}, number = {6}, pages = {685-698}, doi = {10.3109/00498258809041707}, pmid = {3048003}, issn = {0049-8254}, support = {//Wellcome Trust/United Kingdom ; }, mesh = {Animals ; Drug Evaluation, Preclinical/methods ; Kidney/drug effects/*pathology ; Perfusion ; Toxins, Biological/pharmacology ; }, abstract = {1. The kidney is a complex organ in which there is cellular heterogeneity. Many nephrotoxic chemicals target preferentially for discrete cell types, but adjacent, morphologically different cells are unaffected. This selectivity has made the assessment of nephrotoxicity in vivo (and the study of underlying mechanisms) difficult. Discrete renal injury can, however, be exploited in vitro, to study the interactions between the toxic compound and the target cell. 2. Several in vitro models have been used to study the potential interaction between the target cells and chemicals, including perfusion of the isolated kidney, renal slices, freshly isolated fragments, primary cultures and continuous cell lines. Where appropriate, isolated organelles and purified enzymes can also be used. 3. The target cell toxicity in vivo of adriamycin, 2-bromoethanamine and hexachlorobutadiene N-acetyl cysteine conjugate is selectively maintained towards glomerular epithelial, medullary interstitial and proximal tubular cells, respectively, in vitro, showing that the "in vivo-in vitro gap" can be bridged. Characteristics unique to each of these renal cell types, such as the selective uptake of a toxin, enzyme systems for generating biologically reactive intermediates, and the presence of lipid droplets (rich in polyunsaturated fatty acid) and peroxidase activity have been identified, and one or more of these may explain the mechanisms of selective injury in discrete regions of the kidney.}, }
@article {pmid2836109, year = {1988}, author = {Westlin, W and Mullane, K}, title = {Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals?.}, journal = {Circulation}, volume = {77}, number = {6 Pt 2}, pages = {I30-9}, pmid = {2836109}, issn = {0009-7322}, support = {HL31591/HL/NHLBI NIH HHS/United States ; }, mesh = {Adrenochrome/metabolism ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; Arrhythmias, Cardiac/drug therapy/etiology ; Captopril/analogs &amp; derivatives/*pharmacology ; Coronary Disease/complications/drug therapy/*metabolism ; Dogs ; Drug Evaluation, Preclinical ; Epinephrine/metabolism ; Free Radicals ; In Vitro Techniques ; Male ; Myocardial Contraction/drug effects ; Neutrophils/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Perfusion ; Stereoisomerism ; Sulfhydryl Compounds/pharmacology ; Superoxides/*metabolism ; Tetradecanoylphorbol Acetate/pharmacology ; }, abstract = {The abilities of angiotensin converting-enzyme (ACE) inhibitors to suppress superoxide anion formation in vitro and to improve postischemic cardiac function in vivo were examined. Three sulfhydryl-containing ACE inhibitors, captopril, its stereoisomer SQ 14,534, and an analog, zofenopril (SQ 26,703) were compared with enalaprilat and teprotide, which lack the sulfhydryl group but inhibit ACE, and two compounds, N-2-mercaptopropionylglycine (MPG) and N-acetylcysteine (NAC), which contain a thiol moiety but are not ACE inhibitors, for suppression of free radical formation in vitro. The autooxidation of epinephrine to adrenochrome is mediated by superoxide anions and inhibited by captopril, SQ 14,534, and zofenopril, with similar IC50 values of 8 to 10 microM, but not by enalaprilat or teprotide (IC50 greater than 1000 microM). This reaction is also inhibited by MPG and NAC with IC50 values of 19 and 17 microM, respectively. In addition, captopril, MPG, or NAC, but not teprotide or enalaprilat, scavenge superoxide anion production by the purine-xanthine oxidase reaction and by canine neutrophils activated with phorbol myristate acetate. These results indicate that captopril scavenges superoxide anions in vitro independent of an action on ACE, which is probably related to the presence of a sulfhydryl moiety. Myocardial segmental function in the anesthetized, open-chest dog is altered during ischemia from active shortening to passive lengthening. Reperfusion after 15 min of ischemia does not restore active shortening within a 3 hr experimental period. Pretreatment of dogs with captopril intravenously (5 mg/kg) results in a 40% to 60% return to active shortening within 60 min of reperfusion. In contrast, equihypotensive doses of enalaprilat do not improve segmental function during reperfusion. Dogs given captopril immediately before restoring coronary blood flow show a similar return of function as that observed in animals treated with the drug before occlusion. SQ 14,534, the isomer of captopril, which is 100-fold less potent as an ACE inhibitor but equipotent in scavenging superoxide anions, also improves reperfusion-induced cardiac dysfunction when administered at reperfusion (5 mg/kg). Thus captopril improves postischemic contractile derangements by a mechanism independent of ACE inhibition. Restoration of blood supply to the ischemic myocardium provokes ventricular fibrillation in 37.5% of control dogs but in only 9% of those administered enalaprilat and 0% of captopril-treated animals. SQ 14,534 does not reduce the incidence of ventricular fibrillation (40%), indicating that the antifibrillatory actions may be related to ACE inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid2453601, year = {1988}, author = {Giri, SN and Hyde, DM and Schiedt, MJ}, title = {Effects of repeated administration of N-acetyl-L-cysteine on sulfhydryl levels of different tissues and bleomycin-induced lung fibrosis in hamsters.}, journal = {The Journal of laboratory and clinical medicine}, volume = {111}, number = {6}, pages = {715-724}, pmid = {2453601}, issn = {0022-2143}, support = {5RO1 HL27354-06/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bleomycin/pharmacology ; Collagen/metabolism ; Cricetinae ; Lung/metabolism ; Male ; Mesocricetus ; Pulmonary Fibrosis/chemically induced/*metabolism/pathology ; Sulfhydryl Compounds/*metabolism ; Time Factors ; }, abstract = {N-Acetyl-L-cysteine (NAC), 50, 100, 200, or 400 mg/kg, was injected intraperitoneally once a day for 13 days. No change was seen in the total sulfhydryl (TSH) and nonprotein sulfhydryl (NPSH) contents of the liver, kidney, and plasma at any dose. The heart TSH level remained unchanged, but the NPSH level was increased from the control value of 16 nmol/mg to 18, 19, and 18 nmol/mg protein at 50, 100, and 200 mg/kg, respectively. The lung TSH and NPSH levels both were increased from the control values of 65 and 8 nmol/mg to 80 and 16 nmol/mg protein, respectively, at 200 mg/kg. The lung TSH level at 400 mg/kg NAC was not changed, but the NPSH level increased to 13.5 nmol/mg protein. The ratio of TSH to NPSH levels in the liver and kidney was 4:1, whereas in the lung and heart it was 7:1 and 8:1, respectively. Based on amount per milligram of protein, TSH and NPSH levels were highest in the liver, followed by the amounts in the kidney, heart, and lung. The lung had the lowest level of TSH and NPSH. The daily treatment with NAC (200 mg/kg) for 13 days after and 2 days before intratracheal injection of bleomycin (7.5 U/kg) had little effect on lung collagen accumulation. The lung collagen level measured as hydroxyproline in bleomycin and in NAC plus bleomycin was significantly increased to 175% and 183% of the control levels, respectively. There was no difference in the lung hydroxyproline content between the control and NAC groups. The histopathology study also revealed no marked difference between the bleomycin and bleomycin plus NAC groups. Alternatively, treatment with NAC (200 mg/kg) for 13 days before bleomycin made the animals more susceptible to bleomycin toxicity and tended to add to the bleomycin-induced accumulation of collagen in the lung. NAC per se caused no mortality at any dose. The lung TSH and NPSH levels in bleomycin-treated (7.5 U/kg) hamsters were increased to 136% and 111% of control, respectively, whereas the TSH and NPSH levels both were increased to 155% of the levels of their respective controls in hamsters in the NAC plus bleomycin group. The differential effects of NAC treatment on the sulfhydryl content of tissues, the treatment's inability to alter the course of bleomycin-induced lung inflammation and collagen accumulation, and the potential for exacerbation of lung toxicity in response to repeated administration of NAC before exposure to fibrogenic agents are discussed.}, }
@article {pmid3421986, year = {1988}, author = {Khandelwal, S and Kachru, DN and Tandon, SK}, title = {Chelation in metal intoxication. XXVIII: Effect of thiochelators on mercury (II) toxicity: pre- and post treatment.}, journal = {Biochemistry international}, volume = {16}, number = {5}, pages = {869-878}, pmid = {3421986}, issn = {0158-5231}, mesh = {Acetylcysteine/therapeutic use ; Acrylates/therapeutic use ; Animals ; Chelating Agents/*therapeutic use ; Male ; Mercury/*pharmacokinetics ; Mercury Poisoning/*drug therapy ; Mercury Radioisotopes ; Rats ; Rats, Inbred Strains ; Spironolactone/therapeutic use ; Tiopronin/therapeutic use ; }, abstract = {The effect of treatment with alpha-mercapto-beta-(2-furyl)acrylic acid (MFA), N-(N-mercaptopropionyl) glycine (MPG) and N-acetylcysteine (NAC) compared to spironolactone (SPL), a steroid, before and after 203 mercury (II) exposure, on the disposition of Hg and induction of tissue metallothionein (MT), was investigated in rats. The pretreatment with SPL, MFA and MPG enhanced faecal elimination of Hg and reduced its accumulation in liver particularly, the "heat stable fraction" resulting in lowered hepatic MT induction. Neither the renal uptake of Hg nor induction of tissue MT was affected by pre-treatment with the chelating agents; SPL and MFA causing re-distribution of Hg among the renal sub-cellular fractions. The post-Hg exposure treatment with MFA enhanced the faecal and MPG the urinary excretion of Hg. However, both the chelating agents increased the hepatic burden of Hg as reflected in the subcellular fractions and increased MT contents indicating mobilization of Hg from other tissue binding sites. The post-treatment with MPG however, depleted renal Hg as reflected by the sub-cellular distribution, without affecting renal MT levels. The results show that MFA and MPG are more promising preventive than therapeutic agents in Hg intoxication acting as metal chelators.}, }
@article {pmid3130476, year = {1988}, author = {Fung, HL and Chong, S and Kowaluk, E and Hough, K and Kakemi, M}, title = {Mechanisms for the pharmacologic interaction of organic nitrates with thiols. Existence of an extracellular pathway for the reversal of nitrate vascular tolerance by N-acetylcysteine.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {245}, number = {2}, pages = {524-530}, pmid = {3130476}, issn = {0022-3565}, support = {GM-20852/GM/NIGMS NIH HHS/United States ; HL-22273/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Aorta/drug effects/physiology ; Blood Pressure/*drug effects ; Glutathione/*pharmacology ; Humans ; In Vitro Techniques ; Male ; Metabolic Clearance Rate ; Muscle, Smooth, Vascular/drug effects/physiology ; Nitrates/blood ; Nitroglycerin/pharmacokinetics/*pharmacology ; Rats ; Rats, Inbred Strains ; Serine/analogs &amp; derivatives/pharmacology ; Vasodilation/drug effects ; }, abstract = {Recent reports have shown that the coadministration of N-acetylcysteine (NAC) potentiated the hemodynamic actions of i.v. nitroglycerin (NTG) and reversed NTG tolerance in humans. This study has investigated the feasibility of various pharmacokinetic and biochemical mechanisms for the thiol-organic nitrate interaction, using the rat as an animal model. In order to establish that the potentiating interaction between NAC and NTG can be reproduced in the rat, NTG dose-blood pressure response curves were determined before and during concurrent thiol infusion. The hypotensive effect of NTG was enhanced significantly by NAC and glutathione, but not by N-acetylserine, showing clearly that the potentiating effect of NAC was due specifically to its thiol functional group. The systemic clearance of NTG was not affected significantly by NAC coinfusion. In addition, the intracellular metabolism of NTG in thoracic aorta segments from rats infused previously with NAC or N-acetylserine was similar, both with respect to total production of metabolites and their distribution. Thus, the enhancement of NTG action could not be attributed apparently to an effect of NAC on NTG systemic pharmacokinetics or vascular metabolism of NTG. Because glutathione, which does not enter cells readily, also potentiated the effects of NTG, the possibility of an extracellular pathway for the thiol-organic nitrate interaction was examined. In vitro degradation of NTG in plasma and blood was accelerated in the presence of NAC (or glutathione). NAC also promoted the formation of S-nitroso-N-acetylcysteine from NTG in rat and human plasma and human blood.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid2839877, year = {1988}, author = {Llobet, JM and Domingo, JL and Corbella, J}, title = {Comparative effects of repeated parenteral administration of several chelators on the distribution and excretion of cobalt.}, journal = {Research communications in chemical pathology and pharmacology}, volume = {60}, number = {2}, pages = {225-233}, pmid = {2839877}, issn = {0034-5164}, mesh = {Acetylcysteine/pharmacology ; Animals ; Chelating Agents/*pharmacology ; Cobalt/*pharmacokinetics/urine ; Edetic Acid/pharmacology ; Glutathione/pharmacology ; Injections, Intraperitoneal ; Male ; Pentetic Acid/pharmacology ; Rats ; Rats, Inbred Strains ; Succimer/pharmacology ; }, abstract = {Effects of repeated ip administration of glutathione, N-acetyl-L-cysteine (NAC), 2,3-dimercaptosuccinic acid (DMSA), ethylendiamine-tetraacetic acid (EDTA), and diethylentriamepentaacetic acid (DTPA) on the distribution and excretion of cobalt were assessed in Sprague-Dawley rats. Groups of ten animals received intraperitoneally 0.06 mmol CoCl2/kg/day, three days/week for four weeks. 24 hr after the last injection, daily chelation therapy was initiated. Rats received one of the chelators or saline for 5 days. The animals were housed in metabolic cages and urine and feces were collected daily for 5 days after which time the rats were killed and the concentration of cobalt was determined in various tissues. Glutathione, NAC and DTPA significantly increased the excretion of cobalt into urine whereas EDTA, NAC and DMSA were the most effective chelators increasing the fecal elimination of cobalt. The concentration of cobalt in the various tissues was only decreased by NAC (liver and spleen) and glutathione (spleen). The observed increase in the cobalt excretion with certain chelators would suggest that increasing the duration of chelation therapy may decrease the concentrations of cobalt in tissues and hence, reduce the toxicity of the metal.}, }
@article {pmid3294038, year = {1988}, author = {Rasmussen, JB and Glennow, C}, title = {Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis.}, journal = {The European respiratory journal}, volume = {1}, number = {4}, pages = {351-355}, pmid = {3294038}, issn = {0903-1936}, mesh = {Absenteeism ; Acetylcysteine/*administration &amp; dosage/therapeutic use ; Adult ; Bronchitis/*drug therapy ; Chronic Disease ; Clinical Trials as Topic ; Delayed-Action Preparations ; Double-Blind Method ; Female ; Humans ; Male ; Random Allocation ; Time Factors ; }, abstract = {The clinical effect of N-acetylcysteine (NAC) controlled-release tablets, 300 mg b.i.d., and placebo, in chronic bronchitis was investigated. The study was performed as a double-blind six month comparison between active drug and placebo in two parallel groups, with statistical evaluation after four and six months. The patients were chosen from nine centres. One hundred and sixteen out-patients were included and ninety one of them completed the six month study. The acetylcysteine-treated group had a significantly reduced number of sick-leave days caused by exacerbations of chronic bronchitis after the four winter months December-March compared with the control group (NAC 173, placebo 456). The number of exacerbation days was also very much reduced, however, not significantly (NAC 204, placebo 399). At the end of the six month trial, including also two spring months, the absolute numbers of sick-leave days and exacerbation days were still fewer in the acetylcysteine-treated group, (NAC 260, placebo 739) and (NAC 378, placebo 557) respectively. This study demonstrates a significant reduction in sick-leave days after four months of NAC-treatment. A constant tendency to reduction in the number of exacerbations and exacerbation days was also registered after four and six months. The differences in these parameters were, however, not statistically significant. This was probably due to the small number of patients participating.}, }
@article {pmid3135276, year = {1988}, author = {Böhler, S and Neuhäuser-Berthold, M and Wagner, K and Virmani, K and Bässler, KH}, title = {[Cysteine in parenteral nutrition: comparative study of N-acetyl-cysteine and N,N-diacetylcystine in the rat model].}, journal = {Infusionstherapie (Basel, Switzerland)}, volume = {15}, number = {2}, pages = {89-92}, pmid = {3135276}, issn = {1011-6966}, mesh = {Acetylcysteine/*administration &amp; dosage ; Animals ; Cysteine/*blood ; Cystine/administration &amp; dosage/*analogs &amp; derivatives ; Liver/metabolism ; Male ; *Parenteral Nutrition, Total ; Rats ; Rats, Inbred Strains ; }, abstract = {In this study the question of whether N-N-diacetylcystine (DAC), which is more stable than N-acetylcysteine (AcCYS), may provide a useful cysteine source for parenteral nutrition was investigated. In in vitro studies the release of cysteine from DAC was measured. The Michaelis, constant and maximum velocity were compared with the corresponding results for AcCYS. In in vivo studies 3 groups of growing rats were maintained entirely by parenteral nutrition low in methionine for 15 days. Group I (n = 4) received a solution containing AcCYS, and group II (n = 6) was supplied with a corresponding amount of DAC. In the solution given to group III (n = 6) the CYS derivative was replaced by an isonitrogeneous amount of glycine. Utilization of the respective CYS derivatives was judged from weight gain, nitrogen balance, plasma amino acid pattern, and urinary excretion of free amino acids. The results from both the in vitro and in vivo studies indicate that DAC is not a suitable substitute for AcCYS in parenteral nutrition.}, }
@article {pmid3127076, year = {1988}, author = {Horowitz, JD and Henry, CA and Syrjanen, ML and Louis, WJ and Fish, RD and Smith, TW and Antman, EM}, title = {Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris.}, journal = {Circulation}, volume = {77}, number = {4}, pages = {787-794}, doi = {10.1161/01.cir.77.4.787}, pmid = {3127076}, issn = {0009-7322}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Angina Pectoris/*drug therapy ; Angina, Unstable/*drug therapy ; Clinical Trials as Topic ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Hypotension/chemically induced ; Male ; Myocardial Infarction/prevention &amp; control ; Nitroglycerin/administration &amp; dosage/*therapeutic use ; Random Allocation ; Risk Factors ; }, abstract = {The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid3382149, year = {1988}, author = {Penny, AF and Jennings, A}, title = {Reactivation of creatine kinase activity by preincubation with buffered NAC diluent.}, journal = {Annals of clinical biochemistry}, volume = {25 (Pt 2)}, number = {}, pages = {181-185}, doi = {10.1177/000456328802500209}, pmid = {3382149}, issn = {0004-5632}, mesh = {Acetylcysteine/*analysis ; Buffers ; Creatine Kinase/*analysis ; Enzyme Reactivators/*analysis ; Humans ; Temperature ; }, abstract = {We have shown that several commercial control sera containing reversibly inactivated creatine kinase are reactivated by pre-incubation in N-acetyl cysteine assay diluent. The increase in activity can proceed for up to 4 h. This reactivation is not seen in patients' sera even after storage for 14 days at -20 degrees C, 7 days at 4 degrees C, or 2 days at 20 degrees C, during which time no loss of activity was evident. This study brings into question the validity of using consensus values to standardise enzyme assays.}, }
@article {pmid3345201, year = {1988}, author = {Issels, RD and Nagele, A and Eckert, KG and Wilmanns, W}, title = {Promotion of cystine uptake and its utilization for glutathione biosynthesis induced by cysteamine and N-acetylcysteine.}, journal = {Biochemical pharmacology}, volume = {37}, number = {5}, pages = {881-888}, doi = {10.1016/0006-2952(88)90176-1}, pmid = {3345201}, issn = {0006-2952}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Chromatography, High Pressure Liquid ; Cricetinae ; Cricetulus ; Cysteamine/*pharmacology ; Cystine/*pharmacokinetics ; Female ; Glutathione/analogs &amp; derivatives/*biosynthesis/metabolism ; Glutathione Disulfide ; Hydrogen-Ion Concentration ; Ovary/metabolism ; Temperature ; }, abstract = {Chinese hamster ovary (CHO) cells obtain a high capacity to utilize cystine from the growth medium by exposure to cysteamine (2-mercaptoethylamine, MEA) or N-acetylcysteine (NAC). For uptake studies a modified McCoy's 5A medium supplemented with 0.1 mM [35S]cystine was used. The uptake of cystine was dependent on the time of exposure (0-60 min) and the concentrations of MEA or NAC (0-8 mM). At high concentrations of MEA or NAC, the uptake of cystine became saturated. Half-maximal uptake of cysteine was observed at concentrations of 0.12 mM MEA and 0.66 mM NAC, respectively. Increase in temperature (37-44 degrees) or pH (6.0-8.0) during MEA or NAC exposure further increased the cystine uptake. The increased uptake of cystine was not affected in the presence of glutamate or homocysteate which both inhibited the cystine uptake of control cells. Determination of both reduced (GSH) and oxidized (GSSG) cellular glutathione showed a twofold increase in MEA- or NAC-treated CHO cells. DL-buthionine-S,R-sulfoximine (BSO), an inhibitor of GSH biosynthesis completely blocked the promotion of cystine uptake by MEA and NAC. By further analysis using reversed-phase HPLC of cell extracts, more than 90% of the [35S] radioactive cystine taken up by the cells could be recovered within the pool of GSH. The results demonstrate that exposure of CHO cells with MEA and NAC leads to a promoted uptake of cystine from the culture medium and its rapid utilization for cellular GSH biosynthesis.}, }
@article {pmid3287812, year = {1988}, author = {Modig, J and Sandin, R}, title = {Haematological, physiological and survival data in a porcine model of adult respiratory distress syndrome induced by endotoxaemia. Effects of treatment with N-acetylcysteine.}, journal = {Acta chirurgica Scandinavica}, volume = {154}, number = {3}, pages = {169-177}, pmid = {3287812}, issn = {0001-5482}, mesh = {Acetylcysteine/blood/*therapeutic use ; Animals ; Blood Pressure/drug effects ; Endotoxins/administration &amp; dosage ; Escherichia coli ; Female ; Hematocrit ; Humans ; Infant, Newborn ; Leukocyte Count ; Male ; Models, Biological ; Oxygen Consumption/drug effects ; Partial Pressure ; Platelet Count ; Respiratory Distress Syndrome, Newborn/blood/*drug therapy/etiology ; Swine ; }, abstract = {The effects of N-acetylcysteine (NAC)--which is supposed to act as a free radical scavenger--were evaluated on lung function, haemodynamics and oxygen transport in a porcine model of pulmonary and cardiovascular failure induced by endotoxaemia. Three pigs, serving as controls, received NAC without endotoxin (E) for 6 h, and no notable physiological changes were found. Five pigs received a continuous infusion of E alone for 6 h and displayed a 90% decrease in leukocyte count and a 66% decrease in platelet count. Physiologically a four-fold increase in venous admixture (Qva/Qt), a nearly 2-3 fold increase in mean pulmonary arterial pressure (MPAP) and a progressive decline in cardiac output (Qt) of 60% were documented. Extravascular lung water (EVLW) increased 66%, mean arterial pressure (MAP) decreased 46% and oxygen delivery decreased 52%, leading to a metabolic acidosis. Three animals died during the observation period. Contrastingly, eight pigs, pretreated with NAC 150 mg.kg-1 which was continued at 20 mg.kg-1.h-1, showed a significantly attenuated response to E. Thus, leukocyte and platelet counts decreased 70% and 48%, respectively. Physiologically Qva/Qt increased 2.5-3 fold, MPAP increased 1.3-2 fold, and Qt decreased 32%. EVLW increased 27%, MAP decreased 27% and oxygen delivery decreased only 33% which kept the pH in the normal range. All animals survived the observation period, a significant difference from the E alone group. Thus, NAC significantly attenuated all monitored haematological and pathophysiological changes in the endotoxin model of ARDS in pigs. In addition to a reported free radical scavenger effect of NAC, our results support the assumption that NAC may counteract leukocyte and platelet aggregation in the lung thereby contributing to the beneficial outcome.}, }
@article {pmid3360092, year = {1988}, author = {Paulsen, O and Borgström, L and Kågedal, B and Walder, M}, title = {No effect of oral N-acetylcysteine on the bioavailability of erythromycin and bacampicillin.}, journal = {The European respiratory journal}, volume = {1}, number = {2}, pages = {171-175}, pmid = {3360092}, issn = {0903-1936}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Adult ; Ampicillin/*analogs &amp; derivatives/pharmacokinetics ; Biological Availability ; Erythromycin/*pharmacokinetics ; Female ; Humans ; Male ; Middle Aged ; }, abstract = {In vitro studies with N-acetylcysteine (NAC) solutions used for inhalation treatment have demonstrated inactivation of some antibiotics by NAC. Oral NAC treatment is increasingly common for long-term prophylaxis in chronic bronchitis. During exacerbations, treatment with oral antibiotics will often be given simultaneously. We assessed the effect of simultaneous oral administration of NAC on the bioavailability of two antibiotics in ten healthy volunteers. No effect of NAC was found on the bioavailability of ampicillin, after administration of the prodrug bacampicillin. A slight, but not significant statistical increase in erythromycin serum levels was seen with NAC. Acetylator phenotype did not influence the absorption of NAC, which seemed slightly reduced by bacampicillin, but significantly increased by erythromycin. No decrease of antibacterial activity of sera was found in vitro after the addition of NAC or the related thiol glutathione, employing micrococcus luteus and staphylococcus aureus as indicator organisms.}, }
@article {pmid3282911, year = {1988}, author = {Stafanger, G and Garne, S and Howitz, P and Morkassel, E and Koch, C}, title = {The clinical effect and the effect on the ciliary motility of oral N-acetylcysteine in patients with cystic fibrosis and primary ciliary dyskinesia.}, journal = {The European respiratory journal}, volume = {1}, number = {2}, pages = {161-167}, pmid = {3282911}, issn = {0903-1936}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Child ; Child, Preschool ; Cilia/*drug effects/physiology ; Ciliary Motility Disorders/drug therapy/*physiopathology ; Clinical Trials as Topic ; Cystic Fibrosis/drug therapy/*physiopathology ; Double-Blind Method ; Female ; Forced Expiratory Volume ; Humans ; In Vitro Techniques ; Infant ; Male ; Peak Expiratory Flow Rate ; Respiratory System/physiopathology ; Vital Capacity ; }, abstract = {The effect of peroral N-acetylcysteine (NAC) in patients with cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) was investigated. 41 CF patients and 13 PCD patients completed the study which was a double-blind, placebo-controlled, cross-over trial. The patients received either NAC or placebo for two periods of three months followed by a three month follow-up period. Active treatment consisted of NAC, either 200 mg x 3 daily (patients weighing less than 30 kg) or 400 mg x 2 daily (greater than 30 kg). The effect was evaluated in terms of a subjective clinical score, weight, sputum bacteriology, blood leucocyte count, sedimentation rate, titres of specific antimicrobial antibodies, lung function parameters and measurement of the ciliary function. No effect was seen in PCD patients, but in CF patients an improved lung function was seen in the period when the patients suffer most from lower airway infections.}, }
@article {pmid3406571, year = {1988}, author = {Bébéar, JP and Darrouzet, V}, title = {[Efficacy of N-acetylcysteine by oral route in chronic sinusitis].}, journal = {Revue de laryngologie - otologie - rhinologie}, volume = {109}, number = {2}, pages = {185-186}, pmid = {3406571}, issn = {0035-1334}, mesh = {Acetylcholine/administration &amp; dosage ; Acetylcysteine/*therapeutic use ; Administration, Oral ; Chronic Disease ; Drug Evaluation ; Humans ; Sinusitis/*drug therapy ; }, }
@article {pmid3402554, year = {1988}, author = {Honda, S and Matsuo, M}, title = {Relationships between the cellular glutathione level and in vitro life span of human diploid fibroblasts.}, journal = {Experimental gerontology}, volume = {23}, number = {2}, pages = {81-86}, doi = {10.1016/0531-5565(88)90072-1}, pmid = {3402554}, issn = {0531-5565}, mesh = {Acetylcysteine ; Antimetabolites ; Buthionine Sulfoximine ; Cell Survival ; Cells, Cultured ; Culture Media ; Fibroblasts/*physiology ; Glutathione/*physiology ; Humans ; In Vitro Techniques ; Methionine Sulfoximine/analogs &amp; derivatives ; }, abstract = {In order to examine the role of cellular glutathione (GSH) in the in vitro aging of human diploid fibroblasts, we studied the effects of manipulated cellular GSH levels on their in vitro life span. An increase in cellular GSH level was produced by the addition of N-acetylcysteine (NAC), a carrier of cysteine across cell membranes, into the culture medium, while a decrease in GSH level was produced by the addition of L-buthionine-(R,S)-sulfoximine (BSO), a specific inhibitor of GSH synthetase. When the cells were serially subcultivated in a medium containing NAC or BSO, their life spans were markedly extended or shortened, respectively, in comparison to the life span of cells grown in a control medium. These results suggest that the cellular GSH level is a determinant of the in vitro life span of human diploid cells.}, }
@article {pmid3378280, year = {1988}, author = {Mertens, JJ and Weijnen, JG and van Doorn, WJ and Spenkelink, B and Temmink, JH and van Bladeren, PJ}, title = {Differential toxicity as a result of apical and basolateral treatment of LLC-PK1 monolayers with S-(1,2,3,4,4-pentachlorobutadienyl)glutathione and N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine.}, journal = {Chemico-biological interactions}, volume = {65}, number = {3}, pages = {283-293}, doi = {10.1016/0009-2797(88)90113-5}, pmid = {3378280}, issn = {0009-2797}, mesh = {Acetylcysteine/administration &amp; dosage/*analogs &amp; derivatives/pharmacology/toxicity ; Aminooxyacetic Acid/pharmacology ; Animals ; Anion Transport Proteins ; Anions ; Biological Transport ; Butadienes/administration &amp; dosage/pharmacology/*toxicity ; Carrier Proteins/metabolism ; Cations ; Cell Line ; Cell Survival/drug effects ; Epithelial Cells ; Epithelium/metabolism ; Glutathione/administration &amp; dosage/*analogs &amp; derivatives/pharmacology/toxicity ; Isoxazoles/pharmacology ; Kidney/cytology/metabolism ; Kidney Diseases/*chemically induced ; Swine ; Tetraethylammonium ; Tetraethylammonium Compounds/metabolism ; p-Aminohippuric Acid/metabolism ; }, abstract = {Monolayers of LLC-PK1 cells, a cell line with features typical of proximal tubular epithelial cells, were treated at the apical and basolateral side with S-(1,2,3,4,4-pentachlorobutadienyl)glutathione (PCBD-GSH) and N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBD-NAC). Apical treatment with PCBD-GSH (greater than 20 microM) resulted in cytotoxicity, which could be inhibited by acivicin and aminooxyacetic acid (AOAA), inhibitors of gamma-glutamyltranspeptidase (gamma GT) and beta-lyase respectively. In contrast apical treatment with PCBD-NAC was only toxic at high concentrations (greater than 850 microM), and this effect could hardly be inhibited by AOAA. Basolateral treatment of confluent LLC-PK1 monolayers, grown on porous membranes, with PCBD-GSH gave a much smaller response than apical treatment, consistent with the fact that gamma GT is predominantly present at the apical side. Basolateral treatment even with high concentrations of PCBD-NAC (1.1 mM) did not show an increase in cytotoxicity when compared to the effect after apical treatment. These results suggest the absence of an organic anion transporter, by which these conjugates in vivo are transported into the cells from the basolateral side. This supposition was substantiated in a study of transcellular transport of the model ions tetraethyl ammonium (TEA) and para-aminohippurate (PAH), in LLC-PK1 monolayers, grown as indicated above. No active PAH transport could be demonstrated, whereas an active TEA transport was present. The absence of an organic anion transporter limits the usefulness of LLC-PK1 cells for the study of nephrotoxicity of compounds, like PCBD-NAc, needing this transport to enter the cells. However, the finding of an active basolateral organic cation transporter, together with the presence of gamma GT, dipeptidase and beta-lyase, makes this system especially interesting for testing all compounds that use this transporter or these enzymes in order to elicit toxicity.}, }
@article {pmid3377687, year = {1988}, author = {Llobet, JM and Domingo, JL and Corbella, J}, title = {Antidotes for zinc intoxication in mice.}, journal = {Archives of toxicology}, volume = {61}, number = {4}, pages = {321-323}, pmid = {3377687}, issn = {0340-5761}, mesh = {Acetates/poisoning ; Acetic Acid ; Animals ; Antidotes/administration &amp; dosage/*pharmacology ; Chelating Agents/administration &amp; dosage/*pharmacology ; Injections, Intraperitoneal ; Lethal Dose 50 ; Male ; Mice ; Zinc/*poisoning ; }, abstract = {Sixteen chelating agents were examined to determine their relative efficacy as antidotes in acute zinc acetate intoxication in mice after i.p. administration. For a i.p. dose of 0.49 mmol/kg (LD50) of zinc acetate, the i.p. administration of chelating agents at a 2:1 and 5:1 mole ratio resulted in a significant antidotal action for EDTA, DTPA, CDTA, D-penicillamine (D-PA), DMPS and DMSA. EGTA, L-cysteine, triethylentetraamine (TTHA), N-acetylcysteine (NAC), 4,5-dihydroxi-1,3-benzenedisulfonic acid (Tiron), sodium salicylate, glutathione, sodium diethyldithiocarbamate (DDC), 6-mercaptopurine and N-acetyl-D, L-penicillamine (NAPA) were not effective for acute zinc acetate poisoning. The therapeutic indices and therapeutic effectiveness of the most effective chelators were, respectively: EDTA (5.0, 7.0), DTPA (7.3, 13.7), CDTA (8.6, 6.3), D-PA (4.6, 1.9), DMPS (1.3, 1.0), DMSA (3.2, 5.4). DTPA, CDTA, and EDTA appear to be the most effective agents of those tested in offsetting acute zinc intoxication in mice.}, }
@article {pmid3376355, year = {1988}, author = {Wegener, T and Sandhagen, B and Chan, KW and Saldeen, T}, title = {N-acetylcysteine in paraquat toxicity: toxicological and histological evaluation in rats.}, journal = {Upsala journal of medical sciences}, volume = {93}, number = {1}, pages = {81-89}, doi = {10.1517/03009734000000041}, pmid = {3376355}, issn = {0300-9734}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Body Weight/drug effects ; Lung/*drug effects/pathology ; Male ; Organ Size/drug effects ; Paraquat/antagonists &amp; inhibitors/*toxicity ; Pulmonary Edema/chemically induced/pathology/prevention &amp; control ; Rats ; Rats, Inbred Strains ; }, abstract = {The therapeutic effect of N-acetylcysteine (NAC) in paraquat-treated rats was investigated. The animals were divided into four groups: A = control; B = NAC; C = paraquat; D = NAC + paraquat. In the appropriate groups, paraquat 20 mg/kg body weight was administered intraperitoneally and 1% NAC solution was provided as drinking water. All surviving rats were killed on the seventh day after paraquat exposure. The lungs were graded histologically on the basis of oedema and cellular infiltration. On histological examination, the lungs of poisoned rats that had received NAC displayed a tendency towards less oedema and cellular infiltration than those of poisoned rats not treated with NAC. It is concluded that NAC might afford some therapeutic effect against paraquat toxicity in rats.}, }
@article {pmid3367379, year = {1988}, author = {Ceconi, C and Curello, S and Cargnoni, A and Ferrari, R and Albertini, A and Visioli, O}, title = {The role of glutathione status in the protection against ischaemic and reperfusion damage: effects of N-acetyl cysteine.}, journal = {Journal of molecular and cellular cardiology}, volume = {20}, number = {1}, pages = {5-13}, doi = {10.1016/s0022-2828(88)80174-3}, pmid = {3367379}, issn = {0022-2828}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Coronary Disease/*prevention &amp; control ; Creatine Kinase/metabolism ; Free Radicals ; Glutathione/*physiology ; Lactates/metabolism ; Mitochondria, Heart/physiology ; Perfusion ; Rabbits ; }, abstract = {It is known that myocardial ischaemia causes a marked decline of cellular thiol pool and of protein sulphydryl groups content. Reperfusion under these conditions results in oxydative damage which is concomitant with poor recovery of mechanical function. We have evaluated the role of glutathione status in the protection against ischaemic and reperfusion damage by treating the isolated rabbit hearts with N-acetylcysteine (10(-6) M), a sulphydryl group donor. Ischaemic and reperfusion damage was determined in terms of mechanical function, rate of lactate and creatine kinase (CPK) release, mitochondrial function and tissue content of reduced (GSH) and oxidized (GSSG) glutathione and of protein sulphydryl groups (SH). After 60 mins of ischaemia (induced by reducing coronary flow from 24 to 1 ml/min) followed by 30 mins of reperfusion there was an increase of diastolic pressure to 51.6 +/- 3.5 mmHg with only a 22% recovery of systolic pressure, massive CPK release and a deterioration in mitochondrial function. Tissue contents of GSH and of protein SH were severely decreased, while those of GSSG were increased. The GSH/GSSG ratio was reduced from the aerobic value of 50 to 13.4, suggesting that an oxidative stress has occurred. N-acetylcysteine infused for 60 mins before ischaemia determined a 38% increase in tissue content of GSH with no major changes of GSSG or protein SH. The ischaemic-induced decrease of GSH and protein SH was also limited by pretreatment with N-acetylcysteine and there was no accumulation of GSSG after reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid3366508, year = {1988}, author = {Kharazmi, A and Nielsen, H and Schiøtz, PO}, title = {N-acetylcysteine inhibits human neutrophil and monocyte chemotaxis and oxidative metabolism.}, journal = {International journal of immunopharmacology}, volume = {10}, number = {1}, pages = {39-46}, doi = {10.1016/0192-0561(88)90148-8}, pmid = {3366508}, issn = {0192-0561}, mesh = {Acetylcysteine/*pharmacology ; Catalase ; Cell Survival/drug effects ; Chemotaxis, Leukocyte/*drug effects ; Humans ; In Vitro Techniques ; Luminescent Measurements ; Monocytes/immunology/*metabolism ; N-Formylmethionine Leucyl-Phenylalanine/pharmacology ; Neutrophils/immunology/*metabolism ; Oxygen Consumption/drug effects ; Superoxide Dismutase/pharmacology ; Zymosan/pharmacology ; }, abstract = {The effect of N-acetylcysteine (NAC) on human neutrophil and monocyte cell viability, chemotaxis, oxygen consumption and chemiluminescence was studied. It was found that NAC at concentrations higher than 3 X 10(-2) M resulted in neutrophil and monocyte cytotoxicity. The studies on the effect of NAC on neutrophil and monocyte chemotaxis showed that NAC inhibited chemotaxis of both cell types in a concentration dependent manner. NAC at 3 X 10(-2) M inhibited chemotaxis of both cell types by about 50% and at 10(-1) M inhibited PMN chemotaxis by 95% and MNL chemotaxis by 85%. The studies on the effect of NAC on neutrophil chemiluminescence demonstrated that NAC at concentrations of 1.5 X 10(-2) M, or higher, inhibited the response of the activated cells totally. When pH adjusted NAC or Mucomyst was used the inhibition was observed with higher concentrations of the drug (1.5 X 10(-1) M). NAC exhibited a similar pattern of inhibition on monocyte chemiluminescence response. These findings demonstrate that NAC, at concentrations obtainable in vivo by inhalation, impairs the chemotaxis and generation of oxygen radicals by human phagocytic cells. This property of NAC could have important implications concerning the prevention of tissue damage caused by these cells in inflammatory areas.}, }
@article {pmid3360052, year = {1988}, author = {Olsson, B and Johansson, M and Gabrielsson, J and Bolme, P}, title = {Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine.}, journal = {European journal of clinical pharmacology}, volume = {34}, number = {1}, pages = {77-82}, pmid = {3360052}, issn = {0031-6970}, mesh = {Acetylcysteine/administration &amp; dosage/blood/metabolism/*pharmacokinetics ; Administration, Oral ; Adult ; Biological Availability ; Drug Administration Schedule ; Female ; Half-Life ; Humans ; Injections, Intravenous ; Male ; Oxidation-Reduction ; Random Allocation ; Statistics as Topic ; Tablets ; Time Factors ; }, abstract = {The pharmacokinetics and bioavailability of N-acetylcysteine (NAC) have been determined after its intravenous and oral administration to 6 healthy volunteers. According to a randomized cross-over design each subject received NAC 200 mg i.v. and 400 mg p.o., and blood samples were collected for 30 h. Reduced NAC had a volume of distribution (VSS) of 0.59 l.kg-1 and a plasma clearance of 0.84 l.h-1.kg-1. The terminal half-life after intravenous administration was 1.95 h. The oral bioavailability was 4.0%. Based on total NAC concentration, its volume of distribution (VSS) was 0.47 l.kg-1 and its plasma clearance was 0.11 l.h-1.kg-1. The terminal half-life was 5.58 h after intravenous administration and 6.25 h after oral administration. Oral bioavailability of total NAC was 9.1%.}, }
@article {pmid3345250, year = {1988}, author = {Jensen, T and Kharazmi, A and Schiøtz, PO and Nielsen, H and Stenvang Pedersen, S and Stafanger, G and Koch, C and Høiby, N}, title = {Effect of oral N-acetylcysteine administration on human blood neutrophil and monocyte function.}, journal = {APMIS : acta pathologica, microbiologica, et immunologica Scandinavica}, volume = {96}, number = {1}, pages = {62-67}, doi = {10.1111/j.1699-0463.1988.tb05269.x}, pmid = {3345250}, issn = {0903-4641}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Chemotaxis, Leukocyte/drug effects ; Humans ; Luminescent Measurements ; Monocytes/*drug effects/physiology ; Neutrophils/*drug effects/physiology ; }, abstract = {N-acetylcysteine (NAC) is known to be a scavenger of free oxygen radicals, and recent in vitro studies have demonstrated that it is also able to inhibit leukocyte function. The clinical significance of these effects is, however, not known. In this study we have measured the effect on human blood neutrophil and monocyte function of a single 400 mg dose of NAC administered orally. Administration of NAC to ten healthy volunteers resulted in significant reduction of neutrophil chemiluminescence response following activation by opsonized zymosan as compared to four non-treated persons acting as controls. No effect was observed on the chemotaxis of either cell type or on monocyte chemiluminescence response. These findings suggest that NAC may be beneficial in clinical conditions like cystic fibrosis, where tissue damage may be a consequence of the effects of increased release of toxic oxygen radicals and proteolytic enzymes.}, }
@article {pmid3246214, year = {1988}, author = {Scuri, R and Giannetti, P and Paesano, A}, title = {Effect of erdosteine and its metabolites on tracheobronchial mucus production and transport.}, journal = {Drugs under experimental and clinical research}, volume = {14}, number = {11}, pages = {693-698}, pmid = {3246214}, issn = {0378-6501}, mesh = {Administration, Oral ; Animals ; Bronchi/drug effects/*metabolism ; Columbidae ; *Expectorants ; Injections, Intravenous ; Lethal Dose 50 ; Male ; Mice ; Mucociliary Clearance/drug effects ; Mucus/drug effects/*metabolism ; Rabbits ; Thioglycolates/metabolism/*pharmacology ; Thiophenes/metabolism/*pharmacology ; Trachea/drug effects/*metabolism ; }, abstract = {The effect of erdosteine and its metabolites on tracheobronchial mucus production and transport was studied. Erdosteine showed important muco-regulating action (increase of mucus production), and also influenced muciliary clearance. Erdosteine, after intravenous administration, was more active than the muco-regulating drugs used for comparative purposes (about 4 times as active as N-acetyl-cysteine; about 1.8 times as active as sobrerol and bromexine; and about 1.4 times as active as ambroxol). After oral administration erdosteine showed significant action on mucus production, causing an effect quantitatively the same as that produced by bromexine. Erdosteine and its metabolites also increased TMV in pigeons after intravenous administration. Moreover, erdosteine and its metabolites were significantly active and their acute toxicity was extremely low.}, }
@article {pmid3242443, year = {1988}, author = {Pratt, IS and Lock, EA}, title = {Deacetylation and further metabolism of the mercapturic acid of hexachloro-1,3-butadiene by rat kidney cytosol in vitro.}, journal = {Archives of toxicology}, volume = {62}, number = {5}, pages = {341-345}, pmid = {3242443}, issn = {0340-5761}, mesh = {Acetylation ; Acetylcysteine/*analogs &amp; derivatives/*metabolism ; Aminooxyacetic Acid/pharmacology ; Animals ; Binding, Competitive ; Butadienes/*metabolism ; Cytosol/*metabolism ; Female ; Fungicides, Industrial/*metabolism ; In Vitro Techniques ; Kidney/*metabolism ; Male ; Rats ; Rats, Inbred Strains ; Sex Factors ; }, abstract = {Hexachloro-1,3-butadiene (HCBD) is more nephrotoxic to female than male rats. Metabolism of HCBD involves conjugation with glutathione followed by formation of the cysteine conjugate S-(pentachloro-1,3-butadienyl) cysteine (PCBD-CYS) and then the mercapturic acid N-acetyl-S-pentachloro-1,3-butadienyl-cysteine (PCBD-NAC). PCBD-NAC is also more nephrotoxic to female rats than male rats. The deacetylation of [14C]-PCBD-NAC to PCBD-CYS and the binding of radiolabelled metabolites to protein has been studied using renal cytosol preparations from male and female rats in vitro, since a sex-related difference in these reactions could explain the difference in nephrotoxicity found in vivo. PCBD-NAC was rapidly metabolised by renal cytosol. The rate of metabolism was similar with either male or female renal cytosol, and the major metabolite identified was PCBD-CYS. N-Acetylation of PCBD-CYS to PCBD-NAC was not detected in the presence of either male or female renal cytosol. Covalent binding of radioactivity from [14C]-PCBD-NAC to cytosolic protein could be detected after 5 min incubation, and although the extent of binding was similar for both male and female cytosol at early time periods, after 60 min incubation more binding was found in the presence of male cytosol. Covalent binding was largely prevented by aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, suggesting a role for this enzyme in the activation of HCBD. These results indicate that the sex differences in the nephrotoxicity of HCBD and PCBD-NAC in the rat are not attributable to differences in the rate of deacetylation of PCBD-NAC to give the proximate nephrotoxin PCBD-CYS.}, }
@article {pmid3203410, year = {1988}, author = {Pascoe, GA and Calleman, CJ and Baille, TA}, title = {Identification of S-(2,5-dihydroxyphenyl)-cysteine and S-(2,5-dihydroxyphenyl)-N-acetyl-cysteine as urinary metabolites of acetaminophen in the mouse. Evidence for p-benzoquinone as a reactive intermediate in acetaminophen metabolism.}, journal = {Chemico-biological interactions}, volume = {68}, number = {1-2}, pages = {85-98}, doi = {10.1016/0009-2797(88)90008-7}, pmid = {3203410}, issn = {0009-2797}, support = {DK 30699/DK/NIDDK NIH HHS/United States ; }, mesh = {Acetaminophen/*urine ; Acetylcysteine/*analogs &amp; derivatives/urine ; Animals ; *Benzoquinones ; Chromatography, High Pressure Liquid ; Cysteine/*analogs &amp; derivatives/urine ; Hydroquinones/urine ; Male ; Mice ; Mice, Inbred BALB C ; Quinones/*urine ; }, abstract = {S-(2,5-Dihydroxyphenyl)-cysteine and S-(2,5-dihydroxyphenyl)-N-acetyl-cysteine [the cysteine- and N-acetyl-cysteine adducts, respectively, of hydroquinone (HQ)] were identified and quantified in the urine of mice administered [ring-U-14C]acetaminophen [14C]APAP, 200 mg kg-1, i.p.). Urine was collected for 24 h and fractionated by HPLC to isolate the above adducts. These conjugates were then converted to a common derivative, viz. O,O',S-tris-acetyl-3-thio-hydroquinone, which was characterized by GC/MS. Neither of the HQ adducts was detected in the urine of control mice which had not received APAP. Quantification of urinary HQ-cysteine and HQ-N-acetyl-cysteine was performed by HPLC techniques, which indicated that these conjugates accounted for approx. 1.5% of the administered dose of APAP after 24 h, a figure which is equivalent to 6.3% of the corresponding APAP-thiol conjugates in the urine. These findings provide strong indirect evidence that p-benzoquinone is formed as a reactive, but apparently non-hepatotoxic, metabolite of APAP in vivo.}, }
@article {pmid3173602, year = {1988}, author = {Davenport, A and Finn, R}, title = {Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepatic coma.}, journal = {Nephron}, volume = {50}, number = {1}, pages = {55-56}, doi = {10.1159/000185117}, pmid = {3173602}, issn = {1660-8151}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Acute Kidney Injury/*chemically induced/complications/drug therapy ; Adult ; Female ; Hepatic Encephalopathy/*chemically induced ; Humans ; Kidney Tubular Necrosis, Acute/chemically induced ; Male ; }, abstract = {We report two cases of acute renal failure following paracetamol (acetaminophen) poisoning. Both received adequate treatment with N-acetyl cysteine and neither showed any evidence of fulminant liver damage, yet acute renal failure due to tubular necrosis developed.}, }
@article {pmid3150654, year = {1988}, author = {Jastrzebski, Z and Danysz, A and Czyzewska-Szafran, H and Czarnomska, A}, title = {The effect of sodium-2-mercaptoethane-sulphonate, N-acetylcysteine and cysteine on the uptake of cytosine arabinoside by normal and neoplastic thymus cells of mice.}, journal = {Archivum immunologiae et therapiae experimentalis}, volume = {36}, number = {3}, pages = {335-343}, pmid = {3150654}, issn = {0004-069X}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cells, Cultured ; Cysteine/*pharmacology ; Cytarabine/*pharmacokinetics ; Female ; Male ; Mercaptoethanol/*analogs &amp; derivatives ; Mesna/*pharmacology ; Mice ; Thymus Gland/cytology/*metabolism ; Thymus Neoplasms/*metabolism ; Tumor Cells, Cultured ; }, abstract = {The effect of some sulfhydryl compounds on the uptake of cytosine arabinoside (Ara-C) by normal and neoplastically transformed mouse thymus cells was studied. Sodium 2-mercaptoethanesulphonate (Mesna) was found to greatly inhibit (in 80%) the uptake of Ara-C by normal cells. Two other SH-compounds (cysteine and N-acetyl-cysteine) displayed no such effect. None of the three compounds reduced the uptake of Ara-C by neoplastic thymus cells. The possible pharmacological implications of these findings are discussed.}, }
@article {pmid3137075, year = {1988}, author = {Horowitz, JD and Henry, CA and Syrjanen, ML and Louis, WJ and Fish, RD and Antman, EM and Smith, TW}, title = {Nitroglycerine/N-acetylcysteine in the management of unstable angina pectoris.}, journal = {European heart journal}, volume = {9 Suppl A}, number = {}, pages = {95-100}, doi = {10.1093/eurheartj/9.suppl_a.95}, pmid = {3137075}, issn = {0195-668X}, mesh = {Acetylcysteine/administration &amp; dosage/adverse effects/*therapeutic use ; Angina Pectoris/*drug therapy ; Angina, Unstable/blood/*drug therapy ; Double-Blind Method ; Drug Therapy, Combination ; Female ; Humans ; Hypotension/chemically induced ; Infusions, Intravenous ; Male ; Middle Aged ; Nitroglycerin/*administration &amp; dosage/adverse effects ; Random Allocation ; }, abstract = {N-acetylcysteine (NAC) has been shown to potentiate the haemodynamic and antiplatelet effects of nitroglycerine (NTG) in man, and to limit the development of haemodynamic tolerance to NTG. These effects may be mediated. by the formation of S-nitroso-NAC, which induces vasodilation and strongly inhibits platelet aggregation. In a randomized double-blind study in 46 patients with severe unstable angina pectoris unresponsive to standard treatment (including cutaneous nitrates and calcium antagonists in 45 patients) we compared the effects of intravenous (IV) NTG with those of IV NTG combined with IV NAC (5 g 6 hourly). Treatment with NTG/NAC (24 patients) was associated with a similar frequency of episodes of chest pain as treatment with NTG alone (22 patients), but somewhat fewer increments in infusion rate for pain control (10 vs 17; P NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (3 vs 10 patients; P = 0.013). Symptomatic hypotension occurred frequently in the NTG/NAC group (7 vs 0 patients; P = 0.006). It is concluded that combined administration of NTG and NAC in patients with unstable angina pectoris may augment the clinical efficacy of NTG, largely by reducing the incidence of acute myocardial infarction. However, the high incidence of severe hypotension with NTG/NAC suggests that this regimen should be used with some caution.}, }
@article {pmid3133228, year = {1988}, author = {Ericson, D and Schrewelius, C and Bratthall, D}, title = {N-acetylcysteine added to saliva does not affect IgA concentration or the agglutination of Streptococcus mutans in vitro.}, journal = {European journal of clinical pharmacology}, volume = {34}, number = {2}, pages = {201-205}, pmid = {3133228}, issn = {0031-6970}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Agglutination ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunodiffusion ; Immunoelectrophoresis ; Immunoglobulin A/*analysis ; Saliva/*analysis/immunology ; Streptococcus mutans/*immunology ; Tablets ; }, abstract = {N-acetylcysteine (NAC) or placebo were mixed with parotid or whole saliva to a final concentration of 0.004-10 mg/ml saliva. Placebo and NAC-containing parotid saliva had the same bacterial agglutinating capacity for 4 strains of Streptococcus mutans. Immunoglobulin A (IgA) concentration in whole saliva, using ELISA and single radial immunodiffusion assays, did not reveal any differences between NAC and placebo-treated samples. NAC did not affect the immunoelectrophoretic pattern of IgA.}, }
@article {pmid3066411, year = {1988}, author = {Fitzgerald, JE and Green, GG and Birchall, JP and Pearson, JP}, title = {Mucolytic agents and otitis media with effusion.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {42}, number = {8}, pages = {505-511}, pmid = {3066411}, issn = {0753-3322}, mesh = {Amino Acids/analysis ; Child ; Child, Preschool ; Expectorants/*pharmacology ; Glycoproteins/analysis ; Humans ; In Vitro Techniques ; Infant ; Mucus/analysis/drug effects/*physiopathology ; Otitis Media with Effusion/*physiopathology ; Viscosity ; }, abstract = {Middle ear effusion was obtained from children with otitis media with effusion and separated into thick (mucoid) and thin (serous) pools. Both effusion types contained similar amounts of non-dialysable solids. However, the thick effusions contained more mucus glycoprotein than the thin effusions, 25% and 8.2% respectively. Amino acid and carbohydrate analysis of the CsCl purified mucus glycoproteins demonstrated that the glycoprotein from the thick and thin effusions differed in their protein core, those from the thick effusions possessing a higher percentage of serine and threonine, the amino acids to which the sugar side-chains attach. They are also more glycosylated. N-acetyl cysteine and mercaptoethanol caused a fall in the viscosity of solutions of purified middle ear glycoprotein and effusion homogenate. However, longer term incubation caused a rise above the starting viscosity. This effect was concentration-dependent, and was mediated by low molecular weight components in the effusion and not the mucus glycoprotein. S-carboxymethyl cysteine had no effect on the viscosity of either the purified mucus glycoprotein or the effusion homogenate. Therefore, to produce a decrease in effusion viscosity in vivo, the concentration of mucolytic reaching the middle ear and the time it remains there are critical factors.}, }
@article {pmid3061790, year = {1988}, author = {Patterson, CE and Rhoades, RA}, title = {Protective role of sulfhydryl reagents in oxidant lung injury.}, journal = {Experimental lung research}, volume = {14 Suppl}, number = {}, pages = {1005-1019}, doi = {10.3109/01902148809064189}, pmid = {3061790}, issn = {0190-2148}, support = {R01 HL 36745/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Antioxidants/*therapeutic use ; Drug Synergism ; Glutathione/metabolism/therapeutic use ; Lung/drug effects/metabolism ; Lung Diseases/*prevention &amp; control ; Oxidation-Reduction ; Oxygen/poisoning ; Paraquat/poisoning ; Sulfhydryl Compounds/pharmacology/*therapeutic use ; }, abstract = {Recently there has been a great deal of interest in exploring possible ways to protect the lung from oxidant damage. Since sulfhydryl compounds are among the most important endogenous antioxidants, their therapeutic use has been proposed. Glutathione (GSH), the main intracellular nonprotein sulfhydryl, plays an important role in the maintenance of cellular proteins and lipids in their functional state. With oxidant stress, GSH acts to protect cell constituents as evidenced by increased turnover to GSSG, formation of mixed disulfides with proteins, utilization of NADPH, and utilization of glucose in the pentose pathway. When GSH is experimentally lowered (e.g., by protein deficiency or with diethylmaleate) the toxic effects of oxidant stress are exacerbated as evidenced by increased membrane and cell damage, pulmonary edema, and mortality. Several recent investigations have shown that sulfhydryl reagents (particularly N-acetyl cysteine, a cell-permeable GSH precursor) can provide significant protection against certain pulmonary toxins. N-acetyl cysteine reduced the lethal effects of 100% O2 in rats by 65%. Therefore, the therapeutic potential of sulfhydryl reagents in the treatment and prevention of oxidant injury and the mechanisms involved are an important direction for lung research.}, }
@article {pmid2980408, year = {1988}, author = {Endo, A and Watanabe, T}, title = {Analysis of protective activity of N-acetylcysteine against teratogenicity of heavy metals.}, journal = {Reproductive toxicology (Elmsford, N.Y.)}, volume = {2}, number = {2}, pages = {141-144}, doi = {10.1016/0890-6238(88)90010-x}, pmid = {2980408}, issn = {0890-6238}, mesh = {Abnormalities, Drug-Induced/*prevention &amp; control ; Acetylcysteine/*therapeutic use ; Animals ; Cadmium Poisoning/*prevention &amp; control ; Chromium/antagonists &amp; inhibitors/*poisoning ; Drug Synergism ; Mercury Poisoning/*prevention &amp; control ; Mice ; Mice, Inbred ICR ; }, abstract = {N-acetylcysteine (NAC) is known to enhance the renal excretion of heavy metals. Therefore, we investigated whether the teratogenicity of metals (Hg, Cr, and Cd) can be ameliorated by NAC in mice. Contrary to our expectation, the incidence of congenital malformations produced by these metals was two to three times higher in the mice that were fed NAC (0.2% in the diet). The underlying mechanism or mechanisms are unknown and should be investigated.}, }
@article {pmid2899918, year = {1988}, author = {Wong, M and Wells, PG}, title = {Effects of N-acetylcysteine on fetal development and on phenytoin teratogenicity in mice.}, journal = {Teratogenesis, carcinogenesis, and mutagenesis}, volume = {8}, number = {2}, pages = {65-79}, doi = {10.1002/tcm.1770080202}, pmid = {2899918}, issn = {0270-3211}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Embryonic and Fetal Development/*drug effects ; Female ; Mice ; Mice, Inbred Strains ; Phenytoin/*toxicity ; Pregnancy ; *Teratogens ; }, abstract = {The teratogenicity of phenytoin may result from its enzymatic bioactivation to a reactive intermediate, which interacts irreversibly with fetal tissues. Since glutathione (GSH) is involved in the detoxification of many reactive intermediates, N-acetylcysteine (NAC), a glutathione precursor, was evaluated for its effects on murine fetal development and phenytoin teratogenicity. NAC, 100 to 275 mg/kg, was given intraperitoneally (ip) or per os (po), or as 266 to 410 mg/kg in the drinking water, at various times before or after phenytoin, 65 to 75 mg/kg ip, on gestational days 12 and 13. Dams were killed on gestational day 19, fetal resorptions were noted, and fetuses were examined for anomalies. Significant reductions in phenytoin-induced fetal weight loss and cleft palates were observed when NAC was given by gavage 6 hours after phenytoin or in the drinking water with the lower dose of phenytoin. NAC administered in the drinking water also reduced the incidence of resorptions produced by the higher dose of phenytoin and enhanced postpartum survival in fetuses exposed to 65 or 75 mg/kg phenytoin (P less than .05). Conversely, the incidence of resorptions increased when NAC was given by gavage at other times before or after phenytoin, by single or repetitive ip injections, or in high concentrations in the drinking water (P less than .05). When given with the higher dose of phenytoin, NAC administered via the drinking water significantly increased the incidence of phenytoin-induced cleft palates and fetal weight loss (P less than .05). Similar results were obtained with a single ip injection of NAC and a lower dose of phenytoin. Thus, when given orally, NAC can partially reduce phenytoin teratogenicity and embryopathy. However, altering the route of NAC administration, or increasing the dose of phenytoin and/or NAC, enhanced phenytoin embryotoxicity, and NAC alone at higher doses had embryopathic effects.}, }
@article {pmid2833080, year = {1987}, author = {Borregaard, N and Jensen, HS and Bjerrum, OW}, title = {Prevention of tissue damage: inhibition of myeloperoxidase mediated inactivation of alpha 1-proteinase inhibitor by N-acetyl cysteine, glutathione, and methionine.}, journal = {Agents and actions}, volume = {22}, number = {3-4}, pages = {255-260}, pmid = {2833080}, issn = {0065-4299}, mesh = {Acetylcysteine/*pharmacology ; Blood Proteins/*antagonists &amp; inhibitors/pharmacology ; Chlorides/metabolism ; Glutathione/*pharmacology ; Humans ; Hydrogen Peroxide/metabolism ; Methionine/*pharmacology ; Pancreatic Elastase/antagonists &amp; inhibitors ; Peroxidase/*metabolism ; Protease Inhibitors ; alpha 1-Antitrypsin ; }, abstract = {The ability of the sulphur compounds, N-acetyl cysteine, Methionine, and Glutathione to prevent inactivation of alpha 1-proteinase inhibitor by Myeloperoxidase-H2O2-Cl--system was investigated in vitro with purified components. The Myeloperoxidase system, or its main product HOCl by itself, readily abrogated the ability of alpha 1-proteinase inhibitor to inhibit elastase. This inactivation of alpha 1-proteinase inhibitor was effectively prevented by micromolar concentrations of N-acetyl cysteine, Methionine and reduced Glutathione, whereas oxidized Glutathione was much less effective. These results indicate that the sulphydryl compounds work as scavengers of the products of the Myeloperoxidase system, and might be useful in inflammatory disorders, to prevent tissue damage inflicted by this system.}, }
@article {pmid3663288, year = {1987}, author = {Ekins, BR and Ford, DC and Thompson, MI and Bridges, RR and Rollins, DE and Jenkins, RD}, title = {The effect of activated charcoal on N-acetylcysteine absorption in normal subjects.}, journal = {The American journal of emergency medicine}, volume = {5}, number = {6}, pages = {483-487}, doi = {10.1016/0735-6757(87)90166-5}, pmid = {3663288}, issn = {0735-6757}, mesh = {Absorption ; Acetaminophen/poisoning ; Acetylcysteine/administration &amp; dosage/adverse effects/*blood/therapeutic use ; Adult ; Charcoal/*administration &amp; dosage/adverse effects/therapeutic use ; Drug Evaluation ; Female ; Humans ; Male ; Random Allocation ; }, abstract = {The discovery of the effectiveness of oral antidotes such as N-acetylcysteine (NAC) for acetaminophen poisonings has raised questions about the appropriateness of concomitant administration with activated charcoal. A number of studies have attempted to clarify this question without complete success. This study was designed to evaluate the difference in serum levels of NAC when given with activated charcoal. Nineteen patients completed a two-phase cross-over study in which they served as their own controls. Each subject in phase 1 received 140 mg/kg of diluted, chilled NAC orally, and venous blood samples were drawn for analysis. Phase 2 consisted of a 100-g dose of activated charcoal followed by NAC. Samples were transported immediately and assayed using spectrophotometry. A reduction in peak NAC level of 29% (P less than .02) and a reduction of total area under the curve (AUC) of 39% (P less than .001) was noted. Although it may be preferable to avoid completely the use of activated charcoal when using NAC to treat overdoses of acetaminophen, we recommend that if these agents are used together, doses of NAC be increased by 40% to compensate for the decreased oral absorption of NAC.}, }
@article {pmid3667923, year = {1987}, author = {Murray, PR and Heeren, RL and Niles, AC}, title = {Effect of decontamination procedures on recovery of Nocardia spp.}, journal = {Journal of clinical microbiology}, volume = {25}, number = {10}, pages = {2010-2011}, pmid = {3667923}, issn = {0095-1137}, mesh = {Acetylcysteine/*pharmacology ; Benzalkonium Compounds/*pharmacology ; Humans ; Nocardia/*drug effects/growth &amp; development ; Sodium Hydroxide/*pharmacology ; }, abstract = {Exposure to 0.5% N-acetyl-L-cysteine (NAC), 2% NaOH-NAC, or benzalkonium chloride in trisodium phosphate (Zephiran-TSP) was toxic for Nocardia isolates. The number of viable Nocardia cells in a standardized suspension was reduced by 10(2) to 10(6) after a 30-min exposure to 2% NaOH-NAC and by 10(4) or more after a 30-min treatment with Zephiran-TSP.}, }
@article {pmid3652388, year = {1987}, author = {Romert, L and Jenssen, D}, title = {Mechanism of N-acetylcysteine (NAC) and other thiols as both positive and negative modifiers of MNNG-induced mutagenicity in V79 Chinese hamster cells.}, journal = {Carcinogenesis}, volume = {8}, number = {10}, pages = {1531-1535}, doi = {10.1093/carcin/8.10.1531}, pmid = {3652388}, issn = {0143-3334}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Line ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Drug ; Drug Interactions ; *Methylnitronitrosoguanidine ; Mutagenicity Tests ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {Carcinogenic xenobiotics can be detoxified by nucleophilic thiols, which interact directly or through enzyme catalyzed reactions with electrophilic metabolites/compounds or metabolically produced oxidants. Formation of such conjugates is assumed to be a dominating competitive pathway reducing the mutagenic and carcinogenic effects of several known carcinogens. In the case of the potent carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) the situation is different since this carcinogen is transformed to reactive intermediates by nucleophilic agents such as thiols. As a consequence of this, the modulating effect of thiols has to be discussed in relation to the reaction kinetics of this nitroso compound. In this report we present data on the mutagenicity of MNNG which was enhanced by intracellular excess of glutathione, achieved by pre-treatment with N-acetylcysteine, cysteine and glutathione. Depletion of GSH by treatment with diethylmaleate or buthioninesulfoximine resulted in a decreased mutagenic effect of MNNG. A decreased effect of MNNG was also obtained by extracellular excess of thiols. The modification of MNNG-mutagenicity was compared to the effect of thiols on the mutagenicity of N-methyl-N'-nitrosourea (MNU) in V79 Chinese hamster cells. No effect of the thiols could be detected on the mutagenicity of MNU, indicating that the intermediates of MNU and MNNG react, in agreement with the reaction kinetics, in favour of water and thiols become less important. The results indicate that the activation of MNNG to mutagenic intermediates is occurring within the cells. This activation is mediated by reaction of MNNG with thiols (and amines) and subsequent release of short-lived alkylating intermediates. The mutagenic effect of MNNG can be reduced or enhanced respectively by decreasing or increasing the intracellular thiol levels. As demonstrated with MNU, intracellular thiol concentrations (in milli/molar range), which is high enough to bring about the activation of MNNG, are not sufficiently high to protect DNA from damage by the alkylating intermediate. Extracellular levels of thiols 'protect' the cells simply by increasing the decomposition of MNNG in the treatment solution.}, }
@article {pmid3329530, year = {1987}, author = {Parr, GD and Huitson, A}, title = {Oral Fabrol (oral N-acetyl-cysteine) in chronic bronchitis.}, journal = {British journal of diseases of the chest}, volume = {81}, number = {4}, pages = {341-348}, doi = {10.1016/0007-0971(87)90182-3}, pmid = {3329530}, issn = {0007-0971}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Aged, 80 and over ; Bronchitis/*drug therapy ; Chronic Disease ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Patient Compliance ; Random Allocation ; }, abstract = {Five hundred and twenty-six patients suffering from chronic bronchitis were randomized to receive either N-acetylcysteine (NAC) or placebo during a 6-month period. The aim was to compare the number of acute exacerbations in the two groups. General practitioners were asked to enter patients with a diagnosis of chronic bronchitis, based on the MRC criteria. We failed to find any statistically significant difference in the number of exacerbations between the two treatment groups although there was a slight trend towards improvement in the NAC group during the first 3 months of the trial. The tolerability was similar for both treatments. Patients taking NAC showed a reduction in number of days on which they were incapacitated and this result was statistically significant.}, }
@article {pmid2451202, year = {1987}, author = {Ward, HE and Nicholson, A and Berend, N}, title = {Failure of systemic N-acetyl cysteine to protect the rat lung against bleomycin toxicity.}, journal = {Pathology}, volume = {19}, number = {4}, pages = {358-360}, doi = {10.3109/00313028709103883}, pmid = {2451202}, issn = {0031-3025}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bleomycin/*antagonists &amp; inhibitors/toxicity ; Body Weight/drug effects ; Lung/*drug effects/pathology ; Rats ; Rats, Inbred Strains ; }, abstract = {In order to see whether systemically administered N-acetyl cysteine (NAC) could protect the lung from bleomycin lung injury, 24 rats were given a constant subcutaneous infusion of NAC (mean 195 mg.kg-1.day-1) for 7 days while 23 rats were given a similar volume of saline. Two days after the start of infusion, half of each group received an endotracheal injection of bleomycin and the other half received a similar volume of saline. All animals were killed 7 days after intratracheal injection and their lungs were prepared for wet-weight to dry-weight ratio (W:D) and morphometric assessment of histological changes. In animals given intratracheal saline, NAC infusion had no effect on weight gain, W:D or morphometry compared to those animals given saline infusions. However, all bleomycin-treated animals had obvious evidence of lung damage. Compared to either group of animals treated with intratracheal saline, the bleomycin-treated groups gained less weight (p less than 0.001), had a higher W:D (p less than 0.001) and an increase in the volume densities of alveolar and duct walls (p less than 0.001), intra-alveolar cells (p less than 0.05) and consolidation (p less than 0.001). There were no significant differences between the two bleomycin-treated groups in any parameter measured. It is concluded that administration of NAC by a constant subcutaneous infusion was not protective against bleomycin lung injury.}, }
@article {pmid3632716, year = {1987}, author = {Cotgreave, IA and Sandy, MS and Berggren, M and Moldéus, PW and Smith, MT}, title = {N-acetylcysteine and glutathione-dependent protective effect of PZ51 (Ebselen) against diquat-induced cytotoxicity in isolated hepatocytes.}, journal = {Biochemical pharmacology}, volume = {36}, number = {18}, pages = {2899-2904}, doi = {10.1016/0006-2952(87)90200-0}, pmid = {3632716}, issn = {0006-2952}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Azoles/metabolism/*pharmacology ; Carmustine/pharmacology ; Diquat/*pharmacology ; Glutathione/metabolism/*pharmacology ; Hydrogen Peroxide/metabolism ; Isoindoles ; Lipid Peroxides/metabolism ; Liver/*drug effects/metabolism ; Male ; *Organoselenium Compounds ; Oxidation-Reduction ; Pyridinium Compounds/*pharmacology ; Rats ; Rats, Inbred Strains ; Selenium/metabolism/*pharmacology ; }, abstract = {The glutathione peroxidase (GSH-Px)-like reduction of H2O2 by the selenoorganic compound 2-phenyl-1,2-benzoisoselenazol-3(H)-one (PZ51: Ebselen) was studied using glutathione (GSH) and the therapeutic agent N-acetylcysteine (NAC) to provide reducing equivalents. In a purely chemical system containing H2O2 and in an enzymatic system of glucose/glucose oxidase-generated H2O2 Ebselen alone did not reduce H2O2. Ebselen in combination with either GSH (1 mM) or NAC (1 mM) was capable of reducing H2O2 in both systems. In these non-cellular systems GSH was a more effective source of reducing equivalents than NAC. The GSH-Px-like activity of Ebselen was further investigated in a cellular system. The redox-cycling bipyridylium compound diquat generates active oxygen species, depletes intracellular glutathione, and is cytotoxic in isolated hepatocytes pretreated with the glutathione reductase inhibitor 1,3-bis(Z-chloro-ethyl)-1-nitrosourea (BCNU). Ebselen alone did not ameliorate diquat cytotoxicity, but in combination with either GSH (1 mM) or NAC (1 mM) it produced a significant delay in diquat-induced cytotoxicity. Further additions of either GSH (0.5 mM) or NAC (0.5 mM) at 30 min intervals provided significantly more protection against diquat-induced cytotoxicity and intracellular GSH depletion than the single 1 mM addition. Thus, the combination of Ebselen and NAC may provide an effective antidote in cases of overexposure to bipyridylium herbicides, such as diquat and paraquat.}, }
@article {pmid3305057, year = {1987}, author = {Bylin, G and Hedenstierna, G and Lagerstrand, L and Wagner, PD}, title = {No influence of acetylcysteine on gas exchange and spirometry in chronic asthma.}, journal = {European journal of respiratory diseases}, volume = {71}, number = {2}, pages = {102-107}, pmid = {3305057}, issn = {0106-4339}, support = {HL 17731/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Administration, Oral ; Asthma/*drug therapy/physiopathology ; Chronic Disease ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Humans ; Lung/physiopathology ; Male ; Pulmonary Gas Exchange/*drug effects ; Respiratory Function Tests ; *Spirometry ; }, abstract = {Non-smoking patients (n:25) with stable symptomatic asthma were investigated with regard to the pulmonary effects of N-acetylcysteine (NAC), peroral dose 200 mg three times daily, in a crossover double-blind study. They were studied once a week for 9 weeks, with a run-in period and periods with NAC and placebo (3 weeks each). Functional residual capacity and specific airway resistance were 19 and 53% larger, respectively, and forced expiratory variables (FEV%, MEF25) were 20 and 53% lower than reference values. Distribution of ventilation-perfusion ratios (VA/Q), assessed by multiple inert gas elimination technique with peripheral venous sampling, was abnormal, although arterial PO2 and PCO2 were within normal limits. NAC medication had no effect on any spirometric, lung mechanic or gas exchange variable, nor on the frequency of pulmonary symptoms.}, }
@article {pmid3118582, year = {1987}, author = {Brewster, K and Harrison, JM and Leadbeater, L and Newman, J and Upshall, DG}, title = {The fate of 2-chlorobenzylidene malononitrile (CS) in rats.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {17}, number = {8}, pages = {911-924}, doi = {10.3109/00498258709044190}, pmid = {3118582}, issn = {0049-8254}, mesh = {Animals ; Autoradiography ; Biotransformation ; Cyanides/metabolism ; Liver/cytology/metabolism ; Male ; Mice ; Nitriles/*pharmacokinetics ; Rats ; Thiocyanates/metabolism ; o-Chlorobenzylidenemalonitrile/*pharmacokinetics ; }, abstract = {1. The fate of 3H-ring labelled, 14C-cyanide labelled and (14C = C) side chain labelled 2-chlorobenzylidene malononitrile (CS), 2-chlorobenzyl alcohol and 2-chlorobenzyl malononitrile (dihydro CS) in rats and isolated rat liver cells has been examined. 2. CS was administered both i.v. and i.g. to rats at doses from 0.08 to 159 mumol/kg and in most cases the greatest proportion of the dose was eliminated in the urine (44-100%). The principal urinary metabolites were 2-chlorohippuric acid, 1-O-(2-chlorobenzyl) glucuronic acid, 2-chlorobenzyl cysteine and 2-chlorobenzoic acid. Lesser amounts of 2-chlorophenyl acetyl glycine, 2-chlorobenzyl alcohol and 2-chlorophenyl 2-cyano propionate were identified. 3. The major urinary metabolite from 2-chlorobenzyl alcohol was 2-chlorohippuric acid (43%), 2-chlorobenzyl cysteine, 2-chlorobenzoic acid and 2-chlorobenzyl glucuronic acid were identified. 4. The products of dihydro-CS metabolism were 2-chlorophenyl acetyl glycine, 2-chlorophenyl 2-cyanopropionate and 2-chlorophenyl proprionamide. 5. Urinary thiocyanate levels increased with the dose of CS up to 159 mumol/kg. At 212 mumol/kg there was a large increase in the amount of thiocyanate produced (molar conversion: 21.5-29.9%). Similarly malononitrile, the hydrolysis product of CS, gave a dose related increase in urinary thiocyanate levels. However at a higher dose (212 mumol/kg) the molar conversion was greater than 60%. 6. The metabolism of CS by isolated rat liver cells confirmed the results in vivo but demonstrated a marked limitation of this preparation to form conjugates. 7. It is concluded that CS in vivo is hydrolysed mainly to 2-chlorobenzaldehyde which is then either oxidized to 2-chlorobenzoic acid for subsequent glycine conjugation, or reduced to 2-chlorobenzyl alcohol for ultimate excretion as 2-chlorobenzyl acetyl cysteine or 1-O-(2-chlorobenzyl) glucuronic acid. Malononitrile is converted to thiocyanate via the formation of cyanide.}, }
@article {pmid3109888, year = {1987}, author = {Scott, JS and Lakin, CA and Oliver, JR}, title = {The effect of cysteamine, cystamine, and the structurally related compounds taurine, N-acetyl-cysteine, and D-penicillamine on plasma prolactin levels in normal and estrogen-primed hyperprolactinemic rats.}, journal = {Endocrinology}, volume = {121}, number = {2}, pages = {812-818}, doi = {10.1210/endo-121-2-812}, pmid = {3109888}, issn = {0013-7227}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cystamine/pharmacology ; Cysteamine/*pharmacology ; Estradiol ; Hyperprolactinemia/*blood/chemically induced ; Male ; Metoclopramide/pharmacology ; Penicillamine/*pharmacology ; Prolactin/blood ; Rats ; Taurine/*pharmacology ; Thyrotropin-Releasing Hormone/pharmacology ; }, abstract = {Studies were undertaken to evaluate the effects of cysteamine (CSH), cystamine (CS-S), N-acetyl-cysteine, D-penicillamine, and a major metabolite of CSh, taurine, on plasma PRL levels in normal and estrogen-primed hyperprolactinemic rats. Both CSH and CS-S caused a marked decrease in plasma PRL concentration in hyperprolactinemic rats. The effects of CSH and CS-S lasted for at least 6 h but returned toward pretreatment levels 24 h later. In normal rats a fall in basal plasma PRL concentration was not readily observed but after stimulation with TRH or metaclopramide, PRL secretion elicited by these stimuli was markedly inhibited by CSH and CS-S. The response to TRH or MCP 24 h after treatment with CSH was variable with CS-S appearing to cause an unexpected increase in PRL release in response to TRH or metaclopramide. The structurally related compounds, taurine, N-acetyl-cysteine, and D-penicillamine did not cause any reduction of plasma PRL levels in hyperprolactinemic rats. This may be due, in the case of taurine, to a loss of the free sulfydryl group, in the case of N-acetyl-cysteine, a change in basicity because of a carboxyl group and derivatization of the amino group and D-penicillamine, again a change in basicity due to a free carboxyl group as well as an altered structural relationship between the free amino and sulfydryl groups. These studies indicate that CSH and CS-S by possible reduction to CSH cause a reversible depletion in plasma PRL in normal and hyperprolactinemic rats. Because both substances inhibit different receptor-mediated stimuli, their mechanism of action is likely to be mediated at a common locus involved with the synthesis and release of PRL.}, }
@article {pmid3690018, year = {1987}, author = {Stagnaro, R and Pierri, I and Piovano, P and Baracco, F and De Palma, M and Indiveri, F}, title = {Thiol containing antioxidant drugs and the human immune system.}, journal = {Bulletin europeen de physiopathologie respiratoire}, volume = {23}, number = {4}, pages = {303-307}, pmid = {3690018}, issn = {0395-3890}, mesh = {Acetylcysteine/*immunology/therapeutic use ; Antibodies, Monoclonal/immunology ; Antioxidants/*immunology/therapeutic use ; Catalase/immunology ; HLA-D Antigens/immunology ; Humans ; Lung Diseases, Obstructive/drug therapy/*immunology ; Lymphocytes/*drug effects/immunology ; Phenotype ; }, abstract = {The over production of toxic oxygen species (TOS) by the phagocytic cells involved in inflammatory processes plays a crucial role in generating the immune defects which characterize both infections and neoplastic diseases. Since the thiol containing drugs, and N-acetylcysteine possess a high capacity for scavenging and inhibiting TOS, the question of whether these substances are able to protect, in vivo as well as in vitro, the function of lymphocytes isolated from the peripheral blood in patients suffering from chronic pulmonary diseases (CPD) was investigated. The lymphocytes isolated from healthy donors as well as those from CPD patients exposed in vitro to TOS showed a reduced viability and an impairment of functions in: (a) the ability to express HLA Class II and TAC antigens and (b) the capacity to stimulate and proliferate in allogenic (MLR) and autologous mixed lymphocyte reactions (AMLR). The presence of NAC or CAT blocked this toxicity. Cells isolated from healthy donors and patients following treatment with NAC were less sensitive to the in vitro toxicity of TOS.}, }
@article {pmid3620596, year = {1987}, author = {Cotgreave, IA and Berggren, M and Jones, TW and Dawson, J and Moldéus, P}, title = {Gastrointestinal metabolism of N-acetylcysteine in the rat, including an assay for sulfite in biological systems.}, journal = {Biopharmaceutics &amp; drug disposition}, volume = {8}, number = {4}, pages = {377-386}, doi = {10.1002/bdd.2510080408}, pmid = {3620596}, issn = {0142-2782}, mesh = {Acetylcysteine/*metabolism ; Animals ; Chromatography, High Pressure Liquid ; Digestive System/*metabolism ; Epithelium/metabolism ; In Vitro Techniques ; Male ; Models, Biological ; Rats ; Rats, Inbred Strains ; Sulfites/*analysis ; }, abstract = {The intestinal metabolism of N-acetylcysteine was studied in the rat. Isolated intestinal epithelial cells were shown to rapidly deacetylate [14C]-N-acetylcysteine to [14C]-cysteine, with slight oxidation of the latter to disulfide species. The cells did not accumulate reduced or oxidized cysteine, and N-acetylcysteine itself was not detected either free or in oxidized species intracellularly. Further metabolism of this NAC-derived cysteine to inorganic sulfite or glutathione was not detected. Following the administration of [14C]-N-acetylcysteine (50 mg/kg; 25 microCi) in vivo into the ilium, small quantities of both reduced and oxidized [14C]-N-acetylcysteine were demonstrated in hepatic portal vein plasma. [14C]-cysteine and inorganic sulfite were demonstrated as the major metabolites of N-acetylcysteine. These were present in the portal vein plasma at levels five and three times greater than the parent drug, respectively, 30 min after dosing. Additionally, [14C]-glutathione was shown to be a minor metabolite of N-acetylcysteine accumulating in portal vein plasma. These results may provide an explanation for the apparent low bioavailability of N-acetylcysteine when administered orally in humans and are discussed in terms of the origins of the protective effect of the drug in cases of paracetamol intoxication in humans.}, }
@article {pmid3623217, year = {1987}, author = {McNeil, NI and Ling, KL and Wager, J}, title = {Mucosal surface pH of the large intestine of the rat and of normal and inflamed large intestine in man.}, journal = {Gut}, volume = {28}, number = {6}, pages = {707-713}, pmid = {3623217}, issn = {0017-5749}, mesh = {Adult ; Aged ; Animals ; Colon/physiology ; Electrodes ; Female ; Humans ; Hydrogen-Ion Concentration ; Intestinal Mucosa/*physiology ; Intestine, Large/*physiology/physiopathology ; Male ; Microelectrodes ; Middle Aged ; Proctitis/*physiopathology ; Rats ; Rats, Inbred Strains ; Rectum/physiology ; }, abstract = {The surface pH of rat distal colonic mucosa and human rectal mucosa was measured in vitro using first a small pH electrode with a flattened tip. In buffer with pH 7.56 the mean rat colonic surface pH was 6.72. Lowering the buffer pH in steps resulted in a small fall in surface pH, the values being buffer pH 7.06 surface pH 6.64, buffer pH 6.58 surface pH 6.61 and finally buffer pH 6.09 surface pH 6.39. Similar results were obtained with a buffer where butyrate, 30 mmol/l replaced chloride and when a CO2/bicarbonate buffer was used. During the time taken for the study transmural potential difference only changed by 1-2 mV. Serosal surface pH changed with buffer pH, suggesting that the maintained surface pH is a property of the mucosal surface only. The surface pH of human rectal mucosa was similar to that of rat distal colonic mucosa. As buffer pH fell from pH 7.51 to 5.96 mucosal surface pH only fell from pH 6.80 to 6.26. The values obtained in ulcerative proctitis did not differ from normal mucosa. Secondly pH microelectrodes were used to measure the juxta mucosal pH and the pH-microclimate thickness when luminal pH was controlled. The microclimate had a pH 6.63 adjacent to the mucosa with a thickness of 840 micron. The importance of mucus in maintaining the microclimate was shown by n-acetyl cysteine thinning and prostaglandin E2 thickening the layer. These results describe a surface microclimate in the large intestine of appreciable thickness and a constant juxta mucosal pH. Luminal pH changes produce only a small change in microclimate pH.}, }
@article {pmid3609541, year = {1987}, author = {deBethizy, JD and Udinsky, JR and Scribner, HE and Frederick, CB}, title = {The disposition and metabolism of acrylic acid and ethyl acrylate in male Sprague-Dawley rats.}, journal = {Fundamental and applied toxicology : official journal of the Society of Toxicology}, volume = {8}, number = {4}, pages = {549-561}, doi = {10.1016/0272-0590(87)90140-0}, pmid = {3609541}, issn = {0272-0590}, mesh = {Acrylates/*metabolism/toxicity ; Animals ; Biotransformation ; Chromatography, High Pressure Liquid ; Glutathione/metabolism ; Male ; Microsomes, Liver/metabolism ; Organ Size/drug effects ; Rats ; Rats, Inbred Strains ; Stomach/drug effects ; Sulfhydryl Compounds/metabolism ; Time Factors ; }, abstract = {Following oral dosing of [2,3-14C]acrylic acid (AA; 4, 40, or 400 mg/kg) and [2,3-14C]ethyl acrylate (EA; 2, 20, or 200 mg/kg), the dosed radioactivity was rapidly excreted, with 50-75% of the dose for both compounds eliminated within 24 hr. The primary excretory metabolite for both compounds is carbon dioxide, accounting for 44-68% of the dose. HPLC analysis of the urine of AA- and EA-dosed animals indicated the presence of 3-hydroxypropionic acid. The detection of this metabolite suggests the incorporation of AA into propionic acid metabolism and may explain the rapid evolution of carbon dioxide from AA and EA. HPLC analysis of urine from EA-dosed rats revealed the presence of two metabolites derived from glutathione conjugation, N-acetyl-S-(carboxyethyl)cysteine and N-acetyl-S-(carboxyethyl)cysteine ethyl ester. The excretion of the N-acetyl cysteine derivatives of EA, expressed as a percentage of the dosed compound, decreased in a dose-dependent manner that may be attributed to the depletion of glutathione in organs primarily responsible for glutathione conjugation. No significant decrease in hepatic nonprotein sulfhydryl (NPSH) content was observed following oral dosing with EA at 2-200 mg/kg. However, the depletion of NPSH content at the dosing site, forestomach, and glandular stomach, decreased significantly between 0.02 and 0.2% EA in the dose solution (2 and 20 mg/kg). This observation would suggest that the dosing site represents a significant site of conjugation for relatively low doses of EA. Treatment with the carboxylesterase inhibitor, tri-o-cresyl phosphate (TOCP), 18 hr prior to acrylate dosing potentiated the depletion of hepatic nonprotein sulfhydryls, emphasizing the dominance of hydrolysis as a systemic detoxifying mode in this species. In contrast to EA, AA did not significantly decrease NPSH content in the liver, blood, or forestomach at oral doses of less than 8% AA in the dose solution (400 mg/kg), although a significant depletion of NPSH was observed in the glandular stomach at doses greater than 0.08% (4 mg/kg). No conjugation involving the double bond of AA could be detected in in vitro reactions with glutathione or in the in vivo metabolites, suggesting a secondary effect of AA on NPSH content in these organs. The weights of the forestomach and glandular stomach increased with AA dose, reflecting gross edema and inflammation. With EA this effect on organ weight was only demonstrated in the forestomach, and the response was increased when hydrolysis of EA was inhibited with TOCP.(ABSTRACT TRUNCATED AT 400 WORDS)}, }
@article {pmid3582517, year = {1987}, author = {Wegener, T and Sandhagen, B and Saldeen, T}, title = {Effect of N-acetylcysteine on pulmonary damage due to microembolism in the rat.}, journal = {European journal of respiratory diseases}, volume = {70}, number = {4}, pages = {205-212}, pmid = {3582517}, issn = {0106-4339}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Blood Viscosity/drug effects ; Male ; Pulmonary Embolism/*drug therapy ; Rats ; Rats, Inbred Strains ; Respiratory Distress Syndrome/*drug therapy ; }, abstract = {The effect of N-acetylcysteine (NAC), a free radical scavenger, was investigated in a microembolism rat model of adult respiratory distress syndrome (ARDS). Microembolism was induced by an intravenous injection of bovine thrombin and an intraperitoneal injection of a fibrinolysis inhibitor, trans-4-aminomethyl-cyclohexane-carboxylic acid (AMCA). NAC counteracted the experimentally induced increase in lung weight, the development of alveolar oedema, and the amount of fibrin in precapillary vessels. There was also a tendency to a decrease of the experimentally induced interstitial oedema caused by the NAC treatment, although it was not statistically significant. Surprisingly, NAC reduced plasma viscosity in both experimental and control animals. It also seemed to increase PaO2 in animals with pulmonary damage, but had a lowering effect on PaO2 in control animals. The results indicate that NAC has a significant preventive effect in this microembolism rat model of ARDS, and that this effect may be achieved through decreased deposition of fibrin, thus counteracting pulmonary oedema, and a decrease in plasma viscosity.}, }
@article {pmid3108021, year = {1987}, author = {Alfredsson, H and Malmborg, AS and Strandvik, B}, title = {N-acetylcysteine and 2-mercaptoethane sulphonate inhibit anti-pseudomonas activity of antibiotics in vitro.}, journal = {European journal of respiratory diseases}, volume = {70}, number = {4}, pages = {213-217}, pmid = {3108021}, issn = {0106-4339}, mesh = {Acetylcysteine/*pharmacology ; Anti-Bacterial Agents/*antagonists &amp; inhibitors ; Drug Interactions ; Mercaptoethanol/*analogs &amp; derivatives ; Mesna/*pharmacology ; Microbial Sensitivity Tests ; Pseudomonas aeruginosa/*drug effects ; }, abstract = {The in vitro activity against Pseudomonas aeruginosa was investigated for serial dilutions of eight anti-Pseudomonas antibiotics in combination with serial dilutions of N-acetylcysteine (NAC) and 2-mercaptoethane sulphonate (MES). The results indicated that addition of NAC and MES to the antibiotics increased the MIC values for tobramycin, netilmicin, piperacillin, azlocillin, cefsulodin, ceftazidime and imipenem but not for colistin. The decrease of MIC found in high concentrations of NAC and MES was probably due to the bacteriostatic effect of the drugs per se and not to synergism with the antibiotics.}, }
@article {pmid3569447, year = {1987}, author = {Stafanger, G and Bisgaard, H and Pedersen, M and Mørkassel, E and Koch, C}, title = {Effect of N-acetylcysteine on the human nasal ciliary activity in vitro.}, journal = {European journal of respiratory diseases}, volume = {70}, number = {3}, pages = {157-162}, pmid = {3569447}, issn = {0106-4339}, mesh = {Acetylcysteine/*pharmacology ; Cilia/*drug effects ; Humans ; In Vitro Techniques ; Movement/drug effects ; Nasal Mucosa/*drug effects ; Perfusion ; }, abstract = {N-acetylcysteine (NAC) is widely used as a mucolytic agent, but the clinical and pharmacological effects of NAC are still unclear. It has recently been claimed in animal studies that NAC will stimulate ciliary beating frequency at low concentrations, while inhibiting beating at higher concentrations. Using a microphoto-oscillographic method combined with microperfusion technique, we studied the direct effect of NAC on human nasal cilia. NAC caused a direct dose- and time-related decrease in ciliary beating frequency, which was detectable at 2 mg/ml and reached statistically significant levels at 20 mg/ml. NAC at 200 mg/ml caused total cessation of movements within 15 s but this effect was completely reversible within 15 min of perfusion with medium alone. At no concentrations of NAC was beating frequency increased over base-line. NAC, however, had no effect on beating pattern. NAC seems to have a selective and fully reversible inhibitory effect on the beating frequency of human cilia in vitro.}, }
@article {pmid3564073, year = {1987}, author = {Banda, PW and Quart, BD}, title = {The use of N-acetylcysteine long after an acetaminophen overdose in mice.}, journal = {Toxicology letters}, volume = {36}, number = {1}, pages = {89-94}, doi = {10.1016/0378-4274(87)90045-2}, pmid = {3564073}, issn = {0378-4274}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*toxicity ; Animals ; Lethal Dose 50 ; Male ; Mice ; Time Factors ; }, abstract = {N-Acetylcysteine (NAC), given to mice 5 h after an LD50 dose of acetaminophen, decreased 24-h survival to 33%. The reduction in survival observed for late NAC is significantly lower than the survival observed for the LD50 dose alone (53%), and is in sharp contrast to the 100% survival reported for the early use of NAC.}, }
@article {pmid2908770, year = {1987}, author = {Cesarone, CF and Scarabelli, L and Orunesu, M and Bagnasco, M and De Flora, S}, title = {Effects of aminothiols in 2-acetylaminofluorene-treated rats. I. Damage and repair of liver DNA, hyperplastic foci, and Zymbal gland tumors.}, journal = {In vivo (Athens, Greece)}, volume = {1}, number = {2}, pages = {85-91}, pmid = {2908770}, issn = {0258-851X}, mesh = {2-Acetylaminofluorene/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Carcinoma, Squamous Cell/chemically induced/pathology/*prevention &amp; control ; DNA/drug effects ; *DNA Damage ; DNA Repair/*drug effects ; Ear Canal ; Ear Neoplasms/chemically induced/pathology/*prevention &amp; control ; Glutathione/*pharmacology ; Hyperplasia ; Liver/drug effects/*pathology ; Liver Neoplasms/chemically induced/pathology/*prevention &amp; control ; Male ; Rats ; Rats, Inbred Strains ; Reference Values ; Sebaceous Gland Neoplasms/chemically induced/pathology/*prevention &amp; control ; gamma-Glutamyltransferase/analysis ; }, abstract = {One hundred and seventy-nine male Wistar rats were divided into 6 groups and fed with a standard diet supplemented with 0.05% 2-acetylaminofluorene (2AAF) and/or 0.1% glutathione (GSH) or N-acetyl-L-cysteine (NAC). Each treatment cycle lasted for 3 weeks, followed by 1 week of standard meal. After 4 cycles, survival was 100% in the 3 control groups, and 86.0, 100 and 91.7%, in the groups receiving 2AAF, 2AAF plus GSH, and 2AAF plus NAC, respectively. After an additional 4-8 weeks, all the 5 surviving rats fed with 2AAF exhibited deforming ear tumors, which on histological examination were classified as sebaceous squamocellular carcinomas of Zymbal glands. No such tumors were detectable in control groups, nor in the 16 surviving rats fed with 2AAF plus GSH or NAC. In the liver, 2AAF produced significant DNA damage at the 3rd week of each cycle, which was partially repaired during the week of standard meal feeding. Moreover, 2AAF determined the appearance of gamma-glutamyl transpeptidase-positive foci, which tended to increase with time both in number and in size. GSH and NAC exerted similar protective effects on these phenomena, but only at early stages of the experimental model used.}, }
@article {pmid3817074, year = {1987}, author = {Cotgreave, IA and Eklund, A and Larsson, K and Moldéus, PW}, title = {No penetration of orally administered N-acetylcysteine into bronchoalveolar lavage fluid.}, journal = {European journal of respiratory diseases}, volume = {70}, number = {2}, pages = {73-77}, pmid = {3817074}, issn = {0106-4339}, mesh = {Acetylcysteine/administration &amp; dosage/*metabolism ; Administration, Oral ; Adult ; Cysteine/metabolism ; Female ; Glutathione/metabolism ; Humans ; Male ; Pulmonary Alveoli/drug effects/*metabolism ; Therapeutic Irrigation ; }, abstract = {Six healthy volunteers underwent bronchoalveolar lavage (BAL) before and after receiving N-acetylcysteine (NAC) 600 mg daily for 2 weeks. Free and total NAC, cysteine and glutathione were determined in the lavage fluid, lavage cells and plasma. No NAC was demonstrated, free or bound in disulfides, in either of the lavage components; furthermore, the cysteine and glutathione content of these components and their respective redox states were unaltered during therapy. Plasma free and total cysteine content was unaltered by administration of the drug, but both free and total plasma glutathione increased significantly. Free NAC could not be detected in plasma following dosing. However, a mean of 0.3 nmol/100 microliters plasma was released from disulfides in plasma following reduction with dithiothreitol. N-acetylcysteine has been proposed to act as a mucolytic by cleavage of disulfide bonds. Our findings do not support this direct mode of action and alternative mechanisms of action must be sought.}, }
@article {pmid3571937, year = {1987}, author = {Alp, MH and Hickman, R}, title = {The effect of prostaglandins, branched-chain amino acids and other drugs on the outcome of experimental acute porcine hepatic failure.}, journal = {Journal of hepatology}, volume = {4}, number = {1}, pages = {99-107}, doi = {10.1016/s0168-8278(87)80016-8}, pmid = {3571937}, issn = {0168-8278}, mesh = {Acetylcysteine/therapeutic use ; Amino Acids, Branched-Chain/*therapeutic use ; Amino Acids, Essential/blood/cerebrospinal fluid ; Animals ; Carbon Tetrachloride ; Cholestyramine Resin/therapeutic use ; Disease Models, Animal ; Hepatic Encephalopathy/*drug therapy/pathology/physiopathology ; Phosphatidylcholines/therapeutic use ; Prostaglandins/*therapeutic use ; Silymarin/therapeutic use ; Swine ; }, abstract = {Prostaglandins, N-acetyl-cysteine, cholestyramine and essential phospholipids have all been shown to protect experimental animals from severe hepatic damage in various models when used prophylactically. Silibinin has been used in the treatment of Amanita phalloides poisoning. Branched-chain amino acids have been recommended in acute hepatic failure. We have used all these forms of therapy at the time of initiation of hepatic failure in a reliable pig model. Of the above, only prostaglandins have been shown to reverse the effects of the hepatic insult in terms of prolonged survival and histological changes. Although conventional liver function tests and plasma amino acids in prostaglandin-treated animals are not improved, cerebrospinal fluid amino acids remain normal, in contrast to the other groups of untreated and treated hepatic failure animals.}, }
@article {pmid3558591, year = {1987}, author = {Johansson, M and Westerlund, D}, title = {Determination of N-acetylcysteine, intact and oxidized, in plasma by column liquid chromatography and post-column derivatization.}, journal = {Journal of chromatography}, volume = {385}, number = {}, pages = {343-356}, doi = {10.1016/s0021-9673(01)94649-7}, pmid = {3558591}, mesh = {Acetylcysteine/*blood ; Chemical Phenomena ; Chemistry ; Chromatography, Liquid ; Disulfides/blood ; Drug Stability ; Humans ; Hydrogen-Ion Concentration ; Maleimides ; Oxidation-Reduction ; Specimen Handling ; }, abstract = {N-Acetylcysteine in plasma may exist as intact N-acetylcysteine (NAC) or be oxidized to disulphides, either as a dimer or mixed with other thiol-containing compounds. To prevent oxidation of NAC, whole blood was immediately centrifuged after collection and the plasma proteins were precipitated with perchloric acid. NAC was measured by direct injection of the supernatant into the chromatographic system and the oxidized forms, coupled to small sulphides (ONACS), were determined after reductive cleavage of all NAC disulphides in the supernatant with dithiothreitol before injection. The total plasma concentration of the compound, i.e., including the fraction coupled to proteins (ONACP), was assayed after an initial reduction of the disulphide linkages in plasma. After subsequent precipitation of proteins, the supernatant was directly injected. The chromatographic system was a reversed-phase column (C18) with an acidic mobile phase. After a fast (less than 6 s) post-column reaction with pyrenemaleimide, NAC was detected by fluorimetry. The contribution to the band broadening by the reactor was about 10%. The limit of quantification of NAC in plasma was 240 nM, with an intra-assay precision of 14%.}, }
@article {pmid3828067, year = {1987}, author = {Carter, EA}, title = {Enhanced acetaminophen toxicity associated with prior alcohol consumption in mice: prevention by N-acetylcysteine.}, journal = {Alcohol (Fayetteville, N.Y.)}, volume = {4}, number = {1}, pages = {69-71}, doi = {10.1016/0741-8329(87)90063-2}, pmid = {3828067}, issn = {0741-8329}, mesh = {Acetaminophen/antagonists &amp; inhibitors/*toxicity ; Acetylcysteine/*therapeutic use ; Animals ; *Chemical and Drug Induced Liver Injury ; Drug Synergism ; Ethanol/*toxicity ; Liver Diseases/prevention &amp; control ; Male ; Mice ; }, abstract = {It is well established that hepatotoxicity is associated with an overdose of acetaminophen and that this hepatotoxicity can be increased by prior alcohol exposure in either humans or animal models. N-Acetylcysteine (NAC) has been developed as a tool to prevent the hepatotoxicity associated with acetaminophen overdosing. The present investigation observed that prior acute and chronic ingestion of alcohol to mice resulted in enhanced toxicity following acetaminophen injection. This increased toxicity was prevented by treatment with NAC. These results suggest that NAC may be a useful tool for combatting the enhanced acetaminophen toxicity associated with alcohol ingestion.}, }
@article {pmid3328168, year = {1987}, author = {Speeg, KV}, title = {Potential use of cimetidine for treatment of acetaminophen overdose.}, journal = {Pharmacotherapy}, volume = {7}, number = {6 Pt 2}, pages = {125S-133S}, doi = {10.1002/j.1875-9114.1987.tb03537.x}, pmid = {3328168}, issn = {0277-0008}, mesh = {Acetaminophen/*poisoning ; Animals ; Cimetidine/*therapeutic use ; Humans ; }, abstract = {Acetaminophen, a drug frequently taken in intentional and accidental overdose, causes liver toxicity when concentration of the cytochrome P-450-derived metabolite exceeds the metabolic capacity of available glutathione. Present treatment of acetaminophen overdose involves oral N-acetylcysteine (NAC), which enhances liver glutathione synthesis. An alternative or additive approach to therapy would be to inhibit the formation of the toxic metabolite by inhibiting the cytochrome P-450 system. The H2-receptor antagonist cimetidine inhibits the cytochrome P-450 system, does not interfere with the administration or function of NAC, and therefore affords additive protection. Also, it has little effect on the nontoxic routes of elimination of acetaminophen and is itself quite nontoxic. That cimetidine protects against acetaminophen toxicity in animal models has been demonstrated on the basis of improved survival, as well as decreases in several critical elements used to monitor acetaminophen toxicity: classic histologic changes, aminotransferase activity, metabolite covalent binding, and liver glutathione depletion. Administration of cimetidine well after the overdose is also protective. In contrast, animal models of acetaminophen toxicity demonstrate that ranitidine does not afford protection from acetaminophen hepatotoxicity. Clinical data in well-done trials in humans will be needed to support the experimental animal data.}, }
@article {pmid2442568, year = {1987}, author = {Jamieson, DD and Kerr, DR and Unsworth, I}, title = {Interaction of N-acetylcysteine and bleomycin on hyperbaric oxygen-induced lung damage in mice.}, journal = {Lung}, volume = {165}, number = {4}, pages = {239-247}, pmid = {2442568}, issn = {0341-2040}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Bleomycin/*adverse effects ; Hyperbaric Oxygenation/*adverse effects ; Lung/drug effects ; Lung Diseases/chemically induced/*prevention &amp; control ; Male ; Mice ; Mice, Inbred BALB C ; Oxygen/toxicity ; }, abstract = {Lung damage in mice exposed to hyperbaric oxygen was assessed by measurement of wet and dry lung weights. The clinically useful thiol compound, N-acetylcysteine (NAC), which is known to maintain tissue levels of reduced glutathione, was found to protect lungs of mice compressed to 445 and 515 kPa oxygen for 30 min. NAC was administered intraperitoneally and the optimal conditions found to be 400 mg/kg 15 min-1 hr before compression. The antineoplastic agent bleomycin, which frequently causes life-threatening lung damage, was administered intratracheally (5 mg/kg), and potentiated lung damage caused by hyperbaric oxygen (445 kPa). NAC effectively protected the lungs of mice exposed to the combined deleterious effect of bleomycin and hyperbaric oxygen.}, }
@article {pmid3789839, year = {1986}, author = {Henagan, JM and Smith, GS and Schmidt, KL and Miller, TA}, title = {N-acetyl-cysteine and prostaglandin. Comparable protection against experimental ethanol injury in the stomach independent of mucus thickness.}, journal = {Annals of surgery}, volume = {204}, number = {6}, pages = {698-704}, pmid = {3789839}, issn = {0003-4932}, support = {AM 25838/AM/NIADDK NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Ethanol/*toxicity ; Female ; Gastric Mucosa/*drug effects/pathology ; Mucus/drug effects/*physiology ; Prostaglandins E, Synthetic/*pharmacology ; Random Allocation ; Rats ; Rats, Inbred Strains ; }, abstract = {The role of barrier mucus in mediating the protective effects of 16,16 dimethyl PGE2 (dm PGE2) against ethanol-induced gastric injury, with and without concomitant treatment with N-acetyl-cysteine (NAC), a potent mucolytic agent, was evaluated. Fasted rats were orally administered either saline, 10 micrograms/kg dm PGE2, 20% NAC, or 10 micrograms/kg dm PGE2 plus 20% NAC. In the first study, the rats were killed 15 minutes later and their stomachs were removed and assayed for barrier mucus adherent to the gastric wall using the Alcian blue technique. In the second study, the rats were orally given 2 mL of absolute ethanol (EtOH) after receiving one of these pretreatment regimens, and 5 minutes later they were killed and their stomachs were evaluated histologically by light microscopy for the magnitude of EtOH injury. Although NAC significantly reduced the thickness of barrier mucus by 76% when compared with control animals, it did not adversely affect the ability of dm PGE2 to spare the deep epithelium from injury by EtOH. In fact, NAC was as effective a protective agent as dm PGE2. Neither agent prevented damage to the surface epithelium by EtOH, verifying previous studies regarding the protective effects of prostaglandins. These results indicate that both dm PGE2 and NAC prevent EtOH-induced damage to the deeper layers of the gastric mucosa independent of mucus gel layer thickness, suggesting that other mechanisms than mucus are involved in mediating this protection.}, }
@article {pmid2879504, year = {1986}, author = {Jaillon, P}, title = {[Current therapeutic concepts in the treatment of myocardial ischemia. Current and future drugs].}, journal = {Annales de cardiologie et d'angeiologie}, volume = {35}, number = {7 Pt 2}, pages = {453-458}, pmid = {2879504}, issn = {0003-3928}, mesh = {Adrenergic beta-Antagonists/therapeutic use ; Animals ; Calcium Channel Blockers/therapeutic use ; Cardiovascular Agents/*therapeutic use ; Chelating Agents/therapeutic use ; Coronary Disease/*drug therapy/physiopathology ; Coronary Vasospasm/physiopathology ; Epoprostenol/therapeutic use ; Fibrinolytic Agents/therapeutic use ; Humans ; Nitrites/therapeutic use ; Platelet Aggregation/drug effects ; Thromboxane A2/therapeutic use ; }, abstract = {If myocardial ischemia always results from an imbalance between the needs and supplies in oxygen of the myocardium cells, the physiopathology of this process seems today infinitely more complex than the mere diminution or interruption of the output in a coronary artery. The extension of atheromatous lesions, the platelets aggregation, thrombosis, the coronary spasm, the release of products from the arachidonic cascade, the reactivity of the vascular endothelium, the profibrinolytic activity of the tissues are many of the intricate factors inducing myocardial ischemia. Cellular alterations, of which some are triggered by the release of oxygenated free radicals, lead then to an irreversible necrosis. The medications used until now in the treatment of angina are oxygen scavengers and research goes on in this direction with vaso-dilators beta-blockers, prolonged action nitro-compounds (nicorandil) or nitro-compounds with an action reinforced by N-acetyl-cysteine, bradycardiac derivates of alinidine and the new calcium antagonists dihydropyridine. However, the new physiopathological concepts of ischemia have opened new directions for the research: products which modify the arachidonic cascade by increase of synthesis or release of PGI2 (nafazatrom, defibrotide), by inhibition of TXA2 synthesis or blocking of TXA2 receptors, and similar products of PGI2 (iloprost); thrombolytic agents more specific of thrombin (PTA) or fibrinolysis activators (defibrotide), and anticoagulants with extended action; chelating agents of oxygenated free radicals (peroxide dismutase, catalase, peroxidase) or xanthine oxidase inhibitors; platelets anti-aggregates like ticlopidine which blocks the platelets receptors to fibrinogen, or inhibitors of the synthesis of pro-aggregating agents.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid3757165, year = {1986}, author = {Chan, JY and Stout, DL and Becker, FF}, title = {Protective role of thiols in carcinogen-induced DNA damage in rat liver.}, journal = {Carcinogenesis}, volume = {7}, number = {10}, pages = {1621-1624}, doi = {10.1093/carcin/7.10.1621}, pmid = {3757165}, issn = {0143-3334}, support = {CA 20657/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; *Carcinogens ; DNA/*drug effects/metabolism ; *DNA Damage ; Diethylnitrosamine/toxicity ; Female ; Glutathione/analysis ; Liver/*drug effects ; Methylation ; Methylnitronitrosoguanidine/toxicity ; Methylnitrosourea/toxicity ; Rats ; Rats, Inbred Strains ; Sulfhydryl Compounds/*physiology ; Tiopronin/pharmacology ; }, abstract = {Biological thiols are known to play an important role in the detoxification of xenobiotics, including chemical carcinogens. To determine the influence of cellular thiols on carcinogen induction of hepatic DNA damage in the rat, diethylmaleate (DEM) administration was used to deplete intracellular glutathione (GSH). The effects of administration of the synthetic thiols, N-acetylcysteine (NAC) and alpha-mercaptopropionylglycine (alpha MPG), on the induction of DNA lesions were also examined. Pretreatment with DEM reduced liver GSH levels by greater than 70%. As assessed by the technique of alkaline elution, subsequent administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) resulted in DNA damage 4 h post MNNG treatment which was 4- to 8-fold greater than that induced in the livers of rats treated with MNNG alone. However, DEM pretreatment had little effect on the extent of DNA damage induced by methylnitrosourea (MNU). DEM alone did not cause any measurable DNA damage. Pretreatment with alpha MPG or NAC reduced MNNG-induced DNA damage by as much as 77%. In contrast, MNU-induced DNA damage was increased by alpha MPG treatment whereas NAC treatment was without effect. These results indicated that in the rat liver, the activity of some DNA alkylating agents may be modulated in varying degree by the concentration of intracellular thiols. These data support the notion that thiols play an important role in protection against carcinogen damage, and that synthetic thiols such as alpha MPG and NAC may be useful as anti-carcinogenic agents against certain carcinogens.}, }
@article {pmid3750340, year = {1986}, author = {Harman, AW and Self, G}, title = {Comparison of the protective effects of N-acetylcysteine, 2-mercaptopropionylglycine and dithiothreitol against acetaminophen toxicity in mouse hepatocytes.}, journal = {Toxicology}, volume = {41}, number = {1}, pages = {83-93}, doi = {10.1016/0300-483x(86)90106-x}, pmid = {3750340}, issn = {0300-483X}, mesh = {Acetaminophen/adverse effects/*antagonists &amp; inhibitors/pharmacology ; Acetylcysteine/*pharmacology ; Amino Acids, Sulfur/*pharmacology ; Animals ; Cells, Cultured ; Dithiothreitol/*pharmacology ; Glutathione/analysis ; Liver/analysis/cytology/*drug effects ; Male ; Mice ; Tiopronin/*pharmacology ; }, abstract = {The effects of N-acetylcysteine (NAC), 2-mercaptopropionylglycine (MPG) and dithiothreitol (DTT) on the metabolism and toxicity of acetaminophen (APAP) were examined in isolated mouse hepatocytes maintained in primary culture on collagen-coated dishes. Both NAC and MPG increased the formation of the glutathione and sulfate conjugates of APAP and decreased the covalent binding of the APAP reactive metabolite to cellular protein. DTT did not increase APAP metabolism but did decrease covalent binding. NAC, MPG and DTT decreased plasma membrane damage, as measured by leakage of lactate dehydrogenase from hepatocytes, during a 4-h incubation in 5.0 mM APAP. NAC, MPG and DTT also reduced the APAP-induced fall in glutathione levels in these cells. In other experiments, hepatocytes were exposed to 5.0 mM APAP for 1 h and then incubated during a post-exposure period in APAP-free medium. Damage increased during this post-exposure incubation. Addition of DTT, but not NAC or MPG, after APAP exposure protected the hepatocytes from plasma membrane damage during the post-exposure period. These results indicate that NAC and MPG exert their protective effects by their action on the reactive metabolite of APAP. As well as its effect in reducing the formation of the reactive metabolite, DTT has a potent protective effect against the toxic processes initiated by the APAP reactive metabolite.}, }
@article {pmid3753517, year = {1986}, author = {Skoglund, LA and Ingebrigtsen, K and Nafstad, I and Aalen, O}, title = {Efficacy of paracetamol-esterified methionine versus cysteine or methionine on paracetamol-induced hepatic GSH depletion and plasma ALAT level in mice.}, journal = {Biochemical pharmacology}, volume = {35}, number = {18}, pages = {3071-3075}, doi = {10.1016/0006-2952(86)90388-6}, pmid = {3753517}, issn = {0006-2952}, mesh = {Acetaminophen/metabolism/*toxicity ; Acetylcysteine/*metabolism ; Alanine Transaminase/*blood ; Animals ; Drug Compounding ; Glutathione/*metabolism ; Liver/drug effects/*metabolism ; Male ; Methionine/*analogs &amp; derivatives/metabolism ; Mice ; Time Factors ; }, abstract = {The effect of paracetamol-N-acetyl-DL-methionate (PAM) in preventing paracetamol-induced hepatic glutathione (GSH) depletion and hepatic cell damage assessed by plasma ALAT level, was compared to those of concomitantly administered paracetamol and N-acetyl-L-cysteine (NAC) or N-acetyl-DL-methionine (NAM) and paracetamol 400 mg/kg (P) alone. PAM, NAM and NAC reduced hepatic GSH depletion compared to P. The concomitant administration of GSH precursors in either form apparently maintained hepatic cell integrity as evaluated by plasma ALAT compared to predose and 16 hr control measurements. No statistically significant difference between PAM, NAM and NAC was observed. In group P a statistically significant, but transitory, rise in plasma ALAT level following dosage was seen. NAC was more effective than PAM and NAM in the prevention of GSH depletion 1 hr after dosing but was less effective in promoting de novo GSH synthesis towards 16 hr. There was no statistically significant difference between PAM and NAM with respect to effect on GSH depletion or hepatic cell integrity. PAM and NAM increased the GSH level significantly above control level 16 hr after dosing. PAM is rapidly cleaved to paracetamol and methionine following dosage as shown by the observed plasma paracetamol level. PAM compares favourably in hepatoprophylactic effect, to concomitant administration of equimolar doses of free N-acetyl-DL-methionine added to the paracetamol formulation.}, }
@article {pmid3768850, year = {1986}, author = {De Flora, S and Astengo, M and Serra, D and Bennicelli, C}, title = {Inhibition of urethan-induced lung tumors in mice by dietary N-acetylcysteine.}, journal = {Cancer letters}, volume = {32}, number = {3}, pages = {235-241}, doi = {10.1016/0304-3835(86)90175-8}, pmid = {3768850}, issn = {0304-3835}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Diet ; Glutathione/metabolism ; Lung Neoplasms/chemically induced/*prevention &amp; control ; Male ; Mice ; Urethane/metabolism/*toxicity ; }, abstract = {The thiol N-acetylcysteine (NAC), a precursor of intracellular glutathione (GSH), efficiently prevented the induction of lung tumors in Swiss albino mice, when supplemented to the diet (0.2%) both before and after an i.p. injection of the carcinogen urethan (ethyl carbamate). Irrespective of urethan administration, NAC also significantly enhanced GSH S-transferase activity in liver preparations of the same animals. These data show that, under certain conditions, it is possible to prevent chemically induced cancer by increasing the levels of physiological trapping agents.}, }
@article {pmid3467064, year = {1986}, author = {Murakami, S and Mori, Y}, title = {Changes in the structure of rat mucous glycoprotein and prostaglandin cytoprotection.}, journal = {Journal of pharmacobio-dynamics}, volume = {9}, number = {9}, pages = {760-770}, doi = {10.1248/bpb1978.9.760}, pmid = {3467064}, issn = {0386-846X}, mesh = {Acetylcysteine/*pharmacology ; Adhesiveness ; Animals ; Dinoprostone ; Ethanol ; Gastric Mucosa/drug effects/*metabolism ; Glycoproteins/*metabolism ; Male ; Mercaptoethanol/pharmacology ; Molecular Weight ; Prostaglandins E/antagonists &amp; inhibitors/*pharmacology ; Rats ; Rats, Inbred Strains ; Stomach Diseases/chemically induced/prevention &amp; control ; }, abstract = {Using a mucolytic agent, N-acetyl-L-cysteine (NAC), the structure of rat gastric mucous glycoprotein (GP) and its participation in prostaglandin cytoprotection were studied. Treatment of the undegraded native mucous GP with 20% NAC resulted in a marked reduction in molecular weight as obtained in the case of treatment with 0.5 M beta-mercaptoethanol. The amount of GP remaining in the gastric tissue, including the mucous layer after 3 h-incubation was defined as an indication of the mucous adhesiveness to the gastric mucosal surface. The adhesiveness was markedly decreased by the in vitro or in vivo treatment with NAC. The cytoprotective effect of prostaglandin E2 was significantly reduced by pretreatment with NAC. Elution profiles of mucous GP on Sepharose CL-2B showed a good correlation between decrease in the amount of the undegraded native mucous GP and the severity of gastric damage. In addition, the collapse of the native mucous GP into its subunits resulted in a decrease in the adhesiveness. These observations suggest that the maintenance of the native mucous GP is an essential factor for prostaglandin cytoprotection.}, }
@article {pmid3099627, year = {1986}, author = {De Flora, S and Romano, M and Basso, C and Bagnasco, M and Cesarone, CF and Rossi, GA and Morelli, A}, title = {Detoxifying activities in alveolar macrophages of rats treated with acetylcysteine, diethyl maleate and/or aroclor.}, journal = {Anticancer research}, volume = {6}, number = {5}, pages = {1009-1012}, pmid = {3099627}, issn = {0250-7005}, mesh = {Acetylcysteine/*metabolism ; Animals ; Aroclors/*metabolism ; Chlorodiphenyl (54% Chlorine) ; Dihydrolipoamide Dehydrogenase/metabolism ; Glucosephosphate Dehydrogenase/metabolism ; Glutathione Transferase/metabolism ; Inactivation, Metabolic ; Macrophages/*metabolism ; Male ; Maleates/*metabolism ; NAD/metabolism ; NADP/metabolism ; Phosphogluconate Dehydrogenase/metabolism ; Polychlorinated Biphenyls/*metabolism ; Pulmonary Alveoli/*cytology ; Rats ; }, abstract = {Single or sequential treatment of rats with the thiol N-acetyl-L-cysteine (NAC), the glutathione depletor diethyl maleate (DEM) and the enzyme inducer Aroclor 1254 (AR) produced several significant variations on metabolic activities of pulmonary alveolar macrophages (PAM). Specifically, all three compounds elicited an increase in some oxidoreductase activities, including the two dehydrogenases involved in the hexose monophosphate shunt (G6PD and 6PGD) and NADH- or NADPH-dependent diaphorases. Diaphorase activities were especially increased by sequential treatments with AR and DEM or with DEM and NAC. Both NAC and AR also stimulated other detoxifying mechanisms, such as those related to GSH S-transferase activity and to the NADPH-dependent reduction of hexavalent chromium. Therefore, all the monitored parameters were significantly enhanced not only by the enzyme inducer, but also by the thiol, demonstrating its protective role in the biotransformation of mutagenic/carcinogenic compounds.}, }
@article {pmid3741453, year = {1986}, author = {Dekant, W and Metzler, M and Henschler, D}, title = {Identification of S-1,2-dichlorovinyl-N-acetyl-cysteine as a urinary metabolite of trichloroethylene: a possible explanation for its nephrocarcinogenicity in male rats.}, journal = {Biochemical pharmacology}, volume = {35}, number = {15}, pages = {2455-2458}, doi = {10.1016/0006-2952(86)90039-0}, pmid = {3741453}, issn = {0006-2952}, mesh = {Acetylcysteine/*analogs &amp; derivatives/urine ; Animals ; Biotransformation ; Kidney Neoplasms/*chemically induced ; Male ; Rats ; Rats, Inbred Strains ; Trichloroethylene/*metabolism/toxicity ; }, }
@article {pmid3093380, year = {1986}, author = {Vazquez, JA and Paleos, GA and Lochs, H and Langer, K and Brandl, M and Adibi, SA}, title = {A concentrated mixture of amino acids and dipeptides for total parenteral nutrition.}, journal = {Infusionstherapie und klinische Ernahrung}, volume = {13}, number = {4}, pages = {193-198}, doi = {10.1159/000222140}, pmid = {3093380}, issn = {0378-0791}, support = {AM-15861/AM/NIADDK NIH HHS/United States ; }, mesh = {Amino Acids/metabolism/*therapeutic use ; Animals ; Dipeptides/metabolism/*therapeutic use ; Drug Evaluation, Preclinical ; Male ; Metabolic Clearance Rate ; Muscles/metabolism ; Papio ; Parenteral Nutrition, Total/adverse effects/*methods ; Solubility ; }, abstract = {Using a subhuman primate (baboon) we have investigated the utility of a 20% mixture of amino acids and dipeptides as the nitrogen source for total parental nutrition. The mixture, besides containing all 8 essential amino acids and a number of non-essential amino acids (glutamate, aspartate, arginine, histidine, serine, ornithine and alanine), contained 6 dipeptides (Gly-Ile, Gly-Leu, Gly-Val, Gly-Tyr, Gly-Gln, and Ala-Gln) and acetyl-cysteine. A week of total parenteral nutrition was preceded by one week of oral feeding. The caloric intake and composition during the two periods was identical except for the nitrogen source, which was intact protein during the oral period, and the mixture of amino acids and dipeptides during the parenteral period. There was no significant difference between gain in body weight or nitrogen balance during the two periods. There were selective increases in plasma and muscle concentrations of amino acids during the parenteral period, which appeared to reflect the amino acid enrichment of the nitrogen source. The efficient utilization of dipeptides was evidenced by their small concentrations in plasma and urine. The urinary excretion of dipeptides was about 1% of the amount infused. This efficiency of dipeptide utilization persisted even when the infusion rate of the amino acid and dipeptide mixture was increased by 7-fold. There was no alteration in liver, kidney, and immune function during the parenteral period. The data indicate the efficacy and safety of the mixture of amino acids and dipeptides as the nitrogen source for parenteral nutrition.}, }
@article {pmid3729973, year = {1986}, author = {Stewart, FP and Smith, AG}, title = {Metabolism of the "mixed" cytochrome P-450 inducer hexachlorobenzene by rat liver microsomes.}, journal = {Biochemical pharmacology}, volume = {35}, number = {13}, pages = {2163-2170}, doi = {10.1016/0006-2952(86)90587-3}, pmid = {3729973}, issn = {0006-2952}, mesh = {Acetylcysteine/pharmacology ; Aroclors/pharmacology ; Carbon Monoxide/pharmacology ; Chlorobenzenes/metabolism/*pharmacology ; Chlorodiphenyl (54% Chlorine) ; Cytochrome P-450 Enzyme System/*biosynthesis ; Ellipticines/pharmacology ; Enzyme Induction ; Female ; Gas Chromatography-Mass Spectrometry ; Glutathione/pharmacology ; Hexachlorobenzene/*pharmacology ; Male ; Methylcholanthrene/pharmacology ; Metyrapone/pharmacology ; Microsomes, Liver/*enzymology ; Molecular Weight ; NADP/metabolism ; Pentachlorophenol/metabolism ; Phenobarbital/pharmacology ; Polychlorinated Dibenzodioxins/pharmacology ; Proadifen/pharmacology ; Safrole/pharmacology ; }, abstract = {Hexachlorobenzene (HCB) was metabolised by phenobarbital-induced liver microsomes from male rats to pentachlorobenzene, pentachlorophenol, tetrachloro-1,2-benzenediol and tetrachloro-1,4-benzenediol (1:88:2:9). Metabolites were identified and quantified by electron capture g.l.c. Structures were confirmed by selective ion monitoring g.l.c.-m.s. The formation of pentachlorophenol was dependent on the presence of NADPH and O2 and inhibited by CO, SKF 525A and metyrapone. Conversion of HCB to pentachlorophenol was stimulated by pretreatment of rats with phenobarbital (PB) but not by 3-methylcholanthrene (3-MC), or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In contrast, the conversion of pentachlorophenol to tetrachloro-1,4-benzenediol was markedly induced by 3-MC but poorly by PB. HCB, Aroclor 1254 and isosafrole stimulated both hydroxylations. The cytochrome P-450c inhibitor 9-hydroxyellipticine inhibited conversion of pentachlorophenol to tetrachlorobenzenediols by HCB and beta-naphthoflavone induced micromes. In addition to hydroxylation reactions, evidence was obtained for the conjugation of HCB with glutathione catalysed by a microsomal glutathione transferase. Radioactivity from [14C]HCB was bound to microsomal protein during aerobic incubations. Binding was inhibited by GSH and N-acetyl-cysteine. Preliminary studies suggested that the reactive species was derived from tetrachloro-1,4-benzoquinone. No correlation was found between levels of metabolites or covalent binding produced by the two sexes and the marked sex dependent hepatic porphyrogenic and carcinogenic effects of HCB.}, }
@article {pmid3781430, year = {1986}, author = {Bach, PH and Ketley, CP and Ahmed, I and Dixit, M}, title = {The mechanisms of target cell injury by nephrotoxins.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {24}, number = {6-7}, pages = {775-779}, doi = {10.1016/0278-6915(86)90185-7}, pmid = {3781430}, issn = {0278-6915}, mesh = {*Acetylcysteine/*analogs &amp; derivatives ; Animals ; Butadienes/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Cysteine/*analogs &amp; derivatives/toxicity ; Doxorubicin/*toxicity ; Ethylamines/*toxicity ; Kidney/*drug effects/metabolism ; Lipids/analysis ; Male ; Peroxidases/analysis ; Probenecid/pharmacology ; Rats ; Rats, Inbred Strains ; }, abstract = {Hexachlorobutadiene-N-acetylcysteine (HCBD-NAC), adriamycin and 2-bromoethanamine hydrobromide are three renal toxins that have shown in vivo a highly selective target cell toxicity--to the proximal tubules, the glomerular epithelial cells and the medullary interstitial cells, respectively. To study some aspects of the mechanisms of this selective toxicity, the three types of target cell were isolated from the kidneys of Wistar rats, and cultures of the cells or tissue fragments were exposed to various concentrations of the three toxins. Using fluorescence microscopy combined with enzyme and histochemical probes, the selective target-cell toxicity of the three compounds already established in vivo was demonstrated also in vitro. Moreover, the in vitro toxic effect of HCBD-NAC was ameliorated by probenecid, as is the case in vivo. Several functional characteristics specific to each of the target cells, such as the selective uptake of a toxin, the presence of lipid droplets and the level of peroxidative enzyme activity, have been identified as probable factors in the occurrence of the target cell necrosis.}, }
@article {pmid3741538, year = {1986}, author = {Wilpart, M and Speder, A and Roberfroid, M}, title = {Anti-initiation activity of N-acetylcysteine in experimental colonic carcinogenesis.}, journal = {Cancer letters}, volume = {31}, number = {3}, pages = {319-324}, doi = {10.1016/0304-3835(86)90154-0}, pmid = {3741538}, issn = {0304-3835}, mesh = {1,2-Dimethylhydrazine ; Acetylcysteine/*pharmacology ; Animals ; Carcinogens/*toxicity ; Colonic Neoplasms/*chemically induced/pathology ; Dimethylhydrazines/*toxicity ; Intestinal Neoplasms/chemically induced/pathology ; Male ; Methylhydrazines/*toxicity ; Rats ; Rats, Inbred Strains ; }, abstract = {N-Acetylcysteine (NAC) is a soluble nucleophile that has been shown to have antimutagenic activity towards various genotoxic agents including 1,2-dimethylhydrazine (DMH). The present report extends such observations by showing the protective effect of NAC against the carcinogenic activity of DMH. This thiol-containing molecule reduced the incidence of rat intestinal tumors. Moreover, it significantly lowered the colic tumor yield as expressed by the number of tumors per rat bearing tumors. With regard to localisation of colic carcinomas, NAC induced a shift from distal to more proximal sites.}, }
@article {pmid3714342, year = {1986}, author = {Rumack, BH}, title = {Acetaminophen overdose in children and adolescents.}, journal = {Pediatric clinics of North America}, volume = {33}, number = {3}, pages = {691-701}, doi = {10.1016/s0031-3955(16)36050-3}, pmid = {3714342}, issn = {0031-3955}, mesh = {Acetaminophen/metabolism/*poisoning ; Acetylcysteine/therapeutic use ; Adolescent ; Alanine Transaminase/blood ; Aspartate Aminotransferases/blood ; Child ; Child, Preschool ; Glutathione/metabolism ; Humans ; Inactivation, Metabolic ; Intestinal Absorption ; Liver/metabolism ; Medical History Taking ; NADPH-Ferrihemoprotein Reductase ; Oxidoreductases/metabolism ; }, abstract = {Ingestion of acetaminophen by young children and adolescents is common. Most children under the age of 6 who have ingested pediatric products can be safely managed at home. Children under the age of 6 who have taken a significant ingestion should be evaluated with a plasma level 4 or more hours after ingestion and, if toxic, treated with the antidote NAC prior to 16 hours postingestion. Less than 5 per cent of children under the age of 6 with toxic plasma levels will develop transient hepatic abnormalities. Adolescents who use acetaminophen in a suicidal or manipulative attempt should be seen and evaluated with a plasma acetaminophen level 4 or more hours postingestion. If the level is in the potentially toxic range on the nomogram, they should be treated prior to 16 hours postingestion with the antidote NAC. All patients should be evaluated for the possibility of other drugs or ingestants, especially if there is a change in the sensorium early in the course. The expected course of events in a patient with a toxic level of acetaminophen in the plasma is to have nausea, vomiting, and diaphoresis the first 24 hours. Following this, the patient should feel better but may begin to develop abnormalities of SGOT, SGPT, bilirubin, and prothrombin. Toxic patients will have peak enzyme levels at 72 to 96 hours. Over 99 per cent of patients will recover to normal values by 7 to 8 days postingestion. Long-term sequelae are not known.}, }
@article {pmid3702608, year = {1986}, author = {Lerza, R and Bogliolo, G and Muzzulini, C and Pannacciulli, I}, title = {Failure of N-acetylcysteine to protect against cis-dichlorodiammineplatinum(II)-induced hematopoietic toxicity in mice.}, journal = {Life sciences}, volume = {38}, number = {19}, pages = {1795-1800}, doi = {10.1016/0024-3205(86)90131-1}, pmid = {3702608}, issn = {0024-3205}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bone Marrow/drug effects ; Cisplatin/*antagonists &amp; inhibitors/toxicity ; Colony-Forming Units Assay ; Female ; Hematopoiesis/*drug effects ; Male ; Mice ; }, abstract = {In view of the results showing a decrease in cis-dichlorodiammineplatinum(II) (cis-DDP) nephrotoxicity after administration of thiol donors, this study was carried out to test the possibility that N-acetylcysteine (NAC) was active against myelodepressive effects of the anticancer drug. Cis-DDP (15.5 mg/kg body weight, i.v.) was administered to control mice and to mice treated simultaneously or 1 h later with NAC (800 mg/kg body weight, i.v.). At various times after treatment, up to 11 days, assessments were made of peripheral blood cell levels and bone marrow progenitor cell (CFUs and CFUc) concentrations. Cis-DDP caused a decrease in hemopoietic precursor cells in the order of that caused by other hemopoietic precursor cells in the order of that caused by other myelodepressive drugs, whereas there was only a slight decrease in peripheral blood WBC. In this experimental setting, NAC administration did not afford significant protection against platinum toxicity on bone marrow precursors or peripheral blood cells.}, }
@article {pmid3741137, year = {1986}, author = {Lock, EA and Odum, J and Ormond, P}, title = {Transport of N-acetyl-S-pentachloro-1,3-butadienylcysteine by rat renal cortex.}, journal = {Archives of toxicology}, volume = {59}, number = {1}, pages = {12-15}, pmid = {3741137}, issn = {0340-5761}, mesh = {*Acetylcysteine/*analogs &amp; derivatives ; Animals ; Antimetabolites/pharmacology ; Biological Transport, Active ; Butadienes/*metabolism ; Cysteine/*analogs &amp; derivatives/metabolism ; Female ; Kidney Cortex/*metabolism ; Kinetics ; Rats ; Rats, Inbred Strains ; Temperature ; }, abstract = {N-acetyl-S-pentachloro-1,3-butadienyl-L-cysteine (PCBD-NAC) is a postulated metabolite derived from glutathione conjugation of hexachloro-1,3-butadiene and is nephrotoxic in the rat. Because PCBD-NAC causes selective necrosis to the pars recta of the proximal tubule, and is an organic anion it might be expected to be transported by the renal organic anion transport system. Rat renal cortical slices were used to characterise the transport. 14C-PCBD-NAC uptake was temperature dependent and reduced by the metabolic inhibitors cyanide and iodoacetate. Probenecid and sulphinpyrazone, specific competitive inhibitors of the anion transport system, and dinitrophenol, a metabolic inhibitor as well as a competitive inhibitor of anion transport, reduced PCBD-NAC transport. Organic cations or uric acid transport inhibitors did not alter PCBD-NAC accumulation by the slices. These data are consistent with the transport of PCBD-NAC by the renal organic anion secretory system.}, }
@article {pmid3737473, year = {1986}, author = {Schmitt-Gräff, A and Scheulen, ME}, title = {Prevention of adriamycin cardiotoxicity by niacin, isocitrate or N-acetyl-cysteine in mice. A morphological study.}, journal = {Pathology, research and practice}, volume = {181}, number = {2}, pages = {168-174}, doi = {10.1016/S0344-0338(86)80006-1}, pmid = {3737473}, issn = {0344-0338}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Carcinoma, Ehrlich Tumor/drug therapy/pathology ; Doxorubicin/therapeutic use/*toxicity ; Heart/*drug effects ; Isocitrates/*pharmacology ; Male ; Mice ; Mice, Inbred Strains ; Microscopy, Electron ; Myocardium/*pathology/ultrastructure ; Niacin/*pharmacology ; }, abstract = {Adriamycin is known to produce treatment limiting cardiotoxicity. We studied the effect of niacin, isocitrate, and N-acetyl-cysteine on cumulative adriamycin-induced cardiotoxicity in NMRI mice. Pathologic grading of the hearts indicated a significant reduction in myocardial injury. In addition, according to median survival and weight changes there was a significant decrease in toxicity. As demonstrated in Ehrlich ascites tumor, coadministration of N-acetyl-cysteine may interfere with the antitumor activity of adriamycin. In contrast, niacin and isocitrate did not show significant inhibition of antineoplastic activity. Our experiments suggest a promising role of niacin and isocitrate as potential cardioprotectors in the course of chemotherapy with adriamycin.}, }
@article {pmid2871175, year = {1986}, author = {Newton, JF and Hoefle, D and Gemborys, MW and Mudge, GH and Hook, JB}, title = {Metabolism and excretion of a glutathione conjugate of acetaminophen in the isolated perfused rat kidney.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {237}, number = {2}, pages = {519-524}, pmid = {2871175}, issn = {0022-3565}, support = {ES00560/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/*metabolism ; Acetylcysteine/metabolism ; Animals ; Cysteine/metabolism ; Glutathione/*metabolism ; In Vitro Techniques ; Kidney/*metabolism ; Male ; Metabolic Clearance Rate ; Perfusion ; Rats ; Rats, Inbred F344 ; gamma-Glutamyltransferase/physiology ; }, abstract = {Acetaminophen-glutathione (APAP-GSH) is the initial sulfur-containing metabolite of APAP produced by the liver. However, little, if any, APAP-GSH is found in the urine of intact animals. Rather, the cysteine (APAP-CYS) and N-acetylcysteine (APAP-NAC) conjugates are the predominant sulfur-containing metabolites of APAP excreted in the urine. To define more precisely the role of the kidney in total body disposition of APAP, the metabolism and excretion of each of these metabolites was quantified in the isolated perfused rat kidney (IPK). With perfusate concentrations of 0.031, 0.125 and 0.250 mM APAP-GSH, the IPK metabolized APAP-GSH to APAP-CYS rapidly. Further metabolism of APAP-CYS to APAP-NAC proceeded at a much slower rate. Consequently, at 0.031 mM APAP-GSH, negligible amounts of APAP-CYS were found in the urine. However, as the concentration of APAP-GSH was increased so did the excretion of APAP-CYS. In contrast, the excretion of APAP-NAC did not exhibit dependence on APAP-GSH concentration. APAP-NAC was excreted by a probenecid sensitive transport mechanism whereas APAP-CYS excretion appeared to be related only to glomerular filtration. In addition, the disappearance of APAP-GSH was much greater than could be accounted for by glomerular filtration. These data indicate that the IPK is an effective model for the study of metabolism and excretion of xenobiotics that have undergone conjugation with GSH.}, }
@article {pmid3740968, year = {1986}, author = {Such, L and Morcillo, E and Chorro, FJ and Montoro, A and Alberola, A and Aparicio, F and Viña, J}, title = {Beneficial effects of N-acetyl cysteine on acute myocardial infarction in open-chest dogs.}, journal = {Archivos de farmacologia y toxicologia}, volume = {12}, number = {1}, pages = {37-40}, pmid = {3740968}, issn = {0304-8616}, mesh = {Acetylcysteine/pharmacology/*therapeutic use ; Animals ; Coronary Circulation/drug effects ; Dogs ; Female ; Hemodynamics/drug effects ; Male ; Myocardial Infarction/*drug therapy/physiopathology ; }, }
@article {pmid3087329, year = {1986}, author = {Llobet, JM and Domingo, JL and Corbella, J}, title = {Comparison of the effectiveness of several chelators after single administration on the toxicity, excretion and distribution of cobalt.}, journal = {Archives of toxicology}, volume = {58}, number = {4}, pages = {278-281}, pmid = {3087329}, issn = {0340-5761}, mesh = {Acetylcysteine/pharmacology ; Animals ; Chelating Agents/administration &amp; dosage/*pharmacology ; Cobalt/metabolism/*toxicity ; Cysteine/pharmacology ; Edetic Acid/pharmacology ; Glutathione/pharmacology ; Male ; Mice ; Pentetic Acid/pharmacology ; Tissue Distribution ; }, abstract = {The effects of the chelating agents Na2Ca-ethylendiaminetetraacetate (EDTA), Na3Ca-diethylentriaminepentaacetate (DTPA), L-cysteine, 2,3-dimercaptosuccinic acid (DMSA), N-acetyl-L-cysteine (NAC), glutathione, D,L-penicillamine (D,L-PEN) and 2,3-dimercaptopropanol (BAL) on the toxicity, distribution and excretion of intraperitoneally injected cobalt were studied in male Swiss mice. To determine the effect of the various chelators on the toxicity of cobalt, various doses of CoCl2 (0.60-1.80 mmol/kg) were given, followed immediately by the IP administration of the chelator (at a dose equal to one-fourth of their respective LD50). EDTA and DTPA were the most effective. EDTA, DTPA and L-cysteine, NAC and glutathione were also the most effective in increasing the urinary excretion of cobalt and reducing the concentration of the metal in various tissues. EDTA appears to be the most effective agent of those tested in the prevention of acute cobalt intoxication.}, }
@article {pmid3952743, year = {1986}, author = {Banner, W and Koch, M and Capin, DM and Hopf, SB and Chang, S and Tong, TG}, title = {Experimental chelation therapy in chromium, lead, and boron intoxication with N-acetylcysteine and other compounds.}, journal = {Toxicology and applied pharmacology}, volume = {83}, number = {1}, pages = {142-147}, doi = {10.1016/0041-008x(86)90331-5}, pmid = {3952743}, issn = {0041-008X}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Boric Acids/*toxicity/urine ; Chelating Agents/*therapeutic use ; Chromates/*toxicity ; Chromium/urine ; Female ; Kinetics ; Lead/*toxicity/urine ; Lead Poisoning/*drug therapy ; Male ; *Organometallic Compounds ; Potassium Dichromate/*toxicity ; Rats ; Rats, Inbred Strains ; Time Factors ; }, abstract = {The usefulness of N-acetylcysteine (NAC) as a chelating agent was studied for the toxin potassium dichromate, lead tetraacetate, and boric acid. Mature Sprague-Dawley rats were intoxicated with these substances and placed in metabolic cages. Urinary excretion rates of intoxicant and total urine volume were determined during treatment with N-acetylcysteine, calcium EDTA, and/or dimercaptosuccinic acid, N-acetylcysteine proved to be the most effective agent at increasing the excretion of chromium and boron and was also able to reverse the oliguria associated with these toxins. Dimercaptosuccinic acid was most effective at the chelation of lead. NAC did not increase the excretion of lead. We conclude that NAC may be useful in intoxications due to chromate and borate and is effective at reversing the oliguria associated with these intoxicants.}, }
@article {pmid3948331, year = {1986}, author = {Ribeiro, O and Kirkby, CA and Hirom, PC and Millburn, P}, title = {Reactive intermediates from 3-hydroxybenzo[a]pyrene and its glucuronide.}, journal = {Carcinogenesis}, volume = {7}, number = {3}, pages = {481-484}, doi = {10.1093/carcin/7.3.481}, pmid = {3948331}, issn = {0143-3334}, mesh = {Acetylcysteine/metabolism ; Benzopyrenes/*metabolism ; Chromatography, High Pressure Liquid ; Glucuronates/*metabolism ; Horseradish Peroxidase/metabolism ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Spectrophotometry, Ultraviolet ; }, abstract = {3-Hydroxybenzo[a]pyrene (3-OH-BaP) is oxidized by the horseradish peroxidase/H2O2 system to benzo[a]pyrene-3,6-quinone. In the presence of N-acetylcysteine one other product is also formed. This was identified by its chemical, and u.v., mass and n.m.r. spectral properties as 6-(H-acetyl-cystein-S-yl)-3-hydroxybenzo[a]pyrene (6-NAc-cys-3-OH-BaP). Replacement of the N-acetylcysteine by glutathione leads to the formation of a 3-OH-BaP-glutathione adduct. Enzymic hydrolysis of benzo[a]pyrene-3-glucuronide in the presence of N-acetylcysteine yields, in addition to 3-OH-BaP, a product which co-chromatographs with 6-NAc-cys-3-OH-BaP and has identical chemical and spectral characteristics.}, }
@article {pmid3944770, year = {1986}, author = {Hjelle, JJ and Brzeznicka, EA and Klaassen, CD}, title = {Comparison of the effects of sodium sulfate and N-acetylcysteine on the hepatotoxicity of acetaminophen in mice.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {236}, number = {2}, pages = {526-534}, pmid = {3944770}, issn = {0022-3565}, support = {ES 03192/ES/NIEHS NIH HHS/United States ; ES 07079/ES/NIEHS NIH HHS/United States ; }, mesh = {Acetaminophen/analogs &amp; derivatives/metabolism/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Dose-Response Relationship, Drug ; Glutathione/analysis ; Half-Life ; Liver/*drug effects/pathology ; Male ; Mice ; Mice, Inbred Strains ; Phosphoadenosine Phosphosulfate/analysis ; Sulfates/metabolism/*pharmacology ; }, abstract = {N-acetylcysteine (NAC) has been proposed to decrease the toxicity of acetaminophen (AA) via two mechanisms: by increasing cysteine availability for hepatic glutathione biosynthesis and by increasing inorganic sulfate levels, which would increase AA sulfation and elimination. Because administration of sodium sulfate also reportedly decreases AA-induced toxicity, we have investigated the role of inorganic sulfate in the antidotal properties of NAC. Simultaneous administration of NAC (4 mmol/kg) and AA (2.5 and 4 mmol/kg) to male mice prevented AA-induced lethality and hepatotoxicity whereas sodium sulfate (4 mmol/kg) did not. Neither NAC nor sodium sulfate produced significant changes in the half-life (44 min) or clearance (9.0 ml/min/kg) of AA (4.0 mmol/kg) from blood nor were the amounts of AA-sulfate, AA-cysteine or AA-mercapturate excreted in urine altered. Injection of either sodium sulfate or NAC increased serum sulfate concentration and prevented the depletion in serum sulfate produced by AA. Hepatic adenosine 3'-phosphate 5'-phosphosulfate concentrations were decreased 15 and 30 min after AA and injection of either sodium sulfate or NAC lessened this effect. The concentration of glutathione in liver was decreased markedly after AA. NAC attenuated this effect but sodium sulfate did not. Sodium sulfate did not decrease covalent binding of tritium derived from [3H]AA to liver protein whereas NAC decreased binding by 25%. These findings show that administration of sodium sulfate increases serum sulfate concentration and hepatic adenosine 3'-phosphate 5'-phosphosulfate levels but does not protect against acetaminophen-induced hepatotoxicity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid3943776, year = {1986}, author = {Blei, AT and Gottstein, J}, title = {Isosorbide dinitrate in experimental portal hypertension: a study of factors that modulate the hemodynamic response.}, journal = {Hepatology (Baltimore, Md.)}, volume = {6}, number = {1}, pages = {107-111}, doi = {10.1002/hep.1840060120}, pmid = {3943776}, issn = {0270-9139}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Drug Synergism ; Hemodynamics/*drug effects ; Hypertension, Portal/*drug therapy ; Isosorbide Dinitrate/*therapeutic use ; Male ; Rats ; Splanchnic Circulation/drug effects ; }, abstract = {Isosorbide dinitrate, a long-acting vasodilator, has been tested in human portal hypertension with conflicting results. In order to determine some of the factors that could affect the individual response to this drug, we infused isosorbide dinitrate at a low dose (10 to 25 micrograms per kg per min) and a high dose (100 micrograms per kg per min) to rats with portal vein stenosis. Under pentobarbital anesthesia, portal pressure was measured with an ileocolic vein catheter while cardiac output and regional blood flows were measured with the microsphere technique. At a dose that decreased arterial pressure by approximately 10%, cardiac output remained unchanged while portal vein inflow decreased significantly; portal pressure was not reduced (10.7 +/- 0.2 vs. 10.0 +/- 0.3 mm Hg), indicating a rise in portal vascular resistance. At a high dose of isosorbide dinitrate, arterial pressure and cardiac output fell markedly; portal pressure decreased only modestly (11.3 +/- 0.3 vs. 9.8 +/- 0.6 mm Hg, p less than 0.05), but portal flow was unchanged, indicating a reduction in portal vascular resistance. In addition, portal hypertensive rats received a constant i.v. infusion of N-acetyl-cysteine; the combination of the latter and isosorbide dinitrate markedly potentiated the effects on arterial pressure. Thus, the dose of the drug and the presence of cysteine-containing compounds appear to modulate the hemodynamic response to isosorbide dinitrate. Clinical testing with this drug should be undertaken with consideration of these factors.}, }
@article {pmid3815719, year = {1986}, author = {Einhorn, LH and Loehrer, PJ}, title = {Ifosfamide chemotherapy for pancreatic carcinoma.}, journal = {Cancer chemotherapy and pharmacology}, volume = {18 Suppl 2}, number = {}, pages = {S51-4}, pmid = {3815719}, issn = {0344-5704}, support = {1R35 CA 39844-01/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Female ; Humans ; Ifosfamide/adverse effects/*therapeutic use ; Infections/etiology ; Leukopenia/chemically induced ; Male ; Middle Aged ; Pancreatic Neoplasms/*drug therapy ; Thrombocytopenia/chemically induced ; Urologic Diseases/chemically induced ; }, abstract = {From April 1982 through February 1984, 29 patients with pancreatic cancer were treated with ifosfamide (1.25-1.5 g/m2 on days 1-5) + N-acetylcysteine (NAC) 2 g p.o. every 6 h on days 1-7 every 3 weeks. In responding patients without serious toxicity, subsequent courses of ifosfamide were escalated every 3 weeks by 0.25 g/m2 per day to a maximum of 2 g/m2 per day, with escalation of NAC to 12 g/day. Patients with KPS less than 50, serum creatinine or bilirubin greater than 2 mg/d 1, or obstructive uropathy were ineligible. The median age was 54 (range 36-78), median KPS 70, and median pretreatment weight loss 9 kg. Toxicity included nausea, vomiting, moderate myelosuppression, and occasional mental confusion. Hematuria (greater than 11 RBC/HPF) developed in only 1/29 courses (17 patients) of ifosfamide at greater than or equal to 1.75 g/m2 per day, and in 7/52 courses (27 patients) overall (13%). Of 27 evaluable patients 6 responded (22%), including 1 with complete response. The median survival was 6 months. Based upon these results, we are currently evaluating ifosfamide + 5-fluorouracil in pancreatic cancer.}, }
@article {pmid3809742, year = {1986}, author = {De Flora, S and Rossi, GA and De Flora, A}, title = {Metabolic, desmutagenic and anticarcinogenic effects of N-acetylcysteine.}, journal = {Respiration; international review of thoracic diseases}, volume = {50 Suppl 1}, number = {}, pages = {43-49}, doi = {10.1159/000195087}, pmid = {3809742}, issn = {0025-7931}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biotransformation/drug effects ; Carcinogens/metabolism ; Glutathione/metabolism ; Humans ; Lung Neoplasms/chemically induced/*prevention &amp; control ; Mutagens/metabolism ; *Mutation ; Smoking ; }, abstract = {N-acetylcysteine (NAC) is often administered to respiratory patients with histories of exposure to noxious agents (e.g. cigarette smoke and atmospheric pollutants), which are known to act as glutathione (GSH) depletors and as cancer initiators and/or promoters. Since NAC is a precursor of intracellular GSH, we investigated its effects on GSH metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. In vitro, NAC induced a significant increase in oxidized glutathione (GSSG) reductase activity in rat liver preparations and counteracted the mutagenicity of direct-acting compounds (such as epichlorohydrin, hydrogen peroxide, 4-nitroquinoline-N-oxide and dichromate), as a result of its reducing and scavenging properties. At high concentrations, the drug completely inhibited the mutagenicity of procarcinogens (cigarette smoke condensate, tryptophan pyrolysate, cyclophosphamide, 2-aminofluorene, benzo(a)pyrene and aflatoxin B1) by binding their electrophilic metabolites. In contrast, their metabolic activation was stimulated by decreasing NAC concentrations, especially when liver preparations from enzyme-induced rats were used. Lung and liver subcellular preparations of rats treated in vivo with NAC, in various combinations with enzyme inducers and/or GSH depletors, also affected the mutagenicity of a number of compounds. NAC generally increased intracellular GSH and restored its levels following depletion. It did not affect the levels nor the spectral properties of cytochromes P-450 in pulmonary and hepatic microsomes, whereas it stimulated, especially in Aroclor-pretreated animals, cytosolic enzyme activities involved in NADP or GSSG reduction (G6PD, 6PGD and GSSG reductase) and in the reductive detoxification of xenobiotics (DT diaphorase). When administered with the diet, at a nontoxic posology (120 mg/kg b.w.), NAC markedly inhibited the induction of lung tumors in mice by a potent carcinogen (urethane).}, }
@article {pmid3809741, year = {1986}, author = {Moldéus, P and Cotgreave, IA and Berggren, M}, title = {Lung protection by a thiol-containing antioxidant: N-acetylcysteine.}, journal = {Respiration; international review of thoracic diseases}, volume = {50 Suppl 1}, number = {}, pages = {31-42}, doi = {10.1159/000195086}, pmid = {3809741}, issn = {0025-7931}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Biological Availability ; Free Radicals ; Glutathione/physiology ; Humans ; Lung/*drug effects/metabolism ; Lung Diseases, Obstructive/prevention &amp; control ; *Smoking ; }, abstract = {N-acetylcysteine (NAC) is a thiol-containing compound which nonenzymatically interacts and detoxifies reactive electrophiles and free radicals. NAC was shown to effectively protect human bronchial fibroblasts against the toxic effects of tobacco smoke condensates and the isolated perfused lung against the glutathione (GSH)-depleting effect of tobacco smoke. NAC was also shown to reduce the reactive oxygen intermediate hydrogen peroxide (H2O2) and protect against the toxic effects of H2O2. In vivo studies, however, demonstrated that NAC when administered orally has very low bioavailability due to rapid metabolism to GSH among other metabolites. Thus, even though NAC is very effective in protecting cells of different origins from the toxicity of reactive components in tobacco smoke and reactive oxygen species, a direct scavenging effect by NAC in vivo, particularly when administered orally, does not seem likely. The bioavailability of NAC itself is very low when given this route. A more relevant mechanism in vivo for any protective effect NAC may exert against toxic species may be due to NAC acting as a precursor of GSH and facilitating its biosynthesis. GSH will then serve as the protective agent and detoxify reactive species both enzymatically and nonenzymatically.}, }
@article {pmid3809740, year = {1986}, author = {Ziment, I}, title = {Acetylcysteine: a drug with an interesting past and a fascinating future.}, journal = {Respiration; international review of thoracic diseases}, volume = {50 Suppl 1}, number = {}, pages = {26-30}, doi = {10.1159/000195085}, pmid = {3809740}, issn = {0025-7931}, mesh = {Acetylcysteine/administration &amp; dosage/metabolism/*pharmacology ; Animals ; Humans ; Mucus/drug effects ; }, abstract = {N-acetylcysteine (NAC) possesses a free sulfhydryl group that can rupture disulfide bridges. Although it is considered to be a mucolytic, its mucokinetic actions include expectorant, bronchorrheic and mucoregulatory contributions. New uses include the management of acetaminophen poisoning and the scavenging of free radicals liberated by cancer chemotherapy drugs. The antioxidant effects may be of prophylactic value in lungs at risk from smoking, pollution and infection. Other uses proposed for NAC include the therapy of connective tissue diseases and its use as a component in life extension diets.}, }
@article {pmid3793329, year = {1986}, author = {Palermo, MS and Olabuenaga, SE and Giordano, M and Isturiz, MA}, title = {Immunomodulation exerted by cyclophosphamide is not interfered by N-acetyl cysteine.}, journal = {International journal of immunopharmacology}, volume = {8}, number = {6}, pages = {651-655}, doi = {10.1016/0192-0561(86)90038-x}, pmid = {3793329}, issn = {0192-0561}, mesh = {Acetylcysteine/*pharmacology ; *Adjuvants, Immunologic ; Animals ; Antibody Formation/*drug effects ; Antibody-Dependent Cell Cytotoxicity/drug effects ; Cyclophosphamide/*pharmacology ; Cystitis/immunology ; Hemorrhage/immunology ; *Hypersensitivity, Delayed ; Killer Cells, Natural/drug effects/immunology ; Leukemia P388/immunology ; Lymphocytes/drug effects/*immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred Strains ; }, abstract = {Metabolism of cyclophosphamide (Cy) by liver enzymes results in cytostatic products and acrolein, which exerts urotoxicity. Experiments were designed to determine which metabolites are responsible for Cy-induced immunomodulation. For this purpose, mice were treated simultaneously with Cy and N-acetyl-cysteine (NAC), a thiol compound which reacts with acrolein, and different immunological functions were assayed. Results show that NAC did not interfere with Cy effects on antibody-dependent cellular cytotoxicity (ADCC), NK activity, delayed-type hypersensitivity (DTH) or antibody production, indicating that modulation of these functions by Cy is mediated by its cytostatic metabolites.}, }
@article {pmid3764322, year = {1986}, author = {Ishmael, J and Lock, EA}, title = {Nephrotoxicity of hexachlorobutadiene and its glutathione-derived conjugates.}, journal = {Toxicologic pathology}, volume = {14}, number = {2}, pages = {258-262}, doi = {10.1177/019262338601400216}, pmid = {3764322}, issn = {0192-6233}, mesh = {*Acetylcysteine/*analogs &amp; derivatives ; Animals ; Butadienes/*toxicity ; Cysteine/analogs &amp; derivatives/toxicity ; Female ; Glutathione/analogs &amp; derivatives/toxicity ; Kidney Diseases/*chemically induced/pathology ; Kidney Medulla/pathology ; Kidney Tubules, Proximal/pathology ; Male ; Necrosis ; Rats ; Sex Factors ; Urea/blood ; }, abstract = {The nephrotoxicity of hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate (HCBD-CYS), and its N-acetyl cysteine conjugate (HCBD-NAC) were compared in male and female Alderley Park rats. Rats, six to eight weeks of age, were given a single intra-peritoneal injection of HCBD or its conjugates and killed 24 hours later. Nephrotoxicity was assessed by histological examination and plasma urea. All three glutathione-derived conjugates produced an elevation of plasma urea and proximal renal tubular necrosis with a similar localization in the pars recta as seen with HCBD. All the conjugates were more nephrotoxic than HCBD itself. HCBD was about four times more toxic to female rats than males. This sex difference was also shown by all the HCBD metabolites.}, }
@article {pmid3716022, year = {1986}, author = {Wegener, T and Wallin, R and Saldeen, T}, title = {Effect of N-acetylcysteine on fibrin deposition in the rat lung due to intravascular coagulation.}, journal = {Upsala journal of medical sciences}, volume = {91}, number = {1}, pages = {45-52}, doi = {10.3109/03009738609178490}, pmid = {3716022}, issn = {0300-9734}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disseminated Intravascular Coagulation/chemically induced/*metabolism ; Fibrin/*metabolism ; Fibrinogen/metabolism ; Humans ; Iodine Radioisotopes ; Kinetics ; Lung/drug effects/*metabolism ; Male ; Rats ; Rats, Inbred Strains ; Tranexamic Acid ; }, abstract = {Intravascular coagulation was induced in rats by i.p. injection of a fibrinolysis inhibitor, tranexamic acid (AMCA, 200 mg/kg B.W.), and i.v. injection of bovine thrombin (500 NIH units/kg B.W.) and the fibrin deposition in the lungs was assessed with 125I-labelled fibrinogen. Treatment with N-acetylcysteine (NAC) partly prevented the deposition of fibrin in the lungs, and the disappearance of fibrinogen from the blood, but did not seem to influence the elimination of fibrin in the lungs. The results indicate that NAC may counteract pulmonary damage in this experimental model, by inhibiting intravascular fibrin formation.}, }
@article {pmid3698928, year = {1986}, author = {Rogers, DF and Jeffery, PK}, title = {Inhibition by oral N-acetylcysteine of cigarette smoke-induced "bronchitis" in the rat.}, journal = {Experimental lung research}, volume = {10}, number = {3}, pages = {267-283}, doi = {10.3109/01902148609061497}, pmid = {3698928}, issn = {0190-2148}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Animals ; Bronchitis/etiology/*prevention &amp; control ; Cell Count ; Epithelial Cells ; Glycoproteins/metabolism ; Intracellular Fluid/metabolism ; Lung/cytology/metabolism ; Male ; *Plants, Toxic ; Rats ; Rats, Inbred Strains ; Smoke/*adverse effects ; *Nicotiana ; Trachea/cytology ; }, abstract = {Specific pathogen-free rats were exposed to the cigarette smoke (CS) of 25 cigarettes daily for 14 days and concurrently given N-acetylcysteine (Nac) as 1% of their drinking water (average daily dose 973 mg/kg). The thickness of the epithelium was measured at four airway levels and the numbers of mucus-containing secretory cells, stained for neutral or acidic glycoprotein (NGP or AGP respectively), were counted in surface epithelium at eight airway levels. Cigarette smoke increased the thickness of the epithelium at three of the airway levels studied by between 37 and 72%. The number of secretory cells was increased at all airway levels distal to the upper trachea by between 102 and 421%. Secretory cells containing NGP were reduced in number but this was more than offset by a large increase in the number of secretory cells containing AGP at all airway levels. N-acetylcysteine inhibited CS-induced epithelial thickening. Nac also inhibited the CS-induced increase in the number of secretory cells with AGP, but had little effect on the CS-induced reduction in the number of cells with NGP. Thus, prophylactic oral N-acetylcysteine led to an overall inhibition of CS-induced mucous cell hyperplasia and epithelial hypertrophy. The results suggest a novel anti-inflammatory action for a drug with known mucolytic effects.}, }
@article {pmid3697545, year = {1986}, author = {Cotgreave, IA and Grafström, RC and Moldéus, P}, title = {Modulation of pneumotoxicity by cellular glutathione and precursors.}, journal = {Bulletin europeen de physiopathologie respiratoire}, volume = {22}, number = {1}, pages = {263s-266s}, pmid = {3697545}, issn = {0395-3890}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Glutathione/biosynthesis/*metabolism/physiology ; Humans ; Lung Diseases/*metabolism/physiopathology ; }, abstract = {The maintenance of intracellular glutathione levels is essential for both the normal functioning of cells and their protection from both intra- and extracellularly derived oxidative damages. As the lungs are exposed both to airborne reactive xenobiotic agents and to inflammatory stress, which may cause severe localized depletions of intracellular glutathione (GSH) with resultant pathological changes, we have studied the potential of the drug N-acetylcysteine (NAC) as a pneumoprotective agent both in vitro and in vivo. These studies have demonstrated that, depending upon the route of administration, NAC may elicit pneumoprotection through a number of distinct mechanisms. NAC may protect cellular integrity by competing with intracellular GSH and reacting directly with potentially toxic agents by spontaneous conjugation and/or reduction. However, when NAC is given orally, in doses similar to those currently used in the treatment of chronic obstructive airways disease, its poor bioavailability, due probably to extensive first-pass metabolism, makes it unlikely that it is available to organs such as the lung for direct scavenging activity. Despite this, oral NAC may elicit pneumoprotection through a 'prodrug' mechanism, supporting circulatory GSH levels through extensive metabolism to cysteine in the gut. This effect may mimic existing homeostatic mechanisms for the control of circulatory GSH levels during peripheral inflammation.}, }
@article {pmid3697543, year = {1986}, author = {Snapper, JR and Bernard, GR and Brigham, KL}, title = {In vivo oxidants and pulmonary inflammation.}, journal = {Bulletin europeen de physiopathologie respiratoire}, volume = {22}, number = {1}, pages = {257s-260s}, pmid = {3697543}, issn = {0395-3890}, support = {HL 19153/HL/NHLBI NIH HHS/United States ; HL 27274/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Disease Models, Animal ; Endotoxins/*blood ; Respiratory Distress Syndrome/*physiopathology ; Sheep ; }, abstract = {Endotoxemia is used as a model of the adult respiratory distress syndrome in chronically instrumented awake sheep. The toxic effects of endotoxin may be mediated through inflammatory cells and the release of toxic oxidants. N-acetylcysteine (NAC) inhibits the in vivo effects of endotoxemia in chronically instrumented unanesthetized sheep. NAC also functions as a free radical scavenger in vitro. It is possible that the protective effects of pretreatment with NAC result from NAC's ability in vivo to protect against local oxidant injury.}, }
@article {pmid3544111, year = {1986}, author = {Yunis, AA and Lim, LO and Arimura, GK}, title = {DNA damage induced by chloramphenicol and nitroso-chloramphenicol: protection by N-acetylcysteine.}, journal = {Respiration; international review of thoracic diseases}, volume = {50 Suppl 1}, number = {}, pages = {50-55}, doi = {10.1159/000195088}, pmid = {3544111}, issn = {0025-7931}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cell Division/drug effects ; Cells, Cultured ; Chloramphenicol/*analogs &amp; derivatives/*antagonists &amp; inhibitors ; Colony-Forming Units Assay ; *DNA Damage ; DNA, Bacterial/drug effects ; Escherichia coli/genetics ; Mice ; }, abstract = {We have previously demonstrated that nitroso-chloramphenicol (NO-CAP) in small concentrations causes the hydrolysis of isolated double stranded DNA in vitro and this action is blocked by sulfhydryl groups. The present study was designed to assess damage to isolated DNA as well as intact cells DNA and examine the protective effect of N-acetylcysteine (NAC). Using alkaline sucrose gradient sedimentation and the alkali elution technique of Kohn we were able to demonstrate DNA damage in Raji cells as well as phytohemagglutinin stimulated human lymphocytes after exposure to NO-CAP. Damage could be totally blocked by NAC. In preliminary studies we also observed that NAC protects bone marrow cells from the growth-inhibitory effects of chloramphenicol and thiamphenicol.}, }
@article {pmid3536552, year = {1986}, author = {Jeffery, PK}, title = {Anti-inflammatory drugs and experimental bronchitis.}, journal = {European journal of respiratory diseases. Supplement}, volume = {146}, number = {}, pages = {245-257}, pmid = {3536552}, issn = {0106-4347}, mesh = {Animals ; Anti-Inflammatory Agents/*therapeutic use ; Bronchitis/drug therapy/*etiology/prevention &amp; control ; Lung/pathology ; *Plants, Toxic ; Rats ; Smoke/*adverse effects ; *Nicotiana ; }, abstract = {Chronic bronchitis (chronic hypersecretion) and chronic bronchiolitis (small airways disease) are two conditions associated with cigarette smoking: both contribute to airflow obstruction in man, the latter associated with progressive deterioration in lung function. Mucous metaplasia and hyperplasia are characteristic histological changes. Experimentally, cigarette smoke given daily for two weeks, induces similar histological changes in the airways of specific pathogen-free rats, providing a suitable animal model for study: an early proliferation of basal cells, accompanied by mucous metaplasia of surface epithelial serous cells is followed by proliferation of newly formed mucous cells. There is also a significant increase in epithelial thickness due to cell hypertrophy without stratification or prior ulceration. Experimentally, secretory cell hyperplasia is inhibited completely or to varying degrees by prophylactic administration (intraperitoneal injection) of either indomethacin, flurbiprofen, dexamethasone, prednisolone, hydrocortisone (each at 2 or 4 mg/kg body weight) or a mucolytic drug, N-acetylcysteine(Nac), given orally as a 1% solution of the drinking water. Nac also inhibits the associated mucus-hypersecretion. It takes between 21 and 84 days, depending on airway level, for the increase in secretory cell number to return to control values (ie recover). Indomethacin and flurbiprofen (4 mg/kg, by ip injection) shorten recovery to between 4 and 9 days in intrapulmonary airways but have no effect on recovery time in the rat trachea. Nac is effective in 6 of 7 airway levels which showed cigarette smoke-induced mucous cell hyperplasia. In conclusion, in the rat, the response to cigarette smoke is one of mucous cell metaplasia and both basal and mucous cell proliferation. Cigarette smoke-induced mucous cell hyperplasia can be inhibited when selected drugs are given concurrently with the cigarette smoke: indomethacin, fluriprofen and Nac are also therapeutic.}, }
@article {pmid3108189, year = {1986}, author = {Hilgard, P and Pohl, J}, title = {Cause and prevention of mafosfamide-induced venous pain.}, journal = {Investigational new drugs}, volume = {4}, number = {4}, pages = {373-376}, pmid = {3108189}, issn = {0167-6997}, mesh = {Acetylcysteine/pharmacology ; Animals ; Antineoplastic Agents/*toxicity ; Cyclophosphamide/*analogs &amp; derivatives/toxicity ; Mesna/pharmacology ; Pain/*etiology/prevention &amp; control ; Rats ; Veins/*drug effects ; }, abstract = {An experimental rat model for the study of venous pain induced by 4-hydroxy-cyclophosphamide (4-OH-CP) derivatives was developed and validated. Using various metabolites and chemical variants of 4-OH-CP it was found that pain induction was independent from the compound's alkylating activity but possibly related to the spontaneous generation of minute amounts of acrolein from the 4-OH-CP molecule. Accordingly, the pain could be prevented by the addition of thiol compounds such as mesna or N-acetyl-cysteine.}, }
@article {pmid3029208, year = {1986}, author = {Bergstrand, H and Björnson, A and Eklund, A and Hernbrand, R and Larsson, K and Linden, M and Nilsson, A}, title = {Stimuli-induced superoxide radical generation in vitro by human alveolar macrophages from smokers: modulation by N-acetylcysteine treatment in vivo.}, journal = {Journal of free radicals in biology &amp; medicine}, volume = {2}, number = {2}, pages = {119-127}, doi = {10.1016/s0748-5514(86)80060-5}, pmid = {3029208}, issn = {0748-5514}, mesh = {Acetylcysteine/*pharmacology ; Free Radicals ; Humans ; In Vitro Techniques ; Macrophages/*metabolism ; Pulmonary Alveoli/cytology ; *Smoking ; Spirometry ; Superoxides/*metabolism ; }, abstract = {Bronchoalveolar lavage (BAL) was performed on nine healthy nonsmoking subjects and on 11 healthy smokers; in the last mentioned group lavage was performed before and after eight weeks treatment with N-acetylcysteine (NAC; 200 mg t.i.d.). The BAL cells were cultured for 2 h or overnight. Adherent cells were examined for their capacity to generate superoxide radicals (determined by superoxide dismutase (SOD)-inhibitable cytochrome C-reduction) at stimulation with phorbol 12-myristate 13-acetate (PMA), serum-treated zymosan (STZ), the calcium ionophore A23187, or the chemotactic tripeptide formyl-methionylleucylphenylalanine (FMLP). Cells from nonsmokers responded with a very low degree of O(2)-generation to any of the stimuli employed whether cultured for 2 h or overnight. Cells from smokers also responded with low O(2)-generation after 2 h of culture. However, cells from smokers cultured overnight responded with marked O(2)-generation to PMA and STZ but the responses to FMLP and A23187 were low. NAC-treatment of the smokers resulted in a reduced degree of both PMA- and STZ-induced O(2)-generation in five individuals. In two other subjects, PMA-induced (but not STZ-induced) O(2)-generation was reduced. Two individuals showed increased O(2)-generation to PMA- and to STZ-stimulation after NAC-treatment. Mean values of O(2)-generation induced by A23187 or by FMLP were significantly reduced for cells harvested after NAC-treatment. Mean values for PMA-induced O(2)-generation also tended to be reduced by the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)}, }
@article {pmid4094516, year = {1985}, author = {Fukuzawa, K and Kishikawa, K and Tokumura, A and Tsukatani, H and Shibuya, M}, title = {Fluorescent pigments by covalent binding of lipid peroxidation by-products to protein and amino acids.}, journal = {Lipids}, volume = {20}, number = {12}, pages = {854-861}, pmid = {4094516}, issn = {0024-4201}, mesh = {*Amino Acids ; Fluorescent Dyes ; Kinetics ; *Lipid Peroxides ; Mass Spectrometry ; Oleic Acids ; *Polylysine ; *Serum Albumin, Bovine ; Spectrometry, Fluorescence/methods ; Spectrophotometry, Ultraviolet ; Structure-Activity Relationship ; }, abstract = {The fluorescent products formed on reaction of 12-oxo-cis-9-octadecenoic acid (12-keto-oleic acid) with about 20 different amino acids, polylysine and bovine serum albumin (BSA) were studied. Besides glycine, only the basic amino acids histidine, lysine and arginine gave products with strong fluorescence. N-Acetylation of amino acids greatly reduced the fluorescence of their reaction products. The formation of fluorescent products was inhibited strongly by SH-amino acids such as N-acetyl-cysteine and glutathione. Polyacrylamide gel electrophoresis showed that BSA treated with 12-keto-oleic acid was more acidic than untreated or ricinoleic acid-treated BSA, indicating that basic amino acid residues in BSA were modified by reaction with the keto fatty acid. None of the structural analogs of 12-keto-oleic acid tested--12-oxo-trans-10-octadecenoic acid, 12-oxo-octadecanoic acid, 12-hydroxy-cis-9-octadecenoic acid (ricinoleic acid), cis-9-octadecenoic acid (oleic acid) and linoleic acid--reacted with glycine to give a fluorescent product. The fluorescent products formed on reaction of 12-keto-oleic acid methyl ester with benzyl amine and glycine methyl ester were shown to be 8-(N-substituted-4,5-dihydro-4-oxo-5-hexyl-5-hydroxy-2-pyrrolyl) octanoic acid methyl esters. The fluorescence properties of these compounds were attributed to the chromophobic system NC = CC = O which contains 6 pi electrons. This investigation contributes to insight of the mechanism of formation of fluorescent pigments, probably by a similar reaction of other compounds of the beta, gamma-unsaturated carbonyl type.}, }
@article {pmid4082467, year = {1985}, author = {Henderson, P and Hale, TW and Shum, S and Habersang, RW}, title = {N-Acetylcysteine therapy of acute heavy metal poisoning in mice.}, journal = {Veterinary and human toxicology}, volume = {27}, number = {6}, pages = {522-525}, pmid = {4082467}, issn = {0145-6296}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Animals ; Dimercaprol/therapeutic use ; Metals/antagonists &amp; inhibitors/*poisoning ; Mice ; Penicillamine/therapeutic use ; }, abstract = {Therapy of acute heavy metal poisoning is currently limited to a group of moderately toxic drugs containing sulfhydryl groups. N-Acetylcysteine (NAC) was used in these studies to determine if this sulfhydryl containing amino acid would reduce the overall mortality of a group of heavy metal compounds. D-Penicillamine and dimercaprol (BAL) were also used for comparison. Groups of at least 100 mice (28 g) were injected subcutaneously with 2-190 mg/kg of copper, arsenic, thallium or cadmium for LD50 determinations. Other groups were injected 30-60 min later with NAC (200 mg/kg), d-penicillamine (50 mg/kg), or BAL (10 mg/kg), and mortality was monitored for 2 weeks. The LD50 for each treatment group was determined by regression analysis of log-probit transformed data. In arsenite treatment group the survival time was lengthened in NAC-treated animals although the LD50 was not significantly changed. BAL was only slightly more effective than NAC. The mortality in animals given copper and treated with NAC was almost eliminated, except at the highest doses. BAL provided the greatest protection, whereas d-penicillamine produced the least. The LD50 of copper was significantly changed from 60.5 mg/kg in control groups to 139 mg/kg in NAC-treated groups, and to 150 mg/kg and 91 mg/kg in BAL and d-penicillamine-treated groups. NAC and BAL were totally ineffective in the treatment of thallium and cadmium poisoning.}, }
@article {pmid3905042, year = {1985}, author = {De Flora, S and Bennicelli, C and Camoirano, A and Serra, D and Romano, M and Rossi, GA and Morelli, A and De Flora, A}, title = {In vivo effects of N-acetylcysteine on glutathione metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds.}, journal = {Carcinogenesis}, volume = {6}, number = {12}, pages = {1735-1745}, doi = {10.1093/carcin/6.12.1735}, pmid = {3905042}, issn = {0143-3334}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Biotransformation ; Carcinogens/*metabolism/pharmacology ; Cytochrome P-450 Enzyme System/metabolism ; Glutathione/*metabolism ; Liver/*metabolism ; Lung/*metabolism ; Male ; Microsomes/*metabolism ; Microsomes, Liver/metabolism ; Mutagenicity Tests ; Mutagens/*metabolism/pharmacology ; *Mutation ; Rats ; Salmonella typhimurium/drug effects ; Structure-Activity Relationship ; }, abstract = {N-acetylcysteine (NAC) was administered to rats in various combinations with an enzyme inducer (Aroclor 1254) and with depletors of reduced glutathione (GSH), i.e., diethyl maleate (DEM) and buthionine sulfoximine (BSO). NAC increased intracellular glutathione levels in erythrocytes and in liver and lung cells, and replenished its stores following depletion. It did not affect the concentrations nor the spectral properties of cytochromes P-450 in hepatic and pulmonary microsomes, whereas it stimulated, especially in Aroclor-pre-treated animals, cytosolic enzyme activities involved in NADP reduction (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), in glutathione reduction (GSSG-reductase) and in the reductive detoxication of xenobiotics by-passing formation of reactive oxygen species (DT-diaphorase). In vivo treatment with the drug enhanced detoxication by liver and lung S-12 fractions of direct-acting mutagens (ICR 191, epichlorohydrin, 4-nitroquinolino-N-oxide and dichromate) and counteracted opposite effects triggered by administration of GSH depletors. The metabolic activation of procarcinogens (aflatoxin B1, 2-aminofluorene, cyclophosphamide, benzo[a]pyrene, a tryptophan pyrolysate product and cigarette smoke condensate) was inhibited by NAC in uninduced rats, while it was further stimulated in Aroclor-pre-treated animals. Additional assays, performed also with other enzyme inducers (phenobarbital and 3-methylcholanthrene) suggested that the effect of NAC on the metabolic activation of procarcinogens depends on the balance between an increased production of mutagenic metabolites (prevailing in induced animals) and their binding by intracellular thiols (prevailing under normal conditions). Thus, due to its dual role as a nucleophile and as a SH donor, NAC appears to exert protective effects by modulating glutathione metabolism and the biotransformation of mutagenic/carcinogenic compounds. This may have clinical relevance, since NAC is administered to individuals, such as cigarette smokers, who are more heavily exposed to GSH depletors and to carcinogenic agents.}, }
@article {pmid4081320, year = {1985}, author = {Llobet, JM and Domingo, JL and Corbella, J}, title = {Comparison of antidotal efficacy of chelating agents upon acute toxicity of Co(II) in mice.}, journal = {Research communications in chemical pathology and pharmacology}, volume = {50}, number = {2}, pages = {305-308}, pmid = {4081320}, issn = {0034-5164}, mesh = {Animals ; *Antidotes ; Chelating Agents/*pharmacology ; Cobalt/*poisoning ; Lethal Dose 50 ; Male ; Mice ; }, abstract = {The relative efficacy of 14 chelating agents in alleviating acute cobalt (II) chloride (ip) intoxication has been determined. For a level of 0.70 mmol/kg ip of CoCl2 (slightly higher than its LD50), the ip administration of chelating agents at a 2:1 and 5:1 mole ratio resulted in a significant antidotal action for L-cysteine, N-acetyl-cysteine, L-histidine,glutathione,D,L-penicillamine, DMSA, DTPA and EDTA. For a level of 1.18 mmol/kg ip of CoCl2 (slightly higher than its LD99) only L-cysteine, N-acetylcysteine,glutathione, DMSA, DTPA and EDTA resulted in a significant enhancement of the survival rate. The therapeutic indices of these compounds were respectively: 8.3, 11.8, 10.9, 9.1, 20.5 and 26.4; with EDTA and DTPA being the most effective. However, due to their low toxicity, N-acetylcysteine and glutathione should be considered as possible alternatives.}, }
@article {pmid3908111, year = {1985}, author = {Ratjen, F and Wönne, R and Posselt, HG and Stöver, B and Hofmann, D and Bender, SW}, title = {A double-blind placebo controlled trial with oral ambroxol and N-acetylcysteine for mucolytic treatment in cystic fibrosis.}, journal = {European journal of pediatrics}, volume = {144}, number = {4}, pages = {374-378}, pmid = {3908111}, issn = {0340-6199}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Ambroxol/*therapeutic use ; Bromhexine/*analogs &amp; derivatives ; Child ; Clinical Trials as Topic ; Cystic Fibrosis/*drug therapy ; Double-Blind Method ; Expectorants/therapeutic use ; Female ; Humans ; Male ; Mucus/*drug effects ; Respiratory Function Tests ; }, abstract = {The therapeutic efficacy of oral N-acetylcysteine (NAC) and ambroxol as compared with the effect of placebos was studied in 36 cystic fibrosis (CF) patients with mild to moderate pulmonary disease. The patients were randomly assigned to one of three regimens, matched on the basis of age and Chrispin-Norman scores. The trial was conducted over a period of 12 weeks. Patients were assessed clinically and by extensive pulmonary function techniques (body-plethysmography, maximal expiratory flow-volume curves, trapped air determination). Although no clinical differences could be observed between the three groups, significant impairment in the placebo group was found for trapped air and FEV1 when compared to the active groups, suggesting a therapeutic effect of ambroxol and NAC in CF.}, }
@article {pmid3933841, year = {1985}, author = {Moss, EJ and Neal, GE and Judah, DJ}, title = {The mercapturic acid pathway metabolites of a glutathione conjugate of aflatoxin B1.}, journal = {Chemico-biological interactions}, volume = {55}, number = {1-2}, pages = {139-155}, doi = {10.1016/s0009-2797(85)80124-1}, pmid = {3933841}, issn = {0009-2797}, mesh = {Acetylcysteine/*metabolism ; Aflatoxin B1 ; Aflatoxins/*metabolism ; Animals ; Chromatography, High Pressure Liquid ; Cysteine/analogs &amp; derivatives/metabolism ; Dipeptidases/metabolism ; Dipeptides/metabolism ; Glutathione/*analogs &amp; derivatives/metabolism ; Kidney/enzymology/metabolism ; Male ; Rats ; Rats, Inbred F344 ; Swine ; }, abstract = {A glutathione conjugate of aflatoxin B1 (AFB1) which has previously been identified as 8,9-dihydro-8-(S-glutathionyl)-9-hydroxy aflatoxin B1 (AFB1-GSH) (E.J. Moss, D.J. Judah, M. Przybylski and G.E. Neal, Biochem. J., 210 (1983) 227-233) has been degraded in vitro to all of the intermediates of the mercapturic acid pathway (MAP) and the chromatographic and spectral characteristics of each of these compounds investigated. The cysteinylglycyl conjugate (AFB1-Cys.Gly) was prepared by incubating the AFB1-GSH conjugate with a rat hepatoma cell line rich in gamma-glutamyl-transpeptidase (GGT). Incubations of the AFB1-Cys.Gly conjugate with dipeptidase produced a metabolite, which was purified and characterized by 1H-NMR spectroscopy as 8,9-dihydro-8-(S-cysteinyl)-9-hydroxy aflatoxin B1 (AFB1-Cys). The N-acetyl derivative of the AFB1-Cys conjugate resulted from the incubation of the AFB1-GSH conjugate in vitro with isolated rat kidney cells. Mass spectral data were consistent with the compound being 8,9-dihydro-8-(S-cysteinyl-(N-acetyl))-9-hydroxy aflatoxin B1 (AFB1-Nac.Cys). A chromatographically identical compound was obtained by the chemical acetylation of AFB1-Cys.}, }
@article {pmid3908155, year = {1985}, author = {Bowles, WH and Goral, V}, title = {Clinical trial of the anti-plaque activity of a mucolytic agent, N-Acetyl Cysteine.}, journal = {Dental hygiene}, volume = {59}, number = {10}, pages = {454-456}, pmid = {3908155}, issn = {0091-3979}, mesh = {Acetylcysteine/administration &amp; dosage/*therapeutic use ; Clinical Trials as Topic ; Dental Plaque/*prevention &amp; control ; Double-Blind Method ; Humans ; Mouthwashes ; Placebos ; Random Allocation ; }, }
@article {pmid3000092, year = {1985}, author = {Subrahmanyam, VV and O'Brien, PJ}, title = {Peroxidase-catalysed binding of [U-14C]phenol to DNA.}, journal = {Xenobiotica; the fate of foreign compounds in biological systems}, volume = {15}, number = {10}, pages = {859-871}, doi = {10.3109/00498258509045037}, pmid = {3000092}, issn = {0049-8254}, mesh = {Bone Marrow/metabolism ; Carbon Radioisotopes ; Catalysis ; DNA/*metabolism ; Horseradish Peroxidase/*pharmacology ; Humans ; Hydrogen Peroxide/pharmacology ; Oxidation-Reduction ; Peroxidase/analysis ; Peroxidases/*pharmacology ; Phenol ; Phenols/*metabolism ; }, abstract = {14C-Phenol binds irreversibly to calf-thymus DNA in the presence of horseradish peroxidase and hydrogen peroxide, approximately 65% of the added phenol was bound to DNA. Binding was maximal at an equimolar concentration of hydrogen peroxide. Binding also occurred to homopolyribonucleotides polyadenylic acid, polyguanylic acid, polycytidylic acid and polyuridylic acid, and suggests that binding is relatively non-specific with respect to the nucleotide bases. p,p'-Biphenol, p,p'-biphenoquinone, o,o'-biphenol and two unidentified products were formed by the oxidation of phenol, in the presence and in absence of DNA. DNA accelerated phenol oxidation four fold and prevented the polymerization of oxidized phenol products, but was found to have no effect on the range of ethyl acetate-extractable products. Phenol accelerated the metabolism of o,o'-biphenol but had no effect on p,p'-biphenol metabolism. The mechanism of phenol activation is not clear, but p,p'-biphenoquinone binds to protein and not to DNA. DNA binding was prevented by glutathione, N-acetyl-cysteine and ascorbate, and the mechanism was shown to involve reduction of the activated phenol intermediates and the formation of conjugates with glutathione and N-acetyl-cysteine. DNA binding was not inhibited by lysine and proline.}, }
@article {pmid4051406, year = {1985}, author = {Liu, AJ and Richardson, MA}, title = {Effects of N-acetylcysteine on experimentally induced esophageal lye injury.}, journal = {The Annals of otology, rhinology, and laryngology}, volume = {94}, number = {5 Pt 1}, pages = {477-482}, doi = {10.1177/000348948509400513}, pmid = {4051406}, issn = {0003-4894}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Burns, Chemical/*drug therapy ; Esophageal Stenosis/chemically induced/*drug therapy/pathology ; Esophagus/pathology ; Lye ; Rats ; Rats, Inbred Strains ; }, abstract = {The effects of N-acetylcysteine (NAC) in the treatment of caustic alkaline injury to the esophagus is examined. Caustic esophageal burns were produced in rats by irrigation with NaOH. Stricture formation was less frequent in animals concurrently treated with either steroids (48%) or NAC (48%) than in control animals that received only the alkaline injury (74%). In addition, the severity of stenosis was less in drug-treated rats. Thirty percent of strictures in control animals were severe (3 +) compared to 6% in the NAC group and 7% in the steroid group. Both NAC and steroids would seem to ameliorate the tissue reaction to chemical injury as well as temper the degree of stenosis formation. Possibility of synergistic effects warrants future investigation.}, }
@article {pmid2991688, year = {1985}, author = {Clark, DE and Wei, P and Grant, NH}, title = {A novel inhibitor of mammalian collagenase.}, journal = {Life sciences}, volume = {37}, number = {6}, pages = {575-578}, doi = {10.1016/0024-3205(85)90471-0}, pmid = {2991688}, issn = {0024-3205}, mesh = {*Acetylcysteine/*analogs &amp; derivatives ; Angiotensin-Converting Enzyme Inhibitors ; Animals ; Benzothiazoles ; Cell Line ; Clostridium/enzymology ; Cysteine/*analogs &amp; derivatives/pharmacology ; Fibroblasts/enzymology ; Humans ; Kinetics ; Microbial Collagenase/*antagonists &amp; inhibitors ; Protease Inhibitors/*pharmacology ; Rats ; Skin/enzymology ; Substrate Specificity ; Tail ; Tendons ; Thermolysin/antagonists &amp; inhibitors ; Trypsin/metabolism ; }, abstract = {N-[[[(5-chloro-2-benzothiazolyl)thiolphenyllacetyll-L-cysteine (WY-45,368) is a potent inhibitor of human skin fibroblast collagenase. Kinetic data show that the inhibition is competitive, with a Ki of 3.5 microM. WY-45,368 inhibits neither of two other metalloproteinases, thermolysin and angiotensin converting enzyme, nor does it inhibit clostridial collagenase--thus indicating specificity for mammalian collagenase.}, }
@article {pmid4057204, year = {1985}, author = {Hansen, RM and Csuka, ME and McCarty, DJ and Saryan, LA}, title = {Gold induced aplastic anemia. Complete response to corticosteroids, plasmapheresis, and N-acetylcysteine infusion.}, journal = {The Journal of rheumatology}, volume = {12}, number = {4}, pages = {794-797}, pmid = {4057204}, issn = {0315-162X}, mesh = {Acetylcysteine/*therapeutic use ; Anemia, Aplastic/*chemically induced/drug therapy/pathology/therapy ; Arthritis, Rheumatoid/drug therapy ; Bone Marrow/pathology ; Female ; Gold/*adverse effects/blood/urine ; Humans ; Middle Aged ; *Plasmapheresis ; Prednisone/*therapeutic use ; }, abstract = {A 47-year-old woman with rheumatoid arthritis (RA) had been treated with greater than 7 g of gold sodium thiomalate over a 5 year period when aplastic anemia developed. Treatment with corticosteroids, plasmapheresis and infusion of N-acetylcysteine (NAC) resulted in complete hematologic remission. Infusion of NAC increased daily urinary excretion of gold and use of an ambulatory infusion pump with a Hickman catheter allowed protracted outpatient infusion for more than 4 months' duration. It is now 20 months since the onset of aplastic anemia and she remains in complete hematologic remission.}, }
@article {pmid4026031, year = {1985}, author = {Savides, MC and Oehme, FW and Leipold, HW}, title = {Effects of various antidotal treatments on acetaminophen toxicosis and biotransformation in cats.}, journal = {American journal of veterinary research}, volume = {46}, number = {7}, pages = {1485-1489}, pmid = {4026031}, issn = {0002-9645}, mesh = {Acetaminophen/blood/*poisoning/urine ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Administration, Oral ; Animals ; Antidotes/*therapeutic use ; Biotransformation/drug effects ; Cat Diseases/*drug therapy/metabolism ; Cats ; Chromatography, High Pressure Liquid ; Glutathione/blood ; Half-Life ; Injections, Intravenous/veterinary ; Methemoglobin/metabolism ; Sulfates/administration &amp; dosage/*therapeutic use ; }, abstract = {Oral N-acetylcysteine (NAC), IV NAC, and IV sodium sulfate were evaluated as treatments for cats dosed orally with toxic sublethal doses of acetaminophen (APAP). Six cats were given single oral doses of 120 mg of APAP/kg of body weight and the respective antidote at 4.5, 8.5, and 12.5 hours after APAP dosing in 3 separate trials. The cats were given each antidotal treatment in random order with at least 3 weeks separating the individual APAP-treated trials. Clinical signs, plasma APAP half-lives, clinical chemical values, and APAP urinary excretion and metabolites were studied. Results were compared (P less than 0.05) with each other and with those of a control group of 6 cats given identical APAP doses, but given no antidotal treatment. At the dosage levels used, oral NAC, IV NAC, and IV sodium sulfate were equally effective antidotes, as measured by decreased methemoglobinemia, increased whole blood reduced glutathione, decreased APAP half-lives, and increased urinary excretion of the APAP-sulfate conjugate. All the antidotal treatments produced results significantly different from those in the control cats.}, }
@article {pmid4014022, year = {1985}, author = {Unverferth, DV and Leier, CV and Balcerzak, SP and Hamlin, RL}, title = {Usefulness of a free radical scavenger in preventing doxorubicin-induced heart failure in dogs.}, journal = {The American journal of cardiology}, volume = {56}, number = {1}, pages = {157-161}, doi = {10.1016/0002-9149(85)90585-5}, pmid = {4014022}, issn = {0002-9149}, mesh = {Acetylcysteine/*therapeutic use ; Animals ; Cardiac Catheterization ; Dogs ; Doxorubicin/adverse effects/*pharmacology ; Free Radicals ; Heart/drug effects/physiopathology ; Heart Failure/chemically induced/mortality/physiopathology/*prevention &amp; control ; }, abstract = {This study was designed to investigate whether either of 2 dosage schedules of N-acetylcysteine (NAC) was effective in preventing chronic doxorubicin-induced heart failure in dogs. Thirty-eight dogs were randomly assigned to 1 of 4 groups: controls, 10 dogs; doxorubicin only, 12 dogs; doxorubicin + low dose NAC, 8 dogs; and doxorubicin + high dose NAC, 8 dogs. All dogs except the controls received 1 mg/kg of doxorubicin weekly for 8 weeks and then every other week for 8 weeks. The doxorubicin + low-dose NAC group received 140 mg/kg of NAC 30 minutes before each dose of doxorubicin. The doxorubicin + high-dose NAC group received NAC before and then twice a day for 5 days. Systolic time intervals and echocardiograms were obtained weekly; cardiac catheterization was performed at the conclusion of the study. Of the 38 dogs in the study, 9 died; all deaths were in the doxorubicin treatment groups. The incidence of death was not different between the doxorubicin-only, the doxorubicin + low-dose and the doxorubicin + high-dose NAC groups. The noninvasive and the invasive and the catheterization data generally revealed poorer cardiac function of the doxorubicin treatment groups than in controls. However, no significant differences existed between the doxorubicin-only and doxorubicin + low-dose and doxorubicin + high-dose NAC groups. In conclusion, NAC in a low- or high-dose regimen did not significantly ameliorate doxorubicin cardiac toxicity. Because NAC is a free radical scavenger, perhaps doxorubicin cardiac toxicity is not a result of free radical generation.}, }
@article {pmid4009614, year = {1985}, author = {Martin, TA and Comer, WT}, title = {N-[[(Mercaptoacetyl)amino]benzoyl]glycines as mucolytic agents.}, journal = {Journal of medicinal chemistry}, volume = {28}, number = {7}, pages = {910-914}, doi = {10.1021/jm00145a011}, pmid = {4009614}, issn = {0022-2623}, mesh = {Acetylcysteine/pharmacology ; Aminobenzoates/*chemical synthesis/pharmacology/toxicity ; Animals ; Chemical Phenomena ; Chemistry ; Drug Stability ; *Expectorants ; Glycine/*analogs &amp; derivatives/chemical synthesis/pharmacology/toxicity ; Humans ; Isomerism ; Lethal Dose 50 ; Mice ; Mucus/drug effects ; Rats ; Salts ; Sputum/drug effects ; Water ; }, abstract = {m- and p-aminobenzoic acids were converted to the title compounds by sequential use of ClCH2COCl, SOCl2, glycine methyl or ethyl ester, AcSK, and hydrolysis. The title compounds and a number of salts were compared for mucolytic activity, toxicity, stability, and hygroscopicity. When compared to N-acetyl-L-cysteine (NAC), the compounds exhibit several times the in vitro mucolytic activity of NAC on a molar basis. The most promising candidate appears to be the sodium salt 3.5H2O 2 of the meta series.}, }
@article {pmid2410721, year = {1985}, author = {Torresi, J and Horowitz, JD and Dusting, GJ}, title = {Prevention and reversal of tolerance to nitroglycerine with N-acetylcysteine.}, journal = {Journal of cardiovascular pharmacology}, volume = {7}, number = {4}, pages = {777-783}, doi = {10.1097/00005344-198507000-00024}, pmid = {2410721}, issn = {0160-2446}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cattle ; Coronary Vessels/drug effects ; Drug Tolerance ; In Vitro Techniques ; Muscle Relaxation/drug effects ; Muscle Tonus/drug effects ; Nitroglycerin/*pharmacology ; }, abstract = {A recent study demonstrated that the sulfhydryl donor N-acetylcysteine (NAC) potentiated hemodynamic responsiveness to nitroglycerine (NTG) in patients with ischaemic heart disease. The interaction between NTG and NAC in rings of bovine coronary artery was examined. Vasodilator responses to NTG were determined after elevation of tone with the thromboxane mimetic U46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid]. NAC (1 microM-3 mM) induced no changes in tone of the preparation, but 10 microM NAC significantly potentiated responses to NTG (EC50 reduced from 0.69 +/- 0.19 microM to 0.22 +/- 0.06 microM; p less than 0.01). Increasing degrees of tolerance to NTG were produced at pH 7.4 by preincubating coronary rings with NTG in concentrations of 4.4 and 44 microM, and 0.22 mM. With 0.22 mM NTG, EC50 for subsequently administered NTG was increased to 11.0 +/- 1.8 microM (p less than 0.001 vs. control vessels). The degree of tolerance produced with this concentration of NTG was markedly attenuated by simultaneous (EC50 = 0.50 +/- 0.30 microM; p less than 0.001 vs. tolerant vessels) or subsequent (EC50 = 1.17 +/- 0.59 microM, p less than 0.001 vs. control vessels) incubation with 10 microM NAC. These data confirm that responses to NTG are modulated by sulfhydryl (or specifically cysteine) availability and suggest that in vitro tolerance to NTG is related to sulfhydryl (or cysteine) depletion. It is therefore possible that in vivo potentiation of NTG responses by NAC will be of clinical benefit in preventing or reversing loss of hemodynamic responsiveness to NTG.}, }
@article {pmid3994080, year = {1985}, author = {Renzi, FP and Donovan, JW and Martin, TG and Morgan, L and Harrison, EF}, title = {Concomitant use of activated charcoal and N-acetylcysteine.}, journal = {Annals of emergency medicine}, volume = {14}, number = {6}, pages = {568-572}, doi = {10.1016/s0196-0644(85)80781-2}, pmid = {3994080}, issn = {0196-0644}, mesh = {Absorption ; Acetaminophen/*poisoning ; Acetylcysteine/adverse effects/blood/*therapeutic use ; Administration, Oral ; Adsorption ; Adult ; Charcoal/therapeutic use ; Drug Evaluation ; Drug Interactions ; Half-Life ; Humans ; Male ; }, abstract = {Activated charcoal is a safe, effective, inexpensive adjunct in the management of most toxic ingestions. It has the ability to adsorb a wide variety of drugs and chemicals, one of which is acetaminophen. N-acetylcysteine (NAC) is the specific antidote available for serious overdoses of acetaminophen. Current management of acetaminophen overdose, however, does not recommend the concomitant oral administration of these two useful agents because adsorption and inactivation of NAC by charcoal is believed to occur. Our study was designed to help evaluate the effect of activated charcoal on N-acetylcysteine absorption. Ten healthy male volunteers were each given in the first, or control, phase of the study an oral dose of 140 mg/kg NAC, and venous blood samples were obtained. In the second phase, after a washout period, each subject received 60 g activated charcoal orally followed immediately by 140 mg/kg NAC. NAC serum levels were measured using gas-liquid chromatography, and levels were compared with and without the concomitant administration of charcoal. Although only a small number of the subjects completed the study, the results showed that in both phases there were no significant differences in the peak NAC levels, the plasma half-life of NAC, or the calculated area under the curve. We recommend that NAC and activated charcoal not be used clinically until further studies are completed.}, }
@article {pmid4041986, year = {1985}, author = {Whitehouse, LW and Wong, LT and Paul, CJ and Pakuts, A and Solomonraj, G}, title = {Postabsorption antidotal effects of N-acetylcysteine on acetaminophen-induced hepatotoxicity in the mouse.}, journal = {Canadian journal of physiology and pharmacology}, volume = {63}, number = {5}, pages = {431-437}, doi = {10.1139/y85-075}, pmid = {4041986}, issn = {0008-4212}, mesh = {Acetaminophen/antagonists &amp; inhibitors/*toxicity/urine ; Acetylcysteine/*therapeutic use ; Alanine Transaminase/blood ; Animals ; Aspartate Aminotransferases/blood ; Bile/metabolism ; Body Weight/drug effects ; Chemical and Drug Induced Liver Injury/*prevention &amp; control ; Glutathione/metabolism ; Indocyanine Green ; Liver/metabolism ; Liver Function Tests ; Male ; Mice ; Time Factors ; }, abstract = {Male Swiss Webster mice, treated with N-acetylcysteine (NAC, 500 mg/kg po) 1 h following acetaminophen (NAPA, 350 mg/kg po) administration, had control levels of transaminases indicating that NAC protects against NAPA-induced hepatotoxicity by postabsorption antidotal mechanism(s). Hepatic congestion induced by NAPA was reduced by NAC. Significantly higher elimination rate constants (K) for indocyanine green (500 micrograms/kg, iv) in mice treated with NAPA and NAC (K = 0.676 +/- 0.062) than in animals receiving NAPA alone (0.341 +/- 0.105) suggested NAC improved or preserved the hepatic circulation of the compromised liver. This NAC-induced improvement and (or) preservation of hepatic circulation was reflected in biliary and urinary excretion of acetaminophen and its metabolites by a general increase in elimination during the first 6 h (70.2 +/- 2.6 vs. 32.6 +/- 7.1%), and in the repletion of glutathione (GSH) in the liver by a return to control levels more quickly (3 vs. greater than 5 h) following depletion by NAPA. The metabolic consequences of the postabsorption antidotal effect of NAC in the compromised liver was a preferential excretion of sulphydryl-derived metabolites in the 1-4 h bile (GSH conjugate 11.30 +/- 1.25 vs. 7.25 +/- 0.39%) which was subsequently observed in the urine by preferential excretion of glutathione degradation products.}, }
@article {pmid4008118, year = {1985}, author = {Santangelo, G and Lombardo, S and Giannotti, G}, title = {A combination of cefuroxime and N-acetyl-cysteine for the treatment of lower respiratory tract infections in children.}, journal = {International journal of clinical pharmacology, therapy, and toxicology}, volume = {23}, number = {5}, pages = {279-281}, pmid = {4008118}, issn = {0174-4879}, mesh = {Acetylcysteine/*administration &amp; dosage ; Cefuroxime/*administration &amp; dosage ; Cephalosporins/*administration &amp; dosage ; Child ; Child, Preschool ; Drug Therapy, Combination ; Female ; Humans ; Infant ; Male ; Respiratory Tract Infections/*drug therapy ; }, abstract = {One hundred and three children with lower respiratory tract infections were treated with a combination of cefuroxime and N-acetyl-cysteine. Positive clinical results were obtained in 100 patients, symptoms being completely relieved in 58 and distinct improvement produced in 42. Chest x-rays provided objective evidence of recovery or improvement in these 100 patients. Of the 72 pathogenic strains isolated before treatment in the trial population as a whole, none were still detectable at the end of treatment. No side effects or adverse reactions of any kind were observed.}, }
@article {pmid2409763, year = {1985}, author = {Barrett, KE and Minor, JR and Metcalfe, DD}, title = {Histamine secretion induced by N-acetyl cysteine.}, journal = {Agents and actions}, volume = {16}, number = {3-4}, pages = {144-146}, pmid = {2409763}, issn = {0065-4299}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Basophils/drug effects ; Histamine Release/*drug effects ; Hydrogen-Ion Concentration ; In Vitro Techniques ; Mast Cells/drug effects ; Mice ; }, abstract = {The mucolytic drug N-acetyl cysteine has been shown to release histamine from cultured mouse mast cells and from human basophils. At neutral pH the release was moderate and non-cytotoxic. If the acidity of the drug was not neutralized, this histamine release was markedly potentiated, but was then associated with a reduction in the viability of the cells. However, the high level of release could not be reproduced by simply exposing the cells to an acidic medium. The results are discussed in terms of a possible mechanism for the adverse reactions sometimes observed during N-acetyl cysteine therapy.}, }
@article {pmid3973647, year = {1985}, author = {Loehrer, PJ and Williams, SD and Einhorn, LH and Ansari, R}, title = {Ifosfamide: an active drug in the treatment of adenocarcinoma of the pancreas.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {3}, number = {3}, pages = {367-372}, doi = {10.1200/JCO.1985.3.3.367}, pmid = {3973647}, issn = {0732-183X}, support = {M01 RR00-750-06/RR/NCRR NIH HHS/United States ; }, mesh = {Acetylcysteine/adverse effects/therapeutic use ; Adenocarcinoma/*drug therapy ; Adult ; Aged ; Cyclophosphamide/*analogs &amp; derivatives ; Female ; Humans ; Ifosfamide/adverse effects/*therapeutic use ; Male ; Middle Aged ; Pancreatic Neoplasms/*drug therapy ; }, abstract = {From April 1982, until February 1984, 29 patients with biopsy-proven and measurable adenocarcinoma of the pancreas were treated with ifosfamide. Ifosfamide was administered at a dose of 1.25 to 1.5 g/m2 daily for five consecutive days with courses repeated every three weeks. If no serious toxicity was noted, subsequent dosages were escalated to a maximum of 2.0 g/m2/d. In addition, N-acetylcysteine (NAC) (8 to 12 g/d) was administered (in divided daily doses days 1 through 7) as a urothelial protective agent. Nausea and vomiting occurred in the majority of the treated patients. Other toxicities noted were mild myelo-suppression, CNS toxicity, and one case of acute renal failure. One complete response (CR) and five partial responses (PR) were observed in 27 evaluable patients (CRs and PRs = 22%). Ifosfamide has definite activity against pancreatic adenocarcinoma. Doses greater than 1.2 g/m2 for days 1 through 5 can be administered without significant toxicity in the majority of patients. Further trials with ifosfamide alone and/or with other agents are warranted.}, }
@article {pmid3922263, year = {1985}, author = {Badylak, SF and Van Vleet, JF and Herman, EH and Ferrans, VJ and Myers, CE}, title = {Poikilocytosis in dogs with chronic doxorubicin toxicosis.}, journal = {American journal of veterinary research}, volume = {46}, number = {2}, pages = {505-508}, pmid = {3922263}, issn = {0002-9645}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Dog Diseases/blood/*chemically induced/prevention &amp; control ; Dogs ; Doxorubicin/*poisoning ; *Erythrocytes, Abnormal ; Female ; Razoxane/therapeutic use ; Thyroxine/therapeutic use ; }, abstract = {Peripheral blood smears made during 2 studies of chemical antidotes for doxorubicin (DRB) cardiotoxicity in dogs were examined to determine the incidence of poikilocytosis. The 1st study had significantly (P less than 0.05) increased numbers of poikilocytes in 3 groups of 5 dogs, each treated with DRB alone, DRB plus thyroxine (0.5 mg/day), and DRB plus thyroxine (2.0 mg/day), respectively, compared with 1 group of 5 dogs treated with thyroxine alone (2.0 mg/day). In addition, the DRB-treated dogs had regenerative anemia characterized by an increased reticulocyte index. The 2nd study had a significant (P less than 0.05) increase in poikilocytes in 4 groups of 6 dogs, each treated with DRB alone, DRB plus +/- -1,2-bis(3-5-dioxopiperazinyl-1-yl; ICRF-187), DRB plus N-acetylcysteine (NAC), and drb plus ICRF-187 plus NAC, respectively, compared with 4 groups of 3 dogs, each treated with ICRF-187 plus saline solution (SS), NAC plus SS, ICRF-187 plus NAC plus SS, and SS alone, respectively. In both studies, the poikilocytes were identified as echinocytes, spiculated erythrocytes, and schizocytes. Administration of thyroxine and ICRF-187 did not prevent the occurrence of poikilocytosis in DRB-treated dogs. Administration of NAC with DRB resulted in a mild decrease in the extent of poikilocytosis compared with that observed in dogs given DRB alone. The hematologic changes observed in both studies were not accompanied by adverse clinical signs referable to the DRB-induced alterations in erythrocytes.}, }
@article {pmid4081277, year = {1985}, author = {Lurie, A and Pascal, O and Castillon du Perron, M and Grandordy, B and Huchon, G and Chrétien, J}, title = {[Pharmacology of mucociliary transport].}, journal = {Revue des maladies respiratoires}, volume = {2}, number = {3}, pages = {117-126}, pmid = {4081277}, issn = {0761-8425}, mesh = {Anesthetics/pharmacology ; Biological Transport/drug effects ; Bronchi/metabolism/*physiology ; Cilia/drug effects/physiology ; Ciliary Motility Disorders/physiopathology ; Expectorants/pharmacology ; Humans ; Mucus/*physiology ; Parasympatholytics/pharmacology ; Parasympathomimetics/pharmacology ; Sympatholytics/pharmacology ; Trachea/*physiology ; }, abstract = {Muco-ciliary transport is only effective because of the coordination of the ciliary beats (metachronous) and the harmony between mucus and cilia. The tip of the cilia is in contact with a jellyform layer of mucus propelled to the oropharynx. This jellyform layer has a complex rheological behaviour: it flows like a liquid and shapes like solid elastic. When the rheological properties of bronchial secretion are abnormal, mucociliary transport becomes inefficient. However, the most fluid secretions are not necessarily best transported, because the elasticity and viscosity to guarantee efficient muco-ciliary transport can only vary within defined limits. The mechanism regulating the ciliary beats is poorly understood; the bronchial secretions conduct impulses through the autonomic nervous system as well as mediators such as histamine and the metabolites of arachidonic acid. Mucociliary function may be studied either, directly through mucociliary transport or through mucociliary clearance. A fall in mucociliary activity can be produced by a primary ciliary disorder, by bronchial disease or the consequences of respiratory infection. General anaesthetics and Atropine slow mucociliary transport but Ipratropium bromide does not; Theophylline and sympathomimetics speed it up. The expectorants are mucolytics (proteolytic enzymes, N-acetyl-cysteine), there are agents to correct hydration anomalies of the bronchial secretion (water, hypertonic sodium chloride) iodides, antifibrins by substitution, anti-inflammatory agents and mucoregulatory agents (S-carboxymethylcysteine, bromhexine). The efficacy of the greater part of these expectorants has not been established in vivo by controlled therapeutic trials.}, }
@article {pmid4046067, year = {1985}, author = {Schwartz, H and Chu, I and Villeneuve, DC and Viau, A and Benoit, FM}, title = {Metabolites of 1,2,3,4-tetrachlorobenzene in monkey urine.}, journal = {Journal of toxicology and environmental health}, volume = {15}, number = {5}, pages = {603-607}, doi = {10.1080/15287398509530689}, pmid = {4046067}, issn = {0098-4108}, mesh = {Acetylcysteine/metabolism ; Administration, Oral ; Animals ; Chlorobenzenes/*urine ; Chromatography, High Pressure Liquid ; Chromatography, Thin Layer ; Gas Chromatography-Mass Spectrometry ; Saimiri ; }, abstract = {[14C(U)]-Labeled 1,2,3,4-tetrachlorobenzene was administered orally to squirrel monkeys. Urine was collected from these animals, pooled and analyzed for metabolites by thin-layer chromatography, high-performance liquid chromatography, and gas chromatography-mass spectroscopy. N-Acetyl-s-(2,3,4,5-tetrachlorophenyl) cysteine was shown to be the major metabolite and accounted for 85% of the radioactivity found in urine. A minor metabolite was identified as 2,3,4,5-tetrachlorophenol. This study demonstrates for the first time that an N-acetyl cysteine conjugate has been isolated and identified as metabolite of a chlorinated benzene. This pattern of chlorobenzene metabolism is significantly different from the one obtained with the rat and rabbit, where tetrachlorophenols constitute the major metabolites.}, }
@article {pmid4015737, year = {1985}, author = {Lissner, R and Brunner, W and Bolsen, K and Merk, H and Goerz, G}, title = {Influence of N-acetylcysteine on the hexachlorobenzene induced porphyria in rats.}, journal = {Arzneimittel-Forschung}, volume = {35}, number = {4}, pages = {713-715}, pmid = {4015737}, issn = {0004-4172}, mesh = {5-Aminolevulinate Synthetase/metabolism ; Acetylcysteine/*pharmacology ; Animals ; Chlorobenzenes/*toxicity ; Female ; Glutathione/metabolism ; Hexachlorobenzene/*toxicity ; Liver/enzymology ; Mixed Function Oxygenases/metabolism ; Porphyrias/*chemically induced ; Porphyrins/metabolism ; Rats ; Rats, Inbred Strains ; Time Factors ; }, abstract = {The course of hexachlorobenzene (HCB) induced porphyria was not influenced by the concomitant administration of N-acetylcysteine (NAC) to the animals: urinary excretion of total porphyrins and porphyrin precursors as well as the hepatic aminolevulinate synthase activities were not influenced by NAC treatment. In addition, no differences could be shown between the HCB and the HCB/NAC combination group concerning the hepatic cytochrome P-450 contents or the P-450 dependent enzyme activities.}, }
@article {pmid3988359, year = {1985}, author = {Peter, H and Bolt, HM}, title = {Effect of antidotes of the acute toxicity of methacrylonitrile.}, journal = {International archives of occupational and environmental health}, volume = {55}, number = {2}, pages = {175-177}, pmid = {3988359}, issn = {0340-0131}, mesh = {Acrylates/*toxicity ; Acrylonitrile/toxicity ; Animals ; Antidotes/*pharmacology ; Cyanides/metabolism ; Male ; Methacrylates/*toxicity ; Nitriles/*toxicity ; Rats ; Rats, Inbred Strains ; }, abstract = {When rats were exposed for 30 min to methacrylonitrile at concentrations between 3180 and 5700 ppm, the clinical symptoms observed suggested a toxic activity of metabolically formed cyanide. This is in contrast to the signs of toxicity observed in the same species after inhalation of acrylonitrile where metabolic cyanide formation plays only a minor role. The acute toxicity of methacrylonitrile could be antagonized with cyanide antidotes (4-dimethylaminophenol plus sodium thiosulfate) as well as with N-acetyl-cysteine which directly reacts with alpha,beta-unsaturated nitriles.}, }
@article {pmid3965363, year = {1985}, author = {Beckett, GJ and Chapman, BJ and Dyson, EH and Hayes, JD}, title = {Plasma glutathione S-transferase measurements after paracetamol overdose: evidence for early hepatocellular damage.}, journal = {Gut}, volume = {26}, number = {1}, pages = {26-31}, pmid = {3965363}, issn = {0017-5749}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/therapeutic use ; Alanine Transaminase/blood ; *Chemical and Drug Induced Liver Injury ; *Clinical Enzyme Tests ; Glutathione Transferase/*blood ; Humans ; Liver Diseases/diagnosis/enzymology/prevention &amp; control ; }, abstract = {Plasma glutathione S-transferase (GST) measurements have been used to study early changes in hepatocellular integrity after paracetamol overdose and treatment with N-acetylcysteine (NAC). Patients admitted within seven hours and successfully treated had raised or equivocal GST on admission and each showed a transient peak in GST approximately 12 hours after the overdose. Similar, though smaller changes in GST, were seen in untreated patients whose paracetamol level fell below the treatment line. The plasma GST concentrations in successfully treated patients were small compared with values found in patients who subsequently developed severe liver damage. The changes in GST concentration observed in patients who developed severe liver damage indicated that distinct early and late phases of paracetamol-induced hepatotoxicity occurred. Although the mechanism by which paracetamol exerts its early toxic effect is unclear, our data suggest that prompt treatment with NAC can successfully prevent both clinical and subclinical hepatotoxicity in this early period.}, }
@article {pmid3917371, year = {1985}, author = {Herman, EH and Ferrans, VJ and Myers, CE and Van Vleet, JF}, title = {Comparison of the effectiveness of (+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) and N-acetylcysteine in preventing chronic doxorubicin cardiotoxicity in beagles.}, journal = {Cancer research}, volume = {45}, number = {1}, pages = {276-281}, pmid = {3917371}, issn = {0008-5472}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Dogs ; Doxorubicin/antagonists &amp; inhibitors/*toxicity ; Female ; Heart/*drug effects ; Heart Ventricles/pathology ; Hematocrit ; Hemoglobins/analysis ; Leukocyte Count ; Male ; Myocardium/pathology ; Piperazines/*pharmacology ; Razoxane/*pharmacology ; Stereoisomerism ; }, abstract = {This investigation examined the potential of N-acetylcysteine (NAC) and ICRF-187, alone and in combination, to protect against chronic doxorubicin cardiotoxicity. Adult beagles of either sex (7.3 to 12.5 kg) were given doxorubicin (1.75 mg/kg i.v.) either alone or 30 min after either ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), or ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg i.p.), NAC (200 mg/kg i.p.), ICRF-187 (25 mg/kg i.p.) and NAC (200 mg/kg i.p.), or 0.9% NaCl solution without doxorubicin. The experiment was terminated 3 weeks after the seventh injection (total doxorubicin dose, 12.25 mg/kg). Three animals pretreated with NAC and one pretreated with ICRF-187 before receiving doxorubicin died or were in poor condition and were killed before the end of the study. The frequency and extent of myocardial lesions (vacuolization and myofibrillar loss) were assessed on a scale of 0 to 4+. Such lesions were present in all six dogs given doxorubicin alone and were marked to severe (3+ to 4+) in five of these dogs and moderate (2+) in one. Lesions of comparable severity (2+ to 4+) were also apparent in the hearts of dogs given the combination of NAC and doxorubicin. In contrast, no abnormalities (lesion score 0) were found in the hearts of three of six dogs given doxorubicin and ICRF-187 and in four of six dogs given doxorubicin following the combination of ICRF-187 and NAC; the remaining animals in these two groups had minimal lesions. At the dosage regimen used in the present experiments, doxorubicin, NAC, or ICRF-187 alone or in combination did not cause alterations in lungs, liver, kidney, or small intestine. Decreases in WBC count, RBC count, and hemoglobin occurred in dogs given doxorubicin with or without the various pretreatments. Thus, pretreatment with ICRF-187 was effective and pretreatment with NAC was ineffective in reducing chronic doxorubicin cardiotoxicity.}, }
@article {pmid3862608, year = {1985}, author = {Olivieri, D and Marsico, SA and Del Donno, M}, title = {Improvement of mucociliary transport in smokers by mucolytics.}, journal = {European journal of respiratory diseases. Supplement}, volume = {139}, number = {}, pages = {142-145}, pmid = {3862608}, issn = {0106-4347}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Ambroxol/*therapeutic use ; Biological Transport/drug effects ; Bromhexine/*analogs &amp; derivatives ; Bronchitis/*drug therapy ; Cilia/physiology ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Mucus/*metabolism ; Random Allocation ; *Smoking ; Trachea/*metabolism ; }, abstract = {The purpose of the present study was to compare the effects of two mucolytic drugs with different mechanism of action on mucociliary transport (MCT). N-acetylcysteine (NAC-600 mg/day) and ambroxol (AMB-90 mg/day) were administered according to a double-blind cross-over scheme to 12 heavy smokers suffering from hypersecretory bronchitis and homogeneous reduction of the MCT. Placebo of both treatments was administered during an interval of ten days between the administrations of NAC and AMB. The entire treatment period was 30 days. The data were analyzed according to ANOVA for the two-period cross-over clinical trial. The results indicate that: NAC and AMB, administered both before and after placebo, produce a significant increase in MCT, NAC showed a slightly greater efficacy than AMB, but the differences are not statistically significant. The overall efficacy of NAC and AMB is consistently greater than that of placebo. The sequence of administration of the drugs does not influence their effect.}, }
@article {pmid3862606, year = {1985}, author = {Simon, LM and Suttorp, N}, title = {Lung cell oxidant injury: decrease in oxidant mediated cytotoxicity by N-acetylcysteine.}, journal = {European journal of respiratory diseases. Supplement}, volume = {139}, number = {}, pages = {132-135}, pmid = {3862606}, issn = {0106-4347}, mesh = {Acetylcysteine/*pharmacology ; Cells, Cultured ; Cytotoxicity, Immunologic ; Humans ; In Vitro Techniques ; Lung/*cytology/immunology ; Neutrophils/metabolism ; Oxygen/*toxicity ; }, abstract = {Lung cell damage mediate by polymorphonuclear leukocyte (PMN) reactive oxygen metabolites has been suggested as a pathophysiologic mechanism in a variety of acute and chronic pulmonary disease states, while oxidant injury may be a non-specific cytotoxic mechanism. Reducing agents therefore represent one therapeutic direction for decreasing lung cell injury in several clinical circumstances. N-Acetylcysteine (NAC) is a known antioxidant which can be distributed in soluble form to multiple intrapulmonary sites. We have therefore examined a possible role for NAC against oxidant injury in a controlled in vitro model for oxygen metabolite cytotoxicity. Our data suggest that extracellular NAC is able to protect lung cells against PMN mediated oxidant injury. Pre-exposure of lung cells to NAC results in decreased susceptibility to oxidant damage by increasing intracellular antioxidant defense systems. An increase in extracellular and/or intracellular resistance to toxic oxygen metabolites by NAC may be one approach to the prevention of in vivo lung oxidant injury.}, }
@article {pmid3862604, year = {1985}, author = {Jeffery, PK and Rogers, DF and Ayers, MM}, title = {Effect of oral acetylcysteine on tobacco smoke-induced secretory cell hyperplasia.}, journal = {European journal of respiratory diseases. Supplement}, volume = {139}, number = {}, pages = {117-122}, pmid = {3862604}, issn = {0106-4347}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Bronchi/drug effects/metabolism/*pathology ; Germ-Free Life ; Hyperplasia ; Male ; Mucus/*metabolism ; Plants, Toxic ; Rats ; Rats, Inbred Strains ; Smoke/*adverse effects ; Nicotiana ; }, abstract = {The present investigation explores whether N-acetylcysteine (NAC) inhibits the secretory cell hyperplasia known to occur experimentally in specific pathogen-free (SPF) bronchitic rats. The animals were divided into 4 groups: no tobacco smoke (TS), no drug, no TS but NAC (1040 mg/kg body weight), TS but no drug, and TS plus NAC. NAC-treated animals showed no ill effects, TS exposed animals showed an initial fall in weight gain which never fully recovered (P less than 0.01): NAC did not protect. TS caused a significant increase (62-421%) in secretory cell number at all airway levels distal to the upper trachea (P less than 0.01) and NAC significantly inhibited it (P less than 0.01-0.05) in all, mostly in secretory cells containing acidic glycoprotein. TS exposure also induced a significant rise in epithelial cell concentration and of ciliated, mucous and especially basal cell number (P less than 0.001). NAC inhibited the mucous cell increase (P less than 0.001) and had 3 effects on the peak of dividing cells: it was (a) delayed until 3 days (b) greatly reduced in size and (c) prolonged at a lower level until its return to control values at 10 days of TS exposure.}, }
@article {pmid2582337, year = {1985}, author = {Berend, N}, title = {Inhibition of bleomycin lung toxicity by N-acetyl cysteine in the rat.}, journal = {Pathology}, volume = {17}, number = {1}, pages = {108-110}, doi = {10.3109/00313028509063736}, pmid = {2582337}, issn = {0031-3025}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Antioxidants/*pharmacology ; Bleomycin/antagonists &amp; inhibitors/*toxicity ; Lung/*drug effects ; Rats ; }, abstract = {N-acetyl cysteine (NAC) has recently been shown to have antioxidant properties, and since bleomycin produces pulmonary damage via free oxygen radical toxicity, the possible protective effect of NAC on bleomycin lung toxicity was investigated. Rats received saline (n = 7), NAC (n = 6), bleomycin (n = 7) or bleomycin and NAC (n = 6) by direct intratracheal injection. Seven days later the animals were killed and the lungs processed for histology or morphometry. All rats treated with bleomycin only had typical changes of bleomycin lung toxicity whereas the animals treated with bleomycin and NAC had minimal pathology. The control animals had normal lungs. These results were confirmed by morphometry which demonstrated significantly higher volume densities (p less than .01) of alveolar wall and free alveolar cells in the bleomycin group compared to the other 3 groups. It is concluded that NAC inhibits bleomycin lung toxicity when administered by direct intratracheal injection.}, }
@article {pmid6512918, year = {1984}, author = {St Omer, VE and Mohammad, FK}, title = {Effect of antidotal N-acetylcysteine on the pharmacokinetics of acetaminophen in dogs.}, journal = {Journal of veterinary pharmacology and therapeutics}, volume = {7}, number = {4}, pages = {277-281}, doi = {10.1111/j.1365-2885.1984.tb00912.x}, pmid = {6512918}, issn = {0140-7783}, mesh = {Acetaminophen/blood/*metabolism/poisoning ; Acetylcysteine/*pharmacology ; Animals ; *Antidotes ; Colorimetry ; Dogs ; Drug Administration Schedule ; Female ; Kinetics ; }, abstract = {The effects of N-acetylcysteine (NAC) on the pharmacokinetic parameters of acetaminophen (AP) in adult female beagles were studied. Each of eight dogs received a single i.v. injection of 150 mg/kg of AP as a 5% solution in a vehicle of 40% aqueous propylene glycol at 0 h. Each of four AP-treated dogs (Group I) received an oral dose of 140 mg/kg NAC as a 20% aqueous solution at 0 h, and 70 mg/kg at 30 min and 1 h post-AP administration. Four dogs (Group II) served as controls and received isotonic saline orally. Mild signs of AP toxicosis seen in both groups within 2-3 h of AP administration including depression, weakness, recumbency and methaemoglobinaemia. Relative to Group II, treatment with NAC (Group I) enhanced the elimination of AP from the body as indicated by the decreased plasma half-life (t1/2 = 1.06 h for Group I v. 1.78 h for Group II) and a higher elimination rate constant (beta = 0.67/h for Group I v. 0.40/h for Group II). Changes in the area under plasma concentration curve data (AUC = 0.39 mg.h/ml for Group I v. 0.65 mg.h/ml for Group II) were associated with a 61% increase in total body clearance of AP in Group I. The apparent volume of drug distribution Vdarea was not affected.}, }
@article {pmid6487352, year = {1984}, author = {Miners, JO and Drew, R and Birkett, DJ}, title = {Mechanism of action of paracetamol protective agents in mice in vivo.}, journal = {Biochemical pharmacology}, volume = {33}, number = {19}, pages = {2995-3000}, doi = {10.1016/0006-2952(84)90599-9}, pmid = {6487352}, issn = {0006-2952}, mesh = {Acetaminophen/metabolism/*toxicity ; Acetylcysteine/*pharmacology ; Alanine Transaminase/blood ; Animals ; Buthionine Sulfoximine ; Cysteamine/*pharmacology ; Cysteine/*pharmacology ; Glutathione/analysis/biosynthesis ; Liver/analysis/drug effects ; Male ; Methionine/*pharmacology ; Methionine Sulfoximine/analogs &amp; derivatives/pharmacology ; Mice ; Mice, Inbred C3H ; }, abstract = {The mechanism of action of cysteine, methionine, N-acetylcysteine (NAC) and cysteamine in protecting against paracetamol (APAP) induced hepatotoxicity in male C3H mice in vivo has been investigated by, characterising the effect of the individual protective agents on the metabolism of an hepatotoxic dose of APAP, and determining the efficacy of the protective agents in animals treated with buthionine sulphoximine (BSO), a specific inhibitor of glutathione (GSH) synthesis. Co-administration of cysteine, methionine or NAC increased, while co-administration of cysteamine decreased, the proportion of GSH-derived conjugates of APAP excreted in the urine of mice administered APAP, 300 mg/kg. Pretreatment of animals with BSO abolished the protective effect of cysteine, methionine and NAC, whereas cysteamine still afforded protection against APAP after BSO treatment. In conjunction with other data, these results suggest the most likely mechanism for the protective effect of cysteine, methionine and NAC is by facilitating GSH synthesis, while the most likely mechanism for the protective effect of cysteamine is inhibition of cytochrome P-450 mediated formation of the reactive metabolite of APAP.}, }
@article {pmid6500771, year = {1984}, author = {Boner, AL and Valletta, EA and Andreoli, A and Vallone, G and Baronio, L}, title = {A combination of cefuroxime and N-acetyl-cysteine for the treatment of maxillary sinusitis in children with respiratory allergy.}, journal = {International journal of clinical pharmacology, therapy, and toxicology}, volume = {22}, number = {9}, pages = {511-514}, pmid = {6500771}, issn = {0174-4879}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Asthma/complications/therapy ; Cefuroxime/*therapeutic use ; Cephalosporins/*therapeutic use ; Child ; Chronic Disease ; Drug Therapy, Combination ; Humans ; Maxillary Sinus ; Respiratory Hypersensitivity/complications/*therapy ; Sinusitis/complications/*drug therapy ; }, abstract = {Twenty-four atopic children with allergic rhinitis, asthma and maxillary sinusitis were treated with a combination of cefuroxime 50-80 mg/kg/day and N-acetyl-cysteine 15-25 mg/kg/day administered intramuscularly for 10 days. The efficacy of the treatment was judged on the basis of radiological and clinical evolution. The treatment was effective in 95.8% of the children, and 37.5% of them were able to reduce their treatment for asthma. None of the patients suffered severe side effects. The data obtained confirm that appropriate treatment of the sinusitis frequently results in a significant improvement of the asthmatic condition.}, }
@article {pmid6737127, year = {1984}, author = {Lieh-Lai, MW and Sarnaik, AP and Newton, JF and Miceli, JN and Fleischmann, LE and Hook, JB and Kauffman, RE}, title = {Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child.}, journal = {The Journal of pediatrics}, volume = {105}, number = {1}, pages = {125-128}, doi = {10.1016/s0022-3476(84)80376-5}, pmid = {6737127}, issn = {0022-3476}, mesh = {Acetaminophen/blood/metabolism/*poisoning ; Chemical and Drug Induced Liver Injury ; Chromatography, High Pressure Liquid ; Cystine/analogs &amp; derivatives/therapeutic use ; Hepatomegaly/chemically induced ; Humans ; Hypothermia/chemically induced ; Infant ; Kinetics ; Liver Function Tests ; Male ; }, abstract = {A 1-year-old child with severe acetaminophen (APAP) poisoning after ingestion of 10 gm APAP demonstrated central nervous system depression, shock, hypothermia, and metabolic acidosis. There was dramatic improvement during treatment with intravenously administered N-acetylcysteine (NAC) and hemodialysis, and the patient recovered without sequelae. A detailed study of APAP metabolism was carried out during the initial 72 hours after ingestion. APAP-sulfate and APAP-glucuronide accounted for 29% and 33%, respectively, of total drug in urine, whereas cysteine and NAC conjugates accounted for only 12%. The low incidence of severe toxicity in children after overdoses of APAP may be related to greater capacity to metabolize APAP via a nontoxic pathway.}, }
@article {pmid6548620, year = {1984}, author = {Osterloh, JD and Cohen, BS and Popendorf, W and Pond, SM}, title = {Urinary excretion of the N-acetyl cysteine conjugate of cis-1,3-dichloropropene by exposed individuals.}, journal = {Archives of environmental health}, volume = {39}, number = {4}, pages = {271-275}, doi = {10.1080/00039896.1984.10545848}, pmid = {6548620}, issn = {0003-9896}, mesh = {Absorption ; Acetylcysteine/*analogs &amp; derivatives/urine ; Air Pollutants, Occupational/*analysis ; Allyl Compounds/*metabolism ; Gas Chromatography-Mass Spectrometry/methods ; Humans ; Hydrocarbons, Chlorinated ; Male ; }, abstract = {A gas chromatographic-mass spectrometric assay was developed to identify and measure the N-acetyl cysteine conjugate of cis-1,3-dichloropropene. The assay was used to show that individuals exposed to 1,3-dichloropropene vapor during field applications excrete this conjugate in their urine. The recoveries of the conjugate were correlated with the product of airborne concentrations and the duration of exposure (r = 0.83).}, }
@article {pmid6492229, year = {1984}, author = {Lund, ME and Banner, W and Clarkson, TW and Berlin, M}, title = {Treatment of acute methylmercury ingestion by hemodialysis with N-acetylcysteine (Mucomyst) infusion and 2,3-dimercaptopropane sulfonate.}, journal = {Journal of toxicology. Clinical toxicology}, volume = {22}, number = {1}, pages = {31-49}, doi = {10.3109/00099308409035080}, pmid = {6492229}, issn = {0731-3810}, support = {ES01247/ES/NIEHS NIH HHS/United States ; GM07533-05/GM/NIGMS NIH HHS/United States ; GM25329/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetylcysteine/*therapeutic use ; Administration, Oral ; Adult ; Benztropine/poisoning ; Haloperidol/poisoning ; Humans ; Kinetics ; Male ; Mercury/urine ; Methylmercury Compounds/blood/metabolism/*poisoning ; Penicillamine/therapeutic use ; *Renal Dialysis ; Suicide, Attempted ; Unithiol/therapeutic use ; }, abstract = {A case of acute methylmercury ingestion was treated sequentially with oral D-penicillamine, hemodialysis during N-acetylcysteine (NAC) infusion, and 2,3-dimercaptopropane sulfonate (DMPS) an experimental oral agent. Urinary organic mercury elimination rate increased almost 40-fold during and 84-fold after hemodialysis with NAC infusion, compared with elimination during initial D-penicillamine therapy. Mean clearance during hemodialysis was only 13 ml/min with an extraction rate of 3.7 mcg/min. Although whole blood mercury concentrations decreased from 568 to 265 ng/ml during dialysis, a rebound to 525 ng/ml occurred. A total of 1.6 mg mercury was renally eliminated during hemodialysis and in the following 24 hours. A total of 3.3 mg of predominantly organic mercury was renally eliminated during 18 days of combined therapies. Since renal elimination of inorganic mercury is seen with chronic methylmercury poisoning, the high ratio of organic to inorganic mercury in urine supports the acute nature of this exposure. DMPS was begun on day 4 and during the two weeks of administration whole blood concentrations fell by 15% to 355 ng/ml. An expected decrease in elimination half-life to 10 days was not observed during DMPS therapy, possibly due to concurrent administration of vitamins containing zinc and copper. The amount of methylmercury ingested was estimated as 45 mg, based on a post-distribution blood concentration of approximately 450 ng/ml. The patient developed no symptoms of methylmercury poisoning during the one year after the episode. We conclude that NAC may be useful to enhance renal elimination of methylmercury and merits further investigation as a potential binding agent to reduce the body burden of methylmercury.}, }
@article {pmid6238023, year = {1984}, author = {Sekine, T and Takahashi, S and Hikita, S and Sutoh, N and Satake, K}, title = {Selective modification of myosin SH1 with 1,2,4-trinitrobenzene. VIII. Thiols of myosin.}, journal = {Journal of biochemistry}, volume = {96}, number = {1}, pages = {27-33}, doi = {10.1093/oxfordjournals.jbchem.a134824}, pmid = {6238023}, issn = {0021-924X}, mesh = {Adenosine Triphosphatases ; Chemical Phenomena ; Chemistry ; Ethylmaleimide ; Hydrogen-Ion Concentration ; Indicators and Reagents ; Kinetics ; *Myosins ; *Nitrobenzenes ; Solubility ; Spectrophotometry, Ultraviolet ; *Sulfhydryl Compounds ; *Trinitrobenzenes ; }, abstract = {Myosin has 2 mol of the most reactive thiol, named SH1. 1,2,4-Trinitrobenzene (TNB), a novel dinitrophenyl(DNP)ating reagent [Takahashi et al. (1983) Chem. Lett. 1445-1448], was found to react only with SH1 without any other amino acid residues in myosin under the conditions used. Its reaction with myosin SH1 was about 30 times faster than that with N-acetylcysteine (NAC). The reaction rate of TNB with SH1 was about twice compared with that of NEM, the most reactive selective reagent for SH1 so far found, although its rate with NAC was only one sixtieth that of NEM. As to the lambda max of the absorption spectrum of SH1-DNP-myosin, a large red shift of as much as 20 nm was observed compared with low molecular S-DNP derivatives. This red shift disappeared in 8 M urea. This outstanding feature of SH1 modification with TNB was discussed in terms of affinity labeling by interaction with an aromatic amino acid near SH1.}, }
@article {pmid6725559, year = {1984}, author = {Bernard, GR and Lucht, WD and Niedermeyer, ME and Snapper, JR and Ogletree, ML and Brigham, KL}, title = {Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function.}, journal = {The Journal of clinical investigation}, volume = {73}, number = {6}, pages = {1772-1784}, pmid = {6725559}, issn = {0021-9738}, support = {HL 07123/HL/NHLBI NIH HHS/United States ; HL 19153/HL/NHLBI NIH HHS/United States ; HL 27274/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/*pharmacology ; Animals ; Blood Gas Analysis ; Blood Pressure/drug effects ; Endotoxins/*toxicity ; Granulocytes/drug effects/*physiology ; Lung/*drug effects/physiology ; Lymph/drug effects ; Pulmonary Circulation/drug effects ; Sheep ; Vascular Resistance/drug effects ; Wakefulness/physiology ; }, abstract = {Oxygen free radicals released during endotoxemia may contribute to the lung injury of the adult respiratory distress syndrome (ARDS). As this syndrome occurs frequently after gram-negative sepsis in humans, we studied the effect of intravenous N-acetylcysteine (NAC), a free radical scavenger, upon the endotoxin (E)-induced model of ARDS in awake sheep. In vivo studies demonstrated that NAC attenuates the endotoxin-induced rise in pulmonary artery pressure (62 +/- 3 torr with E control vs. 43 +/- 3 torr for E + NAC), and markedly diminishes the rise in lymph flow at 1 h (8.5 +/- 1.2 vs 4.5 +/- 0.6 ml/15 min) and 4 h (5.0 +/- 0.6 vs. 3.3 +/- 0.4 ml/15 min), respectively, for E control vs. E + NAC. NAC also markedly attenuated the alterations in lung mechanics after endotoxemia. Dynamic compliance at 2 h after endotoxemia was 44 +/- 6% of base line for E vs. 76 +/- 10% of base line for E + NAC. Resistance to airflow across the lung at 1 h postendotoxin was 811 +/- 280% of base line for E vs. 391 +/- 233% of base line for E + NAC. NAC substantially reduced the 1 h postendotoxin rise in lymph concentrations of thromboxane B2 (8.29 +/- 3.28 vs. 2.75 +/- 1.93 ng/ml for E vs. E + NAC) and 6-keto-prostaglandin-F1 alpha (0.91 +/- 0.27 vs. 0.23 +/- 0.12 ng/ml for E vs. E + NAC). In addition, in vitro studies were performed which revealed NAC to be a potent free radical scavenger in both biologic and nonbiologic free radical generating systems. NAC decreased phorbol-stimulated granulocyte aggregation in a concentration-dependent manner in vitro. Minimal effects were observed, however, upon leukocyte degranulation at the concentrations of NAC achieved during the in vivo tests. Thus, NAC significantly attenuated all monitored pathophysiologic changes in the endotoxin model of ARDS in sheep, possibly by its ability to scavenge toxic oxygen free radicals. A direct impairment of the ability of inflammatory cells to generate oxygen radicals cannot be ruled out.}, }
@article {pmid6534784, year = {1984}, author = {Buchter, A and Peter, H}, title = {Clinical toxicology of acrylonitrile.}, journal = {Giornale italiano di medicina del lavoro}, volume = {6}, number = {3-4}, pages = {83-86}, pmid = {6534784}, issn = {0391-9889}, mesh = {Acrylonitrile/poisoning/*toxicity ; Animals ; Antidotes/therapeutic use ; Humans ; Lung Neoplasms/chemically induced ; Male ; Middle Aged ; Neoplasms, Experimental/chemically induced ; Nitriles/*toxicity ; Occupational Diseases/chemically induced ; Time Factors ; }, abstract = {Acrylonitrile monomer is used in the production of artificial fibres and resins. It has been used as a fumigant. Acrylonitrile has acute toxic effects for men and animals on over-exposure by inhalation of the vapor, dermal absorption of the liquid and oral intake. Symptoms in men are non-specific and predominantly related to the central nervous system, the respiratory tract, the skin and to the gastrointestinal tract. Severe acrylonitrile intoxication is followed by loss of consciousness, convulsions, respiratory arrest and death. The detailed investigation of a patient with complaints after chronic exposure demonstrates the necessity of objective neurophysiologic studies. Acrylonitrile has carcinogenic properties in animals. It is also embryotoxic and teratogenic. Epidemiological studies in men exposed to acrylonitrile are not convincing. There may be a slight excess of deaths from lung cancers and other malignant tumors. Effects of potential antidotes were studied in animal experiments. Rats were intoxicated with lethal doses of acrylonitrile by different routes of application. The cyanide antidotes 4-dimethylaminophenol plus thiosulfate showed some protective effect only after oral but not after i.p. or inhalational acrylonitrile administration. Of the sulfhydryl compounds cysteine, N-acetyl-cysteine, cysteamine and diethyldithiocarbamate, the two antidotes cysteine and N-acetylcysteine proved to be especially effective. From these experiments a tentative schedule of antidotal therapy for humans accidentally intoxicated with acrylonitrile is inferred, using N-acetylcysteine by analogy with the therapeutic regimen effective in cases of paracetamol poisoning.}, }
@article {pmid6534783, year = {1984}, author = {Peter, H and Bolt, HM}, title = {Experimental pharmacokinetics and toxicology of acrylonitrile.}, journal = {Giornale italiano di medicina del lavoro}, volume = {6}, number = {3-4}, pages = {77-81}, pmid = {6534783}, issn = {0391-9889}, mesh = {Acrylonitrile/*metabolism/toxicity ; Animals ; Chickens ; Environmental Exposure ; Heart Atria/drug effects ; In Vitro Techniques ; Kinetics ; Macaca mulatta ; Male ; Nitriles/*metabolism ; Rats ; Vagus Nerve/drug effects ; }, abstract = {Pharmacokinetic experiments in rats and Rhesus monkeys show that inhaled acrylonitrile is nearly completely retained and metabolized. Metabolism, according to the literature, proceeds via direct reaction of acrylonitrile with biological sulfhydryl compounds and, to a much lesser extent, via glycidonitrile as a DNA-reactive oxidative metabolite. Clinical symptoms of acute acrylonitrile intoxication are in favour of an increased parasympathetic activity. This is confirmed by increased release of acetylcholine, in presence of acrylonitrile, from isolated chicken hearts of which the N. vagus is electrically stimulated. This explains an antidotal effect of atropine. The effectiveness of N-acetyl-cysteine as an acrylonitrile antidote may be explained by decreased alkylation and inactivation of acetylcholine-esterase.}, }
@article {pmid6368036, year = {1984}, author = {De Flora, S and Bennicelli, C and Zanacchi, P and Camoirano, A and Morelli, A and De Flora, A}, title = {In vitro effects of N-acetylcysteine on the mutagenicity of direct-acting compounds and procarcinogens.}, journal = {Carcinogenesis}, volume = {5}, number = {4}, pages = {505-510}, doi = {10.1093/carcin/5.4.505}, pmid = {6368036}, issn = {0143-3334}, mesh = {Acetylcysteine/*toxicity ; Animals ; Biotransformation ; Carcinogens/*toxicity ; Cysteine/toxicity ; Drug Interactions ; Glutathione/analogs &amp; derivatives/*toxicity ; Glutathione Disulfide ; Microsomes, Liver/metabolism ; Mutagenicity Tests ; *Mutagens ; *Mutation ; Rats ; Rats, Inbred Strains ; Salmonella typhimurium/drug effects ; }, abstract = {N-Acetylcysteine (NAC), reduced (GSH) and oxidized (GSSG) glutathione were negative in the Ames test with 7 Salmonella strains, while L-cysteine was activated by rat liver S-9 fractions to metabolites mutagenic to strains TA102, TA97 and TA100. The mutagenic response in S. typhimurium strains (TA1535, TA98, TA100, TA102) and the levels of enzyme activities, responsible for NADP+ or GSSG reduction and for the utilization of NADPH or GSH in rat liver S-9 fractions, were investigated following in vitro preincubation of NAC with four direct-acting mutagens and six procarcinogens. Treatment with this nucleophilic and reducing compound resulted in a dose-related decrease of the direct mutagenicity of epichlorohydrin, hydrogen peroxide and, sharply, of 4-nitroquinolino-N-oxide and sodium dichromate. The mutagenicity of these compounds, both in the absence and in the presence of NAC, was decreased by rat liver S-9 fractions and to some extent by lung S-9 fractions. A diphasic effect was observed in the case of procarcinogens (cyclophosphamide, 2-aminofluorene, cigarette smoke condensate, Trp-P-2, aflatoxin B1 and benzo[a]pyrene), i.e., an enhancement of S-9 requiring mutagenicity at intermediate NAC doses, which could be ascribed to metabolic factors acting in vitro, and a loss of mutagenicity at high NAC doses, which could be ascribed to trapping of electrophilic metabolites. Out of the five S-9 enzyme activities under study, i.e., glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, malic enzyme, GSH peroxidase and GSSG reductase, only the last one showed significant changes following mutagen and/or NAC treatment.}, }
@article {pmid6324374, year = {1984}, author = {Polu, JM and Puchelle, E and Sadoul, P}, title = {[Bronchial expectorants : pharmacology of bronchial mucomodifiers].}, journal = {La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris}, volume = {60}, number = {9}, pages = {643-658}, pmid = {6324374}, mesh = {Animals ; Bronchi/metabolism/physiopathology ; Expectorants/metabolism/*pharmacology/therapeutic use ; Humans ; Mucous Membrane/metabolism ; Rheology ; Trachea/physiopathology ; }, abstract = {Prescription of bronchial mucus modifiers has benefited from recent advances in the knowledge of biochemical constituents of bronchial fluids, their regulation and disturbances on the one hand, and the consequences of biochemical changes in these fluids on rheological characteristics of bronchial secretions on the other. In addition, the significance of these characteristics has been evidenced by the study of mucociliary transportation. Drugs which modify bronchial fluids are studied according to their mode of action upon the organized gel phase, mobilized by ciliary activity, and the aqueous sol phase, which enables this ciliary activity. Drugs which modify the gel phase are either true mucolytic agents or muco-regulators. True mucolytic drugs include reducing agents with a free thiol group, chiefly N-acetyl-cysteine which breaks disulfide bonds linking different protein chains, and proteolytic enzymes which break protein chains. The latter also have an appreciable anti-inflammatory effect but are rarely used at present owing to allergic reactions. Mucoregulating drugs are cysteine derivatives whose thiol group is not free. They are headed by carbocysteine which activates the synthesis of sialidized acid mucins. They enable reorganization of bronchial mucus, reversing former drops in viscosity and elasticity, thereby improving mucociliary transportation. They have a complementary anti-inflammatory action.}, }
@article {pmid6394298, year = {1984}, author = {Linden, CH and Rumack, BH}, title = {Acetaminophen overdose.}, journal = {Emergency medicine clinics of North America}, volume = {2}, number = {1}, pages = {103-119}, pmid = {6394298}, issn = {0733-8627}, mesh = {Acetaminophen/history/metabolism/*poisoning ; Acetylcysteine/metabolism/*therapeutic use ; Adult ; Alanine Transaminase/blood ; Aspartate Aminotransferases/blood ; Bilirubin/blood ; Biotransformation ; *Chemical and Drug Induced Liver Injury ; Child ; Cysteine/biosynthesis ; Dose-Response Relationship, Drug ; Glutathione/metabolism ; History, 20th Century ; Humans ; Kinetics ; Liver Diseases/drug therapy ; Prognosis ; Prothrombin Time ; Time Factors ; }, abstract = {N-acetylcysteine (NAC) is the treatment of choice for acetaminophen overdose. With this therapy, morbidity from overdose can be held to a minimum. Mortality is rare in any case and virtually nonexistent in treated patients. Unless a high index of suspicion is maintained, the diagnosis may be missed until it is too late for effective antidotal treatment.}, }
@article {pmid6715055, year = {1984}, author = {Buchter, A and Peter, H and Bolt, HM}, title = {[N-Acetylcysteine as an antidote in accidental acrylonitrile poisoning].}, journal = {International archives of occupational and environmental health}, volume = {53}, number = {4}, pages = {311-319}, pmid = {6715055}, issn = {0340-0131}, mesh = {Acetylcysteine/*therapeutic use ; Acrylonitrile/administration &amp; dosage/*poisoning ; Aerosols ; Animals ; Antidotes/*therapeutic use ; Nitriles/*poisoning ; Rats ; Rats, Inbred Strains ; }, abstract = {Acute acrylonitrile intoxications are followed by loss of consciousness, convulsions, respiratory arrest, and may end fatally. Common cyanide antidotes have not proved to be effective. In previous animal experiments we could demonstrate that the cyanide antidotes show some protective effect only after oral acrylonitrile application. Only a minimal amount of inhaled acrylonitrile will be transformed into cyanide, in contrast to pharmacokinetics after oral intake. After acrylonitrile inhalation the toxic effect of the whole molecule (cyanethylation) is important, and sulfhydryl compounds show antidotal effects. Further animal experiments demonstrate the superior antidotal effects of N-acetyl-cysteine after acrylonitrile inhalation. Intravenous injection of N-acetyl-cysteine in high doses is recommended according to the treatment of paracetamol poisoning.}, }
@article {pmid6701398, year = {1984}, author = {Banda, PW and Quart, BD}, title = {The effect of alcohol on the toxicity of acetaminophen in mice.}, journal = {Research communications in chemical pathology and pharmacology}, volume = {43}, number = {1}, pages = {127-138}, pmid = {6701398}, issn = {0034-5164}, mesh = {Acetaminophen/antagonists &amp; inhibitors/metabolism/*toxicity ; Acetylcysteine/pharmacology ; Animals ; Antidotes/administration &amp; dosage/pharmacology/*therapeutic use ; Ethanol/administration &amp; dosage/pharmacology/*therapeutic use ; Male ; Mice ; Microsomes, Liver/drug effects ; }, abstract = {A previous study with human subjects has shown that a low dose of alcohol, consumed prior to the ingestion of a therapeutic dose of acetaminophen, significantly reduced the excretion of acetaminophen-mercapturic acid. This study suggested that alcohol may be of value as an antidote in cases of acetaminophen overdose, by inhibiting the oxidative metabolism of acetaminophen. The present report describes our results in using alcohol as an antidote for acetaminophen overdose in the mouse model. We have observed that 0.2 ml per animal of 19% alcohol, given at 3 - 4 hours after an LD50 dose of acetaminophen, produced a 24 hour survival of 92%. N Acetyl-cysteine produced 100% survival. Changes in either the dose or timing of the alcohol produced smaller increases in survival (75%), and in no case of alcohol treatment was survival less than control levels (50%). Alcohol thus appears to be an effective antidote for acetaminophen overdose in the mouse model, when given at an appropriate time and dose. It remains to be determined whether these results are applicable to human subjects.}, }
@article {pmid6588535, year = {1984}, author = {Turnberg, LA and Ross, IN}, title = {Studies of the pH gradient across gastric mucus.}, journal = {Scandinavian journal of gastroenterology. Supplement}, volume = {92}, number = {}, pages = {48-50}, pmid = {6588535}, issn = {0085-5928}, mesh = {Animals ; Gastric Acid/metabolism ; Gastric Mucosa/*physiology ; Hydrogen-Ion Concentration ; Microelectrodes ; Mucus/*physiology ; Rats ; Rats, Inbred Strains ; }, abstract = {We studied the possibility that gastric mucosa protects itself from luminal acid by maintaining a neutral zone adjacent to the mucosa. In the anaesthetised rat pedicles of gastric fundus mucosa with an intact mucus layer were studied. Using pH sensitive antimony chloride microelectrodes, we demonstrated a maximal pH adjacent to the mucosa of 6.68 when luminal pH was 2 (n = 30). The intramucus pH was compromised when luminal acidity was greater than pH 1.5. Addition of 10 mM aspirin or 5% N-acetyl cysteine to the luminal solution also caused a fall in intramucus pH. Sodium taurocholate (10 mM) caused a physical change in the appearance of the mucus which became brittle and fragmented. The pH within the mucus layer fell as a result of this fragmentation. 16, 16 dimethyl prostaglandin E2 prevented the fall in intramucus pH produced by 20 mM aspirin. Similar results were obtained in specimens of human gastric mucosa removed at gastrectomy. These observations suggest that an alkaline zone is maintained within the mucus layer adjacent to the gastric epithelium which may have an important protective role.}, }
@article {pmid6530353, year = {1984}, author = {Christophidis, N and Cosolo, W and Louis, WJ and Louis, CJ}, title = {The effect of penicillamine and related thiols on cyclophosphamide-induced cystitis and bone marrow suppression.}, journal = {International journal of tissue reactions}, volume = {6}, number = {6}, pages = {493-498}, pmid = {6530353}, issn = {0250-0868}, mesh = {Animals ; Bone Marrow/*drug effects ; Cell Survival/drug effects ; Cyclophosphamide/*antagonists &amp; inhibitors/toxicity ; Cystitis/*chemically induced ; Male ; Penicillamine/*pharmacology ; Rats ; Structure-Activity Relationship ; Sulfhydryl Compounds/*pharmacology ; }, abstract = {When adult male Wistar-Kyoto rats had been injected intra-peritoneally with a dose of 100 mg/kg of cyclophosphamide (CP), their urinary bladders showed changes of thickening and haemorrhage visible macroscopically, and oedema, necrosis and haemorrhage of the mucosa visible microscopically. There was an increase in bladder weight from an average of 60 mg in untreated control rats to an average of 125 mg in the CP-treated rats. When in addition they had been given 400 mg/kg of a thiol drug, namely either penicillamine or its disulphide, or N-acetylcysteine (NAC) or its S-carboxymethyl derivative carbocysteine, the increase in bladder weight and the histologic changes of haemorrhagic cystitis were found to be prevented by the co-administration of penicillamine or NAC but not by penicillamine disulphide or carbocysteine. The leucopenia caused by CP was not prevented by co-administration of these thiol drugs. It is concluded that penicillamine, like NAC, is effective in preventing CP-induced cystitis but not at the expense of reducing the cytotoxicity of CP. The inefficacy of penicillamine disulphide and carbocysteine suggests that significant dissociation of the disulphide does not occur in vivo and that the thiol moiety is important in preventing the cystitis. Penicillamine, a thiol compound with anti-rheumatic and possible anti-tumour effects, may thus prove to be a very useful adjunct to CP therapy.}, }
@article {pmid6382125, year = {1984}, author = {Trastotenojo, MS and Harsoyo, N and Sachro, AD and Soemantri, AG and Said, HW}, title = {Use of acetyl cysteine in respiratory tract disease in children.}, journal = {Paediatrica Indonesiana}, volume = {24}, number = {1-2}, pages = {1-10}, pmid = {6382125}, issn = {0030-9311}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Asthma/drug therapy ; Bronchiolitis, Viral/drug therapy ; Bronchopneumonia/drug therapy ; Child ; Child, Preschool ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Humans ; Infant ; Male ; Respiratory Tract Diseases/*drug therapy ; Tuberculosis, Pulmonary/drug therapy ; }, }
@article {pmid6150718, year = {1984}, author = {Maurer, HR and Meckert, C and Ali-Osman, F and Musil, J}, title = {Cytoprotection by somatostatin of normal and malignant clonogenic cells against the in vitro cytotoxicity of bischloroethylnitrosourea (BCNU).}, journal = {Arzneimittel-Forschung}, volume = {34}, number = {9}, pages = {939-943}, pmid = {6150718}, issn = {0004-4172}, mesh = {Acetylcysteine/pharmacology ; Animals ; Carmustine/therapeutic use/*toxicity ; Cell Survival/drug effects ; Cells, Cultured ; Clone Cells ; Granulocytes/drug effects ; Leukemia L1210/drug therapy/*pathology ; Mice ; Somatostatin/*pharmacology ; }, abstract = {The various pharmacological effects of somatostatin may be explained by the hypothesis that the paracrine peptide, by "stabilizing" cell membranes, inhibits the secretion of hormones as well as protects other cells (vascular endothelium, parenchyma) from different lesions (vasculo-, organo-, cytoprotection). This hypothesis was tested in vitro, using bischloroethyl-nitrosourea (BCNU)-intoxicated stem cells of normal mouse granulopoiesis and of the L 1210 leukemia. Clonogenic mouse bone marrow and L 1210 cells were grown in agar-containing glass capillaries. Using these colony assays and a ID90 of BCNU, cyclic somatostatin influenced the BCNU-cytotoxicity neither at simultaneous nor at subsequent application. However, when given 2 h prior to BCNU, the inhibition of colony growth was almost totally abolished. This cytoprotective effect was seen with normal granulopoietic as well as with leukemic cells. The effect did not show up, if the inactive linear somatostatin was used. N-acetyl-cysteine, a SH-compound applied as a chemoprotective adjunct, did not reveal a cytoprotective effect under identical experimental conditions, either. The results were discussed in view of common efforts to reduce the toxicity of cancer chemotherapy.}, }
@article {pmid6315493, year = {1983}, author = {Orrenius, S and Ormstad, K and Thor, H and Jewell, SA}, title = {Turnover and functions of glutathione studied with isolated hepatic and renal cells.}, journal = {Federation proceedings}, volume = {42}, number = {15}, pages = {3177-3188}, pmid = {6315493}, issn = {0014-9446}, mesh = {Animals ; Cells, Cultured ; Chemical Phenomena ; Chemistry ; Cysteine/metabolism ; Cystine/metabolism ; Disulfides/metabolism ; Glutathione/*metabolism ; Kidney/*metabolism/ultrastructure ; Liver/*metabolism/ultrastructure ; Microbial Collagenase ; Rats ; Sulfhydryl Compounds/metabolism ; Trypan Blue ; }, abstract = {Suspensions of freshly isolated rat hepatocytes and renal tubular cells contain high levels of reduced glutathione (GSH), which exhibits half-lives of 3-5 and 0.7-1 h, respectively. In both cells types the availability of intracellular cysteine is rate limiting for GSH biosynthesis. In hepatocytes, methionine is actively converted to cysteine via the cystathionine pathway, and hepatic glutathione biosynthesis is stimulated by the presence of methionine in the medium. In contrast, extracellular cystine can support renal glutathione synthesis; several disulfides, including cystine, are rapidly taken up by renal cells (but not by hepatocytes) and are reduced to the corresponding thiols via a GSH-linked reaction sequence catalyzed by thiol transferase and glutathione reductase (NAD(P)H). During incubation, hepatocytes release both GSH and glutathione disulfide (GSSG) into the medium; the rate of GSSG efflux is markedly enhanced during hydroperoxide metabolism by glutathione peroxidase. This may lead to GSH depletion and cell injury; the latter seems to be initiated by a perturbation of cellular calcium homeostasis occurring in the glutathione-depleted state. In contrast to hepatocytes, renal cells metabolize extracellular glutathione and glutathione S-conjugates formed during drug biotransformation to the component amino acids and N-acetyl-cysteine S-conjugates, respectively. In addition, renal cells contain a thiol oxidase acting on extracellular GSH and several other thiols. In conclusion, our findings with isolated cells mimic the physiological situation characterized by hepatic synthesis and renal degradation of plasma glutathione and glutathione S-conjugates, and elucidate some of the underlying biochemical mechanisms.}, }
@article {pmid6139183, year = {1983}, author = {Horowitz, JD and Antman, EM and Lorell, BH and Barry, WH and Smith, TW}, title = {Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine.}, journal = {Circulation}, volume = {68}, number = {6}, pages = {1247-1253}, doi = {10.1161/01.cir.68.6.1247}, pmid = {6139183}, issn = {0009-7322}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Blood Pressure/drug effects ; Cardiac Catheterization ; Drug Synergism ; Enzyme Activation ; Female ; Guanylate Cyclase/metabolism ; Humans ; Male ; Middle Aged ; Nitroglycerin/*pharmacology ; Oxidation-Reduction ; Sulfhydryl Compounds/pharmacology ; Vasodilator Agents/pharmacology ; }, abstract = {The biochemical basis of the mechanism of vasodilatation by nitroglycerin (NTG) has not been previously investigated in man. However, evidence from in vitro studies suggests that NTG induces activation of guanylate cyclase via a series of enzymatic reactions that are modulated by the availability of sulfhydryl groups. Cysteine appears to be particularly effective in potentiating guanylate cyclase activation by NTG. To determine whether hemodynamic responsiveness to NTG in man might be modulated by sulfhydryl availability, concentration-response curves for effects of intravenously infused NTG on mean arterial pressure (MAP) and mean pulmonary capillary wedge pressure (PCW) were obtained in 10 patients undergoing cardiac catheterization for investigation of chest pain. NTG infusion was repeated 10 min after the intravenous infusion of 100 mg/kg of the cysteine source N-acetylcysteine (NAC). NAC induced no significant hemodynamic effect, but after NAC infusion there was a significant reduction both in the NTG infusion rate associated with a 10% fall from control values in MAP (25.8 +/- 8.3 to 9.3 +/- 2.7 micrograms/min; p less than .01) and in the infusion rate inducing a 30% reduction in PCW (13.6 +/- 4.6 to 4.2 +/- 1.6 micrograms/min; p less than .02). In a control group of five patients who received no NAC, there was no significant change in responsiveness to NTG between infusions. It is concluded that NAC potentiates the vasodilator effects of NTG in man. This suggests that sulfhydryl availability and/or redox state may be determinants of in vivo responsiveness to NTG.}, }
@article {pmid6651870, year = {1983}, author = {Estrela, JM and Sáez, GT and Such, L and Viña, J}, title = {The effect of cysteine and N-acetyl cysteine on rat liver glutathione (GSH).}, journal = {Biochemical pharmacology}, volume = {32}, number = {22}, pages = {3483-3485}, doi = {10.1016/0006-2952(83)90381-7}, pmid = {6651870}, issn = {0006-2952}, mesh = {Acetaminophen/pharmacology ; Acetylcysteine/*administration &amp; dosage/metabolism ; Administration, Oral ; Animals ; Cysteine/*administration &amp; dosage/metabolism ; Glutathione/*metabolism ; Injections, Intraperitoneal ; Liver/drug effects/*metabolism ; Oxidation-Reduction ; Rats ; Rats, Inbred Strains ; }, }
@article {pmid6648979, year = {1983}, author = {Ioannides, C and Hall, DE and Mulder, DE and Steele, CM and Spickett, J and Delaforge, M and Parke, DV}, title = {A comparison of the protective effects of N-acetyl-cysteine and S-carboxymethylcysteine against paracetamol-induced hepatotoxicity.}, journal = {Toxicology}, volume = {28}, number = {4}, pages = {313-321}, doi = {10.1016/0300-483x(83)90005-7}, pmid = {6648979}, issn = {0300-483X}, mesh = {Acetaminophen/*antagonists &amp; inhibitors/metabolism/toxicity ; Acetylcysteine/*pharmacology ; Animals ; Carbocysteine/*pharmacology ; Chemical and Drug Induced Liver Injury/pathology/*prevention &amp; control ; Cricetinae ; Cysteine/*analogs &amp; derivatives ; Humans ; In Vitro Techniques ; Kidney/drug effects/pathology ; Male ; Mesocricetus ; Microsomes, Liver/drug effects/enzymology ; Protein Binding/drug effects ; }, abstract = {The protective effect of the sulphur-containing amino acids N-acetyl-cysteine and S-carboxymethylcysteine against paracetamol-induced hepatotoxicity was evaluated in the hamster by biochemical and histological methods. Of the animals receiving paracetamol alone 25% died within 24 h following administration. All surviving animals showed acute hepatocellular injury and marked loss of cytochrome P-450 and hepatic mixed-function oxidase activities. Simultaneous administration of N-acetylcysteine decreased the mortality rate, partly prevented the paracetamol-induced liver damage and partly restored enzyme activities. Simultaneous administration of S-carboxymethylcysteine with paracetamol afforded no protection. Kidneys from all animals were histologically normal. Human liver microsomes and liver microsomes from 3-methylcholanthrene-pretreated hamsters metabolished paracetamol to intermediate(s) that bind covalently to microsomal proteins. The rate of covalent binding was inhibited markedly by N-acetylcysteine and to a lesser extent by S-carboxylmethylcysteine.}, }
@article {pmid6629112, year = {1983}, author = {Ross, IN and Turnberg, LA}, title = {Studies of the 'mucus-bicarbonate' barrier on rat fundic mucosa: the effects of luminal pH and a stable prostaglandin analogue.}, journal = {Gut}, volume = {24}, number = {11}, pages = {1030-1033}, pmid = {6629112}, issn = {0017-5749}, mesh = {16,16-Dimethylprostaglandin E2/*pharmacology ; Animals ; Aspirin/pharmacology ; Bicarbonates/*metabolism ; Gastric Fundus/drug effects/metabolism ; Gastric Mucosa/drug effects/*metabolism ; Hydrogen-Ion Concentration ; Mucus/drug effects/*metabolism ; Prostaglandins E, Synthetic/*pharmacology ; Rats ; Rats, Inbred Strains ; }, abstract = {Gastric mucosa may protect itself from acid peptic digestion by maintaining an alkaline barrier zone within the layer of mucus coating its surface. We have measured the pH gradient in the mucous layer in vivo, on the gastric mucosa of anaesthetised rats using antimony chloride micro pH electrodes. The maximum pH recordable adjacent to the epithelium was 7.43 +/- 0.56 (n = 8) when the luminal bathing solution pH was 2. Adjusting the luminal pH to 7.0 caused the maximal pH to rise to 7.88 (range 7.59 to 8.08), a value which is significantly higher than either luminal or reported intraepithelial pH and suggests that active secretion of alkali is involved. Pretreatment with 16-16-dimethyl prostaglandin E2 (20 micrograms subcutaneously) significantly increased the maximal intramucus pH to 7.89 +/- 0.45 (n = 8) when luminal pH was 2 and prevented the fall in intramucus pH induced by luminal aspirin (20 mM). It did not prevent falls in pH provoked by the mucolytic agent n-acetyl cysteine or by a high luminal activity (pH 1.4). These data indicate that an alkaline environment is maintained adjacent to gastric mucosa and that while this is enhanced by prostaglandin it may be compromised by high luminal acid concentrations or by removal of the support provided by mucus. These observations may be relevant to the mechanisms of gastric mucosal protection against acid peptic damage.}, }
@article {pmid6580492, year = {1983}, author = {Unverferth, DV and Jagadeesh, JM and Unverferth, BJ and Magorien, RD and Leier, CV and Balcerzak, SP}, title = {Attempt to prevent doxorubicin-induced acute human myocardial morphologic damage with acetylcysteine.}, journal = {Journal of the National Cancer Institute}, volume = {71}, number = {5}, pages = {917-920}, pmid = {6580492}, issn = {0027-8874}, mesh = {Acetylcysteine/*pharmacology ; Adult ; Aged ; Biopsy ; Cardiomyopathies/chemically induced ; Doxorubicin/*adverse effects ; Drug Evaluation ; Endocardium/drug effects/ultrastructure ; Humans ; Microscopy, Electron ; Middle Aged ; Mitochondria, Heart/drug effects/ultrastructure ; Myocardium/*ultrastructure ; }, abstract = {Doxorubicin induced acute as well as chronic myocardial morphologic alterations. Twenty patients with normal cardiovascular function were randomized to 2 groups based on age and dose of doxorubicin. Group I received placebo 1 hour before doxorubicin administration; group II received acetylcysteine (N-acetyl-L-cysteine) (Nac) 1 hour before doxorubicin. Endomyocardial biopsies were performed at base line at 4 and 24 hours after doxorubicin administration. Biopsy tissue was viewed by electron microscopy, and stereoscopic techniques were used to determine tubular and mitochondrial area. The change of the tubular area was similar in the 2 groups, was maximum at 4 hours, and was proportionately spread throughout the cell. The mitochondrial swelling was also similar in the 2 groups and proportionate throughout the cell but was maximum at 24 hours. This study demonstrated that the acute doxorubicin-induced damage was diffuse and not prevented by Nac.}, }
@article {pmid6648037, year = {1983}, author = {Khairy, L and Isom, GE and Kildsig, DO}, title = {Reversal of acetaminophen intoxication with an N-acetylcysteine-liposome preparation.}, journal = {Research communications in chemical pathology and pharmacology}, volume = {42}, number = {1}, pages = {153-156}, pmid = {6648037}, issn = {0034-5164}, mesh = {Acetaminophen/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Lethal Dose 50 ; Liposomes/*administration &amp; dosage ; Liver/*drug effects/pathology ; Male ; Mice ; Necrosis ; }, abstract = {An N-acetyl-l-cysteine (NAC)-liposome drug delivery system was assessed for its ability to reverse acetaminophen toxicity. Positively charged NAC-liposomes, as compared to neutral and negatively charged preparations, were highly effective in reversing acetaminophen-induced lethality in mice. The positively charged liposome preparation, when administered at a dose equivalent to 50 mg/kg NAC, increased the LD50 of acetaminophen from 840 to 1507 mg/kg; free NAC (50 mg/kg) did not significantly alter the LD50 (829 mg/kg). At this dose, only the liposome entrapped NAC protects against acetaminophen-induced lethality suggesting that positively charged liposomes enhance the delivery of NAC to hepatic parenchymal cells, the site of acetaminophen-induced necrosis.}, }
@article {pmid6633540, year = {1983}, author = {Sitzmann, FC and Orth, H}, title = {[N-acetyl-cystein-(NAC)-activated creatinkinase (CK) and isoenzyme CK-MB in the serum of children].}, journal = {Monatsschrift Kinderheilkunde : Organ der Deutschen Gesellschaft fur Kinderheilkunde}, volume = {131}, number = {8}, pages = {509-512}, pmid = {6633540}, issn = {0026-9298}, mesh = {Acetylcysteine ; Adolescent ; Cardiac Catheterization ; Child ; Child, Preschool ; Creatine Kinase/*blood ; Humans ; Infant ; Infant, Newborn ; Infant, Premature ; Injections, Intramuscular ; Isoenzymes ; Myocarditis/enzymology ; Poisoning/enzymology ; Reference Values ; Virus Diseases/enzymology ; }, abstract = {We have examined the variation of creatinekinase levels (NAC-activated) with age in 170 children. The subjects included 40 neonates, 18 premature neonates, 40 small babies, 32 infants and 40 schoolchildren. The enzyme activity of CK-MM was very high in the first hours after delivery and remained high for a few days. The isoenzyme MB in healthy newborns also showed a higher catalytic concentration. These values (about 2-12 U/l) reached normal levels of adults within 4 months of life (0.5-5 U/l). The same rule applied to CK-MM: enzyme activities of 160 U/l and more in the first days of life declined to 16-75 U/l during the first 4 months. No correlation between birth trauma and the increase in serum-CK was found. Because of the increased CK-MM (and CK-MB) found in normal newborns screening for Duchenne-type muscular dystrophy should be postponed for a few weeks after delivery. In view of the relatively high endogenous serum CK-MB in the neonates (release of CK-MB from the skeletal muscle) the test lacks the specificity for cardiac damage. Intramuscular injections of several drugs lead to a distinct increase in CK activity. A rise of CK-MM was seen 4-24 h after catheterization of the heart.}, }
@article {pmid6861067, year = {1983}, author = {Unverferth, BJ and Magorien, RD and Balcerzak, SP and Leier, CV and Unverferth, DV}, title = {Early changes in human myocardial nuclei after doxorubicin.}, journal = {Cancer}, volume = {52}, number = {2}, pages = {215-221}, doi = {10.1002/1097-0142(19830715)52:2&lt;215::aid-cncr2820520206&gt;3.0.co;2-f}, pmid = {6861067}, issn = {0008-543X}, support = {CA-15147/CA/NCI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Cardiomyopathies/chemically induced/pathology ; Cell Nucleolus/drug effects/ultrastructure ; Cell Nucleus/*drug effects/ultrastructure ; Chronic Disease ; Dose-Response Relationship, Drug ; Doxorubicin/adverse effects/*pharmacology ; Heart/*drug effects ; Humans ; Myocardium/ultrastructure ; }, abstract = {Ten nuclei from the endomyocardial biopsies for each of the following 32 patients were examined by electron microscopy: seven patients before and then four and 24 hours after treatment with first-dose doxorubicin; seven patients before and four and 24 hours after treatment with first-dose doxorubicin plus N-acetyl cysteine; nine patients with doxorubicin induced cardiomyopathy; and nine patients with idiopathic congestive cardiomyopathy. Five criteria were used to semiquantitatively compare nuclei and nucleoli from each group. The most dramatic changes in nuclear and nucleolar morphology were seen four hours after doxorubicin administration. Nucleoli were smaller, contracted or segregated and contained fewer fibrillar centers and a collapsed or fragmented nucleolonema. The addition of N-acetylcysteine to treatment did not alter these results. By 24 hours, nuclei had returned to the pre-treatment status. Long-term doxorubicin therapy produced increased chromatin clumping and slightly contracted nucleoli. The idiopathic congestive cardiomyopathic nuclei differed significantly from these doxorubicin cardiomyopathic nuclei in the decreased amount of chromatin clumping and the increase in fibrillar centers and nucleonema pattern. It is concluded from this study that: (1) doxorubicin markedly alters the morphology of the human myocardial nucleus and nucleolus four hours after treatment, but these changes diminish by 24 hours; (2) N-acetylcysteine treatment fails to prevent these changes; and (3) the nuclei and nucleoli of chronic doxorubicin-induced cardiomyopathy differ significantly from other congestive cardiomyopathies, but do resemble changes seen four hours after the first dose of doxorubicin.}, }
@article {pmid6862488, year = {1983}, author = {Huggett, A and Blair, IA}, title = {The mechanism of paracetamol-induced hepatotoxicity: implications for therapy.}, journal = {Human toxicology}, volume = {2}, number = {2}, pages = {399-405}, doi = {10.1177/096032718300200238}, pmid = {6862488}, issn = {0144-5952}, mesh = {Acetaminophen/metabolism/*poisoning ; Antidotes/*therapeutic use ; *Benzoquinones ; Biotransformation ; Chemical and Drug Induced Liver Injury/drug therapy/*metabolism ; Humans ; Imines/metabolism/toxicity ; Inactivation, Metabolic ; Oxidation-Reduction ; }, abstract = {1 The reactive metabolite responsible for paracetamol-induced hepatotoxicity, postulated to be N-acetyl-p-benzoquinoneimine reacts with N-acetyl cysteine. 2 An adduct is formed by an SN2 mechanism and paracetamol is produced by a redox reaction. 3 The adduct produced is capable of further oxidation by N-acetyl-p-benzoquinoneimine. 4 Methionine does not react with the reactive metabolite to any great extent.}, }
@article {pmid6860146, year = {1983}, author = {Draminski, W and Eder, E and Henschler, D}, title = {A new pathway of acrolein metabolism in rats.}, journal = {Archives of toxicology}, volume = {52}, number = {3}, pages = {243-247}, pmid = {6860146}, issn = {0340-5761}, mesh = {Acrolein/*metabolism ; Aldehydes/*metabolism ; Animals ; Female ; Methylation ; Rats ; Rats, Inbred Strains ; }, abstract = {The excretion of metabolites of acrolein in rat urine after single oral administration of 10 mg/kg was investigated. S-Carboxyethylmercapturic acid (S-carboxyethyl-N-acetyl-cysteine), or S-(propionic acid methyl ester)mercapturic acid, was found as the major metabolite. An unidentified metabolite was found in expired air. Acrylic acid and methyl acrylate are suggested as intermediates in the metabolism of acrolein.}, }
@article {pmid6836322, year = {1983}, author = {}, title = {N-acetylcysteine (NAC): a significant chemoprotective adjunct. Proceedings of a symposium, September 8 and 10, 1982.}, journal = {Seminars in oncology}, volume = {10}, number = {1 Suppl 1}, pages = {1-92}, pmid = {6836322}, issn = {0093-7754}, mesh = {*Acetylcysteine ; Drug Therapy, Combination ; Humans ; Neoplasms/*drug therapy ; }, }
@article {pmid6836321, year = {1983}, author = {Muggia, FM}, title = {N-Acetylcysteine (NAC): a significant chemoprotective adjunct. Introduction.}, journal = {Seminars in oncology}, volume = {10}, number = {1 Suppl 1}, pages = {1}, pmid = {6836321}, issn = {0093-7754}, mesh = {Acetylcysteine/*pharmacology ; Antineoplastic Agents/*administration &amp; dosage ; Drug Therapy, Combination ; Humans ; Neoplasms/*drug therapy ; }, }
@article {pmid6832291, year = {1983}, author = {Viña, J and Romero, FJ and Saez, GT and Pallardó, FV}, title = {Effects of cysteine and N-acetyl cysteine on GSH content of brain of adult rats.}, journal = {Experientia}, volume = {39}, number = {2}, pages = {164-165}, pmid = {6832291}, issn = {0014-4754}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Brain/drug effects/*metabolism ; Cysteine/*pharmacology ; Dose-Response Relationship, Drug ; Glutathione/*metabolism ; Rats ; Rats, Inbred Strains ; }, abstract = {Intraperitoneal injections of cysteine or N-acetyl cysteine induce a depletion of reduced glutathione (GSH) in rat brain. The doses required to promote GSH depletion are lower than those reported to cause a disseminate neurodegenerative syndrome. Since physiological GSH concentrations are required to maintain cell membranes, we suggest that consideration of the cysteine-induced GSH depletion is important in attempts to understand the mechanism of cysteine-induced cytotoxicity in brain.}, }
@article {pmid6629687, year = {1983}, author = {Egghart, G and Marquardt, HD and Kastert, HB and Feizelmeier, F}, title = {Percutaneous nephrostomy and irrigation lithochemolysis. A new concept for the treatment of cystine stones.}, journal = {International urology and nephrology}, volume = {15}, number = {2}, pages = {131-136}, pmid = {6629687}, issn = {0301-1623}, mesh = {Acetylcysteine/administration &amp; dosage ; Adult ; Catheterization ; Cystine/*metabolism ; Cystinuria/*etiology/therapy ; Fistula ; Humans ; Kidney Calculi/complications/diagnostic imaging/*therapy ; Kidney Pelvis/diagnostic imaging ; Radiography ; Therapeutic Irrigation ; }, abstract = {A case is reported of the dissolution of a cystine stone in the left renal pelvis by means of irrigation with N-acetyl-cysteine via percutaneous nephrostomy. As a result of this treatment no further operative measures were necessary. In our opinion the surgical removal of cystine stones is probably no longer necessary.}, }
@article {pmid6296910, year = {1983}, author = {Verhey, LJ and Sedlacek, R}, title = {Determination of the radioprotective effects of topical applications of MEA, WR-2721, and N-acetylcysteine on murine skin.}, journal = {Radiation research}, volume = {93}, number = {1}, pages = {175-183}, pmid = {6296910}, issn = {0033-7587}, mesh = {Acetylcysteine/*pharmacology ; Administration, Topical ; Amifostine/*pharmacology ; Animals ; Carbon Dioxide/pharmacology ; Cysteamine/pharmacology ; Dose-Response Relationship, Radiation ; Female ; Hydrogen-Ion Concentration ; Male ; Mice ; Mice, Inbred C3H ; Organothiophosphorus Compounds/*pharmacology ; Oxygen/pharmacology ; Radiotherapy/*methods ; Skin/drug effects/pathology/*radiation effects ; }, abstract = {Topical applications of MEA (beta-mercaptoethylamine or cysteamine), WR-2721 [S-2-(3-aminopropylamino)-ethylphosphorothioic acid], and N-acetylcysteine (NAC) were tested for their ability to protect the normal skin of the hind legs of mice against acute and late damage from single doses of 137Cs radiation. No significant protection was observed with either WR-2721 or NAC. MEA was shown to offer significant protection against acute skin damage in both buffered and unbuffered forms, but no significant protection against late contraction. The use of topical MEA on unanesthetized animals breathing carbogen (95% O2, 5% CO2) appears to give an enhanced level of radioprotection over that shown for anesthetized, air-breathing animals.}, }
@article {pmid7165010, year = {1982}, author = {Dresdale, AR and Barr, LH and Bonow, RO and Mathisen, DJ and Myers, CE and Schwartz, DE and d'Angelo, T and Rosenberg, SA}, title = {Prospective randomized study of the role of N-acetyl cysteine in reversing doxorubicin-induced cardiomyopathy.}, journal = {American journal of clinical oncology}, volume = {5}, number = {6}, pages = {657-663}, doi = {10.1097/00000421-198212000-00015}, pmid = {7165010}, issn = {0277-3732}, mesh = {Acetylcysteine/*therapeutic use ; Adolescent ; Adult ; Cardiomyopathies/chemically induced/*drug therapy ; Child ; Doxorubicin/*adverse effects ; Female ; Heart Function Tests ; Humans ; Male ; Middle Aged ; Prospective Studies ; Random Allocation ; Sarcoma/*drug therapy ; Soft Tissue Neoplasms/*drug therapy ; }, abstract = {We conducted a randomized prospective trial in 19 disease-free soft tissue sarcoma patients with doxorubicin-induced cardiomyopathy identified by ECG radionuclide angiography at rest and during exercise to determine the efficacy of the free radical scavenger, N-Acetyl Cysteine (NAC), in reversing the drug's cardiotoxic effect. Of the 19 patients, 11 received oral NAC (5.5 gm/m2 daily for 30 days) and eight patients served as controls. Patients were stratified for age less than greater than 45 years, time from final dose of doxorubicin to randomization less than greater than 8 months, and history of treatment with mediastinal irradiation. The two groups were well-matched for all parameters. Cumulative mean doxorubicin dose (523 mg/m2 and 532 mg/m2) and range 500-600 mg/m2 was comparable. Left ventricular (LV) ejection fraction before randomization was not significantly different between the two groups either at rest (39 +/- 10% control, 38 +/- 13% NAC) or during exercise (38 +/- 12% control, 35 +/- 11% NAC). Neither rest nor exercise ejection fraction values changed significantly in either group between prerandomization and 1-month postrandomization studies. Late studies performed in seven NAC patients 3-5 months after randomization revealed no difference in LV ejection fraction compared to 1-month postrandomization values. Clinical course in patients with overt congestive heart failure was similar in both groups. LV function did not return to normal in any patient in either group. We conclude that N-Acetyl Cysteine has no effect in reversing long standing doxorubicin-induced cardiomyopathy.}, }
@article {pmid7107854, year = {1982}, author = {Rinaldi, MG and McCoy, EL and Winn, DF}, title = {Gluteal abscess caused by Phialophora hoffmannii and review of the role of this organism in human mycoses.}, journal = {Journal of clinical microbiology}, volume = {16}, number = {1}, pages = {181-185}, pmid = {7107854}, issn = {0095-1137}, mesh = {Abscess/*etiology ; Aged ; Candidiasis/*etiology ; Culture Media ; Female ; Humans ; Muscular Diseases/*etiology ; Phialophora/growth &amp; development/*isolation &amp; purification ; }, abstract = {Infections caused by members of the Phialophora hoffmannii (Beyma) Schol-Schwarz fungal aggregate (a group of related taxa, especially species of uncertain circumscription) are not reported frequently. This case report concerns the development of a gluteal abscess after multiple intramuscular injections of antimicrobial agents. Microbiological examination of the abscess material yielded a pure growth of the mold P. hoffmannii. Hyphal elements in the purulent exudate were only demonstrated when the specimen was digested by an N-acetyl cysteine-NaOH digestion-decontamination procedure or in stained paraffin block sections of the exudate. Other cases of disease caused by members of this fungal aggregate and the status of the mycology of this organism are reviewed.}, }
@article {pmid6813467, year = {1982}, author = {Godfrey, NF and Peter, A and Simon, TM and Lorber, A}, title = {IV N-acetylcysteine treatment of hematologic reactions to chrysotherapy.}, journal = {The Journal of rheumatology}, volume = {9}, number = {4}, pages = {519-526}, pmid = {6813467}, issn = {0315-162X}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Aged ; Agranulocytosis/*chemically induced/drug therapy ; Arthritis, Rheumatoid/*drug therapy ; Aurothioglucose/*adverse effects/therapeutic use ; Dose-Response Relationship, Drug ; Female ; Gold/*adverse effects ; Gold Sodium Thiomalate/*adverse effects/therapeutic use ; Humans ; Infusions, Parenteral ; Male ; Middle Aged ; Pancytopenia/*chemically induced/drug therapy ; }, abstract = {Twelve patients with adverse hematologic reactions to chrysotherapy received intravenous N-acetylcysteine (IV NAC) to achieve removal and/or redistribution of gold. Urine gold excretion while on IV NAC doubled that predicted from control measurements. Treatment within 20 days of the last gold injection was associated with better recovery of hematologic parameters. No untoward reactions from IV NAC were encountered. The pathogenesis of gold induced hematologic reactions is examined from both toxic as well as immunological perspectives.}, }
@article {pmid7105400, year = {1982}, author = {Tippett, PA and Dennis, NR and Machin, D and Price, CP and Clayton, BE}, title = {Creatine kinase activity in the detection of carriers of Duchenne muscular dystrophy: comparison of two methods.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {121}, number = {3}, pages = {345-359}, doi = {10.1016/0009-8981(82)90244-3}, pmid = {7105400}, issn = {0009-8981}, mesh = {Adult ; Autoanalysis ; Colorimetry ; Creatine Kinase/*blood ; Female ; Genetic Carrier Screening/*methods ; Humans ; Muscular Dystrophies/*genetics ; Statistics as Topic ; }, abstract = {Serum creatine kinase activity was estimated in 48 control women and 22 female carriers of Duchenne muscular dystrophy by two different methods. One method is based on the colorimetric determination of creatine liberated from creatine phosphate; the other, an N-acetyl cysteine activated UV system, was used in an automated mode. The two methods were equally efficient in carrier detection, and results were closely correlated over the range of values encountered in controls and carriers. Log creatine kinase values appeared to be normally distributed in controls, but the distribution in carriers appeared skewed towards its upper end. If both distributions are assumed to be Normal, the probability, together with its standard error, that a consultand is a carrier, can be calculated from her creatine kinase value, and if the latter is expressed in standard deviation units of the control log creatine kinase distribution, probability estimates can be compared between laboratories.}, }
@article {pmid7086679, year = {1982}, author = {Van de Graaff, WB and Thompson, WL and Sunshine, I and Fretthold, D and Leickly, F and Dayton, H}, title = {Adsorbent and cathartic inhibition of enteral drug absorption.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {221}, number = {3}, pages = {656-663}, pmid = {7086679}, issn = {0022-3565}, support = {G-07022//PHS HHS/United States ; GM-21727/GM/NIGMS NIH HHS/United States ; GM-22317/GM/NIGMS NIH HHS/United States ; }, mesh = {Acetaminophen/metabolism/toxicity ; Acetylcysteine/pharmacology ; Adsorption ; Animals ; Cathartics/*pharmacology ; Charcoal/*pharmacology ; Chemistry, Pharmaceutical ; Dogs ; Female ; Intestinal Absorption/*drug effects ; Male ; Methionine/pharmacology ; Mice ; Resins, Plant/*pharmacology ; Time Factors ; }, abstract = {The effects on absorption of drugs given by mouth of adsorbents (charcoals and resins) and cathartics (osmotic and oil) were studied in vitro and in vivo using acetaminophen (paracetamol) as a test drug. In vitro adsorption isotherms were measured at 37 degrees C in simulated gastric and gastric plus intestinal juices. Maximum binding capacity (MBC) of 16 charcoals and resins varied 30-fold, from 0.36 to 9.32 mol/kg. Dissociation constants varied directly with MBC. In vitro adsorption was little changed by addition of d-mannitol and d-sorbitol, N-acetylcysteine (NAC) or l-methionine. Acetaminophen (0.6 g/kg by orogastric tube) was given to 17 dogs protected by i.v. injections of NAC and methylene blue. One minute later, dogs were given: 1) water; 2) Norit A or Nuchar 1110 charcoal, 3 g/kg; 3) d-mannitol and d-sorbitol, 2 g/kg or castor oil, 3 ml/kg; or 4) both charcoal and either d-mannitol and d-sorbitol or castor oil. Cathartics alone decreased the area under plasma acetaminophen concentrations 15 to 30%. Charcoals alone reduced the area under plasma acetaminophen concentration 93%. Each cathartic diminished the charcoal inhibition of acetaminophen absorption. In mice given acetaminophen by orgastric tube, the acute lethality was decreased more by a new petroleum-based charcoal than by standard wood-based charcoals. Reduction of acetaminophen lethality in mice paralleled the in vitro MBC of adsorbents. Charcoals did not avidly adsorb l-methionine or NAC in vitro. Charcoal did not decrease the l-methionine or NAC protection of acetaminophen-poisoned mice. Charcoals with large MBC diminish absorption and lethality of acetaminophen taken by mouth; cathartics have little effect on acetaminophen absorption.}, }
@article {pmid7076026, year = {1982}, author = {Bahari, HM and Ross, IN and Turnberg, LA}, title = {Demonstration of a pH gradient across the mucus layer on the surface of human gastric mucosa in vitro.}, journal = {Gut}, volume = {23}, number = {6}, pages = {513-516}, pmid = {7076026}, issn = {0017-5749}, mesh = {Aspirin/pharmacology ; Cystine/analogs &amp; derivatives/pharmacology ; Gastric Mucosa/drug effects/*metabolism ; Humans ; Hydrochloric Acid/pharmacology ; Hydrogen-Ion Concentration ; In Vitro Techniques ; Peptic Ulcer/metabolism ; Stomach Neoplasms/metabolism ; }, abstract = {In previous studies we have demonstrated a hydrogen ion concentration gradient across the mucus on rat and rabbit fundic mucosa, in vivo and in vitro respectively, observations which support the possibility of a 'mucus-bicarbonate' protective barrier. In the present studies we have demonstrated a similar gradient across the mucus on human gastric mucosa in vitro. The minimum mean hydrogen ion concentration at the mucus-epithelium interface was 1 . 1 X 10(-4) mM (pH 6 . 96, n = 10) when the luminal concentration was 5 . 6 mM (pH 2 . 25). Aspirin (10 mM) and N-acetyl cysteine (306 mM) (5%) increased the minimum intra-mucus hydrogen ion concentration and the gradient was overwhelmed by a luminal hydrogen ion concentration of 40 mM (pH 1 . 4). These results suggest that a hydrogen ion concentration gradient exists across the mucus on human gastric mucosa and that potential damaging agents may act by compromising one or other of th components of this 'mucus-alkaline', presumed 'mucus-bicarbonate', barrier.}, }
@article {pmid6804076, year = {1982}, author = {Walker, RM and Massey, TE and McElligott, TF and Racz, WJ}, title = {Acetaminophen toxicity in fed and fasted mice.}, journal = {Canadian journal of physiology and pharmacology}, volume = {60}, number = {3}, pages = {399-404}, doi = {10.1139/y82-058}, pmid = {6804076}, issn = {0008-4212}, mesh = {Acetaminophen/*toxicity ; Animals ; Aryl Hydrocarbon Hydroxylases/metabolism ; Body Temperature/drug effects ; Cytochrome P-450 Enzyme System/metabolism ; *Fasting ; Glucuronosyltransferase/metabolism ; Male ; Mice ; Microsomes, Liver/metabolism ; Proteins/metabolism ; Time Factors ; }, abstract = {Acetaminophen (750 mg/kg) toxicity and its modification by N-acetylcysteine (NAC, 1200 mg/kg) have been compared in fed and fasted mice. There was no significant difference between fed and fasted animals with respect to microsomal protein content, cytochrome(s) P-450 content, and aryl hydrocarbon hydroxylase activity. Glucuronyl transferase activity was significantly higher in fasted mice. Hepatotoxicity, as determined histologically and by liver enlargement was greater in fasted than fed mice. Covalent binding of [3H]acetaminophen metabolite(s) to liver proteins was also greater in fasted animals. NAC administration prevented acetaminophen-induced microscopic changes and liver enlargement and reduced the magnitude of covalent binding of acetaminophen metabolites. Fasting caused a marked fall in liver reduced sulfhydryl concentration. The incidence of acetaminophen-induced hypothermia was greater in fasted than in fed animals. NAC administration reduced hypothermia in fasted mice and abolished it in fed animals. It is concluded that enhanced acetaminophen toxicity in fasted mice compared with fed mice is unlikely to be a consequence of increased reactive metabolite formation, but rather a result of reduced inactivation of reactive metabolite(s) due to reduced hepatic glutathione stores in fasted mice.}, }
@article {pmid6821192, year = {1982}, author = {Griffin, MM and Steven, FS}, title = {Inhibition of trypsin and papain by sodium aurothiomalate mediated by exchange reactions.}, journal = {British journal of pharmacology}, volume = {75}, number = {2}, pages = {333-339}, pmid = {6821192}, issn = {0007-1188}, mesh = {Acetylcysteine/pharmacology ; Gold Sodium Thiomalate/*pharmacology ; Imidazoles/pharmacology ; Kinetics ; Papain/*antagonists &amp; inhibitors ; Serum Albumin, Bovine/pharmacology ; Trypsin Inhibitors/*pharmacology ; }, abstract = {Sodium aurothiomalate has been shown to participate in exchange reactions leading to the inhibition of trypsin; for this exchange to take place it was necessary to include in the test system a suitable thiol, such as N-acetyl-cysteine. Neither N-acetyl-cysteine nor aurothiomalate on their own had any inhibitory action on trypsin. The results indicate that aurothiomalate dissociates in the presence of a carrier to form thiosuccinate and gold. The gold is responsible for trypsin inhibition since independent experiments demonstrated that the total concentration of thiosuccinate was insufficient to cause the observed inhibition of trypsin. Bovine serum albumin was shown to act as a carrier in place of N-acetyl-cysteine. It is known that histidine in the active centre of trypsin binds heavy metal ions with consequent inhibition of the enzyme. In this study, imidazole was shown to act as a carrier for gold from aurothiomalate to trypsin resulting in inhibition. This inhibition by gold was reversed when higher concentrations of imidazole were added to the test system due to competition for the trypsin-bound gold by imidazole. Conversely, the thiol enzyme papain was re-activated in the presence of low concentrations of sodium aurothiomalate and inhibited by higher concentrations of this reagent in a biphasic manner. This observation will be discussed in relation to the dissociation of sodium aurothiomalate. These observations can also be explained in terms of exchange reactions involving thiols and free metal ions.}, }
@article {pmid7112597, year = {1982}, author = {Fairhurst, S and Barber, DJ and Clark, B and Horton, AA}, title = {Studies on paracetamol-induced lipid peroxidation.}, journal = {Toxicology}, volume = {23}, number = {2-3}, pages = {249-259}, doi = {10.1016/0300-483x(82)90102-0}, pmid = {7112597}, issn = {0300-483X}, mesh = {Acetaminophen/*toxicity ; Animals ; Female ; Glutathione/analysis ; Lipid Peroxides/*metabolism ; Liver/metabolism ; Rats ; Rats, Inbred Strains ; Sulfhydryl Compounds/pharmacology ; }, abstract = {Post-mitochondrial supernatants isolated from livers of rats given a single large oral dose of paracetamol (800 mg/kg) showed rapid rates of lipid peroxidation when incubated in vitro. As a result of paracetamol administration the level of reduced glutathione (GSH) declined to approx. 20-25% of the peak physiological value. Addition of reduced GSH to the supernatant inhibited the peroxidation. Paracetamol-induced lipid peroxidation was inhibited in vitro by antioxidants (e.g. vitamin E) but was unaffected by superoxide dismutase and mannitol. N-acetyl cysteine and cysteamine inhibited lipid peroxidation in vitro in a cytosol-dependent manner in the absence of glutathione. Lipid peroxidation probably occurs simultaneously with the proposed covalent binding of the active metabolite of paracetamol. Since the former process is known to cause severe and extensive membrane damage, it may be a very important factor in paracetamol-induced liver necrosis.}, }
@article {pmid6120810, year = {1981}, author = {Bakke, JE and Rafter, J and Larsen, GL and Gustafsson, JA and Gustafsson, BE}, title = {Enterohepatic circulation of the mercapturic acid and cysteine conjugates of propachlor.}, journal = {Drug metabolism and disposition: the biological fate of chemicals}, volume = {9}, number = {6}, pages = {525-528}, pmid = {6120810}, issn = {0090-9556}, mesh = {Acetanilides/*metabolism ; Acetylcysteine/*analogs &amp; derivatives/metabolism ; Animals ; Bile/metabolism ; Cysteine/*analogs &amp; derivatives/metabolism ; *Enterohepatic Circulation ; Feces/analysis ; *Germ-Free Life ; Kanamycin/*pharmacology ; Liver/*metabolism ; Models, Biological ; Rats ; }, abstract = {Germfree (GF) rats and antibiotic-treated rats with cannulated bile ducts (ABC) were given single oral doses of 2-(S-(N-[2H3]acetyl)cysteine)-N-isopropyl[1-14C]acetanilide. The GF rats excreted the dose in about equal quantities in the urine and feces; and the ABC rats excreted the dose in about equal quantities in the urine, feces, and bile. The mercapturate (60-75% of the dose in both cases) was isolated and the amount of exchange of N-acetyl deuterium to N-acetyl hydrogen was determined for all samples by mass spectrometry. The percentages of exchange were: ABC rats, bile 6.5%, urine 13%, feces 0.0%; GF rats, urine 15%, feces 4.7%. The remainder of the doses was present as the mercapturic acid sulfoxide. ABC rats dosed with 2-(S-[3,3-3H]cysteine)-N-isopropyl[1-14C]acetanilide (14C/3H = 0.50) excreted 42% of the dose in the urine and bile as the mercapturic acid that had a 14C/3H ratio the same as the original cysteine conjugate. The results of these studies show that a mercapturic acid and a cysteine conjugate can be absorbed from the gastrointestinal tract and resecreted in the bile or excreted by the kidney without having undergone metabolism other than acetylation of the cysteine nitrogen atom and oxidation of the sulfur to a sulfoxide. ABC rats were also dosed with 2-methylthio-N-isopropyl[1-14C]acetanilide, a suspected metabolic intermediate in the metabolism of propachlor (2-chloro-N-isopropylacetanilide). The dose was excreted in about equal quantities in the bile (48%) and urine (46%) as metabolites with a methylsulfonyl group in the 2-position. All are known metabolites of propachlor in conventional rats.}, }
@article {pmid6794955, year = {1981}, author = {Moss, DW and Whitaker, KB and Parmar, C and Heckmatt, J and Wikowski, J and Sewry, C and Dubowitz, V}, title = {Activity of creatine kinase in sera from healthy women, carriers of Duchenne muscular dystrophy and cord blood, determined by the "European" recommended method with NAC-EDTA activation.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {116}, number = {2}, pages = {209-216}, doi = {10.1016/0009-8981(81)90024-3}, pmid = {6794955}, issn = {0009-8981}, mesh = {Acetylcysteine/*pharmacology ; Adolescent ; Adult ; Creatine Kinase/*blood/genetics ; Edetic Acid/*pharmacology ; Female ; Fetal Blood/*enzymology ; Genetic Carrier Screening ; Humans ; Kinetics ; Middle Aged ; Muscular Dystrophies/*enzymology/genetics ; Pregnancy ; Reference Values ; }, abstract = {Creatine kinase activity has been measured at 37 degrees C in sera from healthy women, carriers of Duchenne muscular dystrophy and cord blood, with activation by N-acetyl cysteine (NAC) and EDTA as recommended by several European committees on standardisation. The upper limit of the reference range for healty women was found to be 170 U/l. The distributions of creatine kinase activities in healthy and carrier women have been used to calculate probability of carrier status as a function of creatine kinase activity. Although the range of creatine kinase activities in normal cord blood is wide, the data provide a basis for interpretation when Duchenne muscular dystrophy is suspected.}, }
@article {pmid7260509, year = {1981}, author = {Pilling, DW and Steiner, GM}, title = {The radiology of Meconium Ileus Equivalent.}, journal = {The British journal of radiology}, volume = {54}, number = {643}, pages = {562-565}, doi = {10.1259/0007-1285-54-643-562}, pmid = {7260509}, issn = {0007-1285}, mesh = {Child ; Child, Preschool ; Cystic Fibrosis/complications ; Humans ; Ileum/diagnostic imaging ; Infant, Newborn ; Infant, Newborn, Diseases/*diagnostic imaging ; Intestinal Obstruction/*diagnostic imaging/etiology ; *Meconium ; Radiography ; }, abstract = {Meconium Ileus Equivalent is a condition which occurs in patients with cystic fibrosis where the ileum becomes obstructed by bowel content of abnormal consistency. Intercurrent chest infection or absence of pancreatic extract supplements are often the exacerbating cause. Plain films of the abdomen show small bowel obstruction and in some a nodular pattern in the small bowel, the nodules being larger than those seen in quiescent cystic fibrosis. Gastrografin enemas and/or enemas with acetyl cysteine can be used in the treatment of the condition, the Gastrografin having the advantage of confirming the diagnosis radiologically. The condition is important as it can be the presenting feature of cystic fibrosis in childhood and even in early adult life, and the operative mortality and morbidity are high. Conservative treatment should be pursued vigorously and operation only undertaken if unavoidable.}, }
@article {pmid6940075, year = {1981}, author = {Golden, DP and Mosby, EL and Smith, DJ and Mackercher, P}, title = {Acetominophen toxicity. Report of two cases.}, journal = {Oral surgery, oral medicine, and oral pathology}, volume = {51}, number = {4}, pages = {385-389}, doi = {10.1016/0030-4220(81)90147-x}, pmid = {6940075}, issn = {0030-4220}, mesh = {Acetaminophen/antagonists &amp; inhibitors/pharmacology/*poisoning ; Acetylcysteine/therapeutic use ; Adult ; Female ; Humans ; Male ; Suicide, Attempted ; }, abstract = {Both chronic low-dose use within accepted therapeutic limits and acute overdosage of acetominophen with as little as 7 Gm or 150 mg./kg. can result in irreversible centrilobular hepatic necrosis. Prompt and proper treatment with N-acetyl-cysteine in strict adherence to accepted protocol will prevent potentially fatal results. Clinicians who prescribe acetominophen must likewise be cognizant of other potential side effects, such as methemoglobinemia, hemolysis, and prothrombin suppression.}, }
@article {pmid7268784, year = {1981}, author = {Whitehouse, LW and Wong, LT and Solomonraj, G and Paul, CJ and Thomas, BH}, title = {N-acetylcysteine-induced inhibition of gastric emptying: a mechanism affording protection to mice from the hepatotoxicity of concomitantly administered acetaminophen.}, journal = {Toxicology}, volume = {19}, number = {2}, pages = {113-125}, doi = {10.1016/0300-483x(81)90093-7}, pmid = {7268784}, issn = {0300-483X}, mesh = {Acetaminophen/metabolism/*toxicity ; Acetylcysteine/*pharmacology ; Animals ; Drug Interactions ; Gastric Emptying/*drug effects ; Intestinal Absorption/drug effects ; Liver/*drug effects ; Male ; Mice ; Sulfhydryl Compounds/analysis ; }, abstract = {Swiss Webster male mice, 22 +/- 3 g, killed 17-18 h following the concomitant oral administration of acetaminophen (350 mg/kg) and N-acetyl-cysteine (NAC, 100-500 mg/kg, treated) had statistically significant lower plasma transaminases (GOT and GPT) than control mice (acetaminophen + water). Possible mechanisms underlying this protective effect of NAC were examined. NAC (500 mg/kg) reduced [14C]acetaminophen-derived radioactivity in the blood and tissues but increased the percentage of the dose in the gastrointestinal tract. Depletion of hepatic sulphydryl compounds below 75% of the control value was prevented by NAC treatment, whereas urinary excretion of mercapturate and sulfate, metabolites derived from sulphydryls, were proportionally increased and excretion of unchanged drug was decreased by NAC. Absorption of acetaminophen from the small intestine was prevented by NAC and this was attributed to an inhibition in gastric emptying. Since all changes observed following NAC treatment could be attributed to inhibition of gastric emptying, it was considered the major mechanism responsible for affording in mice protection from acetaminophen-induced hepatocellular damage following concomitant oral administration.}, }
@article {pmid6970664, year = {1980}, author = {Bradbury, JE and Black, JW and Wyllie, JH}, title = {Stimulation of mucus output from rat colon in vivo.}, journal = {European journal of pharmacology}, volume = {68}, number = {4}, pages = {417-425}, doi = {10.1016/0014-2999(80)90416-1}, pmid = {6970664}, issn = {0014-2999}, mesh = {5-Hydroxytryptophan/pharmacology ; Animals ; Bethanechol Compounds/pharmacology ; Carbachol/pharmacology ; Colon/drug effects/*metabolism ; Drug Interactions ; Male ; Mucus/*metabolism ; Rats ; Serotonin/pharmacology ; Stimulation, Chemical ; }, abstract = {Sodium chloride (155 mM) and N-acetyl cysteine (6 mM) were recirculated through the colons of anaesthetized rats. Mucus accumulated in the perfusion fluid which was changed at intervals to allow mucus output to be estimated by measurement of hexose. The output of mucus could be stimulated by intravenous administration of the cholinergic drugs carbachol and bethanechol; this effect was inhibited by atropine. Mucus output could also be stimulated by intravenous 5-hydroxytryptamine. This was not a muscarinic cholinergic effect because atropine did not prevent it. Neither did methysergide inhibit it; but chlorpromazine did. Precursors of 5-hydroxytryptamine, 5-hydroxytryptophan and L-tryptophan, also stimulated mucus output if given in high dosage. The results suggest that in this preparation mucus output can be stimulated by two distinct mechanisms, one cholinergic, the other involving 5-hydroxytryptamine and perhaps 5-hydroxytryptophan.}, }
@article {pmid7210465, year = {1980}, author = {Chinouth, RW and Czajka, PA and Peterson, RG}, title = {N-acetylcysteine adsorption by activated charcoal.}, journal = {Veterinary and human toxicology}, volume = {22}, number = {6}, pages = {392-394}, pmid = {7210465}, issn = {0145-6296}, mesh = {Acetaminophen/toxicity ; Acetylcysteine/*metabolism ; Adsorption ; Charcoal/*pharmacology ; In Vitro Techniques ; }, abstract = {N-acetylcysteine was adsorbed by activated charcoal, lending in vitro support to previous clinical of activated charcoal for NAC in biologic fluid was significantly greater than in nonbiologic fluid and has important clinical implications. Although some have advocated lavage to remove activated charcoal prior to the administration of NAC, the avid adsorption of NAC suggested that activated charcoal may not be justifiable for acetaminophen overdosage when NAC therapy is indicated. Studies in humans are required to substantiate the clinical significance of this in vitro adsorption.}, }
@article {pmid7192770, year = {1980}, author = {Kupke, IR and Tritschler, W and Kather, B and Bablok, W}, title = {[Creatine kinase "NAC-activated": reference values for children (author's transl)].}, journal = {Klinische Padiatrie}, volume = {192}, number = {4}, pages = {348-350}, doi = {10.1055/s-2008-1035606}, pmid = {7192770}, issn = {0300-8630}, mesh = {*Acetylcysteine ; Adolescent ; Age Factors ; Child ; Child, Preschool ; Creatine Kinase/*blood ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Reference Values ; Sex Factors ; }, abstract = {Reference values for 327 children aged between 1 day and 15 years are given for the revised standard method for the determination of serum creatine kinase (CK) activity by activation with N-acetylcysteine (NAC). No sex-dependence could be observed, but CK activity was found to vary markedly with age. The following values are suggested as upper limits of the reference ranges for measurements at 25 degrees C: neonates: 1-3 days: less than or equal to 370 U/l, 4-10 days: less than or equal to 200 U/l, 11-31 days: less than or equal to 100 U/l; children (2 months-15 years): less than or equal to 90 U/l.}, }
@article {pmid6968166, year = {1980}, author = {Martin, R and Litt, M and Marriott, C}, title = {The effect of mucolytic agents on the rheologic and transport properties of canine tracheal mucus.}, journal = {The American review of respiratory disease}, volume = {121}, number = {3}, pages = {495-500}, doi = {10.1164/arrd.1980.121.3.495}, pmid = {6968166}, issn = {0003-0805}, support = {HL 14271/HL/NHLBI NIH HHS/United States ; }, mesh = {Acetylcysteine/pharmacology ; Animals ; Carbocysteine/pharmacology ; Cysteine/analogs &amp; derivatives/pharmacology ; Dithiothreitol/pharmacology ; Dogs ; Elasticity ; Expectorants/*pharmacology ; In Vitro Techniques ; Mucus/*physiology ; Potassium Iodide/pharmacology ; Rana catesbeiana ; Rheology ; Trachea/*metabolism ; Urea/pharmacology ; Viscosity ; }, abstract = {The effect of several sulfhydryl and other agents on the rheologic and mucociliary transport properties of a model secretion, reconstituted canine tracheal mucus, was investigated. The mucus was obtained via the canine tracheal pouch. Rheologic properties were determined by mirorheometry, and the ciliary transport rate was determined using the frog palate technique. It was found that N-acetyl cysteine decreased the elastic modulus, leading to improved mucociliary transport at concentrations such that the mucin did not precipitate. S-carboxymethyl cysteine had no effect on either mucus properties or mucociliary transport rate, and its reported effectiveness in vivo must be due to some mechanism other than solubilization of mucin. Similar results were found with other blocked sulfhydryl compounds. Urea and potassium iodide to decrease mucus elasticity, but are harmful to cilia at the concentrations needed.}, }
@article {pmid7210734, year = {1980}, author = {Dietzsch, HJ and Berger, G and Gottschalk, B and Leupold, W and Mittenzwey, KW and Rupprecht, E and Wunderlich, P}, title = {[Experiences with oral N-acetyl-cysteine treatment in children suffering from cystic fibrosis (author's transl)].}, journal = {Zeitschrift fur Erkrankungen der Atmungsorgane}, volume = {155}, number = {1}, pages = {109-113}, pmid = {7210734}, issn = {0303-657X}, mesh = {Acetylcysteine/*administration &amp; dosage ; Administration, Oral ; Bronchoscopy ; Child ; Cystic Fibrosis/diagnosis/*drug therapy ; Humans ; Respiratory Function Tests ; }, abstract = {A clinical test with the oral use of Fluimucil was performed by ourselves: Forty-two children, who had been in stable condition for 8--10 years under inhalation therapy with Mucosolvin, were treated for a period of 6 months with Fluimucil used orally. We compared the clinical, bronchoscopic and lung function finding s before and after the 6-month period. In the case of 7 children the oral treatment had to be discontinued and replaced by a resumption of inhalation therapy after 6 to 12 weeks on an account of an exacerbation of the lungstate. The bronchoscopic studies showed results worse in 44% of the cases, unchanged in 22%, and improved in 34%. For lung-function the figures were 31%, 51% and 18% respectively. We can conclude from our results that it is not possible to replace inhalation therapy by an oral treatment for all children with cystic fibrosis. We can, however, surmise that such a treatment will be possible for 50--60% of the children and this must be considered as a significant step forward in the care of these children.}, }
@article {pmid7011834, year = {1980}, author = {Brocard, H and Charpin, J and Germouty, J}, title = {[Multicenter, double-blind study of oral acetylcysteine vs. placebo].}, journal = {European journal of respiratory diseases. Supplement}, volume = {111}, number = {}, pages = {65-69}, pmid = {7011834}, issn = {0106-4347}, mesh = {Acetylcysteine/*therapeutic use ; Acute Disease ; Bronchitis/*drug therapy/physiopathology ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Humans ; Male ; Placebos ; Sputum/physiology ; }, abstract = {The mucolytic activity of acetylcysteine (NAC) was evaluated in a double-blind, placebo controlled, clinical trial performed in three pneumology centres and involving a total of 215 patients with the following diagnoses: 84 acute bronchitis, 95 superinfections of chronic bronchitis, 36 complicated bronchitis in patients with severe chronic respiratory insufficiency. Treatment consisted of 1 sachet of 200 mg NAC t.i.d. for 10 days. Standard antibiotic therapy (amoxycillin 1.5 g/day) was concurrently administered for 7 days. Statistical analysis comparing sputum volume and viscosity, sedation of cough and improvement of PEFR in 108 NAC and in 107 placebo treated patients, showed that NAC was very significantly more effective than placebo. The effect of NAC was negligible in the 36 patients with complicated bronchitis, whereas it was evident and remarkable in patients with acute and chronic bronchitis.}, }
@article {pmid6449980, year = {1980}, author = {Nicol, M and Massart, C and Savouré, N}, title = {[Instability of serum 17 beta-hydroxysteroid dehydrogenases of placental origin].}, journal = {Comptes rendus des seances de la Societe de biologie et de ses filiales}, volume = {174}, number = {1}, pages = {33-39}, pmid = {6449980}, issn = {0037-9026}, mesh = {17-Hydroxysteroid Dehydrogenases/*blood ; Drug Stability ; Female ; Glutathione/pharmacology ; Glycerol/pharmacology ; Humans ; Kinetics ; Placenta/*enzymology ; Pregnancy ; Temperature ; Time Factors ; }, abstract = {The stabilization by glycerol of the serum estradiol 17 beta dehydrogenase has been investigated here in terms of time and temperature. The protected enzyme is stable for a month at least at --20 degrees C. Its activity reaches a maximum at 60 degrees C. In another connection, effect of reduced glutathione, of N. acetyl-cysteine and of various mineral ions on the enzymic conversion has been studied.}, }
@article {pmid119303, year = {1979}, author = {Gerhardt, W and Waldenström, J and Gruber, W}, title = {EDTA effect on creatine kinase (CK) and on the SCE reagent.}, journal = {Scandinavian journal of clinical and laboratory investigation}, volume = {39}, number = {8}, pages = {737-742}, doi = {10.1080/00365517909108165}, pmid = {119303}, issn = {0036-5513}, mesh = {Acetylcysteine ; Calcium/pharmacology ; Chelating Agents ; Creatine Kinase/blood/*standards ; *Drug Stability ; Edetic Acid/*pharmacology ; Ferric Compounds/pharmacology ; In Vitro Techniques ; Indicators and Reagents/*standards ; Isoenzymes ; Mercaptoethanol ; Scandinavian and Nordic Countries ; Sulfhydryl Compounds ; Time Factors ; }, abstract = {The inclusion of EDTA in the creatine kinase reagent recommended by the Scandinavian Committee on Enzymes was shown to increase reagent stability from less than 24 h to 5 days. Part of this effect can be explained by the fact that EDTA delays the formation of inhibitory products formed when N-acetyl cysteine is oxidized. The addition of EDTA to the reagent also results in increased measured CK activity. This effect is more pronounced for CK-BB than for CK-MM. Calcium and ferric ions are shown to inhibit the enzyme and the chelation of these ions can partly explain the observed increase of CK acitivity.}, }
@article {pmid119048, year = {1979}, author = {Timon-David, P and Vanelle, P and Fournier, AM}, title = {[Double contrast studies of the colon. Use of acetyl-cystein or mucofluid? (author's transl)].}, journal = {Journal de radiologie}, volume = {60}, number = {12}, pages = {797-798}, pmid = {119048}, issn = {0221-0363}, mesh = {*Acetylcysteine ; Colon/*diagnostic imaging ; *Contrast Media ; Costs and Cost Analysis ; Humans ; Mercaptoethanol/*analogs &amp; derivatives ; *Mesna ; Radiography ; }, abstract = {The authors propose a replacement product for acetylcysteine which had been suggested for use in order to obtain good double contrast studies of the colon after retrograde barium introduction. Mucofluid gives even better results at a much lower cost.}, }
@article {pmid519312, year = {1979}, author = {Prescott, LF and Illingworth, RN and Critchley, JA and Stewart, MJ and Adam, RD and Proudfoot, AT}, title = {Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning.}, journal = {British medical journal}, volume = {2}, number = {6198}, pages = {1097-1100}, pmid = {519312}, issn = {0007-1447}, mesh = {Acetaminophen/*poisoning ; Acetylcysteine/administration &amp; dosage/*therapeutic use ; Adolescent ; Adult ; Aged ; Chemical and Drug Induced Liver Injury ; Cysteamine/therapeutic use ; Female ; Humans ; Infusions, Parenteral ; Kidney Diseases/chemically induced/prevention &amp; control ; Liver Diseases/prevention &amp; control ; Male ; Methionine/therapeutic use ; Middle Aged ; Risk ; Time Factors ; }, abstract = {One hundred cases of severe paracetamol poisoning were treated with intravenous N-acetylcysteine (acetyl-cysteine). There was virtually complete protection against liver damage in 40 patients treated within eight hours after ingestion (mean maximum serum alanine transaminase activity 27 IU/1). Only one out of 62 patients treated within 10 hours developed severe liver damage compared with 33 out of 57 patients (58%) studied retrospectively who received supportive treatment alone. Early treatment and acetylcysteine also prevented renal impairment and death. The critical ingestion-treatment interval for complete protection against severe liver damage was eight hours. Efficacy diminished progressively thereafter, and treatment after 15 hours was completely ineffective. Intravenous acetylcysteine was more effective than cysteamine and methionine and noticeably free of adverse effects. It is the treatment of choice for paracetamol poisoning.}, }
@article {pmid386962, year = {1979}, author = {Furst, DE and Clements, PJ and Harris, R and Ross, M and Levy, J and Paulus, HE}, title = {Measurement of clinical change in progressive systemic sclerosis: a 1 year double-blind placebo-controlled trial of N-acetylcysteine.}, journal = {Annals of the rheumatic diseases}, volume = {38}, number = {4}, pages = {356-361}, pmid = {386962}, issn = {0003-4967}, mesh = {Acetylcysteine/*therapeutic use ; Adult ; Clinical Trials as Topic ; Double-Blind Method ; Female ; Humans ; Male ; Middle Aged ; Prospective Studies ; Scleroderma, Systemic/*drug therapy/physiopathology ; Skin/physiopathology ; Time Factors ; }, abstract = {N-acetylcysteine was employed as a therapeutic agent in a 1-year, parallel, double-blind, placebo-controlled, prospective study of 22 patients with progressive systemic sclerosis (PSS). Patients were closely followed-up and were extensively evaluated at baseline, 6 and 12 months. Most parameters remained unchanged during 1 year of study in both the NAC and placebo groups, which showed the need for prolonged studies of drugs in PSS if definitive results are to be obtained. Over the year of the study the diffusing capacity decreased in both groups, while several other parameters measured both increased and decreased. Several simple measures of function and skin distensibility were tested and two (oral aperature and handspread) were reproducible and sensitive enough to measure moderate changes of disease activity. They may be useful in future trials of drug effect in PSS.}, }
@article {pmid482324, year = {1979}, author = {Crifò, S and Sartarelli, E and Gagliardi, M and Belussi, L}, title = {Transtympanic iontophoresis of N-acetyl-cysteine.}, journal = {Pharmacological research communications}, volume = {11}, number = {5}, pages = {389-392}, doi = {10.1016/s0031-6989(79)80002-8}, pmid = {482324}, issn = {0031-6989}, mesh = {Acetylcysteine/*metabolism ; Animals ; Guinea Pigs ; Iontophoresis ; Time Factors ; Tympanic Membrane/*metabolism ; }, }
@article {pmid431469, year = {1979}, author = {Schmidt, EW and Bender, W}, title = {[Sensitivity of creatine kinase and creatine kinase MB in myocardial infarction. Evaluation of a new optimized standard method (author's transl)].}, journal = {Medizinische Klinik}, volume = {74}, number = {11}, pages = {391-395}, pmid = {431469}, issn = {0025-8458}, mesh = {Acetylcysteine ; Creatine Kinase/*metabolism ; Humans ; Isoenzymes/metabolism ; Myocardial Infarction/*diagnosis ; }, abstract = {In 70 patients with confirmed transmural myocardial infarction the sensitivity of creatine kinase and creatine kinase MB at different times after admission was investigated by 364 measurements. Beside the number of correctly positive results the optimized standard method hitherto used was compared with the new optimized standard method with N-acetylcystein as activator. During the first 12 hours after admission the percentage of correctly positive results was 64,4% for creatine kinase (GSH) and 86,7% for creatine kinase (NAC). The sensitivity of cretine kinase MB, however, was found to be 71,1% (GSH) and 86,7% (NAC). With respect to the poor specifity of creatine kinase the sensitivity of creatine kinase MB, especially when using the new optimized standard method is superior. Similar results were established 24 and 48 hours after admission. Creatine kinase MB only fails in detection of myocardial infarction if the stroke is older than 3 days or if the enzyme activity determination intervals are too long.}, }
@article {pmid443016, year = {1979}, author = {Kluyskens, P and Gillis, E and Nsabumukunzi, S}, title = {First observations on treatment of cholesteatoma with (N-acetyl)cysteine.}, journal = {Acta oto-laryngologica}, volume = {87}, number = {3-4}, pages = {362-365}, doi = {10.3109/00016487909126433}, pmid = {443016}, issn = {0001-6489}, mesh = {Acetylcysteine/*therapeutic use ; Administration, Topical ; Cholesteatoma/*drug therapy ; Ear Diseases/*drug therapy ; Humans ; Keratins/metabolism ; }, abstract = {In a series of cholesteatoma patients the benefit of local application of acetylcysteine was demonstrated. Chemical studies and fractional analyses were used to reveal the breakdown of keratin. Histochemically the influence of acetylcysteine on keratin is confirmed.}, }
@article {pmid761520, year = {1979}, author = {Chemnitz, G and Schmidt, E and Koller, PU and Busch, EW}, title = {[Creatine kinase: reference values and clinical aspects of the revised standard method (author's transl)].}, journal = {Deutsche medizinische Wochenschrift (1946)}, volume = {104}, number = {7}, pages = {257-260}, doi = {10.1055/s-0028-1103881}, pmid = {761520}, issn = {0012-0472}, mesh = {Adolescent ; Adult ; Age Factors ; Aged ; Aspartate Aminotransferases/blood ; Child ; Creatine Kinase/*blood ; Female ; Humans ; Isoenzymes/blood ; Male ; Methods ; Middle Aged ; Reference Values ; Sex Factors ; }, abstract = {Reference values for the revised standard method for determining N-acetylcysteine (NAC) activated creatine kinase (CK) activity in serum are presented, based on samples from 432 out-patients and 423 in-patients of either sex. CK activity was not age-related. The suggested range of normal values for serum CK activity, measured by the revised standard method at + 25 degree C, is 10--70U/l for females and 10--80U/l for males. Where an elevation of serum CK activity is of uncertain cause, the CK/GOT ratio had been recommended, additional to the CK-MB isoenzyme, for distinguishing between damage to heart and skeletal muscle. The significance of this ratio was checked with the revised standard CK method and the optimized GOT determination. The point of separation between myocardial and skeletal muscle damage is 10 by this methods. In order to use this ratio, total CK activity must be over 150 U/l and liver disease or secondary liver involvement must have been excluded. The CK/GOT ratio gains in importance through findings which limit the specificity of CK-MB as a purely myocardial (infarct)-specific isoenzyme.}, }
@article {pmid762506, year = {1979}, author = {Schmidt, EW and Bender, W}, title = {[Creatine kinase and creatine kinase isoenzyme MB: determination of normal values and values for myocardial infarct, using the new, optimized method with N-acetyl cysteine as the activator (author's transl)].}, journal = {Journal of clinical chemistry and clinical biochemistry. Zeitschrift fur klinische Chemie und klinische Biochemie}, volume = {17}, number = {1}, pages = {9-13}, pmid = {762506}, issn = {0340-076X}, mesh = {Acetylcysteine/*pharmacology ; Creatine Kinase/*blood ; Enzyme Activation ; Glutathione/pharmacology ; Humans ; Isoenzymes/*blood ; Kinetics ; Myocardial Infarction/*enzymology ; }, abstract = {Preliminary results are reported for the determination of creatine kinase and its isoenzyme MB in healthy individuals and in patients with acute, transmural myocardial infarct, using N-acetyl cysteine as the activator of the enzyme. In healthy individuals, the upper normal limit for creatine kinase activity was 54 U/l; the decision level for the presence of creatine kinase MB activity 9 U/l. The limiting values were only slightly different from those for the GSH-activated creatine kinase, and the results with the old and new methods showed a linear relationship with a slope of 1.0. The differences in the activation of creatine kinase MM by GSH and by N-acetyl cysteine are discussed; the activities obtained for creatine kinase and creatine kinase-MB by the GSH-activation method cannot simply be recalculated to give the appropriate values of the N-acetyl cysteine activation method.}, }
@article {pmid688617, year = {1978}, author = {Szasz, G and Gerhardt, W and Gruber, W}, title = {Creatine kinase in serum: 5. Effect of thiols on isoenzyme activity during storage at various temperatures.}, journal = {Clinical chemistry}, volume = {24}, number = {9}, pages = {1557-1563}, pmid = {688617}, issn = {0009-9147}, mesh = {Creatine Kinase/*blood ; Drug Stability ; Enzyme Activation ; Humans ; Isoenzymes/*blood ; Kinetics ; Sulfhydryl Reagents/*pharmacology ; }, abstract = {We studied changes in the activity of human creatine kinase isoenzymes (native MM in serum, MM, MB, and BB preparations in serum matrix) on storage in the presence of 0, 10, 20, and 50 mmol of N-acetyl cysteine, 2-mercaptoethanol, and 1-thioglycerol per liter of serum at 37, 30, 25, 4, and -20 degrees C. We also assessed the stability of the thiols under the same conditions. We generally confirmed increasing stability in the sequence: BB, MB, and MM isoenzyme. Above 30 degrees C irreversible inactivation is very rapid, even in the presence of thiols. At lower temperatures endogenous MM is sufficiently stable; thus, the use of protective thiols can be restricted to sera expected to contain isoenzymes MB or BB. Our studies lead us to prefer use of 50 mmol of N-acetyl cysteine per liter of serum. The other thiols cause turbidity to develop earlier and their decomposittion products diminish the activity more. The initial activity of the MB and BB preparations increased by as much as 2.3- and 1.8-fold on storage with thiols. This effect was not observed with either endogenous MB and MM or with the MM prepartion.}, }
@article {pmid658385, year = {1978}, author = {Bakhishev, GV}, title = {[Cysteine activity in the poisoning of animals by various aliphatic series halogenated hydrocarbons].}, journal = {Farmakologiia i toksikologiia}, volume = {41}, number = {3}, pages = {342-344}, pmid = {658385}, issn = {0014-8318}, mesh = {Acetylcysteine/therapeutic use ; Animals ; Antidotes ; Cysteine/*therapeutic use ; Drug Evaluation, Preclinical ; Glutathione/therapeutic use ; Hydrocarbons, Halogenated/*poisoning ; Rats ; Time Factors ; }, abstract = {In poisoning animals with various aliphatic series haloid-hydrocarbons (LK99 and LD99) free cysteine was found to be a group antidote in rats poisoned with monohaloid-hydrocarbons. It was established that the therapeutic activity of cystein depends not on the nature of haloid and double bonds, but on the number of the haloid atoms in a molecule, the length, ramification and nature of the radical. A good durative action are shown by such cystein derivatives as acetyl-cysteine, glutathione and cystein salts. In poisoning with haloid-alkyls dithiol antidotes (unithiol, mecaptide, BAL) and other drugs proved ineffective.}, }
@article {pmid97741, year = {1978}, author = {Risack, LE and Vandevelde, ME and Gobert, JG}, title = {Effect of thiol derivatives on mixed mucus and blood clots in vitro.}, journal = {Resuscitation}, volume = {6}, number = {1}, pages = {9-20}, doi = {10.1016/0300-9572(78)90031-x}, pmid = {97741}, issn = {0300-9572}, mesh = {Acetylcysteine/*pharmacology ; Blood Coagulation/*drug effects ; Dithiothreitol/*pharmacology ; Expectorants ; Humans ; In Vitro Techniques ; Mercaptoethanol/*analogs &amp; derivatives ; Mesna/*pharmacology ; Mucus/*drug effects ; Respiratory System ; Saline Solution, Hypertonic ; }, abstract = {The disintegrating effect of three reducing thiol derivatives: [sodium mercaptoethane sulphonate (Mesna), N-acetyl-L-cysteine (NAC) and dithio-1,4-threitol (DTT)] was investigated in vitro upon blood clots formed in the absence or in the presence of tracheobronchial secretions and compared with the effect of iso-osmotic saline solution. The amounts of haemoglobin released from the clots after 30 min incubation and the initial rates of haemoglobin release were compared for the different products at different concentrations. All three reducing agents showed some ability to disintegrate mixed clots to an extent depending on their concentration. After 30 min incubation, statistical analysis showed a highly significant difference in favour of Mesna at the three concentrations used, i.e. 0.1, 1.0 and 10 mmol/1. The initial rate of haemoglobin release in presence of Mesna was at all concentrations significantly higher than that of NAC or DTT. The effects on normal blood clots were much less pronounced. The effectiveness of Mesna in splitting up mixed blood and mucus clots in the management of patients who had inhaled blood is discussed.}, }
@article {pmid920933, year = {1977}, author = {Buckpitt, AR and Rollins, DE and Nelson, SD and Franklin, RB and Mitchell, JR}, title = {Quantitative determination of the glutathione, cysteine, and N-acetyl cysteine conjugates of acetaminophen by high-pressure liquid chromatography.}, journal = {Analytical biochemistry}, volume = {83}, number = {1}, pages = {168-177}, doi = {10.1016/0003-2697(77)90522-x}, pmid = {920933}, issn = {0003-2697}, mesh = {*Acetaminophen/metabolism ; Acetylcysteine/*analysis ; Cell-Free System ; Chromatography, High Pressure Liquid/*methods ; Cysteine/*analysis ; Glutathione/*analysis ; Microsomes, Liver/metabolism ; }, }
@article {pmid410565, year = {1977}, author = {Sandifort, CR}, title = {Effects of ethylenediaminetetraacetate on "CK-NAC" reagent stability and measured creatine kinase activities.}, journal = {Clinical chemistry}, volume = {23}, number = {11}, pages = {2169-2170}, pmid = {410565}, issn = {0009-9147}, mesh = {Acetylcysteine/*pharmacology ; Creatine Kinase/*blood ; Drug Stability ; Edetic Acid/*pharmacology ; Enzyme Activation/drug effects ; Humans ; Indicators and Reagents ; Methods ; }, }
@article {pmid145749, year = {1977}, author = {Thielmann, HW}, title = {Detection of strand breaks in phiX 174 RFI and PM2 DNA reacted with ultimate and proximate carcinogens.}, journal = {Zeitschrift fur Krebsforschung und klinische Onkologie. Cancer research and clinical oncology}, volume = {90}, number = {1}, pages = {37-69}, pmid = {145749}, issn = {0084-5353}, mesh = {Benz(a)Anthracenes/pharmacology ; Carcinogens/*pharmacology ; *Coliphages/drug effects/genetics/metabolism ; *DNA, Bacterial ; DNA, Superhelical ; Ethylnitrosourea/pharmacology ; Fluorenes/pharmacology ; Methylnitrosourea/pharmacology ; Molecular Biology ; }, abstract = {Supercoiled DNA duplexes of phages phiX 174 and PM2 were treated in aqueous solution at neutral pH with ultimate and proximate carcinogens. Subsequently, the carcinogen-treated phage DNAs were subjected to velocity sedimentation in neutral and alkaline sucrose to quantitative introduction of single strand breaks. Reaction of phage DNA with the ultimate carcinogens N-methyl-N-nitrosourea (MeNOUr), N-ethyl-N-nitrosourea (EtNOUr), 7-bromomethyl-benza[a]-anthracene, N-acetoxy-2-acetylaminofluorene [(Ac)2ONFln] and K-region oxides for short periods followed by sedimentation in neutral sucrose gradients led to very few breaks. Incubation with the proximate carcinogens N-hydroxy-2-acetylaminofluorene, 2-acetylaminofluorene, 7-methyl-, and 7,12-dimethyl-benza[a]anthracene did not result in breaks. However, when the phage DNAs were reacted with the ultimate carcinogens under the same conditions but subsequently alkali-denatured and sedimented in alkaline sucrose gradients, single strand breaks were readily introduced. Incubation with the proximate carcinogens followed by alkali denaturation and sedimentation in alkaline sucrose showed that only 7,12-dimethyl-benz[a]anthracene and, to a minor extent, 7-methyl-benz[]anthracene caused alkali-inducible breaks. The ability of N-methyl-N'-nitro-N-nitrosoguanidine to effect breakdown of superhelical phage DNA in alkali was found enhanced in the presence of N-acetyl-cysteine.}, }
@article {pmid874931, year = {1977}, author = {Fournier, AM and Timon-David, P and Julien, H and DuVal, F and Mattei, JP}, title = {[Acetyl-cysteine in colonic mucography (author's transl)].}, journal = {Journal de radiologie, d'electrologie, et de medecine nucleaire}, volume = {58}, number = {6-7}, pages = {479-484}, pmid = {874931}, issn = {0368-3966}, mesh = {*Acetylcysteine ; *Barium Sulfate ; Colon/*diagnostic imaging ; Drug Evaluation ; Enema/*methods ; Humans ; Intestinal Mucosa/diagnostic imaging ; Radiography ; Technology, Radiologic ; }, abstract = {Acetyl-cysteine, its origin, nature, the constitution of its molecule and its main properties are reviewed. This study involved essentially the best means of using the mucolytic properties of this amino acid. Acetyl-cysteine has an excellent detergent effect on the mucosa, with good evacuation, and favourises the adhesion of barium, all the better when the particles of the latter are finer. It is thus possible to obtain good thin layer and double contrast pictures. Prior preparation remains of the utmost importance.}, }
@article {pmid340073, year = {1977}, author = {Haut, J and Labrune, P and Ullern, M and Chermet, M}, title = {[New trial treatment of dry eye with acetylcysteine ophthalmic solution].}, journal = {Bulletin des societes d'ophtalmologie de France}, volume = {77}, number = {2}, pages = {165-167}, pmid = {340073}, issn = {0081-1270}, mesh = {Acetylcysteine/*administration &amp; dosage ; Clinical Trials as Topic ; Corneal Ulcer/drug therapy ; Drug Evaluation ; Eye Diseases/*drug therapy ; Humans ; Keratoconjunctivitis/drug therapy ; Ophthalmic Solutions ; Tears/*metabolism ; }, }
@article {pmid65897, year = {1977}, author = {Norn, MS and Opauszki, A}, title = {Effects of ophthalmic vehicles on the stability of the precorneal film.}, journal = {Acta ophthalmologica}, volume = {55}, number = {1}, pages = {23-34}, doi = {10.1111/j.1755-3768.1977.tb06092.x}, pmid = {65897}, issn = {0001-639X}, mesh = {Acetylcysteine/pharmacology ; Adolescent ; Adult ; Aged ; Antifoaming Agents/pharmacology ; Benzalkonium Compounds/pharmacology ; Cocaine/pharmacology ; Cornea/*drug effects/metabolism ; Dextrans/pharmacology ; Female ; Humans ; Male ; Methylcellulose/pharmacology ; Middle Aged ; Oils/pharmacology ; Ointments ; Ophthalmic Solutions/*pharmacology ; Petroleum ; Pharmaceutical Vehicles/*pharmacology ; Polyethylene Glycols/pharmacology ; Polyvinyl Alcohol/pharmacology ; Silicones/pharmacology ; Staining and Labeling ; Stearic Acids/pharmacology ; }, abstract = {The break up time (B.U.T.) of the precorneal film has been studied before and after application of 34 different vehicles. The material examined comprised 646 eyes. Maximum increase of the B.U.T. was obtained with 2% methyl cellulose (four times) and 10% polyvinyl alchohol (seven times). These vehicles in the usually employed concentrations, fat-free ointment (polyethylene glycol), acetyl cysteine and polysaccharide (dextran) affected a less pronounced prolongation. The B.U.T. was reduced four or five times by fatty, anhydrous ointments and by silicone oil, about two or three times by emulsions and oils, and twice by 0.01% benzalkonium chloride. The clinical significance of the B.U.T. alterations is discussed.}, }
@article {pmid597704, year = {1977}, author = {Tolley, DA}, title = {The effect of N-acetyl cysteine on cyclophosphamide cystitis.}, journal = {British journal of urology}, volume = {49}, number = {7}, pages = {659-661}, doi = {10.1111/j.1464-410x.1977.tb04548.x}, pmid = {597704}, issn = {0007-1331}, mesh = {Animals ; Cyclophosphamide/*adverse effects ; Cysteine/*analogs &amp; derivatives/therapeutic use ; Cystitis/chemically induced/*prevention &amp; control ; Female ; Rats ; }, abstract = {Further studies on the effect of various compounds of the rat bladder after treatment with cyclophosphamide are reported. The results show that N-acetyl cysteine is a highly effective drug for the prevention of cyclophosphamide cystitis. N-acetyl cysteine does not significantly impair the anti-tumour effect of cyclophosphamide.}, }
@article {pmid409034, year = {1977}, author = {Kalafatas, P and Voulgaris, E and Vorias, N and Kotsifopoulos, P}, title = {Susceptibility to autoxidation of lipids of paroxysmal nocturnal hemoglobinuria (PNH)-like red cells.}, journal = {Acta haematologica}, volume = {58}, number = {3}, pages = {181-188}, doi = {10.1159/000207826}, pmid = {409034}, issn = {0001-5792}, mesh = {Acetylcysteine/analogs &amp; derivatives/pharmacology ; Adolescent ; Adult ; Erythrocyte Membrane/drug effects/*metabolism ; Erythrocytes/*metabolism ; Hemoglobinuria, Paroxysmal/*blood ; Humans ; Membrane Lipids/*blood ; Oxidation-Reduction/drug effects ; Penicillamine/pharmacology ; }, abstract = {The susceptibility to autoxidation of red cell lipids was studied before and after transformation of normal red cells to PNH-like erythrocytes. The transformation was effected by treatment of the red cells with the sulfydryl compounds D-penicillamine (DP) and N-acetyl-L-cysteine (NAC). The autoxidation was induced by incubating the cells with H2O2 and was estimated by measuring the generated malonyl dialdehyde. The susceptibility to autoxidation was significantly higher in DP-treated cells, while the opposite was true for NAC-treated cells. However, both DP- and NAC-treated cells showed a similar sensitivity to lysis by acid serum and about the same degree of acetylcholinesterase (AChE) activity decrease, thus indicating that the susceptibility to autoxidation of lipids is not involved in the determination of complement sensitivity or in the AChE activity decrease of the sulfydryl-treated cells. Finally, since, as evidenced from most of the reported cases in the literature, increased susceptibility to autoxidation is a feature of PNH cells, it seems reasonable to suggest that DP-treated cells should be used in preference to NAC-treated cells as a laboratory substitute for PNH cells.}, }
@article {pmid401831, year = {1977}, author = {Parry, MF and Neu, HC}, title = {Effect of N-acetylcysteine on antibiotic activity and bacterial growth in vitro.}, journal = {Journal of clinical microbiology}, volume = {5}, number = {1}, pages = {58-61}, pmid = {401831}, issn = {0095-1137}, mesh = {Acetylcysteine/*pharmacology ; Carbenicillin/pharmacology ; Drug Synergism ; Gentamicins/pharmacology ; Humans ; Pseudomonas aeruginosa/*growth &amp; development ; Ticarcillin/pharmacology ; Tobramycin/pharmacology ; }, abstract = {The antibiotic bacerial inactivity of N-acetylcysteine (NAC) and its interaction with penicillin and aminocyclitol antibiotics was evaluated. NAC inhibited growth of both gram-negative and gram-positive bacteria. Strains of Pseudomonas aeruginosa were more susceptible than other microorgainsms tested. P. aeruginosa strains were inhibited synergistically by NAC and carbenicillin or ticarcillin. However, NAC antagonized the activity of gentamicin and tobramycin. These findings have implications for the combined clinical use of NAC and aerosolized antibiotics and are also important for the processing of sputum specimens in the microbiology laboratory.}, }
@article {pmid4240, year = {1976}, author = {Szasz, G and Gruber, W and Bernt, E}, title = {Creatine kinase in serum: 1. Determination of optimum reaction conditions.}, journal = {Clinical chemistry}, volume = {22}, number = {5}, pages = {650-656}, pmid = {4240}, issn = {0009-9147}, mesh = {Blood Glucose ; Buffers ; Creatine Kinase/*blood/metabolism ; Enzyme Activation/drug effects ; Glucose/pharmacology ; Hexokinase/metabolism ; Hydrogen-Ion Concentration ; Indicators and Reagents ; Kinetics ; Magnesium/pharmacology ; Methods ; NADP/pharmacology ; Osmolar Concentration ; Temperature ; }, abstract = {To establish optimum conditions for creatine kinase (EC 2.7.3.2) activity measurement with the creatine phosphate in equilibrium creatine reaction, we re-examined all kinetics factors relevant to an optimal and standardized enzyme assay at 30 and 25 degrees C. We determined the pH optimum in vaious buffers, considering the effect of the type and concentration of the buffer, as well as the influence of various buffer anions on the activity. The relation between activity and substrate concentration was shown and the apparent Michaelis constants of creatine kinase for creatine phosphate and ADP were evaluated. We tested the effect on creatine kinase measurement of the concentration of substrates (glucose and NADP+) in the auxillary and indicator reactions, especially the influence of the added auxiliary (hexokinase) and indicator (glucose-6-phosphate dehydrogenase) enzymes on the lag phase, at different temperatures. The NADP+ concentration proved to be the factor limiting the duration of constant reaction rate. We studied the inhibition of creatine kinase and adenylate kinase by AMP and established a convenient AMP concentration. For reactivation of creatine kinase, N-acetyl cysteine as sulfhydryl compound was introduced. Finally, we examined the relationship between activity and temperature.}, }
@article {pmid1101731, year = {1975}, author = {Winning, TJ and Brock-Utne, JG and Goodwin, NM}, title = {A simple clinical method of quantitating the effects of chest physiotherapy in mechanically ventilated patients.}, journal = {Anaesthesia and intensive care}, volume = {3}, number = {3}, pages = {237-238}, doi = {10.1177/0310057X7500300310}, pmid = {1101731}, issn = {0310-057X}, mesh = {Acetylcysteine/administration &amp; dosage/therapeutic use ; Aerosols ; Humans ; *Intermittent Positive-Pressure Breathing ; Lung Compliance ; *Physical Therapy Modalities ; *Positive-Pressure Respiration ; Pressure ; Pulmonary Alveoli ; Respiratory Insufficiency/therapy ; Ventilators, Mechanical ; }, abstract = {A simple clinical method, allowing quantitive assessment of the effects of chest physiotherapy on patients subjected to I.P.P.V., is presented. The method involves measuring of the "alveolar" pressure using the end-expiratory retard mechanism available on the Bennet MA 1 (volume cycled) ventilator. Using this simple technique three different methods of physiotherapy were shown to significantly lower alveolar pressure, indicating an increase in pulmonary compliance. The inhalation of acetyl cysteine however, appeared to render treatment less effective in this regard.}, }
@article {pmid1178695, year = {1975}, author = {Harris, E and Levy, L and Levy, J}, title = {Inhibition of cylophosphamide (CPA)-induced bladder toxicity by N-acetylcysteine (NAC) in rats.}, journal = {Proceedings of the Western Pharmacology Society}, volume = {18}, number = {}, pages = {354-357}, pmid = {1178695}, issn = {0083-8969}, mesh = {Acetylcysteine/*pharmacology ; Animals ; Cyclophosphamide/*adverse effects/antagonists &amp; inhibitors ; Edema/chemically induced ; Immunosuppression Therapy ; Leukocyte Count ; Rats ; Time Factors ; Urinary Bladder Diseases/*chemically induced ; }, }
@article {pmid165163, year = {1975}, author = {Meban, C}, title = {The mucosubstance coating the pneumonocytes in the lungs of Xenopus laevis and Lacerta viridis.}, journal = {The Histochemical journal}, volume = {7}, number = {1}, pages = {57-65}, pmid = {165163}, issn = {0018-2214}, mesh = {Animals ; Clostridium perfringens/enzymology ; Glycosaminoglycans/*analysis ; Hyaluronoglucosaminidase ; Lizards ; Lung/analysis/*cytology/ultrastructure ; Male ; Microscopy, Electron ; Neuraminidase ; Sheep ; Species Specificity ; Testis/enzymology ; Xenopus ; }, abstract = {The layer of mucosubstance that is associated with the free surface membranes of the pneumonocytes in the lungs of the toad Xenopus laevis and the lizard Lacerta viridis was demonstrated by electron microscopy using iron oxide stain. The form and staining reactions of the mucosubstance layer were similar in both animals. In electron micrographs the mucosubstance was represented by a band of densely stained material (25-50 nm thick) which coated the entire free surface of the pneumonocytes. It appeared to be firmly attached to the outer leaflet of the superficial plasma membrane. Short lengths of osmiophilic membranes, presumed to be fragments of pulmonary surfactant, were often observed lying free in the air spaces but they did not show any affinity for iron stain. Incubation of lung sections in a solution of neuraminidase produced a marked decrease in the intensity of the surface staining; no change was detected after incubation in trypsin, papain, hyaluronidase, N-acetyl cysteine, or phosphate buffer. It is, therefore, concluded that the pneumonocyte surface coat consists mainly of a sialomucin.}, }
@article {pmid4425612, year = {1974}, author = {Marriott, C and Richards, JH}, title = {The effects of storage and of potassium iodide, urea, N-acetyl-cysteine and triton X-100 on the viscosity of bronchial mucus.}, journal = {British journal of diseases of the chest}, volume = {68}, number = {0}, pages = {171-182}, doi = {10.1016/0007-0971(74)90035-7}, pmid = {4425612}, issn = {0007-0971}, mesh = {Acetylcysteine/*pharmacology ; Asthma ; Bronchi ; Bronchitis ; Centrifugation ; Humans ; *Mucus ; Polyethylene Glycols/*pharmacology ; Potassium Iodide/*pharmacology ; *Preservation, Biological ; Specimen Handling ; *Sputum/drug effects ; Surface-Active Agents/*pharmacology ; Urea/*pharmacology ; *Viscosity ; }, }
@article {pmid5130152, year = {1971}, author = {Lightowler, JE and Lightowler, NM}, title = {Comparative mucolytic studies on dithiothreitol, N-acetyl-cysteine and L-cysteine on human respiratory mucus in vitro and their effects on the rate of flow of mucus in the exposed trachea of the rat on topical application.}, journal = {Archives internationales de pharmacodynamie et de therapie}, volume = {189}, number = {1}, pages = {53-58}, pmid = {5130152}, issn = {0003-9780}, mesh = {Acetylcysteine/administration &amp; dosage/*pharmacology ; Animals ; Bronchi ; Cysteine/administration &amp; dosage/*pharmacology ; Dithiothreitol/administration &amp; dosage/*pharmacology ; Humans ; In Vitro Techniques ; Irritants ; Models, Biological ; Mucus/*drug effects/physiology ; Rats ; Rheology ; Stimulation, Chemical ; Trachea/drug effects ; *Viscosity ; }, }
@article {pmid5785191, year = {1969}, author = {Gracey, M and Burke, V and Anderson, CM}, title = {Treatment of abdominal pain in cystic fibrosis by oral administration of n-acetyl cysteine.}, journal = {Archives of disease in childhood}, volume = {44}, number = {235}, pages = {404-405}, pmid = {5785191}, issn = {1468-2044}, mesh = {Abdomen ; Acetylcysteine/*administration &amp; dosage ; Adolescent ; Adult ; Child ; Child, Preschool ; Cystic Fibrosis/*drug therapy ; Female ; Humans ; Male ; Pain ; }, }
@article {pmid6059433, year = {1967}, author = {Lillibridge, CB and Docter, JM and Eidelman, S}, title = {Oral administration of n-acetyl cysteine in the prophylaxis of "meconium ileus equivalent".}, journal = {The Journal of pediatrics}, volume = {71}, number = {6}, pages = {887-889}, doi = {10.1016/s0022-3476(67)80019-2}, pmid = {6059433}, issn = {0022-3476}, mesh = {Acetylcysteine/*administration &amp; dosage ; Adult ; Cystic Fibrosis/*complications ; Enema ; Humans ; Intestinal Obstruction/*prevention &amp; control ; Male ; Meconium ; Mucus ; Pancreas/enzymology ; Pharmaceutical Vehicles ; }, }
@article {pmid5951718, year = {1966}, author = {Saggers, BA and Lawson, D}, title = {Some observations on the penetration of antibiotics through mucus in vitro.}, journal = {Journal of clinical pathology}, volume = {19}, number = {4}, pages = {313-317}, pmid = {5951718}, issn = {0021-9746}, mesh = {Acetylcysteine/pharmacology ; Animals ; *Anti-Bacterial Agents ; *Gastric Mucins ; In Vitro Techniques ; Swine ; }, abstract = {A study has been made on the penetration values in vitro of antibiotics through hog gastric mucin at pH 7.4. Determinations have also been done on the binding of antibiotics to mucus and human plasma. The mucolytic agent N-acetyl cysteine has been studied in regard to its effect on antibiotics penetrating mucus and for any possible inactivation of antibiotics.}, }